PMID- 29967299 TI - The non-additive effects of body size on nest architecture in a polymorphic ant. AB - Like traditional organisms, eusocial insect societies express traits that are the target of natural selection. Variation at the colony level emerges from the combined attributes of thousands of workers and may yield characteristics not predicted from individual phenotypes. By manipulating the ratios of worker types, the basis of complex, colony-level traits can be reduced to the additive and non additive interactions of their component parts. In this study, we investigated the independent and synergistic effects of body size on nest architecture in a seasonally polymorphic harvester ant, Veromessor pergandei Using network analysis, we compared wax casts of nests, and found that mixed-size groups built longer nests, excavated more sand and produced greater architectural complexity than single-sized worker groups. The nests built by polymorphic groups were not only larger in absolute terms, but larger than expected based on the combined contributions of both size classes in isolation. In effect, the interactions of different worker types yielded a colony-level trait that was not predicted from the sum of its parts. In nature, V. pergandei colonies with fewer fathers produce smaller workers each summer, and produce more workers annually. Because body size is linked to multiple colony-level traits, our findings demonstrate how selection acting on one characteristic, like mating frequency, could also shape unrelated characteristics, like nest architecture.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967300 TI - Visualizing aggregate movement in cities. AB - We argue here that despite the focus in cities on location and place, it is increasingly clear that a requisite understanding of how cities evolve and change depends on a thorough understanding of human movements at aggregate scales where we can observe emergent patterns in networks and flow systems. We argue that the location of activities must be understood as summations or syntheses of movements or flows, with a much clearer link between flows, activities and the networks that carry and support them. To this end, we introduce a generic class of models that enable aggregated flows of many different kinds of social and economic activity, ranging from the journey to work to email traffic, to be predicted using ideas from discrete choice theory in economics which has analogies to gravitation. We also argue that visualization is an essential construct in making sense of flows but that there are important limitations to illustrating pictorially systems with millions of component parts. To demonstrate these, we introduce a class of generic spatial interaction models and present two illustrations. Our first application is based on transit flows within the high frequency city over very short time periods of minutes and hours for data from the London Underground. Our second application scales up these models from districts and cities to the nation, and we demonstrate how flows of people from home to work and vice versa define cities and related settlements at much coarser scales. We contrast this approach with more disaggregate, individual studies of flow systems in cities that we consider an essential complement to the ideas presented here.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967301 TI - Exploring nest structures of acorn dwelling ants with X-ray microtomography and surface-based three-dimensional visibility graph analysis. AB - The physical spaces within which organisms live affect their biology and in many cases can be considered part of their extended phenotype. The nests of social insect societies have a fundamental impact on their ability to function as complex superorganisms. Ants in many species excavate elaborate subterranean nests, but others inhabit relatively small pre-formed cavities within rock crevices and hollow seeds. Temnothorax ants, which often nest within acorns, have become a model system for studying collective decision making. While these ants have demonstrated remarkable degrees of rationality and consistent precision with regard to their nest choices, never before has the fine scale internal architecture and spatial organization of their nests been investigated. We used X ray microtomography to record high-resolution three-dimensional (3D) scans of Temnothorax colonies within their acorns. These data were then quantified using image segmentation and surface-based 3D visibility graph analysis, a new computational methodology for analysing spatial structures. The visibility graph analysis method integrates knowledge from the field of architecture with the empirical study of animal-built structures, thus providing the first methodological cross-disciplinary synergy of these two research areas. We found a surprisingly high surface area and degree of spatial heterogeneity within the acorn nests. Specific regions, such as those associated with the locations of queens and brood, were significantly more conducive to connectivity than others. From an architect's point of view, spatial analysis research has never focused on all-surface 3D movement, as we describe within ant nests. Therefore, we believe our approach will provide new methods for understanding both human design and the comparative biology of habitat spaces.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967302 TI - The architecture of network collective intelligence: correlations between social network structure, spatial layout and prestige outcomes in an office. AB - A social network represents interactions and knowledge that transcend the intelligence of any of its individual members. In this study, I examine the correlations between this network collective intelligence, spatial layout, and prestige or status outcomes at the individual and team levels in an organization. I propose that spatially influenced social cognition shapes which individuals become members of prestigious teams in organizations, and the prestige perception of teams by others in the organization. Prestige is a pathway to social rank, influence and upward mobility for individuals in organizations. For groups, perceived prestige of work teams is related to how team members identify with the group and with their collaborative behaviours. Prestige enhances a team's survivability and its access to resources. At the individual level, I ran two stage Heckman sample selection models to examine the correlation between social network position and the number of prestigious projects a person is a member of, contingent on the association between physical space and social ties and networks. At the team level, I used linear regressions to examine the relationship among network structure, spatial proximity and the perceived prestige or innovativeness of a project team. In line with my hypotheses, for individuals there is a significant correlation between physical space and social networks, and contingent on that, between social network positions and the number of prestigious projects that a person is a member of. Also in accordance with my hypotheses, for teams there is a significant correlation between network structure and spatial proximity, and perceived prestige. While cross-sectional, the study findings illustrate the importance of considering the spatial domain in examinations of how network collective intelligence is related to organizational outcomes at the individual and team levels.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967303 TI - The impact of the 'open' workspace on human collaboration. AB - Organizations' pursuit of increased workplace collaboration has led managers to transform traditional office spaces into 'open', transparency-enhancing architectures with fewer walls, doors and other spatial boundaries, yet there is scant direct empirical research on how human interaction patterns change as a result of these architectural changes. In two intervention-based field studies of corporate headquarters transitioning to more open office spaces, we empirically examined-using digital data from advanced wearable devices and from electronic communication servers-the effect of open office architectures on employees' face to-face, email and instant messaging (IM) interaction patterns. Contrary to common belief, the volume of face-to-face interaction decreased significantly (approx. 70%) in both cases, with an associated increase in electronic interaction. In short, rather than prompting increasingly vibrant face-to-face collaboration, open architecture appeared to trigger a natural human response to socially withdraw from officemates and interact instead over email and IM. This is the first study to empirically measure both face-to-face and electronic interaction before and after the adoption of open office architecture. The results inform our understanding of the impact on human behaviour of workspaces that trend towards fewer spatial boundaries.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967304 TI - Predicting collective behaviour at the Hajj: place, space and the process of cooperation. AB - Around 2 million pilgrims attend the annual Hajj to Mecca and the holy places, which are subject to dense crowding. Both architecture and psychology can be part of disaster risk reduction in relation to crowding, since both can affect the nature of collective behaviour-particularly cooperation-among pilgrims. To date, collective behaviour at the Hajj has not been systematically investigated from a psychological perspective. We examined determinants of cooperation in the Grand Mosque and plaza during the pilgrimage. A questionnaire survey of 1194 pilgrims found that the Mosque was perceived by pilgrims as one of the most crowded ritual locations. Being in the plaza (compared with the Mosque) predicted the extent of cooperation, though crowd density did not. Shared social identity with the crowd explained more of the variance than both location and density. We examined some of the process underlying cooperation. The link between shared social identity and giving support to others was stronger in the plaza than in the Mosque, and suggests the role of place and space in modulating processes of cooperation in crowds. These findings have implications for disaster risk reduction and for applications such as computer simulations of crowds in pilgrimage locations.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967305 TI - Architecture, space and information in constructions built by humans and social insects: a conceptual review. AB - The similarities between the structures built by social insects and by humans have led to a convergence of interests between biologists and architects. This new, de facto interdisciplinary community of scholars needs a common terminology and theoretical framework in which to ground its work. In this conceptually oriented review paper, we review the terms 'information', 'space' and 'architecture' to provide definitions that span biology and architecture. A framework is proposed on which interdisciplinary exchange may be better served, with the view that this will aid better cross-fertilization between disciplines, working in the areas of collective behaviour and analysis of the structures and edifices constructed by non-humans; and to facilitate how this area of study may better contribute to the field of architecture. We then use these definitions to discuss the informational content of constructions built by organisms and the influence these have on behaviour, and vice versa. We review how spatial constraints inform and influence interaction between an organism and its environment, and examine the reciprocity of space and information on construction and the behaviour of humans and social insects.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967306 TI - The impact of the built environment on health behaviours and disease transmission in social systems. AB - The environment plays an important role in disease dynamics and in determining the health of individuals. Specifically, the built environment has a large impact on the prevention and containment of both chronic and infectious disease in humans and in non-human animals. The effects of the built environment on health can be direct, for example, by influencing environmental quality, or indirect by influencing behaviours that impact disease transmission and health. Furthermore, these impacts can happen at many scales, from the individual to the society, and from the design of the plates we eat from to the design of cities. In this paper, we review the ways that the built environment affects both the prevention and the containment of chronic and infectious disease. We bring examples from both human and animal societies and attempt to identify parallels and gaps between the study of humans and animals that can be capitalized on to advance the scope and perspective of research in each respective field. By consolidating this literature, we hope to highlight the importance of built structures in determining the complex dynamics of disease and in impacting the health behaviours of both humans and animals.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967308 TI - Can we identify general architectural principles that impact the collective behaviour of both human and animal systems? AB - The search for general common principles that unify disciplines is a longstanding challenge for interdisciplinary research. Architecture has always been an interdisciplinary pursuit, combining engineering, art and culture. The rise of biomimetic architecture adds to the interdisciplinary span. We discuss the similarities and differences among human and animal societies in how architecture influences their collective behaviour. We argue that the emergence of a fully biomimetic architecture involves breaking down what we call 'pernicious dualities' that have permeated our discourse for decades, artificial divisions between species, between organism and environment, between genotype and phenotype, and in the case of architecture, the supposed duality between the built environment and its builders. We suggest that niche construction theory may serve as a starting point for unifying our thinking across disciplines, taxa and spatial scales.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967307 TI - Split between two worlds: automated sensing reveals links between above- and belowground social networks in a free-living mammal. AB - Many animals socialize in two or more major ecological contexts. In nature, these contexts often involve one situation in which space is more constrained (e.g. shared refuges, sleeping cliffs, nests, dens or burrows) and another situation in which animal movements are relatively free (e.g. in open spaces lacking architectural constraints). Although it is widely recognized that an individual's characteristics may shape its social life, the extent to which architecture constrains social decisions within and between habitats remains poorly understood. Here we developed a novel, automated-monitoring system to study the effects of personality, life-history stage and sex on the social network structure of a facultatively social mammal, the California ground squirrel (Otospermophilus beecheyi) in two distinct contexts: aboveground where space is relatively open and belowground where it is relatively constrained by burrow architecture. Aboveground networks reflected affiliative social interactions whereas belowground networks reflected burrow associations. Network structure in one context (belowground), along with preferential juvenile-adult associations, predicted structure in a second context (aboveground). Network positions of individuals were generally consistent across years (within contexts) and between ecological contexts (within years), suggesting that individual personalities and behavioural syndromes, respectively, contribute to the social network structure of these free-living mammals. Direct ties (strength) tended to be stronger in belowground networks whereas more indirect paths (betweenness centrality) flowed through individuals in aboveground networks. Belowground, females fostered significantly more indirect paths than did males. Our findings have important potential implications for disease and information transmission, offering new insights into the multiple factors contributing to social structures across ecological contexts.This article is part of the theme issue 'Interdisciplinary approaches for uncovering the impacts of architecture on collective behaviour'. PMID- 29967309 TI - Short-term benefit of smoking cessation along with glycopirronium on lung function and respiratory symptoms in mild COPD patients: a retrospective study. AB - INTRODUCTION: Tobacco smoke is the leading cause of chronic obstructive pulmonary disease (COPD). Smoking cessation can change the natural history of COPD, as we know from the GOLD guidelines. Little is known about the short-term clinical and functional effects of smoking cessation treatment combined with anti-muscarinic bronchodilators. OBJECTIVE: To determine whether quitting smoking, obtained by smoking cessation treatment combined with the use of a new long-acting muscarinic antagonist bronchodilator (LAMA), can improve lung function tests and respiratory symptoms more than the use of LAMA alone. METHODS: We evaluated, in a retrospective analysis, the functional and clinical data, collected in one year, of 120 patients who were current smokers affected by mild COPD and who quit smoking using smoking cessation treatment combined with glycopirronium. We compared them with a group of 80 patients with mild COPD undergoing the same treatment but who did not quit smoking. All patients underwent functional and clinical tests at baseline and at a third-month check. MEASUREMENTS AND MAIN RESULTS: The two groups were homogeneous in terms of demographic data without significant differences. All patients used varenicline for smoking cessation. They all performed the following tests: a spirometry with detection of resistances, the 6 min walking test, haemogasanalysis, the exhaled CO test, the COPD assessment test (CAT) and finally the modified Medical Research Council test (mMRC). A significant improvement in the functional tests at the third-month check was found in both groups-quitters and non-quitters. However, a notable increase in the examined parameters was registered in the group of patients who quit smoking, in particular, we observed a significant increase at the third month check of the parameter forced expiratory volume in 1 s (FEV1) of more than 200 ml with p < 0.001. A comparison between quitters and non-quitters revealed a major benefit derived from smoking cessation in terms of functional changes and symptom relief. In particular, not only FEV1 but also forced expiratory flow at 25%-75% of vital capacity (FEF 25-75) (p < 0.01) and CAT (p < 0.001) were found to be significantly improved in patients who quit than in patients who did not at the check time point. CONCLUSIONS: Smoking cessation treatment obtained by varenicline was confirmed as a crucial therapeutic option, especially when combined with bronchodilator in mild COPD. Patients who quit smoking could already benefit from both treatments in the short term, improving lung function and respiratory symptoms and therefore improving their quality of life. PMID- 29967310 TI - Focused electrical stimulation using a single current source. AB - OBJECTIVE: Cochlear implants, while providing significant benefits to recipients, remain limited due to broad neural activation. Focussed multipolar stimulation (FMP) is an advanced stimulation strategy that uses multiple current sources to produce highly focussed patterns of neural excitation in order to overcome these shortcomings. APPROACH: This report presents single-source multipolar stimulation (SSMPS), a novel form of stimulation based on a single current source and a passive current divider. Compared to conventional FMP with multiple current sources, SSMPS can be implemented as a modular addition to conventional (i.e. single) current source stimulation systems facilitating charge balance within the cochlea. As with FMP, SSMPS requires the determination of a transimpedance matrix to allow for focusing of the stimulation. The first part of this study therefore investigated the effects of varying the probe stimulus (e.g. current level and pulse width) on the measurement of the transimpedance matrix. SSMPS was then studied using in vitro based measurements of voltages at non-stimulated electrodes along an electrode array in normal saline. The voltage reduction with reference to monopolar stimulation was compared to tripolar and common ground stimulation, two clinically established stimulation modes. Finally, a proof of principle in vivo test of SSMPS in a feline model was performed. MAIN RESULTS: A probe stimulus of at least 40 nC is required to reliably measure the transimpedance matrix. In vitro stimulation using SSMPS resulted in a significantly greater voltage reduction compared to monopolar, tripolar and common ground stimulation. Interestingly, matching measurement and stimulation parameters did not lead to an improved focussing performance. Compared to monopolar stimulation, SSMPS resulted in reduced spread of neural activity in the inferior colliculus, albeit with increased thresholds. SIGNIFICANCE: The present study demonstrates that SSMPS successfully limits the broadening of the excitatory field along the electrode array and a subsequent reduction in the spread of neural excitation. PMID- 29967311 TI - Platelet-rich plasma and alignment enhance myogenin via ERK mitogen activated protein kinase signaling. AB - Volumetric muscle loss is debilitating and involves extensive rehabilitation. One approach to accelerate healing, rehabilitation, and muscle function is to repair damaged skeletal muscle using regenerative medicine strategies. In sports medicine and orthopedics, a common clinical approach is to treat minor to severe musculoskeletal injuries with platelet-rich plasma (PRP) injections. While these types of treatments have become commonplace, there are limited data demonstrating their effectiveness. The goal of this study was to determine the effect of PRP on myoblast gene expression and protein production when incorporated into a polymer fiber. To test this, we generated extracellular matrix mimicking scaffolds using aligned polydioxanone (PDO) fibers containing lyophilized PRP (SmartPReP(r) 2, Harvest Technologies Corporation, Plymouth, MA). Scaffolds with PRP caused a dose dependent increase in myogenin and myosin heavy chain but did not affect myogenic differentiation factor-1 (MyoD). Integrin alpha7beta1D decreased and alpha5beta1A did not change in response to PRP scaffolds. ERK inhibition decreased myogenin and increased Myod on the PDO-PRP scaffolds. Taken together, these data suggest that alignment and PRP produce a substrate-dependent, ERK-dependent, and dose dependent effect on myogenic differentiation. PMID- 29967312 TI - Development and characterization of chloroplast microsatellite markers for Pinus massoniana and their application in Pinus (Pinaceae) species. AB - Pinus massoniana is one of the important afforestation and pioneer tree species, which is widely distribute in southern China. Chloroplast simple sequence repeat markers (cpSSRs) have been widely used in studies of tree genetics, phylogenetic and breeding. We sequenced the whole chloroplast genome sequences of P. massoniana using PCR and Sanger sequencing. A total of 71 cpSSRs were identified, among which mononucleotide repeats were predominant (70.42%). Seventeen primer pairs were developed and amplification tests were conducted with 15 P. massoniana individuals. Also, cross-species amplification tests were conducted among 15 individuals per Pinus species, including P. elliottii, P. bungeana, P. armandii, P. caribaea, P. tabulaeformis, P. taiwanensis and P. yunnanensis which revealed polymorphic information content ranging from 0.2 to 0.8 and average of haploid diversity (h) ranging from 0.29 to 0.63. In addition, the polymorphic cpSSRs were useful in distinguishing the sampled pine species, and could be powerful tool in phylogenetic studies. PMID- 29967313 TI - Identification and characterization of 23 microsatellite loci for Chlorostoma rustica based on RAD-seq. AB - Chlorostoma rustica is an ecologically and economically important species in China, which plays an important role on the overall function of the coastal systems. Understanding of the genetic structure of C. rustica populations is vital to breeding strategies and conservation programmes. In this study, we isolated and characterized 23 microsatellite loci with high polymorphism using the restriction site-associated DNA sequencing approach. The number of alleles per locus ranged from 6 to 18, and the expected heterozygosities varied from 0. 760 to 0.936. All the polymorphism information content values of the 23 loci were greater than 0.5, indicating that these markers were highly informative and laid the foundation for further genetic analysis. PMID- 29967314 TI - Assessment of genetic diversity and population genetic structure of Carthamus species and Iranian cultivar collection using developed SSR markers. AB - This experiment was conducted to assess genetic relationships among safflower genotypes from different geographical regions of Iran and other countries using newly developed simple sequence repeat (SSR) markers. By enrichment method, 32 primer pairs were designed of which 18 pairs were able to detect polymorphism in 105 safflower cultivars from Carthamus tinctorius, C. oxyacanthus, C. lanatus, C. glaucus, C. boissieri and C. dentatus. The selected SSR primers amplified a total of 59 alleles with an average of 3.27 alleles per locus among the cultivars and the average values of gene diversity, heterozygosity and PIC were 0.45, 0.37 and 0.39, respectively. Neighbour-joining cluster analysis based on Nei's genetic distance categorized populations of Carthamus in six major clusters; all wild accessions were grouped differently from cultivated genotypes. Cluster analysis significantly distinguished C. oxyacanthus genotypes in different categories: centre (Arak), northeast (Azarbaiejan), east (Kermanshah) and southeast (Shiraz, Chaharmahal and Kohgiluyeh). The presence of C. boissieri and C. glaucus in one cluster appeared to be in close relationship between each other, indicating a common ancestor. The results revealed that C. dentatus discriminated from the species with n = 10 chromosomes, C. boissieri and C. glaucus assigned in to separate subsection. In summary, this study has shown that domesticated and wild genotypes were clustered into two major groups indicating these markers as appropriate tools to amassment genetic diversity and genome mapping. PMID- 29967315 TI - Expanded Criteria Donor-Related Hyperkalemia and Postreperfusion Cardiac Arrest During Liver Transplantation: A Case Report and Literature Review. AB - BACKGROUND Liver transplantation (LT) using extended criteria donor (ECD) grafts is frequently associated with a high flush fluid potassium concentration (FFK) and acute hyperkalemia after reperfusion, which puts patients at greater risk of postreperfusion cardiac arrest (PRCA). CASE REPORT Herein, we present a case with an extremely high FFK that was successfully pretreated to avoid the risk of PRCA. A 3-year-old boy with biliary atresia underwent LT from a 623-g donation after brain death liver graft with localized frostbite on the right lobe surface. The FFK was 18.8 mmol/L after flushing with 1000 mL of 5% albumin. To prevent PRCA due to acute hyperkalemia, further portal vein (PV) flush, retrograde reperfusion via the inferior vena cava, and antegrade reperfusion via the PV were adopted to remove the excessive potassium ions. Ultimately, the liver graft was reperfused when the perfused blood potassium concentration was 7.5 mmol/L without subsequent development of PRCA during the immediate reperfusion period. Nevertheless, the patient still experienced vasoplegic syndrome during the late reperfusion period. CONCLUSIONS Our case illustrates that the FFK measurement is helpful for identifying ECD-related hyperkalemia and for providing advance warning of PRCA. Future investigations are warranted to confirm the relationship between high FFK and PRCA and to observe the effectiveness of other interventions to prevent PRCA due to ECD-related hyperkalemia. PMID- 29967316 TI - Programmed Death Receptor 1 (PD1) Knockout and Human Telomerase Reverse Transcriptase (hTERT) Transduction Can Enhance Persistence and Antitumor Efficacy of Cytokine-Induced Killer Cells Against Hepatocellular Carcinoma. AB - BACKGROUND The weak antitumor efficacy and limited lifespan are the main obstacles that hinder the therapeutic effect of cytokine-induced killer (CIK) cell immunotherapy. In the study, we enhanced the persistence and the antitumor efficacy of CIK cell through PD-1 knockout and hTERT transduction. MATERIAL AND METHODS CIK cells were cultured from patients with hepatocellular carcinoma and PD-1 gene was knocked out through the Cas9 ribonucleoproteins (Cas9 RNPs) electroporation. TIDE assay, T7E1 mismatch cleavage assay, and clone Sanger sequencing were used to detect PD-1 knockout efficiency. The immunophenotype was analyzed by flow cytometry. After PD-1 knockout, the hTERT gene was transduced into PD-1 KO/CIK cells with lentiviral transduction. The hTERT expression and persistence of hTERT/PD-1 KO/CIK cells were evaluated by Western blotting and proliferation curve. The antitumor efficacy was detected by ELISPOT and cytotoxicity assay. The telomere length was measured by the Q-FISH and qPCR method. The karyotype assay was used to analyze the chromosome structural stability. RESULTS The optimal knockout efficiency of PD-1 gene in CIK cells could reach 41.23+/-0.52%. PD-1 knockout did not affect the immunophenotype of CIK cells. The hTERT transduction enhanced persistence and increased the telomere length. ELISPOT and cytotoxicity assay showed hTERT/PD-1 KO/CIK cells had an enhanced antitumor efficacy. Meanwhile, PD-1 KO/CIK cells transduced with hTERT showed a normal karyotype. CONCLUSIONS PD-1 knockout combined with hTERT transduction could prolong the lifespan and enhance antitumor efficacy of CIK cells against hepatocellular carcinoma cell line. PMID- 29967317 TI - Soft Tissue Primary Neuroendocrine Tumor: A Case Report. AB - BACKGROUND Neuroendocrine tumors found in skin or soft tissues usually represent metastasis from other organs and are considered late manifestations of disease. Therefore, primary cutaneous and soft tissue neuroendocrine tumors are extremely rare. CASE REPORT We report a case of a 48-year-old male with a neuroendocrine tumor occurring in the subcutaneous abdominal fat, which had an echographic appearance of a vascular malformation. The finding was diagnosed as compatible with neuroendocrine tumor based on histopathological and immunohistochemical studies. No other sites of possible internal origin were detected on supplementary investigations. CONCLUSIONS Soft tissue neuroendocrine tumors may have an appearance on imaging studies that challenge physicians to make a correct diagnosis. Despite the rarity of these tumors, they should be included in the differential diagnosis of other soft tissue masses. PMID- 29967318 TI - [Mortality in Colombia traffic accidents. Comparative study with other countries]. AB - OBJECTIVE: Traffic accidents (TA) are a global problem with mortality of 1.25 million each year. The objective of this study was to compare adjusted mortality rates (AMR) by AT of Colombia, with Spain and the United States (US). The selection is justified because Colombia is a country with less development in road safety, Spain a nation that has adhered to European guidelines and US for having little adherence to international guidelines. METHODS: A descriptive cross sectional study was carried out for five-year periods, by calculating the AMRs by the direct method of standardization according to sex and age groups, as well as the adjustment of the motorization index. The mean values, the 95% confidence interval for each country and the relative change between the periods studied were calculated. RESULTS: The AMR of periods P1 and P2 in all countries decreased significantly (p <0.005). In periods P2 and P3 also decreased significantly in Spain, by 52.0% (p = 0.010), and in the US, by 23.6% p = 0.001), while in Colombia the difference of 4.0% it was not significant (p = 0.724). Spain stood out for the reduction in mortality (P1-P3), by 69.0%. CONCLUSIONS: Colombia presented a less favorable evolution of mortality due to AT than Spain and the US. Men aged 15 to 44, motorcyclists and cyclists were the most committed. The TAs are a public health problem that Colombia has raised and must adapt to its reality those successful measures in other countries. PMID- 29967319 TI - Early Palaeozoic ocean anoxia and global warming driven by the evolution of shallow burrowing. AB - The evolution of burrowing animals forms a defining event in the history of the Earth. It has been hypothesised that the expansion of seafloor burrowing during the Palaeozoic altered the biogeochemistry of the oceans and atmosphere. However, whilst potential impacts of bioturbation on the individual phosphorus, oxygen and sulphur cycles have been considered, combined effects have not been investigated, leading to major uncertainty over the timing and magnitude of the Earth system response to the evolution of bioturbation. Here we integrate the evolution of bioturbation into the COPSE model of global biogeochemical cycling, and compare quantitative model predictions to multiple geochemical proxies. Our results suggest that the advent of shallow burrowing in the early Cambrian contributed to a global low-oxygen state, which prevailed for ~100 million years. This impact of bioturbation on global biogeochemistry likely affected animal evolution through expanded ocean anoxia, high atmospheric CO2 levels and global warming. PMID- 29967320 TI - BrlR from Pseudomonas aeruginosa is a receptor for both cyclic di-GMP and pyocyanin. AB - The virulence factor pyocyanin and the intracellular second messenger cyclic diguanylate monophosphate (c-di-GMP) play key roles in regulating biofilm formation and multi-drug efflux pump expression in Pseudomonas aeruginosa. However, the crosstalk between these two signaling pathways remains unclear. Here we show that BrlR (PA4878), previously identified as a c-di-GMP responsive transcriptional regulator, acts also as a receptor for pyocyanin. Crystal structures of free BrlR and c-di-GMP-bound BrlR reveal that the DNA-binding domain of BrlR contains two separate c-di-GMP binding sites, both of which are involved in promoting brlR expression. In addition, we identify a pyocyanin binding site on the C-terminal multidrug-binding domain based on the structure of the BrlR-C domain in complex with a pyocyanin analog. Biochemical analysis indicates that pyocyanin enhances BrlR-DNA binding and brlR expression in a concentration-dependent manner. PMID- 29967321 TI - Death-associated protein kinase 1 mediates interleukin-1beta production through regulating inlfammasome activation in Bv2 microglial cells and mice. AB - Interleukin-1beta (IL-1beta) plays a crucial role in mediating inflammation and innate immunity response in the central nervous system. Death-associated protein kinase 1 (DAPK1) was shown to be involved in several cellular processes. Here, we investigated the effects of DAPK1 on IL-1beta production in microglial cells. We used a combination of in vitro (Bv2 microglial cell cultures) and in vivo (mice injected with amyloid-beta (Abeta)) techniques to address the role of caspase-1 activation in release of IL-1beta. DAPK1 involvement was postulated through genetic approaches and pharmacological blockade of this enzyme. We found that Abeta25-35 stimulation induced IL-1beta production and caspase-1 activation in LPS-primed Bv2 cells and mice. DAPK1 knockdown and catalytic activity inhibition reduced IL-1beta maturation and caspase-1 activation, nevertheless, DAPK1 overexpression attenuated these effects. Abeta25-35-induced lysosomal cathepsin B leakage was required for DAPK1 activation. Furthermore, repeated DAPK1 inhibitor treatment ameliorated the memory impairment in Abeta25-35-injected mice. Taken together, our findings suggest that DAPK1 facilitates Abeta25-35-induced IL-1beta production through regulating caspase-1 activation in microglial cells. PMID- 29967322 TI - Ultraviolet Hyperspectral Interferometric Microscopy. AB - Ultraviolet (UV) spectroscopy is a powerful tool for quantitative (bio)chemical analysis, but its application to molecular imaging and microscopy has been limited. Here we introduce ultraviolet hyperspectral interferometric (UHI) microscopy, which leverages coherent detection of optical fields to overcome significant challenges associated with UV spectroscopy when applied to molecular imaging. We demonstrate that this method enables quantitative spectral analysis of important endogenous biomolecules with subcellular spatial resolution and sensitivity to nanometer-scaled structures for label-free molecular imaging of live cells. PMID- 29967324 TI - Three-stage vertical distribution of seawater conductivity. AB - Seawater conductivity is an important indicator of ocean electromagnetic properties and directly impacts the electromagnetic attenuation characteristics and phase distribution features of the ocean. Few studies have considered how the combined effects of salinity, temperature and pressure affect the vertical conductivity distribution and its formation mechanisms. Here, we analyse the vertical distributions of seawater conductivity from the sea surface to a maximum depth of 7062 m at five different locations. Electric conductivity profiles show similar vertical structures at all locations. Electric conductivity decreases with increasing depth first and then slowly increases from approximately 2000 m to the seabed. We observe an exponential relationship between the conductivity minimum and the water depth. At all five measurement locations, seawater conductivity measurements show a stable three-stage vertical distribution on logarithmic scales, with the middle stage satisfying a power law relationship. We analyse the vertical distribution of temperature in the second stage and investigate the relationship between temperature and conductivity. The results show that temperature also exhibits a power-law relationship with depth and a high linear correlation exists between temperature and conductivity. Our findings suggest that the vertical structure of conductivity is largely temperature dependent. PMID- 29967323 TI - Cluster-assembled zirconia substrates promote long-term differentiation and functioning of human islets of Langerhans. AB - Ex vivo expansion and differentiation of human pancreatic beta-cell are enabling steps of paramount importance for accelerating the development of therapies for diabetes. The success of regenerative strategies depends on their ability to reproduce the chemical and biophysical properties of the microenvironment in which beta-cells develop, proliferate and function. In this paper we focus on the biophysical properties of the extracellular environment and exploit the cluster assembled zirconia substrates with tailored roughness to mimic the nanotopography of the extracellular matrix. We demonstrate that beta-cells can perceive nanoscale features of the substrate and can convert these stimuli into mechanotransductive processes which promote long-term in vitro human islet culture, thus preserving beta-cell differentiation and function. Proteomic and quantitative immunofluorescence analyses demonstrate that the process is driven by nanoscale topography, via remodelling of the actin cytoskeleton and nuclear architecture. These modifications activate a transcriptional program which stimulates an adaptive metabolic glucose response. Engineered cluster-assembled substrates coupled with proteomic approaches may provide a useful strategy for identifying novel molecular targets for treating diabetes mellitus and for enhancing tissue engineering in order to improve the efficacy of islet cell transplantation therapies. PMID- 29967325 TI - Risk stratifiers for arrhythmic and non-arrhythmic mortality after acute myocardial infarction. AB - The effective discrimination between patients at risk of Arrhythmic Mortality (AM) and Non-Arrhythmic Mortality (NAM) constitutes one of the important unmet clinical needs. Successful risk assessment based on Electrocardiography (ECG) records is greatly improved by the combination of different indices reflecting not only the pathological substrate but also the autonomic regulation of cardiac electrophysiology. This study assesses the cardiac risk stratification capacity of two new Heart Rate Variability (HRV) parameters, Breath Concurrence 6 (BC6) sinusoidal RR variability of 6 heart beats per breath cycle- and Primary Ectopia (PE) -presence of early ventricular contractions of any etiology- together with the Deceleration Capacity (DC). While BC6 characterizes the response to physiological and pathophysiological stimuli, PE qualifies autonomic cardiac electrophysiology. The analysis of the European Myocardial Infarct Amiodarone Trial (EMIAT) database indicates that BC6 is related with the risk of Arrhythmic Mortality (AM) and PE with the risk of Non-Arrhythmic Mortality. BC6 is the only single parameter that significantly discriminates between AM and NAM. While the combination of BC6 and DC contributes to the identification of AM risk, PE together with DC improves the prediction of NAM in patients with severe ischemic heart disease. PMID- 29967326 TI - The Role of PET-Based Radiomic Features in Predicting Local Control of Esophageal Cancer Treated with Concurrent Chemoradiotherapy. AB - This study was designed to evaluate the predictive performance of 18F fluorodeoxyglucose positron emission tomography (PET)-based radiomic features for local control of esophageal cancer treated with concurrent chemoradiotherapy (CRT). For each of the 30 patients enrolled, 440 radiomic features were extracted from both pre-CRT and mid-CRT PET images. The top 25 features with the highest areas under the receiver operating characteristic curve for identifying local control status were selected as discriminative features. Four machine-learning methods, random forest (RF), support vector machine, logistic regression, and extreme learning machine, were used to build predictive models with clinical features, radiomic features or a combination of both. An RF model incorporating both clinical and radiomic features achieved the best predictive performance, with an accuracy of 93.3%, a specificity of 95.7%, and a sensitivity of 85.7%. Based on risk scores of local failure predicted by this model, the 2-year local control rate and PFS rate were 100.0% (95% CI 100.0-100.0%) and 52.2% (31.8 72.6%) in the low-risk group and 14.3% (0.0-40.2%) and 0.0% (0.0-40.2%) in the high-risk group, respectively. This model may have the potential to stratify patients with different risks of local failure after CRT for esophageal cancer, which may facilitate the delivery of personalized treatment. PMID- 29967327 TI - Myoepithelial cell-driven acini contraction in response to oxytocin receptor stimulation is impaired in lacrimal glands of Sjogren's syndrome animal models. AB - The purpose of the present studies was to investigate the impact of chronic inflammation of the lacrimal gland, as occurs in Sjogren's syndrome, on the morphology and function of myoepithelial cells (MECs). In spite of the importance of MECs for lacrimal gland function, the effect of inflammation on MECs has not been well defined. We studied changes in MEC structure and function in two animal models of aqueous deficient dry eye, NOD and MRL/lpr mice. We found a statistically significant reduction in the size of MECs in diseased compared to control lacrimal glands. We also found that oxytocin receptor was highly expressed in MECs of mouse and human lacrimal glands and that its expression was strongly reduced in diseased glands. Furthermore, we found a significant decrease in the amount of two MEC contractile proteins, alpha-smooth muscle actin (SMA) and calponin. Finally, oxytocin-mediated contraction was impaired in lacrimal gland acini from diseased glands. We conclude that chronic inflammation of the lacrimal gland leads to a substantial thinning of MECs, down-regulation of contractile proteins and oxytocin receptor expression, and therefore impaired acini contraction. This is the first study highlighting the role of oxytocin mediated MEC contraction on lacrimal gland function. PMID- 29967328 TI - HECIL: A Hybrid Error Correction Algorithm for Long Reads with Iterative Learning. AB - Second-generation DNA sequencing techniques generate short reads that can result in fragmented genome assemblies. Third-generation sequencing platforms mitigate this limitation by producing longer reads that span across complex and repetitive regions. However, the usefulness of such long reads is limited because of high sequencing error rates. To exploit the full potential of these longer reads, it is imperative to correct the underlying errors. We propose HECIL-Hybrid Error Correction with Iterative Learning-a hybrid error correction framework that determines a correction policy for erroneous long reads, based on optimal combinations of decision weights obtained from short read alignments. We demonstrate that HECIL outperforms state-of-the-art error correction algorithms for an overwhelming majority of evaluation metrics on diverse, real-world data sets including E. coli, S. cerevisiae, and the malaria vector mosquito A. funestus. Additionally, we provide an optional avenue of improving the performance of HECIL's core algorithm by introducing an iterative learning paradigm that enhances the correction policy at each iteration by incorporating knowledge gathered from previous iterations via data-driven confidence metrics assigned to prior corrections. PMID- 29967330 TI - Author Correction: Space-Wave Routing via Surface Waves Using a Metasurface System. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967329 TI - Synthetic molecular evolution of hybrid cell penetrating peptides. AB - Peptides and analogs such as peptide nucleic acids (PNA) are promising tools and therapeutics, but the cell membrane remains a barrier to intracellular targets. Conjugation to classical cell penetrating peptides (CPPs) such as pTat48-60 (tat) and pAntp43-68 (penetratin) facilitates delivery; however, efficiencies are low. Lack of explicit design principles hinders rational improvement. Here, we use synthetic molecular evolution (SME) to identify gain-of-function CPPs with dramatically improved ability to deliver cargoes to cells at low concentration. A CPP library containing 8192 tat/penetratin hybrid peptides coupled to an 18 residue PNA is screened using the HeLa pTRE-LucIVS2 splice correction reporter system. The daughter CPPs identified are one to two orders of magnitude more efficient than the parent sequences at delivery of PNA, and also deliver a dye cargo and an anionic peptide cargo. The significant increase in performance following a single iteration of SME demonstrates the power of this approach to peptide sequence optimization. PMID- 29967331 TI - Harnessing Free Energy From Nature For Efficient Operation of Compressed Air Energy Storage System and Unlocking the Potential of Renewable Power Generation. AB - Energy storage technologies have gained considerable momentum in the recent years owing to the rising tide of renewables. The deployment of energy storage is a trend set to continue into 2018 and beyond. In the near future, compressed air energy storage (CAES) will serve as an integral component of several energy intensive sectors. However, the major drawback in promoting CAES system in both large and small scale is owing to its minimum turn around efficiency. In the present work the major drawbacks associated with various existing configurations of CAES system are analysed. Interesting results of Isothermal CAES system are obtained through the present analysis to generate additional output energy compared to the supplied input by harnessing the free energy from the natural water bodies/ocean to enhance the overall turnaround efficiency of the system. The optimum operational characteristics of charging and discharging cycles are also addressed. In the present energy scenario, increasing the percentage of renewable energy (RE) share in the power generation is quite challenging since RE based power generation is intermittent in nature. The integration of energy storage technologies with RE source is imperative as it mitigates the intermittency of available energy. However, the development of efficient energy storage systems is one of the prime challenges in the promotion of renewable energy in a large scale. Among the various storage systems, electrochemical battery storage and pumped hydro storage (PHS) have attracted the commercial market. However, the shorter cycle life makes the battery storage more expensive and the PHS systems involves certain geographical and site constraints. Beyond the said storage systems, compressed air energy storage system which is one of the technically proven system has not been targeted the commercial market owing to its lower turnaround efficiency. Hence, the motivation behind the present research is towards developing efficient CAES configuration with higher turnaround efficiency thereby attaining economic feasibility and sustainability. PMID- 29967332 TI - Dexmedetomidine Added to Sufentanil Patient-Controlled Intravenous Analgesia Relieves the Postoperative Pain after Cesarean Delivery: A Prospective Randomized Controlled Multicenter Study. AB - This study evaluated the efficacy and safety of dexmedetomidine in intravenous patient-controlled analgesia (PCA) after cesarean delivery. This multicenter study enrolled 208 subjects who were scheduled for selective cesarean delivery from 9 research centers. Patients received 0.5 ug/kg dexmedetomidine (study group) or normal saline (control group) after delivery and an intravenous PCA pump after surgery (100 MUg sufentanil +300 MUg dexmedetomidine for the study group, 100 MUg sufentanil for the control group, background infusion: 1 ml/h, bolus dose: 2 ml and lock time: 8 min). The sufentanil consumption, pain scores, rescue analgesia, sedation scores, analgesic satisfaction, the incidence of postoperative nausea and vomiting (PONV) and the first passage of flatus were recorded within 24 h after surgery. The sufentanil consumption in the study group was significantly lower than that in the control group (p = 0.004). Compared with the control group, the study group had lower pain scores (p < 0.01), higher analgesic satisfaction degree [p < 0.001, odd ratio 4.28 and 95% CI (2.46, 7.46)], less requirement of rescue analgesia (p = 0.003), lower incidence of PONV (p = 0.005 and p < 0.001, respectively), and shorter time to first passage of flatus (p = 0.007). Dexmedetomidine added to sufentanil intravenous PCA significantly enhanced the analgesic effects, improved analgesic satisfaction, and had the potential benefits of reducing PONV and the recovery of intestinal functions after cesarean section. PMID- 29967334 TI - A fine-mapping study of central obesity loci incorporating functional annotation and imputation. AB - A recent genome-wide association study (GWAS) of central obesity identified 27 loci, from sex-combined analysis, associated with waist-to-hip ratio adjusted for body-mass index (WHRadjBMI) in European-ancestry individuals. Nevertheless, the identified variants may not be the biological causal ones due to the presence of linkage disequilibrium (LD). To better understand the mechanisms underlying the identified loci from the GWAS meta-analysis, we first imputed summary statistics at GWAS loci to increase genetic resolution, and then we applied a Bayesian statistical fine-mapping method through PAINTOR, incorporating LD structure and functional annotations to select and prioritize the most plausible causal variants across WHRadjBMI-associated regions. Using adipose tissue- and cell specific annotations that showed significant associations with WHRadjBMI, we identified 33 single-nucleotide polymorphisms (SNPs) from 27 sex-combined fine mapping loci with posterior probability of causality greater than 0.9. Six of the selected 33 SNPs belong to at least one of the top five identified annotations. SNPs rs1440372 (SMAD6) and rs12608504 (JUND) are particularly important since they not only have associated functional annotations but are also GWA hits in the original study. Incorporation of functional annotations helps identify additional plausible causal variants, such as rs2213731 (DNM3-PIGC) and rs4531856 (JUND), that did not reach genome-wide significance in GWAS. Our results provide promising candidates for future functional validation experiments. PMID- 29967333 TI - MicroRNAs distribution in different phenotypes of Aortic Stenosis. AB - Aortic valve stenosis (AVS) represents a cluster of different phenotypes, considering gradient and flow pattern. Circulating micro RNAs may reflect specific pathophysiological processes and could be useful biomarkers to identify disease. We assessed 80 patients (81, 76.7-84 years; 46, 57.5%females) with severe AVS. We performed bio-humoral evaluation (including circulating miRNA-1, 21, 29, 133) and 2D-echocardiography. Patients were classified according to ACC/AHA groups (D1-D3) and flow-gradient classification, considering normal/low flow, (NF/LF) and normal/high gradient, (NG/HG). Patients with reduced ejection fractionwere characterized by higher levels of miRNA1 (p = 0.003) and miRNA 133 (p = 0.03). LF condition was associated with higher levels of miRNA1 (p = 0.02) and miRNA21 (p = 0.02). Levels of miRNA21 were increased in patients with reduced Global longitudinal strain (p = 0.03). LF-HG and LF-LG showed higher levels of miRNA1 expression (p = 0.005). At one-year follow-up miRNA21 and miRNA29 levels resulted significant independent predictors of reverse remodeling and systolic function increase, respectively. Different phenotypes of AVS may express differential levels and types of miRNAs, which may retain a pathophysiological role in pro-hypertrophic and pro-fibrotic processes. PMID- 29967335 TI - Pharmacogenomics, a novel section in the European Journal of Human Genetics. PMID- 29967336 TI - Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes. AB - We have developed and validated for the diagnosis of inherited colorectal cancer (CRC) a massive parallel sequencing strategy based on: (i) fast capture of exonic and intronic sequences from ten genes involved in Mendelian forms of CRC (MLH1, MSH2, MSH6, PMS2, APC, MUTYH, STK11, SMAD4, BMPR1A and PTEN); (ii) sequencing on MiSeq and NextSeq 500 Illumina platforms; (iii) a bioinformatic pipeline that includes BWA-Picard-GATK (Broad Institute) and CASAVA (Illumina) in parallel for mapping and variant calling, Alamut Batch (Interactive BioSoftware) for annotation, CANOES for CNV detection and finally, chimeric reads analysis for the detection of other types of structural variants (SVs). Analysis of 1644 new index cases allowed the identification of 323 patients with class 4 or 5 variants, corresponding to a 20% disease-causing variant detection rate. This rate reached 37% in patients with Lynch syndrome, suspected on the basis of tumour analyses. Thanks to this strategy, we detected overlapping phenotypes (e.g., MUTYH biallelic mutations mimicking Lynch syndrome), mosaic alterations and complex SVs such as a genomic deletion involving the last BMPR1A exons and PTEN, an Alu insertion within MSH2 exon 8 and a mosaic deletion of STK11 exons 3-10. This strategy allows, in a single step, detection of all types of CRC gene alterations including SVs and provides a high disease-causing variant detection rate, thus optimizing the diagnosis of inherited CRC. PMID- 29967338 TI - Vasodilator-stimulated phosphoprotein (VASP) is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and antiplatelet effect of prasugrel in rats. AB - Vasodilator-stimulated phosphoprotein (VASP) is a member of actin regulatory proteins implicated in platelet adhesion. In addition, phosphorylation of VASP is utilised for the assessment of platelet reactivity in patients treated with P2Y12 receptor antagonists, a class of antiplatelet agents. However, the role of VASP in platelet aggregation, thrombogenesis, haemostasis, and the antiplatelet effect of P2Y12 receptor antagonists remains unclear. We investigated these effects using heterozygous and homozygous VASP knockout rats generated with a CRISPR/Cas9 system. Baseline characteristics, such as haematology and other biochemical parameters, were comparable among the genotypes. In vitro platelet aggregation stimulated by adenosine diphosphate (ADP) or collagen, P-selectin expression of rat platelets treated with ADP, and in vivo thrombocytopenia induced by collagen were also comparable among the genotypes. In addition, in vivo thrombogenesis in a ferric chloride-induced arterial thrombosis model and bleeding time were also comparable among the genotypes. Furthermore, the in vitro antiplatelet effect of prasugrel, a third-generation P2Y12 receptor antagonist, was unaffected by VASP knockout. Although phosphorylated VASP is still an important surrogate marker specific for P2Y12 antagonists, our findings demonstrate that VASP is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and the antiplatelet effect of prasugrel in rats. PMID- 29967337 TI - De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is a multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3'-untranslated region of the DMPK gene. The repeat expansion is somatically unstable and tends to increase in length with time, contributing to disease progression. In some individuals, the repeat array is interrupted by variant repeats such as CCG and CGG, stabilising the expansion and often leading to milder symptoms. We have characterised three families, each including one person with variant repeats that had arisen de novo on paternal transmission of the repeat expansion. Two individuals were identified for screening due to an unusual result in the laboratory diagnostic test, and the third due to exceptionally mild symptoms. The presence of variant repeats in all three expanded alleles was confirmed by restriction digestion of small pool PCR products, and allele structures were determined by PacBio sequencing. Each was different, but all contained CCG repeats close to the 3'-end of the repeat expansion. All other family members had inherited pure CTG repeats. The variant repeat-containing alleles were more stable in the blood than pure alleles of similar length, which may in part account for the mild symptoms observed in all three individuals. This emphasises the importance of somatic instability as a disease mechanism in DM1. Further, since patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and for patient stratification in DM1 clinical trials. PMID- 29967339 TI - Molybdenum Disulfide Surface Modification of Ultrafine-Grained Titanium for Enhanced Cellular Growth and Antibacterial Effect. AB - The commercially pure Ti (CP Ti) and equal-channel angular pressing (ECAP) processed Ti can contribute to the downsizing of medical devices with their superior mechanical properties and negligible toxicity. However, the ECAP processed pure Ti has the risk of bacterial infection. Here, the coarse- and ultrafine-grained Ti substrates were surface-modified with molybdenum disulfide (MoS2) to improve the cell proliferation and growth with antibacterial effect for further dental applications. According to in vitro tests using the pre-osteoblast of MC3T3-E1 cell and a bacterial model of Escherichia coli (E. coli), MoS2 nanoflakes coated and ECAP-processed Ti substrates showed a significant increase in surface energy and singlet oxygen generation resulting in improved cell attachment and antibacterial effect. In addition, we confirmed the stability of the surface modified Ti substrates in a physiological solution and an artificial bone. Taken together, MoS2 modified and ECAP-processed Ti substrates might be successfully harnessed for various dental applications. PMID- 29967340 TI - Sensitivity to sounds in sport-related concussed athletes: a new clinical presentation of hyperacusis. AB - Sensitivity to sounds is one frequent symptom of a sport-related concussion, but its assessment rarely goes beyond a single question. Here we examined sensitivity to sounds using psychoacoustic and psychometric outcomes in athletes beyond the acute phase of injury. Fifty-eight college athletes with normal hearing who either had incurred one or more sport-related concussions (N = 28) or who had never suffered head injury (N = 30) participated. Results indicated that the Concussed group scored higher on the Hyperacusis questionnaire and displayed greater sensitivity to sounds in psychoacoustic tasks compared to the Control group. However, further analyses that separated the Concussed group in subgroups with Sound sensitivity symptom (N = 14) and Without sound sensitivity symptom (N = 14) revealed that athletes with the sound complaint were the ones responsible for the effect: Concussed athletes with self-reported sound sensitivity had lower Loudness Discomfort Thresholds (LDLs), higher Depression and Hyperacusis scores, and shifted loudness growth functions compared to the other subgroup. A simple mediation model disclosed that LDLs exert their influence both directly on Hyperacusis scores as well as indirectly via depressive symptoms. We thus report a new clinical presentation of hyperacusis and discuss possible mechanisms by which it could arise from concussion. PMID- 29967341 TI - The adhesion molecule cadherin 11 is essential for acquisition of normal hearing ability through middle ear development in the mouse. AB - Cadherin 11 (Cdh11), a member of the cadherin adhesion molecule family, is expressed in various regions of the brain as well as the head and ear. To gain further insights into the roles of Cdh11 in the development of the ear, we performed behavioral tests using Cdh11 knockout (KO) mice. KO mice showed reduced acoustic startle responses and increased thresholds for auditory brainstem responses, indicating moderate hearing loss. The auditory bulla volume and ratio of air-filled to non-air-filled space in the middle ear cavity were reduced in KO mice, potentially causing conductive hearing loss. Furthermore, residual mesenchymal and inflammatory cells were observed in the middle ear cavity of KO mice. Cdh11 was expressed in developing mesenchymal cells just before the start of cavitation, indicating that Cdh11 may be directly involved in middle ear cavitation. Since the auditory bulla is derived from the neural crest, the regulation of neural crest-derived cells by Cdh11 may be responsible for structural development. This mutant mouse may be a promising animal model for elucidating the causes of conductive hearing loss and otitis media. PMID- 29967342 TI - Thyroid cancer stem-like cell exosomes: regulation of EMT via transfer of lncRNAs. AB - Thyroid cancers are the most common endocrine malignancy and approximately 2% of thyroid cancers are anaplastic thyroid carcinoma (ATC), one of the most lethal and treatment resistant human cancers. Cancer stem-like cells (CSCs) may initiate tumorigenesis, induce resistance to chemotherapy and radiation therapy, have multipotent capability and may be responsible for recurrent and metastatic disease. The production of CSCs has been linked to epithelial-mesenchymal transition (EMT) and the acquisition of stemness. Exosomes are small (30-150 nm) membranous vesicles secreted by most cells that play a significant role in cell to-cell communication. Many non-coding RNAs (ncRNA), such as long-non-coding RNAs (lncRNA), can initiate tumorigenesis and the EMT process. Exosomes carry ncRNAs to local and distant cell populations. This study examines secreted exosomes from two in vitro cell culture models; an EMT model and a CSC model. The EMT was induced in a papillary thyroid carcinoma (PTC) cell line by TGFbeta1 treatment. Exosomes from this model were isolated and cultured with naive PTC cells and examined for EMT induction. In the CSC model, exosomes were isolated from a CSC clonal line, cultured with a normal thyroid cell line and examined for EMT induction. The EMT exosomes transferred the lncRNA MALAT1 and EMT effectors SLUG and SOX2; however, EMT was not induced in this model. The exosomes from the CSC model also transferred the lncRNA MALAT1 and the transcription factors SLUG and SOX2 but additionally transferred linc-ROR and induced EMT in the normal thyroid cells. Preliminary siRNA studies directed towards linc-ROR reduced invasion. We hypothesize that CSC exosomes transfer lncRNAs, importantly linc-ROR, to induce EMT and inculcate the local tumor microenvironment and the distant metastatic niche. Therapies directed towards CSCs, their exosomes and/or the lncRNAs they carry may reduce a tumor's metastatic capacity. PMID- 29967343 TI - Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo. AB - Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2. GLI2 appeared to support cell growth by regulating the mitosis, but not the apoptosis, of the cervical cancer cells. Mechanistically, these functions of GLI2 were in part mediated by the activation of AKT pathway. Knockdown of GLI2, but not GLI3, also inhibited xenograft growth of cervical cancer cells in vivo. Finally, analysis of TCGA data showed that high levels of GLI2, but not GLI3, conferred a poor prognosis in cervical cancer patients. These observations for the first time suggest that GLI2, but not GLI3, exerts a tumor-promoting role in cervical cancer and may be targeted as a novel therapeutic strategy. PMID- 29967345 TI - Introduction of a new repair technique in bony avulsion of the FDP tendon: A biomechanical study. AB - The purpose of this study was to determine the biomechanical characteristics of an innovative surgical technique based on a tension banding principle using a suture anchor in the repair of bony avulsions of the flexor digitorum profundus tendon. After injury simulation in 45 fresh frozen distal phalanges from human cadavers, repair was performed with minifragment screws, interosseous sutures and the innovative technique (15 per group). All repairs were loaded for a total of 500 cycles. Subsequently the specimens were loaded to failure. Load at failure, load at first noteworthy displacement (>2 mm), elongation of the system, gap formation at the avulsion site, and the mechanism of failure were assessed. The new techniques' superior performance in load at failure (mean: 100.5 N), load at first noteworthy displacement (mean 77.4 N), and gap formation (median 0 mm) was statistically significant, which implies a preferable rigidity of the repair. No implant extrusion or suture rupture during cyclic loading were recorded when the new technique was applied. This innovative repair technique is superior biomechanically to other commonly used surgical tendon reattachment methods, particularly with respect to an early passive mobilisation protocol. Further, due to its subcutaneous position, reduction of complications may be achieved. PMID- 29967344 TI - Effects of Mild Blast Traumatic Brain Injury on Cognitive- and Addiction-Related Behaviors. AB - Traumatic brain injury (TBI) commonly results in cognitive and psychiatric problems. Cognitive impairments occur in approximately 30% of patients suffering from mild TBI (mTBI), and correlational evidence from clinical studies indicates that substance abuse may be increased following mTBI. However, understanding the lasting cognitive and psychiatric problems stemming from mTBI is difficult in clinical settings where pre-injury assessment may not be possible or accurate. Therefore, we used a previously characterized blast model of mTBI (bTBI) to examine cognitive- and addiction-related outcomes. We previously demonstrated that this model leads to bilateral damage of the medial prefrontal cortex (mPFC), a region critical for cognitive function and addiction. Rats were exposed to bTBI and tested in operant learning tasks several weeks after injury. bTBI rats made more errors during acquisition of a cue discrimination task compared to sham treated rats. Surprisingly, we observed no differences between groups in set shifting and delayed matching to sample, tasks known to require the mPFC. Separate rats performed cocaine self-administration. No group differences were found in intake or extinction, and only subtle differences were observed in drug primed reinstatement 3-4 months after injury. These findings indicate that bTBI impairs acquisition of a visual discrimination task and that bTBI does not significantly increase the ability of cocaine exposure to trigger drug seeking. PMID- 29967346 TI - Autophagy defects and related genetic variations in renal cell carcinoma with eosinophilic cytoplasmic inclusions. AB - The relationship between autophagy and tumour is well studied, but tumour cell morphological changes associated with autophagy defects are rarely reported, especially in renal cell carcinoma (RCC). We collected 10 renal tumour samples with characteristic eosinophilic cytoplasmic inclusions (ECIs) and found that the ECIs were majorly composed of sequestosome 1/P62, neighbor of BRCA1 gene 1 (NBR1), PEX14, and CATALASE1 (CAT1). Further, transmission electron microscopy analysis revealed that ECIs were aggregates of proteinaceous material and peroxisomes. These results confirmed that ECIs in RCCs were the products of autophagy defects. The presence of ECIs was correlated with high Fuhrman grade components of RCCs. Whole-exome sequencing (WES) and Sanger sequencing confirmed that tumours with ECIs showed somatic mutations or high frequency of genetic variations in autophagy-related (ATG) genes, such as ATG7, ATG5, and ATG10. These results indicate that nucleotide changes in ATG genes are associated with autophagy defect, ECI formation, and even tumour grade in RCCs. PMID- 29967347 TI - Author Correction: High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. AB - In the version of this article initially published, Figs. 5a,c and 6a were incorrect because of an error in a metadata spreadsheet that led to the healthy donor patient 2 (HD2) samples being used twice in the analysis of baseline samples and in the analysis at 12 weeks of anti-PD-1 therapy, while HD3 samples had not been used. PMID- 29967348 TI - Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates. AB - Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection. PMID- 29967349 TI - DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. AB - Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 (DPP8/9) induce a lytic form of cell death called pyroptosis in mouse and human monocytes and macrophages1,2. In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known. Here we show that the CARD-containing protein CARD8 mediates DPP8/9 inhibitor-induced pro-caspase-1-dependent pyroptosis in human myeloid cells. We further show that DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML. PMID- 29967350 TI - Mechanisms of NAFLD development and therapeutic strategies. AB - There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression. PMID- 29967351 TI - Metformin reverses established lung fibrosis in a bleomycin model. AB - Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in a number of organs, including the lungs1. Cellular metabolism regulates tissue repair and remodelling responses to injury2-4. AMPK is a critical sensor of cellular bioenergetics and controls the switch from anabolic to catabolic metabolism5. However, the role of AMPK in fibrosis is not well understood. Here, we demonstrate that in humans with idiopathic pulmonary fibrosis (IPF) and in an experimental mouse model of lung fibrosis, AMPK activity is lower in fibrotic regions associated with metabolically active and apoptosis resistant myofibroblasts. Pharmacological activation of AMPK in myofibroblasts from lungs of humans with IPF display lower fibrotic activity, along with enhanced mitochondrial biogenesis and normalization of sensitivity to apoptosis. In a bleomycin model of lung fibrosis in mice, metformin therapeutically accelerates the resolution of well-established fibrosis in an AMPK-dependent manner. These studies implicate deficient AMPK activation in non-resolving, pathologic fibrotic processes, and support a role for metformin (or other AMPK activators) to reverse established fibrosis by facilitating deactivation and apoptosis of myofibroblasts. PMID- 29967353 TI - Unmasking chloride attack on the passive film of metals. AB - Nanometer-thick passive films on metals usually impart remarkable resistance to general corrosion but are susceptible to localized attack in certain aggressive media, leading to material failure with pronounced adverse economic and safety consequences. Over the past decades, several classic theories have been proposed and accepted, based on hypotheses and theoretical models, and oftentimes, not sufficiently nor directly corroborated by experimental evidence. Here we show experimental results on the structure of the passive film formed on a FeCr15Ni15 single crystal in chloride-free and chloride-containing media. We use aberration corrected transmission electron microscopy to directly capture the chloride ion accumulation at the metal/film interface, lattice expansion on the metal side, undulations at the interface, and structural inhomogeneity on the film side, most of which had previously been rejected by existing models. This work unmasks, at the atomic scale, the mechanism of chloride-induced passivity breakdown that is known to occur in various metallic materials. PMID- 29967352 TI - Functional diversity and cooperativity between subclonal populations of pediatric glioblastoma and diffuse intrinsic pontine glioma cells. AB - The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments. PMID- 29967354 TI - Potential formula of an m * n globe network and its application. AB - Searching for the explicit solutions of the potential function in an arbitrary resistor network is important but difficult in physics. We investigate the problem of potential formula in an arbitrary m * n globe network of resistors, which has not been resolved before (the previous study only calculated the resistance). In this paper, an exact potential formula of an arbitrary m * n globe network is discovered by means of the Recursion-Transform method with current parameters (RT-I). The key process of RT method is to set up matrix equation and to transform two-dimensional matrix equation into one-dimensional matrix equation. In order to facilitate practical application, we deduced a series of interesting results of potential by means of the general formula, and the effective resistance between two nodes in the m * n globe network is derived naturally by making use of potential formula. PMID- 29967355 TI - Recognition of candidate transcription factors related to bilberry fruit ripening by de novo transcriptome and qRT-PCR analyses. AB - Bilberry (Vaccinium myrtillus L.) fruits are an excellent natural resource for human diet because of their special flavor, taste and nutritional value as well as medical properties. Bilberries are recognized for their high anthocyanin content and many of the genes involved in the anthocyanin biosynthesis have been characterized. So far, neither genomic nor RNA-seq data have been available for the species. In the present study, we de novo sequenced two bilberry fruit developmental stages, unripe green (G) and ripening (R). A total of 57,919 unigenes were assembled of which 80.2% were annotated against six public protein databases. The transcriptome served as exploratory data to identify putative transcription factors related to fruit ripening. Differentially expressed genes (DEGs) between G and R stages were prominently upregulated in R stage with the functional annotation indicating their main roles in active metabolism and catalysis. The unigenes encoding putative ripening-related regulatory genes, including members of NAC, WRKY, LOB, ERF, ARF and ABI families, were analysed by qRT-PCR at five bilberry developmental stages. Our de novo transcriptome database contributes to the understanding of the regulatory network associated with the fruit ripening in bilberry and provides the first dataset for wild Vaccinium species acquired by NGS technology. PMID- 29967356 TI - Social information can potentiate understanding despite inhibiting cognitive effort. AB - Both reasoning ability and social learning play a crucial role in human adaptation. Cognitive abilities like enhanced reasoning skills have combined with cumulative cultural adaptation to allow our species to dominate the world like no other. Thus, understanding how social learning interacts with individual reasoning ability is crucial for unravelling our evolutionary history. Here we describe a laboratory experiment designed to investigate the effect of social learning on individuals' ability to infer a general rule about unfamiliar problems. In this experiment, social information had both positive and negative effects on individuals' likelihood of inferring the rule. Social learners required more evidence to infer the rule than did individual learners, suggesting that social learning inhibits cognitive effort but social learning provided individuals with information that individual learners were unlikely to gather on their own, especially as the task became more difficult. When individuals are unlikely to discover useful information by themselves, social learning can potentiate understanding even though it reduces individual cognitive effort. PMID- 29967358 TI - Generalized Empirical Bayes Modeling via Frequentist Goodness of Fit. AB - The two key issues of modern Bayesian statistics are: (i) establishing principled approach for distilling statistical prior that is consistent with the given data from an initial believable scientific prior; and (ii) development of a consolidated Bayes-frequentist data analysis workflow that is more effective than either of the two separately. In this paper, we propose the idea of "Bayes via goodness-of-fit" as a framework for exploring these fundamental questions, in a way that is general enough to embrace almost all of the familiar probability models. Several examples, spanning application areas such as clinical trials, metrology, insurance, medicine, and ecology show the unique benefit of this new point of view as a practical data science tool. PMID- 29967357 TI - Phenotypes of Jackhammer esophagus in patients with typical symptoms of gastroesophageal reflux disease responsive to proton pump inhibitors. AB - This trial was designed to assess the prevalence and characteristics of Jackhammer esophagus (JE), a novel hypercontractile disorder associated with progression to achalasia and limited outcomes following anti-reflux surgery in patients with typical symptoms of GERD and responsiveness to proton pump inhibitor (PPI) therapy. Consecutive patients, who were referred for surgical therapy because of PPI responsive typical symptoms of GERD, were prospectively assessed between January 2014 and May 2017. Patients diagnosed with JE subsequently underwent rigorous clinical screening including esophagogastroduodenoscopy (EGD), ambulatory pH impedance monitoring off PPI and a PPI trial. Out of 2443 evaluated patients, 37 (1.5%) subjects with a median age of 56.3 (51.6; 65) years were diagnosed with JE and left for final analysis. Extensive testing resulted in 16 (43.2%) GERD positive patients and 5 (13.9%) participants were observed to have an acid hypersensitive esophagus. There were no clinical parameters that differentiated phenotypes of JE. The prevalence of JE in patients with typical symptoms of GERD and response to PPI therapy is low. True GERD was diagnosed in less than half of this selected cohort, indicating the need for objective testing to stratify phenotypes of JE. (NCT03347903). PMID- 29967359 TI - Neural differences of inhibitory control between adolescents with obesity and their peers. AB - BACKGROUND/OBJECTIVE: Inhibitory control, the ability to suppress prepotent responses and resist irrelevant stimuli, is thought to play a critical role in the manifestation and maintenance of obesity in adolescents. Adolescence is a unique developmental stage characterized by significant maturational changes in cortical structures (i.e., prefrontal cortex: PFC) that relate to inhibitory control processes. The current study investigated the behavioral and neurophysiological correlates of inhibitory control in adolescents with obesity. SUBJECTS/METHODS: We compared 18 normal-weight and 22 adolescents with obesity on performance and electroencephalography (EEG)-based measures during a Go/NoGo task. We investigated N2 and P3 event-related potential (ERP) components. RESULTS: Adolescents with obesity showed lower accuracy compared to their normal weight peers in NoGo trials where greater amounts of inhibitory control effort were required (p = 0.03). Adolescents with obesity had larger NoGo N2 amplitude relative to the Go N2 amplitude (p = 0.03), whereas this difference was not observed in the healthy weight sample. Furthermore, a lower self-efficacy of individual's ability to control eating behaviors in challenging situations (as measured by the Weight Efficacy Lifestyle-Short Form) directly correlated with larger NoGo N2 amplitudes for both obese (p = 0.03) and normal weight groups (p = 0.01). CONCLUSIONS: These findings suggested that obesity in adolescence is associated with a decreased ability to modulate cognitive conflict during the inhibitory control processing. The individual differences in conflict monitoring during situations where greater amounts of inhibitory control effort were required might provide an explanation for overeating behaviors in obese adolescents. PMID- 29967360 TI - Inductively actuated micro needles for on-demand intracellular delivery. AB - Methods that provide controlled influx of molecules into cells are of critical importance for uncovering cellular mechanisms, drug development and synthetic biology. However, reliable intracellular delivery without adversely affecting the cells is a major challenge. We developed a platform for on-demand intracellular delivery applications, with which cell membrane penetration is achieved by inductive heating of micro needles. The micro needles of around 1 MUm in diameter and 5 MUm in length are made of gold using a silicon-based micro fabrication process that provides flexibility with respect to the needles' dimensions, pitch, shell thickness and the covered area. Experiments with HCT 116 colon cancer cells showed a high biocompatibility of the gold needle platform. Transmission electron microscopy of the cell-needle interface revealed folding of the cell membrane around the needle without penetration, preventing any delivery, which was confirmed using the EthD-1 fluorescent dye. The application of an alternating magnetic field, however, resulted in the delivery of EthD-1 by localized heating of the micro needles. Fluorescence quantification showed that intracellular delivery, with as high as 75% efficiency, is achieved for specific treatment times between 1 and 5 minutes. Overexposure of the cells to the heated micro needles, i.e. longer magnetic field application, leads to an increase in cell death, which can be exploited for cleaning the platform. This method allows to perform intracellular deliver by remotely activating the micro needles via a magnetic field, and it is controlled by the application time, making it a versatile and easy to use method. The wireless actuation could also be an attractive feature for in-vivo delivery and implantable devices. PMID- 29967362 TI - Why dystrophin quantification is key in the eteplirsen saga. PMID- 29967361 TI - Parrots have evolved a primate-like telencephalic-midbrain-cerebellar circuit. AB - It is widely accepted that parrots show remarkable cognitive abilities. In mammals, the evolution of complex cognitive abilities is associated with increases in the size of the telencephalon and cerebellum as well as the pontine nuclei, which connect these two regions. Parrots have relatively large telencephalons that rival those of primates, but whether there are also evolutionary changes in their telencephalon-cerebellar relay nuclei is unknown. Like mammals, birds have two brainstem pontine nuclei that project to the cerebellum and receive projections from the telencephalon. Unlike mammals, birds also have a pretectal nucleus that connects the telencephalon with the cerebellum: the medial spiriform nucleus (SpM). We found that SpM, but not the pontine nuclei, is greatly enlarged in parrots and its relative size significantly correlated with the relative size of the telencephalon across all birds. This suggests that the telencephalon-SpM-cerebellar pathway of birds may play an analogous role to cortico-ponto-cerebellar pathways of mammals in controlling fine motor skills and complex cognitive processes. We conclude that SpM is key to understanding the role of telencephalon-cerebellar pathways in the evolution of complex cognitive abilities in birds. PMID- 29967363 TI - Higher mortality and hospital charges in patients with cirrhosis and acute respiratory illness: a population-based study. AB - Both cirrhosis and acute respiratory illness (ARI) carry substantial disease and financial burden. To compare hospitalized patients with cirrhosis with ARI to cirrhotic patients without ARI, a retrospective cohort study was conducted using the California Office of Statewide Health Planning and Development database. To balance the groups, propensity score matching (PSM) was used. We identified a total of 46,192 cirrhotic patients during the three study periods (14,049, 15,699, and 16,444 patients, respectively). Among patients hospitalized with cirrhosis, the ARI prevalence was higher in older age groups (p < 0.001), the Asian population (p = 0.002), non-Hispanic population (p = 0.001), and among Medicare patients (p < 0.001). Compared to controls, patients with ARI had 53.8% higher adjusted hospital charge ($122,555 vs. $79,685 per patient per admission, p < 0.001) and 35.0% higher adjusted in-hospital mortality (p < 0.001). Older patients, patients with alcoholic liver disease or liver cancer were at particularly higher risk (adjusted hazard ratio = 2.94 (95% CI: 2.26-3.83), 1.22 (95% CI: 1.02-1.45), and 2.17 (95% CI: 1.76-2.68) respectively, p = 0.028 to <0.001). Mortality rates and hospital charges in hospitalized cirrhotic patients with ARI were higher than in cirrhotic controls without ARI. Preventive efforts such as influenza and pneumococcal vaccination, especially in older patients and those with liver cancer, or alcoholic liver disease, would be of value. PMID- 29967364 TI - Development, Characterization and Electromechanical Actuation Behavior of Ionic Polymer Metal Composite Actuator based on Sulfonated Poly(1,4-phenylene ether ether-sulfone)/Carbon Nanotubes. AB - This paper presents the development of new cost-effective hybrid-type sulfonated poly(1,4-phenylene ether-ether-sulfone) (SPEES) and functionalized single-walled carbon nanotubes (SWNT) based actuators produced by the film-casting method followed by chemical reduction of Pt ions as electrodes. The preparation of SPEES was investigated in details and sulfonation of polymer was characterized by ion exchange capacity (IEC), Fourier-transform infrared (FTIR) and degree of sulfonation measurements. SPEES having degree of sulfonation of 126% was blended with SWNT and used to fabricate IPMC actuator. The chemical composition and detailed structure of SPEES-SWNT ionic polymer membranes were confirmed by FTIR, EDX and transmittance electron microscopy (TEM) analysis. Scanning electron microscopy (SEM) micrographs revealed the homogeneously distributed layers of Pt electrodes on the surfaces of IPMC membrane. The electrochemical and electromechanical properties of SPEES-SWNT-Pt-based IPMC actuator shows a better actuation performance than conventional IPMC actuators in terms of higher IEC, Proton conductivity, higher current density, electrochemical impedance spectroscopy (EIS), and large bending deflection. The robust, flexible and mechanically strong membranes prepared by the synergistic combination of SPEES and SWNT may have considerable potential as actuator materials for robotic and biomimetic applications. PMID- 29967365 TI - Tissue-specific functions of invariant natural killer T cells. AB - Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) alpha-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (TH1), TH2 and TH17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage. PMID- 29967366 TI - Ernest P. Noble. PMID- 29967368 TI - Targeting the affective brain-a randomized controlled trial of real-time fMRI neurofeedback in patients with depression. AB - Functional magnetic resonance imaging neurofeedback (fMRI-NF) training of areas involved in emotion processing can reduce depressive symptoms by over 40% on the Hamilton Depression Rating Scale (HDRS). However, it remains unclear if this efficacy is specific to feedback from emotion-regulating regions. We tested in a single-blind, randomized, controlled trial if upregulation of emotion areas (NFE) yields superior efficacy compared to upregulation of a control region activated by visual scenes (NFS). Forty-three moderately to severely depressed medicated patients were randomly assigned to five sessions augmentation treatment of either NFE or NFS training. At primary outcome (week 12) no significant group mean HDRS difference was found (B = -0.415 [95% CI -4.847 to 4.016], p = 0.848) for the 32 completers (16 per group). However, across groups depressive symptoms decreased by 43%, and 38% of patients remitted. These improvements lasted until follow-up (week 18). Both groups upregulated target regions to a similar extent. Further, clinical improvement was correlated with an increase in self-efficacy scores. However, the interpretation of clinical improvements remains limited due to lack of a sham-control group. We thus surveyed effects reported for accepted augmentation therapies in depression. Data indicated that our findings exceed expected regression to the mean and placebo effects that have been reported for drug trials and other sham-controlled high-technology interventions. Taken together, we suggest that the experience of successful self-regulation during fMRI-NF training may be therapeutic. We conclude that if fMRI-NF is effective for depression, self-regulation training of higher visual areas may provide an effective alternative. PMID- 29967367 TI - Generation of silent synapses in dentate gyrus correlates with development of alcohol addiction. AB - The brain circuits and synaptic processes that underlie alcohol addiction are currently the subject of intensive research. Here we focus on hippocampal circuitry and show that chemogenetic inhibition of dentate gyrus (DG) during presentation of alcohol-associated cues has long-lasting effects on mice behavior. DG inhibition enhances alcohol seeking and drinking, suggesting that DG regulates addiction-related behaviors. To test this hypothesis, we perform whole cell patch-clamp recordings from the granule cells of DG and look for electrophysiological correlates of alcohol addiction. We observe that presentation of alcohol-associated cue light that induces relapse to alcohol seeking results in generation of silent synapses, that lack functional AMPA receptors. Furthermore, using human criteria of addiction, we differentiate mice controlling their alcohol consumption from those that undergo transition to addiction to discover that the levels of silent synapses induced by alcohol cues are specifically increased in the addicted mice. As the total level of dendritic spines that harbor synapses is constant at this time point, our data indicate that synapses of perforant path to DG are weakened during cue relapse. Finally we demonstrate that, acamprosate, a drug that limits alcohol drinking and seeking in addicts, prevents generation of silent synapses in DG upon presentation of alcohol-associated cues. Altogether, our data suggest that weakening of DG synapses upon cue relapse contributes to persistent alcohol addiction-related behaviors. PMID- 29967370 TI - Early-warning signals for Dansgaard-Oeschger events in a high-resolution ice core record. AB - The Dansgaard-Oeschger (DO) events, as observed in oxygen isotope ratios from the North Greenland Ice Core Project (NGRIP) record, are an outstanding example of past abrupt climate transitions. Their physical cause remains debated, and previous research indicated that they are not preceded by classical early-warning signals (EWS). Subsequent research hypothesized that the DO events are caused by bifurcations of physical mechanisms operating at decadal timescales, and proposed to search for EWS in the high-frequency fluctuation levels. Here, a time series with 5-year resolution is obtained from the raw NGRIP record, and significant numbers of EWS in terms of variance and autocorrelation increases are revealed in the decadal-scale variability. Wavelet analysis indicates that the EWS are most pronounced in the 10-50-year periodicity band, confirming the above hypothesis. The DO events are hence neither directly noise-induced nor purely externally forced, which provides valuable constraints regarding potential physical causes. PMID- 29967369 TI - Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin. AB - Preservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/beta-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1alpha signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/beta-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by oestrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models. PMID- 29967371 TI - Prophylactic Intravenous Lidocaine at Different Doses for Fentanyl-Induced Cough (FIC): A Meta-Analysis. AB - To evaluate whether different doses of intravenous lidocaine are effective at preventing fentanyl-induced cough (FIC), we searched PubMed, Scopus, Cochrane Library, EMBASE and Web of Science, according to predefined criteria, for all articles published until June 2017. A meta-analysis and subgroup analysis were performed by combining the reported incidence of FIC. The odds ratio (OR) was used as a summary statistic. Eleven articles were included, with 965 patients in the lidocaine group and 745 patients in the control group. A pooled analysis indicated that the overall incidence of FIC was significantly different between the lidocaine group and the control group (OR, 0.27; 95% confidence interval (CI), 0.21-0.35; P < 0.05), as well as between the adult and paediatric subgroups. Sensitivity analysis showed that the results were stable. Subgroup analyses showed that compared to a placebo, both low (0.5-1.0 mg/kg) and high doses of lidocaine (1.5-2.0 mg/kg) were effective at reducing FIC incidence. There was no significant difference between low or high doses of lidocaine. Fentanyl doses added no significant heterogeneity as shown by meta-regression. The findings of this meta-analysis indicate that prophylactic intravenous lidocaine is effective at preventing FIC in both adults and children. PMID- 29967372 TI - Direct methanol synthesis from methane in a plasma-catalyst hybrid system at low temperature using metal oxide-coated glass beads. AB - A plasma-catalyst hybrid system was used to synthesize methanol directly from methane. A dielectric barrier discharge (DBD) plasma combined with the catalyst was introduced in order to overcome the difficulties of catalyst-only batch reactions such as high reaction pressure and separation of liquid product. Of the transition metal oxides, Mn2O3-coated glass bead showed the highest methanol yield of about 12.3% in the plasma-catalyst hybrid system. The reaction temperature was maintained below 100 degrees C due to the low plasma input power (from 1.3 kJ/L to 4.5 kJ/L). Furthermore, the reactivity of the catalyst was maintained for 10 hr without changing the selectivity. The results indicated that the plasma-induced OH radical might be produced on the Mn2O3 catalyst, which led to methanol synthesis. PMID- 29967373 TI - Post-ERCP biliary complications in patients with biliary type sphincter of Oddi dysfunction. AB - Sphincter of Oddi dysfunction (SOD) has a high risk of post-ERCP pancreatitis. Cholangitis, colicky pain, and jaundice from cholestasis also occur after ERCP. However, these post-ERCP biliary complications have not been sufficiently evaluated in SOD. Thus, the risk factors and post-ERCP biliary complications in biliary-type SOD were evaluated. From December 1996 to January 2017, 72 patients with suspected biliary-type SOD were selected, and 60 patients who underwent ERCP were included in this study. The incidence of biliary complications compared to control group and factors associated with post-ERCP cholangitis were investigated. More frequent biliary complications, including biliary pain and abnormal liver function, occurred in SOD group than in control group, especially in type I SOD patients. Post-ERCP cholangitis occurred significantly more often with bile duct diameter >=12 mm (26%, 5/19) than with bile duct diameter <11 mm (2.4%, 1/41; p = 0.016). Age >=75 years was also a risk factor for post-ERCP cholangitis (p = 0.013). Multivariate analysis confirmed that bile duct diameter >=12 mm was a significant risk factor for post-ERCP cholangitis. Post-ERCP biliary complications occurred frequently in biliary-type SOD, especially type I. Biliary diameter >=12 mm was an important risk factor for post-ERCP cholangitis. PMID- 29967374 TI - A serine protease KLK8 emerges as a regulator of regulators in memory: Microtubule protein dependent neuronal morphology and PKA-CREB signaling. AB - The multitude of molecular pathways underlying memory impairment in neurological disorders and aging-related disorders has been a major hurdle against therapeutic targeting. Over the years, neuronal growth promoting factors, intracellular kinases, and specific transcription factors, particularly cyclic AMP response element-binding protein (CREB), have emerged as crucial players of memory storage, and their disruption accompanies many cognitive disabilities. However, a molecular link that can influence these major players and can be a potential recovery target has been elusive. Recent reports suggest that extracellular cues at the synapses might evoke an intracellular signaling cascade and regulate memory function. Herein, we report novel function of an extracellular serine protease, kallikrein 8 (KLK8/Neuropsin) in regulating the expression of microtubule associated dendrite growth marker microtubule-associated protein (MAP2)c, dendrite architecture and protein kinase A (PKA)-CREB signaling. Both knockdown of KLK8 via siRNA transfection in mouse primary hippocampal neurons and via intra-hippocampal administration of KLK8 antisense oligonucleotides in vivo reduced expression of MAP2c, dendrite length, dendrite branching and spine density. The KLK8 mediated MAP2c deficiency in turn inactivated PKA and downstream transcription factor phosphorylated CREB (pCREB), leading to downregulation of memory-linked genes and consequent impaired memory consolidation. These findings revealed a protease associated novel pathway of memory impairment in which KLK8 may act as a "regulator of regulators", suggesting its exploration as an important therapeutic target of memory disorders. PMID- 29967376 TI - Surface nanogrooving of carbon microtubes. AB - Extrusion processing of carbon tubes can be problematic due to their poor interfacial interactions with polymeric matrices. Surface chemical modification of carbon tubes can be utilized to create bonding sites to form networks with polymer chains. However, chemical reactions resulting in intermolecular primary bonding limit processability of extrudate, since they cause unstable rheological behaviour, and thus decrease the stock holding time, which is determinative in extrusion. This study presents a method for the synthesis of carbon microtubes with physically modified surface area to improve the filler and matrix interfacial interactions. The key concept is the formation of a nanogrooved topography, through acoustic cavitation on the surface of processing fibres. The effect of nanogrooving on roughness parameters is described, along with the role of surface modified carbon tubes on rheological behaviour, homogeneity, and coherency of extrudate. The measurements showed that nanogrooving increases the surface area of carbon microtubes, as a result, die swelling of the extrudate is reduced. Furthermore, after solidification, the mechanical strength of composite is reinforced due to stronger interactions between nanogrooved carbon tubes and polymer matrix. PMID- 29967375 TI - Early alteration of epigenetic-related transcription in Huntington's disease mouse models. AB - Transcriptional dysregulation in Huntington's disease (HD) affects the expression of genes involved in survival and neuronal functions throughout the progression of the pathology. In recent years, extensive research has focused on epigenetic and chromatin-modifying factors as a causative explanation for such dysregulation, offering attractive targets for pharmacological therapies. In this work, we extensively examined the gene expression profiles in the cortex, striatum, hippocampus and cerebellum of juvenile R6/1 and N171-82Q mice, models of rapidly progressive HD, to retrieve the early transcriptional signatures associated with this pathology. These profiles were largely consistent across HD datasets, contained tissular and neuronal-specific genes and showed significant correspondence with the transcriptional changes in mouse strains deficient for epigenetic regulatory genes. The most prominent cases were the conditional knockout of the lysine acetyltransferase CBP in post-mitotic forebrain neurons, the double knockout of the histone methyltransferases Ezh1 and Ezh2, components of the polycomb repressor complex 2 (PRC2), and the conditional mutants of the histone methyltransferases G9a (Ehmt2) and GLP (Ehmt1). Based on these observations, we propose that the neuronal epigenetic status is compromised in the prodromal stages of HD, leading to an altered transcriptional programme that is prominently involved in neuronal identity. PMID- 29967377 TI - Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms. PMID- 29967378 TI - Whole-exome sequencing exploration of acquired uniparental disomies in B-cell precursor acute lymphoblastic leukemia. PMID- 29967380 TI - Modeling ASXL1 mutation revealed impaired hematopoiesis caused by derepression of p16Ink4a through aberrant PRC1-mediated histone modification. AB - In spite of distinct clinical importance, the molecular mechanisms how Additional sex combs-like 1 (ASXL1) mutation contributes to the pathogenesis of premalignant conditions are largely unknown. Here, with newly generated knock-in mice, we investigated the biological effects of the mutant. Asxl1G643fs heterozygous (Asxl1G643fs/+) mice developed phenotypes recapitulating human low-risk myelodysplastic syndromes (MDS), and some of them developed MDS/myeloproliferative neoplasm-like disease after long latency. H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in Asxl1G643fs/+ hematopoietic stem cells (HSC), suggesting perturbation of Bmi1 driven H2AK119ub1 histone modification by mutated Asxl1. The mutant form of ASXL1 had no ability to interact with BMI1 as opposed to wild-type ASXL1 protein. Restoration of HSC pool and amelioration of increased apoptosis in hematopoietic stem and progenitor cells were obtained from Asxl1G643fs/+ mice heterozygous for p16Ink4a. These results indicated that loss of protein interaction between Asxl1 mutant and Bmi1 affected the activity of PRC1, and subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in Asxl1G643fs/+ mice. This model provides a useful platform to unveil the molecular basis for hematological disorders induced by ASXL1 mutation and to develop therapeutic strategies for these patients. PMID- 29967379 TI - A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis. AB - Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (>=4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches. PMID- 29967382 TI - Taking bioengineered heart valves from faulty to functional. PMID- 29967381 TI - Dedicated surveillance mechanism controls G-quadruplex forming non-coding RNAs in human mitochondria. AB - The GC skew in vertebrate mitochondrial genomes results in synthesis of RNAs that are prone to form G-quadruplexes (G4s). Such RNAs, although mostly non-coding, are transcribed at high rates and are degraded by an unknown mechanism. Here we describe a dedicated mechanism of degradation of G4-containing RNAs, which is based on cooperation between mitochondrial degradosome and quasi-RNA recognition motif (qRRM) protein GRSF1. This cooperation prevents accumulation of G4 containing transcripts in human mitochondria. In vitro reconstitution experiments show that GRSF1 promotes G4 melting that facilitates degradosome-mediated decay. Among degradosome and GRSF1 regulated transcripts we identified one that undergoes post-transcriptional modification. We show that GRSF1 proteins form a distinct qRRM group found only in vertebrates. The appearance of GRSF1 coincided with changes in the mitochondrial genome, which allows the emergence of G4 containing RNAs. We propose that GRSF1 appearance is an evolutionary adaptation enabling control of G4 RNA. PMID- 29967383 TI - Key receptor involved in neuronal signalling visualized. PMID- 29967384 TI - UNESCO's troubled drive for peace through science and culture. PMID- 29967385 TI - Prenatal immune activation alters the adult neural epigenome but can be partly stabilised by a n-3 polyunsaturated fatty acid diet. AB - An unstable epigenome is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism. This is important because the epigenome is potentially modifiable. We have previously reported that adult offspring exposed to maternal immune activation (MIA) prenatally have significant global DNA hypomethylation in the hypothalamus. However, what genes had altered methylation state, their functional effects on gene expression and whether these changes can be moderated, have not been addressed. In this study, we used next generation sequencing (NGS) for methylome profiling in a MIA rodent model of neurodevelopmental disorders. We assessed whether differentially methylated regions (DMRs) affected the chromatin state by mapping known DNase I hypersensitivity sites (DHSs), and selected overlapping genes to confirm a functional effect of MIA on gene expression using qPCR. Finally, we tested whether methylation differences elicited by MIA could be limited by post-natal dietary (omega) n-3 polyunsaturated fatty acid (PUFA) supplementation. These experiments were conducted using hypothalamic brain tissue from 12-week-old offspring of mice injected with viral analogue PolyI:C on gestation day 9 of pregnancy or saline on gestation day 9. Half of the animals from each group were fed a diet enriched with n-3 PUFA from weaning (MIA group, n = 12 units, n = 39 mice; Control group, n = 12 units, n = 38 mice). The results confirmed our previous finding that adult offspring exposed to MIA prenatally had significant global DNA hypomethylation. Furthermore, genes linked to synaptic plasticity were over-represented among differentially methylated genes following MIA. More than 80% of MIA-induced hypomethylated sites, including those affecting chromatin state and MECP2 binding, were stabilised by the n-3 PUFA intervention. MIA resulted in increased expression of two of the 'top five' genes identified from an integrated analysis of DMRs, DHSs and MECP2 binding sites, namely Abat (t = 2.46, p < 0.02) and Gnas9 (t = 2.96, p < 0.01), although these changes were not stabilised by dietary intervention. Thus, prenatal MIA exposure impacts upon the epigenomic regulation of gene pathways linked to neurodevelopmental conditions; and many of the changes can be attenuated by a low-cost dietary intervention. PMID- 29967386 TI - Dispersion characteristics of radioactive materials estimated by wind patterns. AB - The radioactive materials are generally concentrated downwind of their origins when the prevailing winds blow continuously in one direction. If this principle determined the pattern of dispersion in all cases, dispersion directions could be estimated by wind patterns. However, this hypothesis has not been sufficiently verified because of the complexity of dispersion processes and weather systems. Here, we show that dispersion directions, which are divided into four ranges, can be estimated by wind patterns using a machine learning approach. The five-year average hit rates of the directions of dispersion estimated using near-surface winds exceed 0.85 in all months. The dispersion directions can be estimated up to 33 hours in advance using forecast winds. In particular, high hit rates exceeding 0.95 are achieved in January and March, when large-scale weather systems dominate. These results indicate that the dispersion directions are determined by the wind patterns that correspond to large-scale weather systems and diurnal circulation patterns in most cases. Our findings also provide more reliable information on dispersion patterns with reduced uncertainties, given that reasonable skill is achieved at a sufficient lead time for evacuation. PMID- 29967387 TI - Intracytoplasmic sperm injection for male infertility and consequences for offspring. AB - Intracytoplasmic sperm injection (ICSI) has become the most commonly used method of fertilization in assisted reproductive technology. The primary reasons for its popularity stem from its effectiveness, the standardization of the procedure, which means that it can easily be incorporated into the routine practice of fertility centres worldwide, and the fact that it can be used to treat virtually all forms of infertility. ICSI is the clear method of choice for overcoming untreatable severe male factor infertility, but its (over)use in other male and non-male factor infertility scenarios is not evidence-based. Despite all efforts to increase ICSI efficacy and safety through the application of advanced sperm retrieval and cryopreservation techniques, as well as methods for selecting sperm with better chromatin integrity, the overall pregnancy rates from infertile men remain suboptimal. Treating the underlying male infertility factor before ICSI seems to be a promising way to improve ICSI outcomes, but data remain limited. Information regarding the health of ICSI offspring has accumulated over the past 25 years, and there are reasons for concern as risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile have been observed to be greater in infants born as a result of ICSI than in naturally conceived children. However, as subfertility probably influences the risk estimates, it remains to be determined to what extent the observed adverse outcomes are related to parental factors or associated with ICSI. PMID- 29967388 TI - Elevated CO2 and O3 alter the feeding efficiency of Acyrthosiphon pisum and Aphis craccivora via changes in foliar secondary metabolites. AB - Elevated CO2 and O3 can affect aphid performance via altering plant nutrients, however, little is known about the role of plant secondary metabolites in this process, especially for aphids feeding behaviors. We determined the effects of elevated CO2 and O3 on the growth and phenolics of alfalfa (Medicago sativa) and feeding behaviors of the pea aphids (Acyrthosiphon pisum) and cowpea aphids (Aphis craccivora). Elevated CO2 improved plant growth, but could not completely offset the negative effects of elevated O3. Elevated O3 increased foliar genistin content at the vegetative stage, increased ferulic acid at the reproductive stage, and elevated CO2 increased those at both stages. Simultaneously elevated CO2 and O3 increased foliar ferulic acid content at the reproductive stage and increased genistin content at both stages. For pea aphids, feeding efficiency was reduced under elevated CO2 at the reproductive stage and decreased under elevated O3 at the vegetative stage. For cowpea aphids, feeding efficiency was increased under elevated CO2 at the vegetative stage and decreased under elevated O3 at both stages. Simultaneously elevated CO2 and O3 decreased both aphids feeding efficiency. We concluded that CO2 and O3 independently or interactively had different effects on two aphids feeding behaviors through altering foliar ferulic acid and genistin contents. PMID- 29967389 TI - Dependence and Homeostasis of Membrane Impedance on Cell Morphology in Cultured Hippocampal Neurons. AB - The electrical impedance of cell membranes is important for excitable cells, such as neurons, because it strongly influences the amount of membrane potential change upon a flow of ionic current across the membrane. Here, we report on an investigation of how neuronal morphology affects membrane impedance of cultured hippocampal neurons. Microfabricated substrates with patterned scaffolding molecules were used to restrict the neurite growth of hippocampal neurons, and the impedance was measured via whole-cell patch-clamp recording under the inhibition of voltage-dependent ion channels. Membrane impedance was found to depend inversely on the dendrite length and soma area, as would be expected from the fact that its electrical property is equivalent to a parallel RC circuit. Moreover, we found that in biological neurons, the membrane impedance is homeostatically regulated to impede changes in the membrane area. The findings provide direct evidence on cell-autonomous regulation of neuronal impedance and pave the way towards elucidating the mechanism responsible for the resilience of biological neuronal networks. PMID- 29967390 TI - Mycobacterium tuberculosis peptide E7/HLA-DRB1 tetramers with different HLA-DR alleles bound CD4+ T cells might share identical CDR3 region. AB - Human CD4+ T cells play an important role in the immune response to Mycobacterium tuberculosis (MTB). However, little is known about the spectratyping characteristics of the CD4+ T-cell receptor (TCR) alpha- and beta-chains CDR3 region in tuberculosis (TB) patients. We sorted MTB peptide E7-bound CD4+ T cells by using E7/HLA-DR tetramers constructed with different HLA-DRB1 alleles and extracted the CDR3 amino-acid sequences of TCR alpha- and beta-chains. The results showed that the CDR3 sequences of E7-bound CD4+ T cells were completely or partially identical in a single patient. The sequences of MTB peptide C5-bound CD4+ T cells shared another, and non-peptide bound CD4+ T cells, as well as unbound CD4+ T cells with tetramers were different from each other. Specifically, diverse CDR3 sequences of E7-bound CD4+ T cells displayed similar protein tertiary structure in one TB patient. In summary, the TCR alpha- and beta-chains of CDR3 lineage of CD4+ T cells in TB patients apparently drifted, and the predominant CDR3 sequences of TCR alpha- and beta-chains that recognized the MTB antigen exhibited peptide specificity, and certain HLA-DR restriction was also established. This study elucidates the possible causes and mechanisms of peptide specific CD4+ T-cell-related presentation against MTB. PMID- 29967391 TI - Predicting reference soil groups using legacy data: A data pruning and Random Forest approach for tropical environment (Dano catchment, Burkina Faso). AB - Predicting taxonomic classes can be challenging with dataset subject to substantial irregularities due to the involvement of many surveyors. A data pruning approach was used in the present study to reduce such source errors by exploring whether different data pruning methods, which result in different subsets of a major reference soil groups (RSG) - the Plinthosols - would lead to an increase in prediction accuracy of the minor soil groups by using Random Forest (RF). This method was compared to the random oversampling approach. Four datasets were used, including the entire dataset and the pruned dataset, which consisted of 80% and 90% respectively, and standard deviation core range of the Plinthosols data while cutting off all data points belonging to the outer range. The best prediction was achieved when RF was used with recursive feature elimination along with the non-oversampled 90% core range dataset. This model provided a substantial agreement to observation, with a kappa value of 0.57 along with 7% to 35% increase in prediction accuracy for smaller RSG. The reference soil groups in the Dano catchment appeared to be mainly influenced by the wetness index, a proxy for soil moisture distribution. PMID- 29967392 TI - Ramifications of Atmospheric Humidity on Monsoon Depressions over the Indian Subcontinent. AB - In this study, a comprehensive investigation is carried out to examine the sensitivity of tropospheric relative humidity (RH) on monsoon depressions (MDs) under a changing climate regime through surrogate climate change approach over the Indian region. Composite analysis of four MDs show a persistent warming (RH2+) and cooling (RH2-) throughout the troposphere in the sensitivity experiments. In-depth analysis of a MD over the Arabian Sea (AS) exhibits sustained warming for RH2+, which is accredited to 2.6% increase in stratiform clouds accounting for 13% increment in heating, whereas 5% increment in convective clouds hardly contribute to total heating. Frozen hydrometeors (graupel and snow) are speculated to be the major contributors to this heating. Stratiform clouds showed greater sensitivity to RH perturbations in the lower troposphere (1000-750 hPa), albeit very less sensitivity for convective clouds, both in the lower and mid-troposphere (700-500 hPa). Precipitation is enhanced in a moist situation (RH2+) owing to positive feedbacks induced by moisture influx and precipitation efficiency, while negative feedbacks suppressed precipitation in a dry troposphere (RH2-). In a nutshell, it is inferred that under moist (dry) situations, it is highly likely that intense (weak) MDs will occur in the near future over the Indian region. PMID- 29967393 TI - Complex ecological interactions of Staphylococcus aureus in tampons during menstruation. AB - Menstrual toxic shock syndrome (mTSS) is a severe disease that occurs in healthy women vaginally colonized by Staphylococcus aureus producing toxic shock toxin 1 and who use tampons. The aim of the present study was to determine the impact of the composition of vaginal microbial communities on tampon colonisation by S. aureus during menses. We analysed the microbiota in menstrual fluids extracted from tampons from 108 healthy women and 7 mTSS cases. Using culture, S. aureus was detected in menstrual fluids of 40% of healthy volunteers and 100% of mTSS patients. Between class analysis of culturomic and 16S rRNA gene metabarcoding data indicated that the composition of the tampons' microbiota differs according to the presence or absence of S. aureus and identify discriminating genera. However, the bacterial communities of tampon fluid positive for S. aureus did not cluster together. No difference in tampon microbiome richness, diversity, and ecological distance was observed between tampon vaginal fluids with or without S. aureus, and between healthy donors carrying S. aureus and mTSS patients. Our results show that the vagina is a major niche of. S. aureus in tampon users and the composition of the tampon microbiota control its virulence though more complex interactions than simple inhibition by lactic acid-producing bacterial species. PMID- 29967394 TI - Polyyne formation via skeletal rearrangement induced by atomic manipulation. AB - Rearrangements that change the connectivity of a carbon skeleton are often useful in synthesis, but it can be difficult to follow their mechanisms. Scanning probe microscopy can be used to manipulate a skeletal rearrangement at the single molecule level, while monitoring the geometry of reactants, intermediates and final products with atomic resolution. We studied the reductive rearrangement of 1,1-dibromo alkenes to polyynes on a NaCl surface at 5 K, a reaction that resembles the Fritsch-Buttenberg-Wiechell rearrangement. Voltage pulses were used to cleave one C-Br bond, forming a radical, then to cleave the remaining C*-Br bond, triggering the rearrangement. These experiments provide structural insight into the bromo-vinyl radical intermediates, showing that the C=C*-Br unit is nonlinear. Long polyynes, up to the octayne Ph-(C=C)8-Ph, have been prepared in this way. The control of skeletal rearrangements opens a new window on carbon rich materials and extends the toolbox for molecular synthesis by atom manipulation. PMID- 29967395 TI - A designer enzyme for hydrazone and oxime formation featuring an unnatural catalytic aniline residue. AB - Creating designer enzymes with the ability to catalyse abiological transformations is a formidable challenge. Efforts toward this goal typically consider only canonical amino acids in the initial design process. However, incorporating unnatural amino acids that feature uniquely reactive side chains could significantly expand the catalytic repertoire of designer enzymes. To explore the potential of such artificial building blocks for enzyme design, here we selected p-aminophenylalanine as a potentially novel catalytic residue. We demonstrate that the catalytic activity of the aniline side chain for hydrazone and oxime formation reactions is increased by embedding p-aminophenylalanine into the hydrophobic pore of the multidrug transcriptional regulator from Lactococcus lactis. Both the recruitment of reactants by the promiscuous binding pocket and a judiciously placed aniline that functions as a catalytic residue contribute to the success of the identified artificial enzyme. We anticipate that our design strategy will prove rewarding to significantly expand the catalytic repertoire of designer enzymes in the future. PMID- 29967396 TI - Prevalence of severe-profound hearing loss in South Korea: a nationwide population-based study to analyse a 10-year trend (2006-2015). AB - To estimate prevalence of severe-profound hearing loss (HL) in South Korea, and analyse a 10-year trend of HL according to age, sex, and region by using a nationwide population-based database. Retrospective review from Korean National Health Insurance Service from 2006 to 2015. The degree of severe-profound HL was classified into six grades, based mostly on HL worse than 60 dB HL for both ears. Absolute number of HL was the highest in 2011 (0.25 million; males, 0.14 million; females, 0.11 million); it decreased gradually until 2015. Total HL prevalence was the highest in 2010 (0.5%; 251,954), and decreased annually to 2015 (0.46%; 237,272). The trend of HL prevalence showed a gradual decrease from 2010 to 2015. Prevalence of severe-profound HL was always higher in the male population (1.19 times higher than female in 2015). Prevalence of HL was higher in rural areas than in urban areas (1.4 times higher in 2015). Number of severe-profound HL in South Korea decreased gradually in all age groups annually, even though some older age groups had the highest peak in 2010-2011. Prevalence of severe-profound HL decreases gradually in all age groups annually in South Korea, although the absolute number of HL cases increases rapidly among those aged over 80 years. PMID- 29967398 TI - The relative contribution of natural landscapes and human-mediated factors on the connectivity of a noxious invasive weed. AB - Examining how the landscape may influence gene flow is at the forefront of understanding population differentiation and adaptation. Such understanding is crucial in light of ongoing environmental changes and the elevated risk of ecosystems alteration. In particular, knowledge of how humans may influence population structure is imperative to allow for informed decisions in management and conservation as well as to gain a better understanding of anthropogenic impacts on the interplay between gene flow, genetic drift, and selection. Here, we use genome-wide molecular markers to characterize the population genetic structure and connectivity of Ipomoea purpurea (Convolvulaceae), a noxious invasive weed. We, likewise, assess the interaction between natural and human driven influences on genetic differentiation among populations. Our analyses find that human population density is an important predictor of pairwise population differentiation, suggesting that the agricultural and/or horticultural trade may be involved in maintaining some level of connectivity across distant agricultural fields. Climatic variation appears as an additional predictor of genetic connectivity in this species. We discuss the implications of these results and highlight future research needed to disentangle the mechanistic processes underlying population connectivity of weeds. PMID- 29967397 TI - Unraveling the causes of adaptive benefits of synonymous mutations in TEM-1 beta lactamase. AB - While synonymous mutations were long thought to be without phenotypic consequences, there is growing evidence they can affect gene expression, protein folding, and ultimately the fitness of an organism. In only a few cases have the mechanisms by which synonymous mutations affect the phenotype been elucidated. We previously identified 48 mutations in TEM-1 beta-lactamase that increased resistance of Escherichia coli to cefotaxime, 10 of which were synonymous. To better understand the molecular mechanisms underlying the beneficial effect of these synonymous mutations, we made a series of measurements for a panel containing the 10 synonymous together with 10 non-synonymous mutations as a reference. Whereas messenger levels were unaffected, we found that total and functional TEM protein levels were higher for 5 out of 10 synonymous mutations. These observations suggest that some of these mutations act on translation or a downstream process. Similar effects were observed for some small-benefit non synonymous mutations, suggesting a similar causal mechanism. For the synonymous mutations, we found that the cost of resistance scales with TEM protein levels. A resistance landscape for four synonymous mutations revealed strong epistasis: none of the combinations of mutations exceeded the resistance of the largest effect mutation and there were synthetically neutral combinations. By considering combined effects of these mutations, we could infer that functional TEM protein level is a multi-dimensional phenotype. These results suggest that synonymous mutations may have beneficial effects by increasing the expression of an enzyme with low substrate activity, which may be realized via multiple, yet unknown, post-transcriptional mechanisms. PMID- 29967399 TI - Dengue in pregnancy and maternal mortality: a cohort analysis using routine data. AB - Dengue is a mosquito-borne disease with major public health importance due to its growing incidence and geographical spread. There is a lack of knowledge on its contribution to maternal death. We conducted a population-based cohort study to investigate the association between symptomatic dengue during pregnancy and deaths in Brazil from 2007 to 2012. We did this by linking routine records of confirmed dengue cases to records of deaths of women who had a live birth. Using the Firth method, we estimated odds ratios for maternal deaths associated with dengue during pregnancy. Dengue increased the risk of maternal death by 3 times (95%CI,1.5-5.8) and dengue haemorrhagic fever increased the risk of maternal death by 450 times (95%CI,186.9-1088.4) when compared to mortality of pregnant women without dengue. The increase in risk occurred mostly during acute dengue 71.5 (95%CI,32.8-155.8), compared with no dengue cases. This study showed an increased risk of adverse outcomes in pregnant women with dengue. Therefore in areas where dengue is circulating, the health of pregnant women should be not only a public health priority, but health professionals attending pregnant women with dengue should more closely observe these patients to be able to intervene in a timely way and avoid deaths. PMID- 29967402 TI - Plasticity of fat cells. PMID- 29967401 TI - Verapamil is a potential therapy for hypoglycaemic brain injury. PMID- 29967400 TI - Taxonomic and functional diversity change is scale dependent. AB - Estimates of recent biodiversity change remain inconsistent, debated, and infrequently assessed for their functional implications. Here, we report that spatial scale and type of biodiversity measurement influence evidence of temporal biodiversity change. We show a pervasive scale dependence of temporal trends in taxonomic (TD) and functional (FD) diversity for an ~50-year record of avian assemblages from North American Breeding Bird Survey and a record of global extinctions. Average TD and FD increased at all but the global scale. Change in TD exceeded change in FD toward large scales, signaling functional resilience. Assemblage temporal dissimilarity and turnover (replacement of species or functions) declined, while nestedness (tendency of assemblages to be subsets of one another) increased with scale. Patterns of FD change varied strongly among diet and foraging guilds. We suggest that monitoring, policy, and conservation require a scale-explicit framework to account for the pervasive effect that scale has on perceived biodiversity change. PMID- 29967403 TI - Nuclear microtubule filaments mediate non-linear directional motion of chromatin and promote DNA repair. AB - Damaged DNA shows increased mobility, which can promote interactions with repair conducive nuclear pore complexes (NPCs). This apparently random mobility is paradoxically abrogated upon disruption of microtubules or kinesins, factors that typically cooperate to mediate the directional movement of macromolecules. Here, we resolve this paradox by uncovering DNA damage-inducible intranuclear microtubule filaments (DIMs) that mobilize damaged DNA and promote repair. Upon DNA damage, relief of centromeric constraint induces DIMs that cooperate with the Rad9 DNA damage response mediator and Kar3 kinesin motor to capture DNA lesions, which then linearly move along dynamic DIMs. Decreasing and hyper-inducing DIMs respectively abrogates and hyper-activates repair. Accounting for DIM dynamics across cell populations by measuring directional changes of damaged DNA reveals that it exhibits increased non-linear directional behavior in nuclear space. Abrogation of DIM-dependent processes or repair-promoting factors decreases directional behavior. Thus, inducible and dynamic nuclear microtubule filaments directionally mobilize damaged DNA and promote repair. PMID- 29967404 TI - Mesenchymal Stem Cells in Combination with Hyaluronic Acid for Articular Cartilage Defects. AB - Mesenchymal stem cells (MSCs) and hyaluronic acid (HA) have been found in previous studies to have great potential for medical use. This study aimed to investigate the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) combined with HA on articular cartilage repair in canines. Twenty-four healthy canines (48 knee-joints), male or female with weight ranging from 5 to 6 kg, were operated on to induce cartilage defect model and divided into 3 groups randomly which received different treatments: BMSCs plus HA (BMSCs-HA), HA alone, and saline. Twenty-eight weeks after treatment, all canines were sacrificed and analyzed by gross appearance, magnetic resonance imaging (MRI), hematoxylin-eosin (HE) staining, Masson staining, toluidine blue staining, type II collagen immunohistochemistry, gross grading scale and histological scores. MSCs plus HA regenerated more cartilage-like tissue than did HA alone or saline. According to the macroscopic evaluation and histological assessment score, treatment with MSCs plus HA also lead to significant improvement in cartilage defects compared to those in the other 2 treatment groups (P < 0.05). These findings suggested that allogeneic BMSCs plus HA rather than HA alone was effective in promoting the formation of cartilage-like tissue for repairing cartilage defect in canines. PMID- 29967405 TI - Earth's youngest banded iron formation implies ferruginous conditions in the Early Cambrian ocean. AB - It has been proposed that anoxic and iron-rich (ferruginous) marine conditions were common through most of Earth history. This view represents a major shift in our understanding of the evolution of marine chemistry. However, thus far, evidence for ferruginous conditions comes predominantly from Fe-speciation data. Given debate over these records, new evidence for Fe-rich marine conditions is a requisite if we are to shift our view regarding evolution of the marine redox landscape. Here we present strong evidence for ferruginous conditions by describing a suite of Fe-rich chemical sedimentary rocks-banded iron formation (BIF)--deposited during the Early Cambrian in western China. Specifically, we provide new U-Pb geochronological data that confirm a depositional age of ca. 527 Ma for this unit, as well as rare earth element (REE) data are consistent with anoxic deposition. Similar to many Algoma-type Precambrian iron formations, these Early Cambrian sediments precipitated in a back-arc rift basin setting, where hydrothermally sourced iron drove the deposition of a BIF-like protolith, the youngest ever reported of regional extent without direct links to volcanogenic massive sulphide (VMS) deposits. Their presence indicates that marine environments were still characterized by chemical- and redox-stratification, thus supporting the view that-despite a dearth of modern marine analogues-ferruginous conditions continued to locally be a feature of early Phanerozoic seawater. PMID- 29967407 TI - Variability Assessment of Aromatic Rice Germplasm by Pheno-Genomic traits and Population Structure Analysis. AB - While the pleasant scent of aromatic rice is making it more popular, with demand for aromatic rice expected to rise in future, varieties of this have low yield potential. Genetic diversity and population structure of aromatic germplasm provide valuable information for yield improvement which has potential market value and farm profit. Here, we show diversity and population structure of 113 rice germplasm based on phenotypic and genotypic traits. Phenotypic traits showed that considerable variation existed across the germplasm. Based on Shannon-Weaver index, the most variable phenotypic trait was lemma-palea color. Detecting 140 alleles, 11 were unique and suitable as a germplasm diagnostic tool. Phylogenetic cluster analysis using genotypic traits classified germplasm into three major groups. Moreover, model-based population structure analysis divided all germplasm into three groups, confirmed by principal component and neighbors joining tree analyses. An analysis of molecular variance (AMOVA) and pairwise FST test showed significant differentiation among all population pairs, ranging from 0.023 to 0.068, suggesting that all three groups differed. Significant correlation coefficient was detected between phenotypic and genotypic traits which could be valuable to select further improvement of germplasm. Findings from this study have the potential for future use in aromatic rice molecular breeding programs. PMID- 29967406 TI - Effect of chronic unpredictable stress on mice with developmental under expression of the Ahi1 gene: behavioral manifestations and neurobiological correlates. AB - The Abelson helper integration site 1 (Ahi1) gene plays a pivotal role in brain development and is associated with genetic susceptibility to schizophrenia, and other neuropsychiatric disorders. Translational research in genetically modified mice may reveal the neurobiological mechanisms of such associations. Previous studies of mice heterozygous for Ahi1 knockout (Ahi1+/-) revealed an attenuated anxiety response on various relevant paradigms, in the context of a normal glucocorticoid response to caffeine and pentylenetetrazole. Resting-state fMRI showed decreased amygdalar connectivity with various limbic brain regions and altered network topology. However, it was not clear from previous studies whether stress-hyporesponsiveness reflected resilience or, conversely, a cognitive emotional deficit. The present studies were designed to investigate the response of Ahi1+/- mice to chronic unpredictable stress (CUS) applied over 9 weeks. Wild type (Ahi1+/+) mice were significantly affected by CUS, manifesting decreased sucrose preference (p < 0.05); reduced anxiety on the elevated plus maze and light dark box and decreased thigmotaxis in the open field (p < 0.01 0.05); decreased hyperthermic response to acute stress (p < 0.05); attenuated contextual fear conditioning (p < 0.01) and increased neurogenesis (p < 0.05). In contrast, Ahi1+/- mice were indifferent to the effects of CUS assessed with the same parameters. Our findings suggest that Ahi1 under-expression during neurodevelopment, as manifested by Ahi1+/- mice, renders these mice stress hyporesponsive. Ahi1 deficiency during development may attenuate the perception and/or integration of environmental stressors as a result of impaired corticolimbic connectivity or aberrant functional wiring. These neural mechanisms may provide initial clues as to the role Ahi1 in schizophrenia and other neuropsychiatric disorders. PMID- 29967408 TI - Impacts of warming on top-down and bottom-up controls of periphyton production. AB - Global warming profoundly impacts the functioning of aquatic ecosystems. Nonetheless, the effect of warming on primary producers is poorly understood, especially periphyton production, which is affected both directly and indirectly by temperature-sensitive top-down and bottom-up controls. Here, we study the impact of warming on gross primary production in experimental ecosystems with near-realistic foodwebs during spring and early summer. We used indoor mesocosms following a temperate temperature regime (control) and a warmed (+4 degrees C) treatment to measure biomass and production of phytoplankton and periphyton. The mesocosms' primary production was dominated by periphyton (>82%) during the studied period (April-June). Until May, periphyton production and biomass were significantly higher in the warm treatment (up to 98% greater biomass compared to the control) due to direct temperature effects on growth and indirect effects resulting from higher sediment phosphorus release. Subsequently, enhanced grazer abundances seem to have counteracted the positive temperature effect causing a decline in periphyton biomass and production in June. We thus show, within our studied period, seasonally distinct effects of warming on periphyton, which can significantly affect overall ecosystem primary production and functioning. PMID- 29967409 TI - Apparent diffusion coefficient histogram in breast cancer brain metastases may predict their biological subtype and progression. AB - Our aims for this study were to investigate the relationship between diffusion weighted image (DWI) parameters of brain metastases (BMs) and biological markers of breast cancer, and moreover, to assess whether DWI parameters accurately predict patient outcomes. DWI data for 34 patients with BMs from breast cancer were retrospectively reviewed. Apparent diffusion coefficient (ADC) histogram parameters were calculated from all measurable BMs. Two region of interest (ROI) methods are used for the analysis: from the largest BM or from all measurable BMs per one patient. ADC histogram parameters were compared between positive and negative groups depending on ER/PR and HER2 statuses. Overall survival analysis after BM (OSBM) and BM-specific progression-free survival (BMPFS) was analyzed with ADC parameters. Regardless of ROI methods, 25th percentile of ADC histogram was significantly lower in the ER/PR-positive group than in the ER/PR-negative group (P < 0.05). Using ROIs from all measurable BMs, Peak location, 50th percentile, 75th percentile, and mean value of ADC histogram were also significantly lower in the ER/PR-positive group than in the ER/PR-negative group (P < 0.05). However, there was no significant difference between HER2-postive and negative group. On univariate analysis, using ROIs from all measurable BMs, lower 25th percentile, 50th percentile and mean of ADC were significant predictors for poor BMPFS. ADC histogram analysis may have a prognostic value over ER/PR status as well as BMPFS. PMID- 29967410 TI - Complex Network Geometry and Frustrated Synchronization. AB - The dynamics of networks of neuronal cultures has been recently shown to be strongly dependent on the network geometry and in particular on their dimensionality. However, this phenomenon has been so far mostly unexplored from the theoretical point of view. Here we reveal the rich interplay between network geometry and synchronization of coupled oscillators in the context of a simplicial complex model of manifolds called Complex Network Manifold. The networks generated by this model combine small world properties (infinite Hausdorff dimension) and a high modular structure with finite and tunable spectral dimension. We show that the networks display frustrated synchronization for a wide range of the coupling strength of the oscillators, and that the synchronization properties are directly affected by the spectral dimension of the network. PMID- 29967412 TI - Enhancing bulk defect-mediated absorption in silicon waveguides by doping compensation technique. AB - Silicon waveguide photodiodes (SiWG PD) based on the bulk defect-mediated absorption (BDA) of sub-bandgap photons are suitable to realize in-line optical power monitors for silicon photonic integrated circuits. Deep-level states to enable the BDA can be induced by exploiting the ion implantation steps that are used to embed PN junctions for carrier-depletion-based modulators. This manner usually exhibits limited responsivities since relevant processing conditions are optimized for the modulation rather than the BDA. In this letter, we solve this issue with the doping compensation technique. This technique overlaps P-type and N-type implantation windows at the waveguide core. The responsivity is enhanced due to the increased density of lattice defects and the reduced density of free carriers in the compensated silicon. Influences of the dimension of the dopant compensation region on responsivity and operation speed are investigated. As the width of this region increases from 0 MUm to 0.4 MUm, the responsivity at -5 V is improved from 2 mA/W to 17.5 mA/W. This level is comparable to BDA based SiWG PDs relying on dedicated ion bombardments. On the other hand, a bit-error-rate test at 10 Gb/s suggests that the device with 0.2-MUm-wide compensation region exhibits the highest sensitivity. PMID- 29967411 TI - Effect of low-level laser therapy on tooth-related pain and somatosensory function evoked by orthodontic treatment. AB - Low-level laser therapy (LLLT) may have an effect on the pain associated with orthodontic treatment. The aim of this study was to evaluate the effect of LLLT on pain and somatosensory sensitization induced by orthodontic treatment. Forty individuals (12-33 years old; mean +/- standard deviations: 20.8 +/- 5.9 years) scheduled to receive orthodontic treatment were randomly divided into a laser group (LG) or a placebo group (PG) (1:1). The LG received LLLT (810-nm gallium aluminium-arsenic diode laser in continuous mode with the power set at 400 mW, 2 J.cm-2) at 0 h, 2 h, 24 h, 4 d, and 7 d after treatment, and the PG received inactive treatment at the same time points. In both groups, the non-treated side served as a control. A numerical rating scale (NRS) of pain, pressure pain thresholds (PPTs), cold detection thresholds (CDTs), warmth detection thresholds (WDTs), cold pain thresholds (CPTs), and heat pain thresholds (HPTs) were tested on both sides at the gingiva and canine tooth and on the hand. The data were analysed by a repeated measures analysis of variance (ANOVA). The NRS pain scores were significantly lower in the LG group (P = 0.01). The CDTs, CPTs, WDTs, HPTs, and PPTs at the gingiva and the PPTs at the canine tooth were significantly less sensitive on the treatment side of the LG compared with that of the PG (P < 0.033). The parameters tested also showed significantly less sensitivity on the non-treatment side of the LG compared to that of the PG (P < 0.043). There were no differences between the groups for any quantitative sensory testing (QST) measures of the hand. The application of LLLT appears to reduce the pain and sensitivity of the tooth and gingiva associated with orthodontic treatment and may have contralateral effects within the trigeminal system but no generalized QST effects. Thus, the present study indicated a significant analgesia effect of LLLT application during orthodontic treatment. Further clinical applications are suggested. PMID- 29967413 TI - A Nearctic-Neotropical Migratory Songbird's Nesting Phenology and Clutch Size are Predictors of Accumulated Cyclone Energy. AB - The breeding season phenology of Nearctic-Neotropical migratory songbirds is constrained by subsequent seasons resulting in single-brooded behavior (one successful clutch per year) in some species. Early cessation of the nesting season prior to an active hurricane season will allow for behavioral plasticity during a physiologically challenging migration. Hurricane activity shows a high degree of inter-annual variability. I show that a single-brooded Nearctic breeding species' (Catharus fuscescens) nesting phenology and clutch size are significant predictors of Accumulated Cyclone Energy. The most skilled predictive model includes both mean clutch initiation date and mean clutch size (R2 = 0.84). Spearman rank correlation coefficients for both predictors with subsequent major hurricanes (1998-2016) are -0.55 and 0.52, respectively. Therefore, May and June clutch initiation and clutch size showed stronger correlations with subsequent hurricanes than early season (prior to August) meteorological predictions widely publicized by CSU, NOAA, and TSR (<=0.45, 2003-2014). Rainfall anomalies in the southern Amazon basin associated with ENSO cycles are a possible proximate cue affecting phenology and clutch size. This discovery potentially has far-reaching ornithological, meteorological, and social implications and shows that tropical storms significantly constrain breeding season behavior providing renewed evidence that hurricane activity is a primary factor regulating Nearctic Neotropical migratory songbird populations. PMID- 29967414 TI - The epidemiological characteristics and molecular phylogeny of the dengue virus in Guangdong, China, 2015. AB - In 2015, an unexpected multiple outbreak of dengue occurred in Guangdong, China. In total, 1,699 cases were reported, of which 1,627 cases were verified to have DENV infections by nucleic acid or NS1 protein, including 44 DENV-1, 1126 DENV-2, 18 DENV-3 and 6 DENV-4, and the other cases were confirmed by NS1 ELISA. Phylogenetic analyses of DENV-1 isolates identified two genotypes (I and V). The predominant DENV-2 outbreak isolates were the Cosmopolitan genotypes, which likely originated from Malaysia. The DENV-3 isolates were assigned into genotype I and genotype III. All 6 DENV-4 isolates from imported cases were likely originally from Cambodia, Thailand and the Philippines. The entomological surveillance showed a moderate risk for the BI index in Chaozhou and Foshan and a low risk in Guangzhou. The imported cases were mostly detected in Guangzhou and Foshan. Surprisingly, the most serious outbreak occurred in Chaozhou, but not in Guangzhou or Foshan. A combined analyses demonstrated the multiple geographical origins of this outbreak, and highlight the detection of suspected cases after the alerting of imported cases, early implementation of control policies and reinforce the vector surveillance strategies were the key points in the chain of prevention and control of dengue epidemics. PMID- 29967416 TI - Author Correction: Removal of artificial sweeteners and their effects on microbial communities in sequencing batch reactors. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967415 TI - A moisture function of soil heterotrophic respiration that incorporates microscale processes. AB - Soil heterotrophic respiration (HR) is an important source of soil-to-atmosphere CO2 flux, but its response to changes in soil water content (theta) is poorly understood. Earth system models commonly use empirical moisture functions to describe the HR-theta relationship, introducing significant uncertainty in predicting CO2 flux from soils. Generalized, mechanistic models that address this uncertainty are thus urgently needed. Here we derive, test, and calibrate a novel moisture function, fm, that encapsulates primary physicochemical and biological processes controlling soil HR. We validated fm using simulation results and published experimental data, and established the quantitative relationships between parameters of fm and measurable soil properties, which enables fm to predict the HR-theta relationships for different soils across spatial scales. The fm function predicted comparable HR-theta relationships with laboratory and field measurements, and may reduce the uncertainty in predicting the response of soil organic carbon stocks to climate change compared with the empirical moisture functions currently used in Earth system models. PMID- 29967417 TI - Aerobic exercise enhanced endothelium-dependent vasorelaxation in mesenteric arteries in spontaneously hypertensive rats: the role of melatonin. AB - Melatonin, a neuroendocrine hormone synthesized primarily by the pineal gland, provides various cardiovascular benefits. Regular physical activity is an effective non-pharmacological therapy for the prevention and control of hypertension. In the present study, we hypothesized that melatonin plays an important role in the aerobic exercise-induced increase of endothelium-dependent vasorelaxation in the mesenteric arteries (MAs) of spontaneously hypertensive rats (SHRs) in a melatonergic receptor-dependent manner. To test this hypothesis, we evaluated the vascular mechanical and functional properties in normotensive Wistar Kyoto (WKY), SHRs, and SHRs that were trained on a treadmill (SHR-EX) for 8 weeks. Exercise training produced a significant reduction in blood pressure and heart rate in SHR, which was significantly attenuated by the intraperitoneal administration of luzindole, a non-selective melatonin receptor (MT1/MT2) antagonist. Serum melatonin levels in the SHR group were significantly lower than those in the WKY group at 8:00-9:00 and 21:00-22:00, while exercise training reduced this difference. Endothelium-dependent vessel relaxation induced by acetylcholine was significantly blunted in SHR compared with age-matched WKY. Both exercise training and luzindole ameliorated this endothelium-dependent impairment of relaxation in hypertension. Immunohistochemistry and Western blotting showed that the protein expression of the MT2 receptor and eNOS, as well as their colocalization in the endothelial cell layer in SHRs, was significantly decreased; as exercise training suppressed this reduction. These results provide evidence that regular exercise has a beneficial effect on improving endothelium dependent vasorelaxation in MAs, in which melatonin plays a critical role by acting on MT2 receptors to increase NO production and/or NO bioavailability. PMID- 29967420 TI - Ecology and evolution of seafloor and subseafloor microbial communities. AB - Vast regions of the dark ocean have ultra-slow rates of organic matter sedimentation, and their sediments are oxygenated to great depths yet have low levels of organic matter and cells. Primary production in the oxic seabed is supported by ammonia-oxidizing archaea, whereas in anoxic sediments, novel, uncultivated groups have the potential to produce H2 and CH4, which fuel anaerobic carbon fixation. Subseafloor bacteria have very low mutation rates, and their evolution is likely dominated by selection of different pre-adapted subseafloor taxa under oxic and anoxic conditions. In addition, the abundance and activity of viruses indicate that they affect the size, structure and selection of subseafloor communities. This Review highlights how microbial communities survive in the unique, nutrient-poor and energy-starved environment of the seabed, where they have the potential to influence global biochemical cycles. PMID- 29967419 TI - Human in vivo-generated monocyte-derived dendritic cells and macrophages cross present antigens through a vacuolar pathway. AB - Presentation of exogenous antigens on MHC-I molecules, termed cross-presentation, is essential for cytotoxic CD8+ T cell responses. In mice, dendritic cells (DCs) that arise from monocytes (mo-DCs) during inflammation have a key function in these responses by cross-presenting antigens locally in peripheral tissues. Whether human naturally-occurring mo-DCs can cross-present is unknown. Here, we use human mo-DCs and macrophages directly purified from ascites to address this question. Single-cell RNA-seq data show that ascites CD1c+ DCs contain exclusively monocyte-derived cells. Both ascites mo-DCs and monocyte-derived macrophages cross-present efficiently, but are inefficient for transferring exogenous proteins into their cytosol. Inhibition of cysteine proteases, but not of proteasome, abolishes cross-presentation in these cells. We conclude that human monocyte-derived cells cross-present exclusively using a vacuolar pathway. Finally, only ascites mo-DCs provide co-stimulatory signals to induce effector cytotoxic CD8+ T cells. Our findings thus provide important insights on how to harness cross-presentation for therapeutic purposes. PMID- 29967421 TI - Ascertaining when a basin is Wada: the merging method. AB - Trying to imagine three regions separated by a unique boundary seems a difficult task. However, this is exactly what happens in many dynamical systems showing Wada basins. Here, we present a new perspective on the Wada property: A Wada boundary is the only one that remains unaltered under the action of merging the basins. This observation allows to develop a new method to test the Wada property, which is much faster than the previous ones. Furthermore, another major advantage of the merging method is that a detailed knowledge of the dynamical system is not required. PMID- 29967423 TI - Two-stain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency. AB - Universal screening for Lynch syndrome in colorectal cancer is recommended, and immunohistochemistry for the mismatch repair proteins is commonly used. To reduce cost, some screen using only MSH6 and PMS2, with reflex to the partner stain if either are absent (two-stain method). An expression pattern revealing absent MSH2 and intact MSH6 is not expected, but could result in failed Lynch syndrome detection. We analyzed tumors with absent MSH2 but any degree of MSH6 expression to determine if the two-stain method could miss MSH2 mutations. One-thousand seven-hundred thirty colorectal cancer patients from the Ohio Colorectal Cancer Prevention Initiative underwent tumor screening using microsatellite instability and immunohistochemistry. The two-stain method was used for 1235 cases; staining for all four proteins was completed for 495 cases. The proportion of positive cells and staining intensity were reviewed for MSH6, as well as MSH2 when available. Patients with mismatch repair deficiency underwent next-generation sequencing of germline DNA for mismatch repair genes. If negative, tumor next generation sequencing was performed to assess for somatic mutations. Overall, thirty-three (1.9%, 33/1730) MSH2-absent cases were identified. Of those, fourteen had no MSH6 expression but eight (0.5%, 8/1730) had ambiguous and eleven (0.6%, 11/1730) had convincing MSH6 expression that could have been interpreted as intact. Germline next-generation sequencing identified MSH2 mutations in 11/14 cases with absence of both stains, 7/8 cases with ambiguous MSH6 expression, and 9/11 cases with convincing MSH6 expression. All remaining cases, except one, had double somatic mutations. The two-stain method fails to detect some patients with Lynch syndrome: (1) significant staining weaker than the control may be incorrectly interpreted as intact MSH6, or (2) Weak or focal/patchy MSH6 can be retained with the absence of MSH2. Accordingly, we recommend the four-stain method be used for optimal Lynch syndrome screening detection. PMID- 29967422 TI - Investigation of drug release modulation from poly(2-oxazoline) micelles through ultrasound. AB - Among external stimuli used to trigger release of a drug from a polymeric carrier, ultrasound has gained increasing attention due to its non-invasive nature, safety and low cost. Despite this attention, there is only limited knowledge about how materials available for the preparation of drug carriers respond to ultrasound. This study investigates the effect of ultrasound on the release of a hydrophobic drug, dexamethasone, from poly(2-oxazoline)-based micelles. Spontaneous and ultrasound-mediated release of dexamethasone from five types of micelles made of poly(2-oxazoline) block copolymers, composed of hydrophilic poly(2-methyl-2-oxazoline) and hydrophobic poly(2-n-propyl-2 oxazoline) or poly(2-butyl-2-oxazoline-co-2-(3-butenyl)-2-oxazoline), was studied. The release profiles were fitted by zero-order and Ritger-Peppas models. The ultrasound increased the amount of released dexamethasone by 6% to 105% depending on the type of copolymer, the amount of loaded dexamethasone, and the stimulation time point. This study investigates for the first time the interaction between different poly(2-oxazoline)-based micelle formulations and ultrasound waves, quantifying the efficacy of such stimulation in modulating dexamethasone release from these nanocarriers. PMID- 29967418 TI - An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12. AB - Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research. PMID- 29967424 TI - Discordant molecular subtype classification in the basal-squamous subtype of bladder tumors and matched lymph-node metastases. AB - Molecular subtypes of muscle-invasive bladder tumors have emerged as a promising research tool with potential to stratify patients for neoadjuvant treatment. Prior to radical cystectomy, the utility of molecular classification and biomarkers depend on concordance between tissue from transurethrally resected specimens and disseminated disease. We assess the concordance of molecular subtypes and a large number of potential biomarkers in 67 pairs of muscle invasive bladder tumors and synchronous lymph-node metastases. Tissue cores were stained for 29 immunohistochemistry markers and immunohistochemistry-based molecular subtype classification was performed. Molecular subtype was determined by mRNA profiling for 57 bladder tumors and 28 matched lymph-node metastases. Full section immunohistochemistry was performed to assess intra-tumor subtype heterogeneity in discordant cases, and exome sequencing was performed for 20 sample pairs. Discordant subtype classification between the bladder tumor and lymph-node metastasis was generally rare (12/67, 18%), but most (7/12, 58%) involved the Basal/Squamous-like subtype. Discordant Basal/Squamous-like tumors showed either Urothelial-like or Genomically Unstable, luminal-like phenotype in the lymph-node metastasis. Full section immunohistochemistry revealed intra-tumor subtype heterogeneity for six discordant cases including four involving the Basal/Squamous-like subtype. Subtype concordance for non- Basal/Squamous-like tumors was 91%. RNA-based classification agreed with immunohistochemistry classification but quantitative assessment is necessary to avoid false detection of subtype shifts. Most high confidence cancer mutations were shared between samples (n = 93, 78%), and bladder tumor private mutations (n = 20, 17%) were more frequent than those private to the lymph-node metastasis (n = 7, 6%). We conclude that bladder tumors and lymph-node metastases have overall similar molecular subtype, biomarker expression, and cancer mutations. The main exception was tumors of the Basal/Squamous-like subtype where most cases showed discordant classification, some with evidence of intra-tumor heterogeneity. The data are of relevance for neoadjuvant treatment stratification and raises questions on the dynamics of molecular subtypes during bladder cancer progression. PMID- 29967425 TI - Author Correction: A Novel S100A8/A9 Induced Fingerprint of Mesenchymal Stem Cells associated with Enhanced Wound Healing. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29967426 TI - Analysis of Purines and Pyrimidines distribution over miRNAs of Human, Gorilla, Chimpanzee, Mouse and Rat. AB - Meaningful words in English need vowels to break up the sounds that consonants make. The Nature has encoded her messages in RNA molecules using only four alphabets A, U, C and G in which the nine member double-ring bases (adenine (A) and Guanine (G)) are purines, while the six member single-ring bases (cytosine (C) and uracil (U)) are pyrimidines. Four bases A, U, C and G of RNA sequences are divided into three kinds of classifications according to their chemical properties. One of the three classifications, the purine-pyrimidine class is important. In understanding the distribution (organization) of purines and pyrimidines over some of the non-coding RNAs, all miRNAs of the three species (human, gorilla and chimpanzee) of Hominidae family and two species (mouse and rat) from of Muridae family are considered. The distribution of purines and pyrimidines over miRNA shows deviation from randomness. Based on the quantitative metrics (fractal dimension, Hurst exponent, Hamming distance, distance pattern of purine-pyrimidine, density distribution of purine-pyrimidine and Shannon entropy) five different clusters have been made for the five species. We have observed some couple of results including the closeness of different clusters among the five species. PMID- 29967427 TI - The Genome Sequences of 90 Mushrooms. AB - Macrofungus is defined as the fungus that grows an observable sporocarp. The sporocarps of many species are commonly called mushrooms and consumed by people all around the world as food and/or medicine. Most macrofungi belong to the divisions Basidiomycetes and Ascomycetes, which are estimated to contain more than 80,000 species in total. We report the draft genome assemblies of macrofungi (83 Basidiomycetes species and 7 Ascomycetes species) based on Illumina sequencing. The genome sizes of these species ranged from 27.4 Mb (Hygrophorus russula) to 202.2 MB (Chroogomphus rutilus). The numbers of protein-coding genes were predicted in the range of 9,511 (Hygrophorus russula) to 52,289 (Craterellus lutescens). This study provides the largest genomic dataset for macrofungi species. This resource will facilitate the artificial cultivation of edible mushrooms and the discovery of novel drug candidates. PMID- 29967428 TI - Increased activin A levels in prediabetes and association with carotid intima media thickness: a cross-sectional analysis from I-Lan Longitudinal Aging Study. AB - Activin A and its binding protein follistatin may be crucial in glucose homeostasis, as multifunctional proteins mediating inflammatory and anti inflammatory effects. However, clinical data on the activin A level in prediabetes, and the association between the circulating activin A level and carotid intima-media thickness (cIMT), are lacking. We aimed to investigate activin A and follistatin levels and their associations with cIMT. In total, 470 inhabitants of I-Lan county (235 men; mean age 69 +/- 9 years) with measurements of serum activin A and follistatin levels were included. Patients with prediabetes and diabetes had significantly increased activin A concentrations compared with those in the normal glycemic group (both p < 0.001). A multivariable logistic regression model demonstrated that the circulating activin A level was associated with prediabetes and diabetes independently of other risk factors. Moreover, the circulating activin A levels were associated positively with cIMT in prediabetes (rs = 0.264, p = 0.001). In conclusion, activin A level, but not follistatin, was elevated independent of demographic variables with borderline significance and was correlated positively with cIMT in prediabetes. Activin A and follistatin levels were elevated in diabetes. In addition, elevated activin A was an independent risk factor for prediabetes and diabetes. PMID- 29967429 TI - Algae explosive growth mechanism enabling weather-like forecast of harmful algal blooms. AB - As a global problem in coastal environments, harmful algal blooms (HABs) have seriously affected the health of coastal ecosystems and regional economies. Here we report an aerosol-trigger mechanism for the occurrence of HABs based on long term field data and laboratory experiments. The occurrence times of HABs and aerosol events had a significant correlation from 2005 to 2013 in the East China Sea, indicating that aerosol transport was probably an alternative trigger of HABs. HABs mostly occur in the transition time between winter and summer, during which northwest monsoon transport substantial aerosol (rich in phosphate, iron and other trace metals) to coastal waters, as revealed by chemical measurements, transmission electron microscope and electron microprober results. Such nutrients can stimulate algal growth in our incubation experiments, suggesting that such aerosol transport can be important nutrient sources for the East China Sea where phytoplankton growth is relatively phosphate limited. Air-borne nutrients are available for algal growth by rapid downward air flow, which additional results a clear weather condition, and thus adequate light intensity for algal growth. At last, the transition from northwest monsoon to warm southwest monsoon establishes favorable seawater temperature for algal blooms. Such weather-related aerosol trigger mechanism suggests possibly forecast of HABs. PMID- 29967430 TI - A Cosine Similarity Algorithm Method for Fast and Accurate Monitoring of Dynamic Droplet Generation Processes. AB - Droplet microfluidics has attracted significant interests in functional microcapsule synthesis, pharmaceuticals, fine chemicals, cosmetics and biomedical research. The low variability of performing chemical reactions inside droplets could benefit from improved homogeneity and reproducibility. Therefore, accurate and convenient methods are needed to monitor dynamic droplet generation processes. Here, a novel Cosine Similarity Algorithm (CSA) method was developed to monitor the droplet generation frequency accurately and rapidly. With a microscopic droplet generation video clip captured with a high-speed camera, droplet generation frequency can be computed accurately by calculating the cosine similarities between the frames in the video clip. Four kinds of dynamic droplet generation processes were investigated including (1) a stable condition in a single microfluidic channel, (2) a stable condition in multiple microfluidic channels, (3) a single microfluidic channel with artificial disturbances, and (4) microgel fabrication with or without artificial disturbances. For a video clip with 5,000 frames and a spatial resolution of 512 * 62 pixels, droplet generation frequency up to 4,707.9 Hz can be calculated in less than 1.70 s with an absolute relative calculation error less than 0.08%. Artificial disturbances in droplet generation processes can be precisely determined using the CSA method. This highly effective CSA method could be a powerful tool for further promoting the research of droplet microfluidics. PMID- 29967431 TI - Resistance to CymMV and ORSV in artificial microRNA transgenic Nicotiana benthamiana plants. AB - Transgenic plants expressing artificial microRNAs (amiRNAs) have been shown to confer specific resistance to corresponding viruses. Here, we generated Nicotiana benthamiana transgenic lines containing Oryza sativa miR528 as backbone, expressing amiRNAs targeting RNA-dependent RNA polymerase (RdRp) gene of Cymbidium mosaic virus (CymMV) and Odontoglossum ringspot virus (ORSV). The amiRNA transgenic lines could express amiR-CymMV and confer high percentage resistance to CymMV, while lack of detectable level of amiR-ORSV expression in amiR-ORSV transgenic N. benthamiana plants led to weak resistance to ORSV infection. In this project, we provide the first report of CymMV-resistant transgenic N. benthamiana plants based on amiRNA strategy. We believe that this amiRNA approach can be extended to generate CymMV-resistant transgenic orchids. PMID- 29967432 TI - Author Correction: Rainfall seasonality on the Indian subcontinent during the Cretaceous greenhouse. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967433 TI - Different concentrations of lipopolysaccharide regulate barrier function through the PI3K/Akt signalling pathway in human pulmonary microvascular endothelial cells. AB - Lipopolysaccharide (LPS) can lead to vascular endothelial barrier dysfunction, which often results in acute lung injury and acute respiratory distress syndrome. However, the effects of different concentrations of LPS on human pulmonary microvascular endothelial barrier function and the involvement of the phosphatidylinositol-3-kinase-serine/threonine kinase (PI3K/Akt) pathway in this process remain unclear. Human pulmonary microvascular endothelial cells (HPMECs) were stimulated with different doses of LPS, and barrier function was examined by determining cell monolayer permeability, cell migration, and the expression of intercellular junction proteins (VE-Cadherin, Claudin-5, and Connexin-43). LY294002 was used to inhibit PI3K to verify the role of the PI3K/Akt pathway in the regulation of barrier function in HPMECs stimulated by LPS. Low doses of LPS increased HPMEC migration, up-regulated VE-Cadherin and Claudin-5 expression, down-regulated Connexin-43 expression, and promoted Akt phosphorylation, which could collectively decrease monolayer permeability. In contrast, high doses of LPS suppressed HPMEC migration, down-regulated the expression of VE-Cadherin and Claudin-5, up-regulated Connexin-43 expression, and reduced Akt phosphorylation, which could collectively increase monolayer permeability. LPS has a biphasic effect on HPMEC barrier function through the PI3K/Akt pathway, and this effect is concentration-dependent. PMID- 29967434 TI - Author Correction: Neuronal activity regulates DROSHA via autophagy in spinal muscular atrophy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967435 TI - Open monitoring meditation reduces the involvement of brain regions related to memory function. AB - Mindfulness meditation consists of focused attention meditation (FAM) and open monitoring meditation (OMM), both of which reduce activation of the default mode network (DMN) and mind-wandering. Although it is known that FAM requires intentional focused attention, the mechanisms of OMM remain largely unknown. To investigate this, we examined striatal functional connectivity in 17 experienced meditators (mean total practice hours = 920.6) during pre-resting, meditation, and post-resting states comparing OMM with FAM, using functional magnetic resonance imaging. Both FAM and OMM reduced functional connectivity between the striatum and posterior cingulate cortex, which is a core hub region of the DMN. Furthermore, OMM reduced functional connectivity of the ventral striatum with both the visual cortex related to intentional focused attention in the attentional network and retrosplenial cortex related to memory function in the DMN. In contrast, FAM increased functional connectivity in these regions. Our findings suggest that OMM reduces intentional focused attention and increases detachment from autobiographical memory. This detachment may play an important role in non-judgmental and non-reactive attitude during OMM. These findings provide new insights into the mechanisms underlying the contribution of OMM to well-being and happiness. PMID- 29967436 TI - Lithium-ion conducting oxide single crystal as solid electrolyte for advanced lithium battery application. AB - Today, all-solid-state secondary lithium-ion batteries have attracted attention in research and development all over the world as a next-generation energy storage device. A key material for the all-solid-state lithium batteries is inorganic solid electrolyte, including oxide and sulfide materials. Among the oxide electrolytes, garnet-type oxide exhibits the highest lithium-ion conductivity and a wide electrochemical potential window. However, they have major problems for practical realization. One of the major problems is an internal short-circuit in charging and discharging. In the polycrystalline garnet type oxide electrolyte, dendrites of lithium metal easily grow through the void or impurity in grain boundaries of the sintered body, which causes serious internal short-circuits in the battery system. To solve these problems, we present an all-solid-state battery system using a single-crystal oxide electrolyte. We are the first to successfully grow centimeter-sized single crystals of garnet-type by the floating zone method. The single-crystal solid electrolyte exhibits an extremely high lithium-ion conductivity of 10-3 S cm-1 at 298 K. The garnet-type single-crystal electrolyte has an advantageous bulk nature to realize the bulk conductivity without grain boundaries such as in a sintered polycrystalline body, and will be a game-changing technology for achieving highly safe advanced battery systems. PMID- 29967437 TI - Weak Antilocalization and Quantum Oscillations of Surface States in Topologically Nontrivial DyPdBi(110)Half Heusler alloy. AB - Recently, a number of ternary half-Heusler compounds have been predicted independently by several research groups as candidates for 3D topological insulators. In this work, we report the observation of a two-dimensional (2D) weak antilocalization (WAL) effect, one of the hall-marks of topological surface states, and Shubnikov-de Hass (SdH) quantum oscillations in <110> oriented DyPdBi (DPB) thin films grown on MgO (100) substrates. The films prepared by pulsed laser deposition technique under the optimized conditions, showed a textured structure with (110) planes parallel to the (100) plane of MgO. The measured WAL effect follows the Hikami-Larkin-Nagaoka (HLN) model and the extracted values of phase coherence length (lphi) and alpha are ~420 nm and ~-0.52 respectively. The power law variation of lphi (~T-0.46) indicates the presence of the 2D surface states in DPB film. The Dirac nature of the surface states is further confirmed by Landau-level fan diagram analysis of SdH oscillations of the magneto-transport data. This analysis shows a finite Berry phase of 0.90pi +/- 0.16, reasonably close to the expected pi value. Sheet Carrier density, ns ~ 2.56 * 1012 cm-2, calculated from the SdH oscillations (fSdH ~ 106 T) and Hall measurements agree well with each other. These findings demonstrate that the half Heusler DPB thin films (~15-20 nm) can be used as a suitable material for investigating the novel intrinsic quantum transport properties of surface Dirac fermions. PMID- 29967438 TI - Breakdancing on actin. PMID- 29967440 TI - Widespread distribution of prophage-encoded virulence factors in marine Vibrio communities. AB - Prophages are known to encode important virulence factors in the human pathogen Vibrio cholerae. However, little is known about the occurrence and composition of prophage-encoded traits in environmental vibrios. A database of 5,674 prophage like elements constructed from 1,874 Vibrio genome sequences, covering sixty-four species, revealed that prophage-like elements encoding possible properties such as virulence and antibiotic resistance are widely distributed among environmental vibrios, including strains classified as non-pathogenic. Moreover, we found that 45% of Vibrio species harbored a complete prophage-like element belonging to the Inoviridae family, which encode the zonula occludens toxin (Zot) previously described in the V. cholerae. Interestingly, these zot-encoding prophages were found in a variety of Vibrio strains covering both clinical and marine isolates, including strains from deep sea hydrothermal vents and deep subseafloor sediments. In addition, the observation that a spacer from the CRISPR locus in the marine fish pathogen V. anguillarum strain PF7 had 95% sequence identity with a zot gene from the Inoviridae prophage found in V. anguillarum strain PF4, suggests acquired resistance to inoviruses in this species. Altogether, our results contribute to the understanding of the role of prophages as drivers of evolution and virulence in the marine Vibrio bacteria. PMID- 29967439 TI - Cotranslational protein targeting to the membrane: Nascent-chain transfer in a quaternary complex formed at the translocon. AB - Membrane proteins in bacteria are cotranslationally inserted into the plasma membrane through the SecYEG translocon. Ribosomes exposing the signal-anchor sequence (SAS) of a membrane protein are targeted to the translocon by the signal recognition particle (SRP) pathway. SRP scans translating ribosomes and forms high-affinity targeting complexes with those exposing a SAS. Recognition of the SAS activates SRP for binding to its receptor, FtsY, which, in turn, is primed for SRP binding by complex formation with SecYEG, resulting in a quaternary targeting complex. Here we examine the effect of SecYEG docking to ribosome nascent-chain complexes (RNCs) on SRP binding and SAS transfer, using SecYEG embedded in phospholipid-containing nanodiscs and monitoring FRET between fluorescence-labeled constituents of the targeting complex. SecYEG-FtsY binding to RNC-SRP complexes lowers the affinity of SRP to both ribosome and FtsY, indicating a general weakening of the complex due to partial binding competition near the ribosomal peptide exit. The rearrangement of the quaternary targeting complex to the pre-transfer complex requires an at least partially exposed SAS. The presence of SecYEG-bound FtsY and the length of the nascent chain strongly influence nascent-chain transfer from SRP to the translocon and repositioning of SRP in the post-transfer complex. PMID- 29967441 TI - Extremely high strength and work hardening ability in a metastable high entropy alloy. AB - Design of multi-phase high entropy alloys uses metastability of phases to tune the strain accommodation by favoring transformation and/or twinning during deformation. Inspired by this, here we present Si containing dual phase Fe42Mn28Co10Cr15Si5 high entropy alloy (DP-5Si-HEA) exhibiting very high strength (1.15 GPa) and work hardening (WH) ability. The addition of Si in DP-5Si-HEA decreased the stability of f.c.c. (gamma) matrix thereby promoting pronounced transformation induced plastic deformation in both as-cast and grain refined DP 5Si-HEAs. Higher yet sustained WH ability in fine grained DP-5Si-HEA is associated with the uniform strain partitioning among the metastable gamma phase and resultant h.c.p. (epsilon) phase thereby resulting in total elongation of 12%. Hence, design of dual phase HEAs for improved strength and work hardenability can be attained by tuning the metastability of gamma matrix through proper choice of alloy chemistry from the abundant compositional space of HEAs. PMID- 29967442 TI - Optimization of neural networks via finite-value quantum fluctuations. AB - We numerically test an optimization method for deep neural networks (DNNs) using quantum fluctuations inspired by quantum annealing. For efficient optimization, our method utilizes the quantum tunneling effect beyond the potential barriers. The path integral formulation of the DNN optimization generates an attracting force to simulate the quantum tunneling effect. In the standard quantum annealing method, the quantum fluctuations will vanish at the last stage of optimization. In this study, we propose a learning protocol that utilizes a finite value for quantum fluctuations strength to obtain higher generalization performance, which is a type of robustness. We demonstrate the performance of our method using two well-known open datasets: the MNIST dataset and the Olivetti face dataset. Although computational costs prevent us from testing our method on large datasets with high-dimensional data, results show that our method can enhance generalization performance by induction of the finite value for quantum fluctuations. PMID- 29967443 TI - Vapor sublimation and deposition to build porous particles and composites. AB - The vapor deposition of polymers on regular stationary substrates is widely known to form uniform thin films. Here we report porous polymer particles with sizes controllable down to the nanometer scale can be produced using a fabrication process based on chemical vapor deposition (CVD) on a dynamic substrate, i.e., sublimating ice particles. The results indicate that the vapor deposition of a polymer is directed by the sublimation process; instead of forming a thin film polymer, the deposited polymers replicated the size and shape of the ice particle. Defined size and porosity of the polymer particles are controllable with respect to varying the processing time. Extendable applications are shown to install multiple functional sites on the particles in one step and to localize metals/oxides forming composite particles. In addition, one fabrication cycle requires approximately 60 min to complete, and potential scaling up the production of the porous particles is manageable. PMID- 29967445 TI - Publisher Correction: Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. AB - In the version of this article initially published, the Supplementary Text and Figures file was missing Supplementary Tables 4, 6, 8 and 10-14. The correct file has now been provided online. PMID- 29967446 TI - Black-headed gulls synchronise their activity with their nearest neighbours. AB - Animals in groups can benefit from synchronising their behaviour, where multiple individuals conduct similar activities at the same moment in time. Previous studies have demonstrated that some species show synchronisation of vigilance behaviour, but have not explored the mechanism driving this behaviour. Synchronisation could be driven by animals copying their closest neighbours, which would mean that close proximity should lead to increased synchronisation. We simultaneously observed the behaviour of multiple individual black-headed gulls (Chroicocephalus ridibundus) within resting groups, and compared the activity of a focal individual with its two closest neighbours and a randomly selected control individual. Focal individuals were more likely to be synchronised with their closest neighbour. Synchronisation became less likely if individuals were not the closest neighbour. This suggests that synchronisation seen within groups is dependent upon the spatial positions of its members, and black-headed gulls pay more attention to their closest neighbours. PMID- 29967447 TI - Cytoreductive nephrectomy in metastatic renal cancer - less is more. PMID- 29967444 TI - Adaptation and conservation insights from the koala genome. AB - The koala, the only extant species of the marsupial family Phascolarctidae, is classified as 'vulnerable' due to habitat loss and widespread disease. We sequenced the koala genome, producing a complete and contiguous marsupial reference genome, including centromeres. We reveal that the koala's ability to detoxify eucalypt foliage may be due to expansions within a cytochrome P450 gene family, and its ability to smell, taste and moderate ingestion of plant secondary metabolites may be due to expansions in the vomeronasal and taste receptors. We characterized novel lactation proteins that protect young in the pouch and annotated immune genes important for response to chlamydial disease. Historical demography showed a substantial population crash coincident with the decline of Australian megafauna, while contemporary populations had biogeographic boundaries and increased inbreeding in populations affected by historic translocations. We identified genetically diverse populations that require habitat corridors and instituting of translocation programs to aid the koala's survival in the wild. PMID- 29967449 TI - Positive sexuality in men with spinal cord injury. AB - STUDY DESIGN: Prospective study. OBJECTIVES: To analyze determinants of sexual pleasure in men with spinal cord injury (SCI). SETTING: Centre Bouffard-Vercelli, Cerbere, France. METHODS: Face to face interviews with men with chronic SCI who had an active sex life with a female partner, reliable erections permitting intercourse, and sought regular counselling with a sex therapist. Questionnaires: the International Index of Erectile Function (IIEF) and a modified Sexual History Form. RESULTS: Thirty-three men were enroled. IIEF subscores were high for erectile function (mean 27.6/30), sexual desire (mean 8.8/10), intercourse satisfaction (mean 11.9/15) and overall satisfaction (mean 8.7/10). Overall satisfaction was significantly related to the level (p < 0.01) but not the severity of the lesion (p = 0.59), positively correlated with intercourse satisfaction (p < 0.001), negatively with age (p < 0.05) and age at injury (p < 0.01), but not with time since injury (p = 0.80). Orgasm was reported by 14 men (42%), and correlated strongly with antegrade ejaculation (p < 0.001), but not with overall satisfaction (p = 0.81). All men, except one, described enjoyable, long foreplay. Intercourse was associated with sensations of pleasure for 30 men (90%). After intercourse, 26 men (78%) experienced sensations of fulfilment, and 30 (90%) of relaxation. Most men expressed frustration, primarily in the case of absent or intermittent ejaculation or orgasm. Men described their female partners as taking more initiatives, and having a satisfactory sex life. CONCLUSIONS: A positive and satisfying sex life is achievable by the men's willingness to adapt their sexual behaviour coupled with the reward of physical pleasure experienced during intercourse. PMID- 29967448 TI - Placental H3K27me3 establishes female resilience to prenatal insults. AB - Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelopmental disorders. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demonstrate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure. PMID- 29967450 TI - CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection. AB - Dysfunction of CD8+ T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8+ T cells, and the absence of CEACAM1 on virus specific CD8+ T cells limits the antiviral CD8+ T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8+ T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8+ T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus specific CD8+ T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8+ T cells. PMID- 29967451 TI - Author Correction: Free mate choice does not influence reproductive success in humans. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967452 TI - The transcription factor Rfx7 limits metabolism of NK cells and promotes their maintenance and immunity. AB - Regulatory factor X 7 (Rfx7) is an uncharacterized transcription factor belonging to a family involved in ciliogenesis and immunity. Here, we found that deletion of Rfx7 leads to a decrease in natural killer (NK) cell maintenance and immunity in vivo. Genomic approaches showed that Rfx7 coordinated a transcriptional network controlling cell metabolism. Rfx7-/- NK lymphocytes presented increased size, granularity, proliferation, and energetic state, whereas genetic reduction of mTOR activity mitigated those defects. Notably, Rfx7-deficient NK lymphocytes were rescued by interleukin 15 through engagement of the Janus kinase (Jak) pathway, thus revealing the importance of this signaling for maintenance of such spontaneously activated NK cells. Rfx7 therefore emerges as a novel transcriptional regulator of NK cell homeostasis and metabolic quiescence. PMID- 29967453 TI - Giant antidamping orbital torque originating from the orbital Rashba-Edelstein effect in ferromagnetic heterostructures. AB - Enhancing the in-plane current-induced torque efficiency in inversion-symmetry breaking ferromagnetic heterostructures is of both fundamental and practical interests for emerging magnetic memory device applications. Here, we present an interface-originated magnetoelectric effect, the orbital Rashba-Edelstein effect, for realizing large torque efficiency in Pt/Co/SiO2/Pt films with strong perpendicular magnetic anisotropy (PMA). The key element is a pronounced Co 3d orbital splitting due to asymmetric orbital hybridization at the Pt/Co and Co/SiO2 interfaces, which not only stabilizes the PMA but also produces a large orbital torque upon the Co magnetization with current injection. The torque efficiency is found to be strongly magnetization direction- and temperature dependent, and can reach up to 2.83 at room temperature, which is several times to one order of magnitude larger than those previously reported. This work highlights the active role of the orbital anisotropy for efficient torque generation and indicates a route for torque efficiency optimization through orbital engineering. PMID- 29967454 TI - Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self administration without depressive side effects in rats. AB - Cannabinoid CB1 receptors (CB1Rs) have been shown to be a promising target in medication development for the treatment of addiction. However, clinical trials with SR141716A (rimonabant, a selective CB1R antagonist/inverse agonist) for the treatment of obesity and smoking cessation failed due to unwanted side effects, such as depression, anxiety, and suicidal tendencies. Recent preclinical studies suggest that the neutral CB1R antagonist AM4113 may retain the therapeutic anti addictive effects of SR141716A in nicotine self-administration models and possibly has fewer unwanted side effects. However, little is known about whether AM4113 is also effective for other drugs of abuse, such as opioids and psychostimulants, and whether it produces depressive side effects similar to SR141716A in experimental animals. In this study, we demonstrated that systemic administration of AM4113 (3 and 10 mg/kg) dose-dependently inhibited the self administration of intravenous heroin but not cocaine or methamphetamine, whereas SR141716A (3 and 10 mg/kg) dose-dependently inhibited the self-administration of heroin and methamphetamine but not cocaine. In the electrical brain-stimulation reward (BSR) paradigm, SR141716A (3 and 10 mg/kg) dose-dependently increased the BSR stimulation threshold (i.e., decreased the stimulation reward), but AM4113 had no effect on BSR at the same doses, suggesting that SR141716A may produce aversive effects while AM4113 may not. Together, these findings show that neutral CB1R antagonists such as AM4113 deserve further research as a new class of CB1R based medications for the treatment of opioid addiction without SR141716A-like aversive effects. PMID- 29967455 TI - CB2 receptor antibody signal specificity: correlations with the use of partial CB2-knockout mice and anti-rat CB2 receptor antibodies. AB - Cannabinoid CB1 receptors are highly expressed in the brain and functionally modulate presynaptic neurotransmitter release, while cannabinoid CB2 receptors (CB2Rs) were initially identified in the spleen and regarded as peripheral cannabinoid receptors. Recently, growing evidence indicates the presence of functional CB2Rs in the brain. However, this finding is disputed because of the specificity of CB2R antibody signals. We used two strains of currently available partial CB2-knockout (CB2-KO) mice as controls, four anti-rat or anti-mouse CB2R antibodies, and mRNA quantification to further address this issue. Western blot assays using the four antibodies detected a CB2R-like band at ~40 kD in both the brain and spleen. Notably, more bands were detected in the brain than in the spleen, and specific immune peptides blocked band detection. Immunohistochemical assays also detected CB2-like immunostaining in mouse midbrain dopamine neurons. CB2R deletion in CB2-KO mice may reduce or leave CB2R-like immunoreactivity unaltered depending on antibody epitope. Antibodies with epitopes at the receptor deleted region detected a significant reduction in CB2R band density and immunostaining in N-terminal-deleted Deltagen and C-terminal-deleted Zimmer strain CB2-KO mice. Other antibodies with epitopes at the predicted receptor undeleted regions detected similar band densities and immunostaining in wild-type and CB2-KO mice. Quantitative RT-PCR assays detected CB2 mRNA expression using probes that targeted upstream or downstream gene sequences but not the probe that targeted the gene-deleted sequence in Deltagen or Zimmer CB2-KO mice. These findings suggest that none of the tested four polyclonal antibodies are highly mouse CB2R-specific. Non-specific binding may be related to the expression of mutant or truncated CB2R-like proteins in partial CB2-KO mice and the use of anti rat CB2 antibodies because the epitopes are different between rat and mouse CB2Rs. PMID- 29967456 TI - Rigid External Distraction with Intranasal Bone-borne Traction Hooks for Midfacial Hypoplasia. AB - Rigid external distraction is currently performed to correct cases of severe maxillary hypoplasia. As an improvement of this technique, we propose the use of an intranasal bone-borne traction hook. This study is a retrospective chart review of the intranasal bone-borne traction hooks used in the treatment of severe maxillary hypoplasia. There were 110 patients treated with the hooks from 2005 to 2017. The maximum traction force was 7.75 kg, and there were few complications encountered during distraction. There were 76 patients who had the hooks removed under local anaesthesia. A cephalometric analysis was conducted in 56 patients. The average advancement of A-point was 9.9 +/- 4.2 mm, 8.4 +/- 2.5 mm, 11.0 +/- 3.7 mm, 17.9 +/- 4.4 mm for the trans-sutural distraction osteogenesis (DO), maxillary anterior segment DO, Le Fort I osteotomy DO and Le Fort III/II osteotomy DO, respectively. The average changes of sella-nasion-point A (SNA) were 8.89 +/- 4.30 degrees, 8.21 +/- 3.17 degrees, 10.49 +/- 3.26 degrees, and 15.10 +/- 4.00 degrees, respectively. The A point-nasion-B point (ANB) also showed increases in all procedures with P < 0.001. In conclusion, this technique sufficiently advances the midface and ensures the scars are concealed in the nasal base. The traction hook can bear a large traction force, causes minimal complications and is easily removed. PMID- 29967457 TI - Swine influenza viruses in Northern Vietnam in 2013-2014. AB - Swine are an important intermediate host for emergence of pandemic influenza. Vietnam is the largest swine producer in South East Asia. Systematic virological and serological surveillance of swine influenza viruses was carried out in Northern Vietnam from May 2013 to June 2014 with monthly sampling of pigs in local and large collective slaughterhouses and in a live pig market. Influenza A seroprevalence in the local slaughterhouses and in the large collective slaughterhouse was 48.7% and 29.1%, respectively. Seventy-seven influenza A viruses were isolated, all from the large collective slaughterhouse. Genetic analysis revealed six virus genotypes including H1N1 2009 pandemic (H1N1pdm09) viruses, H1N2 with H1 of human origin, H3N2 and H1N1pdm09 reassortants, and triple-reassortant H3N2 viruses. Phylogenetic analysis of swine and human H1N1pdm09 viruses showed evidence of repeated spill-over from humans to swine rather than the establishment of H1N1pdm09 as long-term distinct lineage in swine. Surveillance at the large collective slaughterhouse proved to be the most efficient, cost-effective, and sustainable method of surveillance for swine influenza viruses in Vietnam. PMID- 29967459 TI - Low-voltage electrostatic modulation of ion diffusion through layered graphene based nanoporous membranes. AB - Ion transport in nanoconfinement differs from that in bulk and has been extensively researched across scientific and engineering disciplines1-4. For many energy and water applications of nanoporous materials, concentration-driven ion diffusion is simultaneously subjected to a local electric field arising from surface charge or an externally applied potential. Due to the uniquely crowded intermolecular forces under severe nanoconfinement (<2 nm), the transport behaviours of ions can be influenced by the interfacial electrical double layer (EDL) induced by a surface potential, with complex implications, engendering unusual ion dynamics5-7. However, it remains an experimental challenge to investigate how such a surface potential and its coupling with nanoconfinement manipulate ion diffusion. Here, we exploit the tunable nanoconfinement in layered graphene-based nanoporous membranes to show that sub-2 nm confined ion diffusion can be strongly modulated by the surface potential-induced EDL. Depending on the potential sign, the combination and concentration of ion pairs, diffusion rates can be reversibly modulated and anomalously enhanced by 4~7 times within 0.5 volts, across a salt concentration gradient up to seawater salinity. Modelling suggests that this anomalously enhanced diffusion is related to the strong ion ion correlations under severe nanoconfinement, and cannot be explained by conventional theoretical predictions. PMID- 29967458 TI - Electric-field control of magnetism in a few-layered van der Waals ferromagnetic semiconductor. AB - Manipulating a quantum state via electrostatic gating has been of great importance for many model systems in nanoelectronics. Until now, however, controlling the electron spins or, more specifically, the magnetism of a system by electric-field tuning has proven challenging1-4. Recently, atomically thin magnetic semiconductors have attracted significant attention due to their emerging new physical phenomena5-13. However, many issues are yet to be resolved to convincingly demonstrate gate-controllable magnetism in these two-dimensional materials. Here, we show that, via electrostatic gating, a strong field effect can be observed in devices based on few-layered ferromagnetic semiconducting Cr2Ge2Te6. At different gate doping, micro-area Kerr measurements in the studied devices demonstrate bipolar tunable magnetization loops below the Curie temperature, which is tentatively attributed to the moment rebalance in the spin polarized band structure. Our findings of electric-field-controlled magnetism in van der Waals magnets show possibilities for potential applications in new generation magnetic memory storage, sensors and spintronics. PMID- 29967460 TI - Metallic supercurrent field-effect transistor. AB - In their original formulation of superconductivity, the London brothers predicted1 the exponential suppression of an electrostatic field inside a superconductor over the so-called London penetration depth2-4, lambdaL. Despite a few experiments indicating hints of perturbation induced by electrostatic fields5 7, no clue has been provided so far on the possibility to manipulate metallic superconductors via the field effect. Here, we report field-effect control of the supercurrent in all-metallic transistors made of different Bardeen-Cooper Schrieffer superconducting thin films. At low temperature, our field-effect transistors show a monotonic decay of the critical current under increasing electrostatic field up to total quenching for gate voltage values as large as +/ 40 V in titanium-based devices. This bipolar field effect persists up to ~85% of the critical temperature (~0.41 K), and in the presence of sizable magnetic fields. A similar behaviour is observed in aluminium thin-film field-effect transistors. A phenomenological theory accounts for our observations, and points towards the interpretation in terms of an electric-field-induced perturbation propagating inside the superconducting film. In our understanding, this affects the pairing potential and quenches the supercurrent. These results could represent a groundbreaking asset for the realization of all-metallic superconducting field-effect electronics and leading-edge quantum information architectures8,9. PMID- 29967461 TI - Immediate action is the best strategy when facing uncertain climate change. AB - Mitigating the detrimental effects of climate change is a collective problem that requires global cooperation. However, achieving cooperation is difficult since benefits are obtained in the future. The so-called collective-risk game, devised to capture dangerous climate change, showed that catastrophic economic losses promote cooperation when individuals know the timing of a single climatic event. In reality, the impact and timing of climate change is not certain; moreover, recurrent events are possible. Thus, we devise a game where the risk of a collective loss can recur across multiple rounds. We find that wait and see behavior is successful only if players know when they need to contribute to avoid danger and if contributions can eliminate the risks. In all other cases, act quickly is more successful, especially under uncertainty and the possibility of repeated losses. Furthermore, we incorporate influential factors such as wealth inequality and heterogeneity in risks. Even under inequality individuals should contribute early, as long as contributions have the potential to decrease risk. Most importantly, we find that catastrophic scenarios are not necessary to induce such immediate collective action. PMID- 29967462 TI - Coupling two order parameters in a quantum gas. AB - Controlling matter to simultaneously support coupled properties is of fundamental and technological importance1 (for example, in multiferroics2-5 or high temperature superconductors6-9). However, determining the microscopic mechanisms responsible for the simultaneous presence of different orders is difficult, making it hard to predict material phenomenology10,11 or modify properties12-16. Here, using a quantum gas to engineer an adjustable interaction at the microscopic level, we demonstrate scenarios of competition, coexistence and mutual enhancement of two orders. For the enhancement scenario, the presence of one order lowers the critical point of the other. Our system is realized by a Bose-Einstein condensate that can undergo self-organization phase transitions in two optical resonators17, resulting in two distinct crystalline density orders. We characterize the coupling between these orders by measuring the composite order parameter and the elementary excitations and explain our results with a mean-field free-energy model derived from a microscopic Hamiltonian. Our system is ideally suited to explore quantum tricritical points18 and can be extended to study the interplay of spin and density orders19 as a function of temperature20. PMID- 29967463 TI - Sounds and hydrodynamics of polar active fluids. AB - Spontaneously flowing liquids have been successfully engineered from a variety of biological and synthetic self-propelled units1-11. Together with their orientational order, wave propagation in such active fluids has remained a subject of intense theoretical studies12-17. However, the experimental observation of this phenomenon has remained elusive. Here, we establish and exploit the propagation of sound waves in colloidal active materials with broken rotational symmetry. We demonstrate that two mixed modes, coupling density and velocity fluctuations, propagate along all directions in colloidal-roller fluids. We then show how the six material constants defining the linear hydrodynamics of these active liquids can be measured from their spontaneous fluctuation spectrum, while being out of reach of conventional rheological methods. This active-sound spectroscopy is not specific to synthetic active materials and could provide a quantitative hydrodynamic description of herds, flocks and swarms from inspection of their large-scale fluctuations18-21. PMID- 29967464 TI - Non-specific interactions govern cytosolic diffusion of nanosized objects in mammalian cells. AB - The diffusivity of macromolecules in the cytoplasm of eukaryotic cells varies over orders of magnitude and dictates the kinetics of cellular processes. However, a general description that associates the Brownian or anomalous nature of intracellular diffusion to the architectural and biochemical properties of the cytoplasm has not been achieved. Here we measure the mobility of individual fluorescent nanoparticles in living mammalian cells to obtain a comprehensive analysis of cytoplasmic diffusion. We identify a correlation between tracer size, its biochemical nature and its mobility. Inert particles with size equal or below 50 nm behave as Brownian particles diffusing in a medium of low viscosity with negligible effects of molecular crowding. Increasing the strength of non-specific interactions of the nanoparticles within the cytoplasm gradually reduces their mobility and leads to subdiffusive behaviour. These experimental observations and the transition from Brownian to subdiffusive motion can be captured in a minimal phenomenological model. PMID- 29967465 TI - Sex-specific regional grey matter volume correlates of daily activities. AB - The human brain is plastic and continuously modified throughout life by our daily experiences and behaviours. However, no reports have comprehensively investigated structural brain correlates of our daily activities, including possible sex differences. In this study, we examined the relationship between a self-reported 24-hour Life-Log and regional brain volume measured by structural magnetic resonance imaging. We analysed brain volumes of 64 males and 53 females that were obtained from multiple scanning sites. We found several sex-specific correlations, including a positive correlation between superior frontal gyrus (Brodmann area 8) volume and domestic work hours, and a negative correlation between volume in the same region and job-work hours. Despite being a cross sectional study, this study provides empirical evidence for how and to what extent brain structure is correlated with everyday activity. PMID- 29967466 TI - Author Correction: Selective synaptic remodeling of amygdalocortical connections associated with fear memory. AB - In the version of this article initially published, Fig. 7f purported to show an example of a multi-synapse spine. However, the structure in question included a mitochondrion and microtubules, meaning that it was actually a segment of dendritic shaft. A new image showing an example of a bona fide spine has been substituted. The legend has been changed to state that the image shows two boutons rather than three. The error has been corrected in the HTML and PDF versions of the article. The original and corrected figures are shown in the accompanying Author Correction. PMID- 29967467 TI - Eosinophils support adipocyte maturation and promote glucose tolerance in obesity. AB - Accumulating data have indicated a fundamental role of eosinophils in regulating adipose tissue homeostasis. Here, we performed whole-genome RNA sequencing of the small intestinal tract, which suggested the presence of impaired lipid metabolism in eosinophil-deficient DeltadblGATA mice. DeltadblGATA mice fed a high-fat diet (HFD) showed reduced body fat mass, impaired enlargement of adipocytes, decreased expression of adipogenic genes, and developed glucose intolerance. HFD induced accumulation of eosinophils in the perigonadal white adipose tissue. Concordantly, adipocyte-differentiated 3T3-L1 cells promoted the migration of eosinophils through the expression of CCL11 (eotaxin-1) and likely promoted their survival through the expression of interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor. HFD-fed DeltadblGATA mice showed increased infiltration of macrophages, CD4+ T-cells, and B-cells, increased expression of interferon-gamma, and decreased expression of IL-4 and IL-13 in white adipose tissue. Interferon-gamma treatment significantly decreased lipid deposition in adipocyte-differentiated 3T3-L1 cells, while IL-4 treatment promoted lipid accumulation. Notably, HFD-fed DeltadblGATA mice showed increased lipid storage in the liver as compared with wild-type mice. We propose that obesity promotes the infiltration of eosinophils into adipose tissue that subsequently contribute to the metabolic homeostasis by promoting adipocyte maturation. PMID- 29967468 TI - Modeling and Optimizing a New Culture Medium for In Vitro Rooting of G*N15 Prunus Rootstock using Artificial Neural Network-Genetic Algorithm. AB - The main aim of the present investigation is modeling and optimization of a new culture medium for in vitro rooting of G*N15 rootstock using an artificial neural network-genetic algorithm (ANN-GA). Six experiments for assessing different media culture, various concentrations of Indole - 3- butyric acid, different concentrations of Thiamine and Fe-EDDHA were designed. The effects of five ionic macronutrients (NH4+, NO3-, Ca2+, K+ and Cl-) on five growth parameters [root number (RN), root length (RL), root percentage (R%), fresh (FW) and dry weight (DW)] were evaluated using the ANN-GA method. The R2 correlation values of 0.88, 0.88, 0.98, 0.94 and 0.87 between observed and predicted values were acquired for all five growth parameters, respectively. The ANN-GA results indicated that among the input variables, K+ (7.6) and NH4+ (4.4), K+ (7.7) and Ca2+ (2.8), K+ (36.7) and NH4+ (4.3), K+ (14.7) and NH4+ (4.4) and K+ (7.6) and NH4+ (4.3) had the highest values of variable sensitivity ratio (VSR) in the data set, for RN, RL, R%, FW and DW, respectively. ANN-GA optimized LS medium for G*N15 rooting contained optimized amounts of 1 mg L-1 IBA, 100, 150, or 200 mg L-1 Fe-EDDHA and 1.6 mg L-1 Thiamine. The efficiency of the optimized culture media was compared to other standard media for Prunus rooting and the results indicated that the optimized medium is more efficient than the others. PMID- 29967469 TI - Strain-specific pathogenicity and subversion of phenoloxidase activity in the mosquito Aedes aegypti by members of the fungal entomopathogenic genus Isaria. AB - Development of alternative vector control strategies are becoming more pressing given the rapid evolution of insecticide resistance and the rise of vector borne pathogens affecting public health such as dengue, chikungunya and Zika. Fungal based biopesticides are promising alternatives to synthetic insecticides because they are ecofriendly and are highly effective at infecting insects through contact. This study evaluated the susceptibility of the yellow fever mosquito Ae. aegypti to a range of entomopathogenic fungal strains from the genus Isaria. We observed a diverse variation in the virulence of the Isaria strains tested, with two strains showing high pathogenicity towards adult mosquitoes. Mosquito susceptibility to fungal infection was further corroborated through the molecular quantification of fungal loads and the transcript evaluation of a fungal-specific pathogen recognition molecule in the mosquito body. Moreover, quantitative analysis of transcript abundance coupled with enzymatic assays revealed strain specific subversion of the melanization cascade, an important immune response component. Our study contributes critical insights for a better understanding of fungal-mosquito interactions. PMID- 29967470 TI - A Canonical Biophysical Model of the CsrA Global Regulator Suggests Flexible Regulator-Target Interactions. AB - Bacterial global post-transcriptional regulators execute hundreds of interactions with targets that display varying molecular features while retaining specificity. Herein, we develop, validate, and apply a biophysical, statistical thermodynamic model of canonical target mRNA interactions with the CsrA global post transcriptional regulator to understand the molecular features that contribute to target regulation. Altogether, we model interactions of CsrA with a pool of 236 mRNA: 107 are experimentally regulated by CsrA and 129 are suspected interaction partners. Guided by current understanding of CsrA-mRNA interactions, we incorporate (i) mRNA nucleotide sequence, (ii) cooperativity of CsrA-mRNA binding, and (iii) minimization of mRNA structural changes to identify an ensemble of likely binding sites and their free energies. The regulatory impact of bound CsrA on mRNA translation is determined with the RBS calculator. Predicted regulation of 66 experimentally regulated mRNAs adheres to the principles of canonical CsrA-mRNA interactions; the remainder implies that other, diverse mechanisms may underlie CsrA-mRNA interaction and regulation. Importantly, results suggest that this global regulator may bind targets in multiple conformations, via flexible stretches of overlapping predicted binding sites. This novel observation expands the notion that CsrA always binds to its targets at specific consensus sequences. PMID- 29967472 TI - Analysis of atomic beam collimation by laser cooling. AB - The collimation of a thermal atomic ytterbium beam utilizing a two-dimensional optical molasses is analysed by employing the Monte Carlo simulation. The dependencies of the collimation efficiency on power, frequency detuning and beam size of the laser are studied for various conditions, especially for the case of an imbalanced laser intensity and an impure laser polarization. The influences of these imperfect factors are discussed, and the lowest transverse temperature by the collimation in the experiment is evaluated. PMID- 29967471 TI - Enumerating all possible biosynthetic pathways in metabolic networks. AB - Exhaustive identification of all possible alternate pathways that exist in metabolic networks can provide valuable insights into cellular metabolism. With the growing number of metabolic reconstructions, there is a need for an efficient method to enumerate pathways, which can also scale well to large metabolic networks, such as those corresponding to microbial communities. We developed MetQuest, an efficient graph-theoretic algorithm to enumerate all possible pathways of a particular size between a given set of source and target molecules. Our algorithm employs a guided breadth-first search to identify all feasible reactions based on the availability of the precursor molecules, followed by a novel dynamic-programming based enumeration, which assembles these reactions into pathways of a specified size producing the target from the source. We demonstrate several interesting applications of our algorithm, ranging from identifying amino acid biosynthesis pathways to identifying the most diverse pathways involved in degradation of complex molecules. We also illustrate the scalability of our algorithm, by studying large graphs such as those corresponding to microbial communities, and identify several metabolic interactions happening therein. MetQuest is available as a Python package, and the source codes can be found at https://github.com/RamanLab/metquest . PMID- 29967473 TI - Overgrowth and strain investigation of (11-20) non-polar GaN on patterned templates on sapphire. AB - Non-polar (11-20) GaN with significantly improved crystal quality has been achieved by means of overgrowth on regularly arrayed micro-rod templates on sapphire in comparison with standard non-polar GaN grown without any patterning processes on sapphire. Our overgrown GaN shows massively reduced linewidth of X ray rocking curves with typical values of 270 arcsec along the [0001] direction and 380 arcsec along the [1-100] direction, which are among the best reports. Detailed X-ray measurements have been performed in order to investigate strain relaxation and in-plane strain distribution. The study has been compared with the standard non-polar GaN grown without any patterning processes and an extra non polar GaN sample overgrown on a standard stripe-patterned template. The standard non-polar GaN grown without involving any patterning processes typically exhibits highly anisotropic in-plane strain distribution, while the overgrown GaN on our regularly arrayed micro-rod templates shows a highly isotropic in-plane strain distribution. Between them is the overgrown non-polar GaN on the stripe-patterned template. The results presented demonstrate the major advantages of using our regularly arrayed micro-rod templates for the overgrowth of non-polar GaN, leading to both high crystal quality and isotropic in-plane strain distribution, which is important for the further growth of any device structures. PMID- 29967474 TI - Catalysis of amorpha-4,11-diene synthase unraveled and improved by mutability landscape guided engineering. AB - Amorpha-4,11-diene synthase (ADS) cyclizes the substrate farnesyl pyrophosphate to produce amorpha-4,11-diene as a major product. This is considered the first committed and rate-limiting step in the biosynthesis of the antimalarial artemisinin. Here, we utilize a reported 3D model of ADS to perform mutability landscape guided enzyme engineering. A mutant library of 258 variants along sixteen active site residues was created then screened for catalytic activity and product profile. This allowed for identification of the role of some of these residues in the mechanism. R262 constrains the released pyrophosphate group along with magnesium ions. The aromatic residues (W271, Y519 and F525) stabilize the intermediate carbocations while T296, G400, G439 and L515 help with the 1,6- and 1,10-ring closures. Finally, W271 is suggested to act as active site base along with T399, which ensures regioselective deprotonation. The mutability landscape also helped determine variants with improved catalytic activity. H448A showed ~4 fold increase in catalytic efficiency and the double mutation T399S/H448A improved kcat by 5 times. This variant can be used to enhance amorphadiene production and in turn artemisinin biosynthesis. Our findings provide the basis for the first step in improving industrial production of artemisinin and they open up possibilities for further engineering and understanding of ADS. PMID- 29967476 TI - Whoever is Free from "Placebo Sensitivity", Cast the First Stone! PMID- 29967477 TI - Letter to the Editor Regarding Optimizing Selection of Biologics in Inflammatory Bowel Disease: Development of an Online Patient Decision Aid Using Conjoint Analysis. PMID- 29967475 TI - T315I mutation of BCR-ABL1 into human Philadelphia chromosome-positive leukemia cell lines by homologous recombination using the CRISPR/Cas9 system. AB - In many cancers, somatic mutations confer tumorigenesis and drug-resistance. The recently established clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system is a potentially elegant approach to functionally evaluate mutations in cancers. To reproduce mutations by homologous recombination (HR), the HR pathway must be functional, but DNA damage repair is frequently impaired in cancers. Imatinib is a tyrosine kinase inhibitor for BCR-ABL1 in Philadelphia chromosome-positive (Ph+) leukemia, and development of resistance due to kinase domain mutation is an important issue. We attempted to introduce the T315I gatekeeper mutation into three Ph+ myeloid leukemia cell lines with a seemingly functional HR pathway due to resistance to the inhibitor for poly (ADP) ribose polymerase1. Imatinib-resistant sublines were efficiently developed by the CRISPR/Cas9 system after short-term selection with imatinib; resulting sublines acquired the T315I mutation after HR. Thus, the usefulness of CRISPR/Cas9 system for functional analysis of somatic mutations in cancers was demonstrated. PMID- 29967478 TI - TMUB1 Inhibits BRL-3A Hepatocyte Proliferation by Interfering with the Binding of CAML to Cyclophilin B through its TM1 Hydrophobic Domain. AB - Transmembrane and ubiquitin-like domain-containing 1 (Tmub1) encodes a protein (TMUB1) containing an ubiquitin-like domain and plays a negative regulatory role during hepatocyte proliferation, but its mechanism in this process is still unknown. Here, TMUB1 interfered with the binding of calcium-modulating cyclophilin ligand (CAML) to cyclophilin B, which may represent a key role in the negative regulatory process of TMUB1 in hepatocyte proliferation. Co immunoprecipitation assays in rat BRL-3A cells confirmed the interaction between TMUB1 and CAML; significant regulation of the influx of Ca2+ ([Ca2+]i) and hepatocyte proliferation occurred following TMUB1 overexpression or knockout. Deletion of the TM1 hydrophobic domain of TMUB1 completely abolished this interaction and led to loss of TMUB1's regulatory effects on cytological behavior. Furthermore, overexpression of TMUB1 completely abolished the interaction between CAML and its downstream protein cyclophilin B, which can act upstream of calcineurin by increasing [Ca2+]i during cell proliferation. Taken together, our results indicate that TMUB1 regulates BRL-3A hepatocyte proliferation by interacting with CAML and further interferes with the binding of CAML to cyclophilin B to decrease cellular [Ca2+]i. PMID- 29967479 TI - ETV1 activates a rapid conduction transcriptional program in rodent and human cardiomyocytes. AB - Rapid impulse propagation is a defining attribute of the pectinated atrial myocardium and His-Purkinje system (HPS) that safeguards against atrial and ventricular arrhythmias, conduction block, and myocardial dyssynchrony. The complex transcriptional circuitry that dictates rapid conduction remains incompletely understood. Here, we demonstrate that ETV1 (ER81)-dependent gene networks dictate the unique electrophysiological characteristics of atrial and His-Purkinje myocytes. Cardiomyocyte-specific deletion of ETV1 results in cardiac conduction abnormalities, decreased expression of rapid conduction genes (Nkx2-5, Gja5, and Scn5a), HPS hypoplasia, and ventricularization of the unique sodium channel properties that define Purkinje and atrial myocytes in the adult heart. Forced expression of ETV1 in postnatal ventricular myocytes (VMs) reveals that ETV1 promotes a HPS gene signature while diminishing ventricular and nodal gene networks. Remarkably, ETV1 induction in human induced pluripotent stem cell derived cardiomyocytes increases rapid conduction gene expression and inward sodium currents, converting them towards a HPS phenotype. Our data identify a cardiomyocyte-autonomous, ETV1-dependent pathway that is responsible for specification of rapid conduction zones in the heart and demonstrate that ETV1 is sufficient to promote a HPS transcriptional and functional program upon VMs. PMID- 29967480 TI - N-doped catalytic graphitized hard carbon for high-performance lithium/sodium-ion batteries. AB - Hard carbon attracts wide attentions as the anode for high-energy rechargeable batteries due to its low cost and high theoretical capacities. However, the intrinsically disordered microstructure gives it poor electrical conductivity and unsatisfactory rate performance. Here we report a facile synthesis of N-doped graphitized hard carbon via a simple carbonization and activation of a urea soaked self-crosslinked Co-alginate for the high-performance anode of lithium/sodium-ion batteries. Owing to the catalytic graphitization of Co and the introduction of nitrogen-functional groups, the hard carbon shows structural merits of ordered expanded graphitic layers, hierarchical porous channels, and large surface area. Applying in the anode of lithium/sodium-ion batteries, the large surface area and the existence of nitrogen functional groups can improve the specific capacity by surface adsorption and faradic reaction, while the hierarchical porous channels and expanded graphitic layers can provide facilitate pathways for electrolyte and improve the rate performance. In this way, our hard carbon provides its feasibility to serve as an advanced anode material for high energy rechargeable lithium/sodium-ion batteries. PMID- 29967481 TI - Genetic variants in systemic lupus erythematosus susceptibility loci, XKR6 and GLT1D1 are associated with childhood-onset SLE in a Korean cohort. AB - Impact of genetic variants on the age of systemic lupus erythematosus (SLE) onset was not fully understood. We investigated a cumulative effect of SLE-risk variants on the age of SLE onset and scanned genome-wide SNPs to search for new risk loci of childhood-onset SLE (cSLE). We analyzed 781 Korean single-center SLE subjects who previously genotyped by both Immunochip and genome-wide SNP arrays. Individual genetic risk scores (GRS) from well-validated SLE susceptibility loci were calculated and tested for their association with cSLE (<16 years at onset). Single-variant association tests were performed using a multivariable logistic regression adjusting for population stratification. GRS from SLE susceptibility loci was significantly higher in cSLE than aSLE (p = 1.23 * 10-3). Two SNPs, rs7460469 in XKR6 (p = 1.26 * 10-8, OR = 5.58) and rs7300146 in GLT1D1 p = 1.49 * 10-8, OR = 2.85), showed the most significant associations with cSLE. The model consisting of GRS of SLE and two newly identified loci showed an area under curve (AUC) of 0.71 in a receiver operating characteristics (ROC) curve for prediction of cSLE. In conclusion, cSLE is associated with a high cumulative SLE-risk effect and two novel SNPs rs7460469 and rs7300146, providing the first predictive model for cSLE in Koreans. PMID- 29967482 TI - Somatosensory innervation of the oral mucosa of adult and aging mice. AB - Oral mechanoreception is implicated in fundamental functions including speech, food intake and swallowing; yet, the neuroanatomical substrates that encode mechanical stimuli are not well understood. Tactile perception is initiated by intricate mechanosensitive machinery involving dedicated cells and neurons. This signal transduction setup is coupled with the topology and mechanical properties of surrounding epithelium, thereby providing a sensitive and accurate system to detect stress fluctuations from the external environment. We mapped the distribution of anatomically distinct neuronal endings in mouse oral cavity using transgenic reporters, molecular markers and quantitative histomorphometry. We found that the tongue is equipped with an array of putative mechanoreceptors that express the principal mechanosensory channel Piezo2, including end bulbs of Krause innervating individual filiform papillae and a novel class of neuronal fibers innervating the epithelium surrounding taste buds. The hard palate and gums are densely populated with three classes of sensory afferents organized in discrete patterns including Merkel cell-neurite complexes, Meissner's corpuscles and glomerular corpuscles. In aged mice, we find that palatal Merkel cells reduce in number at key time-points that correlate with impaired oral abilities, such as swallowing and mastication. Collectively, this work identifies the mechanosensory architecture of oral tissues involved in feeding. PMID- 29967483 TI - Severely low serum magnesium is associated with increased risks of positive anti thyroglobulin antibody and hypothyroidism: A cross-sectional study. AB - Trace elements, such as iodine and selenium, are closely related to autoimmune thyroiditis and thyroid function. Low serum magnesium is associated with several chronic diseases; however, its associations with autoimmune thyroiditis and thyroid function are unclear. We investigated the relationships between low serum magnesium, autoimmune thyroiditis, and thyroid function in 1,257 Chinese participants. Demographic data were collected via questionnaires, and levels of serum thyroid stimulating hormone, anti-thyroid peroxidase antibody, anti thyroglobulin antibody (TGAb), free thyroxine, serum magnesium, serum iodine, and urinary iodine concentration were measured. Participants were divided into serum magnesium level quartiles (<=0.55, 0.551-0.85, 0.851-1.15, and >1.15 mmol/L). The median serum magnesium level was 0.89 (0.73-1.06) mmol/L; levels <=0.55 mmol/L were considered severely low (5.9% of participants). The risks of TGAb positivity and Hashimoto thyroiditis (HT) diagnosed using ultrasonography in the lowest quartile group were higher than those in the adequate magnesium group (0.851-1.15 mmol/L) (p < 0.01, odds ratios [ORs] = 2.748-3.236). The risks of total and subclinical-only hypothyroidism in the lowest quartile group were higher than those in the adequate magnesium group (0.851-1.15 mmol/L) (p < 0.01, ORs = 4.482 4.971). Severely low serum magnesium levels are associated with an increased rate of TGAb positivity, HT, and hypothyroidism. PMID- 29967484 TI - The evolutionary road from wild moth to domestic silkworm. AB - The Silk Road, which derives its name from the trade of silk produced by the domestic silkworm Bombyx mori, was an important episode in the development and interaction of human civilizations. However, the detailed history behind silkworm domestication remains ambiguous, and little is known about the underlying genetics with respect to important aspects of its domestication. Here, we reconstruct the domestication processes and identify selective sweeps by sequencing 137 representative silkworm strains. The results present an evolutionary scenario in which silkworms may have been initially domesticated in China as trimoulting lines, then subjected to independent spreads along the Silk Road that gave rise to the development of most local strains, and further improved for modern silk production in Japan and China, having descended from diverse ancestral sources. We find that genes with key roles in nitrogen and amino acid metabolism may have contributed to the promotion of silk production, and that circadian-related genes are generally selected for their adaptation. We additionally identify associations between several candidate genes and important breeding traits, thereby advancing the applicable value of our resources. PMID- 29967486 TI - The value of environmental DNA biobanking for long-term biomonitoring. PMID- 29967485 TI - Multinucleotide mutations cause false inferences of lineage-specific positive selection. AB - Phylogenetic tests of adaptive evolution, such as the widely used branch-site test (BST), assume that nucleotide substitutions occur singly and independently. Recent research has shown that errors at adjacent sites often occur during DNA replication, and the resulting multinucleotide mutations (MNMs) are overwhelmingly likely to be non-synonymous. To evaluate whether the BST misinterprets sequence patterns produced by MNMs as false support for positive selection, we analysed two genome-scale datasets-one from mammals and one from flies. We found that codons with multiple differences account for virtually all the support for lineage-specific positive selection in the BST. Simulations under conditions derived from these alignments but without positive selection show that realistic rates of MNMs cause a strong and systematic bias towards false inferences of selection. This bias is sufficient under empirically derived conditions to produce false positive inferences as often as the BST infers positive selection from the empirical data. Although some genes with BST-positive results may have evolved adaptively, the test cannot distinguish sequence patterns produced by authentic positive selection from those caused by neutral fixation of MNMs. Many published inferences of adaptive evolution using this technique may therefore be artefacts of model violation caused by unincorporated neutral mutational processes. We introduce a model that incorporates MNMs and may help to ameliorate this bias. PMID- 29967487 TI - Author Correction: Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant men. AB - In the version of this Article originally published, the units for the 'Weight' column in Table 1 were incorrect; they should have been kg. This has now been corrected. PMID- 29967488 TI - Identification of Biomarkers Based on Differentially Expressed Genes in Papillary Thyroid Carcinoma. AB - The incidence of papillary thyroid carcinoma (PTC) is increasing rapidly throughout the world. Hence, there is an urgent need for identifying more specific and sensitive biomarkers to explorate the pathogenesis of PTC. In this study, three pairs of stage I PTC tissues and matched normal adjacent tissues were sequenced by RNA-Seq, and 719 differentially expressed genes (DEGs) were screened. KEGG pathway enrichment analyses indicated that the DEGs were significantly enriched in 28 pathways. A total of 18 nodes consisting of 20 DEGs were identified in the top 10% of KEGG integrated networks. The functions of DEGs were further analysed by GO. The 13 selected genes were confirmed by qRT-PCR in 16 stage I PTC patients and by The Cancer Genome Atlas (TCGA) database. The relationship interactions between DEGs were analysed by protein-protein interaction networks and chromosome localizations. Finally, four newly discovered genes, COMP, COL3A1, ZAP70, and CD247, were found to be related with PTC clinical phenotypes, and were confirmed by Spearman's correlation analyses in TCGA database. These four DEGs might be promising biomarkers for early-stage PTC, and provide an experimental foundation for further exploration of the pathogenesis of early-stage PTC. PMID- 29967489 TI - Baclofen acts in the central amygdala to reduce synaptic transmission and impair context fear conditioning. AB - The two main sub-divisions of the Central amygdala (CeA), the lateral-capsular (CeA-LC) and the medial (CeA-M), contain extensive networks of inhibitory interneurons. We have previously shown that activation of GABAB-receptors reduces excitatory transmission between axons of the pontine parabrachial nucleus and neurons of the CeA-LC by inhibiting glutamate release from presynaptic terminals13. Here we have characterised GABAB-receptor activation on other excitatory and inhibitory projections within the CeA. Using whole-cell, patch clamp recordings, we found that the GABAB-receptor agonist baclofen significantly reduced excitatory and inhibitory transmission from all tested inputs into the CeA-LC and CeA-M. In all but one of the inputs, reductions in transmission were accompanied by an increase in paired pulse ratio, indicating that presynaptic GABAB-receptors acted to reduce the release probability of synaptic vesicles. To examine the impact of GABAB-receptors in the CeA on contextual fear-conditioning, we infused baclofen into the CeA immediately prior to training. Compared to vehicle-infused rats, baclofen-infused rats displayed significantly less freezing both during the final stages of the training period and at test 24 hours later. The results of this study demonstrate that, by suppressing excitatory and inhibitory transmission, activation of presynaptic GABAB-receptors in the CeA inhibits the development of context conditioned fear. PMID- 29967490 TI - Author Correction: Temporary microglia-depletion after cosmic radiation modifies phagocytic activity and prevents cognitive deficits. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29967492 TI - Breakdancing on actin. PMID- 29967493 TI - Efficient and precise editing of endogenous transcripts with SNAP-tagged ADARs. AB - Molecular tools that target RNA at specific sites allow recoding of RNA information and processing. SNAP-tagged deaminases guided by a chemically stabilized guide RNA can edit targeted adenosine to inosine in several endogenous transcripts simultaneously, with high efficiency (up to 90%), high potency, sufficient editing duration, and high precision. We used adenosine deaminases acting on RNA (ADARs) fused to SNAP-tag for the efficient and concurrent editing of two disease-relevant signaling transcripts, KRAS and STAT1. We also demonstrate improved performance compared with that of the recently described Cas13b-ADAR. PMID- 29967494 TI - Controlling protein function with HCV protease. PMID- 29967495 TI - Chemogenetic control of gene expression and cell signaling with antiviral drugs. AB - We developed a method in which the NS3 cis-protease from hepatitis C virus can be used as a ligand-inducible connection to control the function and localization of engineered proteins in mammalian cells. To demonstrate the versatility of this approach, we designed drug-sensitive transcription factors and transmembrane signaling proteins, the activities of which can be tightly and reversibly controlled through the use of clinically tested antiviral protease inhibitors. PMID- 29967491 TI - TGF-beta signaling alters H4K20me3 status via miR-29 and contributes to cellular senescence and cardiac aging. AB - Cellular senescence is a well-orchestrated programmed process involved in age related pathologies, tumor suppression and embryonic development. TGF-beta/Smad is one of the predominant pathways that regulate damage-induced and developmentally programmed senescence. Here we show that canonical TGF-beta signaling promotes senescence via miR-29-induced loss of H4K20me3. Mechanistically, oxidative stress triggers TGF-beta signaling. Activated TGF-beta signaling gives rise to acute accumulation of miR-29a and miR-29c, both of which directly suppress their novel target, Suv4-20h, thus reducing H4K20me3 abundance in a Smad-dependent manner, which compromises DNA damage repair and genome maintenance. Loss of H4K20me3 mediated by the senescent TGF-beta/miR-29 pathway contributes to cardiac aging in vivo. Disruption of TGF-beta signaling restores H4K20me3 and improves cardiac function in aged mice. Our study highlights the sequential mechanisms underlying the regulation of senescence, from senescence inducing triggers to activation of responsive signaling followed by specific epigenetic alterations, shedding light on potential therapeutic interventions in cardiac aging. PMID- 29967496 TI - StaPLs: versatile genetically encoded modules for engineering drug-inducible proteins. AB - Robust approaches for chemogenetic control of protein function would have many biological applications. We developed stabilizable polypeptide linkages (StaPLs) based on hepatitis C virus protease. StaPLs undergo autoproteolysis to cleave proteins by default, whereas protease inhibitors prevent cleavage and preserve protein function. We created StaPLs responsive to different clinically approved drugs to bidirectionally control transcription with zinc-finger-based effectors, and used StaPLs to create single-chain, drug-stabilizable variants of CRISPR-Cas9 and caspase-9. PMID- 29967497 TI - Targeting Cas9. PMID- 29967499 TI - Sensing cellular metabolites. PMID- 29967498 TI - Metastasis in a dish. PMID- 29967500 TI - Inferring neuronal activity from gene expression. PMID- 29967501 TI - Speedy optogenetics in red. PMID- 29967502 TI - Higher-order genetic interactions. PMID- 29967503 TI - DNA molecular forceps. PMID- 29967504 TI - US universities go East. PMID- 29967505 TI - Clocking translation in live cells. PMID- 29967507 TI - Transcripts from a spliceosome. PMID- 29967506 TI - Bioconda: sustainable and comprehensive software distribution for the life sciences. PMID- 29967508 TI - Weighing single proteins with light. PMID- 29967509 TI - Correlating behavior and neural activity at high resolution. PMID- 29967510 TI - John T. Ngo. PMID- 29967511 TI - Polymer model predicts chromatin folding. PMID- 29967512 TI - Corrected in vivo imaging. PMID- 29967513 TI - What makes birds and bats the talk of the town. PMID- 29967514 TI - Lead contamination in leafy greens. PMID- 29967515 TI - Manganese binding to Rubisco could drive a photorespiratory pathway that increases the energy efficiency of photosynthesis. AB - Most plants, contrary to popular belief, do not waste over 30% of their photosynthate in a futile cycle called photorespiration. Rather, the photorespiratory pathway generates additional malate in the chloroplast that empowers many energy-intensive chemical reactions, such as those involved in nitrate assimilation. Thus, the balance between carbon fixation and photorespiration determines the plant carbon-nitrogen balance and protein concentrations. Plant protein concentrations, in turn, depend not only on the relative concentrations of carbon dioxide and oxygen in the chloroplast but also on the relative activities of magnesium and manganese, which are metals that associate with several key enzymes in the photorespiratory pathway and alter their function. Understanding the regulation of these processes is critical for sustaining food quality under rising CO2 atmospheres. PMID- 29967516 TI - Fern genomes finally here. PMID- 29967517 TI - Fern genomes elucidate land plant evolution and cyanobacterial symbioses. AB - Ferns are the closest sister group to all seed plants, yet little is known about their genomes other than that they are generally colossal. Here, we report on the genomes of Azolla filiculoides and Salvinia cucullata (Salviniales) and present evidence for episodic whole-genome duplication in ferns-one at the base of 'core leptosporangiates' and one specific to Azolla. One fern-specific gene that we identified, recently shown to confer high insect resistance, seems to have been derived from bacteria through horizontal gene transfer. Azolla coexists in a unique symbiosis with N2-fixing cyanobacteria, and we demonstrate a clear pattern of cospeciation between the two partners. Furthermore, the Azolla genome lacks genes that are common to arbuscular mycorrhizal and root nodule symbioses, and we identify several putative transporter genes specific to Azolla-cyanobacterial symbiosis. These genomic resources will help in exploring the biotechnological potential of Azolla and address fundamental questions in the evolution of plant life. PMID- 29967518 TI - Author Correction: The demise of the largest and oldest African baobabs. AB - In Supplementary Table 1 originally published with this Brief Communication, the authors gave an incorrect GPS easterly coordinate for tree number 12 (Makulu Makete Big baobab); the coordinate '2 degrees 34.584' S, 25 degrees 52.261' E' should have read '22 degrees 34.584' S, 28 degrees 52.261' E'. This has now been amended in the online Supplementary Information file for this Brief Communication. PMID- 29967519 TI - Role of the BUB3 protein in phragmoplast microtubule reorganization during cytokinesis. AB - The evolutionarily conserved WD40 protein budding uninhibited by benzimidazole 3 (BUB3) is known for its function in spindle assembly checkpoint control. In the model plant Arabidopsis thaliana, nearly identical BUB3;1 and BUB3;2 proteins decorated the phragmoplast midline through interaction with the microtubule associated protein MAP65-3 during cytokinesis. BUB3;1 and BUB3;2 interacted with the carboxy-terminal segment of MAP65-3 (but not MAP65-1), which harbours its microtubule-binding domain for its post-mitotic localization. Reciprocally, BUB3;1 and BUB3;2 also regulated MAP65-3 localization in the phragmoplast by enhancing its microtubule association. In the bub3;1 bub3;2 double mutant, MAP65 3 localization was often dissipated away from the phragmoplast midline and abolished upon treatment of low doses of the cytokinesis inhibitory drug caffeine that were tolerated by the control plant. The phragmoplast microtubule array exhibited uncoordinated expansion pattern in the double mutant cells as the phragmoplast edge reached the parental plasma membrane at different times in different areas. Upon caffeine treatment, phragmoplast expansion was halted as if the microtubule array was frozen. As a result, cytokinesis was abolished due to failed cell plate assembly. Our findings have uncovered a novel function of the plant BUB3 in MAP65-3-dependent microtubule reorganization during cytokinesis. PMID- 29967521 TI - Assessment of a shortened informed consent form for pediatric research: a pilot study. AB - BACKGROUND: Inherent to clinical research is the informed consent process, with the informed consent form (ICF), a key component of human participant protections. We wished to examine whether a shortened and simplified ICF, accompanied by an appendix, improved participant understanding of a study compared with a conventional ICF. METHODS: A shortened ICF was developed from an existing conventional ICF for a neonatal study. Either the shortened or conventional ICF was randomly distributed to members of two parental advocacy groups. Participants answered survey questions about the form they received. RESULTS: Thirty-one out of forty-one (76%) parents in the shortened ICF and 28/41 (68%) in the conventional ICF group responded. Significantly more parents in the shortened ICF group found their form "short and to the point". Although they also stated that the shortened ICF did not provide enough information, there were no significant differences between groups measuring the understanding of key study components. CONCLUSION: A shortened ICF did not impact the understanding of the clinical trial. It will be important to compare the shortened and conventional forms in actual clinical trials. PMID- 29967520 TI - An ultra-fast mechanically active cell culture substrate. AB - We present a mechanically active cell culture substrate that produces complex strain patterns and generates extremely high strain rates. The transparent miniaturized cell stretcher is compatible with live cell microscopy and provides a very compact and portable alternative to other systems. A cell monolayer is cultured on a dielectric elastomer actuator (DEA) made of a 30 MUm thick silicone membrane sandwiched between stretchable electrodes. A potential difference of several kV's is applied across the electrodes to generate electrostatic forces and induce mechanical deformation of the silicone membrane. The DEA cell stretcher we present here applies up to 38% tensile and 12% compressive strain, while allowing real-time live cell imaging. It reaches the set strain in well under 1 ms and generates strain rates as high as 870 s-1, or 87%/ms. With the unique capability to stretch and compress cells, our ultra-fast device can reproduce the rich mechanical environment experienced by cells in normal physiological conditions, as well as in extreme conditions such as blunt force trauma. This new tool will help solving lingering questions in the field of mechanobiology, including the strain-rate dependence of axonal injury and the role of mechanics in actin stress fiber kinetics. PMID- 29967522 TI - The lifelong impact of fetal growth restriction on cardiac development. AB - BACKGROUND: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. METHODS: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. RESULTS: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR-FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR-FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR-FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. CONCLUSIONS: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development. PMID- 29967523 TI - Effect of various inspired oxygen concentrations on pulmonary and systemic hemodynamics and oxygenation during resuscitation in a transitioning preterm model. AB - BACKGROUND: The Neonatal Resuscitation Program recommends initial resuscitation of preterm infants with low oxygen (O2) followed by titration to target preductal saturations (SpO2). We studied the effect of resuscitation with titrated O2 on gas exchange, pulmonary, and systemic hemodynamics. METHODOLOGY: Twenty-nine preterm lambs (127 d gestation) were randomized to resuscitation with 21% O2 (n = 7), 100% O2 (n = 6), or initiation at 21% and titrated to target SpO2 (n = 16). Seven healthy term control lambs were ventilated with 21% O2. RESULTS: Preductal SpO2 achieved by titrating O2 was within the desired range similar to term lambs in 21% O2. Resuscitation of preterm lambs with 21% and 100% O2 resulted in SpO2 below and above the target, respectively. Ventilation of preterm lambs with 100% O2 and term lambs with 21% O2 effectively decreased pulmonary vascular resistance (PVR). In contrast, preterm lambs with 21% O2 and titrated O2 demonstrated significantly higher PVR than term lambs on 21% O2. CONCLUSION(S): Initial resuscitation with 21% O2 followed by titration of O2 led to suboptimal pulmonary vascular transition at birth in preterm lambs. Ventilation with 100% O2 in preterm lambs caused hyperoxia but reduced PVR similar to term lambs on 21% O2. Studies evaluating the initiation of resuscitation at a higher O2 concentration followed by titration based on SpO2 in preterm neonates are needed. PMID- 29967524 TI - The impact of extrauterine life on visual maturation in extremely preterm born infants. AB - BACKGROUND: Extrauterine life is an important factor when considering brain maturation. Few studies have investigated the development of visual evoked potentials (VEP) in extremely preterm infants, and only a minority have taken into consideration the impact of extrauterine life. The aim of this study was to assess the normal maturation of VEP in infants born prior to 29 weeks gestational age (GA) and to explore the potential influence of extrauterine life. METHODS: VEP were prospectively recorded in extremely preterm infants, and principal peaks (N0, N1, P1, N2, P2, N3) were identified. The mean of peak-time and percentages of peak appearances were assessed for three GA groups (23/24, 25/26, 27/28 weeks) and four subgroups of increasing postnatal age (PNA), up to 8 weeks after birth. RESULTS: A total of 163 VEP recordings in 38 preterm infants were analyzed. With increasing GA at birth, peak-times decreased. When comparing infants with equal GA but longer extrauterine life, those with the highest PNA demonstrated the shortest VEP peak-times. However, this effect was less present in infants born prior to 25 weeks GA. CONCLUSION: Provided that a certain maturational threshold is reached, extrauterine life appears to accelerate maturation of the visual system in preterm infants. PMID- 29967525 TI - Maternal and infant vitamin B12 status during infancy predict linear growth at 5 years. AB - BACKGROUND: Many children worldwide have poor vitamin B12 status. The objective of this study was to estimate association between maternal and infant vitamin B12 status and long-term growth. METHODS: We randomly selected 500 Nepali mother infant pairs and measured maternal intake and infant and maternal vitamin B12 status using plasma cobalamin, total plasma homocysteine, and methylmalonic acid concentrations. We revisited available children when they were 5 years old and measured growth. The associations between intake and maternal and infant markers of vitamin B12 and growth were estimated in multiple linear regression models adjusting for relevant confounders (n = 331). RESULTS: Maternal vitamin B12 intake and status and vitamin B12 status in infancy predicted linear growth at 5 years of age, but not during infancy. Each microgram increase in the vitamin B12 intake of the mother during infancy was associated with an increase in height of 0.4 (0.2, 0.6) height-for-age z-scores and 1.7 (0.7, 2.7) cm around the child's fifth birthday. CONCLUSION: Vitamin B12 status and intake in early life is an important determinant for linear growth at school age. Our findings should be verified in randomized, placebo controlled trials before translated into public health recommendations. PMID- 29967526 TI - Functional characterization of biallelic RTTN variants identified in an infant with microcephaly, simplified gyral pattern, pontocerebellar hypoplasia, and seizures. AB - BACKGROUND: Biallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants. METHODS AND RESULTS: We performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant's fibroblasts to determine primary ciliary phenotype. RESULTS: We identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia. CONCLUSION: Biallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants. PMID- 29967527 TI - Directed acyclic graphs: a tool for causal studies in paediatrics. AB - Many paediatric clinical research studies, whether observational or interventional, have as an eventual aim the identification or quantification of causal relationships. One might ask: does screen time influence childhood obesity? Could overuse of paracetamol in infancy cause wheeze? How does breastfeeding affect later cognitive outcomes? In this review, we present causal directed acyclic graphs (DAGs) to a paediatric audience. DAGs are a graphical tool which provide a way to visually represent and better understand the key concepts of exposure, outcome, causation, confounding, and bias. We use clinical examples, including those outlined above, framed in the language of DAGs, to demonstrate their potential applications. We show how DAGs can be most useful in identifying confounding and sources of bias, demonstrating inappropriate statistical adjustments for presumed biases, and understanding threats to validity in randomised controlled trials. We believe that a familiarity with DAGs, and the concepts underlying them, will be of benefit both to the researchers planning studies, and practising clinicians interpreting them. PMID- 29967528 TI - NKG2D gene variation and susceptibility to viral bronchiolitis in childhood. AB - BACKGROUND: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. METHODS: GWAS included a Finnish-Swedish case control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10-4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). RESULTS: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population CONCLUSIONS: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis. PMID- 29967530 TI - Bilirubin binding in jaundiced newborns: from bench to bedside? AB - BACKGROUND: Bilirubin-induced neurologic dysfunction (BIND) is a spectrum of preventable neurological sequelae in jaundiced newborns. Current total plasma bilirubin (BT) concentration thresholds for phototherapy and/or exchange transfusion poorly predict BIND. METHODS: The unbound (free) bilirubin (Bf) measured at these BT thresholds provides additional information about the risk for BIND. Bf can be readily adapted to clinical use by determining Bf population parameters at current BT thresholds. These parameters can be established using a plasma bilirubin binding panel (BBP) consisting of BT, Bf, and two empiric constants, the maximum BT (BTmax) and the corresponding equilibrium association bilirubin constant (K). RESULTS: BTmax and K provide the variables needed to accurately estimate Bf at BT < BTmax to obtain Bf at threshold BT in patient samples. Once Bf population parameters are known, the BBP in a newborn can be used to identify poor bilirubin binding (higher Bf at the threshold BT compared with the population) and increased risk of BIND. CONCLUSION: The BBP can also be used in jaundice screening to better identify the actual BT at which intervention would be prudent. The BBP is used with current BT thresholds to better identify the risk of BIND and whether and when to intervene. PMID- 29967529 TI - Early-life antibiotics attenuate regulatory T cell generation and increase the severity of murine house dust mite-induced asthma. AB - INTRODUCTION: Early-life exposure to antibiotics (ABX) has been linked to increases in asthma severity and prevalence in both children and laboratory animals. We explored the immunologic mechanisms behind this association using a mouse model of house dust mite (HDM)-induced asthma and early-life ABX exposure. METHODS: Mice were exposed to three short courses of ABX following weaning and experimental asthma was thereafter induced. Airway cell counts and differentials; serum immunoglobulin E (IgE); pulmonary function; lung histopathology; pulmonary regulatory T cells (Tregs); and the fecal microbiome were characterized following ABX exposure and induction of experimental asthma. RESULTS: Asthma severity was increased in mice exposed to ABX, including: airway eosinophilia, airway hyper reactivity, serum HDM-specific IgE, and lung histopathology. ABX treatment led to sharp reduction in fecal microbiome diversity, including the loss of pro regulatory organisms such as Lachnospira. Pulmonary Tregs were reduced with ABX treatment, and this reduction was directly proportional to diminished microbiome diversity. CONCLUSION: Intermittent exposure to ABX early in life worsened the severity of experimental asthma and reduced pulmonary Tregs; the latter change correlated with decreased microbiome diversity. These data may suggest targets for immunologic or probiotic therapy to counteract the harmful effects of childhood ABX. PMID- 29967531 TI - Intensive and prolonged urine collection in preterm infants reveals three distinct indomethacin metabolic patterns: potential implications for drug dosing. PMID- 29967533 TI - Commentary on "Limited achievement of NIH research independence by K award recipients". PMID- 29967532 TI - Brain abnormalities in children and adolescents with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a risk factor for vascular disease and stroke. The spectrum of brain injury and microstructural white matter abnormalities in children with CKD is largely unknown. METHODS: Cross sectional study at two North American pediatric hospitals. A cohort of 49 children, 29 with CKD, including renal transplant (mean age 14.4 +/- 2.9 years; range 9-18), and 20 healthy controls (mean age 13.7 +/- 3.1 years; range 9-18) had their conventional brain magnetic resonance images (MRIs) reviewed by one neuroradiologist to determine the prevalence of brain injury. Fractional anisotropy (FA) maps calculated from diffusion tensor imaging (DTI) were generated to compare white matter microstructure in CKD compared to controls, using tract-based spatial statistics (TBSS). RESULTS: Focal and multifocal white matter injury was seen on brain MRI in 6 children with CKD (21%). Relative to controls, CKD subjects showed reduced white matter fractional anisotropy and increased mean diffusivity and radial diffusivity in the anterior limb of the internal capsule, suggestive of abnormal myelination. CONCLUSION: Cerebral white matter abnormalities, including white matter injury, are under-recognized in pediatric CKD patients. Brain imaging studies through progression of CKD are needed to determine the timing of white matter injury and any potentially modifiable risk factors. PMID- 29967534 TI - Appetite for knowledge: curiosity and children's academic achievement. PMID- 29967536 TI - Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog. AB - Angiotensin II (AngII) plays a central role in regulating human blood pressure, which is mainly mediated by interactions between AngII and the G-protein-coupled receptors (GPCRs) AngII type 1 receptor (AT1R) and AngII type 2 receptor (AT2R). We have solved the crystal structure of human AT2R binding the peptide ligand [Sar1, Ile8]AngII and its specific antibody at 3.2-A resolution. [Sar1, Ile8]AngII interacts with both the 'core' binding domain, where the small molecule ligands of AT1R and AT2R bind, and the 'extended' binding domain, which is equivalent to the allosteric modulator binding site of muscarinic acetylcholine receptor. We generated an antibody fragment to stabilize the extended binding domain that functions as a positive allosteric modulator. We also identified a signature positively charged cluster, which is conserved among peptide-binding receptors, to locate C termini at the bottom of the binding pocket. The reported results should help with designing ligands for angiotensin receptors and possibly to other peptide GPCRs. PMID- 29967537 TI - Accurate design of translational output by a neural network model of ribosome distribution. AB - Synonymous codon choice can have dramatic effects on ribosome speed and protein expression. Ribosome profiling experiments have underscored that ribosomes do not move uniformly along mRNAs. Here, we have modeled this variation in translation elongation by using a feed-forward neural network to predict the ribosome density at each codon as a function of its sequence neighborhood. Our approach revealed sequence features affecting translation elongation and characterized large technical biases in ribosome profiling. We applied our model to design synonymous variants of a fluorescent protein spanning the range of translation speeds predicted with our model. Levels of the fluorescent protein in budding yeast closely tracked the predicted translation speeds across their full range. We therefore demonstrate that our model captures information determining translation dynamics in vivo; that this information can be harnessed to design coding sequences; and that control of translation elongation alone is sufficient to produce large quantitative differences in protein output. PMID- 29967535 TI - Supraphysiological Levels of Oxygen Exposure During the Neonatal Period Impairs Signaling Pathways Required for Learning and Memory. AB - Preterm infants often require prolonged oxygen supplementation and are at high risk of neurodevelopmental impairment. We recently reported that adult mice exposed to neonatal hyperoxia (postnatal day [P] 2 to 14) had spatial navigation memory deficits associated with hippocampal shrinkage. The mechanisms by which early oxidative stress impair neurodevelopment are not known. Our objective was to identify early hyperoxia-induced alterations in hippocampal receptors and signaling pathways necessary for memory formation. We evaluated C57BL/6 mouse pups at P14, exposed to either 85% oxygen or air from P2 to 14. We performed targeted analysis of hippocampal ligand-gated ion channels and proteins necessary for memory formation, and global bioinformatic analysis of differentially expressed hippocampal genes and proteins. Hyperoxia decreased hippocampal mGLU7, TrkB, AKT, ERK2, mTORC1, RPS6, and EIF4E and increased alpha3, alpha5, and ?2 subunits of GABAA receptor and PTEN proteins, although changes in gene expression were not always concordant. Bioinformatic analysis indicated dysfunction in mitochondria and global protein synthesis and translational processes. In conclusion, supraphysiological oxygen exposure reduced proteins necessary for hippocampus-dependent memory formation and may adversely impact hippocampal mitochondrial function and global protein synthesis. These early hippocampal changes may account for memory deficits seen in preterm survivors following prolonged oxygen supplementation. PMID- 29967538 TI - Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein. AB - Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1. A 53BP1 separation-of function mutation that abolishes TIRR-mediated regulation in cells renders 53BP1 hyperactive in response to DSBs, highlighting the key inhibitory function of TIRR. This 53BP1 inhibition is relieved by TIRR-interacting RNA molecules, providing proof-of-principle of RNA-triggered 53BP1 recruitment to DSBs. PMID- 29967540 TI - UbiSite approach for comprehensive mapping of lysine and N-terminal ubiquitination sites. AB - Ubiquitination is a post-translational modification (PTM) that is essential for balancing numerous physiological processes. To enable delineation of protein ubiquitination at a site-specific level, we generated an antibody, denoted UbiSite, recognizing the C-terminal 13 amino acids of ubiquitin, which remain attached to modified peptides after proteolytic digestion with the endoproteinase LysC. Notably, UbiSite is specific to ubiquitin. Furthermore, besides ubiquitination on lysine residues, protein N-terminal ubiquitination is readily detected as well. By combining UbiSite enrichment with sequential LysC and trypsin digestion and high-accuracy MS, we identified over 63,000 unique ubiquitination sites on 9,200 proteins in two human cell lines. In addition to uncovering widespread involvement of this PTM in all cellular aspects, the analyses reveal an inverse association between protein N-terminal ubiquitination and acetylation, as well as a complete lack of correlation between changes in protein abundance and alterations in ubiquitination sites upon proteasome inhibition. PMID- 29967539 TI - Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4. AB - Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1 Npl4 heterodimer. Here, we report structures of the Cdc48-Ufd1-Npl4 complex from Chaetomium thermophilum. Npl4 interacts through its UBX-like domain with a Cdc48 N domain, and it uses two Zn2+-finger domains to anchor the enzymatically inactive Mpr1-Pad1 N-terminal (MPN) domain, homologous to domains found in several isopeptidases, to the top of the D1 ATPase ring. The MPN domain of Npl4 is located above Cdc48's central pore, a position similar to the MPN domain from deubiquitinase Rpn11 in the proteasome. Our results indicate that Npl4 is unique among Cdc48 cofactors and suggest a mechanism for binding and translocation of polyubiquitinated substrates into the ATPase. PMID- 29967541 TI - The role of tubulin-tubulin lattice contacts in the mechanism of microtubule dynamic instability. AB - Microtubules form from longitudinally and laterally assembling tubulin alpha-beta dimers. The assembly induces strain in tubulin, resulting in cycles of microtubule catastrophe and regrowth. This 'dynamic instability' is governed by GTP hydrolysis that renders the microtubule lattice unstable, but it is unclear how. We used a human microtubule nucleating and stabilizing neuronal protein, doublecortin, and high-resolution cryo-EM to capture tubulin's elusive hydrolysis intermediate GDP*Pi state, alongside the prehydrolysis analog GMPCPP state and the posthydrolysis GDP state with and without an anticancer drug, Taxol. GTP hydrolysis to GDP*Pi followed by Pi release constitutes two distinct structural transitions, causing unevenly distributed compressions of tubulin dimers, thereby tightening longitudinal and loosening lateral interdimer contacts. We conclude that microtubule catastrophe is triggered because the lateral contacts can no longer counteract the strain energy stored in the lattice, while reinforcement of the longitudinal contacts may support generation of force. PMID- 29967542 TI - Mechanism of parkin activation by phosphorylation. AB - Mutations in the ubiquitin ligase parkin are responsible for a familial form of Parkinson's disease. Parkin and the PINK1 kinase regulate a quality-control system for mitochondria. PINK1 phosphorylates ubiquitin on the outer membrane of damaged mitochondria, thus leading to recruitment and activation of parkin via phosphorylation of its ubiquitin-like (Ubl) domain. Here, we describe the mechanism of parkin activation by phosphorylation. The crystal structure of phosphorylated Bactrocera dorsalis (oriental fruit fly) parkin in complex with phosphorylated ubiquitin and an E2 ubiquitin-conjugating enzyme reveals that the key activating step is movement of the Ubl domain and release of the catalytic RING2 domain. Hydrogen/deuterium exchange and NMR experiments with the various intermediates in the activation pathway confirm and extend the interpretation of the crystal structure to mammalian parkin. Our results rationalize previously unexplained Parkinson's disease mutations and the presence of internal linkers that allow large domain movements in parkin. PMID- 29967543 TI - Structure of the core of the type III secretion system export apparatus. AB - Export of proteins through type III secretion systems is critical for motility and virulence of many major bacterial pathogens. Three putative integral membrane proteins (FliP, FliQ, FliR) are suggested to form the core of an export gate in the inner membrane, but their structure, assembly and location within the final nanomachine remain unclear. Here, we present the cryoelectron microscopy structure of the Salmonella Typhimurium FliP-FliQ-FliR complex at 4.2 A. None of the subunits adopt canonical integral membrane protein topologies, and common helix-turn-helix structural elements allow them to form a helical assembly with 5:4:1 stoichiometry. Fitting of the structure into reconstructions of intact secretion systems, combined with cross-linking, localize the export gate as a core component of the periplasmic portion of the machinery. This study thereby identifies the export gate as a key element of the secretion channel and implies that it primes the helical architecture of the components assembling downstream. PMID- 29967544 TI - Engineered Hsp70 chaperones prevent Abeta42-induced memory impairments in a Drosophila model of Alzheimer's disease. AB - Proteinopathies constitute a group of diseases in which certain proteins are abnormally folded leading to aggregation and eventual cell failure. Most neurodegenerative diseases belong to protein misfolding disorders and, among them, Alzheimer's disease (AD) is the most prevalent. AD is characterized by accumulation of the amyloid-beta42 (Abeta42) peptide in the extracellular space. Hence, we genetically engineered a molecular chaperone that was selectively delivered to this cellular location. It has been reported that the heat shock protein 70 (Hsp70) binds Abeta42 preventing self-aggregation. Here, we employed two isoforms of the Hsp70, cytosolic and extracellular, to evaluate their potential protective effect against the memory decline triggered by extracellular deposition of Abeta42. Both Hsp70 isoforms significantly improved memory performance of flies expressing Abeta42, irrespective of their age or the level of Abeta42 load. Using olfactory classical conditioning, we established a Drosophila model of AD based on Abeta42 neurotoxicity and monitored memory decline through aging. The onset of the memory impairment observed was proportional to the cumulative level of Abeta42 in the Drosophila brain. These data support the use of this Drosophila model of AD to further investigate molecules with a protective activity against Abeta42-induced memory loss, contributing to the development of palliative therapies for AD. PMID- 29967545 TI - Hypophosphatemia as a sign of malnutrition in older hospitalized patients. AB - The relationship between hypophosphatemia (HP) and malnutrition in older hospitalized patients has received little attention. We sought to investigate this association among this population. The study participants were consecutively admitted to a geriatric acute care ward in six hospitals. Malnutrition screening was conducted by Mini Nutritional Assessment-Short Form. Patients were divided into two groups according to serum phosphate: HP (<0.68 mmol/l) and non-HP groups (>0.68 mmol/l). Of 335 participants, 7% of subjects had HP. Malnutrition or nutritional risk was present in 86 and 56% of participants with and without HP, respectively (P = 0.003). The analysis indicated 9.8, 86.4, 97.9 and 44.0% sensitivity, positive predictive value, specificity and negative predictive value of HP with regard to malnutrition, respectively. This study demonstrated that HP in older hospitalized patients is associated with malnutrition and may be used as an indicator of nutritional risk. Contrary, normal serum phosphate does not exclude being at nutritional risk. PMID- 29967546 TI - Synchronous tropical and polar temperature evolution in the Eocene. AB - Palaeoclimate reconstructions of periods with warm climates and high atmospheric CO2 concentrations are crucial for developing better projections of future climate change. Deep-ocean1,2 and high-latitude3 palaeotemperature proxies demonstrate that the Eocene epoch (56 to 34 million years ago) encompasses the warmest interval of the past 66 million years, followed by cooling towards the eventual establishment of ice caps on Antarctica. Eocene polar warmth is well established, so the main obstacle in quantifying the evolution of key climate parameters, such as global average temperature change and its polar amplification, is the lack of continuous high-quality tropical temperature reconstructions. Here we present a continuous Eocene equatorial sea surface temperature record, based on biomarker palaeothermometry applied on Atlantic Ocean sediments. We combine this record with the sparse existing data4-6 to construct a 26-million-year multi-proxy, multi-site stack of Eocene tropical climate evolution. We find that tropical and deep-ocean temperatures changed in parallel, under the influence of both long-term climate trends and short-lived events. This is consistent with the hypothesis that greenhouse gas forcing7,8, rather than changes in ocean circulation9,10, was the main driver of Eocene climate. Moreover, we observe a strong linear relationship between tropical and deep-ocean temperatures, which implies a constant polar amplification factor throughout the generally ice-free Eocene. Quantitative comparison with fully coupled climate model simulations indicates that global average temperatures were about 29, 26, 23 and 19 degrees Celsius in the early, early middle, late middle and late Eocene, respectively, compared to the preindustrial temperature of 14.4 degrees Celsius. Finally, combining proxy- and model-based temperature estimates with available CO2 reconstructions8 yields estimates of an Eocene Earth system sensitivity of 0.9 to 2.3 kelvin per watt per square metre at 68 per cent probability, consistent with the high end of previous estimates11. PMID- 29967547 TI - Standardized assays for determining the catalytic activity and kinetics of peroxidase-like nanozymes. AB - Nanozymes are nanomaterials exhibiting intrinsic enzyme-like characteristics that have increasingly attracted attention, owing to their high catalytic activity, low cost and high stability. This combination of properties has enabled a broad spectrum of applications, ranging from biological detection assays to disease diagnosis and biomedicine development. Since the intrinsic peroxidase activity of Fe3O4 nanoparticles (NPs) was first reported in 2007, >40 types of nanozymes have been reported that possess peroxidase-, oxidase-, haloperoxidase- or superoxide dismutase-like catalytic activities. Given the complex interdependence of the physicochemical properties and catalytic characteristics of nanozymes, it is important to establish a standard by which the catalytic activities and kinetics of various nanozymes can be quantitatively compared and that will benefit the development of nanozyme-based detection and diagnostic technologies. Here, we first present a protocol for measuring and defining the catalytic activity units and kinetics for peroxidase nanozymes, the most widely used type of nanozyme. In addition, we describe the detailed experimental procedures for a typical nanozyme strip-based biological detection test and demonstrate that nanozyme-based detection is repeatable and reliable when guided by the presented nanozyme catalytic standard. The catalytic activity and kinetics assays for a nanozyme can be performed within 4 h. PMID- 29967549 TI - The role of laryngectomy in locally advanced thyroid carcinoma. Review of 16 cases. AB - SUMMARY: Locally advanced disease with larynx invasion is a challenge to the surgeon, but laryngectomy is almost never necessary in thyroid carcinoma. The aim of this study was to review the clinical outcomes of patients with locally advanced thyroid carcinoma invading the larynx who underwent laryngectomy. A case series of patients treated in a tertiary care hospital was reviewed. Data about the type of operation, method of reconstruction, complications and overall survival of 16 patients operated on between 2002 and 2015 with larynx invasion is presented. There were 10 females. The mean age was 63 +/- 8.8 years. Besides total thyroidectomy and neck dissection, four patients underwent total pharyngolaryngectomy, 11 total laryngectomy and one hemi-laryngectomy. Reconstruction was made with regional flaps in 10 patients (7 pectoral/Bakamjian flaps and 3 gastric pull-through procedures) and a jejunum free flap in one patient. Two patients needed carotid artery reconstruction. Five tumours were classic (conventional) papillary carcinoma variants, while the others were aggressive histological varieties (insular, tall cell, sclerosing). The mean tumour size was 4.3 +/- 1.6 cm. All tumours had lymphovascular invasion and 12 had positive lymph nodes. Concomitantly, oesophageal/hypopharyngeal invasion was present in 7 cases and invasion of carotid vessels in 2 cases. There were two postoperative deaths and two anastomotic leaks that were treated conservatively. The mean overall survival was 31 +/- 33 months (median 27.6 months, range 0-120). Laryngectomy is an alternative surgical procedure to control selected cases of advanced thyroid carcinoma that offers good local control and long term survival. PMID- 29967550 TI - Cyclamen europaeum improves the effect of oral antibiotics on exacerbations and recurrences of chronic rhinosinusitis: a real-life observational study (CHRONOS). AB - SUMMARY: Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses affecting 11% of the European population. Cyclamen europaeum plant extract (CE) has demonstrated efficacy in treating acute rhinosinusitis, but its role in CRS exacerbations remains unknown. In this real-life, prospective, epidemiological, observational study, a total of 317 patients with exacerbations of CRS without nasal polyps (CRSsNP) of moderate severity were treated using three different options: oral antibiotics, CE extract nasal spray, or the combination of oral antibiotic with CE extract. The main outcomes were the effect of treatment on sinonasal symptoms and endoscopic appearance after 6 weeks of therapy, and the number of recurrences of CRS exacerbations after 6 months of follow-up. On the top of oral antibiotics, CE extract significantly improved sinonasal symptoms and endoscopic findings and caused a 4-fold reduction of CRS recurrences. When administered in monotherapy, CE extract was at least as effective as antibiotic in monotherapy on relief of both symptoms and reduction of CRS recurrences. In patients with CRS exacerbation of moderate severity, CE extract nasal spray in monotherapy or added to standard antibiotic treatment significantly reduces sinonasal symptoms and CRS recurrences compared to antibiotics in monotherapy. PMID- 29967551 TI - Modification of growth, immunologic and feeding parameters in children with OSAS after adenotonsillectomy. AB - SUMMARY: Obstructive sleep apnoea syndrome can cause growth delay in children. Adeno-tonsillectomy can resolve the syndrome in most cases. The aim of our study is to examine modifications in clinical and laboratory growth and immunological parameters and food intake changes in OSAS children after surgery. Twenty-eight children with severe OSAS associated with adeno-tonsillar hypertrophy were submitted to paediatric evaluation to calculate auxologic parameters (weight, height, BMI and standard deviation scores), a blood draw to evaluate growth (GH; IGF-1) and immunological parameters (IgG; IgA; IgM) and a dietitian evaluation to calculate caloric intake before and after 3 months following adeno-tonsillectomy. Mean height and weight values in the study group were slightly inferior to same age children mean according to the percentile values. After surgery, both height and BMI increased significantly at 3-months follow-up: mean height increased 2.93 cm (p = 0.0001); BMI values greatly increased by 0.72 kg/m2 (p = 0.009). Standard deviation scores increased significantly for height (p = 0.03), weight (p = 0.001) and BMI (p = 0.001). These values significantly increased, despite almost unchanged caloric intake between the pre- and post-surgery period (90 +/- 24 vs 91 +/- 27 kcal/kg/day; p > 0.05). In all children, age-related GH values were normal and did not show any significant increase, while IGF-1 values significantly increased during the study period (p = 0.01). Regarding immunological parameters, only IgA levels decreased after surgery and maintained a value that was higher than normal (> 70 mg/dL). In conclusion, children affected by adenotonsillar hypertrophy and OSAS do not show significant growth delay, but they do experience a slowdown in growth rate. After adeno tonsillectomy, the speed of growth soon increases, as weight and growth increase notwithstanding an unchanged food intake. Moreover, surgery does not cause reduction in the efficiency of the immune system. PMID- 29967552 TI - Binocular cyclotorsion in superior vestibular neuritis. AB - SUMMARY: Conjugated cyclotorsion of the eyes toward the affected side can commonly be observed in vestibular neuritis. The aim of this study was to assess the differences in cyclotorsion between the ipsi- and contralesional eye during selective involvement of the superior branch of the vestibular nerve. We studied binocular cyclotorsion through ocular fundus photographs in 10 patients affected by acute superior vestibular neuritis (SVN). Cyclotorsion was also studied in 20 normal subjects. All SVN patients showed an ipsilesional cycloversion of the eyes. Normal subjects exhibited a constant mild excyclovergence (6.42 +/- 2.34 degrees ). In SVN patients, contralateral incyclotorsion (8.4 +/- 8.14 degrees ) was lower and not normally distributed compared to ipsilateral eye excyclotorsion (17.9 +/- 4.36 degrees ) with no correlation between them. The interocular difference in cyclodeviation could be related to the starting physiological excyclovergence, to different tonic effects on the extraocular muscles of the two eyes and to the different influence of spontaneous nystagmus on cyclodeviation in the two eyes. We recommend referring only to ipsilateral excyclotorsion in the evaluation of utricular function during SVN and its subsequent compensation. Further studies are required to determine the binocular cyclotorsion in the case of other kinds of selective involvement of the vestibular nerve. PMID- 29967553 TI - Transtracheal endoscopic-assisted resection of a rare inflammatory myofibroblastic tumour in adult trachea: a case report. AB - SUMMARY: Inflammatory myofibroblastic tumours (IMTs) are rare and clinically benign in childhood, and malignant in adults. The aetiology of IMTs is not clear, and recent studies report it as true neoplasm rather than a reactive or inflammatory lesion. IMTs can involve any part of the body, but are usually common in lungs. These are rarely seen in adults and tracheal involvement is also rare in both adults and children. We describe an 18-year-old woman who presented with respiratory difficulty to the emergency department. On clinical examination, the patient had complete absence of breath sounds on the right side of the chest. CT of the chest and virtual bronchoscopy revealed a polypoidal soft tissue mass lesion involving the carina with occlusion of right main bronchus. Endoscopic assisted resection was performed under general anaesthesia and the final pathological diagnosis was tracheal IMT. PMID- 29967554 TI - The efficacy of telerehabilitation in dysphagic patients: a systematic review. AB - SUMMARY: Telerehabilitation is the use of telecommunications technology for rehabilitation. Recently, some studies have shown positive effects of telerehabilitation of swallowing disorders, yet there are no systematic reviews verifying the evidence. The aim of this review is to assess the effects of telerehabilitation in the field of dysphagia as an alternative to face-to-face patient care, considering swallowing recovery and/or quality of life in different patient populations. We searched the Cochrane Library, MEDLINE, EMBASE, Google Scholar, Google Search and the grey literature from inception until December 2016 for publications written in English (keywords: telerehabilitation, telemedicine, dysphagia, swallowing disorders), which resulted in 330 records. Abstract screening and data extraction was carried out independently by two reviewers. Four papers were selected to read in full, and the methodological quality of the studies included was evaluated using Cochrane Collaboration's tool for assessing risk of bias. One study met our inclusion criteria (Wall et al. 2016), which showed that telerehabilitation improves adherence to treatment compared to patient-directed intervention. Although adherence is an important factor that influences the treatment outcome, clinical outcomes have to be examined in randomised controlled trials in order to reach evidence in this field. Lastly, this systematic review did not demonstrate the efficacy of telerehabilitation compared with face-to face therapy. PMID- 29967555 TI - Elective neck dissection during salvage surgery after radiotherapy in patients with head and neck squamous cell carcinoma. AB - SUMMARY: Elective neck dissection in patients with recurrent head and neck squamous cell carcinoma (HNSCC) without evidence of neck disease (crN0) is poorly defined. A retrospective review was carried out on 165 crN0 patients treated with salvage surgery and elective neck dissection. Multivariate Cox analysis and recursive partitioning analysis were used to evaluate prognostic factors. The frequency of occult neck node metastases in the neck dissection (rpN+) was 16.4%. The risk of occult metastases for glottic rpT1-T2 recurrences was 5.9%, for glottic rpT3-T4 recurrences 13.2%, for non-glottic rpT1-T2 recurrences 16.1% and for locally advanced (rpT3-T4) non-glottic recurrences 31.1%. Patients with occult neck node metastases (rpN+) had a 5-year adjusted survival rate of 38.1%, while patients without nodal disease (rpN0) had a 5-year adjusted survival rate of 71.1% (p = 0.0001). Elective neck dissection can be omitted in crN0 patients with rT1-T2 glottic recurrence. We consider it advisable to perform elective neck dissection in all other situations. PMID- 29967556 TI - IFN-gamma and other serum cytokines in head and neck squamous cell carcinomas. AB - SUMMARY: Altered immune responses have been reported in head and neck cancer, and some of these responses have been associated with poor clinical outcomes. A multiple-array technology platform was used to simultaneously evaluate the levels of 25 cytokines. Pre-treatment serum levels were evaluated in 31 HNSCC patients and 6 healthy controls. The levels of 8 cytokines, specifically IL-1ra, IL-2, IL 5, IL-6, IL-8, IL-17, IFN-gamma and IP-10, were significantly higher in patients than in controls. Among cancer patients we observed lower levels of IFN-gamma and IL-7 in cases with nodal metastases compared to those with cN0 disease. We observed increases in the levels of some serum cytokines in HNSCC patients, as well as reductions in selected cytokines associated with regional progression. These findings provide an intriguing perspective on the development and validation of novel markers for follow-up evaluations and predictions of regional spreading in HNSCC patients. PMID- 29967557 TI - Long-term outcomes of alternating chemoradiotherapy in patients with advanced nasopharyngeal cancer: a single-centre experience over the last decade. AB - SUMMARY: We assessed the long-term outcomes of alternating chemoradiotherapy (ACRT) using 5-fluorouracil and cisplatin (FP) in 25 patients with stage II or advanced nasopharyngeal cancer treated at our institution between April 1999 and April 2010. Median follow-up duration was 87 months (range 2-189). According to the 2009 TNM classification (UICC), six patients were in stage II, nine in stage III, and 10 in stage IV. Treatment completion, response and five-year survival rates were retrospectively assessed. ACRT was performed with a first course of chemotherapy administered followed by the initial round of radiotherapy (36 Gy). Then, a second course of chemotherapy with additional radiotherapy (20-30 Gy) was administered, followed by a final third course of chemotherapy. For chemotherapy, 5-fluorouracil (5-FU, 800 mg/m2/24 h) was intravenously administered for five days, and cisplatin (CDDP, 50 mg/m2/24 h) was administered on the last two days. Treatment completion rate was 96% (24 of 25 cases), and the response rate was 100% (CR: 24 cases and PR: 1 case). Additionally, the five-year overall survival rate was 89.3%. We have demonstrated that ACRT is an effective regimen to treat nasopharyngeal cancer, revealing higher treatment completion, response, and five year overall survival rates compared with other combinatorial radiotherapy and chemotherapy treatment regimens. PMID- 29967548 TI - Emerging and re-emerging infectious disease in otorhinolaryngology. AB - SUMMARY: Emerging and re-emerging infectious disease in otorhinolaryngology (ENT) are an area of growing epidemiological and clinical interest. The aim of this section is to comprehensively report on the epidemiology of key infectious disease in otorhinolaryngology, reporting on their burden at the national and international level, expanding of the need of promoting and implementing preventive interventions, and the rationale of applying evidence-based, effective and cost- effective diagnostic, curative and preventive approaches. In particular, we focus on i) ENT viral infections (HIV, Epstein-Barr virus, Human Papilloma virus), retrieving the available evidence on their oncogenic potential; ii) typical and atypical mycobacteria infections; iii) non-specific granulomatous lymphadenopathy; iv) emerging paediatric ENT infectious diseases and the prevention of their complications; v) the growing burden of antimicrobial resistance in ENT and the strategies for its control in different clinical settings. We conclude by outlining knowledge gaps and action needed in ENT infectious diseases research and clinical practice and we make references to economic analysis in the field of ENT infectious diseases prevention and care. PMID- 29967558 TI - Objective assessment of subjective tinnitus through contralateral suppression of otoacoustic emissions by white noise: effects of frequency, gender, tinnitus bilaterality and age. AB - SUMMARY: Accumulating evidence seems to support an association between tinnitus and medial olivocochlear bundle (MOCB) dysfunction. Most studies use patient/control comparisons to support this correlation. The aim of this study was to investigate the hypothesis in a substantially different way and evaluate the roles of gender, age, frequency and tinnitus bilaterality as possible confounding factors. The population consisted of 78 normal hearing patients with chronic tinnitus, 28 normal hearing controls, 19 presbycousic tinnitus patients and 13 presbycousic controls (n = 276 ears). Mean suppression amplitudes of transient evoked otoacoustic emissions (TEOAEs) and distortion product OAEs (DPOAEs) by contralateral white noise (50 dB SPL) were computed. Mean suppression values < 1 dB SPL or < 2 dB SPL were validated as positive test results. Overall suppression (OS) values < 1 dB SPL were qualified as a diagnostic test of moderate positive predictive value for both DPOAEs and TEOAEs, while OS values < 2 dB SPL were found to be of large negative predictive value for DPOAEs and moderate for TEOAEs. Mean suppression values (for all frequencies, OS) are of higher diagnostic value than suppression values corresponding to either lower (1 2 kHz) or higher frequencies (2.8-4 kHz for TEOAEs and 2.8-6 kHz for DPOAEs). After excluding patients with unilateral tinnitus from the analysis, correlations were found to be stronger. Useful correlations were also attributed for all age groups < 61 years. In females, OAE suppression seems to have a stronger positive predictive value, while in males it seems to have a stronger negative predictive value. OAE-based assays of MOCB function as an objective diagnostic tool for subjective tinnitus might deserve further investigation. Tinnitus uni- or bi laterality is a confounding factor, which probably confirms the observation that defective function of the MOCB usually applies to the contralateral ear as well. Gender is an additional confounding factor, while correlations can be verified for all age groups < 61 years old. PMID- 29967559 TI - Vertigo returning to the sitting position after the Semont manoeuvre. Is it a prognostic symptom? AB - SUMMARY: Benign paroxysmal positional vertigo (BPPV) is a frequent benign vestibular condition usually managed with particle repositioning manoeuvres, such as Semont manoeuvre (SM). Since few authors have described prognostic aspects of liberatory manoeuvres, the purpose of the present study was to investigate the possibility of considering vertigo in the final sitting position of the SM as a prognostic symptom in the outcome of posterior BPPV. One hundred and thirteen patients with diagnosis of unilateral posterior BPPV were taking into account in our retrospective cohort study: 41 men and 72 women, aged 22 to 85 years. All were submitted to one repositioning SM and afterwards controlled 3 to 5 days later by means of an additional Dix-Hallpike manoeuvre. The main outcomes investigated were the occurrence of Ny and vertigo in the different phases of the SM, as well as their characteristics in relation to outcome of the disease. Among all patients, 75 (66%) presented both orthotropic Ny and vertigo in the second SM position and 72% obtained a complete resolution of the disease after the liberatory manoeuvre. Contrarily, 17 subjects (15%) manifested vertigo in the final sitting position of the SM and among these, only 7 (41%) completely recovered from BPPV. According to our data, in case of sudden vertigo returning to the final sitting position of the SM, the failure rate of the liberatory manoeuvre was higher, even though not statistically significant: therefore, it can be considered as a negative prognostic factor of posterior BPPV after SM. PMID- 29967560 TI - Acquisition of surgical skills for endoscopic ear and lateral skull base surgery: a staged training programme. AB - SUMMARY: Endoscopic ear surgery is radically changing the treatment of several middle and inner ear pathology, but its learning presents well-known manual and technical difficulties. The aim of this paper is be to present a training programme based on a modular model of increased difficulties. The experience from 2007 to 2016 at the University Hospital of Modena and University Hospital of Verona was reviewed and analysed for further considerations and to establish stages of training. The increasing experience of expert surgeons who deal with this kind of surgery represented the main guide to establish the steps and progression of training. In addition, the potential risk of damage of vascular structures or nerves represents fundamental criteria for progression toward higher levels. Some not-mandatory skills were also suggested for stage of difficulty. Five stages of training were deemed appropriate for progressive learning of endoscopic ear and lateral skull base surgery, ranging from simple middle and external ear procedures to surgery of inner ear and internal auditory canal. Mastering of each level is suggested before attempting procedures at a higher level, in particular for procedures involving lateral skull base. Standardisation and adoption of modular incremental training are expected to facilitate improvement of otolaryngologists and neurosurgeons starting with endoscopic middle ear and lateral skull base surgery. Adherence to such a programme during the growth phase may potentially decrease the rate of complications, making the training programme safer. PMID- 29967561 TI - Retrospective epidemiological study of mandibular rotational types in patients with orthodontical malocclusion. AB - SUMMARY: The primary aim of this study was to illustrate the prevalence of facial skeletal discrepancy in an Italian sample. Another aim was to evaluate the effectiveness of the sagittal skeletal discrepancy classification in order to establish a morphologic pattern of growth useful for diagnosis and prediction of therapeutic results. The authors considered a sample of 732 patients (426 females and 306 males) aged between 6 and 17 years old. Cephalometric parameters were evaluated in order to establish a relationship between sagittal skeletal discrepancy and the classification of facial rotations (Lavergne and Petrovic). Facial types with neutral mandibular growth direction were the most prevalent, and were most observed in classes I and II; the latter was more represented than others in our sample. Facial types with posterior mandibular growth direction were the most prevalent in class III. Sagittal skeletal discrepancy classification is not able to establish a specific facial type or predict an individual responsiveness to treatment. PMID- 29967562 TI - Eagle's Syndrome, from clinical presentation to diagnosis and surgical treatment: a case report. AB - SUMMARY: Eagle's syndrome is a condition associated with the elongation of the styloid process or calcification of the stylohyoid ligament, clinically characterised by throat and neck pain, radiating into the ear. In this report, we describe the case of a 60-year-old woman who presented with a severe unilateral trigeminal and glossopharyngeal neuralgia. The patient was subjected to conservative therapy for four months and did not report improvement of the symptoms. After several consultations with different physicians, a diagnosis was accomplished by radiological investigation (multidetector computer tomography with multi-planar reconstructions and 3D volumetric reconstructions). Surgical styloidectomy was performed, with subsequent sudden remission of symptoms. Eagle's syndrome represents a commonly unrecognised nosological entity, clinically characterised by non-specific cranio-facial pain. Differential diagnosis includes glossopharyngeal and trigeminal neuralgia, temporal arteritis, migraine, myofascial pain dysfunction and cervical arthritis. Eagle's syndrome should always be suspected, mostly in adult women when the pain is unilateral and not responsive to painkillers. PMID- 29967563 TI - Retinal abnormatilites as a diagnostic or prognostic marker of schizophrenia. AB - The review is a summary of structural and functional changes in the human retina observed in patients with schizophrenia. The main focus is on the potential of these changes to serve as schizophrenia-specific biomarkers accessible to clinicians. We identified three features of the retina that can be detected non invasively in humans and which appear to show charateristic changes in schizophrenia: (1) retinal microvasculature displaying abnormally wide venules; (2) electroretinograms indicating altered function of photoreceptors or other cells in the retinal component of the visual pathway; (3) optical coherence tomography pointing to structural differences between the retinae of patients with schizophrenia and those of healthy volunteers. We propose that the most feasible approach to evaluating the data would be to study the genetic and epigenetic background of the schizophrenia-associated retinal abnormalities and establish their significance and specificity as potential biomarkers for the disease. The studies should include longitudinal observations focusing on the possible involvement of medication and comorbid conditions in the mechanism of the disease; a comparison of schizophrenia with other mental disorders; and investigating retinal abnormalities in animal models of psychoses. Biomarkers identified in the process could represent an important addition to the arsenal of non-invasive techniques available to both clinicians and researchers. These novel biomarkers could facilitate research of the biological basis of psychosis and help to address the diagnostic, predicitive, preventative, prophylactic and therapeutic aspects of schizophrenia. PMID- 29967564 TI - 25-gauge vitrectomy and gas for the management of rhegmatogenous retinal detachment. AB - AIMS: To evaluate the anatomical and functional results in patients with rhegmatogenous retinal detachment (RRD) who underwent 25-gauge pars plana vitrectomy (PPV) with gas tamponade. MATERIALS AND METHODS: A retrospective evaluation of 126 eyes of 126 patients (79 men, 47 women) with RRD who underwent 25-gauge PPV with gas tamponade (13% C3F8 in 87 eyes, 20% SF6 in 39 eyes). 113 patients (89.7%), were operated on under local anaesthesia, 13 patients (10.3%) under general anaesthesia. Macula was detached in 85 eyes (67.5%). 53 eyes had pseudophakic RRD, 73 eyes were phakic. Anatomical success of the primary intervention, change in best corrected visual acuity (BCVA) and incidence of complications were assessed. An average follow-up period is 7.2 months (6-15). RESULTS: With single operation, retinal attachment was achieved in 125 eyes (99.2%); the final anatomical success was 100%. The initial mean BCVA was 0.89 logMar (2.00 to 0.00); at the end of the follow-up period, it improved to 0.23logMAR (1.00 to -0.10), P < 0,0001. During the first post-intervention day, hypotony of the eye below 10 mmHg was observed in 1 patient (0.8%); on the contrary, intraocular pressure was temporarily increased to 25 mmHg and more in 36 patients (28.6%). CONCLUSION: The surgical treatment of RRD using 25-gauge PPV with expansive gas tamponade renders excellent anatomical results and improvement in BCVA. The incidence of complications and necessity of sclerotomy suturing are low. PMID- 29967565 TI - ZIKV Infection Induces an Inflammatory Response but Fails to Activate Types I, II, and III IFN Response in Human PBMC. AB - The recent epidemic in the Americas caused by Zika virus (ZIKV), Asian lineage, spurred the research towards a better understanding of how ZIKV infection affects the host immune response. The aim of this study was to evaluate the effects of Asian and East African ZIKV strain infection on the induction of IFN and proinflammatory and Th2 cytokines in human PBMC. We reported a slight modulation of type II IFN in PBMC exposed to Asian strain, but not to African strain, and a complete lack of type I and III IFN induction by both strains, suggesting the ability of ZIKV to evade the IFN system not only inhibiting the antiviral IFN response but also IFN production. Moreover, we highlighted a polyfunctional immune activation only in PBMC exposed to Asian strain, due to the induction of an inflammatory profile (IL-6, IL-8) and of a Th9 (IL-9) response. Overall, our data show a different ability of the ZIKV Asian strain, with respect to the African strain, to activate host immune response that may have pathogenetic implications for virus spread in vivo, including mother-to-child transmission and induction of severe fetal complications, as birth defects and neurological disorders. PMID- 29967566 TI - Pathway-Wide Genetic Risks in Chlamydial Infections Overlap between Tissue Tropisms: A Genome-Wide Association Scan. AB - Chlamydia trachomatis is the most commonly diagnosed bacterial sexually transmitted infection and can lead to tubal factor infertility, a disease characterised by fibrosis of the fallopian tubes. Genetic polymorphisms in molecular pathways involving G protein-coupled receptor signalling, the Akt/PI3K cascade, the mitotic cell cycle, and immune response have been identified in association with the development of trachomatous scarring, an ocular form of chlamydia-related fibrotic pathology. In this case-control study, we performed genome-wide association and pathways-based analysis in a sample of 71 Dutch women who attended an STI clinic who were seropositive for Chlamydia trachomatis antibodies and 169 high-risk Dutch women who sought similar health services but who were seronegative. We identified two regions of within-gene SNP association with Chlamydia trachomatis serological response and found that GPCR signalling and cell cycle pathways were also associated with the trait. These pathway-level associations appear to be common to immunological sequelae of chlamydial infections in both ocular and urogenital tropisms. These pathways may be central mediators of human refractoriness to chlamydial diseases. PMID- 29967567 TI - CRP Stimulates GDF15 Expression in Endothelial Cells through p53. AB - Growth differentiation factor 15 (GDF15) is a multifunctional, secreted protein that is a direct target gene of p53. GDF15 is a prospective biomarker of cardiovascular disease (CVD). C-reactive protein (CRP), like GDF15, is implicated in inflammation and an independent biomarker of CVD. However, the molecular interactions between GDF15 and CRP remain unexplored. In women, we found a significant relationship between hsCRP and GDF15 serum and mRNA levels. In vitro treatment of cultured human aortic endothelial cells (HAECs) with purified CRP or transfection of a CRP plasmid into HAECs induced GDF15 expression. Dual luciferase reporter assays confirmed that CRP significantly increased the levels of GDF15 promoter luciferase activity, indicating that CRP induces GDF15 transcription. Chromatin immunoprecipitation (ChIP) assays confirmed that p53 was recruited to both p53 binding sites 1 and 2 in the GDF15 promoter in response to CRP. We have uncovered a linkage between CRP and GDF15, a new clue that could be important in the pathogenesis of endothelial inflammation. PMID- 29967568 TI - Dynamics of Immune Responses during Experimental Mycobacterium kansasii Infection of Cynomolgus Monkeys (Macaca fascicularis). AB - To profile the dynamic changes of immune responses for M. kansasii infection, 3 cynomolgus monkeys were experimentally infected with M. kansasii by intratracheal inhalation of 1 * 106 CFU bacteria per monkey. Every 2 to 4 weeks, tuberculin skin testings (TSTs) were performed and blood samples were collected for immunoassay. Multiple cytokines in a single sample were measured by Luminex xMAP technologies. IgM and IgA were detected by double-antibody sandwich ELISA. IgG against PPD and 11 M. tuberculosis proteins were detected by using of indirect ELISA. At week 16, all animals were euthanized for necropsy and histological analysis. Positivities of TSTs emerged from week 2 to 6 postinfection. Leukocyte counts and T lymphocyte subsets experienced moderate increases. Among 44 kinds of cytokines, 36 kinds of them showed increases of different dynamic types and 8 kinds of them showed no specific changes. Total IgM and IgA showed a transient increase at an early infection stage. Positivities of M. tuberculosis specific IgM and IgA emerged as early as week 2 postinfection. All animals showed positive IgG against PPD and negative IgG responses to 38 kDa, MPT64L, TB16.3, 16 kDa, U1, and MTB81 antigens during the infection period. IgG against ESAT-6, CFP10, CFP10 ESAT-6, Ag85b, and 14 kDa antigens reached positive levels. The IgG avidities of PPD, ESAT-6, CFP10-ESAT-6, and Ag85b were all above 50 percent. In conclusion, the data indicate that M. kansasii infection in monkeys can induce positivities of TSTs, increases of multiple cytokines, and cross-reactive antibody responses to M. tuberculosis antigens. PMID- 29967569 TI - Article Watch: July 2018. AB - This column highlights recently published articles that are of interest to the readership of this publication. We encourage ABRF members to forward information on articles they feel are important and useful to Clive Slaughter, MCG-UGA Medical Partnership, 1425 Prince Ave., Athens, GA 30606, USA. Tel: (706) 713 2216; Fax: (706) 713-2221; E-mail: cslaught@uga.edu; or to any member of the editorial board. Article summaries reflect the reviewer's opinions and not necessarily those of the association. PMID- 29967570 TI - The Utility of Color Duplex Ultrasonography in the Diagnosis of Giant Cell Arteritis: A Prospective, Masked Study. (An American Ophthalmological Society Thesis). AB - Purpose: To evaluate the diagnostic yield and concordance of color duplex ultrasound (CDU) of the superficial temporal artery (STA), temporal artery biopsy (TAB), and American College of Rheumatology (ACR) criteria in the diagnosis of giant cell arteritis (GCA). Methods: Prospective, masked study of all patients evaluated in one institution suspected of having GCA. All patients with a suspected diagnosis of GCA were admitted for pulsed intravenous corticosteroids. Patients underwent serologic work-up and ACR criteria were documented. All patients had a CDU and TAB performed within 3 days of initiation of systemic corticosteroid therapy. Main outcome measure: Concordance of CDU and TAB. Secondary outcome measures: Concordance between unilateral and bilateral CDU and TAB by side and segment, concordance between TAB and ACR criteria, and statistical analysis of serologic markers for GCA. Results: The diagnosis of biopsy-proven GCA was found in 14 of 71 (19.7%) patients. The sensitivity of CDU compared to the reference standard of TAB ranged between 5.1% and 30.8% depending on the signs studied on CDU and correlation of specific TAB parameters. Of the serologic studies, a platelet count threshold of 400,000MUL had the highest positive (18.32) and lowest negative (0.37) likelihood ratios for a diagnosis of GCA. Conclusions: In this study, CDU showed minimal value in diagnosing GCA compared to TAB. There was poor correlation between CDU results and ACR criteria for GCA. The threshold platelet count had higher positive and negative predictive values for GCA than CDU and is a useful serologic marker for GCA. PMID- 29967572 TI - Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice. AB - Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [11C]AM7 and [11C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([11C]AM7 n = 2; [11C]MT107, n = 4) and after administration of cyclosporine ([11C]MT107, n = 4). The modelling revealed a significant reduction in [11C]MT107 hepatobiliary clearance from 35.2 +/- 10.9 to 17.1 +/- 5.6 MUl/min after cyclosporine administration. The excretion profile of [11C]MT107 was shifted from predominantly hepatobiliary (CLH/CLR = 3.8 +/- 3.0) to equal hepatobiliary and renal clearance (CLH/CLR = 0.9 +/- 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics. PMID- 29967573 TI - Case Presentation - IgA Nephropathy. PMID- 29967571 TI - Multimodal Molecular Imaging: Current Status and Future Directions. AB - Molecular imaging has emerged at the end of the last century as an interdisciplinary method involving in vivo imaging and molecular biology aiming at identifying living biological processes at a cellular and molecular level in a noninvasive manner. It has a profound role in determining disease changes and facilitating drug research and development, thus creating new medical modalities to monitor human health. At present, a variety of different molecular imaging techniques have their advantages, disadvantages, and limitations. In order to overcome these shortcomings, researchers combine two or more detection techniques to create a new imaging mode, such as multimodal molecular imaging, to obtain a better result and more information regarding monitoring, diagnosis, and treatment. In this review, we first describe the classic molecular imaging technology and its key advantages, and then, we offer some of the latest multimodal molecular imaging modes. Finally, we summarize the great challenges, the future development, and the great potential in this field. PMID- 29967574 TI - Plin4-Dependent Lipid Droplets Hamper Neuronal Mitophagy in the MPTP/p-Induced Mouse Model of Parkinson's Disease. AB - Epidemiological studies have shown that both lipid metabolism disorder and mitochondrial dysfunction are correlated with the pathogenesis of neurodegenerative diseases (NDDs), including Parkinson's disease (PD). Emerging evidence suggests that deposition of intracellular lipid droplets (LDs) participates in lipotoxicity and precedes neurodegeneration. Perilipin family members were recognized to facilitate LD movement and cellular signaling interactions. However, the direct interaction between Perilipin-regulated LD deposition and mitochondrial dysfunction in dopaminergic (DA) neurons remains obscure. Here, we demonstrate a novel type of lipid dysregulation involved in PD progression as evidenced by upregulated expression of Plin4 (a coating protein and regulator of LDs), and increased intracellular LD deposition that correlated with the loss of TH-ir (Tyrosine hydroxylase-immunoreactive) neurons in the MPTP/p-induced PD model mouse mesencephalon. Further, in vitro experiments showed that inhibition of LD storage by downregulating Plin4 promoted survival of SH SY5Y cells. Mechanistically, reduced LD storage restored autophagy, leading to alleviation of mitochondrial damage, which in turn promoted cell survival. Moreover, the parkin-poly-Ub-p62 pathway was involved in this Plin4/LD-induced inhibition of mitophagy. These findings were further confirmed in primary cultures of DA-nergic neurons, in which autophagy inhibitor treatment significantly countermanded the ameliorations conferred by Plin4 silencing. Collectively, these experiments demonstrate that a dysfunctional Plin4/LD/mitophagy axis is involved in PD pathology and suggest Plin4-LDs as a potential biomarker as well as therapeutic strategy for PD. PMID- 29967575 TI - Differential Bilateral Primary Motor Cortex tDCS Fails to Modulate Choice Bias and Readiness in Perceptual Decision Making. AB - One of the critical factors that guide choice behavior is the prior bias of the decision-maker with respect to different options, namely, the relative readiness by which the decision-maker opts for a specific choice. Although previous neuroimaging work has shown decision bias related activity in the orbitofrontal cortex, intraparietal sulcus (IPS) and dorsolateral prefrontal cortex, in a recent work by Javadi et al. (2015), primary motor cortex was also implicated. By applying transcranial direct current stimulation (tDCS), they have revealed a causal role of the primary motor cortex excitability in the induction of response time (RT) differences and decision bias in the form of choice probability. The current study aimed to replicate these recent findings with an experimental design that contained a sham group to increase experimental control and an additional testing phase to investigate the possible after-effects of tDCS. The conventional decision outputs such as choice proportion and RT were analyzed along with the theory-driven estimates of choice bias and non-decision related components of RTs (e.g., motor implementation speed of choices made). None of the statistical comparisons favored the alternative hypotheses over the null hypotheses. Consequently, previous findings regarding the effect of primary motor cortex excitability on choice bias and response times could not be replicated with a more controlled experimental design that is recommended for tDCS studies (Horvath et al., 2015). This empirical discrepancy between the two studies adds to the evidence demonstrating inconsistent effects of tDCS in establishing causal relationships between cortical excitability and motor behavior. PMID- 29967576 TI - Impaired Neurofilament Integrity and Neuronal Morphology in Different Models of Focal Cerebral Ischemia and Human Stroke Tissue. AB - As part of the neuronal cytoskeleton, neurofilaments are involved in maintaining cellular integrity. In the setting of ischemic stroke, the affection of the neurofilament network is considered to mediate the transition towards long lasting tissue damage. Although peripheral levels of distinct neurofilament subunits are shown to correlate with the clinically observed severity of cerebral ischemia, neurofilaments have so far not been considered for neuroprotective approaches. Therefore, the present study systematically addresses ischemia induced alterations of the neurofilament light (NF-L), medium (NF-M), and heavy (NF-H) subunits as well as of alpha-internexin (INA). For this purpose, we applied a multi-parametric approach including immunofluorescence labeling, western blotting, qRT-PCR and electron microscopy. Analyses comprised ischemia affected tissue from three stroke models of middle cerebral artery occlusion (MCAO), including approaches of filament-based MCAO in mice, thromboembolic MCAO in rats, and electrosurgical MCAO in sheep, as well as human autoptic stroke tissue. As indicated by altered immunosignals, impairment of neurofilament subunits was consistently observed throughout the applied stroke models and in human tissue. Thereby, altered NF-L immunoreactivity was also found to reach penumbral areas, while protein analysis revealed consistent reductions for NF-L and INA in the ischemia-affected neocortex in mice. At the mRNA level, the ischemic neocortex and striatum exhibited reduced expressions of NF-L- and NF-H associated genes, whereas an upregulation for Ina appeared in the striatum. Further, multiple fluorescence labeling of neurofilament proteins revealed spheroid and bead-like structural alterations in human and rodent tissue, correlating with a cellular edema and lost cytoskeletal order at the ultrastructural level. Thus, the consistent ischemia-induced affection of neurofilament subunits in animals and human tissue, as well as the involvement of potentially salvageable tissue qualify neurofilaments as promising targets for neuroprotective strategies. During ischemia formation, such approaches may focus on the maintenance of neurofilament integrity, and appear applicable as co treatment to modern recanalizing strategies. PMID- 29967577 TI - Cortical Plasticity After Surgical Tendon Transfer in Tetraplegics. AB - Background: Developmental cortical plasticity with reorganization of cerebral cortex, has been known to occur in young and adult animals after permanent, restricted elimination of afferent (visual or somatosensory) input. In animals, cortical representation of unaffected muscles or sensory areas has been shown to invade the neighboring cortex when this is deprived of its normal sensory input or motor functions. Some studies indicate that similar cortical plasticity may take place in adult humans. Methods: In patients with a high cervical spinal cord injury leaving the patient without any movements of the fingers, we performed fMRI studies of the cortical representation of an elbow flexor muscle before and after a surgical procedure that changed its function to a thumb flexor, thus providing the patient with a useful grip. Results: Preoperatively, the elbow flexion movement was elicited from a cortical area corresponding with the "elbow area" in healthy individuals. Despite the fact that an elbow flexor was used for the post-operative key-grip, this movement in the tetraplegic patients was elicited from a similar brain region as in healthy controls (the "hand area"). This supports our hypothesis that control of that muscle shifts from a brain region typically associated with elbow movement, to one typically associated with wrist movements. Conclusion: The findings presented here show with fMRI that the human cortex is capable of reorganizing itself spatially after a relatively acute change in the periphery. PMID- 29967578 TI - The Relation Between Brain Amyloid Deposition, Cortical Atrophy, and Plasma Biomarkers in Amnesic Mild Cognitive Impairment and Alzheimer's Disease. AB - Background: Neuritic plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease (AD), while the role of brain amyloid deposition in the clinical manifestation or brain atrophy remains unresolved. We aimed to explore the relation between brain amyloid deposition, cortical thickness, and plasma biomarkers. Methods: We used 11C-Pittsburgh compound B-positron emission tomography to assay brain amyloid deposition, magnetic resonance imaging to estimate cortical thickness, and an immunomagnetic reduction assay to measure plasma biomarkers. We recruited 39 controls, 25 subjects with amnesic mild cognitive impairment (aMCI), and 16 subjects with AD. PiB positivity (PiB+) was defined by the upper limit of the 95% confidence interval of the mean cortical SUVR from six predefined regions (1.0511 in this study). Results: All plasma biomarkers showed significant between-group differences. The plasma Abeta40 level was positively correlated with the mean cortical thickness of both the PiB+ and PiB- subjects. The plasma Abeta40 level of the subjects who were PiB+ was negatively correlated with brain amyloid deposition. In addition, the plasma tau level was negatively correlated with cortical thickness in both the PiB+ and PiB- subjects. Moreover, cortical thickness was negatively correlated with brain amyloid deposition in the PiB+ subjects. In addition, the cut-off point of plasma tau for differentiating between controls and AD was higher in the PiB- group than in the PiB+ group (37.5 versus 25.6 pg/ml, respectively). Lastly, ApoE4 increased the PiB+ rate in the aMCI and control groups. Conclusion: The contributions of brain amyloid deposition to cortical atrophy are spatially distinct. Plasma Abeta40 might be a protective indicator of less brain amyloid deposition and cortical atrophy. It takes more tau pathology to reach the same level of cognitive decline in subjects without brain amyloid deposition, and ApoE4 plays an early role in amyloid pathogenesis. PMID- 29967579 TI - Integrated Analysis and Identification of Novel Biomarkers in Parkinson's Disease. AB - Parkinson's disease (PD) is a quite common neurodegenerative disorder with a prevalence of approximately 1:800-1,000 in subjects over 60 years old. The aim of our study was to determine the candidate target genes in PD through meta-analysis of multiple gene expression arrays datasets and to further combine mRNA and miRNA expression analyses to identify more convincing biological targets and their regulatory factors. Six included datasets were obtained from the Gene Expression Omnibus database by systematical search, including five mRNA datasets (150 substantia nigra samples in total) and one miRNA dataset containing 32 peripheral blood samples. A chip meta-analysis of five microarray data was conducted by using the metaDE package and 94 differentially expressed (DE) mRNAs were comprehensively obtained. And 19 deregulated DE miRNAs were obtained through the analysis of one miRNAs dataset by Qlucore Omics Explorer software. An interaction network formed by DE mRNAs, DE miRNAs, and important pathways was discovered after we analyzed the functional enrichment, protein-protein interactions, and miRNA targetome prediction analysis. In conclusion, this study suggested that five significantly downregulated mRNAs (MAPK8, CDC42, NDUFS1, COX4I1, and SDHC) and three significantly downregulated miRNAs (miR-126-5p, miR-19-3p, and miR-29a 3p) were potentially useful diagnostic markers in clinic, and lipid metabolism (especially non-alcoholic fatty liver disease pathway) and mitochondrial dysregulation may be the keys to biochemically detectable molecular defects. However, the role of these new biomarkers and molecular mechanisms in PD requires further experiments in vivo and in vitro and further clinical evidence. PMID- 29967580 TI - Metabolomic Analysis by Nuclear Magnetic Resonance Spectroscopy as a New Approach to Understanding Inflammation and Monitoring of Pharmacological Therapy in Children and Young Adults With Cystic Fibrosis. AB - 15-F2t-Isoprostane, a reliable biomarker of oxidative stress, has been found elevated in exhaled breath condensate (EBC), a non-invasive technique for sampling of airway secretions, in patients with cystic fibrosis (CF). Azithromycin has antioxidant properties in experimental models of CF, but its effects on oxidative stress in CF patients are largely unknown. Primary objective of this pilot, proof-of-concept, prospective, parallel group, pharmacological study, was investigating the potential antioxidant effects of azithromycin in CF patients as reflected by EBC 15-F2t-isoprostane. Secondary objectives included studying the effect of azithromycin on EBC and serum metabolic profiles, and on serum 15-F2t-isoprostane. In CF patients who were on maintenance treatment with oral vitamin E (200 UI once daily), treatment with oral azithromycin (250 or 500 mg depending on body weight) plus vitamin E (400 UI once daily) (group A) (n = 24) or oral vitamin E alone (400 UI once daily) (group B) (n = 21) was not associated with changes in EBC 15-F2t-isoprostane concentrations compared with baseline values after 8-weeks treatment or 2 weeks after treatment suspension. There was no between-group difference in post-treatment EBC 15-F2t-isoprostane. Likewise, no within- or between-group differences in serum 15-F2t-isoprostane concentrations were observed in either study group. NMR spectroscopy-based metabolomics of EBC shows that suspension of both azithromycin plus vitamin E and vitamin E alone has a striking effect on metabolic profiles in EBC. Between-group comparisons show that EBC metabolite distribution after treatment and 2 weeks after treatment suspension is different. Quantitative differences in ethanol, saturated fatty acids, acetate, acetoin/acetone, and methanol are responsible for these differences. Our study was unable to show antioxidant effect of azithromycin as add-on treatment with doubling the dose of oral vitamin E as reflected by 15-F2t-isoprostane concentrations in EBC. Add-on therapy with azithromycin itself does not induce EBC metabolite changes, but its suspension is associated with EBC metabolic profiles that are different from those observed after vitamin E suspension. The pathophysiological and therapeutic implications of these findings in patients with stable CF are unknown and require further research. Preliminary data suggest that EBC NMR-based metabolomics might be used for assessing the effects of pharmacological treatment suspension in stable CF patients. PMID- 29967581 TI - Mangiferin Ameliorates Cisplatin Induced Acute Kidney Injury by Upregulating Nrf 2 via the Activation of PI3K and Exhibits Synergistic Anticancer Activity With Cisplatin. AB - Occurrence of oxidative stress is the principal cause of acute kidney injury induced by cisplatin. Mangiferin, a naturally occurring antioxidant molecule, is found to ameliorate several oxidative stress mediated pathophysiological conditions including cancer. Cisplatin induced cytotoxicity was measured in NKE cells by MTT assay and microscopic analysis. Induction of oxidative stress and regulation of proapoptotic molecules were subsequently investigated by using different spectrophotometric analyses, FACS and immunocytochemistry. Induction of nephrotoxicity was determined by analyzing different serum biomarkers and histological parameters in vivo using swiss albino mice. Activation of NF-kappaB mediated pro-inflammatory and caspase dependent signaling cascades were investigated by semi-quantitative RT-PCR and immunoblotting. Mangiferin was found to ameliorate cisplatin induced nephrotoxicity in vitro and in vivo by attenuating the induction of oxidative stress and upregulating Nrf-2 mediated pro survival signaling cascades via the activation of PI3K. Additionally, mangiferin showed synergistic anticancer activity with cisplatin in cancer cell lines (MCF-7 and SKRC-45) and EAC cell induced solid tumor bearing experimental mice. The ameliorative effect of mangiferin is primarily attributed to its anti-oxidant and anti-inflammatory properties. It acts differentially in normal tissue cells and tumor cells by modulating different cell survival regulatory signaling molecules. For the first time, the study reveals a mechanistic basis of mangiferin action against cisplatin induced nephrotoxicity. Since Mangiferin shows synergistic anticancer activity with cisplatin, it can be considered as a promising drug candidate, to be used in combination with cisplatin. PMID- 29967582 TI - Human Mutations in SLC2A9 (Glut9) Affect Transport Capacity for Urate. AB - SLC2A9 or Glut9 is a voltage sensitive urate transporter, mainly expressed in the kidneys, the liver, and the intestine. Human Glut9 loss-of-function mutations were identified in familial hypouricemia, and several single nucleotide polymorphisms (SNPs) were associated with lower serum urate, further indicating that Glut9 is a major determinant of serum uric acid level. To get insights in Glut9 transport characteristics, we systematically analyzed the function of known human Glut9 mutants using 14C-urate uptake assay and two-electrode voltage clamp (TEVC) in the Xenopus laevis oocyte expression system. Surface expression was assessed by immunostaining and biotinylation. We found decreased urate transport by flux studies for most of the variants. No variant was permissive for glucose transport. We could further differentiate two behaviors among the mutants: those harboring poor overall and cell-surface expression leading to low activity and those fully expressed at the cell surface, but presenting decreased activity. We studied the latter by TEVC and observed, in depolarized conditions, decreased inward currents measured in presence of 400 MUM urate, partially reversed in 1 mM urate. In addition, we showed that C210F displays lower transport ability. By contrast, N333S showed decreased urate transport activity and urate affinity, suggesting that it may belong to the urate binding pocket. Systematic analysis of Glut9 mutants confirms Glut9 as putative target for the treatment of hyperuricemia and brings new insights in Glut9 structure - function. PMID- 29967583 TI - Quantitative Analysis of the Antiepileptogenic Effects of Low Frequency Stimulation Applied Prior or After Kindling Stimulation in Rats. AB - Background and Objective: Developing quantitative measures based on spectral analysis of electroencephalograph (EEG) recordings of neural activities plays an important role in developing efficient treatments for epilepsy. Such biomarkers can be used for developing open or closed loop approaches for seizure prediction or prevention. This study aims to quantitatively evaluate antiepileptogenic effects of low frequency stimulation (LFS) applied immediately before or after kindling stimulations using spectral power analysis of extracellular EEG in rat. Methods: Nineteen adult rats were used: seven for kindle, six for LFS+Kindle (LFSK) and six for Kindle+LFS (KLFS). Four packages of LFS (1Hz) were applied immediately before or after rapid kindling stimulations. The power spectral densities of afterdischarge (AD) sections of EEG corresponding to different stages of kindling for delta (0-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12 28 Hz), gamma (28-40 Hz) sub-bands, and theta/alpha ratio were comparatively investigated. Moreover, correlation between AD duration (ADD) and its different frequency components was calculated. Results: Both LFSK and KLFS significantly increased delta and reduced beta and gamma oscillations, compared with kindle group. However, just the reduction in LFSK group was significant. Both protocols increased theta/alpha ratio, but just LFSK showed significant increase (p < 0.05). Although LFSK enhanced theta/alpha ratio more than KLFS, the difference was not statistically significant. Furthermore, strong correlation between each frequency sub band and ADD was not observed in kindle and LFS treated groups (both LFSK and KLFS). Conclusion: Although behavioral assessments showed relatively the same level of antiepileptogenic effects for KLFS and LFSK, quantitative assessments showed more significant differences in the quantitative measures between the two protocols. Developing more quantitative EEG based measures correlated with LFS-induced effects can facilitate developing open or closed loop seizure prevention modalities. PMID- 29967584 TI - Effects of Consecutive Versus Non-consecutive Days of Resistance Training on Strength, Body Composition, and Red Blood Cells. AB - Health authorities worldwide recommend 2-3 days per week of resistance training (RT) performed ~48-72 h apart. However, the influence of recovery period between RT sessions on muscle strength, body composition, and red blood cells (RBCs) are unclear. Aim: Examine the effects of three consecutive (C) or non-consecutive (NC) days of RT per week for 12 weeks on strength, body composition, and RBCs. Methods: Thirty young, healthy and recreationally active males were randomly assigned to 3 C (~24 h between sessions) or NC (~48-72 h between sessions) days of RT per week for 12 weeks. Both groups performed three sets of 10 repetitions at 10-repetition maximum (RM) of leg press, latissimus pulldown, leg curl, shoulder press, and leg extension for each session. Ten RM and body composition were assessed pre- and post-RT. RBC parameters were measured on the first session before RT, and 0 and 24 h post-3rd session in untrained (week 1) and trained (week 12) states. Results: No training * group interaction was found for all strength and body composition parameters (p = 0.075-0.974). Training increased strength for all exercises, bone mineral density, and total body mass via increased lean and bone mass (p < 0.001). There was no interaction (p = 0.076 0.994) and RT induced temporal changes in all RBC parameters (p < 0.001-0.003) except RBC corrected for plasma volume changes (time * training interaction; p = 0.001). Training increased hematocrit and lowered mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (p = 0.001-0.041) but did not alter uncorrected RBC, hemoglobin, mean corpuscular volume and RBC distribution width (p = 0.178-0.797). Conclusion: Both C and NC RT induced similar improvements in strength and body composition, and changes in RBC parameters. PMID- 29967585 TI - A Rising Star in Pancreatic Diseases: Pancreatic Stellate Cells. AB - Pancreatic stellate cell (PSC) is a type of pluripotent cell located between pancreatic lobules and the surrounding area of acinars. When activated, PSC can be transformed into myofibroblast-like cell. A number of evidences suggest that activated PSC is the main source of the accumulation of extracellular matrix (ECM) protein under the pathological conditions, which lead to pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. Recent studies have found that PSC also plays an important role in the endocrine cell function, islet fibrosis and diabetes. In order to provide new strategies for the treatment of pancreatic diseases, this paper systematically summarizes the recent researches about the biological behaviors of PSC, including its stem/progenitor cell characteristics, secreted exosomes, cellular senescence, epithelial mesenchymal transformation (EMT), energy metabolism and direct mechanical reprogramming. PMID- 29967586 TI - The Future of Technology in Positive Psychology: Methodological Advances in the Science of Well-Being. AB - Advances in biotechnology and information technology are poised to transform well being research. This article reviews the technologies that we predict will have the most impact on both measurement and intervention in the field of positive psychology over the next decade. These technologies include: psychopharmacology, non-invasive brain stimulation, virtual reality environments, and big-data methods for large-scale multivariate analysis. Some particularly relevant potential costs and benefits to individual and collective well-being are considered for each technology as well as ethical considerations. As these technologies may substantially enhance the capacity of psychologists to intervene on and measure well-being, now is the time to discuss the potential promise and pitfalls of these technologies. PMID- 29967587 TI - Emotional Response and Changes in Heart Rate Variability Following Art-Making With Three Different Art Materials. AB - Art therapy encourages the use of art materials to express feelings and thoughts in a supportive environment. Art materials differ in fluidity and are postulated to thus differentially enhance emotional response (the more fluid the material the more emotion elicited). Yet, to the best of our knowledge, this assumption has not been empirically tested. The current study aimed to examine the emotional and physiological responses to art-making with different art materials. We were particularly interested in vagal activity, indexed by heart rate variability (HRV), because of its association with numerous health related outcomes. In this study, 50 adults (mean age 33 +/- 10.27 years, 52% males) participated in a repeated measures experiment, in which they were requested to draw with three art materials (order randomized) differing in their level of fluidity (pencil, oil pastels, and gouache paint) intermittent with periods of music. We measured the emotional response to art-making with each material using a self-report measure and matrices of HRV using a wearable electrocardiogram device. We calculated two indices of HRV, one indicative of parasympathetic nervous system (PNS) activity, and one indicative of sympathetic nervous system (SNS) activity. Art-making with gouache paint and oil-pastels resulted in improved positive mood, while pencil did not. Art-making explained approximately 35% of the variability in parasympathetic reactivity, which may indicate changes in emotional regulation processes during the art-making task. Yet, fluidity was not sufficient to explain the reaction to art-making. Surprisingly, the largest suppression of PNS and augmentation of the SNS occurred during art-making with oil-pastels and not with Gouache. Moreover, PNS and SNS reactivity to oil-pastels were related to emotional valance, which may point to emotional engagement. We can conclude that art-making with oil-pastels, first created in Japan in 1924 to increase self expression of students, results in a unique emotional and physiological responses. These findings might be explained by the enhanced tactile experience of art-making with oil-pastels along with their relative fluidity, triggering an arousal pattern. Further studies that take the format and presentation of the materials as well as the content of the artwork, into account, are needed. PMID- 29967589 TI - Mapping the Neural Dynamics of Korean-English Bilinguals With Medium Proficiency During Auditory Word Processing. AB - Bilingualism is a worldwide phenomenon and provides an opportunity to understand how the brain represents language processing. Although many studies have investigated the neural mechanism of bilingualism, it still remain unclear how brain systems are involved in the second language processing. Here, we examined the neural dynamics of bilinguals with medium proficiency during auditory word processing. Korean-English (K-E) bilinguals were recruited for the study (L1: Korean and L2: English). They performed a word comprehension task on phonological and semantic aspects by hearing words. We compared their task performance, task induced regional activity, and functional connectivity (FC) between L1 and L2 processing. Brain activation analyses revealed that L2 evoked more widespread and stronger activation in brain regions involved in auditory word processing and the increased regional activity in L2 was prominent during phonological processing. Moreover, L2 evoked up-regulation during semantic processing was associated with L2 proficiency. FC analyses demonstrated that the intra-network connectivity showed stronger in the language network (LN), dorsal attention network (DAN), and default mode network (DMN) in L2 than L1. For the L2 phonological processing, the increased FC within the DAN was positively correlated with individuals' L2 proficiency. Also, L2 semantic processing induced the enhanced internetwork connectivity between the LN and DMN. Our findings suggest that L2 processing in K E bilinguals induces dynamic changes in the brain at a regional and network-level and FC analysis can disentangle the different networks involvement in L2 auditory word processing according to two key features: phonology and semantics. PMID- 29967588 TI - Understanding the Positive Associations of Sleep, Physical Activity, Fruit and Vegetable Intake as Predictors of Quality of Life and Subjective Health Across Age Groups: A Theory Based, Cross-Sectional Web-Based Study. AB - Background: Due to the increase in unhealthy lifestyles and associated health risks, the promotion of healthy lifestyles to improve the prevention of non communicable diseases is imperative. Thus, research aiming to identify strategies to modify health behaviors has been encouraged. Little is known about addressing multiple health behaviors across age groups (i.e., young, middle-aged, and older adults) and the underlying mechanisms. The theoretical framework of this study is Compensatory Carry-Over Action Model which postulates that different health behaviors (i.e., physical activity and fruit and vegetable intake) are interrelated, and they are driven by underlying mechanisms (more details in the main text). Additionally, restful sleep as one of the main indicators of good sleep quality has been suggested as a mechanism that relates to other health behaviors and well-being, and should therefore also be investigated within this study. The present study aims to identify the interrelations of restful sleep, physical activity, fruit and vegetable intake, and their associations with sleep quality as well as overall quality of life and subjective health in different age groups. Methods: A web-based cross-sectional study was conducted in Germany and the Netherlands. 790 participants aged 20-85 years filled in the web-based baseline questionnaire about their restful sleep, physical activity, fruit and vegetable intake, sleep quality, quality of life, and subjective health. Descriptive analysis, multivariate analysis of covariance, path analysis, and multi-group analysis were conducted. Results: Restful sleep, physical activity, and fruit and vegetable intake were associated with increased sleep quality, which in turn was associated with increased overall quality of life and subjective health. The path analysis model fitted the data well, and there were age-group differences regarding multiple health behaviors and sleep quality, quality of life, and subjective health. Compared to young and older adults, middle-aged adults showed poorest sleep quality and overall quality of life and subjective health, which were associated with less engagement in multiple health behaviors. Conclusion: A better understanding of age-group differences in clustering of health behaviors may set the stage for designing effective customized age-specific interventions to improve health and well-being in general and clinical settings. Trial Registration: A clinical trial registration was conducted with ClinicalTrials.gov (NCT01909349) https://clinicaltrials.gov/ct2/show/NCT01909349. PMID- 29967590 TI - Brain-Derived Steroids, Behavior and Endocrine Conflicts Across Life History Stages in Birds: A Perspective. AB - Biological steroids were traditionally thought to be synthesized exclusively by the adrenal glands and gonads. Recent decades have seen the discovery of neurosteroid production that acts locally within the central nervous system to affect physiology and behavior. These actions include, for example, regulation of aggressive behavior, such as territoriality, and locomotor movement associated with migration. Important questions then arose as to how and why neurosteroid production evolved and why similar steroids of peripheral origin do not always fulfill these central roles? Investigations of free-living vertebrates suggest that synthesis and action of bioactive steroids within the brain may have evolved to regulate expression of specific behavior in different life history stages. Synthesis and secretion of these hormones from peripheral glands is broadcast throughout the organism via the blood stream. While widespread, general actions of steroids released into the blood might be relevant for regulation of morphological, physiological, and behavioral traits in one life history stage, such hormonal release may not be appropriate in other stages. Specific and localized production of bioactive steroids in the brain, but not released into the periphery, could be a way to avoid such conflicts. Two examples are highlighted. First, we compare the control of territorial aggression of songbirds in the breeding season under the influence of gonadal steroids with autumnal (non breeding) territoriality regulated by sex steroid production in the brain either from circulating precursors such as dehydroepiandrosterone or local central production of sex steroids de novo from cholesterol. Second, we outline the production of 7alpha-hydroxypregnenolone within the brain that appears to affect locomotor behavior in several contexts. Local production of these steroids in the brain may provide specific regulation of behavioral traits throughout the year and independently of life history stage. PMID- 29967591 TI - Correlation Between Oral Lichen Planus and Thyroid Disease in China: A Case Control Study. AB - Background: A possible relationship between oral lichen planus (OLP) and thyroid disease has received attention in recent years. Objective: This study aimed to evaluate the correlation between OLP and thyroid diseases in Chinese ethnic patients. Methods: 192 OLP patients, 123 patients with oral lichenoid lesions (OLLs), and 162 controls were recruited in this case-control study. All participants received screening for thyroid function and underwent ultrasound. Sex and age of the patients in the three groups were matched. The prevalence of thyroid diseases in the subjects was analyzed. Using logistic regression, the odds ratio (OR) with 95% confidence intervals was appraised for associations between OLP, OLL, and different types of thyroid diseases [Hashimoto's thyroiditis (HT), hypothyroidism, and thyroid nodule]. Results: The prevalence of thyroid diseases in the OLP group (72.4%) and OLL group (68.3%) was higher than the control group (49.4%) with statistical significance. The OR of HT was 3.16 (1.87-5.33) for OLP, 2.09 (1.18-3.70) for OLL, while the OR of thyroid nodule was 2.31 (1.30-4.09) for OLP. Conclusion: Our study suggested a close relationship between OLP/OLL and HT and thyroid nodule in a Chinese population. The possible mechanism behind this association warrants further investigation. PMID- 29967592 TI - Androgen Receptor-CaMKK2 Axis in Prostate Cancer and Bone Microenvironment. AB - The skeletal system is of paramount importance in advanced stage prostate cancer (PCa) as it is the preferred site of metastasis. Complex mechanisms are employed sequentially by PCa cells to home to and colonize the bone. Bone-resident PCa cells then recruit osteoblasts (OBs), osteoclasts (OCs), and macrophages within the niche into entities that promote cancer cell growth and survival. Since PCa is heavily reliant on androgens for growth and survival, androgen-deprivation therapy (ADT) is the standard of care for advanced disease. Although it significantly improves survival rates, ADT detrimentally affects bone health and significantly increases the risk of fractures. Moreover, whereas the majority patients with advanced PCa respond favorably to androgen deprivation, most experience a relapse of the disease to a hormone-refractory form within 1-2 years of ADT. The tumor adapts to surviving under low testosterone conditions by selecting for mutations in the androgen receptor (AR) that constitutively activate it. Thus, AR signaling remains active in PCa cells and aids in its survival under low levels of circulating androgens and additionally allows the cancer cells to manipulate the bone microenvironment to fuel its growth. Hence, AR and its downstream effectors are attractive targets for therapeutic interventions against PCa. Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2), was recently identified as a key downstream target of AR in coordinating PCa cell growth, survival, and migration. Additionally, this multifunctional serine/threonine protein kinase is a critical mediator of bone remodeling and macrophage function, thus emerging as an attractive therapeutic target downstream of AR in controlling metastatic PCa and preventing ADT-induced bone loss. Here, we discuss the role played by AR-CaMKK2 signaling axis in PCa survival, metabolism, cell growth, and migration as well as the cell-intrinsic roles of CaMKK2 in OBs, OCs, and macrophages within the bone microenvironment. PMID- 29967593 TI - Biogenic Synthesis of Novel Functionalized Selenium Nanoparticles by Lactobacillus casei ATCC 393 and Its Protective Effects on Intestinal Barrier Dysfunction Caused by Enterotoxigenic Escherichia coli K88. AB - Selenium (Se) is an essential element for human and animal health. Biogenic selenium nanoparticles (SeNPs) by microorganism possess unique physical and chemical properties and biological activities compared with inorganic Se and organic Se. The study was conducted to investigate the mainly biological activities of SeNPs by Lactobacillus casei ATCC 393 (L. casei 393). The results showed that L. casei 393 transformed sodium selenite to red SeNPs with the size of 50-80 nm, and accumulated them intracellularly. L. casei 393-SeNPs promoted the growth and proliferation of porcine intestinal epithelial cells (IPEC-J2), human colonic epithelial cells (NCM460), and human acute monocytic leukemia cell (THP-1)-derived macrophagocyte. L. casei 393-SeNPs significantly inhibited the growth of human liver tumor cell line-HepG2, and alleviated diquat-induced IPEC J2 oxidative damage. Moreover, in vivo and in vitro experimental results showed that administration with L. casei 393-SeNPs protected against Enterotoxigenic Escherichia coli K88 (ETEC K88)-caused intestinal barrier dysfunction. ETEC K88 infection-associated oxidative stress (glutathione peroxidase activity, total superoxide dismutase activity, total antioxidant capacity, and malondialdehyde) was ameliorated in L. casei 393-SeNPs-treated mice. These findings suggest that L. casei 393-SeNPs with no cytotoxicity play a key role in maintaining intestinal epithelial integrity and intestinal microflora balance in response to oxidative stress and infection. PMID- 29967595 TI - Establishment of an Endogenous Clostridium difficile Rat Infection Model and Evaluation of the Effects of Clostridium butyricum MIYAIRI 588 Probiotic Strain. AB - Clostridium difficile is well known as an agent responsible for pseudomembranous colitis and antibiotic-associated diarrhea. The hamster model utilizing an oral route for infection of C. difficile has been considered to be the standard model for analysis of C. difficile infection (CDI) but this model exhibits differences to human CDI, most notably as most hamsters die without exhibiting diarrhea. Therefore, we attempted to develop a new non-lethal and diarrheal rat CDI model caused by endogenous C. difficile using metronidazole (MNZ) and egg white. In addition, the effects of probiotic strain Clostridium butyricum MIYAIRI 588 (CBM) on CDI were examined using this model. Syrian Golden hamsters received clindamycin phosphate orally at 30 mg/kg on 5 days before challenge with either C. difficile VPI10463 (hypertoxigenic strain) or KY34 (low toxigenic clinical isolate). Mortality and the presence of diarrhea were observed twice a day for the duration of the experiment. Wistar rats received 10% egg white dissolved in drinking water for 1 week ad libitum following intramuscular administration of 200 mg/kg MNZ twice a day for 3 days. Diarrhea score was determined for each day and fecal water content, biotin concentration, and cytotoxin titer in feces were examined. More than 70% of hamsters orally infected with C. difficile died without exhibiting diarrhea regardless of toxigenicity of strain. The rats receiving egg white after MNZ administration developed diarrhea due to overgrowth of endogenous C. difficile. This CDI model is non-lethal and diarrheal, and some rats in this model were spontaneously cured. The incidence of diarrhea was significantly decreased in C. butyricum treated rats. These results indicate that the CDI model using egg white and MNZ has potentially better similarity to human CDI, and implies that treatment with C. butyricum may reduce the risk of CDI. PMID- 29967594 TI - DnaA and LexA Proteins Regulate Transcription of the uvrB Gene in Escherichia coli: The Role of DnaA in the Control of the SOS Regulon. AB - The uvrB gene belongs to the SOS network, encoding a key component of the nucleotide excision repair. The uvrB promoter region contains three identified promoters with four LexA binding sites, one consensus and six potential DnaA binding sites. A more than threefold increase in transcription of the chromosomal uvrB gene is observed in both the DeltalexA DeltasulA cells and dnaAA345S cells, and a fivefold increase in the DeltalexA DeltasulA dnaAA345S cells relative to the wild-type cells. The full activity of the uvrB promoter region requires both the uvrBp1-2 and uvrBp3 promoters and is repressed by both the DnaA and LexA proteins. LexA binds tightly to LexA-box1 at the uvrBp1-2 promoter irrespective of the presence of DnaA and this binding is important for the control of the uvrBp1-2 promoter. DnaA and LexA, however, compete for binding to and regulation of the uvrBp3 promoter in which the DnaA-box6 overlaps with LexA-box4. The transcription control of uvrBp3 largely depends on DnaA-box6. Transcription of other SOS regulon genes, such as recN and dinJ, is also repressed by both DnaA and LexA. Interestingly, the absence of LexA in the presence of the DnaAA345S mutant leads to production of elongated cells with incomplete replication, aberrant nucleoids and slow growth. We propose that DnaA is a modulator for maintenance of genome integrity during the SOS response by limiting the expression of the SOS regulon. PMID- 29967596 TI - Effectiveness of Interventions to Modulate the Rumen Microbiota Composition and Function in Pre-ruminant and Ruminant Lambs. AB - Modulating the assembly of the ruminal microbiota might have practical implications in production. We tested how an early-life dietary intervention in lambs influences the diversity and function of the ruminal microbiota during and after the intervention. Microbiota resilience during a repeated dietary intervention was also tested. The treatment, aiming to mitigate enteric methane emissions, combined garlic essential oil and linseed oil. Fifty-six lambs and their dams were allocated to two groups and treatment (T1) or placebo (C1) was drenched from birth until 10 weeks of life. Lambs were weaned at 8 weeks. From 16 to 20 weeks, lambs in each group were divided in two subgroups that received (T1 T2 and C1-T2) or not (T1-C2 and C1-C2) the same treatment. Measurements were done at 8, 14, and 20 weeks. Average daily gain was similar between groups. Methane production was reduced by treatment at 8 and 20 weeks but at 14 weeks it was similar between C1 and T1. Interestingly, early-life treated lambs displayed a numerical increase (P = 0.12) in methane emissions at 20 weeks compared with non treated lambs. Concentration of VFA was not affected by the intervention at 8 or 14 weeks but a lower concentration was observed in T2 lambs compared with C2 at week 20. Metataxonomics (rRNA gene) revealed differences in archaeal communities between groups of lambs when treatment was applied (weeks 8 and 20); whereas, in accord with methane emissions, these differences disappeared when treatment was discontinued (week 14). Protozoal community structure was not affected by treatment. In contrast, bacterial community structure differed between treated and non-treated lambs during and after the intervention. Rumen and urine LC-MS and NMR metabolomics at week 20 separated C2 from T2 lambs and correlation analysis highlighted interactions between microbes and metabolites, notably that of methylated compounds and Methanomassiliicocceae methanogens. This study demonstrates that a long-term early-life intervention induced modifications in the composition of the rumen bacterial community that persisted after the intervention ceased with little or no effect on archaeal and protozoal communities. However, there was no persistency of the early-life intervention on methanogenesis indicating resilience for this function. PMID- 29967597 TI - Current Status of the Use of Antibiotics and the Antimicrobial Resistance in the Chilean Salmon Farms. AB - The Chilean salmon industry has undergone a rapid development making the country the world's second largest producer of farmed salmon, but this growth has been accompanied by an intensive use of antibiotics. This overuse has become so significant that Chilean salmon aquaculture currently has one of the highest rates of antibiotic consumption per ton of harvested fish in the world. This review has focused on discussing use of antibiotics and current status of scientific knowledge regarding to incidence of antimicrobial resistance and associated genes in the Chilean salmonid farms. Over recent years there has been a consistent increase in the amount of antimicrobials used by Chilean salmonid farms, from 143.2 tons in 2010 to 382.5 tons in 2016. During 2016, Chilean companies utilized approximately 0.53 kg of antibiotics per ton of harvested salmon, 363.4 tons (95%) were used in marine farms, and 19.1 tons (5%) in freshwater farms dedicated to smolt production. Florfenicol and oxytetracycline were by far the most frequently used antibiotics during 2016 (82.5 and 16.8%, respectively), mainly being used to treat Piscirickettsia salmonis, currently considered the main bacterial threat to this industry. However, the increasing development of this industry in Chile, as well as the intensive use of antimicrobials, has not been accompanied by the necessary scientific research needed to understand the impact of the intensive use of antibiotics in this industry. Over the last two decades several studies assessing antimicrobial resistance and the resistome in the freshwater and marine environment impacted by salmon farming have been conducted, but information on the ecological and environmental consequences of antibiotic use in fish farming is still scarce. In addition, studies reporting the antimicrobial susceptibility of bacterial pathogens, mainly P. salmonis, have been developed, but a high number of these studies were aimed at setting their epidemiological cut-off values. In conclusion, further studies are urgently required, mainly focused on understanding the evolution and epidemiology of resistance genes in Chilean salmonid farming, and to investigate the feasibility of a link between these genes among bacteria from salmonid farms and human and fish pathogens. PMID- 29967599 TI - Efficacy and Mechanism of Cinnamon Essential Oil on Inhibition of Colletotrichum acutatum Isolated From 'Hongyang' Kiwifruit. AB - In this study, one of the dominant pathogens, which caused postharvest diseases such as anthracnose, was isolated from decayed 'Hongyang' kiwifruit. It was identified as Colletotrichum acutatum by its morphological characteristics and standard internal transcribed spacer ribosomal DNA sequence. Further, the efficacy and possible mechanism of cinnamon essential oil on inhibition of C. acutatum were investigated. Results showed that C. acutatum was dose-dependently inhibited by cinnamon essential oil. Meanwhile, the mycelial growth and spore germination of C. acutatum were completely inhibited at the concentrations of 0.200 MUL/mL and 0.175 MUL/mL (v/v), respectively. Indeed, both minimal inhibitory and minimum fungicidal concentrations of cinnamon essential oil were measured as 0.200 MUL/mL. Additionally, the possible antifungal mechanism of cinnamon essential oil on C. acutatum was demonstrated. Results showed that the cinnamon essential oil could destroy the cell membrane integrity of C. acutatum, and the structure of cell membrane was changed. Indeed, the cell cytoplasm including soluble protein, sugar, and nucleic acid was released, which significantly changed the extracellular conductivity. Results suggested that the cinnamon essential oil exerted great potential to be used as a natural and efficient preservative for kiwifruit postharvest storage, which were helpful for the better understanding of the efficacy and mechanism of cinnamon essential oil on inhibition of pathogens isolated from decayed 'Hongyang' kiwifruit. PMID- 29967598 TI - Plasmids of Psychrotolerant Polaromonas spp. Isolated From Arctic and Antarctic Glaciers - Diversity and Role in Adaptation to Polar Environments. AB - Cold-active bacteria of the genus Polaromonas (class Betaproteobacteria) are important components of glacial microbiomes. In this study, extrachromosomal replicons of 26 psychrotolerant Polaromonas strains, isolated from Arctic and Antarctic glaciers, were identified, sequenced, and characterized. The plasmidome of these strains consists of 13 replicons, ranging in size from 3,378 to 101,077 bp. In silico sequence analyses identified the conserved backbones of these plasmids, composed of genes required for plasmid replication, stable maintenance, and conjugal transfer. Host range analysis revealed that all of the identified plasmids are narrow-host-range replicons, only able to replicate in bacteria of closely related genera (Polaromonas and Variovorax) of the Comamonadaceae family. Special attention was paid to the identification of plasmid auxiliary genetic information, which may contribute to the adaptation of bacteria to environmental conditions occurring in glaciers. Detailed analysis revealed the presence of genes encoding proteins potentially involved in (i) protection against reactive oxygen species, ultraviolet radiation, and low temperatures; (ii) transport and metabolism of organic compounds; (iii) transport of metal ions; and (iv) resistance to heavy metals. Some of the plasmids also carry genes required for the molecular assembly of iron-sulfur [Fe-S] clusters. Functional analysis of the predicted heavy metal resistance determinants demonstrated that their activity varies, depending on the host strain. This study provides the first molecular insight into the mobile DNA of Polaromonas spp. inhabiting polar glaciers. It has generated valuable data on the structure and properties of a pool of plasmids and highlighted their role in the biology of psychrotolerant Polaromonas strains and their adaptation to the environmental conditions of Arctic and Antarctic glaciers. PMID- 29967600 TI - Disentangling the Drivers of Diversity and Distribution of Fungal Community Composition in Wastewater Treatment Plants Across Spatial Scales. AB - Activated sludge microbial community composition is a key bio-indicator of the sustainability of wastewater treatment systems. Therefore, a thorough understanding of the activated sludge microbial community dynamics is critical for environmental engineers to effectively manage the wastewater treatment plants (WWTPs). However, fungal communities associated with activated sludge have been poorly elucidated. Here, the activated sludge fungal community in 18 geographically distributed WWTPs was determined by using Illumina sequencing. The results showed that differences in activated sludge fungal community composition were observed among all WWTPs and also between oxidation ditch and anaerobic anoxic-aerobic (A/A/O) systems. Ascomycota was the largest phyla, followed by Basidiomycota in all samples. Sporidiobolales and Pezizales were the most abundant order in oxidation ditch and A/A/O systems, respectively. The network analysis indicated cooperative and co-occurrence interactions between fungal taxa in order to accomplish the wastewater treatment process. Hygrocybe sp., Sporobolomyces sp., Rhodotorula sp., Stemphylium sp., Parascedosporium sp., and Cylindrocarpon sp., were found to have statistically significant interactions. Redundancy analysis revealed that temperature, total phosphorus, pH, and ammonia nitrogen were significantly affected the fungal community. This study sheds light on providing the ecological characteristics of activated sludge fungal communities and useful guidance for improving wastewater treatment performance efficiency. PMID- 29967601 TI - Isolation, Diversity, and Antimicrobial and Immunomodulatory Activities of Endophytic Actinobacteria From Tea Cultivars Zijuan and Yunkang-10 (Camellia sinensis var. assamica). AB - Endophytic actinobacteria exist widely in plant tissues and are considered as a potential bioresource library of natural products. Tea plants play important roles in human health and in the lifestyles of Asians, especially the Chinese. However, little is known about the endophytic actinobacteria of tea plants. In this study, 16 actinobacteria of 7 different genera and 28 actinobacteria of 8 genera were isolated and analyzed by 16S rRNA gene sequencing from tea cultivars of Zijuan and Yunkang-10 (Camellia sinensis var. assamica), respectively. The diversity of actinobacteria species from Zijuan were higher in July than December (6 vs. 3 genera), but the diversity of species from Yunkang-10 were higher in December than July (7 vs. 3 genera). No actinobacteria isolates were obtained from any tea cultivar in September. Ten isolates from Yunkang-10 exhibited antimicrobial activity against at least one human pathogenic microorganism (Staphylococcus epidermidis, Shigella flexneri, and Escherichia coli), but none of the isolates from Zijuan exhibited antimicrobial activities. Fourteen strains were further exammined the genes of polyketide synthetase (PKS)-I and PKS-II and non-ribosomal peptide synthetase (NRPS). Brevibacterium sp. YXT131 from Yunkang 10 showed strong inhibitory activity against S. epidermidis, Sh. flexneri, and E. coli, and PKS-I and PKS-II and NRPS genes were obtained from the strain. In in vitro assays, extracts from 14 actinobacteria that were tested for antibiotic biosynthetic genes showed no inhibition of concanavalin A (ConA)-induced murine splenocyte proliferation. In in vivo assays, the crude extract of YXT131 modulated the immune response by decreasing the proinflammatory cytokines interleukin (IL)-12/IL-23 p40 and tumor necrosis factor (TNF)-alpha in the serum of mice. These results confirm that endophytic actinobacteria from tea plants might be an undeveloped bioresource library for active compounds. PMID- 29967602 TI - Follicular CD4 T Helper Cells As a Major HIV Reservoir Compartment: A Molecular Perspective. AB - Effective antiretroviral therapy (ART) has prevented the progression to AIDS and reduced HIV-related morbidities and mortality for the majority of infected individuals. However, a lifelong administration of ART is necessary, placing an inordinate burden on individuals and public health systems. Therefore, discovering therapeutic regimens able to eradicate or functionally cure HIV infection is of great importance. ART interruption leads to viral rebound highlighting the establishment and maintenance of a latent viral reservoir compartment even under long-term treatment. Follicular helper CD4 T cells (TFH) have been reported as a major cell compartment contributing to viral persistence, consequent to their susceptibility to infection and ability to release replication-competent new virions. Here, we discuss the molecular profiles and potential mechanisms that support the role of TFH cells as one of the major HIV reservoirs. PMID- 29967603 TI - Plasminogen Activator Inhibitor 1 for Predicting Sepsis Severity and Mortality Outcomes: A Systematic Review and Meta-Analysis. AB - Objectives: Plasminogen activator inhibitor-1 (PAI-1), a crucial regulator of fibrinolysis, is increased in sepsis, but its values in predicting disease severity or mortality outcomes have been controversial. Therefore, we conducted a systematic review and meta-analysis of its predictive values in sepsis. Methods: PubMed and Embase were searched until August 18, 2017 for studies that evaluated the relationships between PAI-1 levels and disease severity or mortality in sepsis. Results: A total of 112 and 251 entries were retrieved from the databases, of which 18 studies were included in the final meta-analysis. A total of 4,467 patients (36% male, mean age: 62 years, mean follow-up duration: 36 days) were analyzed. PAI-1 levels were significantly higher in non-survivors than survivors [odds ratios (OR): 3.93, 95% confidence interval (CI): 2.31-6.67, P < 0.0001] and in patients with severe sepsis than in those less severe sepsis (OR: 3.26, 95% CI: 1.37-7.75, P = 0.008). Conclusion: PAI-1 is a significant predictor of disease severity and all-cause mortality in sepsis. Although the predictive values of PAI-1 reached statistical significance, the clinical utility of PAI-1 in predicting outcomes will require carefully designed prospective trials. PMID- 29967604 TI - Hsa-miR-99b/let-7e/miR-125a Cluster Regulates Pathogen Recognition Receptor Stimulated Suppressive Antigen-Presenting Cells. AB - Antigen-presenting cells (APCs) regulate the balance of our immune response toward microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently, we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro toward an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GM-CSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell suppressive factors, such as programmed death ligand 1 (PD-L1) and indolamin-2,3-dioxygenase (IDO) through cytokine receptor mediated STAT3 activation. Here, we reveal an essential role for the microRNA (miR, miRNA) hsa-miR-99b/let-7e/miR-125a cluster in stabilizing the suppressive phenotype of R848-stimulated APCs on different levels. On the one hand, the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles pseudokinase 2, thereby enhancing cytokine stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally, hsa-miR-99b/let-7e/miR-125a cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl-tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR-99b/let-7e/miR-125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs. PMID- 29967605 TI - Restoring T Cell Homeostasis After Allogeneic Stem Cell Transplantation; Principal Limitations and Future Challenges. AB - For several leukemia patients, allogeneic stem cell transplantation (allogeneic SCT) is the unique therapeutic modality that could potentially cure their disease. Despite significant progress made in clinical management of allogeneic SCT, acute graft-versus-host disease (aGVHD) and infectious complications remain the second and third cause of death after disease recurrence. Clinical options to restore immunocompetence after allogeneic-SCT are very limited as studies have raised awareness about the safety with regards to graft-versus-host disease (GVHD). Preclinical works are now focusing on strategies to improve thymic functions and to restore the peripheral niche that have been damaged by alloreactive T cells. In this mini review, we will provide a brief overview about the adverse effects of GVHD on the thymus and the peripheral niche and the resulting negative outcome on peripheral T cell homeostasis. Finally, we will discuss the potential relevance of coordinating our studies on thymic rejuvenation and improvement of the peripheral lymphoid niche to achieve optimal T cell regeneration in GVHD patients. PMID- 29967607 TI - Glioblastoma Stem-Like Cells Are More Susceptible Than Differentiated Cells to Natural Killer Cell Lysis Mediated Through Killer Immunoglobulin-Like Receptors Human Leukocyte Antigen Ligand Mismatch and Activation Receptor-Ligand Interactions. AB - Glioblastoma (GBM) is the most aggressive brain malignancy in adults, where survival is approximately 14.6 months. Novel therapies are urgently needed and immunotherapy has hailed a new dawn for treatment of solid tumors. Natural killer (NK) cells may be amenable therapeutic effectors against heterogeneous GBM, since they also do not require co-stimulation and antigen specificity. However, it is unclear how culture media routinely used in pre-clinical studies affect GBM cell responses to NK-mediated cytotoxicity. We hypothesized that the culture medium would affect GBM cell phenotype, proliferation, and responses to NK cytotoxicity. We investigated in paired analyses n = 6 patient-derived primary GBM cells propagated in stem cell or serum-containing medium for morphology, proliferation, as well as susceptibility to NK cytolysis and related this to expression of surface and intracellular lineage markers, as well as ligands for NK cell activating and inhibitory receptors. We genotyped the GBM cells for human leukocyte antigen (HLA) as well as the killer immunoglobulin-like receptors (KIR) of the n = 6 allogeneic NK cells used as effector cells. Culture in serum containing medium induced a switch in GBM cell morphology from suspension neuropsheres to adherent epithelial-mesenchymal-like phenotypes, which was partially reversible. The differentiated cells diminished expression of nestin, CD133 (prominin-1), and A2B5 putative glioma stem-cell markers, attenuated growth, diminished expression of ligands for activating NK cell receptors, while upregulating class I HLA ligands for NK cell inhibitory receptors. When maintained in serum-containing medium, fewer GBM cells expressed intercellular cell adhesion molecule-1 (ICAM-1) and were less susceptible to lysis by NK cells expressing alphaLbeta2 integrin receptor (LFA-1), mediated through combination of inhibitory KIR-HLA ligand mismatch and diminished activation receptor-ligand interactions compared to cells maintained in stem cell media. We conclude that development of preclinical immunotherapy strategies against GBM should not use cells propagated in serum-containing media to avoid misinterpretation of potential therapeutic responses. PMID- 29967606 TI - Inflammation-Induced Adverse Pregnancy and Neonatal Outcomes Can Be Improved by the Immunomodulatory Peptide Exendin-4. AB - Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Inflammation is causally linked to preterm birth; therefore, finding an intervention that dampens maternal and fetal inflammatory responses may provide a new strategy to prevent adverse pregnancy and neonatal outcomes. Using animal models of systemic maternal inflammation [intraperitoneal injection of lipopolysaccharide (LPS)] and fetal inflammation (intra-amniotic administration of LPS), we found that (1) systemic inflammation induced adverse pregnancy and neonatal outcomes by causing a severe maternal cytokine storm and a mild fetal cytokine response; (2) fetal inflammation induced adverse pregnancy and neonatal outcomes by causing a mild maternal cytokine response and a severe fetal cytokine storm; (3) exendin-4 (Ex4) treatment of dams with systemic inflammation or fetal inflammation improved adverse pregnancy outcomes by modestly reducing the rate of preterm birth; (4) Ex4 treatment of dams with systemic, but not local, inflammation considerably improved neonatal outcomes, and such neonates continued to thrive; (5) systemic inflammation facilitated the diffusion of Ex4 through the uterus and the maternal-fetal interface; (6) neonates born to Ex4-treated dams with systemic inflammation displayed a similar cytokine profile to healthy control neonates; and (7) treatment with Ex4 had immunomodulatory effects by inducing an M2 macrophage polarization and increasing anti-inflammatory neutrophils, as well as suppressing the expansion of CD8+ regulatory T cells, in neonates born to dams with systemic inflammation. Collectively, these results provide evidence that dampening maternal systemic inflammation through novel interventions, such as Ex4, can improve the quality of life for neonates born to women with this clinical condition. PMID- 29967608 TI - Metabolic Reprogramming and Longevity of Tissue-Resident Memory T Cells. AB - Tissue-resident memory T cells (TRM) persist in peripheral tissues for long periods of time in the absence of antigenic stimulation. Upon re-encounter with cognate antigen, TRM trigger an immediate immune response at the local tissue microenvironment and provide the first line of host defense. TRM have been reported to play significant roles in host antimicrobial infection, cancer immunotherapy, and pathogenesis of a number of human autoimmune diseases, such as psoriasis, vitiligo, and atopic dermatitis. TRM display a distinct gene transcriptome with unique gene expression profiles related to cellular metabolism that is different from naive T cells (TN), central memory T cells (TCM), and effector memory T cells (TEM). Skin CD8+ TRM upregulate expression of genes associated with lipid uptake and metabolism and utilize mitochondria fatty acid beta-oxidation to support their long-term survival (longevity) and function. In this review, we will summarize the recent progresses in the metabolic programming of TRM and will also discuss the potential to target the unique metabolic pathways of TRM to treat TRM-mediated diseases. PMID- 29967609 TI - A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931. AB - Purpose: A phase 3 randomized study (COG ANBL0032) demonstrated significantly improved outcome by adding immunotherapy with ch14.18 antibody to isotretinoin as post-consolidation therapy for high-risk neuroblastoma (NB). This study, ANBL0931, was designed to collect FDA-required safety/toxicity data to support FDA registration of ch14.18. Experimental design: Newly diagnosed high-risk NB patients who achieved at least a partial response to induction therapy and received myeloablative consolidation with stem cell rescue were enrolled to receive six courses of isotretinoin with five concomitant cycles of ch14.18 combined with GM-CSF or IL2. Ch14.18 infusion time was 10-20 h per dose. Blood was collected for cytokine analysis and its association with toxicities and outcome. Results: Of 105 patients enrolled, five patients developed protocol defined unacceptable toxicities. The most common grade >= 3 non-hematologic toxicities of immunotherapy for cycles 1-5, respectively, were neuropathic pain (41, 28, 22, 31, 24%), hypotension (10, 17, 4, 14, 8%), allergic reactions (ARs) (3, 10, 5, 7, 2%), capillary leak syndrome (1, 4, 0, 2, 0%), and fever (21, 59, 6, 32, 5%). The 3-year event-free survival and overall survival were 67.6 +/- 4.8% and 79.1 +/- 4.2%, respectively. AR during course 1 was associated with elevated serum levels of IL-1Ra and IFNgamma, while severe hypotension during this course was associated with low IL5 and nitrate. Higher pretreatment CXCL9 level was associated with poorer event-free survival (EFS). Conclusion: This study has confirmed the significant, but manageable treatment-related toxicities of this immunotherapy and identified possible cytokine biomarkers associated with select toxicities and outcome. EFS and OS appear similar to that previously reported on ANBL0032. PMID- 29967610 TI - Hodgkin Lymphoma-Derived Extracellular Vesicles Change the Secretome of Fibroblasts Toward a CAF Phenotype. AB - Secretion of extracellular vesicles (EVs) is a ubiquitous mechanism of intercellular communication based on the exchange of effector molecules, such as growth factors, cytokines, and nucleic acids. Recent studies identified tumor derived EVs as central players in tumor progression and the establishment of the tumor microenvironment (TME). However, studies on EVs from classical Hodgkin lymphoma (cHL) are limited. The growth of malignant Hodgkin and Reed-Sternberg (HRS) cells depends on the TME, which is actively shaped by a complex interaction of HRS cells and stromal cells, such as fibroblasts and immune cells. HRS cells secrete cytokines and angiogenic factors thus recruiting and inducing the proliferation of surrounding cells to finally deploy an immunosuppressive TME. In this study, we aimed to investigate the role of tumor cell-derived EVs within this complex scenario. We observed that EVs collected from Hodgkin lymphoma (HL) cells were internalized by fibroblasts and triggered their migration capacity. EV treated fibroblasts were characterized by an inflammatory phenotype and an upregulation of alpha-smooth muscle actin (alpha-SMA), a marker of cancer associated fibroblasts. Analysis of the secretome of EV-treated fibroblast revealed an enhanced release of pro-inflammatory cytokines (e.g., IL-1alpha, IL 6, and TNF-alpha), growth factors (G-CSF and GM-CSF), and pro-angiogenic factors such as VEGF. These soluble factors are known to promote HL progression. In line, ingenuity pathway analysis identified inflammatory pathways, including TNF alpha/NF-kappaB-signaling, as key factors directing the EV-dependent phenotype changes in fibroblasts. Confirming the in vitro data, we demonstrated that EVs promote alpha-SMA expression in fibroblasts and the expression of proangiogenic factors using a xenograft HL model. Collectively, we demonstrate that HL EVs alter the phenotype of fibroblasts to support tumor growth, and thus shed light on the role of EVs for the establishment of the tumor-promoting TME in HL. PMID- 29967612 TI - Lenalidomide and Programmed Death-1 Blockade Synergistically Enhances the Effects of Dendritic Cell Vaccination in a Model of Murine Myeloma. AB - The therapeutic efficacy of dendritic cell (DC)-based immunotherapy may be potentiated in combination with other anticancer therapies that enhance DC function by modulating immune responses and the tumor microenvironment. In this study, we investigated the efficacy of DC vaccination in combination with lenalidomide and programmed death (PD)-1 blockade in a model of murine myeloma. MOPC-315 cell lines were injected subcutaneously to establish myeloma-bearing mice and the following five test groups were established: PBS control, DCs, DCs + lenalidomide, DCs + PD-1 blockade, and DCs + lenalidomide + PD-1 blockade. The combination of DCs plus lenalidomide and PD-1 blockade more potently inhibited tumor growth compared to the other groups. This effect was associated with a reduction in immune suppressor cells (such as myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells) and an increase in immune effector cells [such as CD4+ and CD8+ T cells, natural killer (NK) cells, and M1 macrophages] in the spleen. Functional activities of cytotoxic T lymphocytes and NK cells were also enhanced by the triple combination. Levels of immunosuppressive cytokines, such as TGF-beta and IL-10, were significantly reduced in the tumor microenvironment. These findings suggest that the combination of DCs plus lenalidomide and PD-1 blockade synergistically establishes a robust anti-myeloma immunity through a two-way mechanism, which inhibits immunosuppressive cells while activating effector cells with superior polarization of the Th1/Th2 balance in favor of the tumor immune response. This result should provide an experimental ground for incorporating check point inhibitors to existing immunotherapeutic modalities against multiple myeloma. PMID- 29967611 TI - Activation and Regulation of B Cell Responses by Invariant Natural Killer T Cells. AB - CD1d-restricted invariant natural killer T (iNKT) cells play central roles in the activation and regulation of innate and adaptive immunity. Cytokine-mediated and CD1d-dependent interactions between iNKT cells and myeloid and lymphoid cells enable iNKT cells to contribute to the activation of multiple cell types, with important impacts on host immunity to infection and tumors and on the prevention of autoimmunity. Here, we review the mechanisms by which iNKT cells contribute to B cell maturation, antibody and cytokine production, and antigen presentation. Cognate interactions with B cells contribute to the rapid production of antibodies directed against conserved non-protein antigens resulting in rapid but short-lived innate humoral immunity. iNKT cells can also provide non-cognate help for the generation of antibodies directed against protein antigens, by promoting the activation of follicular helper T cells, resulting in long-lasting adaptive humoral immunity and B cell memory. iNKT cells can also regulate humoral immunity by promoting the development of autoreactive B cells into regulatory B cells. Depletions and functional impairments of iNKT cells are found in patients with infectious, autoimmune and malignant diseases associated with altered B cell function and in murine models of these conditions. The adjuvant and regulatory activities that iNKT cells have for B cells makes them attractive therapeutic targets for these diseases. PMID- 29967613 TI - The Interleukin-20 Cytokines in Intestinal Diseases. AB - Autoimmune/inflammatory intestinal diseases, such as Crohn's disease and ulcerative colitis, infectious gastrointestinal diseases, and gastrointestinal cancers, such as colorectal cancer, are worldwide a significant health problem. Intercellular communication and direct contact with the environment as the microbiota colonizes the gastrointestinal surface facilitates these diseases. Cytokines mediate the intercellular communication to maintain the equilibrium between host and environment and to regulate immune responses. One cytokine family that exchange information between immune cells and epithelial cells is the IL-20 cytokine family which includes the cytokines IL-19, IL-20, IL-22, IL-24, and IL-26. These cytokines share common receptor subunits and signaling pathways. IL-22 is the most intensively studied cytokine within this family in contexts of gastrointestinal disease, but the importance of other family members is more and more appreciated. In this review, the potential function of IL-20 cytokines concerning gastrointestinal conditions is discussed. PMID- 29967614 TI - Multiple Regulatory Levels of Growth Arrest-Specific 6 in Mucosal Immunity Against an Oral Pathogen. AB - Growth arrest-specific 6 (GAS6) expressed by oral epithelial cells and dendritic cells (DCs) was shown to play a critical role in the maintenance of oral mucosal homeostasis. In this study, we demonstrate that the induction of pathogen specific oral adaptive immune responses is abrogated in Gas6-/- mice. Further analysis revealed that GAS6 induces simultaneously both pro- and anti inflammatory regulatory pathways upon infection. On one hand, GAS6 upregulates expression of adhesion molecules on blood vessels, facilitating extravasation of innate inflammatory cells to the oral mucosa. GAS6 also elevates expression of CCL19 and CCL21 chemokines and enhances migration of oral DCs to the lymph nodes. On the other hand, expression of pro-inflammatory molecules in the oral mucosa are downregulated by GAS6. Moreover, GAS6 inhibits DC maturation and reduces antigen presentation to T cells by DCs. These data suggest that GAS6 facilitates bi-directional trans-endothelial migration of inflammatory cells and DCs, whereas inhibiting mucosal activation and T-cell stimulation. Thus, the orchestrated complex activity of GAS6 enables the development of a rapid and yet restrained mucosal immunity to oral pathogens. PMID- 29967615 TI - The Microenvironment in Barrett's Esophagus Tissue Is Characterized by High FOXP3 and RALDH2 Levels. AB - Metaplasia in Barrett's esophagus (BE) is characterized by the transition of squamous epithelium into intestinal-type columnar epithelium. The immune response in BE shares many similarities with the response found in the gut, which is different from the response found in a normal-looking esophagus. Here, we investigated the role of the genes associated with the retinoic acid (RA) pathway in BE, as RA is important not only in shaping the gut's immune response but also in the induction of metaplasia in vitro. mRNA was isolated from esophageal and duodenal biopsies from BE (n = 14), reflux esophagitis patients (n = 9), and controls (n = 12). cDNA was made and qPCR was performed. The expression of RALDH1, CYP26A1, MAdCAM1 were similar for both the BE and duodenum, but different when compared to squamous esophageal epithelium. BE was characterized by a higher expression of RALDH2 and FOXP3, compared to the duodenum. In BE, RALDH2 correlated with expression of the myeloid dendritic cell-specific genes: CD11c and CD1c. Also, RALDH2 expression correlated with RAR-beta and FOXP3. Hierarchical clustering on the expression of multiple relevant genes demonstrated that BE, duodenum, and SQ tissues are clustered as three different groups. The differential expression of RA-specific genes and dendritic cell (DC)-subsets indicates that BE resembles duodenal tissue. The higher expression of RALDH2 and FOXP3 in BE points at a mechanism associated with a possible anti-inflammatory microenvironment. This aberrant immune regulation might contribute to the altered tissue and immune responses found in BE. PMID- 29967616 TI - CD4+ T Cell Fate Decisions Are Stochastic, Precede Cell Division, Depend on GITR Co-Stimulation, and Are Associated With Uropodium Development. AB - During an immune response, naive CD4+ T cells proliferate and generate a range of effector, memory, and regulatory T cell subsets, but how these processes are co ordinated remains unclear. A traditional model suggests that memory cells use mitochondrial respiration and are survivors from a pool of previously proliferating and glycolytic, but short-lived effector cells. A more recent model proposes a binary commitment to either a memory or effector cell lineage during a first, asymmetric cell division, with each lineage able to undergo subsequent proliferation and differentiation. We used improved fixation and staining methods with imaging flow cytometry in an optimized in vitro system that indicates a third model. We found that cell fates result from stochastic decisions that depend on GITR co-stimulation and which take place before any cell division. Effector cell commitment is associated with mTORC2 signaling leading to uropodium development, while developing memory cells lose mitochondria, have a nuclear localization of NFkappaB and depend on TGFbeta for their survival. Induced, T helper subsets and foxp3+ regulatory T cells were found in both the effector and memory cell lineages. This in vitro model of T cell differentiation is well suited to testing how manipulation of cytokine, nutrient, and other components of the microenvironment might be exploited for therapeutic purposes. PMID- 29967617 TI - TNF Receptor Type II as an Emerging Drug Target for the Treatment of Cancer, Autoimmune Diseases, and Graft-Versus-Host Disease: Current Perspectives and In Silico Search for Small Molecule Binders. AB - There is now compelling evidence that TNF receptor type II (TNFR2) is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs), and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF-TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation. PMID- 29967618 TI - The Role of Endothelial Progenitors in the Repair of Vascular Damage in Systemic Sclerosis. AB - Systemic sclerosis (SSc) is a connective tissue disease characterized by a complex pathological process where the main scenario is represented by progressive loss of microvascular bed, with the consequent progressive fibrotic changes in involved organ and tissues. Although most aspects of vascular injury in scleroderma are poorly understood, recent data suggest that the scleroderma impairment of neovascularization could be related to both angiogenesis and vasculogenesis failure. Particularly, compensatory angiogenesis does not occur normally in spite of an important increase in many angiogenic factors either in SSc skin or serum. Besides insufficient angiogenesis, the contribution of defective vasculogenesis to SSc vasculopathy has been extensively studied. Over the last decades, our understanding of the processes responsible for the formation of new vessels after tissue ischemia has increased. In the past, adult neovascularization was thought to depend mainly on angiogenesis (a process by which new vessels are formed by the proliferation and migration of mature endothelial cells). More recently, increased evidence suggests that stem cells mobilize from the bone marrow into the peripheral blood (PB), differentiate in circulating endothelial progenitors (EPCs), and home to site of ischemia to contribute to de novo vessel formation. Significant advances have been made in understanding the biology of EPCs, and molecular mechanisms regulating EPC function. Autologous EPCs now are becoming a novel treatment option for therapeutic vascularization and vascular repair, mainly in ischemic diseases. However, different diseases, such as cardiovascular diseases, diabetes, and peripheral artery ischemia are related to EPC dysfunction. Several studies have shown that EPCs can be detected in the PB of patients with SSc and are impaired in their function. Based on an online literature search (PubMed, EMBASE, and Web of Science, last updated December 2017) using keywords related to "endothelial progenitor cells" and "Systemic Sclerosis," "scleroderma vasculopathy," "angiogenesis," "vasculogenesis," this review gives an overview on the large body of data of current research in this issue, including controversies over the identity and functions of EPCs, their meaning as biomarker of SSc microangiopathy and their clinical potency. PMID- 29967619 TI - Conformational Flexibility in the CD81-Binding Site of the Hepatitis C Virus Glycoprotein E2. AB - Numerous antibodies have been described that potently neutralize a broad range of hepatitis C virus (HCV) isolates and the majority of these antibodies target the binding site for the cellular receptor CD81 within the major HCV glycoprotein E2. A detailed understanding of the major antigenic determinants is crucial for the design of an efficient vaccine that elicits high levels of such antibodies. In the past 6 years, structural studies have shed additional light on the way the host's humoral immune system recognizes neutralization epitopes within the HCV glycoproteins. One of the most striking findings from these studies is that the same segments of the E2 polypeptide chain induce antibodies targeting distinct antigen conformations. This was demonstrated by several crystal structures of identical polypeptide segments bound to different antibodies, highlighting an unanticipated intrinsic structural flexibility that allows binding of antibodies with distinct paratope shapes following an "induced-fit" mechanism. This unprecedented flexibility extends to the entire binding site for the cellular receptor CD81, underlining the importance of dynamic analyses to understand (1) the interplay between HCV and the humoral immune system and (2) the relevance of this structural flexibility for virus entry. This review summarizes the current understanding how neutralizing antibodies target structurally flexible epitopes. We focus on differences and common features of the reported structures and discuss the implications of the observed structural flexibility for the viral replication cycle, the full scope of the interplay between the virus and the host immune system and-most importantly-informed vaccine design. PMID- 29967620 TI - High Plasma Levels of sTNF-R1 and CCL11 Are Related to CD4+ T-Cells Fall in Human Immunodeficiency Virus Elite Controllers With a Sustained Virologic Control. AB - Our aim was to analyze the relationship between plasma inflammatory biomarkers and CD4+ T-cells evolution in human immunodeficiency virus (HIV) elite controllers (HIV-ECs) with a suppressed viremia. We carried out a retrospective study in 30 HIV-ECs classified into two groups: those showing no significant loss of CD4+ T-cells during the observation period (stable CD4+, n = 19) and those showing a significant decrease of CD4+ T-cells (decline CD4+, n = 11). Baseline plasma biomarkers were measured using a multiplex immunoassay: sTNF-R1, TRAIL, sFas (APO), sFasL, TNF-alpha, TNF-beta, IL-8, IL-18, IL-6, IL-10, IP-10, MCP-1, MIP-1alpha, MIP-1beta, RANTES, SDF1alpha, GRO-alpha, and CCL11. Baseline levels of sTNF-R1 and CCL11 and sTNF-R1/TNF-alpha ratio correlated with the slope of CD4+ T-cells (cells/MUl/year) during follow-up [r = -0.370 (p = 0.043), r = 0.314 (p = 0.091), and r = -0.381 (p = 0.038); respectively]. HIV-ECs with declining CD4+ T-cells had higher baseline plasma levels of sTNF-R1 [1,500.7 (555.7; 2,060.7) pg/ml vs. 450.8 (227.9; 1,263.9) pg/ml; p = 0.018] and CCL11 [29.8 (23.5; 54.9) vs. 19.2 (17.8; 29.9) pg/ml; p = 0.041], and sTNF-R1/TNF-alpha ratio [84.7 (33.2; 124.2) vs. 25.9 (16.3; 75.1); p = 0.012] than HIV-1 ECs with stable CD4+ T-cells. The area under the receiver operating characteristic (ROC) curve [area under ROC curve (AUROC)] were 0.758 +/- 0.093 (sTNF-R1), 0.727 +/- 0.096 (CCL11), and 0.777 +/- 0.087 (sTNF-R1/TNF-alpha). The cut-off of 75th percentile (high values) for these biomarkers had 71.4% positive predictive value and 73.9% negative predictive value for anticipating the evolution of CD4+ T cells. In conclusion, the loss of CD4+ T-cells in HIV-ECs was associated with higher levels of two plasma inflammatory biomarkers (sTNF-R1 and CCL11), which were also reasonably accurate for the prediction of the CD4+ T-cells loss. PMID- 29967621 TI - Involvement of MicroRNAs in the Aging-Related Decline of CD28 Expression by Human T Cells. AB - Loss of CD28 is a characteristic feature of T cell aging, but the underlying mechanisms of this loss are elusive. As differential expression of microRNAs (miRNAs) has been described between CD28+ and CD28- T cells, we hypothesized that altered miRNA expression contributes to the age-associated downregulation of CD28. To avoid the confounding effects of age-associated changes in the proportions of T cells at various differentiation stages in vivo, an experimental model system was used to study changes over time in the expression of miRNA associated with the loss of CD28 expression in monoclonal T cell populations at a lower or higher number of population doublings (PDs). This approach allows identification of age-associated miRNA expression changes in a longitudinal model. Results were validated in ex vivo samples. The cumulative number of PDs but not the age of the donor of the T cell clone was correlated with decreased expression of CD28. Principal component analysis of 252 expressed miRNAs showed clustering based on low and high PDs, irrespective of the age of the clone donor. Increased expression of miR-9-5p and miR-34a-5p was seen in clones at higher PDs, and miR-9-5p expression inversely correlated with CD28 expression in ex vivo sorted T-cells from healthy subjects. We then examined the involvement of miR-9 5p, miR-34a-5p, and the members of the miR-23a~24-2 cluster, in which all are predicted to bind to the 3'UTR of CD28, in the IL-15-induced loss of CD28 in T cells. Culture of fresh naive CD28+ T cells in the presence of IL-15 resulted in a gradual loss of CD28 expression, while the expression of miR-9-5p, miR-34a-5p, and members of the miR-23a~24-2 cluster increased. Binding of miR-9-5p, miR-34a 5p, miR-24-3p, and miR-27- 3p to the 3'UTR of CD28 was studied using luciferase reporter constructs. Functional binding to the 3'UTR was shown for miR-24-3p and miR-27a-3p. Our results indicate involvement of defined miRNAs in T cells in relation to specific characteristics of T cell aging, i.e., PD and CD28 expression. PMID- 29967622 TI - Impact of Mothers' Schistosomiasis Status During Gestation on Children's IgG Antibody Responses to Routine Vaccines 2 Years Later and Anti-Schistosome and Anti-Malarial Responses by Neonates in Western Kenya. AB - The potential consequences of parasitic infections on a person's immune responsiveness to unrelated antigens are often conjectured upon in relationship to allergic responses and autoimmune diseases. These considerations sometimes extend to whether parasitic infection of pregnant women can influence the outcomes of responses by their offspring to the immunizations administered during national Expanded Programs of Immunization. To provide additional data to these discussions, we have enrolled 99 close-to-term pregnant women in western Kenya and determined their Schistosoma mansoni and Plasmodium falciparum infection status. At 2 years of age, when the initial immunization schedule was complete, we determined their children's IgG antibody levels to tetanus toxoid, diphtheria toxoid, and measles nucleoprotein (N-protein) antigens using a multiplex assay. We also monitored antibody responses during the children's first 2 years of life to P. falciparum MSP119 (PfMSP119), S. mansoni Soluble Egg Antigen (SEA), Ascaris suum hemoglobin (AsHb), and Strongyloides stercoralis (SsNIE). Mothers' infections with either P. falciparum or S. mansoni had no impact on the level of antibody responses of their offspring or the proportion of offspring that developed protective levels of antibodies to either tetanus or diphtheria antigens at 2 years of age. However, children born of S. mansoni-positive mothers and immunized for measles at 9 months of age had significantly lower levels of anti-measles N-protein antibodies when they were 2 years old (p = 0.007) and a lower proportion of these children (62.5 vs. 90.2%, OR = 0.18, 95% CI = 0.04 0.68, p = 0.011) were considered positive for measles N-protein antibodies. Decreased levels of measles antibodies may render these children more susceptible to measles infection than children whose mothers did not have schistosomiasis. None of the children demonstrated responses to AsHb or SsNIE during the study period. Anti-SEA and anti-PfMSP119 responses suggested that 6 and 70% of the children acquired schistosomes and falciparum malaria, respectively, during the first 2 years of life. PMID- 29967623 TI - Transcriptome Analysis of Bronchoalveolar Lavage Fluid From Children With Mycoplasma pneumoniae Pneumonia Reveals Natural Killer and T Cell-Proliferation Responses. AB - Background: Mycoplasma pneumoniae pneumonia (MPP) is one of the most common community-acquired pneumonia; this study is to explore the immune-pathogenesis of children MPP. Methods: Next-generation transcriptome sequencing was performed on the bronchoalveolar lavage fluid cells from six children with MPP and three children with foreign body aspiration as control. Some of the results had been validated by quantitative real-time PCR in an expanded group of children. Results: Results revealed 810 differentially expressed genes in MPP group comparing to control group, of which 412 genes including RLTPR, CARD11 and RASAL3 were upregulated. These upregulated genes were mainly enriched in mononuclear cell proliferation and signaling biological processes. Kyoto encyclopedia of genes and genomes pathway analysis revealed that hematopoietic cell linage pathway, natural killer cell-mediated cytotoxicity pathway, and T cell receptor signaling pathway were significantly upregulated in MPP children. In addition, significant alternative splicing events were found in GNLY and SLC11A1 genes, which may cause the differential expressions of these genes. Conclusion: Our results suggest that NK and CD8+ T cells are over activated and proliferated in MPP children; the upregulated IFNgamma, PRF1, GZMB, FASL, and GNLY may play important roles in the pathogenesis of children MPP. PMID- 29967624 TI - The Complement System of Agnathans. AB - Agnathans (lamprey and hagfish) are a group of primitive jawless fish. Jawed vertebrates possess adaptive immunity including immunoglobulins, while agnathans lack immunoglobulins but have alternative adaptive immunity in which variable lymphocyte receptors (VLRs) function as antibodies. The complement system consists of many proteins involved in the elimination of pathogens. In mammals, it is activated via the three different pathways, resulting in the generation of C3b followed by the lytic pathway. Complement components including C3, mannose binding lectin (MBL), and MBL-associated serine proteases (MASP) of the lectin pathway and factor B of the alternative pathway have been identified from lamprey and/or hagfish, while lytic pathway components have not been identified. In mammals, C1q binds to IgM/IgG-antigen complexes and activates the classical pathway in association with C1r and C1s. Lamprey also has C1q (LC1q), but its function differs from that of mammalian C1q. LC1q acts as a lectin and activates C3 in association with MASP via the lectin pathway. Furthermore, LC1q may interact with a secreted type of VLR (VLRB) in complex with antigens and mediate activation of C3, potentially via MASP, leading to cytolysis. Cytolysis is mediated by a newly identified serum protein named lamprey pore-forming protein (LPFP). In conclusion, lamprey has a complement activation pathway, which could be regarded as the classical pathway and also has a cytolytic system that is distinct from the mammalian lytic pathway. Thus, it appears that the complement system of agnathans is very unique and may have developed independently from jawed vertebrates. PMID- 29967625 TI - Dominance and Epistasis Interactions Revealed as Important Variants for Leaf Traits of Maize NAM Population. AB - Leaf orientation traits of maize (Zea mays) are complex traits controlling by multiple loci with additive, dominance, epistasis, and environmental interaction effects. In this study, an attempt was made for identifying the causal loci, and estimating the additive, non-additive, environmental specific genetic effects underpinning leaf traits (leaf length, leaf width, and upper leaf angle) of maize NAM population. Leaf traits were analyzed by using full genetic model and additive model of multiple loci. Analysis with full genetic model identified 38~47 highly significant loci (-log10PEW > 5), while estimated total heritability were 64.32~79.06% with large contributions due to dominance and dominance related epistasis effects (16.00~56.91%). Analysis with additive model obtained smaller total heritability ( hT2 ? 18.68~29.56%) and detected fewer loci (30~36) as compared to the full genetic model. There were 12 pleiotropic loci identified for the three leaf traits: eight loci for leaf length and leaf width, and four loci for leaf length and leaf angle. Optimal genotype combinations of superior line (SL) and superior hybrid (SH) were predicted for each of the traits under four different environments based on estimated genotypic effects to facilitate maker assisted selection for the leaf traits. PMID- 29967626 TI - VvBAP1 Is Involved in Cold Tolerance in Vitis vinifera L. AB - The majority of commercial grape cultivars originate from the European grape. While these cultivars have excellent organoleptic qualities, they suffer from a relatively poor tolerance to the cold experienced during winter, resulting in significant damage to grapevines. Thus, low temperature is one of the bottlenecks that restrict the further growth of the grape industry. Research on the mechanism of cold tolerance in grapes is therefore very important. BON association protein 1 (BAP1) is a recently discovered phospholipid-binding protein. In Arabidopsis, the expression of AtBAP1 can be regulated via low temperature; however, the function of BAP1 in the grapevine has not been reported. The VvBAP1 gene was cloned in our previous studies in grapes, and bioinformatics analysis showed that it harbors the conservative calcium-dependent C2 protein domain. However, little is known about its function and underlying mechanism. In this study, cold treatment was applied to the cold-resistant grape varieties 'F-242' and 'Zuoyouhong' as well as to the cold-sensitive grape varieties 'Cabernet Sauvignon' and 'Chardonnay.' The expression level of VvBAP1 in the cold-resistant varieties was significantly higher than in the cold-sensitive varieties, indicating that VvBAP1 could be associated with the cold response processes in the grapevine. Using the cold-resistant grape variety 'F-242' as material, with the 4 degrees C and CaCl2 treatment, the relative expression of VvBAP1 was determined via qRT-PCR. Both low temperature and low-temperature signal Ca2+ induced VvBAP1 expression. In addition, the VvBAP1 gene was cloned and transferred into Arabidopsis to generate VvBAP1 overexpressing plants. Biochemical assays and gene expression analyses were conducted on plants subjected to low temperature treatments (4 and -8 degrees C). The obtained results showed that the activities of superoxide dismutase and peroxidase in these transgenic plants were higher than those in wild type (WT) plants, and that cell membrane permeability and malondialdehyde content were both lower compared to WT plants. Furthermore, the content of soluble sugars and the expression levels of sugar-metabolizing related genes, such as BAM4-7, SS4, and G6PD5, were significantly higher than those of WT plants. Furthermore, the expression of low temperature response signal genes, including CBF1, CBF3, COR15a, COR6.6, COR27, and KIN1, were also enhanced. In summary, these results showed that VvBAP1 could strengthen the cold resistance in the grapevine through adjusting and controlling the sugar content and activating antioxidant enzyme activity. PMID- 29967627 TI - Infection of Powdery Mildew Reduces the Fitness of Grain Aphids (Sitobion avenae) Through Restricted Nutrition and Induced Defense Response in Wheat. AB - In natural ecological systems, plants are often simultaneously attacked by both insects and pathogens, which can affect each other's performance and the interactions can be extended to higher trophic levels, such as parasitoids. The English grain aphid (Sitobion avenae) and powdery mildew (Blumeria graminis f. sp. tritici) are two common antagonists that pose a serious threat to wheat production. Numerous studies have investigated the effect of a single factor (insect or pathogen) on wheat production. However, investigation on the interactions among insect pests, pathogens, and parasitoids within the wheat crop system are rare. Furthermore, the influence of the fungicide, propiconazole, has been found to imitate the natural ecosystem. Therefore, this study investigated the effects of B. graminis on the biological performance of grain aphids and the orientation behavior of its endoparasitic wasp Aphidius gifuensis in the wheat system. Our findings indicated that B. graminis infection suppressed the feeding behavior, adult and nymph weight, and fecundity and prolonged the developmental time of S. avenae. We found that wheat host plants had decreased proportions of essential amino acids and higher content of sucrose following aggravated B. graminis infection. The contents of Pro and Gln increased in the wheat plant tissues after B. graminis infection. In addition, B. graminis infection elicited immune responses in wheat: increase in the expression of defense genes, content of total phenolic compounds, and activity of three related antioxidant enzymes. Moreover, co-infection of B. graminis and S. avenae increased the attraction to A. gifuensis compare to that after infestation with aphids alone. In conclusion, our results indicated that B. graminis infection adversely affected the performance of S. avenae in wheat through restricted nutrition and induced defense response. Furthermore, the preference of parasitoids in such an interactive environment might provide an important basis for pest management control. PMID- 29967628 TI - The Vacuolar Protein Sorting-38 Subunit of the Arabidopsis Phosphatidylinositol-3 Kinase Complex Plays Critical Roles in Autophagy, Endosome Sorting, and Gravitropism. AB - The family of phosphatidylinositols (PtdIns) plays essential roles in membrane identity and intracellular trafficking events. In animals and yeast, PtdIn-3 phosphate, which is particularly important for endosomal sorting, lysosomal/vacuolar transport and autophagy, is assembled by two conserved kinase complexes comprised of the catalytic VACUOLAR PROTEIN SORTING (VPS)-34 subunit, along with VPS15, AUTOPHAGY-RELATED (ATG)-6, and either ATG14 (complex I) or VPS38 (complex II). Here, we describe the Arabidopsis ortholog of VPS38 and show by interaction assays that it assembles into a tetrameric PtdIn-3 kinase complex II. Plants missing VPS38 are viable but have dampened pollen germination and heightened seed abortion, and display a dwarf rosette phenotype, with defects in leaf and vascular development and sucrose sensing. vps38 seeds accumulate irregular protein storage vesicles and suppress processing of storage proteins into their mature forms. Consistent with a role for PtdIn-3-phosphate in autophagy, vps38 mutants are hypersensitive to nitrogen and fixed-carbon starvation and show reduced autophagic transport of cargo into vacuoles. vps38 seedlings also have dampened root gravitropism, which is underpinned by aberrant vectoral auxin transport likely caused by defects in plasma membrane/endosome cycling of the PIN-FORMED family of auxin transporters necessary for asymmetric cell elongation. Collectively, this study places VPS38 and its class-III PtdIn-3 kinase complex at the nexus of numerous endosomal trafficking events important to plant growth and development. PMID- 29967629 TI - Simple Culture Methods and Treatment to Study Hormonal Regulation of Ovule Development. AB - Ovule development is one of the most important processes in the reproductive development of higher plants and is a determinant of seed quality and quantity. Phytohormones play key roles in this process since loss-of-function mutants in hormone signaling show defective ovule phenotypes and reduced fertility. However, it is difficult to distinguish the direct effects of hormones on ovule development because it is parts of reproductive development and the defective phenotypes would be the indirect effects following the defective vegetative development. The treatment of hormones is a direct method to investigate the hormonal regulation of ovule development, but ovule is embedded inside several layers of floral organs, and traditional methods for hormone (or inhibitor) treatments have various limitations. We have developed simple methods to apply treatments to the flowers in a living plant, where an inflorescence apex is immersed into a solution in an inverted tube. We have also developed a specific system to culture and treat excised flowers/pistils. These procedures will be useful for research on the hormonal regulation of ovule development. We provide examples of how treatments with brassinosteroids (BR) and BR biosynthesis inhibitor. We cultured and treated plant materials using our newly developed methods, and observed the morphology of wild type ovules and fluorescence signals in a marker line to monitor the progress of ovule development. The results demonstrate BR promotes ovule development and our new methods are efficient and repeatable. PMID- 29967630 TI - Aluminum-Nitrogen Interactions in the Soil-Plant System. AB - Aluminum (Al) is the most abundant metal in the Earth's crust and is not an essential element for plant growth. In contrast, nitrogen (N) is the most important mineral element for plant growth, but this non-metal is often present at low levels in soils, and plants are often N deficient. Aluminum toxicity is dominant in acid soils, and so plants growing in acid soils have to overcome both Al toxicity and N limitation. Because of low N-use efficiency, large amounts of N fertilizers are applied to crop fields to achieve high yields, leading to soil acidification and potential Al toxicity. Aluminum lowers plant N uptake and N-use efficiency because Al inhibits root growth. Although numerous studies have investigated the interactions between Al and N, a complete review of these studies was lacking. This review describes: (1) the link between plant Al tolerance and ammonium/nitrate (NH4+/NO3-) preference; (2) the effects of NH4+/NO3- and pH on Al toxicity; (3) the effects of Al on soil N transformations; and (4) the effects of Al on NH4+/NO3- uptake and assimilation by plants. Acid soils are characterized chemically by a relatively high ratio of NH4+ to NO3- and high concentrations of toxic Al. Aluminum-tolerant plants generally prefer NH4+ as an N source, while Al-sensitive plants prefer NO3-. Compared with NO3-, NH4+ increases the solubilization of toxic Al into soil solutions, but NH4+ generally alleviates Al phytotoxicity under solution culture because the protons from NH4+ compete with Al3+ for adsorption sites on the root surface. Plant NO3- uptake and nitrate reductase activity are both inhibited by Al, while plant NH4+ uptake is inhibited to a smaller degree than NO3-. Together, the results of numerous studies indicate that there is a synergistic interaction between plant Al tolerance and NH4+ nutrition. This has important implications for the adaptation of plants to acid soils that are dominated chemically by toxic Al as well as NH4+. Finally, we discuss how this knowledge can be used to increase plant Al tolerance and N-use efficiency in acid soils. PMID- 29967631 TI - Using Nectar-Related Traits to Enhance Crop-Pollinator Interactions. AB - Floral nectar and other reward facilitate crop pollination, and in so doing, increase the amount and breadth of food available for humans. Though abundance and diversity of pollinators (particularly bees) have declined over the past several decades, a concomitant increase in reliance on pollinators presents a challenge to food production. Development of crop varieties with specific nectar or nectar-related traits to attract and retain pollinating insects is an appealing strategy to help address needs of agriculture and pollinators for several reasons. First, many crops have specific traits which have been identified to enhance crop-pollinator interactions. Also, an improved understanding of mechanisms that govern nectar-related traits suggest simplified phenotyping and breeding are possible. Finally, the use of nectar-related traits to enhance crop pollination should complement other measures promoting pollinators and will not limit options for crop production or require any changes by growers (other than planting varieties that are more attractive or rewarding to pollinators). In this article, we review the rationale for improving crop pollinator interactions, the effects of specific plant traits on pollinator species, and use cultivated sunflowers as a case study. Recent research in sunflower has (i) associated variation in bee visitation with specific floral traits, (ii) quantified benefits of pollinators to hybrid yields, and (iii) used genetic resources in sunflower and other plants to find markers associated with key floral traits. Forthcoming work to increase pollinator rewards should enable sunflower to act as a model for using nectar-related traits to enhance crop pollinator interactions. PMID- 29967632 TI - Identification of Quantitative Trait Loci for Clubroot Resistance in Brassica oleracea With the Use of Brassica SNP Microarray. AB - Increasing clubroot resistance (CR) of Brassica oleracea by ascertaining the molecular mechanisms has been the key focus in modern B. oleracea breeding. In order to identify the quantitative trait loci (QTLs) associated with CR in B. oleracea, 94 F2 vegetative lines which were developed by tissue culture of selfed seeds from the F1 generation between a clubroot-resistant B. oleracea inbred line and a susceptible line, were identified for disease incidence and six CR associated traits under a lab inoculation by Plasmodiophora brassicae and were genotyped with the 60K Brassica SNP array. Significant correlations were detected for numbers of fibrous roots and P. brassicae content in roots with disease incidence. Nine linkage groups were constructed from 565 bins which covered around 3,000 SNPs, spanning 1,028 cM of the B. oleracea genome with an average distance of 1.82 cM between adjacent bins. A total of 23 QTLs were identified for disease incidence and the other two correlated traits, individually explaining 6.1-17.8% of the phenotypic variation. Several overlaps were detected among traits, including one three-traits-overlapped locus on linkage group C08 and two important overlapped regions between the two CR-associated traits on C06. The QTLs were compared with known CR loci/genes and the novelty of our QTLs was discussed. PMID- 29967633 TI - Cari p 1, a Novel Polygalacturonase Allergen From Papaya Acting as Respiratory and Food Sensitizer. AB - Papaya has been reported to elicit IgE-mediated hypersensitivity via pollen inhalation and fruit consumption. Certain papaya sensitive patients with food allergy were found to experience recurrent respiratory distresses even after quitting the consumption of fruits. This observation prompted us to investigate the allergens commonly present in fruits and pollen grains of papaya. A discovery approach consisting of immunoproteomic detection followed by molecular characterization led to the identification of a novel papaya allergen designated as Cari p 1. This allergen was detected as a 56 kDa IgE-reactive protein from pollen as well as fruit proteome through serological analysis. The protein was identified as an endopolygalacturonase by tandem mass spectrometry. Full length Cari p 1 cDNA was isolated from papaya pollen, cloned in expression vector, and purified as recombinant allergen. The recombinant protein was monomeric and displayed pectinolytic activity. Recombinant Cari p 1 reacted with IgE-antibodies of all the papaya sensitized patient sera. In addition to IgE-reactivity, rCari p 1 displayed allergenic activity by stimulating histamine release from IgE sensitized granulocytes. CD-spectroscopy of rCari p 1 revealed the presence of predominantly beta-sheet characters. The melting curve of the allergen showed partial refolding from a fully denatured state indicating the possible presence of conformational IgE-epitopes characteristic of inhalant allergens in addition to the linear IgE-epitopes of food allergens. The expression of this allergen in papaya fruits was detected by immunoblot with anti-Cari p 1 rabbit IgG and reconfirmed by PCR. In an in vivo mouse model, rCari p 1 exhibited a comparable level of inflammatory responses in the lung and duodenum tissues explaining the dual role of Cari p 1 allergen in respiratory sensitization via pollen inhalation and sensitization of gut mucosa via fruit consumption. Purified rCari p 1 can be used a marker allergen for component-resolved molecular diagnosis. Further immunological studies on Cari p 1 are warranted to design immunotherapeutic vaccine for the clinical management of papaya allergy. PMID- 29967634 TI - The Making of Leaves: How Small RNA Networks Modulate Leaf Development. AB - Leaf development is a sequential process that involves initiation, determination, transition, expansion and maturation. Many coding genes and a few non-coding small RNAs (sRNAs) have been identified as being involved in leaf development. sRNAs and their interactions not only determine gene expression and regulation, but also play critical roles in leaf development through their coordination with other genetic networks and physiological pathways. In this review, we first introduce the biogenesis pathways of sRNAs, mainly microRNAs (miRNAs) and trans acting small interfering RNAs (ta-siRNAs), and then describe the function of miRNA-transcription factors in leaf development, focusing on guidance by interactive sRNA regulatory networks. PMID- 29967635 TI - The Anticancer Activities of Some Nitrogen Donor Ligands Containing bis-Pyrazole, Bipyridine, and Phenanthroline Moiety Using Docking Methods. AB - The anticancer study of nitrogen-chelating ligands can be of tremendous help in choosing ligands for the anticancer metal complexes design especially with ruthenium(II). The inhibitory anticancer activities of some nitrogen-chelating ligands containing bis-pyrazole, bipyridine, and phenanthroline were studied using experimental screening against cancer cell and theoretical docking methods. In vitro anticancer activities showed compound 11 as the most promising inhibitor, and the computational docking further indicates its strong inhibitory activities towards some cancer-related receptors. Among the twenty-one modelled ligands, pyrazole-based compounds 7, 11, and 15 are the most promising inhibitors against the selected receptors followed by 18 and 21 which are derivatives of pyridine and phenanthroline, respectively. The presence of the carboxylic unit in the top five ligands that displayed stronger inhibitory activities against the selected receptors is an indication that the formation of noncovalent interactions such as hydrogen bonding and a strong electron-withdrawing group in these compounds are very important for their receptor interactions. The thermodynamic properties, the polarizabilities, and the LUMO energy of the compounds are in the same patterns as the observed inhibitory activities. PMID- 29967636 TI - Overweight or Obese Individuals at Eighteen Years of Age Develop Pancreatic Adenocarcinoma at a Significantly Earlier Age. AB - Background: Adolescent obesity is a national epidemic that recently has been shown to increase risk for pancreatic adenocarcinoma (PC) and is associated with an earlier age of PC onset. We hypothesized that PC patients who are overweight or obese at age 18 would have an earlier age of PC onset. Methods: Retrospective review of 531 patients in our PC registry was completed. Self-reported weight at age 18 and maximum lifetime weight were used to calculate body mass index (BMI) at age 18 (BMI-18) and maximum lifetime BMI. Results: Complete BMI and baseline covariate data was available in 319 PC patients. Mean age (in years) of PC diagnosis for patients whose BMI-18 was overweight (64.0) or obese (59.9) was significantly different when compared to patients with a normal BMI-18 (66.7). No significant difference was observed in the mean age of PC diagnosis in those patients who maintained a normal BMI-18 when compared to those patients who subsequently became overweight or obese (67.0 versus 66.6; p = 0.65). Conclusions: An elevated BMI at age 18 is associated with an earlier age of PC onset and should be factored into determining the optimal age of beginning screening for patients at high risk for PC. PMID- 29967637 TI - The Combination of Seven Preoperative Markers for Predicting Patients with Gastric Cancer to Be Either Stage IV or Non-Stage IV. AB - To assess whether preoperative markers could predict the stage of patients with gastric cancer. We analyzed retrospectively the preoperative indicators between stage IV and non-stage IV gastric cancer at the Gastrointestinal Surgery of Nanjing Drum Tower Hospital. A total of 500 patients with gastric cancer were screened. Of all the variables, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, carbohydrate antigen (CA) 199, carbohydrate antigen (CA) 724, carbohydrate antigen (CA) 242, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), blood platelet count (PLT), white blood cell (WBC) count, C-reactive protein (CRP), neutrophil count (NC), lymphocyte count (LC), neutrophil-lymphocyte ratio (NLR), hemoglobin (HB), aspartate aminotransferase (AST), and ascites were found to have statistical differences between the two groups. Then, Stepwise Discriminant Analysis was conducted to establish a prediction model including 7 indexes (CA724, CA242, TT, PLT, CRP, AST, and ascites). According to the model, 90.6% of original grouped cases were correctly classified and 90.6% of cross-validated grouped cases were correctly classified. We built a discriminant including CA724, CA242, TT, PLT, CRP, AST, and ascites for predicting patients with gastric cancer to be either stage IV or non-stage IV. According to this discriminant, 90.6% of patients could be correctly predicted. PMID- 29967638 TI - Effect of Esophageal Endoscopic Submucosal Dissection on Motility and Symptoms: A Prospective Study. AB - Background: Endoscopic submucosal dissection (ESD) of esophageal tumors can cause stenosis, yet the effect of esophageal ESD on motility remains unclarified. This study aimed to compare esophageal motility and symptoms, before and after ESD, using high-resolution manometry (HRM) and symptom scoring. Methods: Twenty-eight patients with 35 cT1a cancers were prospectively enrolled between December 2014 and February 2016. Pre- and post-ESD symptom score and HRM were recorded. Based on circumferential resection (CR), patients were divided into group A (n = 17, <2/3 CR) or B (n = 11, 2/3 CR or greater). HRM parameters evaluated were distal contractile integral (DCI), contractile front velocity (CFV), intrabolus pressure, integrated relaxation pressure, distal latency, and peristaltic breaks. Results: Symptom scores worsened after ESD in 8/11 patients in group B, and 0/17 patients in group A. There was no significant difference in any HRM parameter after ESD in the whole study group but mean DCI tended to increase (p = 0.07). In group B, DCI increased significantly after ESD (p = 0.04), and CFV tended to decrease after ESD (p = 0.08). Conclusions: DCI tended to increase after esophageal ESD. ESD affected the symptom score and esophageal motility in cases with 2/3 CR or greater. This trial is registered with UMIN000015829. PMID- 29967639 TI - Cross-Talk between Gut Microbiota and Heart via the Routes of Metabolite and Immunity. AB - Considering the prevalence of cardiovascular disease (CVD), significant interest has been focused on the gut microbiota-heart interaction because the gut microbiota has been recognized as a barometer of human health. Dysbiosis, characterized by changes in the gut microbiota in CVD, has been reported in cardiovascular pathologies, such as atherosclerosis, hypertension, and heart failure. Conversely, gut microbiota-derived metabolites, such as trimethylamine/trimethylamine N-oxide (TMA/TMAO), can impact host physiology. Further, bacterial dysbiosis can disturb gut immunity, which increases the risk of acute arterial events. Moreover, studies of germ-free mice have provided evidence that microbiota diversity and the presence of a specific microbe in the gut can affect immune cells in hosts. Therefore, the changes in the composition of the gut microbiota can affect host metabolism and immunity. Importantly, these effects are not only confined to the gut but also spreaded to distal organs. The purpose of the current review is to highlight the complex interplay between the microbiota and CVD via TMAO and different immune cells and discuss the roles of probiotics and nutrition interventions in modulating the intestinal microbiota as novel therapeutic targets of CVD. PMID- 29967640 TI - Altered Intestinal Microbiota with Increased Abundance of Prevotella Is Associated with High Risk of Diarrhea-Predominant Irritable Bowel Syndrome. AB - Alterations in gut microbiota are postulated to be an etiologic factor in the pathogenesis of irritable bowel syndrome (IBS). To determine whether IBS patients in China exhibited differences in their gut microbial composition, fecal samples were collected from diarrhea-predominant IBS (IBS-D) and healthy controls and evaluated by 16S ribosomal RNA gene sequence and quantitative real-time PCR. A mouse model of postinfectious IBS (PI-IBS) was established to determine whether the altered gut microbiota was associated with increased visceral hypersensitivity. The results indicated that there were significant differences in the bacterial community profiles between IBS-D patients and healthy controls. Prevotella was more abundant in fecal samples from IBS-D patients compared with healthy controls (p < 0.05). Meanwhile, there were significant reductions in the quantity of Bacteroides, Bifidobacteria, and Lactobacillus in IBS-D patients compared with healthy controls (p < 0.05). Animal models similarly showed an increased abundance of Prevotella in fecal samples compared with control mice (p < 0.05). Finally, after the PI-IBS mice were cohoused with control mice, both the relative abundance of Prevotella and visceral hypersensitivity of PI-IBS mice were decreased. In conclusion, the altered intestinal microbiota is associated with increased visceral hypersensitivity and enterotype enriched with Prevotella may be positively associated with high risk of IBS-D. PMID- 29967642 TI - Application of Diffusion Kurtosis Imaging and Histogram Analysis for Assessing Preoperative Stages of Rectal Cancer. AB - Objective: To explore the value of diffusion kurtosis imaging (DKI) and histogram analysis for assessing preoperative stages and heterogeneity in rectal cancer. Methods: Fifty patients with pathologically confirmed rectal adenocarcinoma were enrolled. The value of DKI parameters and histogram metrics for assessing the preoperative stages and heterogeneity in rectal cancer was analyzed retrospectively. Results: (1) ADC-10th percentile and ADC-25th percentile were significantly higher in T1-2 than in the T3-4 rectal cancer (the ADC values were 0.65 +/- 0.08 * 10-3 mm2/s versus 0.58 +/- 0.11 * 10-3 mm2/s and 0.73 +/- 0.11 * 10-3 mm2/s versus 0.65 +/- 0.11 * 10-3 mm2/s; p values were 0.035 and 0.024, resp.). (2) D-10th percentile and D-25th percentile were also significantly higher in T1-2 than in T3-4 rectal cancer (the D values were 0.96 +/- 0.19 * 10-3 mm2/s versus 0.84 +/- 0.16 * 10-3 mm2/s and 1.15 +/- 0.27 * 10-3 mm2/s versus 0.99 +/- 0.18 * 10-3 mm2/s; p values were 0.017 and 0.044, resp.). (3) K value and its histogram metrics showed no statistically significant difference between T1-2 and T3-4. (4) D-10th had the largest area under the curve (AUC 0.799) among all the parameters; the sensitivity and specificity were 84.2 and 61.3%, respectively. (5) DKI combined with traditional MRI had an accuracy of 68% while assessing the lymph node of rectal cancer. Conclusion: DKI parameters and histogram metrics are rather valuable in assessing the preoperative stages of rectal cancer; D-10th percentile exhibits the highest diagnostic efficiency. PMID- 29967643 TI - The Common Clinical Presentation of Patients Selected for Septoplasty in Northern Saudi Arabia. AB - Background: Nasal septal deviation (NSD) plays a critical role in nasal obstruction symptoms, aesthetic look of the nose, increased nasal resistance, and occasionally snoring. Septoplasty is the most common method for correction of deviated nasal septum (DNS). Therefore, the aim of the present study was to assess the association between initial clinical presentations of patients selected for septoplasty and demographical characteristics in Northern Saudi Arabia. Methodology: Archives related to all patients selected for septoplasty between 2012 and 2017 were retrieved from ENT Department at King Khalid Hospital in Hail, Northern Saudi Arabia. Only adults over 18 years of age were included in this study. Results: With regard to the clinical presentations, almost all patients presented with variable degrees of nasal congestions, nasal blockages, breathing troubles, sleeping troubles, and exercise problems. Conclusion: Nasal obstruction is prevalent in Northern Saudi Arabia with peaks being in the years 2016 and 2014 with the most etiological factor being DNS. PMID- 29967641 TI - Prognostic Value of MUC2 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis. AB - Background: The reliability of MUC2 as a prognostic marker in colorectal cancer (CRC) is controversial. This study evaluated the association between MUC2 expression levels in CRC tissues and prognosis. Methods: The PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine disc (CBMdisc), Wanfang Database, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies exploring the relationship between MUC2 expression in CRC tissues and overall survival (OS). Pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs) were used to evaluate the associations between MUC2 expression levels and prognosis and MUC2 expression levels and CRC clinicopathological characteristics, respectively. Results: The meta-analysis included 11 studies (2619 patients). Low MUC2 expression level was significantly associated with poor OS (HR, 1.67; 95% CI, 1.43-1.94; P < 0.00001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR, 1.60; 95% CI, 1.21-2.12; P = 0.001) in patients with CRC. Low MUC2 expression level was associated with advanced TNM stage (RR, 1.42; 95% CI, 1.26-1.60; P < 0.00001), lymph node metastasis (RR, 1.41; 95% CI, 1.25-1.60; P < 0.00001), lymphatic invasion (RR,1.64; 95% CI, 1.26-2.12; P = 0.0002), rectal tumor site (RR, 1.26; 95% CI, 1.09-1.46; P = 0.001), and large tumor size (RR,1.32; 95% CI, 1.02-1.70; P = 0.03). There were no associations between low MUC2 expression level and gender, histological grade, depth of invasion, and distant metastasis. Conclusion: The low levels of MUC2 in CRC tissues are poor prognostic factor independent of stage or other well-recognized markers of later-stage disease. Large well-designed cohort studies are required to validate MUC2 as a biomarker for poor prognosis in CRC. PMID- 29967644 TI - Influence of microbiome and diet on immune responses in food allergy models. AB - The intestinal immune system is intimately connected with the vast array of microbes present within the gut and the diversity of food components that are consumed daily. The discovery of novel molecular mechanisms, which mediate host microbe-nutrient communication, have highlighted the important roles played by microbes and dietary factors in influencing mucosal inflammatory and allergic responses. In this review, we summarize the recent important findings in this field, which are important for food allergy and particularly relevant to animal models of food allergy. PMID- 29967645 TI - Can a Traditional Korean Manual Therapy Be a Complementary and Alternative Strategy for Cervicogenic Dizziness? A Study Protocol for a Randomized Controlled Trial. AB - Cervicogenic dizziness is dizziness triggered by movement or positioning of the cervical spine and is often accompanied by neck pain or stiffness. This is a prospective, pragmatic, assessor-blind, randomized controlled trial aimed at testing the efficacy and safety of adjuvant Chuna Manual Therapy (CMT) in patients with cervicogenic dizziness under usual care treatments. Fifty patients with cervicogenic dizziness will be randomly allocated to CMT or usual care (UC) groups in a 1 : 1 ratio. Extensive screening procedures, including examinations for central nervous system problems and nystagmus, will be applied to exclude other dizziness-inducing disorders. The eligible participants will receive 12 sessions of CMT plus UC or only UC over 6 weeks. CMT includes mandatory and discretionary techniques, whereas UC includes electrotherapy, thermotherapy, and patient education. The efficacy will be evaluated primarily as Dizziness Handicap Inventory score. The severity and frequency of dizziness, the level of neck pain or stiffness, and the cervical range of motion will also be evaluated. Safety will be assessed by adverse events. The data will be statistically analyzed at p < 0.05. Trial Registration. This trial was registered with Clinical Research Information Service (CRIS) in Korea, KCT0002565, on 29 November 2017, https://cris.nih.go.kr/cris/search/search_result_st01_kren.jsp?seq=9610<ype=&rt pe=. PMID- 29967646 TI - In Vitro and Ex Vivo Chemopreventive Action of Mauritia flexuosa Products. AB - Mauritia flexuosa (Arecaceae), known as "Buriti," is a Brazilian palm tree with high economic potential for local communities. Herein, we investigated the phytochemistry profile and antioxidant potential of M. flexuosa fruits and determined the bioaccessibility of phenolic compounds. Peels revealed upper values for phenols, flavonoids, carotenoids, tannins, and ascorbic acid when compared to the pulps and endocarps. All samples showed capacity to scavenger free radicals (0.5, 1.0, 2.0, 4.0, and 8.0 mg/mL) but peels presented higher scavenger action in all methods explored. Phenolic compounds identified by HPLC displayed reduced bioaccessibility after in vitro simulated gastrointestinal digestion for pulp (38.7%), peel (18.7%), and endocarp (22.3%) extracts (P < 0.05). Buriti fruits also protected rat blood cells against lysis induced by peroxyl radicals. We demonstrated the promising chemopreventive potentialities of M. flexuosa fruits and their by-products and peels with higher quantities of bioactive compounds and phenolic substances before and after in vitro bioaccessibility investigation. In Brazil, these parts are discarded or underused, mainly as feed for ruminant animals. Consequently, it is extremely important to explore nutritional characteristics of these by-products for human/livestock foods and to install biofriendly techniques and sustainable biotechnology handling of natural resources. PMID- 29967647 TI - Observational Study of the Association between TCM Zheng and Types of Coronary Artery Stenosis: Protocol of a Multicenter Case Series Study. AB - Background: Coronary artery stenosis is the major pathological change of coronary heart disease (CHD). Within the framework of traditional Chinese medicine (TCM) theory, some kinds of TCM Zheng could exist in patients with CHD; accordingly, TCM practitioners could provide appropriate TCM therapy. However, little is known about the association between TCM Zheng and types of coronary artery stenosis. Such knowledge could help improve the accuracy and effectiveness of efforts to combine CHD treatment with TCM therapy. Therefore, the aim of this study is to determine the association between TCM Zheng and types of coronary artery stenosis. Methods and Design: This is a multicenter, large sample, case series study in 4 tertiary A hospitals from 3 provinces in China. A total of 3,000 eligible patients diagnosed with atherosclerosis or CHD and selected to undergo coronary angiography (CAG) will be enrolled in this study. We will use electronic case report forms (eCRF) to collect information, including baseline characteristics, TCM symptoms, CAG results, and GRACE scores according to standard operating procedures (SOP). Data will be analyzed by SPSS 20.0. Ethics: This study is approved by the Ethics Committee of Guang'anmen Hospital of the China Academy of Chinese Medical Sciences (no. 2017-058-KY-01) and is registered with chictr.org (registration number ChiCTR-ROC-17013221). PMID- 29967648 TI - Anti-Inflammatory Effect of ETAS(r)50 by Inhibiting Nuclear Factor-kappaB p65 Nuclear Import in Ultraviolet-B-Irradiated Normal Human Dermal Fibroblasts. AB - Ultraviolet (UV) irradiation induces proinflammatory responses in skin cells, including dermal fibroblasts, accelerating premature skin aging (photoaging). ETAS 50, a standardized extract from the Asparagus officinalis stem, is a novel and unique functional food that suppresses proinflammatory responses of hydrogen peroxide-stimulated skin fibroblasts and interleukin- (IL-) 1beta-stimulated hepatocytes. To elucidate its antiphotoaging potencies, we examined whether ETAS 50 treatment after UV-B irradiation attenuates proinflammatory responses of normal human dermal fibroblasts (NHDFs). UV-B-irradiated NHDFs showed reduced levels of the cytosolic inhibitor of nuclear factor-kappaB alpha (IkappaBalpha) protein and increased levels of nuclear p65 protein. The nuclear factor-kappaB nuclear translocation inhibitor JSH-23 abolished UV-B irradiation-induced IL 1beta mRNA expression, indicating that p65 regulates transcriptional induction. ETAS 50 also markedly suppressed UV-B irradiation-induced increases in IL-1beta mRNA levels. Immunofluorescence analysis revealed that ETAS 50 retained p65 in the cytosol after UV-B irradiation. Western blotting also showed that ETAS 50 suppressed the UV-B irradiation-induced increases in nuclear p65 protein. Moreover, ETAS 50 clearly suppressed UV-B irradiation-induced distribution of importin-alpha protein levels in the nucleus without recovering cytosolic IkappaBalpha protein levels. These results suggest that ETAS 50 exerts anti inflammatory effects on UV-B-irradiated NHDFs by suppressing the nuclear import machinery of p65. Therefore, ETAS 50 may prevent photoaging by suppressing UV irradiation-induced proinflammatory responses of dermal fibroblasts. PMID- 29967649 TI - Functional Improvements in Parkinson's Disease Following a Randomized Trial of Yoga. AB - Individuals with Parkinson's Disease (PD) experience significant limitations in motor function, functional gait, postural stability, and balance. These limitations often lead to higher incidences of falls, which have significant complications for individuals with PD. Yoga may improve these functional deficits in individuals with PD. The objective of this study was to determine changes in motor function, functional gait, postural stability, and balance control for community dwelling individuals with PD. This randomized, wait-list controlled pilot study examined the influence of an 8-week yoga intervention for people with PD who met the following inclusion criteria: endorsing a fear of falling, being able to speak English, scoring 4/6 on the minimental state exam, and being willing to attend the intervention twice weekly for 8-weeks. Participants in the yoga group (n=15) experienced improvements in motor function, postural stability, functional gait, and freezing gait, as well as reductions in fall risk. Participants in the wait-list control (n=12) also significantly improved in postural stability, although their fall risk was not reduced. Individuals in the yoga group significantly reduced their fall risk. An 8-week yoga intervention may reduce fall risk and improve postural stability, and functional and freezing gait in individuals with PD. This clinical trial is registered as protocol record Pro00041068 in clinicaltrials.gov. PMID- 29967650 TI - Molecular evolution methods to study HIV-1 epidemics. AB - Nucleotide sequences of HIV isolates are obtained routinely to evaluate the presence of resistance mutations to antiretroviral drugs. But, beyond their clinical use, these and other viral sequences include a wealth of information that can be used to better understand and characterize the epidemiology of HIV in relevant populations. In this review, we provide a brief overview of the main methods used to analyze HIV sequences, the data bases where reference sequences can be obtained, and some caveats about the possible applications for public health of these analyses, along with some considerations about their limitations and correct usage to derive robust and reliable conclusions. PMID- 29967652 TI - A New Skeleton Model and the Motion Rhythm Analysis for Human Shoulder Complex Oriented to Rehabilitation Robotics. AB - Rehabilitation robotics has become a widely accepted method to deal with the training of people with motor dysfunction. In robotics medium training, shoulder repeated exercise training has been proven beneficial for improving motion ability of human limbs. An important and difficult paradigm for motor function rehabilitation training is the movement rhythm on the shoulder, which is not a single joint but complex and ingenious combination of bones, muscles, ligaments, and tendons. The most robots for rehabilitation were designed previously considering simplified biomechanical models only, which led to misalignment between robots and human shoulder. Current biomechanical models were merely developed for rehabilitation robotics design. This paper proposes a new hybrid spatial model based on joint geometry constraints to describe the movement of the shoulder skeletal system and establish the position analysis equation of the model by a homogeneous coordinate transformation matrix and vector method, which can be used to calculate the kinematics of human-robot integrated system. The shoulder rhythm, the most remarkable particularity in shoulder complex kinematics and important reference for shoulder training strategy using robotics, is described and analyzed via the proposed skeleton model by three independent variables in this paper. This method greatly simplifies the complexity of the shoulder movement description and provides an important reference for the training strategy making of upper limb rehabilitation via robotics. PMID- 29967651 TI - Latent versus productive infection: the alpha herpesvirus switch. AB - Alpha herpesviruses are common pathogens of mammals. They establish a productive infection in many cell types, but a life-long latent infection occurs in PNS neurons. A vast majority of the human population has latent HSV-1 infections. Currently, there is no cure to clear latent infections. Even though HSV-1 is among the best studied viral pathogens, regulation of latency and reactivation is not well understood due to several challenges including a lack of animal models that precisely recapitulate latency/reactivation episodes; a difficulty in modeling in vitro latency; and a limited understanding of neuronal biology. In this review, we discuss insights gained from in vitro latency models with a focus on the neuronal and viral factors that determine the mode of infection. PMID- 29967653 TI - Using a Module-Based Analysis Framework for Investigating Muscle Coordination during Walking in Individuals Poststroke: A Literature Review and Synthesis. AB - Factorization methods quantitatively group electromyographic signals from several muscles during dynamic tasks into multiple modules where each module consists of muscles that are coactive during the movement. Module-based analyses may provide an analytical framework for testing theories of poststroke motor control recovery based on one's ability to move independently from mass flexion-extension muscle group coactivation. Such a framework may be useful for understanding the causality between underlying neural impairments, biomechanical function, and walking performance in individuals poststroke. Our aim is to synthesize current evidence regarding the relationships between modules, gait mechanics, and rehabilitation in individuals poststroke. We synthesized eleven studies that performed module-based analyses during walking tasks for individuals poststroke. Modules were primarily identified by nonnegative matrix factorization, and fewer modules correlated with poor walking performance on biomechanical and clinical measures. Fewer modules indicated reduced ability to control individual muscle timing during paretic leg stance. There was evidence that rehabilitation can lead to the use of more and/or better-timed modules. While future work will need to establish the ability of modules to identify impairment mechanisms, they appear to offer a promising analytical approach for evaluating motor control. PMID- 29967655 TI - Vision System-Based Design and Assessment of a Novel Shoulder Joint Mechanism for an Enhanced Workspace Upper Limb Exoskeleton. AB - Exoskeletons arise as the common ground between robotics and biomechanics, where rehabilitation is the main field in which these two disciplines find cohesion. One of the most relevant challenges in upper limb exoskeleton design relies in the high complexity of the human shoulder, where current devices implement elaborate systems only to emulate the drifting center of rotation of the shoulder joint. This paper proposes the use of 3D scanning vision technologies to ease the design process and its implementation on a variety of subjects, while a motion tracking system based on vision technologies is applied to assess the exoskeleton reachable workspace compared with an asymptomatic subject. Furthermore, the anatomic fitting index is proposed, which compares the anatomic workspace of the user with the exoskeleton workspace and provides insight into its features. This work proposes an exoskeleton architecture that considers the clavicle motion over the coronal plane whose workspace is determined by substituting the direct kinematics model with the dimensional parameters of the user. Simulations and numerical examples are used to validate the analytical results and to conciliate the experimental results provided by the vision tracking system. PMID- 29967654 TI - Effect of Task Failure on Intermuscular Coherence Measures in Synergistic Muscles. AB - The term "task failure" describes the point when a person is not able to maintain the level of force required by a task. As task failure approaches, the corticospinal command to the muscles increases to maintain the required level of force in the face of a decreased mechanical efficacy. Nevertheless, most motor tasks require the synergistic recruitment of several muscles. How this recruitment is affected by approaching task failure is still not clear. The increase in the corticospinal drive could be due to an increase in synergistic recruitment or to overlapping commands sent to the muscles individually. Herein, we investigated these possibilities by combining intermuscular coherence and synergy analysis on signals recorded from three muscles of the quadriceps during dynamic leg extension tasks. We employed muscle synergy analysis to investigate changes in the coactivation of the muscles. Three different measures of coherence were used. Pooled coherence was used to estimate the command synchronous to all three muscles, pairwise coherence the command shared across muscle pairs and residual coherence the command peculiar to each couple of muscles. Our analysis highlights an overall decrease in synergistic command at task failure and an intensification of the contribution of the nonsynergistic shared command. PMID- 29967656 TI - Assessing User Transparency with Muscle Synergies during Exoskeleton-Assisted Movements: A Pilot Study on the LIGHTarm Device for Neurorehabilitation. AB - Exoskeleton devices for upper limb neurorehabilitation are one of the most exploited solutions for the recovery of lost motor functions. By providing weight support, passively compensated exoskeletons allow patients to experience upper limb training. Transparency is a desirable feature of exoskeletons that describes how the device alters free movements or interferes with spontaneous muscle patterns. A pilot study on healthy subjects was conducted to evaluate the feasibility of assessing transparency in the framework of muscle synergies. For such purpose, the LIGHTarm exoskeleton prototype was used. LIGHTarm provides gravity support to the upper limb during the execution of movements in the tridimensional workspace. Surface electromyography was acquired during the execution of three daily life movements (reaching, hand-to-mouth, and hand-to nape) in three different conditions: free movement, exoskeleton-assisted (without gravity compensation), and exoskeleton-assisted (with gravity compensation) on healthy people. Preliminary results suggest that the muscle synergy framework may provide valuable assessment of user transparency and weight support features of devices aimed at rehabilitation. PMID- 29967657 TI - Numerical Analysis of Occupant Head Injuries in Impacts with Dump Truck Panel. AB - The human head will inevitably impact on the panel causing injury due to the inertia during dump truck collisions or emergency braking. Therefore, this paper aims to analyze the effects of panel design parameters on occupant head injuries via simulations using finite element (FE) models of a human head and a dump truck cockpit. Special focus was applied to understand how panel type (soft and hard), elastic modulus of the filling and frame, and the fixing distance for the soft panel could affect head injuries in head-to-panel impacts under different impact conditions (impact speed and location). Simulation results show that a soft panel is beneficial for head protection in impacts with the truck instrument panel, and a soft panel using a lower filling elastic modulus, lower frame elastic modulus, and longer fixing distance is helpful for head injury prevention. The findings also indicate that the head peak acceleration and maximum skull stress are more sensitive to the fixing distance and elastic modulus of frame than elastic modulus of the filling of the panel. Moreover, these trends are not affected by changing the impact speed and impact location. The findings of this study suggest that a safer panel design for head injury prevention should firstly have a long fixing distance and then followed by using softer filling and frame materials. PMID- 29967658 TI - Conducting Polymer-Based Cantilever Sensors for Detection Humidity. AB - This paper describes the use of different conducting polymers (polyaniline, poly(o-ethoxyaniline), and polypyrrole) as a sensitive layer on a silicon cantilever sensor. The mechanical response (deflection) of the bimaterial (the coated cantilever) was investigated under the influence of relative humidity. The variations in the deflection of the coated cantilevers when exposed to relative humidity were evaluated. The results indicated a linear sensitivity in ranges, where the high value was obtained for a polypyrrole-sensitive layer between 20 and 45% of humidity. Furthermore, the sensor shows excellent performance along with rapid response and recovery times, relatively low hysteresis, and excellent stability. The sensors developed are potentially excellent materials for sensing low humidity for long time. PMID- 29967659 TI - Synthesis, Morphology, and Hydrogen Absorption Properties of TiVMn and TiCrMn Nanoalloys with a FCC Structure. AB - TiVMn and TiCrMn alloys are promising hydrogen storage materials for onboard application due to their high hydrogen absorption content. However, the traditional synthesis method of melting and continuous necessary heat treatment and activation process are energy- and time-consuming. There is rarely any report on kinetics improvement and nanoprocessing in TiVMn- and TiCrMn-based alloys. Here, through ball milling with carbon black as additive, we synthesized face centered cubic (FCC) structure TiVMn- and TiCrMn-based nanoalloys with mean particle sizes of around a few to tens of MUm and with the crystallite size just 10 to 13 nm. Differential scanning calorimetry (DSC) measurements under hydrogen atmosphere of the two obtained TiVMn and TiCrMn nanoalloys show much enhancement on the hydrogen absorption performance. The mechanism of the property improvement and the difference in the two samples were discussed from microstructure and morphology aspects. The study here demonstrates a new potential methodology for development of next-generation hydrogen absorption materials. PMID- 29967660 TI - Effective Removal of Congo Red by Triarrhena Biochar Loading with TiO2 Nanoparticles. AB - A composite of pyrolytic Triarrhena biochar loading with TiO2 nanoparticles has been synthesized by the sol-gel method. The composite shows a well-developed hollow mesoporous and macropore structure as characterized by XRD, BET, and SEM. When used as an absorbent to remove Congo red from aqueous solution, it was found that as-prepared composite performed better absorption capacity than single biochar or TiO2. The results suggest that biochar loading with TiO2 could be promisingly implemented as an environmentally friendly and inexpensive adsorbent for Congo red removal from wastewater. PMID- 29967661 TI - Comparison of Pulmonary and Systemic NO- and PGI2-Dependent Endothelial Function in Diabetic Mice. AB - Diabetes increases the risk of pulmonary hypertension and is associated with alterations in pulmonary vascular function. Still, it is not clear whether alterations in the phenotype of pulmonary endothelium induced by diabetes are distinct, as compared to peripheral endothelium. In the present work, we characterized differences between diabetic complications in the lung and aorta in db/db mice with advanced diabetes. Male, 20-week-old db/db mice displayed increased HbA1c and glucose concentration compatible with advanced diabetes. Diabetic lungs had signs of mild fibrosis, and pulmonary endothelium displayed significantly ultrastructural changes. In the isolated, perfused lung from db/db mice, filtration coefficient (Kf,c) and contractile response to TXA2 analogue were enhanced, while endothelial NO-dependent modulation of pulmonary response to hypoxic ventilation and cumulative production of NO2- were impaired, with no changes in immunostaining for eNOS expression. In turn, 6-keto-PGF1alpha release from the isolated lung from db/db mice was increased, as well as immunostaining of thrombomodulin (CD141). In contrast to the lung, NO-dependent, acetylcholine induced vasodilation, ionophore-stimulated NO2- generation, and production of 6 keto-PGF1alpha were all impaired in aortic rings from db/db mice. Although eNOS immunostaining was not changed, that of CD141 was clearly lowered. Interestingly, diabetes-induced nitration of proteins in aorta was higher than that in the lungs. In summary, diabetes induced marked ultrastructural changes in pulmonary endothelium that were associated with the increased permeability of pulmonary microcirculation, impaired NO-dependent vascular function, with compensatory increase in PGI2 production, and increased CD141 expression. In contrast, endothelial dysfunction in the aorta was featured by impaired NO-, PGI2-dependent function and diminished CD141 expression. PMID- 29967662 TI - Impaired Mitophagy of Nucleated Erythroid Cells Leads to Anemia in Patients with Myelodysplastic Syndromes. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by cytopenia and dysplasia. Anemia is the most common symptom in patients with MDS. Mitophagy and mitochondrial dysfunction might be involved in the development of MDS. In this study, we investigated the change of mitophagy in erythroid precursors in MDS patients. We found that NIX-mediated mitophagy was impaired in bone marrow nucleated red blood cells (NRBC) of MDS patients, associated with an increased amount of damaged mitochondria and increased ROS level which might lead to apoptosis and ineffective erythropoiesis. The results showed that the amount of mitochondria in GlycoA+ NRBC positively correlated with the count of ring sideroblasts in bone marrow samples. Meanwhile, the level of autophagy-associated marker LC3B in GlycoA+ NRBC had a positive correlation with hemoglobin (Hb) levels, and the amount of mitochondria in GlycoA+ NRBC had a negative correlation with Hb levels in high-risk MDS patients. Our results indicated that mitophagy might involve the pathogenesis of anemia associated with MDS. Autophagy might be a novel target in treatments of MDS patients. PMID- 29967663 TI - Occupational Exposure to Pesticides in Tobacco Fields: The Integrated Evaluation of Nutritional Intake and Susceptibility on Genomic and Epigenetic Instability. AB - Pesticides used at tobacco fields are associated with genomic instability, which is proposed to be sensitive to nutritional intake and may also induce epigenetic changes. We evaluated the effect of dietary intake and genetic susceptibility polymorphisms in MTHFR (rs1801133) and TERT (rs2736100) genes on genomic and epigenetic instability in tobacco farmers. Farmers, when compared to a nonexposed group, showed increased levels of different parameters of DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds), evaluated by cytokinesis block micronucleus cytome assay. Telomere length (TL) measured by quantitative PCR was shorter in exposed individuals. Global DNA methylation was significantly decreased in tobacco farmers. The exposed group had lower dietary intake of fiber, but an increase in cholesterol; vitamins such as B6, B12, and C; beta carotene; and alpha-retinol. Several trace and ultratrace elements were found higher in farmers than in nonfarmers. The MTHFR CT/TT genotype influenced nucleoplasmic bridges, nuclear buds, and TL in the exposed group, whereas TERT GT/TT only affected micronucleus frequency. We observed a positive correlation of TL and lipids and an inverse correlation of TL and fibers. The present data suggest an important role of dietary intake and subjects' genetic susceptibility to xenobiotics-induced damages and epigenetic alterations in tobacco farmers occupationally exposed to mixtures of pesticides. PMID- 29967664 TI - Polyphenol Stilbenes from Fenugreek (Trigonella foenum-graecum L.) Seeds Improve Insulin Sensitivity and Mitochondrial Function in 3T3-L1 Adipocytes. AB - Fenugreek (Trigonella foenum-graecum L.) is a well-known annual plant that is widely distributed worldwide and has possessed obvious hypoglycemic and hypercholesterolemia characteristics. In our previous study, three polyphenol stilbenes were separated from fenugreek seeds. Here, we investigated the effect of polyphenol stilbenes on adipogenesis and insulin resistance in 3T3-L1 adipocytes. Oil Red O staining and triglyceride assays showed that polyphenol stilbenes differently reduced lipid accumulation by suppressing the expression of adipocyte-specific proteins. In addition, polyphenol stilbenes improved the uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) by promoting the phosphorylation of protein kinase B (AKT) and AMP-activated protein kinase (AMPK). In present studies, it was found that polyphenol stilbenes had the ability to scavenge reactive oxygen species (ROS). Results from adenosine triphosphate (ATP) production and mitochondrial membrane potentials suggested that mitochondria play a critical role in insulin resistance and related signaling activation, such as AKT and AMPK. Rhaponticin, one of the stilbenes from fenugreek, had the strongest activity among the three compounds in vitro. Future studies will focus on mitochondrial biogenesis and function. PMID- 29967665 TI - Benzbromarone Attenuates Oxidative Stress in Angiotensin II- and Salt-Induced Hypertensive Model Rats. AB - Oxidative stress induced by hyperuricemia is closely associated with the renin angiotensin system, as well as the onset and progression of cardiovascular disease (CVD) and chronic kidney disease (CKD). It is therefore important to reduce oxidative stress to treat hyperuricemia. We previously found that benzbromarone, a uricosuric agent, has a direct free radical scavenging effect in vitro. The antioxidant effects of benzbromarone were evaluated in vivo via oral administration of benzbromarone for 4 weeks to model rats with angiotensin II- and salt-induced hypertension. Benzbromarone did not alter plasma uric acid levels or blood pressure but significantly reduced the levels of advanced oxidation protein products, which are oxidative stress markers. Furthermore, dihydroethidium staining of the kidney revealed a reduction in oxidative stress after benzbromarone administration. These results suggest that benzbromarone has a direct antioxidant effect in vivo and great potential to prevent CVD and CKD. PMID- 29967666 TI - The Effects of Sinapic Acid on the Development of Metabolic Disorders Induced by Estrogen Deficiency in Rats. AB - Sinapic acid is a natural phenolic acid found in fruits, vegetables, and cereals, exerting numerous pharmacological effects. The aim of the study was to investigate the influence of sinapic acid on biochemical parameters related to glucose and lipid metabolism, as well as markers of antioxidant abilities and parameters of oxidative damage in the blood serum in estrogen-deficient rats. The study was performed on 3-month-old female Wistar rats, divided into 5 groups, including sham-operated control rats, ovariectomized control rats, and ovariectomized rats administered orally with estradiol (0.2 mg/kg) or sinapic acid (5 and 25 mg/kg) for 28 days. The levels of estradiol, progesterone, interleukin 18, insulin, glucose, fructosamine, lipids, and enzymatic and nonenzymatic antioxidants (superoxide dismutase, catalase, and glutathione); total antioxidant capacity; and oxidative damage parameters (thiobarbituric acid reactive substances, protein carbonyl groups, and advanced oxidation protein products) were determined in the serum. Estradiol counteracted the carbohydrate and cholesterol metabolism disorders induced by estrogen deficiency. Sinapic acid increased the serum estradiol concentration; decreased insulin resistance and the triglyceride and total cholesterol concentrations; and favorably affected the parameters of antioxidant abilities (reduced glutathione, superoxide dismutase) and oxidative damage (advanced oxidation protein products). PMID- 29967667 TI - Diagnosis of Meningitis Caused by Pathogenic Microorganisms Using Magnetic Resonance Imaging: A Systematic Review. AB - Introduction: Bacterial meningitis is an acute infectious inflammation of the protective membranes covering the brain. Its early diagnosis is vital because of its high morbidity and mortality. It is mostly diagnosed by a gold standard diagnostic tool i.e. Cerebrospinal Fluid (CSF) analysis. However, it is sometimes difficult and or impossible to do this procedure and an alternative diagnostic tool is needed. Contrast enhanced magnetic resonance imaging can detect the pus or other changes in subarachnoid space. But our optimal aim is to use an imaging method without using contrast to be useable and available in more specific condition. Methods: This study aimed to survey the role of non-contrast Magnetic Resonance Imaging (MRI) in the diagnosis of the bacterial meningitis. MEDLINE/PubMed Central, Web of Science and Scopus were searched without time period and language limitation until March 2017. We found 6410 papers in our initial search. After assessing the content of the papers based on Cochrane library guidelines and inclusion/exclusion criteria, 6 relevant studies were included in the systematic review. All of included studies were observational studies. Results: MRI studies demonstrated that Fluid Attenuation Inversion Recovery (FLAIR) and Diffusion-Weighted Image (DWI) MR imaging among all MRI modalities can detect some abnormalities compatible with bacterial meningitis. FLAIR and DWI-MR imaging are potentially useful to diagnose bacterial meningitis and can be used in emergent condition in which bacterial meningitis is highly suspicious and the other diagnostic tools are not available or feasible. PMID- 29967668 TI - The Neuroprotective Effects of Long-Term Repetitive Transcranial Magnetic Stimulation on the Cortical Spreading Depression-induced Damages in Rat's Brain. AB - Introduction: Cortical Spreading Depression (CSD) is a propagating wave of neural and glial cell depolarization with important role in several clinical disorders. Repetitive Transcranial Magnetic Stimulation (rTMS) is a potential tool with preventive treatment effects in psychiatric and neuronal disorders. In this paper, we study the effects of rTMS on CSD by using behavioral and histological approaches in hippocampus and cortical regions. Methods: Twenty-four rats were divided into four groups. A group of control rats were kept in their home cage during the experiment. The CSD group received four CSD inductions during 4 weeks with 1 week intervals. The CSD-rTMS group were treated with rTMS stimulation (figure-eight coils, 20 Hz, 10 min/d) for 4 weeks. The fourth group, i.e. rTMS group received rTMS stimulation similar to the CSD-rTMS group without CSD induction. Results: Long-term rTMS application in treated groups significantly reduced production of dark neurons, increased the mean volume of normal neurons, and decreased the number of apoptotic neurons in cortical regions compared to the control group. The protective effects of long-term treatment by rTMS in the hippocampal regions were also studied. It was effective in some regions; however, rTMS effects on hippocampal regions were lower than cortical ones. Conclusion: Based on the study results, rTMS has significant preventive and protective effects in CSD-induced damages in cortical and hippocampal regions of the rat's brain. PMID- 29967669 TI - Opioid Receptors Gene Polymorphism and Heroin Dependence in Iran. AB - Introduction: Genes often have multiple polymorphisms that interact with each other and the environment in different individuals. Variability in the opioid receptors can influence opiate withdrawal and dependence. In humans, A118G Single Nucleotide Polymorphisms (SNP) on MU-Opioid Receptor (MOR), 36 G>T in kappa Opioid Receptor (KOR), and T921C in the delta-Opioid Receptor (DOR) have been found to associate with substance dependence. Methods: To investigate the association between opioid receptors gene polymorphism and heroin addiction, 100 control subjects with no history of opioid use, and 100 heroin addicts (50% males and 50% females) in Tehran (capital of Iran), were evaluated. A118G, 36 G>T, and T921C SNPs on the MOR, KOR, DOR genes, respectively, were genotyped by sequencing. Results: We found no differences in either allele or genotype frequency for MOR, KOR and DOR genes SNPs between controls and subjects addicted to heroin. Conclusion: The relationships among polymorphisms may be important in determining the risk profile for complex diseases such as addiction, but opioid addiction is a multifactorial syndrome which is partially hereditary and partially affected by the environment. PMID- 29967670 TI - Stress and Perception of Emotional Stimuli: Long-term Stress Rewiring the Brain. AB - Introduction: Long-term stressful situations can drastically influence one's mental life. However, the effect of mental stress on recognition of emotional stimuli needs to be explored. In this study, recognition of emotional stimuli in a stressful situation was investigated. Four emotional conditions, including positive and negative states in both low and high levels of arousal were analyzed. Methods: Twenty-six healthy right-handed university students were recruited within or after examination period. Participants' stress conditions were measured using the Perceived Stress Scale-14 (PSS-14). All participants were exposed to some audio-visual emotional stimuli while their brains responses' were measured using the Electroencephalography (EEG) technique. During the experiment, the subject's perception of emotional stimuli is evaluated using the Self Assessment Manikin (SAM) questionnaire. After recording, EEG signatures of emotional states were estimated from connectivity patterns among 8 brain regions. Connectivity patterns were calculated using Phase Slope Index (PSI), Directed Transfer Function (DTF), and Generalized Partial Direct Coherence (GPDC) methods. The EEG-based connectivity features were then labeled with SAM responses. Subsequently, the labeled features were categorized using two different classifiers. Classification accuracy of the system was validated by leave-one-out method. Results: As expected, performance of the system is significantly improved by grouping the subjects to stressed and stress-free groups. EEG-based connectivity pattern was influenced by mental stress level. Conclusion: Changes in connectivity patterns related to long-term mental stress have overlapped with changes caused by emotional stimuli. Interestingly, these changes are detectable from EEG data in eyes-closed condition. PMID- 29967671 TI - Management of Pituitary Adenomas: Mononostril Endoscopic Transsphenoidal Surgery. AB - Introduction: The endoscopic transsphenoidal approach for pituitary adenomas and other sellar lesions is quickly becoming the procedure of choice in their surgical management. The most common approach is binostril three-hand technique which requires a large exposure and subjects both nasal cavities to potential trauma. To reduce nasal morbidity, we employ a mononostril two-hand technique with the help of the endoscope holder. In this research, we review our series to determine efficacy of this approach in the management of pituitary adenomas. Methods: We performed a retrospective analysis of our initial series of 64 consecutive patients with pituitary adenomas operated by the same surgical team from 2008 till 2014 using a mononostril endoscopic approach. After categorizing the lesions into microadenomas, noninvasive macroadenomas, and invasive macroadenomas, we reviewed the radiological and biochemical outcomes of the surgeries after 3 months, 12 months, and 18 months. We also assessed recurrences and complications. Extent of resection was divided into gross total resection, near total resection (>90% resection), and partial resection for the remaining. Results: Our results show resection rates comparable to most series in the literature, with a gross total resection of 87% in non-invasive macroadenomas, and surgical disease control in 75% of invasive nonfunctioning adenomas. The remission rate in Cushing's disease was 81%, where it achieved up to 58% surgical remission in growth hormone secreting pituitary adenomas (including the invasive adenomas). The complication rate was very low. Conclusion: We conclude that the mononostril endoscopic approach is well suited for most pituitary tumor operations and carries comparable remission and resection rates to most endoscopic series with minimal complications and nasal morbidity. PMID- 29967672 TI - Genes Encoding GABA-beta and HT1D Receptors in Bipolar I (Manic Phase) Patients. AB - Introduction: According to the cumulative evidence, genes encoding GABA receptors inhibit neurotransmitters in CNS and are intricately involved in the pathogenesis of mood disorders. Based on this hypothesis, these genes may be expressed in bipolar patients. As a result, we evaluated the gene expressions of GABA-beta3 and HT1D receptors to assess their associations with bipolar mood disorder. Methods: In this study, 22 patients with bipolar I disorder (single manic episode) and 22 healthy individuals were enrolled. All participants were older than 15 years and had referred to Farshchian Hospital, Hamadan, Iran. They were diagnosed based on DSM IV-TR criteria and young mania rating scale in order to determine the severity of mania by a psychiatrist as bipolar Type 1 disorder in manic episode. We evaluated the expression of GABA-beta3 and HT1D receptor genes in peripheral blood mononuclear cells, using real-time RT-PCR analysis. Results: In our study, a reduction in the gene expression of GABA-beta3 and HT1D receptors was observed in peripheral blood mononuclear cells of the patients with bipolar disorders compared to the healthy controls. Conclusion: The results of this study supports the hypothesis that the gene expression for serotonin and GABA receptors can be employed in elucidating the pathogenesis of bipolar disorders. PMID- 29967673 TI - Normal Electrical Activity of the Brain in Obsessive-Compulsive Patients After Anodal Stimulation of the Left Dorsolateral Prefrontal Cortex. AB - Introduction: Transcranial Direct Current Stimulation (tDCS) has been used as a non-invasive method to increase the plasticity of brain. Growing evidence has shown several brain disorders such as depression, anxiety disorders, and chronic pain syndrome are improved following tDCS. In patients with Obsessive-Compulsive Disorder (OCD), increased brain rhythm activity particularly in the frontal lobe has been reported in several studies using Eectroencephalogram (EEG). To our knowledge, no research has been done on the effects of electrical stimulation on brain signals of patients with OCD. We measured the electrical activity of the brain using EEG in patients with OCD before and after tDCS and compared it to normal participants. Methods: Eight patients with OCD (3 males) and 8 matched healthy controls were recruited. A 64-channel EEG was used to record a 5-min resting state before and after application of tDCS in both groups. The intervention of tDCS was applied for 15 minutes with 2 mA amplitude where anode was placed on the left Dorsolateral Prefrontal Cortex (DLPFC) and cathode on the right DLPFC. Results: In line with previous studies, the results showed that the power of Delta frequency band in OCD patients are significantly higher than the normal group. Following anodal tDCS, hyperactivity in Delta and Theta bands declined in most channels, particularly in DLPFC (F3, F4) and became similar to normal signals pattern. The reduction in Delta band was significantly more than the other bands. Conclusion: Anodal tDCS over the left DLPFC significantly decreased the power of frequency bands of Delta and Theta in Patients with OCD. The pattern of EEG activity after tDCS became particularly similar to normal, so tDCS may have potential clinical application in these patients. PMID- 29967674 TI - Sleep Architecture in Patients With Primary Snoring and Obstructive Sleep Apnea. AB - Introduction: This study aimed to investigate sleep architecture in patients with primary snoring and obstructive sleep apnea. Methods: In this study, we analyzed polysomnographic data of 391 clients who referred to Sleep Disorders Research Center (SDRS). These people were classified into three groups based on their Apnea-Hypopnea Index (AHI) and snoring; control, Primary Snoring (PS), and Obstructive Sleep Apnea (OSA) group. Sleep architecture variables were then assessed in all groups. Results: The results of this study indicated a decrease in deep sleep or Slow Waves Sleep (SWS) and increase in light sleep or stage 1 of non-REM sleep (N1) in OSA patients compared with the control and PS groups. After controlling the effects of confounding factors, i.e. age and Body Mass Index (BMI) (which was performed through multiple regression analysis) significant differences were observed among the three groups with regard to N1. However, with regard to SWS, after controlling confounding variables (age and BMI), no significant difference was found among the groups. Conclusion: The results indicated that OSA, regardless of age and BMI, may increase light (N1) sleep possibly via a decline in blood oxygen saturation (SpO2 ). Such increase in N1 may be responsible for brain arousal. In addition, by controlling confounding factors (age and BMI), OSA did not affect SWS in OSA patients. However, further research is necessary to determine sleep architecture in more detail in the patients with OSA. PMID- 29967677 TI - Pacing in Vasovagal Syncope. PMID- 29967675 TI - Characterization of trimethoprim resistant E. coli dihydrofolate reductase mutants by mass spectrometry and inhibition by propargyl-linked antifolates. AB - Pathogenic Escherichia coli, one of the primary causes of urinary tract infections, has shown significant resistance to the most popular antibiotic, trimethoprim (TMP), which inhibits dihydrofolate reductase (DHFR). The resistance is modulated by single point mutations of DHFR. The impact of two clinically relevant mutations, P21L and W30R, on the activity of DHFR was evaluated via measurement of Michaelis-Menten and inhibitory kinetics, and structural characterization was undertaken by native mass spectrometry with ultraviolet photodissociation (UVPD). Compared to WT-DHFR, both P21L and W30R mutants produced less stable complexes with TMP in the presence of co-factor NADPH as evidenced by the relative abundances of complexes observed in ESI mass spectra. Moreover, based on variations in the fragmentation patterns obtained by UVPD mass spectrometry of binary and ternary DHFR complexes, notable structural changes were localized to the substrate binding pocket for W30R and to the M20 loop region as well as the C-terminal portion containing the essential G-H functional loop for the P21L mutant. The results suggest that the mutations confer resistance through distinctive mechanisms. A novel propargyl-linked antifolate compound 1038 was shown to be a reasonably effective inhibitor of the P21L mutant. PMID- 29967676 TI - Evolution of the Editorial Board Underpins the Integrity of Arrhythmia and Electrophysiology Review. PMID- 29967678 TI - Risk Stratification in Brugada Syndrome: Current Status and Emerging Approaches. AB - Brugada syndrome (BrS) is one of the most common inherited channelopathies associated with an increased risk of sudden cardiac death. Appropriate use of an ICD in high-risk patients is life-saving. However, there remains a lack of consensus on risk stratification, and even on the diagnosis of BrS itself. Some argue that people with a type 1 Brugada ECG pattern but no symptoms should not be diagnosed with BrS, and guidelines recommend observation without therapy in these patients. Others argue that the presence of a spontaneous (rather than drug induced) type 1 ECG pattern alone is enough to label them as high-risk for arrhythmic events, particularly if syncope is also present. Syncope and a spontaneous type 1 ECG pattern are the only factors that have consistently been shown to predict ventricular arrhythmic events and sudden cardiac death. Other markers have yielded conflicting data. However, in combination they may have roles in risk scoring models. Epicardial catheter ablation in the right ventricular outflow tract has shown promise in studies as an alternative management option to an ICD, but longer follow-up is required to ensure that the ablation effect is permanent. PMID- 29967679 TI - Atrial Fibrillation Ablation in Patients with Heart Failure: One Size Does Not Fit All. AB - Atrial fibrillation (AF) is common in patients with heart failure and is associated with poorer clinical outcomes compared with patients with heart failure alone. Recent evidence has challenged previous treatment paradigms in which rate control was considered equivalent to rhythm control in this population. Catheter ablation has emerged as a safe and effective treatment strategy in selected patients and overcomes the issues of limited efficacy and drug toxicities associated with pharmacological rhythm control. Numerous studies have explored the benefits of catheter ablation in patients with heart failure, but these have included heterogeneous patient cohorts and variable ablation strategies. This state-of-the-art review explores the evidence from these trials and examines the need for tailored, patient-specific strategies for AF ablation in patients with heart failure. PMID- 29967680 TI - Treatment of Atrial Fibrillation in Patients with Co-existing Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines? AB - AF in patients with heart failure and reduced ejection fraction (HFrEF) is common and is associated with an increased risk of stroke, heart failure hospitalisation and all-cause mortality. Rhythm control of AF in this population has been traditionally limited to the use of antiarrhythmic drugs. Clinical trials assessing superiority of pharmacological rhythm control over rate control have been largely disappointing. Catheter ablation has emerged as a viable alternative to pharmacological rhythm control in symptomatic AF and has enjoyed significant technological advancements over the past decade. Recent clinical trials have suggested that catheter ablation is superior to pharmacological interventions in patients with co-existing AF and HFrEF. In this article, we will review the therapeutic options for AF in patients with HFrEF in the context of the latest clinical trials beyond the current established guidelines. PMID- 29967681 TI - Pacing for Vasovagal Syncope. AB - Vasovagal syncope (VVS) is due to a common autonomic reflex involving the cardiovascular system. It is associated with bradycardia (cardioinhibitory response) and/or hypotension (vasodepressor response), likely mediated by parasympathetic activation and sympathetic inhibition. While generally a situational, isolated and/or self-limited event, for some, VVS is recurrent, unpredictable and debilitating. Conservative, non-pharmacological management may help, but no specific medical therapy has been proven widely effective. Permanent pacing may have specific benefit, but its value has been debated. The temporal causative association of bradycardia with syncope in those with VVS may help identify which patient could benefit from pacing but the timing and type of pacing in lieu of blood pressure changes may be critical. The mode, rate, pacing algorithm and time to initiate dual-chamber pacing preferentially with respect to the vasovagal reflex may be important to prevent or ameliorate the faint but completely convincing data are not yet available. Based on available data, DDD pacing with the closed loop stimulation algorithm appears a viable, if not the best, alternative presently to prevent recurrent VVS episodes. While several knowledge gaps remain, permanent pacing appears to have a role in managing select patients with VVS. PMID- 29967682 TI - His Bundle Pacing: A New Frontier in the Treatment of Heart Failure. AB - Biventricular pacing has revolutionised the treatment of heart failure in patients with sinus rhythm and left bundle branch block; however, left ventricular-lead placement is not always technically possible. Furthermore, biventricular pacing does not fully normalise ventricular activation and, therefore, the ventricular resynchronisation is imperfect. Right ventricular pacing for bradycardia may cause or worsen heart failure in some patients by causing dyssynchronous ventricular activation. His bundle pacing activates the ventricles via the native His-Purkinje system, resulting in true physiological pacing, and, therefore, is a promising alternate site for pacing in bradycardia and traditional CRT indications in cases where it can overcome left bundle branch block. Furthermore, it may open up new indications for pacing therapy in heart failure, such as targeting patients with PR prolongation, but a narrow QRS duration. In this article we explore the physiology, technology and potential roles of His bundle pacing in the prevention and treatment of heart failure. PMID- 29967683 TI - Sudden Cardiac Death and Arrhythmias. AB - Sudden cardiac death (SCD) and arrhythmia represent a major worldwide public health problem, accounting for 15-20 % of all deaths. Early resuscitation and defibrillation remains the key to survival, yet its implementation and the access to public defibrillators remains poor, resulting in overall poor survival to patients discharged from hospital. Novel approaches employing smart technology may provide the solution to this dilemma. Though the majority of cases are attributable to coronary artery disease, a thorough search for an underlying cause in cases where the diagnosis is unclear is necessary. This enables better management of arrhythmia recurrence and screening of family members. The majority of cases of SCD occur in patients who do not have traditional risk factors for arrhythmia. New and improved large scale screening tools are required to better predict risk in the wider population who represent the majority of cases of SCD. PMID- 29967686 TI - The Cost of Hybrid Treatment for Atrial Fibrillation. PMID- 29967685 TI - Premature Ventricular Complex-induced Cardiomyopathy. AB - Premature ventricular complex-induced cardiomyopathy is a potentially reversible condition in which left ventricular dysfunction is induced by the occurrence of frequent premature ventricular complexes (PVCs). Various cellular and extracellular mechanisms and risk factors for developing cardiomyopathy in this context have been suggested but the exact pathophysiological mechanism remains unclear. The suppression of PVCs is usually indicated in symptomatic patients with frequent PVCs and also those with left ventricular dysfunction. Antiarrhythmic drugs are a useful non-invasive treatment to eliminate PVCs, but the side effect profile, including the risk of pro-arrhythmia, along with suboptimal clinical effectiveness, should be weighed against the usually more effective but not risk-free treatment with catheter ablation. The latter has progressively become first line therapy in many patients with PVC-induced cardiomyopathy and should be particularly considered in specific scenarios. PMID- 29967684 TI - Risk Factor Management in Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with increased morbidity and mortality. There is growing evidence that numerous cardiovascular diseases and risk factors are associated with incident AF and that lone AF is rare. Beyond oral anticoagulant therapy, rate and rhythm control, therapy targeting risk factors and underlying conditions is an emerging AF management strategy that warrants better implementation in clinical practice. This review describes current evidence regarding the association between known modifiable risk factors and underlying conditions and the development and progression of AF. It discusses evidence for the early management of underlying conditions to improve AF outcomes. It also provides perspective on the implementation of tailored AF management in daily clinical practice. PMID- 29967687 TI - Pharmacological Therapy in Brugada Syndrome. AB - Brugada syndrome (BrS) is a cardiac disease caused by an inherited ion channelopathy associated with a propensity to develop ventricular fibrillation. Implantable cardioverter defibrillator implantation is recommended in BrS, based on the clinical presentation in the presence of diagnostic ECG criteria. Implantable cardioverter defibrillator implantation is not always indicated or sufficient in BrS, and is associated with a high device complication rate. Pharmacological therapy aimed at rebalancing the membrane action potential can prevent arrhythmogenesis in BrS. Quinidine, a class 1A antiarrhythmic drug with significant Ito blocking properties, is the most extensively used drug for the prevention of arrhythmias in BrS. The present review provides contemporary data gathered on all drugs effective in the therapy of BrS, and on ineffective or contraindicated antiarrhythmic drugs. PMID- 29967688 TI - Emerging insights into HAUSP (USP7) in physiology, cancer and other diseases. AB - Herpesvirus-associated ubiquitin-specific protease (HAUSP) is a USP family deubiquitinase. HAUSP is a protein of immense biological importance as it is involved in several cellular processes, including host-virus interactions, oncogenesis and tumor suppression, DNA damage and repair processes, DNA dynamics and epigenetic modulations, regulation of gene expression and protein function, spatio-temporal distribution, and immune functions. Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein, extensive studies have assessed its complex roles in p53-MDM2-related networks, identified numerous additional interacting partners, and elucidated the different roles of HAUSP in the context of cancer, development, and metabolic and neurological pathologies. Recent analyses have provided new insights into its biochemical and functional dynamics. In this review, we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases, which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention. PMID- 29967690 TI - Neurophysiological Effects of Aging: A P200 ERP Study. AB - Age-related effects were studied in 14 younger (M = 34 years) and 14 (M = 47 years) older healthy participants. Event-related potential (ERP) recording was done using a 256-channel EEG system. Results indicated that ERP is affected by advanced age. There was a significant difference in P200 mean latency between the younger participants and older participants for the target (low-probability) stimuli, but no such significance was evident for the P200 mean latency during the presentation of the standard (high-probability) stimuli. As for the P200 mean peak amplitude, the results for the target (low-probability) stimuli did show a significant difference between the two age groups, while the results for the standard (high-probability) stimuli did not show any significant difference between the two age groups. The results of this study are explained in light of aging effects on attentional recruitment and frontal lobe intactness. PMID- 29967691 TI - Photobiomodulation Optimization for Spinal Cord Injury Rat Phantom Model. AB - Spinal Cord Injury (SCI) causes interruption along the severed axonal tract(s) resulting in complete or partial loss of sensation and motor function. SCI can cause tetraplegia or paraplegia. Both these conditions can have lifelong excessive medical costs, as well as can reduce life expectancy. Preclinical research showed that Photobiomodulation therapy (PBMT), also known as Low-level laser (light) therapy (LLLT), possesses reparative and regenerative capabilities that have the potential to be used as a complimentary or supplementary SCI therapy. Despite the promising effects of PBMT, there are still no standardized irradiation parameters (i.e. different wavelengths, power, fluence, irradiance, beam type, beam diameters, and irradiation time) and there is also a lack of standardized experimental protocol(s), which makes it difficult to compare different studies. It is, nonetheless, essential to standardize such irradiation parameters in order to provide better PBMTs. The aim of this study, therefore, is to evaluate the delivery of light in a 3D voxelated SCI rat model for PBMT using different irradiation parameters (wavelengths: 660, 810, and 980 nm; beam types: Gaussian and Flat beam; and beam diameters: 0.04-1.2 cm) using Monte Carlo simulation. This study also aids in providing standardization for preclinical research for PBMT, which will eventually translate into clinical standardization upon clinical research studies and results. PMID- 29967692 TI - Sex Differences in Electrophysiology: P200 Event-related Potential Evidence. AB - We conducted an event-related potential (ERP) study using a 256-channel dense sensor array electroencephalography (EEG) system to examine how, and if the P200 neurophysiological signal is sexually dimorphic. We had two groups of participants: females (n= 15, mean age = 40.6 years old) and males (n = 15, mean age = 39.0 years old). ERPs from all participants were recorded while the participants performed an oddball task. Results showed that males on average had a significantly larger P200 peak amplitude and a significantly shorter P200 latency period. These results indicate that the P200 ERP is affected by sex. Therefore, suggesting that sex differences exist on an electrophysiological level, which may aid in better understanding of sex-biased biological influences, behaviors, neuropsychiatric disorders, and general brain function. PMID- 29967693 TI - The Schizophrenia Coping Oral Health Profile. Development and Feasibility. AB - Background: The aim of this work was to present the creation of appropriate tools to evaluate the coping strategies in Oral-Health-related Quality of Life (OHrQOL) implemented by persons with schizophrenia (PWS), the Schizophrenia Coping Oral Health Profile (SCOOHP), and the results of a feasibility study. Methods: A qualitative investigation was conducted between June 2016 and May 2017.The first step included 26 semi-structured individual interviews, 20 with PWS and 6 with health professionals (HPs), and 2 focus groups (PWS and HPs) to explore the experiences of the participants and how they felt about coping strategies in OHrQOL. The second step was a feasibility study involving a statistical analysis to test the acceptability and internal consistency (Cronbach's alpha) of the SCOOHP. Results: The analysis of these interviews allowed for us to obtain 277 items from 3545 verbatim transcriptions related to various dimensions of OHrQOL. We presented the items selected in coping concepts in this study. After selecting items in several stages, we drew up the SCOOHP scale with 23 items (15 items for positive coping and 8 items for negative coping). The feasibility study showed good acceptability, good understanding of the items and good consistency reliability (alpha = 0.59). Conclusions: This is the first study that has enabled us to draw up a specific tool to assess coping strategies in OHrQOL of PWS. A multicentre study involving a larger sample of PWS is underway in order to perform the psychometric validation of the SCOOHP. Trial registration: Clinical Trials Gov NCT02730832. Date registered: 21 March 2016. PMID- 29967694 TI - Protection of Corneal Limbus from Riboflavin Prevents Epithelial Stem Cell Loss after Collagen Cross-Linking. AB - Purpose: To investigate whether the protection of corneal limbus from riboflavin exposure during collagen cross-linking (CXL) prevents limbal epithelial stem cell (LESC) loss. Methods: Ten New Zealand white rabbits received an epithelium-off CXL using an accelerated protocol. Seven days before procedure, 5-bromo-2 deoxyuridine (BrdU) was intraperitoneally injected. During procedure, riboflavin was applied to the corneal surface within a 9 mm diameter retention ring in 5 rabbits, thereby preventing the limbus from riboflavin exposure. In other 5 rabbits, riboflavin was instilled every 2 min, allowing the spillover to the limbus. One day after UVA irradiation, corneas were subjected to histological and molecular assays. Results: There were no differences in corneal thickness and epithelial healing between the groups. The numbers of BrdU-labelled and p63+ limbal epithelial cells were markedly reduced in the group without a ring, but significantly increased when a ring was used. Robust expression of CK3/12 was observed in the limbal epithelium in the group with a ring. The mRNA levels of ABCG2, FGF2, IL-1beta, and IL-6 were significantly increased in the corneas with a ring. Conclusions: Protection of limbus from riboflavin during CXL was effective in preserving LESCs. However, inflammation was increased in the cornea treated with riboflavin using a ring. PMID- 29967689 TI - The independence of and associations among apoptosis, autophagy, and necrosis. AB - Cell death is an essential biological process for physiological growth and development. Three classical forms of cell death-apoptosis, autophagy, and necrosis-display distinct morphological features by activating specific signaling pathways. With recent research advances, we have started to appreciate that these cell death processes can cross-talk through interconnecting, even overlapping, signaling pathways, and the final cell fate is the result of the interplay of different cell death programs. This review provides an insight into the independence of and associations among these three types of cell death and explores the significance of cell death under the specific conditions of human diseases, particularly neurodegenerative diseases and cancer. PMID- 29967695 TI - The Effects of Uncomplicated Cataract Surgery on Retinal Layer Thickness. AB - Purpose: Our aim was to assess changes in the total retinal thickness (TRT), total retinal volume (TRV), and retinal layer thickness after uncomplicated cataract surgery. Methods: A total of 32 eyes of 32 patients who had undergone uncomplicated phacoemulsification surgery and intraocular lens implantation in one eye were enrolled. Effective phacoemulsification time (EPT) and total energy (TE) were recorded. Thickness and TRV were measured using optical coherence tomography. Data were collected preoperatively and at postoperative day 1, 7, 30, 90, and 180. Results: The study results showed a decrease in TRT, TRV, and most retinal layer thicknesses at the first postoperative day visit and then increasing at week 1, and months 1 and 3, and then relatively decreasing at month 6 although not returning to preoperative levels. The least affected layers were the retinal pigment epithelium and outer plexiform layer. There was a positive correlation between EPT and TE and ganglion cell layer in a 1 mm circle and inner nuclear layer in a 1-3 mm circle (p < 0.05). Conclusion: The results suggest that long-term follow-up of more than 6 months is necessary after cataract surgery to see whether total retinal and segmental values return to preoperative levels. This study was registered with Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12618000763246. PMID- 29967696 TI - High Iodine Deficiency among Pregnant Women in Periurban Ghana: A Hospital-Based Longitudinal Study. AB - Background: Iodine deficiency causes maternal hypothyroidism which can lead to growth, cognitive, and psychomotor deficit in neonates, infants, and children. This study examined the iodine status of pregnant women in a periurban setting in Ghana. Methods: This longitudinal study recruited 125 pregnant women by purposeful convenience sampling from the antenatal clinic of the Sefwi Wiawso municipal hospital in Ghana. Urinary iodine concentration (UIC) was estimated by the ammonium persulfate method at an estimated gestational age (EGA) of 11, 20, and 32 weeks. Demographic information, iodized salt usage, and other clinical information were collected using a questionnaire. Results: The prevalence of iodine deficiency among the pregnant women was 47.2% at EGA 11 and 60.8% at both EGA of 20 and 32, whereas only 0.8% of participants not using iodized salt had iodine sufficiency at EGA 32. 18.4%, 20%, and 24% of participants using iodized salt had iodine sufficiency at EGA 11, 20, and 32, respectively. Conclusion: A high prevalence of iodine deficiency was observed among our study cohort. PMID- 29967697 TI - Factors Associated with Successful Trial of Labor after Cesarean Section: A Retrospective Cohort Study. AB - Objective: To determine the effectiveness of trial of labor after cesarean section (TOLAC) and the factors associated with a successful TOLAC. Materials and Methods: A retrospective cohort study was conducted on consecutive singleton pregnancies with a previous single low-transverse cesarean section planned for TOLAC at a tertiary teaching hospital. The potential risk factors of a successful TOLAC were compared with those associated with a failed TOLAC. A simple audit system used in the first two years was also taken into account in the analysis as a potential factor for success. Results: During the study period, 2,493 women were eligible for TOLAC and 704 of them were scheduled for TOLAC, but finally 592 underwent TOLAC. Among them, 355 (60%) had a successful vaginal birth and 237 (40%) had a failed TOLAC. The independent factors associated with the success rate included the audit system, prior vaginal birth, low maternal BMI, and lower birth weight or gestational age, whereas induction of labor and recurring indications in previous pregnancy significantly increased the risk of having a failed TOLAC. Strikingly, the strongest predictor of a successful TOLAC was the audit system with OR of 6.4 (95%CI: 3.9-10.44), followed by a history of vaginal birth in previous pregnancies (OR: 3.2; 95%CI: 1.87-5.36). Conclusion: The simple audit system had the greatest impact on the success rate of TOLAC, instead of the less powerful obstetrical factors as reported in previous reports. The audit system is the only potential factor that could be strengthened to improve the success rate. PMID- 29967698 TI - The Impact of Locoregional Therapy in Nonmetastatic Inflammatory Breast Cancer: A Population-Based Study. AB - Background: Inflammatory breast cancer (IBC) is a rare but most aggressive breast cancer subtype. The impact of locoregional therapy on survival in IBC is controversial. Methods: Patients with nonmetastatic IBC between 1988 and 2013 were identified in the Surveillance, Epidemiology, and End Results (SEER) registry. Results: We identified 7,304 female patients with nonmetastatic inflammatory breast cancer (IBC) who underwent primary tumor surgery. Most patients underwent total mastectomy with only 409 (5.6%) undergoing a partial mastectomy. In addition, 4,559 (62.4%) were also treated with radiation therapy. The patients who underwent mastectomy had better survival compared to partial mastectomy (49% versus 43%, p = 0.003). The addition of radiation therapy was also associated with improved 5-year survival (55% versus 40%, p < 0.001). Multivariate analysis showed that black race HR (1.22, 95% CI 1.18-1.35), ER negative status (HR 1.22, 95% CI 1.16-1.28), and higher grade (HR 1.14, 95% CI 1.07-1.20) were associated with poor outcome. Cox proportional hazards model showed that total mastectomy (HR 0.75, 95% CI 0.65-0.85) and radiation (HR 0.64, 95% CI 0.61-0.69) were associated with improved survival. Conclusions: Optimal locoregional therapy for women with nonmetastatic IBC continues to be mastectomy and radiation therapy. These data reinforce the prevailing treatment algorithm for nonmetastatic IBC. PMID- 29967699 TI - An Interesting Case and Literature Review of a Coronary Stent Fracture in a Current Generation Platinum Chromium Everolimus-Eluting Stent. AB - Coronary interventions are the mainstay of treatment for stenotic coronary vascular lesions. New stent designs are constantly being evaluated to improve stent performances and clinical outcomes. Coronary stent fracture is uncommon; however, it is associated with potential major consequences including acute coronary syndrome and the need for repeated target vessel revascularization due to in-stent restenosis or stent thrombosis. We report a case of a 66-year-old man with an extensive cardiac disease history, who presented with intractable angina and was found to have a fracture of a current generation, platinum chromium everolimus-eluting stent (Synergy, Boston Scientific Inc.). PMID- 29967700 TI - Elevated Intracranial Pressure as a Cause of Sick Sinus Syndrome. AB - Sick sinus syndrome (SSS) has multiple causes both familial and acquired. The most common cause is usually idiopathic. In the past literature, elevated intracranial pressure (ICP) has not been reported to be a cause of SSS. We present a case of a 55-year-old male that developed SSS after surgical resection of a brain tumor. We have investigated the causal relationship between increased ICP and SSS. We have concluded that elevated ICP creates a sympathovagal imbalance leading to SSS. PMID- 29967701 TI - Large Draining Focal Fibrous Hyperplasia Secondary to Periapical Granuloma. AB - Periapical granuloma is a pathological diagnosis associated clinically and radiographically with a nonvital tooth and a periapical radiolucency, respectively. It is frequently seen as a sequela of long-standing pulpal necrosis. Often times, a draining fistula is observed near the nonvital tooth. We report an unusual case of a large draining focal fibrous hyperplasia in association with a large periapical granuloma treated at our clinic. The diagnosis was made by the clinical presentation, radiologic and histopathologic findings. PMID- 29967702 TI - Seemingly Harmless Differentiated Thyroid Carcinoma Presenting as Bone Metastasis. AB - Thyroid carcinoma is the most common endocrine neoplasia. Differentiated thyroid carcinomas (DTCs) represent the majority of cases, which usually follow an indolent clinical course with low mortality rates. The authors describe two cases of well DTC without classic histological poor prognosis features, presenting as extensive and unresectable osteolytic bone metastases. DTCs are considered harmless tumours, due to their benign and silent behaviour. The authors want to underline the importance of clinical awareness during follow-up in cases of DTC, which can be aggressive in presentation and behaviour. Timely identification and diagnosis of these tumours are essential for prompt treatment initiation and improvement of overall survival. PMID- 29967703 TI - Lipschutz Genital Ulceration as Initial Manifestation of Primary Sjogren's Syndrome. AB - Genital ulcers are challenging to any clinician and causes transcend many specialties. Skin ulceration in patients with primary Sjogren's syndrome is infrequent but an established feature of cutaneous involvement. Although gynecological symptoms, such as vulvovaginal dryness, dyspareunia, and pruritus, are common in women with primary Sjogren's syndrome, patients affected by vulvar ulcers are unknown. We describe an exceptional case of necrotic aphthous-type vulvar ulceration as initial presentation of primary Sjogren's syndrome that was possibly triggered by an infectious agent. Successful healing was achieved with oral corticosteroids, despite some loss of labia minora and labia majora as sequelae of the necrotizing process. Reactive acute genital ulcers (Lipschutz ulcers) should be considered as a possible manifestation of many autoimmune/inflammatory disorders, beyond the classic associations such as Behcet's syndrome or Crohn's disease. PMID- 29967704 TI - Innovative Uses of Condom Uterine Balloon Tamponade for Postpartum Hemorrhage in India and Tanzania. AB - Background: Postpartum hemorrhage is the most common cause of maternal deaths worldwide, the majority of which occur in low-resource settings. Uterine balloon tamponade (UBT) is an effective method of addressing uncontrolled postpartum hemorrhage (PPH) from uterine atony; however, UBT devices are often not affordable. We report on three novel uses of an ultra-low-cost condom uterine balloon tamponade (ESM-UBT) device. Cases: ESM-UBT devices were used in innovative ways to arrest severe uncontrolled pregnancy-related hemorrhage among three women in India and Tanzania. The first had sustained deep vaginal lacerations, the second a cervical pregnancy, and the third a complete molar pregnancy. Conclusion: The ESM-UBT device may be useful for control of obstetric hemorrhage caused by complex vaginal tears as well as cervical and molar pregnancies. PMID- 29967705 TI - Epithelioid Angiosarcoma Arising from a Huge Leiomyoma: A Case Report and a Literature Review. AB - Uterine mesenchymal tumors other than leiomyosarcoma, carcinosarcoma, and endometrial stromal sarcomas are extremely uncommon. We describe a case of epithelioid angiosarcoma of the uterus and review previous literature on such rare tumors. A 48-year-old woman presented with a 1-year history of abdominal fullness and 10kg weight loss. Pelvic magnetic resonance imaging (MRI) revealed a huge (30*18cm) uterus accompanied by degeneration and necrosis. She underwent supracervical hysterectomy and right salpingo-oophorectomy. We postoperatively diagnosed the mass as an epithelioid angiosarcoma arising from a leiomyoma. Vasodilatation was observed within the range of 2 cm * several mm in the leiomyoma, and proliferation of atypical cells was observed covering the surface of the luminal side. The tumor showed a partly fine vascular structure and was associated with obvious nuclear atypia and mitotic figures. She received 6 courses of adjuvant chemotherapy with paclitaxel, epirubicin, and carboplatin, and there have been no signs of recurrence for 10 months. PMID- 29967706 TI - Simultaneous Subconjunctival Triamcinolone and Bevacizumab Injections for Management of Blepharokeratoconjunctivitis in Children. AB - Purpose: To report the efficacy of subconjunctival triamcinolone (Kenalog A-40, Alcon) and bevacizumab (Avastin, Genentech) injections in fraternal twins with blepharokeratoconjunctivitis (BKC) causing progressive, bilateral corneal neovascularization and scarring. Methods: In this retrospective observational case series, two three-year-old male twins with BKC had presented with bilateral red eyes, photophobia, and frequent blinking. Examination of each child showed bilateral deep stromal and superficial corneal neovascularization, corneal infiltrates, multiple follicles on the palpebral conjunctiva bilaterally with blepharitis, and thick turbid sebum expressed from the Meibomian glands. Their disease progressed despite conventional treatment. Both twins were managed with subconjunctival triamcinolone injection and subconjunctival bevacizumab injection of each eye. Results: The treatment resulted in improvement of symptoms, and examination over an 8-10-month period postinjections showed fading stromal corneal infiltrates, partially regressed corneal neovascularization, and reduced conjunctival injection without complications. Conclusion: This case series highlights the potential vision threatening complications of BKC. In addition to conventional management options, this report is the first published use of subconjunctival triamcinolone and bevacizumab injections for BKC in children in an attempt to minimize and improve corneal neovascularization and scarring and subsequently to retain useful vision. PMID- 29967707 TI - Full Thickness Retinal Hole Formation after Nd:YAG Laser Hyaloidotomy in a Case with Valsalva Retinopathy. AB - A 27-year-old male was presented with a sudden onset of visual loss in his right eye. A secondary care center referred the patient with fundus photographs which were screened 4 days before and after the Nd: YAG laser hyaloidotomy treatment. Snellen acuity was 10/10 in both eyes. Fundus examinations revealed a retinal pigment epithelium (RPE) alteration at the margin of the inferior temporal arterial vascular arcade in the right eye and resolved preretinal and subretinal hemorrhages were seen in the macula. A diagnosis of Valsalva retinopathy was made based on the history and the treatment photographs of Nd:YAG laser hyaloidotomy. At 1st month examination all hemorrhages were resolved but RPE alterations were still at the margin of the inferior temporal arterial vascular arcade. The optical coherence tomography angiography (OCTA) images revealed 2 lesions. On en face OCT angiogram of OCTA full thickness retinal hole formation and ellipsoid zone damage at the superior and inferior margin of the inferior temporal arterial vascular arcade were seen. Superficial vascular plexus was also damaged at that region. The projection of the evacuation of blood from subhyaloid space and the full thickness retinal hole formation were the same, indicating that the partial and full thickness retinal holes were created by the laser treatment. PMID- 29967708 TI - Vaginal Bleeding as Initial Presentation of an Aggressive Renal Cell Carcinoma: A Case Report and Review of the Literature. AB - Introduction: Renal cell carcinoma is the third most common urogenital cancer. In some patients, it can metastasize to distant organs. Metastasis to the vagina is extremely rare. Case Presentation: A 54-year-old female with unremarkable history presented to the clinic with a chief complaint of vaginal bleeding. Further examination identified a pedunculated mass on the vaginal wall. Histologic examination revealed a metastatic clear cell renal cell carcinoma. Radiological studies then revealed a left renal mass and bilateral adrenal masses. The patient underwent a nephrectomy, adrenalectomy, and resection of the vaginal mass. The mass in the vagina has since recurred. Conclusion: We report the first known case of vaginal metastasis as initial presentation of a renal cell carcinoma with rhabdoid features. Postmenopausal women with renal cell carcinoma who present with vaginal bleeding should undergo a thorough inspection of the vaginal wall for the potential of metastatic neoplasms. PMID- 29967709 TI - Two Surgical Cases of Combined Hepatocellular-Cholangiocarcinoma, Intermediate Cell Subtype: Potentially Characteristic Gross Features. AB - We herein reported two rare surgical cases of primary combined hepatocellular cholangiocellular carcinoma, intermediate-cell subtype (CHC-INT), showing potentially characteristic and specific gross findings on their cut surface: both CHC-INTs demonstrated poorly demarcated and expansive and/or infiltrative hepatic nodules in lobulated margins, appearing clearly whitish in color. We were finally able to accurately diagnose the current lesions after thorough analyses including an appropriate and wide panel of immunohistochemical antibodies. Despite that, all pathologists should be aware that the potentially characteristic gross features of primary CHC-INT might also be one of the powerful supplementary tools for reaching its correct, conclusive diagnosis. PMID- 29967710 TI - Development of an Enzyme-Linked Immunosorbent Assay and Gold-Labelled Immunochromatographic Strip Assay for the Detection of Ancient Wool. AB - The identification of ancient wool is of great importance in archaeology. Despite lots of meaningful information can be achieved by conventional detection methods, that is, light and electron microscopy, spectroscopy, and chromatography, the efficacy is likely to be limited in the detection of ancient samples with contamination or severe degradation. In this work, an immunoassay was proposed and performed for the identification of ancient wool. First, a specific antibody, which has the benefits of low cost, easy operation, and extensive applicability, was developed directly through immunizing rabbits with complete antigen (keratin). Then, an enzyme-linked immunosorbent assay (ELISA) and a colloidal gold-labelled immunochromatographic strip (ICS) were developed to qualitatively identify the corresponding protein in ancient wool samples unearthed from Kazakhstan and China. The anti-keratin antibody exhibited high sensitivity and specificity for the identification of modern and ancient wool. The limit of detection (LOD) of the ELISA method was 10 ng/mL, and no cross-reactions with other interfering antigens have been noted. It is concluded that the immunoassays are reliable methods for the identification of ancient wool. PMID- 29967711 TI - Solid-Liquid Separation Properties of Thermoregulated Dicationic Ionic Liquid as Extractant of Dyes from Aqueous Solution. AB - Two thermoregulated dicationic ionic liquids were synthesized and applied for effective extraction of the common dye malachite green oxalate (MG). The extraction parameters such as amount of ionic liquids, pH of water phase, extraction time, cooling time, and centrifugal time on the extraction efficiency were investigated systematically. It revealed that the dye has been successfully extracted into the ionic liquids, with high extraction efficiency higher than 98%, and recovery of 98.2%-100.8%, respectively. Furthermore, these ionic liquids can be recycled easily after elution. The reusable yields were 87.1% and 88.7%. The extraction of the dye into the thermoregulated ionic liquid provides a method of minimizing pollution of waste water potentially. PMID- 29967712 TI - Establishing Analytical Performance Criteria for the Global Reconnaissance of Antibiotics and Other Pharmaceutical Residues in the Aquatic Environment Using Liquid Chromatography-Tandem Mass Spectrometry. AB - The occurrence of antibiotics in the environment from discharges of wastewater treatment plants (WWTPs) and from the land application of antibiotic-laden manure from animal agriculture is a critical global issue because these residues have been associated with the increased emergence of antibiotic resistance in the environment. In addition, other classes of pharmaceuticals and personal care products (PPCPs) have been found in effluents of municipal WWTPs, many of which persist in the receiving environments. Analysis of antibiotics by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in samples from different countries presents unique challenges that should be considered, from ion suppression due to matrix effects, to lack of available stable isotopically labeled standards for accurate quantification. Understanding the caveats of LC MS/MS is important for assessing samples with varying matrix complexity. Ion ratios between quantifying and qualifying ions have been used for quality assurance purposes; however, there is limited information regarding the significance of setting criteria for acceptable variabilities in their values in the literature. Upon investigation of 30 pharmaceuticals in WWTP influent and effluent samples, and in receiving surface water samples downstream and upstream of the WWTP, it was found that ion ratios have higher variabilities at lower concentrations in highly complex matrices, and the extent of variability may be exacerbated by the physicochemical properties of the analytes. In setting the acceptable ion ratio criterion, the overall mean, which was obtained by taking the average of the ion ratios at all concentrations (1.56 to 100 ppb), was used. Then, for many of the target analytes included in this study, the tolerance range was set at 40% for WWTP influent samples and 30% for WWTP effluent, upstream, and downstream samples. A separate tolerance range of 80% was set for tetracyclines and quinolones, which showed higher variations in the ion ratios compared to the other analytes. PMID- 29967713 TI - Characterization and Botanical Differentiation of Monofloral and Multifloral Honeys Produced in Cyprus, Greece, and Egypt Using Physicochemical Parameter Analysis and Mineral Content in Conjunction with Supervised Statistical Techniques. AB - Thirty-four honey samples donated by beekeepers and purchased from supermarkets were collected during harvesting years 2010-2014 from Cyprus, Greece, and Egypt. The aims of this study were to characterize honey samples and, if possible, to differentiate honeys according to the honey type on the basis of physicochemical parameter values, mineral content, and their combination using supervised statistical techniques (linear discriminant analysis (LDA)). Physicochemical parameters (colour, pH, free acidity, total dissolved solids, salinity, electrical conductivity, and moisture content) were determined according to official methods, while minerals (Al, As, B, Ba, Be, Ca, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Mo, Ni, P, Pb, Sb, Si, Ti, Tl, V, and Zn) using inductively coupled plasma optical emission spectrometry. The majority of honey samples analyzed met the quality criteria set by the European directive and national decision related to honey. Implementation of multivariate analysis of variance (MANOVA) and LDA on specific physicochemical parameters, minerals, or their combination provided a satisfactory classification of honeys according to floral type. The overall correct classification rate (based on the cross-validation method) was 79.4% using 7 minerals and 91.2% using 8 physicochemical parameters. When the 15 parameters were combined, the classification rate of Egyptian honeys was improved by 25%. PMID- 29967715 TI - A new species of Middle Miocene baleen whale from the Nupinai Group, Hikatagawa Formation of Hokkaido, Japan. AB - A fossil whale from the Hikatagawa Formation (Middle Miocene, 15.2-11.5 Ma) of Hokkaido, Japan is described as a new genus and species Taikicetus inouei and its phylogenetic position is examined. Consistent with the result of Marx, Lambert & de Muizon (2017), the Cetotheriidae form a clade with the Balaenopteroidea, and "a clade comprising Isanacetus, Parietobalaena and related taxa" is located basal to the Balaenopteroidea + Cetotheriidae clade. Taikicetus inouei is placed in the clade with most of members of "Cetotheres" sensu lato comprising Isanacetus, Parietobalaena and related taxa. Taikicetus inouei can be distinguished from the other members of "Cetotheres" sensu lato in having an anteriorly swollen short zygomatic process, high triangular coronoid process, and angular process, which does not reach as far posterior as the mandibular condyle. Taikicetus inouei is only record of "Cetotheres" sensu lato from Hokkaido, Japan and the northern-most records of "Cetotheres" sensu lato in Japan. PMID- 29967714 TI - TISSUE REPAIR AND EPIMORPHIC REGENERATION: AN OVERVIEW. AB - Purpose of the Review: This manuscript discusses wound healing as a component of epimorphic regeneration and the role of the immune system in this process. Recent findings: Epimorphic regeneration involves formation of a blastema, a mass of undifferentiated cells capable of giving rise to the regenerated tissues. The apical epithelial cap plays an important role in blastemal formation. Summary: True regeneration is rarely observed in mammals. With the exception of transgenic strains, tissue repair in mammals usually leads to non-functional fibrotic tissue formation. In contrast, a number of lower order species including planarians, salamanders, and reptiles, have the ability to overcome the burden of scarring and tissue loss through complex adaptations that allow them to regenerate various anatomic structures through epimorphic regeneration. Blastemal cells have been suggested to originate via various mechanisms including de-differentiation, transdifferentiation, migration of pre-existing adult stem cell niches, and combinations of these. PMID- 29967716 TI - Systematics and phylogeny of the Zygodactylidae (Aves, Neognathae) with description of a new species from the early Eocene of Wyoming, USA. AB - Zygodactylidae are an extinct lineage of perching birds characterized by distinct morphologies of the foot and wing elements. Although the clade has a complex taxonomic history, current hypotheses place Zygodactylidae as the sister taxon to Passeriformes (i.e., songbirds). Given the rather sparse fossil record of early passeriforms, the description of zygodactylid taxa is important for inferring potentially ancestral states in the largest radiation of living birds (i.e., the ~6,000 species of extant passeriforms). Despite the exceptional preservation of many specimens and considerable species diversity in Zygodactylidae, the relationships among species have not been previously evaluated in a phylogenetic context. Herein, we review the fossil record of Zygodactylidae from North America and describe five new well-preserved fossils from the early Eocene Green River Formation of Wyoming. Two specimens are identified as representing a new species and the first records of the taxon Zygodactylus outside Europe. Anatomical comparisons with previously named taxa and the results of phylogenetic analysis including newly described specimens and previously named zygodactylid taxa provide the first hypothesis of the species-level relationships among zygodactylids. The monophyly of Zygodactylidae is supported in these new analyses. However, the monophyly of Primozygodactylus and the taxonomic distinction between Zygodactylus and Eozygodactylus remain unresolved and would likely benefit from the description of additional specimens. PMID- 29967717 TI - Synthesis, enzyme inhibitory kinetics mechanism and computational study of N-(4 methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides as novel therapeutic agents for Alzheimer's disease. AB - The present study comprises the synthesis of a new series of sulfonamides derived from 4-methoxyphenethylamine (1). The synthesis was initiated by the reaction of 1 with 4-methylbenzenesulfonyl chloride (2) in aqueous sodium carbonate solution at pH 9 to yield N-(4-methoxyphenethyl)-4-methylbenzensulfonamide (3).This parent molecule 3 was subsequently treated with various alkyl/aralkyl halides, (4a-j), using N,N-dimethylformamide (DMF) as solvent and LiH as activator to produce a series of new N-(4-methoxyphenethyl)-N-(substituted)-4-methylbenzenesulfonamides (5a-j). The structural characterization of these derivatives was carried out by spectroscopic techniques like IR, 1H-NMR, and 13C-NMR. The elemental analysis data was also coherent with spectral data of these molecules. The inhibitory effects on acetylcholinesterase and DPPH were evaluated and it was observed that N-(4-Methoxyphenethyl)-4-methyl-N-(2-propyl)benzensulfonamide (5c) showed acetylcholinesterase inhibitory activity 0.075 +/- 0.001 (IC50 0.075 +/- 0.001 uM) comparable to Neostigmine methylsulfate (IC50 2.038 +/- 0.039 uM).The docking studies of synthesized ligands 5a-j were also carried out against acetylcholinesterase (PDBID 4PQE) to compare the binding affinities with IC50 values. The kinetic mechanism analyzed by Lineweaver-Burk plots demonstrated that compound (5c) inhibits the acetylcholinesterase competitively to form an enzyme inhibitor complex. The inhibition constants Ki calculated from Dixon plots for compound (5c) is 2.5 uM. It was also found from kinetic analysis that derivative 5c irreversible enzyme inhibitor complex. It is proposed on the basis of our investigation that title compound 5c may serve as lead structure for the design of more potent acetylcholinesterase inhibitors. PMID- 29967719 TI - Nectopsyche of Ecuador: a new species from the high Andean paramo and redescription of Nectopsyche spiloma (Ross) (Trichoptera: Leptoceridae). AB - The male and female of a new species of long-horned caddisfly, Nectopsyche paramo, are described from the high Andes of Ecuador. The new species was found above 4,000 m, representing the highest recorded elevation for a species in the genus. The larval stage of the species is also described. Only a total of 13 larvae were collected during a 17-month sampling program and 11 adults, suggesting that the species is rare. Larvae were found mainly in leaf packs. A male and female were observed in a mating swarm ca. 3 m above a stream during late afternoon. In addition, we redescribe the adult male of Nectopsyche spiloma (Ross), previously known from Ecuador from unsubstantiated literature records. PMID- 29967718 TI - Transcriptome profiling by RNA-Seq reveals differentially expressed genes related to fruit development and ripening characteristics in strawberries (Fragaria * ananassa). AB - Strawberry (Fragaria * ananassa) is an ideal plant for fruit development and ripening research due to the rapid substantial changes in fruit color, aroma, taste, and softening. To gain deeper insights into the genes that play a central regulatory role in strawberry fruit development and ripening characteristics, transcriptome profiling was performed for the large green fruit, white fruit, turning fruit, and red fruit stages of strawberry. A total of 6,608 differentially expressed genes (DEGs) with 2,643 up-regulated and 3,965 down regulated genes were identified in the fruit development and ripening process. The DEGs related to fruit flavonoid biosynthesis, starch and sucrose biosynthesis, the citrate cycle, and cell-wall modification enzymes played important roles in the fruit development and ripening process. Particularly, some candidate genes related to the ubiquitin mediated proteolysis pathway and MADS box were confirmed to be involved in fruit development and ripening according to their possible regulatory functions. A total of five ubiquitin-conjugating enzymes and 10 MADS-box transcription factors were differentially expressed between the four fruit ripening stages. The expression levels of DEGs relating to color, aroma, taste, and softening of fruit were confirmed by quantitative real time polymerase chain reaction. Our study provides important insights into the complicated regulatory mechanism underlying the fruit ripening characteristics in Fragaria * ananassa. PMID- 29967720 TI - Disentangling the link between supplemental feeding, population density, and the prevalence of pathogens in urban stray cats. AB - Background: Supplemental feeding of free-roaming animals, including wildlife and feral or stray animals, is well known to have a substantial impact on various aspects of animal ecology including habitat use, activity patterns, and host pathogen interactions. Among them, an increased population density (PD) of animals receiving supplemental food raises concerns regarding the transmission of pathogens in these host populations. The primary aim of this study was to investigate how supplemental feeding is associated with host PD and prevalence of pathogens with different transmission modes in urban stray cats. We hypothesized that supplemental feeding would be positively associated with host PD and the prevalence of pathogens with density-dependent transmission modes compared with pathogens with transmission modes that are considered relatively density independent. Methods: This study was conducted in six districts in Seoul, Republic of Korea which were selected based on different degrees of supplemental feeding and cat caretaker activity (CCA). The PD of stray cats was estimated by mark-recapture surveys. Stray cat blood samples (N = 302) were collected from stray cats by local animal hospitals from each district performing the trap neuter-release which tested for eight pathogens with different transmission modes (feline immunodeficiency virus, feline leukemia virus (FeLV), feline panleukopenia virus, feline calicivirus, feline herpesvirus-1, Bartonella henselae, hemoplasma, and Toxoplasma gondii) with molecular or serological assays. Associations between the prevalence of each pathogen and PD, CCA, and sex of cats were statistically analyzed. Results: In contrast to initial predictions, the cat PD was generally higher in low CCA districts. The prevalence of (FeLV), which is transmitted through direct contact, was significantly higher in areas with a high CCA, conforming to our hypothesis. On the other hand, the prevalence of feline parvovirus, which can be spread by environmental transmission, was higher in low CCA districts. The remaining six pathogens did not show any association with the CCA; however, they had a unique association with the PD or the sex of the stray cats. Discussion: Our findings suggest that in addition to influencing the PD, supplemental feeding may affect the prevalence of pathogens in urban animals by mechanisms such as increased aggregation and/or altered foraging strategies, with different consequences depending on the transmission mode of each pathogen. PMID- 29967721 TI - Effects of temperature and salinity stress on DNA methylation in a highly invasive marine invertebrate, the colonial ascidian Didemnum vexillum. AB - Environmentally induced epigenetic changes may contribute to phenotypic plasticity, increase adaptive potential in changing environments, and play a key role in the establishment and spread of invasive species in new habitats. In this study, we used methylation-sensitive amplified polymorphism (MSAP) to assess environmentally induced DNA methylation changes in a globally invasive clonal ascidian, Didemnum vexillum. We tested the effect of increasing temperature (19, 25 and 27 degrees C) and decreasing salinity (34, 32, 30, 28 and 26 practical salinity units (PSU)) on global DNA methylation, growth and survival rates. Exposure to 27 degrees C resulted in significant changes in DNA methylation over time. Growth also decreased in colonies exposed to high temperatures, suggesting they were under thermal stress. In contrast, no differences in growth nor DNA methylation patterns were observed in colonies exposed to a decreasing salinity gradient, potentially due to prior adaptation. The results of this study show that environmental stress can induce significant global DNA methylation changes in an invasive marine invertebrate on very rapid timescales, and that this response varies depending on the type, magnitude, and duration of the stressor. Changes in genomic DNA methylation and the rate of growth may act to 'buy survival time' under stressful conditions, expanding the distribution limits of this globally invasive species. PMID- 29967722 TI - DNA barcoding of marine fish species from Rongcheng Bay, China. AB - Rongcheng Bay is a coastal bay of the Northern Yellow Sea, China. To investigate and monitor the fish resources in Rongcheng Bay, 187 specimens from 41 different species belonging to 28 families in nine orders were DNA-barcoded using the mitochondrial cytochrome c oxidase subunit I gene (COI). Most of the fish species could be discriminated using this COI sequence with the exception of Cynoglossus joyneri and Cynoglossus lighti. The average GC% content of the 41 fish species was 47.3%. The average Kimura 2-parameter genetic distances within the species, genera, families, and orders were 0.21%, 5.28%, 21.30%, and 23.63%, respectively. Our results confirmed that the use of combined morphological and DNA barcoding identification methods facilitated fish species identification in Rongcheng Bay, and also established a reliable DNA barcode reference library for these fish. DNA barcodes will contribute to future efforts to achieve better monitoring, conservation, and management of fisheries in this area. PMID- 29967723 TI - Alpha-mangostin inhibits the migration and invasion of A549 lung cancer cells. AB - Several studies have indicated that alpha-mangostin exerts anti-metastasis and anti-subsistence effects on several types of cancer cells. Especially, the anti metastatic effect of alpha-mangostin on cancer cells is a prospective function in cancer treatment. However, the metastasis process is complicated, and includes migration, invasion, intravasation, and extravasation; thus, the main target of anti-metastatic effect of alpha-mangostin is not known. In this study, we investigated the effects of alpha-mangostin on the invasion, subsistence, and migration of lung cancer cells under co-culture conditions with normal cells and regular mono-culture conditions. We found that alpha-mangostin killed the lung cancer and normal cells in a dose-dependent manner. Furthermore, the alteration in the surface mechanical properties of cells was examined by using atomic force microscopy. Although the alpha-mangostin concentrations of 5 and 10 uM did not affect the short-term cell viability, they considerably decreased the Young's modulus of lung cancer cells implying a decline in cell surface actin cytoskeletal properties. Additionally, these concentrations of alpha-mangostin inhibited the migration of lung cancer cells. In co-culture conditions (cancer cells with normal cells), the invasive activities of cancer cells on normal cells were discernibly observed, and was inhibited after treatment with 5 and 10 uM of alpha-mangostin. Taken together, alpha-mangostin suppressed the subsistence of lung cancer cells and displayed anti-metastatic activities by inhibiting the migration and invasion, and reducing the actin cytoskeleton of cancer cells. Our findings suggest that alpha-mangostin could be a potential therapeutic agent for cancer treatment. PMID- 29967724 TI - Osteohistology of Late Triassic prozostrodontian cynodonts from Brazil. AB - The Prozostrodontia includes a group of Late Triassic-Early Cretaceous eucynodonts plus the clade Mammaliaformes, in which Mammalia is nested. Analysing their growth patterns is thus important for understanding the evolution of mammalian life histories. Obtaining material for osteohistological analysis is difficult due to the rare and delicate nature of most of the prozostrodontian taxa, much of which comprises mostly of crania or sometimes even only teeth. Here we present a rare opportunity to observe the osteohistology of several postcranial elements of the basal prozostrodontid Prozostrodon brasiliensis, the tritheledontid Irajatherium hernandezi, and the brasilodontids Brasilodon quadrangularis and Brasilitherium riograndensis from the Late Triassic of Brazil (Santa Maria Supersequence). Prozostrodon and Irajatherium reveal similar growth patterns of rapid early growth with annual interruptions later in ontogeny. These interruptions are associated with wide zones of slow growing bone tissue. Brasilodon and Brasilitherium exhibit a mixture of woven-fibered bone tissue and slower growing parallel-fibered and lamellar bone. The slower growing bone tissues are present even during early ontogeny. The relatively slower growth in Brasilodon and Brasilitherium may be related to their small body size compared to Prozostrodon and Irajatherium. These brasilodontids also exhibit osteohistological similarities with the Late Triassic/Early Jurassic mammaliaform Morganucodon and the Late Cretaceous multituberculate mammals Kryptobaatar and Nemegtbaatar. This may be due to similar small body sizes, but may also reflect their close phylogenetic affinities as Brasilodon and Brasilitherium are the closest relatives to Mammaliaformes. However, when compared with similar-sized extant placental mammals, they may have grown more slowly to adult size as their osteohistology shows it took more than one year for growth to attenuate. Thus, although they exhibit rapid juvenile growth, the small derived, brasilodontid prozostrodontians still exhibit an extended growth period compared to similar sized extant mammals. PMID- 29967725 TI - Specalyzer-an interactive online tool to analyze spectral reflectance measurements. AB - Low-cost phenotyping using proximal sensors is increasingly becoming popular in plant breeding. As these techniques generate a large amount of data, analysis pipelines that do not require expertise in computer programming can benefit a broader user base. In this work, a new online tool Specalyzer is presented that allows interactive analysis of the spectral reflectance data generated by proximal spectroradiometers. Specalyzer can be operated from any web browser allowing data uploading, analysis, interactive plots and exporting by point and click using a simple graphical user interface. Specalyzer is evaluated with case study data from a winter wheat fertilizer trial with two fertilizer treatments. Specalyzer can be accessed online at http://www.specalyzer.org. PMID- 29967727 TI - Unsupervised segmentation of greenhouse plant images based on modified Latent Dirichlet Allocation. AB - Agricultural greenhouse plant images with complicated scenes are difficult to precisely manually label. The appearance of leaf disease spots and mosses increases the difficulty in plant segmentation. Considering these problems, this paper proposed a statistical image segmentation algorithm MSBS-LDA (Mean-shift Bandwidths Searching Latent Dirichlet Allocation), which can perform unsupervised segmentation of greenhouse plants. The main idea of the algorithm is to take advantage of the language model LDA (Latent Dirichlet Allocation) to deal with image segmentation based on the design of spatial documents. The maximum points of probability density function in image space are mapped as documents and Mean shift is utilized to fulfill the word-document assignment. The proportion of the first major word in word frequency statistics determines the coordinate space bandwidth, and the spatial LDA segmentation procedure iteratively searches for optimal color space bandwidth in the light of the LUV distances between classes. In view of the fruits in plant segmentation result and the ever-changing illumination condition in greenhouses, an improved leaf segmentation method based on watershed is proposed to further segment the leaves. Experiment results show that the proposed methods can segment greenhouse plants and leaves in an unsupervised way and obtain a high segmentation accuracy together with an effective extraction of the fruit part. PMID- 29967726 TI - A new species of the deep-bodied actinopterygian Dapedium from the Middle Jurassic (Aalenian) of southwestern Germany. AB - Dapedium is one of the most abundant and diverse genera of ganoid fishes from the Early Jurassic fossil lagerstatte of Europe. In spite of its abundance, however, its timing of extinction is poorly constrained, with the youngest described material being Early Jurassic in age. We describe new diagnostic and relatively complete material of a large species of Dapedium (standard length estimated at 50 cm) from the Middle Jurassic (earliest Aalenian) Opalinuston Formation of Baden Wurttemberg, Germany. The Aalenian material represents a distinct species, D. ballei sp. nov., differing from Early Jurassic species in a unique combination of characters pertaining to the shape of the dermal skull elements, pectoral fin position, and scale shape and ornamentation. However, although D. ballei sp. nov. exhibits a unique combination of characters, there are no autapomorphies with which to distinguish it from the Toarcian species of Dapedium. Dapedium ballei represents the geologically youngest species of Dapedium, extending the range of this genus into the Middle Jurassic. The Opalinuston Formation fills an important gap in the marine vertebrate fossil record, and finds from this horizon have the potential to greatly improve our understanding of evolutionary dynamics over this period of faunal transition. PMID- 29967728 TI - Potamopyrgus antipodarum as a potential defender against swimmer's itch in European recreational water bodies-experimental study. AB - Swimmer's itch is a re-emerging human disease caused by bird schistosome cercariae, which can infect bathing or working people in water bodies. Even if cercariae fail after penetrating the human skin, they can cause dangerous symptoms in atypical mammal hosts. One of the natural methods to reduce the presence of cercariae in the environment could lie in the introduction of non host snail species to the ecosystem, which is known as the "dilution" or "decoy" effect. The caenogastropod Potamopyrgus antipodarum-an alien in Europe-could be a good candidate against swimmer's itch because of its apparent resistance to invasion by European bird schistosome species and its high population density. As a pilot study on this topic, we have carried out a laboratory experiment on how P. antipodarum influences the infestation of the intermediate host Radix balthica (a native lymnaeid) by the bird schistosome Trichobilharzia regenti. We found that the co-exposure of 200 P. antipodarum individuals per one R. balthica to the T. regenti miracidia under experimental conditions makes the infestation ineffective. Our results show that a non-host snail population has the potential to interfere with the transmission of a trematode via suitable snail hosts. PMID- 29967729 TI - Pathway analysis identifies altered mitochondrial metabolism, neurotransmission, structural pathways and complement cascade in retina/RPE/ choroid in chick model of form-deprivation myopia. AB - Purpose: RNA sequencing analysis has demonstrated bidirectional changes in metabolism, structural and immune pathways during early induction of defocus induced myopia. Thus, the aim of this study was to investigate whether similar gene pathways are also related to the more excessive axial growth, ultrastructural and elemental microanalytic changes seen during the induction and recovery from form-deprivation myopia (FDM) in chicks and predicted by the RIDE model of myopia. Methods: Archived genomic transcriptome data from the first three days of induction of monocularly occluded form deprived myopia (FDMI) in chicks was obtained from the GEO database (accession # GSE6543) while data from chicks monocularly occluded for 10 days and then given up to 24 h of normal visual recovery (FDMR) were collected. Gene set enrichment analysis (GSEA) software was used to determine enriched pathways during the induction (FDMI) and recovery (FDMR) from FD. Curated gene-sets were obtained from open access sources. Results: Clusters of significant changes in mitochondrial energy metabolism, neurotransmission, ion channel transport, G protein coupled receptor signalling, complement cascades and neuron structure and growth were identified during the 10 days of induction of profound myopia and were found to correlate well with change in axial dimensions. Bile acid and bile salt metabolism pathways (cholesterol/lipid metabolism and sodium channel activation) were significantly upregulated during the first 24 h of recovery from 10 days of FDM. Conclusions: The gene pathways altered during induction of FDM are similar to those reported in defocus induced myopia and are established indicators of oxidative stress, osmoregulatory and associated structural changes. These findings are also consistent with the choroidal thinning, axial elongation and hyperosmotic ion distribution patterns across the retina and choroid previously reported in FDM and predicted by RIDE. PMID- 29967730 TI - Significance and potential of marine microbial natural bioactive compounds against biofilms/biofouling: necessity for green chemistry. AB - Natural products from the unique environments of sea water and oceans represent a largely unfamiliar source for isolation of new microbes, which are potent producers of secondary bioactive metabolites. These unique life-forms from the marine ecosphere have served as an important source of drugs since ancient times and still offer a valuable resource for novel findings by providing remedial treatments. Therefore, it can be expected that many naturally bioactive marine microbial compounds with novel structures and bioactivities against those from terrestrial environments may be found among marine metabolites. Biofilms in aquatic environment possess serious problems to naval forces and oceanic industries around the globe. Current anti-biofilm or anti-biofouling technology is based on the use of toxic substances that can be harmful to their surrounding natural locales. Comprehensive research has been done to examine the bioactive potential of marine microbes. Results are remarkably varied and dynamic, but there is an urgent need for bioactive compounds with environmentally friendly or "green" chemical activities. Marine microbes have the potential as upcoming and promising source of non-toxic compounds with sustainable anti-biofouling/anti biofilm properties as they can produce substances that can inhibit not only the chemical components required for biofilm production but also the attachment, microorganism growth, and/or cell-cell communication. PMID- 29967731 TI - A new, three-dimensional geometric morphometric approach to assess egg shape. AB - This paper proposes a new methodology to quantify patterns of egg shape variation using geometric morphometrics of three-dimensional landmarks captured on digitally reconstructed eggshells and demonstrates its performance in capturing shape variation at multiple biological levels. This methodology offers unique benefits to complement established linear measurement or two-dimensional (2D) contour profiling techniques by (i) providing a more precise representation of eggshell curvature by accounting for variation across the entire surface of the egg; (ii) avoids the occurrence of correlations from combining multiple egg shape features; (iii) avoids error stemming from projecting a highly-curved three dimensional (3D) object into 2D space; and (iv) enables integration into 3D workflows such as finite elements analysis. To demonstrate, we quantify patterns of egg shape variation and estimate morphological disparity at multiple biological levels, within and between clutches and among species of four passerine species of different lineages, using volumetric dataset obtained from micro computed tomography. The results indicate that species broadly have differently shaped eggs, but with extensive within-species variation so that all four-focal species occupy a range of shapes. Within-species variation is attributed to between-clutch differences in egg shape; within-clutch variation is surprisingly substantial. Recent comparative analyses that aim to explain shape variation among avian taxa have largely ignored potential biases due to within species variation, or use methods limited to a narrow range of egg shapes. Through our approach, we suggest that there is appreciable variation in egg shape across clutches and that this variation needs to be accounted for in future research. The approach developed in this study to assess variation in shape is freely accessible and can be applied to any spherical-to-conical shaped object, including eggs of non-avian dinosaurs and reptiles through to other extant taxa such as poultry. PMID- 29967732 TI - Wolf spider burrows from a modern saline sandflat in central Argentina: morphology, taphonomy and clues for recognition of fossil examples. AB - Pavocosa sp. (Lycosidae) burrows found in an open sparsely vegetated area on the edge of the Gran Salitral saline lake, in central Argentina, are described. Burrows were studied by capturing the occupant and casting them with dental plaster. The hosting sediments and vegetation were also characterized. Inhabited Pavocosa sp. burrows display distinctive features as open, cylindrical, nearly vertical, silk lined shafts about 120 mm long, subcircular entrances, a gradual downward widening, and a particularly distinctive surface ornamentation in the form of sets of two linear parallel marks at a high angle to the burrow axis. Instead, casts of vacated Pavocosa sp. burrows showed some disturbances caused either by the reoccupation by another organism or by predation of the dweller. Two morphologies are related to reoccupation of burrows: those with a structure in form of an "umbrella" and another with smaller excavations at the bottom of the burrow. Predation by small mammals produces funnel-shaped burrows. Both active and abandoned Pavocosa sp. burrow casts are compared with existing ichnogenera and inorganic sedimentary structures, highlighting its distinction. It is argued that key features like the presence of a neck, a downward widening and the described surface texture will allow recognition of wolf spider burrows in the fossil record. However, the putative spider burrows described in the literature either lack the necessary preservational quality or do not show ornamentation similar to the modern wolf spider burrows. Fossil wolf spiders are recorded since the Paleogene (possibly Late Cretaceous), therefore Cenozoic continental rocks can contain wolf spider burrows awaiting recognition. In addition, the particular distribution of Pavocosa sp. in saline lakes may imply that this type of burrow is linked to saline environments. PMID- 29967733 TI - Seasonal dynamics of terrestrial vertebrate abundance between Amazonian flooded and unflooded forests. AB - The flood pulse is the main factor structuring and differentiating the ecological communities of Amazonian unflooded (terra firme) and seasonally-flooded (varzea) forests as they require unique adaptations to survive the prolonged annual floods. Therefore, varzea and terra firme forests hammer out a spatio-temporal mosaic of resource availability, which may result in landscape scale seasonal movements of terrestrial vertebrates between adjacent forest types. Yet the lateral movements of terrestrial vertebrates between hydrologically distinct neighbouring forest types exhibiting staggered resource availability remains poorly understood, despite the important implications of this spatial dynamic for the ecology and conservation of forest wildlife. We examined the hypothesis of terrestrial fauna seasonal movements between two adjacent forest types at two contiguous sustainable-use forest reserves in Western Brazilian Amazonia. We used camera trapping data on the overall species richness, composition, and abundance of nine major vertebrate trophic guilds to infer on terrestrial vertebrate movements as a function of seasonal changes in floodplain water level. Species richness differed in neighboring terra firme forests between the high-and low water phases of the flood pulse and terra firme forests were more species rich than varzea forests. There were clear differences in species composition between both forest types and seasons. Generalized Linear Models showed that water level was the main factor explaining aggregate abundance of all species and three trophic guilds. Our results indicate that the persistence of viable populations of large terrestrial vertebrates adjacent to major Amazonian rivers requires large, well-connected forest landscapes encompassing different forest types to ensure large-scale lateral movements by forest wildlife. PMID- 29967734 TI - Mitochondrial diversity of Bulgarian native dogs suggests dual phylogenetic origin. AB - The dog has been the first domesticated animal to have a central role in human society from ancient times to present day. Although there have been numerous investigations of dog phylogeny and origin, genetic data of dogs in the region of the Balkan Peninsula (South-Eastern Europe) are still scarce. Therefore, the aim of the present study was to perform phylogenetic analysis of three native Bulgarian dog breeds. A total of 130 samples were analyzed at HVR1 (hypervariable region, D-loop region). The samples were taken from two hunting dog breeds (Bulgarian Hound Dog: Barak, n = 34; Bulgarian Scenthound Dog: Gonche, n = 45) as well as from a Bulgarian Shepherd Dog (n = 51). The first two breeds are reared in a flat region of the country (the Northern part of Bulgaria, the Danubian Plain), while the last breed is a typical representative of the mountainous part of the country. The results have shown the presence of almost all main clades-A, B, C and D-in the three dog breeds taken together, except clades E and F, as expected. With regard to haplogroups distribution, there are clear differences among investigated breeds. While hunting breeds exhibit a prevalence of clade C, the mountainous Shepherd dog shows presence of the D2 haplogroup but absence of the C clade. In conclusion, the present study has been the first to investigate the mitochondrial DNA diversity of native dog breeds in Bulgaria. The results have revealed a clear difference of haplogroups dissemination in native hunting and shepherd dogs, which suggests a dual independent phylogenetic origin, without hybridization events between these dogs. PMID- 29967735 TI - One-pot multicomponent nitro-Mannich reaction using a heterogeneous catalyst under solvent-free conditions. AB - An environmentally-friendly, one-pot multicomponent reaction of various aldehydes, amines and nitroalkanes for the synthesis of beta-nitroamines is here described. Amberlyst A-21 supported CuI was found to be a highly efficient novel heterogeneous catalyst for the three-component nitro-Mannich reaction between aldehydes, amines and nitroalkanes. The developed protocol is performed in a solvent-free medium to produce a variety of beta-nitroamines in good to excellent yields within short reaction times. The catalyst can be easily prepared and recovered. It has been tested up to eight times with only a minor activity loss. PMID- 29967736 TI - Non-linear curve adjustments widen biological interpretation of relative growth analyses of the clam Tivela mactroides (Bivalvia, Veneridae). AB - Evaluation of relative (allometric) growth provides useful information to understand the development of organisms, as well as to aid in the management of fishery-exploited species. Usually, relative growth analyses use classical models such as the linear equation or the power function (allometric equation). However, these methods do not consider discontinuities in growth and may mask important biological information. As an alternative to overcome poor results and misleading interpretations, recent studies have suggested the use of more complex models, such as non-linear regressions, in conjunction with a model selection approach. Here, we tested differences in the performance of diverse models (simple linear regression, power function, and polynomial models) to assess the relative growth of the trigonal clam Tivela mactroides, an important fishing resource along the South American coast. Regressions were employed to relate parameters of the shell (length (L), width (W), height (H) and weight (SW)) among each other and with soft parts of the organism (dry weight (DW) and ash-free dry weight (ASDW)). Then, model selection was performed using the information theory and multi-model inference approach. The power function was more suitable to describe the relationships involving shell parameters and soft parts weight parameters (i.e., L vs. SW, DW, and AFDW, and SW vs. DW). However, it failed in unveiling changes in the morphometric relationships between shell parameters (i.e., L vs. W and H; W vs. H) over time, which were better described by polynomial functions. Linear models, in turn, were not selected for any relationship. Overall, our results show that more complex models (in this study polynomial functions) can unveil changes in growth related to modifications in environmental features or physiology. Therefore, we suggest that classical and more complex models should be combined in future studies of allometric growth of molluscs. PMID- 29967737 TI - Methods matter: the relationship between strength and hypertrophy depends on methods of measurement and analysis. AB - Purpose: The relationship between changes in muscle size and strength may be affected by both measurement and statistical approaches, but their effects have not been fully considered or quantified. Therefore, the purpose of this investigation was to explore how different methods of measurement and analysis can affect inferences surrounding the relationship between hypertrophy and strength gain. Methods: Data from a previous study-in which participants performed eight weeks of elbow flexor training, followed by an eight-week period of detraining-were reanalyzed using different statistical models, including standard between-subject correlations, analysis of covariance, and hierarchical linear modeling. Results: The associative relationship between strength and hypertrophy is highly dependent upon both method/site of measurement and analysis; large differences in variance accounted for (VAF) by the statistical models were observed (VAF = 0-24.1%). Different sites and measurements of muscle size showed a range of correlations coefficients with one another (r = 0.326 0.945). Finally, exploratory analyses revealed moderate-to-strong relationships between within-individual strength-hypertrophy relationships and strength gained over the training period (rho = 0.36-0.55). Conclusions: Methods of measurement and analysis greatly influence the conclusions that may be drawn from a given dataset. Analyses that do not account for inter-individual differences may underestimate the relationship between hypertrophy and strength gain, and different methods of assessing muscle size will produce different results. It is suggested that robust experimental designs and analysis techniques, which control for different mechanistic sources of strength gain and inter-individual differences (e.g., muscle moment arms, muscle architecture, activation, and normalized muscle force), be employed in future investigations. PMID- 29967738 TI - The effect of biochar amendments on phenanthrene sorption, desorption and mineralisation in different soils. AB - The contamination of soils and waters with organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), affect a large number of sites worldwide that need remediation. In this context soils amendments can be used to immobilise PAHs while maintaining soil functioning, with biochar being a promising amendment. In this experiment, phenantrene (Phe) was used as a frequent PAH contaminating soils and we studied the effect of three biochars at 1% applications to three different substrates, two agricultural topsoils and pure sand. We evaluated the changes in soil properties, sorption-desorption of Phe, and mineralisation of Phe in all treatments. Phe in pure sand was effectively sorbed to olive pruning (OBC) and rice husk (RBC) biochars, but pine biochar (PBC) was not as effective. In the soils, OBC and RBC only increased sorption of Phe in the silty soil. Desorption was affected by biochar application, RBC and OBC decreased water soluble Phe independently of the soil, which may be useful in preventing leaching of Phe into natural waters. Contrastingly, OBC and RBC slightly decreased the mineralisation of Phe in the soils, thus indicating lower bioavailability of the contaminant. Overall, biochar effects in the two tested soils were low, most likely due to the rather high soil organic C (SOC) contents of 2.2 and 2.8% with Koc values in the same range as those of the biochars. However, OBC and RBC additions can substantially increase adsorption of Phe in soils poor in SOC. PMID- 29967739 TI - It's a matter of design-how pitfall trap design affects trap samples and possible predictions. AB - Background: Pitfall traps are commonly used to assess ground dwelling arthropod communities. The effects of different pitfall trap designs on the trapping outcome are poorly investigated however they might affect conclusions drawn from pitfall trap data greatly. Methods: We tested four pitfall trap types which have been used in previous studies for their effectiveness: a simple type, a faster exchangeable type with an extended plastic rim plate and two types with guidance barriers (V- and X-shaped). About 20 traps were active for 10 weeks and emptied biweekly resulting in 100 trap samples. Results: Pitfall traps with guidance barriers were up to five times more effective than simple pitfall traps and trap samples resulted in more similar assemblage approximations. Pitfall traps with extended plastic rim plates did not only perform poorly but also resulted in distinct carabid assemblages with less individuals of small species and a larger variation. Discussion: Due to the obvious trait filtering and resulting altered assemblages, we suggest not to use pitfall traps with extended plastic rim plates. In comprehensive biodiversity inventories, a smaller number of pitfall traps with guidance barriers and a larger number of spatial replicates is of advantage, while due to comparability reasons, the use of simple pitfall traps will be recommended in most other cases. PMID- 29967740 TI - Re-emergence of the leaf clip gesture during an alpha takeover affects variation in male chimpanzee loud calls. AB - Loud calls are used by many species as long-distance signals for group defense, mate attraction, and inter- and intragroup spacing. Chimpanzee loud calls, or pant hoots, are used in a variety of contexts including group coordination and during male contests. Here, we observed an alpha male takeover in wild chimpanzees (Pan troglodytes verus) during which the leaf clipping gesture re emerged after disappearing for almost two years in this community. Leaf clipping only occurred in males and was observed almost exclusively prior to pant hoot vocalizations, as has been observed in other chimpanzee communities of the Tai forest in Cote d'Ivoire. Consequently, we hypothesized that leaf clipping may be important for male-male competition by affecting variation in the acoustic properties of male chimpanzee loud calls. We therefore investigated whether pant hoots preceded by leaf clipping differed acoustically from those without, while also testing the influence of social context on pant hoot variation, namely male dominance rank and hierarchy instability, i.e., before, during and after the alpha takeover. We found that pant hoots preceded by leaf clipping were longer, contained more call elements and drum beats, and lower fundamental and peak frequencies. Moreover, during the alpha takeover pant hoots were shorter, contained fewer drum beats and higher fundamental frequencies. Additionally, pant hoot and aggression rates were also highest during the alpha takeover with leaf clipping more likely to occur on days when pant hooting rates were high. Overall social rank had limited effects on pant hoot variation. We suggest that elevated arousal and aggression during the alpha takeover triggered the re-emergence of leaf clipping and the associated acoustic changes in pant hoots. Further research should focus on the potential mechanisms by which leaf clipping is connected to variation in pant hoots and cross-population comparisons of the behaviour. PMID- 29967741 TI - Annual plankton community metabolism in estuarine and coastal waters in Perth (Western Australia). AB - The planktonic metabolic balance that is the balance between gross primary production (GPP) and community respiration (CR) was determined in Matilda Bay (estuarine) and Woodman Point (coastal) in Perth, Western Australia. The rates of net community production (NCP = GPP - CR) and the ratio between GPP and CR (P/R) were assessed to evaluate whether the metabolic balance in the two coastal locations tends to be net autotrophic (production exceeding community respiration) or net heterotrophic (respiration exceeding production). We also analyzed environmental variability by measuring temperature, salinity, and nutrients and chlorophyll a concentration. Samples were collected biweekly from March 2014 to March 2015. During the study period the metabolic rates were three times higher in Matilda Bay than in Woodman Point. The predominant metabolism was net autotrophic at both sites with P/R ratios >1 in the majority of the sampling dates. In Matilda Bay, the metabolic rates were negatively correlated with salinity denoting river dynamics influence, and positively with chlorophyll a. In Woodman Point only the GPP was positively correlated with chlorophyll a. The positive correlation between P/R ratio and GPP in Matilda Bay and the positive correlations between the metabolic rates and chlorophyll a suggest that factors controlling autotrophic processes are modulating the planktonic metabolic balance in the coastal marine ecosystem in Perth. Significant correlations were found between CR and GPP-standardized to chlorophyll a and water temperature. The net autotrophic metabolic balance indicates that in both ecosystems planktonic communities are acting as a sink of CO2 and as a source of organic matter and oxygen to the system and are able to export organic matter to other ecosystems. PMID- 29967742 TI - Mulch and groundcover effects on soil temperature and moisture, surface reflectance, grapevine water potential, and vineyard weed management. AB - The objectives of this research were to identify alternatives to glyphosate for intra-row (under-trellis) vineyard floor management and to evaluate the potential for intra-row and inter-row (alleyway) groundcovers to reduce vegetative vigor of 'Marquette' grapevines (Vitis spp.) in a southeast Nebraska vineyard. The experiment was a randomized factorial design with five intra-row treatments (crushed glass mulch [CG], distillers' grain mulch [DG], creeping red fescue [CRF], non-sprayed control [NSC], and glyphosate [GLY]) and three inter-row treatments (creeping red fescue [CRF], Kentucky bluegrass [KB], and resident vegetation [RV]). Treatments were established in 2010-2011 and measurements were conducted during 2012 and 2013 on 5- and 6-year-old vines. Soil temperatures were mostly higher under mulches and lower under intra-row groundcovers, compared to GLY. Weed cover in CG, DG, and CRF treatments was the same or less than GLY. At most sampling dates, inter-row soil moisture was lowest under KB. Intra-row soil moisture was highest under DG mulch and lowest under CRF and NSC; CG had the same or lower soil moisture than GLY. Surprisingly, we did not detect differences in mid-day photosynthetically active radiation (PAR) reflectance, despite visual differences among the intra-row treatments. Mid-day vine water potential did not differ among treatments. We concluded it is not necessary to maintain a bare soil strip under established vines in this region, where soil fertility and moisture are non-limiting. PMID- 29967743 TI - The impact of the Wenchuan earthquake on early puberty: a natural experiment. AB - Background: The factors influencing pubertal timing have gained much attention due to a secular trend toward earlier pubertal onset in many countries. However, no studies have investigated the association between the Great earthquake and early puberty. We aimed to assess whether the Wenchuan earthquake is associated with early puberty, in both boys and girls. Methods: We used data from two circles of a survey on reproductive health in China to explore the impact of the Wenchuan earthquake on early puberty , and a total of 9,785 adolescents (4,830 boys, 49.36%) aged 12-20 years from 29 schools in eight provinces were recruited. Wenchuan earthquake exposure was defined as those Sichuan students who had not experienced oigarche/menarche before May 12, 2008. Early puberty was identified as a reported onset of oigarche/menarche at 11 years or earlier. We tested the association between the Wenchuan earthquake and early puberty in boys and girls. Then, subgroup analysis stratified by the age at earthquake exposure also was performed. Results: In total, 8,883 adolescents (4,543 boys, 51.14%) with a mean (SD) age of 15.13 (1.81) were included in the final sample. In general, children exposed to the earthquake had three times greater risk of early puberty (boys, RR [95% CI] = 3.18 [2.21-4.57]; girls: RR [95%CI] =3.16 [2.65-3.78]). Subgroup analysis showed that the adjusted RR was 1.90 [1.19-3.03] for boys and 2.22 [1.75 2.80] for girls. Earthquake exposure predicted almost a fourfold (RR [95%CI] = 3.91 [1.31-11.72]) increased risk of early puberty in preschool girls, whereas the increase was about twofold (RR [95%CI] = 2.09 [1.65-2.64]) in schoolgirls. Among boys, only older age at earthquake exposure was linked to early puberty (RR [95%CI] = 1.93 [1.18-3.16]). Conclusions: Wenchuan earthquake exposure increased the risk of early puberty in boys and girls, and preschoolers were more at risk than schoolchildren. The implications are relevant to support policies for those survivors, especially children, to better rebuild after disasters. PMID- 29967744 TI - Association of Crohn's disease-related chromosome 1q32 with ankylosing spondylitis is independent of bowel symptoms and faecal calprotectin. AB - Background: Genome-wide association studies have identified a plethora of risk genes for both Crohn's disease (CD) and ankylosing spondylitis (AS). A subset of genes found to be risk factors for CD have also been found to be risk factors for AS. The objective of our study was to assess whether CD risk genes were associated with non-invasive clinical markers of gut inflammation in patients with AS, indicating a potential subset of patients with clinical as well as genetic overlap. Methods: A total of 308 Caucasian patients who fulfilled the modified New York Criteria for AS, were assessed for bowel symptoms using the Dudley Inflammatory Bowel Symptom Questionnaire (DISQ). Of these patients, 157 also had faecal calprotectin measured. All AS patients and 568 healthy controls were genotyped for 10 CD risk loci using predesigned single nucleotide polymorphism (SNP) genotyping assays. Chi-square analysis was used to test for association between genotype and DISQ score and faecal calprotectin level. Results: The minor allele of two SNPs, one in chromosome region 1q32 SNP (rs11584383), and one in the gene coding for IL23R (rs11209026) conferred protection against AS. Only the association of 1q32 remained significant after Bonferroni correction for multiple testing. Stratification by DISQ score and faecal calprotectin did not influence the association of 1q32 with AS. Conclusion: In patients with AS, the association of the CD 1q32 SNP was independent of non-invasive markers of bowel inflammation. Other CD related SNPs were not found have a significant association with AS. PMID- 29967746 TI - Direct and legacy effects of plant-traits control litter decomposition in a deciduous oak forest in Mexico. AB - Background: Litter decomposition is a key process in the functioning of forest ecosystems, because it strongly controls nutrient recycling and soil fertility maintenance. The interaction between the litter chemical composition and the metabolism of the soil microbial community has been described as the main factor of the decomposition process based on three hypotheses: substrate-matrix interaction (SMI), functional breadth (FB) and home-field advantage (HFA). The objective of the present study was to evaluate the effect of leaf litter quality (as a direct plant effect, SMI hypothesis), the metabolic capacity of the microbial community (as a legacy effect, FB hypothesis), and the coupling between the litter quality and microbial activity (HFA hypothesis) on the litter decomposition of two contiguous deciduous oak species at a local scale. Methods: To accomplish this objective, we performed a litterbag experiment in the field for 270 days to evaluate mass loss, leaf litter quality and microbial activity in a complete factorial design for litter quality and species site. Results: The litter of Quercus deserticola had higher rate of decomposition independently of the site, while the site of Quercus castanea promoted a higher rate of decomposition independently of the litter quality, explained by the specialization of the soil microbial community in the use of recalcitrant organic compounds. The Home-Field Advantage Index was reduced with the decomposition date (22% and 4% for 30 and 270 days, respectively). Discussion: We observed that the importance of the coupling of litter quality and microbial activity depends on decomposition stage. At the early decomposition stage, the home-advantage hypothesis explained the mass loss of litter; however, in the advanced decomposition stage, the litter quality and the metabolic capacity of the microbial community can be the key drivers. PMID- 29967745 TI - Bibliometric analysis of research on the role of intestinal microbiota in obesity. AB - Background: Obesity is a key public health problem. The advancement of gut microbiota research sheds new light on this field. This article aims to present the research trends in global intestinal microbiota studies within the domain of obesity research. Methods: Bibliographic information of the publications on intestinal microbiota and obesity was retrieved from the Scopus database, and then analyzed by using bibliometric approaches. Results: A total of 3,446 references were retrieved; the data indicated a steady growth and an exponential increase in publication numbers. The references were written in 23 different languages (93.8% in English). A number of 3,056 English journal papers were included in the further analyses. Among the 940 journals, the most prolific ones were PLOS ONE, Scientific Reports, and British Journal of Nutrition. North America and Europe were the highest publication output areas. The US (995 publications) ranked first in the number of publications, followed by the China (243 publications) and France (242 publications). The publication numbers were significantly correlated with gross domestic product (GDP), human development index (HDI), and population number (PN). International collaboration analysis also shows that most of the collaborations are among developed countries. Discussion: This comprehensive bibliometric study indicates that gut microbiota is a significant topic in the obesity research. The structured information may be helpful in understanding research trends, and locating research hot spots and gaps in this domain. PMID- 29967747 TI - Dry season diet composition of four-horned antelope Tetracerus quadricornis in tropical dry deciduous forests, Nepal. AB - It is essential to assess the feeding strategies of threatened species during resource-scarce seasons to understand their dietary niche breadth and inform appropriate habitat management measures. In this study, we examined the diet composition of four-horned antelope (FHA) Tetracerus and quadricornis, one of the least studied ungulate species, in Banke National Park, Nepal. A total of 53 fresh pellet groups were collected between December 2015 and January 2016 and analyzed using micro-histological fecal analysis technique. First, we prepared 133 micro-histological photographs of different parts of 64 reference plant species. Then we compared 1,590 fragments of 53 fecal samples with photographs of reference plants to assess the percentage of occurrence of different plant species in FHA diet. A total of 30 plant species belonging to 18 different families were identified in fecal samples. Chi-square goodness of fit tests showed that FHA appeared not to feed all plant uniformly. Out of 1,520 identified fragments in fecal samples, 1,300 were browse species and 220 were grass species. Browse represented 85.5% of the identified plant fragments, suggesting that FHA might be adopting a browser strategy at least during winter when grasses are low in abundance and their nutritive quality is poor. Tree species had the highest contribution in the diet (46.55%) followed by shrubs (24.52%). The family Gramineae was consumed in the highest proportion (27.68%) followed by Euphorbiaceae (11.95%). Overall, our results suggest that FHA has the feeding plasticity to adapt to resource fluctuation. Based on the findings of this study, we recommend that dicot plant species-particularly fruit trees and shrubs, which are the major source of nutrients for FHA during resource-lean, dry season-be conserved and natural regeneration of these taxa be promoted. PMID- 29967748 TI - Differing responses of red abalone (Haliotis rufescens) and white abalone (H. sorenseni) to infection with phage-associated Candidatus Xenohaliotis californiensis. AB - The Rickettsiales-like prokaryote and causative agent of Withering Syndrome (WS) Candidatus Xenohaliotis californiensis (Ca. Xc)-decimated black abalone populations along the Pacific coast of North America. White abalone-Haliotis sorenseni-are also susceptible to WS and have become nearly extinct in the wild due to overfishing in the 1970s. Candidatus Xenohaliotis californiensis proliferates within epithelial cells of the abalone gastrointestinal tract and causes clinical signs of starvation. In 2012, evidence of a putative bacteriophage associated with Ca. Xc in red abalone-Haliotis rufescens-was described. Recently, histologic examination of animals with Ca. Xc infection in California abalone populations universally appear to have the phage-containing inclusions. In this study, we investigated the current virulence of Ca. Xc in red abalone and white abalone at different environmental temperatures. Using a comparative experimental design, we observed differences over time between the two abalone species in mortality, body condition, and bacterial load by quantitative real time PCR (qPCR). By day 251, all white abalone exposed to the current variant of Ca. Xc held in the warm water (18.5 degrees C) treatment died, while red abalone exposed to the same conditions had a mortality rate of only 10%, despite a relatively heavy bacterial burden as determined by qPCR of posterior esophagus tissue and histological assessment at the termination of the experiment. These data support the current status of Ca. Xc as less virulent in red abalone, and may provide correlative evidence of a protective phage interaction. However, white abalone appear to remain highly susceptible to this disease. These findings have important implications for implementation of a white abalone recovery program, particularly with respect to the thermal regimes of locations where captively-reared individuals will be outplanted. PMID- 29967749 TI - Complex characterization of oat (Avena sativa L.) lines obtained by wide crossing with maize (Zea mays L.). AB - Background: The oat * maize addition (OMA) lines are used for mapping of the maize genome, the studies of centromere-specific histone (CENH3), gene expression, meiotic chromosome behavior and also for introducing maize C4 photosynthetic system to oat. The aim of our study was the identification and molecular-cytogenetic characterization of oat * maize hybrids. Methods: Oat DH lines and oat * maize hybrids were obtained using the wide crossing of Avena sativa L. with Zea mays L. The plants identified as having a Grande-1 retrotransposon fragment, which produced seeds, were used for genomic in situ hybridization (GISH). Results: A total of 138 oat lines obtained by crossing of 2,314 oat plants from 80 genotypes with maize cv. Waza were tested for the presence of maize chromosomes. The presence of maize chromatin was indicated in 66 lines by amplification of the PCR product (500 bp) generated using primers specific for the maize retrotransposon Grande-1. Genomic in situ hybridization (GISH) detected whole maize chromosomes in eight lines (40%). All of the analyzed plants possessed full complement of oat chromosomes. The number of maize chromosomes differed between the OMA lines. Four OMA lines possessed two maize chromosomes similar in size, three OMA-one maize chromosome, and one OMA-four maize chromosomes. In most of the lines, the detected chromosomes were labeled uniformly. The presence of six 45S rDNA loci was detected in oat chromosomes, but none of the added maize chromosomes in any of the lines carried 45S rDNA locus. Twenty of the analyzed lines did not possess whole maize chromosomes, but the introgression of maize chromatin in the oat chromosomes. Five of 66 hybrids were shorter in height, grassy type without panicles. Twenty-seven OMA lines were fertile and produced seeds ranging in number from 1-102 (in total 613). Sixty three fertile DH lines, out of 72 which did not have an addition of maize chromosomes or chromatin, produced seeds in the range of 1-343 (in total 3,758). Obtained DH and OMA lines were fertile and produced seeds. Discussion: In wide hybridization of oat with maize, the complete or incomplete chromosomes elimination of maize occur. Hybrids of oat and maize had a complete set of oat chromosomes without maize chromosomes, and a complete set of oat chromosomes with one to four retained maize chromosomes. PMID- 29967750 TI - Gene buddies: linked balanced polymorphisms reinforce each other even in the absence of epistasis. AB - The fates of genetic polymorphisms maintained by balancing selection depend on evolutionary dynamics at linked sites. While coevolution across linked, epigenetically-interacting loci has been extensively explored, such supergenes may be relatively rare. However, genes harboring adaptive variation can occur in close physical proximity while generating independent effects on fitness. Here, I present a model in which two linked loci without epistasis are both under balancing selection for unrelated reasons. Using forward-time simulations, I show that recombination rate strongly influences the retention of adaptive polymorphism, especially for intermediate selection coefficients. A locus is more likely to retain adaptive variation if it is closely linked to another locus under balancing selection, even if the two loci have no interaction. Thus, two linked polymorphisms can both be retained indefinitely even when they would both be lost to drift if unlinked. While these results may be intuitive, they have important implications for genetic architecture: clusters of mutually reinforcing genes may underlie phenotypic variation in natural populations, and such genes cannot be assumed to be functionally associated. Future studies that measure selection coefficients and recombination rates among closely linked genes will be fruitful for characterizing the extent of this phenomenon. PMID- 29967752 TI - A reference cytochrome c oxidase subunit I database curated for hierarchical classification of arthropod metabarcoding data. AB - Metabarcoding is a popular application which warrants continued methods optimization. To maximize barcoding inferences, hierarchy-based sequence classification methods are increasingly common. We present methods for the construction and curation of a database designed for hierarchical classification of a 157 bp barcoding region of the arthropod cytochrome c oxidase subunit I (COI) locus. We produced a comprehensive arthropod COI amplicon dataset including annotated arthropod COI sequences and COI sequences extracted from arthropod whole mitochondrion genomes, the latter of which provided the only source of representation for Zoraptera, Callipodida and Holothyrida. The database contains extracted sequences of the target amplicon from all major arthropod clades, including all insect orders, all arthropod classes and Onychophora, Tardigrada and Mollusca outgroups. During curation, we extracted the COI region of interest from approximately 81 percent of the input sequences, corresponding to 73 percent of the genus-level diversity found in the input data. Further, our analysis revealed a high degree of sequence redundancy within the NCBI nucleotide database, with a mean of approximately 11 sequence entries per species in the input data. The curated, low-redundancy database is included in the Metaxa2 sequence classification software (http://microbiology.se/software/metaxa2/). Using this database with the Metaxa2 classifier, we performed a cross-validation analysis to characterize the relationship between the Metaxa2 reliability score, an estimate of classification confidence, and classification error probability. We used this analysis to select a reliability score threshold which minimized error. We then estimated classification sensitivity, false discovery rate and overclassification, the propensity to classify sequences from taxa not represented in the reference database. Our work will help researchers design and evaluate classification databases and conduct metabarcoding on arthropods and alternate taxa. PMID- 29967751 TI - Single-nucleotide polymorphisms of uracil-processing genes affect the occurrence and the onset of recurrent depressive disorder. AB - Depressive disorders (DD) are known to be associated with increased DNA damage, the impairment of DNA damage repair, and the presence of single-nucleotide polymorphisms (SNPs) in DNA damage repair genes. Some indirect evidence also suggests that uracil metabolism may be disrupted in depressed patients. Therefore, the current study genotypes three SNPs localized in genes encoding uracil-processing proteins: two glycosylases, i.e., UNG g.7245G>C (rs34259), SMUG1 c.-31A>G (rs3087404), and dUTPase, i.e., DUT g.48638795G>T (rs4775748). The polymorphisms were analyzed in 585 DNA samples (282 cases and 303 controls) using TaqMan probes. The G/G genotype and G allele of UNG polymorphism decreased the risk of depression, while the G/C genotype and C allele of the same SNP increased it. It was also found that G/G carriers had their first episode significantly later than the heterozygotes. Although there was no association between the occurrence of depression and the SMUG1 SNP, a significant difference was found between the homozygotes regarding the onset of DD. In conclusion, the SNPs localized in the uracil-processing genes may modulate the occurrence and the onset of depression, which further supports the hypothesis that impairment of DNA damage repair, especially base-excision repair, may play an important role in the pathogenesis of the disease. PMID- 29967753 TI - Two sugar beet chitinase genes, BvSP2 and BvSE2, analysed with SNP Amplifluor like markers, are highly expressed after Fusarium root rot inoculations and field susceptibility trial. AB - Background: The pathogens from Fusarium species can cause Fusarium root rot (RR) and other diseases in plant species including sugar beet (Beta vulgaris L.), and they have a strong negative impact on sugar beet yield and quality. Methods: A total of 22 sugar beet breeding lines were evaluated for the symptoms of RR after inoculation with Fusarium oxysporum Sch., isolate No. 5, and growth in a field trial. Two candidate genes for RR resistance, BvSP2 and BvSE2, encoding chitinases Class IV and III, respectively, were previously identified in sugar beet, and used for genotyping using modern Amplifluor-like single nucleotide polymorphism (SNP) genotyping approach. The qPCR expression analysis was used to verify responses of the candidate genes for RR infections. Results: A strong association of two SNP markers for BvSP2 and BvSE2 with resistance to RR in sugar beet was found in our study. Very high BvSP2 expression (100-fold compared to Controls) was observed in three RR resistant accessions (2182, 2236 and KWS2320) 14 days after inoculation which returned to the control level on Day 18. RR sensitive breeding line 2210 showed a delay in mRNA level, reaching maximal expression of BvSP2 18 days after inoculation. The gene BvSE2, showed a strong expression level in leaf samples from the infected field trial only in the breeding line 2236, which showed symptoms of RR, and this may be a response to other strains of F. oxysporum. PMID- 29967754 TI - Triple stable isotope analysis to estimate the diet of the Velvet Scoter (Melanitta fusca) in the Baltic Sea. AB - This study quantifies contributions of different food sources in the winter diet of the Velvet Scoter (Melanitta fusca) in coastal waters of the Lithuanian Baltic Sea using non-lethal avian sampling. We highlight the application of stable sulphur isotope ratios as complementary to stable carbon and nitrogen isotope analysis in order to discriminate sandy bottom macrozoobenthos organisms as potential food sources for the Velvet Scoter. Selection of the most relevant trophic enrichment factors and Monte Carlo simulations in order to choose the best fitted model were undertaken. The stable isotope mixing model revealed the main contributions of a group of bivalves, Mya arenaria and Cerastoderma glaucum, to be 46-54%, and while the crustacean, Saduria entomon, comprised 26-35% of the diet. PMID- 29967755 TI - Forecasting influenza epidemics by integrating internet search queries and traditional surveillance data with the support vector machine regression model in Liaoning, from 2011 to 2015. AB - Background: Influenza epidemics pose significant social and economic challenges in China. Internet search query data have been identified as a valuable source for the detection of emerging influenza epidemics. However, the selection of the search queries and the adoption of prediction methods are crucial challenges when it comes to improving predictions. The purpose of this study was to explore the application of the Support Vector Machine (SVM) regression model in merging search engine query data and traditional influenza data. Methods: The official monthly reported number of influenza cases in Liaoning province in China was acquired from the China National Scientific Data Center for Public Health from January 2011 to December 2015. Based on Baidu Index, a publicly available search engine database, search queries potentially related to influenza over the corresponding period were identified. An SVM regression model was built to be used for predictions, and the choice of three parameters (C, gamma, epsilon) in the SVM regression model was determined by leave-one-out cross-validation (LOOCV) during the model construction process. The model's performance was evaluated by the evaluation metrics including Root Mean Square Error, Root Mean Square Percentage Error and Mean Absolute Percentage Error. Results: In total, 17 search queries related to influenza were generated through the initial query selection approach and were adopted to construct the SVM regression model, including nine queries in the same month, three queries at a lag of one month, one query at a lag of two months and four queries at a lag of three months. The SVM model performed well when with the parameters (C = 2, gamma = 0.005, E = 0.0001), based on the ensemble data integrating the influenza surveillance data and Baidu search query data. Conclusions: The results demonstrated the feasibility of using internet search engine query data as the complementary data source for influenza surveillance and the efficiency of SVM regression model in tracking the influenza epidemics in Liaoning. PMID- 29967756 TI - The antimicrobial action of polyaniline involves production of oxidative stress while functionalisation of polyaniline introduces additional mechanisms. AB - Polyaniline (PANI) and functionalised polyanilines (fPANI) are novel antimicrobial agents whose mechanism of action was investigated. Escherichia coli single gene deletion mutants revealed that the antimicrobial mechanism of PANI likely involves production of hydrogen peroxide while homopolymer poly(3 aminobenzoic acid), P3ABA, used as an example of a fPANI, disrupts metabolic and respiratory machinery, by targeting ATP synthase and causes acid stress. PANI was more active against E. coli in aerobic, compared to anaerobic, conditions, while this was apparent for P3ABA only in rich media. Greater activity in aerobic conditions suggests involvement of reactive oxygen species. P3ABA treatment causes an increase in intracellular free iron, which is linked to perturbation of metabolic enzymes and could promote reactive oxygen species production. Addition of exogenous catalase protected E. coli from PANI antimicrobial action; however, this was not apparent for P3ABA treated cells. The results presented suggest that PANI induces production of hydrogen peroxide, which can promote formation of hydroxyl radicals causing biomolecule damage and potentially cell death. P3ABA is thought to act as an uncoupler by targeting ATP synthase resulting in a futile cycle, which precipitates dysregulation of iron homeostasis, oxidative stress, acid stress, and potentially the fatal loss of proton motive force. PMID- 29967757 TI - Huperzine A attenuates nonalcoholic fatty liver disease by regulating hepatocyte senescence and apoptosis: an in vitro study. AB - Objective: This study was undertaken to detect if free fatty acids (FFA) induce hepatocyte senescence in L-02 cells and if huperzine A has an anti-aging effect in fatty liver cells. Methods: L-02 cells were treated with a FFA mixture (oleate/palmitate, at 3:0, 2:1, 1:1, 1:2 and 0:3 ratios) at different concentrations. Cell viability and fat accumulation rate were assessed by a Cell Counting Kit 8 and Nile Red staining, respectively. The mixture with the highest cell viability and fat accumulation rate was selected to continue with the following experiment. The L-02 cells were divided into five groups, including the control group, FFA group, FFA + 0.1 MUmol/L huperzine A (LH) group, FFA + 1.0 MUmol/L huperzine A (MH) group and FFA + 10 MUmol/L huperzine A (HH) group, and were cultured for 24 h. The expression of senescence-associated beta galactosidase (SA-beta-gal) was detected by an SA-beta-gal staining kit. The expression levels of aging genes were measured by qRT-PCR. The expression levels of apoptosis proteins were detected by a Western blot. ELISA kits were used to detect inflammatory factors and oxidative stress products. The expression of nuclear factor (NF-kappaB) and IkappaBalpha were detected by immunofluorescence. Results: The FFA mixture (oleate/palmitate, at a 2:1 ratio) of 0.5 mmol/L had the highest cell viability and fat accumulation rate, which was preferable for establishing an in vitro fatty liver model. The expression of inflammatory factors (TNF-alpha and IL-6) and oxidants Malonaldehyde (MDA), 4-hydroxynonenal (HNE) and reactive oxygen species (ROS) also increased in the L-02 fatty liver cells. The expression levels of aging markers and aging genes, such as SA-beta gal, p16, p21, p53 and pRb, increased more in the L-02 fatty liver cells than in the L-02 cells. The total levels of the apoptosis-associated proteins Bcl2, Bax, Bax/Bcl-2, CyCt and cleaved caspase 9 were also upregulated in the L-02 fatty liver cells. All of the above genes and proteins were downregulated in the huperzine A and FFA co-treatment group. In the L-02 fatty liver cells, the expression of IkappaBalpha decreased, while the expression of NF-kappaB increased. After the huperzine A and FFA co-treatment, the expression of IkappaBalpha increased, while the expression of NF-kappaB decreased. Conclusion: Fatty liver cells showed an obvious senescence and apoptosis phenomenon. Huperzine A suppressed hepatocyte senescence, and it might exert its anti-aging effect via the NF-kappaB pathway. PMID- 29967758 TI - Hi-MC: a novel method for high-throughput mitochondrial haplogroup classification. AB - Effective approaches for assessing mitochondrial DNA (mtDNA) variation are important to multiple scientific disciplines. Mitochondrial haplogroups characterize branch points in the phylogeny of mtDNA. Several tools exist for mitochondrial haplogroup classification. However, most require full or partial mtDNA sequence which is often cost prohibitive for studies with large sample sizes. The purpose of this study was to develop Hi-MC, a high-throughput method for mitochondrial haplogroup classification that is cost effective and applicable to large sample sizes making mitochondrial analysis more accessible in genetic studies. Using rigorous selection criteria, we defined and validated a custom panel of mtDNA single nucleotide polymorphisms that allows for accurate classification of European, African, and Native American mitochondrial haplogroups at broad resolution with minimal genotyping and cost. We demonstrate that Hi-MC performs well in samples of European, African, and Native American ancestries, and that Hi-MC performs comparably to a commonly used classifier. Implementation as a software package in R enables users to download and run the program locally, grants greater flexibility in the number of samples that can be run, and allows for easy expansion in future revisions. Hi-MC is available in the CRAN repository and the source code is freely available at https://github.com/vserch/himc. PMID- 29967759 TI - Resveratrol reduces the inflammatory response in adipose tissue and improves adipose insulin signaling in high-fat diet-fed mice. AB - Background: Obesity-induced glucose metabolism disorder is associated with chronic, low-grade, systemic inflammation and is considered a risk factor for diabetes and metabolic syndrome. Resveratrol (RES), a natural anti-inflammatory compound, is observed to improve glucose tolerance and insulin sensitivity in obese rodents and humans. This study aimed to test the effects of RES administration on insulin signaling and the inflammatory response in visceral white adipose tissue (WAT) caused by a high-fat diet (HFD) in mice. Methods: A total of 40 wild-type C57BL/6 male mice were divided into four groups (10 in each group): the standard chow diet (STD) group was fed a STD; the HFD group was fed a HFD; and the HFD-RES/L and HFD-RES/H groups were fed a HFD plus RES (200 and 400 mg/kg/day, respectively). The L and H in RES/L and RES/H stand for low and high, respectively. Glucose tolerance, insulin sensitivity, circulating inflammatory biomarkers and lipid profile were determined. Quantitative PCR and Western blot were used to determine the expression of CC-chemokine receptor 2 (CCR2), other inflammation markers, glucose transporter 4 (GLUT4), insulin receptor substrate 1 (IRS-1) and pAkt/Akt and to assess targets of interest involving glucose metabolism and inflammation in visceral WAT. Results: HFD increased the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and proinflammatory cytokines in serum, decreased the high-density lipoprotein cholesterol level in serum, and induced insulin resistance and WAT inflammation in mice. However, RES treatment alleviated insulin resistance, increased the expressions of pAkt, GLUT4 and IRS-1 in WAT, and decreased serum proinflammatory cytokine levels, macrophage infiltration and CCR2 expression in WAT. Conclusion: Our results indicated that WAT CCR2 may play a vital role in macrophage infiltration and the inflammatory response during the development of insulin resistance in HFD-induced obesity. These data suggested that administration of RES offers protection against abnormal glucose metabolism and inflammatory adaptations in visceral WAT in mice with HFD-induced obesity. PMID- 29967760 TI - Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2. AB - In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H2Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2+ myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2-/-). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2-/- human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2+/+, but not of NOX2-/- human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML. PMID- 29967762 TI - Editorial: Controversies in the Local Management of Lung Cancer. PMID- 29967763 TI - Why Is a High Temperature Needed by Thermus thermophilus Argonaute During mRNA Silencing: A Theoretical Study. AB - Thermus thermophiles Argonaute (TtAgo) is a complex, which is consisted of 5' phosphorylated guide DNA and a series of target DNA with catalytic activities at high temperatures. To understand why high temperatures are needed for the catalytic activities, three molecular dynamics simulations and binding free energy calculations at 310, 324, and 338K were performed for the TtAgo-DNA complex to explore the conformational changes between 16-mer guide DNA/15-mer target DNA and TtAgo at different temperatures. The simulation results indicate that a collapse of a small beta-strand (residues 507-509) at 310 K caused Glu512 to move away from the catalytic residues Asp546 and Asp478, resulting in a decrease in catalytic activity, which was not observed in the simulations at 324 and 338 K. The nucleic acid binding channel became enlarged at 324 and 338K, thereby facilitating the DNA to slide in. Binding free energy calculations and hydrogen bond occupancy indicated that the interaction between TtAgo and the DNA was more stable at 324K and 338K than at 310 K. The DNA binding pocket residues Lys575 and Asn590 became less solvent accessible at 324 and 338K than at 310 K to influence hydrophilic interaction with DNA. Our simulation studies shed some light on the mechanism of TtAgo and explained why a high temperature was needed by TtAgo during gene editing of CRISPR. PMID- 29967764 TI - Novel Features and Considerations for ERA and Regulation of Crops Produced by Genome Editing. AB - Genome editing describes a variety of molecular biology applications enabling targeted and precise alterations of the genomes of plants, animals and microorganisms. These rapidly developing techniques are likely to revolutionize the breeding of new crop varieties. Since genome editing can lead to the development of plants that could also have come into existence naturally or by conventional breeding techniques, there are strong arguments that these cases should not be classified as genetically modified organisms (GMOs) and be regulated no differently from conventionally bred crops. If a specific regulation would be regarded necessary, the application of genome editing for crop development may challenge risk assessment and post-market monitoring. In the session "Plant genome editing-any novel features to consider for ERA and regulation?" held at the 14th ISBGMO, scientists from various disciplines as well as regulators, risk assessors and potential users of the new technologies were brought together for a knowledge-based discussion to identify knowledge gaps and analyze scenarios for the introduction of genome-edited crops into the environment. It was aimed to enable an open exchange forum on the regulatory approaches, ethical aspects and decision-making considerations. PMID- 29967765 TI - Transcriptome and Expression Profiling Analysis of Recalcitrant Tea (Camellia sinensis L.) Seeds Sensitive to Dehydration. AB - The tea plant (Camellia sinensis (L.) O. Kuntze) is an economically important woody perennial nonalcoholic health beverage crop. Tea seeds are categorized as recalcitrant and are sensitive to dehydration treatment. However, the molecular basis of this phenomenon has not been investigated. Thus, we analyzed the genome wide expression profiles of three dehydration stages using RNA-Seq and digital gene expression (DGE) technologies. We performed de novo assembly and obtained a total of 91,925 nonredundant unigenes, of which 58,472 were extensively annotated. By a hierarchical clustering of differentially expressed genes (DEGs), we found that 8929 DEGs were downregulated and 5875 DEGs were upregulated during dehydration treatment. A series of genes related to ABA biosynthesis and signal transduction, transcription factor, antioxidant enzyme, LEA protein, and proline metabolism that have been reported to function in dehydration process were found to be downregulated. Additionally, the expression profiles of 12 selected genes related to tea seed dehydration treatment were confirmed by qRT-PCR analysis. To our knowledge, this is the first genome-wide study elucidating the possible molecular mechanisms of sensitivity of recalcitrant tea seeds to dehydration. The results obtained in this study contribute to the preservation of tea seeds as genetic resources and can also be used to explore the mechanism of dehydration sensitivity of other recalcitrant seeds. PMID- 29967766 TI - Upregulation of Immune Process-Associated Genes in RAW264.7 Macrophage Cells in Response to Burkholderia pseudomallei Infection. AB - Melioidosis is a severe and fatal tropical zoonosis, which is triggered by Burkholderia pseudomallei. To better understand the host's response to infection of B. pseudomallei, an RNA-Seq technology was used to confirm differentially expressed genes (DEGs) in RAW264.7 cells infected with B. pseudomallei. In total, 4668 DEGs were identified across three time points (4, 8, and 11 hours after infection). Short Time-Series Expression Miner (STEM) analysis revealed the temporal gene expression profiles and identified seven significant patterns in a total of 26 profiles. Kyoto Encyclopedia of Genes and Genomes (KEGG) was utilized to confirm significantly enriched immune process-associated pathways, and 10 DEGs, including Ccl9, Ifnb1, Tnfalpha, Ptgs2, Tnfaip3, Zbp1, Ccl5, Ifi202b, Nfkbia, and Nfkbie, were mapped to eight immune process-associated pathways. Subsequent quantitative real-time PCR assays confirmed that the 10 DEGs were all upregulated during infection. Overall, the results showed that B. pseudomallei infection can initiate a time-series upregulation of immune process-associated DEGs in RAW264.7 macrophage cells. The discovery of this article helps us better understand the biological function of the immune process-associated genes during B. pseudomallei infection and may aid in the development of prophylaxis and treatment protocols for melioidosis. PMID- 29967768 TI - Contemporary Perspective on Addictive Behaviors: Underpinning Mechanisms, Assessment, and Treatment. PMID- 29967767 TI - Immunological Compatibility of Bone Tissues from Alpha-1,3-galactosyltransferase Knockout Pig for Xenotransplantation. AB - We investigated whether the lack of galactosyltransferase (alpha-Gal) expression in bone tissue is associated with reduced immune response of human peripheral blood mononuclear cells (PBMCs) against pig bone tissue. When human PBMC obtained from heparinized blood of healthy volunteers was stimulated with bone extracts of pigs with alpha-1,3-galactosyltransferase knock out (alpha-Gal KO), the proliferation of human PBMCs and production of proinflammatory cytokines such as TNF-alpha and IL-1beta were significantly reduced compared to those stimulated with bone extracts of wild type (WT) pigs. In addition, activation of CD4+ helper T cells and production of IL-2, IFN-gamma, and IL-17 were reduced upon stimulation with bone tissue extracts from alpha-Gal KO pigs. This is possibly due to the lowered activities of the NF-kappaB, p38, ERK, and JNK signaling pathways. Our findings can be used to evaluate the compatibility of bone tissues from alpha-Gal KO pigs with human bone grafting as novel natural biomaterials, thereby increasing the feasibility of future clinical applications. PMID- 29967761 TI - Non-Coding RNAs and Resistance to Anticancer Drugs in Gastrointestinal Tumors. AB - Non-coding RNAs are important regulators of gene expression and transcription. It is well established that impaired non-coding RNA expression especially the one of long non-coding RNAs and microRNAs is involved in a number of pathological conditions including cancer. Non-coding RNAs are responsible for the development of resistance to anticancer treatments as they regulate drug resistance-related genes, affect intracellular drug concentrations, induce alternative signaling pathways, alter drug efficiency via blocking cell cycle regulation, and DNA damage response. Furthermore, they can prevent therapeutic-induced cell death and promote epithelial-mesenchymal transition (EMT) and elicit non-cell autonomous mechanisms of resistance. In this review, we summarize the role of non-coding RNAs for different mechanisms resulting in drug resistance (e.g., drug transport, drug metabolism, cell cycle regulation, regulation of apoptotic pathways, cancer stem cells, and EMT) in the context of gastrointestinal cancers. PMID- 29967769 TI - Dosimetric Comparisons of Volumetric Modulated Arc Therapy and Tomotherapy for Early T-Stage Nasopharyngeal Carcinoma. AB - Purpose: To compare the dosimetric differences between volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT) in treating early T-stage nasopharyngeal carcinoma (NPC). Method: Ten patients with early T-stage NPC who received tomotherapy using simultaneously integrated boost (SIB) strategies were replanned with VMAT (RapidArc of Varian, dual-arc). Dosimetric comparisons between the RapidArc plan and the HT plan included the following: (1) D98, homogeneity, and conformity of PTVs; (2) sparing of organs at risk (OARs); (3) delivery time and monitor units (MUs). Results: (1) Compared with RapidArc, HT achieved better dose conformity (CI of PGTVnx + nd: 0.861 versus 0.818, P = 0.004). (2) In terms of OAR protection, RapidArc exhibited significant superiority in sparing ipsilateral optic nerve (Dmax: 27.5Gy versus 49.1Gy, P < 0.001; D2: 23.5Gy versus 48.2Gy, P < 0.001), contralateral optic nerve (Dmax: 30.4Gy versus 49.2Gy, P < 0.001; D2: 26.2Gy versus 48.1Gy, P < 0.001), and optic chiasm (Dmax: 32.8Gy versus 48.3Gy, P < 0.001; D2: 30Gy versus 47.6Gy, P < 0.001). HT demonstrated a superior ability to protect the brain stem (D1cc: 43.0Gy versus 45.2Gy, P = 0.012), ipsilateral temporal lobe (Dmax 64.5Gy versus 66.4 Gy, P = 0.015), contralateral temporal lobe (Dmax: 62.8Gy versus 65.1Gy, P = 0.001), ipsilateral lens (Dmax: 4.27Gy versus 5.24Gy, P = 0.009; D2: 4.00Gy versus 5.05Gy, P = 0.002; Dmean: 2.99Gy versus 4.31Gy, P < 0.001), contralateral lens (Dmax: 4.25Gy versus 5.09Gy, P = 0.047; D2: 3.91Gy versus 4.92Gy, P = 0.005; Dmean: 2.91Gy versus 4.18Gy, P < 0.001), ipsilateral parotid (Dmean: 36.4Gy versus 41.1Gy, P = 0.002; V30Gy: 54.8% versus 70.4%, P = 0.009), and contralateral parotid (Dmean: 33.4Gy versus 39.1Gy, P < 0.001; V30Gy: 48.2% versus 67.3%, P = 0.005). There were no statistically significant differences in spinal cord or pituitary protection between the RapidArc plan and the HT plan. (3) RapidArc achieved a much shorter delivery time (3.8 min versus 7.5 min, P < 0.001) and a lower MU (618MUs versus 5646MUs, P < 0.001). Conclusion: Our results show that RapidArc and HT are comparable in D98, dose homogeneity, and protection of the spinal cord and pituitary gland. RapidArc performs better in shortening delivery time, lowering MUs, and sparing the optic nerve and optic chiasm. HT is superior in dose conformity and protection of the brain stem, temporal lobe, lens, and parotid. PMID- 29967770 TI - No Association of CALCA Polymorphisms and Aseptic Loosening after Primary Total Hip Arthroplasty. AB - Studies of aseptic loosening showed an influence of calcitonin and alpha-CGRP, both encoded from the calcitonin/alpha-CGRP (CALCA) gene by alternative splicing. The aim of this study was to detect a possible association of the CALCA polymorphisms P1(rs1553005), P2(rs35815751), P3(rs5240), and P4(rs2956) with the time to aseptic loosening after THA. 320 patients suffering from aseptic loosening after primary total hip arthroplasty were genotyped for CALCA-P1 polymorphism and 161 patients for CALCA-P2 and CALCA-P3 polymorphisms and 160 patients for CALCA-P4 polymorphism. CALCA genotypes were determined by polymerase chain reaction and restriction-fragment length polymorphism. The genotype distribution of CALCA-P1 was CC 10%, CT 43%, and 46% TT. CALCA-P2 showed a distribution of 90.7%II, 8.7% ID, and 0.6% DD. The CALCA-P3 genotype distribution was 97.5% TT and 2.5% TC. The CALCA-P4 genotype distribution was 48.1% AA, 40% AT, and 11.9% TT. Significant differences between the CALCA genotypes were not found concerning age at implantation and replantation, BMI, gender, and cementation technique. No associations of the time for aseptic loosening were found. In conclusion, we did not find a significant association of CALCA polymorphisms and the time to aseptic loosening after primary THA in a Western European group. PMID- 29967771 TI - Comment on "Physical Exercise and Patients with Chronic Renal Failure: A Meta Analysis". PMID- 29967772 TI - Relation of Lean Body Mass and Muscle Performance to Serum Creatinine Concentration in Hemodialysis Patients. AB - Introduction: Serum creatinine concentration is an important uremic marker and predictor of survival in dialysis patients. This cross-sectional case-control study was made to quantitatively describe the relation between lean body mass (LBM), physical performance measures, and serum creatinine values. Methods: Ninety hemodialysis patients and 106 controls were measured by bioimpedance spectroscopy, handgrip strength, sit-to-stand test, and biochemical serum tests. Univariate and multivariate general linear models were used to analyze quantitative relations. Results: At univariate regression LBM accounted for 13.6% variability of serum creatinine concentration. In adjusted analyses with age, height, and body mass, LBM persisted as the only significant predictor of midweek predialysis serum creatinine concentration. Physical performance measures handgrip strength and sit-to-stand performance did not improve prediction of serum creatinine. With addition of serum urea concentration and residual diuresis the predictive value of the regression model improved to account for 45% of serum creatinine variability. Each kg of LBM was associated with 7.7 MUmol/l increase in creatinine concentration (95% CI 3.4-12.1, p=0.001). Conclusion: Bioimpedance derived LBM has a significant linear relation with predialysis serum creatinine concentrations. Hereby described quantitative relation should help clinicians to better evaluate observed creatinine concentrations of hemodialysis patients when bioimpedance derived LBM is available. PMID- 29967773 TI - Effect of the Use of Different Acoustic Stimuli on Cortical Auditory Evoked Potentials and Autonomic Cardiac Modulation. AB - Purpose: The aim of this study was to analyze the relationship between Cortical Auditory Evoked Potentials (CAEPs) measurements and autonomic cardiac modulation in relation to different acoustic stimuli and to verify which of these stimuli have more influence on the autonomic nervous system. Methods: Sixty healthy women, aged between 18 and 25 years, participated in this study. Prior to the CAEP examination, blood pressure and resting heart rate were measured using a stethoscope, sphygmomanometer, and the Polar RS800CX cardiofrequency measures. After the collection of these measures, the CAEP test was started simultaneously with the HRV collection. Results: All the HRV indices presented correlations with the components of the CAEPs. During the acoustic stimulation, a predominance of the modulation of the autonomic parasympathetic nervous system was observed. The harmonic and disharmonic stimuli were the ones that presented the most correlations between the measures analyzed in this study. Conclusions: There was an association between CAEP and cardiac autonomic modulation in relation to different acoustic stimuli. Among the acoustic stimuli used in this study, the ones that most influenced the autonomic cardiac modulation were harmonic and disharmonic stimuli, which are acoustically more complex stimuli. PMID- 29967774 TI - Expression of miR-652-3p and Effect on Apoptosis and Drug Sensitivity in Pediatric Acute Lymphoblastic Leukemia. AB - MicroRNAs (miRNAs) expression profiles were screened in plasma samples from pediatric patients with acute lymphoblastic leukemia (ALL) and healthy controls, using qRT-PCR-based TaqMan low-density miRNA arrays. MiR-652-3p (a circulating miRNA) was downregulated in new diagnosis (ND) patients compared with healthy controls. The levels of miR652-3p were restored in complete remission (CR) but were downregulated again in disease relapse (RE). The expression pattern of miR 652-3p was validated in bone marrow (BM) samples from other pediatric ALL patients. MiR-652-3p was significantly upregulated in BM when the patients (n=86) achieved CR, as compared with the matched ND samples (p<0.001). Moreover, the miR 652-3p levels in BM decreased again in two patients at RE. In addition, the lymphoblastic leukemia cell lines Reh and RS4:11 were found to have lower levels of miR-625-3p than the normal B-cell line. Overexpression of miR-652-3p using agomir increased the sensitivity to vincristine and cytarabine (all p<0.05) and promoted apoptosis (both p<0.05) in Reh and RS4:11 cells. In conclusion, the results suggested that a low level of miR-652-3p might be involved in the pathogenesis of pediatric ALL. Overexpression of miR-652-3p might suppress lymphoblastic leukemia cells, promoting apoptosis and increasing sensitivity to chemotherapeutic drugs. PMID- 29967775 TI - The Bioactive Substance Secreted by MSC Retards Mouse Aortic Vascular Smooth Muscle Cells Calcification. AB - Background: Vascular calcification, which is associated with low-level chronic inflammation, is a complication that occurs during aging, atherosclerosis, chronic kidney disease, diabetes mellitus, and hyperlipaemia. In this study, we used conditioned media from mesenchymal stem cells (MSC-CM), a source of autologous cytokines, to test the hypothesis that MSC-CM inhibits vascular smooth muscle cell (VSMC) calcification by suppressing inflammation and apoptosis. Methods: VSMCs were treated with beta-glycerophosphate (beta-GP) to induce calcification and MSC-CM was used as a treatment. Calcium deposition was evaluated using alizarin red and von Kossa staining after a 7-day induction period. Intracellular calcium contents were measured via the o-cresolphthalein complexone method, and alkaline phosphatase (ALP) activity was determined using the para-nitrophenyl phosphate method. The expressions of specific-osteogenic markers, inflammatory cytokines, and apoptosis-associated genes/proteins were examined by real-time polymerase chain reaction or western blotting. Results: MSC CM inhibited beta-GP-induced calcium deposition in VSMCs and decreased intracellular calcium content and ALP activity. Additionally, MSC-CM suppressed the beta-GP-induced increases in BMP2, Msx2, Runx2, and osteocalcin expression. Additionally, MSC-CM decreased the expression of TNF-alpha, IL-1beta, and IL-6 in VSMC. MSC-CM also partly blocked beta-GP-induced VSMC apoptosis, which was associated with an increase in the Bcl-2/Bax expression ratio and a decrease in caspase-3 expression. Conclusion: Our study results suggest that MSC-CM can inhibit VSMC calcification. This suggests a potential novel clinical application for MSCs in the treatment of vascular calcification and associated diseases. PMID- 29967777 TI - Clinically Symptomatic Pericardial Effusions in Hospitalized Systemic Sclerosis Patients: Demographics and Management. AB - Background: Pericardial effusions in systemic sclerosis (SSc) may present as acute or chronic with or without clinical symptoms. Best treatment is unknown and whether patients receive medical therapy or a surgical procedure is clinician dependent. Objective: To describe the clinical characteristics, treatment, and outcomes of patients with SSc and clinically symptomatic pericardial effusions treated in the inpatient setting. Methods: We evaluated all SSc admissions over a 10-year period to a tertiary care hospital which has a dedicated SSc clinic. Patients who had a clinically symptomatic pericardial effusion were evaluated based on their demographics, disease pattern, and medical or surgical management. Results: From January 2005 till October 2015, there were 462 SSc admissions with 32 (6.9%) of them being for a clinically symptomatic pericardial effusion in 23 unique patients. Eleven (47%) of these patients had right heart failure, seventeen (74%) had pulmonary arterial hypertension (PAH), and 4 (17%) had tamponade physiology. Five (22%) patients were treated by a surgical procedure, while eighteen (78%) patients had medical therapy. Patients who received medical therapy tended to be older, have a lower serum Cr level, and more likely have right heart failure. Conclusion: Clinically symptomatic pericardial effusion is a rare cause for hospital admissions in SSc, with a high percentage of these patients having PAH. Medical therapy tends to be reserved for older patients with right heart failure, while surgical therapy was more likely in patients with higher serum Cr levels. PMID- 29967779 TI - Long-Term In Vivo Evaluation of Chitosan Nerve Guide Properties with respect to Two Different Sterilization Methods. AB - Severe peripheral nerve injuries are reconstructed either with autologous nerve grafts (gold standard) or alternatively with clinically approved artificial nerve guides. The most common method used to sterilize these medical products is ethylene oxide gassing (EO). However, this method has several disadvantages. An alternative, which has been barely studied so far, represents beta irradiation (beta). In previous studies, we developed an artificial nerve guide made of chitosan (chitosan nerve guide, CNG), a biomaterial that is known to potentially retain toxic residues upon EO sterilization. Therefore, we analyzed the long-term regeneration-supporting and mechanical properties of CNGs upon their sterilization with EO or beta and their following application in unilateral repair of 12 mm gaps of the rat sciatic nerve. Over a period of 76 weeks, we serially evaluated the recovery of motor functions, the possible emergence of an inflammation in the surrounding connective tissue, the regrowth of axons into the distal nerve, and possible changes in the material properties. Our first long term evaluation did not reveal significant differences between both sterilization methods. Thus, beta is as appropriate as commonly used EO for sterilization of CNGs; however, it may slightly increase the stiffness of the biomaterial over time. PMID- 29967778 TI - The Pathology of Type II Modic Changes: Fat Deposition or Osteosclerosis? A Study Using CT Scan. AB - Study Design: A retrospective cross-sectional study of type II Modic changes (MCs). Objective: To evaluate the CT values of type II MCs and determine their relationship with disc degeneration. Methods: 124 type II MCs from 66 patients' MRI and CT were included and analyzed. Disc degeneration adjacent to MCs was evaluated based on Pfirrmann classification. CT values of bone marrow area and endplate from MC regions, adjacent non-MC regions, and L1 vertebra were measured. CT value changes (DeltaCT value) were defined as MCs' CT value minus non-MCs'. According to the types of variables, paired t-test, signed-rank test, two-way ANOVA, and Friedman test were used. Results: The CT value of MCs was significantly higher than that of non-MCs at both bone marrow area and endplate (P<0.0001, resp.). Good consistency was found between non-MCs and L1 vertebra in the CT value of bone marrow area and endplate (P=0.2129, P=0.2272, resp.), suggesting the control group was valid. Adjacent to type II MCs, there were 8 (6.4%) discs with grade III degeneration, 58 (46.8%) with grade IV, and 58 (46.8%) with grade V. The DeltaCT value of grade V disc degeneration was larger than that of grade IV at the endplate (P=0.0150). Conclusions: Osteosclerosis may exist in type II MCs. The more severe the degeneration of the adjacent disc, the greater the degree of osteosclerosis. PMID- 29967776 TI - Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts. AB - Cancer associated fibroblasts (CAFs) are the main stromal cell type of solid tumour microenvironment and undergo an activation process associated with secretion of growth factors, cytokines, and paracrine interactions. One of the important features of solid tumours is the metabolic reprogramming that leads to changes of bioenergetics and biosynthesis in both tumour cells and CAFs. In particular, CAFs follow the evolution of tumour disease and acquire a catabolic phenotype: in tumour tissues, cancer cells and tumour microenvironment form a network where the crosstalk between cancer cells and CAFs is associated with cell metabolic reprogramming that contributes to CAFs activation, cancer growth, and progression and evasion from cancer therapies. In this regard, the study of CAFs metabolic reprogramming could contribute to better understand their activation process, the interaction between stroma, and cancer cells and could offer innovative tools for the development of new therapeutic strategies able to eradicate the protumorigenic activity of CAFs. Therefore, this review focuses on CAFs metabolic reprogramming associated with both differentiation process and cancer and stromal cells crosstalk. Finally, therapeutic responses and potential anticancer strategies targeting CAFs metabolic reprogramming are reviewed. PMID- 29967780 TI - Relationship Between Emotional Intelligence and Health Behaviours among University Students: The Predictive and Moderating Role of Gender. AB - This study investigated the role of gender as a potential predictor of health behaviour and potential moderator of the relationship between emotional intelligence and health behaviour. This cross-sectional study included 1214 students (597 males and 617 females). Data were collected using the Schutte Self Report Inventory and the Health Behaviour Checklist. Stepwise multiple regression analysis was executed with the components of health behaviour as the dependent variables to examine the predictive value of the emotional intelligence indicators as the independent variables. Gender predicted all categories of health behaviours. Only one indicator of emotional intelligence, appraisal, predicted the Accident Control and Traffic Risk Taking categories. The emotional intelligence indicator of social skills emerged only as a predictor of Wellness Maintenance and Enhancement in university students. Gender moderates the relationship between all emotional intelligence indicators and health behaviour components except the relationship between Appraisal and Substance Risk Taking and the relationship between Utilization and traffic risk taking. PMID- 29967781 TI - Deep Transcranial Magnetic Stimulation: Improved Coil Design and Assessment of the Induced Fields Using MIDA Model. AB - Stimulation of deep brain structures by transcranial magnetic stimulation (TMS) is a method for activating deep neurons in the brain and can be beneficial for the treatment of psychiatric and neurological disorders. To numerically investigate the possibility for deeper brain stimulation (electric fields reaching the hippocampus, the nucleus accumbens, and the cerebellum), combined TMS coils using the double-cone coil with the Halo coil (HDA) were modeled and investigated. Numerical simulations were performed using MIDA: a new multimodal imaging-based detailed anatomical model of the human head and neck. The 3D distributions of magnetic flux density and electric field were calculated. The percentage of volume of each tissue that is exposed to electric field amplitude equal or greater than 50% of the maximum amplitude of E in the cortex for each coil was calculated to quantify the electric field spread (V50). Results show that only the HDA coil can spread electric fields to the hippocampus, the nucleus accumbens, and the cerebellum with V50 equal to 0.04%, 1.21%, and 6.2%, respectively. PMID- 29967782 TI - The Diagnostic Ability of rs-DWI to Detect Subtle Acute Infarction Lesion in the Different Regions of the Brain and the Comparison between Different b-Values. AB - Objective: To evaluate the diagnostic ability of rs-DWI to detect subtle acute infarction lesion in the different regions of the brain in comparison to routine DWI and the comparison between different b-values. Method: 35 acute brain infarction patients were included. The subtle acute infarction lesions in ss-DWI and rs-DWI sequence were evaluated in 9 anatomical regions of the brain, and the ss-EPI DWI was also acquired with different b-values of 0, 1000, 2000, and 3000s/mm2. The McNemar test was performed for comparing the diagnostic ability of ss-DWI and rs-DWI and different b-values. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the whole brain and in each anatomical region were calculated. Result: A total of 406 subtle acute infarction lesions were confirmed. The ss-DWI detected 338 subtle lesions, out of which 318 were true positive and 20 were false positive lesions. The rs DWI detected 386 subtle lesions, out of which 385 were true positive lesions and 1 was true negative lesion. Sensitivity, specificity, positive predictive value, and negative predictive value in rs-DWI were better than ss-DWI in all anatomical regions of the brain. In the comparison of different b-values, b2000 was found better among b1000, b2000, and b3000. Conclusion: The rs-DWI offers a useful alternative to routine DWI for detecting the subtle acute infarctions, especially in the regions that are susceptible to distortion as in frontal cortex. In addition, high b-value can also provide benefit by increasing diffusion weighting but further raising can deteriorate image quality as SNR is decreased. PMID- 29967783 TI - Development of a SCAR Marker-Based Diagnostic Method for the Detection of the Citrus Target Spot Pathogen Pseudofabraea citricarpa. AB - Target spot, a recently observed citrus disease that is caused by Pseudofabraea citricarpa, can cause substantial economic losses in citrus production. In this study, a 797 bp marker specific to Ps. citricarpa was identified via random amplified polymorphic DNA (RAPD) technique. The primer pair Pc-SFP/Pc-SRP, which was designed from RAPD amplicons, was utilized as a sequence-characterized amplified region (SCAR) marker. This marker identified Ps. citricarpa with a single and distinct band of 389 bp but did not amplify DNA from other tested fungal species. The PCR assay was highly sensitive to the target DNA at picogram levels and could reliably amplify Ps. citricarpa sequences with the Pc-SFP/Pc-SRP primer pair. The SCAR marker that was identified in the present study can facilitate rapid decision-making and precise disease forecasting and management. PMID- 29967784 TI - The Effect of Breed, Gender, and Acid Stimulation in Dog Saliva Proteome. AB - Saliva gained interest as a potential noninvasive source of biomarkers in humans and that interest starts to be extended also to other animal species. For this purpose, the knowledge of the salivary proteome in healthy conditions and the factors that affect it and how they affect it are necessary. The aim of the present study was to assess the effect that gender and breed have in saliva proteome and the changes in it induced by stimulation with acid. Saliva from 4 different purebred dogs (Portuguese Podengo, Greyhound, Rafeiro Alentejano, and Beagle) of both genders was collected without and after stimulation with lemon juice. SDS-PAGE and two-dimensional gel electrophoresis (2-DE) profiles were compared and the proteins of interest in-gel digested and identified by mass spectrometry. Acid stimulation decreased total protein concentration and the relative amounts of some protein bands/spots. Gender appeared to have minimal effect in saliva proteome, whereas the influence of breed varies. Beagles and Portuguese Podengos were the two breeds with higher differences. In conclusion, stimulation procedures and dog breed should be considered in data analysis when using salivary proteins for diagnostic purposes. PMID- 29967785 TI - Colorectal Cancer: How Familiar Are Our Future Doctors with the Cancer of Tomorrow? AB - Background: Colorectal cancer (CRC) is one of the common cancers affecting both genders. Although the incidence of CRC is low in India there has been an increase in the past few decades. Objective: To assess the awareness regarding colorectal cancer and its screening among medical students and interns. Methods: This cross sectional study was conducted among 290 participants (final year medical students and interns) from Kasturba Medical College, Mangalore. A pretested semistructured questionnaire was used to collect information. Data was analyzed using SPSS 17.0. Results: Majority of participants had satisfactory knowledge regarding CRC. 38% of them scored excellently, 64.8% had good knowledge, and 5.2% scored poorly. Knowledge regarding CRC symptoms was good (95%). 92% of the participants were aware of risk factors of CRC. Only 49% of the participants identified FOBT as a screening tool and 30.7% participants knew that 50 years is the recommended age to begin CRC screening. Interns and international students had better knowledge than final year medical students and Indian students and this was found to be statistically significant. Conclusion: There is a need to improve participant's knowledge regarding CRC screening although majority of them are aware of CRC symptoms and risk factors. PMID- 29967786 TI - Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations. AB - Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer dimer interface, whereas dimers (formed by monomers which pair to form two extended beta-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects. PMID- 29967787 TI - Molecular Evolutionary Analysis of the HCRTR Gene Family in Vertebrates. AB - Hypocretin system is composed of hypocretins (hcrts) and their receptors (hcrtrs), which has multiple vital functions. Hypocretins work via hypocretin receptors and it is reported that functional differentiation occurred in hcrtrs. It is necessary to figure out the evolution process of hypocretin receptors. In our study, we adopt a comprehensive approach and various bioinformatics tools to analyse the evolution process of HCRTR gene family. It turns out that the second round of whole genome duplication in early vertebrate ancestry and the independent round in fish ancestry may contribute to the diversity of HCRTR gene family. HCRTR1 of fishes and mammals are not the same receptor, which means that there are three members in the family. HCRTR2 is proved to be the most ancient one in HCRTR gene family. After duplication events, the structure of HCRTR1 diverged from HCRTR2 owing to relaxed selective pressure. Negative selection is the predominant evolutionary force acting on the HCRTR gene family but HCRTR1 of mammals is found to be subjected to positive selection. Our study gains insight into the molecular evolution process of HCRTR gene family, which contributes to the further study of the system. PMID- 29967788 TI - Increased Risk for Hip Fractures among Patients with Cholangitis: A Nationwide Population-Based Study. AB - Background: Cholangitis is the infectious disease involving the biliary tract, which may induce systemic inflammation. Bone loss is a well-known sequelae after systemic inflammatory disease, and one grave complication after osteoporosis is hip fracture. We want to know whether cholangitis can contribute to increased risk of hip fracture. Methods: All the patients diagnosed with cholangitis since January 1, 2001, to December 31, 2009, were assessed. All the subjects with cancer history, traumatic accident, and previous fracture were excluded. We selected the controls without cholangitis and matched the controls to cholangitis patients by age, sex, osteoporosis, and the use of steroid for more than 30 days by approximately 1:4 ratio. Results: There were 2735 subjects in the cholangitis cohort and 10915 in the noncholangitis cohort. There were 101 hip fractures in the cholangitis cohort with the incidence density of 7.58 per 1000 person-years. As for the noncholangitis cohort, 366 individuals suffered from hip fracture with the incidence density of 5.86 per 1000 person-years. The risk of hip fracture was higher in the cholangitis cohort with a 1.29-fold increased risk than the noncholangitis cohort (hazard ratio = 1.29, 95% confidence interval = 1.03-1.61). The association between cholangitis and the hip fracture was more prominent among subjects less than 65 years (hazard ratio = 2.65, 95% confidence interval =1.30 5.39) and the subjects without comorbidities (hazard ratio = 3.01, 95% confidence interval = 1.42-6.41). Conclusions: Cholangitis is associated with higher risk for hip fracture, especially among young subjects free from medical comorbidities. PMID- 29967789 TI - Benefits of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A Systematic Review and Meta-Analysis. AB - Background: The adjuvant use of mitotane on adrenocortical carcinoma (ACC) has always been in controversy. We aimed to assess the prognostic benefits of adjuvant mitotane after resection of ACC in patients without distant metastasis. Methods: The PubMed, WoS, Embase, and Cochrane Library databases were systematically searched. Recurrence-free survival (RFS) and overall survival (OS) were adopted as measurements. A meta-analysis was conducted based on hazard ratio (HR) with 95% confidence interval (CI). A study was included only if the enrolled patients underwent resection of ACC without adjuvant chemotherapy except mitotane. Results: A total of 5 retrospective studies reporting on 1249 patients were included for this meta-analysis. The meta-analysis showed that adjuvant mitotane was significantly associated with prolonged RFS (HR = 0.62; 95%CI, 0.42 0.94; P < 0.05) and prolonged OS (HR = 0.69; 95%CI, 0.55-0.88, P < 0.05). Conclusion: After comprehensive review, current evidence suggests that adjuvant mitotane significantly decreases the recurrence rate and mortality after resection of ACC in patients without distant metastasis, but these findings need further demonstration from prospective controlled trials. PMID- 29967790 TI - Identification of Peptide Antagonists to Thioredoxin Glutathione Reductase of Schistosoma japonicum. AB - Schistosomiasis is one of the world's major public health problems. Praziquantel is currently the only effective drug against schistosomiasis. As resistance of praziquantel has emerged in some endemic areas, development of new antischistosomal agents should be a high priority. In this study, a phage display peptide library was used for screening for peptide antagonists of thioredoxin glutathione reductase of Schistosoma japonicum (SjTGR), which has been identified as an alternative drug target. Three rounds of panning produced four different fusion phages. ELISA proved that all four phages could bind to SjTGR. One peptide, JIPDys1 (aa, WPHNWWPHFKVK), reduced enzyme activity of SjTGR by more than 50%. 2 MUM of the synthesized peptide of JIPDys1 inhibited the activity of TrxR, GR, and Grx of SjTGR by 32.5%, 100%, and 100%, respectively. The IC50 values of the synthetic peptide JIPDys1 for TrxR, GR, and Grx were 3.67 MUM, 0.11 MUM, and 0.97 MUM, respectively. Based on computer simulation, it appeared that JIPDys1 binds to the substrate binding sites of glutathione reductase (GR) and glutaredoxin (Grx). Our data show that the peptide, JIPDys1 (aa, WPHNWWPHFKVK), is a promising candidate to develop novel drugs against S. japonicum which acts by binding with SjTGR and reduces enzyme activity of SjTGR. PMID- 29967791 TI - Evaluation of Erythroid Disturbance and Thiol-Disulphide Homeostasis in Patients with Psoriasis. AB - This study aims to assess how mean corpuscular volume (MCV), red cell distribution width (RDW), and thiol-disulphide homeostasis are altered in psoriasis patients. This is a cross-sectional review of 76 healthy volunteers and 87 psoriasis patients who were consecutively admitted to the department of dermatology. Psoriasis patients and healthy controls were statistically similar with respect to age, sex, body mass index, blood pressures, and disease duration (p > 0.05 for all). When compared to healthy controls, psoriasis patients had significantly higher MCV, RDW, C-reactive protein (CRP), disulphide, disulphide/native thiol, and disulphide/total thiol (p < 0.001 for all). However, psoriasis patients had significantly lower native thiol and native thiol/total thiol (p = 0.009 and p < 0.001, respectively). When compared to healthy controls, the patients with Psoriasis Area Severity Index (PASI) <= 10 and patients with PASI > 10 had significantly higher MCV, disulphide, disulphide/native thiol, and disulphide/total thiol (p < 0.001 for all). The patients with PASI <= 10 and patients with PASI > 10 had significantly lower native thiol/native thiol than healthy controls (p < 0.001 for all). The psoriasis patients with PASI > 10 had significantly higher RDW and CRP than healthy controls and patients with PASI <= 10 (p < 0.001 for all). Disulphide, disulphide/native thiol, disulphide/total thiol, and native thiol/total thiol correlate significantly with both PASI scores and disease duration. Thiol-disulphide homeostasis is enhanced in psoriasis patients. Ongoing inflammation and increased oxidative stress in psoriasis patients also trigger the formation of prooxidants which are neutralized by antioxidants such as thiols. That is why plasma thiol levels are decreased in psoriasis patients. PMID- 29967792 TI - Electrical Impedance Changes at Different Phases of Cerebral Edema in Rats with Ischemic Brain Injury. AB - Cerebral edema contributes significantly to the morbidity and mortality associated with many common neurologic conditions. Clinically, a diagnostic tool that can be used to monitor cerebral edema in real-time and differentiate between different types of cerebral edema is urgently needed. Because there are differences in electrical impedance between normal cortical tissue and cerebral edema tissue, electrical impedance tomography (EIT) can potentially be used to detect cerebral edema. Accurate recording of the electrical impedance properties of cerebral edema tissue at different time points is important when detecting cerebral edema with EIT. In this study, a rat cerebral edema model was established; then, following the onset of ischemic brain injury, variation in the electrical impedance of cerebral edema was measured at different time points within a 24-hour period and the corresponding morphologic variation was analyzed. After the first six hours, following the onset of ischemic brain injury, the resistivity of brain tissue increased (p < 0.05); during this period, brain cell volume increased (p < 0.05) and the intercellular space decreased (p < 0.05) (behaving like cytotoxic cerebral edema). From 6 to 24 hours, the resistivity of brain tissue decreased; during this time, brain cell volume unchanged (p > 0.05) while intercellular space increased (p < 0.05) (behaving like vasogenic cerebral edema). These findings support the notion that EIT can be used to monitor the development of cerebral edema in real-time and differentiate between different types of brain edema. PMID- 29967793 TI - Higher Concentrations of BCAAs and 3-HIB Are Associated with Insulin Resistance in the Transition from Gestational Diabetes to Type 2 Diabetes. AB - Aim: Determine the metabolic profile and identify risk factors of women transitioning from gestational diabetes mellitus (GDM) to type 2 diabetes mellitus (T2DM). Methods: 237 women diagnosed with GDM underwent an oral glucose tolerance test (OGTT), anthropometrics assessment, and completed lifestyle questionnaires six years after pregnancy. Blood was analysed for clinical variables (e.g., insulin, glucose, HbA1c, adiponectin, leptin, and lipid levels) and NMR metabolomics. Based on the OGTT, women were divided into three groups: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and T2DM. Results: Six years after GDM, 19% of subjects had T2DM and 19% IGT. After BMI adjustment, the IGT group had lower HDL, higher leptin, and higher free fatty acid (FFA) levels, and the T2DM group higher triglyceride, FFA, and C-reactive protein levels than the NGT group. IGT and T2DM groups reported lower physical activity. NMR measurements revealed that levels of branched-chain amino acids (BCAAs) and the valine metabolite 3-hydroxyisobyturate were higher in T2DM and IGT groups and correlated with measures of insulin resistance and lipid metabolism. Conclusion: In addition to well-known clinical risk factors, BCAAs and 3-hydroxyisobyturate are potential markers to be evaluated as predictors of metabolic risk after pregnancy complicated by GDM. PMID- 29967794 TI - Alpinia oxyphylla Miq. Extract Prevents Diabetes in Mice by Modulating Gut Microbiota. AB - Recently, the role of gut microbiota in the development of obesity and type 2 diabetes mellitus (T2DM) has been highlighted. We performed an 8-week administration protocol on T2DM (C57BL/6J db-/db-) mice and fecal samples were collected. Comparisons of fecal bacterial communities were performed between db /db- mice and normal mice (DB/DB) and between the db-/db mice treated and untreated with AOE using next-generation sequencing technology. Our results showed that the db-/db-AOE group had improved glycemic control and renal function compared with the db-/db-H2O group. Compared with the db-/db-H2O group, AOE administration resulted in significantly increased ratio of Bacteroidetes-to Firmicutes in db-/db- mice. In addition, the abundance of Akkermansia was significantly increased, while Helicobacter was significantly suppressed in the db-/db-AOE group compared with the db-/db-H2O group. Our data suggest that AOE treatment decreased blood glucose levels and significantly reduced damage of renal pathology in the T2DM mice by modulating gut microbiota composition. PMID- 29967795 TI - Effects of Type 2 Diabetic Serum on Proliferation and Osteogenic Differentiation of Mesenchymal Stem Cells. AB - Diabetic patients have an increased risk of osteoporosis-associated fractures. However, the results of most studies of the effects of diabetes on bone mass in patients with type 2 diabetes (T2DM) have been contradictory. To clarify these conflicting findings, we investigated the effects of diabetic serum on the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). We used human sera from subjects with different levels of glycemic control to culture the MSCs and induce osteogenic differentiation. The rate of MSC proliferation differed when MSCs were cultured with sera from diabetic subjects with different levels of hyperglycemia. Hyperglycemic sera promoted MSC proliferation to some extent, but all the diabetic sera inhibited the differentiation of MSCs to osteoblasts. The effects of type 2 diabetic sera on the proliferation and osteogenic differentiation of MSCs are closely related to glycemic control. Our data demonstrate the importance of stratifying the study population according to glycemic control in clinical research into diabetic osteoporosis. PMID- 29967796 TI - Effects of High Glucose on the Expression of LAMA1 and Biological Behavior of Choroid Retinal Endothelial Cells. AB - Hyperglycemia is one of the main causes of proliferative diabetic retinopathy (PDR) characterized by thickening of the vascular basement membrane. Laminin alpha 1 (LAMA1) is a primary component of laminin, a major protein constituent of the basement membrane. In this study, we investigated the role of LAMA1 in the development of PDR. Retinal choroidal vascular endothelial cells (RF/6A line) were exposed to glucose at different concentrations (5 mM, 15 mM, 25 mM, and 35 mM) and analyzed for cell growth, migration, proliferation, and adhesion. LAMA1 expression was examined 24 and 48 h following glucose treatment using Western blotting, RT-PCR, and immunofluorescence. The results showed that the proliferation, migration, and adhesion of RF/6A cells were increased by high glucose, whereas LAMA1 expression was slightly higher at 15 mM but decreased at 25 mM and 35 mM glucose compared to control. Thus, the changes in the biological behavior of high glucose-exposed retinal vascular endothelial cells correspond to variations in LAMA1 expression, indicating a possibility for LAMA1 involvement in PDR development. Our findings suggest that LAMA1 may play a role in PDR and, thus, may serve as a potential target for DR diagnosis and/or treatment. PMID- 29967797 TI - The Association between Eating Traits and Weight Change after a Lifestyle Intervention in People with Type 2 Diabetes Mellitus. AB - Aims: To date, studies on the role of eating traits in weight loss success have only included obese people without type 2 diabetes mellitus (T2DM), thereby disregarding negative effects of T2DM-related metabolic changes. Our aim was to assess the association between eating traits and weight change after a lifestyle intervention in people with T2DM. Methods: For the current study, we reexamined data from a six-month intervention in 120 participants. We determined eating traits at baseline, using the DEBQ, which were used to produce three groups: unsuccessful dietary restrained (high restraint, high emotional/external eating scores), successful dietary restrained (high restraint, low emotional/external eating scores), and reference (low restraint, high or low emotional/external eating scores). Linear regression was used to study the association between the eating trait groups and weight changes after six months, while correcting for possible confounders. Results: On average, the weight loss success was limited, with a third of the participants being weight stable, a third losing weight > -1 kg (average loss -2.6 +/- 1.9 kg), and a third gaining weight > +1 kg (average gain +3.3 +/- 1.9 kg). When compared to the reference group, the unsuccessful dietary restrained gained weight during the intervention (beta = 1.2 kg, confidence interval (CI)% = 0.1; 2). No significant change was observed in the succesful dietary restrained group. Conclusions: The eating trait of being unsuccessfully dietary restrained is associated with weight-loss failure after a six-month lifestyle intervention in people with T2DM. PMID- 29967799 TI - Modulation of Inflammatory Reactions by Low-Dose Ionizing Radiation: Cytokine Release of Murine Endothelial Cells Is Dependent on Culture Conditions. AB - Background: In many European countries, patients with a variety of chronical inflammatory diseases are treated with low-dose radiotherapy (LD-RT). In contrast to high-dose irradiation given to tumor patients, little is known about radiobiological mechanisms underlying this clinical successful LD-RT application. The objective of this study was to gain a better insight into the modulation of inflammatory reactions after LD-RT on the basis of endothelial cells (EC) as major participants and regulators of inflammation. Methods: Three murine EC lines were cultivated under 2D and 3D culture conditions and irradiated with doses from 0.01 Gy to 2 Gy. To simulate an inflammatory situation, cells were activated with TNF-alpha. After LD-RT, a screening of numerous inflammatory markers was determined by multiplex assay, followed by detailed analyses of four cytokines (KC, MCP-1, RANTES, and G-CSF). Additionally, the monocyte binding to EC was analyzed. Results: Cytokine concentrations were dependent on culture condition, IR dose, time point after IR, and EC origin. IR caused nonlinear dose-dependent effects on secretion of the proinflammatory cytokines KC, MCP-1, and RANTES. The monocyte adhesion was significantly enhanced after IR as well as activation. Conclusions: The study shows that LD-RT, also using very low radiation doses, has a clear immunomodulatory effect on EC as major participants and regulators of inflammation. PMID- 29967798 TI - Microbiota Composition and the Integration of Exogenous and Endogenous Signals in Reactive Nasal Inflammation. AB - The prevalence of reactive nasal inflammatory conditions, for example, allergic rhinitis and chronic rhinosinusitis, is steadily increasing in parallel with significant environmental changes worldwide. Allergens and as yet undefined environmental agents may trigger these conditions via the involvement of host intrinsic factors, including the innate and adaptive immune system, the nasal epithelium, and the nasal nervous system. The critical role of the nasal microbiota in coordinating these components has emerged in recent studies documenting a significant association between microbial composition and the onset and progression of allergic or nonallergic inflammation. It is now clear that the local microbiota is a major player in the development of the mucosa-associated lymphoid tissue and in the regulation of such adaptive responses as IgA production and the function of effector and regulatory T cells. Microbial components also play a major role in the regulation of epithelial barrier functions, including mucus production and the control of paracellular transport across tight junctions. Bacterial components, including lipopolysaccharide, have also been shown to induce or amplify neuroinflammatory responses by engaging specific nociceptors. Finally, bacterial products may promote tissue remodeling processes, including nasal polyp formation, by interacting with formyl peptide receptors and inducing the expression of angiogenic factors and matrix-degrading enzymes. PMID- 29967800 TI - Polysaccharides from Chinese Herbal Lycium barbarum Induced Systemic and Local Immune Responses in H22 Tumor-Bearing Mice. AB - Lycium barbarum polysaccharide (LBP) is isolated from the fruit of Chinese herbal Lycium barbarum. Previous studies had demonstrated that LBP could inhibit tumor growth and enhance the immunity in mice. However, the effect of LBP on systemic and local immune responses in vivo, especially on phenotypic and functional changes of T cells, is still largely unknown. In the present study, we investigated the effects of LBP on systemic and local T cell-dependent antitumor immune responses in H22 tumor-bearing mice. The results showed that LBP could inhibit the solid tumor growth in mice, but showed little effect on the body weight or spleen index. Furthermore, LBP could maintain high levels of T cells in peripheral blood (PB), tumor draining lymph node (TDLN), and tumor tissue, prevent the increase of Tregs while promote infiltration of CD8+ T cells in tumor tissue, inhibit the production of TGF-beta1 and IL-10 in serum, decrease the exhaustion phenotype of T cells, and maintain cytotoxicity of lymphocytes. Taken together, our results demonstrated that LBP simultaneously induced systemic and local immune responses in H22 tumor-bearing mice by alleviating immunosuppression and maintaining antitumor immune responses in mice. PMID- 29967802 TI - Macrophage Functions and Regulation: Roles in Diseases and Implications in Therapeutics. PMID- 29967803 TI - Crotoxin Isolated from Crotalus durissus terrificus Venom Modulates the Functional Activity of Dendritic Cells via Formyl Peptide Receptors. AB - The Crotalus durissus terrificus rattlesnake venom, its main toxin, crotoxin (CTX), and its crotapotin (CA) and phospholipase A2 (CB) subunits modulate the immune system. Formyl peptide receptors (FPRs) and lipoxin A4 (LXA4) are involved in CTX's effect on macrophages and neutrophils. Dendritic cells (DCs) are plasticity cells involved in the induction of adaptive immunity and tolerance maintenance. Therefore, we evaluated the effect of CTX, CA or CB on the maturation of DCs derived from murine bone marrow (BM). According to data, CTX and CB-but not CA-induced an increase of MHC-II, but not costimulatory molecules on DCs. Furthermore, CTX and CB inhibited the expression of costimulatory and MHC II molecules, secretion of proinflammatory cytokines and NF-kappaBp65 and p38/ERK1/2-MAPK signaling pathways by LPS-incubated DCs. Differently, CTX and CB induced IL-10, PGE2 and LXA4 secretion in LPS-incubated DCs. Lower proliferation and IL-2 secretion were verified in coculture of CD3+ cells and DCs incubated with LPS plus CTX or CB compared with LPS-incubated DCs. The effect of CTX and CB on DCs was abolished in cultures incubated with a FPRs antagonist. Hence, CTX and CB exert a modulation on functional activity of DCs; we also checked the involvement the FPR family on cell activities. PMID- 29967801 TI - Modulation of Immune-Inflammatory Responses in Abdominal Aortic Aneurysm: Emerging Molecular Targets. AB - Abdominal aortic aneurysm (AAA), a deadly vascular disease in human, is a chronic degenerative process of the abdominal aorta. In this process, inflammatory responses and immune system work efficiently by inflammatory cell attraction, proinflammatory factor secretion and subsequently MMP upregulation. Previous studies have demonstrated various inflammatory cell types in AAA of human and animals. The majority of cells, such as macrophages, CD4+ T cells, and B cells, play an important role in the diseased aortic wall through phenotypic modulation. Furthermore, immunoglobulins also greatly affect the functions and differentiation of immune cells in AAA. Recent evidence suggests that innate immune system, especially Toll-like receptors, chemokine receptors, and complements are involved in the progression of AAAs. We discussed the innate immune system, inflammatory cells, immunoglobulins, immune-mediated mechanisms, and key cytokines in the pathogenesis of AAA and particularly emphasis on a further trend and application of these interventions. This current understanding may offer new insights into the role of inflammation and immune response in AAA. PMID- 29967806 TI - Modality general and modality specific coding of hedonic valence. AB - The pleasant or unpleasant qualities that attach to our perceptions help to determine whether we approach or avoid environmental stimuli, shaping their affordances. How do brains create this affective perceptual dimension? The traditional answer is that sensory areas serve only as conduits for external impressions that are then modulated by heteromodal limbic structures in subsequent phases. Here we raise the possibility that, in addition to these well established gain control effects, sensory systems might also have a more direct role in representing the pleasantness component of perception, as supported by several strands of recent brain imaging evidence. In conjunction with a shared valence code that is independent of its sensory origins, valence representations interleaved within sensory brain areas may support finer grained experiential distinctions between how things look, sound, feel, taste and smell good or bad to us, offering a higher dimensional space of evaluative discriminations. PMID- 29967807 TI - Bladder Malakoplakia in Systemic Sclerosis Patient: A Case Report and Review Literature. AB - Malakoplakia, an anecdotal reactive granulomatous lesion, is a rare pathologic entity but relatively more common in genitourinary tracts. Here we report a case of malakoplakia in the urinary bladder in systemic sclerosis. The patient was a 66-year-old female treated with long-term corticosteroid and cyclophosphamide. She presented with gross hematuria, and cystoscopy and biopsy revealed malakoplakia. There was no tumor and the stains for infectious organism were all negative. To the best of our knowledge, this is the first case report of malakoplakia in a systemic sclerosis patient. PMID- 29967808 TI - Critical Thinking for Critical Care. PMID- 29967805 TI - Sample Aging Profoundly Reduces Monocyte Responses in Human Whole Blood Cultures. AB - Human whole blood cultures are widely used for the investigation of physiological pathways and drug effects in vitro. Detailed information on the effect of "sample aging" (the time span between blood collection and experimental start) on the experimental outcome is not readily available in the public domain. We studied the effect of sample aging on the ability of immune cells to respond to cell specific immune triggers (LPS, PMA/ionomycin, and SEB). Sample aging at room temperature profoundly inhibited the LPS-induced monocytic cytokine release in minimally diluted whole blood cultures. The reduction ranged from 20-50% after 30 minutes to 80-100% after 10 hours and differed between cytokines (IL-1beta, IL-2, IL-6, IFNgamma, and TNFalpha). Sample storage at 4 degrees C or 37 degrees C even worsened this. PMA/ionomycin- and SEB-induced cytokine release, both mainly T cell-driven, were also reduced by sample aging but to a lesser extent (20-50% after 24 hours). Intracellular cytokine staining revealed that the number of LPS responding cells was not impacted by sample aging and reduced LPS responsivity could also not be explained by apoptosis or downregulated TLR4 expression. Thus, we speculate that sample aging induces an inhibitory pathway downstream from TLR4 in monocytes. These results underline the importance of quick sample handling when investigating innate immune responses in whole blood, especially for monocyte responses. PMID- 29967804 TI - A Multiagent Alphavirus DNA Vaccine Delivered by Intramuscular Electroporation Elicits Robust and Durable Virus-Specific Immune Responses in Mice and Rabbits and Completely Protects Mice against Lethal Venezuelan, Western, and Eastern Equine Encephalitis Virus Aerosol Challenges. AB - There remains a need for vaccines that can safely and effectively protect against the biological threat agents Venezuelan (VEEV), western (WEEV), and eastern (EEEV) equine encephalitis virus. Previously, we demonstrated that a VEEV DNA vaccine that was optimized for increased antigen expression and delivered by intramuscular (IM) electroporation (EP) elicited robust and durable virus specific antibody responses in multiple animal species and provided complete protection against VEEV aerosol challenge in mice and nonhuman primates. Here, we performed a comparative evaluation of the immunogenicity and protective efficacy of individual optimized VEEV, WEEV, and EEEV DNA vaccines with that of a 1 : 1 : 1 mixture of these vaccines, which we have termed the 3-EEV DNA vaccine, when delivered by IM EP. The individual DNA vaccines and the 3-EEV DNA vaccine elicited robust and durable virus-specific antibody responses in mice and rabbits and completely protected mice from homologous VEEV, WEEV, and EEEV aerosol challenges. Taken together, the results from these studies demonstrate that the individual VEEV, WEEV, and EEEV DNA vaccines and the 3-EEV DNA vaccine delivered by IM EP provide an effective means of eliciting protection against lethal encephalitic alphavirus infections in a murine model and represent viable next generation vaccine candidates that warrant further development. PMID- 29967809 TI - Current Concepts and New Trends in the Treatment of Cardiogenic Shock Complicating Acute Myocardial Infarction. AB - Cardiogenic shock (CS) is a critical condition which often complicates the evolution of an acute myocardial infarction (AMI). At the same time, co-existence of chronic multi-vessel disease can lead to the development of cardiogenic shock in cases with pronounced haemodynamic instability. Different clinical studies have tried to identify the most appropriate treatment for critical cases of CS complicating AMI. This review aims to present the current status of recommended therapeutic strategies for severe cases of CS presenting as a complication of AMI, and try to shed light on the most appropriate therapeutic strategy as outlined in the current literature. The paper will discuss the different current strategies available for use in the treatment of this condition, includig interventional revascularisation, (complete or culprit), the role of new devices for providing mechanical circulatory support, and the potential role of new drug therapies and of hypothermia. PMID- 29967811 TI - The Role of Angiopoietine-2 in the Diagnosis and Prognosis of Sepsis. AB - Introduction: Angiopoietin-2 (ANG-2) is a new biomarker whose blood-serum values increase in sepsis and its expression is elevated in line with the severity of the degree of inflammation. The aim of this study was to identify the diagnostic role of ANG-2 in patients with non-surgical sepsis addmitted to an intensive care unit. Material and methods: This was a prospective randomized study including 74 patients admitted in the Clinic of Intensive Care of the County Clinical Emergency Hospital Tirgu Mures, divided into two groups: Group S: patients with sepsis (n=40, 54%) and Group C:control, without sepsis (n=34, 46%). ANG-2 levels were determined in both groups. Results: From the Group S, 14 patients (35%) had positive haemocultures. ANG-2 values varied between 1 and 43 ng/mL, with an average of 6.0 ng/mL in patients without sepsis and 10.38 ng/mL in patients with sepsis (p=0.021). A positive correlation between ANG-2 and SAPS II, SOFA and APACHE II severity scores was demonstrated, as was a positive correlation between serum levels of ANG-2 and procalcitonine. ANG-2 had a 5.71% specificity and 74.36% sensitivity for diagnosis of sepsis. Conclusions: ANG-2 serum levels were elevated in sepsis, being well correlated with PCT values and prognostic scores. ANG-2 should be considered as a useful biomarker for the diagnosis and the prognosis of this pathology. PMID- 29967810 TI - The Value of the "Lab-Score" Method in Identifying Febrile Infants at Risk for Serious Bacterial Infections. AB - Introduction: Most children with fever without source will have a self limited viral infection though a small percent will develop a serious bacterial infection (SBI) like urinary tract infection, pneumonia, bacteraemia, meningitis or sepsis. The challenge facing practitioners is to distinguish between these two groups and currently biomarkers, like C-reactive protein (CRP) and Procalcitonin (PCT), are available for this purpose.The aim of the current study was to identify SBI in infants with fever without an identifiable cause using the recently introduced "Lab-score" combining C-reactive protein, procalcitonin and urine dipstick results. Methods: This survey is part of an observational study aimed at identifying children with fever without source at risk of SBI. Patients were recruited from the Emergency Department of Tirgu Mures Emergency Clinical County Hospital, Romania, during 2013. SBI diagnosis was based on urine, blood and cerebrospinal fluid cultures and chest radiographs. For infants, aged 7 days to 12 months, CRP and PCT were determined and the "Lab-score" was calculated. Positive and negative likelihood ratios and post test probabilities were calculated for each parameter and score. Results: Of the ninety infants included in the study, SBI was diagnosed in nineteen (21.11%). Ten had a urinary tract infection, seven had pneumonia, one had a urinary tract infection and bacteraemia, and one had sepsis. Positive and negative likelihood ratios for CRP (>=40.0 mg/L) and PCT (>=0.5 ng/mL) were 10.27/0.45 and 7.07/0.24 and post-test probabilities 73%/65%. For a "Lab-score" (>=3), positive and negative likelihood ratios were 10.43/0.28, and the posttest probability was 73%. Conclusions: In our survey the "Lab-score" proved a strong predictor for the identification of febrile infants at risk of SBI, but showed no significant difference compared with CRP and PCT which both proved equally good predictors for SBI. PMID- 29967812 TI - Intra-arterial Thrombolysis in Second Trimester of Pregnancy. A Case Report. AB - Here we present a successful intra-arterial thrombolysis performed in the second trimester of pregnancy (21 weeks). The intervention resulted in complete recanalization of the occluded right middle cerebral artery and favourable clinical and gestational outcome. Together with cases described in respective medical literature our report affirms that in pregnancy acute ischemic stroke could be treated effectively applying intra-arterial thrombolysis (using rt-PA). This therapy could provide opportunity to help in such desperate situations. PMID- 29967813 TI - Drug Closure of a Patent Ductus Arteriosus in An Extremely Low Birth Weight Premature Newborn. A Case Report. AB - Introduction: Patent ductus arteriosus involves maintaining the permeability of the vascular ductus located between the pulmonary artery and the descending aorta, due to the failure of transition from foetal to adult type circulation. This malformation is characteristic to premature newborns with extremely low birth weight. The main pathophysiological factors identified in this pathology are immaturity of the smooth muscles, presence of vasodilator mediators and persistent hypoxaemia. Ductal-dependent cardiac malformations require drug therapy for keeping the permeability of the ductus arteriosus until the time of corrective surgery. Case presentation: We present the case of an extremely low birth weight premature newborn, derived from twin pregnancy with suspected specific pathology, respectively feto-fetal transfusion syndrome, admitted to the Regional Centre of Neonatal Intensive Care Unit Tirgu-Mures.Premature newborn with gestational age 31-32 weeks, extremely low birth weight, derived from twin pregnancy, with adequate prenatal follow up, was born by caesarean section for severe intrauterine growth restriction secondary to feto-fetal transfusion syndrome suspicion. The newborn developed respiratory distress syndrome by surfactant deficiency, intraventricular-haemorrhage grade I/II, and severe retinopathy. The detection of a systolic murmur in the second week of life, the diastolic theft revealed by trans-fontanellar ultrasound as well as lowered diastolic blood pressure values raised the suspicion of a patent ductus arteriosus and therefore specific treatment with ibuprofen, a cyclooxygenase inhibitor, was initiated. Progressive alteration of the newborn's condition and the evidence of a coarctation of the aorta imposed the initiation of Prostaglandin E1 therapy and subsequent surgical correction. Conclusions: Although beneficial, prophylactic or therapeutic closure of persistent ductus arteriosus may worsen the evolution of a newborn with a "silent" cardiac malformation and associated pathology. PMID- 29967814 TI - Fading Sugammadex, or Just Cautiously (re) Considered?! PMID- 29967815 TI - Statins as Pleiotropic Modifiers of Vascular Oxidative Stress and Inflammation. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the industrialized world and in the future is expected to be the number one killer worldwide. The main cause underlying CVD is atherosclerosis. A key event in atherosclerosis initiation and progression is oxidative stress through the production of reactive oxygen species as well as endothelial dysfunction. Several pro- inflammatory and anti-inflammatory cytokines and proteins are involved in this process, complemented by activation of adhesion molecules that promote leukocyte rolling, tethering and infiltration into the sub-endothelial space. Statins represent the agent of choice since numerous clinical trials have verified that their pharmacological action extends beyond lipid lowering. Statins demonstrate direct anti-oxidant effects by scavenging free radicals and stimulating anti-oxidant enzymes while acting as regulators for cytokine, protein and adhesion molecule expression, all of which are involved in the atherosclerotic process. Statin use is considered one of the most efficient currently used interventions in managing CVD with the likely hood of remaining so in the near future. PMID- 29967816 TI - Differential Diagnosis and Management Issues of Idiopathic Angiooedema and their Resolution. AB - Angiooedema is a local and self-limiting swelling of the subcutaneous and sub mucosal tissues, produced by vasoactive peptides that temporary increase the vascular permeability. It is recognized that recurrent angiooedema exposes patients to the risk of fatalities and reduced quality of life, being in some circumstances associated with a critical condition. Angiooedema can occur with or without wheals. The first symptom is urticaria, the second is a distinct nosologic entity. In absence of an identifiable cause, recurrent angiooedema without wheals can be defined as idiopathic and marked"idiopathic histaminergic angiooedema" when it is responsive to anti histamine treatment, and "idiopathic non-histaminergic angiooedema" when it is not. Furthermore, idiopathic non histaminergic angiooedema can be diagnosed as hereditary or sporadic by family history. In this review, we summarize the approaches to diagnose and treat different forms of idiopathic angiooedema. PMID- 29967817 TI - Residual Curarization and Postoperative Respiratory Complications Following Laparoscopic Sleeve Gastrectomy. The Effect of Reversal Agents: Sugammadex vs. Neostigmine. AB - Background: Incomplete muscle relaxant reversal or re-curarization may be associated with postoperative respiratory complications. In this retrospective study we compared the incidence of postoperative residual curarization and respiratory complications in association with the type of muscle relaxant reversal agent, sugammadex or neostigmine, in patients undergoing laparoscopic sleeve gastrectomy. Material and methods: We reviewed the charts of all patients (179) undergoing laparoscopic sleeve gastrectomy from July 2012 to July 2013 at Wolfson Medical Center. Sugammadex 1.5-2 mg/kg (112 patients) or neostigmine 2.5 mg (67 patients) were used as reversal agents. Results were compared by the type of reversal agent employed. Compared parameters included demographic and anaesthetic data, residual curarization, oxyhemoglobin saturation (SpO2) in the recovery room (PACU), episodes of SpO2 lower than 90% in PACU, unexpected intensive care (ICU) admissions, incidence of atelectasis and pneumonia, re intubation and duration of hospitalization. Results: Obstructive sleep apnea syndrome (OSAS) was more frequent in the sugammadex group (19% vs. 8%; p = 0.026). Total intravenous anesthesia (TIVA) was more frequently associated with sugammadex (33% vs. 16%; p = 0.007). There were no differences in postoperative residual curarization, SpO2 < 90% episodes, reintubation, ICU admissions, pulmonary complications and duration of hospitalization. Conclusion: With the inherent limitations of a retrospective study, the use of sugammadex following laparoscopic sleeve gastrectomy showed no advantage over neostigmine in terms of residual curarization and respiratory complications. PMID- 29967818 TI - Acute Ischaemic Stroke Secondary to a Mobile Thrombus in the Common Carotid Artery - Case Report. AB - A mobile thrombus in the carotid arteries is a very rare ultrasonographic finding and is usually diagnosed after a neurological emergency, such as a transient ischemic attack or cerebral infarction. We present the case of a 54-year-old man with vascular risk factors (a heavy smoker, untreated hypertension) who was admitted to the emergency unit with right sided hemiparesis and aphasia. A cerebral CT scan showed a left middle cerebral artery territory infarction. The duplex ultrasound examination revealed mild atherosclerotic changes in the right common and internal carotid arteries, right-sided complete subclavian steal phenomenon and a complicated hypoechoic atherosclerotic plaque in the left common carotid artery with a large mobile thrombus. Due to the high embolization risk, the patient was hospitalised and prescribed Aspirin together with low molecular weight Heparin. We recorded an improvement in the patient's neurological status and the control duplex scan revealed disappearance of the thrombus. The presence of floating thrombus in a patient with clinical and imagistic evidence of stroke is a major therapheutic challenge for the neurologist. The treatment strategies are not standardized and must be individualized, however in our case parenteral anticoagulation proved to be successful. PMID- 29967819 TI - Is Therapeutic Hypothermia Viable in Our Region as a New Option for Sudden Cardiac Arrest Caused by Acute Myocardial Infarction? PMID- 29967820 TI - The Significance of Cardiac Arrhythmias in Septic ICU Patients. PMID- 29967821 TI - Invasive Candida Infections in the ICU: Diagnosis and Therapy. AB - Invasive fungal infections have become a serious problem in the critically ill. One of the main reasons is the development of an immunocompromised condition. The most frequently found pathogens are Candida species. In order to provide adequate treatment, understanding this potentially life-threatening infection is mandatory. The aim of this summary is to view Candida infections from a different perspective and to give an overview on epidemiology, the range of pathophysiology from colonization to the invasive infections, and its impact on mortality. New therapeutic options will also be discussed and how these relate to current guidelines. Finally, the key issue of the choice of anti-fungal agents will be evaluated. PMID- 29967822 TI - Cardiac Arrhythmias in a Septic ICU Population: A Review. AB - Progressive cardiovascular deterioration plays a central role in the pathogenesis of multiple organ failure (MOF) caused by sepsis. Evidence of various cardiac arrhythmias in septic patients has been reported in many published studies. In the critically ill septic patients, compared to non-septic patients, new onset atrial fibrillation episodes are associated with high mortality rates and poor outcomes, amongst others being new episodes of stroke, heart failure and long vasopressor usage. The potential mechanisms of the development of new cardiac arrhythmias in sepsis are complex and poorly understood. Cardiac arrhythmias in critically ill septic patients are most likely to be an indicator of the severity of pre-existing critical illness. PMID- 29967823 TI - An Evaluation of Serum Procalcitonin and C-Reactive Protein Levels as Diagnostic and Prognostic Biomarkers of Severe Sepsis. AB - Background: Recommendations have been made, following the multicenter Surviving Sepsis Campaign study, to standardize the definition of severe sepsis with reference to several parameters such as haemodynamic stability, acid-base balance, bilirubin, creatinine, International Normalized Ratio (INR), urine output and pulmonary functional value of the ratio between arterial oxigen partial pressure and inspiratory oxigen concentration. Procalcitonin (PCT) is considered to be a gold standard biomarker for the inflammatory response, and recent studies have shown that it may help to discover whether a seriously ill person is developing sepsis. C-reactive protein (CRP) is also used as a marker of inflammation in the body, as its blood levels increase if there is any inflammation in the body. The aim of this study was to evaluate serum procalcitonin and C-reactive protein levels as diagnostic and prognostic biomarkers of severe sepsis. Material and method: Sixty patients, diagnosed as being "septic", were admitted to the intensive care unit (ICU). Based on laboratory results and clinical findings a diagnosis of "severe sepsis" was made, and correlated with PCT and CRP values. The APACHE II, SAPS II and SOFA severity scores were calculated, analyzed and correlated with PCT and CRP. Results: Fifty two patients (86.67%) presented with criteria for severe sepsis. Multivariate correlation analysis indicated a significant positive association between procalcitonin and all severity scores (APACHEII p<0.0001, SOFA p<0.0001, SAPS II p<0.0001). CRP proved to be significantly correlated only with the SAPS II score (p=0.0145). Mortality rate was high, with 48 patients (80%) dying. There was no significant correlation between the levels of the PCT and CRP biomarkers and severe sepsis (p=0.2059 for PCT, p=0.6059 for CRP). Conclusions: The procalcitonin levels are highly correlated with the severity scores (APACHE II, SAPS II, SOFA) regularly used in ICUs and therefore can be used for determining the severity of the septic process. Quantitive procalcitonin and C-reactive protein analysis was not shown to be useful in diagnosing severe sepsis. However, PCT and CRP can be used to predict the fatal progression of the septic patient. PMID- 29967824 TI - Plasma Neutrophil Gelatinase Associated Lipocalin (NGAL) - Early Biomarker for Acute Kidney Injury in Critically Ill Patients. AB - Introduction: NGAL (Neutrophil Gelatinase Associated Lipocalin) is a biomarker recently introduced into clinical practice for the early diagnosis of acute kidney injury (AKI). The aim of this study was to correlate the plasmatic NGAL value determined at admission with clinical progression and severity of AKI in critically ill patients. Material and method: Thirty two consecutive critically ill adult patients at risk of developing AKI (trauma, sepsis), admitted in Intensive Care Unit of the Clinical County Emergency Hospital Mures, between January to March 2015 were enrolled in the study. For each patient included in the study plasma NGAL levels were determined on admission, and these were correlated with the degree of AKI development (according to AKIN criteria) at 48 hours and 5 days post admission. The discriminatory power of NGAL, creatinine, creatinine clearance and corrected creatinine (depending on water balance) were determined using the ROC (receiver-operating characteristic) and likelihood ratios. Results: ROC curve analysis showed a better discriminatory capacity in terms of early diagnosis of AKI for NGAL (AUC=0.81 for NGAL, AUC=0.59 for creatinine, AUC=0.62 for corrected creatinine, AUC=0.29 for creatinine clearance). The value of likelihood ratio was also significantly higher for NGAL (3.01+/-2.73 for NGAL, 1.27+/-1.14 for creatinine, 1.78+/-1.81 for corrected creatinine, and 0.48+/-0.33 for creatinine clearance). Conclusions: NGAL biomarker has a better discrimination capacity for early prediction of acute kidney injury compared to previously used markers. PMID- 29967826 TI - Sudden Cardiac Death and Post Cardiac Arrest Syndrome. An Overview. AB - A satisfactory neurologic outcome is the key factor for survival in patients with sudden cardiac death (SCD), however this is highly dependent on the haemodynamic status. Short term cardiopulmonary resuscitation and regained consciousness on the return of spontaneous circulation (ROSC) is indicative of a better prognosis. The evaluation and treatment of SCD triggering factors and of underlying acute and chronic diseases will facilitate prevention and lower the risk of cardiac arrest. Long term CPR and a prolonged unconscious status after ROSC, in the Intensive Care Units or Coronary Care Units, indicates the need for specific treatment and supportive therapy including efforts to prevent hyperthermia. The prognosis of these patients is unpredictable within the first seventy two hours, due to unknown responses to therapeutic management and the lack of specific prognostic factors. Patients in these circumstances require the highest level of intensive care and aetiology driven treatment without any delay, independently of their coma state. Current guidelines sugest the use of multiple procedures in arriving at a diagnosis and prognosis of these critical cases. PMID- 29967827 TI - Acquired Tracheal Diverticulum as an Unexpected Cause of Endotracheal Tube Cuff Leak. AB - Introduction: Tracheal diverticulum has been associated with problems during endotracheal intubation but there are no reports concerning air leakage around an endotracheal tube (ETT). Case report: The case of an elderly woman under mechanical ventilatory support because an exacerbation of chronic obstructive pulmonary disease (COPD) is reported. She presented with an inexplicably air leak around the endotracheal tube not attributed to structural defects. The intra-cuff pressure value was as high as 30 mmHg to prevent an air leakage. Bronchoscopy revealed a tracheal diverticulum at the site ofthe tube cuff that allowed air leakage around it. The problem was overcome by re-intubating the patient with a larger diameter tube and positioning its distal end above the diverticular opening. Discussion: Endotracheal tube air leak is a frequently neglected problem. COPD and other inflammatory conditions are associated with changes in the elastic properties of the airways resulting in tracheomegaly or acquired tracheal diverticulum. Both entities have been linked to problems during intubation or ventilation of patients. However tracheal diverticulum has not been described previously as a cause of air leakage. Conclusion: Acquired tracheal diverticulum should be recognized as a cause of air leakage in the intubated patient, especially if associated with a normal or elevated intracuff pressure. PMID- 29967825 TI - Ventricular Septal Rupture - A Critical Condition as a Complication of Acute Myocardial Infarction. AB - Ventricular septal rupture is a potentially fatal complication of acute myocardial infarction. The key to management of this critical condition is an aggressive approach to haemodynamic stabilization and surgical closure of the rupture. Where there is a small rupture and the patient is in a haemodynamically stable condition, surgery can be delayed with the prospect of achieving better perioperative results. However, in unstable critically ill patients either immediate surgery or extracorporeal membranous oxygenation support and delayed surgery is indicated. In some patients, trans-catheter closure may be considered as an alternative to surgery. PMID- 29967828 TI - Delayed Recovery from General Anaesthesia: A Post-operative Diagnostic Dilemma and Implications of ICU Management of Serotonin Toxicity. Case report. AB - We report a case of delayed recovery from general anesthesia following a routine parathyroidectomy. Our objectives are to describe the process of establishing a differential diagnosis and subsequent management of a patient presenting with atypical neurological signs from an unknown etiology and to increase awareness about the potential for serotonin syndrome and neurotoxicity due to known interactions between methylene blue and selective serotoninnoradrenaline re uptake inhibitors. ICU management of Serotonin Toxicity is briefly described. PMID- 29967829 TI - Dual Role of Angiopoietine II in the Complex Management of Critically Ill Patients with Sepsis. PMID- 29967830 TI - Out-of-Hospital Cardiac Arrest in Acute Myocardial Infarction and STEMI Networks. PMID- 29967832 TI - Sugammadex: An Update. AB - The purpose of this update is to provide recent knowledge and debates regarding the use of sugammadex in the fields of anesthesia and critical care. The review is not intended to provide a comprehensive description of sugammadex and its clinical use. PMID- 29967831 TI - Anti-platelet Therapy Resistance - Concept, Mechanisms and Platelet Function Tests in Intensive Care Facilities. AB - It is well known that critically ill patients require special attention and additional consideration during their treatment and management. The multiple systems and organ dysfunctions, typical of the critical patient, often results in different patterns of enteral absorption in these patients. Anti-platelet drugs are the cornerstone in treating patients with coronary and cerebrovascular disease. Dual anti-platelet therapy with aspirin and clopidogrel is the treatment of choice in patients undergoing elective percutaneous coronary interventions and is still widely used in patients with acute coronary syndromes. However, despite the use of dual anti-platelet therapy, some patients continue to experience cardiovascular ischemic events. Recurrence of ischemic events is partly attributed to the fact that some patients have poor inhibition of platelet reactivity despite treatment. These patients are considered low- or non responders to therapy. The underlying mechanisms leading to resistance are not yet fully elucidated and are probably multifactorial, cellular, genetic and clinical factors being implicated. Several methods have been developed to asses platelet function and can be used to identify patients with persistent platelet reactivity, which have an increased risk of thrombosis. In this paper, the concept of anti-platelet therapy resistance, the underlying mechanisms and the methods used to identify patients with low responsiveness to anti-platelet therapy will be highlighted with a focus on aspirin and clopidogrel therapy and addressing especially critically ill patients. PMID- 29967833 TI - Predictors of Mortality in Patients with ST-Segment Elevation Acute Myocardial Infarction and Resuscitated Out-of-Hospital Cardiac Arrest. AB - Introduction: In patients with out-of-hospital cardiac arrest (OHCA) complicating an ST-segment elevation myocardial infarction (STEMI), the survival depends largely on the restoration of coronary flow in the infarct related artery. The aim of this study was to determine clinical and angiographic predictors of in hospital mortality in patients with OHCA and STEMI, successfully resuscitated and undergoing primary percutaneous intervention (PCI). Methods: From January 2013 to July 2015, 78 patients with STEMI presenting OHCA, successfully resuscitated, transferred immediately to the catheterization unit and treated with primary PCI, were analyzed. Clinical, laboratory and angiographic data were compared in 28 non survivors and 50 survivors. Results: The clinical baseline characteristics of the study population showed no significant differences between the survivors and non survivors in respect to age (p=0.06), gender (p=0.8), the presence of hypertension (p=0.4), dyslipidemia (p=0.09) obesity (p=1), smoking status (p=0.2), presence of diabetes (p=0.2), a clinical history of acute myocardial infarction (p=0.7) or stroke (p=0.17). Compared to survivors, the non-survivor group exhibited a significantly higher incidence of cardiogenic shock (50% vs 24%, p=0.02), renal failure (64.3% vs 30.0%, p=0.004) and anaemia (35.7% vs 12.0%, p=0.02). Three-vessel disease was significantly higher in the non-survivor group (42.8% vs. 20.0%, p=0.03), while there was a significantly higher percentage of TIMI 3 flow postPCI in the infarct-related artery in the survivor group (80.% vs. 57.1%, p=0.03). The time from the onset of symptoms to revascularization was significantly higher in patients who died compared to those who survived (387.5 +/- 211.3 minutes vs 300.8 +/- 166.1 minutes, p=0.04), as was the time from the onset of cardiac arrest to revascularization (103.0 +/- 56.34 minutes vs 67.0 +/- 44.4 minutes, p=0.002). Multivariate analysis identified the presence of cardiogenic shock (odds ratio [OR]: 3.17, p=0.02), multivessel disease (OR: 3.0, p=0.03), renal failure (OR: 4.2, p=0.004), anaemia (OR: 4.07, p=0.02), need for mechanical ventilation >48 hours (OR: 8.07, p=0.0002) and a duration of stay in the ICU longer than 5 days (OR: 9.96, p=0.0002) as the most significant independent predictors for mortality in patients with OHCA and STEMI. Conclusion: In patients surviving an OHCA in the early phase of a myocardial infarction, the presence of cardiogenic shock, renal failure, anaemia or multivessel disease, as well as a longer time from the onset of symptoms or of cardiac arrest to revascularization, are independent predictors of mortality. However, the most powerful predictor of death is the duration of stay in the ICU and the requirement of mechanical ventilation for more than forty-eight hours. PMID- 29967834 TI - Recent Advances of Mucosal Capnometry and the Perspectives of Gastrointestinal Monitoring in the Critically Ill. A Pilot Study. AB - Mucosal capnometry involves the monitoring of partial pressure of carbon dioxide (PCO2) in mucous membranes. Different techniques have been developed and applied for this purpose, including sublingual or buccal sensors, or special gastrointestinal tonometric devices. The primary use of these procedures is to detect compensated shock in critically ill patients or patients undergoing major surgery. Compensatory mechanisms, in the early phases of shock, lead to the redistribution of blood flow towards the vital organs, within ostensibly typical macro-haemodynamic parameters. Unfortunately, this may result in microcirculatory disturbances, which can play a pivotal role in the development of organ failure. In such circumstances mucosal capnometry monitoring, at different gastrointestinal sites, can provide a sensitive method for the early diagnosis of shock. The special PCO2 monitoring methods assess the severity of ischaemia and help to define the necessary therapeutic interventions and testing of these monitors have justified their prognostic value. Gastrointestinal mucosal capnometry monitoring also helps in determining the severity of ischaemia and is a useful adjunctive in the diagnosis of occlusive splanchnic arterial diseases. The supplementary functional information increases the diagnostic accuracy of radiological techniques, assists in creating individualized treatment plans, and helps in follow-up the results of interventions. The results of a pilot study focusing on the interrelation of splanchnic perfusion and gastrointestinal function are given and discussed concerning recent advances in mucosal capnometry. PMID- 29967835 TI - Factors Favouring the Development of Clostridium Difficile Infection in Critically Ill Patients. AB - : Clostridium difficile, an anaerobic, spore-forming, toxin-forming, gram positive bacillus present in the bacterial flora of the colon is the principal cause of nosocomial diarrhoea in adults. Aim: Assessment of favouring factors of Clostridium difficile infections as well as the interactions between them, in critically ill hospitalized patients undergoing complex medical and surgical treatments. Material and Methods: A retrospective case-control study involving eighty patients admitted in the Intensive Care Unit (ICU) of the County Clinical Emergency Hospital Tirgu-Mures was conducted between January and October 2014. Patients aged eighteen years and over, who had undergone complex medical and surgical treatment, were divided into two subgroups. Group 1 included patients who developed diarrhoea but were not diagnosed as having a Clostridium difficile infection (CDI). Group 2 included patients who developed diarrhoea due to CDI as indicated by a positive culture and the expression of exotoxin. The assessed parameters were age, length of stay (LOS), antibiotic spectrum, association with proton pump inhibitors (PPI) or H2-receptor antagonists, immunological status, the presence or lack of gastrointestinal tract surgery. Results: The mean age was 64.6 years with an average LOS of 10 days. Fifty-six percent of patients came to the ICU from internal medicine wards and forty-three percent from surgical wards. 20.5% of them were immunosuppressed. Co-association of ceftriaxone and pantoprazole significantly increased the risk of CDI compared to co administration of any other antibiotic or pantoprazole (p=0.01). The odds ratio for Pantoprazole together with any antibiotic versus antibiotic therapy alone was significantly higher (p=0.018) with a sevenfold increase in the risk of positive exotoxin increase. Conclusions: Antibiotic use is associated with "no risk to develop CDI" in the first five days of administration. PPIs associated therapy increased the risk of CDI in first seventy-two hours regardless of the antibiotic type, and contributes to an active expression of CD exotoxin. PMID- 29967836 TI - Total Intravenous Versus Inhalation Anesthesia in Patients Undergoing Laparoscopic Cholecystectomies. Effects on Two Proinflammatory Cytokines Serum Levels: Il-32 and TNF-Alfa. AB - Introduction: It has been reported that as compared with total intravenous anesthesia (TIVA), inhalation anesthesia is increasing the postoperative level of proinflammatory interleukins.The aim of the study is to investigate if there is an in-vivo relationship between proinflammatory cytokines, Interleukin-32 (IL-32) and Tumour necrosis factor - alpha (TNF-alpha), in patients undergoing laparoscopic cholecystectomies with two different anesthetic techniques, TIVA or inhalation anesthesia. Material and Methods: Twenty two consecutive patients undergoing laparoscopic cholecystectomies were prospectively randomized into two groups: Group 1: TIVA with target-controlled infusion (TIVA-TCI) (n=11) and Group 2: isoflurane anesthesia (ISO) (n=11). IL-32 and TNF-alpha were determined before the induction of anesthesia (T1), before incision (T2) and at 2h (T3) and 24h (T4) postoperatively. Our primary outcome was to compare plasma levels of IL-32 and TNF-alpha concentrations (expressed as area-under-the-curve) over 24 hours between study groups. Our secondary outcome was to establish whether there is a correlation between plasma levels of IL-32 and of TNF-alpha at each time point between the two groups. Results: Area-under-the-curve (AUC) of IL-32 plasma concentration was 7.53 in Group 1 (TIVA) versus 3.80 in Group 2 (ISO), p= 1. For TNF-alpha, AUC of plasma concentration was 733.9 in Group 1 (TIVA) and 668.7 in Group 2 (ISO), p=0.066. There were no significant differences in plasma concentrations of both IL-32 and TNF-alpha between the groups. Conclusions: IL-32 expression in response to minor surgery is very low. There were no significant difference between plasma levels of TNF-alpha and IL-32 after TIVA versus inhalation anesthesia during the first 24 hours postoperatively. Further studies are needed on larger groups to investigate whether there can be a correlation between these interleukins after 2 different anesthetic techniques and the impact of this correlation on postoperative outcome. PMID- 29967837 TI - Staphylococcal Toxic Shock Syndrome Caused by an Intravaginal Product. A Case Report. AB - Staphylococcal toxic shock syndrome (STSS) represents a potentially lethal disease, and survival depends primarily on the early initiation of appropriate treatment. As the clinical picture at presentation is usually common, frequently this could lead to misdiagnosis and delays in the initiation of the proper therapy. The case of a 43-years old female who developed a staphylococcal septic shock syndrome caused by a forgotten intravaginal tampon is reported. PMID- 29967838 TI - Role of Plasma Neutrophil Gelatinase Associated Lipocalin as a New Biomarker. PMID- 29967839 TI - Knowledge is Power. AB - When Sir Francis Bacon published in his work, Meditationes Sacrae (1597), the saying: "knowledge itself is power", he most likely wanted to transmit the idea that having and sharing knowledge is the cornerstone of reputation and influence, and therefore power; all achievements emanate from this. Today, scientific knowledge is shared through publications that not only inform, but have the capacity to influence decision making. The Journal of Critical Care Medicine, a publication of the University of Medicine and Pharmacy Tirgu Mures, Romania launched in 2015, was recently included in the Master Journal List of the Emerging Sources Citation Index (ESCI), which is part of the Thomson Reuters Web of Science Core Collection. This new index ensures the indexing of high-quality medical articles that undergo a specific peer-review process prior to publication. The inclusion of the journal in this international database ensures a larger and more consistent international profile, as well as a probable increase in the citation of published articles. PMID- 29967840 TI - Much Ado About the New Definitions of Sepsis. AB - Following the publication of the new definition of sepsis (Sepsis-3), a plethora of articles have been published in medical journals. Recognizing the epidemiological importance of the previous definitions, first issued in 1992 (Sepsis-1), and subsequently revised in 2001 (Sepsis-2), the most recent opinion emphasizes the failure "to provide adequate groups of patients with homogenous aetiologies, presentations and outcomes", and blamed one of the causes "for the failure of several randomized controlled trials (RCTs), that tested the efficacy of adjuvant sepsis therapies". This review summarizes the recent advances in sepsis definition. PMID- 29967842 TI - Influence of Ventilation Parameters on Intraabdominal Pressure. AB - Introduction: Intraabdominal pressure monitoring is not routinely performed because the procedure assumes some invasiveness and, like other invasive procedures, it needs to have a clear indication to be performed. The causes of IAH are various. Mechanically ventilated patients have numerous parameters set in order to be optimally ventilated and it is important to identify the ones with the biggest interference in abdominal pressure. Although it was stated that mechanical ventilation is a potential factor of high intraabdominal pressure the set parameters which may lead to this diagnostic are not clearly named. Objectives: To evaluate the relation between intraabdominal pressure and ventilator parameters in patients with mechanical ventilation and to determine the correlation between intraabdominal pressure and body mass index. Material and method: This is an observational study which enrolled 16 invasive ventilated patients from which we obtained 61 record sheets. The following parameters were recorded twice daily: ventilator parameters, intraabdominal pressure, SpO2, Partial Oxygen pressure of arterial blood. We calculated the Body Mass Index (BMI) for each patient and the volume tidal/body weight ratio for every recorded data point. Results: We observed a significant correlation between intraabdominal pressure (IAP) and the value of PEEP (p=0.0006). A significant statistical correlation was noted regarding the tidal volumes used for patient ventilation. The mean tidal volume was 5.18 ml/kg. Another significant correlation was noted between IAP and tidal volume per kilogram (p=0.0022). A positive correlation was found between BMI and IAP (p=0.0049), and another one related to the age of the enrolled patients. (p=0.0045). Conclusions: The use of positive end-expiratory pressures and high tidal volumes during mechanical ventilation may lead to the elevation of intraabdominal pressure, a possible way of reducing this risk would be using low values of PEEP and also low volumes for the setting of ventilation parameters. There is a close positive correlation between the intraabdominal pressure levels and body mass index. PMID- 29967841 TI - Intubation-Surfactant: Extubation on Continuous Positive Pressure Ventilation. Who are the Best Candidates? AB - Introduction: Respiratory distress syndrome (RDS) continues to be the leading cause of illness and death in preterm infants. Studies indicate that INSURE strategy (INtubate-SURfactant administration and Extubate to nasal continuous positive airway pressure [nCPAP]) is better than mechanical ventilation (MV) with rescue surfactant, for the management of respiratory distress syndrome (RDS) in very low birth weight (VLBW) neonates, as it has a synergistic effect on alveolar stability. Aim of the study: To identify the factors associated with INSURE strategy failure in preterm infants with gestational age (GA) <= 32 weeks. Materials and Methods: This was a retrospective cohort study, based on data collected in the Romanian National Registry for RDS patients by three regional (level III) centers between 01.01.2010 and 31.12.2011. All preterm infants of <= 32 weeks GA were included. Prenatal and neonatal information were compared between (Group 1), the preterm infants successfully treated using INtubation SURfactant-Extubation on nasal CPAP (INSURE) strategy and (Group 2 ), those who needed mechanical ventilation within seventy two hours after INSURE. Results: A total of 637 preterm infants with GA <= 32 weeks were included in the study. INSURE strategy was performed in fifty seven cases (8.9%) [ Group 1] and was successful in thirty one patients (54.4%). No differences were found as regards the studied prenatal and intranatal characteristics between (Group 1) and Group 2 who needed mechanical ventilation. Group 2 preterm infants who needed mechanical ventilation within 72 hours after INSURE had significantly lower mean Apgar scores at 1 and 5 minutes and lower peripheral oxygen saturation (SpO2) during resuscitation at birth (p<0.05). Successful INSURE strategy was associated with greater GA, birth weight (BW), fraction of inspired oxygen (FiO2) during resuscitation, and an increased mean dose of surfactant but these associations were not statistically significant (p>0.5). Conclusion: In preterm infants <= 32 weeks gestation, increased INSURE failure rates are associated with complicated pregnancies, significantly lower Apgar scores at 1 and 5 minutes, and lower peripheral oxygen saturation during resuscitation. PMID- 29967844 TI - Parkinsonian Syndrome and Toxoplasmic Encephalitis. AB - Toxoplasmosis encephalitis in patients with human immunodeficiency virus may progress rapidly with a potentially fatal outcome. Less common neurological symptoms associated with this are Parkinsonism, focal dystonia, rubral tremor and hemichorea-hemiballismus syndrome. A 58 year old woman suddenly lost consciousness and was admitted to the emergency service. Her medical history was unremarkable, except for frequent headaches in the last year, recurrent herpes simplex skin lesions and an episode of urticaria. A computer tomography scan showed supra and infra-tentorial lesions on suggestive of cerebral toxoplasmosis. Both Toxoplasma gondii and HIV tests were positive. In the intensive care unit, antiparasitic and antiretroviral drugs were administered, and she recovered from the coma after six weeks but presented with tetraparesis, diplopia, and depression. The LCD4 count increased from 7 to 128/mm3. The neurological lesions slowly resolved over the next two months, although postural instability, rigidity, bradykinesia and predominantly left side tremor persisted. Mild improvement was achieved after the administration of levodopa. Associated Parkinsonian syndrome in HIV patients is a rare condition, explained by the location of the brain and basal ganglia lesions, and by the observed effect of Toxoplasma gondii which increases dopamine metabolism in neural cells. Early HIV diagnostic and treatment are necessary to prevent neurological disability. PMID- 29967843 TI - The Management of Staphylococcal Toxic Shock Syndrome. A Case Report. AB - Staphylococcal toxic shock syndrome (TSS) is most frequently produced by TSS toxin-1 (TSST-1) and Staphylococcal enterotoxin B (SEB), and only rarely by enterotoxins A, C, D, E, and H. Various clinical pictures can occur depending on severity, patient age and immune status of the host. Severe forms, complicated by sepsis, are associated with a death rate of 50-60%. The case of a Caucasian female infant, aged seven weeks, hospitalized with a diffuse skin rash, characterized as allergodermia, who initially developed TSS with axillary intertrigo, is reported. TSS was confirmed according to 2011 CDC criteria, and blood cultures positive for Methicillin-sensitive Staphylococcus aureus (MSSA). Severe development occurred initial, including acidosis, consumption coagulopathy, multiple organ failures (MOF), including impaired liver and kidney function. Central nervous system damage was manifest by seizures. Clinical management included medical supervision by a multidisciplinary team of infectious diseases specialist and intensive care specialist, as well as the initiation of a complex treatment plan to correct hydro electrolytic imbalances and acidosis. This treatment included antibiotic and antifungal therapy, diuretic therapy, immunoglobulins, and local treatment similar to a patient with burns to prevent superinfection of skin and mucous membranes lesions. There was a favourable response to the treatment with resolution of the illness. PMID- 29967845 TI - The Pitfalls of Febrile Jaundice. A Case Report. AB - Jaundice in sepsis is usually caused by cholestasis, and its onset can precede other manifestations of the infection. Inflammation-induced cholestasis is a common complication in patients with an extrahepatic infection or those with inflammatory processes. We describe the case of a 47 years old female who presented with low back pain and paravertebral muscular contracture. She subsequently developed a cholestatic syndrome with clinical manifestations such as jaundice, followed by fever and sepsis with multiple organ dysfunction. Initially labeled as biliary sepsis, the diagnosis was crucially reoriented as the blood cultures were positive for Streptococcus pyogenes and the magnetic resonance imaging (MRI) findings suggested spondylodiscitis as well as a paravertebral abscess. PMID- 29967846 TI - Complications of Sepsis in Infant. A Case Report. AB - Sepsis is a systemic inflammatory response (SIRS) characterized by two or more of the following: fever > 38.5 degrees C or <36 degrees C, tachycardia, medium respiratory frequency over two SD for age, increased number of leukocytes. The following is a case of an eight months old, female infant, admitted in to the clinic for fever (39.7 C), with an onset five days before the admission, following trauma to the inferior lip and gum. Other than the trauma to the lip and gum, a clinical exam did not reveal any other pathological results. The laboratory tests showed leukocytosis, positive acute phase reactants (ESR 105 mm/h, PCR 85 mg/dl), with positive blood culture for Staphylococcus aureus MSSA. at 24 hours. Three days from admission, despite the administration of antibiotics (Vancomycin+Meronem), there was no remission of fever, and the infant developed a fluctuant collection above the knee joint. This was drained, and was of a serous macroscopic nature. A decision was made to perform a CT, which confirmed the diagnosis of septic arthritis. At two days after the intervention, the fever reappeared, therefore the antibiotic regime were altered (Oxacillin instead of Vancomycin), resulting in resolution of the fever. Sepsis in infant is a complex pathology, with non-specific symptoms and unpredictable evolution. PMID- 29967847 TI - Have Severity Scores a Place in Predicting Septic Complications in ICU Multiple Trauma Patients? PMID- 29967848 TI - Anemia in Intensive Care: A Review of Current Concepts. AB - Anemia in patients admitted to an intensive care unit is common and affects almost all critically ill patients. The intensivist is faced with the challenge of treating multifactorial etiologies, mainly bleeding and blood loss due to phlebotomy and decreased erythropoiesis. Red cell transfusion, the most common treatment for anemia, comes with associated risks, which may further reduce the chance of survival of these patients. The best evidence suggests the practice of restrictive RBC transfusion (transfusion at Hb<7 g/dl). In this article, the etiopathogenesis of the anemia in critically ill is reviewed, and current opinion on the pros and cons of various management strategies are discussed with emphasize on restrictive transfusion policy. PMID- 29967849 TI - The Diagnosis and Hemodynamic Monitoring of Circulatory Shock: Current and Future Trends. AB - Circulatory shock is a complex clinical syndrome encompassing a group of conditions that can arise from different etiologies and presented by several different hemodynamic patterns. If not corrected, cell dysfunction, irreversible multiple organ insufficiency, and death may occur. The four basic types of shock, hypovolemic, cardiogenic, obstructive and distributive, have features similar to that of hemodynamic shock. It is therefore essential, when monitoring hemodynamic shock, to making accurate clinical assessments which will guide and dictate appropriate management therapy. The European Society of Intensive Care has recently made recommendations for monitoring hemodynamic shock. The present paper discusses the issues raised in the new statements, including individualization of blood pressure targets, prediction of fluid responsiveness, and the use of echocardiography as the first means during the initial evaluation of circulatory shock. Also, the place of more invasive hemodynamic monitoring techniques and future trends in hemodynamic and metabolic monitoring in circulatory shock, will be debated. PMID- 29967850 TI - Can APACHE II, SOFA, ISS, and RTS Severity Scores be used to Predict Septic Complications in Multiple Trauma Patients? AB - Background: Physiological composite scores are used to predict mortality in multiple trauma patients. Sepsis is the leading cause of late mortality in trauma victims brought about by immune suppression due to homeostasis dysregulation. Objective: To determine whether APACHE II, SOFA, ISS and RTS scores can predict the occurrence of sepsis in multiple trauma patients. Methods: APACHE II, SOFA, ISS, and RTS scores were calculated during the first twenty-four hours after the injury for sixty-four adult poly-traumatic patients. The occurrence of infectious complications was investigated over a fourteen-day period. The infection-free rates for the multiple trauma patients were considered as end-points in the Kaplan-Meier plot analysis. Results: For SOFA, a cutoff score of 4 points was identified as a predictor of the occurrence of sepsis, with 89% of the patients with SOFA<4 being infection-free, while 37% of those with SOFA>4 were infection free (p<0.01). None of the patients with APACHE II<=5 points developed infections. Eighty-four percent of patients with APACHE II scores of 5-10 did not develop sepsis, while 49% with APACHE II>=11 were infection-free (p<0.01). A cutoff of 7 points was found to be most discriminative for RTS. Eighty-eight percent of the patients with RTS<=7 and 43% of those with RTS<7 were infection free (p<0.01). Eighty-eight percent of patients with ISS>=22 did not develop sepsis and 56% with ISS>22 did not develop sepsis (p<0.01). Conclusion: APACHE II, SOFA, ISS, and RTS functional severity scores can predict mortality as well as the occurrence of sepsis in multiple trauma patients. PMID- 29967851 TI - The Placement of Post-pyloric Feeding Tubes Using DRX-Revolution Mobile X-Ray System in an ICU. A Case Series. AB - Enteral nutrition is crucial for ensuring that critically ill patients have a proper intake of food, water, and medicine. Methods to ensure this requirement should be initiated as early as possible. The use of PPF has several advantages compared to the use of a nasogastric feeding tube. In the present paper, the cases of three critically ill patients with a nonfunctional gastrointestinal system on admission to ICU, are detailed. Enteral feeding through a nasogastric tube by prokinetic agent therapy had been unsuccessful. The bedside placement of a post-pyloric feeding tube by the DRX-Revolution X-ray system is described. PMID- 29967852 TI - Malignant Middle Cerebral Artery Infarction Secondary to Traumatic Bilateral Internal Carotid Artery Dissection. A Case Report. AB - Traumatic bilateral dissection of the carotid arteries is a rare condition with potentially life-threatening complications. The case of a 57-year-old male patient with acute onset left sided hemiparesis, twelve hours after a blunt head injury, caused by a horse kick, is reported. A cerebral CT scan revealed right middle cerebral artery (MCA) territory infarction. Based on Duplex ultrasound and Angio CT scan findings, a diagnosis of bilateral ICA dissection was established. Despite antithrombotic treatment, the patient presented with a progressive worsening of his neurological status. The control CT scan evidenced malignant right MCA territory infarction that required decompressive craniotomy. The patient was discharged with significant neurological deficits. Together with this case, the aetiologies, clinical manifestations, diagnostic and therapeutical options and outcome of carotid artery dissection are discussed. PMID- 29967853 TI - Nosocomial Staphylococcal Toxic Shock. Case Report. AB - Staphylococcal toxic shock syndrome (STSS) is a rare, potentially lethal infection, with a clinical picture of multiple organ dysfunction and shock. The etiology is Staphylococcus aureus exotoxin, while enterotoxins act as superantigens. Most cases are identified in women using a vaginal tampon. A 51 year-old female, with a past medical history of biliary dyskinesia, presented in the emergency room complaining of sudden onset of abdominal pain, vomiting, headache, myalgia, and chills. The initial diagnosis was biliary colic and was treated parenterally with Amoxi-clavulanate and fluid replacement. Initially, progress was unsatisfactory. Four days after admission she developed a systemic inflammatory syndrome, diffuse rash, jaundice, oliguria, confusion, persistent hypotension and biological evidence of thrombocytopenia, nitrogen retention, and cholestasis. She was admitted to the intensive care unit. A gluteal phlegmon induced after intramuscular injections was identified and surgically treated. Blood bacteriological cultures were negative, though MRSA was isolated in phlegmon pus. A diagnosis of STSS was based on CDC criteria. The risks of similar infections could be prevented by limiting intramuscular treatments and monitoring invasive procedures. PMID- 29967854 TI - Epidural Anaesthesia: How Easy Is It to Walk on Quicksand? PMID- 29967855 TI - Sepsis-Associated Coagulopathy. AB - Systemic inflammatory activation in sepsis often leads to coagulation activation, but the relationship is bilateral, as coagulation also modulates the inflammatory response. This close associate has significant consequences for the pathogenesis of microvascular thrombosis and organ dysfunction in sepsis. While coagulation activation can be beneficial for immune defense, it can also be detrimental once it becomes widespread and uncontrolled. The knowledge of the pathophysiologic mechanisms involved in the interaction between infection and coagulation may lead to the better timing for the administration of targeted antithrombotic therapies in septic patients. This brief review highlights the pathophysiologic pathways leading to the prothrombotic state in sepsis and the mechanisms that play a role in the interaction between infection and coagulation. PMID- 29967856 TI - Extracorporeal Life Support and New Therapeutic Strategies for Cardiac Arrest Caused by Acute Myocardial Infarction - a Critical Approach for a Critical Condition. AB - This review summarizes the most recent developments in providing advanced supportive measures for cardiopulmonary resuscitation, and the results obtained using these new therapies in patients with cardiac arrest caused by acute myocardial infarction (AMI). Also detailed are new approaches such as extracorporeal cardiopulmonary resuscitation (ECPR), intra-arrest percutaneous coronary intervention, or the regional models for systems of care aiming to reduce the critical times from cardiac arrest to initiation of ECPR and coronary revascularization. PMID- 29967857 TI - Persistent Ductus Arteriosus in Critically Ill Preterm Infants. AB - Introduction: Persistent ductus arteriosus (PDA) is found with increased incidence in preterm infants, significantly affecting neonatal morbidity and mortality rates. Aim: To evaluate the association between the presence of PDA and the severity of clinical condition at birth in critically ill preterm infants, with gestational ages (GA) <= 32 weeks and severe respiratory distress. Methods: All preterm infants with GA <= 32 weeks admitted to the neonatal intensive care unit (NICU) of the Clinical County Emergency Hospital, Sibiu between 1 January 2010 and 31 December 2015 were included in the study. These were categorized as Group 1 [Preterm infants with PDA; n=154] and Group 2 [Preterm infants without PDA; n=186]. Epidemiological and clinical data were collected in the National Registry for Respiratory Distress Syndrome for all children, and data related to prenatal period, clinical characteristics at birth i.e GA, weight, gender, Apgar scores, and clinical features such as resuscitation at birth, surfactant administration, need and duration of respiratory support, neonatal sepsis, complications associated with prematurity, and death, were analyzed. Results: Group 1 infants had significantly lower GA and birth weights, were more often out born (p=0.049, HR 1.69), and had significantly lower Apgar scores at 1 and 10 minutes (p=0.022, p=0.000). They presented a significantly higher need for surfactant administration (42.9% vs 24.7%, p<0.0001) and respiratory support (96.8% vs 90.3%, HR 3.19, p=0.019 for need of CPAP and 22.1% vs 10.8%, HR 2.35, p=0.004 for mechanical ventilation). Duration of respiratory support was also significantly higher in the Group 1 (7.6%+/-7.5 vs. 5.1+/-3.8 days, p<0.0001 for CPAP and 20.1+/-22.5 vs. 12.0+/-15.7 days, p<0.0001 for mechanical ventilation). Conclusion: In very preterm infants, PDA may be associated with a critical clinical condition leading to serious complications. The presence of PDA after the seventh day of life was associated with an increased need for respiratory support, both CPAP and mechanical ventilation, increased severity of the respiratory distress syndrome, requiring a longer duration of respiratory support, and increased the hospitalization length. In very preterm infants, PDA presence was also associated with a higher rate of severe complications and death, indicating the need for a careful and proper management of these critical cases in neonatal intensive care units. PMID- 29967858 TI - Congenital Heart Disease Requiring Maintenance of Ductus Arteriosus in Critically Ill Newborns Admitted at a Tertiary Neonatal Intensive Care Unit. AB - Introduction: Congenital heart diseases (CHD) have been reported to be responsible for 30 to 50% of infant mortality caused by congenital disabilities. In critical cases, survival of newborns with CHD depends on the patency of the ductus arteriosus (PDA), for maintaining the systemic or pulmonary circulation. The aim of the study was to assess the efficacy and side effects of PGE (prostaglandin E) administration in newborns with critical congenital heart disease requiring maintenance of the ductus arteriosus. Material and method: All clinical and paraclinical data of 66 infants admitted to one referral tertiary level academic center and treated with Alprostadil were analyzed. Patients were divided into three groups: Group 1: PDA dependent pulmonary circulation (n=11) Group 2: PDA dependent systemic circulation (n=31) Group 3: PDA depending mixed circulation (n=24). Results: The mean age of starting PGE1 treatment was 2.06 days, 1.91 (+/-1.44) days for PDA depending pulmonary flow, 2.39 (+/-1.62) days for PDA depending systemic flow and 1.71 (+/1.12) for PDA depending mixing circulation. PEG1 initiation was commenced 48 hours after admission for 72%, between 48-72 hours for 6%, and after 72 to 120 hours for 21% of newborns detected with PDA dependent circulation. Before PEG1 initiation the mean initial SpO2 was 77.89 (+/- 9.2)% and mean initial oxygen pressure (PaO2) was 26.96(+/ 6.45) mmHg. At the point when stable wide open PDA was achieved their mean SpO2increased to 89.73 (+/-8.4)%, and PaO2 rose to 49 (+/-7.2) mmHg. During PGE1 treatment, eleven infants (16.7%) had apnea attacks, five children (7.5%) had convulsions, 33 (50%) had fever, 47 (71.2%) had leukocytosis, 52 (78.8%) had edema, 25.8% had gastrointestinal intolerance, 45.5% had hypokalemia, and 63.6% had irritability. Conclusions: For those infants with severe cyanosis or shock caused by PDA dependent heart lesions, the initiation and maintenance of PGE1 infusion is imperative. The side effects of this beneficial therapy were transient and treatable. PMID- 29967859 TI - Staphylococcal Scalded Skin Syndrome in Child. A Case Report and a Review from Literature. AB - Staphylococcal scalded skin syndrome (SSSS) is the medical term used to define a skin condition induced by the exfoliative toxins produced by Staphylococcus aureus. The disorder is also known as Ritter disease, bullous impetigo, neonatal pemphigus, or staphylococcal scarlet fever. The disease especially affects infants and small children, but has also been described in adults. Prompt therapy with proper antibiotics and supportive treatment has led to a decrease in the mortality rate. The current case report describes the clinical progress of a patient with generalized erythema and fever, followed by the appearance of bullous lesions with tendency to rupture under the smallest pressure, and with extended areas of denudation. The patient aged four years and six months was admitted to our clinic to establish the aetiology and treatment of a generalized bullous exanthema, followed by a skin denudation associated with fever and impaired general status. Based on clinical and paraclinical examinations a diagnosis of Staphylococcal scalded skin syndrome was established which responded favourably to antibiotic treatment, hydro-electrolytic re-equilibration, and adequate local hygiene. Staphylococcal infection can represent a problem of significant pathological importance sometimes requiring a multidisciplinary approach involving paediatricians, dermatologists, infectious diseases specialists, and plastic surgeons. PMID- 29967860 TI - Pneumoretroperitoneum after Attempted Epidural Anesthesia. AB - Air may extend to the retroperitoneal space from retroperitoneal perforation of a hollow viscus, infection of the anterior pararenal space with gas-forming organisms and from pneumothorax or pneumomediastinum [1]. Rare pathologies, such as open reduction and internal fixation of femoral fractures and anaerobic abscess of the hip joint have also been described in relation to this complication [1,2]. A rare case of pneumoretroperitoneum caused by insufflation of air during an attempt to achieve epidural anesthesia is described. PMID- 29967861 TI - A Fatal Case of Community Acquired Cupriavidus Pauculus Pneumonia. AB - Introduction: Cupriavidus pauculus is a rarely isolated non-fermentative, aerobic bacillus, which occasionally causes severe human infections, especially in immunocompromised patients. Strains have been isolated from various clinical and environmental sources. Case presentation: A 67-year-old man was admitted to the Intensive Care Unit with acute respiratory failure. The patient was diagnosed with bilateral pneumonia, pulmonary sepsis and underwent invasive mechanical ventilation. Examination revealed diminished bilateral vesicular breath sounds, fever, intense yellow tracheal secretions, a respiratory rate of 24/minute, a heart rate of 123/minute, and blood pressure of 75/55 mmHg. Vasoactive treatment was initiated. Investigations revealed elevated lactate and C-reactive protein levels. A chest X-ray showed bilateral infiltration. Parenteral ciprofloxacin and ceftriaxone were administered. Tracheal aspirate culture and blood culture showed bacterial growth of Cupriavidus pauculus. Colistin was added to the treatment. There was a poor clinical response despite repeated blood culture showing negative results. The diagnosis of multiple organ dysfunction syndrome (MODS) caused by C. pauculus was made. The patient died eleven days after admission. Conclusions: Clinical improvement cannot always be expected in spite of targeted antibiotic therapy. This pathogen should be considered responsible for infections that usually develop in immunocompromised patients. PMID- 29967862 TI - Should Critical Care Professionals Take Hoaxes/Rumours Seriously? PMID- 29967863 TI - Simulation-based Training as Perceived by Young Anesthesiology and Intensive Care Residents. PMID- 29967865 TI - Pulse Oximetry During the First 24 Hours as a Screening Tool for Congenital Heart Defects. AB - Introduction: Although screening for congenital heart defects (CHD) relies mainly on antenatal ultrasonography and clinical examination after birth, life threatening cardiac malformations are often not diagnosed before the patient is discharged. Aim: To assess the use of routine pulse oximetry in the delivery room and at 24 hours postpartum, and to study its feasibility as a screening test for CHD. Material and Methods: In this prospective study, all infants born in "Cuza Voda" Maternity Hospital, Iasi, Romania, were enrolled over a thirteen-month period. Preductal oximetry was assessed during the first hour, and postductal oximetry was evaluated at twenty-four hours postpartum. Data were then analyzed to establish the sensitivity and specificity of pulse oximetry, as a screening test for CHD. Results: 5406 infants were included in the study, with a mean gestational age of 38.2 weeks and a mean birth weight of 3175 grams. During the first minute, blood oxygen saturation varied between 40% and 90% and at 24 hours of life, it ranged between 90% and 100%. Following oximetry assessment, 14 infants with critical CHD were identified. Blood oxygen saturation values in infants with CHD were lower throughout the entire period of evaluation. Pulse oximetry had good sensitivity and specificity at 1 hour (Se=87.5%, Sp=95.5%) and 24 hours (Se=92.5%, Sp=97.4%) for the diagnosis of CHD. Blood oxygen saturation values at one minute, 1 hour and 24 hours are strong discriminative parameters for the early diagnosis of CHD. Conclusion: Routine pulse oximetry during the first 24 hours postpartum represents an early indicator of CHD to facilitate timely intervention. Pulse oximetry provides excellent sensitivity and specificity and has tremendous potential as a standard screening test for CHD during the first 24 hours of life. PMID- 29967864 TI - The Relevance of Coding Gene Polymorphysms of Cytokines and Cellular Receptors in Sepsis. AB - Sepsis is an injurious systemic host response to infection, which can often lead to septic shock and death. Recently, the immune-pathogenesis and genomics of sepsis have become a research topic focusing on the establishment of diagnostic and prognostic biomarkers. As yet, none have been identified as having the necessary specificity to be used independently of other factors in this respect. However the accumulation of current evidence regarding genetic variations, especially the single nucleotide polymorphisms (SNPs) of cytokines and other innate immunity determinants, partially explains the susceptibility and individual differences of patients with regard to the evolution of sepsis. This article outlines the role of genetic variation of some serum proteins which have the potential to be used as biomarker values in evaluating sepsis susceptibility and the progression of the condition. PMID- 29967866 TI - Anaesthesia and Intensive Care Residents' Perception of Simulation Training in Four Romanian Centres. AB - Introduction: Simulation training offers an opportunity to educate anaesthesia and intensive care (AIC) residents safely. At present, it is not yet a mandatory part of residency curriculum.The aim of the study was to evaluate the residents' perception of the inclusion of simulation-based training in the Romanian AIC residency program. Material and methods: Romanian AlCs in anaesthesia and intensive care from four training centres completed a twenty-question survey regarding their views on simulation during their residency training. Residents were divided into junior, in the first three years, or senior groups, in the last two years of residency training. The questionnaire included Likert-scale multiple choice, open-ended, and "yes" or "no"questions regarding simulator learning, the frequency of simulation sessions, and the value of the simulation sessions in improving practice, skills or teamwork. The open-ended questions, asked which were the respondents' preferred topics to be included in simulation sessions. Results: Fifty-six percent of residents completed and returned the questionnaire. Ninety-eight percent of them considered simulation-learning useful once a month or every three months especially in the first two years of training. All residents thought simulation sessions would improve their skills, communication abilities, and teamwork. Senior residents paid more attention to clinical scenarios (p=0.007), haemodynamic monitoring (p=0.017) and mechanical ventilation (p=0.004) as compared to juniors. All residents considered difficult airway management, and cardiac life support to be very important issues to be included in simulation sessions. Conclusion: The survey demonstrated that simulation-based training should play a greater role and eventually became compulsory in training program in AIC academic centres. PMID- 29967867 TI - Neutrophil Gelatinase-Associated Lipocalin as a Marker for Renal Dysfunction Detection in Critically Ill Patients with Increased Intraabdominal Pressure. AB - Introduction: Elevated intraabdominal pressure (IAP) it is known to have an impact on renal function trough the pressure transmitted from the abdominal cavity to the vasculature responsible for the renal blood flow. Intraabdominal pressure is found to be frequent in intensive care patients and also to be a predictor of mortality. Intra-abdominal high pressure is an entity that can have serious impact on intensive care admitted patients, studies concluding that if this condition progresses to abdominal compartment syndrome mortality is as high as 80%. Aim: The aim of this study was to observe if a link between increased intraabdominal pressure and modification in renal function exists (NGAL, creatinine clearance). Material and Method: The study enrolled 30 critically ill patients admitted in the Intensive Care Unit of SCJU TirguMures between November 2015 and August 2016. The study enrolled adult, hemodynamically stable patients admitted in intensive critical care - defined by a normal blood pressure maintained without any vasopressor or inotropic support, invasive monitoring using PICCO device and abdominal pressure monitoring. Results: The patients were divided into two groups based on the intraabdominal pressure values: normal intraabdominal pressure group= 52 values and increased intraabdominal group= 35 values. We compared the groups in the light of NGAL values, 24 hours diuresis, GFR and creatinine clearance. The groups are significantly different when compared in the light of NGAL values and GFR values. We obtained a statistically significant correlation between NGAL value and 24 hour diuresis. No other significant correlations were encountered between the studied items. Conclusions: NGAL values are increased in patients with high intraabdominal pressure which may suggest its utility as a cut off marker for patients with increased intraabdominal pressure. There is a significant decreased GFR in patient with elevated intraabdominal pressure, observation which can help in early detection of renal injury in patients due to high intraabdominal pressure. No correlation was found between creatinine clearance and increased intraabdominal pressure. PMID- 29967868 TI - Toxic Epidermal Necrolysis - A Case Report. AB - Toxic epidermal necrolysis (TEN) is an acute, life-threatening muco-cutaneous disease, often induced by drugs. It is characterized by muco-cutaneous erythematous and purpuric lesions, flaccid blisters which erupt, causing large areas of denudation. The condition can involve the genitourinary, pulmonary and, gastrointestinal systems. Because of the associated high mortality rate early diagnosis and treatment are mandatory. This article presents the case of a sixty six years old male patient, known to have cirrhosis, chronic kidney failure, and diabetes mellitus. His current treatment included haemodialysis. He was hospitalized as an emergency to the Dermatology Department for erythemato violaceous, purpuric patches and papules, with acral disposition, associated with rapidly spreading erosions of the oral, nasal and genital mucosa and the emergence of flaccid blisters which erupted quickly leaving large areas of denudation. Based on the clinical examination and laboratory investigations the patient was diagnosed with TEN, secondary to carbamazepine intake for encephalopathic phenomena. The continuous alteration in both kidney and liver function and electrolyte imbalance, required him to be transferred to the intensive care unit. Following pulse therapy with systemic corticosteroids, hydro electrolytic re-equilibration, topical corticosteroid and antibiotics, there was a favourable resolution of TEN. The case is of interest due to possible life threatening cutaneous complications, including sepsis and significant fluid loss, in a patient with associated severe systemic pathology, highlighting the importance of early recognition of TEN, and the role of a multidisciplinary team in providing suitable treatment. PMID- 29967869 TI - Emergency Surgery in a Critically Ill Patient with Major Drug-Induced Bleeding and Severe Ischaemic Heart Failure. AB - Introduction: Anticoagulant overdose frequently occurs in elderly populations especially in remote areas where medical services are scarce. When emergency surgery is required, such patients offer major anaesthetic challenges. Case presentation: We describe the case of an elderly patient admitted to a surgical ward with acute abdominal pain, on dual anti-platelet therapy and acenocoumarol for a recent acute myocardial infarction treated percutaneously with two drug eluting stents. Laboratory tests showed severe anticoagulant overdose with uncoagulable INR. The decision was made to use of both light transmission aggregometry [LTA] for platelet function testing and thromboelastography to aid in the management of perioperative haemostasis in order to prevent both severe bleeding and stent thrombosis. Surgery revealed haemoperitoneum, volvulus of the ileum and a venous mesenteric infarction. Intraoperative blood loss was minimal and no blood products were administered. Postoperative course was uneventful without either thrombotic or haemorrhagic complications and the patient was discharged from the Postanaesthesia Care Unit on postoperative day two. Conclusion: The use of aggregometry and thrombography helped in both evaluation and management of haemostasis of a high-risk patient by goal-directed administration of pro-and anti-coagulants. PMID- 29967870 TI - Toxic Megacolon - A Three Case Presentation. AB - Introduction: Toxic megacolon is a life-threatening disease and is one of the most serious complications of Clostridium difficile infection (CDI), usually needing prompt surgical intervention. Early diagnosis and adequate medical treatment are mandatory. Cases presentation: In the last two years, three Caucasian female patients have been diagnosed with toxic megacolon and treated in the Clinical Infectious Diseases Hospital, Constanta. All patients had been hospitalized for nonrelated conditions. The first patient was in chemotherapy for non-Hodgkin's lymphoma, the second patient had undergone surgery for colon cancer, and the third patient had surgery for disc herniation. In all cases the toxin test (A+B) was positive and ribotype 027 was present. Abdominal CT examination, both native and after intravenous contrast, showed significant colon dilation, with marked thickening of the wall. Resolution of the condition did not occur using the standard treatment of metronidazole and oral vancomycin, therefore the therapy was altered in two cases using intracolonic administration of vancomycin and intravenous tigecycline. Conclusions: In these three cases of CDI, the risk factors for severe evolution were: concurrent malignancy, renal failure, obesity, and immune deficiencies. Ribotype 027, a marker for a virulent strain of CD, was found in all three cases complicated by toxic megacolon. The intracolonic administration of vancomycin, and intravenous tigecycline was successful when prior standard therapy had failed, and surgery was avoided. PMID- 29967871 TI - The Eleventh Hour: Neurosyphilis, Still Fashionable but a Controversial Diagnosis. PMID- 29967872 TI - Perioperative Management of Lactic Acidosis in End-Stage Liver Disease Patient. AB - Lactic acidosis (LA) in end-stage liver disease (ESLD) patients has been recognized as one of the most complicated clinical problems and is associated with increased morbidity and mortality. Multiple-organ failure, associated with advanced stages of cirrhosis, exacerbates dysfunction of numerous parts of lactate metabolism cycle, which manifests as increased lactate production and impaired clearance, leading to severe LA-induced acidemia. These problems become especially prominent in ESLD patients, that undergo partial hepatectomy and, particularly, liver transplantation. Perioperative management of LA and associated severe acidemia is an inseparable part of anesthesia, post-operative and critical care for this category of patients, presenting a wide variety of challenges. In this review, lactic acidosis applied pathophysiology, clinical implications for ESLD patients, diagnosis, role of intraoperative factors, such as anesthesia and surgery-related, vasoactive agents impact, and also current treatment options and modalities have been discussed. PMID- 29967874 TI - Neurosyphilis Masquerading as Stroke in an 84-year-old. AB - The case of an 84 years old woman with uncharacteristic neurologic and cognitive symptoms, suspected of ischemic stroke is presented. Following an extensive assessment in the departments of neurology and internal medicine, the unusual aetiology of stroke was identified as meningovascular neurosyphilis. The patient fully recovered after antibiotic therapy. To our knowledge, this the eldest patient with tertiary neurosyphilis reported in the literature. PMID- 29967873 TI - Anticoagulant Therapy in Sepsis. The Importance of Timing. AB - Sepsis associated coagulopathy is due to the inflammation-induced activation of coagulation pathways concomitant with dysfunction of anticoagulant and fibrinolytic systems, leading to different degrees of haemostasis dysregulation. This response is initially beneficial, contributing to antimicrobial defence, but when control is lost coagulation activation leads to widespread microvascular thrombosis and subsequent organ failure. Large clinical trials of sepsis-related anticoagulant therapies failed to show survival benefits, but posthoc analysis of databases and several smaller studies showed beneficial effects of anticoagulants in subgroups of patients with early sepsis-induced disseminated intravascular coagulation. A reasonable explanation could be the difference in timing of anticoagulant therapy and patient heterogeneity associated with large trials. Proper selection of patients and adequate timing are required for treatment to be successful. The time when coagulation activation changes from advantageous to detrimental represents the right moment for the administration of coagulation targeted therapy. In this way, the defence function of the haemostatic system is preserved, and the harmful effects of overwhelming coagulation activation are avoided. PMID- 29967875 TI - The Use of Endotoxin Adsorption in Extracorporeal Blood Purification Techniques. A Case Report. AB - Sepsis and septic shock are major healthcare problems, resulting in high morbidity and mortality. The Surviving Sepsis Campaign (SSC), which standardised the approach to sepsis, was recently updated. Strategies to decrease the systemic inflammatory response have been proposed to modulate organ dysfunctions. Endotoxin, derived from the membrane of Gram-negative bacteria, is considered a major factor in the pathogenesis of sepsis. Endotoxin adsorption, if effective, has the potential to reduce the biological cascade of Gram-negative sepsis. We present a case of a 64-year-old man with severe Gram-negative sepsis, following purulent peritonitis secondary to rectosigmoid adenocarcinoma. To reduce the amplitude of the general effects of endotoxins we used a novel device, the Alteco(r) LPS Adsorber (Alteco Medical AB, Lund, Sweden), for lipopolysaccharide (LPS) adsorption. The efficacy markers were: the overall haemodynamic profile, translated into decreased vasopressor requirements, the normalisation of the cardiac index, the systemic vascular resistance index combined with the lactate level and the reduction in procalcitonin (PCT) levels. A decrease in the sequential organ failure assessment (SOFA) score at twenty-four hours was demonstrated. The clinical course following treatment was favourable for the days immediately following the treatment.This was attributed to the removal of endotoxin from the systemic circulation. The patient died one week after the endotoxin removal session, developing an ischemic bowel perforation with subsequent multiple organ failures. PMID- 29967876 TI - Non-Obvious, Post-Traumatic, Life-Threatening Bleeding in Two Elderly Patients. AB - The main complication of anticoagulant therapy is major bleeding. Clinicians are usually aware of these side effects and are careful when managing the therapeutic range of vitamin K antagonist drugs. But major bleeding, while life-threatening, can be overlooked if there are no visible signs of bleeding. Two cases are described in which inaccurate diagnoses lead to inadequate treatment. PMID- 29967877 TI - Extracorporeal Membrane Oxygenation in Nivolumab Associated Pneumonitis. AB - Background: Newly approved immunotherapeutic agents, like CTLA-4 inhibitors and antibodies against PD-1, are a promising therapeutic option in cancer therapy. Case presentation: A 74-year-old man, with a history of advanced stage melanoma and treatment with ipilimumab, pembrolizumab and nivolumab, was admitted to the hospital due to respiratory failure with hypoxemia and dyspnoea. He rapidly developed severe acute respiratory distress syndrome (ARDS), which required treatment in the intensive care unit which included mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Computed tomographic imaging (CT) showed signs of a pneumonitis, with an ARDS pattern related to the use of PD-1 antibodies. Treating the patient with high-dose immunosuppressive steroids led to an overall improvement. He was transferred to a rehabilitation hospital and subsequently to his home. Discussion and conclusion: This is a unique case report of a patient suffering a grade 4 adverse event under nivolumab who survived having been treated with ECMO. It highlights the possibility of associated adverse reactions as well as the use of ECMO in palliative care patients. ECMO can be of great success even in patients with malignancies, but careful decision making should be done on a case by case basis. PMID- 29967878 TI - Highlights for Improvement of Scientific Writing for Publication in High Impact Journals. PMID- 29967879 TI - Use of Transcranial Doppler in Intensive Care Unit. AB - Use of transcranial Doppler has undergone much development since its introduction in 1982, making the technique suitable for general use in intensive care units. The main application in intensive care units is to assess intracranial pressure, confirm the lack of cerebral circulation in brain death, detect vasospasm in subarachnoid haemorrhage, and monitor the blood flow parameters during thrombolysis and carotid endarterectomy, as well as measuring stenosis of the main intracranial arteries in sickle cell disease in children. This review summarises the use of transcranial Doppler in intensive care units. PMID- 29967880 TI - The Importance of Haemogram Parameters in the Diagnosis and Prognosis of Septic Patients. AB - Sepsis represents a severe pathology that requires both rapid and precise positive and differential diagnosis to identify patients who need immediate antimicrobial therapy. Monitoring septic patients' outcome leads to prolonged hospitalisation and antibacterial therapy, often accompanied by substantial side effects, complications and a high mortality risk. Septic patients present with complex pathophysiological and immunological disorders and with a predominance of pro-inflammatory or anti-inflammatory mediators which are heterogeneous with respect to the infectious focus, the aetiology of sepsis or patients' immune status or comorbidities. Previous studies performed have analysed inflammatory biomarkers, but a test or combinations of tests that can quickly and precisely establish a diagnosis or prognosis of septic patients has yet to be discovered. Recent research has focused on re-analysing older accessible parameters found in the complete blood count to determine the sensitivity, specificity, positive and negative predictive values for the diagnosis and prognosis of sepsis. The neutrophil/lymphocyte count ratio (NLCR), mean platelet volume (MPV) and red blood cells distribution width (RDW) are haemogram indicators which have been evaluated and which are of proven use in septic patients' management. PMID- 29967881 TI - The First Manifestation of a Left Atrial Myxoma as a Consequence of Multiple Left Coronary Artery Embolisms. AB - A case of multiple embolisms in the left coronary artery as a rare first manifestation of left atrial myxoma is reported. A patient with embolic myocardial infarction and congestive heart failure was treated by percutaneous aspirations and balloon dilatations. Transesophageal echocardiography disclosed a villous myxoma with high embolic potential. Surgical resection of the tumour, suturing of a patent foramen ovale suture and an annuloplasty of the dilated tricuspid annulus was performed the third day after the admission. Recovery of the documented left ventricular systolic function can be explained by resorption of myxomatous material. The patient was discharged ten days after the surgery. PMID- 29967882 TI - Reoccurrence of Bleeding of a Chronic Subdural Haematoma Following a Fall. AB - The case of a 60-year-old patient who presented with an acute-on-chronic subdural haematoma is reported. Chronic haematoma usually remains asymptomatic, and this is considered to be an unusual course of events. Trivial or minor injury may cause the cortical bridge veins and fragile vessels in the former haematoma to rupture with concomitant reoccurrence of bleeding. Old age, repeated traumatic brain injuries, brain atrophy, antiplatelet agents and oral anticoagulants such as warfarin are considered to be the underlying conditions to cause the reoccurrence of bleeding. However, our patient did not have any of those conditions. PMID- 29967883 TI - Raoultella Ornithinolytica Diagnosed in a Neurointensive Patient. A Rare Case with Recovery without Antibiotics. AB - Infection with Raoultella ornithinolytica is rare and normally the infection is present in patients with underlying malignancies or chronic diseases. It is normally treated with antibiotics. In this case report, a neuro-intensive patient without malignancies or other severe chronic diseases was colonized with Pseudomonas aeruginosa but infected with Raoultella ornithinolyca. The patient recovered without treatment with antibiotics. PMID- 29967884 TI - Lung Abscess Remains a Life-Threatening Condition in Pediatrics - A Case Report. AB - Pulmonary abscess or lung abscess is a lung infection which destroys the lung parenchyma leading to cavitations and central necrosis in localised areas formed by thick-walled purulent material. It can be primary or secondary. Lung abscesses can occur at any age, but it seems that paediatric pulmonary abscess morbidity is lower than in adults. We present the case of a one year and 5-month-old male child admitted to our clinic for fever, loss of appetite and an overall altered general status. Laboratory tests revealed elevated inflammatory biomarkers, leukocytosis with neutrophilia, anaemia, thrombocytosis, low serum iron concentration and increased lactate dehydrogenase level. Despite wide-spectrum antibiotic therapy, the patient's progress remained poor after seven days of treatment and a CT scan established the diagnosis of a large lung abscess. Despite changing the antibiotic therapy, surgical intervention was eventually needed. There was a slow but steady improvment and eventually, the patient was discharged after approximately five weeks. PMID- 29967885 TI - Diagnosing "Brain Death" in Intensive Care. PMID- 29967886 TI - Let's Talk about Sepsis. PMID- 29967887 TI - Clinical Features and Outcomes of Fusobacterium Species Infections in a Ten-Year Follow-up. AB - Objective: Although uncommon, Fusobacterium infections have a wide clinical spectrum, ranging from local pharyngeal infections to septic shock. Our aim was to characterize and analyze the clinical features and outcomes in patients with Fusobacterium infections, and determine which variables were able to predict a poor outcome. Methods: We conducted a retrospective, hospital-based study using the computerized records of a second-level Spanish general hospital, serving a population of 155,000 inhabitants. The cohort was enrolled among patients cared for at the hospital between 2007 and 2016. Demographic, clinical data, microbiological characterization and outcomes at discharge, were analyzed. Results: We collected data for all 26 patients over a 10-year period (annual incidence of 1.78 per 100,000), with an incidence of bacteremia of 0.53 cases per 100,000 population per year. F. nucleatum and F. necrophorum were the most frequent isolations (53.8% and 38.5%, respectively). F. necrophorum was found to be associated with a younger population. Although we found no deaths attributable to Fusobacterium, 15 patients (57%) were found to have severe infections due to this pathogen, and 7 patients (26.9%) were admitted to the Intensive Care Unit (ICU). The only identifiable risk factor for a severe infection (sepsis, septic shock or ICU admission) was the presence of bacteremia. Conclusions: Fusobacterium infections are uncommon. F. necrophorum tends to cause infection in younger individuals, while F. nucleatum has a preference for older patients. The clinical spectrum is wide, ranging from local, nonsevere infections, such as sinusitis or pharyngitis, to abscess formation and life-threatening infections. PMID- 29967888 TI - The Use of Continuous Ketamine for Analgesia and Sedation in Critically Ill Patients with Opioid Abuse: A Case Series. AB - Managing pain and agitation in patients with opioid abuse is becoming more common in intensive care units. Tolerance to commonly used agents is often observed, leading to inadequate pain control and increased agitation. Ketamine's unique mechanism of action and opioid-sparing effects make it an ideal agent for patients with suboptimal response to opioid therapy. This report describes our experience using continuous ketamine infusions for analgesia and sedation in four mechanically ventilated patients with histories of opioid abuse that had suboptimal response to standard therapy. Ketamine was successful in improving analgesia and sedation in three patients while reducing the need for other analgesics and sedatives with minimal adverse effects. Continuous ketamine infusions may be useful to facilitate mechanical ventilation in patients with histories of opioid abuse with minimal toxicity. More information is needed on the optimal dose and titration parameters. PMID- 29967889 TI - Lethal Subarachnoid and Intracerebral Haemorrhage Associated with Temporal Arteritis. A Case Report. AB - Giant cell arteritis is a systemic inflammatory vasculitis, typically involving the superficial temporal arteries, but with possible ischemic and hemorrhagic cerebrovascular complications. The case is reported of a patient with a clinical picture of giant cell arteritis, who had multiple occupational exposures to various infectious agents. His initial favourable progress was followed by an atypical outcome. Despite immunosuppressive treatment, he developed fatal subarachnoid and intracerebral haemorrhages, possibly due to rupture of a microaneurysm of the posterior cerebral artery. PMID- 29967890 TI - Cytoreduction with Hyperthermic Intraperitoneal Chemotherapy and Renal Insufficiency Related to Diabetes Mellitus: An Anesthetic Challenge. AB - Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) improves the prognosis in selected patients with peritoneal surface malignancies but it is an extensive procedure predisposing to major complications. Among them renal toxicity was reported. Severe renal insufficiency is considered a contraindication for this complex procedure. We present a patient with diabetic nephropathy with renal insufficiency KDOQI 3 and peritoneal metastasis from sigmoid adenocarcinoma with a good clinical outcome after CRS with HIPEC, highlighting the anesthetic precautions considered for this particular clinical case. PMID- 29967891 TI - Repeated Bronchoscopy - Treatment of Severe Respiratory Failure in a Fire Victim. AB - A case of respiratory failure in a domestic fire victim presenting with 1-3 degree skin burns on 10% of the total body surface, is reported. Forty-eight hours after admission to hospital, the patient developed severe respiratory failure that did not respond to mechanical ventilation. Severe obstruction of the airway had resulted from secretions and deposits of soot forming bronchial casts. The patient required repeated bronchoscopies to separate and remove the bronchial secretions and soot deposits. An emergency bronchial endoscopic exam was crucial in the patient's survival and management. The patient was discharged from the hospital after twenty-four days. PMID- 29967892 TI - Neutropenia and T-Wave Inversion as Toxin-Mediated Complications of a Streptococcal Infection. AB - Introduction: Streptococcal infection can be responsible for multiple complications, such as toxic, septic or allergic disorders. Toxin-mediated complications (TMC) can appear during the acute phase of disease and can involve any organ, causing carditis, arthritis, nephritis, hepatitis etc. Case presentation: The case of a young woman without a history of recurrent streptococcal tonsillitis, admitted to "Matei Bals" National Institute for Infectious Diseases, Bucharest, Romania, presenting with fever, sore throat and exudative tonsillitis, is detailed. The initial test for Streptococcus pyogenes was negative. The patient had leukopenia with severe neutropenia, high values of inflammatory biomarkers and electrocardiographic (ECG) changes with inverted T waves in leads V1-4 and flattened T waves in V5-6. There were no other cardiac signs or symptoms. The patient received cefuroxime for two days. On admission, the patient was prescribed Penicillin G and dexamethasone which resulted in a rapid recovery. The leucocytes count returned to normal as did the ECG abnormalities. At the time of discharge, the antistreptolysin O titre was high. Conclusions: The case highlights the toxin-mediated complications (TMC) of streptococcal infection which occur from the outset of the disease. PMID- 29967893 TI - The Importance of Referencing. PMID- 29967894 TI - Neurological Critical Care Services' Influence Following Large Hemispheric Infarction and Their Impact on Resource Utilization. AB - Introduction: Acute ischemic stroke (AIS) is the fourth leading cause of death in the US. Numerous studies have demonstrated the use of comprehensive stroke units and neurological intensive care units (NICU) in improving outcomes after stroke. We hypothesized that an expanded neurocritical care (NCC) service would decrease resource utilization in patients with LHI. Methods: Retrospective data from consecutive admissions of large hemispheric infarction (LHI) patients requiring mechanical ventilation were acquired from the hospital medical records. Between 2011-2013, there were 187 consecutive patients admitted to the Jefferson Hospital for Neuroscience (Philadelphia, USA) with AIS and acute respiratory failure. Our intention was to determine the number of tracheostomies done over time. The primary outcome measure was the number of tracheostomies over time. Secondary outcomes were, ventilator-free days (Vfd), total hospital charges, intensive care unit length of stay (ICU-LOS), and total hospital length of stay (hospital-LOS), including ICU LOS. Hospital charges were log-transformed to meet assumptions of normality and homoscedasticity of residual variance terms. Generalized Linear Models were used and ORs and 95% CIs calculated. The significance level was set at alpha = 0.05. Results: Of the 73 patients included in this analysis, 33% required a tracheostomy. There was a decrease in the number of tracheostomies undertaken since 2011. (OR 0.8; 95% CI 0.6-0.9: p=0.02).Lower Vfd were seen in tracheostomized patients (OR 0.11; 95%CI 0.1-0.26: p<0.0001). The log-hospital charges decreased over time but not significantly (OR 0.9; 95%CI 0.78-1.07: p=0.2) and (OR 0.99; 95%CI 0.85-1.16: p=0.8) from 2012 to 2013 respectively.The ICU-LOS at 23 days vs 10 days (p=0.01) and hospital-LOS at 33 days vs 11 days (p=0.008) were higher in tracheostomized patients. Conclusion: The data suggest that in LHI-patients requiring mechanical ventilation, a dedicated NCC service reduces the overall need for tracheostomy, increases Vfd, and decreases ICU and hospital-LOS. PMID- 29967895 TI - Brain Death in Children: Incidence, Donation Rates, and the Occurrence of Central Diabetes Insipidus. AB - Introduction: Brain death is currently defined as the loss of full brain function including the brainstem. The diagnosis and its subsequent management in the pediatric population are still controversial. The aim of this study was to define the demographic characteristics, clinical features and outcomes of patients with brain death and determine the incidence of brain death, donation rates and occurrence of central diabetes insipidus accompanying brain death in children. Methods: This retrospective study was conducted at a twelve-bed tertiary-care combined medical and surgical pediatric intensive care unit of the Ondokuz Mayis University Medical School, Samsun, Turkey. In 37 of 341 deaths (10.8%), a diagnosis of brain death was identified. The primary insult causing brain death was post-cardiorespiratory arrest in 8 (21.6%), head trauma in 8 (21.6%), and drowning in 4 (18.9%). In all patients, transcranial Doppler ultrasound was utilised as an ancillary test and test was repeated until it was consistent with brain death. Results: In 33 (89%) patients, central diabetes insipidus was determined at or near the time brain death was confirmed. The four patients not diagnosed with CDI had acute renal failure, and renal replacement treatment was carried out. The consent rate for organ donation was 18.9%, and 16.7% of potential donors proceeded to actual donation. Conclusion: In the current study the consent rate for organ donation is relatively low compared to the rest of the world. The prevalence of central diabetes insipidus in this pedaitric brain death population is higher than reports in the literature, and acute renal failure accounted for the lack of central diabetes insipidus in four patients with brain death. Further studies are needed to explain normouria in brain-dead patients. PMID- 29967896 TI - Severe Austrian Syndrome in an Immunocompromised Adult Patient - A Case Report. AB - Background: Known also as Osler's triad, Austrian syndrome is a complex pathology which consists of pneumonia, meningitis and endocarditis, all caused by the haematogenous dissemination of Streptococcus pneumoniae. The multivalvular lesions are responsible for a severe and potential lethal outcome. Case Report: The case of a 51-year-old female patient, with a past medical history of splenectomy, is presented. She developed bronchopneumonia, acute meningitis and infective endocarditis as a result of Streptococcus pneumoniae infection and subsequently developed multiple organ dysfunction syndromes which led to a fatal outcome. Bacteriological tests did not reveal the etiological agent. The histopathological examination showed a severe multivalvular endocarditis, while a PCR based molecular analysis from formalin fixed valvular tissue identified Streptococcus pneumoniae as the etiologic agent. Conclusions: The presented case shows a rare syndrome with a high risk of morbidity and mortality. Following the broad-spectrum treatment and intensive therapeutic support, the patient made unfavourable progress which raised differential diagnosis problems. In this case, the post-mortem diagnosis demonstrated multiple valvular lesions occurred as a result of endocarditis. PMID- 29967897 TI - Stroke Secondary to Traumatic Carotid Artery Injury - A Case Report. AB - Introduction: Lesions of the carotid and vertebral arteries secondary to direct trauma, called blunt cerebrovascular injuries (BCVI) are relatively rare and are markedly different from spontaneous dissections. Ischaemic stroke is a significant complication, with high morbidity and mortality rates. The basis of a diagnosis relies on appropriate, high sensitivity imaging screening. Case report: We present the case of a 31 years old male patient with polytraumatism secondary to a motor vehicle accident, who was admitted to an orthopaedic clinic for multiple lower extremity fractures. His fractures were treated surgically. He developed in the 3rd day after the admission left sided hemiparesis secondary to ischaemic stroke. The diagnosis of traumatic carotid artery injury (TCAI) was based on duplex ultrasound and angio CT scans. The outcome was favourable despite the severe carotid lesions presenting with occlusion secondary to dissection. Conclusions: In the majority of BCVI cases there is a variable latent period between the time of injury and the development of stroke. The management of cases is challenging because in the majority of cases there are multiple associated injuries. Although antithrombotics are widely used in the treatment, there is no consensus regarding the type of agent, the optimal dose or treatment duration. PMID- 29967898 TI - Serratia Marcescens Sepsis in a Child with Deep Venous Thrombosis - A Case Report. AB - Introduction: Venous thromboembolism is a rare condition in paediatrics that included both deep venous thrombosis and pulmonary embolism. Serratia marcescens is a gram-negative bacterium that belongs to the Enterobacteriaceae family and tends to affect immunocompromised hosts. Case report: We report the case of an 11 year-old boy, admitted in the Pediatric Clinic I from Emergency County Hospital Tirgu Mures, Romania with intense pain, swelling, cyanosis and claudication of the left foot. His personal history revealed a recent appendectomy. A close family was reported to have had a deep venous thrombosis. The laboratory tests, performed on the day of admission, revealed increased inflammatory biomarkers and D-dimer. Coagulation tests gave a low activated partial thromboplastin time (APTT). Doppler venous ultrasound and CT-exam established a diagnosis of deep venous thrombosis. Anticoagulant therapy was initiated, but on the tenth day of admission, the patient developed signs and symptoms of sepsis, and the blood culture revealed Serratia marcescens. After antibiotic and anticoagulant therapy, the patient progressed favourably. The patient was a carrier of the heterozygous form of Factor V Leiden. Conclusions: The association between deep venous thrombosis and Serratia marcescens sepsis can compromise a condition in pediatric patients. PMID- 29967899 TI - Post-Pneumonectomy ARDS and Ogilvie Syndrome - A Case Report. AB - Introduction: The Acute Respiratory Distress Syndrome (ARDS) is a severe hypoxemic acute lung injury that may complicate lung resections. Reported mortality is very high, up to 50%. This report covers an ARDS case occurring post left pneumonectomy, with a favorable outcome, despite association with an acute colonic pseudo-obstruction syndrome (Ogilvie syndrome) that required abdominal surgery for decompression. Case Report: A 60-year old Caucasian male, diagnosed with a stage IIIA left lung tumor underwent a left pneumonectomy. On the second postoperative day, the patient developed ARDS, requiring ventilatory support. Two days later, as the multiple organ dysfunction worsened, a bowel obstruction occurred. With an acute colonic pseudo-obstruction diagnosis, the decision was to perform laparotomy and a temporary cecostomy. A subsequent improvement in the respiratory parameters and vital functions resulted in weaning from ventilator 8 days after the onset of the ARDS and transfer to the surgery ward 14 days after pneumonectomy. PMID- 29967900 TI - Editorial: What's new in digital implant dentistry? PMID- 29967901 TI - In vitro comparison of guided versus freehand implant placement: use of a new combined TRIOS surface scanning, Implant Studio, CBCT, and stereolithographic virtually planned and guided technique. AB - Implant placement requires precise planning and execution to avoid collision with critical anatomical structures. Technology advances may improve placement outcomes. The purpose of this study was to trial and measure in an in vitro environment the accuracy of placing a single dental implant in the planned position using a specific guided surgery technique compared with a freehand surgery technique. The dental model of a patient missing tooth 16 was printed 30 times (EnvisionTEC 3Dent). Each print was scanned (TRIOS color scanner) to create a 3D surface model, and radiographed (Gendex CB-500) to create cone beam computed tomography (CBCT) data. The surface data and CBCT data were merged (Implant Studio software), and a Straumann RC bone level O 4.1 * 8 mm implant placement was planned. A surgical guide was printed (Stratasys OrthoDesk) for each case (n = 30). Simulated cases were assigned to Group A (guided) or Group B (freehand, where the fabricated guide was discarded). Implants were placed, and the models rescanned (TRIOS). The new data was superimposed on the original data, and the surgical implant location compared with the planned position for each model (Convince software) by a researcher blinded to group allocation. Differences in angulation (degrees); shoulder, apex, and depth displacements (mm); and direction of displacement were assessed with Mann-Whitney U and Fisher exact tests. Data was expressed as medians bounded by interquartile ranges (IQRs). Implant angulation and apical displacement were significantly closer to the planned position in the guided group compared with the freehand group (3.91 degrees: IQR 2.45 to 5.38 degrees vs 8.82 degrees: IQR 4.84 to 9.84 degrees, P = 0.005; and 0.87 mm: IQR 0.53 to 1.11 mm vs 1.48 mm: IQR 1.14 to 1.72 mm, P < 0.001, respectively). Implant shoulder displacement, depth displacements, and direction of displacement did not differ between the groups. Within the in vitro environment, merged 3D surface scan data and 3D CBCT scan data can be used to plan and guide implant placement with greater accuracy than with the freehand technique. PMID- 29967902 TI - Precision of sleeveless 3D drill guides for insertion of one-piece ceramic implants: a prospective clinical trial. AB - OBJECTIVE: The insertion of implants through template-guided surgery is an established method. At the present time, the static navigation is based on sleeves integrated into the guides, through which drill bits of the corresponding size are passed. The present clinical trial is designed to test a new sleeveless system to determine the precision of implant insertion for one-piece ceramic implants. MATERIALS AND METHODS: For 12 patients, implant bed preparation and the insertion of the implants were done using a sleeveless implant guide. Twenty implants were inserted in this way and checked for precision. The check was done using a noninvasive method, which permitted comparison of the planning data with the actually realized positions after superimposition. RESULTS: The mean deviations were 0.52 mm (95% CI: 0.37 to 0.67 mm) at the crestal position of the implant, and 0.82 mm (95% CI: 0.56 to 1.08 mm) at the apical tip of the implant. The height deviation was 0.35 mm (95% CI: 0.01 to 0.68 mm). The mean angular deviation was measured as 2.85 degrees (95% CI: 2.18 to 3.51 degrees). CONCLUSION: The values showed good precision in all the parameters measured. The results were thus in a range equal to or better than the mean precision found in numerous clinical trials described in the literature. In particular, the method showed little deviation, as illustrated by the confidence interval (CI), but also by the clinically critical maximum deviations. PMID- 29967903 TI - Accuracy (trueness and precision) of dental models fabricated using additive manufacturing methods. AB - OBJECTIVE: This study evaluated the accuracy (trueness and precision) of dental models fabricated using additive manufacturing (AM) methods such as PolyJet and fused deposition modeling (FDM). MATERIALS AND METHODS: 10 stone models were acquired for the control group by scanning a complete arch model. For the experimental groups, 10 PolyJet models and 10 FDM models were fabricated from digital impressions using an intraoral scanner. All 30 models were then scanned, and root mean square values were measured using three-dimensional (3D) analysis software. RESULTS: Trueness did not significantly differ between the stone and PolyJet models. The precision of the AM models was significantly higher than that of the stone models. The layer thicknesses of the FDM models were greater than those of the PolyJet models. CONCLUSION: The results of this study show that it might be possible for the dental models fabricated using additive manufacturing methods to be used in clinical settings. PMID- 29967904 TI - Two digital strategies in modern implantology - root-analogue implants and the digital one-abutment/one-time concept. AB - The irreversible trend toward digitization in dentistry and dental technology has resulted in technical progress and continuous changes to conventional workflows. In particular, implantology and prosthetics have benefited from a multitude of interesting new possibilities. Three-dimensional (3D) computed radiography and digital surface scanning can be invaluable in terms of backward planning and making implant surgery and denture fabrication more predictable. In this context, two digital implant-prosthetic treatment strategies are presented that allow for an efficient digital workflow while ensuring a minimally invasive surgical procedure. By means of digital intraoperative scanning of the implant position, the digital one-abutment/one-time concept allows for the insertion of computer aided design/computer-aided manufacturing (CAD/CAM)-manufactured single crowns instantly after uncovering the implant. The second approach uses 3D radiographic data to preoperatively manufacture a one-piece root-analogue implant (RAI) and insert it immediately after tooth extraction. Both ideas promise some advantages in terms of quality and preservation of periimplant tissues as well as a noticeable reduction in overall treatment time. PMID- 29967905 TI - Digital implantological workflow for a CAD/CAM immediate long-term temporary restoration for the edentulous maxilla. AB - The rehabilitation of the edentulous jaw using angulated implants and screw retained retrievable fixed prosthetic dentures is a well-established treatment method. Possible advantages include the option to avoid bone augmentation, to provide an immediate long-term provisional restoration, and, where appropriate, to perform a minimally invasive procedure. A variety of prosthodontic solutions are available for the definitive restoration, not least allowing the patient's financial situation to be accommodated. Implementing this concept requires systematic planning and an exacting surgical procedure. It makes sense to rely on a computer-assisted process for this purpose as it standardizes the procedure and makes it reproducible, with all the benefits this entails. The present report highlights the consistent integration of virtual planning and computer-aided design/computer-aided manufacturing (CAD/CAM), from the surgical template to the immediate long-term provisional restoration. The relevant procedures are described in general terms and illustrated by a patient case. PMID- 29967906 TI - Possibilities and limitations of computer-assisted implant planning and guided surgery in the anterior region. AB - Three-dimensional (3D) implant positioning is an important prognostic factor for anterior dental implants. Modern 3D imaging and implant treatment planning systems are available today for precise dental implant planning and placement. The transfer of implant position information to industrially manufactured templates for guided implant surgery has been possible for years now. What is new is the possibility of combining the datasets with the surface scan data of a diagnostic wax-up and setup for prosthetic-driven implant planning. Digital setups can also be used. This article describes and discusses the available options for digital implant planning and guided surgery. PMID- 29967907 TI - Monolithic zirconia multiple-unit implant reconstructions on titanium bonding bases. AB - The development of titanium bonding bases allows for the use of implant-supported monolithic reconstructions in a digital workflow. Different base configurations are available according to each clinical indication. In this case report, the selection of titanium bonding bases for crowns was considered for a multiple-unit fixed dental prosthesis (FDP). PMID- 29967909 TI - Energy landscape of polymorphic amyloid generation of beta2-microglobulin revealed by calorimetry. AB - Understanding of amyloid aggregation in terms of thermodynamics and kinetics is still limited. We herein examined the mechanism of beta2-microglobulin amyloidogenesis using our unique method of isothermal titration calorimetry-based thermodynamic/kinetic measurements, and revealed the energy landscape of polymorphic amyloidogenesis under biological environment-mimicking conditions including shear forces and crowding effects. PMID- 29967910 TI - Redox behaviour of ([fc(NPiPr2)2]Fe)2, formation of an iron-iron bond and cleavage of azobenzene. AB - The redox behaviour of the dimeric tetrairon complex, ([fc(NPiPr2)2]Fe)2 (where fc(NPiPr2)2 = 1,1'-(C5H4NPiPr2)2Fe) has been investigated. Upon reduction with KC8 an Fe-Fe bond is formed with the complex maintaining a high spin configuration and having the formula [K(THF)6]([fc(NPiPr2)2]Fe)2. In contrast, oxidation of the complex is ligand based; for example, addition of the 1,2 diiodoethane (I2 equivalent) results in the formation of the monomeric iron(ii) diiodide [fc(NiPr2I)2]FeI2 wherein the phosphine is oxidized. The dimeric tetrairon complex reacts photolytically with azobenzene, cleaving the N[double bond, length as m-dash]N double bond and forming the new monomeric bis(phosphoramidate) iron complex. [fc(NP(NPh)iPr2)2]Fe. Characterization of these paramagnetic complexes was accomplished by magnetic susceptibility studies and X-ray analyses. PMID- 29967911 TI - Facile synthesis of a red light-inducible overall water-splitting photocatalyst using gold as a solid-state electron mediator. AB - We facilely prepared a solid-state heterojunction photocatalyst in which zinc rhodium oxide (ZnRh2O4) and bismuth vanadium oxide (Bi4V2O11) as hydrogen (H2) and oxygen (O2) evolution photocatalysts, respectively, were connected with gold (Au) to generate ZnRh2O4/Au/Bi4V2O11. ZnRh2O4/Au/Bi4V2O11 photocatalyzed the overall pure-water splitting under irradiation with red light at wavelengths of up to 740 nm. PMID- 29967912 TI - Modification of oligodeoxynucleotides by on-column Suzuki cross-coupling reactions. AB - The on-column functionalization of oligodeoxynucleotides via base-free Suzuki cross-coupling reactions is reported herein. These cross-coupling reactions were carried out with various boronic acids and either full-length modified oligonucleotides containing one or more 2'-deoxy-5-iodouridine (5IdU) monomer(s) or on oligonucleotide fragments immediately after incorporation of 5IdU. Five different functionalities were coupled to oligonucleotides containing one or three attachment points. PMID- 29967913 TI - Gold nanoparticle-decorated graphene as a nonlinear optical material in the visible and near-infrared spectral range. AB - There have been numerous reports of boosting nonlinear optical phenomena in plasmonic nanostructures through local-field enhancement as well as through intrinsic metal nonlinearities. Here, we study the possibility of plasmonic enhancement of graphene's nonlinear absorption by creating a composite material: gold nanoparticle-decorated graphene dispersed in water. To evaluate the additive effect of combining the two materials on the saturable absorption efficiency we performed a series of f-scan (modified Z-scan) measurements using femtosecond laser pulses in the broad spectral range from 530 to 1600 nm. These studies are supplemented by TEM, UV-vis, ATR and Raman spectroscopy, revealing the mechanisms behind the formation of the composite material. PMID- 29967914 TI - Diruthenium(ii)-capped oligothienylethynyl bridged highly soluble organometallic wires exhibiting long-range electronic coupling. AB - Organometallic molecular wires with pi-conjugation along their molecular backbones are of considerable interest for application in molecular-scale electronics. In this regard, thienylethynyl-based pi-conjugated oligomers of three, five and seven thienylethynyl units with -C[triple bond, length as m dash]C-H termini have been successfully synthesized through stepwise Pd(0)/Cu(i) catalyzed Sonogashira coupling. The corresponding highly soluble diruthenium(ii) diacetylide complexes (O1-Ru2, O3-Ru2, O5-Ru2 and O7-Ru2, respectively) have been prepared by the reaction of cis-Ru(dppe)2Cl2 and NaPF6 in DCM with the corresponding rigid rod-like thienylethynyl oligomers with one, three, five and seven thienylethynyl pi-conjugated segments containing alkynyl termini (O1, O3, O5 and O7). These Ru(ii)-Cl capped diacetylide complexes have been further functionalized by incorporating a phenylacetynyl moiety to afford [Ru(ii) C[triple bond, length as m-dash]C-Ph]-capped diacetylide organometallic wires (O1 Ru2-Ph, O3-Ru2-Ph, O5-Ru2-Ph and O7-Ru2-Ph). The photophysical properties of the highly soluble thienylethynyl-based oligomers and Ru(ii)-organometallic wires have been explored to understand their electronic properties. Electrochemical studies of the binuclear ruthenium(ii)-alkynyl complexes showed highly interesting results, revealing long-range electrochemical communication between the two remote Ru(ii) termini connected even with five and seven thienylethynyl units. DFT computational studies further support the long range electrochemical communication between the redox active metal termini through heavy participation of the thienylethynyl bridge in the corresponding mono-oxidized mixed valence species of the organometallic wire-like complexes. PMID- 29967915 TI - Continuum of covalent to intermolecular bonding in the halogen-bonded complexes of 1,4-diazabicyclo[2.2.2]octane with bromine-containing electrophiles. AB - A gradual change of BrN bond lengths and strengths from the values typical for intermolecular associates to that characteristic of a covalent bond was observed in a series of halogen-bonded complexes. This continuum reveals a fundamental relationship between the limiting types of bonding and implies the onset of covalency in the intermolecular interactions. PMID- 29967916 TI - DFT investigation on the adsorption of munition compounds on alpha-Fe2O3: similarity and differences with alpha-Al2O3. AB - Arid environments have long been a testing and training ground for novel munitions. However, these activities leave behind unknown quantities of munition residues with unknown impact on local flora and fauna. In particular, arid soil contains Lewis acidic metal oxides which bind and catalyze the electron rich substituent groups commonly found in munition compounds, although the exact mechanisms are poorly understood. The current study remedies this lack of knowledge by utilizing density functional theory (DFT) to explore various orientations of four important munition compounds on the alpha-Fe2O3(0001) and alpha-Al2O3(0001) surfaces. Our findings reveal that while alpha-Fe2O3 binds the munition compounds more strongly than alpha-Al2O3, all four compounds experienced elongation of their nitro (-NO2) groups, indicating their susceptibility towards degradation on these surfaces. PMID- 29967917 TI - Superstructure manipulation and electronic measurement of monolayers comprising discotic liquid crystals with intrinsic dipole moment using STM/STS. AB - In this work, we studied the discotic liquid crystals (DLCs) of dibenzo[a,c]phenazine at the liquid-solid interface using scanning tunnelling microscopy/spectroscopy, by which we show how to tailor the DLC assemblies and in turn their electron-transfer efficiency. This study presents an alternative method for phase control and electronic measurements for DLCs, especially at the microscopic level. PMID- 29967918 TI - Highly stable CsPbBr3@SiO2 nanocomposites prepared via confined condensation for use as a luminescent ink. AB - We have firstly prepared CsPbBr3@SiO2 nanocomposites with a spherical morphology and diameters less than 125 nm via confined condensation into polystyrene. The obtained CsPbBr3@SiO2 exhibits high stability in polar solvents and can be used as a solution-processable luminescent ink. PMID- 29967919 TI - Probing the early stages of prion protein (PrP) aggregation with atomistic molecular dynamics simulations. AB - Prions are self-replicating infectious proteinaceous agents whose conformations are capable of forming amyloid-like aggregate fibrils. Here we present molecular dynamics simulations aimed at investigating the aggregation process of the beta rich H2H3 domain of the ovine prion protein (H2H3-OvPrPSc), known to be the portion of prion protein carrying oligomerization activity. PMID- 29967920 TI - Machine learning for predicting product distributions in catalytic regioselective reactions. AB - Gaining predictable control over various forms of selectivities, such as enantio- and/or regio-selectivities, has been a long-standing goal in chemical catalysis. Although a number of factors such as the molecular features of the reactants and catalysts, as well as the reaction conditions, can influence the outcome of a reaction, it is not quite conspicuous as to what combinations of these parameters would offer a desired form of selectivity. We use machine learning tools, such as the neural network (NN), decision tree (DT), logistic regression (LR) and Random forest algorithms, to (a) analyze the outcome of an important catalytic regio selective difluorination reaction of alkenes, and (b) decipher the complex interplay of various molecular parameters and their non-linear dependencies. The connection between what features of alkenes will yield 1,1-difluorination and how subtle changes would steer the reaction to 1,2-difluorination under identical conditions is enunciated. The NN was able to accurately predict whether a given alkene would yield a 1,1- or 1,2-difluorinated product. A combination of DT and the random forest classifier offered important chemical insights, which could be used in making a more rational choice of the reactant alkene for the desired regioisomeric product. The results could have far reaching implications in predicting which regioisomer is likely to be formed under a given set of conditions, and thus this technique is capable of expediting the development of catalytic transformations. PMID- 29967921 TI - Clinically relevant drug-drug interactions among elderly people with dementia. AB - PURPOSE: Increased numbers of drugs and changes in pharmacokinetic and pharmacodynamic parameters among elderly people contribute to increased prevalence of adverse drug reactions. Drug-drug interactions (DDIs) are an important reason for admission to hospital and elderly people with dementia are particularly vulnerable. The aims of the present study were to assess the occurrence and characteristics of clinically relevant DDIs and to investigate potential risk factors associated with DDIs among elderly people with dementia. METHODS: People >= 65 years with dementia, admitted to two hospitals in Northern Sweden, were included. The medical records of 458 patients were reviewed. Clinically relevant DDIs were identified using the Janusmed interactions database. Pharmacological classification was conducted using Stockley's classification system. RESULTS: A total of 401 DDIs were identified among 43.2% of the study population, of which 98.5% had interactions that may require dose adjustment and 7.6% had drug combinations that should be avoided. Pharmacodynamic interactions were most common, of which furosemide-citalopram (n = 35) were most frequently observed. Omeprazol-citalopram (n = 25) was the most common drug combination among pharmacokinetic interactions. Citalopram and warfarin were the most commonly involved drug substances. An association was found between a higher number of medications being prescribed and having at least one DDI. CONCLUSION: Clinically relevant drug-drug interactions are prevalent among elderly people with dementia living in Northern Sweden. Drug-drug interactions should be identified in order to manage and prevent adverse outcomes. This is particularly important among this group of people especially when multiple medications are being prescribed. PMID- 29967922 TI - The Mite Tyrophagus putrescentiae Hosts Population-Specific Microbiomes That Respond Weakly to Starvation. AB - The effect of short-term nutrient deprivation was studied in five populations of the mite Tyrophagus putrescentiae with different microbiomes. The fresh weight, nutrient status, respiration, and population growth of the mites were observed for the five mite population-scale samples. The starvation caused the larvae and nymphs to be eliminated, resulting in a significant increase in the fresh weight of starved adult specimens. Three populations were negatively influenced by starvation, and the starved specimens were characterized by a decrease in nutrient status, respiration, and population growth. One population was not influenced or was slightly influenced by starvation, which had no effect on population growth or nutrient contents but caused a significant decrease in respiration. One population was positively influenced by starvation; the population growth increased in starved specimens, and starvation had no effect on respiration. Although starvation altered the bacterial profiles of the microbiomes, these differences were much smaller than those between the populations. The bacterial profiles of Staphylococcus, Bacillus, Kocuria, Brevibacterium, and unidentified Micrococcaceae and Enterobacteriaceae increased in starved specimens, whereas those of Bartonella and Solitalea-like genera were reduced in the starved mite populations. The profiles of the intracellular symbiont Cardinium decreased in the starved specimens, and the Wolbachia profile changes were dependent on the mite population. In mite populations, when the symbionts were rare, their profiles varied stochastically. Correlations between changes in the profiles of the bacterial taxa and mite fitness parameters, including nutrient status (lipids, proteins, saccharides, and glycogen contents), mite population growth, and respiration, were observed. Although the microbiomes were resistant to the perturbations caused by nutrition deficiency, the responses of the mites differed in terms of their population growth, respiration, and nutrient status. PMID- 29967923 TI - Experiences, expectations, and fears of adolescents with epilepsy or bronchial asthma. AB - : Epilepsy and bronchial asthma are frequent in adolescents. Data on adolescents' experiences with their disease and on their expectations for the future, however, is scarce. Patients of a university hospital aged 12 to 17 with epilepsy or bronchial asthma were interviewed based on a questionnaire. Forty-five patients with epilepsy and 47 with bronchial asthma were interviewed. Adolescents with epilepsy felt more impaired by their disease (median 2.5; Q25/Q75 0.75/3.0; 6 level Likert scales: 0 = not at all, 5 = very strong) than those with asthma (1.0; 0/3.0; p = 0.017). Seventy-nine patients (85.9%) had never used the Internet to gain information about their disease. Adolescents with epilepsy felt more limited in their career possibilities by their disease (2.0; 0/4.0) than those with asthma (0; 0/2.0; p = 0.001) and had a higher level of concern about passing their disease on to their children (3.0; 0/4.0) than their peers with asthma (1.5; 1.5/3.0; p = 0.016). Girls with epilepsy were more anxious (4.0; 0.5/5.0) than girls with asthma (0; 0/4.0) about complications of the disease regarding pregnancy (p = 0.019). CONCLUSION: As well adolescents with epilepsy as with asthma described limitations of their daily life and concerns about the future. What is Known: * Epilepsy and bronchial asthma are frequent chronic diseases in adolescents. * Those diseases can affect psychosocial development. What is New: * Adolescents with epilepsy and bronchial asthma described a high burden of their disease, and most adolescents had not used the Internet to inform themselves on their disease. * Especially adolescents with epilepsy fear limitations in their job possibilities, inheritance of their disease and complications in their prospective pregnancy. PMID- 29967924 TI - Stress of working abroad: a systematic review. AB - PURPOSE: Many companies target international markets to expand their business. Companies need to manage international teams with a wide variety of skills, knowledge and values to run their business effectively; however, there are many issues of acculturation stress. Not only business travellers and expatriates, but also immigrant workers have issues adjusting to foreign culture. The aim of the present study is to identify the stress factors affecting foreign-born workers via a systematic review. METHODS: The systematic review was conducted using PubMed, PsycINFO, Embase and Cochrane Library databases. Articles on the subject of workers living abroad, such as immigrants, expatriates and business travellers, were included. The risk of bias in the included articles was assessed using the Cochrane Collaboration's tool for assessing risk of bias for randomised controlled trials (RCTs), RoBANS for non-RCT studies, and CASP for qualitative studies. RESULTS: For the systematic review, 45 out of 14,994 articles were analysed. Six components, communication, cultural differences in the workplace, daily life, relationships with family and colleagues, financial problems and social inequality, were extracted. CONCLUSION: Foreign-born workers are suffering from acculturation and occupational stress. The results of the present study can help greatly with understanding of the stress structure of working abroad. PMID- 29967926 TI - The impact of hypermobility spectrum disorders on musculoskeletal tissue stiffness: an exploration using strain elastography. AB - Hypermobility spectrum disorders (HSDs) are conditions associated with chronic joint pain and laxity. HSD's diagnostic approach is highly subjective, its validity is not well studied, and it does not consider many of the most commonly affected joints. Strain elastography (SEL) reflects musculoskeletal elasticity with sonographic images. The study explored the impact of HSD on musculoskeletal elasticity using SEL. A cross-sectional design compared 21 participants with HSD against 22 controls. SEL was used to assess the elasticity of the deltoid, biceps brachii, brachioradialis, rectus femoris, and gastrocnemius muscles, and the patellar and Achilles tendon. SEL images were analyzed using strain index, strain ratio, and color pixels. Mean strain index (standard deviation) was significantly reduced in the HSD group compared to the control group in the brachioradialis muscle 0.43 (0.10) vs. 0.59 (0.24), patellar 0.30 (0.10) vs. 0.44 (0.11), and Achilles tendons 0.24 (0.06) vs. 0.49 (0.13). Brachioradialis muscle and patellar tendon's strain ratios were significantly lower in the HSD group compared to the control group, 6.02 (2.11) vs. 8.68 (2.67) and 5.18 (1.67) vs. 7.62 (1.88), respectively. The percentages (%) of red color (soft tissues) in the SEL images were significantly increased in the HSD group compared to the control group in the biceps brachii muscle, 34.72 (7.82) vs. 26.69 (3.89), and Achilles tendon, 18.14 (13.21) vs. 5.59 (8.23) (p <= 0.01). The elasticity of the musculoskeletal system seems to be lower in people with HSD. SEL could be a supplementary tool for diagnosing and monitoring HSD. PMID- 29967925 TI - The best cardiovascular risk calculator to predict carotid plaques in rheumatoid arthritis patients. AB - Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in patients with rheumatoid arthritis (RA). Chronic inflammation and traditional risk factors increase cardiovascular risk (CVR) in these patients. Several CVR calculators are used in general population and in RA patients to predict cardiovascular outcomes and tailor therapy but the precision of these calculators in RA patients has yet to be determined. The aim of this study is to determine which risk calculator correlates best with carotid ultrasound (US) findings, specifically carotid plaque (CP) and carotid intima-media thickness (CIMT) in RA patients without clinical manifestations. This was a cross-sectional observational study relating CVR scores in RA patients with the presence of carotid US findings. A total of 97 patients 40 to 75 years old who fulfilled the 2010 ACR/EULAR and/or the 1987 ACR classification criteria for RA were selected. Clinical assessment of cardiovascular risk was performed using seven calculators and carotid US measurement of intima-media thickness and plaque. The tests with the highest sensitivity for CIMT were the Framingham BMI, Framingham lipids, ACC/AHA 2013, and QRISK2. In CP, the highest sensitivity was in QRISK2, SCORE, and ACC/AHA 2013. RA patients should be comprehensively evaluated to detect cardiovascular risk. Carotid US may be routinely recommended to detect subclinical atherosclerosis in RA patients. A lower cutoff point in CVR scales may be necessary to identify patients with a low and intermediate CVR to detect subclinical atherosclerosis earlier and personalize therapy. PMID- 29967927 TI - Degradation of Vanillin During Lignin Valorization Under Alkaline Oxidation. AB - The preparation of vanillin from lignin is one of the lignin valorization strategies. However, obtaining high vanillin yield is still a challenge. Therefore, the process of vanillin production and factors that affect yield of vanillin has attracted much attention. Here, oxidation of vanillin was performed to study its degradation behavior under lignin alkaline oxidation conditions. High-performance liquid chromatography, liquid chromatography-electrospray mass spectrometry, gas chromatography-mass spectrometer and gel permeation chromatography were employed to analyze the products including monomers and dimers. Results demonstrated that reaction temperature and time greatly affected vanillin degradation; vanillin can be completely converted in 5 h at 160 degrees C. At 160 degrees C, the main products of vanillin oxidation were small molecule acids and alcohols, other monophenols, and even condensed dimers. A possible vanillin degradation pathway was proposed. The results indicate that vanillin degradation and condensation are the main reasons for decreasing vanillin yield during lignin valorization under alkaline oxidation circumstances. PMID- 29967928 TI - The Iron Chelator and Anticancer Agent Dp44mT Relieves Allergic Inflammation in Mice With Allergic Rhinitis. AB - Our previous study showed that an iron chelator and anticancer agent Di-2 pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has an antiinflammatory effect in human mast cells. However, antiinflammatory effect of Dp44mT remains unclear in animal models. In this study, we assessed whether administration of Dp44mT could relieve clinical symptoms of ovalbumin (OVA)-induced allergic rhinitis (AR) mice. After administration of Dp44mT, number of rubs was significantly decreased, and levels of histamine and IgE were suppressed in serum of AR mice. Also, serum levels of interleukin (IL)-1beta, thymic stromal lymphopoietin (TSLP), and tumor necrosis factor (TNF)-alpha increased by OVA challenge were significantly lowered by administration of Dp44mT. T helper type 1 (Th1) cytokine interferon-gamma level was significantly increased by administration of Dp44mT, whereas Th2 cytokines such as IL-4, IL-5, and IL-13 were significantly reduced by administration of Dp44mT. In intranasal tissues of AR mice, levels of IL-1beta, TSLP, TNF-alpha, and IL-6 and activities and protein levels of caspase-1 were significantly reduced by administration of Dp44mT. Interestingly, administration of Dp44mT reduced number of infiltrated eosinophils and mast cells through the inhibition of macrophage inflammatory protein-2 and intercellular adhesion molecule-1 in intranasal tissues of AR mice. In conclusion, these results indicate that Dp44mT also has potential antiinflammatory effects in vivo as well as in vitro. PMID- 29967929 TI - Type 2 diabetes is associated with higher trabecular bone density but lower cortical bone density: the Vietnam Osteoporosis Study. AB - : It is not clear why type 2 diabetes (T2D) has an increased risk of fracture despite higher areal bone mineral density. This study showed that compared with controls, T2D patients had higher trabecular bone density but lower cortical bone density, resulting in a lower bone strength. INTRODUCTION: To define the association between type 2 diabetes and bone architecture and measures of bone strength. METHODS: The study was part of the Vietnam Osteoporosis Study, in which 1115 women and 614 men aged >= 30 were randomly recruited from Ho Chi Minh City. HbA1c levels were measured with analyzers ADAMSTM A1c HA-8160 (Arkray, Kyoto, Japan). The diagnosis of T2D was made if HbA1c was >= 6.5%. Trabecular and cortical volumetric bone density (vBMD) was measured in the forearm and leg by a pQCT XCT2000 (Stratec, Germany). Polar stress strain index (pSSI) was derived from the pQCT measurements. Difference in bone parameters between T2D and non diabetic individuals was assessed by the number of standard deviations (effect size [ES]) by the propensity score analysis. RESULTS: The prevalence of T2D was ~ 8%. The results of propensity score matching for age, sex, and body mass index in 137 pairs of diabetic and non-diabetic individuals showed that T2D patients had significantly higher distal radius trabecular vBMD (ES 0.26; 95% CI, 0.02 to 0.50), but lower cortical vBMD (ES - 0.22; - 0.46 to 0.00) and reduced pSSI (ES - 0.23; - 0.47 to - 0.02) compared with non-diabetic individuals. Multiple linear regression analysis based on the entire sample confirmed the results of the propensity score analysis. CONCLUSION: Compared with non-diabetic individuals, patients with T2D have greater trabecular but lower cortical vBMD which leads to lower bone strength. PMID- 29967930 TI - Reappearance of hypomineralized bone after discontinuation of asfotase alfa treatment for severe childhood hypophosphatasia. PMID- 29967931 TI - Long-term oral bisphosphonates delay healing after tooth extraction: a single institutional prospective study. AB - : Tooth extraction in patients receiving bisphosphonates is thought to be a risk factor for osteonecrosis of the jaw (ONJ); however, ONJ did not develop, even when tooth extraction was performed with continued oral bisphosphonate therapy. A drug holiday from bisphosphonates before tooth extraction may not be necessary. INTRODUCTION: It is controversial whether bisphosphonate withdrawal is necessary prior to invasive procedures such as tooth extraction in order to prevent bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to evaluate the clinical safety of continuing oral bisphosphonate therapy in patients undergoing tooth extraction. METHODS: We prospectively enrolled 132 patients (20 men, 112 women) who were receiving oral bisphosphonates for the prevention or treatment of osteoporosis and required tooth extraction. All patients were managed using an identical protocol, which included preoperative antibiotic prophylaxis and did not necessarily require complete wound closure. The patients were classified into groups according to the duration of bisphosphonate administration: < 2 years (n = 51), 2-5 years (n = 41), 5-10 years (n = 28), and > 10 years (n = 12). The groups were compared regarding the time taken for the extraction socket to heal, and the occurrence of BRONJ. Follow-up duration was at least 3 months. RESULTS: A total of 274 teeth were removed. Long term oral bisphosphonate therapy for > 5 years significantly delayed the healing of the extraction socket in comparison with administration for < 5 years; however, BRONJ did not develop in any group. There was no prolongation of wound healing due to systemic risk factors such as glucocorticoid administration and diabetes mellitus. There were no adverse skeletal events such as bone fracture. CONCLUSIONS: Patients who underwent tooth extraction with continued oral bisphosphonate therapy showed delayed healing of the extraction socket as the cumulative administration period prolonged, but BRONJ did not develop. PMID- 29967932 TI - Zebrafish larvae heartbeat detection from body deformation in low resolution and low frequency video. AB - Zebrafish (Danio rerio) is a powerful animal model used in many areas of genetics and disease research. Despite its advantages for cardiac research, the heartbeat pattern of zebrafish larvae under different stress conditions is not well documented quantitatively. Several effective automated heartbeat detection methods have been developed to reduce the workload for larva heartbeat analysis. However, most require complex experimental setups and necessitate direct observation of the larva heart. In this paper, we propose the Zebrafish Heart Rate Automatic Method (Z-HRAM), which detects and tracks the heartbeats of immobilized, ventrally positioned zebrafish larvae without direct larva heart observation. Z-HRAM tracks localized larva body deformation that is highly correlated with heart movement. Multiresolution dense optical flow-based motion tracking and principal component analysis are used to identify heartbeats. Here, we present results of Z-HRAM on estimating heart rate from video recordings of seizure-induced larvae, which were of low resolution (1024 * 760) and low frame rate (3 to 4 fps). Heartbeats detected from Z-HRAM were shown to correlate reliably with those determined through corresponding electrocardiogram and manual video inspection. We conclude that Z-HRAM is a robust, computationally efficient, and easily applicable tool for studying larva cardiac function in general laboratory conditions. Graphical abstract Flowchart of the automatic zebrafish heartbeat detection. PMID- 29967933 TI - Multiobjective design optimization of stent geometry with wall deformation for triangular and rectangular struts. AB - The stent geometrical design (e.g., inter-strut gap, length, and strut cross section) is responsible for stent-vessel contact problems and changes in the blood flow. These changes are crucial for causing some intravascular abnormalities such as vessel wall injury and restenosis. Therefore, structural optimization of stent design is necessary to find the optimal stent geometry design. In this study, we performed a multiobjective stent optimization for minimization of average stress and low wall shear stress ratio while considering the wall deformation in 3D flow simulations of triangular and rectangular struts. Surrogate-based optimization with Kriging method and expected hypervolume improvement (EHVI) are performed to construct the surrogate model map and find the best configuration of inter-strut gap (G) and side length (SL). In light of the results, G-SL configurations of 2.81-0.39 and 3.00-0.43 mm are suggested as the best configuration for rectangular and triangular struts, respectively. Moreover, considering the surrogate model and flow pattern conditions, we concluded that triangular struts work better to improve the intravascular hemodynamics. ? Graphical abstract. PMID- 29967934 TI - Short-term prediction of glucose in type 1 diabetes using kernel adaptive filters. AB - This study aims at presenting a nonlinear, recursive, multivariate prediction model of the subcutaneous glucose concentration in type 1 diabetes. Nonlinear regression is performed in a reproducing kernel Hilbert space, by either the fixed budget quantized kernel least mean square (QKLMS-FB) or the approximate linear dependency kernel recursive least-squares (KRLS-ALD) algorithm, such that a sparse model structure is accomplished. A multivariate feature set (i.e., subcutaneous glucose, food carbohydrates, insulin regime and physical activity) is used and its influence on short-term glucose prediction is investigated. The method is evaluated using data from 15 patients with type 1 diabetes in free living conditions. In the case when all the input variables are considered: (i) the average root mean squared error (RMSE) of QKLMS-FB increases from 13.1 mg dL 1 (mean absolute percentage error (MAPE) 6.6%) for a 15-min prediction horizon (PH) to 37.7 mg dL-1 (MAPE 20.8%) for a 60-min PH and (ii) the RMSE of KRLS-ALD, being predictably lower, increases from 10.5 mg dL-1 (MAPE 5.2%) for a 15-min PH to 31.8 mg dL-1 (MAPE 18.0%) for a 60-min PH. Multivariate data improve systematically both the regularity and the time lag of the predictions, reducing the errors in critical glucose value regions for a PH >= 30 min. Graphical abstract ?. PMID- 29967935 TI - Augmented reality surgical navigation with accurate CBCT-patient registration for dental implant placement. AB - It is challenging to achieve high implant accuracy in dental implant placement, because high risk tissues need to be avoided. In this study, we present an augmented reality (AR) surgical navigation with an accurate cone beam computed tomography (CBCT)-patient registration method to provide clinically desired dental implant accuracy. A registration device is used for registration between preoperative data and patient outside the patient's mouth. After registration, the registration device is worn on the patient's teeth for tracking the patient. Naked-eye 3D images of the planning path and the mandibular nerve are superimposed onto the patient in situ to form an AR scene. Simultaneously, a 3D image of the drill is overlaid accurately on the real one to guide the implant procedure. Finally, implant accuracy is evaluated postoperatively. A model experiment was performed by an experienced dentist. Totally, ten parallel pins were inserted into five 3D-printed mandible models guided by our AR navigation method and through the dentist's experience, respectively. AR-guided dental implant placement showed better results than the dentist's experience (mean target error = 1.25 mm vs. 1.63 mm; mean angle error = 4.03 degrees vs. 6.10 degrees ). Experimental results indicate that the proposed method is expected to be applied in the clinic. Graphical abstract ?. PMID- 29967936 TI - Relative trajectory-driven virtual dynamic occlusal adjustment for dental restorations. AB - The abnormal occlusal contact can disrupt the coordination and health of the oral jaw system. Therefore, the dynamic adjustment of the occlusal surface is of great significance for assessing the status of occlusal contact and clarifying jaw factors of stomatognathic system diseases. To solve this problem, a trajectory subtraction algorithm based on screw theory to improve the accuracy of the occlusal movement trajectory is proposed in our paper. Driving by the relative trajectory, a virtual dynamic occlusal adjustment system is developed to realize 3D occlusal movement simulating, automatic occluding relation detection, and automatic occlusal adjustment. Furthermore, we adapt an active occlusal adjustment method based on Laplacian deformation to increase the contact areas of the occlusal surface, which can aid dentists to realize the automatic adjustment of the non-interference regions. As a consequence, the proposed subtraction algorithm is feasible and the root-mean-square is 0.097 mm, and the adjusted occlusal surface is more consistent with the natural occlusal morphology. Graphical abstract ?. PMID- 29967937 TI - Conjugation of para-benzoquinone of Cigarette Smoke with Human Hemoglobin Leads to Unstable Tetramer and Reduced Cooperative Oxygen Binding. AB - Besides multiple life-threatening diseases like lung cancer and cardiovascular disease, cigarette smoking is known to produce hypoxia, a state of inadequate oxygen supply to tissues. Hypoxia plays a pivotal role in the development of chronic obstructive pulmonary disease. Smoking during pregnancy imposes risk for the unborn child. In addition to carbon monoxide, conjugation of para benzoquinone (pBQ), derived from cigarette smoke, with human hemoglobin (HbA) was also reported to contribute in hypoxia. In fact, conjugation of pBQ is more alarming than carbon monoxide as it is an irreversible covalent modification. In the present study, the functional assay of Hb-pBQ, performed through oxygen equilibrium curve, showed a significant decrease in both P50 and cooperativity. However, the structural changes associated with the observed functional perturbation of the hemoglobin conjugate (Hb-pBQ) are unknown to date. Enhanced sensitivity and high resolution of nano-ESI mass spectrometry platform have enabled to investigate the native structure of oligomers of hemoglobin in a single scan. The structural integrity of Hb-pBQ measured through the dissociation equilibrium constants (Kd) indicated that compared to HbA, Kd of tetramer-dimer and dimer-monomer equilibria were increased by 4.98- and 64.3-folds, respectively. Using isotope exchange mass spectrometry, we observed perturbations in the inter-subunit interactions of deoxy and oxy states of Hb-pBQ. However, the three-dimensional architecture of Hb-pBQ, monitored through collision cross sectional area, did not show any change. We propose that the significant destabilization of the functionally active structure of hemoglobin upon conjugation with pBQ results in tighter oxygen binding that leads to hypoxia. Graphical Abstract ?. PMID- 29967938 TI - [Recommendations for extracorporeal cardiopulmonary resuscitation (eCPR) : Consensus statement of DGIIN, DGK, DGTHG, DGfK, DGNI, DGAI, DIVI and GRC]. AB - Extracorporeal cardiopulmonary resuscitation (eCPR) may be considered as a rescue attempt for highly selected patients with refractory cardiac arrest and potentially reversible etiology. Currently there are no randomized, controlled studies on eCPR, and valid predictors of benefit and outcome which might guide the indication for eCPR are lacking. Currently selection criteria and procedures differ across hospitals and standardized algorithms are lacking. Based on expert opinion, the present consensus statement provides a proposal for a standardized treatment algorithm for eCPR. PMID- 29967941 TI - Combined Used of Rheology and LF-NMR for the Characterization of PVP-Alginates Gels Containing Liposomes. AB - PURPOSE: This paper is based on the characterization of the rheological and Low Field NMR (LF-NMR) properties of an interpenetrated hydrogel made up by poly(N vinyl-2-pyrrolidone) and sodium alginate. The final aim is to use the hydrogel as a delivery matrix for liposomes, widely used tools in the drug delivery field. METHODS: Rheology, LF-NMR, TEM, cryo-TEM, confocal laser scanning microscopy and release test were employed to characterize the interpenetrated hydrogel. Different theoretical approaches such as Flory, Chui, Scherer and Schurz theories were used to interpret the experimental results. RESULTS: We found that the crosslinking mechanisms of the two polymers produced an anti-synergistic effect on the final mechanical properties of the interpenetrated hydrogel. Instead of creating a continuous network, alginate formed isolated, cross-linked, clusters embedded in a continuous network of poly(N-vinyl-2-pyrrolidone). Additionally, gel structure significantly influenced liposome delivery. CONCLUSIONS: The rheological and LF-NMR characterization were confirmed and supported by the independent techniques TEM, cryo-TEM and release tests Thus, our findings reiterate the potentiality of both rheology and LF-NMR for the characterisation of soft materials such as interpenetrated polymeric networks. PMID- 29967940 TI - Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience. AB - Recently, we described a machine learning approach for classification of central nervous system tumors based on the analysis of genome-wide DNA methylation patterns [6]. Here, we report on DNA methylation-based central nervous system (CNS) tumor diagnostics conducted in our institution between the years 2015 and 2018. In this period, more than 1000 tumors from the neurosurgical departments in Heidelberg and Mannheim and more than 1000 tumors referred from external institutions were subjected to DNA methylation analysis for diagnostic purposes. We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios. PMID- 29967942 TI - Restoration of mucosal integrity and epithelial transport function by concomitant anti-TNFalpha treatment in chronic DSS-induced colitis. AB - : Impaired salt and water absorption is a hallmark of diarrhea in IBD. In the present study, the therapeutic effect of continuous anti-TNFalpha treatment on the progression of inflammation and colonic transport dysfunction during chronic dextran sulfate sodium (DSS)-induced colitis was investigated. Chronic colitis was induced by three DSS exposure cycles. Mice received TNFalpha monoclonal antibody treatment twice weekly after the end of the first 5-day DSS drinking period. Mice developed chronic DSS-induced colitis characterized by a typical immune cell infiltration composed of CD3+ T cells and CD68+ macrophages, both expressing high levels of the pro-inflammatory cytokines IL-1beta and TNFalpha, a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and a decrease of colonic fluid absorption in vivo, measured by colonic single pass perfusion. Concomitant anti-TNFalpha treatment resulted in a significant reduction of mucosal immune cell infiltration and expression of the pro inflammatory cytokines IL-1beta and TNFalpha. It also resulted in a normalization of NHE3-mediated fluid absorption and a restoration of NHE3 and PDZK1 location in the apical and subapical region of the enterocytes. Here, we show for the first time that in this chemically induced murine colitis model, anti-TNFalpha treatment significantly decreased inflammatory activity, improved mucosal integrity and restored transport function despite an ongoing inflammatory insult. Anti-TNFalpha treatment may therefore be beneficial in patients with IBD even in spite of an absence of complete mucosal healing. KEY MESSAGES: Chronic DSS treatment caused a loss of NHE3 and PDZK1 in the brush border region of the absorptive enterocyte and decreases colonic fluid absorption. In DSS-induced colitis, anti-TNFalpha treatment reduced mucosal immune cell infiltration and expression of the pro-inflammatory cytokines IL-1beta and TNFalpha. In DSS induced colitis, anti-TNFalpha treatment normalized NHE3-mediated fluid absorption and restored NHE3 and PDZK1 location in the enterocytes. In DSS induced colitis, anti-TNFalpha treatment decreased inflammatory activity, improved mucosal integrity, and restored transport function. PMID- 29967944 TI - Positive pre-biopsy MRI: are systematic biopsies still useful in addition to targeted biopsies? AB - PURPOSE: The diagnostic strategy implementing multiparametric magnet resonance tomography (mpMRI) and targeted biopsies (TB) improves the detection and characterization of significant prostate cancer (PCa). We aimed to assess the clinical usefulness of systematic biopsies (SB) in the setting of patients having a pre-biopsy positive MRI. METHODS: A review of the literature was performed in March 2018. All studies investigating the performance of SB in addition to TB (all techniques) were assessed, both in the biopsy-naive and repeat biopsy setting. RESULTS: Evidence demonstrates that TB improves the detection of index significant PCa compared with SB alone, in both initial and repeat biopsy settings. However, the combination of both TB and SB improved the overall (around 30%) and significant (around 10%) PCa detection rates as compared with TB alone. Significant differences between both biopsy approaches exist regarding cancer location favoring SB for the far lateral sampling, and TB for the anterior zone. Main current pitfalls of pure TB strategy are the learning curve and experience required for mpMRI reading and biopsy targeting, as well as the precision assessment in TB techniques. CONCLUSION: A pure TB strategy omitting SB leads to the risk of missing up to 15% of significant cancer, due to limitations of mpMRI performance/reading and of precision during lesion targeting. SB remain necessary, in addition to the TB, to obtain the most accurate assessment of the entire prostate gland in this sub-group of patients at risk of significant disease. PMID- 29967945 TI - Increased amount and duration of tea consumption may be associated with decreased risk of renal stone disease. AB - PURPOSE: Previous studies have looked into the association between tea consumption and renal stone disease, but the impact of tea consumption over time has not yet been fully clarified. Our study aimed to examine the amount and duration of tea consumption concomitantly in relation to the risk of renal stone disease. METHODS: A total of 13,842 subjects who underwent health check-ups were recruited. Average tea consumption per day was defined as the amount of tea consumption per day multiplied by the frequency per week divided by seven. A "cup" was defined as 120 mL for each Chinese traditional teapot," and "cup-year" was calculated by multiplying the number of daily cups and the years of tea consumption to express the cumulative dose of tea consumption over time. The diagnosis of renal stone disease was established based on the results of abdominal sonography. RESULTS: The amount of daily tea consumption was 119.2 +/- 306.8 and 131.7 +/- 347.3 mL in groups with and without renal stone disease. After adjusting for other clinical variables, daily tea consumption >= 240 mL vs. none was related to lower risk of renal stone disease (OR = 0.84, CI 0.71-0.99, p = 0.037). In another model, the associated risk of renal stone disease decreased significantly with tea consumption >= 20 cup-year (OR = 0.79, CI 0.66-0.94, p = 0.008), but not < 20 cup-year (OR = 0.92, CI 0.78-1.09, p = 0.34). CONCLUSIONS: Daily tea consumption >= 240 mL (two cups) was associated with a lower risk of renal stone disease. Tea consumption >= 20 cup-year also had a decreased associated risk of renal stone disease. PMID- 29967943 TI - Imaging of chemokine receptor CXCR4 expression in culprit and nonculprit coronary atherosclerotic plaque using motion-corrected [68Ga]pentixafor PET/CT. AB - PURPOSE: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4+ cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [68Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT. METHODS: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [68Ga]Pentixafor PET/CT was performed in 37 patients after stent based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared. RESULTS: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68+ inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUVmax 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUVmax 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUVmax 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability. CONCLUSION: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque. PMID- 29967946 TI - Defining the target prior to prostate fusion biopsy: the effect of MRI reporting on cancer detection. AB - PURPOSE: Definition of targets in multiparametric MRI (mpMRI) prior to MRI/TRUS fusion prostate biopsy either by urologist or radiologist, as a prose report or by illustration is crucial for accurate targeted biopsies (TB). The objective was to analyze the effect of MRI reporting on target definition and cancer detection. METHODS: 202 patients underwent MRI/TRUS fusion biopsy with ArtemisTM (Eigen, USA). mpMRI results were submitted in written form to urologists, who marked the targets in the proprietary software. An expert uroradiologist reviewed and marked mpMRI targets blinded to biopsy data. We compared number, localization and volume of targets between the observers and analyzed whether variations impaired TB results by bivariate and logistic regression models. RESULTS: Interobserver variability was moderate regarding number and low regarding localization of targets. Urologists overestimated target volumes significantly compared to radiologists (p = 0.045) and matching target volume between both observers was only 43.9%. Overall cancer detection rate was 69.8 and 52.0% by TB. A higher matching target volume was a significant predictor of cancer in TB (p < 0.001). Logistic regression revealed prostate volume and PI-RADS as independent predictors. Defining targets in incorrect T2w slices in the cranio-caudal axis are one presumable reason for missing cancer in TB. CONCLUSIONS: A high concordance of the target definition between radiologist and urologist is mandatory for accurate TB. Optimized ROI definition is recommended to improve TB results, preferably as contouring in MRI sequences by the radiologist or, if not feasible, by precise MRI reports including specific localization in sequence and slice as well as an illustration. High prostate volume and low PI-RADS score have to be considered as limiting factors for target definition. PMID- 29967947 TI - Do patients have to choose between ejaculation and miction? A systematic review about ejaculation preservation technics for benign prostatic obstruction surgical treatment. AB - PURPOSE: Ejaculatory dysfunction is the most common side effect related to surgical treatment of benign prostatic obstruction (BPO). Nowadays, modified surgical techniques and non-ablative techniques have emerged with the aim of preserving antegrade ejaculation. Our objective was to conduce a systematic review of the literature regarding efficacy on ejaculatory preservation of modified endoscopic surgical techniques, and mini-invasive non-ablatives techniques for BPO management. METHODS: A systematic review of the literature was carried out on the PubMed database using the following MESH terms: "Prostatic Hyperplasia/surgery" and "Ejaculation", in combination with the following keywords: "ejaculation preservation", "photoselective vaporization of the prostate", "photoselective vapo-enucleation of the prostate", "holmium laser enucleation of the prostate", "thulium laser", "prostatic artery embolization", "urolift", "rezum", and "aquablation". RESULTS: The ejaculation preservation rate of modified-TURP ranged from 66 to 91%. The ejaculation preservation rate of modified-prostate photo-vaporization ranged from 87 to 96%. The only high level of evidence studies available compared prostatic urethral lift (PUL) and aquablation versus regular TURP in prospective randomized-controlled trials. The ejaculation preservation rate of either PUL or aquablation compared to regular TURP was 100 and 90 versus 34%, respectively. CONCLUSIONS: Non-ablative therapies and modified endoscopic surgical techniques seemed to be reasonable options for patients eager to preserve their ejaculatory functions. PMID- 29967948 TI - Comparison between the effects of deep and moderate neuromuscular blockade during transurethral resection of bladder tumor on endoscopic surgical condition and recovery profile: a prospective, randomized, and controlled trial. AB - PURPOSE: To compare between deep neuromuscular blockade (NMB) and moderate NMB with respect to endoscopic surgical conditions and recovery profiles in patients with general anesthesia for transurethral resection of bladder (TURB). METHODS: 108 patients undergoing elective TURB were randomized into two groups: the moderate NMB (n = 54) or deep NMB (n = 54) group. After the operation, NMB was reversed with 2 mg/kg sugammadex at a train-of-four (TOF) count of 1 or 2 (moderate NMB group) or with 4 mg/kg sugammadex at post-tetanic count (PTC) of 2 (deep NMB group). Surgeons, who were blinded to the study design, rated the endoscopic surgical condition on a 5-point scale (1 = extremely poor, 2 = poor, 3 = acceptable, 4 = good, 5 = optimal) immediately following the operation. Recovery profiles, including postoperative residual curarization (PORC), respiratory complication, and recovery time, were recorded. RESULTS: No difference was observed between the two groups regarding patients and anesthesia characteristics. There were statistically significant differences in endoscopic surgical conditions between the two groups (P < 0.001). Thirty-eight patients in the deep NMB group (74%) showed optimal surgical conditions, whereas 16 patients in the moderate NMB group (30%) showed optimal endoscopic surgical conditions. No PORC and respiratory complications occurred in both groups, and no difference was found between the two groups in terms of recovery profiles, including recovery time and other adverse events. CONCLUSIONS: Deep NMB and reversal with sugammadex improved the endoscopic surgical condition without complications compared with moderate NMB and reversal with sugammadex in patients undergoing TURB. PMID- 29967939 TI - Sex-specific genetic predictors of Alzheimer's disease biomarkers. AB - Cerebrospinal fluid (CSF) levels of amyloid-beta 42 (Abeta42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Abeta42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Abeta42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (beta = - 0.03, p = 4.25 * 10-8; beta = 0.03, p = 3.97 * 10-8) than males (beta = - 0.02, p = 0.009; beta = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (beta = 0.05, p = 4.57 * 10-10) compared to males (beta = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p >= 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture. PMID- 29967950 TI - View from inside. PMID- 29967949 TI - Dialysis assisted ligand exchange on gold nanorods: Amplification of the performance of a lateral flow immunoassay for E. coli O157:H7. AB - Ligand exchange on the surface of gold nanorods (AuNRs) is widely used, but conventional methods usually require multiple centrifugation cycles to completely remove cetyltrimethylammonium bromide (CTAB). This can lead to undesired aggregation of AuNRs. A dialysis-assisted protocol is described here for ligand exchange on AuNRs. Dialysis driven by a concentration gradient is shown to be a powerful tool to separate CTAB from aqueous solutions. The concentration gradient of CTAB in a dialysis bag can avoid the possible aggregation of AuNRs that can be caused by drastic environmental changes. It also supports the rate of ligand exchange on the surfaces of the AuNRs. The modified AuNRs were employed in a lateral-flow test strip immunoassay (LFTS-IAs) for the food pathogen E. coli O157:H7 in order to study of efficiency of ligand exchange. Compared to AuNRs where ligand exchange was performed via multiple centrifugation cycles, the AuNRs prepared by dialysis-assisted ligand exchange show improved conjugation to antibody and enhanced visual signals in the test line of the LFTS-IAs. A portable strip reader (absorption wavelength = 525 nm) is used to records the testing results. The sensitivity of AuNRs modified by dialysis has been achieved even as low as 1 * 102 cfu.mL-1 in a short time (within 15 min), and the working range is 1 * 102 to 1 * 106 cfu.mL-1, which is superior over the detection performance of conventional test strip using AuNRs modified by centrifugation. Graphical abstract Schematic presentation of the ligand exchange of AuNRs. The AuNRs were dialysed in water to decrease the CTAB concentration. Then, 11-mercaptoundecanoic acid (MUA) replaces the CTAB capped on the surface of AuNRs. The modified AuNRs were employed in a lateral flow immunoassay for E. coli O157:H7. PMID- 29967951 TI - Development and characterization of an inducible mouse model for glycogen storage disease type Ib. AB - BACKGROUND AND AIMS: Glycogen storage disease type Ib (GSD1b) is a rare metabolic and immune disorder caused by a deficiency in the glucose-6-phosphate transporter (G6PT) and characterized by impaired glucose homeostasis, myeloid dysfunction, and long-term risk of hepatocellular adenomas. Despite maximal therapy, based on a strict diet and on granulocyte colony-stimulating factor treatment, long-term severe complications still develop. Understanding the pathophysiology of GSD1b is a prerequisite to develop new therapeutic strategies and depends on the availability of animal models. The G6PT-KO mouse mimics the human disease but is very fragile and rarely survives weaning. We generated a conditional G6PT deficient mouse as an alternative model for studying the long-term pathophysiology of the disease. We utilized this conditional mouse to develop an inducible G6PT-KO model to allow temporally regulated G6PT deletion by the administration of tamoxifen (TM). METHODS: We generated a conditional G6PT deficient mouse utilizing the CRElox strategy. Histology, histochemistry, and phenotype analyses were performed at different times after TM-induced G6PT inactivation. Neutrophils and monocytes were isolated and analyzed for functional activity with standard techniques. RESULTS: The G6PT-inducible KO mice display the expected disturbances of G6P metabolism and myeloid dysfunctions of the human disorder, even though with a milder intensity. CONCLUSIONS: TM-induced inactivation of G6PT in these mice leads to a phenotype which mimics that of human GSD1b patients. The conditional mice we have generated represent an excellent tool to study the tissue-specific role of the G6PT gene and the mechanism of long-term complications in GSD1b. PMID- 29967952 TI - Impact of infection severity on clinical outcomes in critical limb ischemia with tissue loss after endovascular treatment. AB - Critical limb ischemia with infected wounds is known to have a poor prognosis and evaluation of infection severity using the Wound, Ischemia, and foot Infection classification system has been recommended. However, little is known about how infection severity influences the clinical outcomes of critical limb ischemia in patients with tissue loss. We investigated the impact of infection severity on the clinical outcomes in critical limb ischemia with tissue loss after endovascular treatment. In April 2007-August 2014, we enrolled 263 patients (328 limbs) who received endovascular treatment for critical limb ischemia with tissue loss. In the limbs examined, 369 individual wounds existed. We evaluated wound infection using the Infectious Disease Society of America (IDSA) classification. We also investigated wound healing rates at 12 months and limb salvage and major amputation-free survival rates at 2 years after endovascular treatment. Wound healing rates at 12 months for class 0, 1, 2, and 3 were 89, 81, 58, and 33%, respectively (log rank P < 0.001). Limb salvage and major amputation-free survival rates at 2 years were lower in patients with lower vs. higher IDSA classes (classes 0-3: limb salvage rate: 97, 90, 61, and 0%, respectively; P < 0.001; major amputation-free survival: 67, 61, 38, and 0%, respectively; P < 0.001). In Rutherford category 5, only wound healing rates at 12 months and limb salvage and major amputation-free survival rates at 2 years were stratified according to wound infection severity (wound healing rates: 87% in classes 0 and 1 and 65% in classes 2 and 3; P < 0.001; limb salvage rates: 93% in classes 0 and 1 and 69% in classes 0 and 2; P < 0.0001; major amputation-free survival rates: 61% in classes 0 and 1 and 46% in classes 2 and 3; P < 0.001). Wound infection severity affects clinical outcomes of critical limb ischemia with tissue loss, especially in critical limb ischemia with systemic inflammatory response syndrome. In Rutherford category 5, only clinical outcomes of critical limb ischemia were well-stratified according to infection severity. Wound infection affects clinical outcomes of patients with critical limb ischemia with tissue loss. PMID- 29967953 TI - Seasonal variations of weather conditions on acute myocardial infarction onset: Oita AMI Registry. AB - The onset of acute myocardial infarction (AMI) has been reportedly related to weather conditions. The aim of this study was to investigate the impact of weather conditions on AMI onset. Our study population consisted of 274 patients enrolled in the Oita AMI Registry who were admitted with AMI between June 2012 and May 2013. We divided the 365 days of the year into the four seasons: spring (March, April, May), summer (June, July, August), autumn (September, October, November), and winter (December, January, February). We classified each day as a day of onset of AMI (onset day) or a day of non-onset of AMI (non-onset day). Information on maximum temperature, minimum temperature, mean humidity, and mean atmospheric pressure was obtained from the Japan Meteorological Agency. In summer, the temperatures and intraday temperature differences were significantly lower on onset days than on non-onset days. Receiver operating characteristic analysis for predicting AMI onset in each season showed that the maximum temperature 2 days before AMI onset in summer had the largest area under the curve (AUC = 0.72, p = 0.0005). Our analysis demonstrated that there exist specific weather conditions that influence AMI onset in each season in Oita prefecture. AMI onset in summer was particularly associated with the maximum temperature 2 days before AMI onset. PMID- 29967955 TI - Dynamic contrast-enhanced CT for the assessment of tumour response in malignant pleural mesothelioma: a pilot study. AB - OBJECTIVES: The aim of this pilot study was to investigate the utility of haemodynamic parameters derived from dynamic contrast-enhanced computed tomography (DCE-CT) scans in the assessment of tumour response to treatment in malignant pleural mesothelioma (MPM) patients. METHODS: The patient cohort included nine patients undergoing chemotherapy and five patients on observation. Each patient underwent two DCE-CT scans separated by approximately 2 months. The DCE-CT parameters of tissue blood flow (BF) and tissue blood volume (BV) were obtained within the dynamically imaged tumour. Mean relative changes in tumour DCE-CT parameters between scans were compared between the on-treatment and on observation cohorts. DCE-CT parameter changes were correlated with relative change in tumour bulk evaluated according to the modified RECIST protocol. RESULTS: Differing trends in relative change in BF and BV between scans were found between the two patient groups (p = 0.19 and p = 0.06 for BF and BV, respectively). No significant rank correlations were found when comparing relative changes in DCE-CT parameters with relative change in tumour bulk. CONCLUSIONS: Differing trends in the relative change of BF and BV between patients on treatment and on observation indicate the potential of DCE-CT for the assessment of pharmacodynamic endpoints with respect to treatment in MPM. A future study with a larger patient cohort and unified treatment regimens should be undertaken to confirm the results of this pilot study. KEY POINTS: * CT derived haemodynamic parameters show differing trends between malignant pleural mesothelioma patients on treatment and patients off treatment * Changes in haemodynamic parameters do not correlate with changes in tumour bulk as measured according to the modified RECIST protocol * Differing trends across the two patient groups indicate the potential sensitivity of DCE-CT to assess pharmacodynamic endpoints in the treatment of MPM. PMID- 29967954 TI - Lower on-treatment platelet reactivity during everolimus-eluting stent implantation contributes to the resolution of post-procedural intra-stent thrombus: serial OCT observation in the PRASFIT-Elective study. AB - Intra-stent thrombus (IS-Th) formed immediately after percutaneous coronary intervention (PCI) is associated with subsequent adverse coronary events. However, the impact of on-treatment platelet reactivity on IS-Th is unknown. PRASFIT-Elective is a multicenter study of PCI patients receiving prasugrel (20/3.75 mg, loading/maintenance dose) or clopidogrel (300/75 mg), with aspirin (100 mg). Among the 742 study patients, 111 were pre-specified for the OCT sub study. Of these, 82 underwent OCT immediately after PCI to assess IS-Th and at an 8-month follow-up to evaluate the fate of the IS-Th. Lesions were considered resolved when IS-Th were detected after PCI but not on the follow-up or persistent when IS-Th were observed on both scans. The P2Y12 Reactive Unit (PRU) value was determined at the initial PCI and 4 and 48 weeks post-PCI. In 76 patients (86 lesions), we detected 230 IS-Th initially, and 196 IS-Th (85.2%) were resolved at the 8-month OCT. At PCI, but not 4 or 48 weeks after, the resolved IS-Th group had a lower PRU than the persistent IS-Th group (199 +/- 101 vs. 266 +/- 102, p = 0.008). Multivariate logistic regression analyses revealed that lower PRU at PCI and less calcified lesions were independent predictive factors for the resolution of IS-Th. Local lesion-related factors and lower on treatment platelet reactivity at the time of PCI may contribute to the resolution of IS-Th after EES implantation, potentially improving clinical outcome. PMID- 29967956 TI - Radiomics signature: a biomarker for the preoperative discrimination of lung invasive adenocarcinoma manifesting as a ground-glass nodule. AB - OBJECTIVES: To identify the radiomics signature allowing preoperative discrimination of lung invasive adenocarcinomas from non-invasive lesions manifesting as ground-glass nodules. METHODS: This retrospective primary cohort study included 160 pathologically confirmed lung adenocarcinomas. Radiomics features were extracted from preoperative non-contrast CT images to build a radiomics signature. The predictive performance and calibration of the radiomics signature were evaluated using intra-cross (n=76), external non-contrast-enhanced CT (n=75) and contrast-enhanced CT (n=84) validation cohorts. The performance of radiomics signature and CT morphological and quantitative indices were compared. RESULTS: 355 three-dimensional radiomics features were extracted, and two features were identified as the best discriminators to build a radiomics signature. The radiomics signature showed a good ability to discriminate between invasive adenocarcinomas and non-invasive lesions with an accuracy of 86.3%, 90.8%, 84.0% and 88.1%, respectively, in the primary and validation cohorts. It remained an independent predictor after adjusting for traditional preoperative factors (odds ratio 1.87, p < 0.001) and demonstrated good calibration in all cohorts. It was a better independent predictor than CT morphology or mean CT value. CONCLUSIONS: The radiomics signature showed good predictive performance in discriminating between invasive adenocarcinomas and non-invasive lesions. Being a non-invasive biomarker, it could assist in determining therapeutic strategies for lung adenocarcinoma. KEY POINTS: * The radiomics signature was a non-invasive biomarker of lung invasive adenocarcinoma. * The radiomics signature outweighed CT morphological and quantitative indices. * A three-centre study showed that radiomics signature had good predictive performance. PMID- 29967957 TI - Comparison of performance metrics with digital 2D versus tomosynthesis mammography in the diagnostic setting. AB - OBJECTIVES: To compare performance metrics between digital 2D mammography (DM) and digital breast tomosynthesis (DBT) in the diagnostic setting. METHODS: Consecutive diagnostic examinations from August 2008 to February 2011 (DM group) and from January 2013 to July 2015 (DM/DBT group) were reviewed. Core biopsy and surgical pathology results within 365 days after the mammogram were collected. Performance metrics, including cancer detection rate (CDR), abnormal interpretation rate (AIR), positive predictive value (PPV) 2, PPV3, sensitivity, and specificity were calculated. Multivariable logistic regression models were fit to compare performance metrics in the DM and DM/DBT groups while adjusting for clinical covariates. RESULTS: A total of 22,883 mammograms were performed before DBT integration (DM group), and 22,824 mammograms were performed after complete DBT integration (DM/DBT group). After adjusting for multiple variables, the CDR was similar in both groups (38.2 per 1,000 examinations in the DM/DBT group versus 31.3 per 1,000 examinations in the DM group, p = 0.14); however, a higher proportion of cancers were invasive rather than in situ in the DM/DBT group [83.7% (731/873) versus 72.3% (518/716), p < 0.01]. The AIR was lower in the DM/DBT group (p < 0.01), and PPV2, PPV3, and specificity were higher in the DM/DBT group (all p = 0.01 or p < 0.01). CONCLUSIONS: Complete integration of DBT into the diagnostic setting is associated with improved diagnostic performance. Increased utilization of DBT may thus result in better patient outcomes and lead to a shift in the benchmarks that have been established for DM. KEY POINTS: * Integration of tomosynthesis into the diagnostic setting is associated with improved performance. * A higher proportion of cancers are invasive rather than in situ with digital breast tomosynthesis. * Increased utilization of tomosynthesis may lead to a shift in established benchmarks. PMID- 29967958 TI - The complete genomic sequence of a novel botybirnavirus isolated from a phytopathogenic Bipolaris maydis. AB - Bipolaris maydis is the causal agent of corn southern leaf blight. Here, we report a novel double-stranded RNA (dsRNA) mycovirus designated Bipolaris maydis botybirnavirus 1 (BmBRV1) from B. maydis strain JZ11 in Jingzhou, Hubei province of China. BmBRV1 has a genome consisting of two dsRNAs (dsRNA1 and dsRNA2) with a size of 6435 and 5987 bp, respectively, each of which contains a single open reading frame (ORF). The two polyproteins encoded by dsRNA1 and dsRNA2 share the highest amino acid identities of 81.8 and 75.3%, respectively, with the RdRp and coat protein of Sclerotinia sclerotiorum botybirnavirus 1 (SsBRV1), a tentative species of the genus Botybirnavirus. Phylogenetic analysis based on the amino acid sequences of RdRp indicated that BmBRV1 belongs to a distinct species of the newly proposed family Botybirnaviridae. PMID- 29967959 TI - Functioning of cognitive codes in autobiographical memory and the self-Is the self visual? AB - The main goal was to test the relationship between types of cognitive codes (perceptual-imaginative and verbal-propositional) and autobiographical memory. The purpose of this research was to evaluate whether there are independent processes serving the self, depending on separate cognitive codes. Sixty adult participants completed the NEO-FFI inventory using two kinds of procedure: perceptual-imaginative code or verbal-propositional code. Both quantitative and qualitative methods were used for analysis. The study has shown the dynamic of the self, depending on two cognitive perspectives. The results indicate that the reflection of the self in autobiographical memory brings different knowledge about the self and its motives. PMID- 29967960 TI - Investigation of the effect of the CAB/A3 system on HNIW-based PBXs using molecular dynamics. AB - The influences of the temperature and the BDNPA/BDNPF (A3) content on the mechanical properties of and the binding energies between hexanitrohexaazaisowurtzitane (HNIW) and cellulose acetate butyrate (CAB)/A3 were studied via molecular dynamics simulations. The morphology of HNIW in acetone was simulated using an attachment energy (AE) model to elucidate the HNIW surfaces that are present under real-world conditions. The simulation results were consistent with the experimentally derived ones, and they indicated that the exposed HNIW surfaces were (0 0 1), (1 1 0), and (1 1 -1). The mechanical properties of CAB with different amounts of A3 were calculated at different temperatures, and the results showed that the amount of A3 was a stronger influence than the temperature on the mechanical properties. The binding energies between CAB/A3 and the exposed HNIW surfaces were calculated. Based on the binding energy and the area of each exposed surface, the weighted-average binding energy was calculated and then used instead of the total binding energy to evaluate the effect of the temperature and the A3 content on the binding energy. The average binding energy was found to be highest when the temperature was 313 K and the mass fraction of A3 was 0.15. PMID- 29967961 TI - Do additional colonoscopic biopsies increase the yield of Mycobacterium tuberculosis culture in suspected ileo-colonic tuberculosis? AB - BACKGROUND: Isolation of Mycobacterium tuberculosis on culture is vital for differentiating intestinal tuberculosis (ITB) from Crohn's disease (when histology is not diagnostic) and for diagnosis of multidrug-resistant tuberculosis. The current yield of TB culture (< 50%) from colonoscopic biopsy tissue is not satisfactory. AIM: To determine whether more colonoscopic biopsies can increase the yield of TB culture in patients with ITB. METHODS: In this prospective study, in patients who underwent colonoscopy for suspected ITB, four biopsies were taken (container 1) followed by an additional four biopsies (container 2) for TB culture, from involved regions. The culture was done using Mycobacterium Growth Indicator Tube (MGIT) 960. A final diagnosis of ITB was made if TB culture was positive, there was unequivocal histological evidence of TB, or there was unequivocal evidence of TB elsewhere in the body, in the absence of another diagnosis. RESULTS: Of 182 patients enrolled (mean age 37.5 [SD 17.2] years; 93 [51.5%] women), 70 (38.4%) were finally diagnosed to have ITB. MGIT culture was positive in 29 (41.4%), 27 (38.5%), and 37 (52.8%) of 70 patients from containers 1, container 2, and combined eight biopsies, respectively. The incremental yield of eight biopsies was 11.4% (95% confidence interval [CI] 5.1 to 21.3%) as compared to container 1 and 14.3% (95% CI 7.1 to 24.7%) as compared to container 2. CONCLUSION: Additional four (total eight) colonoscopic biopsies improved the yield of TB culture positivity over four biopsies by 11.4% to 14.3%, to 52.8%; this increase is clinically useful. PMID- 29967962 TI - Genome-wide association analysis of intra-specific QTL associated with the resistance for enteric septicemia of catfish. AB - Disease resistance is one of the most important traits for aquaculture industry. For catfish industry, enteric septicemia of catfish (ESC), caused by the bacterial pathogen Edwardsiella ictaluri, is the most severe disease, causing enormous economic losses every year. In this study, we used three channel catfish families with 900 individuals (300 fish per family) and the 690K catfish SNP array, and conducted a genome-wide association study to detect the quantitative trait loci (QTL) associated with ESC resistance. Three significant QTL, with two of located on LG1 and one on LG26, and three suggestive QTL located on LG1, LG3, and LG21, respectively, were identified to be associated with ESC resistance. With a well-assembled- and -annotated reference genome sequence, genes around the involved QTL regions were identified. Among these genes, 37 genes had known functions in immunity, which may be involved in ESC resistance. Notably, nlrc3 and nlrp12 identified here were also found in QTL regions of ESC resistance in the channel catfish * blue catfish interspecific hybrid system, suggesting this QTL was operating within both intra-specific channel catfish populations and interspecific hybrid backcross populations. Many of the genes of the Class I MHC pathway, for mediated antigen processing and presentation, were found in the QTL regions. The positional correlation found in this study and the expressional correlation found in previous studies indicated that Class I MHC pathway was significantly associated with ESC resistance. This study validated one QTL previously identified using the second and fourth generation of the interspecific hybrid backcross progenies, and identified five additional QTL among channel catfish families. Taken together, it appears that there are only a few major QTL for ESC disease resistance, making marker-assisted selection an effective approach for genetic improvements of ESC resistance. PMID- 29967963 TI - Massive phenotyping of multiple cranberry populations reveals novel QTLs for fruit anthocyanin content and other important chemical traits. AB - Because of its known phytochemical activity and benefits for human health, American cranberry (Vaccinium macrocarpon L.) production and commercialization around the world has gained importance in recent years. Flavonoid compounds as well as the balance of sugars and acids are key quality characteristics of fresh and processed cranberry products. In this study, we identified novel QTL that influence total anthocyanin content (TAcy), titratable acidity (TA), proanthocyanidin content (PAC), Brix, and mean fruit weight (MFW) in cranberry fruits. Using repeated measurements over the fruit ripening period, different QTLs were identified at specific time points that coincide with known chemical changes during fruit development and maturation. Some genetic regions appear to be regulating more than one trait. In addition, we demonstrate the utility of digital imaging as a reliable, inexpensive and high-throughput strategy for the quantification of anthocyanin content in cranberry fruits. Using this imaging approach, we identified a set of QTLs across three different breeding populations which collocated with anthocyanin QTL identified using wet-lab approaches. We demonstrate the use of a high-throughput, reliable and highly accessible imaging strategy for predicting anthocyanin content based on cranberry fruit color, which could have a large impact for both industry and cranberry research. PMID- 29967964 TI - Human microvasculature-on-a chip: anti-neovasculogenic effect of nintedanib in vitro. AB - Idiopathic pulmonary fibrosis is characterized by a progressive scarring and stiffening of the peripheral lung tissue that decreases lung function. Over the course of the disease, the lung microvasculature undergoes extensive remodeling. There is increased angiogenesis around fibrotic foci and an absence of microvessels within the foci. To elucidate how the anti-fibrotic drug nintedanib acts on vascular remodeling, we used an in vitro model of perfusable microvessels made with primary endothelial cells and primary lung fibroblasts in a microfluidic chip. The microvasculature model allowed us to study the impact of nintedanib on permeability, vascularized area, and cell-cell interactions. The anti-vasculogenic impact of nintedanib was visible at the minimal concentrations of 10 nM, showing a significant increase in vessel permeability. Furthermore, nintedanib decreased microvessel density, diameter, and influenced fibroblast organization around endothelial microvessels. These results show that nintedanib acts on the endothelial network formation and endothelial-perivascular interactions. Advanced in vitro microvasculature models may thus serve to pinpoint the mechanistic effect of anti-fibrotic drugs on the microvascular remodeling in 3D and refine findings from animal studies. PMID- 29967965 TI - Relationship Among Intron Length, Gene Expression, and Nucleotide Diversity in the Pacific Oyster Crassostrea gigas. AB - Crassostrea gigas is a model mollusk, but its genetic features have not been studied comprehensively. In this study, we used whole-genome resequencing data to identify and characterize nucleotide diversity and population recombination rate in a diverse collection of 21 C. gigas samples. Our analyses revealed that C. gigas harbors both extremely high genetic diversity and recombination rates across the whole genome as compared with those of the other taxa. The noncoding regions, introns, intergenic spacers, and untranslated regions (UTRs) showed a lower level diversity than the synonymous sites. The larger introns tended to have lower diversity. Moreover, we found a negative association of the non synonymous diversity with gene expression, which suggested that purifying selection played an important role in shaping genetic diversity. The nucleotide diversity at the 100- and 50-kb levels was positively correlated with population recombination rates, which was expected if the diversity was shaped by purifying selection or hitchhiking of advantageous mutants. Our work gives a general picture of the oyster's polymorphism pattern and its association with recombination rates. PMID- 29967966 TI - A simulated patient study assessing over the counter supply and counseling in Jordan: responding to headache complaints. AB - Background Community pharmacists are the most accessible health professionals for patients seeking advice on minor ailments and over the counter supply. Objectives To assess the management of patients seeking advice for headache in community pharmacies in Jordan. Method A cross-sectional study was conducted using simulated patient in three cities in Jordan. A trained simulated patient enacted an advice-seeking scenario for the treatment of a headache. The visits were evaluated using pre-defined criteria relating to content and communication skills. Results Of 72 community pharmacies invited, 50 (69.4%) agreed to participate. Of these, 38 (76%) pharmacies were visited. The median duration of the visit was 2 min (20 s-4 min). All visits resulted in selling a drug. Paracetamol combinations often with caffeine were recommended in over 50% of visits. Drug sale recommendations were often made without obtaining essential information about symptoms or patient medical history. Only brand names and doses were often highlighted to the simulated patient. No written information was offered. Conclusion Community pharmacies in Jordan appear not to offer adequate counseling for patients seeking advice for headache. Both counseling and communication skills are suboptimal. Exploration of factors and reasons of suboptimal practice is recommended. PMID- 29967967 TI - Perspectives on Genetic Testing and Return of Results from the First Cohort of Presymptomatically Tested Individuals At Risk of Huntington Disease. AB - This qualitative study gathered opinions about genetic testing from people who received presymptomatic testing for Huntington's disease (HD) 20-30 years ago and have lived with the implications of that testing for decades. During the last section of a semi-structured interview, participants were asked open-ended questions about their opinions on the importance of autonomy in the decision to be tested for HD, whether a formal HD testing protocol is necessary, whether physician ordering for HD is acceptable without a formal protocol, whether online direct-to-consumer (DTC) genetic testing for HD is acceptable, and whether incidental/secondary findings should be returned in the context of whole exome/genome sequencing. Most-but not all-participants were in favor of an individual's right to decide whether and when to pursue HD testing, use of a formal HD testing protocol, and returning medically actionable secondary findings. However, the majority of participants were opposed not only to physician ordering and DTC HD testing in the absence of a formal protocol but also to returning a secondary finding of an expanded HD allele. This study presents the opinions of a unique and extremely well-informed cohort on issues that need to be taken into careful consideration by genetic counselors and other medical professionals who are developing genetic testing protocols, making decisions about the availability of genetic tests, and making decisions about whether and how to return incidental findings. PMID- 29967968 TI - Effect of Inclusion of Oral Antibiotics with Mechanical Bowel Preparation on the Risk of Clostridium Difficile Infection After Colectomy. AB - BACKGROUND/PURPOSE: While the use of oral antibiotic (OA) for bowel preparation is gaining popularity, it is unknown whether it increases the risk of Clostridium difficile infection (CDI). This study aimed to evaluate the impact of OA on the development of CDI after colectomy. METHODS: Patients who underwent colectomy from the ACS-NSQIP data (2015 and 2016) were included. Patients who received OA as bowel preparation were compared to those who did not with respect to demographics, comorbidities, primary diagnosis, procedure type and approach, and 30-day postoperative complications. Multivariable analysis was performed to characterize the association between OA and CD infection after colectomy. A sub group analysis was also conducted for patients who did not develop any postoperative infectious complication. RESULTS: Of 36,374 included patients, 18,177 (50%) received OA and 527 (1.4%) developed CDI for the whole cohort. OA group had more younger, functionally independent and obese patients with lower American Society of Anesthesiologists and wound class. Smoking, diabetes, hypertension, dyspnea or ventilator-dependence, congestive heart failure, disseminated cancer, bleeding disorder, and perioperative transfusion were significantly higher for non-OA group. Mechanical bowel preparation, minimally invasive surgery, conversion to open and operative duration >= 180 min were more prevalent in the OA group. The OA group had significantly reduced occurrence of CDI; superficial, deep, and organ space infections; wound disruption; anastomotic leak; reoperation; and infections including sepsis, septic shock, pneumonia, and urinary tract infection. On multivariable analysis, OA reduced the odds for CDI after colectomy (OR = 0.6, 95% CI = [0.5-0.8]). For patients who did not develop infectious postoperative complications, OA was associated with lower risk of CDI (OR = 0.7, CI = [0.5-0.9]). While complications, reoperation, and readmission rates were the same, postoperative ileus and hospital stay were significantly lower for those who developed CDI after receiving OA when compared to non-OA. CONCLUSION: The use of OA as bowel preparation may reduce, rather than increase, the risk of 30-day CDI after colectomy. This effect may partly be due to the other recovery advantages associated with oral antibiotics. These data further support current data recommending the use of oral antibiotics for bowel preparation before colectomy. PMID- 29967970 TI - Prognostic Potential of the Panfungal Marker (1 -> 3)-beta-D-Glucan in Invasive Mycoses Patients. AB - We analyze the prognostic potential of (1 -> 3)-beta-D-glucan (BG) levels in predicting clinical outcomes in patients with invasive fungal infections, on a population undergoing 253 episodes (177 with positive and 76 with negative outcome). Using linear regression analysis, we assessed the prognostic potential of kinetically evaluated BG levels and we found an overall sensitivity and specificity of 68 and 82%, respectively. Moreover, using an interpretative algorithm based on two distinct cutoff values, we were able to predict the outcome in 84% of the studied population with a diagnostic accuracy of 82%. PMID- 29967969 TI - A Prospective, Randomized, Phase III Study to Evaluate the Efficacy and Safety of Fibrin Sealant Grifols as an Adjunct to Hemostasis as Compared to Cellulose Sheets in Hepatic Surgery Resections. AB - BACKGROUND: Local hemostatic agents have a role in limiting bleeding complications associated with liver resection. METHODS: In this randomized, phase III study, we compared the efficacy and safety of Fibrin Sealant Grifols (FS Grifols) with oxidized cellulose sheets (Surgicel(r)) as adjuncts to hemostasis during hepatic resections. The primary efficacy endpoint was the proportion of patients achieving hemostasis at target bleeding sites (TBS) within 4 min (T4) of treatment application. Secondary efficacy variables were time to hemostasis (TTH) at a later time point if re-bleeding occurs and cumulative proportion of patients achieving hemostasis by time points T2, T3, T5, T7, and T10. RESULTS: The rate of hemostasis by T4 was 92.8% in the FS Grifols group (n = 163) and 80.5% in the Surgicel(r) group (n = 162) (p = 0.01). The mean TTH was significantly shorter (p < 0.001) in the FS Grifols group (2.8 +/- 0.14 vs. 3.8 +/- 0.24 min). The rate of hemostasis by T2, T5, and T7 was higher and statistically superior in the FS Grifols group compared to Surgicel(r). No substantial differences in adverse events (AE) were noted between treatment groups. The most common AEs were procedural pain (36.2 vs. 37.7%), nausea (20.9 vs. 23.5%), and hypotension (14.1 vs 6.2%). CONCLUSIONS: FS Grifols was safe and well tolerated as a local hemostatic agent during liver resection surgeries. Overall, data demonstrate that the hemostatic efficacy of FS Grifols is superior to Surgicel(r) and support the use of FS Grifols as an effective local hemostatic agent in these surgical procedures. PMID- 29967971 TI - Widespread Lichtheimia Infection in a Patient with Extensive Burns: Opportunities for Novel Antifungal Agents. AB - The Mucorales fungi-formerly classified as the zygomycetes-are environmentally ubiquitous fungi, but generally rare causes of clinical infections. In the immunocompromised host, however, they can cause invasive, rapidly spreading infections that confer a high risk of morbidity and mortality, often despite surgical and antifungal therapy. Patients with extensive burn injuries are particularly susceptible to skin and soft-tissue infections with these organisms. Here, we present a case of Lichtheimia infection in a patient with extensive full thickness burns that required significant and repeated surgical debridement successfully treated with isavuconazole and adjunctive topical amphotericin B washes. We also review the available literature on contemporary antifungal treatment for Lichtheimia species and related Mucorales fungi. PMID- 29967972 TI - The Oomycete Pythium oligandrum Can Suppress and Kill the Causative Agents of Dermatophytoses. AB - Pythium oligandrum (Oomycota) is known for its strong mycoparasitism against more than 50 fungal and oomycete species. However, the ability of this oomycete to suppress and kill the causal agents of dermatophytoses is yet to be studied. We provide a complex study of the interactions between P. oligandrum and dermatophytes representing all species dominating in the developed countries. We assessed its biocidal potential by performing growth tests, on both solid and liquid cultivation media and by conducting a pilot clinical study. In addition, we studied the molecular background of mycoparasitism using expression profiles of genes responsible for the attack on the side of P. oligandrum and the stress response on the side of Microsporum canis. We showed that dermatophytes are efficiently suppressed or killed by P. oligandrum in the artificial conditions of cultivations media between 48 and 72 h after first contact. Significant intra- and interspecies variability was noted. Of the 69 patients included in the acute regimen study, symptoms were completely eliminated in 79% of the patients suffering from foot odour, hyperhidrosis disappeared in 67% of cases, clinical signs of dermatomycoses could no longer be observed in 83% of patients, and 15% of persons were relieved of symptoms of onychomycosis. Our investigations provide clear evidence that the oomycete is able to recognize and kill dermatophytes using recognition mechanisms that resemble those described in oomycetes attacking fungi infecting plants, albeit with some notable differences. PMID- 29967973 TI - Prefrontal modulation during chewing performance in occlusal dysesthesia patients: a functional near-infrared spectroscopy study. AB - OBJECTIVES: Neuropsychological associations can be considerable in occlusal dysesthesia (OD) patients who routinely complain of persistent occlusal discomfort, and somatization effects in the superior medial prefrontal cortex and the temporal and parietal regions are also present. However, the relationship between physical activity, i.e., chewing, prefrontal cognitive demand, and psychiatric states in OD patients remains unclear. We investigated this relationship in this study. MATERIALS AND METHODS: OD patients (n = 15) and healthy control (n = 15; HC) subjects were enrolled in this study. Occlusal contact, chewing activities of the masticatory muscles, prefrontal activities, and psychiatric states such as depression and somatization, of the participants were evaluated. Functional near-infrared spectroscopy was used to determine prefrontal hemodynamics and the Symptom Checklist-90-R was used to score the psychiatric states. RESULTS: We observed a significant association between prefrontal deactivation during chewing and somatization subscales in OD patients. Further, there were no significant differences with regard to the occlusal state and chewing physical activities between the OD patients and HC subjects. CONCLUSIONS: Chewing-related prefrontal deactivation may be associated with somatization severity in OD patients. CLINICAL RELEVANCE: fNIRS is a functional imaging method that uses the principal of neuro-vascular couplings. It is applicable for evaluation of psychiatric state based on prefrontal cortex blood flow in patients with psychiatric disorders. PMID- 29967974 TI - Carotid calcifications in panoramic radiographs are associated with future stroke or ischemic heart diseases: a long-term follow-up study. AB - OBJECTIVE: To assess if carotid calcifications detected in panoramic radiographs are associated with future events of stroke, and/or ischemic heart diseases over 10-13 years in individuals between 60 and 96 years. MATERIALS AND METHODS: Baseline (2001-2004) panoramic radiographs were assessed for evidence of carotid calcifications from individuals with no previous history of stroke and/or ischemic heart diseases. A radiopaque nodular mass adjacent to the cervical vertebrae, at or below the intervertebral space C3-C4, was interpreted as carotid calcification. Annual medical records were searched for ICD 10 codes through 2014. RESULTS: Signs of carotid calcification was demonstrated in 238/635 (37.5%) of the study individuals. Signs of carotid calcification was associated with future stroke and/or ischemic heart diseases (chi2 = 9.1, OR 1.6, 95% CI 1.2, 2.2, p < 0.002). In individuals 60-72 years, a significant association between radiographic signs of carotid calcification and stroke and/or ischemic heart diseases (chi2 = 12.4, OR 2.4, 95% CI 1.5, 4.0, p < 0.000) (adjusted for high blood pressure, diabetes type 2, BMI; OR 1.9, 95% CI 1.1, 3.5, p = 0.03). Individuals (60-72 years) with radiographic evidence of carotid calcifications had a mean cumulative stroke and/or ischemic heart diseases survival time of 12.1 years compared to those without such evidence (13.0 years) (log rank Mantel-Cox chi2 = 10.7, p = 0.001). CONCLUSIONS: Evidence of carotid calcifications in panoramic radiographs is associated with an event of stroke and/or ischemic heart diseases in 60-96-year-old individuals. CLINICAL RELEVANCE: Radiographic evidence of carotid calcifications is associated with stroke and/or ischemic heart diseases. Patients with signs of carotid calcifications should therefore be referred for medical examination. PMID- 29967975 TI - Antimicrobial susceptibilities of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis strains from periodontitis patients in Morocco. AB - BACKGROUND AND OBJECTIVE: Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis have been frequently isolated in periodontitis patients in Morocco. Its persistence after the subgingival debridement of the biofilm has been correlated with worse clinical outcomes. The aim of this study was to evaluate the antimicrobial susceptibilities of A. actinomycetemcomitans and P. gingivalis, to amoxicillin, amoxicillin plus clavulanate, metronidazole, and azithromycin. In addition, microbiological profiles of patients harbouring A. actinomycetemcomitans, P. gingivalis, or both were compared. MATERIAL AND METHODS: In 45 consecutive periodontitis Moroccan patients, subgingival samples were taken and processed by culture. Twenty-four A. actinomycetemcomitans and 30 P. gingivalis colonies were isolated (54 strains) and susceptibility tests, using the epsilometric method, were run for amoxicillin, amoxicillin plus clavulanate, metronidazole, and azithromycin. Minimum inhibitory concentrations for 50 (MIC50) and 90% (MIC90) of the organisms were calculated. RESULTS: The prevalence of A. actinomycetemcomitans and P. gingivalis was 79.5 and 84.4%, respectively. A. actinomycetemcomitans showed susceptibility to amoxicillin, amoxicillin plus clavulanate, while 28% of the isolated strains were resistant to azithromycin and 61.7% towards metronidazole. No P. gingivalis resistance towards amoxicillin, amoxicillin plus clavulanate, metronidazole, and azithromycin was found. CONCLUSION: A. actinomycetemcomitans and P. gingivalis were frequently detected in Moroccan patients with periodontitis, while antimicrobial resistance was only detected for A. actinomycetemcomitans to metronidazole and azithromycin. CLINICAL RELEVANCE: A. actinomycetemcomitans resistance against some antimicrobials in periodontitis patients in Morocco can influence the selection of the therapeutic approaches. PMID- 29967977 TI - Correction to: Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia. AB - The corresponding author should be ''Masataka Ishimura'', and not ''Motoshi Sonoda'' as given in the original publication of the article. PMID- 29967976 TI - Cardiac differentiation at an initial low density of human-induced pluripotent stem cells. AB - A high density of human-induced pluripotent stem cells (hiPSCs) improves the efficiency of cardiac differentiation, suggesting the existence of indispensable cell-cell interaction signals. The complexity of interactions among cells at high density hinders the understanding of the roles of cell signals. In this study, we determined the minimum cell density that can initiate differentiation to facilitate cell-cell interaction studies. First, we co-induced cardiac differentiation in the presence of the glycogen synthase kinase-3beta inhibitor CHIR99021 and activin A at various cell densities. At an initial low density, cells died within a few days in RPMI-based medium. We then investigated the culture conditions required to maintain cell viability. We used a basal medium excluding important components for the maintenance of hiPSC pluripotency, including activin A, basic fibroblast growth factor, and insulin. Supplementation of the basal medium with Rho-associated protein kinase inhibitor and insulin improved cell viability. Interestingly, addition of basic fibroblast growth factor enabled the expression of cardiac markers at the mRNA level but not the protein level. After further modification of the culture conditions, 10% of the cells expressed the cardiac troponin T protein, which is associated with cell contraction. The novel protocol for cardiac differentiation at an initial low cell density can also be used to evaluate high cell density conditions. The findings will facilitate the identification of cell signals required for cardiomyocyte formation. PMID- 29967978 TI - Getting a grip on sensorimotor effects in lexical-semantic processing. AB - One of the strategies that researchers have used to investigate the role of sensorimotor information in lexical-semantic processing is to examine the effects of words' rated body-object interaction (BOI; i.e., the ease with which the human body can interact with a word's referent). Processing tends to be facilitated for words with high as compared with low BOI, across a wide variety of tasks. Such effects have been referenced in debates over the nature of semantic representations, but their theoretical import has been limited by the fact that BOI is a fairly coarse measure of sensorimotor experience with words' referents. In the present study, we collected ratings for 621 words on seven semantic dimensions (graspability, ease of pantomime, number of actions, animacy, size, danger, and usefulness), in order to investigate which attributes are most strongly related to BOI ratings and to lexical-semantic processing. BOI ratings were obtained from previous norming studies (Bennett, Burnett, Siakaluk, & Pexman in Behavior Research Methods, 43, 1100-1109, 2011; Tillotson, Siakaluk, & Pexman in Behavior Research Methods, 40, 1075-1078, 2008), and measures of lexical semantic processing were obtained from previous behavioral megastudies involving either the semantic categorization task (concrete/abstract decision; Pexman, Heard, Lloyd, & Yap in Behavior Research Methods, 49, 407-417, 2017) or the lexical decision task (Balota et al., Behavior Research Methods, 39, 445-459, 2007). The results showed that the motor dimensions of graspability, ease of pantomime, and number of actions were all related to BOI, and that these dimensions together explained more variance in semantic processing than did the BOI ratings alone. These ratings will be useful for researchers who wish to study how different kinds of bodily interactions influence lexical-semantic processing and cognition. PMID- 29967979 TI - Word prevalence norms for 62,000 English lemmas. AB - We present word prevalence data for 61,858 English words. Word prevalence refers to the number of people who know the word. The measure was obtained on the basis of an online crowdsourcing study involving over 220,000 people. Word prevalence data are useful for gauging the difficulty of words and, as such, for matching stimulus materials in experimental conditions or selecting stimulus materials for vocabulary tests. Word prevalence also predicts word processing times, over and above the effects of word frequency, word length, similarity to other words, and age of acquisition, in line with previous findings in the Dutch language. PMID- 29967980 TI - Salt tolerance mechanisms in three Irano-Turanian Brassicaceae halophytes relatives of Arabidopsis thaliana. AB - Salt tolerance mechanisms were studied in three Irano-Turanian halophytic species from the Brassicaceae (Lepidium latifolium, L. perfoliatum and Schrenkiella parvula) and compared with the glycophyte Arabidopsis thaliana. According to seed germination under salt stress, L. perfoliatum was the most tolerant species, while L. latifolium and S. parvula were rather susceptible. Contrastingly, based on biomass production L. perfoliatum was more salt sensitive than the other two species. In S. parvula biomass was increased up to 2.8-fold by 100 mM NaCl; no significant growth reduction was observed even when exposed to 400 mM NaCl. Stable activities of antioxidative defense enzymes, nil or negligible accumulation of superoxide anion and hydrogen peroxide, as well as stable membrane integrity in the three halophytes revealed that no oxidative stress occurred in these tolerant species under salt stress. Proline levels increased in response to salt treatment. However, it contributed only by 0.3-2.0% to the total osmolyte concentration in the three halophytes (at 400 mM NaCl) and even less (0.04%) in the glycophyte, A. thaliana (at 100 mM NaCl). Soluble sugars in all three halophytes and free amino acids pool in S. parvula decreased under salt treatment in contrast to the glycophyte, A. thaliana. The contribution of organic osmolytes to the total osmolyte pool increased by salt treatment in the roots, while decreased in halophyte and glycophyte, A. thaliana leaves. Interestingly, this reduction was compensated by a higher relative contribution of K in the leaves of the halophytes, but of Na in A. thaliana. Taken together, biomass data and biochemical indicators show that S. parvula is more salt tolerant than the two Lepidium species. Our data indicate that L. latifolium, as a perennial halophyte with a large biomass, is highly suitable for both restoration of saline habitats and saline agriculture. PMID- 29967981 TI - Sedation and care at the end of life. AB - This special issue of Theoretical Medicine and Bioethics takes up the question of palliative sedation as a source of potential concern or controversy among Christian clinicians and thinkers. Christianity affirms a duty to relieve unnecessary suffering yet also proscribes euthanasia. Accordingly, the question arises as to whether it is ever morally permissible to render dying patients unconscious in order to relieve their suffering. If so, under what conditions? Is this practice genuinely morally distinguishable from euthanasia? Can one ever aim directly at making a dying person unconscious, or is it only permissible to tolerate unconsciousness as an unintended side effect of treating specific symptoms? What role does the rule of double effect play in making such decisions? Does spiritual or psychological suffering ever justify sedation to unconsciousness? What are the theological and spiritual aspects of such care? This introduction describes how the authors in this special issue wrestle with such questions and shows how each essay relates to the author's individual position on palliative sedation, as developed in greater detail within his contribution. PMID- 29967982 TI - MR texture analysis: potential imaging biomarker for predicting the chemotherapeutic response of patients with colorectal liver metastases. AB - PURPOSE: The purpose of the study was to determine whether the pre-treated MR texture features of colorectal liver metastases (CRLMs) are predictive of therapeutic response after chemotherapy. METHODS: The study included twenty-six consecutive patients (a total of 193 liver metastasis) with unrespectable CRLMs at our institution from August 2014 to February 2016. Lesions were categorized into either responding group or non-responding group according to changes in size. Texture analysis was quantified on T2-weighted images by two radiologists with consensus on regions of interest which were manually drawn on the largest cross-sectional area of the lesions. Five histogram features (mean, variance, skewness, kurtosis, and entropy1) and five gray level co-occurrence matrix features (GLCM; angular second moment (ASM), entropy2, contrast, correlation, and inverse difference moment (IDM)) were extracted. The texture parameters were statistically analyzed to identify the differences between the two groups, and the potential predictive parameters to differentiate the responding group from the non-responding group were subsequently tested using multivariable logistic regression analysis. RESULTS: A total of 107 responding and 86 non-responding lesions were evaluated. A higher variance, entropy1, contrast, entropy2 and a lower ASM, correlation, IDM were independently (P < 0.05) associated with a good response to chemotherapy with the areas under the ROC curves (AUCs) of 0.602 0.784. Variance (P < 0.001) and ASM (P = 0.001) remained potential predictive values to discriminate responding lesions from non-responding lesions when tested using multivariable logistic regression analysis. The highest AUC of the predictors from the association of variance and ASM was 0.814. CONCLUSION: MR texture features on pre-treated T2 images have the potential to predict the therapeutic response of colorectal liver metastases. PMID- 29967983 TI - MRI findings of absorbable hydrogel spacer for prostate cancer therapy: a pictorial review. AB - Prior studies have shown that dose-escalated radiation therapy for prostate cancer improves clinical outcomes. However, this is associated with increased rectal toxicity. Hydrogel spacer for prostate cancer therapy is an effective way of decreasing rectal toxicity in the late post-therapeutic stages. In some occasions, the gel spacer may not be placed symmetrically between the rectum and prostate. There are several forms of a malpositioned spacer, including lateral displacement, rectal wall infiltration, and prostate capsule infiltration. This manuscript is aimed at evaluating appropriately positioned and malpositioned gel spacers, primarily via magnetic resonance imaging. There are limited educational imaging guides that address what radiologists should evaluate on post-spacer placement imaging. This pictorial review will specifically evaluate post injection pitfalls such as asymmetry, rectal wall infiltration, and subcapsular injection. PMID- 29967984 TI - Extramural venous invasion in rectal cancer: overview of imaging, histopathology, and clinical implications. AB - OBJECTIVE: Extramural venous invasion (EMVI) is an independent prognostic factor for prediction of overall unfavorable outcomes in rectal cancer. While EMVI has traditionally been detected in postoperative pathologic specimens, MRI can provide this important piece of information preoperatively. This article reviews the methods of EMVI detection and their clinical implications for treatment and outcomes of rectal cancer. CONCLUSION: EMVI has fundamental implications for rectal cancer prognosis and long-term outcomes. Since MRI has the advantage of preoperative detection of EMVI, it has been suggested that MRI-detected EMVI be incorporated for preoperative chemoradiotherapy (CRT) treatment stratification of rectal cancer for better patient triage and outcomes. PMID- 29967985 TI - What the radiologist needs to know: the role of preoperative computed tomography in selection of operative approach for adrenalectomy and review of operative techniques. AB - Adrenalectomy is the standard of care for management of many adrenal tumor types and, in the United States alone, approximately 6000 adrenal surgeries are performed annually. Two general approaches to adrenalectomy have been described; (1) the open approach, in which a diseased adrenal is removed through a large (10 20 cm) abdominal wall incision, and (2) the minimally invasive approach, in which laparoscopy is used to excise the gland through incisions generally no longer than 1-2 cm. Given these disparate technique options, clear preoperative characterization of those specific disease features that inform selection of adrenalectomy approach is critically important to the surgeon. Because most of these features are directly assessed via preoperative abdominal imaging, in particular computed tomography (CT) scanning, a clear mutual understanding among surgeons and radiologists of those adrenal tumor features impacting operative approach selection is vital for planning adrenal surgery. In this context, we review the preoperative CT imaging features that specifically inform adrenalectomy approach selection, provide illustrative examples from our institution's imaging and surgical archives, and provide a stepwise guide to both the open and laparoscopic adrenalectomy approaches. PMID- 29967986 TI - MRI evaluation of pancreatic ductal adenocarcinoma: diagnosis, mimics, and staging. AB - The radiologist's role in the evaluation of pancreatic ductal adenocarcinoma remains critical in the management of this deadly disease. Imaging plays a vital role in the diagnosis and staging of pancreatic cancer. Although CT is more commonly used for staging pancreatic cancer, MR is increasingly playing an important role in this regard. In our institution, all pancreatic malignancies undergo staging with MRI. In this pictoral essay, we illustrate the MR imaging features of pancreatic ductal adenocarcinoma and its mimics, and we also discuss pearls and pitfalls in MR staging of pancreatic carcinoma. PMID- 29967987 TI - Wnt-7a Stimulates Dendritic Spine Morphogenesis and PSD-95 Expression Through Canonical Signaling. AB - Wnt signaling regulates brain development and synapse maturation; however, the precise molecular mechanism remains elusive. Here, we report that Wnt-7a stimulates dendritic spine morphogenesis in the hippocampus via glycogen synthase kinase-3 beta (GSK-3beta) inhibition, triggering beta-catenin/T cell factor/lymphoid enhancer factor (TCF/LEF)-dependent gene transcription and promoting postsynaptic density-95 (PSD-95) protein expression. In addition, wild type mice treated with an inhibitor of beta-catenin/TCF/LEF-mediated transcription showed a reduction in spatial memory acquisition accompanied by a reduction in PSD-95 and decreases in spine density measured by Golgi staining, suggesting that PSD-95 is a novel Wnt target gene. Together, our data strongly demonstrate that Wnt-dependent target gene transcription is essential to hippocampal synaptic plasticity. PMID- 29967988 TI - Molecular Detection of Streptococcus pyogenes by Strand Invasion Based Amplification Assay. AB - INTRODUCTION: Streptococcus pyogenes (group A Streptococcus, GAS) is responsible for a variety of highly communicable infections, accounting for 5-15 and 20-30% of sore throat hospital visits in adults and children, respectively. Prompt diagnosis of GAS can improve the quality of patient care and minimize the unnecessary use of antibiotics. OBJECTIVE: Our objective was to develop an alternative nucleic acid amplification method for the diagnosis of GAS. METHOD: We developed and evaluated a strand invasion based amplification (SIBA) assay to rapidly and specifically detect GAS. The performance of the developed GAS SIBA assay was compared with an established GAS polymerase chain reaction (PCR) assay. RESULTS: The GAS SIBA assay detected small amounts (ten copies) of S. pyogenes DNA within 13 min. The rapid detection time was achieved in part by optimization of magnesium concentration and reaction temperature. The sensitivity and specificity of the GAS SIBA assay for detection of S. pyogenes from clinical specimens were both 100%, and clinical specimens were detected within ~ 8 min of starting the reaction. CONCLUSION: Because the GAS SIBA assay is performed at low and constant temperature, it can be used both in centralized laboratories and for point-of-care testing. Furthermore, given its short detection time and strong analytical performance, the GAS SIBA assay could help to improve patient care and minimize unnecessary prescription of antibiotics. PMID- 29967990 TI - Residual mesorectum on postoperative magnetic resonance imaging following transanal total mesorectal excision (TaTME) and laparoscopic total mesorectal excision (LapTME) in rectal cancer. AB - BACKGROUND: The standard treatment for mid- and low-rectal cancer is total mesorectal excision. Incomplete excision is an important predictor of local recurrence after rectal cancer surgery. Transanal TME (TaTME) is a new treatment option in which the rectum is approached with both laparoscopic and transanal endoscopic techniques. The aim of the present study was to determine the prevalence and localisation of residual mesorectal tissue by postoperative magnetic resonance imaging (MRI) of the pelvis and compare this between TaTME and laparoscopic TME (LapTME) patients. In addition, we assessed correspondence with histopathological quality. METHODS: Two groups of patients with cT1-T3 rectal cancer who underwent TME surgery with primary anastomosis were included, each group consisting of 32 patients. Postoperative T2-weighted MRI of the pelvis was performed at least 6 months after TME surgery and evaluated by two radiologists independently. Residual mesorectum was defined as any residual mesorectal tissue detectable after TME. Localisation of the tissue was categorised in relation to height in the pelvis and position of the level of anastomosis. RESULTS: Residual mesorectal tissue was detected in 3.1% of TaTME patients and of 46.9% in LapTME patients (p < 0.001). Multivariate analysis identified only type of surgery as a significant risk factor for leaving residual mesorectum. Other known risk factors for incomplete TME, such as body mass index (BMI) and male gender, were not significant. No relation was seen between specimen quality and prevalence of residual mesorectum. CONCLUSIONS: The completeness of mesorectal excision was significantly better with TaTME than with standard laparoscopic technique. PMID- 29967989 TI - Pm61: a recessive gene for resistance to powdery mildew in wheat landrace Xuxusanyuehuang identified by comparative genomics analysis. AB - KEY MESSAGE: A single recessive powdery mildew resistance gene Pm61 from wheat landrace Xuxusanyuehuang was mapped within a 0.46-cM genetic interval spanning a 1.3-Mb interval of the genomic region of chromosome arm 4AL. Epidemics of powdery mildew incited by the biotrophic fungus Blumeria graminis f. sp. tritici (Bgt) have caused significant yield reductions in many wheat (Triticum aestivum) producing regions. Identification of powdery mildew resistance genes is required for sustainable improvement of wheat for disease resistance. Chinese wheat landrace Xuxusanyuehuang was resistant to several Bgt isolates at the seedling stage. Genetic analysis based on the inoculation of Bgt isolate E09 on the F1, F2, and F2:3 populations produced by crossing Xuxusanyuehuang to susceptible cultivar Mingxian 169 revealed that the resistance of Xuxusanyuehuang was controlled by a single recessive gene. Bulked segregant analysis and simple sequence repeat (SSR) mapping placed the gene on chromosome bin 4AL-4-0.80-1.00. Comparative genomics analysis was performed to detect the collinear genomic regions of Brachypodium distachyon, rice, sorghum, Aegilops tauschii, T. urartu, and T. turgidum ssp. dicoccoides. Based on the use of 454 contig sequences and the International Wheat Genome Sequence Consortium survey sequence of Chinese Spring wheat, four EST-SSR and seven SSR markers were linked to the gene. An F5 recombinant inbred line population derived from Xuxusanyuehuang * Mingxian 169 cross was used to develop the genetic linkage map. The gene was localized in a 0.46-cM genetic interval between Xgwm160 and Xicsx79 corresponding to 1.3-Mb interval of the genomic region in wheat genome. This is a new locus for powdery mildew resistance on chromosome arm 4AL and is designated Pm61. PMID- 29967991 TI - Short-term outcomes of transanal completion total mesorectal excision (cTaTME) for rectal cancer: a case-matched analysis. AB - BACKGROUND: Local excision of early rectal tumors as a rectal preserving treatment is gaining popularity, especially since bowel cancer screening programs result in a shift towards the diagnosis of early stage rectal cancers. However, unfavorable histological features predicting high risk for recurrence within the "big biopsy" may mandate completion total mesorectal excision (cTME). Completion surgery is associated with higher morbidity, poorer specimen quality, and less favorable oncological outcomes compared to primary TME. Transanal approach potentially improves outcome of completion surgery for rectal cancer. The aim of this study was to compare radical completion surgery after local excision for rectal cancer by the transanal approach (cTaTME) with conventional abdominal approach (cTME). METHODS: All consecutive patients who underwent cTaTME for rectal cancer between 2012 and 2017 were case-matched with cTME patients, according to gender, tumor height, preoperative radiotherapy, and tumor stage. Surgical, pathological, and short-term postoperative outcomes were evaluated. RESULTS: In total, 25 patients underwent completion TaTME and were matched with 25 patients after cTME. Median time from local excision to completion surgery was 9 weeks in both groups. In the cTaTME and cTME groups, perforation of the rectum occurred in 4 and 28% of patients, respectively (p = 0.049), leading to poor specimen quality in these patients. Number of harvested lymph nodes was higher after cTaTME (median 15; range 7-47) than after cTME (median 10; range 0-17). No significant difference was found in end colostomy rate between the two groups. Major 30-day morbidity (Clavien-Dindo>= III) was 20 and 32%, respectively (p = 0.321). Hospital stay was significantly longer after cTME. CONCLUSION: TaTME after full-thickness excision is a promising technique with a significantly lower risk of perforation of the rectum and better specimen quality compared to conventional completion TME. PMID- 29967992 TI - Minimally invasive surgery for stage III colon adenocarcinoma is associated with less delay to initiation of adjuvant systemic therapy and improved survival. AB - BACKGROUND: Minimally invasive surgery (MIS) may improve surgical recovery and reduce time to adjuvant systemic therapy after colon cancer resection. The objective of this study was to determine the effect of MIS on the initiation of adjuvant systemic therapy and survival in patients with stage III colon cancer. METHODS: The 2010-2014 National Cancer Database was queried for patients with resected stage III colon adenocarcinoma, and divided into MIS, which included laparoscopic and robotic approaches, and open surgery. Propensity-score matching was used to balanced open and MIS groups. The main outcome measures were delayed initiation of adjuvant systemic therapy (defined as > 8 weeks after surgery) and 5-year overall survival (OS). Multiple Cox regression was performed to identify independent predictors for 5-year OS, including an interaction between delayed systemic therapy and MIS, and adjusted for clustering at the hospital level. RESULTS: There were 86,680 patients that were included in this study. Overall, 45% (38,713) underwent MIS colectomy, of which 93% underwent laparoscopic and 7% robotic surgery. After matching, 33,183 open patients were balanced to 33,183 MIS patients. Patient, tumor, and facility characteristics were similar in the matched cohort. More patients in the MIS group received adjuvant therapy within 8 weeks of surgery (49% vs. 42%, p < 0.001), and fewer MIS patients did not receive any systemic therapy (30% vs. 35%, p < 0.001). Delayed initiation of systemic therapy > 8 weeks was associated with worse 5-year OS (HR 1.27, 95%CI 1.19-1.36). MIS was independently associated with improved survival (HR 0.92, 95%CI 0.86 0.97). This relationship remained even if 90-day mortality was excluded. CONCLUSIONS: MIS approaches are associated with less delay to the initiation of adjuvant systemic therapy and improved survival in patients with stage III colon adenocarcinoma. Surgeons should favor MIS approaches for the treatment of stage III colon adenocarcinoma whenever possible. PMID- 29967993 TI - Intraocular pressure increases after complex simulated surgical procedures in residents: an experimental study. AB - BACKGROUND: Surgeons' overload is one of the main causes of medical errors that might compromise patient safety. Due to the drawbacks of current options to monitor surgeons' load, new, sensitive, and objective indices of task (over)load need to be considered and tested. In non-health-care scenarios, intraocular pressure (IOP) has been proved to be an unbiased physiological index, sensitive to task complexity (one of the main variables related to overload), and time on task. In the present study, we assessed the effects of demanding and complex simulated surgical procedures on surgical and medical residents' IOP. METHODS: Thirty-four surgical and medical residents and healthcare professionals took part in this study (the experimental group, N = 17, and the control group, N = 17, were matched for sex and age). The experimental group performed two simulated bronchoscopy procedures that differ in their levels of complexity. The control group mimicked the same hand-eye movements and posture of the experimental group to help control for the potential effects of time on task and re-measurement on IOP. We measured IOP before and after each procedure, surgical performance during procedures, and perceived task complexity. RESULTS: IOP increased as consequence of performing the most complex procedure only in the experimental group. Consistently, residents performed worse and reported higher perceived task complexity for the more complex procedure. CONCLUSIONS: Our data show, for the first time, that IOP is sensitive to residents' task load, and it could be used as a new index to easily and rapidly assess task (over)load in healthcare scenarios. An arousal-based explanation is given to describe IOP variations due to task complexity. PMID- 29967994 TI - Quality of life after rectal cancer surgery: differences between laparoscopic and transanal total mesorectal excision. AB - BACKGROUND: Transanal total mesorectal excision (TaTME) is a safe alternative to laparoscopic TME for mid and low rectal cancer. TaTME allows improved visualization of the surgical planes and margins, and may potentially improve oncological outcomes. However, functional results after total mesorectal excision (TME) are variable and there are currently only a few published studies that include functional data related to the outcomes of TaTME. METHODS: Fifty-four consecutive patients were included in this study: one group included 27 patients who underwent laparoscopic low anterior and the other included 27 patients who underwent TaTME. All patients were asked to complete five questionnaires related to quality of life (QOL) and function [EQ-5D-3L, EORTC-QLQ C30, EORTC-QLQ C29, Low Anterior Resection Syndrome score (LARS), and International Prostate Symptom Score IPSS]. All TaTME patients were operated on at The Gelderse Vallei Hospital by a single surgeon and had a follow-up of at least 6.6 months. RESULTS: The EORTC-QLQ C30 and EQ-5D-3L questionnaires showed comparable outcomes in terms of QOL between the two groups. Almost all items evaluated by the EORTC-QLQ C29, including sexual outcomes, were similar between the two groups. One item concerning fecal incontinence, however, was scored worse for TaTME. There were no significant differences between the groups in terms of LARS symptoms or urinary function. CONCLUSIONS: Patients undergoing laparoscopic or transanal TME showed comparable functional and QOL outcomes. Although the TaTME technique is still evolving, this study indicates that this technique is a safe alternative to laparoscopic surgery in terms of functional outcomes for mid and low rectal cancers. PMID- 29967995 TI - Review of an emergency general surgery process improvement program at a verified military trauma center. AB - INTRODUCTION: Decreasing combat-based admissions to our military facility have made it difficult to maintain a robust trauma process improvement (PI) program. Since emergency general surgery (EGS) and trauma patients share similarities, we merged the care of our EGS and trauma patients into one acute care surgery (ACS) team. An EGS PI program was developed based on trauma PI principles to facilitate continued identification of opportunities for improvement despite our decline in trauma admissions. Analysis of the first 18 months of combined ACS PI data is presented. METHODS: EGS registry inclusion criteria was based on published Association for the Surgery of Trauma's recommendations. Program components and PI categories were based on our existing trauma PI program. Dedicated coordinators actively reviewed and cataloged patient care and outcomes. Deviations from standard practice patterns, unplanned interventions, and other complications were abstracted, categorized, and evaluated through levels of review similar to accepted trauma PI principles. Data for the first six quarters were collated and trends were analyzed. RESULTS: Over 18 months, 696 EGS patients met registry inclusion criteria, with 468 patients (67%) undergoing operative intervention. Over the same time, 353 trauma patients were admitted with 158 undergoing operative intervention (56.4%). Of the 696 EGS patients and 353 trauma patients, 226 (32%) and 243 (69%) PI events were identified, respectively. Common events included unplanned therapies, re-admissions, and unplanned ICU admissions. Based on analysis of all events, four new areas for improvement initiatives were identified. Results of these initiatives included implementation of a multi disciplinary EGS PI committee, consensus protocols, and departmental and hospital wide actions. CONCLUSION: In an 18-month period, integration of our EGS patients into a novel, combined ACS PI program facilitated recognition of an additional 226 PI events and provided a substrate for continued improvements in patient care. PMID- 29967996 TI - A prospective study of the safety and usefulness of a new miniature wide-angle camera: the "BirdView camera system". AB - BACKGROUND: The performance of endoscopic surgery has quickly become widespread as a minimally invasive therapy. However, complications still occur due to technical difficulties. In the present study, we focused on the problem of blind spots, which is one of the several problems that occur during endoscopic surgery and developed "BirdView," a camera system with a wide field of view, with SHARP Corporation. METHODS: In the present study, we conducted a clinical trial (Phase I) to confirm the safety and usefulness of the BirdView camera system. We herein report the results. RESULTS: In this study, surgical adverse events were reported in 2 cases (problems with ileus and urination). There were no cases of device failure, damage to the surrounding organs, or mortality. CONCLUSIONS: We evaluated the safety of the BirdView camera system. We believe that this camera system will contribute to the performance safe endoscopic surgery and the execution of robotic surgery, in which operators do not have the benefit of tactile feedback. PMID- 29967998 TI - Biomarkers in Neuropsychiatry: A Prospect for the Twenty-First Century? AB - The search for biomarkers to aid in the diagnosis and prognosis of psychiatric conditions and predict response to treatment is a focus of twenty-first century medicine. The current lack of biomarkers in routine use is attributable in part to the existing way mental health conditions are diagnosed, being based upon descriptions of symptoms rather than causal biological evidence. New ways of conceptualizing mental health disorders together with the enormous advances in genetic, epidemiological, and neuroscience research are informing the brain circuits and physiological mechanisms underpinning behavioural constructs that cut across current diagnostic DSM-5 categories. Combining these advances with 'Big Data', analytical approaches offer new opportunities for biomarker development. Here we provide an introductory perspective to this volume, highlighting methodological strategies for biomarker identification; ranging from stem cells, immune mechanisms, genomics, imaging, network science to cognition. Thereafter we emphasize key points made by contributors on affective disorders, psychosis, schizophrenia, and autism spectrum disorder. An underlying theme is how preclinical and clinical research are informing biomarker development and the importance of forward and reverse translation approaches. In considering the exploitation of biomarkers we note that there is a timely opportunity to improve clinical trial design informed by patient 'biological' and 'psychological' phenotype. This has the potential to reinvigorate drug development and clinical trials in psychiatry. In conclusion, we are poised to move from the descriptive and discovery phase to one where biomarker panels can be evaluated in real-life cohorts. This will necessitate resources for large-scale collaborative efforts worldwide. Ultimately this will lead to new interventions and personalized medicines and transform our ability to prevent illness onset and treat complex psychiatric disorders more effectively. PMID- 29967997 TI - Changing trends and outcomes associated with the adoption of minimally invasive hepatectomy: a contemporary single-institution experience with 400 consecutive resections. AB - BACKGROUND: Several studies published mainly from pioneers and early adopters have documented the evolution of minimally invasive hepatectomy (MIH). However, questions remain if these reported experiences are applicable and reproducible today. This study examines the changing trends, safety, and outcomes associated with the adoption of MIH based on a contemporary single-institution experience. METHODS: This is a retrospective review of 400 consecutive patients who underwent MIH between 2006 and 2017 of which 360 cases (90%) were performed since 2012. To determine the evolution of MIH, the study population was stratified into four equal groups of 100 patients. Analyses were also performed of predictive factors and outcomes of open conversion. RESULTS: Four hundred patients underwent MIH of which 379 (94.8%) were totally laparoscopic/robotic. Eighty-eight (22.0%) patients underwent major hepatectomy and 160 (40.0%) had resection of tumors located in the posterosuperior segments. There were 38 (9.5%) open conversions. Comparison across the four groups demonstrated that patients were older, had higher ASA score, and had increased frequency of previous abdominal surgery and repeat liver resections. There was also an increase in the proportion of patients who underwent totally laparoscopic/robotic surgery, major liver resection, resection of >= 3 segments, and multiple resections. Comparison of outcomes demonstrated that there was a significant decrease in open conversion rate, longer operation time, and increased use of Pringles maneuver. The presence of cirrhosis and institution experience (1st 100 cases) were independent predictors of open conversion. Patients who required open conversion had significantly increased operation time, blood loss, blood transfusion rate, morbidity, and mortality. CONCLUSION: The case volume of MIH performed increased rapidly at our institution over time. Although the indications of MIH expanded to include higher risk patients and more complex hepatectomies, there was a decrease in open conversion rate and no change in other perioperative outcomes. PMID- 29967999 TI - Sexual Differentiation and Sex Differences in Neural Development. AB - Sex determination occurs at the moment of conception, as a result of XX or XY chromosome pairing. From that point, the body undergoes the process of sexual differentiation, inducing the development of physical characteristics that are easily distinguishable between the sexes and are often reflected in one's physical appearance and gender identity. Although less apparent, the brain also undergoes sexual differentiation. Sex differences in the brain are organized during a critical period of neural development and have an instrumental role in determining the physiology and behavior of an individual throughout the lifespan. Understanding the extent of sex differences in neurodevelopment also influences our understanding of the potential risk for a number of neurodevelopmental, neurological, and mental health disorders that exhibit strong sex biases. Advances made in our understanding of sexually dimorphic brain nuclei, sex differences in neural cell communication, and sex differences in the communication between the brain and peripheral organs are all research fields that have provided valuable information related to the physiological and behavioral outcomes of sex differences in brain development. More recently, investigations into the impact of epigenetic mechanisms on sexual differentiation of the brain have indicated that changes in gene expression, via epigenetic modifications, also contribute to sexual differentiation of the developing brain. Still, there are a number of important questions and ideas that have arisen from our current understanding of sex differences in neurodevelopmental processes that necessitate more time and attention in this field. PMID- 29968001 TI - Structural and functional evolution of an auxin efflux carrier PIN1 and its functional characterization in common wheat. AB - Particularly PIN1, PIN protein-mediated rate-limiting auxin distribution plays a critical role in plant differentiation. Although well-characterized in Arabidopsis, little is known about the structural and functional relationship of the PIN1 gene among other plants. Here, we report that the gene structure remained conserved among bryophytes and angiosperms while the gene size varied by ~ 17%. Although the positions were conserved, highly variable intron phase suggests preference for specific regions in the gene sequence for independent events of intron insertion. Significant variation was observed across gene length for insertions and deletions that were mainly localized to the exonic regions flanking intron 1, possibly demarcating the sequences prone to deletions/duplications. The N and C-terminals showed a higher protein sequence similarity (~ 80%) compared to the central hydrophilic loop (~ 26%). In addition to the signature domains and motifs, we identified four novel uncharacterized motifs in the central divergent loop of PIN1 protein. Three different homo-loci, one each on chromosome groups 4, 6, and 7, were identified in wheat each showing dramatically different expression patterns during different plant developmental stages. Virus-induced gene silencing of the TaPIN1 gene resulted up to 26% reduction in plant height. Because of its direct role in controlling plant height along with a higher expression during stem elongation, the TaPIN1 gene can be manipulated to regulate plant height. PMID- 29968002 TI - A grid-based variational method to the solution of the Schrodinger equation: the q-exponential and the near Hartree-Fock results for the ground state atomic energies. AB - A grid-based variational method was proposed and applied to the ground state energies of atoms from the first to the third period of the periodic table. The nonuniform grid in the radial coordinate was defined by a q-exponential sequence. Some unusual properties between the optimum q-parameters and the electronic energies or atomic numbers are described. The behavior of the electronic energy, with respect to the q-parameter, yields near Hartree-Fock accuracy with a relatively small number of integration points. A simple relationship between the optimum q-parameters and the atomic numbers was found, which allowed the determination of the optimum q-parameters for atoms of the same period from two results. The remarkable results provide a simple alternative route to reach accurate results. The consistent results also suggest that this is not a random or accidental effect, but some optimum condition achieved by using a q exponential mesh grid. Graphical abstract The q-exponential and the near Hartree Fock results for the ground state atomic energies. PMID- 29968000 TI - Management of brain abscesses: where are we now? AB - INTRODUCTION: Brain abscesses affect all age groups and are not peculiar to a particular country, race, or geographical location. It is a disease that, in the past, carried a high morbidity and mortality. With improvements in medical technology and expertise, outcomes have improved tremendously. The causative organisms vary vastly and have evolved with time. Treatment of brain abscesses is primarily with antimicrobial therapy but surgery plays a vital role in achieving better outcomes. CONTENT: In this article, we review the literature to find out how the epidemiology of this disease has changed through the years and re-visit the basic pathological process of abscess evolution and highlight the new research in the biochemical pathways that initiate and regulate this process. We also highlight how magnetic resonance imaging and its various modalities have improved diagnostic accuracy. Finally, we discuss the pros and cons of traditional open surgery versus newer minimally invasive methods. PMID- 29968003 TI - Depression, Anxiety, Post-traumatic Stress Disorder and a History of Pervasive Gender-Based Violence Among Women Asylum Seekers Who Have Undergone Female Genital Mutilation/Cutting: A Retrospective Case Review. AB - We sought to evaluate the frequency of anxiety, depression, PTSD, and any experiences of violence in women who had undergone Female Genital Mutilation/Cutting (FGM/C) and were seeking asylum in the United States. We undertook a retrospective qualitative descriptive study of FGM/C cases seen in an asylum clinic over a 2-year period. Standardized questionnaires provided quantitative scores for anxiety, depression and PTSD. Clients' personal and physician medical affidavits were analyzed for experiences of violence. Of the 13 cases, anxiety and depression were exhibited by 92 and 100% of women, while all seven women screened for PTSD had symptoms. Qualitative analysis revealed extensive violence perpetrated against these women, demonstrating that FGM/C is only part of the trauma experienced. The high level of mental health disorders and endured violence has implications for providers working with FGM/C survivors and indicates the need for accessible mental health services and trauma-informed care. PMID- 29968004 TI - Breast and Colorectal Cancer Screening Barriers Among Immigrants and Refugees: A Mixed-Methods Study at Three Community Health Centres in Toronto, Canada. AB - Mammography and fecal occult blood testing (FOBT) improve the detection, management, and prognosis of breast and colorectal cancer, respectively, but are underperformed in the recent immigrant and refugee population. We aimed to identify barriers to screening and potential solutions in this population. A mixed-methods study involving a retrospective chart review and focus group interviews was conducted, with data analyzed using univariate logistic regression and thematic analysis, respectively. Mammography completion was associated with greater time in Canada (p = 0.01) and region of origin (p = 0.04), while FOBT completion was associated with region of origin (p = 0.03). Barriers included time constraints, language and cultural differences, and poor interprofessional communication. This study of recent immigrants and refugees identifies barriers to screening and supports potential solutions including culturally-congruent peer workers, targeted screening workshops, and visual screening aids. Further work is needed to address the unique healthcare needs of this diverse and growing population. PMID- 29968005 TI - [Use of alternative medicine for cancer and impact on survival]. PMID- 29968007 TI - Observed Family and Friendship Dynamics in Adolescence: a Latent Profile Approach to Identifying "Mesosystem" Adaptation for Intervention Tailoring. AB - Nuanced understanding of adolescents' interpersonal relationships with family and peers is important for developing more personalized interventions that prevent problem behaviors and adjustment issues. We used latent profile analysis (LPA) to classify a community sample of 784 adolescents with respect to their observed relationship dynamics with friends and family using videotaped observations and five-minute audiotaped speech samples collected at ages 16-17. The resulting latent classes served to predict behavioral and emotional health in early adulthood. The LPA of the video- and audio-coded observational variables revealed a three-class model: (1) the healthy relationship group (n = 587), representing low levels of deviant and drug use talk with friends and positive, noncoercive relationship with parents; (2) the disaffected group (n = 90), representing high levels of drug use talk with friends and negativity about their parent(s) in the five-minute speech sample; and (3) the antisocial group (n = 107), representing high levels of deviant talk, drug use talk, coercive joining with friends, and coerciveness in family interactions. In contrast to the healthy relationship group, the disaffected group showed elevated risk for substance use problems and depression and the antisocial group showed higher risk for substance use problems and committing violent crimes in early adulthood. Outcome differences between disaffected and antisocial groups were mostly nonsignificant. We discuss the viability of applying these findings to tailoring and personalizing family-based interventions with adolescents to address key dynamics in the family and friendship relationships to prevent adult substance use problems, depression, and violence. PMID- 29968008 TI - [Conflict of interests]. PMID- 29968006 TI - The Jefferson Scale of Empathy: a nationwide study of measurement properties, underlying components, latent variable structure, and national norms in medical students. AB - The Jefferson Scale of Empathy (JSE) is a broadly used instrument developed to measure empathy in the context of health professions education and patient care. Evidence in support of psychometrics of the JSE has been reported in health professions students and practitioners with the exception of osteopathic medical students. This study was designed to examine measurement properties, underlying components, and latent variable structure of the JSE in a nationwide sample of first-year matriculants at U.S. colleges of osteopathic medicine, and to develop a national norm table for the assessment of JSE scores. A web-based survey was administered at the beginning of the 2017-2018 academic year which included the JSE, a scale to detect "good impression" responses, and demographic/background information. Usable surveys were received from 6009 students enrolled in 41 college campuses (median response rate = 92%). The JSE mean score and standard deviation for the sample were 116.54 and 10.85, respectively. Item-total score correlations were positive and statistically significant (p < 0.01), and Cronbach alpha = 0.82. Significant gender differences were observed on the JSE scores in favor of women. Also, significant differences were found on item scores between top and bottom third scorers on the JSE. Three factors of Perspective Taking, Compassionate Care, and Walking in Patient's Shoes emerged in an exploratory factor analysis by using half of the sample. Results of confirmatory factor analysis with another half of the sample confirmed the 3-factor model. We also developed a national norm table which is the first to assess students' JSE scores against national data. PMID- 29968009 TI - PermacolTM Collagen Paste Injection in Anal Fistula Treatment: A Retrospective Study with One-Year Follow-Up. AB - INTRODUCTION: This study aimed to evaluate the applicability, safety, results, and functional performance of PermacolTM collagen paste injection in patients with an anal fistula. METHODS: Thirty-one patients with anal fistula underwent PermacolTM collagen paste injection between February 2015 and February 2017. The patients were followed up for a total of 12 months with recovery conditions monitored at intervals of 3, 6, and 12 months. Preoperative insertion of seton was performed in 15 patients for a period of 6-8 weeks and 2 patients for a period of 12 weeks. RESULTS: A trans-sphincteric anal fistula was present in 20 patients and an intersphincteric fistula was present in 11 patients. There was a recurrence in 7 patients (22.5%): 1 patient (3.2%) after 1-month follow-up, 3 patients (9.7%) after 3-month follow-up, 2 patients (6.5%) after 6-month follow up, and 1 patient (3.2%) after 12-month follow-up. A complete recovery was observed in 24 (77.5%) patients after a 12-month follow-up. The mean Fecal Incontinence Severity Index score was 0.29 +/- 0.64 preoperatively and 0.55 +/- 1.03 after 12 months. CONCLUSION: In this study, we show that treatment of patients with an anal fistula by injection of PermacolTM is a safe and successful method that does not compromise continence. PMID- 29968010 TI - Pharmacokinetics and Safety of DS-8500a, an Antidiabetic Drug, in Japanese Subjects with Hepatic or Renal Impairment: A Single-Center, Open-Label, Single Dose Study. AB - INTRODUCTION: The pharmacokinetics, safety, and tolerability of DS-8500a (a G protein receptor 119 agonist) up to 100 mg have been investigated in healthy Japanese adults. The objective of this study was to evaluate the effects of hepatic or renal impairment on the pharmacokinetics of a single 25-mg oral dose of DS-8500a. METHODS: This single-center, open-label study enrolled subjects into eight groups according to hepatic function (normal; mild or moderate impairment) and renal function [normal; mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]. Drug concentrations were measured by liquid-chromatography tandem mass spectrometry. Pharmacokinetic parameters were evaluated by non compartmental analysis. Adverse events (AEs) were evaluated for safety. RESULTS: The hepatic and renal groups enrolled 15 and 30 subjects, respectively. Pharmacokinetic parameters of DS-8500a were comparable between the normal hepatic function and mild hepatic impairment groups, but the mean area under the concentration-time curve (AUC) was 1.37-fold higher, and the half-life was longer in the moderate hepatic impairment group compared with the normal hepatic function group. The maximum concentration (Cmax) and AUC values were 0.704- and 0.609-fold lower, respectively, in the ESRD group compared with the values in the other renal impairment groups; no clear differences in AUC and time to Cmax were observed in the normal function and mild, moderate, and severe renal impairment groups. There was no relationship between apparent total body clearance and estimated glomerular filtration rate. The incidence of AEs was similar among all groups. CONCLUSION: DS-8500a exposure in the mild hepatic impairment and mild to severe renal impairment groups was similar to that in the corresponding normal hepatic and renal function groups, but dose adjustments may be required in those with moderate hepatic impairment and ESRD. TRIAL REGISTRATION: Japic CTI-No. 163135. FUNDING: Daiichi Sankyo Co. Ltd., Tokyo, Japan. PMID- 29968011 TI - Colorimetric determination of Hg(II) via the gold amalgam induced deaggregation of gold nanoparticles. AB - A method is described for the colorimetric determination of mercury(II). In the absence of Hg(II), aminopropyltriethoxysilane (APTES) which is positively charged at pH 7 is electrostatically absorbed on the surface of gold nanoparticles (AuNPs). This neutralizes the negative charges of the AuNPs and leads to NP aggregation and a color change from red to blue-purple. However, in the presence of Hg(II), reduced Hg (formed through the reaction between Hg(II) and citrate on the AuNP surface) will replace the APTES on the AuNPs. Hence, the formation of aggregates is suppressed and the color of the solution does not change. The assay is performed by measuring the ratio of absorbances at 650 and 520 nm and can detect Hg(II) at nanomolar levels with a 10 nM limit of detection. The specific affinity between mercury and gold warrants the excellent selectivity for Hg(II) over other environmentally relevant metal ions. Graphical Abstract Schematic of the method for determination of Hg2+ based on the gold amalgam-induced deaggregation of gold nanoparticles in the presence of APTES with the LOD of 10.1 nM. PMID- 29968012 TI - The Boldt scandal still in need of action: the example of colloids 10 years after initial suspicion of fraud. PMID- 29968013 TI - Premorbid functional status as a predictor of 1-year mortality and functional status in intensive care patients aged 80 years or older. AB - PURPOSE: We assessed the association between the premorbid functional status (PFS) and 1-year mortality and functional status of very old intensive care patients. METHODS: Using a nationwide quality registry, we retrieved data on patients treated in Finnish intensive care units (ICUs) during the period May 2012-April 2013. Of 16,389 patients, 1827 (11.1%) were very old (aged 80 years or older). We defined a person with good functional status as someone independent in activities of daily living (ADL) and able to climb stairs without assistance; a person with poor functional status was defined as needing assistance for ADL or being unable to climb stairs. We adjusted for severity of illness and calculated the impact of PFS. RESULTS: Overall, hospital mortality was 21.3% and 1-year mortality was 38.2%. For emergency patients (73.5% of all), hospital mortality was 28% and 1-year mortality was 48%. The functional status at 1 year was comparable to the PFS in 78% of the survivors. PFS was poor for 43.3% of the patients. A poor PFS predicted an increased risk of in-hospital death, adjusted odds ratio (OR) 1.50 (95% confidence interval, 1.07-2.10), and of 1-year mortality, OR 2.18 (1.67-2.85). PFS data significantly improved the prediction of 1-year mortality. CONCLUSIONS: Of very old ICU patients, 62% were alive 1 year after ICU admission and 78% of the survivors had a functional status comparable to the premorbid situation. A poor PFS doubled the odds of death within a year. Knowledge of PFS improved the prediction of 1-year mortality. PMID- 29968014 TI - Predicting outcomes in very old ICU patients: time to focus on the past? PMID- 29968015 TI - Singapore Modifies the U.K. Montgomery Test and Changes the Standard of Care Doctors Owe to Patients on Medical Advice. PMID- 29968016 TI - Bioethics and the Freedom Road. The JBI Community and the Change We Want To See. PMID- 29968017 TI - Legislating Patient Representation: A Comparison Between Austrian and German Regulations on Self-Help Organizations as Patient Representatives. AB - Governments are increasingly inviting patient organizations (POs) to participate in healthcare policymaking. By inviting POs that claim to represent patients, representation comes into being. However, little is known about the circumstances under which governments accept POs as patient representatives. Based on the analysis of relevant legislation, this article investigates the criteria that self-help organizations (SHOs), a special type of PO, must fulfil in order to be accepted as patient representatives by governments in Austria and Germany. Thereby, it aims to contribute to the discussion on the role of governments in steering SHOs. There are different degrees of regulation (very little in Austria, more in Germany). Governments in both countries not only formulate explicit criteria for SHOs with respect to patient representation but also guide SHOs representing patients through implicit criteria for associations. We discuss the findings against concepts of responsiveness, authorization, and accountability. Our findings indicate that governmental steering is not negative per se as indicated by previous research but-depending on legislative criteria-can promote transparency and democratic quality in patient representation. PMID- 29968018 TI - Ethical Issues of Using CRISPR Technologies for Research on Military Enhancement. AB - This paper presents an overview of the key ethical questions of performing gene editing research on military service members. The recent technological advance in gene editing capabilities provided by CRISPR/Cas9 and their path towards first-in human trials has reinvigorated the debate on human enhancement for non-medical purposes. Human performance optimization has long been a priority of military research in order to close the gap between the advancement of warfare and the limitations of human actors. In spite of this focus on temporary performance improvement, biomedical enhancement is an extension of these endeavours and the ethical issues of such research should be considered. In this paper, we explore possible applications of CRISPR to military human gene editing research and how it could be specifically applied towards protection of service members against biological or chemical weapons. We analyse three normative areas including risk benefit analysis, informed consent, and inequality of access as it relates to CRISPR applications for military research to help inform and provide considerations for military institutional review boards and policymakers. PMID- 29968019 TI - Attitudes Towards the Donation of Human Embryos for Stem Cell Research Among Chinese IVF Patients and Students. AB - Bioethical debates on the use of human embryos and oocytes for stem cell research have often been criticized for the lack of empirical insights into the perceptions and experiences of the women and couples who are asked to donate these tissues in the IVF clinic. Empirical studies that have investigated the attitudes of IVF patients and citizens on the (potential) donation of their embryos and oocytes have been scarce and have focused predominantly on the situation in Europe and Australia. This article examines the viewpoints on the donation of embryos for stem cell research among IVF patients and students in China. Research into the perceptions of patients is based on in-depth interviews with IVF patients and IVF clinicians. Research into the attitudes of students is based on a quantitative survey study (n=427). The empirical findings in this paper indicate that perceptions of the donation of human embryos for stem cell research in China are far more diverse and complex than has commonly been suggested. Claims that ethical concerns regarding the donation and use of embryos and oocytes for stem cell research are typical for Western societies but absent in China cannot be upheld. The article shows that research into the situated perceptions and cultural specificities of human tissue donation can play a crucial role in the deconstruction of politicized bioethical argumentation and the (often ill-informed) assumptions about "others" that underlie socio-ethical debates on the moral dilemmas of technology developments in the life sciences. PMID- 29968020 TI - Economic Evaluations of Guideline-Based Care for Chronic Wounds: a Systematic Review. AB - OBJECTIVES: The aim of this study was to review all published economic evaluations of guideline-based care for chronic wounds and to assess how useful these studies are for decision making in health services. METHODS: Embase, PubMed, Scopus, Health Technology Assessment (HTA) and National Health Service Economic Evaluation Database (NHS EED) were searched on April 16th, 2018. We included studies that evaluated the economic impact and health outcomes associated with implementing evidence-based guidelines as a bundle of care for the prevention and/or treatment of chronic wounds. Information was extracted from each eligible study and organized by the type of chronic wound. The quality of published economic evaluation studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). RESULTS: A total of 24 economic evaluation studies met the inclusion criteria, of which 12 applied decision analytic models. The compliance with the CHEERS checklist ranged between 43 and 83%. LIMITATIONS: We may have missed some economic evaluation studies despite the use of broad search terms. The quality assessment was conducted based on judgment. Using the CHEERS checklist may reflect the way evaluations were reported rather than conducted. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: We found that guideline-based care may be cost-saving or cost-effective in most circumstances. The quality and usefulness of reviewed studies for decision making were variable. Better information and higher-quality economic evaluations will increase decision makers' confidence to promote guideline-based care. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42017051859. PMID- 29968021 TI - Repeating of local therapy of distant metastases increases overall survival in patients with synchronous metastasized rectal cancer-a monocentric analysis. AB - PURPOSE: The aim was to evaluate the outcome of treatment-naive patients with synchronous metastatic rectal cancer after chemotherapy with FOLFOXIRI followed by local therapeutic procedures of all tumor lesions as complete as possible. METHODS: We reviewed data of 30 patients with synchronous distant metastatic rectal cancer who underwent chemotherapy with FOLFOXIRI and subsequent local therapy in our institution. RESULTS: Median follow-up was 28 months (range: 8; 74). Cumulative overall survival (OS) and progression-free survival (PFS) was 93.3, 76.9, 55.6% and 46.2, 29.7, 29.7% after 1, 2, 4 years. Non-response to chemotherapy with FOLFOXIRI was associated with a highly significant decreased OS (p < 0.0001). The consistent use of local ablative procedures led to a statistically significant increase in OS (p < 0.0001), but not in PFS (p = 0.635). Patients with <= 4 distant metastases showed a better OS (p = 0.033). CONCLUSIONS: Response to intensified first-line chemotherapy with FOLFOXIRI, treatment of the primary rectal tumor, and repeated thorough local ablative procedures in patients with synchronous metastasized rectal cancer may lead to long-term survival, even in a subset of patients with unresectable disease at initial diagnosis. PMID- 29968022 TI - Land-use/cover change in Coimbatore urban area (Tamil Nadu, India)-a remote sensing and GIS-based study. AB - The purpose of the present study was to explain land-use/cover changes in Coimbatore City Corporation using Landsat ETM+ and Landsat 8 Operational Land Imager (OLI) and Thermal Infrared Sensor (TIRS) data for the period of 2003-2014. Two Landsat images from years 2003 and 2014 were downloaded from USGS Earth Explorer. Maximum likelihood method was used to classify the images into five classes: urban fabric, vegetation, water bodies, agriculture lands, and barren lands. Overall kappa accuracy measure is about to 87.60 and 86.15% for the years 2003 and 2014, respectively. The change detection analysis has been performed for years 2003 and 2014 postclassified images. The results of the study have indicated that Coimbatore City has experienced rapid modifications in LULC, particularly in terms of urban/built-up area. Over the past 11 years, urban/built up areas have increased by 94.5 km2, resulting in a significant drop in the area of agricultural land and vegetation cover. It is found that (1) urban areas are increased 200% due to population growth cum rapid economic progress. (2) Vegetation cover decreased 38.76% due to conversion into urban features. (3) Water bodies in area increased to 15.78% due to eradication of encroachment. (4) There is loss of 1.89% of agricultural lands due to demand for construction activities. (5) About 85.24% of barren lands were converted into other uses, particularly 57.33% to urban areas. (6) Urban growth has accelerated towards north-eastern, northern, and eastern parts, where national highways exist. The built-up areas were dropped from 85.32 to 22.28%, within 5-km distance from the city center. PMID- 29968023 TI - A Comparison of Patient-Reported Outcomes After Nipple-Sparing Mastectomy and Conventional Mastectomy with Reconstruction. AB - INTRODUCTION: Nipple-sparing mastectomy (NSM) is increasingly used for breast cancer risk reduction and treatment. Prior small studies with variable control for baseline characteristics suggest superior satisfaction with NSM. The purpose of this study was to compare patient satisfaction following NSM and total mastectomy (TM) utilizing the BREAST-Q patient-reported outcome measure in a well characterized patient population. METHODS: Patients at a single institution undergoing NSM or TM with immediate tissue expander/implant reconstruction who completed a follow-up BREAST-Q from 2007 to 2017 were identified by retrospective review of a prospective database. Baseline characteristics were compared, and linear mixed models were used to analyze associations with BREAST-Q scores over time. RESULTS: Of 1866 eligible patients, 219 (12%) underwent NSM, and 1647 (88%) underwent TM. Median time from baseline to BREAST-Q was 658 days. Patients with NSM were younger, more likely to be white, and had lower BMI. They more often had prophylactic surgery, bilateral mastectomies, lower-stage disease, and less often received chemotherapy/radiation than patients with TM. On multivariable analysis, after controlling for relevant clinical variables, there was no difference in satisfaction with breasts or satisfaction with outcome overall between NSM and TM patients. Psychosocial well-being and sexual well-being were significantly higher in the NSM group. After additionally controlling for preoperative BREAST-Q score in a subset of patients (72 NSM; 443 TM), only psychosocial well-being remained significantly higher in NSM patients. CONCLUSIONS: Patient-reported outcomes should be discussed with women weighing the risks and benefits of NSM to provide a better understanding of expected quality of life. PMID- 29968024 TI - Basic Oncoplastic Surgery for Breast Conservation: Tips and Techniques. AB - BACKGROUND: The demand for oncoplastic breast surgery has increased significantly in recent years. However, these procedures are often not taught in standard training for breast surgeons, and a simple guide for surgeons to start performing basic oncoplastic breast surgery techniques is not available. METHODS: The basic concepts of oncoplastic breast surgery and the tools needed prior to starting these types of procedures are discussed, and the procedure, in a stepwise pattern, for the building blocks of oncoplastic techniques is outlined. RESULTS: The importance of oncoplastics from a quality of life and oncologic standpoint are described. Key concepts are defined and the decision on when it is necessary to consult reconstructive plastic surgery is delineated. The basic necessities for oncoplastic breast surgery, including patient photographs, important intraoperative tools, anatomic knowledge, and patient selection, are discussed. The building block procedures include aesthetic scar placement, parenchymal closure, deepithelialization, and donut therapeutic mastopexy, which are described in detail. CONCLUSIONS: Oncoplastic breast surgery techniques and clinical reasoning build on one another, allowing a surgeon to move from level I to level II oncoplastic procedures. Even the most basic level I breast conservation oncoplastic skills can improve a patient's cosmetic outcome and are easily learned by a general surgeon. PMID- 29968025 TI - 'Nudging' Surgeons and Patients to De-Escalation of Surgery for Breast Cancer. PMID- 29968026 TI - Select Choices in Benign Breast Disease: An Initiative of the American Society of Breast Surgeons for the American Board of Internal Medicine Choosing Wisely(r) Campaign. AB - BACKGROUND: Up to 50% of all women encounter benign breast problems. In contrast to breast cancer, high-level evidence is not available to guide treatment. Management is therefore largely based on individual physician experience/training. The American board of internal medicine (ABIM) initiated its Choosing Wisely(r) campaign to promote conversations between patients and physicians about challenging the use of tests or procedures which may not be necessary. The American society of breast surgeons (ASBrS) Patient safety and quality committee (PSQC) chose to participate in this campaign in regard to the management of benign breast disease. METHODS: The PSQC solicited initial candidate measures. PSQC surgeons represent a wide variety of practices. The resulting measures were ranked by modified Delphi appropriateness methodology in two rounds. The final list was approved by ASBrS and endorsed by the ABIM. RESULTS: The final five measures are as follows. (1) Don't routinely excise areas of pseuodoangiomatous stromal hyperplasia (PASH) of the breast in patients who are not having symptoms from it. (2) Don't routinely surgically excise biopsy proven fibroadenomas that are < 2 cm. (3) Don't routinely operate for a breast abscess without an initial attempt to percutaneously aspirate. (4) Don't perform screening mammography in asymptomatic patients with normal exams who have less than a 5-years life expectancy. (5) Don't routinely drain nonpainful, fluid filled cysts. CONCLUSIONS: The ASBrS Choosing Wisely(r) measures that address benign breast disease management are easily accessible to patients via the internet. Consensus was reached by PSQC regarding these recommendations. These measures provide guidance for shared decision-making. PMID- 29968027 TI - Effect of Primary Breast Tumor Location on Axillary Nodal Positivity. AB - BACKGROUND: Variables such as tumor size, histology, and grade, tumor biology, presence of lymphovascular invasion, and patient age have been shown to impact likelihood of nodal positivity. The aim of this study is to determine whether primary location of invasive disease within the breast is associated with nodal positivity. PATIENTS AND METHODS: Patients with invasive breast cancer undergoing axillary staging from 2010 to 2014 were identified from the National Cancer Data Base. Rates of axillary nodal positivity by primary tumor locations were compared, and multivariable analysis performed using logistic regression to control for factors known to impact nodal positivity. RESULTS: A total of 599,722 patients met inclusion criteria. Likelihood of nodal positivity was greatest with primary tumors located in the nipple (43.8%), followed by multicentric disease (40.8%), central breast lesions (39.4%), and axillary tail lesions (38.4%). Tumor location remained independently associated with nodal positivity on multivariable analysis adjusting for variables known to affect nodal positivity with odds ratio 2.8 for tumors in the nipple [95% confidence interval (CI) 2.5-3.1], 2.2 for central breast (95% CI: 2.2-2.3), and 2.7 for axillary tail (95% CI: 2.4-2.9). When restricted to patients with clinically negative nodes (n = 430,949), a similar association was seen. CONCLUSION: Patients with invasive breast cancer located in the nipple, central breast, and axillary tail have the highest risk of positive axillary lymph nodes independent of patient age, tumor grade, biologic subtype, histology, and size. This should be considered along with other factors in preoperative counseling and decision-making regarding plans for axillary lymph node staging. PMID- 29968028 TI - Lymph Node Status in Breast Cancer Does Not Predict Tumor Biology. AB - BACKGROUND/OBJECTIVE: The 21-gene Oncotype DX(r) Breast Recurrence Score(r) (RS) assay has been prospectively validated as prognostic and predictive in node negative, estrogen receptor-positive (ER+)/HER2- breast cancer patients. Less is known about its prognostic role in node-positive breast cancer. We compared RS results among patients with lymph node-negative (N0), micrometastatic (N1mi), and macrometastatic (N+) breast cancer to determine if nodal metastases are associated with more aggressive biology, as determined by RS. METHODS: Overall, 610,350 tumor specimens examined by the Genomic Health laboratory from February 2004 to August 2017 were studied. Histology was classified centrally, while lymph node status was determined locally. RS distribution (low: < 18; intermediate: 18 30; high: >= 31) was compared by nodal status. RESULTS: Eighty percent (n = 486,013) of patients were N0, 4% (n = 24,325) were N1mi, 9% (n = 56,100) were N+, and 7% (n = 43,912) had unknown nodal status. Mean RS result was 18, 16.7, 17.3 and 18.9 in the N0, N1mi, N+, and unknown groups, respectively. An RS >= 31 was seen in 10% of N0 patients, 7% of N1mi patients, and 8.0% of N+ patients. The likelihood of an RS >= 31 in N1mi and N+ patients varied with tumor histology, with only 2% of patients with classic infiltrating lobular cancer having an RS >= 31, versus 7-9% of those with ductal carcinoma. CONCLUSIONS: RS distribution among N0, N1mi, and N+ patients is similar, suggesting a spectrum of biology and potential chemotherapy benefit exists among node-negative and node-positive ER+/HER2- breast cancer patients. If RxPONDER does not show a chemotherapy benefit in N+ patients with a low RS result, our findings indicate that substantial numbers of patients could be spared the burden of chemotherapy. PMID- 29968029 TI - Axillary Nodal Evaluation in Elderly Breast Cancer Patients: Potential Effects on Treatment Decisions and Survival. AB - BACKGROUND: Recent studies suggest that surgical lymph node (LN) evaluation may be omitted in select elderly breast cancer patients as it may not influence adjuvant therapy decisions. To evaluate differences in adjuvant therapy receipt and overall survival (OS), we compared clinically node-negative (cN0) elderly patients who did and did not undergo axillary surgery. METHODS: Patients aged >=70 years in the National Cancer Database (2004-2014) with cT1-3, cN0 breast cancer were divided into two cohorts-those with surgical LN evaluation (one or more nodes removed) and those without (no nodes removed). Propensity scores were used to match patients based on age, year of diagnosis, tumor grade, cT stage, estrogen receptor status, and Charlson-Deyo comorbidity score. A Cox proportional hazards model was used to estimate the effect of LN surgery on OS. RESULTS: Overall, 133,778 patients were matched, of whom 102,247 patients (76.4%) underwent nodal surgery. Patients undergoing nodal surgery were more likely to receive chemotherapy (pN1-3: 22.2%; pN0: 5.8%; cN0-no nodal surgery: 2.8%; p < 0.001), radiation (pN1-3: 49.7%; pN0: 47.5%; cN0-no nodal surgery: 26%; p < 0.001), and endocrine therapy (pN1-3: 72%; pN0: 58.5%; cN0-no nodal surgery: 46.5%; p < 0.001). After adjustment for known covariates, patients who did not undergo nodal surgery had a worse OS (hazard ratio 1.66, 95% confidence interval 1.61-1.70). CONCLUSIONS: For elderly cN0 breast cancer patients, axillary surgery was associated with higher rates of adjuvant therapy and improved OS. A selective approach to omitting nodal surgery should be considered in elderly patients with cN0 breast cancer as axillary staging may influence subsequent treatment decisions and long-term outcomes. PMID- 29968030 TI - Intraoperative Radiation Therapy (IORT): A Series of 1000 Tumors. AB - BACKGROUND: Two prospective, randomized trials, TARGIT-A and ELIOT, have shown intraoperative radiation therapy to be a safe alternative, with a low-risk of local recurrence, compared with whole breast radiation therapy, following breast conserving surgery, for selected low-risk patients. We report the first 1000 tumors treated with this modality at our facility. METHODS: A total of 1000 distinct breast cancers in 984 patients (16 bilateral) were treated with breast conserving surgery and X-ray IORT from June 2010 to August 2017. Patients were enrolled in an IORT registry trial. Local recurrence was the primary endpoint. RESULTS: There have been 28 ipsilateral local recurrences, ten DCIS and 18 invasive. Four local recurrences were within the IORT field, 13 outside of the IORT field but within the same quadrant as the index cancer, and 11 were new cancers in different quadrants. There have been four regional nodal recurrences and one distant recurrence. There have been no breast cancer related deaths and 14 non-breast cancer deaths. With a median follow-up of 36 months, Kaplan-Meier analysis projects 3.9% of patients will recur locally at 4 years. This includes all ipsilateral events in all quadrants. CONCLUSIONS: The local, regional, and distant recurrence rates observed in this trial were comparable to those of the prospective randomized TARGIT-A and ELIOT trials. The low complication rates previously reported by our group as well as the low recurrence rates reported in this study support the cautious use and continued study of X-ray IORT in women with low-risk breast cancer. PMID- 29968032 TI - Outcomes of Autologous Fat Grafting in Mastectomy Patients Following Breast Reconstruction. AB - BACKGROUND: Autologous fat grafting (AFG) is utilized for cosmetic improvement of the reconstructed breast following mastectomy. Fat necrosis (FN), a benign complication of AFG, can raise suspicion of malignancy and require further evaluation. OBJECTIVE: The aim of this study was to determine the incidence of FN in patients who have undergone AFG following mastectomy and reconstruction, and to identify factors contributing to FN. METHODS: A retrospective chart review was conducted of all patients who received AFG following mastectomy and reconstruction at our institution between 2011 and 2016, with a minimum 6-month follow-up period. Patient information, operative details, receipt of radiation, complications, and incidence of cancer recurrence were collected. RESULTS: A total of 171 patients were included in this study. AFG was performed by seven surgeons. Patients received an average of 1.18 treatments, with average follow-up of 26 months. Eighteen patients (10.5%) developed FN an average of 3.4 months following AFG. Patients with a larger volume injected at initial session (p = 0.044) and longer length of follow-up (p = 0.026) had significant increases in risk of developing FN. Core needle biopsy was performed in seven patients and two patients required excision. The rate of cancer recurrence was 1.7% for all patients and 0% in the AFG cohort. CONCLUSIONS: Increased risk of FN following AFG is associated with greater volume injected at the initial session and higher incidence over time. Although AFG is oncologically safe, patients should be counseled on the 10.5% incidence of FN presenting as a palpable abnormality, and the approximately 5% chance of requiring biopsy or excision. PMID- 29968031 TI - Timing and Delays in Breast Cancer Evaluation and Treatment. AB - BACKGROUND: Even small delays in the treatment of breast cancer are a frequently expressed concern of patients. Knowledge about this subject is important for clinicians to counsel patients appropriately and realistically, while also optimizing care. Although data and quality measures regarding time to chemotherapy and radiotherapy have been present for some time, data regarding surgical care are more recent and no standard exists. This review was written to discuss our current knowledge about the relationship of treatment times to outcomes. METHODS: The published medical literature addressing delays and optimal times to treatment was reviewed in the context of our current time-dependent standards for chemotherapy and radiotherapy. The surgical literature and the lack of a time-dependent surgical standard also were discussed, suggesting a possible standard. RESULTS: Risk factors for delay are numerous, and tumor doubling times are both difficult to determine and unhelpful to assess the impact of longer treatment times on outcomes. Evaluation components also have a time cost and are inextricable from the patient's workup. Although the published literature has lack of uniformity, optimal times to each modality are strongly suggested by emerging data, supporting the current quality measures. Times to surgery, chemotherapy, and radiotherapy all have a measurable impact on outcomes, including disease-free survival, disease-specific survival, and overall survival. CONCLUSIONS: Delays have less of an impact than often thought but have a measurable impact on outcomes. Optimal times from diagnosis are < 90 days for surgery, < 120 days for chemotherapy, and, where chemotherapy is administered, < 365 days for radiotherapy. PMID- 29968033 TI - The Changing Paradigms for Breast Cancer Surgery: Performing Fewer and Less Invasive Operations. AB - Historically, through the conduct of prospective clinical trials, breast cancer surgeons have performed less radical breast and axillary surgeries with no survival decrement to our patients. Currently, other opportunities exist for the treating breast surgeon to do less. Possibilities include active surveillance for ductal carcinoma in situ, ablative therapy for small primary breast cancers, selective omission of a sentinel node biopsy, and selective elimination of breast surgery after neoadjuvant systemic therapy. Breast surgeons must be leaders in the development and testing of effective therapy with the least intervention possible. PMID- 29968034 TI - Isomerases and epimerases for biotransformation of pentoses. AB - Pentoses represent monosaccharides with five carbon atoms. They are organized into two main groups, aldopentoses and ketopentoses. There are eight aldopentoses and four ketopentoses and each ketopentose corresponds to two aldopentoses. Only D-xylose, D-ribose, and L-arabinose are natural sugars, but others belong to rare sugars that occur in very small quantities in nature. Recently, rare pentoses attract much attention because of their great potentials for commercial applications, especially as precursors of many important medical drugs. Pentoses Izumoring strategy provides a complete enzymatic approach to link all pentoses using four types of enzymes, including ketose 3-epimerases, aldose-ketose isomerases, polyol dehydrogenases, and aldose reductases. At least 10 types of epimerases and isomerases have been used for biotransformation of all aldopentoses and ketopentoses, and these enzymes are reviewed in detail in this article. PMID- 29968035 TI - The role of laboratory-scale bioreactors at the semi-continuous and continuous microbiological and biotechnological processes. AB - Laboratory-scale bioreactors represent an important part of microbiological, biotechnological, and biochemical researches. The small volume bioreactors enable the biomass growth, extracellular metabolite production, solid-state fermentation, and biocatalytic processes in a controlled open system. Using the lab-scale bioreactors, the processes which were optimized in experiments can be scaled up to a pilot level. In turn, the manufacturing scale processes can be scaled down to study the heterogeneity of the system and its effect on the producer. This mini-review is focused on a short description of features of the most popular designs of continuous and semi-continuous bioreactors applied at the present time as well as their application area. PMID- 29968036 TI - Fitting replacement of signal peptide for highly efficient expression of three penicillin G acylases in E. coli. AB - High level expression of penicillin G acylase (PGA) in Escherichia coli is generally constricted by a complex maturation process and multiple limiting steps. In this study, three PGAs isolated from Providencia rettgeri (PrPGA), Alcaligenes faecalis (AfPGA), and Achromobacter xylosoxidans (AxPGA) were efficiently expressed in E. coli by replacing with applicable signal peptide. Different bottlenecks of the expression process were analyzed for PrPGA, AfPGA, and AxPGA. Subsequently, five efficient signal peptides, including OmpA, pelB, Lpp, PhoA, and MalE, were used to replace the original signal peptides of the PGAs. With respect to AfPGA and AxPGA, translocation was the primary limitation, and the use of pelB signal peptide effectively overcame this barrier. For PrPGA, which was almost not expressed in wild type, the translation initiation efficiency was optimized by replacing with MalE signal peptide. In addition, low temperature (20 degrees C) slowed down the transcription and translation, thereby facilitating the posttranslational process and preventing the formation of inclusion bodies. Furthermore, combined induction with IPTG and arabinose not only enhanced the cell density but also remarkably improved the expression of PGAs. Final specific activities of the three PGAs reached 2100 (PrPGA), 9200 (AfPGA), and 1400 (AxPGA) U/L/OD600, respectively. This simple and robust strategy by fitting replacement of signal peptide might dramatically improve the expression of PGAs from various bacteria, which was significant in the production of many valuable beta-lactam antibiotics. PMID- 29968037 TI - Depression and Victimization in a Community Sample of Bisexual and Lesbian Women: An Intersectional Approach. AB - Mental health inequities among bisexual and lesbian women are well-documented. Compared to heterosexual women, both bisexual and lesbian women are more likely to report lifetime depressive disorders, with bisexual women often faring the worst on mental health outcomes. Risk factors for depression, such as victimization in childhood and adulthood, are also more prevalent among bisexual women. Less is known about the intersection of racial/ethnic and sexual minority identities, and how depression and victimization may differ across these multiple, co-occurring identities. Data were from Wave 3 of the Chicago Health and Life Experiences of Women study, an 18-year, community-based longitudinal study of sexual minority women's health. We constructed a six-category "intersection" variable based on sexual identity and race/ethnicity to examine group differences in lifetime depression and victimization. We tested childhood and adult victimization as moderators of lifetime depression (n = 600). A majority (58.2%) of the total sample met criteria for lifetime depression. When considering the intersection of race/ethnicity and sexual identity, Black bisexual and Black lesbian women had significantly lower odds of depression than White lesbian women, despite their higher reports of victimization. Latina bisexual and lesbian women did not differ from White lesbians on depression. Victimization did not moderate the association between the intersection variable and depression. More research is needed to better understand risk and protective factors for depression among racially/ethnically diverse sexual minority women (SWM). We highlight the need to deliberately oversample SWM of color to accomplish this goal. PMID- 29968038 TI - Molecular phylogeny of Blastocystis isolates from wild rodents captured in Indonesia and Japan. AB - Blastocystis sp. is a common intestinal protist found worldwide in a variety of animals, including humans. Currently, 17 subtypes (STs) of Blastocystis isolates from mammalian and avian host species have been reported based on the small subunit ribosomal RNA gene (SSU rDNA). Among these, human Blastocystis were only identified among STs 1-9. Except ST9, all other STs comprised isolates from humans and other animal species. Entire sequence data of the SSU rDNA of nine Blastocystis isolates from laboratory rats or guinea pigs previously showed ST4, whereas Blastocystis isolates from wild rodents have not been addressed genetically. In this study, Blastocystis infection in wild rodents was surveyed in Indonesia and Japan, and 11 and 12 rodent Blastocystis parasites were obtained from Rattus exulans and R. novercious, respectively. All new Blastocystis isolates from wild rodents were identified as ST4 based on the SSU rDNA sequences. The best tree inferred with the entire sequences of the SSU rDNA of all ST4 isolates including 17 data registered in GenBank clearly showed monophyletic ST4A and ST4B clades. Although ST4 isolates from laboratory rats were separated into these two clades, all Blastocystis isolates from wild rodents in the present study were positioned into the clade ST4A and further separated into two sub-clusters within the clade ST4A according to the location of the host species. Considering the fact that laboratory rats were susceptible to both ST4A and ST4B, separation of the monophyletic sub-clusters of Blastocystis isolates from Indonesian Polynesian rats and Japanese brown rats may indicate the presence of geographical variations rather than a host-specific separation. In either way, the robust host preference to rodent species of ST4 Blastocystis was also confirmed. PMID- 29968039 TI - BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma. AB - PURPOSE: Primary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL. METHODS: Pretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients' statuses for various markers, which were also evaluated for associations with survival outcomes. RESULTS: According to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of >= 40%), 33 cases (41.8%) were positive for BCL2 (expression of >= 70%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B cell subtypes. Furthermore, MYC positivity was not associated with overall survival (p = 0.369) or progression-free survival (PFS) (p = 0.253). However, BCL2 positivity was significantly associated with poor overall survival (p = 0.039) and PFS (p = 0.036). Co-expression of MYC and BCL2 was not associated with survival. CONCLUSION: Our data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL. PMID- 29968040 TI - Clinical features, treatments and long-term follow-up outcomes of spinal chondroblastoma: report of 13 clinical cases in a single center. AB - PURPOSE: Chondroblastoma (CB) in the spine is extremely rare and there is little published information regarding this subject. We attempt to explore the clinical features of spinal CB and address the importance of total resection, especially total en bloc spondylectomy (TES) for the treatment of spinal CB. METHODS: Clinical data of 13 consecutive CB patients who received surgical treatment in our center between January 2006 and December 2016 were reviewed retrospectively. Recurrence-free survival (RFS) was estimated by Kaplan-Meier method and Log-rank test. RESULTS: The 13 CB patients included 9 men and 4 women with a mean age of 32 years. The lesions were located in the cervical spine in 2 cases, thoracic spine in 5 cases, and lumbar spine in 6 cases. All the patients were treated surgically using either curettage, piecemeal total resection, or TES. Postoperative radiotherapy was administered in 2 cases. The mean follow-up period was 41.6 months. Relapse occurred in 3 (23.1%) cases, resulting in one death in 60 months. The mean RFS duration was 28.7 months. CONCLUSIONS: CB predominantly affects males and various age groups. Spinal CB more commonly involves the thoracic and lumbar segments. Spinal CB usually appears as an aggressive and destructive bony lesion with a soft tissue mass on imaging, forming compression on the spinal cord in some cases. Recurrence is not uncommon for spinal CB. Total resection, especially TES, has been confirmed as a powerful method to control the disease, while curettage is more likely to associate with local recurrence. Radiotherapy does not seem to reduce local recurrence. PMID- 29968042 TI - Development and Characterization of Dapsone Cocrystal Prepared by Scalable Production Methods. AB - In this study, the formation of caffeine/dapsone (CAF/DAP) cocrystals by scalable production methods, such as liquid-assisted grinding (LAG) and spray drying, was investigated in the context of the potential use of processed cocrystal powder for pulmonary delivery. A CAF/DAP cocrystal (1:1 M ratio) was successfully prepared by slow evaporation from both acetone and ethyl acetate. Acetone, ethyl acetate, and ethanol were all successfully used to prepare cocrystals by LAG and spray drying. The powders obtained were characterized by X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetry (TGA), and Fourier transform infrared spectroscopy (FTIR). Laser diffraction analysis indicated a median particle size (D50) for spray-dried powders prepared from acetone, ethanol, and ethyl acetate of 5.4 +/- 0.7, 5.2 +/- 0.1, and 5.1 +/- 0.0 MUm respectively, which are appropriate sizes for pulmonary delivery by means of a dry powder inhaler. The solubility of the CAF/DAP cocrystal in phosphate buffer pH 7.4, prepared by spray drying using acetone, was 506.5 +/- 31.5 MUg/mL, while pure crystalline DAP had a measured solubility of 217.1 +/- 7.8 MUg/mL. In vitro cytotoxicity studies using Calu-3 cells indicated that the cocrystals were not toxic at concentrations of 0.1 and of 1 mM of DAP, while an in vitro permeability study suggested caffeine may contribute to the permeation of DAP by hindering the efflux effect. The results obtained indicate that the CAF/DAP cocrystal, particularly when prepared by the spray drying method, represents a possible suitable approach for inhalation formulations with applications in pulmonary pathologies. PMID- 29968041 TI - Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology. AB - This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40 degrees C/75% RH. In summary, HME is a novel technique for developing CTDDS. PMID- 29968043 TI - First report of an Asian family with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) revealed with the germline mutation of the APC exon 1B promoter region. AB - A 48-year-old Japanese female with left hypochondralgia presented at our hospital. Esophagogastroduodenoscopy (EGD) revealed gastric cancers and carpeting fundic gland polyposis (FGPs) without Helicobacter pylori infection. Computed tomography showed multiple liver metastases. Total colonoscopy revealed a colonic tubular adenoma but not polyposis. She was diagnosed as having advanced gastric cancer with liver metastasis and received chemotherapy. Her mother had died from gastric cancer, and her elderly brother and niece had FGPs as revealed by EGD. Thus, the pedigree was diagnosed as gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Germline mutation analysis exhibited a point mutation in exon1B of the APC gene (c.-191T > C). Adenocarcinoma showed a gastric mucinous phenotype and was positive for a somatic mutation of p53, suggesting that p53 mutation may play a role in FGPs carcinogenesis. This is the first family with GAPPS in Asia in whom germline mutation of APC exon 1B has been detected. PMID- 29968044 TI - Acquired resistance to cancer immunotherapy. AB - In recent times, advances in cancer immunotherapy have yielded impressive, durable clinical responses in patients with varied subtypes of cancer. However, a significant proportion of patients who initially demonstrate encouraging tumor regression develop resistance and progress over time. The identification of novel therapeutic approaches to overcome resistance may result in significantly improved clinical outcomes and remains an area of high scientific priority. This review aims to summarize the current knowledge regarding the role of both tumor intrinsic and tumor-extrinsic factors in the development of resistance to cancer immunotherapy and to discuss current and possible future therapeutic strategies targeting these mechanisms. PMID- 29968045 TI - The T-win(r) technology: immune-modulating vaccines. AB - The T-win(r) technology is an innovative investigational approach designed to activate the body's endogenous anti-regulatory T cells (anti-Tregs) to target regulatory as well as malignant cells. Anti-Tregs are naturally occurring T cells that can directly react against regulatory immune cells because they recognize proteins that these targets express, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase, arginase, and programmed death ligand 1 (PD-L1). The T-win(r) technology is characterized by therapeutic vaccination with long peptide epitopes derived from these antigens and therefore offers a novel way to target genetically stable cells with regular human leukocyte antigen expression in the tumor microenvironment. The T-win(r) technology thus also represents a novel way to attract pro-inflammatory cells to the tumor microenvironment where they can directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens. The modification of an immune regulatory environment into a pro inflammatory milieu potentiates effective anti-tumor T cell responses. Many regulatory immune cells may be reverted into effector cells given the right stimulus. Because T-win(r) technology is based on the immune-modulatory function of the vaccines, the vaccines activate both CD4 and CD8 anti-Tregs. Of importance, in clinical trials, vaccinations against IDO or PD-L1 to potentiate anti-Tregs have so far proved to be safe, with minimal toxicity. PMID- 29968046 TI - The role of EIF1AX in thyroid cancer tumourigenesis and progression. AB - PURPOSE: The EIF1AX gene was recently described as a new thyroid cancer-related gene. Its mutations were mainly reported in poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC), but also in well-differentiated thyroid cancer (WDTC) and in benign thyroid lesions, although less frequently. Our aim was to address whether EIF1AX mutations are present in the different stages of thyroid tumourigenesis (from hyperplasia to well-differentiated and to poorly differentiated/undifferentiated lesions), and to clarify its role in this process. METHODS: We analysed the EIF1AX gene in a series of 16 PDTC and ATC cases with coexistent well-differentiated regions and/or benign lesions. In EIF1AX mutant cases we also assessed the presence of RAS genes mutations. RESULTS: We identified the mutation p.Ala113_splice in the EIF1AX gene in two PDTCs (neither present in the well-differentiated counterparts nor in the benign areas). One of these tumours also evidenced the mutation p.Glu61Arg in NRAS in both poorly and well-differentiated regions, further suggesting that the EIF1AX p.Ala113_splice mutation could be associated with tumoural progression. In another patient we did not find any EIF1AX alteration in the PDTC component, but we detected the EIF1AX p.Gly6_splice mutation in the PTC area (both regions were RAS wild-type). This mutation did not seem to be related with dedifferentiation. CONCLUSIONS: According to our results, distinct mutations on EIF1AX may be related to different phenotypes/behaviours. Despite being a small series, which reflects the difficulty in retrieving PDTC and ATC surgical samples with well differentiated and/or benign areas, our study may provide new insights into thyroid cancer tumourigenesis and dedifferentiation. PMID- 29968047 TI - Quick Microwave Assisted Synthesis and In Vitro Imaging Application of Oxygen Doped Fluorescent Carbon Dots. AB - In this paper, a fast and simplest one-pot tactic was used to synthesis fluorescent oxygen doped carbon dots from Tween-20 (TTO-CDs) is reported. The TTO CDs were microwavically synthesized by using Tween-20 as both the carbon precursor and the oxygen dopant as well. The surface morphology, crystalline and/or amorphous nature, composition and optical assets of synthesized TTO-CDs were studied by means of existing techniques. From the results, it was confirmed that the as-synthesized TTO-CDs are amorphous in nature, monodispersed, sphere shaped and the typical particle size range is 5 +/- 1.5 nm. The synthesized TTO CDs emits strong blue fluorescence at 390 nm under excitation of 335 nm. Most interestingly, the excitation dependent emission property of synthesized TTO-CDs was exposed from fluorescence results. The synthesized TTO-CDs have quantum yield of about 14% against quinine sulfate as reference standard. The biotoxicity of synthesized TTO-CDs on HeLa cells was assessed through cytotoxicity assay. These results implied that the fluorescent TTO-CDs showed less biotoxicity, and further which was efficaciously applied as a multicolor staining and bioimaging probe for the confocal imaging of HeLa cells. PMID- 29968048 TI - Saponin-adjuvanted vaccine protects chickens against velogenic Newcastle disease virus. AB - Despite extensive vaccination campaigns, Newcastle disease virus (NDV) remains endemic in many countries worldwide, and factors that contribute to this failure include mismatched vaccines, partial immunization, and poor husbandry practices. In order to overcome the problem of genetic divergence between circulating field strains and vaccine strains, we saponin-adjuvanted an Egyptian field strain and assessed its safety and immunogenicity in chickens. Immunization of chickens with the vaccine followed by challenge with a velogenic reference strain revealed the potential of the saponin-adjuvanted vaccine to induce a strong immune response that resulted in complete protection of chickens. Importantly, in vaccinated chickens, virus shedding was abolished, providing an added advantage over the currently available commercial live-attenuated and inactivated vaccines, which are unable to prevent shedding. A histopathological investigation demonstrated that the vaccinated chickens had less-severe lesions than challenged unvaccinated and mock-vaccinated chickens. We propose using this formulation as an alternative and improved NDV vaccine platform that can be exploited to control disease not only in Egypt but also in other disease-endemic countries. PMID- 29968049 TI - Keratosis Punctata of the Palmar Creases. PMID- 29968050 TI - Time of Day is Associated with Opioid Prescribing for Low Back Pain in Primary Care. PMID- 29968051 TI - Eliciting the Patient's Agenda- Secondary Analysis of Recorded Clinical Encounters. AB - BACKGROUND: Eliciting patient concerns and listening carefully to them contributes to patient-centered care. Yet, clinicians often fail to elicit the patient's agenda and, when they do, they interrupt the patient's discourse. OBJECTIVE: We aimed to describe the extent to which patients' concerns are elicited across different clinical settings and how shared decision-making tools impact agenda elicitation. DESIGN AND PARTICIPANTS: We performed a secondary analysis of a random sample of 112 clinical encounters recorded during trials testing the efficacy of shared decision-making tools. MAIN MEASURES: Two reviewers, working independently, characterized the elicitation of the patient agenda and the time to interruption or to complete statement; we analyzed the distribution of agenda elicitation according to setting and use of shared decision-making tools. KEY RESULTS: Clinicians elicited the patient's agenda in 40 of 112 (36%) encounters. Agendas were elicited more often in primary care (30/61 encounters, 49%) than in specialty care (10/51 encounters, 20%); p = .058. Shared decision-making tools did not affect the likelihood of eliciting the patient's agenda (34 vs. 37% in encounters with and without these tools; p = .09). In 27 of the 40 (67%) encounters in which clinicians elicited patient concerns, the clinician interrupted the patient after a median of 11 seconds (interquartile range 7-22; range 3 to 234 s). Uninterrupted patients took a median of 6 s (interquartile range 3-19; range 2 to 108 s) to state their concern. CONCLUSIONS: Clinicians seldom elicit the patient's agenda; when they do, they interrupt patients sooner than previously reported. Physicians in specialty care elicited the patient's agenda less often compared to physicians in primary care. Failure to elicit the patient's agenda reduces the chance that clinicians will orient the priorities of a clinical encounter toward specific aspects that matter to each patient. PMID- 29968052 TI - A human touch. PMID- 29968053 TI - Trends and regional variation in rates of orthopaedic surgery in Germany: the impact of competition. AB - Competition in hospital services has been fostered in an increasing number of OECD countries with the goal that hospitals improve quality and/or efficiency. With the same intention competition has been promoted in Germany when introducing a system of prospective payments based on diagnosis-related groups (DRGs) in 2003. Beyond its intended effects, however, the reform led to a substantial increase in hospital activity, particularly for orthopaedic surgery. To shed more light on these developments, this paper analyses the relationship between the rates of certain orthopaedic surgical procedures and hospital competition across and within each of Germany's 402 districts. We measured competition with the Herfindahl-Hirschman Index (HHI) based on market shares for hip replacements, knee replacements and spine surgeries. Using spatial panel regression, which allows for spatial dependency and unobserved individual heterogeneity, we found that the rate of hip and knee replacements rose as market concentration increased. A potential explanation might be that hospitals specialize in these particular procedures. PMID- 29968054 TI - Redescription of Philometra pellucida (Jagerskiold, 1893) (Nematoda: Philometridae) parasitic in the abdominal cavity of the blackspotted puffer Arothron nigropunctatus (Bloch & Schneider) (Teleostei: Tetraodontidae) off Australia and Japan. AB - The nematode Philometra pellucida (Jagerskiold, 1893) (Philometridae) is redescribed from female specimens obtained from the abdominal cavity of the marine tetraodontiform fish (blackspotted puffer) Arothron nigropunctatus (Bloch & Schneider) (Tetraodontidae) off Lizard Island, Australia and off Okinawa, Japan. This is just the second record of this parasite since its description 125 years ago. Light and scanning electron microscopical examination of these nematodes revealed some taxonomically important, previously unreported morphological features, such as the number and arrangement of cephalic papillae, presence of the oesophageal cell nucleus and the size of first-stage larvae in the uterus. This new report of P. pellucida infecting A. nigropunctatus off Australia and Japan represents new host and geographical records. A key to the species of Philometra Costa, 1845 parasitising tetraodontiform fishes is provided. PMID- 29968055 TI - Two new species of Bacciger Nicoll, 1914 (Trematoda: Faustulidae) in species of Herklotsichthys Whitley (Clupeidae) from Queensland waters. AB - Two new species of Bacciger Nicoll, 1914 (Faustulidae) are described infecting clupeids collected from the waters off Queensland, Australia; Bacciger minor n. sp. is described from Herklotsichthys castelnaui (Ogilby) in Moreton Bay, southern Queensland and Bacciger major n. sp. is described from Herklotsichthys quadrimaculatus (Ruppell) collected off Lizard Island, on the northern Great Barrier Reef. The two species both differ from previously described species of Bacciger in the combination of their generally elongate bodies, an entire rather than deeply lobed ovary, vitelline follicles that reach to at least the intestinal bifurcation, instead of restricted to further posteriorly but principally distributed in the hindbody, and intestinal caeca extending posteriorly well past the ventral sucker. The two new species have non overlapping size ranges and differ in their sucker ratios, the distribution of the vitelline follicles and in the shape of the cirrus-sac. ITS2 and 28S rDNA sequence data distinguish the two new species unambiguously. Phylogenetic analysis of available 28S data show they are most closely related to Pseudobacciger cheneyae Sun, Bray, Yong, Cutmore & Cribb, 2014, also recorded off Lizard Island. These are the first faustulids reported from species of Herklotsichthys Whitley, but overall members of the Clupeidae undoubtedly harbours the richest faustulid fauna of any fish family. Baccigeroides ovatus (Price, 1934) n. comb. is proposed for Bacciger ovatus (Price, 1934) Bray & Gibson, 1980 (syn. B. opisthonema Nahhas & Cable, 1964) based on the position of the genital pore being far anteriorly removed from the ventral sucker. PMID- 29968056 TI - Two species of Neometadena Hafeezullah & Siddiqi, 1970 (Digenea: Cryptogonimidae) from Moreton Bay, Australia, including the description of Neometadena paucispina n. sp. from Australian Lutjanidae. AB - A survey of the trematode fauna of lutjanid fishes off the east coast of Queensland (QLD), Australia revealed the presence of two species of Neometadena Hafeezullah & Siddiqi, 1970 (Digenea: Cryptogonimidae). Neometadena paucispina n. sp. is described from the intestine and pyloric caeca of Lutjanus fulviflamma (Forsskal) and L. russellii (Bleeker) from Moreton Bay, in southeast QLD. Specimens of the type- and only other species, N. ovata (Yamaguti, 1952) Miller & Cribb, 2008, were recovered from L. carponotatus (Richardson), L. fulviflamma, L. fulvus (Forster), L. russellii, and L. vitta (Quoy & Gaimard) off Lizard Island, on the northern Great Barrier Reef (GBR). Neometadena paucispina is distinguished from N. ovata in having fewer oral spines (55-65 vs 67-80). Alignment of novel molecular data for these two taxa revealed that they differ consistently by 13 nucleotides (1.5%) over the partial large subunit (LSU), 34 nucleotides (6.6%) over the internal transcribed spacer 1 (ITS1), 0 nucleotides over the 5.8S, and 21 nucleotides (7.3%) over the ITS2 rDNA regions. Despite relatively large samples of L. carponotatus, L. fulviflamma and L. russellii from three distinct locations along the east coast of QLD (i.e. Moreton Bay in the south, Heron Island in central QLD and Lizard Island in northern QLD), these two species have been found at only one site each with neither species at Heron Island. These distributions are discussed in the context of the wide distribution of other cryptogonomid species in the same hosts elsewhere in the Indo-West Pacific. PMID- 29968057 TI - The Impact of the Affordable Care Act Young Adult Provision on Childbearing: Evidence From Tax Data. AB - We use panel U.S. tax data spanning 2008-2013 to study the impact of the Affordable Care Act (ACA) young adult provision on an important demographic outcome: childbearing. The impact is theoretically ambiguous: gaining insurance may increase access to contraceptive services while also reducing the out-of pocket costs of childbirth. Because employer-reported U.S. Wage and Tax Statements (W-2 forms) record access to employer-provided benefits, we can examine the impact of the coverage expansion by focusing on young adults whose parents have access to benefits. We compare those who are slightly younger than the age threshold with those who are slightly older. Our results suggest that the ACA young adult provision led to a modest decrease in childbearing. PMID- 29968058 TI - Maybe Next Month? Temperature Shocks and Dynamic Adjustments in Birth Rates. AB - We estimate the effects of temperature shocks on birth rates in the United States between 1931 and 2010. We find that days with a mean temperature above 80 degrees F cause a large decline in birth rates 8 to 10 months later. Unlike prior studies, we demonstrate that the initial decline is followed by a partial rebound in births over the next few months, implying that populations mitigate some of the fertility cost by shifting conception month. This shift helps explain the observed peak in late-summer births in the United States. We also present new evidence that hot weather most likely harms fertility via reproductive health as opposed to sexual activity. Historical evidence suggests that air conditioning could be used to substantially offset the fertility costs of high temperatures. PMID- 29968060 TI - ? PMID- 29968059 TI - Sampling Weights for Analyses of Couple Data: Example of the Demographic and Health Surveys. AB - In some surveys, women and men are interviewed separately in selected households, allowing matching of partner information and analyses of couples. Although individual sampling weights exist for men and women, sampling weights specific for couples are rarely derived. We present a method of estimating appropriate weights for couples that extends methods currently used in the Demographic and Health Surveys (DHS) for individual weights. To see how results vary, we analyze 1912 estimates (means; proportions; linear regression; and simple and multinomial logistic regression coefficients, and their standard errors) with couple data in each of 11 DHS surveys in which the couple weight could be derived. We used two measures of bias: absolute percentage difference from the value estimated with the couple weight and ratio of the absolute difference to the standard error using the couple weight. The latter shows greater bias for means and proportions, whereas the former and a combination of both measures show greater bias for regression coefficients. Comparing results using couple weights with published results using women's weights for a logistic regression of couple contraceptive use in Turkey, we found that 6 of 27 coefficients had a bias above 5 %. On the other hand, a simulation of varying response rates (27 simulations) showed that median percentage bias in a logistic regression was less than 3 % for 17 of 18 coefficients. Two proxy couple weights that can be calculated in all DHS surveys perform considerably better than either male or female weights. We recommend that a couple weight be calculated and made available with couple data from such surveys. PMID- 29968061 TI - Plant small RNAs: advancement in the understanding of biogenesis and role in plant development. AB - MAIN CONCLUSION: Present review addresses the advances made in the understanding of biogenesis of plant small RNAs and their role in plant development. We discuss the elaborate role of microRNAs (miRNAs) and trans-acting small interfering RNAs (ta-siRNAs) in various aspects of plant growth and development and highlight relevance of small RNA mobility. Small non-coding RNAs regulate various aspects of plant development. Small RNAs (sRNAs) of 21-24 nucleotide length are derived from double-stranded RNAs through the combined activity of several biogenesis and processing components. These sRNAs function by negatively regulating the expression of target genes. miRNAs and ta-siRNAs constitute two important classes of endogenous small RNAs in plants, which play important roles in plant growth and developmental processes like embryogenesis, organ formation and patterning, shoot and root growth, and reproductive development. Biogenesis of miRNAs is a multistep process which includes transcription, processing and modification, and their loading onto RNA-induced silencing complex (RISC). RISC-loaded miRNAs carry out post-transcriptional silencing of their target(s). Recent studies identified orthologues of different biogenesis components of novel and conserved small RNAs from different model plants. Although many small RNAs have been identified from diverse plant species, only a handful of them have been functionally characterized. In this review, we discuss the advances made in understanding the biogenesis, functional conservation/divergence in miRNA-mediated gene regulation, and the developmental role of small RNAs in different plant species. PMID- 29968062 TI - The tomato IQD gene SUN24 regulates seed germination through ABA signaling pathway. AB - MAIN CONCLUSION: Gene expression and functional analysis of the tomato IQD gene SUN24 revealed that it regulates seed germination through ABA signaling pathway. Ca2+ signaling plays crucial roles in diverse biological processes including ABA mediated seed germination. The plant-specific IQ67-Domain (IQD) proteins are hypothesized to regulate Ca2+ signaling and plant development through interactions with calmodulins (CaMs). Despite a few IQD genes have been identified to regulate herbivore resistance and plant growth and development, the molecular functions of most members in this gene family are not known. In this study, we characterized the role of the tomato IQD gene SUN24 in seed germination. Using pSUN24::GUS reporter lines and by quantitative reverse transcription PCR analysis, we show that SUN24 is mainly expressed in the roots, flowers, young fruits, seeds, and other young developing tissues, and its expression is repressed by ABA treatments. Functional analysis shows that knockdown of SUN24 expression by RNA interference delays seed germination, whereas overexpression of this IQD gene promotes germination. Further gene expression analysis reveals that SUN24 negatively regulates expression of two key ABA signaling genes Solanum lycopersicum ABA-insensitive 3 (SlABI3) and SlABI5 in germinating seeds. Moreover, SUN24, targeting to microtubule and nuclear bodies, can interact with four tomato CaMs (SlCaM1, 2, 3, and 6) in yeast cells. Our results demonstrate that SUN24 regulates seed germination through ABA signaling pathway, expanding our understanding of the roles of the IQD protein family members in plant physiological processes. PMID- 29968063 TI - Jasmonic acid to boost secondary growth in hemp hypocotyl. AB - MAIN CONCLUSION: The application of jasmonic acid results in an increased secondary growth, as well as additional secondary phloem fibres and higher lignin content in the hypocotyl of textile hemp (Cannabis sativa L.). Secondary growth provides most of the wood in lignocellulosic biomass. Textile hemp (Cannabis sativa L.) is cultivated for its phloem fibres, whose secondary cell wall is rich in crystalline cellulose with a limited amount of lignin. Mature hemp stems and older hypocotyls are characterised by large blocks of secondary phloem fibres which originate from the cambium. This study aims at investigating the role of exogenously applied jasmonic acid on the differentiation of secondary phloem fibres. We show indeed that the exogenous application of this plant growth regulator on young hemp plantlets promotes secondary growth, differentiation of secondary phloem fibres, expression of lignin-related genes, and lignification of the hypocotyl. This work paves the way to future investigations focusing on the molecular network underlying phloem fibre development. PMID- 29968064 TI - The Effects of Neighborhood Context on Exposure to Adverse Childhood Experiences (ACE) Among Adolescents Involved in the Juvenile Justice System: Latent Classes and Contextual Effects. AB - Adverse childhood experiences (ACEs) have been identified as a key risk factor associated with a wide range of negative life outcomes, including juvenile delinquency. Much less work has explored whether certain combinations of ACEs, or typologies of trauma, exist, and whether or not these subgroups are differentially associated with certain youth-level and/or community-level characteristics. The current study uses latent class analysis to examine ACE typologies among a sample of over 92,000 juvenile offenders between the ages of 10 and 18 in the state of Florida (52% male, 37.3% White, 46.8% Black, 15.9% Hispanic). Multilevel multinomial logistic regression is used to assess the relationship between both individual- and community-level factors and class membership. The findings suggest that a total of five distinct ACE typologies exist among the sample of juvenile offenders, and age, race, and sex were significantly associated with class membership. Additionally, controlling for individual-level characteristics, community-level measures of immigrant concentration, residential instability, and two separate measures of concentrated disadvantage and affluence were significantly related to class membership. This study contributes to the understanding of adverse childhood experiences, and adds to existing knowledge regarding the relationship between contextual factors and childhood abuse, maltreatment, and trauma. The identification of ACE subgroups with distinct characteristics may help guide prevention strategies and tailor treatment provided by the juvenile justice system. PMID- 29968065 TI - Critical Hopefulness Among Urban High School Students. AB - Psychological empowerment encompasses several key aspects of youth civic and sociopolitical development. Most research has focused on psychological empowerment's emotional component, which entails learned hopefulness about one's own ability to participate in and lead community change efforts. Fewer studies have assessed critical awareness of how social power operates-psychological empowerment's cognitive component. The confluence of these two components has been termed critical hopefulness. A complex relationship exists between these two components, and previous research has found relatively small proportions of participants reporting both high levels of critical awareness and simultaneously high levels of hopefulness about their ability to exert influence in the sociopolitical domain. The current study of urban high school students in the Northeastern U.S. (n = 389; 53.5% female) investigates heterogeneity according to these two components of psychological empowerment. Latent class cluster analyses were conducted and seven distinct groups of participants emerged. Students identifying as Hispanic/Latinx were more likely to be classified into a profile group exhibiting critical hopefulness. Differences were observed between psychological empowerment profile groups on self-reported levels of psychological sense of community, civic engagement, and social justice orientation. Furthermore, a larger proportion of this overall sample was classified into groups that exhibited critical hopefulness than in a previous study of adults. These findings provide useful insights for efforts to engage young people in civic life and to promote sociopolitical development. PMID- 29968068 TI - Lack of emotional gaze preferences using eye-tracking in remitted bipolar I disorder. AB - BACKGROUND: Bipolar disorder is associated with heightened and persistent positive emotion (Gruber in Curr Dir Psychol Sci 20:217-221, 2011; Johnson in Clin Psychol Rev 25:241-262, 2005). Yet little is known about information processing biases that may influence these patterns of emotion responding. METHODS: The current study adopted eye-tracking methodology as a continuous measure of sustained overt attention to monitor gaze preferences during passive viewing of positive, negative, and neutral standardized photo stimuli among remitted bipolar adults and healthy controls. Percentage fixation durations were recorded for predetermined areas of interest across the entire image presentation, and exploratory analyses were conducted to examine early versus late temporal phases of image processing. RESULTS: Results suggest that the bipolar and healthy control groups did not differ in patterns of attention bias. CONCLUSIONS: Findings provide insight into apparently intact attention processing despite disrupted emotional responding in bipolar disorder. PMID- 29968069 TI - Oviductal glycoprotein 1 (OVGP1) is expressed by endometrial epithelium that regulates receptivity and trophoblast adhesion. AB - PURPOSE: To study the regulation and functions of oviductal glycoprotein 1 (OVGP1) in endometrial epithelial cells. METHODS: Expression of OVGP1 in mouse endometrium during pregnancy and in the endometrial epithelial cell line (Ishikawa) was studied by immunofluorescence, Western blotting, and RT-PCR. Regulation of OVGP1 in response to ovarian steroids and human chorionic gonadotropin (hCG) was studied by real-time RT-PCR. OVGP1 expression was knockdown in Ishikawa cells by shRNA, and expression of receptivity associated genes was studied by real-time RT-PCR. Adhesion of trophoblast cell line (JAr) was studied by in vitro adhesion assays. RESULTS: OVGP1 was localized exclusively in the luminal epithelial cells of mouse endometrium at the time of embryo implantation. Along with estrogen and progesterone, hCG induced the expression of OVGP1 in Ishikawa cells. Knockdown of OVGP1 in Ishikawa cells reduced mRNA expression of ITGAV, ITGB3, ITGA5, HOXA10, LIF, and IL15; it increased the expression of HOXA11, MMP9, TIMP1, and TIMP3. Supernatants derived from OVGP1 knockdown Ishikawa cells reduced the adhesiveness of JAr cells in vitro. Expression of OVGP1 mRNA was found to be significantly lowered in the endometrium of women with recurrent implantation failure. CONCLUSION: OVGP1 is specifically induced in the luminal epithelium at the time of embryo implantation where it regulates receptivity-related genes and aids in trophoblast adhesion. PMID- 29968071 TI - Beneficial Effect of Silymarin in Pressure Overload Induced Experimental Cardiac Hypertrophy. AB - The present investigation was undertaken to study the effect of silymarin on cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) in Wistar rats. Silymarin was administered for 9 weeks at the end of which we evaluated hypertrophic, hemodynamic, non-specific cardiac markers, oxidative stress parameters, and determined mitochondrial DNA concentration. Hypertrophic control animals exhibited cardiac hypertrophy, altered hemodynamics, oxidative stress, and decreased mitochondrial DNA (mtDNA) concentration. Treatment with silymarin prevented cardiac hypertrophy, improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Docking studies revealed that silymarin produces maximum docking score with mitogen activated protein kinases (MAPK) p38 as compared to other relevant proteins docked. Moreover, PAAC-control rats exhibited significantly increased expression of MAPK p38beta mRNA levels which were significantly decreased by the treatment of silymarin. Our data suggest that silymarin produces beneficial effects on cardiac hypertrophy which are likely to be mediated through inhibition of MAPK p38beta. PMID- 29968070 TI - Real-time fusion-imaging in low back pain: a new navigation system for facet joint injections. AB - AIMS AND OBJECTIVES: The aim of the current study is to present our experience in lumbar spine interventional procedures performed with a newly developed multimodal echo-navigator (EcoNav) and to evaluate short-term clinical outcomes of a series of patients affected by facet joint disease (FJD) treated with steroid and anaesthetic injection under fusion-imaging guidance, compared to a cohort of patients that received the same treatment under computed tomography (CT) guidance. METHODS: Sixty-five consecutive patients (34 females; mean age 68.3 +/- 12.8 years) with a clinical diagnosis of non-radicular low back pain lasting for more than 6-weeks and magnetic resonance (MR) or CT confirmed FJD were enrolled for image-guided FJI. Twenty-eight patients underwent FJI with fusion-guided technique, while CT-guided procedures were performed in the other cases. Clinical and procedural data were recorded and compared at a mean follow up of 6.1 +/- 2.0 months. RESULTS: A significant improvement in clinical parameters was observed for both fusion-guided and CT-guided group. Comparing both groups, no statistically significant difference could be detected neither at baseline conditions nor during the follow-up period. No significant periprocedural complication occurred in both groups. A satisfaction rate of 92.3 and 81.1% was reported for fusion-guided and CT-guided group, respectively. CONCLUSION: EcoNav fusion-imaging system represents a safe, feasible, effective and reproducible guidance option in FJD infiltration procedures, also avoiding use of ionising radiations. PMID- 29968072 TI - Poly(ADP-ribose) Polymerase (PARP) and PARP Inhibitors: Mechanisms of Action and Role in Cardiovascular Disorders. AB - Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue. This generates ribosyl-ribosyl linkages that act as a signal for other DNA-repairing enzymes and DNA base repair. Extensive DNA breakage in cells results in excessive activation of PARP with resultant depletion of the cellular stores of nicotinamide adenine dinucleotide (NAD+) which slows the rate of glycolysis, mitochondrial electron transport, and ultimately ATP formation in these cells. This paper focuses on PARP in DNA repair in atherosclerosis, acute myocardial infarction/reperfusion injury, and congestive heart failure and the role of PARP inhibitors in combating the effects of excessive PARP activation in these diseases. Free oxygen radicals and nitrogen radicals in arteries contribute to disruption of the vascular endothelial glycocalyx, which increase the permeability of the endothelium to inflammatory cells and also low-density lipoproteins and the accumulation of lipid in the vascular intima. Mild inflammation and DNA damage within vascular cells promote PARP1 activation and DNA repair. Moderate DNA damage induces caspase-dependent PARP cleavage and vascular cell apoptosis. Severe DNA damage due to vascular inflammation causes excessive activation of PARP1. This causes endothelial cell depletion of NAD+ and ATP, downregulation of atheroprotective SIRT1, necrotic cell death, and ultimately atherosclerotic plaque disruption. Inhibition of PARP decreases vascular endothelial cell adhesion P-selectin and ICAM-1 molecules, inflammatory cells, pro-death caspase-3, and c-Jun N-terminal kinase (JNK) activation and upregulates prosurvival extracellular signal-regulated kinases and AKT, which decrease vascular cell apoptosis and necrosis and limit atherosclerosis and plaque disruption. In myocardial infarction with coronary occlusion then reperfusion, which occurs with coronary angioplasty or thrombolytic therapy, reperfusion injury occurs in as many as 31% of patients and is caused by inflammatory cells, free oxygen and nitrogen radicals, the rapid transcriptional activation of inflammatory cytokines, and the activation of PARP1. Inhibition of PARP attenuates neutrophil infiltration and inflammatory cytokine expression in the reperfused myocardium and preserves myocardial NAD+ and ATP. In addition, PARP inhibition increases the activation of myocyte survival enzymes protein kinase B (Akt) and protein kinase C epsilon (PKCepsilon), and decreases the activity of myocardial ventricular remodeling enzymes PKCalpha/beta, PKCzeta/lambda, and PKCdelta. As a consequence, cardiomyocyte and vascular endothelial cell necrosis is decreased and myocardial contractility is preserved. In heart failure and circulatory shock in animal models, PARP inhibition significantly attenuates decreases in left ventricular systolic pressure, ventricular contractility and relaxation, stroke volume, and increases survival by limiting or preventing upregulation of adhesion molecules, proinflammatory cytokines, myocardial mononuclear cell infiltration, and PKCalpha/beta and PKC lambda/zeta. In this manner, PARP inhibition partially restores the myocardial concentrations of NAD+, limits ventricular remodeling and fibrosis, and prevents significant decreases in myocardial contractility. Based primarily on investigations in preclinical models of atherosclerosis, myocardial infarction, and heart failure, PARP inhibition appears to be beneficial in limiting or inhibiting cardiovascular dysfunction. These studies indicate that investigations of acute and chronic PARP inhibition are warranted in patients with atherosclerotic coronary artery disease. PMID- 29968073 TI - Pseudo-continuous arterial spin labeling MR images in Warthin tumors and pleomorphic adenomas of the parotid gland: qualitative and quantitative analyses and their correlation with histopathologic and DWI and dynamic contrast enhanced MRI findings. AB - PURPOSE: We investigated the correlation between tumor blood flow (TBF) and histopathologic features of Warthin tumors (WTs) and pleomorphic adenomas (PAs) to determine the TBF in the differential diagnosis of these tumors and evaluated how well pCASL-MRI can differentiate PAs from WTs compared to conventional MRI. METHODS: The ADC, time intensity curve (TIC) pattern of dynamic contrast enhancement, and pCASL (visual assessment and TBF of the MR images of 10 WTs and 13 PAs) were reviewed. We compared the pCASL and ADC or TIC patterns in WT and PA images. Tissue sections were stained with CD34 to evaluate microvessel density (MVD). The TBF and MVD results were compared. The Mann-Whitney U test was used to compare the TBFs, ADCs, and MVDs of these tumors. The diagnostic accuracy was determined by analyzing the receiver operating characteristic curve. RESULTS: On visual assessment, the signal intensity was higher in all but three cases of WT. The TBF and MVD of the WTs were significantly higher (both, p < 0.01) than the PAs, and the ADC was significantly lower (p < 0.01). Many WTs had early enhancement of the TIC pattern and high washout; many PAs had gradual enhancement. The diagnostic accuracies of visual analysis, TBF, and ADC for differentiation between WTs and PAs were 91.3, 95.7, and 87.0%, respectively. CONCLUSIONS: The TBF were significantly higher in WTs than in PAs, and there was a positive correlation between TBF and MVD. Moreover, pCASL-MRI provides more accurate imaging than conventional MRI to differentiate WTs and PAs. PMID- 29968074 TI - United States Congressmen support the legalization of environmental health injustice in Puerto Rico. AB - OBJECTIVES: Analyze the role of two members of the United States Congress, two private enterprises, and the government of Puerto Rico in the approval of the counterproductive law "Ban on the Deposit and Disposal of Coal Ash or Coal Combustion Residuals in Puerto Rico" (Law No. 40) in the framework of the four principles for environmental policy making. METHODS: The gathered text documents were structured, reviewed, and coded using a content analysis protocol to produce coding categories and the final analysis. RESULTS: Two US congressmen, apparently influenced by private enterprises, had a decisive role in the approval of Law No. 40 which failed to comply with any of the four principles for environmental public policy making. CONCLUSIONS: Puerto Rico's Government succumbed to the extortion strategy of two US congressmen and private economic interests, and finally approved Law No. 40 which mistreats the general public and the environmental health of two low socioeconomic status communities in the municipalities of Guayama and Penuelas. This law has the potential to negatively affect public health and the environment island-wide. PMID- 29968075 TI - The impact of neighborhood socioeconomic disparities on injury. AB - OBJECTIVES: To examine the relationship between neighborhood socioeconomic level (NSEL) and injury-related hospitalization. METHODS: The National Trauma Registry (INTR) and the National Population Census (NPC), including NSEL, were linked by individual identity number. Age-adjusted logistic regression predicted injury hospitalization. Mantel-Haenszel X2 was used for linear trends. NSEL was divided into 20 clusters. RESULTS: The population comprised 7,412,592 residents, of which 125,829 (1.7%) were hospitalized due to injury. The injury hospitalization rate was at least 42 per 10,000 per year. Except for the very low SEL, an inverse relationship between NSEL and all-cause injury was found: 46.1/10,000 in cluster 3 compared to 22.9/10,000 in cluster 20. Hip fracture-related hospitalizations among ages 65 + decreased as SEL increased (2.19% o in cluster 2 compared to 0.95% in cluster 19). In comparison with Jews, non-Jews were 1.5 times more likely to have an injury-related hospitalization [OR 1.5 (95% CI 1.50-1.55)]. CONCLUSIONS: The INTR and the NPC were successfully linked providing individual and injury hospitalization data. The outcomes confirm the strong relationship between injury mechanism and NSEL. PMID- 29968077 TI - Sex and age modulate the visual perception of distance. AB - An experiment was conducted to evaluate the ability of 28 younger and older adults to visually bisect distances in depth both indoors and outdoors; half of the observers were male and half were female. Observers viewed 15-m and 30-m distance extents in four different environmental settings (two outdoor grassy fields and an indoor hallway and atrium) and were required to adjust the position of a marker to place it at the midpoint of each stimulus distance interval. Overall, the observers' judgments were more accurate indoors than outdoors. In outdoor environments, many individual observers exhibited perceptual compression of farther distances (e.g., these observers placed the marker closer than the actual physical midpoints of the stimulus distance intervals). There were significant modulatory effects of both age and sex upon the accuracy and precision of the observers' judgments. The judgments of the male observers were more accurate than those of the female observers and they were less influenced by environmental context. In addition, the accuracies of the younger observers' judgments were less influenced by context than those of the older observers. With regard to the precision of the observers' judgments, the older females exhibited much more variability across repeated judgments than the other groups of observers (younger males, younger females, and older males). The results of our study demonstrate that age and sex are important variables that significantly affect the visual perception of distance. PMID- 29968078 TI - Rapid recalibration to audiovisual asynchrony follows the physical-not the perceived-temporal order. AB - In natural scenes, audiovisual events deriving from the same source are synchronized at their origin. However, from the perspective of the observer, there are likely to be significant multisensory delays due to physical and neural latencies. Fortunately, our brain appears to compensate for the resulting latency differences by rapidly adapting to asynchronous audiovisual events by shifting the point of subjective synchrony (PSS) in the direction of the leading modality of the most recent event. Here we examined whether it is the perceived modality order of this prior lag or its physical order that determines the direction of the subsequent rapid recalibration. On each experimental trial, a brief tone pip and flash were presented across a range of stimulus onset asynchronies (SOAs). The participants' task alternated over trials: On adaptor trials, audition either led or lagged vision with fixed SOAs, and participants judged the order of the audiovisual event; on test trials, the SOA as well as the modality order varied randomly, and participants judged whether or not the event was synchronized. For test trials, we showed that the PSS shifted in the direction of the physical rather than the perceived (reported) modality order of the preceding adaptor trial. These results suggest that rapid temporal recalibration is determined by the physical timing of the preceding events, not by one's prior perceptual decisions. PMID- 29968076 TI - Immune cell profiling in the age of immune checkpoint inhibitors: implications for biomarker discovery and understanding of resistance mechanisms. AB - Immunotherapy has changed the landscape of cancer treatment. The introduction of immune checkpoint inhibitors has seen tremendous success in improving overall survival of patients with advanced metastatic cancers and has now become the standard of care for multiple tumor types. However, efficacy of immune checkpoint blockade appears to be limited to immunogenic cancers, and even amongst immune reactive cancers, response rates are low and variable between patients. Recent data have also demonstrated the rapid emergence of resistance to immune checkpoint inhibitors, with some patients progressing on treatment within one year. Significant research efforts are now directed at identifying predictive biomarkers and mechanisms of resistance to immune checkpoint blockade. These studies are underpinned by comprehensive and detailed profiling of the immune milieu. In this review, we discuss the utility and efficacy of immune cell profiling to uncover biomarkers of response and mechanisms of resistance to immune checkpoint inhibitors. PMID- 29968079 TI - Processing overlap-dependent distractor dilution rather than perceptual target load determines attentional selectivity. AB - The perceptual load theory of attentional selection argues that the degree to which distractors interfere with target processing is determined by the "perceptual load" (or discrimination difficulty) of target processing: when perceptual load is low, distractors interfere to a greater extent than when it is high. A well-known exception is load-independent interference effects from face distractors during processing of name targets. This finding was reconciled with load theory by proposing distinct processing resources for faces versus names. In the present study, we revisit this effect to test (a) whether increasing the processing overlap (perceptual, lexical, conceptual) between potential targets and distractors would reinstate the classic load effect, and (b) whether this data pattern could be better explained by load theory or by a rival account that argues that distractor dilution rather than target load determines the degree of distractor interference. Over four experiments, we first replicate the original finding and then show that load effects grow with increasing processing overlap between potential targets and distractors. However, by adding dilution conditions, we also show that these processing overlap dependent modulations of distractor interference can be explained by the distractor dilution perspective but not by perceptual load theory. Thus, our findings support a processing overlap dilution account of attentional selection. PMID- 29968080 TI - Statistical regularities modulate attentional capture independent of search strategy. AB - An earlier study using the additional singleton task showed that statistical regularities regarding the distractor location can cause an attentional bias that affects the amount of attentional capture by distractors and the efficiency of selection of targets. The distractor singleton was systematically present more often in one location than in all other locations. The present study investigated whether this bias also occurs when observers adopt a feature search mode, i.e., when they search for a specific feature (circle) between elements with different shapes, while ignoring a colored distractor singleton. It is assumed that in feature search, observers can ignore distractors in a top-down way and as such one expects that statistical regularities about the distractor location should not play a role. Contrary to this prediction, we found that even in feature search, both attentional capture by the distractors and the efficiency of selecting the target were impacted by these statistical regularities. Moreover, statistical regularities regarding the feature value of the distractor (its color) had no effect on the amount of capture or the efficiency of selection. We claim that statistical regularities cause passive lingering biases of attention such that on the priority map, the location containing a high probability distractor competes less for attention than locations that are less likely to contain distractors. PMID- 29968081 TI - Set similarity modulates object tracking in dynamic environments. AB - Based on the observation that sports teams rely on colored jerseys to define group membership, we examined how grouping by similarity affected observers' abilities to track a "ball" target passed between 20 colored circle "players" divided into two color "teams" of 10 players each, or five color teams of four players each. Observers were more accurate and exerted less effort (indexed by pupil diameter) when their task was to count the number of times any player gained possession of the ball versus when they had to count only the possessions by a given color team, especially when counting the possessions of one team when players were grouped into fewer teams of more individual members each. Overall, results confirm previous reports of costs for segregating a larger set into smaller subsets and suggest that grouping by similarity facilitates processing at the set level. PMID- 29968083 TI - The curious case of spillover: Does it tell us much about saccade timing in reading? AB - In completing daily activities, the eyes make a series of saccades by gazing at stimuli in succession. The duration of gaze on each stimulus has been used to infer how the initiation of a saccade is timed relative to the underlying mental processing. In reading, gaze dwells longer on a word that occurs infrequently in English text (low frequency) than on a more frequent word (high frequency), but also on the following word, which is referred to as spillover. Accounts of spillover attribute it to mechanisms of lexical access. A low-frequency word n is assumed to delay the onset of cognitive processing of word n+1 more than it delays the saccade to n+1, leaving more processing to be done on n+1 once it is fixated. We tested this assumption by having participants perform a series of speeded lexical decisions on a linear array of letter strings spaced 5 degrees apart, using low- and high-frequency words to vary the lexical difficulty. Lexical decision adds a response selection stage that is absent in reading, which should eliminate differential effects on saccades and cognitive processing. Nonetheless, we found the typical pattern of lengthened gaze duration and spillover for low-frequency words, with effects that were consistent in magnitude with those seen in studies of reading. These data challenge existing accounts of spillover and argue against the idea that reading has a unique interaction with oculomotor control. Instead, the similarity of our gaze patterns to those of reading suggests a common pattern of saccade initiation across tasks. PMID- 29968082 TI - The role of attention in eye-movement awareness. AB - People are unable to accurately report on their own eye movements most of the time. Can this be explained as a lack of attention to the objects we fixate? Here, we elicited eye-movement errors using the classic oculomotor capture paradigm, in which people tend to look at sudden onsets even when they are irrelevant. In the first experiment, participants were able to report their own errors on about a quarter of the trials on which they occurred. The aim of the second experiment was to assess what differentiates errors that are detected from those that are not. Specifically, we estimated the relative influence of two possible factors: how long the onset distractor was fixated (dwell time), and a measure of how much attention was allocated to the onset distractor. Longer dwell times were associated with awareness of the error, but the measure of attention was not. The effect of the distractor identity on target discrimination reaction time was similar whether or not the participant was aware they had fixated the distractor. The results suggest that both attentional and oculomotor capture can occur in the absence of awareness, and have important implications for our understanding of the relationship between attention, eye movements, and awareness. PMID- 29968084 TI - Multiple high-reward items can be prioritized in working memory but with greater vulnerability to interference. AB - Emerging literature indicates that working memory and attention interact in determining what is retained over time, though the nature of this relationship and the impacts on performance across different task contexts remain to be mapped. In the present study, four experiments examined whether participants can prioritize one or more high-reward items within a four-item target array for the purposes of an immediate cued recall task, and the extent to which this mediates the disruptive impact of a postdisplay to-be-ignored suffix. All four experiments indicated that endogenous direction of attention toward high-reward items results in their improved recall. Furthermore, increasing the number of high-reward items from one to three (Experiments 1-3) produces no decline in recall performance for those items, while associating each item in an array with a different reward value results in correspondingly graded levels of recall performance (Experiment 4). These results suggest the ability to exert precise voluntary control in the prioritization of multiple targets. However, in line with recent outcomes drawn from serial visual memory, this endogenously driven focus on high-reward items results in greater susceptibility to exogenous suffix interference, relative to low-reward items. This contrasts with outcomes from cueing paradigms, indicating that different methods of attentional direction may not always result in equivalent outcomes on working memory performance. PMID- 29968085 TI - Task and distribution sampling affect auditory category learning. AB - There is substantial evidence that two distinct learning systems are engaged in category learning. One is principally engaged when learning requires selective attention to a single dimension (rule-based), and the other is drawn online by categories requiring integration across two or more dimensions (information integration). This distinction has largely been drawn from studies of visual categories learned via overt category decisions and explicit feedback. Recent research has extended this model to auditory categories, the nature of which introduces new questions for research. With the present experiment, we addressed the influences of incidental versus overt training and category distribution sampling on learning information-integration and rule-based auditory categories. The results demonstrate that the training task influences category learning, with overt feedback generally outperforming incidental feedback. Additionally, distribution sampling (probabilistic or deterministic) and category type (information-integration or rule-based) both affect how well participants are able to learn. Specifically, rule-based categories are learned equivalently, regardless of distribution sampling, whereas information-integration categories are learned better with deterministic than with probabilistic sampling. The interactions of distribution sampling, category type, and kind of feedback impacted category-learning performance, but these interactions have not yet been integrated into existing category-learning models. These results suggest new dimensions for understanding category learning, inspired by the real-world properties of auditory categories. PMID- 29968087 TI - Correction to: Gestalt grouping cues can improve filtering performance in visual working memory. AB - The original version of this article unfortunately contained a mistake. PMID- 29968086 TI - Personality assimilation across species: enfacing an ape reduces own intelligence and increases emotion attribution to apes. AB - Seeing another person's face while that face and one's own face are stroked synchronously or controlling a virtual face by moving one's own induces the illusion that the other face has become a part of oneself-the enfacement effect. Here, we demonstrate that humans can enface even members of another species and that this enfacement promotes "feature migration" in terms of intelligence and emotional attribution from the representation of other to the representation of oneself, and vice versa. We presented participants with a virtual human face moving in or out of sync with their own face, and then morphed it into an ape face. Participants tended to perceive the ape face as their own in the sync condition, as indicated by body-ownership and inclusion-of-others-in-the-self ratings. More interestingly, synchrony also reduced performance in a fluid intelligence task and increased the willingness to attribute emotions to apes. These observations, which fully replicated in another experiment, fit with the idea that self and other are represented in terms of feature codes, just like non social events (as implied by the Theory of Event Coding), so that representational self-other overlap invites illusory conjunctions of features from one representation to the other. PMID- 29968088 TI - No sex difference in an everyday multitasking paradigm. AB - According to popular beliefs and anecdotes, females best males when handling multiple tasks at the same time. However, there is relatively little empirical evidence as to whether there truly is a sex difference in multitasking and the few available studies yield inconsistent findings. We present data from a paradigm that was specifically designed to test multitasking abilities in an everyday scenario, the computerized meeting preparation task (CMPT), which requires participants to prepare a room for a meeting and handling various tasks and distractors in the process. Eighty-two males and 66 females with a wide age range (18-60 years) and a wide educational background completed the CMPT. Results revealed that none of the multitasking measures (accuracy, total time, total distance covered by the avatar, a prospective memory score, and a distractor management score) showed any sex differences. All effect sizes were d <= 0.18 and thus not even considered "small" by conventional standards. The findings are in line with other studies that found no or only small gender differences in everyday multitasking abilities. However, there is still too little data available to conclude if, and in which multitasking paradigms, gender differences arise. PMID- 29968089 TI - Extraction-free colorimetric determination of thymol and carvacrol isomers in essential oils by pH-dependent formation of gold nanoparticles. AB - An extraction-free method is described for the colorimetric determination of thymol (TY) and carvacrol (CA) isomers in essential oils by making use of the pH dependent formation of gold nanoparticles (AuNPs). In solutions of pH 12, TY and CA form gold nanoparticles, while at pH <= 11 only CA does so. By taking advantage of this finding, two different approaches based on colorimetric assay (absorption at 550 nm) were developed: one at pH 12 for the determination of total CA and TY, and other at pH 9 and pH 12 for differential quantification of TY and CA. The former agrees with the well-established Folin-Ciocalteu method, and the latter provides a simple way for calculation of TY/CA ratio. The linear ranges are from 100 to 1000 MUM at pH 9, and from 50 to 200 MUM at pH 12. The limits of detection are 0.09 MUM at pH 9, and 0.02 MUM at pH 12. These features make this method simple, fast and reliable. Conceivably, it can be used to assess the quality of essential oils and may become a valuable alternative to more sophisticated, laborious and high time-consuming methods. Graphical abstract Schematic of the assay: At pH 12 (blue color), thymol and carvacrol form gold nanoparticles (Au), while at pH 9 (red color) only carvacrol does so. This finding resulted in a colorimetric method for the differential quantification of both compounds in essential oils. PMID- 29968091 TI - Clinical implications of the anatomical position of the urethra meatus in women with recurrent post-coital cystitis: a case-control study. AB - INTRODUCTION AND HYPOTHESIS: Recurrent post-coital urinary infection (rUTI) usually cystitis-is a common entity among otherwise healthy young women. However, little is known about the possible influence of genital anatomical variations. Only a shorter urethral meatus-anus distance has been described as a risk factor. The aim of this study was to evaluate our hypothesis that a shorter urethra vagina distance is involved in the etiology of post-coital urinary infection. METHODS: In this prospective case-control study, 61 young women aged between 18 and 40 years with an acute post-coital UTI and a history of intercourse-related rUTI were consecutively recruited between January 2013 and February 2018. Fifty six age-matched, sexually active women with no history of UTI served as controls. Perineal measurements included the distances between the clitoris-urethra (C-U), urethra-vagina (U-V), urethra-anus (U-A) and perineum. Demographic and sexual behavior characteristics and the morphology of the urethral meatus were also noted. Univariate analysis compared variables between groups. ROC analysis was used to define the efficiency of perineal measurements in predicting outcome. Odds ratios and 95% confidence intervals for UTI-predisposing variables were estimated using logistic regression analysis. RESULTS: The U-V and U-A distance was shorter in patients compared with controls [median (interquatile range): 16 mm (14-18) vs. 21 mm (19-23) and 51 mm (47-53) vs. 59 mm (55-62), respectively, p < 0.001]. The U-V performed better in ROC analysis than the U-A distance (AUC 0.952 vs. 0.875, p = 0.023). The only statistically significant parameters in multivariate analysis influencing UTI were BMI (OR: 0.702; 0.510-0.967, p = 0.030) and U-V (OR: 0.297; 0.161-0.549, p < 0.001). CONCLUSIONS: Our results indicate an association between shorter urethra-vagina distance and post-coital rUTIs. PMID- 29968090 TI - Drug Distribution and Basic Pharmacology of Paclitaxel/Resveratrol-Coated Balloon Catheters. AB - PURPOSE: To experimentally investigate a new homogenously paclitaxel/resveratrol coated balloon catheter in terms of transport of the coating to the treated tissue and local effects including histology and functional tests. METHODS: Adherence of the coating to the balloon was explored by in vitro simulation of its passage to the lesion. Paclitaxel and resveratrol transfer to the vessel wall was investigated in porcine coronary and peripheral arteries. Matrix-assisted laser desorption/ionization (MALDI) was used for direct microscopic visualization of paclitaxel in arterial tissue. Inhibition of neointimal proliferation and tolerance of complete coating and resveratrol-only coating was investigated in pigs 4 weeks after treatment, and the effect of resveratrol on inflammation and healing after 3 and 7 days. RESULTS: Drug loss on the way to the lesion was < 10% of dose, while 65 +/- 13% was detected at the site of balloon inflation. After treatment similar proportions of drug were detected in coronary and peripheral arteries, i.e., 7.4 +/- 4.6% of dose or 125 +/- 74 ng/mg tissue. MALDI showed circumferential deposition. Inhibition of neointimal proliferation by paclitaxel/resveratrol coating was significant (p = 0.001) whereas resveratrol only coating did not inhibit neointimal proliferation. During the first week after treatment of peripheral arteries with resveratrol-only balloons, we observed nominally less inflammation and fibrin deposition along with a significant macrophage reduction and more pronounced re-endothelialization. No safety issues emerged including left ventricular ejection fraction for detection of potential distal embolization after high-dose treatment of coronary arteries. CONCLUSIONS: Paclitaxel/resveratrol-coated balloons were effective and safe in animal studies. Beyond acting as excipient resveratrol may contribute to vascular healing. PMID- 29968092 TI - A review and outlook on visual analytics for uncertainties in functional magnetic resonance imaging. AB - Analysis of functional magnetic resonance imaging (fMRI) plays a pivotal role in uncovering an understanding of the brain. fMRI data contain both spatial volume and temporal signal information, which provide a depiction of brain activity. The analysis pipeline, however, is hampered by numerous uncertainties in many of the steps; often seen as one of the last hurdles for the domain. In this review, we categorise fMRI research into three pipeline phases: (i) image acquisition and processing; (ii) image analysis; and (iii) visualisation and human interpretation, to explore the uncertainties that arise in each phase, including the compound effects due to the inter-dependence of steps. Attempts at mitigating uncertainties rely on providing interactive visual analytics that aid users in understanding the effects of the uncertainties and adjusting their analyses. This impetus for visual analytics comes in light of considerable research investigating uncertainty throughout the pipeline. However, to the best of our knowledge, there is yet to be a comprehensive review on the importance and utility of uncertainty visual analytics (UVA) in addressing fMRI concerns, which we term fMRI-UVA. Such techniques have been broadly implemented in related biomedical fields, and its potential for fMRI has recently been explored; however, these attempts are limited in their scope and utility, primarily focussing on addressing small parts of single pipeline phases. Our comprehensive review of the fMRI uncertainties from the perspective of visual analytics addresses the three identified phases in the pipeline. We also discuss the two interrelated approaches for future research opportunities for fMRI-UVA. PMID- 29968093 TI - Hands train the brain-what is the role of hand tremor and anxiety in undergraduate microsurgical skills? AB - INTRODUCTION: Physiological hand tremor occurs naturally, due to oscillations of the upper extremities. Tremor can be exacerbated by stress and anxiety, interfering with fine motor tasks and potentially impact on surgical performance, particularly in microsurgery. We investigated the link between tremor, anxiety and performance in a neurosurgical module as part of an international surgical course. METHODS: Essential Skills in the Management of Surgical Cases (ESMSC) course recruits medical students from European Union (EU) medical schools. Students are asked to suture the dura mater in an ex vivo swine model, of which the first suture completed was assessed. Questionnaires were distributed before and after the module, eliciting tremor risk factors, self-perception of tremor and anxiety. Johnson O'Connor dexterity pad was used to objectively measure dexterity. Direct Observation of Procedural Skills (DOPS) was used to assess skills-based performance. Anxiety was assessed using the Westside Test Anxiety Scale (WTAS). Tremor was evaluated by four qualified neurosurgeons. RESULTS: Forty delegates participated in the study. Overall performance decreased with greater subjective perception of anxiety (p = 0.032, rho = - 0.392). Although increasing scores for tremor at rest and overall WTAS score were associated with decreased performance, this was not statistically significant (p > 0.05). Tremor at rest did not affect dexterity (p = 0.876, rho = - 0.027). CONCLUSIONS: Physiological tremor did not affect student performance and microsurgical dexterity in a simulation-based environment. Self-perception of anxiety affected performance in this module, suggesting that more confident students perform better in a simulated neurosurgical setting. PMID- 29968094 TI - Ecological invasion in competition-diffusion systems when the exotic species is either very strong or very weak. AB - Reaction-diffusion systems with a Lotka-Volterra-type reaction term, also known as competition-diffusion systems, have been used to investigate the dynamics of the competition among m ecological species for a limited resource necessary to their survival and growth. Notwithstanding their rather simple mathematical structure, such systems may display quite interesting behaviours. In particular, while for [Formula: see text] no coexistence of the two species is usually possible, if [Formula: see text] we may observe coexistence of all or a subset of the species, sensitively depending on the parameter values. Such coexistence can take the form of very complex spatio-temporal patterns and oscillations. Unfortunately, at the moment there are no known tools for a complete analytical study of such systems for [Formula: see text]. This means that establishing general criteria for the occurrence of coexistence appears to be very hard. In this paper we will instead give some criteria for the non-coexistence of species, motivated by the ecological problem of the invasion of an ecosystem by an exotic species. We will show that when the environment is very favourable to the invading species the invasion will always be successful and the native species will be driven to extinction. On the other hand, if the environment is not favourable enough, the invasion will always fail. PMID- 29968095 TI - Karl-Peter Hadeler: His legacy in mathematical biology. AB - Karl-Peter Hadeler is a first-generation pioneer in mathematical biology. His work inspired the contributions to this special issue. In this preface we give a brief biographical sketch of K.P. Hadelers scientific life and highlight his impact to the field. PMID- 29968096 TI - A multi-model intervention including an occlusive dressing and parental engagement to prevent pediatric surgical site infections for elective ambulatory procedures in a resource-constrained setting: an observational retrospective study from a tertiary center in Central Haiti. AB - PURPOSE: In resource-limited settings, up to two-thirds of surgical patients develop surgical site infections (SSIs). Our aim was to implement a multimodal protocol including an occlusive dressing and parental engagement to achieve low SSI rates in patients undergoing elective ambulatory pediatric surgery at a tertiary center in Haiti. METHODS: An observational retrospective review of pediatric patients who underwent elective ambulatory procedures from August 2015 to May 2016 following the implementation of a multimodal protocol consisting of: washing and prepping the operative site with chlorhexidine; review of the surgical safety checklist; one dose of cefazolin before incision; after wound closure application of steri strips, gauze, and tegaderm; and with parental engagement maintenance of the dressing until the follow-up visit. RESULTS: We performed 119 procedures in 99 patients. Mean age was 6.2 years. The most common procedure was inguinal hernia repair (66%); 89% of parents returned to clinic with their children for the follow-up visit, which occurred on average on day 7.6 (range 3-40 days). The SSI rate was 1% (CI 0.00-0.03). CONCLUSION: Implementing a multimodal protocol including an occlusive dressing and parental engagement led to a 1% SSI rate in a resource-constrained setting. PMID- 29968097 TI - Exploring ensembles of bioactive or virtual analogs of X-ray ligands for shape similarity searching. AB - Shape similarity searching is a popular approach for ligand-based virtual screening on the basis of three-dimensional reference compounds. It is generally thought that well-defined experimentally determined binding modes of active reference compounds provide the best possible basis for shape searching. Herein, we show that experimental binding modes are not essential for successful shape similarity searching. Furthermore, we show that ensembles of analogs of X-ray ligands-in the absence of these ligands-further improve the search performance of single crystallographic reference compounds. This is even the case if ensembles of virtually generated analogs are used whose activity status is unknown. Taken together, the results of our study indicate that analog ensembles representing fuzzy reference states are effective starting points for shape similarity searching. PMID- 29968098 TI - Reflection- and Distortion-Source Otoacoustic Emissions: Evidence for Increased Irregularity in the Human Cochlea During Aging. AB - Previous research on distortion product otoacoustic emission (DPOAE) components has hinted at possible differences in the effect of aging on the two basic types of OAEs: those generated by a reflection mechanism in the cochlea and those created by nonlinear distortion (Abdala and Dhar in J Assoc Res Otolaryngol 13:403-421, 2012). This initial work led to the hypothesis that micromechanical irregularity ("roughness") increases in the aging cochlea, perhaps as the result of natural tissue degradation. Increased roughness would boost the backscattering of traveling waves (i.e., reflection emissions) while minimally impacting DPOAEs. To study the relational effect of aging on both types of emissions and address our hypothesis of its origin, we measured reflection- and distortion-type OAEs in 77 human subjects aged 18-76 years. The stimulus-frequency OAE (SFOAE), a reflection emission, and the distortion component of the DPOAE, a nonlinear distortion emission, were recorded at multiple stimulus levels across a four octave range in all ears. Although the levels of both OAE types decreased with age, the rate of decline in OAE level was consistently greater for DPOAEs than for SFOAEs; that is, SFOAEs are relatively preserved with advancing age. Multiple regression analyses and other controls indicate that aging per se, and not hearing loss, drives this effect. Furthermore, SFOAE generation was simulated using computational modeling to explore the origin of this result. Increasing the amount of mechanical irregularity with age produced an enhancement of SFOAE levels, providing support for the hypothesis that increased intra-cochlear roughness during aging may preserve SFOAE levels. The characteristic aging effect relatively preserved reflection-emission levels combined with more markedly reduced distortion-emission levels-indicates that SFOAE magnitudes in elderly individuals depend on more than simply the gain of the cochlear amplifier. This relative pattern of OAE decline with age may provide a diagnostic marker for aging-related changes in the cochlea. PMID- 29968099 TI - Chronic Deafness Degrades Temporal Acuity in the Electrically Stimulated Auditory Pathway. AB - Electrical stimulation of the auditory nerve with a penetrating intraneural (IN) electrode in acutely deafened cats produces much more restricted spread of excitation than is obtained in that preparation with a conventional cochlear implant (CI) as reported by Middlebrooks and Snyder (J Assoc Res Otolaryngol 8:258-279, 2007). That suggests that a future auditory prosthesis employing IN stimulation might offer human patients greater frequency selectivity than is available with a present-day CI. Nevertheless, it is a concern that the electrical field produced by an IN electrode might be too restricted to produce adequate stimulation of the partially depopulated auditory nerve of a deaf patient. We evaluated this by testing responses to IN and CI stimulation in adult deafened cats. Activation of the auditory pathway was monitored by recording from the central nucleus of the inferior colliculus (ICC). Cats deaf for 153-277 days exhibited a ~ 30 % loss of auditory nerve fibers compared to cats deaf for < 18 h. Contrary to our concern, measures of thresholds and dynamic ranges showed no significant deafness-related impairment of excitation by IN or CN stimulation. Surprisingly, however, temporal acuity decreased dramatically in these adult deafened cats, as demonstrated by a marked decrease in the maximum rate of electrical cochlear stimulation to which ICC neurons synchronized to IN or CI stimulation. For instance, half of ICC neurons synchronized to IN stimulation up to 203 pulses per second (pps) in acute deafness, whereas that number dropped to 79 pps for chronic deafness. Such a loss of temporal acuity might contribute to the poor sensitivity to temporal fine structure that has been reported in human CI users. Seemingly, the degraded temporal acuity that we observed in cats was even worse than the fine-structure sensitivity of human CI users, suggesting that most patients experience some improvement of temporal acuity resulting from restoration of patterned auditory nerve stimulation by a CI. PMID- 29968100 TI - Afferent Loop Decompression Technique is Associated with a Reduction in Pancreatic Fistula Following Pancreaticoduodenectomy. AB - OBJECTIVES: Postoperative pancreatic fistula (POPF) is a major complication and main cause of mortality after pancreaticoduodenectomy (PD). Afferent loop decompression technique (ALDT) has theoretical feasibility to reduce the rate of POPF. The aim of this study is to determine whether ALDT is a protective factor for POPF. METHODS: A total of 492 consecutive patients who underwent PD between January 2012 and December 2014 were identified from a prospective database. All data were extracted and events were judged based on medical records. Propensity score matching was conducted to balance several variables. Univariate and multivariate analyses were performed, respectively, to investigate the independent risk factors for pancreatic fistula. ALDT required a nasogastric tube with multiple side holes to be placed deep into the afferent jejunal limb. The rationale for this technique was to prevent pancreatic fistula by decreasing intraluminal pressure in the afferent jejunal loop by placement of the nasogastric tube and the application of continuous low-pressure suction after surgery. RESULTS: The total rate of POPF for the entire cohort was 30.7%, and ISGPS grade-A/B/C POPF rates were 18.1, 10.6 and 2.0%, respectively. In-hospital mortality was 1.6%. Among the 331 patients who received ALDT, 89 developed pancreatic leakage (26.9 vs. 38.5% for non-ALDT; P = 0.009) and eight developed biliary leakage (2.4 vs. 6.2% for non-ALDT; P = 0.035). Apart from ALDT, decreased preoperative ALT, soft pancreas, long operative time and tumour presence in the lower common bile duct (as opposed to the pancreas) were identified as other independent risk factors for POPF following multivariate logistic regression analysis. CONCLUSIONS: ALDT may reduce the incidence of POPF after PD. PMID- 29968102 TI - [In-label treatment of inflammatory joint diseases]. AB - The correct use of therapeutic agents in accordance with their approved label is a requirement for a safe therapy and is often linked to the possibility of reimbursement; however, the use of drugs outside the label approval (off-label treatment) is a commonly used practice in rheumatology. This occurs because sufficient clinical trials are often lacking, particularly for rare diseases. This overview gives an insight into the correct use of disease-modifying antirheumatic drugs (DMARDs). It should be noted that there are divergent treatment guidelines that are based on guidelines or recommendations from public authorities, such as the Federal Joint Committee (GBA). A further example is that modifying the dose when the treatment goal is reached is only intended for some of the drugs in the course of the disease. Clinical trials which address such questions could help to modify or add to the label, as for example has now been successfully achieved for the treatment with certolizumab in pregnancy. PMID- 29968103 TI - One- vs two-phase extraction: re-evaluation of sample preparation procedures for untargeted lipidomics in plasma samples. AB - Lipidomics is a rapidly developing field in modern biomedical research. While LC MS systems are able to detect most of the known lipid classes in a biological matrix, there is no single technique able to extract all of them simultaneously. In comparison with two-phase extractions, one-phase extraction systems are of particular interest, since they decrease the complexity of the experimental procedure. By using an untargeted lipidomics approach, we explored the differences/similarities between the most commonly used two-phase extraction systems (Folch, Bligh and Dyer, and MTBE) and one of the more recently introduced one-phase extraction systems for lipid analysis based on the MMC solvent mixture (MeOH/MTBE/CHCl3). The four extraction methods were evaluated and thoroughly compared against a pooled extract that qualitatively and quantitatively represents the average of the combined extractions. Our results show that the lipid profile obtained with the MMC system displayed the highest similarity to the pooled extract, indicating that it was most representative of the lipidome in the original sample. Furthermore, it showed better extraction efficiencies for moderate and highly apolar lipid species in comparison with the Folch, Bligh and Dyer, and MTBE extraction systems. Finally, the technical simplicity of the MMC procedure makes this solvent system highly suitable for automated, untargeted lipidomics analysis. PMID- 29968101 TI - [S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. AB - BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm. PMID- 29968104 TI - Increased optical pathlength through aqueous media for the infrared microanalysis of live cells. AB - The study of live cells using Fourier transform infrared spectroscopy (FTIR) and FTIR microspectroscopy (FT-IRMS) intrinsically yields more information about cell metabolism than comparable experiments using dried or chemically fixed samples. There are, however, a number of barriers to obtaining high-quality vibrational spectra of live cells, including correction for the significant contributions of water bands to the spectra, and the physical stresses placed upon cells by compression in short pathlength sample holders. In this study, we present a water correction method that is able to result in good-quality cell spectra from water layers of 10 and 12 MUm and demonstrate that sufficient biological detail is retained to separate spectra of live cells based upon their exposure to different novel anti-cancer agents. The IR brilliance of a synchrotron radiation (SR) source overcomes the problem of the strong water absorption and provides cell spectra with good signal-to-noise ratio for further analysis. Supervised multivariate analysis (MVA) and investigation of average spectra have shown significant separation between control cells and cells treated with the DNA cross linker PL63 on the basis of phosphate and DNA-related signatures. Meanwhile, the same control cells can be significantly distinguished from cells treated with the protein kinase inhibitor YA1 based on changes in the amide II region. Each of these separations can be linked directly to the known biochemical mode of action of each agent. Graphical abstract. PMID- 29968105 TI - Graphene oxide-based biosensing platform for rapid and sensitive detection of HIV 1 protease. AB - HIV-1 protease is essential for the life cycle of the human immunodeficiency virus (HIV), and is one of the most important clinical targets for antiretroviral therapies. In this work, we developed a graphene oxide (GO)-based fluorescence biosensing platform for the rapid, sensitive, and accurate detection of HIV-1 protease, in which fluorescent-labeled HIV-1 protease substrate peptide molecules were covalently linked to GO. In the absence of HIV-1 protease, fluorescein was effectively quenched by GO. In contrast, in the presence of HIV-1 protease, it would cleave the substrate peptide into short fragments, thus producing fluorescence. Based on this sensing strategy, HIV-1 protease could be detected at as low as 1.18 ng/mL. More importantly, the sensor could successfully detect HIV 1 protease in human serum. Such GO-based fluorescent sensors may find useful applications in many fields, including diagnosis of protease-related diseases, as well as sensitive and high-throughput screening of drug candidates. Graphical abstract ?. PMID- 29968106 TI - Stepwise frontal affinity chromatography model for drug and protein interaction. AB - Frontal affinity chromatography is an efficient technique that combines affinity interaction and high-performance liquid chromatography, and frontal analysis has been used in studying the interaction between drugs and proteins. Based on frontal analysis, stepwise frontal analysis has been established. The present study aimed to use the Lineweaver-Burk plot in stepwise frontal analysis by taking the weighted average of time data. Commercial human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP) columns were used as an affinity column. Warfarin and digitoxin were chosen as model drugs for the HSA column, whereas verapamil and tamsulosin were selected as model drugs for the AGP column. The time data obtained by frontal analysis and stepwise frontal analysis were compared, and the results revealed good correlation (r2 = 0.9946-0.9998). Frontal analysis and stepwise frontal analysis were also used to analyze the equilibrium dissociation constants (Kd) of model drugs on the HSA and AGP columns. The Kd values were compared with literature values, which revealed the same order of magnitude. These results illustrate that conversion of the time data is reasonable and feasible. The Lineweaver-Burk plot can be used in the stepwise frontal analysis model to study the characteristics of the interaction between drugs and proteins. Graphical abstract ?. PMID- 29968107 TI - Preparation and evaluation of surface-bonded phenylglycine zwitterionic stationary phase. AB - 4-Hydroxy-D-phenylglycine was modified with methacrylic anhydride and then immobilized on silica through thiol-initiated surface polymerization; the prepared material was applied as stationary phase for HPLC. The obtained stationary phase was characterized by elemental analysis, infrared spectroscopy, and thermogravimetric analysis. The chromatographic performance of the packed column was evaluated in reversed-phase liquid chromatograph (RPLC) and hydrophilic interaction liquid chromatograph (HILIC) mode; this column has shown excellent selectivity to both the hydrophobic and hydrophilic solutes. The selectivity towards polycyclic aromatic hydrocarbons relative to that towards alkylbenzenes exhibited by the prepared column was higher than the corresponding selectivity exhibited by commercial C18 column, which could be explained by electronic pi-pi interaction between phenylglycine and electron-rich aromatic rings. On the other hand, the prepared column has also shown better selectivity for polar compounds, which was based on the multiple interaction and retention mechanisms. It was also used to separate sulfonamides and organic acid compared with a commercial C18 and HILIC column; the results show its great chromatographic performance with distinctive selectivity. All the results indicated the prepared column had potential application in a wide range. PMID- 29968109 TI - Modeling Human Perception of Image Quality. AB - Humans can determine image quality instantly and intuitively, but the mechanism of human perception of image quality is unknown. The purpose of this work was to identify the most important quantitative metrics responsible for the human perception of digital image quality. Digital images from two different datasets CT tomography (MedSet) and scenic photographs of trees (TreeSet)-were presented in random pairs to unbiased human viewers. The observers were then asked to select the best-quality image from each image pair. The resulting human-perceived image quality (HPIQ) ranks were obtained from these pairwise comparisons with two different ranking approaches. Using various digital image quality metrics reported in the literature, we built two models to predict the observed HPIQ rankings, and to identify the most important HPIQ predictors. Evaluating the quality of our HPIQ models as the fraction of falsely predicted pairwise comparisons (inverted image pairs), we obtained 70-71% of correct HPIQ predictions for the first, and 73-76%for the second approach. Taking into account that 10-14% of inverted pairs were already present in the original rankings, limitations of the models, and only a few principal HPIQ predictors used, we find this result very satisfactory. We obtained a small set of most significant quantitative image metrics associated with the human perception of image quality. This can be used for automatic image quality ranking, machine learning, and quality-improvement algorithms. PMID- 29968108 TI - Round robin study of formalin-fixed paraffin-embedded tissues in mass spectrometry imaging. AB - Mass spectrometry imaging (MSI) has provided many results with translational character, which still have to be proven robust in large patient cohorts and across different centers. Although formalin-fixed paraffin-embedded (FFPE) specimens are most common in clinical practice, no MSI multicenter study has been reported for FFPE samples. Here, we report the results of the first round robin MSI study on FFPE tissues with the goal to investigate the consequences of inter- and intracenter technical variation on masking biological effects. A total of four centers were involved with similar MSI instrumentation and sample preparation equipment. A FFPE multi-organ tissue microarray containing eight different types of tissue was analyzed on a peptide and metabolite level, which enabled investigating different molecular and biological differences. Statistical analyses revealed that peptide intercenter variation was significantly lower and metabolite intercenter variation was significantly higher than the respective intracenter variations. When looking at relative univariate effects of mass signals with statistical discriminatory power, the metabolite data was more reproducible across centers compared to the peptide data. With respect to absolute effects (cross-center common intensity scale), multivariate classifiers were able to reach on average > 90% accuracy for peptides and > 80% for metabolites if trained with sufficient amount of cross-center data. Overall, our study showed that MSI data from FFPE samples could be reproduced to a high degree across centers. While metabolite data exhibited more reproducibility with respect to relative effects, peptide data-based classifiers were more directly transferable between centers and therefore more robust than expected. Graphical abstract ?. PMID- 29968110 TI - App Review Series: CTisus iPearls. AB - Thousands of "pearls" or facts related to radiology or imaging are accessible through a categorically organized user interface. Pearls are divided up into anatomical regions, as well as non-organ-specific categories. Information is easily accessible with an ad-free interface matched with full offline capability. User interface leaves much to be desired as it appears dated and difficult to navigate at first. Pearls are not easily searchable within the application and unexperienced users may find it difficult to quickly answer targeted questions using this application alone. This application compiles pearls of wisdom pulled from thousands of peer-reviewed publications and organizes them in an easy to use format. While this is designed with the well-informed user in mind, it can serve as an excellent resource for users of all levels of experience seeking bite-sized pieces of imaging-related information. PMID- 29968111 TI - App Review Series: Cardiac Imaging Planes 1-2-3. PMID- 29968112 TI - Coordination numbers in hydrated Cu(II) ions. AB - The potential energy surface of [Cu(H2O)n]2+ clusters with n = 12, 16, and 18 was explored by using a modified version of the simulated annealing method. Such exploration was carried out by using the PM7 semiempirical method to obtain around 100,000 isomers, which provide candidates to be optimized with PBE0-D3, M06-2X, and BHLYP exchange-correlation functionals coupled with the 6-311++G** basis set. These methods based on the Kohn-Sham approach delivered isomers with coordination numbers of 4, 5, and 6. The analysis used to obtain coordination numbers was based on geometrical parameters and the quantum theory of atoms in molecules (QTAIM) approach. Our methodology found only one isomer with fourfold coordination and its probabilities to appear in these clusters are quite small for high temperatures. The procedure used in this article predicts important populations of fivefold and sixfold coordination clusters, in fact, the fivefold coordination dominates for PBE0-D3 and BHLYP methods, although the sixfold coordination starts to be important when the number of water molecules is increased. The nature of axial and equatorial contacts is discussed in the context of the QTAIM and the noncovalent interaction index (NCI), which gives a clear classification of such orientations. Also, these methods suggest a partial covalent interaction between the Cu2+ and water molecules in both positions; equatorial and axial. PMID- 29968113 TI - Clinical use of an opto-nuclear probe for hybrid sentinel node biopsy guidance: first results. AB - INTRODUCTION: Guidelines advocate the use of combined detection techniques to achieve optimal results for sentinel node (SN) biopsy. The fluorescent and radioactive (dual-) tracer ICG-99mTc-nanocolloid has been shown to facilitate SN biopsy in several indications. It was reported that an opto-nuclear probe permitted the detection of near-infrared fluorescence and gamma-rays. The aim of the current study was to evaluate this device in a large patient group and to test it in both open and laparoscopic surgery implications. METHODS: Thirty-three patients scheduled for SN biopsy with the dual-tracer were retrospectively analyzed. Pre-operative lymphoscintigraphy was performed in all patients; in 18 patients (55%), a SPECT/CT scan was also performed. Radioactive and fluorescent signatures in the SNs were assessed in vivo and ex vivo using the opto-nuclear probe. RESULTS: One or more SNs were identified in all patients (identification rate 100%). Planar lymphoscintigraphic images revealed 95 hot spots that were considered as SNs. This number increased to 103 SNs when SPECT/CT was used. During surgery, 106 SNs were excised. In vivo, the fluorescence mode of the opto nuclear probe was able to locate 79 SNs (74.5%). When the gamma-ray detection option of the same probe was used, this number increased to 99 SNs (93.3%). Ex vivo analysis revealed fluorescence in 93.3% of the excised nodes and radioactivity in 95.2%. CONCLUSIONS: This study underlines the feasibility of using the dual-tracer/opto-nuclear probe combination for SN resections. The use of the opto-nuclear technology has been extended to laparoscopic surgery. This study also underlines the fluorescence tracing can complement traditional radio tracing approaches. PMID- 29968114 TI - Characteristics of Religious and Spiritual Beliefs of Danish Physicians: And Likelihood of Addressing Religious and Spiritual Issues with Patients. AB - This study investigated the association between physicians' R/S characteristics and frequency of addressing patients' R/S issues. Information was obtained through a questionnaire mailed to 1485 Danish physicians (response rate 63%) (42% female). We found significant associations between physicians' personal R/S and the frequency of addressing R/S issues. Moreover, we identified significant gender differences in most R/S characteristics. However, no differences in frequency of addressing R/S issues were identified across gender. This raises some questions regarding the effects of gender on associations between R/S characteristics and frequency of addressing R/S issues. PMID- 29968115 TI - The impacts of internal versus external fixation for tibial fractures with simultaneous acute compartment syndrome. AB - PURPOSE: High-energy tibial fractures may cause compartment syndrome, which needs fasciotomy. However, in this procedure, close fractures become an open wound and choosing the best type of fixation for this situation has been a problem. We assumed early open reduction and internal fixation (ORIF) instead of late internal fixation or external fixation, or stage-based approach is a better method. METHODS: We collected fifty-seven medical records from 2012 to 2017 stored in Alzahra and Kashani University Hospital databases. We selected important information of their medical files, called the submitted phone numbers, and asked them to come to our clinic and examined their leg for any malunion and/or movement restriction postoperatively. We asked about pain and paresthesia in their leg. Twelve cases were excluded. RESULTS: Demographic variables were not significantly different between these two groups. Deep infection, malunion, decreased range of motion in both knee and ankle joints, pain and paresthesia mainly occurred in external fixation group, except malunion (p value = 0.032), other variables were not statistically significant between two groups. More surgeries were performed predominantly for external fixation group (p value < 0.001). External fixation stayed 4.7 days longer at hospital although it was not statistically significant (p value = 0.108). CONCLUSION: It is better to perform fasciotomy and ORIF simultaneously in one surgery to lower the number of surgeries, days of hospitalization, decrease the risk of deep infection, malunion and movement restriction although its postoperative outcomes were not considerably different from external fixation. We indicate that stage-based approach is accompanied by poor outcomes and lesser satisfaction. PMID- 29968117 TI - KIRs gene content diversity in Iranians with urothelial bladder cancer. AB - Natural killer cells (NK) are the first arm of the innate immune system in defense against tumor and infection. 16 distinct Killer-cell immunoglobulin-like receptors (KIRs) are involved in orchestrating NK cell function. The KIR family contains 14 genes and 2 pseudogenes. Six of these receptors are activating (aKIR) and the remaining receptors are inhibitory KIRs (iKIR), that interact with MHC-I molecules; producing signals which stop NK cell function. In the current study, we have investigated the genomic diversity of KIRs and determining the A and B haplotypes as well as Bx subsets in 119 patients with bladder cancer and 200 healthy controls to find out if there is an association between KIR system and susceptibility to bladder cancer. Polymerase chain reaction with sequence specific primers (SSP-PCR) typing system was used to determine the KIR gene profile. The results implicated decreased frequency of inhibitory KIR2DL2 and activating KIR2DS2 while increased frequency of CxT4 genotypes in patients compared with healthy controls. Among Bx subsets, the CxT4 gene cluster is more frequent in bladder cancer patients compared to controls. Our results provide a conclusion that KIR2S2 and KIR2L2 may play a protective role against bladder cancer development while the CxT4 gene cluster may underlie susceptibility to bladder cancer in Iranian population. PMID- 29968116 TI - Effects of electromagnetic field, cisplatin and morphine on cytotoxicity and expression levels of DNA repair genes. AB - Morphine (Mor) is widely used as an analgesic drug in cancers and in combination with chemotherapy is known to have DNA damaging effects on non-targeted cell. This study surveyed the effect of Mor in combination with 50-Hz electromagnetic field (EMF) and co-treatment of cisplatin in combination with Mor and EMF on the expression of genes involved in DNA repair pathways. MCF-7 and SH-SY5Y cells were treated with 5.0 uM Mor and then exposed to 50-Hz 0.50 mT EMF in the intermittent pattern of 15 min field-on/15 min field-off. Gene expression, cisplatin and bleomycin cytotoxicity were measured using real-time PCR and MTT assay. Mor treated cells showed significant down-regulation of the examined genes, while in "Mor + EMF" treatments the genes were not significantly changed. IC50 of cisplatin was significantly elevated in both cell lines when co-treated with "Mor + EMF" compared with Mor treated cells. Non-homologous end joining (NHEJ) related genes were significantly decreased in co-treatment of cisplatin and "Mor + EMF" which led to bleomycin higher cytotoxicity in SH-SY5Y not in MCF-7. Our data is promising for providing a cell line-specific sensitization by combination of cisplatin and "Mor + EMF" treatment with local administration of double strand breaking agents. PMID- 29968118 TI - Clinical Interest and Economic Impact of Preoperative SMS Reminders before Ambulatory Surgery: A Propensity Score Analysis. AB - Patient contact by telephone the day before ambulatory surgery is considered as a best practice. The Short Message Service (SMS) could be a suitable alternative. The objective of this prospective study was to evaluate the interest of preoperative instruction (PI) reminders by SMS compared to telephone calls. This was a prospective single center before-and-after study. Patients scheduled in ambulatory surgery were included during 2 consecutive periods of 10 weeks. The "Call" group received a telephone call for preoperative instructions (PI) and the "SMS" group received an automated protocol SMS reminder. The primary endpoint was patient compliance with PI and time of convocation. The two populations were compared with a non-inferiority hypothesis and the impact of the contact modality on compliance with the PI was assessed using a propensity score. The analysis concerned 301 patients in the Call group and 298 in the SMS group. The absence of dysfunction was observed in 75% of patients in the SMS group compared with 61% in the Call group (Risk difference: 14% [95%CI: 7-21]). The use of SMS was associated with a significant improvement in compliance with the PI (Odds ratio: 1.90 [1.48-2.42]; p < 0.0001). Patient satisfaction was similar regardless of the method of PI reminders. The automation of preoperative SMS reminders is associated with a better respect of the PI compared to the conventional calling method. This PI reminder method satisfies the majority of patients and may have a favorable financial impact. PMID- 29968119 TI - Vascular endothelial growth factor plasma levels in depression and following electroconvulsive therapy. AB - Both animal and human studies have implicated the neurotrophic and angiogenic mediator vascular endothelial growth factor (VEGF) in depression, with meta analyses, indicating that protein levels are raised in patients with depression. In line with this, we have previously shown that VEGFA mRNA levels are higher in whole blood from patients with depression compared to controls, in particular in patients with psychotic unipolar depression, and that treatment with electroconvulsive therapy (ECT) alters VEGFA mRNA levels. The aim of the present study was, therefore, to extend this previous work by assessing plasma VEGF protein levels in patients with depression compared to healthy controls, and in patients following treatment with ECT. We found that there was no difference between controls and patients with depression with regard to plasma VEGF (p = 0.59), and that VEGF levels were unaltered by ECT (p = 0.09) after correction for potential covariates. We found no correlation between VEGF protein and mRNA levels. Within the subgroup of patients receiving treatment with bitemporal ECT (n = 34), we identified a moderate negative correlation (rho = - 0.54, p = 0.001) between the change in VEGF and the change in depression severity following treatment; however, no other association between VEGF and mood, responder/remitter status, polarity of depression, or presence of psychosis were found. Overall, our results indicate that the measurement of VEGF protein is not a useful marker for depression or response to treatment, and suggest that the measurement of VEGFA mRNA may prove more useful. PMID- 29968120 TI - One-pot synthesis, biological evaluation and molecular docking studies of fused thiazolo[2,3-b]pyrimidinone-pyrazolylcoumarin hybrids. AB - As a part of our endeavor toward the synthesis of a new class of biologically potent heterocyclic hybrids, a series of newly fused thiazolo[2,3-b]pyrimidinones bearing a pyrazolylcoumarin moiety (6a-p) were synthesized in acceptable yields. Anticipated structures of all titled compounds were in agreement with spectral and analytical (C, H and N) analyses. The compounds were screened for in vitro antibacterial activity against both G+ and G- bacterial strains and antiproliferative activity against K562 (chronic myelogenous leukemia), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), COLO 205 (colorectal adenocarcinoma), HepG2 (hepatocellular carcinoma) cell lines. Further, potent antibacterial compounds were subjected to molecular docking studies in order to gain insight into their plausible binding modes and mechanism of action against MurB. The modeling results were in agreement with the experimental data. PMID- 29968121 TI - Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity. AB - A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1 (5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a 2f with substituted sulfonyl chlorides in portions furnished the target bis sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 MUM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 MUM and could be a promising antiproliferative agent. PMID- 29968122 TI - Revisiting the famous farm foxes: A psychological perspective. AB - Five decades ago, Dmitry Belyaev, Lyudmila Trut, and colleagues began a now famous experiment, selectively breeding foxes based on one criterion: perceived tame behavior. Over generations, the fox population changed in behavior (as predicted) but, intriguingly, also changed markedly in appearance-for example, many had wider mouths, curlier tails, different fur coloring, and floppy ears. These researchers concluded that the morphological changes that appeared in their foxes were a by-product of the researchers' selecting for genetic variants that are implicated both in behavior and in appearance. For decades, scientists have largely accepted this "shared genetic variants" interpretation to fully account for the co-occurrence of behavioral and morphological phenotypes in these foxes and in other domesticated animals. However, several decades of psychological research on human social cognition, human-canine interaction, and canine behavior strongly suggest that such an account may be incomplete. I forward a supplementary perspective, based on psychological research, that the covariation of appearance and behavior among these foxes may be partly an artifact of human psychological processes at play in selection. These processes include humans' tendency to infer individuals' traits based on their physical features; trait inferences, in turn, influence how humans treat those individuals. If accurate, this account bears on our understanding of these famous foxes, human-canine interactions, as well as humans' role in domestication. PMID- 29968123 TI - Trace Metals in the Freshwater Fish Cyprinus carpio: Effect to Serum Biochemistry and Oxidative Status Markers. AB - Interactions between trace metals, serum biochemical parameters, and oxidative status markers were observed. Freshwater fish Cyprinus carpio blood samples (n = 38) were collected at the beginning of May (n = 19) and at the end of July (n = 19) of 2015. The concentrations of metals (As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Se, Sr, and Zn) were analyzed in blood serum samples of fishes by inductively coupled plasma optical emission spectrometry (ICP-OES), and Hg was determined by cold vapor atomic absorption spectroscopy (CV-AAS). The general scheme of descending concentrations of metals in blood serum samples was as follows: Zn > Fe > Cu > Sr > Cr > Ni > Mn > Pb > Se > As > Cd > Hg. Zn was the most accumulated element (4.42-119.64 mg/L) in both seasons. Overall, the trace element content was higher in spring season, except Hg, Ni, Se, and Sr. The seasonal effect was confirmed for Mn, Zn, Mg, Glu, AST, and Chol levels and for most oxidative status markers. The gender effect was confirmed for Sr, GPx, PC, Chol, and CK concentrations. Trace metals (especially Cd, Cr, Cu, Fe, Hg, Mn, Ni, Sr, Zn, As) significantly affected some blood serum chemistry parameters. The correlation analysis between oxidative status markers (ROS, TAC, MDA, SOD, GSH, UA, BHB, and Alb) and trace metal (Cd, Cu, Ni, Sr, Hg, Pb, Fe, Mn) content confirmed statistically significant interactions in both seasons. Obtained results indicate specific actions of trace metals. PMID- 29968124 TI - Levels of Essential and Xenobiotic Elements and Their Relationships in Milk Available on the Slovak Market with the Estimation of Consumer Exposure. AB - The monitoring of various elements in the cow milk is important in the agricultural sector. The goal of this study was to determine the concentrations of calcium (Ca), cadmium (Cd), copper (Cu), iron (Fe), mercury (Hg), potassium (K), magnesium (Mg), sodium (Na), nickel (Ni), lead (Pb), and zinc (Zn) in the milk samples coming from different origins (local region in Nitra, nationwide sample represents the common Slovak brands of milk and common brands of milk from Czech Republic widely available in Slovakia). The samples were analyzed using atomic absorption spectrometry. A high level of variability in the Cu, Fe, Na, Ni, and Zn contents was observed. Magnesium was comparatively high in the milk sample from Slovakia (273.23 +/- 16.32 MUg/mL) against sample from Nitra (230.91 +/- 9.48 MUg/mL) and Czech Republic (202.70 +/- 10.83 MUg/mL). Potassium was significantly higher in milk from Nitra region (3301.98 +/- 95.66) against SK sample (2925.16 +/- 75.74 MUg/mL). There were no significant differences in other elements among the three regions. The provisional tolerable weekly intake (PTWI) contribution suggested low dietary exposure to observed toxic metals (Cd, Hg, and Pb) in milk samples. Margin of exposure (MOE) evaluation denoted that even higher consumption of milk poses no high cardiovascular and nephrotoxicity threat. However, Cd and Pb are known for their cumulative effect and the monitoring of these elements in milk is strongly required. PMID- 29968125 TI - Differences in peritoneal solute transport rates in peritoneal dialysis. AB - BACKGROUND: Ultrafiltration failure associated with peritoneal membrane dysfunction is one of the main complications for patients on long-term peritoneal dialysis (PD). The dialysate-to-plasma concentration ratio (D/P) of creatinine is widely used to assess peritoneal membrane function. However, other small-sized solutes have not been studied in detail as potential indicators of peritoneal permeability. METHODS: We studied the D/Ps of small, middle-sized and large molecules in peritoneal equilibration tests in 50 PD patients. We applied metabolomic analysis of comprehensive small molecular metabolites using capillary electrophoresis time-of-flight mass spectrometry. RESULTS: D/Ps of middle-sized and large molecules correlated positively with D/P creatinine. Most D/Ps of small molecules correlated positively with D/P creatinine. Among 38 small molecules contained in the dialysate, urea, citrulline and choline showed significantly lower ability to permeate than creatinine. In the relationship between D/Ps of creatinine and small molecules, regression coefficients of three molecules were less than 0.3, representing no correlation to D/P creatinine. Five molecules showed negative regression coefficients. Among these molecules, hippurate and 3 indoxyl sulfate showed relatively high teinpro binding rates, which may affect permeability. Serum concentrations of two molecules were higher in the Low Kt/V group, mainly due to high protein binding rates. CONCLUSIONS: D/Ps of some molecules did not correlate with D/P creatinine. Factors other than molecular weight, such as charge and protein binding rate, are involved in peritoneal transport rates. Metabolomic analysis appears useful to analyze small molecular uremic toxins, which could accumulate in PD patients, and the status of peritoneal membrane transport for each molecule. PMID- 29968126 TI - 22-oxacalcitriol prevents acute kidney injury via inhibition of apoptosis and enhancement of autophagy. AB - BACKGROUND: The pathophysiology of ischemic acute kidney injury (AKI) is thought to include a complex interplay between tubular cell damage and regeneration. Several lines of evidences suggest a potential renoprotective effect of vitamin D. In this study, we investigated the effect of 22-oxacalcitriol (OCT), a synthetic vitamin D analogue, on renal fate in a rat model of ischemia reperfusion injury (IRI) induced acute kidney injury (AKI). METHODS: 22 oxacalcitriol (OCT) was administered via intraperitoneal (IP) injection before ischemia, and continued after IRI that was performed through bilateral clamping of the renal pedicles. 96 h after reperfusion, rats were sacrificed for the evaluation of autophagy, apoptosis, and cell cycle arrest. Additionally, assessments of toll-like receptors (TLR), interferon gamma (IFN-g) and sodium hydrogen exchanger-1 (NHE-1) were also performed to examine their relations to OCT-mediated cell response. RESULTS: Treatment with OCT-attenuated functional deterioration and histological damage in IRI induced AKI, and significantly decreased cell apoptosis and fibrosis. In comparison with IRI rats, OCT + IRI rats manifested a significant exacerbation of autophagy as well as reduced cell cycle arrest. Moreover, the administration of OCT decreased IRI-induced upregulation of TLR4, IFN-g and NHE-1. CONCLUSION: These results demonstrate that treatment with OCT has a renoprotective effect in ischemic AKI, possibly by suppressing cell loss. Changes in the expression of IFN-g and NHE-1 could partially link OCT to the cell survival-promoted effects. PMID- 29968128 TI - A systematic review of interventions for healthcare professionals to improve screening and referral for perinatal mood and anxiety disorders. AB - Postpartum depression affects approximately 11% of women. However, screening for perinatal mood and anxiety disorders (PMAD) is rare and inconsistent among healthcare professionals. When healthcare professionals screen, they often rely on clinical judgment, rather than validated screening tools. The objective of the current study is to review the types and effectiveness of interventions for healthcare professionals that have been used to increase the number of women screened and referred for PMAD. Preferred Reporting Items for Systematic Reviews and Meta-Analyses was utilized to guide search and reporting strategies. PubMed/Medline, PsychInfo/PsychArticles, Cumulative Index to Nursing, Allied Health Literature (CINAHL), and Health Source: Nursing/Academic Edition databases were used to find studies that implemented an intervention for healthcare professionals to increase screening and referral for PMAD. Twenty-five studies were included in the review. Based on prior quality assessment tools, the quality of each article was assessed using an assessment tool created by the authors. The four main outcome variables were the following: percentage of women screened, percentage of women referred for services, percentage of women screened positive for PMAD, and provider knowledge, attitudes, and/or skills concerning PMAD. The most common intervention type was educational, with others including changes in electronic medical records and standardized patients for training. Study quality and target audience varied among the studies. Interventions demonstrated moderate positive impacts on screening completion rates, referral rates for PMAD, and patient-provider communication. Studies suggested positive receptivity to screening protocols by mothers and providers. Given the prevalence and negative impacts of PMAD on mothers and children, further interventions to improve screening and referral are needed. PMID- 29968129 TI - Postpartum depression and social support in a racially and ethnically diverse population of women. AB - Lack of social support is an important risk factor for postpartum depression (PPD), whereas the presence of social support can buffer against PPD. However, the relationship between social support and PPD in racial/ethnic minority women is still largely unknown. Our purpose was to examine the role of social support in a large, diverse population of PPD cases and controls. Participants (N = 1517) were recruited at the routine 6-week postpartum visit (+/- 1-2 weeks) from four different outpatient clinics in North Carolina. Case status was determined using the MINI International Neuropsychiatric Interview. Social support was measured using the Medical Outcomes Social (MOS) Support survey and the Baby's Father Support Scale (DAD). We found that higher levels of social support had a strong protective association against PPD (MOS total score OR, 0.23; 95% CI, 0.19-0.27; p = 6.92E-90; DAD total score OR, 0.89; 95% CI, 0.88-0.92; p = 1.69E-29), and the effects of social support did not differ when accounting for race/ethnicity. Additionally, PPD symptom severity is significantly and negatively correlated with the degree of social support. Our findings suggest that multi-dimensional aspects of social support may be protective for racial/ethnic minority women. We believe this study is currently the largest and most robust characterizing PPD case status and its association with social support in a diverse cohort of mothers. Future work is required to understand how best to implement culturally sensitive interventions to increase social support in minority perinatal women. PMID- 29968127 TI - Diagnosis, Natural History and Treatment of Eosinophilic Enteritis: a Review. AB - PURPOSE OF REVIEW: To review recent findings regarding eosinophilic enteritis, including epidemiology, pathogenesis, natural history, and treatment. RECENT FINDINGS: A 2017 population-based study using a US healthcare system database identified 1820 patients with a diagnosis of eosinophilic enteritis among 35,826,830 individuals. The majority of patients with eosinophilic enteritis in this study were women (57.7%), Caucasian (77.5%), and adults (> 18 years of age) (83.5%). The overall prevalence of eosinophilic enteritis was estimated at 5.1/100,000 persons. Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathological examination of the intestinal mucosa. The etiology of eosinophilic enteritis remains unknown. However, there is evidence to support the role of allergens in the pathogenesis of this disorder, as children and adults with EGIDs often have positive skin testing to food allergens and a family history of allergic diseases. Recent studies unraveling the role of IgE mediated but also delayed Th2-type responses have provided insight into the pathogenesis of this disease. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating, or ascites, and its diagnosis requires a high degree of clinical likelihood, given the nonspecific clinical presentation and physical examination findings. Oral corticosteroids are considered to be the mainstay of treatment and are generally used for a short period with good response rates. Antihistamine drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. Preliminary studies have demonstrated the potential benefit of biological therapies targeting the eosinophilic pathway such as mepolizumab, an anti-IL5 antibody, or omalizumab, an anti-IgE monoclonal antibody. Eosinophilic enteritis is generally considered to be a benign disease without relapse, but up to 50% of patients may present a more complex natural history characterized by unpredictable relapses and a chronic course. PMID- 29968130 TI - Impact of maternal depression on perinatal outcomes in hospitalized women-a prospective study. AB - Scarce data exists regarding the prevalence of antenatal depression in hospitalized pregnant women, and its effect on perinatal outcome. We aimed to estimate the risk of maternal depression among women hospitalized in a high-risk pregnancy department, and to evaluate its potential association with adverse perinatal outcome. A depression screening self-questionnaire-based prospective study was performed, in which hospitalized pregnant women who screened positive for depression were compared to those who screened negative. The Edinburgh Postnatal Depression Scale (EPDS) was used for antenatal depression screening. Pregnancy course and perinatal outcome were compared between the groups. A multivariate logistic regression model was constructed to control for clinically relevant confounders. During the study period, 279 women met the inclusion criteria. Among them, 28.3% (n = 79) screened positive for depression (>= 10 points on the EPDS). In the univariate analysis, a significantly higher incidence of preterm delivery (< 37 weeks), low birthweight (< 2500 g), low Apgar scores (at 1 and 5 min), and neonatal intensive care unit (NICU) admissions were noted among the screen positive group. In the multivariate regression model, controlled for maternal age, ethnicity, gestational diabetes mellitus, preeclampsia, past preterm delivery, and gestational age upon admission, maternal antenatal depression during hospitalization was noted as an independent risk factor for preterm delivery (adjusted OR 3.32, 95%CI 1.16-9.52, p = 0.026). Maternal antenatal depression during hospitalization is very common and appears to play a significant and independent role in the prediction of preterm delivery. PMID- 29968131 TI - GABAA dysregulation as an explanatory model for late-onset postpartum depression associated with weaning and resumption of menstruation. AB - It is well established that a subgroup of women are particularly vulnerable to affective dysregulation during times of hormonal fluctuation. One underrecognized reproductive transition may be late-onset postpartum depression (PPD) in the context of weaning from breastfeeding and the resumption of menstruation. The goal of this review is to propose a biologically plausible mechanism for affective dysregulation during these transitions. The relationship between affective symptoms and neurohormonal changes associated with weaning will be investigated through a hypothesis-driven review of relevant literature. Neurosteroids, like allopregnanolone (ALLO), are widely recognized for augmenting GABAergic inhibition and having a powerful anxiolytic effect (Belelli D and Lambert JL, Nature Reviews Neuroscience 6:565-575, 2005). However, when ALLO is administered after prolonged withdrawal, there may be a paradoxical anxiogenic effect (Smith et al., Psychopharmacology 186:323-333, 2006; Shen et al., Nat Neurosci 10:469-477, 2007). Weaning from breastfeeding is a physiologic example of fluctuating levels of ALLO after prolonged withdrawal. We propose that the complex hormonal milieu during weaning and resumption of menstruation may modify GABAA receptors such that ALLO may contribute to rather than ameliorate depressive symptoms in vulnerable individuals. The proposed model provides an initial step for understanding the mechanisms by which the changing hormonal environment during weaning and resumption of menstruation may contribute to an increased risk of depression in a subgroup of women who are hormonally sensitive. Future research investigating this model would be valuable both to identify women at increased risk for developing mood symptoms late in postpartum and to inform treatment for this and related reproductive depressive disorders. PMID- 29968132 TI - Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) Gene Expression and Urinary CTLA4 Levels in Idiopathic Nephrotic Syndrome. AB - OBJECTIVES: To detect Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) single nucleotide polymorphisms (SNPs) at +49A/G (rs231775) and -318C/T (rs5742909) positions in children with idiopathic nephrotic syndrome (INS) and also assay urinary soluble CTLA4 (sCTLA4) levels in children with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and steroid sensitive nephrotic syndrome (SSNS) in remission. METHODS: The study included 59 patients of INS (MCD-23, FSGS 15 and SSNS in remission-21) and 35 healthy controls. The CTLA4 SNPs profiling was done in peripheral blood mononuclear cells and urinary sCTLA4 level was assayed by ELISA kit. RESULTS: Although frequency of homozygous +49 GG (rs4553808) genotype (26.3% vs. 11.4%; p = 0.231) and G allele (52.6% vs. 40%; p = 0.216) were found to be higher in INS as compared to controls, the differences were statistically non-significant. Genotypes GG, AG, AA and alleles A and G frequencies were comparable among MCD, FSGS and controls. SNP at -318 C/T (rs5742909) did not show homozygous TT genotype both in INS as well as controls. Median urinary sCTLA4/creatinine level was significantly higher in MCD as compared to FSGS (p = 0.027), SSNS in remission (p = 0.001) and controls (p = 0.003). CONCLUSIONS: The positive associations of +49 GG genotype and G allele in patients with nephrotic syndrome were not observed. The frequencies did not differ significantly among MCD, FSGS and controls. Urinary sCTLA4 level was significantly increased in MCD; suggesting its possible role in the pathogenesis of disease. PMID- 29968133 TI - Antenatally Diagnosed Surgical Conditions: Fetus As Our Patient. AB - In today's era of improved antenatal care and screening modalities (3D high resolution fetal ultrasound, fetal magnetic resonance imaging, fetal echocardiography, maternal serum markers and fetal blood sampling), an early diagnosis of surgical fetal abnormalities is routinely possible. A thorough knowledge about the incidence of such defects, the means of detection and evaluation, the scope of fetal intervention, postnatal management and long-term outcomes of common surgical conditions diagnosed antenatally is essential. This knowledge would not only help in proper patient care and management but also to ensure appropriate counselling of the expectant parents. This article highlights the fetal anomalies which are amenable to some form of fetal intervention from a pediatric surgical perspective as also those which can be treated after birth. PMID- 29968135 TI - Prognostic analysis of stage III gastric cancer after curative surgery according to the newest TNM classification. AB - AIM: To study the prognostic factors of gastric cancer (GC) patients who were classified with stage III disease according to the newest TNM classification. METHODS: This study retrospectively enrolled 279 patients who underwent radical gastrectomy from January 2012 to December 2014 at our hospital and who were diagnosed with stage III GC according to the new 8th edition of the TNM classification. The patient data that were collected included age, sex, pathological parameters, survival, lymph node ratio, neo-adjuvant chemotherapy with oxaliplatin and S-1, and operation type. The characteristics, survival, and prognostic factors of the patients were analyzed by univariate and multivariate analyses. RESULTS: The median OS of the patients after curative surgery was 19 months, and the 3-year survival rate (3-YSR) was 25.3%. A univariate analysis showed that tumor location (P = 0.01), neo-adjuvant chemotherapy (P = 0.005), pathological T stage (P = 0.002), pathological N stage (P < 0.001), lymph node ratio (LNR) (P < 0.001), and operation type (P = 0.032) were significantly associated with overall survival. A multivariate analysis revealed that neo adjuvant chemotherapy (P = 0.009), pathological T stage (P = 0.012), and LNR (P < 0.001) were independent prognostic factors. CONCLUSIONS: Neo-adjuvant chemotherapy, pathological T stage, and LNR were independent prognostic factors for the overall survival of patients with stage III GC. The neo-adjuvant chemotherapy with oxaliplatin and S-1 can be used for the patients to improve their survival. PMID- 29968134 TI - Gram-negative bacilli-derived peptide antibiotics developed since 2000. AB - Gram-negative bacilli such as Pseudomonas spp., Pseudoalteromonas sp., Angiococcus sp., Archangium sp., Burkholderia spp., Chromobacterium sp., Chondromyces sp., Cystobacter sp., Jahnella sp., Janthinobacterium sp., Lysobacter spp., Paraliomyxa sp., Photobacterium spp., Photorhabdus sp., Pontibacter sp., Ruegeria sp., Serratia sp., Sorangium sp., Sphingomonas sp., and Xenorhabdus spp. produce an enormous array of short peptides of 30 residues or fewer that are potential pharmaceutical drugs and/or biocontrol agents. The need for novel lead antibiotic compounds is urgent due to increasing drug resistance, and this review summarises 150 Gram-negative bacilli-derived compounds reported since 2000, including 40 cyclic lipopeptides from Pseudomonas spp.; nine aromatic peptides; eight glycopeptides; 45 different cyclic lipopeptides; 24 linear lipopeptides; eight thiopeptides; one lasso peptide; ten typical cyclic peptides; and five standard linear peptides. The current and potential therapeutic applications of these peptides, including structures and antituberculotic, anti cyanobacterial, antifungal, antibacterial, antiviral, insecticidal, and antiprotozoal activities are discussed. PMID- 29968136 TI - Proper benefit of a three dimensional pre-operative planning software for glenoid component positioning in total shoulder arthroplasty. AB - PURPOSE: Glenoid loosening after total shoulder arthroplasty (TSA) is influenced by the position of the glenoid component. 3D planning software and patient specific guides seem to improve positioning accuracy, but their respective individual application and role are yet to be defined. The aim of this study was to evaluate the accuracy of freehand implantation after 3D pre-operative planning and to compare its accuracy to that of a targeting guide. METHOD: Seventeen patients scheduled for TSA for primary glenohumeral arthritis were enrolled in this prospective study. Every patient had pre-operative planning, based on a CT scan. Glenoid component implantation was performed freehand, guided by 3D views displayed in the operating room. The position of the glenoid component was determined by manual segmentation of post-operative CT scans and compared to the planned position. The results were compared to those obtained in a previous work with the use of a patient-specific guide. RESULTS: The mean error for the central point was 2.89 mm (SD +/- 1.36) with the freehand method versus 2.1 mm (SD +/- 0.86) with use of a targeting guide (p = 0.05). The observed difference was more significant (p = 0.03) for more severely retroverted glenoids (> 10 degrees ). The mean errors for version and inclination were respectively 4.82 degrees (SD +/- 3.12) and 4.2 degrees (SD +/- 2.14) with freehand method, compared to 4.87 degrees (SD +/- 3.61) and 4.39 degrees (SD +/- 3.36) with a targeting guide (p = 0.97 and 0.85, respectively). CONCLUSION: 3D pre-operative planning allowed accurate glenoid component positioning with a freehand method. Compared to the freehand method, patient-specific guides slightly improved the position of the central point, especially for severely retroverted glenoids, but not the orientation of the component. PMID- 29968137 TI - Electric cautery does not reduce blood loss in primary total knee arthroplasty compared with scalpel only surgery a double-blinded randomized controlled trial. AB - PURPOSE: The purpose of this study was to systematically compare blood loss between the electric cautery and scalpel used in primary total knee arthroplasty (TKA). METHODS: We performed a double-blind trial randomizing osteoarthritic knee patients undergoing unilateral TKA done by either using scalpel (group S) or cautery (group C). Primary outcomes were total blood loss calculated from maximum haemoglobin drop and blood loss collected in drain. Secondary outcomes were systemic inflammatory response (serum C-reactive protein), wound complications, and functional outcomes assessed over three months. RESULTS: A total of 80 patients were recruited. Group S had similar calculated total blood loss compared to group C (1070 (S) vs 1128 (C) mL, 95% CI - 219 to 103, p = 0.47). There was no difference in the mean drain-collected blood loss between the two groups (443 (S) vs 486 (C) mL, 95% CI - 128 to 47, p = 0.36). Group C had higher serum C-reactive protein level at 48 hours after TKA compare to group S (105 vs 140 mg/dL, 95% CI 66 to - 4, p = 0.03). Wound complications and functional outcomes at three months were also similar between the two groups. CONCLUSIONS: Using electric cautery does not reduce total blood loss as we thought it would be in primary TKA compare to scalpel only surgery and it is also associated with a greater systemic inflammatory response. Cautery used in TKA which operated under tourniquet may not be worthwhile for the risk of hazardous smoke and the increasing cost. PMID- 29968138 TI - Burnout and Quality of Life Among Massage Therapists with Visual Impairment. AB - Purpose The aim of this study was to evaluate the level of burnout syndrome and quality of life (QoL) among Polish massage therapists, and determine their relationship with sociodemographic and work-related variables. Methods A group of 43 participants aged 28-63, who were blind or poor-sighted were recruited for the study. They were surveyed with sociodemographic data questionnaire and the Polish versions of the Maslach Burnout Inventory-General Survey and WHOQOL-BREF. Results The overall level of exhaustion was 6.79 +/- 4.45, cynicism was estimated at 7.30 +/- 3.43, and professional efficacy was 23.3 +/- 5.44. Regarding QoL, the psychological domain was the highest (73.6 +/- 10.0), while the physical domain was the lowest (61.1 +/- 6.94). None of the sociodemographic variables or occupational factors had any statistical relationship with any burnout subscale. Significant correlations were found between the psychological domain of QoL and marital status (H = 6.570; p = 0.037), years of practice (rho = 0.315; t = 2.124; p = 0.039), hours of practice per week (rho = 0.364; t = 2.505; p = 0.016) and private practice (z = 2.393; p = 0.017). Significant relationships were found between the environmental domain of QoL and the place of residence (H = 5.977; p = 0.050) and between hours of practice per week (rho = 0.335; t = 2.276; p = 0.028). A significant positive correlation was noted between professional efficacy and the social relationship domain (rho = 0.306; t = 2.056; p = 0.046). Conclusion Job activity plays a crucial function in the psychosocial rehabilitation of massage therapists with visual impairment. This was confirmed by the low risk of burnout, and the psychological domain being the highest of QoL. PMID- 29968140 TI - Low Birthweight, Retention in HIV Care, and Adherence to ART Among Postpartum Women Living with HIV in Ghana. AB - Care for low birthweight (LBW) infants can contribute to psychological difficulties and stigma among mothers living with HIV, creating challenges for antiretroviral therapy (ART) adherence and retention in HIV care. We explored how caring for LBW infants affects maternal ART adherence and retention in care. We conducted 30 in-depth interviews with postpartum women living with HIV in Accra, Ghana: 15 with LBW infants and 15 with normal birthweight (NBW) infants. Compared to mothers with NBW infants, mothers with LBW infants described how caring for their newborns led to increased caregiver burden, prolonged hospital stays, and stigma-contributing to incomplete ART adherence and missed clinical appointments. For a few women, care for LBW infants created opportunities for re-engagement in HIV care and motivation to adhere to ART. Results suggest women living with HIV and LBW babies in Ghana face increased challenges that impact their adherence to care and ART. PMID- 29968139 TI - Correction to: The EURO-FORTA (Fit fOR The Aged) List: International Consensus Validation of a Clinical Tool for Improved Drug Treatment in Older People. AB - In the original publication of this article, the members of the FORTA group were provided in such a way that they could not be indexed as collaborators on PubMed. The article should have included an Acknowledgement section as shown below. PMID- 29968141 TI - Characterizing the Patterns of HIV Disclosure to Clients Among South African Female Sex Workers in Port Elizabeth. AB - Female sex workers (FSW) in South Africa are disproportionately affected by HIV, yet little is known about their HIV-status disclosure with clients. Among 410 FSW participating in a cross-sectional study, 213 were HIV positive and aware of their status prior to enrollment. Among FSW aware of their HIV-status, 35% (74/213) reported disclosing their HIV-status to paying clients, whereas 75% (118/158) of those with regular, non-paying partners disclosed to them. In a multivariable analysis, disclosure to clients was associated with more years of education, disclosure to non-paying partners, and meeting clients at established sex work venues, whereas a history of sexual violence was associated with less disclosure. There was also evidence of mutual disclosure with clients, however disclosure was not associated with condom use with clients or being on antiretrovirals. Safer working environments may improve FSW HIV disclosure practices, however disclosure must also be linked with protective behaviors in this population. PMID- 29968142 TI - Syndemic Vulnerability and Condomless Sex Among Incarcerated Men in Mexico City: A Latent Class Analysis. AB - In order to address common statistical and population-based limitations in epidemiological literature applying syndemic theory, this study uses latent class analysis (LCA) to explore how health and social problems coalesce and shape sexual risk behaviors linked to HIV transmission in three Mexico City prisons. Among the studied male inmates, LCA identified four classes, defined by low syndemic risk (61.4%); marijuana (14.3%); depression, substances, and trauma (19.7%); and depression, substances, and marijuana (4.7%). In multinomial regression models, classes with a greater number of syndemic exposures were associated with increased odds of condomless anal sex during incarceration. In analyses stratified by pre-incarceration sexual risk behaviors, however, high syndemic burden classes were associated with condomless anal sex during incarceration differently. Overall, the study findings suggest that LCA has potential utility for syndemic analyses and highlight the need to attend to health and social adversities when addressing sexual risk behaviors and HIV transmission during incarceration. PMID- 29968143 TI - A Study of Optimal Screening for Latent Tuberculosis in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Reactivation of LTBI in patients with IBD on anti-TNF-alpha agents can lead to serious life-threatening illness. No gold standard exists for the detection of LTBI. We examined whether a dual testing strategy with TST and IGRA would improve the detection of LTBI. METHODS: Consecutive IBD patients being considered for anti-TNF-alpha treatment underwent testing with a TST, IGRA and CXR. All patients completed a self-administered questionnaire. The association of both tests with demographic factors, LTBI risk factors, BCG vaccination, IS therapy and agreement between the TST and IGRA were evaluated. RESULTS: One hundred and fifty-five IBD patients were included, 6% were TST positive and 5% were IGRA positive. Concordance between TST and IGRA was fair (kappa = 0.21, 95% CI - 0.081-0.498). Neither test was affected by age, gender or BCG vaccination. The presence of risk factors for LTBI was found to be positively associated with TST (OR 19.8, 95% CI 3.9-102.1), but not IGRA. IGRA was negatively associated with IS therapy (OR 0.06, 95% CI 0.007-0.5), but not TST. Four patients who were IGRA positive but TST negative were treated for LTBI by a respirologist. CONCLUSION: An IGRA result was negatively associated with IS therapy, while the presence of risk factors for LTBI was found to be positively associated with TST results. There was fair agreement between positive TST and IGRA results. The addition of IGRA to the standard practice of TST and CXR increased the number of cases that were initiated on LTBI therapy. PMID- 29968144 TI - Non-invasive evaluation of botulinum-A toxin treatment efficacy in children with refractory overactive bladder. AB - OBJECTIVE: We aimed to evaluate the efficacy and safety of intravesical onabotulinum toxin A (onaBoNTA) injections for the treatment of children diagnosed with refractory overactive bladder (OAB) by using non-invasive methods. METHODS: A total of 31 pediatric patients with a mean age of 10.2 years received intravesical onaBoNTA injection at the dose of 10 U/kg (max: 200 U). Twenty-one patients who failed to respond to the first injection, received second injection 6 months after the first one. The patients were retrospectively evaluated after the 1st and the 2nd injections by means of standardized questionnaire forms and voiding diary records. RESULTS: In the 6-month follow-up, 10 patients (32.2%) were determined to have full response after the first injection. The number of patients with partial response and no response were found to be 15 (48.4%) and 6 (19.4%), respectively. The mean value of Dysfunctional Voiding and Incontinence Symptom Score (DVISS) of the patients with full response was 8.5 before the injection, which decreased to 1 at 6-month follow-up and to 0.5 at 12-month follow-up (p < 0.001). Twenty-one patients without full response after the first injection received a second injection 6 months after the first one. Full response was achieved in 9 (42.9%) of the 21 patients who had a second injection, but only partial response was achieved in 9 (42.9%). Three (14.3%) of the remaining patients did not respond to the second injection either. 1-year follow-up evaluations revealed that the rates of the full response, partial response, and no response were 61.3, 29, and 9.7%, respectively. CONCLUSIONS: Based on our results, onaBoNTA therapy is an effective and reliable second-line off-label therapy in the management of patients with non-neurogenic OAB that is refractory to medical therapy. Asking the patients/guardians to fill out a standardized questionnaire form before and after the therapy enables easy and non-invasive assessment of the response to the therapy. PMID- 29968145 TI - Peripheral and Central Aortic Pressure, Wave-Derived Reflection Parameters, Local and Regional Arterial Stiffness and Structural Parameters in Children and Adolescents: Impact of Body Mass Index Variations. AB - AIM: The aim was to analyze and compare the associations between body mass index (BMI) and structural and functional cardiovascular variables measured in children and adolescents. METHODS: 609 healthy subjects (mean age/range 12/4-18 years, 45% females) were studied. Subjects' BMI and the corresponding z-scores (z-BMI) were determined. Cardiovascular measurements: peripheral and aortic blood pressure (BP), aortic wave-derived parameters, common carotid, femoral and brachial artery diameters and stiffness, carotid intima-media thickness, carotid-radial and carotid-femoral pulse wave velocity (crPWV, cfPWV) and cfPWV/crPWV ratio. Cardiovascular data were standardized (z-scores) using equations (fractional polynomials) obtained from a sub-group (reference population, n = 241) non exposed to cardiovascular risk factors (CVRFs). Simple and multiple regression models were obtained for the associations between cardiovascular z-scores and z BMI and/or z-BMI, age, sex and CVRFs. RESULTS: z-BMI was associated with standardized cardiovascular variables, regardless of age, sex and CVRFs. BP (peripheral rather than aortic) was the variable with the greatest variations associated with z-BMI. Systolic (SBP) and pulse pressure (PP; in that order) were the variables with the highest variations associated with z-BMI. Carotid, but not femoral or brachial stiffness showed BP-dependent variations associated with z BMI. Arterial diameters were associated with z-BMI, without differences among arteries. CONCLUSION: In children and adolescents, z-BMI was gradually and positively associated with haemodynamic (peripheral and central BP) and vascular parameters (structural and functional) with independence of age, sex and other CVRFs (Dyslipidemia, Hypertension, Smoke, Diabetes). There were differences in the associations depending on the arteries studied and on whether central or peripheral haemodynamic parameters were analyzed. PMID- 29968146 TI - Educating Psychiatric Residents in the Age of Organizations and RVUs: a Debate. PMID- 29968147 TI - Identification of a Novel Feruloyl Esterase by Functional Screening of a Soil Metagenomic Library. AB - A cosmid metagenomic library containing 1.3 * 105 clones was created from a soil sample. A novel gene (fae-xuan) encoding a feruloyl esterase was identified through functional screening. Primary sequence analysis showed that the gene consisted of 759 base pairs and encoded a protein of 252 amino acids. The gene was expressed in Escherichia coli BL21 (DE3) and the corresponding purified recombinant enzyme exhibited a molecular weight of 29 kDa. The FAE-Xuan showed high activity (40.0 U/mg) toward methyl ferulate with an optimal temperature and pH of 30 degrees C and 5.0, respectively. Besides methyl ferulate, FAE-Xuan can also hydrolyze methyl sinapate and methyl p-coumarate. The substrate utilization preferences and phylogenetic analysis indicated that FAE-Xuan belongs to type A FAE. FAE-Xuan was quite stable over a broad pH range from 3.0 to 10.0. The activity reduced remarkably in presence of Cu2+. FAE-Xuan can enhance the quantity of ferulic acid from de-starched wheat bran in presence of xylanase. The work presented here highlighted the effectiveness of metagenomic strategy in identifying novel FAEs with diverse properties for potential use in industrial production. PMID- 29968148 TI - Providing Mental Health Services in the Primary Care Setting: the Experiences and Perceptions of General Practitioners at a New York City Clinic. AB - Mental illness is a significant cause of disability worldwide, including here in the United States. Given the shortage of trained mental health professionals, a significant portion of patients needing care are managed in the primary care setting. Accountable Care Organizations (ACOs), for example, are seeking to improve the quality of care for this vulnerable population, but many are facing significant challenges relating to integration of new services. We sought to elucidate barriers faced by primary care practitioners (PCPs)-physicians, physician trainees and nurse practitioners-at a New York primary care clinic, which impede delivery of optimal care to those suffering from mental illness. The study was conducted with 32 PCPs in 2016-2017 at Mount Sinai Internal Medicine Associates in New York City. For the quantitative component of the study, a 54 item questionnaire was devised to assess their attitude, behavior and confidence in managing psychiatric patients. For the qualitative component, data was obtained from 3 open-ended questions. Responses were coded for salient themes. Analysis revealed a range of difficulties faced by PCPs. Overall, participants felt that the need to integrate mental health care into primary care was important, however they reported significant barriers in terms of lack of time, lack of resources, low confidence in treating more complex mental health conditions and difficulties with referring patient to mental health specialists. Despite a growing body of evidence that integration of mental health services in primary care leads to improved outcomes, addressing barriers to care will be key to ensuring feasibility of integration measures. PMID- 29968150 TI - Proteomic biomarkers of cognitive impairment in obstructive sleep apnea syndrome. AB - PURPOSE: There are currently no biomarkers that are associated with cognitive impairment (CI) in patients with obstructive sleep apnea syndrome (OSAS). This pilot study performed an exploratory plasma proteomic analysis to discover potential biomarkers and explore proteomic pathways that differentiate OSAS subjects with and without CI. METHODS: Participants were selected from a cohort of women within 5 years of menopause not on hormone replacement therapy between the ages of 45-60 years. The Berlin questionnaire was used to select OSAS participants who then completed the MCFSI (Mail-In Cognitive Function Screening Instrument) to measure cognition. Six subjects with the highest MCFSI scores (>= 5 denoting CI) were compared to six with normal scores. Proteomic analysis was done by Myriad RBM using a targeted ELISA for 254 serum proteins. Pathway analysis of differentially expressed proteins was performed using STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) software. RESULTS: Distinct proteomic signatures were seen in OSAS subjects with CI as compared to those without CI. Proteins including insulin, prostasin, angiopoietin-1, plasminogen activator inhibitor 1, and interleukin-1 beta were overexpressed in OSAS subjects with CI. Proteins underexpressed in CI participants included cathepsin B, ceruloplasmin, and adiponectin. Pathway analysis revealed prominence of insulin regulated vascular disease biomarkers. CONCLUSIONS: Proteomic biomarkers in participants with cognitive impairment suggest roles for insulin, and vascular signaling pathways, some of which are similar to findings in Alzheimer's disease. A better understanding of the pathogenic mechanisms of CI in OSAS will help focus clinical trials needed in this patient population. PMID- 29968151 TI - Erenumab: First Global Approval. AB - Amgen and Novartis are developing erenumab (AIMOVIGTM, erenumab-aooe)-a fully human monoclonal antibody calcitonin gene-related peptide (CGRP) receptor antagonist-for the prevention of migraine. CGRP is a vasodilatory neuropeptide implicated in the pathophysiology of migraine and treatment with erenumab was associated with significant reductions in migraine frequency in phase II and III clinical trials. Based on these positive results erenumab was recently approved in the US for the preventive treatment of migraine in adults and has received a positive opinion in the EU for the prophylaxis of migraines in adults who have at least 4 migraine days per month. This article summarizes the milestones in the development of erenumab leading to this first approval. PMID- 29968149 TI - Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus. AB - The neonatal exposure to general anesthetics has been associated with neuronal apoptosis and dendritic spines morphologic changes in the developing brain. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated short- and long term effects of a single ketamine (20 mg/kg, s.c.) neonatal exposure at postnatal day 7 in rats on the hippocampal and frontal cortical cellular viability. Additionally, putative neurochemical alterations and neurobehavioral impairments were evaluated in the adulthood. Ketamine neonatal administration selectively decreased cellular viability in the hippocampus, but not in the frontal cortex, 24 h after the treatment. Interestingly, a single ketamine neonatal exposure prevented the vulnerability to glutamate-induced neurotoxicity in the frontal cortex of adult rats. No short- or long-term damage to cellular membranes, as an indicative of cell death, was observed in hippocampal or cortical slices. However, ketamine induced a long-term increase in hippocampal glutamate uptake. Regarding behavioral analysis, neonatal ketamine exposure did not alter locomotor activity and anxiety-related parameters evaluated in the open-field test. However, ketamine administration disrupted the hippocampal-dependent object recognition ability of adult rats, while improved the motor coordination addressed on the rotarod. These findings indicate that a single neonatal ketamine exposure induces a short-term reduction in the hippocampal, but not in cortical, cellular viability, and long-term alterations in hippocampal glutamate transport, improvement on motor performance, and short-term recognition memory impairment. PMID- 29968153 TI - mTOR-mediated glycolysis contributes to the enhanced suppressive function of murine tumor-infiltrating monocytic myeloid-derived suppressor cells. AB - Immune cell activation occurs concurrently with metabolic reprogramming. As important components of the tumor microenvironment, monocytic myeloid-derived suppressor cells (M-MDSCs) are featured by their potent immunosuppressive abilities on anti-tumor effector cells. However, little is known about the contribution of metabolic adaptations to their suppressive roles. In this study, we found that tumor-infiltrating M-MDSCs had the same phenotype with splenic M MDSCs. Compared with splenic M-MDSCs, tumor-infiltrating M-MDSCs exhibited stronger suppressive activities which was accompanied by higher glycolysis. Inhibition of glycolysis impaired the suppressive function of tumor M-MDSCs. Meanwhile, the results demonstrated that mTOR was responsible for this function regulation. mTOR inhibition by rapamycin decreased the glycolysis and reduced the suppressive activities of these cells. Furthermore, rapamycin treatment inhibited the tumor growth and reduced the percentage of M-MDSCs in 3LL tumor bearing mice. These results demonstrated that modulation of metabolism in immune cells can be an effective way to enhance anti-tumor effects. PMID- 29968152 TI - The Future of IL-1 Targeting in Kidney Disease. AB - Interleukin (IL)-1alpha and IL-1beta are proinflammatory cytokines that play a role in many diseases such as rheumatoid arthritis, juvenile rheumatoid arthritis, gout, and periodic inflammatory syndromes, including familial Mediterranean fever and Muckle-Wells syndrome. Drugs targeting IL-1 such as recombinant IL-1Ra (anakinra), neutralizing anti-IL-1beta antibodies (canakinumab) and IL-1beta traps (rilonacept) are in clinical use to treat these diseases. Additionally, experimental evidence suggests a role of IL-1 in kidney disease and hypertension and targeting IL-1 showed promising results in high cardiovascular risk patients, hemodialysis and renal transplantation patients. We now summarize knowledge on the potential role of IL-1 targeting in patients with kidney disease. PMID- 29968155 TI - The ASNC Industry Forum: Advancing a Cherished Relationship. PMID- 29968154 TI - Peripheral monocytes and neutrophils predict response to immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer. AB - We carried out a retrospective cohort study on patients with metastatic non-small cell lung cancer (mNSCLC) to identify the peripheral blood count parameters associated with response to immune checkpoint inhibitors (ICIs). There were 17 males and 15 females. Their median age was 64.5 years (range 20-84). History of smoking was present in 25/32 (78%) patients. Twelve patients received pembrolizumab, 19 patients nivolumab, and one patient nivolumab followed by pembrolizumab. Responses were observed in 19/32 (59%) patients, all partial responses. There was no difference in the distribution of sex, age, and smoking status between responders and non-responders. The median time to response (TTR) was 12 weeks (range 6-24) and the median duration of response (DoR) was 24 weeks (range 7-112). Higher pre-therapy absolute monocyte counts (AMCs) correlated to shorter TTR (p = 0.03), but not to response rate or DoR. Within the group of responders, those with AMCs > 700/mm3 had a significantly shorter median TTR than those with AMCs <= 700/mm3 (8 weeks vs 12 weeks; p = 0.048). Although baseline absolute neutrophil counts (ANCs) did not have any prognostic value, ANCs after first dose predicted response to ICI (p = 0.02). Patients with ANCs <= 4200/mm3 after first dose were more likely to respond than those with ANCs > 4200/mm3 (OR = 6.8; 95% CI 1.1-41.8; p = 0.05). Analysis of AMC and ANC before and during therapy may, therefore, provide an easy method to identify those mNSCLC patients most likely to benefit from ICI therapy. PMID- 29968156 TI - Emerging imaging targets for infiltrative cardiomyopathy: Inflammation and fibrosis. AB - Molecular imaging in infiltrative cardiomyopathies is increasingly penetrating the clinical arena. Current approaches target the infiltrate directly, or its metabolic, physiologic, or functional consequences. Inflammation may not just play a role as the infiltrative mechanism itself. It is also thought to play a key role in the development and progression of heart failure in general, because it promotes the development of tissue fibrosis. The cascade leading from tissue damage to inflammation and further to fibrosis and loss of function has emerged as a therapeutic target. This review focuses (1) on novel tracers of inflammation, which are on the brink of clinical applicability and may be more specific than the gross metabolic marker F-18 deoxyglucose; and (2) on novel biologic imaging targets in fibrosis, which may be exploited for interrogation of the crosstalk between inflammation and loss of contractile function. Ultimately, the success of any novel molecular imaging assay will depend on whether it can be used for successful guidance of novel, targeted therapies aiming at tissue regeneration. PMID- 29968157 TI - Stomach interference in 82Rb-PET myocardial perfusion imaging. AB - BACKGROUND: 82Rubidium(82Rb)-positron-emission-tomography (PET) is prone to some of the same imaging artifacts as single-photon-emission-computed-tomography myocardial perfusion imaging (MPI) including interference from excessive subdiaphragmatic activity. Our aim was to determine associations between clinical parameters and MPI interference including any potential correlation between interference severity and stomach volume. METHODS AND RESULTS: Two hundred men and women fasted two hours prior to standard clinical 82Rb myocardial perfusion rest/stress PET. Images were analyzed for radiotracer interference between left ventricle myocardium and extracardiac activity. Furthermore, volume of the stomach was measured. Interference, predominantly caused by 82Rb activity in the stomach, was less severe in stress PET compared to rest (absent in 46% vs 31% of patients during stress and rest, P < 0.05). In addition, a large stomach volume was associated with more severe interference in rest (P < 0.05) while a high body mass index was associated with less interference. CONCLUSION: Among clinical parameters associated with patient size, BMI was the strongest predictor of MPI interference. Furthermore, a large stomach volume was associated with more severe MPI interference, suggesting that sufficient fasting prior to imminent 82Rb PET may be important to reduce interference from adjacent radiotracer activity and consequently improve interpretation of MPI results, especially in small patients. PMID- 29968159 TI - Circadian clock pathway genes associated with colorectal cancer risk and prognosis. AB - Circadian clock genes influence biological processes and may be involved in tumorigenesis. We systematically evaluated genetic variants in the circadian clock pathway genes associated with colorectal cancer risk and survival. We evaluated the association of 119 single nucleotide polymorphisms (SNPs) in 27 circadian clock pathway genes with the risk of colorectal cancer in a case control study (1150 cases and 1342 controls). The false discovery rate (FDR) method was applied to correct for multiple comparisons. Gene-based analysis was performed by the sequence kernel association test (SKAT). Cox proportional hazards regression was used to calculate the effects of SNPs on the overall survival of patients. We identified that compared to those with the G allele, individuals with the rs76436997 A allele in RORA had a significant 1.33-fold increased risk of colorectal cancer (P = 3.83 * 10- 4). Specifically, the GA/AA genotypes were related to an enhanced risk of colorectal cancer compared with that associated with the GG genotype, which was more common in patients with well and moderately differentiated tumors and Dukes A/B stages. The SNP rs76436997 significantly increased the overall survival time of colorectal cancer patients (P = 0.044). Furthermore, RNA-seq data showed that the mRNA levels of RORA were significantly lower in colorectal tumors than the paired normal tissues. Gene based analysis revealed a significant association between RORA and colorectal cancer risk. These findings highlight the important roles of genetic variations in circadian clock pathway genes play in colorectal cancer risk and suggest that RORA is potentially related to colorectal carcinogenesis. PMID- 29968158 TI - CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-kappaB/RelA in maintaining the homeostasis of human vascular cells. AB - Vascular cell functionality is critical to blood vessel homeostasis. Constitutive NF-kappaB activation in vascular cells results in chronic vascular inflammation, leading to various cardiovascular diseases. However, how NF-kappaB regulates human blood vessel homeostasis remains largely elusive. Here, using CRISPR/Cas9 mediated gene editing, we generated RelA knockout human embryonic stem cells (hESCs) and differentiated them into various vascular cell derivatives to study how NF-kappaB modulates human vascular cells under basal and inflammatory conditions. Multi-dimensional phenotypic assessments and transcriptomic analyses revealed that RelA deficiency affected vascular cells via modulating inflammation, survival, vasculogenesis, cell differentiation and extracellular matrix organization in a cell type-specific manner under basal condition, and that RelA protected vascular cells against apoptosis and modulated vascular inflammatory response upon tumor necrosis factor alpha (TNFalpha) stimulation. Lastly, further evaluation of gene expression patterns in IkappaBalpha knockout vascular cells demonstrated that IkappaBalpha acted largely independent of RelA signaling. Taken together, our data reveal a protective role of NF-kappaB/RelA in modulating human blood vessel homeostasis and map the human vascular transcriptomic landscapes for the discovery of novel therapeutic targets. PMID- 29968160 TI - Highlight report: quality control of stem cell-derived hepatocytes. PMID- 29968162 TI - Mechanochemical modeling of neutrophil migration based on four signaling layers, integrin dynamics, and substrate stiffness. AB - Directional neutrophil migration during human immune responses is a highly coordinated process regulated by both biochemical and biomechanical environments. In this paper, we developed an integrative mathematical model of neutrophil migration using a lattice Boltzmann-particle method built in-house to solve the moving boundary problem with spatiotemporal regulation of biochemical components. The mechanical features of the cell cortex are modeled by a series of spring connected nodes representing discrete cell-substrate adhesive sites. The intracellular signaling cascades responsible for cytoskeletal remodeling [e.g., small GTPases, phosphoinositide-3-kinase (PI3K), and phosphatase and tensin homolog] are built based on our previous four-layered signaling model centered on the bidirectional molecular transport mechanism and implemented as reaction diffusion equations. Focal adhesion dynamics are determined by force-dependent integrin-ligand binding kinetics and integrin recycling and are thus integrated with cell motion. Using numerical simulations, the model reproduces the major features of cell migration in response to uniform and gradient biochemical stimuli based on the quantitative spatiotemporal regulation of signaling molecules, which agree with experimental observations. The existence of multiple types of integrins with different binding kinetics could act as an adaptation mechanism for substrate stiffness. Moreover, cells can perform reversal, U-turn, or lock-on behaviors depending on the steepness of the reversal biochemical signals received. Finally, this model is also applied to predict the responses of mutants in which PTEN is overexpressed or disrupted. PMID- 29968161 TI - A theoretical model of inflammation- and mechanotransduction-driven asthmatic airway remodelling. AB - Inflammation, airway hyper-responsiveness and airway remodelling are well established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and pro-contractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms. PMID- 29968163 TI - Symptomatic cord compression by paraspinal musculature following cervical laminectomy: rare complication. AB - PURPOSE: Cervical laminectomy is an effective treatment for multilevel cervical compressive myelopathy. Symptomatic spinal cord compression (SSCC) by paraspinal musculature (PSM) following cervical laminectomy is rarely reported. The aim of this study was to evaluate the frequency and pathogenesis of this complication after cervical laminectomy. METHODS: Between 2007 and 2016, the medical records of 1309 cervical laminectomy patients were reviewed. From these 1309 records, seven patients (five men and two women; average age, 64.12 years; range 48-78 years) with SSCC by PSM following cervical laminectomy were identified. The incidence and possible risk factors of this rare condition were evaluated. RESULTS: The frequency of SSCC by PSM following cervical laminectomy was 0.53%. Presenting symptoms included paralyses and paresthesias, depending on the level and severity of cervical spinal cord compression. The initial onset of neurologic deterioration varied from 12 h to 21 days after operation. Most patients recovered well after surgical management with an average Barthel index of 74.3 at 6 months after surgery. In comparison with 63 controls, this rare complication was associated with preoperative cervical kyphosis, prior antiplatelet therapy, and posterior decompression with prone position. CONCLUSIONS: SSCC by PSM is a rare but devastating complication following cervical laminectomy, especially in those patients with preoperative kyphosis, prior antiplatelet treatment, and decompression with prone position. MRI is an ideal tool to identify this complication. Rapid cervical cord decompression and avoidance of recurrent compressive events can achieve a good clinical outcome. These slides can be retrieved under Electronic Supplementary Material. PMID- 29968165 TI - sFlt-1/PlGF ratio for the prediction of the time of delivery. AB - PURPOSE: The soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio has been shown to be a useful parameter for the diagnosis and prediction of preeclampsia (PE). An increased sFlt-1/PlGF ratio can be closely linked to the need to deliver. The aim of the study was to examine the mean time until delivery (MTUD) in pregnant women with a strongly increased sFlt-1/PlGF ratio. METHODS: From 2010 to 2018, the sFlt-1/PlGF ratio was determined in 995 singleton pregnancies with diagnosis or suspicion of PE/HELLP syndrome and/or intrauterine growth restriction (IUGR). MTUD of patients with a value above 655 in < 34 weeks of gestation (group 1: n = 13) and above 201 in >= 34 weeks of gestation (group 2: n = 15) was calculated. Patients with a value > 85 but < 655 in < 34 weeks of gestation (group 3: n = 70) and a value > 110 but < 201 (group 4: n = 44) in >= 34 weeks of gestation acted as controls. RESULTS: 28 pregnant women with severely elevated sFlt-1/PlGF ratio and 114 controls were included. In group 1, MTUD was longer compared to group 2 without reaching statistical significance (96.7 h +/- 132.2 vs. 47.7 h +/- 44, p = 0.222). In pregnancies < 34 weeks of gestation (early onset), MTUD was significantly longer in group 3 compared to group 1 (361 h +/- 317.3 vs. 96.7 h +/- 132.2, p < 0.001). In pregnancies >= 34 weeks of gestation (late onset), MTUD was significantly longer in group 4 compared to group 2 (123.6 h +/- 139.2 vs. 47.7 h +/- 44, p = 0.002). CONCLUSIONS: The sFlt-1/PlGF ratio is suitable for decision-making regarding close monitoring of high-risk patients and need for lung maturation. However, for planning of delivery itself further prospective interventional studies are required to define its role as outcome predictor. PMID- 29968164 TI - TRPC6 in simulated microgravity of intervertebral disc cells. AB - PURPOSE: Prolonged bed rest and microgravity in space cause intervertebral disc (IVD) degeneration. However, the underlying molecular mechanisms are not completely understood. Transient receptor potential canonical (TRPC) channels are implicated in mechanosensing of several tissues, but are poorly explored in IVDs. METHODS: Primary human IVD cells from surgical biopsies composed of both annulus fibrosus and nucleus pulposus (passage 1-2) were exposed to simulated microgravity and to the TRPC channel inhibitor SKF-96365 (SKF) for up to 5 days. Proliferative capacity, cell cycle distribution, senescence and TRPC channel expression were analyzed. RESULTS: Both simulated microgravity and TRPC channel antagonism reduced the proliferative capacity of IVD cells and induced senescence. While significant changes in cell cycle distributions (reduction in G1 and accumulation in G2/M) were observed upon SKF treatment, the effect was small upon 3 days of simulated microgravity. Finally, downregulation of TRPC6 was shown under simulated microgravity. CONCLUSIONS: Simulated microgravity and TRPC channel inhibition both led to reduced proliferation and increased senescence. Furthermore, simulated microgravity reduced TRPC6 expression. IVD cell senescence and mechanotransduction may hence potentially be regulated by TRPC6 expression. This study thus reveals promising targets for future studies. These slides can be retrieved under Electronic Supplementary Material. PMID- 29968166 TI - Response of DNA damage genes in acrolein-treated lung adenocarcinoma cells. AB - Acrolein is a alpha-beta-unsaturated aldehyde and is toxic to human upon its exposure from the environment. Sources of exposure to acrolein can be from heating cooking oil, automobile exhaust, tobacco smoke, and plastic waste. Acrolein exposure to lung is a major concern because of its volatile nature and due to its presence in the urban atmospheric air. Acrolein being highly reactive forms DNA and protein adducts, thereby making the cells vulnerable to long-term damage. Such long-term effect can lead to high susceptibility towards malignant transformation as has been reported in cigarette smokers. The response of DNA damaging genes by acrolein can perhaps give an insight to the cause of damage in the DNA by acrolein. The aim of this study was to examine the response of the DNA damage responsive genes by acrolein in A549 lung adenocarcinoma cells. Acrolein treatment at IC50 concentration showed a robust response of the DNA repair genes but eventually failed to rescue the cells from undergoing apoptosis. The cells pretreated with acrolein and followed by growing the same cells in fresh medium in the absence of acrolein did not help the cells to proliferate. These results conclude that exposure to acrolein marks long-lasting damage to DNA, irrespective of the DNA repair response. PMID- 29968167 TI - (I-3,II-3)-Biacacetin-mediated cell death involves mitochondria. AB - Dysregulation of the dynamic balance between cell proliferation and cell death leads to several malignancies including cancer. Biflavones are known to possess anti-proliferative activity against numerous cancer cell lines. The current study was undertaken to understand the mechanism of action of the biflavonoid (I-3,II 3)-biacacetin on MDA-MB-231. Biacacetin induces dose-dependent cell death in MDA MB-231 cells from concentrations as low as 0.5 MUM, which was further confirmed by an increase in sub-G1 cells. Furthermore, the cell death induced by biacacetin was found to be mitochondria-dependent, since cells devoid of mitochondria were viable in the presence of biacacetin even at the highest concentration tested (25 MUM). Fluorescence studies clearly indicated nuclear changes and apoptotic body formation that are characteristic of apoptosis. These results were further corroborated by studies that demonstrate biacacetin to regulate several key markers of apoptosis like Caspase 3, p53, Bax, and poly-ADP-ribose polymerase-1. Furthermore, biacacetin did not induce cell death in normal macrophage cell line, RAW at concentrations up to 15 MUM. In addition to MDA-MB-231 cells, biacacetin also induces apoptotic cell death in the highly chemo-resistant cell line, OVISE, where the cells stained positive for annexin. Biacacetin also induces cell death in the highly malignant fibrosarcoma cell line HT1080. Furthermore, biacacetin also induces significant cell death (50%) in 3D tumor spheroids, at a concentration of 25 MUM. Taken together, these results provide an understanding of biacacetin-mediated cell death and thereby provides a strong basis for the use of such compounds as novel templates for anti-cancer therapeutics. PMID- 29968168 TI - Clinical outcomes of brain metastases from hepatocellular carcinoma: a multicenter retrospective study and a literature review. AB - INTRODUCTION: The introduction of systemic chemotherapy for advanced hepatocellular carcinoma in recent years has led to the prediction that cases of brain metastases from hepatocellular carcinoma will increase. However, because brain metastases from hepatocellular carcinoma are relatively rare, the characteristics of this pathology are poorly understood. METHODS: We carried out a multicenter retrospective study to verify the characteristics of brain metastases from hepatocellular carcinoma in Japan. RESULTS: A total of 38 patients were enrolled and patient characteristics were poor general condition in many patients due to the progression of primary cancers. Stereotactic radiosurgery/stereotactic radiotherapy alone was the most common treatment (39.5%), with best supportive care provided for 10.5%. Median survival was 6 months, the neurological death rate was 28%, and the rate of brain hemorrhage was high (39.5%). Overall survival was analyzed for correlations with age, etiology of chronic liver disease, albumin-bilirubin (ALBI) grade, RPA classification, control of the primary tumor, number of brain metastases, brain hemorrhage, surgical resection, and radiotherapy. In multivariate analysis, ALBI grade, number of brain metastases and brain hemorrhage showed statistically significant correlation. CONCLUSIONS: A multivariate analysis extracted three items-ALBI grade, number of brain metastases, and brain hemorrhage-as prognostic factors for survival of brain metastases from hepatocellular carcinoma. PMID- 29968169 TI - Low physical performance determined by chair rising test muscle mechanography is associated with prevalent fragility fractures. AB - : This study examined associations between physical performance assessed by chair rising test muscle mechanography and DXA T-score as well as body composition in a large patient cohort. Next to various significant interrelationships between these muscle and bone parameters, lower physical performance was associated with prevalent fragility fractures. PURPOSE: Although the interaction between muscle and bone has been demonstrated in various aspects, the clinical focus in the diagnosis of musculoskeletal disorders mainly lies on the skeletal assessments. Accordingly, the association between muscle function, bone mineral density (BMD), and fragility fractures remains to be further elucidated with a feasible muscle assessment in a clinical setting. METHODS: Patient data (2076 patients, 1538 women, 538 men) were evaluated retrospectively from a large dual energy X-ray absorptiometry (DXA) database as well as from chair rising test (CRT) that was performed on a muscle mechanograph. To determine potential predictors of the CRT time and maximum force, a multivariate regression analysis was performed including age, DXA T-score, and body composition indices. Furthermore, CRT results were compared between non-fracture and fracture cases. RESULTS: We determined independent predictors for CRT time such as age, femoral DXA T-score, and total fat mass, whereas CRT force was only influenced by total lean mass. Both women and men with previous fragility fractures displayed a longer CRT time (women p = 0.009, men p = 0.001) and lower CRT force (women p < 0.001, men p < 0.001) than those with no fractures, while no clear differences in CRT results could be detected between normal BMD, osteopenia, and osteoporosis based on DXA T scores. CONCLUSIONS: Our study demonstrates that in addition to the associations between chair rising time and femoral T-score assessed by DXA, low muscle strength is associated with previous fragility fractures. PMID- 29968170 TI - Enhancing the Safety and Efficacy of Food Allergy Immunotherapy: a Review of Adjunctive Therapies. AB - Food allergy is a potentially life-threatening condition with no approved curative therapy. A number of food allergen immunotherapies are being investigated in phase II/III trials; however, these are limited in their ability to restore immune tolerance to food allergens and often result in high rates of allergic side effects, sometimes involving anaphylaxis, that may curtail their impact. A variety of adjunctive therapies have been developed in order to enhance the efficacy and/or improve the safety of food allergen immunotherapy through either shifting the immune response from a Th2 polarized response to a Th1 and regulatory T cell dominated response or by blocking downstream effects of the allergic inflammatory response by targeting IgE or mast cell mediators. Upstream therapies that shift towards a Th1/Treg response include toll-like receptor (TLR) 4 agonists (e.g., MPL and GLA), TLR9 agonists (CpG oligonucleotides), nanoparticles encapsulating peanut allergen (with and without adjuvants, such as CpG or rapamycin), Chinese herbal medicine (food allergy herbal formula (FAHF 2)), probiotics, and interferon-gamma. In contrast, anti-IgE therapies such as omalizumab, anti-histamines like ketotifen, and leukotriene receptor antagonists all target the downstream allergic response. Anti-IgE-based therapies appear to be furthest along with probiotics, Chinese herbal medicines, and TLR-4 agonists currently in early phase clinical trials. Meanwhile, nanoparticles represent an innovative delivery vehicle for immunotherapy that could improve both efficacy and decrease allergic side effects. Furthermore, other biologic therapies directed towards the allergic immune response are on the horizon. A number of factors will need to be evaluated in comparing these treatments, including ability to decrease allergic adverse events, safety of the adjunctive therapies themselves, effect on long-term sustained unresponsiveness, and cost. Further phenotyping of food allergy patients may be necessary to determine which ones respond best to each therapy. However, with so many promising adjunctive therapies, it appears likely that clinicians will have a variety of options to optimize the administration of food allergen immunotherapy. We provided a review of these methods, their influence on allergic adverse events, and utility in improving the immunomodulatory effects of food allergen immunotherapy. PMID- 29968172 TI - Ventriculostomy-related hemorrhage in patients on antiplatelet therapy for endovascular treatment of acutely ruptured intracranial aneurysms. A meta analysis. AB - The risk of ventriculostomy-related hemorrhage among patients requiring antiplatelet therapy (AT) for the endovascular treatment of acutely ruptured intracranial aneurysms needed further investigation. The authors performed a systematic review and meta-analysis of the literature examining the EVD-related hemorrhage rate among patients with and without AT (controls). According to PRISMA guidelines, a comprehensive review of studies published between January 1990 and April 2018 was carried out. The authors identified series with > 5 patients reporting the EVD-associated hemorrhage rate among the AT group and the control group. Variables influencing outcomes were analyzed using a random effects meta-analysis model. We included 13 studies evaluating 516 (with AT) and 647 (without AT) patients requiring ventriculostomy. EVD-related hemorrhage rates were higher among the AT group (125/516 = 20.9%, 95% CI = 11.9-30%, I2 = 90% vs 57/647 = 9%, 95% CI = 5.5-12.5%, I2 = 45.8%) (p < 0.0001). Major EVD-associated hemorrhage rates were low in both the AT and control group (25/480 = 4.4%, 95% CI = 1.7-7.7%, I2 = 53.9% vs 6/647 = 0.7%, 95% CI = 0.03-1.7%, I2 = 0%) (p < 0.0001). Ventriculostomy before embolization and intraprocedural AT were associated with lower rates of EVD-related bleeding (32/230 = 9.6%, 95% CI = 2.1 17.1%, I2 = 75.4% vs 6/24 = 25.1%, 95% CI = 8.8-41%, I2 = 0%) (p < 0.02). The rate of major hemorrhage was higher after dual AT (CP + ASA) compared to single AT (ASA or CP) used as an intraprocedural loading dose (13/173 = 7%, 95% CI = 3.3 10.7%, I2 = 0% vs 6/210 = 1.7%, 95% CI = 0.1-3.4%, I2 = 0%) (p < 0.009). AT during endovascular treatment of acutely ruptured intracranial aneurysms increases the risk of EVD-related hemorrhages, although most of them are small and asymptomatic. When ventriculostomy is performed before endovascular procedures requiring antiplatelet administration, the hemorrhagic risk is minimized. A single antiplatelet therapy is associated with a lower rate of major bleeding than a dual therapy. PMID- 29968171 TI - The dark side of granulocyte-colony stimulating factor: a supportive therapy with potential to promote tumour progression. AB - Granulocyte-colony stimulating factor (G-CSF) is one of several cytokines that can expand and mobilize haematopoietic precursor cells from bone marrow. In particular, G-CSF mobilizes neutrophils when the host is challenged by infection or tissue damage. Severe neutropenia, or febrile neutropenia is a life threatening event that can be mitigated by administration of G-CSF. Consequently, G-CSF has been used to support patients undergoing chemotherapy who would otherwise require dose reduction due to neutropenia. Over the past 10-15 years it has become increasingly apparent, in preclinical tumour growth and metastasis models, that G-CSF can support tumour progression by mobilization of tumour associated neutrophils which consequently promote tumour dissemination and metastasis. With the increasing use of G-CSF in the clinic, it is pertinent to ask if there is any evidence of a similar promotion of tumour progression in patients. Here, we have reviewed the preclinical and clinical data on the potential contribution of G-CSF to tumour progression. We conclude that, whilst the evidence for a promotion of metastasis is strong in preclinical models and that limited data indicate that high serum G-CSF levels in patients are associated with poorer prognosis, no studies published so far have revealed evidence of increased tumour progression associated with supportive G-CSF use during chemotherapy in patients. Analysis of G-CSF receptor positive cohorts within supportive trials, as well as studies of the role of G-CSF blockade in appropriate tumours in the absence of chemotherapy could yield clinically translatable findings. PMID- 29968173 TI - Federal Response to the Opioid Crisis. AB - PURPOSE OF REVIEW: In light of the current crisis in opioid involved overdose deaths, the federal Department of Health and Human Services operating divisions are working together to implement a data-driven, research-based strategy to reduce opioid misuse and its consequences. RECENT FINDINGS: The strategy has five elements: (1) strengthening public health data collection and reporting; (2) advancing the practice of pain management; (3) improving access to addiction prevention, treatment, and recovery support services; (4) increasing availability of overdose-reversing drugs; and (5) supporting cutting-edge research in treatment of pain, opioid use disorder, and associated conditions. The Department of Health and Human Services has developed a concerted, coordinated evidence based effort across department divisions to reduce opioid misuse, prevalence of opioid use disorder, and reduce deaths due to opioid use. PMID- 29968174 TI - Polarized Secretion of Extracellular Vesicles by Mammary Epithelia. AB - Extracellular vesicles (EVs) are secreted by many cell types and are increasingly investigated for their role in human diseases including cancer. Here we focus on the secretion and potential physiological function of non-pathological EVs secreted by polarized normal mammary epithelial cells. Using a transwell system to allow formation of epithelial polarity and EV collection from the apical versus basolateral compartments, we found that impaired secretion of EVs by knockdown of RAB27A or RAB27B suppressed the establishment of mammary epithelial polarity, and that addition of apical but not basolateral EVs suppressed epithelial polarity in a dose-dependent manner. This suggests that apical EV secretion contributes to epithelial polarity, and a possible mechanism is through removal of certain intracellular molecules. In contrast, basolateral but not apical EVs promoted migration of mammary epithelial cells in a motility assay. The protein contents of apical and basolateral EVs from MCF10A and primary human mammary epithelial cells were determined by mass spectrometry proteomic analysis, identifying apical-EV-enriched and basolateral-EV-enriched proteins that may contribute to different physiological functions. Most of these proteins differentially secreted by normal mammary epithelial cells through polarized EV release no longer showed polarized secretion in MCF10A-derived transformed epithelial cells. Our results suggest an essential role of EV secretion in normal mammary epithelial polarization and distinct protein contents and functions in apical versus basolateral EVs secreted by polarized mammary epithelia. PMID- 29968176 TI - Evaluation of a reducible disulfide linker for siderophore-mediated delivery of antibiotics. AB - Bacterial iron uptake machinery can be hijacked for the targeted delivery of antibiotics into pathogens by attaching antibiotics to siderophores, iron chelators that are employed by bacteria to obtain this essential nutrient. We synthesized and evaluated Ent-SS-Cipro, a siderophore-antibiotic conjugate comprised of the triscatecholate siderophore enterobactin and the fluoroquinolone antibiotic ciprofloxacin that contains a self-immolative disulfide linker. This linker is designed to be cleaved after uptake into the reducing environment of the bacterial cytoplasm. We show that the disulfide bond of Ent-SS-Cipro is cleaved by reducing agents, including the cellular reductant glutathione, which results in release of the unmodified fluoroquinolone antibiotic. Antibacterial activity assays against a panel of Escherichia coli show that Ent-SS-Cipro exhibits activity against some, but not all, E. coli. This work informs the design of siderophore-antibiotic conjugates, particularly those carrying antibiotics with cytoplasmic targets that require release after uptake into bacterial cells, and indicates that disulfide linkers may not be generally applicable for conjugation strategies of antibiotics. PMID- 29968177 TI - Mn(III) species formed by the multi-copper oxidase MnxG investigated by electron paramagnetic resonance spectroscopy. AB - The multi-copper oxidase (MCO) MnxG from marine Bacillus bacteria plays an essential role in geochemical cycling of manganese by oxidizing Mn2+(aq) to form manganese oxide minerals at rates that are three to five orders of magnitude faster than abiotic rates. The MCO MnxG protein is isolated as part of a multi protein complex, denoted as Mnx, which includes one MnxG unit and a hexamer of MnxE3F3 subunit. During the oxidation of Mn2+(aq) catalyzed by the Mnx protein complex, an enzyme-bound Mn(III) species was trapped recently in the presence of pyrophosphate (PP) and analyzed using parallel-mode electron paramagnetic resonance (EPR) spectroscopy. Herein, we provide a full analysis of this enzyme bound Mn(III) intermediate via temperature dependence studies and spectral simulations. This Mnx-bound Mn(III) species is characterized by a hyperfine coupling value of A(55Mn) = 4.2 mT (corresponding to 120 MHz) and a negative zero field splitting (ZFS) value of D = - 2.0 cm-1. These magnetic properties suggest that the Mnx-bound Mn(III) species could be either six-coordinate with a 5B1g ground state or square-pyramidal five-coordinate with a 5B1 ground state. In addition, as a control, Mn(III)PP is also analyzed by parallel-mode EPR spectroscopy. It exhibits distinctly different magnetic properties with a hyperfine-coupling value of A(55Mn) = 4.8 mT (corresponding to 140 MHz) and a negative ZFS value of D = - 2.5 cm-1. The different ZFS values suggest differences in ligand environment of Mnx-bound Mn(III) and aqueous Mn(III)PP species. These studies provide further insights into the mechanism of biological Mn2+(aq) oxidation. PMID- 29968175 TI - Pharmacotherapy in Secondary Progressive Multiple Sclerosis: An Overview. AB - Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuroaxonal loss and a heterogeneous clinical course. Multiple sclerosis presents with different phenotypes, most commonly a relapsing-remitting course and, less frequently, a progressive accumulation of disability from disease onset (primary progressive multiple sclerosis). The majority of people with relapsing-remitting multiple sclerosis, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive multiple sclerosis. We have a limited understanding of the mechanisms underlying multiple sclerosis, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for relapsing-remitting multiple sclerosis, but none of these has provided evidence of effectiveness in secondary progressive multiple sclerosis. Recently, there has been some early modest success with siponimod in secondary progressive multiple sclerosis and ocrelizumab in primary progressive multiple sclerosis. Finding treatments to delay or prevent the courses of secondary progressive multiple sclerosis is an unmet and essential goal of the research in multiple sclerosis. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for secondary progressive multiple sclerosis. We examine the field broadly to include trials where participants have progressive or relapsing phenotypes. We summarise the most relevant results from newer investigations from phase II and III randomised controlled trials over the past decade, with particular attention to the last 5 years. PMID- 29968178 TI - Random-amplitude sinusoidal linear acceleration causes greater vestibular modulation of skin sympathetic nerve activity than constant-amplitude acceleration. AB - We tested the hypothesis that random variations in the magnitude of sinusoidal linear acceleration cause greater modulation of skin sympathetic nerve activity (SSNA), but not muscle sympathetic nerve activity (MSNA), than sinusoidal stimuli of the same frequency but constant amplitude. Subjects (n = 22) were seated in a sealed room mounted on a linear motor that could deliver peak sinusoidal accelerations of 30 mG in the antero-posterior direction. Subjects sat on a padded chair with their neck and head supported vertically, thereby minimizing somatosensory cues, facing the direction of motion in the anterior direction. Each block of sinusoidal motion was delivered at 0.2 Hz, either with a constant amplitude (root mean square 14 mG) or randomly fluctuating amplitudes of the same mean amplitude. MSNA (n = 12) and SSNA (n = 10) were recorded via tungsten microelectrodes inserted into muscle or cutaneous fascicles of the common peroneal nerve. Cross-correlation analysis was used to measure the magnitude of vestibular modulation. The modulation index for SSNA was significantly higher during delivery of random vs constant-amplitude acceleration (31.4 +/- 1.9 vs 24.5 +/- 2.5%), but there was no significant difference in the modulation indices for MSNA (28.8 +/- 2.9 vs 33.4 +/- 4.1%). We conclude that the pattern of vestibular stimulation affects the magnitude of modulation of sympathetic outflow to skin but not to muscle. Presumably, this is related to the subperceptual development of nausea, which is known to be associated with greater vestibular modulation of SSNA but not MSNA. PMID- 29968179 TI - Oh, the Places We'll Go: Patient-Reported Outcomes and Electronic Health Records. AB - The growing measurement of patient-reported outcomes (PROs) and adoption of electronic health records (EHRs) presents an unprecedented opportunity to improve health care for patients and populations. The integration of PROs into EHRs can promote patient-centered care and advance quality improvement initiatives, research, and population health. Despite these potential benefits, there are few best practices to help organizations achieve integration. To integrate PROs into EHRs, organizations should evaluate the advantages and disadvantages of various approaches within three themes: Planning, Selection, and Engagement. Planning considerations for integration include what strategy will be used, how the integrated system will be governed, ethical and legal issues, and how data from multiple EHRs can be pooled across organizations. Selection considerations involve identifying which patient population to target for PRO data collection on the basis of the intended use of the data in the health care system, and then choosing specific outcomes and their measures. Engagement considerations include how, where, and with what frequency patients will respond to PRO measures, how to display PRO data in EHRs, how clinical teams will act upon PRO data, and how to train, support and incent clinical teams and patients to incorporate PRO data into care. There is no most effective model that will work in all contexts. Organizations wishing to integrate PROs and EHRs should assemble the multidisciplinary expertise needed to evaluate the advantages and disadvantages of the various approaches for their particular context. We specifically recommend that organizations think carefully about stakeholder participation; design their system with data sharing in mind; develop a framework to aid in PRO selection; create guidelines to support PRO interpretation and action for patients and clinicians; and ensure patients have access to their own PRO data. PMID- 29968180 TI - Understanding 'Good Health care' from the Patient's Perspective: Development of a Conceptual Model Using Group Concept Mapping. AB - BACKGROUND: There is an increasing focus on measuring performance indicators of health care providers, but there is a lack of patient input into what defines 'good care.' OBJECTIVE: The primary objective was to develop a conceptual model of 'good health care' from the patient's perspective. Exploratory analyses were also conducted to investigate (1) differences in patient priorities based on demographic and clinical factors, and (2) differences between patients and health stakeholders (e.g., clinicians, researchers) with respect to patient health care priorities. METHOD: These objectives were accomplished using group concept mapping. Following statement generation, PatientsLikeMe members, Baltimore community members recruited through a university-affiliated clinic, and stakeholders individually sorted the statements into meaningful categories and rated the statements with respect to importance. Qualitative and quantitative analyses generated a final conceptual model. RESULTS: One hundred and fifty-seven patients and 17 stakeholders provided input during statement generation. The 1779 statement pool was reduced to 79 statements for the structuring (sorting and rating) activities. In total, 221 patients and 16 stakeholders completed structuring activities through group concept mapping software. Results yielded a 10-cluster solution, and patient priorities were found to be relatively invariant across demographic/clinical groups. Results were also similar between patients and stakeholders. CONCLUSIONS: This comprehensive qualitative and quantitative investigation is an important first step in developing patient-reported outcome performance measures that capture the aspects of health care that are most important and relevant for patients. Limitations and future directions are discussed. PMID- 29968181 TI - Aberrant expression of TdT in seminomatous germ cell neoplasia. PMID- 29968182 TI - Effects of a Ketogenic Diet on [18F]FDG-PET Imaging in a Mouse Model of Lung Cancer. AB - PURPOSE: Myocardial uptake can hamper visualization of lung tumors, atherosclerotic plaques, and inflammatory diseases in 2-deoxy-2-[18F]fluoro-D glucose ([18F]FDG) studies because it leads to spillover in adjacent structures. Several preparatory pre-imaging protocols (including dietary restrictions and drugs) have been proposed to decrease physiological [18F]FDG uptake by the heart, although their effect on tumor glucose metabolism remains largely unknown. The objective of this study was to assess the effects of a ketogenic diet (as an alternative protocol to fasting) on tumor glucose metabolism assessed by [18F]FDG positron emission tomography (PET) in a mouse model of lung cancer. PROCEDURES: PET scans were performed 60 min after injection of 18.5 MBq of [18F]FDG. PET data were collected for 45 min, and an x-ray computed tomograph (CT) image was acquired after the PET scan. A PET/CT study was obtained for each mouse after fasting and after the ketogenic diet. Quantitative data were obtained from regions of interest in the left ventricular myocardium and lung tumor. RESULTS: Three days on a ketogenic diet decreased mean standard uptake value (SUVmean) in the myocardium (SUVmean 0.95 +/- 0.36) more than one night of fasting (SUVmean 1.64 +/- 0.93). Tumor uptake did not change under either dietary condition. CONCLUSIONS: These results show that 3 days on high-fat diets prior to [18F]FDG PET imaging does not change tumor glucose metabolism compared with one night of fasting, although high-fat diets suppress myocardial [18F]FDG uptake better than fasting. PMID- 29968184 TI - Model-Based Residual Post-Processing for Residual Model Identification. AB - The purpose of this study was to investigate if model-based post-processing of common diagnostics can be used as a diagnostic tool to quantitatively identify model misspecifications and rectifying actions. The main investigated diagnostic is conditional weighted residuals (CWRES). We have selected to showcase this principle with residual unexplained variability (RUV) models, where the new diagnostic tool is used to scan extended RUV models and assess in a fast and robust way whether, and what, extensions are expected to provide a superior description of data. The extended RUV models evaluated were autocorrelated errors, dynamic transform both sides, inter-individual variability on RUV, power error model, t-distributed errors, and time-varying error magnitude. The agreement in improvement in goodness-of-fit between implementing these extended RUV models on the original model and implementing these extended RUV models on CWRES was evaluated in real and simulated data examples. Real data exercise was applied to three other diagnostics: conditional weighted residuals with interaction (CWRESI), individual weighted residuals (IWRES), and normalized prediction distribution errors (NPDE). CWRES modeling typically predicted (i) the nature of model misspecifications, (ii) the magnitude of the expected improvement in fit in terms of difference in objective function value (DeltaOFV), and (iii) the parameter estimates associated with the model extension. Alternative metrics (CWRESI, IWRES, and NPDE) also provided valuable information, but with a lower predictive performance of DeltaOFV compared to CWRES. This method is a fast and easily automated diagnostic tool for RUV model development/evaluation process; it is already implemented in the software package PsN. PMID- 29968183 TI - X-ray-Based 3D Virtual Histology-Adding the Next Dimension to Histological Analysis. AB - Histology and immunohistochemistry of thin tissue sections have been the standard diagnostic procedure in many diseases for decades. This method is highly specific for particular tissue regions or cells, but mechanical sectioning of the specimens is required, which destroys the sample in the process and can lead to non-uniform tissue deformations. In addition, regions of interest cannot be located beforehand and the analysis is intrinsically two-dimensional. Micro X-ray computed tomography (MUCT) on the other hand can provide 3D images at high resolution and allows for quantification of tissue structures, as well as the localization of small regions of interest. These advantages advocate the use of MUCT for virtual histology tool with or without subsequent classical histology. This review summarizes the most recent examples of virtual histology and provides currently known possibilities of improving contrast and resolution of MUCT. Following a background in MUCT imaging, ex vivo staining procedures for contrast enhancement are presented as well as label-free virtual histology approaches and the technologies, which could rapidly advance it, such as phase-contrast CT. Novel approaches such as zoom tomography and nanoparticulate contrast agents will also be considered. The current evidence suggests that virtual histology may present a valuable addition to the workflow of histological analysis, potentially reducing the workload in pathology, refining tissue classification, and supporting the detection of small malignancies. PMID- 29968185 TI - Medication Allergy and Adverse Drug Reaction Documentation Discrepancies in an Urban, Academic Emergency Department. AB - INTRODUCTION: Medication histories, including knowledge of allergies and adverse drug reactions (ADRs), are a nationally recognized quality measure. Medication histories in the emergency department (ED) are often inaccurate or incomplete. Our objective was to determine the prevalence and nature of medication allergy and ADR discrepancies in an urban ED. METHODS: This was a prospective observational descriptive study, enrolling a convenience sample of adults over 7 months at a single academic urban ED. Trained personnel recorded patient demographics and number of daily medications. Patients listed any prior drug allergies or non-allergic ADRs. Following the ED encounter, the patients' self reported allergies and ADRs were compared to the electronic medical record (EMR) to identify and describe discrepancies. RESULTS: A sample of 1014 patients, predominantly black (81%), female (60%), and in the 18- to 59-year-old range (69%), was recruited. Most patients were taking at least one daily medication (74%). Three hundred fifteen patients reported at least one allergy (31%), and 252 (25%) at least one ADR. Four hundred sixteen patients (41%) had a discrepancy between their self-report of allergy or ADR and the EMR. Omissions were the most frequent discrepancy. Full descriptions of allergies or ADR were present in 18.4% of charts. Fifty-seven patients (5.6%) were administered a medication which could have interacted with a documented allergy or ADR; none of the allergy EMR records were updated to reflected this. CONCLUSIONS: In this cross-sectional ED study, drug allergies and ADRs were both highly prevalent. There were significant discrepancies in documentation of allergies and ADRs between patient self-report and the EMR. PMID- 29968186 TI - Generic Health-Related Quality of Life May Not Be Associated with Weight Loss 4 Years After Bariatric Surgery: a Cross-Sectional Study. AB - BACKGROUND: There seems to exist a belief that weight loss is proportionally associated with improvement of health-related quality of life (HRQoL) after bariatric surgery. HRQoL is a complex multidimensional construct of one's perception of health and well-being and is measured through generic and disease specific questionnaires. OBJECTIVES: This study aimed to test the associations between weight loss after bariatric surgery and both generic and obesity-specific HRQoL, and mental distress, controlling for other patient characteristics. METHODS: The study was conducted at the Department of Surgery at Haugesund Hospital (Norway) based on a cohort of bariatric surgery patients operated between 2010 and 2013. Primary outcome measures included the SF-36 (generic HRQoL), IWQoL-Lite (obesity-specific HRQoL), and HADS (mental distress). Blocks of variables (time since surgery, personal characteristics, socioeconomics, comorbidities, surgical complications, experienced life crisis, and weight loss) were entered into hierarchical linear regression models with the four outcome measures as dependent variables. Cumulative explained variance (r2) and increase in r2 after the entry of each block of variables is reported. RESULTS: A total of 206 completed the outcome measures with a mean (SD) of 4.4 (1.1) years after surgery. The generic SF-36 physical and mental composite scores were significantly associated (p < .05) with socioeconomics, baseline comorbidities, and surgical complications. Obesity-specific IWQoL-Lite scores were significantly (p < .05) associated with weight loss. CONCLUSIONS: The study indicates that post operative weight loss is associated with obesity-specific HRQoL but demonstrates no associations between weight loss and generic HRQoL, when controlling for other patient characteristics. PMID- 29968188 TI - Posterior laxity increases over time after PCL reconstruction. AB - PURPOSE: Restoration of posterior tibial translation (PTT) after reconstruction of the posterior cruciate ligament (PCL) is deemed necessary to restore physiological knee kinematics. However, current surgical techniques have failed to show a complete reduction of posterior laxity. It was hypothesized that early postoperative PTT increases over time. METHODS: The study comprised of 46 patients (10 female, 36 male; 30 +/- 9 years), who underwent PCL reconstruction in a single-surgeon series. Patients were evaluated by bilateral stress radiographs in a prospective manner preoperatively; at 3, 6, 12 and 24 months; and at a final follow-up (FFU) of at least 5 years. Covariants included age, gender, BMI, tibial slope (TS) and the number of operated ligaments. Two blinded observers reviewed all radiographs, evaluating the TS and the posterior tibial translation. RESULTS: All patients were evaluated at a mean final follow-up of 102 (range 65-187) months. Mean side-to-side difference of the PTT significantly improved from preoperative to 3-month postoperative values (10.9 +/- 3.1 vs. 3.6 +/- 3.8 mm; P < 0.0001). The PTT increased to 4.6 +/- 3.7 mm at 6 months, to 4.8 +/- 3.3 mm at 12 months, to 4.8 +/- 3.2 mm at 24 months, to 5.4 +/- 3.4 mm at FFU. Consequently, there was a significant increase of PTT between 3-month and final follow-up (3.6 +/- 3.8 vs. 5.4 +/- 3.4 mm; P = 0.02). Flattening of the TS resulted in a significantly higher PTT compared to subjects with a high TS at 24 months and FFU. There was no significant influence by BMI, age, gender and the number of operated ligaments. CONCLUSIONS: Early results after PCL reconstruction seem promising as posterior tibial translation is significantly improved. However, there is a significant increase in PTT from early postoperative values to the final follow-up of at least 5 years. This is particularly notable in patients with flattening of the TS. As a consequence, surgeons and patients need to be aware that initial posterior stability should not be equated with the final outcome. LEVEL OF EVIDENCE: Cohort study, Level III. PMID- 29968187 TI - Changes in Bone Mineral Density Following Weight Loss Induced by One-Anastomosis Gastric Bypass in Patients with Vitamin D Supplementation. AB - BACKGROUND: Little is known about changes in bone mineral density (BMD) following weight loss after one-anastomosis gastric bypass (OAGB) and the role of serum vitamin D and its supplementation on bone metabolism. We evaluated BMD after OAGB as a function of vitamin D supplementation with respect to a minimum threshold of 25-hydroxy-vitamin-D [25(OH)D] concentration, which could prevent or decelerate an eventual bone loss. METHODS: Fifty bariatric patients who participated in the randomized controlled trial were included in this analysis. BMD and anthropometric measurements by DXA and laboratory parameters were assessed before (T0), at 6 (T6), and 12 months (T12) after surgery. RESULTS: OAGB resulted in a 36% total body weight loss with a decrease in body fat and an increase in lean body mass. A significant decrease in BMD was seen in lumbar spine by 7%, left hip 13%, and total body 1%, but not in forearm. Bone turnover markers increased significantly but with normal parathyroid hormone concentrations. Weight loss was not associated with changes in BMD. A serum 25(OH)D concentration > 50 nmol/l at T6 and T12 (adequate-vitamin-D-group; AVD) showed a significant lower bone loss, compared to the inadequate-vitamin-D-group (IVD; < 50 nmol/l). Lower bone loss in the left hip showed a strong correlation with higher 25(OH)D concentrations (r = 0.635, p = 0.003). CONCLUSION: These findings support a dose effect of vitamin D supplementation on bone health and suggest that 25(OH)D concentrations need to be above 50 nmol/l at least during the first postoperative year to decelerate bone loss in patients undergoing OAGB. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: Clinicaltrials.gov (NCT02092376) at https://clinicaltrials.gov /. EudraCT (2013 003546-16) at https://eudract.ema.europa.eu /. PMID- 29968189 TI - Femoral tunnel length in anatomical single-bundle ACL reconstruction is correlated with height, weight, and knee bony morphology. AB - PURPOSE: The purpose of this study was to reveal the correlation between femoral tunnel length in anatomical single-bundle anterior cruciate ligament (ACL) reconstruction and body size and/or knee morphology. METHODS: Thirty-one subjects undergoing anatomical single-bundle ACL reconstruction were included in this study (20 female, 11 male; median age 46, 15-63). Pre-operative height, body weight, and body mass index (BMI) were measured. In pre-operative magnetic resonance imaging, the thickness of the quadriceps tendon and the whole anterior posterior (AP) length of the knee were measured using the sagittal slice. Using post-operative three-dimensional computed tomography, accurate axial and lateral views of the femoral condyle were evaluated. The correlation of femoral tunnel length, which was measured intra-operatively, with the height, weight, BMI, quadriceps tendon thickness, AP length of the knee, trans-epicondylar length, the notch area (axial), length of Blumensaat's line, and the height and area of the lateral wall of the femoral intercondylar notch were statistically analyzed. Tunnel placement was also evaluated using a Quadrant method. RESULTS: The average femoral tunnel length was 35.6 +/- 4.4 mm. The average height, body weight, and BMI were 162.7 +/- 7.2 cm, 61.9 +/- 10 kg, and 23.4 +/- 3.5, respectively. Femoral tunnel length was significantly correlated with height, body weight and the height and area of lateral wall of the femoral intercondylar notch, and the length of the Blumensaat's line. CONCLUSION: For clinical relevance, the risk of creating a femoral tunnel of insufficient length in anatomical single-bundle ACL reconstruction exists in subjects with small body size. Surgeons should pay careful attention to prevent this from occurring. LEVEL OF EVIDENCE: Case controlled study, Level III. PMID- 29968190 TI - Chmp4c is required for stable kinetochore-microtubule attachments. AB - Formation of stable kinetochore-microtubule attachments is essential for accurate chromosome segregation in human cells and depends on the NDC80 complex. We recently showed that Chmp4c, an endosomal sorting complex required for transport protein involved in membrane remodelling, localises to prometaphase kinetochores and promotes cold-stable kinetochore microtubules, faithful chromosome alignment and segregation. In the present study, we show that Chmp4c associates with the NDC80 components Hec1 and Nuf2 and is required for optimal NDC80 stability and Hec1-Nuf2 localisation to kinetochores in prometaphase. However, Chmp4c-depletion does not cause a gross disassembly of outer or inner kinetochore complexes. Conversely, Nuf2 is required for Chmp4c kinetochore targeting. Constitutive Chmp4c kinetochore tethering partially rescues cold-stable microtubule polymers in cells depleted of the endogenous Nuf2, showing that Chmp4c also contributes to kinetochore-microtubule stability independently of regulating Hec1 and Nuf2 localisation. Chmp4c interacts with tubulin in cell extracts, and binds and bundles microtubules in vitro through its highly basic N-terminal region (amino acids 1-77). Furthermore, the N-terminal region of Chmp4c is required for cold stable kinetochore microtubules and efficient chromosome alignment. We propose that Chmp4c promotes stable kinetochore-microtubule attachments by regulating Hec1-Nuf2 localisation to kinetochores in prometaphase and by binding to spindle microtubules. These results identify Chmp4c as a novel protein that regulates kinetochore-microtubule interactions to promote accurate chromosome segregation in human cells. PMID- 29968191 TI - [New possibilities with retroflexed functional endoscopy]. AB - BACKGROUND: Anterograde transnasal flexible endoscopy of the pharynx, larynx, and proximal trachea without sedation has been established since the 1990s. Retroflexed endoscopic functional analysis has recently been introduced. OBJECTIVES: Adding retroflexed functional endoscopy from the oral cavity up to the duodenum to anterograde diagnostics allows the precise demonstration of how different factors interact in a complex way, e. g., in case of dysphagia or pathological reflux. MATERIALS AND METHODS: A 70-cm-long high-definition endoscope without a channel system is equipped with a 200 degrees retroflexed view, a mm-cm scale, and a roller system. The endoscope can be lengthened, stopped, or shortened during the procedure. Standard positions, viewing directions and display details ensure that findings are comparable. Mastication, food transport and digestion are observed in the unsedated patient. RESULTS: Depending on indication and symptoms, we defined a diagnostic algorithm including three specific pathways: (1) for conditions that originate in the oral cavity, larynx or pharynx, (2) for suspected reflux disease, or for neurological or neuromuscular disorders of food transport, (3) for duodenogastric, gastroesophageal and esophagopharyngeal reflux, as well for benign or malignant tumors. CONCLUSION: The advantages of functional endoscopy have an impact not only on the medical staff and patients. Its precise and participatory approach is relevant to healthcare, enlarges the diagnostic horizon, and forms a basis for interdisciplinary collaboration. PMID- 29968194 TI - Radiation shielding parameters of some antioxidants using Monte Carlo method. AB - In this paper, radiation shielding parameters such as mass attenuation coefficients and half value layer (HVL) of some antioxidants are investigated using MCNPX (version 2.4.0). The validation of the generated MCNPX simulation geometry for antioxidant structures is provided by comparing the results with standard WinXcom data for radiation mass attenuation coefficients of antioxidants. Very good agreement between WINXCOM and MCNPX was obtained. The results from the validated geometry were used to calculate the shielding parameters of different antioxidants. The radiation attenuation properties of each antioxidant were compared with each other. The results showed that, on average, the highest and the lowest radiation mass attenuation coefficients were observed on hesperidin and delphinidin chloride, respectively. It can be concluded that Monte Carlo simulation is a strong tool and an alternate method where experimental investigations are not possible and a standard simulation setup can be used in further studies for different biological structures. It can also be concluded that the obtained results from this study are very useful for radiology and radiotherapy applications where antioxidants are frequently used. PMID- 29968195 TI - Correction to: Acute and long-term outcomes of epicardial left atrial appendage ligation with the second-generation LARIAT device: a high-volume electrophysiology center experience. AB - Unfortunately, an error occurred in the conclusion section of this article. The corrected conclusion text is given below. PMID- 29968196 TI - Progress in heart failure treatment in Germany. AB - Acute and chronic heart failure is still a major cause of morbidity and mortality in Europe. Nevertheless, significant progress has been made in diagnosis and treatment of heart failure as well as in unraveling its molecular causes. Here, we focus on some relevant contributions to these achievements by German cardiovascular clinicians and scientists. PMID- 29968197 TI - Risk of Hepatitis B Reactivation in Patients with Psoriasis on Ustekinumab. AB - BACKGROUND AND OBJECTIVES: Ustekinumab is used to treat moderate-to-severe psoriasis by blocking the interleukin-12/23 pathway, which is also essential against intracellular pathogens. Because there is a high prevalence of hepatitis B viral infection in Taiwan, the expected risk of reactivation is higher among ustekinumab-treated patients. We performed this study to investigate the risk of hepatitis reactivation. SUBJECTS AND METHODS: Patients with psoriasis treated with ustekinumab from October 2011 to June 2016 were enrolled in a prospective cohort study. All patients were tested for hepatitis B serology and serum viral DNA at baseline. For those positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibodies (anti-HBc) testing for HBV DNA was conducted at least annually. An increase of HBV DNA > 2 log scale or emergence of HBV DNA were defined as reactivation. The primary outcome of this study was HBV reactivation. RESULTS: Ninety-three psoriasis patients receiving ustekinumab were included. The average duration of treatment and follow-up was 24 +/- 12 months. There were 39 patients classified as naive to HBV or vaccinated, and none of these patients had HBV reactivation. Among the remaining 54 patients classified as inactive HBV carriers, resolved HBV infection, or isolated anti-HBc positivity, only 3 patients experienced virologic reactivation, and none had liver failure. CONCLUSION: The study outcomes indicate that ustekinumab could be safe for psoriasis patients since none developed persistent hepatitis or acute liver failure during therapy. However, the re-appearance of plasma HBV DNA requires appropriate monitoring of HBV viral load during ustekinumab treatment. PMID- 29968198 TI - Triple Therapy: When, if Ever? AB - PURPOSE OF REVIEW: More than 9% of patients who undergo percutaneous coronary intervention (PCI) carry a concomitant indication for long-term anticoagulation (OAC). The optimal combination of anticoagulation and antiplatelet therapy for these patients remains uncertain. RECENT FINDINGS: Numerous studies have demonstrated that dual antiplatelet therapy (DAPT) remains superior to vitamin K antagonists (VKA) in the prevention of stent-related events. Nonetheless, OAC therapy is more efficacious than DAPT at reducing thromboembolism in patients with atrial fibrillation. The combination of DAPT and OAC, known as triple therapy, portends as much as a threefold increased risk of fatal and nonfatal bleeding compared to warfarin monotherapy. Recent studies have demonstrated the safety of shorter durations of triple therapy with subsequent transition to a P2Y12 inhibitor in combination with an OAC. Here, we review the evidence regarding the safety and efficacy of dual therapy with OAC in combination with a P2Y12 inhibitor versus triple therapy among recently stented patients with a long term requirement for OAC. PMID- 29968199 TI - Corticosteroids in chronic inflammatory demyelinating polyneuropathy : A retrospective, multicentre study, comparing efficacy and safety of daily prednisolone, pulsed dexamethasone, and pulsed intravenous methylprednisolone. AB - BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) can be treated with corticosteroids or intravenous immunoglobulins. Various corticosteroid regimens are currently used in CIDP, but it is unknown whether they are equally efficacious. In this retrospective study, we compared efficacy and safety of three corticosteroid regimens in CIDP patients. METHODS: We included treatment naive patients that fulfilled the EFNS/PNS criteria for CIDP. Patients were treated with corticosteroids according to the local protocol of three CIDP expertise centres. Corticosteroid regimens consisted of daily oral prednisolone, pulsed oral dexamethasone, or pulsed intravenous methylprednisolone. Outcomes were number of responders to treatment, remission rate of treatment responders, overall probability of 5-year remission, and the occurrence of adverse events. RESULTS: A total of 125 patients were included. Sixty-seven (54%) patients received daily prednisone or prednisolone, 37 (30%) pulsed dexamethasone, and 21 (17%) pulsed intravenous methylprednisolone. Overall, 60% (95% CI 51-69%) responded to corticosteroids, with no significant difference between the three treatment regimens (p = 0.56). From the 75 responders, 61% (95% CI 50-73%) remained in remission, during a median follow-up of 55 months (range 1-197 months). The probability of responders reaching 5-year remission was 55% (95% Cl 44-70%), with no difference between the three groups. Adverse events leading to a change in treatment occurred in ten patients (8%). Two patients had a serious adverse event. CONCLUSION: Corticosteroids lead to improvement in 60% of patients and to remission in 61% of treatment responders. There were no differences between treatment modalities in terms of efficacy and safety. PMID- 29968200 TI - Coordination and timing deficits in speech and swallowing in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). AB - BACKGROUND: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early onset neurodegenerative disease that typically results in ataxia, upper motor neuron dysfunction and sensorimotor peripheral neuropathy. Dysarthria and dysphagia are anecdotally described as key features of ARSACS but the nature, severity and impact of these deficits in ARSACS are not known. A comprehensive quantitative and qualitative characterization of speech and swallowing function will support diagnostics, provide insights into the underlying pathology, and guide day-to-day clinical management. METHODS: 11 consecutive non-Quebec ARSACS patients were recruited, and compared to healthy participants from several published and unpublished cohorts. A comprehensive behavioural assessment including objective acoustic analysis and expert perceptual ratings of motor speech, the Clinical Assessment of Dysphagia in Neurodegeneration (CADN), videofluoroscopy and standardized tests of dysarthria and swallowing related quality of life was conducted. RESULTS: Speech in this ARSACS cohort is characterized by pitch breaks, prosodic deficits including reduced rate and prolonged intervals, and articulatory deficits. The swallowing profile was characterized by delayed initiation of the swallowing reflex and late epiglottic closure. Four out of ten patients were observed aspirating thin liquids on videofluoroscopy. Patients report that they regularly cough or choke on thin liquids and solids during mealtimes. Swallowing and speech-related quality of life was worse than healthy controls on all domains except sleep. CONCLUSIONS: The dysphagia and dysarthria profile of this ARSACS cohort reflects impaired coordination and timing. Dysphagia contributes to a significant impairment in functional quality of life in ARSACS, and appears to manifest distinctly from other ARSACS dysfunctions such as ataxia or spasticity. PMID- 29968202 TI - MIStore: a Blockchain-Based Medical Insurance Storage System. AB - Currently, blockchain technology, which is decentralized and may provide tamper resistance to recorded data, is experiencing exponential growth in industry and research. In this paper, we propose the MIStore, a blockchain-based medical insurance storage system. Due to blockchain's the property of tamper-resistance, MIStore may provide a high-credibility to users. In a basic instance of the system, there are a hospital, patient, insurance company and n servers. Specifically, the hospital performs a (t, n)-threshold MIStore protocol among the n servers. For the protocol, any node of the blockchain may join the protocol to be a server if the node and the hospital wish. Patient's spending data is stored by the hospital in the blockchain and is protected by the n servers. Any t servers may help the insurance company to obtain a sum of a part of the patient's spending data, which servers can perform homomorphic computations on. However, the n servers cannot learn anything from the patient's spending data, which recorded in the blockchain, forever as long as more than n - t servers are honest. Besides, because most of verifications are performed by record-nodes and all related data is stored at the blockchain, thus the insurance company, servers and the hospital only need small memory and CPU. Finally, we deploy the MIStore on the Ethererum blockchain and give the corresponding performance evaluation. PMID- 29968201 TI - Radiofrequency ablation versus cryoablation for T1b renal cell carcinoma: a multi center study. AB - PURPOSE: To compare the clinical outcomes between radiofrequency ablation (RFA) and cryoablation for the treatment of clinical T1b (cT1b) renal cell carcinoma (RCC). MATERIALS AND METHODS: The data of 46 patients [(39 men and 7 women, median age; 73 years, range 39-87 years)] were gathered from 3 institutions. RFA and cryoablation were performed on 23 patients each. The median number of ablation needle was 2 (range 1-4) and 4 (range 3-5, p < 0.0001) in RFA and cryoablation, respectively. Technique efficacy defined as coverage of the tumor by ablative zone, adverse events, local tumor progression, and survival were compared between the RFA and cryoablation groups. RESULTS: The primary technique efficacy rate was significantly higher in the cryoablation group (96%, 22/23) than in the RFA group (65%, 15/23, P = 0.02). There was no significant difference in the secondary technique efficacy rate after additional RFA and cryoablation [21/23 (91%) vs. 23/23 (100%); P = 0.24]. The incidence of grade 3 or higher adverse events was similar between the 2 groups (P > 0.99). There was no significant difference between local tumor progression rate after RFA and cryoablation [3/21 (14%) vs. 2/23 (9%); P = 0.66]. The 5-year overall survival rates were comparable between RFA and cryoablation (78 vs. 82%; P =0.82). CONCLUSION: Other than primary technique efficacy, the clinical outcomes between RFA and cryoablation were similar in patients with cT1b RCC. PMID- 29968203 TI - The clinical value of the multi-channel PVEP and PERG in the diagnosis and management of the patient with pituitary adenoma: a case report. AB - PURPOSE: To present a patient with a diagnosis of pituitary adenoma and progressive visual pathway dysfunction detected in the electrophysiological tests in one-year follow-up. Patient is a 59-year-old male with a non-secreting pituitary macroadenoma. METHODS: Routine ophthalmological evaluation, standard automatic perimetry (SAP), retinal nerve fibers layer and the ganglion cell complex thickness in optical coherent tomography (OCT), as well as electrophysiological examinations (pattern electroretinogram-PERG, multi-channel pattern visual evoked potentials-multi-channel PVEPs record according to ISCEV standards) were performed. The examination and additional tests were conducted 3 times (in 0, 6 and 12 months) and 6 months after neurosurgery. RESULTS: Visual acuity, funduscopic examinations, SAP, OCT and electrophysiological test results at the first visit were all normal. In both eyes, the abnormalities were observed only in the multi-channel PVEP and PERG despite the absence of the changes in the routine ophthalmological examination and additional tests after 6- and 12-month follow-up. The tumor growth but without chiasmal compression was confirmed by magnetic resonance imaging. The progression of the optic pathway dysfunction in the electrophysiological tests was a cause of surgical removal of the pituitary tumor. CONCLUSION: This case highlights novel observations that in patients with pituitary tumor, detection of the early dysfunction of the visual pathway may lead to modification of the medical treatment regimen and reduce the incidence of irreversible optic nerve damage. PMID- 29968205 TI - Speeded multielement decision-making as diffusion in a hypersphere: Theory and application to double-target detection. AB - We generalize the circular 2D diffusion model of Smith (Psychological Review, 123, 425-451: 2016) to provide a new model of speeded decision-making in multielement visual displays. We model decision-making in tasks with multielement displays as evidence accumulation by a vector-valued diffusion process in a hypersphere, whose radius represents the decision criterion for the task. We show that the methods used to derive response time and accuracy predictions for the 2D model can be applied, with only minor changes, to predict performance in higher dimensional spaces as well. We apply the model to the double-target deficit paradigm of Duncan (Psychological Review, 87, 272-300: 1980) in which participants judge whether briefly presented four-element displays contain one- or two-digit targets among letter distractors. A 4D version of the hyperspherical diffusion model correctly predicted distributions of response times and response accuracy as a function of task difficulty in single-target and double-target versions of the task. The estimated drift rate parameters from the model imply that the mental representation of the decision alternatives, which we term the "decision template" for the task, encodes configural stimulus properties that reflect the number of targets in the display. Along with its application to multielement decision-making, the model has the potential to characterize the speed and accuracy of multiattribute decisions in studies of cognitive categorization, visual attention, and other areas. PMID- 29968204 TI - Nab-paclitaxel in combination with gemcitabine for the treatment of metastatic pancreas cancer: the South Wales experience. AB - The prognosis of pancreatic cancer remains very poor, with a 5-year survival rate of around 3%. There has been little impact from various chemotherapy regimens on improving outcome for several decades. Gemcitabine has been the mainstay chemotherapy for around two decades with little improvement in overall survival (OS) for patients with advanced disease. However, more recently, there has been a paradigm shift in treatment options for these patients. Reported in 2011, combination therapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil) showed a long awaited but modest improvement in survival, but is reserved only for a small proportion of very fit patients due to concerns over its toxicities. In 2013, the landmark phase III international study MPACT demonstrated an improvement in OS with the combination of nab-paclitaxel and gemcitabine (GEMBRAX) for the treatment of patients more akin to the real-world population. In the United Kingdom (UK), it was first made widely available on the National Health Service (NHS) in Wales in September 2014 and only recently received a final positive appraisal by NICE (National Institute of Clinical Excellence) for England in 2017. In this paper, we present our data on the use of this treatment for patients in South Wales and compare real-life practical experience with the MPACT data and reflecting the impact of this paradigm shift. PMID- 29968206 TI - Using experiential optimization to build lexical representations. AB - To account for natural variability in cognitive processing, it is standard practice to optimize a model's parameters by fitting it to behavioral data. Although most language-related theories acknowledge a large role for experience in language processing, variability reflecting that knowledge is usually ignored when evaluating a model's fit to representative data. We fit language-based behavioral data using experiential optimization, a method that optimizes the materials that a model is given while retaining the learning and processing mechanisms of standard practice. Rather than using default materials, experiential optimization selects the optimal linguistic sources to create a memory representation that maximizes task performance. We demonstrate performance on multiple benchmark tasks by optimizing the experience on which a model's representation is based. PMID- 29968207 TI - Peroxisomes: role in cellular ageing and age related disorders. AB - Peroxisomes are dynamic organelles essential for optimum functioning of a eukaryotic cell. Biogenesis of these organelles and the diverse functions performed by them have been extensively studied in the past decade. Their ability to perform functions depending on the cell type and growth conditions is unique and remarkable. Oxidation of fatty acids and reactive oxygen species metabolism are the two most important functions of these ubiquitous organelles. They are often referred to as both source and sink of reactive oxygen species in a cell. Recent research connects peroxisome dysfunction to fatal oxidative damage associated with ageing-related diseases/disorders. It is now widely accepted that mitochondria and peroxisomes are required to maintain oxidative balance in a cell. However, our understanding on the inter-dependence of these organelles to maintain cellular homeostasis of reactive oxygen species is still in its infancy. Herein, we summarize findings that highlight the role of peroxisomes in cellular reactive oxygen species metabolism, ageing and age-related disorders. PMID- 29968209 TI - Triiodothyronine replacement in critically ill adults with non-thyroidal illness syndrome. AB - PURPOSE: Non-thyroidal illness syndrome is commonly encountered in critically ill patients, many of whom are treated with thyroid hormones despite uncertainty regarding their safety and effectiveness. This retrospective observational study sought to evaluate the utilization, safety, and effectiveness of triiodothyronine (T3) supplementation in critically ill adults admitted to either of two non cardiac surgery mixed-medical/surgical intensive care units (ICU). METHODS: Consecutive adults admitted to an ICU and treated with enterally administered T3 were identified over a two-year period. Data pertaining to demographics, T3 utilization, safety, and clinical outcomes were collected. RESULTS: Data were extracted from the medical records of 70 consecutive patients. All had baseline serum free T3 concentrations below the lower limit of our laboratory's reference range and 22 (31%) patients also had low thyroxine (T4) concentrations. The most commonly prescribed replacement doses were 25 and 50 ug for a median of seven days and almost half of the patients also received concomitant T4 supplementation. Serum thyroid hormones were available in 48 of 70 patients (69%) at a median [interquartile range (IQR)] of 7 [6-38] days. Normalization of free T3 serum concentrations occurred in 30 of 48 patients (63%) at a median [IQR] of 8 [7-33] days. A dose-response relationship was identifiable. New adverse events (atrial fibrillation/flutter, hypertension, sinus tachycardia, myocardial infarction) during therapy were less frequent than at baseline. CONCLUSIONS: This study suggests that with T3 supplementation there was evidence of serum free T3 normalization without evidence of associated harms. A definitive trial is needed to evaluate clinical effectiveness. PMID- 29968208 TI - Neuroinflammation in acute hepatic encephalopathy rats: imaging and therapeutic effectiveness evaluation using 11C-PK11195 and 18F-DPA-714 micro-positron emission tomography. AB - Neuroinflammation has an important influence in pathogenesis of acute hepatic encephalopathy (AHE). 11C-PK11195 and 18F-DPA-714 targeted to translocator protein (TSPO) have potential application in positron emission tomography (PET) as a molecular probe of neuroinflammation. The aim of this study was to compare these two radiotracers and their effectiveness in detecting neuroinflammation for the imaging of AHE rat models. Furthermore, using the new radiotracer 18F-DPA 714, we analyzed the effectiveness of therapeutic treatment for neuroinflammation in AHE. First, we performed a comparative study of 11C-PK1195 and 18F-DPA-714 PET to image neuroinflammation in AHE rats induced by thioacetamide. Twenty-four rats were divided into either control group (n = 12) or AHE group (n = 12). Next, each group was subdivided depending on the radiotracer used during PET imaging (n = 6). Radiotracer uptake values encompassing the whole brain were compared. Lastly, we used the optimized tracer to monitor anti-neuroinflammation effects in AHE induced rats. Forty-six rats were divided into four groups: [normal saline (NS) group (n = 13), minocycline (MINO) group (n = 11), dexamethasone (DEXA) group (n = 11), MINO+DEXA group (n = 11)]. 18F-DPA-714 PET was performed and the uptake values were calculated. The rotarod test, biochemical indices, and histopathological examinations were quantitatively measured and compared. AHE rats showed reduced motor ability, elevated ammonia levels, and higher liver function indices (all P < 0.05) with unchanged inflammatory factors (all P > 0.05), compared to control group. Both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation of AHE rats. Behavioral studies showed that MINO and/or DEXA improved the motor ability in AHE rats (P < 0.05); however, no differences were found for liver function or inflammatory markers among the four groups (all P > 0.05). The average uptake values of whole brain and multiple brain areas in the MINO+DEXA group were lower compared to all other groups (all P < 0.05), which was demonstrated by CD11b stains of microglia. Our results show that both 11C-PK11195 and 18F-DPA-714 PET can detect neuroinflammation in AHE-induced rat models. Additionally, the combined use of minocycline and dexamethasone can effectively inhibit neuroinflammation in AHE-induced rats, which can be sensitively monitored by 18F-DPA-714 PET. PMID- 29968210 TI - Magnetic flocculants synthesized by Fe3O4 coated with cationic polyacrylamide for high turbid water flocculation. AB - A novel magnetic flocculant (CPAMF) was synthesized by using Fe3O4 coated with cationic polyacrylamide (CPAM) for flocculation of high turbid water. The surface morphology and chemical structures of CPAMF were confirmed by Fourier transform infrared spectroscopy (FTIR) and thermo-gravimetric analysis (TGA). X-ray diffraction (XRD) was employed to verify the crystal structure of CPAMF. The magnetic property of CPAMF was compared with Fe3O4 in this study. The flocculation performance by using flocculants CPAMF was evaluated in high turbid water treatment. The maximum transmittance 92.4% of kaolin suspension was achieved at corresponding optimal flocculation conditions. The result indicated that CPAMF was efficient in high turbid water flocculation. Analysis of FTIR, XRD of flocs, and zeta potential (ZP) of supernatant were accomplished for flocculation mechanism investigation. Because of low recovery factor in reflocculation under the effect of shear force on flocs, the bridging effect was found to be dominant in both acidic and alkaline conditions. Sedimentation experiments under the role of permanent magnet indicated that nano-Fe3O4 could effectively improve the settling property of CPAM. Graphical abstract ?. PMID- 29968211 TI - Bioadsorption of trivalent and hexavalent chromium from aqueous solutions by sericin-alginate particles produced from Bombyx mori cocoons. AB - In this study, particles produced from sericin-alginate blend were used as non conventional bioadsorbent for removing Cr(III) and Cr(VI) from aqueous solutions. Besides chromium mitigation, the use of sericin-alginate particles as bioadsorbent aims to offer an environmental solution of added value for sericin, which is a by-product from silk industry. Sericin-alginate particles in natura and loaded with Cr(III) and Cr(VI) were characterized using N2 physical adsorption analysis, optical microcopy, mercury porosimetry, helium pycnometry, scanning electron microscope coupled with energy dispersive X-ray spectrometer, Fourier transform infrared spectrometer, and X-ray diffraction. Kinetic studies on the removal of Cr(III) (at pH = 3.5) and Cr(VI) (at pH = 2) indicate the ion exchange mechanism with Ca(II) and the predominance of external mass transfer resistance. Cr(VI) uptake occurs through an adsorption-coupled reduction process, and bioadsorption equilibrium is reached after ~ 1000 min. Cr(III) bioadsorption occurs faster (~ 210 min). The Cr(VI) bioadsorption is endothermic, as bioadsorption capacity increases with temperature: 0.0783 mmol/g (20 degrees C), 0.1960 mmol/g (30 degrees C), 0.4570 mmol/g (40 degrees C), and 0.7577 mmol/g (55 degrees C). The three-parameter isotherm model of Toth best represents the equilibrium data of total chromium. From Langmuir isotherm model, the maximum bioadsorption capacity is higher for total chromium, 0.25 mmol/g (30 degrees C), than for trivalent chromium, 0.023 mmol/g (30 degrees C). The comparison of bioadsorption capacities with different biomaterials confirms sericin-alginate particles as potential bioadsorbent of chromium. PMID- 29968212 TI - Fermented camel milk by Lactococcus lactis subsp. cremoris attenuates erythrocytes oxidative stress-induced hematological and immunological damage in CCl4-intoxicated mice. AB - Fermented camel by Lactococcus lactis subsp. cremoris has been recently discovered to protect against the toxic effect of carbon tetrachloride (CCl4), but its beneficial effects in the presence of oxidative stress in the erythrocytes have not been established. In the present study, 28 mice were randomly divided into four groups: control group; CCl4 group: intoxicated by a single intraperitoneal injection (ip) of CCl4; group FCM-LLC + CCl4: pretreated with FCM-LLC daily during 14 days, and received a single dose of CCl4. FCM-LLC group received FCM-LLC alone. The occurrence of oxidative stress in erythrocytes was evidenced by an increase in lipid peroxidation, protein carbonyl, and changes in antioxidant enzyme activities and non-enzymatic antioxidant. The oxidative injury induced by CCl4 in the erythrocytes was confirmed by modifications in hematological parameters and decreases in protein, albumin, and globulin content in the serum of intoxicated mice. Therefore, CCl4 caused a significant decrease in immunotoxic indices, including immunoglobulin G (IgG), immunoglobulin M (Ig M), and immunoglobulin A (IgA) levels, and an increase of inflammatory markers such as C-reactive protein (CRP) level. Meanwhile, FCM-LLC effectively restored the parameters cited above to near-normal values. It can be suggested that fermented camel milk could regulate deviant physiological effects induced by CCl4 which is due to its powerful antioxidant and immunomodulatory and anti inflammatory capacity. PMID- 29968213 TI - Biomonitoring of atmospheric particulate pollution via chemical composition and magnetic properties of roadside tree leaves. AB - Particulate matter (PM) is a main atmospheric pollution which threats human health and well-being. In this research, we chemically and magnetically analysed roadside tree leaves, collected from three tree species in two main roads (from two different cities) and a reference area, for 28 elements and the saturation isothermal remanent magnetisation. Comparison of unwashed and washed leaves revealed that deposited particles on the leaf surface contain various elements including Al, Ca, Fe, Mg, Mn, Na, Si, Ti, Ba, Co, Cr, Cu, Ni, Rb, V, Zn and Zr. Moreover, there was no significant difference between washed/unwashed leaves in Cl, K, P, S, As, Cd, Cs, Pb, Sn and Sr concentrations, which indicates tree leaves may not be a suitable biomonitor for these elements. Our results showed that site and tree species are important factors which affect atmospheric elements deposition. Among the three considered tree species, Chamaecyparis lawsoniana showed the highest potential for atmospheric particle accumulation. The PCA results revealed that Al, Fe, Ti, Co, Cr, Cu, Ni, Rb, Si, V, Zn and Zr indicated emissions from road traffic activities and soil dust; Ca, Mg and Na from sea salts and Mn and Sb from industrial activity. The biplot results showed that the site effect was much stronger than the species effect for all elements and saturation isothermal remanent magnetisation (SIRM) values. Moreover, elements from traffic, industrial activity and soil dust are significantly correlated with leaf SIRM indicating that leaf SIRM can be a suitable bioindicator of exposure to traffic-derived particles and soil dust, and not from sea salts. It is concluded that chemical composition and SIRM of urban tree leaves can serve as a good indicator of atmospheric PM pollution in Iran and anywhere else where the studied trees grow. PMID- 29968214 TI - CO2 emission thresholds for inclusive human development in sub-Saharan Africa. AB - We provide policy-relevant critical masses beyond which, increasing CO2 emissions negatively affects inclusive human development. This study examines how increasing CO2 emissions affects inclusive human development in 44 sub-Saharan African countries for the period 2000-2012. The empirical evidence is based on fixed effects and Tobit regressions. In order to increase the policy relevance of this study, the dataset is decomposed into fundamental characteristics of inclusive development and environmental degradation based on income levels (low income versus (vs.) middle income); legal origins (English common law vs. French civil law); religious domination (Christianity vs. Islam); openness to sea (landlocked vs. coastal); resource-wealth (oil-rich vs. oil-poor) and political stability (stable vs. unstable). All computed thresholds are within policy range. Hence, above these thresholds, CO2 emissions negatively affect inclusive human development. PMID- 29968215 TI - Odorous emission reduction from a waste landfill with an optimal protection system based on fuzzy logic. AB - Effective landfill management and operation require an accurate evaluation of the occurrence and extent of odour emission events, which are among the main causes of resident complaints and concerns, in particular in densely urbanised areas. This paper proposes a fuzzy optimal protection system (FOPS) based on fuzzy logic to manage odour production from a municipal solid waste (MSW) landfill. The case study is a MSW landfill in an old quarry site located 6 km north-west of Naples city centre (Italy). The aim is to reduce the odour nuisance in the area surrounding the landfill where there are several sensitive receptors. FOPS is based on logical relationships between local atmospheric dynamics, number and intensity of odour pollution events detected by certain fixed receptors and odour emission rate via an optimal fuzzy approach. Such system allows to start, in real time, established mitigation actions required to further reduce the odorous emissions from the landfill itself (e.g. spraying of perfumed substances and activation of extraction wells), especially when weather conditions might not be favourable and cause by causing a higher odour perception. The fuzzy system was coupled with the air pollutant transport software CALPUFF to simulate the odour dispersion in the considered area taking into account both different odour emission rates and local weather conditions. FOPS results show that this approach can be very useful as, by measuring the odour concentrations, a significant reduction of the odour exceedances over the thresholds fixed, to minimise the olfactory harassment, was observed in the whole area studied. PMID- 29968216 TI - Regulation on the toxicity of microcystin-LR target to protein phosphatase 1 by biotransformation pathway: effectiveness and mechanism. AB - Biotransformation was an important pathway to regulate the toxicity of microcystins (MCs) targeted to protein phosphatases (PPs). To explore the regulation effectiveness and mechanism, several typical biothiol transformation products originated from MCLR were prepared by nucleophilic addition reaction. The reduced inhibition effect of MCLR transformation products on PP1 was evaluated and compared with their original toxin. Though molecular simulation showed the introduced biothiols enhanced the total combination areas and energies for target complexes, the steric hindrance of introduced biothiols inhibited the combination between the key action sites (Mdha7 and Adda5 residues) and PP1. Furthermore, the introduced biothiols also weakened the hydrogen bonds for some key interaction sites and altered the ion bonds between PP1 and the two Mn2+ ions in the catalytic center. The discrepant regulation effect for biothiols on the toxicity of MCLR was closely related to above indexes and influenced by molecular sides. PMID- 29968217 TI - Financial instability and CO2 emissions: the case of Saudi Arabia. AB - This study aims to investigate the nexus between financial instability and CO2 emissions within the multivariate framework in Saudi Arabia's economy over 1971 2016. Autoregressive Distributed Lag (ARDL) model is used to estimate long-run dynamics followed by Vector Error Correction Model (VECM) to detect the direction of causality. The result of the study reveals that financial instability has an insignificant impact on CO2 emissions. However, electricity consumption has an adverse impact on environmental quality by producing a huge amount of CO2 emissions in the atmosphere. The coefficients of oil and non-oil GDPs also suggest that both oil and non-oil GDPs contribute to producing a massive amount of CO2 emissions. Bi-directional causality is observed among all the core variables of the study. Moreover, the reliability and validity are confirmed by applying several diagnostic tests. This study provides novel findings which not only help to advance the existing literature but can be a particular interest to the country's policymakers regarding financial sector and its role in environmental degradation. PMID- 29968218 TI - Optimization of preparation of monolithic carbon foam from rice husk char for benzene leakage emergency. AB - In the aim of BTEX leakage emergency, monolithic carbon foam (MCF) was designed and prepared via a simple method. Rice husk char (RHC) was chosen as raw material, polyurethane sponge (PUS) was used as sacrificed template to form inner channel, and corn starch and ZnO were employed as binder and reinforcing filler, respectively. The optimized preparation parameter was determined by adopting of Taguchi experimental design method. Both MCF-RHC and MCF-CAC were made from RHC and commercial activated carbon (CAC) under the same condition, and three reported monolithic carbon adsorbents were selected for comparative study with MCFs. The surface and structural properties were characterized by XRD, SEM, and N2 adsorption/desorption isotherm analyses. XRD analysis results reveal that MCF RHC was the composites of carbon, SiO2, and ZnO, and MCF-RHC and MCF-CAC have good potential in organic adsorption. Hierarchical structure of MCF was constructed by inner macro-channel from burning up of PUS and micro- and meso pores from resultant carbon composite, and these inner macro-channels play a more important role in benzene rapid adsorption. Specific surface area of MCF-RHC was 465.5 m2 g-1, which included micro- and meso-pores, which mainly come from RHC during the carbonization process. Adsorption kinetics study demonstrated that the benzene equilibrium uptake of MCF-RHC and MCF-CAC was similar, and both of data well fitted the pseudo-second-order kinetic model. However, MCF-RHC has the ability to absorb benzene more quickly, which meets the demand of absorbent utilizing in benzene leakage emergency. PMID- 29968219 TI - In vitro inhalation/ingestion bioaccessibility, health risks, and source appointment of airborne particle-bound elements trapped in room air conditioner filters. AB - The airborne particle-bound elements (Ca, Fe, Al, Mg, K, Na, Zn, Mn, P, Pb, Cu, Sr, Ti, Ba, Cr, Ni, As, Sb, Cd, Co, and V) trapped in room air conditioners' filters (filter dusts) during recirculating indoor air from different types of rooms were analyzed, and the objectives of this study were to assess the potential sources of those elements and their potential health risks via inhalation/ingestion exposure. Main crustal elements such as Ca, Fe, Al, Mg, and K with an average value of 60.6, 17.9, 11.3, 7.58, and 6.90 mg g-1, respectively, are the preponderant elements, and the mean values of main toxic elements were 2230, 344, 508, 85.7, 71.5, 36.0, 8.02, and 16.9 mg kg-1 for Zn, Cu, Pb, Cr, Ni, As, Cd, and Sb, respectively. The enrichment factors indicated the significant enrichment of Cd, Pb, Cr, Cu, Sb, and Zn in the filter dusts. Four potential sources with the contributions of 33.5, 29.1, 22.6, and 14.8%, respectively, were identified by absolute principal component scores-multiple linear regression analysis (APCS-MLR). Enrichment factor and APCS-MLR model reveal the outdoor input of toxic elements. In vitro inhalation and ingestion bioaccessibility of toxic elements showed elemental and in vitro procedure dependence. There are potential carcinogenic risks via ingestion exposure and no non-carcinogenic risks to both children and adults based on bioaccessible contents of toxic elements. This study reveals the potential health risks posed by the particle-bound elements. PMID- 29968220 TI - Effects of inorganic ions on the photolysis of propranolol in FA solution. AB - Photolysis of the widely used beta-blocker propranolol (PRO) was investigated in the presence of fulvic acid (FA) and inorganic ions under simulated solar irradiation. PRO undergoes direct photolysis proceeding mainly via degradation of the triplet excited state, 3PRO*. FA and inorganic ions inhibited photolysis of PRO in the order of FA > Fe3+ > Cl- > Ca2+ > Mg2+ > NO3- > K+. An antagonistic effect between FA and inorganic ions toward the suppression of PRO photolysis was exhibited. The binding behaviors of PRO, FA, and inorganic ions were examined through fluorescence quenching experiments, which showed that inorganic ions affected the binding between FA and PRO through competing for the binding sites of FA or PRO. The correlation analysis demonstrated a positive correlation between the binding constant (KOC) of FA-PRO and the inhibition rate of FA on PRO photolysis. The observed rate constants of photolysis (kobs) have opposite correlations with the concentration of singlet oxygen (1O2). These findings strongly suggest that inorganic ions decrease the inhibition effect of FA on PRO photolysis via restraining the complexation of FA-PRO and production of 1O2. PMID- 29968221 TI - Cardiac resynchronization therapy improves left ventricular remodeling and function compared with right ventricular pacing in patients with atrioventricular block. AB - Right ventricular pacing (RVP) exerts a detrimental effect on left ventricular (LV) remodeling. In patients with atrioventricular block (AVB) that require ventricular pacing, the effect of biventricular pacing (BiVP) versus RVP on LV remodeling and function has not been comprehensively assessed in a meta-analysis. Electric databases MEDLINE and Cochrane Library were retrieved for randomized controlled trials (RCT) comparing RVP and BiVP in patients with AVB. Data on left ventricular ejection fraction (LVEF) and LV volumes were analyzed, stratified by different time points. Eleven RCTs were included in the final analysis. There was a significant reduction of LV end-systolic volume in BiVP compared with RVP, at 3, 6, 12, and 24 months follow-up (P < 0.05 for all). BiVP was associated with a decreased LV end-diastolic volume in comparison to RVP at 3, 6, and 12 months. Compared with RVP, BiVP had a higher LVEF at all follow-up visits, with mean difference of 5.91, 3.29, 3.9, 6.66, and 8.69% at 3, 6, 12, 24, and beyond 24 months follow-up, respectively. The results were not significantly changed in sensitivity analysis after removal of studies with mean baseline LVEF < 50% or excluding studies with ablation-induced AVB. In patients with AVB and bradycardia that require ventricular pacing, BiVP is superior to RVP in improving LV remodeling and function. PMID- 29968222 TI - Response to the editor. PMID- 29968223 TI - Prognostic value of T1 mapping and extracellular volume fraction in cardiovascular disease: a systematic review and meta-analysis. AB - T1 mapping and extracellular volume (ECV) fraction are useful new magnetic resonance imaging (MRI) techniques to evaluate myocardial fibrosis; however, their prognostic value has not been well described. In this study, a systematic review and meta-analysis evaluating the prognostic value of these techniques is performed in patients with ischemic and non-ischemic cardiomyopathy. PubMed, Cochrane CENTRAL, and Meta-Register of Controlled Trials were searched for studies that utilized T1 mapping and ECV and that also had >= 12 months of follow up data. The primary endpoints included were cardiovascular death and non-fatal cardiac events (heart failure, acute coronary syndrome). Six studies involving a total of 1524 patients and a mean follow-up of 26.3 months were included. Patients had a mean age of 57.6 years and 56.5% were male. Summary effect estimates were generated with fixed/random-effects modeling and hazard ratios were assessed. Patients with a higher ECV value had a significantly higher incidence of cardiovascular death (hazard ratio [HR] 1.79 [95% CI 1.24 to 2.58; P = 0.09) and combined cardiac events (HR 1.11 [95% CI 1.08-1.15]; P < 0.0001). Patients with higher native T1 values and (HR 1.06 [95% CI 0.96 to 1.17]; P = 0.27) and lower post contrast T1 value (HR 0.99 [95% CI 0.98-0.99], P < 0.001) overall had no increased risk for cardiovascular events. Comparing with other CMR parameters, ECV has excellent potential prognostic value and can help guide risk stratification of patients with ischemic or non-ischemic cardiomyopathy into high and low risk for adverse cardiovascular events. PMID- 29968224 TI - Therapeutic plasmapheresis in thyrotoxic patients. AB - PURPOSE: For the treatment of thyrotoxicosis, alternative treatment modalities may be necessary if anti-thyroid drugs cannot be used due to side effects, inefficiencies, or there is a need to start a rapid action such as thyroid storm. By using therapeutic plasma exchange (TPE), it is possible to effectively and rapidly remove the increased thyroid hormones. We evaluated our results and experience on a rapid, effective, and reliable alternative treatment modality in thyrotoxic patients. METHODS: TPE was performed in 46 thyrotoxic patients at the Adult Therapeutic Apheresis Center. RESULTS: Forty six patients with a median age of 30 years (interquartile range [IQR] 30-50) were assessed. In 40 (87%) of the cases, the diagnosis was Graves' disease. The other causes of thyrotoxicosis were amiodarone-induced thyrotoxicosis (n = 4) and toxic nodular goiter (n = 2). The median and IQR of fT3 values in patients before TPE were 9.9 (6.5-16.8) pg/mL (N: 2.3-4.2) and the median and IQR of fT4 values were 2.9 (2.3-4.1) ng/dL (N: 0.74 1.52). When the procedure was terminated, the median and IQR of fT3 values in patients were 4.0 (3.1-5.2) pg/mL and the median and IQR fT4 values were 1.6 (1.4 2.0) ng/dL. The decrease in both free thyroid hormones was found to be statistically significant (p < 0.000). CONCLUSION: Our study is the largest series of TPE in the literature used for thyrotoxicosis. In the light of the literature and our results, we conclude that TPE is an effective alternative treatment option to prepare for ablative treatment for cases that have side effects or ineffectiveness of anti-thyroid drugs. PMID- 29968225 TI - Perioperative serum cortisol levels in ACTH sufficient and ACTH deficient patients during transsphenoidal surgery of pituitary adenoma. AB - PURPOSE: No previous study has analyzed serum cortisol levels during transsphenoidal endoscopic pituitary surgery in patients with and without hydrocortisone (HC) substitution. METHODS: A total of 15 patients undergoing surgery for a pituitary adenoma were studied. Those with normal ACTH function were either not given HC (n = 7) or received 50 mg intravenous HC at the start of surgery (n = 4). Patients with ACTH deficiency received intravenous HC of 100 mg in the morning before surgery (n = 4) with the additional 50 mg for an afternoon operation (n = 2). Propofol and remifentanil were used as anesthetics. Serum cortisol was measured at the start of and every 30 min during surgery. RESULTS: Among 7 patients with normal ACTH function without HC substitution, cortisol levels before surgery were 126-244 nmol/L, among the 4 patients undergoing surgery in the morning, whereas the 3 who underwent surgery in the afternoon had lower levels, 38-76 nmol/L. During nose/sinus surgery cortisol levels decreased to 79-139 and 24-54 nmol/L, respectively. At intrasellar manipulation a distinct rise was noted. Also, in the 4 ACTH sufficient patients receiving HC, cortisol levels decreased during nose/sinus surgery, but only with a slight increase during intrasellar surgery. In the 4 ACTH deficient patients cortisol peaked at 1914-2582 nmol/L. CONCLUSIONS: Patients with normal ACTH function without HC substitution had very low cortisol levels during the first part of surgery, likely suppressed by the anesthetics. After mechanical impact in the sella, a marked increase in cortisol was noted. Supraphysiological cortisol levels were achieved with our routine HC substitution, advising us to reduce the supplementation. PMID- 29968227 TI - Autoimmune pituitary involvement in Prader-Willi syndrome: new perspective for further research. AB - The role of antipituitary antibodies in the pathophysiology of pituitary hormone deficiency has been increasingly elucidated over the last decade. Prader-Willi syndrome is a genetic disorder which includes hypothalamic/pituitary dysfunction as one of its main features. We looked for autoimmune pituitary involvement in 55 adults with Prader-Willi syndrome, discovering that about 30% of them have a positive titer of antipituitary antibodies. Although the presence of these autoantibodies could only be an "epiphenomenon", our results suggest that autoimmune mechanisms might contribute, at least in part, to the pituitary impairment of Prader-Willi syndrome, and in addition to genetically determined dysfunction of the central nervous system. This paper provides a new perspective on pituitary impairment in these patients, suggesting that the search for hypophisitis could be a reasonable and interesting field for further research. PMID- 29968226 TI - Sentinel lymph node biopsy in small papillary thyroid cancer. A review on novel surgical techniques. AB - PURPOSE: Sentinel lymph node biopsy (SNB) in patients with papillary thyroid carcinoma (PTC) and negative for clinically neck lymph node metastatic involvement (N0) has emerged as a promising minimally invasive procedure to detect metastatic nodes. METHODS: The MEDLINE database was searched via the PubMed interface on 10 January 2018 for the MeSH headings "sentinel lymph node biopsy" and "thyroid carcinoma". RESULTS: Vital blue dye, radioisotope, and the combination of both techniques are used in PTC patients. These methods and the emerging role of SPECT/CT are discussed in this review. The sentinel lymph node (SLN) identification rates ranged from 0 to 100% for blue dye, 83 to 100% for radioisotopes, and 66 to 100% for the combination of both techniques, respectively. CONCLUSIONS: SNB based on radioisotope technique with the use of intraoperative gamma-probe is an accurate and safe method that allows the highest SLN detection rate. There is sufficient evidence to propagate the increasing use of SNB procedure that has the potential to avoid prophylactic lymph node surgery in patients clinically N0. PMID- 29968228 TI - Nanosensing of ATP by fluorescence recovery after surface energy transfer between rhodamine B and curcubit[7]uril-capped gold nanoparticles. AB - The authors describe a method for functionalization of gold nanoparticles (AuNPs) with the supramolecular host molecule, curcubit[7]uril (CB[7]) which can bind rhodamine B (RhB). The fluorescence of RhB is quenched by the AuNPs via surface energy transfer. On addition of ATP, a dimeric RhB-ATP complex is formed and RhB is pushed out of CB[7]. Hence, fluorescence increases by a factor of 8. This fluorescence recovery effect has been utilized to develop a new detection scheme for ATP. The assay, measured at fluorescence excitation and emission wavelengths of 500 nm and 574 nm respectively, works in the 0.5-10 MUM concentration range and has a 100 nM detection limit. The method is not interfered by UTP, GTP, CTP, TTP, ascorbic acid and glutathione. Graphical abstract Schematic of a method for determination of ATP in the 500 nM to 10 MUM concentration range by using fluorescence recovery after surface energy transfer (SET) between rhodamine B (RhB) and gold nanoparticles capped with curcubit[7]uril (CB[7]). PMID- 29968229 TI - Factors that positively or negatively mediate the effects of age on working memory across the adult life span. AB - Working memory abilities significantly decrease with advancing age; hence, the search for factors that may increase or mitigate this decline is critical. Several factors have been identified that influence working memory; however, their effects have been mainly assessed separately and rarely together with other factors in the same sample. We examined 120 variables to search for factors that jointly act as mediators of working memory decay across the adult life span. A sample of 1652 healthy adults was assessed in spatial and verbal working memory domains. Structural equation modeling analyses were conducted to search for potential mediators that intervened between age and working memory. Only 14 and 10 variables reliably mediated spatial and verbal working memory, respectively. Factors from several domains remained in the models, such as individual characteristics, physiological traits, consumption habits, and regular activities. These factors are sufficiently powerful to influence working memory decline when they jointly interact, as in everyday living. PMID- 29968231 TI - Production and characterization of drug-loaded toroidal vortices from a novel ocular drug delivery device. AB - For the last several decades, the predominant method for delivering medicine to the surface of the eye has been the standard multiuse eye dropper. While being the most popular, this method has significant limitations. Recently, an effort has been made to explore the use of a directed toroidal vortex or "smoke ring" aerosol delivery system that may help overcome these limitations and enable delivery of precise amounts of formulation and drug to the ocular surface. Promising preliminary in vitro studies indicated dosing control, but the physical characteristics of the toriodal aerosol device performance and impaction forces related to patient comfort have yet to be established. Here, we experimentally investigate the mechanics and dynamics of these ocular aerosol vortices, including translational and rotational velocities, spatial droplet size distributions, and relative impaction forces in order to optimize the device performance and evaluate potential for clinical use. Maximal droplet velocity at various actuation forces was determined, and they were found to be all less than 6 m/s even at the highest actuation forces. Moreover, plume impaction forces were determined across a range of conditions and were all less than about 4.5 MUN. Collectively, these studies showed that the physical and mechanical properties of the emitted drug-loaded vortices would be suitable for ocular administration. PMID- 29968230 TI - Effects of Warm-Up, Post-Warm-Up, and Re-Warm-Up Strategies on Explosive Efforts in Team Sports: A Systematic Review. AB - BACKGROUND: In team sports, it is imperative that the warm-up improves acute explosive performance. However, the exact strategies, methods, and consequences of different warm-up practices remain unclear. A time delay between the warm-up and match and during half-time could negate the positive metabolic effects of the warm-up. OBJECTIVES: We conducted a systematic review to synthesize and analyze the potential effects of strategies during a warm-up (before match), post-warm-up (time between the end of warm-up and the start of a match), and re-warm-up (half time break within a match) on explosive performance in team sports. Furthermore, we examined optimal warm-up strategies based on the included studies. METHODS: We performed a search of four databases (Web of Science, Scopus, PubMed, and ScienceDirect) for original research articles published between January 1981 and August 2017. A total of 30 articles met the inclusion criteria, and the Cochrane risk of bias tool was used to assess the risk of bias. The results of the included studies were recalculated to determine effect sizes using Cohen's d. RESULTS: A warm-up comprising 8 sets of 60-m sprints (- 2.19%, d = 1.20) improved sprint performance. Additionally, 7 min of dynamic exercises after 5 min of jogging improved sprint (- 7.69%, d = 1.72), jumping (8.61%, d = 0.61), and agility performance (- 6.65%, d = 1.40). The use of small-sided games also seems to be a valid strategy, especially for jumping performance (6%, d = 0.8). These benefits resulted from the warm-up strategies combined with some passive rest (between 2 and 10 min) before the main performance. In this post-warm-up period, the use of heated garments could result in better outcomes than simple rest (- 0.89%, d = 0.39). However, if the transition was longer than 15 min, before entering the match, performing a re-warm-up with short-term explosive tasks to reactivate was the most effective approach (- 1.97%, d = - 0.86). At half-time, heated garments maintained better sprint (- 1.45%, d = 2.21) and jumping performance (3.13%, d = 1.62). CONCLUSION: Applying properly structured strategies in the warm-up and avoiding a long rest in the post-warm-up improves explosive performance. Studies tend to recommend a short active warm-up strategy (10-15 min), gradually increasing intensity (~ 50-90% of maximum heart rate), and the use of heated garments soon after the warm-up to maintain muscle temperature. However, 2 min of active re-warm-up with short-term sprints and jumps should be needed for transitions longer than 15 min (~ 90% of maximum heart rate). Last, at the half-time re-warm-up, combining heated garments to maintain muscle temperature and performing an active strategy, with explosive tasks or small sided games for 5 min before re-entering the game, resulted in better explosive performance than 15 min of resting. PMID- 29968233 TI - Clinical outcomes in periarticular knee fractures with flexible fixation using far cortical locking screws in locking plate: a prospective study. AB - PURPOSE: Periarticular fractures around the knee joint are treated traditionally by locking plates which provide excellent stability but suppress callus formation. Far cortical locking (FCL) screws allow axial motion and enhance uniform callus formation. Our study aims to evaluate the outcomes of FCL screws in traditional locking plate in periarticular fractures of the knee. METHODS: Thirty patients with periarticular fractures of the knee joint were operated with locking plate using FCL screws. All patients were evaluated clinically and radiographically using X-rays at 6, 12, 24 weeks, 1 year and with CT scan at 12 weeks follow-up. RESULTS: The average time for complete union was 20 weeks in tibial fractures and 24 weeks in femur fractures. Average time to full weight bearing ambulation was 4.8 +/- 0.93 weeks. One patient had delayed union in which union was complete after 9 months. CONCLUSION: This study shows that FCL screws in locking plates allow uniform callus formation and fracture union with minimal complication rates. PMID- 29968232 TI - Regulation of Glycogen Content in Astrocytes via Cav-1/PTEN/AKT/GSK-3beta Pathway by Three Anti-bipolar Drugs. AB - Here we present the data indicating that chronic treatment with three antibipolar drugs, lithium, carbamazepine and valproic acid regulates Cav-1/PTEN/PI3K/AKT/GSK 3beta signalling pathway and glycogen content in primary cultured astrocytes. All three drugs down-regulate gene expression of Caveoline 1 (Cav-1), decrease membrane content of phosphatase and tensin homolog (PTEN), increase activity of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and serine-threonine kinase (AKT), and elevate glycogen synthase kinase 3beta (GSK-3beta) phosphorylation thus suppressing its activity. As expected, treatment with any of these three drugs increases glycogen content in astrocytes. Our findings indicate that regulation of glycogen content via Cav-1/PTEN/AKT/GSK-3beta pathway by the three anti-bipoar drugs may be responsible for therapeutic effects of these drugs, and Cav-1 is an important signal element that may contribute to pathogenesis of various CNS diseases and regulation of its gene expression may be one of the underlying mechanisms of drug action for antibipolar drugs and antidepressants currently in clinical use. PMID- 29968234 TI - Endocrine paraneoplastic syndromes in lung cancer. AB - Paraneoplastic syndromes are defined as a combination of clinical disorders associated with malignant diseases that are caused by the secretion of various substances by the tumor without, however, being caused by the direct growth and infiltration of the primary tumor, or due to the development of distant metastases. Despite the fact that lung cancer represents the number one cause of death from cancer worldwide, the new methods of treatment increase patient survival and the incidence of paraneoplastic syndromes. The most important ones of these are humoral hypercalcemia of malignancy, syndrome of inappropriate antidiuretic hormone, hyponatremia of malignancy, ectopic Cushing's syndrome, carcinoid syndrome, and hypoglycemia and are usually a poor prognostic marker. Early diagnosis of those syndromes is achieved using specific criteria and may lead to early diagnosis of the underlying malignancy. It is essential to treat them with the overriding objective of improving the patients' quality of life. PMID- 29968235 TI - [China Guideline for Diagnosis and Comprehensive Treatment of Colorectal Liver Metastases (Version 2018)]. AB - The liver is the most common anatomical site for hematogenous metastases of colorectal cancer, and colorectal liver metastases is one of the most difficult and challenging points in the treatment of colorectal cancer. In order to improve the diagnosis and comprehensive treatment in China, the Guidelines have been edited and revised for several times since 2008, including the overall evaluation, personalized treatment goals and comprehensive treatments, to prevent the occurrence of liver metastases, improve the resection rate of liver metastases and survival. The revised Guideline includes the diagnosis and follow up, prevention, MDT effect, surgery and local ablative treatment, neoadjuvant and adjuvant therapy, and comprehensive treatment, and with advanced experience, latest results, detailed content, and strong operability. PMID- 29968236 TI - [Choice of neoadjuvant therapy for rectal cancer: simple chemotherapy or synchronous chemoradiotherapy]. AB - Rectal cancer is one of the most common malignancies in China. Total mesorectal excision (TME) plus neoadjuvant therapy is the standard treatment for locally advanced rectal cancer. After a development of over 20 years, neoadjuvant synchronous chemoradiotherapy has become the standard treatment and cornerstone of neoadjuvant therapy for rectal cancer. However, radiotherapy does not really increase the overall survival and is associated with long-term impact on the functions of anus, sex, urinary system and fertility, so the application of simple neoadjuvant chemotherapy rises gradually and becomes a potentially better treatment option. This paper elaborates the reason, present research status and future trend of the rising neoadjuvant chemotherapy. PMID- 29968237 TI - [Pathological evaluation after preoperative neoadjuvant treatment in rectal cancer]. AB - Preoperative neoadjuvant therapy of rectal cancer has been widely promoted, and postoperative standardized pathological assessment has gradually attracted widespread attention. Accurate pathological examination plays an indicating role in the diagnosis and treatment of rectal cancer, which can not only evaluate the effects of neoadjuvant chemoradiation and surgical resection, but also guide postoperative adjuvant therapy and assess the prognosis. Tumor regression grade (TRG) and TNM staging are the bases of routine pathological diagnosis of rectal cancer, and they are closely related to patient survival and prognosis. At present, TRG evaluation methods for neoadjuvant chemoradiation include NCCN, AJCC, Becke, Mandard, Dowrak/Rodel, MSKCC, and RCRG. However, there is still no universally accepted best standard. The commonly used classifications in practice are AJCC and NCCN TRG grading standards. The prerequisite for accurate TRG classification is a detailed and standardized pathological assessment, which includes both gross assessment of the specimen and microscopic examination. How to evaluate the therapeutic response to lymph node metastasis after neoadjuvant therapy and improve the assessment consistency among pathologists are the two major issues that remain to be resolved. PMID- 29968238 TI - [Application of magnetic resonance imaging in TN re-staging and efficacy evaluation after neoadjuvant therapy for rectal cancer]. AB - Neoadjuvant chemoradiotherapy (NCRT) combined with total mesorectal excision (TME) has become the recommended standard treatment strategy for local advanced rectal cancer (cT3 or cN+). After neoadjuvant chemoradiotherapy, preoperative T/N re-staging and efficacy evaluation of rectal cancer are directly related to the available treatment options and prognosis, so they are the common questions concerned by physicians. At present, magnetic resonance imaging (MRI) is acknowledged to be one of the more effective and feasible methods of T/N re staging and efficacy evaluation, especially in the molecular microscopic scale. The diffusion weighted imaging (DWI) can reflect the movement of water molecules outside the tumor cells, and the multi-phase dynamic contrast enhanced MRI (DCE MRI) can indirectly reflect the permeability of tumor vascular wall and local blood perfusion of tumor from the view of pathophysiological point. Because of the influence of edema, inflammatory response and fibrous tissue proliferation after radiotherapy, scholars both at home and abroad increasingly pay more attentions to the accuracy of T/N re-staging and efficacy prediction in MRI following neoadjuvant therapy. In this review, we elucidate the application value and limitation of MRI based on T/N re-staging and local efficacy evaluation. PMID- 29968239 TI - [Short-term outcome of transanal total mesorectal excision for male low rectal cancer patients with "difficult pelvis" : a single center report from Peking University Cancer Hospital]. AB - OBJECTIVE: To explore the applicable value of transanal total mesorectal excision (taTME) in male low rectal cancer patients with narrow pelvis-"difficult pelvis", which remains difficult for both open and laparoscopic sphincter-saving operations. METHODS: Clinical data of male low rectal cancer patients diagnosed by pathology undergoing taTME between June 2016 and January 2018 at Peking University Cancer Hospital were collected. A retrospective cohort study was performed. Patients were selected according to the following criteria: (1) low rectal cancer, the distance between inferior margin of tumor and anal verge <=5 cm; (2) the distance between two sciatic tubercles <5 cm; (3) body mass index (BMI) >25 kg/m2; (4) tumor horizontal diameter <=4 cm. Operation time, intraoperative blood loss, postoperative hospital stay, postoperative complications and anal function were analyzed. RESULTS: A total of 20 patients were included in this study. All the patients received preoperative neoadjuvant chemoradiation and hybrid transabdominal and transanal surgery. The median BMI was 27.7(26.2-36.4) kg/m2; the median distance between two sciatic tubercles was 92.5 (78-100) mm; the median distance between the inferior margin of tumor to the anal verge was 4 (2-5) cm; the median operation time was 302 (215-402) min; the median intraoperative blood loss was 100 (50-200) ml; the median postoperative hospital stay was 9 (5-15) d. Postoperative complications occurred in 5 patients (25%), including 3 pelvic infection, 1 intestinal obstruction, 1 anastomotic leakage receiving sigmoid colostomy. There was no perioperative death. Sphincter preservation rate was 100%. Nineteen patients received anal manometry 1 month after operation with normal resting pressure (41.5+/-8.6) mmHg and squeeze pressure (121.0+/-11.6) mmHg. All the patients were followed up to March 2018, and the median follow-up time was 4.5 months. Only 1 patient had supraclavicular lymph node metastasis and no local recurrence was found. CONCLUSIONS: The safety of transanal total mesorectal excision for male patients with low rectal cancer and difficult pelvis is acceptable. TaTME is helpful to preserve the anal sphincter. PMID- 29968240 TI - [Radical surgery combined with adjuvant radiotherapy for elderly patients aged over 75 years with stage II( or III( rectal cancer: a retrospective study from a single center]. AB - OBJECTIVE: To evaluate the outcome of radical surgery combined with adjuvant radiotherapy for patients aged over 75 years with stage II( or III( rectal cancer. METHODS: From 2000 to 2010, 178 patients aged over 75 years at diagnosis who underwent radical surgery in National Cancer Center, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were selected from 3995 patients with stage II( or III( rectal cancer in the database of the above center and enrolled into this retrospective cohort study, which was approved by ethics committee of the above hospital (ClinicalTrials.gov number, NCT02312284). RESULTS: Median age of patients was 77 years (range 75-87). There were 37 (20.8%), 69 (38.8%), and 72 (40.4%) patients with tumors locating in the high, middle and low rectum respectively; 89(50%) patients of pathological stages II( and III( respectively; 21(11.8%), 137(77%), 19(10.7%), and 1(0.6%) patients with poorly, moderately, well differentiated adenocarcinoma, and mucinous adenocarcinoma respectively. The Charlson/Deyo comorbidity index (CCI) score was 0 in the majority (73.6%) of patients. Fifty-three patients underwent abdominoperineal resection, 116 underwent low anterior resection and 9 underwent Hartmann resection. All the patients received computed tomography-based simulation and treatment planning using an anal marker in a prone or supine position. Patients were treated with linear accelerator by megavoltage photons (6MV), with 2D technique in early years and 3D conformal or simplified intensity modulated radiotherapy technique later, at a dose of 50 Gy in 25 fractions to the pelvis within an overall treatment time of 35 days. Sixty-one patients (34.3%) received surgery combined with radiation (ART group), in whom 16 received radiation alone 117 patients did not receive radiation(NORT group). The baseline data between ART and NORT group were not significantly different(all P>0.05). There was no significant difference in 5-year overall survival between ART and NORT groups (61.0% vs. 63.0%, P=0.586). The cumulative local relapse was 10.9% and 25.4% in ART and NORT group respectively (P=0.032). Cox multivariate analysis revealed that surgery combined with radiation improved local control significantly(HR=0.27, 95%CI:0.11-0.68, P=0.005). CONCLUSIONS: For elderly patients aged over 75 years with stage II( or III( rectal cancer, radical surgery combined with radiation does not increase the overall survival, but can improve local control rate. It is reasonable to selectively apply adjuvant radiotherapy to the elderly patients in the setting of radical surgery. PMID- 29968241 TI - [Diagnosis and treatment of iatrogenic colonoscopic perforation]. AB - OBJECTIVE: To summarize the diagnosis and treatment of iatrogenic colonoscopic perforation (ICP). METHODS: Clinical data, treatment course and outcome of 17 patients who developed ICP following colonoscopic examination or operation at Department of Colorectal Surgery, Changhai Hospital from January 2000 to December 2013 were retrospectively analyzed. RESULTS: During above 13 years, a total of 127 106 patients underwent colonoscopic examination or operation, of whom 17 cases (0.013%) had ICP. There were 8 males and 9 females with an average age of 65.2 (32-85) years. The interval between the onset of ICP and clinically diagnosed ICP was 0 to 6 days after performance. ICP occurred in 8 patients following colonoscopy operations, including simple colonic polyp excision, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), while in 9 patients following simple colonoscopy examination. Except for one patient who was immediately diagnosed with ICP through the finding of "yellow adipose tissue visible in the vision field" during operation,7 early cases (41.2%) were diagnosed by abdominal X-ray examination, and 9 later cases were confirmed by abdominal CT examination. The perforation sites included sigmoid colon in 5 cases, caecum in 3 cases, descending colon in 3 cases, descending and sigmoid junction in 2 cases, ileum in 1 case, splenic flexure in 1 case, sigmoid and rectum junction in 1 case, retum in 1 case. One case with ICP following ESD after resection of polyp in caecum was cured successfully with conservative treatment, including fasting, gastrointestinal decompression, fluid infusion, anti-infection and nutritional support. One case with ICP, which was found during colonoscopic operation and the perforation was immediately closed with titanium clip, received conservative treatment, including anti-infection and then was cured. Fifteen patients underwent surgery, including 8 patients with primary intention intestinal perforation repair, 4 patients with primary intention resection of associated intestine and anastomosis, 2 patients with primary intention resection of associated intestine and ostomy, 1 patient with primary intention intestinal perforation repair and ostomy. Postoperative abdominal incision infection occurred in 4 cases, pulmonary infection in 1 case, incision infection with cardiovascular event or urinary tract infection in 1 case each. All the patients were cured and discharged. Average hospital stay was 18.6(3-45) days. CONCLUSIONS: ICP should be diagnosed by physical examination and imaging examination as soon as possible. For perforation during colonoscopic performance, colonoscopic titanium clip can be used for closure. Perforation repair is still the main procedure for ICP. If necessary, partial intestinal resection and anastomosis or ostomy can be selected. PMID- 29968242 TI - [Treatment of anastomotic tubular stricture after anterior resection of rectal cancer]. AB - OBJECTIVE: To investigate the treatment of colorectal anastomotic tubular stricture after anterior resection of rectal cancer. METHODS: A retrospective study on 23 cases of anastomotic tubular stricture after anterior resection of rectal cancer from 2008 to 2017 at the Division of Colorectal Surgery, Department of General Surgery of Peking Union Medical College Hospital was performed. The general conditions of the patients, surgical procedures of rectal cancer, perioperative treatment, specific conditions of anastomotic stricture, treatment methods and outcomes were summarized and analyzed. Anastomotic tubular stricture was defined as follows: (1) The length of scar stenosis was >1 cm with thickening anastomotic intestinal wall and a 12 mm diameter colonoscopy could not pass through the anastomosis; (2) Patients were often accompanied by left abdominal pain when exhaust and defecation, increased frequency of defecation, fecal thinning and difficulty in defecation; (3) Anastomotic stricture was indicated by anal examination, colonoscopy, transanal proctography, and rectal MRI. RESULTS: Among 2035 patients undergoing anterior resection of rectal cancer from 2008 to 2017, 23 patients (1.1%) had anastomotic tubular stricture after operation, including 20 males and 3 females with age of 36 to 78 (58.3+/-10.2) years old. The anastomotic distance from the anal verge was less than 6 cm in 7 cases, 6 to 10 cm in 12 cases, and more than 10 cm in 4 cases. Twelve patients received radiotherapy, among whom 6 patients received neoadjuvant chemoradiation before surgery, and 6 patients received postoperative radiotherapy and chemotherapy. The initial treatment after anastomotic stricture: 9 cases (39.1%) underwent balloon dilation; 1 case(4.3%) underwent stenting; 1 case (4.3%) underwent transanal endoscopic microsurgery (TEM); 7 cases (30.5%) underwent permanent stoma and 5 patients (21.7%) underwent digestive tract reconstruction. Of the 12 patients receiving radiotherapy, 4 cases initially failed to undergo balloon dilatation; 1 case initially received a bare stent to relieve obstruction due to intestinal obstruction, but had re-stricture 1 month after stent removal, then was followed by permanent stoma surgery; 7 cases underwent resection of stenosis and permanent stoma, because the remaining intestine was too short for anastomosis. Of the 11 patients without radiotherapy, 5 patients were treated with balloon dilatation to relieve stenosis; 1 patient was initially treated with TEM, while posterior urethra was injured intraoperatively, and the urinary fistula finally healed with indwelling catheter; 5 patients underwent resection of the anastomotic stenosis, and no stenosis occurred after reconstruction of digestive tract, but 1 patient suffered from intraoperative presacral bleeding. CONCLUSIONS: Balloon dilatation is considered an effective treatment of anastomotic tubular stricture following anterior resection of rectal cancer, but with the risk of re-stenosis. Stricture resection and digestive tract reconstruction can be a radical way to improve stricture but with high risk of complications. PMID- 29968243 TI - [Application value of the clearance of No.253 lymph nodes with priority to fascial space and preserving left colic artery in laparoscopic radical proctectomy]. AB - OBJECTIVE: To investigate the application value of the clearance of No.253 lymph nodes with priority to fascial space and preserving left colic artery (LCA) in patients undergoing laparoscopic radical proctectomy. METHODS: From August 2015 to August 2016, 97 consecutive middle-low rectal cancer patients underwent laparoscopic radical proctectomy using the clearance of No.253 lymph nodes with priority to fascial space and preserving LCA at Department of General Surgery, Tangdu Hospital. Among 97 patients, 45 were females , 52 were males, mean age was (64.3+/-5.5) years and mean BMI was (22.4+/-1.8) kg/m2. Brief steps of this clearance: traditional medial approach was the commencement of the dissection at the membrane bridge line in front of iliac vascular bifurcation, then entering into the Toldt's space; superior rectal artery served as the top of the tent and the Toldt's space was extended as far as possible; blunt separation was developed caudally (reaching 2 cm below the sacral promontory), cephalad (reaching the lower part of the pancreas), left laterally (reaching Toldt's line), dextrally (reaching abdominal aorta); after giving priority to fascias space, from the root of inferior mesenteric artery, LCA was exposed and No.253 lymph nodes were dissected. This regimen was suitable for the rectal adenocarcinoma patients without distant metastasis. RESULTS: There was no tension in the intestine and mesenteria after anastomosis in all the 97 patients. One patient received LCA ligation during the clearance, because of thinner LCA resulting in bleeding. The other 96 cases completed the clearance and operation successfully. The mean No.253 lymphadenectomy time was 11-27(17.1+/-5.3) minutes. The mean number of harvested No.253 lymph node was 0-6(4+/-2). The No.253 lymph nodes of 6 patients were positive. No.253 regional mesentery was complete in 95 patients. The total harvested number of lymph node was 11-26(17.3+/-5.3). Six patients with positive lymph nodes aged from 68 to 72 years old and all of them underwent TME operation 6-8 weeks after neoadjuvant chemoradiotherapy. The mean operative time was 89 189(125+/-35) minutes. The mean estimated blood loss was 10.5-38.6(22.4+/-10.5) ml. The first exhaust time was 3.0-6.0(5.6+/-2.1) days. The mean time to extracting the drainage tube was 3.0-5.0(4.5+/-2.5) days. Anastomotic fistula appeared in 1 case and hemorrhage appeared in 1 case, and these 2 cases were cured by conservative treatment. No perioperative death occurred. The mean postoperative hospital stay was 3.0-10.0(3.6+/-2.6) days. CONCLUSION: The clearance of No.253 lymph nodes with priority to fascial space and preserving LCA in laparoscopic radical proctectomy is safe and feasible. PMID- 29968244 TI - [Distribution characteristics and risk factors of colorectal adenomas]. AB - OBJECTIVE: To determine the detection rate and distribution characteristics of colorectal adenomas in Ningbo area of China, and to identify the risk factors for colorectal adenoma, in order to provide reference for colorectal cancer screening. METHODS: A cross-sectional study was performed among 8660 subjects undergoing colonoscopy in the Ningbo No.2 Hospital between January and December 2016, using a questionnaire, including demographic data (age, gender, height and weight), history of diseases (diabetes, hypertension, hyperlipidemia, and family history of malignant neoplasm), lifestyle (smoking, alcohol, dietary bias on red meat, dietary bias on fruit and vegetables, dietary frequency of pickled food and physical activities), and intestinal early warning symptoms. All colonoscopically detected polyps were removed for histological examination. Polyps were histologically divided into non-adenomatous (hyperplastic polyps and inflammatory polyps) and adenomatous polyps (tubular, villous, tubulovillous and serrated adenomas). Pathologic features were analyzed according to anatomical site. Multivariate logistic regression analysis was used to identify the risk factors for colorectal adenoma. RESULTS: A total of 7077 subjects who received colonoscopic examination and completed the questionnaire survey were enrolled in this study. There were 3633 males and 3444 females with a median age of 53 (ranged 17 to 83) years. Adenoma detection rate was 15.6% (1103/7077) in all cases, 21.0%(762/3633) for males, and 9.9%(341/3444) for females(P=0.000). Detection rate of 6.2%(29/469) was recorded in individuals aged less than 30 years, 8.0%(87/1086) in those from 30 to 39 years, 12.1%(148/1222) in those from 40 to 49 years, 16.8%(272/1623) in those from 50 to 59 years, 20.4%(326/1601) in those from 60 to 69 years, and 22.4%(241/1076) in those >=70 years. The detection rate increased according to age(P=0.000). A total of 1521 adenomas were detected in 1103 cases, including 1455 tubular adenomas, 33 tubulovillous adenomas, 9 villous adenomas and 24 serrated adenomas. Among 1521 adenomas, 44.1%(n=671) located in the right hemicolon, 39.0%(n=593) in the left hemicolon, and 16.9%(n=257) in the rectum. Significantly larger number of serrated adenomas and advanced adenomas (advanced adenoma was defined as any adenoma with high-grade intraepithelial neoplasia, diameter >=10 mm or with villous component) was observed in the right hemicolon compared to left hemicolon and rectum [serrated adenomas: 2.5%(17/671) vs. 0.8% (5/593) and 0.8% (2/257), P=0.029; advanced adenoma: 9.2% (62/671) vs. 5.2% (31/953) and 6.6% (17/257), P=0.021]. Multivariate analysis showed that malely (P=0.003), elderly (P=0.000), obesity (P=0.014), smoking (P=0.001), alcohol (P=0.032), and family history of malignancy (P=0.000) were independent risk factors of colorectal adenoma. CONCLUSIONS: In view of a higher detection rate of colorectal adenoma in population aged 40 to 49 years especially in male individuals, the starting age of colonoscopy screening may be advanced to 40 years old. People with family history of malignancy, obesity, and habit of smoking or drinking should be regarded as important subjects for colonoscopy screening. During colonoscopy screening, special emphasis should be given to right hemicolon. PMID- 29968245 TI - [Effect of continuous negative pressure drainage with intermittent irrigation on surgical site infection after laparoscopic extralevator abdominoperineal excison]. AB - OBJECTIVE: To explore the effect of continuous negative pressure drainage with intermittent irrigation on surgical site infection (SSI) after laparoscopic extralevator abdominoperineal excison (ELAPE). METHODS: Clinical data of 28 rectal cancer patients who underwent continuous negative pressure drainage with intermittent irrigation following laparoscopic ELAPE (negative irrigation group) at our department from March 2016 to August 2017 were analyzed retrospectively. At the same time, 32 rectal cancer patients who underwent laparoscopic ELAPE and simple presacral drainage from January 2014 to February 2016 were included as controls (simple drainage group). Self-made double cannula: one silicon rubber drainage tube was used; 3 side holes were cut at the front end with 1-2 cm interval; tube was ranked intermittently and oppositely; a small hole was cut in the middle of rear; the infusion tube was placed through the small hole to the front side of the drainage tube (to rinse when the drainage was turbid). The placement and use of self-made double cannula: it was placed in the presacral space and was drawn from the medial to the sciatic tubercle, then was connected to drainage bag for 24 hours; when no blood was observed, the drainage tube was connected to negative pressure drainage ball, keeping negative pressure status. The development of SSI within 30 days postoperatively and other perioperative parameters were compared between the two groups. RESULTS: There were no statistically significant differences in baseline data between two groups (all P>0.05). Incidence of SSI in negative irrigation group was significantly lower than that in simple drainage group [14.3% (4/28) vs. 43.8% (14/32), chi2=6.173, P=0.013]. Additionally, a shorter postoperative hospital stay was observed in negative irrigation group [(9.8+/-1.5) days vs. (11.4+/-2.6) days, t=2.918, P=0.005]. Besides, other perioperative parameters, including operative time, intraoperative blood loss, time to removal of drainage tube, etc were not significantly different between two groups (all P>0.05). After adjusting to confounders, multivariate analysis showed that negative pressure drainage was an independent protective factor for SSI following laparoscopic ELAPE (OR=0.214, 95%CI:0.060-0.762, P=0.002). CONCLUSION: Continuous negative pressure drainage with intermittent irrigation can effectively decrease the incidence of SSI following laparoscopic ELAPE, and is safe and simple. PMID- 29968246 TI - [Changes in diameter of superior mesenteric vein and gastrocolic trunk in patients with cecum-ascending colon cancer]. AB - OBJECTIVE: To compare the difference of the diameters of superior mesenteric vein (SMV) and gastrocolic trunk (GCT) between patients with cecum-ascending colon cancer and normal individuals, and to assess the diagnostic value of the diameters of SMV and GCT in cecum-ascending colon cancer. METHODS: Preoperative imaging data of 60 patients with primary cecum-ascending colon cancer confirmed by postoperative pathology at the First Affiliated Hospital of Sun Yat-sen University from June 2014 to December 2016 were retrospectively analyzed. The diameters of SMV and GCT were measured on preoperative CT images. SMV was measured at about 2 cm below the junction of SMV and splenic vein. GCT was measured at 1 cm near the proximal junction of right colon vein, right gastroepiploic vein and anterior pancreaticoduodenal vein. Another 60 people receiving pelvic CT examination without organ illness were collected as control. The diameter differences of SMV and GCT between cancer group and control group were compared. The diagnostic value of the diameters of SMV and GCT in cecum ascending colon cancer was evaluated by receiver operating characteristic (ROC) curves. RESULTS: Among 60 cases of cecum-ascending colon cancer, 36 were males and 24 were females with median age of 48 years (range 28-84); 13 were cecum cancer, 47 were ascending colon cancer; 11 had no lymph node and liver metastasis, 40 had lymph node metastasis, 9 had liver metastasis (all with lymph node metastasis). Compared to control group, the diameters of SMV and GCT in cancer group were significantly longer [SMV:(11.2+/-1.3) mm vs. (9.5+/-1.7) mm, t=6.04, P<0.001; GCT:(5.5+/-0.9) mm vs. (3.5+/-1.0) mm, t=11.51, P<0.001]. However, there were no statistically significant differences in diameters of SMV and GCT among hepatic metastasis, lymph node metastasis and no metastasis cancer groups (all P>0.05). The ROC curve analysis showed that the area under the curve of SMV diameter was 0.777, and the optimal cut-off point was 10.5 mm in the diagnosis of cecum-ascending colon cancer, with the sensitivity and specificity of 95.0%(57/60) and 46.7%(28/60) respectively. The area under the curve of GCT diameter was 0.923, and the optimal cut-off point was 4.5 mm in the diagnosis of cecum-ascending colon cancer, with sensitivity and specificity of 88.3%(53/60) and 85.0%(51/60) respectively. CONCLUSION: The dilation of the SMV and GCT may be used as warning factors for cecum-ascending colon cancer, especially the diameter of GCT. PMID- 29968247 TI - [Research progress of neoadjuvant therapy for locally advanced rectal cancer]. AB - The clinical application of novel chemotherapeutic drugs including oral 5-FU and targeted drugs and preoperatively accurate imaging grading has brought challenges to the indication criteria developed by NCCN and ESMO for neoadjuvant chemoradiotherapy in locally advanced rectal cancer (LARC). Extended hotspots have focused on the effectiveness of using capecitabine instead of fluorouracil infusion, the combination of multiple drugs and the feasibility of using neoadjuvant chemotherapy instead of neoadjuvant chemoradiotherapy for selective patients. Traditionally, the evaluation of the effect of neoadjuvant therapy has been based on the effect on the pathological complete remission (pCR) rate. However, current studies recommend the disease-free survival (DFS) as a more important outcome. Besides, seeking for effective biomarkers as predictive markers for neoadjuvant therapies or as prognostic markers remains a hotspot in the field of neoadjuvant chemoradiotherapy. The "watch and wait" approach refers to taking a close follow-up strategy instead of direct operation for patients achieving clinically complete remission (cCR) after neoadjuvant therapy. However, there is no unified evaluation criteria and time point for the evaluation of cCR following neoadjuvant therapy. Therefore, there remain a lot of controversies regarding the clinical application of neoadjuvant chemoradiotherapy in LARC. In this manuscript, research progress in the indication for neoadjuvant therapy, improvement in the neoadjuvant therapeutic schedule, advancement of the efficacy evaluation criteria of neoadjuvant therapy, the "watch and wait" approach and other hot topics is summarized to provide references for clinical practice. PMID- 29968248 TI - [Impacts of microsatellite status, RAS and BRAF mutation on postoperative follow up strategy in stage II( and III( colorectal cancer]. AB - Colorectal cancer is the third tumor in the world, and nearly half of the stage II( and III( patients undergoing radical resection develop relapse. At present, the survival benefit of follow-up strategy is still unclear, partly due to the neglect of the risk of recurrence and the factors affecting prognosis. Studies found that microsatellite status, BRAF and RAS genotype had certain value for prognosis of colorectal cancer patients after radical resection, but there were differences in prediction among these three factors. Patients with high-frequency microsatellite instability in stage II( have good prognosis, so the follow-up strategy in this set of patients can be appropriately simplified. Locally advanced colorectal cancer patients with BRAF-V600E mutations usually have poor survival after recurrence, and survival benefit appears minimal by intensive follow-up strategy. Besides, standard follow-up strategy, or less intensive follow-up strategy seems an acceptable option for patients with this subtype. In contrast, for patients with wild-type BRAF and RAS in stage II( or III(, the prognosis is usually good after recurrence. Such patients are sensitive to both systemic treatment and local therapy. Therefore, for patients with wild-type BRAF and RAS, early detection of recurrence by intensive follow-up strategy can potentially increase the possibility of second radical resection and prolong survival. It is of clinical significance to explore the feasibility of individualized follow-up strategy for patients with different biological characteristics. In addition, the establishment of individual risk prediction model should take clinical, pathological and molecular features into consideration. Combination of TNM staging and molecular markers for more stratified management and establishment of individualized follow-up system are clinically meaningful in the future. PMID- 29968250 TI - Secondary Hydrogeologic Regions of the Conterminous United States. AB - The U.S. Geological Survey (USGS) previously identified and mapped 62 Principal Aquifers (PAs) in the U.S., with 57 located in the conterminous states. Areas outside of PAs, which account for about 40% of the conterminous U.S., were collectively identified as "other rocks." This paper, for the first time, subdivides this large area into internally-consistent features, defined here as Secondary Hydrogeologic Regions (SHRs). SHRs are areas of other rock within which the rocks or deposits are of comparable age, lithology, geologic or physiographic setting, and relationship to the presence or absence of underling PAs or overlying glacial deposits. A total of 69 SHRs were identified. The number and size of SHRs identified in this paper are comparable to the number and size of PAs previously identified by the USGS. From a two-dimensional perspective, SHRs are complementary to PAs, mapped only where the PAs were not identified on the USGS PA map and not mapped where the PAs were identified. SHRs generally consist of low permeability rocks or deposits, but can include locally productive aquifers. The two maps, taken together, provide a comprehensive, national-scale hydrogeologic framework for assessing and understanding groundwater systems. PMID- 29968249 TI - Sex-specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signalling. AB - BACKGROUND AND PURPOSE: Autism spectrum disorder (ASD) is more commonly diagnosed in males than in females. Prenatal exposure to the antiepileptic drug valproic acid (VPA) is an environmental risk factor of ASD. Male rats prenatally exposed to VPA show socio-emotional autistic-like dysfunctions that have been related to changes in the activity of the endocannabinoid anandamide. Here, we have investigated if prenatal VPA induced sex-specific autistic endophenotypes involving anandamide signalling. EXPERIMENTAL APPROACH: We studied sex-specific differences in the ASD-like socio-emotional, cognitive and repetitive symptoms displayed during development of Wistar rats of both sexes, prenatally exposed to VPA. The involvement of anandamide was followed by Western blotting of cannabinoid CB1 receptors and by inhibiting its metabolism. KEY RESULTS: Female rats were less vulnerable to the deleterious effects of prenatal VPA exposure on social communication, emotional reactivity and cognitive performance than male rats. Conversely, as observed in male rats, prenatal VPA exposure induced selective deficits in social play behaviour and stereotypies in the female rat offspring. At the neurochemical level, prenatal VPA exposure altered phosphorylation of CB1 receptors in a sex-specific, age-specific and tissue specific manner. Enhancing anandamide signalling through inhibition of its degradation reversed the behavioural deficits displayed by VPA-exposed animals of both sexes. CONCLUSIONS AND IMPLICATIONS: These findings highlight sexually dimorphic consequences of prenatal VPA exposure that may be related to sex specific effects of VPA on endocannabinoid neurotransmission in the course of development and introduce a new therapeutic target for reversing autistic-like symptoms in both sexes. PMID- 29968251 TI - The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end-points. AB - Loss of muscle mass and insulin sensitivity are common phenotypic traits of immobilisation and increased inflammatory burden. The suppression of muscle protein synthesis is the primary driver of muscle mass loss in human immobilisation, and includes blunting of post-prandial increases in muscle protein synthesis. However, the mechanistic drivers of this suppression are unresolved. Immobilisation also induces limb insulin resistance in humans, which appears to be attributable to the reduction in muscle contraction per se. Again mechanistic insight is missing such that we do not know how muscle senses its "inactivity status" or whether the proposed drivers of muscle insulin resistance are simply arising as a consequence of immobilisation. A heightened inflammatory state is associated with major and rapid changes in muscle protein turnover and mass, and dampened insulin-stimulated glucose disposal and oxidation in both rodents and humans. A limited amount of research has attempted to elucidate molecular regulators of muscle mass loss and insulin resistance during increased inflammatory burden, but rarely concurrently. Nevertheless, there is evidence that Akt (protein kinase B) signalling and FOXO transcription factors form part of a common signalling pathway in this scenario, such that molecular cross-talk between atrophy and insulin signalling during heightened inflammation is believed to be possible. To conclude, whilst muscle mass loss and insulin resistance are common end-points of immobilisation and increased inflammatory burden, a lack of understanding of the mechanisms responsible for these traits exists such that a substantial gap in understanding of the pathophysiology in humans endures. PMID- 29968253 TI - Disparities in dental healthcare utilization in China. AB - OBJECTIVES: The goal of this study was to investigate inequality in dental service utilization in Chinese middle-aged and senior adults and changes in inequality over time and to determine the sources of inequality. METHODS: The data included 17 648 individuals aged 45 years and older in 2013 and 15 450 individuals in 2015 who participated in the China Health and Retirement Longitudinal Study (CHARLS). The concentration index was used to quantify the degree of inequality. A decomposition method was employed to determine the sources of inequality, including need variables (demographic characteristics, self-reported health status, and presence of chronic diseases), living standard (measured by household consumption expenditure per capita), other non-need variables (education level, marital status, region of residence, urban-rural difference and type of health insurance plans). RESULTS: The better-off not only had a higher likelihood of using dental care services than did the worse-off but also used them more often than the worse-off. The concentration index for probability of dental care utilization increased from 0.074 to 0.112 between 2013 and 2015, and the concentration index for total number of dental visits increased from 0.085 to 0.127. Living standard, education, health insurance plans and urban rural disparities showed a pro-rich contribution to the inequality. The living standard contributed about 70% to the pro-rich inequality. CONCLUSIONS: Dental care utilization in the Chinese middle-aged and older adults was concentrated in the better-off. Inequality in dental care utilization widened from 2013 to 2015. Achieving equity in dental care utilization remains a challenge for the healthcare system in China. PMID- 29968254 TI - Analysis of Solute Transport from a Source with Finite Leachable Mass. AB - A general approach is developed for the analysis of solute transport from a source with a finite initial mass. The approach uses an effective retardation factor to assign the initial mass that can be leached from the source. Demonstration analyses are presented to illustrate the approach with the numerical simulator MT3DMS. For cases that are tractable with analytical solutions, comparisons between the numerical and analytical results confirm that the proposed approach yields correct results. The approach is straightforward to apply and can accommodate conditions ranging from pure advection to pure diffusion, effectively extending the capabilities of models to simulate sources with finite leachable masses for complex flow fields, reactions and distributions of sources. PMID- 29968252 TI - Consensus molecular subtype classification of colorectal adenomas. AB - Consensus molecular subtyping is an RNA expression-based classification system for colorectal cancer (CRC). Genomic alterations accumulate during CRC pathogenesis, including the premalignant adenoma stage, leading to changes in RNA expression. Only a minority of adenomas progress to malignancies, a transition that is associated with specific DNA copy number aberrations or microsatellite instability (MSI). We aimed to investigate whether colorectal adenomas can already be stratified into consensus molecular subtype (CMS) classes, and whether specific CMS classes are related to the presence of specific DNA copy number aberrations associated with progression to malignancy. RNA sequencing was performed on 62 adenomas and 59 CRCs. MSI status was determined with polymerase chain reaction-based methodology. DNA copy number was assessed by low-coverage DNA sequencing (n = 30) or array-comparative genomic hybridisation (n = 32). Adenomas were classified into CMS classes together with CRCs from the study cohort and from The Cancer Genome Atlas (n = 556), by use of the established CMS classifier. As a result, 54 of 62 (87%) adenomas were classified according to the CMS. The CMS3 'metabolic subtype', which was least common among CRCs, was most prevalent among adenomas (n = 45; 73%). One of the two adenomas showing MSI was classified as CMS1 (2%), the 'MSI immune' subtype. Eight adenomas (13%) were classified as the 'canonical' CMS2. No adenomas were classified as the 'mesenchymal' CMS4, consistent with the fact that adenomas lack invasion associated stroma. The distribution of the CMS classes among adenomas was confirmed in an independent series. CMS3 was enriched with adenomas at low risk of progressing to CRC, whereas relatively more high-risk adenomas were observed in CMS2. We conclude that adenomas can be stratified into the CMS classes. Considering that CMS1 and CMS2 expression signatures may mark adenomas at increased risk of progression, the distribution of the CMS classes among adenomas is consistent with the proportion of adenomas expected to progress to CRC. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29968255 TI - Effect of informal financial support for health care on health Insurance uptake: Evidence from a mixed-methods study in Tamale metropolis of northern Ghana. AB - Attempts to study the determinants of health insurance enrollment in resource poor settings have often given less consideration to the potential influence of informal risk-sharing systems on individuals and households' decisions about health insurance. This paper contributes to existing discussions in this area by examining the effect of informal financial support for health care, an example of informal risk-sharing arrangement, on enrollment in the Ghana National Health Insurance Scheme (NHIS). It is based on a mixed-methods research in Tamale metropolis of northern Ghana. The study found widespread availability and reliance on informal support among low-income households to finance out-of-pocket health-care expenditure. Informal financial support for enrollment into the NHIS was noted to be less available. The study further found less strong but suggestive evidence that the perceived availability of informal financial support for health care by individuals diminishes their enrollment in the NHIS. The paper emphasizes the need for theory and policy on health insurance uptake in resource constrained settings to consider existing informal risk-sharing arrangements as much as other known determinants of enrollment. PMID- 29968256 TI - Genotype-phenotype correlation in type 1 neurofibromatosis: pMet992del mutation and milder disease. AB - A few genotype-phenotype correlations have been described in type 1 neurofibromatosis. One deletion, p.Met992del, seems to be responsible for a mild form of the condition, in which there is absence of externally visible neurofibromas. We report a mother and a son with this mutation. PMID- 29968257 TI - Identification of ligand binding activity and DNA recognition by RhlR protein from opportunistic pathogen Pseudomonas aeruginosa-a molecular dynamic simulation approach. AB - RhlR protein from opportunistic pathogen Pseudomonas aeruginosa is involved in the transcription of virulence genes of the organism. The RhlR protein functions as a dimer and binds to the cognate promoter DNA with the help of an autoinducer ligand BHL to initiate the transcription of the virulence genes. Till date, there are no reports that detail the mechanism of virulence gene expression by RhlR protein in P. aeruginosa. In this work, we tried to analyse the molecular aspects of the various binding interactions of the RhlR protein while formimg the dimmer as well as with the promoter DNA. We analysed the mode of dimerisation of the RhlR protein and its binding interactions with the autoinducer BHL ligand. From our analyses, we could identify the potential amino acid residues which are involved in the binding interactions. We also predicted how the autoinducer BHL would help in making contacts with the DNA as well as with itself. Thus, the autoinducer BHL would serve as an important mediator of molecular interactions involved in binding the RhlR protein to itself as well as with the promoter DNA. Therefore, any other molecule which would be able to compete with the autoinducer ligand BHL to bind to RhlR protein but would not let the RhlR protein bind the promoter DNA would be an ideal drug candidate to prevent the transcription process of the virulence genes in P. aeruginosa. Our future aim is to predict suitable ligands which would compete with BHL to thwart the transcription process. PMID- 29968258 TI - Oxidative stress index is increased in children exposed to industrial discharges and is inversely correlated with metabolite excretion of voc. AB - : Although the Atoyac River has been classified as highly polluted by environmental authorities, several communities are settled on its banks, affecting around 1.5 million persons, as well as farmland, due to an environmental distribution of toxics in the area. Our aim was to demonstrate that this environment affects important physiological processes that have an impact in health, so we conducted a study of schoolchildren from small communities on the banks of the river and in another similar town located far from it. 91 and 93 students, boys and girls, were studied from each site for oxidative stress index (OSI), calculated from the total antioxidant capacity and the total oxidative status, BTEX metabolite excretion and relevant metabolic polymorphisms participating in the bioactivation-detoxification of most VOC: CYP2E1 RsaI, NQO1 C609T, and null polymorphisms of GSTT1 and GSTM1. Results showed that OSI was significantly higher in children living by the river (5.23 +/- 3.4 vs 2.59 +/- 1.46, 95% C.I.). At this site, OSI was correlated with diminished metabolite excretion and a diminished antioxidant capacity; an association with genotypes CYP2E1RsaI (c2c2), GSTT1 present and NQO1*2 (CC) was also observed. Furthermore, boys at this site exhibited a diminished BMI compared to boys from the other community who were younger. IN CONCLUSION: children living at polluted sites like this, show early biological effects that might lead to health problems in their adult life. Environmental protection should be enforced to protect people's health in these sites where not even environmental monitoring is done. Environ. Mol. Mutagen. 59:639-652, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29968259 TI - Exploring home care nurses' perceptions regarding their services in economic crisis: A qualitative approach. AB - This article explores the home care nurses' perceptions on the services they provide in Cyprus, which has been hit by a financial crisis. Semistructured interviews were conducted in Greek at the home care nurses' offices. Data were analyzed using qualitative content analysis. The participants' perceptions are described in terms of provision of home care nursing, administration of homecare nursing, job satisfaction, financial issues, and suggesting improvements. The financial crisis influences the home care services with regard to workload increase, staff shortage, and lack of resources. Home care nurses are well engaged in the provision of proper services in order to address the patients' needs. However, the financial crisis has set obstacles in the provision of care. PMID- 29968260 TI - Thermal and asphyxia exposure risk to freshwater fish in feral-pig-damaged tropical wetlands. AB - Acute thermal and asphyxia exposure risks for freshwater fish occupying three tropical wetland typologies were examined. Field water-quality data revealed that fish in wetlands grazed by pigs had the highest exposure risks, because they are shallow and heavily damaged by pig activities. In contrast, with the exception is dissolved oxygen (which still reached critical conditions because of aquatic vegetation respiration), deeper permanent and pig-managed wetlands provides the best opportunity for the same fish species to survive in a heavily pig-modified tropical landscape. PMID- 29968261 TI - Predictive value of preoperative serum albumin levels on outcomes in patients undergoing LVAD implantation. AB - BACKGROUND: We performed a single-center retrospective analysis to determine whether preoperative serum albumin levels were associated with postoperative adverse events and short- and long-term survival in patients who underwent continuous-flow left ventricular assist device (CF-LVAD) implantation. METHODS: From November 2003 through March 2016, 526 patients underwent CF-LVAD implantation. Patients whose preoperative serum albumin level was normal (>=3.5 g/dL) were compared to patients with preoperative hypoalbuminemia (<3.5 g/dL), which was further categorized as moderate (2.5-3.5 g/dL) or severe (<2.5 g/dL). These groups were compared regarding preoperative demographics, incidence of postoperative complications, and long-term survival. RESULTS: Patients with hypoalbuminemia had higher serum levels of liver enzymes (P < 0.05) and total bilirubin (P < 0.001) and significantly lower platelet counts (P = 0.02) and prealbumin levels (P < 0.001) than patients with normal preoperative albumin levels. Survival in patients with moderate and severe preoperative hypoalbuminemia was significantly decreased compared with patients with normal preoperative serum albumin levels (P < 0.001). Preoperative hypoalbuminemia was also associated with higher incidences of postoperative infection, gastrointestinal bleeding, neurological dysfunction, and acute kidney injury (P <= 0.01 for all) but did not affect the success of bridge to transplantation or survival after transplantation. CONCLUSIONS: Our data demonstrated that there is a significant association of preoperative low serum albumin levels with postoperative adverse outcomes and lower survival rates. This highlights the importance of a patient's preoperative nutritional status on postoperative outcomes after CF-LVAD implantation. PMID- 29968262 TI - Tissue-Penetrating, Hypoxia-Responsive Echogenic Polymersomes For Drug Delivery To Solid Tumors. AB - Hypoxia in solid tumors facilitates the progression of the disease, develops resistance to chemo and radiotherapy, and contributes to relapse. Due to the lack of tumor penetration, most of the reported drug carriers are unable to reach the hypoxic niches of the solid tumors. We have developed tissue-penetrating, hypoxia responsive echogenic polymersomes to deliver anticancer drugs to solid tumors. The polymersomes are composed of a hypoxia-responsive azobenzene conjugated and a tissue penetrating peptide functionalized polylactic acid-polyethylene glycol polymer. The drug-encapsulated, hypoxia-responsive polymersomes substantially decreased the viability of pancreatic cancer cells in spheroidal cultures. Under normoxic conditions, polymersomes were echogenic at diagnostic ultrasound frequencies but lose the echogenicity under hypoxia. In-vivo imaging studies with xenograft mouse model further confirmed the ability of the polymersomes to target, penetrate, and deliver the encapsulated contents in hypoxic pancreatic tumor tissues. PMID- 29968263 TI - The principal-agent problem and owner-managers: An instrumental variables application to nursing home quality. AB - The literature on provider ownership has primarily focused broadly on for-profits compared with nonprofits and chains versus nonchains. However, the understanding of more nuanced ownership arrangements within individual facilities is limited. Utilizing the principal-agent and managerial control frameworks, we study the role of managerial ownership and its relationship to quality among for-profit nursing homes (NHs). We identify NH administrators with more than 5% ownership (owner-manager) from Ohio Medicaid Cost Reports (2005-2010) and link these data to long-stay resident records in the Minimum Data Set. Using differential distance to the nearest NHs with a salaried manager relative to an owner-manager, we address the differential selection into these two types of NHs. After instrumenting for admissions to owner-managed NHs, quality among long-stay residents at owner-managed NHs is generally better than NHs with salaried managers. We find suggestive evidence that the magnitudes of quality difference are larger when the principal-agent problem is likely more pronounced, such as when NHs that are part of a multifacility chain and located in more concentrated markets. PMID- 29968264 TI - The embodied experience of pregnancy with an ileostomy. AB - AIMS AND OBJECTIVES: To understand women's experience of pregnancy with an ileostomy following bowel resection for inflammatory bowel disease or familial adenomatous polyposis. BACKGROUND: While symptoms of IBD/FAP can be debilitating and life-threatening, ostomy formation can effectively manage symptoms. Research on pregnant women with an ostomy is sparse. While some literature suggests pregnant women with an ostomy can have a normal pregnancy and birth, documented stoma complications include intestinal obstruction, peristomal hernia, retraction, stenosis, laceration, bleeding, prolapse, pouching problems, nausea, vomiting and dehydration. DESIGN: Hermeneutic phenomenology. METHODS: All known women (n = 8) who had been pregnant with an ileostomy were recruited from the stomal therapy departments of two teaching hospitals. Single in-depth interviews were digitally recorded and transcribed verbatim. Hermeneutic phenomenological analysis was guided by the philosophy of Merleau-Ponty. Reporting rigour was guided by the consolidated criteria for reporting qualitative research. RESULTS: There was a lower level of concern among pregnant woman with an ostomy than anticipated. Women described the following: the "hell" of the disease; the stoma as a lifeline; heading into uncharted waters; wanting to be normal; the shared space of the baby and the diseased abdomen; pregnancy as a dark tunnel; and the unreliable body. CONCLUSION: Women with inflammatory bowel disease frequently experience debilitating symptoms and serious ill health. Ileostomy formation improves symptoms and the sense of "feeling normal," facilitating readiness for conception, pregnancy and motherhood. However, women's uncertainty about conception and pregnancy persists due to the scarce information and experiences offered by clinicians, and fears around their unreliable body during pregnancy. Given this uncertainty for both women and their treating clinicians, outcomes should be documented and shared to reassure women of child-bearing age that pregnancy and birth can be safe with a stoma. RELEVANCE TO PRACTICE: Women and clinicians should aim for disease remission, peer support, ongoing monitoring and involvement of a Stomal Therapy Nurse. PMID- 29968265 TI - Fenvalerate decreases semen quality in puberty rat through germ cell apoptosis. AB - Fenvalerate, a widely used synthetic pyrethroid insecticide, may adversely affect semen quality in males, but the possible mechanism remains unclear. In our study, forty male SD rats were randomly divided into one control group and three treatment groups administered with fenvalerate (0.02, 1 and 50 mg kg-1 day-1 ) by gavage from post-natal day 28 (PND 28) to PND 88. Semen quality parameters were measured by computer-assisted sperm analysis, histological changes in testes were observed by hematoxylin-eosin (HE) staining, germ cell apoptosis was measured by TdT-mediated dUTP Nick-End Labeling (TUNEL) and caspases protein levels were measured by western blotting. Results showed that the increased body weight, the relative testis weight, the sperm concentration and the sperm motility were all significantly reduced in the 50 mg kg-1 day-1 fenvalerate group. Increased inner diameter of seminiferous tubules and disturbed array of spermatogenic cells in testicular were observed in fenvalerate exposure groups. Meanwhile, TUNEL-positive germ cells significantly increased in 1 and 50 mg kg-1 day-1 fenvalerate exposure groups, and the expression of caspase-8 and caspase-3 in rat testes were also significantly up-regulated. Taken together, our results indicate that fenvalerate has an adverse effect on semen quality, which may be related to germ cell apoptosis. PMID- 29968266 TI - Effect of Zirconia Core Thickness and Veneer Firing Cycle on the Biaxial Flexural Strength of Veneering Ceramic. AB - PURPOSE: To evaluate the influence of various Y-TZP thicknesses and veneer firing cycles on the strength of two ceramic veneers. MATERIALS AND METHODS: 180 Y-TZP cores of 0.5, 1.0, and 5.0 mm thickness were prepared followed by sintering in a high temperature furnace; 180 presintered veneering ceramic discs (Vita VM9 porcelain and e.max Ceram) were also prepared using a mold. The discs were placed on zirconia plates (zirconia cores) of different thickness (0.5, 1.0, and 5.0 mm) and exposed to different firing cycles (Vita VM9 porcelain-910, 930, and 950 degrees C; e.max Ceram-750, 770, and 790 degrees C). Ball-on-three-balls flexural strength test was performed (universal testing machine) at a crosshead speed of 0.5 mm/min. Scanning electron microscopy of fractured specimens was performed. Means and standard deviations of flexural strength were analyzed using Tukey Kramer HSD test for multiple comparisons. RESULTS: Specimens within material groups showed no significant difference (p > 0.05) for flexural strength with respect to Y-TZP core thickness (0.5, 1.0, and 5.0 mm) (VM9 [117.30 +/- 14.328, 117.75 +/- 13.66, 113.75 +/- 20.10], e.max Ceram [94.79 +/- 17.5, 100.02 +/- 14.7, 95.23 +/- 15.4]). Flexural strength within material groups with respect to different firing cycles ([VM9-910, 930, 950 degrees C], e.max Ceram [750, 770, 790 degrees C]), for VM9 (111.49 +/- 15.7, 120.86 +/- 13.2, 116.46 +/- 18.4), and e.max Ceram (94.64 +/- 15.2, 101.6 +/- 16.69, 93.8 +/- 15.20) showed no significant difference (p > 0.05). CONCLUSIONS: Different zirconia thicknesses (0.5, 1.0, and 5.0 mm) and veneer firing cycles for Vita VM9 and e.max ceramics failed to show any significant influence on their biaxial flexural strengths. PMID- 29968267 TI - Examining the factor structure of the Motives for Playing Drinking Games measure among Australian university students. AB - INTRODUCTION AND AIMS: Given the prevalence of drinking games among university students and the health risks associated with playing drinking games, it is important to consider motivations for participation. The psychometric properties of the Motives for Playing Drinking Games (MPDG) measure have been examined among US college student samples, but mixed findings have been reported regarding the number of factors in the measure. This is the first study to examine the factor structure and applicability of the MPDG measure among a sample of Australian university students. DESIGN AND METHODS: University students (N = 254; aged 18-46 years; 62% female) with prior drinking experience completed an online survey which included questions pertaining to demographics, drinking game frequency and consumption, drinking game consequences and the MPDG measure. RESULTS: Confirmatory factor analyses demonstrated that the originally proposed 8-factors within the MPDG measure were problematic in the current sample and a revised 7 factor solution was preferred. Analyses examining the relations of the revised 7 MPDG factors with drinking game behaviours (e.g. gaming-specific consequences and amount consumed during play) highlighted the importance of some MPDG (enhancement/thrills, conformity and sexual pursuit motives). DISCUSSION AND CONCLUSIONS: While the MPDG measure shows promise for assessing drinking game specific motives, the need to consider the applicability of MPDG subscales across different samples was apparent. PMID- 29968268 TI - Construction of nursing-sensitive quality indicators for haemodialysis using Delphi method. AB - AIMS AND OBJECTIVES: To provide a set of nursing-sensitive quality indicators (NSQIs) for the evaluation of clinical nursing quality in haemodialysis unit. BACKGROUND: There are no established objective indicators for evaluation of the quality of nursing care in haemodialysis units in China. DESIGN AND METHODS: We performed a literature search for eligible studies published from 2006-2016. A total of six studies were screened out from which 13 potential NSQIs were identified. Two rounds of Delphi surveys were conducted with the purpose of collecting opinions from a panel of independent experts. At last, 11 NSQIs were selected by consensus after exclusion of 8 NSQIs and addition of another 6 NSQIs. RESULTS: Two rounds of expert inquiry were conducted; the questionnaire recovery rate was 100%. The average authoritative coefficients Cr for the two rounds were 0.79 and 0.90, respectively. The Kendall W values ranged from 0.273-0.388 (p < 0.001). Eleven NSQIs were identified: nurse-to-patient ratio, dialysis ultrafiltration rate compliance rate, KT/V compliance rate, incidence of emergency during haemodialysis, person-time incidence rate of haemodialysis catheter-related bloodstream infections, incidence of coagulation in extracorporeal circulation, incidence of blood loss in extracorporeal circulation, incidence of pseudoaneurysm induced by fistula puncture, incidence of falls among haemodialysis patients, emergency dialysis rate of outpatients and incidence of fistula complications. CONCLUSION: The identified NSQIs reflect three aspects of haemodialysis nursing quality: importance, rationality of calculation formula and applicability of data collection methods. RELEVANCE TO CLINICAL PRACTICE: The study provides a reference for the evaluation of clinical nursing quality in haemodialysis units. PMID- 29968269 TI - Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of Hetero-triarylmethanes from Racemic Indolyl Alcohols. AB - The direct enantioselective 1,4- and 1,8-arylations of 7-methide-7H-indoles and 6 methide-6H-indoles, respectively, generated in situ from diarylmethanols, with electron-rich arenes as nucleophiles, has been achieved in the presence of chiral phosphoric acids (CPAs). These two remote activation protocols provide an efficient approach for the construction of diverse hetero-triarylmethanes in high yields (up to 97 %) and with excellent enantioselectivities (up to 96 %). Mechanistically inspired experiments tentatively indicate that the catalytic enantioselective 1,4-addition as well as the formal SN 1 substitution could proceed efficiently in the similar catalytic systems. Furthermore, the modification of the catalytic system and diarylmethanol structure successfully deviates the reactivity toward a remote, highly enantioselective 1,8-arylation reaction. This flexible activation mode and novel reactivity of diarylmethanols expand the synthetic potential of chiral phosphoric acids. PMID- 29968270 TI - Targeting eotaxin-1 and CCR3 receptor alleviates enteric neuropathy and colonic dysfunction in TNBS-induced colitis in guinea pigs. AB - BACKGROUND: The accumulation of eosinophils is mediated by the chemokine receptor 3 (CCR3)-eotaxin axis. Increased expression of eotaxin and its receptor is associated with inflammatory bowel disease (IBD). Activation of eosinophils causes the release of cationic proteins that are neurotoxic such as eosinophil derived neurotoxin (EDN). Damage to enteric neurons alters neurally controlled functions of the gut correlated with intestinal inflammation. We hypothesized that inhibition of the CCR3-eotaxin axis will prevent inflammation-induced functional changes to the gastrointestinal tract. METHODS: Hartley guinea pigs were administered with trinitrobenzene sulfonate (TNBS; 30 mg/kg in 30% ethanol) intrarectally to induce colitis. A CCR3 receptor antagonist (SB 328437 [SB3]) was injected intraperitoneally 1 hour postinduction of colitis. Animals were euthanized 7 days post-treatment and colon tissues were collected for ex vivo studies. The EDN-positive eosinophils in the colon, indicating eosinophil activation, were quantified by immunohistochemistry. Effects of SB3 treatment on gross morphological damage, enteric neuropathy, and colonic dysmotility were determined by histology, immunohistochemistry, and organ bath experiments. KEY RESULTS: The number of EDN-positive eosinophils was significantly increased in the lamina propria in close proximity to myenteric ganglia in inflamed colon. The TNBS-induced inflammation caused significant damage to colonic architecture and inhibition of colonic motility. Treatment with SB3 antagonist attenuated inflammation-associated morphological damage in the colon, reduced infiltration of EDN-positive eosinophils and restored colonic motility to levels comparable to control and sham-treated guinea pigs. CONCLUSION & INFERENCES: This is the first study demonstrating that inhibition of CCR3-eotaxin axis alleviates enteric neuropathy and restores functional changes in the gut associated with TNBS induced colitis. PMID- 29968271 TI - Qualitative exploration of the experiences of renal dietitians and how they help patients with end stage kidney disease to understand the renal diet. AB - AIM: Dietary modification is integral to the management of end stage kidney disease. However, adherence to the renal diet is poor. Few studies have explored the perspectives of renal dietitians and how they work with patients to facilitate dietary change. The objectives of this study were to explore the experiences of renal dietitians about educating patients with end stage kidney disease; and to describe the strategies perceived to help patients understand the renal diet. METHODS: Semi-structured interviews based on Sensemaking theory were conducted with renal dietitians (n = 27) working in Australia and New Zealand from a range of metropolitan, regional and remote areas. RESULTS: Five major themes across two categories were derived from the data. The renal dietitians in this study experienced feelings of frustration, frequently worked in practice environments with limited or inadequate resources and perceived that establishing trust and demonstrating empathy were important to sense making. Renal dietitians helped patients make sense of and understand the diet by clarifying ambiguities and conflicting information; and simplifying complexity by using simple explanations, individualised advice and practical support. These strategies were considered critical to the renal diet sense making process. CONCLUSIONS: The experience of providing renal diet advice to adults with end stage kidney disease was emotionally and professionally challenging. Alternative approaches to patient education may help dietitians to empower patients to better understand the renal diet. Further research exploring the experiences of learning about the renal diet from the patient and carer perspective would also help to inform future alternative approaches. PMID- 29968272 TI - Development and effect of a rational-emotive-behaviour-therapy-based self management programme for early renal dialysis patients. AB - AIMS AND OBJECTIVES: This study attempts to develop and determine the effect a rational-emotive-behaviour-therapy-based self-management programme can have on the self-efficacy, self-care, depression and dyssomnia of patients undergoing early renal dialysis. BACKGROUND: When renal dialysis is initiated, changes in everyday life are inevitable, and patients can suffer from both psychological and physical symptoms. Hence, to obtain the best results from renal dialysis, active self-management is required. DESIGN: Quasi-experimental and longitudinal. METHODS: Forty-eight early-stage renal dialysis patients registered for and undergoing renal dialysis at a hospital located in S city participated in this study. These individuals were divided into an experimental and control group. The former group engaged in a self-management programme consisting of eight weekly sessions of 50 min in duration, while the latter received traditional nursing care. Data were collected from June 2012-May 2014 through the use of a preliminary survey, a postsurvey that was distributed after the eight sessions of the self-management programme had been completed, and a follow-up survey allocated 4 weeks after the postsurvey. Data collection was conducted using the Self-efficacy Scale, Self-care Practice Scale, Beck Depression Inventory, and Korean Sleep Scale, and a repeated-measures ANOVA was used to perform analysis. RESULTS: The experimental group significantly differed from the control group in regard to self-efficacy (p = 0.006) and self-care (p = 0.031), but differences in terms of depression (p = 0.492) and dyssomnia (p = 0.141) were nonsignificant. In the experimental group, the depression decreased but then increased again, while the dyssomnia gradually decreased. CONCLUSIONS: The provision of a rational emotive-behaviour-therapy-based self-management programme that involves lectures, discussions, teach-backs, demonstrations and posters explaining diet choices improves the self-efficacy and self-care of patients receiving renal dialysis. RELEVANCE TO CLINICAL PRACTICE: Rational-emotive-behaviour-therapy-based self management programmes can be used in clinical nursing sites to improve the self efficacy and self-care of early renal dialysis patients. PMID- 29968273 TI - Alternative access for transcatheter aortic valve replacement in older adults: A collaborative study from France and United States. AB - BACKGROUND: We examined the outcomes of older adults undergoing nontrans-femoral (non-TF) transcatheter aortic valve replacement (TAVR) procedures including trans apical (TA), trans-aortic (TAo), trans-subclavian (TSub), and trans-carotid (TCa) techniques. METHODS AND RESULTS: This is an observational study of all consecutive older patients who underwent non-TF TAVR for symptomatic severe AS with Edwards Sapien (ES), Medtronic CoreValve, ES3 or Lotus Valve at three centers in France and the United States from 04/2008 to 02/2017. Baseline characteristics and clinical outcomes were defined according to VARC-2 criteria. Of 857 patients who received TAVR, 172 (20%) had an alternative access procedure. Of these, 45 (26%) were TA, 67 (39%) TAo, 17 (10%) TSub, and 43 (25%) TCa procedures. The preference for non-TF access site was different between the two countries (US: TA 39%, TAo 52%, TSub 9%; TCa 0% vs. France: TA 9%, TAo 23%, TSub 11%, and TCa 57%, P-value < .001). Most patients who underwent TAo TAVR were older women (median age: TA 82, TAo 84, TSub 81, TCa 81, P-value = 0.043; female gender: TA 32 (27%), TAo 30 (55%), TSub 10 (41%), TCa 27 (37%), P-value = .021). The predicted Society of Thoracic Surgery risk of mortality was similar among groups (TA 7%, TAo 7%, TSub 6%, TCa 7%, P-value= .738). No differences were observed in the frequency of para-valvular leak, intra-procedural bleeding, vascular complications, conversion to open-heart surgery, or development of acute kidney injury. The highest in-hospital mortality was observed in the TAo group (TA 2%, TAo 15%, TSub 0%, TCa 2%, P-value = .014). However, hospital length of stay, one-month, and one-year mortality were similar among non-TF techniques. CONCLUSION: Although regional differences exist in the choice of alternative access techniques, centers with high technical expertise can provide a safe alternative to traditional TF TAVR. TAo TAVR was associated with higher in hospital mortality than other non-TF approaches, and this may have reflected patient rather than procedural factors. All alternative access techniques had similar mortality rates and clinical outcomes at one-year follow-up. Trans carotid access is safe and feasible compared to other non-TF access techniques. PMID- 29968274 TI - DNA Primer Extension with Cyclopropenylated 7-Deaza-2'-deoxyadenosine and Efficient Bioorthogonal Labeling in Vitro and in Living Cells. AB - A deoxyadenosine triphosphate (dATP) analogue for DNA labeling was synthesized with the 1-methylcyclopropene (1MCP) group at the 7-position of 7-deaza-2' deoxyadenosine and applied for primer extension experiments. The real-time kinetic data reveals that this 1MCP-modified dATP analogue is incorporated into DNA much faster than that of the similarly 1MCP-modified deoxyuridine triphosphate (dUTP) analogue. The postsynthetic fluorescent labeling of these oligonucleotides works efficiently according to PAGE analysis, and can be applied for immobilization of a functional antibody on a surface. Site-specific labeling at two different positions in DNA was achieved and the bioorthogonality of the postsynthetic fluorescent labeling was demonstrated in living HeLa cells. PMID- 29968275 TI - Paracoccus denitrificans can utilize various long-chain N-acyl homoserine lactones and sequester them in membrane vesicles. AB - Many gram-negative bacteria utilize N-acyl homoserine lactone (AHL) signals to communicate with each other. Once they have been released, these signals are assumed to be shared among the population in the local environment. In contrast to this canonical quorum-sensing (QS) model, recent study in Paracoccus denitrificans showed that they can traffic their signals to each other via membrane vesicles (MVs). Here, we demonstrate that various long-chain AHLs inhibited cell aggregation in P. denitrificans, whereas the short-chain AHLs alone did not. Furthermore, MVs released from P. denitrificans were able to take up the long-chain AHLs from the environment into MVs. The AHLs associated with MVs triggered gene expression in P. denitrificans, indicating their role in QS. Our results suggest that P. denitrificans can sequester the AHL produced by other bacteria and deliver the signals to themselves via MVs. Utilizing the signals from other bacteria may be advantageous for P. denitrificans to reach the threshold QS concentration in a polymicrobial community in which the population of its own species is relatively low. PMID- 29968276 TI - In Vitro Effect of Mastication on the Retention and Wear of Locator Attachments in a Flat Mandibular Ridge Model. AB - PURPOSE: The effect of masticatory loads on the retention of overdenture attachments is poorly documented. The aim of this in vitro study is to assess the effect of simulated mastication on the retentive properties and dimensions of Locator inserts. MATERIALS AND METHODS: 30 specimens simulating nonanatomic edentulous flat ridges with two implant replicas each were fabricated. Overdenture units were connected to the implants with Locator attachments and 3 types of inserts: transparent (Group T; n = 10 pairs), pink (Group P; n = 10 pairs), and blue (Group B; n = 10 pairs). The overdenture units were subjected to simulated bi-axial masticatory loads of 68.6 N. Locator retention was assessed using axial dislodging forces at baseline (T0) and following 100,000 (T1) and 200,000 (T2) masticatory cycles. The inner diameter of the insert (XY) and the diameter of the central core (AB) were measured under stereomicroscope at T0 and T2. Retention changes and dimensional variations of the inserts were statistically analyzed. RESULTS: The 3 groups showed significantly different retentions with the highest values recorded for group T followed by group P, and finally group B at T0, T1, and T2. Groups T and P were not affected by loading while group B showed a significant mean retention loss from T0 to T1. XY and AB were significantly different between the 3 color-coded inserts at baseline and at T2. No correlation could be established between retention changes and dimensional variations of the 3 types of inserts. CONCLUSIONS: Within the limitations of this in vitro study, simulated mastication seems to significantly affect the extra light blue Locator inserts but not the more-retentive ones. The transparent and pink inserts may require less frequent replacements and could therefore be recommended under clinical conditions. PMID- 29968277 TI - Transplanting organs from hepatitis B positive donors: Is it safe? Is it ethical? AB - Liver transplant centres throughout the USA face a huge shortage of liver organs for their wait-listed patients. Various types of innovations are being considered for expansion of this donor pool. Organs that were previously deemed to be high risk are now being considered for transplantation. For the last 25 years, hepatitis B core antibody (anti-HBc+) organs have been used for liver transplantation. While the initial transplantations did reveal a high incidence of de novo hepatitis (DNH) in the recipients, the medical knowledge and experience have evolved and this risk has been markedly decreased. In this paper, medical literature evaluating the safety of such organ transplants has been reviewed. There is strong evidence to suggest that using anti-HBc+ organs with appropriate prophylaxis after transplant is a safe practice with good patient and graft survivals. In the second half of the paper, we discuss whether it is ethical to use anti-HBc+ organs. We argue that the use of such organs is in compliance with the principles of medical ethics and that society at large benefits from the use of these organs. Hence, we recommend that the use of such organs is both safe and ethical and this practice should be continued in the future. PMID- 29968279 TI - Paliperidone palmitate once-every-3-months in adults with early illness schizophrenia. AB - AIM: This post hoc analysis of a double-blind (DB), randomized, placebo controlled, relapse-prevention study evaluated the effects of paliperidone palmitate once-every-3-months (PP3M) in a subpopulation of adults with early illness schizophrenia (duration <=5 years) from a clinical trial. METHODS: Patients received either PP3M or placebo every 3 months in the DB phase. The primary efficacy variable was time from randomization to first relapse. Symptom severity, patient functioning, and safety were also assessed. RESULTS: A total of 119 patients who entered the DB phase met the criteria for early illness schizophrenia (PP3M, n = 62; placebo, n = 57). PP3M significantly delayed time to relapse vs placebo (P = .035; hazard ratio, 3.08; 95% CI, 1.08-8.80). Symptomatic control and patient functioning were maintained in the PP3M group but significantly worsened in the placebo group. There were no unexpected tolerability findings. CONCLUSIONS: PP3M reduced relapse risk and maintained symptomatic and functional improvements compared with placebo in patients with early illness schizophrenia. PMID- 29968278 TI - A Potential Golden Age to Come-Current Tools, Recent Use Cases, and Future Avenues for De Novo Sequencing in Proteomics. AB - In shotgun proteomics, peptide and protein identification is most commonly conducted using database search engines, the method of choice when reference protein sequences are available. Despite its widespread use the database-driven approach is limited, mainly because of its static search space. In contrast, de novo sequencing derives peptide sequence information in an unbiased manner, using only the fragment ion information from the tandem mass spectra. In recent years, with the improvements in MS instrumentation, various new methods have been proposed for de novo sequencing. This review article provides an overview of existing de novo sequencing algorithms and software tools ranging from peptide sequencing to sequence-to-protein mapping. Various use cases are described for which de novo sequencing was successfully applied. Finally, limitations of current methods are highlighted and new directions are discussed for a wider acceptance of de novo sequencing in the community. PMID- 29968280 TI - Perceptions of attenuated psychosis in a diverse sample of undergraduates. AB - AIM: Prior to the release of the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders, experts in the field of psychosis research considered including a psychosis high-risk syndrome-attenuated psychosis syndrome as a formal diagnosis. Opponents argued that such a diagnosis may increase the risk of stigmatization of individuals whose symptoms often remit. Although previous research has examined provider perceptions of attenuated psychosis syndrome, little work has focused on lay perceptions. METHODS: A total of 455 college students read three vignettes, each depicting a character with a different level of psychotic disorder (attenuated psychosis syndrome, schizophrenia or no psychosis). Following each vignette, participants responded to questions assessing: (1) identification of the character as mentally ill, (2) stigmatizing attitudes and (3) beliefs regarding the helpfulness of potential treatments. RESULTS: Compared to a character with no psychosis, participants identified the attenuated psychosis syndrome character as more likely to be experiencing mental illness, but endorsed only slightly more stigmatizing attitudes. Participants tended to rate psychological types of treatment as more helpful than other types for an attenuated psychosis syndrome character. CONCLUSIONS: Non-expert undergraduates appear to view attenuated psychosis symptoms as indicative of mental illness, though not as severe as schizophrenia symptoms. The minimal level of stigma endorsement indicates that college students may not be especially likely to spontaneously stigmatize peers with attenuated psychosis syndrome. PMID- 29968281 TI - Giant Optical Activity in an All-Dielectric Spiral Nanoflower. AB - Optical activity is an effect of prominent importance in stereochemistry, analytical chemistry, metamaterials, spin photonics, and astrobiology, but is naturally minuscule. Metallic nanostructures are commonly exploited as basic elements for artificially producing large optical activity by virtue of surface plasmon resonance (SPR) on the nanostructures. However, their intrinsic high ohmic loss amplified by the SPR results in low energy efficiency and large photothermal heat generation, severely limiting their performance and practical utility. Giant optical activity by inducing magnetic resonance in an all dielectric spiral nanoflower (spiral-flower-shaped nanostructure) is demonstrated here. Specifically, a large circular-intensity difference of ~35% is theoretically predicted and experimentally demonstrated by optimizing the magnetic quadrupole contribution of the nanoflower to scattered light. The nanoflower overcomes the bottleneck of the traditional metallic platforms and enables the development of diverse chiroptical devices and applications. PMID- 29968282 TI - Highly Efficient, Cost Effective, and Safe Sodiation Agent for High-Performance Sodium-Ion Batteries. AB - The development of sodium-ion batteries has been hindered so far by the large irreversible capacity of hard carbon anodes and other anode materials in the initial few cycles, as sodium ions coming from cathode materials is consumed in the formation of the solid-electrolyte interface (SEI) and irreversibly trapped in anodes. Herein, the successful synthesis of an environmentally benign and cost effective sodium salt (Na2 C4 O4 ) is reported that could be applied as additive in cathodes to solve the irreversible-capacity issues of anodes in sodium-ion batteries. When added to Na3 (VO)2 (PO4 )2 F cathode, the cathode delivered a highly stable capacity of 135 mAh g-1 and stable cycling performance. The water stable Na3 (VO)2 (PO4 )2 F cathode in combination with a water-soluble sacrificial salt eliminates the need for using any toxic solvents for laminate preparation, thus paving way for greener electrode fabrication techniques. A 100 % increase in capacity of sodium cells (full-cell configuration) has been observed when using the new sodium salt at a C-rate of 2C. Regardless of the electrode fabrication technique, this new salt finds use in both aqueous and non aqueous cathode-fabrication techniques for sodium-ion batteries. PMID- 29968283 TI - Selective alpha-Monomethylation by an Amine-Borane/N,N-Dimethylformamide System as the Methyl Source. AB - A new and practical alpha-monomethylation strategy using an amine-borane/N,N dimethylformamide (R3 N-BH3 /DMF) system as the methyl source was developed. This protocol has been found to be effective in the alpha-monomethylation of arylacetonitriles and arylacetamides. Mechanistic studies revealed that the formyl group of DMF delivered the carbon and one hydrogen atoms of the methyl group, and R3 N-BH3 donated the remaining two hydrogen atoms. Such a unique reaction pathway enabled controllable assemblies of CDH2 -, CD2 H-, and CD3 - units using Me2 NH-BH3 /d7 -DMF, Me3 N-BD3 /DMF and Me3 N-BD3 /d7 -DMF systems, respectively. Further application of this method to the facile synthesis of anti inflammatory flurbiprofen and its varied deuterium-labeled derivatives was demonstrated. PMID- 29968284 TI - Phosphorescence Resulting from Interaction between Two Non-equivalent Metals on a Helical pi-Conjugated Surface. AB - A [7]helicene bis-ruthenium complex, with one ruthenium atom bound to the cyclopentadienyl (Cp) ring and the other coordinated to the arene ring at the edge of the helicene, was synthesized. This complex showed phosphorescence both in butyronitrile (Phi=31 %, 77 K) and in the solid state (Phi=18 %, 77 K). The two non-equivalent ruthenium metal atoms, attached to the helicene ligand, interact with each other upon photoabsorption and emission. PMID- 29968286 TI - Contesting the "territorial aggression thesis" in environmental psychology, ca. 1965-1980. AB - In the latter part of the 1960s, the ethologically derived idea of territoriality as an explanation for human aggression became widely debated among social scientists. The instinctual basis of human territorial aggression was promoted by so-called popular ethologists and consequently embraced by lay audiences. The article examines how the emerging field of environmental psychology adopted the notion of human territoriality from ethology and made it into a part of their own research agenda. It shows how environmental psychologists were inspired by the fashion around the claimed relevance of human territoriality for the large-scale social problems, such as aggression, war and population growth. Despite of the obvious influences and comparisons between animal and human behavior, many environmental psychologists wanted to contest not only the 'territorial aggression thesis' but also the relevance of animal studies for the analysis of human behavior. PMID- 29968285 TI - Vocational engagement among young people entering mental health treatment compared with their general population peers. AB - AIM: To compare rates of vocational engagement for youth entering specialist mental health treatment with the general population. METHODS: A file audit retrieved vocational data for 145 youth aged 15 to 25 entering treatment. Clinical and population data were stratified by age and sex and compared between cohorts. RESULTS: Compared to the population, young people entering mental health treatment were less likely to have completed at least Year 11 in school (77% vs 42%, P < 0.001); and demonstrated higher rates of "Not in Education, Employment or Training" (9% vs 33%, P < 0.001). Individuals aged 15 to 18 years entering treatment experienced greater rates of educational disengagement than the population (30% vs 11%, P < 0.001), whereas people aged 19 to 25 years showed higher unemployment rates (52% vs 35%, P = 0.003). CONCLUSIONS: Youth entering specialist mental health treatment have marked levels of vocational disengagement compared to demographically-matched peers. Early vocational intervention for these young people is essential. PMID- 29968287 TI - Right of reply to: The surgical 'Robot' in gynaecology: It isn't a robot at all, and it doesn't make anything better. PMID- 29968289 TI - Profiles of Women in Science: Prof. Stephanie Cragg of the University of Oxford, Oxford, UK. PMID- 29968288 TI - Ecophysiology and lipid dynamics of a eukaryotic mangrove decomposer. AB - Aurantiochytrium limacinum is an osmo-heterotrophic Stramenopile and a pioneering mangrove decomposer which is taxonomically assigned to the family of Thraustochytriaceae (class: Labyrinthulomycetes). The life cycle of A. limacinum involves different cell types including mono- and multi-nucleated cells as well as flagellated zoospores which colonize new fallen leaves. The ecological relevance of thraustochytrids is underestimated and eclipsed by their biotechnological importance, due to their ability to accumulate large amount of lipids, mainly triacylglycerols (TAGs). In this study, we aimed to understand the ecophysiological parameters that trigger zoospore production and the interplay between the life cycle of A. limacinum and its lipid metabolism. When grown in a rich medium, cells accumulated large amounts of TAGs at the end of their growth period, but no zoospores were produced. In poor media such as artificial sea water, zoospores were produced in massive quantities. In the absence of organic carbon, the zoospores remained swimming for at least 6 days, consuming their TAGs in the process. Addition of glucose rapidly triggered the maturation of the zoospores. On the basis of these data, we propose a life cycle for A. limacinum integrating the potential perturbations/changes in the environment surrounding a mangrove leaf that could lead to the production of zoospores and colonization of new areas. PMID- 29968290 TI - Accuracy of patient recall for self-reported doctor visits: Is shorter recall better? AB - In health economics, the use of patient recall of health care utilisation information is common, including in national health surveys. However, the types and magnitude of measurement error that relate to different recall periods are not well understood. This study assessed the accuracy of recalled doctor visits over 2-week, 3-month, and 12-month periods by comparing self-report with routine administrative Australian Medicare data. Approximately 5,000 patients enrolled in an Australian study were pseudo-randomised using birth dates to report visits to a doctor over three separate recall periods. When comparing patient recall with visits recorded in administrative information from Medicare Australia, both bias and variance were minimised for the 12-month recall period. This may reflect telescoping that occurs with shorter recall periods (participants pulling in important events that fall outside the period). Using shorter recall periods scaled to represent longer periods is likely to bias results. There were associations between recall error and patient characteristics. The impact of recall error is demonstrated with a cost-effectiveness analysis using costs of doctor visits and a regression example predicting number of doctor visits. The findings have important implications for surveying health service utilisation for use in economic evaluation, econometric analyses, and routine national health surveys. PMID- 29968291 TI - Clinical nurses' experiences and perceptions after the implementation of an interprofessional team intervention: A qualitative study. AB - AIMS AND OBJECTIVES: To explore clinical nurses' experiences and perceptions following a purposeful interprofessional (IP) team intervention in practice. BACKGROUND: Despite increasing interest in IP collaborative practice to improve teamwork, nursing outcomes and quality of care, there has been little research that focused on nurses' perspectives of IP collaboration after a purposeful IP team intervention. DESIGN: A qualitative descriptive study using focus group interviews of registered nurses who care for patients with advanced heart failure. METHODS: This study is part of a larger study that conducted and evaluated a purposeful IP team intervention. Registered nurses (n = 10) were invited to participate in three focus groups following the IP team intervention. Data were audio-recorded, transcribed and analysed using a conventional content analysis approach and constant comparative method. RESULTS: We identified six interrelated themes: (a) IP team building, (b) psychological safety and cultural change, (c) efficiency in delivery of care, (d) quality of patient care, (e) job outcomes and (f) team challenges. Notably, participants reported that they could better understand the patient's care plan of the day because every team member was "on the same page at the same time." Registered nurses perceived that they were more satisfied with their job through improved IP team performance, enhanced psychological safety and cultural change, efficient workflow and better quality of patient care. CONCLUSIONS: The IP team intervention contributed to enhancing IP team functioning as well as improving registered nurse job satisfaction. To sustain the improved perceptional and behavioural changes, team strategies to improve workflow and communication should be considered. RELEVANCE TO CLINICAL PRACTICE: Effective teamwork and communication between multiple healthcare professionals including nurses are the cornerstones to improve care delivery, nursing outcomes and quality of patient care in clinical settings. PMID- 29968292 TI - Retraction: Intra-arterial transplantation of human bone marrow mesenchymal stem cells (hBMMSCs) improves behavioral deficits and alters gene expression in rodent stroke mode. AB - : 'Intra-arterial transplantation of human bone marrow mesenchymal stem cells (hBMMSCs) improves behavioral deficits and alters gene expression in rodent stroke mode' by Vibhuti, Khan, R., Sharma, A., Jain, S., Mohanty, S. and Prasad, K. The above article, published in the Journal of Neurochemistry on 13 December 2017 on Wiley Online Library (www.onlinelibrary.com), and in Volume 143, Issue 6, pp. 722-735, is being retracted by agreement between the Journal's Editor-in Chief, Jorg Schulz, and John Wiley & Sons Ltd. The Editorial Office was alerted and investigated that the same Western Blot lane has been used to represent two different proteins. The western blot signal of ANP in Fig. 5a in the referenced paper is identical to the western blot signal of BDNF in Fig. 5c, as marked up in the figure below (red square). It appears that the contrast was increased for the BDNF lane and the lane was stretched a bit. In addition, the arrows mark a clear line in the background which is visible in both the ANP and BDNF lanes. Our subjecting the BDNF lane to contrast enhancement for verification purposes revealed that both lanes are identical (see blue square in the figure below). The authors were contacted and asked to provide a statement; however, the Editorial Office did not receive any feedback within an appropriate time frame. REFERENCE: Vibhuti, Khan R., Sharma A., Jain S., Mohanty S. and Prasad K. (2017) Intra arterial transplantation of human bone marrow mesenchymal stem cells (hBMMSCs) improves behavioral deficits and alters gene expression in rodent stroke model. J. Neurochem. 143, 722-735. https://doi.org/10.1111/jnc.14241. PMID- 29968294 TI - Nickel-Catalyzed Asymmetric [2+2] Cycloaddition Reaction of Hetero-Bicyclic Alkenes with Internal Alkynes. AB - Enantioselective [2+2] cycloaddition reaction of azabenzonorbornadienes and oxabenzonorbornadienes with internal alkynes has been enabled by a catalyst system comprising Ni(COD)2 and (R)-SIPHOS-Ph-Mor. This transformation represents the first asymmetric [2+2] cycloaddition reaction of azabenzonorbornadienes with internal alkynes, providing a straightforward method to prepare four-membered carbocycles. PMID- 29968295 TI - EndoAbS dataset: Endoscopic abdominal stereo image dataset for benchmarking 3D stereo reconstruction algorithms. AB - BACKGROUND: 3D reconstruction algorithms are of fundamental importance for augmented reality applications in computer-assisted surgery. However, few datasets of endoscopic stereo images with associated 3D surface references are currently openly available, preventing the proper validation of such algorithms. This work presents a new and rich dataset of endoscopic stereo images (EndoAbS dataset). METHODS: The dataset includes (i) endoscopic stereo images of phantom abdominal organs, (ii) a 3D organ surface reference (RF) generated with a laser scanner and (iii) camera calibration parameters. A detailed description of the generation of the phantom and the camera-laser calibration method is also provided. RESULTS: An estimation of the overall error in creation of the dataset is reported (camera-laser calibration error 0.43 mm) and the performance of a 3D reconstruction algorithm is evaluated using EndoAbS, resulting in an accuracy error in accordance with state-of-the-art results (<2 mm). CONCLUSIONS: The EndoAbS dataset contributes to an increase the number and variety of openly available datasets of surgical stereo images, including a highly accurate RF and different surgical conditions. PMID- 29968296 TI - Neonatal exposure to T3 disrupts male reproductive functions by altering redox homeostasis in immature testis of rats. AB - T3 is the active hormone, produced by peripheral deiodination of thyroxine. Exposure to excess thyroid hormones leads to hypermetabolic state and thus generates oxidative stress which seems to be involved in hyperthyroidism-induced testicular pathophysiology. We investigated the effects of T3 administration on the testis during development throughout sexual maturation in rats. Male pups were divided into two groups. T3 group was administered 80 ug/kg body weight intraperitoneal T3 injections daily for 21 days from the 1st postnatal day, while the control group was administered saline intraperitoneal injections. The pups were sacrificed at pnd 10, 20 and 30. T3 treatment resulted in a significant decrease in body weight at all ages tested and an increase in testis weight during the treatment period. The treatment produced imbalance in their testicular redox status, reflected by a significant increase in the amount of thiobarbituric acid-reactive substances and protein carbonyl content in the testicular homogenates of 20-day-old rats. We observed a significant increase in antioxidant system activities gamma-glutamyl transferase, glucose-6-phosphate dehydrogenase, catalase and superoxide dismutase, reduced glutathione content and lactate dehydrogenase activity. Histological examination showed altered seminiferous tubules, degenerated germ cells and decreased height of the germinal epithelium. Chronic neonatal exposure to T3 resulted in redox state alterations which contribute to testicular impairment. PMID- 29968297 TI - Gastrointestinal: Olmesartan-induced enteropathy. PMID- 29968298 TI - Stability of retrospective self-reports of childhood trauma in first-episode psychosis. AB - AIM: Childhood trauma (CT), abuse and neglect are commonly reported by individuals experiencing psychosis. However, there are concerns that acute psychotic symptoms, in particular delusions, may contribute to inaccurate reporting of CT. As a result, individuals experiencing psychosis may not be asked about their experiences of abuse when they are being seen in psychiatric settings. This lack of attention can directly impact on the tailoring of their clinical care. This study aimed to investigate the stability of reports of CT by young people experiencing a first psychotic episode (FEP) compared to healthy comparison subjects. METHODS: Responses of 24 young people during the acute FEP and 3 months later to items on the Childhood Trauma Questionnaire (CTQ) were compared to 30 non-psychiatric controls. All participants were aged 15 to 25 years. RESULTS: FEP participants reported higher CT than controls at both time points. Reliability analyses (interclass correlation coefficients [ICCs]) suggested strong agreement between CT reports at baseline and follow-up for FEP participants (.81) and controls (.91). Positive psychotic symptoms were unrelated to CT reports. Although the severity of CT reports fluctuated between assessments, complete retractions of severe abuse claims occurred rarely. CONCLUSIONS: The results suggest that retrospective self-report can be used to reliably assess CT in young people experiencing acute psychosis. PMID- 29968299 TI - Aldehyde dehydrogenase 2 polymorphism affects the outcome of methanol poisoning in exposed humans. AB - As the susceptibility of humans to xenobiotics often depends on genetic factors, we assumed that ADH1B and ALDH2 genetic variants may affect susceptibility to the acute methanol exposure. To evaluate the role of genetic variants of enzymes involved in methanol catabolism in humans, we analysed ADH1B (rs1229984) and ALDH2 (rs441) polymorphisms in 50 adults who survived acute methanol poisoning, 246 individuals with alcoholic liver cirrhosis, and in 545 healthy controls. GG homozygotes of ADH1B were more common among methanol-poisoned patients (98%) and among patients with alcoholic liver cirrhosis (98%) than among healthy controls (90%) (P = 0.08 and < 0.001, respectively). Minor C allele carriers of the ALDH2 were significantly more common among methanol-poisoned persons (46%) than among patients with alcoholic liver cirrhosis or healthy controls (31% in both groups, P < 0.05 and 0.025, respectively); the odds ratios were 1.89 (95% CI 1.02-3.52) and 1.94 (1.08-3.48), respectively. As there was a substantial amount of subjects with alcohol abuse between both groups of patients, ADH1B is unlikely to affect the susceptibility to methanol poisoning. By contrast, the genetic variant of the ALDH2 enzyme seems to specifically affect the susceptibility to methanol in acutely exposed humans and potentially plays a role in the outcome of methanol poisoning. PMID- 29968300 TI - Multimodality Imaging Agents with PET as the Fundamental Pillar. AB - Positron emission tomography (PET) provides quantitative information in vivo with ultra-high sensitivity but is limited by its relatively low spatial resolution. Therefore, PET has been combined with other imaging modalities, and commercial systems such as PET/CT and PET/MR have become available. Inspired by the emerging field of nanomedicine, many PET-based multimodality nanoparticle imaging agents have been developed in recent years. This Minireview highlights recent progress in the design of PET-based dual-modality and tri-or-more modality imaging nanoprobes with an aim to overview the major advances and key challenges in this field and substantially improve our knowledge of this fertile research area. PMID- 29968302 TI - On the extraordinary winter flood episode over the North Atlantic Basin in 1936. AB - In this study, we analyze the linkage between atmosphere and ocean modes and winter flood variability over the 20th century based on long-term flow-discharge series, historical archives, and tree-ring records of past floods in the North Atlantic Basin (NAB). The most extreme winter floods occurred in 1936 and had strong impacts on either side of the Atlantic. We hypothesize that the joint effects of sea surface temperatures (SSTs) over the Atlantic and Pacific Oceans and the Arctic Oscillation (AO), which is closely related to the North Atlantic Oscillation, play a significant role when describing flood variability in North America and Europe since 1900. Statistical modeling supports the assumption that the response of flood anomalies over the NAB to AO phases is subsidiary of SST phases. Besides, we shed light on the extraordinarily winter flood of 1936 that was characterized by very high SSTs over both the Atlantic and Pacific (>98th percentile) and very low, negative values of AO (<1st percentile). This outstanding winter flood episode was most likely characterized by stratospheric polar vortex anomalies, which can usually be linked to an increased probability of storms in western and southwestern Europe and increased snowfall events in eastern North America. By assessing the flood anomalies over the NAB as a coupled AO and SST function, one could further the understanding of such large-scale events and presumably improve anticipation of future extreme flood occurrences. PMID- 29968303 TI - Recent Progress in (Dynamic) Kinetic Resolution Catalyzed by N-Heterocyclic Carbenes. AB - Catalytic kinetic resolution is often the "method of choice" for the preparation of optically enriched functionalized compounds and, over the past decade, kinetic resolutions and dynamic kinetic resolutions catalyzed by N-heterocyclic carbenes (NHCs) have been employed for the synthesis of a variety of optically enriched functionalized molecules. Herein we provide an overview of reported NHC-catalyzed kinetic resolutions in terms of the structure of the substrate, the reaction type, and the activation mode. This Focus Review is arranged according to the structure of the racemic compounds and includes the kinetic resolution of alcohols, amines, imines, and aldehydes, as well as dynamic kinetic resolution. In each section, the activation mode and reaction mechanism are discussed. We conclude with a summary of the current state-of-play in NHC-catalyzed kinetic resolution and provide an outlook for the development of this field in the future. PMID- 29968301 TI - Beta2 -adrenoceptor agonist salbutamol increases protein turnover rates and alters signalling in skeletal muscle after resistance exercise in young men. AB - KEY POINTS: Animal models have shown that beta2 -adrenoceptor stimulation increases protein synthesis and attenuates breakdown processes in skeletal muscle. Thus, the beta2 -adrenoceptor is a potential target in the treatment of disuse-, disease- and age-related muscle atrophy. In the present study, we show that a few days of oral treatment with the commonly prescribed beta2 adrenoceptor agonist, salbutamol, increased skeletal muscle protein synthesis and breakdown during the first 5 h after resistance exercise in young men. Salbutamol also counteracted a negative net protein balance in skeletal muscle after resistance exercise. Changes in protein turnover rates induced by salbutamol were associated with protein kinase A-signalling, activation of Akt2 and modulation of mRNA levels of growth-regulating proteins in skeletal muscle. These findings indicate that protein turnover rates can be augmented by beta2 -adrenoceptor agonist treatment during recovery from resistance exercise in humans. ABSTRACT: The effect of beta2 -adrenoceptor stimulation on skeletal muscle protein turnover and intracellular signalling is insufficiently explored in humans, particularly in association with exercise. In a randomized, placebo-controlled, cross-over study investigating 12 trained men, the effects of beta2 -agonist (6 * 4 mg oral salbutamol) on protein turnover rates, intracellular signalling and mRNA response in skeletal muscle were investigated 0.5-5 h after quadriceps resistance exercise. Each trial was preceded by a 4-day lead-in treatment period. Leg protein turnover rates were assessed by infusion of [13 C6 ]-phenylalanine and sampling of arterial and venous blood, as well as vastus lateralis muscle biopsies 0.5 and 5 h after exercise. Furthermore, myofibrillar fractional synthesis rate, intracellular signalling and mRNA response were measured in muscle biopsies. The mean (95% confidence interval) myofibrillar fractional synthesis rate was higher for salbutamol than placebo [0.079 (95% CI, 0.064 to 0.093) vs. 0.066 (95% CI, 0.056 to 0.075%) * h-1 ] (P < 0.05). Mean net leg phenylalanine balance 0.5-5 h after exercise was higher for salbutamol than placebo [3.6 (95% CI, 1.0 to 6.2 nmol) * min-1 * 100 gLeg Lean Mass-1 ] (P < 0.01). Phosphorylation of Akt2, cAMP response element binding protein and PKA substrate 0.5 and 5 h after exercise, as well as phosphorylation of eEF2 5 h after exercise, was higher (P < 0.05) for salbutamol than placebo. Calpain-1, Forkhead box protein O1, myostatin and Smad3 mRNA content was higher (P < 0.01) for salbutamol than placebo 0.5 h after exercise, as well as Forkhead box protein O1 and myostatin mRNA content 5 h after exercise, whereas ActivinRIIB mRNA content was lower (P < 0.01) for salbutamol 5 h after exercise. These observations suggest that beta2 -agonist increases protein turnover rates in skeletal muscle after resistance exercise in humans, with concomitant cAMP/PKA and Akt2 signalling, as well as modulation of mRNA response of growth-regulating proteins. PMID- 29968304 TI - Sexual dysfunctions and related variables with sexual function in patients who undergo dialysis for chronic renal failure. AB - AIMS AND OBJECTIVES: To evaluate personality characteristics and psychological symptoms believed to have an effect on the sexual functions and performances of patients undergoing dialysis treatment. BACKGROUND: Chronic renal failure is a life-threatening condition which can often have a poor prognosis. The loss of vital kidney function and other complications can affect almost all age groups. DESIGN: A quantitative descriptive study. METHODS: The study sample included 225 patients selected randomly from patients who have undergone dialysis treatment for at least 3 months at a dialysis centre in a university hospital. In this study, the Golombok Rust Inventory of Sexual Satisfaction (GRISS), the Eysenck Personality Inventory (EPI) and the Brief Symptom Inventory (BSI) were used. RESULTS: In the correlation test, made to investigate the relation between the patients' sexual satisfaction and their personalities, a significant positive relation was found between the communication subscale of the GRISS and the Lie dimension of the EPI, and a significant negative relation was found between the Communication subscale of the GRISS and the Lie dimension of the EPI, and between the Vaginismus and Orgasm subscales of the GRISS and the Extroversion dimension of the EPI. CONCLUSION: Results showed that sexual problems, in the areas of nonsensuality, anorgasmia, avoidance and communication, are associated with extroversion and psychological symptoms. RELEVANCE TO CLINICAL PRACTICE: Sexual health and the psychological well-being of patients with renal failure is an important issue that should be considered in nursing practice. Nurses should take the psychological problems of patients and their relations with partners into account and consider these problems in a holistic manner within the framework of nursing practice. They would then be able to play an effective role in intervening at an early stage and would be better equipped to help and control the psychological and sexual problems that some patients may experience. PMID- 29968305 TI - Synthetic Multifunctional Graphene Composites with Reshaping and Self-Healing Features via a Facile Biomineralization-Inspired Process. AB - Since graphene is a type of 2D carbon material with excellent mechanical, electrical, thermal, and optical properties, the efficient preparation of graphene macroscopic assemblies is significant in the potentially large-scale application of graphene sheets. Conventional preparation methods of graphene macroscopic assemblies need strict conditions, and, once formed, the assemblies cannot be edited, reshaped, or recycled. Herein, inspired by the biomineralization process, a feasible approach of shapeable, multimanipulatable, and recyclable gel-like composite consisting of graphene oxide/poly(acrylic acid)/amorphous calcium carbonate (GO-PAA-ACC) is designed. This GO-PAA-ACC material can be facilely synthesized at room temperature with a cross-linking network structure formed during the preparation process. Remarkably, it is stretchable, malleable, self-healable, and easy to process in the wet state, but tough and rigid in the dried state. In addition, these two states can be readily switched by adjusting the water content, which shows recyclability and can be used for 3D printing to form varied architectures. Furthermore, GO-PAA-ACC can be functionalized or processed to meet a variety of specific application requirements (e.g., energy-storage, actuators). The preparation method of GO-PAA ACC composite in this work also provides a novel strategy for the versatile macroscopic assembly of other materials, which is low-cost, efficient, and convenient for broad application. PMID- 29968306 TI - An acute acral papulovesicular eruption. PMID- 29968307 TI - Attitudes of health care professionals toward people with intellectual disability: a comparison with the general population. AB - BACKGROUND: Few studies have examined attitudes that may promote the social inclusion of persons with an intellectual disability (ID) among health care providers (HCPs). Yet these attitudes could impact the accessibility and quality of services provided to this population, as well as the general attitudes of HCPs. The objectives of this study were to (1) examine HCPs' pro-inclusion attitudes toward people with ID, (2) compare these to the general population's attitudes and (3) examine how HCPs' attitudes vary as a function of their socio demographic characteristics. METHOD: The Attitudes Toward Intellectual Disability Questionnaire was administered to 367 HCPs and a representative sample of the Quebec population (N = 1605). RESULTS: Results indicated that at least half of HCPs displayed positive attitudes, that is, attitudes that are compatible with notions of social inclusion and equal rights, toward individuals with ID. Positive attitudes were less frequently observed for the Interaction and the Sensitivity or tenderness factors measured by the Attitudes Toward Intellectual Disability Questionnaire. In comparison with the general population, HCPs exhibited more positive attitudes on the Knowledge of causes and Sensitivity or tenderness factors and less positive attitudes on the Interaction factor. HCPs who regarded themselves as more knowledgeable about ID and those who reported higher quality contacts or interactions with persons with ID expressed attitudes that were more favourable toward social inclusion. CONCLUSIONS: In addition to providing general knowledge about ID and the specific health care needs of individuals with ID, training programmes should also promote interactions with this population. Further studies are needed to document HCPs' pro-inclusion attitudes toward people with ID and to assess the impact of interventions on these attitudes. PMID- 29968309 TI - Frequency and outcome of post-extubation dysphagia using nurse-performed swallowing screening protocol. AB - BACKGROUND: Post-extubation dysphagia reportedly occurs in 3%-60% of patients and is independently associated with poor patient outcomes. AIM: The aim of this study was to investigate the frequency of post-extubation dysphagia, as diagnosed using our novel nurse-performed swallowing screening protocol, and to evaluate patient outcomes, including the frequency of discharge home, the length of the intensive care unit and hospital stays, the frequency of hospital-acquired pneumonia and death in the intensive care unit and hospital. DESIGN: This was a prospective cohort study. METHODS: This study was conducted in a mixed intensive care unit in a critical care hospital in Japan. Between October 2016 and September 2017, the swallowing functions of 216 patients were assessed using our novel screening protocol. To investigate the correlation between dysphagia and patient outcomes, we compared a dysphagia group with a no dysphagia group. RESULTS: Twenty-five patients (11.6%) were diagnosed with dysphagia. The frequency of discharge home, which was the primary outcome, was significantly lower in the patients with dysphagia (60% versus 87.4%, P = 0.002). Dysphagia was also correlated with longer hospital stay and higher mortality. A binomial logistic regression analysis, including the variables of dysphagia, Acute Physiology and Chronic Health Evaluation II score and duration of ventilator use, showed that dysphagia was an independent risk factor for a lower incidence of discharge home. CONCLUSION: Among patients admitted to a mixed intensive care unit, post-extubation dysphagia was correlated with a poor prognosis. RELEVANCE TO CLINICAL PRACTICE: The current study emphasizes the poor prognosis of patients with dysphagia after extubation. Dysphagia developed in more than 1 in 10 patients post-extubation; therefore, monitoring for a swallowing disorder is crucial in daily nursing in the intensive care unit. PMID- 29968308 TI - Chronic exercise impairs nitric oxide pathway in rabbit carotid and femoral arteries. AB - KEY POINTS: Some of the beneficial effects of exercise in preventing vascular related diseases are mediated by the enhancement of endothelial function where the role of nitric oxide (NO) is well documented, although the relevance of calcium activated potassium channels is not fully understood. The impact of oxidative stress induced by training on endothelial function remains to be clarified. By evaluating different endothelial vasodilator pathways on two vascular beds in a rabbit model of chronic exercise, we found a decreased NO bioavailability and endothelial nitric oxide synthase expression in both carotid and femoral arteries. Physical training induced carotid endothelial dysfunction as a result of an increase in oxidative stress and a reduction in superoxide dismutase expression. In the femoral artery, the lower production of NO was counteracted by an increased participation of large conductance calcium activated potassium channels, preventing endothelial dysfunction. ABSTRACT: The present study aimed to evaluate the effects of chronic exercise on vasodilator response in two different arteries. Rings of carotid and femoral arteries from control and trained rabbits were suspended in organ baths for isometric recording of tension. Endothelial nitric oxide synthase (eNOS), Cu/Zn and Mn-superoxide dismutase (SOD), and large conductance calcium activated potassium (BKCa) channel protein expression were measured by western blotting. In the carotid artery, training reduced the relaxation to ACh (10-9 to 3 * 10-6 m) that was reversed by N acetylcysteine (10-3 m). l-NAME (10-4 m) reduced the relaxation to ACh in both groups, although the effect was lower in the trained group (in mean +/- SEM, 39 +/- 2% vs. 28 +/- 3%). Physical training did not modify the relaxation to ACh in femoral arteries, although the response to l-NAME was lower in the trained group (in mean +/- SEM, 41 +/- 5% vs. 17 +/- 2%). Charybdotoxin (10-7 m) plus apamin (10-6 m) further reduced the maximal relaxation to ACh only in the trained group. The remaining relaxation in both carotid and femoral arteries was abolished by KCl (2 * 10-2 m) and BaCl2 (3 * 10-6 m) plus ouabain (10-4 m) in both groups. Physical training decreased eNOS expression in both carotid and femoral arteries and Cu/Zn and Mn-SOD expression only in the carotid artery. BKCa channels were overexpressed in the trained group in the femoral artery. In conclusion, chronic exercise induces endothelial dysfunction in the carotid artery as a result of oxidative stress. In the femoral artery, it modifies the vasodilator pathways, enhancing the participation of BKCa channels, thus compensating for the impairment of NO-mediated vasodilatation. PMID- 29968310 TI - Increases in temperature and nutrient availability positively affect methane cycling microorganisms in Arctic thermokarst lake sediments. AB - Arctic permafrost soils store large amounts of organic matter that is sensitive to temperature increases and subsequent microbial degradation to methane (CH 4 ) and carbon dioxide (CO 2 ). Here, we studied methanogenic and methanotrophic activity and community composition in thermokarst lake sediments from Utqiagvik (formerly Barrow), Alaska. This experiment was carried out under in situ temperature conditions (4 degrees C) and the IPCC 2013 Arctic climate change scenario (10 degrees C) after addition of methanogenic and methanotrophic substrates for nearly a year. Trimethylamine (TMA) amendment with warming showed highest maximum CH 4 production rates, being 30% higher at 10 degrees C than at 4 degrees C. Maximum methanotrophic rates increased by up to 57% at 10 degrees C compared to 4 degrees C. 16S rRNA gene sequencing indicated high relative abundance of Methanosarcinaceae in TMA amended incubations, and for methanotrophic incubations Methylococcaeae were highly enriched. Anaerobic methanotrophic activity with nitrite or nitrate as electron acceptor was not detected. This study indicates that the methane cycling microbial community can adapt to temperature increases and that their activity is highly dependent on substrate availability. PMID- 29968311 TI - Proposal of a new scoring formula for the Dermatology Life Quality Index in psoriasis. AB - BACKGROUND: 'Not relevant' responses (NRRs) on the Dermatology Life Quality Index (DLQI) may occur in up to 40% of patients with psoriasis. As these responses are scored as the item of the questionnaire having no impact on the patients' lives at all, it is more difficult for these patients to fulfil the DLQI > 10 criterion required by clinical guidelines to become candidates for systemic treatment including biologics. OBJECTIVES: We propose a new scoring system for the DLQI that corrects for the bias in the NRR option and test its construct validity in a sample of patients with psoriasis. METHODS: Data from 242 patients (104 of whom marked at least one NRR) from two earlier cross-sectional surveys were reanalysed. For each patient, the DLQI score was calculated in two ways: (i) according to the original scoring and (ii) by applying a new scoring formula (DLQI-R) that adjusts the total score for the number of NRRs. The construct validity of the DLQI-R was tested against the Psoriasis Area and Severity Index (PASI) and EQ-5D-3L. RESULTS: The mean DLQI and DLQI-R scores were 9.99 +/- 7.52 and 11.0 +/- 8.02, respectively. The DLQI-R allowed eight more patients (3.3%) to achieve the 'PASI > 10 and DLQI > 10' threshold. The results were robust when limiting the maximum number of NRRs allowed to two or three. Compared with the DLQI, DLQI-R correlated slightly better with PASI (rs = 0.59 vs. 0.57) and EQ-5D 3L index scores (rs = -0.58 vs. -0.54). CONCLUSIONS: The DLQI-R seems to be a valid scoring system for avoiding the bias in the NRR option and can help to improve patients' access to biologics. PMID- 29968313 TI - Abstracts of the AAGBI GAT Annual Scientific Meeting, Glasgow, UK, 04-06 July 2018. PMID- 29968315 TI - "Operating in the dark": Nurses' attempts to help patients and families manage the transition from oncology to comfort care. AB - AIMS AND OBJECTIVES: To investigate challenges nurses face when providing care for oncology patients transitioning from curative to palliative care and to identify educational and support opportunities for nurses. BACKGROUND: Communicating with oncology patients/families transitioning from curative treatments to care focused on comfort can be problematic for a variety of reasons. Research suggests discrepancies exist between physicians' and patients' perceptions of probable length of life. These disconnects can deepen suffering. Oncology and palliative care nurses are well positioned to facilitate this transition. However, they receive little formal instruction regarding these complex scenarios beyond what occurs through on-the-job training. METHODS: Twenty eight nurses working in oncology (n = 14) and palliative care (n = 14) settings participated. The constant comparative method was used to analyse the data. RESULTS: Four themes emerged that characterise oncology and palliative care nurses' experiences: (a) coping with interprofessional communication errors during the transition, (b) responding to patient/family reactions to miscommunication about the goals of care, (c) navigating emotional connection to patients, and (d) adapting to sociocultural factors that influence information exchange. CONCLUSIONS: This study supports previous research regarding challenges related to patient reactions, family relationships and emotional burden during end-of-life care. However, it adds to the literature by a providing a more in depth explication of interprofessional and patient-physician communication barriers that negatively impact care. RELEVANCE TO CLINICAL PRACTICE: Misunderstandings between patients, physicians and nurses have the potential to distress complicate nurses' efforts to support patients and families. Nurses reported a problematic power dynamic that impedes their ability to facilitate communication between patient and physician or to offer insights that could enhance patient care. Medical education and continuing education initiatives are needed to build understanding across professional roles and specialties and to improve comfort discussing worsening prognosis and end-of-life issues. PMID- 29968312 TI - Towards a predictive model of species interaction beta diversity. AB - Species interactions are fundamental to community dynamics and ecosystem processes. Despite significant progress in describing species interactions, we lack the ability to predict changes in interactions across space and time. We outline a Bayesian approach to separate the probability of species co-occurrence, interaction and detectability in influencing interaction betadiversity. We use a multi-year hummingbird-plant time series, divided into training and testing data, to show that including models of detectability and occurrence improves forecasts of mutualistic interactions. We then extend our model to explore interaction betadiversity across two distinct seasons. Despite differences in the observed interactions among seasons, there was no significant change in hummingbird occurrence or interaction frequency between hummingbirds and plants. These results highlight the challenge of inferring the causes of interaction betadiversity when interaction detectability is low. Finally, we highlight potential applications of our model for integrating observations of local interactions with biogeographic and evolutionary histories of co-occurring species. These advances will provide new insight into the mechanisms that drive variation in patterns of biodiversity. PMID- 29968316 TI - Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials. AB - Mitochondrial dysfunction is considered as a crucial contributory factor in cardiac pathology. This has highlighted the therapeutic potential of targeting mitochondria to prevent or treat cardiac disease. Mitochondrial dysfunction is associated with aberrant electron transport chain activity, reduced ATP production, an abnormal shift in metabolic substrates, ROS overproduction and impaired mitochondrial dynamics. This review will cover the mitochondrial functions and how they are altered in various disease conditions. Furthermore, the mechanisms that lead to mitochondrial defects and the protective mechanisms that prevent mitochondrial damage will be discussed. Finally, potential mitochondrial targets for novel therapeutic intervention will be explored. We will highlight the development of small molecules that target mitochondria from different perspectives and their current progress in clinical trials. PMID- 29968317 TI - Pediatric CD8+/CD56+ mycosis fungoides with cytotoxic marker expression: A variant with indolent course. AB - Mycosis fungoides is predominantly a disease of older patients, but occasionally occurs in children. We report a rare case of CD8+/CD56+ mycosis fungoides with cytotoxic marker (perforin, TIA-1, and granzyme B) expression in a 10-year-old boy. Disease presented with three asymptomatic, slowly progressive erythematous and scaling plaques, surrounded by hypochromic alone in the left tight and lower trunk. UVB narrow band associated with topical corticosteroids resulted in complete remission in about 2 months, and no recurrence at 2-year follow-up. Three similar cases have been retrieved in children through PubMed search, showing similar clinical presentation with erythematous scaling lesions, good response to skin-directed treatments and a favorable prognosis. PMID- 29968318 TI - EPA plays multiple roles in regulating lipid accumulation of grass carp Ctenopharyngodon idella adipose tissue in vitro and in vivo. AB - This study was conducted to assess the effect of eicosapentaenoic acid (20:5n-3, EPA) on lipid accumulation in grass carp Ctenopharyngodon idella adipose tissue both in vitro and in vivo. EPA was observed to inhibit the adipocyte viability in a time and dose-dependent manner. EPA was also found to induce reactive oxygen species accumulation in vitro. The mRNA levels of caspase 3a and caspase 3b, as well as the activity of Caspase 3 increased significantly in vitro and in vivo, whereas the value of B cell leukemia 2-Bcl-2 associated X protein decreased significantly. Besides, the pro-apoptotic effect was relieved by alpha tocopherol. Dietary 0.52% EPA had no apparent effect on intraperitoneal fat index. Moreover, EPA promoted the hydrolytic gene expressions in vitro and in vivo, including adipose triglyceride lipase and hormone sensitive lipase-a. Meanwhile, the lipogenic gene expressions of liver X receptor alpha, sterol regulatory element binding protein-1c and fatty-acid synthase were down-regulated by EPA in vitro and in vivo. However, EPA also acted to promote the marker gene expressions of adipogenesis, including peroxisome proliferator-activated receptor gamma and lipoprotein lipase in vitro and in vivo. Contents of EPA increased significantly in the treatment groups in vitro and in vivo. These results support that EPA affects multiple aspects of lipid metabolism, including hydrolysis, lipogenesis, adipogenesis and apoptosis. However, it barely functioned in decreasing the lipid accumulation of Ctenopharyngodon idella under the current culture conditions. PMID- 29968319 TI - Effect of different penetrating and non-penetrating cryoprotectants and media temperature on the cryosurvival of vitrified in vitro produced porcine blastocysts. AB - The aim of this study was to determine the most efficient vitrification protocol for the cryopreservation of day 7 in vitro produced (IVP) porcine blastocysts. The post-warm survival rate of blastocysts vitrified in control (17% dimethyl sulfoxide + 17% ethylene glycol [EG] + 0.4 mol/L sucrose) and commercial media did not differ, nor did the post-warm survival rate of blastocysts vitrified in medium containing 1,2-propandiol in place of EG. However, vitrifying embryos in EG alone decreased the cryosurvival rate (55.6% and 33.6%, respectively, p < .05). Furthermore, the post-warm survival rates of blastocysts vitrified with either trehalose or sucrose as the non-penetrating cryoprotectant did not differ. There was also no significant difference in post-warm survival of blastocysts vitrified in control (38 degrees C) media and room temperature (22 degrees C) media with extended equilibration times, although when blastocysts were vitrified using control media at room temperature, the post-warm survival rate increased (56.8%, 57.3%, 72.5%, respectively, p < .05). The findings show that most cryoprotectant combinations examined proved equally effective at supporting the post-warm survival of IVP porcine blastocysts. The improved post-warm survival rate of blastocysts vitrified using media held at room temperature suggests that the cryoprotectant toxicity exerted in 22 degrees C media was reduced. PMID- 29968320 TI - High-mobility group box 1 protein modulated proliferation and radioresistance in esophageal squamous cell carcinoma. AB - BACKGROUND AND AIM: The high-mobility group box 1 (HMGB1) protein plays an important role in a lot of biological behaviors, including DNA damage repair, gene transcription, cell replication, and cell death, and its expression is higher in many solid tumors tissues than in their adjacent normal tissues, and it is always involved in tumor proliferation, metastasis, therapeutic tolerance, and poor prognosis. However, HMGB1 in proliferation and radioresistance of esophageal squamous cell carcinoma (ESCC) remains poorly understood. In this study, the effect of HMGB1 on proliferation, cell death, DNA damage repair and radioresistance, and its underlying mechanism was investigated in human ESCC. METHODS: The immunohistochemistry scores of tumor and adjacent normal tissues in ESCC tissue microarray were analyzed. Stable HMGB1 knockdown cell lines were constructed using Kyse150 and Kyse450 cells. Cell viability, radioresistance, apoptosis, autophagy, and DNA damage were determined using CCK-8, 5-ethynyl-2' deoxyuridine, clonogenic survival assay, immunofluorescence, flow cytometry, and western blot assays. RESULTS: Differential analyses showed that the expression of HMGB1 in esophageal cancer tissue was significantly higher than that in adjacent normal tissues. The downregulation of HMGB1 could effectively inhibit proliferation, increase radiosensitivity, impair DNA damage repair abilities, reduce autophagy, and increase apoptosis rates in ESCC cells after irradiation. CONCLUSIONS: HMGB1 is expected to be a potential target for ESCC therapy and radiosensitization. PMID- 29968321 TI - Reflections on, and visions for, the changing field of pollination ecology. AB - Since the launch of Ecology Letters in 1998, the field of Pollination Ecology has changed considerably in its focus. In this review, we discuss the major discoveries across the past two decades. We quantitatively synthesise the frequency by which different concepts and topics appeared in the peer-reviewed literature, as well as the connections between these topics. We then look forward to identify pressing research frontiers and opportunities for additional integration in the future. We find that there has been a shift towards viewing plant-pollinator interactions as networks and towards understanding how global drivers influence the plants, pollinators and the ecosystem service of pollination. Future frontiers include moving towards a macroecological view of plant-pollinator interactions, understanding how ecological intensification and urbanisation will influence pollination, considering other interactions, such as plant-microbe-pollinator networks, and understanding the causes and consequences of extinctions. Pollination Ecology is poised to advance our basic understanding of the ecological and evolutionary factors that shape plant-animal interactions and to create applied knowledge that informs conservation decision making. PMID- 29968322 TI - IL-1RA VNTR and IL-1alpha 4845G>T polymorphisms and risk of idiopathic male infertility in Iranian men: A case-control study and an in silico analysis. AB - This study aimed to investigate the association of IL-1RA VNTR and IL-1alpha 4845G>T polymorphisms with idiopathic male infertility followed by an in silico analysis. In a case-control study, we collected blood samples from 230 infertile and 230 healthy men. Genotyping of IL-1RA VNTR was performed by PCR whereas IL 1alpha 4845G>T was genotyped by polymerase chain reaction-restriction fragment length polymorphism. An in silico approach was employed for the detection of IL 1RA VNTR and IL-1alpha 4845G>T effects on some molecular aspects of IL-1RA and IL 1alpha respectively. The result of our genetic association study for IL-1alpha 4845G>T revealed that there was a significant association between GT genotype, TT genotype, T allele and idiopathic male infertility. Although there was no significant association between IL-1RA VNTR and male infertility in the overall analysis. However, subgroup analysis revealed that the subjects with VNTR 4R/5R genotype were at a higher risk of oligozoospermia. Furthermore, 4845TT genotype, and 4845T allele were associated with oligozoospermia, asthenozoospermia and nonobstructive azoospermia. Bioinformatics analysis showed that IL-1RA VNTR may affect the splicing pattern of IL-1RA. Moreover, IL-1alpha 4845G>T has a significant effect on RNA structure and protein function. Based on our findings, both IL-1RA VNTR and IL-1alpha 4845G>T polymorphisms could be considered as potential biomarkers for screening of susceptible individuals. PMID- 29968323 TI - Nuclear Lamin is required for Winged Eye-mediated transdetermination of Drosophila imaginal disc. AB - Drosophila imaginal discs often change their cell fate under stress conditions, and this phenomenon, called transdetermination (TD), has long been a useful model for studying cell fate plasticity during regeneration. We previously identified a chromatin-associated protein, Winged Eye (Wge), which induces eye-to-wing TD upon its over-expression in eye imaginal discs. However, the molecular mechanism of Wge-mediated TD remains obscure. Here, we analyzed Wge-interacting proteins and found that several heterochromatin-related proteins, including a nuclear lamina protein, Lamin (Lam), were associated with Wge protein in cultured cells. Knockdown experiments revealed that Lam is indeed required for Wge-mediated eye to-wing TD. Moreover, Wge over-expression altered the spatial organization of genomic DNA inside the cell nuclei. Accordingly, we suggest that Wge interacts with Lam to link some genomic regions with the nuclear periphery and regulates chromatin dynamics in imaginal disc TD. PMID- 29968324 TI - Hypoxic pulmonary vasoconstriction: Building a solid base. PMID- 29968325 TI - Paresthesia frequency in fibromyalgia and its effects on personality traits. AB - AIM: Paresthesia and personality disorders are common conditions among patients with fibromyalgia. However, no previous study has examined a possible relation of paresthesia with personality traits in fibromyalgia. This study investigates the frequency of paresthesia in fibromyalgia patients and its relation with personality traits. METHOD: Female patients with fibromyalgia (n = 101) were divided into two groups according to the presence (n = 49; mean age 40.63 +/- 7.62 years; range 23-55 years) or absence (n = 52; mean age 40.50 +/- 7.12 years; range 27-53 years) of paresthesia. Also, a healthy control group (n = 53; mean age 39.34 +/- 5.26 years; range 23-55 years) was included. The groups were evaluated by the Temperament and Character Inventory. Accordingly, temperament includes four dimensions: harm avoidance, novelty seeking, persistence, reward dependence; and character consists of three dimensions: cooperativeness, self transcendence, self-directedness. RESULTS: There were no significant differences among the three groups in the scores of novelty seeking, persistence, reward dependence and cooperativeness (for all P > 0.05). Both fibromyalgia groups had significantly higher scores in harm avoidance and had lower scores in self directedness compared to the control group (P < 0.001). Also, fibromyalgia patients with paresthesia had significantly higher harm avoidance and self directedness scores than those in patients without paresthesia (P < 0.001). In both fibromyalgia groups, self-transcendence scores were similar (P = 0.465) but significantly higher than in the control group (P < 0.001). CONCLUSION: This is the first study evaluating the association of paresthesia and personality traits in fibromyalgia. These results suggest that psychological distress associated with high harm avoidance and low self-directedness scores are more prominent in fibromyalgia patients, and especially of those who have paresthesia. PMID- 29968326 TI - Multifocal osteolysis with chylous polyserositis and intrathoracic vein thrombosis: a diagnostic challenge for rheumatologists. AB - Vanishing bone disease with multisystemic involvement may mimic systemic autoimmune or autoinflammatory diseases. We present a 19-year-old man who was hospitalized due to chest pain following a progressive osteolysis of the bony thorax. The disease later expanded into the pleura, peritoneum and pericardium in a form of massive chylous polyserositis. The patient also developed thrombosis of multiple central veins, which in turn worsened the chylothorax by increasing the pressure in the thoracic duct. This is the first case of vanishing bone disease complicated by triple chylous effusions and central vein thrombosis. PMID- 29968327 TI - Incidence of knee chondrocalcinosis and its risk factors in a community-based cohort. AB - AIM: Chondrocalcinosis results from deposition of calcium pyrophosphate dihydrate in articular cartilage. It is a relatively common radiographic finding of the joints, especially the knee. This study investigated the incidence and the risk factors for the development of knee chondrocalcinosis in the general population. METHOD: We used a prospective, ongoing cohort, composed of 5018 people, which was established in 2001 to investigate the epidemiologic characteristics of major chronic diseases in the Republic of Korea. The incidence of knee chondrocalcinosis was assessed per 1000 person-years, and the risk factors were explored by Cox proportional hazard regression analyses. RESULTS: A total of 4543 patients who did not have knee chondrocalcinosis at enrollment, year 2001-2002, were evaluated with a mean follow-up duration of 8.4 +/- 4.2 years. The crude incidence of knee chondrocalcinosis was 3.19 per 1000 person-years (women, 3.55; men, 2.70), and the whole cumulative incidence of knee chondrocalcinosis was 2.7%. Older age (> 55 years) and higher HbA1C were associated with increased risk of knee chondrocalcinosis. CONCLUSION: This is the first study to report the incidence of knee chondrocalcinosis in the general population of Korea. Older age and high HbA1C were independent risk factors for development of knee chondrocalcinosis. PMID- 29968328 TI - Significance of combined anti-CCP antibodies and rheumatoid factor in a New Zealand cohort of patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) can present as an overlap syndrome with rheumatoid arthritis (SSc-RA overlap). OBJECTIVE: To evaluate the frequency of rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) in our SSc cohort and their association with clinical features. METHODS: Data were gathered prospectively from the Waikato Hospital Systemic Sclerosis Clinics. Patients with SSc and SOS (systemic sclerosis overlap syndrome) underwent baseline auto-antibody profiling including RF and anti-CCP along with annual clinical review. RESULTS: Our cohort comprised of 132 patients (two had incomplete data); 115 (87.1%) were female. Out of 89 limited cutaneous SSc (lcSSc) patients, arthralgia, synovitis, contractures, tendon crepitus and erosions on imaging were found in three, 10, 31, five and nine patients, respectively. Within the 33 diffuse cutaneous SSc (dcSSc) patients, arthralgia, synovitis, contractures, tendon crepitus and erosion were found in 15, five, 27, five and one patient, respectively. In the 10 SOS patients, arthralgia, synovitis and contractures were found in six, three and two patients; none had tendon crepitus or erosions. RF positivity was found in 15.7%, 9% and 20% of patients with lcSSc, dcSSc and SOS, and anti-CCP positivity was found in 13.5%, 6.1% and 0% in lcSSc, dcSSc and SOS patients. A statistically significant relationship of double antibody positivity with arthralgia (P = 0.03) and erosions (P < 0.001) was found. Anti-CCP positivity association with erosions was significant at P = 0.007. CONCLUSION: Our study confirms that articular manifestations are common in SSc. Statistically significant associations of double antibody positivity with arthralgia and erosions were demonstrated. Significant association between anti CCP antibody and erosions was also confirmed. PMID- 29968329 TI - Interstitial lung disease in non-sicca onset primary Sjogren's syndrome: a large scale case-control study. AB - AIM: This study investigated the common initial clinical presentations of primary Sjogren's syndrome (pSS) with interstitial lung disease (ILD) and explored differences between sicca and non-sicca onset pSS-ILD patients. METHOD: A total of 1341 SS patients hospitalized between 2003 and 2012 were retrospectively reviewed. Of them, 102 were analyzed and recruited to examine the differences between non-sicca and sicca onset. RESULTS: Fifty-one percent of pSS-ILD patients presented with non-sicca onset. Although the mean diagnosis time was equal, only 4% of non-sicca onset patients were diagnosed with pSS at onset versus 34% with sicca onset (P = 0.000). Hyperglobulinemia, elevated rheumatoid factor (RF) titer, and anti-SSA and/or anti-SSB presence were less predominant in patients with non-sicca onset (immunoglobulin G, 16 [12-21] vs. 21 [15-28] g/L, P = 0.032; RF, 22 [20-171] vs. 104 [20-237] IU/mL, P = 0.048; anti-SSA and/or anti-SSB presence, 33% vs. 72%, P = 0.000). The usual interstitial pneumonia pattern was more commonly seen in non-sicca onset patients (20.0% vs. 14.3%). The high resolution computed tomography score was higher (12 [88-15] vs. 8 [5-13], P = 0.070) and predicted total lung capacity and forced vital capacity were lower (87 +/- 23% vs. 97 +/- 20%, P = 0.050; 88 +/- 28% vs. 100 +/- 27%, P = 0.089) in non sicca patients. CONCLUSION: Non-sicca is a common initial manifestation in pSS ILD. Anti-SSA presence, elevated RF titer and hyperglobulinemia were less predominant, and pulmonary complications were more progressive and severe in non sicca onset patients than sicca onset patients. PMID- 29968330 TI - Autoreactive T cells to citrullinated HSP90 are associated with interstitial lung disease in rheumatoid arthritis. AB - AIM: Previous analysis of comparative anti-citrullinated heat shock protein 90 (citHSP90) antibody profiles between bronchoalveolar lavage fluid and serum indicates that the lung plays a direct role in shaping the immune repertoire of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). METHODS: To address the contribution of citHSP90beta-specific T cells in this process, we evaluated in vitro cytokine responses to citHSP90beta in RA patients with different stages of ILD as well as in controls with non-RA connective tissue disease-associated ILD (CTD-ILD). Cultures derived from whole blood were individually stimulated with HSP90beta, citHSP90beta, citrullinated BSA, or no antigen. The concentrations of 13 cytokines and chemokines in the plasma supernatant were then measured using Luminex xMAP technology. RESULTS: CitHSP90beta induced significantly higher levels of interferon-gamma (IFN-gamma) levels in RA-ILD (interstitial lung abnormalities = 2 + 3) groups compared to the RA-no ILD group (P = 0.01), but did not stimulate the production of other cytokines (P > 0.05). Furthermore, citHSP90beta did not stimulate the production of IFN-gamma or other cytokines in those individuals with non-RA CTD-ILD. CONCLUSION: Overall, the production of IFN-gamma by T cells stimulated with citHSP90beta demonstrates a bias toward TH1 immune responses that are likely involved in the pathogenesis of RA-ILD. PMID- 29968331 TI - Global research trends in stem cells for osteoarthritis: a bibliometric and visualized study. AB - AIM: There have been increased interests in the use of stems cells in the research of osteoarthritis (OA). The present study aimed to investigate the global status and trends in this field. METHOD: Publications related to stem cells search in OA from 1994 to 2017 were retrieved from the Science Citation Index-Expanded Web of Science. The source data were studied and indexed using a bibliometric methodology. For visualized study, VOS viewer software was used to conduct bibliographic coupling, co-authorship, co-citation and co-occurrence analysis and to analyze the publication trends in stem cells for OA research. RESULT: A total of 1933 articles were included. The relative research interests and number of publications were globally increasing per year. The USA made the highest contributions to the global research with the most citations and the highest H-index. The journal Osteoarthritis and Cartilage had the highest publication number. The Tokyo Medical and Dental University, University of Pittsburgh and Shanghai Jiaotong University were the most contributive institutions. Studies could be divided into four clusters: mechanism study, animal study, clinical trials and tissue engineering. The clinical studies were predicted to be the next popular topic in this field. CONCLUSION: The number of publications about stem cells for OA would be increasing based on the current global trends. The USA was the largest contributor in this field. Most efforts could be put into clinical studies involving mesenchymal stem cells for OA, which may be the next hot spots in OA and stem cells research. PMID- 29968332 TI - MiR-146a levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis. AB - OBJECTIVE: To evaluate the relationship between miR-146a levels and rheumatoid arthritis (RA), and the correlation with RA activity. METHODS: For the meta analysis, we searched the PubMed, MEDLINE, EMBASE and Cochrane databases, comparing miR-146a levels in patients with RA and controls, and correlation coefficients between miR-146a levels and Disease Activity Score for 28 joints (DAS28) and erythrocyte sedimentation rate (ESR) in patients with RA. RESULTS: Fourteen studies, totaling 683 patients with RA and 477 controls, were available. miR-146a levels were significantly higher in the RA group than in the control group (standardized mean difference [SMD] = 0.546, 95% CI = 0.033-1.059, P = 0.037). Stratification by adjustment for age and/or sex revealed significantly higher miR-146a levels in the adjusted, but not in the non-adjusted group (SMD = 0.747, 95% CI = 0.094-1.400, P = 0.025; SMD = 0.431, 95% CI = -0.430-1.291, P = 0.326, respectively). Stratification by sample size showed significantly higher miR-146a levels in RA groups of large sample sizes (N >= 50), but not in those of small size. miR-146a levels in synovial tissue/fluid were significantly higher in the RA group than in the OA group (SMD = 1.305, 95% CI = 1010-1.639, P < 0.001). A significant positive correlation was found between miR-146a levels and ESR (correlation coefficient = 0.534, 95% CI = 0.029-0.822, P = 0.039). CONCLUSIONS: Circulating and synovial tissue/fluid miR-146a levels are high in patients with RA, and circulating miR-146a levels positively correlate with ESR. PMID- 29968333 TI - Evaluation of low bone mass and prediction of fracture risk using metacarpal radiogrammetry method: a comparative study with DXA and X-ray phantom. AB - OBJECTIVES: (i) To predict the future risk of osteoporotic fracture in women using a simple forearm radiograph. (ii) To assess osteoporosis in southern Indian women by using radiogrammetric technique in comparison with dual-energy X-ray absorptiometry (DXA) and X-ray phantom study. METHODS: The bone mineral density (BMD) of the right proximal femur by DXA and the X-ray measurements were acquired from the right forearm. The combined cortical thickness at the second to fourth metacarpal region (M-CCT), radius (R-CCT) and ulna (U-CCT) were derived in all the studied population. The aluminium phantom study was conducted by varying the X-ray source to film distance at 100 cm and 150 cm, respectively. The feed forward back propagation neural network was used for classification of low bone mass group and normal. RESULTS: The combined cortical thickness of M-CCT, R-CCT and U-CCT of the total studied population was strongly correlated with DXA femur Th.BMD measurements (r = 0.77, r = 0.61 and r = 0.59 [P < 0.01]). The predicted future osteoporotic fracture risk for the low bone mass group, post-menopausal women and old-aged women population was found to be 92%, 62.8%, and 64.7%, respectively. The accuracy of neural network classifier for training set, testing set was found to be 97.5% and 87.5% in the studied population. CONCLUSION: The results suggested that M-CCT and M-CCT (%) at the second metacarpal region are useful in predicting the future risk of osteoporotic fracture in women. The aluminium phantom study with an X-ray tube to film distance of 100 cm mimics an exact condition of forearm radiogrammetry. PMID- 29968334 TI - Caregivers' nutritional knowledge and attitudes mediate seasonal shifts in children's diets. AB - Smallholder farmers dependent on rain-fed agriculture experience seasonal variations in food and nutrient availability occasioned by seasonality of production patterns. This results in periods of nutrient abundance in the plenty seasons followed closely by periods of nutrient inadequacies and malnutrition. This pattern contributes to a cycle of deteriorating health and nutrition status and deprives children of their ability to realize full developmental potential. This study investigates the role of caregiver's nutritional knowledge and attitudes in mediating effects of seasonality on children's diets. Repeated cross sectional surveys were conducted on 151 randomly selected households in the plenty and lean seasons to collect dietary data using two non-consecutive quantitative 24-hr recalls and caregiver's nutritional knowledge and attitudes assessed using interviewer administered questionnaire. Sixty-five percent of the caregivers had attained a primary level education or less. There was a positive modest correlation between caregivers' nutritional knowledge and their attitudes (r = 0.3, P < 0.000, alpha = 0.01). Children's mean adequacy ratio was significantly higher in the plenty season than in the lean season (0.84 vs. 0.80, P < 0.000). A two-block hierarchical regression to predict the seasonal changes in dietary quality of children using caregiver's nutritional knowledge and attitude scores while controlling for the effect of sociodemographics and mean adequacy ratio at first season (plenty) found that caregiver's nutritional knowledge (beta = -0.007, SE = 0.003, P = 0.027, 95% CI [-0.013, -0.001] n2 = 0.034) but not attitudes had significant contribution to the prediction. Maternal nutritional knowledge mediates seasonal variation in child nutrient intakes. PMID- 29968335 TI - An adaptive method for identifying marine areas of high conservation priority. AB - Identifying priority areas for biodiversity conservation is particularly challenging in the marine environment due to the open and dynamic nature of the ocean, the paucity of information on species distribution, and the necessary balance between marine biodiversity conservation and essential supporting services such as seafood provision. We used the Patagonian seabird breeding community as a case study to propose an integrated and adaptive method for delimiting key marine areas for conservation. Priority areas were defined through a free decision-support tool (Marxan) that included projected at-sea distributions of seabirds (approximately 2,225,000 individuals of 14 species); BirdLife Important Bird and Biodiversity Areas (IBAs) for pelagic bird species; and the economic costs of potential regulations in fishing practices. The proposed reserve network encompassed approximately 300,000 km2 that was largely concentrated in northern and southern inshore and northern and central offshore regions. This reserve network exceeded the minimum threshold of 20% conservation of the abundance of each species proposed by the World Parks Congress. Based on marine currents in the study area, we further identified the 3 primary water masses that may influence areas of conservation priority through water inflow. Our reserve network may benefit from enhanced marine productivity in these highly connected areas, but they may be threatened by human impacts such as marine pollution. Our method of reserve network design is an important advance with respect to the more classical approaches based on criteria defined for one or a few species and may be particularly useful when information on spatial patterns is data deficient. Our approach also accommodates addition of new information on seabird distribution and population dynamics, human activities, and alterations in the marine environment. PMID- 29968336 TI - Identifying labile DOM components in a coastal ocean through depleted bacterial transcripts and chemical signals. AB - Understanding which compounds comprising the complex and dynamic marine dissolved organic matter (DOM) pool are important in supporting heterotrophic bacterial production remains a major challenge. We eliminated sources of labile phytoplankton products, advected terrestrial material and photodegradation products to coastal microbial communities by enclosing water samples in situ for 24 h in the dark. Bacterial genes for which expression decreased between the beginning and end of the incubation and chemical formulae that were depleted over this same time frame were used as indicators of bioavailable compounds, an approach that avoids augmenting or modifying the natural DOM pool. Transport- and metabolism-related genes whose relative expression decreased implicated osmolytes, carboxylic acids, fatty acids, sugars and organic sulfur compounds as candidate bioreactive molecules. FT-ICR MS analysis of depleted molecular formulae implicated functional groups ~ 30-40 Da in size cleaved from semi-polar components of DOM as bioreactive components. Both gene expression and FT-ICR MS analyses indicated higher lability of compounds with sulfur and nitrogen heteroatoms. Untargeted methodologies able to integrate biological and chemical perspectives can be effective strategies for characterizing the labile microbial metabolites participating in carbon flux. PMID- 29968337 TI - Changes in penile length after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy. AB - Although reports have shown evidence for penile length (PL) shortening after radical prostatectomy (RP), the association between neoadjuvant androgen deprivation therapy (NADT) and PL after RP has yet to be determined. This study evaluates chronological changes in PL after NADT and RP. Stretched PLs (SPLs) of 143 patients, 41 of whom had undergone NADT, were measured before, 10 days after, and 1, 3, 6, 9, 12, 18, and 24 months after RP. Chronological erectile function and testosterone levels were then evaluated. SPL was shortest 10 days after RP in both the NADT (-) and NADT (+) groups and gradually recovered in length thereafter. SPL in the NADT (-) group was significantly longer than that in the NADT (+) group before RP. However, no significant differences in SPLs were found between both groups 6 months after RP. Although all subjects in the NADT (+) group had testosterone levels of <50 ng/dL before RP, such levels increased after RP. Before RP, the NADT (-) group was found to have significantly better erectile function than the NADT (+) group. However, differences in erectile function between the NADT (-) and NADT (+) groups after RP were not significant. This report is the first to show that among patients with prostate cancer, those who underwent NADT had greater PL recovery after RP than those who did not. Data regarding PL recovery after NADT and RP obtained in this study could be useful for patients with prostate cancer who plan to undergo such procedures. PMID- 29968338 TI - Better horizontal transmission of a US non-InDel strain compared with a French InDel strain of porcine epidemic diarrhoea virus. AB - From the severe porcine epidemic diarrhoea (PED) epidemics that struck in 2013 in the United States of America and other countries of North and South America, two types of porcine epidemic diarrhoea virus (PEDV) were isolated, namely the InDel and the non-InDel strains. They are differentiated by insertions/deletions in the S1 nucleotide sequence of the S gene, and differences in virulence were observed from the clinical cases. In 2014, a PED outbreak occurred in a pig farm in France, from which an InDel strain was isolated. This study aimed at comparing, under experimental conditions, the pathogenicity and the direct and indirect transmissions between a non-InDel strain isolated from a PED-affected piglet in 2014 in the USA and the French InDel strain. All infected pigs showed clinical signs with the non-InDel strain although only the inoculated and direct contact pigs showed clinical signs in the InDel strain group. Although viral RNA was detected in air samples with both strains, the indirect contact pigs remained free from infection with the InDel strain in contrast to the non-InDel group in which airborne transmission occurred in the indirect contact pigs. All infected pigs shed virus in faeces regardless of PEDV strain with 9 of 30 pigs showing intermittent faecal shedding. The transmission rate by direct contact was found to be 2.17-fold higher than the non-InDel strain compared with the InDel. In conclusion, the InDel strain was less pathogenic than the non-InDel strain in our experimental conditions. The transmission route differed between the two strains. Direct contact was the main transmission route for the InDel strain, although the non-InDel strain was transmitted through direct contact and indirectly through the air. PMID- 29968339 TI - Accuracy of pen-type laser fluorescence device and radiographic methods in detecting approximal carious lesions in primary teeth - an in vivo study. AB - BACKGROUND: The diagnosis of approximal lesions is limited due to the difficulty of direct examination of these areas. AIM: To determine the accuracy of pen-type laser fluorescence (LFpen) device, compared to digital bitewing (BW) radiography, in diagnosing approximal carious lesions in posterior primary teeth at cavitation and non-cavitation thresholds. DESIGN: A total of 46 children (aged 3-9 years) were assessed and 195 approximal surfaces of 184 primary molars were examined by digital BW and LFpen. Visual-tactile inspection based on the International Caries Detection and Assessment System (ICDAS-II) was used as the reference standard. All examinations were performed by the same examiner. Sensitivity, specificity, and accuracy were calculated. Spearman's correlation coefficients were calculated between LFpen and BW readings and the reference standard. RESULTS: Sensitivity, specificity and AUC were 81.8, 86.7, and 0.84 for BW and 49.1, 87.9, and 0.69 for LFpen both at non-cavitation thresholds. At cavitation thresholds, BW showed higher specificity (96.0), sensitivity (93.0), and AUC (0.98) than did LFpen (72.0, 86.9, and 0.82, respectively), but a lower correlation was indicated by LFpen readings. CONCLUSION: Bitewing had a better diagnostic accuracy and significantly outperformed LFpen in the detection of non-cavitated lesions. Similar results were obtained by the two methods at the cavitation threshold. PMID- 29968340 TI - Indium Phosphite-Based Porous Solids Exhibiting Organic Sensing and a Facile Route to Superhydrophobicity. AB - In searching for practical crystalline porous solids, two unique hybrid materials with featured functions, In-bpy and In-dpe, were prepared without deliberately designed organic linker units or complex post-modification procedures. Composed of oxalate-embedded metal phosphite (MPO) sheets and bipyridyl-type ligands of varied molecular lengths, they show a common pillar-layered topology but are the first well-characterized organo-MPOs to possess genuine porosity, substantiated by CO2 adsorption, and structural stability under harsh conditions. In-bpy exhibits a turn-on fluorescence signal when in contact with p-xylene, making it the first MPO-based sensing material with selectivity and recyclability. Furthermore, In-dpe demonstrates a facile and unprecedented route to the superhydrophobicity of porous solids via a [2+2] photocycloaddition reaction between linker and foreign units. Our findings suggest that MPO may serve as a promising platform for hybrid frameworks to create many more functional porous materials. PMID- 29968341 TI - Hierarchical modeling of melanocortin 1 receptor variants with skin cancer risk. AB - The human MC1R gene is highly polymorphic among lightly pigmented populations, and several variants in the MC1R gene have been associated with increased risk of both melanoma and nonmelanoma skin cancers. The functional consequences of MC1R gene variants have been studied in vitro and in vivo in postulated causal pathways, such as G-protein-coupled signaling transduction, pigmentation, immune response, inflammatory response, cell proliferation, and extracellular matrix adhesion. In a case-control study nested within the Nurses' Health Study, we utilized hierarchical modeling approaches, incorporating quantitative information from these functional studies, to examine the association between particular MC1R alleles and the risk of skin cancers. Different prior matrices were constructed according to the phenotypic associations in controls, cell surface expression, and enzymatic kinetics. Our results showed the parameter variance estimates of each single nucleotide polymorphism (SNP) were smaller when using a hierarchical modeling approach compared to standard multivariable regression. Estimates of second-level parameters gave information about the relative importance of MC1R effects on different pathways, and odds ratio estimates changed depending on prior models (e.g., the change ranged from -21% to 7% for melanoma risk assessment). In addition, the estimates of prior model hyperparameters in the hierarchical modeling approach allow us to determine the relevance of individual pathways on the risk of each of the skin cancer types. In conclusion, hierarchical modeling provides a useful analytic approach in addition to the widely used conventional models in genetic association studies that can incorporate measures of allelic function. PMID- 29968342 TI - Variation of measured values associated with different lots of sensors for the FreeStyle Libre. PMID- 29968343 TI - Facts and Possibilities: A Model-Based Theory of Sentential Reasoning. AB - This article presents a fundamental advance in the theory of mental models as an explanation of reasoning about facts, possibilities, and probabilities. It postulates that the meanings of compound assertions, such as conditionals (if) and disjunctions (or), unlike those in logic, refer to conjunctions of epistemic possibilities that hold in default of information to the contrary. Various factors such as general knowledge can modulate these interpretations. New information can always override sentential inferences; that is, reasoning in daily life is defeasible (or nonmonotonic). The theory is a dual process one: It distinguishes between intuitive inferences (based on system 1) and deliberative inferences (based on system 2). The article describes a computer implementation of the theory, including its two systems of reasoning, and it shows how the program simulates crucial predictions that evidence corroborates. It concludes with a discussion of how the theory contrasts with those based on logic or on probabilities. PMID- 29968344 TI - A Polymerization-Cutting Strategy: Self-Protection Synthesis of Thiol-Based Nanoporous Adsorbents for Efficient Mercury Removal. AB - Highly toxic heavy metal ions such as mercury ions (Hg2+ ) are a great threat to human life and the environment. Developing new strategies and materials to remove the toxic heavy metal ions has attracted more and more attentions. Herein a facile self-protection synthesis of thiol-based nanoporous adsorbents for efficient mercury removal via a polymerization-cutting strategy is reported. The direct free-radical polymerization of divinyl disulfide derivative and subsequently cutting off the disulfide linkage, without post-synthesis or modification, can give rise to an exceptionally high density of thiol chelating sites. Moreover, the resultant thiol-based nanoporous adsorbents (NAs-SH) exhibit a high saturation uptake capacity (1240 mg g-1 ) and reused ability for mercury removal from water solution. The proposed polymerization-cutting strategy may provide an alternative and cost-effective method for the design and synthesis of various efficient nanoporous adsorbents at large scale in the future. PMID- 29968345 TI - Effects of Sugars, Furans, and their Derivatives on Hydrodeoxygenation of Biorefinery Lignin-Rich Wastes to Hydrocarbons. AB - Hydrodeoxygenation of biorefinery lignin-rich wastes to jet fuel hydrocarbons offers a significant opportunity for enhancing the overall operational efficiency, carbon conversion efficiency, economic viability, and sustainability of biofuels production. However, these wastes usually mainly contain lignin with sugars, furans, and their derivatives as "impurities". Although several factors, including reactant structure, solvents, or the decreased ratio of catalyst to reactant, could be responsible for the jet fuel hydrocarbons yield loss, we found evidence that glucose, xylose, and 5-hydroxymethylfurfural dramatically decreased conversion yields. For example, xylose and glucose lowered the final hydrocarbon yield by 78 and 63 %, respectively. The results revealed that these compounds could suppress metal catalysts and inhibit lignin depolymerization and hydrodeoxygenation (HDO) reactions thus decrease yields of jet fuel range hydrocarbons from biomass-derived lignin. The first-principles calculations and TGA results from spent catalysts validated these findings. PMID- 29968346 TI - Antibiotics alter the window of competence for natural transformation in streptococci. AB - Streptococcus pneumoniae transformation occurs within a short competence window, during which the alternative sigma factor X (SigX) is activated to orchestrate the expression of genes allowing extracellular DNA uptake and recombination. Importantly, antibiotic stress promotes transcriptional changes that may affect more than 20% of the S. pneumoniae genome, including competence genes. These can be activated or repressed, depending on the antibiotic agent. For most antibiotics, however, it remains unknown whether transcriptional effects on competence translate into altered transformability. Here we investigate the effect of antibiotic subinhibitory concentrations on sigX expression using a luciferase reporter, and correlate for the first time with transformation kinetics. Induction of sigX expression by ciprofloxacin and novobiocin correlated with increased and prolonged transformability in S. pneumoniae. The prolonged effect of ciprofloxacin on competence and transformation was also observed in the streptococcal relatives Streptococcus mitis and Streptococcus mutans. In contrast, tetracycline and erythromycin, which induced S. pneumoniae sigX expression, had either an inhibitory or a nonsignificant effect on transformation, whereas streptomycin and the beta-lactam ampicillin, inhibited both sigX expression and transformation. Thus, the results show that antibiotics may vary in their effects on competence, ranging from inhibitory to stimulatory effects, and that responses affecting transcription of sigX do not always correlate with the transformation outcomes. Antibiotics that increase or decrease transformation are of particular clinical relevance, as they may alter the ability of S. pneumoniae to escape vaccines and antibiotics. PMID- 29968348 TI - Abbreviations, acronyms and pedants. PMID- 29968347 TI - Cross-species systems analysis of evolutionary toolkits of neurogenomic response to social challenge. AB - Social challenges like territorial intrusions evoke behavioral responses in widely diverging species. Recent work has showed that evolutionary "toolkits" genes and modules with lineage-specific variations but deep conservation of function-participate in the behavioral response to social challenge. Here, we develop a multispecies computational-experimental approach to characterize such a toolkit at a systems level. Brain transcriptomic responses to social challenge was probed via RNA-seq profiling in three diverged species-honey bees, mice and three-spined stickleback fish-following a common methodology, allowing fair comparisons across species. Data were collected from multiple brain regions and multiple time points after social challenge exposure, achieving anatomical and temporal resolution substantially greater than previous work. We developed statistically rigorous analyses equipped to find homologous functional groups among these species at the levels of individual genes, functional and coexpressed gene modules, and transcription factor subnetworks. We identified six orthogroups involved in response to social challenge, including groups represented by mouse genes Npas4 and Nr4a1, as well as common modulation of systems such as transcriptional regulators, ion channels, G-protein-coupled receptors and synaptic proteins. We also identified conserved coexpression modules enriched for mitochondrial fatty acid metabolism and heat shock that constitute the shared neurogenomic response. Our analysis suggests a toolkit wherein nuclear receptors, interacting with chaperones, induce transcriptional changes in mitochondrial activity, neural cytoarchitecture and synaptic transmission after social challenge. It shows systems-level mechanisms that have been repeatedly co-opted during evolution of analogous behaviors, thus advancing the genetic toolkit concept beyond individual genes. PMID- 29968349 TI - Polymerization-Induced Self-Assembly of Functionalized Block Copolymer Nanoparticles and Their Application in Drug Delivery. AB - Drug delivery systems (DDS) based on functionalized polymeric nanoparticles have attracted considerable attention. Although great advances have been reported in the past decades, the fabrication efficiency and reproducibility of polymeric nanoparticles are barely satisfactory due to the intrinsic limitations of the traditional self-assembly method, which severely prevent further applications of the intelligent DDS. In the last decade, a new self-assembly method, which is usually called polymerization-induced self-assembly (PISA), has become a powerful strategy for the fabrication of the polymeric nanoparticles with bespoke morphology. The PISA strategy efficiently simplifies the fabrication of polymeric nanoparticles (combination of the polymerization and self-assembly in one pot) and allows the fabrication of polymeric nanoparticles at a relatively high concentration (up to 50 wt%), making it realistic for large-scale production of polymeric nanoparticles. In this review, the developments of PISA-based polymeric nanoparticles for drug delivery are discussed. PMID- 29968350 TI - Assembly of a Wheel-Like Eu24 Ti8 Cluster under the Guidance of High-Resolution Electrospray Ionization Mass Spectrometry. AB - A building blocks strategy is an effective approach for constructing the large molecular systems. Herein, we demonstrate that high-resolution electro-spray ionization mass spectrometry (HRESI-MS) provides an effective chance to insight the assemble process of the building blocks and guides the construction of high nuclearity metal clusters on the basis of the reaction of Ti(Oi Pr)4 , Eu(acac)3 , and salicylic acid. The time-dependent HRESI-MS indicates that not only a Eu3 Ti building block can be formed, but that it can further assemble into a Eu24 Ti8 compound. Temperature-dependent HRESI-MS reveals that increase of the reaction temperature favors the formation and crystallization of the stable Eu24 Ti8 structure. Single-crystal structural analysis demonstrates that the Eu24 Ti8 has a wheel-like structure with diameter of ca. 4.1 nm and is the highest nuclearity lanthanide-titanium oxo cluster reported to date. PMID- 29968351 TI - New Magnetically Recyclable Reduced Graphene Oxide rGO/MFe2 O4 (M= Ca, Mg)/Ag3 PO4 Nanocomposites With Remarkably Enhanced Visible-light Photocatalytic Activity and Stability. AB - New magnetically separable CaFe2 O4 /Ag3 PO4 , MgFe2 O4 /Ag3 PO4 , rGO/CaFe2 O4 /Ag3 PO4 and rGO/MgFe2 O4 /Ag3 PO4 photocatalysts were synthesized by the hydrothermal and ion-exchange deposition method. These four types of photocatalyst were used for degradation of Methylene blue (MB), Methyl orange (MO) and 4-chlorophenol (4-CP) in aqueous solution under visible-light illumination. The optimized photocatalyst, i.e. rGO/CaFe2 O4 /Ag3 PO4 with a mass ratio of (1:3:9) composite not only shows the highest photocatalytic performance for the degradation of MB, MO and 4-CP under visible light irradiation among the other synthesized photocatalysts but also exhibits high reusability and stability for at least five cycles. It was found that the impressive separation of electron hole pairs as well as presence of rGO sheets which act as a high speed charge transfer were responsible for increasing photocatalytic activity over the optimized photocatalyst under visible-light irradiation. A possible mechanism for the increased photocatalytic activity of the rGO/CaFe2 O4 /Ag3 PO4 with a mass ratio of (1:3:9) composite was discussed in detail. PMID- 29968352 TI - Nano-TiO2 Drives Epithelial-Mesenchymal Transition in Intestinal Epithelial Cancer Cells. AB - The majority of cancer mortality is associated with cancer metastasis. Epithelial to-mesenchymal transition (EMT) is a process by which cells attain migratory and invasive properties, eventually leading to cancer metastasis. Here, it is shown that titanium dioxide nanoparticles (nano-TiO2 ), a common food additive, can induce the EMT process in colorectal cancer cells. Nano-TiO2 exposure is observed to activate transforming growth factor-beta (TGF-beta)/mitogen-activated protein kinase (MAPK) and wingless (Wnt) pathways, and drive the EMT process. Similarly, silica nanoparticles (nano-SiO2 ) and hydroxyapatite nanoparticles (nano-HA), as food-based additives, can be ingested and accumulated in the stomach, and are found to be able to induce the EMT progression. The implication of this work can be profound for colorectal cancer patients where these food additives may unknowingly and unnecessarily hasten the progression of their cancers. PMID- 29968353 TI - Deficiency of the basic helix-loop-helix transcription factor DEC1 prevents obesity induced by a high-fat diet in mice. AB - Obesity is a major public health problem in developed countries resulting from increased food intake and decreased energy consumption and usually associated with abnormal lipid metabolism. Here, we show that DEC1, a basic helix-loop-helix transcription factor, plays an important role in the regulation of lipid consumption in mouse brown adipose tissue (BAT), which is the major site of thermogenesis. Homozygous Dec1 deletion attenuated high-fat-diet-induced obesity, adipocyte hypertrophy, fat volume and hepatic steatosis. Furthermore, DEC1 deficiency increased body temperature during daytime and enhanced the expression of uncoupler protein 1, a key factor of thermogenesis, and various lipolysis related genes in interscapular BAT. In vitro experiments suggested that DEC1 suppresses the expression of various lipolysis-related genes induced by the heterodimer of peroxisome proliferator-activated receptor gamma and retinoid X receptor alpha (RXRalpha) through direct binding to RXRalpha. These observations suggest that enhanced lipolysis in BAT caused by DEC1 deficiency leads to an increase in lipid consumption, thereby decreasing lipid accumulation in adipose tissues and the liver. Thus, DEC1 may serve as an energy-saving factor that suppresses lipid consumption, which may be relevant to managing obesity. PMID- 29968354 TI - Toxoplasma gondii stabilises tetrameric complexes of tyrosine-phosphorylated signal transducer and activator of transcription-1 and leads to its sustained and promiscuous DNA binding. AB - Toxoplasma gondii is an obligate intracellular parasite that infects up to 30% of humans worldwide. It can lead to severe diseases particularly in individuals with immature or defective immune responses. Control of T. gondii relies on the IFN gamma-induced signal transducer and activator of transcription-1 (STAT1) pathway. T. gondii, however, largely inactivates STAT1-mediated gene transcription by T. gondii inhibitor of STAT1-dependent transcription (TgIST), a parasite effector protein binding to STAT1. Here, we have analysed requirements of STAT1 to bind TgIST and characterised downstream effects on STAT1 signalling. TgIST bound to STAT1 dimers but more efficiently assembled with STAT1 tetramers, which are essential for effective IFN-gamma responsiveness. Such binding was abrogated in N terminal, but not C-terminal deletion mutants of STAT1. Furthermore, TgIST did not bind to the STAT1F77A substitution mutant that cannot form STAT1 tetramers, resulting in a complete unresponsiveness of parasite-infected STAT1F77A expressing cells to IFN-gamma. Remarkably, binding of TgIST considerably increased the affinity of the aberrant STAT1 tetramers for DNA consensus sequence binding motifs and even enabled binding to nonconsensus sequences. Consistent with the increased DNA binding, STAT1 from parasite-infected cells remained phosphorylated at Tyr701 and Ser727 and was retained within the nucleus in a DNA bound state. The sustained and promiscuous binding activity particularly of STAT1 tetramers to unspecific DNA sites lacking a consensus STAT1-binding motif is an as yet unrecognised mechanism contributing to the defective IFN-gamma-mediated signalling in T. gondii-infected cells. PMID- 29968355 TI - Sulfur-Center-Involved Photocatalyzed Reactions. AB - Sulfur-containing compounds (SCCs) exist widely in, for example, natural sources, pharmaceuticals, materials, and foods. Their multifarious functions have stimulated scientists to construct them in greener and more efficient ways and further exploit their properties. Different photosensitizers with sulfur atoms have been developed and exploited. Furthermore, SCCs display excellent ability in hydrogen-atom-transfer reactions. In addition to acting as catalysts, SCCs can also be efficiently transformed under visible-light-promoted conditions. Bond dissociation and oxygenation reactions that involve sulfur centers are emphasized here. PMID- 29968357 TI - Metabolic potential of microbial communities from ferruginous sediments. AB - Ferruginous (Fe-rich, SO4 -poor) conditions are generally restricted to freshwater sediments on Earth today, but were likely widespread during the Archean and Proterozoic Eons. Lake Towuti, Indonesia, is a large ferruginous lake that likely hosts geochemical processes analogous to those that operated in the ferruginous Archean ocean. The metabolic potential of microbial communities and related biogeochemical cycling under such conditions remain largely unknown. We combined geochemical measurements (pore water chemistry, sulfate reduction rates) with metagenomics to link metabolic potential with geochemical processes in the upper 50 cm of sediment. Microbial diversity and quantities of genes for dissimilatory sulfate reduction (dsrAB) and methanogenesis (mcrA) decrease with increasing depth, as do rates of potential sulfate reduction. The presence of taxa affiliated with known iron- and sulfate-reducers implies potential use of ferric iron and sulfate as electron acceptors. Pore-water concentrations of acetate imply active production through fermentation. Fermentation likely provides substrates for respiration with iron and sulfate as electron donors and for methanogens that were detected throughout the core. The presence of ANME-1 16S and mcrA genes suggests potential for anaerobic methane oxidation. Overall our data suggest that microbial community metabolism in anoxic ferruginous sediments support coupled Fe, S and C biogeochemical cycling. PMID- 29968356 TI - Atrial fibrillation in an African-American cohort: The Jackson Heart Study. AB - BACKGROUND: Atrial fibrillation (AF) is an important public health problem across race/ethnic groups. Data from US cohort studies initiated in the 1980s suggest a higher prevalence of AF risk factors among African-Americans (AAs) than whites, but lower AF incidence. The Jackson Heart Study (JHS) is a community-based study of 5306 AAs recruited starting in 2000. HYPOTHESIS: Demographic, anthropometric, cardiovascular, and/or electrocardiographic factors are associated with AF incidence in JHS. METHODS: Using baseline participant characteristics and incident AF identified through hospital surveillance, study electrocardiogram, and Medicare claims, we estimated age- and sex-specific AF incidence rates, compared them with rates in AA participants in the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS), and examined associations of cardiovascular risk factors with AF. RESULTS: A total of 66 participants had prevalent AF at baseline. Over an average follow-up of 8.5 years, 242 cases of incident AF were identified. Age- and sex-specific AF incidence rates in JHS were similar to those among AAs in MESA and appeared slightly lower than those among AAs in CHS. In an age- and sex-adjusted model, associations with incident AF were observed for modifiable risk factors: high body weight (HR = 1.23 per 15 kg, 95%CI 1.13-1.35), systolic blood pressure (HR = 1.29 per 20 mmHg, 95%CI 1.13-1.47), and current smoking (HR = 1.80, 95%CI 1.27 2.55). Risk estimates associated with these risk factors were only slightly attenuated after multivariable adjustments. CONCLUSIONS: These findings underscore the potential additional benefits of interventions for weight management, control of hypertension, and smoking cessation for the prevention of AF among AAs. PMID- 29968358 TI - Frequency, nature and timing of clinical deterioration in the early postoperative period. AB - AIMS AND OBJECTIVES: To establish the frequency of clinical deterioration in the early postoperative period in patients who have undergone general or orthopaedic surgery. BACKGROUND: Worldwide, clinical deterioration is a significant problem in acute care settings. Early recognition and response to clinical deterioration is one of the ten National Safety and Quality Health Service Standards in Australia. However, there is limited understanding of the frequency of clinical deterioration in surgical patients. METHODS: A point prevalence study was conducted from September-October 2014. The records of 100 consecutive in patients admitted for orthopaedic (n = 48) or general surgery (n = 52) to a health service in Melbourne, Australia, were audited. The frequency of clinical deterioration episodes was summarised using descriptive statistics. RESULTS: Baseline characteristics of the two patient groups were equivalent except that orthopaedic patients were older than the general surgery patients (median age 71 [IQR 19] years vs. 62 [IQR 17] years). There were 17 medical emergency team calls and 23 calls for urgent clinical review in 28 patients. The main indications for emergency calls were hypotension (26%), fever (19%), hypoxia (15%), tachycardia (13%) and altered blood glucose level (11%). The majority of episodes were managed on the ward, and there were one ICU transfer and no cardiac arrest calls. CONCLUSION: One in four patients experienced early postoperative clinical deterioration. Hypotension was the most common trigger for escalation of care highlighting a need to optimise fluid and haemodynamic management of postoperative patients. RELEVANCE TO CLINICAL PRACTICE: Haemodynamic instability leading to the activation of rapid response systems is very common in the immediate postoperative period. There is the need for locally tailored interventions to optimise fluid management and decrease incidence of further complications. PMID- 29968359 TI - Effect of inoculation with a microbial consortium that degrades organic acids on the composting efficiency of food waste. AB - In order to overcome the excessive acidification problem, a microbial consortium for the degradation of organic acids (MCDOA), which acts synergistically in degrading organic acids, was developed and used as an inoculum to improve the efficiency of food waste composting. MCDOA could eliminate the initial lag phase of the pile temperature rise because of excessive acidification and effectively shorten the composting period. Fluorescence regional integration analysis of the excitation-emission matrix spectra of dissolved organic matter showed that compared with raw material, in compost with MCDOA inoculation, the percent fluorescence response (Pi,n ) values of Regions I, II and IV decreased by 95.11%, 94.19% and 87.41%, respectively, and Pi,n of Region V increased by 172.57%. The decreased and increased levels were markedly higher than in the two control groups (MgO and K2 HPO4 treatment, and uninoculated compost). These findings revealed that MCDOA accelerated the degradation of proteinaceous compounds and the formation of complicated humic-like materials. Bacterial profiles implied that MCDOA could improve the indigenous bacterial community structure and diversities of acetic and propionic acid-degrading and lignin-degrading bacteria, which might account for the high composting efficiency and degree of humification of the inoculated compost. PMID- 29968360 TI - Activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis by the Epstein-Barr virus-encoded latent membrane protein 1 (LMP1) promotes cell proliferation and progression of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. The EBV-encoded latent membrane protein 1 (LMP1), which is commonly expressed in NPC, engages multiple signaling pathways that promote cell growth, transformation, and metabolic reprogramming. Here, we report a novel function of LMP1 in promoting de novo lipogenesis. LMP1 increases the expression, maturation and activation of sterol regulatory element-binding protein 1 (SREBP1), a master regulator of lipogenesis, and its downstream target fatty acid synthase (FASN). LMP1 also induces de novo lipid synthesis and lipid droplet formation. In contrast, small interfering RNA (siRNA) knockdown of LMP1 in EBV infected epithelial cells diminished SREBP1 activation and lipid biosynthesis. Furthermore, inhibition of the mammalian target of rapamycin (mTOR) pathway, through the use of either mTOR inhibitors or siRNAs, significantly reduced LMP1 mediated SREBP1 activity and lipogenesis, indicating that LMP1 activation of the mTOR pathway is required for SREBP1-mediated lipogenesis. In primary NPC tumors, FASN overexpression is common, with high levels correlating significantly with LMP1 expression. Moreover, elevated FASN expression was associated with aggressive disease and poor survival in NPC patients. Luteolin and fatostatin, two inhibitors of lipogenesis, suppressed lipogenesis and proliferation of nasopharyngeal epithelial cells, effects that were more profound in cells expressing LMP1. Luteolin and fatostatin also dramatically inhibited NPC tumor growth in vitro and in vivo. Our findings demonstrate that LMP1 activation of SREBP1-mediated lipogenesis promotes tumor cell growth and is involved in EBV driven NPC pathogenesis. Our results also reveal the therapeutic potential of utilizing lipogenesis inhibitors in the treatment of locally advanced or metastatic NPC. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29968361 TI - ISPAD Annual Conference 2017 Highlights. PMID- 29968362 TI - "She doesn't want to go to hospital. That's one thing she hates": Collective performativity in avoidable nursing home to hospital transfers. AB - Older people who live with a combination of conditions experience fluctuations over time, which others may interpret as a need for medical attention. For some nursing home residents, this results in transitions in and out of hospital. Such transfers may be arranged without expectation of improved quality of life, can be associated with significant morbidity and mortality, and may preclude end-of-life preferences. Factors affecting avoidable hospitalization for nursing home residents are not well understood. I aim to explore potential drivers, moving beyond deficit explanations relating to funding, training, and resources. I use a framework of analysis that firstly considers medicalization of frailty, as a state of vulnerability that provides focus for others' action. I then draw on Judith Butler's theory of performativity, to explore nursing homes as sites of identity work for staff, residents and families. I consider ways subjectivities can be effected through reiterative practice that is compelled by normative conventions. Trouble may arise when citational practice of health care staff, and performative acquiescence of residents and families, culminates in an inevitability of hospitalization when navigating grey areas of assumed clinical risk. Principles of coproduction could present a disruptive opening, to rework power asymmetries, and move toward aspirations for residents and their relatives to be at the centre of decisions about care. PMID- 29968363 TI - Sperm cryopreservation in the Far-Eastern wildcat (Prionailurus bengalensis euptilurus). AB - The Far-Eastern wildcat (Prionailurus bengalensis euptilurus) is a rare and poorly investigated nondomestic felid species. An attempt of freezing and cryopreserving Far-Eastern wildcat spermatozoa in CaniPlus Freeze (CPF) medium is reported. Sperm was collected by electroejaculation from five adult Far-Eastern wildcat captive-born males. Epididymal spermatozoa from five adult randomly bred domestic cat males were used as a reference. The viability of frozen-thawed spermatozoa evaluated by double staining with SYBR Green I and PI followed by the subsequent confocal laser scanning microscopy (CLSM) was 38.2% +/- 3.0% for the domestic cat and 38.0% +/- 10.2% for the Far-Eastern wildcat. The motility of frozen-thawed spermatozoa was 30.8% +/- 9.8% for the domestic cat and 33.7% +/- 15.1% for the Far-Eastern wildcat. Sperm morphology was assessed by light microscopy. The total percentage of normal spermatozoa after freezing and thawing was 51.9 +/- 5.9 for the domestic cat and 55.0% +/- 6.4% for the Far-Eastern wildcat. Defects of flagella were the most frequently observed abnormalities in both species (32.2% +/- 4.8% and 30.8% +/- 4.4% of all reported anomalies for the domestic cat and Far-Eastern wildcat, respectively). Domestic cat epididymal and Far-Eastern ejaculatory spermatozoa fertilized in vitro-matured oocytes of the domestic cat (30.0% +/- 5.5% and 35.5% +/- 15.0%, respectively). Taken together, these results suggest that the freezing of Far-Eastern wildcat spermatozoa with CPF medium is a suitable method for Felidae cryopreservation. PMID- 29968364 TI - A multiscale computational modeling for cerebral blood flow with aneurysms and/or stenoses. AB - A 1-dimensional (1D)-3-dimensional (3D) multiscale model for the human vascular network was proposed by combining a low-fidelity 1D modeling of blood circulation to account for the global hemodynamics with a detailed 3D simulation of a zonal vascular segment. The coupling approach involves a direct exchange of flow and pressure information at interfaces between the 1D and 3D models and thus enables patient-specific morphological models to be inserted into flow network with minimum computational efforts. The proposed method was validated with good agreements against 3 simplified test cases where experimental data and/or full 3D numerical solution were available. The application of the method in aneurysm and stenosis studies indicated that the deformation of the geometry caused by the diseases may change local pressure loss and as a consequence lead to an alteration of flow rate to the vessel segment. PMID- 29968365 TI - Too big to be seen: Weight-based discrimination among nursing students. AB - An educational intervention was conducted to determine the efficacy of an obesity sensitivity program to determine nursing students' attitudes toward obese clients. As part of the clinical curriculum, nursing students (N = 103) received weekly obesity sensitivity education on weight-based discrimination. Students' completed a preproject and postproject attitudes toward obese persons scale (Barra, 2015) to evaluate discriminatory beliefs and actions. All clinical groups had a significant positive change in their own weight prejudices postobesity education intervention. Chi-square analysis was utilized as a measure of association between pre- and postobesity education with clinical application concerning obesity size, body odor, appearance, and lifestyle, along with provider fear of a back injury. Promoting nursing student awareness of obese client bias can dissipate negative stigmas to promote a therapeutic patient provider relationship. PMID- 29968366 TI - The prevalence of mental health problems in adults with intellectual disabilities in Japan, associated factors and mental health service use. AB - BACKGROUND: People with intellectual disabilities are more likely than people in the general population to experience life events associated with an increased risk of mental health problems. However, there has been little research in Japan on the prevalence of mental health problems in adults with intellectual disability (ID) or on associated factors and access to relevant services. METHODS: Informants completed the Japanese version of the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist, and questions on the use of mental health services, for 126 adults with ID living in Tokyo. RESULTS: A total of 23.8% of adults with ID had scores above the Psychiatric Assessment Schedule for Adults with Developmental Disabilities Checklist threshold score. Mental health problems were associated with age, gender and life events and not associated with the level of ID or living environment. Approximately 60% of participants with mental health problems were treated by psychiatrists and 6% of them received psychotherapy. CONCLUSION: In the present study, mental health problems occurred in adults with ID at similar frequencies as in previous studies. Adults with ID who experienced mental health problems tended to receive less psychological therapy than the general Japanese population experiencing such problems. This result may indicate poor provision of psychological services for people with intellectual disabilities in Japan. PMID- 29968367 TI - Widespread nitrogen fixation in sediments from diverse deep-sea sites of elevated carbon loading. AB - Nitrogen fixation, the biological conversion of N2 to NH3 , is critical to alleviating nitrogen limitation in many marine ecosystems. To date, few measurements exist of N2 fixation in deep-sea sediments. Here, we conducted > 400 bottle incubations with sediments from methane seeps, whale falls and background sites off the western coast of the United States from 600 to 2893 m water depth to investigate the potential rates, spatial distribution and biological mediators of benthic N2 fixation. We found that N2 fixation was widespread, yet heterogeneously distributed with sediment depth at all sites. In some locations, rates exceeded previous measurements by > 10*, and provided up to 30% of the community anabolic growth requirement for nitrogen. Diazotrophic activity appeared to be inhibited by pore water ammonium: N2 fixation was only observed if incubation ammonium concentrations were <= 25 MUM, and experimental additions of ammonium reduced diazotrophy. In seep sediments, N2 fixation was dependent on CH4 and coincident with sulphate reduction, consistent with previous work showing diazotrophy by microorganisms mediating sulphate-coupled methane oxidation. However, the pattern of diazotrophy was different in whale-fall and associated reference sediments, where it was largely unaffected by CH4 , suggesting catabolically different diazotrophs at these sites. PMID- 29968368 TI - Carrier frequencies of hearing loss variants in newborns of China: A meta analysis. AB - OBJECTIVE: The objective of this study was to review the carrier frequencies of hearing loss gene variants, such as GJB2, SLC26A4, and MT-RNR1 in newborns of China. DESIGN: PubMed, Embase, BioCentral, CNKI, WanFang, and VIP databases were used for searching relevant literature studies published during the period of January 2007 and January 2016. Meta-analysis was performed by using the R software. The estimated rate and its 95% confidence intervals (CI) of the relevant indexes in newborns were collected and calculated using a fixed-effects model or a random-effects model when appropriate. RESULTS: In total, 35 of 958 published literature studies in Chinese and English were selected. The overall results showed that in newborns of China, the carrier frequencies of GJB2 variants (235 delC, 299 delAT) were 1.64% (95% CI 1.52% to 1.77%) and 0.33% (95% CI 0.19% to 0.51%); SLC26A4 variants (IVS7-2 A > G, 2168 A > G) were 1.02% (95% CI 0.91% to 1.15%) and 0.14% (95% CI 0.06% to 0.25%); MT-RNR1 variants (1555 A > G, 1449 C > T) were 0.20% (95% CI 0.17% to 0.23%) and 0.03% (95% CI 0.02% to 0.05%). CONCLUSIONS: There are high carrier frequencies of GJB2 variants among newborns in China, followed by SLC26A4 and MT-RNR1 variants. In order to achieve "early detection, early diagnosis and early treatment" and reduce the incidence of hereditary hearing loss in offspring, a comprehensive combination of neonatal hearing screening and deafness gene detection should be recommended and implemented in China. PMID- 29968369 TI - Reoperation for left atrioventricular valve failure in repaired atrioventricular septal defect: Can more valves be preserved in the current era? AB - OBJECTIVE: Left atrio-ventricular valve (LAVV) regurgitation after repair of an atrio-ventricular septal defect (AVSD) may necessitate further surgery. However, redo-LAVV repair remains challenging. We sought to determine if more LAVV valves are preserved in the current era, and analyze early and longer-term results. PATIENTS: All consecutive patients with repaired AVSD who underwent redo-LAVV surgery from January 2004 to April 2017 were included. Patients with single ventricles, atrial isomerism, and complex associated anomalies were excluded. METHODS: This was a single-center study using retrospective chart review and an institutional database for follow-up information. Data analyzed included number and year of primary AVSD and redo-LAVV operation, presence of trisomy 21, morphology of AVSD, mortality, and reoperation. Univariate analysis included repair and replacement rates and early and long-term survival. RESULTS: During the study period 36 redo-LAVV operations were performed, with repair in 28 and replacement in eight. The number of redo-operations increased from 13 in the first part to 23 in the second part of the study. The rate of LAVV preservation significantly increased over time (54% vs 91%, P < 0.01), and was not affected by morphology of AVSD or trisomy 21. There was one in-hospital death at Day 42 and overall estimated survival was 94.5% at 5 years. Freedom from reoperation after redo-LAVV repair was 87% at 5 years with no significant difference between repair and replacement groups. CONCLUSION: In the current era, more LAVVs can be preserved at the time of redo-operation with excellent early and long-term survival and acceptable reoperation rates. LAVV morphology and presence of trisomy 21 did not affect outcome. PMID- 29968370 TI - Development of brain functional connectivity and its relation to infant sustained attention in the first year of life. AB - The study of brain functional connectivity is crucial to understanding the neural mechanisms underlying the improved behavioral performance and amplified ERP responses observed during infant sustained attention. Previous investigations on the development of functional brain connectivity during infancy are primarily confined to the use of functional and structural MRI techniques. The current study examined the relation between infant sustained attention and brain functional connectivity and their development during infancy with high-density EEG recordings. Fifty-nine infants were tested at 6 (N = 15), 8 (N =14), 10 (N = 17), and 12 (N = 13) months. Infant sustained attention was defined by measuring infant heart rate changes during infants' looking. Functional connectivity was estimated from the electrodes on the scalp and with reconstructed cortical source activities in brain regions. It was found that infant sustained attention was accompanied by attenuated functional connectivity in the dorsal attention and default mode networks in the alpha band. Graph theory analyses showed that there was an increase in path length and a decrease in clustering coefficient during infant sustained attention. The functional connectivity within the visual, somatosensory, dorsal attention, and ventral attention networks and graph theory measures of path length and clustering coefficient were found to increase with age. These findings suggest that infant sustained attention is accompanied by distinct patterns of brain functional connectivity. The current findings also suggest the rapid development of functional connectivity in brain networks during infancy. PMID- 29968371 TI - Long-term improvements after mindfulness-based group therapy of depression, anxiety and stress and adjustment disorders: A randomized controlled trial. AB - BACKGROUND: Although mindfulness-based group therapies (MGTs) for depressive, anxiety or stress and adjustment disorders are promising, there is a substantial lack of knowledge regarding the long-term improvements after such therapies in these common psychiatric disorders. METHODS: Two hundred and fifteen patients were randomized in a randomized clinical trial (RCT) (ClinicalTrials.gov ID: NCT01476371) conducted in 2012 at 16 primary healthcare centres in southern Sweden. The patients were randomized to MGT or treatment as usual (TAU) and completed four psychometric self-rated scales after 8 weeks of treatment. Approximately 12 months after the completion of the 8-week treatment, the same scales were repeated. Ordinal and generalized linear-mixed models, adjusted for cluster effects, were used for the analysis. RESULTS: For all four psychometric scales (MADRS-S [Montgomery-Asberg Depression Rating Scale-S], HADS-D, HADS-A [Hospital Anxiety and Depression Scale A and D] and PHQ-9 [Patient Health Questionnaire-9]) the scores at the 1-year follow-up were significantly improved (all P values <0.001) in both groups. Furthermore, there were no significant differences between the MGT and TAU in the psychometric scores at the 1-year follow-up. CONCLUSIONS: To the best of our knowledge, this is the first RCT comparing the long-term improvements after MGT with TAU. Although it cannot be excluded that our findings are a result of the natural course of common psychiatric disorders or other factors, they suggest a long-term positive improvement after both MGT and TAU. PMID- 29968372 TI - Health risk and health seeking behaviours among people who inject performance and image enhancing drugs who access needle syringe programs in Australia. AB - INTRODUCTION AND AIMS: People who use performance and image enhancing drugs (PIED) are a growing population in needle syringe programs (NSP) in Australia. Previous international research has identified heterogeneity among the PIED-using population. This study investigated health behaviours among NSP attendees who had recently (last 12 months) injected PIEDs and examined differences among this group according to recent psychoactive drug use. DESIGN AND METHODS: The Australian Needle and Syringe Program Survey is an annually repeated cross sectional survey conducted at approximately 50 NSPs nationally. In 2015, respondents provided information on their demographic characteristics, health risk and health monitoring behaviours, and provided a capillary dried blood spot for HIV and hepatitis C virus antibody testing. Univariable and multivariable logistic regressions assessed factors associated with recent (last 12 months) use (all routes of administration) of psychoactive drugs. RESULTS: Among recent PIED injectors (n = 156), 59% had recently used psychoactive substances. Those who had recently used psychoactive drugs were significantly younger, less educated and more likely to have experienced redness at an injection site in the previous 12 months but were more likely to report recent HIV/hepatitis C virus testing. DISCUSSION AND CONCLUSIONS: This study identified significant differences in demographic characteristics, risk and health seeking behaviour among PIED users who did and did not also use psychoactive substances. There is a need to enhance and tailor harm reduction efforts and to build the capacity of NSP staff to better meet the needs of this diverse group. PMID- 29968374 TI - Abstracts for the British Association of Dermatologists 98th Annual Meeting, Edinburgh, U.K., 3-5 July 2018. PMID- 29968373 TI - Nasal surgery handled by CFD tools. AB - Annually, hundreds of thousands of surgical interventions to correct nasal airway obstruction are performed throughout the world. Recent studies have noted that a significant number of patients have persistent symptoms of nasal obstruction postoperatively. In the present work, we introduce a new methodology that raises the success rate of nasal cavity surgery. In this procedure, the surgeon performs virtual surgery on a 3D nasal model of a patient prior to the real surgery. The main goal of the methodology is to guide the surgeon throughout the virtual operation using mathematical estimators based on CFD results. The virtual surgery intervention ends as soon as the estimators fall into a region of a Cartesian coordinate system with a high success probability. This region is defined according to a statistical analysis of estimators corresponding to sets of healthy and diseased cavities. As examples of this application, this study includes 2 surgical operations performed with this innovative methodology on patients with severe nasal obstruction. The patients underwent nasal surgery according to the final nasal geometry revealed by CFD-guided virtual surgery. Currently, both subjects show high degrees of satisfaction. PMID- 29968375 TI - Placentas on treadmills? Exercise may be more beneficial when started before pregnancy. PMID- 29968376 TI - In their shoes: An ontological perspective on empathy in nursing practice. AB - AIMS AND OBJECTIVES: To present an enquiry into empathy as part of nursing ontology. The work aims to improve understanding of how empathy is developed and used in practice. BACKGROUND: Empathy is the ability to grasp the frame of reference of another. As such, empathy is a key feature of nursing practice involving self-awareness and the use of emotion in interpersonal understanding. METHOD: As part of a larger study into the commonality of emotion in nursing, thirty-three nurses across a range of settings talked exhaustively about their experiences with empathy in the context of their relationships with service users. The interviews were audio-taped and transcribed verbatim. The transcripts were analysed using Grounded Theory Method. RESULTS: Empathy was experienced as a libidinal entity motivating care dependent on a number of allied skills which formed a process: listening and echoing, knowing another's circumstances, imagining and representing the imagined perception within the self. Empathy was viewed as a tool for person-centred care with two distinct levels: phenomena related and biography related. Sensitivity to care context in the use of nurses' life experience also enabled empathy in an emotional kinship. Person-centred care and empowerment were inhibited where empathy could not be achieved. DISCUSSION: The findings confirm the place of empathy in the hierarchy of embodied nursing skills and add to the current bank of knowledge on the sharing of emotions and the value of emotion to professional judgement. CONCLUSION: Empathy is a tool with which to ascertain the cognitive and emotional perspective of others. Empathy's libidinal properties mean that shared understanding enhances care. Emotional kinship means that life experience can be harnessed for empathy in practice. RELEVANCE TO CLINICAL PRACTICE: Insight into the ontology of empathy provides a basis for the construction of teaching tools and learning objects for character and skill development in practice. PMID- 29968378 TI - Using Ultrafast Responsive Phosphorescent Nanoprobe to Visualize Elevated Peroxynitrite In Vitro and In Vivo via Ratiometric and Time-Resolved Photoluminescence Imaging. AB - Peroxynitrite (ONOO- ), a potent biological oxidant, which has a short half-life in physiological conditions, is related to many diseases. Accurate peroxynitrite determination with superior selectivity and sensitivity is important for understanding biological roles of peroxynitrite in different health and disease tissues. Autofluorescence is an inevitable interference in luminescence biodetection and bioimaging, which often reduces signal-to-noise ratio during detection. In this work, a phosphorescent peroxynitrite nanoprobe (MSN-ONOO) which displays two emission bands is prepared by immobilizing two long-lived phosphorescent iridium(III) complexes that are peroxynitrite-activable and inert, respectively, into water-dispersible mesoporous silica nanoparticles. Owing to the fast response rate, excellent sensitivity and outstanding selectivity of the nanoprobe toward peroxynitrite, it is further used for peroxynitrite determination in vitro and in vivo via ratiometric photoluminescence imaging. More notably, taking advantage of the long-lived phosphorescence of MSN-ONOO, in vivo elevated peroxynitrite is imaged with diminished autofluorescence interference and improved signal-to-noise ratio via time-resolved photoluminescence imaging. As far as it is known, this is the first time for endogenous peroxynitrite detection in vivo via the time-resolved photoluminescence imaging. Furthermore, the production of peroxynitrite in inflamed tissues is visualized. PMID- 29968377 TI - Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells. AB - BACKGROUND AND PURPOSE: Transmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca2+ -activated Cl- channel, is involved in vascular smooth muscle cell (VSMC) proliferation and hypertension-induced cerebrovascular remodelling. However, the functional significance of TMEM16A for apoptosis in basilar artery smooth muscle cells (BASMCs) remains elusive. Here, we investigated whether and how TMEM16A contributes to apoptosis in BASMCs. EXPERIMENTAL APPROACH: Cell viability assay, flow cytometry, Western blot, mitochondrial membrane potential assay, immunogold labelling and co immunoprecipitation (co-IP) were performed. KEY RESULTS: Hydrogen peroxide (H2 O2 ) induced BASMC apoptosis through a mitochondria-dependent pathway, including by increasing the apoptosis rate, down-regulating the ratio of Bcl-2/Bax and potentiating the loss of the mitochondrial membrane potential and release of cytochrome c from the mitochondria to the cytoplasm. These effects were all reversed by the silencing of TMEM16A and were further potentiated by the overexpression of TMEM16A. Endogenous TMEM16A was detected in the mitochondrial fraction. Co-IP revealed an interaction between TMEM16A and cyclophilin D, a component of the mitochondrial permeability transition pore (mPTP). This interaction was up-regulated by H2 O2 but restricted by cyclosporin A, an inhibitor of cyclophilin D. TMEM16A increased mPTP opening, resulting in the activation of caspase-9 and caspase-3. The results obtained with cultured BASMCs from TMEM16A smooth muscle-specific knock-in mice were consistent with those from rat BASMCs. CONCLUSIONS AND IMPLICATIONS: These results suggest that TMEM16A participates in H2 O2 -induced apoptosis via modulation of mitochondrial membrane permeability in VSMCs. This study establishes TMEM16A as a target for therapy of several remodelling-related diseases. PMID- 29968379 TI - Hepatitis B surface antigen positivity during pregnancy and risk of gestational diabetes mellitus: A systematic review and meta-analysis. AB - Chronic hepatitis B virus (HBV) infection is a prevalent public health issue worldwide. Its impact on important pregnancy outcomes, such as gestational diabetes mellitus (GDM), has not been clearly established. The findings from published studies are inconsistent. In this systematic review and meta-analysis, we aimed to clarify whether HBV infection manifested during pregnancy is associated with an increased risk of GDM. We searched MEDLINE and EMBASE for cohort studies and case-control studies that investigated the association between maternal hepatitis B surface antigen (HBsAg) positivity and GDM. We pooled adjusted odds ratio (aOR) and unadjusted OR, respectively, using the random effect generic inverse variance method. We assessed risk of bias using the Quality in Prognosis Studies tool and conducted five pre-specified subgroup analyses. In total, 23 cohort studies involving 3 529 223 participants were included. The risk of GDM was 6.48% (1868/28 829) among HBsAg-positive pregnant women and 3.41% (119 283/3 500 394) among HBsAg-negative pregnant women. Meta analyses of both unadjusted and adjusted effect estimates showed that HBsAg positivity during pregnancy was associated with higher risk of developing GDM (unadjusted OR 1.35, 95% CI: 1.17 to 1.56, I2 = 82.6%; adjusted OR 1.47, 1.22 to 1.76, I2 = 62%). Among pre-specified subgroup analysis, significant differences were found among studies with high vs low or moderate risk of bias. The results were robust to sensitivity analyses. In conclusion, HBsAg positivity during pregnancy has a moderate effect on an increased risk of GDM. Given the size of the population with HBV infection worldwide, however, this effect could have substantial impact on pregnancy. Further studies are warranted to investigate whether active infection with HBeAg positivity would further elevate the risk of adverse events during pregnancy. PMID- 29968380 TI - Icariin improves SHR erectile function via inhibiting eNOS uncoupling. AB - The aim of the study was to investigate whether or not the effect of icariin on erectile function of SHR is associated with inhibition of eNOS uncoupling. Ten 12 week-old male WKY rats and 10 age-matched male SHR were evenly randomised into SHR control group, SHR+ icariin treatment group, WKY control group and WKY+ icariin group. After being treated for 4 weeks, ICPmax/MAP, the expression of NT, monomer and dimer of eNOS and the level of BH4, BH2, DHFR, NADPH oxidase and GTPCH1 in the corpus cavernosum were determined. The ICPmax/MAP and the value of BH4, DHFR and GTPCH1 in the SHR icariin treatment group were significantly higher than that of the SHR group and less than that of the WYK group and icariin treated WKY group (p < 0.05). The value of BH2, NADPH oxidase, the ratio of eNOS monomers/dimmers and NT in the SHR icariin treatment group was significantly less than that of in the SHR group and higher than that of the WYK control group and icariin-treated WKY group (p < 0.05). Hypertension increases eNOS uncoupling in the corpus cavernosum of SHR. Inhibiting uncoupling of eNOS may be an important mechanism of icariin to improve SHR erectile function. PMID- 29968381 TI - Metabolomic and lipidomic analysis of the effect of pioglitazone on hepatic steatosis in a rat model of obese Type 2 diabetes. AB - BACKGROUND AND PURPOSE: Thiazolidinediones, acting as PPAR-gamma ligands, reduce hepatic steatosis in humans and animals. However, the underlying mechanism of this action remains unclear. The purpose of this study was to investigate changes in hepatic metabolites and lipids in response to treatment with the thiazolidinedione pioglitazone in an animal model of obese Type 2 diabetes. EXPERIMENTAL APPROACH: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were orally administered either vehicle (control) or pioglitazone (30 mg.kg-1 ) and fed a high-fat diet (60% kcal fat) for 12 weeks. Hepatic metabolites were analysed via metabolomic and lipidomic analyses. Gene expression and PLA2 activity were analysed in livers from pioglitazone-treated and control rats. KEY RESULTS: OLETF rats that received pioglitazone showed decreased fat accumulation and improvement of lipid profiles in the liver compared to control rats. Pioglitazone treatment significantly altered levels of hepatic metabolites, including free fatty acids, lysophosphatidylcholines and phosphatidylcholines, in the liver. In addition, pioglitazone significantly reduced the expression of genes involved in hepatic de novo lipogenesis and fatty acid uptake and transport, whereas genes related to fatty acid oxidation were up-regulated. Gene expression and enzyme activity of PLA2 , which hydrolyzes phosphatidylcholines to release lysophosphatidylcholines and free fatty acids, were significantly decreased in the livers of pioglitazone-treated rats compared to control rats. CONCLUSIONS AND IMPLICATIONS: Our results present evidence for the ameliorative effect of pioglitazone on hepatic steatosis, largely due to the regulation of lipid metabolism, including fatty acids, lysophosphatidylcholines, phosphatidylcholines and related gene-expression patterns. PMID- 29968382 TI - Light-Triggered Genome Editing: Cre Recombinase Mediated Gene Editing with Near Infrared Light. AB - A light-activated genome editing platform based on the release of enzymes from a plasmonic nanoparticle carrier when exposed to biocompatible near-infrared light pulses is described. The platform relies on the robust affinity of polyhistidine tags to nitrilotriacetic acid in the presence of copper which is attached to double-stranded nucleic acids self-assembled on the gold nanoparticle surface. A protein fusion of the Cre recombinase containing a TAT internalization peptide sequence to achieve endosomal localization is also employed. High-resolution gene knock-in of a red fluorescent reporter is observed using a commercial two-photon microscope. High-throughput irradiation is described to generate useful quantities of edited cells. PMID- 29968383 TI - High phylogenetic diversity and abundance pattern of Labyrinthulomycete protists in the coastal waters of the Bohai Sea. AB - The unicellular Labyrinthulomycete protists have long been considered to play a significant role in ocean carbon cycling. However, their distribution and biogeochemical function remain poorly understood. We present a large-scale study of their spatiotemporal abundance and diversity in the coastal waters of Bohai Sea using flow cytometry and high-throughput sequencing. These protists display niche preferences and episodic higher biomass than that of bacterioplankton with much phylogenetic diversity (> 4000 OTUs) ever reported. They were ubiquitous with a typical abundance range of 100-1000 cells ml-1 and biomass range of 0.06 574.59 MUg C L-1 . The observed spatiotemporal abundance variations support the current 'left-over scavengers' nutritional model and highlight these protists as a significant component of the marine microbial loop. The higher average abundance and phylogenetic diversity in the nearshore compared with those in the offshore reveal their predominant role in the terrigenous matter decomposition. Furthermore, the differential relationship of the protist genera to environmental conditions together with their co-occurrence network suggests their unique substrate preferences and niche partitioning. With few subnetworks and possible keystone species, their network topology indicates community resilience and high connectance level of few operational taxonomic units (OTUs). We demonstrate the significant contribution of these protists to the secondary production and nutrient cycling in the coastal waters. As secondary producers, their role will become more important with increasingly coastal eutrophication. PMID- 29968385 TI - Efficacy and safety of fixed-dose combination of drotaverine hydrochloride (80 mg) and paracetamol (500 mg) in amelioration of abdominal pain in acute infectious gastroenteritis: A randomized controlled trial. AB - BACKGROUND AND AIM: This randomized controlled trial was undertaken to assess efficacy and safety of fixed-dose combination of drotaverine hydrochloride (80 mg) and paracetamol (PCM) (500 mg). This was performed by comparison of mean pain intensity difference, total pain relief at 2 h, onset of pain relief, decrease in number of pain episodes, global improvement, and adverse effects. METHODS: A randomized double-blind controlled trial for adults between 18 and 59 years of either gender with acute infectious diarrhea (>= 3 unformed, watery, or soft stools with symptoms at least within the last 24 h preceding randomization with duration of illness not more than 72 h) with moderate-to-severe abdominal pain. Participants were treated with either a fixed-dose combination of oral drotaverine hydrochloride (80 mg) and PCM (500 mg) or oral PCM (500 mg) three times a day for 3 days. RESULTS: Of 252 (126 in each group) participants, all received at least one dose of medication. Two hundred forty-two completed the study. Mean pain intensity difference at 60 min after administration of study medication by Visual Analogue Scale (VAS) and total pain relief at 2 h using both VAS and Verbal Rating Scale showed statistically significant improvement in drotaverine hydrochloride (80 mg) and PCM (500 mg) group. The onset of pain relief was also significantly better in drotaverine hydrochloride (80 mg) and PCM (500 mg) group when using VAS. CONCLUSION: Fixed-dose combination of drotaverine hydrochloride (80 mg) and PCM (500 mg) is an effective and safe antispasmodic agent in abdominal pain associated with acute infectious gastroenteritis. PMID- 29968384 TI - Cadherins: cellular adhesive molecules serving as signalling mediators. AB - The single pass, transmembrane proteins of the cadherin family have been appreciated as important proteins that regulate intercellular adhesion. In addition to this critical function, cadherins contribute to important signalling events that control cellular homeostasis. Many examples exist of classical, desmosomal and atypical cadherins participating in the regulation of signalling events that control homeostatic functions in cells. Much of the work on cadherin mediated signalling focuses on classical cadherins or on specific disease states such as pemphigus vulgaris. Cadherin mediated signalling has been shown to play critical roles during development, in proliferation, apoptosis, disease pathobiology and beyond. It is becoming increasingly clear that cadherins operate through a range of molecular mechanisms. The diversity of pathways and cellular functions regulated by cadherins suggests that we have only scratched the surface in terms of the roles that these versatile proteins play in signalling and cellular function. PMID- 29968386 TI - Clinical issues in cannabis use. AB - Cannabis is the most commonly used illicit substance worldwide and the prevalence of users continues to increase. Over the last 2 decades, the world has seen significant changes regarding cannabis for recreational use as well as application in its use as a therapeutic medicine. This is likely to have influenced the decreasing perception of risks associated with the use of cannabis. Cannabis, however, is not benign and, depending on the pattern of its use, can incur a range of harmful effects, which have implications when prescribing medicinal cannabinoids for individuals. Based on research evidence from recreational use of cannabis as well as the emerging data from trials of medicinal cannabis, we propose some clinical domains that will need specific considerations when prescribing medicinal cannabis. PMID- 29968387 TI - Photobiomodulation therapy promotes in vitro wound healing in nicastrin KO HaCaT cells. AB - Mutations in NCSTN gene (encoding for nicastrin protein) are associated with hidradenitis suppurativa (HS), a chronic inflammatory disease involving hair follicles. HS is clinically handled with drugs but the most severe cases are treated with surgery. Photobiomodulation (PBM) therapy, already used in the treatment of skin diseases such as acne, herpes virus lesions, ultraviolet damage, vitiligo, hypertrophic scar, keloid, burn, psoriasis and diabetic chronic wounds, could be beneficial as an adjuvant supportive treatment to promote and foster the healing process after skin excision in HS. The effects of PBM therapy in promoting the wound closure are evaluated in a HaCaT cells NCSTN-/-, assessing cell metabolism, migration rate, proliferation and cell cycle progression. In our experimental model, PBM exerts a potent action on metabolism of mutated keratinocytes, incrementing adenosine triphosphate (ATP) production at 2 hours, while after 24 hours an increase of metabolism with a decrement of intracellular ATP levels were recorded. Moreover, PBM speeds up the wound closure, inducing cells' migration without affecting their proliferation.Based on our findings, we suggest the use of PBM in HS patients, who undergo major surgery with large skin excision. PMID- 29968388 TI - CALD Assist-Nursing: Improving communication in the absence of interpreters. AB - AIMS AND OBJECTIVES: To develop a communication app to support nursing staff during the provision of standard care of patients from non-English-speaking backgrounds (NESBs), when an interpreter is not available. This paper reports on the user needs analysis phase that informed the development, content and functionality of the app. BACKGROUND: In 2014 we developed CALD Assist, a communication app to support patient interactions with allied health clinicians when interpreters are not present. It includes 95 commonly used phrases professionally interpreted into 10 languages and grouped by discipline. This work expands upon our previous app to meet the needs of the nursing workforce. DESIGN: Qualitative through focus groups, observations and interviews, with a quantitative component from observational data and staff surveys. METHODS: Four focus groups with hospital staff, ten interviews with patients from NESBs and 85 observation sessions of everyday patient-staff interactions followed by staff surveys (n = 85) were held between January and June 2017. RESULTS: Baseline data prior to app development revealed that staff confidence of the patients' level of understanding and the success of the interaction were significantly greater for English-speaking (ES) patients, than for non-English-speaking patients. A total of 143 phrases were identified and subdivided into 16 categories for inclusion in the new app. CONCLUSION: Staff participants highlighted that patients from NESBs are a challenging patient group to interact with. Patient and staff participants identified a range of areas where the nursing app could benefit, including pain management, mobility, hygiene and nutrition. RELEVANCE TO CLINICAL PRACTICE: The proposed app can be used to reduce variances in practice and provide a timely and positive patient experience for patients from NESBs who are unable to communicate in English during hospital admissions. PMID- 29968389 TI - Comparison of the neurocognitive profiles of individuals with elevated psychotic or depressive symptoms. AB - AIM: Neurocognitive deficits are pervasive and enduring features of severe mental illness that appear before the onset of clinical symptoms and contribute to functional disability. However, it remains unclear how individuals who display warning signs for psychotic or mood disorders compare on their neurocognitive profiles since previous studies have separately examined neurocognition in both groups. Therefore, the purpose of this study was to directly compare performance on a range of neurocognitive tasks in individuals with emerging psychotic or mood symptoms. METHODS: Participants were drawn from a database of individuals who completed a comprehensive assessment at a university-based assessment centre. We examined 3 groups: individuals who endorsed elevated psychotic symptoms (EPS; n = 64), individuals who endorsed elevated depressive symptoms (EDS; n = 58), or non clinical comparisons (NCC; n = 57) without any elevated psychiatric symptoms or diagnoses. RESULTS: EPS participants performed worse than NCC and EDS groups on verbal comprehension, working memory and cognitive flexibility, and worse than NCC, but not EDS, on perceptual reasoning. There were no significant differences between groups on processing speed, verbal fluency and set-shifting. EDS performed worse than both EPS and NCC groups on psychomotor speed. Dimensionally, poorer cognitive functioning was more strongly related to EPS than depressive symptoms. CONCLUSIONS: These findings highlight the distinct yet overlapping neurocognitive profiles of both groups with emerging psychiatric symptoms, and suggest that, despite having no formal diagnosis, individuals with EPS exhibit observable cognitive impairment and may still benefit from interventions within academic and workplace contexts. PMID- 29968390 TI - TFE3 translocation and protein expression in renal cell carcinoma are correlated with poor prognosis. AB - AIMS: Since Xp11.2 translocation-associated renal cell carcinoma (TRCC) was first recognised, its morphological features and the clinical significance of TFE3 expression, frequency of gene translocation and diagnostic criteria have been the subject of limited studies. The present retrospective analysis aimed to evaluate the correlation between TFE3 immunoreactivity and its gene translocation status using fluorescence in-situ hybridisation (FISH) and determine how TFE3 translocation and expression affect patient prognosis differently. METHODS AND RESULTS: We enrolled 303 consecutive renal cell carcinoma cases. Immunohistochemical staining for TFE3 was performed in 303 cases, and FISH analysis was performed for molecular testing. The TCGA data set of renal cell carcinoma was evaluated to validate TFE3 expression and survival analysis. TFE3 expression was associated significantly with the nested alveolar pattern, papillary pattern, eosinophilic cytoplasm, voluminous expansile cytoplasm, nuclear grade, tumour necrosis, sarcomatoid pattern and picket fence appearance. FISH analysis showed break-apart signals in 26 of 32 (81.25%) cases expressing strong or moderate nuclear TFE3 immunoreactivity. Thirteen of 56 samples that showed no or weak TFE3 expression with morphologically suspicious cases were translocation-positive in the FISH assay. The TFE3-translocation group (harbouring TFE3 translocation regardless of TFE3 expression) showed the poorest progression-free survival (PFS), and the TFE3-expressing group (expressing TFE3 but negative for translocation) was correlated significantly with decreased PFS. CONCLUSION: Increased TFE3 expression in RCC was associated with poor PFS regardless of the gene translocation status. Moreover, morphological analysis should help to select candidates who would benefit from TFE3 staining and FISH analysis. PMID- 29968391 TI - Potentially toxic pyrrolizidine alkaloids in Eupatorium perfoliatum and three related species. Implications for herbal use as boneset. AB - INTRODUCTION: Pro-toxic dehydropyrrolizidine alkaloids are associated with liver disease in humans. The potential for long-term, low-level or intermittent exposures to cause or contribute to chronically-developing diseases is of international concern. Eupatorium perfoliatum is a medicinal herb referred to as boneset. While the presence of dehydropyrrolizidine alkaloids in some Eupatorium species is well-established, reports on Eupatorium perfoliatum are scant and contradictory. OBJECTIVE: To investigate the presence of dehydropyrrolizidine alkaloids in a survey of boneset samples and related alcoholic tinctures, and hot water infusions and decoctions. METHODS: Methanol, hot water or aqueous ethanol extracts of Eupatorium perfoliatum and three closely-related species were subjected to HPLC-ESI(+)MS and MS/MS analysis using three complementary column methods. Dehydropyrrolizidine alkaloids were identified from their MS data and comparison with standards. RESULTS: Forty-nine samples of Eupatorium perfoliatum were shown to contain dehydropyrrolizidine alkaloids (0.0002-0.07% w/w), the majority dominated by lycopsamine and intermedine, their N-oxides and acetylated derivatives. Alcoholic tinctures and hot water infusions and decoctions had high concentrations of the alkaloids. Different chemotypes, hybridisation or contamination of some Eupatorium perfoliatum samples with related species were suggested by the co-presence of retronecine- and heliotridine-based alkaloids. CONCLUSIONS: Sampling issues, low and high alkaloid chemotypes of Eupatorium perfoliatum or interspecies hybridization could cause the wide variation in dehydropyrrolizidine alkaloid concentrations or the different profiles observed. Concerns associated with dehydropyrrolizidine alkaloids provide a compelling reason for preclusive caution until further research can better define the toxicity and carcinogenicity of the dehydropyrrolizidine alkaloid content of Eupatorium perfoliatum. [Correction added on 12 July 2018, after first online publication: The 'Conclusions' section in the abstract has been added.]. PMID- 29968392 TI - Hepatic DNA damage in harbour porpoises (Phocoena phocoena) stranded along the English and Welsh coastlines. AB - One level at which persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons PAHs) can exert damage is by causing DNA strand-breaks or nucleotide base modifications, which, if unrepaired, can lead to embryonic mutations, abnormal development and cancer. In marine ecosystems, genotoxicity is expected to be particularly strong in long-lived apex predators due to pollutant bioaccumulation. We conducted 32 P-postlabeling analyses optimized for the detection and quantification of aromatic/hydrophobic DNA adducts in the livers of 40 sexually-mature North Atlantic harbour porpoises (Phocoena phocoena) stranded along the English and Welsh coastlines. We examined hepatic tissue to search for inflammatory and preneoplastic lesions and examine their association with adduct levels. Adducts were found in all porpoises (mean: 17.56 +/- 11.95 per 108 nucleotides), and were higher than levels reported for marine vertebrates from polluted sites. The pollutants causing the induced DNA adducts could not be further characterized. Hepatic DNA damage did not correlate with levels of blubber POP concentrations (including total polychlorinated biphenyl [PCBs], dichlorodiphenyltrichloroethane [DDT] and dieldrin); PAH concentrations were not available for the present study. However, DNA damage predicted occurrence of inflammatory and preneoplastic lesions. Further, our data showed a reduction in hepatic DNA adduct levels with age in the 40 animals examined while POP concentrations, particularly PCBs, increased with age. Using a different dataset of 145 mature male harbour porpoises confirmed that higher contaminant levels (total PCBs, DDT and dieldrin) are found in older animals. The reduction in hepatic DNA adduct levels in older animals was in accordance with other studies which show that suppression of hepatic CYP1A enzyme activity at high PCB concentrations might impact on CYP1A-mediated DNA adduct formation of PAHs which are ubiquitous environmental pollutants and readily metabolized by CYP1A to species binding to DNA. In summary, our study shows that pollutant-induced DNA damage is prevalent in harbour porpoises from UK waters and may lead to detectable sub-lethal hepatic damage. Environ. Mol. Mutagen. 59:613-624, 2018. (c) 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 29968394 TI - Delamination and Photochemical Modification of a Novel Two-Dimensional Zr-Based Metal-Organic Frameworks. AB - In this contribution we present a novel two-dimensional Zr-based metal-organic framework (MOF) which offers the possibility for delamination and post-synthetic photochemical modification at the linker molecule derived from benzophenone-4,4' dicarboxylic acid (H2 bzpdc). The new Zr-bzpdc-MOF crystallizes in the orthorhombic system as crystals with rhombic shape. The structure was determined from single-crystal diffraction data. The MOF is stable up to 300 degrees C in air and exhibits a moderate BET surface area of 650 m2 g-1 . The material can be obtained as thin sheets of a few nanometer thickness. Single crystals were modified post-synthetically, exploiting the intrinsic reactivity of the benzophenone group with C-H bond containing molecules. In this way, the surface properties of the MOF crystals (e.g., dispersibility in different solvents) can be changed drastically. Delamination and adaptation of the surface chemistry open up novel ways for shaping MOFs, for example, for the incorporation into polymer composites, and pave the way for various applications. PMID- 29968393 TI - Regulation of antitumor miR-144-5p targets oncogenes: Direct regulation of syndecan-3 and its clinical significance. AB - In the human genome, miR-451a, miR-144-5p (passenger strand), and miR-144-3p (guide strand) reside in clustered microRNA (miRNA) sequences located within the 17q11.2 region. Low expression of these miRNAs is significantly associated with poor prognosis of patients with renal cell carcinoma (RCC) (miR-451a: P = .00305; miR-144-5p: P = .00128; miR-144-3p: P = 9.45 * 10-5 ). We previously reported that miR-451a acted as an antitumor miRNA in RCC cells. Involvement of the passenger strand of the miR-144 duplex in the pathogenesis of RCC is not well understood. Functional assays showed that miR-144-5p and miR-144-3p significantly reduced cancer cell migration and invasive abilities, suggesting these miRNAs acted as antitumor miRNAs in RCC cells. Analyses of miR-144-5p targets identified a total of 65 putative oncogenic targets in RCC cells. Among them, high expression levels of 9 genes (FAM64A, F2, TRIP13, ANKRD36, CENPF, NCAPG, CLEC2D, SDC3, and SEMA4B) were significantly associated with poor prognosis (P < .001). Among these targets, expression of SDC3 was directly controlled by miR-144-5p, and its expression enhanced cancer cell aggressiveness. We identified genes downstream by SDC3 regulation. Data showed that expression of 10 of the downstream genes (IL18RAP, SDC3, SH2D1A, GZMH, KIF21B, TMC8, GAB3, HLA-DPB2, PLEK, and C1QB) significantly predicted poor prognosis of the patients (P = .0064). These data indicated that the antitumor miR-144-5p/oncogenic SDC3 axis was deeply involved in RCC pathogenesis. Clustered miRNAs (miR-451a, miR-144-5p, and miR-144-3p) acted as antitumor miRNAs, and their targets were intimately involved in RCC pathogenesis. PMID- 29968395 TI - Loss of DNA polymerase beta induces cellular senescence. AB - We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymerasebeta. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-beta-gal staining (fourfold increase, P < 0.001), increased p16 transcript abundance (threefold increase, P < 0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, P < 0.01). We also find that DNA polymerase beta expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, P < 0.01). To evaluate whether DNA polymerase beta might be causative in senescence induction, we evaluated the impact of murine DNA polymerase beta nullizygosity on senescence. We find that unexposed DNA polymerase beta -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, P < 0.001), demonstrating that loss DNA polymerase beta is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (threefold greater than WT-HU, P < 0.05). These data demonstrate that loss of DNA polymerase beta is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase beta null MEFs (fivefold increase from wild-type, P < 0.0001). Our findings strongly suggest that DNA polymerase beta is causative in senescence induction, reasonably pointing to DNA polymerase beta as a likely factor driving the premature senescence in Down syndrome. Environ. Mol. Mutagen. 59:603-612, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29968396 TI - Alterations in the primary teeth of children with microcephaly in Northeast Brazil: a comparative study. AB - BACKGROUND: The outbreak of microcephaly between 2015 and 2017 in Brazil created an international public health emergency. AIM: This study sought to evaluate the chronology, sequence of eruption, and the presence of anomalies amongst children with microcephaly compared with normoreactive children. DESIGN: A comparative study of 108 children aged 0-2 years attending public services was conducted. The microcephaly group (MG; n = 54) and the nonmicrocephaly group (NMG; n = 54) were matched by age, gender, and family income at a 1 : 1 ratio. Erupted teeth and the presence of anomalies were evaluated and compared. Chi-square tests, Pearson's correlations, Fisher's exact tests, and Student's t-tests were applied (alpha = 0.05). RESULTS: No between-group differences were found with regard to gender (P = 0.560) or age (P = 0.529). The MG presented with a higher percentage of alterations in eruption sequence, opacity, self-injury, and delayed eruption compared with the NMG (P < 0.05). The MG was more likely to exhibit changes in tooth eruption sequence (OR = 12.23, 95% CIs = 3.25-46.03, P < 0.001), delayed eruption (OR = 23.12; 95% CIs = 7.09-75.40, P < 0.001), and opacity (n = 12.19, 95% CIs = 1.44-103.28, P = 0.022) than the NMG. CONCLUSION: Children with microcephaly present with greater delays in chronology, alterations in eruption sequence, and enamel defects than normoreactive children. PMID- 29968397 TI - Moderation of baclofen response by a GABAB receptor polymorphism: results from the BacALD randomized controlled trial. AB - BACKGROUND AND AIMS: Baclofen has been shown to reduce alcohol consumption in alcohol-dependent individuals, but there is marked heterogeneity in response. An association between GABBR1 rs29220 and alcohol dependence has been demonstrated previously. The present study evaluated whether the response to baclofen is moderated by a single nucleotide polymorphism (rs29220) in the GABAB receptor subunit 1 gene (GABBR1). DESIGN: Double-blind, placebo-controlled study. SETTING: Australia. PARTICIPANTS: Seventy-two alcohol-dependent men and women receiving 12 weeks of 30 mg/day of baclofen, 75 mg baclofen or placebo. MEASUREMENTS: Primary outcomes included time to lapse (any drinking) and relapse (> 5 drinks per day in men and > 4 in women). We also examined alcohol consumption at follow-up (drinks per drinking day, number of heavy drinking days and percentage days abstinent). FINDINGS: We observed significant medication * genotype interaction effect for time to relapse (P = 0.049) and a near-significant interaction effect for time to lapse (P = 0.055). For the CC genotype group, the relapse hazard ratio for baclofen versus placebo was 0.32 [95% confidence interval (CI) = 0.14-0.75] and for the G- group it was 1.07 (95% CI = 0.43-2.63). There was also a significant medication * genotype interaction for follow-up alcohol consumption (drinks per drinking day, heavy drinking days and days abstinent) (P = 0.02). Covarying for baseline levels of craving, aspartate aminotransferase and abstinence before enrolment reduced the medication * genotype effect for time to lapse and relapse but not for alcohol consumption at follow-up. CONCLUSIONS: The GABBR1 rs29220 polymorphism may influence treatment response and possibly predict adverse effects to baclofen in the treatment of alcohol dependence. PMID- 29968398 TI - Receptive and expressive language characteristics of school-aged children with non-syndromic cleft lip and/or palate. AB - BACKGROUND: Research investigating language skills in school-aged children with non-syndromic cleft lip and/or palate is sparse. Past studies focus on younger populations, lack key comparisons to demographically matched control cohorts or explore language as a component of broader academic skills. Trends of existing studies suggest that affected children may perform at a lower level compared with typically developing peers. AIMS: To examine the receptive and expressive language skills of middle-school-aged children with non-syndromic cleft lip and palate (CLP) and cleft palate only (CP). Additionally, to explore the language skills of children with clefts compared with a non-cleft control group. METHODS & PROCEDURES: Thirty-seven participants with orofacial clefts (aged 7;1-14;1 years) participated in the study: 19 with CLP (10 males; 9 females) and 18 with CP (8 males; 10 females). A non-cleft comparison group consisted of 129 individuals matched on age, sex and maternal education level. Participants completed formal language (Clinical Evaluation of Language Fundamentals, Fourth Edition) and non verbal intellectual measurements (Wechsler Abbreviated Scale of Intelligence WASI). Demographic and developmental information was obtained via parental interview. Further clinical details (e.g., surgery; hearing status) were extracted from patient medical files. Cleft and non-cleft language and non-verbal IQ outcomes were reported separately. Language outcomes were then compared between groups. OUTCOMES & RESULTS: Participants with clefts achieved core (mean = 103.31, standard deviation (SD) = 10.31), receptive (mean = 102.51, SD = 11.60) and expressive (mean = 102.89, SD = 12.17) language index scores within the normative average range. A total of 14.1% and 17.8% of the cleft and non-cleft groups respectively had impairment (i.e., >= 1.25 SD below the mean) in one or more language domains. No significant differences were found in the three language index scores between cleft and non-cleft groups. CONCLUSIONS & IMPLICATIONS: This study is the first formally to examine language skills alongside non-verbal IQ in school-aged children with clefts compared with a large matched non-cleft population. Results suggest that health professionals should evaluate each child as they present and not assume that a child with non syndromic CLP or CP will also have co-occurring language difficulties. Where language falls in the average range, these skills can be harnessed to support areas of difficulty often associated with orofacial clefting, such as speech. PMID- 29968399 TI - Plasma Cystine Levels and Cardiovascular and All-Cause Mortality in Hemodialysis Patients. AB - Oxidative stress accelerates the development of cardiovascular disease. Plasma cystine, a thiol oxidative stress marker, is related to several established factors for cardiovascular disease risk and prognosis. Although a comprehensive oxidative stress index is clinically required for hemodialysis patients with high oxidative stress, there are few reports concerning thiol oxidative stress markers predicting their prognosis. We investigated the relationship between plasma amino acids including cystine levels and cardiovascular disease-related and all-cause mortality in 132 maintenance hemodialysis patients. Higher cystine levels were associated with old age, longer hemodialysis duration, hemodialysis-associated hypotension, higher cardiothoracic ratio, higher blood urea nitrogen, and lower ankle-brachial index. Multivariate Cox regression analysis revealed that high plasma cystine was independently related with both cardiovascular disease mortality and all-cause mortality. Thus, high plasma cystine levels predict the prognosis of hemodialysis patients. High cystine levels necessitate a careful investigation for the cause of oxidative stress and comorbidities like vascular injury. PMID- 29968400 TI - Effectiveness of biologics in Australian patients with rheumatoid arthritis: a large observational study: REAL. AB - BACKGROUND: The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown. AIM: To assess the effectiveness of biological disease-modifying anti-rheumatic drugs (bDMARD) as monotherapy or in combination with methotrexate and/or other conventional DMARD (cDMARD) for the treatment of rheumatoid arthritis (RA). METHODS: A retrospective, non interventional study was conducted that investigated the use of bDMARD in adult patients with RA in routine clinical practice. Data were extracted from the Optimising Patient Outcomes in Australian Rheumatology - Quality Use of Medicines Initiative database. Real-world effectiveness was measured using the 28-joint disease activity score (DAS28) and clinical disease activity index (CDAI) by treatment group at baseline, weeks 12 and 24. RESULTS: A total of 2970 patients was included with a median (min-max) age of 60.0 (19.0-94.0) years and median (min-max) duration of RA before first bDMARD treatment of 6.0 (0.2-58.3) years. A total of 1177 patients received more than one bDMARD during the analysis period of 1 January 1997 to 15 August 2015. Patients had 4922 treatment 'episodes' (defined as a cycle of continuous individual bDMARD prescribing in a single patient). Patients received a mean (SD) of 1.7 (1.0) episodes of treatment with median (min-max) treatment duration of 0.7 (0-11.8) years; median treatment duration was higher with the first treatment episode. bDMARD were most commonly initiated in combination with methotrexate (73.9% of episodes) and least commonly as monotherapy (9.9% of episodes). Median (min-max) baseline DAS28 decreased from 5.3 (0-8.7) with the first bDMARD to 3.7 (0-8.8) with the second. Median baseline CDAI similarly decreased. CONCLUSIONS: Patients tended to persist longer on their first bDMARD treatment. bDMARD as monotherapy or in combination appear to be accepted treatment strategies in the real world. PMID- 29968401 TI - Vitamin C deficiency in Australian hospitalized patients: an observational study. AB - BACKGROUND: Vitamin C has anti-oxidant properties and acts as a co-factor for a number of enzymes. Hypovitaminosis C has been associated with bleeding, endothelial dysfunction and death. The prevalence of hypovitaminosis C is unknown in Australian hospitalized patients and its clinical relevance is uncertain. AIMS: To determine prevalence, characteristics and clinical outcomes of hospitalized patients with hypovitaminosis C. METHODS: This observational study included general-medical inpatients in a tertiary-level hospital in Australia. High performance liquid chromatography (HPLC) was used to determine plasma vitamin C levels. As per Johnston's criteria, vitamin C levels of >=28 MUmol/L were classified as normal and <28 MUmol/L as low. Clinical outcomes determined included length of hospital stay (LOS), nosocomial complications, intensive care unit admission and in-hospital mortality. RESULTS: Two-hundred patients participated in this study and vitamin C levels were available for 149 patients, of which, 35 (23.5%) had normal vitamin C levels and 114 (76.5%) had hypovitaminosis C. Patients with hypovitaminosis C were older and had higher C reactive protein (C-RP) levels. Median LOS was two days longer in patients with hypovitaminosis C (6 days (IQR 4, 8) vs. 4 days (IQR 3, 6), p=0.02) and they had four-fold higher odds of staying in hospital for >5 days than those with normal vitamin C levels. Other clinical outcomes were similar between the two groups CONCLUSIONS: Hypovitaminosis C is common in hospitalized patients and is associated with prolonged LOS. Further research is needed to ascertain the benefits of vitamin C supplementation in vitamin C depleted patients. This article is protected by copyright. All rights reserved. PMID- 29968402 TI - Circulating Tumor Cell Phenotyping via High-Throughput Acoustic Separation. AB - The study of circulating tumor cells (CTCs) offers pathways to develop new diagnostic and prognostic biomarkers that benefit cancer treatments. In order to fully exploit and interpret the information provided by CTCs, the development of a platform is reported that integrates acoustics and microfluidics to isolate rare CTCs from peripheral blood in high throughput while preserving their structural, biological, and functional integrity. Cancer cells are first isolated from leukocytes with a throughput of 7.5 mL h-1 , achieving a recovery rate of at least 86% while maintaining the cells' ability to proliferate. High-throughput acoustic separation enables statistical analysis of isolated CTCs from prostate cancer patients to be performed to determine their size distribution and phenotypic heterogeneity for a range of biomarkers, including the visualization of CTCs with a loss of expression for the prostate specific membrane antigen. The method also enables the isolation of even rarer, but clinically important, CTC clusters. PMID- 29968403 TI - Protocol graft biopsy in kidney transplantation. AB - Accurate interpretation of renal allograft biopsy is necessary to guide therapy, especially when an episode biopsy is taken to rescue the graft. Contrarily, a protocol biopsy is carried out routinely to identify baseline conditions (biopsy at 0 or 1 h), subclinical rejection, histological change under current immunosuppression regimen, drug nephrotoxicity, viral infection, and recurrence of glomerulonephritis. Semiquantitative scoring for active lesions including tubulitis, glomerulitis, capillaritis, arteritis, arteriopathy, and others such as polyomavirus infection are key factors in transplant pathology. Recently, the Banff classification has proposed several novel concepts focused on antibody mediated rejection (ABMR). This review presents the interpretation of transplant pathology from rejection to infection, recurrence of glomerulonephritis, and drug nephrotoxicity, with a description of ABMR according to the 2013 and 2017 Banff classification. PMID- 29968404 TI - Interlobular hyaline arteriopathy reflects severe arteriolopathy in renal allografts. AB - AIM: The present study was performed to examine the clinicopathological significance of hyaline deposits in the smooth muscle of the interlobular artery (interlobular hyaline arteriopathy [IHA]) in renal allografts. METHODS: Tissue specimens that included the interlobular artery from biopsies performed from January 2012 to December 2015, as well as specimens from biopsies performed >=1 year after living kidney transplantation were analyzed. Biopsies of recipients with new-onset diabetes mellitus after transplantation were excluded, as well as those of recipients who had undergone transplantation because of diabetic nephropathy. Arteriolopathy was evaluated using the aah score determined by the Banff 2007 classification. RESULTS: In total, 51 specimens with IHA lesions were identified among 381 biopsies obtained from 243 recipients performed >=1 year after kidney transplantation. Among these 51 biopsies, 18 specimens had a score of aah3, 29 had a score of aah2, and four had a score of aah1. The incidence of IHA lesions was 3.6% at >=1 to <4 years, 18.5% at >=4 to <8 years, and 54.1% at >=8 years. Older kidney grafts exhibited more IHA lesions. Among the biopsy specimens obtained >=8 years after transplantation, no significant differences in the recipient or donor age, duration after transplantation, or prevalence of hypertension were observed between the IHA and non-IHA groups. The aah scores were significantly higher in the IHA group >=8 years after transplantation as determined by the mean score test (P < 0.01). CONCLUSION: IHA in renal allografts is associated with severe arteriolopathy. PMID- 29968405 TI - Antibody-mediated rejection due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. AB - Herein, we report a case of antibody-mediated rejection (ABMR) due to anti-HLA-DQ antibody after pregnancy and delivery in a female kidney transplant recipient. A 34-year-old female recipient was admitted at 2 years after delivery for an examination of an elevated serum creatinine (S-Cr) level. The patient had received a living kidney transplantation from her mother at 22 years of age, and her kidney graft function was almost stable. The episode biopsy showed peritubular capillaritis and transplant capillaropathy with C4d immunoreactivity in the peritubular capillaries. Additional examination revealed expression of a donor-specific antibody (DSA) against HLA-DQ5, leading to the diagnosis of chronic active ABMR. Intravenous immunoglobulin, plasma exchange, and rituximab were administered, and her S-Cr level was maintained stable. This case demonstrates a possible relationship between pregnancy/delivery and development of ABMR due to a de novo DSA in a female kidney transplant recipient. PMID- 29968406 TI - Post-transplant immunoglobulin A deposition and nephropathy in allografts. AB - Post-transplant immunoglobulin A (IgA) nephropathy (IgAN) in the allograft is the major cause of allograft loss. Using a protocol biopsy, latent mesangial IgA deposition (IgAD) can be detected in the allograft. Latent IgAD is distinguished from IgAN by the absence of urinary abnormalities, although IgA is observed in the mesangium. However, the pathophysiology and most appropriate treatment strategy for latent mesangial IgAD in the allograft remain to be fully determined. Importantly, it is unknown whether all cases of post-transplant asymptomatic IgAD progress to symptomatic IgAN; indeed, IgA deposits disappear in some cases. The differences in allograft prognosis between asymptomatic IgAD and IgAN have also not been determined. Non-invasive methods of diagnosis of IgAD in the allograft using serological and pathological biomarkers are being developed. Possible serum biomarkers include serum galactose-deficient IgA1 (Gd-IgA1), Gd IgA1-specific IgG and Gd-IgA1-specific IgA, and its immune complexes. Immunofluorescence analysis using Gd-IgA1 monoclonal antibody may provide a pathological biomarker. These serological and pathological biomarkers may be suitable for the characterization of the stage of IgAD. However, there is insufficient information regarding whether serological and pathological biomarkers can predict the progression of asymptomatic IgAD to symptomatic IgAN. We propose that the pathogenesis of IgAN can be defined through the clinical study of IgAD in the allograft using protocol biopsies conducted by nephrologists involved in clinical kidney transplantation. PMID- 29968407 TI - Clinicopathological study of de novo membranous nephropathy of 'stage 0' after kidney transplantation. AB - AIM: De novo membranous nephropathy (dnMN) contributes to graft failure, but the pathophysiology of the disease remains poorly understood. We defined cases exhibiting granular Immunoglobulin G (IgG) immunofluorescence staining but lacking dense deposits on electron microscopy as being of 'dnMN stage 0'; we studied the associated clinicopathological features. METHODS: We studied 4653 allograft biopsy specimens (from 1747 cases treated in the Department of Urology, Tokyo Women's Medical University) and found 42 cases of allograft membranous nephropathy, of which 28 (1.6%) were diagnosed as dnMN. Of these, five cases (0.06%) fulfilled the criteria for dnMN stage 0. RESULTS: All five cases were diagnosed based on biopsies indicating increased serum levels of creatinine. Proteinuria status varied from negative to 2+. The median period from transplantation to allograft biopsy was 4068 days. Four of the five cases exhibited suspicious antibody-mediated rejection together with dnMN. The glomerular capillaries of all cases were C4d-positive, as were the peritubular capillaries of three of the four ABO-compatible transplants. In terms of IgG subclass, IgG1 and IgG3 predominated in all cases, and phospholipase A2 receptor status (evaluated via immunoreactivity) was negative in all cases. We examined two cases by immunoelectron microscopy using anti-IgG and anti-C4d antibodies. We found subendothelial and intramembranous deposits expressing both IgG and C4d, corresponding to positivity in immunofluorescence analysis. CONCLUSION: We confirmed the existence of dnMN stage 0 by focusing on granular IgG immunofluorescence positivity. PMID- 29968408 TI - Viral infections directly involved in kidney allograft function. AB - Modern immunosuppressive therapy has dramatically reduced the incidence of acute rejection and improved graft survival in kidney transplant patients. However, infectious complications remain an important issue. Amongst the various pathogens, viruses such as adenovirus and polyomavirus BK can directly cause acute or chronic graft dysfunction. Adenovirus mainly causes haemorrhagic cystitis and tubulointerstitial nephritis in kidney transplant patients. While patients show apparent clinical symptoms such as fever, dysuria, gross haematuria, frequency and urgency of urination, and most patients show acute graft dysfunction, these symptoms and graft dysfunction are reversible. Polyomavirus BK infection, however, is asymptomatic but graft outcome is poor if the patient develops tissue-invasive nephropathy confirmed by graft biopsy. Recently, an attempt to create a pathological classification for predicting the clinical course has been made by the Banff Working Group on Polyomavirus Nephropathy. With regards to treatment, the basic strategy is a reduction of calcineurin inhibitor and/or antimetabolites, and the effectiveness of several adjunct treatments has been investigated in several clinical trials. There are other unresolved issues, such as the diagnosis of subsequent acute rejection, the definition of remission, methods of resuming immunosuppression and long-term follow-up. Most of all, development of effective vaccines and novel drug discovery are necessary to prevent the development and progression of BKV associated nephropathy. PMID- 29968410 TI - Introduction. PMID- 29968409 TI - Two novel APOA1 gene mutations in a Japanese renal transplant recipient with recurrent apolipoprotein A-I related amyloidosis. AB - Apolipoprotein A-I amyloidosis is a rare, autosomal dominant disorder of APOA-1 gene characterized by the deposition of apolipoprotein A-I in various organs and can be classified into either hereditary or nonhereditary form in the absence of a family history. Renal disease caused by Apolipoprotein A-I amyloidosis commonly manifested as slowly progressive renal function impairment without heavy proteinuria. Apolipoprotein A-I-related amyloidosis of kidney is of pathogenetic interest because the renal failure is due to peritubular and interstitial amyloid deposits without glomerular deposits. Tubulointerstitial lesion of amyloid deposits was diagnosed in half of carriers of APOA1 gene mutation, only 13% of patients progressed to renal failure requiring hemodialysis or kidney transplantation. Recurrence of apolipoprotein A-I-related amyloidosis after kidney transplantation is very rare. We report a case of a 63-year-old Japanese female without a family history of kidney and/or liver disease who showed slowly progressive renal graft dysfunction without overt proteinuria. Graft biopsy revealed characteristic Congo red stain positive amyloid deposits localized in the renal interstitial area. No glomerular, vascular and tubular amyloid deposits were noted. Laser microdissection-liquid chromatography tandem mass spectrometry based proteomic analysis elucidated the type of amyloidosis as apolipoprotein A-I amyloidosis. Genetic analysis of DNA sequence study revealed two novel APOA1 gene mutations of Leu202Arg and Lys262Asn. This is a first and very rare case report of the recurrence of non-familial hereditary apolipoprotein A-I amyloidosis in Japanese transplant recipient. PMID- 29968411 TI - A case of recurrent proliferative glomerulonephritis with monoclonal IgG deposits or de novo C3 glomerulonephritis after kidney transplantation. AB - Proliferative glomerulonephritis with monoclonal immunoglobulin (Ig)G deposits (PGNMID) is a rare disease with a treatment that is not well established. Several cases of recurrent PGNMID after kidney transplantation have been documented, but almost all cases reported symptoms such as elevated serum creatinine and/or urinary protein levels; subsequently, episode biopsies were performed and a diagnosis was made. This is the case of a 27-year-old man who underwent living donor kidney transplantation. The aetiology of renal failure was membranoproliferative glomerulonephritis type III, which had been diagnosed at the age of 9 years. Protocol biopsy performed on postoperative day 62 revealed isolated granular C3 deposits in the glomerular capillaries and mesangium. We reviewed the native kidney biopsy and confirmed IgG3 deposition alone, with strong glomerular staining for lambda light chains and negative staining for kappa light chains. Accordingly, we re-diagnosed the aetiology of his renal failure as PGNMID and suspected recurrent PGNMID in the early stage; therefore, we administered plasma exchange therapy. Thereafter, protocol biopsies were performed twice, which revealed persistent isolated C3 deposition; therefore, we made a diagnosis of recurrent PGNMID or C3 glomerulonephritis. Currently, the patient has normal renal function, with negative urine findings for >1 year. Here, we present the histological findings of consecutive allograft biopsies performed in this patient. PMID- 29968412 TI - Clinicopathological and immunohistochemical analysis of plasma cell-rich rejection in renal transplantation: Involvement of intratubular Th1/Th2 balance in plasma cell enrichment. AB - AIM: Plasma cell-rich rejection (PCRR) has been considered a subtype of acute T cell-mediated rejection (ATCR). However, PCRR is recognized as refractory rejection and different from ATCR in various ways. In order to elucidate the pathogenesis of PCRR, we analysed PCRR clinicopathologically and immunohistochemically by comparing it with ATCR. METHODS: Twelve cases of PCRR (PCRRs) and 22 cases of usual ATCR (ATCRs) diagnosed at our hospital between January 2008 and March 2017 were included. Between PCRRs and ATCRs, we compared clinical data, Banff classification, graft outcome and the total sum number of T bet- and GATA3-positive lymphocytes infiltrating in tubular epithelium using immunohistochemistry. RESULTS: Plasma cell-rich rejections occurred later than ATCRs (median time after transplantation 1340.5 days vs. 52.5 days). Serum creatinine levels at discharge after treatment were significantly higher in PCRRs than in ATCRs (median 2.38 vs. 1.65 mg/dL). Cumulative rate of graft loss was significantly higher in PCRRs than in ATCRs (1-, 2- and 5-year: 26.7%, 51.1% and 51.1% vs. 0%, 0% and 17.5%). For profiles of Th1 and Th2, we found significantly lower ratio of T-bet/GATA3-positive lymphocytes in PCRRs compared with ATCRs. CONCLUSION: This study suggests that PCRR is more refractory than ATCR and there are significant differences in populations of helper T-cell subsets between them. We consider helper T-cell subset analysis valuable for developing new treatment strategies for PCRR. PMID- 29968413 TI - Recurrence of native kidney disease after kidney transplantation. AB - The extent of recurrence of original kidney disease after kidney transplantation has been underestimated for several reasons. First, the duration of observation varies among studies. Second, the criteria used to schedule protocol and episode biopsies differ among institutions. And third, diagnostic modalities used for early detection of recurrent original kidney disease also vary. Thus, rates of graft loss attributable to a recurrence of original kidney disease vary among institutions and are often underestimated. However, the recurrence of original disease is often thought to be less important than chronic rejection followed by loss of a functioning allograft. It is important to note that recent data have shown that in patients with certain limited primary kidney diseases (e.g., membranous proliferative glomerulonephritis [MPGN], IgA nephritis [IgAN], focal segmental glomerulonephritis [FSGS], and membranous nephropathy [MN]), the predominant (60%) cause of graft loss is the recurrence of original kidney disease. In addition, the rate of 5-year graft survival in patients with recurrent original kidney disease averages 45%. Thus, research must address the recurrence of original kidney disease. Here we focus on this recurrence and discuss diagnoses, preventive strategies, treatments, and future research directions. PMID- 29968414 TI - Clinicopathological features and outcomes of kidney allografts in plasma cell rich acute rejection: A case series. AB - Plasma cell-rich acute rejection (PCAR) is a rare type of acute rejection in renal transplantation. Despite aggressive immunotherapy, approximately 40-60% of patients develop graft loss within 1 year after an episode of PCAR. However, the reason for this outcome remains obscure. This study retrospectively identified six patients with PCAR diagnosed between 2009 and 2015 at a single university hospital. Clinicopathological data were collected. Five of the six patients were male, and mean age at the onset of PCAR was 49.0 +/-14.5 years. None of the patients showed overall poor adherence to medication. Mean time to diagnosis was 302 +/-234 days post-transplantation. All patients had preceding or concurrent viral infection. Four patients developed PCAR alone and two patients developed PCAR with antibody-mediated rejection. One of the six patients showed both severe tubulointerstitial and microvascular inflammation (total of Banff tubulitis 't' + interstitial inflammation 'i' + glomerulitis 'g' + peritubular capillaritis 'ptc' scores >10). This patient had progressive worsening of graft function and re initiated dialysis at 74 months after a PCAR episode. In addition, three of the six patients had long-term recurrence of PCAR. With the recurrence of PCAR, patients with both moderate tubulointerstitial and microvascular inflammation (total of Banff 't' + 'i' + 'g' + 'ptc' scores >6) had progressive worsening of graft function. In summary, the present results suggest that concurrent moderate to severe tubulointerstitial and microvascular inflammation may lead to poor outcomes of graft function after a PCAR episode. PMID- 29968415 TI - Effect of steroid pulse therapy on post-transplant immunoglobulin A nephropathy. AB - AIM: Recent studies have suggested that patients with post-transplant immunoglobulin A nephropathy have poor graft survival. There is limited research on the therapeutic effectiveness for post-transplant immunoglobulin A nephropathy, especially steroid pulse therapy. The present study evaluated the efficacy of steroid pulse therapy on post-transplant immunoglobulin A nephropathy. METHODS: We retrospectively analyzed patients diagnosed with de novo or recurrent immunoglobulin A nephropathy at Kyushu University Hospital between January 2013 and August 2015. Patients with moderate proteinuria (>=0.5 g/g creatinine) and/or cellular or fibrocellular crescents on a graft biopsy were treated with steroid pulse therapy. Steroid pulse therapy was 500 mg/day for 3 days in weeks 1 and 2, followed by 20 mg of oral prednisolone that was tapered after 6 months. Patients were followed for 2 years, and the estimated glomerular filtration rate, urinary findings, and adverse events were recorded. RESULTS: Seven patients received steroid pulse therapy. The mean duration after kidney transplantation was 6.6 +/- 4.7 years. After 2 years of treatment, 85.7% of patients reached complete remission of proteinuria, urinary protein excretion declined (0.82 +/- 0.51 to 0.26 +/- 0.22 g/g creatinine, P = 0.007), and the estimated glomerular filtration rate was maintained (48.7 +/- 12.8 to 47.4 +/- 14.0 mL/min per 1.73 m2 , P = 0.98). Adverse events were observed in one patient who developed herpes zoster infection. CONCLUSION: Steroid pulse therapy for post transplant immunoglobulin A nephropathy effectively reduces proteinuria over 2 years. However, comparison of steroid pulse therapy and other regimens with a high-quality design is required. PMID- 29968416 TI - Cell mediated rejection revisited: Past, current, and future directions. AB - The Banff histopathology classification system is the gold standard for assessing the causes of kidney allograft dysfunction triggered by antibody-mediated and T cell-mediated immune reactions, thereby providing mechanistic insight and guiding therapeutic decisions. The original Banff classification (1993) consisted of four histological categories representing cell-mediated rejection: interstitial inflammation (i), tubulitis (t), endoarteritis (v), and transplant glomerulitis (g). The revised Banff 2007 classification added total inflammation score (ti) from both scarred and unscarred areas based on evolving interpretations of interstitial infiltrates. Further reappraisal of cell-mediated interstitial inflammation led to the introduction of a new inflammation score specific for areas of interstitial fibrosis and tubular atrophy, termed i-IF/TA, in the Banff 2015 scheme, establishment of a new Banff working group on T-cell-mediated rejection (TCMR), and revised criteria of chronic active TCMR in Banff 2017 classification. These Banff scheme updates reflect the general recognition that chronic interstitial inflammation is a common denominator of poor kidney allograft outcome. However, revised theories on the pathogenic importance of interstitial infiltrates have created difficulties in interpretation of chronic tubulointerstitial inflammation, as there are currently no histological criteria to discriminate immune-mediated tissue injury from 'non-specific' injury. Evolving theories on vascular lesions, both active and chronic, have also complicated histological assessment by obscuring the distinction between antibody mediated and T-cell-mediated tissue injury. This review provides an overview of recent ideas on interstitial inflammation and vascular lesions based on emerging concepts of T-cell-mediated rejection. PMID- 29968417 TI - Impact of primary diabetic nephropathy on arteriolar hyalinosis lesions in patients following kidney transplantation. AB - AIM: Arteriolar hyalinosis (AH) is a common lesion in allograft biopsies taken following kidney transplantation. Recent studies have shown that severe AH may predict transplant outcomes and provide information about previous exposure to certain drugs, such as calcineurin inhibitors (CNI). However, the incidence of AH as a direct result of diabetic nephropathy (DN) after kidney transplantation has not been fully evaluated. This study aimed to assess the impact of primary DN on the development of AH lesions in patients who underwent kidney transplantation. METHODS: Eighty-three patients who underwent living-donor kidney transplantation between April 2005 and June 2015 were enrolled in this study. A total of 33 patients had DN prior to transplantation. Allograft biopsies were scored according to the Banff classification, and the relationship between the individual histological lesions and clinical baseline data was assessed. RESULTS: At early biopsy (3-12 months), there were no differences in the rates of AH lesions between the DN group and the non-DN group (ah >= 1: 37% vs. 41.3%, P = 0.719; aah >= 1: 14.8% vs. 6.5%; P = 0.453). However, there were significant differences between the groups in biopsies taken more than 3 years after the transplant (ah >= 2: 83.3% vs. 36.8%, P = 0.013; aah >= 2: 66.7% vs. 21.1%, P = 0.011). Multivariable analysis showed that both the length of time after transplantation and the presence of DN were independent risk factors for ah >= 2 (odds ratio [OR]: 2.55, 95% confidence interval [CI]: 1.47-19.54, P = 0.011) and aah >= 2 (OR: 7.55, 95% CI: 1.49-38.33, P = 0.015). CONCLUSION: This is the first report showing that the presence of primary DN disease contributes to the development of severe AH late in the course after kidney allografts. PMID- 29968418 TI - Deformation of Mesoporous Titania Nanostructures in Contact with D2 O Vapor. AB - For many applications, mesoporous titania nanostructures are exposed to water or need to be backfilled via infiltration with an aqueous solution, which can cause deformations of the nanostructure by capillary forces. In this work, the degree of deformation caused by water infiltration in two types of mesoporous, nanostructured titania films exposed to water vapor is compared. The different types of nanostructured titania films are prepared via a polymer template assisted sol-gel synthesis in conjunction with a polymer-template removal at high temperatures under ambient conditions versus nitrogen atmosphere. Information about surface and inner morphology is extracted by scanning electron microscopy and grazing incidence small-angle neutron scattering (GISANS) measurements, respectively. Furthermore, complementary information on thin film composition and porosity are probed via X-ray reflectivity. The backfilling induced deformation of near surface structures and structures inside the mesoporous titania films is determined by GISANS before and after D2 O infiltration. The respective atmosphere used for template removal influences the details of the titania nanostructure and strongly impacts the degree of water induced deformation. Drying of the films shows reversibility of the deformation. PMID- 29968419 TI - Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy. AB - Lysine-specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A-tri-/di-methylated histone 3 protein-protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple-negative breast cancer (TNBC) cell lines, MDA-MB-231 and 4T1. Finally, 1 exhibited potent anti-tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal-based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC. PMID- 29968420 TI - Extensive clinical experience: Hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess. AB - OBJECTIVE: To identify predictors of hypothalamic-pituitary-adrenal (HPA) axis recovery interval and severity of glucocorticoid withdrawal symptoms (GWS) in patients undergoing adrenalectomy for corticotropin-independent cortisol excess. DESIGN: This is a retrospective study of patients with mild autonomous cortisol excess (MACE), moderate and severe Cushing syndrome (CS) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. RESULTS: Adrenalectomy was performed in 81 patients (79% women, median age 52 years [IQR 42-62]). HPA axis recovery occurred at a median of 4.3 months (IQR 1.6-11.4) after adrenalectomy (severe CS vs moderate CS vs MACE: median 11.4 vs 2.8 vs 2.1 months, P < 0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1-mg overnight dexamethasone suppression test >10 MUg/dL or >276 nmol/L (9.7 vs 1.3 months if cortisol <=10 MUg/dL or <=276 nmol/L, P < 0.01); body mass index (for every 3 kg/m2 decrease, glucocorticoid taper increased by 1 month, P < 0.05); age <45 (11.4 vs 2.3 months if >=45 years, P < 0.05); duration of symptoms prior to diagnosis >1 year (11.4 vs 2.8 months if <=1 year); moon facies (11.4 vs 2.2 months if no rounding of the face); and myopathy (13.1 vs 2.7 months if no myopathy, P < 0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P < 0.05) with a median of 1 and 0 events/patient, respectively. CONCLUSIONS: The HPA axis recovery interval was the longest for patients with severe CS. Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE. Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS. This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters. PMID- 29968421 TI - Chemical and pharmacological aspects of neutralization of heparins from different animal sources by protamine. AB - : Essentials Bovine (HBI) and porcine (HPI) heparins differ in structure and anticoagulant activity. Protamine-neutralization was evaluated on a variety of physical-chemical methods. HBI requires more protamine than HPI to fully neutralize its anticoagulant activity. Protamine preferentially removes higher sulfated chains of HBI while HPI is evenly precipitated. SUMMARY: Background Protamine neutralization is an essential step for the safe use and inactivation of the unfractionated heparin (UFH) that is widely employed in surgical and non surgical procedures involving extracorporeal circulation. Objective To compare protamine neutralization of different pharmaceutical-grade UFHs prepared from porcine or bovine intestine (HPI and HBI, respectively). HBI has approximately half the anticoagulant potency of HPI, mostly as consequence of its fraction enriched with N-sulfated alpha-glucosamine disaccharides. Methods Protamine neutralization of HPI and HBI was evaluated with in vitro, ex vivo and in vivo assays. We also performed in-depth assessments of the complexation of protamine with these distinct UFHs by using nuclear magnetic resonance and mass spectroscopy. Results HPI and HBI interact similarly with protamine on a mass/mass basis; however, HBI requires more protamine than HPI to have its anticoagulant activity fully neutralized, because of its lower potency, which entails the use of higher doses. Nuclear magnetic resonance spectra revealed that HPI precipitates homogeneously with protamine. On the other hand, the low sulfated fraction of HBI, enriched with N-sulfated alpha-glucosamine, precipitates at higher concentrations of protamine than the fraction more like HPI, with a preponderance of N,6-disulfated alpha-glucosamine disaccharides. Finally, mass spectroscopy spectra showed that some of the different peptide components of protamine interact preferentially with the heparins, irrespective of their animal origin. Conclusion Our results have important medical implications, indicating that protamine neutralization of HBI, determined exclusively by point-of-care coagulation assessments, must fail because of its lower-sulfated fraction with reduced anticoagulant activity that could remain in the circulation after the neutralization procedure. PMID- 29968422 TI - The effect of chronic disease family history on the adoption of healthier lifestyles. AB - AIM: To determine the influence of family history (FH) and personal history (PH) of chronic disease (CD) in the adoption of healthy lifestyles. METHODS: This cross-sectional study was based on the EPIPorto cohort (n = 1588). Participants were grouped taking into account FH and PH of CD, such as diabetes, myocardial infarction, stroke, asthma, and cancer, and if at least one of the first-degree relatives had died from the CD. Age-, sex-, and education-adjusted odds ratios and corresponding 95% confidence intervals were computed using multinomial logistic regression. RESULTS: Subjects with PH and FH of CD were more likely to follow recommendations regarding salt intake but less likely regarding obesity measures. Overall, similar results were observed when repeating the analyses according to the type of CD, particularly in those with diabetes. CONCLUSIONS: Recommendations towards healthier lifestyles are not followed by individuals with history of CD, at least in what concerns obesity measures. Our study suggests reducing obesity as a major target for interventions in these groups of individuals. PMID- 29968423 TI - Developmental programming of the female neuroendocrine system by steroids. AB - Developmental programming refers to processes that occur during early life that may have long-term consequences, modulating adult health and disease. Complex diseases, such as diabetes, cancer and cardiovascular disease, have a high prevalence in different populations, are multifactorial, and may have a strong environmental component. The environment interacts with organisms, affecting their behaviour, morphology and physiology. This interaction may induce permanent or long-term changes, and organisms may be more susceptible to environmental factors during certain developmental stages, such as the prenatal and early postnatal periods. Several factors have been identified as responsible for inducing the reprogramming of various reproductive and nonreproductive tissues. Among them, both natural and synthetic steroids, such as endocrine disruptors, are known to have either detrimental or positive effects on organisms depending on the dose of exposure, stage of development and biological sexual background. The present review focuses on the action of steroids and endocrine disruptors as agents involved in developmental programming and on their modulation and effects on female neuroendocrine functions. PMID- 29968424 TI - Accuracy of Dental Replica Models Using Photopolymer Materials in Additive Manufacturing: In Vitro Three-Dimensional Evaluation. AB - PURPOSE: To evaluate the accuracy (trueness and precision) of dental replica models produced by using photopolymer materials in additive manufacturing. MATERIALS AND METHODS: A complete arch model was scanned using an extraoral scanner (Identica Blue) and established as reference. For the control group, 10 stone models were acquired through the conventional method from the reference model. For the experimental groups, digital data were acquired using an intraoral scanner (CEREC Omnicam), and 10 stereolithographic apparatus (SLA) models and 10 PolyJet models were made. All models were scanned with an extraoral scanner. Three-dimensional analysis software was used to measure differences between the 3D scanned images in root mean square values. The ISO-5725-1 specification was followed to measure trueness and precision between two 3D scanned data. Trueness was calculated by overlapping scanned data with the reference model and precision by performing pairwise intragroup comparisons. Also the ratio of region out of tolerance (> +/-50 MUm) was measured. One-way ANOVA and Tukey's post hoc analysis were applied. RESULTS: There was no statistically significant difference in trueness between the stone and the SLA models (p > 0.05). Dental replica models using photopolymer materials showed statistically significantly better precision than that of the stone model (p < 0.05). Regarding tolerance, no statistically significant difference was observed between the stone and the SLA models (p > 0.05). CONCLUSIONS: Although the dental replica models using photopolymer materials did not show better trueness than the conventional stone models, there was no significant difference between the SLA and the stone models. Concerning precision, dental replica models using photopolymer materials presented better results than that of the conventional stone models. In sum, dental replica models using photopolymer materials showed sufficient accuracy for clinical use. PMID- 29968425 TI - Focused update of expert consensus statement: Use of invasive assessments of coronary physiology and structure: A position statement of the society of cardiac angiography and interventions. PMID- 29968426 TI - Hydroxypyridonecarboxylic Acids as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease. AB - Human cytomegalovirus (HCMV) infection poses a major health threat to immunocompromised individuals. Until recently, treatment of HCMV infection has relied solely on polymerase inhibitors that have safety and resistance issues. pUL89 provides the enzymatic functions for the HCMV terminase complex in viral DNA packaging and is an attractive target for developing a new class of HCMV drugs. However, inhibitors of the endonuclease activity of the C terminus of pUL89 (pUL89-C) were unknown before our recently characterized hydroxypyridonecarboxylic acid (HPCA) hit 7 r (1-(3-chloro-4-fluorobenzyl)-5 hydroxy-4-oxo-1,4-dihydropyridine-3-carboxylic acid; numbered as 10 k in our previous publication: Y. Wang, L. Mao, J. Kankanala, Z. Wang, R. J. Geraghty, J. Virol. 2017, 91, e02152-16). Herein, we explored the structure-activity relationship (SAR) of the HPCA chemotype mainly with regard to the N1 site through the synthesis of 35 analogues. The SAR studies, along with molecular modeling, identified a possible pharmacophore model minimally consisting of a chelating triad and a hydrophobic phenyl or biphenyl methyl substituent at N1. Lastly, our best compounds consistently inhibited pUL89-C in the low micromolar range in biochemical assays and exhibited strong antiviral activity without cytotoxicity, laying a solid medicinal chemistry foundation for further HCMV drug discovery efforts targeting pUL89-C. PMID- 29968427 TI - Toll-like receptors TLR-2, TLR-4, TLR-7, and TLR-9 in tumor tissue and serum of the patients with esophageal squamous cell carcinoma and gastro-esophageal junction cancer. AB - BACKGROUND: Stimulation of toll-like receptors (TLRs) has been linked to the development of esophageal and gastric cancers. OBJECTIVES: The aim of the study was to evaluate the clinical significance of tissue expression and serum concentration of TLR-2, TLR-4, TLR-7 and TLR-9 in patients with esophageal squamous cell carcinoma and gastro-esophageal junction adenocarcinoma. MATERIAL AND METHODS: The study group consisted of 97 individuals: 32 with esophageal squamous cell carcinoma, 27 with gastro-esophageal junction cancer, and 38 ageand gender-matched controls. The mRNA expression and protein concentration of TLRs in tissues and sera were measured by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) tests. RESULTS: In esophageal cancer patients, mRNA expressions of TLR-2, TLR-4 and TLR-7, and protein concentrations of all TLRs were significantly higher in tumor than in control tissue (p < 0.05). In esophageal cancer patients with lymph node metastasis, a tendency toward higher protein concentrations of tumor TLR-4 was observed. In gastro-esophageal junction adenocarcinoma subgroup, only the mRNA expression of TLR-7 and protein concentrations of TLR-4, TLR-7 and TLR-9 were significantly higher in tumors than in normal mucosa (p < 0.05). Protein concentration of TLR-9 was significantly higher in tumors of gastro-esophageal junction cancer with lymph node metastasis and depth of tumor invasion. Diagnostic potential of serum TLR-4 as a marker of gastro-esophageal junction cancer presence was reported. CONCLUSIONS: We demonstrated differences in the expression patterns of TLRs between esophageal squamous cell carcinoma and adenocarcinoma of gastro-esophageal junction, and showed circulating TLR-4 to be a potential marker of gastro-esophageal junction cancer. PMID- 29968429 TI - White-Coat Hypertension: the Neglected Subgroup in Hypertension. AB - The clinical prognostic importance of white coat hypertension (WCH), that is, the clinical condition characterized by an increase of office but a normal ambulatory or home blood pressure (BP) is since a long time matter of considerable debate. WCH accounts for a consistent portion of hypertensive patients (up to 30-40%), particularly when hypertension is mild or age is more advanced. Although scanty and inconsistent information is available on the response of office and out office BP to antihypertensive treatment and the cardiovascular (CV) protection provided by treatment, an increasing body of evidence focusing on the association of WCH with CV risk factors, subclinical cardiac and extra-cardiac organ damage and, more importantly, with CV events indicates that the risk entailed by this condition is intermediate between true normotension and sustained hypertension. This review will address a number of issues concerning WCH with particular attention to prevalence and clinical correlates, relation with subclinical target organ damage and CV morbidity/mortality, therapeutic perspectives. Several topics covered in this review are based on data acquired over the past 20 years by the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, a longitudinal survey performed by our group on the general population living in the surroundings of Milan area in the north part of Italy. PMID- 29968428 TI - The Evolving Concept of Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: Focus on Unique Feature of East Asian and "Asian Paradox". AB - Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is essential after percutaneous coronary intervention (PCI), while many studies have focused on determining the optimal degree of platelet inhibition and optimal DAPT duration to minimize complications after PCI. Current guidelines developed by the American College of Cardiology/American Heart Association and the European Society of Cardiology summarize previous studies and provide recommendations. However, these guidelines are mainly based on Western patients, and their characteristics might differ from those of East Asian patients. Previous data suggested that East Asian patients have unique features with regard to the response to antiplatelet agents. On comparing Western and East Asian patients, it was found that East Asian patients have a lower rate of ischemic events and higher rate of bleeding events after PCI, despite a higher on-treatment platelet reactivity, which is referred to as the "East Asian paradox." As the main purpose of DAPT is to minimize ischemic and bleeding complications after PCI, these differences should be clarified before adopting the guidelines for East Asian patients. Therefore, in this article, we will review various issues regarding DAPT in East Asian patients, with a focus on the unique characteristics of East Asian patients, previous studies regarding antiplatelet agents in East Asian patients, and a guideline from an East Asian perspective. PMID- 29968430 TI - The Past, Present and Future of Heart Transplantation. AB - Heart transplantation (HTx) has become standard treatment for selected patients with end-stage heart failure. Improvements in immunosuppressant, donor procurement, surgical techniques, and post-HTx care have resulted in a substantial decrease in acute allograft rejection, which had previously significantly limited survival of HTx recipients. However, limitations to long term allograft survival exist, including rejection, infection, coronary allograft vasculopathy, and malignancy. Careful balance of immunosuppressive therapy and vigilant surveillance for complications can further improve long-term outcomes of HTx recipients. PMID- 29968431 TI - Effect of Pioglitazone in Combination with Moderate Dose Statin on Atherosclerotic Inflammation: Randomized Controlled Clinical Trial Using Serial FDG-PET/CT. AB - BACKGROUND AND OBJECTIVES: Non-statin therapy plus lower intensity statin might be an alternative in patients with coronary artery disease (CAD). A recent data suggested an anti-inflammatory therapy can reduce recurrent cardiovascular events and pioglitazone is also an intriguing inflammatory-modulating agent. However, limited data exist on whether pioglitazone on top of statins further attenuates plaque inflammation. METHODS: Statin-naive patients with stable CAD and carotid plaques of >=3 mm were randomly prescribed moderate dose atorvastatin (20 mg/day), or moderate dose atorvastatin plus pioglitazone (30 mg/day) for 3 months. The primary endpoint was the change in the arterial inflammation of the carotid artery measured by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) during 3 months. RESULTS: Of the 41 randomized patients, 33 underwent an evaluation by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT; 17 atorvastatin plus pioglitazone and 16 atorvastatin patients). The addition of pioglitazone significantly improved the insulin sensitivity and increased the high-density lipoprotein cholesterol after 3 months. Although a reduction in the (FDG) uptake by pioglitazone on top of atorvastatin in carotid arteries with plaque showed marginally statistical significance in the entire patient group (atorvastatin plus pioglitazone; -0.10+/-0.07 and atorvastatin -0.06+/-0.04, p=0.058), pioglitazone showed a further reduction of the fluorodeoxyglucose (FDG) uptake among patients who had a baseline FDG uptake above the median (atorvastatin plus pioglitazone; -0.14+/-0.04 and atorvastatin -0.03+/-0.03, p<0.001). CONCLUSIONS: Pioglitazone demonstrated marginally significant anti-inflammatory effects in addition to moderate dose atorvastatin. This may have been due to the lack of power of the study. However, pioglitazone may have an anti-inflammatory effect in those patients with high plaque inflammation (Trial registry at ClinicalTrials.gov, NCT01341730). PMID- 29968432 TI - Effects of Combination Therapy of Statin and Thiazolidinedione on Vascular Inflammation. PMID- 29968433 TI - Gender-related Difference in Clinical Outcome of the Patient with Atrial Fibrillation after Radiofrequency Catheter Ablation. AB - BACKGROUND AND OBJECTIVES: Previous studies provided controversial result about gender differences in the clinical outcome after radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF). We assessed pure difference after adjustment of referral bias. METHODS: The clinical outcomes including freedom from AF/atrial tachycardia (AT) recurrence after RFCA were compared between women and men in 1:1 confounding factor matching with age, AF type, periods since diagnosis (+/-12 months), and procedure era (+/-12 months). Subgroup analysis was performed in categories defined by AF type and age of 55 (mean menopausal age of Asian women). RESULTS: Total 1,875 patients with AF underwent 2,307 RFCA between January 1998 and May 2014 in a single center. Total 367 women (19.6%, 59+/-10 years) who had undergone first ablation were included. Women had larger left atrial diameter index (26+/-4 vs. 23+/-4 mm/m2; p<0.001) and higher peri-procedural complications (9.2% vs. 4.9%; p=0.030) compared to men. The freedom from AF/AT recurrence after RFCA was not different between both groups (71% vs. 76%; log-rank p=0.131, mean follow-up of 55 months). Women with non-paroxysmal AF (PAF) had significantly worse outcome (54% vs. 69%; p=0.014), especially in subgroup with age <=55 (48% vs. 71%; p=0.010). In multivariate analysis, female gender was an independent predictor of recurrence in subgroup with non-PAF and age <=55 (hazard ratio [HR], 2.539; 95% confidence interval [CI], 1.112-5.801; p=0.027). CONCLUSIONS: The clinical outcome after RFCA was not different between both genders regardless of referral bias. However, the gender difference became evident in patients under 55 years with non-PAF. PMID- 29968434 TI - Gender Difference in Catheter Ablation: Atrial Fibrillations from Mars and Venus? PMID- 29968435 TI - Prevalence of Non-valvular Atrial Fibrillation Based on Geographical Distribution and Socioeconomic Status in the Entire Korean Population. AB - BACKGROUND AND OBJECTIVES: Prevalence of atrial fibrillation (AF) varies based on geographical location and socioeconomic status. We aimed to evaluate the prevalence of AF and utilization of antithrombotic therapy based on geographical regions and income levels in the entire Korean population. METHODS: We performed a cross-sectional analysis of Korean adults (aged >=20 years) using the 2015 National Health Insurance Service database (n=41,505,679). The study population was stratified into 17 geographical regions and 21 income levels. RESULTS: We identified 276,842 patients diagnosed with AF. Overall prevalence of AF in suburban/rural regions was significantly higher than that observed in urban regions (0.72% vs. 0.61%, respectively, p<0.001). Elderly patients (age >=75 years) showed a higher prevalence of AF and comorbidities related to AF development showed a higher prevalence among the population residing in suburban/rural regions. Among AF patients with a CHA2DS2-VASc score >=2, oral anticoagulation (OAC) therapy utilization was lower in the suburban/rural regions than that observed in the urban regions (48.2% vs. 51.8%, respectively, p<0.001). The relationship between income levels and AF prevalence showed a J-shaped curve. The OAC prescription rate showed a positive correlation with income levels. Non vitamin K antagonist oral anticoagulants tended to be more commonly prescribed among the higher income groups. CONCLUSIONS: Geographical location of residence and income levels were closely associated with the prevalence of AF and antithrombotic therapy utilization. This information may provide further insights for more effective surveillance of AF and stroke prevention for improved clinical outcomes. PMID- 29968436 TI - Regional and Socioeconomic Inequality of Atrial Fibrillation with Regular Hospital Visit. PMID- 29968438 TI - Lifestyle Modification, the Effective but Neglected Strategy in Lowering Blood Pressure. PMID- 29968437 TI - The Effects of Diet Alone or in Combination with Exercise in Patients with Prehypertension and Hypertension: a Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Supervised lifestyle interventions, including dietary and exercise programs, may be infeasible to implement in real-world settings. Therefore, this study aimed to evaluate the effectiveness of a home-based lifestyle modification intervention on blood pressure (BP) management. METHODS: Eighty-five patients aged over 20 years and diagnosed with prehypertension or mild hypertension were randomly assigned to an advice-only comparison group (C group, n=28), a Dietary Approaches to Stop Hypertension (DASH) diet education group (D group, n=30), or a DASH and home-based exercise group (D+Ex group, n=27). The intervention lasted for 8 weeks. The primary outcome was the difference in office systolic blood pressure (SBP) before and after the study period (Trial registry at ClinicalTrials.gov, NCT01637909). RESULTS: Seventy-two participants (87.8%) completed the trial. The degree of change in office SBP did not significantly differ among the intervention groups; however, the D+Ex group demonstrated a tendency toward decreased SBP. Upon analysis of 24-hour ambulatory BP measurements, daytime ambulatory SBP was significantly lower in the D+Ex group (134 mmHg; 95% confidence interval [CI], 131 to 137; p=0.011) than in the C group (139.5 mmHg; 95% CI, 130.9 to 137), and daytime ambulatory SBP was significantly decreased in the D+Ex group (-5.2 mmHg; 95% CI, -8.3 to -2.1; p=0.011) compared to the C group (0.4 mmHg, 95% CI, -2.5 to 3.3). CONCLUSIONS: In conclusion, lifestyle modification emphasizing both diet and exercise was effective for lowering BP and should be favored over diet-only modifications. PMID- 29968439 TI - Successful Medical Management of a Rare Loeffler Endocarditis Case. PMID- 29968440 TI - Assessment of Tissue Perfusion with Blood Oxygenation Level-Dependent Magnetic Resonance Imaging in Critical Limb Ischemia. PMID- 29968441 TI - Erratum: Acute Pulmonary Embolism: Focus on the Clinical Picture. AB - This corrects the article on p. 365 in vol. 48, PMID: 29737640. PMID- 29968442 TI - Mother-to-child transmission of hepatitis C virus. AB - This review reinforce the lack of a single maternal risk factor that is highly associated with vertical transmission (VT) of the infection with hepatitis C virus (HCV): indeed HCV RNA levels, mode of delivery, breast feeding, viral genotype of maternal IL28B status were not associated with HCV VT. PMID- 29968443 TI - Radiation exposure in very low birth weight infants. AB - BACKGROUND: The survival of very low birth weight (VLBW) infants increased in the past few decades. These neonates often require multiple diagnostic and management image procedures that involve ionizing radiation, which can have long term implications. The aim of our study was to evaluate the level of radiation exposure in VLBW infants during their stay in the neonatal intensive care unit (NICU). METHODS: We collected demographic and medical data of 149 VLBW who were admitted to our NICU between January 2011 and December 2014. All radiographic procedures were reviewed retrospectively. Absorbed ionizing radiation was calculated according to literature reference values. RESULTS: A total of 1496 images were obtained. Infants underwent 10.0 +/-11.3 examinations, and the maximum of images registered per patient was 65. Four babies (2.7%) received more than 1000 MUSv, the recommended maximum of ionizing radiation exposure. Infants of lower birth weight, who needed invasive ventilation, with bronchopulmonary dysplasia, sepsis, and surgical pathology required significantly more radiographs (p<0.001). CONCLUSIONS: In this study, lower birth weight, need of invasive ventilation, bronchopulmonary dysplasia and sepsis were associated with the need of more X ray studies. In order to protect the vulnerable population of severely ill newborns, guidelines for radiation exposure in newborns should be issued and implemented. PMID- 29968444 TI - Novel algorithm to screen for heart murmurs using computer-aided auscultation in neonates. A prospective single center pilot observational study. AB - BACKGROUND: Automated detection of heart murmurs with computer-aided auscultation is not yet in clinical routine use. Aim of this study was to test sensitivity and specificity of a novel prototype algorithm in automated detection of heart murmurs from digitally recorded phonocardiograms in neonates admitted at the neonatal intensive care unit. METHODS: In a prospective pilot observational study from November 2012 to December 2013 auscultations by pediatricians and computer aided auscultation were performed within 12 hours of neonatal echocardiography. Echocardiographic were defined pathological findings when resulting in any clinical consequences and findings without clinical consequences but causing murmur. Phonocardiograms and auscultation were defined as pathological if a murmur was detected. Phonocardiograms were analysed offline with a novel algorithm prototype (CSD Labs,Graz,Austria) for detection of murmurs in neonates in a first run and with an optimized algorithm in a second run and were compared with echocardiography. Sensitivity and specificity of auscultation by pediatrician and computer aided auscultation were analysed. RESULTS: 36 neonates (gestational age: 36+/-3weeks) were included. 23 (64%) neonates had pathological or murmur causing findings in echocardiography (positive echocardiography). Sensitivity and specificity of auscultation by paediatrician were 17% and 100%, respectively. In comparison to auscultation by paediatrician sensitivity of first run and second run were significantly higher with 70% and 83%, respectively. Specificity of first run and second run were 77% and 85%, respectively. CONCLUSIONS: Phonocardiogram analysis using the novel algorithm prototype had a higher sensitivity than auscultation by paediatrician in detecting positive echocardiography findings in neonates. PMID- 29968445 TI - Evaluation of two RNA extraction methods for human parechovirus detection on pediatric stool specimens. AB - BACKGROUND: Human parechovirus (HPeVs), along with human enteroviruses are associated with gastrointestinal and respiratory infections. The aim of this study was to assess the performance characteristics of two nucleic acid extraction for HPeV-RNA quantitation, the RNAlev Extraction Kit associated with Maxwell automated nucleic acid extractor (Promega, Mi, Italy) and RNAzol manually protocol. METHODS: A total of 137 fecal specimens previously routinely screened for rotavirus and adenovirus were tested for HPeV virus. RESULTS: Methods 1 and 2 detected HPeV-RNA in 11 and 10 samples, respectively, with a 96.2% concordance. In particular, 124/137 (90.5%) were concordantly negative by both methods; 8/137 (5.8%) concordantly positive. For the 8 specimens that were positive by both tests, the population mean (SD) was 320 (601) copies/mg with method 1 and 1216 (2338) copies/mg with method 2. By referring to the 8 specimens that were concordantly positive, the correlation value between the two methods was not statistically significant (r = 0.381 and p=0.3599). Bland-Altman analysis showed that differences between the two methods were within +/-1000 copies/mg of the averaged results for all of the tested specimens. CONCLUSIONS: Method 2, being a semi-automated method, provides benefits over a manual method, in terms of turnaround time, less errors and reliability. PMID- 29968446 TI - Irisin concentration in infant formulas and breast milk. AB - BACKGROUND: Irisin is a newly discovered myokine with anti-obesity properties. The delivery of irisin with the breast milk or formula is an emerging concept that myokine present at human milk influences postnatal energy balance and developmental parameters. The aim of the study was to evaluate irisin concentration in breast milk of mothers with term and preterm babies and in infant formulas. METHODS: A total of 49 lactating mothers were enrolled in the study: 31 mothers of very low birth weight preterm infants and 18 mothers of term infants. Milk samples were collected twice: during the first week after delivery and after 4 weeks of delivery. Irisin concentration was determined using ELISA kits both in human milk and in samples of 14 different infant formulas. RESULTS: There were no differences in milk irisin levels between preterm and full-term milk samples during both the 1st and the 4th week after delivery. There were also no differences in irisin concentration between transitional milk and mature milk in both tested groups. Irisin concentrations in preterm and full-term milk were significantly higher than in formulas during 30 days period after delivery. A significant increase of irisin concentration in natural milk 4 weeks post delivery in comparison to 1st week after delivery was observed (mean difference 0.362 MUg/ml; p=0.0063). CONCLUSIONS: This study provides evidence that irisin is present in infant formulas, although in less amount than in human milk. Further research is needed to assess, if children fed with infant formulas may disadvantage from lower irisin supply. PMID- 29968447 TI - Longitudinal effects of biopsychosocial variables on physical activity after menarche. AB - BACKGROUND: The aim of the current study is to analyze the longitudinal effects of certain biopsychosocial variables (socioeconomic status, body mass index (BMI), body image and well-being (QL)), measured at three different menarche stages (S1: before menarche, S2: soon after menarche, and S3: one year after S2), on physical activity and inactivity levels in early adolescence. METHODS: The sample comprised 136 Brazilian teenagers (10-13 years old), showing BMI 18.98 kg/m2 at the initial assessment, who voluntarily participated in the study. Data concerning the following variables were collected in 2010 (S1), 2011 (S2) and 2012 (S3): family income (FI) (socioeconomic anamnesis), BMI (body mass and height), well-being (Autoquestionnaire Qualite de Vie Enfant Image) and body image (Body Shape Questionnaire). The physical activity and inactivity levels were measured in S3, only, through the International Physical Activity Questionnaire. The Pearson's correlation and the longitudinal path analysis technique were used to statistically analyze the data. RESULTS: The main results indicated that just family income and BMI, measured soon after menarche (S2), showed significant effect on physical activity and inactivity levels. More specifically, family income has positively influenced (beta = 0.25) physical inactivity levels and negatively influenced (beta = -0.14) moderate physical activity levels, whereas BMI has positively influenced (beta = 0.15) walking levels and negatively influenced (beta = -0.13) vigorous physical activity levels. CONCLUSIONS: These results suggest that the body image and well-being perceived by the teenagers at different menarche stages are not determining factors of their physical activity levels in early adolescence. On the other hand, the effects of socioeconomic status and body mass index on early adolescent girls' physical activity and inactivity levels depend on the assessment period. PMID- 29968448 TI - Duration of topical therapy in the maintenance of atopic dermatitis remission in paediatric age. AB - BACKGROUND: Topical Corticosteroids (TCS) are the first-choice treatment for atopic dermatitis (AD) flares. In literature there are clear advices about the potency, dosage and frequency of application of TCS, but there are no shared indications about duration of the treatment during a flare. The aim of the study is to demonstrate if the use of a steroid cream for less than or 5 days , could be equal or more effective than the application for more than 5 days during a flare episode, in keeping a remission state of DA. METHODS: The study population (n=122) was selected according to the following inclusion criteria: at least one specialist allergological and dermatological examination in the period November 2015 to February 2017, age between 1 and 11 years; mild to moderate atopic dermatitis. All patients were given a standardized telephone questionnaire, which concerns on multiple aspects: parents' self-reported perceptions of the severity of their child's condition; actual use of emollients, moisturizers and steroid creams; number of consecutive days of using of topical steroid cream during an exacerbation of AD; average number of AD exacerbations per month in the last year; total number of AD exacerbations in the last year. RESULTS: Data from 96 patients was examined. We classified three groups of patients from data collected: group 1 (n=40): use of TCS for <= 5 consecutive days during an exacerbation event of AD; group 2 (n=12): use of TCS for > 5 consecutive days during an exacerbation event of AD; group 3 (n=44): non use of TCS or use of TCS with a different posology. We found a further subgroup in group 3 (3a, n=27) with patients using only emollient creme in AD management. In group 1, 27 patients (67.5%) didn't show a good AD control; on the contrary, 13 patients (27.5%) reported a good AD control. In group 2, 4 patients (25%) didn't show a good AD control; on the contrary, 8 patients (75%) reported a good AD control. By comparing the data obtained in the presence of good DA control, the difference between the percentages obtained was found to be statistically significant (p = 0.034). CONCLUSIONS: The results obtained show that a therapeutic pattern based on the use of TCS for a duration of more than 5 consecutive days during an episode of DA exacerbation is more efficient than the proposed alternative therapeutic scheme in the maintenance of DA remission. PMID- 29968449 TI - Measles vaccine in the school settings: a cross-sectional study about knowledge, personal beliefs, attitudes and practices of school teachers in northern Italy. AB - BACKGROUND: School teachers (STs) might have a crucial role in countering students' and parents' hesitancy towards immunization. Such role is associated with STs own knowledge, attitudes and practices (KAP) towards vaccines. In this cross-sectional study we assess Measles vaccine KAP in a sample of Italian STs. METHODS: Between 01/2012 and 08/2015, 376 STs from the Lombardy region were enrolled in the study; data were retrieved on socio-demographic characteristics, KAP towards MeV, including immunization status. The association between knowledge, practices and a favorable attitude towards MeV was assessed calculating Odds Ratio (OR) and respective 95% Confidence Intervals (95%CI) through multivariate regression analysis. RESULTS: 16.7% of STs in Italy know national recommendations on MeV and 16.0% were favorable to MeV and 12.8% of STs reported to have been vaccinated against MeV as adults and only 5.9% reported fears of MeV side effects (e.g. autisms). MeV propensity was associated with previous vaccination as adults (OR 5.222; 95%CI 1.752-15.567), knowledge of national recommendations, and the understanding that MeV prevents natural infection and disease transmission (OR 2.274; IC95% 1.246-4.149, OR 14.061; IC95% 7.048-28.063, and OR 2.085; IC95% 1.125-3.864, respectively). CONCLUSIONS: The share of STs holding false beliefs and misconceptions towards MeV was lower than expected. STs might actively contribute to fight parents' vaccine hesitancy and such social role should be further acknowledged and promoted by policy makers and the wider public health community. PMID- 29968450 TI - Brain cooling reduces the risk of post-neonatal epilepsy in newborns affected by moderate to severe hypoxic-ischemic encephalopathy. AB - BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is still a significant cause of neonatal death and neurodevelopmental disabilities, such as cerebral palsy, mental delay, and epilepsy. After the introduction of therapeutic hypothermia, the prognosis of hypoxic-ischemic encephalopathy has improved, with reduction of death and disabilities. However, few studies evaluated whether hypothermia affects rate and severity of post-neonatal epilepsy. We evaluated rates, characteristics and prognostic markers of post-neonatal epilepsy in infants with moderate to severe hypoxic-ischemic encephalopathy treated or not with therapeutic hypothermia. METHODS: We analyzed clinical data, EEG recordings, cerebral Magnetic Resonance Imaging (MRI) and outcome in 23 cooled and 26 non cooled asphyxiated neonates (>=36 weeks' gestation), admitted from 2004 to 2012. RESULTS: Among 49 neonates 11 (22%) had post-neonatal epilepsy, of which 9 (18%) were non-cooled and 2 (4%) were cooled (p=0.05). Six of 11 infants (55%) had West syndrome, 4 (36%) had focal epilepsy and 1 (9%) had Lennox- Gastaut syndrome. At multiple logistic regression analysis MRI pattern significantly correlated with post-neonatal epilepsy (OR 0.19, 95% CI 0.04-0.88, p=0.03). Extensive lesions in basal ganglia and thalami plus cortical and white matter were associated with post-neonatal epilepsy. CONCLUSIONS: Only perinatal asphyxia with extensive lesions in basal ganglia and thalami plus cortical and white matter lesion conveys an high risk for early and severe post-neonatal epilepsy. Moreover therapeutic hypothermia is associated with a decrease of the risk of developing post-neonatal epilepsy. PMID- 29968451 TI - Empathy and behavior in children affected by Autism Spectrum Disorders. AB - BACKGROUND: Many studies have already shown that individuals suffering from Autism Spectrum Disorders (ASD) present low levels of empathy: in fact, reduced emotional reciprocity is considered a clinically significant indicator of autistic functioning. We decided to investigate the role of empathy in determining pathological behaviors in children affected by ASD considering parents' point of view and to evaluate the presence of differences between mothers and fathers' perception of their child's empathy and behaviors. METHODS: We compared empathy levels in a sample of 58 patients with ASD as reported by a parent-filled questionnaire with the results of a global evaluation conducted by means of play observations, clinician-rated scales, a semi-structured interview with both caregivers and parent-filled questionnaires. RESULTS: The majority of ASD patients have low levels of empathy according to both parents' points of view; noteworthy, mothers and fathers are highly concordant in this respect. Children's levels of empathy negatively correlate with many behavioral problems, both internalizing and externalizing. Furthermore, we found that mothers tend to perceive more internalizing problems, while fathers are more willing to notice externalizing ones. CONCLUSIONS: Involving both caregivers in children's diagnostic assessment could deepen patient's evaluation and finally the therapeutic results. Mothers and fathers seem to be highly consistent in describing the psychological characteristics of their child, but not in respect to symptoms. PMID- 29968452 TI - Early childhood eye diseases and perinatal risk factors. Potential of record linkage between current information flows. AB - BACKGROUND: The aim of this study was to analyse the occurrence of specific maternal, obstetric or neonatal factors, by performing a comparison between children with refractive error, strabismus and/or amblyopia (cases) and unaffected children (controls) in the province of Trento (north-east Italy). METHODS: In 2012-2014, 14,346 children attending the second year of nursery school were assessed through the pre-school orthoptic screening scheme (covering 91% of the pre-school population). Record linkage was performed between the orthoptic screening database and birth records (birth confirmation certificate database) for the corresponding birth cohorts (2008-2010), to examine specific maternal factors (age, smoking, nationality/race), obstetric factors (type of delivery) and neonatal factors (gestational age, weight at birth, Apgar score, congenital birth defects, hospitalisation at birth). The correlations were investigated using univariate and multivariate analysis in accordance with the logistic regression method. RESULTS: During orthoptic screening, 6.4% of children were found to have at least one refractive error, with astigmatism being the most common condition (5.1%). 1.9% of children were found to have strabismus and 1.8% amblyopia. Multivariate logistic regression analysis showed that the risk of developing a refractive error is associated with: maternal age >=45 years, foreign nationality, vacuum-assisted delivery and neonatal weight <1500 grams. An excessive risk of strabismus was observed in children whose mother had smoked during pregnancy (adjusted OR 1.64). CONCLUSIONS: Pre-school orthoptic screening is a well-consolidated practice in the province of Trento, with adhesion values consistently over 90%. Studies of this type show the potential of record linkage between current information flows. PMID- 29968453 TI - Metabolic syndrome severity and lifestyle factors among adolescents. AB - The continued rise of pediatric obesity globally has raised concerns for related sequalae. One marker of risk is the metabolic syndrome, a cluster of cardiovascular risk factors that is associated with future cardiovascular disease and type 2 diabetes. MetS has at its core visceral adipocytes exhibiting dysfunction as a result of excess fat content. MetS in children and adolescents is linked to unhealthy lifestyle practices such as sedentary lifestyles and excess consumption calories. As such, the optimal means of addressing MetS is targeting a decrease in adiposity through lifestyle modification, a decrease in MetS following increases in physical activity and improvements in the quality and content of food intake. Efforts remain needed in increasing motivation to these changes and maintaining adherence to avoid long-term sequelae. PMID- 29968454 TI - The application value of standardized ultrasonography in early pregnancy for fetal malformation screening in a Chinese population. PMID- 29968455 TI - Purification of Perovskite Quantum Dots Using Low-Dielectric-Constant Washing Solvent "Diglyme" for Highly Efficient Light-Emitting Devices. AB - Cesium lead halide (CsPbX3, X = Cl, Br, or I) perovskite quantum dots (QDs) are known as ionic nanocrystals, and their optical properties are greatly affected by the washing solvent used during the purification process. Here, we demonstrate the purification process of CsPbBr3 perovskite QDs using low-dielectric-constant solvents to completely remove impurities, such as the reaction solvent and desorbed ligands. The use of the ether solvent diethylene glycol dimethyl ether (diglyme), having a low dielectric constant of epsilon = 7.23, as a poor solvent for reprecipitation allowed for multiple wash cycles, which led to high purity and high photoluminescence quantum yield for CsPbBr3 QDs. The light-emitting device constructed with the CsPbBr3 QDs and washed twice with diglyme (two-wash) showed a low turn-on voltage of 2.7 V and a peak external quantum efficiency of over 8%. Thus, the purification of perovskite QDs with multiple wash cycles using a low-dielectric-constant solvent is an effective approach for enhancing not only the optical properties but also the efficiency of perovskite quantum dot light emitting devices. PMID- 29968456 TI - Transition States of Nanocrystal Thin Films during Ligand-Exchange Processes for Potential Applications in Wearable Sensors. AB - Ligand exchange is an advanced technique for tuning the various properties of nanocrystal (NC) thin films, widely used in the NC thin-film device applications. Understanding how the NC thin films transform into functional thin-film devices upon ligand exchange is essential. Here, we investigated the process of structural transformation and accompanying property changes in the NC thin films, by monitoring the various characteristics of silver (Ag) NC thin films at each stage of the ligand-exchange process. A transition state was identified in which the ligands are partially exchanged, where the NC thin films showed unexpected electromechanical features with high gauge factors up to 300. A model system was established to explain the origin of the high gauge factors, supported by the observation of spontaneously formed nanocracks and metal-insulator transition from the structural analysis and charge transport study, respectively. Taking advantages of the unique electromechanical properties of the NC thin films, we fabricated flexible strain gauge sensor devices with high sensitivity, reliability, and stability. We introduce a one-step fabrication process, namely, "the time- and spatial-selective ligand-exchange process", for the design of low cost and high-performance wearable sensors that effectively detect human motion, such as finger or neck muscle movement. This study provides a fundamental understanding of the ligand-exchange process in NCs, as well as an insight into the functionalities of the NC thin films for technological applications. PMID- 29968457 TI - Electron-Conducting PbS Nanocrystal Superlattices with Long-Range Order Enabled by Terthiophene Molecular Linkers. AB - PbS nanocrystals are surface-functionalized with the organic semiconductor 5,5" dithiol-[2,2':5,2"-terthiophene] and assembled to afford hybrid nanostructured thin films with a large structural coherence and an electron mobility of 0.2 cm2/(V s). Electrochemistry, optical spectroscopy, and quantum mechanical calculations are applied to elucidate the electronic structure at the inorganic/organic interface, and it is established that electron injection into the molecule alters its (electronic) structure, which greatly facilitates coupling of the neighboring PbS 1Se states. This is verified by field-effect and electrochemically gated transport measurements, and evidence is provided that carrier transport occurs predominantly via the 1Se states. The presented material allows studying structure-transport correlations and exploring transport anisotropies in semiconductor nanocrystal superlattices. PMID- 29968459 TI - Comparative Life Cycle Assessment of Advanced Wastewater Treatment Processes for Removal of Chemicals of Emerging Concern. AB - The potential health effects associated with contaminants of emerging concern (CECs) have motivated regulatory initiatives and deployment of energy- and chemical-intensive advanced treatment processes for their removal. This study evaluates life cycle environmental and health impacts associated with advanced CEC removal processes, encompassing both the benefits of improved effluent quality as well as emissions from upstream activities. A total of 64 treatment configurations were designed and modeled for treating typical U.S. medium strength wastewater, covering three policy-relevant representative levels of carbon and nutrient removal, with and without additional tertiary CEC removal. The USEtox model was used to calculate characterization factors of several CECs with missing values. Stochastic uncertainty analysis considered variability in influent water quality and uncertainty in CEC toxicity and associated characterization factors. Results show that advanced tertiary treatment can simultaneously reduce nutrients and CECs in effluents to specified limits, but these direct water quality benefits were outweighed by even greater increases in indirect impacts for the toxicity-related metrics, even when considering order-of magnitude uncertainties for CEC characterization factors. Future work should consider water quality aspects not currently captured in life cycle impact assessment, such as endocrine disruption, in order to evaluate the full policy implications of the CEC removal. PMID- 29968458 TI - All-Inorganic Bismuth Halide Perovskite-Like Materials A3Bi2I9 and A3Bi1.8Na0.2I8.6 (A = Rb and Cs) for Low-Voltage Switching Resistive Memory. AB - As silicon-based metal oxide semiconductor field effect transistors get closer to their scaling limit, the importance of resistive random-access memory devices increases due to their low power consumption, high endurance and retention performance, scalability, and fast switching speed. In the last couple of years, organic-inorganic lead halide perovskites have been used for resistive switching applications, where they outperformed conventional metal oxides in terms of large on/off ratio and low power consumption. However, there were scarce reports on lead-free perovskites for such applications. In this report, we prepared lead free Au/A3Bi2I9/Pt/Ti/SiO2/Si (A is either Cs+ or Rb+) devices and tested their resistive switching characteristics. They showed a forming step prior to repeating switching, low operating voltage (0.09 V for Rb3Bi2I9 and 0.1 V for Cs3Bi2I9), large on/off ratio (>107), relatively high endurance (200 cycles for Rb3Bi2I9 and 400 cycles for Cs3Bi2I9 cycles), and high retention (1000 s). Such low voltage could be explained by grain boundary-modulated ion drift. Difference in endurance was speculated to be due to the difference in the surface roughness of films because Cs3Bi2I9 films are smoother. To get rid of the forming step, 10% of the Bi3+ cations were substituted with Na+ cations. However, this method only worked on Rb-based structures. This phenomenon was explained by the defect formation energy, which can only be negative in a corner-sharing Rb3Bi2I9 structure compared to a face-sharing octahedral Cs3Bi2I9 structure. As a result, the forming step was removed, and 100 cycles endurance and 1000 s retention performance were obtained. Similarly, the lower endurance is suspected to be due to the poor surface quality of the film. PMID- 29968460 TI - Cigarette Smoking: An Assessment of Tobacco's Global Environmental Footprint Across Its Entire Supply Chain. AB - While the health effects of cigarette smoking are well recognized and documented, the environmental impacts of tobacco are less appreciated and often overlooked. Here, we evaluate tobacco's global footprint across its entire supply chain, looking at resource needs, waste, and emissions of the full cradle-to-grave life cycle of cigarettes. The cultivation of 32.4 Mt of green tobacco used for the production of 6.48 Mt of dry tobacco in the six trillion cigarettes manufactured worldwide in 2014, were shown to contribute almost 84 Mt CO2 equiv emissions to climate change-approximately 0.2% of the global total, 490 000 tonnes 1,4 dichlorobenzene equiv to ecosystem ecotoxicity levels, and over 22 billion m3 and 21 Mt oil equiv to water and fossil fuel depletion, respectively. A typical cigarette was shown to have a water footprint of 3.7 L, a climate change contribution of 14 g CO2 equiv, and a fossil fuel depletion contribution of 3.5 g oil equiv. Tobacco competes with essential commodities for resources and places significant pressures on the health of our planet and its most vulnerable inhabitants. Increased awareness, as well as better monitoring and assessment of the environmental issues associated with tobacco, should support the current efforts to reduce global tobacco use as an important element of sustainable development. PMID- 29968461 TI - Tuning the K+ Concentration in the Tunnels of alpha-MnO2 To Increase the Content of Oxygen Vacancy for Ozone Elimination. AB - alpha-MnO2 is a promising material for ozone catalytic decomposition and the oxygen vacancy is often regarded as the active site for ozone adsorption and decomposition. Here, alpha-MnO2 nanowire with tunable K+ concentration was prepared through a hydrothermal process in KOH solution. High concentration K+ in the tunnel can expand crystal cell and break the charge balance, leading to a lower average oxidation state (AOS) of Mn, which means abundant oxygen vacancy. DFT calculation has also proven that the samples with higher K+ concentration exhibit lower formation energy for oxygen vacancy. Due to the enormous active oxygen vacancies existing in the alpha-MnO2 nanowire, the lifetime of the catalyst (corresponding to 100% ozone removal rate, 25 degrees C) is increased from 3 to 15 h. The FT-IR results confirmed that the accumulation of intermediate oxygen species on the catalyst surface is the main reason why it is deactivated after long time reaction. In this work, the performance of the catalyst has been improved because the abundant active oxygen vacancies are fabricated by the electrostatic interaction between oxygen atoms inside the tunnels and the introduced K+, which offers us a new perspective to design a high efficiency catalyst and may promote manganese oxide for practical ozone elimination. PMID- 29968462 TI - Phosphorothioated Primers Lead to Loop-Mediated Isothermal Amplification at Low Temperatures. AB - Loop-mediated isothermal amplification (LAMP) is an extremely powerful tool for the detection of nucleic acids with high sensitivity and specificity. However, LAMP shows optimal performance at around 65 degrees C, which limits applications in point-of-care-testing (POCT). Here, we have developed a version of LAMP that uses phosphorothioated primers (PS-LAMP) to enable more efficient hairpin formation and extension at the termini of growing concatamers, and that therefore works at much lower temperatures. By including additional factors such as chaotropes (urea) and single-stranded DNA binding protein (SSB), the sensitivities and selectivities for amplicon detection with PS-LAMP at 40 degrees C were comparable with a regular LAMP reaction at 65 degrees C. PMID- 29968463 TI - Janus Polyvinylidene Fluoride Membrane with Extremely Opposite Wetting Surfaces via One Single-Step Unidirectional Segregation Strategy. AB - Janus membranes with asymmetric wettability have attracted intense attention in oil/water separation, membrane distillation, liquid/fog collection, liquid diode, etc. Facile manipulation of the paradoxical wetting/antiwetting property on opposite surfaces of a 2D membrane is challenging. Different from most postmodification methods, herein, we propose one single-step unidirectional segregation strategy to fabricate a polymeric Janus membrane with extremely opposite wetting surfaces showing almost a 150 degrees contact angle difference for the first time. We achieved the unidirectional segregation of the hydrophilic copolymer poly(vinylpyrrolidone-vinyltriethoxysilane) in a polyvinylidene fluoride (PVDF) membrane during phase separation. A glycerol coating on the nonwoven fabric support locally limited the phase separation on the bottom surface, blocked the segregation of hydrophilic copolymer, and promoted the segregation to the top surface. Working collaboratively with the asymmetric micro /nanostructure on both surfaces, the resulting Janus membrane exhibited a superhydrophilic top surface and a superhydrophobic bottom surface. The Janus PVDF membrane showed switchable separation performance and high separation efficiency for both oil-in-water emulsions and water-in-oil emulsions because of its anisotropic wettability compared with solely hydrophobic or hydrophilic PVDF membranes. PMID- 29968464 TI - Swift Acid Rain Sensing by Synergistic Rhizospheric Bioelectrochemical Responses. AB - Acid rain poses significant threats to crops and causes a decline in food production, but current monitoring and response to acid rain damage is either slow or expensive. The direct damage observation on plants can take several hours to days when the damage is irreversible. This study presents a real time bioelectrochemical monitoring approach that can detect acid rain damage within minutes. The rhizospheric bioelectrochemical sensor (RBS) takes advantage of the fast chain responses from leaves to roots, and then to the microbial electrochemical reactions in the rhizosphere. Immediate and repeatable current fluctuations were observed within 2 min after acid rain, and such changes were found to correspond well to the changes in rhizospheric organic concentration and electrochemical responses. Such correlation not only can be observed during acid rain events that can be remedied via rinsing, but it was also validated when such damage is irreversible, resulted in zero current, photosynthetic efficiency, and electrochemical signals. The alanine, aspartate, and glutamate metabolism and galactose metabolism in leaves and roots were inhibited by the acid rain, which resulted in the decrease of rhizodeposits such as fumaric acid, d-galactose, and d-glucose. These changes resulted in reduced electroactivity of anodic microorganisms, which was confirmed by a reduced redox current, a narrower spectrum in differential pulse voltammetry, and the loss of peak in the Bode plot. These findings indicate that the RBS process can be a simple, swift, and low-cost monitoring tool for acid rain that allows swift remediation measures, and its potential may be broadened to other environmental monitoring applications. PMID- 29968465 TI - A Two-Photon Fluorescent Probe for Imaging Endogenous ONOO- near NMDA Receptors in Neuronal Cells and Hippocampal Tissues. AB - In this study, we developed a two-photon fluorescent probe for detection of peroxynitrite (ONOO-) near the N-methyl-d-aspartate (NMDA) receptor. This naphthalimide-based probe contains a boronic acid reactive group and an ifenprodil-like tail, which serves as an NMDA receptor targeting unit. The probe displays high sensitivity and selectivity, along with a fast response time in aqueous solution. More importantly, the probe can be employed along with two photon fluorescence microscopy to detect endogenous ONOO- near NMDA receptors in neuronal cells as well as in hippocampal tissues. The results suggest that the probe has the potential of serving as a useful imaging tool for studying ONOO- related diseases in the nervous system. PMID- 29968466 TI - How a Solvent Molecule Affects Competing Elimination and Substitution Dynamics. Insight into Mechanism Evolution with Increased Solvation. AB - Competiting SN2 substitution and E2 elimination reactions are of central importance in preparative organic synthesis. Here, we unravel how individual solvent molecules may affect underlying SN2/E2 atomistic dynamics, which remains largely unclear with respective to their effects on reactivity. Results are presented for a prototype microsolvated case of fluoride anion reacting with ethyl bromide. Reaction dynamics simulations reproduce experimental findings at near thermal energies and show that the E2 mechanism dominates over SN2 for solvent-free reaction. This is energetically quite unexpected and results from dynamical effects. Adding one solvating methanol molecule introduces strikingly distinct dynamical behaviors that largely promote the SN2 reaction, a feature which attributes to a differential solute-solvent interaction at the central barrier that more strongly stabilizes the transition state for substitution. Upon further solvation, this enhanced stabilization of the SN2 mechanism becomes more pronounced, concomitant with drastic suppression of the E2 route. This work highlights the interplay between energetics and dynamics in determining mechanistic selectivity and provides insight into the impact of solvent molecules on a general transition from elimination to substitution for chemical reactions proceeding from gas- to solution-phase environments. PMID- 29968467 TI - Simultaneous Quantification of Electron Transfer by Carbon Matrices and Functional Groups in Pyrogenic Carbon. AB - Pyrogenic carbon contains redox-active functional groups and polyaromatic carbon matrices that are both capable of transferring electrons. Several techniques have been explored to characterize the individual electron transfer process of either functional groups or carbon matrices individually. However, simultaneous analysis of both processes remains challenging. Using an approach that employs a four electrode configuration and dual-interface electron transfer detection, we distinguished the electron transfer by functional groups from the electron transfer by carbon matrices and simultaneously quantified their relative contribution to the total electron transfer to and from pyrogenic carbon. Results show that at low to intermediate pyrolysis temperatures (400-500 degrees C), redox cycling of functional groups is the major mechanism with a contribution of 100-78% to the total electron transfer; whereas at high temperatures (650-800 degrees C), direct electron transfer of carbon matrices dominates electron transfer with a contribution of 87-100%. Spectroscopic and diffraction analyses of pyrogenic carbon support the electrochemical measurements by showing a molecular-level structural transition from an enrichment in functional groups to an enrichment in nanosized graphene domains with increasing pyrolysis temperatures. The method described in this study provides a new analytical approach to separately quantify the relative importance of different electron transfer pathways in natural pyrogenic carbon and has potential applications for engineered carbon materials such as graphene oxides. PMID- 29968468 TI - Refreshable Tactile Display Based on a Bistable Electroactive Polymer and a Stretchable Serpentine Joule Heating Electrode. AB - The demand for tactile interactive devices has been growing exponentially as the sense of touch enriches the human-machine interaction experience. However, the tactile devices reported so far cannot offer high-quality performance, compact form factor, and relatively simple system architecture for low-cost production. We report the fabrication of a 4 * 4 pneumatic tactile display with Braille standard resolution using a bistable electroactive polymer (BSEP) thin film and a serpentine-patterned carbon nanotube electrode. The BSEP is a variable stiffness material that exhibits a stiffness change of 3000-fold within the narrow temperature range of 43 +/- 3 degrees C. The carbon nanotube electrode was patterned on the polymer film via a P3R process, Prestretch-Pattern-Protect Release, which leads to a serpentine-patterned composite electrode that is highly stretchable, retains its high electrical conductivity up to an ~200% area strain, and provides a fast Joule heating rate of 31 degrees C/s. The tactile pixels are diaphragm actuators that can be individually controlled to produce 0.7 mm out of plain deformation and greater than 50 g of blocking force by application of local heating and pneumatic pressure. The device can operate under low voltage supply (30 V) and has a lifetime of over 100 000 cycles without much performance degradation. This work could open a path to building compact, user-friendly, and cost-effective tactile devices for a variety of important applications. PMID- 29968469 TI - Sulfanilic Acid Pending on a Graphene Scaffold: Novel, Efficient Synthesis and Much Enhanced Polymer Solar Cell Efficiency and Stability Using It as a Hole Extraction Layer. AB - In this contribution, we describe a novel, facile, and scalable methodology for high degree functionalization toward graphene by the reaction between bulk graphite fluoride and in situ generated amine anion. Using this, the rationally designed sulfanilic acid pending on a graphene scaffold (G-SO3H), a two dimensional (2D) pi-conjugated counterpart of poly(styrenesulfonate), is available. Combined reliable characterizations demonstrate that a very large quantity of sulfanilic blocks are linked to graphene through the foreseen substitution of carbon-fluorine units and an unexpected reductive defluorination simultaneously proceeds during the one-step reaction, endowing the resultant G SO3H with splendid dispersity in various solvents and film-forming property via the former, and with recovered 2D pi-conjugation via the latter. Besides, the work function of G-SO3H lies at -4.8 eV, well matched with the P3HT donor. Awarded with these fantastic merits, G-SO3H behaves capable in hole collection and transport, indicated by the enhanced device efficiency and stability of polymer solar cells (PSCs) based on intensively studied P3HT:PCBM blends as an active layer. In particular, comparison with conventional poly(3,4 ethylenedioxythiophene) doped with poly(styrenesulfonate) and recently rising and shining graphene oxide, G-SO3H outperforms above 17 and 24%, respectively, in efficiency. More impressively, when these three unencapsulated devices are placed in a N2-filled glovebox at around 25 degrees C for 7 weeks, or subject to thermal treatment at 150 degrees C for 6 h also in N2 atmosphere, or even rudely exposed to indoor air, G-SO3H-based PSCs exhibit the best stability. These findings enable G-SO3H to be a strongly competitive alternative of the existing hole extraction materials for PSC real-life applications. PMID- 29968470 TI - Soft Display Using Photonic Crystals on Dielectric Elastomers. AB - Soft display has been intensively studied in recent years in the wake of rapid development of a variety of soft materials. The currently existing solutions for translating the traditional hard display into the more convenient soft display mainly include light-emitting diodes, liquid crystals, quantum dots, and phosphors. The desired soft display should take the advantages of facile fabrication processes and cheap raw materials. Besides, the device should be colorful, nontoxic, and not only flexible but also stretchable. However, the foregoing devices may not own all of the desired features. Here, a new type of soft display, which consists of dielectric elastomer and photonic crystals that cover all of the features mentioned above and can achieve the color change dynamically and in situ, is reported. In addition to the above features, the angle-dependent characteristic and the excellent mechanical reliability make it a great candidate for the next generation of soft display. Finally, the vast applications of the present concept in a variety of fields are also prospected. PMID- 29968471 TI - One-Pot Multienzyme Cofactors Recycling (OPME-CR) System for Lactose and Non natural Saccharide Conjugated Polyphenol Production. AB - A one-pot multienzyme cofactors recycling (OPME-CR) system was designed for the synthesis of UDP-alpha-d-galactose, which was combined with LgtB, a beta-(1,4) galactosyltransferase from Neisseria meningitidis, to modify various polyphenol glycosides. This system recycles one mole of ADP and one mole of UDP to regenerate one mole of UDP-alpha-d-galactose by consuming two moles of acetylphosphate and one mole of d-galactose in each cycle. The ATP additionally used to generate UDP from UMP was also recycled at the beginning of the reaction. The engineered cofactors recycling system with LgtB efficiently added a d galactose unit to a variety of sugar units such as d-glucose, rutinose, and 2 deoxy-d-glucose. The temperature, pH, incubation time, and divalent metal ions for the OPME-CR system were optimized. The maximum number of UDP-alpha-d galactose regeneration cycles (RCmax) was 18.24 by fed batch reaction. The engineered system generated natural and non-natural polyphenol saccharides efficiently and cost-effectively. PMID- 29968472 TI - Effect of Isomerization on High-Performance Nonfullerene Electron Acceptors. AB - We design and synthesize two isomeric fused-ring electron acceptors, FNIC1 and FNIC2, which have the same end-groups and side-chains, but isomeric fused-nine ring cores. Subtle changes in the two isomers influence their electronic, optical, charge-transport, and morphological properties. As compared with FNIC1, FNIC2 film exhibits a red-shifted absorption peak at 794 nm (752 nm for FNIC1), larger electron affinity of 4.00 eV (3.92 eV for FNIC1), smaller ionization energy of 5.56 eV (5.61 eV for FNIC1), and higher electron mobility of 1.7 * 10-3 cm2 V-1 s-1 (1.2 * 10-3 cm2 V-1 s-1 for FNIC1). The as-cast organic solar cells based on PTB7-Th:FNIC2 blends exhibit a power conversion efficiency (PCE) of 13.0%, which is significantly higher than that of PTB7-Th:FNIC1-based devices (10.3%). Semitransparent devices based on PTB7-Th:FNIC2 blends exhibit PCEs varying from 9.51% to 11.6% at different average visible transmittance (AVT, 20.3 13.6%), significantly higher than those of PTB7-Th:FNIC1-based devices (7.58 9.14% with AVT of 20.2- 14.7%). PMID- 29968473 TI - Theoretical Investigation of Plutonium-Based Single-Molecule Magnets. AB - The electronic structure of a plutonium-based single-molecule magnet (SMM) was theoretically examined by means of multiconfigurational electronic structure theory calculations, including spin-orbit coupling effects. All Pu 5f to 5f transitions for all possible spin states were computed, as well as ligand to metal charge transfer and Pu 5f to 6d transitions. Spin-orbit coupling effects were included a posteriori to accurately describe the electronic transitions. The spin-orbit coupled energies and magnetic moments were then used to compute the magnetic susceptibility curves. The experimental electronic structure and magnetic susceptibility curve were reproduced well by our calculations. A compound with a modified electron-donating ligand (namely a carbene ligand) was also investigated in an attempt to tune the electronic properties of the plutonium SMM, revealing a higher ligand field splitting of the 5f orbitals of Pu, which could in turn enhance the barrier against magnetic relaxation. PMID- 29968474 TI - Keratinases as an Alternative Method Designed To Solve Keratin Disposal on the Environment: Its Relevance on Agricultural and Environmental Chemistry. PMID- 29968475 TI - Rearrangement of Hydroxylated Pinene Derivatives to Fenchone-Type Frameworks: Computational Evidence for Dynamically-Controlled Selectivity. AB - An acid-catalyzed Prins/semipinacol rearrangement cascade reaction of hydroxylated pinene derivatives that leads to tricyclic fenchone-type scaffolds in very high yields and diastereoselectivity has been developed. Quantum chemical analysis of the selectivity-determining step provides support for the existence of an extremely flat potential energy surface around the transition state structure. This transition state structure appears to be ambimodal, i.e., the fenchone-type tricyclic scaffolds are formed in preference to the competing formation of a bornyl (camphor-type) skeleton under dynamic control via a post transition state bifurcation (PTSB). PMID- 29968476 TI - Fermi Level Determination for Charged Systems via Recursive Density of States Integration. AB - Determining the Fermi level position for a given material is important to understand many of its electronic and chemical properties. Ab initio methods are effective in computing Fermi levels when using charge-neutral supercells. However, in the case where charges are explicitly included, the compensating homogeneous background charge, which is necessary to maintain charge neutrality in periodic models, causes the vacuum potential to be ill-defined - which would otherwise have been a reliable reference potential. Here, we develop a method based on recursively integrating the density of states to determine shifts in the Fermi level upon charging. By introducing incremental charges, one can compute the density of states profile and determine the shift in the Fermi level that corresponds to adding or removing a given increment of charge deltaq, which allows the evaluation of the Fermi level for any arbitrary charge q. We test this method for a range of materials (graphene, h-BN, C3N4, Cu, and MoS2) and demonstrate that this method can produce a reasonable agreement with models that rely on localized compensating background charges. PMID- 29968477 TI - Randomness-Induced Phonon Localization in Graphene Heat Conduction. AB - Through nonequilibrium molecular dynamics simulations, we report the direct numerical evidence of the coherent phonons participating in thermal transport at room temperature in graphene phononic crystal (GPnC) structure and evaluate their contribution to thermal conductivity based on the two-phonon model. With decreasing period length in GPnC, the transition from the incoherent to coherent phonon transport is clearly observed. When a random perturbation to the positions of holes is introduced in a graphene sheet, the phonon wave-packet simulation reveals the presence of notable localization of coherent phonons, leading to the significant reduction of thermal conductivity and suppressed length dependence. Finally, the effects of period length and temperature on the coherent phonon contribution to thermal conductivity are also discussed. Our work establishes a deep understanding of the coherent phonons transport behavior in periodic phononic structures, which provides effective guidance for engineering thermal transport based on a new path via phonon localization. PMID- 29968478 TI - Enantioselective Access to Chiral 2-Substituted 2,3-Dihydrobenzo[1,4]dioxane Derivatives through Rh-Catalyzed Asymmetric Hydrogenation. AB - Rh-catalyzed asymmetric hydrogenation of various benzo[ b][1,4]dioxine derivatives was successfully developed to prepare chiral 2-substituted 2,3 dihydrobenzo[1,4]dioxane derivatives using ZhaoPhos and N-methylation of ZhaoPhos ligands with high yields and excellent enantioselectivities (up to 99% yield, >99% enantiomeric excess (ee), turnover number (TON) = 24 000). Moreover, this asymmetric hydrogenation methodology, as the key step with up to 10 000 TON, was successfully applied to develop highly efficient synthetic routes for the construction of some important biologically active molecules, such as MKC-242, WB4101, BSF-190555, and ( R)-doxazosin.HCl. PMID- 29968479 TI - New hepatoprotective isoflavone glucosides from Pueraria lobata (Willd.) Ohwi. AB - Two new isoflavone glucosides, 3'-methoxyneopuerarin A (1) and 3' methoxyneopuerarin B (2), together with nine known isoflavones including puerarin (3), neopuerarin A (4), neopuerarin B (5), daidzin (6), daidzein (7), 3' methoxypuerarin (PG-3) (8), puerarin xyloside (9), mirificin (10), 3' hydroxypuerarin (11) were isolated from the water extraction of the dried roots of Pueraria lobata (Willd.) Ohwi. Their structures were elucidated by the means of spectroscopic and chromatographic analysis methods. All compounds were evaluated for their hepatoprotective activity on HepG2 cells. All of them showed statistically significant hepatoprotective effect. PMID- 29968480 TI - Augmented anticancer activity of naringenin-loaded TPGS polymeric nanosuspension for drug resistive MCF-7 human breast cancer cells. AB - Naringenin (NAR) is a naturally occurring plant flavonoid, found predominantly in citrus fruits, possesses a wide range of pharmacological properties. However, despite the therapeutic potential of NAR, its clinical development has been hindered due to low aqueous solubility and inefficient transport across biological membranes resulting in low bioavailability at tumor sites. In our previous studies, nanosuspension of naringenin (NARNS) was prepared using high pressure homogenization method using different polymers. D-alpha-Tocopheryl polyethylene glycol succinate 1000 (TPGS) was added as a co-stabilizer. All formulation characterization studies were performed. As a continuation of our previous research, current study has further evaluated the ability of the TPGS coated NARNS, to reverse drug-resistance of P-gp-over expressing MCF-7 human breast adenocarcinoma cell line and animal model. MTT-based colorimetric assay revealed higher cytotoxic efficacy of NARNS than free NAR in MCF-7 cells. NARNS treatment significantly increased intracellular ROS level, mitochondrial membrane potential, caspase-3 activity, lipid peroxidation status (TBARS) and decreased GSH levels when compared to free NAR treatment in MCF-7 cells. It has been also noticed that the presence of apoptotic indices (membrane blebbing, nuclear fragmentation) in NARNS treated cancer cells. Further, NARNS exhibited dose dependent in vitro antitumor activity with DLA cells. A significant increase in the life span and a decrease in the cancer cell number and tumor weight were noted in the tumor-induced mice after treatment with NARNS. PMID- 29968481 TI - Prevalence of hypothyroidism among patients with isthmus-preserved thyroid lobectomy. AB - Objective To investigate the prevalence of hypothyroidism following thyroid lobectomy with isthmus preservation. Methods This retrospective, case series study included patients who had undergone thyroid lobectomy with preserved isthmus that was reversed onto the contralateral lobe. Neck ultrasound was performed in all patients and the patients were followed for 2 years. Results Out of 170 patients enrolled into the study, three were excluded due to preoperative hypothyroidism and one due to isthmusectomy; of the remaining 166 included in the final analyses, 139 patients (83.7%) were female, 27 (16.3%) were male, and patient age ranged between 17 and 77 years. The indication for intervention was thyroid swelling in 141 patients (84.9%). Final diagnoses following histopathological examination comprised benign lesion in 145 cases (87.3%), malignancy (follicular carcinoma and papillary thyroid carcinoma) in 12 cases (7.2%) and thyroiditis in nine cases (5.4%). During the 2-year post-surgery follow-up, 165 patients (99.4%) were euthyroid and one patient (0.6%) developed hypothyroidism. Conclusion Postoperative hypothyroidism following thyroid lobectomy appears to be very rare when the isthmus is preserved and reversed onto the contralateral lobe. PMID- 29968482 TI - Synthesis of some novel orsellinates and lecanoric acid related depsides as alpha glucosidase inhibitors. AB - Sixteen novel orsellinic esters (6a-l, 7a-d) along with four lecanoric acid related depsides (3a-c, 4) were synthesized and confirmed their structures by spectroscopic data (1H, 13C & HRMS). The synthesized compounds were evaluated for their in vitro alpha-glucosidase (Saccharomyces cerevisiae) inhibitory potential. Among the tested compounds, 3c (IC50: 140.9 MUM) and 6c (IC50: 203.9 MUM) displayed potent alpha-glucosidase inhibitory activity and found more active than the standard drug acarbose (IC50: 686.6 MUM). Both the test compounds were subjected to in vivo antihyperglycemic activity using sucrose loaded model in Wistar rats and found compound 3c exhibited significant reduction in glucose levels. PMID- 29968483 TI - The sensitivity of fecal calprotectin in predicting deep remission in ulcerative colitis. AB - BACKGROUND: Mucosal healing is proposed as treat-to-target in ulcerative colitis (UC), even though the definition of mucosal healing remains contested as it has been suggested to be assessed by either endoscopy, histology or both. However, all definitions require an endoscopic evaluation of the mucosa. As endoscopies are invasive and uncomfortable to the patient we aimed to calibrate noninvasive predictors of mucosal inflammatory status defined by both endoscopy and histology. METHODS: UC patients (n = 106) undergoing a sigmoid-/colonoscopy were prospectively included. Feces (fecal calprotectin, FC), blood samples (hemoglobin, C-reactive protein, orosomucoid, erythrocyte sedimentation rate, albumin) and symptom scores (Simple Clinical Colitis Activity Index, SSCAI) were collected and analyzed. The colonic mucosa was assessed by the Mayo endoscopic sub score and biopsies were obtained for a histologic grading by Geboes score. Predictive cutoff values were analyzed by receiver operating characteristics (ROC). A combined endoscopic and histologic assessment defined deep remission (Mayo =0 and Geboes <=1) and activity (Mayo >=2 and Geboes >3). RESULTS: Only FC showed a significant ROC curve (p < .05). We suggest FC (mg/kg) cutoffs for detection of following: Deep remission: FC <=25; Indeterminate: FC 25-230 - an endoscopy is recommended if a comprehensive status of both endoscopic and histologic assessed activity is needed; Active disease: FC >230. The complete ROC data is presented, enabling extraction of an FC cutoff value's sensitivity and specificity. CONCLUSIONS: FC predicts endoscopic and histologic assessed deep remission and inflammatory activity of colon mucosa. Neither the markers in blood nor the SCCAI performed significant ROC results. PMID- 29968484 TI - Chronic heart failure in patients with nonalcoholic fatty liver disease: prevalence, clinical features, and relevance. AB - Objective This study was performed to assess the prevalence of nonalcoholic fatty liver (NAFL) in patients with symptomatic congestive heart failure (CHF) and compare the clinical features with those of patients without NAFL. Methods In total, 102 patients with CHF were divided into NAFL and non-NAFL groups according to their hepatic ultrasonography findings. All patients underwent transthoracic echocardiography and cardiac magnetic resonance examination. Follow-up was performed for major cardiovascular events (MACE) and readmission due to heart failure at 1, 3, 6, and 12 months after the index hospitalization. Results NAFL was detected in 37 of 102 patients (36.27%). Compared with the non-NAFL group, patients with NAFL were younger, had a higher body mass index and left ventricular (LV) mass index, and had more severe fibrosis. MACE and readmission occurred in 15 patients in the NAFL group and 29 patients in the non-NAFL group, without a significant difference. Linear regression analysis revealed that after adjusting for confounders, NAFL was independently associated with the LV fibrosis size and the ratio of the LV fibrosis size to the LV mass index. Conclusions NAFL is present in more than one-third of patients with CHF and is associated with the severity of LV fibrosis. PMID- 29968485 TI - Undergraduate education in anaesthesia, intensive care, pain, and perioperative medicine: The development of a national curriculum framework. AB - INTRODUCTION: The study describes the development of the first UK national framework to guide undergraduate education in anesthesia, perioperative medicine, critical care, and pain medicine. METHODS: We followed an inclusive process of curriculum design aiming to promote high-level learning amongst students. We conducted telephone interviews with senior anesthetic educators at 33 UK medical schools to establish current provision and practice. We then held a consultative national workshop for educators, using focus group interviews to set broad aims for the final framework and gather information. RESULT: Anesthesia undergraduate educators demonstrated a conceptual focus that moves beyond simple acquisition of knowledge to one geared to encouraging clinical behavioral change in learners to equip them for practice as new doctors. Respondents also highlighted the opportunities for promoting spiral, integrated, and longitudinal learning within the undergraduate curriculum. We also formulated eight key domains of practice in anesthesia and critical care and mapped 63 of the 106 General Medical Council's Outcomes for Graduates against these domains, and created a brief suggested syllabus. CONCLUSIONS: The framework aims to provide support and guidance for medical schools in the development of competent, well-rounded doctors who are able to provide safe, patient-centered care in all areas of medical practice. PMID- 29968486 TI - Microneedles Improve the Immunogenicity of DNA Vaccines. AB - DNA vaccines can elicit both humoral and cellular immune responses in mice. However, their poor immunogenicity is a major obstacle toward clinical applications. Improving the efficiency of delivery of DNA vaccines has become a key issue. Vaccination via microneedles penetrating the epidermis can dramatically enhance the stimulation of immune responses. This study showed that by using microneedles to deliver DNA vaccines, gene expression and corresponding immune responses were greatly improved compared to conventional needle injection. The quantitative analysis of gene expressions was made at 6, 24, 72, and 144 h after the DNA delivery. DNA expression levels increased in a time-dependent manner and were substantially greater than with syringe injection after 6 h and 24 h. This elevated expression was followed by markedly enhanced immune responses, with 6-10 times higher levels of antibody and T-cell responses. PMID- 29968487 TI - Chronic kidney disease is associated with carotid atherosclerosis and symptomatic ischaemic stroke. AB - Objective We aimed to investigate the relationships among chronic kidney disease (CKD), symptomatic ischaemic stroke, and carotid atherosclerosis. Methods We enrolled 455 patients who underwent carotid ultrasonography in our hospital, including 311 patients with symptomatic ischaemic stroke and 144 patients without symptomatic ischaemic stroke. Carotid intima-media thickness (IMT), the rate of internal carotid artery stenosis, and maximal plaque size were evaluated. Results The mean age of the patients was 68.5 +/- 11.0 years and the mean estimated glomerular filtration rate (eGFR) was 68.8 +/- 18.2 mL/min/1.73 m2. After adjustment for cardiovascular risk factors, the mean IMT was significantly higher in patients with CKD than in those without CKD. The IMT and eGFR were negatively correlated in patients with stroke (r = -0.169). Multiple logistic regression analyses showed that mean IMT, plaque size, and internal carotid artery stenosis were significant determinants of symptomatic ischaemic stroke after adjustment of multivariate risk factors. Furthermore, the eGFR was a negative determinant of symptomatic ischaemic stroke after adjusting for classical risk factors (odds ratio [95% confidence interval] = 0.868 [0.769-0.979]). Conclusion CKD might be associated with the carotid atherosclerosis and symptomatic ischaemic stroke. PMID- 29968488 TI - Effect of platelet-rich plasma (PRP) on ovarian structures in cyclophosphamide induced ovarian failure in female rats: a stereological study. AB - BACKGROUND: Ovarian failure is diagnosed by ovarian destruction and reducing sex hormonal levels. Platelet-rich plasma (PRP) contains several growth factors that induce tissue repair and may induce folliculogenesis. OBJECTIVE: This study evaluates the effect of PRP on ovarian structures and function in cyclophosphamide (Cy)-induced ovarian failure in female rats by a stereological method. METHODS: Thirty-two adult female rats were divided into four groups (Control, Cy, Cy + PRP, and PRP). Female infertility was induced by Cy (75 mg/kg, single dose, intraperitoneally). Animals were treated by PRP which was obtained from age-matched male rats (200 MUL, single dose, intraperitoneally). Blood samples were collected for measurement of hormones. The animals were dissected and the right ovaries were removed, fixed, sectioned, and stained by H&E. Stereological methods were used to estimate cortex and medulla volume, and the number and diameter of follicles, follicular cell, and oocyte using light microscopy. RESULTS: Cyclophosphamide had the maximum effect in decreasing on cortex volume, the pre-antral follicles number, a diameter of follicular cells and oocyte diameter in the antral follicle and the reduction of estradiol and progesterone levels compared with the control group. PRP had a dominant positive effect on the ovarian cortex volume, pre-antral follicles number and antral follicle diameter relative to the control group. PRP also decreased oocyte diameter in pre-antral follicle in infertile animals (p < 0.001). CONCLUSION: It seems that PRP has a protective effect on ovarian failure in the infertile female rat model. PMID- 29968489 TI - Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy. AB - Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted beta-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants. PMID- 29968490 TI - Immunity and longevity. AB - The role of immune system is to protect the organism from the not built-in program-like alterations inside and against the agents penetrating from outside (bacteria, viruses, and protozoa). These functions were developed and formed during the evolution. Considering these functions, the immune system promotes the lengthening of lifespan and helps longevity. However, some immune functions have been conveyed by men to medical tools (e.g., pharmaceuticals, antibiotics, and prevention), especially in our modern age, which help the struggle against microbes, but evolutionarily weaken the immune system. Aging is a gradual slow attrition by autoimmunity, directed by the thymus and regulated by the central nervous system and pineal gland. Considering this, thymus could be a pacemaker of aging. The remodeling of the immune system, which can be observed in elderly people and centenarians, is probably not a cause of aging, but a consequence of it, which helps to suit immunity to the requirements. Oxidative stress also helps the attrition of the immune cells and antioxidants help to prolong lifespan. There are gender differences in the aging of the immune system as well as in the longevity. There is an advantage for women in both cases. This can be explained by hormonal differences (estrogens positively influences both processes); however, social factors are also not excluded. The endocrine disruptor chemicals act similar to estrogens, like stimulating or suppressing immunity and provoking autoimmunity; however, their role in longevity is controversial. There are some drugs (rapamycin, metformin, and selegiline) and antioxidants (as vitamins C and E) that prolong lifespan and also improve immunity. It is difficult to declare that longevity is exclusively dependent on the state of the immune system; however, there is a parallelism between the state of immune system and lifespan. It seems likely that there is not a real decline of immunity during aging, but there is a remodeling of the system according to the claims of senescence. This is manifested in the remaining (sometimes stronger) function of memory cells in contrast to the production and number of the new antigen-reactive naive T-cells. PMID- 29968491 TI - High-shear granulation of high-molecular weight hypromellose: effects of scale-up and process parameters on flow and compaction properties. AB - CONTEXT: Knowledge of the effects of high-shear granulation process parameters and scale-up on the properties of the produced granules is essential for formulators who face challenges regarding poor flow and compaction during development of modified release tablets based on high-molecular weight hypromellose (hydroxypropylmethylcellulose (HPMC)) polymers. Almost none of the existing studies deal with realistic industrial formulation. OBJECTIVE: The aim was to investigate the effects of scale-up and critical process parameters (CPPs) of high-shear granulation on the quality attributes of the granules, particularly in terms of the flow and compaction, using a realistic industrial formulation based on HPMC K100M polymer. METHODS: The flow properties were determined using flow time, Carr index, tablet mass, and crushing strength variations. The compaction properties were quantified using the 'out-of-die' Heckel and modified Walker models, as well as the tensile strength profile and elastic recovery. High shear granulation was performed at different scales: 4 L, 300 L, and 600 L. RESULTS AND CONCLUSION: The scale itself had larger effects on the granule properties than the CPPs, which demonstrated high robustness of formulation on the individual scale level. Nevertheless, to achieve the desired flow and compaction, the values of the CPPs need to be precisely selected to fine-tune the process conditions. The best flow was achieved at high volumes of water addition, where larger and more spherical granules were obtained. The CPPs showed negligible influence on the compaction with no practical implications, however, the volume of water addition volume was identified as having the largest effects on compaction. PMID- 29968492 TI - Epstein-Barr Virus-Positive CD20- and CD45-Negative Diffuse Large B-Cell Lymphoma: A Diagnostic Challenge. AB - Diffuse large B-cell lymphoma (DLBCL) is characterized by medium- to large-sized neoplastic cells that express a wide range of B-cell markers including CD19, CD20, CD22, and CD79a. Also, as this is a hematopoietic malignancy, there is expression of the leukocyte common antigen CD45. Lack of CD20 expression occurs in a specific rare heterogeneous subgroup of DLBCL including primary effusion lymphoma, plasmablastic lymphoma, ALK-positive large B-cell lymphoma, and large B cell lymphoma arising in HHV8+ multicentric Castleman disease. In this article, we report a rare case of CD20- and CD45-negative Epstein-Barr virus-positive DLBCL in which the entities listed above were ruled out, thereby posing a significant diagnostic challenge. Arriving at the correct diagnosis of Epstein Barr virus-positive DLBCL was supported by immunoreactivity for the B-cell transcription factor Oct-2 and the pan-B cell marker CD79a. PMID- 29968493 TI - Turning disability into ability: barriers and facilitators to initiating and maintaining exercise among older men living with HIV. AB - Physical activity reduces the risk for comorbidities, but little is known about barriers to exercise among older adults living with HIV. Three focus groups were conducted among 19 adults living with HIV, aged >= 50 years, who were enrolled in or recently completed a supervised exercise intervention. Sessions were recorded, transcribed, and coded first using inductive methods. All participants were male, and the majority were white, non-Hispanic; 53% were receiving disability benefits. All had suppressed HIV infection on antiretroviral therapy, with almost 20 years since HIV diagnosis. Participants noted a lack of self-efficacy, motivation, and physical limitations that contributed to a sense of "disability" as barriers to exercise prior to the intervention. Through social support and improvements in self-efficacy, participants were motivated to start and continue exercising. Perceived sense of disability may impede (or interfere with) exercise initiation and maintenance; self-efficacy and social support may facilitate exercise maintenance in older adults living with HIV. PMID- 29968494 TI - Type 2 diabetes management among older American Indians: beliefs, attitudes, and practices. AB - OBJECTIVE: The purpose of this study was to examine beliefs, attitudes, and practices of older American Indians regarding their type 2 diabetes mellitus (T2DM) management. T2DM is one of the leading causes of morbidity and mortality among American Indians. American Indians are more than twice as likely to have T2DM and have over three times a T2DM mortality rate as Whites. DESIGN: Study participants were older members of a federally recognized tribe who had T2DM. A low-inference qualitative descriptive design was used. Data were collected through semi-structured in-depth qualitative interviews with a mixed inductive, deductive, and reflexive analytic team process. RESULTS: Our study sample included 28 participants with a mean age of 73.0 +/- 6.4 years of whom 16 (57%) were women. Participants' mean self-confidence score of successful T2DM management was 8.0 +/- 1.7 on a scale from 1 to 10 with 10 representing the greatest amount of confidence. Participants' mean HbA1c was 7.3% +/- 1.5%. Overall, participants discussed T2DM management within five themes: 1) sociocultural factors, 2) causes and consequences, 3) cognitive and affective assessment, 4) diet and exercise, and 5) medical management. CONCLUSIONS: It is important to be aware of the beliefs and attitudes of patients. Lay understandings can help identify factors underlying health and illness behaviors including motivations to maintain healthy behaviors or to change unhealthy behaviors. Such information can be helpful for health educators and health promotion program staff to ensure their efforts are effective and in alignment with patients' realities. PMID- 29968497 TI - Double simultaneous intussusception caused by Meckel's diverticulum and intestinal duplication in a child. AB - Intussusception is common in children. Double simultaneous intussusception is a peculiar variety of intussusception with only 14 previously reported cases. We report a unique case of a child who suffered from double simultaneous intussusception with two lead points (Meckel's diverticulum and intestinal duplication). The patient was successfully treated with manual reduction along with resection of Meckel's diverticulum and intestinal duplication. The child recovered well. PMID- 29968498 TI - Fecal fusobacterium nucleatum for detecting colorectal cancer: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the efficacy of fecal Fusobacterium nucleatum ( Fn) for detecting colorectal cancer. It is the first systematic review and meta-analysis to focus exclusively on fecal Fn for colorectal cancer. MATERIALS AND METHODS: Comprehensive searches of several databases before January 2018 were conducted. Fecal Fn for detecting colorectal cancer was evaluated via pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve. Heterogeneity was explored using meta regression and subgroup analyses. The publication bias and the overall quality of evidence were also analyzed. RESULTS: Our analysis included six papers containing seven case-control studies in the systematic review and meta-analysis. Overall sensitivity and specificity were 0.68 (95% confidence interval (CI) 0.64, 0.72) and 0.78 (95% CI 0.75, 0.81), respectively. The positive likelihood ratio and negative likelihood ratio in detecting colorectal cancer were 2.87 (95% CI 1.62, 5.10) and 0.40 (95% CI 0.30, 0.54) respectively. The diagnostic odds ratio (OR) was 8.75 (95% CI 4.86, 15.78) and the area under the curve was 0.80. A subgroup analysis showed that in Asia, the colorectal cancer sample size ?50 had higher specificity (specificity 0.85, 95% CI 0.80, 0.88). No publication bias existed. The GRADEpro showed a moderate level of the available evidence. CONCLUSIONS: Compared to other examinations, the fecal Fn test seems a good choice for detecting colorectal cancer. It also has better diagnostic performance in Asians. However, more clinical trials with large sample sizes and strict randomization are needed to further verify the evidence. PMID- 29968495 TI - Broad-Spectrum and Personalized Guide RNAs for CRISPR/Cas9 HIV-1 Therapeutics. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-associated Cas9 system has been used to excise the HIV-1 proviral genome from latently infected cells, potentially offering a cure for HIV-infected patients. Recent studies have shown that most published HIV-1 guide RNAs (gRNAs) do not account for the diverse viral quasispecies within or among patients, which continue to diversify with time even in long-term antiretroviral therapy (ART)-suppressed patients. Given this observation, proviral genomes were deep sequenced from 23 HIV-1-infected patients in the Drexel Medicine CNS AIDS Research and Eradication Study cohort at two different visits. Based on the spectrum of integrated proviral DNA polymorphisms observed, three gRNA design strategies were explored: based on the patient's own HIV-1 sequences (personalized), based on consensus sequences from a large sample of patients [broad-spectrum (BS)], or a combination of both approaches. Using a bioinformatic algorithm, the personalized gRNA design was predicted to cut 46 of 48 patient samples at 90% efficiency, whereas the top 4 BS gRNAs (BS4) were predicted to excise provirus from 44 of 48 patient samples with 90% efficiency. Using a mixed design with the top three BS gRNAs plus one personalized gRNA (BS3 + PS1) resulted in predicted excision of provirus from 45 of 48 patient samples with 90% efficiency. In summary, these studies used an algorithmic design strategy to identify potential BS gRNAs to target a spectrum of HIV-1 long teriminal repeat (LTR) quasispecies for use with a small HIV-1 infected population. This approach should advance CRISPR/Cas9 excision technology taking into account the extensive molecular heterogeneity of HIV-1 that persists in situ after prolonged ART. PMID- 29968496 TI - The paradigm shift for drug delivery systems for oral and maxillofacial implants. AB - Along with the development of nanotechnological strategies for biomaterials associated with the prevention of infections, a myriad of clinically unproven techniques have been described to date. In this work, the aim was to perform a critical analysis of the literature available concerning antibacterial biomaterials for oral implantology and to provide a practical derivation for such a purpose. As anti-adhesive strategies may affect osseointegration, they should no longer be recommended for inclusion in this class of biomaterials, despite promising results in biomedical engineering for other, non-bone load bearing organs. Targeted, antibacterial drug delivery is most likely desirable in the case of intraosseous implants. Interfering factors such as the oral cavity environment, saliva, the bacterial microbiome, as well as, the characteristics of the alveolar mucosa and peri-implant space must be taken into account when calculating the local pharmacokinetics for antibacterial coatings. Effective release is crucial for tailoring antibacterial implant longevity providing minimal inhibitory concentration (MIC) for the desired amount of time, which for oral implants, should be at least the cumulative time for the osseointegration period and functional loading period within the tissues. These parameters may differ between the implant type and its anatomical site. Also, the functional drug concentration in the peri-implant space should be calculated as the amount of the drug released from the implant surface including the concentration of the drug inactivated by biological fluids of the peri-implant space or saliva flow throughout the effective release time. PMID- 29968499 TI - Flow-metabolism uncoupling in patients with asymptomatic unilateral carotid artery stenosis assessed by multi-modal magnetic resonance imaging. AB - Oxygen extraction (OEF), oxidative metabolism (CMRO2), and blood flow (CBF) in the brain, as well as the coupling between CMRO2 and CBF due to cerebral autoregulation are fundamental to brain's health. We used a clinically feasible MRI protocol to assess impairments of these parameters in the perfusion territories of stenosed carotid arteries. Twenty-nine patients with unilateral high-grade carotid stenosis and thirty age-matched healthy controls underwent multi-modal MRI scans. Pseudo-continuous arterial spin labeling (pCASL) yielded absolute CBF, whereas multi-parametric quantitative blood oxygenation level dependent (mqBOLD) modeling allowed imaging of relative OEF and CMRO2. Both CBF and CMRO2 were significantly reduced in the stenosed territory compared to the contralateral side, while OEF was evenly distributed across both hemispheres similarly in patients and controls. The CMRO2-CBF coupling was significantly different between both hemispheres in patients, i.e. significant interhemispheric flow-metabolism uncoupling was observed in patients compared to controls. Given that CBF and CMRO2 are intimately linked to brain function in health and disease, the proposed easily applicable MRI protocol of pCASL and mqBOLD imaging might serve as a valuable tool for early diagnosis of potentially harmful cerebral hemodynamic and metabolic states with the final aim to select clinically asymptomatic patients who would benefit from carotid revascularization therapy. PMID- 29968500 TI - Amiloride modulation of carbon dioxide hypersensitivity and thermal nociceptive hypersensitivity induced by interference with early maternal environment. AB - BACKGROUND: Early life adversities are risk factors for anxiety disorders and for pain syndromes, which are, in turn, highly comorbid with anxiety disorders. Repeated cross-fostering mouse pups to adoptive lactating females induces epigenetic modification and heightened mRNA-expression of the acid-sensing-ion channel-1 gene, altered nociception, and hypersensitivity to 6% carbon dioxide air mixtures, a trait marker of specific human anxiety disorders such as, most clearly and prominently, panic disorder. AIMS: We hypothesized that the acid sensing ion channel inhibitor amiloride can modulate repeated cross-fostering animals' exaggerated responses to carbon dioxide and nociceptive thermal stimulation. METHODS: Respiratory carbon dioxide sensitivity was assessed by plethysmography during 6% carbon dioxide air mixture challenges, and nociception was assessed by latency of paw withdrawal to thermal stimulation, in repeated cross-fostering and control animals. To circumvent the blood-brain barrier, prior to testing, amiloride was nebulized in a plethysmograph. Data were analyzed by general linear models. RESULTS: Analyses of tidal volume responses to 6% carbon dioxide of animals pre-treated with nebulized amiloride/saline in a randomized crossover design showed significant modulatory effect of amiloride, and amiloride*repeated cross-fostering interaction. In contrast, repeated cross fostering animals' responses to 6% carbon dioxide after intraperitoneal amiloride, saline, or no treatment, were no different. Analyses of responses to thermal stimuli showed a significant modulatory effect of nebulized amiloride, and repeated cross-fostering*amiloride interaction. CONCLUSIONS: Single-dose nebulized amiloride decreased repeated cross-fostering animals' carbon dioxide sensitivity and nociception indices to levels that were no different from those of control animals. Inasmuch as these results pertain to human anxiety and/or pain hypersensitivity, our findings provide a rationale for studying inhaled amiloride in some anxiety disorders and/or pain syndromes. PMID- 29968501 TI - One-Year Results of First-Line Treatment Strategies in Patients With Critical Limb Ischemia (CRITISCH Registry). AB - PURPOSE: To examine the outcomes of all first-line strategies for the treatment of critical limb ischemia (CLI), identify factors that influenced the treatment choice, and determine the risk of amputation or death after each treatment. METHODS: CRITISCH ( ClinicalTrials.gov identifier NCT01877252) is a multicenter, national, prospective registry evaluating all available treatment strategies applied in 1200 consecutive CLI patients in 27 vascular centers in Germany. The recruitment started in January 2013 and was completed in September 2014. Treatment options were endovascular revascularization (642, 53.5%), bypass surgery (284, 23.7%), femoral artery patchplasty (126, 10.5%) with or without concomitant peripheral intervention, conservative treatment (118, 9.8%), and primary major amputation (30, 2.5%). The primary endpoint of this study was amputation-free survival (AFS). The Society of Vascular Surgery's suggested objective performance goal (OPG) for AFS (71%) was used as the effectiveness criterion. Multivariable regression methods were employed to identify variables that influenced the treatment selection and AFS after each treatment; results are presented as the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: The 12-month AFS estimates following endovascular therapy, bypass grafting, femoral patchplasty, and conservative treatment were 75%, 72%, 73%, and 72%, respectively. Factors influencing treatment choice were age, chronic kidney disease (CKD), diabetes, smoking, prior vascular procedures in the index leg, TransAtlantic Inter-Society Consensus II C/D lesions, and absence of runoff vessels. Cox regression analysis identified CKD (HR 2.07, 95% CI 1.26 to 3.41, p=0.004), the use of a prosthetic bypass conduit (HR 1.97, 95% CI 1.23 to 3.14, p=0.004), and previous vascular intervention in the index limb (HR 1.52, 95% CI 0.94 to 2.43, p=0.085) as independent risk factors for diminished AFS after bypass surgery. CKD (HR 1.47, 95% CI 1.09 to 1.99, p=0.012) and Rutherford category 6 (HR 1.81, 95% CI 1.30 to 2.52, p<0.001) compromised the performance of endovascular revascularization. CONCLUSION: CRITISCH registry data revealed that all first-line treatment strategies selected and indicated by the treating physicians met the suggested OPGs. CKD was an important determinant of patient prognosis after treatment regardless of the revascularization method. PMID- 29968502 TI - Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test. AB - BACKGROUND: Cannabidiol is a non-psychotomimetic compound with antidepressant like effects. However, the mechanisms and brain regions involved in cannabidiol effects are not yet completely understood. Brain-derived neurotrophic factor/tropomyosin-receptor kinase B/mammalian target of rapamycin (BDNF-TrkB mTOR) signaling, especially in limbic structures, seems to play a central role in mediating the effects of antidepressant drugs. AIM: Since it is not yet known if BDNF-TrkB-mTOR signaling in the hippocampus is critical to the antidepressant like effects of cannabidiol, we investigated the effects produced by cannabidiol (10/30/60 nmol/0.2 uL) micro-injection into the hippocampus of mice submitted to the forced swim test and to the open field test. METHODS: Independent groups received intra-hippocampal injections of rapamycin (mTOR inhibitor, 0.2 nmol/0.2 uL) or K252 (Trk antagonist, 0.01 nmol/0.2 uL), before the systemic (10 mg/kg) or hippocampal (10 nmol/0.2uL) injection of cannabidiol, and were submitted to the same tests. BDNF levels were analyzed in the hippocampus of animals treated with cannabidiol (10 mg/kg). RESULTS: Systemic cannabidiol administration induced antidepressant-like effects and increased BDNF levels in the dorsal hippocampus. Rapamycin, but not K252a, injection into the dorsal hippocampus prevented the antidepressant-like effect induced by systemic cannabidiol treatment (10 mg/kg). Differently, hippocampal administration of cannabidiol (10 nmol/0.2 uL) reduced immobility time, an effect that was blocked by both rapamycin and K252a local microinjection. CONCLUSION: Altogether, our data suggest that the hippocampal BDNF-TrkB-mTOR pathway is vital for cannabidiol-induced antidepressant-like effect when the drug is locally administered. However, other brain regions may also be involved in cannabidiol-induced antidepressant effect upon systemic administration. PMID- 29968503 TI - Botox in reverse: a useful adjunct for acromial fractures. PMID- 29968504 TI - A simple alternative to Chinese finger traps for wrist fracture reduction. PMID- 29968505 TI - Thy 3F and 3a malignancy rate, a multisite regional retrospective case series. AB - Introduction The aim of this study was to ascertain the incidence of thyroid cancer for patients categorised as Thy3, 3a or 3f across four tertiary thyroid multidisciplinary centres in the UK. Material and methods This is a retrospective case series examining patients who presented with a thyroid nodule and diagnosed as Thy3, 3a or 3f according to the Royal College of Pathologists modified British Thyroid Association and Royal College of Physicians Thy system. Results In total, 395 patients were included in this study. Of these, 136 turned out to have benign thyroid disease and 24 had micropapillary thyroid carcinomas. The overall rate of thyroid malignancy was 28.8%. For each subcategory, the rate of malignancy was Thy3 24.7.7%, Thy3a 30.4% and Thy3f 29.2. However, the incidence of thyroid malignancy varied considerably between the four centres (Thy 3f 18-54%). Discussion The diagnosis of thyroid cancer is evolving but detection for malignancy for indeterminate nodules remains below 50% for most centres around the world. In 2014, the British Thyroid Association subdivided the original Thy3 category into Thy3a and Thy3f and recommended a more conservative approach to management for Thy3a nodules. Despite this, only two centres yielded a higher conversion rate of malignancy in the new higher graded Thy3f group compared with Thy3a. Conclusion It is debateable whether the new 'Thy3' subcategories are more useful than the original. Local thyroid malignancy rates may also be more useful than national averages to inform treatment decisions. PMID- 29968506 TI - Influence of meteorological factors on the onset of primary spontaneous pneumothorax. AB - Introduction Although links between meteorological conditions and primary spontaneous pneumothorax have been proposed, the reports are controversial. The aim of the study is to correlate between climatic changes and the development of this condition. Materials and methods A retrospective chart review included all patient presenting with primary spontaneous pneumothorax to King Fahd Hospital, Imam Abdulrahman Bin Faisal University, Alkhobar, Saudi Arabia, from 1 January 2005 to 31 December 2016. Meteorological data were collected from King Abdulaziz airbase station using an online source for the same time interval. The data were analysed to determine differences in weather conditions between days on which primary spontaneous pneumothorax occurred and those in which it did not. Logistic regression model was used to obtain predicted risks for the onset of primary spontaneous pneumothorax with respect to weather conditions. Result Two hundred and eighty-nine patients were found to have primary spontaneous pneumothorax in the 281 days included in the study. Among the meteorological parameters, significant differences were found in average temperature and atmospheric pressure difference between day of admission and two days before the admission, between days with primary spontaneous pneumothorax and days without. There was no significant difference in the other meteorological factors between days with primary spontaneous pneumothorax and days without. Conclusion Two hundred and eighty-nine patients were found to have primary spontaneous pneumothorax in the 281 days included in the study. Among the meteorological parameters, significant differences were found in average temperature and atmospheric pressure difference between day of admission and two days before the admission, between days with primary spontaneous pneumothorax and days without. There was no significant difference in the other meteorological factors between days with primary spontaneous pneumothorax and days without. PMID- 29968507 TI - Will children ever learn? Removal of nasal and aural foreign bodies: a study of hospital episode statistics. AB - Introduction Foreign body removal is a common reason for children to attend the emergency department. Generally, aural and nasal foreign bodies are not associated with immediate morbidity unless they are button batteries. There can be consequences of migration and removal. Methods Hospital Episode Statistics for 2010-2016 were used to calculate the number of nasal and aural foreign bodies that have been removed in hospital. Data for adults and children have been compared. Results 8752 nasal and 17,325 aural foreign bodies have been removed from adults and children over the course of 6 years. Children were responsible for 95% of the 8353 nasal and 85% of the 14,875 aural foreign body presentations. Children aged 1-4 years are most at risk of injury. Conclusion Children are more likely to present to hospital than adults with a foreign body in the ear or nose. Aural bodies were more likely to need removal in hospital for both populations. Authors believe that these require identification and removal by an ear, nose and throat specialist to prevent morbidity. The overall number of procedures performed annually in children has not reduced over the study period; an average of 1218 nasal and 2479 aural foreign body removals are performed each year with an annual cost of L2,880,148 to NHS England. PMID- 29968508 TI - An innovative and cost-effective method for the targeted delivery of autologous bone grafts in foot and ankle surgery. PMID- 29968510 TI - Family caregivers' reports of hospitalizations and emergency department visits in community-dwelling individuals with dementia. AB - Individuals with dementia in the United States have higher rates of hospitalizations and emergency department visits compared to those without. This descriptive study examined the frequency of hospitalizations and emergency department visits among community-dwelling individuals with dementia, reasons for hospitalizations and emergency department visits, and caregivers' actions to prevent these events. Family caregivers ( n = 63) from education/support groups offered through Alzheimer's Association chapters in western Ohio completed a survey. Twenty-two percent of caregivers reported that their care recipient stayed overnight in the hospital and 30% reported that their care recipient visited the emergency department at least once in the past three months. The most frequent reasons for hospitalization and emergency department visits, such as urinary tract infections and fall-related injuries, were potentially avoidable. Caregivers reported giving medications, seeking healthcare services, and obtaining home care services, as the most frequently used preventive actions. Family caregivers of individuals with dementia should be provided substantive education about preventable hospitalizations and emergency department visits. PMID- 29968511 TI - Editorial: Innovative Practice. PMID- 29968513 TI - Iron Deficiency May Predict Greater Risk for Hypothyroxinemia: A Retrospective Cohort Study of Pregnant Women in China. AB - BACKGROUND: Pregnant women are highly vulnerable to iron deficiency (ID) due to the increased iron needs during pregnancy. ID decreases circulating thyroid hormone concentrations likely through impairment of iron-dependent thyroid peroxidase. The present study aimed to explore the association between ID and hypothyroxinemia in a retrospective cohort of pregnant women in China. METHODS: To investigate the relationship between ID and hypothyroxinemia, 723 pregnant women were retrospectively analyzed, including 675 and 309 women in the second and third trimesters, respectively. Trimester-specific hypothyroxinemia was defined as free thyroxine (fT4) levels below the 2.5th percentile of the reference range with normal serum thyrotropin (TSH) or TSH higher than the 97.5th percentile of the reference range in each trimester of pregnancy. Serum TSH, fT4, thyroid peroxidase antibodies, thyroglobulin antibodies, serum ferritin, soluble transferrin receptor, and urinary iodine concentrations were measured. Serum ferritin, soluble transferrin receptor, and total body iron were used to indicate the nutritional iron status. RESULTS: Cross-sectional multiple linear regression analysis showed that iron status was positively associated with serum fT4 levels in the first and second trimesters of pregnancy, but not in the third trimester. Logistic regression analysis showed that ID was an independent risk factor for hypothyroxinemia (odds ratio = 14.86 [confidence interval 2.31-95.81], p = 0.005 in the first trimester and odds ratio = 3.36 [confidence interval 1.01-11.21], p = 0.048 in the second trimester). The prospective analysis showed that pregnant women with ID during the first trimester of pregnancy had lower serum fT4 levels and a higher rate of hypothyroxinemia in the second or third trimester than those without ID. CONCLUSIONS: ID appears to be a risk factor to predict hypothyroxinemia in the first and second trimesters of pregnancy, but not in the third trimester. Pregnant women with ID in the first and second trimesters should be regarded as a high-risk group for maternal hypothyroxinemia. PMID- 29968512 TI - Advanced physical techniques for gene delivery based on membrane perforation. AB - Gene delivery as a promising and valid tool has been used for treating many serious diseases that conventional drug therapies cannot cure. Due to the advancement of physical technology and nanotechnology, advanced physical gene delivery methods such as electroporation, magnetoporation, sonoporation and optoporation have been extensively developed and are receiving increasing attention, which have the advantages of briefness and nontoxicity. This review introduces the technique detail of membrane perforation, with a brief discussion for future development, with special emphasis on nanoparticles mediated optoporation that have developed as an new alternative transfection technique in the last two decades. In particular, the advanced physical approaches development and new technology are highlighted, which intends to stimulate rapid advancement of perforation techniques, develop new delivery strategies and accelerate application of these techniques in clinic. PMID- 29968514 TI - Comparing health care workforce in circumpolar regions: patterns, trends and challenges. AB - BACKGROUND: The eight Arctic States exhibit substantial health disparities between their remote northernmost regions and the rest of the country. This study reports on the trends and patterns in the supply and distribution of physicians, dentists and nurses in these 8 countries and 25 regions and addresses issues of comparability, data gaps and policy implications Methods: We accessed publicly available databases and performed three types of comparisons: (1) among the 8 Arctic States; (2) within each Arctic State, between the northern regions and the rest of the country; (3) among the 25 northern regions. The unit of comparison was density of health workers per 100,000 inhabitants, and the means of three 5 year periods from 2000 to 2014 were computed. RESULTS: The Nordic countries consistently exceed North America in the density of all three categories of health professionals, whereas Russia reports the highest density of physicians but among the lowest in terms of dentists and nurses. The largest disparities between "north" and "south" are observed in the Northwest Territories and Nunavut of Canada for physicians, and in Greenland for all three categories. The disparity is much less pronounced in the northern regions of Nordic countries, while Arctic Russia tends to be oversupplied in all categories. CONCLUSIONS: Despite efforts and standardisation of definitions by international organisations such as OECD, it is difficult to obtain an accurate and comparable estimate of the health workforce even in the basic categories of physicians, dentists and nurses . The use of head counts is particularly problematic in jurisdictions that rely on short-term visiting staff. Comparing statistics also needs to take into account the health care system, especially where primary health care is nurse based. List of Abbreviations ADA: American Dental Association; AHRF: Area Health Resource File; AMA: American Medical Association; AO: Autonomous Okrug; AVI: Aluehallintovirasto; CHA: Community Health Aide; CHR: Community Health Representative; CHW: Community Health Worker; CIHI: Canadian Institute for Health Information; DO: Doctor of Osteopathic Medicine; FTE: Full Time Equivalent; HPDB: Health Personnel Database; MD: Doctor of Medicine; NOMESCO: Nordic Medico Statistical Committee; NOSOSCO: Nordic Social Statistical Committee; NOWBASE: Nordic Welfare Database; NWT: Northwest Territories; OECD: Organization for Economic Co-operation and Development; RN: Registered Nurse; SMDB: Scott's Medical Database; WHO: World Health Organization. PMID- 29968516 TI - A novel compound purified from Alstonia boonei inhibits Plasmodium falciparum Lactate dehydrogenase and Plasmepsin II. PMID- 29968515 TI - Women's experience of wearing a portable fetal-electrocardiogram device to monitor small-for-gestational age fetus in their home environment. AB - OBJECTIVE: To determine the acceptability, to women, of wearing a portable fetal electrocardiogram recording device at different stages of pregnancy and to gain insight into their experience of its use for long-periods of monitoring of small for-gestational fetuses in the home environment. METHODS: A qualitative study using both a questionnaire and focus group involving women with singleton pregnancy >24 weeks gestation, no evidence of fetal malformation and an estimated fetal weight below 10th gestational centile on ultrasound scan. Fetal heart rate recordings were collected for up to 20 h. RESULTS: In total, 59 questionnaires were completed; 35 after wearing the monitor for the first time and an additional 24 from the women who wore the device for a second time. Six women participated in the focus group; the principal theme identified related to the practicality of the fetal electrocardiogram device. Other themes identified were the discomfort that resulted from wearing the monitor and the reassurance provided in knowing that the baby's heart rate was being monitored. CONCLUSION: Long-term ambulatory fetal electrocardiogram monitoring is an acceptable method of monitoring small for-gestational fetuses. Overall, women concluded that benefits of wearing the device outweighed any discomfort it caused. PMID- 29968517 TI - Ergosterol and its derivatives from Grifola frondosa inhibit antigen-induced degranulation of RBL-2H3 cells by suppressing the aggregation of high affinity IgE receptors. AB - Grifola frondosa is an edible mushroom consumed as a health food and/or traditional medicine in Asia. However, the anti-allergic effects of G. frondosa are not yet understood. In this study, we demonstrated the effects of G. frondosa extract (GFE) on IgE-mediated allergic responses, using antigen-stimulated RBL 2H3 cells. Three active compounds: ergosterol, 6beta-methoxyergosta-7,22-dien 3beta,5alpha-diol (MEDD), and 6-oxoergosta-7,22-dien-3beta-ol (6-OXO) were isolated from GFE and shown to inhibit the antigen-induced release of beta hexosaminidase and histamine. Among the three active components, we focused on ergosterol because of its high content in GFE. Ergosterol inhibited the aggregation of high-affinity IgE receptor (FcepsilonRI), which is the first step in the activation of mast cells and antigen-induced tyrosine phosphorylation. Furthermore, ergosterol suppressed antigen-increased IL-4 and TNF-alpha mRNA. Taken together, our findings suggest that G. frondosa, including ergosterol and its derivatives as active components, has the potential to be a novel functional food that prevents type I allergies. PMID- 29968519 TI - Training working memory updating in Parkinson's disease: A randomised controlled trial. AB - Frontostriatal dysfunction in Parkinson's disease (PD) increases the risk for working memory (WM) impairment and depression, calling for counteractive measures. Computerised cognitive rehabilitation is a promising option, but targeted training protocols are lacking and lab-based training can be demanding due to the repeated visits. This study tested the feasibility and efficacy of home-based computerised training targeting mainly WM updating in PD. Fifty-two cognitively well-preserved PD patients were randomised to a WM training group and an active control group for five weeks of training (three 30-min sessions per week). WM training included three computerised adaptive WM tasks (two updating, one maintenance). The outcomes were examined pre- and post-training with trained and untrained WM tasks, tasks tapping other cognitive domains, and self-ratings of executive functioning and depression. Home-based training was feasible for the patients. The training group improved particularly on the updating training tasks, and showed posttest improvement on untrained WM tasks structurally similar to the trained ones. Moreover, their depression scores decreased compared to the controls. Our study indicates that patients with mild-to-moderate PD can self administer home-based computerised WM training, and that they yield a similar transfer pattern to untrained WM tasks as has been observed in healthy older adults. PMID- 29968518 TI - TRPA1 sensitization during diabetic vascular impairment contributes to cold hypersensitivity in a mouse model of painful diabetic peripheral neuropathy. AB - Background Diabetic peripheral neuropathy is a common long-term complication of diabetes. Accumulating evidence suggests that vascular impairment plays important roles in the pathogenesis of diabetic peripheral neuropathy, while the mechanism remains unclear. We recently reported that transient receptor potential ankyrin 1 (TRPA1) is sensitized by hypoxia, which can contribute to cold hypersensitivity. In this study, we investigated the involvement of TRPA1 and vascular impairment in painful diabetic peripheral neuropathy using streptozotocin-induced diabetic model mice. Results Streptozotocin-induced diabetic model mice showed mechanical and cold hypersensitivity with a peak at two weeks after the streptozotocin administration, which were likely to be paralleled with the decrease in the skin blood flow of the hindpaw. Streptozotocin-induced cold hypersensitivity was significantly inhibited by an antagonist HC-030031 (100 mg/kg) or deficiency for TRPA1, whereas mechanical hypersensitivity was unaltered. Consistent with these results, the nocifensive behaviors evoked by an intraplantar injection of the TRPA1 agonist allyl isothiocyanate (AITC) were enhanced two weeks after the streptozotocin administration. Both streptozotocin-induced cold hypersensitivity and the enhanced AITC-evoked nocifensive behaviors were significantly inhibited by a vasodilator, tadalafil (10 mg/kg), with recovery of the decreased skin blood flow. Similarly, in a mouse model of hindlimb ischemia induced by the ligation of the external iliac artery, AITC-evoked nocifensive behaviors were significantly enhanced three and seven days after the ischemic operation, whereas mechanical hypersensitivity was unaltered in TRPA1-knockout mice. However, no difference was observed between wild-type and TRPA1-knockout mice in the hyposensitivity for current or mechanical stimulation or the deceased density of intraepidermal nerve fibers eight weeks after the streptozotocin administration. Conclusion These results suggest that TRPA1 sensitization during diabetic vascular impairment causes cold, but not mechanical, hypersensitivity in the early painful phase of diabetic peripheral neuropathy. However, TRPA1 may play little or no role in the progression of diabetic peripheral neuropathy. PMID- 29968520 TI - CRISPR-Cas systems: ushering in the new genome editing era. AB - In recent years there has been great progress with the implementation and utilization of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) and CRISPR-associated protein (Cas) systems in the world of genetic engineering. Many forms of CRISPR-Cas9 have been developed as genome editing tools and techniques and, most recently, several non-genome editing CRISPR-Cas systems have emerged. Most of the CRISPR-Cas systems have been classified as either Class I or Class II and are further divided among several subtypes within each class. Research teams and companies are currently in dispute over patents for these CRISPR-Cas systems as numerous powerful applications are concurrently under development. This mini review summarizes the appearance of CRISPR-Cas systems with a focus on the predominant CRISPR-Cas9 system as well as the classifications and subtypes for CRISPR-Cas. Non-genome editing uses of CRISPR-Cas are also highlighted and a brief overview of the commercialization of CRISPR is provided. PMID- 29968521 TI - Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study. AB - BACKGROUND: An increase in the incidence of congenital hypothyroidism (CH) with a normally located gland has been reported worldwide. Affected individuals display transient or permanent CH during follow-up in childhood. This study aimed to determine the prevalence of transient CH and to investigate the possibility of distinguishing between transient and permanent CH in early infancy. METHODS: This observational cohort study included all patients identified by systematic neonatal screening for CH in the northern Parisian region between 2002 and 2012 and treated for CH with a normally sited gland. A standardized data collection form was completed prospectively at diagnosis. Patients were classified during follow-up as having transient or permanent CH. RESULTS: Of the 92 patients initially treated for CH with a normally located gland during the neonatal period, 49 (54%) had a transient form of CH after the cessation of levothyroxine (LT4) treatment at 1.5 (0.6-3.2) years of age. Multivariate analysis revealed that transient CH was associated with a lower likelihood of having a first-degree family history of CH (p = 0.03) and a lower LT4 dose at six months of age (p = 0.03) than permanent CH. Sex, ethnicity, neonatal problems (e.g., prematurity, being small for gestational age, and/or neonatal distress), iodine status, coexisting malformations, initial CH severity, and thyroid morphology at diagnosis had no effect. Receiver operating characteristics curve analysis showed that a cutoff of 3.2 MUg/kg/day for LT4 dose requirement at six months of age had a sensitivity of 71% and a specificity of 79% for predicting transient CH, with values below this threshold considered predictive of transient CH. CONCLUSION: In patients with CH and a normally located gland, these findings highlight the need to evaluate LT4 dose requirements early, at six months of age, particularly in patients with no family history of CH, for early identification of the approximately 50% of patients for whom treatment should be stopped. PMID- 29968523 TI - Regarding "Comparison of Medical Therapy Alone to Medical Therapy with Surgical Treatment of Peritonsillar Abscess". PMID- 29968522 TI - A method for improving the accuracy of non-invasive prenatal screening by cell free foetal DNA size selection. AB - Background Non-invasive prenatal screening (NIPS) using cell-free foetal DNA (cfDNA) has been widely used for identifying common foetal aneuploidies (e.g. trisomy 21 (T21), trisomy (T18) and trisomy 13 (T13)) in clinical practice. The sensitivity and specificity of NIPS exceeds 99%, but the positive prediction value (PPV) is approximately 70% (combined T21, T18 and T13). Thus, some 30% of pregnant women who have positive NIPS results are eventually identified as normal by amniocentesis. These women therefore must undertake needless invasive tests and risk miscarrying healthy babies because of false positive NIPS results. Methods In order to achieve higher accuracy, we amended the standard NIPS (s NIPS) protocol with an additional cfDNA size selecting step in agarose electrophoresis. The advantage of the new method (named e-NIPS) was validated by comparing the results of e-NIPS and s-NIPS using 114 retrospective cases selected from 15,930 cases. Results Our results showed that the foetal cfDNA fraction can be enriched significantly by a size selection step. With this modification, all 98 negative cases and 9 of 11 false positive cases of s-NIPS were correctly identified by e-NIPS, resulting in an increased PPV from 71% to 77%. Additionally, a simulation test showed that e-NIPS is more reliable than s-NIPS, especially when the foetal cfDNA concentration and sequencing coverage are low. Conclusion cfDNA size selection is an important step in improving the accuracy of non-invasive prenatal screening for chromosomal abnormalities. PMID- 29968524 TI - Highlights from the Current Issue: July 2018. PMID- 29968526 TI - News Update. PMID- 29968525 TI - Patient Safety/Quality Improvement Primer, Part I: What PS/QI Means to Your Otolaryngology Practice. AB - Patient safety/quality improvement (PS/QI) is the cornerstone of 21st-century health care. Otolaryngology-Head and Neck Surgery is excited to provide a dedicated PS/QI primer. The overarching goal for this PS/QI series is to provide a comprehensive and practical resource that assists readers, authors, and peer reviewers in understanding PS/QI research, its unique methodology, and the associated reporting standards for trustworthy performance measures. The target audience includes resident and fellows, faculty from the private sector and academia, and allied health professionals. This inaugural primer reviews PS/QI background as it relates to otolaryngology practice. It explores the history, goals, and development of performance measurement. In addition, it highlights opportunities for integrating PS/QI into otolaryngology practice. Payers will drive patients to quality care based on outcomes. Otolaryngologists have a responsibility to embrace a culture of PS/QI. In doing so, we will define optimal, quality otolaryngology care through objective data and metrics. PMID- 29968527 TI - Safety: Practice of caring for the welfare of others. PMID- 29968528 TI - The 70th birthday of the National Health Service. PMID- 29968529 TI - On-call: ready, steady, go! PMID- 29968530 TI - The SAFE Operating Room course. PMID- 29968532 TI - Dyslipidemias and Microcirculation. AB - Dyslipidemia is widely accepted as one of the major risk factors in cardiovascular disease mainly due to its contribution in the pathogenesis of atherosclerosis in medium-sized and large arteries. However, it has become increasingly accepted that high-cholesterol levels can also adversely affect the microvasculature prior to the development of overt atherosclerosis. Moreover, hypercholesterolemia has shown, in preclinical animal models, to exert detrimental effects beyond the vascular tree leading to larger infarcts and adverse cardiac remodeling post-myocardial infarction. At a functional level, hypercholesterolemia has shown to impair endotheliumdependent vasodilation because on defects on nitric oxide bioavailability. The pathogenic mechanisms underlying microvascular dysfunction involve an enhanced arginase activity, enhanced production of free radicals and the activation, recruitment and accumulation of leukocytes, primarily neutrophils, via their diffusion through postcapillary venules. In turn, recruited inflammatory cells and certain inflammatory mediators enhance platelet adhesion, overall inducing a proinflammatory and prothrombotic phenotype. Within the present review, we aim to discuss the existing evidence regarding the presence of dyslipidemia - particularly high low density lipoprotein-cholesterol levels - and the occurrence of microvascular dysfunction, the mechanism by which high cholesterol levels induce functional alterations in the microvascular bed and, finally comment on the impact of dislipidemia-induced microvascular dysfunction at the myocardial level. PMID- 29968533 TI - Editorial: Drug Discovery for Neglected Diseases. PMID- 29968534 TI - Verification between Original and Biosimilar Therapeutic Antibody Infliximab Using nSMOL Coupled LC-MS Bioanalysis in Human Serum. AB - BACKGROUND: Infliximab (IFX) is a chimeric therapeutic monoclonal antibody targeting tumor necrosis factor alpha (TNFalpha)-mediated inflammatory immune diseases. However, despite of an initial good clinical response, decrease in response to long-term treatment is a common observation. OBJECTIVE: Recent studies suggest that IFX level in circulation has a correlation with clinical bioavailability. Therefore, the management of IFX dosage for individual manifestation by IFX monitoring may be valuable for the improvement of therapeutic response and outcomes. METHOD: In order to develop a broad IFX therapeutic monitoring in human serum, we have developed the validated IFX bioanalysis for RemicadeTM and its biosimilar product using our nano-surface and molecular-orientation limited proteolysis (nSMOL) technology coupled with liquid chromatographytandem mass spectrometry (LC-MS/MS). The nSMOL chemistry has a unique property of Fabselective proteolysis, and makes it possible a global bioanalysis for many monoclonal antibodies. RESULTS: The quantitation range of IFX in serum was from 0.293 to 300 MUg/ml with good linearity. Quantitation verification at the concentrations of 0.293, 0.879, 14.1 and 240 ug/ml was within 1.56- 7.53% of precision and 98.9-111% of accuracy using H-chain signature peptide SINSATHYAESVK. Moreover, cross-verified bioanalysis of Remicade quantitation using biosimilar standard, and its opposite combination, obtained an identical and inter-comparative results. CONCLUSION: The nSMOL strategy has the potential as a practical therapeutic monitoring technology in IFX therapeutic applications. PMID- 29968535 TI - 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one, a Novel Curcumin Analogue, Inhibits Cellular and Humoral Immune Responses in Male Balb/c Mice. AB - BACKGROUND: 3,5-Bis[4-(diethoxymethyl)benzylidene]-1-methyl-piperidin-4-one (BBP), a novel synthetic curcumin analogue has previously been shown to manifest potent immunosuppressive effects on the in vitro phagocytosis process of human neutrophils. OBJECTIVE: In the present study, BBP was investigated for it's in vivo innate and adaptive immune responses mediated by different humoral and cellular immune factors. METHODS: Male Balb/c mice were orally fed with BBP (5, 10 and 20 mg/kg) for a period of 14 days and immunized with sheep red blood cells (sRBC) on day 0 for the determination of adaptive responses. The effects of BBP on phagocytosis process of neutrophils isolated from blood of treated/untreated animals were determined. The ceruloplasmin and lysozyme serum levels and myeloperoxidase (MPO) plasma level were also monitored. The mechanism was further explored by assessing its effects on the proliferation of T and B lymphocytes, T lymphocytes subsets CD4+ and CD8+ and on the secretion of Th1/Th2 cytokines as well as serum immunoglobulins (IgG, IgM) and delayed type hypersensitivity (DTH) reaction. RESULTS: BBP showed a significant dose-dependent reduction on the migration of neutrophils, Mac-1 expression, phagocytic activity and reactive oxygen species (ROS) production. In comparison to the sensitized control group, a dose-dependent inhibition was observed on lymphocyte proliferation along with the downregulation of effector cells expression and release of cytokines. Moreover, a statistically significant decrease was perceived in serum levels of ceruloplasmin, lysozyme and immunoglobulins and MPO plasma level of BBP-treated mice. BBP also dose-dependently inhibited sheep red blood cells (sRBC)-induced swelling rate of mice paw in DTH. CONCLUSION: These findings suggest the potential of BBP as a potent immunosuppressive agent. PMID- 29968536 TI - Lipid-based Nanocarriers for siRNA Delivery: Challenges, Strategies and the Lessons Learned from the DODAX: MO Liposomal System. AB - The possibility of using the RNA interference (RNAi) mechanisms in gene therapy was one of the scientific breakthroughs of the last century. Despite the extraordinary therapeutic potential of this approach, the need for an efficient gene carrier is hampering the translation of the RNAi technology to the clinical setting. Although a diversity of nanocarriers has been described, liposomes continue to be one of the most attractive siRNA vehicles due to their relatively low toxicity, facilitated siRNA complexation, high transfection efficiency and enhanced pharmacokinetic properties. This review focuses on RNAi as a therapeutic approach, the challenges to its application, namely the nucleic acids' delivery process, and current strategies to improve therapeutic efficacy. Additionally, lipid-based nanocarriers are described, and lessons learned from the relation between biophysical properties and biological performance of the dioctadecyldimethylammonium:monoolein (DODAX: MO) system are explored. Liposomes show great potential as siRNA delivery systems, being safe nanocarriers to protect nucleic acids in circulation, extend their half-life time, target specific cells and reduce off-target effects. Nevertheless, several issues related to delivery must be overcome before RNAi therapies reach their full potential, namely target-cell specificity and endosomal escape. Understanding the relationship between biophysical properties and biological performance is an essential step in the gene therapy field. PMID- 29968537 TI - Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer. AB - Polyploidy is associated with increased cell size and commonly found in a subset of adult organs and blastomere stage of human embryo. The polyploidy is formed through endoreplication or cell fusion to support specific need of development including earliest embryogenesis. Recent data demonstrated that polyploid giant cancer cells (PGCCs) may have acquired an activated early embryonic-like program in response to oncogenic and therapeutic stress to generate reprogrammed cancer cells for drug resistance and metastasis. Targeting PGCCs may open up new opportunities for cancer therapy. PMID- 29968538 TI - Galectin-3 and arterial stiffness in patients with heart failure: a pilot study. AB - BACKGROUND: Cardiac performance depends on optimum ventriculoarterial coupling which is impaired in patients with heart failure (HF). Galectin-3 is a mediator of myocardial fibrosis and remodeling, and is associated with clinical status in patients with chronic HF. We examined the association of arterial stiffness with galectin-3 levels in patients with HF of ischemic etiology. METHODS: We consecutively enrolled 40 patients with stable ischemic HF and reduced ejection fraction. Central aortic stiffness was evaluated non-invasively by measuring carotid femoral pulse wave velocity (PWV). Among other factors, serum levels of galectin-3 and b-type natriuretic peptide (BNP) were measured. RESULTS: The median galectin-3 levels in our study population were 12.9 (10.8-18.7) ng/ml and the mean PWV was 9.31+/-2.79 m/sec. There was significant association of galectin 3 levels with age (r=0.48, p=0.003), creatinine clearance (r=-0.66, p<0.001) and BNP levels (r=0.36, p=0.05). There was a significant association of galectin-3 levels with PWV (r=0.37, p=0.03) and patients with PWV above median also had significantly increased levels of galectin-3 compared with patients with lower values of PWV [16.1(11.8-25.2) vs 12.1(10.5-14) ng/ml, p=0.03]. CONCLUSIONS: We found an association of arterial stiffness and PWV with galectin-3 levels in patients with chronic HF of ischemic etiology. These findings suggest a pathway driving arterial stiffening and myocardial remodelling in HF. This may provide insight into the mechanism determining prognosis and clinical status of patients with HF. PMID- 29968540 TI - Synthesis and structural elucidation of novel benzothiazole derivatives as anti tubercular agents: In-silico screening for possible target identification. AB - BACKGROUND: Benzothiazole derivatives are known for anti-TB properties. Based on the known antiTB benzothiazole pharmacophore, in the present study, we described the synthesis, structural elucidation, and anti-tubercular screening of a series of novel benzothiazole (BNTZ) derivatives (BNTZ 1-7 and BNTZ 8-13). OBJECTIVE: Development of benzothiazole based anti-TB compounds. METHODS: Title compounds are synthesized by microwave method and purified by column chromatography. Characterization of the compounds is achieved by FT-IR, NMR (1H and 13C), LCMS and elemental analysis. Screening of test compounds for anti-TB activity is achieved by Resazurin Microplate Assay (REMA) Plate method. RESULTS: It was noted that the BNTZ compound with an isoquinoline nucleus (BNTZ 9) exhibited remarkable anti-tubercular activity at 8 MUg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of Mycobacterium tuberculosis. On the other hand, the BNTZ compound with a naphthalene nucleus (BNTZ 2) revealed anti-tubercular activity at 6 MUg/mL and 11 MUg/mL against both the susceptible strain H37Rv and the multi-drug resistant tuberculosis strains of M. tuberculosis, respectively. One of the selected BNTZ derivative BNTZ 13 was used for single crystal X-ray studies. CONCLUSION: To identify the appropriate target for potent BNTZ compounds from the series, molecular modeling studies revealed the multiple strong binding of several BNTZs with mycobacterium lysine-E aminotransferase and decaprenylphosphoryl-beta-D-ribose 2'-oxidase. The interaction is derived by forming favorable hydrogen bonds and stacking interactions. This new class of BNTZ compounds gave promising antitubercular actions in the low micromolar range, and can be further optimized on a structural basis to develop promising, novel, BNTZ pharmacophore-based anti-tubercular drugs. PMID- 29968541 TI - New Resensitizers for the Nicotinic Acetylcholine Receptor by Ligand-based Pharmacophore Modeling. AB - Irreversible inhibition of the acetylcholinesterase upon intoxication with organophosphorus compounds leads to an accumulation of acetylcholine in the synaptic cleft and a subsequent desensitization of nicotinic acetylcholine receptors which may ultimately result in respiratory failure. A direct intervention at the nicotinic acetylcholine receptor nAChR was proposed as an alternative therapeutic approach to the treatment with atropine and oximes. The bispyridinium compound MB327 has been found to recover functional activity of nAChR thus representing a promising starting point for the development of new drugs for the treatment of organophosphate poisoning. Recent solid-supported membrane-based electrophysiological experiments have identified symmetrically substituted bispyridinium compounds e.g. MB327, MB583, and PTM0001 that are able to resensitize nAChR of Torpedo californica. In addition, six compounds have been found not to show any resensitizing potential and were thus classified as inactive. This set of active and inactive bispyridinium compounds was taken to develop a pharmacophore model and in silico screening of a virtual database of bispyridinium compounds to identify new compounds that are able to restore the functional activity of desensitized nAChR. Screening of a virtual compound database of symmetrically substituted bispyridinium compounds with the derived pharmacophore yielded several promising compounds which satisfy the pharmacophore and ought to have the same or even better resensitizing effect on nAChR as the parent compound MB327. PMID- 29968539 TI - Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy. AB - BACKGROUND: The role and mechanism of drug use or abuse in Antiretroviral Therapy (ART)-treated HIV disease are not completely known. METHODS: To investigate the impact of drug use on HIV pathogenesis without confounding by HIV replication and ART adherence, we first analyzed the data from our clinical database in 103 HIV+ subjects with viral-suppressed ART treatment by a multiple regression test. RESULTS: We found that HIV+ drug users had lower CD4+ T cell counts but higher CD8+ T cell counts compared to HIV+ non-drug users, and both drug use and nadir CD4+ T cell counts was independently associated with CD4+ T cell recovery after controlling for sex and age. Next, we enrolled individuals from four study groups, HIV-negative and HIV+ subjects without any substance use, HIV-negative and HIV+ subjects with current illicit drug use (either non-injection cocaine or cannabis). All HIV+ subjects were viral-suppressed with ART treatment (>= 2 years). Notably, HIV+ drug users had increased plasma anti-CD4 IgG levels compared to the other three study groups which were inversely correlated with decreased CD4+ T cell counts only in HIV+ drug users. There was a significant increase in CD4+ T cell recovery following ART in HIV+ non-drug users but not in HIV+ drug users. Anti-CD4 IgGs purified from plasma of HIV+ drug users induced CD4+ T cell death in vitro through Antibody-Dependent Cytotoxicity (ADCC). CONCLUSION: These results suggest that drug use prevents immune reconstitution in HIV-infected individuals despite long-term ART treatment and viral suppression. PMID- 29968542 TI - Evaluation of hMSCs response to sodium alginate / bioactive glass composite paste: effect of CaO/P2O5, sodium alginate concentration and P/L ratios. AB - BACKGROUND: Bioactive glasses with different compositions have been extensively used as bone tissue engineering. Preparation, development and characterization of alginate pastes containing bioglass for bone repair applications were the purpose of this study. OBJECTIVE: The injectable bone pastes were produced from sol-gel derived bioactive glass nanoparticles with various CaO/P2O5 ratios of 19, 9.5 and 4.75 and sodium alginate solutions with different concentrations of 1, 2 and 4 wt.%. The effect of CaO/P2O5 and powder to liquid (P/L) ratios and alginate concentration on injectability, biodegradation, rheological properties, bioactivity and cellular behavior of the pastes have been studied. The behavior of human mesenchymal stem cells (hMSCs) in presence of the pastes was assessed by MTT assay, biomineralization assay, ALP activity, Acridine orange staining and Alizarin red staining tests. RESULTS: By adding sodium alginate, the pastes exhibited a thixotropy behavior. The storage modulus of all pastes was larger than the loss modulus in the frequency range of 0.1-100 s-1. Cytotoxicity evaluation results revealed that, there was a critical amount of bioactive glass in pastes which above the limit; the viability of hMSCs will be at risk. The pastes made of bioactive glass nanoparticles with CaO/P2O5=9.5 and sodium alginate 1% with P/L ratio of 0.8 showed optimum behavior in terms of mineral carrying capacity, injectability characteristics, accellular bioactivity in SBF, loss weight and wash out behavior, proliferation and differentiation of hMSCs. CONCLUSION: According to the results, the pastes prepared with sodium alginate solution and bioactive glass nanoparticles can be beneficial in bone tissue engineering. PMID- 29968543 TI - Amalgamation of stem cells with nanotechnology: A unique therapeutic approach. AB - In last few years, the stem cell therapy gets much popularity among researchers and scientists of biomedical field. It became an effective and alternative approach for the treatment of various physiological conditions (like accidental injuries, burn damage, organ failure, bone marrow transfusion, etc.) and chronic disorders (diabetes, cancer, neurodegenerative disorders, periodontal diseases, etc.). Due to the unique ability of cellular differentiation and regeneration stem cell therapy serves as the last hope for various incurable conditions and severe damages. The amalgamation of stem cell therapy with nanotechnology brings new prospects to the stem cell research. As it improves the specificity of the treatment and controls the stem cell proliferation and differentiation. In this review article, we have discussed various nanocarrier systems such as carbon nanotubes, quantum dots, nanofibers, nanoparticles, nanodiamonds, nanoparticle scaffold, etc. utilized for the delivery of stem cell inside the body. PMID- 29968544 TI - Evaluation of hemostatic behavior of micro and nano gelatin/silica hybrid in severe bleeding. AB - The pH variation of the injury site is an important factor in the failure of styptic and its structural damage. In this study, the behaviour of a gelatin silica hybrid in severe bleeding was evaluated under different pH values. On the other hand, the effect of the hybrid particle size, which is one of the key physical properties of the hybrid, has been studied in rapid control of haemostasis. The hybrid haemostatic behaviour varied drastically by changing the particle size, so that the hybrid containing SiO2 with the average particle size of about 1 micro-meter (Hyb Gel-MSiO2) demonstrated very poor ability in platelet adhesion in neutral pH, about 24%. Also, the aPTT was not shorter than the normal time, whereas reduction of the particle size beyond a certain limit (with nano meter SiO2 for Hyb Gel-NSiO2) led to both increasing platelet adhesion to 32% and very considerable reduction of aPTT. Alignment of all results showed that the particle size reduction improves the haemostatic behaviour of the hybrid toward its best performance by controlling excessive bleeding. By changing the pH for a certain particle size, structural integrity, and thereby the hybrid haemostatic behaviour changed dramatically. Therefore, the nano-hybrid showed the most blood absorption (around 470%) in natural pH and acceded to a coherent structure. The results demonstrated that in alkaline or acidic environment, the hybrid haemostatic behaviour was limited. Based on the results of this study, it was found that changes in the hybrid behaviour in acidic pH were much more drastic than in alkaline pH, and also the hybrid with the optimum particle size (Hyb Gel NSiO2) can maintain the structural integrity with rapid haemostasis (<3 seconds). Based on the objective that the pH at the injury site change to the alkaline side, the resulting hybrid has an excellent ability to control excessive bleeding and can be proposed for further in vivo studies as a novel styptic. PMID- 29968545 TI - The Effects of Tryptophan Catabolites on Negative Symptoms and Deficit Schizophrenia are Partly Mediated by Executive Impairments: Results of Partial Least Squares Path Modeling. AB - : Aim & Objective: To delineate the associations between executive impairments and changes in tryptophan catabolite (TRYCAT) patterning, negative symptoms and deficit schizophrenia. METHODS: We recruited 80 schizophrenic patients and 40 healthy controls and assessed 10 key cognitive tests using the Cambridge Neuropsychological Test Automated Battery (CANTAB), IgA/IgM responses to tryptophan catabolites (TRYCATs), the Scale for the Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale. RESULTS: Partial Least Squares path modeling shows that a large part of the variance in negative symptoms and the deficit phenotype (39-53%) is explained by executive impairments, TRYCAT levels and male sex and that 53.4% of the variance in executive impairments is explained by TRYCATs, lower education, age and a familial history of psychosis. Specific indirect effects of TRYCATs, age and education on negative symptoms are mediated by executive impairments. Nevertheless, sustained attention, memory and emotion recognition also mediate the effects of TRYCATS, lower education and male sex on negative symptoms. CONCLUSION: Deficit schizophrenia is accompanied by a broader spectrum of cognitive impairments than nondeficit schizophrenia, including executive functions, sustained attention, episodic and semantic memory and emotion recognition. Furthermore, neuro-immune disorders underpin executive impairments, whilst neuro-immune disorders coupled with executive and other cognitive impairments to a large extent determine negative symptoms and the deficit phenotype. PMID- 29968546 TI - The Matrix Metalloproteinases Panel in Multiple Sclerosis Patients Treated with Natalizumab: A Possible Answer to Natalizumab Non- Responders. AB - BACKGROUND: In the lymphocyte migration across the blood-brain barrier (BBB) in multiple sclerosis (MS), matrix metalloproteinases (MMPs) play an important role in the degradation of the basal membrane. Natalizumab (NAT), a monoclonal antibody, binds to the alpha-4 (alpha4) integrin leading to BBB impermeability. Approximately 30% of NAT-treated patients show clinical or MRI signs of BBB disruption. OBJECTIVE: To determine whether NAT significantly influences the MMPs serum levels and to what extent these could be used as biomarkers in relapsing remitting MS (RRMS) patients. MATERIALS AND METHODS: This prospective study over a period of 8 months of NAT treatment, included 30 RRMS patients (mean age 38 +/- 6 years; mean MS duration 12 +/- 5 years), of which ten were initially naive to NAT and 15 were healthy controls. We determined the serum levels of the MMPs Panel (MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP12, and MMP13) quantified by a multiplex method at the beginning and end of the study. RESULTS: After 8 months of NAT treatment, a statistically significant decrease was found in MMP9, MMP2, MMP3, MMP8, and MMP10 levels. Relapses during the study were correlated with a variation of MMP12 and MMP13 serum levels. MMP9 had the most numerous correlations with the EDSS score, Rio score, and duration of NAT treatment. MMPs signature (the sum of all MMPs) and the MMP9/MMP2 ratio significantly decreased during the study. CONCLUSION: 1. The serum level of MMP9 significantly decreased by NAT treatment and correlates with MS activity; 2. After eight months of NAT treatment, the MMPs signature and the MMP9/MMP2 ratio decreased; 3. MMP9 might be used as a biomarker in MS patients treated with NAT. PMID- 29968547 TI - Light-Emitting Diode (LED) Therapy Attenuates Neurotoxicity of Methanol-Induced Memory Impairment and Apoptosis in The Hippocampus. AB - BACKGROUND & OBJECTIVE: The adolescent brain has a higher vulnerability to alcoholinduced neurotoxicity, compared to adult's brain. Most studies have investigated the effect of ethanol consumption on the body, however, methanol consumption, which peaked in the last years, is still poorly explored. METHOD: In this study, we investigated the effects of methanol neurotoxicity on memory function and pathological outcomes in the hippocampus of adolescent rats and examined the efficacy of Light- Emitting Diode (LED) therapy. Methanol induced neurotoxic rats showed a significant decrease in the latency period, in comparison to controls, which was significantly improved in LED treated rats at 7, 14 and 28 days, indicating recovery of memory function. In addition, methanol neurotoxicity in hippocampus caused a significant increase in cell death (caspase3+ cells) and cell edema at 7 and 28 days, which were significantly decreased by LED therapy. Furthermore, the number of glial fibrillary acid protein astrocytes was significantly lower in methanol rats, compared to controls, whereas LED treatment caused their significant increase. Finally, methanol neurotoxicity caused a significant decrease in the number of brain derived neurotrophic factor (BDNF+) cells, but also circulating serum BDNF, at 7 and 28 days, compared to controls, which were significantly increased by LED therapy. Importantly, LED significantly increased the number of Ki-67+ cells and BDNF levels in the serum and hypothalamus in control-LED rats, compared to controls without LED therapy. CONCLUSION: In conclusion, chronic methanol administration caused severe memory impairments and several pathological outcomes in the hippocampus of adolescent rats which were improved by LED therapy. PMID- 29968548 TI - Effect of Vitamin K Supplementation on Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Multiple cross sectional and longitudinal studies reported the benefits of vitamin K intake for management of cardiometabolic risk factors so as to minimize the risk of cardiovascular diseases. OBJECTIVE: In present systematic review and meta-analysis, we aimed to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors. METHODOLOGY: A systematic literature search of PubMed, Cochrane central, Clinicaltrials.gov, Google Scholar, Web of Science, EBSCO and Scopus databases was done from inception to November, 2017. A total of 13 trials were selected for inclusion into the present systematic review to evaluate the effect of vitamin K supplementation on cardiometabolic risk factors in healthy or in population at high risk of cardiovascular diseases. RESULTS: Significant beneficial effects of vitamin K supplementation were found only in case of C-reactive protein ( p = 0.01) and insulin sensitivity index ( p <0.001), while no significant effects of vitamin K supplementation were found in case of total cholesterol (p=0.857), low density lipoprotein - cholesterol (p=0.964), high density lipoprotein - cholesterol (p=0.998), interleukin - 6 (p=0.766), systolic blood pressure (p=0.660), diastolic blood pressure (p=0.818), fasting plasma glucose (p=0.362), fasting plasma insulin (p=0.928) and homeostasis model assessment for insulin resistance (p=0.672). CONCLUSION: Presently available evidence are insufficient to ascertain the beneficial effects of vitamin K supplementation for the management of cardiometabolic risk factors. In order to explore the true potential of vitamin K supplementation for management of cardiometabolic diseases, large randomized placebo controlled trials are required in population with disturbed cardiometabolic profile. Present systematic review and meta-analysis is registered with PROSPERO (Registration number: CRD42018084608). PMID- 29968549 TI - Dr. Adel A. F. Mahmoud. PMID- 29968550 TI - The Effect of Nonrandom Mating on Wolbachia Dynamics: Implications for Population Replacement and Sterile Releases in Aedes Mosquitoes. AB - Wolbachia bacteria are known to cause deviations from random mating and affect sperm competition (SC) in some of their arthropod hosts. Because these effects could influence the effectiveness of Wolbachia in mosquito population replacement and suppression programs, we developed a theoretical framework to investigate them and we collected relevant data for the wMel infection in Aedes aegypti. Using incompatibility patterns as a measure of mating success of infected versus uninfected mosquitoes, we found some evidence that uninfected males sire more offspring than infected males. However, our theoretical framework suggests that this effect is unlikely to hamper Wolbachia invasion and has only minor effects on population suppression programs. Nevertheless, we suggest that mating effects and SC need to be monitored in an ongoing manner in release programs, given the possibility of ongoing selection for altered mating patterns. PMID- 29968552 TI - Ruth Nussenzweig (1928-2018) Malaria Vaccine and Immunology Pioneer. PMID- 29968551 TI - A Systematic Review and Meta-Analysis of the Association between Water, Sanitation, and Hygiene Exposures and Cholera in Case-Control Studies. AB - Case-control studies are conducted to identify cholera transmission routes. Water, sanitation, and hygiene (WASH) exposures can facilitate cholera transmission (risk factors) or interrupt transmission (protective factors). To our knowledge, the association between WASH exposures and cholera from case control studies has not been systematically analyzed. A systematic review was completed to close this gap, including describing the theory of risk and protection, developing inclusion criteria, searching and selecting studies, assessing quality of evidence, and summarizing associations between cholera and seven predicted WASH protective factors and eight predicted WASH risk factors using meta-analysis and sensitivity analysis. Overall, 47 articles describing 51 individual studies from 30 countries met the inclusion criteria. All eight predicted risk factors were associated with higher odds of cholera (odds ratio [OR] = 1.9-5.6), with heterogeneity (I2) of 0-92%. Of the predicted protective factors, five of seven were associated with lower odds of cholera (OR = 0.35 1.4), with heterogeneity of 57-91%; exceptions were insignificant associations for improved water source (OR = 1.1, heterogeneity 91%) and improved sanitation (OR = 1.4, heterogeneity 68%). Results were robust; 3/70 (5%) associations changed directionality or significance in sensitivity analysis. Meta-analysis results highlight that predicted risk factors are associated with cholera; however, predicted protective factors are not as consistently protective. This variable protection is attributed to 1) cholera transmission via multiple routes and 2) WASH intervention implementation quality variation. Water, sanitation, and hygiene interventions should address multiple transmission routes and be well implemented, according to international guidance, to ensure that field effectiveness matches theoretical efficacy. In addition, future case-control studies should detail WASH characteristics to contextualize results. PMID- 29968553 TI - Case Report: Orbital Tumor Revealing Adult T-Cell Leukemia/Lymphoma Associated with Human T-Cell Lymphotropic Virus Type-1. AB - Adult T-cell Leukemia/Lymphoma (ATLL) is a sight- and life-threatening complication of human T-cell lymphotropic virus type 1 (HTLV-1) infection. Ophthalmic manifestations include uveitis, optic nerve oedema, retinal vasculitis, and lymphomatous infiltration. Orbital lesions are rare. We report the case of an orbital tumor revealing systemic ATLL in a 45-year-old Dominican patient who died despite treatment. Apart from late-grade cutaneous T-cell lymphoma, ATLL is the only T-lymphoma to develop in the orbit. Diagnosis is based on serologic evidence of HTLV-1 infection, cytology, and blood sample analysis. Biopsy is deemed necessary. Given the poor prognosis of ATLL and the worldwide presentation of HTLV-1, physicians should consider ATLL in the differential diagnosis of orbital malignant tumor and look for HTLV-1 infection in populations at risk. PMID- 29968554 TI - Endotoxin at the Maternal-Fetal Interface in a Resource-Constrained Setting: Risk Factors and Associated Birth Outcomes. AB - Low- and middle-income countries (LMICs) carry a high burden of infectious diseases associated with impaired gut integrity, leading to microbial translocation. Pregnancies in this setting are at high risk of fetal growth restriction (FGR). We examined the association among specific risk factors for impaired gut integrity (schistosomiasis, hookworm infection, and alcohol consumption), blood endotoxin levels, and FGR. Endotoxins, lipopolysaccharide binding proteins (LBPs), and cytokines were measured in blood from women at 32 weeks gestation, the maternal-fetal interface (MFI) at delivery, and cord blood at delivery. Resolution of schistosomiasis had no impact on endotoxin levels; however, maternal hookworm infection and alcohol consumption were associated with modest increases in endotoxin at the MFI. Cytokines responses within the maternal peripheral blood and blood from the MFI were positively associated with endotoxins, but many cord blood cytokines were negatively associated with endotoxins. Newborns with FGR also had higher levels of endotoxins at the MFI. Risk factors for microbial translocation may lead to increased levels of endotoxins at the MFI, which may contribute to poor growth in utero. PMID- 29968555 TI - Important Clinical Features of Japanese Spotted Fever. AB - Japanese spotted fever (JSF) is a zoonosis transmitted by ticks carrying the pathogen Rickettsia japonica. The classic triad of JSF symptoms is high fever, erythema, and tick bite eschar. About 200 people in Japan develop the disease every year. Japanese spotted fever is also a potentially fatal disease. At Minami Ise Municipal Hospital in Japan, 55 patients were diagnosed with JSF from 2007 to 2015, which was equivalent to 4.3% of the total JSF cases in Japan. In this retrospective study, we examined the medical records of these 55 JSF cases. Fever, erythema, eschar, and elevated C-reactive protein (CRP) are characteristic clinical features of the disease. We confirmed four of these in the reviewed cases; however, eschar was not present in occasional cases. We confirmed that eosinopenia appeared in nearly all cases. Using fever, erythema, elevated CRP, and eosinopenia in diagnostic screening, our positivity rate was 90.9%. In our clinical practice, including eosinopenia improves the initial diagnosis of JSF. PMID- 29968556 TI - Plasmodium falciparum Histidine-Rich Protein 2 Gene Variation in a Malaria Endemic Area of Papua New Guinea. AB - Histidine-rich protein 2 of Plasmodium falciparum (PfHRP2) forms the basis of many current malaria rapid diagnostic tests (RDTs). It is concerning that there are parasites that lack part or all of the pfhrp2 gene, and thus do not express the PfHRP2 protein; such parasites are not identifiable by PfHRP2-detecting RDTs. Very limited information is available regarding pfhrp2 genetic variation in Papua New Guinea (PNG). In the present study, this gene variation was evaluated using 169 samples previously collected from the Wosera area in East Sepik Province of PNG. Molecular diagnosis of these samples showed that 81% were infected, and P. falciparum was present in 91% of those infected samples. One hundred and twenty samples were amplified for pfhrp2 exon-2, from which 12 randomly selected amplicons were sequenced, yielding 18 sequences, all of which were unique. Baker repeat type 2 * type 7 numbers ranged from 0 to 108. Epitope mapping analysis revealed that three major epitopes, DAHHAHHA, AHHAADAHHA, and AHHAADAHH, were present in high prevalence and frequencies. These major epitopes have been shown to be recognized by the monoclonal antibodies 3A4 and PTL-3 (DAHHAHHA), C1-13 (AHHAADAHHA), and S2-5 and C2-3 (AHHAADAHH). This study provides further information on the high genetic variation of pfhrp2 and its unclear relationship with prediction of RDT detection sensitivity, and identifies major epitopes in this gene from PNG. These results could be relevant and useful to understand the genetic diversity of this gene and the performance of current and future RDTs in this malarious region of the world. PMID- 29968558 TI - Bowlegs and Intensive Football Training in Children and Adolescents. AB - BACKGROUND: In many countries around the world, football (association football, or "soccer" predominantly in North America) is the sport most commonly played by children and adolescents. It is widely thought that football players are more likely to develop genu varum (bowlegs); an association with knee arthritis also seems likely. The goals of this systematic review and meta-analysis are to provide an overview of the available evidence on genu varum after intensive soccer training in childhood and adolescence, and to discuss the possible pathogenetic mechanisms. METHODS: We systematically searched the PubMed, Medline, Embase, and Coch- rane Library databases for studies of the relation between leg axis development and intensive football playing during the growing years. RESULTS: Controlled studies employing the intercondylar distance (ICD) as the target variable were evaluated in a meta-analysis, with the mean difference as a measure of effect strength. This meta-analysis included 3 studies with a total of 1344 football players and 1277 control individuals. All three studies individually showed a signifi- cant difference in the mean ICD values of the two groups. The pooled effect esti- mator for the mean difference was 1.50 cm (95% confidence interval [0.53; 2.46]). Two further studies that could not be included in the meta-analysis had similar con- clusions. Asymmetrical, varus muscle forces and predominantly varus stress on the osseous growth plates neighboring the knee joint, especially during the prepubertal growth spurt, seem to be the cause of this phenomenon. CONCLUSION: Intensive soccer playing during the growing years can promote the devel- opment of bowlegs (genu varum) and, in turn, increase the risk of knee arthritis. Phy- sicians should inform young athletes and their parents of this if asked to advise about the choice of soccer as a sport for intensive training. It cannot be concluded, however, that football predisposes to bowlegs when played merely as a leisure activity. PMID- 29968560 TI - Neonatal Cerebellar Hemorrhage Due to Vitamin K Deficiency. PMID- 29968557 TI - Dried Blood Spots for Global Health Diagnostics and Surveillance: Opportunities and Challenges. AB - There is increasing interest in using dried blood spot (DBS) cards to extend the reach of global health and disease surveillance programs to hard-to-reach populations. Conceptually, DBS offers a cost-effective solution for multiple use cases by simplifying logistics for collecting, preserving, and transporting blood specimens in settings with minimal infrastructure. This review describes methods to determine both the reliability of DBS-based bioanalysis for a defined use case and the optimal conditions that minimize pre-analytical sources of data variability. Examples by the newborn screening, drug development, and global health communities are provided in this review of published literature. Sources of variability are linked in most cases, emphasizing the importance of field-to laboratory standard operating procedures that are evidence based and consider both stability and efficiency of recovery for a specified analyte in defining the type of DBS card, accessories, handling procedures, and storage conditions. Also included in this review are reports where DBS was determined to not be feasible because of technology limitations or physiological properties of a targeted analyte. PMID- 29968559 TI - Exercise Testing in Sports Medicine. AB - BACKGROUND: Bicycle and treadmill exercise tests are used in sports medicine and occupational medicine to detect latent disease, to monitor treatment, and to measure patients' physical performance ability and reserve. In this review, we describe the indications, contraindications, and manner of performance of these tests, along with the variables tested, criteria for evaluation, (sub)maximal stress, and the factors that affect these tests, including age, sex, and medications. METHODS: This review is based on pertinent articles retrieved by a selective literature search and on the ergometry guidelines of four medical specialty societies. RESULTS: The proper performance of ergometric stress tests calls for preparation and monitoring by qualified staff as well as standardized testing conditions. Ergometric studies are indispensable as a clinical diagnostic method for the early recognition of disease, for follow-up over time, and for individual counseling. The patient's maximal achievable performance is a predictor of morbidity and mortality. Among the variables that can be measured in the submaximal performance range, the respiratory rate, heart rate, and lactate performance curves are more accurate prognostic predictors than the so-called threshold values (physical working capacity, anaerobic-aerobic threshold). Ergometric stress tests can be used to detect (among other conditions) latent hypertension, pulmonary diseases (e.g., exertional asthma), pabnormal ECG changes, and cardiovascular disorders (e.g., ischemia, arrhythmia, congestive heart failure). The ergometric findings are influenced by the choice of stress inducing protocol. They provide important information for the planning and monitoring of exercise training and for the treatment of persons suffering from diverse physical conditions, as well as for leisure-time athletes. They are less suit- able for use in the design of training programs for high-performance athletes. CONCLUSION: Ergometric stress tests provide important data in clinical and preventive medicine. The findings are often difficult to interpret because of the wide range of normal findings, the use of different stress-inducing protocols, and the lack of gen- erally accepted reference values. The establishment of a nationwide fitness and health registry for ergometric data would be very helpful for the individualized inter- pretation of test findings and for the monitoring of exercise training and therapy. PMID- 29968561 TI - Some Necessary Additional Points. PMID- 29968563 TI - 12 Vertebral-Body Fractures and Simultaneous Skin Changes. PMID- 29968562 TI - In Reply. PMID- 29968564 TI - Single-color, ratiometric biosensors for detecting signaling activities in live cells. AB - Genetically encoded fluorescent biosensors have revolutionized the study of signal transduction by enabling the real-time tracking of signaling activities in live cells. Investigating the interaction between signaling networks has become increasingly important to understanding complex cellular phenomena, necessitating an update of the biosensor toolkit to allow monitoring and perturbing multiple activities simultaneously in the same cell. We therefore developed a new class of fluorescent biosensors based on homo-FRET, deemed FLuorescence Anisotropy REporters (FLAREs), which combine the multiplexing ability of single-color sensors with a quantitative, ratiometric readout. Using an array of color variants, we were able to demonstrate multiplexed imaging of three activity reporters simultaneously in the same cell. We further demonstrate the compatibility of FLAREs for use with optogenetic tools as well as intravital two photon imaging. PMID- 29968565 TI - Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury. AB - Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain. PMID- 29968566 TI - Beyond the RfD: Broad Application of a Probabilistic Approach to Improve Chemical Dose-Response Assessments for Noncancer Effects. AB - BACKGROUND: The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk specific dose, a framework for which was recently developed by the World Health Organization (WHO). OBJECTIVES: Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDMI). METHODS: We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose-response workflow implementing the WHO framework. RESULTS: We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 HDMI values. Traditional RfDs are generally within an order of magnitude of the HDMI lower confidence bound for I=1% and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality. CONCLUSIONS: Overall, replacing RfDs with HDMI estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit-cost analysis, risk-risk tradeoffs, life-cycle impact analysis, and emergency response. https://doi.org/10.1289/EHP3368. PMID- 29968568 TI - CVD-grown MoSe2 with high modulation depth for ultrafast mode-locked erbium-doped fiber laser. AB - Two-dimensional materials have been widely used as optical modulator materials in mode-locked fiber lasers. In terms of the performance of the fiber laser, one with an ultrashort pulse and high stability has great commercial value. Herein, the MoSe2 grown by the chemical vapor deposition (CVD) method with high modulation depth, quality lattice structure and uniformity is successfully applied in a mode-locked erbium-doped fiber laser. The pulse duration and signal to-noise ratio of the laser are 207 fs and 85 dB, respectively. The multifarious performance comparisons indicate that the CVD-based MoSe2 saturable absorber with the tapered fiber structure has unique advantages not only in the generation of ultrashort pulses, but also in the optimization of laser stability. PMID- 29968567 TI - Elucidating Gene-by-Environment Interactions Associated with Differential Susceptibility to Chemical Exposure. AB - BACKGROUND: Modern societies are exposed to vast numbers of potentially hazardous chemicals. Despite demonstrated linkages between chemical exposure and severe health effects, there are limited, often conflicting, data on how adverse health effects of exposure differ across individuals. OBJECTIVES: We tested the hypothesis that population variability in response to certain chemicals could elucidate a role for gene-environment interactions (GxE) in differential susceptibility. METHODS: High-throughput screening (HTS) data on thousands of chemicals in genetically heterogeneous zebrafish were leveraged to identify a candidate chemical (Abamectin) with response patterns indicative of population susceptibility differences. We tested the prediction by generating genome-wide sequence data for 276 individual zebrafish displaying susceptible (Affected) vs. resistant (Unaffected) phenotypes following identical chemical exposure. RESULTS: We found GxE associated with differential susceptibility in the sox7 promoter region and then confirmed gene expression differences between phenotypic response classes. CONCLUSIONS: The results for Abamectin in zebrafish demonstrate that GxE associated with naturally occurring, population genetic variation play a significant role in mediating individual response to chemical exposure. https://doi.org/10.1289/EHP2662. PMID- 29968569 TI - Blown bubble assembly of ultralong 1D bismuth sulfide nanostructures with ordered alignment and shape control. AB - Recently, semiconducting chalcogenide nanostructures have attracted intense attention due to their excellent properties and broad applications, especially metal chalcogenides in the form of A2(V)B3(VI). Here we synthesized one dimensional (1D) bismuth sulfide (Bi2S3) nanostructures with a length of more than 100 MUm via a one-step hydrothermal method, and found that the reaction temperature and the alkali concentration play vital roles in the morphology of the 1D nanostructures. Since the as-synthesized Bi2S3 nanostructures were disordered in powder form, it is necessary to align them with ordered orientation and uniform distribution before further application. A blown bubble method was specifically applied to align these ultralong 1D nanostructures, and the assembly mechanism was also deeply analyzed, including the drift of nanostructures in the bubble film thickness direction, the relationship between (nanowire) NW spacing and array density, and the angle deviation of aligned arrays assembled from different bubble solutions. Interestingly, the initial straight Bi2S3 NWs could also be converted into buckled nanosprings (NSs) with regular pitches during the assembly process, and different NS formation stages were observed. A possible deformation mechanism or load bearing model of the wavy NS was proposed and verified, and the Young's modulus of an individual NW was figured out for the first time. After annealing under a N2 atmosphere, the aligned Bi2S3 NWs embedded in the bubble film were exposed, and the clean arrays were fabricated into functional optoelectronic devices such as photodetectors with a high performance. PMID- 29968570 TI - A free-standing, flexible PEDOT:PSS film and its nanocomposites with graphene nanoplatelets as electrodes for quasi-solid-state supercapacitors. AB - Research and development on all-solid-state, flexible supercapacitors is the prime concern of the scientific community these days due to their various advantages including their easy transportability, miniaturization, and compactness in different appliances. We report the novel configuration of all solid symmetrical supercapacitors employing free-standing, flexible films of poly(3,4-ethylenedioxythiophene) poly(styrene sulfonate) (PEDOT:PSS) and its nanocomposite electrodes with graphene nanoplatelets (GNPs), separated by ionic liquid (IL) (1-ethyl 3-methylimidazolium trifluoromethanesulfonate (EMITf))-based gel polymer electrolyte (GPE) films. The free-standing and flexible form of PEDOT:PSS/GNP nanocomposite films have been prepared via simple mixing of the two counterparts. Scanning electron microscopy, x-ray diffraction, Raman analysis, and thermal and mechanical characterizations have been performed to ascertain the suitability of pristine and nanocomposite PEDOT:PSS films as potential supercapacitor electrodes. The GPE film, comprising of a solution of NH4CF3SO3 (NH4-triflate or NH4Tf) in IL, entrapped in poly(vinylidine fluoride-co hexafluoropropylene) (PVdF-HFP), is a promising electrolyte due to its high ionic conductivity and sufficient electrochemical stability window. The supercapacitor with a PEDOT:PSS nanocomposite containing ~3.8 wt.% of GNP has been found to give an optimum specific capacitance of ~106 F g-1 (evaluated from electrochemical impedance spectroscopy), and specific energy and power of ~6.95 Wh kg-1 and 2.58 kW kg-1, respectively (evaluated from galvanostatic charge-discharge). More importantly, the capacitors demonstrate stable performance for more than 2000 charge-discharge cycles, with only ~10% initial fading in capacitance. Interestingly, the PEDOT:PSS/GNP nanocomposite-based solid-state supercapacitors with the IL-incorporated GPE have shown comparable (even better) performance than other reported PEDOT:PSS-based supercapacitors. PMID- 29968571 TI - Direct imaging of the interaction between spin wave and transverse wall in magnetic nanostrip. AB - By micromagnetic simulations, the dynamical interaction between spin wave (SW) and a transverse wall (TW) in a magnetic nanostrip is studied. We find the dynamical interaction can be directly demonstrated by SW-induced TW oscillation, which can be obtained by calculating the total magnetic moment within the area of TW as a function of time. Two cases of the initial TW, in equilibrium state and in metastable state, are investigated and compared. Before SW reaches TW, the metastable TW oscillates naturally with a constant frequency, whereas the equilibrium TW does not oscillate. After SW acts on TW, both the metastable TW and the equilibrium TW will oscillate with a frequency that always equal to the frequency of the applied SW. The amplitude of the SW-induced TW oscillation for both the metastable case and the equilibrium case strongly depends on the frequency of the applied SW. Through tuning the frequency of the applied SW, we confirm that the natural oscillation of the metastable TW, which is independent of the applied SW, will not affect the amplitude of the SW-induced TW oscillation and the velocity of the TW motion in compare with those of the equilibrium TW. Interestingly, the frequency-response curves of the SW-induced TW oscillations display multiple resonance peaks. Moreover, we find the frequency-response curves of the SW-induced TW oscillation, SW reflection coefficient and TW velocity driven by SW share the same multiple-resonance property. It may suggest the SW induced TW oscillation in the domain wall plays an important role in the SW driven TW motion. PMID- 29968572 TI - Design and assessment of a flexible fish robot actuated by shape memory alloys. AB - In this paper, we present a fish-like underwater robot inspired by the black bass fish. This robot is composed of a deformable structure and muscle-like linear actuators based on shape memory alloy wires. Such actuators are used to bend a continuous structure representing the backbone of the fish. The prototype is also equipped with a bio-inspired synthetic skin made of liquid silicone rubber and Lycra microfiber mesh. We present the mechatronics of the prototype and its control scheme, which take advantage of flex sensors for proprioception. Experiments under different conditions (in air and in water) assess the effectiveness of the mechatronics design and demonstrate that a relatively simple PID controller provides high precision of the muscles' position control. Here, the implementation of biomimetic kinematics and silent actuation technology in bio-inspired underwater robotics are demonstrated. Progress in this technology could provide multiple applications, including fish farming, coastal protection and live animal monitoring where silent robotics are necessary. PMID- 29968573 TI - Rolled-up SiO x /SiN x microtubes with an enhanced quality factor for sensitive solvent sensing. AB - The microtubes made through rolling-up of strain-engineered nanomembranes have received growing research attention after their first invention due to the technology's high flexibility, integrability, and versatility. These rolled-up microtubes have been used for a variety of device applications including sensors, batteries and transistors, among others. This paper reports the development of highly sensitive whispering-gallery mode (WGM) chemical sensors based on rolled up microtube optical microcavities (RUM-OCs). For the first time, such microcavities were batch fabricated through rolling-up of plasma-enhanced chemical vapor deposition (PECVD)-synthesized SiO x /SiN x bilayer nanomembranes, which have better optical properties than the conventional electron-beam deposited SiO/SiO2 bilayers. Benefiting from the high refractive index (RI) of PECVD-deposited SiN x , our RUM-OC shows an enhanced quality factor of 880 that is much higher than that (50) of a SiO/SiO2 RUM-OC with the same dimensions. The developed RUM-OC is used for sensitive WGM solvent sensing, and demonstrate a limit of detection of 10-4 refractive index unit (RIU), which is 10 times lower than that (10-3 RIU) of a SiO/SiO2 RUM-OC. PMID- 29968574 TI - Near-field imaging of graphene triangles patterned by helium ion lithography. AB - Plasmon nanoresonators in graphene have many applications in biosensing, photodetectors and modulators. As a result, an efficient and precise patterning technique for graphene is required. Helium ion lithography (HIL) emerges as a promising tool for direct writing fabrication because it owns improved fabrication precision compared to electron beam lithography and conventional gallium focused ion beam technique. In this paper, utilizing HIL, a set of graphene triangles are patterned and excellent plasmon response is detected. Particularly, the evolution of breathing mode in these structures is unveiled by scattering-type scanning near-field optical microscopy. Besides, the plasmon response of graphene structures can be efficiently tuned by adjusting the irradiated ion dose during the etching process, which can be explained by the phenomenal simulation model. Our work demonstrates that HIL is a feasible way for precise plasmonic nanostructure fabrication, and can be applied to graphene plasmon control at the nanoscale as well. PMID- 29968575 TI - The effect of inkjetted nanoparticles on metal part properties in binder jetting additive manufacturing. AB - Binder jetting AM has been used to fabricate metal parts by first jetting a binder into a powder bed, and then sintering the resulting green part wherein the binder is removed and the metal particles are fused. Sintered part properties can be enhanced when nanoparticles are suspended into a solvent-based organic binder, as the inkjetted nanoparticles can reduce sintering shrinkage and increase mechanical strength. In this work, the authors also used a nanoparticle suspension without organic adhesives as a means for binding metal powder bed particles together. After being deposited into the powder particles' interstices, the jetted nanoparticles are sintered at a temperature lower than the powder sintering temperature via a heated powder bed, to provide strength to the printed green part. Compared to organic binders, the use of jetted nanoparticles provided a permanent bonding which improved the structural integrity of printed parts during sintering. PMID- 29968576 TI - Enhanced reconstruction algorithm for moire artifact suppression in Talbot-Lau x ray imaging. AB - Talbot-Lau x-ray imaging (TLXI) is an innovative and promising imaging technique providing information about the x-ray attenuation, scattering, and refraction features of objects. However, the method is susceptible to vibrations and system component imprecisions, which are inevitable in clinical and industrial practice. Those influences provoke grating displacements and hence errors in the acquired raw data, which cause moire artifacts in the reconstructed images. We developed an enhanced reconstruction algorithm capable of compensating these errors by adjusting the grating positions and thus suppressing the occurrence of moire artifacts. The algorithm has been developed with regard to a future application in medical practice. The capability of the algorithm is demonstrated on a medical data set of a human hand (post-mortem) acquired under clinical conditions using a pre-clinical TXLI prototype. It is shown that the algorithm reliably suppresses moire artifacts, preserves image contrast, does not blur anatomical structures or prevent quantitative imaging, and is executable on low-dose data sets. In addition, the algorithm runs autonomously without the need of interaction or rework of the final results. In conclusion, the proposed reconstruction algorithm facilitates the use of TLXI in clinical practice and allows the exploitation of the method's full diagnostic potential in future medical applications. PMID- 29968577 TI - Spin-orbit effects on the spin and pseudospin polarization in ac-driven silicene. AB - We study the pseudospin and spin dynamical effects in single-layer silicene due to a perpendicular electric field periodically driven and its interplay with the intrinsic and extrinsic (Rashba) spin-orbit interaction. We find that the spin nonconserving processes of the real spin of the quasiparticles in silicene, induced by the rather weak spin-orbit mechanisms, manifest themselves as shifts of the resonances of its quasienergy spectrum in the low coupling regime to the driving field. We show that there is an interesting cooperative effect among the, in principle, competing Rashba and intrinsic spin-orbit contributions. This is explicitly illustrated by exact and approximated analytical solutions of the dynamical equations. In addition, we show that a finite Rashba spin-orbit interaction is indeed necessary in order to achieve a nonvanishing spin polarization. As additional feature, trivial and nontrivial topological phases might be distinguished from each other as fast or slow dynamical fluctuations of the spin polarization. We mention the possible experimental detection schemes of our theoretical results and their relevance in new practical implementation of periodically driven interactions in silicene physics and related two-dimensional systems. PMID- 29968578 TI - Nanowire-core/double-shell of NiMoO4@C@Ni3S2 arrays on Ni foam: insights into supercapacitive performance and capacitance degradation. AB - The one-dimensional-core/double-shell arrays on Ni foam were prepared by the hydrothermal, carbonized and electrodeposition processes, consisting of NiMoO4 nanowire as a core, an ultrathin carbon layer as an internal shell and Ni3S2 nanosheets an external shell (abbr. NiMoO4@C@Ni3S2), respectively. The ternary heterostructure demonstrates the synergistic effect on the dimensional, interface, surface structures and compositions, resulting from the ordered and functionalized architectures. Therefore, the NiMoO4@C@Ni3S2 electrode integrated the advantages of the electron transfer, electrolyte penetration and ion diffusion. The asymmetric supercapacitor exhibited a high energy density of 1.29 mW h cm-3 at a power density of 13.99 W cm-3. Furthermore, we compared the changes in composition, structure and morphology before and after 3000 cycles using the three electrode system. These observations demonstrated that the dissolution of NiMoO4@C@Ni3S2 induced the decay of capacitance and cycling stability, suggesting that we can further develop a strategy to consolidate the electrode structure. PMID- 29968580 TI - Calculation of water equivalent ratios for various materials at proton energies ranging 10-500 MeV using MCNP, FLUKA, and GEANT4 Monte Carlo codes. AB - Dosimetry of proton beams is generally evaluated in liquid water, or alternatively in solid phantoms via water equivalent ratios (WER). WER is defined as the ratio of proton range in liquid water to that in a phantom of certain material. Presently, WER is not available in the literature neither for a wide range of energies nor for variety of relevant materials. Thus, the goal of this study is to provide such data through Monte Carlo simulations. WER is calculated for 10-500 MeV energies for compact bone, adipose tissue, polymethyl methacrylate (PMMA), PTFE (teflon), graphite (C), aluminum (Al), copper (Cu), titanium (Ti), and gold (Au) using MCNPX.2.70, GEANT4, and FLUKA Monte Carlo (MC) codes. The MCNPX code was considered as the reference to which other codes were compared. The mean values of WER obtained through the MCNPX simulations for Au, Cu, Ti, Al, PTFE, graphite, PMMA, bone, and adipose tissue were 8.83, 5.40, 3.18, 2.03, 1.87, 1.52, 1.13, 1.71, and 0.96, respectively, for 10-500 MeV energy range. The maximum deviations of WER values between MCNPX and GEANT4 results were about 6.85% for adipose tissue at energies <20 MeV, whereas they were about 7.74%, 7.74% between MCNPX and FLUKA, for adipose and Al, respectively. This inter-code uncertainties are mainly due to different physic models and stopping powers in each code. Comparing the results to that in the literature, the range of discrepancy was found to be 0-8% with greatest discrepancy for Au. Based on the materials evaluated, the PMMA remained the closest to water, for a non-tissue solid material, with an average WER of 1.13, for proton energy ranging 10-500 MeV. PMID- 29968579 TI - Scalp sensor for simultaneous acoustic emission detection and electroencephalography during transcranial ultrasound. AB - Focused ultrasound is now capable of noninvasively penetrating the intact human skull and delivering energy to specific areas of the brain with millimeter accuracy. The ultrasound energy is supplied in high-intensities to create brain lesions or at low-intensities to produce reversible physiological interventions. Conducting acoustic emission detection (AED) and electroencephalography (EEG) during transcranial focused ultrasound may lead to several new brain treatment and research applications. This study investigates the feasibility of using a novel scalp senor for acquiring concurrent AED and EEG during clinical transcranial ultrasound. A piezoelectric disk is embedded in a plastic cup EEG electrode to form the sensor. The sensor is coupled to the head via an adhesive/conductive gel-dot. Components of the sensor prototype are tested for AED and EEG signal quality in a bench top investigation with a functional ex vivo skull phantom. PMID- 29968581 TI - High performance self-gating graphene/MoS2 diode enabled by asymmetric contacts. AB - A graphene-MoS2 (GM) heterostructure based diode is fabricated using asymmetric contacts to MoS2, as well as an asymmetric top gate (ATG). The GM diode exhibits a rectification ratio of 5 from asymmetric contacts, which is improved to 105 after the incorporation of an ATG. This improvement is attributed to the asymmetric modulation of carrier concentration and effective Schottky barrier height (SBH) by the ATG during forward and reverse bias. This is further confirmed from the temperature dependent measurement, where a difference of 0.22 eV is observed between the effective SBH for forward and reverse bias. Moreover, the rectification ratio also depends on carrier concentration in MoS2 and can be varied with the change in temperature as well as back gate voltage. Under laser light illumination, the device demonstrates strong opto-electric response with 100 times improvement in the relative photo current, as well as a responsivity of 1.9 A W-1 and a specific detectivity of 2.4 * 1010 Jones. These devices can also be implemented using other two dimensional (2D) materials and suggest a promising approach to incorporate diverse 2D materials for future nano-electronics and optoelectronics applications. PMID- 29968583 TI - Strained germanium nanowire optoelectronic devices for photonic-integrated circuits. AB - Strained germanium nanowires have recently become an important material of choice for silicon-compatible optoelectronic devices. While the indirect bandgap nature of germanium had long been problematic both in light absorption and emission, recent successful demonstrations of bandstructure engineering by elastic strain have opened up the possibility of achieving direct bandgap in germanium, paving the way towards the realization of various high-performance optical devices integrated on a silicon platform. In particular, the latest demonstration of a low-threshold optically pumped laser in a highly strained germanium nanowire is expected to vitalize the field of silicon photonics further. Here, we review recent advances and challenges in strained germanium nanowires for optoelectronic applications such as photodetectors and lasers. We firstly introduce the theoretical foundation behind strained germanium nanowire optoelectronics. And several practical approaches that have been proposed to apply tensile strain in germanium nanowires are further discussed. Then we address the latest progress in the developments of strained germanium nanowire optoelectronic devices. Finally, we discuss the implications of these experimental achievements and the future outlook in this promising research field. PMID- 29968582 TI - Noise spectroscopy of tunable nanoconstrictions: molecule-free and molecule modified. AB - Devices with metallic nanoconstrictions functionalized by organic molecules are promising candidates for the role of functional devices in molecular electronics. However, at the moment little is known about transport and noise properties of nanoconstriction devices of this kind. In this paper, transport properties of bare gold and molecule-containing tunable cross-section nanoconstrictions are studied using low-frequency noise spectroscopy. Normalized noise power spectral density (PSD) S I /I 2 dependencies are analyzed for a wide range of sample resistances R from 10 Ohm to 10 MOhm. The peculiarities and physical background of the flicker noise behavior in the low-bias regime are studied. It is shown that modification of the sample surface with benzene-1,4-dithiol molecules results in a decrease of the normalized flicker noise spectral density level in the ballistic regime of sample conductance. The characteristic power dependence of normalized noise PSD as a function of system resistance is revealed. Models describing noise behavior for bare gold and BDT modified samples are developed and compared with the experimental data for three transport regimes: diffusive, ballistic and tunneling. Parameters extracted from models by fitting are used for the characterization of nanoconstriction devices. PMID- 29968584 TI - Ising-like behaviour of mesoscopic magnetic chains. AB - We demonstrate an experimental realization of the short range magnetic order in a one-dimensional Ising chain using fabricated mesospins. We confirm an excellent agreement between the experimental findings and simulations obtained using the original Ising model. In particular, we are able to show that the thermal behaviour of the mesoscopic Ising chain dominates over the thermal behaviour of the individual mesospins themselves, confirming that fabricated mesospins can be viewed as artificial magnetic atoms. PMID- 29968585 TI - Helium in-plane migration behavior on <1 0 0> symmetric tilt grain boundaries in tungsten. AB - We present the results of an atomistic modeling study of small helium cluster migration in the plane of symmetric tilt grain boundaries. The relevant migration pathways and energies were determined by way of temperature accelerated dynamics and the nudged elastic band method. We find that small helium clusters show much higher migration energies when bound to the grain boundary than in the bulk for all types of grain boundaries, indicating strongly-impeded helium transport behavior. Larger helium clusters (up to three helium atoms) tend to have higher migration energies compared with smaller clusters. Longer-distance migrations also tend to have higher migration energies, but helium cluster migration is highly affected by the structure of the grain boundary. The binding energy of the grain boundaries studied is high enough that helium clusters would be unlikely to leave the grain boundary plane. However, vacancy migration energies are relatively low compared to the bulk, and are also much lower than helium cluster migration energies on the grain boundary plane. This suggests that helium cluster migration on the grain boundary is actually governed by the rate of vacancy migration: in the bulk, helium clusters are mobile, but they become bound to and immobilized by grain boundaries, forming bubbles. Bubbles, however, are likely more mobile on the grain boundary than they are in the bulk due to the increased rate of vacancy migration on the grain boundary. We expect similar migration behavior for other types of grain boundaries because of the increased excess volume found near all grain boundaries. PMID- 29968587 TI - Automatic Detection of Depression by Using a Neural Network. AB - Depression is the most common psychiatric disorder worldwide, which affects more than 300 million people. We aimed to detect depressed patients and healthy people automatically. We work on the PHQ-9 questionnaires and reduced it to a PHQ-5 questionnaires with a new cut-off value of 8 to detect depressed patients. We trained a Neural Network with 70% of our dataset. Then, the proposed classifier was tested with two datasets. The first one consists of 30% of PHQ-5 datasets, which could achieve 85.69%, 99.11% and 90.56% for accuracy, sensitivity and specificity respectively. The second test dataset consists of physical patient's parameters which recorded during a study in the Hanover Medical School. This classifier has shown good results in the detection of depression based on these two datasets. PMID- 29968588 TI - Concept for Sharing Distributed Personal Health Records with Blockchains. AB - The characteristics of the "blockchain" technology and especially its decentralized nature lead to the notion of neutrality, censorship resistance, and absolute truths, which makes the concept interesting for many different domains, such as finance, supply chain management, or the energy sector - of course also for the healthcare area (eHealth). Blockchains also offer the possibility for well-known access points for a distributed system with easy to use and simple to integrate programming interfaces, which makes it interesting as a central point for electronic healthcare data exchange in a distributed environment. This paper presents a concept for integrating and sharing distributed personal healthcare records based on smart contracts implemented on an Ethereum blockchain. PMID- 29968589 TI - Towards Preventative Healthcare: A Review of Wearable and Mobile Applications. AB - Wearable and mobile devices are now commonly used in our daily activities, giving users instant access to various information. One the one hand, wearable and mobile technologies are developing at a fast rate and have been increasingly ubiquitous. On the other hand, the potential of their application in health is yet to be fully explored. This paper attempts to sketch an overview of wearable and mobile applications in the healthcare domain. We first review how various wearable and mobile applications are being used to monitor and manage health conditions. Then how connections between physiological factors and psychological factors can help with disease prevention is presented. Finally, challenges and future directions for further developments of these emerging technologies in health are discussed. PMID- 29968590 TI - Unmet Needs of Persons with Down Syndrome: How Assistive Technology and Game Based Training May Fill the Gap. AB - The use of new technology seems to be an important factor that contributes to the overall ability to adapt and achieve higher independence. Technologies using digital games have gained the great interest of the scientific community as there are many advantages for both effectiveness and benefits, physically and mentally, providing the opportunity for essential and enjoyable training. This study presents an important initial step utilizing the LLM Care service which focuses on the needs and challenges for the health and daily living of people with Down syndrome (DS) by applying new technology hardware and software. People with cognitive impairments, such as memory, attention and motivation problems may also benefit from this kind of cognitive support that assistive technology offers. PMID- 29968591 TI - Risk Thresholds and Risk Classifications Pose Problems for Person-Centred Care. AB - Classification of a continuous risk score into risk levels is common. However, while the absolute risk score is essential, it is arguably unethical to label anyone at 'high, moderate or low risk' of a serious event, simply because management based on a single criterion (e.g. avoiding the target condition) has been determined to be effective or cost-effective at a population level. Legally, mono-criterial risk labeling can inhibit the obtaining of a fully-informed, preference-based consent, since multiple considerations (various benefits and harms) matter to most individuals, not only the single criterion that is the basis of the provided risk category. These ethical and legal challenges can be met by preference-sensitive multi-criteria decision support tools. In this future vision paper, we demonstrate, at a conceptual proof-of-method level, how such decision support can and should be developed without reference to risk-level classifications. The statin decision is used as illustration, without any empirical claims. PMID- 29968592 TI - Separating Risk Assessment from Risk Management Poses Legal and Ethical Problems in Person-Centred Care. AB - Accelerating progress in screening technologies, e.g. genetic testing, means more individuals are facing the stressful decision of whether to request the test. Fully-informed and preference-based consent, as well as ethical practice, requires the full range of benefits and harms from any test or treatment to be identified and assessed from the individual's point of view. For both ethical and legal reasons, we see the decision on whether to undertake a genetic screening test being increasingly seen, in future, as calling for a personalised analysis of the full range of subsequent management options. The conventional dissociation of 'risk assessment' and 'risk management' phases is thereby ruled out. One way of addressing the resulting challenge is through personalised multi-criterial decision support tools. In this vision paper we provide conceptual proof of method of how such an interactive online tool could function. The polygenetic genetic screening decision is used, solely as illustration. PMID- 29968593 TI - Blockchains in IHE-Based Networks. AB - INTRODUCTION: Interoperability of health information systems is one of the key challenges of modern healthcare systems. A weak spot in this technology stack of interoperability protocols as defined by HL7 and IHE is cross affinity domain exchange of access control information and policies. In several industries the Blockchain technology had a major breakthrough. The goal of this paper is to elaborate how to exchange cross affinity domain access information enhancing well established IHE networks with block chain technology. METHODS: Using literature analysis and research on current interoperability standards the state of the art of securely exchanging medical information was elaborated. We enhanced this system with the capabilities of the peer2peer based Blockchain network elaborating the workflows of exchanging the access control specific information. RESULTS: We extended an IHE based affinity domain by adding a block chain ledger to the deployment. This ledger is fed with XACML based policies which are propagated through the peer2peer based system. Using the Blockchain protocol other affinity domains are informed of the change and can retrieve the information. Acting as an additional source of policies and consents the policy decision point is capable of querying this network and building a decision based on the retrieved information. PMID- 29968594 TI - Advantages of Modular Hybrid Network Communication on Clinical Wards. AB - The ever-increasing flood of information, especially in the medical-clinical field, inter alia due to the increase of data-intensive mobile/wearable devices, is one of the biggest challenges of medical informatics. In this work different possibilities of the integration of wearable devices on the example of the development of a fall prevention system are presented and classified. We started with a commercial off-the-shelf one-on-one system (Shimmer/Arduino) using a Bluetooth connection, integrated via nurse call system as Human-Machine Interface. During the evaluation of the system we mentioned several new requirements and optimization possibilities. Thus, we adjusted the hardware software-system; the near-field communication was realized by IEEE802.15.4, we replaced commercial off-the-shelf devices with highly-specialized open hardware in-house developments and we transferred the nurse call integration by setting up our own network and integrating this into an existing (wireless) local area network. With this development, the energy-efficient, simple and intuitive mechanisms of proximity communication via IEEE802.15.4 can be combined with the benefits broadband functionalities, e.g. of Wi-Fi, with both worlds benefits and the compensation of some disadvantages. PMID- 29968595 TI - Deploying Cloud Computing in the Greek Healthcare System: A Modern Development Proposal Incorporating Clinical and Laboratory Data. AB - Cloud computing is a reality in most business sectors. Hospitals have been more reluctant to adopt cloud technology due to strict data security regulations. Cloud could provide economies of scale reducing Information Technology spending in the Greek state-owned hospitals, while giving the opportunity to the hospitals to upgrade their profile offering web-based services. We propose a simple, robust and easy to apply approach for the Greek hospitals, focusing on clinical and laboratory data in order to move to the cloud environment. To the best of our knowledge, there is no other study regarding the adoption of cloud infrastructure in the Greek hospital sector. This innovative method could transform the business model of the hospitals. PMID- 29968596 TI - A Computer-Based Speech Sound Disorder Screening System Architecture. AB - This paper reviews several architectures of Computer-Based Speech Therapy (CBST) systems and solutions and describes an architecture for an Entropy-Based Sound Speech Disorder (SSD) Screening System aimed at by our research project. The proposed architecture and data flow scenario aim to provide a fully-automated Entropy-based SSD Screening System, to be connected with CBSTs and to be used as a research infrastructure for further refinement of the objectives of our research project. PMID- 29968597 TI - Hand Rehabilitation Using a 3D Environment and Leap Motion Device. AB - The paper presents a 3D healthcare informatics support for Hand Rehabilitation after injury. As a novelty, the application uses the Leap Motion sensor for patient's gestures recognition, and videos to illustrate to the users the hand exercise to perform. The implemented application provides feedback to users regarding the correctness of the performed recovery gestures/exercises. The data related to hand rehabilitation is saved in a database and offers to the Medical Rehabilitation Experts the possibility to monitor the patients in a more consistent manner. To assess the efficiency and accuracy of the application the application will be tested following a usability plan. PMID- 29968598 TI - An Approach for Dynamic Vital Parameter Monitoring - Prototype Development. AB - The alpine space is characterized with rural regions, often hard to reach for mobile care. As part of the EU-funded INTESI project, a mobile platform for vital sign self-monitoring for patients who receive mobile care was developed. Based on a thorough analysis of user requirements and available technology a platform was established, that integrates several Bluetooth low energy devices for measuring vital signs. The developed VITAMO app further enables clients and nurses to easily govern measurements and jointly take control of a client's health during the care process. In addition, the system supports the communication of clients and nurses electronically. The internal data structure adheres to current healthcare standards e.g. FHIR and offers easy interfaces for future applications. The complete system was applied in a pilot study and got formally evaluated. PMID- 29968599 TI - Matching Ontologies to HL7 FHIR Towards Their Syntactic and Semantic Similarity. AB - Current medical systems need to be able to communicate complex and detailed medical data securely and efficiently. However, the quantity of available healthcare data is rising rapidly, far exceeding the capacity to deliver personal or public health benefits from analyzing this data. Thus, a substantial overhaul of methodology is required to address the real complexity of health. This can be achieved by constructing medical domain ontologies for representing medical terminologies, considered to be a difficult task, requiring a profound analysis of the structure and the concepts of medical terminologies. In this paper, a mechanism is presented for constructing healthcare ontologies, while matching them to HL7 FHIR Resources ontologies both in terms of syntactic and semantic similarity, in order to understand their nature and translate them into a common standard to improve the quality of patient care, research, and health service management. PMID- 29968600 TI - Home-Based Training Support for Stroke Patients Using the Leap Motion and StandInExercise Stand. AB - Rehabilitation aims at brain rewiring through intensive practice following brain injury. This paper presents a new supportive mechanism that will be used to isolate wrist movement and in combination to the use of serious games, to act as a motivational tool to improve adherence during home-based practice. The paper describes the proposed methodology employed to carry out the home-based programme while leap motion is used to monitor and evaluate these exercises. PMID- 29968601 TI - Clinical Data Warehouse Query and Learning Tool Using a Human-Centered Participatory Design Process. AB - BMI Investigator (BMII) is an interactive web-based tool with a learning knowledge base, which provides a way for researchers to query structured, unstructured, genomic and image data contained in a data warehouse. We demonstrate how development of an efficient, usable, and learnable web interface for a diverse group of research stakeholders benefits from an iterative human centered participatory design process utilizing a team of clinicians, students, programmers, and informatics experts. PMID- 29968602 TI - Gamifying Motion Control Assessments Using Leap Motion Controller. AB - In rehabilitation, exergames and serious games are widely usedin order to motivate patients in the therapeutic procedure. Patients are asked to modify their incorrect motor patterns or reinforce the proper ones through activity rather than exercise. Interactive applications as such, can have a huge impact on a patient's motivation making repetitive physical exercises into pleasant experiences, thus maximizing the gains of therapy. In this paper we present the design and implementation of a serious game platform based on virtual 3D game environment and leap motion controller for interaction. For each session, achieved goals and response to stimuli is recorded and analyzed. Preliminary analysis results from evaluating the game with healthy subjects are encouraging. PMID- 29968603 TI - UMOD: A Device for Monitoring Postoperative Urination. AB - A Urine Monitoring Device (UMOD) has been designed and implemented for monitoring postoperative urination. This device has been created primarily to assist nurses and doctors monitor patients during their postoperative and recovery period. Furthermore, to reduce the burden of the nursing staff required to regularly monitor and empty the urine bags saving them precious time. The device consists of a stand and a load cell where the urine bag is attached. The stand is light and can easily move shall the patient require to move. An ESP Wi-Fi microprocessor module is used to calculate the rate of flow of urine in real time, identify and ignore any false readings due to accidental movements of the urine bag using an accelerometer and transmit the readings to a server / cloud through the local Wi-Fi. PMID- 29968604 TI - Design and Development of a Mobile Application Supporting Planning for Future Parents. AB - Life is changing after recognizing a pregnancy. Then the future parents, who are often healthy individuals, need to change their lifestyles, meet different healthcare institutions, follow new rules, and reschedule their everyday activities. This paper illustrates the design and development of a novel mobile application supporting future parents in planning their activities after recognizing the pregnancy. The focus is on identifying and sharing relevant data between future-parents, healthcare institutions, and the supporting social groups. First, the design and development of the application are sketched, and then we present early evaluation results with major stakeholders: future parents and responsible actors from healthcare institutions, based on data from interviews. The results contribute to increased understanding of developing mobile applications for future parents, considering temporal, situation dependent needs during the pregnancy process, but also after having given birth. To handle temporal and longer-term needs, and provide contextualized information, considering patient-pathways are beneficial. PMID- 29968605 TI - Computer Virus Models - The Susceptible Infected Removed (SIR) Model. AB - The healthcare domain requires security against possible threats, such as viruses to defend the integrity of the health and patient records. During the system analysis, different parts of the sub systems are connected under a main system. Under these connections into the Internet, malicious programs are spread into the system network and damages to vital information have been appearing. For that reason, it is crucial to model the spreading of the computer virus using dynamic equation systems and the solution of these systems will be presented. In this work an epidemiological model SIR is presented, and the analysis of its performance is illustrated. PMID- 29968606 TI - Exergames for Parkinson's Disease Patients: How Participatory Design Led to Technology Adaptation. AB - Parkinson's disease (PD) is a neurodegenerative disorder that affects more than 10 million people worldwide. Assistive technology and exergames come to play a beneficial role in positive mood and socialization improvement, overall quality of life and improved confidence with everyday functional activities. More and more Exergames inserts in the market but how many of that are fitting the patient's needs? How many of that took into consideration theirs's opinion. This study describes the Minimum Viable Product (MVP) model "Develop-measure-learn" circle in a co-creation way with the PD patients to develop and improve Exergames for them, and the tools that are needed to accomplish. The most important outcome of this procedure was the proposed development of more realistic games, giving the researchers the step of starting the investigation of 3D solutions. PMID- 29968607 TI - Augmented Reality Glasses and Head-Mounted Display Devices in Healthcare. AB - Augmented Realty (AR) technology has a significant contribution in healthcare sector by offering valuable solutions the last two decades. The aim of this paper is to investigate the implementations of Augmented Reality technologies in healthcare, which include wearable devices such as AR Glasses and Optical Head Mounted Display Devices (OHMD), by searching the international scientific literature. Relevant studies were retrieved online from scientific databases using keywords related to Augmented Reality in healthcare. The results indicate the numerous applications of these technologies in healthcare procedures, like diagnosis, treatment, and rehabilitation, as well as in the education of healthcare professionals. The international scientific community encourages the usage of the AR wearable technologies like AR glasses in Healthcare. PMID- 29968609 TI - Structuring Clinical Decision Support Rules for Drug Safety Using Natural Language Processing. AB - Drug safety is an important aspect in healthcare, resulting in a number of inadvertent events, which may harm the patients. IT based Clinical Decision Support (CDS), integrated in electronic-prescription or Electronic Health Records (EHR) systems, can provide a means for checking prescriptions for errors. This requires expressing prescription guidelines in a way that can be interpreted by IT systems. The paper uses Natural Language Processing (NLP), to interpret drug guidelines by the UK NICE BNF offered in free text. The employed NLP component, MetaMap, identifies the concepts in the instructions and interprets their semantic meaning. The UMLS semantic types that correspond to these concepts are then processed, in order to understand the concepts that are needed to be implemented in software engineering for a CDS engine. PMID- 29968610 TI - Data Collectors' Design Preferences for Mobile Electronic Data Capturing Forms. AB - Data collectors collect health data using Mobile Electronic Data Collection Forms (MEDCFs) particularly in hard to reach areas. However, the usability and user acceptance of these forms by the data collectors are seldom considered, and yet these have an implication on the quality of the data collected and on the health decisions thereof. In this study we aimed at collecting the design preferences the data collectors felt would improve their data collection experience. For that purpose, a mid-fidelity prototype was used to accomplish six tasks and a semi structured usability questionnaire was given. Forty eight data collectors from Uganda participated in the study between December 2017 and January 2018, indicating their preferences after interacting with the prototype. The results included a detailed feedback regarding the presentation of the forms content, form navigation, error handling, data input, and visualization of progress status. Involvement of users and other stakeholders in the design of MEDCFs using the User Centred Design (UCD) will presumably enhance usability of the data collection forms. PMID- 29968611 TI - On the Representation of Machine Learning Results for Delirium Prediction in a Hospital Information System in Routine Care. AB - Digitalisation of health care for the purpose of medical documentation lead to huge amounts of data, hence having an opportunity to derive knowledge and associations of different attributes recorded. Many health care events can be prevented when identified. Machine learning algorithms could identify such events but there is ambiguity in understanding the suggestions especially in clinical setup. In this paper we are presenting how we explain the decision based on random forest to health care professionals in the course of the project predicting delirium during hospitalisation on the day of admission. PMID- 29968612 TI - An Exemplar Dashboard for the Assessment of Home Health Comorbidities. AB - Comorbidities are multiple co-occurring disorders associated with a primary diagnosis and affect health outcomes and cost of care. Using home health medical claims data, a comorbidity database with frequent item-sets, and an exemplar dashboard were created. The dashboard extends the decision making capacity of clinicians by providing data-driven information about (i) the frequency of comorbidities for any primary diagnosis, and (ii) primary diagnoses sufficiently exclusive to a given comorbidity. Regression models estimate total charges, for any underlying patient comorbidity profile. Using the exemplar dashboard, a panel of healthcare researchers recommended appropriate system parameters to adjust system sensitivity and improve construct validity. The comorbidity database will be useful in future research efforts to study comorbidity, while the exemplar dashboard can provide the foundation for integrated home healthcare decision support systems. PMID- 29968613 TI - Dataware for Improvement of Clinical Practice Quality in Phthisiology. AB - A hot point of phthisiology in Russia during the last decade is the rising morbidity of tuberculosis associated with the drug resistant Micobacteria tuberculosis. The causes of MBT resistance are often related with human factor. Reducing the errors rate in complex Clinical Decision-making in phthisiology requires adequate software support and treatment monitoring. The methodology for structuring of the diagnosis characteristics at the moments of Clinical Decisions in phthisiology is represented. The Quality models and real Clinical Situations have the digital codes. The ontological modeling of the real Clinical Situations is used for analysis, construction the inference rules and improvement of Clinical Decisions and treatment results. PMID- 29968614 TI - Learning Healthcare Systems in Pediatrics: Cross-Institutional and Data-Driven Decision-Support for Intensive Care Environments (CADDIE). AB - BACKGROUND: The vast amount of data generated in healthcare can be reused to support decision-making by developing clinical decision-support systems. Since evidence is lacking in Pediatrics, it seems to be beneficial to design future systems towards the vision of generating evidence through cross-institutional data analysis and continuous learning cycles. OBJECTIVES: Presentation of an approach for cross-institutional and data-driven decision support in pediatric intensive care units (PICU), and the long-term vision of Learning Healthcare Systems in Pediatrics. METHODS: Using a four-step approach, including the design of interoperable decision-support systems and data-driven algorithms, for establishing a Learning Health Cycle. RESULTS: We developed and started to follow that approach on exemplary of systemic inflammatory response syndrome (SIRS) detection in PICU. CONCLUSIONS: Our approach has great potential to establish our vision of learning systems, which support decision-making in PICU by analyzing cross-institutional data and giving insights back to both, their own knowledge base and clinical care, to continuously learn about practices and evidence in Pediatrics. PMID- 29968615 TI - Striving for Use Case Specific Optimization of Data Quality Assessment for Health Data. AB - Data quality (DQ) assessment is advisable before (re)using datasets. Besides supporting DQ-assessment, DQ-tools can indicate data integration issues. The objective of this contribution is to put up for discussion the identified current state of scientific knowledge in DQ-assessment for health data and the planned work resulting from that state of knowledge. The state of scientific knowledge bases on a continuous literature survey and tracking of related working groups' activities. 95 full text publications constitute the considered state of scientific knowledge of which a representative selection of six DQ-tools and frameworks is presented. The delineated future work explores multi-institutional machine learning on the DQ-measurement results of an interoperable DQ-tool, with the goal to optimize DQ-measurement method combinations and reference values for DQ-issue recognition. PMID- 29968616 TI - Using Innovation-Decision Model to Describe the Adoption to Utilization of HIV Data for Decision-Making in LMICs. AB - Data informed decision-making (DIDM) plays a fundamental role in the fight against HIV and AIDS in Low-and-Middle-Income Countries (LMICs). Despite the scale-up of HIV care services, supported by health information systems (HIS), cases of under-utilization of data in decision-making are still being reported at different levels of the health system. Literature revealing the process involved in data users' decision to adopt DIDM in LMICs is meager. To fill this gap, we employ the innovation-decision model to describe the stages of adoption of DIDM by data users. Thus, we extract reports on efforts to promote DIDM in HIV from existing literature, and map this to the model. We then identify important stages, which require emphasis in the adoption process. Hence, implementers could benefit from use of the innovation-decision model in understanding adoption process of DIDM. PMID- 29968617 TI - Knowledge Management for Brazilian Cancer Care Services. AB - Nowadays Brazil has a complex cancer care scenario. There are nearly 600.000 new cancer cases each year in Brazil, and the huge majority of patients have some contact with hospital services. However, long waiting queues for diagnostics and treatments have become common. One of the critical success factors in a cancer treatment is early diagnosis. The reduction of waiting time to start therapeutic procedures is one of the main issues for improvement of patient's quality of life and possibilities of cure. The objective of this work is to describe the development of a decision support system that improves the identification of access alternatives, appointment scheduling and employment of available resources. The Theory of Constraints was used to identify bottlenecks in patient treatment flow and a Discrete Events Simulation model was used to reduce patients' waiting time to start cancer treatment. PMID- 29968618 TI - Physical Fitness Forecasting and Risk Estimation in Slovenian Schoolchildren. AB - Physical fitness is important in view of reducing risks for a number of non communicable diseases, both for individuals and policy-makers. In this paper, we present a prototype tool that combines forecasting of individual fitness parameters of schoolchildren to early adulthood with estimation of relative risk for all-cause early mortality in adulthood based on the forecasted fitness. This tool is a first step in the development of a platform that will show age, gender, and geographical distributions of risk and suggest potential interventions. PMID- 29968619 TI - An Individual Patient Outcome Tool for Joint Replacement Patients. AB - Patient specific forecasting tools are an area of active research and very much seen as a necessary tool for future improvements in healthcare. In order to succeed with decision making tools, fine-grained data are required to build models relevant and valid at an individual level. Location and assemble of data to build such tools is not trivial. Even then the ability to perform accurate predictions is not guaranteed. This study outlines a method to integrate existing data sources to base predictions on. A key benefit of the method is the minimal extra burden on the patient and the healthcare system. A pilot study is performed to implement the system architecture on data from total knee arthroplasty. Output from the system is presented using web technologies. In doing so, the viability of the method to implement a tool for the prediction of pre-operative and post operative follow-up is demonstrated. Future steps will include testing and deployment of the system. PMID- 29968620 TI - Alternative Medicine Patient Records Moving to a Digital Environment. AB - As technology immerses in daily life, all types of clinical practices migrate more on storing medical records on electronically media. The issue is up for debate on several fronts, as both paper and electronic records offer strengths and weaknesses. This paper presents the process of changing from paper medical records to a digital environment in the case of an alternative medicine clinic, having years of stored paper records, with its benefits and challenges. Focusing on quality criteria, the current study shows how beneficial an electronic medical record could be, while arguing how the diagnosis coding from the paper-based patient record resulted in major qualitative disadvantages. PMID- 29968621 TI - Health Analytics Types, Functions and Levels: A Review of Literature. AB - Health analytics is a business-driven term that encompasses a wide spectrum of aspects and dimensions of business intelligence applications and big data analysis. Healthcare organizations recently are eager to know whether they are getting the full value from the massive amounts of data and information they already have, to achieve their strategic effectiveness goals and operational efficiency objectives. It is very crucial to learn more about the diverse functions, types and levels through which health analytics can support such tasks. A careful review of literature was conducted, and a qualitative analysis was used to classify health analytics. Five main types of analytics could be identified; these are descriptive, diagnostic, predictive, prescriptive and discovery analytics, each has its own distinct role in improving healthcare. In addition to the five types, health analytics could also be classified into three levels of performance and engagement, these are the operational, tactical and strategic health analytics. PMID- 29968622 TI - Using Predictive Model for Screening Bacterial Meningitis in National Surveillance System in Iran. AB - Bacterial meningitis is a dangerous infectious disease that the entire community can be influenced by its epidemics. The objective of this study is to develop a predictive model as a screening tool to accelerate distinguishing between patients with acute bacterial meningitis and non-bacterial ones to prevent bacterial meningitis epidemics in Iran. This study was conducted on Iranian meningitis registry, which consists of 7,945 suspected cases of the disease between 2009 and 2011. Each sample has 8 predictive and a target variables. The predictive model was developed by decision tree algorithm and, the overall accuracy was 78%, with a sensitivity of 87%, and a specificity of 70%, respectively. This model can help health policymakers and epidemiologists to identify bacterial meningitis outbreaks and support them to make a decision in infection dynamics. In conclusion, we developed and validated a predictive model that can be used in meningitis surveillance system in Iran. However, further research is needed to use the model in practice with different pathogen types of bacterial meningitis in order to proper antimicrobial therapy planning. PMID- 29968623 TI - Intensive Care Decision Making: Using Prognostic Models for Resource Allocation. AB - Accurate outcome prediction by the means of available clinical contributing factors will support researchers and administrators in realistic planning, workload determination, resource optimization, and evidence-based quality control process. This study is aimed to evaluate APACHE II and SAPS II prediction models in an Iranian population. A a prospective cross-sectional study was conducted in four tertiary care referral centers located in the top two most populated cities in Iran, from August 2013 to August 2015. The Brier score, Area under the Receiver Operating Characteristics Curve (AUC), and Hosmer-Lemeshow (H-L) goodness-of-fit test were employed to quantify models' performance. A total of 1799 patients (58.5% males and 41.5% females) were included for further score calculation. The overall observed mortality (24.4%) was more than international rates due to APACHE II categories. The Brier score for APACHE II and SAPS II were 0.17 and 0.196, respectively. Both scoring systems were associated with acceptable AUCs (APACHE II = 0.745 and SAPS II = 0.751). However, none of prediction models were fitted to dataset (H-L rho value < 0.01). With regards to poor performance measures of APACHE II and SAPS II in this study, finding recalibrated version of current prediction models is considered as an obligatory research question before applying it as a clinical prioritization or quality control instrument. PMID- 29968624 TI - Oncology Information System Data - Implications for 'Big Data'. AB - Our Oncology Information Systems (OIS) with local User Documentation manages the medical data explored in this 26 item report of a minimal medical dataset. Over 10 years to 2016, 12906 diagnoses were registered (ICD10: C00-C80), with 18.84% of cases, and 63.9% of data points complete. Two sites were quality assured with high completion rates (H&N - 97.4% [4.26% of total cases], RECTUM - 88.74% [4.06%]). Sites lacking clinician attention varied from poor (eg, LUNG - 23.23% [13.24%]) to largely incomplete (eg, BRAIN - 2.01% [0.38%]).This disappointing medical data completion rate makes its use in a 'Big Data' effort suspect. Data extrapolation is compromised by variable natural history. Extrapolation techniques are unlikely to cope with only 18.84% complete data. Data mining requires input from domain experts. The 4 requirements of Big Data are not evident in oncological data. PMID- 29968625 TI - Supporting Prescriptions with Synonym Matching of Section Names in Prospectuses. AB - The field of medicine still reports errors because of insufficient knowledge or resources, work load or data not available at the right time and place, and this may be fatal for a patient. To improve the healthcare quality, a doctor needs accurate and complex information processing when accessing drug information. Our work builds on improvement of accessing drug information for a better treatment through homogenization of sections in a prospectus. The sections names in a prospectus may be different for one source to another, and in this article, we propose a method to homogenize the content of all drug prospectuses. Once a correct homogenization of the sections has been established, the prospectuses can be used in clinical decision applications to provide the necessary data for physicians. Classification of the section names is using the Cousine similarity method and the Scikit-learn machine learning software. The best results were obtained with the Scikit-learn software. PMID- 29968626 TI - Structural Risk Evaluation of a Deep Neural Network and a Markov Model in Extracting Medical Information from Phonocardiography. AB - This paper presents a method for exploring structural risk of any artificial intelligence-based method in bioinformatics, the A-Test method. This method provides a way to not only quantitate the structural risk associated with a classification method, but provides a graphical representation to compare the learning capacity of different classification methods. Two different methods, Deep Time Growing Neural Network (DTGNN) and Hidden Markov Model (HMM), are selected as two classification methods for comparison. Time series of heart sound signals are employed as the case study where the classifiers are trained to learn the disease-related changes. Results showed that the DTGNN offers a superior performance both in terms of the capacity and the structural risk. The A-Test method can be especially employed in comparing the learning methods with small data size. PMID- 29968628 TI - Lack of Patient Data Privacy Challenges Patient Safety. AB - Patient data privacy is emphasized due to increase in electronic health data processing. This paper highlights the importance of data privacy in healthcare and its connection to the European Union's (EU) General Data Protection Regulation, which aims to protect all EU citizens from privacy and data violations. The clinical environment is prone to hazards in information management, especially in care coordination, the management of patient data, and verbal communication. The Swiss cheese model was used to discuss the importance of patient data privacy based on statistics from a national patient safety incident registry. Patient identification proved an important factor leading to hazards that can cause severe harm to patients. PMID- 29968629 TI - Developing an Evidence-Based Clinical Dataset for the Comprehensive Implantable Medical Device Registry (CIMDR). AB - Medical registries are in a need of a data set that is based on clinical evidence. In 2014, the Saudi Food and Drug Administration (SFDA) launched a plan to develop the national Comprehensive Implantable Medical Device Registry (CIMDR). One of the primary goals of the CIMDR is to develop a clinical -and population- based data set. The aim of this study is to report on the process of developing the data elements for the CIMDR. We used an iterative process of multi stakeholder consultation over a two year period (2014-2016). The goal of the multi-stakeholder consultations was to build a dataset to address the need for device traceability, effectiveness, safety, and the recall of implantable medical devices. We investigated international and local standards for implantable medical device information capture, conducted a review of the literature, and consulted expert opinions in the development of the CIMDR dataset. The CIMDR data framework includes demographics, patient history, diagnosis, procedure information, and follow-up details for orthopedic and cardiac related implantable medical devices. Most of the dataset elements are logically validated with minimal free text entry to avoid human error and facilitate ease of entry. We use the International Classification for Diseases-Australian Modification as the standardized nomenclature for the CIMDR. PMID- 29968630 TI - Financial Management and Spatial Geomapping of Medical Equipment: The Case of Ultrasound Scan and Respirators. AB - The proposed application is based on Geographic Information Systems (GIS) and it's used for medical devices spatial mapping. The application aims at improving the efficiency of hospital units. By using appropriate software, digital maps are created. The technical and financial data of the respirators and ultrasound systems are displayed on the maps. The respirators are installed in the Intensive Care Units (ICU) of public hospitals in Peloponnese. The ultrasound scan systems are also installed in the Radiology Departments of the same units. The user is enabled to create interactive maps and visualize a large amount of real-time information. The overarching aim is to develop an integrated surveillance system of medical equipment. This process will promote the loss-making machinery replacement. Furthermore, the efficient management of revenue and expenditure operations of hospital units will be promoted. The reliable decision-making by the Ministry of Health or the Health and Social Welfare Departments will also be enhanced. PMID- 29968631 TI - GIS Platform for Management of Diagnostic Examinations. AB - Greece is one of the European countries with the largest number of CT and MRI scans. Geographic Information Systems (GIS) are a useful tool for efficient cost reduction in the health sector. ArcGIS software is used to create interpretable maps. Data represents the number of imaging examinations per type and population size. All available data is acquired in 2012-2015. By using special symbols, pop up windows emerge. The windows contain a large number of data. The results are filtered and uploaded to a digital control panel. This central information system combined with the digital maps form a digital platform for estimating the exact number of diagnostic examinations. The survey confirms that the General Hospital of Tripolis performed 27.000 CT examinations in 2012-2015, corresponding to approximately 57% of the population of Tripolis. The approximate percentage of CT scans of the Hospital Unit of Pyrgos was found 55%. The implementation of this platform confirms the large number of diagnostic examinations in most areas of Peloponnese. PMID- 29968632 TI - How Connected Insurance Is Reshaping the Health Insurance Industry. AB - The role of today's insurer is changing towards a more preventive and digital or connected approach. In this context, connected health insurance has the potential to contribute towards the general wellbeing of the population. New technologies put to use by the insurance industry might even help deal with major issues related to the rising number of people globally, of chronic disease patients and that of elders while keeping them healthier and the same time protected by insurance. PMID- 29968633 TI - IT Infrastructure for Registries in Health Services Research: A Market Study in Germany. AB - Registries are increasingly implemented to record the practice of health care. Within a national funding scheme for registries, an accompanying project was launched to support the design of the registries' IT infrastructure amongst other tasks for 16 projects. A challenge of data management systems was organized by the accompanying project in order to enable the projects to define realistic expectations towards IT support in their research protocols. Twelve vendors participated in the challenge. They presented their solutions for selected use cases. In advance, the projects considered a sufficient authorization concept and the possibility to export data to be of highest importance. However, the systems covered mainly core processes of electronic data capture. The accompanying project will continue its support for the next stage of the funding scheme, which will be the implementation of the registries that win a competitive review of their research protocols prepared in the concept development stage. PMID- 29968634 TI - Facilitators and Barriers of Electronic Medical Records Systems Implementation in Low Resource Settings: A Holistic View. AB - Electronic Medical Records (EMR) systems show promise for facilitating health care improvement in quality patient care, patient safety and cost reduction. Nevertheless, their adoption requires careful planning and execution for successful implementation and optimal benefits. The main objective of this review was to identify, analyse and categorize facilitators and barriers to the implementation of EMRs in resource constrained settings in order to gain insight for successful EMR implementation. A literature review on papers from 2007 to 2017 concerning facilitators and barriers to EMRs implementation was conducted. The study included 18 articles that met selection criteria. Four categories of facilitators and barriers including a total of 28 sub-categories were identified from content analysis. These are technical, human, processes and organizational. EMR implementers should pay attention to these issues and adopt a change management strategy for sustainable EMR use in resource-constrained settings. PMID- 29968635 TI - Adoption of ICT by Elderly with Hip Fracture After a Fall. AB - The purpose of this study is to investigate the adoption of Information and Communication Technologies (ICTs) of elderly with hip fracture after a fall. Demographic and clinical data using a general questionnaire were obtained from 67 elderly patients with a hip fracture after fall and compared with 67 gender-age matched elderly healthy controls regarding their knowledge and use of ICT-based devices. Univariate and multivariate analyses were conducted at p=0.05. 25.4% of the patients vs 10.5% of the controls uses ICT-based devices (p=0.024). Among patients, the demographic factors significantly associated with the use of ICT based devices included area of residence, educational level and financial status (p<0.001 to p=0.045). In conclusion, based on a small sample, it seems that the adoption of ICT by the elderly vulnerable populations is limited. PMID- 29968636 TI - Smart Oncology Care Networks: An Approach in Information Systems to Support Brazilian National Cancer Institute. AB - In last decades Information Technology (IT) has been established as the main tool to support processes. Medical area has noticed the opportunity for improvement and interacting with IT has enabled solid interdisciplinary instruments for improvement. The aim in this project is composed by an analysis of the relationship between the application of information technologies, oncological assistance and innovation. Next, the project will focus to present the case of a proposal to reformulate the national cancer care system, with IT and Innovation being the base instrument for this process. PMID- 29968637 TI - Decision Support Systems in Cancer Treatment: A Case Study at Brazilian National Cancer Institute. AB - Nowadays Brazil has a complex cancer care scenario. There are nearly 600.000 new cancer cases each year in Brazil, and the huge majority of patients have some contact with hospital services. However, long waiting queues for diagnostics and treatments have become common. One of the critical success factors in a cancer treatment is early diagnosis. The reduction of waiting time to start therapeutic procedures is one of the main issues for improvement of patient's quality of life and possibilities of cure. The objective of this work is to describe the development of a decision support system that improves the identification of access alternatives, appointment scheduling and employment of available resources. The Theory of Constraints was used to identify bottlenecks in patient treatment flow and a Discrete Events Simulation model was used to reduce patients' waiting time to start cancer treatment. PMID- 29968638 TI - A Hospital Information System Application May Facilitate Staff Compliance with Quality Protocols in a Medical Unit: A Case Study. AB - Quality standards have been widely adopted in healthcare, while the Hospital Information Systems (HIS) support quality management in modern hospitals. However, staff compliance lags behind. In this study, we investigated the effect of a novel application, implemented in the HIS, on staff compliance in the Intensive Care Unit of a tertiary teaching hospital. This application integrates quality protocols to the HIS, which is routinely used by the nursing staff. Demographic data and self-reported compliance were recorded before and after the intervention. We found that the compliance rate was significantly increased and the application was well accepted by the majority of the staff. We also showed that previous ICU working experience is independently and positively associated with compliance (p=0.02, OR=2.86; 95% CI: 1.16 - 7.06), after adjustment for age and total nursing experience In conclusion, we developed an effective application for quality improvement aiming at facilitating educational processes and enhancing staff compliance. PMID- 29968639 TI - Healthcare IT Strategic Alignment: Challenges and Recommendations. AB - Information technology (IT) has dramatically transformed business processes in many industries including healthcare, where electronic health records, electronic prescribing and computerized provider order entry systems have positively changed the practice of healthcare. Recently, King Faisal Specialist Hospital and Research Center, Saudi Arabia, implemented various IT systems in multiple clinical and administrative departments leading to major transformation in healthcare workflows and business processes. At the pharmacy department, many Healthcare-IT alignment challenges are still perceived. Information about challenges of strategic alignment were gathered using qualitative survey methods, through conducting semi-structures interviews, to collect opinions, experiences and suggestions. Findings were first validated, according to published literature and research work, then sorted into fourteen challenges categorized into four main areas and recommended solutions: 1) Improving organizational communication, 2) Enhancing organizational governance, 3) Specifying the alignment scope and building the architecture and 4) Developing organizational and human skills. PMID- 29968640 TI - Human Based Digital Intelligence Analyses for Health Care Ecosystems. AB - The maturity level of the digital transformation in health care ecosystems is heavily depending on human factors. Primarily the digital intelligence of the human beings - e.g. medical or nursing staff - should be taken seriously in the transformation processes. To derive sustainable strategies in a holistic manner an innovative, multi-dimensionaland human centred socio-economic capability model had to be developed and applied. By the use of our model health care ecosystems can be analysed, scored and benchmarked successfully. Furthermore, each ecosystems' digital intelligence based on their employees can be derived holistically from our four scoring scopes. PMID- 29968641 TI - Developing a Policy and Procedure Framework and Manual for a National Comprehensive Implantable Medical Device Registry in Saudi Arabia. AB - Policy and procedure manuals provide guidance on the operation and governance of medical device registries. In Saudi Arabia, the Saudi Food and Drug Authority (SFDA) has been developing and implementing a comprehensive national registry for implantable medical devices to facilitate the monitoring of device outcomes through post-market surveillance studies. To help guide the operations of this registry, the SFDA developed a policy and procedure manual. This paper reports on the design of the framework used to develop that manual over the course of one year (2015-2016), using a variety of literature sources, and working with medical device registry and health systems experts. The policy and procedure manual included five key principal level categories, which led to the subsequent creation of seven policies and 28 relevant procedures. The five principal categories were: Staff Engagement, Information Governance, Quality and Auditing, Research, and Reporting. The results of this work could be used to guide the development of policies and procedures for other implantable medical device registries. PMID- 29968642 TI - Designing and Developing a Multi-Center/Multi-Device National Registry for Implantable Medical Devices. AB - Designing, developing, and establishing the multi-device/multi-center Comprehensive Implantable Medical Device Registry (CIMDR) for Saudi Arabia is a strategic objective of the Saudi Food and Drug Administration (SFDA). The goal of the CIMDR is to capture all related clinical data along with device related information for implantable medical devices and study population-related outcomes. There is an immediate need in Saudi Arabia to establish the CIMDR to carryout device surveillance, gauge the efficiency and efficacy of various implantable medical devices, and track and recall implantable medical devices.In this work, we report on the development of the SFDA's CIMDR. We specifically focus on the project organization, five primary modules of the CIMDR, and development of the CIMDR through dynamic forms. We anticipate that the collected information in the CIMDR will be used by hospitals and the SFDA to improve patient safety relating to implantable medical devices in Saudi Arabia. Future development of the CIMDR will include a wide range of reporting and embedded analytical tools that will help researchers improve clinical standards and contribute to the research and development of implantable medical device technology. PMID- 29968643 TI - The Effect of Electronic Medication Administration Records on the Culture of Patient Safety: A Literature Review. AB - Medication errorsare a leading cause of deathacross many parts of the world. Several factors increase medication errors. These can be individual-related factors, such as the burden ofa heavy workload, often experiencedby nurses, or organizational-related factors, such as inadequate space for documenting and poor labeling of medication. This paper shares the results of a preliminary literaturereview on the impacts of electronic medication administration records (eMAR) on patient safety. UsingPubMed and Google Scholar, we searchedthe following terms: "eMAR", "medication errors", and "workflow". Our preliminary findings revealthat eMAR can have impacton nursing workflow, and reducemedication errors, thus improving patient safety. Although the results are preliminary, they provide some insight into the impacts of eMAR on nursing workflow and patient safety. Our plans for future researchare to conduct a systematic review study to further examine the impacts of eMAR on patient safety. PMID- 29968645 TI - Accessibility and Readability of Dementia-Related Information on Websites. AB - The study aimed to identify websites with dementia-related content and evaluate their readability and accessibility. A purposeful sample of 300 websites, which provided information on dementia, were identified from searches using the Google, Yahoo and Bing search engines. Two generic evaluation tools based on WCAG2.0 were used to assess the accessibility of information on dementia and two readability tests (Flesh-Kincaid Grade level and SMOG) were used to evaluate the websites. Only 94 websites have a HON certificate (31.3%), while 38 of the finally selected websites have an average of 56.89 and 32 problems in relation to the Axe and Achecker tools respectively. The most common problems (for images on 19 and 17 of the websites respectively) were related to text resize and the lack of text explanation, and an insufficient color contrast was found on 35 websites. The readability score was 8.2 (FKG) and 7.4 (SMOG) on average, which meant that the sites in question were not recommendable for the general population. PMID- 29968646 TI - User Evaluation of a Multiple Sclerosis Self-Management Mobile Application. AB - This paper presents user evaluation of a high-fidelity prototype of a mobile application for patient self-management within the field of Multiple Sclerosis (MS). The application named msHelse consists of four modules: Diary module, Summary module, Stress management module, and a Todo-list. Four study subjects were interviewed in semi-structured interviews with questions regarding the functionalities and the user experience after using the application, as well as using System Usability Scale (SUS). User feedback resulted in functionality adjustments of the high-fidelity prototype, especially in data representation of the Summary module and the way the Diary module would assess user entered data. Thus, the msHelse application has been refined to tune into the needs of Norwegian users. PMID- 29968647 TI - Patients' Perception of Privacy of Personal Data, Shared in Online Communities: Are We in the Presence of a Paradox? AB - Virtual online communities help people in coping with complex health issues, such as those present in patients suffering chronic diseases. Further research is required in order to clarify the impact of sharing of personal experiences on the perception of privacy and confidentiality by patients. We studied the case of Carenity an online social network created in France in 2011 bringing together 300,000 patients across Europe, and selected patients suffering Multiple Sclerosis. We conducted an exploratory-descriptive survey, and 253 patients completed an online questionnaire. Most participants did not consider that their privacy was threatened when sharing their personal experiences and data associated with their health condition. As common sense prevents one to share information to strangers to ensure privacy, such paradox may be explained by new strategies to face challenges imposed by chronic conditions disease, where sharing personal experiences may be considered as a complementary source of social support by patients. PMID- 29968648 TI - Applying Deep Learning to Understand Predictors of Tooth Mobility Among Urban Latinos. AB - We applied deep learning algorithms to build correlate models that predict tooth mobility in a convenience sample of urban Latinos. Our application of deep learning identified age, general health, soda consumption, flossing, financial stress, and years living in the US as the strongest correlates of self-reported tooth mobility among 78 variables entered. The application of deep learning was useful for gaining insights into the most important modifiable and non-modifiable factors predicting tooth mobility, and maybe useful for guiding targeted interventions in urban Latinos. PMID- 29968649 TI - Designing Interaction and Guidance Technologies for Remote Consultations in Healthcare. AB - We present our work in designing mobile interaction and guidance technologies for the application of remote consultation between healthcare professionals. We describe design case studies which address the needs and scenarios in this application: a hybrid and rich media tool which supports mobile one-on-one consultations; a remote guidance tool which allows an expert to remotely guide a nurse or junior clinician to perform clinical procedures; an integrated collaboration platform which supports remote consultations in a group meeting environment by enabling shared interaction with patient records and mobile interaction with large displays. These tools have been evaluated in usability studies in which the usefulness and potential value have been demonstrated. By presenting these case studies, we highlight the trend of incorporating emerging collaboration technologies and the need of integrated and multi-model interaction systems in a broader telehealth context. PMID- 29968650 TI - Evaluating the Impact of Incorrect Diabetes Coding on the Performance of Multivariable Prediction Models. AB - The use of electronic health records for risk prediction models requires a sufficient quality of input data to ensure patient safety. The aim of our study was to evaluate the influence of incorrect administrative diabetes coding on the performance of a risk prediction model for delirium, as diabetes is known to be one of the most relevant variables for delirium prediction. We used four data sets varying in their correctness and completeness of diabetes coding as input for different machine learning algorithms. Although there was a higher prevalence of diabetes in delirium patients, the model performance parameters did not vary between the data sets. Hence, there was no significant impact of incorrect diabetes coding on the performance for our model predicting delirium. PMID- 29968651 TI - Machine Learning to Identify Behavioral Determinants of Oral Health in Inner City Older Hispanic Adults. AB - We applied machine learning techniques to a community-based behavioral dataset to build prediction models to gain insights about minority dental health and population aging as the foundation for future interventions for urban Hispanics. Our application of machine learning techniques identified emotional and systemic factors such as chronic stress and health literacy as the strongest predictors of self-reported dental health among hundreds of possible variables. Application of machine learning algorithms was useful to build prediction models to gain insights about dental health and minority population aging. PMID- 29968652 TI - Understanding the Roles of EMR Systems in Japanese Antenatal Care Settings. AB - Electronic Medical Records (EMR)s are intrinsic to modern-day clinics. Understanding the roles, i.e., the unintended functions of EMR systems in their context of use can guide the design of EMR systems and clinics to better integrate them. To understand the roles of EMR systems in antenatal care check ups, we conducted a field-based observational study at an antenatal care clinic in a Japanese university hospital. We observed 37 antenatal care check-ups where we looked at how the EMR system affects the communication between the involved parties and supports or hinders the clinical process. Our data analysis resulted in 10 EMR roles, namely: the wingman, the third wheel, the accomplice, the bouncer, the messenger, the summarizer, the bureaucrat, the assistant, the gossip, and the alien. Through the roles, this study reveals multiple EMR design considerations and opportunities for improving both the human-EMR and human interactions in antenatal care settings. PMID- 29968653 TI - Identifying Biomedical and Health Informatics Competencies in Higher Education Curricula. AB - This study describes the knowledge, skills and competencies found in bachelor's degree curricula for health and social care, engineering and business. The International Medical Informatics Association (IMIA) biomedicine and health information (BMHI) management recommendations was used as a framework to analyse bachelor's degree curricula (n=14). The results showed that the curricula contained a variety of subjects related to competencies in the IMIA's BMHI. The information technology (IT) engineering curriculum included the highest number of competencies and the business curricula the fewest. The nursing curricula included more competencies than any other health care curricula. When educating students in various professions, their diverse backgrounds and expertise must be considered. As future eHealth developers, students will learn to work as multidisciplinary teams. PMID- 29968654 TI - Classifying Provider-EHR Screen Interactions During ICU Pre-Rounds. AB - Electronic health records (EHR) usability is paramount for high quality of care delivery, clinician productivity and effectiveness, and patient outcomes. This paper investigates clinicians EHR pathways during pre-rounds by characterizing the top EHR screens, duration per screen, and the path taken to complete a task. Structured observations were conducted of ICU providers interacting with the EHR in a real-time, real-world setting to better characterize the information retrieval process. Based on preliminary results of the observations, key areas of information needs have been identified and a preliminary model of EHR workflow has been established. The study highlights that there is a clear discrepancy in usage in EHR screens among ICU residents suggesting that there is a perceived clinician's pathology to finding patient information. PMID- 29968655 TI - Barriers for Implementation and Use of Health Information Systems from the Physicians' Perspectives. AB - This study aimed to investigate barriers to the implementation and use of health information systems (HIS) in Iran by physician's view. This cross-sectional study was conducted in 2016 on 163 physicians employed in 10 teaching hospitals. Data collection was carried out through a questionnaire with questions about the technical, organizational, ethical and personal barrier categories. Data analysis demonstrated that technical (e.g. inadequate planning for implementation and use of HIS) (3.56+/-1.32), organizational (e.g. inadequate facilities for fast and easy access to the Internet) (3.67+/-1.91), personal (e.g. inadequate awareness of healthcare providers about the benefits of HIS) (3.33+/-1.28), as well as legal and ethical (e.g. concern about the security and confidentially of HIS) (3.15+/-1.31) were the most important barriers to the implementation and use of HIS. Reducing barriers, especially technical and personal ones will increase the implementation and use of HIS based on the physicians' perspectives. PMID- 29968656 TI - Identifying Consumer Health Terms of Side Effects in Twitter Posts. AB - Prevalence of social media has driven a growing number of health related applications with the information shared by online users. It is well known that a gap exists between healthcare professionals and laypeople in expressing the same health concepts. Filling this gap is particularly important for health related applications using social media data. A data-driven, attributional similarity based method was developed to identify Twitter terms related to side effect concepts. For the 10 most common side effect (symptom) concepts, our method was able to identify a total of 333 Twitter terms, among which only 90 are mapped to those in the consumer health vocabulary (CHV). The identified Twitter terms are specific to Twitter data, indicating a need to expand the existing CHV, and many of them seem to have less ambiguity in word senses than those in CHV. PMID- 29968657 TI - Towards Understanding the Impact of EHR-Related Information Overload on Provider Cognition. AB - Information overload is a significant problem in the digital age of healthcare and plays key a role in diagnostic errors, near misses, and patient safety, especially in critical care settings. Because of this, we propose a new mixed methods approach for evaluating EHR-related information overload on clinicians in the ICU. We describe a three-part approach to better understand ICU clinicians' information needs and workflow as they relate to the EHR, and to explore the effects of the EHR on provider workload, performance, and satisfaction. Based on discussions with ICU providers, key areas of information needs have been identified and a preliminary model of EHR workflow has been established. PMID- 29968658 TI - Usability of Telerehabilitation System Supporting Multipronged Exercise in Patients with Multiple Sclerosis. AB - Multipronged exercise interventions comprising aerobic, resistance and corrective therapeutic components were shown to result in endurance and strength improvement and reduction of fatigue and spasticity in patients with multiple sclerosis (PwMS). Telerehabilitation systems may have significant potential in improving patient access to multipronged exercise, however it is not clear whether PwMS can successfully use a multipronged exercise system at home without assistance. The goal of this project was to assess usability and acceptance of a multipronged exercise system in PwMS. Usability assessment was based on evaluation of patient ability to successfully carry out a standardized list of common tasks necessary to operate the system. For each task, time to completion, perceived difficulty and satisfaction were documented. Our results indicated high level of acceptance of the system by these patients. On average, it took about 1-2 minutes for the patients to complete the study tasks essential for the system operation. They were able to successfully use the system and follow their individualized exercise prescription. The resulting system is warranted for a definitive systematic evaluation in a randomized controlled trial to demonstrate its clinical impact in PwMS. PMID- 29968659 TI - Methods to Measure the Impact of mHealth Applications: Preliminary Results of a Scoping Review. AB - Important requirements for mHealth, the availability of devices and network connectivity have dramatically improved in the past years globally. mHealth applications are being developed at a rapid pace. But a thorough impact assessment is not routinely performed. We performed a scoping review to compile an overview of evaluation methods used to assess mHealth applications. Preliminary results are reported here, and a full scoping review is in preparation. Qualitative measurement of user experience is common. A number of studies measured the impact of the mHealth intervention on clinical outcomes. Few measured usability and end-user experience. Assessment of the impact on treatment process was rare and evaluations of cost and cost-effectiveness analyses are rarely ever done. An evaluation framework for mHealth interventions that includes disease-appropriate clinical outcome measures, use experience measure but also an economic component in form of cost comparison of the intervention with the standard of care should be developed. PMID- 29968660 TI - Benefits of Using Mobile Technologies in Education from the Viewpoints of Medical and Nursing Students. AB - Increasing the use of mobile phones in education depends on the understanding of its benefits. The purpose of this study was to assess the vision of medical and nursing students about the benefits of using mobile technology in education. This study was conducted on medical and nursing students in 8 hospitals affiliated to Tehran University of Medical Sciences in 2016. 372 students participated in the study. Data were collected by a questionnaire consisting of 11 questions in Likert scale. Students' efficiency, improvement in quality of care, faster access to information and the positive effect on education were emphasized. Nursing students have more positive attitude regarding the use of this technology to save time at the time of providing services, faster access to patient information and influence on education. In summary, students considered mobile technology to be useful for educational purposes, so by eliminating the barriers in this field, it is possible to promote mobile learning for medical and nursing students. PMID- 29968661 TI - The Technology Use and Information Flow at a Municipal Telemedicine Service. AB - Health care services facechallenges with providing individualised treatment to an ageing population prone to chronic conditions and multi-morbidities. The research project Patients and Professionals in Productive Teams aims to study patient centred teamworkservice models. This paper presents an evaluation of a telemedicine service for chronic obstructive pulmonary disease patients integrated with municipal health care services. Qualitative methods were used to study the technology use and information flow. The results showed that the telemedicine technology was a standalone system, not integrated with the electronic health record of the municipality. A benefit of the system was a function to provide the patient with written instructions on agreements and advices. As a constraint for the patient-centred team approach, the information in the telemedicine system was available only for the telemedicine nurses and not to other health care professionals. PMID- 29968662 TI - Evaluation of a Telemedicine Service Run with a Patient-Centred Care Model. AB - The number of patients with chronic conditions and multi-morbidities is increasing, addressing a need for patient-centred care. The research project Patients and Professionals in Productive Teams aims to study patient-centred teamwork for this patient group. This paper presents an evaluation of a telemedicine service for chronic obstructive pulmonary disease patientsrun with a patient-centred care model. Observations and interviews were made to study the technology use and information flow. The results showed that the technology worked well in a patient-centred care perspective, even though the system was a standalone system for telemedicine services. The information in the system was only available for professionals providing the telemedicine services and was not shared with other health care providers. PMID- 29968663 TI - The Stratified Framework for Enhancement of Study Programs in Public Health in Montenegro. AB - Montenegro plans to enhance its educational system in the area of health information management, in accordance with well-known EU best practices. Within the Erasmus+ project PH-ELIM, a Stratified Framework was developed to provide education of public health professionals making them highly skilled to support the nation in creating a sustainable and flexible health system, in providing good quality health, in protecting citizens against health threats, all by a cost effective and straightforward approach. The objective of this presentation is to present the intermediate results of the Framework and lessons learned until now. PMID- 29968664 TI - Diagnostic Games as a Teaching Tool. AB - Diagnostic games were developed in the 70s of the last century for elicitation and formalization of the physician's clinical experience. This laborious technique was successfully used to elaborate decision rules for several complex clinical problems but had no further development. Modern information and communication technologies and achievements of medical informatics allow developing digital transformation of diagnostic games. One of the areas of application of this new technology may be simulating of clinical decision making for educational purposes. PMID- 29968665 TI - Co-Creation of an Innovative Vocational Training Platform to Improve Autonomy in the Context of Alzheimer's Disease. AB - Support of autonomy, at the onset and while Alzheimer's Disease progresses, is of utmost importance for both older adults and their caregivers. AD-Autonomy project aims at co-creating an innovative training platform with and for elderly people and their caregivers. Main aim of the project is to increase the competencies of older adults and their caregivers to cope with the disease effects, by leveraging existing ICT tools and applications, while transferring their applicability in real life contexts and activities. Initial anecdotal feedback is collected through a co-creation session, where all above themes were discussed and analyzed between seniors, family caregivers and professionals. PMID- 29968666 TI - Education in Biomedical and Health Informatics: A Mapping Approach. AB - The emergence of the information technologies has seriously changed the healthcare system. Thus, health professionals need to be well-educated in order to respond successfully to the challenges of their job. In higher education programs in, biomedical informatics and health informatics are continuously developing. At this study more than 500 universities and colleges in Europe were checked in order to find related educational programs at all academic levels. The outcome of the research includes 316 study programs at undergraduate and postgraduate level including a variety of specializations. The majority of these programs are taking place in Czech Republic, Ireland and Austria. In contrast, countries such as Croatia and Cyprus have very low number of study programs in these fields. PMID- 29968667 TI - Evaluation of a Laboratory e-Learning Course in Health Informatics. AB - The current paper presents the students' evaluation of a laboratory e-learning course in Health Informatics. After attending the e-learning course, students assessed the e-learning course through an anonymous questionnaire. The study results present the positive attitude of the students towards the e-learning course in Health Informatics. The current e-learning course is easy to use, and it is preferred on the same extent as the hybrid one (e-learning and in-class learning combination). The majority of the participants believed that the e learning method is at least the same or more efficient compared to the traditional learning approach. Based on the study findings, it seems that this e learning course could offer important advantages on the learning process as long as it helps students learn in a more effective manner than traditional learning. PMID- 29968668 TI - Survival Models in Computer Virus. AB - During the communication between various computer system parts under a basic unit various threats can appear causing different damages into the system. The spreading of the computer virus into the system must be investigated under modeling analysis and simulations must be applied. In this work survival analysis models have been introduced to overcome the problem with the computer virus. During that process of spreading two main considerations analyzed: (1) the epidemiological models of the spreading and (2) the survival of the computer virus inside the system under mathematical modeling. PMID- 29968669 TI - A Medical Decisions Support System in Diagnosis of the Jejunum and Ileum Neoplastic Diseases (Tumors) Based on Video Capsule Endoscopy. AB - Search of tumors in video capsule endoscopy (VCE) record in some cases presents significant difficulties even for experienced specialist. We made an attempt to develop rules supporting clinical decision for processing of VCE images. An algorithm for assessment of neoplastic diseases of the jejunum and ileum on the basis of VCE to support tactical decision-making of doctors was conducted. The algorithm was implemented as a software module "The conclusion in a capsule" with integrated development environment Visual Studio and the programming language C#. PMID- 29968670 TI - SIMBAD: a sequence-independent molecular-replacement pipeline. AB - The conventional approach to finding structurally similar search models for use in molecular replacement (MR) is to use the sequence of the target to search against those of a set of known structures. Sequence similarity often correlates with structure similarity. Given sufficient similarity, a known structure correctly positioned in the target cell by the MR process can provide an approximation to the unknown phases of the target. An alternative approach to identifying homologous structures suitable for MR is to exploit the measured data directly, comparing the lattice parameters or the experimentally derived structure-factor amplitudes with those of known structures. Here, SIMBAD, a new sequence-independent MR pipeline which implements these approaches, is presented. SIMBAD can identify cases of contaminant crystallization and other mishaps such as mistaken identity (swapped crystallization trays), as well as solving unsequenced targets and providing a brute-force approach where sequence-dependent search-model identification may be nontrivial, for example because of conformational diversity among identifiable homologues. The program implements a three-step pipeline to efficiently identify a suitable search model in a database of known structures. The first step performs a lattice-parameter search against the entire Protein Data Bank (PDB), rapidly determining whether or not a homologue exists in the same crystal form. The second step is designed to screen the target data for the presence of a crystallized contaminant, a not uncommon occurrence in macromolecular crystallography. Solving structures with MR in such cases can remain problematic for many years, since the search models, which are assumed to be similar to the structure of interest, are not necessarily related to the structures that have actually crystallized. To cater for this eventuality, SIMBAD rapidly screens the data against a database of known contaminant structures. Where the first two steps fail to yield a solution, a final step in SIMBAD can be invoked to perform a brute-force search of a nonredundant PDB database provided by the MoRDa MR software. Through early-access usage of SIMBAD, this approach has solved novel cases that have otherwise proved difficult to solve. PMID- 29968671 TI - MR-REX: molecular replacement by cooperative conformational search and occupancy optimization on low-accuracy protein models. AB - Molecular replacement (MR) has commonly been employed to derive the phase information in protein crystal X-ray diffraction, but its success rate decreases rapidly when the search model is dissimilar to the target. MR-REX has been developed to perform an MR search by replica-exchange Monte Carlo simulations, which enables cooperative rotation and translation searches and simultaneous clash and occupancy optimization. MR-REX was tested on a set of 1303 protein structures of different accuracies and successfully placed 699 structures at positions that have an r.m.s.d. of below 2 A to the target position, which is 10% higher than was obtained by Phaser. However, cases studies show that many of the models for which Phaser failed and MR-REX succeeded can be solved by Phaser by pruning them and using nondefault parameters. The factors effecting success and the parts of the methodology which lead to success are studied. The results demonstrate a new avenue for molecular replacement which outperforms (and has results that are complementary to) the state-of-the-art MR methods, in particular for distantly homologous proteins. PMID- 29968672 TI - From deep TLS validation to ensembles of atomic models built from elemental motions. II. Analysis of TLS refinement results by explicit interpretation. AB - TLS modelling was developed by Schomaker and Trueblood to describe atomic displacement parameters through concerted (rigid-body) harmonic motions of an atomic group [Schomaker & Trueblood (1968), Acta Cryst. B24, 63-76]. The results of a TLS refinement are T, L and S matrices that provide individual anisotropic atomic displacement parameters (ADPs) for all atoms belonging to the group. These ADPs can be calculated analytically using a formula that relates the elements of the TLS matrices to atomic parameters. Alternatively, ADPs can be obtained numerically from the parameters of concerted atomic motions corresponding to the TLS matrices. Both procedures are expected to produce the same ADP values and therefore can be used to assess the results of TLS refinement. Here, the implementation of this approach in PHENIX is described and several illustrations, including the use of all models from the PDB that have been subjected to TLS refinement, are provided. PMID- 29968673 TI - Structure of the flavocytochrome c sulfide dehydrogenase associated with the copper-binding protein CopC from the haloalkaliphilic sulfur-oxidizing bacterium Thioalkalivibrio paradoxusARh 1. AB - Flavocytochrome c sulfide dehydrogenase from Thioalkalivibrio paradoxus (TpFCC) is a heterodimeric protein consisting of flavin- and monohaem c-binding subunits. TpFCC was co-purified and co-crystallized with the dimeric copper-binding protein TpCopC. The structure of the TpFCC-(TpCopC)2 complex was determined by X-ray diffraction at 2.6 A resolution. The flavin-binding subunit of TpFCC is structurally similar to those determined previously, and the structure of the haem-binding subunit is similar to that of the N-terminal domain of dihaem FCCs. According to classification based on amino-acid sequence, TpCopC belongs to a high-affinity CopC subfamily characterized by the presence of a conserved His1 Xxx-His3 motif at the N-terminus. Apparently, a unique alpha-helix which is present in each monomer of TpCopC at the interface with TpFCC plays a key role in complex formation. The structure of the copper-binding site in TpCopC is similar to those in other known CopC structures. His3 is not involved in binding to the copper ion and is 6-7 A away from this ion. Therefore, the His1-Xxx-His3 motif cannot be considered to be a key factor in the high affinity of CopC for copper(II) ions. It is suggested that the TpFCC-(TpCopC)2 heterotetramer may be a component of a large periplasmic complex that is responsible for thiocyanate metabolism. PMID- 29968675 TI - Identifying G protein-coupled receptor dimers from crystal packings. AB - Dimers of G protein-coupled receptors (GPCRs) are believed to be important for signaling with their associated G proteins. Low-resolution electron microscopy has shown rhodopsin dimers in native retinal membranes, and CXCR4 dimers have been found in several different crystal structures. Evidence for dimers of other GPCRs is more indirect. An alternative to computational modeling studies is to search for parallel dimers in the packing environments of the reported crystal structures of GPCRs. Two major structural types of GPCR dimers exist (as predicted by others), but there is considerable structural variation within each cluster. The different structural variants described here might reflect different functional properties and should provide a range of model structures for computational and experimental examination. PMID- 29968674 TI - Crystal structure of the spliceosomal DEAH-box ATPase Prp2. AB - The DEAH-box ATPase Prp2 plays a key role in the activation of the spliceosome as it promotes the transition from the Bact to the catalytically active B* spliceosome. Here, four crystal structures of Prp2 are reported: one of the nucleotide-free state and three different structures of the ADP-bound state. The overall conformation of the helicase core, formed by two RecA-like domains, does not differ significantly between the ADP-bound and the nucleotide-free states. However, intrinsic flexibility of Prp2 is observed, varying the position of the C terminal domains with respect to the RecA domains. Additionally, in one of the structures a unique ADP conformation is found which has not been observed in any other DEAH-box, DEAD-box or NS3/NPH-II helicase. PMID- 29968676 TI - Crystal structures of two tandem malectin-like receptor kinases involved in plant reproduction. AB - Complex cell-to-cell communication between the male pollen tube and the female reproductive organs is required for plant fertilization. A family of Catharanthus roseus receptor kinase 1-like (CrRLK1L) membrane receptors has been genetically implicated in this process. Here, crystal structures of the CrRLK1Ls ANXUR1 and ANXUR2 are reported at 1.48 and 1.1 A resolution, respectively. The structures reveal a novel arrangement of two malectin-like domains connected by a short beta hairpin linker and stabilized by calcium ions. The canonical carbohydrate interaction surfaces of related animal and bacterial carbohydrate-binding modules are not conserved in plant CrRLK1Ls. In line with this, the binding of chemically diverse oligosaccharides to ANXUR1 and HERCULES1 could not be detected. Instead, CrRLK1Ls have evolved a protein-protein interface between their malectin domains which forms a deep cleft lined by highly conserved aromatic and polar residues. Analysis of the glycosylation patterns of different CrRLK1Ls and their oligomeric states suggests that this cleft could resemble a binding site for a ligand required for receptor activation of CrRLK1Ls. PMID- 29968678 TI - A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease. AB - Crystal structures of inactive variants of HIV-1 protease bound to peptides have revealed how the enzyme recognizes its endogenous substrates. The best of the known substrates is, however, a nonnatural substrate that was identified by directed evolution. The crystal structure of the complex between this substrate and the D25N variant of the protease is reported at a resolution of 1.1 A. The structure has several unprecedented features, especially the formation of additional hydrogen bonds between the enzyme and the substrate. This work expands the understanding of molecular recognition by HIV-1 protease and informs the design of new substrates and inhibitors. PMID- 29968677 TI - The structure of the C-terminal domain of the nucleoprotein from the Bundibugyo strain of the Ebola virus in complex with a pan-specific synthetic Fab. AB - The vast majority of platforms for the detection of viral or bacterial antigens rely on immunoassays, typically ELISA or sandwich ELISA, that are contingent on the availability of suitable monoclonal antibodies (mAbs). This is a major bottleneck, since the generation and production of mAbs is time-consuming and expensive. Synthetic antibody fragments (sFabs) generated by phage-display selection offer an alternative with many advantages over Fabs obtained from natural antibodies using hybridoma technology. Unlike mAbs, sFabs are generated using phage display, allowing selection for binding to specific strains or for pan-specificity, for identification of structural epitopes or unique protein conformations and even for complexes. Further, they can easily be produced in Escherichia coli in large quantities and engineered for purposes of detection technologies and other applications. Here, the use of phage-display selection to generate a pan-specific Fab (MJ20), based on a Herceptin Fab scaffold, with the ability to bind selectively and with high affinity to the C-terminal domains of the nucleoproteins (NPs) from all five known strains of the Ebola virus is reported. The high-resolution crystal structure of the complex of MJ20 with the antigen from the Bundibugyo strain of the Ebola virus reveals the basis for pan specificity and illustrates how the phage-display technology can be used to manufacture suitable Fabs for use in diagnostic or therapeutic applications. PMID- 29968679 TI - Crystal structure of the FAS1 domain of the hyaluronic acid receptor stabilin-2. AB - Recent research has identified a potential role of the hyaluronic acid receptor stabilin-2 (Stab2) in cancer metastasis. Stab2 belongs to a group of scavenger receptors and is responsible for the clearance of more than ten ligands, including hyaluronic acid (HA). In vivo experiments on mice have shown that the absence of Stab2, or its blocking by an antibody, effectively opposes cancer metastasis, which is accompanied by an increase in the level of circulating HA. Knowledge of ligand recognition and signal transduction by Stab2 is limited and no three-dimensional structures of any protein fragments of this receptor have been solved to date. Here, a high-resolution X-ray structure of the seventh FAS1 domain of Stab2 is reported. This structure provides the first insight into the Stab2 structure. PMID- 29968680 TI - Engineering glycoside hydrolase stability by the introduction of zinc binding. AB - The development of robust enzymes, in particular cellulases, is a key step in the success of biological routes to 'second-generation' biofuels. The typical sources of the enzymes used to degrade biomass include mesophilic and thermophilic organisms. The endoglucanase J30 from glycoside hydrolase family 9 was originally identified through metagenomic analyses of compost-derived bacterial consortia. These studies, which were tailored to favor growth on targeted feedstocks, have already been shown to identify cellulases with considerable thermal tolerance. The amino-acid sequence of J30 shows comparably low identity to those of previously analyzed enzymes. As an enzyme that combines a well measurable activity with a relatively low optimal temperature (50 degrees C) and a modest thermal tolerance, it offers the potential for structural optimization aimed at increased stability. Here, the crystal structure of wild-type J30 is presented along with that of a designed triple-mutant variant with improved characteristics for industrial applications. Through the introduction of a structural Zn2+ site, the thermal tolerance was increased by more than 10 degrees C and was paralleled by an increase in the catalytic optimum temperature by more than 5 degrees C. PMID- 29968682 TI - [How Does Advance Provision of Emergency Contraceptives Affect Contraceptive Use and Sexual Activity Among Adolescents? Systematic Review and Meta-Analysis]. AB - PURPOSE: The purpose of this study was to analyze the effect of emergency contraceptive pill on adolescent sexuality and contraceptive behaviors through a meta - analysis of intervention studies on advance provision of emergency contraceptives. This study aimed to provide objective data on the transition of general medicines to be discussed in relation to the reclassification of emergency contraceptive pills. METHODS: Using electronic database, 1,820 studies written in Korean or English without limitation of the year were reviewed and for analysis, 5 studies were selected, in which emergency contraceptives were provided to adolescents. RESULTS: The advance provision of emergency contraceptives has increased their use and shortened the time it takes to take contraceptive pills after unprotected sex. There was no change in the frequency of engaging in sexual intercourse and unprotected sex or in existing contraceptive behavior, pregnancy rates decreased, but there was no increase in sexually transmitted infection. CONCLUSION: The results of this study provide objective grounds for the reclassification of emergency contraceptive pills and propose effective interventional programs on contraceptive education, such as on efficacy and side effects of the contraceptive drug and its proper use among the youth who engage in sexual activity, to improve their reproductive health. PMID- 29968683 TI - [Self-Management Experiences of the Adolescents with Chronic Kidney Disease]. AB - PURPOSE: The aim of this study was to develop a substantive theory on self management conducted by the adolescents with chronic kidney disease from their lived experience. METHODS: Data was collected through in-depth interviews from May to December in 2015 with thirteen adolescents with chronic kidney disease. The data collected were analyzed on the basis of Strauss and Corbin's grounded theory. RESULTS: The core of the category found in this study was "overcoming the unstable sense of self-control and integrating disease experience into their life". The causal conditions triggering the central phenomenon were "restriction in daily life" and "manifestation and aggravation of symptom". The central phenomenon in the experience of self-management within the adolescents with chronic kidney disease was "unstable sense of self control". The intervening condition for unstable self control were "micro system support" and "motivational resources". This study found that the adolescents with chronic kidney disease followed a series of strategies when they faced the central phenomenon, including; passive coping, reappraisal of illness, active coping, compliance with treatment, controlling physical activity, and adjusting school life. With these strategic approaches, the adolescents with chronic kidney disease could maintain their active lifestyles and achieve their health behaviors. The process of self management by these adolescents passed through four phases; limited experience caused by diseases, effort for normalization, reorganizing their daily lives, and integration with daily lives and self-management. CONCLUSION: This Study explored the process and experience of self-management of adolescents with chronic kidney disease. These findings can be used for basis for developing substantive theory and nursing intervention strategy for adolescents with chronic kidney diseases. PMID- 29968684 TI - [Effect of Breathing Exercise Using Panflutes on the Postoperative Compliance, Pulmonary Infections and Life Satisfaction in Elderly Patients Undergoing Spinal Surgery]. AB - PURPOSE: The purpose of this study was to examine the effects of breathing exercises performed using panflutes in elderly patients undergoing spinal surgery. METHODS: The study design was a nonequivalent control group non synchronized pre-post test. The study included 24 patients in both the experimental group and the control group. The experimental group completed a daily breathing exercise regimen using panflutes for 30minutes after meals, whereas the control group was provided standard preoperative education, including breathing exercises using incentive spirometers. After the exercise regimen, breathing exercise compliance, pulmonary infections, and life satisfaction were measured in both groups, and the data were analyzed using the SPSS/WIN program. RESULTS: The compliance rate of breathing exercises was significantly higher in the experimental group. The experimental group presented no pulmonary infections in the later period, whereas the control group presented higher pulmonary infection rates in the same period. In addition, the life satisfaction score in the experimental group significantly increased. CONCLUSION: The breathing exercise program using panflutes for elderly patients undergoing spinal surgery enhanced their breathing exercise compliance and their daily life satisfaction in addition to reducing their pulmonary infection rates. PMID- 29968685 TI - [Usefulness of Korean Version of Behavioral Cue Checklist for Predicting of Patient Violence in Emergency Departments]. AB - PURPOSE: This study aimed to evaluate the usefulness of a behavioral cue checklist (BCC) containing 17 items developed by Wilkes et al. (2010) for identifying potentially violent patients in emergency departments. METHODS: This was a prospective observational study to evaluate the usefulness of the Korean version of a BCC (K-BCC) as an assessment tool for predicting patient violence in emergency departments, and was conducted over 4 weeks in a regional emergency medical center located in B City. A total of 1,324 patients were finally analyzed. RESULTS: Logistic regression analysis was performed to investigate whether each item of the K-BCC predicts violence, and a parsimonious set of 8 statistically significant items was selected for the tool. Receiver operating characteristic analysis of the BCC showed that the area under the curve was .97 (95% confidence interval: .94~1.0). The sensitivity, specificity, positive predictive value, and negative predictive value at the cut-off score of 2 were 75.6%, 98.9%, 68.2%, and 99.2%, respectively. CONCLUSION: The K-BCC was found to be useful in predicting patient violence toward emergency department staff. This tool is simple, and fast to use and can play a significantly role identifying potentially violent patients. Owing to this advance identification, this tool can be helpful in preventing the potential for violence from manifesting as violent behaviors. PMID- 29968686 TI - [The Effects of Laughter Therapy Program on Perceived Stress, and Psycho-Neuro Endocrino-Immuno Responses in Obese Women]. AB - PURPOSE: The purpose of this study was to examine the effects of the laughter therapy program on perceived stress and psycho-neuro-endocrine-immune responses in obese women. METHODS: A nonequivalent control group with a pretest-posttest design was used. The participants (n=60), whose age ranged from 30 to 50 years (pre-menopausal and body mass index of over 25 kg/m2), were assigned to the experimental group (n=24) or control group (n=26). The experimental group was provided with the laughter therapy program (12 sessions) for 6 weeks. RESULTS: There were significant differences in perceived stress, psychological stress response, fasting blood sugar, interleukin-6, and tumor necrosis factor alpha between the two groups after the program. However, there were no significant differences in normalized low frequency (norm LF), normalized high frequency (norm HF), LF/HF ratio, and cortisol between the two groups after the program. CONCLUSION: It was found that the laughter therapy program had positive effects on some variables in terms of perceived stress and psycho-neuro-endocrine-immuno responses. It is suggested that the laughter therapy in this study can provide the direction for developing a program for obese women. PMID- 29968687 TI - [Chronically Ill Patients' Perception of Hospital Nurses]. AB - PURPOSE: The purpose of this qualitative research was to investigate chronically ill patients' perception of hospital nurses. METHODS: Individual in-depth interviews and qualitative content analysis were used for data collection and analysis respectively. Participants were 13 chronically ill hospitalized patients or outpatients in three universities hospitals. All interviews were recorded and transcribed verbatim. Data were analyzed using the qualitative content analysis suggested by Graneheim and Lundman (2004). RESULTS: Three themes emerged from the 10 sub-themes, which were categorized from the 21 condensed meaning units by interpreting the underlying meanings. The three themes were "person giving comfort and support by caring", "person facilitating the process of healing", and "person taking the initiative in power relations". Two themes involved positive experiences of patients and the other included negative ones. CONCLUSION: The results showed that the participants perceived the hospital nurses as devoted to caring for patients and facilitating treatments, but authoritative in performing their duty. Based on these results, it is recommended that hospital nurses improve their nursing knowledge, skills and humanistic attitude. PMID- 29968688 TI - [Development and Validation of a Measurement to Assess Person-centered Critical Care Nursing]. AB - PURPOSE: The purpose of this study was to develop a scale to measure person centered critical care nursing and verify its reliability and validity. METHODS: A total of 38 preliminary items on person-centered critical care nursing were selected using content validity analysis of and expert opinion on 72 candidate items derived through literature review and qualitative interviews. We conducted a questionnaire survey with 477 nurses who worked in intensive care units. The collected data were analyzed using exploratory factor analysis (EFA) and confirmative factor analysis (CFA) with SPSS and AMOS 24.0 program. RESULTS: EFA was performed with principal axis factor analysis and Varimax rotation. The 15 items in 4 factors that accounted for 50.8% of the total variance were identified by deleting the items that were not meet the condition that the commonality should be .30 or more and the factor loading over .40. We named the factors as compassion, individuality, respect, and comfort, respectively. The correlation coefficient between this scale and the Caring Perception Scale was r=.57 (p<.001), which determined concurrent validity. The item-total correlation values ranged from .39 to .63, and the internal consistency for the scale was Cronbach's alpha=.84. CONCLUSION: The reliability and validity of the 15 item person centered critical care nursing scale were verified. It is expected that the use of this scale would expand person-centered care in critical care nursing. PMID- 29968689 TI - [Perception on Parental Coping on Unintentional Injury of Their Early Infants and Toddlers: Q Methodological Approach]. AB - PURPOSE: The purpose of this study was to identify parental coping strategies in the face of early infant and toddler injury, and to provide basic data for a parental education program and the most desirable directions it should take. METHODS: A Q-methodology to analyze the subjectivity of each item was used. Thirty-four Q-statements were derived from a literature review and interviews. Forty-seven parents were classified into a shape of normal distribution using a 9 point scale. Collected data were analyzed by the pc-QUANL program. RESULTS: Five types of parental coping in early infant and toddler injury were identified. Type I was "hospital treatment focused", type II was "Improving the safety of the child's environment", type III was "expression of negative emotion", type IV was "taking the lead in problem solving", and type V was "Interrogating the person in charge of the situation in which the injury occurred". CONCLUSION: The results of this study indicate that different approaches to educational programs can be used for parents in early childhood injury. PMID- 29968690 TI - [An Ethnography on the Healthy Life of the Aged Women Participating the Senior Centers]. AB - PURPOSE: This ethnography was performed to explore patterns and meanings of healthy life among aged women using senior centers. METHODS: The informants were 21 individuals aged 65 years and older at 2 community-based senior centers. Data were collected from iterative fieldwork through in-depth interviews and participant observations and analyzed using text analysis and taxonomic methods developed by Spradley. Field notes were used with follow-up interviews and dialogue between authors to enhance interpretation. RESULTS: Patterns of healthy life among aged women using senior centers were categorized by age groups within the context of the four cultural elements of taking care of the body, relationality, temporality, and spatiality: active and passive control, maintenance of interdependence and individuality, expansion and maintenance of the daily routine, unity of peer relations and sustenance of family relations, spending time productively and tediously, and complementary and alternative space of the family relations. CONCLUSION: The informants in this study demonstrated healthy life by maintaining and strengthening continuous relationships developed in the senior centers without being isolated from the family and society. Patterns of their healthy life differed across age groups within the socio cultural context. Therefore, interventions should be tailored to address age groups and community needs. PMID- 29968691 TI - [Development of a Triage Competency Scale for Emergency Nurses]. AB - PURPOSE: This study aimed to develop a triage competency scale (TCS) for emergency nurses, and to evaluate its validity and reliability. METHODS: Preliminary items were derived based on the attributes and indicators elicited from a concept analysis study on triage competency. Ten experts assessed whether the preliminary items belonged to the construct factor and determined the appropriateness of each item. A revised questionnaire was administered to 250 nurses in 18 emergency departments to evaluate the reliability and validity of the scale. Data analysis comprised item analysis, confirmatory factor analysis, contrasted group validity, and criterion-related validity, including criterion related validity of the problem solving method using video scenarios. RESULTS: The item analysis and confirmatory factor analysis yielded 5 factors with 30 items; the fit index of the derived model was good (chi2/df =2.46, Root Mean squared Residual=.04, Root Mean Squared Error of Approximation=.08). Additionally, contrasted group validity was assessed. Participants were classified as novice, advanced beginner, competent, and proficient, and significant differences were observed in the mean score for each group (F=6.02, p=.001). With reference to criterion-related validity, there was a positive correlation between scores on the TCS and the Clinical Decision Making in Nursing Scale (r=.48, p<.001). Further, the total score on the problem solving method using video scenarios was positively correlated with the TCS score (r=.13, p=.04). The Cronbach's alpha of the final model was .91. CONCLUSION: Our TCS is useful for the objective assessment of triage competency among emergency nurses and the evaluation of triage education programs. PMID- 29968692 TI - Reliability and Validity of the Korean Version of the Coping and Adaptation Processing Scale-Short-Form in Cancer Patients. AB - PURPOSE: This study was conducted to assess the reliability and validity of the Korean version of the Coping and Adaptation Processing Scale-Short-Form in patients with cancer. METHODS: The original scale was translated into Korean using Brislin's translation model. The Korean Short-Form and the Functional Assessment Cancer Therapy-General were administered to 164 Korean patients with cancer using convenience sampling method. The collected data were analyzed using SPSS 23.0 and AMOS 23.0. Construct validity, criterion validity, test-retest reliability, and internal consistency reliability of the Korean Coping and Adaptation Processing Scale-Short-Form were evaluated. RESULTS: Exploratory factor analysis supported the construct validity with a four-factor solution that explained 60.6% of the total variance. Factor loadings of the 15 items on the four subscales ranged .52~.86. The four-subscale model was validated by confirmatory factor analysis (Normed chi2=1.38 (p =.013), GFI=.92, SRMR=.02, RMSEA=.05, TLI=.94, and CFI=.95), and criterion validity was demonstrated with the Functional Assessment Cancer Therapy-General. Cronbach's alpha for internal consistency of the total scale was .83 and ranged .68~.81 for all subscales, demonstrating sufficient test-retest reliability. CONCLUSION: The Korean version showed satisfactory construct and criterion validity, as well as internal consistency and test-retest reliability. PMID- 29968693 TI - Prognostic factors in adrenocortical carcinoma: data from a large Polish series. PMID- 29968694 TI - Microbiota and diabetes: an increasingly relevant association. PMID- 29968695 TI - Interferon-lambda4 gene polymorphisms, circulating interferon lambda3, and clinical variables in hemodialysis patients exposed to hepatitis E virus. AB - Introduction Factors associated with hepatitis E virus (HEV) infection are rarely recognized in patients on renal replacement therapy (RRT), and the results of studies are inconsistent. Objectives We aimed to search for determinants of HEV seroprevalence among polymorphisms of the interferon-lambda4 gene (IFNL4) associated with seroclearance of hepatotropic viruses (IFNL4 rs12979860, rs8099917 near IFNL4), circulating interferon lambda3 (IFN-lambda3), and clinical variables of patients treated with hemodialysis (HD) in a HEV-endemic region. Patients and methods The study was carried out in 90 HD patients. HEV open reading frame 2 antigen (HEV Ag), immunoglobulin M and G antibodies to HEV (anti HEV IgM and anti-HEV IgG, respectively) and IFN-lambda3 were tested, and IFNL4 polymorphic variants (rs8099917, rs12979860) were genotyped. Survival analysis was conducted concerning anti-HEV IgG positivity. Results In the study group, there were 37.8% anti-HEV IgG-positive subjects. None was HEV Ag or anti-HEV IgM positive. HD modalities utilizing high-flux dialyzers (adjusted odds ratio [OR], 3.586; 95% confidence interval [CI], 1.142-11.263; P = 0.03) as well as major homozygosity in rs8099917 (adjusted OR, 4.933; 95% CI, 1.516-16.054; P = 0.008) and rs12979860 (adjusted OR, 3.537; 95% CI, 1.136-11.014, P = 0.03), but not circulating IFN-lambda3 levels, were positive determinants of anti-HEV IgG positivity. Liver enzyme activities and C-reactive protein levels tested as response variables to HEV exposure, as well as survival probability, were not different between patients stratified by anti-HEV IgG positivity. Conclusions Among HD patients, IFNL4 polymorphisms and treatment with high-flux HD are explanatory variables for isolated anti-HEV IgG positivity indicating spontaneous HEV resolution. PMID- 29968696 TI - Cancer ratio and other new parameters for differentiation between malignant and nonmalignant pleural effusions. AB - Introduction In contrast to tuberculous pleurisy (TP), no accurate and commonly accepted biochemical marker of malignant pleural effusion (MPE) has been established. Objectives We aimed to evaluate the ability of a previously reported cancer ratio (CR) to discriminate between MPEs and non-MPEs; to test whether age may have additional value in differentiating MPEs from non-MPEs; and if so, to combine lactate dehydrogenase (LDH) and age with other TP biomarkers in search of an index useful in the identification of MPEs. Patients and methods A retrospective analysis of data from 140 patients with malignant (n = 74), tuberculous (n = 37), and parapneumonic (n = 29) pleural effusions was performed. The diagnostic performance of a test to discriminate between MPEs and non-MPEs was evaluated using the receiver operating characteristic curve analysis. Results Three ratios showed the largest area under the curve (AUC): serum LDH to pleural fluid soluble Fas ligand, age to pleural fluid adenosine deaminase (ADA), and serum LDH to pleural fluid interleukin 18; moreover, the ratios were characterized by high sensitivity (95%, 93.2%, and 92.9%, respectively) and fair specificity (64.8%, 71.2%, and 58.5%, respectively) for differentiating MPEs from non-MPEs. The AUC for CR was lower and showed a sensitivity of 94.6% and a specificity of 68.2%. Conclusions Our study showed a lower specificity of the CR for discriminating between MPEs and non-MPEs than previously reported. We demonstrated that the combinations of serum LDH with other pleural fluid biomarkers of TP have a similar diagnostic performance. We also found that age might be an important factor differentiating between MPEs and non-MPEs and proposed a new age to pleural fluid ADA ratio which has a discriminative potential similar to that of the CR. PMID- 29968697 TI - How and when to measure anticoagulant effects of direct oral anticoagulants? Practical issues. AB - Direct oral anticoagulants (DOACs) do not require dose adjustment based on laboratory testing. However, it might be necessary to measure their plasma concentrations in the following specific situations: 1) before thrombolytic therapy in patients with stroke; 2) before surgery or invasive procedure; 3) in case of adverse events (thrombosis or hemorrhage); 4) when immediate reversal of anticoagulation is needed; 5) in patients with extreme body weight; 6) when administering additional drugs potentially interfering with DOACs; and 7) when overdosage is suspected regardless of concomitant bleeding. Basic coagulation tests, such as prothrombin and activated partial thromboplastin time, should not be used as standalone tests to assess the levels of anticoagulation as they are not specific for DOACs and their results are dependent on the type of reagent used for testing. Plasma DOAC concentrations should be assessed by dedicated tests: dilute thrombin time or ecarin tests (for dabigatran) or anti-factor Xa assays (for anti-factor Xa inhibitors). Dedicated tests should be calibrated against their respective plasma calibrators at certified DOAC concentrations and results should be expressed as ng/ml. Caution should be exerted when interpreting the results of the most common hemostatic parameters such as antithrombin, proteins C and S, lupus anticoagulant, or individual coagulation factors, as they may be strongly affected by the presence of a DOAC. Whenever possible, these parameters should be measured 4 to 5 days after discontinuation of DOAC anticoagulation. PMID- 29968698 TI - Significant response to dabrafenib in a patient with Erdheim-Chester disease with BRAFV600E mutation. PMID- 29968699 TI - Catatonia as a presenting symptom of ectopic adrenocorticotropic hormone syndrome caused by thymic carcinoid tumor. PMID- 29968700 TI - Validation of transurethral intra-abdominal pressure measurement in acute heart failure. PMID- 29968701 TI - Pathogenesis of Abnormal Hepatic Lipid Metabolism Induced by Chronic Intermittent Hypoxia in Rats and the Therapeutic Effect of N-Acetylcysteine. AB - BACKGROUND The pathogenesis of chronic intermittent hypoxia (CIH)-induced abnormal hepatic lipid metabolism in rats remains unclear. Here, we investigated the therapeutic effect of N-acetylcysteine (NAC) on abnormal hepatic lipid metabolism. MATERIAL AND METHODS Rats were subjected to hypoxia and NAC treatment, and evaluated in terms of hepatic lipid metabolism, hepatocyte ultrastructure, oxidative stress in hepatocytes, expression of nuclear factor kappa B (NF-kappaB) and inflammatory cytokines (IL-1beta, IL-6, and TNFalpha), serum lipoprotein lipase (LPL) levels, and blood lipids (triglycerides and cholesterol). RESULTS Compared to the normoxic control group, animals in the hypoxic model group showed significant body weight gain; abnormal hepatic lipid metabolism; lipid vacuolization; accumulation of lipid droplets; abundant autophagosomes and lysosomes; significant increases in oxidative stress, inflammation level, and blood lipid levels; and significantly reduced LPL levels. Compared to control animals, rats in the treatment group exhibited normal body weight gain, improved lipid metabolism, fewer lipid droplets, alleviated ultrastructural injuries, decreased oxidative stress and inflammation level, as well as elevated LPL and reduced blood lipid levels. CONCLUSIONS The harmful effects of CIH on rat liver are possibly associated with the reactive oxygen species (ROS)/NF-kappaB signaling pathway. NAC is capable of attenuating lipid metabolism alterations and abnormal body weight gain in the CIH rat model, via a possible mechanism related to inhibition of ROS/NF-kappaB signaling. PMID- 29968702 TI - Spin-phonon couplings in transition metal complexes with slow magnetic relaxation. AB - Spin-phonon coupling plays an important role in single-molecule magnets and molecular qubits. However, there have been few detailed studies of its nature. Here, we show for the first time distinct couplings of g phonons of CoII(acac)2(H2O)2 (acac = acetylacetonate) and its deuterated analogs with zero field-split, excited magnetic/spin levels (Kramers doublet (KD)) of the S = 3/2 electronic ground state. The couplings are observed as avoided crossings in magnetic-field-dependent Raman spectra with coupling constants of 1-2 cm-1. Far IR spectra reveal the magnetic-dipole-allowed, inter-KD transition, shifting to higher energy with increasing field. Density functional theory calculations are used to rationalize energies and symmetries of the phonons. A vibronic coupling model, supported by electronic structure calculations, is proposed to rationalize the behavior of the coupled Raman peaks. This work spectroscopically reveals and quantitates the spin-phonon couplings in typical transition metal complexes and sheds light on the origin of the spin-phonon entanglement. PMID- 29968703 TI - Coherent modulation of the sea-level annual cycle in the United States by Atlantic Rossby waves. AB - Changes in the sea-level annual cycle (SLAC) can have profound impacts on coastal areas, including increased flooding risk and ecosystem alteration, yet little is known about the magnitude and drivers of such changes. Here we show, using novel Bayesian methods, that there are significant decadal fluctuations in the amplitude of the SLAC along the United States Gulf and Southeast coasts, including an extreme event in 2008-2009 that is likely (probability >=68%) unprecedented in the tide-gauge record. Such fluctuations are coherent along the coast but decoupled from deep-ocean changes. Through the use of numerical and analytical ocean models, we show that the primary driver of these fluctuations involves incident Rossby waves that generate fast western-boundary waves. These Rossby waves project onto the basin-wide upper mid-ocean transport (top 1000 m) leading to a link with the SLAC, wherein larger SLAC amplitudes coincide with enhanced transport variability. PMID- 29968704 TI - High energy flexible supercapacitors formed via bottom-up infilling of gel electrolytes into thick porous electrodes. AB - Formation of thick, high energy density, flexible solid supercapacitors is challenging because of difficulties infilling gel electrolytes into porous electrodes. Incomplete infilling results in a low capacitance and poor mechanical properties. Here we report a bottom-up infilling method to overcome these challenges. Electrodes up to 500 MUm thick, formed from multi-walled carbon nanotubes and a composite of poly(3,4-ethylenedioxythiophene), polystyrene sulfonate and multi-walled carbon nanotubes are successfully infilled with a polyvinyl alcohol/phosphoric acid gel electrolyte. The exceptional mechanical properties of the multi-walled carbon nanotube-based electrode enable it to be rolled into a radius of curvature as small as 0.5 mm without cracking and retain 95% of its initial capacitance after 5000 bending cycles. The areal capacitance of our 500 MUm thick poly(3,4-ethylenedioxythiophene), polystyrene sulfonate, multi-walled carbon nanotube-based flexible solid supercapacitor is 2662 mF cm-2 at 2 mV s-1, at least five times greater than current flexible supercapacitors. PMID- 29968705 TI - The REN4 rheostat dynamically coordinates the apical and lateral domains of Arabidopsis pollen tubes. AB - The dynamic maintenance of polar domains in the plasma membrane (PM) is critical for many fundamental processes, e.g., polar cell growth and growth guidance but remains poorly characterized. Rapid tip growth of Arabidopsis pollen tubes requires dynamic distribution of active ROP1 GTPase to the apical domain. Here, we show that clathrin-mediated endocytosis (CME) coordinates lateral REN4 with apical ROP1 signaling. REN4 interacted with but antagonized active ROP1. REN4 also interacts and co-localizes with CME components, but exhibits an opposite role to CME, which removes both REN4 and active ROP1 from the PM. Mathematical modeling shows that REN4 restrains the spatial distribution of active ROP1 and is important for the robustness of polarity control. Hence our results indicate that REN4 acts as a spatiotemporal rheostat by interacting with ROP1 to initiate their removal from the PM by CME, thereby coordinating a dynamic demarcation between apical and lateral domains during rapid tip growth. PMID- 29968706 TI - Uhrf1 regulates active transcriptional marks at bivalent domains in pluripotent stem cells through Setd1a. AB - Embryonic stem cells (ESCs) maintain pluripotency through unique epigenetic states. When ESCs commit to a specific lineage, epigenetic changes in histones and DNA accompany the transition to specialized cell types. Investigating how epigenetic regulation controls lineage specification is critical in order to generate the required cell types for clinical applications. Uhrf1 is a widely known hemi-methylated DNA-binding protein, playing a role in DNA methylation through the recruitment of Dnmt1 and in heterochromatin formation alongside G9a, Trim28, and HDACs. Although Uhrf1 is not essential in ESC self-renewal, it remains elusive how Uhrf1 regulates cell specification. Here we report that Uhrf1 forms a complex with the active trithorax group, the Setd1a/COMPASS complex, to maintain bivalent histone marks, particularly those associated with neuroectoderm and mesoderm specification. Overall, our data demonstrate that Uhrf1 safeguards proper differentiation via bivalent histone modifications. PMID- 29968707 TI - Modulation of M1/M2 polarization by capsaicin contributes to the survival of dopaminergic neurons in the lipopolysaccharide-lesioned substantia nigra in vivo. AB - The present study examined the neuroprotective effects of capsaicin (CAP) and explored their underlying mechanisms in a lipopolysaccharide (LPS)-lesioned inflammatory rat model of Parkinson's dieases (PD). LPS was unilaterally injected into the substantia nigra (SN) in the absence or presence of CAP or capsazepine (CZP, a TRPV1 antagonist). The SN tissues were prepared for immunohistochemical staining, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, western blot analysis, blood-brain barrier (BBB) permeability evaluation, and reactive oxygen species (ROS) detection. We found that CAP prevented the degeneration of nigral dopamine neurons in a dose-dependent manner and inhibited the expression of proinflammatory mediators in the LPS-lesioned SN. CAP shifted the proinflammatory M1 microglia/macrophage population to an anti-inflammatory M2 state as demonstrated by decreased expression of M1 markers (i.e., inducible nitric oxide synthase; iNOS and interleukin-6) and elevated expression of M2 markers (i.e., arginase 1 and CD206) in the SN. RT-PCR, western blotting, and immunohistochemical analysis demonstrated decreased iNOS expression and increased arginase 1 expression in the CAP-treated LPS-lesioned SN. Peroxynitrate production, reactive oxygen species levels and oxidative damage were reduced in the CAP-treated LPS-lesioned SN. The beneficial effects of CAP were blocked by CZP, indicating TRPV1 involvement. The present data indicate that CAP regulated the M1 and M2 activation states of microglia/macrophage in the LPS-lesioned SN, which resulted in the survival of dopamine neurons. It is therefore likely that TRPV1 activation by CAP has therapeutic potential for treating neurodegenerative diseases, that are associated with neuroinflammation and oxidative stress, such as PD. PMID- 29968708 TI - The role of momentum-dark excitons in the elementary optical response of bilayer WSe2. AB - Monolayer transition metal dichalcogenides (TMDs) undergo substantial changes in the single-particle band structure and excitonic optical response upon the addition of just one layer. As opposed to the single-layer limit, the bandgap of bilayer (BL) TMD semiconductors is indirect which results in reduced photoluminescence with richly structured spectra that have eluded a detailed understanding to date. Here, we provide a closed interpretation of cryogenic emission from BL WSe2 as a representative material for the wider class of TMD semiconductors. By combining theoretical calculations with comprehensive spectroscopy experiments, we identify the crucial role of momentum-indirect excitons for the understanding of BL TMD emission. Our results shed light on the origin of quantum dot formation in BL crystals and will facilitate further advances directed at opto-electronic applications of layered TMD semiconductors in van der Waals heterostructures and devices. PMID- 29968709 TI - Task-dependent representations of stimulus and choice in mouse parietal cortex. AB - The posterior parietal cortex (PPC) has been implicated in perceptual decisions, but whether its role is specific to sensory processing or sensorimotor transformation is not well understood. Here, we trained mice to perform a go/no go visual discrimination task and imaged the activity of neurons in primary visual cortex (V1) and PPC during engaged behavior and passive viewing. Unlike V1 neurons, which respond robustly to stimuli in both conditions, most PPC neurons respond exclusively during task engagement. To test whether signals in PPC primarily encoded the stimulus or the animal's impending choice, we image the same neurons before and after re-training mice with a reversed sensorimotor contingency. Unlike V1 neurons, most PPC neurons reflect the animal's choice of the new target stimulus after re-training. Mouse PPC is therefore strongly task dependent, reflects choice more than stimulus, and may play a role in the transformation of visual inputs into motor commands. PMID- 29968710 TI - Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression. AB - Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4 dependent macrophage activation and provide potential targets for cancer therapy. PMID- 29968711 TI - Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase. AB - Type II topoisomerases alter DNA topology to control DNA supercoiling and chromosome segregation and are targets of clinically important anti-infective and anticancer therapeutics. They act as ATP-operated clamps to trap a DNA helix and transport it through a transient break in a second DNA. Here, we present the first X-ray crystal structure solved at 2.83 A of a closed clamp complete with trapped T-segment DNA obtained by co-crystallizing the ATPase domain of S. pneumoniae topoisomerase IV with a nonhydrolyzable ATP analogue and 14-mer duplex DNA. The ATPase dimer forms a 22 A protein hole occupied by the kinked DNA bound asymmetrically through positively charged residues lining the hole, and whose mutagenesis impacts the DNA decatenation, DNA relaxation and DNA-dependent ATPase activities of topo IV. These results and a side-bound DNA-ParE structure help explain how the T-segment DNA is captured and transported by a type II topoisomerase, and reveal a new enzyme-DNA interface for drug discovery. PMID- 29968712 TI - Photo-tautomerization of acetaldehyde as a photochemical source of formic acid in the troposphere. AB - Organic acids play a key role in the troposphere, contributing to atmospheric aqueous-phase chemistry, aerosol formation, and precipitation acidity. Atmospheric models currently account for less than half the observed, globally averaged formic acid loading. Here we report that acetaldehyde photo-tautomerizes to vinyl alcohol under atmospherically relevant pressures of nitrogen, in the actinic wavelength range, lambda = 300-330 nm, with measured quantum yields of 2 25%. Recent theoretical kinetics studies show hydroxyl-initiated oxidation of vinyl alcohol produces formic acid. Adding these pathways to an atmospheric chemistry box model (Master Chemical Mechanism) demonstrates increased formic acid concentrations by a factor of ~1.7 in the polluted troposphere and a factor of ~3 under pristine conditions. Incorporating this mechanism into the GEOS-Chem 3D global chemical transport model reveals an estimated 7% contribution to worldwide formic acid production, with up to 60% of the total modeled formic acid production over oceans arising from photo-tautomerization. PMID- 29968713 TI - Microscopic structure of the polymer-induced liquid precursor for calcium carbonate. AB - Many biomineral crystals form complex non-equilibrium shapes, often via transient amorphous precursors. Also in vitro crystals can be grown with non-equilibrium morphologies, such as thin films or nanorods. In many cases this involves charged polymeric additives that form a polymer-induced liquid precursor (PILP). Here, we investigate the CaCO3 based PILP process with a variety of techniques including cryoTEM and NMR. The initial products are 30-50 nm amorphous calcium carbonate (ACC) nanoparticles with ~2 nm nanoparticulate texture. We show the polymers strongly interact with ACC in the early stages, and become excluded during crystallization, with no liquid-liquid phase separation detected during the process. Our results suggest that "PILP" is actually a polymer-driven assembly of ACC clusters, and that its liquid-like behavior at the macroscopic level is due to the small size and surface properties of the assemblies. We propose that a similar biopolymer-stabilized nanogranular phase may be active in biomineralization. PMID- 29968714 TI - Coupling of ocean redox and animal evolution during the Ediacaran-Cambrian transition. AB - The late Ediacaran to early Cambrian interval witnessed extraordinary radiations of metazoan life. The role of the physical environment in this biological revolution, such as changes to oxygen levels and nutrient availability, has been the focus of longstanding debate. Seemingly contradictory data from geochemical redox proxies help to fuel this controversy. As an essential nutrient, nitrogen can help to resolve this impasse by establishing linkages between nutrient supply, ocean redox, and biological changes. Here we present a comprehensive N isotope dataset from the Yangtze Basin that reveals remarkable coupling between delta15N, delta13C, and evolutionary events from circa 551 to 515 Ma. The results indicate that increased fixed nitrogen supply may have facilitated episodic animal radiations by reinforcing ocean oxygenation, and restricting anoxia to near, or even at the sediment-water interface. Conversely, sporadic ocean anoxic events interrupted ocean oxygenation, and may have led to extinctions of the Ediacaran biota and small shelly animals. PMID- 29968715 TI - Novofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation. AB - Novofumigatonin (1), isolated from the fungus Aspergillus novofumigatus, is a heavily oxygenated meroterpenoid containing a unique orthoester moiety. Despite the wide distribution of orthoesters in nature and their biological importance, little is known about the biogenesis of orthoesters. Here we show the elucidation of the biosynthetic pathway of 1 and the identification of key enzymes for the orthoester formation by a series of CRISPR-Cas9-based gene-deletion experiments and in vivo and in vitro reconstitutions of the biosynthesis. The novofumigatonin pathway involves endoperoxy compounds as key precursors for the orthoester synthesis, in which the Fe(II)/alpha-ketoglutarate-dependent enzyme NvfI performs the endoperoxidation. NvfE, the enzyme catalyzing the orthoester synthesis, is an Fe(II)-dependent, but cosubstrate-free, endoperoxide isomerase, despite the fact that NvfE shares sequence homology with the known Fe(II)/alpha-ketoglutarate dependent dioxygenases. NvfE thus belongs to a class of enzymes that gained an isomerase activity by losing the alpha-ketoglutarate-binding ability. PMID- 29968716 TI - Synthesis of polymers with on-demand sequence structures via dually switchable and interconvertible polymerizations. AB - The synthesis of polymers with on-demand sequence structures is very important not only for academic researchers but also for industry. However, despite the existing polymerization techniques, it is still difficult to achieve copolymer chains with on-demand sequence structures. Here we report a dually switchable and controlled interconvertible polymerization system; in this system, two distinct orthogonal polymerizations can be selectively switched ON/OFF independent of each other and they can be interconverted promptly and quantitatively according to external stimuli. Thus, the external stimuli can manipulate the insertion of distinct monomers into the resulting copolymer chains temporally, spatially, and orthogonally, allowing the on-demand precise arrangement of sequence structures in the resulting polymers. This dually switchable and interconvertible polymerization system provides a powerful tool for synthesizing materials that are not accessible by other polymerization methods. PMID- 29968717 TI - A senataxin-associated exonuclease SAN1 is required for resistance to DNA interstrand cross-links. AB - Interstrand DNA cross-links (ICLs) block both replication and transcription, and are commonly repaired by the Fanconi anemia (FA) pathway. However, FA-independent repair mechanisms of ICLs remain poorly understood. Here we report a previously uncharacterized protein, SAN1, as a 5' exonuclease that acts independently of the FA pathway in response to ICLs. Deletion of SAN1 in HeLa cells and mouse embryonic fibroblasts causes sensitivity to ICLs, which is prevented by re expression of wild type but not nuclease-dead SAN1. SAN1 deletion causes DNA damage and radial chromosome formation following treatment with Mitomycin C, phenocopying defects in the FA pathway. However, SAN1 deletion is not epistatic with FANCD2, a core FA pathway component. Unexpectedly, SAN1 binds to Senataxin (SETX), an RNA/DNA helicase that resolves R-loops. SAN1-SETX binding is increased by ICLs, and is required to prevent cross-link sensitivity. We propose that SAN1 functions with SETX in a pathway necessary for resistance to ICLs. PMID- 29968718 TI - Fractal modes and multi-beam generation from hybrid microlaser resonators. AB - Fractals are ubiquitous in nature, and prominent examples include snowflakes and neurons. Although it has long been known that intricate optical fractal patterns can be realized with components such as gratings and reflecting spheres, generating fractal transverse modes from a laser has proven to be elusive. By introducing a 2D network of microspheres into a Fabry-Perot cavity bounding a gain medium, we demonstrate a hybrid optical resonator in which the spheres enable the simultaneous generation of arrays of conventional (Gaussian) and fractal laser modes. Within the interstices of the microsphere crystal, several distinct fractal modes are observed, two of which resemble the Sierpinski Triangle. Coupling between adjacent fractal modes is evident, and fractal modes may be synthesized through design of the microsphere network. Owing to a unique synergy between the gain medium and the resonator, this optical platform is able to emit hundreds of microlaser beams and probe live motile cells. PMID- 29968721 TI - Reply to "On the origin of molecular oxygen in cometary comae". PMID- 29968719 TI - Evidence for line width and carrier screening effects on excitonic valley relaxation in 2D semiconductors. AB - Monolayers of transition metal dichalcogenides (TMDC) have recently emerged as excellent platforms for exploiting new physics and applications relying on electronic valley degrees of freedom in two-dimensional (2D) systems. Here, we demonstrate that Coulomb screening by 2D carriers plays a critical role in excitonic valley pseudospin relaxation processes in naturally carrier-doped WSe2 monolayers (1L-WSe2). The exciton valley relaxation times were examined using polarization- and time-resolved photoluminescence spectroscopy at temperatures ranging from 10 to 160 K. We show that the temperature-dependent exciton valley relaxation times in 1L-WSe2 under various exciton and carrier densities can be understood using a unified framework of intervalley exciton scattering via momentum-dependent long-range electron-hole exchange interactions screened by 2D carriers that depend on the carrier density and the exciton linewidth. Moreover, the developed framework was successfully applied to engineer the valley polarization of excitons in 1L-WSe2. These findings may facilitate the development of TMDC-based opto-valleytronic devices. PMID- 29968720 TI - On the origin of molecular oxygen in cometary comae. PMID- 29968723 TI - Topochemical conversion of an imine- into a thiazole-linked covalent organic framework enabling real structure analysis. AB - Stabilization of covalent organic frameworks (COFs) by post-synthetic locking strategies is a powerful tool to push the limits of COF utilization, which are imposed by the reversible COF linkage. Here we introduce a sulfur-assisted chemical conversion of a two-dimensional imine-linked COF into a thiazole-linked COF, with full retention of crystallinity and porosity. This post-synthetic modification entails significantly enhanced chemical and electron beam stability, enabling investigation of the real framework structure at a high level of detail. An in-depth study by electron diffraction and transmission electron microscopy reveals a myriad of previously unknown or unverified structural features such as grain boundaries and edge dislocations, which are likely generic to the in-plane structure of 2D COFs. The visualization of such real structural features is key to understand, design and control structure-property relationships in COFs, which can have major implications for adsorption, catalytic, and transport properties of such crystalline porous polymers. PMID- 29968724 TI - Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis. AB - Farnesoid-X-Receptor (FXR) plays a central role in maintaining bile acid (BA) homeostasis by transcriptional control of numerous enterohepatic genes, including intestinal FGF19, a hormone that strongly represses hepatic BA synthesis. How activation of the FGF19 receptor at the membrane is transmitted to the nucleus for transcriptional regulation of BA levels and whether FGF19 signaling posttranslationally modulates FXR function remain largely unknown. Here we show that FXR is phosphorylated at Y67 by non-receptor tyrosine kinase, Src, in response to postprandial FGF19, which is critical for its nuclear localization and transcriptional regulation of BA levels. Liver-specific expression of phospho defective Y67F-FXR or Src downregulation in mice results in impaired homeostatic responses to acute BA feeding, and exacerbates cholestatic pathologies upon drug induced hepatobiliary insults. Also, the hepatic FGF19-Src-FXR pathway is defective in primary biliary cirrhosis (PBC) patients. This study identifies Src mediated FXR phosphorylation as a potential therapeutic target and biomarker for BA-related enterohepatic diseases. PMID- 29968722 TI - Genomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics. AB - The incidence of Plasmodium vivax infection has declined markedly in Malaysia over the past decade despite evidence of high-grade chloroquine resistance. Here we investigate the genetic changes in a P. vivax population approaching elimination in 51 isolates from Sabah, Malaysia and compare these with data from 104 isolates from Thailand and 104 isolates from Indonesia. Sabah displays extensive population structure, mirroring that previously seen with the emergence of artemisinin-resistant P. falciparum founder populations in Cambodia. Fifty four percent of the Sabah isolates have identical genomes, consistent with a rapid clonal expansion. Across Sabah, there is a high prevalence of loci known to be associated with antimalarial drug resistance. Measures of differentiation between the three countries reveal several gene regions under putative selection in Sabah. Our findings highlight important factors pertinent to parasite resurgence and molecular cues that can be used to monitor low-endemic populations at the end stages of P. vivax elimination. PMID- 29968725 TI - Discovery of coexisting Dirac and triply degenerate magnons in a three dimensional antiferromagnet. AB - Topological magnons are emergent quantum spin excitations featured by magnon bands crossing linearly at the points dubbed nodes, analogous to fermions in topological electronic systems. Experimental realisation of topological magnons in three dimensions has not been reported so far. Here, by measuring spin excitations (magnons) of a three-dimensional antiferromagnet Cu3TeO6 with inelastic neutron scattering, we provide direct spectroscopic evidence for the coexistence of symmetry-protected Dirac and triply degenerate nodes, the latter involving three-component magnons beyond the Dirac-Weyl framework. Our theoretical calculations show that the observed topological magnon band structure can be well described by the linear-spin-wave theory based on a Hamiltonian dominated by the nearest-neighbour exchange interaction J1. As such, we showcase Cu3TeO6 as an example system where Dirac and triply degenerate magnonic nodal excitations coexist, demonstrate an exotic topological state of matter, and provide a fresh ground to explore the topological properties in quantum materials. PMID- 29968726 TI - Breastfeeding and myopia: A cross-sectional study of children aged 6-12 years in Tianjin, China. AB - This study aimed to determine whether an association existed between breastfeeding and myopia in children aged 6-12 years in Tianjin, China, using a cross-sectional study of 527 children. The spherical equivalent refraction (SER) and axial length (AL) were determined by ocular examination, and information regarding the children's demographics, breastfeeding history and other myopia related risk factors were investigated using a questionnaire. The myopia prevalence rate, mean SER, and mean AL were 53.9%, -0.99 +/- 1.69 D, and 23.56 +/ 1.11 mm, respectively. In total, 442 (83.9%) participants were breastfed; among the breastfed participants, 132 (29.9%) were breastfed <6 months. Children who were breastfed were less likely to have myopia (breastfeeding duration <6 months: OR = 0.399, P = 0.011; >6 months: OR = 0.502, P = 0.033, multiple logistical regression). The mean SER of children breastfed <6 months was 0.653 D more hyperopic than that of non-breastfed children (P = 0.008, multiple linear regression). No significant association was observed between breastfeeding and AL. In conclusion, breastfeeding was associated with a decreased risk of myopia among children aged 6-12 years in Tianjin. Breastfeeding during the first 6 months of infancy was associated with more hyperopic SER. Furthermore, breastfeeding was associated with myopic refraction and was not related to AL, and this association could exist in childhood. PMID- 29968727 TI - Entomological signatures in honey: an environmental DNA metabarcoding approach can disclose information on plant-sucking insects in agricultural and forest landscapes. AB - Honeydew produced from the excretion of plant-sucking insects (order Hemiptera) is a carbohydrate-rich material that is foraged by honey bees to integrate their diets. In this study, we used DNA extracted from honey as a source of environmental DNA to disclose its entomological signature determined by honeydew producing Hemiptera that was recovered not only from honeydew honey but also from blossom honey. We designed PCR primers that amplified a fragment of mitochondrial cytochrome c oxidase subunit 1 (COI) gene of Hemiptera species using DNA isolated from unifloral, polyfloral and honeydew honeys. Ion Torrent next generation sequencing metabarcoding data analysis assigned Hemiptera species using a customized bioinformatic pipeline. The forest honeydew honeys reported the presence of high abundance of Cinara pectinatae DNA, confirming their silver fir forest origin. In all other honeys, most of the sequenced reads were from the planthopper Metcalfa pruinosa for which it was possible to evaluate the frequency of different mitotypes. Aphids of other species were identified from honeys of different geographical and botanical origins. This unique entomological signature derived by environmental DNA contained in honey opens new applications for honey authentication and to disclose and monitor the ecology of plant-sucking insects in agricultural and forest landscapes. PMID- 29968728 TI - LSD1-ERRalpha complex requires NRF1 to positively regulate transcription and cell invasion. AB - Lysine-specific demethylase 1 (LSD1) exerts dual effects on histone H3, promoting transcriptional repression via Lys4 (H3K4) demethylation or transcriptional activation through Lys9 (H3K9) demethylation. These activities are often exerted at transcriptional start sites (TSSs) and depend on the type of enhancer-bound transcription factor (TFs) with which LSD1 interacts. In particular, the Estrogen Receptor Related alpha (ERRalpha) TF interacts with LSD1 and switches its activities toward H3K9 demethylation, resulting in transcriptional activation of a set of common target genes. However, how are the LSD1-TF and, in particular LSD1-ERRalpha, complexes determined to act at TSSs is not understood. Here we show that promoter-bound nuclear respiratory factor 1 (NRF1), but not ERRalpha, is essential to LSD1 recruitment at the TSSs of positive LSD1-ERRalpha targets. In contrast to ERRalpha, NRF1 does not impact on the nature of LSD1 enzymatic activity. We propose a three factor model, in which the LSD1 histone modifier requires a TSS tethering factor (NRF1) as well as an activity inducer (ERRalpha) to transcriptionally activate common targets. The relevance of this common network is illustrated by functional data, showing that all three factors are required for cell invasion in an MMP1 (Matrix MetalloProtease 1)-dependent manner, the expression of which is regulated by NRF1/LSD1/ERRalpha-mediated H3K9me2 demethylation. PMID- 29968729 TI - Age-Related Changes in Global Motion Coherence: Conflicting Haemodynamic and Perceptual Responses. AB - Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response. PMID- 29968730 TI - Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) Utilizing Free-Text Clinical Narratives. AB - We propose a deep learning model - Probabilistic Prognostic Estimates of Survival in Metastatic Cancer Patients (PPES-Met) for estimating short-term life expectancy (>3 months) of the patients by analyzing free-text clinical notes in the electronic medical record, while maintaining the temporal visit sequence. In a single framework, we integrated semantic data mapping and neural embedding technique to produce a text processing method that extracts relevant information from heterogeneous types of clinical notes in an unsupervised manner, and we designed a recurrent neural network to model the temporal dependency of the patient visits. The model was trained on a large dataset (10,293 patients) and validated on a separated dataset (1818 patients). Our method achieved an area under the ROC curve (AUC) of 0.89. To provide explain-ability, we developed an interactive graphical tool that may improve physician understanding of the basis for the model's predictions. The high accuracy and explain-ability of the PPES Met model may enable our model to be used as a decision support tool to personalize metastatic cancer treatment and provide valuable assistance to the physicians. PMID- 29968731 TI - Comparison of intestinal bacterial and fungal communities across various xylophagous beetle larvae (Coleoptera: Cerambycidae). AB - The microbial gut communities associated with various xylophagous beetles offer great potential for different biotechnologies and elaboration of novel pest management strategies. In this research, the intestinal bacterial and fungal communities of various cerambycid larvae, including Acmaeops septentrionis, Acanthocinus aedilis, Callidium coriaceum, Trichoferus campestris and Chlorophorus herbstii, were investigated. The intestinal microbial communities of these Cerambycidae species were mostly represented by members of the bacterial phyla Proteobacteria and Actinobacteria and the fungal phylum Ascomycota. However, the bacterial and fungal communities varied by beetle species and between individual organisms. Furthermore, bacterial communities' metagenomes reconstruction indicated the genes that encode enzymes involved in the lignocellulose degradation (such as peroxidases, alpha-L-fucosidases, beta xylosidases, beta-mannosidases, endoglucanases, beta-glucosidases and others) and nitrogen fixation (nitrogenases). Most of the predicted genes potentially related to lignocellulose degradation were enriched in the T. campestris, A. aedilis and A. septentrionis larval gut consortia, whereas predicted genes affiliated with the nitrogenase component proteins were enriched in the T. campestris, A. septentrionis and C. herbstii larval gut consortia. Several bacteria and fungi detected in the current work could be involved in the nutrition of beetle larvae. PMID- 29968733 TI - Group size effects on inter-blink interval as an indicator of antipredator vigilance in wild baboons. AB - Vigilance in animals is an important means for predator detection. Animals living in groups reduce their predation risk as more individuals are present. In contrast to most other animals studied, many studies on primates do not support the prediction that individual vigilance will decline as group size increases. For animals to obtain visual information during vigilance behaviour, their eyes must be open. Therefore, if animals are able to perceive differential risk of predation, the inter-blink interval (eye-opening) should increase, and the blink duration (eye-closure) should decrease under higher predation risk. We tested this prediction by measuring inter-blink interval in wild anubis baboons (Papio anubis) in peripheral and centre individuals within a group, and between larger and smaller groups. We found that the inter-blink interval for young males, often located at the front edge of the group, was longer than that of adult males, adult females, and young females, often located in the center of the group, and that the inter-blink interval for adult males was longer when the group was smaller. These results suggest that inter-blink interval can be used as an indicator of primate vigilance toward predators. PMID- 29968732 TI - Tunable and switchable magnetic dipole patterns in nanostructured superconductors. AB - Design and manipulation of magnetic moment arrays have been at the focus of studying the interesting cooperative physical phenomena in various magnetic systems. However, long-range ordered magnetic moments are rather difficult to achieve due to the excited states arising from the relatively weak exchange interactions between the localized moments. Here, using a nanostructured superconductor, we investigate a perfectly ordered magnetic dipole pattern with the magnetic poles having the same distribution as the magnetic charges in an artificial spin ice. The magnetic states can simply be switched on/off by applying a current flowing through nanopatterned area. Moreover, by coupling magnetic dipoles with the pinned vortex lattice, we are able to erase the positive/negative poles, resulting in a magnetic dipole pattern of only one polarity, analogous to the recently predicted vortex ice. These switchable and tunable magnetic dipole patterns open pathways for the study of exotic ordering phenomena in magnetic systems. PMID- 29968734 TI - Author Correction: Causal Pathways from Blood Pressure to Larger QRS Amplitudes: a Mendelian Randomization Study. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29968735 TI - Broadband (550-1350 nm) diffuse optical characterization of thyroid chromophores. AB - Thyroid plays an important role in the endocrine system of the human body. Its characterization by diffuse optics can open new path ways in the non-invasive diagnosis of thyroid pathologies. Yet, the absorption spectra of tyrosine and thyroglobulin-key tissue constituents specific to the thyroid organ-in the visible to near infrared range are not fully available. Here, we present the optical characterization of tyrosine (powder), thyroglobulin (granular form) and iodine (aqueous solution) using a time domain broadband diffuse optical spectrometer in the 550-1350 nm range. Various systematic errors caused by physics of photo migration and sample inherent properties were effectively suppressed by means of advanced time domain diffuse optical methods. A brief comparison with various other known tissue constituents is presented, which reveals key spectral regions for the quantification of the thyroid absorbers in an in vivo scenario. PMID- 29968737 TI - Development of a screening strategy for new modulators of T cell receptor signaling and T cell activation. AB - Activation of the T cell receptor (TCR) leads to the generation of a network of signaling events critical to the developmental decision making and activation of T cells. Various experimental approaches continue to identify new signaling molecules, adaptor proteins, and other regulators of TCR signaling. We propose a screening strategy for the identification of small molecules affecting TCR signaling based on the uncoupling of TCR stimulation from cellular responses in developing thymocytes. We demonstrate that this strategy successfully identifies inhibitors of kinases already shown to act downstream of TCR engagement, as well as new inhibitors. The proposed strategy is easily scalable for high throughput screening and will contribute to the identification of new druggable targets in T cell activation. PMID- 29968736 TI - A selective high affinity MYC-binding compound inhibits MYC:MAX interaction and MYC-dependent tumor cell proliferation. AB - MYC is a key player in tumor development, but unfortunately no specific MYC targeting drugs are clinically available. MYC is strictly dependent on heterodimerization with MAX for transcription activation. Aiming at targeting this interaction, we identified MYCMI-6 in a cell-based protein interaction screen for small inhibitory molecules. MYCMI-6 exhibits strong selective inhibition of MYC:MAX interaction in cells and in vitro at single-digit micromolar concentrations, as validated by split Gaussia luciferase, in situ proximity ligation, microscale thermophoresis and surface plasmon resonance (SPR) assays. Further, MYCMI-6 blocks MYC-driven transcription and binds selectively to the MYC bHLHZip domain with a KD of 1.6 +/- 0.5 MUM as demonstrated by SPR. MYCMI 6 inhibits tumor cell growth in a MYC-dependent manner with IC50 concentrations as low as 0.5 MUM, while sparing normal cells. The response to MYCMI-6 correlates with MYC expression based on data from 60 human tumor cell lines and is abrogated by MYC depletion. Further, it inhibits MYC:MAX interaction, reduces proliferation and induces massive apoptosis in tumor tissue from a MYC-driven xenograft tumor model without severe side effects. Since MYCMI-6 does not affect MYC expression, it is a unique molecular tool to specifically target MYC:MAX pharmacologically and it has good potential for drug development. PMID- 29968738 TI - Strong Solar Radiation Forces from Anomalously Reflecting Metasurfaces for Solar Sail Attitude Control. AB - We examine the theoretical implications of incorporating metasurfaces on solar sails, and the effect they can have on the forces applied to the sail. This would enable a significant enhancement over state-of-the- art attitude control by demonstrating a novel, propellant-free and low-mass approach to induce a roll torque on the sail, which is a current limitation in present state-of-the-art technology. We do so by utilizing anomalous optical reflections from the metasurfaces to generate a net in-plane lateral force, which can lead to a net torque along the roll axis of the sail, in addition to the other spatial movements exhibited by the sail from solar radiation pressure. We characterize this net lateral force as a function of incidence angle. In addition, the influence of the phase gradients and anomalous conversion efficiencies characteristics of the metasurfaces are independently considered. The optimum incidence angle that corresponded with the maximum net lateral-to-normal force ratio was found to be -30 degrees for a metasurface exhibiting 75% anomalous conversion efficiency with a phase gradient of 0:71k0. PMID- 29968739 TI - Litter quality drives the differentiation of microbial communities in the litter horizon across an alpine treeline ecotone in the eastern Tibetan Plateau. AB - Cellulose and lignin are the main polymeric components of the forest litter horizon. We monitored microbial community composition using phospholipid fatty acid (PLFA) analysis and investigated the ligninolytic and cellulolytic enzyme activities of the litter horizon across an alpine treeline ecotone in the eastern Tibetan Plateau. The activities of ligninolytic and cellulolytic enzymes and the biomass of microbial PLFAs were higher in the initial stage of litter decomposition than in the latter stage in the three vegetation types (coniferous forest, alpine shrubland and alpine meadow). Soil microbial community structure varied significantly over the course of litter decomposition in the three vegetation types. Furthermore, the BIOENV procedure revealed that the carbon to nitrogen (C:N) ratio, carbon to phosphorus (C:P) ratio and moisture content (MC) were the most important determinants of microbial community structure in the initial stage of litter decomposition, whereas pH and the lignin concentration were the major factors influencing the microbial community structure in the later stage of litter decomposition. These findings indicate that litter quality drives the differentiation of microbial communities in the litter horizon across an alpine treeline ecotone in the eastern Tibetan Plateau. PMID- 29968740 TI - Proteomic and metagenomic insights into prehistoric Spanish Levantine Rock Art. AB - The Iberian Mediterranean Basin is home to one of the largest groups of prehistoric rock art sites in Europe. Despite the cultural relevance of prehistoric Spanish Levantine rock art, pigment composition remains partially unknown, and the nature of the binders used for painting has yet to be disclosed. In this work, we present the first omic analysis applied to one of the flagship Levantine rock art sites: the Valltorta ravine (Castellon, Spain). We used high throughput sequencing to provide the first description of the bacterial communities colonizing the rock art patina, which proved to be dominated by Firmicutes species and might have a protective effect on the paintings. Proteomic analysis was also performed on rock art microsamples in order to determine the organic binders present in Levantine prehistoric rock art pigments. This information could shed light on the controversial dating of this UNESCO Cultural Heritage, and contribute to defining the chrono-cultural framework of the societies responsible for these paintings. PMID- 29968741 TI - Exploring the amphibian exposome in an agricultural landscape using telemetry and passive sampling. AB - This is the first field study of its kind to combine radio telemetry, passive samplers, and pesticide accumulation in tissues to characterize the amphibian exposome as it relates to pesticides. Understanding how habitat drives exposure in individuals (i.e., their exposome), and how that relates to individual health is critical to managing species in an agricultural landscape where pesticide exposure is likely. We followed 72 northern leopard frogs (Lithobates pipiens) in two agricultural wetlands for insight into where and when individuals are at high risk of pesticide exposure. Novel passive sampling devices (PSDs) were deployed at sites where telemetered frogs were located, then moved to subsequent locations as frogs were radio-tracked. Pesticide concentration in PSDs varied by habitat and was greatest in agricultural fields where frogs were rarely found. Pesticide concentrations in frogs were greatest in spring when frogs were occupying wetlands compared to late summer when frogs occupied terrestrial habitats. Our results indicate that habitat and time of year influence exposure and accumulation of pesticides in amphibians. Our study illustrates the feasibility of quantifying the amphibian exposome to interpret the role of habitat use in pesticide accumulation in frogs to better manage amphibians in agricultural landscapes. PMID- 29968742 TI - Identification of novel DeltaNp63alpha-regulated miRNAs using an optimized small RNA-Seq analysis pipeline. AB - Advances in high-throughput sequencing have enabled profiling of microRNAs (miRNAs), however, a consensus pipeline for sequencing of small RNAs has not been established. We built and optimized an analysis pipeline using Partek Flow, circumventing the need for analyzing data via scripting languages. Our analysis assessed the effect of alignment reference, normalization method, and statistical model choice on biological data. The pipeline was evaluated using sequencing data from HaCaT cells transfected with either a non-silencing control or siRNA against DeltaNp63alpha, a p53 family member protein which is highly expressed in non melanoma skin cancer and shown to regulate a number of miRNAs. We posit that 1) alignment and quantification to the miRBase reference provides the most robust quantitation of miRNAs, 2) normalizing sample reads via Trimmed Mean of M-values is the most robust method for accurate downstream analyses, and 3) use of the lognormal with shrinkage statistical model effectively identifies differentially expressed miRNAs. Using our pipeline, we identified previously unrecognized regulation of miRs-149-5p, 18a-5p, 19b-1-5p, 20a-5p, 590-5p, 744-5p and 93-5p by DeltaNp63alpha. Regulation of these miRNAs was validated by RT-qPCR, substantiating our small RNA-Seq pipeline. Further analysis of these miRNAs may provide insight into DeltaNp63alpha's role in cancer progression. By defining the optimal alignment reference, normalization method, and statistical model for analysis of miRNA sequencing data, we have established an analysis pipeline that may be carried out in Partek Flow or at the command line. In this manner, our pipeline circumvents some of the major hurdles encountered during small RNA-Seq analysis. PMID- 29968744 TI - Melt-induced buoyancy may explain the elevated rift-rapid sag paradox during breakup of continental plates. AB - The division of the earth's surface into continents and oceans is a consequence of plate tectonics but a geological paradox exists at continent-ocean boundaries. Continental plate is thicker and lighter than oceanic plate, floating higher on the mantle asthenosphere, but it can rift apart by thinning and heating to form new oceans. In theory, continental plate subsides in proportion to the amount it is thinned and subsequently by the rate it cools down. However, seismic and borehole data from continental margins like the Atlantic show that the upper surface of many plates remains close to sea-level during rifting, inconsistent with its thickness, and subsides after breakup more rapidly than cooling predicts. Here we use numerical models to investigate the origin and nature of this puzzling behaviour with data from the Kwanza Basin, offshore Angola. We explore an idea where the continental plate is made increasingly buoyant during rifting by melt produced and trapped in the asthenosphere. Using finite element simulation, we demonstrate that partially molten asthenosphere combined with other mantle processes can counteract the subsidence effect of thinning plate, keeping it elevated by 2-3 km until breakup. Rapid subsidence occurs after breakup when melt is lost to the embryonic ocean ridge. PMID- 29968743 TI - Acute Exposure to Commonly Ingested Emulsifiers Alters Intestinal Mucus Structure and Transport Properties. AB - The consumption of generally regarded as safe emulsifiers has increased, and has been associated with an increased prevalence of inflammatory bowel and metabolic diseases, as well as an altered microbiome. The mucus barrier, which selectively controls the transport of particulates and microorganisms to the underlying epithelial layer, has been previously shown to be altered by dietary salts and lipids. However, the potential impact of emulsifiers on the protective mucus barrier, its permeability, and associated structural changes are not clear. In this study, we analyzed changes in the mucus barrier to both passively diffusing nanoparticles and actively swimming E. coli upon exposure to two emulsifiers, carboxymethylcellulose (CMC) and polysorbate 80 (Tween). When exposed to CMC, mucus pore size decreased, which resulted in significantly slower E. coli speed and particle diffusion rates through mucus. Tween exposure minimally impacted mucus microstructure and particle diffusion, but increased E. coli speed in mucus. Moreover, both emulsifiers appeared to alter mucus amount and thickness in rat intestinal tissue and mucus-producing cell cultures. These results indicate that acute exposure to emulsifiers impacts barrier and structural properties of intestinal mucus, modulating interactions between intestinal lumen contents, microbes, and underlying tissue, which may contribute to development of intestinal inflammation. PMID- 29968745 TI - Stem cells purified from human induced pluripotent stem cell-derived neural crest like cells promote peripheral nerve regeneration. AB - Strategies for therapeutic cell transplantation have been assessed for use in the treatment of massive peripheral nerve defects. To support safe and efficient cell transplantation, we have focused on the purification of cells using cell surface markers. Our group previously reported low-affinity nerve growth factor receptor (LNGFR)- and thymocyte antigen-1 (THY-1)-positive neural crest-like cells (LT NCLCs), generated from human induced pluripotent stem cells (hiPSCs). In the present study, we investigated the efficacy of transplantation of hiPSC-derived LT-NCLCs in a murine massive peripheral nerve defect model. Animals with a sciatic nerve defect were treated with a bridging silicone tube prefilled with LT NCLCs or medium in the transplantation (TP) and negative control (NC) groups, respectively. The grafted LT-NCLCs survived and enhanced myelination and angiogenesis, as compared to the NC group. Behavioral analysis indicated that motor functional recovery in the TP group was superior to that in the NC group, and similar to that in the autograft (Auto) group. LT-NCLCs promoted axonal regrowth and remyelination by Schwann cells. Transplantation of LT-NCLCs is a promising approach for nerve regeneration treatment of massive peripheral nerve defects. PMID- 29968746 TI - Angiogenin and Osteoprotegerin are type II muscle specific myokines protecting pancreatic beta-cells against proinflammatory cytokines. AB - Tissue cross-talk is emerging as a determinant way to coordinate the different organs implicated in glucose homeostasis. Among the inter-organ communication factors, muscle-secreted myokines can modulate the function and survival of pancreatic beta-cells. Using primary human myotubes from soleus, vastus lateralis and triceps brachii muscles, we report here that the impact of myokines on beta cells depends on fiber types and their metabolic status. We show that Type I and type II primary myotubes present specific mRNA and myokine signatures as well as a different sensitivity to TNF-alpha induced insulin resistance. Finally, we show that angiogenin and osteoprotegerin are triceps specific myokines with beta-cell protective actions against proinflammatory cytokines. These results suggest that type I and type II muscles could impact insulin secretion and beta-cell mass differentially in type 2 diabetes through specific myokines secretion. PMID- 29968747 TI - Tunable directional subwavelength acoustic antenna based on Mie resonance. AB - Modulating the emission pattern of classic sound sources with a sub-wavelength scale dimension is a challenging. In this letter, we demonstrate theoretically and experimentally that a Mie-resonance based antenna can be designed in various modes to effectively enhance the emissivity of the radiated power and directivity of radiation pattern. A 2.33-fold enhancement of the radiated power and an 8.93 fold enhancement of the sound intensity are achieved in the mainlobe direction. Furthermore, we propose reconfigurable antenna scanning where the selectable beam direction is free to be controlled from 0 degrees to 360 degrees . The tunable directional acoustic antenna offers a new way to control sound with the improved performance. PMID- 29968748 TI - Complex spectrum of phenobarbital effects in a mouse model of neonatal hypoxia induced seizures. AB - Seizures in neonates, mainly caused by hypoxic-ischemic encephalopathy, are thought to be harmful to the brain. Phenobarbital remains the first line drug therapy for the treatment of suspected neonatal seizures but concerns remain with efficacy and safety. Here we explored the short- and long-term outcomes of phenobarbital treatment in a mouse model of hypoxia-induced neonatal seizures. Seizures were induced in P7 mice by exposure to 5% O2 for 15 minutes. Immediately after hypoxia, pups received a single dose of phenobarbital (25 mg.kg-1) or saline. We observed that after administration of phenobarbital seizure burden and number of seizures were reduced compared to the hypoxic period; however, PhB did not suppress acute histopathology. Behavioural analysis of mice at 5 weeks of age previously subjected to hypoxia-seizures revealed an increase in anxiety-like behaviour and impaired memory function compared to control littermates, and these effects were not normalized by phenobarbital. In a seizure susceptibility test, pups previously exposed to hypoxia, with or without phenobarbital, developed longer and more severe seizures in response to kainic acid injection compared to control mice. Unexpectedly, mice treated with phenobarbital developed less hippocampal damage after kainic acid than untreated counterparts. The present study suggests phenobarbital treatment in immature mice does not improve the long lasting functional deficits induces by hypoxia-induced seizures but, unexpectedly, may reduce neuronal death caused by exposure to a second seizure event in later life. PMID- 29968749 TI - Fiber density of collagen grafts impacts rabbit urethral regeneration. AB - There is a need for efficient and "off-the-shelf" grafts in urethral reconstructive surgery. Currently available surgical techniques require harvesting of grafts from autologous sites, with increased risk of surgical complications and added patient discomfort. Therefore, a cost-effective and cell free graft with adequate regenerative potential has a great chance to be translated into clinical practice. Tubular cell-free collagen grafts were prepared by varying the collagen density and fiber distribution, thereby creating a polarized low fiber density collagen graft (LD-graft). A uniform, high fiber density collagen graft (HD-graft) was engineered as a control. These two grafts were implanted to bridge a 2 cm long iatrogenic urethral defect in a rabbit model. Histology revealed that rabbits implanted with the LD-graft had a better smooth muscle regeneration compared to the HD-graft. The overall functional outcome assessed by contrast voiding cystourethrography showed patency of the urethra in 90% for the LD-graft and in 66.6% for the HD-graft. Functional regeneration of the rabbit implanted with the LD-graft could further be demonstrated by successful mating, resulting in healthy offspring. In conclusion, cell-free low-density polarized collagen grafts show better urethral regeneration than high-density collagen grafts. PMID- 29968750 TI - Hexane-Isopropanolic Extract of Tungrymbai, a North-East Indian fermented soybean food prevents hepatic steatosis via regulating AMPK-mediated SREBP/FAS/ACC/HMGCR and PPARalpha/CPT1A/UCP2 pathways. AB - This study for the first time examined the prophylactic role of Tungrymbai, a well-known fermented soybean food of North-East India, against hepatic steatosis. Treatment with hexane-isopropanolic (2:1, HIET) but not hydro-alcoholic (70% ethanol, HAET) extract dose-dependently (0.1, 0.2, or 0.3 ug/mL) reduced the intracellular lipid accumulation as shown by lower triglyceride levels and both Oil Red O and Nile Red staining in palmitate (PA, 0.75 mM)-treated hepatocytes. Immunobloting, mRNA expression, and knock-down studies demonstrated the role of AMPK-mediated SREBP/FAS/ACC/HMGCR and PPARalpha/CPT1A/UCP2 signaling pathways in facilitating the beneficial role of HIET against lipid accumulation in PA-treated hepatocytes. Animal studies further showed a positive effect of HIET (20 ug/kg BW, 8 weeks, daily) in regulating AMPK/SREBP/PPARalpha signaling pathways and reducing body weight gain, plasma lipid levels, and hepatic steatosis in high fat diet (HFD)-fed mice. Histological analyses also revealed the beneficial effect of HIET in reducing hepatic fat accumulation in HFD mice. Chemical profiling (HRMS, IR, and HPLC) demonstrated the presence of menaquinone-7 (vitamin K2) as one of the bio-active principle(s) in HIET. Combining all, this study demonstrates the positive effect of HIET on reducing hepatic steatosis via regulating AMPK/SREBP/PPARalpha signaling pathway. PMID- 29968751 TI - Hybrid rf SQUID qubit based on high kinetic inductance. AB - We report development and microwave characterization of rf SQUID (Superconducting QUantum Interference Device) qubits, consisting of an aluminium-based Josephson junction embedded in a superconducting loop patterned from a thin film of TiN with high kinetic inductance. Here we demonstrate that the systems can offer small physical size, high anharmonicity, and small scatter of device parameters. The work constitutes a non-tunable prototype realization of an rf SQUID qubit built on the kinetic inductance of a superconducting nanowire, proposed in Phys. Rev. Lett. 104, 027002 (2010). The hybrid devices can be utilized as tools to shed further light onto the origin of film dissipation and decoherence in phase slip nanowire qubits, patterned entirely from disordered superconducting films. PMID- 29968752 TI - Tailoring recombinant lipases: keeping the His-tag favors esterification reactions, removing it favors hydrolysis reactions. AB - We determined the effect of the His-tag on the structure, activity, stability and immobilization of LipC12, a highly active lipase from a metagenomic library. We purified LipC12 with a N-terminal His-tag and then removed the tag using tobacco etch virus (TEV) protease. Circular dichroism analysis showed that the overall structure of LipC12 was largely unaffected by His-tag removal. The specific hydrolytic activities against natural and artificial substrates were significantly increased by the removal of the His-tag. On the other hand, His tagged LipC12 was significantly more active and stable in the presence of polar organic solvents than untagged LipC12. The immobilization efficiency on Immobead 150 was 100% for both forms of LipC12 and protein desorption studies confirmed that the His-tag does not participate in the covalent binding of the enzyme. In the case of immobilized LipC12, the His-tag negatively influenced the hydrolytic activity, as it had for the free lipase, however, it positively influenced the esterification activity. These results raise the possibility of tailoring recombinant lipases for different applications, where the His-tag may be retained or removed, as appropriate for the desired activity. PMID- 29968754 TI - The Significance of Interstitial Fibrosis on Left Ventricular Function in Hypertensive versus Hypertrophic Cardiomyopathy. AB - Extracellular volume (ECV) has been validated as a surrogate measure of interstitial fibrosis, that is increased in both hypertension-induced left ventricular hypertrophy (H-LVH) and hypertrophic cardiomyopathy (HCM). We aimed to explore the correlation between ECV and left ventricular cardiac function. Eighty-one patients with HCM, 44 with H-LVH and 35 controls were prospectively enrolled. Even among patients with normal diastolic function, patients in HCM group had increased- ECV. In terms of diastolic dysfunction (DD), a similar increase in ECV was associated with a larger percentage of patients with severe or moderate-to-severe DD in HCM group. In addition, there was a compensatory increase in the left ventricular ejection fraction (LVEF) in HCM, but no hyperdynamic LVEF was observed in H-LVH. ECV was negatively correlated with LVEF in the late gadolinium enhancement (+) (LGE+) subgroups in the H-LVH group, while no significant linear correlation was observed in HCM group. The increased ECV in HCM patients with normal diastolic function warrants further exploration of the prognostic value of ECV assessments in the early stages of HCM. The associations between ECV and left ventricular functional parameters differed and taking both LGE and ECV into account might be reasonable way to differentiate between the two disorders. PMID- 29968753 TI - Control over the emerging chirality in supramolecular gels and solutions by chiral microvortices in milliseconds. AB - The origin of homochirality in life is a fundamental mystery. Symmetry breaking and subsequent amplification of chiral bias are regarded as one of the underlying mechanisms. However, the selection and control of initial chiral bias in a spontaneous mirror symmetry breaking process remains a great challenge. Here we show experimental evidences that laminar chiral microvortices generated within asymmetric microchambers can lead to a hydrodynamic selection of initial chiral bias of supramolecular systems composed of exclusively achiral molecules within milliseconds. The self-assembled nuclei with the chirality sign affected by the shear force of enantiomorphic microvortices are subsequently amplified into almost absolutely chirality-controlled supramolecular gels or nanotubes. In contrast, turbulent vortices in stirring cuvettes fail to select the chirality of supramolecular gels. This study reveals that a laminar chiral microflow can induce enantioselection far from equilibrium, and provides an insight on the origin of natural homochirality. PMID- 29968755 TI - Expression of periaxin (PRX) specifically in the human cerebrovascular system: PDZ domain-mediated strengthening of endothelial barrier function. AB - Regulation of cerebral endothelial cell function plays an essential role in changes in blood-brain barrier permeability. Proteins that are important for establishment of endothelial tight junctions have emerged as critical molecules, and PDZ domain containing-molecules are among the most important. We have discovered that the PDZ-domain containing protein periaxin (PRX) is expressed in human cerebral endothelial cells. Surprisingly, PRX protein is not detected in brain endothelium in other mammalian species, suggesting that it could confer human-specific vascular properties. In endothelial cells, PRX is predominantly localized to the nucleus and not tight junctions. Transcriptome analysis shows that PRX expression suppresses, by at least 50%, a panel of inflammatory markers, of which 70% are Type I interferon response genes; only four genes were significantly activated by PRX expression. When expressed in mouse endothelial cells, PRX strengthens barrier function, significantly increases transendothelial electrical resistance (~35%; p < 0.05), and reduces the permeability of a wide range of molecules. The PDZ domain of PRX is necessary and sufficient for its barrier enhancing properties, since a splice variant (S-PRX) that contains only the PDZ domain, also increases barrier function. PRX also attenuates the permeability enhancing effects of lipopolysaccharide. Collectively, these studies suggest that PRX could potentially regulate endothelial homeostasis in human cerebral endothelial cells by modulating inflammatory gene programs. PMID- 29968756 TI - Motor-like DNA motion due to an ATP-hydrolyzing protein under nanoconfinement. AB - We report that long double-stranded DNA confined to quasi-1D nanochannels undergoes superdiffusive motion under the action of the enzyme T4 DNA ligase in the presence of necessary co-factors. Inside the confined environment of the nanochannel, double-stranded DNA molecules stretch out due to self-avoiding interactions. In absence of a catalytically active enzyme, we see classical diffusion of the center of mass. However, cooperative interactions of proteins with the DNA can lead to directed motion of DNA molecules inside the nanochannel. Here we show directed motion in this configuration for three different proteins (T4 DNA ligase, MutS, E. coli DNA ligase) in the presence of their energetic co factors (ATP, NAD+). PMID- 29968757 TI - Transcriptional synergy as an emergent property defining cell subpopulation identity enables population shift. AB - Single-cell RNA sequencing allows defining molecularly distinct cell subpopulations. However, the identification of specific sets of transcription factors (TFs) that define the identity of these subpopulations remains a challenge. Here we propose that subpopulation identity emerges from the synergistic activity of multiple TFs. Based on this concept, we develop a computational platform (TransSyn) for identifying synergistic transcriptional cores that determine cell subpopulation identities. TransSyn leverages single cell RNA-seq data, and performs a dynamic search for an optimal synergistic transcriptional core using an information theoretic measure of synergy. A large scale TransSyn analysis identifies transcriptional cores for 186 subpopulations, and predicts identity conversion TFs between 3786 pairs of cell subpopulations. Finally, TransSyn predictions enable experimental conversion of human hindbrain neuroepithelial cells into medial floor plate midbrain progenitors, capable of rapidly differentiating into dopaminergic neurons. Thus, TransSyn can facilitate designing strategies for conversion of cell subpopulation identities with potential applications in regenerative medicine. PMID- 29968758 TI - Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1. AB - The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes. PMID- 29968759 TI - Identification of pathways and genes associated with synovitis in osteoarthritis using bioinformatics analyses. AB - Synovitis in osteoarthritis (OA) is a very common condition. However, its underlying mechanism is still not well understood. This study aimed to explore the molecular mechanisms of synovitis in OA. The gene expression profile GSE82107 (downloaded from the Gene Expression Omnibus database) included 10 synovial tissues of the OA patients and 7 synovial tissues of healthy people. Subsequently, differentially expressed gene (DEG) analysis, GO (gene ontology) enrichment analysis, pathway analysis, pathway network analysis, and gene signal network analysis were performed using Gene-Cloud of Biotechnology Information (GCBI). A total of 1,941 DEGs consisting of 1,471 upregulated genes and 470 downregulated genes were determined. Genes such as PSMG3, LRP12 MIA-RAB4B, ETHE1, SFXN1, DAZAP1, RABEP2, and C9orf16 were significantly regulated in synovitis of OA. In particular, the MAPK signalling pathway, apoptosis, and pathways in cancer played the most important roles in the pathway network. The relationships between these pathways were also analysed. Genes such as NRAS, SPHK2, FOS, CXCR4, PLD1, GNAI2, and PLA2G4F were strongly implicated in synovitis of OA. In summary, this study indicated that several molecular mechanisms were implicated in the development and progression of synovitis in OA, thus improving our understanding of OA and offering molecular targets for future therapeutic advances. PMID- 29968760 TI - Changes in intestinal gene expression and microbiota composition during late pregnancy are mouse strain dependent. AB - Hormones and placental factors are thought to underlie the maternal immunological changes during pregnancy. However, as several intestinal microbiota are linked to immune modulations, we hypothesized that the intestinal microbiota are altered during pregnancy in favor of species associated with pregnancy associated immune modulations. We studied the fecal microbiota composition (MITchip) and intestinal and peripheral immune cells (microarray and flow cytometry) in pregnant and non pregnant C57BL/6 and BALB/c mice. Pregnancy influenced intestinal microbiota diversity and composition, however in a mouse strain dependent way. Pregnant BALB/c mice had, among others, a relative higher abundance of Lactobacillus paracasei et rel., Roseburia intestinalis et rel. and Eubacterium hallii et rel., as compared to non-pregnant BALB/c mice, while the microbiota composition in B6 mice hardly changed during pregnancy. Additionally, intestinal immunological pathways were changed during pregnancy, however again in a mouse strain dependent way. Correlations between various bacteria and immunological genes were observed. Our data do support a role for the microbiome in changing immune responses in pregnancy. However, other factors are also involved, such as for instance changes in SCFA or changes in sensitivity to bacteria, since although immunological changes are observed in B6 mice, hardly any changes in microbiota were found in this strain. Follow up studies are needed to study the exact relationship between these parameters. PMID- 29968761 TI - 3D Maps of Mineral Composition and Hydroxyapatite Orientation in Fossil Bone Samples Obtained by X-ray Diffraction Computed Tomography. AB - Whether hydroxyapatite (HA) orientation in fossilised bone samples can be non destructively retrieved and used to determine the arrangement of the bone matrix and the location of muscle attachments (entheses), is a question of high relevance to palaeontology, as it facilitates a detailed understanding of the (micro-)anatomy of extinct species with no damage to the precious fossil specimens. Here, we report studies of two fossil bone samples, specifically the tibia of a 300-million-year-old tetrapod, Discosauriscus austriacus, and the humerus of a 370-million-year-old lobe-finned fish, Eusthenopteron foordi, using XRD-CT - a combination of X-ray diffraction (XRD) and computed tomography (CT). Reconstructed 3D images showing the spatial mineral distributions and the local orientation of HA were obtained. For Discosauriscus austriacus, details of the muscle attachments could be discerned. For Eusthenopteron foordi, the gross details of the preferred orientation of HA were deduced using three tomographic datasets obtained with orthogonally oriented rotation axes. For both samples, the HA in the bone matrix exhibited preferred orientation, with the unit cell c-axis of the HA crystallites tending to be parallel with the bone surface. In summary, we have demonstrated that XRD-CT combined with an intuitive reconstruction procedure is becoming a powerful tool for studying palaeontological samples. PMID- 29968763 TI - Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept. AB - There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naive to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8-9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733 11.267]in MC-patients and 5.1 months [95% CI: 4.098-6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5-6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370-0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations. PMID- 29968762 TI - Actin polymerization is activated by terahertz irradiation. AB - Polymerization of monomeric actin into filaments has pivotal roles in cell motility, growth, differentiation, and gene expression. Therefore, techniques of manipulating actin polymerization, including actin-binding chemicals, have been developed for understanding and regulating multiple biological functions. Here, we demonstrate that irradiation with terahertz (THz) waves is a novel method of modulating actin polymerization. When actin polymerization reaction is performed under irradiation with 0.46 THz waves generated by a Gyrotron, actin polymerization was observed to be activated by monitoring the fluorescence of pyrene actin fluorophores. We also observed the number of actin filaments under a fluorescence microscope using the polymerized actin probe SiR-actin. The number of actin filaments was increased by 3.5-fold after THz irradiation for 20 min. When the THz irradiation was applied to a steady-state actin solution, in which elongation and depolymerization of actin filaments were equilibrated, increased actin polymerization was observed, suggesting that the THz irradiation activates actin polymerization, at least in the elongation process. These results suggest that THz waves could be applied for manipulating biomolecules and cells. PMID- 29968764 TI - Optimal neural inference of stimulus intensities. AB - In natural data, the class and intensity of stimuli are correlated. Current machine learning algorithms ignore this ubiquitous statistical property of stimuli, usually by requiring normalized inputs. From a biological perspective, it remains unclear how neural circuits may account for these dependencies in inference and learning. Here, we use a probabilistic framework to model class specific intensity variations, and we derive approximate inference and online learning rules which reflect common hallmarks of neural computation. Concretely, we show that a neural circuit equipped with specific forms of synaptic and intrinsic plasticity (IP) can learn the class-specific features and intensities of stimuli simultaneously. Our model provides a normative interpretation of IP as a critical part of sensory learning and predicts that neurons can represent nontrivial input statistics in their excitabilities. Computationally, our approach yields improved statistical representations for realistic datasets in the visual and auditory domains. In particular, we demonstrate the utility of the model in estimating the contrastive stress of speech. PMID- 29968765 TI - Optimization of growth and production parameters of walnut (Juglans regia) saplings with response surface methodology. AB - Straw mulching is an effective conservation tillage tool that utilizes waste resources and reduces environmental pollution. To determine the optimal levels of quality, placement and quantity of straw mulching, we performed a field experiment that used the Box-Behnken design combined with response surface methodology. The treatments designed for walnut saplings (Juglans regia) considered three independent variables: quality, placement, and quantity of straw mulching. Tree height of walnut saplings (THW) and net photosynthesis rate (NPR) were used as the response variables in a full, quadratic polynomial model. Analysis of variance (ANOVA) results showed that the selected models were significant (P < 0.05), expressing ideal relationships between the independent and dependent variables (R2 >= 0.9225). The optimum conditions for the THW and NPR responses were determined to be a straw mulching quality which mixed rice and rapeseed straws, a straw mulching placement which covered the entire soil surface of experimental plots, and a straw mulching quantity applied as 3 kg/m2 (i.e., the low level). This optimized scheme of straw mulching combinations offers an alternate choice for optimizing the growth and potential yield of walnut saplings, but practical field experiments should also be carried out to obtain more site-specific results. PMID- 29968766 TI - Validation of Assaying Carcinoembryonic Antigen in Human Serum by Using Immunomagnetic Reduction. AB - Immunomagnetic reduction (IMR) is a method to assay biomolecules by utilizing antibody functionalized magnetic nanoparticles. For clinical validation, important analytic performances of assaying carcinoembryonic antigen (CEA) using IMR are characterized. Furthermore, IMR is applied to assay carcinoembryonic antigen (CEA) in human serum for clinical validation. A total of 118 healthy controls and 79 patients with colorectal cancer (CRC) are recruited in this study. For comparison, assays using chemiluminometric immunoassay (CLIA) are also done for quantizing CEA in these serum samples. The results reveal a high correlation in terms of serum CEA concentration detected via IMR and CLIA is found (r = 0.963). However, IMR shows higher clinical sensitivity and specificity than those of CLIA. Moreover, the rate of false positives for smoking subjects is clearly reduced through the use of IMR. All the results demonstrate IMR is a promising alternative assay for serum CEA to diagnose CRC. PMID- 29968767 TI - Striatonigral neurons divide into two distinct morphological-physiological phenotypes after chronic L-DOPA treatment in parkinsonian rats. AB - Dendritic regression of striatal spiny projection neurons (SPNs) is a pathological hallmark of Parkinson's disease (PD). Here we investigate how chronic dopamine denervation and dopamine replacement with L-DOPA affect the morphology and physiology of direct pathway SPNs (dSPNS) in the rat striatum. We used a lentiviral vector optimized for retrograde labeling (FuG-B-GFP) to identify dSPNs in rats with 6-hydroxydopamine (6-OHDA) lesions. Changes in morphology and physiology of dSPNs were assessed through a combination of patch clamp recordings and two photon microscopy. The 6-OHDA lesion caused a significant reduction in dSPN dendritic complexity. Following chronic L-DOPA treatment, dSPNs segregated into two equal-sized clusters. One group (here called "cluster-1"), showed sustained dendritic atrophy and a partially normalized electrophysiological phenotype. The other one ("cluster-2") exhibited dendritic regrowth and a strong reduction of intrinsic excitability. Interestingly, FosB/?FosB induction by L-DOPA treatment occurred preferentially in cluster-2 dSPNs. Our study demonstrates the feasibility of retrograde FuG-B-GFP labeling to study dSPNs in the rat and reveals, for the first time, that a subgroup of dSPNs shows dendritic sprouting in response to chronic L-DOPA treatment. Investigating the mechanisms and significance of this response will greatly improve our understanding of the adaptations induced by dopamine replacement therapy in PD. PMID- 29968768 TI - Transcranial focused ultrasound neuromodulation of the human primary motor cortex. AB - Transcranial focused ultrasound is an emerging form of non-invasive neuromodulation that uses acoustic energy to affect neuronal excitability. The effect of ultrasound on human motor cortical excitability and behavior is currently unknown. We apply ultrasound to the primary motor cortex in humans using a novel simultaneous transcranial ultrasound and magnetic stimulation paradigm that allows for concurrent and concentric ultrasound stimulation with transcranial magnetic stimulation (TMS). This allows for non-invasive inspection of the effect of ultrasound on motor neuronal excitability using the motor evoked potential (MEP). We test the effect of ultrasound on single pulse MEP recruitment curves and paired pulse protocols including short interval intracortical inhibition (SICI) and intracortical facilitation (ICF). In addition, we test the effect of ultrasound to motor cortex on a stimulus response reaction time task. Results show ultrasound inhibits the amplitude of single-pulse MEPs and attenuates intracortical facilitation but does not affect intracortical inhibition. Ultrasound also reduces reaction time on a simple stimulus response task. This is the first report of the effect of ultrasound on human motor cortical excitability and motor behavior and confirms previous results in the somatosensory cortex that ultrasound results in effective neuronal inhibition that confers a performance advantage. PMID- 29968770 TI - Estimation of chimpanzee age based on DNA methylation. AB - In wild animal conservation, knowing the age of an individual animal is extremely beneficial. However, estimating the age is difficult for many species. Recently, epigenetics-based methods of estimating age have been reported. These studies were predominantly on humans with few reports on other animals, especially wild animals. In the present study, a chimpanzee (Pan troglodytes) age prediction model was developed based on the ELOVL2, CCDC102B, and ZNF423 genes that may also have application in human age prediction. Pyrosequencing was used to measure methylation in 20 chimpanzee blood samples and correlation between age and methylation status was calculated. Age and methylation of sites in ELOVL2 and CCDC102B were significantly correlated and an age prediction model was created using these genes. In the regression equation using only ELOVL2, the highest correlation coefficient was 0.741, with a mean absolute deviation (MAD) of 5.41, compared with the combination of ELOVL2 and CCDC102B, where the highest correlation coefficient was 0.742 and the MAD was 5.41. Although larger MADs were observed in chimpanzees than in humans based on these genes, the results indicate the feasibility of estimating chimpanzee age using DNA methylation, and can have implications in understanding the ecology of chimpanzees and chimpanzee conservation. PMID- 29968769 TI - Dual role of HDAC10 in lysosomal exocytosis and DNA repair promotes neuroblastoma chemoresistance. AB - Drug resistance is a leading cause for treatment failure in many cancers, including neuroblastoma, the most common solid extracranial childhood malignancy. Previous studies from our lab indicate that histone deacetylase 10 (HDAC10) is important for the homeostasis of lysosomes, i.e. acidic vesicular organelles involved in the degradation of various biomolecules. Here, we show that depleting or inhibiting HDAC10 results in accumulation of lysosomes in chemotherapy resistant neuroblastoma cell lines, as well as in the intracellular accumulation of the weakly basic chemotherapeutic doxorubicin within lysosomes. Interference with HDAC10 does not block doxorubicin efflux from cells via P-glycoprotein inhibition, but rather via inhibition of lysosomal exocytosis. In particular, intracellular doxorubicin does not remain trapped in lysosomes but also accumulates in the nucleus, where it promotes neuroblastoma cell death. Our data suggest that lysosomal exocytosis under doxorubicin treatment is important for cell survival and that inhibition of HDAC10 further induces DNA double-strand breaks (DSBs), providing additional mechanisms that sensitize neuroblastoma cells to doxorubicin. Taken together, we demonstrate that HDAC10 inhibition in combination with doxorubicin kills neuroblastoma, but not non-malignant cells, both by impeding drug efflux and enhancing DNA damage, providing a novel opportunity to target chemotherapy resistance. PMID- 29968771 TI - Antibody responses to alpha-Gal in African children vary with age and site and are associated with malaria protection. AB - Naturally-acquired antibody responses to malaria parasites are not only directed to protein antigens but also to carbohydrates on the surface of Plasmodium protozoa. Immunoglobulin M responses to alpha-galactose (alpha-Gal) (Galalpha1 3Galbeta1-4GlcNAc-R)-containing glycoconjugates have been associated with protection from P. falciparum infection and, as a result, these molecules are under consideration as vaccine targets; however there are limited field studies in endemic populations. We assessed a wide breadth of isotype and subclass antibody response to alpha-Gal in children from Mozambique (South East Africa) and Ghana (West Africa) by quantitative suspension array technology. We showed that anti-alpha-Gal IgM, IgG and IgG1-4 levels vary mainly depending on the age of the child, and also differ in magnitude in the two sites. At an individual level, the intensity of malaria exposure to P. falciparum and maternally transferred antibodies affected the magnitude of alpha-Gal responses. There was evidence for a possible protective role of anti-alpha-Gal IgG3 and IgG4 antibodies. However, the most consistent findings were that the magnitude of IgM responses to alpha-Gal was associated with protection against clinical malaria over a one-year follow up period, especially in the first months of life, while IgG levels correlated with malaria risk. PMID- 29968772 TI - Detection of the Cell Cycle-Regulated Negative Feedback Phosphorylation of Mitogen-Activated Protein Kinases in Breast Carcinoma using Nanofluidic Proteomics. AB - Mitogen-activated protein kinases (MAPKs) play an important role in the regulation of cell proliferation, oncogenic transformation, and drug resistance. This study examined the capability of nanofluidic proteomics to identify aberrations in the MAPK signaling cascade, monitor its drug response, and guide the rational design of intervention strategies. Specifically, the protein post translational modification (PTM) profiles of MEK1, MEK2, and ERK1/2 were measured in breast carcinoma and breast cancer cell lines. Nanofluidic proteomics revealed hyper-phosphorylation of MAPKs in breast carcinoma and breast cancer cells treated with kinase inhibitors that interfere with cell cycle regulation, such as dinaciclib, an inhibitor of cyclin-dependent kinases, and rigosertib, an inhibitor of polo-like kinase 1. A pMEK1 (Thr286) phosphor-isoform, which serves as a biomarker of cell cycle-regulated negative feedback phosphorylation in breast cancer cells, was detected in breast carcinoma. Inhibition of the MAPK pathway with dabrafenib, a B-Raf inhibitor, or trametinib, a MEK1/2 inhibitor, suppressed both the positively regulated phosphorylation of MAPKs and the negatively regulated phosphorylation of MEK1. Interestingly, the combinations of dabrafenib and rigosertib or trametinib and rigosertib permitted the suppression of positively regulated MAPK phosphorylation together with the promotion of negatively regulated MEK1 phosphorylation. The effectiveness of protein PTM guided drug combinations for inhibition of the MAPK pathway remains to be experimentally tested. Via protein PTM profiling, nanofluidic proteomics provides a robust means to detect anomalies in the MAPK signaling cascade, monitor its drug response, and guide the possible design of drug combinations for MAPK pathway-focused targeting. PMID- 29968773 TI - Phospholipase D1 regulation of TNF-alpha protects against responses to LPS. AB - Sepsis is a systemic inflammatory disorder with organ dysfunction and represents the leading cause of mortality in non-coronary intensive care units. A key player in septic shock is Tumor Necrosis Factor-alpha (TNF-alpha). Phospholipase (PL)D1 is involved in the regulation of TNF-alpha upon ischemia/reperfusion injury in mice. In this study we analyzed the impact of PLD1 in the regulation of TNF alpha, inflammation and organ damage in experimental sepsis. PLD1 deficiency increased survival of mice and decreased vital organ damage after LPS injections. Decreased TNF-alpha plasma levels and reduced migration of leukocytes and platelets into lungs was associated with reduced apoptosis in lung and liver tissue of PLD1 deficient mice. PLD1 deficient platelets contribute to preserved outcome after LPS-induced sepsis because platelets exhibit an integrin activation defect suggesting reduced platelet activation in PLD1 deficient mice. Furthermore, reduced thrombin generation of PLD1 deficient platelets might be responsible for reduced fibrin formation in lungs suggesting reduced disseminated intravascular coagulation (DIC). The analysis of Pld1fl/fl-PF4-Cre mice revealed that migration of neutrophils and cell apoptosis in septic animals is not due to platelet-mediated processes. The present study has identified PLD1 as a regulator of innate immunity that may be a new target to modulate sepsis. PMID- 29968774 TI - Saturated fatty acid attenuates anti-obesity effect of green tea. AB - Green tea and its major polyphenol epigallocatechin-3-O-gallate (EGCG) have suppressive effect on dietary obesity. However, it remains unsolved what type of diet on which they exhibit high or low anti-obesity effect. In the present study, we investigated whether anti-obesity effect of green tea differs depending on composition of fats or fatty acids that consist high-fat (HF) diet in mouse model. Green tea extract (GTE) intake dramatically suppressed weight gain and fat accumulation induced by olive oil-based HF diet, whereas the effects on those induced by beef tallow-based HF diet were weak. GTE also effectively suppressed obesity induced by unsaturated fatty acid-enriched HF diet with the stronger effect compared with that induced by saturated fatty acid-enriched HF diet. These differences would be associated with the increasing action of GTE on expression of PPARdelta signaling pathway-related genes in the white adipose tissue. Expressions of genes relating to EGCG signaling pathway that is critical for exhibition of physiological effects of EGCG were also associated with the different effects of GTE. Here, we show that anti-obesity effect of GTE differs depending on types of fats or fatty acids that consist HF diet and could be attenuated by saturated fatty acid. PMID- 29968775 TI - Spermine increases acetylation of tubulins and facilitates autophagic degradation of prion aggregates. AB - Autolysosomal dysfunction and unstable microtubules are hallmarks of chronic neurodegenerative diseases associated with misfolded proteins. Investigation of impaired protein quality control and clearance systems could therefore provide an important avenue for intervention. To investigate this we have used a highly controlled model for protein aggregation, an in vitro prion system. Here we report that prion aggregates traffic via autolysosomes in the cytoplasm. Treatment with the natural polyamine spermine clears aggregates by enhancing autolysosomal flux. We demonstrated this by blocking the formation of mature autophagosomes resulting in accumulation of prion aggregates in the cytoplasm. Further we investigated the mechanism of spermine's mode of action and we demonstrate that spermine increases the acetylation of microtubules, which is known to facilitate retrograde transport of autophagosomes from the cellular periphery to lysosomes located near the nucleus. We further report that spermine facilitates selective autophagic degradation of prion aggregates by binding to microtubule protein Tubb6. This is the first report in which spermine and the pathways regulated by it are applied as a novel approach towards clearance of misfolded prion protein and we suggest that this may have important implication for the broader family of protein misfolding diseases. PMID- 29968776 TI - Relationship between interleukin (IL)-6 and brain morphology in drug-naive, first episode major depressive disorder using surface-based morphometry. AB - There is a growing body of evidence to support the involvement of proinflammatory cytokines in the pathophysiology of depression; however, no previous studies have examined the relationship between cytokines and the brain morphology of patients with major depressive disorder (MDD). We therefore evaluated the relationship between serum cytokine levels and cortical thinning during the first depressive episode in drug-naive patients with MDD. We measured the serum cytokine levels (IL-1beta, IL-6, IFN-gamma, and TNFalpha), and whole-brain cortical thickness and hippocampal subfield volumes on brain magnetic resonance imaging (MRI) using surface-based morphometry in 40 patients with MDD and 47 healthy volunteers (controls). Only the serum IL-6 level was significantly higher in patients with MDD than in controls. The prefrontal cortex (PFC) thickness was significantly reduced in patients with MDD, and showed a significant inverse correlation with the serum IL-6 level. Although high serum IL-6 levels were correlated with reduced left subiculum and right CA1, CA3, CA4, GC-DG, subiculum, and whole hippocampus volumes, the presence or absence of MDD had no effect on the volume of any hippocampal subfields. Our results suggest that IL-6 may play a key role in the morphological changes in the PFC during the early stage of MDD. PMID- 29968777 TI - Estimating missing values in China's official socioeconomic statistics using progressive spatiotemporal Bayesian hierarchical modeling. AB - Due to a large number of missing values, both spatially and temporally, China has not published a complete official socioeconomic statistics dataset at the county level, which is the country's basic scale of official statistics data collection. We developed a procedure to impute the missing values under the Bayesian hierarchical modeling framework. The procedure incorporates two novelties. First, it takes into account spatial autocorrelations and temporal trends for those easier-to-impute variables with small missing percentages. Second, it further uses the first-step complete variables as covariate information to improve the modeling of more-difficult-to-impute variables with large missing percentages. We applied this progressive spatiotemporal (PST) method to China's official socioeconomic statistics during 2002-2011 and compared it with four other widely used imputation methods, including k-nearest neighbors (kNN), expectation maximum (EM), singular value decomposition (SVD) and random forest (RF). The results show that the PST method outperforms these methods, thus proving the effects of sophisticatedly incorporating the additional spatial and temporal information and progressively utilizing the covariate information. This study has an outcome that allows China to construct a complete socioeconomic dataset and establishes a methodology that can be generally useful for estimating missing values in large spatiotemporal datasets. PMID- 29968778 TI - Pirfenidone decreases mesothelioma cell proliferation and migration via inhibition of ERK and AKT and regulates mesothelioma tumor microenvironment in vivo. AB - Malignant mesothelioma is an aggressive cancer with poor prognosis. It is characterized by prominent extracellular matrix, mesenchymal tumor cell phenotypes and chemoresistance. In this study, the ability of pirfenidone to alter mesothelioma cell proliferation and migration as well as mesothelioma tumor microenvironment was evaluated. Pirfenidone is an anti-fibrotic drug used in the treatment of idiopathic pulmonary fibrosis and has also anti-proliferative activities. Mesothelioma cell proliferation was decreased by pirfenidone alone or in combination with cisplatin. Pirfenidone also decreased significantly Transwell migration/invasion and 3D collagen invasion. This was associated with increased BMP pathway activity, decreased GREM1 expression and downregulation of MAPK/ERK and AKT/mTOR signaling. The canonical Smad-mediated TGF-beta signaling was not affected by pirfenidone. However, pirfenidone blocked TGF-beta induced upregulation of ERK and AKT pathways. Treatment of mice harboring mesothelioma xenografts with pirfenidone alone did not reduce tumor proliferation in vivo. However, pirfenidone modified the tumor microenvironment by reducing the expression of extracellular matrix associated genes. In addition, GREM1 expression was downregulated by pirfenidone in vivo. By reducing two major upregulated pathways in mesothelioma and by targeting tumor cells and the microenvironment pirfenidone may present a novel anti-fibrotic and anti-cancer adjuvant therapy for mesothelioma. PMID- 29968779 TI - Improved recovery time and sensitivity to H2 and NH3 at room temperature with SnOx vertical nanopillars on ITO. AB - Nanostructured SnO2 is a promising material for the scalable production of portable gas sensors. To fully exploit their potential, these gas sensors need a faster recovery rate and higher sensitivity at room temperature than the current state of the art. Here we demonstrate a chemiresistive gas sensor based on vertical SnOx nanopillars, capable of sensing < 5 ppm of H2 at room temperature and 10 ppt at 230 degrees C. We test the sample both in vacuum and in air and observe an exceptional improvement in the performance compared to commercially available gas sensors. In particular, the recovery time for sensing NH3 at room temperature is more than one order of magnitude faster than a commercial SnO2 sensor. The sensor shows an unique combination of high sensitivity and fast recovery time, matching the requirements on materials expected to foster widespread use of portable and affordable gas sensors. PMID- 29968780 TI - Comparative studies of alignment, alignment-free and SVM based approaches for predicting the hosts of viruses based on viral sequences. AB - Predicting the hosts of newly discovered viruses is important for pandemic surveillance of infectious diseases. We investigated the use of alignment-based and alignment-free methods and support vector machine using mononucleotide frequency and dinucleotide bias to predict the hosts of viruses, and applied these approaches to three datasets: rabies virus, coronavirus, and influenza A virus. For coronavirus, we used the spike gene sequences, while for rabies and influenza A viruses, we used the more conserved nucleoprotein gene sequences. We compared the three methods under different scenarios and showed that their performances are highly correlated with the variability of sequences and sample size. For conserved genes like the nucleoprotein gene, longer k-mers than mono- and dinucleotides are needed to better distinguish the sequences. We also showed that both alignment-based and alignment-free methods can accurately predict the hosts of viruses. When alignment is difficult to achieve or highly time consuming, alignment-free methods can be a promising substitute to predict the hosts of new viruses. PMID- 29968782 TI - The Association between Daytime Napping Characteristics and Bone Mineral Density in Elderly Thai Women without Osteoporosis. AB - Low bone mass is more prevalent with increasing age. Studies have found associations between sleep duration, sleep quality and obstructive sleep apnea and bone mineral density (BMD). However, less is known about the relationship between daytime napping and BMD. We aimed to investigate the association between daytime napping and BMD in elderly Thai women. Demographic data, lifestyle information and sleep characteristics were obtained by interviewing 387 elderly women. Weight and height were measured. Serum 25-hydroxyvitamin D [25(OH)D] was measured by radioimmunoassay. BMD was measured by dual-energy X-ray absorptiometry (DXA). Higher BMI and having type 2 diabetes (T2DM) were correlated with higher lumbar spine 2-4 (L2-4) BMD, while younger age, higher BMI and higher serum 25(OH)D level were correlated with higher femoral neck (FN) and total hip (TH) BMD. After adjusting for age, age at menopause, BMI, 25(OH)D level and T2DM, a higher frequency of weekly daytime napping was associated with lower FN and TH BMD but not at L2-4 BMD. Additionally, longer daytime napping duration was negatively associated with BMD at TH. In summary higher frequency and longer duration of daytime napping are associated with lower femoral BMD in elderly women. Mechanisms underlying these associations should be further explored. PMID- 29968783 TI - Modality-specific temporal constraints for state-dependent interval timing. AB - The ability to discriminate temporal intervals in the milliseconds-to-seconds range has been accounted for by proposing that duration is encoded in the dynamic change of a neuronal network state. A critical limitation of such networks is that their activity cannot immediately return to the initial state, a restriction that could hinder the processing of intervals presented in rapid succession. Empirical evidence in the literature consistently shows impaired duration discrimination performance for 100 ms intervals demarked by short auditory stimuli immediately preceded by a similar interval. Here we tested whether a similar interference is present with longer intervals (300 ms) demarked either by auditory or by visual stimuli. Our results show that while temporal estimates of auditory stimuli in this range are not affected by the interval between them, duration discrimination with this duration is significantly impaired with visual intervals presented in rapid succession. The difference in performance between modalities is overall consistent with state-dependent temporal computations, as it suggests that the limits due to slow neuronal dynamics greatly depends on the sensory modality with which the intervals are demarked, in line with the idea of intrinsic, modality-specific neural mechanisms for interval timing. PMID- 29968781 TI - Enteric Species F Human Adenoviruses use Laminin-Binding Integrins as Co Receptors for Infection of Ht-29 Cells. AB - The enteric species F human adenovirus types 40 and 41 (HAdV-40 and -41) are the third most common cause of infantile gastroenteritis in the world. Knowledge about HAdV-40 and -41 cellular infection is assumed to be fundamentally different from that of other HAdVs since HAdV-40 and -41 penton bases lack the alphaV integrin-interacting RGD motif. This motif is used by other HAdVs mainly for internalization and endosomal escape. We hypothesised that the penton bases of HAdV-40 and -41 interact with integrins independently of the RGD motif. HAdV-41 transduction of a library of rodent cells expressing specific human integrin subunits pointed to the use of laminin-binding alpha2-, alpha3- and alpha6 containing integrins as well as other integrins as candidate co-receptors. Specific laminins prevented internalisation and infection, and recombinant, soluble HAdV-41 penton base proteins prevented infection of human intestinal HT 29 cells. Surface plasmon resonance analysis demonstrated that HAdV-40 and -41 penton base proteins bind to alpha6-containing integrins with an affinity similar to that of previously characterised penton base:integrin interactions. With these results, we propose that laminin-binding integrins are co-receptors for HAdV-40 and -41. PMID- 29968784 TI - The piecewise parabolic method for elastic-plastic flow in solids. AB - A numerical technique of high-order piecewise parabolic method in combination of HLLD ("D" denotes Discontinuities) Riemann solver is developed for the numerical simulation of elastic-plastic flow. The introduction of the plastic effect is realized by decomposing the total deformation gradient tensor as the product of elastic and plastic deformation gradient tensors and adding plastic source term to the conservation law model equation with the variable of the elastic deformation gradient tensor. For the solution of the resulting inhomogeneous equation system, a temporal splitting strategy is adopted and a semi-implicit scheme is performed to solve the ODES in the plastic step, which is conducted to account for the contributions from plastic source terms. As seen from the results of test cases involving large deformation and high strain rate, the computational model used can reflect the characteristics of constitutive relation of material under strong impact action and our numerical method can realize the exact simulation of the elastic-plastic behavior of solid material, especially the accurate capture of the elastic-plastic waves. Further, it could also deal with high-speed impact problems with multi-material components, catching material interfaces correctly and keeping the interfaces sharp, when combined with interface tracking technique such as the level-set algorithm. PMID- 29968785 TI - Collagen Fingerprinting and the Earliest Marine Mammal Hunting in North America. AB - The submersion of Late Pleistocene shorelines and poor organic preservation at many early archaeological sites obscure the earliest effects of humans on coastal resources in the Americas. We used collagen fingerprinting to identify bone fragments from middens at four California Channel Island sites that are among the oldest coastal sites in the Americas (~12,500-8,500 cal BP). We document Paleocoastal human predation of at least three marine mammal families/species, including northern elephant seals (Mirounga angustirostris), eared seals (Otariidae), and sea otters (Enhydra lutris). Otariids and elephant seals are abundant today along the Pacific Coast of North America, but elephant seals are rare in late Holocene (<1500 cal BP) archaeological sites. Our data support the hypotheses that: (1) marine mammals helped fuel the peopling of the Americas; (2) humans affected marine mammal biogeography millennia before the devastation caused by the historic fur and oil trade; and (3) the current abundance and distribution of recovering pinniped populations on the California Channel Islands may mirror a pre-human baseline. PMID- 29968787 TI - SSPIM: a beam shaping toolbox for structured selective plane illumination microscopy. AB - Selective plane illumination microscopy (SPIM) represents a preferred method in dynamic tissue imaging, because it combines high spatiotemporal resolution with low phototoxicity. The OpenSPIM system was developed to provide an accessible and flexible microscope set-up for non-specialist users. Here, we report Structured SPIM (SSPIM), which offers an open-source, user-friendly and compact toolbox for beam shaping to be applied within the OpenSPIM platform. SSPIM is able to generate digital patterns for a wide range of illumination beams including static and spherical Gaussian beams, Bessel beams and Airy beams by controlling the pattern of a Spatial Light Modulator (SLM). In addition, SSPIM can produce patterns for structured illumination including incoherent and coherent array beams and tiling for all types of the supported beams. We describe the workflow of the toolbox and demonstrate its application by comparing experimental data with simulation results for a wide range of illumination beams. Finally, the capability of SSPIM is investigated by 3D imaging of Drosophila embryos using scanned Gaussian, Bessel and array beams. SSPIM provides an accessible toolbox to generate and optimize the desired beam patterns and helps adapting the OpenSPIM system towards a wider range of biological samples. PMID- 29968788 TI - Examining the utility of the CD64 index compared with other conventional indices for early diagnosis of neonatal infection. AB - As specific clinical manifestations and detection tools for early neonatal infections are lacking, early detection and treatment are ongoing challenges. The present study aimed to investigate the role and clinical significance of the CD64 index in comparison with conventional examination indices (WBC, PCT and CRP) for the early diagnosis of neonatal infection. Of 74 in-patient newborns, non-sepsis (non-specific infection but free of sepsis), sepsis and control [newborns with ABO hemolytic disease of the newborn (ABOHDN) but without infection] groups involved 32, 16 and 26 cases, respectively. Peripheral blood WBC, PCT, CRP and CD64 indices were acquired for all groups. The sepsis group showed significantly higher WBC, PCT and CRP levels than the control group. Compared with the non sepsis group, the sepsis group demonstrated significant increases in PCT but not in WBC or CRP. Compared with the control group, the non-sepsis and sepsis groups had higher CD64 indices. Combined, compared with the WBC, PCT and CRP indices, the CD64 index is unique in its capacity to diagnose neonatal infections early. The CD64 index combined with other conventional indices may lay a basis for the future early diagnosis and effective treatment of neonatal infections. PMID- 29968786 TI - Quasi-Periodic Patterns of Neural Activity improve Classification of Alzheimer's Disease in Mice. AB - Resting state (rs)fMRI allows measurement of brain functional connectivity and has identified default mode (DMN) and task positive (TPN) network disruptions as promising biomarkers for Alzheimer's disease (AD). Quasi-periodic patterns (QPPs) of neural activity describe recurring spatiotemporal patterns that display DMN with TPN anti-correlation. We reasoned that QPPs could provide new insights into AD network dysfunction and improve disease diagnosis. We therefore used rsfMRI to investigate QPPs in old TG2576 mice, a model of amyloidosis, and age-matched controls. Multiple QPPs were determined and compared across groups. Using linear regression, we removed their contribution from the functional scans and assessed how they reflected functional connectivity. Lastly, we used elastic net regression to determine if QPPs improved disease classification. We present three prominent findings: (1) Compared to controls, TG2576 mice were marked by opposing neural dynamics in which DMN areas were anti-correlated and displayed diminished anti-correlation with the TPN. (2) QPPs reflected lowered DMN functional connectivity in TG2576 mice and revealed significantly decreased DMN-TPN anti correlations. (3) QPP-derived measures significantly improved classification compared to conventional functional connectivity measures. Altogether, our findings provide insight into the neural dynamics of aberrant network connectivity in AD and indicate that QPPs might serve as a translational diagnostic tool. PMID- 29968789 TI - Discovery of peptide probes to modulate oxytocin-type receptors of insects. AB - The oxytocin/vasopressin signalling system is conserved across the animal kingdom. In insects, the role of oxytocin-type (inotocin) neuropeptides has only been studied in locusts, beetles and ants, but their physiology continues to be poorly understood. One reason for this knowledge deficit is the lack of available research tools to complement functional genomics efforts. Consequently, ligands to probe insect inotocin receptors are essential. In this study, we sought to identify novel agonists and antagonists of the inotocin receptor from the representative model species Tribolium castaneum and Lasius niger. Drawing upon known ligands of the human receptors, we examined the pharmacology of the plant derived cyclotide kalata B7 and the synthetic oxytocin analogue atosiban. Kalata B7 is a weak partial agonist of both inotocin receptors. This is the first reported direct interaction of cyclotides with an insect receptor, an observation that may explain their presumed role in herbivore defence. Furthermore, we discovered atosiban is an antagonist of the Tribolium receptor, which may provide a useful probe to investigate the functionality of inotocin signalling in beetles and related insect species. Our findings will enable further examination of insect inotocin receptor pharmacology and physiology, and may trigger studies to comprehend the interaction of plant cyclotides and insects. PMID- 29968790 TI - Switchable genome editing via genetic code expansion. AB - Multiple applications of genome editing by CRISPR-Cas9 necessitate stringent regulation and Cas9 variants have accordingly been generated whose activity responds to small ligands, temperature or light. However, these approaches are often impracticable, for example in clinical therapeutic genome editing in situ or gene drives in which environmentally-compatible control is paramount. With this in mind, we have developed heritable Cas9-mediated mammalian genome editing that is acutely controlled by the cheap lysine derivative, Lys(Boc) (BOC). Genetic code expansion permitted non-physiological BOC incorporation such that Cas9 (Cas9BOC) was expressed in a full-length, active form in cultured somatic cells only after BOC exposure. Stringently BOC-dependent, heritable editing of transgenic and native genomic loci occurred when Cas9BOC was expressed at the onset of mouse embryonic development from cRNA or Cas9BOC transgenic females. The tightly controlled Cas9 editing system reported here promises to have broad applications and is a first step towards purposed, spatiotemporal gene drive regulation over large geographical ranges. PMID- 29968791 TI - Development of optokinetic tracking software for objective evaluation of visual function in rodents. AB - The aim of this study was to develop software that performs the optokinetic tracking assessment without the involvement of experimenters to increase the objectivity of the test. To check the effectiveness of the software, several videos were analyzed and the results were compared to those produced by two experimenters. Videos consisted of visual acuity and contrast sensitivity tests on normal animals and pigmented P23H rats (animal model of retinitis pigmentosa). Our software showed a reasonably high success rate: in approximately 78% of the cases, both the software program and the experimenters were in agreement, including the direction of rotation. The software detected 7% false positive cases, 10% false negative cases, and it was wrong in 5% of the cases. Decrease in visual function with age in pigmented P23H rats was observed from the first time interval, although minimum thresholds were found in visual parameters at advanced ages. We developed simple software based on current functions included in the Matlab image processing toolbox that was able to recognize, with a reasonably high percentage of success, the subtle head movements of the rodent produced when visual perception of the optokinetic optotype occurs. PMID- 29968792 TI - High level of IgG4 as a biomarker for a new subset of inflammatory bowel disease. AB - The roles of B and plasma cells in the pathogenesis of inflammatory bowel disease (IBD) are largely unrevealed. Data on the characteristics of IgG4 in patients with IBD are scarce. In this case-control study, serum IgG4 levels were comparable between patients with IBD and healthy individuals, whereas patients with IBD had dramatically higher mucosal IgG4 counts than healthy individuals. In patients with UC, mucosal IgG4 counts were positively correlated with serum IgG4 levels, serum IgG4/IgG ratios, and the Mayo Index; serum IgG4 levels and IgG4/IgG ratios were associated with a history of intestinal surgery and medications. A significant mucosal IgG4 count was found in 33.3% of patients with IBD, whereas, elevated serum IgG4 levels were found in only 9.9% of patients with IBD. Lesions were more severe and extensive in IBD patients with high levels of serum and mucosal IgG4. High levels of serum and mucosal IgG4 decreased after treatment with glucocorticoids or other immunosuppressants. High IgG4 level may be a biomarker for a new subset of IBD. More studies are warranted to explore this new subset of IBD for personalized therapy in the future. PMID- 29968793 TI - A new genus and tribe of freshwater mussel (Unionidae) from Southeast Asia. AB - The freshwater mussel genus Oxynaia Haas, 1911 is thought to be comprised of two geographically disjunct and morphologically variable species groups but the monophyly of this taxon has yet to be tested in any modern cladistic sense. This generic hypothesis has important systematic and biogeographic implications as Oxynaia is the type genus of the currently recognized tribe Oxynaiini (Parreysiinae) and is one of the few genera thought to cross several biogeographically important barriers in Southeast Asia. Morphological and molecular data clearly demonstrate that Oxynaia is not monophyletic, and the type species and its allies (O. jourdyi group) belong to the Unioninae, and more specifically as members of the genus Nodularia Conrad, 1853. Therefore, neither Oxynaia syn. nov. nor Oxynaiini Starobogatov, 1970 are applicable to the Parreysiinae and in the absence of an available name, Indochinella gen. nov. and Indochinellini trib. nov. are described. Several combinations are proposed as follows: Indochinella pugio (Benson, 1862) gen. et comb. nov., Nodularia jourdyi (Morlet, 1886) comb. res., N. gladiator (Ancey, 1881) comb. res., N. diespiter (Mabille, 1887) comb. res. and N. micheloti (Morlet, 1886) comb. res. Finally, we provide an updated freshwater biogeographic division of Southeast Asia. PMID- 29968794 TI - High Magnesium Corrosion Rate has an Effect on Osteoclast and Mesenchymal Stem Cell Role During Bone Remodelling. AB - The aim of this study was to gain an understanding on the collective cellular effects of magnesium (Mg) corrosion products on the behaviour of cells responsible for bone formation and remodelling. The response of mesenchymal stem cells (MSCs) and osteoclast cells to both soluble (Mg ions) and insoluble (granule) corrosion products were recapitulated in vitro by controlling the concentration of the corrosion products. Clearance of corrosion granules by MSCs was also inspected by TEM analysis at sub-cellular level. The effect of Mg corrosion products varied depending on the state of differentiation of cells, concentration and length of exposure. The presence of the corrosion products significantly altered the cells' metabolic and proliferative activities, which further affected cell fusion/differentiation. While cells tolerated higher than physiological range of Mg concentration (16 mM), concentrations below 10 mM were beneficial for cell growth. Furthermore, MSCs were shown to contribute to the clearance of intercellular corrosion granules, whilst high concentrations of corrosion products negatively impacted on osteoclast progenitor cell number and mature osteoclast cell function. PMID- 29968795 TI - Periodic breathing in patients with NALCN mutations. AB - Biallelic mutations in NALCN are responsible for infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1). Common features of this condition include severe neonatal-onset hypotonia and profound global developmental delay. Given the rarity of this condition, long-term natural history studies are limited. Here, we present a 9-year-old male with a homozygous nonsense mutation in NALCN (c.3910C>T, p.Arg1304X) leading to profound intellectual disability, seizures, feeding difficulties, and significant periodic breathing. Breathing irregularity was also reported in three previous patients; similar to our patient, those children demonstrated periodic breathing that was characterized by alternating apneic periods with deep, rapid breathing. As the phenotype associated with NALCN mutations continues to be delineated, attention should be given to abnormal respiratory patterns, which may be an important distinguishing feature of this condition. PMID- 29968796 TI - ChemDIS-Mixture: an online tool for analyzing potential interaction effects of chemical mixtures. AB - The assessment of bioactivity and toxicity for mixtures remains a challenging work. Although several computational models have been developed to accelerate the evaluation of chemical-chemical interaction, a specific biological endpoint should be defined before applying the models that usually relies on clinical and experimental data. The development of computational methods is desirable for identifying potential biological endpoints of mixture interactions. To facilitate the identification of potential effects of mixture interactions, a novel online system named ChemDIS-Mixture is proposed to analyze the shared target proteins, and common enriched functions, pathways, and diseases affected by multiple chemicals. Venn diagram tools have been implemented for easy analysis and visualization of interaction targets and effects. Case studies have been provided to demonstrate the capability of ChemDIS-Mixture for identifying potential effects of mixture interactions in clinical studies. ChemDIS-Mixture provides useful functions for the identification of potential effects of coexposure to multiple chemicals. ChemDIS-Mixture is freely accessible at http://cwtung.kmu.edu.tw/chemdis/mixture . PMID- 29968797 TI - Global assessment of early warning signs that temperature could undergo regime shifts. AB - Climate change metrics have been used to quantify the exposure of geographic areas to different facets of change and relate these facets to different threats and opportunities for biodiversity at a global scale. In parallel, a suite of indicators have been developed to detect approaching transitions between alternative stable states in ecological systems at a local scale. Here, we explore whether particular geographic areas over the world display evidence for upcoming critical transitions in the temperature regime using five Early Warning Indicators (EWIs) commonly used in the literature. Although all EWIs revealed strong spatial variations regarding the likelihood of approaching transitions we found differences regarding the strength and the distribution of trends across the world, suggesting either that different mechanisms might be at play or that EWIs differ in their ability to detect approaching transitions. Nonetheless, a composite EWI, constructed from individual EWIs, showed congruent trends in several areas and highlighted variations across latitudes, between marine and terrestrial systems and among ecoregions within systems. Although the underlying mechanisms are unclear, our results suggest that some areas over the world might change toward an alternative temperature regime in the future with potential implications for the organisms inhabiting these areas. PMID- 29968798 TI - Monitoring ratio of carbon to nitrogen (C/N) in wheat and barley leaves by using spectral slope features with branch-and-bound algorithm. AB - Ratio of carbon to nitrogen concentration (C/N) that can illuminate metabolic status of C and N in crop leaves is one valuable indicator for crop nutrient diagnosis. This study explored the feasibility of using spectral slope features from hyperspectral measurements with Branch-and-Bound (BB) algorithm to monitor leaf C/N in wheat and barley. Experimental data from barley in 2010 and wheat in 2012 were collected and used. The analyses prove that leaf C/N is closely related to leaf N concentration (LNC), which implies that it is feasible to apply spectral technology to monitor leaf C/N in that LNC may have been effectivly estimated by hyperspectral measurements. The results also show that many spectral slope features proposed in this study exhibit the significant correlations with leaf C/N. The best slope feature could evaluate changes of leaf C/N well, with R2 of 0.63 for wheat, 0.68 for barley and 0.65 for both species combined, respectively. using BB algorithm with input of optiaml four slope features can improve the accuracy of leaf C/N estimations with R2 over 0.81. It is concluded that using the spectral slope new features with BB method appears very promising and potential for remotely monitoring leaf C/N in crops. PMID- 29968799 TI - New betaN-octadecanoyl-5-hydroxytryptamide: antinociceptive effect and possible mechanism of action in mice. AB - The present study examined the potential antinociceptive activity of C18 5-HT (betaN-octadecanoyl-5-hydroxytryptamide) using chemical and thermal nociception models in mice. Orally administered C18 5-HT (0.1, 1 and 10 mg/kg) produced significant dose-dependent antinociceptive effects in formalin-, capsaicin- and glutamate-induced licking models. This compound also induced a significant increase in the response to thermal stimuli in the hot plate test, and its antinociceptive effect was not related to muscle relaxant or sedative actions. In a thermal hyperalgesia model, C18 5-HT presented an anti-hyperalgesic profile as evidenced by the increase in the response time of the animals. Furthermore, intraperitoneal (i.p) pretreatment with naloxone (a non-selective opioid receptor antagonist, 1 mg/kg), ondansetron (serotoninergic receptor antagonist (5-HT3 subtype), 0.5 mg/kg) or AM241 (CB1 cannabinoid receptor antagonist, 1 mg/kg) reversed the antinociceptive effects of C18 5-HT in the hot plate model. In the formalin-induced licking model, pretreatment with naloxone reversed the antinociceptive effects of C18 5-HT, as demonstrated by an increase in the paw licking response when compared with the C18 5-HT-treated group. These findings suggest that C18 5-HT has peripheral and central antinociceptive effects and that its mechanism of action involves, ate least in part, opioid, serotoninergic and cannabinoid pathways. PMID- 29968800 TI - The influence of meteorological factors on tuberculosis incidence in Southwest China from 2006 to 2015. AB - The influence of meteorological determinants on tuberculosis (TB) incidence remains severely under-discussed, especially through the perspective of time series analysis. In the current study, we used a distributed lag nonlinear model (DLNM) to analyze a 10-year series of consecutive surveillance data. We found that, after effectively controlling for autocorrelation, the changes in meteorological factors related to temperature, humidity, wind and sunshine were significantly associated with subsequent fluctuations in TB incidence: average temperature was inversely associated with TB incidence at a lag period of 2 months; total precipitation and minimum relative humidity were also inversely associated with TB incidence at lag periods of 3 and 4 months, respectively; average wind velocity and total sunshine hours exhibited an instant rather than lagged influence on TB incidence. Our study results suggest that preceding meteorological factors may have a noticeable effect on future TB incidence; informed prevention and preparedness measures for TB can therefore be constructed on the basis of meteorological variations. PMID- 29968801 TI - Higher dialysate calcium concentration is associated with incident myocardial infarction among diabetic patients with low bone turnover: a longitudinal study. AB - This is a longitudinal study on 53,560 hemodialysis patients from the Japan Renal Data Registry. Predictor was D[Ca] >=3.0 vs 2.5 mEq/L. Outcomes were the first CV events during 1-year observation period. Association of D[Ca] with CV events and effect modifications were tested using multivariate logistic regression analyses. Diabetes mellitus (DM) was a significant effect modifier for association of higher D[Ca] and myocardial infarction (MI) (OR: 1.26 (1.03-1.55) among DM and 0.86 (0.72-1.03) among non-DM, p for interaction <0.01). The effect size was not affected by further adjustment for serum albumin-corrected Ca or intact parathyroid hormone (iPTH) levels, but was attenuated by adjustment for intradialytic change in serum Ca concentration (DeltaCa) (1.16 [0.89-1.51]). Among DM, D[Ca] >=3.0 mEq/L was significantly associated with MI in the first tertile of corrected Ca or iPTH <=60 pg/ml (p for interaction 0.03 and 0.03, respectively). In conclusion, higher D[Ca] was associated with incident MI in DM, especially with low serum Ca or iPTH levels. Attenuation of the effect size by adjustment for DeltaCa and stratified analyses suggest that larger Ca influx during dialysis with higher D[Ca] in patients suggestive of low bone turnover leads to vascular calcification and subsequent MI in DM. PMID- 29968803 TI - A low-cost and high-performance thin-film composite forward osmosis membrane based on an SPSU/PVC substrate. AB - A low-cost sulfonated polysulfone (SPSU)/poly(vinyl chloride) (PVC) substrate based high-performance thin-film composite (TFC) forward osmosis (FO) membrane was fabricated in this work. The results showed that the morphologies of the substrates were looser and more porous, and the porosity, pure water permeability, surface hydrophilicity, and average pore size of the substrates significantly improved after the SPSU was introduced into the PVC substrates. Furthermore, the SPSU/PVC-based TFC membranes exhibited rougher, looser and less crosslinked polyamide active layers than the neat PVC-based TFC membrane. The water permeability obviously increased, and the structure parameter dramatically declined. Moreover, the FO performance significantly improved (e.g. the water flux of TFC2.5 reached 25.53/48.37 LMH under FO/PRO mode by using 1.0 M NaCl/DI water as the draw/feed solution, while the specific salt flux exhibited a low value of 0.10/0.09 g/L). According to the results, it can be concluded that 2.5% of SPSU was the optimal blend ratio, which exhibited the lowest sulfonated material blend ratio compared to the data reported in the literature. Hence, this is a feasible and low-cost fabrication approach for high-performance FO membrane by using the cheap PVC and low blend-ratio SPSU as the membrane materials. PMID- 29968802 TI - Adolescent social stress increases anxiety-like behavior and ethanol consumption in adult male and female C57BL/6J mice. AB - Exposure to social stress is an important risk factor for comorbid affective disorders and problem alcohol use. To better understand mechanisms involved in social stress-induced affective disorder and alcohol use co-morbidity, we studied the effects of adolescent social stress on anxiety- and depression-like behaviors and binge-like ethanol consumption. Male and female C57BL/6J mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence (postnatal days, PND, 25-59) and then tested for anxiety-like behavior in the elevated plus maze and a novel open field environment, or depression-like behavior using the forced swim test on PND 64-66. Mice were then tested for binge-like ethanol consumption using the Drinking-in-the-Dark model. Male and female mice exposed to adolescent CVSS had increased adult anxiety-like behavior and increased locomotor adaptation to a novel environment. Further, CVSS mice consumed significantly more ethanol, but not saccharin, than controls. Despite group differences in both anxiety-like behavior and ethanol consumption, there was no relationship between these outcomes within individual mice. These data suggest that exposure to adolescent social stress is an important risk factor for later alcohol use and affective behaviors, but that social stress does not necessarily dictate co-morbidity of these outcomes. PMID- 29968804 TI - Cold atmospheric plasma causes a calcium influx in melanoma cells triggering CAP induced senescence. AB - Cold atmospheric plasma (CAP) is a promising approach in anti-cancer therapy, eliminating cancer cells with high selectivity. However, the molecular mechanisms of CAP action are poorly understood. In this study, we investigated CAP effects on calcium homeostasis in melanoma cells. We observed increased cytoplasmic calcium after CAP treatment, which also occurred in the absence of extracellular calcium, indicating the majority of the calcium increase originates from intracellular stores. Application of previously CAP-exposed extracellular solutions also induced cytoplasmic calcium elevations. A substantial fraction of this effect remained when the application was delayed for one hour, indicating the chemical stability of the activating agent(s). Addition of ryanodine and cyclosporin A indicate the involvement of the endoplasmatic reticulum and the mitochondria. Inhibition of the cytoplasmic calcium elevation by the intracellular chelator BAPTA blocked CAP-induced senescence. This finding helps to understand the molecular influence and the mode of action of CAP on tumor cells. PMID- 29968805 TI - Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. AB - The pathogenesis of ME/CFS, a disease characterized by fatigue, cognitive dysfunction, sleep disturbances, orthostatic intolerance, fever, irritable bowel syndrome (IBS), and lymphadenopathy, is poorly understood. We report biomarker discovery and topological analysis of plasma metabolomic, fecal bacterial metagenomic, and clinical data from 50 ME/CFS patients and 50 healthy controls. We confirm reports of altered plasma levels of choline, carnitine and complex lipid metabolites and demonstrate that patients with ME/CFS and IBS have increased plasma levels of ceramide. Integration of fecal metagenomic and plasma metabolomic data resulted in a stronger predictive model of ME/CFS (cross validated AUC = 0.836) than either metagenomic (cross-validated AUC = 0.745) or metabolomic (cross-validated AUC = 0.820) analysis alone. Our findings may provide insights into the pathogenesis of ME/CFS and its subtypes and suggest pathways for the development of diagnostic and therapeutic strategies. PMID- 29968806 TI - Different gaze strategies during eye versus hand tracking of a moving target. AB - The ability to visually track, using smooth pursuit eye movements, moving objects is critical in both perceptual and action tasks. Here, by asking participants to view a moving target or track it with their hand, we tested whether different task demands give rise to different gaze strategies. We hypothesized that during hand tracking, in comparison to eye tracking, the frequency of catch-up saccades would be lower, and the smooth pursuit gain would be greater, because it limits the loss of stable retinal and extra-retinal information due to saccades. In our study participants viewed a visual target that followed a smooth but unpredictable trajectory in a horizontal plane and were instructed to either track the target with their gaze or with a cursor controlled by a manipulandum. Although the mean distance between gaze and target was comparable in both tasks, we found, consistent with our hypothesis, an increase in smooth pursuit gain and a decrease in the frequency of catch-up saccades during hand tracking. We suggest that this difference in gaze behavior arises from different tasks demands. Whereas keeping gaze close to the target is important in both tasks, obtaining stable retinal and extra-retinal information is critical for guiding hand movement. PMID- 29968807 TI - Different changes of microarchitectures of cortical and cancellous bones in sheep femoral head after long-term glucocorticoid interventions. AB - This study investigatedthe different effects of long-term glucocorticoid (GC) interventions on the microarchitectures of cortical and cancellous bones of the femoral head. Eighteen female skeletal mature sheep were randomly allocated into 3 groups, 6 each. Group 1 received prednisolone interventions (0.60 mg/kg/day, 5 times weekly) for 7 months. Group 2 received the same interventions as Group 1 and then further observed 3 months without interventions. Control Group was left nonintervention. After killing the animals, all femoral heads were scanned by micro-CT to determine their microstructural properties. In cancellous bone of femoral head, GC interventions led to significant decrease of bone volume fraction, trabecular thickness, trabecular separation, but increase of structure model index and bone surface density (p < 0.05). While in cortical bone, there were no differences between the Group 1 and in microstructural properties (p > 0.05) except greater trabecular thickness in the control group. In addition, three months after cessation of glucocorticoid interventions, most microstructural properties of cancellous bone were significant reversed, but not cortical thickness of femoral head. In contrast to cancellous bone, the microarchitectures of cortical bone were not changed obviously after long-term GC interventions. PMID- 29968808 TI - Synergy of Physico-chemical and Biological Experiments for Developing a Cyclooxygenase-2 Inhibitor. AB - The physiological consequences of COX-2 overexpression in the development of cancer, diabetes and neurodegenerative diseases have made this enzyme a promising therapeutic target. Herein, COX-2 active site was analyzed and new molecules were designed. We identified a highly potent molecule (S)-3a with IC50 value and the selectivity for COX-2 0.6 nM and 1666, respectively. The MTD of (S)-3a was 2000 mg kg-1 and its pharmacokinetic studies in rat showed t1/2 7.5 h. This compound reversed acetic acid induced analgesia and carragennan induced inflammation by 50% and 25% in rat when used at a dose 10 mg kg-1. Mechanistically, it was found that compound (S)-3a inhibits COX-2. Overall, the combination of physico-chemical and biological experiments facilitated the development of a new lead molecule to anti-inflammatory drug. PMID- 29968809 TI - Elimination of all redundant climbing fiber synapses requires granule cells in the postnatal cerebellum. AB - Different afferent synapse populations interact to control the specificity of connections during neuronal circuit maturation. The elimination of all but one climbing-fiber onto each Purkinje cell during the development of the cerebellar cortex is a particularly well studied example of synaptic refinement. The suppression of granule cell precursors by X irradiation during postnatal days 4 to 7 prevents this synaptic refinement, indicating a critical role for granule cells. Several studies of cerebellar development have suggested that synapse elimination has a first phase which is granule cell-independent and a second phase which is granule cell-dependent. In this study, we show that sufficiently strong irradiation restricted to postnatal days 5 or 6 completely abolishes climbing fiber synaptic refinement, leaving the olivo-cerebellar circuit in its immature configuration in the adult, with up to 5 climbing fibers innervating the Purkinje cell in some cases. This implies that the putative early phase of climbing fiber synapse elimination can be blocked by irradiation-induced granule cell loss if this loss is sufficiently large, and thus indicates that the entire process of climbing fiber synapse elimination requires the presence of an adequate number of granule cells. The specific critical period for this effect appears to be directly related to the timing of Purkinje cell and granule cell development in different cerebellar lobules, indicating a close, spatiotemporal synchrony between granule-cell development and olivo-cerebellar synaptic maturation. PMID- 29968810 TI - Upregulation of chemokine CXCL10 enhances chronic pulmonary inflammation in tree shrew collagen-induced arthritis. AB - Chronic pulmonary inflammation (CPI) gives rise to serious lung injuries in rheumatoid arthritis (RA) patients. However, the molecular mechanism underlying the pathogenesis of RA-associated CPI remains little understood. Here we established a novel tree shrew-based collagen-induced arthritis (TsCIA) model to study RA-associated CPI. Our results showed that typical CPI but not fibrosis developed pathologically in the TsCIA model. Furthermore, abnormal up-regulation of pulmonary chemokine CXCL10 was directly associated with lung damage. Specific blockage of CXCR3 (a CXCL10 receptor) significantly decreased the severity of CPI by decreasing the recruitment of inflammatory cells. Therefore, CXCL10 is proposed as a key player responsible for the development of TsCIA-associated CPI. Our findings also suggest that CXCR3 could be developed as a potential diagnosis biomarker for RA-associated CPI. PMID- 29968811 TI - Author Correction: Towards Millimeter-wavelength: Transmission-Mode Fresnel-Zone Plate Lens Antennas using Plastic Material Porosity Control in Homogeneous Medium. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29968812 TI - Lipid rafts are essential for release of phosphatidylserine-exposing extracellular vesicles from platelets. AB - Platelets protect the vascular system during damage or inflammation, but platelet activation can result in pathological thrombosis. Activated platelets release a variety of extracellular vesicles (EVs). EVs shed from the plasma membrane often expose phosphatidylserine (PS). These EVs are pro-thrombotic and increased in number in many cardiovascular and metabolic diseases. The mechanisms by which PS exposing EVs are shed from activated platelets are not well characterised. Cholesterol-rich lipid rafts provide a platform for coordinating signalling through receptors and Ca2+ channels in platelets. We show that cholesterol depletion with methyl-beta-cyclodextrin or sequestration with filipin prevented the Ca2+-triggered release of PS-exposing EVs. Although calpain activity was required for release of PS-exposing, calpain-dependent cleavage of talin was not affected by cholesterol depletion. P2Y12 and TPalpha, receptors for ADP and thromboxane A2, respectively, have been reported to be in platelet lipid rafts. However, the P2Y12 antagonist, AR-C69931MX, or the cyclooxygenase inhibitor, aspirin, had no effect on A23187-induced release of PS-exposing EVs. Together, these data show that lipid rafts are required for release of PS-exposing EVs from platelets. PMID- 29968814 TI - Comparison of AOD from CALIPSO, MODIS, and Sun Photometer under Different Conditions over Central China. AB - Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) provides three-dimensional information on aerosol optical properties across the globe. However, the performance of CALIPSO aerosol optical depth (AOD) products under different air quality conditions remains unclear. In this research, three years of CALIPSO level 2 AOD data (November 2013 to December 2017) were employed to compare with the Moderate Resolution Imaging Spectroradiometer (MODIS) level 2 columnar AOD products and ground-based sun photometer measurements for the same time period. To investigate the effect of air quality on AODs retrieved from CALIPSO, the AODs obtained from CALIPSO, MODIS, and sun photometer were inter compared under different air quality conditions over Wuhan and Dengfeng. The average absolute bias of AOD between CALIPSO and sun photometer was 0.22 +/- 0.21, 0.11 +/- 0.07, and 0.14 +/- 0.13 under clean, moderate, and polluted weather, respectively. The result indicates that the CALIPSO AOD were more reliable under moderate and polluted days. Moreover, the deviation of AOD between CALIPSO and sun photometer was largest (0.23 +/- 0.21) in the autumn season, and lowest (0.13 +/- 0.12) in the winter season. The results show that CALIPSO AOD products were more applicable to regions and seasons with high aerosol concentrations. PMID- 29968813 TI - Characterization of the second- and third-harmonic optical susceptibilities of atomically thin tungsten diselenide. AB - We report the first detailed characterization of the sheet third-harmonic optical susceptibility, chi(3)s, of tungsten diselenide (WSe2). With a home-built multiphoton microscope setup developed to study harmonics generation, we map the second and third-harmonic intensities as a function of position in the sample, pump power and polarization angle, for single- and few-layers flakes of WSe2. We register a value of |chi(3)s| ~ 0.9 * 10-28 m3 V-2 at a fundamental excitation frequency of homega = 0.8 eV, which is comparable in magnitude to the third harmonic susceptibility of other group-VI transition metal dichalcogenides. The simultaneously recorded sheet second-harmonic susceptibility is found to be |chi(2)s| ~ 0.7 * 10-19 m2 V-1 in very good agreement on the order of magnitude with recent reports for WSe2, which asserts the robustness of our values for |chi(3)s|. PMID- 29968815 TI - Female Japanese quail visually differentiate testosterone-dependent male attractiveness for mating preferences. AB - Biased mating due to female preferences towards certain traits in males is a major mechanism driving sexual selection, and may constitute an important evolutionary force in organisms with sexual reproduction. In birds, although the role of male ornamentation, plumage coloration, genetic dissimilarity, and body size have on mate selection by females have been examined extensively, few studies have clarified exactly how these characteristics affect female mate preferences. Here, we show that testosterone (T)-dependent male attractiveness enhances female preference for males of a polygamous species, the Japanese quail. A significant positive correlation between female mating preference and circulating T in the male was observed. The cheek feathers of attractive males contained higher levels of melanin and were more brightly colored. The ability of females to distinguish attractive males from other males was negated when the light source was covered with a sharp cut filter (cutoff; < 640 nm). When females were maintained under short-day conditions, the expression of retinal red sensitive opsin decreased dramatically and they became insensitive to male attractiveness. Our results showed that female preference in quail is strongly stimulated by male feather coloration in a T-dependent manner and that female birds develop a keen sense for this coloration due to upregulation of retinal red sensitive opsin under breeding conditions. PMID- 29968816 TI - Changes in cognitive function in patients with intractable dizziness following vestibular rehabilitation. AB - The purpose of the present study was to investigate changes in cognitive functions, including visuospatial ability, attention, and executive function in patients with intractable dizziness following vestibular rehabilitation. The correlations between improvements in cognitive function and dizziness-related variables and emotional distress were also explored. During hospitalization for 5 days, participants were trained on a vestibular rehabilitation program. Participants completed questionnaires including the Dizziness Handicap Inventory (DHI), Hospital Anxiety and Depression Scale (HADS), and Trail Making Test (TMT), which were used to assess cognitive function. The center of gravity fluctuation measurement and timed up and go test (TUG), which were objective dizziness severity indexes, were performed before, 1 month after, and 4 months after hospitalization. Following vestibular rehabilitation, participants exhibited a significant improvement in the TMT, DHI, HADS, and TUG scores. Correlation analysis between the variables at each time point indicated that TMT scores positively correlated with TUG at baseline. The correlation between changes observed in the TUG and TMT scores was not significant. The degree of improvement of the TUG score did not bear a linear relationship with that of the TMT scores. However, these correlation results were not completely consistent with those in the multiply imputed dataset. PMID- 29968817 TI - Coherent backscattering in quasi-ballistic ultra-high mobility GaAs/AlGaAs 2DES. AB - A small and narrow negative-magnetoresistance (MR) effect that appears about null magnetic field over the interval -0.025 <= B <= 0.025 T in magnetotransport studies of the GaAs/AlGaAs 2D system with MU ~ 107cm2/Vs is experimentally examined as a function of the sample temperature, T. The temperature dependent magnetoresistance data were fit using the Hikami et al. theory, without including the spin-orbit correction, to extract the inelastic length, li, which decreases rapidly with increasing temperature. It turns out that li < le, where le is the elastic length, for all T. Thus, we measured the single particle lifetime, taus, and the single particle mean free path ls = vFtaus. A comparison between li and ls indicates that li > ls. The results suggest that the observed small and narrow magnetoresistance effect about null magnetic field could be a manifestation of coherent backscattering due to small angle scattering from remote ionized donors in the high mobility GaAs/AlGaAs 2DES. PMID- 29968818 TI - Effects of Total Dissolved Gas Supersaturation on the Swimming Performance of Two Endemic Fish Species in the Upper Yangtze River. AB - Total dissolved gas (TDG) supersaturation has been identified as one of the possible negative environmental effects of the construction of dams in the upper Yangtze River. Juvenile Chinese sucker and Prenant's schizothoracin fish were selected to evaluate the impact of TDG supersaturation on the swimming performance of fish in the Upper Yangtze River. The critical swimming speeds (Ucrit) of Chinese sucker were 4.06, 2.83, 2.87, 2.68, and 2.29 BLs-1 at the TDG supersaturation levels of 100, 117, 122, 125 and 130%, respectively. The Ucrit of Prenant's schizothoracin were 7.38, 4.32, 3.98, and 3.74 BLs-1 at the TDG supersaturation levels of 100, 117, 125 and 130%, respectively. The burst swimming speed (Uburst) of the two species also significantly declined with increases in the TDG supersaturation level. The present results demonstrate that the swimming speeds of Prenant's schizothoracin that were exposed to 130% TDG supersaturation for 2 h exhibited significant recovery after 2 days, whereas the swimming speeds of Chinese sucker did not. The swimming speeds of Chinese sucker after 2 days of recovery were significantly reduced compared with those of control fish, whereas the speeds of Prenant's schizothoracin returned to normal levels. PMID- 29968819 TI - Intradermal injection of low dose human regulatory T cells inhibits skin inflammation in a humanized mouse model. AB - Recent regulatory T cell (Treg) based clinical trials support their therapeutic potential in transplantation and auto-inflammatory diseases. However, large numbers of Treg are needed to accomplish therapeutic efficacy. Local injection at the site of inflammation (targeted delivery) may lower the numbers needed for therapy. We evaluated if local delivery of low numbers of human Treg by intradermal injection was able to prevent skin inflammation, using the humanized mouse huPBL-SCID-huSkin allograft model. A dose of only 1 * 105 freshly isolated, non expanded Treg injected intradermally in close proximity to the transplanted human skin prevented inflammation of the grafted tissue induced by 4 * 107 IP injected human allogeneic PBMCs, (ratio Treg:PBMC = 1:400), as indicated by the inhibition of epidermal thickening, sustained Keratin-10 expression, the absence of Keratin-16 up regulation and prevention of human CD3+ T cell influx. A concomitant reduction of human T cells was observed in lymph nodes and spleen of the mice. Injection of Treg at the contralateral side was also shown to inhibit skin inflammation, suggesting that the inflammatory response was regulated both locally and systemically. In conclusion, local application of Treg may be an attractive way to suppress inflammation in vivo without the need for prior ex vivo expansion. PMID- 29968821 TI - Unravelling the physics of knitting. PMID- 29968820 TI - To make plastic, just add blood. PMID- 29968822 TI - 'Eyes in the sky' spot hidden threat to Italy's olive trees. PMID- 29968823 TI - Mouse embryos' balancing act revealed. PMID- 29968824 TI - First known haven for baby rays found off Texas coast. PMID- 29968825 TI - CRISPR with a heart of gold helps ailing mice. PMID- 29968826 TI - Molecular fog cooled to 40 millionths of a degree. PMID- 29968827 TI - Cyprus asserts itself as regional hub for climate-change research. PMID- 29968828 TI - Brain-protein structure could point way to safer prescription drugs. PMID- 29968830 TI - Consumers soften to genetically engineered foods after addition of labels. PMID- 29968829 TI - Delays mount for NASA's $8-billion Hubble successor. PMID- 29968831 TI - There's no limit to longevity, says study that revives human lifespan debate. PMID- 29968832 TI - Mars's river valleys whisper of a rainy past. PMID- 29968833 TI - Gigantic study of Chinese babies yields slew of health data. PMID- 29968834 TI - 50 & 100 years ago. PMID- 29968835 TI - Harness the power of groups to beat the 'PhD blues'. PMID- 29968836 TI - Doubt cast on how the pace of global glacial erosion responds to climate cooling. PMID- 29968837 TI - General relativity verified by a triple-star system. PMID- 29968838 TI - Speaking in code: how to program by voice. PMID- 29968839 TI - LGBTQ scientists are still left out. PMID- 29968840 TI - Italy is squeezing out wet biology research. PMID- 29968841 TI - Evaluation woes: we're on it, responds DORA. PMID- 29968842 TI - University came to the rescue of accused researcher. PMID- 29968843 TI - Personalized medicine should not be restricted to the wealthy. PMID- 29968844 TI - A welcome from the new Nature editor. PMID- 29968847 TI - Renal artery fibromuscular dysplasia and its effect on the kidney. AB - Fibromuscular dysplasia is a heterogeneous group of systemic, noninflammatory, and nonatherosclerotic diseases of the vascular wall. It is the second-most common abnormality of the renal artery. Although hypertension is the most common presenting symptom, other symptoms, such as pulsatile tinnitus, stroke, chest pain, or abdominal discomfort, may result from other affected vascular beds. Revascularization of the renal artery appears to be effective at lowering blood pressure in many patients with renal artery fibromuscular dysplasia. For a long time, the intrarenal pathophysiological changes and mechanisms leading to hypertension had hardly been studied in patients with renal artery fibromuscular dysplasia. Recent data, however, has provided more insight into the effects of renal artery fibromuscular dysplasia on the intrarenal microvasculature and the intra-renal renin-angiotensin system in these patients. Moreover, these data have changed our view of the pathophysiological mechanisms leading to hypertension in patients with renal artery fibromuscular dysplasia. In this review, we will discuss recent clinical and scientific developments regarding renal artery fibromuscular dysplasia with an emphasis on its effects on the kidney. PMID- 29968848 TI - Healthy aging and carotid performance: strain measures and beta-stiffness index. AB - Arterial stiffness is related to the risk of cardiovascular disease (CVD) and increases with aging. Functional impairment of the arterial wall can occur before structural changes and can be detectable before CVD symptoms. The elastic properties of the carotid arterial wall during the cardiac cycle can be evaluated by standard 2-dimensional (2D) ultrasound longitudinal or circumferential imaging of vascular deformation (strain) using speckle tracking. The purpose of this study was to compare standard 2D ultrasound circumferential and longitudinal images of vascular tissue motion and strain using speckle tracking in young and older individuals. Participants underwent recording of 2D ultrasound circumferential and longitudinal images of the common carotid artery. Circumferential carotid strain (CS) and CS rate were obtained and analyzed via speckle tracking software. Following the strain analysis, the circumferential strain beta-stiffness (C-beta) was calculated. Conventional longitudinal beta stiffness (L-beta) was calculated and non-invasive blood pressure measurements were obtained from carotid artery pressure measurements in a resting supine position using applanation tonometry. C-beta was significantly higher than L beta, and the association with age was greater (r = .824 vs. r = .547). CS and CS rate were significantly higher in the young compared to the older group. L-beta does not explain as much of the age-dependent differences in the carotid artery compared with C-beta. This is possibly due to the inclusion of whole arterial wall motion and deformation observed in the CS image. The ability of C-beta to accurately predict the future risk of CVD independent of age still needs further investigation. PMID- 29968849 TI - Identification of compound D2923 as a novel anti-tumor agent targeting CSF1R. AB - Colony-stimulating factor 1 receptor (CSF1R) plays a critical role in promoting tumor progression in various types of tumors. Here, we identified D2923 as a novel and selective inhibitor of CSF1R and explored its antitumor activity both in vitro and in vivo. D2923 potently inhibited CSF1R in vitro kinase activity with an IC50 value of 0.3 nM. It exhibited 10- to 300-fold less potency against a panel of kinases tested. D2923 markedly blocked CSF-1-induced activation of CSF1R and its downstream signaling transduction in THP-1 and RAW264.7 macrophages and thus inhibited the in vitro growth of macrophages. Moreover, D2923 dose dependently attenuated the proliferation of a small panel of myeloid leukemia cells, mainly by arresting the cells at G1 phase as well as inducing apoptosis in the cells. The results of the in vivo experiments further demonstrated that D2923 displayed potent antitumor activity against M-NFS-60 xenografts, with tumor growth inhibition rates of 50% and 88% at doses of 40 and 80 mg/kg, respectively. Additionally, D2923 was well tolerated with no significant body-weight loss observed in the treatment groups compared with the control. Furthermore, a western blot analysis and the immunohistochemistry results confirmed that the phosphorylation of CSF1R in tumor tissue was dramatically reduced after D2923 treatment, and this was accompanied by the depletion of macrophages in the tumor. Meanwhile, the expression of the proliferation marker Ki67 was also markedly decreased in the D2923 treatment group compared with the control group. Taken together, we identified D2923 as a novel and effective CSF1R inhibitor, which deserves further investigation. PMID- 29968846 TI - Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis. AB - The rewarding properties of social interactions are essential for the expression of social behavior and the development of adaptive social relationships. Here, we review sex differences in social reward, and more specifically, how oxytocin (OT) acts in the mesolimbic dopamine system (MDS) to mediate the rewarding properties of social interactions in a sex-dependent manner. Evidence from rodents and humans suggests that same-sex social interactions may be more rewarding in females than in males. We propose that there is an inverted U relationship between OT dose, social reward, and neural activity within structures of the MDS in both males and females, and that this dose-response relationship is initiated at lower doses in females than males. As a result, depending on the dose of OT administered, OT could reduce social reward in females, while enhancing it in males. Sex differences in the neural mechanisms regulating social reward may contribute to sex differences in the incidence of a large number of psychiatric and neurodevelopmental disorders. This review addresses the potential significance of a sex-dependent inverted U dose-response function for OT's effects on social reward and in the development of gender-specific therapies for these disorders. PMID- 29968850 TI - Correction: TERT promoter mutation in adult granulosa cell tumor of the ovary. AB - The original version of this Article omitted the author Hannah van Meurs from the Department of Gynecology, Center for Gynecologic Oncology Amsterdam, Academic Medical Center, 1100 DD Amsterdam, The Netherlands. This has been corrected in both the PDF and HTML versions of the article. PMID- 29968851 TI - Discovery of hybrids of indolin-2-one and nitroimidazole as potent inhibitors against drug-resistant bacteria. AB - With antibiotics resistance developing rapidly, new antibacterial agents are needed to be discovered. We readily synthesized 11 indolin-2-one compounds and found a hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H imidazol-2-yl)methylene)indolin-2-one to be effective on Staphylococcus aureus strains. Six derivatives of this compound were further designed and synthesized in order to enhance its efficacy. After a second turn of structural refinement, a novel hybrid of indolin-2-one and nitroimidazole 3-((1-methyl-5-nitro-1H-imidazol 2-yl)methylene)-5-nitroindolin-2-one with a nitro group on C-5 position of indolin-2-one was shown to exhibit remarkable antibacterial activities with a low MIC value against MRSA ATCC 33591. Besides, this molecule demonstrated its potency on Gram-negative bacteria and VRE strain. The time-killing curve experiment showed its good bactericidal activity. Low hemolytic rate suggested its promising safety profile. PMID- 29968852 TI - Establishment and analysis of a mouse model that regulates sex-related differences in liver drug metabolism. AB - The adult liver performs many metabolic functions for maintaining homeostasis. There are several sex differences in liver function and disease pathogenesis. One important function of the liver is drug metabolism, where cytochrome p450s (CYPs) in hepatocytes are the main enzymes involved. The toxicity of various drugs and chemicals differs with sex due to differences in hepatocytic CYP expression. However, the molecular mechanism regulating sex-related differences in drug metabolism remains unknown. In this study, we identified transcriptional regulator B-cell lymphoma 6 (Bcl6) as an important factor in sex-biased differential CYP expression. Microarray analysis of livers derived from liver specific Bcl6-knockout mice showed that Bcl6 is required for sex-biased CYP expression patterns in the liver. Additionally, quantitative PCR analysis revealed that hepatocytic expression of male-biased genes, such as Cyp2d9, Cyp2u1, Cyp4a12a/12b, and Cyp7b1, in liver-specific Bcl6-knockout male mice significantly decreased to levels similar to those observed in wild-type female mice. Conversely, hepatocytic expression of female-biased genes, such as Cyp2a4/2a5, Cyp2b9, Cyp3a41, and Cyp17a1, significantly increased in liver specific Bcl6-knockout male mice. Deletion of Bcl6 caused female-like expression of CYPs in male livers. These results suggest that Bcl6 is a key regulator of sex related differential regulation of drug metabolism. Moreover, serum sex hormone levels and fertility did not change in liver-specific, Bcl6-knockout mice. Hepatocytic Bcl6 regulates sex-related differential CYP expression in the liver without changing the sex of the whole body. Thus, this mouse model is useful for analyzing liver-specific sex-dependent regulation of drug metabolism and pathogenesis. PMID- 29968853 TI - Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. AB - Circulating tumour DNA (ctDNA) refers to the fraction of cell-free DNA in a patient's blood that originates from a tumour. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumours have resulted in increased interest in exploiting ctDNA as a tool to facilitate earlier detection of cancer and thereby improve therapeutic outcomes by enabling early intervention. ctDNA analysis might also have utility in the adjuvant therapeutic setting by enabling the identification of patients at a high risk of disease recurrence on the basis of the detection of post-surgical minimal (or molecular) residual disease (MRD). This approach could provide the capability to adapt clinical trials in the adjuvant setting in order to optimize risk stratification, and we argue that this objective is achievable with current technologies. Herein, we evaluate contemporary next-generation sequencing (NGS) approaches to ctDNA detection with a focus on non-small-cell lung cancer. We explain the technical and analytical challenges to low-frequency mutation detection using NGS-based ctDNA profiling and evaluate the feasibility of ctDNA profiling in both screening and MRD assessment contexts. PMID- 29968857 TI - [Does oncology change its paradigm? The challenge of agnostic approval of new therapies.] AB - Oncology drugs have been traditionally approved for the treatment of specific cancer diseases. Recently, regulatory decisions about new cancer therapies have been taken by the Food and Drug Administration starting from biomarker data irrespective of organ site or histology. This new pattern can be defined as a "mutational model". A drug is approved and put on the market because it is active on a certain driver mutation and is approved regardless of the primary disease site, age, or gender. To face this kind of challenge in a non-disruptive way, the healthcare system should be able to anticipate these changes, so as to put in place regulatory procedures aimed at guaranteeing appropriateness and economic sustainability. The answer to this challenge should be obtained through multidisciplinary networks of health professionals (oncologists, pathologists, epidemiologists, health decision makers, etc.) supported by updated disease registries. In this way, it would be possible to gather data and evidence in real time, guaranteeing the needed governance of the system. PMID- 29968858 TI - [The National Health Service needs to train doctors who are leaders in change.] AB - Several new health technologies are going to be introduced in the healthcare system, as well as new ways of making diagnoses, new drugs, new strategies for customizing therapy. Introducing innovation requires a considerable effort from healthcare decision-makers. In fact, every innovation may have an impact in terms of altering diagnostic and clinical pathways, but also in terms of processes, organizational structures, services and interventions delivery, costs. Facing these continuous changes, we need to support the growth of leading doctors: leadership development should start during medical school. Health systems should identify potential leaders, characterized by intelligence, deep medical culture, humanity and passion, involving them in task forces, committees, periodic retreat teams protected by the pharmaceutical industry influence, experiential training programs. Being trained on organizational, communication and team-building aspects, new medical leaders can master core competencies such as strategic planning and change management. Continuous support, through a system of tutoring by other leaders, will increase emotional intelligence, facilitating decision making processes and improving communication and collaboration skills. Adopting strategies like those described, the health system will achieve the efficiency and organizational effectiveness needed to prevent waste and to grant the benefits of pharmacological and technological innovation to all the stakeholders. PMID- 29968859 TI - [Cancer and risk of suicide: follow-up and multidisciplinarity may offer opportunities for prevention.] AB - Suicide rate is two-fold higher among cancer patients than in the general population. General and cancer-related risk factors for suicide are easily identified by caregivers interacting with patients, but with the exception of depression - the strongest one. This hampers the feasibility of screening of patients by the treating personnel. While new treatments tend to make cancer a chronic disease, which exposes patients to prolonged periods of uncertainty about recurrences, two recent advances have improved the possibility to prevent suicide. On the one hand, the emerging concept of cancer survivorship care has placed the identification of long-term consequences of cancer and its treatments, including an increased risk for suicide, among the objectives of patient follow up. On the other hand, models of multidisciplinary team care have been implemented in several areas of cancer management. Although the psycho-oncologist has a complementary role, a clear definition of its relationship with the multidisciplinary teams facilitates the adoption of screening programmes for the detection of conditions of increased risk for suicide in cancer care facilities. PMID- 29968860 TI - [Narrative medicine in the oncological clinical practice: the path from a story telling intervention to a narrative digital diary.] AB - To introduce a systematic narrative approach into clinical practice, not only training to improve narrative skills among physicians, but also a change in their perspective towards care, is required. This paper describes the development of a narrative path started at the IRCSS "Regina Elena" National Cancer Institute, based on training and research projects. The programme started in 2015 with a story-sharing intervention, named "Raccontami di te" ("Tell me about you"), involving patients, their relatives and health professionals, with the aim to improve the knowledge about the role of self-narration as well as the listening attitude. In 2017 a pilot study based on the use of a digital diary (digital narrative medicine - DNM), which is a platform for the application of narration in clinical practice started. The study aimed to evaluate the feasibility and the utility of a model integrating the patient theme-oriented narratives with clinical data during chemotherapy treatment, through a mixed qualitative quantitative analysis method. The results supported the value of the integration of patients narratives with clinical data; however the success of the intervention is strongly related to the whole care team participation and to an appropriate health organization. PMID- 29968861 TI - [Checkpoint inhibitors in the decision-making algorithm of advanced non-small cell lung cancer.] AB - The checkpoint inhibitors opened a new era in the treatment of advanced non-small cell lung cancer (NSCLC) initially by replacing second-line standard chemotherapy with docetaxel and subsequently by replacing platinum-based chemotherapy in the first line, albeit in patients selected for a high expression of PD-L1. The decision algorithm has therefore been radically modified for patients who do not have activating mutations. However, we are only at the beginning of a new era from which we expect in the near future the use of immunotherapy in most patients as a first line treatment in substitution or in combination with chemotherapy. These strategies are now the objective of recent studies that have shown a benefit with the combination of chemotherapy and immunotherapy in patients with non-squamous histotype compared to chemotherapy alone or a benefit in patients selected for high mutational burden (TMB) with anti-PD1 and anti-CTLA-4 compared to chemotherapy alone. However, there are many questions regarding immunotherapy that should be considered in clinical practice as: response evaluation, validation of predictive factors such as TMB potentially complementary to the expression of PD-L1, proper education of the patients and of the medical staff to prompt recognition and adequate management of toxicities. In this article we discuss the current decisional algorithm and future perspectives of treatment with immunotherapy in advanced NSCLC. PMID- 29968862 TI - [Influence of geographic barriers and care pathways on radiotherapy treatment and survival of breast cancer patients.] AB - Evidence on outcome-volume relation and resource shortage are forcing the oncology department towards concentrating of cancer care in large specialized centres. We report a study on radiotherapy for breast cancer patients in Umbria, Italy, where geographic barriers reduced appropriate radiotherapy for patients with a travel burden as low as >40 minutes and the under-treatment was associated with low survival probabilities. The creation of additional radiotherapy centres (i.e. decentralization) improved appropriate care. However, evidence pointed also to a role of access to the oncology service through rural surgical centres in determining suboptimal treatment and health outcomes. We introduced radiotherapy in breast cancer patients as an instance of the complexity of cancer care. The oncology network is actively introduced in Italian health services as a tool to face problems of equity, quality of care and effective use of available resources. Meaningful information on care process and outcomes will be central to set cancer control strategies within the network and to assess the network results. Cancer registries can contribute to network effectiveness providing surveillance and evaluation data. PMID- 29968863 TI - [The treatment of cancer patients near their residence in the territorial structure "Casa della salute": preliminary results in the province of Piacenza (Italy).] AB - INTRODUCTION: In the field of oncology, we are all stimulated by the desire to improve the lives of patients with cancer; however little data are available about the amount of time and travel discomfort that patients and families typically spend for clinical examinations and for antitumoral/supportive treatments. The purpose of this study was to determine the advantages for cancer patients to receive clinical, test examinations, and anticancer treatment near their residence in a territorial clinical structure called "Casa della Salute" (CdS). METHODS: Since July 2016 to all the cancer patients treated at the Oncology Unit of the General Hospital in Piacenza, was offered the possibility to be treated near their residence at the CdS located in the mid valley (Val Nure), or to continue the treatment at the Oncology Unit of the General Hospital in Piacenza. The treatments were delivered by an oncology nurse under the supervision of a medical oncologist. RESULTS: From 18 July 2016 to 20 July 2017, 54 patients with cancer were managed in the CdS in Bettola, province of Piacenza in North Italy. All these patients received the planned antitumoral and supportive treatments. The average distance from the patient's residence to the Oncology Unit in Piacenza was 81,65 km (range 31,6-131 km), while it was 21,06 km (range 3-54,2 km) to the CdS (p<0,001). The average time for the round trip to the Oncology Unit in Piacenza was 93,35 minutes (range 40-162) while it took 16,35 minutes (range 10-78) to reach the CdS (p<0,001). 98,5% of patients were very satisfied to receive oncological treatment at the CdS, and 65% of patients who needed a caregiver to reach the Oncology Unit in Piacenza, could travel alone to the CdS. DISCUSSION: The increase in the incidence of cancer, especially in elderly patients with comorbidity, has been accompanied by an increase in the overall survival rate of these patients thus requiring organizational innovations. The results of this study hightlight the possibility of treating cancer patients in territorial structures near their residence, with advantages for the patients, their caregivers and for the entire community. PMID- 29968864 TI - [Conflict and divorce management in the field of pediatric care. Experience in pediatric oncology.] AB - Divorces and separations have become more frequent over the last 20 years and for this reason they are issues of great importance with possible effects on medical treatments. Conflicts between the adults frequently affect the children involved in the separation of their parents. If, on the one hand, the parental conflict is a hard and distressing experience for the whole family, on the other hand this situation gets even more complicated if a child is affected by a serious illness. Since there is a lack of studies about the management arrangements of these situations, this article aims to illustrate the experiences gained in a pediatric ward of a big oncology hospital and the appropriate multidisciplinary management arrangements. These experiences, however, can be applied also in other contexts where children are being treated and where the conflict between parents can either produce different difficulties in the performance of the therapy or prejudice the child's serenity. PMID- 29968865 TI - [The management of cancer patients during natural disasters: the oncologist's resilience and the role of scientific societies.] AB - The earthquake that shook Central Italy during 2016 and 2017 confirmed once again the country's vulnerability. These catastrophic events have serious consequences both on the lives of cancer patients and on the organization of healthcare assistance. After the earthquake that devastated the city of L'Aquila in 2009, the nearby hospitals were declared unfit, thus, patients were deprived of their natural reference center. We think that it's time to act and open a discussion having in mind that each event has its own specific set of critical characteristics: standardized protocols to be activated in all situations could become inapplicable in some specific circumstances. We strongly recommend the creation of a task force including oncologists, nurses and psychologists with hands-on experience, able to support colleagues working in the affected areas immediately after the event. Scientific societies could play an extremely important role in fostering a better training of the health professionals in case of natural disasters. PMID- 29968866 TI - Long-term survival in advanced pancreatic cancer. PMID- 29968867 TI - ? PMID- 29968868 TI - Towards mapping electrostatic interactions between Kdo2-lipid A and cationic antimicrobial peptides via ultraviolet photodissociation mass spectrometry. AB - Cationic antimicrobial peptides (CAMPs) have been known to act as multi-modal weapons against Gram-negative bacteria. As a new approach to investigate the nature of the interactions between CAMPs and the surfaces of bacteria, native mass spectrometry and two MS/MS strategies (ultraviolet photodissociation (UVPD) and higher energy collisional activation (HCD)) are used to examine formation and disassembly of saccharolipid.peptide complexes. Kdo2-lipid A (KLA) is used as a model saccharolipid to evaluate complexation with a series of cationic peptides (melittin and three analogs). Collisional activation of the KLA.peptide complexes results in the disruption of electrostatic interactions, resulting in apo sequence ions with shifts in the distribution of ions compared to the fragmentation patterns of the apo-peptides. UVPD of the KLA.peptide complexes results in both apo- and holo-sequence ions of the peptides, the latter in which the KLA remains bound to the truncated peptide fragment despite cleavage of a covalent bond of the peptide backbone. Mapping both the N- and C-terminal holo product ions gives insight into the peptide motifs (specifically an electropositive KRKR segment and a proline residue) that are responsible for mediating the electrostatic interactions between the cationic peptides and saccharolipid. PMID- 29968876 TI - Hierarchical heterostructure of Ag-nanoparticle decorated fullerene nanorods (Ag FNRs) as an effective single particle freestanding SERS substrate. AB - A hierarchical heterostructure composed of silver nanoparticles (Ag-NPs: average diameter ~10 nm) on fullerene nanorods (FNRs: average length ~11 MUm and average diameter ~200 nm) was fabricated using a simple solution route. It was used as an effective single particle freestanding surface enhanced Raman scattering (SERS) substrate for the detection of target molecules (Rhodamine 6G: R6G). FNRs were formed ultra-rapidly (formation process completed in a few seconds) at a liquid liquid interface of methanol and C60/mesitylene solution then Ag-NPs were grown directly on the surfaces of the FNRs by treatment with a solution of silver nitrate in ethanol. This unique hierarchical heterostructure allows efficient adsorption of target molecules also acting as an effective SERS substrate capable of detecting the adsorbed R6G molecules in the nanomolar concentration range. In this study, SERS spectra are acquired on an isolated single Ag-FNR for the detection of the absorbed molecule rather than from a bulk, large area film composed of silver/gold nanoparticles as used in conventional methods. Thus, this work provides a new approach for the design and fabrication of freestanding SERS substrates for molecular detection applications. PMID- 29968869 TI - Biocompatibility of polymer-based biomaterials and medical devices - regulations, in vitro screening and risk-management. AB - Biomaterials play an increasing role in modern health care systems. Biocompatibility poses a significant challenge for manufacturers of medical devices and contemporary intelligent drug delivery technologies from materials development to market approval. Despite a highly regulated environment, biocompatibility evaluation of biomaterials for medical devices is a complex task related to various factors that include mainly chemical nature and physical properties of the material, the contact tissue and duration of contact. Although international standards, such as ISO 10993-1, are generally employed to prove regulatory compliance needed for market clearance or for initiating clinical investigations, they may not offer sufficient guidance, or risk-management perspective when it comes to choosing materials or appropriate in vitro biocompatibility screening methods when developing medical devices. The global normative approach towards the biocompatibility evaluation of medical devices is presented in this review, with a focus on in vitro studies. Indeed, a risk management approach towards the judicial choice of in vitro tests throughout the development and production of medical devices and drug delivery systems will facilitate rapid regulatory approval, avoid unnecessary animal studies, and ultimately reduce risks for patients. A detailed overview towards the construction of a comprehensive biological evaluation plan is described herein, with a focus on polymer-based materials used in medical applications. Polymeric materials offer a broad spectrum of applications in the manufacturing of medical devices. They are extensively employed within both conventional and innovative drug delivery systems with superior attributes supporting robust, extended use capacity, capable of meeting specific requirement such as adhesion, drug release, and more. Various methods of biocompatibility assessment are detailed within, with an emphasis on scientific analysis. This review may be of interest to those involved in the design, manufacturing and in vitro testing of medical devices and innovative drug delivery technologies, specifically with respect to a risk management approach towards the biocompatibility assessment of polymer-based devices. PMID- 29968877 TI - Evaluation of the stability of tyrosol esters during in vitro gastrointestinal digestion. AB - Lipophenols such as tea polyphenol palmitate derivatives (palmitoyl esters of tea polyphenols) have been classified as non-toxic food additives due to their better protective effects on lipidic food matrices from oxidation, but their digestion and absorption have remained unexplored. In this study, the digestive stability of tyrosol acyl esters (TYr-Es) with fatty acids of different chain lengths and different degrees of unsaturation such as C12:0, C14:0, C16:0, C18:0, C18:1, C18:2, and C22:6 was evaluated using an in vitro simulated gastrointestinal tract model containing various digestive enzymes (pancreatin, pancreatic lipase and phospholipase A2). HPLC-UV measurements demonstrated that only pancreatin and pancreatic lipase, but not phospholipase A2, could hydrolyze TYr-Es to free TYr. The degree of TYr-E hydrolysis negatively correlated with the chain length but positively correlated with the degree of unsaturation of their lipid moiety. In addition, the fact that TYr in fatty acid ester forms could be absorbed by the intestinal lumen, at least partially in the form of free TYr, may explain a sustained release behavior of TYr-Es to TYr during the time-course following the digestion process. PMID- 29968878 TI - Detection of sulfide ion and gaseous H2S using a series of pyridine-2,6 dicarboxamide based scaffolds. AB - Pyridine-2,6-dicarboxamide based scaffolds with different appendages act as chemosensors for the selective detection of S2- ion, as well as gaseous H2S, in primarily aqueous media. Out of nine synthesized chemosensors, one with benzothiazole ring appendages was found to be highly selective for S2- ion and gaseous H2S. A series of spectroscopic studies confirmed that sulfide ion abstracts amidic N-H groups thus leading to the in situ generation of HS- ion, which remain bound to the pincer cavity of the resultant anionic chemosensor, and it was found that acetic acid could be used to reverse this process. It was essential for a chemosensor to feature a pincer cavity to recognize sulfide ion, whereas the sensing mechanism involved the deprotonation of the amidic N-H groups. We also illustrate the detection of sulfide ions and gaseous H2S in live cells and paper-strip sensing applications. PMID- 29968880 TI - 2D amphiphilic organoplatinum(ii) metallacycles: their syntheses, self-assembly in water and potential application in photodynamic therapy. AB - Two 2D amphiphilic organoplatinum(ii) metallacycles with a porphyrin unit as the core and hydrophilic glycol units as the tail were designed and fabricated successfully through a new method called "coordination-driven self-assembly". They can self-assemble into micelles in water and have potential applications in photodynamic therapy. PMID- 29968884 TI - Viscous field-aligned water exhibits cubic-ice-like structural motifs. AB - Strong electric fields are known to greatly accelerate the freezing of water in molecular dynamics simulations, and have also been shown to affect the thermodynamics of the phase transition. In this work, a mechanistic explanation for field-induced crystallization of water is presented. Due to the coupling between the rotational and the translational degrees of freedom of individual water molecules, an applied field can directly drive the formation of cubic-ice like local motifs in water. Analysis of the angular distributions of water molecules in TIP4P-2005 water at field strengths between 0.0 and 0.32 V A-1 demonstrates the existence of such motifs in the field-aligned liquid phase that is observed prior to the onset of the freezing transition. The dynamic properties of this field-aligned liquid phase are also studied, and its viscosity is shown to be within a factor of two of that of regular liquid water using the Green-Kubo method as well as mean squared displacements. The choice between the NPT and the NVT ensembles is shown to have a strong impact on the evolution of molecular dynamics trajectories at field strengths close to the threshold for the freezing transition, and the importance of properly accounting for the electric field terms in the pressure virial is emphasized. PMID- 29968885 TI - Triterpenoids from Ziziphus jujuba induce apoptotic cell death in human cancer cells through mitochondrial reactive oxygen species production. AB - Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1-8) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB 231). The structures of compounds 1-8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3-O-cis-p-coumaroyl alphitolic acid (3), 3-O trans-p-coumaroyl alphitolic acid (4), 2-O-trans-p-coumaroyl alphitolic acid (5), and 2-O-cis-p-coumaroyl alphitolic acid (6). Moreover, compounds 3-6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound 4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound 4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound 4 which suggests that compound 4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine. PMID- 29968886 TI - Determinants of quality of life as measured with variants of SF-36 in patients with predialysis chronic kidney disease. AB - OBJECTIVES: To determine the average health-related quality of life (HRQOL) score levels and their determinants in patients with predialysis chronic kidney disease (CKD). METHODS: A systematic literature search was conducted for relevant observational studies published between April 2007 and April 2017 in MEDLINE, EBSCOhost, and CINAHL databases. RESULTS: Thirteen observational studies with a total sample of 8635 subjects comprising 53.3% male with an aggregate mean age of 59.5 (SD 14.9) years were included in this review. Of the 8 generic HRQOL domains of the Short-Form Health Surveys, Social Functioning had the highest mean score whereas General Health had the lowest mean score in patients with predialysis CKD. Physical component summary (PCS) was more impaired than mental component summary (MCS). The determinants of poor HRQOL in predialysis CKD patients included both modifiable risk factors such as comorbidities (namely anxiety and depression), low serum hemoglobin level, sedentary lifestyle, unemployment and non-modifiable risk factors such as poor glomerular filtration rate, female gender, and older age. The risk factors impeded PCS more than MCS. CONCLUSION: Several risk factors influence HRQOL impairment in patients with predialysis CKD, with PCS being more impacted than MCS. The risk factors for poor HRQOL are important for future research and for improving renal care in patients with predialysis CKD. PMID- 29968887 TI - Association between asthma control and Interleukin-17F expression levels in adult patients with atopic asthma. AB - OBJECTIVES: To investigate the correlation between Interleukin 17 (IL-17F) and the level of asthma control. METHODS: This is a cross-sectional study of 40 subjects who were diagnosed with atopic asthma. All participants were recruited from the Allergy and Immunology Clinic, Prof. R.D. Kandou General Hospital, Manado, Indonesia, between April 2015 and April 2016. Total serum IL-17F measured by using Enzyme-Linked Immunosorbent Assay methods; and mRNA IL-17F was obtained by using real-time reverse transcriptase polymerase chain reaction. Level of asthma control was quantified by using asthma control test (ACT) scoring system. The correlation between IL-17F, mRNA, and level of asthma control was analyzed by using Pearson's correlation coefficient (r). RESULTS: There is a strong positive correlation between IL-17F serum level and Nathan's ACT-score (r=0.969) which is statistically significant (p less than 0.001). Analysis of the correlation between mRNA IL-17F serum level and Nathan's ACT-score revealed a strong positive correlation (r=0.963), which is statistically significant (p less than 0.001). CONCLUSION: These findings suggest that IL-17F plays an important role in asthma control. However, the role played by IL-17F in asthma pathogenesis are still questions to be answered. PMID- 29968889 TI - Growth characteristics in children with congenital adrenal hyperplasia. AB - OBJECTIVES: To evaluate the growth parameters in congenital adrenal hyperplasia patients in Jeddah, Saudi Arabia. Methods: This is a descriptive retrospective study over the period of 5 years. Data analysis was using Statistical Package for Social Science. The study included 90 participants in which 61 were girls and 29 were boys aged 0 to 18 years . They were evaluated in Pediatric Endocrinology Clinic at King Abdulaziz University Hospital in Jeddah, Saudi Arabia, between January 2012 and January 2017. RESULTS: A total of 90 subjects, of which 67.8% were females and 32.2% were males. Subjects who were underweight constituted 19.1% of the population, while those who were obese were estimated up to 17.6% of the population. Of the children, 25.7% were suffering from short stature and 74.3% had normal height. Approximately 11.8% of the children who suffered from short stature also suffered from hypothyroidism. Mid-parental height of those who suffered from short stature is 159.8 cm. CONCLUSION: This study showed a significant effect of congenital adrenal hyperplasia on both height, weight, and body mass index. Risk factors includes glucocorticoids dosage, compliance to treatment, and regular follow up. Personalized treatment approach should be followed with all patients diagnosed with congenital adrenal hyperplasia as well as close monitoring and targeted therapy. PMID- 29968888 TI - Trend, clinical presentations and diagnosis of eosinophilic esophagitis in Saudi children. AB - OBJECTIVES: To observe the frequency of eosinophilic esophagitis (EoE), pattern of clinical presentation and diagnosis among Saudi children at 2 tertiary carehospitals in Riyadh, Saudi Arabia. METHODS: The database of children admitted or seen, and aged less than 18 years over 5 years period and diagnosed with EoE was collected and reviewed. Patients with esophagitis other than EoE were excluded. Patients who had eosinophils count more than 15/high power field (HPF) on esophageal biopsies were given the diagnosis of EoE. Demographic database, clinical parameters, and diagnostic modalities were analyzed by using the Statistical Package for Social Sciences version 22. RESULTS: A total of 37 children with the diagnosis of EoE were gathered from 398 upper gastrointestinal endoscopic procedures with the frequency of 9.3%. There were 22 (59.4%) males with a mean+/-SD age of 9.6+/-2.3 years and all were Saudi nationals. Dysphagia was the leading presentation in 21 (56.7%) children followed by vomiting in 18 (48.6%), impaction of food bolus in 8 (21.6%) and foreign body in 3 (8.1%). Allergic symptoms were present in 13 (35.1%) children in the form of asthma, 11 (29.7%) multiple food allergies and 5 (13.5%) eczema. Peripheral eosinophil count and immunoglobulin E were raised more than normal in 6 and 5 children respectively. The pH measurements were carried out in 16 (43.2%) and ruled out the reflux. Contrast studies with barium (n=6; 16.2%) and endoscopic findings were significant (n=27; 72.9%). CONCLUSION: Eosinophilic esophagitis is an emerging disease and have a rising trend in Saudi children. Dysphagia, vomiting, and food impaction are the more common presenting features in older children and recurrent vomiting in younger children in addition to associated allergic conditions. PMID- 29968890 TI - Are Fetuin-A levels beneficial for estimating timing of sepsis occurrence? AB - OBJECTIVES: To evaluated Fetuin-A levels of patients admitted in the intensive care unit with a diagnosis of sepsis. Methods: This study was conducted at the Faculty of Medicine, Canakkale Onsekiz Mart University Hospital, Canakkal, Turkey, between February 2015 and October 2015. Forty septic patients were included in the study. Subsequent to clinical suspicion of sepsis, serum levels of C-reactive protein (CRP) and procalcitonin; and white blood cell (WBC) counts were evaluated at 3 time-points: 0 (basal), 24, and 72 hours. Results: The mean Fetuin-A levels at the 3 time-points were 58.5 +/- 29.2 ng/mL, 40.9 +/- 23.6 ng/mL, and 47.8 +/- 25.7 ng/mL, respectively. Fetuin-A levels at 24 hours were significantly lower than the basal level (p greater than 0.05), where as no significant difference was observed between the basal levels and those at 72 hours (p greater than 0.05). Correlation between the temporal changes in Fetuin-A levels and the changes in other inflammatory markers (CRP, procalcitonin and WBC) was examined. Fetuin A was found to have only a negative correlation with serum procalcitonin level (p less than 0.05). Conclusion: In this study, serum Fetuin-A levels in septic patients decreased significantly in the first 24 hours, followed by an insignificant increase at 72 hours. These findings suggest that monitoring of Fetuin-A levels may help predict the time of occurrence of sepsis and prognosis of sepsis. PMID- 29968891 TI - Prevalence of lipid abnormalities and cholesterol target value attainment in patients with stable coronary heart disease or an acute coronary syndrome in Saudi Arabia. AB - OBJECTIVES: To provide an overview of the extent of hyperlipidemia in very high risk patients, and how lipid-lowering therapy (LLT) is used in a real-world setting. Methods: In this multicenter observational study, data were collected from LLT-treated patients with stable CHD or an ACS in Saudi Arabia between 2013 and 2014. Individuals were included if they were greater than 18 years and had a full lipid profile available, recorded either prior to the baseline physician visit (CHD patients) or within 24-hours of admission to hospital (ACS patients). Results: A total of 737 patients were included in the study, 597 with stable CHD and 140 with ACS. Few patients in either group had an LDL-C level of greater than 70 mg/dl, which is advocated for very high-risk patients (24.3% and 11.4%, respectively). The median distances to this value were 19.0 mg/dl (CHD) and 25.0 mg/dl (ACS). Low doses of statins were being utilized (31 and 24 mg/day for CHD and ACS, respectively), with only minimal intensification for the ACS patients after hospital admission (41 mg/day at follow-up). Conclusions: Achievement of recommended LDL-C levels was poor for patients with stable CHD or an ACS. Statin intensity was low, indicating huge scope for intensifying the treatment of these very high-risk patients. PMID- 29968892 TI - Beliefs, attitudes, and barriers associated with the uptake of the seasonal influenza vaccine among patients visiting primary healthcare clinics. AB - OBJECTIVES: To explore beliefs, attitudes, and barriers associated with uptake of the seasonal influenza vaccine among visitors to primary healthcare clinics. METHODS: This was a cross-sectional, self-administered questionnaire-based study of 300 people visiting Family Medicine Centers, King Abdulaziz Medical City, Riyadh, Saudi Arabia, between May 2017 and October 2017. RESULTS: Most respondents reported that they never get vaccinated (63.3%), but most intend to get the vaccination in future. Only 7.7% of respondents had ever experienced side effects from the influenza vaccine. Reported barriers to vaccination include: a desire to avoid medication, the fact that the Ministry of Health has not made vaccination obligatory, concerns about the side-effects of the vaccine, the belief that one is at low risk of acquiring influenza, and the idea that influenza is a simple disease with no need for prevention. The rate of vaccination was higher among males than females. More females than males said they refused the influenza vaccine because of concerns about side effects or having a phobia of injections. CONCLUSION: Although most respondents said they were concerned about influenza and believed the vaccine to be effective, this study revealed a low rate of influenza vaccination. More public education and better arrangements for vaccination are required in the healthcare setting to overcome several reported barriers to vaccination. PMID- 29968893 TI - First description of plasmid mediated quinolone resistance genes in salmonella isolates from Saudi hospitals. AB - OBJECTIVES: To detect resistance genes to fluoroquinolones and beta-lactams in Salmonella strains from a Saudi hospital. METHODS: From October 2015 to December 2016, a total of 149 Salmonella strains were collected from stool specimens from patients admitted to King Fahad Hospital of the University, AlKhobar, Saudi Arabia using CHROMagar Salmonella. The organism identification and antimicrobial susceptibility testing were performed using Vitek 2 system. Strain serogrouping was performed using Wellcolex color Salmonella kit. Fluoroquinolone resistance genes, extended-spectrum beta-lactamases (ESBLs), and AmpC beta-lactamase were determined using polymerase chain reaction (PCR). Enterobacterial repetitive intergenic consensus sequence-based PCR (ERIC-PCR) was used to determine clonal relatedness. RESULTS: The resistance rates to cefotaxime were 1.3% and ciprofloxacin 19.5%. Plasmid mediated quinolone resistance (PMQR) genes, qnrB and qnrS, were detected in 8 strains, qnrB (n=5) and qnrS (n=3), respectively. No ESBLs, AmpC, or mutations in the topoisomerases were detected. Salmonella isolates formed 7 clusters with similarity. CONCLUSIONS: This study reveals the emergence of fluoroquinolone resistant Salmonella in the region imposing public health concerns. PMID- 29968894 TI - Impact of a multidisciplinary intensive education program on type 2 diabetes mellitus patients' glycemic control and cardiovascular risk factors. AB - OBJECTIVES: To evaluate the impact of a multidisciplinary intensive education program (MIEP) on type 2 diabetes mellitus (T2DM) patients' outcomes. METHODS: A retrospective study was used to evaluate the impact of MIEP on T2DM patients' outcomes for between May 2016 and May 2017. Data were collected from the diabetes education clinic in King Saud University Medical City (KSUMC), Riyadh, Saudi Arabia where patients were referred from diabetes outpatient clinics to the diabetes education clinic to receive MIEP. In terms of measuring the clinical outcomes of the T2DM patients, glycemic control, blood pressure, weight, and lipid profiles were assessed before MIEP at 3, 6, and 12 months. Results: A total of 174 patients with T2DM fulfilled study inclusion criteria. The results indicate improved glycemic control where patients' HbA1c and blood sugar levels were significantly reduced 3, 6, and 12 months after MIEP compared to the baseline (p less than 0.005). Moreover, blood pressure improved after education; a significant improvement was observed in the mean systolic blood pressure (SBP) from baseline to 12 months (p=0.036), and in the mean diastolic blood pressure (DBP) after 12 months (p=0.016). Additionally, the study found significant differences in total cholesterol and low-density lipoprotein (LDL) cholesterol 6 months after the intervention (p=0.014, p=0.02, respectively). Conclusion: Implementing an MIEP for T2DM patients can improve their clinical outcomes, which consequently may delay the disease's long-term complications. PMID- 29968895 TI - Analysis of kyphosis, vertebral fracture and bone mineral density measurement in women living in nursing homes. AB - OBJECTIVES: To analyze the relationship between vertebral fracture, degree of kyphosis, and BMD in women living in nursing homes. METHODS: This cross-sectional study was carried out in the Department of Physical Medicine and Rehabilitation, Hitit University Hospital, Corum, Turkey, betweenJanuary 2014 and January 2015. Of the 126 female patients who participated in the study, 48 lived in nursing homes (nursing-home-group [NHG]), 78 lived in non-nursing home settings (control group [CG]). Vertebral fractures were evaluated via the semi-quantitative Genant method. Cases in which a Cobb angle measured 40 degrees or more resulted in a diagnosis of kyphosis. RESULTS: The mean age of participants in the NHG was 77.2+/-7.6 years and 76.8+/-6.2 years in the CG (p greater than 0.05). The kyphosis rate in the NHG was found to be higher at 52.1% compared to 27.7% for the CG (p less than 0.001). In the NHG, 68.7% had osteoporosis, 31.3% had osteopenia; in the CG, 55.2% had osteoporosis, 32% had osteopenia, 12.8% had normal values (p less than 0.05).The vertebral fracture rate was 37.5% in the NHG and 24.3% in the CG (p greater than 0.05). The Cobb angle had correlation with the number of fractures in both groups (p less than 0.05). CONCLUSIONS: The osteoporosis and kyphosis rates of women living in NHG were higher than those of women living in CG. As kyphosis and the number of fractures are correlated, it is important to analyze kyphosis in women residing in NHG. PMID- 29968897 TI - Schistosomiasis as a cause of acute cholecystitis. AB - Schistosomal cholecystitis is remarkably uncommon disease which is associated with concomitant gallstone disease. The disease prevails with low socio-economic conditions of population. It is still not clear that the widespread fibrocalcific reaction in the wall of gallbladder and the cystic duct, observed for all the reports, predisposes to cholelithiasis or gallstones coexist. In the present study, we report a case of the Saudi male patient affected with schistosomal granulomatous lithiasic cholecystitis. The patient's gallbladder was badly inflamed therefore performing a safe cholecystectomy in the patient was extremely difficult. Also, infection with schistosoma is related with chronic granulomatous inflammation making the cholecystectomy procedure difficult and risky, therefore, we mainly focused on preventing the injury of bile duct by being prepared that the patient will present a complicated case. This was achieved by using the technique of laparoscopy to safely excise the gall bladder. PMID- 29968896 TI - Assessing periapical dental radiographs as a screening parameter for early indications of osteoporosis in postmenopausal periodontal patients and root surface evaluation using spectrochemical analysis. AB - OBJECTIVES: To assess the usefulness of periapical dental radiograph as a screening tool aimed at early signs of osteoporosis in postmenopausal periodontal patients and root surface evaluation using spectrochemical analysis. Methods: This study was conducted at the Department of Periodontics, Riyadh Elm University, Riyadh, Saudi Arabia, for 12 months between December 2016 and November 2017. Two groups consisted healthy postmenopausal women having chronic periodontitis and postmenopausal women having chronic periodontitis with osteoporosis. Osteoporosis were evaluated for plaque index (PI); gingival index (GI); clinical attachment level (CAL); probing pocket depth (PPD), and bone mineral density (BMD). A standardized digital dental periapical radiographs were taken for every patient. The spectrochemical analysis was carried out using the self-assembled Laser-Induced Breakdown Spectroscopy (LIBS) system used for qualitative and quantitative analysis of Calcium (Ca), Potassium (K), Phosphorus (P), Fluoride (F), and Magnesium (Mg). Results: There was no statistically significant difference between both groups for GI and PI. Similarly PPD and CAL were showing the difference but statistically, significant difference was only for CAL. Value of distance starting from cement enamel junction to the alveolar crest (CEJ-AC) and BMD were having a statistically significant variance between both groups. The differences between osteoporotic and control group were statistically significant regarding Ca with the mean higher in the control group. Furthermore, the variances between the groups in both K and Mg were statistically significant with higher mean in the osteoporotic group (p less than 0.05). Conclusion: The clinical, radiographic, and experimental findings of this study indicated that osteoporosis has a direct effect on the progression rate of periodontal tissue destruction and dental radiographic can be suggested as a screening tool for an early sign of osteoporosis. PMID- 29968898 TI - Untreated submandibular megalith for over 60 years. AB - Intra-parenchymal sialolithiasis and subsequent fibrosis of the submandibular salivary glands is a rare disorder. The resulting swelling, pain, and infection derives affected patients to seek treatment. We present the case of an 85-years old Saudi male patient who suffered from repeated swelling and infection in the left submandibular region which was misdiagnosed and treated for over 60 years as dental infection, infected skin sebaceous gland or lipoma. The presented case represents the largest intra-glandular submandibular stone with the longest duration ever reported in the medical literature. PMID- 29968899 TI - Spectrum of lymphoma in Bahrain. A retrospective analysis according to the World Health Organization classification. AB - OBJECTIVES: To determine the spectrum of various types of lymphoma in Bahrain according to the latest World Health Organization classification criteria. Methods: A retrospective review was conducted for all new lymphoma cases diagnosed at Salmaniya Medical Complex, Manama, Bahrain during the period from January 2010 to December 2015. Results: Two hundred and twenty-one new cases of lymphoma in Bahraini patients were diagnosed in the study period. Eighty patients had Hodgkin lymphoma, 140 had non-Hodgkin lymphoma, and one patient had composite lymphoma. In the Hodgkin lymphoma group, nodular sclerosis type was the most frequent type (48.75%), followed by mixed-cellularity type (27.5%), and nodular lymphocyte predominant type (16.25%). In the non-Hodgkin lymphoma group, 124 (88.6%) cases were B-cell lymphomas, while the remaining were T-cell lymphomas. Diffuse large B-cell lymphoma was the most frequent type of non-Hodgkin B-cell type lymphoma (55.7%), followed by follicular lymphoma (10%). Conclusion: The distribution of lymphoma in Bahrain is similar to neighboring Middle East countries with a predominance of Hodgkin lymphoma and diffuse large B-cell lymphoma. PMID- 29968900 TI - Serum anti-mullerian hormone levels in evaluation of chemotherapy effect on ovarian reserve in women with breast cancer. A follow-up study. AB - OBJECTIVES: To investigate the role of serum anti mullerian hormone (AMH) pre chemotherapy treatment levels in prediction of post-chemotherapy effect on the ovarian reserve of women with breast cancer. METHODS: This cohort prospective study was carried out at the Biochemistry Department, College of Medicine, University of Baghdad and at the Oncology Clinic, Oncology Teaching Hospital, Baghdad, Iraq. It included 58 women with regular menstrual cycle (25-45 years) who were newly diagnosed with breast cancer. The women were classified into 3 groups: GI: 30 women with breast cancer before starting chemotherapy, GII: the same 30 women of GI who finished 4 cycles of anthracycline chemotherapy (course 1) and GIII: which involved another 28 women who had finished both courses of chemotherapy, (course 1) and (course 2). RESULTS: The mean (+/-SEM) value of AMH levels was significantly decreased in GII and GIII when compared with GI (for both, p less than 0.0005). However, there was no significant difference in serum AMH levels between GII and GIII. CONCLUSION: The measurement of serum AMH may be a useful biochemical marker of the chemotherapy extent induced ovarian reserve damage and the incidence of amenorrhea. PMID- 29968901 TI - Asthma prevalence among adults in Saudi Arabia. AB - [No Abstract Available]. PMID- 29968902 TI - Glomerulonephritis disease pattern at Saudi tertiary care center. AB - [No Abstract Available]. PMID- 29968903 TI - PRP and MSCs on tenocytes artificial wound healing: an in vitro study comparing fresh and frozen PRP. AB - Tendon tissue has poor regenerative capacity due to its low vascularization, cell density and extracellular matrix (ECM) production. Therefore, tendon injuries are an increasing clinical problem because of the formation of scar tissue with traditional therapies. Regenerative medicine aims at triggering a healing response through the use of biological treatments such as mesenchymal stromal cells (MSCs) and growth factors (GFs). MSCs show several advantages in tendon clinical setting, while platelet rich plasma (PRP) has gained popularity because of its high GF concentration, although its applications in the tendon clinical setting are still controversial. The aim of the present study was to evaluate a combined treatment of MSCs and PRP in an in vitro microwound model of tendon injuries. In addition, fresh and frozen PRP were compared. Single human tenocytes cultures or co-cultures with bone marrow derived MSCs (BMSCs) were set up with or without human PRP, fresh or frozen. After 24 hours of culture, it was observed that MSCs alone significantly increased tenocyte migration speed, microwound healing rate, fibronectin, collagen I and aggrecan production. These effects were enhanced by the combination with PRP, fresh being more effective than frozen PRP. In addition, the number of MSCs and tenocytes inside the microwound was significantly increased, especially with fresh PRP. In conclusion, the combination of MSCs and PRP, especially the fresh one, increases tenocytes and MSC migration speed, as well as ECM protein production compared to the use of MSCs alone. PMID- 29968904 TI - Nucleolin protects against doxorubicin-induced cardiotoxicity via upregulating microRNA-21. AB - Nucleolin is a multifunctional protein and participates in many important biological processes. Our previous study found that nucleolin protects the heart against myocardial ischemia-reperfusion injury. In this study, we aimed to investigate the role of nucleolin in doxorubicin (DOX)-induced cardiotoxicity. The expression pattern of nucleolin in hearts subjected to DOX injury was investigated, and we found that administration of DOX induced nucleolin expression significantly in vivo and in vitro. Gene transfection and RNA interference approaches were used in cardiomyocytes to investigate the function of nucleolin. Nucleolin overexpression protects cardiomyocytes against DOX induced injury. Nucleolin-ablated cardiomyocytes become susceptible to the injury induced by DOX. The hearts of cardiac-myocyte-specific nucleolin transgenic mice are more resistant to DOX injury. Furthermore, nucleolin upregulates microRNA(miRNA)-21 expression in vivo and in vitro, and the miRNA-21 inhibitor negates the protective effect of nucleolin against injury induced by DOX. These results have demonstrated that nucleolin is involved in the regulation of DOX induced cardiac injury and dysfunction via the regulation of miRNA-21 expression, and may be a novel therapeutic target for DOX-induced cardiotoxicity. PMID- 29968905 TI - The role of hypoxia-inducible factor-2 alpha in angiogenesis. AB - Angiogenesis is a key enabling feature of mammalian embryonic development and tumor progression, which provides oxygen and nutrients that are required for vessel growth and tumor cell growth, respectively. Hypoxia is a driver of this phenomenon and is considered to be one of the most potent initiators of angiogenesis both in vitro and in vivo through stabilization of the transcription factors, hypoxia-inducible factor-1 and -2 (HIF-1 and HIF-2). Although these proteins are highly homologous, emerging evidence suggests that they have unique transcriptional targets and differential impact on angiogenesis. Although HIF 1alpha is the best known and widely described isoform, recent studies suggest that HIF-2alpha is a critical regulator of physiological and pathophysiological angiogenesis and, at least, the similiarly important as HIF-1alpha. Indeed, HIF 2alpha has been shown to regulate multiple aspects of angiogenesis, including cell proliferation, migration, maturation of blood vessels, and metastasis. In this review, we focus on recent insights into HIF-2alpha expression, activation, and function under hypoxic and nonhypoxic conditions. We also summarize the current knowledge on the crosstalk between HIF-2 and angiogenesis, describing reported phenotypical changes of HIF-2alpha genetic models and HIF-2 target genes implicated in angiogenesis. Finally, we provide a survey of recent pharmacologic strategies to specifically target HIF-2 activity. PMID- 29968907 TI - Integrating loop gain into the understanding of obstructive sleep apnoea mechanisms. PMID- 29968908 TI - Endometrial pinopode biomarkers: Molecules and microRNAs. AB - Ultrastructural changes on the apical surface of the luminal epithelium of the uterus are known as pinopodes. Their morphology in species and in special species is associated with different results about size, duration, and percentage of surface area covered by pinopodes. The content of pinopodes is different in rodents and humans. In mice and rats pinopodes have many vacuoles and no organelle that extends to the actin stalk above the microvilli. Human pinopodes do not have a large vacuole and contain the golgi complex, a rough endoplasmic reticulum, secretory vesicles, and mitochondria that extend from the entire cell surface. It has been suggested that pinopodes are good markers of endometrial receptivity and implantation window. There are several molecular markers related to the presence of pinopodes, including integrins, leukemia inhibiting factor (LIF), l-selectin, HOXA10, glutaredoxin, glycodelinA, heparin-binding epidermal growth factor, mucins, and microRNAs (miRNAs). Multiple lines of evidence have indicated that miRNAs could affect the expression of LIF and pinopodes in the endometrium and these molecules play key roles in implantation window processes. Here, we have summarized the morphology and function of pinopodes. Moreover, we have highlighted several molecules in relation to pinopodes that could be used as biomarkers. PMID- 29968909 TI - Trajectory analysis among African hominoids can provide insights into genetic and epigenetic influences during ontogeny. AB - OBJECTIVES: Prior examination of the ontogeny of Hominoid talo-crural joint morphology using Singular Warp analysis suggested both a genetic and epigenetic signal during development. This question is examined using trajectory analysis and its implications for the Hominin fossil record explored. MATERIALS AND METHODS: Trajectory analysis was used to examine talo-crural joint shape at different molar eruption stages during development among a cohort of 221 specimens of Homo sapiens, Gorilla gorilla, Pan troglodytes, and Pan paniscus. Trajectory length, angle, and shape were compared among species. Trajectories that showed a consistent pattern of shape change were predicted to show a genetic signal, while change in that pattern an epigenetic signal. RESULTS: The trajectories of all four hominoid tali were consistent during M1-M2 development, but there was a change in Pan paniscus alone at M2-M3. The tibial trajectories were again consistent in M1-M2 development, however, only Pan paniscus persisted in this trajectory at M2-M3 while the other three changed. DISCUSSION: Trajectory analysis demonstrated an epigenetic signal in Pan paniscus in the talus and among the other three hominoids in the tibia. Behavioral (epigenetic) changes may impact hominoid ankle shape in extant species. These changes may reflect differences in locomotor repertoire altering shape, as has been suggested in the Hominin fossil record. Further examination of closely related hominoid species may provide insights into potential behavioral influences in the rapid change and diversity of Hominin talo-crural shape in the Plio-pleistocene. PMID- 29968906 TI - Epithelial-to-mesenchymal transition and cancer stem cells contribute to breast cancer heterogeneity. AB - Breast cancer is the most common cancer in women, and accounts for ~30% of new cancer cases and 15% of cancer-related deaths. Tumor relapse and metastasis are primary factors contributing to breast cancer-related deaths. Therefore, the challenge for breast cancer treatment is to sustain remission. A driving force behind tumor relapse is breast cancer heterogeneity (both intertumor, between different patients, and intratumor, within the same tumor). Understanding breast cancer heterogeneity is necessary to develop preventive interventions and targeted therapies. A recently emerging concept is that intratumor heterogeneity is driven by cancer stem cells (CSCs) that are capable of giving rise to a multitude of different cells within a tumor. Studies have highlighted linkage of CSC formation with epithelial-to-mesenchymal transition (EMT). In this review, we summarize the current understanding of breast cancer heterogeneity, links between EMT and CSCs, regulation of EMT by Runx transcription factors, and potential therapeutic strategies targeting these processes. PMID- 29968910 TI - C6 ceramide motivates the anticancer sensibility induced by PKC412 in preclinical head and neck squamous cell carcinoma models. AB - The purpose of this study was to evaluate the anti-head and neck squamous cell carcinoma (anti-HNSCC) cell activity by C6 ceramide and multikinase inhibitor PKC412. Experiments were performed on HNSCC cell lines (SQ20B and SCC-9) and primary human oral carcinoma cells. Results showed that PKC412 inhibited HNSCC cell proliferation without provoking apoptosis activation. Cotreatment of C6 ceramide significantly augmented PKC412-induced lethality in HNSCC cells. PKC412 decreased Akt-mammalian target of rapamycin (mTOR) activation in HNSCC cells, facilitated with cotreatment of C6 ceramide. In contrast, exogenous expression of a constitutively active Akt restored Akt-mTOR activation and attenuated lethality by the cotreatment. We propose that Mcl-1 is a primary resistance factor of PKC412. The cytotoxicity of PKC412 in HNSCC cells was potentiated with Mcl-1 short hairpin RNA knockdown, but was attenuated with Mcl-1 overexpression. Intriguingly, C6 ceramide downregulated Mcl-1 in HNSCC cells. In vivo, PKC412 oral administration inhibited SQ20B xenograft tumor growth in severe combined immunodeficient mice. The antitumor activity of PKC412 was further sensitized with coadministration of liposomal C6 ceramide. Together, we suggest that PKC412 could be further studied as a promising anti-HNSCC strategy, alone or in combination with C6 ceramide. PMID- 29968911 TI - High prevalence of serum IgG antibodies reacting to specific mimotopes of BK polyomavirus, a human oncogenic polyomavirus, in patients affected by uveal melanoma. AB - The uveal melanoma (UM) is the most common human intraocular tumor. The BK polyomavirus (BKPyV) is a small DNA tumor virus whose footprints have been detected in different human cancers. BKPyV has oncogenic potential. Indeed, BKPyV, when inoculated into experimental animals, induces tumors of different histotypes, whereas in vitro, it transforms mammalian cells, including human cells from distinct tissues. In this investigation, the association between UM and BKPyV was studied employing indirect enzyme-linked immunosorbent assays (ELISAs) using synthetic peptides that mimic BKPyV viral capsid 1 (VP1) antigens. Indirect ELISAs were used to detect serum IgG antibodies against this polyomavirus with oncogenic potential in samples from patients with UM and controls, represented by healthy subjects (HS). It was found that serum samples from patients with UM had a higher prevalence of BKPyV antibodies, 85% (51/60), compared with that detected in HS1, 62% (54/87), and HS2, 57% (68/120). The different prevalence of BKPyV antibodies detected in UM versus the two control groups, HS1 and HS2, is statistically significant (p < 0.005). Our immunologic data suggest a significantly higher prevalence of antibodies against BKPyV VP1 epitopes in serum samples from patients with UM compared with HS. These results indicate an association between UM and BKPyV, suggesting that this small DNA tumor virus may be a cofactor in the UM onset or progression. PMID- 29968912 TI - Study on the mechanism behind lncRNA MEG3 affecting clear cell renal cell carcinoma by regulating miR-7/RASL11B signaling. AB - The goal of this research was to study the relationships between maternally expressed gene 3 (MEG3), microRNA-7 (miR-7), and RASL11B, and explore their influence on the progression of clear cell renal cell carcinoma (CCRCC). Microarray analysis was conducted using the data provided by The Cancer Genome Atlas. The expression levels of MEG3 and miR-7 in CCRCC and adjacent tissue samples were ascertained by quantitative real-time polymerase chain reaction (qRT PCR). The cell proliferation activity was unmasked by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay, and cell apoptosis and cell cycle were investigated by flow cytometry. A dual luciferase reporter assay was used to verify target relationships. Wound healing assay and transwell assay were used to detect cell migration and invasion ability. Decreased MEG3 expression was observed in CCRCC tissues and cells. Overexpression of MEG3 accelerated apoptosis; inhibited cell proliferation, migration and invasion; and induced G0/G1 phase cell cycle arrest in CCRCC. MiR-7, directly binding to MEG3, was overexpressed in the CCRCC tissues and could inhibit the apoptosis and promote the migration and invasion of CCRCC cells. RASL11B, lowly expressed in CCRCC, was a target of miR-7. After the overexpression of RASL11B, G0/G1 phase cell cycle arrest was induced; cell apoptosis was promoted; and the proliferation, invasion, and migration of CCRCC cells were inhibited. MEG3 could up-regulate RASL11B to inhibit the cell proliferation, invasion, and migration; induce G0/G1 cell cycle arrest; and promote cell apoptosis by suppressing miR-7 in CCRCC. PMID- 29968914 TI - Scientific Presentation Abstracts: 2018 European College Veterinary Surgeons Annual Scientific Meeting, July 4-6, 2018 - Athens, Greece. PMID- 29968913 TI - The protective role of curcumin in myocardial ischemia-reperfusion injury. AB - Coronary artery disease (CAD) is a well-known pathological condition that is characterized by high morbidity and mortality. The main pathological manifestation of CAD is myocardial injury due to ischemia-reperfusion (I-R). Currently, no efficacious treatment of protecting the heart against myocardial I R exists. Hence, it is necessary to discover or develop novel strategies to prevent myocardial-reperfusion injury to improve clinical outcomes in patients with CAD. A large body of experimental evidence supports cardioprotective properties of curcumin and the ability of this phytochemical to modify some cardiovascular risk factors. However, the detailed effects of curcumin in myocardial I-R injury are still unclear and there is a lack of evidence concerning which curcumin regimen may be ideal for myocardial I-R injury. This paper presents a brief review of the pathophysiology of myocardial I-R injury and the mechanisms of action of curcumin in reducing myocardial I-R injury. PMID- 29968915 TI - Living on the Margins of Democratic Representation: Socially Connected Community Responsibility as Civic Engagement in an Unincorporated Area. AB - We examine the civic engagement processes and practices among Viva Live Oak! photovoice project participants residing in an unincorporated area with limited local democratic representation and institutional resources. Eight individual interviews and thirty-one group photovoice meetings were conducted, audio recorded, transcribed, and analyzed. We describe how social structures of unincorporation shaped community life, and how this unique context informed participants' civic engagement. We argue for a conceptualization of civic engagement that centers a social connection model of community responsibility, to make legible the social, relational, and civic actions of unincorporated area residents. PMID- 29968916 TI - Sentinel lymphadenectomy in cervical cancer using near infrared fluorescence from indocyanine green combined with technetium-99m-nanocolloid. AB - OBJECTIVE: Sentinel diagnostic in cervical cancer is performed using Technetium 99m-nanocolloid as a radioactive marker with or without patent blue. In the last years, indocyanine green has been evaluated for sentinel diagnostic in different tumor entities. Indocyanine green is a fluorescent molecule which emits a light signal in the near infrared band after excitation. Our study aims to evaluate indocyanine green compared to the gold standard Tc-99m-nanocolloid. MATERIALS AND METHODS: We included patients with early cervical cancer up to FIGO stage IIA with clinically node-negative pelvic sites and the indication for nodal staging in this prospective trial. Sentinel diagnostic was carried out using Tc-99m nanocolloid, indocyanine green and patent blue. We examined each pelvic site for light signals from the near infrared band, for radioactivity and for blue staining. A sentinel lymph node was defined as a Tc-99m-nanocolloid positive lymph node. All sentinel lymph nodes and all additional blue or fluorescent lymph nodes were excised and tested; then sent to histologic examination. RESULTS: Thirty-three patients were included in which we found 211 Tc-99m-nanocolloid positive sentinel lymph nodes in 66 pelvic sites. Two hundred and seven of these lymph nodes were positive for indocyanine green, too, giving a sensitivity of 98.1% (95%CI 94.9-99.4%) compared to Tc-99m-nanocolloid. One hundred and sixty additional lymph nodes showed indocyanine green fluorescence but no Tc-99m positivity, so that the sensitivity was 79.6% (95%CI 76.6-82.3%). In one patient, a pelvic site was only identified to be tumor infiltrated due to an ICG-positive, but Tc-99m-negative lymph node. CONCLUSION: Our results show that indocyanine green is a promising approach for pelvic sentinel identification in cervical cancer. ICG has a similar sensitivity as radioactive Tc-99m-nanocolloid and may enhance both patient safety and surgeons' comfort. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 29968917 TI - Inflammation Due to Voriconazole-induced Photosensitivity Enhanced Skin Phototumorigenesis in Xpa-knockout Mice. AB - Voriconazole is an antifungal agent and used as a prophylactic measure, especially in immunocompromised patients. However, there have been several reports of its adverse reactions, namely photosensitivity with intense inflammatory rashes and subsequent skin cancer development. To assess the effects of photosensitizing drugs voriconazole and hydrochlorothiazide (HCTZ) on the enhancement of UV-induced inflammatory responses and UV-induced tumorigenesis, we utilized Xpa-knockout mice, which is DNA repair-deficient and more susceptible to UV-induced inflammation and tumor development than wild-type mice. Administration of voriconazole prior to broadband UVB exposure significantly upregulated multiple inflammatory cytokines compared with the vehicle- or HCTZ-administered groups. Voriconazole administration along with chronic UVB exposure produced significantly higher number of skin tumors than HCTZ or vehicle in Xpa-knockout mice. Furthermore, the investigation of UVB-induced DNA damage using embryonic fibroblasts of Xpa-knockout mice revealed a significantly higher 8-oxo-7,8 dihydroguanine level in cells treated with voriconazole N-oxide, a voriconazole metabolite during UV exposure. The data suggest that voriconazole plus UVB induced inflammatory response may be related to voriconazole-induced skin phototumorigenesis. PMID- 29968918 TI - IS REFLECTIVE SUPERVISION ENOUGH? AN EXPLORATION OF WORKFORCE PERSPECTIVES. AB - Infant mental health practice requires the performance of intense emotional labor. Professionals comprising the infant mental health (IMH) field are largely women at seminal points in adult life-span development. The purpose of this article is to explore the day-to-day challenges faced by clinical infant mental health professionals and their perspectives on the supports available for effective job performance. We review reflective supervision as a long-cherished professional support in the IMH field designed to hold the practitioner's fears, worries, and ambivalence, so that she may return to the work fortified to remain in therapeutic alliance with families despite unsolvable problems and an unknowable future (Weatherston, D., 2009). Yet, we propose that reflective supervision alone may not be an adequate protective measure for a workforce performing intensive emotional labor for extended periods and therefore at potentially increased risk for burnout and high turnover (Hochschild, A.R. ; C. Maslach, , C.M. Brotheridge & A.A. Grandey, 2009; A.S. Wharton, ). We suggest that structural factors concerning organizational culture, flexibility in scheduling, and professional growth and versatility bear deeper examination for their merits in supporting the IMH workforce. Finally, we contend that the overrepresentation of women in practitioner positions in IMH leaves an empirical gap where little is known about the experience of male IMH practitioners and the ramifications of their performance of emotional labor. PMID- 29968919 TI - Estimating the mitigation effect of Tokai earthquake measures on housing damage: a counterfactual approach. AB - This paper evaluates the mitigation effect of Tokai earthquake measures on housing damage using a counterfactual approach. It focuses on those measures that stimulate ex-ante investment in disaster prevention in the supposedly affected area, including earthquake-proof retrofitting and improved housing construction; the effect of the measures on housing losses is estimated monetarily. The study compares factual disaster damage computed using a real distribution of houses with counterfactual damage to a hypothetical housing distribution that would occur if the measures were not implemented. The key findings are: (i) the disaster mitigation effects of Tokai earthquake measures on housing amount to approximately JPY 18 billion (USD 0.18 billion) for Yamanashi Prefecture and JPY 0.26 trillion (USD 2.6 billion) for Shizuoka Prefecture, which would be at the centre of the event; (ii) a before-after comparison biases estimates of the mitigation effect; and (iii) statistically, the measures do not mitigate the housing damage predicted for an earthquake in Tokai. PMID- 29968920 TI - Insulin stimulus-secretion coupling is triggered by a novel thiazolidinedione/sulfonylurea hybrid in rat pancreatic islets. AB - New compounds with promising antidiabetic activity were synthesized. For the first time, a portion of the glibenclamide molecule was bound to a part of the core structure of thiazolidinedione to evaluate insulin secretagogue activity. Following studies in our laboratory, 4-{2-[2-(3,4-dichlorophenyl)-4-oxo-1,3 thiazolidin-3-yl]ethyl}benzene-1-sulfonamide (DTEBS) was selected to evaluate glycemia using the glucose tolerance test and insulin secretagogue activity by E.L.I.S.A. The mechanism of action of this compound was studied by 45 Ca2+ influx and whole-cell patch-clamp in rat pancreatic isolated islets. Furthermore, AGE formation in vitro was investigated. We herein show that this novel hybrid compound (DTEBS) exhibits an insulinogenic index and a profile of serum insulin secretion able to maintain glucose homeostasis. Its mechanism of action is mediated by ATP-sensitive potassium channels (KATP) and L-type voltage-dependent calcium channels (VDCC) and by activating protein kinase C and A (PKC and PKA). In addition, the stimulatory action of the compound on calcium influx and insulin secretion indicates that the potentiation of voltage-sensitive K+ currents (Kv) is due to the repolarization phase of the action potential after secretagogue excitation-secretion in pancreatic islets. Furthermore, under these experimental conditions, the compound did not induce toxicity and the in vitro late response of the compound to protein glycation reinforces its use to prevent complications of diabetes. DTEBS exerts an insulin secretagogue effect by triggering KATP, VDCC, and Kv ionic currents, possibly via PKC and PKA pathway signal transduction, in beta-cells. Furthermore, DTEBS may hold potential for delaying the late complications of diabetes. PMID- 29968922 TI - Corrigendum. PMID- 29968925 TI - Ribosomal RNA - a tail wagging the dog? AB - It is an intriguing hypothesis that the complex organization of neuronal dynamics important for a memory engram is largely underpinned by the regulation of nucleolar functioning. This Editorial highlights a study by Capitano and coworkers in this issue of the Journal of Neurochemistry, in which the authors tackle this hypothesis with a behavioral approach. The study investigates the role of axo-dendritic mRNAs within learning-induced plasticity and in vivo modulation of rRNA transcription in response to spatial learning. The authors confirm with their in vivo approach what is known from many earlier in vitro experiments: efficient learning and memory requires a proper homeostasis of hippocampal neurons in general, which, however, depends crucially on proper integrity of the nucleolus. Read the highlighted article 'RNA polymerase I transcription is modulated by spatial learning in different brain regions' on page 706. PMID- 29968926 TI - Cistanche deserticola polysaccharide attenuates osteoclastogenesis and bone resorption via inhibiting RANKL signaling and reactive oxygen species production. AB - Osteoporosis is a metabolic disease characterized by osteopenia and bone microstructural deterioration. Osteoclasts are the primary effector cells that degrade bone matrix and their abnormal function leads to the development of osteoporosis. Reactive oxygen species (ROS) accumulation during cellular metabolism promotes osteoclast proliferation and differentiation, therefore, playing an important role in osteoporosis. Cistanche deserticola polysaccharide (CDP) possesses antitumor, anti-inflammatory, and antioxidant activity. However, the impact of CDP on osteoclasts is unclear. In this study, tartrate-resistant acid phosphatase staining, immunofluorescence, reverse transcription-polymerase chain reaction, and western blot analysis were utilized to demonstrate that CDP inhibited osteoclastogenesis and hydroxyapatite resorption. In addition, CDP also inhibited the expression of osteoclast maker genes including Ctsk, Mmp9, and Acp5 and had no effect on receptor activator of nuclear factor kappaB (RANK) expression. Mechanistic analyses revealed that CDP increases the expression of antioxidant enzymes to attenuate RANKL-mediated ROS production in osteoclasts and inhibits nuclear factor of activated T cells and mitogen-activated protein kinase activation. These results suggest that CDP may represent a candidate drug for the treatment of osteoporosis caused by excessive osteoclast activity. PMID- 29968927 TI - IMPACT OF REFLECTIVE SUPERVISION ON EARLY CHILDHOOD INTERVENTIONISTS' PERCEPTIONS OF SELF-EFFICACY, JOB SATISFACTION, AND JOB STRESS. AB - Despite widespread recognition of the importance of reflective practice in the field of infant mental health, little quantitative research exists regarding the impact of reflective supervision on professionals' self-efficacy, job satisfaction, and work-related stress. Thirty-three early childhood interventionists received approximately 9 months of reflective supervision and completed pre- and post-assessments of their job-related stress and self-efficacy using a modified version of the Reflective Supervision Self-Efficacy Scales for Supervisees (S. Shea, S. Goldberg, & D.J. Weatherston, 2012). At the post assessment, participants also rated their overall experience of reflective supervision. Reported self-efficacy increased significantly from pre- to post assessment, and participants reported a positive overall impact of reflective supervision with respect to a variety of indices, such as job satisfaction, professional development, and the ability to cope with job-related stress. These results provide necessary quantitative data demonstrating a positive impact of reflective supervision on early childhood professionals and suggest the value of reflective supervision for supporting workforce development. PMID- 29968928 TI - Pregnancy unshackled: Increasing equity through implementation of perinatal depression screening, shared decision making, and treatment for incarcerated women. AB - BACKGROUND: Perinatal depression (PD) is one of the most common medical complications of pregnancy. The prevalence of women in correctional settings has grown eight-fold in the last 30 years. A quarter of these women were either pregnant or within a year postpartum when entering custody. Recommendations to screen and treat all pregnant women for PD are being implemented nationwide. LOCAL PROBLEM: In 2016, 71% of pregnant women entering Milwaukee County Jail had minimal or no prenatal care and significant rates of high-risk medical and social risk factors. The jail system was not screening for PD. METHODS: The Plan-Do Study-Act method of quality improvement (QI), with four rapid cycles, was utilized. Patient tracer interviews and refusal rates were collected for baseline data two months preceding implementation. Data was analyzed using run charts to evaluate the impact of interventions on outcomes. INTERVENTION: PD screening was implemented with the Edinburgh Perinatal Depression Scale, and if scored positive, the Healthwise shared decision-making tool was utilized for therapy options and treatment initiated. RESULTS: A total of 101 women were seen, 93 were offered screening, 76 were screened, 43 were positive, and 37 started treatment within the facility. That is, 46% to 57 % of this aggregate of women who screen positive for PD and a decrease in patient refusal rates was seen throughout the process. CONCLUSION: Rapid cycle QI was effective in standardizing PD screening and treatment. Replication of this project across correctional systems would help to bridge a gap of equitable care for incarcerated women. PMID- 29968929 TI - Hurricane storm surge in Volusia County, Florida: evidence of a tipping point for infrastructure damage. AB - Storm surge often is the most destructive consequence of hurricanes and tropical storms, causing significant economic damage and loss of life. Many coastal communities that are located in high-risk areas vis-a-vis hurricanes and tropical storms are prepared for moderate (between six and eight feet) storm surges. Such preparation, though, is not commensurate with more severe, but less frequent, storm surges (greater than eight feet). These gaps in preparedness have serious implications for community resilience. This paper explores elements of the vulnerability and resilience of coastal communities during major storm surge events, drawing on Volusia County, Florida, United States, as a case study. It simulates the impacts of five hurricanes (Categories I-V) and their associated storm surges on local infrastructure systems, populations, and access to resources. The results suggest that Volusia County is subject to a 'tipping point' , where surge damage from Category IV storms is significantly greater than that from Category III and lower hurricanes. PMID- 29968930 TI - Barriers or enablers? Chiefs, elite capture, disasters, and resettlement in rural Malawi. AB - Chiefs are at the centre of household and community development efforts in most low-income countries around the world. Yet, researchers and scholars have paid limited attention to the institution of chieftaincy and to understanding its role in the management of climate change adaptation and disaster risk reduction. This paper draws on a micro ethnographic evaluation conducted in two predominantly rural districts of Malawi in southeast Africa to assess two different manifestations of elite control. In the first case, a resettlement programme was implemented where chiefs were co-opted and took the lead. In the second case, a food insecurity response programme was designed to exclude chiefs. The study finds that neither co-opting nor countering chiefs prevents elite capture. Rather, the majority of chiefs oscillate between malevolent and benevolent capture. The findings require that states focus on the cultural and political dimensions of rural life when designing climate change adaptation and disaster risk reduction programmes. PMID- 29968931 TI - Role of differentially expressed genes and long non-coding RNAs in papillary thyroid carcinoma diagnosis, progression, and prognosis. AB - Currently, the combination of ultrasonography and fine-needle aspiration biopsy (FNAB) can not discriminate between benign and malignant tumor of thyroid in some cases. The main issue in assessing the patients with thyroid nodules is to distinguish thyroid cancer from benign nodules, and reduce diagnostic surgery. To identify potential molecular biomarkers for patients with indeterminate FNAB, we explored the differentially expressed genes (DEGs) and differentially expressed long non-coding RNAs (DElncRNAs) in TCGA database between 318 papillary thyroid carcinoma (PTC) tissues and 35 normal thyroid gland tissues by DESeq R. Furthermore, DEGs were verified by gene expression profile GSE33630. Ten top DEGs and DElncRNAs were identified as candidate biomarkers for diagnosis and Lasso (Least Absolute Shrinkage and Selection Operator) logistic regression analysis were performed to improve the diagnostic accuracy of them. Besides, partial molecular biomarkers of top DEGs and DElncRNAs were closely related to the tumor stage (T), lymph node metastasis (N), metastasis (M) and pathological stage of PTC, which could reflect behavior of tumor progression. According to multivariate Cox analysis, the combination of two DEGs (METTL7B and KCTD16) and two DElncRNAs (LINC02454 and LINC02471) could predict the outcome in a more exact way. In conclusion, top DEGs and DElncRNAs could raise diagnosis of PTC in indeterminate FNAB specimens, and some could function as molecule biomarkers for tumor progression and prognosis. PMID- 29968932 TI - Effects of lentiviral transfection containing bFGF gene on the biological characteristics of rabbit BMSCs. AB - To investigate the effect of lentiviral transfection containing bFGF gene on the biological characteristics of bone marrow stromal cells (BMSCs). BMSCs were obtained by density gradient centrifugation and adherence screening. The bFGF gene was transfected into BMSCs by lentiviral vector and divided into bFGF transfection group, empty virus group, and untransfected group according to the transfection conditions. After transfection, the morphology, expression of bFGF mRNA and protein, cell proliferation, cell cycle, and alkaline phosphatase (ALP) activity were observed in three groups of cells. High density BMSCs were successfully obtained by density gradient centrifugation and adherence screening. After transfection of BMSCs with bFGF gene, the cell morphology did not change significantly, while the expression of bFGF mRNA and protein were significantly increased, the cell proliferation curve shifted upward, the proportion of proliferating cells increased, and the activity of ALP was significantly enhanced. Compared with empty virus group and untransfected group, there was significant difference (P < 0.05). The rabbit bFGF gene was successfully introduced into the BMSCs cultured in vitro by lentiviral vector, and the target gene was stably expressed. And the expression of bFGF can promote the proliferation and osteogenic differentiation of BMSCs. PMID- 29968933 TI - Stratification of hepatocellular carcinoma risk through modified FIB-4 index in chronic hepatitis B patients on entecavir therapy. AB - BACKGROUND AND AIM: Noninvasive fibrosis indices can predict the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Modified FIB-4 (mFIB-4) is a promising noninvasive index for predicting liver fibrosis. To investigate the predictive accuracy of several extant noninvasive fibrosis indices, including mFIB-4, for HCC incidence in CHB patients receiving long-term entecavir therapy. METHODS: We enrolled 1325 nucleos(t)ide analogue naive CHB patients (noncirrhotic 844; cirrhotic 481) treated with entecavir. Baseline clinical features and fibrosis indices were collected and evaluated for predicting HCC risk through univariate and multivariate Cox regression analyses. RESULTS: Of the 1325 patients, 105 (7.9%) developed HCC during a median follow-up period of 4.1 years. Age (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.020-1.059; P < 0.0001), diabetes mellitus (DM) (HR, 1.902; 95% CI, 1.185-3.052; P = 0.0077), and mFIB-4 (HR, 4.619; 95% CI, 1.810-11.789; P = 0.0014) were independent predictors of HCC in all patients (mFIB-4 >= 1.5 for the noncirrhotic cohort; DM and mFIB-4 >= 2.0 for the cirrhotic cohort). A combination of mFIB-4 and the DM status stratified the cumulative risk of HCC into three subgroups in all patients (high: mFIB-4 >= 1.5/DM; intermediate: mFIB-4 >= 1.5/non-DM; and low: mFIB-4 < 1.5, P < 0.0001) and in the cirrhotic cohort (high: mFIB-4 >= 2.0/DM; intermediate: mFIB-4 >= 2.0/non-DM; and low: mFIB-4 < 2.0, P = 0.0007). An mFIB-4 cutoff value of 1.5 stratified the cumulative risk of HCC in the noncirrhotic cohort (P = 0.015). CONCLUSIONS: The mFIB-4 index alone or in combination with DM is the optimal noninvasive predictor of HCC risk in CHB patients receiving entecavir therapy. PMID- 29968935 TI - A Crisis of Care: The Politics and Therapeutics of a Rape Crisis Hotline. AB - This article explores the politics and contingencies of care provided to survivors of sexual assault on a rape crisis hotline in the U.S.'s mid-Atlantic region. The support provided to survivors on the hotline represents a crisis of care, one fomented by the victim services sector's failure to address the limitations of a crisis-oriented paradigm or survivors' chronic trauma. The tension between the survivor-centered model of the hotline and the mental health needs of clients represents a friction of utility-a misalignment between the care hotline advocates provide and the support survivors seek. The anonymous care and internal contradictions of the hotline also results in high rates of vicarious trauma for advocates. Given the polysemic dimensions of care exhibited on the hotline, the service represents a form of negative care, one that accounts for gaps in survivors' care yet still fails to empower proactive means of recovery. PMID- 29968934 TI - Use of a national identification database to determine the lifetime prognosis in cattle with necrotic laryngitis and the predictive value of venous pCO2. AB - BACKGROUND: Necrotic laryngitis, caused by Fusobacterium necrophorum, frequently requires surgical intervention (laryngostomy) in the chronic stage. HYPOTHESIS/OBJECTIVES: To determine survival until slaughter of cattle surgically treated for necrotic laryngitis and to identify predictors of mortality. ANIMALS: A total of 221 cattle diagnosed with necrotic laryngitis by laryngoscopy and surgically treated METHODS: Retrospective cohort study. Clinical records were matched with the national cattle identification, registration, and movement database. Information on possible predictors including clinical examination, biochemistry, and surgery was collected. A multivariable Cox proportional hazard model was used to identify predictors of mortality. RESULTS: The overall survival rate was 65.2% and 58.6% of the animals with a completed life cycle could be slaughtered. Animals <6 months old experienced significantly higher mortality risk (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5). The venous partial pressure of carbon dioxide (pCO2 ; HR, 2.4; 95% CI, 1.4-4.2) at a 64.5 mm Hg cut-off was most significantly associated with mortality. Sensitivity and specificity of the final model consisting of age and pCO2 were 49.1 and 86.4%, respectively. Instead of pCO2 , total carbon dioxide (TCO2 ) could also be used, with similar diagnostic accuracy. CONCLUSIONS AND CLINICAL RELEVANCE: The lifetime prognosis for chronic necrotic laryngitis in cattle with surgical intervention appears fair. Age, venous pCO2 and TCO2 are easily accessible predictors of survival to support owners and veterinarians in their decision process of whether or not to operate and to identify high risk animals that require more intensive follow-up. PMID- 29968937 TI - Fecal immunochemical test in colorectal cancer screening: Colonoscopy findings by different cut-off levels. AB - BACKGROUND AND AIM: Fecal immunochemical test (FIT) is used in colorectal cancer (CRC) screening, but number of tests and cut-off level differ by program. The aim was to evaluate CRC screening with two FIT samples in average-risk 60-year-old men and women and to investigate hemoglobin (Hb) level in correlation to adenoma characteristics. METHODS: We analyzed a cohort from Screening of Swedish Colons trial where participants with at least one of two FIT samples >=10 MUg Hb/g are offered colonoscopy. FIT levels and colonoscopy findings were assessed in multivariable analyses. Cut-off levels 10-80 MUg Hb/g for one and two samples were assessed. FIT levels and advanced neoplasia (AN) were investigated by gender. RESULTS: A total of 12 383 participated and 1182 positives (551 women) completed colonoscopy diagnosing 27 (2.3%) CRC and 269 (23%) advanced adenomas (AA). Median FIT level was 241.0 and 23.8 for CRC and AA compared with 13.4-15.8 in other subgroups (P = 0.002) correlating with adenoma size (P = 0.038). CRC was detected in 22 and 19 subjects for the first sample at cut-off 20 and 40 MUg Hb/g, compared with 20 and 17 for the mean of two samples at cut-off 40 and 80 MUg Hb/g (P < 0.05). Men had more AN (CRC + AA), (P = 0.003). In women, similar number of AN would be detected with cut-off lowered from 40 to 20 or from 80 to 40 MUg Hb/g, requiring additional 26-34% colonoscopies. CONCLUSION: In average risk 60-year-olds, FIT was higher in participants with AN and correlated with adenoma size. FIT screening with one sample at low cut-off detected more CRC than two samples at higher cut-off. Applying lower cut-off in women to equalize gender differences in AN would result in considerable increase in colonoscopy workload. PMID- 29968936 TI - Acute echocardiographic effects of sotalol on ventricular systolic function in dogs with ventricular arrhythmias. AB - BACKGROUND: Sotalol is a commonly used antiarrhythmic drug that may alter ventricular function. OBJECTIVE: To determine the effect of sotalol on echocardiographic indices of ventricular systolic function in dogs with ventricular arrhythmias. ANIMALS: Thirty-five client-owned dogs with ventricular arrhythmias. METHODS: Dogs with ventricular arrhythmias (n = 27) had an echocardiogram and 5-minute ECG performed at baseline and 2-4 hours post-sotalol (2-2.5 mg/kg PO once). Eight additional dogs underwent the same protocol but did not receive sotalol (within-day variability controls). Left ventricular (LV) internal dimension at end-systole normalized to bodyweight (LVIDs_N), LV ejection fraction (LV EF), LV shortening area, LV fractional shortening, tricuspid annular plane systolic excursion (TAPSE), and right ventricular systolic myocardial velocity were evaluated as indices of systolic function. RESULTS: All indices except TAPSE had mild decreases in systolic function post-sotalol (all P <= .0007) compared with baseline but only the percent change in LVIDs_N and LV EF were significantly (P <= .0079) different from the percent change of the same indices in control dogs. Sinus heart rate, ventricular premature complexes/5 minutes, and arrhythmia grade also were decreased post-sotalol (all P <= .01) compared with baseline when assessed by a 5-minutes ECG. No dog experienced an adverse event post-sotalol, including dogs with systolic dysfunction or atrial enlargement. CONCLUSIONS AND CLINICAL IMPORTANCE: A single dose of sotalol may cause a mild decrease in LV systolic function in dogs with ventricular arrhythmias. Sotalol appears to be well tolerated, even in dogs with atrial enlargement or systolic dysfunction. PMID- 29968938 TI - Normal, Abnormal, and Cascade Wittig Olefinations of alpha-Oxoketenes. AB - alpha-Oxoketenes generated in situ by a thermal Wolff rearrangement have been found to participate as 1,2- and 1,4-ambident C-electrophilic/O-nucleophilic reagents towards donor/acceptor carbonyl-stabilized Wittig ylides. This resulted in the very direct and practical syntheses of functionalized allenes by a normal Wittig olefination, 4H-pyran-4-ones by an abnormal Wittig olefination, or 4H pyranylidenes following a Wittig/abnormal Wittig cascade sequence as a function of the substrates combination employed. Mechanistic experimental and computational studies provided a full rational for these reactivity switches. Some unusual mechanistic features for Lewis acid-free Wittig olefinations were identified in this series such as the involvement of betaine intermediates and some degree of reversibility in the normal Wittig olefination. The abnormal Wittig olefination was fully uncovered. PMID- 29968939 TI - The Binds of Global Health Partnership: Working out Working Together in Sierra Leone. AB - Global health partnerships (GHPs) are the conceptual cousin of partnerships in the development sphere. Since their emergence in the 1990s, the GHP mode of working and funding has mainly been applied to single-disease, vertical interventions. However, GHPs are increasingly being used to enact Health Systems Strengthening and to address the global health worker shortage. In contrast to other critical explorations of GHPs, we explore in this article how the fact, act, and aspiration of binding different actors together around the ideology and modes of partnership working produces the perpetual state of being in a bind. This is an original analytical framework drawing on research in Sierra Leone and London. We offer new insights into the ways in which GHPs function and are experienced, showing that along with the successes of partnership work, such arrangements are often and unavoidably tense, uncomfortable, and a source of frustration and angst. PMID- 29968940 TI - The planning of propeller perforator flap on previously transferred musculocutaneous flap via multidetector computed tomography for the reconstruction of tissue defect overlying Achilles tendon. PMID- 29968941 TI - Supplemental methionine sources have a neutral impact on oxidative status in broiler chickens. AB - To determine the effect of different dietary Met sources on oxidative status, male Cobb 500 broiler chickens were fed from day of hatch to 26 days of age (d26) a diet deficient in sulfur amino acids (control) or a diet containing 0.22% DL Met, 0.22% L-Met or 0.31% Met precursor, DL-2-hydroxy-4-(methylthio) butanoic acid (DL-HMTBA) to meet the Met + Cys requirements. Liver, breast muscle, duodenum, jejunum, and ileum were collected at day 10 (d10) and d26 to assay markers of oxidative stress, including total glutathione (TGSH), oxidized glutathione (GSSG), reduced glutathione (rGSH), protein carbonyls, thiobarbituric acid reactive substances (TBARS) and ferric reducing/antioxidant power (FRAP). In breast muscle, TGSH and rGSH were greater in L-Met and DL-HMTBA groups than in the control group (p < 0.05). An interaction of treatment and age was observed for TGSH in ileum (p = 0.01) and jejunum (p = 0.01), for GSSG in jejunum (p < 0.001), and for rGSH in ileum (p = 0.02). The ratios of rGSH to GSSG and GSSG to TGSH, which define oxidative status, were not affected by Met source. Protein carbonyls varied among groups in jejunum (p = 0.05) and breast muscle (p < 0.001), but were in the normal physiological range. No difference among treatment groups was observed for TBARS and FRAP in different tissues. Age effects were observed in all tissues for multiple oxidative stress markers. In conclusion, consuming different sources of supplementary Met did not alter the oxidative status in several tissues of broilers. Met + Cys deficiency did not compromise antioxidant capacity of chickens although growth was retarded. PMID- 29968942 TI - The LncRNA H19/miR-193a-3p axis modifies the radio-resistance and chemotherapeutic tolerance of hepatocellular carcinoma cells by targeting PSEN1. AB - This study was designated to verify if the lncRNA H19/miR-193a-3p axis would play a regulatory role in the radio-/chemo-resistances of HCC cells through targeting PSEN1. Within the study, five human HCC cell lines were prepared, including Bel 7402, HepG2, Hep3b, QGY-7703, and SMMC-7721. Moreover, docetaxel (DT), paclitaxel (Pt), vinorelbine (Vb), and 5-fluorouracil (5-Fu) were managed as the chemo therapeutics, and single-dose X-rays were performed as radio-therapies. Besides, lncRNA H19 and miR-193a-3p were detected by qRT-PCR and Western blot were implemented to quantify the expressional levels of PSEN1, Ku80, gamma-H2AX, and RAD51. Luciferase reporter gene assay was advanced to verify the targeted relationship between lncRNA H19 and miR-193a-3p. As a consequence, QGY-7703 and Bel-7402 were, respectively, the most radiation-sensitive and radiation-proof cell lines, and Bel-7402 was associated with the highest resistances to DT, Pt, Vb, and 5-FU. The restrained lncRNA H19 and over-expressed miR-193a-3p expressions tended to significantly elevate the survival rate and proliferation of Bel-7402 cells, when they were exposed to radiation and subject to chemo therapies. The lncRNA H19 was also found to directly target miR-193a-3p in inducing the HCC development. PSEN1 appeared to be subject to the modification of lncRNA H19 and miR-193a-3p in its acting on the survival rates and proliferative abilities of HCC cells. The lncRNA H19/miR-193a-3p/PSEN1 axis could be regarded as the treatment targets for HCC, so as to further improve the treatment efficacy of chemo- and radio-therapies for HCC. PMID- 29968943 TI - Effects of oral administration of different dosages of carvacrol essential oils on intestinal barrier function in broilers. AB - Essential oils are widely used in the pharmaceutical, food and cosmetic industries, and many plant essential oils have shown that they have positive effects on broilers nutrition. This experiment was conducted to study the effects of orally administered different dosages of carvacrol essential oils on intestinal barrier function in broiler chickens. A total of eighty 28-day-old (1.28 +/- 0.15 kg) ROSS 308 broilers were randomly allocated to four groups of 20 replicates each, with one chicken per replicate per cage, and all were fed with the same diet. Four experimental groups were orally administered 0, 200, 300 or 400 MUl carvacrol essential oils at 18:00 hr every day during the 2-week experimental period. As a result of which, the gene expression of the occludin, claudin-1, claudin-5, ZO-1 and ZO-2 in intestinal mucosa of small intestine (p < 0.05) and the goblet cell content in small intestine epithelium (p < 0.05) were significantly increased; test subjects with 300 or 400 MUl carvacrol essential oils reduced the microbial counts of Salmonella spp. and Escherichia coli in the intestines (p < 0.05); Essential oils administration also significantly increased activity of the sucrase (p < 0.05) and lactase (p < 0.05) in intestinal mucosa. In conclusion, the carvacrol essential oils have positive effects on growth performance and intestinal barriers function of broilers; those effects may be related to the dosage, as administration of 300 or 400 MUl was more effective than that of 200 MUl. PMID- 29968944 TI - Left ventricular function during exercise in trained pre-adolescent soccer players. AB - It is unclear, what the underlying cardiovascular mechanisms are that give rise to the high level of aerobic fitness seen in youth soccer players. The aim of the study was to evaluate global and regional markers of systolic and diastolic function in a group of pre-adolescent soccer players during an incremental exercise test. Twenty-two, male soccer players (SP) from two professional soccer clubs (age: 12.0 +/- 0.3 years) volunteered for the study. Fifteen recreationally active boys (CON), of similar age (age: 11.7 +/- 0.2 years) were also recruited. All boys underwent a cycle ergometer test to exhaustion. Cardiac dimensions were determined using M-mode echocardiography. During submaximal and maximal exercise, continuous-wave Doppler ultrasound techniques were used to derive stroke volume (SVIndex). Tissue-Doppler imaging was used to quantify systolic (S'adj) and diastolic function (E; E'adj and E/E') at rest and both submaximal and maximal exercise intensities. Speckle tracking echocardiography was used to determine peak longitudinal epsilon at submaximal exercise intensities. SP demonstrated significantly (P <= 0.05) greater peak VO2 values than CON (SP: 48.0 +/- 5.0 vs CON: 40.1 +/- 7.5 mL/kg/min). Allometrically scaled to body surface area left ventricular end-diastolic volume (LVEDV) was larger (P <= 0.05) in the SP (51.3 +/- 9.0) compared to CON (44.6 +/- 5.8 mL.BSA1.5 ). At the same relative, submaximal exercise intensities, the SP demonstrated greater SVIndex, cardiac output (QIndex), and E. No differences were noted for peak longitudinal epsilon during submaximal exercise. Factors that augment pre-load and LV volume appear to determine the superior aerobic fitness seen in the soccer players. PMID- 29968945 TI - Heteroatom-Doping Increases Cluster Nuclearity: From an [Ag20 ] to an [Au3 Ag18 ] Core. AB - A templated galvanic exchange performed on [Ag20 {Se2 P(OiPr)2 }12 ] of C3 symmetry with three equiv AuI yields a mixture of [Au1+x Ag20-x {Se2 P(OiPr)2 }12 ]+ (x=0-2) from which [Au@Ag20 {Se2 P(OiPr)2 }12 ]+ and [Au@Au2 Ag18 {Se2 P(OiPr)2 }12 ]+ are successfully characterized to have T and C1 symmetry, respectively. Crystal structural analyses combined with DFT calculations on the model compounds explicitly demonstrate that the central Ag0 of Ag20 being oxidized by AuI migrates to the protecting atomic shell as a new capping AgI , and both second and third Au dopants prefer occupying non-adjacent icosahedron vertices. The differences in symmetry, T and C1 , are manifested in the spatial orientation of their protecting atomic shell composed of eight capping Ag atoms as well as re-construction upon the replacement of Ag atoms on the vertices of AuAg12 icosahedral core with second and third Au dopants. As a result, a unique pathway for substitutional-doped clusters with increased nuclearity is proposed. PMID- 29968946 TI - Disentangling Ultrafast Electronic and Structural Dynamics with X-Ray Lasers. AB - Directing the functionality of molecules, materials and biophysical systems is challenging both from fundamental and applied standpoints. For example, understanding the elementary processes responsible for light-induced transformations require watching electronic and structural reorganizations on their intrinsic timescales. The X-ray free electron lasers (X-FEL) represent a new generation of incredibly short and ultra-bright X-ray source, which open new possibilities for developing the multidisciplinary field of ultrafast science. Experiments around X-FEL provide probes, sensitive to electronic and structural reorganizations, able to monitor transformations on the femtosecond timescale (1 fs=10-15 s). Recent years have seen terrific successes in providing a detailed view on light-induced processes, compared to what was understood from conventional optical pump-probe spectroscopy. This Concept article aims at illustrating, through recent studies mainly focussing on light-induced excited spin state trapping, how these X-FEL based techniques can help understanding light-activated functions, by monitoring elementary electronic and structural processes that may occur beyond the Born-Oppenheimer approximation. PMID- 29968947 TI - Recurrent membranous nephropathy and acute cellular rejection in a patient treated with direct anti-HCV therapy (ledipasvir/sofosbuvir). AB - Direct-acting antiviral agents (DAAs) are very effective therapy for chronic hepatitis C infection, and have revolutionized the treatment of hepatitis C in kidney allograft recipients. Although well tolerated in general, rare renal complications have been reported. We describe a case of recurrent membranous nephropathy and acute cellular rejection in a kidney allograft recipient after DAA (ledipasvir/sofosbuvir) therapy, whose allograft function had been stable for more than 30 years. The patient was presented with nephrotic range proteinuria with stable creatinine. The kidney allograft biopsy revealed recurrent membranous nephropathy with fine granular deposits of IgG1/IgG4 codominance and positive phospholipase A2 receptor (PLA2R) staining. The patient was treated with pulse steroid and rituximab, leading to a decrease in proteinuria. As DAAs are more frequently used, physicians should be aware of immune-related renal complications. PMID- 29968948 TI - Stereoselective and Modular Assembly Method for Heterocycle-Fused Daucane Sesquiterpenoids. AB - A stereoselective synthetic method is reported for the molecular framework found in common daucane and isodaucane sesquiterpenoid natural products. The synthetic method constitutes a scalable, modular, and also asymmetric access to a complex natural product scaffold, wherein the substitution pattern and the stereochemistry can be adjusted simply by choosing different starting materials. The method allows the rapid introduction of diverse heterocyclic substructures such as (benzo)furans, (benzo)thiophenes, dithiins, thiazoles, and indoles, which actually also facilitate and direct the key intramolecular annulation step. PMID- 29968949 TI - Near-Infrared Ratiometric Luminescent Thermometer Based on a New Lanthanide Silicate. AB - A new lanthanide silicate system, Na2 K[Ln3 Si6 O18 ] (Ln=Lu, Yb/ Er, Lu/Eu, or Lu/Yb/Er), comprising microcrystals embedded in an amorphous siliceous matrix, obtained by sintering at 1373 K a Na3 K[Ln2 Si6 O17 ]?3 H2 O nano-crystalline precursor, is reported. The crystal structure of these lanthanide silicates was solved from high-resolution synchrotron power X-ray diffraction data collected at 110 K, and further supported by 29 Si MAS NMR and Eu3+ luminescence. The materials crystallize in the Pi triclinic centrosymmetric space group, exhibiting a dense framework consisting of hexameric [Si6 O18 ]12- cyclosilicate units, and chains of two distinct {LnO6 } octahedra. Na2 K[(Lu0.75 Yb0.20 Er0.05 )3 Si6 O18 ] is the first example of a lanthanide silicate operative as a near-infrared ratiometric luminescent thermometer, with good sensitivity at cryogenic temperatures (<100 K). Upon excitation at 903 nm, the ratio between the 2 F7/2 >2 F5/2 (Yb3+ ) and 4 I13/2 ->4 I15/2 (Er3+ ) emissions was used for sensing temperature in the 12-450 K range, reaching a maximum thermal sensitivity of 2.6 % K-1 at 26.8 K. PMID- 29968950 TI - Asymmetric Synthesis of Spirocyclic beta-Lactams through Copper-Catalyzed Kinugasa/Michael Domino Reactions. AB - The first copper-catalyzed highly chemo-, regio-, diastereo-, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne-tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic beta-lactams possessing four contiguous stereocenters, including one quaternary and one tetra-substituted stereocenter. PMID- 29968951 TI - MicroRNA-760 Inhibits Doxorubicin Resistance in Hepatocellular Carcinoma through Regulating Notch1/Hes1-PTEN/Akt Signaling Pathway. AB - Accumulating studies have suggested that microRNA-760 (miR-760) plays an important role in chemoresistance of various cancer cells. However, whether miR 760 regulates the chemoresistance of hepatocellular carcinoma (HCC) remains unclear. In this study, we found that miR-760 was decreased in HCC cell lines, and doxorubicin (Dox) treatment significantly decreased miR-760 expression in HCC cells. Overexpression of miR-760 sensitized HCC cells to Dox-induced cytotoxicity and apoptosis, whereas miR-760 inhibition showed the opposite effects. Notch1 was predicted as a target gene of miR-760. miR-760 negatively regulated Notch1 expression and Notch1/Hes1 signaling. Overexpression of miR-760 increased PTEN expression and decreased the phosphorylation of Akt. Activation of Notch signaling significantly reversed the inhibitory effect of miR-760 on Dox resistance and abrogated the effect of miR-760 on the PTEN/Akt signaling pathway in HCC cells. Overall, our results demonstrate that miR-760 inhibits Dox resistance in HCC cells through inhibiting Notch1 and promoting PTEN expression. PMID- 29968953 TI - Copper-Catalyzed Ring-Opening Silylation of Benzofurans with Disilane. AB - The catalytic ring-opening silylation of benzofurans has been achieved by employing a copper catalyst and 1,2-di-tert-butoxy-1,1,2,2-tetramethyldisilane, which could be easily prepared and handled without special care. The reaction afforded (E)-o-(beta-silylvinyl)phenols with complete stereoselectivity. The scope of benzofurans was well explored, and functional groups such as chloro, fluoro, and acetal were compatible with the reaction conditions. DFT calculations were used to determine the energy profile of the silylation and the origin of the stereoselectivity. The silylated product was proven to be useful as a synthetic intermediate and subsequently underwent transformations such as Pd-catalyzed cross-coupling with iodoarenes. PMID- 29968952 TI - Hypoxic Preconditioning of Mesenchymal Stem Cells with Subsequent Spheroid Formation Accelerates Repair of Segmental Bone Defects. AB - Cell-based approaches for musculoskeletal tissue repair are limited by poor cell survival and engraftment. Short-term hypoxic preconditioning of mesenchymal stem cells (MSCs) can prolong cell viability in vivo, while the aggregation of MSCs into spheroids increases cell survival, trophic factor secretion, and tissue formation in vivo. We hypothesized that preconditioning MSCs in hypoxic culture before spheroid formation would increase cell viability, proangiogenic potential, and resultant bone repair compared with that of individual MSCs. Human MSCs were preconditioned in 1% O2 in monolayer culture for 3 days (PC3) or kept in ambient air (PC0), formed into spheroids of increasing cell density, and then entrapped in alginate hydrogels. Hypoxia-preconditioned MSC spheroids were more resistant to apoptosis than ambient air controls and this response correlated with duration of hypoxia exposure. Spheroids of the highest cell density exhibited the greatest osteogenic potential in vitro and vascular endothelial growth factor (VEGF) secretion was greatest in PC3 spheroids. PC3 spheroids were then transplanted into rat critical-sized femoral segmental defects to evaluate their potential for bone healing. Spheroid-containing gels induced significantly more bone healing compared with gels containing preconditioned individual MSCs or acellular gels. These data demonstrate that hypoxic preconditioning represents a simple approach for enhancing the therapeutic potential of MSC spheroids when used for bone healing. Stem Cells 2018;36:1393-1403. PMID- 29968954 TI - Choreoathetoid movements associated with methamphetamine: A case report and review of literature. AB - BACKGROUND AND OBJECTIVES: Physicians and psychiatrists often encounter patients in the emergency department presenting after methamphetamine use. While physical and psychiatric manifestations associated with methamphetamine use are well known, movement disorders are relatively less common. The aim of this case report is to add to existing literature awareness about the possibility of movement disorders occurring after methamphetamine use, discuss the possible mechanism by which such use leads to dyskinesia, and describe possible management strategies. METHODS AND RESULTS: In this case report, we describe choreoathetoid movements occurring in a young female after relatively short-term methamphetamine use. DISCUSSION AND CONCLUSIONS: Evidence for treatment of methamphetamine induced choreoathetosis is limited. Expectant management of such symptoms is a viable option if there are no additional comorbidities that require therapy. SCIENTIFIC SIGNIFICANCE: Clinicians should be alert to the possibility of movement disorders in methamphetamine users and familiar with treatment options. (Am J Addict 2018;XX:1-4). PMID- 29968955 TI - Characterisation of the Carboxypeptidase G2 Catalytic Site and Design of New Inhibitors for Cancer Therapy. AB - The enzyme carboxypeptidase G2 (CPG2) is used in antibody-directed enzyme prodrug therapy (ADEPT) to catalyse the formation of an active drug from an inert prodrug. Free CPG2 in the bloodstream must be inhibited before administration of the prodrug in order to avoid a systemic reaction in the patient. Although a few small-molecule CPG2 inhibitors have been reported, none has been taken forward thus far. This lack of progress is due in part to a lack of structural understanding of the CPG2 active site as well as the absence of small molecules that can block the active site whilst targeting the complex for clearance. The work described here aimed to address both areas. We report the structural/functional impact of extensive point mutation across the putative CPG2 catalytic site and adjacent regions for the first time, revealing that residues outside the catalytic region (K208A, S210A and T357A) are crucial to enzyme activity. We also describe novel molecules that inhibit CPG2 whilst maintaining the accessibility of galactosylated moieties aimed at targeting the enzyme for clearance. This work acts as a platform for the future development of high affinity CPG2 inhibitors that occupy new chemical space and will advance the safe application of ADEPT in cancer treatment. PMID- 29968957 TI - Study on the influence of caffeic acid against sodium valproate-induced nephrotoxicity in rats. AB - Renal injury is a hallmark adverse reaction to sodium valproate (SVP), and caffeic acid (CAFF) is a phenolic compound that has anti-inflammatory and antioxsidant properties. So, this investigation was assessed to evaluate the nephrotoxic potential of SVP and the defensive impact of CAFF against SVP nephrotoxicity. SVP was given at a dose of 500 mg/kg (i.p.) once daily for 2 weeks, while CAFF was given at a dose of 50 mg/kg (orally), simultaneously with SVP. Concurrent treatment with CAFF reduced urea and creatinine, lipid peroxidation (malondialdehyde), tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), nuclear factor kappa B (NF-kappaB/p65), and transforming growth factor beta (TGF-beta) levels. However, with increased glutathione content, CAFF also halted the activated Notch signaling cascade. Furthermore, CAFF suppressed caspase-3 and inducible nitric oxide synthase expressions. To conclude, on the basis of the results obtained, CAFF proved to protect against SVP-induced nephrotoxicity via its antioxidant, anti inflammatory, and antiapoptotic properties. PMID- 29968958 TI - Synthesis of Bifunctional Allylic Compounds by Using Cyclopropenes as Functionalized Allyl Equivalents. AB - The synthesis of uncommon bifunctional allylic derivatives bearing a silane and an alcohol within the same allylic framework is reported. This method relies on the coupling of hydrosilanes with substituted and functionalized cyclopropenes, which deliver the allyl fragment. Rhodium(II) catalysts provide regioselective access to vinyl carbene intermediates, which easily undergo Si-H bond insertions. The transformation occurs with complete atom economy and shows a remarkably broad scope, including a intramolecular version for the synthesis of cyclic O-Si-linked compounds as well as the synthesis of the corresponding allyl amines. PMID- 29968956 TI - Emergence of symmetry selectivity in the visual areas of the human brain: fMRI responses to symmetry presented in both frontoparallel and slanted planes. AB - Symmetry is effortlessly perceived by humans across changes in viewing geometry. Here, we re-examined the network subserving symmetry processing in the context of up-to-date retinotopic definitions of visual areas. Responses in object selective cortex, as defined by functional localizers, were also examined. We further examined responses to both frontoparallel and slanted symmetry while manipulating attention both toward and away from symmetry. Symmetry-specific responses first emerge in V3 and continue across all downstream areas examined. Of the retinotopic areas, ventral occipital VO1 showed the strongest symmetry response, which was similar in magnitude to the responses observed in object selective cortex. Neural responses were found to increase with both the coherence and folds of symmetry. Compared to passive viewing, drawing attention to symmetry generally increased neural responses and the correspondence of these neural responses with psychophysical performance. Examining symmetry on the slanted plane found responses to again emerge in V3, continue through downstream visual cortex, and be strongest in VO1 and LOB. Both slanted and frontoparallel symmetry evoked similar activity when participants performed a symmetry-related task. However, when a symmetry-unrelated task was performed, fMRI responses to slanted symmetry were reduced relative to their frontoparallel counterparts. These task-related changes provide a neural signature that suggests slant has to be computed ahead of symmetry being appropriately extracted, known as the "normalization" account of symmetry processing. Specifically, our results suggest that normalization occurs naturally when attention is directed toward symmetry and orientation, but becomes interrupted when attention is directed away from these features. PMID- 29968959 TI - Coronarin D induces apoptotic cell death through the JNK pathway in human hepatocellular carcinoma. AB - Coronarin D, a diterpene derived from the rhizomes of Hedychium coronarium, has been used to treat inflammatory diseases. Coronarin D can exert strong anticancer effects through cell growth prevention and cell cycle arrest in many cancer cells. In this study, we investigated the molecular mechanism through which coronarin D suppresses cell proliferation and triggers cell death in human hepatocellular carcinoma (HCC) cells. Treatment of Huh7 and Sk-hep-1 cells with coronarin D resulted in a significantly increased loss of mitochondrial membrane potential, leading to the cleavage and activation of caspase-9, caspase-8, and caspase-3 and changes in Bax, Bcl-2, and Bcl-xL protein levels. Coronarin D significantly induced autophagy by increasing the expression of Beclin-1 and LC3 II and reducing the expression of p62. Moreover, Huh7 and Sk-hep-1 cells exposed to coronarin D had decreased expression of phosphorylated AKT, p38, and ERK and increased expression of phosphorylated JNK. Exposure of cells to the JNK-specific inhibitor SP600125 attenuated the apoptotic effects of coronarin D. Taken together, this is the first study to report that coronarin D may effectively inhibit cell growth through apoptosis. We have provided evidence indicating that coronarin D induces cell death through the upregulation of JNK mitogen-activated protein kinases in human HCC cells. PMID- 29968960 TI - Design of a phosphinate-based bioluminescent probe for superoxide radical anion imaging in living cells. AB - Superoxide radical anion (O2 - ) as an important member of reactive oxygen species (ROS) plays a vital role both in physiology and pathology. Herein we designed and synthesized a novel phosphinate-based bioluminescence probe for O2 - detection in living cells, which exhibited good sensitivity for capturing O2 - at the nanomole level and high selectivity against other ROS. The probe was further found to be of low toxicity for living cells and was then successfully employed for sensing endogenous O2 - by using phorbol-12-myristate-13-acetate (PMA) as a traditional O2 - stimulator in Huh7 cells. Moreover, the increasing production and use of nanoparticles, has given rise to many concerns and debates among the public and scientific authorities regarding their safety and final fate in biological systems. Herein it was found that mondisperse polystyrene particles could stimulate O2 - generation in Huh7 cells. Overall, the probe was demonstrated to have a great potential as a novel bioluminescent sensor for detecting O2 - in living cells. To our knowledge, this is the first small molecule phosphinate-based bioluminescence probe that will open up great opportunities for unlocking the mystery of O2 - in human health and disease. PMID- 29968961 TI - Origins of STIL-TAL1 fusion genes in children who later developed paediatric T cell acute lymphoblastic leukaemia: An investigation of neonatal blood spots. AB - SCL/TAL1 interrupting locus (STIL)-T-cell acute leukaemia (TAL1) fusion genes are present in approximately 11-27% of children with paediatric T-cell acute lymphoblastic leukaemia (T-ALL), but the developmental timing of the rearrangement is still unknown. To investigate whether the fusion gene can be detected in neonatal blood spots (NBSs) from paediatric patients diagnosed with T cell ALL, we analysed DNA from 38 paediatric patients with T-ALL by nested polymerase chain reaction and electrophoresis. The STIL-TAL1 fusion gene was not detected in NBSs from any of the 38 patients with T-ALL, suggesting that STIL TAL1 fusion genes are most probably postnatal events in paediatric T-ALL. PMID- 29968962 TI - Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers. AB - Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers. PMID- 29968963 TI - Relative Abundance Trends of Bird Populations in High Intensity Croplands in the Central United States. AB - Declining bird populations across the United States have been noted in a number of studies. Although multiple explanations have been proposed as causes of these declines, agricultural intensification has often been suggested as a significant driver of bird population dynamics. Using spatially explicit USDA-NASS Cropland Data Layer, we examined this relationship by comparing bird count data from the Breeding Bird Survey collected between 1995 and 2016 across 13 states in the central United States to corresponding categorical changes in land cover within a 2-km radius of each survey transect. This approach allowed us to compare the slopes of counts for 31 species of birds between grassland- and cropland dominated landscapes and against increasing levels of cropland (all types combined) and pooled corn and soybean land cover types. Nearly all birds demonstrated significant responses to land cover changes. In all cases, the number of species exhibiting positive or negative responses was comparable, and median differences in percent change per year ranged from -0.5 to 0.7%. Species that responded either positively or negatively did not appear to fall into any particular foraging guild. If changes in agricultural practices are a major cause of declines, we would expect to see it across the spatial scale studied and across the majority of species. While these results do not rule out potential agricultural effects, such as toxicity resulting from pesticide exposure, which may have species-specific or localized effects, a variety of factors related to habitat are likely the most significant contributor overall. Given these results over a large spatial scale basis (multistate) and across numerous bird species, there is not a broad general trend of greater decline in crop-intensive areas. Integr Environ Assess Manag 2018;14:692-702. (c) 2018 SETAC. PMID- 29968964 TI - Renal cell carcinoma risk associated with lower intake of micronutrients. AB - Kidney cancer incidence in African Americans (AA) is higher than among European Americans (EA); reasons for this disparity are not fully known. Dietary micronutrients may have a protective effect on renal cell carcinoma (RCC) development by inhibiting oxidative DNA damage and tumor growth. We evaluated whether any micronutrient associations differed by race in the US Kidney Cancer Study. 1142 EA and AA RCC cases and 1154 frequency-matched controls were enrolled in a population-based case-control study between 2002 and 2007. Dietary micronutrient intake was derived from an interviewer-administered diet history questionnaire. RCC risk associated with micronutrient intake was estimated using adjusted odds ratios from logistic regression comparing lower to highest quartiles of intake and sample weighting. Inverse associations with RCC risk were observed for alpha-carotene, beta-carotene, lutein zeaxanthin, lycopene, vitamin A, folate, thiamin, vitamin C, alpha-tocopherol, beta-tocopherol, gamma tocopherol, and selenium. A trend for beta-cryptoxanthin was suggested among EA but not AA or the total sample (P-interaction = .04). Otherwise, findings did not differ by race, gender, age, or smoking status. The increase in RCC risk associated with lower micronutrient intake is similar within AA and EA populations. A diet rich in sources of micronutrients found in fruits, vegetables, and nuts may help to reduce the overall risk of RCC. PMID- 29968965 TI - Upregulated IQUB promotes cell proliferation and migration via activating Akt/GSK3beta/beta-catenin signaling pathway in breast cancer. AB - Breast cancer was the highest incidence of tumor in women, which seriously threaten women's health. Our previous study found that the expression of IQUB (IQ motif and ubiquitin domain containing) was significantly increased in the development of breast cancer by transcriptome sequencing. However, there were no studies on the mechanism of IQUB in tumorigenesis. Further study showed that IQUB expression was significantly increased in breast cancer, which had a significantly positive correlation with pathological differentiation of breast cancer by tissue microarray analysis. Furthermore, we also discovered that IQUB overexpression could obviously promote the proliferation and migration of MCF-7 cells and increase the proportion of MCF-7 cells in S and G2/M phase in vitro study, while knockdown of IQUB caused inhibition of cell proliferation and migration in MDA-MB-231 cells and increased the proportion of MDA-MB-231 cells in G1 phase. Furthermore, IQUB overexpression or knockdown combined with treatment of Licl or MG-132 showed that IQUB activated Akt to promote GSK3beta phosphorylation, which in turn activated Wnt/beta-catenin signaling pathway in breast cancer cells. Taken together, these results indicated that upregulated IQUB promoted breast cancer cell proliferation and migration via activating Akt/GSK3beta/beta-catenin signaling pathway, which played an important part in the tumorigenesis and development of breast cancer. PMID- 29968966 TI - Enhanced photoluminescence properties of electrospun Dy3+ -doped ZnO nanofibres for white lighting devices. AB - Dy3+ -doped ZnO nanofibres with diameters from 200 to 500 nm were made using an electrospinning technique. The as-fabricated amorphous nanofibres resulted in good crystalline continuous nanofibres through calcination. Dy3+ -doped ZnO nanofibres were characterized using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), ultraviolet-visible (UV-vis) light spectroscopy, Fourier transform infrared spectroscopy (FTIR), and photoluminescence (PL). XRD showed the well defined peaks of ZnO. UV-vis spectra showed a good absorption band at 360 nm. FTIR spectra showed a Zn-O stretching vibration confirming the presence of ZnO. Photoluminescence spectra of Dy3+ doped ZnO nanofibres showed an emission peak in the visible region that was free from any ZnO defect emission. Emissions at 480 nm and 575 nm in the Dy3+ -doped ZnO nanofibres were the characteristic peaks of dopant Dy3+ and implied efficient energy transfer from host to dopant. Luminescence intensity was found to be increased with increasing doping concentration and reduction in nanofibre diameter. Colour coordinates were calculated from photometric characterizations, which resembled the properties for warm white lighting devices. PMID- 29968967 TI - 2.45 GHz microwave radiation induced oxidative and nitrosative stress mediated testicular apoptosis: Involvement of a p53 dependent bax-caspase-3 mediated pathway. AB - Deleterious effects of MW radiation on the male reproduction are well studied. Previous reports although suggest that 2.45 GHz MW irradiation induced oxidative and nitrosative stress adversely affects the male reproductive function but the detailed molecular mechanism occurring behind it has yet to be elucidated. The aim of present study was to investigate the underlying detailed pathway of the testicular apoptosis induced by free radical load and redox imbalance due to 2.45 GHz MW radiation exposure and the degree of severity along with the increased exposure duration. Twelve-week old male mice were exposed to 2.45 GHz MW radiation [continuous-wave (CW) with overall average Power density of 0.0248 mW/cm2 and overall average whole body SAR value of 0.0146 W/kg] for 2 hr/day over a period of 15, 30, and 60 days. Testicular histology, serum testosterone, ROS, NO, MDA level, activity of antioxidant enzymes, expression of pro-apoptotic proteins (p53 and Bax), anti-apoptotic proteins (Bcl-2 and Bcl-xL ), cytochrome c, inactive/active caspase-3, and uncleaved PARP-1 were evaluated. Findings suggest that 2.45 GHz MW radiation exposure induced testicular redox imbalance not only leads to enhanced testicular apoptosis via p53 dependent Bax-caspase-3 mediated pathway, but also increases the degree of apoptotic severity in a duration dependent manner. PMID- 29968968 TI - Nucleobase Modified Adefovir (PMEA) Analogues as Potent and Selective Inhibitors of Adenylate Cyclases from Bordetella pertussis and Bacillus anthracis. AB - A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 MUm in HEK293 cell-based assays. PMID- 29968969 TI - Cutaneous melanoma in adolescents and young adults. AB - Cutaneous melanoma is rare in children, but has greater incidence in adolescents and young adults (AYAs). Diagnosis may be challenging due to its rarity in these age groups. Few studies have specifically addressed the topic of AYA melanoma. Though young-age melanoma may have particular biological characteristics, available data suggest that its clinical history is similar to that of adults. However, advances in treatment of adult melanoma have not been reflected in the treatment of AYAs. There is no standard treatment, and access to clinical trials is difficult for AYAs. Further efforts are needed to overcome these issues by improving cooperation with experts on adult melanoma. PMID- 29968970 TI - Creating prognostic systems for cancer patients: A demonstration using breast cancer. AB - Integrating additional prognostic factors into the tumor, lymph node, metastasis staging system improves the relative stratification of cancer patients and enhances the accuracy in planning their treatment options and predicting clinical outcomes. We describe a novel approach to build prognostic systems for cancer patients that can admit any number of prognostic factors. In the approach, an unsupervised learning algorithm was used to create dendrograms and the C-index was used to cut dendrograms to generate prognostic groups. Breast cancer data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute were used for demonstration. Two relative prognostic systems were created for breast cancer. One system (7 prognostic groups with C-index = 0.7295) was based on tumor size, regional lymph nodes, and no distant metastasis. The other system (7 prognostic groups with C-index = 0.7458) was based on tumor size, regional lymph nodes, no distant metastasis, grade, estrogen receptor, progesterone receptor, and age. The dendrograms showed a relationship between survival and prognostic factors. The proposed approach is able to create prognostic systems that have a good accuracy in survival prediction and provide a manageable number of prognostic groups. The prognostic systems have the potential to permit a thorough database analysis of all information relevant to decision making in patient management and prognosis. PMID- 29968971 TI - Immobilized Poly(aryleneethynylene) pH Strips Discriminate Different Brands of Cola. AB - Fluorescent, water-soluble poly(p-aryleneethynylene)s (PAE) were immobilized on commercially available nylon membranes by using a slot plotter, creating fluorescent, barcode-like sensor strips. Digital imaging by using a standard digital camera, before and after immersion of the strips in buffers of different pH, displays a unique color for each pH value. Statistical evaluation, multivariate analysis of variance (MANOVA) and principal component analysis (PCA), of the acquired data revealed that the immobilized PAEs are superior to the identical fluorophores when dissolved. The pH sensor array discriminates 20 different brands of commercial-cola soft drinks through differences in pH and colorant-PAE interactions. PMID- 29968972 TI - The construct validity of the Inventory of Psychotic-Like Anomalous Self Experiences (IPASE) as a measure of minimal self-disturbance: Preliminary data. AB - AIM: The Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE) is a self report measure of minimal self-disturbance. The aim of the current report was to assess the construct validity of the scale by examining its convergent validity with the gold-standard measure of minimal self-disturbance, the Examination of Anomalous Self-Experience (EASE), and its discriminant validity. METHOD: The sample consisted of 46 participants (21 ultra-high risk for psychosis patients, 14 first episode psychosis patients, 11 healthy controls). Correlations between the clinical instruments were examined. RESULTS: The IPASE correlated strongly with general psychopathology and positive psychotic symptoms, moderately with negative symptoms, and weakly with manic symptoms. The strongest correlation (r = 0.92) was apparent between IPASE and EASE total scores. CONCLUSION: These preliminary data indicate construct validity of the IPASE, demonstrating both convergent and discriminant validity. The IPASE may be suitable as a screener measure for minimal self-disturbance, but should not be used as a replacement to measure the construct of minimal self-disturbance, which requires considerable psychopathological sophistication. PMID- 29968973 TI - Tracheostomy in children: Epidemiology and clinical outcomes. AB - BACKGROUND: Tracheotomy is performed in children for a variety of indications, but can place them at increased risk of lower airway infection with pathogenic organisms. While prior studies have identified Pseudomonas aeruginosa and Staphylococcus aureus as the most common lower airway pathogens in children with tracheostomies, little is known about the clinical implications of chronic growth of pathogens. METHODS: The North Carolina Children's Airway Center database was utilized to identify all pediatric patients with tracheostomy from 2007 to 2012; these data were cross-referenced to a microbiology database of all tracheostomy cultures. Data on hospitalizations, intensive care unit admissions, and length-of stay were abstracted from the medical record and analyzed using multivariate methods. RESULTS: We identified 185 children with tracheostomy, of whom chronic bacterial growth status could be defined in 69. P aeruginosa was a common pathogen isolated from tracheostomy cultures, with 49% (91/185) of patients growing this organism at least once. P aeruginosa combined with other gram negative rods were isolated in 63% (116/185) of subjects at least once. Those who chronically grew gram-negative rods had significantly more hospitalizations, longer total lengths-of-stay, and longer intensive care unit lengths-of-stay than those who did not. These differences remained significant when data were normalized to account for number of available cultures. CONCLUSION: These data suggest that clinical outcomes may be worse in children with tracheostomies who chronically grow gram-negative rods. Our findings may help guide clinicians in managing children with tracheostomies, though further studies are needed to establish best practice guidelines in these patients. PMID- 29968974 TI - Compared with intensity-modulated radiotherapy, image-guided radiotherapy reduces severity of acute radiation-induced skin toxicity during radiotherapy in patients with breast cancer. AB - Radiotherapy (RT) is an effective treatment for breast cancer. The side effects of breast irradiation, including skin toxicity in the irradiation field, cause considerable discomfort. This study compared the severity of skin toxicity caused by image-guided RT (IGRT) and intensity-modulated RT (IMRT) combined with an electronic portal imaging device (EPID) in breast cancer. This study retrospectively analyzed 458 patients with breast cancer who had received RT. The patients were divided into two groups: 302 and 156 patients in the IMRT and IGRT groups. In the IGRT group, 8 and 148 patients had received helical tomotherapy irradiation and IMRT with cone-beam computed tomography. Simple and multiple logistic regression analyses were used to estimate the relationship between RT technique and the severity of radiation skin toxicity. In our study, 284, 97, and 6 patients exhibited grades I, II, and III radiation dermatitis (RD). Moreover, 75 patients in the IMRT group (24.80%) and 22 patients in the IGRT group (14.10%) exhibited grade II RD. All patients with grade III RD were in the IMRT group (2.00%). No patient exhibited grade IV RD. The patients in the IGRT group exhibited less severity of RD than in the IMRT group. The severity of acute RD due to IGRT is significantly lower than that due to IMRT with EPID. PMID- 29968975 TI - Utility of ninhydrin reagent for spectrofluorimetric determination of heptaminol in human plasma. AB - For the determination of heptaminol (HEP) in its authentic and dosage form as well as in human plasma, a new simple, sensitive and cheap fluorimetric method of analysis was developed and validated. The presented method is based on the reaction between aliphatic primary amino moiety present in HEP with ninhydrin and phenylacetaldehyde using Torell and Stenhagen buffer at pH 8.2 that yields a highly fluorescent derivative which after excitation at 390 nm showed a fluorescence emission at 464 nm. The effects of various experimental factors on both the development and stability of the fluorescent product was evaluated and optimized. In the concentration range (0.5-6.0 MUg/ml), the constructed calibration curve was linear with a good correlation coefficient (0.9997) and the calculated limit of detection (LOD) and limit of quantitation (LOQ) were 0.14 and 0.43 respectively. The presented method was successfully applied for determination of Corasore(r) tablets and validated according to ICH guidelines. PMID- 29968976 TI - Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. METHODS: A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. RESULTS: Twelve patients with a median age of 12 years (range = 1-17; number of females = 7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC = 2; early HCC arising in focal nodular hyperplasia = 1, well-differentiated [wd] HCC = 1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy = 2; mesocaval shunt and portal vein thrombosis = 2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2 = 2, alpha-1 antitrypsin deficiency = 1, Alagille syndrome = 1). Seven patients underwent LT (multifocal = 5; solitary = 2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy = 2; hemihepatectomy = 3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range = 28.1 157.7 months). CONCLUSIONS: Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT. PMID- 29968977 TI - Review of Disinfection and Sterilization - Back to the Basics. AB - In-depth knowledge of disinfection and sterilization is a key component of infection control. Sterilization completely removes a spore, whereas disinfection cannot. Disinfectants are classified as oxidants and non-oxidants. The decision regarding which method to apply is based on Spaulding's classification. In this article, disinfection and sterilization are thoroughly reviewed, and extensive information from basic to practical points is discussed. PMID- 29968978 TI - Low Lymphocyte Proportion in Bronchoalveolar Lavage Fluid as a Risk Factor Associated with the Change from Trimethoprim/sulfamethoxazole used as First-Line Treatment for Pneumocystis jirovecii Pneumonia. AB - BACKGROUND: Trimethoprim/sufamethoxazole (TMP/SMX) is the recommended treatment for Pneumocystis jirovecii pneumonia (PCP). However, the efficacy and the safety of alternative salvage treatments are less guarauteed especially when patient experiences treatment failure and/or an adverse drug reactions (ADR). The purpose of this study is to recognize potential risk factors imitating successful treatment with TMP/SMX among PCP patients. MATERIALS AND METHODS: Ninety one adult patients diagnosed with PCP were included after searching electronical medical records from January 2013 through July 2015 at Asan Medical Center Seoul, Korea. We compared clinical characteristics and laboratory findings including bronchoalveolar lavage (BAL) fluid analysis in patients who experienced TMP/SMX treatment failure or ADR (the case group) versus those who did not (the control group). RESULTS: Among the enrolled PCP patients, 39 (42.9%) required salvage treatment owing to either treatment failure (28, 28.6%) and/or ADR (17, 18.7%). The BAL lymphocyte percentage (25% [IQR, 8-40%] vs. 47% [IQR, 15-62%]; P = 0.005) was lower in the case group. Diabetes mellitus (adjusted odds ratio [aOR] 4.98, 95% confidence interval [95% CI] 1.20-18.58), glomerular filtration rate <=50 mL/min (aOR 4.48, 95% CI 1.08-18.66), and BAL lymphocyte percentage <=45% (aOR 9.25, 95% CI 2.47-34.58) were independently associated with the case group in multivariate analysis. CONCLUSION: This study suggests that BAL lymphocyte count may play some role during PCP treatment. Further studies should be followed to reveal what the role of BAL lymphocyte is in the PCP treatment. PMID- 29968979 TI - Absence of a Seasonal Variation of Hemorrhagic Fever with Renal Syndrome in Yeoncheon Compared to Nationwide Korea. AB - BACKGROUND: Yeoncheon is an endemic region for hemorrhagic fever with renal syndrome (HFRS) and has been reporting HFRS cases intermittently in other seasons, including autumn. This study was conducted to determine whether a seasonal variation pattern of HFRS exists in Yeoncheon. MATERIALS AND METHODS: From 2002 to 2016, raw data of the number of patients with HFRS in Yeoncheon and nationwide was collected from the Korea Center for Disease Control and Prevention. On the basis of the raw data, the incidence per 100,000 population was calculated for each month of the year. The twelve months were divided into four quarters, and the proportion of the disease by each quarter was calculated. The effects of sex, age, quarter, and time on HFRS occurrence were analyzed by Poisson regression analysis. RESULTS: A total of 6,132 HFRS cases occurred nationwide, and 62 cases occurred in Yeoncheon. The incidence of the disease in Yeoncheon (9.07/100,000) was statistically higher than that nationwide (0.81/100,000). The quarterly incidence showed that occurrence proportion of HFRS was high in the third and fourth quarters (12.9%, 67.5%) nationwide, whereas it was relatively similar in all quarters in Yeoncheon (17.7%, 21.0%, 25.8%, 35.5%). The Poisson regression model showed that the relative risk of HFRS nationwide was 1.322 in the third quarter and 6.903 in the fourth quarter, but Yeoncheon had no risk increase by quarter. CONCLUSION: In this study, HFRS in Yeoncheon demonstrated no seasonal variation pattern compared to that in nationwide Korea, which may be considered a regional characteristic. Furthermore, in other regions where HFRS is endemic, like Yeoncheon, HFRS may arise regardless of seasonal variations. PMID- 29968980 TI - Neutrophil Gelatinase-associated Lipocalin as a Predictor of Acute Kidney Injury in Patients during Treatment with Colistimethate Sodium. AB - BACKGROUND: The emergence of multidrug-resistant, Gram-negative bacteria has resulted in reconsideration of colistimethate sodium (CMS) as a last resort for treatment of such infections. However, acute kidney injury (AKI) may represent a major limiting adverse effect of use of CMS. Early AKI detection in CMS-treated patients can help prevent progression to acute failure and reduce the need of renal replacement therapy. We hypothesized that plasma neutrophil gelatinase associated lipocalin (NGAL) may be an early biomarker of AKI in CMS-treated patients. MATERIALS AND METHODS: This prospective cohort study included patients aged >=20 years who received intravenous CMS between March 2014 and November 2015. AKI was defined according to Kidney Disease: Improving Global Outcomes criteria. The primary endpoint was the difference between the average time to AKI onset based on serum creatinine and empirically derived plasma NGAL levels. RESULTS: Among 109 CMS-treated patients, 23 patients (mean age, 61.3 +/- 16.1 years; men, 65.2%) were evaluated. Thirteen (56.5%) patients fulfilled the AKI criteria. The mean time to AKI onset based on serum creatinine after CMS initiation was 78.15 +/- 30.49 hours. AKI was detected approximately 22 hours earlier using plasma NGAL than when using serum creatinine as an indicator of AKI (P = 0.035). The baseline plasma NGAL level was 264.0 +/- 167.3 ng/mL and 192.7 +/- 65.3 ng/mL in patients with and without AKI, respectively (P = 0.218). The area under the curve for plasma NGAL level at 56 hours was 0.796 (95% confidence interval, 0.609-0.983; P = 0.017), with a sensitivity and specificity of 69.2% and 90.0%, respectively (cutoff value, 285 ng/mL). CONCLUSION: NGAL level was found to be a strong predictor of AKI. This study provides additional evidence of the utility of NGAL for AKI in patients with treated CMS. Plasma NGAL represent sensitive and specific predictive early biomarkers for AKI in patient treated CMS. PMID- 29968981 TI - Catheter-Related Trichosporon asahii Bloodstream Infection in a Neutropenic Patient with Myelodysplastic Syndrome. AB - Because primary antifungal prophylaxis is widely used for immunocompromised hosts, the incidences of unusual fungal infections have increased. Trichosporon asahii has emerged as an important life-threatening opportunistic systemic pathogen because of the increased use of cytotoxic or immunosuppressant agents, along with high mortality rates. Here, we describe a case of catheter-related T. asahii bloodstream infection with multiple septic skin nodules in both the arms and legs of the patient who was in the neutropenic period after allogeneic stem cell transplantation for myelodysplastic syndrome treated with prophylactic ciprofloxacin and itraconazole. We successfully treated her with intravenous voriconazole for more than a month without any complications. Clinicians should consider breakthrough Trichosporon infections when clinical progress in an immunocompromised patient with unexplained infection signs and symptoms does not improve despite proper treatment with antibiotics or various antifungal agents. In addition, voriconazole can be a good treatment choice for achieving better treatment results and prognosis. PMID- 29968982 TI - A Case of Community-acquired Bacteremic Empyema Caused by Kocuria kristinae. AB - Kocuria kristinae, part of the normal flora of the skin and oral mucosa, is seldom reported as a human pathogen; infection is mostly associated with immunocompromised patients in healthcare facilities. Here, we describe the first case of bacteremic empyema caused by K. kristinae acquired from the community. K. kristinae was isolated from pleural effusion and two sets of peripheral blood samples drawn from two different sites. The empyema resolved after the insertion of a chest tube and intravenous administration of piperacillin-tazobactam and levofloxacin. PMID- 29968983 TI - An Imported Case of Brucella melitensis Infection in South Korea. AB - Brucellosis is a zoonotic infection that is usually transmitted from cattle to humans through ingestion of animal milk, direct contact with animal parts, or inhalation of aerosolized particles. In Korea, brucellosis seem to be transmitted through close contact with blood, fetus, urine, and placenta of domestic cow that has been infected by Brucella abortus, or inhalation of B. arbortus while examining or slaughtering cow. Brucella melitensis infection is rare in Korea and there have been no reported cases of B. melitensis originating from other countries until now. This report details a case of complicated brucellosis with infective spondylitis in a 48-year-old male construction worker recently returned from Iraq. Infection with B. melitensis was confirmed using 16s rRNA sequencing and omp31 gene analysis. The patient was successfully treated using a combination of rifampin, doxycycline, and streptomycin, in accordance with WHO guidelines. This is the first reported case of complicated brucellosis with infective spondylitis in Korea caused by B. melitensis originating from Iraq. PMID- 29968984 TI - Cytomegalovirus Colitis during Dasatinib Treatment for Patients with Hematologic Malignancy: Case Series and Literature Review. AB - Dasatinib, a tyrosine kinase inhibitor, is widely used for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Although the drug has a potent immunosuppressive effect, infectious complications during dasatinib treatment have been reported rarely. We describe five patients who developed cytomegalovirus (CMV) colitis during dasatinib treatment, in whom the colitis was initially confused with other causes. The patients, three with chronic myeloid leukemia, and two with acute lymphoblastic leukemia, were diagnosed with CMV colitis based on endoscopic and histologic findings. The patients who examined blood CMV polymerase chain reaction were all positive. The patients received antiviral therapy in the form of either ganciclovir or valganciclovir, and the overall treatment outcome was fair. These cases suggest that physicians should consider the possibility of CMV reactivation when treating diarrhea and/or hematochezia in patients on dasatinib. PMID- 29968986 TI - [The Problems of Socially Dangerous Acts of Medical Workers in Sphere of Biomedical Technologies]. AB - The complex problem is considered related to socially dangerous acts of medical workers in the sphere of biomedical technologies covering, besides "traditional" iatrogenic crimes, other risks of application of the mentioned technologies for criminal purposes. The study uses the results of original observations and theoretical findings and data of information content analysis of 2012-1017, data of analysis of medical and judicial practice and also result of sociological survey of experts-medical workers of various profiles professionally related to application of biomedical technologies (n=278). The social legal status of medical worker conditions a potential possibility of application of corresponding abilities, skills, competences, official position and authority to commit crimes in the sphere of their professional activities. The backlog of legal regulation of the sphere of biomedical technologies causes both possibility for committing by medical workers socially dangerous acts and so-called gray zones of responsibility that significantly impacts on potential of applying the given technologies for criminal purposes. The risks of criminal application of biomedical technologies by medical workers are related first of all to such most criminogenic spheres of medical activity as transplantology (mentioned by 79% of respondents), extra-corporal insemination (67%), implementation of various biomedical examinations involving patient (59%), bio-pharmaceutics (55%). The article emphasizes that risks of criminal application of biomedical technologies by medical workers is to be considered both from position of established actual medical legal practices and taking into account potential of biotechnological development of medicine in the future. PMID- 29968987 TI - [On the Issue of Development of the International Classification of Diseases]. AB - The article presents history of development and becoming of the International Classification of Diseases (ICD), including its importance and necessity for health care. PMID- 29968988 TI - [The Analysis of Morbidity of Urban Population Older than Able-Bodied Age in Russia]. AB - The aging of population ia an important social, economic and medical problem. The purpose of study is evaluating of morbidity of urban population older than able bodied age in the Russian Federation in 2010-2014.The article presents the results of studying of primary and total morbidity of urban population older than able-bodied age according classes of diseases in the Russian Federation in 2010 2015. The analysis was applied to morbidity of narcological disorders and particular valuable diseases in population older than able-bodied age and residing in city. PMID- 29968989 TI - [The Development of General Practitioner Practice in the Russian Federation]. AB - The purpose of study. To analyze problems and perspectives of development of primary medical sanitary care according the principle of general practitioner practices in the Russian Federation. The article presents historical aspects of main stages of development of service of general practices in our country. Also article considers characteristics of development of general practitioner practices in various regions. In particular, from 2011, number of departments of service increased up to 2.5 times and number of rural out-patient clinics increased up to 1.6 times. The experience of implementation of system of general practitioner practices demonstrates that after corresponding training general practitioner is able to undertake up to one third-one fourth of all visits of patients to specialists. In spite of particular achievements, nowadays no real reform of primary health care occurred mainly because of complicity of problems of reforming not only primary health care but factually all health care services, resources inadequacy and shortcoming of system of professional training of personnel and insufficient development of legal and financial base. PMID- 29968990 TI - [The Dynamics of Primary Disability and Establishment of Losses of Healthy Life Span of Able-Bodied Population of the Ryazan Oblast]. AB - The problem of disability being a cause of decreasing of healthy life-span is actual especially nowadays when during last decade rate of increasing of primary disability of able-bodied population significantly advances mortality harming economics. The article considers dynamics of primary disability of population of the Ryazan oblast. The analysis of losses of healthy life-span of able-bodied population of the region caused by disability is implemented. PMID- 29968991 TI - [The Dynamics of General Morbidity of Salpingoophoritis as a Problem of the Regional Health Care]. AB - The article presents the results of studying dynamics of total morbidity of salpingoophoritis in the Belgorod oblast in 2009-2014 testifying negative tendencies. The maximal increasing of of total morbidity of salpingoophoritis among female adolescents and adult women in oblast rural districts was established. The obtained data can be used as a basis for developing target regional programs directed to improvement of functioning of specialized obstetrician gynecological service. PMID- 29968992 TI - [The Analysis of Results of Sociological Survey Concerning Attitude to Palliative Care Support in the Russian Federation]. AB - The palliative care is a regulatory determined form of medical care in the Russian Federation since 2011. Until now, no complex analysis was applied to problems occurring during provision of the given form of care. The actual study provides analysis of the results of questionnaire survey of population of Russia with the purpose of determining public demand in development of palliative care (level of awareness, social cultural attitudes and main needs of population). And also, concepts of effective forms of its development. The article presents and considers data obtained during the study. PMID- 29968985 TI - Guideline for Antibiotic Use in Adults with Community-acquired Pneumonia. AB - Community-acquired pneumonia is common and important infectious disease in adults. This work represents an update to 2009 treatment guideline for community acquired pneumonia in Korea. The present clinical practice guideline provides revised recommendations on the appropriate diagnosis, treatment, and prevention of community-acquired pneumonia in adults aged 19 years or older, taking into account the current situation regarding community-acquired pneumonia in Korea. This guideline may help reduce the difference in the level of treatment between medical institutions and medical staff, and enable efficient treatment. It may also reduce antibiotic resistance by preventing antibiotic misuse against acute lower respiratory tract infection in Korea. PMID- 29968993 TI - [The Clinical Economic Evaluation When Choosing and Purchasing Consumables: Optimization of Expenses of Medical Organizations]. AB - The article presents a description of the new methodological guidelines and substantiates its actuality for practical health care in conditions of budget limitations. PMID- 29968994 TI - [The Normative Legal Base of Providing Quality of Security of Medical Activities]. AB - The article substantiates the actuality of legal normative support of maintenance of quality of medical activities. The analysis is presented concerning actual normative legal base in the Russian Federation regulating control of volumes, terms, quality and conditions of medical care provision. The evaluation is given concerning actual executive orders of Minzdrav of Russia regulating quality of medical care. PMID- 29968995 TI - [From Experience of Training of Foreign Physicians by Complementary Training Programs]. AB - The national publications related to characteristics of organization of education of foreign specialists, mainly cover processes of their adaptation in medical universities. The purpose of study was to establish a rational system of organization of process of education of physicians on the basis of education of training of foreign specialists in the research institute of orthopedic traumatological profile. The analysis was applied to process of education of foreign specialists in 1979-2015 in the academician G.A. Ilizarov Russian research center "Restorative traumatology and orthopedics" using cohort analysis and questionnaire survey and observation techniques. The concept of educational activities was developed to increase satisfaction of students and implementation of programs of supplementary professional training. It is determined that the presented experience of activities related to increasing quality of education is a perspective one and is in the process of active approximating experience of foreign countries. The implemented activities related to organization of educational activity will have a delayed result and ultimate estimation of effectiveness can be implemented only in 5-10 years. It is determined that medical institutions of the Russian Federation can be asked-for training of foreign physicians by programs of supplementary professional training in case of availability of one's own original techniques of diagnostic and treatment, specialists with higher publication activity and teaching capacities in implementation of complex of organizational activities. The full value educational complex can interest foreign physicians in case of availability of clear-cut program including various by time-frame and profoundness of learning thematic sections and modes of training courses. The modern continuous medical professional education is impossible without application of simulators, computer technologies and Internet. The education at workplace with full-value immersion into treatment process continues to be nevertheless important and required at the market of educational services. PMID- 29968996 TI - [The Social Networks and Organization of Extracurricular Teaching of Students in the System of Higher Medical Education]. AB - The article considers problem of implementation of interactive technologies into educational environment of medical universities. The experience is considered related to usage of the social network "VKontakte" in 2015/2016 academic year and first half of 2016/2017 academic year as a platform for extracurricular activities of the student scientific research circle on history of medicine of the "The I.M. Sechenov First Moscow State Medical University". The methodological recommendations are proposed concerning organization of extracurricular activity of the student scientific research circle in social networks. The possibility of implementation of education in habitual for student youth social media environment and availability of large spectrum of technical resources assignable by "VKontakte" permit to draw a conclusion about expediency of application of the given technology promoting efficiency of organization of extracurricular independent activity of students in the educational process. PMID- 29968997 TI - [The Organization of Medicine Principles Education in Theological Seminaries]. AB - The article, on the basis of discovered archive documents, a historical reconstruction of organization of system of education of basics of medicine in theological seminaries in Russia in 1837-1866. The initiators of making and organizers of this system are named. The main results of its functioning are analyzed. PMID- 29968998 TI - [Two Concepts of Organization of the USSR Academy of Medical Sciences (January February 1944)]. AB - Two conceptions of organization of the USSR Academy of medical sciences existed in January-February 1944. The conception of N.N. Burdenko, the chairman of the Scientific medical council of the USSR Narkomzdrav reflected views of national scientific medical elite of those times about state of theoretical medicine of middle of XX century and exactly its development was considered as main strategic task of future Academy. N.N. Burdenko considered the Academy as a structure subordinated to the USSR Sovnarkom and having equal rights with the Narkomzdrav but as opposed to it in more degree developing theoretical than practical issues of medicine. The conception of G.A. Miterev, the Narkom of health care, substantiated necessity of organization of the Academy of medical sciences mainly by practical causes and concrete tasks of the Soviet health care. G.A. Miterev, as opposed to N.N. Burdenko, proposed organization subordinated to the USSR Narkomzdrav and resolving besides theoretical issues, merely practical ones according tasks of his department. PMID- 29968999 TI - Long-term outcomes of high-grade T1 bladder cancer treated with intravesical bacillus Calmette-Guerin: experience of a single center. AB - BACKGROUND: To assess the outcomes of patients with high-grade (HG) pT1 bladder cancer (BC) treated with intravesical BCG therapy. METHODS: The study population consisted of 185 patients with HG pT1 BC treated between 1998 and 2010. We aimed to determine recurrence-free (RFS) and progression-free survival (PFS), as well as the predictors of RFS and PFS. RESULTS: Overall, 143 (77.3%) patients were males. Median age was 72 years (IQR: 66-78). Tumor size was >=3 cm in 100 (54.1%) individuals. Most patients had single tumors (125; 67.6%). Primary, progressive and recurrent patterns of presentation were observed in 146 (78.9%), 21 (11.4%), and 18 (9.7%) cases, respectively. After 2nd-look TURB, 127 (68.6%) patients had no residual disease, 44 (23.8%) had Ta/CIS, and 14 (7.6%) had T1 HG BC. Twenty two (11.9%) patients experience early recurrence after BCG. Of these, 12 patients (54.5%) were diagnosed with Ta/CIS, while 10 (45.5%) were diagnosed with HG pT1 BC. The median follow-up was 93 months (IQR: 63-147). Ten-year RFS and PFS rates were 69.6 and 79.2%. In multivariable Cox regression models, female gender (HR=2.41; P=0.001), progressive (HR=2.03; P=0.030) and recurrent (HR=3.87; P<0.001) pattern of presentation emerged as independent predictors of RFS, while age >=70 years (HR=2.13; P=0.027), presence of multiple tumors (HR=2.06; P=0.019), and early recurrence (HR=3.88; P<0.001) emerged as independent predictors of PFS. CONCLUSIONS: Intravesical BCG appears to be an effective treatment for HG pT1 BC. Caution should be used in patients aged >=70 years, with multiple tumors or experiencing early recurrence. PMID- 29969001 TI - Management of ureteric duplications identified during robotic cystectomy and intracorporeal urinary diversion. AB - Ureteral duplication is rarely seen malformation that could be diagnosed during radiological imaging. Herein, we present 5 patients with ureteral duplication who underwent robotic radical cystectomy with intracorporeal urinary diversion for bladder cancer. Preoperative computerized tomography did not show presence of a ureteral duplication in any patient and all were identified intraoperatively. A Wallace type uretero-ureteral anastomosis was performed in all patients. During the follow-up period, we did not detect any ureterointestinal anastomotic strictures or complication related to the presence of a ureteral duplication following robotic cystectomy. We conclude that ureteral duplication might be missed during preoperative radiological imaging, might be a surprising and challenging issue for the robotic surgeon that could be safely managed intraoperatively. PMID- 29969000 TI - Entry techniques in laparoscopic radical and partial nephrectomy: a multicenter international survey of contemporary practices. AB - BACKGROUND: There is no clear consensus as to the optimal method of entry in laparoscopic renal surgery and no reports have compared them in Urology. To analyze contemporary practice patterns in entry technique and port placement for laparoscopic kidney surgery. METHODS: We identified 60 high volume urological laparoscopic centers. A purpose-built questionnaire was sent to surgeons. The survey included 22 questions regarding access techniques and port configuration during laparoscopic kidney surgery. Data on were collected and retrospectively analyzed. Concordance among port configurations was assessed using Cohen's Kappa statistics. RESULTS: The survey was sent to 60 surgeons and completed by 32 of them. Surgical procedures included were laparoscopic radical nephrectomy (1177 LRN/year) and laparoscopic partial nephrectomy (1047 LPN/year). The transperitoneal route was preferred (85%). Hasson technique was used for the access in 55% of the cases. Patient lateral recumbent position is the most frequently used during the port placement (41%). Although there is a high variability in the port positioning among the surgeons, in more than 90% of cases it was found a specific concordance in triangulation of optics and operating trocars. There were no significant differences between port configuration in LRN and LPN. Limitations include retrospective design and limited sample. CONCLUSIONS: A standard port configuration has not been previously reported in urological literature. Our study suggests that the transperitoneal approach, the Hasson technique and a specific triangulation of optics and operating trocars have a significant concordance in some high volume laparoscopic urologic centers. PMID- 29969002 TI - National 10-year trends and outcomes of isolated and concomitant tricuspid valve surgery. AB - BACKGROUND: The data on the trends and comparative outcomes after isolated and concomitant tricuspid valve repair/replacement (TVR) is scarce. METHODS: The International Classification of Diseases - 9th version was used to identify the patients who underwent TVR, using the National Inpatient Sample. Outcomes were evaluated using the analysis of variance and Chi-square test, and trends across the years were tested via Cochran-Armitage test. RESULTS: Of 6,868 patients who underwent TVR between 2005-14, 1,601 (23%) were isolated. Over the 10-years period, the number of total and isolated TVR has steadily increased (p < 0.001). The proportion of patients undergoing repair has increased compared to replacement. Overall in-hospital mortality was 8.5% and 7.7% (p=0.28), permanent pacemaker requirement was 11.24% and 10.69% (p=0.53), blood transfusion rates were 32.6% and 37.9% (p<0.001), and the post-procedure length of stay (LOS) was 14.1+/-0.44 and 12.5+/-0.17 days (p<0.001) after isolated and concomitant TVR respectively. High (26.25%) number of patients were discharged to skilled facility. The operative mortality associated with TV repair was lower than with replacement (6.8% versus 11.15%, p < 0.001), but the mortality trend over the 10- years has stayed relatively stable. Independent predictors of mortality were age > 50 years, heart failure, cerebrovascular accident, end-stage renal disease, peripheral vascular disease, liver disease, and TV replacement. CONCLUSIONS: Both isolated and concomitant TVR has increased over the last 10 years, however is associated with high mortality, complications, need for skilled facility placement, and longer LOS. The mortality after TV replacement was significantly higher than that after repair. PMID- 29969003 TI - Current Enhancement and Bipolar Current Modulation of Top-Gate Transistors Based on Monolayer MoS2 on Three-Layer W xMo1- xS2. AB - We demonstrated the top-gate transistors composed of monolayer MoS2 grown on three-layer alloys Mo xW1- xS2 prepared by sequential sulfurization of predeposited transition metal films. The elemental mapping of the alloy indicates a uniform distribution of both cations Mo and W in the grown samples. Surprisingly, we find that the drain current of transistors could be enhanced by 2 orders of magnitude as the composition of Mo increases, whereas the gate controlled current modulation turns bipolar and ultimately vanishes. These features might originate from the formation of in-gap defect states, with modest activation energy for transport and moderate hopping probability for current conduction, or a reduced electronic band gap of the conducting channel because of strain. PMID- 29969004 TI - Self-Polarization in Epitaxial Fully Matched Lead-Free Bismuth Sodium Titanate Based Ferroelectric Thin Films. AB - The Bi0.5Na0.5TiO3-based ferroelectric is one of the most promising candidates for environment-friendly lead-free ferroelectric/piezoelectric materials for various applications such as actuators and micro-electromechanical systems. The understanding and tailoring of the ferro-(piezo-)electric properties of thin films, however, are strongly hindered by the formation of the defects such as dislocations, ion vacancies in the film, as well as by the complexity of the interface between the film and the substrate. An ideal system for the study of the polarization behavior in the ferro-(piezo-)electric film would be a fully matched system. In this work, monocrystalline 0.89Bi0.5Na0.5TiO3-0.11BaTiO3 thin films were epitaxially grown on (001)-oriented Nb-doped SrTiO3 substrates using a sol-gel technique. The films were almost fully lattice- and thermally matched with the substrate, thus avoiding the impact of dislocations and thermal stress. The films were self-poled by a built-in electric field, originating from the sedimentation of heavier atoms during the film preparation. As a consequence, an upward self-polarization was introduced into the films, giving rise to asymmetric phase hysteresis loops and domain switching current responses. These results highlight the importance of the interface complexity for the self-polarization of piezoelectric thin films, even for fully matched films, which will therefore facilitate the control of properties of piezoelectric films and their applications for various functional devices. PMID- 29969005 TI - High Current Density and Low Hysteresis Effect of Planar Perovskite Solar Cells via PCBM-doping and Interfacial Improvement. AB - We propose a doping method by using [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) to fill the grain boundary interstices of the methylammonium lead iodide (CH3NH3PbI3) perovskite for the elimination of pinholes. A sandwiched PCBM layer is also used between the perovskite and TiO2 layers to improve the interfacial contact. By using these two methods, the fabricated perovskite solar cells show a low hysteresis effect and high current density, which result from the improved compactness at the grain boundaries of the perovskite surface and the interface between the TiO2/perovskite layers. The theoretical and experimental results indicate that PCBM can effectively suppress carrier recombination, regardless of the interfacial layer or dopant. We also found that the dark current reduced during the analysis of dark state current-voltage ( I- V) characteristics. The slopes of the I- V curves for the fluorine-doped tin oxide/PCBM-doped perovskite/Au device reduce monotonically with the increase in the PCBM concentration from 0.01 to 0.1 wt %, which suggest the decreasing defects in the perovskite layer. By tuning the PCBM doping and controlling the preparation process, we have successfully fabricated a planar TiO2/PCBM-based PCBM-doped perovskite photovoltaic device that reaches a high current density of 22.6 mA/cm2 and an outstanding photoelectric conversion efficiency up to 18.3%. The controllability of the PCBM doping concentration and interfacial preparation shed light on further optimization of the photoelectric conversion efficiency of perovskite solar cells. PMID- 29969006 TI - Bismuth Subcarbonate with Designer Defects for Broad-Spectrum Photocatalytic Nitrogen Fixation. AB - A facial hydrothermal method is applied to synthesize bismuth subcarbonate (Bi2O2CO3, BOC) with controllable defect density (named BOC- X) using sodium bismuthate (NaBiO3) and graphitic carbon nitride (GCN) as precursors. The defects of BOC- X may originate from the extremely slow decomposition of GCN during the hydrothermal process. The BOC- X with optimal defect density shows a photocatalytic nitrogen fixation amount of 957 MUmol L-1 under simulated sunlight irradiation within 4 h, which is 9.4 times as high as that of pristine BOC. This superior photocatalytic performance of BOC- X is attributed to the surface defect sites. These defects in BOC- X contribute to a defect level in the forbidden band, which extends the light-harvest region of the photocatalyst from the ultraviolet to the visible-light region. Besides, surface defects prevent electron-hole recombination by accommodating photogenerated electrons in the defect level to promote the separation efficiency of charge carrier pairs. This work not only demonstrates a novel and scalable strategy to synthesize defective Bi2O2CO3 but also presents a new perspective for the synthesis of photocatalysts with controllable defect density. PMID- 29969007 TI - Thickness-Dependent Evolution of Piezoresponses and Stripe 90 degrees Domains in (101)-Oriented Ferroelectric PbTiO3 Thin Films. AB - High-index ferroelectric films as (101)-orientated ones exhibit enhanced dielectric responses, piezoelectric responses, and exotic ferroelectric switching behaviors, which are potential candidates for applications in memories and capacitors. However, possible domain patterns and domain wall structures in (101) oriented ferroelectric thin films are still elusive, which results in difficulties in understanding the origin and further modulating their special properties. In this work, a series of PbTiO3 (PTO) thin films with 35, 50, 60, and 70 nm in thickness were grown on (101)-oriented (LaAlO3)0.29(SrTa1/2Al1/2O3)0.71 (LSAT(101)) substrates by pulsed laser deposition and investigated by both piezoresponse force microscopy (PFM) and (scanning) transmission electron microscopy ((S)TEM). PFM measurements reveal that periodic stripe domains are dominant in 50 nm thick PTO films. Besides stripe domains, a/ c domains appear in films with thickness more than 60 nm. A thickness-dependent evolution of piezoresponse amplitude indicates that the 50 nm thick PTO films demonstrate a superior piezoresponse. Electron diffraction and contrast analysis clarify that all these (101)-oriented PTO films contain periodic stripe ferroelectric 90 degrees domains. The domain periods increase with the film thickness following Kittel's law. Aberration-corrected STEM imaging reveals that the stripe ferroelectric 90 degrees domains have an alternate arrangement of wide and narrow c domains with polarization directions along [100] for c1 domains and [001] for c2 domains, forming a "head-to-tail" polarization configuration. Further strain analysis reveals that stripe domains have uniform strain distributions and distinct lattice rotations around domain walls. It is proposed that the periodic arrangement of high-density stripe 90 degrees domains in 50 nm thick PTO films is the main contributor to the superior piezoresponse behavior. These results are expected to provide useful information to understand the domain structures in (101)-oriented PTO thin films and thus facilitate further modulation of the properties for potential applications. PMID- 29969008 TI - Distinguishing Interface Magnetoresistance and Bulk Magnetoresistance through Rectification of Schottky Heterojunctions. AB - High performance of many spintronic devices strongly depends on the spin polarized electrical transport, especially the magnetoresistance (MR) in magnetic heterojunctions. However, it has been a great challenge to distinguish the bulk MR and interface MR by transport measurements because the bulk resistance and interface resistance formed a series circuit in magnetic heterojunctions. Here, a unique interface-sensitive rectification MR method is proposed to distinguish the interface MR and bulk MR of nonmagnetic In/GeO x/n-Ge and magnetic Co/GeO x/n-Ge diode-like heterojunctions. It is demonstrated that the low-field "butterfly" hysteresis loop observed only in the conventional MR curve originates from the anisotropic MR of ferromagnetic bulk Co layer, whereas the orbit-related large nonsaturating positive MR contains contributions from both the Schottky interface and bulk Ge substrate. This rectification MR method could be extended to magnetic heterojunctions with asymmetric potential barriers to realize a deeper understanding of the fundamental interface-related functionalities. PMID- 29969009 TI - Reset Voltage-Dependent Multilevel Resistive Switching Behavior in CsPb1- xBi xI3 Perovskite-Based Memory Device. AB - All-inorganic CsPb1- xBi xI3 perovskite film was successfully fabricated by incorporating Bi3+ in CsPbI3 to stabilize the cubic lattice. Furthermore, the perovskite film was applied to manufacture a simple Ag/CsPb1- xBi xI3/indium tin oxide (ITO) memory device with a bipolar resistive switching behavior. Nonvolatile, reliable, and reproducible switching properties are demonstrated through retention and endurance test under fully open-air conditions. The memory device also presents highly uniform and long-term stable characteristics. Importantly, by modulating the reset stop voltages, multilevel high-resistance states are observed for the first time in lead halide perovskite memory device. The resistive switching behavior is proposed to explain the formation and partial rupture of conductive multifilament that are dominated by the migration of iodine ions and their corresponding vacancies in perovskite film. This study suggests Ag/CsPb1- xBi xI3/ITO device potential application for multilevel data storage in a nonvolatile memory device. PMID- 29969010 TI - Mapping the Inhomogeneity in Plasmonic Catalysis on Supported Gold Nanoparticles Using Surface-Enhanced Raman Scattering Microspectroscopy. AB - The characterization of a catalyst often occurs by averaging over large areas of the catalyst material. On the other hand, optical probing is easily achieved at a resolution at the micrometer scale, specifically in microspectroscopy. Here, using surface-enhanced Raman scattering (SERS) mapping of larger areas with micrometer-sized spots that contain tens to hundreds of supported gold nanoparticles each, the photoinduced dimerization of p-aminothiophenol (PATP) to 4,4'-dimercaptoazobenzene (DMAB) was monitored. The mapping data reveal an inhomogeneous distribution of catalytic activity in the plasmon-catalyzed reaction in spite of a very homogeneous plasmonic enhancement of the optical signals in SERS. The results lead to the conclusion that only a fraction of the nanostructures may be responsible for a high catalytic activity. The high spot-to spot variation in catalytic activity is also demonstrated for DMAB formation by the plasmon-catalyzed reduction from p-nitrothiophenol (PNTP) and confirms that an improvement of the accuracy and reproducibility in the characterization of catalytic reactions can be achieved by microspectroscopic probing of many positions. Using SERS micromapping during the incubation of PATP, we demonstrate that the reaction occurs during the incubation process and is influenced by different parameters, leading to the conclusion of dimerization in a gold catalyzed, nonphotochemical reaction as an alternative to the plasmon-catalyzed process. The results have implications for the future characterization of new catalyst materials as well as for optical sensing using plasmonic materials. PMID- 29969011 TI - Synthesis of 2-Alkylsulfonyl-imidazoles with Three Diversity Positions from Immobilized alpha-Acylamino Ketones. AB - The synthesis of novel imidazole derivatives via immobilized alpha-acylamino ketones is reported in this article. The key intermediates were prepared from the Wang-piperazine resin-supported Fmoc-amino acids. After their sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), followed by alkylation with alpha bromoketones and cleavage of Nos group, the resulting alpha-acylamino ketones were reacted with Fmoc-isothiocyanate. The corresponding Fmoc-thioureas were subjected to the Fmoc-cleavage and spontaneous ring-closure to imidazole scaffold. The resulting imidazole-thiones were alkylated with alkyl halides and oxidized using meta-chloroperbenzoic acid ( mCPBA). Trifluoroacetic acid (TFA) mediated cleavage yielded the corresponding trisubstituted 2-alkylsulfonyl imidazoles in good crude purity and acceptable overall yields. In the case of sulfides, prepared from alkyl bromides, the unexpected products brominated at the C4 position of the imidazole were obtained. PMID- 29969012 TI - Magnesium-Doped MAPbI3 Perovskite Layers for Enhanced Photovoltaic Performance in Humid Air Atmosphere. AB - Despite the high efficiency of MAPbI3 perovskite solar cells, the long term stability and degradation in humid atmosphere are issues that still needed to be addressed. In this work, magnesium iodide (MgI2) was first successfully used as a dopant into MAPbI3 perovskite prepared in humid air atmosphere. Mg doping decreased the valence band level, which was determined from photoelectron yield spectroscopy. Compared to the pristine MAPbI3 perovskite film, the 1.0% Mg-doped perovskite film showed increased crystal grain size and formation of pinhole-free perovskite film. Performance of the solar cell was increased from 14.2% of the doping-free solar cell to 17.8% of 1.0% Mg-doped device. Moreover, 90% of the original power conversion efficiency was still retained after storage in 30-40% relative humidity for 600 h. PMID- 29969013 TI - Optimally Hierarchical Nanostructured Hydroxyapatite Coatings for Superior Prosthesis Biointegration. AB - Bone osteogenesis is a complex phenomenon dependent on numerous microenvironmental cues, with their synchrony regulating cellular functions, such as mechanical signaling, survival, proliferation, and differentiation, as well as controlled regional specification of skeletal progenitor cell fate. Therefore, obtaining a mechanistic understanding of cellular response to a microenvironment is now coming into intense focus, which will facilitate the design of programmable biomaterials for regenerative medicine. State-of-the-art nanomaterial synthesis and self-assembly processes yield complex structures that mimic surface properties, composition, and partially the morphology of the extracellular matrix. However, determining key structural properties that control cell attachment has been challenging and contradictory results are reported regarding the mechanisms and roll of nanostructured materials. Here, we significantly improve osteogenesis on bioinert substrates, demonstrating an exemplary organic-inorganic interface for superior prosthesis biointegration. We identify critical microscale hierarchical features that drastically enhance the cellular response to the same nanoscale architecture. It was observed that hierarchical morphologies, with a porosity above 80%, promote early-stage osteoinduction, as indicated by extensive coating ingrowth and nanofilopodia formation. We determined that cellular integration was mediated by two-way recognition of specific nano- and microtopographical cues between the host tissue and cellular microenvironment. This has allowed us to detail a set of determinant features for the nanofabrication of advanced prosthesis coatings that may ultimately improve implant longevity. PMID- 29969014 TI - Reducing the Universal "Coffee-Ring Effect" by a Vapor-Assisted Spraying Method for High-Efficiency CH3NH3PbI3 Perovskite Solar Cells. AB - Organic-inorganic perovskite solar cells (PSCs) are one of the most attractive and efficient burgeoning thin-film photovoltaics. The perovskite films have been fabricated via lots of deposition methods, but these laboratory-based fabrication methods are not well-matched with large-area manufacture. Herein, spray coating as a deposition technique was explored to prepare perovskite films and break the bottleneck that plagued large-scale production. However, it is hard to reduce the notorious "coffee-ring effect" during the process of spraying perovskite films especially in a one-step spraying method. Thus, the vapor-assisted spraying method (VASM), namely, fabricating perovskite films through a vapor-solid in situ reaction between CH3NH3I vapor and sprayed PbI2 films, was creatively applied to the preparation of dense and uniform perovskite films. The surfaces of the sprayed PbI2 films were optimized by adjusting the wettability, viscosity, and contact quality via various methods such as the selection of solvent, solution concentration, and substrate temperature to inhibit the capillary flow and release the pinning contact line. The application of a component solvent could effectively crush the dense structure of the PbI2 film, optimizing the morphology of PbI2 films and reducing the influence of the coffee-ring effect. Integrating the above aspects, the optimized PbI2 films could form uniform perovskite films via an in situ reaction, and a best power conversion efficiency of 17.56% was achieved for planar structure PSCs, which is high among the PSCs fabricated by the spraying method. In addition, the VASM could be applied in the actual conditions for mass production, exhibiting excellent optical and electrical properties and paving the way of the commercialization of PSCs. PMID- 29969015 TI - Correction to A Comprehensive History of Arynes in Natural Product Total Synthesis. PMID- 29969016 TI - Quantitative Characterization of Molecular-Stream Separation. AB - Molecular-stream separation (MSS), for example, by free flow electrophoresis or continuous annular chromatography, has great potential for applications that require continuous downstream separation such continuous flow synthesis. Despite its potential, MSS still needs to be greatly advanced, which requires currently lacking tools for quantitative characterization of streams in MSS. We developed and introduce here an analytical toolbox for this task. The first tool is a method to convolute 3D raw MSS data into a 2D "angulagram" via signal integration over the whole separation zone using a polar coordinate system. The second tool is three quantitative parameters characterizing stream width, linearity, and deflection, which are determined from an angulagram. The third tool is the analysis of the three parameters in relation to physicochemical characteristics of MSS which reveals deficiencies and guides improvements in MSS devices and methods. Examples of toolbox application to validation of previously published MSS data are provided. PMID- 29969017 TI - Sandwich DNA Hybridization Fluorescence Resonance Energy-Transfer Strategy for miR-122 Detection by Core-Shell Upconversion Nanoparticles. AB - An upconversion nanoparticle (UCNP)-based fluorescence resonance energy-transfer (FRET) strategy is normally restricted by the complicated preparations, low energy-transfer efficiency, and the challenge on improving specificity. Herein, simple DNA-functionalized UCNPs were designed as energy donors for constructing a FRET-based probe to detect the liver-specific microRNA 122 (miR-122). To improve FRET efficiency, UCNPs were constructed with confined core-shell structures, in which emitting ions were precisely located in the thin shell to make them close enough to external energy acceptors. Subsequently, capture DNA was simply functionalized on the outer surface of UCNPs based on ligand exchange that contributed to shortening the energy-transfer distance without extra modification. To gain high specificity, the donor-to-acceptor distance of FRET was controlled by a sandwich DNA hybridization structure using two shorter DNAs with designed complementary sequences (capture DNA and dye-labeled report DNA) to capture the longer target of miR-122. Therefore, the sensitive detection of miR 122 was achieved based on the decreased signals of UCNPs and the increased signals of the dye labeled on reported DNA. With good biocompatibility, this method has been further applied to cancer cell imaging and in vivo imaging, which opened up a new avenue to the sensitive detection and imaging of microRNA in biological systems. PMID- 29969018 TI - Transformation and Speciation Analysis of Silver Nanoparticles of Dietary Supplement in Simulated Human Gastrointestinal Tract. AB - Knowledge of the physicochemical properties of ingestible silver nanoparticles (AgNPs) in the human gastrointestinal tract (GIT) is essential for assessing their bioavailability, bioactivity, and potential health risks. The gastrointestinal fate of AgNPs and silver ions from a commercial dietary supplement was therefore investigated using a simulated human GIT. In the mouth, no dissolution or aggregation of AgNPs occurred, which was attributed to the neutral pH and the formation of biomolecular corona, while the silver ions formed complexes with biomolecules (Ag-biomolecule). In the stomach, aggregation of AgNPs did not occur, but extensive dissolution was observed due to the low pH and the presence of Cl-. In the fed state (after meal), 72% AgNPs (by mass) dissolved, with 74% silver ions forming Ag-biomolecule and 26% forming AgCl. In the fasted state (before meal), 76% AgNPs dissolved, with 82% silver ions forming Ag-biomolecule and 18% forming AgCl. A biomolecular corona around AgNPs, comprised of mucin with multiple sulfhydryl groups, inhibited aggregation and dissolution of AgNPs. In the small intestine, no further dissolution or aggregation of AgNPs occurred, while the silver ions existed only as Ag biomolecule. These results provide useful information for assessing the bioavailability of ingestible AgNPs and their subsequently potential health risks, and for the safe design and utilization of AgNPs in biomedical applications. PMID- 29969019 TI - Investigation of the Preferential Doping Site and Regulating on the Visible Light Response and Redox Performance for Fe- and/or La-Doped InNbO4. AB - The preferential doping site, visible light response, and redox potential of Fe- and/or La-doped InNbO4 (INO) were investigated using first-principles density functional theory. Eight designed doping models, including Fe and/or La doping at In or/and Nb sites of INO are constructed, respectively. It was found that Fe doping and Fe,La-codoping to substitute In into an INO cell are energetically favorable, confirming that the steric hindrance plays a vital role for the selective doping site than the charge of the dopants. Fe doping always formed two impurity bands between the conduction and valence bands, originated from Fe 3d state, inferring the well visible light response. Furthermore, the presence of La has a specific regulation effects for Fe doping although the energy levels of the single La-doped models were completely similar to those of the undoped INO. The electron exchange between La and Fe dopants results in the significant interaction for codoping INO. Importantly, by doping La into INO cell, the redox potentials of Fe-doped INO could be well-regulated. The band potential moved to the more positive energy level of the models Fe-doped at Nb sites, while it shifted to the more negative level if Fe was doped at In site of La-INO. The present investigation may provide the guidance for the designative dopants to construct the photocatalyst with stable, visible response, and good redox performance. PMID- 29969020 TI - Radical Relatives: Facile Oxidation of Hetero-Diarylmethene Anions to Neutral Radicals. AB - Furan and thiophene diarylmethenes are potential redox-active ligands for metal centers that could be exploited in the development of nontraditional, stoichiometric, and catalytic redox reactions. As such, we describe here the selective meso-deprotonations of dithiophene, difuran, and diimine-difuran diarylmethanes to form the pi-conjugated anions, for which only the diimino difuryl anion is truly isolable and studied by X-ray crystallography. In all cases, facile one-electron oxidation of these anions occurs, which allows the isolation of the neutral dithienyl and diimino-difuryl radicals. UV-Visible and time-dependent density functional theory studies reveal that the oxidation of the dithienyl anion to its radical is associated with an increase in the highest (singly) occupied molecular orbital-lowest unoccupied molecular orbital gap, evident through a hypsochromic shift of the main absorption band in the electronic spectrum, whereas oxidation of the diimino-difuryl anion causes only minor spectroscopic changes. Electrochemical studies support the stability of the radicals with respect to the anion, showing strongly negative oxidation potentials. The control of the redox activity of these diarylmethene carbanions through variation of the nature of the substituents, donor-atom, and the conjugated pi-system and their potential as ligands for redox-inert metal centers makes them intriguing candidates as noninnocent partners for redox reactions. PMID- 29969021 TI - Kineticomechanistic Study of the Redox pH Cycling Processes Occurring on a Robust Water-Soluble Cyanido-Bridged Mixed-Valence {CoIII/FeII}2 Square. AB - A kineticomechanistic study of reversible electron-transfer processes undergone by the water-soluble, cyanido-bridged mixed-valence [{CoIII{(Me)2(MU ET)cyclen}}2{(MU-NC)2FeII(CN)4}2]2- square has been carried out. The oxidation reaction consists of a two-step process with the participation of a solvent assisted outer-sphere complex, as a result of the establishment of hydrogen bonds that involve the oxo groups of the oxidant (peroxodisulfate) and the terminal cyanido ligands of the tetrametallic square. The formally endergonic reduction reaction of the fully oxidized ([{CoIII{(Me)2(MU-ET)cyclen}}2{(MU NC)2FeIII(CN)4}2]) core by water, producing hydrogen peroxide from water even at low pH values, is also a two-step process. Each one of these processes requires a set of two preequilibria involving the association of OH- and its subsequent deprotonation by a further OH- anion. The structure of the square compound in its fully protonated form has also been determined by X-ray diffraction and shows the existence of strong hydrogen-bonding interactions, in agreement with the rather high basicity of the terminal cyanido ligands. Likewise, density functional theory calculations on the tetrametallic complex showed zones with negative electrostatic potential around the FeII centers of the square that would account for the establishment of the hydrogen bonds found in the solid state. Spectroelectrochemistry experiments demonstrated the singular stability of the {CoIII/FeII}22- complex, as well as that of their partially, {Co2III/FeIIIFeII}-, and fully, {CoIII/FeIII}2, oxidized counterparts because no hysteresis was observed in these measurements. PMID- 29969022 TI - Shungite Carbon as Unexpected Natural Source of Few-Layer Graphene Platelets in a Low Oxidation State. AB - The paper reports on the feasibility of obtaining graphene nanomaterials with remarkable structural and chemical features from shungite rocks. The investigation of the composition and structural modifications induced in the pristine, natural C-containing mineraloid by a specifically designed physicochemical purification treatment is performed by a combined use of several techniques (scanning electron microscopy, high resolution transmission electron microscopy, X-ray diffraction, Raman and X-ray photoelectron spectroscopies). The adopted material processing enables efficient extraction of the C phase in the form of thin polycrystalline platelets of a few hundred nanometers sizes, and formed by 6-10 graphene sheets. About 80% of such nanostructures are characterized by a regular sp2 C honeycomb lattice and an ordered stacking of graphene layers with a d-spacing of ~0.34 nm. The low oxygen content (~5%), mainly found in the form of hydroxyl functional groups, provides the graphene platelets (GP) with a chemistry strictly close to that of conventional rGO materials. Such a feature is supported by the high conductivity value of 1.041 * 103 S cm-1 found for pelletized GP, which can be considered a valuable active material for a wide spectrum of advanced applications. PMID- 29969023 TI - Role of Anation on the Mechanism of Proton Reduction Involving a Pentapyridine Cobalt Complex: A Theoretical Study. AB - Kinetic and thermodynamic aspects of proton reduction involving pentapyridine cobalt(II) complex were investigated with the help of quantum chemical calculations. Free energy profile of all possible mechanistic routes for proton reduction was constructed with the consideration of both anation and solvent bound pathways. The computed free energy profile shows that acetate ion plays a significant role in modulating the kinetic aspects of Co(III)-hydride formation which is found to be the key intermediate for proton reduction. Upon replacing solvent by acetate ion, one electron reduction and protonation of CoI species become more rapid along with slow displacement reaction. Most favorable pathways for hydrogen evolution from Co(III)-hydride species is also investigated. Among the four possible pathways, reduction followed by protonation of Co(III)-hydride (RPP) is found to be the most feasible pathway. On the basis of QTAIM and NBO analyses, the electronic origin of most favorable pathway is explained. The basicity of cobalt center along with thermodynamic stability of putative CoIII/II H species is essentially a prime factor in deciding the most favorable pathway for hydrogen evolution. Our computed results are in good agreement with experimental observations and also provided adequate information to design cobalt based molecular electrocatalysts for proton reduction in future. PMID- 29969024 TI - Recent Progress in the Discovery of Allosteric Inhibitors of Kidney-Type Glutaminase. AB - Kidney-type glutaminase (GLS), the first enzyme in the glutaminolysis pathway, catalyzes the hydrolysis of glutamine to glutamate. GLS was found to be upregulated in many glutamine-dependent cancer cells. Therefore, selective inhibition of GLS has gained substantial interest as a therapeutic approach targeting cancer metabolism. Bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2 yl]ethyl sulfide (BPTES), despite its poor physicochemical properties, has served as a key molecular template in subsequent efforts to identify more potent and drug-like allosteric GLS inhibitors. This review article provides an overview of the progress made to date in the development of GLS inhibitors and highlights the remarkable transformation of the unfavorable lead into "druglike" compounds guided by systematic SAR studies. PMID- 29969025 TI - Serendipitous Synthesis Found in the Nuances of Homoleptic Zinc Complex Formation. AB - A series of aminophenolate and aminonaphtholate homoleptic zinc complexes were obtained using a simple and unique synthetic strategy. A rigorous analysis of the byproduct supported modifications of the main course of the bis-chelation reaction. Controlled alcoholysis was followed by alternation and controlled anaerobic hydrolysis of ethyl-zinc aminophenolate or aminonaphtholate complexes. This new and intriguing reaction yielded a new class of zinc corona complexes. All the synthesized complexes were fully characterized in the solid state and in solution using X-ray and spectroscopic methods as well as density functional theory calculations. PMID- 29969027 TI - In Situ Formation of N-Heterocyclic Carbene-Bound Single-Molecule Junctions. AB - Self-assembled monolayers (SAMs) formed using N-heterocyclic carbenes (NHCs) have recently emerged as thermally and chemically ultrastable alternatives to those formed from thiols. The rich chemistry and strong sigma-donating ability of NHCs offer unique prospects for applications in nanoelectronics, sensing, and electrochemistry. Although stable in SAMs, free carbenes are notoriously reactive, making their electronic characterization challenging. Here we report the first investigation of electron transport across single NHC-bound molecules using the scanning tunneling microscope-based break junction (STM-BJ) technique. We develop a series of air-stable metal NHC complexes that can be electrochemically reduced in situ to form NHC-electrode contacts, enabling reliable single-molecule conductance measurements of NHCs under ambient conditions. Using this approach, we show that the conductance of an NHC depends on the identity of the single metal atom to which it is coordinated in the junction. Our observations are supported by density functional theory (DFT) calculations, which also firmly establish the contributions of the NHC linker to the junction transport characteristics. Our work demonstrates a powerful method to probe electron transfer across NHC-electrode interfaces; more generally, it opens the door to the exploitation of surface-bound NHCs in constructing novel, functionalized electrodes and/or nanoelectronic devices. PMID- 29969026 TI - Purification, Characterization, and Crystal Structure of Parvalbumins, the Major Allergens in Mustelus griseus. AB - Fish play important roles in human nutrition and health, but also trigger allergic reactions in some population. Parvalbumin (PV) represents the major allergen of fish. While IgE cross-reactivity to PV in various bony fish species has been well characterized, little information is available about allergens in cartilaginous fish. In this study, two shark PV isoforms (named as SPV-I and SPV II) from Mustelus griseus were purified. Their identities were further confirmed by mass spectroscopic analysis. IgE immunoblot analysis showed that sera from fish-allergic patients reacted to both SPV-I and SPV-II, but the majority of sera reacted more intensely to SPV-I than SPV-II. Thermal denaturation monitored by CD spectrum showed that both of the SPV allergens are highly thermostable. SPV-I maintained its IgE-binding capability after heat denaturation, while the IgE binding capability of SPV-II was reduced. The results of crystal structure showed that SPV-I and SPV-II were similar in their overall tertiary structure, but their amino acid sequences shared lower similarities, indicating that the differences in the IgE-binding capabilities of SPV-I and SPV-II might be due to differential antigen epitopes in these two isoforms. PMID- 29969028 TI - Cytochalasans Produced by the Coculture of Aspergillus flavipes and Chaetomium globosum. AB - The cocultivation of Aspergillus flavipes and Chaetomium globosum, rich sources of cytochalasans, on solid rice medium, resulted in the production of 13 new, highly oxygenated cytochalasans, aspochalasinols A-D (1-4) and oxichaetoglobosins A-I (5-13), as well as seven known compounds (14-20). Of these compounds, 13 is a novel cytochalasan with an unexpected 2-norindole group. The isolated compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD experiments. Compounds 1-4 represent the first examples of Asp-type cytochalasans with C-12 hydroxy groups, which may be a result of the coculture, as hydroxylated Me-12 groups are frequently found in Chae-type cytochalasans from C. globosum. In addition, 5-10 are unusual cytochalasans with an oxygenated C-10. Interestingly, 13 is the first example of a naturally occurring cytochalasan possessing a uniquely degraded indole ring that is derived from chaetoglobosin W, with 11 and 12 both serving as its biosynthetic intermediates. In the coculture of A. flavipes and C. globosum, most of these cytochalasans are more functionalized than normal cytochalasans, and the underlying causes may attract substantial attention from synthetic biologists. The cytotoxicities against five human cancer cell lines (SW480, HL-60, A549, MCF-7, and SMMC-7721) and the immunomodulatory activities of these new compounds were evaluated in vitro. PMID- 29969029 TI - De Novo Design, Synthesis, and Biological Evaluation of 3,4-Disubstituted Pyrrolidine Sulfonamides as Potent and Selective Glycine Transporter 1 Competitive Inhibitors. AB - The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities. PMID- 29969030 TI - Contilisant, a Tetratarget Small Molecule for Alzheimer's Disease Therapy Combining Cholinesterase, Monoamine Oxidase Inhibition, and H3R Antagonism with S1R Agonism Profile. AB - Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecular modeling. In addition, contilisant significantly restores the cognitive deficit induced by Abeta1-42 in the radial maze assay in an in vivo Alzheimer's disease test, comparing very favorably with donepezil. PMID- 29969031 TI - (3 + 3) Annulation of Nitroallylic Acetates with Stabilized Sulfur Ylides for the Synthesis of 2-Aryl Terephthalates. AB - A novel (3 + 3) annulation approach has been developed for the synthesis of 2 aryl terephthalates from nitroallylic acetates and stabilized sulfur ylides. The 2-aryl terephthalates, which are also biaryls bearing a terephthalate moiety, are formed through a cascade of reactions such as a gamma-selective SN2' reaction, gamma-selective intramolecular Michael addition, and two eliminations in the presence of Cs2CO3 in CH3CN at room temperature. The products are formal precursors of farnesyltransferase inhibitors and are also potential monomers in polymer chemistry. PMID- 29969032 TI - Substrate Controlled Regioselective Bromination of Acylated Pyrroles Using Tetrabutylammonium Tribromide (TBABr3). AB - Electrophilic bromination of pyrroles bearing carbonyl substituents at C-2 typically results in a mixture of the 4- and 5-brominated species, generally favoring the 4-position. Herein, we describe a substrate-controlled regioselective bromination in which tetra-butyl ammonium tribromide (TBABr3) reacts with pyrrole-2-carboxamide substrates to yield the 5-brominated species as the predominant (up to >10:1) product. PMID- 29969033 TI - Iridium(III) Complexes Bearing Tridentate Chromophoric Chelate: Phosphorescence Fine-Tuned by Phosphine and Hydride Ancillary. AB - Functional 2-pyrazolyl-6-phenylpyridine chelates-namely, (pzpyphBu)H2 and (pzpyphCF3)H2 and phosphines-are successfully employed in the preparation of emissive Ir(III) metal complexes, for which the reaction with phosphine such as PPh3, PPh2Me, and PPh2(CH2Ph) afford corresponding Ir(III) complexes [Ir(pzpyphBu)(PPh3)2H] (1a), [Ir(pzpyphCF3)(PPh2R)2H] (2a-2c), R = Ph, Me, CH2Ph, which also show an equatorial coordinated hydride. In contrast, treatment with 1,2-bis(diphenylphosphino)benzene (dppb) and 1,2-bis(diphenylphosphino)ethane (dppe) yields the isomeric products [Ir(pzpyphBu)(dppb)H] (3a) and [Ir(pzpyphBu)(dppe)H] (3b), for which the distinctive, axial hydride undergoes rapid chlorination, forming chlorinated complexes [Ir(pzpyphBu)(dppb)Cl] (4a) and [Ir(pzpyphBu)(dppe)Cl] (4b), respectively. On the other hand, upon extensive heating of 2c, one of its coordinated PPh2(CH2Ph) exhibits benzyl cyclometalation and hydride elimination to afford [Ir(pzpyphCF3)(PPh2R)(PPh2R')] (5c and 6c) R = CH2Ph and R' = CH2( o-C6H4) as the kinetic and thermodynamic products, respectively. Their structural, photophysical, and electrochemical properties are examined and further affirmed by the computational approaches. PMID- 29969034 TI - Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process. AB - An unprecedented three-component reaction of arynes, tertiary amines, and nucleophiles has been demonstrated through ammonium salt intermediates. This protocol allows access to tertiary aniline derivatives containing the piperazine motif in good-to-excellent yields. Expansively, this reaction can produce biologically important 2-(4-phenylpiperazin-1-yl)ethyl-containing molecules using arynes, 1,4-diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a one-pot process. PMID- 29969035 TI - Synovial Fluid Metabolites Differentiate between Septic and Nonseptic Joint Pathologies. AB - Osteoarthritis (OA), osteochondrosis (OC), and synovial sepsis in horses cause loss of function and pain. Reliable biomarkers are required to achieve accurate and rapid diagnosis, with synovial fluid (SF) holding a unique source of biochemical information. Nuclear magnetic resonance (NMR) spectroscopy allows global metabolite analysis of a small volume of SF, with minimal sample preprocessing using a noninvasive and nondestructive method. Equine SF metabolic profiles from both nonseptic joints (OA and OC) and septic joints were analyzed using 1D 1H NMR spectroscopy. Univariate and multivariate statistical analyses were used to identify differential metabolite abundance between groups. Metabolites were annotated via 1H NMR using 1D NMR identification software Chenomx, with identities confirmed using 1D 1H and 2D 1H 13C NMR. Multivariate analysis identified separation between septic and nonseptic groups. Acetate, alanine, citrate, creatine phosphate, creatinine, glucose, glutamate, glutamine, glycine, phenylalanine, pyruvate, and valine were higher in the nonseptic group, while glycylproline was higher in sepsis. Multivariate separation was primarily driven by glucose; however, partial-least-squares discriminant analysis plots with glucose excluded demonstrated the remaining metabolites were still able to discriminate the groups. This study demonstrates that a panel of synovial metabolites can distinguish between septic and nonseptic equine SF, with glucose the principal discriminator. PMID- 29969036 TI - Spin Signature of the C60 Fullerene Anion: A Combined X- and D-Band EPR and DFT Study. AB - Fullerenes attract much attention in various scientific fields, but their electronic properties are still not completely understood. Here we report on a combined EPR and DFT study of the fullerene anion C60- in solid glassy environment. DFT calculations were used to characterize its electronic structure through spin density distribution and magnetic resonance parameters. The electron spin density is not uniformly distributed throughout the C60- cage but shows a pattern similar to PC61BM-. EPR spectroscopy reveals a rhombic g-tensor sensitive to the environment in the frozen glassy solutions, which can be rationalized by deformation of the fullerenes along low-frequency vibrational modes upon cooling. DFT modeling confirms that these deformations lead to variation in the C60- g values. The decrease in g-tensor anisotropy with sample annealing is related to the lessening of g-tensor strain upon temperature relaxation of the most distorted sites in the glassy state. PMID- 29969037 TI - Reduction in the Repulsive Forces between Two Charged Surfaces in Aqueous Solutions Containing Salts by a Liquid Flow. AB - In spite of the fact that a flow is often present in the liquid in which charged particles are dispersed, the effect of a flow on the forces controlling the dispersion is not clear. Here, we used a combined atomic force microscope peristaltic pump system to determine the effect of a flow in aqueous solutions between a negatively charged silica particle and a negatively charged silicon wafer on the forces in the system. The effect of a flow on the forces in water or aqueous solutions of NaCl or MgCl2.6H2O was studied for salt concentrations lower than the concentrations needed to invert the charge of the silica and silicon surfaces. This was done to prevent the formation of a reversed flow in the system due to a charge inversion of the silica surface. A flow was seen to decrease the intersurface repulsive forces, if the water contained salt (NaCl or MgCl2.6H2O). An increased bulk salt concentration was also seen to decrease the repulsive forces further in the presence of a liquid flow. The surface potentials and effective ionic concentrations of the systems were determined by comparing the experimental curves with the theoretically calculated ones. The surface potentials and effective ionic concentrations were seen to decrease and increase, respectively, as the flow rate and bulk salt concentrations were increased. This change was explained by the shrinking of the diffuse layers by the liquid flow, due to part of the diffuse layer being washed away by the flowing liquid. PMID- 29969038 TI - Metformin Protects against LPS-Induced Intestinal Barrier Dysfunction by Activating AMPK Pathway. AB - Metformin not only regulates energy metabolism but also participates in many cellular processes. In this study, we investigated the effect of metformin on lipopolysaccharide (LPS)-induced intestinal barrier damage. We found that LPS treatment decreased the expression of tight junction proteins and caused a proinflammatory response and oxidative stress in the intestine. Interestingly, metformin treatments attenuated LPS-induced intestinal barrier damage, inflammation, and oxidative stress. We found that metformin improved the expression of intestinal tight junction proteins (ZO1, occludin, and Claudin1) that were reduced by LPS stimulation. Moreover, metformin alleviated LPS-induced NF-kappaB phosphorylation, promoted Nrf2 nuclear translocation, and increased the expression of the antioxidative genes (HO-1 and NQO-1), leading to reduced intestinal ROS content. Mechanistically, we found that metformin protects against LPS-induced intestinal barrier dysfunction by activating AMPK. These results reveal the potential of metformin as an effective therapy for treating intestinal diseases. PMID- 29969039 TI - 3D Molecular ToF-SIMS Imaging of Artificial Lipid Membranes Using a Discriminant Analysis-Based Algorithm. AB - Artificial lipid membranes play a growing role in technical applications such as biosensors in pharmacological research and as model systems in the investigation of biological lipid films. In the standard procedure for displaying the distribution of membrane components, fluorescence microscopy, the fluorophores used can influence the distribution of the components and usually not all substances can be displayed at the same time. The discriminant analysis-based algorithm used in combination with scanning time-of-flight secondary ion mass spectrometry (ToF-SIMS) enables marker-free, quantitative, simultaneous recording of all membrane components. These data are used for reconstruction of distribution patterns. In the model system used for this survey, a tear fluid lipid layer, the distribution patterns of all lipids correlate well in calculated ToF-SIMS images and epi-fluorescence microscopic images. All epi-fluorescence microscopically viewable structures are visible when using both positive and negative secondary ions and can be reproduced with high lateral resolution in the submicrometer range despite the very low signal intensity and a very low signal to-noise ratio. In addition, three-dimensional images can be obtained with a subnanometer depth resolution. Furthermore, structures and the distribution of substances that cannot be made visible by epi-fluorescence microscopy can be displayed. This enables new insights that cannot be gained by epi-fluorescence microscopy alone. PMID- 29969040 TI - Brain structure and function related to headache: Brainstem structure and function in headache. AB - Objective To review and discuss the literature relevant to the role of brainstem structure and function in headache. Background Primary headache disorders, such as migraine and cluster headache, are considered disorders of the brain. As well as head-related pain, these headache disorders are also associated with other neurological symptoms, such as those related to sensory, homeostatic, autonomic, cognitive and affective processing that can all occur before, during or even after headache has ceased. Many imaging studies demonstrate activation in brainstem areas that appear specifically associated with headache disorders, especially migraine, which may be related to the mechanisms of many of these symptoms. This is further supported by preclinical studies, which demonstrate that modulation of specific brainstem nuclei alters sensory processing relevant to these symptoms, including headache, cranial autonomic responses and homeostatic mechanisms. Review focus This review will specifically focus on the role of brainstem structures relevant to primary headaches, including medullary, pontine, and midbrain, and describe their functional role and how they relate to mechanisms of primary headaches, especially migraine. PMID- 29969041 TI - Impact of Guideline Changes on Indications for Inhaled Corticosteroids among Veterans with Chronic Obstructive Pulmonary Disease. PMID- 29969042 TI - Development and in vitro evaluation of pH-independent release matrix tablet of weakly acidic drug valsartan using quality by design tools. AB - The main objective of this study was the development of pH-independent controlled release valsartan matrix tablet in Quality by design (QbD) framework. The quality target product profile (QTPP), critical quality attributes (CQAs) and critical material attributes (CMAs) were defined by science and risk-based methodologies. Potential risk factors were identified with Fishbone diagram. Following, CMAs were further investigated with a semi-quantitative risk assessment method, which has been revised with mitigated risks after development and optimization studies. According to defined critical material attributes, which one of them was determined to be the dissolution, formulation optimization study was performed by using a statistical design of experiment. Formulation variables have been identified and fixed first with a 'One factor at a time (OFAT)' approach. After OFAT studies, a statistical experimental design was conducted with the most critical material attributes. Statistical design space and mathematical prediction equations have been developed for dissolution and hardness, which is important to predict drug dissolution behavior. In conclusion, a pH-independent release has been achieved for weakly acidic drug valsartan with a deeper understanding of drug product quality, with the science and risk-based approaches of QbD tools. PMID- 29969043 TI - First-in-Human Pilot Study of Implantation of a Scaffold-Free Tissue-Engineered Construct Generated From Autologous Synovial Mesenchymal Stem Cells for Repair of Knee Chondral Lesions. AB - BACKGROUND: Articular cartilage has limited healing capacity, owing in part to poor vascularity and innervation. Once injured, it cannot be repaired, typically leading to high risk for developing osteoarthritis. Thus, cell-based and/or tissue-engineered approaches have been investigated; however, no approach has yet achieved safety and regenerative repair capacity via a simple implantation procedure. PURPOSE: To assess the safety and efficacy of using a scaffold-free tissue-engineered construct (TEC) derived from autologous synovial membrane mesenchymal stem cells (MSCs) for effective cartilage repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Five patients with symptomatic knee chondral lesions (1.5-3.0 cm2) on the medial femoral condyle, lateral femoral condyle, or femoral groove were included. Synovial MSCs were isolated from arthroscopic biopsy specimens and cultured to develop a TEC that matched the lesion size. The TECs were then implanted into chondral defects without fixation and assessed up to 24 months postoperatively. The primary outcome was the safety of the procedure. Secondary outcomes were self-assessed clinical scores, arthroscopy, tissue biopsy, and magnetic resonance image-based estimation of morphologic and compositional quality of the repair tissue. RESULTS: No adverse events were recorded, and self-assessed clinical scores for pain, symptoms, activities of daily living, sports activity, and quality of life were significantly improved at 24 months after surgery. Secure defect filling was confirmed by second-look arthroscopy and magnetic resonance imaging in all cases. Histology of biopsy specimens indicated repair tissue approaching the composition and structure of hyaline cartilage. CONCLUSION: Autologous scaffold-free TEC derived from synovial MSCs may be used for regenerative cartilage repair via a sutureless and simple implantation procedure. Registration: 000008266 (UMIN Clinical Trials Registry number). PMID- 29969044 TI - Univariate Outliers: A Conceptual Overview for the Nurse Researcher. AB - The presence of statistical outliers is a shared concern in research. If ignored or improperly handled, outliers have the potential to distort the estimate of the parameter of interest and thus compromise the generalizability of research findings. A variety of statistical techniques are available to assist researchers with the identification and management of outlier cases. The purpose of this paper is to provide a conceptual overview of univariate outliers with special focus on common techniques used to detect and manage univariate outliers. Specifically, this paper discusses the use of histograms, boxplots, interquartile range, and z-score analysis as common univariate outlier identification techniques. The paper also discusses the outlier management techniques of deletion, substitution, and transformation. PMID- 29969046 TI - Clinical significance of HLA-E genotype and surface/soluble expression levels between healthy individuals and patients with acute leukemia. AB - Human leukocyte antigen (HLA)-E is a nonclassical HLA molecule with limited polymorphisms. Genotype frequency and expression of HLA-E were examined here for the first time in acute leukemia patients and healthy controls. The frequency of HLA-E*01:03/*01:03 individuals was significantly higher (p = .008, OR = 1.845), while the frequency of HLA-E*01:01/*01:01 individuals was much lower in the patient group (p = .002, OR = .363) than in control group. The surface expression on HLA-E*01:03/*01:03 individuals was found to be significantly higher than on HLA-E*01:01/*01:01 individuals in both of acute leukemia and control groups, but no significant difference was observed between the corresponding genotypes in two groups. However, the level of expression of soluble HLA-E is significantly higher in patients than in the control group, but there was no genotype-specific expression in either group. These findings indicate that soluble HLA-E secretion and HLA-E*01:03/*01:03 genotype that brings higher surface expression might play important roles in the mechanisms underlying tumor escape in acute leukemia. PMID- 29969045 TI - Atrial arrhythmias are associated with increased mortality in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a deadly vascular disease, characterized by increased pulmonary arterial pressures and right heart failure. Considering prior non-US studies of atrial arrhythmias in PAH, this retrospective, regional multi-center US study sought to define more completely the risk factors and impact of paroxysmal and non-paroxysmal forms of atrial fibrillation and flutter (AF/AFL) on mortality in this disease. We identified patients seen between 2010 and 2014 at UPMC (Pittsburgh) hospitals with hemodynamic and clinical criteria for PAH or chronic thromboembolic pulmonary hypertension (CTEPH) and determined those meeting electrocardiographic criteria for AF/AFL. We used Cox proportional hazards regression with time-varying covariates to analyze the association between AF/AFL occurrence and survival with adjustments for potential cofounders and hemodynamic severity. Of 297 patients with PAH/CTEPH, 79 (26.5%) suffered from AF/AFL at some point. AF/AFL was first identified after PAH diagnosis in 42 (53.2%), identified prior to PAH diagnosis in 27 (34.2%), and had unclear timing in the remainder. AF/AFL patients were older, more often male, had lower left ventricular ejection fractions, and greater left atrial volume indices and right atrial areas than patients without AF/AFL. AF/AFL (whether diagnosed before or after PAH) was associated with a 3.81-fold increase in the hazard of death (95% CI 2.64-5.52, p < 0.001). This finding was consistent with multivariable adjustment of hemodynamic, cardiac structural, and heart rate indices as well as in sensitivity analyses of patients with paroxysmal versus non-paroxysmal arrhythmias. In these PAH/CTEPH patients, presence of AF/AFL significantly increased mortality risk. Mortality remained elevated in the absence of a high burden of uncontrolled or persistent arrhythmias, thus suggesting additional etiologies beyond rapid heart rate as an explanation. Future studies are warranted to confirm this observation and interrogate whether other therapies beyond rate and rhythm control are necessary to mitigate this risk. PMID- 29969047 TI - Do they teach what they need to? An analysis of the impact of curriculum mapping on the learning objectives taught in a lecture series in surgery. AB - INTRODUCTION: Curriculum mapping shows concordances and differences between the intended and the taught curriculum. To our knowledge, no previous studies describe the effects that this mapping has on the curriculum. The aim of the present study is to map the content of a lecture series in surgery to the National Catalogue of Learning Objectives in Surgery and analyze the effects this mapping has on the content of the following lecture series. METHODS: All lecturers in the lecture series were directly observed by a minimum of two reviewers and learning objectives and the level of competence were documented. After the lecture series, the results were visualized within the catalog of learning objectives and were sent to the lecturers. In the following lecture series, learning objectives were documented correspondingly. RESULTS: In the first lecture series, 47% of the learning objectives were taught. After the mapping, the number of learning objectives that were taught increased to 59% (p < 0.001). The increase was found in all surgical disciplines and in all levels of competences without any changes in the average duration of the lectures. CONCLUSIONS: The presented method for mapping a curriculum effectively increased the number of taught learning objectives without requiring longer lecture durations. PMID- 29969048 TI - How ameliorate the adherence in patients with inflammatory bowel disease? PMID- 29969049 TI - Late onset sepsis: comparison between coagulase-negative staphylococci and other bacteria in the neonatal intensive care unit. AB - OBJECTIVE: To compare demographic and clinical features of neonates with late onset sepsis due to coagulase-negative-staphylococcus with those due to other bacterial pathogens. STUDY DESIGN: Retrospective, population-based cohort study. Data on infants less than 90 days old diagnosed with late-onset bacterial sepsis in the neonatal intensive care unit were reviewed. Univariable and multivariable analysis were performed. RESULTS: Two hundred and sixteen sepsis episodes were identified: coagulase-negative-staphylococcus caused 113 (52.3%) and other pathogen 103 (47.7%). Patients with coagulase-negative-staphylococcus sepsis had lower gestational age and younger age at onset, higher rates of parenteral nutrition exposure and normal temperature, lower rates of necrotizing enterocolitis, meningitis and neutropenia than patients with sepsis caused by other pathogens. In multivariable analysis, parenteral nutrition was the only independent risk factor for coagulase-negative-staphylococcus sepsis (odds ratio: 3.5, 95% confidence interval: 1.4-8.6). CONCLUSIONS: Initial empiric treatment for suspected sepsis should be targeted for other pathogens than coagulase negative-staphylococci and vancomycin treatment should be reserved for infants with specific risk factors and according to local antimicrobial susceptibility. PMID- 29969050 TI - Repeatability analysis of ADC histogram metrics of the uterus. AB - Background Recently, histogram analysis based on voxel-wise apparent diffusion coefficient (ADC) value distribution has been increasingly performed. However, few studies have been reported regarding its repeatability. Purpose To evaluate the repeatability of ADC histogram metrics of the uterus in clinical magnetic resonance imaging (MRI). Material and Methods Thirty-three female patients who underwent pelvic MRI including diffusion-weighted imaging (DWI) were prospectively included after providing informed consent. Two sequential DWI acquisitions with identical parameters and position were obtained. Regions of interest (ROIs) for histologically confirmed uterine lesions (five cervical and three endometrial cancers, and one endometrial hyperplasia) and normal appearing tissues (21 endometrium and 33 myometrium) were assigned on the first DWI dataset and then pasted onto the second DWI dataset. ADC histogram metrics within the ROIs were calculated and repeatability was evaluated by calculating within subject coefficient of variance (%) (wCV (%)) and Bland-Altman plot (%). Results ADC 10%, 25%, median, 75%, 90%, maximum, mean, and entropy showed high repeatability (wCV (%) < 7, 95% limit of agreement in Bland-Altman plot (%) < +/ 20), followed by ADC minimum (wCV (%) = 8.12, 95% limit of agreement in Bland Altman plot (%) < +/-30). However, ADC skewness and kurtosis showed very low repeatability in all evaluations. Conclusion ADC histogram metrics like ADC 10%, 25%, median, 75%, 90%, maximum, mean, and entropy are robust biomarkers and could be applicable to clinical use. However, ADC skewness and kurtosis lack robustness. Radiologists should keep these characteristics and limitations in mind when interpreting quantitative DWI. PMID- 29969051 TI - Elastography and diffusion-weighted MRI in patients with testicular microlithiasis, normal testicular tissue, and testicular cancer: an observational study. AB - Background Ultrasound elastography is increasingly available in clinical practice. Recent studies showed higher velocity stiffness in testicular tumors compared to normal testicles. Purpose To evaluate ultrasound elastography in combination with the apparent diffusion coefficient measurements in diffusion weighted (DW) magnetic resonance imaging (MRI) in testicles. DW can be a useful tool in evaluating testicular malignancies. However, the relationship between velocity stiffness and MRI diffusion is not well established. Material and Methods We prospectively included 132 patients with testicular microlithiasis (n = 53), or normal testicular tissue (n = 53), or suspected for testicular cancer (n = 26). All 132 patients underwent ultrasonography including shear wave elastography and MRI diffusion coefficient examination of the scrotum. Results No clinically relevant difference in velocity stiffness was found between normal and testicles with microlithiasis. There was a significant difference in stiffness between patients with testicular microlithiasis (0.78 m/s), normal testicular tissue (0.77 m/s), and patients with testicular cancer (1.95 m/s) ( P <= 0.001). Similarly, there was a statistically significant difference in MRI diffusion values between patients with testicular microlithiasis (0.978 * 10-3 mm2 s-1), normal testicular tissue (0.929 * 10-3 mm2 s-1), and testicular cancers (0.743 * 10-3 mm2 s-1) ( P < 0.01). Conclusion Patients with testicular microlithiasis had no malignant characteristics measured with shear wave elastography or MRI diffusion. MRI diffusion and elastography may be useful to preoperatively differentiate benign from malignant testicular lesions. PMID- 29969052 TI - Evaluation of a commercial enzyme-linked immunosorbent assay (ELISA) for detecting antibodies against Toxoplasma gondii from naturally and experimentally infected pigs. AB - BACKGROUND: Toxoplasmosis is one of the most frequent parasitic infections in animals causing reproductive disorders and thus notable economic losses in productivity. Among food animals, pigs along with sheep and goats possess the highest incidence of Toxoplasma gondii cysts in meat, and play a role as a source of human infection. METHODS: The commercial ELISA kit (PrioCHECK(r) Toxoplasma Ab SR, Prionics Schlieren-Zurich, Switzerland) for the detection of specific antibodies against T. gondii in swine serum was compared with a commercial IFAT (indirect fluorescent antibody test) (Toxo-Spot IF, bioMerieux, France), used as the reference test. RESULTS: The kappa value obtained comparing the results performed on sera by ELISA with the by IFAT was 1. By a receiver operating characteristics curve analysis, the commercial ELISA had a relative sensitivity of 100%, and a relative specificity of 100% respect to IFAT. CONCLUSIONS: The commercial ELISA showed a very good agreement with the commercial IFAT in the detection of serum antibodies to Toxoplasma in pigs. Our study confirmed the usefulness of the commercial ELISA kit for the detection of antibodies against T. gondii in pigs, representing a valuable tool to improve the diagnostic activity for T. gondii in swine populations at the farm level or at the slaughterhouse, contributing to the control of this widespread infection. PMID- 29969053 TI - A new MAPT deletion in a case of speech apraxia leading to corticobasal syndrome. AB - Speech apraxia is a disorder of speech motor planning/programming leading to slow rate, articulatory distortion, and distorted sound substitutions. We describe the clinical profile evolution of a patient presenting with slowly progressive isolated speech apraxia that eventually led to the diagnosis of corticobasal syndrome (CBS), supporting the evidence that this rare speech disorder can be the first presentation of CBS. Moreover, we found a novel variant in MAPT gene, which is hypothesized to be disease-causing mutation. These results underscore the importance of genetic analysis - particularly in selected atypical cases - for in vivo understanding of possible pathophysiological disease process. PMID- 29969054 TI - Bedaquiline and Repurposed Drugs for Fluoroquinolone-Resistant Multidrug Resistant Tuberculosis: How Much Better Are They? PMID- 29969055 TI - Evaluation of Lineage Changes in the Gastric Mucosa Following Infection With Helicobacter pylori and Specified Intestinal Flora in INS-GAS Mice. AB - Gastric adenocarcinoma develops in metaplastic mucosa associated with Helicobacter pylori infection in the stomach. We have sought to evaluate the precise lineage changes in the stomachs of insulin-gastrin (INS-GAS) mice infected with H. pylori and/or intestinal flora (Altered Schaedler's Flora; ASF). Stomachs from groups infected with H. pylori contained progressive spasmolytic polypeptide-expressing metaplasia (SPEM) compared with germ-free and mice infected with ASF alone. The overall phenotype of the H. pylori-infected mice was dominated by Ulex europaeus lectin (UEAI)-positive foveolar hyperplasia that was distinct from GSII/CD44v9-positive SPEM. However, in the mice with H. pylori co infected with ASF, we identified a subpopulation of UEAI-positive foveolar cells that co-expressed intestinal mucin 4 (MUC4). These regions of foveolar cells were variably positive for CD44v9 as well as TFF3. Interestingly, an intravascular lesion identified in a dual H. pylori/ASF-infected mouse expressed both UEAI and Muc4. Finally, we identified an increase in the number of tuft cells within the mucosa of H. pylori-infected groups. Our findings suggest that H. pylori infection promotes foveolar hyperplasia as well as metaplasia, while co-infection may promote progressive foveolar and metaplastic lesions as well as dysplasia. Grading of gastric lesions in mice as preneoplastic requires multiple immunostaining markers to assign lineage derivation and behavior. PMID- 29969057 TI - Draft Genome Resource for the Potato Powdery Scab Pathogen Spongospora subterranea. AB - The Plasmodiophorida (Phytomyxea, Rhizaria) are a group of protists that infect plants. Of this group, Spongospora subterranea causes major problems for the potato industry by causing powdery scab and root galling of potatoes and as vector for the Potato mop-top virus (PMTV) (genus Pomovirus, family Virgaviridae). A single tuber isolate (SSUBK13) of this uncultivable protist was used to generate DNA for Illumina sequencing. The data were assembled to a draft genome of 28.08 Mb consisting of 2,340 contigs and an L50 of 280. A total of 10,778 genes were predicted and 93% of the BUSCO genes were detected. The presented genome assembly is only the second genome of a plasmodiophorid. The data will accelerate functional genomics to study poorly understood interaction of plasmodiophorids and their hosts. PMID- 29969056 TI - Agitation Modules: Flexible Means to Accelerate Automated Freeze Substitution. AB - For ultrafast fixation of biological samples to avoid artifacts, high-pressure freezing (HPF) followed by freeze substitution (FS) is preferred over chemical fixation at room temperature. After HPF, samples are maintained at low temperature during dehydration and fixation, while avoiding damaging recrystallization. This is a notoriously slow process. McDonald and Webb demonstrated, in 2011, that sample agitation during FS dramatically reduces the necessary time. Then, in 2015, we (H.G. and S.R.) introduced an agitation module into the cryochamber of an automated FS unit and demonstrated that the preparation of algae could be shortened from days to a couple of hours. We argued that variability in the processing, reproducibility, and safety issues are better addressed using automated FS units. For dissemination, we started low-cost manufacturing of agitation modules for two of the most widely used FS units, the Automatic Freeze Substitution Systems, AFS(1) and AFS2, from Leica Microsystems, using three dimensional (3D)-printing of the major components. To test them, several labs independently used the modules on a wide variety of specimens that had previously been processed by manual agitation, or without agitation. We demonstrate that automated processing with sample agitation saves time, increases flexibility with respect to sample requirements and protocols, and produces data of at least as good quality as other approaches. PMID- 29969058 TI - Association of Maternal Prepregnancy Body Mass Index With Placental Histopathological Characteristics in Uncomplicated Term Pregnancies. AB - Introduction Prepregnancy obesity is a growing global health problem and has several risks for mother and child. The aim of this study was to systematically examine the effect of increased maternal body mass index (BMI) on placental pathology in otherwise uneventful term pregnancies. Methods In this analysis, we studied data of the Netherlands Amniotic Fluid study, a prospective study of women delivering in Utrecht, the Netherlands, between 2006 and 2007. We included women with uncomplicated pregnancies, vaginal delivery, and data on prepregnancy weight and height (n = 382). Placental histopathology was compared between women of normal BMI (<=24.9 kg/m2), overweight (25-29.9 kg/m2), and obese (>=30 kg/m2). Results Increasing prepregnancy BMI was associated with heavier placentas and higher mean infant's birth weight. In addition, obesity was positively associated with high-grade chronic villitis (odds ratio [OR]: 18.1, 95% confidence interval [CI]: 1.6-205.2), accelerated villous maturation (OR: 1.1, 95% CI: 1.0-1.2), and lower incidence of placental weight below the 10th percentile for gestational age (OR: 0.5, 95% CI: 0.3-1.0). There was a substantial effect of parity on maternal, placental, and neonatal weights. Conclusions Even in uncomplicated pregnancies, maternal obesity is associated with characteristic changes in placental pathology. Further research is needed to evaluate these changes in view of later life health of infants born to obese mothers. PMID- 29969060 TI - The presence and prevalence of Legionella spp in collected rainwater and its aerosolisation during common gardening activities. AB - AIMS: To determine the presence and prevalence of Legionella spp in domestic rainwater storage butts and to quantify its aerosolisation when collected rainwater is used for common gardening activities. METHODS: Volunteers were asked to take a water sample from their garden rainwater storage butt. The presence of Legionella was determined using quantitative polymerase chain reaction (qPCR). Two new rainwater storage butts were installed on-site at PHE Porton and positioned in sunlight or in the shade. Ambient conditions and those within the two 'experimental' water butts were continually monitored. A cyclone air sampler was used to detect the presence of Legionella in the air when collected rainwater was poured from a watering can or delivered via a hosepipe attached to a submersible water butt pump. RESULTS: A total of 63 volunteers provided water samples from 113 different rainwater storage butts. Legionella spp was detected in 107 of these samples at a mean concentration of 4.7 * 104 genomic units l-1. Two of these samples also contained L. pneumophila. The water butt positioned in the shade stored water at a significantly lower temperature than that exposed to sunlight. While the concentration of Legionella was significantly higher in this cooler water, meteorological conditions rather than conditions within the water butt had the greatest effect upon Legionella concentration. No Legionella was detected in the air when rainwater was poured from a watering can. However, using a hose pipe on a 'fine spray' setting increased both the number of organisms detected in the air and their dissemination. CONCLUSION: In this study, Legionella spp were common contaminants of collected rainwater. However, the use of rainwater for common gardening activities should not be discouraged. Aerosolisation of Legionella when using a watering can is minimal and any increased risk associated with hose pipe use can be mitigated by using a coarse spray setting. PMID- 29969061 TI - Does ball carrier technique influence tackler head injury assessment risk in elite rugby union? AB - The aim of this study was to use video evidence of tackles in elite level rugby union to identify ball carrier proficiency characteristics, for both lower and upper body tackles, that have a higher propensity to result in Head Injury Assessments(HIA) for the tackler. HIA (n = 74) and non-HIA tackles (n = 233) were categorised as either front-on or side-on upper or lower body tackles and scored for ball carrying proficiency characteristics. Side-on tackles included tackles from behind. A Chi-Square test (p < 0.05) and Cramer's V were calculated to compare proficiency characteristics in HIA and non-HIA cases. For front-on upper body tackles, the ball carrier "fending into contact" (p < 0.01;ES = Moderate) and "explosiveness on contact" (p = 0.04;ES = Moderate) had a higher propensity to result in a HIA for the tackler. Fending into contact was exhibited in 47% of all upper body Tackle front-on HIA cases. The fending arm contacted the tackler's head in 67% of these cases. Fending into contact can potentially be dangerous and therefore emphasis should be placed on safe fending during tackle-based training drills. Referees should also be alert to arm-to-head contact during the fend. Given the low number of ball carrier characteristics identified, focus should be placed on tackler characteristics for HIA prevention strategies. PMID- 29969062 TI - Liposomal-based lidocaine formulation for the improvement of infiltrative buccal anaesthesia. AB - This study describes the encapsulation of the local anaesthetic lidocaine (LDC) in large unilamellar liposomes (LUV) prepared in a scalable procedure, with hydrogenated soybean phosphatidylcholine, cholesterol and mannitol. Structural properties of the liposomes were assessed by dynamic light scattering, nanoparticle tracking analysis and transmission electron microscopy. A modified, two-compartment Franz-cell system was used to evaluate the release kinetics of LDC from the liposomes. The in vivo anaesthetic effect of liposomal LDC 2% (LUVLDC) was compared to LDC 2% solution without (LDCPLAIN) or with the vasoconstrictor epinephrine (1:100 000) (LDCVASO), in rat infraorbital nerve blockade model. The structural characterization revealed liposomes with spherical shape, average size distribution of 250 nm and low polydispersity even after LDC incorporation. Zeta potential laid around -30 mV and the number of suspended liposomal particles was in the range of 1012 vesicles/mL. Also the addition of cryoprotectant (mannitol) did not provoke structural changes in liposomes properties. In vitro release profile of LDC from LUV fits well with a biexponential model, in which the LDC encapsulated (EE% = 24%) was responsible for an increase of 67% in the release time in relation to LDCPLAIN (p < 0.05). Also, the liposomal formulation prolonged the sensorial nervous blockade duration (~70 min), in comparison with LDCPLAIN (45 min), but less than LDCVASO (130 min). In this context, this study showed that the liposomal formulations prepared by scalable procedure were suitable to promote longer and safer buccal anaesthesia, avoiding side effects of the use of vasoconstrictors. PMID- 29969063 TI - Grape Sour Rot: A Four-Way Interaction Involving the Host, Yeast, Acetic Acid Bacteria, and Insects. AB - Sour rot, a disease affecting berries of cultivated Vitis spp. worldwide, has not been clearly defined. Reported symptoms of the disease include browning of the berry skin, oozing of disintegrated berry pulp, and the smell of acetic acid, all in the presence of fruit flies (Drosophila spp.). We determined acetic acid concentrations in multiple collections of symptomatic berries, isolated and identified microbes from them, and inoculated commonly isolated organisms into healthy berries with and without concurrent exposure to wild-type or axenic Drosophila melanogaster. Coinoculations combining one of several yeasts (Metschnikowia spp., Pichia spp., and a Saccharomyces sp.) plus an acetic acid bacterium (an Acetobacter sp. and Gluconobacter spp.) reproduced sour rot symptoms, defined here as decaying berries with a loss of turgor and containing acetic acid at a minimum of 0.83 g/liter, based on observed field levels. Symptoms developed only in the presence of D. melanogaster, either wild type or axenic, indicating a nonmicrobial contribution of these insects in addition to a previously suggested microbial role. We conclude that sour rot is the culmination of coinfection by various yeasts, which convert grape sugars to ethanol, and bacteria that oxidize the ethanol to acetic acid, and that this process is mediated by Drosophila spp. PMID- 29969064 TI - Automated Analysis of Aggregated Datasets to Identify Climatic Predictors of Botrytis Bunch Rot in Wine Grapes. AB - Botrytis bunch rot (BBR), caused by Botrytis cinerea, results in serious losses to wine-grape production in some seasons during the preharvest period. In order to predict seasons that are at risk from BBR, datasets consisting of 25 disease, weather and vine phenology variables were aggregated from 101 SiteYears across seven regions and nine growing seasons. Automated analyses were used to compare a range of statistical methods for their ability to predict BBR epidemics, including the Kruskal-Wallis test, logistic regression, receiver operating characteristic analysis, and skill-scores. Variables based on relative humidity and surface-wetness duration were significant and consistent predictors of BBR epidemics across the range of analyses applied. Variables integrating temperature and wetness duration, including the Bacchus and Broome models, also demonstrated high predictive ability; however, they did not outperform their constituent components in all analyses. Automation of data analyses was an effective way to compare a wide range of statistical methods and a large number of variables with minimal user input, following initial code development. Significant time was needed to check input data and software code, but a greater return on investment would occur should the analytical process be applied to new datasets, including those from other pathosystems. PMID- 29969065 TI - Novel Insights Into the Early Stages of Ratoon Stunting Disease of Sugarcane Inferred from Transcript and Protein Analysis. AB - Despite of the importance of ratoon stunting disease, little is known on the responses of sugarcane to its causal agent, the vascular bacterial endophyte Leifsonia xyli subsp. xyli. The transcriptome and proteome of young plants of a susceptible cultivar with no symptoms of stunting but with relative low and high bacterial titers were compared at 30 and 60 days after inoculation. Increased bacterial titers were associated with alterations in the expression of 267 cDNAs and in the abundance of 150 proteins involved in plant growth, hormone metabolism, signal transduction and defense responses. Some alterations are predicted to benefit the pathogen, such as the up-regulation of genes involved in the synthesis of methionine. Also, genes and proteins of the cell division cycle were all down-regulated in plants with higher titers at both times. It is hypothesized that the negative effects on cell division related to increased bacterial titers is cumulative over time and its modulation by other host and environmental factors results in the stunting symptom. PMID- 29969066 TI - Hybrid SPECT Perfusion Imaging and Coronary CT Angiography: Long-term Prognostic Value for Cardiovascular Outcomes. AB - Purpose To determine the value of cardiac hybrid imaging, performed by combining SPECT myocardial perfusion imaging (MPI) with coronary CT angiography, as a long term predictor for major adverse cardiac events (MACEs) (death, myocardial infarction [MI], unstable angina requiring hospitalization, coronary revascularization). Materials and Methods For this retrospective single-center study, 428 patients referred between May 2005 and December 2008 were classified according to hybrid imaging findings into the following groups: (a) those with stenosis of 50% or greater (at coronary CT angiography) with ischemia (at SPECT) in subtended territory (matched), (b) those with coronary CT angiography and/or SPECT findings in unrelated territories (unmatched), and (c) those with normal findings at coronary CT angiography and SPECT. End points were all-cause death or MI ("hard events") and a composite of MACEs. The Kaplan-Meier method was used to identify survival free of MACEs, and Cox proportional hazard regression analysis was used to determine independent predictors for MACE. Results During a median follow-up of 6.8 years, a total of 160 MACEs, including 45 deaths, were observed in the final study population (mean age, 62 years +/- 11 [standard deviation]; 132 women). The annual hard event rate was more than fivefold higher for patients with matched findings (n = 46 [7.0%]) and was threefold higher for patients with unmatched findings (n = 113 [3.7%]) compared with that for patients with normal findings (1.2%; n = 216 [1.2%]; P < .001). The MACE rates were 21.8%, 9.0%, and 2.4% for matched, unmatched, and normal findings, respectively. A matched finding was an independent predictor for MACE and hard events. Conclusion In patients evaluated for coronary artery disease, cardiac hybrid imaging is an excellent long-term predictor of adverse cardiac events. A matched hybrid finding is associated with a high annual cardiac event rate. (c) RSNA, 2018. PMID- 29969068 TI - Abbreviations in Radiology: MRI. PMID- 29969067 TI - Identifying At-Risk Patients with Combined Pre- and Postcapillary Pulmonary Hypertension Using Interventricular Septal Angle at Cardiac MRI. AB - Purpose To assess interventricular septal (IVS) angle in the identification of combined pre- and postcapillary pulmonary hypertension (Cpc-PH) in patients with pulmonary hypertension (PH) due to left-sided heart disease. Materials and Methods In this retrospective study, consecutive, incident patients suspected of having PH underwent same-day right-sided heart catheterization (RHC) and MRI at a PH referral center between April 2012 and April 2017. The diagnostic accuracy of the IVS angle to identify Cpc-PH in patients with pulmonary arterial wedge pressure (PAWP) greater than 15 mmHg was assessed by using receiver operator characteristic curves, sensitivity, specificity, and negative and positive predictive values. IVS angle also was assessed as a predictor of all-cause mortality by using Cox uni- and multivariable proportional hazards regression. Results A total of 708 patients underwent same-day MRI and RHC, and 171 patients had PAWP greater than 15 mmHg. Mean age was 70 years (range, 21-90 years) (women: mean age, 69 years; range, 21-88 years) (men: mean age, 71 years; range, 43-90 years). Systolic IVS angle correlated with diastolic pulmonary gradient (DPG) (r = 0.739, P < .001). Receiver operating characteristic curve analysis showed septal angle enabled identification of Cpc-PH (DPG >= 7), with an area under the receiver operating characteristic curve of 0.911 (P < .001). A 160 degrees threshold, derived from the first half of patients with raised PAWP, enabled identification of a DPG of at least 7 mmHg with 67% sensitivity and 93% specificity (P < .001) in the second cohort of patients with raised PAWP. IVS angle was predictive of all-cause mortality (standardized univariable hazard ratio, 1.615; P < .01). Conclusion The systolic interventricular septal angle is elevated in patients with combined pre- and postcapillary pulmonary hypertension and enables one to predict those patients who have PH due to left-sided heart disease who have an increased risk of death. Published under a CC BY 4.0 license. Online supplemental material is available for this article. PMID- 29969069 TI - Creating Value through Incremental Innovation: Managing Culture, Structure, and Process. AB - While the looming threat of large-scale disruptive innovation consumes disproportionate attention, incremental innovation remains an important tool for preserving and growing radiology practices within a dynamic marketplace. Incremental innovation, defined as the process of making improvements or additions to an organization while maintaining the organization's core product or service model, is accessible to practices of all sizes and must not be overlooked if practices are to maintain their competitive advantage. This article explores cultural, structural, and process enablers for incremental innovation. Successful innovation cultures foster the ability to import and exploit external knowledge (adaptive capacity), encourage creative thought from all levels of the organization, display sensitivity toward the competency-destroying potential of certain changes, cultivate a positive perceptual bias toward organizational threats, and build tolerance for risk and uncertainty when prototyping new ideas. Structural elements promoting incremental innovation include dedicated resources for innovation planning, flexible and organic team structures, strong centralized governance models, robust communication systems, and organizational incentives encouraging exploration of new concepts. Processes important to innovation include periodic environmental scanning, strategic and scenario planning, use of an objectively gated system for testing and filtering new ideas, and use of an approach to implementation that emphasizes empowerment of project managers, removal of barriers, and proactive communication around change. PMID- 29969070 TI - Circumferential Thick Enhancement at Vessel Wall MRI Has High Specificity for Intracranial Aneurysm Instability. AB - Purpose To identify wall enhancement patterns on vessel wall MRI that discriminate between stable and unstable unruptured intracranial aneurysm (UIA). Materials and Methods Patients were included from November 2012 through January 2016. Vessel wall MR images were acquired at 3 T in patients with stable (incidental and nonchanging over 6 months) or unstable (symptomatic or changing over 6 months) UIA. Each aneurysm was evaluated by using a four-grade classification of enhancement: 0, none; 1, focal; 2, thin circumferential; and 3, thick (>1 mm) circumferential. Inter- and intrareader agreement for the presence and the grade of enhancement were assessed by using kappa statistics and 95% confidence interval (CI). The sensitivity, specificity, and negative and positive predictive values of each enhancement grade for differentiating stable from unstable aneurysms was compared. Results The study included 263 patients with 333 aneurysms. Inter- and intrareader agreement was excellent for both the presence of enhancement (kappa values, 0.82 [95% CI: 0.67, 0.99] and 0.87 [95% CI: 0.7, 1.0], respectively) and enhancement grade (kappa = 0.92 [95% CI: 0.87, 0.95]). In unruptured aneurysms (n = 307), grade 3 enhancement exhibited the highest specificity (84.4%; 233 of 276; 95% CI: 80.1%, 88.7%; P = .02) and negative predictive value (94.3%; 233 of 247) for differentiating between stable and unstable lesions. There was a significant association between grade 3 enhancement and aneurysm instability (P < .0001). Conclusion In patients with intracranial aneurysm, a thick (>1 mm) circumferential pattern of wall enhancement demonstrated the highest specificity for differentiating between stable and unstable aneurysms. (c) RSNA, 2018. PMID- 29969071 TI - An Intravascular Tantalum Oxide-based CT Contrast Agent: Preclinical Evaluation Emulating Overweight and Obese Patient Size. AB - Purpose To compare the CT imaging performance of a carboxybetaine zwitterionic coated tantalum oxide (TaCZ) nanoparticle CT contrast agent with that of a conventional iodinated contrast agent in a swine model meant to simulate overweight and obese patients. Materials and Methods Four swine were evaluated inside three different-sized adipose-equivalent encasements emulating abdominal girths of 102, 119, and 137 cm. Imaging was performed with a 64-detector row CT scanner at six scan delays after intravenous injection of 240 mg element (Ta or I) per kilogram of body weight of TaCZ or iopromide. For each time point, contrast enhancement of the aorta and liver were measured by using regions of interest. Two readers independently recorded the clarity of vasculature using a five-point Likert scale. Findings were compared by using paired t tests and Wilcoxon signed-rank tests. Results Mean peak enhancement was higher for TaCZ than for iopromide in the aorta (270 HU [sigma = 24.5] vs 199 HU [sigma = 10.2], P < .001) and liver (61.3 HU [sigma = 11.7] vs 45.2 HU [sigma = 8], P < .001). Vascular clarity was higher for TaCZ than for iopromide in 63% (132 of 208), 82% (170 of 208), and 86% (178 of 208) of the individual vessels at the 102-, 119-, and 137-cm girths, respectively (P < .01). Arterial clarity scores were higher for TaCZ than for iopromide in 62% (208 of 336) of vessels. Venous clarity scores were higher for TaCZ than for iopromide in 89% (128 of 144) of the veins in the venous phase and in 100% (144 of 144) of veins in the delayed phase (P < .01). No vessel showed higher clarity score with iopromide than with TaCZ. Conclusion An experimental tantalum nanoparticle-based contrast agent showed greater contrast enhancement compared with iopromide in swine models meant to simulate overweight and obese patients. (c) RSNA, 2018. PMID- 29969072 TI - Update on MRI Safety in Patients with Cardiac Implantable Electronic Devices. PMID- 29969073 TI - Juxtapleural (Perifissural) Nodules: Does Location Mean a Benign Lesion? PMID- 29969074 TI - The Evolving Role of MRI in Pulmonary Hypertension Evaluation: A Noninvasive Approach from Diagnosis to Follow-up. PMID- 29969075 TI - Reversal of the Jejunoileal Fold in Celiac Disease. PMID- 29969076 TI - Classification of CT Pulmonary Opacities as Perifissural Nodules: Reader Variability. AB - Purpose To study interreader variability for classifying pulmonary opacities at CT as perifissural nodules (PFNs) and determine how reliably radiologists differentiate PFNs from malignancies. Materials and Methods CT studies were obtained retrospectively from the National Lung Screening Trial (2002-2009). Nodules were eligible for the study if they were noncalcified, solid, within the size range of 5 to 10 mm, and scanned with a section thickness of 2 mm or less. Six radiologists classified 359 nodules in a cancer-enriched data set as PFN, non PFN, or not applicable. Nodules classified as not applicable by at least three radiologists were excluded, leaving 316 nodules for post-hoc statistical analysis. Results The study group contained 22.2% cancers (70 of 316). The median proportion of nodules classified as PFNs was 45.6% (144 of 316). All six radiologists uniformly classified 17.7% (56 of 316) of the nodules as PFNs. The Fleiss kappa was 0.50. Compared with non-PFNs, nodules classified as PFNs were smaller and more often located in the lower lobes and attached to a fissure (P < .001). Thirteen (18.6%) of 70 cancers were misclassified 21 times as PFNs. Individual readers' misclassification rates ranged from 0% (0 of 125) to 4.9% (eight of 163). Of 13 misclassified malignancies, 11 were in the upper lobes and two were attached to a fissure. Conclusion There was moderate interreader agreement when classifying nodules as perifissural nodules. Less than 2.5% of perifissural nodule classifications were misclassified lung cancers (21 of 865) in this cancer-enriched study. Allowing nodules classified as perifissural nodules to be omitted from additional follow-up in a screening setting could substantially reduce the number of unnecessary scans; excluding perifissural nodules in the upper lobes would greatly decrease the misclassification rate. PMID- 29969077 TI - Ablation versus Resection for Stage 1A Renal Cell Carcinoma: National Variation in Clinical Management and Selected Outcomes. AB - Purpose To compare patients in a national U.S. database who underwent thermal ablation or nephrectomy for renal cell carcinoma (RCC) in terms of demographic differences, perioperative outcomes, and survival. Materials and Methods This National Cancer Database study included patients who underwent thermal ablation or nephrectomy for biopsy-proven T1aN0M0 RCC between 2004 and 2013. Demographic factors were analyzed as treatment predictors. Unplanned hospital readmission, mean hospital stay, 30- and 90-day postoperative mortality, and survival were analyzed in a propensity score-matched cohort by using chi2 tests, Cox proportional hazards models, and Renyi family tests. Results Included were 4817 of 56 065 patients (8.6%) who underwent thermal ablation and 51 248 of 56 065 patients (91.4%) who underwent nephrectomy. Patients who underwent thermal ablation skewed older (mean, 52 years vs 44 years, respectively) with more comorbidities (9% vs 7.6% Charlson Comorbidity Index score of >=2, respectively). Male sex, white race, nonprivate insurance, therapy at academic centers, and south Atlantic state urban residence with lower income and education were associated with higher thermal ablation treatment likelihood (P < .001). After matching, perioperative outcomes were superior for thermal ablation: unplanned hospital readmission, mean hospital stay, and 30- and 90-day postoperative mortality were lower for thermal ablation (2% vs 3.3%, 1.3 days vs 4.3 days, 0% vs 0.9%, and 0% vs 1.4%, respectively; each P < .001). Survival was comparable for thermal ablation and nephrectomy in patients older than 65 years, and during the 1st postoperative year for all patients. Conclusion Thermal ablation for RCC varied by national region and with multiple clinical and nonclinical demographic factors. Thermal ablation demonstrates superior perioperative outcomes with short mean hospital stay, low unplanned hospital readmission, and 30- and 90-day mortality. In selected patients, thermal ablation survival may be comparable to nephrectomy. PMID- 29969078 TI - Another evidence for pressure transfer mechanism in incomplete partition two anomaly via enlarged vestibular aqueduct. AB - A female patient with unilateral enlarged vestibular aqueduct (EVA) demonstrated scala vestibuli dilatation on that side while on the contralateral side both vestibular aqueduct and scala vestibuli were normal. This important radiological finding demonstrates that modiolar defects (hence 'cystic apex') observed in Incomplete partition-II is due to pressure transfer via EVA during embryological development. Therefore, it supports the previous histopathological ideas radiologically. Depending on the patency of EVA, variety of modiolar defects may arise. PMID- 29969079 TI - Air pollution: A silent common killer for stroke and dementia. PMID- 29969080 TI - Efficiency and effectiveness of orthodontic treatment within United Kingdom secondary care: a service evaluation. AB - OBJECTIVES: To evaluate the efficiency and effectiveness of Orthodontic treatment in the National Health Service (NHS) hospitals in England and to identify factors that may be predictive of the duration of Orthodontic treatment and number of patients' visits. DESIGN: Retrospective service evaluation. SETTING: The orthodontic departments of two NHS hospitals. METHODS: The data were collected from the clinical notes, the hospital data base and the pre- and post-treatment study models of 70 patients who were treated with fixed appliances. The pre- and post-treatment models were assessed using the Index of Orthodontic Treatment Need (IOTN) and the Peer Assessment Rating (PAR) index. RESULTS: (1) 98.5% of the patients treated with fixed appliances in both hospitals were in definite need for treatment, (2) The mean percentage PAR score reduction was 81.5%, (3) The mean treatment duration was 27 months with an average of 21 appointments, (4) Factors increasing treatment duration included being a female patient, class I malocclusion, IOTN 5, extractions, prescribing headgear wear, using functional appliances or quadhelixes and increased number of missed appointments, (5) Factors reducing the treatment time were male patients, class II or class III malocclusions and an increased number of emergency appointments. CONCLUSIONS: The hospitals demonstrated a high standard of orthodontic treatment. PMID- 29969081 TI - Sensorineural Deafness Following Tacrolimus Use. AB - Early trials of tacrolimus in renal transplant recipients have not revealed hearing loss as an adverse effect. Here, we present a case report and a review of the literature of deafness after tacrolimus use. The review of the literature and our experience suggested that the possible reason for hearing loss could be due to an initiation of a sudden spike in the tacrolimus serum level, which was later worsened by its cumulative toxic effect. PMID- 29969082 TI - A Retrospective Comparison of TECAM and BEAM Conditioning Regimens Before Autologous Hematopoietic Stem Cell Transplant in Lymphoma Patients: Efficacy and Toxicity. AB - OBJECTIVES: The aim of our study was to evaluate the efficacy and toxicity of TECAM (thiotepa, etoposide, cyclophosphamide, cytarabine, and melphalan) and BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning regimens before autologous hematopoietic stem cell transplant in patients with lymphoma. MATERIALS AND METHODS: We retrospectively analyzed 108 relapsed/refractory lymphoma patients who had high-dose treatments followed by autologous hematopoietic stem cell transplant between October 2012 and February 2017. RESULTS: At a median follow-up period of 16 months, the estimated 2-year progression-free survival rates for the TECAM and BEAM groups were 55.7% and 52.9%, respectively (P = .811). The estimated 2-year overall survival rate in the TECAM group (55.9%) was relatively inferior to that shown in the BEAM group (67%), but the differences were not significant (P = .238). No differences were observed for time to hematopoietic recovery and duration of hospitalization. Incidences of transplant-related infectious and noninfectious complications were similar for each conditioning regimen. CONCLUSIONS: Our experience shows that the TECAM regimen is an effective high-dose chemotherapy for lymphoma patients before autologous hematopoietic stem cell transplant. PMID- 29969083 TI - Evaluation of a Medically Supervised Concussion Protocol for Youth Hockey in Canada. AB - OBJECTIVES: The objective of this study was to evaluate the feasibility and implementation of a standardized medically supervised concussion protocol established between a city-wide AAA hockey league and a multi-disciplinary concussion program. METHODS: We conducted a retrospective review of injury surveillance, clinical and healthcare utilization data from all athletes evaluated and managed through the Winnipeg AAA Hockey concussion protocol during the 2016-2017 season. We also conducted post-season email surveys of head coaches and parents responsible for athletes who competed in the same season. RESULTS: During the 2016-2017 season, 28 athletes were evaluated through the medically supervised concussion protocol, with two athletes undergoing evaluation for repeat injuries (a total of 30 suspected injuries and consultations). In all, 96.7% of the athletes managed through the concussion protocol were captured by the league-designated Concussion Protocol Coordinator and 100% of eligible athletes underwent complete medical follow-up and clearance to return to full hockey activities. Although 90% of responding head coaches and 91% of parents were aware of the concussion protocol, survey results suggest that some athletes who sustained suspected concussions were not managed through the protocol. Head coaches and parents also indicated that athlete education and communication between medical and sport stakeholders were other elements of the concussion protocol that could be improved. CONCLUSION: Successful implementation of a medically supervised concussion protocol for youth hockey requires clear communication between sport stakeholders and timely access to multi-disciplinary experts in traumatic brain and spine injuries. Standardized concussion protocols for youth sports may benefit from periodic evaluations by sport stakeholders and incorporation of national guideline best practices and resources. PMID- 29969084 TI - Detection of tetracycline and other antimicrobial residues in milk from cows with clinical mastitis treated by combination therapy. AB - The purpose of this study was to determine tetracycline and other antimicrobial residues in milk from dairy cows treated for clinical mastitis. Data on cow health and drugs used were obtained from the farm veterinarians. A milk sample from each affected udder quarter of each cow was taken for bacterial identification before treatment. All 35 cows in the study were treated with an intramammary product containing tetracycline, neomycin, bacitracin, and prednisolone (tetracycline injector) and also simultaneously with other drugs via the intramammary or parenteral route. The withhold period of the 'tetracycline product' was eight milkings but, in all cases, longer withhold periods were prescribed due to off-label application of additional combinations of drugs. Milk samples from treated udder quarters, taken two milkings before and two after the prescribed withhold period, were analysed for antimicrobial residues. Additionally, milk samples were taken from untreated healthy udder quarters to check if any crossover of drugs had occurred. Three screening tests were used for antimicrobial detection. In 15 (42.9%) cows the milk samples from the treated infected quarters contained tetracycline residues above the maximum residue limit (MRL) after the prescribed withhold period and, in two cases (5.7%) the same was true for neomycin and cefquinome residues. Cephalexin above the MRL was detected in only one case (2.9%). Beta-lactams did not exceed the MRL after the prescribed withhold period. Antimicrobial residues were not detected in milk samples from untreated quarters. Cow condition including parity, decreased milk production and severity of mastitis significantly influenced the excretion of antimicrobials in milk (P <= 0.05). No significant differences were found between the tetracycline positive and tetracycline negative cows regarding the bacteria involved, combination antimicrobial therapy, or treatment interval and duration. PMID- 29969085 TI - Human cumulus cell sensitivity to vitrification, an ultrastructural study. AB - SummaryCumulus cells (CCs) play an important role in the regulation of female gamete development, meiotic maturation, oocyte-sperm interaction, capacitation and acrosome reaction. However, their role in maintaining oocyte competence after vitrification is unclear as controversial data on their protecting action against oocyte cryoinjuries are available. Here we described the effects of vitrification on the ultrastructure of human CCs collected from women undergoing assisted reproductive technologies (ARTs). In total, 50 patches of CCs, sampled from high quality human cumulus-oocyte complexes, were randomly allocated into two groups after patient informed consent: 1, fresh CCs (controls, n = 25); 2, vitrified CCs (n = 25). Samples were then prepared and observed by transmission electron microscopy. In fresh CCs, in which small cell clusters were visible, cell membranes were joined by focal gap junctions. Microvilli were rare and short. Nuclei, mitochondria, smooth endoplasmic reticulum (SER), Golgi apparatus and lipid droplets appeared well preserved; vacuoles were scarce. After vitrification, we observed two populations of CCs: light CCs, with a smooth appearance and few short microvilli; and dark CCs, with numerous and long microvilli. In both, most of the organelles appeared similar to those of fresh CCs. Lipid droplets were denser and more numerous, with respect to fresh CCs. They were mainly located in the peri-nuclear and sub-plasmalemmal regions. Numerous packed electron-negative vacuoles were visible. The vitrification procedure did not cause alterations in the fine structure of major organelles, except for an increased amount of lipid droplets and vacuoles. This specific sensitivity of human CCs to vitrification should be considered during ARTs. PMID- 29969086 TI - Nesterenkonia endophytica sp. nov., isolated from roots of Glycyrrhiza uralensis. AB - A Gram-positive and non-motile actinobacterium, designated strain EGI 60016T, was isolated from healthy roots of Glycyrrhiza uralensis F. collected from Xinyuan County, Xinjiang Province, China. The 16S rRNA gene sequence of strain EGI 60016T was found to show 97.5 and 97.3 % sequence similarities to Nesterenkonia rhizosphaerae EGI 80099T and Nesternkonia massiliensis NP1T, respectively. The neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain EGI 60016T formed a distinct clade with N. rhizosphaerae EGI 80099T and N. massiliensis NP1T. The polar lipids detected for strain EGI 60016T were diphosphatidylglycerol, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, an unidentified glycolipid, an unidentified lipid and an unidentified phospholipid. The DNA G+C content was determined to be 64.1 mol%. Other chemotaxonomic features of strain EGI 60016T included MK-7, MK-8 and MK-9 as the respiratory quinones, and anteiso-C15 : 0 and anteiso-C17 : 0 as the major fatty acids. Based on the results of the phylogenetic analysis supported by morphological, physiological, chemotaxonomic and other differentiating phenotypic characteristics, strain EGI 60016T is considered to represent a novel species of the genus Nesterenkonia, for which the name Nesterenkonia endophytica sp. nov. is proposed. The type strain is EGI 60016T (=CCTCC AB 2017176T=NBRC 112398T). PMID- 29969087 TI - Novel multiplex PCR assay for identification and subtyping of enteroinvasive Escherichia coli and differentiation from Shigella based on target genes selected by comparative genomics. AB - PURPOSE: Both Shigella and enteroinvasive Escherichia coli (EIEC) can cause enterocolitis, but they have a distinct epidemiology and public health relevance. Current culture-independent testing (CIT) methods to identify Shigella in faecal samples rely on the ipaH gene as the target, which is also found in EIEC genomes. The aim of this study was to design an assay that can identify EIEC in cultures from CIT ipaH-positive samples. METHODOLOGY: Shigella and EIEC genomes were screened to find unique regions present in EIEC genomes using a comparative genomics approach and differentiating genetic loci that are suitable PCR targets were identified. The primers for these loci were designed and tested in 6501 and 104 genomes of Shigella and EIEC, respectively. RESULTS: An assay with two sets of multiplex PCR reactions that differentiates Shigella and EIEC based on the presence/absence of at least two out of six loci was developed and evaluated. The majority of Shigella genomes lacked all six loci, while at least two loci were present in most EIEC genomes. This assay successfully differentiated clinical EIEC from Shigella with a limit of detection of 105 cells ml-1. The sensitivity and specificity were over 95 and 99%, respectively. The assay can further subtype EIEC genomes into their genetic lineages. CONCLUSION: This new highly specific assay can assist in the identification of EIEC in ipaH PCR-positive samples and augment the public health laboratory surveillance of EIEC and shigellosis. PMID- 29969088 TI - Evaluation of a novel outer membrane surface-exposed protein, LIC13341 of Leptospira, as an adhesin and serodiagnostic candidate marker for leptospirosis. AB - The outer membrane proteins of the pathogen are targeted to understand host pathogen interactions and are central to the development of diagnostics. We report that Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 contains a gene LIC13341 that encodes a conserved outer membrane/periplasmic lipoprotein. The gene LIC13341 was cloned into expression vector pET28a and the recombinant LIC13341 (r-LIC13341) protein was purified from Escherichia coli BL21 (DE3) using affinity chromatography. The secondary structure of the purified r LIC13341 protein featured a typical beta-strand when observed by circular dichroism spectroscopy. Immunoblotting using antibodies raised against r-LIC13341 in BALB/c mice can detect LIC13341 expression in the Leptospira lysates and suggested that antigen LIC13341 is immunogenic. Phase separation and protease assays determined that LIC13341 is a surface-exposed outer membrane protein of Leptospira. The r-LIC13341 can bind to a wide spectrum of host extracellular matrices (ECMs). The specific adherence of Leptospira to laminin and hyaluronic acid of the ECM was competitively inhibited in the presence of r-LIC13341. The enzyme-linked immunosorbent assay and immunoblot performed using human or bovine leptospirosis serum (n=50) recognized r-LIC13341, suggesting that LIC13341 is expressed in diverse hosts during Leptospira infection. Thus, the present finding suggests that the Leptospira LIC13341 antigen is a versatile outer membrane adhesin of diagnostic importance. PMID- 29969089 TI - Distribution of genes encoding virulence factors and multilocus variable-number tandem-repeat analysis (MLVA) of entero-aggregative Escherichia coli (EAEC) isolated in Iran from patients with diarrhoea. AB - PURPOSE: Entero-aggregative Escherichia coli (EAEC) is one of the main causes of diarrhoea worldwide. Several virulence factors have been identified in EAEC. This study was conducted to investigate the distribution of virulence factor genes in EAEC strains isolated in Iran from children with diarrhoea, as well as the genetic similarity of these isolates. METHODOLOGY: A total of 37 EAEC isolates were tested for the presence of 11 virulence genes by PCR, and the genetic relatedness of these strains was further determined by multilocus variable-number tandem-repeat analysis (MLVA). RESULTS: All EAEC isolates were typical EAEC. pic, set1A and set1B were the most prevalent genes, detected in 54.1 % of the isolates, followed by sat (43.2 %), astA (32.4 %), pet (24.3 %), agg4A (24.3 %), sepA (18.9 %), agg3A (13.5 %), sigA (8.1 %), aggA (8.1 %) and aafA (5.4 %). Using MLVA, the 37 isolates were divided into 32 types and classified into five clonal complexes. CONCLUSION: This study showed that EAEC is a heterogeneous group of E. coli possessing a broad range of virulence factors. There was no notable association between MLVA patterns and virulence profiles. PMID- 29969090 TI - Blastococcus atacamensis sp. nov., a novel strain adapted to life in the Yungay core region of the Atacama Desert. AB - A polyphasic study was undertaken to establish the taxonomic status of a Blastococcus strain isolated from an extreme hyper-arid Atacama Desert soil. The isolate, strain P6T, was found to have chemotaxonomic and morphological properties consistent with its classification in the genus Blastococcus. It was shown to form a well-supported branch in the Blastococcus 16S rRNA gene tree together with the type strains of Blastococcus capsensis and Blastococcus saxobsidens and was distinguished from the latter, its close phylogenetic neighbour, by a broad range of phenotypic properties. The draft genome sequence of isolate P6T showed 84.6 % average nucleotide identity, 83.0 % average amino acid identity and a digital DNA-DNA hybridisation value of 27.8 % in comparison with the genome sequence of B. saxobsidens DSM 44509T, values consistent with its assignment to a separate species. Based on these data it is proposed that isolate P6T (NCIMB 15090T=NRRL B-65468T) be assigned to the genus Blastococcus as Blastococcus atacamensis sp. nov. Analysis of the whole genome sequence of B. atacamensis P6T, with 3778 open reading frames and a genome size of 3.9 Mb showed the presence of genes and gene clusters that encode for properties that reflect its adaptation to the extreme environmental conditions that prevail in Atacama Desert soils. PMID- 29969091 TI - Intergenic evolution during host adaptation increases expression of the metallophore pseudopaline in Pseudomonas aeruginosa. AB - Regulating intracellular levels of biological metal ions is essential for all bacterial species, as they are needed for virulence and a range of metabolic processes. Zinc is the second most abundant metal ion in Pseudomonas aeruginosa, but little is known about its regulation. Recent studies have identified a novel operon, zrmABCD (also called cntOLMI), encoding a metallophore system (pseudopaline) involved in zinc acquisition. Expression of this operon has been implicated in human infections and is regulated by the transcriptional regulator Zur (Zn2+ uptake regulator). In this study, we show that the intergenic promoter region in front of zrmABCD is a target for recurrent adaptive mutations during chronic infection of cystic fibrosis (CF) patients. We characterize the inter- and intraclonal sequence polymorphisms found in the promoter region of the metallophore system and find that most alterations increase promoter activity. One of the evolved promoters displays a more than 10-fold increase compared to the ancestral strain due to the combined effect of an altered binding site of Zur and changes to the RpoD-binding motif. This specific evolved promoter responds differently to changes in metal ion concentrations in chelated medium. We have previously shown that P. aeruginosa evolves toward iron acquisition from haemoglobin during long-term CF infections. We hereby provide the second example of adaptive mutations targeting intergenic regions that affect metal ion uptake systems during CF infections, and the first involving zinc uptake. Our results suggest that the scarcity of metal ions (including iron and zinc) is an important evolutionary driver in CF host adaptation. PMID- 29969092 TI - Health Education Workforce: Opportunities and Challenges. PMID- 29969093 TI - Development of the PEA-PODS (Perceptions of the Environment and Patterns of Diet at School) Survey for Students. AB - INTRODUCTION: Few instruments assess key outcomes of school-based obesity interventions, including student perceptions of school environments and school specific dietary intake patterns. This study describes development of PEA-PODS (Perceptions of the Environment and Patterns of Diet at School), a 2-part survey to measure these outcomes. METHODS: Part 1 (PEA) assessed student perceptions of policies, physical environment, and practices related to healthy eating and physical activity at school. Part 2 (PODS) assessed usual intake (ie, frequency, location obtained, and foods consumed) of breakfast and lunch. Foods consumed were presented by MyPlate categories (eg, Fruits, Grains). Students in grades 3, 6, and 9 participated in 2 phases: cognitive pre-testing (n = 10) and reliability/validation testing (n = 58). Both surveys were administered 1 week apart to assess test-retest reliability and 5-day food records validated PODS. Analyses included percent agreement (70% = acceptable), Pearson correlations, and Cronbach alpha. RESULTS: Cognitive pre-testing provided feedback on content, length, and age-appropriateness. Percent agreements were acceptable for test retest reliability of PEA (71%-96%). The final version included 34 items with Likert-type responses in 4 subscales (alpha >=0.78). For PODS, agreement for breakfast and lunch location was >=75% for both reliability and validation. For foods consumed at breakfast, reliability agreement ranged from 74% to 93%, and validation agreement from 68% to 91%. For foods consumed at lunch, agreement ranges were 76% to 95% and 73% to 88%, respectively. CONCLUSION: Both parts of the instrument demonstrate acceptable reliability, and PODS demonstrates acceptable validity. This demonstrates appropriateness for assessing perceptions of the environment and usual dietary intake patterns for school-based obesity prevention initiatives. PMID- 29969094 TI - Single, Dual, and Poly Use of Flavored Tobacco Products Among Youths. AB - INTRODUCTION: Flavoring has become the leading reason for current tobacco use among adolescents. This study sought to evaluate patterns of flavored tobacco product use and associated risk factors among youths. METHODS: Weighted estimates of single, dual, and poly use of flavored tobacco products were calculated from the 2014 National Youth Tobacco Survey (n = 21,926). Multinomial logistic regression was performed to assess factors associated with flavored product use. RESULTS: Among current tobacco users (n = 3,805), 70.0% of students were current users of flavored tobacco products: 42.6% used a single flavored product, 16.8% used 2 flavored products (dual users), and 10.6% used more than 2 flavored products (poly users). Flavored product use, especially dual and poly use, was higher among high school students compared with middle school students. Compared with single flavored tobacco product users (36%), dual (57%) and poly users (79%) of flavored tobacco products had higher prevalences of using flavored e cigarettes (P < .001). Non-Hispanic blacks and those of other races had lower prevalences than non-Hispanic whites of using flavored products but not nonflavored products. Tobacco use by household members, no perception of harm from tobacco products, and more frequent exposure to tobacco advertisement in newspapers/magazines and stores were associated with increased odds of flavored product use. CONCLUSION: The concurrent use of flavored tobacco products is prevalent among youths. E-cigarettes were the leading flavored product and often concurrently used with other flavored tobacco products. Comprehensive control and prevention strategies to reduce flavored tobacco use among youths are needed. PMID- 29969095 TI - Neurogenic decisions require a cell cycle independent function of the CDC25B phosphatase. AB - A fundamental issue in developmental biology and in organ homeostasis is understanding the molecular mechanisms governing the balance between stem cell maintenance and differentiation into a specific lineage. Accumulating data suggest that cell cycle dynamics play a major role in the regulation of this balance. Here we show that the G2/M cell cycle regulator CDC25B phosphatase is required in mammals to finely tune neuronal production in the neural tube. We show that in chick neural progenitors, CDC25B activity favors fast nuclei departure from the apical surface in early G1, stimulates neurogenic divisions and promotes neuronal differentiation. We design a mathematical model showing that within a limited period of time, cell cycle length modifications cannot account for changes in the ratio of the mode of division. Using a CDC25B point mutation that cannot interact with CDK, we show that part of CDC25B activity is independent of its action on the cell cycle. PMID- 29969097 TI - We are not so special. AB - New sequence data from choanoflagellates improves our understanding of the genetic changes that occurred along the branch of the evolutionary tree that gave rise to animals. PMID- 29969096 TI - A multispecies coalescent model for quantitative traits. AB - We present a multispecies coalescent model for quantitative traits that allows for evolutionary inferences at micro- and macroevolutionary scales. A major advantage of this model is its ability to incorporate genealogical discordance underlying a quantitative trait. We show that discordance causes a decrease in the expected trait covariance between more closely related species relative to more distantly related species. If unaccounted for, this outcome can lead to an overestimation of a trait's evolutionary rate, to a decrease in its phylogenetic signal, and to errors when examining shifts in mean trait values. The number of loci controlling a quantitative trait appears to be irrelevant to all trends reported, and discordance also affected discrete, threshold traits. Our model and analyses point to the conditions under which different methods should fare better or worse, in addition to indicating current and future approaches that can mitigate the effects of discordance. PMID- 29969099 TI - Comparative effectiveness of 8- and 12-week ledipasvir/sofosbuvir regimens for HCV infection. AB - BACKGROUND: Real-world studies have aimed to compare the effects of 8- and 12 week ledipasvir/sofosbuvir regimens on sustained virological response (SVR) among HCV infection genotype-1 (HCV-1) treatment-naive patients. Nevertheless, real world comparative effectiveness studies pose unique challenges, such as confounding by indication, that were not adequately addressed in prior studies. We thus aimed to address limitations in prior studies and compare overall- and subgroup-specific effectiveness of 8- and 12-week ledipasvir/sofosbuvir regimens among HCV-1 treatment-naive patients. METHODS: Patients eligible for our study were aged >=18 years and initiated 8- or 12-week ledipasvir/sofosbuvir regimens for treatment-naive HCV-1 at an urban public hospital network. We excluded patients with HIV or cirrhosis. We used marginal structural models to estimate overall and subgroup-specific risk ratios (RRs) and 95% confidence limits (CL) comparing the effect of 8- and 12-week ledipasvir/sofosbuvir regimens on 12-week SVR. RESULTS: Our study population comprised 191 patients. Among both regimens, the majority were aged >50 years, non-Hispanic White and uninsured. The overall risk of SVR was comparable between the 8- and 12-week regimens (RR=1.01, 95% CL: 0.92, 1.11). The risk of SVR did not vary by race/ethnicity (non-Hispanic Black: RR=1.01, 95% CL: 0.84, 1.21; non-Hispanic White: RR=1.01, 95% CL: 0.89, 1.04). CONCLUSIONS: Our real-world results suggest that 8- and 12-week ledipasvir/sofosbuvir have comparable effects on SVR among HCV-1 patients without cirrhosis or HIV. In addition, the comparable effectiveness of 8- and 12-week regimens among non-Hispanic Black individuals adds to the growing body of evidence that supports the removal of race-based treatment guidelines. PMID- 29969098 TI - Recurrent network model for learning goal-directed sequences through reverse replay. AB - Reverse replay of hippocampal place cells occurs frequently at rewarded locations, suggesting its contribution to goal-directed path learning. Symmetric spike-timing dependent plasticity (STDP) in CA3 likely potentiates recurrent synapses for both forward (start to goal) and reverse (goal to start) replays during sequential activation of place cells. However, how reverse replay selectively strengthens forward synaptic pathway is unclear. Here, we show computationally that firing sequences bias synaptic transmissions to the opposite direction of propagation under symmetric STDP in the co-presence of short-term synaptic depression or afterdepolarization. We demonstrate that significant biases are created in biologically realistic simulation settings, and this bias enables reverse replay to enhance goal-directed spatial memory on a W-maze. Further, we show that essentially the same mechanism works in a two-dimensional open field. Our model for the first time provides the mechanistic account for the way reverse replay contributes to hippocampal sequence learning for reward seeking spatial navigation. PMID- 29969100 TI - Physical realization of 2D spin liquid state by ab initio design and strain engineering in FeX3. AB - So far, no real physical two dimensional (2D) monolayer materials with spin liquid (SL) state have been identified, although the SL state has been analytically predicted to be present in 2D triangular, honeycomb and kagome model lattices. Identifying a realistic monolayer, 2D SL material thus enables one to more clearly observe and understand the physics of the fractional quantum Hall effect, high-temperature superconductivity and magnetic monopole. In this work, we have performed first principles calculations within density functional theory to investigate the magnetic phase diagram in monolayer FeCl3, which reveals that the SL state may exist near the quantum phase transition between different antiferromagnetic (AFM) phases. Fundamentally, under a biaxial in-plane strain, the quantum phase transition appear and the ratio between the second neighboring exchange interaction (J 2) and the first neighboring interaction (J 1) falls into the SL range (0.21 ~ 0.28). Through comparison, the exchange energy ratio of monolayer FeBr3 (0.327 ~ 0.565) is beyond the SL range and thus FeBr3 could not exhibit SL characters. During the quantum phase transition induced by strain, the magnetic ground state transforms from AFM-Neel phase to AFM-stripy. Near the critical point, the semiconductor FeCl3 transforms from indirect to direct band gap. Our findings provide insights that the monolayer FeCl3 is a realistic 2D SL prototype material and the SL state could be observed by strain engineering. PMID- 29969101 TI - Structural polymorphism of the Escherichia coli poly-alpha-L-glutamate synthetase RimK. AB - Bacterial RimK is an enzyme that catalyzes the polyglutamylation of the C terminus of ribosomal protein S6 and the synthesis of poly-alpha-L-glutamate peptides using L-glutamic acid. In the present study, the crystal structure of the Escherichia coli RimK protein complexed with the ATP analogue AMP-PNP was determined at 2.05 A resolution. Two different conformations of RimK, closed and open forms, were observed in the crystals. The structural polymorphism revealed in this study provided important information to understand the mechanism by which RimK catalyzes the synthesis of poly-alpha-L-glutamate peptides and the polyglutamylation of ribosomal protein S6. PMID- 29969102 TI - Crystallization and X-ray analysis of all of the players in the autoregulation of the ataRT toxin-antitoxin system. AB - The ataRT operon from enteropathogenic Escherichia coli encodes a toxin-antitoxin (TA) module with a recently discovered novel toxin activity. This new type II TA module targets translation initiation for cell-growth arrest. Virtually nothing is known regarding the molecular mechanisms of neutralization, toxin catalytic action or translation autoregulation. Here, the production, biochemical analysis and crystallization of the intrinsically disordered antitoxin AtaR, the toxin AtaT, the AtaR-AtaT complex and the complex of AtaR-AtaT with a double-stranded DNA fragment of the operator region of the promoter are reported. Because they contain large regions that are intrinsically disordered, TA antitoxins are notoriously difficult to crystallize. AtaR forms a homodimer in solution and crystallizes in space group P6122, with unit-cell parameters a = b = 56.3, c = 160.8 A. The crystals are likely to contain an AtaR monomer in the asymmetric unit and diffracted to 3.8 A resolution. The Y144F catalytic mutant of AtaT (AtaTY144F) bound to the cofactor acetyl coenzyme A (AcCoA) and the C-terminal neutralization domain of AtaR (AtaR44-86) were also crystallized. The crystals of the AtaTY144F-AcCoA complex diffracted to 2.5 A resolution and the crystals of AtaR44-86 diffracted to 2.2 A resolution. Analysis of these structures should reveal the full scope of the neutralization of the toxin AtaT by AtaR. The crystals belonged to space groups P6522 and P3121, with unit-cell parameters a = b = 58.1, c = 216.7 A and a = b = 87.6, c = 125.5 A, respectively. The AtaR-AtaT DNA complex contains a 22 bp DNA duplex that was optimized to obtain high resolution data based on the sequence of two inverted repeats detected in the operator region. It crystallizes in space group C2221, with unit-cell parameters a = 75.6, b = 87.9, c = 190.5 A. These crystals diffracted to 3.5 A resolution. PMID- 29969103 TI - Crystal structure of Escherichia coli purine nucleoside phosphorylase complexed with acyclovir. AB - Escherichia coli purine nucleoside phosphorylase (PNP), which catalyzes the reversible phosphorolysis of purine ribonucleosides, belongs to the family I hexameric PNPs. Owing to their key role in the purine salvage pathway, PNPs are attractive targets for drug design against some pathogens. Acyclovir (ACV) is an acyclic derivative of the PNP substrate guanosine and is used as an antiviral drug for the treatment of some human viral infections. The crystalline complex of E. coli PNP with acyclovir was prepared by co-crystallization in microgravity using counter-diffusion through a gel layer in a capillary. The structure of the E. coli PNP-ACV complex was solved at 2.32 A resolution using the molecular replacement method. The ACV molecule is observed in two conformations and sulfate ions were located in both the nucleoside-binding and phosphate-binding pockets of the enzyme. A comparison with the complexes of other hexameric and trimeric PNPs with ACV shows the similarity in acyclovir binding by these enzymes. PMID- 29969105 TI - A novel bacterial class V dye-decolourizing peroxidase from the extremophile Deinococcus radiodurans: cloning, expression optimization, purification, crystallization, initial characterization and X-ray diffraction analysis. AB - Deinococcus radiodurans is a bacterium with extreme resistance to desiccation and radiation. The resistance mechanism is unknown, but an efficient reactive oxygen species (ROS) scavenging system and DNA-repair and DNA-protection mechanisms are believed to play important roles. Here, the cloning and small- and medium-scale expression tests of a novel dye-decolourizing peroxidase from D. radiodurans (DrDyP) using three different Escherichia coli strains and three different temperatures in order to identify the optimum conditions for the expression of recombinant DrDyP are presented. The best expression conditions were used for large-scale expression and yielded ~10 mg recombinant DrDyP per litre of culture after purification. Initial characterization experiments demonstrated unusual features with regard to the haem spin state, which motivated the crystallization experiment. The obtained crystals were used for data collection and diffracted to 2.2 A resolution. The crystals belonged to the trigonal space group P31 or P32, with unit-cell parameters a = b = 64.13, c = 111.32 A, and are predicted to contain one DrDyP molecule per asymmetric unit. Structure determination by molecular replacement using previously determined structures of dye-decolourizing peroxidases with ~30% sequence identity at ~2 A resolution as templates are ongoing. PMID- 29969104 TI - Cinder: keeping crystallographers app-y. AB - The process of producing suitable crystals for X-ray diffraction analysis most often involves the setting up of hundreds (or thousands) of individual crystallization trials, each of which must be repeatedly examined for crystals or hints of crystallinity. Currently, the only real way to address this bottleneck is to use an automated imager to capture images of the trials. However, the images still need to be assessed for crystals or other outcomes. Ideally, there would exist some rapid and reliable machine-analysis tool to translate the images into a quantitative result. However, as yet no such tool exists in wide usage, despite this being a well recognized problem. One of the issues in creating robust automatic image-analysis software is the lack of reliable data for training machine-learning algorithms. Here, a mobile application, Cinder, has been developed which allows crystallization images to be scored quickly on a smartphone or tablet. The Cinder scores are inserted into the appropriate table in a crystallization database and are immediately available to the user through a more sophisticated web interface, allowing more detailed analyses. A sharp increase in the number of scored images was observed after Cinder was released, which in turn provides more data for training machine-learning tools. PMID- 29969106 TI - Crystal structure of human anterior gradient protein 3. AB - Oxidative protein folding in the endoplasmic reticulum is catalyzed by the protein disulfide isomerase family of proteins. Of the 20 recognized human family members, the structures of eight have been deposited in the PDB along with domains from six more. Three members of this family, ERp18, anterior gradient protein 2 (AGR2) and anterior gradient protein 3 (AGR3), are single-domain proteins which share sequence similarity. While ERp18 has a canonical active-site motif and is involved in native disulfide-bond formation, AGR2 and AGR3 lack elements of the active-site motif found in other family members and may both interact with mucins. In order to better define its function, the structure of AGR3 is required. Here, the recombinant expression, purification, crystallization and crystal structure of human AGR3 are described. PMID- 29969107 TI - Crystal structures and kinetic analyses of N-acetylmannosamine-6-phosphate 2 epimerases from Fusobacterium nucleatum and Vibrio cholerae. AB - Sialic acids are nine-carbon sugars that are found abundantly on the cell surfaces of mammals as glycoprotein or glycolipid complexes. Several Gram negative and Gram-positive bacteria have the ability to scavenge and catabolize sialic acids to use as a carbon source. This gives them an advantage in colonizing sialic acid-rich environments. The genes of the sialic acid catabolic pathway are generally present as the operon nanAKE. The third gene in the operon encodes the enzyme N-acetylmannosamine-6-phosphate 2-epimerase (NanE), which catalyzes the conversion of N-acetylmannosamine 6-phosphate to N acetylglucosamine 6-phosphate, thus committing it to enter glycolysis. The NanE enzyme belongs to the isomerase class of enzymes possessing the triose phosphate isomerase (TIM) barrel fold. Here, comparative structural and functional characterizations of the NanE epimerases from two pathogenic Gram-negative bacteria, Fusobacterium nucleatum (Fn) and Vibrio cholerae (Vc), have been carried out. Structures of NanE from Vc (VcNanE) with and without ligand bound have been determined to 1.7 and 2.7 A resolution, respectively. The structure of NanE from Fn (FnNanE) has been determined to 2.2 A resolution. The enzymes show kinetic parameters that are consistent with those of Clostridium perfringens NanE. These studies allowed an evaluation of whether NanE may be a good drug target against these pathogenic bacteria. PMID- 29969108 TI - Quantification of Total and Intracellular Sodium Concentration in Primary Prostate Cancer and Adjacent Normal Prostate Tissue With Magnetic Resonance Imaging. AB - OBJECTIVES: The aim of this study was to measure the tissue sodium concentration (TSC) within tumors and normal prostate in prostate cancer patients, using prostatectomy as pathological criterion standard. MATERIALS AND METHODS: Fifteen patients with biopsy-proven, magnetic resonance imaging (MRI) visible, intermediate- or high-risk prostate cancer underwent a dedicated research sodium MRI, before treatment with radical prostatectomy. All participants signed written informed consent for this institutional review board-approved prospective study. 3 T MRI acquired using a dedicated multinuclear clamshell transmit coil and a bespoke dual-tuned H/Na endorectal receive coil, with intracellular-sodium imaging acquired using inversion recovery sequences; a phantom-based calibration enabled quantitative sodium maps. Regions of interest were defined for normal peripheral zone (PZ) and transition zone (TZ) and tumor regions, referenced from histopathology maps. A 1-way analysis of variance compared normal and tumor tissue, using Tukey test for multiple comparisons. RESULTS: Two patients were excluded due to artifact; software error resulted in 1 further intracellular sodium failure. Fifteen tumors were detected (13 PZ, 2 TZ) in 13 patients: Gleason 3 + 3 (n = 1), 3 + 4 (6), 3 + 5 (2), 4 + 3 (5), 4 + 5 (1). Both mean TSC and intracellular-sodium were significantly higher in normal PZ (39.2 and 17.5 mmol/L, respectively) versus normal TZ (32.9 and 14.7; P < 0.001 and P = 0.02). Mean TSC in PZ tumor (45.0 mmol/L) was significantly higher than both normal PZ and TZ tissue (P < 0.001). Intracellular sodium in PZ tumors (19.9 mmol/L) was significantly higher than normal TZ (P < 0.001) but not normal PZ (P = 0.05). Mean TSC and intracellular-sodium was lower in Gleason <=3 + 4 tumors (44.4 and 19.5 mmol/L, respectively) versus >=4 + 3 (45.6 and 20.2), but this was not significant (P = 0.19 and P = 0.29). CONCLUSIONS: Tissue sodium concentration and intracellular sodium concentrations of prostate tumors were quantified, with PZ tumors demonstrating a significantly increased TSC. PMID- 29969109 TI - Thumb Basal Joint Arthritis. AB - The thumb basal joint is the second most common site of osteoarthritis in the hand, and osteoarthritis of this joint can contribute to painful movement and debilitating function. To achieve a high degree of prehensile and manipulative function, this highly mobile joint is constrained by both the saddle morphology of the trapezium and a stout complement of ligamentous constraints. The disease proceeds progressively with several wear patterns. Substantial new biomechanical and longitudinal clinical studies have changed some of the prevailing opinions on the process of serial degenerative changes. Diagnosis is made with a thorough clinical examination and radiographic staging, as described by Eaton and Littler. Thumb basal joint arthritis can be initially managed with medications, orthoses, and steroid injections; however, it frequently progresses despite these interventions. Surgical management commonly consists of trapeziectomy with or without interposition or suspension, arthroplasty with implant, volar ligament reconstruction, osteotomy, or arthrodesis; none of these techniques has been proved to be superior to the others. PMID- 29969111 TI - Corrigendum: The Centennial Trends Greater Horn of Africa precipitation dataset. AB - This corrects the article DOI: 10.1038/sdata.2015.50. PMID- 29969110 TI - Viruses of the Nahant Collection, characterization of 251 marine Vibrionaceae viruses. AB - Viruses are highly discriminating in their interactions with host cells and are thought to play a major role in maintaining diversity of environmental microbes. However, large-scale ecological and genomic studies of co-occurring virus-host pairs, required to characterize the mechanistic and genomic foundations of virus host interactions, are lacking. Here, we present the largest dataset of cultivated and sequenced co-occurring virus-host pairs that captures ecologically representative fine-scale diversity. Using the ubiquitous and ecologically diverse marine Vibrionaceae as a host platform, we isolate and sequence 251 dsDNA viruses and their hosts from three time points within a 93-day time-series study. The virus collection includes representatives of the three Caudovirales tailed virus morphotypes, a novel family of nontailed viruses, and the smallest (10,046 bp) and largest (348,911 bp) Vibrio virus genomes described. We provide general characterization and annotation of the viruses and describe read-mapping protocols to standardize genome presentation. The rich ecological and genomic contextualization of hosts and viruses make the Nahant Collection a unique platform for high-resolution studies of environmental virus-host infection networks. PMID- 29969112 TI - Smart subsidies for catchment conservation in Malawi. AB - Conservation agriculture (CA) is a management paradigm in which soil is covered outside of cropping seasons, minimally disturbed, and recharged with nitrogen fixing legumes. Finding effective ways to encourage CA is a centuries-old problem playing out acutely today in Sub-Saharan Africa. To better understand this issue, we have collected data on rural livelihoods and CA adoption during a two-year intervention in southern Malawi. The intervention evaluated rates of CA adoption under two different structures of payment and three levels of monitoring. The dataset includes a baseline and endline survey covering 1,900 households, along with surveys conducted with participants opting into the intervention. Baseline and endline questions included modules on farm-level inputs and production at the plot-crop level; plot characteristics; household composition and assets; savings, loans, and other sources of income; neighborhood characteristics; and perceptions regarding CA. Registration questionnaires in the intervention included detailed assessments of recent production in plots being registered to the intervention, and basic information for all other plots; and basic information on household structure and assets. PMID- 29969113 TI - Marine phytoplankton community composition data from the Belgian part of the North Sea, 1968-2010. AB - The Belgian Phytoplankton Database (BPD) is a comprehensive data collection comprising quantitative phytoplankton cell counts from multiple research projects conducted since 1968. The collection is focused on the Belgian part of the North Sea, but also includes data from the French and the Dutch part of the North Sea. The database includes almost 300 unique sampling locations and more than 3,000 sampling events resulting in more than 86,000 phytoplankton cell count records. The dataset covers two periods: 1968 to 1978 and 1994 to 2010. The BPD can be accessed online and provides high quality phytoplankton count data. The species taxonomy is updated, and the count values are quality checked and standardized. Important metadata like sampling date, sampling location, sampling depth and methodology is provided and standardized. Additionally, associated abiotic data and biovolume values are available. The dataset allows to conduct analyses of long-term temporal and spatial trends in phytoplankton community structure in the southern part of the North Sea, including changes in phytoplankton phenology and seasonality. PMID- 29969114 TI - OceanRAIN, a new in-situ shipboard global ocean surface-reference dataset of all water cycle components. AB - OceanRAIN-the Ocean Rainfall And Ice-phase precipitation measurement Network provides in-situ along-track shipboard data of precipitation, evaporation and the resulting freshwater flux at 1-min resolution over the global oceans from June 2010 to April 2017. More than 6.83 million minutes with 75 parameters from 8 ships cover all routinely measured atmospheric and oceanographic state variables along with those required to derive the turbulent heat fluxes. The precipitation parameter is based on measurements of the optical disdrometer ODM470 specifically designed for all-weather shipboard operations. The rain, snow and mixed-phase precipitation occurrence, intensity and accumulation are derived from particle size distributions. Additionally, microphysical parameters and radar-related parameters are provided. Addressing the need for high-quality in-situ precipitation data over the global oceans, OceanRAIN-1.0 is the first comprehensive along-track in-situ water cycle surface reference dataset for satellite product validation and retrieval calibration of the GPM (Global Precipitation Measurement) era, to improve the representation of precipitation and air-sea interactions in re-analyses and models, and to improve understanding of water cycle processes over the global oceans. PMID- 29969115 TI - Multi-frequency electrical impedance tomography and neuroimaging data in stroke patients. AB - Electrical Impedance Tomography (EIT) is a non-invasive imaging technique, which has the potential to expedite the differentiation of ischaemic or haemorrhagic stroke, decreasing the time to treatment. Whilst demonstrated in simulation, there are currently no suitable imaging or classification methods which can be successfully applied to human stroke data. Development of these complex methods is hindered by a lack of quality Multi-Frequency EIT (MFEIT) data. To address this, MFEIT data were collected from 23 stroke patients, and 10 healthy volunteers, as part of a clinical trial in collaboration with the Hyper Acute Stroke Unit (HASU) at University College London Hospital (UCLH). Data were collected at 17 frequencies between 5 Hz and 2 kHz, with 31 current injections, yielding 930 measurements at each frequency. This dataset is the most comprehensive of its kind and enables combined analysis of MFEIT, Electroencephalography (EEG) and Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) data in stroke patients, which can form the basis of future research into stroke classification. PMID- 29969116 TI - High-resolution hydrometeorological data from a network of headwater catchments in the tropical Andes. AB - This article presents a hydrometeorological dataset from a network of paired instrumented catchments, obtained by participatory monitoring through a partnership of academic and non-governmental institutions. The network consists of 28 headwater catchments (<20 km2) covering three major biomes in 9 locations of the tropical Andes. The data consist of precipitation event records at 0.254 mm resolution or finer, water level and streamflow time series at 5 min intervals, data aggregations at hourly and daily scale, a set of hydrological indices derived from the daily time series, and catchment physiographic descriptors. The catchment network is designed to characterise the impacts of land-use and watershed interventions on the catchment hydrological response, with each catchment representing a typical land use and land cover practice within its location. As such, it aims to support evidence-based decision making on land management, in particular evaluating the effectiveness of catchment interventions, for which hydrometeorological data scarcity is a major bottleneck. The data will also be useful for broader research on Andean ecosystems, and their hydrology and meteorology. PMID- 29969118 TI - Sharing data from the Ecosystem Services for Poverty Alleviation programme. PMID- 29969117 TI - A quasi-experimental study of impacts of Tanzania's wildlife management areas on rural livelihoods and wealth. AB - Since the 2000s, Tanzania's natural resource management policy has emphasised Wildlife Management Areas (WMAs), designed to promote wildlife and biodiversity conservation, poverty alleviation and rural development. We carried out a quasi experimental impact evaluation of social impacts of WMAs, collecting data from 24 villages participating in 6 different WMAs across two geographical regions, and 18 statistically matched control villages. Across these 42 villages, we collected participatory wealth ranking data for 13,578 households. Using this as our sampling frame, we conducted questionnaire surveys with a stratified sample of 1,924 household heads and 945 household heads' wives. All data were collected in 2014/15, with a subset of questions devoted to respondents' recall on conditions that existed in 2007, when first WMAs became operational. Questions addressed household demographics, land and livestock assets, resource use, income generating activities and portfolios, participation in natural resource management decision-making, benefits and costs of conservation. Datasets permit research on livelihood and wealth trajectories, and social impacts, costs and benefits of conservation interventions in the context of community-based natural resource management. PMID- 29969119 TI - A pyrene-involved luminescent MOF for monitoring 1-hydroxypyrene, a biomarker for human intoxication of PAH carcinogens. AB - 1-Hydroxypyrene (1-HP) is a urinary metabolite of polycyclic aromatic hydrocarbons (PAHs), and can function as a convenient biomarker for human intoxication of PAH carcinogens. The development of simple 1-HP sensors with high sensitivity and fast response is highly desirable. Herein, we demonstrate that a robust microcrystalline MOF with fluorescent pyrene cores, NU-1000, exhibits sensitive luminescence detection of urinary 1-HP. The pyrene core within NU-1000 behaves as the signal converter, whose luminescence is significantly quenched upon coming into contact with 1-HP owing to the efficient pi-pi charge transfer interactions between highly conjugated 1-HP and pyrene cores in NU-1000. The pore confinement effect of the molecular-sized channel of NU-1000 facilitates the preconcentration of 1-HP within NU-1000, which makes 1-HP contact with NU-1000 more sufficient therefore enhancing the detection efficiency. The charge transfer related quenching mechanism is elucidated by diffuse-reflectance UV-vis and electron paramagnetic resonance (EPR) measurements, and a radical pair state is observed in NU-1000 upon accommodation of 1-HP. This work provides important insights into the development of MOF-based luminescent sensors for 1-HP, and should stimulate further studies toward designing more efficient MOFs with highly conjugated luminescent cores for 1-HP sensing. PMID- 29969120 TI - Design synthesis of a controllable flower-like Pt-graphene oxide architecture through electrostatic self-assembly for DNA damage biomarker 8-hydroxy-2' deoxyguanosine biosensing research. AB - A controllable flower-like Pt-graphene oxide (PtNF-GO) architecture was synthesized through layer-by-layer electrostatic self-assembly. Hexadecyltrimethylammonium chloride (CTAC) micelles were employed as the template and Pt nanoflowers with different sizes were selectively synthesized by controlling the dissolved K2PtCl4 precursor and CTAC amounts in the reaction system. The prepared PtNF-GO was applied for DNA damage biomarker 8-hydroxy-2' deoxyguanosine (8-OHdG) biosensing research. With the distinctive flower-like morphology of PtNFs and high electrical conductivity of GO, the PtNF-GO architecture shows excellent electrochemical biosensing performance towards the oxidation of 8-OHdG. A very low detection limit of 0.025 nM is obtained. Moreover, the fabricated PtNF-GO was used for the detection of 8-OHdG generated from the damaged DNA sample, which can be used to evaluate and confirm the mechanism of DNA damage, and it is of great importance in gene diagnosis, clinical and life sciences. PMID- 29969121 TI - Aggregation and fragmentation in liquids with dispersed nanoparticles. AB - Nanoparticle-induced aggregation and fragmentation phenomena in liquid media are investigated by applying a model of preferential attachment of dispersing molecules to randomly chosen nanoparticles and larger particles, each containing a single nanoparticle. The model is based on the assumption that immersed nanoparticles, media molecules, and the resulting composite particles do not form any self-linked structures, i.e., that they do not undergo homoaggregation as a consequence of, e.g., electrostatic repulsion. Probabilities of both connecting and disconnecting a molecule are considered as being proportional to the surface area of a target particle. Additionally, the aggregation probability is assumed to be driven by van der Waals interactions. The interplay between aggregation and fragmentation processes is studied for different relative efficiencies (frequencies) of these processes. In particular, the time evolution of the particle size distribution is analyzed at various values of the relative frequency rate between aggregation and fragmentation events. It is shown that the evolution of an ensemble of particles over relatively long time periods can lead to very peculiar particle size distributions, including nearly homogeneous and highly heterogeneous partitioning. This indicates that, by controlling the frequency rate, one can obtain materials with very diverse and unique properties. Theoretical results obtained within the studied model are compared with corresponding experimental data. PMID- 29969122 TI - A novel magnetite nanorod-decorated Si-Schiff base complex for efficient immobilization of U(vi) and Pb(ii) from water solutions. AB - A novel silicon Schiff base complex (Si-SBC) and magnetite nanorod-decorated Si SBC (M/SiO2-Si-SBC) were synthesized and well characterized in detail. The synthesized materials were applied for the removal of U(vi) and Pb(ii) from water solutions under various experimental conditions. The monolayer maximum adsorption capacities of M/SiO2-Si-SBC (6.45 * 10-4 mol g-1 for Pb(ii) and 4.82 * 10-4 mol g 1 for U(vi)) obtained from the Langmuir model at 25 degrees C and pH = 5.00 +/- 0.05 were higher than those of Si-SBC (5.18 * 10-4 mol g-1 for Pb(ii) and 3.70 * 10-4 mol g-1 for U(vi)). Moreover, DFT calculations showed that the high adsorption energies (Ead) of 7.61 kcal mol-1 for Pb2+-(Si-SBC) and 2.72 kcal mol 1 for UO22+-(Si-SBC) are mainly attributed to stronger electrostatic interactions. The results revealed that the Si-SBC and M/SiO2-Si-SBC could be used as efficient adsorbents for the effective elimination of U(vi) and Pb(ii) from contaminated wastewater. High sorption capacity and reusability indicated the practical applications of the synthesized materials in environmental pollution cleanup. PMID- 29969123 TI - Increasing the ion-exchange capacity of MFI zeolites by introducing Zn to aluminosilicate frameworks. AB - MFI zeolites exchanged with various cations have gained a great deal of attention as catalysts. Increase in the ion-exchange capacity of zeolites can improve their catalytic properties by introducing more active sites; however, the ion-exchange capacity of MFI zeolites is limited by maximum aluminum content in the structure. To improve the ion-exchange capability of the MFI zeolites beyond the upper limit of the aluminosilicate MFI zeolites, we propose herein an approach to incorporate Zn(ii) in the zeolitic framework, because Zn in the framework sites generates two negative charges per atom. Using zincoaluminosilicate gels prepared via co precipitation, organic-free synthesis of zincoaluminosilicate MFI zeolites was achieved. The obtained zincoaluminosilicate MFI zeolites had high Zn contents comparable to those in the initial zincoaluminosilicate gels with both Zn and Al in the zeolite framework. In contrast, the use of conventional sources of Si, Al, and Zn resulted in zeolites with extra-framework zinc oxide species. The obtained Zn-substituted MFI zeolites were shown to possess higher ion-exchange capacity compared to aluminosilicate MFI zeolites. It was also revealed that the zincoaluminosilicate MFI zeolites have high affinity for the divalent cation compared to the aluminosilicate analog, likely due to the two negative charges in close proximity. Because of these higher ion-exchange efficiencies, especially for divalent cations, the obtained zincoaluminosilicate MFI zeolites are expected to be efficient platforms for several important catalytic reactions. PMID- 29969124 TI - Synthesis and organic solar cell performance of BODIPY and coumarin functionalized SWCNTs or graphene oxide nanomaterials. AB - The synthesis and characterization of new hybrid materials based on reduced graphene oxide (rGO) or single walled carbon nanotubes (SWCNTs) covalently functionalized by 4,4'-difluoro-8-(4-propynyloxy)-phenyl-1,3,5,7-tetramethyl-4 bora-3a,4a-diaza-s-indacene (BODIPY) (2) or 7-(prop-2-yn-1-yloxy)-3-(3',4',5' trimethoxyphenyl)-coumarin (4) as light harvesting groups have been described. The organic solar cell performances of these novel nanomaterials in P3HT:PCBM blends were investigated. These covalently bonded hybrid materials (reduced graphene oxide:BODIPY (GB), reduced graphene oxide:Coumarin (GC), SWCNTs:BODIPY (CB) and SWCNTs:Coumarin (CC)) were prepared by an azide-alkyne Huisgen cycloaddition (click) reaction between the azide bearing SWCNTs or rGO and terminal ethynyl functionalized BODIPY (2) or coumarin (4) derivatives. The formation of novel nanomaterials was confirmed by FT-IR, UV-Vis and Raman spectroscopies and thermogravimetric analysis. The best performance on P3HT:PCBM organic solar cells was produced by SWCNTs:Coumarin (CC) hybrids which were coated on an indium tin oxide coated polyethylene terephthalate film (ITO-PET). The reference device based on the P3HT:PCBM blend without CC showed a power conversion efficiency (PCE) of 1.16%, an FF of 35% and a short-circuit current density (Jsc) of 5.51 mA cm-2. The reference device with CC hybrids within the P3HT:PCBM blend increased the values significantly to 1.62% for PCE, 40% for FF and 6.8 mA cm-2 for Jsc. PMID- 29969125 TI - Rational synthesis of a luminescent uncommon (3,4,6)-c connected Zn(ii) MOF: a dual channel sensor for the detection of nitroaromatics and ferric ions. AB - The articulate combination of intriguing functional groups and luminescence properties can deliver metal-organic frameworks (MOFs) with multifarious applications viz. selective and specific sensing of nitroaromatic compounds (NACs), an important constituent of explosives, as well as sensing of toxic metal ions. In this regard, a new d10 configuration based Zn(ii) metal-organic framework (MOF) {(NH2(CH3)2)[Zn4(ddn)2(COO)(H2O)4].solvent}n (1) has been synthesized using a pi-conjugated and rigid multicarboxylate ligand 3,5-di(3,5 dicarboxylphenyl)nitrobenzene (H4ddn). 1 displays a 3D (3,4,6)-c connected net which is based on two types of binuclear [Zn2(MU2-COO)2(MU1-COO)2] and [Zn2(MU2 COO)4] clusters. Sensing studies of 1 to detect nitro-aromatic compounds reveal highly specific detection of 2,4-dinitophenol (DNP) with remarkable quenching (KSV = 8.93 * 103 M-1) and a low limit of detection (LOD: 1.12 ppm). The luminescence quenching mechanism in the case of 1 in the presence of NACs has been ascribed to the concurrent presence of the charge transfer as well as the weak interaction between the MOF and NACs. The activated framework of 1 also displayed highly selective detection of ferric ions with KSV = 1.13 * 104 M-1 with a low limit of detection (LOD: 1.24 ppm). PMID- 29969126 TI - Expression of concern: Synthesis of octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals and their structure-activity relationship for the decomposition of hydrazine in aqueous solution to hydrogen. AB - Expression of concern for 'Synthesis of octahedral, truncated octahedral, and cubic Rh2Ni nanocrystals and their structure-activity relationship for the decomposition of hydrazine in aqueous solution to hydrogen' by Chun Li et al., Nanoscale, 2016, 8, 7043-7055. PMID- 29969132 TI - Water and hydrophobic gates in ion channels and nanopores. AB - Ion channel proteins form nanopores in biological membranes which allow the passage of ions and water molecules. Hydrophobic constrictions in such pores can form gates, i.e. energetic barriers to water and ion permeation. Molecular dynamics simulations of water in ion channels may be used to assess whether a hydrophobic gate is closed (i.e. impermeable to ions) or open. If there is an energetic barrier to water permeation then it is likely that a gate will also be impermeable to ions. Simulations of water behaviour have been used to probe hydrophobic gates in two recently reported ion channel structures: BEST1 and TMEM175. In each of these channels a narrow region is formed by three consecutive rings of hydrophobic sidechains and in both cases such analysis demonstrates that the crystal structures correspond to a closed state of the channel. In silico mutations of BEST1 have also been used to explore the effect of changes in the hydrophobicity of the gating constriction, demonstrating that substitution of hydrophobic sidechains with more polar sidechains results in an open gate which allows water permeation. A possible open state of the TMEM175 channel was modelled by the in silico expansion of the hydrophobic gate resulting in the wetting of the pore and free permeation of potassium ions through the channel. Finally, a preliminary study suggests that a hydrophobic gate motif can be transplanted in silico from the BEST1 channel into a simple beta-barrel pore template. Overall, these results suggest that simulations of the behaviour of water in hydrophobic gates can reveal important design principles for the engineering of gates in novel biomimetic nanopores. PMID- 29969130 TI - Evaluation of biological and antimicrobial properties of freeze-dried whey fermented by different strains of Lactobacillus plantarum. AB - The aim of this study was to evaluate the biological and antimicrobial activities of commercial freeze-dried whey fermented by lactic acid bacteria in order to valorize this high polluting liquid waste of the dairy industry. Freeze-dried whey was fermented by different strains of Lactobacillus plantarum (CECT 220, 221, 748) at three different times of fermentation (24, 48, 72 h). Afterwards, the extract was purified on centricon amicon with a cut-off of 3 kDa to obtain a permeate consisting of small bioactive compounds reported in the literature to show greater bioactivity. The purified and diluted samples were subjected to the biological and antimicrobial tests for the evaluation of antioxidant, antihypertensive, iron binding, and antifungal activities and identification of phenolic compounds. The results highlighted a radical cation scavenging activity ranging from 1.415 to 2.083 mmol trolox equivalents TE per kg of dry weight, a percentage of iron binding capacity ranging between 23-55% and a percentage of ACE inhibitory activity ranging between 67-85%. The optimal biological activity was obtained from whey fermented by L. plantarum 220 for all the assays performed, except for the iron chelating activity. Furthermore, the antifungal analysis showed a good activity against the mycotoxigenic fungi belonging to Fusarium generum (F. moniliformis, F. graminearum and F. verticillioides), while a slight activity was obtained for Aspergillus and Penicillium generum. This antifungal activity could be correlated to the production of phenolic compounds during fermentation. The obtained results support the hypothesis of using whey as a functional ingredient to improve food preservation. PMID- 29969133 TI - It Takes a Village. PMID- 29969136 TI - Chronic Obstructive Pulmonary Disease in Older Adults: Part I: Case Study. AB - Chronic obstructive pulmonary disease (COPD) is a distressing respiratory disease that may greatly impact a patient's quality of life. Although many treatment options exist, the Global Initiative for Chronic Obstructive Lung Disease Guidelines outline management strategies based on severity of daily symptoms and exacerbations. Although it is important to weigh the risks and benefits of medication use, involvement of patients in their overall care plan is imperative to optimal outcomes. According to recent studies, the prevalence of COPD in older adults is increasing, along with the complexity of care due to comorbidities, drug interactions, and side effects. A thorough evaluation of a patient case provides insight into the everyday challenges of COPD management. [Journal of Gerontological Nursing, 44(7), 10-14.]. PMID- 29969137 TI - Evidence-Based Practice Guideline: Elder Abuse Prevention. AB - Elder abuse occurs in all practice settings and presents in various forms. The purpose of the current evidence-based practice guideline is to facilitate health care professionals' assessment of older adults in domestic and institutional settings who are at risk for elder abuse, and to recommend interventions to reduce the incidence of mistreatment. Limited research has been conducted on interventions to prevent or reduce elder abuse. Research is available on the prevalence of elder abuse and indicators of individuals who may be more susceptible to harm. The current article summarizes prevalence and risk factors for elder abuse, instruments available to assess individuals at risk for or victims of abuse, and potential interventions to prevent or reduce elder abuse. [Journal of Gerontological Nursing, 44(7), 21-30.]. PMID- 29969138 TI - Enabling Advance Directive Completion: Feasibility of a New Nurse-Supported Advance Care Planning Intervention. AB - Adults who complete an advance directive (AD) are not consistently offered information about the risks, benefits, or alternatives (RBA) of the life sustaining medical procedures addressed on standardized forms. The current article describes a new patient-centered nurse-supported advance care planning (NSACP) intervention focused on providing information about RBA of life sustaining procedures. Fifty participants (mean age = 50.26 years) at a Veterans Affairs medical center were randomized to the NSACP intervention or a comparison condition. Before randomization, 78% (n = 39) expressed interest in RBA information. Of participants in the NSACP group, 94% (n = 30) completed an AD. Participants who received NSACP made more decisions to decline life-sustaining treatment than those who were randomized to the comparison group. Promising feasibility data include brevity (mean = 46 minutes), high patient satisfaction, participant retention, and treatment fidelity. The NSACP holds promise as a brief, educational intervention to support patients in completing an AD. [Journal of Gerontological Nursing, 44(7), 31-42.]. PMID- 29969139 TI - Photovoice: A Research Method and Intervention to Engage Older Adults. AB - The purpose of the current article is to describe the use of photovoice with individuals from vulnerable population groups. Ten African American men and women ages 66 to 72 with heart failure from three different low income public housing facilities were recruited for participation in a qualitative photovoice project. Participants were given 5 weeks to take photographs of images that represented facilitators of and barriers to engaging in self-care behaviors. Each week, participants met as a group to discuss the photographs and their meanings to other participants. The photovoice method was empowering to participants, easy to use, and shown to be appropriate within African American older adults with heart failure. The photovoice method assisted in providing the opportunity for this vulnerable population to share their personal beliefs and perspectives. Use of this method assisted in identification of themes that represented facilitators of and barriers to engaging in self-care and was effective in meeting the specific aims of the research project. Findings from the current study support photovoice as a valuable method to use with vulnerable individuals with chronic conditions. [Journal of Gerontological Nursing, 44(7), 43-49.]. PMID- 29969140 TI - Association of Comorbid Burden and Patient Outcomes of Residents With Dementia in Jordanian Nursing Homes. AB - Medical and psychiatric comorbidity in individuals with dementia is often associated with serious adverse health outcomes. Using a convenience sample of 76 residents with dementia in Jordanian nursing homes, the current study aimed to examine the relationship among comorbid burden, ability to verbally self-report symptoms, severity of dementia, and patient outcomes of pain and agitation. Comorbid burden and ability to verbally self-report symptoms were found to be significant predictors of patient outcomes of pain and agitation. However, the ability to verbally self-report symptoms did not explain the relationship between comorbid burden and patient outcomes. Nurses must understand the impact of comorbid burden and the ability to verbally self-report symptoms regarding pain and agitation in individuals with dementia. [Journal of Gerontological Nursing, 44(7), 50-58.]. PMID- 29969142 TI - ? PMID- 29969141 TI - Award-Winning Research at #AGS18 Speaks to Depth, Breadth of Geriatrics' Reach. PMID- 29969143 TI - [ST-elevation myocardial infarction and dual antiplatelet therapy: new guidelines]. AB - This report summarizes some of the most important changes and new recommendations from the ESC ST-elevation myocardial infarction and double antiplatelet therapy guidelines for 2017, which are of interest for physicians managing patients with coronary artery disease. PMID- 29969144 TI - [Is the current level of investigation for vestibular schwannoma reasonable?] AB - The main aim of this study was to evaluate if the level of investigation with MRT or BRA (Brainstem Response Audiometry) is adequate in relation to the number of vestibular schwannomas (VS) found in a county like Dalarna (277 000 inhabitants) in Sweden. The reason to investigate was asymmetrical sensorineural hearing loss (ASHL) defined as a one-sided hearing loss exceeding 10 dB compared to the contralateral side. Between 2007-2014 a total of 55 patients (incidence 2.5/100 000) were diagnosed with a VS in the county. The local ENT department found two thirds of these patients. In the year of 2010, MRT was advocated by SBU (Swedish Agency for Health Technology Assessment and Assessment of Social Services) as the primary step of investigation. During 2011-2014, 981 patients underwent MRT and 482 patients BRA, because of ASHL. Seventeen VS were found, meaning that 58 MRT and 29 BRA were conducted to find one VS. According to earlier studies, only one third of VS show growth tendency. Taking this into consideration, 174 (58 * 3) investigations with MRT will only diagnose approximately 1 patient with a growing VS. We therefore question today's level of investigation and ask for new uniform recommendations on how to investigate for VS in cases of ASHL. PMID- 29969145 TI - [Life-threatening ketoacidosis in patients with type 2 diabetes on LCHF diet]. AB - Patients with type 2 diabetes may develop severe ketoacidosis. A low carb high fat (LCHF) diet is oftentimes used by these patients for weight loss purposes but is also ketogenic. Antidiabetic SGLT2 inhibitors may increase glucagon secretion and may predispose to ketoacidosis, which is normoglycemic and thus makes it more difficult to suspect. We present two cases of severe ketoacidosis in type 2 diabetes patients on LCHF diet, one of which was also on SGLT2 inhibitor therapy. PMID- 29969147 TI - Proactive conservation and restoration of botanical diversity in the Anthropocene's "rambunctious garden". PMID- 29969148 TI - Factors influencing disordered eating behavior based on the theory of triadic influence. AB - PURPOSE: The objective of this study was to identify factors influencing disordered eating behaviors in female college students based on the theory of triadic influence. DESIGN AND METHOD: The participants in this study were 307 college females in Korea. Data were analyzed using t-tests, correlation coefficients, and multiple regression analyses. FINDINGS: Multiple regression analysis revealed that objectified body consciousness, social physique anxiety, and sociocultural attitudes toward appearance influenced disordered eating behavior (R2 = 0.33, F = 51.32, P < 0.001). PRACTICE IMPLICATIONS: This study suggests the development of a nursing program for college females that considers the factors influencing personal, social, and cultural streams will be effective. PMID- 29969146 TI - Pituitary Adenylate Cyclase-Activating Polypeptide-27 (PACAP-27) in the Thalamic Paraventricular Nucleus Is Stimulated by Ethanol Drinking. AB - BACKGROUND: The paraventricular nucleus of the thalamus (PVT) is a limbic brain structure that affects ethanol (EtOH) drinking, but the neurochemicals transcribed in this nucleus that may participate in this behavior have yet to be fully characterized. The neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), is known to be transcribed in other limbic areas and to be involved in many of the same behaviors as the PVT itself, possibly including EtOH drinking. It exists in 2 isoforms, PACAP-38 and PACAP-27, with the former expressed at higher levels in most brain regions. The purpose of this study was to characterize PACAP in the PVT and to assess its response to EtOH drinking. METHODS: First, EtOH-naive, Sprague Dawley rats were examined using quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry, to characterize PACAP mRNA and peptide throughout the rostrocaudal axis of the PVT. Next, EtOH-naive, vGLUT2-GFP transgenic mice were examined using immunohistochemistry, to identify the neurochemical phenotype of the PACAPergic cells in the PVT. Finally, Long Evans rats were trained to drink 20% EtOH under the intermittent-access paradigm and then examined with PCR and immunohistochemistry, to determine the effects of EtOH on endogenous PACAP in the PVT. RESULTS: Gene expression of PACAP was detected across the entire PVT, denser in the posterior than the anterior portion of this nucleus. The protein isoform, PACAP-27, was present in a high percentage of cell bodies in the PVT, again particularly in the posterior portion, while PACAP-38 was instead dense in fibers. All PACAP-27+ cells colabeled with glutamate, which itself was identified in the majority of PVT cells. EtOH drinking led to an increase in PACAP gene expression and in levels of PACAP-27 in individual cells of the PVT. CONCLUSIONS: This study characterizes the PVT neuropeptide, PACAP, and its understudied protein isoform, PACAP-27, and demonstrates that it is involved in pharmacologically relevant EtOH drinking. This indicates that PACAP-27 should be further investigated for its possible role in EtOH drinking. PMID- 29969149 TI - Identifying Inhibitory Subcomponents Associated with Changes in Binge Drinking Behavior: A 6-Month Longitudinal Design. AB - BACKGROUND: Links between response inhibition and young adult problematic drinking (e.g., binge drinking) have been established, but only to an extent. Considering the presence of some inconsistent findings associated with these 2 variables, this study proposes the need to investigate the extent in which different inhibitory subcomponents are associated with binge drinking behaviors of the same sample. METHODS: Through the use of a 6-month longitudinal design, changes in Alcohol Use Questionnaire (AUQ) binge score of 163 college students (50.3% female) with a mean age of 21.06 years (SD = 1.83) were correlated with performance on 3 different inhibitory control tasks. Each task was selected to assess separate inhibitory subcomponents: Stop Signal Task (e.g., cancellation of a response), Go/No-Go Task (e.g., withholding of a response), and Simon Task (e.g., inhibiting response interference). Response inhibition was also compared between 2 groups, those who had a substantial increase in AUQ binge score during participation (inAUQ) and those who had a substantial decrease in AUQ binge score (deAUQ). RESULTS: A significant correlation was found with a change in AUQ binge score and stop signal reaction time among females only, where an increase in binge drinking score positively correlated with a reduced ability to cancel an already-initiated inhibitory response. Differences in inhibitory performance, where inAUQ performed worse than deAUQ, approached significance. CONCLUSIONS: The results suggest that the cancellation of a prepotent response, as opposed to the withholding of response or interference inhibition, is a more sensitive inhibitory measure associated with increases in binge drinking behavior among female young adult college students. Further exploration of inhibitory subcomponents relative to substance use is greatly needed (e.g., more extensive longitudinal designs and neuroimaging techniques). PMID- 29969150 TI - Tu Youyou winning the Nobel Prize: Ethical research on the value and safety of traditional Chinese medicine. AB - In 2015, the Chinese pharmacologist, Tu Youyou, was awarded the Nobel Prize for Physiology or Medicine for the discovery of artemisinin. Traditional Chinese medicine (TCM) was the source of inspiration for Tu's discovery and provides an opportunity for the world to know more about TCM as a source of medical knowledge and practice. In this article, the value of TCM is evaluated from an ethical perspective. The characteristics of 'jian, bian, yan, lian' are explored in the way they promote accessibility and economic efficiency for TCM. The article also examines how the increased use and prevalence of TCM reflects the scientific, cultural, and ethical values of TCM and their increasing attraction in meeting major challenges to medicine and health systems currently and in the future. The article discusses safety issues within TCM, which is a controversial area, and also comments on some shortcomings and challenges which pose difficulties for more widespread and greater uptake of TCM-derived clinical or therapeutic interventions. The article concludes that TCM is generally safe if it is used according to TCM theory and where such applications are cognizant of the strengths and weaknesses of TCM. TCM has important bioethical values which may inform potential measures for meeting challenges facing global health care systems and the article argues that it can have an increasing role in improving human health. PMID- 29969151 TI - Modeling Relapse to Pavlovian Alcohol-Seeking in Rats Using Reinstatement and Spontaneous Recovery Paradigms. AB - BACKGROUND: Animal models are critical for studying causal explanations of relapse. Using a Pavlovian conditioning procedure with alcohol, we examined relapse after extinction triggered by either re-exposure to alcohol (reinstatement) or a delay between extinction and test (spontaneous recovery). METHODS: Male, Long-Evans rats were acclimated to 15% alcohol in the home-cage using an intermittent-access 2-bottle choice procedure. Next, they received Pavlovian conditioning sessions in which an auditory-conditioned stimulus (CS; 20 second white noise; 8 trials/session; variable time 240 seconds) was paired with 15% alcohol (0.3 ml/CS; 2.4 ml/session) that was delivered into a fluid port for oral ingestion. In subsequent extinction and test sessions, CS presentations occurred as before, but without alcohol. RESULTS: In experiment 1, exposure to either alcohol or water in the fluid port following extinction reinstated CS elicited port entries at test 24 hours later. In a follow-up study using the same procedure (experiment 2), reinstatement was more robustly stimulated by alcohol, compared to a familiar lemon-flavored liquid. In experiment 3, systemic alcohol injections (0, 0.5, or 1.0 g/kg, intraperitoneal) administered either 24 hours or 15 minutes before test did not reinstate CS-elicited alcohol-seeking. Importantly, enzymatic assays in experiment 4 revealed detectable levels of alcohol in the blood following oral alcohol intake or intraperitoneal injection, suggesting that a pharmacological effect was likely with either route of administration. Last, in experiment 5, a 23-day delay between extinction and test resulted in a robust spontaneous recovery of CS-elicited alcohol-seeking. CONCLUSIONS: The reinstatement and spontaneous recovery effects revealed herein provide evidence of viable new behavioral paradigms for testing interventions against relapse. PMID- 29969152 TI - Solvent-dependent inversion of circular dichroism signal in naproxen: An unusual effect! AB - The electronic circular dichroism (ECD) spectra of naproxen enantiomers were studied as a function of solvents using experimental (circular dichroism) and theoretical (time-dependent density functional theory) approaches. The (R)- and (S)-naproxen enantiomers presented an unusual inversion in their ECD signals in the presence of ethanol and water when compared with polar aprotic solvents such as acetonitrile. From a practical point of view, these findings deserve great attention because these solvents are widely used for high-performance liquid chromatography analysis in quality control of chiral pharmaceutical drugs. This is particularly relevant to naproxen because the (S)-naproxen has anti inflammatory properties, whereas (R)-naproxen is hepatotoxic. A time-dependent density functional theory computer simulation was conducted to investigate the signal inversion using the solvation model based on density, a reparameterization of polarized continuum model. Electronic circular dichroism signals of conformers were calculated by computer simulation and their contribution to the combined spectra obtained according to Boltzmann weighting. It was found that the experimentally observed ECD signal inversion can be associated with the minor or major contribution of different conformers of naproxen. PMID- 29969153 TI - Evaluation of the perceived health of caregivers of patients in mild-to-moderate stage Alzheimer's disease. AB - PURPOSE: To know the health perceived by the family caregivers of Alzheimer's disease, according to the relationship of kinship and the duration of the care in mild-to-moderate stage of dementia. DESIGN AND METHODS: Cross-sectional descriptive study in 255 caregivers. The instruments used were an ad hoc questionnaire and the Goldberg General Health Questionnaire (GHQ-28). FINDINGS: The presence of acute and chronic mental pathology has been observed. Specifically in the spouses and children, severe depression and social dysfunction, and in periods of care between 2 and 5 years, mainly anxiety and insomnia have been observed. PRACTICE IMPLICATIONS: The relationship of kinship and the duration of care must be taken into account in the planning of specific interventions in these caregivers. PMID- 29969155 TI - Clinical significance of PDEF factor expression and its relation to androgen receptor in ER- breast cancer. AB - AIMS: The mechanism of androgen receptor (AR) promoting tumour growth in oestrogen receptor-negative (ER- ) breast cancer (BC) is undetermined. Prostate derived ETS factor (PDEF) is highly restricted to the hormone-regulated tissues of epithelial cells, such as those in the prostate, breast and other tissues. It has been demonstrated that PDEF expression is associated with AR in prostate cancer. In this research, we aimed to investigate the relationship between PDEF and AR in ER- BC. METHODS AND RESULTS: We immunohistochemically evaluated the correlation between PDEF and AR expression in 246 cases of ER- invasive BC, and investigated their relationship in ER- BC cell lines. The expression of PDEF was associated with the positive expression of AR (P < 0.001) and a worse survival rate (P = 0.006). PDEF+ tumours were significantly more often AR+ (P < 0.001). AR and PDEF were more often co-expressed and the series of AR+ PDEF+ (126 of 246, 51.2%) had a poor survival rate (P = 0.046). In Cox models, PDEF expression (P = 0.028) was an independent predictor for overall survival (OS). At the cellular protein and mRNA levels, our experiments also showed a statistically significant positive correlation between PDEF and AR, and that PDEF may be regulated by AR. CONCLUSIONS: PDEF is associated with markers of bad prognosis, supporting its role as a growth promoter in ER- BC. Our findings also provide evidence that PDEF is strongly correlated with AR expression in ER- breast cancer; it may be a downstream target gene of AR and a potential prognostic factor in ER- BC. PMID- 29969154 TI - Influence of Parental Alcohol Dependence Symptoms and Parenting on Adolescent Risky Drinking and Conduct Problems: A Family Systems Perspective. AB - BACKGROUND: Parental alcohol problems are associated with adverse adolescent outcomes such as risky drinking and conduct problems. Important questions remain about the unique roles of fathers' and mothers' alcohol problems and differences and/or similarities in pathways of risk across ethnicity and gender. In this study, we used a family systems approach to consider spillover and crossover effects of fathers' and mothers' alcohol problems (number of alcohol dependence symptoms [ADS]) and parenting behaviors in relation to adolescents' risky drinking and conduct problems. METHODS: The sample included 1,282 adolescents (aged 12 to 17) and their parents from the Collaborative Study on the Genetics of Alcoholism. Parents completed the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), and adolescents completed an adolescent version of SSAGA. Data were analyzed using multivariate structural equation modeling. RESULTS: Fathers' ADS count was associated with higher adolescent risky drinking and conduct problems indirectly via disruption to fathers' and mothers' positive parenting behaviors, whereas mothers' ADS count was not associated with adolescents' risky drinking and conduct problems directly or indirectly via positive parenting behaviors. No differences in these associations were found across ethnic background and offspring gender. CONCLUSIONS: Findings highlight the importance of considering the unique roles of fathers' and mothers' ADS in influencing family processes and adolescent outcomes. PMID- 29969156 TI - Overcoming the "Valley of Death" in Medications Development for Alcohol Use Disorder. AB - As the development of novel pharmacotherapies for alcohol use disorder (AUD) has been slow, the discovery and testing of more efficacious pharmacotherapies for AUD represent a high priority research area. In fact, the transition from preclinical to clinical testing of novel compounds has been termed the "valley of death" in medications development. One key obstacle consists of the lack of an articulated set of goals for each stage of medications development. Specifically, the knowledge outputs required to make the transition from safety testing, to early efficacy detection, to confirming clinical efficacy remain unclear, and this is despite a great deal of interest and substantial financial investment in developing novel therapeutics for AUD. This qualitative critical review seeks to draw parallels and lessons from the well-established stage model for behavioral therapies research with alcohol and other substance use disorders and to apply these insights into AUD pharmacotherapy development. We argue that human laboratory models and/or pilot randomized controlled trials should serve as intermediaries in the transition from preclinical studies to large, and costly, randomized controlled efficacy trials. The relative strengths and weaknesses of pilot clinical trials versus human laboratory studies for bridging the "valley of death" are discussed and explored via a Monte Carlo data simulation study. Multiple permutations of suitable research designs informed by the behavioral therapies development model are discussed with the overall goal of promoting consilience and maximizing efficiency across all phases of clinical testing of novel AUD pharmacotherapies. PMID- 29969157 TI - Competition lifespan survival analysis in the Norwegian-Swedish Coldblooded Trotter racehorse. AB - BACKGROUND: Studies of large racing populations have established clear differences in the career profile of stallions, mares and geldings. Multiple studies have also demonstrated positive effects on racing careers for horses that commence racing at a younger age. However, the applicability of these studies to small, native racing populations is unknown and warrants investigation. OBJECTIVES: To provide summary statistics for performance outcomes for the Norwegian-Swedish Coldblooded Trotter and to document and provide evidence on the current differences in racing careers across age at first start groups, sexes and country of birth. STUDY DESIGN: Cohort study. METHODS: Performance data on the population of Norwegian-Swedish Coldblooded Trotters born between 2000 and 2009 (n = 14,548) were acquired and used to describe and compare the racing careers of this native racing breed. Career length, career starts and career earnings were evaluated. Kaplan-Meier survival curves, stratified by sex, age group and country of birth were produced for career length. A Cox proportional hazards model was fitted to assess factors influencing the hazard rate of retirement from racing. RESULTS: Log-rank test for equality of career length survival functions showed significant differences (P<0.001) across sexes, countries of birth and age at first start groups. An increased age at first start increased the hazard rate of retirement from racing. MAIN LIMITATIONS: Racing career length is influenced by many factors. While this study accounts for some of the known influences on career length, the analysis would be strengthened by the inclusion of additional information, such as trainer and reasons for retirement. CONCLUSIONS: The results of this study suggest no adverse effects to the racing of young Norwegian-Swedish Coldblooded trotters. The study also establishes significant differences in career length based on sex and identifies that these differences are the opposite of what is seen in many other horse racing breeds. The Summary is available in Spanish - see Supporting Information. PMID- 29969161 TI - Reconstruction of cranioplasty using the thoracodorsal artery perforator (TDAP) flap: A case series. AB - BACKGROUND: Complex defects resulting in ablation of the scalp, the calvaria, the dura, and the underlying brain are still challenging. These defects require cranioplasty to restore the bone cosmetic and functional roles and free-flap soft tissue reconstruction to prevent cranioplasty exposure and further infection. Different materials have been used in cranioplasty, while different free flaps have been proposed in those cases. In this article, we present a case series of cranioplasty reconstruction with thoracodorsal artery perforator flap (TDAP). PATIENTS AND METHODS: From April 2016 to January 2018, 5 patients underwent cranioplasty reconstruction using alloplastics and TDAP flap. Two patients underwent primary cranioplasty and 3 patients underwent secondary cranioplasty. The superficial temporal vessels were always dissected as recipient vessels. RESULTS: The flap sizes range from 40 to 80 cm2 (mean 57 cm2 ) and the maximum pedicle length was 12 cm (mean 10 cm). All the donor sites were closed primary with minimal morbidity. No postoperative complications were experienced. All the flaps provided stable coverage with an acceptable color match. The mean follow-up time was 4 months. CONCLUSIONS: Our data suggest that the TDAP may be employed in postcranioplasty reconstruction. The TDAP has more advantages compared to other flaps used in alloplastic reconstruction: a broad large surface, a long pedicle, and a thinner thickness. PMID- 29969159 TI - Do anticoagulation medications increase the risk of haematoma in ultrasound guided fine needle aspiration of thyroid lesions? AB - BACKGROUND: A feared complication of thyroid fine needle aspiration (FNA) is bleeding diathesis and haematoma at the biopsy site. Patients are often advised to discontinue antithrombotic/anticoagulant (AT/AC) medications prior to the procedure. The aim of this study was to examine the risk of bleeding in patients on AT/AC medications undergoing cervical ultrasound (US)-guided FNA. METHODS: A retrospective chart review of 803 patients who underwent US-guided FNA of thyroid nodules over 8 years by a single endocrine surgeon was undertaken. Clinical variables, patient demographics and use of AT/AC medications were collected and analysed. The principle outcome measures included the incidence of procedure related haematoma formation. Multivariable logistic regression was used to investigate the possible independent association between post-FNA haematoma and anticoagulation, adjusting for age, African American race, body mass index, vascularity and lesion size. RESULTS: A total of 1568 lesions were included in 803 patients. The mean age for the patients on AT/AC was 63.0 +/- 10.4 years and those not on AT/AC was 50.1 +/- 14.2 years (P < 0.001). Of those, 148 patients had 336 lesions (21%) biopsied while taking one or more daily AT/AC agent (81 patients: aspirin; 11 patients: Plavix; 17 patients: aspirin and warfarin; 30 patients: aspirin and Plavix; seven patients: rivaroxaban and aspirin; and two patients: ticagrelor and aspirin). Three patients (0.89%) in the AT/AC group compared to six patients (0.49%) not receiving AT/AC medications developed a haematoma (P = 0.41). All complications were treated conservatively and none required intervention. CONCLUSIONS: US-guided FNA of thyroid lesions can be safely performed on patients taking AT/AC including newer agents, without an increase in adverse outcomes or decreased diagnostic rate. Further larger prospective multi-institutional studies are warranted to further investigate this important finding. PMID- 29969162 TI - Mesoscopic FRET Antenna Materials by Self-Assembling Iridium(III) Complexes and BODIPY Dyes. AB - This study presents a new design of light-harvesting antenna materials using two dyes organised into mesoporous silica: an iridium(III) complex and a BODIPY derived surfactant that undergo Forster resonance energy transfer (FRET), acting, respectively, as donor and acceptor. The chemical structure of each dye determines the position taken within the micellar templates used for the synthesis of the silica host, which maintains mesopore order as shown by TEM imaging. Steady-state and time-resolved UV-visible spectroscopy revealed that incorporation of the iridium complex into the silica shields it from oxygen induced quenching and allows a degree of control over the donor-acceptor distance, yielding FRET efficiencies from 24 to 76 % and tuneable emission ranges. Such silica-based antennae show promising properties for the realisation of polychromatic sensitisers for photovoltaics and photocatalysis. PMID- 29969160 TI - A Strongly Luminescent Chromium(III) Complex Acid. AB - The synthesis, structure, reactivity, and photophysical properties of a novel acidic, luminescent chromium(III) complex [Cr(H2 tpda)2 ]3+ (23+ ) bearing the tridentate H2 tpda (2,6-bis(2-pyridylamino)pyridine) ligand are presented. Excitation of 23+ at 442 nm results in strong, long-lived NIR luminescence at 782 nm in water and in acetonitrile. X-ray diffraction analysis and IR spectroscopy reveal hydrogen-bonding interactions of the counter ions to the NH groups of 23+ in the solid state. Deprotonation of the NH groups of 23+ by using a non nucleophilic Schwesinger base in CH3 CN switches off the luminescence. Re protonation by using HClO4 restores the emission. In water, the pKa value of 23+ amounts to 8.8, yet deprotonation is not reversible in the presence of hydroxide ions. Dioxygen quenches the emission of 23+ , but to a weaker extent than expected. This is possibly due to the strong ion-pairing properties of 23+ even in solution, reducing the energy transfer efficiency to O2 . Deuteration of the NH groups of 23+ approximately doubles the quantum yield and lifetime in water, demonstrating the importance of multiphoton relaxation in these NIR emitters. PMID- 29969158 TI - Water associated with residential areas and tourist resorts is the key predictor of Asian tiger mosquito presence on a Mediterranean island. AB - The Asian tiger mosquito, Aedes albopictus (Diptera: Culicidae), is a highly invasive species and a vector of several viruses of serious concern to public health. Investigating the habitat selection of this species at small to medium scales is essential to the planning of effective prevention and control campaigns. The present group considered detailed data for this species' presence/absence collected at 228 sites on Mallorca Island (Spain) in autumn 2015, 3 years after the first detection of the species on the island. Site occupancy models accounting for false negative detections and imperfect monitoring were used to evaluate the relationships between mosquito presence and habitat variables. In the study area, mosquito presence was negatively associated with altitude, probably as a result of greater human presence at low altitudes near the coast. Moreover, the presence of Ae. albopictus was positively associated with swimming pools as a result of associated gardens, plants and sources of fresh water. These two variables were combined to predict the presence of the species across the entire island. PMID- 29969167 TI - Erratum. PMID- 29969163 TI - Stable 2D Bisthienoacenes: Synthesis, Crystal Packing, and Photophysical Properties. AB - Two novel 2D bisthienoacenes with annulated thiophene units at different positions were developed. Both 1,2- and 1,4-addition of the alpha,beta unsaturated ketone moieties lead to the major formation of four-fold alkylsilylethynyl substituted 2D heteroacenes (namely BTT-4TIPS and BTP-4TIPS). The photophysical, electrochemical properties, crystal packing structures, and charge carrier transport performances were investigated in detail. PMID- 29969165 TI - High-Resolution NMR of Folded Proteins in Hyperpolarized Physiological Solvents. AB - Hyperpolarized 2D exchange spectroscopy (HYPEX) to obtain high-resolution nuclear magnetic resonance (NMR) spectra of folded proteins under near-physiological conditions is reported. The technique is based on hyperpolarized water, which is prepared by dissolution dynamic nuclear polarization and mixed in situ in an NMR spectrometer with a protein in a physiological saline buffer at body temperature. Rapid exchange of labile protons with the hyperpolarized solvent, combined with cross-relaxation effects (NOEs), leads to boosted signal intensities for many amide 1 H-15 N correlations in the protein ubiquitin. As the introduction of hyperpolarization to the target protein is mediated via the solvent, the method is applicable to a broad spectrum of target molecules. PMID- 29969164 TI - Factor analysis and validity of the Polish version of the Peritraumatic Distress Inventory in mothers of seriously ill children. AB - AIMS AND OBJECTIVES: The purpose of this study was to evaluate and validate the Peritraumatic Distress Inventory (PDI) in mothers of severely ill children hospitalised currently or in the past within a paediatric hospital setting. BACKGROUND: Serious illness in a child causes a sense of fear in her parents, which may occur in variously manifested stress. METHODS/SETTING/PARTICIPANTS: The participants were 135 mothers of children treated in the Intensive Care Unit (ICU), Hematology & Oncology Department, and with perinatal history, who filled out Authors' Questionnaire and the Polish version of the Peritraumatic Distress Inventory. Mothers of all children except those hospitalised in the Intensive Care Unit, additionally filled out the Hospital Anxiety and Depression Scale Modified (HADS-M) and Impact of Event Scale-Revised (IES-R). RESULTS: Statistical analyses demonstrated a bifactor structure explaining 49.28% of the total variance. The first factor refers to the distress associated with the feeling of threat and somatic reactions, explaining 34.99% of the variance. The second factor, describing negative emotions, explains 14.99% of the variance. Cronbach's alpha coefficient for the whole scale, eventually consisting of 11 items, is 0.80; for the subscale Feeling of Threat and Somatic Reactions is 0.75, and Negative Emotions is 0.72. The general severity of peritraumatic distress correlates positively with the level of anxiety (rho = 0.50; p < 0.01) and depression (rho = 0.49; p < 0.01). CONCLUSIONS: Polish adaptation of the PDI appears to be a valuable tool for studying distress in parents of seriously ill children. RELEVANCE TO CLINICAL PRACTICE: All parents of hospitalised children are at risk of distress so personnel should pay attention to that and report to a clinical psychologist. PMID- 29969166 TI - Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase. AB - A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3 minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell. PMID- 29969169 TI - Kinetically Stable Bicelles with Dilution Tolerance, Size Tunability, and Thermoresponsiveness for Drug Delivery Applications. AB - Mixtures of a phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, DPPC) and a sodium-cholate-derived surfactant (SC-C5 ) at room temperature formed phospholipid bilayer fragments that were edge-stabilized by SC-C5 : so-called "bicelles". Because the bilayer melting point of DPPC (41 degrees C) is above room temperature and because SC-C5 has an exceptionally low critical micelle concentration (<0.5 mm), the bicelles are kinetically frozen at room temperature. Consequently, they exist even when the mixture is diluted to a concentration of 0.04 wt %. In addition, the lateral size of the bicelles can be fine-tuned by altering the molar ratio of DPPC to SC-C5 . On heating to ~37 degrees C, the bicelles transformed into micelles composed of DPPC and SC-C5 . By taking advantage of the dilution tolerance, size tunability, and thermoresponsiveness, we demonstrated in vitro drug delivery based on use of the bicelles as carriers, which suggests their potential utility in transdermal drug delivery. PMID- 29969171 TI - Deferential Trespassing: Looking Through and at an Intersectional Lens. AB - In this article, I comment on the prospect of integrating an intersectionality perspective into the developmental sciences. I do this by sharing impressions, insights, and questions that have emerged whilst attempting to look at and to look through an intersectionality lens. My comments focus on three main topics. First, I speculate what forms such an integration could take and argue that an integration that productively contributes to shaping developmental science into a transdisciplinary field is likely to change intersectionality research itself. I then reflect on the perceived ambiguity in terms of the unit of analysis (e.g., social systems vs. individuals) and the focus of research questions (i.e., description vs. explanation vs. intervention) in intersectionality research. Clarity and transparency in this regard is instrumental to productively identifying conceptual and methodological overlaps or intersections with other subdisciplines in developmental sciences. Finally, I highlight the importance of development being more comprehensively reflected in the conceptualizations, the research questions, and the subsequently employed methodologies in intersectionality research. I conclude with a plea for allowing our expertise to intersect to transdisciplinarily work toward creating systemic and perpetual progress in the developmental sciences-something, I believe to resonate strongly with intersectionality researchers. PMID- 29969172 TI - Use of machine learning to predict early biochemical recurrence after robot assisted prostatectomy. AB - OBJECTIVES: To train and compare machine-learning algorithms with traditional regression analysis for the prediction of early biochemical recurrence after robot-assisted prostatectomy. PATIENTS AND METHODS: A prospectively collected dataset of 338 patients who underwent robot-assisted prostatectomy for localized prostate cancer was examined. We used three supervised machine-learning algorithms and 19 different training variables (demographic, clinical, imaging and operative data) in a hypothesis-free manner to build models that could predict patients with biochemical recurrence at 1 year. We also performed traditional Cox regression analysis for comparison. RESULTS: K-nearest neighbour, logistic regression and random forest classifier were used as machine-learning models. Classic Cox regression analysis had an area under the curve (AUC) of 0.865 for the prediction of biochemical recurrence. All three of our machine learning models (K-nearest neighbour (AUC 0.903), random forest tree (AUC 0.924) and logistic regression (AUC 0.940) outperformed the conventional statistical regression model. Accuracy prediction scores for K-nearest neighbour, random forest tree and logistic regression were 0.976, 0.953 and 0.976, respectively. CONCLUSIONS: Machine-learning techniques can produce accurate disease predictability better that traditional statistical regression. These tools may prove clinically useful for the automated prediction of patients who develop early biochemical recurrence after robot-assisted prostatectomy. For these patients, appropriate individualized treatment options can improve outcomes and quality of life. PMID- 29969168 TI - Characterization of spliceogenic variants located in regions linked to high levels of alternative splicing: BRCA2 c.7976+5G > T as a case study. AB - Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976 + 5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers. We have also detected several isoforms (Delta16-18, Delta17,18, Delta18, and ?17q224 ) at different expression levels among carriers and controls. This study remarks the challenge of interpreting genetic variants when multiple alternative isoforms are present, and that caution must be taken when using in silico tools to identify potential spliceogenic variants located in GC-AG introns. PMID- 29969173 TI - gamma-, Diastereo-, and Enantioselective Addition of MEMO-Substituted Allylboron Compounds to Aldimines Catalyzed by Organoboron-Ammonium Complexes. AB - The first catalytic, broadly applicable, efficient, gamma-, diastereo-, and enantioselective method for addition of O-substituted allyl-B(pin) compounds to phosphinoylimines (MEM=methoxyethoxymethyl, pin=pinacolato) is presented. The identity of the most effective catalyst and the optimal protecting group for the organoboron reagent were determined by consideration of the steric and electronic requirements at different stages of the catalytic cycle, namely, the generation of the chiral allylboronate, the subsequent 1,3-borotropic shift, and the addition step. Aryl-, heteroaryl-, alkenyl- and alkyl-substituted vicinal phosphinoylamido MEM-ethers were thus accessed in 57-92 % yield, 89:11 to >98:2 gamma:alpha selectivity, 76:24-97:3 diastereomeric ratio, and 90:10-99:1 enantiomeric ratio. The method is scalable, and the phosphinoyl and MEM groups may be removed selectively or simultaneously. Utility is highlighted by enantioselective synthesis of an NK-1 receptor antagonist. PMID- 29969170 TI - Whole genome sequencing and mutation rate analysis of trios with paternal dioxin exposure. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human mutation rate in trios has not yet been elucidated at the whole genome level. To identify and characterize the genetic alterations in the individuals exposed to dioxin, we performed whole genome sequencing (WGS) of nine Vietnamese trios whose fathers were exposed to dioxin. In total, 846 de novo point mutations, 26 de novo insertions and deletions, 4 de novo structural variations, and 1 de novo copy number variation were identified. The number of point mutations and dioxin concentrations were positively correlated (P-value < 0.05). Considering the substitution pattern, the number of A > T/T > A mutation and the dioxin concentration was positively correlated (P-value < 0.05). Our analysis also identified one possible disease-related mutation in LAMA5 in one trio. These findings suggested that dioxin exposure might affect father genomes of trios leading to de novo mutations in their children. Further analysis with larger sample sizes would be required to better clarify mutation rates and substitution patterns in trios caused by dioxin. PMID- 29969174 TI - Perceived Subfecundity and Contraceptive Use Among Young Adult U.S. Women. AB - CONTEXT: Women who view themselves as having difficulty becoming pregnant (i.e., being subfecund) may feel that they do not need to use contraceptives to prevent unintended pregnancy. However, subfecundity perceptions are not always medically accurate and may therefore confer a false sense of protection. The extent to which perceived fecundity is related to contraceptive use is not well understood. METHODS: Multinomial logistic regression was used to investigate the relationship between perceived fecundity at age 25-30 and contraceptive use among 2,091 women from the National Longitudinal Survey of Youth 1997 cohort. RESULTS: Compared with women who considered themselves very likely to become pregnant, those who thought that they were only somewhat likely and those who viewed themselves as not very likely to do so had significantly higher risks of not using contraceptives within the next year (risk ratios, 1.9 and 2.4, respectively). Results were similar in analyses controlling for either a medical diagnosis of infertility, a history of multiple miscarriages or stillbirths, or absence of pregnancy following at least six months of unprotected sex, suggesting that perceived subfecundity operates independently of experienced subfecundity. CONCLUSION: Because few studies have investigated fecundity perceptions in their own right, more research is needed to understand how women evaluate their fecundity and to integrate these perceptions into broader frameworks describing women's perception of pregnancy risk. Such work may help identify potential levers to improve contraceptive use. PMID- 29969175 TI - Rare RELN variants affect Reelin-DAB1 signal transduction in autism spectrum disorder. AB - The Reelin-DAB1 signaling pathway plays a crucial role in regulating neuronal migration and synapse function. Although many rare heterozygous variants in the Reelin gene (RELN) have been identified in patients with autism spectrum disorder (ASD), most variants are still of unknown clinical significance. Also, genetic data suggest that heterozygous variants in RELN alone appear to be insufficient to cause ASD. Here, we describe the identification and functional characterization of rare compound heterozygous missense variants in RELN in a patient with ASD in whom we have previously reported hyperfunctional mTORC1 signaling of yet unknown etiology. Using iPSC-derived neural progenitor cells (NPCs) from this patient, we provide experimental evidence that the identified variants are deleterious and lead to diminished Reelin secretion and impaired Reelin-DAB1 signal transduction. Also, our results suggest that mTORC1 pathway overactivation may function as a second hit event contributing to downregulation of the Reelin-DAB1 cascade in patient-derived NPCs, and that inhibition of mTORC1 by rapamycin attenuates Reelin-DAB1 signaling impairment. Taken together, our findings point to an abnormal interplay between Reelin-DAB1 and mTORC1 networks in nonsyndromic ASD. PMID- 29969177 TI - Enzymatic Control of the Conformational Landscape of Self-Assembling Peptides. AB - Post-translational modification is a common mechanism to affect conformational change in proteins, which in turn, regulates function. Herein, this principle is expanded to instruct the formation of supramolecular assemblies by controlling the conformational bias of self-assembling peptides. Biophysical and mechanical studies show that an engineered phosphorylation/dephosphorylation couple can affectively modulate the folding of amphiphilic peptides into a conformation necessary for the formation of well-defined fibrillar networks. Negative design principles based on the incompatibility of hosting residue side-chain point charge within hydrophobic environments proved key to inhibiting the peptide's ability to adopt its low energy fold in the assembled state. Dephosphorylation relieves this restriction, lowers the energy barrier between unfolded and folded peptide, and allows the formation of self-assembled fibrils that contain the folded conformer, thus ultimately enabling the formation of a cytocompatible hydrogel material. PMID- 29969178 TI - Integrating an Intersectionality Lens in Theory and Research in Developmental Science. AB - This article discusses key issues in the integration of an intersectionality lens in the developmental sciences and introduces a peer-reviewed thematic journal issue on this topic. We begin by briefly situating the importance of an intersectionality lens within the changing demographics and sociopolitical history in the United States, and within developmental science as a field. We provide a brief overview of recommendations on responsible use of intersectionality in developmental science. We then introduce contributions contained within this volume, and how each contributor grappled with the following question: How can an intersectionality perspective inform the developmental phenomena of interest and particular developmental theories you draw upon in your area of research? We end by noting that these contributions offer a collection of manuscripts that aim to increase dialogue among developmental scientists on ways to productively integrate an intersectionality lens in developmental science. PMID- 29969180 TI - CRISPR/Cas9-mediated knockout of six glycosyltransferase genes in Nicotiana benthamiana for the production of recombinant proteins lacking beta-1,2-xylose and core alpha-1,3-fucose. AB - Plants offer fast, flexible and easily scalable alternative platforms for the production of pharmaceutical proteins, but differences between plant and mammalian N-linked glycans, including the presence of beta-1,2-xylose and core alpha-1,3-fucose residues in plants, can affect the activity, potency and immunogenicity of plant-derived proteins. Nicotiana benthamiana is widely used for the transient expression of recombinant proteins so it is desirable to modify the endogenous N-glycosylation machinery to allow the synthesis of complex N glycans lacking beta-1,2-xylose and core alpha-1,3-fucose. Here, we used multiplex CRISPR/Cas9 genome editing to generate N. benthamiana production lines deficient in plant-specific alpha-1,3-fucosyltransferase and beta-1,2 xylosyltransferase activity, reflecting the mutation of six different genes. We confirmed the functional gene knockouts by Sanger sequencing and mass spectrometry-based N-glycan analysis of endogenous proteins and the recombinant monoclonal antibody 2G12. Furthermore, we compared the CD64-binding affinity of 2G12 glycovariants produced in wild-type N. benthamiana, the newly generated FX KO line, and Chinese hamster ovary (CHO) cells, confirming that the glyco engineered antibody performed as well as its CHO-produced counterpart. PMID- 29969179 TI - Real-world multicentre experience of the pathological features of colonic ischaemia and their relationship to symptom duration, disease distribution and clinical outcome. AB - AIM: To determine the pathological features of colonic ischaemia (CI) and their relationship to symptom duration, disease distribution and clinical outcome in a real-world, clinical setting. METHOD: A retrospective, multicentre chart review was performed in patients diagnosed with CI at Montefiore Medical Center (January 2005 to July 2015), and Yale-New Haven Hospital (January 2005 to June 2010). Patients were included if clinical presentation, colonoscopic findings and colonic pathology were all consistent with CI. RESULTS: Six hundred and sixteen patients with pathologically proven CI were included. Common pathological findings included inflammation (51.1%), ulceration (38.2%), fibrosis (26.0%) and necrosis (20.4%). Infarction and ghost cells were seen in 1.6% and 0.2% of cases, respectively. There was a significant relationship between symptom duration and hyalinization of the lamina propria (P = 0.05) and cryptitis/crypt abscesses (P = 0.01). Patients with isolated right CI (IRCI) were more likely than patients with isolated left CI (ILCI) to exhibit necrosis (P < 0.01), cryptitis/crypt abscess (P < 0.01) and inflammation (P = 0.03). Patients with poor outcomes were more likely to exhibit necrosis (P < 0.01) and capillary fibrin thrombi (P < 0.01) and less likely to exhibit fibrosis (P < 0.01) and epithelial changes (P < 0.01). CONCLUSION: CI is accompanied by a broad spectrum of pathological findings. The traditional pathognomonic findings of CI are rare and cannot be relied upon to exclude the diagnosis. Patients with IRCI and/or poor outcomes were more likely to have pathological findings of necrosis than patients who had ILCI and/or nonpoor outcomes. PMID- 29969183 TI - Impact of Cationic Charge Density and PEGylated Poly(Amino Acid) Tercopolymer Architecture on Their Use as Gene Delivery Vehicles. Part 2: DNA Protection, Stability, Cytotoxicity, and Transfection Efficiency. AB - The impact of the molecular architecture on the transfection efficiency of PEGylated poly(amino acid) block copolymers was investigated for PEG-b-p(l-Lys)x b-p(l-Leu)y , PEG-b-p(l-Leu)x -b-p(l-Lys)y , and PEG-b-p((l-Leu)x -co-(l-Lys)y ). The block lengths of p(l-Lys) and p(l-Leu) were varied between 10, 20, and 40; and 10 and 20, respectively, to study the influence of the ionic/hydrophobic balance. The results show that ABC triblock copolymers form smaller and more stable polyplexes with plasmid DNA than AB diblock copolymers-as verified by long term aggregation and ethidium bromide exclusion studies-protect the DNA more effectively against nucleases, and provide better transfection efficiencies, as indicated by total protein as well as luciferase expression. More detailed studies revealed that triblock copolymers with p(l-Leu) forming the C-block were most efficient in DNA complexation with a 2.3 times higher transfection rate. Furthermore, increasing the cationic character by increasing the p(l-Lys) chain length led to up to 25% higher transfection but at the same time induced some cytotoxicity. Diblock copolymers, where the amino acid-building blocks exist as a random copolymer, bind more loosely with DNA leading to less compact and less stable aggregates with lower transfection efficiencies. PMID- 29969182 TI - Premarket Approval Through the 510(k) Process: Lessons from the Translation Process of Magnetic Resonance Elastography. PMID- 29969176 TI - UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma. AB - Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome-wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case-control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV-related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA-seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA-seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV-related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1. PMID- 29969184 TI - Composite-Structure Material Design for High-Energy Lithium Storage. AB - High-energy storage devices are in demand for the rapid development of modern society. Until now, many kinds of energy storage devices, such as lithium-ion batteries (LIBs), sodium-ion batteries (NIBs), and so on, have been developed in the past 30 years. However, most of the commercially exploited and studied active electrode materials of these energy storage devices possess a single phase with low reversible capacity or unsatisfied cycle stability. Continuous and extensive research efforts are made to develop alternative materials with a higher specific energy density and long cycle life by element doping or surface modification. A novel strategy of forming composite-structure electrode materials by introducing structure units has attracted great attention in recent years. Herein, based on previous publications on these composite-structure materials, some important scientific points focusing on the design of composite-structure materials for better electrochemical performances reveal the distinction of composite structures based on average and local structure analysis methods, and an understanding of the relationship between these interior composite structures and their electrochemical performances is discussed thoroughly. The lithiation/delithiation mechanism and the remaining challenges and perspectives for composite-structure electrode materials are also elaborated. PMID- 29969187 TI - Emerging relevance of circadian rhythms in headaches and neuropathic pain. AB - Circadian rhythms of physiology are the keys to health and fitness, as dysregulation, by genetic mutations or environmental factors, increases disease risk and aggravates progression. Molecular and physiological studies have shed important light on an intrinsic clock that drives circadian rhythms and serves essential roles in metabolic homoeostasis, organ physiology and brain functions. One exciting new area in circadian research is pain, including headache and neuropathic pain for which new mechanistic insights have recently emerged. For example, cluster headache is an intermittent pain disorder with an exceedingly precise circadian timing, and preliminary evidence is emerging linking several circadian components (eg, Clock and Nr1d1) with the disease. In this review, we first discuss the broad metabolic and physiological relevance of the circadian timing system. We then provide a detailed review of the circadian relevance in pain disease and physiology, including cluster headache, migraine, hypnic headache and neuropathic pain. Finally, we describe potential therapeutic implications, including existing pain medicines and novel clock-modulating compounds. The physiological basis for the circadian rhythms in pain is an exciting new area of research with profound basic and translational impact. PMID- 29969192 TI - Imaging biomarkers in oncology: Basics and application to MRI. AB - : Cancer remains a global killer alongside cardiovascular disease. A better understanding of cancer biology has transformed its management with an increasing emphasis on a personalized approach, so-called "precision cancer medicine." Imaging has a key role to play in the management of cancer patients. Imaging biomarkers that objectively inform on tumor biology, the tumor environment, and tumor changes in response to an intervention complement genomic and molecular diagnostics. In this review we describe the key principles for imaging biomarker development and discuss the current status with respect to magnetic resonance imaging (MRI). LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5 J. Magn. Reson. Imaging 2018;48:13-26. PMID- 29969194 TI - Phenomenology and Intersectionality: Using PVEST as a Frame for Adolescent Identity Formation Amid Intersecting Ecological Systems of Inequality. AB - Beginning with Erikson, identity formation has often been framed as a salient developmental challenge for adolescents. Recent theoretical advances situate this identity formation as a central life course process involving ecological and social context associated with diverse experiences and characteristics. Some scholars have employed intersectionality as a call to study experiences of individuals who belong to multiple marginalized groups. In this article, we argue that developmental research would be served by a return to Crenshaw's formulation of intersectionality-that is, that marginalization involves systematic inequality and interlocking systems of oppression-as integrated with Spencer's phenomenological variant of ecological systems theory (PVEST). The latter was formulated as a needed critique of traditional developmental theories that generally ignored the problem of inequality as experienced through multiple layers of navigated contexts. Problematic ecological contexts can be understood through intersectionality's forefronting of complex structures and social positionality-that power dynamics and interconnected systems lead to differential outcomes within socially constructed categories like class, race, and gender. PVEST complements these insights through an attentiveness to phenomenological interpretations and responses-the "how" and "why" of the process. Therefore, we argue that adolescent outcomes should be understood both from the top and the bottom, including how youth interpret and cope with their vulnerability, based upon experiences of interlocking systems of oppression. The consequent synthesis should bolster the identification of pillar-like supports needed by youth and which afford effective assistance across respective socialization contexts. PMID- 29969186 TI - Azopyridine-Containing Three-arm Star Compounds with Aggregation-induced Fluorescence. AB - Three-arm star azopyridinium salts self-organize into various morphologies in water/organic mixed solvents. Interesting AIE and self-assembling features are observed due to the strong interaction of the azopyridinium moieties with the highly polar H2 O molecules causing the salts to aggregate, which restricts the molecular motion and induces the fluorescence. PMID- 29969195 TI - Monocyte and Neutrophil Isolation, Migration, and Phagocytosis Assays. AB - This article describes methods for isolating mouse monocytes and neutrophils, as well as in vitro protocols for measuring cell phagocytosis, migration, and polarization. The method employed here for the isolation of naive phagocytes overcomes many of the difficulties previously encountered concerning phagocyte activation. Three in vitro protocols are provided for the analysis of cell migration, one requiring no specialized equipment, one requiring a modified Boyden chamber, and the other employing a flow chamber, which measures cell adhesion, rolling, and migration. Three in vitro protocols to examine phagocytosis have been included in this updated version. Finally, a method is provided for imaging polarized cells by confocal microscopy. (c) 2018 by John Wiley & Sons, Inc. PMID- 29969185 TI - Promises and Pitfalls in the Integration of Intersectionality with Development Science. AB - In this commentary, we use the manuscripts in this volume as source material from which to highlight what we view as critical issues in integrating intersectionality with developmental science. In reading and meditating on the manuscripts, we abstracted two key themes that were evident, to some extent, in all of the manuscripts: (1) the disciplinary use of intersectionality as a theory and (2) the nature of development for an intersectional developmental science. These two themes reflect the current state of the integration of intersectionality with developmental science, in that they represent both areas of strength and success, but also areas of challenge and weakness. PMID- 29969188 TI - DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation. AB - DEPTOR is an evolutionarily conserved cell-intrinsic binding partner of mTOR that functions as a negative regulator of signaling responses. In this study, we show that DEPTOR is expressed within CD4+ T cells, and we observed that its relative level of expression modulates differentiation as well as glucose utilization within CD4+ T effectors in vitro. Using knock-in mice, we also find that induced expression of DEPTOR within CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, and increases survival and suppressive function. In vivo, fully MHC mismatched cardiac allograft survival is significantly prolonged in knock-in recipients and sustained recipient expression of DEPTOR in combination with costimulatory blockade induces long-term graft survival. Furthermore, we show that the induced expression of DEPTOR in CD4+ T effectors fails to inhibit acute allograft rejection. Rather, prolonged survival is dominantly mediated via induced expression and function of DEPTOR within recipient CD4+ T regulatory cells. These collective findings identify DEPTOR as a novel protein that functions in CD4+ T cells to augment immunoregulation in vitro and in vivo. PMID- 29969191 TI - Guidelines for qualitative/subjective research image assessments. PMID- 29969189 TI - Rapid Optimization of Reaction Conditions Based on Comprehensive Reaction Analysis Using a Continuous Flow Microwave Reactor. AB - Generally, the flow method has the advantage of a precise control over the reaction parameters and a facile modification of the reaction conditions, while a continuous flow microwave reactor allows for the quick optimization of reaction conditions owing to the rapid uniform heating. In this study, we developed a "9+4+1 method" to optimize reaction conditions based on comprehensive reaction analysis using a flow microwave reactor. The proposed method is expected to contribute to the synthesis of various fine and bulk chemicals by reducing cost and wastage, and by conserving time. PMID- 29969197 TI - Contents: J. Sep. Science 22'15. PMID- 29969196 TI - New editor on the block. PMID- 29969198 TI - Contents: J. Sep. Science 22'15. PMID- 29969199 TI - Contents: J. Sep. Science 18'15. PMID- 29969200 TI - Contents: J. Sep. Science 18'15. PMID- 29969193 TI - Applications of PET-MRI in musculoskeletal disease. AB - : New integrated PET-MRI systems potentially provide a complete imaging modality for diagnosis and evaluation of musculoskeletal disease. MRI is able to provide excellent high-resolution morphologic information with multiple contrast mechanisms that has made it the imaging modality of choice in evaluation of many musculoskeletal disorders. PET offers incomparable abilities to provide quantitative information about molecular and physiologic changes that often precede structural and biochemical changes. In combination, hybrid PET-MRI can enhance imaging of musculoskeletal disorders through early detection of disease as well as improved diagnostic sensitivity and specificity. The purpose of this article is to review emerging applications of PET-MRI in musculoskeletal disease. Both clinical applications of malignant musculoskeletal disease as well as new opportunities to incorporate the molecular capabilities of nuclear imaging into studies of nononcologic musculoskeletal disease are discussed. Lastly, we discuss some of the technical considerations and challenges of PET-MRI as they specifically relate to musculoskeletal disease. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3 J. Magn. Reson. Imaging 2018;48:27-47. PMID- 29969203 TI - Emergency management of burns: part 2. AB - Infrequent presentation of this patient group to emergency departments can cause stress and anxiety to front-line clinicians when they are faced with patients with a traumatic burn injury. Assessment relies on accurate evaluation of burn aetiology, size and depth, and initial management is directly responsible for patients' outcomes and quality of life. This is the second article in a two-part series that gives an overview of the minimum standard of care in burns first aid, and highlights the likely challenges in assessment of burn depth and size. The aim of the two articles is to enhance emergency clinicians' knowledge and confidence in burn management, and to build awareness of the life-changing implications of the initial clinical interventions in burn care. PMID- 29969204 TI - Reimbursement of Qualifying Adoption Expenses for Certain Veterans. Interim final rule. AB - The Department of Veterans Affairs (VA) amends its regulation to provide for reimbursement of qualifying adoption expenses incurred by a veteran with a service-connected disability that results in the inability of the veteran to procreate without the use of fertility treatment. Under the Continuing Appropriations and Military Construction, Veterans Affairs, and Related Agencies Appropriations Act, 2017, and Zika Response and Preparedness Act, VA may use funds appropriated or otherwise made available to VA for the "Medical Services" account to provide adoption reimbursement to these veterans. Under the law, reimbursement may be for the adoption-related expenses for an adoption that is finalized after the date of the enactment of this Act under the same terms as apply under the adoption reimbursement program of the Department of Defense (DoD), as authorized in DoD Instruction 1341.09, including the reimbursement limits and requirements set forth in such instruction. This rulemaking implements the new adoption reimbursement benefit for covered veterans. PMID- 29969201 TI - Aggregation-Induced Emission Luminogens: Union Is Strength, Gathering Illuminates Healthcare. AB - The rapid development of healthcare techniques encourages the emergence of new molecular imaging agents and modalities. Fluorescence imaging that enables precise monitoring and detection of biological processes/diseases is extensively investigated as this imaging technique has strengths in terms of high sensitivity, excellent temporal resolution, low cost, and good safety. Aggregation-induced emission luminogens (AIEgens) have recently emerged as a new class of emitters that possess several notable features, such as high brightness, large Stokes shift, marked photostability, good biocompatibility, and so on. So far, AIEgens are widely explored and exhibit superb performance in the area of biomedicine and life sciences. Herein, this review summarizes and discusses the recent investigations of AIEgens for in vivo diagnosis and therapy including long term tracking, 3D angiography, multimodality imaging, disease theranostics, and activatable sensing. Collectively, these results reveal that AIEgens are of great promise for in vivo biomedical applications. It is hoped that this review will lead to new insights into the development of advanced healthcare materials. PMID- 29969206 TI - Medical Devices; Exemption From Premarket Notification; Class II Devices; Over the-Counter Denture Repair Kit. Final order. AB - The Food and Drug Administration (FDA or Agency) is publishing an order granting a petition requesting exemption from premarket notification requirements for over the-counter (OTC) denture repair kits (Product Code EBO). These devices consist of material, such as a resin monomer system of powder and liquid glues, which is intended to be applied permanently to a denture to mend cracks or breaks. This order exempts OTC denture repair kits, class II devices, from premarket notification (510(k)). This exemption from 510(k) is immediately in effect for OTC denture repair kits. FDA is publishing this order in accordance with the section of the Federal Food, Drug, and Cosmetic Act (FD&C Act) permitting the exemption of a device from the requirement to submit a 510(k). PMID- 29969207 TI - Medicare Program; Prior Authorization Process for Certain Durable Medical Equipment, Prosthetics, Orthotics, and Supplies (DMEPOS) Items; Update tothe Master List of Items Frequently Subject to Unnecessary Utilization. Master list deletions. AB - This document announces the deletion of four Healthcare Common Procedure Coding System (HCPCS) codes from the Master List of Items Frequently Subject to Unnecessary Utilization that could be potentially subject to Prior Authorization as a condition of payment. PMID- 29969209 TI - Evaluation of pretreatment with Cetrotide in an antagonist protocol for patients with PCOS undergoing IVF/ICSI cycles: a randomized clinical trial. AB - OBJECTIVE: This study aimed to evaluate the effect of three days of GnRH antagonist pretreatment on the pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) on GnRH antagonist protocols for IVF/ICSI. METHODS: Fifty women with PCOS in the control group received conventional antagonist protocols, starting on day 2 of the cycle. In the pretreatment group (n=38), a GnRH antagonist was administered from day 2 of the menstrual cycle for three days. RESULTS: Controlled ovarian stimulation (COS) duration and gonadotropin dosages were similar in both groups. The number of metaphase II (MII) oocytes, 2PN oocytes, embryos, along with implantation and clinical pregnancy rates, were higher in the pretreatment group when compared with controls, although the increment was not significant (P value >=0.05). The chemical pregnancy rate was significantly higher in the pretreatment group. The rate of OHSS was significantly lower in the pretreatment than in the control group. CONCLUSION: Women with PCOS offered early follicular phase GnRH antagonist pretreatment for three consecutive days had significantly fewer cases of OHSS and higher chemical pregnancy rates. There were trends toward greater numbers of MII oocytes, 2PN oocytes, and embryos, and higher clinical pregnancy rates in the pretreatment group. PMID- 29969181 TI - Infusing the Study of Social Responsibilities with an Intersectional Approach. AB - Social responsibilities are a central component of adolescents' and young adults' development, particularly for those from immigrant backgrounds. Social responsibility-a sense of responsibility and duty that extends beyond the self (Wray-Lake & Syvertsen, 2011) includes both family obligations (Fuligni, 2001; 2007) and community engagement (Jensen, 2008; Lerner et al., 2002). What is often missing, however, are the ways in which social identities and social inequality shape young adult's development of social responsibilities. An intersectional perspective (Crenshaw, 1989; Cole, 2009) is particularly well-suited to do so. Therefore, this manuscript discusses the ways in which an intersectional approach can augment studies of social responsibilities, highlights progress and challenges in the field, and outlines future directions. The majority of extant literature focuses on "single-axis" (Bowleg, 2008) static demographic features such as ethnic group differences in values of social responsibilities. An intersectional approach could more meaningfully attend to the ways in which ethnicity, sexual orientation, gender, SES, and immigration status come together to shape experiences of social responsibilities. In addition, taking an intersectional approach can provide the tools necessary to understand how social inequality shapes opportunities and necessity for social responsibilities. Future directions for the field are discussed including design, methodological, and analytic choices in conducting future work. PMID- 29969224 TI - Application of an A-A'-A-Containing Acceptor Polymer in Sequentially Deposited All-Polymer Solar Cells. AB - PNNT has been prepared as a polymeric electron acceptor for organic solar cells. The polymer has an A-A'-A acceptor motif linked alternatively with thiophene and vinyl moieties. The A'-unit is a naphthalene diimide, while the A groups are thiazoles. PNNT films were found to have an estimated electron affinity of ~4.3 eV and an electron mobility of the order of 10-4 cm2 V-1 s-1. Its relatively low solubility in common chlorinated solvents at ambient temperature allowed the manufacture of sequentially deposited (SD) devices, which were found to have significantly higher efficiency than that of bulk heterojunction (BHJ) solar cells containing the same materials. Grazing-incidence wide-angle X-ray scattering measurements indicated that the SD films retained the ordering of the individual polymers to a greater extent compared to the BHJ films. The best SD devices were found to have a power conversion efficiency of up to 4.5%, with stable performance under thermal stress. PMID- 29969205 TI - Medical Devices; General and Plastic Surgery Devices; Classification of the Extracorporeal Shock Wave Device for Treatment of Chronic Wounds. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the extracorporeal shock wave device for treatment of chronic wounds into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the extracorporeal shock wave device for treatment of chronic wounds' classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29969225 TI - Conductive Graphene-Melamine Sponge Prepared via Microwave Irradiation. AB - A conductive graphene-melamine sponge (MS) prepared via microwave irradiation is reported in this paper. Graphene oxide supported on the MS was prereduced first at 100 degrees C and then further reduced in a household microwave oven at over 1000 degrees C. It was surprising to find that graphene oxide on the MS was reduced perfectly while the three-dimensional structure of the MS was kept well after high-temperature reduction via microwave irradiation. Slight pyrolysis of MS was also found during 5 s microwave irradiation, resulting in nitrogen generation from the pyrolysis of the MS being doped into graphene, which could benefit the electric conductivity of the prepared graphene-MS. The electric conductivity of the prepared graphene-MS is about 0.12-1.0 S/m because of the high reduction degree of graphene oxide and nitrogen doping. On the other hand, different from the pure MS, the newly developed conductive graphene-MS possesses superhydrophobic and superoleophilic properties. Overall, the newly developed conductive graphene-MS contained 94.3 wt % MS and 5.7 wt % N-doped graphene and is a cost-effective material with good elasticity, high conductivity, superhydrophobicity, and superoleophilicity. PMID- 29969226 TI - Vascular Interventional Radiology-Guided Photothermal Therapy of Colorectal Cancer Liver Metastasis with Theranostic Gold Nanorods. AB - We report sub-100 nm optical/magnetic resonance (MR)/X-ray contrast-bearing theranostic nanoparticles (TNPs) for interventional image-guided photothermal therapy (PTT) of solid tumors. TNPs were composed of Au@Gd2O3:Ln (Ln = Yb/Er) with X-ray contrast (~486 HU; 1014 NPs/mL, 0.167 nM) and MR contrast (~1.1 * 108 mM-1 S-1 at 9.4 T field strength). Although TNPs are deposited in tumors following systemic administration via enhanced permeation and retention effect, the delivered dose to tumors is typically low; this can adversely impact the efficacy of PTT. To overcome this limitation, we investigated the feasibility of site-selective hepatic image-guided delivery of TNPs in rats bearing colorectal liver metastasis (CRLM). The mesenteric vein of tumor-bearing rats was catheterized, and TNPs were infused into the liver by accessing the portal vein for site-selective delivery. The uptake of TNPs with hepatic delivery was compared with systemic administration. MR imaging confirmed that delivery via the hepatic portal vein can double the CRLM tumor-to-liver contrast compared with systemic administration. Photothermal ablation was performed by inserting a 100 MUm fiber-optic carrying 808 nm light via a JB1, 3-French catheter for 3 min under DynaCT image guidance. Histological analysis revealed that the thermal damage was largely confined to the tumor region with minimal damage to the adjacent liver tissue. Transmission electron microscopy imaging validated the stability of core-shell structure of TNPs in vivo pre- and post-PTT. TNPs comprising Gd-shell-coated Au nanorods can be effectively employed for the site directed PTT of CRLM by leveraging interventional radiology methods. PMID- 29969227 TI - Glucose-Responsive Metal-Organic-Framework Nanoparticles Act as "Smart" Sense-and Treat Carriers. AB - Zeolitic Zn2+-imidazolate cross-linked framework nanoparticles, ZIF-8 NMOFs, are used as "smart" glucose-responsive carriers for the controlled release of drugs. The ZIF-8 NMOFs are loaded with the respective drug and glucose oxidase (GOx), and the GOx-mediated aerobic oxidation of glucose yields gluconic acid and H2O2. The acidification of the NMOFs' microenvironment leads to the degradation of the nanoparticles and the release of the loaded drugs. In one sense-and-treat system, GOx and insulin are loaded in the NMOFs. In the presence of glucose, the nanoparticles are unlocked, resulting in the release of insulin. The release of insulin is controlled by the concentration of glucose. In the second sense-and treat system, the NMOFs are loaded with the antivascular endothelial growth factor aptamer (VEGF aptamer) and GOx. In the presence of glucose, the ZIF-8 NMOFs are degraded, leading to the release of the VEGF aptamer, which acts as a potential inhibitor of the angiogenetic regeneration of blood vessels by VEGF. As calcination of the VEGF-generated blood vessels leads to blindness of diabetic patients, the functional NMOFs might act as "smart" materials for the treatment of macular diseases. The potential cytotoxicity of the NMOFs originated from the GOx-generated H2O2 is resolved by the co-immobilization of the H2O2-scavanger catalase in the NMOFs. PMID- 29969228 TI - Facilitated Transport of CO2 Through the Transparent and Flexible Cellulose Membrane Promoted by Fixed-Site Carrier. AB - Facilitated transport cellulose membranes with different zinc ion loadings are fabricated via a facile and green solvent system (zinc chloride/calcium chloride solution). Zn2+ ions lower the pristine hydrogen bonds that normally reinforce the cellulose chains, and Ca2+ ions facilitate interactions among the Zn cellulose chains to form nanofibrils. The strategy provides an effective route to immobilize zinc species into membrane matrix and constructs facilitated transport pathway for CO2 molecules. The self-standing membranes are transparent, flexible and demonstrate ultraselective CO2 permeation. The optimum separation performance is achieved over CM-0 with the highest zinc content (22.2%), and it exhibits a CO2 permeability of 155.0 Barrer, with selectivity ratios of 27.2 (CO2/N2) and 100.6 (CO2/O2). The excellent separation performance is assigned to the pi complexation mechanism between Zn2+ and CO2. PMID- 29969229 TI - Molecular Approaches To Address the Challenges of RNA Analysis in Complex Matrices. AB - We present on a design change and addition of an internal polyethylene glycol (PEG) spacer to an existing biosensor. There were two reasons for changing the sensor design. The first was to increase the stability of the biosensor to avoid binding off-analytes with single nucleotide polymorphisms. The second was to prevent sensor degradation by nucleases. The biosensor, designed for detection of short noncoding RNA strands, is composed of Reporter and Probe nucleic acid strands that form a partially complementary duplex. The internal PEG was added to the Reporter, and subsequently diminished false negatives that resulted from off oligonucleotide binding. Furthermore, the PEG eliminated degradation of the sensor by DNase1 endonuclease. Currently, in situ and crude cell lysate RNA analysis is hindered by nonspecific interactions and degradation by endogenous nucleases. Together, the design changes presented here mitigate these matrix effects and allow for robust RNA analysis in complex media. PMID- 29969231 TI - Creating a Mass Spectral Reference Library for Oligosaccharides in Human Milk. AB - We report the development and availability of a mass spectral reference library for oligosaccharides in human milk. This represents a new variety of spectral library that includes consensus spectra of compounds annotated through various data analysis methods, a concept that can be extended to other varieties of biological fluids. Oligosaccharides from the NIST Standard Reference Material (SRM) 1953, composed of human milk pooled from 100 breastfeeding mothers, were identified and characterized using hydrophilic interaction liquid chromatography electrospray ionization tandem mass spectrometry (HILIC-ESI-MS/MS) and the NIST 17 Tandem MS Library. Consensus reference spectra were generated, incorporated into a searchable library, and matched using the newly developed hybrid search algorithm to elucidate unknown oligosaccharides. The NIST hybrid search program facilitates the structural assignment of complex oligosaccharides especially when reference standards are not commercially available. High accuracy mass measurement for precursor and product ions, as well as the relatively high MS/MS signal intensities of various oligosaccharide precursors with Fourier transform ion trap (FT-IT) and higher energy dissociation (HCD) fragmentation techniques, enabled the assignment of multiple free and underivatized fucosyllacto- and sialyllacto-oligosaccharide spectra. Neutral and sialylated isomeric oligosaccharides have distinct retention times, allowing the identification of 74 oligosaccharides in the reference material. This collection of newly characterized spectra based on a searchable, reference MS library of annotated oligosaccharides can be applied to analyze similar compounds in other types of milk or any biological fluid containing milk oligosaccharides. PMID- 29969230 TI - Tracking Metal Electrodeposition Dynamics from Nucleation and Growth of a Single Atom to a Crystalline Nanoparticle. AB - In electrodeposition the key challenge is to obtain better control over nanostructure morphology. Currently, a lack of understanding exists concerning the initial stages of nucleation and growth, which ultimately impact the physicochemical properties of the resulting entities. Using identical location scanning transmission electron microscopy (STEM), with boron-doped diamond (BDD) serving as both an electron-transparent TEM substrate and electrode, we follow this process, from the formation of an individual metal atom through to a crystalline metal nanoparticle, under potential pulsed conditions. In doing so, we reveal the importance of electrochemically driven atom transport, atom cluster formation, cluster progression to a nanoparticle, and the mechanism by which neighboring particles interact during growth. Such information will help formulate improved nucleation and growth models and promote wider uptake of electrodeposited structures in a wide range of societally important applications. This type of measurement is possible in the TEM because the BDD possesses inherent stability, has an extremely high thermal conductivity, is electron beam transparent, is free from contamination, and is robust enough for multiple deposition and imaging cycles. Moreover, the platform can be operated under conditions such that we have confidence that the dynamic atom events we image are truly due to electrochemically driven deposition and no other factors, such as electron-beam-induced movement. PMID- 29969232 TI - Measuring Aerosol Phase Changes and Hygroscopicity with a Microresonator Mass Sensor. AB - The interaction between atmospheric aerosol particles and water vapor influences aerosol size, phase, and composition, parameters which critically influence their impacts in the atmosphere. Methods to accurately measure aerosol water uptake for a wide range of particle types are therefore merited. We present here a new method for characterizing aerosol hygroscopicity, an impaction stage containing a microelectromechanical systems (MEMS) microresonator. We find that deliquescence and efflorescence relative humidities (RHs) of sodium chloride and ammonium sulfate are easily diagnosed via changes in resonant frequency and peak sharpness. These agree well with literature values and thermodynamic models. Furthermore, we demonstrate that, unlike other resonator-based techniques, full hygroscopic growth curves can be derived, including for an inorganic-organic mixture (sodium chloride and malonic acid) which remains liquid at all RHs. The response of the microresonator frequency to temperature and particle mechanical properties and the resulting limitations when measuring hygroscopicity are discussed. MEMS resonators show great potential as miniaturized ambient aerosol mass monitors, and future work will consider the applicability of our approach to complex ambient samples. The technique also offers an alternative to established methods for accurate thermodynamic measurements in the laboratory. PMID- 29969234 TI - Identification of Isomers by Multidimensional Isotopic Shifts in High-Field Ion Mobility Spectra. AB - Nearly all molecules incorporate elements with stable isotopes. The resulting isotopologue envelopes in mass spectra tell the exact stoichiometry but nothing about the geometry. Chromatography and electrophoresis at high resolution also can distinguish isotopologues, again without revealing structural information. In high-definition differential ion mobility (FAIMS) spectra, these envelopes universally split in a structure-specific manner, providing a new general approach to isomer delineation. Here, we show that the peak shifts from instances of the same isotope are equal and can be averaged into characteristic elemental shifts, namely 13C and 37Cl for dichloroanilines (DCA). Matrices of these shifts, including the gas composition dimension, are unique to the structure. Hence, all six DCA isomers (with four making two unresolved pairs) are readily delineated in the 13C/37Cl maps with He/CO2 buffer gases. Mixtures of coeluting isomers are also distinguished from pure components. PMID- 29969233 TI - Photocatalytic CO2 Transformation to CH4 by Ag/Pd Bimetals Supported on N-Doped TiO2 Nanosheet. AB - To develop photocatalysts with desirable compositions and structures for improving the efficiency and selectivity of CO2 conversion to CH4 under mild conditions is of great importance. Here, we design an effective photocatalyst of bimetal (Ag/Pd) nanoalloys supported on nitrogen-doped TiO2 nanosheet for CO2 conversion. Such a novel photocatalyst combines multiple advantages of abundant Ti3+ ions, oxygen vacancies, and substitutional nitrogen that are favorable for catalyzing CO2 reduction. It was found that CO2 could be efficiently transformed to CH4 under mild conditions, i.e., in aqueous solution and at atmospheric pressure and room temperature. The maximum production rate of CH4 can reach 79.0 MUmol g-1 h-1. Moreover, the Ag/Pd bimetals supported on N-doped TiO2 nanosheet exhibit high selectivity to CH4. The as-synthesized photocatalyst can be well recycled for CO2 reduction. PMID- 29969202 TI - Early propranolol treatment ameliorates endothelial dysfunction in experimental septic lung. AB - BACKGROUND: Recent reports have indicated an improved prognosis in sepsis with beta blocker agents; however, the underlying action mechanism is still under debate. OBJECTIVES: The aim of this study was to investigate the potential effect of propranolol on endothelial dysfunction in septic rats. MATERIAL AND METHODS: The cecal ligation and puncture model (CLP) was used to generate sepsis. Adult male Wistar-Albino rats were divided into 4 groups: group 1 was a sham group, group 2 received sterile saline, group 3 received 10 mg/kg of propranolol 3 days before the intervention, and group 4 received 10 mg/kg of propranolol 30 min after CLP. Six rats from each group were sacrificed 24 h postoperatively. The remaining rats were followed for survival. We have also evaluated the effects on systemic inflammation, coagulation and the lung tissue with immunohistochemical and electron microscopic evaluation. RESULTS: Serum tumor necrosis factor alpha (TNF-alpha) and plasminogen activator inhibitor-1 (PAI-1) levels, as well as tissue TNF-alpha scores were elevated in septic rats. Electron microscopic examination of the lung tissue showed endothelial dysfunction in the sepsis group. Pretreatment significantly improved survival. Moreover, pre-treatment altered serum vascular endothelial growth factor receptor-1 (VEGFR-1) levels and post-treatment reduced serum PAI-1 and VEGFR-1 levels. In both the preand post treatment groups, electron microscopic examination revealed improvement of the destroyed lung endothelium and showed only mild alterations in the cytoplasmic organelles, especially in the mitochondria of the endothelial cells. CONCLUSIONS: These results suggest that the improved outcome with beta blockers in sepsis may be due to the ameliorated endothelial dysfunction. Further studies focusing on the potential effect of beta blockers on the endothelium may lead to a better understanding of sepsis. PMID- 29969235 TI - Sustainable Flow Synthesis of Encoded Beads for Combinatorial Chemistry and Chemical Biology. AB - Monosized beads of polar resins were synthesized for combinatorial chemistry and chemical biology by sustainable microchannel flow synthesis. Regular, biocompatible, and optically encoded beads could be efficiently prepared on large scale and in high yield. In a preparative flow polymerization instrument, taking advantage of a designed T-connector for droplet formation, quality beads were synthesized with accurate size control using a minimal amount of recirculating silicon oil as suspension medium. Bead-size was controlled through shear imposed by the silicon oil flow rate. This process provided 86% yield of ~500 MUm macrobeads beads within a 20 MUm size range with no deformities or vacuoles, ideally suited for combinatorial chemistry and protein binding studies. The simple flow equipment consisted of a syringe pump for monomer and initiator delivery, a T-connector, a gear pump for oil recirculation, a long, heated coil of Teflon tubing and a collector syringe. The method was used for preparation of PEGA1900 beads, optically encoded with fluorescent microparticles. The microparticle matrix (MPM) encoded beads were tested in a MPM-decoder showing excellent recognition in bead decoding. PMID- 29969236 TI - Comprehensive Single-Shot Proteomics with FAIMS on a Hybrid Orbitrap Mass Spectrometer. AB - Liquid chromatography (LC) prefractionation is often implemented to increase proteomic coverage; however, while effective, this approach is laborious, requires considerable sample amount, and can be cumbersome. We describe how interfacing a recently described high-field asymmetric waveform ion mobility spectrometry (FAIMS) device between a nanoelectrospray ionization (nanoESI) emitter and an Orbitrap hybrid mass spectrometer (MS) enables the collection of single-shot proteomic data with comparable depth to that of conventional two dimensional LC approaches. This next generation FAIMS device incorporates improved ion sampling at the ESI-FAIMS interface, increased electric field strength, and a helium-free ion transport gas. With fast internal compensation voltage (CV) stepping (25 ms/transition), multiple unique gas-phase fractions may be analyzed simultaneously over the course of an MS analysis. We have comprehensively demonstrated how this device performs for bottom-up proteomics experiments as well as characterized the effects of peptide charge state, mass loading, analysis time, and additional variables. We also offer recommendations for the number of CVs and which CVs to use for different lengths of experiments. Internal CV stepping experiments increase protein identifications from a single shot experiment to >8000, from over 100 000 peptide identifications in as little as 5 h. In single-shot 4 h label-free quantitation (LFQ) experiments of a human cell line, we quantified 7818 proteins with FAIMS using intra-analysis CV switching compared to 6809 without FAIMS. Single-shot FAIMS results also compare favorably with LC fractionation experiments. A 6 h single-shot FAIMS experiment generates 8007 protein identifications, while four fractions analyzed for 1.5 h each produce 7776 protein identifications. PMID- 29969237 TI - Antibacterial Performance of TiCaPCON Films Incorporated with Ag, Pt, and Zn: Bactericidal Ions Versus Surface Microgalvanic Interactions. AB - It is very important to prevent bacterial colonization at the early postoperative stages. There are four major strategies and their corresponding types of antibacterial surfaces specifically designed to fight infection: bactericide release, anti-adhesion, pH-sensitive, and contact-killing. Herein, we aimed at determining the antibacterial efficiency of different types of bactericidal ions and revealing the possible contribution of surface microgalvanic effects arising from a potential difference on heterogeneous surfaces. We considered five types of TiCaPCON films, with Ag, Zn, Pt, Ag + Zn, and Pt + Zn nanoparticles (NPs) on their surface. The Ag-modified film demonstrated a pronounced antibacterial effect at a very low Ag ion concentration of 0.11 ppb in physiological solution that was achieved already after 3 h of immersion in Escherichia coli ( E. coli) bacterial culture. The Zn-containing sample also showed a noticeable antibacterial effect against E. coli and Staphylococcus aureus ( S. aureus) strains, wherein the concentration of Zn ions was 2 orders of magnitude higher (15 ppb) compared with the Ag ions. The presence of Ag NPs accelerated the leaching of Zn ion out of the TiCaPCON-Ag-Zn film, but no synergistic effect of the simultaneous presence of the two bactericidal components was observed. After the incubation of the samples with Ag, Zn, and Ag + Zn NPs in E. coli and S. aureus suspensions for 24 and 8 h, respectively, all bacterial cells were completely inactivated. The Pt-containing film showed a very low Pt ion release, and therefore the contribution of this type of ions to the total bactericidal effect could be neglected. The results of the electrochemical studies and Kelvin probe force microscopy indicated that microgalvanic couples were formed between the Pt NPs and the TiCaPCON film, but no noticeable antibacterial effect against either E. coli or S. aureus strains was observed. All ion-modified samples provided good osteoblastic cell attachment, spreading, and proliferation and therefore were concluded to be nontoxic for cells. In addition, the TiCaPCON films with Ag, Pt, and Zn NPs on their surface demonstrated good osteoconductive characteristics. PMID- 29969238 TI - Mutually Orthogonal DNA Replication Systems In Vivo. AB - The yeast cytoplasmically localized pGKL1/TP-DNAP1 plasmid/DNA polymerase pair forms an orthogonal DNA replication system whose mutation rate can be drastically increased without influencing genomic replication, thereby supporting in vivo continuous evolution. Here, we report that the pGKL2/TP-DNAP2 plasmid/DNA polymerase pair forms a second orthogonal replication system. We show that custom genes can be encoded and expressed from pGKL2, that error-prone TP-DNAP2s can be engineered, and that pGKL2 replication by TP-DNAP2 is both orthogonal to genomic replication in Saccharomyces cerevisiae and mutually orthogonal with pGKL1 replication by TP-DNAP1. This demonstration of two mutually orthogonal DNA replication systems with tunable error rates and properties should enable new applications in cell-based continuous evolution, genetic recording, and synthetic biology at large. PMID- 29969240 TI - Reduced Transcriptomic Approach for Screening and Prediction of Chemical Toxicity. AB - The reduced transcriptomic approach allows full dose range testing of hundreds of chemicals or mixtures using human cells or zebrafish embryos. Points of departure of genes and pathways can be used for potency ranking and to classify chemicals by disrupted biological pathways. PMID- 29969239 TI - NHCs in Main Group Chemistry. AB - Since the discovery of the first stable N-heterocyclic carbene (NHC) in the beginning of the 1990s, these divalent carbon species have become a common and available class of compounds, which have found numerous applications in academic and industrial research. Their important role as two-electron donor ligands, especially in transition metal chemistry and catalysis, is difficult to overestimate. In the past decade, there has been tremendous research attention given to the chemistry of low-coordinate main group element compounds. Significant progress has been achieved in stabilization and isolation of such species as Lewis acid/base adducts with highly tunable NHC ligands. This has allowed investigation of numerous novel types of compounds with unique electronic structures and opened new opportunities in the rational design of novel organic catalysts and materials. This Review gives a general overview of this research, basic synthetic approaches, key features of NHC-main group element adducts, and might be useful for the broad research community. PMID- 29969242 TI - A Series of Lanthanide Compounds Constructed from Ln8 Rings Exhibiting Large Magnetocaloric Effect and Interesting Luminescence. AB - A series of lanthanide compounds, [Ln8(CH2OHCH2OH)8(SO4)12]. m(C2H7N). nH2O (Ln = Gd (1), Sm (2), Tb (3), La (5), m = 2, n = 2; Ln = Eu (4), m = 0, n = 8), which contain Ln8 rings by sulfate and glycol as the ligand have been synthesized and characterized. Besides, small organic amine and l-tartaric acid act as dual templating roles during the synthetic process. Magnetic investigation of compound 1 reveals the existence of weak antiferromagnetic interactions between GdIII ions and the data of magnetic entropy change (-Delta Sm) is 36.86 J K-1 kg-1 (108.55 mJ cm-3 K-1) for Delta H = 7 T at 2.0 K, which is comparatively large among GdIII based compounds. Additionally, because of the excellent luminescence properties of SmIII, TbIII, and EuIII, compounds 2-4 were investigated. PMID- 29969241 TI - Hydrogen-Atom Noninnocence of a Tridentate [SNS] Pincer Ligand. AB - Double deprotonation of bis(2-mercapto-4-methylphenyl)amine ([SNS]H3) followed by addition to NiCl2(PR3)2 in air-free conditions afforded [SN(H)S]Ni(PR3) (1a, R = Cy; 1b, R = Ph) complexes, characterized as diamagnetic, square-planar nickel(II) complexes. When the same reaction was conducted with 3 equiv of KH, the diamagnetic anions K{[SNS]Ni(PR3)} were obtained (K[2a], R = Cy; K[2b], R = Ph). In the presence of air, the reaction proceeds with a concomitant one-electron oxidation. When R = Cy, a square-planar, S = 1/2 complex, [SNS]Ni(PCy3) (3a), was isolated. When R = Ph, the bimetallic complex {[SNS]Ni(PPh3)}2 ({3b}2) was obtained. This bimetallic species is diamagnetic; however, in solution it dissociates to give S = 1/2 monomers analogous to 3a. Complexes 1-3 represent a hydrogen-atom-transfer series. The bond dissociation free energies (BDFEs) for 1a and 1b were calculated to be 63.9 +/- 0.1 and 62.4 +/- 0.2 kcal mol-1, respectively, using the corresponding p Ka and E degrees ' values. Consistent with these BDFE values, TEMPO* reacted with 1a and 1b, resulting in the abstraction of a hydrogen atom to afford 3a and 3b, respectively. PMID- 29969243 TI - Palladium Acetate Revisited: Unusual Ring-Current Effects, One-Electron Reduction, and Metal-Metal Bonding. AB - Palladium(II) acetate (1) and two new complexes of the ligand alpha,alpha,alpha',alpha'-tetramethyl-1,3-benzenedipropionate (esp2-), C s Pd3(esp)3 ( Cs-2) and C3 h-Pd3(esp)3 ( C3 h-2), are studied in the solid state and in solution. Variable-temperature NMR and DFT studies of C s-2 reveal an unusual shielding region above the Pd atoms. The compounds show a surprising quasi-reversible reduction between -880 and -1200 mV versus Fc/Fc+, and the Pd3(esp)3 complexes may be cleanly reduced electrochemically. EPR spectra of reduced samples show pseudo-axial signals with 105Pd hyperfine coupling, consistent with unprecedented, isostructural Pd35+ species with a valence-trapped PdII-PdII-PdI electronic structure. PMID- 29969244 TI - Conductive Polymers: Opportunities and Challenges in Biomedical Applications. AB - Research pertaining to conductive polymers has gained significant traction in recent years, and their applications range from optoelectronics to material science. For all intents and purposes, conductive polymers can be described as Nobel Prize-winning materials, given that their discoverers were awarded the Nobel Prize in Chemistry in 2000. In this review, we seek to describe the chemical forms and functionalities of the main types of conductive polymers, as well as their synthesis methods. We also present an in-depth analysis of composite conductive polymers that contain various nanomaterials such as graphene, fullerene, carbon nanotubes, and paramagnetic metal ions. Natural polymers such as collagen, chitosan, fibroin, and hydrogel that are structurally modified for them to be conductive are also briefly touched upon. Finally, we expound on the plethora of biomedical applications that harbor the potential to be revolutionized by conductive polymers, with a particular focus on tissue engineering, regenerative medicine, and biosensors. PMID- 29969245 TI - Luminescent Tetrahedral Molecular Cages Containing Ruthenium(II) Chromophores. AB - We have designed linear metalloligands which contain a central photoactive [Ru(N?N)3]2+ unit bordered by peripheral metal binding sites. The combination of these metalloligands with Zn(II) and Fe(II) ions leads to heterometallic tetrahedral cages, which were studied by NMR spectroscopy, mass spectrometry, and photophysical methods. Like the parent metalloligands, the cages remain emissive in solution. This approach allows direct incorporation of the favorable properties of ruthenium(II) polypyridyl complexes into larger self-assembled structures. PMID- 29969246 TI - Jasmonic Acids Facilitate the Degradation and Detoxification of Herbicide Isoproturon Residues in Wheat Crops ( Triticum aestivum). AB - Jasmonic acid (JA) [or methyl-jasmonic acid (MeJA)] is one of the important regulators of plant growth, development, and defense with respect to environmental stresses, but how JA is involved in mediation of pesticide accumulation and degradation in plants is largely unknown. This study investigated the contribution of MeJA to detoxification and degradation of isoproturon (IPU) residues in wheat ( Triticum aestivum). Wheat plants were exposed to 4 mg of isoproturon kg-1 (environmentally realistic concentration). The level of growth and chlorophyll concentration were reduced, while the electrolyte permeability in plants was enhanced. When plants were sprayed with 0.1 MUM MeJA, the phytotoxicity induced by isoproturon was significantly assuaged, which was manifested by an increased chlorophyll concentration and a reduced level of cellular damage in wheat. Activities of several stress marker enzymes with isoproturon were repressed in the presence of MeJA. We measured accumulation of isoproturon in wheat and its residues in soil by high-performance liquid chromatography. The concentration of isoproturon in wheat and soils with MeJA was drastically reduced. Using ultraperformance liquid chromatography-tandem mass spectrometry, 12 isoproturon derivatives (eight metabolites and four conjugates) in wheat were characterized. We further provided evidence that the concentration of endogenous MeJA was significantly increased in IPU-exposed plants. These results suggest that MeJA was able to detoxify or degrade isoproturon in wheat when grown in a realistic environmental isoproturon-polluted soil. PMID- 29969248 TI - Catalytic Glycosylations in Oligosaccharide Synthesis. AB - Catalytic glycosylation has been a central reaction in carbohydrate chemistry since its introduction by Fischer 125 years ago, but it is only in the past three to four decades that catalytic methods for synthesizing oligosaccharides have appeared. Despite the development of numerous elegant and ingenious catalytic glycosylation methods, only a few are in general use. This review covers all methods of catalytic glycosylation with the focus on the development and application in oligosaccharide synthesis and provide an overview of the scope and limitations of these. The review also includes relevant mechanistic studies of catalytic glycosylations. The future of catalytic glycosylation chemistry is discussed, including specific, upcoming methods and possible directions for the field of research in general. PMID- 29969247 TI - A Series of 4- and 5-Coordinate Ni(II) Complexes: Synthesis, Characterization, Spectroscopic, and DFT Studies. AB - A series of four- and five-coordinate Ni(II) complexes Cz tBu(Pyr iPr)2NiX (1-3 and 1.THF-3.THF), where X = Cl, Br, and I, were synthesized and fully characterized by NMR and UV-vis spectroscopy, X-ray crystallography, cyclic voltammetry, and density functional theory calculations. The solid-state structures of 1-3 reveal rare examples of seesaw Ni(II) complexes. In solution, 1 3 bind reversibly to a THF molecule to form five-coordinate adducts. The electronic transitions in the visible region (630-680 nm), attributed to LMCT bands, for 1 -> 3 exhibit a bathochromic shift. The thermochromic tendency of the five-coordinate complexes implies the loss of THF coordination at elevated temperatures. Finally, the electronic properties of all Ni(II) complexes were studied by time-dependent density functional theory calculations to characterize the nature of the excited states. PMID- 29969249 TI - Quantification of DNA and Protein Adducts of 1-Nitropyrene: Significantly Higher Levels of Protein than DNA Adducts in the Internal Organs of 1-Nitropyrene Exposed Rats. AB - 1-Nitropyrene (1NP) level is closely associated with the mutagenicity of diesel exhaust and is being used as the marker molecule for diesel exhaust. Thus, quantitation of the exposure to 1NP may provide an efficient method for biomonitoring human exposure to diesel exhaust and risk assessment. Using ultra performance liquid chromatography coupled with fluorescence or tandem mass spectrometric detection methods, we quantitated and compared in this study the DNA and protein adducts of 1NP in internal organs of 1NP-exposed rats. While previous studies using radioactivity-based detection methods were descriptive in nature and focused on the mutation-associated genetic materials, the results of our quantitative analysis showed, for the first time, a significantly higher concentration of the protein adduct than the DNA adduct in the tissue samples. The data also revealed higher in vivo stability of the protein adduct than that of the DNA adduct. Our results provide solid evidence that demonstrates that the protein adduct might be a more-sensitive dosimeter for 1-NP and, thus, diesel exhaust exposure. PMID- 29969251 TI - Influencing the Optoelectronic Properties of a Heteroleptic Iridium Complex by Second-Sphere H-Bonding Interactions. AB - The use of a new second-sphere coordination methodology for emission color tuning of iridium complexes is presented. We demonstrate that a complementary H-bonding guest molecule binding through contiguous triple H-bonding interactions can induce a shift in the emission of the iridium complex from green to blue without the need to alter the ligand structure around the metal center, while simultaneously increasing the photoluminescence quantum yield in solution. The association constant for this host-guest interaction was determined to be Ka = 4.3 * 103 M-1 in a solution of 2% dimethyl sulfoxide in chloroform by UV-vis titration analysis and the impact of the hydrogen bonding interaction further probed by photoluminescence, electrochemical, and computational methods. Our findings suggest that directed self-assemblies are an effective approach to influencing emission properties of phosphorescent iridium(III) complexes. PMID- 29969252 TI - Tuning the Magnetic Interactions in Dy(III)4 Single-Molecule Magnets. AB - The study of mononuclear lanthanide-based systems, where the observed single molecule magnets (SMMs) properties originate from the local description of the magnetic properties of the lanthanide ion, has been widely investigated through the literature. The case of polynuclear SMMs becomes more challenging both experimentally and theoretically due to the complexity of such architectures involving interactions between the magnetic centers. Many efforts have been focused on the understanding of the nature of these interactions and their effects on the SMM properties. In this work, a series of three structurally related tetranuclear dysprosium(III) SMMs, namely, [Dy4(L)4(OH)2(DMF)4(NO3)2].2(DMF).(H2O) (1), [Dy4(L)4(OH)2(DMF)2(tfaa)2].2(CH3CN) (2), and [Dy4(L)4(OH)2(DMF)2(acac)2].2(DMF) (3) (H2L = 2-(2-hydroxy-3 methoxybenzylideneamino)phenol, Htfaa = trifluoroacetylactone, Hacac = acetylacetonate), has been synthesized and investigated. By a fine-tuning of the ligands on the changeable coordination sites in these Dy(III)4 SMMs, the intramolecular magnetic interactions can be modified, switching from antiferromagnetic (for 1 and 2) to ferromagnetic (for 3). Ab initio calculations support these statements. In addition, the formation of 1 has been analyzed by ESI-MS analysis of the reaction mixture, indicating rather quick and high-yield formation of the [Dy4] framework in solution. The combination of experimental work and ab initio calculations offers further insight into the relationship between structures and magnetic properties and sheds light on how to tune magnetic interactions in future polynuclear dysprosium complexes. PMID- 29969250 TI - Stereospecific Radical-Mediated B12-Dependent Methyl Transfer by the Fosfomycin Biosynthesis Enzyme Fom3. AB - Fom3, the antepenultimate enzyme in the fosfomycin biosynthetic pathway in Streptomyces spp., is a class B cobalamin-dependent radical SAM methyltransferase that catalyzes methylation of (5'-cytidylyl)-2-hydroxyethylphosphonate (2-HEP CMP) to form (5'-cytidylyl)-2-hydroxypropylphosphonate (2-HPP-CMP). Previously, the reaction of Fom3 with 2-HEP-CMP produced 2-HPP-CMP with mixed stereochemistry at C2. Mechanistic characterization has been challenging because of insoluble expression and poor cobalamin (B12) incorporation in Escherichia coli. Recently, soluble E. coli expression and incorporation of cobalamin into Fom3 were achieved by overexpression of the BtuCEDFB cobalamin uptake system. Herein, we use this new method to obtain Fom3 from Streptomyces wedmorensis. We show that the initiator 5'-deoxyadenosyl radical stereospecifically abstracts the pro- R hydrogen atom from the C2 position of 2-HEP-CMP and use the downstream enzymes FomD and Fom4 to demonstrate that our preparation of Fom3 produces only (2 S)-2 HPP-CMP. Additionally, we show that the added methyl group originates from SAM under multiple-turnover conditions, but the first turnover uses a methyl donor already present on the enzyme; furthermore, cobalamin isolated from Fom3 reaction mixtures contains methyl groups derived from SAM. These results are consistent with a model in which Fom3 catalyzes methyl transfer from SAM to cobalamin and the resulting methylcobalamin (MeCbl) is the ultimate methyl source for the reaction. PMID- 29969253 TI - Selective Lanthanide Distribution within a Comprehensive Series of Heterometallic [LnPr] Complexes. AB - The preparation of heterometallic, lanthanide-only complexes is an extremely difficult synthetic challenge. By a ligand-based strategy, a complete isostructural series of dinuclear heterometallic [LnPr] complexes has been synthesized and structurally characterized. The two different coordination sites featured in this molecular entity allow study of the preferences of the praseodymium ion for a specific position depending on the ionic radii of the accompanying lanthanide partner. The purity of each heterometallic moiety has been evaluated in the solid state and in solution by means of crystallographic and spectrometric methods, respectively, revealing the limits of this strategy for ions with similar sizes. DFT calculations have been carried out to support the experimental results, confirming the nature of the site-selective lanthanide distribution. The predictable selectivity of this system has been exploited to assess the magnetic properties of the [DyPr] and [LuPr] derivatives, showing that the origin of the slow dynamics observed in the former arises from the dysprosium ion. PMID- 29969254 TI - Impact of High Pressure on Metallophilic Interactions and Its Consequences for Spectroscopic Properties of a Model Tetranuclear Silver(I)-Copper(I) Complex in the Solid State. AB - Structure-property relationships were investigated via combined high-pressure spectroscopic and X-ray diffraction techniques for a model luminescent Ag2Cu2L4 (L = 2-diphenylphosphino-3-methylindole) complex in the crystalline state. The experimental results were contributed by theoretical calculations, compared with the previously evaluated light-induced geometrical changes, and discussed in the context of available literature to date. To the best of our knowledge, this is the first study of this kind devoted to a coinage-metal complex for which the argentophilic interactions are crucial. High-pressure X-ray diffraction and optical spectroscopy experiments showed close correspondence between structural changes and optical properties. The unit-cell angles, absorption edges, emission maxima, decay lifetimes and silver-copper bond trends, all change around 2-3 GPa. A blue-shift to red-shift switch when increasing the pressure was observed for both absorption and emission spectra. This is unique behavior when compared to the literature-reported coinage metal systems. It also occurred that the pressure induced structural changes differ notably from the geometrical distortions observed for the excited state. Interestingly, shortening of the Ag-Ag bond itself does not ensure the red shift of the absorption and emission spectra. All the optical spectroscopy data are suggestive of an important role of defects, likely related to the lack of a hydrostatic pressure transmitting medium, for pressures higher than 3 GPa. PMID- 29969255 TI - Synthesis and Characterization of MgCr2S4 Thiospinel as a Potential Magnesium Cathode. AB - Magnesium-ion batteries are a promising energy storage technology because of their higher theoretical energy density and lower cost of raw materials. Among the major challenges has been the identification of cathode materials that demonstrate capacities and voltages similar to lithium-ion systems. Thiospinels represent an attractive choice for new Mg-ion cathode materials owing to their interconnected diffusion pathways and demonstrated high cation mobility in numerous systems. Reported magnesium thiospinels, however, contain redox inactive metals such as scandium or indium, or have low voltages, such as MgTi2S4. This article describes the direct synthesis and structural and electrochemical characterization of MgCr2S4, a new thiospinel containing the redox active metal chromium and discusses its physical properties and potential as a magnesium battery cathode. However, as chromium(III) is quite stable against oxidation in sulfides, removing magnesium from the material remains a significant challenge. Early attempts at both chemical and electrochemical demagnesiation are discussed. PMID- 29969256 TI - Fibrogenic Disorders in Human Diseases: From Inflammation to Organ Dysfunction. AB - Fibrosis is an inadequate response to tissue stress with very few therapeutic options to prevent its progression to organ dysfunction. There is an urgent need to identify drugs with a therapeutic potential for fibrosis, either by designing and developing new compounds or by repurposing drugs already in clinical use which were developed for other indications. In this Perspective, we summarize some pathways and biological targets involved in fibrosis development and maintenance, focusing on common mechanisms between organs and diseases. We review the therapeutic agents under experimental development, clinical trials, or in clinical use for the treatment of fibrotic disorders, evaluating the reasons for the discrepancies observed between preclinical and clinical results. We also discuss the improvement that we envision in the development of therapeutic molecules able to achieve improved potential for treatment, including indirect modulators, targeting approaches, or drug combinations. PMID- 29969257 TI - Integrated Utilization of Red Radish for the Efficient Production of High-Purity Procyanidin Dimers. AB - Red radish was extracted by methanol to obtain crude radish procyanidin extracts. The purity of procyanidin (PP) and procyanidin dimers (PD) of crude radish procyanidin extracts under different ratios of methanol to radish was optimized to achieve the best extraction performance. Then the crude radish procyanidin extracts was, respectively, processed six macroporous resins separation to separate radish procyanidin oligomers (RPO) and polymers (RPP). Depolymerization of radish procyanidin polymers (RPP) into oligomers was then conducted. N Acetylneuraminate lyase (NAL) was first used as the enzyme to depolymerize RPP. The depolymerization yield (DY) under different depolymerized conditions was also investigated. Results showed the DY of RPP would achieve 53.24 +/- 0.35% at the best conditions. Then the high-purity procyanidin dimers was prepared by depolymerized procyanidin oligomers and PRO. Additionally, the chemical structure of the preparative radish procyanidin dimers was elucidated by high-resolution mass spectrometry and one- and two-dimensional NMR. PMID- 29969258 TI - Correction to Discovery of Novel 3-Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase. PMID- 29969259 TI - Identification of Thiourea-Based Inhibitors of the B-Cell Lymphoma 6 BTB Domain via NMR-Based Fragment Screening and Computer-Aided Drug Design. AB - Protein-protein interactions (PPI) between the transcriptional repressor B-cell lymphoma 6 (BCL6) BTB domain (BCL6BTB) and its corepressors have emerged as a promising target for anticancer therapeutics. However, identification of potent, drug-like inhibitors of BCL6BTB has remained challenging. Using NMR-based screening of a library of fragment-like small molecules, we have identified a thiourea compound (7CC5) that binds to BCL6BTB. From this hit, the application of computer-aided drug design (CADD), medicinal chemistry, NMR spectroscopy, and X ray crystallography has yielded an inhibitor, 15f, that demonstrated over 100 fold improved potency for BCL6BTB. This gain in potency was achieved by a unique binding mode that mimics the binding mode of the corepressor SMRT in the aromatic and the HDCH sites. The structure-activity relationship based on these new inhibitors will have a significant impact on the rational design of novel BCL6 inhibitors, facilitating the identification of therapeutics for the treatment of BCL6-dependent tumors. PMID- 29969262 TI - Antiplasmodial beta-Triketone-Flavanone Hybrids from the Flowers of the Australian Tree Corymbia torelliana. AB - The methanol extract of the flowers of the Australian eucalypt tree Corymbia torelliana yielded six new beta-triketone-flavanone hybrids, torellianones A-F (1 6), the tetrahydroxycyclohexane torellianol A (7), and known beta-triketones (4 S)-ficifolidione (8) and (4 R)-ficifolidione (9), and beta-triketone-flavanones kunzeanone A (10) and kunzeanone B (11). Torellianones A and B, C and D, and E and F were each isolated as inseparable diastereomeric mixtures. Exchange correlations observed in a ROESY spectrum indicated that 5 and 6 also interconverted between stable conformers. The structures of 1-7 were elucidated from the analysis of 1D/2D NMR and MS data. Relative configurations of torellianones C-F and torrellianol A were determined from analysis of ROESY data. Compounds 1-10 were tested for antiplasmodial activity against a drug-sensitive (3D7) strain of Plasmodium falciparum, with 3-6 and 8-10 showing limited antiplasmodial activity, with IC50 values ranging from 3.2 to 16.6 MUM. PMID- 29969260 TI - Natural Inhibitors of the RhoA-p115 Complex from the Bark of Meiogyne baillonii. AB - In an effort to find potent natural inhibitors of RhoA and p115 signaling G proteins, a systematic in vitro evaluation using enzymatic and plasmonic resonance assays was undertaken on 11 317 plant extracts. The screening procedure led to the selection of the New Caledonian endemic species Meiogyne baillonii for a chemical investigation. Using a bioguided isolation procedure, three enediyne gamma-butyrolactones (1-3) and two enediyne-gamma-butenolides (4 and 5), named sapranthins H-L, respectively, two enediyne carboxylic acid (6 and 7), two depsidones, stictic acid (8) and baillonic acid (9), aristolactams AIa and AIIa (10 and 11), and two aporphines, dehydroroemerine (12) and noraristolodione (13), were isolated from the ethyl acetate extract of the bark. The structures of the new compounds (1-6, 9, and 11) and their relative configurations were established by NMR spectroscopic analysis and by X-ray diffraction analysis for compound 9. Only stictic acid (8) exhibited a significant inhibiting activity of the RhoA p115 complex, with an EC50 value of 0.19 +/- 0.05 mM. This is the first time that a natural inhibitor of the complex RhoA-p115's activity was discovered from an HTS performed over a collection of higher plant extracts. Thus, stictic acid (8) could be used as the first reference compound inhibiting the interaction between RhoA and p115. PMID- 29969261 TI - Gastric Protective Activities of Sea Cucumber Fucoidans with Different Molecular Weight and Chain Conformations: A Structure-Activity Relationship Investigation. AB - A variety of bioactivities has been established for fucoidan extracted from sea cucumber, whereas its structure-activity relationships have been seldom investigated. In this study, sea cucumber ( Thelenota ananas) fucoidans with different molecular weights were prepared with enzymatic degradation. The chain stiffness and molecular size decreased with the decreasing of molecular weight. Fucoidans with molecular weight of 1380.0, 828.7, and 483.0 kDa exhibited random coil conformations, while fucoidan molecular weight of 215.0 kDa existed as sphere in solution. All examined fucoidans could effectively prevent the ethanol induced gastric ulcer, of which mechanism involved antioxidation and anti inflammation. Within the range of the study, the performance of fucoidans adopted random coil conformations declined with the decreasing of molecular weight, and the performance recovered when the chain conformation transited from coil to sphere, indicating the subtle influences of molecular weight and chain conformation on the gastric protective activity of sea cucumber fucoidan. PMID- 29969263 TI - Effects of Heat Treatment of Green Protein on in Situ Protein Disappearance and in Vitro Fatty Acid Biohydrogenation. AB - Soluble protein extracted from leaves and stems of grasses and forage legumes is defined as green protein. The present study was conducted to evaluate in situ green protein degradability, intestinal protein disappearance, and in vitro fatty acids biohydrogenation (BH) in dairy cows. Three green protein concentrates (red clover, ryegrass, and grass clover) were heat treated as follows: oven-drying at 70 degrees C, subsequent autoclaving at 121 degrees C for 45 min, and for grass clover also spin flash-drying. Freeze-dried green protein was considered as a control (untreated). Autoclaving and oven-drying of green protein reduced the crude protein and dry matter degradability. The linolenic acid BH rate was lowest in heat-treated grass clover concentrate ( P < 0.01). In conclusion, green proteins are heat sensitive, and oven-drying can be an appropriate method to increase the amount of protein and unsaturated fatty acids escaping from the rumen. PMID- 29969264 TI - Transition-Metal-Free Approach for the Synthesis of 4-Aryl-quinolines from Alkynes and Anilines. AB - An efficient and transition-metal-free approach for the synthesis of 4 arylquinolines from readily available anilines and alkynes in the presence of K2S2O8 and DMSO has been developed. A variety of alkynes and anilines having a diverse range of substitution patterns can undergo the one-pot cascade process successfully. Effectively, this method uses DMSO as one carbon source, thus providing a highly atom-economical and environmentally benign approach for the synthesis of 4-arylquinolines. PMID- 29969266 TI - Radical Addition Cascade Cyclization of 1,6-Enynes with DMSO To Access Methylsulfonylated and Carbonylated Benzofurans under Transition-Metal-Free Conditions. AB - A mild and direct addition/cyclization cascade to construct methylsulfonylated and carbonylated benzofurans was accomplished using oxygen-linked 1,6-enynes as the starting materials. The interaction of NH4I and DMSO promoted the generation of sulfur-containing radical and initiated the radical addition to the C?C double bond of 1,6-enyne cascade intramolecular 5- exo- dig cyclization. A wide range of oxygen-linked 1,6-enynes bearing various substituents were found to be suitable in this cascade process, providing benzofurans with dual functional groups in moderate to high yields. This method could also be utilized to synthesize benzothiophenes from sulfur-linked 1,6-enynes. PMID- 29969265 TI - Calculations of Differential Cross Sections Using Mixed Quantum/Classical Theory of Inelastic Scattering. AB - It is shown that the mixed quantum/classical theory (MQCT) for the description of molecular scattering is considerably improved by using integer values of orbital angular momentum l, just like in quantum theory, instead of treating it as a continuous classical variable related to the impact parameter. This conclusion is justified by the excellent accuracy of the modified theory for prediction of the differential cross sections, at various values of collision energy and in both forward and backward scattering regimes. This approach requires fewer trajectories, compared to the random Monte Carlo sampling, and the only convergence parameter is lmax (maximum orbital angular momentum) similar to Jmax in the full quantum theory (maximum total angular momentum). Calculations of differential and integral cross sections for elastic and inelastic channels are presented, and the role of the scattering phase is discussed. The low-energy range is analyzed in detail to obtain insight into how the mixed quantum/classical treatment works in the scattering regime dominated by resonances. The differential cross section for rotationally inelastic scattering, computed by MQCT approach, is presented for the first time. PMID- 29969267 TI - Iodine in Metal-Organic Frameworks at High Pressure. AB - Capture of highly volatile radioactive iodine is a promising application of metal organic frameworks (MOFs), thanks to their high porosity with flexible chemical architecture. Specifically, strong charge-transfer binding of iodine to the framework enables efficient and selective iodine uptake as well as its long-term storage. As such, precise knowledge of the electronic structure of iodine is essential for a detailed modeling of the iodine sorption process, which will allow for rational design of iodophilic MOFs in the future. Here we probe the electronic structure of iodine in MOFs at variable iodine...framework interaction by Raman and optical absorption spectroscopy at high pressure ( P). The electronic structure of iodine in the straight channels of SBMOF-1 (Ca- sdb, sdb = 4,4'-sulfonyldibenzoate) is modified irreversibly at P > 3.4 GPa by charge transfer, marking a polymerization of iodine molecules into a 1D polyiodide chain. In contrast, iodine in the sinusoidal channels of SBMOF-3 (Cd- sdb) retains its molecular (I2) character up to at least 8.4 GPa. Such divergent high pressure behavior of iodine in the MOFs with similar port size and chemistry illustrates adaptations of the electronic structure of iodine to channel topology and strength of the iodine...framework interaction, which can be used to tailor iodine-immobilizing MOFs. PMID- 29969268 TI - Cu(II)-Catalyzed Ortho-C-H Nitration of Aryl Ureas By C-H Functionalization. AB - A novel protocol for the aromatic ortho C-H nitration of aryl ureas with Fe(NO3)3.9H2O is developed. The reaction utilizes CuCl2.2H2O as catalyst and p TSA as additive, showing good functional group tolerance and furnishing the desired products in moderate to excellent yields. PMID- 29969273 TI - Experimental Measurement of Parameters Governing Flow Rates and Partial Saturation in Paper-Based Microfluidic Devices. AB - Paper-based microfluidic devices are rapidly becoming popular as a platform for developing point-of-care medical diagnostic tests. However, the design of these devices largely relies on trial and error, owing to a lack of proper understanding of fluid flow through porous membranes. Any porous material having pores of multiple sizes contains partially saturated regions, i.e., regions where less than 100% of the pores are filled with fluid. The capillary pressure and permeability of the material change as a function of the extent of saturation. Although methods to measure these relationships have been developed in other fields of study, these methods have not yet been adapted for paper for use by the larger community of analytical chemists. In the current work, we present a set of experimental methods that can be used to measure the relationships between capillary pressure, permeability, and saturation for any commercially available paper membrane. These experiments can be performed using commonly available lab instruments. We further demonstrate the use of the Richards equation in modeling imbibition into two-dimensional paper networks, thus adding new capability to the field. Predictions of spatiotemporal saturation from the model were in strong agreement with experimental measurements. To make these methods readily accessible to a wide community of chemists, biologists, and clinicians, we present the first report of a simple protocol to measure the flow rates considering the effect of partial saturation. Use of this protocol could drastically reduce the trial and error involved in designing paper-based microfluidic devices. PMID- 29969271 TI - Green Reduced Graphene Oxide Toughened Semi-IPN Monolith Hydrogel as Dual Responsive Drug Release System: Rheological, Physicomechanical, and Electrical Evaluations. AB - Macroporous hydrogel monoliths having tailor-made features, conductivity, superstretchability, excellent biocompatibility, and biodegradability, have become the most nurtured field of interest in soft biomaterials. Green method assisted reduced graphene oxide has been inserted by in situ free radical gelation into semi-IPN hydrogel matrix to fabricate conducting hydrogel. Mechanical toughness has been implemented for the graphene-polymer physisorption interactions with graphene basal planes. Moreover, the as-prepared 3D scaffold type monolith hydrogel has been rheologically superior regarding their high elastic modulus and delayed gel rupturing. kappa-Carragenaan, one of the components of the hydrogel, has biodegradable nature. The most significant outcome is their low electrical percolation threshold and reversibly ductile nature. Reversible ductility provides them with rubber-like consistency in flow conditions. Surprising, the hydrogels showed dual stimuli-responsiveness, that is, environmental pH and external electrical stimulation. Electro-stimulation has been adopted here for the first time in semi-IPN systems, which could be an ideal alternative for iontopheretic devices and pulsatile drug release through skin. Regarding this, the hydrogel also has been passed to biocompatibility assay; they are noncytotoxic and show cell proliferation without negligible cell death in live-dead assay. The porosity of the nanocomposite scaffold-like gels was also analyzed by microcomputed tomography (MU-CT), which exhibited their connectivity in cell/voids inside the matrix. Thus, the experimentations are on the support of biocompatible soft material for dual-responsive tunable drug delivery. PMID- 29969269 TI - Influence of Encapsulated Water on Luminescence Energy, Line Width, and Lifetime of Carbon Nanotubes: Time Domain Ab Initio Analysis. AB - In a broad range of applications, carbon nanotubes (CNTs) are in direct contact with a condensed-phase environment that perturbs CNT properties. Experiments show that water molecules encapsulated inside of semiconducting CNTs reduce the electronic energy gap, enhance elastic and inelastic electron-phonon scattering, and shorten the excited-state lifetime. We rationalize the observed effects at the atomistic level using real-time time-dependent density functional theory combined with nonadiabatic molecular dynamics. Encapsulated water makes the nanotube more rigid, suppressing radial breathing modes while enhancing and slightly shifting the optical G-mode. Water screens Coulomb interactions and shifts charge carrier energies and wave functions. The screening, together with distortion of the CNT geometry and lifting of orbital degeneracy, produces a luminescence red shift. Enhanced elastic and inelastic electron-phonon scattering explains line width broadening and shortening of the excited-state lifetime. The influence of water on the CNT properties is similar to that of defects; however, in contrast to defects, water creates no new phonon modes or electronic states in the CNTs. The atomistic understanding of the influence of the condensed-phase environment on CNT optical, electronic, and vibrational properties, and electron vibrational dynamics guides design of novel CNT-based materials. PMID- 29969272 TI - Controlled Surface Silanization for Actin-Myosin Based Nanodevices and Biocompatibility of New Polymer Resists. AB - Molecular motor-based nanodevices require organized cytoskeletal filament guiding along motility-promoting tracks, confined by motility-inhibiting walls. One way to enhance motility quality on the tracks, particularly in terms of filament velocity but also the fraction of motile filaments, is to optimize the surface hydrophobicity. We have investigated the potential to achieve this for the actin myosin II motor system on trimethylchlorosilane (TMCS)-derivatized SiO2 surfaces to be used as channel floors in nanodevices. We have also investigated the ability to supress motility on two new polymer resists, TU7 (for nanoimprint lithography) and CSAR 62 (for electron beam and deep UV lithography), to be used as channel walls. We developed a chemical-vapor deposition tool for silanizing SiO2 surfaces in a controlled environment to achieve different surface hydrophobicities (measured by water contact angle). In contrast to previous work, we were able to fabricate a wide range of contact angles by varying the silanization time and chamber pressure using only one type of silane. This resulted in a significant improvement of the silanization procedure, producing a predictable contact angle on the surface and thereby predictable quality of the heavy meromyosin (HMM)-driven actin motility with regard to velocity. We observed a high degree of correlation between the filament sliding velocity and contact angle in the range 10-86 degrees , expanding the previously studied range. We found that the sliding velocity on TU7 surfaces was superior to that on CSAR 62 surfaces despite similar contact angles. In addition, we were able to suppress the motility on both TU7 and CSAR 62 by plasma oxygen treatment before silanization. These results are discussed in relation to previously proposed surface adsorption mechanisms of HMM and their relationship to the water contact angle. Additionally, the results are considered for the development of actin myosin based nanodevices with superior performance with respect to actin-myosin functionality. PMID- 29969275 TI - Regioselective Synthesis of Chirally Enriched Tetrahydrocarbazolones and Tetrahydrocarbazoles. AB - A new one-step, reagent-directed regioselective synthesis of chirally enriched tetrahydrocarbazolones and tetrahydrocarbazoles from a common type of substrate has been developed. The salient features of this method include inherited stereodiversity, a broad substrate scope, a quick reaction time, and a benign catalyst. The method is applicable to the synthesis of a bioactive cryptosanguinolentine precursor. PMID- 29969276 TI - Electrophilic Trifluoromethylthiolation/Semipinacol Rearrangement: Preparation of beta-SCF3 Carbonyl Compounds with alpha-Quaternary Carbon Center. AB - A new and modular electrophilic trifluoromethylthiolation/semipinacol rearrangement of allylic silyl ethers has been developed under mild conditions. This approach allows the formation of a number of beta-SCF3 carbonyl compounds with a cyclic and all-carbon quaternary center framework in moderate to good yields. It should be noted that this achievement is a metal-free process and just requires the use of simple acetyl chloride as an acidic promoter. Additionally, an interesting H-migration in competition with aryl-migration process was revealed. PMID- 29969274 TI - Ultrabright Room-Temperature Sub-Nanosecond Emission from Single Nitrogen-Vacancy Centers Coupled to Nanopatch Antennas. AB - Solid-state quantum emitters are in high demand for emerging technologies such as advanced sensing and quantum information processing. Generally, these emitters are not sufficiently bright for practical applications, and a promising solution consists in coupling them to plasmonic nanostructures. Plasmonic nanostructures support broadband modes, making it possible to speed up the fluorescence emission in room-temperature emitters by several orders of magnitude. However, one has not yet achieved such a fluorescence lifetime shortening without a substantial loss in emission efficiency, largely because of strong absorption in metals and emitter bleaching. Here, we demonstrate ultrabright single-photon emission from photostable nitrogen-vacancy (NV) centers in nanodiamonds coupled to plasmonic nanocavities made of low-loss single-crystalline silver. We observe a 70-fold difference between the average fluorescence lifetimes and a 90-fold increase in the average detected saturated intensity. The nanocavity-coupled NVs produce up to 35 million photon counts per second, several times more than the previously reported rates from room-temperature quantum emitters. PMID- 29969278 TI - Phosphine-Catalyzed [8 + 2]-Annulation of Heptafulvenes with Allenoates and Its Asymmetric Variant: Construction of Bicyclo[5.3.0]decane Scaffold. AB - In this paper, a phosphine-catalyzed [8 + 2]-annulation of heptafulvene with allenoates has been achieved under mild conditions, giving functionalized bicyclo[5.3.0]decane derivatives in moderate to excellent yields. Using chiral phosphine as the catalyst, optically active products were obtained in moderate to high yields with excellent enantioselectivities. PMID- 29969284 TI - Conditional effects of mindfulness on sleep quality among clinical nurses: the moderating roles of extraversion and neuroticism. AB - The present study aimed to examine the potential moderating role of personality traits in the psychological mechanisms by which mindfulness can lead to better sleep quality. A total of 172 oncology nurses participated in this study, and completed self-reported measures, including the Mindful Attention Awareness Scale (MAAS), Pittsburgh Sleep Quality Index (PSQI), and 44-item Big Five Inventory (BFI-44). Results showed that mindfulness was correlated with the global PSQI score (r = -0.281, p < 0.01).Trait extraversion and neuroticism moderated the mindfulness-sleep relationship. The simple slope analysis indicated that the negative relationship between mindfulness and the global PSQI score was only significant at higher levels of extraversion (beta = -0.419, p < 0.001) and lower levels of neuroticism (beta = -0.344, p = 0.001). Additionally, the Johnson Neyman technique revealed that, within a specific region (extraversion values above 21.93 and/or neuroticism values below 23.78), mindfulness was significantly associated with the global PSQI score; beyond the value regions, the significant association was lost. It suggests that mindfulness might play a protective role against sleep disturbance only among certain oncology nurses. The findings are valuable for identifying those who are more vulnerable to sleep dysfunction and may aid in targeted intervention planning. PMID- 29969279 TI - Subject specific finite element mesh generation of the pelvis from biplanar x-ray images: application to 120 clinical cases. AB - Several Finite Element (FE) models of the pelvis have been developed to comprehensively assess the onset of pathologies and for clinical and industrial applications. However, because of the difficulties associated with the creation of subject-specific FE mesh from CT scan and MR images, most of the existing models rely on the data of one given individual. Moreover, although several fast and robust methods have been developed for automatically generating tetrahedral meshes of arbitrary geometries, hexahedral meshes are still preferred today because of their distinct advantages but their generation remains an open challenge. Recently, approaches have been proposed for fast 3D reconstruction of bones based on X-ray imaging. In this study, we adapted such an approach for the fast and automatic generation of all-hexahedral subject-specific FE models of the pelvis based on the elastic registration of a generic mesh to the subject specific target in conjunction with element regularity and quality correction. The technique was successfully tested on a database of 120 3D reconstructions of pelvises from biplanar X-ray images. For each patient, a full hexahedral subject specific FE mesh was generated with an accurate surface representation. PMID- 29969270 TI - Reversible Phase Transitions in the Phospholipid Monolayer. AB - The polymorphism of phospholipid monolayers has been extensively studied because of its importance in surface thermodynamics, soft matter physics, and biomembranes. To date, the phase behavior of phospholipid monolayers has been nearly exclusively studied with the classical Langmuir-type film balance. However, because of experimental artifacts caused by film leakage, the Langmuir balance fails to study the reversibility of two-dimensional surface phase transitions. We have developed a novel experimental methodology called the constrained drop surfactometry capable of providing a leakage-proof environment, thus allowing reversibility studies of two-dimensional surface phase transitions. Using dipalmitoylphosphatidylcholine (DPPC) as a model system, we have studied the reversibility of isothermal and isobaric phase transitions in the monolayer. It is found that not only the compression and expansion isotherms but also the heating and cooling isobars, completely superimpose with each other without hysteresis. Microscopic lateral structures of the DPPC monolayer also show reversibility not only during the isothermal compression and expansion processes but also during the isobaric heating and cooling processes. It is concluded that the two-dimensional surface phase transitions in phospholipid monolayers are reversible, which is consistent with the reversibility of phase transitions in bulk pure substances. Our results provide a better understanding of surface thermodynamics, phase change materials, and biophysical studies of membranes and pulmonary surfactants. PMID- 29969281 TI - How Accurate Is Using Parent-Reported Height and Weight for Screening Children and Adolescents for Overweight and Obesity? Meta-Analyses at Both Population and Individual Levels. AB - OBJECTIVE: To explore the accuracy of using parent-reported data for screening children and adolescents with overweight and/or obesity at both population and individual levels by quantitatively synthesizing previous inconsistent findings in the research literature. METHOD: PubMed, Web of Science, and EBSCOhost were searched up to December 2017. A study was included if it explored the accuracy of using parent-reported data (i.e., BMI based on parent-reported height and weight; BMIpr) relative to directly measured data (i.e., BMI based on measured height and weight; BMIm) for screening children and adolescents with overweight and/or obesity. RESULTS: Fourteen studies were identified for the meta-analysis at population level. Using a random-effects model, the use of BMIpr overestimated the prevalence of overweight and obesity among children and adolescents compared with BMIm, with prevalence ratio = 1.118 (95% confidence interval [CI]: 1.027 1.216). Thirteen studies were included in the meta-analysis at individual level. The use of BMIpr for screening children and adolescents with overweight and/or obesity showed a pooled sensitivity of 0.713 (95% CI: 0.700-0.726) and a pooled specificity of 0.918 (95% CI: 0.915-0.922). Moreover, subgroup analyses and meta regressions showed that its accuracy at both levels differed by certain conditions. CONCLUSION: Based on the results of the current two meta-analyses, the use of BMIpr was not accurate at either population level or individual level. However, considering that its accuracy varied by certain conditions, future researchers using BMIpr may consider these findings to achieve a more accurate screening of overweight and obesity among children and adolescents. PMID- 29969277 TI - A Thermally Induced Hydride Transfer from an Amine to an Allene Triggers an Annulation Reaction, Giving Dihydrofuropyridinones. AB - A thermal rearrangement leading to dihydrofuropyridinones and related polycyclic ring systems from furanones and cyclobutenones is described. A key feature of the reaction is the thermally induced hydride transfer from a 3 degrees -amine to a conjugated allene to trigger cyclization. PMID- 29969283 TI - An analysis of the characteristics of road traffic injuries and a prediction of fatalities in China from 1996 to 2015. AB - OBJECTIVES: This study analyzed the characteristics and burdens of road traffic injuries (RTIs) from the 3 perspectives of time, space, and population in China and predicted traffic fatalities using 2 models. METHODS: By extracting data from the China Statistical Yearbooks and GBD 2015 (Global Health Data Exchange), we described the change in the time trend of traffic crashes and economic losses associated with the rate of motorization in China from 1996 to 2015; analyzed the geographical distribution of these events by geographic information system; and evaluated the age-, sex-, and cause-specific death rate, disability-adjusted life year (DALY) rate, years of life lost (YLL) rate, and years lost due to disability (YLD) rate lost from RTIs from 1990 to 2015. In addition, we predicted the traffic fatality (per population or vehicles) trend using the log-linear model derived from Smeed's and Borsos' models. RESULTS: From 1996 to 2015, the motorization rate showed rapid growth, increasing from 0.023 to 0.188. With the growth in the motorization rate, the time trends of traffic crashes and economic losses in China changed, showing a tendency to first increase and then later decrease. The crashes and losses were closely correlated and mainly distributed in some of the economically developed provinces, including Zhejiang, Jiangsu, Anhui, Sichuan, and Guangdong provinces. The health burden of RTIs presented a time trend similar to that of the economic burden, and it was higher among males than females. The death rate among older pedestrians was higher. The DALY rate and YLL rate among young and middle-aged pedestrians were higher. The YLD rate among older motor vehicle drivers was higher. In addition, the fatalities per 10,000 vehicles continued to decline, and Borsos's model was better fitted to the reported traffic fatalities than Smeed's model. CONCLUSIONS: Although the burden of RTIs in China has declined, the burden of RTIs is still heavy. Hence, RTIs remain a universal problem of great public health concern in China, and we need to work hard to reduce them. PMID- 29969282 TI - A Comparative Study on Anti-Invasion, Antimigration, and Antiadhesion Effects of the Bioactive Carotenoids of Saffron on 4T1 Breast Cancer Cells Through Their Effects on Wnt/beta-Catenin Pathway Genes. AB - Crocus sativus L. (saffron) has been used as a spice and as a medicine for the past four thousand years. Recently, saffron has been well documented to possess anticancer effects on primary tumors. However studies of its antimetastatic potential are lacking. The present study is a comparative investigation of the antimetastatic effects of saffron carotenoids, crocin and crocetin, on triple negative metastatic breast cancer cells (4T1) and their effects on the Wnt/beta catenin pathway. It was found that treatment of 4T1 cells with crocin and crocetin resulted in the inhibition of viability in a dose-dependent manner. Scratch and Transwell chamber assays showed that the nontoxic doses of crocin and crocetin significantly inhibited migration, cell mobility, and invasion, also attenuating adhesion to extracellular matrix. Crocin downregulated mRNA expression of FZD7, NEDD9, VIM, and VEGF-alpha genes and upregulated E-CAD. Crocin and crocetin exhibited comparable anti-invasion properties on 4T1 cells. However, crocin and crocetin exerted more pronounced antimigration and antiadhesion potency, respectively. Furthermore, we showed that the antimetastatic effects of crocin can occur through interfering with the Wnt/beta catenin pathway. PMID- 29969285 TI - Systemic-inflammation-based score can predict prognosis in metastatic gastric cancer patients before first-line chemotherapy. AB - AIM: Systemic inflammatory response affects survival of gastric cancer (GC) patients. This study was carried out to create a prognostic inflammatory-based score to predict survival in metastatic GC (mGC) before first-line chemotherapy. MATERIALS & METHODS: We studied the prognostic value of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio in 151 patients with mGC at the diagnosis. RESULTS: Median overall survival (OS) was significantly lower in patients with high NLR. Performance status 1-2 according to the Eastern Cooperative Oncology Group scale and NLR were predictors of shorter OS at multivariate analysis. Based on these results, we defined a prognostic OS score, showing a better median OS in favorable risk group. CONCLUSION: Elevated pretreatment NLR and Eastern Cooperative Oncology Group are independent predictors of shorter OS in mGC patients before first-line chemotherapy. PMID- 29969286 TI - Selective Actionable and Druggable Protein Kinases Drive the Progression of Neuroendocrine Prostate Cancer. AB - Current clinical anti-androgen therapies in advanced prostate cancer (PCa) are driving an increased incidence of neuroendocrine prostate cancer (NEPC), a histological variant exhibiting reduced androgen receptor levels and expression of neuroendocrine markers. The mechanisms underlying the development of NEPC are poorly understood. A set of available data from a well-validated xenograft model of NEPC was used to analyze the exact role of protein kinase (PK) played in the development of NEPC. Fifty-four actionable and druggable PKs, mainly enriched in PI3K-Akt, mTOR, and MAPK signaling pathways, were screened out from the drastically changed PKs during NEPC transdifferentiation. Further analysis based on the crosstalk of these above signaling pathways finally singled out 10 PKs considered drivers and therapeutic targets in the development and treatment of NEPC. In vitro, the variation trend of PK expression observed during NEPC transdifferentiation could be recapitulated in PCa cell lines with different malignant degree. The predicted kinase targets exhibited different sensibilities in the restriction of PC3 cell growth. Selective actionable and druggable PKs may act as drivers in the progression of NEPC, and most of them can be used as potential therapeutic targets in clinical practice. PMID- 29969287 TI - Effect of nutritional interventions with quercetin, oat hulls, beta-glucans, lysozyme and fish oil on performance and health status related parameters of broilers chickens. AB - 1. An experiment was conducted to evaluate the effects of technical feed ingredients between 14 and 28 d of age on performance and health status of broilers (d 14-35) fed diets with a high inclusion rate of rapeseed meal as a nutritional challenge. It was hypothesized that the feed ingredients would improve health status related parameters. 2. A total of 1008 one-day-old male Ross 308 chicks were distributed over 36 floor pens and allocated to one of six iso-caloric (AMEN 13 MJ/kg) growing diets (d 15-28): a control and five test diets supplemented with quercetin (400 mg/kg), oat hulls (50 g/kg), beta-glucan (100 mg/kg), lysozyme (40 mg/kg) or fish oil omega-3 fatty acids (40 g/kg), with six replicate pens per treatment. 3. Dietary inclusion of oat hulls and lysozyme resulted in a reduction in broiler performance during the first week after providing the experimental diets. 4. No effect of interventions on the microbiota diversity in the jejunum and ileum was observed. Ileal microbiota composition of birds fed oat hulls differed from the other groups, as shown by a higher abundance of the genus Enterococcus, mainly at the expense of the genus Lactobacillus. 5. In the jejunum, villus height and crypt depth of lysozyme-fed birds at d 28 were decreased compared to the control group. Higher total surface area of villi occupied by goblet cells and total villi surface area in jejunum (d 21 and 28) were observed in chickens fed oat hulls compared to other groups. 6. Genes related to the growth-factor-activity pathway were more highly expressed in birds fed beta-glucan compared to the control group, while the genes related to anion-transmembrane-transporter-activity pathway in the quercetin- and oat hull fed birds were less expressed. The genes differently expressed between dietary interventions did not seem to be directly involved in immune related processes. 7. It was concluded that the tested nutritional interventions in the current experiment only marginally effected health status related parameters. PMID- 29969289 TI - Serum-Free Cryopreservation of Primary Rat Hepatocytes in a Modified Cold Storage Solution: Improvement of Cell Attachment and Function. AB - AIMS: The use of primary hepatocytes in pharmacological and toxicological research as well as for clinical and biotechnological applications requires adequate storage options for these cells. However, hepatocytes are very susceptible to cryopreservation injury. Based on experience in hypothermic storage of hepatocytes, we, in this study, aimed to optimize hepatocyte cryopreservation. MATERIALS AND METHODS: Rat hepatocytes were cryopreserved in serum-containing cell culture medium or in serum-free solutions optimized for hypothermic storage, all with 10% dimethyl sulfoxide, using a standard protocol ( 1 degrees C/min in a controlled-rate freezer). After rapid thawing, cells were seeded in supplemented Leibovitz-15 cell culture medium without further purification steps. Cell attachment and metabolic activity were assessed. RESULTS: Cell attachment (37% +/- 15% vs. 9% +/- 7% of noncryopreserved control cells) and metabolic activity (resazurin reduction: 47% +/- 23% vs. 25% +/- 8%; glucose release: 44% +/- 6% vs. 15% +/- 7%; and urea production: 31% +/- 16% vs. 5% +/- 8%) were significantly higher after cryopreservation in the new solution compared to cryopreservation in cell culture medium. Experiments with modified solutions suggested that the protective effect of the new solution is multifactorial. CONCLUSIONS: In summary, significant improvement of cell attachment and function compared to cell culture medium was achieved after cryopreservation in serum-free hepatocyte cold storage solution. PMID- 29969288 TI - Daily and weekly training load and wellness status in preparatory, regular and congested weeks: a season-long study in elite volleyball players. AB - The study aimed to assess the changes in the perceived internal load and wellness status of volleyball players in preparatory, regular (i.e. uncongested), and congested weeks during a full season. Thirteen elite volleyball players were studied (237 training sessions and 37 official matches). Session-RPE, muscle soreness, stress, fatigue, sleep quality, and the Hooper Index were measured daily using questionnaires. Training sessions were classified based on the number of matches per week and the days before or after a match: preparatory (no match), regular (one match), and congested weeks (two or more matches). Pairwise comparisons found significantly greater session-RPE scores (p < 0.05) one day before the match (304.74 A.U.), in regular weeks than in congested weeks (204.40 A.U.). Matches during the congested weeks (364.71 A.U.) had significantly higher session-RPE scores (p < 0.05) than regular weeks (252.97 A.U.). Three days before the match involved significantly higher values of muscle soreness, fatigue, stress, and sleep quality than regular weeks. Match accumulation increased the session-RPE training load of the matches. This study provides insights into the training load and well-being status before competition, for training the day of competition, and after the competition. PMID- 29969290 TI - Foot internal stress distribution during impact in barefoot running as function of the strike pattern. AB - The aim of the present study is to examine the impact absorption mechanism of the foot for different strike patterns (rearfoot, midfoot and forefoot) using a continuum mechanics approach. A three-dimensional finite element model of the foot was employed to estimate the stress distribution in the foot at the moment of impact during barefoot running. The effects of stress attenuating factors such as the landing angle and the surface stiffness were also analyzed. We characterized rear and forefoot plantar sole behavior in an experimental test, which allowed for refined modeling of plantar pressures for the different strike patterns. Modeling results on the internal stress distributions allow predictions of the susceptibility to injury for particular anatomical structures in the foot. PMID- 29969292 TI - Does the angulation of the mandibular third molar influence the fragility of the mandibular angle after trauma to the mandibular body? A three-dimensional finite element study. AB - The relationship between mandibular third molar (M3) angulation and mandibular angle fragility is not well established. The aim of this study was to evaluate the impact of M3 angulation on the mandibular angle fragility when submitted to a trauma to the mandibular body region. A three-dimensional (3D) mandibular model without M3 (Model 0) was obtained by means of finite-element analysis (FEA). Four models were generated from the initial model, representing distoangular (Model D), horizontal (Model H), mesioangular (Model M) and vertical (Model V) angulations. A blunt trauma with a magnitude of 2000 N was applied perpendicularly to the sagittal plane in the mandibular body. Maximum principal stress (Pmax) (tensile stress) values were calculated in the bone. The lowest Pmax stress values were noted in Model 0. When the M3 was present extra stress fields were found around marginal bone of second molar and M3. Comparative analysis of the models with M3 revealed that the highest level of stress was found in Model V, whereas Model D showed the lowest stress values. The angulation of M3 affects the stress levels in the mandibular angle and has an impact on mandibular fragility. The mandibular angle becomes more fragile in case of vertical impaction when submitted to a trauma to the mandibular body region. PMID- 29969293 TI - Group Cognitive Behavioral Therapy and Attention Bias Modification for Childhood Anxiety Disorders: A Factorial Randomized Trial of Efficacy. AB - BACKGROUND: The objective of this study is to assess group differences in symptom reduction between individuals receiving group cognitive behavioral therapy (G CBT) and attention bias modification (ABM) compared to their respective control interventions, control therapy (CT), and attention control training (ACT), in a 2 * 2 factorial design. METHODS: A total of 310 treatment-naive children (7-11 years of age) were assessed for eligibility and 79 children with generalized, separation or social anxiety disorder were randomized and received G-CBT (n = 42) or CT (n = 37). Within each psychotherapy group, participants were again randomized to ABM (n = 38) or ACT (n = 41) in a 2 * 2 factorial design resulting in four groups: G-CBT + ABM (n = 21), G-CBT + ACT (n = 21), CT + ABM (n = 17), and CT + ACT (n = 20). Primary outcomes were responder designation as defined by Clinical Global Impression-Improvement (CGI-I) scale (<=2) and change on the Pediatric Anxiety Rating Scale (PARS). RESULTS: There were significant improvements of symptoms in all groups. No differences in response rates or mean differences in PARS scores were found among groups: G-CBT + ABM group (23.8% response; 3.9 points, 95% confidence interval [CI] -0.3 to 8.1), G-CBT + ACT (42.9% response; 5.6 points, 95% CI 2.2-9.0), CT + ABM (47.1% response; 4.8 points 95% CI 1.08-8.57), and CT + ACT (30% response; 0.8 points, 95% CI -3.0 to 4.7). No evidence or synergic or antagonistic effects were found, but the combination of G-CBT and ABM was found to increase dropout rate. CONCLUSIONS: We found no effect of G-CBT or ABM beyond the effects of comparison groups. Results reveal no benefit from combining G-CBT and ABM for anxiety disorders in children and suggest potential deleterious effects of the combination on treatment acceptability. PMID- 29969291 TI - Severe Obstructive Sleep Apnea is Associated with Alterations in the Nasal Microbiome and Increase in Inflammation. AB - RATIONALE: Obstructive Sleep Apnea (OSA) is associated with recurrent obstruction, sub-epithelial edema, and airway inflammation. The resultant inflammation may influence or be influenced by the nasal microbiome. OBJECTIVES: To evaluate whether the composition of the nasal microbiota is associated with obstructive sleep apnea and inflammatory biomarkers. METHODS: Two large cohorts were utilized: 1) a discovery cohort of 472 subjects from the WTCSNORE cohort; and 2) a validation cohort of 93 subjects from the Zaragoza Sleep cohort. Sleep apnea was diagnosed using home sleep tests. Nasal lavages were obtained from cohort subjects to measure: 1) microbiome composition (based on 16S rRNA gene sequencing); 2) biomarkers for inflammation (inflammatory cells, IL-8, and IL-6). Longitudinal 3 months samples were obtained in the validation cohort including post-CPAP treatment when indicated. RESULTS: In both cohorts, we identified that: 1) severity of OSA correlated with differences in microbiome diversity and composition; 2) the nasal microbiome of subjects with severe OSA were enriched with Streptococcus, Prevotella, and Veillonella; 3) the nasal microbiome differences were associated with inflammatory biomarkers. Network analysis identified clusters of co-occurring microbes that defined communities. Several common oral commensals (e.g., Streptococcus, Rothia, Veillonella, and Fusobacterium) correlated with apnea-hypopnea index. Three months of treatment with CPAP did not change the composition of the nasal microbiota. CONCLUSIONS: We demonstrate that the presence of an altered microbiome in severe OSA is associated with inflammatory markers. Further experimental approaches to explore causal links are needed. PMID- 29969294 TI - Detection and Quantification of Seven Major Serogroups of Shiga Toxin-Producing Escherichia coli on Hides of Cull Dairy, Cull Beef, and Fed Beef Cattle at Slaughter?. AB - Dehiding during beef cattle processing can introduce fecal contaminants, including Shiga toxin-producing Escherichia coli (STEC), from hides onto carcass surfaces, creating the potential for contaminated beef. Fecal shedding of major STEC serogroups (O26, O45, O103, O111, O121, O145, and O157; STEC-7) may differ among cattle populations, yet no study has been conducted to isolate STEC-7 on hides of multiple cattle types on the same production days at the same processing plant. Our objective was to estimate and compare prevalence and concentrations of STEC-7 on hides of cull dairy, cull beef, and fed beef cattle from the same date and processing plant. Overall, 1,500 cattle hides were sponge sampled from cull dairy ( n = 500), cull beef ( n = 500) and fed beef cattle ( n = 500) over 10 processing days. To determine prevalence, samples were subjected to an immunomagnetic separation culture method, and presumptive STEC isolates were tested by PCR for serogroup and major virulence genes. A spiral plate method was used to enumerate STEC-7 from hide samples. Data were analyzed with linear mixed models. All STEC-7 serogroups except O121 were detected and quantified on cattle hides in this study population. Slightly more fed beef hides (77 of 500; 15.4%) and cull beef hides (76 of 500; 15.2%) were positive for at least one STEC-7 strain compared with cull dairy hides (57 of 500; 11.4%), but cattle type was not significantly associated ( P = 0.19) with STEC-7 prevalence. Fed beef hides had a significantly higher prevalence ( P < 0.05) of STEC O103, O145, and O157 serogroups than did either of the other cattle types. The highest proportions of quantifiable samples were for STEC O145 (32 of 1,500 samples; 2.1%) and O157 (31 of 1,500 samples; 2.1%) serogroups, with the majority of concentrations at 3 to 5 and 2 to 4 log CFU/100 cm2 of hide, respectively. Results indicate that hide contamination with some major STEC serogroups differs significantly among cattle types at harvest, even within the same day and location. PMID- 29969295 TI - Inactivation of Escherichia coli O157:H7 and Salmonella and Native Microbiota on Fresh Strawberries by Antimicrobial Washing and Coating. AB - Antimicrobial washing (AW), antimicrobial coating (AC), and a combination of washing followed by coating (AW+AC) were evaluated for their ability to inactivate artificially inoculated foodborne pathogens and native microbiota on strawberries stored at 4 degrees C. Strawberries were inoculated with a six strain composite of Escherichia coli O157:H7 and Salmonella; treated by AW, AC, or AW+AC; and stored at 4 degrees C for 3 weeks. The washing solution contained 90 ppm of peracetic acid, and the coating solution consisted of chitosan (1%, w/v), allyl isothiocyanate (1%, v/v), and corn-bio fiber gum (5%, w/v). The effectiveness of the antimicrobial treatments against E. coli O157:H7 and Salmonella pathogens and native microflora on strawberries and their impact on fruit quality (appearance, weight loss, color, and firmness) were determined. By the end of storage, pathogen populations on strawberries were 2.5 (AW+AC), 2.9 (AC), 3.8 (AW), and 4.2 log CFU for the positive (untreated) control. AW+AC treatments also inactivated the greatest population of native microflora, followed by the AC treatment alone. AW+AC treatments showed additional antimicrobial effectiveness against these two pathogens and native microflora. Both AW+AC and AC treatments preserved the color, texture, and appearance of strawberries throughout storage. The coating treatments (AW+AC and AC alone) further reduced the loss of moisture throughout storage. The AW treatment was the least effective in reducing populations of pathogens and native microflora and in maintaining the quality of strawberries throughout storage. This study demonstrates a method to improve the microbiological safety, shelf life, and quality of strawberries. PMID- 29969296 TI - Effects of High Pressure Processing and Hot Water Pasteurization of Cooked Sausages on Inactivation of Inoculated Listeria monocytogenes, Natural Populations of Lactic Acid Bacteria, Pseudomonas spp., and Coliforms and Their Recovery during Storage at 4 and 10 degrees C. AB - The study investigated the effects of high pressure processing (HPP; 600 MPa for 3 min) and hot water (HW; 75 degrees C for 15 min) pasteurization on the inactivation of inoculated Listeria monocytogenes, natural populations of lactic acid bacteria, Pseudomonas spp., and coliforms in vacuum-packaged cooked sausages and their recovery during storage at 4 and 10 degrees C for 35 days. Cooking sausages to an internal temperature of 72 degrees C resulted in a >6-log reduction in numbers of inoculated L. monocytogenes. Storage at 4 degrees C resulted in no significant difference ( P > 0.05) in L. monocytogenes numbers in sausages pasteurized by either HPP or HW compared with unpasteurized control. However, at 10 degrees C, L. monocytogenes numbers in unpasteurized control sausages increased to about 7 log CFU/g by day 35, whereas in HPP-pasteurized sausages, numbers remained below the detection limit for up to 21 days and then increased to 4.5 log CFU/g by day 35. HW pasteurization resulted in inhibition of L monocytogenes to below the detection limit throughout the 35-day storage at 10 degrees C. Natural lactic acid bacteria populations were significantly reduced by HPP and HW pasteurization and continued to be significantly lower at the end of the 35-day storage. Unlike most studies that focus on HPP or HW treatment of postcooking surface contamination of meat with Listeria, this study examined the combined effect of cooking, HPP, and HW on raw meat with a high contamination level. This scenario is important in countries where raw meat supply and in-store refrigeration are a challenge. The results suggest that HPP and HW pasteurization could be used to successfully enhance the safety and shelf life of cooked sausages and that HW pasteurization (75 degrees C) was more effective than HPP (600 MPa) to control L. monocytogenes. PMID- 29969297 TI - The effect of omalizumab on hematological and inflammatory parameters in patients with chronic spontaneous urticaria. AB - PURPOSE: The mechanism of action of omalizumab in chronic spontaneous urticaria (CSU) is not exactly known. In previous studies, d-dimer which is a fibrin degradation product and interleukin-31 which has a role in inflammation were found to be decreased in patients with chronic urticaria treated with omalizumab. However, to our knowledge, there is no study on the effects of omalizumab on the ratio of neutrophil to lymphocyte (NLR) and the ratio of platelet to lymphocyte (PLR) which are inflammatory parameters in patients with CSU in the PubMed database. In this study, we aimed to evaluate the effects of omalizumab on hematological and inflammatory parameters in patients with CSU. MATERIALS AND METHODS: One hundred six CSU patients treated with omalizumab were evaluated retrospectively. Complete blood count (CBC) and C-reactive protein (CRP) levels before treatment and at the third month of treatment were recorded. NLR and PLR were calculated from the CBC results. CBC parameters, CRP levels, NLR and PLR of the patients before treatment and at the end of third month of treatment were compared. RESULTS: There was a significant decrease in white blood cell count, platelet count, neutrophil count, CRP level, NLR and PLR and a significant increase in mean platelet volume and eosinophil count with omalizumab treatment in CSU patients (p < 0.05). Basophil count increased; but there was no statistically significant difference (p = 0.293). CONCLUSION: This study shows that omalizumab has not only anti Ig E effect, but also it may have inhibitory effects on inflammation and coagulation in patients with CSU. Further prospective studies are warranted in order to evaluate the effect of omalizumab on hematological and inflammatory parameters and correlation between omalizumab response rate and these inflammatory parameters in patients with CSU. PMID- 29969298 TI - Effects of Pycnogenol on cisplatin-induced optic nerve injury: an experimental study. AB - AIM: To determine the effects of Pycnogenol on cisplatin-induced optic nerve damage. MATERIAL AND METHOD: Totally 18 albino Wistar male rats were assigned into three groups, with six rats in each group as follows: healthy controls (HC group), only cisplatin (2.5 mg/kg) administered group (CIS group) and Pycnogenol (40 mg/kg) + cisplatin (2.5 mg/kg) administered group (PYC group). We analyzed the levels of malondialdehyde (MDA) as a marker of lipid peroxidation and oxidative stress, total glutathione (tGSH) as a marker of antioxidant status, nuclear factor-kappa B (NF-kappaB) and tumor necrosis factor alpha (TNF-alpha) as inflammatory markers, total oxidative status (TOS) and total antioxidant status (TAS) on eye tissue together with histopathological evaluation of optic nerve in an experimental model. RESULTS: In CIS group MDA, TOS, TNF-alpha and NF-kappaB levels were statistically significantly higher (p < 0.001) than HC group while tGSH and TAS levels were significantly lower (p < 0.001). On the other hand, in PYC group MDA, TOS, TNF-alpha and NF-kappaB levels were statistically significantly lower (p < 0.001) than CIS group while tGSH and TAS levels were significantly higher (p < 0.001). CONCLUSION: Pycnogenol pretreatment was highly effective in preventing augmentation of cisplatin-induced oxidative stress and inflammation in eye tissue. PMID- 29969299 TI - Articulation or phonology? Evidence from longitudinal error data. AB - Children's speech difficulties can be motor (phone misarticulation) or linguistic (impaired knowledge of phonological contrasts and constraints). These two difficulties sometimes co-occur. This paper reports longitudinal data from the Early Language in Victoria Study (ELVS) at 4 and 7 years of age. Of 1494 participants, 93 made non-age appropriate speech errors on standardised assessments at 4 years, and were able to be reassessed at 7 years. At 4 years, 85% of these children only made phonological errors, 14% made both articulation and phonological errors and one child only made articulation errors (a lateral lisp). In total, 8 of 13 children making both articulation and phonological errors at 4 years had resolved by 7 years. Unexpectedly, eight children who had demonstrated articulation of fricatives at 4 years, acquired distorted production of >= 50% of occurrences of/s, z/ by 7 years. In total, then, 22 children (24% of children with speech difficulties) made articulatory errors at one or both assessments. Case data for all children are presented. Theoretical and clinical implications are considered. PMID- 29969300 TI - Comparative enhancement of curcumin cytotoxic photodynamic activity by nanoliposomes and gold nanoparticles with pharmacological appraisal in HepG2 cancer cells and Erlich solid tumor model. AB - Curcumin is a natural pigment that generates singlet oxygen upon light excitation, hence it can be used as a photosensitizer in photodynamic therapy. The extremely low water solubility and poor systemic bioavailability make curcumin a challenging molecule to be used clinically. In this study, two nanocarrier systems for curcumin were prepared and characterized; nanoliposomes and polyvinyl pyrrolidone-capped gold nanoparticles. The dark and photocytotoxicity were investigated as a function of light fluence rate (100 and 200 mW/cm2) on HepG2 cancer cells. In vivo Erlich tumor model was developed and comparison of the tumor volume, survival rate, and histopathological alterations was made for the two nanocarriers. Results showed that both curcumin nanocarriers were successfully prepared and characterized. Light irradiation was able to augment the cytotoxicity of both curcumin liposomes and gold nanoparticles, with the former being superior in cytotoxicity compared to the latter. The tumor size was almost diminished 1 month post-photodynamic treatment for both systems with regression in the number of tumor cells upon histopathological evaluation, with curcumin liposomes producing better tumor regression than gold nanoparticles with comparable survival rate. Liposomes were confirmed to be superior to gold nanoparticles as a photodynamic treatment modality for cancer. PMID- 29969301 TI - A randomized, double-blind and placebo-controlled crossover trial on the effect of l-ornithine ingestion on the human circadian clock. AB - In mammals, daily physiological events are regulated by the circadian rhythm, which comprises two types of internal clocks: the central clock and peripheral clocks. Circadian rhythm plays an important role in maintaining physiological functions including the sleep-wake cycle, body temperature, metabolism and organ functions. Circadian rhythm disorder, which is caused, for example, by an irregular lifestyle or long-haul travel, increases the risk of developing disease; therefore, it is important to properly maintain the rhythm of the circadian clock. Food and the circadian clock system are known to be closely linked. Studies on rodents suggest that ingesting specific food ingredients, such as the flavonoid nobiletin, fish oil, the polyphenol resveratrol and the amino acid L-ornithine affects the circadian clock. However, there are few reports on the foods that affect these circadian clocks in humans. In this study, therefore, we examined whether L-ornithine affects the human central clock in a crossover design placebo-controlled human trial. In total, 28 healthy adults (i.e. >=20 years) were randomly divided into two groups and completed the study protocol. In the 1st intake period, participants were asked to take either L-ornithine (400 mg) capsules or placebo capsules for 7 days. After 7 days' interval, they then took the alternative test capsules for 7 days in the 2nd intake period. On the final day of each intake period, saliva was sampled at various time points in the dim light condition, and the concentration of melatonin was quantified to evaluate the phase of the central clock. The results revealed that dim light melatonin onset, a recognized marker of central circadian phase, was delayed by 15 min after ingestion of L-ornithine. Not only is this finding an indication that L-ornithine affects the human central clock, but it also demonstrates that the human central clock can be regulated by food ingredients. PMID- 29969302 TI - Role of oxidative stress and antioxidant therapy in acute and chronic phases of sulfur mustard injuries: a review. AB - Sulfur mustard (SM) is a chemical compound that preferentially targets ocular, cutaneous and pulmonary tissues. Although pathologic effect of SM has been extensively considered, molecular and cellular mechanism of its toxicity, especially at the chronic phase of injury is not well-understood. Excessive production of reactive oxygen species (ROS) and oxidative stress (OS) appears to be involved in SM-induced injuries. SM may trigger several molecular and cellular pathways linked to OS and inflammation that can subsequently result in cell death and apoptosis. At the acute phase of injury, SM can enhance ROS production and OS by reducing the activity of antioxidants, depletion of intercellular glutathione (GSH), decreasing the productivity of GSH-dependent antioxidants, mitochondrial deficiency, accumulation of leukocytes and pro-inflammatory cytokines. Overexpression of ROS producing enzymes and down-regulation of antioxidant enzymes are probably the major events by which SM leads to OS at the chronic phase of injury. Therefore, antioxidant therapy with potent antioxidants such as N-acetylcysteine and curcumin may be helpful to mitigate SM-induced OS damages. This review aims to discuss the proposed cellular and molecular mechanisms of acute and delayed SM toxicity, the importance of OS and mechanisms by which SM increases OS either at the acute or chronic phases of injuries along with research on antioxidant therapy as a suitable antidote. PMID- 29969303 TI - Leveraging a Legacy of Activism: Black Lives Matter and the Future of HIV Prevention for Black MSM. AB - This year marks the 30th anniversary of AIDS Education and Prevention. As we approach the United Nations goal of ending the AIDS epidemic by 2030, it is a useful time to reflect on and learn from history. In the United States, no such endeavor can be successful without addressing the specific context of Black men who have sex with men. In this commentary I highlight factors that led us to a state in which Black MSM represent approximately a quarter of all people living with HIV in the United States. I also look back at the power of activism during the beginning of the HIV epidemic. Using Black Lives Matter as a contemporary framework, I highlight natural linkages between activism 30 years ago, its incarnation and relationship to public health today, and its promise as the way forward in achieving the elimination of AIDS for Black MSM by 2030. PMID- 29969304 TI - The Evolution of HIV Prevention Programming: Moving From Intervention to System. AB - Accelerating the fight against HIV globally and achieving the goals of the U.S. National HIV/AIDS Strategy will require an integrated health system that addresses all dimensions of wellness and is not limited to disease diagnosis and treatment or to monolithic prevention strategies. Since the HIV/AIDS epidemic was first recognized in 1981, HIV prevention strategies have evolved from early, information-based efforts to theory-informed and evidence-based approaches. More recently, the growing recognition that social and economic factors play a major role in shaping population health outcomes has driven HIV prevention and care programs in the direction of "people-centered health systems," as called for in the 2016 United Nations General Assembly declaration to end AIDS by 2030. This commentary examines recent innovations in HIV program design and implementation (e.g., using data in novel ways to improve HIV health outcomes, providing incentives to promote integrated HIV prevention and care, and developing mechanisms to proactively address the social determinants affecting health) that embrace a comprehensive vision of health that is much broader than the absence of detectable virus. PMID- 29969305 TI - Introduction to the Special Issue: Ending the AIDS Pandemic by 2030: Accelerating Efforts to Prevent HIV. PMID- 29969306 TI - Women and HIV in the Twenty-First Century: How Can We Reach the UN 2030 Goal? AB - Women have always been part of the HIV/AIDS epidemic. As with other populations affected by HIV, for many years the only prevention strategy available was behavior change. Behavioral interventions for women were developed and evaluated, with some success. Because women did not control the use of male condoms, efficacious interventions needed to build skills for partner negotiation. Woman controlled technologies such as the female condom and vaginal spermicide were unable to solve the problem of male control of the condom and enable the development of safe methods for women to protect themselves. The modern era of HIV prevention has produced biomedical solutions based on highly active retroviral chemoprophylaxis, which can be hidden from the male partner and thus eliminate his possible negative reactions. Pre-exposure prophylaxis holds promise for HIV prevention among women. This article reviews the literature on HIV prevention for women, including both successes and challenges. PMID- 29969307 TI - Global Citizen, Immigrant, Survivor, Activist, Gayby Boomer, Academic, and Editor: Dr. Sy and the History of AIDS Education and Prevention. AB - In this 30th anniversary of AIDS Education and Prevention, we turn our attention to its founder and editor, Dr. Francisco Sy. I trace Dr. Sy's trajectory, from growing up in a Filipino-Chinese family in Manila to Harvard, Johns Hopkins, South Carolina, and then to the journal. The loss of friends and colleagues to the AIDS epidemic stands out as Sy's driving force behind the journal. AIDS Education and Prevention was also created to fill a tremendous gap in the field: a scientific platform to circulate and discuss research on HIV and AIDS prevention. Over its life course, the content of the journal has mirrored the life of epidemic. Initially, the articles focused on knowledge, attitudes, and behaviors, mostly in the United States. Now, the articles deal with health interventions and pre-exposure prophylaxis, with authors coming from all over the globe. In Sy's opinion, HIV will become endemic, as other infectious diseases have over our history of epidemics, so the role of journals such as AIDS Education and Prevention will remain vital. PMID- 29969309 TI - Cutting-Edge Success in Preventing Heterosexual HIV Transmission in Africa: Voluntary Medical Male Circumcision Has Reached 15 Million Men. AB - Male circumcision is a minor surgery performed for religious and medical reasons. Three randomized clinical trials demonstrated it could reduce heterosexual HIV transmission from infected females to males by over 60%, paving the way in 2006 for multinational efforts to circumcise 27 million men in sub-Saharan Africa by 2021. It is estimated that by 2030 male circumcision will avert at least 500,000 HIV infections in Africa, saving lives and budgets. Voluntary medical male circumcision (VMMC) of adults and adolescents has challenged policy makers, implementers, funders, and civil society in bringing surgery to the frontline of HIV prevention. Five key challenges are discussed: policy, clinical, demand, supply, and scaling up. A unique Israel-Senegal-South Africa collaboration, which enhanced high-volume (100 VMMCs per day) and high-quality (less than 2% minor adverse events) procedures, is described, highlighting VMMC as one of the most impressive public health collaborative interventions in HIV/AIDS prevention globally. PMID- 29969308 TI - Community-Engaged Research as an Approach to Expedite Advances in HIV Prevention, Care, and Treatment: A Call to Action. AB - Throughout the world, we continue to face profound challenges to reducing the impact of the HIV epidemic. Community-engaged research has emerged as an approach to increase our understanding of HIV and reduce health disparities, increase health equity, and promote community and population health. Our partnership has conducted more than 25 community-engaged research studies in the U.S. and Guatemala, and members have identified nine themes to facilitate community engaged research and expedite advances in HIV prevention, care, and treatment. These themes include the inclusion of multisectoral partners, trust building and maintenance, the alignment of partner priorities, a can-do attitude, capacity and desire to move beyond service and conduct research, flexibility, power sharing, empowerment, an assets orientation, the shared and timely use of findings, and a stepwise approach. To reduce HIV disparities, community-engaged research is as critical now as ever, and we desperately need to reinvigorate our commitment to and support of it. PMID- 29969310 TI - Economic and Policy Analytic Approaches to Inform the Acceleration of HIV Prevention in the United States: Future Directions for the Field. AB - The fields of economic and policy analysis have long played a role in quantifying the burden of the HIV epidemic and informing how to best deploy interventions and policies aimed at maximizing HIV care and reducing transmission. Looking towards the ultimate goal of ending the AIDS epidemic, we describe five areas for further development and application towards HIV policies: (1) setting measurable objectives to create a vision and monitor progress, (2) taking a health and wellness approach to goal-setting, (3) using impact matrices to inform quantitative analysis to explicitly address health disparities, (4) conducting budget impact analyses to project annual program costs and benefits, and (5) advancing the public health systems and services research agenda. PMID- 29969311 TI - HIV Education: Reflections on the Past, Priorities for the Future. AB - From early in the epidemic, education has been central to HIV prevention, treatment, and care. This paper reflects on lessons learned over the last 30 years. It signals the limits of high level international commitments to education and HIV and the strategies of information-giving and life skills development adopted in their wake. It argues for the adoption of a more genuinely educational approach to HIV, sex, and sexuality education in which difficult questions are raised, diversity is recognized, and options are provided for a differentiated yet effective response. The lead currently offered by community organizations and the social media should be built upon in developing forms of HIV education that are more honest and contextually relevant than previously. PMID- 29969312 TI - Getting to Zero: We Can't Do It Without Addressing Substance Use. AB - HIV elimination by 2030 cannot occur without attention to substance use. It cuts across risk groups and affects sexual risk behavior, treatment adherence, and systemic processes such as immunity and inflammation. There continues to be often limited attention to non-injection drug use and the syndemic character of HIV and substance use. There is a need for a more comprehensive approach that addresses the multiple influences of substance use on HIV prevention and care, integrating this into evidence-based services and building on the successes of comprehensive Seek, Test, Treat, and Retain approaches to substantially reducing new HIV cases among drug users. PMID- 29969314 TI - Formoterol treatment prevents the effects of endotoxin on muscle TNF/NF-kB, Akt/mTOR, and proteolytic pathways in a rat model. Role of IGF-I and miRNA 29b. AB - Inflammatory diseases are associated with muscle wasting as a result of an increase in proteolysis. The purpose of this study was to elucidate whether administration of a beta2 adrenergic agonist, formoterol, was able to prevent the acute effects of sepsis induced by liposaccharide (LPS) injection on rat gastrocnemius muscle and to evaluate the possible roles of corticosterone, IGF-I, miR-23a, and miR-29b. For this purpose, male Wistar rats were injected with LPS and/or formoterol. Formoterol treatment decreased LPS-induced increase in serum corticosterone, TNFalpha upregulation, and NF-kappaB(p65) and Forkhead box protein O1 activation in the gastrocnemius. Atrogin-1, muscle RING-finger protein 1, microtubule-associated protein-1 light chain 3b (LC3b), and the lipidation of LC3b-I to LC3b-II were increased by LPS, and formoterol blocked these effects. Serum IGF-I and its mRNA levels in the gastrocnemius were decreased, whereas mecano growth factor and IGF binding protein 3 mRNA levels were increased in the rats injected with LPS but not in the rats that received LPS and formoterol. Similarly, LPS decreased Akt and mammalian target of rapamycin phosphorylation, and formoterol blocked these decreases. Finally, miR-29b expression in the gastrocnemius was upregulated by endotoxin injection, whereas miR-23a was not significantly different. Formoterol treatment did not significantly modify LPS induced increase in muscle miR-29b. Furthermore, in control rats formoterol increased the expression of this miRNA. We conclude that formoterol decreases endotoxin-induced inflammation and proteolysis in rat skeletal muscle. Those responses can be a direct effect of beta2 adrenergic receptor stimulation or/and of blocking the effects of LPS on corticosterone and IGF-I. Muscle miR-23a and 29b do not seem to play an important role in those responses. PMID- 29969313 TI - The role of language proficiency and linguistic distance in cross-linguistic treatment effects in aphasia. AB - Current findings from intervention in bilingual aphasia are inconclusive regarding the extent to which levels of language proficiency and degree of linguistic distance between treated and non-treated languages influence cross language generalisation and changes in levels of language activation and inhibition following treatment. In this study, we enrolled a 65-year-old multilingual speaker with aphasia and administered treatment in his L1, Dutch. We assessed pre- and post-treatment performance for seven of his languages, five of high proficiency and two of lower proficiency. We asked whether treatment in L1 would generalise to his other languages or increase interference among them. Forty hours of treatment were completed over the course of five weeks. Each language was tested three times at pretreatment and at post-treatment. Testing included measures of narrative production, answering questions, picture description and question generation. Dependent measures examined language efficiency, defined as Correct Information Units (CIUs)/min, as well as language mixing, defined as proportion of code-mixed whole words. We found that our participant's improved efficiency in Dutch was mirrored by parallel improvement in the four languages of high proficiency: English, German, Italian and French. In contrast, in his languages of lower proficiency, Norwegian and Spanish, improved efficiency was limited. An increase in code-mixing was noted in Spanish, but not in Norwegian. We interpret the increased code-mixing in Spanish as indication of heightened inhibition following improvement in a language of close linguistic proximity, Italian. We conclude that an interaction of language proficiency and linguistic similarity affects cross-language generalisation following intervention in multilingual aphasia. PMID- 29969315 TI - Antipsychotics and glucose metabolism: how brain and body collide. AB - Since the serendipitous discovery of the first antipsychotic (AP) drug in the 1950's, APs remain the cornerstone of treatment for schizophrenia. A shift over the past two decades away from first generation, conventional APs to so-called "atypical" (or second/ third generation) APs parallels acknowledgment of serious metabolic side-effects. As will be reviewed, AP drugs and type 2 diabetes are now inextricably linked, likely contributing to the 2-3-fold increased risk of type 2 diabetes observed in schizophrenia. However, this association is not straightforward. Biological and lifestyle-related illness factors contribute to the association between type 2 diabetes and metabolic disease independent of antipsychotic treatment. In addition, APs have a well-established weight gain propensity which could also account for elevated risk of insulin resistance and type 2 diabetes. However, compelling preclinical and clinical evidence now suggests that these drugs can rapidly influence pathways of glucose metabolism independently of weight gain, and even in absence of psychiatric illness. The clinical relevance of studying "direct" effects of these drugs on glucose metabolism is underscored by the widespread use of these medications both on- and off- label for a growing number of mental illnesses, extending safety concerns beyond schizophrenia. PMID- 29969316 TI - Effects of starvation and short-term refeeding on gastric emptying and postprandial blood glucose regulation in adolescent girls with anorexia nervosa. AB - Postprandial glucose is reduced in malnourished patients with anorexia nervosa (AN), but the mechanisms and duration for this remain unclear. We examined blood glucose, gastric emptying, and glucoregulatory hormone changes in malnourished patients with AN and during 2 wk of acute refeeding compared with healthy controls (HCs). Twenty-two female adolescents with AN and 17 age-matched female HCs were assessed after a 4-h fast. Patients were commenced on a refeeding protocol of 2,400 kcal/day. Gastric emptying (13C-octanoate breath test), glucose absorption (3-O-methylglucose), blood glucose, plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, C-peptide, and glucagon responses to a mixed-nutrient test meal were measured on admission and 1 and 2 wk after refeeding. HCs were assessed once. On admission, patients had slower gastric emptying, lower postprandial glucose and insulin, and higher glucagon and GLP-1 than HCs ( P < 0.05). In patients with AN, the rise in glucose (0-30 min) correlated with gastric emptying ( P < 0.05). With refeeding, postprandial glucose and 3-O-methylglucose were higher, gastric emptying faster, and baseline insulin and C-peptide less ( P < 0.05), compared with admission. After 2 wk of refeeding, postprandial glucose remained lower, and glucagon and GLP-1 higher, in patients with AN than HCs ( P < 0.05) without differences in gastric emptying, baseline glucagon, or postprandial insulin. Delayed gastric emptying may underlie reduced postprandial glucose in starved patients with AN; however, postprandial glucose and glucoregulatory hormone changes persist after 2 wk of refeeding despite improved gastric emptying. Future research should explore whether reduced postprandial glucose in AN is related to medical risk by examining associated symptoms alongside continuous glucose monitoring during refeeding. PMID- 29969317 TI - Recurrent non-severe hypoglycemia exacerbates imbalance of mitochondrial homeostasis leading to synapse injury and cognitive deficit in diabetes. AB - Recurrent non-severe hypoglycemia (RH) can lead to cognitive dysfunction in diabetic patients, although the involved mechanisms remain unclear. Here, we aimed to investigate the mechanism underlying RH-induced cognitive deficits with a focus on mitochondrial homeostasis. To establish a model that mimicked RH in type 1 diabetic (T1DM) patients receiving insulin therapy, streptozotocin (STZ) induced mice with T1DM were subjected to recurrent, twice-weekly, insulin injections over 4 weeks. We found that RH disrupted the mitochondrial fine structure, reduced the number of mitochondria, and upregulated the expression of mitochondrial dynamics and mitophagy markers, including dynamin-related protein 1 (Drp1), Bcl-2/adenovirus E1B 19-kDa-interacting protein-3 (BNIP3), and LC3 in the hippocampus of T1DM mice. Moreover, RH and chronic hyperglycemia synergistically promoted the production of reactive oxygen species, impaired mitochondrial membrane potential, and suppressed mitochondrial energy metabolism. Under diabetic conditions, RH also altered the synaptic morphology and reduced the expression of synaptic marker proteins. Long-term recognition memory and spatial memory, assessed with the Morris water maze test, were also impaired. However, these effects were largely prevented by mitochondrial division inhibitor 1 (Mdivi 1) - a potent and selective Drp1 inhibitor. Thus, it appears that RH exacerbates the imbalance of mitochondrial homeostasis, leading to synapse injury and cognitive deficits in diabetes. The adjustment of mitochondrial homeostasis could serve as an effective neuroprotective approach when addressing low blood sugar conditions. PMID- 29969318 TI - Circulatory exosomal miRNA following intense exercise is unrelated to muscle and plasma miRNA abundances. AB - MicroRNAs (miRNAs) regulate gene expression via transcript degradation and translational inhibition, and they may also function as long distance signaling molecules. Circulatory miRNAs are either protein-bound or packaged within vesicles (exosomes). Ten young men (24.6 +/- 4.0 yr) underwent a single bout of high-intensity interval cycling exercise. Vastus lateralis biopsies and plasma were collected immediately before and after exercise, as well as 4 h following the exercise bout. Twenty-nine miRNAs previously reported to be regulated by acute exercise were assessed within muscle, venous plasma, and enriched circulatory exosomes via qRT-PCR. Of the 29 targeted miRNAs, 11 were altered in muscle, 8 in plasma, and 9 in the exosome fraction. Although changes in muscle and plasma expression were bidirectional, all regulated exosomal miRNAs increased following exercise. Three miRNAs were altered in all three sample pools (miR-1 3p, -16-5p, and -222-3p), three in both muscle and plasma (miR-21-5p, -134-3p, and -107), three in both muscle and exosomes (miR-23a-3p, -208a-3p, and -150-5p), and three in both plasma and exosomes (miR-486-5p, -126-3p, and -378a-5p). There was a marked discrepancy between the observed alterations between sample pools. A subset of exosomal miRNAs increased in abundance following exercise, suggesting an exercise-induced release of exosomes enriched in specific miRNAs. The uniqueness of the exosomal miRNA response suggests its relevance as a sample pool that needs to be further explored in better understanding biological functions. PMID- 29969321 TI - Role of Mushroom as Dietary Supplement on Performance of Poultry. AB - The objective of this review is to summarize the effect of commonly used mushrooms (particularly Pleurotus ostreatus or oyster mushroom, Agaricus bisporus or Button mushroom, Lentimula edodes or shiitake mushroom, and Ganoderma lucidum or reishi mushroom) in poultry diets on performance of broilers and layers. It can be concluded from different studies that mushrooms and their polysaccharides can play important roles in poultry production: (1) Polysaccharides in mushrooms may act as immune enhancers or immunomodulators and show antibacterial, antiviral, antiparasitic bioactivities; (2) phenolic compounds of mushrooms may act as antioxidants; (3) mushrooms in broiler's diet may be used as growth promoters as an alternative to antibiotics; (4) mushrooms in the diet may improve egg production and quality; (5) mushrooms may be used as a safe and effective alternative for inducing molt, enhancing immunity, reducing Salmonella growth, and returning to egg production. Further studies are needed to investigate the effects of mushrooms to improve productive performance in chickens and to illuminate the possible modes of action related to the gut ecosystem and the immune response. PMID- 29969320 TI - Procalcitonin-guided antibiotic therapy algorithms for different types of acute respiratory infections based on previous trials. AB - INTRODUCTION: Although evidence indicates that use of procalcitonin to guide antibiotic decisions for the treatment of acute respiratory infections (ARI) decreases antibiotic consumption and improves clinical outcomes, algorithms used within studies had differences in PCT cut-off points and frequency of testing. We therefore analyzed studies evaluating procalcitonin-guided antibiotic therapy and propose consensus algorithms for different respiratory infection types. Areas covered: We systematically searched randomized-controlled trials (search strategy updated on February 2018) on procalcitonin-guided antibiotic therapy of ARI in adults using a pre-specified Cochrane protocol and analyzed algorithms from 32 trials that included 10,285 patients treated in primary care settings, emergency departments (ED), and intensive care units (ICU). We derived consensus algorithms for use of procalcitonin by the type of ARI including community-acquired pneumonia, bronchitis, chronic obstructive pulmonary disease or asthma exacerbation, sepsis, and post-operative sepsis due to respiratory infection. Consensus algorithm recommendations differ with regard to timing of treatment (i.e. timing of initiation in low-risk patients or discontinuation in high-risk patients) and procalcitonin cut-off points for the recommendation/strong recommendation to discontinue antibiotics (<= 0.25/<= 0.1 ug/L in ED and inpatients, <= 0.5/<= 0.25 ug/L in ICU patients, and reduction by >= 80% from peak levels in sepsis patients). Expert commentary: Our proposed algorithms may facilitate safe and efficient implementation of procalcitonin-guided antibiotic protocols in diverse healthcare settings. Still, the decision about initiation and cessation of antibiotic treatment remains a clinical decision based on the patient assessment and the severity of illness and use of procalcitonin should not delay empirical treatment in high risk situations. PMID- 29969322 TI - Balancing efficacy and toxicity of targeted agents currently used for the treatment of patients with chronic lymphocytic leukemia. AB - INTRODUCTION: In recent years, innovative mechanism-based drugs have enriched the therapeutic armamentarium for patients with chronic lymphocytic leukemia (CLL) and are widely used in the clinical practice. These small molecules targeting the B-cell receptor signaling pathway and the BCL-2 anti-apoptotic protein offer new chemo-free options to both unfit patients and high-risk patients who show a poor response to chemoimmunotherapy. Nonetheless, treatment with ibrutinib, idelalisib and venetoclax is associated with unique side effects. Awareness, prevention and the appropriate management of these specific toxicities are of crucial importance for a successful treatment. Areas covered: The purpose of this review is to discuss the most relevant studies on small molecules in CLL, with particular attention to the emerging toxicity profile of these agents and to the factors that should be considered to address the most appropriate treatment approach for each patient. Expert opinion: The increased knowledge on the biology of CLL has translated into the development of targeted agents that are highly effective and produce deep responses. Toxicities potentially associated with these agents should be known for an optimal management of CLL patients. PMID- 29969324 TI - Evaluation of the growth factors VEGF-a and VEGF-B in the vitreous and serum of patients with macular and retinal vascular diseases. AB - VEGF-A and VEGF-B are proangiogenic and key regulating factors for blood vessel growth. This study aims to compare VEGF-A and VEGF-B levels in the serum and vitreous of patients with neovascular pathology versus non-neovascular pathology. Our findings showed vitreous VEGF-A and VEGF-B levels increased in patients with neovascular disease, with higher levels of VEGF-A compared to VEGF-B (p <= .05). In the diabetic retinopathy (DR) group, higher vitreous VEGF-A or VEGF-B were found in proliferative diabetic retinopathy (PDR) than in non-PDR. The strong correlation between VEGF-A and VEGF-B demonstrates a simultaneous pathological increase of cytokines (p < .001), suggesting besides VEGF-A, VEGF-B is another contributor to ocular pathologies involving angiogenesis. There was no correlation between vitreous and serum VEGF-A or VEGF-B; however, a correlation between vitreous (VEGF-A or VEGF-B) and macular volume (p < .05) in DR patients was found. Targeting VEGF-A and VEGF-B in macular and retinal vascular diseases, involving neovascularization, may improve treatment outcomes. PMID- 29969325 TI - Effect of Genistein on the Transgenic Drosophila Model of Parkinson's Disease. AB - Parkinson's disease (PD) is the second-most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress has also been linked with the progression of PD, hence the involvement of a natural plant product could offer neuroprotection. The present study deals with the effect of genistein on the transgenic flies expressing normal human alpha synuclein panneurally. The PD flies were exposed to 10, 20, 30, and 40 uM of genistein (mixed in diet) for 24 days. A significant dose-dependent increase in the life span and delay in the loss of climbing ability were observed in the PD flies exposed to genistein (p < .05). A significant dose-dependent decrease in oxidative stress markers and increase in dopamine content were observed in PD flies exposed to genistein. However, the exposure of genistein did not inhibit the expression of alpha synuclein in the brains of PD flies. PMID- 29969326 TI - Beta-Hydroxy-Beta-Methyl-Butyrate, L-glutamine, and L-arginine Supplementation Improves Radiation-Induce Acute Intestinal Toxicity. AB - We aimed to evaluate effects of beta-hydroxy-beta-methylbutyrate, L-glutamine, and L-arginine (HMB/GLN/ARG) on radiation-induced acute intestinal toxicity. Forty rats were divided into four groups: group (G) 1 was defined as control group, and G2 was radiation therapy (RT) control group. G3 and G4 were HMB/GLN/ARG control and RT plus HMB/GLN/ARG groups, respectively. HMB/GLN/ARG started from day of RT and continued until the animals were sacrificed 10 days after RT. The extent of surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis, crypt distortion, regenerative atypia, vascular dilatation and congestion, and fibrosis were quantified on histological sections of intestinal mucosa. Statistical analyses were performed using the analysis of variance (ANOVA) test. There were significant differences between study groups regarding extent of surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis and crypt distortion, regenerative atypia, vascular dilatation and congestion, and fibrosis (p values were 0.019 for fibrosis, <.001 for the others). Pair-wise comparisons revealed significant differences regarding surface epithelium smoothing, villous atrophy, lamina propria inflammation, cryptitis, vascular dilatation, and congestion between G2 and G4 (p values were <.001, .033, <.001, .007, and <.001, respectively). Fibrosis score was significantly different only between G1 and G2 (p = .015). Immunohistochemical TGF-beta score of G2 was significantly higher than G1 and G3 (p values were .006 and .017, respectively). There was no difference between TGF-beta staining scores of G2 and G4. Concomitant use of HMB/GLN/ARG appears to ameliorate radiation induced acute intestinal toxicity; however, this finding should be clarified with further studies. PMID- 29969327 TI - Mothers' emotional states and attitudes regarding their children with asthma. AB - OBJECTIVES: The aim of this study was to investigate the associations of asthma with the psychological profile (depression and anxiety) of children with asthma and their mothers as well as the attitudes of these mothers toward their children and their family relationships. METHODS: Sixty-four children with asthma, 60 healthy children and their mothers were included in the study. The Children's Depression Inventory (CDI) and Childhood Anxiety Sensitivity Index (CASI) were applied to the children. All mothers completed the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Parental Attitude Research Instrument and the Family Assessment Device. RESULTS: CASI scores were significantly higher in children with asthma (p < 0.001) than in healthy children. The increasing duration and severity of asthma were associated with increasing anxiety levels in children with asthma. Depression and anxiety scores were significantly higher in the mothers of children with asthma than in the comparison group. The mothers of children with asthma did not have supportive and friendly relationships with their children. In addition, these mothers had significantly higher Attitude of Hostility and Rejection, Attitude of Over-parenting and Authoritarian Attitude scores than those of the comparison group. Increasing duration and severity of asthma influenced family functions and the attitude of the mothers of children with asthma. There was a correlation between an increasing number of emergency department visits and increasing depression in the mothers of children with asthma. CONCLUSIONS: This cross-sectional study revealed that the disease may negatively affect the lives of children with asthma and their mothers and their family relationships. PMID- 29969328 TI - An interactive faculty development workshop designed to improve knowledge, skills (competence), attitudes, and practice in interprofessional continuing education. AB - PURPOSE: Interprofessional continuing education (IPCE) health care educators must plan activities as members of interprofessional teams and deliver activities to an interprofessional audience. Evidence in the literature suggests they are not well prepared to meet this challenge. This paper reviews one strategy to improve the knowledge, skills, attitudes, and practices of IPCE educators. METHODS: Seven faculty development workshops were conducted within the USA, Europe, Asia, and the Middle East. Approximately 250 learners participated in the workshops in total, with 107 in an IRB-approved research study. RESULTS: From the research cohorts demonstrated improved knowledge and skills over a 12-month period. Knowledge and skills scores increased most significantly from baseline to 3 months and remained above baseline at 6-12 months. The workshop was not an effective strategy to improve attitudes towards IPCE, though attitude scores were already high prior to participating. CONCLUSIONS: All participants actively engaged in the workshops. There were no observed differences in engagement by geographic region, gender, age, or profession. Participants stated they were better able to understand the roles of other team members; perspectives of patients, families, and caregivers; and their own roles on clinical teams. Participants described gaining a new appreciation for the complexity of designing IPCE. PMID- 29969329 TI - Test-retest and inter-rater reliability of the Danish version of the management of everday technology assessment for use with older adults with and without COPD. AB - BACKGROUND: The trend towards telemedicine increasingly requires clients to manage everyday technology (ET) to access and use health services. The Management of Everday Technology Assessment (META) is an observation-based instrument developed to evaluate the ability to manage ET. AIM: To examine test-retest (TRR) and inter-rater reliability (IRR) of the Danish translation of the META for older adults with and without COPD. METHOD AND MATERIALS: 47 older adults with COPD (n = 23) and without (n = 24) were recruited. IRR was examined by four raters paired across 30 participants. TRR was examined for 21 participants by the same rater administering the META twice within four weeks. A rank-based method for paired ordinal data was used to calculate percentage agreement (PA) and measures of systematic disagreement and individual variability. Mann Whitney U tests were used to compare PA to health status (presence/absence of COPD). RESULTS: Inter rater PA was acceptable across 10 of 11 items and test-retest PA across 8 of 11 items. Systematic disagreement was present for one item in TRR. No significant differences in PA were found regarding health status. CONCLUSION: The Danish META generates reliable scores for this sample. However, conclusive statements cannot be made for all items. PMID- 29969330 TI - Tuberculous Uveitis Presenting with a Bullous Exudative Retinal Detachment: A Case Report and Systematic Literature Review. AB - PURPOSE: To describe tuberculous uveitis (TU) presenting as a bullous retinal detachment (RD) and to perform a comprehensive literature review on TU with similar features. METHODS: Observational case report and systematic literature review. RESULTS: An 84-year-old woman presented with bilateral granulomatous uveitis and bullous RD in the left eye. The interferon gamma release assay was strongly positive, but all other tests were unremarkable. The patient was diagnosed with TU and started on anti-tubercular therapy (ATT) and systemic steroids with excellent treatment response. Twenty-six articles (32 cases) reported TU with exudative RD. Choroidal tuberculoma was the most common clinical manifestation, followed by optic disc edema and retinal exudate. Systemic steroids with ATT improved vision in more patients (78.6%) than ATT alone (50.0%) or oral steroids followed by ATT (50.0%). CONCLUSION: Atypical presentations of TU make diagnosis and treatment difficult. A high level of suspicion for TU is needed to minimize ocular morbidity. PMID- 29969331 TI - Anxiety and Depression among Patients with Uveitis and Ocular Inflammatory Disease at a Tertiary Center in Southern Thailand: Vision-Related Quality-of Life, Sociodemographics, and Clinical Characteristics Associated. AB - PURPOSE: To estimate the prevalence of positive anxiety and depression screening in patients with ocular inflammatory disease (OID). The predictors associated with anxiety and depressive symptoms were investigated. METHODS: A cross sectional study was conducted. The Thai Hospital Anxiety and Depression Scale (HADS), a sociodemographic questionnaire, and the Thai Visual Functioning Questionnaire 28 were administered to all participants. Associations were estimated using the Cox regression. RESULTS: Of the 86 participants, 12.8% and 8.1% screened positive for anxiety and depression, respectively. Predictors of an increase in both HADS-Anxiety and HADS-Depression scores comprised poor understanding of OIDs [adjusted relative probability (aRP) = 1.56; p = 0.021 and 1.59; p = 0.012, respectively], and low overall composite score (aRP = 1.45; p = 0.022 and 1.6; p = 0.002, respectively). CONCLUSIONS: Approximately one-tenth of our patients screened positive for anxiety and depression. Patients with poor understanding of their OID and poor self-reported visual function were at an increased risk. PMID- 29969332 TI - Phase I and phase II clinical trials for the treatment of male sexual dysfunction a systematic review of the literature. AB - INTRODUCTION: The prevalence of sexual dysfunctions has increased over the last decades; despite a number of available treatments for erectile dysfunction (ED), premature ejaculation (PE), and Peyronie's disease (PD), still several unmet therapeutic needs deserve to be fulfilled. The aim of this review is to detail on phase I and II clinical trials investigating novel medical treatments for ED, PE, and PD. Areas covered: We conducted a systematic review of the literature including both published and ongoing phase I and II registered trials focused on medical treatment of ED, PE, and PD during the last 5 years. A total of 35 trials have been identified. Most studies (63%) investigated ED treatments and 26% were still ongoing. Stem cells (SCs) therapy was assessed in 28% of trials. Expert opinion: SCs therapy represent a promising treatment for ED although only few patients have been treated to date. Likewise, the oral selective oxytocin receptor antagonists for treating PE showed excellent safety profile and deserve further investigations in phase III trials. Preliminary results of novel topical treatments for PD with fibrinolytic and antiinflammatory drugs are encouraging, but urgently need to be confirmed in large placebo-controlled trials. PMID- 29969333 TI - Cognitive apprenticeship in the ICU: Ward round activities to enhance student learning. PMID- 29969334 TI - Streptococcus Dysgalactiae Subspecies Equisimilis Endogenous Endophthalmitis Associated with Aortic Valve Abscess. AB - PURPOSE: To describe a case of endogenous endophthalmitis from Streptococcus dysgalactiae subspecies equisimilis in the setting of an aortic valve abscess Methods: Retrospective case report. RESULTS: A 72-year-old white male presented with fevers, encephalopathy, and decreased vision in his left eye. His visual acuity was 20/20 in his right eye and finger counting in the left eye. Workup revealed an aortic valve abscess. Examination of his left eye revealed dense anterior chamber fibrin and no view of the retina. B-scan ultrasonography revealed loculated hyperechoic areas consistent with vitreous inflammation. A vitreous tap and injections with vancomycin and ceftazidime were performed. Visual acuity worsened to no-light perception 5 days later. Vitreous and blood cultures grew Streptococcus dysgalactiae subspecies equisimilis. He received another intravitreal injection of vancomycin with no improvement. CONCLUSIONS: Streptococcus dysgalactiae subspecies equisimilis is an emerging pathogen and may cause severe intraocular infections with a poor visual outcome. PMID- 29969336 TI - Characteristics and outcomes of progressive multifocal leukoencephalopathy in hematologic malignancies and stem cell transplant - a case series. AB - Progressive multifocal leukoencephalopathy (PML) is a life-threatening opportunistic infection of immunomodulatory therapies. PML cases reported in PubMed (1995-2017) following stem-cell transplantation (HSCT) or chemoimmunotherapy (CIT) for hematologic malignancies were reviewed. We found 107 cases, 40% were HSCT recipients (32 allogeneic, 11 autologous) and 40% indolent lymphomas receiving monoclonal antibodies (mAbs). HSCT cases had longer time to PML diagnosis (10.8 vs. 4 months, p < .001), higher proportion of PML therapy response (58% vs. 25%, p = .019), lower mortality rate (56% vs. 88%, p < .001), and longer median survival (8 vs. 2 months, p < .001). Outcome differences might be caused by selection bias as HSCT patients are most likely treated aggressively; however, time-dependent immune reconstitution might also contribute to their better prognosis. Increased use of mAbs and HSCT are associated with rising PML incidence in hematological malignancies, currently constituting the second largest vulnerable population after HIV-infected patients; further research is needed for its optimal treatment. PMID- 29969337 TI - The key informant strategy to determine the prevalence and causes of functional low vision among children in South India. AB - PURPOSE: To report the prevalence and causes of functional low vision (FLV) in school-age children in Coimbatore District, Tamil Nadu, India and to report our experience using the key informant (KI) method in this setting. METHODS: Children suspected of having low vision were identified by KIs or Aravind Eye Hospital personnel in Coimbatore District. All identified children underwent a cycloplegic refraction and full eye exam. A primary cause of decreased vision was determined for each child. The prevalence of FLV was calculated for children 6-14 years old. Spectacles and low vision devices were provided free of charge. RESULTS: 345 children aged 6-14 years were referred and 231 had FLV. The positive-predictive value of KI referrals was 64.5%. The prevalence of FLV was 0.071% (7.1 per 10,000; 95% CI 0.062-0.080%) and ranged from 0.026% to 0.141% across the district's blocks. Older children (age 11-14 years; OR 1.41; 95% CI 1.09-1.82) and males (OR 1.52; 95% CI 1.16-1.98) had greater odds of being diagnosed with FLV. The most common causes of FLV were retinal disorders (30.0%) and amblyopia (25.5%). Low vision devices were provided to 169 children who had a mean near and distance visual acuity improvement of 0.31 and 0.63 logMAR, respectively (p < 0.001). CONCLUSIONS: This study reports a moderate prevalence of FLV and demonstrates the ability of KIs to identify school-age children with FLV in South India. The provision of basic low vision services can improve visual outcomes in this population. PMID- 29969338 TI - Expression and inducibility of cytochrome P450s in human hepatocytes isolated from chimeric mice with humanised livers. AB - The evaluation of drug-mediated cytochrome P450 (P450) induction using human hepatocytes is important for predicting drug interactions. In this study, we prepared hepatocytes from chimeric mice with humanised livers (Hu-Liver mice) and evaluated the expression and inducibility of P450s in these hepatocytes. Up to 95% of the Hu-Liver cells stained positive for human leukocyte antigen and the mean viability exceeded 85% (n = 10). Monolayer-cultured Hu-Liver cells displayed a similar morphology to cultures of the corresponding human hepatocytes used as transplantation donors. The mRNA expression levels in Hu-Liver cells of 16 P450 forms belonging to P450 subfamilies 1-4 correlated well with the expression levels of the same enzymes in human hepatocytes. The variations in individual P450 mRNA levels between Hu-Liver cells and the corresponding human hepatocytes were within five-fold for 13 P450 forms. The production of 6beta hydroxytestosterone in Hu-Liver cells was significantly increased (p < .05) following treatment with the CYP3A inducer, rifampicin. Hu-Liver cells have characteristics similar to those of human hepatocytes in terms of mRNA expression levels and the inducibility of the various P450 forms. Thus, Hu-Liver cells can potentially be used for in vitro drug-mediated induction assays of human hepatic P450s. PMID- 29969339 TI - Psychosocial impact of human papillomavirus on women's sexual dissatisfaction and quality of life. AB - PURPOSE: This study assessed how psychological, socio-demographic and clinical variables were associated and moderated the relationship between sexual dissatisfaction and the psychosocial impact of the human papillomavirus (HPV) on the quality of life (QOL) of infected women. METHODS: A cross-sectional design was used with a sample of 194 women. Participants completed a sociodemographic and clinical questionnaire, and were assessed on the psychosocial impact of HPV on quality of life (HPV Impact Profile), sexual dissatisfaction (Index of Sexual Satisfaction), psychological morbidity (Hospital Anxiety and Depression Scale), emotional suppression (Courtauld Emotional Control Scale) and spirituality (Spiritual and Religious Attitudes in Dealing with Illness). RESULTS: Women with greater psychological morbidity and emotional suppression showed greater psychosocial impact of HPV on QOL. Greater psychological morbidity and emotional suppression, being older, having less education and not using condoms were associated with greater sexual dissatisfaction. Sexual dissatisfaction, psychological morbidity and age were associated with the impact of HPV on QOL. The variables that contributed to sexual dissatisfaction were age, emotional suppression and condom use. The use of condoms moderated the relationship between emotional suppression and sexual dissatisfaction. CONCLUSION: Interventions should focus on psychological morbidity and condom use, particularly in older and less educated women. PMID- 29969340 TI - Reproductive Health Knowledge, Attitudes, and Behaviors Among Women Enrolled in Medication-Assisted Treatment for Opioid Use Disorder. AB - BACKGROUND: The lifetime prevalence of unintentional pregnancy among women enrolled in medically assisted treatment (MAT) for opioid use disorder (OUD) has been reported to exceed 80%. Consistent voluntary contraception use by women enrolled in MAT programs can reduce their risk of unintended pregnancies and increase their opportunity to plan the family size they want, yet little is understood about past and current contraception use or associated barriers and facilitators for this population of women. MATERIALS AND METHODS: Women enrolled in treatment for OUD at two MAT clinics in East Tennessee were invited to participate in an anonymous survey about contraception. We describe the sociodemographic and health characteristics of the women (N = 287; estimated response rate of 81.0%), report on their contraception knowledge and attitudes, and assess how these characteristics are associated with current contraception use. RESULTS: Most of the 287 women had been sexually active in the past 12 months (88%), were pregnant at least once (98%), and were insured (58%). Women having undergone bilateral tubal ligation had a greater average number of pregnancies (including those while on birth control), lower mean levels of depressed mood, and higher mean level of agreement that avoiding pregnancy now was important and that pregnant women should not use painkillers, compared to the women not using contraception. CONCLUSIONS: Strategies to ensure all women enrolled in MAT for OUD have knowledge of effective contraception and affordable, quality contraception care that is responsive to their complicated and oftentimes traumatic histories are necessary to enhance the women's reproductive health. PMID- 29969341 TI - Psychosocial stress promotes food intake and enhances the neuroenergetic level in men. AB - Psychosocial stress may lead to increased food consumption and overweight. In turn, obesity is related to reduced brain energy content. We hypothesized that psychosocial stress influencing food intake may alter the neuroenergetic status in the human brain. We tested 14 healthy normal weight men in a randomized crossover design. A modified version of the Trier Social Stress Test (TSST) was carried out to induce psychosocial stress vs. control in a neuroimaging setting. Cerebral energy content, i.e. high energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr), was measured by 31phosphorus magnetic resonance spectroscopy. Food intake was quantified by an ad libitum buffet test. Stress hormonal response and alterations in glucose metabolism were monitored by blood sampling. Before data collection, we mainly expected a stress-induced reduction in cerebral high energy phosphates, followed by higher food intake. Psychosocial stress increased serum cortisol concentrations (p = .003) and fat intake of all participants by 25% (p = .043), as well as food intake of "stress-eaters" by 41.1% (p = .003) compared with controls. Blood glucose and insulin concentrations were not affected (p > .174 for both). Cerebral ATP and PCr levels generally increased upon stress-induction (p > = .022 and p = .037, respectively). Our data confirm that psychosocial stress may enhance food intake. Contrary to our expectations, stress induces a distinct increase in the neuroenergetic status. This insight suggests that the underlying central nervous mechanisms of stress induced overeating may involve the regulation of the brain energy homeostasis. PMID- 29969342 TI - Associations of Maternal Beliefs and Distress in Pregnancy and Postpartum With Breastfeeding Initiation and Early Cessation. AB - BACKGROUND: Breastfeeding plays an important role in both maternal and infant health and well-being. While researchers have examined the relationship between postpartum psychological distress and breastfeeding behaviors, few have investigated links between prenatal distress, postpartum distress, and breastfeeding behaviors over time. Research Aim: We aimed to determine if prenatal breastfeeding beliefs and psychological distress during and after pregnancy were associated with initiation and early cessation rates of breastfeeding. METHODS: In our secondary data analysis, a nonexperimental longitudinal one-group design was used. We assessed pregnant women ( N = 70) during four perinatal visits (early, mid, and late pregnancy and 7-10 weeks postpartum). Participants completed self-report surveys about psychological distress and depressive symptoms at each visit, breastfeeding beliefs during the third visit, and breastfeeding behaviors at the postpartum visit. RESULTS: Participants who breastfed for ?8 weeks had more positive beliefs about breastfeeding prior to delivery than participants with early cessation, who in turn had more positive beliefs than those who never initiated. Participants with early cessation reported heightened levels of pregnancy-specific distress in early pregnancy compared to those who continued breastfeeding or never initiated. Participants who continued breastfeeding for ?8 weeks reported less general anxiety and depressive symptoms in postpartum than those who discontinued or never initiated. CONCLUSIONS: Prenatal beliefs about breastfeeding, pregnancy specific distress in early pregnancy, and general anxiety and depressive symptoms in postpartum are associated with breastfeeding initiation and continuation. Of clinical relevance, addressing prenatal and postpartum distress in the implementation of breastfeeding practice interventions could improve breastfeeding rates. PMID- 29969343 TI - Medication Use During Pregnancy and Lactation in a Dutch Population. AB - BACKGROUND: Medication use during pregnancy and lactation can be unavoidable, but knowledge on safety for the fetus or breastfed infant is limited among patients and healthcare providers. Research aim: This study aimed to determine (a) the prevalence of medication use in pregnant and lactating women in a tertiary academic center, (b) the types and safety of these medicines, and (c) the influence of medication use on initiation of breastfeeding. METHODS: This study used a cross-sectional survey among women ( N = 292) who underwent high-risk or low-risk deliveries. Data about their use of prescribed, over-the-counter, and homeopathic medication during pregnancy were obtained through a structured interview, followed by a questionnaire during lactation. Safety was classified according to the risk classification system from the Dutch Teratological Information Service. RESULTS: Overall, 95.5% of participants used medication. One third of participants used at least one medicine with an unknown risk for the fetus. Teratogenic medication was used by 6.5% of participants, whereas 29.5% used medication with a (suspected) pharmacological effect on the fetus. Lactation was initiated by 258 (88.7%) participants, of which 84.2% used medication while breastfeeding. In 3.8% of participants, this medication was classified unsafe, but none used medication with an unknown risk. One-third of the nonlactating participants decided not to initiate breastfeeding because of medication use. In 70% of participants, this decision was appropriate. CONCLUSION: The prevalence of overall use of medication in Dutch pregnant and lactating women admitted to a tertiary center was high. There is an urgent need for pharmacometric studies for determination of the safe use of the most frequently used medicines during pregnancy or lactation. PMID- 29969344 TI - Geographic Access to International Board-Certified Lactation Consultants in Pennsylvania. AB - BACKGROUND: Availability of professional lactation support has been associated with increased breastfeeding rates; however, data about access to international board-certified lactation consultants are limited. Research Aims: The aims were (a) to assess geographic access to international board-certified lactation consultants in Pennsylvania, (b) to compare access in rural/urban counties, and (c) to compare access by county-level breastfeeding initiation rates. METHODS: Using geographic information systems methodology and a cross-sectional observational design, we calculated the proportion of young children living within 15, 30, and 60 miles of international board-certified lactation consultants in Pennsylvania. We calculated these proportions for all children in Pennsylvania, for children in urban and rural counties, and for children in counties with low, medium, and high breastfeeding initiation rates. Comparisons were done to answer the research aims. RESULTS: Over 90% of young children live within 30 miles of an international board-certified lactation consultant. Compared to children in urban counties, fewer children in rural counties live within 15 and 30 miles of these providers. In counties with high breastfeeding initiation rates, a larger percentage of children live within 15 miles of an international board-certified lactation consultant than in counties with low breastfeeding initiation rates. CONCLUSION: While most Pennsylvania children live in proximity of an international board-certified lactation consultant, this was true for a lower percentage of children in rural counties and in counties with lower breastfeeding rates. PMID- 29969345 TI - Body mass index and survival in patients with myelodysplastic syndromes. PMID- 29969346 TI - Discoidin domain receptors: multitaskers for physiological and pathological processes. PMID- 29969347 TI - Impacts of continuous quality improvement in Aboriginal and Torres Strait islander primary health care in Australia. AB - Purpose Continuous quality improvement (CQI) programmes have been taken up widely by indigenous primary health care services in Australia, but as yet there has not been a systematic assessment of their focus and achievements. A scoping review of the literature from studies of CQI in indigenous primary health care services was undertaken to explore impacts on service systems, care and client outcomes with the aim of providing guidance on future evaluation efforts. The paper aims to discuss these issues, Design/methodology/approach Searches were conducted in MEDLINE, CINAHL and the Cochrane Database of Systematic Reviews to December 2016 and handsearching of key websites and publications. Studies of CQI programs or activities in Indigenous primary health care services which demonstrated some combination of CQI characteristics, as described by Rubenstein (2013) were included. A two-stage approach to analysis was undertaken. Stage 1 identified the range and scope of literature, and Stage 2 investigated impacts to service systems, care and client outcomes. The Framework for Performance Assessment in Primary Health Care was used to frame the Stage 2 analysis. Findings The majority of Aboriginal community controlled health services have been involved in CQI but there are gaps in knowledge about uptake in general practice and government clinics. There are as many baseline studies as studies on impacts over time. Of the 14 studies included for further analysis, 6 reported on impacts on service systems; all 14 reported on impacts on care and 6 on client outcomes. Changes to services systems are variable and studies of impacts on care and client outcomes show promising though uneven improvements. There are no economic studies or studies addressing community engagement in CQI activities. Research limitations/implications To supplement existing limited knowledge about which service system change strategies are effective and sustainable for which problems in which settings, there needs to be investment in research and development. Research needs to be grounded in the realities of service delivery and contribute to the development of CQI capacity at the service level. Knowledge translation needs to be built into implementation to ensure maximum benefit to those endeavouring on a daily basis to constantly reflect on and improve the quality of the care they deliver to clients, and to the stewardship structures supporting services at regional, state/territory and national levels. Practical implications Improved approaches, methods, data capture and reporting arrangements are needed to enhance existing activity and to ensure maximum benefit to services endeavouring to reflect on and improve quality of care and to the stewardship structure supporting services at regional, state/territory and national levels. Originality/value Although there is a growing body of research evidence about CQI both nationally and internationally, and considerable investment by the federal government in Australia to support CQI as part of routine practice, there has not been a systematic assessment of the achievements of CQI in Indigenous primary health care services. Many unanswered questions remain about the extent of uptake, implementation and impacts. This is a barrier to future investment and regional and local programme design, monitoring and evaluation. The authors conducted a scoping review to address these questions. From this, the authors draw conclusions about the state of knowledge in Australia with a view to informing how future CQI research and evaluation might be intensified. PMID- 29969348 TI - The persistent problem of integrated care in English NHS hospitals. AB - Purpose The purpose of this paper is to determine whether some aspects of the distinctive Mayo Clinic care model could be translated into English National Health Service (NHS) hospital settings, to overcome the fragmented and episodic nature of non-emergency patient care. Design/methodology/approach The authors used a rapid review to assess the literature on integrated clinical care in hospital settings and critical analysis of links between Mayo Clinic's care model and the organisation's performance and associated patient outcomes. Findings The literature directly concerned with Mayo Clinic's distinctive ethos and approach to patient care is limited in scope and largely confined to "grey" sources or to authors and institutions with links to Mayo Clinic. The authors found only two peer-reviewed articles which offer critical analysis of the contribution of the Mayo model to the performance of the organisation. Research limitations/implications Mayo Clinic is not the only organisation to practice integrated, in-hospital clinical care; however, it is widely regarded as an exemplar. Practical implications There are barriers to implementing a Mayo-style model in English NHS hospitals, but they are not insurmountable and could lead to much better coordination of care for some patients. Social implications The study shows that there is an appetite among NHS patients and staff for better coordinated, multi-specialty care within NHS hospitals. Originality/value In the English NHS integrated care generally aims to improve coordination between primary, community and secondary care, but problems remain of fragmented care for non-emergency hospital patients. Use of a Mayo-type care model, within hospital settings, could offer significant benefits to this patient group, particularly for multi-morbid patients. PMID- 29969349 TI - Digital displacements in patient-professional relations. AB - Purpose The purpose of this paper is to examine the relational consequences of electronic patient records based on co-produced data from pregnant women's IT supported self-reporting. The analysis unfolds how the clinical encounter between patient and professional is reconfigured in the digitized society. Design/methodology/approach The paper provides a grounded theory analysis based on observations and interviews in an antenatal care unit. The study draws on empirical material generated through observations of the clinical encounters between pregnant women and midwifes, interviews with managers and midwifes, field notes and policy documents. Findings The author argues that the use of technology and co-produced data displace tasks and relations between healthcare professional and patient. The analysis shows that four modes of organizational patient involvement are enacted: involvement in administrative tasks, involvement in professional resistance, individualized involvement, and homogenized involvement of patients that tends to categorize the pregnancy roughly as either "normal" or "abnormal." Originality/value This study contributes to qualitative research in digitization and patient involvement in health organization studies by showing how digital technology distributes the midwife's autonomy, tasks and knowledge about the patient with both intended and unintended consequences. The argument goes beyond the prevalent prescriptive approaches to e-government and co production, instead providing a critical analytical perspective on the promises of delivering efficient and patient-centered healthcare. PMID- 29969350 TI - Post-surgery length of stay using multi-criteria decision-making tool. AB - Purpose Length of stay (LOS) in hospital after surgery varies for each patient depending on surgeon's decision that considers criticality of the surgery, patient's conditions before and after surgery, expected time to recovery and experience of the surgeon involved. Decision on patients' LOS at hospital post surgery affects overall healthcare performance as it affects both cost and quality of care. The purpose of this paper is to develop a model for deriving the most appropriate LOS after surgical interventions. Design/methodology/approach The study adopts an action research involving multiple stakeholders (surgeon, patients/patients' relatives, hospital management and other medics). First, a conceptual model is developed using literature and experts' opinion. Second, the model is applied in three surgical interventions in a public hospital in Malta to demonstrate the effectiveness of the model. Third, the policy alternatives developed are compared to a selection of current international standards for each surgical intervention. The proposed model analyses three LOS threshold policies for three procedures using efficiency and responsiveness criteria. The entire analysis is carried out using 325 randomly selected patient files along with structured interactions with more than 50 stakeholders (surgeon, patients/patients' relatives, hospital management and other medics). A multiple criteria decision-making method is deployed for model building and data analysis. The method involves combining the analytic hierarchy process (AHP) for verbal subjective judgements on prioritizing the four predictors of surgical LOS medical, financial, social and risk, with pairwise comparisons of the sub criteria under each criterion in line with the concerned interventions-the objective data of which are obtained from the patients' files. Findings The proposed model was successfully applied to decide on the best policy alternative for LOS for the three interventions. The best policy alternatives compared well to current international benchmarks. Research limitations/implications The proposed method needs to be tested for other interventions across various healthcare settings. Practical implications Multi-criteria decision-making tools enable resource optimization and overall improvement of patient care through the application of a scientific management technique that involves all relevant stakeholders while utilizing both subjective judgements as well as objective data. Originality/value Traditionally, the duration of post-surgery LOS is mainly based on the surgeons' clinical but also arbitrary decisions, with, as a result, having insufficiently explicable variations in LOS amongst peers for similar interventions. According to the authors' knowledge, this is the first attempt to derive post-surgery LOS using the AHP, a multiple criteria decision-making method. PMID- 29969351 TI - Funding profiles of multisector health care alliances and their positioning for sustainability. AB - Purpose The purpose of this paper is to examine the relationship between different aspects of alliance funding profiles (e.g. range of sources, dependence on specific sources) and participant' perceptions of how well the organization is positioned for the future. Design/methodology/approach A mixed method study in the context of eight alliances participating in the Robert Wood Johnson Foundation's Aligning Forces for Quality program. Data collection approaches included surveys of alliance participants and semi-structured interviews with alliance leaders. Findings The findings indicate that dependence on grant revenues, in particular, may be problematic for how well alliances are positioned for sustainability. While a number of approaches were identified to reduce dependence on grants, implementing these strategies presented more of a challenge for alliances due to the contextual demands of their external environment and a need to strike a balance between pursuing alternative revenue sources and fidelity to the mission and identity of the organization. Practical implications Alliance leaders need to have not only a broad and accurate understanding of their external environment, but also an appreciation of the alliance's identity in that environment. Collectively, the findings can help organizational leaders be more informed about their funding choices and the implications those choices have for the future of their organization. Originality/value Collaborative forms of organizations (e.g. alliances, coalitions, networks) are increasingly viewed as an effective means of addressing complex, multifaceted health, and social challenges. For collaborative organizations that depend on the coordinated efforts of volunteers, addressing such complex issues is predicated on sustaining programmatic activities as well as the interest and participation of stakeholders over extended periods of time. This study sheds light on how leaders of these organizations may improve their prospects for sustainability. PMID- 29969352 TI - From one-sized to over-individualized? Service logic's value creation. AB - Purpose There is a current trend in healthcare management away from produced and standardized one-size-fits-all processes toward co-created and individualized services. The purpose of this paper is to increase understanding of the value concept in healthcare organization and management by recognizing different levels of value (private, group and public) and the interconnectedness among these levels. Design/methodology/approach The paper uses social constructionism as a lens to problematize the individualization of service logic's value concept. Theories from consumer culture theory/transformative service research and public management add group and public levels of value to the private level. Findings An intersubjective (rather than subjective) approach to value creation entails the construction and sharing of value perceptions among groups of people. Such an approach also implies that group members may face similar barriers in their value creation efforts. Practical implications Healthcare management should be aware of the inherent individualism of service logic and, consequently, the need to balance private value with group and public levels of value. Social implications Identifying and addressing disadvantaged groups and the reasons for their disadvantaged positions is important in order to enhance the individual's value creation prerequisites as well as to address public and societal values, such as equal/equitable health(care). Originality/value It is important to complement service logic's value creation with group and public levels in order to understand the complexity and interconnectedness of value and the creation thereof. PMID- 29969354 TI - Paradox of Prior Authorization: How Do We Get Value? PMID- 29969353 TI - No one can whistle a symphony: how hospitals design for daily cross-boundary collaboration. AB - Purpose The purpose of this paper is to investigate how and with which mechanisms health care professionals in practice design for collaboration to solve collective hospital tasks, which cross occupational and departmental boundaries. Design/methodology/approach An in-depth multiple-case study of five departments across four hospitals facing fast to slow response task requirements was carried out using interviews and observations. The selected cases were revealing as the departments had designed and formalized their daily hospital operations differently to solve collaboration and performance issues. Findings Local collaboration across occupational and departmental boundaries requires bundles of behavioral formalization elements (e.g. standardized plans, resource allocation decisions, assigned formal roles, and handoff routines), and liaison devices (e.g. huddles, boards, and physical proximity), which are used in parallel or sequence. The authors label this "designed collaboration bundles." These bundles supplement the central organizational structures, processes, and support systems less capable of ensuring fluent coordination at the front line. Practical implications Health care professionals and hospital managers can consider designing bundles of organizational design features to proactively develop and ensure collaboration capable of solving collective tasks and bridging departmental and occupational silos to improve health care delivery. Originality/value This research paper addresses the fundamental organizational challenge of how to achieve efficient collaboration by studying how formal structures and processes are used in combination on the hospital floor, thereby going beyond previous research that studies these mechanisms individually. PMID- 29969355 TI - Antitubercular evaluation of root extract and isolated phytochemicals from Lophira lanceolata against two resistant strains of Mycobacterium tuberculosis. AB - CONTEXT: The roots of Lophira lanceolata Van Tiegh. Ex Keay (Ochnaceae) have numerous medicinal values in the Central African region. Even though the MeOH extract of the roots has shown antimycobacterial activities, the constituents responsible for this inhibitory activity remain unknown. OBJECTIVE: Phytochemical investigation of the MeOH root extract of L. lanceolata and determination of the antimycobacterial activities of that extract and constituents against the growth of Mycobacterium tuberculosis. MATERIALS AND METHODS: Column chromatography was used to provide bioactive phytoconstituents. Those compounds were elucidated using MS and NMR spectroscopic data. Antimycobacterial screening of the extract (4.882-5000 ug/mL in DMSO during 24 h at 37 degrees C) and isolated compounds (0.244-250 ug/mL in DMSO during 24 h at 37 degrees C) was performed by microplate alamar blue assay (MABA) against two mycobacterial strains. RESULTS: The investigation of L. lanceolata MeOH roots extract provided of mixture of unseparated biflavonoids with a newly described one, dihydrolophirone A (1a) associated to lophirone A (1b). The bioactive compounds that effectively inhibited the growth of M. tuberculosis AC45 were found to be compounds 1 and 2. They exhibited MIC values of 31.25 and 15.75 ug/mL, respectively, and their MIC was found to be 62.5 ug/mL against resistant strain AC83. DISCUSSION AND CONCLUSIONS: It is clearly evident from the results obtained that the mycobacterial activity of L. lanceolata could be related mainly to its steroid and flavonoid contents. Therefore, this study suggests the potential of the above mentioned classes of compounds as promising candidate agents for developing new anti-tuberculosis drugs. PMID- 29969357 TI - Metabolic Syndrome After Preeclamptic Pregnancy: A Longitudinal Cohort Study. AB - INTRODUCTION: History of preeclampsia increases the risk of cardiovascular disease in women. Most formerly, preeclamptic women have generally one or even more traditional cardiovascular and/or cardiometabolic risk factors consistent with metabolic syndrome in the first year after delivery. The objective of this study was to analyze the prevalence and persistence of risk factors contributing to metabolic syndrome for the course of years after preeclamptic pregnancy. METHODS: In a longitudinally cohort study, 107 formerly preeclamptic women were assessed for traditional risk factors (insulin resistance, obesity, dyslipidemia, hypertension, and microalbuminuria) of metabolic syndrome (World Health Organization criteria) at two time points: at 3-30 months postpartum (visit 1) and 24-65 months later (visit 2). RESULTS: At visit 1, 10 of 107 (9%) formerly preeclamptic women had metabolic syndrome, and at visit 2, 14 of 107 (13%) (p = 0.21) had metabolic syndrome. Most formerly, preeclamptic women (90%) did not change their metabolic syndrome status over the years, as 7 of 107 (7%) women had persistent metabolic syndrome and 90 of 107 (84%) women did not meet the criteria for metabolic syndrome on either visit. In 3 of 107 (3%) formerly preeclamptic women, metabolic syndrome disappeared over time, whereas 7 of 107 (7%) preeclamptic women developed it. CONCLUSION: The presence or absence of metabolic syndrome remains unchanged in 90% of formerly preeclamptic women for the first years after preeclampsia. Only in 10% of women, metabolic syndrome developed or recovered, indicating that early screening within the first year postpartum in these women effectively detects those with metabolic syndrome who are known to be at increased risk for cardiovascular disease later in life. PMID- 29969356 TI - Effect of citral on mouse hepatic cytochrome P450 enzymes. AB - CONTEXT: Citral is used as a potential natural treatment for various infectious diseases. OBJECTIVE: To examine the effect of citral on the mRNA expression and activities of cytochrome P450 (CYP450) enzymes and establish the relationship between citral-induced liver injury and oxidative stress. MATERIALS AND METHODS: ICR mice were randomly divided into citral (20, 200, and 2000 mg/kglow), Tween 80, and control groups (0.9% saline), 10 mice in each group. The citral-treated groups were intragastrically administered citral for 3 d, control groups treated with 0.5% Tween-80 and 0.9% saline in the same way. Liver injury and CYP450 enzymes were analyzed by analyzing the histopathological changes and the changes of related enzymes. RESULTS: Citral treatment (2000 mg/kg) for 3 d increased serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels, as well as glutathione, gydroxyl radicals, malonaldehyde and total superoxide dismutase contents, but decreased the content of total antioxidant capacity. In doses of 20 and 200 mg/kg groups mice, the contents of NO were decreased significantly and other changes were similar to the 2000 mg/kg group mice, but the liver damage was most severe in the 2000 mg/kg group. Citral induced the mRNA expression and activities of CYP450 1A2, 2D22, and 2E1 in the liver of mice at doses of 20 and 200 mg/kg. There were no changes in testing indexes in Tween-80 treated group mice. Due to its toxic effects, the CYP induction effect of citral negatively correlated with its dose. Although the mRNA expression of CYP450 3A11 was induced by citral, its activity was not affected by low and moderate doses of citral. CYP450 3A11 activity was significantly decreased by high-dose citral. CONCLUSIONS: Citral is hepatotoxic and induced oxidative stress in higher dose, which has a negative effect on CYP450 enzymes. These data suggest caution needs to be taken in order to avoid citral-drug interactions in human beings. PMID- 29969358 TI - Rectal wall MRI radiomics in prostate cancer patients: prediction of and correlation with early rectal toxicity. AB - PURPOSE: To investigate MRI radiomic analysis to assess IMRT associated rectal wall changes and also for predicting radiotherapy induced rectal toxicity. MATERIAL AND METHODS: At first, a machine learning radiomic analysis was applied on T2-weighted (T2W) and apparent diffusion coefficient (ADC) rectal wall MR images of prostate cancer patients' pre- and post-IMRT to predict rectal toxicity. Next, Wilcoxon singed ranked test was performed to find radiomic features with significant changes pre- and post-IMRT. A logistic regression classifier was used to find correlation between features with significant changes and radiation toxicity. Area under the curve (AUC) of receiver operating characteristic (ROC) curve was used in two levels of study for finding performances. RESULTS: AUCmean, 0.68 +/- 0.086 and 0.61 +/- 0.065 were obtained for pre- and post-IMRT T2 radiomic models, respectively. For ADC radiomic models, AUCmean was 0.58 +/- 0.034 for pre-IMRT and was 0.56 +/- 0.038 for post-IMRT. Wilcoxon-signed rank test revealed that 9 T2 radiomic features vary significantly post-IMRT. The AUC of logistic-regression was in the range of 0.46-0.58 for single significant features and was 0.81 when all significant features were combined. CONCLUSIONS: Pre-IMRT MR image radiomic features could predict rectal toxicity in prostate cancer patients. Radiotherapy associated complications may be assessed by studying the changes in the MR radiomic features. PMID- 29969360 TI - Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling. AB - The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population. A first evidence-based rating system to evaluate the quality of the source data used to derive pediatric-specific mPBPK model parameter was proposed. A stepwise approach was used to examine the best combination of age/weight effect on the parameters of the mPBPK model in adult and pediatric subjects. IgG synthesis rate (Ksyn), extravasation rate (ER) and FcRn were fitted simultaneously to the PK of bevacizumab and native-IgG in both adult and pediatric. All fitting showed good fits based on the graphs and the coefficient of variation of the fitted parameters (< 50%). Estimated weight normalized Ksyn increased while weight-normalized FcRn and ER decreased with increasing age. The age and weight effect on FcRn were successfully estimated from the data. The final mPBPK model developed with native IgG and bevacizumab was able to predict the PK of palivizumab in pediatric subjects. Implementation of the mPBPK model enables us to analyze the relationships of age, weight, FcRn, ER and Ksyn in both adult and pediatric subject. This information may benefit the understanding of complex interaction between the FcRn developmental pharmacology and PK parameters, and improve the prediction of the antibody disposition in pediatric subjects. PMID- 29969359 TI - Red Pepper (Capsicum annuum L.) Seed Extract Decreased Hepatic Gluconeogenesis and Increased Muscle Glucose Uptake In Vitro. AB - Red pepper seed, a by-product of red pepper, has been reported to have antioxidant and antiobesity activities. However, its role in diabetes has not yet been highly investigated. Glucose homeostasis is mainly maintained by insulin, which suppresses glucose production in the liver and enhances glucose uptake in peripheral tissues. In this study, we investigated the underlying mechanisms through which red pepper seed extract (RPSE) affects glucose production in AML12 hepatocytes and glucose uptake in C2C12 myotubes. RPSE reduced glucose production in a dose-dependent manner in AML12 cells. The levels of glucose 6 phosphatase, phosphoenolpyruvate carboxykinase, and critical enzymes for hepatic gluconeogenesis were decreased by RPSE. Gluconeogenesis regulating proteins, Akt and forkhead box protein O1, were also activated by RPSE. In addition, RPSE increased glucose uptake in C2C12 via inducing translocation of glucose transporter type 4 from cytosol to plasma membrane. Analysis of the insulin dependent pathway showed that the activities of insulin receptor substrate 1, phosphatidylinositol 3-kinase, and Akt were significantly stimulated by RPSE. In conclusion, RPSE might improve glucose homeostasis by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. Results obtained also suggest that RPSE can be a compelling antidiabetic nutraceutical. PMID- 29969361 TI - Screenplay of flax phloem fiber behavior during gravitropic reaction. AB - Flax phloem fibers act as constitutively formed "muscles" that support the vertical position of the high but narrow stem. The specific mechanical properties of flax fibers and of similar fibers in other plant species are provided by the development of tertiary cell wall with tensed cellulose microfibrils. The work of phloem fibers becomes especially pronounced during the restoration of stem vertical position if it was disturbed. Gravistimulation of flax plants induces considerable modification of phloem fibers at the pulling stem side - the lumen diameter increases, while the cell wall thickness goes down. Here we show that the action of phloem fibers as motors of stem vertical position restoration is coupled to the cell wall remodelling as well as the increase of osmolytes (mainly potassium and malate) content, and accumulation of the gamma-amino-butyric acid that may be involved in signalling events. The molecular players that take part in these processes are suggested. PMID- 29969362 TI - Targeting Cdc42 with the anticancer compound MBQ-167 inhibits cell polarity and growth in the budding yeast S. cerevisiae. AB - The Rho GTPase Cdc42 is highly conserved in structure and function. Mechanical or chemical cues in the microenvironment stimulate the localized activation of Cdc42 to rearrange the actin cytoskeleton and establish cell polarity. A role for Cdc42 in cell polarization was first discovered in the budding yeast Saccharomyces cerevisiae, and subsequently shown to also regulate directional motility in animal cells. Accordingly, in cancer Cdc42 promotes migration, invasion, and spread of tumor cells. Therefore, we targeted Cdc42 as a therapeutic strategy to treat metastatic breast cancer and designed the small molecule MBQ-167 as a potent inhibitor against Cdc42 and the homolog Rac. MBQ-167 inhibited cancer cell proliferation and migration in-vitro, and tumor growth and spread in-vivo in a mouse xenograft model of metastatic breast cancer. Since haploid budding yeast express a single Cdc42 gene, and do not express Rac, we used this well characterized model of polarization to define the contribution of Cdc42 inhibition to the effects of MBQ-167 in eukaryotic cells. Growth, budding pattern, and Cdc42 activity was determined in wildtype yeast or cells expressing a conditional knockdown of Cdc42 in response to vehicle or MBQ-167 treatment. As expected, growth and budding polarity were reduced by knocking-down Cdc42, with a parallel effect observed with MBQ-167. Cdc42 activity assays confirmed that MBQ 167 inhibits Cdc42 activation in yeast, and thus, bud polarity. Hence, we have validated MBQ-167 as a Cdc42 inhibitor in another biological context and present a method to screen Cdc42 inhibitors with potential as anti-metastatic cancer drugs. PMID- 29969364 TI - Possible ameliorative effect of aqueous extract of date (Phoenix dactylifera) pits in rats exposed to gamma radiation. AB - PURPOSE: To evaluate the radioprotective efficacy of date (Phoenix dactylifera) pits extract (DPE) against gamma-irradiation-induced liver damage in the male albino rats. For this study, 30-day survival, dose reduction factor (DRF), antioxidant status and some biochemical changes in the serum and hepatic tissue were evaluated. MATERIALS AND METHODS: To calculate 30-day survival, median lethal dose of 30 days (LD50/30) and DRF, DPE was orally administered to rats for 21 days before irradiation with different doses (5, 6, 8, 10 and 12 Gy) of gamma rays and the rats were observed for 30 days post-irradiation. To evaluate the radioprotective efficacy of DPE against gamma-irradiation induced-liver tissue damage, animals were divided into four groups (eight animals in each group). (i) Control: rats not subjected to any treatment; (ii) DPE: DPE was orally administrated (1000 mg/kg body weight) for 21 days; (iii) RAD: rats' whole body exposed to 5 Gy of gamma-rays; (iv) DPE + RAD: rats received DPE treatment for 21 days before gamma-irradiation. Animals were sacrificed on the seventh day postexposure to radiation. RESULTS: The results showed that pretreatment prior to irradiation with DPE resulted in a significantly higher 30-day survival rate of rats after exposure to different doses of gamma-irradiation. Furthermore, DPE treatment resulted in a significant improvement in the hepatic redox state, manifested by a marked increase of superoxide dismutase (SOD) and catalase (CAT) activities and glutathione content associated with a significant decrease of malondialdehyde (MDA) level. In addition, DPE exhibited hepatoprotective effect evidenced by a marked increase in serum levels of insulin, testosterone, high density lipoprotein-cholesterol (HDL-c) and hepatic glucose 6 phosphate dehydrogenase (G6PHD) activity associated with a significant decrease in serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (gamma-GT), glucose, total cholesterol (TC), triglycerides (TG), low density-lipoprotein cholesterol (LDL-c) and hepatic glucose 6 phosphatase (G6Pase) activity, compared with irradiated group. Moreover, DPE showed positive modulation in the levels of hepatic metals [(iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn)]. CONCLUSIONS: DPE treatment prior to gamma irradiation produced biochemical changes that could lead to a reduction in radiation-induced oxidative stress. Hence, we suggest that DPE may be useful as a new natural radioprotective agent. PMID- 29969363 TI - What Slows Down Phytoplasma Proliferation? Speculations on the Involvement of AtSEOR2 Protein in Plant Defence Signalling. AB - Considering the crude methods used to control phytoplasma diseases, a deeper knowledge on the defence mechanisms recruited by the plant to face phytoplasma invasion is required. Recently, we demonstrated that Arabidopsis mutants lacking AtSEOR1 gene showed a low phytoplasma titre. In wild type plants AtSEOR1 and AtSEOR2 are tied in filamentous proteins. Knockout of the AtSEOR1 gene may pave the way for an involvement of free AtSEOR2 proteins in defence mechanisms. Among the proteins conferring resistance against pathogenic bacteria, AtRPM1 interacting protein has been found to interact with AtSEOR2 in a high-quality, matrix-based yeast-two hybrid assay. For this reason, we investigated the expression levels of Arabidopsis AtRIN4, and the associated AtRPM1 and AtRPS2 genes in healthy and Chrysanthemum yellows-infected wild-type and Atseor1ko lines. PMID- 29969366 TI - Brain morphology and information processing at the completion of chemotherapy only treatment for pediatric acute lymphoblastic leukemia. AB - BACKGROUND: Approximately 50% of survivors of childhood acute lymphoblastic leukemia (ALL) demonstrate cognitive impairments. However, the trajectory of change and contributing neuropathology is unclear, limiting our ability to tailor intervention content and timing. This study aimed to explore information processing abilities and brain morphology early post-treatment for pediatric ALL. PROCEDURE: Twenty-one children at the end of ALL treatment and 18 controls underwent neuropsychological assessment. A subset also completed structural magnetic resonance imaging. RESULTS: A principal component analysis generated two cognitive factors: information processing capacity and information processing speed. Compared to control group, the ALL group displayed deficits in capacity, but not speed. No group differences were identified in morphology. No relationship was identified between capacity or speed and morphology. CONCLUSION: Early cognitive intervention should target information processing abilities using a system-wide approach. Future studies should employ alternative imaging techniques sensitive to white-matter microstructure when exploring pathology underlying information processing deficits. PMID- 29969365 TI - The mechanism of GM-CSF inhibition by human GM-CSF auto-antibodies suggests novel therapeutic opportunities. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that can stimulate a variety of cells, but its overexpression leads to excessive production and activation of granulocytes and macrophages with many pathogenic effects. This cytokine is a therapeutic target in inflammatory diseases, and several anti-GM-CSF antibodies have advanced to Phase 2 clinical trials in patients with such diseases, e.g., rheumatoid arthritis. GM-CSF is also an essential factor in preventing pulmonary alveolar proteinosis (PAP), a disease associated with GM-CSF malfunction arising most typically through the presence of GM-CSF neutralizing auto-antibodies. Understanding the mechanism of action for neutralizing antibodies that target GM-CSF is important for improving their specificity and affinity as therapeutics and, conversely, in devising strategies to reduce the effects of GM-CSF auto-antibodies in PAP. We have solved the crystal structures of human GM-CSF bound to antigen-binding fragments of two neutralizing antibodies, the human auto-antibody F1 and the mouse monoclonal antibody 4D4. Coordinates and structure factors of the crystal structures of the GM-CSF:F1 Fab and the GM-CSF:4D4 Fab complexes have been deposited in the RCSB Protein Data Bank under the accession numbers 6BFQ and 6BFS, respectively. The structures show that these antibodies bind to mutually exclusive epitopes on GM CSF; however, both prevent the cytokine from interacting with its alpha receptor subunit and hence prevent receptor activation. Importantly, identification of the F1 epitope together with functional analyses highlighted modifications to GM-CSF that would abolish auto-antibody recognition whilst retaining GM-CSF function. These results provide a framework for developing novel GM-CSF molecules for PAP treatment and for optimizing current anti-GM-CSF antibodies for use in treating inflammatory disorders. PMID- 29969367 TI - Effect of BCLAF1 on HDAC inhibitor LMK-235-mediated apoptosis of diffuse large B cell lymphoma cells and its mechanism. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma. It is a group of malignant tumors with a large number of clinical manifestations and prognoses. Therefore, it is necessary to explore its unknown potential therapeutic targets. Histone deacetylase inhibitor (HDACi) is a novel drug for the treatment of DLBCL, however pan-HDACis cannot be ignored because of their clinical efficacy. By contrast, specific HDACi is well-tolerated, and LMK-235 is a novel HDACi that is a specific inhibitor of HDAC4 and HDAC5. In this study, we investigated the up-regulation of BCLAF1 through NF-kappaB signaling pathways in LMK-235, mediating the apoptosis of two diffuse large B-cell lymphoma cell lines, OCI-LY10 and OCI-LY3. Further studies showed that BCLAF1 expression was increased in DLBCL cells after treatment with the NF-kappaB inhibitor Bay11-7082. The combination of Bay11-7082 and siRNA si-HDAC4 significantly increased BCLAF1 expression and further increased apoptosis. These results indicate that BCLAF1 plays an important role in LMK-235-mediated apoptosis and may be a potential target for the treatment of diffuse large B-cell lymphoma. PMID- 29969369 TI - Mosquito-Borne Uveitis. PMID- 29969368 TI - Mechanochemical Effects on Extracellular Signal-Regulated Kinase Dynamics in Stem Cell Differentiation. AB - Understanding how key signaling molecules are coregulated by biochemical agents and physical stimuli during stem cell differentiation is critical but often lacking. Due to the important role of extracellular signal-regulated kinase (ERK), this study has examined its temporal dynamics to determine the coregulation of mechanochemical cues on ERK phosphorylation for smooth muscle cell (SMC) differentiation. To assess ERK1/2 activity, a fluorescence resonance energy transfer-based biosensor was transfected into mesenchymal stem cells. The influences of nanopatterned substrates, growth factors, and drugs on ERK activities were related to their effects on SMC differentiation. Results revealed that nanopatterned substrates significantly increased ERK activity in cells, overriding ERK response from administered biochemical factors. The nanopatterned substrates reduced expression of SMC markers after a 48-h biochemical treatment, except for the combination with ERK inhibitor PD98059 treatment, which enhanced expression of mature SMC marker MYH11. Immunofluorescent staining for focal adhesion proteins, vinculin and zyxin, indicated no significant differences in vinculin cluster distribution or dimension, while the location of zyxin changed from adhesion sites of cell periphery on nonpatterned substrate to actin filaments on nanopatterned substrate. The zyxin-reinforced stress fibers likely enhanced the cytoskeletal tension to increase ERK dynamics. Collectively, results suggest that physical stimuli play a dominating role in initial ERK signaling and early-stage differentiation through focal adhesion changes, and the capability of monitoring signaling events in real time could be exploited to guide the engineering of cell microenvironment. PMID- 29969370 TI - Virus-Induced Anterior Uveitis (VIAU) in Immunocompromised Patients. AB - PURPOSE: To describe the clinical characteristics, diagnosis, and treatment of VIAU in immunocompromised patients. METHODS: A critical review of literature was performed. RESULTS: Diagnosis and treatment of VIAU in immunocompromised patients may be a challenge due to atypical clinical-courses, severe presentations, and more frequent recurrences. A conclusive diagnosis can be made by aqueous-humour PCR-analysis. Visual prognosis depends on early diagnosis and prompt treatment. Frequent ocular examinations are recommended in HIV patients with CD-4-counts below 100 in order to rule out opportunistic ocular coinfections. It is essential to bear in mind the potential side-effects of therapeutic interventions and consider the possibility of Immune Recovery Uveitis (IRU) in eyes with treated viral retinitis after the initiation of HAART. CONCLUSIONS: Early diagnosis and treatment of VIAU in immunocompromised patients can be achieved with high suspicion, recognizing clinical features, and obtaining specimens for molecular diagnostic testing in order to avoid usually severe ocular morbidity. PMID- 29969372 TI - Life-Threatening Allergies: Using a Patient-Engaged Approach. AB - BACKGROUND: Adolescents at risk for anaphylaxis are a growing concern. Novel training methods are needed to better prepare individuals to manage anaphylaxis in the community. INTRODUCTION: Didactic training as the sole method of anaphylaxis education has been shown to be ineffective. We developed a smartphone based interactive teaching tool with decision support and epinephrine auto injector (EAI) training to provide education accessible beyond the clinic. METHODS: This study consisted of two parts: (1) Use of food allergy scenarios to assess the decision support's ability to improve allergic reaction management knowledge. (2) An assessment of our EAI training module on participant's ability to correctly demonstrate the use of an EAI by comparing it to label instructions. RESULTS: Twenty-two adolescents were recruited. The median (range) baseline number of correct answers on the scenarios before the intervention was 9 (3-11). All subjects improved with decision support, increasing to 11 (9-12) (p < .001). The median (range) demonstration score was 6 (5-6) for the video training module group and 4.5 (3-6) for the label group (p < 0.001). DISCUSSION: Results suggest that the use of this novel m-health application can improve anaphylaxis symptom recognition and increase the likelihood of choosing the appropriate treatment. In addition, performing EAI steps in conjunction with the video training resulted in more accurate medication delivery with fewer missed steps compared to the use of written instructions alone. CONCLUSION: The results suggest that mobile health decision support technology for anaphylaxis emergency preparedness may support traditional methods of training by providing improved access to anaphylaxis training in the community setting. PMID- 29969371 TI - Cladribine in combination with entinostat synergistically elicits anti proliferative/anti-survival effects on multiple myeloma cells. AB - : Cladribine (2CdA), a synthetic purine analog interfering with DNA synthesis, is a medication used to treat hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia. Entinostat, a selective class I histone deacetylase (HDAC) inhibitor, shows antitumor activity in various human cancers, including hematological malignancies. The therapeutic potential of cladribine and entinostat against multiple myeloma (MM) remains unclear. Here we investigate the combinatorial effects of cladribine and entinostat within the range of their clinical achievable concentrations on MM cells. While either agent alone inhibited MM cell proliferation in a dose-dependent manner, their combinations synergistically induced anti-proliferative/anti-survival effects on all MM cell lines (RPMI8226, U266, and MM1.R) tested. Further studies showed that the combinations of cladribine and entinostat as compared to either agent alone more potently induced mitotic catastrophe in the MM cells, and resulted in a marked increase of the cells at G1 phase associated with decrease of Cyclin D1 and E2F-1 expression and upregulation of p21waf-1. Apoptotic ELISA and western blot analyses revealed that the combinations of cladribine and entinostat exerted a much more profound activity to induce apoptosis and DNA damage response, evidenced by enhanced phosphorylation of histone H2A.X and the DNA repair enzymes Chk1 and Chk2. Collectively, our data demonstrate that the combinations of cladribine and entinostat exhibit potent activity to induce anti proliferative/anti-survival effects on MM cells via induction of cell cycle G1 arrest, apoptosis, and DNA damage response. Regimens consisting of cladribine and/or entinostat may offer a new treatment option for patients with MM. ABBREVIATIONS: MM, multiple myeloma; HCL, hairy cell leukemia; HDAC, histone deacetylase; Ab, antibody; mAb, monoclonal Ab; FBS, fetal bovine serum; CI, combination index; PAGE, polyacrylamide gel electrophoresis; ELISA, enzyme-linked immunosorbent assay; PARP, poly(ADP-ribose) polymerase; MTS, 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium,inner salt. PMID- 29969373 TI - Use of GreenZyme(r) for remediation of porous media polluted with jet fuel JP-5. AB - Jet fuel may be released in the environment either by in-flight fuel jettisoning (fuel dumping) or accidentally from spills and leaks, and eventually can reach subsurface formations where it can remain as long-term source of pollution. Remediation of aquifers contaminated by jet fuels is not a trivial task. This experimental study examined the effectiveness of a water-soluble, DNA-protein based biodegradable non-living catalyst, with commercial name GreenZyme(r) for the remediation of water saturated porous media polluted with jet fuel (JP-5). Also for comparison purposes, the commercial surfactant sodium dodecyl sulfate (SDS) was used. Bench scale experiments were conducted in a glass column packed with glass beads. The migration of JP-5 in the glass column under various conditions, with and without the presence of GreenZyme(r) was monitored by a well established photographic method. Digital photographs of the packed column were captured under fluorescent lighting. The fluorescent intensity of JP-5 dyed with Red Oil O within the column was analyzed using the Matlab Image Processing Toolbox. The colour intensities were converted to concentrations via appropriate calibration curves. The experimental results suggested that GreenZyme(r) was an efficient biosurfactant capable of enhancing significantly the migration of JP-5 in the glass column, which performed considerably better that SDS under the experimental conditions of this study. PMID- 29969374 TI - Infrastructure designs and traffic safety: the road to vision zero. PMID- 29969375 TI - Impact of Health Care and Socioeconomic Needs on Health Care Utilization and Disease Management: The University of New Mexico Hospital Care One Program. AB - Understanding how unmet basic needs impact health care in patients with complex conditions is vital to improve health outcomes and reduce health care costs. The purpose of this observational study was to explore the association between health care and socioeconomic needs and health care utilization and disease management among patients with chronic conditions at an intensive, patient-centered, office based program. The study used a cross-sectional design and a convenience sampling approach. Data were collected through a patient questionnaire and medical records. Analysis included descriptive and inferential statistics. Data from 48 established patients were analyzed. Financial and lack of transportation were the 2 most frequently reported unmet needs. More than 65% of participants had their chronic condition(s) under control. Sex and ethnicity were the only 2 demographic variables that yielded significant differences (P <= 0.01) on visits to the emergency room and having chronic condition(s) under control. Those who reported having unmet transportation needs were more likely to have a condition uncontrolled and to have lost medical appointments compared to those who had this social need met (P <= 0.05). Statistically significant differences in terms of missing medical appointments also were found between those whose overall financial and housing needs were unmet and those who had those needs met (P <= 0.05). Results indicate that participating patients generally had good control of their conditions. The study adds evidence in support of the call for health care to address patients' socioeconomic needs, and the health care benefits of intensive case management programs. The model may be considered for adoption throughout New Mexico, and nationally. PMID- 29969376 TI - Feramyces austinii, gen. nov., sp. nov., an anaerobic gut fungus from rumen and fecal samples of wild Barbary sheep and fallow deer. AB - Anaerobic gut fungi are common inhabitants of the alimentary tracts of herbivorous animals. Nine different Neocallimastigomycota genera have been described so far. However, culture-independent diversity surveys suggest the presence of numerous, yet-uncultured Neocallimastigomycota genera. Here, we report on the isolation and characterization of the first cultured representatives of Neocallimastigomycota clade AL6, originally identified in culture-independent surveys of fecal samples from captive wild animals. Six strains were isolated from rumen and fecal samples of a wild Barbary sheep (Ammotragus lervia) and a wild fallow deer (Dama dama) in Texas, USA. The isolates displayed medium-sized (3-7 mm), circular, beige colonies with filamentous edges and a dark center on agar roll tubes. Microscopic analysis revealed monocentric thalli with both endogenous and exogenous sporangial development patterns. Zoospores were spherical, with a diameter of 9.6 +/- 1.9 MUm, and polyflagellated, with 7-16 flagella. Phylogenetic analysis based on nuc rDNA ITS1 region and D1-D2 domains of nuc 28S rDNA revealed that the isolated strains formed a single monophyletic and bootstrap-supported clade distinct from all currently described Neocallimastigomycota genera. Substrate utilization experiments using the type strain (F3a) demonstrated robust and fast growth on sugars and plant biomass, as well as the capability to metabolize a wide range of mono-, oligo-, and polysaccharides, including galactose, arabinose, alginate, and pectin. On the basis of the morphological, physiological, and phylogenetic analyses, we propose to accommodate these isolates in a new genus, Feramyces (derived from the Latin word for "wild" to reflect their isolation and apparent distribution in undomesticated herbivores), and a new species, F. austinii. The type strain is Feramyces austinii F3a. PMID- 29969377 TI - Single contaminant and combined exposures of polyethylene microplastics and fluoranthene: accumulation and oxidative stress response in the blue mussel, Mytilus edulis. AB - The microplastic "vector effect" has received increasing attention. The aim of this study was to investigate the influence of polyethylene microplastic beads (PE MP) on accumulation and associated oxidative stress responses attributed to fluoranthene (Flu) in blue mussels, Mytilus edulis. Blue mussels were exposed for 96 h to four treatment groups: Flu-only, MP-only, Flu and MP coexposure, and Flu incubated MP. Treatments were conducted at a low and high concentration (50 MUg/L and 100 Flu MUg/L and 100, and 1000 MP/mL). Results demonstrated that in both the gill and digestive gland, coexposure did not markedly affect Flu uptake, but this treatment significantly decreased tissue Flu concentrations. Antioxidant responses including activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidases (GPx), and levels of total glutathione (GSH) in both gills and digestive glands were significantly altered suggesting a perturbation of redox state induced by the exposure conditions. Although individual biomarkers varied, the biomarker profile enabled certain generalizations to be made. Antioxidant responses occurred more likely in gill tissue than in digestive gland. Individual contaminant exposures to Flu or MP led to varying responses, but coexposures and incubated exposures did not result in additive or synergistic effects. Exposure concentrations (i.e., low or high treatments) were not a consistent a predictor of response; and the internal Flu dose did not consistently predict outcome of various biomarkers. Importantly, MP-only exposure appeared to be capable of eliciting direct effects on the oxidative stress system as demonstrated by the activities of CAT and GPx. These findings warrant further investigation. PMID- 29969378 TI - The Impact of a Heart Failure Management Program in a Medicare Advantage Population. AB - Heart failure (HF) is currently among the most prevalent and costly chronic diseases among older adults, who are at increased risk because of other chronic conditions and the aging process. HF has a significant impact on the health care system, patient outcomes, and the unsustainable rising costs of care. The primary objectives were to: (1) determine cost savings differences in medical expenditures between engaged and non-engaged members referred to a HF management program; (2) examine differences in length of stay and time to first post engagement acute inpatient admission; and (3) examine the impact of using a remote weight monitoring scale on medical expenditures and inpatient admissions. Generalized linear modeling was used to compare key outcomes among individuals who engaged in the program and a propensity-matched cohort of those who were eligible but did not engage. Key outcomes included post-engagement acute inpatient medical service utilization, all-cause per-member-per-month medical expenses, and acute inpatient length of stay. When paired with regular use of a remote weight monitoring scale, engagement in this HF management program appears to be associated with decreased risk for acute inpatient admission and lower all cause medical expenditures. Participation in a clinically based HF management program may improve health-related and financial outcomes among older individuals. However, further development and evaluation of disease management programs could help to improve their effectiveness and thus patient outcomes. PMID- 29969379 TI - Genome sequence and comparative analyses of atoxigenic Aspergillus flavus WRRL 1519. AB - Aflatoxins are toxic secondary metabolites produced by Aspergillus flavus and a few other closely related species of Aspergillus. These highly toxigenic and carcinogenic mycotoxins contaminate global food and feed supplies, posing widespread health risks to humans and domestic animals. Field application of nonaflatoxigenic strains of A. flavus to compete against aflatoxigenic strains has emerged as one of the best management practices for reducing aflatoxins contamination, yielding successful commercial products for corn, cotton seed, and peanuts. In this study, we sequenced the genome and transcriptome of atoxigenic (does not produce aflatoxin or cyclopiazonic acid) A. flavus strain WRRL 1519 isolated from a tree nut orchard to define the genetic characteristics of the strain in relation to aflatoxigenic and other nonaflatoxigenic A. flavus strains. WRRL 1519 strain was similar to other strains in size (38.0 Mb), GC content (47.2%), number of predicted secondary metabolite gene clusters (46), and number of putative proteins (12 121). About 87.4% of the predicted proteome had high shared identity with protein sequences derived from other A. flavus genomes. However, the atoxigenic A. flavus strain WRRL 1519 had deletions, or low shared identity, for many genes in the clusters required for aflatoxins and cyclopiazonic acid (CPA) synthesis. Over half of the aflatoxin synthesis gene cluster was missing, and none of the components of the CPA gene cluster were identified with high sequence similarity. Importantly, the strain appeared to maintain functional sequences of several genes thought to be required for high infectivity. Since the ability to grow on target crop is an important attribute for a successful biocontrol agent, these results indicate that the nonaflatoxigenic A. flavus strain WRRL 1519 would be a good candidate as a biocontrol agent for reducing aflatoxin and CPA accumulation in high-value nut crops. PMID- 29969380 TI - Quantitative decision-making in randomized Phase II studies with a time-to-event endpoint. AB - One of the most critical decision points in clinical development is Go/No-Go decision-making after a proof-of-concept study. Traditional decision-making relies on a formal hypothesis testing with control of type I and type II error rates, which is limited by assessing the strength of efficacy evidence in a small isolated trial. In this article, we propose a quantitative Bayesian/frequentist decision framework for Go/No-Go criteria and sample size evaluation in Phase II randomized studies with a time-to-event endpoint. By taking the uncertainty of treatment effect into consideration, we propose an integrated quantitative approach for a program when both the Phase II and Phase III trials share a common endpoint while allowing a discount of the observed Phase II data. Our results confirm the argument that an increase in the sample size of a Phase II trial will result in greater increase in the probability of success of a Phase III trial than increasing the Phase III trial sample size by equal amount. We illustrate the steps in quantitative decision-making with a real example of a randomized Phase II study in metastatic pancreatic cancer. PMID- 29969381 TI - Key Characteristics for Successful Adoption and Implementation of Home Telehealth Technology in Veterans Affairs Home-Based Primary Care: An Exploratory Study. AB - BACKGROUND/OBJECTIVES: The Department of Veteran Affairs (VA) Home-Based Primary Care (HBPC) program provides care to over 37,000 high-risk, high-need, medically complex, and costly patients in their home. The VA's Home Telehealth (HT) program can potentially amplify HBPC's efficiency and reach, yet scarce data on use and experience with HT in HBPC exist. This exploratory study sought to provide a glimpse of HT use in HBPC and identify drivers and barriers for HT implementation. DESIGN: National VA data were used to evaluate HBPC patients concurrently using HT. We conducted a cross-sectional survey of HBPC program directors to explore HT use, understand communication processes, and elicit open comments. Semistructured interviews were conducted of 18 HBPC program directors with varying HT use to clarify themes and understand HBPC experience with HT. RESULTS: Fifteen percent of the overall HBPC patients used HT in 2011, with a wide variation in HT use by HBPC site. The national survey and semistructured interviews revealed that most HBPC staff recognized advantages of using HT, including increased patient engagement and staff efficiency. Crucial practices among sites with successful telehealth adoption included HT staff attending HBPC meetings and evaluating all HBPC patients for HT. CONCLUSION: Much remains to be done for effective HT integration in HBPC. Improving communication between HT and HBPC programs and establishing a system for identifying suitable patients for HT are vital. Future studies need to delineate operational processes and gather data on the added value of HT in HBPC to guide evidence-based integration of HT in VA and Medicare HBPC programs. PMID- 29969383 TI - Development of an Open-Source Laparoscopic Simulator Capable of Motion and Force Assessment: High Tech at Low Cost. AB - OBJECTIVE: Laparoscopic simulators help improve surgical skills in an ex vivo setting. New simulators incorporate force and motion assessment, but often at high financial cost. Our goal is to establish global access to a laparoscopic simulator, which offers both traditional summative assessment (time to task completion and precision) as well as advanced formative assessment (force and motion sensing capabilities) so that educators anywhere may be able to create simulators with increased educational value. DESIGN: A low-cost laparoscopic simulator incorporating an off-the-shelf optical sensor, inertial measurement unit, holders, and a housing unit for a microcontroller was integrated into a plastic box with a high-definition digital camera and a three-dimensional mouse. Open source software was developed to offer real-time feedback in force and motion. The system was calibrated for accuracy and consistency. RESULTS: The simulator was assembled from off-the-shelf components and open-source software. Total estimated cost was $350 United States Dollars. The mouse was calibrated by applying known forces in known directions. Linear forces measured in all axes showed linear output trends with r2-values of between 0.988 and 0.999. Accuracy in motion evaluation was evaluated and this demonstrated low average errors in the motion sensors of 5.4% to 6.8%. CONCLUSIONS: This low-cost, off-the-shelf, open-access laparoscopic simulator provides accurate and consistent measures of force and motion. We believe that collaborative efforts between surgeons and engineers can allow the creation of these surgical teaching devices at a reasonable cost such that they can be used in resource-rich and resource-limited settings. PMID- 29969382 TI - Serological Evidence of Borrelia burgdorferi, Anaplasma phagocytophilum and Ehrlichia Spp. Infections in Horses from Southeastern Bulgaria. AB - Lyme Borreliosis and granulocytic anaplasmosis are less extensively studied in horses than in dogs and humans. Equine ehrlichiosis is not known in Europe and is in the initial stage of investigation in South, Central, and North America. The aim of this study was to determine the seroprevalence of these infections in Bulgaria. A total of 155 horses were investigated from five regions in Southeastern Bulgaria. Horses were tested for Borrelia burgdorferi, Anaplasma phagocytophilum, and Ehrlichia spp. antibodies by a commercial rapid ELISA test. B. burgdorferi and A. phagocytophilum antibodies were found in all five regions (Burgas, Sliven, Stara Zagora, Haskovo, and Kardzhali) at frequencies of 36/155 (23.2%; 95% CI: 16.8-30.7%; ranging by region from 6.4% to 50%) and 31/155 (20%; 95% CI: 14-27.2%; ranging by region from 10% to 30.8%), respectively. Antibodies against Ehrlichia spp. were found in horses from three regions (Burgas, Stara Zagora, and Haskovo) at a rate of 6/155 (3.9%; 95% CI: 1.4-8.2%; ranging by region from 5.7% to 6.4%). The combination of B. burgdorferi/A. phagocytophilum (11/155; 7.1%; 95% CI: 3.6-12.3%) was the most common coexposure observed, followed by B. burgdorferi/Ehrlichia spp. (2/155; 1.3%; 95% CI: 0.2-4.6%) and A. phagocytophilum/Ehrlichia spp. (1/155; 0.6%; 95% CI: 0-3.5%). The study shows that horses in Bulgaria are exposed or coexposed to three tick-transmitted zoonotic bacterial species. Furthermore, it reports Ehrlichia spp. seroreactivity in equines in Europe. PMID- 29969384 TI - Automated Systems Based on Wearable Sensors for the Management of Parkinson's Disease at Home: A Systematic Review. AB - BACKGROUND: Parkinson's disease is a common neurodegenerative pathology that significantly influences quality of life (QoL) of people affected. The increasing interest and development in telemedicine services and internet of things technologies aim to implement automated smart systems for remote assistance of patients. The wide variability of Parkinson's disease in the clinical expression, as well as in the symptom progression, seems to address the patients' care toward a personalized therapy. OBJECTIVES: This review addresses automated systems based on wearable/portable devices for the remote treatment and management of Parkinson's disease. The idea is to obtain an overview of the telehealth and automated systems currently developed to address the impairments due to the pathology to allow clinicians to improve the quality of care for Parkinson's disease with benefits for patients in QoL. DATA SOURCES: The research was conducted within three databases: IEEE Xplore(r), Web of Science(r), and PubMed Central(r), between January 2008 and September 2017. STUDY ELIGIBILITY CRITERIA: Accurate exclusion criteria and selection strategy were applied to screen the 173 articles found. RESULTS: Ultimately, 55 articles were fully evaluated and included in this review. Divided into three categories, they were automated systems actually tested at home, implemented mobile applications for Parkinson's disease assessment, or described a telehealth system architecture. CONCLUSION: This review would provide an exhaustive overview of wearable systems for the remote management and automated assessment of Parkinson's disease, taking into account the reliability and acceptability of the implemented technologies. PMID- 29969385 TI - Keeping Up with the Applications: Lessons Learned Evaluating Gout Apps. AB - In June 2017, we embarked on a study to test the efficacy of available smartphone applications (apps) for gout, a type of inflammatory arthritis, which is associated with severe joint inflammation causing significant joint pain. Several noteworthy challenges arose as we grappled with issues such as apps no longer being available (or functional), the poor quality and misinformation of apps, and the rapid and unforeseen updating (or complete lack of updating) of existing apps. These are critical issues that researchers and health professionals working in the rapidly developing digital health field must learn how to contend with. In this study, we offer some of our insights regarding issues that need to be considered when working in m-Health, especially when the research is being conducted in the health sector or with patients. PMID- 29969386 TI - Thermal sensitivity of Calonectria henricotiae and Calonectria pseudonaviculata conidia and microsclerotia. AB - Knowledge of the thermal sensitivity of conidia and microsclerotia is useful for developing plant disease management approaches that deploy heat to inactivate infectious vegetative propagules of fungal pathogens. For boxwood blight disease, heat treatment of cuttings that harbor conidia and microsclerotia would provide a useful management tool for suppressing the pathogenic activity of Calonectria pseudonaviculata (present in the United States) and C. henricotiae (a quarantine pathogen not present in the United States). In this study, we investigated the thermal sensitivity of conidia and microsclerotia of the boxwood blight pathogens C. henricotiae and C. pseudonaviculata treated in water at 45, 47.5, 50, 52.5, and 55 C. For conidia, as time of exposure increased at each temperature, the proportion of germinated conidia decreased. The predicted time required to inactivate 90% of C. pseudonaviculata conidia (LD90) decreased as water temperature increased from 45 to 55 C and ranged from 35.4 to 5.6 min, respectively. Inactivation of conidia was dependent on isolate, species of Calonectria, and length of exposure at each temperature tested. Microsclerotia of C. henricotiae and C. pseudonaviculata displayed reduced germination with increasing exposure and higher temperatures of hot water. Microsclerotia of C. henricotiae were significantly more resistant to heat treatment than C. pseudonaviculata at 47.5 and 50 C, whereas microsclerotia of both species were rapidly killed at 55 C. PMID- 29969387 TI - Regression: binary logistic. PMID- 29969388 TI - Study of the Effect of Metal Complexes on Morphology and Viability of Embryonated Toxocara canis Eggs. AB - An organic salt and four metal complexes derived from azole were evaluated against embryonated Toxocara canis eggs (TCE). The new organic salt, (LH)+(FeCl4) , where L = 3,5-bis(3,5-dimethylpyrazole-1-ylmethyl)toluene (5), a potential environmental disinfectant, was isolated as an air-stable yellow solid and characterized by elemental analysis, electrical conductivity, mass spectrometry, and infrared and ultraviolet/visible spectroscopy. In addition, the structure of 5 was determined by single-crystal X-ray diffraction. Compound 2 showed high anti TCE activity. Interestingly, these compounds showed little effect on hepatocytes, indicating that they are not cytotoxic. These results will assist in the design of anti-TCE compounds. PMID- 29969389 TI - A Nationwide Seroepidemiologic Study on Q Fever Antibodies in Sheep of Portugal. AB - INTRODUCTION: Q fever is an almost global zoonotic disease caused by Coxiella burnetii. Human infections can produce acute and chronic disease that can lead to abortions and stillbirths in pregnant women, usually infected by the inhalation of C. burnetii-contaminated aerosols or through consumption of contaminated products. Sheep are one of the primary animal reservoirs with disease being associated with vast shedding of bacteria in placentas, feces, milk, and birth fluids. Although almost neglected in the past, recent outbreaks of sheep origin have alerted the public and the scientific community. MATERIALS AND METHODS: An epidemiologic survey to estimate the seroprevalence of Q fever antibodies was performed in a representative number of sheep of all regions of continental Portugal (n = 1068), using a commercial ELISA (ID Screen Q Fever Indirect Multi species Kit; IDvetTM, Montpellier, France). RESULTS AND DISCUSSION: An anti-C. burnetii seroprevalence of 11.4% (95% confidence interval 9.6-13.5) was found, with a clear distinction between the Center region with highest seroprevalence, and the rest of the territory. Sheep traditional farming is widely present in Portugal and is part of the cultural and gastronomical background of the country. This close proximity to small ruminants may contribute to the zoonotic transfer to humans. PMID- 29969390 TI - Dentistry's Great Awakening. PMID- 29969392 TI - Combining Acoustic Trapping With Plane Wave Imaging for Localized Microbubble Accumulation in Large Vessels. AB - The capability of accumulating microbubbles using ultrasound could be beneficial for enhancing targeted drug delivery. When microbubbles are used to deliver a therapeutic payload, there is a need to track them, for a localized release of the payload. In this paper, a method for localizing microbubble accumulation with fast image guidance is presented. A linear array transducer performed trapping of microbubble populations interleaved with plane wave imaging, through the use of a composite pulse sequence. The acoustic trap in the pressure field was created parallel with the direction of flow in a model of a vessel section. The acoustic trapping force resultant from the large gradients in the acoustic field was engendered to directly oppose the flowing microbubbles. This was demonstrated numerically with field simulations, and experimentally using an Ultrasound Array Research Platform II. SonoVue microbubbles at clinically relevant concentrations were pumped through a tissue-mimicking flow phantom and exposed to either the acoustic trap or a control ultrasonic field composed of a single-peak acoustic radiation force beam. Under the flow condition at a shear rate of 433 s-1, the use of the acoustic trap led to lower speed estimations ( ) in the center of the acoustic field, and an enhancement of 71% +/- 28%( ) in microbubble image brightness. PMID- 29969393 TI - Robust Foreground Estimation via Structured Gaussian Scale Mixture Modeling. AB - Recovering the background and foreground parts from video frames has important applications in video surveillance. Under the assumption that the background parts are stationary and the foreground are sparse, most of existing methods are based on the framework of robust principal component analysis (RPCA), i.e., modeling the background and foreground parts as a low-rank and sparse matrices, respectively. However, in realistic complex scenarios, the conventional norm sparse regularizer often fails to well characterize the varying sparsity of the foreground components. How to select the sparsity regularizer parameters adaptively according to the local statistics is critical to the success of the RPCA framework for background subtraction task. In this paper, we propose to model the sparse component with a Gaussian scale mixture (GSM) model. Compared with the conventional norm, the GSM-based sparse model has the advantages of jointly estimating the variances of the sparse coefficients (and hence the regularization parameters) and the unknown sparse coefficients, leading to significant estimation accuracy improvements. Moreover, considering that the foreground parts are highly structured, a structured extension of the GSM model is further developed. Specifically, the input frame is divided into many homogeneous regions using superpixel segmentation. By characterizing the set of sparse coefficients in each homogeneous region with the same GSM prior, the local dependencies among the sparse coefficients can be effectively exploited, leading to further improvements for background subtraction. Experimental results on several challenging scenarios show that the proposed method performs much better than most of existing background subtraction methods in terms of both performance and speed. PMID- 29969394 TI - Fried Binary Embedding: From High-Dimensional Visual Features to High-Dimensional Binary Codes. AB - Most existing binary embedding methods prefer compact binary codes ( dimensional) to avoid high computational and memory cost of projecting high dimensional visual features ( -dimensional, ). We argue that long binary codes ( ) are critical to fully utilize the discriminative power of high-dimensional visual features, and can achieve better results in various tasks such as approximate nearest neighbor search. Generating long binary codes involves large projection matrix and high-dimensional matrix-vector multiplication, thus is memory and compute intensive. We propose Fried binary embedding (FBE) and Supervised Fried Binary Embedding (SuFBE), to tackle these problems. FBE is suitable for most of the practical applications in which the labels of training data are not given, while SuFBE can significantly boost the accuracy in the cases that the training labels are available. The core idea is to decompose the projection matrix using adaptive Fastfood transform, which is the multiplication of several structured matrices. As a result, FBE and SuFBE can reduce the computational complexity from to , and memory cost from to , respectively. More importantly, by using the structured matrices, FBE and SuFBE can well regulate projection matrix by reducing its tunable parameters and lead to even better accuracy than using either unconstrained projection matrix (like ITQ) or sparse matrix such as SP and SSP with the same long code length. Experimental comparisons with state-of-the-art methods over various visual applications demonstrate both the efficiency and performance advantages of FBE and SuFBE. PMID- 29969391 TI - Cryo-EM structure of alpha-synuclein fibrils. AB - Parkinson's disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1-121), determined by cryo-electron microscopy at a resolution of 3.4 A. Two protofilaments form a polar fibril composed of staggered beta-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies. PMID- 29969395 TI - Superpixel Hierarchy. AB - Superpixel segmentation has been one of the most important tasks in computer vision. In practice, an object can be represented by a number of segments at finer levels with consistent details or included in a surrounding region at coarser levels. Thus, a superpixel segmentation hierarchy is of great importance for applications that require different levels of image details. However, there is no method that can generate all scales of superpixels accurately in real time. In this paper, we propose the superhierarchy algorithm which is able to generate multi-scale superpixels as accurately as the state-of-the-art methods but with one to two orders of magnitude speed-up. The proposed algorithm can be directly integrated with recent efficient edge detectors to significantly outperform the state-of-the-art methods in terms of segmentation accuracy. Quantitative and qualitative evaluations on a number of applications demonstrate that the proposed algorithm is accurate and efficient in generating a hierarchy of superpixels. PMID- 29969396 TI - Scalable Online Convolutional Sparse Coding. AB - Convolutional sparse coding (CSC) improves sparse coding by learning a shift invariant dictionary from the data. However, most existing CSC algorithms operate in the batch mode and are computationally expensive. In this paper, we alleviate this problem by online learning. The key is a reformulation of the CSC objective so that convolution can be handled easily in the frequency domain, and much smaller history matrices are needed. To solve the resultant optimization problem, we use the alternating direction method of multipliers (ADMMs), and its subproblems have efficient closed-form solutions. Theoretical analysis shows that the learned dictionary converges to a stationary point of the optimization problem. Extensive experiments are performed on both the standard CSC benchmark data sets and much larger data sets such as the ImageNet. Results show that the proposed algorithm outperforms the state-of-the-art batch and online CSC methods. It is more scalable, has faster convergence, and better reconstruction performance. PMID- 29969397 TI - IPAD: Intensity Potential for Adaptive De-Quantization. AB - Display devices at bit depth of 10 or higher have been mature but the mainstream media source is still at bit depth of eight. To accommodate the gap, the most economic solution is to render source at low bit depth for high bit-depth display, which is essentially the procedure of de-quantization. Traditional methods, such as zero-padding or bit replication, introduce annoying false contour artifacts. To better estimate the least-significant bits, later works use filtering or interpolation approaches, which exploit only limited neighbor information, cannot thoroughly remove the false contours. In this paper, we propose a novel intensity potential (IP) field to model the complicated relationships among pixels. The potential value decreases as the spatial distance to the field source increases and the potentials from different field sources are additive. Based on the proposed IP field, an adaptive de-quantization procedure is then proposed to convert low-bit-depth images to high-bit-depth ones. To the best of our knowledge, this is the first attempt to apply potential field for natural images. The proposed potential field preserves local consistency and models the complicated contexts well. Extensive experiments on natural, synthetic, and high-dynamic range image data sets validate the efficiency of the proposed IP field. Significant improvements have been achieved over the state-of the-art methods on both the peak signal-to-noise ratio and the structural similarity. PMID- 29969398 TI - Glass Reflection Removal Using Co-Saliency-Based Image Alignment and Low-Rank Matrix Completion in Gradient Domain. AB - The images taken through glass often capture a target transmitted scene as well as undesired reflected scenes. In this paper, we propose a novel reflection removal algorithm using multiple glass images taken from slightly different camera positions. We first find co-saliency maps for input multiple glass images based on the center prior assumption, and then align multiple images reliably with respect to the transmitted scene by selecting feature points with high co saliency values. The gradients of the transmission images are consistent while the gradients of the reflection images are varying across the aligned multiple glass images. Based on this observation, we compute gradient reliability such that the pixels belonging to consistent salient edges of the transmission image are assigned high reliability values. We restore the gradients of the transmission images and suppress the gradients of the reflection images by formulating a low-rank matrix completion problem in gradient domain. Finally, we reconstruct desired transmission images from the restored transmission gradients. Experimental results show that the proposed algorithm removes the reflection artifacts from glass images faithfully and outperforms the existing methods on challenging glass images with diverse characteristics. PMID- 29969399 TI - Accurate Light Field Depth Estimation With Superpixel Regularization Over Partially Occluded Regions. AB - Depth estimation is a fundamental problem for light field photography applications. Numerous methods have been proposed in recent years, which either focus on crafting cost terms for more robust matching, or on analyzing the geometry of scene structures embedded in the epipolar-plane images. Significant improvements have been made in terms of overall depth estimation error; however, current state-of-the-art methods still show limitations in handling intricate occluding structures and complex scenes with multiple occlusions. To address these challenging issues, we propose a very effective depth estimation framework which focuses on regularizing the initial label confidence map and edge strength weights. Specifically, we first detect partially occluded boundary regions (POBR) via superpixel-based regularization. Series of shrinkage/reinforcement operations are then applied on the label confidence map and edge strength weights over the POBR. We show that after weight manipulations, even a low-complexity weighted least squares model can produce much better depth estimation than the state-of the-art methods in terms of average disparity error rate, occlusion boundary precision-recall rate, and the preservation of intricate visual features. PMID- 29969400 TI - Luminance Enhancement and Detail Preservation of Images and Videos Adapted to Ambient Illumination. AB - When images and videos are displayed on a mobile device in bright ambient illumination, fewer details can be perceived than in the dark. The detail loss in dark areas of the images/videos is usually more severe. The reflected ambient light and the reduced sensitivity of viewer's eyes are the major factors. We propose two tone mapping operators to enhance the contrast and details in images/videos. One is content independent and thus can be applied to any image/video for the given device and the given ambient illumination. The other tone mapping operator uses simple statistics of the content. Display contrast and human visual adaptation are considered to construct the tone mapping operators. Both operators can be solved efficiently. Subjective tests and objective measurement show the improved quality achieved by the proposed methods. PMID- 29969401 TI - Validation of a Commercial Android Smartwatch as an Activity Monitoring Platform. AB - Activity monitoring (AM) is an established technique for the assessment of a person's physical activity. With the rapid rise of smartwatch technology, this platform presents an interesting opportunity to use a device for AM that has both the ability to monitor activity and also the ability to interface seamlessly with other healthcare systems. There are questions however around the suitability of smartwatches as monitoring devices. This paper presents a validation of one smartwatch, the ZGPAX S8, for use as an activity monitor. Two experiments are presented: a physical manipulation test and a co-location test. In the physical manipulation test, three S8s are compared to a reference accelerometer under human physical manipulation. In the co-location test, the smartwatch is used alongside a reference device for a period of three hours by four participants to assess both the accelerometer data and the results of processing on data from both devices. Findings from these experiments show that the S8 accelerometer has a good correlation and limits of agreement in the physical manipulation test (r2 ~ 0.95, CR ~ 2.5 m/s 2), and excellent correlation and limits of agreement in the analysis of processed data from the co-location experiment (r2 ~ 0.99, CR ~ 0.23). From these results, the S8 is evaluated to be a suitable device for AM. Some specific limitations in the S8 are identified such as data range clipping, time drift and sample rate consistency, but these are not found to impact on the suitability of the device once algorithmic processing is applied to the data. PMID- 29969403 TI - Maximum-Entropy-Rate Selection of Features for Classifying Changes in Knee and Ankle Dynamics During Running. AB - This paper investigates deteriorations in knee and ankle dynamics during running. Changes in lower limb accelerations are analyzed by a wearable musculoskeletal monitoring system. The system employs a machine-learning technique to classify joint stiffness. A maximum-entropy-rate method is developed to select the most relevant features. Experimental results demonstrate that distance travelled and energy expended can be estimated from observed changes in knee and ankle motions during 5-km runs. PMID- 29969402 TI - Estimating SpO2 via Time-Efficient High-Resolution Harmonics Analysis and Maximum Likelihood Tracking. AB - The accuracy of noninvasive oxygen saturation (SpO2), which is defined by the measurements based on photoplethysmographic (PPG) signals, is intensively affected by motion artifacts (MAs) and low perfusion. This study introduces a novel approach called ESPRIT-MLT to measure SpO2 when such interferences are present. In contrast to previous studies, the work focuses on the harmonic model of the PPG signal and the probability model of results from harmonic analysis. The optimized parametric ESPRIT method is applied to improve the accuracy of harmonic power estimation, and the maximum likelihood SpO2 tracking (MLT) technique is proposed to track the most probable uncontaminated harmonic of heart rate frequency. We construct an evaluation platform for testing the proposed method via generated signals and subject tests. Compared with the nonparametric periodogram method, the probability of correct harmonics being found is improved by 18.7% or 19.7%, when the signal is contaminated by motion artifacts or affected by low perfusion, respectively. In comparison with the reference methods, the proposed ESPRIT-MLT method exhibits a lower average root mean square error (RMSE) (1.17%) in the simulation using an MA-contaminated PPG signal, and a lower RMSE (2.70%) in the simulation using an extremely low (0.05%) perfusion index. A comprehensive subject test that consists of 4 activities and 20 subjects shows an average RMSE of 0.84% ( 0.44%). Furthermore, the time-efficiency is optimized to be adaptable with wearable devices. Therefore, the proposed method has potential in enhancing the performance of clinical pulse oximetry and wearable SpO2 measurement devices for daily use. PMID- 29969404 TI - S-EMG Signal Compression in One-Dimensional and Two-Dimensional Approaches. AB - This paper presents algorithms designed for one-dimensional (1-D) and 2-D surface electromyographic (S-EMG) signal compression. The 1-D approach is a wavelet transform based encoder applied to isometric and dynamic S-EMG signals. An adaptive estimation of the spectral shape is used to carry out dynamic bit allocation for vector quantization of transformed coefficients. Thus, an entropy coding is applied to minimize redundancy in quantized coefficient vector and to pack the data. In the 2-D approach algorithm, the isometric or dynamic S-EMG signal is properly segmented and arranged to build a 2-D representation. The high efficient video codec is used to encode the signal, using 16-bit-depth precision, all possible coding/prediction unit sizes, and all intra-coding modes. The encoders are evaluated with objective metrics, and a real signal data bank is used. Furthermore, performance comparisons are also shown in this paper, where the proposed methods have outperformed other efficient encoders reported in the literature. PMID- 29969405 TI - Optimized Computer-Aided Segmentation and Three-Dimensional Reconstruction Using Intracoronary Optical Coherence Tomography. AB - We present a novel and time-efficient method for intracoronary lumen detection, which produces three-dimensional (3-D) coronary arteries using optical coherence tomographic (OCT) images. OCT images are acquired for multiple patients and longitudinal cross-section (LOCS) images are reconstructed using different acquisition angles. The lumen contours for each LOCS image are extracted and translated to 2-D cross-sectional images. Using two angiographic projections, the centerline of the coronary vessel is reconstructed in 3-D, and the detected 2-D contours are transformed to 3-D and placed perpendicular to the centerline. To validate the proposed method, 613 manual annotations from medical experts were used as gold standard. The 2-D detected contours were compared with the annotated contours, and the 3-D reconstructed models produced using the detected contours were compared to the models produced by the annotated contours. Wall shear stress (WSS), as dominant hemodynamics factor, was calculated using computational fluid dynamics and 844 consecutive 2-mm segments of the 3-D models were extracted and compared with each other. High Pearson's correlation coefficients were obtained for the lumen area (r = 0.98) and local WSS (r = 0.97) measurements, while no significant bias with good limits of agreement was shown in the Bland-Altman analysis. The overlapping and nonoverlapping areas ratio between experts' annotations and presented method was 0.92 and 0.14, respectively. The proposed computer-aided lumen extraction and 3-D vessel reconstruction method is fast, accurate, and likely to assist in a number of research and clinical applications. PMID- 29969406 TI - Connectivity in fMRI: Blind Spots and Breakthroughs. AB - In recent years, driven by scientific and clinical concerns, there has been an increased interest in the analysis of functional brain networks. The goal of these analyses is to better understand how brain regions interact, how this depends upon experimental conditions and behavioral measures and how anomalies (disease) can be recognized. In this paper, we provide, first, a brief review of some of the main existing methods of functional brain network analysis. But rather than compare them, as a traditional review would do, instead, we draw attention to their significant limitations and blind spots. Then, second, relevant experts, sketch a number of emerging methods, which can break through these limitations. In particular we discuss five such methods. The first two, stochastic block models and exponential random graph models, provide an inferential basis for network analysis lacking in the exploratory graph analysis methods. The other three addresses: network comparison via persistent homology, time-varying connectivity that distinguishes sample fluctuations from neural fluctuations, and network system identification that draws inferential strength from temporal autocorrelation. PMID- 29969407 TI - Interactive Medical Image Segmentation Using Deep Learning With Image-Specific Fine Tuning. AB - Convolutional neural networks (CNNs) have achieved state-of-the-art performance for automatic medical image segmentation. However, they have not demonstrated sufficiently accurate and robust results for clinical use. In addition, they are limited by the lack of image-specific adaptation and the lack of generalizability to previously unseen object classes (a.k.a. zero-shot learning). To address these problems, we propose a novel deep learning-based interactive segmentation framework by incorporating CNNs into a bounding box and scribble-based segmentation pipeline. We propose image-specific fine tuning to make a CNN model adaptive to a specific test image, which can be either unsupervised (without additional user interactions) or supervised (with additional scribbles). We also propose a weighted loss function considering network and interaction-based uncertainty for the fine tuning. We applied this framework to two applications: 2 D segmentation of multiple organs from fetal magnetic resonance (MR) slices, where only two types of these organs were annotated for training and 3-D segmentation of brain tumor core (excluding edema) and whole brain tumor (including edema) from different MR sequences, where only the tumor core in one MR sequence was annotated for training. Experimental results show that: 1) our model is more robust to segment previously unseen objects than state-of-the-art CNNs; 2) image-specific fine tuning with the proposed weighted loss function significantly improves segmentation accuracy; and 3) our method leads to accurate results with fewer user interactions and less user time than traditional interactive segmentation methods. PMID- 29969408 TI - Adaptive Spatiotemporal SVD Clutter Filtering for Ultrafast Doppler Imaging Using Similarity of Spatial Singular Vectors. AB - Singular value decomposition of ultrafast imaging ultrasonic data sets has recently been shown to build a vector basis far more adapted to the discrimination of tissue and blood flow than the classical Fourier basis, improving by large factor clutter filtering and blood flow estimation. However, the question of optimally estimating the boundary between the tissue subspace and the blood flow subspace remained unanswered. Here, we introduce an efficient estimator for automatic thresholding of subspaces and compare it to an exhaustive list of thirteen estimators that could achieve this task based on the main characteristics of the singular components, namely the singular values, the temporal singular vectors, and the spatial singular vectors. The performance of those fourteen estimators was tested in vitro in a large set of controlled experimental conditions with different tissue motion and flow speeds on a phantom. The estimator based on the degree of resemblance of spatial singular vectors outperformed all others. Apart from solving the thresholding problem, the additional benefit with this estimator was its denoising capabilities, strongly increasing the contrast to noise ratio and lowering the noise floor by at least 5 dB. This confirms that, contrary to conventional clutter filtering techniques that are almost exclusively based on temporal characteristics, efficient clutter filtering of ultrafast Doppler imaging cannot overlook space. Finally, this estimator was applied in vivo on various organs (human brain, kidney, carotid, and thyroid) and showed efficient clutter filtering and noise suppression, improving largely the dynamic range of the obtained ultrafast power Doppler images. PMID- 29969409 TI - Cardiac Motion Correction for Helical CT Scan With an Ordinary Pitch. AB - Cardiac X-ray computed tomography (CT) imaging is still challenging due to the cardiac motion during CT scanning, which leads to the presence of motion artifacts in the reconstructed image. In response, many cardiac X-ray CT imaging algorithms have been proposed, based on motion estimation (ME) and motion compensation (MC), to improve the image quality by alleviating the motion artifacts in the reconstructed image. However, these ME/MC algorithms are mainly based on an axial scan or a low-pitch helical scan. In this paper, we propose a ME/MC-based cardiac imaging algorithm for the data set acquired from a helical scan with an ordinary pitch of around 1.0 so as to obtain the whole cardiac image within a single scan of short time without ECG gating. In the proposed algorithm, a sequence of partial angle reconstructed (PAR) images is generated by using consecutive parts of the sinogram, each of which has a small angular span. Subsequently, an initial 4-D motion vector field (MVF) is obtained using multiple pairs of conjugate PAR images. The 4-D MVF is then refined based on an image quality metric so as to improve the quality of the motion-compensated image. Finally, a time-resolved cardiac image is obtained by performing motion compensated image reconstruction by using the refined 4-D MVF. Using digital XCAT phantom data sets and a human data set commonly obtained via a helical scan with a pitch of 1.0, we demonstrate that the proposed algorithm significantly improves the image quality by alleviating motion artifacts. PMID- 29969410 TI - Joint Optic Disc and Cup Segmentation Based on Multi-Label Deep Network and Polar Transformation. AB - Glaucoma is a chronic eye disease that leads to irreversible vision loss. The cup to disc ratio (CDR) plays an important role in the screening and diagnosis of glaucoma. Thus, the accurate and automatic segmentation of optic disc (OD) and optic cup (OC) from fundus images is a fundamental task. Most existing methods segment them separately, and rely on hand-crafted visual feature from fundus images. In this paper, we propose a deep learning architecture, named M-Net, which solves the OD and OC segmentation jointly in a one-stage multi-label system. The proposed M-Net mainly consists of multi-scale input layer, U-shape convolutional network, side-output layer, and multi-label loss function. The multi-scale input layer constructs an image pyramid to achieve multiple level receptive field sizes. The U-shape convolutional network is employed as the main body network structure to learn the rich hierarchical representation, while the side-output layer acts as an early classifier that produces a companion local prediction map for different scale layers. Finally, a multi-label loss function is proposed to generate the final segmentation map. For improving the segmentation performance further, we also introduce the polar transformation, which provides the representation of the original image in the polar coordinate system. The experiments show that our M-Net system achieves state-of-the-art OD and OC segmentation result on ORIGA data set. Simultaneously, the proposed method also obtains the satisfactory glaucoma screening performances with calculated CDR value on both ORIGA and SCES datasets. PMID- 29969411 TI - Induced Current Magnetic Resonance Electrical Conductivity Imaging With Oscillating Gradients. AB - In this paper, induced current magnetic resonance electrical impedance tomography (ICMREIT) by means of current induction due to time-varying gradient fields of magnetic resonance imaging (MRI) systems is proposed. Eddy current and secondary magnetic flux density distributions are calculated for a numerical model composed of a z-gradient coil and a cylindrical conductor. An MRI pulse sequence is developed for the experimental evaluation of ICMREIT on a 3T MRI scanner. A relationship between the secondary magnetic flux density and the low-frequency (LF) MR phase is formulated. Characteristics of the LF phase, the eddy current, and the reconstructed conductivity distributions based on the simulated and the physical measurements are in agreement. Geometric shifts, which may contaminate the LF phase measurements, are not observed in the MR magnitude images. Low sensitivity of the LF phase measurements is a major limitation of ICMREIT towards clinical applications. The reconstructed conductivity images are rough estimates of true conductivity distribution of the experimental phantoms. Although the experimental results show that ICMREIT is safe and potentially applicable, its measurement sensitivity and reconstruction accuracy need to be optimized in order to improve the technique towards clinical applications. PMID- 29969413 TI - Development and Implementation of a PIN-Diode Controlled, Quadrature-Enhanced, Double-Tuned RF Coil for Sodium MRI. AB - Sodium (23Na) MRI provides complementary cellular and metabolic information. However, the intrinsic MR sensitivity of 23Na is considerably lower compared with that of the proton, making it difficult to measure MR-detectable sodium signals. It is therefore important to maintain the signal-to-noise ratio (SNR) of the sodium signal as high as possible. Double-tuned coils are often employed in combinationwith a 1H coil, providing structural images and B0 shimming capability. The double-tuned coil design can be achieved with the use of two geometrically decoupled coils whose B1 field directions are perpendicular to each other. This can be used to design quadrature-driven, single-nucleus coils to improve SNR, and additionally, this coil can also be utilized as a linear-driven double-resonant mode. Here, we have developed and evaluateda quadrature-enhanced, double-tuned coil. The novel coil uses PIN-diode switches, inserted only in the loop coil, to shift the resonance frequency between 1H and 23Na so that 23Na signals can be acquired in quadrature and the capability of using 1H function remains. Consequently, the 23Na SNR values obtained with the double-tuned coil are nearly 33% and 17% higher in comparison with geometrically identical single tuned coils. SNR plots also show the superiority of double-tuned coil in 23Na. PMID- 29969412 TI - Repeatability Assessment of Intravascular Polarimetry in Patients. AB - Intravascular polarimetry with polarization sensitive optical frequency domain imaging (PS-OFDI) measures polarization properties of the vessel wall and offers characterization of coronary atherosclerotic lesions beyond the cross-sectional image of arterial microstructure available to conventional OFDI. A previous study of intravascular polarimetry in cadaveric human coronary arteries found that tissue birefringence and depolarization provide valuable insight into key features of atherosclerotic plaques. In addition to various tissue components, catheter and sample motion can also influence the polarization of near infrared light as used by PS-OFDI. This paper aimed to evaluate the robustness and repeatability of imaging tissue birefringence and depolarization in a clinical setting. 30 patients scheduled for percutaneous coronary intervention at the Erasmus Medical Center underwent repeated PS-OFDI pullback imaging, using commercial imaging catheters in combination with a custom-built PS-OFDI console. We identified 274 matching cross sections among the repeat pullbacks to evaluate the reproducibility of the conventional backscatter intensity, the birefringence, and the depolarization signals at each spatial location across the vessel wall. Bland-Altman analysis revealed best agreement for the birefringence measurements, followed by backscatter intensity, and depolarization, when limiting the analysis to areas of meaningful birefringence. Pearson correlation analysis confirmed highest correlation for birefringence (0.86), preceding backscatter intensity (0.83), and depolarization (0.78). Our results demonstrate that intravascular polarimetry generates robust maps of tissue birefringence and depolarization in a clinical setting. This outcome motivates the use of intravascular polarimetry for future clinical studies that investigate polarization properties of arterial atherosclerosis. PMID- 29969414 TI - Simultaneous Variable-Slab Dual-Echo TOF MR Angiography and Susceptibility Weighted Imaging. AB - In this paper, we propose a new 3-D dual-echo method for simultaneous multislab time-of-flight MR angiography (TOF MRA) and single-slab susceptibility-weighted imaging (SWI). The previous echo-specific k-space reordering scheme for compatible dual-echo arteriovenography (CODEA) was advanced to applying excitation RF pulses for multiple thin slabs and a single thick slab to the first (TOF MRA) and second (SWI) echoes, respectively. Single-slab CODEA and multislab CODEA (fixed-slab CODEAs) were additionally acquired as comparison reference to the proposed variable-slab CODEA. Parallel imaging was also tested for feasibility of accelerating the proposed method. TOF MRA and SWI from the proposed variable-slab CODEA were visually and quantitatively comparable to multislab TOF MRA and single-slab SWI, respectively, separately acquired from the fixed-slab CODEAs. The parallel imaging reduced the scan time from 10.3 to 5.6 min. Furthermore, the proposed variable-slab approach improved the vessel continuities at slab boundaries of TOF MRA for CODEA as well as for the conventional single echo method. The proposed variable-slab CODEA provided multislab TOF MRA and single-slab SWI simultaneously in a clinically reasonable scan time of ~5 min with minimal impact on image qualities, while suppressing slab boundary artifacts in TOF MRA. PMID- 29969415 TI - Histopathological Whole Slide Image Analysis Using Context-Based CBIR. AB - Histopathological image classification (HIC) and content-based histopathological image retrieval (CBHIR) are two promising applications for the histopathological whole slide image (WSI) analysis. HIC can efficiently predict the type of lesion involved in a histopathological image. In general, HIC can aid pathologists in locating high-risk cancer regions from a WSI by providing a cancerous probability map for the WSI. In contrast, CBHIR was developed to allow searches for regions with similar content for a region of interest (ROI) from a database consisting of historical cases. Sets of cases with similar content are accessible to pathologists, which can provide more valuable references for diagnosis. A drawback of the recent CBHIR framework is that a query ROI needs to be manually selected from a WSI. An automatic CBHIR approach for a WSI-wise analysis needs to be developed. In this paper, we propose a novel aided-diagnosis framework of breast cancer using whole slide images, which shares the advantages of both HIC and CBHIR. In our framework, CBHIR is automatically processed throughout the WSI, based on which a probability map regarding the malignancy of breast tumors is calculated. Through the probability map, the malignant regions in WSIs can be easily recognized. Furthermore, the retrieval results corresponding to each sub region of the WSIs are recorded during the automatic analysis and are available to pathologists during their diagnosis. Our method was validated on fully annotated WSI data sets of breast tumors. The experimental results certify the effectiveness of the proposed method. PMID- 29969416 TI - TRACE: A Topological Graph Representation for Automatic Sulcal Curve Extraction. AB - A proper geometric representation of the cortical regions is a fundamental task for cortical shape analysis and landmark extraction. However, a significant challenge has arisen due to the highly variable, convoluted cortical folding patterns. In this paper, we propose a novel topological graph representation for automatic sulcal curve extraction (TRACE). In practice, the reconstructed surface suffers from noise influences introduced during image acquisition/surface reconstruction. In the presence of noise on the surface, TRACE determines stable sulcal fundic regions by employing the line simplification method that prevents the sulcal folding pattern from being significantly smoothed out. The sulcal curves are then traced over the connected graph in the determined regions by the Dijkstra's shortest path algorithm. For validation, we used the state-of-the-art surface reconstruction pipelines on a reproducibility data set. The experimental results showed higher reproducibility and robustness to noise in TRACE than the existing method (Li et al. 2010) with over 20% relative improvement in error for both surface reconstruction pipelines. In addition, the extracted sulcal curves by TRACE were well-aligned with manually delineated primary sulcal curves. We also provided a choice of parameters to control quality of the extracted sulcal curves and showed the influences of the parameter selection on the resulting curves. PMID- 29969417 TI - Robust Estimation of Displacement in Real-Time Freehand Ultrasound Strain Imaging. AB - We present a novel and efficient approach for robust estimation of displacement in real-time strain imaging for freehand ultrasound elastography by utilizing pre and post-deformation ultrasound images. We define a quality factor for image lines and find the line with the highest value of quality factor to serve as the seed line for generating the displacement map. We also develop an analytical framework for coarse-to-fine displacement estimation, obtain an initial estimate of the seed line's displacement with subsample precision, and propagate it to the entire image to obtain a high quality strain image. Our fast strategy for estimating the seed line's displacement enables us to enhance the robustness without sacrificing the speed by identifying a new seed line when the quality falls below a given threshold. This is more efficient than the existing approaches that utilize multiple seed lines to improve robustness. Simulations, phantom experiments, and clinical studies show high signal-to-noise-ratio and contrast-to-noise-ratio values in our method for a wide range of average strain levels (1%-10%). Phantom experiments also demonstrate that our method is robust against corrupt and decorrelated data. Our method is superior to the existing real-time methods as it can produce high-quality strain images for up to 10% average strain levels at the rate of 20 frames/s on conventional CPUs. PMID- 29969418 TI - Fully Automatic Lesion Localization and Characterization: Application to Brain Tumors Using Multiparametric Quantitative MRI Data. AB - When analyzing brain tumors, two tasks are intrinsically linked, spatial localization, and physiological characterization of the lesioned tissues. Automated data-driven solutions exist, based on image segmentation techniques or physiological parameters analysis, but for each task separately, the other being performedmanually or with user tuning operations. In this paper, the availability of quantitative magnetic resonance (MR) parameters is combined with advancedmultivariate statistical tools to design a fully automated method that jointly performs both localization and characterization. Non trivial interactions between relevant physiologicalparameters are capturedthanks to recent generalized Student distributions that provide a larger variety of distributional shapes compared to the more standard Gaussian distributions. Probabilisticmixtures of the former distributions are then consideredto account for the different tissue types and potential heterogeneity of lesions. Discriminative multivariate features are extracted from this mixture modeling and turned into individual lesion signatures. The signatures are subsequently pooled together to build a statistical fingerprintmodel of the different lesion types that captures lesion characteristics while accounting for inter-subject variability. The potential of this generic procedure is demonstrated on a data set of 53 rats, with 36 rats bearing 4 different brain tumors, for which 5 quantitative MR parameters were acquired. PMID- 29969419 TI - Locally Affine Diffeomorphic Surface Registration and Its Application to Surgical Planning of Fronto-Orbital Advancement. AB - Metopic craniosynostosis is a condition caused by the premature fusion of the metopic cranial suture. If untreated, it can result into brain growth restriction, increased intra-cranial pressure, visual impairment, and cognitive delay. Fronto-orbital advancement is the widely accepted surgical approach to correct cranial shape abnormalities in patients with metopic craniosynostosis, but the outcome of the surgery remains very dependent on the expertise of the surgeon because of the lack of objective and personalized cranial shape metrics to target during the intervention. We propose in this paper a locally affine diffeomorphic surface registration framework to create an optimal interventional plan personalized to each patient. Our method calculates the optimal surgical plan by minimizing cranial shape abnormalities, which are quantified using objective metrics based on a normative model of cranial shapes built from 198 healthy cases. It is guided by clinical osteotomy templates for fronto-orbital advancement, and it automatically calculates how much and in which direction each bone piece needs to be translated, rotated, and/or bent. Our locally affine framework models separately the transformation of each bone piece while ensuring the consistency of the global transformation. We used our method to calculate the optimal surgical plan for 23 patients, obtaining a significant reduction of malformations (p < 0.001) between 40.38% and 50.85% in the simulated outcome of the surgery using different osteotomy templates. In addition, malformation values were within healthy ranges (p > 0.01). PMID- 29969420 TI - Ex Vivo and In Vivo Monitoring and Characterization of Thermal Lesions by High Intensity Focused Ultrasound and Microwave Ablation Using Ultrasonic Nakagami Imaging. AB - The feasibility of ultrasonic Nakagami imaging to evaluate thermal lesions by high-intensity focused ultrasound and microwave ablation was explored in ex vivo and in vivo liver models. Dynamic changes of the ultrasonic Nakagami parameter in thermal lesions were calculated, and ultrasonic B-mode and Nakagami images were reconstructed simultaneously. The contrast-to-noise ratio (CNR) between thermal lesions and normal tissue was used to estimate the contrast resolution of the monitoring images. After thermal ablation, a bright hyper-echoic region appeared in the ultrasonic B-mode and Nakagami images, identifying the thermal lesion. During thermal ablation, mean values of Nakagami parameter showed an increasing trend from 0.72 to 1.01 for the ex vivo model and 0.54 to 0.72 for the in vivo model. After thermal ablation, mean CNR values of the ultrasonic Nakagami images were 1.29 dB (ex vivo) and 0.80 dB (in vivo), significantly higher ( ) than those for B-mode images. Thermal lesion size, assessed using ultrasonic Nakagami images, shows a good correlation to those obtained from the gross-pathology images (for the ex vivo model: length, = 0.96; width, = 0.90; for the in vivo model: length, = 0.95; width, = 0.85). This preliminary study suggests that ultrasonic Nakagami parameter may have a potential use in evaluating the formation of thermal lesions with better image contrast. Moreover, ultrasonic Nakagami imaging combined with B-mode imaging may be utilized as an alternative modality in developing monitoring systems for image-guided thermal ablation treatments. PMID- 29969421 TI - Ordinal Pattern: A New Descriptor for Brain Connectivity Networks. AB - Brain connectivity networks based on magnetic resonance imaging (MRI) or functional MRI (fMRI) data provide a straightforward way to quantify the structural or functional systems of the brain. Currently, there are several network descriptors developed for representing and analyzing brain connectivity networks. However, most of them are designed for unweighted networks, regardless of the valuable weight information of edges, or do not take advantage of the ordinal relationship of weighted edges (even though they are designed for weighted networks). In this paper, we propose a new network descriptor (i.e., ordinal pattern that contains a sequence of weighted edges) for brain connectivity network analysis. Compared with previous network properties, the proposed ordinal patterns cannot only take advantage of the weight information of edges but also explicitly model the ordinal relationship of weighted edges in brain connectivity networks. We further develop an ordinal pattern-based learning framework for brain disease diagnosis using resting-state fMRI data. Specifically, we first construct a set of brain functional connectivity networks, where each network is corresponding to a particular subject. We then develop an algorithm to identify ordinal patterns that frequently appear in brain connectivity networks of patients and normal controls. We further perform discriminative ordinal pattern selection and extract feature representations for subjects based on the selected ordinal patterns, followed by a learning model for automated brain disease diagnosis. Experimental results on both Alzheimer's Disease Neuroimaging Initiative and attention deficit hyperactivity disorder-200 data sets demonstrate that our method outperforms the several state-of-the-art approaches in the tasks of disease classification and clinical score regression. PMID- 29969422 TI - Investigating the Influence of Spatial Constraints on Ultimate Receive Coil Performance for Monkey Brain MRI at 7 T. AB - The RF receive coil array has become increasingly vital in current MR imaging practice due to its extended spatial coverage, maintained high SNR, and improved capability of accelerating data acquisition. The performance of a coil array is intrinsically determined by the current patterns generated in coil elements as well as by the induced electromagnetic fields inside the object. Investigations of the ultimate performance constrained by a specific coil space, which defines all possible current patterns flowing within, offer the opportunity to evaluate coil-space parameters (i.e., coverage, coil-to-object distance, layer thickness, and coil element type) without the necessity of considering the realistic coil element geometry, coil elements layout, and number of receive channels in modeling. In this paper, to mimic 7-T monkey RF head coil design, seven hypothetical ultimate coil arrays with different coil-space configurations were mounted over a numerical macaque head model; by using Huygens's surface approximation method, the influences of coil-space design parameters were systematically investigated through evaluating the spatial constrained ultimate intrinsic SNR and ultimate g-factor. Moreover, simulations were also conducted by using four coil arrays with limited number of loop-only elements, in order to explore to what extent the ultimate coil performance can be achieved by using practical coil designs, and hence several guidelines in RF coil design for monkey brain imaging at 7 T have been tentatively concluded. It is believed that the present analysis will offer important implications in novel receive array design for monkey brain MR imaging at ultra-high field. PMID- 29969423 TI - Corrections to "Bioluminescence Tomography Based on Gaussian Weighted Laplace Prior Regularization for Morphological Imaging of Glioma". AB - The correct affiliation for Yuan Gao, Kun Wang, and Jie Tian is as follows. PMID- 29969424 TI - Early strut protrusion and late neointima thickness in Absorb bioresorbable scaffold: A serial wall shear stress analysis up to five years. AB - AIMS: To evaluate the effect of strut protrusion(SP) on wall shear stress(WSS) and neointimal growth(NG) one and five-year after implantation of Absorb bioresorbable vascular scaffold. METHODS AND RESULTS: Eight patients were selected from the first-in-man study.Following three-dimensional(3D) reconstruction of the coronaries, WSS was quantified using Newtonian steady-flow simulation in each cross-section at 5 degrees -subunit(sector) of the circumferential luminal surface.At 1-year, neointimal thickness(NT) was measured by optical coherence tomography(OCT) and correlated to WSS and SP post procedure.Median-SP was 112.9(90.8,133.1)um post-implantation. Post-procedure, a logarithmic inverse relationship between SP and post-implantation WSS(r= 0.425,p<0.001;correlation-coefficients range from -0.143 to -0.553)was observed whereas a correlation between baseline logarithmic-transformed-WSS(log-WSS) and NT(r=-0.451,p<0.001;correlation-coefficients ranged from -0.140 to -0.662)was documented at one-year.Mixed-effects analysis between baseline log-WSS and NT at follow-up yielded a slope of 30um/ln Pascal(Pa) and a y-intercept of 98um. As result of NG, median flow-area decreased from 6.91(6.53,7.48)mm2 post implantation to 5.65(5.47,6.02)mm2 at 1-year(p=0.01) and to 5.75+/-1.37mm2 at 5 year follow-up(p=0.024).However, vessel surface exposed to low-WSS(<1Pa) decreased significantly post-procedure(42%) to one-year(35.9%) and five year(15.2%)(p-overall<0.0001). CONCLUSIONS: SP disturbs laminar flow, creates regions of low-WSS(<1.0Pa) that are associated with NG and lumen-area reduction. Low-WSS post-implantation significantly reduced at long-term follow-up. Thin strut with effective vessel wall embedment would substantially reduce NG and accelerate homogenization of WSS towards physiological values. PMID- 29969425 TI - Ten-year clinical outcome of patients treated with a drug-eluting stent in the proximal left anterior descending artery segment compared with patients stented in other non-left main coronary segments. AB - AIMS: The aim of the study was to determine whether patients treated with drug eluting stents in the proximal left anterior descending artery (LAD) carried a different long-term prognosis from patients treated in other coronary artery segments. METHODS AND RESULTS: Ten-year clinical outcome expressed as all-cause mortality and major adverse cardiac events (MACE: cardiac death, acute myocardial infarction, or target vessel revascularisation) was determined for 1,479 patients with a single non-left main coronary stenosis treated with a first-generation drug-eluting stent in the SORT OUT II trial. The outcome of patients treated with stents in the proximal LAD (n=365) was compared with that of patients treated in a non-proximal LAD segment (n=1,114). Follow-up was 99.3% complete. All-cause mortality was 24.9% in the proximal LAD group vs. 26.3% in the non-proximal LAD group (p=0.60). MACE occurred less frequently in the proximal LAD group, 24.6% vs. 31.0% with a hazard ratio of 0.77 (95% confidence interval [CI]: 0.61-0.97, p=0.024). After multivariate analysis which included baseline characteristics that were unevenly distributed between the groups, the hazard ratio for MACE was 0.82 (95% CI: 0.65-1.03, p=0.09). CONCLUSIONS: Patients treated with a drug eluting stent in the proximal LAD have similar, if not better, long-term clinical outcome compared with patients stented in other coronary artery segments. PMID- 29969426 TI - Multiple treatment approaches following incomplete endovascular closure of abdominal aneurysm rupture-related aortocaval fistula. PMID- 29969427 TI - Propensity-matched comparison of clinical outcomes after transaortic versus transfemoral aortic valve replacement. AB - AIMS: We aimed to compare the long-term outcomes of transaortic (TAo-AVR) and transfemoral (TF-AVR) transcatheter aortic valve replacement. METHODS AND RESULTS: Between January 2012 and December 2015, consecutive TAo-AVR and TF-AVR cases were compared using a propensity score-matching analysis. Primary endpoints were 30-day and one-year mortality; 644 TAVR patients were included (163 TAo-AVR and 481 TF-AVR). Peripheral artery disease (31.9% vs. 5%, p<0.001) and coronary artery disease (50.0% vs. 39.3%, p=0.009) were more frequent in TAo-AVR patients. The Society of Thoracic Surgeons scores were not different (6.9% vs. 6.5%, p=0.243). Propensity matching identified 124 well-matched patient pairs. Thirty day and one-year mortality rates were similar in the overall population of TAo AVR and TF-AVR patients (7.3% vs 7.6%, p=0.8 and 18.4% vs. 15.8%, p=0.6, respectively), and in the matched cohort (7.3% vs. 6.5%, p=0.8 and 15.3% vs. 16.1%, p=0.8, respectively). Transaortic access was associated with higher risk of new onset of atrial fibrillation (NOAF) (24.4% vs. 9.6%, p=0.012), life threatening bleedings (6.5% vs. 0.8%, p=0.036) and transfusion (41% vs. 16.7%, p<0.001). CONCLUSIONS: No significant differences were observed between the respective 30-day and one-year mortality rates of TAo-AVR and TF-AVR patients. The transaortic approach thus constitutes a valid alternative to TF-AVR, but is associated with higher rates of NOAF, bleedings, and transfusion. PMID- 29969428 TI - Main pulmonary artery perforations after left atrial appendage occluder implantation. PMID- 29969429 TI - Ischaemic preconditioning of the spinal cord to prevent spinal cord ischaemia during endovascular repair of thoracoabdominal aortic aneurysm: first clinical experience. AB - AIMS: The purpose of our study was to report our experience with minimally invasive segmental artery coil embolisation (MISACE) to prevent spinal cord ischaemia (SCI) after endovascular repair (ER) of thoracoabdominal aortic aneurysm (TAAA). METHODS AND RESULTS: A cohort of 57 patients with TAAAs was treated by MISACE followed by ER between October 2014 and December 2017. The TAAA Crawford classification was: type I, n=5; type II, n=12; type III, n=27; type IV, n=13. The average maximum aortic diameter was 62.7+/-8.8 mm. Patients had a median of 5 coiled SAs (range: 1-19). MISACE was completed in one (n=22), two (n=24), three (n=7), four (n=3) or five (n=1) sessions. The maximum number of coiled SAs per session was six. After completion of MISACE, 77.7% of direct segmental arterial flow was occluded. After a mean of 83+/-62 days, 55 of the patients received total ER of their TAAA. At 30 days after ER, no patient developed SCI and three patients had died. CONCLUSIONS: MISACE to precondition the paraspinous collateral network prior to endovascular repair of thoracoabdominal aortic aneurysm is clinically feasible. The safety profile is promising and there is good reason to explore this new staging strategy further. PMID- 29969430 TI - International LAMPOON: first European experience with laceration of the anterior mitral valve leaflet prior to transseptal transcatheter mitral valve implantation. PMID- 29969431 TI - Impact of age on the effect of pre-hospital P2Y12 receptor inhibition in primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: the ATLANTIC-Elderly analysis AB - AIMS: The aim of the study was to examine the main results of the ATLANTIC trial in patients with ST-elevation myocardial infarction (STEMI), randomised to pre- versus in-hospital ticagrelor, according to age. METHODS AND RESULTS: Patients were evaluated by age class (<75 vs. >=75 years) for demographics, prior cardiovascular history, risk factors, management, and outcomes. Elderly patients (>=75 years; 304/1,862) were more likely to be women, diabetic, lean, with a prior history of myocardial infarction and CABG, and with comorbidities (p<0.01 for all). Elderly patients presented more frequently with acute heart failure and less frequently had thromboaspiration, a stent implanted (p<0.01) and an aggressive antithrombotic regimen. Elderly patients had lower rates of pre- and post-PCI >=70% ST-segment elevation resolution (43.9% vs. 51.6%; p=0.035), of pre and post-PCI TIMI 3 flow (17.1% vs. 27.5%, p=0.0002), and a higher rate of the composite of death/MI/stroke/urgent revascularisation (9.9% vs. 2.9%; OR 3.67, 95% CI [2.27; 5.93], p<0.0001) and mortality (8.5% vs. 1.5%; OR 6.45, 95% CI [2.75; 15.11], p<0.0001). There was a non-significant trend towards more frequent major bleedings among elderly patients (TIMI major 2.3% vs. 1.1%; OR 2.13, 95% CI [0.88; 5.18], p=0.095). There was no significant interaction between time of ticagrelor administration (pre-hospital versus in-lab) and class of age for all outcomes. CONCLUSIONS: Elderly patients, who represented one sixth of the patients randomised in the ATLANTIC trial, had less successful mechanical reperfusion and a sixfold increase in mortality at 30 days, probably due to comorbidities and possible undertreatment. The effect of early ticagrelor was consistent irrespective of age. PMID- 29969432 TI - Transcatheter aortic valve implantation with the self-expanding Portico valve system in an all-comers population: procedural and clinical outcomes. AB - AIMS: Transcatheter aortic valve implantation (TAVI) is an established therapy for patients with severe aortic stenosis (AS). The aim of this study was to evaluate the newer-generation Portico TAVI system in an all-comers population. METHODS AND RESULTS: This single-centre study included 216 patients with severe AS (Society of Thoracic Surgeons [STS] score 4.3+/-3.0%). The Portico valve was implanted using the transfemoral (91.2%), transsubclavian (5.6%) and transcaval (3.2%) access. Device success was achieved in 94.4% of cases. At 30 days, mortality and stroke rates were 2.3% and 0.5%, respectively. Early safety was achieved in 91.7% of cases. More-than-mild paravalvular leak (PVL), as assessed by echocardiogram, was observed in 3.4% of the patients, with rates of 4.9% and 1.9% in the first and second half of the cohort, respectively. A permanent pacemaker was implanted in 15.8% of those without prior pacemaker, with a rate of 11.1% in the second half of the cohort. At one year, incidence rates for all cause mortality and stroke were 12.3% and 2.3%, respectively. In the low-risk group (STS <4%; n=128), Kaplan-Meier estimates at 30 days and one year were 0% and 7.5% for all-cause mortality and 0.8% and 2.2% for stroke, respectively. Haemodynamic improvements persisted over time with a mean transvalvular gradient of 7.0+/-3.0 mmHg at one-year follow-up. CONCLUSIONS: The Portico TAVI system was safe to implant and achieved a high device success rate. With learning curve effects, the device achieves lower rates of PVL and pacemaker implantation and provides adequate clinical and haemodynamic outcomes up to one year. PMID- 29969433 TI - Acute and Long-term Relocation of Minimal Lumen Area after Bioresorbable Scaffold or Metallic Stent Implantation. AB - AIMS: To investigate relocation of minimal lumen area (MLA) after implantation of bioresorbable scaffold (BRS). METHODS AND RESULTS: In the ABSORB II randomized trial [BRS vs. everolimus-eluting stent (EES)], lesions were investigated by serial intravascular ultrasound pre-procedure, post-procedure, and at 3-year. MLA relocation was defined as an axial MLA shift of more than 2.4 mm. MLA relocation from post-procedure to 3-year was observed in 163/237 (68.8%) and 75/129 (58.1%) of lesions treated by BRS and EES, respectively (p=0.041). When matching pre procedural MLA site with the same topographical sites post-procedure and at 3 year, BRS showed significant late lumen enlargement and expansive remodelling compensating for significant plaque increase, whereas EES showed significant late lumen narrowing with significant plaque growth not compensated by expansive remodelling from post-procedure to 3-year. In the multivariate analysis, female gender, previous PCI, BRS implantation, total device length, and maximal pressure either at device implantation or post-dilatation were independently associated with MLA relocation from post-procedure to 3-year. CONCLUSIONS: MLA relocation from post-procedure to 3-year was more frequent in BRS than EES. Late lumen enlargement and expansive vessel remodelling at the pre-procedural MLA site was observed in BRS, but not in EES. PMID- 29969434 TI - First-in-man implantation of the Tricento transcatheter heart valve for the treatment of severe tricuspid regurgitation. AB - Here we describe the first implantation of the novel bicavally anchored Tricento transcatheter heart valve via the transvenous transfemoral access in a 74-year old woman with severe tricuspid regurgitation and holosystolic hepatic vein backflow. Following successful implantation, caval vein regurgitant volume was reduced leading to symptomatic and clinical improvement at three-month follow-up. The Tricento device represents a promising, novel therapeutic option for patients with severe tricuspid regurgitation who are not candidates for open heart surgery. PMID- 29969435 TI - Delayed Appearance of Intramural Hematoma After Stent Implantation: Diagnosis by Optical Coherence Tomography. PMID- 29969436 TI - Usefulness of bevacizumab-induced hypertension in patients with metastatic colorectal cancer: an updated meta-analysis. AB - We tested the hypothesis that bevacizumab-induced hypertension may be a useful predictor for objective response rate, progression-free and overall survival in patients with metastatic colorectal cancer via a comprehensive meta-analysis. Search process, article selection and data extraction were independently performed by two investigators. Statistical analyses were conducted using the STATA/SE software. Fourteen independent studies and 2292 study subjects were synthesized. Overall relative risk of objective response rate for bevacizumab induced hypertension was 2.03 (95% confidence interval [CI]: 1.18-3.48, p=0.01), with significant heterogeneity and publication bias, whereas unbiased estimate was nonsignificant after considering potentially missing studies. Overall hazard ratio for progression-free survival was 0.58 (95% CI: 0.43-0.77, p<0.001), with significant heterogeneity and publication bias, and unbiased estimate was significant (hazard ratio: 0.52, 95% CI: 0.41-0.66, p<0.001). Overall hazard ratio for overall survival was 0.51 (95% CI: 0.39-0.65, p<0.001), and this estimate was not likely confounded by heterogeneity or publication bias. Subgroup and meta-regression analyses suggested that hypertension grade of controls, sample size, age and gender were possible causes of heterogeneity. Taken together, our findings indicate that bevacizumab-induced hypertension can predict progress-free survival and overall survival in patients with metastatic colorectal cancer, whereas its prediction for objective response rate was nonsignificant. PMID- 29969438 TI - Long Noncoding RNA LINC003121 Inhibits Proliferation and Invasion of Thyroid Cancer Cells by Suppression of the Phosphatidylinositol-3-Kinase (PI3K)/Akt Signaling Pathway. AB - BACKGROUND The aim of this study was to explore the potential effects of long noncoding RNA (lncRNA) LINC003121 on thyroid cancer (TC) cell proliferation and invasion and to explore their possible mechanisms with the involvement of the PI3K/Akt signaling pathway. MATERIAL AND METHODS We enrolled 211 thyroid cancer tissues and 70 adjacent normal tissues in this study. TC cell lines K1, SW579, and 8505C and the human thyroid follicular cell line Nthy-ori3-1 were selected and assigned into blank, control vectors, LINC00312 vectors, si-control, and si LINC00312 groups. Quantitative real-time PCR was used to determine the levels of LINC003121 and Western blotting was used to detect the protein expression of MMP 9, PI3K, t-Akt, and p-Akt. Cell proliferation was assessed by CCK8 assay and EdU incorporation assay, and cell invasion was assessed by Transwell assay. RESULTS The expression of LINC00312 was significantly decreased in TC tissues and cell lines. In an in vitro experiment, si-LINC00312 significantly promoted the invasion and proliferation of TC cells. Conversely, overexpression of LINC00312 decreased cell proliferation and invasion in vitro, and decreased tumorigenicity in TC xenograft models in nude mice. LINC00312-mediated tumor suppression in TC cells may occur via suppression of activation of the PI3K/Akt signaling pathway and expression of MMP-9, and the role of MMP-9 expression induced by overexpressed LINC00312 or si-LINC00312 could be weakened by LY294002 (PI3K inhibitor). CONCLUSIONS LINC00312 can act as a tumor-suppressor in TC by attenuating the PI3K/Akt signaling pathway, and LINC00312 could be a novel diagnosis biomarker and a promising therapeutic target for TC patients. PMID- 29969441 TI - Multi-scale multi-level marine spatial planning: A novel methodological approach applied in South Africa. AB - This study proposes and discusses a multi-scale spatial planning method implemented simultaneously at local and national level to prioritize ecosystem management actions across landscapes and seascapes. Mismatches in scale between the occurrence of biodiversity patterns and ecological processes, and the size and nature of the human footprint, and the different levels and scope of governance, are a significant challenge in conservation planning. These scale mismatches are further confounded by data resolution disparities across and amongst the different scales. To address this challenge, we developed a multi resolution scale-linked marine spatial planning method. We tested this approach in the development of a Conservation Plan for a significant portion of South Africa's exclusive economic zone, adjacent to the east coast province of KwaZulu Natal (the SeaPlan project). The study's dataset integrated the geographic distribution of 390 biodiversity elements (species, habitats, and oceanographic processes) and 38 human activities. A multi-resolution system of planning unit layers (PUL), with individual PUs ranging in resolution from 0.2 to 10 km, was designed to arrange and analyse these data. Spatial priorities for conservation were selected incrementally at different scales, contributing conservation targets from the fine-, medium- and large-scale analyses, and from the coast to the offshore. Compared to a basic single-resolution scale-unlinked plan, our multi-resolution scale-linked method selects 6% less conservation area to achieve the same targets. Compared to a multi-resolution scale-unlinked plan, our method requires only an additional 5% area. Overall, this method reflects the multi scale nature of marine social-ecological systems more realistically, is relatively simple and replicable, and serves to better connect fine-scale and large-scale spatial management policies. We discuss the impacts of this study on protected area expansion planning processes in South Africa. This study showcases a methodological advance that has the potential to impact marine spatial planning practices and policies. PMID- 29969439 TI - Optimized base editors enable efficient editing in cells, organoids and mice. AB - CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created. The reengineered base editors enable target modification in a wide range of mouse and human cell lines, and intestinal organoids. We also show that the optimized base editors mediate efficient in vivo somatic editing in the liver in adult mice. PMID- 29969442 TI - Anticipated burden and mitigation of carbon-dioxide-induced nutritional deficiencies and related diseases: A simulation modeling study. AB - BACKGROUND: Rising atmospheric carbon dioxide concentrations are anticipated to decrease the zinc and iron concentrations of crops. The associated disease burden and optimal mitigation strategies remain unknown. We sought to understand where and to what extent increasing carbon dioxide concentrations may increase the global burden of nutritional deficiencies through changes in crop nutrient concentrations, and the effects of potential mitigation strategies. METHODS AND FINDINGS: For each of 137 countries, we incorporated estimates of climate change, crop nutrient concentrations, dietary patterns, and disease risk into a microsimulation model of zinc and iron deficiency. These estimates were obtained from the Intergovernmental Panel on Climate Change, US Department of Agriculture, Statistics Division of the Food and Agriculture Organization of the United Nations, and Global Burden of Disease Project, respectively. In the absence of increasing carbon dioxide concentrations, we estimated that zinc and iron deficiencies would induce 1,072.9 million disability-adjusted life years (DALYs) globally over the period 2015 to 2050 (95% credible interval [CrI]: 971.1 1,167.7). In the presence of increasing carbon dioxide concentrations, we estimated that decreasing zinc and iron concentrations of crops would induce an additional 125.8 million DALYs globally over the same period (95% CrI: 113.6 138.9). This carbon-dioxide-induced disease burden is projected to disproportionately affect nations in the World Health Organization's South-East Asia and African Regions (44.0 and 28.5 million DALYs, respectively), which already have high existing disease burdens from zinc and iron deficiencies (364.3 and 299.5 million DALYs, respectively), increasing global nutritional inequalities. A climate mitigation strategy such as the Paris Agreement (an international agreement to keep global temperatures within 2 degrees C of pre industrial levels) would be expected to avert 48.2% of this burden (95% CrI: 47.8%-48.5%), while traditional public health interventions including nutrient supplementation and disease control programs would be expected to avert 26.6% of the burden (95% CrI: 23.8%-29.6%). Of the traditional public health interventions, zinc supplementation would be expected to avert 5.5%, iron supplementation 15.7%, malaria mitigation 3.2%, pneumonia mitigation 1.6%, and diarrhea mitigation 0.5%. The primary limitations of the analysis include uncertainty regarding how food consumption patterns may change with climate, how disease mortality rates will change over time, and how crop zinc and iron concentrations will decline from those at present to those in 2050. CONCLUSIONS: Effects of increased carbon dioxide on crop nutrient concentrations are anticipated to exacerbate inequalities in zinc and iron deficiencies by 2050. Proposed Paris Agreement strategies are expected to be more effective than traditional public health measures to avert the increased inequality. PMID- 29969437 TI - Inherited p40phox deficiency differs from classic chronic granulomatous disease. AB - Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD. PMID- 29969443 TI - An in vitro and in vivo study on the properties of hollow polycaprolactone cell delivery particles. AB - The field of dermal fillers is evolving rapidly and numerous products are currently on the market. Biodegradable polymers such as polycaprolactone (PCL) have been found to be compatible with several body tissues, and this makes them an ideal material for dermal filling purposes. Hollow PCL spheres were developed by the Council for Scientific and Industrial Research (CSIR) to serve both as an anchor point and a "tissue harbour" for cells. Particles were tested for cytotoxicity and cell adherence using mouse embryo fibroblasts (MEF). MEFs adhered to the particles and no significant toxic effects were observed based on morphology, cell growth, cell viability and cell cycle analysis, suggesting that the particles are suitable candidates for cell delivery systems in an in vivo setting. The objective of providing a "tissue harbour" was however not realized, as cells did not preferentially migrate into the ported particles. In vivo studies were conducted in BALB/c mice into whom particles were introduced at the level of the hypodermis. Mice injected with PCL particles (ported and non-ported; with or without MEFs) showed evidence of local inflammation and increased adipogenesis at the site of injection, as well as a systemic inflammatory response. These effects were also observed in mice that received apparently inert (polystyrene) particles. Ported PCL particles can therefore act as a cell delivery system and through their ability to induce adipogenesis, may also serve as a dermal bulking agent. PMID- 29969440 TI - Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. AB - Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ~750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 +/- 0.9% vs. 2.5 +/- 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ~99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function. PMID- 29969444 TI - Chile's 2014 sugar-sweetened beverage tax and changes in prices and purchases of sugar-sweetened beverages: An observational study in an urban environment. AB - BACKGROUND: On October 1, 2014, the Chilean government modified its previous sugar-sweetened beverage (SSB) tax, increasing the tax rate from 13% to 18% on industrialized beverages with high levels of sugar (H-SSBs) (greater than 6.25 grams [g] sugar/100 milliliters [mL]) and decreasing the tax rate from 13% to 10% on industrialized beverages with low or no sugar (L-SSBs) (less than 6.25 g sugar/100 mL). This study examines changes in beverage prices and household beverage purchases following the implementation of the tax reform. METHODS AND FINDINGS: We used longitudinal data collected between January 1, 2013, and December 31, 2015, from 2,000 households. We defined the pretax period as January 1, 2013, to September 30, 2014, and the posttax period as October 1, 2014, to December 31, 2015. We conducted a pre-post analysis for changes in prices and purchases, with the latter examined by volume and calories. We compared posttax changes in prices and purchases to a counterfactual, defined as what would have been expected in the posttax period based on pretax trends. All results are stated as comparisons to this counterfactual. We linked beverages at the bar code level to nutrition facts panel data collected by a team of Chilean nutritionists who categorized them by taxation level and beverage subcategory, which included carbonated and noncarbonated H-SSBs and concentrated, ready-to-drink L-SSBs and untaxed beverages. We reconstituted concentrated beverages and analyzed all beverages using as-consumed volumes and calories. Posttax monthly prices of H SSBs increased, but these changes were small. Prices of carbonated H-SSBs increased by 2.0% (95% confidence interval [CI] 1.0%-3.0%), while those of noncarbonated H-SSBs increased by 3.9% (95% CI 1.6%-6.2%). Prices of L-SSB concentrates decreased after the tax by 6.7% (95% CI -8.2%--4.6%), and prices of ready-to-drink L-SSBs increased by 1.5% (95% CI 0.3%-2.7%). Households decreased monthly per capita purchases of H-SSBs by 3.4% by volume (95% CI -5.9%--0.9%) and 4.0% by calories (95% CI -6.3%--1.9%), and this change was greater among high socioeconomic status (SES) households. The volume of household purchases of L SSBs increased 10.7% (95% CI 7.5%-13.9%), while that of untaxed beverage purchases decreased by 3.1% (95% CI -5.1%--1.1%). The main limitation of this study was that there was no control group, so we were unable to assess the causal impact of the tax. CONCLUSIONS: The modifications of Chile's SSB tax were small, and observed changes in prices and purchases of beverages after the tax were also small. Our results are consistent with previous evidence indicating that small increases in SSB taxes are unlikely to promote large enough changes in SSB purchases to reduce obesity and noncommunicable diseases (NCDs). PMID- 29969445 TI - Clinical characteristics and cytokine profiles of children with acute lower respiratory tract infections caused by human rhinovirus. AB - The clinical profile of human rhinovirus (HRV) with regard to lower respiratory infections remains unclear. We analyzed the clinical features and cytokine responses of HRV isolates in children with respiratory infections. Quantitative analysis and genotyping of the HRV-positive samples from 601 nasopharyngeal aspirates (NPAs) were performed using VP4/VP2 sequencing. To compare T-helper1 (Th1) type (IFN-gamma, TNF-alpha) and Th2 type (IL-4, IL-10) cytokine responses between HRV-A, B and C, the levels of the four cytokines were measured. The HRV positive children had shorter fever duration (P = 0.018), and higher frequencies of chest retraction (P = 0.002) and wheezing (P = 0.022) than did the HRV negative group. HRV-A was identified in 55 cases (58.5%), HRV-B in 8 (8.5%), and HRV-C in 31 (33.0%). There were no significant differences in the clinical data or NPA cytokines levels between patients with HRV-A and HRV-C infections. HRV is an important pathogen of the lower respiratory tract in young children. HRV-A and HRV-C are the dominant species that cause respiratory difficulty in young children. PMID- 29969447 TI - Increases in atmospheric carbon dioxide: Anticipated negative effects on food quality. AB - In a Perspective, Kristie Ebi and Lewis Ziska discuss Weyant and colleagues' accompanying study on the projected effects of atmospheric carbon dioxide on nutrition and disease. PMID- 29969446 TI - Future ozone-related acute excess mortality under climate and population change scenarios in China: A modeling study. AB - BACKGROUND: Climate change is likely to further worsen ozone pollution in already heavily polluted areas, leading to increased ozone-related health burdens. However, little evidence exists in China, the world's largest greenhouse gas emitter and most populated country. As China is embracing an aging population with changing population size and falling age-standardized mortality rates, the potential impact of population change on ozone-related health burdens is unclear. Moreover, little is known about the seasonal variation of ozone-related health burdens under climate change. We aimed to assess near-term (mid-21st century) future annual and seasonal excess mortality from short-term exposure to ambient ozone in 104 Chinese cities under 2 climate and emission change scenarios and 6 population change scenarios. METHODS AND FINDINGS: We collected historical ambient ozone observations, population change projections, and baseline mortality rates in 104 cities across China during April 27, 2013, to October 31, 2015 (2013 2015), which included approximately 13% of the total population of mainland China. Using historical ozone monitoring data, we performed bias correction and spatially downscaled future ozone projections at a coarse spatial resolution (2.0 degrees * 2.5 degrees ) for the period April 27, 2053, to October 31, 2055 (2053 2055), from a global chemistry-climate model to a fine spatial resolution (0.25 degrees * 0.25 degrees ) under 2 Intergovernmental Panel on Climate Change Representative Concentration Pathways (RCPs): RCP4.5, a moderate global warming and emission scenario where global warming is between 1.5 degrees C and 2.0 degrees C, and RCP8.5, a high global warming and emission scenario where global warming exceeds 2.0 degrees C. We then estimated the future annual and seasonal ozone-related acute excess mortality attributable to both climate and population changes using cause-specific, age-group-specific, and season-specific concentration-response functions (CRFs). We used Monte Carlo simulations to obtain empirical confidence intervals (eCIs), quantifying the uncertainty in CRFs and the variability across ensemble members (i.e., 3 predictions of future climate and air quality from slightly different starting conditions) of the global model. Estimates of future changes in annual ozone-related mortality are sensitive to the choice of global warming and emission scenario, decreasing under RCP4.5 (-24.0%) due to declining ozone precursor emissions but increasing under RCP8.5 (10.7%) due to warming climate in 2053-2055 relative to 2013-2015. Higher ambient ozone occurs under the high global warming and emission scenario (RCP8.5), leading to an excess 1,476 (95% eCI: 898 to 2,977) non-accidental deaths per year in 2053-2055 relative to 2013-2015. Future ozone-related acute excess mortality from cardiovascular diseases was 5-8 times greater than that from respiratory diseases. Ozone concentrations increase by 15.1 parts per billion (10-9) in colder months (November to April), contributing to a net yearly increase of 22.3% (95% eCI: 7.7% to 35.4%) in ozone-related mortality under RCP8.5. An aging population, with the proportion of the population aged 65 years and above increased from 8% in 2010 to 24%-33% in 2050, will substantially amplify future ozone-related mortality, leading to a net increase of 23,838 to 78,560 deaths (110% to 363%). Our analysis was mainly limited by using a single global chemistry-climate model and the statistical downscaling approach to project ozone changes under climate change. CONCLUSIONS: Our analysis shows increased future ozone-related acute excess mortality under the high global warming and emission scenario RCP8.5 for an aging population in China. Comparison with the lower global warming and emission scenario RCP4.5 suggests that climate change mitigation measures are needed to prevent a rising health burden from exposure to ambient ozone pollution in China. PMID- 29969448 TI - Structural and functional studies of histidine biosynthesis in Acanthamoeba spp. demonstrates a novel molecular arrangement and target for antimicrobials. AB - Acanthamoeba is normally free-living, but sometimes facultative and occasionally opportunistic parasites. Current therapies are, by necessity, arduous and yet poorly effective due to their inabilities to kill cyst stages or in some cases to actually induce encystation. Acanthamoeba can therefore survive as cysts and cause disease recurrence. Herein, in pursuit of better therapies and to understand the biochemistry of this understudied organism, we characterize its histidine biosynthesis pathway and explore the potential of targeting this with antimicrobials. We demonstrate that Acanthamoeba is a histidine autotroph, but with the ability to scavenge preformed histidine. It is able to grow in defined media lacking this amino acid, but is inhibited by 3-amino-1,2,4-triazole (3AT) that targets Imidazoleglycerol-Phosphate Dehydratase (IGPD) the rate limiting step of histidine biosynthesis. The structure of Acanthamoeba IGPD has also been determined in complex with 2-hydroxy-3-(1,2,4-triazol-1-yl) propylphosphonate [(R)-C348], a recently described novel inhibitor of Arabidopsis thaliana IGPD. This compound inhibited the growth of four Acanthamoeba species, having a 50% inhibitory concentration (IC50) ranging from 250-526 nM. This effect could be ablated by the addition of 1 mM exogenous free histidine, but importantly not by physiological concentrations found in mammalian tissues. The ability of 3AT and (R)-C348 to restrict the growth of four strains of Acanthamoeba spp. including a recently isolated clinical strain, while not inducing encystment, demonstrates the potential therapeutic utility of targeting the histidine biosynthesis pathway in Acanthamoeba. PMID- 29969449 TI - RES complex is associated with intron definition and required for zebrafish early embryogenesis. AB - Pre-mRNA splicing is a critical step of gene expression in eukaryotes. Transcriptome-wide splicing patterns are complex and primarily regulated by a diverse set of recognition elements and associated RNA-binding proteins. The retention and splicing (RES) complex is formed by three different proteins (Bud13p, Pml1p and Snu17p) and is involved in splicing in yeast. However, the importance of the RES complex for vertebrate splicing, the intronic features associated with its activity, and its role in development are unknown. In this study, we have generated loss-of-function mutants for the three components of the RES complex in zebrafish and showed that they are required during early development. The mutants showed a marked neural phenotype with increased cell death in the brain and a decrease in differentiated neurons. Transcriptomic analysis of bud13, snip1 (pml1) and rbmx2 (snu17) mutants revealed a global defect in intron splicing, with strong mis-splicing of a subset of introns. We found these RES-dependent introns were short, rich in GC and flanked by GC depleted exons, all of which are features associated with intron definition. Using these features, we developed and validated a predictive model that classifies RES dependent introns. Altogether, our study uncovers the essential role of the RES complex during vertebrate development and provides new insights into its function during splicing. PMID- 29969450 TI - CellProfiler 3.0: Next-generation image processing for biology. AB - CellProfiler has enabled the scientific research community to create flexible, modular image analysis pipelines since its release in 2005. Here, we describe CellProfiler 3.0, a new version of the software supporting both whole-volume and plane-wise analysis of three-dimensional (3D) image stacks, increasingly common in biomedical research. CellProfiler's infrastructure is greatly improved, and we provide a protocol for cloud-based, large-scale image processing. New plugins enable running pretrained deep learning models on images. Designed by and for biologists, CellProfiler equips researchers with powerful computational tools via a well-documented user interface, empowering biologists in all fields to create quantitative, reproducible image analysis workflows. PMID- 29969451 TI - Activation of Th2 cells downregulates CRTh2 through an NFAT1 mediated mechanism. AB - CRTh2 (encoded by PTGDR2) is a G-protein coupled receptor expressed by Th2 cells as well as eosinophils, basophils and innate lymphoid cells (ILC)2s. Activation of CRTh2, by its ligand prostaglandin (PG)D2, mediates production of type 2 cytokines (IL-4, IL-5 and IL-13), chemotaxis and inhibition of apoptosis. As such, the PGD2-CRTh2 pathway is considered important to the development and maintenance of allergic inflammation. Expression of CRTh2 is mediated by the transcription factor GATA3 during Th2 cell differentiation and within ILC2s. Other than this, relatively little is known regarding the cellular and molecular mechanisms regulating expression of CRTh2. Here, we show using primary human Th2 cells that activation (24hrs) through TCR crosslinking (alphaCD3/alphaCD28) reduced expression of both mRNA and surface levels of CRTh2 assessed by flow cytometry and qRT-PCR. This effect took more than 4 hours and expression was recovered following removal of activation. EMSA analysis revealed that GATA3 and NFAT1 can bind independently to overlapping sites within a CRTh2 promoter probe. NFAT1 over-expression resulted in loss of GATA3-mediated CRTh2 promoter activity, while inhibition of NFAT using a peptide inhibitor (VIVIT) coincided with recovery of CRTh2 expression. Collectively these data indicate that expression of CRTh2 is regulated through the competitive action of GATA3 and NFAT1. Though prolonged activation led to NFAT1-mediated downregulation, CRTh2 was re-expressed when stimulus was removed suggesting this is a dynamic mechanism and may play a role in PGD2-CRTh2 mediated allergic inflammation. PMID- 29969452 TI - Combined acetyl-11-keto-beta-boswellic acid and radiation treatment inhibited glioblastoma tumor cells. AB - Glioblastoma multiforme (GBM) is the most common and most aggressive subtype of malignant gliomas. The current standard of care for newly diagnosed GBM patients involves maximal surgical debulking, followed by radiation therapy and temozolomide chemotherapy. Despite the advances in GBM therapy, its outcome remains poor with a median survival of less than two years. This poor outcome is partly due to the ability of GBM tumors to acquire adaptive resistance to therapy and in particular to radiation. One of the mechanisms contributing to GBM tumor progression and resistance is an aberrant activation of NF-KB, a family of inducible transcription factors that play a pivotal role in regulation of many immune, inflammatory and carcinogenic responses. Acetyl-11-keto-beta-boswellic acid (AKBA) is a pentacyclic terpenoid extracted from the gum Ayurvedic therapeutic plant Boswellia serrata. AKBA is anti-inflammatory agent that exhibits potent cytotoxic activities against various types of tumors including GBM. One of the mechanisms underlying AKBA anti-tumor activity is its ability to modulate the NF-KB signaling pathway. The present study investigated in vitro and in vivo the effect of combining AKBA with ionizing radiation in the treatment of GBM and assessed AKBA anti-tumor activity and radio-enhancing potential. The effect of AKBA and/or radiation on the survival of cultured glioblastoma cancer cells was evaluated by XTT assay. The mode of interaction of treatments tested was calculated using CalcuSyn software. Inducing of apoptosis following AKBA treatment was evaluated using flow cytometry. The effect of combined treatment on the expression of PARP protein was analysed by Western blot assay. Ectopic (subcutaneous) GBM model in nude mice was used for the evaluation of the effect of combined treatment on tumor growth. Immunohistochemical analysis of formalin fixed paraffin-embedded tumor sections was used to assess treatment-related changes in Ki-67, CD31, p53, Bcl-2 and NF-KB-inhibitor IKB-alpha. AKBA treatment was found to inhibit the survival of all four tested cell lines in a dose dependent manner. The combined treatment resulted in a more significant inhibitory effect compared to the effect of treatment with radiation alone. A synergistic effect was detected in some of the tested cell lines. Flow cytometric analysis with Annexin V-FITC/PI double staining of AKBA treated cells indicated induction of apoptosis. AKBA apoptotic activity was also confirmed by PARP cleavage detected by Western blot analysis. The combined treatment suppressed tumor growth in vivo compared to no treatment and each treatment alone. Immunohistochemical analysis showed anti-angiogenic and anti-proliferative activity of AKBA in vivo. It also demonstrated a decrease in p53 nuclear staining and in Bcl-2 staining and an increase in IKB-alpha staining following AKBA treatment both alone and in combination with radiotherapy. In this study, we demonstrated that AKBA exerts potent anti-proliferative and apoptotic activity, and significantly inhibits both the survival of glioblastoma cells in vitro and the growth of tumors generated by these cells. Combination of AKBA with radiotherapy was found to inhibit factors which involved in cell death regulation, tumor progression and radioresistence, therefore it may serve as a novel approach for GBM patients. PMID- 29969453 TI - Development of a novel immunoproteasome digestion assay for synthetic long peptide vaccine design. AB - Recently, many autologous tumor antigens have been examined for their potential use in cancer immunotherapy. However, the success of cancer vaccines in clinical trials has been limited, partly because of the limitations of using single, short peptides in most attempts. With this in mind, we aimed to develop multivalent synthetic long peptide (SLP) vaccines containing multiple cytotoxic T-lymphocyte (CTL) epitopes. However, to confirm whether a multivalent vaccine can induce an individual epitope-specific CTL, the only viable screening strategies currently available are interferon-gamma (IFN-MU enzyme-linked immunospot (ELISPOT) assays using human peripheral blood mononuclear cells, or expensive human leukocyte antigen (HLA)-expressing mice. In this report, we evaluated the use of our developed murine-20S immunoproteasome (i20S) digestion assay, and found that it could predict the results of IFN-MU ELISPOT assays. Importantly, the murine-i20S digestion assay not only predicted CTL induction, but also antitumor activity in an HLA-expressing mouse model. We conclude that the murine-i20S digestion assay is an extremely useful tool for the development of "all functional" multivalent SLP vaccines. PMID- 29969454 TI - Genetic and biological characterization of H9N2 avian influenza viruses isolated in China from 2011 to 2014. AB - The genotypes of the H9N2 avian influenza viruses have changed since 2013 when almost all H9N2 viruses circulating in chickens in China were genotype 57 (G57) with the fittest lineage of each gene. To characterize the H9N2 variant viruses from 2011 to 2014, 28 H9N2 influenza viruses were isolated from live poultry markets in China from 2011-2014 and were analyzed by genetic and biological characterization. Our findings showed that 16 residues that changed antigenicity, two potential N-linked glycosylation sites, and one amino acid in the receptor binding site of the HA protein changed significantly from 2011-2014. Moreover, the HA and NA genes in the phylogenetic tree were mainly clustered into two independent branches, A and B, based on the year of isolation. H9N2 virus internal genes were related to those from the human-infected avian influenza viruses H5N1, H7N9, and H10N8. In particular, the NS gene in the phylogenetic tree revealed genetic divergence of the virus gene into three branches labeled A, B, and C, which were related to the H9N2, H10N8, and H7N9 viruses, respectively. Additionally, the isolates also showed varying levels of infection and airborne transmission. These results indicated that the H9N2 virus had undergone an adaptive evolution and variation from 2011-2014. PMID- 29969455 TI - Proton pump inhibitor as an independent factor of progression of abdominal aortic calcification in patients on maintenance hemodialysis. AB - BACKGROUNDS: Proton pump inhibitors (PPIs) can be associated with vascular calcification in patients undergoing dialysis through hypomagnesemia. However, only few studies have demonstrated the influence of PPIs on vascular calcification in patients on maintenance hemodialysis (HD). This study aimed to investigate whether the use of PPIs accelerates vascular calcification in patients on HD. MATERIALS AND METHODS: We retrospectively evaluated 200 HD patients who underwent regular blood tests and computed tomography (CT) between 2016 and 2017. The abdominal aortic calcification index (ACI) was measured using abdominal CT. The difference in the ACI values between 2016 and 2017 was evaluated as DeltaACI. Patients were divided into PPI and non-PPI groups, and variables, such as patient background, medication, laboratory data, and DeltaACI were compared. Factors independently associated with higher DeltaACI progression (>= third tertile value of DeltaACI in this study) were determined using multivariate logistic regression analysis. RESULTS: The PPI and non-PPI groups had 112 (56%) and 88 (44%) patients, respectively. Median and third tertile value of DeltaACIs were 4.2% and 5.8%, respectively. Serum magnesium was significantly lower in the PPI (2.1 mg/dL) than in the non-PPI (2.3 mg/dL) group (P <0.001). Median DeltaACI was significantly higher in the PPI (5.0%) than in the non-PPI (3.8%) group (P = 0.009). A total of 77 (39%) patients had a higher DeltaACI. Multivariate analysis revealed that PPIs (odds ratio = 2.23; 95% confidence interval = 1.11-4.49), annual mean calcium phosphorus product, ACI in 2016, baseline serum magnesium levels, and HD vintage were independent factors associated with higher DeltaACI progression after adjusting for confounders. CONCLUSION: PPI use may accelerate vascular calcification in patients on HD. Further studies are necessary to elucidate their influence on vascular calcification. PMID- 29969456 TI - Evaluating the 2014 sugar-sweetened beverage tax in Chile: An observational study in urban areas. AB - BACKGROUND: In October 2014, Chile implemented a tax modification on sugar sweetened beverages (SSBs) called the Impuesto Adicional a las Bebidas Analcoholicas (IABA). The design of the tax was unique, increasing the tax on soft drinks above 6.25 grams of added sugar per 100 mL and decreasing the tax for those below this threshold. METHODS AND FINDINGS: This study evaluates Chile's SSB tax, which was announced in March 2014 and implemented in October 2014. We used household-level grocery-purchasing data from 2011 to 2015 for 2,836 households living in cities representative of the urban population of Chile. We employed a fixed-effects econometric approach and estimated the before-after change in purchasing of SSBs controlling for seasonality, general time trend, temperature, and economic fluctuations as well as time-invariant household characteristics. Results showed significant changes in purchasing for the statistically preferred model: while there was a barely significant decrease in the volume of all soft drinks, there was a highly significant decrease in the monthly purchased volume of the higher-taxed, sugary soft drinks by 21.6%. The direction of this reduction was robust to different empirical modelling approaches, but the statistical significance and the magnitude of the changes varied considerably. The reduction in soft drink purchasing was most evident amongst higher socioeconomic groups and higher pretax purchasers of sugary soft drinks. There was no systematic, robust pattern in the estimates by household obesity status. After tax implementation, the purchase prices of soft drinks decreased for the items for which the tax rate was reduced, but they remained unchanged for sugary items, for which the tax was increased. However, the purchase prices increased for sugary soft drinks at the time of the policy announcement. The main limitations include a lack of a randomised design, limiting the extent of causal inference possible, and the focus on purchasing data rather than consumption or health outcomes. CONCLUSIONS: The results of subgroup analyses suggest that the policy may have been partially effective, though not necessarily in ways that are likely to reduce socioeconomic inequalities in diet-related health. It remains unclear whether the policy has had a major, overall population-level impact. Additionally, because the present study examined purchasing of soft drinks for only 1 year, a longer-term evaluation-ideally including an assessment of consumption and health impacts should be conducted in future research. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02926001. PMID- 29969457 TI - Factors associated with wasting among children under five years old in South Asia: Implications for action. AB - South Asia continues to carry the greatest share and number of wasted children worldwide. Understanding the determinants of wasting is important as policymakers renew efforts to tackle this persistent public health and development problem. Using data from national surveys in Bangladesh, India, the Maldives, Nepal, Pakistan and Afghanistan, this analysis explores factors associated with wasting among children aged 0 to 59 months (n = 252,797). We conducted multivariate mixed logistic regression and backwards stepwise methods to identify parsimonious models for each country separately (all p values <0.05). Younger children (0 to 5 months), and those whose mothers had a low body mass index (<18.5 kg/m2) had greater odds of being wasted in all countries. Later birth order, being male, maternal illiteracy, short maternal stature, lack of improved water source, and household poverty were also associated with wasting in various countries, but not systematically in all. Seasonality was also not consistently associated with wasting in the final models. These findings suggest that pre-conception (adolescence), pregnancy and early postpartum, represent windows of opportunity for tackling child wasting, not only stunting. Our analysis suggests that the underlying determinants of wasting and stunting in South Asia are similar, but not universal across geographies. Cost-effective interventions to prevent both stunting and wasting, and to treat severe wasting, need to be scaled up urgently. Separating these two manifestations of child undernutrition in conceptual and programmatic terms may unnecessarily impair progress to reach the Sustainable Development Goals targets aimed at addressing both child stunting and wasting. PMID- 29969458 TI - Nonlinear structure-extended cavity interaction simulation using a new version of harmonic balance method. AB - This study addresses the nonlinear structure-extended cavity interaction simulation using a new version of the multilevel residue harmonic balance method. This method has only been adopted once to solve a nonlinear beam problem. This is the first study to use this method to solve a nonlinear structural acoustic problem. This study has two focuses: 1) the new version of the multilevel residue harmonic balance method can generate the higher-level nonlinear solutions ignored in the previous version and 2) the effect of the extended cavity, which has not been considered in previous studies, is examined. The cavity length of a panel cavity system is sometimes longer than the panel length. However, many studies have adopted a model in which the cavity length is equal to the panel length. The effects of excitation magnitude, cavity depth, damping and number of structural modes on sound and vibration responses are investigated for various panel cases. In the simulations, the present harmonic balance solutions agree reasonably well with those obtained from the classical harmonic balance method. There are two important findings. First, the nonlinearity of a structural acoustic system highly depends on the cavity size. If the cavity size is smaller, the nonlinearity is higher. A large cavity volume implies a low stiffness or small acoustic pressure transmitted from the source panel to the nonlinear panel. In other words, the additional volume in an extended cavity affects the nonlinearity, sound and vibration responses of a structural acoustic system. Second, if an acoustic resonance couples with a structural resonance, nonlinearity is amplified and thus the insertion loss is adversely affected. PMID- 29969459 TI - A revised understanding of Tribolium morphogenesis further reconciles short and long germ development. AB - In Drosophila melanogaster, the germband forms directly on the egg surface and solely consists of embryonic tissue. In contrast, most insect embryos undergo a complicated set of tissue rearrangements to generate a condensed, multilayered germband. The ventral side of the germband is embryonic, while the dorsal side is thought to be an extraembryonic tissue called the amnion. While this tissue organisation has been accepted for decades and has been widely reported in insects, its accuracy has not been directly tested in any species. Using live cell tracking and differential cell labelling in the short germ beetle Tribolium castaneum, I show that most of the cells previously thought to be amnion actually give rise to large parts of the embryo. This process occurs via the dorsal-to ventral flow of cells and contributes to germband extension (GBE). In addition, I show that true 'amnion' cells in Tribolium originate from a small region of the blastoderm. Together, my findings show that development in the short germ embryos of Tribolium and the long germ embryos of Drosophila is more similar than previously proposed. Dorsal-to-ventral cell flow also occurs in Drosophila during GBE, and I argue that the flow is driven by a conserved set of underlying morphogenetic events in both species. Furthermore, the revised Tribolium fate map that I present is far more similar to that of Drosophila than the classic Tribolium fate map. Lastly, my findings show that there is no qualitative difference between the tissue structure of the cellularised blastoderm and the short/intermediate germ germband. As such, the same tissue patterning mechanisms could function continuously throughout the cellularised blastoderm and germband stages, and easily shift between them over evolutionary time. PMID- 29969461 TI - Air-quality-related health impacts from climate change and from adaptation of cooling demand for buildings in the eastern United States: An interdisciplinary modeling study. AB - BACKGROUND: Climate change negatively impacts human health through heat stress and exposure to worsened air pollution, amongst other pathways. Indoor use of air conditioning can be an effective strategy to reduce heat exposure. However, increased air conditioning use increases emissions of air pollutants from power plants, in turn worsening air quality and human health impacts. We used an interdisciplinary linked model system to quantify the impacts of heat-driven adaptation through building cooling demand on air-quality-related health outcomes in a representative mid-century climate scenario. METHODS AND FINDINGS: We used a modeling system that included downscaling historical and future climate data with the Weather Research and Forecasting (WRF) model, simulating building electricity demand using the Regional Building Energy Simulation System (RBESS), simulating power sector production and emissions using MyPower, simulating ambient air quality using the Community Multiscale Air Quality (CMAQ) model, and calculating the incidence of adverse health outcomes using the Environmental Benefits Mapping and Analysis Program (BenMAP). We performed simulations for a representative present-day climate scenario and 2 representative mid-century climate scenarios, with and without exacerbated power sector emissions from adaptation in building energy use. We find that by mid-century, climate change alone can increase fine particulate matter (PM2.5) concentrations by 58.6% (2.50 MUg/m3) and ozone (O3) by 14.9% (8.06 parts per billion by volume [ppbv]) for the month of July. A larger change is found when comparing the present day to the combined impact of climate change and increased building energy use, where PM2.5 increases 61.1% (2.60 MUg/m3) and O3 increases 15.9% (8.64 ppbv). Therefore, 3.8% of the total increase in PM2.5 and 6.7% of the total increase in O3 is attributable to adaptive behavior (extra air conditioning use). Health impacts assessment finds that for a mid-century climate change scenario (with adaptation), annual PM2.5 related adult mortality increases by 13,547 deaths (14 concentration-response functions with mean incidence range of 1,320 to 26,481, approximately US$126 billion cost) and annual O3-related adult mortality increases by 3,514 deaths (3 functions with mean incidence range of 2,175 to 4,920, approximately US$32.5 billion cost), calculated as a 3-month summer estimate based on July modeling. Air conditioning adaptation accounts for 654 (range of 87 to 1,245) of the PM2.5 related deaths (approximately US$6 billion cost, a 4.8% increase above climate change impacts alone) and 315 (range of 198 to 438) of the O3-related deaths (approximately US$3 billion cost, an 8.7% increase above climate change impacts alone). Limitations of this study include modeling only a single month, based on 1 model-year of future climate simulations. As a result, we do not project the future, but rather describe the potential damages from interactions arising between climate, energy use, and air quality. CONCLUSIONS: This study examines the contribution of future air-pollution-related health damages that are caused by the power sector through heat-driven air conditioning adaptation in buildings. Results show that without intervention, approximately 5%-9% of exacerbated air pollution-related mortality will be due to increases in power sector emissions from heat-driven building electricity demand. This analysis highlights the need for cleaner energy sources, energy efficiency, and energy conservation to meet our growing dependence on building cooling systems and simultaneously mitigate climate change. PMID- 29969460 TI - Post-Turing tissue pattern formation: Advent of mechanochemistry. AB - Chemical and mechanical pattern formation is fundamental during embryogenesis and tissue development. Yet, the underlying molecular and cellular mechanisms are still elusive in many cases. Most current theories assume that tissue development is driven by chemical processes: either as a sequence of chemical patterns each depending on the previous one, or by patterns spontaneously arising from specific chemical interactions (such as "Turing-patterns"). Within both theories, mechanical patterns are usually regarded as passive by-products of chemical pre patters. However, several experiments question these theories, and an increasing number of studies shows that tissue mechanics can actively influence chemical patterns during development. In this study, we thus focus on the interplay between chemical and mechanical processes during tissue development. On one hand, based on recent experimental data, we develop new mechanochemical simulation models of evolving tissues, in which the full 3D representation of the tissue appears to be critical for obtaining a realistic mechanochemical behaviour. The presented modelling approach is flexible and numerically studied using state of the art finite element methods. Thus, it may serve as a basis to combine simulations with new experimental methods in tissue development. On the other hand, we apply the developed approach and demonstrate that even simple interactions between tissue mechanics and chemistry spontaneously lead to robust and complex mechanochemical patterns. Especially, we demonstrate that the main contradictions arising in the framework of purely chemical theories are naturally and automatically resolved using the mechanochemical patterning theory. PMID- 29969462 TI - Dysbiosis of oral microbiota and its association with salivary immunological biomarkers in autoimmune liver disease. AB - The gut microbiota has recently been recognized to play a role in the pathogenesis of autoimmune liver disease (AILD), mainly primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH). This study aimed to analyze and compare the composition of the oral microbiota of 56 patients with AILD and 15 healthy controls (HCs) and to evaluate its association with salivary immunological biomarkers and gut microbiota. The subjects included 39 patients with PBC and 17 patients with AIH diagnosed at our hospital. The control population comprised 15 matched HCs. Salivary and fecal samples were collected for analysis of the microbiome by terminal restriction fragment length polymorphism of 16S rDNA. Correlations between immunological biomarkers measured by Bio-Plex assay (Bio-Rad) and the oral microbiomes of patients with PBC and AIH were assessed. Patients with AIH showed a significant increase in Veillonella with a concurrent decrease in Streptococcus in the oral microbiota compared with the HCs. Patients with PBC showed significant increases in Eubacterium and Veillonella and a significant decrease in Fusobacterium in the oral microbiota compared with the HCs. Immunological biomarker analysis showed elevated levels of inflammatory cytokines (IL-1beta, IFN-gamma, TNF-alpha, IL-8) and immunoglobulin A in the saliva of patients with AILD. The relative abundance of Veillonella was positively correlated with the levels of IL-1beta, IL-8 and immunoglobulin A in saliva and the relative abundance of Lactobacillales in feces. Dysbiosis of the oral microbiota is associated with inflammatory responses and reflects changes in the gut microbiota of patients with AILD. Dysbiosis may play an important role in the pathogenesis of AILD. PMID- 29969464 TI - Assessing the success of hydrological restoration in two conservation easements within Central Florida ranchland. AB - In the USA, the United States Department of Agriculture (USDA) Natural Resource Conservation Service (NRCS) has restored millions of acres of wetlands through its Wetland Reserve Easement (WRE) programs. However, few quantitative studies have explored whether WREs have enhanced wetland hydrology and wetland plant communities. Additionally, USDA Compatible Use Permits for cattle grazing and other management practices are sometimes issued for WREs, but little is known about potential benefits/detriments of such practice on the success of wetland restoration. In this study, we tested if hydrological restoration of previously drained species poor pastures increased water depth and hydroperiod. Restoration involved plugging key ditches, adding water control structures and a berm. We also tested if hydrological restoration increased plant diversity (alpha and beta), floristic quality (using coefficient of conservatism) and increased the cover of wetland species (using species wetland status). Finally, we tested if cattle grazing had an effect on the success of restoration by comparing grazed plots to fenced plots. We studied two conservation easements (a total of 748 acres) located on semi-native pastures in central Florida, USA. We monitored vegetation using permanent transects stratified by vegetation type before (2004 2005) and after (2012) the restoration (2008). We assessed wetland hydroperiod using groundwater wells set up in 2003 and located within and outside the boundaries of these two easements. We used linear mixed models and multivariate analyses to compare vegetation and hydroperiods pre- and post-restoration. Number of flooded days increased following restoration in one of the easements, but we did not detect significant changes in hydrology in the other easement. Floristic quality, beta diversity and cover of obligate wetland species increased in both conservation easements and in most vegetation types. These vegetation changes were likely due to restoration activities since annual rainfall was not significantly different pre- and post-restoration. Cattle grazing did not have a negative or positive effect on the success of restoration, nor did we detect any positive effect of grazing on the success of restoration. Overall, our study shows that hydrological restoration can enhance wetland hydroperiod, water depth and wetland vegetation, but more resources should be allocated to short- and long term monitoring of the restoration success. PMID- 29969465 TI - Reciprocal expression of Slug and Snail in human oral cancer cells. AB - Snail, also called Snai1, is a key regulator of EMT. Snail plays crucial roles in cancer progression, including resistance to anti-tumor drugs and invasion by various cancer cells. Slug, also known as Snai2, is also involved in the aggravation of certain tumors. In this study, we examined the roles of Slug in human oral squamous cell carcinoma (OSCC) cells. Slug is highly expressed in these cells, and Slug siRNA effectively represses anti-tumor drug resistance and invasive properties. In addition, transforming growth factor (TGF)-beta upregulates the expression of Snail and Slug and promotes resistance to anti tumor drugs in OSCC cells. Surprisingly, Slug siRNA appears to upregulate Snail expression considerably in OSCC cells. Snail siRNA also appears to upregulate Slug expression. Thus, either Slug or Snail siRNA alone partially mitigates malignant phenotypes in the presence of TGF-beta, whereas both Slug and Snail siRNAs together dramatically suppress them. Therefore, Slug and Snail in tandem, but not alone, are potential therapeutic targets for nucleic acid medicines to treat oral cancer. PMID- 29969463 TI - Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies. AB - BACKGROUND: Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. METHODS AND FINDINGS: We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34 7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. CONCLUSION: TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone. PMID- 29969466 TI - Urban sanitation coverage and environmental fecal contamination: Links between the household and public environments of Accra, Ghana. AB - Exposure to fecal contamination in public areas, especially in dense, urban environments, may significantly contribute to enteric infection risk. This study examined associations between sanitation and fecal contamination in public environments in four low-income neighborhoods in Accra, Ghana. Soil (n = 72) and open drain (n = 90) samples were tested for E. coli, adenovirus, and norovirus. Sanitation facilities in surveyed households (n = 793) were categorized by onsite fecal sludge containment ("contained" vs. "uncontained") using previous Joint Monitoring Program infrastructure guidelines. Most sanitation facilities were shared by multiple households. Associations between spatial clustering of household sanitation coverage and fecal contamination were examined, controlling for neighborhood and population density (measured as enumeration areas in the 2010 census and spatially matched to sample locations). E. coli concentrations in drains within 50m of clusters of contained household sanitation were more than 3 log-units lower than those outside of clusters. Further, although results were not always statistically significant, E. coli concentrations in drains showed consistent trends with household sanitation coverage clusters: concentrations were lower in or near clusters of high coverage of household sanitation facilities-especially contained facilities-and vice versa. Virus detection in drains and E. coli concentrations in soil were not significantly associated with clustering of any type of household sanitation and did not exhibit consistent trends. Population density alone was not significantly associated with any of the fecal contamination outcomes by itself and was a significant, yet inconsistent, effect modifier of the association between sanitation clusters and E. coli concentrations. These findings suggest clustering of contained household sanitation, even when shared, may be associated with lower levels of fecal contamination within drains in the immediate public domain. Further research is needed to better quantify these relationships and examine impacts on health. PMID- 29969467 TI - Dynamical Hurst analysis identifies EEG channel differences between PTSD and healthy controls. AB - We employ a time-dependent Hurst analysis to identify EEG signals that differentiate between healthy controls and combat-related PTSD subjects. The Hurst exponents, calculated using a rescaled range analysis, demonstrate a significant differential response between healthy and PTSD samples which may lead to diagnostic applications. To overcome the non-stationarity of EEG data, we apply an appropriate window length wherein the EEG data displays stationary behavior. We then use the Hurst exponents for each channel as hypothesis test statistics to identify differences between PTSD cases and controls. Our study included a cohort of 12 subjects with half healthy controls. The Hurst exponent of the PTSD subjects is found to be significantly smaller than the healthy controls in channel F3. Our results indicate that F3 may be a useful channel for diagnostic applications of Hurst exponents in distinguishing PTSD and healthy subjects. PMID- 29969468 TI - Cost analysis of improving emergency care for aged care residents under a Hospital in the Nursing Home program in Australia. AB - BACKGROUND: This study aims to examine the costs associated with a Hospital in the Nursing Home (HiNH) program in Queensland Australia directed at patients from residential aged care facilities (RACFs) with emergency care needs. METHODS: A cost analysis was undertaken comparing the costs under the HiNH program and the current practice, in parallel with a pre-post controlled study design. The study was conducted in two Queensland public hospitals: the Royal Brisbane and Women's Hospital (intervention hospital) and the Logan Hospital (control hospital). Main outcome measures were the associated incremental costs or savings concerning the HiNH program provision and the acute hospital care utilisation over one year after intervention. RESULTS: The initial deterministic analysis calculated the total induced mean costs associated with providing the HiNH program over one year as AU$488,116, and the total induced savings relating to acute hospital care service utilisation of AU$8,659,788. The total net costs to the health service providers were thus calculated at -AU$8,171,671 per annum. Results from the probabilistic sensitivity analysis (based on 10,000 simulations) showed the mean and median annual net costs associated with the HiNH program implementation were AU$8,444,512 and-AU$8,202,676, and a standard deviation of 2,955,346. There was 95% certainty that the values of net costs would fall within the range from AU$15,018,055 to -AU$3,358,820. CONCLUSIONS: The costs relating to implementing the HiNH program appear to be much less than the savings in terms of associated decreases in acute hospital service utilisation. The HiNH service model is likely to have the cost-saving potential while improving the emergency care provision for RACF residents. PMID- 29969469 TI - Near infrared spectroscopy with a vascular occlusion test as a biomarker in children with mitochondrial and other neuro-genetic disorders. AB - BACKGROUND: Mitochondrial and neurogenetic diseases can present diagnostic challenges. We investigated if near infrared spectroscopy with the vascular occlusion test is able to differentiate between children with mitochondrial disease and children with neurogenetic disease or healthy controls. METHODS: Prospective observational study conducted in a tertiary children's hospital. RESULTS: Forty-three children with mitochondrial disease (including both genetically confirmed primary mitochondrial disease and cases with biochemical evidence of mitochondrial dysfunction), 19 children with non-mitochondrial neurogenetic disease and 13 healthy controls were recruited. The delta tissue oxygen index (DeltaTOI) values showed greater variability amongst children with mitochondrial disease and neurogenetic disease than healthy controls despite the median DeltaTOI being similar (median 14.1 and 18.8, t-test, p = 0.16). A low DeltaTOI identifies cases with a higher probability of mitochondrial disease or neurogenetic disease compared to healthy controls (positive likelihood ratio: 3.67; 95%CI:1.01-13). A high DeltaTOI with the near infrared spectroscopy with vascular occlusion test identifies cases with a lower probability of having a disease (negative likelihood ratio: 0.51; 95%CI:0.36-0.74). CONCLUSION: Near infrared spectroscopy with vascular occlusion test might be able to discriminate children with mitochondrial disease and neurogenetic disease from healthy controls. PMID- 29969470 TI - The duration of hypothermia affects short-term neuroprotection in a mouse model of neonatal hypoxic ischaemic injury. AB - Neonatal hypoxic-ischaemic encephalopathy (HIE) is major cause of neonatal mortality and morbidity. Therapeutic hypothermia is standard clinical care for moderate hypoxic-ischaemic (HI) brain injury, however it reduces the risk of death and disability only by 11% and 40% of the treated infants still develop disabilities. Thus it is necessary to develop supplementary therapies to complement therapeutic hypothermia in the treatment of neonatal HIE. The modified Rice-Vannucci model of HI in the neonatal mouse is well developed and widely applied with different periods of hypothermia used as neuroprotective strategy in combination with other agents. However, different studies use different periods, time of initiation and duration of hypothermia following HI, with subsequent varying degrees of neuroprotection. So far most rodent data is obtained using exposure to 5-6h of therapeutic hypothermia. Our aim was to compare the effect of exposure to three different short periods of hypothermia (1h, 1.5h and 2h) following HI insult in the postnatal day 7 C57/Bl6 mouse, and to determine the shortest period providing neuroprotection. Our data suggests that 1h and 1.5h of hypothermia delayed by 20min following a 60min exposure to 8%O2 do not prove neuroprotective. However, 2h of hypothermia significantly reduced tissue loss, TUNEL+ cell death and microglia and astroglia activation. We also observed improved functional outcome 7 days after HI. We suggest that the minimal period of cooling necessary to provide moderate short term neuroprotection and appropriate for the development and testing of combined treatment is 2h. PMID- 29969471 TI - The influence of pressure on crude oil biodegradation in shallow and deep Gulf of Mexico sediments. AB - A significant portion of oil released during the Deepwater Horizon disaster reached the Gulf of Mexico (GOM) seafloor. Predicting the long-term fate of this oil is hindered by a lack of data about the combined influences of pressure, temperature, and sediment composition on microbial hydrocarbon remineralization in deep-sea sediments. To investigate crude oil biodegradation by native GOM microbial communities, we incubated core-top sediments from 13 GOM sites at water depths from 60-1500 m with crude oil under simulated aerobic seafloor conditions. Biodegradation occurred in all samples and followed a predictable compound class sequence dictated by molecular weight and structure. 45 to ~100% of total n alkane and 3 to 60% of total polycyclic aromatic hydrocarbons (PAH) were depleted. In reactors incubated at 4 degrees C and at pressures of 6-15 MPa, the depletion in total n-alkane was inversely correlated to pressure (R2 ~ 0.85), equivalent to a 4% decrease in total n-alkane depletion for every 1 MPa increase. Our results indicated a modest inhibitory effect of pressure on biodegradation over our experimental range. However, the expansion of oil exploration to deeper waters (e.g., 5000 m) opens the risk of spills at conditions at which pressure might have a more pronounced effect. PMID- 29969472 TI - A cohort study of maternal cardiometabolic risk factors and primary cesarean delivery in an integrated health system. AB - BACKGROUND: Maternal cardiometabolic risk factors (i.e., hyperglycemia, pre existing hypertension and high body mass index) impact fetal growth and risk of having a cesarean delivery. However, the independent and joint contribution of maternal cardiometabolic risk factors to primary cesarean section is unclear. We aimed to elucidate the degree to which maternal cardiometabolic risk factors contribute to primary cesarean deliveries and whether associations vary by infant size at birth in an integrated health system. METHODS: A cohort study of 185,045 singleton livebirths from 2001 to 2010. Poisson regression with robust standard errors provided crude and adjusted relative risks (RR) and 95% confidence intervals (CIs) for cesarean delivery risk associated with risk factors. We then estimated the proportion of cesarean sections that could be prevented if the cardiometabolic risk factor in pregnant women were eliminated (the population attributable risk [PAR]). RESULTS: In a single multivariable model, maternal cardiometabolic risk factors were independently associated with cesarean delivery: RR (95% CI) abnormal glucose screening 1.04 (1.01-1.08); gestational diabetes 1.18 (1.11-1.18) and pre-existing diabetes 1.60 (1.49-1.71); pre existing hypertension 1.16 (1.10-1.23); overweight 1.27 (1.24-1.30); obese class I 1.46 (1.42-1.51); obese class II 1.73 (1.67-1.80); and obese class III 1.97 (1.88-2.07); adjusting for established risk factors, medical facility and year. The associations between maternal cardiometabolic risk factors and primary cesarean delivery remained among infants with appropriate weights for gestational age. The PARs were 17.4% for overweight/obesity, 7.0% for maternal hyperglycemia, 2.0% for pre-existing hypertension and 20.5% for any cardiometabolic risk factor. CONCLUSIONS: Maternal cardiometabolic risk factors were independently associated with risk of primary cesarean delivery, even among women delivering infants born at an appropriate size for gestational age. Effective strategies to increase the proportion of women entering pregnancy at an optimal weight with normal blood pressure and glucose before pregnancy could potentially eliminate up to 20% of cesarean deliveries. PMID- 29969473 TI - Perioperative cytokine profile during lung surgery predicts patients at risk for postoperative complications-A prospective, clinical study. AB - BACKGROUND: Postoperative complications after lung surgery are frequent, having a detrimental effect on patients' further course. Complications may lead to an increased length of hospital stay and cause additional costs. Several risk factors have been identified but it is still difficult to predict contemporary which patients are at risk. We hypothesized that patients who show an increased inflammatory response at the time of wound closure and 24 hours after surgery are at risk of postoperative complications within 30 days after surgery. METHODS: Postoperative complications (pulmonary, cardiac, neurological and renal) of 96 patients scheduled for lung surgery at the Medical Center-University of Freiburg were analyzed in this prospective, clinical study. Blood samples for cytokine analysis (Interleukin (IL)-6, IL-8, IL-10, Tumor necrosis factor [TNF]-alpha, IL 1beta and IL12p70) were taken before surgery, at wound closure and 24 hours after surgery. Cytokine levels of patients with and without postoperative complications were analyzed by Receiver operating characteristic (ROC) curve analysis. To adjust the results according to existing covariates a multivariate logistic regression analysis was conducted. RESULTS: The complication and non-complication group differed significantly according to nicotine dependency, Angiotensin receptor-II blocker medication, rate of thoracotomy and preoperative lung function. The intraoperative hemodynamic parameters and therapy did not differ between the groups. Twenty-nine patients (30%) developed postoperative complications within 30 days after surgery. Plasma concentrations of IL-6, IL-10 and IL-8 at the time of wound closure and 24 hours after surgery were higher in the complication group. Multivariate regression analysis on postoperative complications revealed an Odds ratio of 56 for patients with IL-6 and IL-8 levels above the 3rd quartile measured on the first postoperative day. CONCLUSIONS: Perioperative detection of increased plasma concentrations of inflammatory cytokines in lung surgery may be used in addition to other clinical predictors to identify patients at risk for postoperative complications. TRIAL REGISTRATION: German Clinical Trials Register 00006961. PMID- 29969474 TI - Screening for developmental disabilities in HIV positive and HIV negative children in South Africa: Results from the Asenze Study. AB - BACKGROUND: While neurodevelopmental abnormalities are common in children with HIV infection, their detection can be challenging in settings with limited availability of health professionals. The aim of this study was to assess the ability to identify developmental disability among HIV positive and HIV negative children living in South Africa with an internationally used screen. METHODS AND FINDINGS: This analysis uses a sample of 1,330 4-6 year old children and 1,231 of their caregivers in KwaZulu-Natal, South Africa, including administration of the Ten Questions (TQ) screen, a standardized medical history and physical examination conducted by a medical doctor, with hearing and vision screening, psychological assessment for cognition and language delay, and voluntary HIV testing. There was a high prevalence of disability among the sample. Compared to HIV negative children, HIV positive children were more likely to screen positive on at least one TQ item (59.3 vs 42.8%, p = 0.01), be delayed in sitting, standing or walking (OR 3.89, 95% CI = 2.1-7.2) and have difficulty walking or weakness in the arms or legs (OR = 2.7, 95%CI = 0.8-9.37). By medical doctor assessment, HIV positive children were more likely to be diagnosed with gross motor disability (OR = 3.5, 95%CI = 1.3-9.2) and hearing disability (OR = 2.5, 95%CI = 1.2-5.3). By independent psychological assessment, HIV positive children were more likely to have cognitive delay (OR = 2.2, 95%CI = 1.2-3.9) and language delay (OR = 4.3, 95%CI = 2.2-8.4). Among HIV positive children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 100% and 51.2%, respectively. Among HIV-negative children, the sensitivity and specificity of the TQ for serious disability (vs. no disability) was 90.2% and 63.9%, respectively. CONCLUSIONS: In this first report of the use of the TQ screen in the isiZulu language, it was found to have high sensitivity for detecting serious developmental disabilities in children, especially HIV positive children. The performance of the TQ in this sample indicates utility for making best use of limited neurodevelopmental resources by screening HIV positive children. PMID- 29969475 TI - Utilizing host endogenous microRNAs to negatively regulate the replication of porcine reproductive and respiratory syndrome virus in MARC-145 cells. AB - MicroRNAs (miRNAs) contribute to gene regulation at the post-transcriptional level and are capable of mRNA silencing by binding to target sites exhibiting high degrees of complementarity. Therefore, cloning host miRNA-recognition sequences into the genome of RNA viruses represents a rational strategy for manipulating viral replication. Here, we performed deep sequencing to obtain small-RNA (sRNA)-expression profiles from in vitro-cultured MARC-145 cells post infection with porcine reproductive and respiratory syndrome virus (PRRSV) and chose six candidate miRNAs of different abundance (miR-21, miR-140-3p, miR-185, miR-26a, miR-505, and miR-199a) for further study. Based on the full-length cDNA clone p7USC, we constructed a number of PRRSV mutants that provided complementary base-pairing target sites for the miRNAs in 3' untranslated regions. Our results showed that all low- and moderate- abundant miRNA-target mutants showed similar growth properties, whereas the highest-abundant miRNA-target mutant blocked both viral transcription and replication. Discontinuous mutations in high-abundant miRNA-target sites subsequently recovered viral viability and propagation. These results demonstrated the copy number of endogenous miRNAs and the extent of sRNA complementarity were key factors to silence potential mRNA expression/translation, thereby determining PRRSV viability. Interestingly, the mutant containing miR-140-target sites (v140-t) showed strong suppression of viral replication from P1 to P3 in vitro, as shown by virus titer, plaque morphology, and qRT-PCR assays. To assess genetic stability, sequencing of v140-t (P1, P3, P5 and P10) revealed spontaneous mutations preferentially located among several nucleotides near the 3' end of the insertion region and corresponding to the "seed region" of miR-140-3p, explaining the induced viral repression and the direction of virus evolution. This approach provided a general silencing strategy for limiting PRRSV replication by endogenous miRNAs in MARC-145 cells. PMID- 29969476 TI - Phenotypic signatures and genetic determinants of oxacillin tolerance in a laboratory mutant of Staphylococcus aureus. AB - Addition of beta-lactam antibiotics to growing cultures of bacteria inhibit synthesis of the bacterial cell wall peptidoglycan accompanied by killing (loss of viable titer) and lysis (physical disintegration) of the cells. However, it has also been well established that these antibiotics are not effective in killing non-growing or slow-growing bacteria and the mechanism of this "antibiotic tolerance" is not well understood. In this study, we report on the genetic basis and phenotypic properties of an antibiotic tolerant derivative of the methicillin susceptible S. aureus strain 27s. Cultures were exposed to "pulses" of high concentrations of oxacillin followed by outgrowth of the surviving bacteria. This procedure quickly selected for antibiotic tolerant mutants with an increased ability to survive antibiotic treatment without increase in the MIC value for the antibiotic. Such mutants also exhibited longer lag phase, decreased lysis, virtually no change in antibiotic susceptibilities, cross tolerance to D-cycloserine and vancomycin, and increase in biofilm formation in the presence of high concentrations of oxacillin. Whole genome sequencing showed that these altered properties were linked to mutations in the atl and gdpP genes. PMID- 29969477 TI - Antibiotic use on German pig farms - A longitudinal analysis for 2011, 2013 and 2014. AB - To study antibiotic use in livestock in a temporal context with the development of antimicrobial resistance, long-term changes in antibiotic use must be mapped and their possible causes must be explored. Therefore, the present work assesses the changes in antibiotic use over time in German livestock husbandry. In addition, factors associated with antibiotic use were analyzed to identify possible strategies for further reducing antimicrobial usage. For 2011, 2013 and 2014, antibiotic usage data were collected and examined within the VetCAb project. Three hundred participating pig holdings provided information on their antibiotic use based on obligatory application and delivery forms (ADFs) filled in by their veterinarian as well as information on their current stabling capacities for each production type held. Data on sow, piglet, weaner and fattening pig holdings were described separately, using the semi-annual treatment frequency (TF) to measure antibiotic consumption. Multiple linear mixed models were used to investigate the effects of time, farm size, region and farm management category on the treatment frequency. The study yielded significant time changes with p-values below 0.001 in antibiotic administration with a decreasing median TF in piglets from 3.8 in the first half of 2011 (IQR = 1.1 10.6) to 1.7 in the second half of 2014 (IQR = 0.2-4.5) and in fattening pigs from 5.1 in the first half of 2011 (IQR = 0.2-15.4) to 0.7 in the second half of 2014 (IQR = 0.1-6.7). Meanwhile the TF fluctuated between 8.2 and 12.2 in weaners during the observational period (IQRs between zero (lower quartile) and 37.9 (upper quartile)). Piglet, weaner and fattening pig holdings belonging to the upper third of the holdings in size used significantly more antibiotics than the other holdings investigated. Particularly for weaner and fattening pig holdings, a higher TF was noted for farms without breeding units. The region was only a significant factor in weaners. In conclusion, for 2011, 2013 and 2014, the present study shows a clear reduction in antibiotic treatment frequency in German pig holdings. In addition, the association with various factors such as herd size and farm organization on the antibiotic usage frequency is indisputable. Therefore, these factors should be included in monitoring systems and considered when evaluating intervention measures. PMID- 29969478 TI - Copper conductive patterns through spray-pyrolysis of copper-diethanolamine complex solution. AB - A simple and low-cost method to fabricate copper conductive patterns at low temperature is critical for printed electronics. Low-temperature spray-pyrolysis of copper-alkanolamine complex solution shows high potential for this application. However, the produced copper patterns exhibit a granular structure consisting of connected fine copper particles. In this work, low-temperature spray-pyrolysis of copper formate-diethanolamine complex solution under N2 flow at a temperature of 200 degrees C was investigated. The effects of spraying conditions on microstructure and electrical properties of the patterns were examined. Our results revealed that the spraying rate is a critical parameter determining the degree of sintering and electrical resistivity of the patterns. A low spraying rate facilitates sintering, and hence well-sintered copper patterns with the lowest resistivity of 6.12 MUOmega.cm (3.6 times of bulk copper) on a polyimide substrate could be fabricated. PMID- 29969480 TI - 65% of Americans believe they are above average in intelligence: Results of two nationally representative surveys. AB - Psychologists often note that most people think they are above average in intelligence. We sought robust, contemporary evidence for this "smarter than average" effect by asking Americans in two independent samples (total N = 2,821) whether they agreed with the statement, "I am more intelligent than the average person." After weighting each sample to match the demographics of U.S. census data, we found that 65% of Americans believe they are smarter than average, with men more likely to agree than women. However, overconfident beliefs about one's intelligence are not always unrealistic: more educated people were more likely to think their intelligence is above average. We suggest that a tendency to overrate one's cognitive abilities may be a stable feature of human psychology. PMID- 29969479 TI - Unfocused shockwaves for osteoinduction in bone substitutes in rat cortical bone defects. AB - Bone substitutes are frequently used in clinical practice but often exhibit limited osteoinductivity. We hypothesized that unfocused shockwaves enhance the osteoinductivity of bone substitutes and improve osteointegration and angiogenesis. Three different bone substitutes, namely porous tricalcium phosphate, porous hydroxyapatite and porous titanium alloy, were implanted in a critical size (i.e. 6-mm) femoral defect in rats. The femora were treated twice with 1500 shockwaves at 2 and 4 weeks after surgery and compared with non-treated controls. The net volume of de novo bone in the defect was measured by microCT scanning during 11-weeks follow-up. Bone ingrowth and angiogenesis in the bone substitutes was examined at 5 and 11 weeks using histology. It was shown that hydroxyapatite and titanium both had an increase of bone ingrowth with more bone in the shockwave group compared to the control group, whereas resorption was seen in tricalcium phosphate bone substitutes over time and this was insensitive to shockwave treatment. In conclusion, hydroxyapatite and titanium bone substitutes favour from shockwave treatment, whereas tricalcium phosphate does not. This study shows that osteoinduction and osteointegration of bone substitutes can be influenced with unfocused shockwave therapy, but among other factors depend on the type of bone substitute, likely reflecting its mechanical and biological properties. PMID- 29969481 TI - Influence of social network on drug use among clients of methadone maintenance treatment centers in Kunming, China. AB - AIMS: To examine drug use behavior of clients attending Methadone Maintenance Treatment (MMT) programs and its relationship with the clients' social network characteristics. DESIGN: Cross-sectional study. SETTING: Four MMT clinics in Kunming, Yunnan province, China. PARTICIPANTS: 324 consecutive MMT clients. MEASUREMENTS: A structured, self-completed questionnaire on background characteristics and existing social network. Current drug use was assessed by urine test for opiate metabolites. ANALYSIS: The association between client's social network characteristics and their own current drug use behavior is analysed using multiple logistic regression adjusting for socio-demographic characteristics. Adjusted odds ratios (AOR) with 95% confidence intervals (CI) are obtained to give the strength of the associations. FINDINGS: MMT clients were more likely to concurrently use heroin while attending MMT if their social network had any of the following characteristics: more than half of the members were older than them (AOR = 1.03, 95% CI = 1.00,1.06), any member had a high level of influence on them (AOR = 6.47, 95% CI = 2.86,14.65) and any member joined them in using drugs (AOR = 1.94, 95% CI = 1.04,3.63). Having a social network member who could provide emotional support (AOR = 0.11, 95% CI = 0.03,0.35), having a spouse and/or child in their social network (AOR = 0.44, 95% CI = 0.24,0.81) and having a social network member with a high level of closeness (AOR = 0.28, 95% CI = 0.09,0.90) were associated with a decreased odds of heroin use. CONCLUSION: Social networks who could provide MMT clients with emotional support and a close relationship were significant factors for reducing the risk of concurrent drug use among clients attending MMT clinics in Kunming, China. Behavioral interventions should address the role of family and social network members in providing support to these clients. PMID- 29969482 TI - Inactivation of non-proteolytic Clostridium botulinum type E in low-acid foods and phosphate buffer by heat and pressure. AB - The effect of high pressure thermal (HPT) treatments on the inactivation of spores of non-proteolytic type E Clostridium botulinum TMW 2.990 was investigated at high pressures (300 to 600 MPa) and elevated temperatures (80 to 100 degrees C) in four low-acid foods (steamed sole, green peas with ham, vegetable soup, braised veal) and imidazole phosphate buffer (IPB). In addition, corresponding conventional thermal treatments at ambient pressure were performed to expose possible synergisms of pressure and temperature on spore inactivation. In general, spore count reduction was more efficient by combining pressure and temperatures < 100 degrees C and the overall process duration could be shortened due to accelerated heating rates (adiabatic effect). Processing at 90 degrees C and 600 MPa resulted in inactivation below the detection limit after 5 min in all foods except steamed sole. Traditional thermal processing of spores at 90 degrees C for 10 min, on the other hand, did not result in an estimated 6-log reduction. Additional HPT treatments in steamed sole and IPB did not reveal pronounced food matrix dependent protective effects. Here, varying pressure levels did not appear to be the driving force for spore count reduction in steamed sole at any temperature. By applying a Weibull distribution on destruction kinetics of isobaric/isothermal holding times, 6D-values were calculated. Compression and decompression phase (1 s pressure holding time) had a considerable impact on spore count reduction (max. -2.9 log units) in both, foods and buffer. Hence, compression and decompression phases should directly be included into the total lethal effect of HPT treatments to avoid prolonged holding times and overprocessing. PMID- 29969483 TI - Identifying common factors of functioning, participation and environment amongst adults requiring specialist oral health care using the International Classification of Functioning, disability and health. AB - INTRODUCTION: Persons unable to access oral health care in the conventional primary health care setting suffer from inequalities in oral health, particularly in terms of unmet dental need. The International Classification of Functioning, disability and health (ICF) is designed to look beyond medical diagnosis and to describe individuals or populations in terms of their ability to function and participate in a social environment. The objective of the study was to describe an adult population requiring specialist oral health care using the ICF and to identify common factors of functioning, participation and environmental context. METHOD: The ICF Checklist for Oral Health was completed for 246 participants from five specialist dental services in five countries (mean age 36 +/-16.44 years; 16 92). 'Developmental disability' and 'Medically compromised' groups were identified (72% and 28%). RESULTS: Participants presented with oral disease (92%) and dysfunction (66% impaired chewing). 33 ICF items were affected in over 50% of participants in both groups. Impaired body functions included 'ingestion functions', 'energy and drive functions' and 'emotional functions'. Participation was restricted for "Acquiring, keeping and terminating a job", "Intimate relationships", "Handling stress and psychological demands", "Economic self sufficiency", "Carrying out a daily routine", "Recreation and leisure", "Community life" and "Looking after one's health". In the environment domain, "Support and relationships" and "Attitudes" were rated as facilitators. Environmental barriers reported for over 25% of the whole group were related to "Services, systems and policies" including, health, social security, general support, transportation, and labour and employment. DISCUSSION AND PERSPECTIVES: Common aspects of functioning, participation and environment were found amongst a heterogeneous population of adults attending specialist dental services, alongside poor oral health and function. The ICF may be used to describe populations that suffer inequality in oral health in order to develop services that effectively target those in need of additional means. PMID- 29969485 TI - Improved detectability of acute and subacute brainstem infarctions by combining standard axial and thin-sliced sagittal DWI. AB - BACKGROUND AND PURPOSE: Most false negative findings in DWI of ischemic stroke are in patients with minor deficits clinically localized to the brainstem. Our goal was to evaluate the benefit of a thin-sliced sagittal DWI in addition to conventional axial DWI at 1.5T for the detection of brainstem infarctions. METHODS: Data of patients with symptoms consistent with acute and subacute brainstem infarction and an MRI examination including standard axial DWI and thin sliced sagittal DWI were retrospectively analyzed. Patients with the later diagnosis of a TIA, an inflammation or a tumor of the brainstem were excluded from analysis. Diffusion restrictions were identified by two independent raters blinded for the final clinical diagnosis in three separate reading steps: First, only axial DWI, secondly only sagittal DWI, and lastly both DWIs together. Presence and size of DWI-lesions were documented for each plane. Differences between the observers were settled in consensus in a separate joint reading. RESULTS: Of 73 included patients, 46 patients were clinically diagnosed with brainstem infarction. Inter-observer agreement was excellent for the detection of brainstem lesions in axial and sagittal DWI (kappa = 0.94 and 0.97). In 28/46 patients (60.9%) lesions were detected in the axial plane alone, whereas in 6 more patients (73.9%) lesions were detected in the review of both sequences together. All lesions undetectable in the axial plane were smaller than 5 mm in cranio-caudal direction. CONCLUSIONS: Thin-sliced sagittal DWI in addition to axial DWI improves the detection rate of brainstem infarction with little additional expenditure of time. PMID- 29969484 TI - Chemo-mapping and biochemical-modulatory and antioxidant/prooxidant effect of Galium verum extract during acute restraint and dark stress in female rats. AB - Galium verum is a well-known medicinal plant which is used in various pathologies. G. verum extracts are characterized here using chromatography, where among the rich pool of phenolic acids of flavonoids two known anti-stress modulators, chlorogenic acid and rutin are identified in high quantities. Additionally, the extracts are characterized using a series of in vitro assays (EPR, DPPH, TPC and TEAC). Considering the chemical findings, the potential beneficial effects of the G. verum extract are explored here in a living organism exposed to stress induced oxidative damages. Thus, the biochemical-modulatory and antioxidant roles of two doses of G. verum extract are examined in animals exposed to acute restraint and dark stress (S). The animals were divided in groups [control, S, SG1 (exposed to 25 mg G. verum extract), SG2 (50 mg extract)]. Increased levels of lipid peroxidation (TBARS from 4.43 to 8.06 nmol/mL), corticosterone from 0.43 to 1.96 MUg/dL and epinephrine from 44.43 to 126.7 MUg/mL, as well as decreased antioxidant enzymes activities (SOD/CAT) were observed in the S group. The G. verum extract afforded a near-normal equilibrium within the biochemical parameters of animals exposed to RS, by reducing oxidative damage (TBARS at a 3.73 nmol/mL; CS at 0.90 MUg/dL; EP at 63.72 MUg/mL) and by restoring the antioxidant balance. PMID- 29969486 TI - Using mHealth to improve tuberculosis case identification and treatment initiation in South Africa: Results from a pilot study. AB - BACKGROUND: Tuberculosis (TB) incidence in South Africa is among the highest globally. Initial loss to follow-up (ILFU), defined as not starting on TB treatment within 28 days of testing positive, is undermining control efforts. We assessed the feasibility, acceptability, and potential of a mHealth application to reduce ILFU. METHODS: An mHealth application was developed to capture patients TB investigation data, provide results and monitor treatment initiation. This was implemented in two primary health clinics (PHC) in inner-city Johannesburg. Feasibility was assessed by comparing documentation of personal details, specimen results for same individuals during implementation period (paper register and Mhealth application). Effectiveness was assessed by comparing proportion of patients with results within 48 hours, and proportion started on treatment within 28 days of testing TB positive during pre- implementation (paper register) and implementation (mHealth application) periods. In-depth interviews with patients and providers were conducted to assess acceptability of application. RESULTS: Pre implementation, 457 patients were recorded in paper registers [195 (42.7%) male, median age 34 years (interquartile range IQR (28-40), 45 (10.5%) sputum Xpert positive]. During implementation, 319 patients were recorded in paper register and the mHealth application [131 (41.1%) male, median age 32 years (IQR 27-38), 33 (10.3%) sputum Xpert positive]. The proportion with complete personal details: [mHealth 95.0% versus paper register 94.0%, (p = 0.54)] and proportion with documented results: [mHealth 97.4% versus paper register 97.8%, (p = 0.79)] were not different in the two methods. The proportion of results available within 48 hours: [mHealth 96.8% versus paper register 68.6%), (p <0.001)], and the proportion on treatment within 28 days [mHealth 28/33 (84.8%) versus paper register 30/44 (68.2%), (p = 0.08)] increased during implementation but was not statistically significant. In-depth interviews showed that providers easily integrated the mHealth application into routine TB investigation and patients positively received the delivery of results via text message. Time from sputum collection to TB treatment initiation decreased from 4 days (pre-implementation) to 3 days but was not statistically significant. CONCLUSIONS: We demonstrated that implementation of the mHealth application was feasible, acceptable to health care providers and patients, and has potential to reduce the time to TB treatment initiation and ILFU in PHC settings. PMID- 29969487 TI - Retinal degeneration mutation in Sftpa1tm1Kor/J and Sftpd -/- targeted mice. AB - Surfactant proteins are important collectin immune molecules with a wide distribution throughout the body, including the ocular system. Mice with gene deletions for the surfactant protein genes Sftpa1 and Sftpd were observed to have visual impairment and thinning of the outer nuclear layers of the retina. We hypothesized that gene deletion of Sftpa1 and Sftpd (Sftpa1tm1Kor/J and Sftpd-/-) results in early retinal degeneration in these mice. Sftpa1tm1Kor/J and Sftpd-/- retinas were evaluated by histopathology and optical coherence tomography (OCT). Retinas from Sftpa1tm1Kor/J and Sftpd -/- mice showed early retinal degeneration with loss of the outer nuclear layer. After screening of mice for known retinal degeneration mutations, the mice were found to carry a previously unrecognized Pde6brd1 genotype which resulted from earlier breeding of the strain with Black Swiss mice during their generation. The mutation was outbred and the genotype of Sftpa1tm1Kor/J and Sftpd-/- was confirmed. Outbreeding of the Pde6brd1 mutation resulted in restoration of normal retinal architecture confirmed by in vivo and in vitro examination. We can therefore conclude that loss of Sftpa1 and Sftpd do not result in retinal degeneration. We have now generated retinal Sftpa1 and Sftpd targeted mice that exhibit normal retinal histology. PMID- 29969488 TI - Feeding sows resistant starch during gestation and lactation impacts their faecal microbiota and milk composition but shows limited effects on their progeny. AB - BACKGROUND: Establishment of a beneficial microbiota profile for piglets as early in life as possible is important as it will impact their future health. In the current study, we hypothesized that resistant starch (RS) provided in the maternal diet during gestation and lactation will be fermented in their hindgut, which would favourably modify their milk and/or gut microbiota composition and that it would in turn affect piglets' microbiota profile and their absorptive and immune abilities. METHODS: In this experiment, 33% of pea starch was used in the diet of gestating and lactating sows and compared to control sows. Their faecal microbiota and milk composition were determined and the colonic microbiota, short chain fatty acids (SCFA) production and gut health related parameters of the piglets were measured two days before weaning. In addition, their overall performances and post-weaning faecal score were also assessed. RESULTS: The RS diet modulated the faecal microbiota of the sows during gestation, increasing the Firmicutes:Bacteroidetes ratio and the relative abundance of beneficial genera like Bifidobacterium but these differences disappeared during lactation and maternal diets did not impact the colonic microbiota of their progeny. Milk protein concentration decreased with RS diet and lactose concentration increased within the first weeks of lactation while decreased the week before weaning with the RS diet. No effect of the dietary treatment, on piglets' bodyweight or diarrhoea frequency post-weaning was observed. Moreover, the intestinal morphology measured as villus height and crypt depths, and the inflammatory cytokines in the intestine of the piglets were not differentially expressed between maternal treatments. Only zonula occludens 1 (ZO-1) was more expressed in the ileum of piglets born from RS sows, suggesting a better closure of the mucosa tight junctions. CONCLUSION: Changes in the microbiota transferred from mother to piglets due to the inclusion of RS in the maternal diet are rather limited even though milk composition was affected. PMID- 29969489 TI - Reproductive strategy and gamete development of an invasive fanworm, Sabella spallanzanii (Polychaeta: Sabellidae), a field study in Gulf St Vincent, South Australia. AB - Several reproductive strategies have been identified as key factors that contribute to the establishment and dispersal of invasive species in new environments. These strategies include early maturity, high reproductive capacity and flexibility in timing of reproduction. It is therefore critical to investigate the reproductive biology of target exotic species to understand their potential for population increase and invasive spread, and to inform management control strategies. The European fanworm, Sabella spallanzanii (Gmelin 1791), has established invasive populations along the southern coast of Australia. Gamete development and reproductive periodicity of this worm were investigated in two populations in Gulf St Vincent in South Australia over a 1 year period (July 2012 to June 2013). Samples of worms were collected monthly and dissected for histological analysis. Most individuals reached reproductive maturity at 70 mm body length (thorax and abdomen). Individuals from both populations contained mature and developing gametes year-round and a distinct spawning season was not observed. This may indicate sustained spawning by the population over the year, which provides a constant supply of new recruits to the area. Body length and egg size of worms from these populations were smaller than conspecifics in its native range and other invasive locations. Reproduction and development of S. spallanzanii differs not only between native and invasive locations, but also within invasive locations. This study has shown that S. spallanzanii exhibits a higher phenotypic plasticity and reproductive flexibility than previously known. PMID- 29969490 TI - Molecular phylogeography of East Asian Boea clarkeana (Gesneriaceae) in relation to habitat restriction. AB - Subfamily Cyrtandroideae (Gesneriaceae) comprises a broadly distributed group of rocky-slope herbs, with China being the center of its distributional range. The normal growth of many species within the family is particularly dependent on special habitats. Due to the paucity of molecular studies, very little is known regarding East Asian herb phylogeographic pattern. Here, we investigate the molecular phylogeography of Boea clarkeana Hemsl., a unique resurrection herb endemic to China, focusing on geographically restrictive effects of habitat distribution on evolutionary history. Variation in three chloroplast DNA (cpDNA) intergenic spacers (psbA-trnH, rps12-rpl20, and trnL-trnF), the ribosomal internal transcribed spacer (ITS) and simple sequence repeats in expressed sequence tags (EST-SSRs) was investigated across 18 populations to assess genetic diversity, genetic structure and historical dynamics. Genetic diversity was low within populations (cpDNA, hS = 0.03, piS*103 = 0.17; ITS, hS = 0.16, piS*103 = 0.43) but high for species (cpDNA, hT = 0.82, piT*103 = 3.12; ITS, hT = 0.88, piT*103 = 6.39); 76 alleles were detected in this highly inbred species (FIS = 0.22), with a significantly low average of 1.34 alleles per locus. No cpDNA or ITS haplotypes were shared between regions. Based on cpDNA results, the Mt. Huangshan-Tianmu and Mt. Qinling-Daba haplotypes are ancestral; these two regions represent potential refugia. Although no evidence of significant retreat migration phenomena during glacial cycles was detected, interglacial range expansion from northern Mt. Qinling-Daba was identified (121,457 yr BP). Rapid agricultural growth caused bottlenecks in many populations, especially on Mt. Huang-Tianmu. Habitat restriction and fragmentation, weak seed and pollen dispersal abilities, and long-term isolation caused by human-induced or environmental changes are considered the main causes of extinction of several populations and low genetic diversity within populations and regions. These analyses clarify the effects of habitat restriction on B. clarkeana, representing an evolutionary reference for similar gesneriads, and enrich our understanding of the molecular phylogeography of East Asian rocky-slope herbs. PMID- 29969491 TI - Narrative comprehension beyond language: Common brain networks activated by a movie and its script. AB - Narratives surround us in our everyday life in different forms. In the sensory brain areas, the processing of narratives is dependent on the media of presentation, be that in audiovisual or written form. However, little is known of the brain areas that process complex narrative content mediated by various forms. To isolate these regions, we looked for the functional networks reacting in a similar manner to the same narrative content despite different media of presentation. We collected 3-T fMRI whole brain data from 31 healthy human adults during two separate runs when they were either viewing a movie or reading its screenplay text. The independent component analysis (ICA) was used to separate 40 components. By correlating the components' time-courses between the two different media conditions, we could isolate 5 functional networks that particularly related to the same narrative content. These TOP-5 components with the highest correlation covered fronto-temporal, parietal, and occipital areas with no major involvement of primary visual or auditory cortices. Interestingly, the top-ranked network with highest modality-invariance also correlated negatively with the dialogue predictor, thus pinpointing that narrative comprehension entails processes that are not language-reliant. In summary, our novel experiment design provided new insight into narrative comprehension networks across modalities. PMID- 29969492 TI - Effects of field history on resistance to Bt maize by western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae). AB - Western corn rootworm, Diabrotica virgifera virgifera LeConte, has evolved resistance to transgenic maize, Zea maize L., that produces the insecticidal protein Cry3Bb1, which is derived from the bacterium Bacillus thuringiensis. We hypothesized that the level of Cry3Bb1 resistance in populations of western corn rootworm could be influenced by farming practices. To test this hypothesis, we evaluated the effect of field history on resistance to Cry3Bb1 maize by western corn rootworm. In 2013 and 2014, rootworm adults were collected from the four types of maize fields: 1) current problem fields, 2) past problem fields, 3) rotated maize fields, and 4) continuous maize fields. Those field populations along with seven Bt-susceptible control populations were tested for Cry3Bb1 resistance with both plant-based and diet-based bioassays. All field populations were resistant to Cry3Bb1 regardless of field history, however, some variation in the degree of resistance was found. For all categories of field populations, larval survivorship on Cry3Bb1 maize was significantly higher than control populations, and did not differ from survival on non-Bt maize. Evidence of resistance to Cry3Bb1 maize in plant-based bioassays was further supported by diet-based bioassays and we found a positive relationship between LC50 values from diet-based bioassays and the larval survivorship in plant-based bioassays. This study provides evidence of Cry3Bb1 resistance throughout the agricultural landscape studied, irrespective of the field history, and highlights the need for improved resistance management approaches, such as better use of integrated pest management to better delay pest resistance. PMID- 29969493 TI - Hyperpolarization by activation of halorhodopsin results in enhanced synaptic transmission: Neuromuscular junction and CNS circuit. AB - Optogenetics offers a unique method to regulate the activity of select neural circuits. However, the electrophysiological consequences of targeted optogenetic manipulation upon the entire circuit remain poorly understood. Analysis of the sensory-CNS-motor circuit in Drosophila larvae expressing eHpHR and ChR2-XXL revealed unexpected patterns of excitability. Optical stimulation of motor neurons targeted to express eNpHR resulted in inhibition followed by excitation of body wall contraction with repetitive stimulation in intact larvae. In situ preparations with direct electrophysiological measures showed an increased responsiveness to excitatory synaptic activity induced by sensory stimulation within a functional neural circuit. To ensure proper function of eNpHR and ChR2 XXL they were expressed in body wall muscle and direct electrophysiological measurements were obtained. Under eNpHR induced hyperpolarization the muscle remained excitable with increased amplitude of excitatory postsynaptic synaptic potentials. Theoretical models to explain the observations are presented. This study aids in increasing the understanding of the varied possible influences with light activated proteins within intact neural circuits. PMID- 29969494 TI - Exploring C-peptide loss in type 1 diabetes using growth curve analysis. AB - OBJECTIVES: C-peptide (CP) loss in type 1 diabetes (T1D) is highly variable, and factors influencing it are poorly understood. We modelled CP values in T1D patients from diagnosis for up to 6 years, treating the serial data as growth curves plotted against time since diagnosis. The aims were to summarise the pattern of CP loss (i.e. growth curve shape) in individual patients in simple terms, and to identify baseline characteristics that predict this pattern in individuals. MATERIALS AND METHODS: Between 1976 and 2011, 442 T1D patients initially aged <18y underwent 120-minute mixed meal tolerance tests (MMTT) to calculate area under the curve (AUC) CP, at 3, 9, 18, 30, 48 and 72 months after diagnosis (n = 1537). The data were analysed using the novel SITAR mixed effects growth curve model (SuperImposition by Translation And Rotation). It fits a mean AUC growth curve, but also allows the curve's mean level and rate of fall to vary between individuals so as to best fit the individual patient curves. These curve adjustments define individual curve shape. RESULTS: The square root (?) AUC scale provided the best fit. The mean levels and rates of fall for individuals were normally distributed and uncorrelated with each other. Age at diagnosis and ?AUC at 3 months strongly predicted the patient-specific mean levels, while younger age at diagnosis (p<0.0001) and the 120-minute CP value of the 3-month MMTT (p = 0.002) predicted the patient-specific rates of fall. CONCLUSIONS: SITAR growth curve analysis is a useful tool to assess CP loss in type 1 diabetes, explaining patient differences in terms of their mean level and rate of fall. A definition of rapid CP loss could be based on a quantile of the rate of fall distribution, allowing better understanding of factors determining CP loss and stratification of patients into targeted therapies. PMID- 29969496 TI - Oncogenic c-terminal cyclin D1 (CCND1) mutations are enriched in endometrioid endometrial adenocarcinomas. AB - Cyclin D1 (CCND1) is a core cell cycle regulator and is frequently overexpressed in human cancers, often via amplification, translocation or post-transcription regulation. Accumulating evidence suggests that mutations of the CCND1 gene that result in nuclear retention and constitutive activation of CDK4/6 kinases are oncogenic drivers in cancer. However, the spectrum of CCND1 mutations across human cancers has not been systematically investigated. Here, we retrospectively mined whole-exome sequencing data from 124 published studies representing up to 29,432 cases from diverse cancer types and sites of origin, including carcinoma, melanoma, sarcoma and lymphoma/leukemia, via online tools to determine the frequency and spectrum of CCND1 mutations in human cancers and their associated clinico-pathological characteristics. Overall, in contrast to gene amplification, which occurred at a frequency of 4.8% (1,419 of 28,769 cases), CCND1 mutations were of very low frequency (0.5%, 151 of 29,432 cases) across all cancers, but were predominantly enriched in uterine endometrioid-type adenocarcinoma (6.5%, 30 of 458 cases) in both primary tumors and in advanced, metastatic endometrial cancer samples. CCND1 mutations in endometrial endometrioid adenocarcinoma occurred most commonly in the c-terminus of cyclin D1, as putative driver mutations, in a region thought to result in oncogenic activation of cyclin D1 via inhibition of Thr-286 phosphorylation and nuclear export, thereby resulting in nuclear retention and protein overexpression. Our findings implicate oncogenic c terminal mutations of CCND1 in the pathogenesis of a subset of human cancers and provide a key resource to guide future preclinical and clinical investigations. PMID- 29969495 TI - Augmenting the antinociceptive effects of nicotinic acetylcholine receptor activity through lynx1 modulation. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) of the cholinergic system have been linked to antinociception, and therefore could be an alternative target for pain alleviation. nAChR activity has been shown to be regulated by the nicotinic modulator, lynx1, which forms stable complexes with nAChRs and has a negative allosteric action on their function. The objective in this study was to investigate the contribution of lynx1 to nicotine-mediated antinociception. Lynx1 contribution was investigated by mRNA expression analysis and electrophysiological responses to nicotine in the dorsal raphe nucleus (DRN), a part of the pain signaling pathway. In vivo antinociception was investigated in a test of nociception, the hot-plate analgesia assay with behavioral pharmacology. Lynx1/alpha4beta2 nAChR interactions were investigated using molecular dynamics computational modeling. Nicotine evoked responses in serotonergic and GABAergic neurons in the DRN are augmented in slices lacking lynx1 (lynx1KO). The antinociceptive effect of nicotine and epibatidine is enhanced in lynx1KO mice and blocked by mecamylamine and DHbetaE. Computer simulations predict preferential binding affinity of lynx1 to the alpha:alpha interface that exists in the stoichiometry of the low sensitivity (alpha4)3(beta2)2 nAChRs. Taken together, these data point to a role of lynx1 in mediating pain signaling in the DRN through preferential affinity to the low sensitivity alpha4beta2 nAChRs. This study suggests that lynx1 is a possible alternative avenue for nociceptive modulation outside of opioid-based strategies. PMID- 29969497 TI - Characterization of Chlorella sorokiniana growth properties in monosaccharide supplemented batch culture. AB - To reveal growth properties of Chlorella sorokiniana UTEX 1230, four monosaccharides (glucose, fructose, galactose and xylose) were individually supplemented into medium as carbon sources for the cultivation of C. sorokiniana UTEX 1230. Supplementation with glucose increased OD750, biomass and lipid yield but decreased protein abundance per unit dry weight of biomass under all concentrations examined, the maximum OD750, biomass and lipid yield increased 2.04, 6.78 and 12.43 times, respectively, compared with autotrophic controls. A low concentration of glucose (<4 g/L) simultaneously promoted the biosynthesis of chlorophylls and protein abundance per unit culture volume, but decreased the lipid content per unit dry weight of biomass and all supplemented glucose can be exhausted within 7 days. Higher glucose concentrations (>=4 g/L) decreased the biosynthesis of chlorophylls and protein abundance per unit culture volume, but increased the lipid content per unit dry weight of biomass. In glucose supplemented scenario, C. sorokiniana UTEX 1230 growth was light-independent. Supplementation with fructose promoted C. sorokiniana UTEX 1230 growth to a much lesser extent compared with glucose, whereas supplementation with galactose had no effect and supplementation with xylose even inhibited growth. Our findings represent basic experimental data on the effect of monosaccharides and can serve as the basis for a robust cultivation system to increase biomass and lipid yield. PMID- 29969498 TI - Intracranial compliance is associated with symptoms of orthostatic intolerance in chronic fatigue syndrome. AB - Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS. PMID- 29969499 TI - Correction: Peak oxygen uptake in Paralympic sitting sports: A systematic literature review, meta- and pooled-data analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0192903.]. PMID- 29969501 TI - Correction: Leading causes of cardiovascular hospitalization in 8.45 million US veterans. AB - [This corrects the article DOI: 10.1371/journal.pone.0193996.]. PMID- 29969500 TI - Disruption of microbial community composition and identification of plant growth promoting microorganisms after exposure of soil to rapeseed-derived glucosinolates. AB - Land plants are engaged in intricate communities with soil bacteria and fungi indispensable for plant survival and growth. The plant-microbial interactions are largely governed by specific metabolites. We employed a combination of lipid fingerprinting, enzyme activity assays, high-throughput DNA sequencing and isolation of cultivable microorganisms to uncover the dynamics of the bacterial and fungal community structures in the soil after exposure to isothiocyanates (ITC) obtained from rapeseed glucosinolates. Rapeseed-derived ITCs, including the cyclic, stable goitrin, are secondary metabolites with strong allelopathic affects against other plants, fungi and nematodes, and in addition can represent a health risk for human and animals. However, the effects of ITC application on the different bacterial and fungal organisms in soil are not known in detail. ITCs diminished the diversity of bacteria and fungi. After exposure, only few bacterial taxa of the Gammaproteobacteria, Bacteriodetes and Acidobacteria proliferated while Trichosporon (Zygomycota) dominated the fungal soil community. Many surviving microorganisms in ITC-treated soil where previously shown to harbor plant growth promoting properties. Cultivable fungi and bacteria were isolated from treated soils. A large number of cultivable microbial strains was capable of mobilizing soluble phosphate from insoluble calcium phosphate, and their application to Arabidopsis plants resulted in increased biomass production, thus revealing growth promoting activities. Therefore, inclusion of rapeseed derived glucosinolates during biofumigation causes losses of microbiota, but also results in enrichment with ITC-tolerant plant microorganisms, a number of which show growth promoting activities, suggesting that Brassicaceae plants can shape soil microbiota community structure favoring bacteria and fungi beneficial for Brassica plants. PMID- 29969502 TI - Retraction: A Novel Alkaloid from Marine-Derived Actinomycete Streptomyces xinghaiensis with Broad-Spectrum Antibacterial and Cytotoxic Activities. PMID- 29969503 TI - Detection of equine atypical myopathy-associated hypoglycin A in plant material: Optimisation and validation of a novel LC-MS based method without derivatisation. AB - Hypoglycin A (HGA) toxicity, following ingestion of material from certain plants, is linked to an acquired multiple acyl-CoA dehydrogenase deficiency known as atypical myopathy, a commonly fatal form of equine rhabdomyolysis seen worldwide. Whilst some plants are known to contain this toxin, little is known about its function or the mechanisms that lead to varied HGA concentrations between plants. Consequently, reliable tools to detect this amino acid in plant samples are needed. Analytical methods for HGA detection have previously been validated for the food industry, however, these techniques rely on chemical derivatisation to obtain accurate results at low HGA concentrations. In this work, we describe and validate a novel method, without need for chemical derivatisation (accuracy = 84 94%; precision = 3-16%; reproducibility = 3-6%; mean linear range R2 = 0.999). The current limit of quantitation for HGA in plant material was halved (from 1MUg/g in previous studies) to 0.5MUg/g. The method was tested in Acer pseudoplatanus material and other tree and plant species. We confirm that A. pseudoplatanus is most likely the only source of HGA in trees found within European pastures. PMID- 29969504 TI - New avatars for Myriapods: Complete 3D morphology of type specimens transcends conventional species description (Myriapoda, Chilopoda). AB - We present high-resolution X-ray microtomography (microCT) to enhance the standard morphological description of a recently described centipede, Eupolybothrus liburnicus Akkari, Komericki, Weigand, Edgecombe and Stoev, 2017. The 3D images of the holotype and paratype specimens are considered here as cybertypes for the species-a universal and virtual representation of the type material. This 'avatar' of the holotype is the first published male centipede cybertype. The microtomographic data of both types revealed further characters of systematic value and allowed us to hypothesise on the function of some of the male secondary structures and the mating behaviour of the species. Additionally, we compared part of the female reproductive system of E. liburnicus to species from the same genus, including E. cavernicolus Stoev & Komericki 2013, its closest congener. The high-resolution 3D image data have been uploaded to an open repository (MorphoSource.org) to serve in any subsequent study on the species and genus, as we believe this would catalyse biosystematic research on this and other arthropod groups. PMID- 29969505 TI - Magnetic layered perovskites of [CH3C(NH2)2]2[M(HCOO)4] (M = Co2+ and Ni2+): synthesis, structures and properties. AB - We present two layered perovskites of the formula [CH3C(NH2)2]2[M(HCOO)4] (M = Co and Ni). The two materials are isostructural and crystallize in the orthorhombic space group Pccn. The structures consist of anionic 100-oriented perovskite or square metal-formate layers and interlayer [CH3C(NH2)2]+ cations. In each layer octahedral M2+ ions are linked by equatorial anti-anti HCOO- bridges and are further coordinated by apical monodentate HCOO- groups. The interlayer acetamidinium cations form N-HO H-bonds with the anionic layers to support the 3D structure. As the directions of most vibrations of the interlayer atoms are approximately along the a-axis, the two materials exhibit nearly zero thermal expansion (a few (MK)-1) along the b-direction perpendicularly to the layers and positive thermal expansion along the a- (~40 (MK)-1) and c- (~20 (MK)-1) axes parallel to the layers. They are both weak ferromagnets, and the Neel temperatures are 6.0 K and 17.0 K for M = Co and Ni, respectively. The Co compound exhibited high spontaneous magnetization of 444 cm3 G mol-1 under a field of 10 Oe and an unusually low coercive field of 38 Oe at 2 K. IR spectroscopic, thermal and dielectric properties were investigated. PMID- 29969506 TI - A robust fluorescent probe for detection of telomerase activity in vitro and imaging in living cells via telomerase-triggering primer extension to desorb DNA from graphene oxide. AB - We have developed a robust nanoprobe, named graphene oxide (GO) loaded fluorophore labeled DNA oligonucleotide probe (GO nanoprobe), for the detection of telomerase activity and demonstrated its application for imaging of telomerase in living cells. Two DNA oligonucleotides were used in the sensing system including a FAM-DNA template probe and a short TS primer. Upon the addition of telomerase and dNTPs, the TS primer produced a telomeric repeated sequence at the 3' end, which was just complementary to the single strand tail of FAM-DNA absorbed on the GO surface; the resulting DNA duplex chain could easily detach from the GO, due to the weak binding force between long dsDNA and GO, which led to the separation of the FAM from the GO surface and brought about an amplified fluorescence emission. The fluorescence signal intensity depended on the amount of telomerase, leading to a novel strategy for detecting and in situ imaging of the cytoplasmic telomerase activity. The GO nanoprobe provided a one-step incubation technique for monitoring the telomerase activity in living cells. The proposed approach also distinguished normal cells from cancer cells and monitored the change in telomerase activity in response to a telomerase inhibitor, demonstrating its potential in clinical diagnostic and therapeutic monitoring. PMID- 29969507 TI - Simple generation of a dirhodium MU-carbido complex via thiocarbonyl reduction. AB - The reaction of [RhCl(CS)(PPh3)2] with excess catecholborane affords the cumulenic carbido complex [Rh2(MU-C)Cl2(PPh3)4] which undergoes phosphine and halide substitution to afford a range of complexes in which the Rh[double bond, length as m-dash]C[double bond, length as m-dash]Rh spine remains intact. Amongst these, the reactions with K[L] (L = H2B(pz)2, H2B(pzMe2)2, HB(pz)3; pz = pyrazol 1-yl) afford [Rh2(MU-C)(PPh3)2(L)2] whilst with K[HB(pzMe2)3] the unsymmetrical complex [Rh2H(MU-C)(MU-C6H4PPh2-2){HB(pzMe2)3}2] is obtained in which the carbido ligand spans d6-Rh(iii) and d8-Rh(i) centres. PMID- 29969508 TI - Microfluidic single-cell analysis of oxidative stress in Dictyostelium discoideum. AB - Microfluidic chemical cytometry is a powerful technique for examining chemical contents of individual cells, but applications have focused on cells from multicellular organisms, especially mammals. We demonstrate the first use of microfluidic chemical cytometry to examine a unicellular organism, the social amoeba Dictyostelium discoideum. We used the reactive oxygen species indicator dichlorodihydrofluorescein diacetate to report on oxidative stress and controlled for variations in indicator loading and retention using carboxyfluorescein diacetate as an internal standard. After optimizing indicator concentration, we investigated the effect of peroxide treatment through single-cell measurements of 353 individual cells. The peak area ratio of dichlorofluorescein to carboxyfluorescein increased from 1.69 +/- 0.89 for untreated cells to 5.19 +/- 2.72 for cells treated with 40 mM hydrogen peroxide. Interestingly, the variance of the data also increased with oxidative stress. While preliminary, these results are consistent with the hypothesis that heterogeneous stress responses in unicellular organisms may be adaptive. PMID- 29969510 TI - Effects of in vitro Human Digestion on the Antioxidant Activity and Stability of Lycopene and Phenolic Compounds in Pork Patties Containing Dried Tomato Prepared at Different Temperatures. AB - : The antioxidant activity can be changed during digestion. The effects of in vitro human digestion on the antioxidant activity and stability of tomato powders (TPs), dried at three different temperatures (60, 80, and 100 degrees C) and added to pork patties (1% TP by weight), were investigated. The pork patties with three TPs underwent in vitro human digestion with enterobacteria. Lycopene and individual phenolic compounds were analyzed by using HPLC. The highest total phenolic compounds (6.96 g/100 g) and lycopene concentrations (2.68 mg/100 g) were observed in pork patties with TP dried at 100 degrees C. In addition, antioxidant activity of pork patties containing TPs were measured during in vitro human digestion. Gallic acid (23.8 to 41.6 g/100 g), chlorogenic acid (11.2 to 25.7 g/100 g), and caffeic acid (11.1 to 21.7 g/100 g) were detected as the main phenolic compounds in the TPs. Lycopene, and total and individual phenolic compound contents increased with increasing drying temperatures. Moreover, in vitro human digestion increased the antioxidant activity of TP-containing pork patties. The lycopene and total phenolics contents were increased during in vitro human digestion with enterobacteria by 146% to 220% and 1549% to 2095%, respectively as compared to the samples of before digestion. Hence, we hypothesized that the antioxidant activity of each TP increased during in vitro human digestion and depended on the amount of lycopene and phenolic compounds released. The TP dried at the highest temperature (100 degrees C) had the highest antioxidant activity in pork patties during in vitro human digestion. PRACTICAL APPLICATION: In this study, we revealed that in vitro human digestion increases the antioxidant activities of tomato powder. In addition, tomato powder dried at the highest temperature (100 degrees C) showed the highest antioxidant activity. Therefore, tomato powder at 100 degrees C could be used as strong antioxidants in meat products. PMID- 29969509 TI - Effect of Xanthan Gum/Soybean Fiber Ratio in the Batter on Oil Absorption and Quality Attributes of Fried Breaded Fish Nuggets. AB - : Xanthan gum (XG) and soybean fiber (SF) at varying ratios were incorporated into the batter to inhibit oil absorption in fried battered and breaded fish nuggets (BBFNs). BBFNs were prepared with 1.2% XG and SF blends (at ratios 1:3, 1:2, 1:1, 2:1, and 3:1 w/w), fried at 170 degrees C (40 s) followed by 190 degrees C (30 s), then evaluated for pickup, oil absorption, textural characteristics, and other quality attributes. Compared with the control (without the addition of XG and SF), fried BBFNs prepared with XD and SF had a significantly reduced fat content (P < 0.05). Among all the treatments, fried BBFNs with a 1:2 w/w ratio of XG and SF had the lowest fat content in the crust and the core (16.2% and 0.6%, respectively) and the highest moisture content. When compared with other treatments, the 1:2 w/w treatment group displayed a more intense golden yellow color, higher crispness, lower hardness, and a more compact structure in the crust, a greater elasticity and chewiness of the core, and the least oil penetration. The results proved that the combined addition of XG and SF in the batter can effectively inhibit oil absorption, which may be used to guide the production of low-fat fried BBFNs. PRACTICAL APPLICATION: This study clearly showed that the combined addition of XG and SF at different ratios in the batter significantly affected fat content and quality attributes of fried BBFNs. The inhibition of oil absorption and improvement of color and textural characteristics in fried BBFNs depended on the XG/SF ratio added to the batter, and a 1:2 w/w ratio was found to produce the maximum enhancement. PMID- 29969511 TI - Parsing in vivo and in vitro contributions to microcrystalline cellulose hydrolysis by multidomain glycoside hydrolases in the Caldicellulosiruptor bescii secretome. AB - Six multidomain glycoside hydrolases (GHs), CelA (Athe_1867), CelB (Athe_1859), CelC (Athe_1857), CelD (Athe_1866), CelE (Athe_1865), and CelF (Athe_1860) are encoded in the Caldicellulosiruptor bescii glucan degradation locus (GDL). Each GH was affinity-tagged, overexpressed, and purified from recombinant C. bescii for side-by-side characterization in vitro and to examine the contribution of each of these enzymes to microcrystalline cellulose hydrolysis in vivo. All six recombinant GDL GHs were glycosylated, and deletion of glycosyltransferase Athe_1864 eliminated this posttranslational modification. A simplex centroid mixture experimental design revealed that in vitro optimal mixtures of the GDL GHs were predominantly CelA, CelC, and CelE, had low to moderate proportions of CelB and CelD, and minimal CelF. The best binary mixture contained CelA + CelB in a 3:2 molar ratio, whereas the best ternary mixture was composed of CelA + CelC + CelE in equimolar amounts. Neither the native C. bescii secretome nor cocktails of GDL GHs in vitro exceeded 25% of cellulose hydrolysis observed for wild-type C. bescii in vivo. C. bescii deletion strains lacking specific GDL GHs could be restored to wild-type degradation levels with the exogenous addition of either 5 ug/ml of recombinant GDL GH cocktails based on the natural secretome or mixtures optimized in vitro. Also, the addition of CelA up to 100 ug/ml provided no significant additional benefit. These results suggest that the C. bescii secretome is naturally balanced to achieve optimal synergy for cellulose degradation. They also reinforce the importance of microbial contributions to microcrystalline cellulose hydrolysis and suggest that mass action effects from glucan fermentation shift equilibria to drive degradation. PMID- 29969512 TI - Uptake and Transport Mechanism of Dihydromyricetin Across Human Intestinal Caco-2 Cells. AB - : A variety of beneficial pharmacological activities have been reported for dihydromyricetin (DMY), however, its oral bioavailability is poor and the intestinal absorption profiles of DMY remains unknown. The aim of this study was to investigate the uptake and transport mechanism of DMY in human intestinal Caco 2 cells. DMY was detected using a liquid chromatography-tandem mass spectrometry method. Several factors including time, concentration, pH, temperature and efflux transporters were systematically evaluated. DMY was poorly absorbed by a passive diffusion mechanism. The uptake and transport of DMY were time and concentration dependent. Interestingly, decreasing the pH from 8.0 to 6.0 markedly enhanced the DMY uptake, but didn't significantly affect its bidirectional transport. Efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein also influenced the DMY uptake and transport processes. This work details the uptake and transport characteristics of DMY and provides basis for future study. PRACTICAL APPLICATION: This study elucidated the uptake and transport characteristics of dihydromyricetin (DMY). DMY was poorly absorbed by a passive diffusion mechanism. The uptake and transport of DMY were time and concentration dependent. Interestingly, pH affected DMY uptake but not its bidirectional transport. MRP2 and BCRP were involved in the uptake and transport of DMY, which hindered the absorption of DMY in the intestinal. Thus, the present study may provide useful information for designing DMY delivery systems and avoiding DMY drug interactions. PMID- 29969513 TI - Humanitarian medical aid to the Syrian people: Ethical implications and dilemmas. AB - Medical professionals providing humanitarian aid in times of crisis face complicated ethical and clinical challenges. Today, humanitarian aid is given in accordance with existing guidelines developed by international humanitarian organizations and defined by international law. This paper considers the ethical aspects and frameworks of an atypical humanitarian project, namely one that provides medical support through an Israeli civilian hospital to Syrian Civil War casualties. We explore new ethical questions in this unique situation that pose a serious challenge for the medical community and conventional ethical norms, a challenge Israeli medical staff meet on a daily basis. Before discussing the ethical challenges, we give a description of the project and its unique status. PMID- 29969514 TI - Sex differences in juvenile play behavior differ among rat strains. AB - Juvenile male rats frequently play more than female rats, but the presence of sex differences is affected by testing conditions and may also depend on the strain of rat. In this experiment, we tested play and defensive behaviors in male and female Long-Evans, Sprague-Dawley, and Wistar rats. When observed with a cage mate during the juvenile period, Long-Evans rats played more than Wistar animals, but there were no sex differences in any strain. When tested with an unfamiliar sibling (not seen since weaning), both Long-Evans and Wistar rats played more than Sprague-Dawley animals, and Long-Evans females played more than males. We did not observe any sex or strain differences in defensive behaviors. Our data indicate that there are strain differences in play behavior, and sex differences in play depend on both strain and context. Variation among strains may reflect underlying differences in anxiety, novelty seeking, and circadian rhythms. PMID- 29969515 TI - Capability of four sigmoidoscopy-based screening strategies to predict proximal neoplasia in an asymptomatic Chinese population. AB - BACKGROUND AND AIM: A proper colonoscopy referral criterion is essential for flexible sigmoidoscopy-based colorectal cancer screening. We aimed to compare the predictive capability of four existing criteria to detect proximal neoplasia (PN) and advanced proximal neoplasia (APN) in a Chinese population. METHODS: Asymptomatic Chinese participants aged 50-75 years, who received screening colonoscopy, were consecutively recruited. The four criteria included (i) UK flexible sigmoidoscopy; (ii) Italian Screening for COlon REctum; (iii) NORwegian Colorectal Cancer Prevention trial; and (iv) US clinical index. The sensitivity, specificity, positive/negative predictive value, and the number of subjects needed to screen (NNS)/refer (NNR) to detect one APN/PN were examined. The area under receiver operating characteristic curve was evaluated. RESULTS: Among 5833 subjects, 749 (12.8%) and 151 (2.6%) cases were found to have PN and APN, respectively. US criteria achieved the highest sensitivity for PN (49%) and APN (66%), while UK criteria attained the highest specificity (93%) for PN/APN. The lowest NNS was required by US criteria for PN (16 vs 19-38) and APN (58 vs 69 86), while the lowest NNR was required by UK criteria for PN (3.2 vs 4.0-4.8) and APN (7 vs 10-16). The receiver operating characteristic of all four criteria was 0.57-0.61 for PN and 0.68-0.70 for APN. CONCLUSIONS: Among all the four criteria, US criteria had the highest sensitivity and lowest NNS, while UK criteria achieved the highest specificity and lowest NNR. Their limited discriminatory capability highlighted the need for a new score to predict PN/APN in Chinese populations. PMID- 29969517 TI - A case of acute liver failure due to carfilzomib in multiple myeloma. AB - WHAT IS KNOWN AND STUDY OBJECTIVE: Carfilzomib is a newer drug approved for the treatment of relapsing and refractory multiple myeloma. It has been rarely associated with acute liver failure (ALF). CASE SUMMARY: We present a case of 58 year-old man presenting with abnormal liver function tests and subsequently diagnosed with ALF due to carfilzomib. Liver enzymes improved significantly after discontinuation of the drug. WHAT IS NEW AND CONCLUSION: Even though ALF due to carfilzomib has been documented rarely in clinical studies, no detailed case report has been published so far. Patients on carfilzomib should be monitored for ALF, and prompt discontinuation of drug is necessary in such cases. PMID- 29969516 TI - Hyper-Cross-Linked Polyacetylene-Type Microporous Networks Decorated with Terminal Ethynyl Groups as Heterogeneous Acid Catalysts for Acetalization and Esterification Reactions. AB - Heterogeneous catalysts based on materials with permanent porosity are of great interest owing to their high specific surface area, easy separation, recovery, and recycling ability. Additionally, porous polymer catalysts (PPCs) allow us to tune catalytic activity by introducing various functional centres. This study reports the preparation of PPCs with a permanent micro/mesoporous texture and a specific surface area SBET of up to 1000 m2 g-1 active in acid-catalyzed reactions, namely aldehyde and ketone acetalization and carboxylic acid esterification. These PPC-type conjugated hyper-cross-linked polyarylacetylene networks were prepared by chain-growth homopolymerization of 1,4 diethynylbenzene, 1,3,5-triethynylbenzene and tetrakis(4-ethynylphenyl)methane. However, only some ethynyl groups of the monomers (from 58 to 80 %) were polymerized into the polyacetylene network segments while the other ethynyl groups remained unreacted. Depending on the number of ethynyl groups per monomer molecule and the covalent structure of the monomer, PPCs were decorated with unreacted ethynyl groups from 3.2 to 6.7 mmol g-1 . The hydrogen atoms of the unreacted ethynyl groups served as acid catalytic centres of the aforementioned organic reactions. To the best of our knowledge, this is first study describing the high activity of hydrogen atoms of ethynyl groups in acid-catalyzed reactions. PMID- 29969518 TI - Electronic and Steric Effects on the Reductive Elimination of Anionic Arylferrate(III) Complexes. AB - Arylferrate(III) complexes Ph3 FeR- (R=para- and ortho-substituted aryl) are proposed as model systems for the in-depth investigation of reductive eliminations from organoiron(III) species. Electrospray ionization transfers the arylferrate complexes prepared in situ from solution into the gas phase, where mass selection ensures a well-defined population of reactant ions. Upon gas-phase fragmentation, the arylferrate complexes undergo reductive elimination of the cross-coupling product PhR as well as the homo-coupling product Ph2 . The measured branching ratios between the two competing reaction channels are used to construct a Hammett plot, which shows that electron-donating aryl groups R favor the formation of the cross-coupling product. In this way, the complexes avoid the build-up of too much electron density at the iron center during the reductive elimination. ortho Substitution in R increases the fraction of the homo-coupling product, presumably by hindering the approach between the two aryl groups participating in the reductive elimination. The obtained mechanistic insight substantially advances our understanding of one of the central elementary steps of transition-metal-catalyzed cross-coupling reactions. PMID- 29969519 TI - Albumin disposition in critically Ill patients. AB - WHAT IS KNOWN AND OBJECTIVE: The purpose of this critical narrative review is to analyse studies evaluating the disposition of albumin in critically ill patients and to compare the findings to studies involving healthy subjects and less severely ill patients. COMMENT: PubMed and EMBASE were reviewed for prospective studies involving the disposition of radiolabelled albumin. Studies of normal volunteers, patients undergoing surgical procedures and critically ill patients indicate a relationship between increasing disease acuity or severity and increasing transcapillary escape of albumin. In the only study that directly compared the disposition of radiolabelled albumin in healthy subjects and patients with septic shock, the transcapillary escape rate of albumin was more than twice as rapid in the patients with shock. WHAT IS NEW AND CONCLUSION: Limited studies suggest that increasing disease severity increases transcapillary escape of albumin. Only one study compared the disposition of radiolabelled albumin in healthy subjects and critically ill patients. More studies are needed in subsets of critically ill patients. PMID- 29969520 TI - Effects of Interval Aerobic Training Program with Recovery bouts on cardiorespiratory and endurance fitness in seniors. AB - Interval aerobic training programs (IATP) improve cardiorespiratory and endurance parameters. They are, however, unsuitable to seniors as frequently associated with occurrence of exhaustion and muscle pain. The purpose of this study was to measure the benefits of an IATP designed with recovery bouts (IATP-R) in terms of cardiorespiratory and endurance parameters and its acceptability among seniors (>=70 years). Sedentary healthy volunteers were randomly assigned either to IATP R or sedentary lifestyle. All participants performed an incremental cycle exercise and 6-minute walk test (6-MWT) at baseline and 9.5 weeks later. The first ventilatory threshold (VT1 ); maximal tolerated power (MTP); peak of oxygen uptake (VO2peak ); maximal heart rate (HRmax ); and distance walked at 6-MWT were thus measured. IATP-R consisted of 19 sessions of 30-minute (6 * 4-min at VT1 + 1-minute at 40% of VT1 ) cycling exercise over 9.5 weeks. With an adherence rate of 94.7% without any significant adverse events, 9.5 weeks of IATP-R, compared to controls, enhanced endurance (VT1 : +18.3 vs -4.6%; HR at baseline VT1 : -5.9 vs +0.2%) and cardiorespiratory parameters (VO2peak : +14.1 vs -2.7%; HRmax : +1.6 vs -1.7%; MTP: +19.2 vs -2.3%). The walk distance at the 6-MWT was also significantly lengthened (+11.6 vs. -3.1%). While these findings resulted from an interim analysis planned when 30 volunteers were enrolled in both groups, IATP-R appeared as effective, safe, and applicable among sedentary healthy seniors. These characteristics are decisive for exercise training prescription and adherence. PMID- 29969521 TI - Negative pressure wound therapy for open traumatic wounds. AB - BACKGROUND: Traumatic wounds (wounds caused by injury) range from abrasions and minor skin incisions or tears, to wounds with extensive tissue damage or loss as well as damage to bone and internal organs. Two key types of traumatic wounds considered in this review are those that damage soft tissue only and those that involve a broken bone, that is, open fractures. In some cases these wounds are left open and negative pressure wound therapy (NPWT) is used as a treatment. This medical device involves the application of a wound dressing through which negative pressure is applied and tissue fluid drawn away from the area. The treatment aims to support wound management, to prepare wounds for further surgery, to reduce the risk of infection and potentially to reduce time to healing (with or without surgical intervention). There are no systematic reviews assessing the effectiveness of NPWT for traumatic wounds. OBJECTIVES: To assess the effects of NPWT for treating open traumatic wounds in people managed in any care setting. SEARCH METHODS: In June 2018 we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published and unpublished randomised controlled trials that used NPWT for open traumatic wounds involving either open fractures or soft tissue wounds. Wound healing, wound infection and adverse events were our primary outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted data, carried out a 'Risk of bias' assessment and rated the certainty of the evidence. Data were presented and analysed separately for open fracture wounds and other open traumatic wounds (not involving a broken bone). MAIN RESULTS: Seven RCTs (1377 participants recruited) met the inclusion criteria of this review. Study sample sizes ranged from 40 to 586 participants. One study had three arms, which were all included in the review. Six studies compared NPWT at 125 mmHg with standard care: one of these studies did not report any relevant outcome data. One further study compared NPWT at 75 mmHg with standard care and NPWT 125mmHg with NPWT 75 mmHg.Open fracture wounds (four studies all comparing NPWT 125 mmHg with standard care)One study (460 participants) comparing NPWT 125 mmHg with standard care reported the proportions of wounds healed in each arm. At six weeks there was no clear difference between groups in the number of participants with a healed, open fracture wound: risk ratio (RR) 1.01 (95% confidence interval (CI) 0.81 to 1.27); moderate-certainty evidence, downgraded for imprecision.We pooled data on wound infection from four studies (596 participants). Follow-up varied between studies but was approximately 30 days. On average, it is uncertain whether NPWT at 125 mmHg reduces the risk of wound infection compared with standard care (RR 0.48, 95% CI 0.20 to 1.13; I2 = 56%); very low-certainty evidence downgraded for risk of bias, inconsistency and imprecision.Data from one study shows that there is probably no clear difference in health-related quality of life between participants treated with NPWT 125 mmHg and those treated with standard wound care (EQ-5D utility scores mean difference (MD) -0.01, 95% CI -0.08 to 0.06; 364 participants, moderate-certainty evidence; physical component summary score of the short-form 12 instrument MD -0.50, 95% CI -4.08 to 3.08; 329 participants; low-certainty evidence downgraded for imprecision).Moderate-certainty evidence from one trial (460 participants) suggests that NPWT is unlikely to be a cost-effective treatment for open fractures in the UK. On average, NPWT was more costly and conferred few additional quality-adjusted life years (QALYs) when compared with standard care. The incremental cost-effectiveness ratio was GBP 267,910 and NPWT was shown to be unlikely to be cost effective at a range of cost-per-QALYs thresholds. We downgraded the certainty of the evidence for imprecision.Other open traumatic wounds (two studies, one comparing NPWT 125 mmHg with standard care and a three arm study comparing NPWT 125 mmHg, NPWT 75 mmHg and standard care)Pooled data from two studies (509 participants) suggests no clear difference in risk of wound infection between open traumatic wounds treated with NPWT at 125 mmHg or standard care (RR 0.61, 95% CI 0.31 to 1.18); low-certainty evidence downgraded for risk of bias and imprecision.One trial with 463 participants compared NPWT at 75 mmHg with standard care and with NPWT at 125 mmHg. Data on wound infection were reported for each comparison. It is uncertain if there is a difference in risk of wound infection between NPWT 75 mmHg and standard care (RR 0.44, 95% CI 0.17 to 1.10; 463 participants) and uncertain if there is a difference in risk of wound infection between NPWT 75 mmHg and 125 mmHg (RR 1.04, 95% CI 0.31 to 3.51; 251 participants. We downgraded the certainty of the evidence for risk of bias and imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence for no clear difference between NPWT and standard care on the proportion of wounds healed at six weeks for open fracture wounds. There is moderate-certainty evidence that NPWT is not a cost-effective treatment for open fracture wounds. Moderate-certainty evidence means that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. It is uncertain whether there is a difference in risk of wound infection, adverse events, time to closure or coverage surgery, pain or health related quality of life between NPWT and standard care for any type of open traumatic wound. PMID- 29969523 TI - The Importance of Length and Flexibility of Macrocycle-Containing Molecular Translocators for the Synthesis of Improbable [2]Rotaxanes. AB - This work reports on the use of molecular translocators to capture a dibenzo-24 crown-8 (DB24C8) and then release it onto targeted molecular axles to afford, after removal of the translocator, [2]rotaxanes that do not hold any template site. Various translocators were studied and successfully aided the synthesis, with more or less efficacy, of [2]rotaxanes of different lengths. During the releasing step, the DB24C8 macrocycle shuttles along the thread, and the localization of the macrocycle might be driven by steric repulsion on the translocator part and/or electronic attraction of the targeted part of the axle to be encircled, which depends on both the nature of the translocator and the targeted thread to be encircled. PMID- 29969522 TI - Arginine/Tryptophan-Rich Cyclic alpha/beta-Antimicrobial Peptides: The Roles of Hydrogen Bonding and Hydrophobic/Hydrophilic Solvent-Accessible Surface Areas upon Activity and Membrane Selectivity. AB - The bacterial selectivity of an amphiphilic library of small cyclic alpha/beta tetra-, alpha/beta-penta-, and alpha/beta-hexapeptides rich in arginine/tryptophan (Arg/Trp) residues, which contains asymmetric backbone configurations and differ in hydrophobicity and alternating d,l-amino acids, was investigated against Bacillus subtilis and Escherichia coli. The structural analyses showed that the peptides tend to form assemblies of different shapes. All-l-peptides, especially the most hydrophobic pentamers, were more strongly anti-B. subtilis. With the exception to cyclo(Phe-d-Trp-beta3 hArg-Arg-d-Trp) (Phe=phenylalanine), the peptides had no effects on inner membrane of E. coli, but lyzed the lipopolysaccharide layer according to their activity pattern. The activities adversely changed with a decrease in the number of amide intramolecular hydrogen bonds in assemblies of diastereomeric peptides and the ratio of hydrophobic/hydrophilic solvent-accessible surface areas. The remarkable enhanced entropic contribution for the partitioning of the least conformationally constrained cyclo(Trp-d-Phe-beta3 hTrp-Arg-d-Arg) sequence into the membranes supported the strong self-assembly behavior, therefore making the peptide less penetrable through the E. coli outer layer. PMID- 29969524 TI - Antidiabetic Effect of High-Chromium Yeast Against Type 2 Diabetic KK-Ay Mice. AB - : High chromium yeast has attracted many researchers for its high efficiency and high safety among chromium supplements. The preventive effect of oral high chromium yeast on diabetes was assessed using KK-AY mice. Sixteen-wk-old type 2 diabetic KK-AY mice were divided into five groups and orally administered with two types of drying processed high-chromium yeast, chromium picolinate at 1000 MUg Cr/kg/d, metformin (positive control), and normal yeast (negative control) for 13 weeks. The spray-dried high-chromium yeast significantly delayed the onset of hyperglycemia in type 2 diabetic KK-AY mice (P < 0.05) and significantly improved fasting blood glucose, TG(triglyceride), and TCHO(total cholesterol) . Histopathological analysis showed that the spray-dried high-chromium yeast led to high affinities for the stains to the beta-cells in the islets of Langerhans and alleviated hepatic steatosis. High-chromium yeast could be a potential candidate for nutritional supplement to ameliorate diabetes. PRACTICAL APPLICATION: Chromium plays an important role in fat and carbohydrate metabolism. The result show that spray-dried high chromium yeast significantly delayed the onset of hyperglycemia in type 2 diabetic KK-AY mice. As one of chromium supplements, the purpose of this study is to examine the efficacy of high chromium yeast on the type 2 diabetes and drying method on its bioactivity, which will be useful for research and development of high-chromium yeast and improvement of pharmacological activity-based quality control. PMID- 29969525 TI - MicroRNA miR-223 as regulator of innate immunity. AB - MicroRNAs were discovered more than 2 decades ago and have profound impact on diverse biological processes. Specific microRNAs have important roles in modulating the innate immune response and their dysregulation has been demonstrated to contribute to inflammatory diseases. MiR-223 in particular, is very highly expressed and tightly regulated in hematopoietic cells. It functions as key modulator for the differentiation and activation of myeloid cells. The central role of miR-223 in myeloid cells, especially neutrophil and macrophage differentiation and activation has been studied extensively. MiR-223 contributes to myeloid differentiation by enhancing granulopoiesis while inhibiting macrophage differentiation. Uncontrolled myeloid activation has detrimental consequences in inflammatory disease. MiR-223 serves as a negative feedback mechanism controlling excessive innate immune responses in the maintenance of myeloid cell homeostasis. This review summarizes several topics covering the function of miR-223 in myeloid differentiation, neutrophil and macrophage functions, as well as in inflammatory diseases including acute respiratory distress syndrome and inflammatory bowel disease. In addition, nonmyeloid functions of miR-223 are also discussed in this review. Therapeutic enhancement of miR-223 to dampen inflammatory targets is also highlighted as potential treatment to control excessive innate immune responses during mucosal inflammation. PMID- 29969526 TI - Noncoding RNAs: Potential players in the self-renewal of mammalian spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs), a unique population of male germ cells with self-renewal ability, are the foundation for maintenance of spermatogenesis throughout the life of the male. Although many regulatory molecules essential for SSC self-renewal have been identified, the fundamental mechanism underlying how SSCs acquire and maintain their self-renewal activity remains largely to be elucidated. In recent years, many types of noncoding RNAs (ncRNAs) have been suggested to regulate the SSC self-renewal through multiple ways, indicating ncRNAs play crucial roles in SSC self-renewal. In this paper, we mainly focus on four types of ncRNAs including microRNA, long ncRNA, piwi-interacting RNA, as well as circular RNAs, and reviewed their potential roles in SSC self-renewal that discovered recently to help us gain a better understanding of molecular mechanisms by which ncRNAs perform their function in regulating SSC self-renewal. PMID- 29969527 TI - Folate-producing lactic acid bacteria reduce inflammation in mice with induced intestinal mucositis. AB - AIM: To evaluate two folate-producing strains, Streptococcus (Strep.) thermophilus CRL 808 and Strep. thermophilus CRL 415, against chemically induced mucositis in mice. METHODS AND RESULTS: In vitro assays with Caco-2 cells were performed to evaluate the effect of the bacteria in the presence of 5 fluorouracil (5-FU). For in vivo studies, mice were daily injected with 5-FU to induce intestinal mucositis (IM) and orally administered with folate-producing strains during 6 days. Clinical symptoms, histological parameters and cytokine profiles were assessed. The results showed that Strep. thermophilus CRL 808 increased the cytotoxicity of 5-FU against Caco-2 cells. Administration of this strain in mice with chemically induced IM resulted in a reduction in diarrhoea score and restoration of the intestinal architecture. Cytokine analysis showed that the anti-inflammatory effect by the bacterium is not associated with an immune mechanism. Regarding Strep. thermophilus CRL 415, no improvements were observed in any of the parameters evaluated. CONCLUSION: The administration of the folate-producing Strep. thermophilus CRL 808 has the potential to prevent IM induced by 5-FU in mice. SIGNIFICANCE AND IMPACT OF THE STUDY: Folate-producing LAB could be used in chemotherapy patients to reduce the symptoms of IM, improve their nutritional status and increase the effectiveness of 5-FU. PMID- 29969528 TI - Direct Catalytic Asymmetric Vinylogous Additions of alpha,beta- and beta,gamma Butenolides to Polyfluorinated Alkynyl Ketimines. AB - We report a Zn-ProPhenol catalyzed asymmetric Mannich reaction between butenolides and polyfluorinated alkynyl ketimines to obtain vinylogous products featuring two contiguous tetrasubstituted stereogenic centers. Notably, this is the first successful use of ketimines in the ProPhenol Mannich process, and the reaction offers a new approach for the preparation of pharmaceutically relevant products possessing trifluoromethylated tetrasubstituted alkylamines. The reaction can be performed on large scale with reduced catalyst loading without impacting its efficiency. Moreover, the acetylene moiety can be further elaborated using various methods. PMID- 29969529 TI - In This Issue: Volume 109, Issue 7, July 2018. PMID- 29969530 TI - CRISPR-Cas9-mediated mutation revealed BSPH2 protein is dispensable for male fertility. AB - Members of the Binder of SPerm (BSP) superfamily have been identified in both human and mouse epididymis. These proteins are known to bind sperm membrane and promote sperm capacitation. Studies suggest that BSPH2 might play a different role in sperm functions from its counterparts; however, the role of BSPH2 remains mainly unexplored. To investigate whether the absence of one member of the BSP family could affect fertility, mice lacking Bsph2 expression were generated using clustered regularly interspaced short palindromic repeats (CRISPR) associated 9 (Cas9) technology. Knockout (KO) male mice were mated with wild-type (WT) females, and the number and weight of the pups were determined. Sperm motility in WT and KO was assessed using sperm class analyzer (SCA). Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used for protein identification. Fertility analysis of null Bsph2 mice did not reveal any phenotype. No differences were noticed on average litter size or average pup weight. Normal testis weight and morphology were observed in Bsph2+/- and Bsph2-/- compared to the WT. Quantitative polymerase chain reaction analyses revealed that Bsph1 messenger RNA expression was increased in mutant mice, whereas LC-MS/MS analysis displayed no increase in protein expression level. Taken together, we show the existence of redundant function for murine BSPH2 and the lack of BSPH2 itself does not lead to sterility. PMID- 29969531 TI - Selective Functionalization of Aminoheterocycles by a Pyrylium Salt. AB - The functionalization of aminoheterocycles by using a pyrylium tetrafluoroborate reagent (Pyry-BF4 ) is presented. This reagent efficiently condenses with a great variety of heterocyclic amines and primes the C-N bond for nucleophilic aromatic substitution. More than 60 examples for the formation of C-O, C-N, C-S, or C-SO2 R bonds are disclosed herein. In contrast to C-N activation through diazotization and polyalkylation, this method is characterized by its mild conditions and impressive functional-group tolerance. In addition to small-molecule derivatization, Pyry-BF4 allows the introduction of functional groups in a late stage fashion to furnish highly functionalized structures. PMID- 29969532 TI - Late-Stage Peptide Diversification by Position-Selective C-H Activation. AB - The late-stage modification of structurally complex peptides bears great potential for drug discovery, crop protection, and the pharmaceutical industry, among others. Whereas traditional approaches largely rely on prefunctionalizations, C-H activation catalysis has in recent years emerged as an increasingly powerful tool for post-translational peptide modifications in a step economic manner. Herein, we summarize recent progress in organometallic C-H activation on peptides until June 2018, including position- and chemoselective palladium-, ruthenium-, and manganese-catalyzed processes. PMID- 29969533 TI - Pumilol, a Diterpenoid with a Rare Strobane Skeleton from Pinus pumila (Pinaceae). AB - Pumilol (1), a strobane diterpenoid, reported herein for the first time, was isolated from the bark of Pinus pumila (Pall.) Regel (Siberian Dwarf Pine or Japanese Stone Pine), along with 17 known compounds including serratane triterpenoids, not previously reported from this species, and four ferulate derivatives. The absolute configuration of pumilol was established using HR-ESI MS, NMR, the DP4+ probabilities and by comparison of the experimental and calculated electronic circular dichroism (ECD) spectra. Labda-8(17),13-dien-15 oic acid (4), bornyl (E)-4-hydroxycinnamate (14) and bornyl (E)-ferulate (15) showed activity against S. aureus and/or E. faecalis with MIC90 values 12.5 - 50 MUm. PMID- 29969534 TI - Facile Preparation of Hydrophobic Colloidal MFI and CHA Crystals and Oriented Ultrathin Films. AB - We report novel routes for synthesis of defect-free, hydrophobic and monodispersed 10 nm (5 unit cells) thick MFI crystals and 100 nm CHA crystals. The crystals are obtained in high yield and display very high 1-butanol adsorption from aqueous solution. These crystals are assembled in monolayers for the growth of ultrathin and uniformly oriented films with thicknesses of 36 nm and 330 nm, respectively, using a synthesis gel in the form of a powder. This method is very simple and may open up for industrial preparation of materials with improved performances. PMID- 29969535 TI - A Solvent-Free Synthesis of Lignin-Derived Renewable Carbon with Tunable Porosity for Supercapacitor Electrodes. AB - Synthesis of multiphase materials from lignin, a biorefinery coproduct, offers limited success owing to the inherent difficulty in controlling dispersion of these renewable hyperbranched macromolecules in the product or its intermediates. Effective use of the chemically reactive functionalities in lignin, however, enables tuning morphologies of the materials. Here, we bind lignin oligomers with a rubbery macromolecule followed by thermal crosslinking to form a carbon precursor with phase contrasted morphology at submicron scale. The solvent-free mixing is conducted in a high-shear melt mixer. With this, the carbon precursor is further modified with potassium hydroxide for a single-step carbonization to yield activated carbon with tunable pore structure. A typical precursor with 90 % lignin yields porous carbon with 2120 m2 g-1 surface area and supercapacitor with 215 F g-1 capacitance. The results show a simple route towards manufacturing carbon-based energy-storage materials, eliminating the need for conventional template synthesis. PMID- 29969537 TI - Brain-Penetrant Triazolopyrimidine and Phenylpyrimidine Microtubule Stabilizers as Potential Leads to Treat Human African Trypanosomiasis. AB - In vitro whole-organism screens of Trypanosoma brucei with representative examples of brain-penetrant microtubule (MT)-stabilizing agents identified lethal triazolopyrimidines and phenylpyrimidines with sub-micromolar potency. In mammalian cells, these antiproliferative compounds disrupt MT integrity and decrease total tubulin levels. Their parasiticidal potency, combined with their generally favorable pharmacokinetic properties, which include oral bioavailability and brain penetration, suggest that these compounds are potential leads against human African trypanosomiasis. PMID- 29969536 TI - Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure. AB - AIMS: The arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well-known inhibitor of AVP secretion) in HF is unknown. METHODS AND RESULTS: We studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme-linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83-1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6-0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized beta = 0.32; 95% CI = 0.09-0.56; P = 0.0073) and the ANP/LA volume ratio (standardized beta = -0.23; 95% CI = -0.42 to -0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (beta = 0.26; 95% CI = 0.09-0.43; P = 0.003) and with an increased risk of death or HF admissions during follow-up (hazard ratio = 1.61; 95% CI = 1.13-2.29; P = 0.008). CONCLUSIONS: Arginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess. PMID- 29969538 TI - How Practice Managers and Physicians Can Work Together to Meet Demands. AB - The demand for healthcare and the need for healthcare workers are expected to keep growing. Practice managers are taking on more autonomous roles to best fill employment demands. As physicians take on more entrepreneurial roles in their practice, practice managers are acting as intrapreneurs to further health-care innovation while adding more value to the practice. PMID- 29969539 TI - MACRA Meets Your Revenue Cycle: Four Steps for the Value Journey. AB - The shift from fee-for-service to value-based reimbursement models represents one of the biggest billing transitions and greatest financial opportunities for physician practices. On the heels of ICD-10 adoption and against the backdrop of new digital infrastructure and workflows, practices face a new journey toward the Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) and the Quality Payment Program. Knowledge of how to traverse the path, navigate the intersections, and optimize the opportunities of healthcare payment reform is essential. This article offers an overview of the new Medicare reimbursement landscape and specific steps that practices can take to protect revenue streams today and ensure they thrive tomorrow. PMID- 29969540 TI - Potential Association Between Physician Burnout Rates and Operating Margins: Specialty-Specific Analysis. AB - Physician burnout rates have increased across most specialties betweer 2011 and 2014, and there may be an association with financial metrics. WE examined the ordinal ranking of operating margins for each physician spe. cialty from the University of Vermont Medical Center and the correspond. ing physician burnout ranking according to previously published data Physician specialties were categorized into one of four groups accordinc to high or low operating margin and burnout. Radiology, dermatology, otolaryngology, emergency medicine, family medicine, anesthesia, anc neurology were consistently categorized by high operating margin and high burnout rank. Our study provides a framework to explore the impaci of financial metrics on specialty-specific satisfaction and burnout. This information is relevant to the way hospital administrators guide revenue streams, medical students select specialties, and the extent to which physicians pursue their careers. PMID- 29969541 TI - Five Trends in Healthcare that Will Change the Way Managers Manage. AB - The pace of change in the field of medical practice management is unprecedented. Five major trends are affecting the business of healthcare: quality as a criterion for reimbursement; regulatory controls on fees and services; consumer influence on healthcare payments; full disclosure of claims data (i.e., transpar- ency); and increases in active patient load per physician. Successful practice administrators must remain well-informed about these trends in order to guide their practices toward modifications that will allow them to continue to flourish. The changes have been driven by economics, government regulations, and shifts in the country's population. In particular, the aging of the baby boomer generation has opened the eyes of the nation to the potential for costs of healthcare that are unsupportable within the current system: Independent physician practices can still be financially viable if the leadership team becomes nimble in adopting necessary operational changes that support opportunities for revenue optimization. PMID- 29969542 TI - The Ten Most Common Job Search Mistakes. AB - Finding and getting a job can be a challenging process. Knowing more about job search methods and application techniques may increase your chances of success. Your job search will be more effective if you first take the time to create a plan and avoid the very common mistakes we list in this article. Also included is a list of steps you can take now. PMID- 29969543 TI - Operating Room Management at the Edge of Order and Chaos. AB - The operating room (OR) management literature tends to view management problems as having finite solutions and assumes that equilibrium exists in the intricate encounters that occur every day. In this article, we review complexity theory and assess its applicability to the strategic, tactical, and operational issues facing OR managers. By building on complexity theory and its assumptions, we also show that as complex systems, ORs resemble high-reliability organizations more than they resemble ultra-safe organizations. This distinction and the limitations of the current, linear modeling may have potential implications for the future of OR management research and practice. Opening the door to complexity, understanding the underpinnings of high-reliability organizations, and admitting that OR systems are complex adaptive systems, will lead to self-governing, transparent processes that envision the OR as a living, growing, sustainable human endeavor. PMID- 29969544 TI - Developing Connections in Collections: Building Your Team with C.A.R.E. AB - In light of the ever-increasing cost of medical care, coupled with growing patient responsibility-and, as a result, growing bad debt-healthcare organizations are working harder than ever to reduce costs and improve collections in order to maintain a healthy revenue cycle. One major factor influencing your medical practice's success that is often overlooked is the culture of the organization and the engagement and quality of the team that upholds it. Receivables Management Partners has developed the C.A.R.E. model of hiring, which can aid your practice in establishing a culture of success and hiring and maintaining an engaged and committed workforce. Engaged employees will nurture an exceptional patient experience, and can improve your bottom line. PMID- 29969545 TI - Blundering into Liability: Unwitting Creation of Employment Contracts. AB - You think you are an employer at will. Think again! This article discusses how employers too often create binding contracts of which they are completely unaware until the employee or former employee seeks to enforce the "contract" and collect on the liabilities the organization did not know it had. Such lack of awareness may lead to the creation of full-blown contracts of employment, or a variety of mini-contracts that can be enforced for smaller, specific issues, or huge liability for wages and commissions. It may even eliminate the ability to enforce the organization's work rules and discipline. This article focuses on the contract area. PMID- 29969546 TI - Managing a Lazy Employee. AB - Managing a lazy employee can be a huge source of frustration for a medica practice manager. It can also be baffling, especially when the manager is highly self-motivated and cannot relate to an employee's penchant for laziness. This article defines laziness and explores the most likely reasons behind an employee's lazy behavior. It suggests that medical practice managers look to their owr management prior to taking disciplinary action against a lazy employee, anc provides specific guidance. It then offers practice managers 10 strategies for dealing effectively with lazy employees and 15 do's and don'ts for them to share with employees who are dealing with a lazy coworker. This article also provides five suggestions for overcoming one's own temptation to be lazy and advice for instituting a mentorship program to bring lazy employees up to speed. Finally, this article explores whether laziness is an innate characteristic or learned be- havior and suggests how managers can use this information in their approach to managing a lazy employee. PMID- 29969547 TI - Project Management for Healthcare Practices: Costs and Timing. AB - Every medical practice and every hospital will at some point decide to incorporate a new technology, a new procedure, or a new building; hire a new doctor; or embark on literally hundreds of other projects that require going outside of the box and outside of the usual routine in order to bring the project to fruition. This article discusses project management for implementing a new brand into a medical practice or a hospital, and how to prepare a time schedule and a cost analysis to see that the project is completed on time and within budget. PMID- 29969548 TI - Implementation of a Web-Based Provider Care Team System at the VA North Texas Health Care System. AB - Concern that our Department of Veterans Affairs (VA) suffers low relational coordination led us to seek a system that might improve domains of relational coordination. The lack of an accurate system to identify the physician caring for a patient at any given time was a ready target. We conducted forward effect analysis, a novel methodology we adapted from our shared experience in software development and entrepreneurship. This study sought to implement a Web-based patient care team system in the critical care units at the VA North Texas Health System. Surveys were distributed to nurses before and after the intervention. Nursing confidence in the system improved from a median of 40% to 70%, and median satisfaction improved from 20% to 80%. Forty percent of nurses believed the old paging system resulted in harm to patients, compared with none with the new paging system. This study demonstrates technical and organizational implementation of a paging system as a two-sided platform with the ability to improve relational coordination between these sides. PMID- 29969549 TI - Advanced Alternative Payment Models. Part I: Understanding the Medicare Shared Savings Program. AB - With CMS establishing preliminary definitions for fully qualifying Advanced Alternative Payment Models (APMs) in May 2016, it has become of interest to many care providers accepting Medicare and Medicaid payments to understand the nature of these entities if they wish to eventually participate in one of the current or future payment models. Changes under the Medicare Access and CHIP Reauthorization Act of 2015 specifically identify subsets of APMs that allow providers to avoid possible negative adjustments for poor relative performance compared with their respective peer groups through the Merit-Based Incentive Payment System beginning in 2017. This article reviews the nature of one of the fully qualifying Advanced APMs, the Medicare Shared Savings Program, and its risk/benefit sharing principles. Due to the lack of specialty-specific elements, this program acts as a very broad APM for practices and organizations seeking participation in either a simple or Advanced APM for the 2018 reporting period and beyond. PMID- 29969550 TI - Medical Malpractice Stress Syndrome: A "Forme Fruste" of Posttraumatic Stress Disorder. AB - Physicians practicing medicine face many challenges in today's healthcare arena. The stress of practicing medicine is increasing exponentially as new medical information is exploding on a daily basis and new stresses to practicing are occurring in a burgeoning telecommunication world. The impact of rapidly increasing medical information and the era of electronic medical records allowing physicians to communicate with patients and physicians electronically, without the benefit of observing body language or clarifying misunderstandings, has had a huge impact on practicing physician-patient risk for misinterpretation of the electronically transmitted medical information. The risk of malpractice allegations is real even under the best circumstances. The potential risk to physicians alleged to be negligent has resulted in a clinical entity called medical malpractice stress syndrome; it is a "forme fruste" of posttraumatic stress disorder. PMID- 29969551 TI - Ten Bad Habits that Should Be Banned from the Workplace Forever. AB - It turns out that taking care of worker health and well-being is the most effective way to increase engagement and performance. Putting yourself and your health first isn't selfish; it's exactly what we all need to do to make our businesses thrive. It is a minimum requirement for doing your job well, and the perfect New Year's reso.lution. This article offers a comprehensive list of the "don'ts," with suggestions on what to do instead, including strategies that increase movement and exercise, improve sleep and eating habits, reduce stress, improve air quality, and reduce chronic and infectious disease in medical offices. Healthy workers are more productive. The most obvious benefits to the bottom line are the avoidance of healthcare costs, but companies that make investments in employee health and wellbeing also are seeing increases in creativity, engagement, and productivity, and, as a result, business growth. PMID- 29969552 TI - Kinetic-Energy Density-Functional Theory on a Lattice. AB - We present a kinetic-energy density-functional theory and the corresponding kinetic-energy Kohn-Sham (keKS) scheme on a lattice and show that, by including more observables explicitly in a density-functional approach, already simple approximation strategies lead to very accurate results. Here, we promote the kinetic-energy density to a fundamental variable alongside the density and show for specific cases (analytically and numerically) that there is a one-to-one correspondence between the external pair of on-site potential and site-dependent hopping and the internal pair of density and kinetic-energy density. On the basis of this mapping, we establish two unknown effective fields, the mean-field exchange-correlation potential and the mean-field exchange-correlation hopping, which force the keKS system to generate the same kinetic-energy density and density as the fully interacting one. We show, by a decomposition based on the equations of motions for the density and the kinetic-energy density, that we can construct simple orbital-dependent functionals that outperform the corresponding exact-exchange Kohn-Sham (KS) approximation of standard density-functional theory. We do so by considering the exact KS and keKS systems and comparing the unknown correlation contributions as well as by comparing self-consistent calculations based on the mean-field exchange (for the effective potential) and a uniform (for the effective hopping) approximation for the keKS and the exact exchange approximation for the KS system, respectively. PMID- 29969554 TI - Modular Construction of Photoanodes with Covalently Bonded Ru- and Ir-Polypyridyl Visible Light Chromophores. AB - 1,10-phenanthroline is grafted to indium tin oxide (ITO) and titanium dioxide nanoparticle (TiO2) semiconductors by electroreduction of 5-diazo-1,10 phenanthroline in 0.1 M H2SO4. The lower and upper potential limits (-0.20 and 0.15 VSCE, respectively) were set to avoid reduction and oxidation of the 1,10 phenanthroline (phen) covalently grafted at C5 to the semiconductor. The resulting semiconductor-phen ligand (ITO-phen or TiO2-phen) was air stable, and was bonded to Ru- or Ir- by reaction with cis-[Ru(bpy)2(CH3CN)2]2+ (bpy = 2,2' bipyridine) or cis-[Ir(ppy)2(CH3CN)2]+ (ppy = ortho-Cphenyl metalated 2 phenylpyridine) in CH2Cl2 and THF solvent at 50 degrees C. Cyclic voltammetry, X ray photoelectron spectroscopy, solid-state UV-vis, and inductively coupled plasma-mass spectrometry all confirmed that the chromophores SC [(phen)Ru(bpy)2]2+ and SC-[(phen)Ir(ppy)2]+ (SC = ITO or TiO2) formed in near quantitative yields by these reactions. The resulting photoanodes were active and relatively stable to photoelectrochemical oxidation of hydroquinone and triethylamine under neutral and basic conditions. PMID- 29969553 TI - Hyaluronic Acid Conjugates of TLR7/8 Agonists for Targeted Delivery to Secondary Lymphoid Tissue. AB - Immunogens carried in lymphatic fluid drain via afferent vessels into regional lymph nodes and facilitate the efficient induction of appropriate immune responses. The lymphatic system possesses receptors recognizing hyaluronic acid (HA). Covalent conjugates of small-molecule TLR7/8 agonists with HA are entirely devoid of immunostimulatory activity in vitro. In murine models of immunization, however, such conjugates traffic to lymph nodes, where they are "unmasked", releasing the small molecule TLR7/8 agonist from the carrier polysaccharide. The resulting focal immunostimulation is manifested in potent adjuvantic effects with negligible systemic exposure. The efficient delivery of immunogens has been a major challenge in the development of subunit vaccines, and enhancing targeted delivery of immunogens to secondary lymphoid organs might be a promising approach for improving vaccine efficacy, as well as safety. PMID- 29969555 TI - Two-Dimensional-Layered Perovskite ALaTa2O7:Bi3+ (A = K and Na) Phosphors with Versatile Structures and Tunable Photoluminescence. AB - Topological chemical reaction methods are indispensable for fabricating new materials or optimizing their functional properties, which is particularly important for two-dimensional (2D)-layered compounds with versatile structures. Herein, we demonstrate a low-temperature (~350 degrees C) ion exchange approach to prefabricate metastable phosphors ALa1- xTa2O7: xBi3+ (A = K and Na) with RbLa1- xTa2O7: xBi3+ serving as precursors. The as-prepared ALa0.98Ta2O7:0.02 Bi3+ (A = Rb, K, and Na) share the same Dion-Jacobson type 2D-layered perovskite phase, and photoluminescence analyses show that ALa0.98Ta2O7:0.02 Bi3+ (A = Rb, K, and Na) phosphors exhibit broad emission bands peaking at 540, 550, and 510 nm, respectively, which are attributed to the nonradiative transition of Bi3+ from excited state 3P1 or 3P0 to ground state 1S0. The various Bi3+ local environments at the crystallographic sites enable the different distributions of emission and excitation spectra, and the photoluminescence tuning of ALa0.98Ta2O7:0.02 Bi3+ (A = Rb, K, and Na) phosphors are realized through alkali metal ion exchange. Notably, the combination of superior trivalent bismuth emission and low-temperature ion exchange synthesis leads to a novel yellow emitting K(La0.98Bi0.02)Ta2O7 phosphor which is successfully applied in a white LED device based on a commercially available 365 nm LED chip. Our realizable cases of this low-temperature ion exchange strategy could promote exploration into metastable phosphors with intriguing properties. PMID- 29969557 TI - Increasing the antimicrobial activity of amphiphilic cationic copolymers by the facile synthesis of high molecular weight stars by SARA ATRP. AB - Infections caused by bacteria represent great motif of concern in health area. Therefore, there is a huge demand for more efficient antimicrobial agents. Antimicrobial polymers have attracted special attention as promising materials to prevent infectious diseases. In this study, a new polymeric system exhibiting antimicrobial activity against a range of Gram-positive and Gram-negative bacterial strains at micromolar concentrations (e.g., 0.8 uM) was developed. Controlled linear and star-shaped copolymers, comprising hydrophobic poly(butyl acrylate) (PBA) and cationic poly(3-acrylamidopropyl)trimethylammonium chloride) (PAMPTMA) segments, were obtained by SARA ATRP at 30 degrees C. The antibacterial activity of the polymers was studied by varying systematically the molecular weight, hydrophilic/hydrophobic balance and architecture. The molecular weight was found to exert the greatest influence on the antimicrobial activity of the polymers, with minimum inhibitory concentration values decreasing with increasing molecular weight. Live/dead membrane integrity assays and scanning electron microscopy analysis confirmed the bactericidal character of the synthesized PAMPTMA-(b)co-PBA polymers. PMID- 29969556 TI - Simple and Precise Counting of Viable Bacteria by Resazurin-Amplified Picoarray Detection. AB - Simple, fast, and precise counting of viable bacteria is fundamental to a variety of microbiological applications such as food quality monitoring and clinical diagnosis. To this end, agar plating, microscopy, and emerging microfluidic devices for single bacteria detection have provided useful means for counting viable bacteria, but they also have their limitations ranging from complexity, time, and inaccuracy. We present herein our new method RAPiD (Resazurin-Amplified Picoarray Detection) for addressing this important problem. In RAPiD, we employ vacuum-assisted sample loading and oil-driven sample digitization to stochastically confine single bacteria in Picoarray, a microfluidic device with picoliter-sized isolation chambers (picochambers), in <30 s with only a few minutes of hands-on time. We add AlamarBlue, a resazurin-based fluorescent dye for bacterial growth, in our assay to accelerate the detection of "microcolonies" proliferated from single bacteria within picochambers. Detecting fluorescence in picochambers as an amplified surrogate for bacterial cells allows us to count hundreds of microcolonies with a single image taken via wide-field fluorescence microscopy. We have also expanded our method to practically test multiple titrations from a single bacterial sample in parallel. Using this expanded "multi RAPiD" strategy, we can quantify viable cells in E. coli and S. aureus samples with precision in ~3 h, illustrating RAPiD as a promising new method for counting viable bacteria for microbiological applications. PMID- 29969558 TI - Dendrimer Scaffold for the Amplification of In Vivo Pretargeting Ligations. AB - The development of immunoconjugates requires a careful balance between preserving the functionality of the antibody and modifying the immunoglobulin with the desired cargo. Herein, we describe the synthesis, development, and in vivo evaluation of a novel bifunctional dendrimeric scaffold and its application in pretargeted PET imaging. The site-specific modification of the huA33 antibody with this dendrimeric scaffold yields an immunoconjugate-sshuA33-DEN-TCO decorated with ~8 trans-cyclooctene (TCO) moieties, a marked increase compared to the ~2 TCO/mAb of a nondendrimeric control immunoconjugate (sshuA33-PEG12-TCO). Pretargeted PET imaging and biodistribution experiments were used to compare the in vivo performance of these two immunoconjugates in athymic nude mice bearing subcutaneous SW1222 human colorectal cancer xenografts. To this end, the mice were administered 100 MUg of each immunoconjugate followed 120 h later by the injection of a tetrazine-bearing radioligand, [64Cu]Cu-SarAr-Tz. Pretargeting with sshuA33-DEN-TCO produced excellent tumoral uptake at 24 h (8.9 +/- 1.9 %ID/g), more than double that created by sshuA33-PEG12-TCO (4.1 +/- 1.3 %ID/g). Critically-and somewhat surprisingly-the attachment of the G0.5 dendrimeric structures did not hamper the in vivo behavior of the immunoconjugate, suggesting that this versatile bifunctional scaffold may have applications beyond pretargeting. PMID- 29969559 TI - Tuning the Stiffness of Surfaces by Assembling Genetically Engineered Polypeptides with Tailored Amino Acid Sequence. AB - We introduce elastin-like recombinamers (ELRs) as polypeptides with precise amino acid positioning to generate polypeptide coatings with tunable rigidity. Two ELRs are used: V84-ELR, a hydrophobic monoblock, and EI-ELR, an amphiphilic diblock. Both were modified with the amine-reactive tetrakis (hydroxymethyl) phosphonium chloride compound. We evaluated the affinity, conformation, and dissipative behavior of ELRs assembled on alkanethiol self-assembled coatings by quartz crystal microbalance with dissipation monitoring, multiparametric surface plasmon resonance, and atomic force microscopy. The thickness of the polypeptide coatings showcases the preferential affinity of ELRs to NH2- and CH3-terminated surfaces. We demonstrate that V84-ELR strongly bonded to the substrate and reorganizes into an extended and more hydrated layer as the adsorbed amount increases, whereas EI ELR has a less dissipative behavior. The results suggest that ELR adsorption depends on the amino acid sequence and the substrate chemistry, ultimately influencing the stiffness of the polypeptide coatings. PMID- 29969560 TI - Double Precision Is Not Needed for Many-Body Calculations: Emergent Conventional Wisdom. AB - Using single-precision floating-point representation reduces the size of data and computation time by a factor of 2 relative to double precision conventionally used in electronic structure programs. For large-scale calculations, such as those encountered in many-body theories, reduced memory footprint alleviates memory and input/output bottlenecks. Reduced size of data can lead to additional gains due to improved parallel performance on CPUs and various accelerators. However, using single precision can potentially degrade the accuracy of the computed quantities. Here we report an implementation of coupled-cluster and equation-of-motion coupled-cluster methods with single and double excitations in single precision. We consider both standard implementation and one using Cholesky decomposition or resolution-of-the-identity representation of electron-repulsion integrals. Numerical tests illustrate that when single precision is used in correlated calculations, the loss of accuracy is insignificant, and pure single precision implementation can be used for computing energies, analytic gradients, excited states, and molecular properties. In addition to pure single-precision calculations, our implementation allows one to follow a single-precision calculation by cleanup iterations, fully recovering double-precision results while retaining significant savings. PMID- 29969561 TI - Understanding Processes Following Resonant Electron Attachment: Minimum-Energy Crossing Points between Anionic and Neutral Potential Energy Surfaces. AB - The equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) method with and without a complex absorbing potential (CAP) is applied for the study of the complex potential energy surfaces (CPES) of temporary anions and their parent neutral molecules. Crossings between the anionic state and the neutral state can be connected to the emission of nearly zero-energy electrons, which is demonstrated by the examples of acrylonitrile and methacrylonitrile. We show that the location of the minimum-energy crossing point (MECP) relative to the equilibrium structures of the neutral molecule and the anion can explain experimentally observed peaks on the threshold line of two-dimensional electron energy loss spectra. The location and energy of the MECP is also crucial in dissociative electron attachment as we illustrate for chloro-substituted ethylenes. It is demonstrated that both the metastable region of the anionic CPES and the crossing with the neutral PES need to be considered to explain trends in the chloride ion formation cross sections of dichloroethylenes. PMID- 29969562 TI - Importance of Accurate Structures for Quantum Chemistry Embedding Methods: Which Strategy Is Better? AB - Quantum chemistry embedding methods have become a popular approach to calculate molecular properties of larger systems. In order to account for finite temperature effects, including both configurational and conformational averaging, embedding methods are often combined with molecular dynamics (MD) simulations either in a direct or sequential manner. One of the decisive factors for a successful application of embedding methods is that that the underlying structures provided by the MD simulation are accurate, if not this will result in low-quality prediction of the molecular properties in question. Here we investigate different approaches for generating a set of molecular structures to be used in subsequent embedding calculations ranging from classical MD using a standard molecular mechanics (MM) force field to combined quantum mechanics/molecular mechanics (QM/MM) MD. Overall, we find an intermediate approach relying on classical MD followed by a constrained QM/MM geometry optimization to be a fairly accurate and very cost-effective approach, although this procedure naturally leads to underestimation of, for example, spectral bandwidths. PMID- 29969564 TI - Partial Edge Dislocations Comprised of Metallic Ga Bonds in Heteroepitaxial GaN. AB - We investigated the atomic structure of inclined threading edge dislocation (TED) typically observed in GaN grown on Si(111) through (scanning) transmission electron microscopy. Atomic observations verified that the inclined TED consisted of two partial dislocations. These results imply that the inclined TED possesses a Ga-Ga atomic configuration that is energetically unfavorable. However, the introduction of such structures is considered unavoidable because the TEDs should climb regularly to mediate the applied stress or the increasing surface due to the buffer layer. This Ga-Ga configuration is highly likely to form metallic bonds and appears to be the primary reason for the inferior efficacy of a GaN light-emitting diode grown on Si(111). PMID- 29969563 TI - Specific Drug Delivery to Cancer Cells with Double-Imprinted Nanoparticles against Epidermal Growth Factor Receptor. AB - Epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is over expressed in many tumors, including almost half of triple-negative breast cancers. The latter belong to a very-aggressive and drug-resistant form of malignancy. Although humanized anti-EGFR antibodies can work efficiently against these cancers both as monotherapy and in combination with genotoxic drugs, instability and high production costs are some of their known drawbacks in clinical use. In addition, the development of antibodies to target membrane proteins is a very challenging task. Accordingly, the main focus of the present work is the design of supramolecular agents for the targeting of membrane proteins in cancer cells and, hence, more-specific drug delivery. These were produced using a novel double-imprinting approach based on the solid-phase method for preparation of molecularly imprinted polymer nanoparticles (nanoMIPs), which were loaded with doxorubicin and targeted toward a linear epitope of EGFR. Additionally, upon binding, doxorubicin-loaded anti-EGFR nanoMIPs elicited cytotoxicity and apoptosis only in those cells that over-expressed EGFR. Thus, this approach can provide a plausible alternative to conventional antibodies and sets up a new paradigm for the therapeutic application of this class of materials against clinically relevant targets. Furthermore, nanoMIPs can promote the development of cell imaging tools against difficult targets such as membrane proteins. PMID- 29969565 TI - Unraveling Spatially Heterogeneous Ultrafast Carrier Dynamics of Single-Layer WSe2 by Femtosecond Time-Resolved Photoemission Electron Microscopy. AB - Studies of the ultrafast carrier dynamics of transition metal dichalcogenides have employed spatially averaged measurements, which obfuscate the rich variety of dynamics that originate from the structural heterogeneity of these materials. Here, we employ femtosecond time-resolved photoemission electron microscopy (TR PEEM) with sub-80 nm spatial resolution to image the ultrafast subpicosecond to picosecond carrier dynamics of monolayer tungsten diselenide (WSe2). The dynamics observed following 2.41 eV pump and 3.61 eV probe occurs on two distinct time scales. The 0.1 ps process is assigned to electron cooling via intervalley scattering, whereas the picosecond dynamics is attributed to exciton-exciton annihilation. The 70 fs decay dynamics observed at negative time delay reflects electronic relaxation from the Gamma point. Analysis of the TR-PEEM data furnishes the spatial distributions of the various time constants within a single WSe2 flake. The spatial heterogeneity of the lifetime maps is consistent with increased disorder along the edges of the flake and the presence of nanoscale charge puddles in the interior. Our results indicate the need to go beyond spatially averaged time-resolved measurements to understand the influence of structural heterogeneities on the elementary carrier dynamics of two-dimensional materials. PMID- 29969566 TI - Synthesis of 8-Hydroxygeraniol. AB - An operationally simple protocol for the conversion of geranyl acetate to 8 hydroxygeraniol is reported. The convenient two-step procedure relies on an efficient, chemo- and regioselective SeO2-promoted oxidation, followed by straightforward deacetylation. This facile means to prepare 8-hydroxygeraniol is expected to enable biosynthetic studies pertaining to thousands of monoterpene indole alkaloids. PMID- 29969567 TI - Ionic Diffusoosmosis in Nanochannels Grafted with End-Charged Polyelectrolyte Brushes. AB - In this paper, we develop a theory to study the imposed axial salt-concentration gradient-driven ionic diffusioosmosis (IDO) in soft nanochannels or nanochannels grafted with end-charged polyelectrolyte (PE) brushes. Our analysis first quantifies the diffusioosmotically induced electric field, which is primarily dictated by the imposed concentration gradient (CG) with little contribution of the induced osmosis. This induced electric field triggers an electroosmotic (EOS) transport, while the net diffusioosmotic (DOS) transport results from a combination of this EOS transport and a chemiosmotic (COS) transport arising from the pressure gradient induced by the applied CG. Our results demonstrate that the DOS transport is massively enhanced in nanochannels grafted with PE brushes with weak grafting density stemming from the significantly enhanced EOS transport caused by the localization of the EOS body force away from the nanochannel walls. This augmentation is even stronger for cases where the COS transport aids the EOS transport. On the other hand, the DOS transport gets severely reduced in nanochannels grafted with dense PE brushes owing to the severity of the brush induced additional drag force. We anticipate that these findings will help to unravel an entirely new understanding of induced electrokinetic transport in soft nanochannels. PMID- 29969568 TI - Horizon meeting on cardiovascular physiology: Dedicated to Dr. Mike Sharratt. AB - This perspective document summarizes discussions held at the Canadian Society for Exercise Physiology Annual Meeting in Winnipeg on October 27, 2017, when an expert panel was assembled to discuss the key questions and challenges for future research in cardiovascular exercise physiology. We were inspired by the example of the late Dr. Mike Sharratt, an accomplished and impactful Professor in the Faculty of Kinesiology at the University of Waterloo. Dr. Sharratt had a unique ability to bring experts together and translate theory into action, with a central goal of optimizing the health benefits of exercise, particularly in the fields of cardiac rehabilitation and aging (University of Waterloo Applied Health Science Department 2016; University of Waterloo Health Science Newsletter, 10-1 2017 ( http://uwaterloo.ca/applied-health-sciences/news/remembering-mike-sharratt )). PMID- 29969569 TI - Validity of injury self-reports by novice runners: comparison with reports by sports medicine physicians. AB - : This study examined the criterion validity of self-reported running-related injuries (RRI) by novice runners. Fifty-eight participants (41 females; age 46 +/ 11 yrs) of the "Start-to-Run" program provided self-reports on their RRIs using an online questionnaire. Subsequently, they attended injury consultations with sports medicine physicians who provided physician-reports (blinded for the self reports) as a reference standard. Self-reports and physician-reports included information on injury location (i.e., hip/groin, upper leg, knee, lower leg, and ankle/foot) and injury type (i.e., muscle-tendon unit, joint, ligament, or bone). Sensitivity, specificity, and positive predictive values were 100% for all five injury locations. For injury type, sensitivity was low (66% for muscle-tendon unit, 50% for ligament, and 40% for bone) and lowest for joint injuries (17%). In conclusion, the validity of self-reported RRIs by novice runners is good for injury locations but not for injury types. In particular for joint injuries, the validity of novice runners' self-reports is low. ABBREVIATIONS: RRI: Running Related Injury; SMC: Sports Medicine Centre; MTU: Muscle Tendon Unit; PPV: Positive Predictive Value. PMID- 29969570 TI - Arduino-Based Novel Hardware Design for Liquid Helium Level Measurement. AB - Liquid helium (LHe) is used as a cryogen in a variety of applications involving superconductivity and is routinely monitored for conducting low-temperature experiments. Thermoacoustic oscillations, which are inevitably present inside closed LHe containers, are utilized for level detection by sensing the vibrations at the warm end of a thin capillary tube inserted into the Dewar. The position of the capillary tube at which a sudden change occurs in these oscillations is manually sensed to identify the liquid level. The present work proposes a novel hardware design to identify the thermoacoustic oscillations in a reliable way using an accelerometer driven by an Arduino microcontroller. Further, an automated approach has been devised to quantify the rate of change of these helium oscillations to measure the LHe level. The proposed method has been tested during several trials on a 120 L and 100 L capacity Dewar using the proposed hardware, and the mean error in measuring the LHe level was calculated to be less than 1 cm in comparison with the gold standard niobium-titanium level sensor. The results encourage the use of the proposed method to evolve as a cost-effective alternative to the widely used superconducting level sensors in measuring LHe level. PMID- 29969571 TI - Association between Major Dietary Patterns and Polycystic Ovary Syndrome: evidence from a case-control study. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a multifactorial endocrine disorder in women. Change in lifestyle, especially dietary pattern, might have a role in prevalence of PCOS. The limited number of studies has made it difficult to draw any conclusion about the dietary patterns with PCOS. This study aimed to investigate the association between dietary patterns with PCOS. METHODS: This case-control study was performed on 225 new diagnosed patients and 345 healthy women in Isfahan, Iran. The presence of PCOS was confirmed by the expert gynecologists based on Rotterdam criteria. Usual dietary intake was assessed by a 168-items food frequency questionnaire. Dietary patterns were identified by principal component analysis. RESULTS: Three major dietary patterns including western, plant-based, and mixed were identified that explained 53.93% of the variance of food intake. Top tertile of western dietary pattern significantly increased the odds of PCOS (OR, 2.03; 95%CI, 1.12-3.67), either before or after adjustments for covariates. After adjustments for potential confounders, the highest tertile of plant-based dietary pattern was related to higher odds of PCOS than the lowest one (OR, 2.32; 95%CI, 1.23-4.37). In addition, those in the second tertile of mixed dietary pattern were 66% less likely to have PCOS compared with the lowest one (OR, 0.34; 95%CI, 0.18-0.61). CONCLUSIONS: We found that western and plant-based dietary patterns were associated with an increased risk of PCOS. Also, moderate adherence to the mixed dietary pattern was associated with reduced risk of PCOS. To confirm our findings more studies with longitudinal design are required. PMID- 29969572 TI - Hyperpolarization-activated cyclic-nucleotide-gated channels: pathophysiological, developmental, and pharmacological insights into their function in cellular excitability. AB - The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both Na+ and K+, blocked by millimolar concentrations of extracellular Cs+ and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, If, in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical If occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular If and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines. PMID- 29969574 TI - Ameliorative effects of aspirin against lipopolysaccharide-induced preeclampsia like symptoms in rats by inhibiting the pro-inflammatory pathway. AB - Preeclampsia is an inflammatory disease and has connection with increased pro inflammatory cytokines. Aspirin reduces the incidence of preeclampsia complications. However, the effects of aspirin on lipopolysaccharide-induced preeclampsia-like symptoms in rats have not been reported and the underlying molecular mechanism has not been illuminated. Hence, we investigated the anti inflammatory effects of aspirin on lipopolysaccharide-induced preeclampsia-like phenotypes in pregnant rats and elucidated the potential molecular mechanism. Preeclampsia-like phenotypes were induced by tail vein injection of lipopolysaccharide (1 MUg/kg) on gestational day 14. Aspirin (2 mg/kg per day) were administered from gestational day 14 to 19. Clinical phenotypes were recorded. Placenta tissues and serum were obtained to measure inflammatory cytokines levels using ELISA kit on gestational day 20. The mRNA expressions of IL-6, IL-1beta, and MCP-1 were measured by real-time PCR. Protein expressions including TLR4, MyD88, NF-kappaBp65, and TLR2 were determined by Western blot analysis in the rat placentas of each group. Aspirin obviously assuaged lipopolysaccharide-induced preeclampsia-like phenotypes in pregnant rats. Aspirin treatment significantly decreased the levels of pro-inflammatory cytokines in serum and placenta tissues of preeclampsia rats. Aspirin also obviously downregulated the mRNA expressions of IL-6, IL-1beta, and MCP-1 and assuaged the activation of TLR4, MyD88, NF-kappaBp65, and TLR2 in the placental tissue. Our results indicated that aspirin could assuage preeclampsia-like phenotypes, and this improvement effect is possibly the result of the suppression of pro inflammatory cytokines via the TLR4, MyD88, NF-kappaBp65, and TLR2 signaling pathway. PMID- 29969573 TI - Is Targeting the Inflammasome a Way Forward for Neuroscience Drug Discovery? AB - Neuroinflammation is becoming increasingly recognized as a critical factor in the pathology of both acute and chronic neurological conditions. Inflammasomes such as the one formed by NACHT, LRR, and PYD domains containing protein 3 (NLRP3) are key regulators of inflammation due to their ability to induce the processing and secretion of interleukin 1beta (IL-1beta). IL-1beta has previously been identified as a potential therapeutic target in a variety of conditions due to its ability to promote neuronal damage under conditions of injury. Thus, inflammasome inhibition has the potential to curtail inflammatory signaling, which could prove beneficial in certain diseases. In this review, we discuss the evidence for inflammasome contributions to the pathology of neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease, epilepsy, and acute degeneration following brain trauma or stroke. In addition, we review the current landscape of drug development targeting the NLRP3 inflammasome. PMID- 29969575 TI - The Limits and Potential Future Applications of Personalized Medicine to Prevent Complex Chronic Disease. PMID- 29969577 TI - Physiological responses to partial-body cryotherapy performed during a concurrent strength and endurance session. AB - This investigation examined the effect of partial-body cryostimulation (PBC) performed in the recovery time between a strength training and an interval running (IR). Nine rugby players [age 23.7+/-3.6, BMI 28.0+/-2.6 kg/m2] were randomly exposed to two different conditions: i) PBC: 3-min at -160 degrees C; ii) passive recovery at 21 degrees C. We recorded the bioelectrical impedance analysis (BIA), temperature, and cardiac autonomic variables in three moments: at baseline, after strength training (R0) and after 90-min of recovery (R90). Additionally, the blood lactate concentration was measured 1-min before and 2.5 min after the IR. The heart rate, energy cost, minute ventilation, oxygen uptake and metabolic power were assessed during the IR. The homeostatic hydration status was affected by the execution of intense strength training sub-session. Then, after PBC the BIA vector was restored back, close to normohydration status. Autonomic variables changed over time in both conditions, although the mean differences and effect sizes were higher in the PBC condition. During IR, the heart rate was 3.5% lower after PBC, and the same result was observed for the oxygen uptake (~4.9%) and ventilation (~6.5%). The energy cost measured after cryotherapy was ~9.0% lower than after passive recovery. Cryotherapy enhances recovery after a single strength training, while during the subsequent interval running it shows a reduction in cardiorespiratory and metabolic parameters. PBC may be used in those athletes who compete or train more than once in the same day to improve recovery between successive training sessions or competitions. PMID- 29969576 TI - Effects of garlic polysaccharide on alcoholic liver fibrosis and intestinal microflora in mice. AB - CONTEXT: Alcoholic liver fibrosis (ALF) is treatable and reversible consequence of liver disease. Intestinal microflora plays an important role in the progression of liver disease. Garlic (Allium sativum L. [Amaryllidaceae]) has been consumed as a traditional medicine to treat liver injury. OBJECTIVE: To investigate the effects of garlic polysaccharide (GP) on ALF and intestinal microflora in mice. MATERIALS AND METHODS: KM mice were orally administered with alcohol (56%, 6 mL/kg) for 30 d to establish ALF model, and divided into four groups together with control group (water only). Hugan tablet (60 mg/kg) or GP (250 and 150 mg/kg) were given 5 h after each dose of alcohol. Biochemical markers in serum and liver homogenate were determined with kits. Alteration of intestinal microflora, and protein expressions of TGF-beta1, TNF-alpha and decorin were detected. RESULTS: In GP-H group, ALT and AST decreased to 18.85 +/- 4.71 U/L and 40.84 +/- 7.89 U/L. MDA, TC, TG and LDL-C decreased to 2.32 +/- 0.86 mmol/mg, 0.21 +/- 0.12 mmol/L, 0.96 +/- 0.31 mmol/L and 0.084 +/- 0.027 mmol/L. SOD, GSH-Px and GSH increased to 118.32 +/- 16.32 U/mg, 523.72 +/- 64.20 U/mg and 0.56 +/- 0.05 mg/g. Ratios of TGF-beta1 and TNF-alpha decreased to 0.608 +/- 0.170 and 1.057 +/- 0.058, decorin increased to 2.182 +/- 0.129. Lachnospiraceae and Lactobacillus increased, Facklamia and Firmicutes decreased with GP pretreatment. DISCUSSION AND CONCLUSIONS: Intestinal microflora provides novel insight into the mechanisms of GP that may be used to treat ALF and intestinal microflora dysbiosis. PMID- 29969578 TI - SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation. AB - A key member of the sentrin/small ubiquitin-like modifier (SUMO)-specific protease (SENP) family, SENP2 has been shown to implicate embryonic development, fatty acid metabolism, atherosclerosis, and neurodegenerative diseases. However, other biologic functions of SENP2 and its specific targets are incompletely understood. Here, we uncovered a novel role of SENP2 in negative regulation of keratinocyte migration, a process crucial to wound epithelialization. Defects in this function are often associated with the clinical phenotypes of chronic nonhealing wounds. Mechanistically, SENP2 as a specific de-SUMOylase targets NDR1 (nuclear Dbf2-related 1), also called STK38 (serine-threonine kinase 38), for de SUMOylation and SUMO conjugation of NDR1 on Lys-465 attenuates its inhibition of p38/ERK1/2 activation by decreasing the association of NDR1 with MEK kinase 1/2. Significantly, low-level laser (LLL) irradiation increases NDR1 SUMOylation and subsequent p38/ERK1/2 activation via down-regulation of SENP2, leading to faster keratinocyte migration. Our findings fill the gaps that linger in the basic mechanisms underlying LLL therapy.-Xiao, N., Li, H., Yu, W., Gu, C., Fang, H., Peng, Y., Mao, H., Fang, Y., Ni, W., Yao, M. SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation. PMID- 29969579 TI - G-protein receptor kinases 2, 5 and 6 redundantly modulate Smoothened-GATA transcriptional crosstalk in fetal mouse hearts. AB - G-protein receptor kinases (GRKs) regulate adult hearts by modulating inotropic, chronotropic and hypertrophic signaling of 7-transmembrane spanning neurohormone receptors. GRK-mediated desensitization and downregulation of beta-adrenergic receptors has been implicated in adult heart failure; GRKs are therefore a promising therapeutic target. However, germ-line (but not cardiomyocyte-specific) GRK2 deletion provoked lethal fetal heart defects, suggesting an unexplained role for GRKs in heart development. Here we undertook to better understand the consequences of GRK deficiency on fetal heart development by creating mice and cultured murine embryonic fibroblasts (MEFs) having floxed GRK2 and GRK5 alleles on the GRK6 null background; simultaneous conditional deletion of these 3 GRK genes was achieved using Nkx2-5 Cre or adenoviral Cre, respectively. Phenotypes were related to GRK-modulated gene expression using whole-transcriptome RNA sequencing, RT-qPCR, and luciferase reporter assays. In cultured MEFs the atypical 7-transmembrane spanning protein and GRK2 substrate Smoothened (Smo) stimulated Gli-mediated transcriptional activity, which was interrupted by deleting GRK2/5/6. Mice with Nkx2-5 Cre mediated GRK2/5/6 ablation died between E15.5 and E16.5, whereas mice expressing any one of these 3 GRKs (i.e. GRK2/5, GRK2/6 or GRK5/6 deleted) were developmentally normal. GRK2/5/6 triple null mice at E14.5 exhibited left and right heart blood intermixing through single atrioventricular valves or large membranous ventricular septal defects. Hedgehog and GATA pathway gene expression promoted by Smo/Gli was suppressed in GRK2/5/6 deficient fetal hearts and MEFs. These data indicate that GRK2, GRK5 and GRK6 redundantly modulate Smo-GATA crosstalk in fetal mouse hearts, orchestrating transcriptional pathways previously linked to clinical and experimental atrioventricular canal defects. GRK modulation of Smo reflects convergence of conventional neurohormonal signaling and transcriptional regulation pathways, comprising an unanticipated mechanism for spatiotemporal orchestration of developmental gene expression in the heart. PMID- 29969580 TI - Brain correlates of adult attachment style: A voxel-based morphometry study. AB - Evidence from human and animal studies has shown that experiences of early attachment can influence brain development and structure. Adult attachment style develops from early attachment experiences. However, little is known about the relationship between gray matter volume and attachment style. Further, the structural bases of sex-related differences in adult attachment styles remain unknown. We used voxel-based morphometry to investigate the neuroanatomical basis underlying adult attachment styles and the structural basis of sex-related differences in adult attachment styles. Participants were 106 healthy young adults (57 women and 49 men; age, 20.8 +/- 1.55 years). Negative correlations were found between attachment avoidance and the volumes of the left middle temporal gyrus and the right parahippocampal gyrus, and between attachment anxiety and the right ventral anterior cingulate volume. Further analysis revealed that attachment avoidance was negatively correlated with the volume of the right middle occipital gyrus in women, but the inverse correlation was found in men. These findings suggest that differences in adult attachment styles are correlated with structural brain differences in adulthood, and that sex-related differences in adult attachment styles are associated with intrinsic structural brain differences involved in visual processing. These findings may improve our understanding of the pathophysiology of attachment-related disorder. PMID- 29969582 TI - Nano-sized CA125 antigen glycocamouflage: Mucin - Extracellular vesicles alliance to watch? AB - Mucin 16 (MUC16) is a transmembrane type mucin and its released extracellular portion is designated as CA125 antigen. It is considered to be part of a supramolecular glycoprotein complex having a complicated epitope map and extreme structural heterogeneity. Starting from the initial transmembrane localization of MUC16/CA125 antigen and its alternative routes of release by shedding or putative secretion, CA125 antigen from human amniotic fluid soluble and extracellular vesicles (EVs)-containing fractions were characterized aiming at the possible glycosylation-associated mode of distribution as a factor contributing to the reported conflicting structural data. Ultracentrifugation, sucrose density gradient centrifugation, ion-exchange chromatography and TEM were used for analysis. The results indicated that the smeared abundantly glycosylated high molecular mass CA125-immunoreactive species, which follow the wheat germ agglutinin-binding pattern, were shared across amniotic fluid soluble and particulate fractions. A lower molecular mass glycoprotein-like CA125 immunoreactive species which follows the peanut agglutinin-binding pattern and was specifically associated with the EVs-enriched fraction was observed. CA125 presentation in the particulate amniotic fluid fraction was found to be shaped by a complex interactome partially involving lactose-sensitive galectin-3 binding. The MUC16 - EVs alliance as well as heterogeneous mucin/macromolecular complexes, at membranes or extracellularly, may represent cryptic pools of distinct CA125 species. PMID- 29969583 TI - The effect of electrophoretic parameters on separation performance of short DNA fragments. AB - Effective separation of short DNA fragments is important for the identification of PCR or LAMP products. We investigated the effect of electric field strength, sample plug width, effective length of the capillary, concentration and molecular weight of polymer on the separation performance of small DNA. Results demonstrated that the sample plug played a non-negligible role in the peak broadening. The migration time of DNA was exponentially decreased with the increase of electric field strength. Increasing effective length of capillary, concentration or molecular weight of HEC may improve the separation performance, but it was at the cost of long migration time. PMID- 29969581 TI - Terminal Regions Confer Plasticity to the Tetrameric Assembly of Human HspB2 and HspB3. AB - Heterogeneity in small heat shock proteins (sHsps) spans multiple spatiotemporal regimes-from fast fluctuations of part of the protein, to conformational variability of tertiary structure, plasticity of the interfaces, and polydispersity of the inter-converting, and co-assembling oligomers. This heterogeneity and dynamic nature of sHsps has significantly hindered their structural characterization. Atomic coordinates are particularly lacking for vertebrate sHsps, where most available structures are of extensively truncated homomers. sHsps play important roles in maintaining protein levels in the cell and therefore in organismal health and disease. HspB2 and HspB3 are vertebrate sHsps that are found co-assembled in neuromuscular cells, and variants thereof are associated with disease. Here, we present the structure of human HspB2/B3, which crystallized as a hetero-tetramer in a 3:1 ratio. In the HspB2/B3 tetramer, the four alpha-crystallin domains (ACDs) assemble into a flattened tetrahedron which is pierced by two non-intersecting approximate dyads. Assembly is mediated by flexible "nuts and bolts" involving IXI/V motifs from terminal regions filling ACD pockets. Parts of the N-terminal region bind in an unfolded conformation into the anti-parallel shared ACD dimer grooves. Tracts of the terminal regions are not resolved, most likely due to their disorder in the crystal lattice. This first structure of a full-length human sHsp heteromer reveals the heterogeneous interactions of the terminal regions and suggests a plasticity that is important for the cytoprotective functions of sHsps. PMID- 29969584 TI - Development of a lateral flow immunoassay of C-reactive protein detection based on red fluorescent nanoparticles. AB - We have developed a reliable and rapid immunoassay based on a facile synthesis of fluorescent nanoparticles integrated in immunochromatography technique to quantitatively detect C-reactive protein (CRP). The method is based on a sandwich immunoassay using the Nile-red doped nanoparticles/CRP monoclonal antibody conjugate. The method is simple and fast, with a detection limit of 0.091 mg/L. It provides quantitative analysis in the range of 0.1-160 mg/L, which is adequate for detecting CRP of acute inflammatory or cardiovascular disease. This strategy displayed a good reproducibility and stability to straightforwardly analyze the plasma samples without complicated washing steps, thereby reducing the operating procedures for non-professionals and promoting the detection efficiency and the whole detection process can be completed in 3 min. This approach for carrying out immunoassays can be applied to the detection of CRP in the point-of-care tests. PMID- 29969585 TI - Disability and the Rohingya Displacement Crisis: A Humanitarian Priority. PMID- 29969586 TI - Association among depression, symptom experience, and quality of life in polycystic ovary syndrome. AB - BACKGROUND: Clinical stigmata of polycystic ovary syndrome include hirsutism, obesity, menstrual disturbances, and infertility. These symptoms impair health related quality of life. Depression is also common. The relationship among depression, symptom self-perception, and quality of life in polycystic ovary syndrome is poorly understood. OBJECTIVE: We sought to investigate the relationship between health-related quality of life and depression in women with polycystic ovary syndrome. STUDY DESIGN: We conducted a secondary analysis of a multicenter, randomized clinical trial (Pregnancy in Polycystic Ovary Syndrome II, NCT00719186) comparing clomiphene citrate vs letrozole in the treatment of infertility. Subjects included 732 women ages 18-40 years with polycystic ovary syndrome by modified Rotterdam criteria. The validated Polycystic Ovary Syndrome Health-Related Quality of Life survey was self-administered, assessing the following domains: emotions, body hair, body weight, menstrual problems, and infertility; scores range from 1-7, with lower numbers indicating poorer quality of life. Depression was evaluated via the Primary Care Evaluation of Mental Disorders Patient Health Questionnaire. Quality-of-life scores were compared between depressed and nondepressed women. Multivariate linear regression models analyzed the association between depression and quality-of-life scores, controlling for age, body mass index, hirsutism score, and duration of infertility. RESULTS: In all, 64 women (8.4%) met criteria for depression. Depressed women reported reduced quality of life in all domains compared to nondepressed women: mood (3.1 vs 4.6, P < .001), body hair (3.5 vs 4.2, P = .002), weight (2.0 vs 3.5, P < .001), menstrual problems (3.3 vs 4.1, P < .001), and infertility (1.9 vs 3.0, P < .001). Global quality-of-life score was reduced in depressed women (2.8 vs 3.9, P < .001). Impairments in quality of life in depressed women persisted in all domains after controlling for objective parameters including age, body mass index, hirsutism score, and infertility duration. CONCLUSION: Depression is associated with reduced quality of life related to polycystic ovary syndrome symptoms. Disturbances in health-related quality of life in depressed women are not explained by objective measures including body mass index, hirsutism scores, and duration of infertility. Depression may color the experience of polycystic ovary syndrome symptoms and should be considered when there is significant discordance between subjective and objective measures in women with polycystic ovary syndrome. PMID- 29969587 TI - Setup of luminescence-based serum bactericidal assay against Salmonella Paratyphi A. AB - Increasing awareness of Salmonella Paratyphi A's contribution to enteric fever episodes throughout Asia has led to the development of new S. Paratyphi A vaccines. Assays are needed to measure functional antibodies elicited by the new vaccine candidates to assess their immunogenicity and potential protective capacities. Serum bactericidal assay (SBA) is the method of choice to measure functional antibody titers against various bacterial pathogens, but it is rarely been used for large dataset and clinical samples because it is time consuming and labor-intensive. Recently we developed a high-throughput luminescence-based SBA method, against different pathogens, including Salmonella Typhimurium and Enteritidis, Shigella flexneri serovars 2a and 3a, Shigella sonnei and Neisseria meningitidis. Here we further demonstrated the applicability of such method with invasive isolates of S. Paratyphi A to assess the complement-mediated antibody dependent killing of both preclinical and clinical standard sera. As already found for other organisms, titers obtained by the luminescence-based SBA strongly correlated with those obtained by the conventional agar plate-based assay. The SBA assay described here is a useful tool for measuring functional antibodies elicited by Salmonella vaccines, with the potential of being applied to immunogenicity assessment in clinical trials. PMID- 29969588 TI - Desmoglein 3 - Influence on oral carcinoma cell migration and invasion. AB - Desmoglein 3 (Dsg3) is an adhesion receptor in desmosomes, but its role in carcinoma cell migration and invasion is mostly unknown. Our aim was to quantitatively analyse the motion of Dsg3-modified carcinoma cells in 2D settings and in 3D within tumour microenvironment mimicking (TMEM) matrices. We tested mutant constructs of C-terminally truncated Dsg3 (?238 and ?560), overexpressed full-length (FL) Dsg3, and empty vector control (Ct) of buccal mucosa squamous cell carcinoma (SqCC/Y1) cells. We captured live cell images and analysed migration velocities and accumulated and Euclidean distances. We compared rodent collagen and Matrigel(r) with human Myogel TMEM matrices for these parameters in 3D sandwich, in which we also tested the effects of monoclonal antibody AK23, which targets the EC1 domain of Dsg3. In monolayer culture, FL and both truncated constructs migrated faster and had higher accumulated distances than Ct cells. However, in the 3D assays, only the mutants invaded faster relative to Ct cells. Of the mutants, the shorter form (Delta238) exhibited faster migration and invasion than Delta560 cells. In the Transwell, all of the cells invaded faster through Myogel than Matrigel(r) coated wells. In 3D sandwich, AK23 antibody inhibited only the invasion of FL cells. We conclude that different experimental 2D and 3D settings can markedly influence the movement of oral carcinoma cells with various Dsg3 modifications. PMID- 29969589 TI - Dehydration Study of Piracetam Co-Crystal Hydrates. AB - A hydrate of co-crystal of piracetam and 3,5-dihydroxybenzoic acid was obtained via crystallization from water. Single-crystal X-ray data show that piracetam/3,5 dihydroxybenzoic acid tetrahydrate (P35TH) crystallizes in the triclinic system with a P1 space group. The physicochemical properties of co-crystal hydrate were characterized using powder X-ray diffractometry, differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA), and FTIR spectroscopy. The dehydration kinetics of P35TH was monitored at various temperatures and heating rates by DSC and TGA. Activation energy of P35TH dehydration was obtained using temperature ramp DSC, isothermal and nonisothermal TGA methods. Kinetic analysis of isothermal TGA data was fitted to various solid-state reaction models. Mechanistic models derived from isothermal dehydration kinetic data are best described as a 2-dimensional diffusion mechanism. A correlation was noted between the dehydration behavior and the bonding environment of the water molecules in the crystal structure. This study is a good demonstration of complexity of co crystal hydrate and their dehydration behavior. PMID- 29969590 TI - Analysis of Toxoplasma gondii clonal type-specific antibody reactions in experimentally infected turkeys and chickens. AB - Due to their ground-feeding behaviour, free-ranging chickens and turkeys are exposed to oocysts and are good indicators of the presence of Toxoplasma gondii in the environment. In addition, poultry may become infected by ingestion of tissues of infected intermediate hosts such as small rodents. Free-ranging poultry are considered an important source of T. gondii infection in humans, especially in developing countries. Knowledge on T. gondii genotypes in infected animals and humans is important for understanding the epidemiology of T. gondii infections. The aim of the present study was to analyse the ability of experimentally infected turkeys and chickens to develop a T. gondii clonal type specific antibody response (IgY) after i.v. inoculation with tachyzoites of three T. gondii clonal lineages, types I, II and III. A peptide microarray displaying a panel of 101 different synthetic peptides was used for serotyping. Peptide sequences were derived from polymorphic regions of 16 T. gondii proteins (GRA1, GRA3-7, SAG1, SAG2A, SAG3, SAG4, SRS1, SRS2, ROP1, NTPase I and NTPase III and BSR4). The array was probed with 120 sera from experimentally infected chickens and turkeys inoculated with different doses of T. gondii tachyzoites (104, 103 and 102) collected from isolates representative for T. gondii clonal types I (RH), II (ME49) or III (NED) and uninfected controls. After screening of the peptides with reference sera from chickens and turkeys, and evaluation of data by Receiver Operating Characteristics analysis, 41 and 40 peptides were identified that appeared suitable to detect type-specific reactions with sera collected at 2, 5, 7 and 9 weeks p.i. Selected peptides allowed the identification of T. gondii clonal types, until 9 week p.i., which the chickens or turkeys had been inoculated with. At 9 weeks p.i., a high proportion of the experimentally infected chickens (67% (12/18)) and turkeys (61% (11/18)) no longer reacted with the selected peptides. Serotyping of the infection in individual chickens or turkeys was only possible when the whole peptide panel was applied. Clonal type specific antibody responses were dynamic in both poultry species and depended on the individual animal and the time after infection. PMID- 29969591 TI - Functional reorganization of population receptive fields in a hemispherectomy patient with blindsight. AB - Blindsight refers to the ability of some patients with destruction of the primary visual cortex (V1) to respond to stimuli presented in their clinically blind visual field despite lack of visual awareness. Here we tested a rare and well known patient with blindsight following hemispherectomy, DR, who has had the entire cortex in the right hemisphere removed, and in whom the right superior colliculus is the only post-chiasmatic visual structure remaining intact. Compared to more traditional cases of blindsight after damage confined to V1, the study of blindsight in hemispherectomy has offered the invaluable opportunity to examine directly two outstanding questions: the contribution of the intact hemisphere to visual processing without awareness, and the nature of plastic and compensatory changes in these remaining contralesional visual areas. Population receptive field (pRF) mapping was used to define retinotopic maps, delineate the boundaries between the visual areas, examine changes in the sizes of receptive field centres within each visual area, and their variability as a function of eccentricity. Aside from the dorsal visual areas showing blurred borders between V2d and V3d, not otherwise detected with perimetric mapping, the retinotopic maps of DR did not differ substantially from those of three matched healthy controls. Interestingly, those dorsal compartments showed a significant increase in the RF sizes toward values typical of higher-order processing cortices, while no differences were observed in the corresponding ventral visual areas. Findings showed that whereas receptive field sizes at foveal and parafoveal eccentricities (<= 4 degrees ) were not measurably altered, the pRF size increased by ~ 270% at 4-6 degrees of eccentricity, and the size difference reached ~ 300% between 8 degrees and 10 degrees . We interpret these findings to suggest that an increase in pRF sizes could be indicative of cerebral plasticity involving the retinotopic reorganization of the dorsal visual areas. PMID- 29969592 TI - The highly selective 5-HT2A antagonist EMD-281,014 reduces dyskinesia and psychosis in the l-DOPA-treated parkinsonian marmoset. AB - Blockade of serotonin 2A (5-HT2A) receptors is regarded as an anti-dyskinetic and anti-psychotic strategy in Parkinson's disease (PD). However, the 5-HT2A antagonists tested so far exhibited affinity for other receptors, which might have played a role in their action. EMD-281,014 is the most selective 5-HT2A antagonist available, with approximately 2,000-fold selectivity over serotonin 2C (5-HT2C) receptors. EMD-281,014 was previously tested in the clinic and has high translational potential. In the present study, we assessed the effect of EMD 281,014 on dyskinesia and psychosis in the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-lesioned common marmoset. We first determined the pharmacokinetic profile of EMD-281,014 in the marmoset, after which doses leading to clinically-relevant plasma levels (0.01, 0.03 and 0.1 mg/kg) or vehicle were administered to MPTP-lesioned marmosets, in combination with L-3,4 dihydroxyphenylalanine (l-DOPA). The effects of EMD-281,014 on dyskinesia, psychosis-like behaviours (PLBs) and parkinsonism were then evaluated. When added to l-DOPA, EMD-281,014 (0.03 and 0.1 mg/kg) reduced peak dose dyskinesia, by 41.8% and 54.5% (P < 0.05 and P < 0.001), when compared to l-DOPA/vehicle. EMD 281,014 (0.03 and 0.1 mg/kg) also significantly reduced the severity of peak dose PLBs, by 42.5% and 45.9% (P < 0.05 and P < 0.001), when compared to vehicle. The anti-dyskinetic and anti-psychotic effects of EMD-281,014 were achieved without interfering with l-DOPA anti-parkinsonian action. Our results suggest that highly selective 5-HT2A receptor blockade with EMD-281,014 is an effective way to alleviate both dyskinesia and psychosis in PD, without adversely affecting parkinsonian disability. PMID- 29969593 TI - Polymorphisms of PTH (Parathyroid Hormone) Gene and Risk of Kidney Stone Disease: A Case-Control Study from West Bengal, India. AB - OBJECTIVE: To investigate the potential contribution of parathyroid hormone (PTH) gene polymorphisms in kidney stone disease (KSD), a global clinical problem impacting major burden on public health care system worldwide. METHODS: A case control study was performed in West Bengal (India) with 152 patients reported with calcium-rich stone in kidney and 144 corresponding normal healthy individuals as controls. To identify genetic variants of PTH, the entire coding region, exon-intron boundaries and a few hundred nucleotides downstream the exon 3 (3' UTR region) was bi-directionally sequenced for all the study participants. RESULTS: Two intronic (rs694 and rs6254) and one synonymous (rs6256, located in exon 3) variant were identified along with 2 single nucleotide polymorphisms (SNPs) (rs307247 and rs307248) in the 3' UTR of the PTH gene. Allele and genotype frequency analysis of these SNPs revealed that rs6254 and rs6256 had moderate association with increased risk of KSD. The 2 SNPs (rs307247 and rs307248) of the 3' UTR, which were in strong linkage disequilibrium, were found to be significantly associated with kidney stone risk in the population of West Bengal, India. CONCLUSION: This is the first time report in the world, regarding association of PTH gene polymorphisms with KSD. Our finding suggests that PTH gene polymorphisms can be used as potential genetic markers for early detection of KSD and for preventing its occurrence. Additional studies with larger sample size are essential to validate our result. PMID- 29969594 TI - It's time: A commentary on fear extinction in the human brain using fMRI. AB - The recent meta-analysis by Fullana et al. (2018) is both timely and significant, providing a vital milestone towards understanding the neural networks involved in threat extinction in humans. Fullana et al. (2018) examined both threat extinction and recall separately using sophisticated meta-analytic methods based on raw contrast maps. Importantly, the meta-analysis highlighted a lack of consistent activation across studies for key neural "players" in the threat extinction circuit: the amygdala and ventromedial prefrontal cortex (vmPFC). In the current commentary, we highlight reasons for which this key circuitry may not have resulted from this meta-analysis, and call for a 'gold standard' in the examination of threat extinction using fMRI. PMID- 29969595 TI - Epigenetic and redox biomarkers: Novel insights from the MARK-AGE Study. AB - Ageing is a multifactorial process that affects most, if not all, of the body's tissues and organs and can be defined as the accumulation of physical and psychological changes in a human being over time. The rate of ageing differs between individuals of the same chronological age, meaning that 'biological age' of a person may be different from 'chronological age'. Furthermore, ageing represents a very potent risk factor for diseases and disability in humans. Therefore, establishment of markers of biological ageing is important for preventing age-associated diseases and extending health span. MARK-AGE, a large scale European study, aimed at identifying a set of biomarkers which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. But beyond the identification of useful biomarkers, MARK-AGE provided new insights in age-associated specific cellular processes, such as DNA methylation, oxidative stress and the regulation of zinc homeostasis. PMID- 29969597 TI - Multi-center evaluation of GenoType MTBDRsl line probe assay for rapid detection of pre-XDR and XDR Mycobacterium tuberculosis in China. AB - OBJECTIVES: The implementation of rapid and reliable drug susceptibilities diagnosis is fundamental for effective treatment of multidrug-resistant tuberculosis(MDR-TB). The present study aimed to assess the diagnostic performance of the 2nd-version GenoType MTBDRsl kit as well as the impact of its implementation on the turnaround time in a multi-center Chinese study. METHODS: Totally 353 MDR-TB patient specimens were consecutively tested. The 2nd-version GenoType MTBDRsl assay, drug susceptibility testing with the MGIT 960 system, and sequencing were performed and compared. RESULTS: MTBDRsl testing identified the major genotypes associated with fluoroquinolones resistance, predominated by gyrA MUT3B (Asp94Asn and Asp94Tyr, 26.5%) and MUT3C (Asp94Gly, 19.5%). The genotypes associated with resistance to 2nd-line injectable drugs(SLIDs) were rrsMUT1(A1401G, 64.9%) and absence of WT1(C1402T, 10.5%). The sensitivities for detection of resistance to fluoroquinolones, SLIDs, and their combination (extensively drug resistance, XDR) were 80.5%, 80.7% and 73.5% and specificities were 100.0%, 99.3% and 99.1%, respectively. Implementation of this test significantly reduced the turnaround time between sample collection and result reporting from 45 to 3 days, a reduction by 93.3% (p, 0.001). CONCLUSION: With a favorable diagnostic performance and short turnaround time, the 2nd-version GenoType MTBDRsl assay proves its value for early diagnosis of resistance to 2nd line drugs as well as of XDR-TB in China. PMID- 29969596 TI - Comparison of Dual beta-Lactam therapy to penicillin-aminoglycoside combination in treatment of Enterococcus faecalis infective endocarditis. AB - BACKGROUND: Dual beta-lactam therapy and a penicillin-aminoglycoside combination are first line regimens in the treatment of penicillin-susceptible Enterococcus faecalis infective endocarditis (EFIE). Our aim was to compare ampicillin plus ceftriaxone (A+C) to ampicillin plus gentamicin (A+G) in the treatment of EFIE. METHODS: This was a retrospective cohort study of adults (>=18 years) patients diagnosed with EFIE at Mayo Clinic campuses in Rochester, Minnesota, and Phoenix, Arizona and treated with either A+C or A+G. Main outcome measurements were 1 year mortality, nephrotoxicity, and EFIE relapse rates. RESULTS: Eighty-five cases of EFIE were included in this investigation. The majority (n=67, 79%) of patients received A+G while 18 (21%) patients received A+C as initial treatment. On admission, patients who received A+C had a higher Charlson Comorbidity Index (median [IQR], 4 [3, 4 vs. 2 [1, 4]; P=.008) and a higher baseline serum creatinine (median [IQR], 1.2 [0.9, 1.6] vs. 0.9 [0.8, 1.2] mg/dL, P=.020). The 1 year mortality rates were similar for both treatment groups, 17% vs. 17%, P=.982. Each group had 1 case of relapsing EFIE. Patients who received A+G had worse kidney function outcome demonstrated by a greater increase in serum creatinine at end of therapy (median [IQR] difference, +0.4 [0.2, 0.8] vs. -0.2 [-0.3, 0.1] mg/dL, P<=.001). CONCLUSION: A+C appears to be a safe and efficacious regimen in the treatment of EFIE. Patients treated with A+C had lower rates of nephrotoxicity and no differences in relapse rate and 1-year mortality as compared to that of the A+G group. PMID- 29969598 TI - The dynamics of integration, viral suppression and cell-cell transmission in the development of occult Hepatitis B virus infection. AB - BACKGROUND: Out of several phases of HBV infection, the least understood phase is occult hepatitis B virus infection. The paucity of data due to non-availability of biological tissues and the prerequisite of ultra-sensitive assays for the detection of occult hepatitis B virus infection prompted us to utilize mathematical modeling in determining mechanisms that lead to occult hepatitis B virus infection and characteristics of HBV infection during occult hepatitis B virus infection. METHODS: We proposed two mathematical models (M1 and M2), considering two different phenomenon for episomal maintenance and accumulation of covalently closed circular DNA (cccDNA) in infected hepatocytes: (i) M1 - recirculation of the relaxed circular DNA/double-stranded linear DNA from cytoplasm to the nucleus, and (ii) M2 - reinfection of infected hepatocytes with virions. We further incorporated the dynamics of integrated Hepatitis B virus DNA (iHBV) to investigate its role in the development of occult hepatitis B virus infection. RESULTS: The analysis showed that the main mechanism for the spread of infection during occult hepatitis B virus infection is cell-to-cell transmission and not cell-free virus transmission. A significant viral suppression (of at least 99% from its peak production values) was essential but not sufficient in the development of occult hepatitis B virus infection under M1; however under M2, the viral suppression was neither sufficient nor essential as the inhibition of the production of HBsAg without viral suppression can also explain the development of occult hepatitis B virus infection. Our analysis also revealed that occult hepatitis B virus infection seropositive cases are more likely to progress into liver cirrhosis compared to occult hepatitis B virus infection seronegative cases. The iHBV was found to be mostly silent (by either being absent or non-productive for HBsAg) during occult hepatitis B virus infection. CONCLUSION: The viral suppression is neither essential nor sufficient to explain the development of occult hepatitis B virus infection on its own. Not only the viral suppression but the inhibition -of the production and the export of HBsAg from cccDNA and iHBV also plays an important role in the development of occult hepatitis B virus infection. This is the first study, which incorporates the dynamics of iHBV and shows that HBV primarily spreads via cell-cell transmission during occult hepatitis B virus infection. PMID- 29969599 TI - Propagation of regulatory fluctuations induces coordinated switching of flagellar motors in chemotaxis signaling pathway of single bacteria. AB - The random motion of E. coli is driven by multiple flagella motors. When all motors rotate in the counter clockwise direction, the bacteria swims smoothly. A recent experimental report by Terasawa et al. [Biophys J,100,2193,(2011)] demonstrated that a coordination of the motors can occur through signaling pathways, and perturbation of a regulatory molecule disrupted the coordination. Here, we develop a mathematical model to show that a large temporal fluctuation in the regulator concentration can induce a correlated switching of the multiple motors. Such a large fluctuation is generated by a chemotaxis receptor cluster in unilateral cell pole, which then exhibits a spatial propagation through the cytoplasm from the receptor position to the motor around cell periphery. Our numerical simulation successfully reproduces synchronized switching and the lag time in the motions of two distant motors, which has been observed experimentally. We further show that the large fluctuation in the regulator concentration at the motor positions can expand the dynamic range that the motor can respond, which confers robustness to the signaling system. PMID- 29969600 TI - Murine genetic variance in muscarinic cholinergic receptor antagonism of acquisition and expression of sucrose-conditioned flavor preferences in three inbred mouse strains. AB - Conditioned flavor preferences (CFP) are elicited by sucrose relative to saccharin in inbred mice with both the robustness of the preferences and sensitivity to pharmacological receptor antagonists sensitive to genetic variance. Dopamine, opioid and N-methyl-d-aspartate receptor antagonists differentially interfere with the acquisition (learning) and expression (maintenance) of sucrose-CFP in BALB/c and SWR inbred mice. Further, the muscarinic cholinergic receptor antagonist, scopolamine (SCOP) more potently reduces both sucrose and saccharin intake in BALB/c and C57BL/6 relative to SWR inbred mice. The present study examined whether SCOP altered the expression and acquisition of sucrose-CFP in BALB/c, C57BL/6 and SWR mice. In expression experiments, food-restricted mice alternately consumed a flavored (CS+, e.g., cherry, 5 sessions) 16% sucrose solution and a differently-flavored (CS-, e.g., grape, 5 sessions) 0.05% saccharin solution. Two-bottle CS choice tests with the two flavors mixed in 0.2% saccharin solutions occurred following vehicle or SCOP at doses of 1 or 5 mg/kg. SCOP significantly reduced the magnitude of the expression of sucrose-CFP in BALB/c, but not either C57BL/6 or SWR mice. In acquisition experiments, separate groups of BALB/c, C57BL/6 and SWR mice were treated prior to acquisition training sessions with vehicle or 2.5 or 5 mg/kg SCOP doses that was followed by six two-bottle CS choice tests without injections. SCOP dose-dependently reduced (1 mg/kg) and eliminated (2.5 mg/kg) the acquisition of sucrose-CFP in BALB/c mice, and reduced the magnitude of acquisition of sucrose-CFP in SWR mice. In contrast, neither SCOP dose affected the acquisition of sucrose-CFP in C57BL/6 mice. Thus, muscarinic cholinergic receptor signaling is essential for the learning of sucrose-CFP in BALB/c mice, to a lesser degree in SWR mice, but not in C57BL/6 mice. Murine genetic variance differentially modulates muscarinic cholinergic receptor control of sweet intake per se relative to learned conditioned flavor preferences of sweets. PMID- 29969601 TI - Analysis of drug resistance mutations in whole blood DNA from HIV-1 infected patients by single genome and ultradeep sequencing analysis. AB - In HIV-1 infected patients blood CD4+ T lymphocytes could be a valuable target to analyse drug resistance mutations (DRM) selected over the course of the infection. However, detection of viral resistance mutations in cellular DNA by standard genotype resistance techniques (SGRT) is suboptimal. Whole blood DNA (wbDNA) from 12 HIV-1 infected patients on ART was studied by Single Genome Sequencing (SGS) and 8 of them also by Ultradeep pyrosequencing (UDP). Results were compared with contemporary and historical DRM detected in plasma by SGRT during follow up. All the contemporary DRM detected in plasma from the viremic patients were detected by SGS and UDP (20 from 7 patients and 4 from 5 patients respectively). Out of the 67 historical DRM detected in plasma and no longer present at the time of testing, 38 (57%) were detected by SGS in 12 patients and 27 out of 46 (59%) by UDP in 8 patients. Additional DRM never reported in plasma by SGRT were detected by SGS (12 from 8 patients) and UDP (10 from 8 patients). Analysis of wbDNA from HIV-1 infected patients by SGS and UDP provides proof of concept of the value of blood DNA to investigate current and archived DRM in HIV 1 infected patients on ART. PMID- 29969602 TI - Temporal multivariate pattern analysis (tMVPA): A single trial approach exploring the temporal dynamics of the BOLD signal. AB - BACKGROUND: fMRI provides spatial resolution that is unmatched by non-invasive neuroimaging techniques. Its temporal dynamics however are typically neglected due to the sluggishness of the hemodynamic signal. NEW METHODS: We present temporal multivariate pattern analysis (tMVPA), a method for investigating the temporal evolution of neural representations in fMRI data, computed on single trial BOLD time-courses, leveraging both spatial and temporal components of the fMRI signal. We implemented an expanding sliding window approach that allows identifying the time-window of an effect. RESULTS: We demonstrate that tMVPA can successfully detect condition-specific multivariate modulations over time, in the absence of mean BOLD amplitude differences. Using Monte-Carlo simulations and synthetic data, we quantified family-wise error rate (FWER) and statistical power. Both at the group and single-subject levels, FWER was either at or significantly below 5%. We reached the desired power with 18 subjects and 12 trials for the group level, and with 14 trials in the single-subject scenario. COMPARISON WITH EXISTING METHODS: We compare the tMVPA statistical evaluation to that of a linear support vector machine (SVM). SVM outperformed tMVPA with large N and trial numbers. Conversely, tMVPA, leveraging on single trials analyses, outperformed SVM in low N and trials and in a single-subject scenario. CONCLUSION: Recent evidence suggesting that the BOLD signal carries finer-grained temporal information than previously thought, advocates the need for analytical tools, such as tMVPA, tailored to investigate BOLD temporal dynamics. The comparable performance between tMVPA and SVM, a powerful and reliable tool for fMRI, supports the validity of our technique. PMID- 29969603 TI - Taking the lead - how keratinocytes orchestrate skin T cell immunity. AB - The skin comprises a complex coordinated system of epithelial tissue cells and immune cells that ensure adequate immune reactions against trauma, toxins and pathogens, while maintaining tissue homeostasis. Keratinocytes form the outermost barrier of the skin, and sense changes in barrier integrity, intrusion of microbial components and stress molecules. Thus, they act as sentinels that continuously communicate the status of the organ to the cutaneous immune system. Upon damage the keratinocytes initiate a pro-inflammatory signaling cascade that leads to the activation of resident immune cells. Simultaneously, the tissue mediates and supports immune-suppressive functions to contain inflammation locally. After resolution of inflammation, the skin provides a niche for regulatory and effector memory T cells that can quickly respond to reoccurring antigens. In this review we discuss the central role of keratinocyte-derived signals in controlling cutaneous T cell immunity. PMID- 29969604 TI - TNF signalling via the TNF receptors mediates the effects of exercise on cognition-like behaviours. AB - BACKGROUND: Altered TNF levels are associated with cognitive impairment in depression, schizophrenia, bipolar disorder, and Alzheimer's disease (AD). Exercise improves cognition-like behaviours, reduces the expression of tumour necrosis factor alpha (TNF), and increases expression of the soluble TNF receptors soluble TNFR1 (sTNFR1) and sTNFR2. We suggest TNF and its receptors are involved in cognitive function and dysfunction, and investigate whether exercise mediates its effects on cognitive function via TNF and its receptors. METHODS: We utilised C57BL/6, TNF-/-, TNFR1-/-, and TNFR2-/- mice to compare exercise to non exercise control groups to investigate whether exercise exerts its effects on various types of cognition-like behaviours via TNF and its receptors. RESULTS: Recognition memory improved with exercise in WT mice, was impaired in TNFR1-/- exercise mice, showed non-significant impairment with exercise in TNF-/- mice, and no changes in TNFR2-/- mice. In spatial learning there were exercise related improvements in WT mice, non-significant but meaningful impairments evident in TNFR1-/- exercise mice, modest improvement in TNF-/- exercise mice, and potentially meaningful non-significant improvements in TNFR2-/- exercise mice. Moreover, WT and TNFR2-/- mice displayed noteworthy non-significant improvements in spatial memory, whereas TNFR1-/- exercise mice demonstrated non-significant spatial memory impairment. Exercise did not alter cognitive flexibility in any strain. DISCUSSION: TNF receptor signalling via the TNFR1 and TNFR2 appears to mediate the effects of exercise on cognitive-like behaviours. The potential for exercise to regulate human TNF and TNF signalling and cognitive dysfunction needs investigation under inflammatory conditions including depression and neuropsychiatric disorders. PMID- 29969605 TI - The contribution of contextual fear in the anxiolytic effect of chlordiazepoxide in the fear-potentiated startle test. AB - This study evaluated the extent to which a reduction in contextual fear contributes to the anxiolytic effect of benzodiazepines in the fear-potentiated startle response. To this end, chlordiazepoxide, an anxiolytic often used as positive control in preclinical drug studies, and zolpidem, known to have sedative properties and to be devoid of anxiolytic effects, were tested in two contexts: the same context as training had taken place and an alternative context. In addition, the level of muscle relaxation was assessed in a grip strength test. Chlordiazepoxide (2.5-10 mg/kg) decreased the fear-potentiated startle response, confirming its anxiolytic activity. In addition, it dose dependently decreased the overall startle response in the same, but not the alternative context, and did not affect grip strength, indicating that chlordiazepoxide inhibits contextual fear in the absence of non-specific drug effects. Zolpidem (1.0-10 mg/kg) reduced the overall startle response in both contexts equally and decreased grip strength, indicating that its effects on fear potentiated startle are due to non-specific drug effects, and not anxiolytic effects. The present findings show that chlordiazepoxide reduces contextual conditioned fear in the absence of non-specific drug effects. In addition, they show that training and testing rats in different contexts makes it possible to distinguish between cued, contextual and non-specific drug effects. As exaggerated contextual fear conditioning contributes to the fear generalization processes implicated in pathological anxiety, focus in screening of anxiolytic effects could be directed more towards the suppression of contextual fear and, therefore, this approach would be a valuable addition to standard preclinical screening. PMID- 29969606 TI - PD-L1 expression in tumor cells and the immunologic milieu of bladder carcinomas: a pathologic review of 165 cases. AB - Programmed death ligand 1 (PD-L1) is a transmembrane protein that plays a major role in immune suppression. Its interaction with the receptor PD-1 results in downregulation of antitumoral immunity. Humanized monoclonal antibodies that interrupt the PD-L1/PD-1 interaction have shown therapeutic efficacy in patients with advanced urothelial cancer. However, immunohistochemical staining of PD-L1 in bladder tumors and its relationship to tumor histologic type, grade, and overall survival has been incompletely analyzed. Slides from 165 cystectomy specimens were reviewed for tumor type, grade of urothelial carcinoma, pathologic stage, and overall survival. A tissue microarray (TMA) using four 0.6 mm cores from each case was constructed. Immunohistochemistry was performed on the TMA using a variety of new PD-L1 antibodies and platforms now widely available. For each case, the percent of tumor cells positive for PD-L1 and the percent of positive immune cells were scored. The overall number of bladder cancers positive for PD-L1 depended on the antibody/platform combination used and the threshold for considering a tumor "PD-L1-positive." Squamous cell carcinomas (SCCs) of the bladder demonstrated PD-L1 positivity more frequently than urothelial cell carcinomas (UCCs). High-grade UCCs were positive for PD-L1 on tumor cells more frequently than low-grade UCCs. There was no difference in survival between PD-L1 positive and PD-L1-negative bladder cancers in our study. Further studies should consider examining the predictive significance of PD-L1 IHC in bladder cancers. PMID- 29969607 TI - Benign TdT-positive cells in pediatric and adult lymph nodes: a potential diagnostic pitfall. AB - Benign terminal deoxynucleotidyl transferase (TdT)-positive cells have been documented in a variety of nonhematopoietic tissues. Scant data are, however, available on their presence in nonneoplastic lymph nodes. This study is aimed to (1) characterize the presence/distribution of benign TdT-positive cells in pediatric and adult reactive lymph nodes and (2) define the phenotype and nature of such elements. This retrospective study considered 141 reactive lymph nodes from pediatric and adult patients without history of neoplastic disease. TdT positive cells were characterized by immunohistochemical and morphometric analyses, and their presence was correlated with the clinical-pathological features. The nature of TdT-positive cells was investigated by (1) double immunostaining for early lymphoid cell markers and (2) assessment of TdT expression in fetal lymph nodes. Sparse TdT-positive cells were documented in all pediatric cases and in most (76%) adult lymph nodes. TdT-positive cell density was higher in children than adults (15.9/mm2 versus 8.6/mm2; P < .05). TdT positivity did not correlate with any clinical or histological parameter, and double immunostaining disclosed a phenotype compatible with early lymphoid precursors (positivity for CD34 and CD10, and variable expression of CD7). A very high TdT-positive cell density (802.4/mm2) was reported in all fetal lymph nodes. In conclusion, TdT-positive cells are a common finding in pediatric and adult lymph nodes. The interstitial distribution and low number of such cells allow for the differential diagnosis with precursor lymphoid neoplasms. The high density in fetal lymph nodes and the phenotype of such cells suggest their belonging to an immature lymphoid subset gradually decreasing with age. PMID- 29969608 TI - Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting endothelial-to-mesenchymal transition. AB - AIMS: Endothelial-to-mesenchymal transition (EndoMT) was shown to lead to endothelial cell (EC) dysfunction in pulmonary arterial hypertension (PAH). Baicalein was reported to inhibit epithelial-to-mesenchymal transition (EMT), a biological process that has many regulatory pathways in common with EndoMT. Whether it can attenuate PAH by inhibiting EndoMT remains obscure. MAIN METHODS: PAH was induced by a single subcutaneous injection of MCT (60 mg/kg) in male Sprague Dawley rats. Two weeks after MCT administration, the rats in the treatment groups received baicalein orally (50 or 100 mg/kg/day) for an additional 2 weeks. Hemodynamic changes and right ventricular hypertrophy (RVH) were evaluated on day 28. Cardiopulmonary interstitial fibrosis was detected using Masson's trichrome, Picrosirius-red, and immunohistochemical staining. The reactivity of pulmonary arteries (PAs) was examined ex vivo. The protein expresson of EndoMT molecules, bone morphogenetic protein receptor 2 (BMPR2), and nuclear factor-kappaB (NF-kappaB) was examined to explore the mechanism of protective action of baicalein. KEY FINDINGS: Baicalein (50 and 100 mg/kg) significantly alleviated MCT-induced PAH and cardiopulmonary interstitial fibrosis. Furthermore, baicalein treatment enhanced PA responsiveness to acetylcholine (ACh) in PAH rats. The upregulation of EndoMT molecules (N cadherin, vimentin, Snail, and Slug) strongly suggest that EndoMT participates in MCT-induced PAH, which was reversed by baicalein (50 and 100 mg/kg) treatment. Moreover, baicalein partially reversed MCT-induced reductions in BMPR2 and NF kappaB activation in the PAs. SIGNIFICANCE: Baicalein attenuated MCT-induced PAH in rats by inhibiting EndoMT partially via the NF-kappaB-BMPR2 pathway. Thus, baicalein might be considered as a promising treatment option for PAH. PMID- 29969609 TI - Wnt signaling in bone metastasis: mechanisms and therapeutic opportunities. AB - Bone metastasis frequently occurs in advanced cancer patients, who will develop osteogenic/osteolytic bone lesions in the late stage of the disease. Wnt signaling pathway, which is mainly grouped into the beta-catenin dependent pathway and beta-catenin independent pathway, is a well-organized cascade that has been reported to play important roles in a variety of physiological and pathological conditions, including bone metastasis. Regulation of Wnt signaling in bone metastasis involves multiple stages, including dissemination of primary tumor cells to bone, dormancy and outgrowth of metastatic tumor cells, and tumor induced osteogenic and osteolytic bone destruction, suggesting the importance of Wnt signaling in bone metastasis pathology. In this review, we will introduce the involvement of Wnt signaling components in specific bone metastasis stages and summarize the promising Wnt modulators that have shown potential as bone metastasis therapeutics, in the hope to maximize the therapeutic opportunities of Wnt signaling for bone metastasis. PMID- 29969610 TI - The Physician's Prayer. PMID- 29969611 TI - Modern Trends in Dental Medicine: An Update for Internists. AB - Traumatic injuries, genetic diseases, and external harmful agents such as bacteria and acids often compromise tooth integrity. There is an unmet medical need to develop alternative, innovative dental treatments that complement traditional restorative and surgery techniques. Stem cells have transformed the medical field in recent years. The combination of stem cells with bioactive scaffolds and nanostructured materials turns out to be increasingly beneficial in regenerative dental medicine. Stem cell-based regenerative approaches for the formation of dental tissues will significantly improve treatments and will have a major impact in dental practice. To date there is no established and reliable stem cell-based treatment translated into the dental clinics, however, the advances and improved technological knowledge are promising for successful dental therapies in the near future. Here, we review some of the contemporary challenges in dental medicine and describe the benefits and future possibilities of certain novel approaches in the emerging field of regenerative dentistry. PMID- 29969612 TI - Development and Resolution of Cutaneous Lesions Caused by Black Fly Bites (Diptera: Simuliidae). PMID- 29969613 TI - When Guidelines Cause Hypertension. PMID- 29969614 TI - Associations of Multidomain Lifestyle Intervention with Frailty: Secondary Analysis of a Randomized Controlled Trial. AB - BACKGROUND: The objective of this study was to investigate whether a long-term multidomain lifestyle intervention was associated with the severity and incidence of frailty in older adults. METHODS: A 3-year randomized controlled trial was conducted among 1637 French community dwellers age >=70: 821 controls and 816 who received a multidomain lifestyle intervention (cognitive training, nutrition counseling, and advice on physical activity). The intervention involved 12 2-hour sessions (in the first 2 months) followed by a 1-hour session each month until the study end. Controls received the usual care but did not receive any personalized lifestyle intervention. A frailty index (FI; range = 0-1, higher is worse) composed of 32 items was calculated at baseline, 6 months, 1 year, 2 years, and 3 years and constituted our main endpoint. FI >= 0.25 defined frailty. The 4 outcomes were severity of frailty (continuous FI score), incident frailty, incidence of persistent frailty (frailty at 2 consecutive time points), and reversibility of frailty (from frailty to nonfrailty). RESULTS: Mixed-effect linear regression did not find a significant effect of the multidomain intervention on FI score. Frailty incidence occurred in 241 of 1146 subjects (138 controls and 103 in the multidomain group), whereas incidence of persistent frailty occurred in 75 of 1042 subjects (48 controls and 27 in the multidomain group). Cox models adjusted for baseline FI scores showed that compared with controls, subjects in the multidomain group had a decreased risk of developing both frailty (hazard ratio 0.72; 95% confidence interval, 0.55-0.93) and persistent frailty (hazard ratio 0.53; 95% confidence interval, 0.33-0.85). CONCLUSIONS: This multidomain lifestyle intervention was associated with a reduced risk of developing frailty but did not affect the severity of frailty in community-dwelling older adults. PMID- 29969615 TI - Treatment of Syphilis-Associated Cerebral Vasculitis: Reappearance of an Old Question. AB - BACKGROUND: Cerebral vasculitis caused by neurosyphilis is a re-emerging problem with diagnostic and treatment issues, especially for human immunodeficiency virus patients. METHODS: We present a case of relapsing syphilis-associated cerebral vasculitis, despite the recommended first-line antibiotic treatment, that was successfully treated with a second intravenous penicillin G course and corticosteroids. RESULTS: A 50-year old man went to the emergency department for bilateral episodes of red and painful eyes with progressive but severe visual acuity loss. He was diagnosed with bilateral panuveitis and neurosyphilis favored by an unknown human immunodeficiency virus infection with a CD4 count of 236 mm3. Despite appropriate and well-conducted treatment including intravenous penicillin G, short-term corticosteroid, and highly active antiretroviral therapy, a symptomatic relapse of the syphilis-associated cerebral vasculitis occurred. After a second course of penicillin and corticosteroids, he made a complete recovery. CONCLUSIONS: Neurosyphilis and human immunodeficiency virus co infection is a reappearing challenging situation that should be considered with care by physicians because recommended antibiotic treatment sometimes fails. Corticosteroid therapy should be discussed in case of cerebral vasculitis. PMID- 29969616 TI - New Injectable Agents for the Treatment of Type 2 Diabetes Part 2-Glucagon-Like Peptide-1 (GLP-1) Agonists. AB - The US Food and Drug Administration has recently approved several new glucagon like peptide-1 (GLP-1) agonists alone and in combination with various insulin products. The second of 2 articles in a series, this review will describe the potential advantages and disadvantages of the GLP-1 agonist class of products. PMID- 29969617 TI - Tetralogy of Fallot Repair in Developing Countries: International Quality Improvement Collaborative. AB - BACKGROUND: Isolated reports from low- and middle-income countries (LMICs) for surgical results in tetralogy of Fallot (TOF) are available. The International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) seeks to improve surgical results promoting reductions in infection and mortality in LMICs. METHODS: All cases of TOF in the IQIC database performed between 2010 and 2014 at 32 centers in 20 LMICs were included. Excluded from the analysis were TOF with any associated lesions. A logistic regression analysis was performed to identify risk factors for in-hospital mortality after surgery for TOF. RESULTS: A total of 2,164 patients were identified. There were 1,839 initial primary repairs, 200 with initial systemic-to-pulmonary artery shunt, and 125 underwent secondary repair after initial palliation. Overall mortality was 3.6% (78 of 2,164), initial primary repair was 3.3% (60 of 1,839), initial systemic-to pulmonary artery shunt was 8.0% (16 of 200), and secondary repair was 1.6% (2 of 125; p = 0.003). Major infections occurred in 5.9% (128 of 2,164) of the entire cohort. Risk factors for death after the initial primary repair were oxygen saturation less than 90% and weight/body mass index for age below the fifth percentile (p < 0.001). The initial primary repair occurred after age 1 year in 54% (991 of 1,839). Older age at initial primary repair was not a risk factor for death (p = 0.21). CONCLUSIONS: TOF patients are often operated on after age 1 year in LMICs. Unlike in developed countries, older age is not a risk factor for death. Nutritional and hypoxemic status were associated with higher mortality and infection. This information fills a critical knowledge gap for surgery in LMIC. PMID- 29969618 TI - Reply. PMID- 29969619 TI - Invited Commentary. PMID- 29969620 TI - Perioperative Risk Profiles and Volume-Outcome Relationships in Proximal Thoracic Aortic Surgery. AB - BACKGROUND: Using the national Society of Thoracic Surgeons Adult Cardiac Surgery Database data for thoracic aortic surgical procedures for aortic aneurysm, this study aimed to (1) characterize patients' risk profiles and outcomes, (2) evaluate center volume-outcome relationships across US centers, and (3) identify risk factors for operative mortality. METHODS: Between 2011 and 2016, 53,559 operations for ascending aortic aneurysm performed across 1,045 centers in the United States were identified. Logistic regression related baseline characteristics and comorbidities to operative mortality. Ten-fold cross validation was performed to estimate sensitivity and specificity across a range of the discrimination threshold. Centers were stratified into five strata by average annual case volume. Predicted probability of operative mortality was calculated from the model and was used to evaluate patients' risk profiles across the volume strata. RESULTS: Operative mortality occurred in 3.2% of all cases and in 2.2% of elective cases. Only 24 (2.3%) centers performed >=50 cases annually, whereas 609 (58.3%) centers performed fewer than five cases annually. Multiple logistic regression, of which the c-index was 0.80, revealed that compared with centers with >=50 cases, centers with fewer than five cases had an increased risk of mortality (odds ratio, 2.50; 95% confidence interval, 2.08 to 3.01; p < 0.0001). The predicted probability of operative mortality was similar across the volume strata, but the observed mortality rate varied significantly, with lower volume yielding higher operative mortality. CONCLUSIONS: Proximal thoracic aortic surgical procedures for aortic aneurysms in the United States are associated with a low operative mortality rate of 2.2% for elective cases. Risk of operative death decreases significantly at an annual center volume of more than 20 to 25 cases per year. PMID- 29969622 TI - Software updates of Tosoh HPLC analyzers can cause and resolve interference of Hb variants for HbA1c. PMID- 29969621 TI - Triglyceride to high density lipoprotein cholesterol ratio may serve as a useful predictor of major adverse coronary event in female revascularized ST-elevation myocardial infarction. AB - BACKGROUND: Elevated triglyceride to high density lipoprotein cholesterol (TG/HDL C) ratio has been identified as a surrogate marker of insulin resistance and an independent predictor for cardiovascular events in the general population. However, the prognostic value of TG/HDL-C ratio in revascularized ST-elevation myocardial infarction(STEMI) patients remains unclear. We examined the association between TG/HDL-C ratio and clinical outcome of revascularized STEMI patients in the Chinese population. METHODS: 464 STEMI patients who underwent successful revascularization were enrolled to determine the relationship between TG/HDL-C ratio and major adverse coronary events(MACEs) with a 30-month follow up. The Kaplan-Meier analysis and Cox regression proportional hazard model were applied to assess the prognostic value of TG/HDL-C ratio. RESULTS: TG/HDL-C ratio was found to be significantly associated with age (p = 0.017), history of diabetes(p = 0.017), heart rate(p = 0.011), TG(p < 0.001), HDL-C(p < 0.001) and Gensini score(p = 0.034). The multivariate Cox regression analysis revealed that elevated TG/HDL-C ratio was an independent prognostic factor for MACE in female patients (HR = 2.624,95%CI = 1.211-5.687,p = 0.014) but not in male patients(HR = 0.756, 95%CI = 0.484-1.179,p = NS) after adjustment with other MACE-related prognostic factors. CONCLUSION: The TG/HDL-C ratio may be independently associated with MACEs in female revascularized STEMI patients in the Chinese population. PMID- 29969623 TI - Clinical and prognostic significance of glomerular C1q deposits in primary MN. AB - BACKGROUND: Although complement activation is believed to be important in mediating PMN, the pathways involved and clinical consequences remain controversial. Many cases of idiopathic or primary membranous nephropathy (PMN) present with subepithelial C1q deposits along with IgG and C3 on glomerular capillary walls but without deposits of IgA or IgM ("full house") by immunofluorescence or any causes of secondary MN. We sought to define the clinical and pathological significance of these C1q deposits in PMN by comparing a variety of clinical parameters, outcomes and other serum and urine factors in patients with and without significant glomerular C1q deposits. METHODS: Two hundred eighty-eight patients with biopsy-proven PMN were enrolled. We compared the clinical and pathological features, treatment responses and kidney outcomes, between patients with and without C1q deposition. Circulating anti-PLA2R antibodies and complement components in plasma and urine were detected by ELISA. RESULTS: Glomerular C1q deposition was detected on capillary walls by immunofluorescence in 66/288 (22.9%) patients. C1q-positive patients presented with lower concentrations of serum IgG (5.3 +/- 3.1 vs. 6.6 +/- 3.5 g/l, p = 0.008), a higher frequency of IgA (37.9% vs. 15.8%, p < 0.001), IgM (48.5% vs. 31.5%, p = 0.011) and C3c (100% vs. 88.3%, p = 0.004) deposits in glomeruli and more stage III of MN (24.2% vs. 11.7%, p < 0.001) by pathologic criteria. Other features, including gender, age, anti-PLA2R antibody positivity and concentrations, proteinuria, albumin and serum creatinine, were not different between the patients with and without C1q deposition (p > 0.05). The IgG subclasses of anti-PLA2R antibodies in circulation or in glomeruli showed no difference (p > 0.05). C1q deposition, and C1q concentrations in circulation and urine had no apparent effect on the treatment responses or kidney outcomes (p > 0.05). CONCLUSION: The classical pathway of complement is activated in some patients with PMN, but may not play an essential role in mediating the kidney injury seen in this disease. PMID- 29969624 TI - Whole genome sequencing identifies a de novo 2.1 Mb balanced paracentric inversion disrupting FOXP1 and leading to severe intellectual disability. AB - The FOXP1 gene, located on chromosome 3p13, encodes the Forkhead-box protein P1, one of the four forkhead transcription factors which repress transcription by forming active homo- and heterodimers and regulate distinct patterns of gene expression crucial for embryogenesis and normal development. FOXP1 mutations, mostly truncating, have been described in patients with mild to moderate intellectual disability (ID), autism spectrum disorder (ASD), and speech and language impairment (MIM #613670). Here, we report a small de novo heterozygous balanced inversion of 2.1 Mb located at 3p14.1p13 identified by Whole Genomic Sequencing (WGS) and disrupting the genes FAM19A4 and FOXP1. This inversion was found in a patient with severe ID, ASD, seizures and very unusual vascular anomalies which were never described in the clinical spectrum of FOXP1 mutations. We show that the neurodevelopmental phenotype observed in the patient most likely results from FOXP1 haploinsufficiency as this heterozygous inversion leads to a 60 to 85% decrease of FOXP1 mRNA levels and to the complete absence of FOXP1 full length protein. These findings, in addition to expanding the molecular spectrum of FOXP1 mutations, emphasize the emerging role of WGS in identifying small balanced chromosomal rearrangements responsible for neurodevelopmental disorders and not detected by conventional cytogenetics. PMID- 29969625 TI - Serum bikunin is a biomarker of linkeropathies. PMID- 29969626 TI - Gastrodin pretreatment alleviates myocardial ischemia/reperfusion injury through promoting autophagic flux. AB - Gastrodin (GAS), a monomeric component exacted from the herb Gastrodia elata Bl, may have cardioprotective effects during injury caused by myocardial ischemia/reperfusion (I/R). For the significant role of autophagy in I/R process, we targeted to explore whether autophagy was contributing to the GAS-induced protective effects during I/R procedure. Male C57BL/6 mice were subjected to reversible left coronary artery ligation and cultured neonatal rat cardiomyocytes (NRCs) exposed to hypoxia were preconditioned with GAS prior to ischemia or hypoxia, following reperfusion for 2 h or re-oxygennation for 3 h respectively. Our results demonstrated that GAS pretreatment increased autophagy and reduced apoptosis during I/R, this effect was weakened by co-treatment with the autophagic flux inhibitor chloroquine (Cq). Compared to mice subjected solely to I/R, GAS-pretreated mice had a notably smaller heart infarct size and an elevation in cardiac function. In GAS-pretreated NRCs, WB data showed that autophagy was promoted (expression of p62 was inhibited and LC3II was increased). In addition, tandem fluorescent mRFP-GFP-LC3 assays illustrated that autophagosomes were degraded duo to an increase in autophagic flux. Co administration of Cq blocked the autophagic flux. Furthermore, GAS pretreatment increased the mitochondrial membrane potential of NRCs with subjected to H/R and increased the cardiomyocyte survival rate. These protective effects were reversed with Cq. Besides, GAS-induced the enhaucement of autophagy may correlated with activating AMP-activated protein kinase (AMPK) phosphorylation and reduced Mammalian target of rapamycin (mTOR) phosphorylation, which was abrogated by Compound C (Com C, AMPK-specific inhibitor). Our results establish that GAS pretreatment attenuates myocardial I/R injury by increasing autophagic flux aimed at eliminating dysfunctional mitochondria, therefore protecting neighbouring mitochondria and cardiomyocytes. PMID- 29969627 TI - The miR-31-SOX10 axis regulates tumor growth and chemotherapy resistance of melanoma via PI3K/AKT pathway. AB - MicroRNAs were thought to play a regulatory role through complementarity to target messenger RNA (mRNA). Our previous study revealed a miR-31-SOX10 axis that regulated tumor growth and resistance to chemotherapy of melanoma. Up-regulation of SOX10 and down-regulation of miR-31 were found in melanoma tissues. SOX10 was further identified as a target of miR-31. Overexpression of SOX10 dramatically promoted melanoma cell proliferation and chemotherapy resistance both in vitro and in vivo. While enforced miR-31 expression suppressed cell growth and enhanced the chemosensitivity of melanoma cells, the re-expression of SOX10 rescued these effects by activating PI3K/AKT signaling pathway. In conclusion, our results demonstrated that SOX10 acted as an oncogene and was negatively regulated by miR 31, which supports the potential therapeutic strategy against melanoma by targeting the miR-31-SOX10 axis. PMID- 29969628 TI - MicroRNA-124-3p represses cell growth and cell motility by targeting EphA2 in glioma. AB - MiR-124-3p and EphA2 are aberrantly expressed in glioma tissue specimens. In the present study, we firstly investigated that miR-124-3p inhibits EphA2 expression mediated by binding its 3'-UTR to regulate the progression of human glioma. The U87MG and LN229 cells were transfected with miR-124-3p mimics and/or siRNA-EphA2, and then the role of miR-124-3p and EphA2 in the colony-formation, cell-cycle, migration and invasion of glioma cells in vitro were examined. Proteins involved in the epithelial-mesenchymal transition were examined using western blot. The results showed that miR-124-3p was significantly downregulated in glioma tissues, whereas a marked upregulation of EphA2 expression was found. Colony-formation and flow cytometry assays demonstrated that EphA2 downregulation or miR-124-3p mimics caused growth and cell-cycle inhibition in glioma. Transwell migration and invasion assays demonstrated that EphA2 downregulation or miR-124-3p mimics suppressed the migration and invasion of glioma cells. EphA2 downregulation or miR-124-3p mimics reduced the level of vimentin in U87MG and LN229 cells. In conclusion, miR-124-3p was found to suppress the growth, migration and invasion of glioma cells in vitro via EphA2. Furthermore, we validated miR-124-3p enforced its biological modulation via targeting EphA2 through the rescue experiment. Conclusively, our study proclaimed that miR-124-3p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the EphA2. PMID- 29969629 TI - Mouse models of cancer-induced cachexia: Hind limb muscle mass and evoked force as readouts. AB - The majority of patients with advanced cancer suffer from cachexia, a systemic wasting syndrome, which subsequently impacts the tolerance to anti-cancer treatments, response to therapy, quality of life, and eventually, survival. Despite a high unmet medical need, there is currently no specific remedy available for an effective treatment of cachexia and its sequelae. A key feature of cachexia is the inexorable loss of skeletal muscle mass, which constitutes a main contributor to body weight loss and progressive functional impairments. Therefore, it's crucial to identify early readouts to detect and monitor the loss of muscle mass and function to initiate appropriate treatments timely. Here, we describe experimental cancer models using mouse (syngeneic) or human (xenograft) cancer cell lines with a rapid onset of tumor growth and cachexia. These models are easier to establish, monitor and reproduce compared to the genetically engineered mouse models currently available. Moreover, we establish readouts such as hind limb muscle mass and volume, as well as evoked force and food intake measurements, to allow the evaluation of potential therapeutic agents for the early treatment of cachexia and associated impairments. PMID- 29969630 TI - miR-410-3p promotes prostate cancer progression via regulating PTEN/AKT/mTOR signaling pathway. AB - Prostate cancer has become one of commonest urologic tumors in male. In recent years, miRNAs are continually attracting attentions of researchers for their special regulatory function in human cancers. Previous study has revealed that miR-410 acts as a biomarker for the diagnosis of prostate cancer. Whereas, the specific biological function of miR-410-3p in prostate cancer remains unknown. The aim of this study is to explore the function and molecular mechanism of miR 410-3p in prostate cancer. The high expression of miR-410-3p was examined in prostate cancer tissues and cell lines by qRT-PCR. Next, the prognostic value was identified by Kaplan Meier method. High expression of miR-410-3p indicated poor prognosis of prostate cancer patients. To investigate the biological function of miR-410-3p in prostate cancer, loss-of function assays were designed and performed in two prostate cancer cell lines (PC3 and DU145). As a result, downregulated miR-410-3p suppressed cell proliferation, migration and EMT progress. Moreover, flow cytometry analysis was performed to determine that the acceleration effects of miR-410-3p on cell apoptosis. Mechanistically, further analysis demonstrated that the effects of miR-410-3p exert oncogenic functions through downregulating PTEN. All findings in this study revealed that miR-410-3p inhibits prostate cancer progression via downregulating PTEN/AKT/mTOR signaling pathway. PMID- 29969631 TI - CircRNA circ-BANP-mediated miR-503/LARP1 signaling contributes to lung cancer progression. AB - Recently, circular RNAs (circRNAs) attract much attention due to their potential vital functions in multiple human diseases, including cancer. circ-BANP has been reported to modulate colorectal cancer growth. Nevertheless, the relationship between circ-BANP and lung cancer requires to be investigated. In this study, we found circ-BANP was overexpressed in lung cancer tissues. Higher circ-BANP expression was associated with lower survival rate. Moreover, silencing circ-BANP markedly inhibited proliferation, migration and invasion of lung cancer cells in vitro and impaired tumor propagation in vivo. In mechanism, circ-BANP was identified as the sponge of miR-503 while miR-503 targets LARP1. Circ-BANP induced inhibition of miR-503 led to increased expression of LARP1 in lung cancer. Finally, rescue assays indicated that LARP1 restoration partially reversed the effects of circ-BANP knockdown in lung cancer. In sum, our study illustrated that circ-BANP-mediated miR-503/LARP1 signaling promoted lung cancer growth, migration and invasion, providing a novel insight on the mechanism underlying lung cancer progression. PMID- 29969632 TI - Faecal microRNA as a biomarker of the activity and prognosis of inflammatory bowel diseases. AB - Reasons underlying the individual differences in the clinical manifestations of inflammatory bowel diseases (IBD) and the mechanism by which the host screens the intestinal microbiota remain unclear. The presence of miRNA in faeces might be a potential clue into differences in gut microbiota among these patients. In this study, we analysed the differences in miRNA levels in faecal samples from 117 patients diagnosed with IBD. There was a significant difference in faecal miRNAs between healthy subjects and those with inactive IBD. Further analysis showed that some miRNAs might indicate the severity of IBD activity and prognosis. Sequencing analysis of the 16S RNA V4 region in faecal microbiota in these IBD patients revealed significant differences in the phylogenetic architecture between subjects with active or inactive IBD and between IBD patients and healthy subjects. Finally, in vitro studies showed that these differentially expressed miRNAs have different effects on the proliferative activity of the intestinal microorganisms Fusobacterium nucleatum (Fn), Escherichia coli (E. coli) and segmental filamentous bacteria (SFB). We observed the dynamic uptake of miRNA by these bacteria using flow cytometry. This study reveals a potential link between faecal miRNA, intestinal microbiota, IBD activity and prognosis. PMID- 29969633 TI - Evaluation of food allergy candidate loci in the Genetics of Food Allergy study. PMID- 29969634 TI - Genetic variants with gene regulatory effects are associated with diisocyanate induced asthma. AB - BACKGROUND: Isocyanates are major causes of occupational asthma, but susceptibility and mechanisms of diisocyanate-induced asthma (DA) remain uncertain. OBJECTIVE: The aim of this study was to identify DA-associated functional genetic variants through next-generation sequencing (NGS), bioinformatics, and functional assays. METHODS: NGS was performed in 91 workers with DA. Fourteen loci with known DA-associated single nucleotide polymorphisms (SNPs) were sequenced and compared with data from 238 unexposed subjects. Ranking of DA-associated SNPs based on their likelihood to affect gene regulatory mechanisms in the lung yielded 21 prioritized SNPs. Risk and nonrisk oligonucleotides were tested for binding of nuclear extracts from A549, BEAS-2B, and IMR-90 lung cell lines by using electrophoretic mobility shift assays. DNA constructs were cloned into a pGL3 promoter vector for luciferase gene reporter assays. RESULTS: NGS detected 130 risk variants associated with DA (3.1 * 10-6 to 6.21 * 10-4), 129 of which were located in noncoding regions. The 21 SNPs prioritized by using functional genomic data sets were in or proximal to 5 genes: cadherin 17 (CDH17; n = 10), activating transcription factor 3 (ATF3; n = 7), family with sequence similarity, member A (FAM71A; n = 2), tachykinin receptor 1 (TACR1; n = 1), and zinc finger and BTB domain-containing protein 16 (ZBTB16; n = 1). Electrophoretic mobility shift assays detected allele-dependent nuclear protein binding in A549 cells for 8 of 21 variants. In the luciferase assay 4 of the 21 SNPs exhibited allele-dependent changes in gene expression. DNA affinity precipitation and mass spectroscopy of rs147978008 revealed allele-dependent binding of H1 histones, which was confirmed by using Western blotting. CONCLUSIONS: We identified 5 DA-associated potential regulatory SNPs. Four variants exhibited effects on gene regulation (ATF rs11571537, CDH17 rs2446824 and rs2513789, and TACR1 rs2287231). A fifth variant (FAM71A rs147978008) showed nonrisk allele preferential binding to H1 histones. These results demonstrate that many DA-associated genetic variants likely act by modulating gene regulation. PMID- 29969635 TI - Modulation of probe-genomic DNA interaction within the confined interior of a reverse micelle: Is the bulk-like properties of water truly achieved in large reverse micelles? AB - The prime motivation of the present study is to explore the effect of reverse micellar confinement on the binding interaction of an anthracene-based probe 9 methyl anthroate with herring-sperm DNA. The structural modification of the genomic DNA from its native B-form to the non-native C-form and subsequently to the condensed Psi-form as a function of the level of hydration (W0, defined as [water] / [surfactant]) of the reverse micellar core is found to reveal a remarkable regulatory role on the stability of the stacking interaction (intercalation) of the probe within the DNA helix; the interaction being progressively stabilized at higher W0. Particularly, a close perusal of the dynamical aspects of the interaction is found to be counter-intuitive to the popular notion of the properties of the confined water within the reverse micelles typically approaching bulk-like properties at sufficiently high hydration levels (W0 > 10). PMID- 29969636 TI - Inhibition of advanced glycation end products by isoferulic acid and its free radical scavenging capacity: An in vitro and molecular docking study. AB - Non-enzymatic glycation and Oxidation of some essential biological macromolecules are paramount in the pathogenesis of various diseases including diabetes and atherosclerosis. Hyperglycemia plays a key role in the pathological process of diabetic complications by progressive accumulation of advanced glycation end products (AGEs) in body tissues. Formation of AGEs as a result of protein glycation is followed by an increased free radical activity that additionally contributes towards the bio-macromolecular damage. The present study aimed to evaluate the free radical scavenging and antiglycation capacity of isoferulic acid (IFA). The free radical scavenging activity of IFA was measured using DPPH, FRAP, and metal chelating assays. IFA showed effective reducing power, free radical scavenging activity and metal chelation activity in concentration dependent manner. The antiglycation activity of IFA was studied using various spectroscopic techniques. The obtained results were validated with free amino, sulfhydryl group, carbonyl content and AGEs formation. Secondary structural alterations were monitored using circular dichroism, morphology of aggregates was analyzed using transmission electron microscopy. Molecular docking reveals the possible binding location of IFA with in the sub-domain IIA of human serum albumin (HSA). PMID- 29969637 TI - Multifunctional modification of linen fabric using chitosan-based formulations. AB - Chitosan is a new-age functional biopolymer which can be utilized for functional finishing of cellulose-based textile materials. In the current work, linen fabric was modified using two-stage finishing using chitosan-citric acid and phytic acid thiourea thus imparting multiple performance characteristics such as wrinkle free, antibacterial, flame retardant and antioxidant properties. The multifunctional linen fabrics were characterized using FTIR, TGA, SEM and EDX analysis. The fabrics were evaluated for textile properties like tensile strength, bending length, yellowness index, absorbency and functional properties like crease recovery angle, antibacterial activity, UV protection, flame retardancy and antioxidant properties. The durability of functional properties was also evaluated. The finished linen fabric displayed efficient multifunctional properties which were retained to a moderate level till 20 washes. PMID- 29969638 TI - Protective effect of polysaccharide from Agaricus bisporus in Tibet area of China against tetrachloride-induced acute liver injury in mice. AB - In this study, we systematically investigated the physicochemical properties, hepatoprotective activities and the underlying mechanisms of Agaricus bisporus polysaccharide (FPS). The physicochemical evaluations indicate that FPS is mainly composed of glucose, mannose, galactose, fucose, arabinose and glucuronic acid with the mole percentages of 70.30%, 8.70%, 12.88%, 0.79%, 5.04% and 1.57%, respectively. The results of methylation analysis indicated that FPS mainly included 1-linked-glc, 1,4-linked-glc, 1,6-linked-glc, 1,3-linked-gal and 1,3,6 linked-man glycosidic bonds. The results from hepatoprotective studies showed that FPS significantly decreased the liver index, serum gamma glutamyltranspeptidase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST) activities and malondialdehyde (MDA) contents in liver tissue, and increased antioxidant capacities of hepatic glutathione (GSH) and superoxide dismutase (SOD). Furthermore, histological examination of liver tissues showed that FPS alleviated CCl4-induced liver injury. Finally, the Western blot results showed that FPS could significantly decrease the expression levels of TGF-beta1 and Smad3 in the liver. These results together suggest that FPS possesses hepatoprotective effect against CCl4-induced liver damage, in part through the downregulation of TGF beta1/Smad signaling pathway, therefore FPS could be considered as a hepatoprotective medicine or functional food. PMID- 29969639 TI - In vivo study on scaffolds based on chitosan, collagen, and hyaluronic acid with hydroxyapatite. AB - Scaffolds based on chitosan, collagen, and hyaluronic acid supplemented with nano hydroxyapatite were obtained with the use of the freeze-drying method. Composites swelling behavior was assessed by the liquid uptake test. The adhesion and proliferation of human osteosarcoma SaOS-2 cells on the scaffolds were examined in 4-day culture. The biocompatibility of the chosen scaffolds was further studied by in vivo implantation into subcutaneous tissue of rabbits. The results showed low stability of the scaffolds based on chitosan, collagen, and hyaluronic acid supplemented with hydroxyapatite. The addition of hydroxyapatite delayed the degradation process of the obtained scaffolds. The X-ray images of the tissues surrounding the scaffolds showed that both, the control scaffold without hydroxyapatite (HAp) and those with addition of 50% wt. HAp underwent degradation after 6 months. However, the scaffolds supplemented with 80% wt. HAp premained in the implanted place. The results showed satisfactory tissue response on the implanted scaffolds. PMID- 29969640 TI - Rheology and microstructure of myofibrillar protein-starch composite gels: Comparison of native and modified starches. AB - Composite gels were prepared from 2% myofibrillar protein (MP) imbedded with native starch (potato or tapioca starch) or their modified starches in 0.6 M NaCl at pH 6.2. The role of native starch (potato or tapioca) and their modified counterparts in the rheology and microstructure of MP gels was evaluated. Dynamic rheological testing with temperature sweeping (20-80 degrees C) showed substantial increases in the storage modulus (G') of the MP sols/gels with the addition of starch. The increase in G' was inversely related to the pasting temperature of specific starch types. The strength and water-holding capacity (WHC) of the MP composite gels containing esterified starches were superior to those containing native or cross-linked esterified starches. Microstructural analysis showed that the "packing effect" of potato starch (PS) on MP gels was more remarkable than that of tapioca starch (TS) because of the larger granule size of the PS. However, esterified TS (ETS) and native TS made the greatest contribution to the WHC of the MP gels at 80 degrees C. PMID- 29969641 TI - Biocompatible magnetic nanoparticles grafted by poly(carboxybetaine acrylamide) for enzyme immobilization. AB - Herein, the zwitterionic material poly (carboxybetaine acrylamide) was grafted onto iron oxide to obtain biocompatible magnetic nanoparticles Fe3O4-pCBAA which were employed to immobilize enzymes. The nanocomplxes Fe3O4-pCBAA were characterized using scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta potential, Fourier transform-infrared (FT-IR) spectra and energy dispersive X-ray spectrometry (EDX). The urease as a model enzyme was immobilized with the novel supports and the properties of immobilized urease were further investigated in comparison with the free urease counterpart. The immobilized urease exhibited excellent thermodynamic and chemical stability. Particularly, 60% of initial activity was remained after being stored at 70 degrees C for 2 h while the free urease only remained 30%. Besides, the relative activity of immobilized enzyme was 1.7 times that of free ones after disposed in ethanol and 2-propanol for 2 h, and 7 times in DMF. Moreover, immobilized urease retained >80% of its initial activity after 5 cycles. In addition, the immobilization carrier Fe3O4-pCBAA displayed famous biocompatibility, and the immobilized urease performed better in complex biological samples, which were >85% and <60% of its initial activity for the immobilized and dissociative urease, respectively, in 20% and 25% of serum. These results confirm that the nanoparticles Fe3O4-pCBAA are biofriendly and efficient supports for enzyme immobilization and potential for practical applications in bio-microenvironments. PMID- 29969642 TI - Extraction of value-added components from food industry based and agro-forest biowastes by deep eutectic solvents. AB - The scientific community, experts in technology and marketing have been seeking cost-competitive and green solvents with good dissolving capacity for the valorisation of biomass and biowaste. Along with traditional solvents and techniques, deep eutectic solvents (DESs) and their bio-analogues, natural deep eutectic solvents (NADESs) are currently emerging as a new class of promising liquid media. In this review, a comprehensive summary of recent contribution of DESs to the processing and valorisation of various kinds of plant and animal based biomass and biowaste is provided. In the field of food industry based and agro-forest waste valorisation, through treatment of the waste, by-products, and natural materials by DESs, several types of compounds, such as flavonoids and other plant phenolics, phenolic acids, stilbenes, tannins, lignans, and lignin were obtained. Extraction of algae by DESs led to isolation mainly of proteins, carbohydrates, lipids and nucleic acids. Vegetable oils, spent oils, residues and by-products of their processing are a rich source of phenolic compounds such as phenolic acids and phenolic alcohols, secoiridoid derivatives (aglycone and ligstroside), lignans (pino and acetoxypinoresinol), flavones (luteolin and apigein), tocopherols and tocotrienols. Dietary fibre serves as a source of lignin, pectic substances, gums, resistant starch, inulin, as well as non carbohydrate components, e.g., polyphenols, waxes, saponins, cutin, phytates, resistant proteins. Valorisation of wastes originated from animal processing by DESs means obtaining high-value chemicals including amino acids, proteins, bioactive peptides, collagen peptides, albumin etc. Through the valorisation of the mentioned waste types value-added products with potential applications in the pharmaceutical, food and cosmetic industries are produced. The paper gathered data on the used DESs, treated substances and obtained products, together with treatment conditions and the products yields. The evaluation of the state-of-the art in the field of biowaste valorisation using DESs and NADESs led to conclusions and indication of future prospects and predicted development in this field. PMID- 29969643 TI - Can chest compression release rate or recoil velocity identify rescuer leaning in out-of-hospital cardiopulmonary resuscitation? AB - BACKGROUND: Measurement of chest velocity has been proposed as an alternative method to identify responder leaning during cardiopulmonary resuscitation (CPR). Leaning is defined in terms of force, but no study has tested the utility of chest velocity in the presence of force measurements that directly measure leaning. MATERIALS AND METHODS: We analyzed 1004 out-of-hospital cardiac arrest (OHCA) files collected with Q-CPR monitors in the Portland, Oregon, USA metro region from 2006 to 2017. Records contained accelerometry and force signals. For each chest compression, the following metrics were computed: minimum force at the end of the compression (Frelease), compression depth, compression rate, maximum chest velocity during recoil (vrecoil) and maximum rate of change in force during chest release (vrelease). A compression was classified as having leaning if Frelease was greater than 2.5 kg-f. The ability of vrecoil and vrelease to predict Frelease was estimated with generalized linear models, and their ability to identify leaning with logistic regression. RESULTS: The data set contained over 1.5 million chest compressions, 21% compliant with 2015 rate and depth guidelines for CPR (the G2015 population). Leaning was uncommon generally (12%), and less common in G2015 compliant compressions (5%). Leaning and Frelease decreased with both vrecoil and vrelease but with extensive overlap. Neither vrecoil nor vrelease, alone or in combination with chest compression rate and depth, reliably predicted leaning or Frelease. CONCLUSION: Leaning cannot be reliably identified from vrecoil or vrelease, alone or in combination with currently recommended chest compression metrics in out-of-hospital CPR. PMID- 29969644 TI - Optimal platelet inhibition with cangrelor in comatose survivors of out-of hospital cardiac arrest undergoing primary percutaneous coronary intervention. PMID- 29969645 TI - Neural circuitry among connecting the hippocampus, prefrontal cortex and basolateral amygdala in a mouse depression model: Associations correlations between BDNF levels and BOLD - fMRI signals. AB - BACKGROUND: Depression is a heterogeneous disorder, but the exact neuronal mechanisms causing the disease have not yet been discovered. METHODS/MATERIALS: We have established a chronic unpredictable mild stress (CUMS) mouse model to explore the blood oxygen level-dependent (BOLD) activity in the hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA) using amplitude of low frequency fluctuations (ALFF) in functional magnetic resonance imaging (fMRI). We initially studied the relationship between brain-derived neurotrophic factor (BDNF) expression and BOLD activity using BDNFtm1Krj/J mice. RESULTS: We found that CUMS induced depressive-like behaviours and stimulated changes in brain regions expressing a different BDNF level, which was decreased in the hippocampus and PFC but increased in the BLA. In contrast, the BOLD activity was elevated in the hippocampus and PFC but reduced in the BLA after CUMS exposure, indicating that the BDNF level negatively correlated with the BOLD activity in the WT CUMS exposed mice. Moreover, the depressive-like behaviours and region-specific BOLD activity in BDNFtm1Krj/J mice were consistent with those in WT CUMS-exposed mice. CONCLUSION: We surmised that critical neural circuitry connects the hippocampus, PFC and BLA in mice, which was regulated by BDNF to protect against depression. These findings suggested a potential central role of BDNF expression in functional changes in the brain. PMID- 29969646 TI - Quantitative analysis of peri-tumor fat in different molecular subtypes of breast cancer. AB - BACKGROUND AND PURPOSES: The aim of this study was to develop morphological analytic methods to analyze the tumor-fat interface and in different peritumoral shells away from the tumor, and to compare the results among three molecular subtypes of breast cancer. MATERIALS AND METHODS: A total of 102 women (mean age 48.5 y/o) with solitary well-defined breast cancers were analyzed, including 46 human epidermal growth factor receptor 2 (HER2) (+), 46 HER2(-) hormonal receptor (HR) (+), and 10 triple negative (TN) breast cancers. The tumor lesion, the breast, the fibroglandular and fatty tissue were segmented using well-established methods. The whole breast fat percentage and the peri-tumor interface fat percentage were measured. Three shells (SH1, SH2, SH3) surrounding the convex hall of the three dimensional (3D) tumor were defined and in each shell the volumetric percentage of fat was calculated. The peri-tumor interface fat percentage and the volumetric percentage of fat in the three peri-tumoral shells were compared among different subtypes. RESULTS: In the TN group, the fat percentage on the tumor boundary was 43 +/- 20% and 78 +/- 12% for two dimensional (2D) and 3D measurement, respectively, which were the highest among the three subtypes but not significantly different. The fat percentage in SH2 and SH3 in the TN group was 82 +/- 7% and 85 +/- 7%, which was significantly higher compared to the two other two subtypes. The results remained after controlling for the whole breast fat percentage. CONCLUSIONS: This study provided a feasible method for quantitative analysis of peri-tumoral tissue characteristics. Because of small patient number, the finding that TN tumors had the highest peri-tumor fat content among the three subtypes needs to be further verified with a large cohort study. PMID- 29969647 TI - Are there facial indicators of positive emotions in birds? A first exploration in Japanese quail. AB - The positive aspect of emotions, like pleasure, remains overlooked in birds. Our aim was to contribute to the exploration of facial indicators of positive emotions. To observe contrasting emotional expressions, we used two lines of Japanese quail divergently selected on their inherent fearfulness: a fearful line (long tonic immobility duration: LTI) and a less fearful line (short tonic immobility duration: STI). To induce positive emotions, we gave individual quail the opportunity to perform a rewarding behaviour, dustbathing, in an unfamiliar cage. More STI than LTI quail expressed dustbathing and latencies to dustbathe were significantly shorter in STI than LTI quail. This result indicated that the lines of quail differed in their fearfulness of the situation. We observed crown feather height, throat feather angle and pupil surface before (control) and during dustbathing. We found significant increases in crown feather height, pupil area and angle of throat feathers between the control and the dustbathing phases in STI quail, and pupil area correlated positively with crown feather height. In LTI quail, the angle of throat feathers increased during dustbathing, but the other parameters did not differ. We argue that variation in crown feather height and pupil area may provide indications of positive emotions in Japanese quail. PMID- 29969648 TI - Oxytocin modulates the expression of norepinephrine transporter, beta3 adrenoceptors and muscarinic M2 receptors in the hearts of socially isolated rats. AB - Social stress produces behavioral alterations, and autonomic and cardiac dysfunction in animals. In addition to the well-known roles of oxytocin on birth and maternal bonding, recent evidence shows that this neuropeptide possesses cardio-protective properties. However less is known about its role in the regulation of the autonomic nervous system. The direct influence of oxytocin on the cardiac catecholamine synthesizing enzyme, transport beta-adrenoceptors and muscarinic receptors in animals exposed to chronic social isolation stress has not yet been studied. In this study, we examined the influence of peripheral chronic oxytocin treatment on anxiety-related behavior, the morphology and content of epinephrine and norepinephrine, mRNA and protein levels of tyrosine hydroxylase (TH), norepinephrine transporter (NET) and receptors 3 (beta3 AR) and muscarinic 2 (M2 MR) in the right and left cardiac atrium and ventricle of chronically socially isolated male rats. Our results show that oxytocin treatment exhibits an anxiolytic effect, decreases the heart/body weight ratio and prevents the hypertrophy of cardiomyocytes in the wall of the left ventricle of stressed rats. Epinephrine and TH protein levels were unchanged after prolonged oxytocin treatment. Peripheral oxytocin administration led to the enhancement of gene expression of beta3-AR in both atria, NET protein in the left ventricle and gene expression of M2 MR in the right atrium and the left ventricle of chronically socially isolated rats. The study provides evidence that oxytocin treatment in chronically socially isolated animals enhances norepinephrine uptake and expression of cardio-inhibitory receptors in cardiac tissues, which could have a beneficial effect on the cardiovascular system under the increased activity of the sympathoneural system. PMID- 29969649 TI - Meroterpenoid dimers from Ganoderma cochlear and their cytotoxic and COX-2 inhibitory activities. AB - (+)- and (-)-Spirocochlealactones A-C (1-3), three pairs of new spiro meroterpenoidal dimeric enantiomers together with one known compound ganodilactone (4), were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by using spectroscopic methods and ECD calculations. All the isolated compounds were tested for their COX-2 inhibitory and cytotoxic activities toward human cancer lines (A549, K562, and Huh-7). The results show that all the compounds could inhibit COX-2 with IC50 values in the range of 1.29 to 3.63 MUM. In addition, (+) spirocochlealactone A and (+)-ganodilactone were found to be moderate activities against human cancer cell line A549 with the IC50 values of 7.14 and 9.47 MUM, respectively. PMID- 29969650 TI - Anticipatory postural adjustments as a function of response complexity in simple reaction time tasks. AB - The central nervous system preplans postural responses to successfully perform complex multi-joint movements. These responses have been termed anticipatory postural adjustments (APAs), and they constitute a general type of response to stabilize posture prior to movement initiation. APA sequences are elicited with shorter latency when a startling acoustic stimulus is applied, demonstrating their preplanned nature. Increasing task complexity using a simple reaction time (RT) paradigm has been shown to delay limb movement RT as a result of additional planning or sequencing requirements; however, the effect of task complexity on APA dynamics is unclear. The purpose of the present study was to investigate if task complexity modulates APA onset in a manner analogous to that observed in the primary effector. 13 participants completed 150 trials of simple (1-target) and complex (2- or 3-target) arm movements while standing on a force plate. Results indicated participants had significantly faster arm movement RTs in the simple versus the most complex condition. Similar to the primary effector, APA RTs were longer in the most complex (3-target) movement compared to both the 1-target and 2-target movements. Furthermore, APA excursion velocities were scaled to the complexity of the upcoming movement: the rate of APAs increased from simplest to most complex movements. These findings clearly demonstrate APAs are sensitive to task complexity, further elucidating their preplanned role in stabilizing posture which enables the successful completion of intended movements. PMID- 29969651 TI - The posterior pituitary expresses the serotonin receptor 2C. AB - The serotonin receptor 2C (5HT2C) is an important drug target to treat obesity and depression. Its pre-mRNA undergoes alternative splicing, encoding a short RNA1 isoform that is localized intracellularly and a full-length isoform (RNA2) that can reach the cell membrane. These splicing isoforms are deregulated in Prader-Willi syndrome (PWS), due to the loss of a trans-acting regulatory RNA, SNORD115. Here we show that the 5HT2C mRNA is expressed in the posterior pituitary, suggesting that 5HT2C mRNA is generated in the hypothalamus and subsequently conveyed by axonal transport. In the pituitary, the ratio of 5HT2C isoforms is regulated by feeding, and can be manipulated using a splice-site changing oligonucleotide injected into the blood. The pituitary expression of the 5HT2C mRNA may constitute a previously unknown mechanism whereby serotonin in the circulation or drugs targeting the 5HT2C might induce side-effects. Finally, the deregulation of 5HT2C splicing isoforms in PWS could contribute to the known hormonal imbalances. PMID- 29969652 TI - Depletion of follicles accelerated by combined exposure to phthalates and 4 vinylcyclohexene diepoxide, leading to premature ovarian failure in rats. AB - Humans are at daily risk by simultaneous exposures to a broad spectrum of man made chemicals in the commercial products. Several classes of chemicals have been shown to alter follicle development and reduce fertility, leading to premature ovarian failure (POF) in mammals. We investigate the synergistic effects of 4 vinylcyclohexene diepoxide (VCD) and phthalate, including di(2-ethylhexyl) phthalate (DEHP), butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP) on POF. Combination exposure with VCD and phthalate significantly reduced the numbers of primary follicles. The expressions of Amh and Sohlh2 were significantly decreased in the combination groups. Serum Amh levels were significantly lower in the combination groups. Additionally, serum levels of follicle-stimulating hormone were significantly increased in combination groups. Taken together, exposure to phthalates promotes the depletion of follicular follicles and consequently increases the risk of premature menopause, and combined exposure of phthalates and VCD to early menopausal women is likely to aggravate the POF syndrome. PMID- 29969653 TI - Exploration of toxicological impacts following acute and sub-chronic exposure to ethyl anthranilate-loaded mosquito repellent patch. AB - In the recent years, growing concern about the potential toxicity of synthetic repellents has led to the development of environmentally safe non-toxic insect control methods. Present investigation explores the toxicological impacts of ethyl anthranilate-loaded mosquito repellent patch (EAMRP) on respiratory system following acute and sub-chronic inhalation exposure in Wistar rats. Lungs parameters such as enhanced pause, tidal volume, respiration rate, inspiration time, and expiration time were determined using whole body plethysmograph. X-ray, scanning electron microscopy and histology were utilized to study the morphology and microscopical architecture of lungs. Hematological and serum biochemical markers were estimated. Cytokines such as IL-1beta, IL-2, and IL-12 were also estimated in bronchoalveolar lavage fluid using ELISA kits. Finally, acute oral and dermal toxicity studies were carried out to study the accidental or intentional poisoning due to the ingestion and skin contact of EAMRP, respectively. The findings demonstrate that inhalation exposure to EAMRP did not pose any significant dose related toxicity in above mentioned experiments. Further, no appreciable toxicity was observed in both acute oral and dermal exposure. Thus, these results revealed the non toxic nature of EAMRP in preclinical studies. Hence, EAMRP can be used successfully as an alternative to existing synthetic repellents without any potential health hazards. PMID- 29969655 TI - Involvement of l-afadin, but not s-afadin, in the formation of puncta adherentia junctions of hippocampal synapses. AB - A hippocampal mossy fiber synapse has a complex structure in which presynaptic boutons attach to the dendritic trunk by puncta adherentia junctions (PAJs) and wrap multiply-branched spines, forming synaptic junctions. It was previously shown that afadin regulates the formation of the PAJs cooperatively with nectin 1, nectin-3, and N-cadherin. Afadin is a nectin-binding protein with two splice variants, l-afadin and s-afadin: l-afadin has an actin filament-binding domain, whereas s-afadin lacks it. It remains unknown which variant is involved in the formation of the PAJs or how afadin regulates it. We showed here that re expression of l-afadin, but not s-afadin, in the afadin-deficient cultured hippocampal neurons in which the PAJ-like structure was disrupted, restored this structure as estimated by the accumulation of N-cadherin and alphaNu-catenin. The l-afadin mutant, in which the actin filament-binding domain was deleted, or the l afadin mutant, in which the alphaNu-catenin-binding domain was deleted, did not restore the PAJ-like structure. These results indicate that l-afadin, but not s afadin, regulates the formation of the hippocampal synapse PAJ-like structure through the binding to actin filaments and alphaN-catenin. We further found here that l-afadin bound alphaN-catenin, but not gamma-catenin, whereas s-afadin bound gamma-catenin, but hardly alphaN-catenin. These results suggest that the inability of s-afadin to form the hippocampal synapse PAJ-like structure is due to its inability to efficiently bind alphaN-catenin. PMID- 29969656 TI - Topological support and data quality can only be assessed through multiple tests in reviewing Blattodea phylogeny. AB - Assessing support for molecular phylogenies is difficult because the data is heterogeneous in quality and overwhelming in quantity. Traditionally, node support values (bootstrap frequency, Bayesian posterior probability) are used to assess confidence in tree topologies. Other analyses to assess the quality of phylogenetic data (e.g. Lento plots, saturation plots, trait consistency) and the resulting phylogenetic trees (e.g. internode certainty, parameter permutation tests, topological tests) exist but are rarely applied. Here we argue that a single qualitative analysis is insufficient to assess support of a phylogenetic hypothesis and relate data quality to tree quality. We use six molecular markers to infer the phylogeny of Blattodea and apply various tests to assess relationship support, locus quality, and the relationship between the two. We use internode-certainty calculations in conjunction with bootstrap scores, alignment permutations, and an approximately unbiased (AU) test to assess if the molecular data unambiguously support the phylogenetic relationships found. Our results show higher support for the position of Lamproblattidae, high support for the termite phylogeny, and low support for the position of Anaplectidae, Corydioidea and phylogeny of Blaberoidea. We use Lento plots in conjunction with mutation saturation plots, calculations of locus homoplasy to assess locus quality, identify long branch attraction, and decide if the tree's relationships are the result of data biases. We conclude that multiple tests and metrics need to be taken into account to assess tree support and data robustness. PMID- 29969654 TI - Depletion of astrocytic transglutaminase 2 improves injury outcomes. AB - Astrocytes play an indispensable role in maintaining a healthy, functional neural network in the central nervous system (CNS). A primary function of CNS astrocytes is to support the survival and function of neurons. In response to injury, astrocytes take on a reactive phenotype, which alters their molecular functions. Reactive astrocytes have been reported to be both beneficial and harmful to the CNS recovery process subsequent to injury. Understanding the molecular processes and regulatory proteins that determine the extent to which an astrocyte hinders or supports neuronal survival is important within the context of CNS repair. One protein that plays a role in modulating cellular survival is transglutaminase 2 (TG2). Global deletion of TG2 results in beneficial outcomes subsequent to in vivo ischemic brain injury. Ex vivo studies have also implicated TG2 as a negative regulator of astrocyte viability subsequent to injury. In this study we show that knocking down TG2 in astrocytes significantly increases their ability to protect neurons from oxygen glucose deprivation (OGD)/reperfusion injury. To begin to understand how deletion of TG2 in astrocytes improves their ability to protect neurons from injury, we performed transcriptome analysis of wild type and TG2-/- astrocytes. TG2 deletion resulted in alterations in genes involved in extracellular matrix remodeling, cell adhesion and axon growth/guidance. In addition, the majority of genes that showed increases in the TG2-/- astrocytes had predicted cJun/AP-1 binding motifs in their promoters. Furthermore, phospho cJun levels were robustly elevated in TG2-/- astrocytes, a finding which was consistent with the increase in expression of AP-1 responsive genes. These in vitro data were subsequently extended into an in vivo model to determine whether the absence of astrocytic TG2 improves outcomes after CNS injury. Our results show that, following a spinal cord injury, scar formation is significantly attenuated in mice with astrocyte-specific TG2 deletion compared to mice expressing normal TG2 levels. Taken together, these data indicate that TG2 plays a pivotal role in mediating reactive astrocyte properties following CNS injury. Further, the data suggest that limiting the AP-1 mediated pro-survival injury response may be a contributing factor to that the detrimental effects of astrocytic TG2. PMID- 29969657 TI - From tree tops to the ground: Reversals to terrestrial habit in Galeandra orchids (Epidendroideae: Catasetinae). AB - The colonization of the epiphytic niche of Neotropical forest canopies played an important role in orchid's extraordinary diversification, with rare reversions to the terrestrial habit. To understand the evolutionary context of those reversals, we investigated the diversification of Galeandra, a Neotropical orchid genus which includes epiphytic and terrestrial species. We hypothesized that reversion to the terrestrial habit accompanied the expansion of savannas. To test this hypothesis we generated a comprehensive time-calibrated phylogeny and employed comparative methods. We found that Galeandra originated towards the end of the Miocene in Amazonia. The terrestrial clade originated synchronously with the rise of dry vegetation biomes in the last 5 million years, suggesting that aridification dramatically impacted plant diversification and habits in the Neotropics. Shifts in habit impacted floral spur lengths and geographic range size, but not climatic niche. The longer spurs and narrower ranges characterize epiphytic species, which probably adapted to specialized long-tongued Euglossini bee pollinators inhabiting forested habits. The terrestrial species present variable floral spurs and wider distribution ranges, with evidence of self pollination, suggesting the loss of specialized pollination system and concomitant range expansion. Our study highlights how climate change impacted habit evolution and associated traits such as mutualistic interactions with pollinators. PMID- 29969658 TI - Downregulation of lncRNA GAS5 confers tamoxifen resistance by activating miR-222 in breast cancer. AB - Long noncoding RNAs (lncRNAs) work as oncogenes or tumor suppressors that play important roles in tumorigenesis and chemotherapeutic drug resistance. This study investigates the role of lncRNA growth arrest-specific transcript 5 (GAS5) in tamoxifen resistance in breast cancer. A microarray of lncRNAs was screened in tamoxifen-resistant MCF-7R cells and the parental, non-resistant MCF-7 cells. Downregulation of lncRNA GAS5 was found in MCF-7R cells. Besides, decreased expression of GAS5 was found in breast cancer tissues, which was associated with advanced TNM stage and shorter overall survival time. We further found that GAS5 overexpression enhanced cell sensitivity to tamoxifen in MCF-7R cells both in vitro and in vivo. Moreover, GAS5 increased sensitivity of breast cancer cells to tamoxifen by serving as a molecular sponge for miR-222, contributing to suppression of phosphatase and tensin homologs (PTEN) (one endogenous target of miR-222). Collectively, our study demonstrates that GAS5 enhances the efficacy of tamoxifen in the treatment of breast cancer and could be a novel prognostic biomarker. PMID- 29969659 TI - IL6/STAT3 axis mediates resistance to BRAF inhibitors in thyroid carcinoma cells. AB - Thyroid carcinomas (TCs) bearing BRAF mutations represent approximately 26-53% of human thyroid malignancies and, differently from melanomas, are poorly sensitive to BRAF inhibitors (BRAFi), and develop acquired resistance through activation of alternative signaling pathways. A whole-genome gene expression analysis of TC BRAF V600E cells exposed to PLX4032 identified JAK/STAT among the most significantly modulated signaling pathways. Interestingly, both transient exposure and chronic adaptation to PLX4032 resulted in upregulation of IL6/STAT3 axis and this impaired the cytostatic activity of PLX4032. Mechanistically, exposure to PLX4032 enhanced IL6 secretion and this, in turn, was responsible for STAT3 upregulation, activation of ERK signaling and poor sensitivity to BRAF inhibition. Consistently, the dual blockade of STAT3 (by siRNA or pharmacological inhibition) or IL6 signaling (by the humanized anti-human IL6 receptor antibody, tocilizumab) and BRAF (by PLX4032) improved the inhibition of cell cycle progression compared to PLX4032 single agent. These data support the role of IL6/STAT3 signaling pathway in modulating TC cell response to PLX4032 and candidate IL6 targeting as a strategy to improve the activity of PLX4032 in BRAF V600E TC cells. PMID- 29969660 TI - The relationship between trauma and weight status among adolescents in eating disorder treatment. AB - A relationship between trauma and eating disorders in adolescence is well established, though less is known about how different types of trauma, apart from childhood sexual abuse, associate with eating disorders. The purpose of this study is to describe the prevalence of various trauma types in a clinical sample of adolescents presenting at an outpatient eating disorder treatment facility (N = 182). Thirty-five percent of the sample reported experiencing one or more traumatic events during their lifetime. Bullying was the most prevalent type of trauma (10%), followed by significant death/loss (9%), and sexual abuse (8%). Adolescents with any trauma exposure had higher body mass index (BMI), BMI percentile, and percent expected body weight (%EBW) compared to those without any trauma exposure. Specifically, patients who were exposed to bullying and domestic violence reported a significantly higher %EBW than those who were not exposed. On average, adolescents exposed to bullying had a %EBW that was 7 percentage points higher than their non-exposed peers. Patients with bulimia nervosa were more likely to report trauma exposure than those with other eating disorder diagnosis. Providers working with adolescents diagnosed with eating disorders of all weight statuses should consider assessing for past and current trauma, including bullying and exposure to domestic violence. Trauma informed approaches to eating disorder treatment are needed to avoid potentially activating or exacerbating trauma related distress for adolescents in eating disorder treatment. PMID- 29969661 TI - Genetic variants of resistin and its plasma levels: Association with obesity and dyslipidemia related to type 2 diabetes susceptibility. AB - Resistin, an adipokine, is involved in obesity and Type 2 Diabetes (T2D). The current study evaluates the association between RETN polymorphisms (-638 G/A, 420C/G & -358 G/A) and the risk towards T2D. Controls and T2D patients were enrolled from Gujarat, India. Polymorphisms of RETN were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. For the genotype phenotype correlation analysis Fasting Blood Glucose (FBG), Body Mass Index (BMI) and plasma lipid profile were used. Plasma levels of resistin were assayed by ELISA. Our study suggests an association of RETN -420C/G polymorphism with T2D risk. The CC genotype of RETN -420C/G polymorphism was found to be associated with FBG, BMI, and total cholesterol. Plasma resistin levels were found to be significantly increased in diabetic patients as compared to controls. Our findings suggest -420C/G polymorphism of RETN as an important factor which could pose a powerful risk towards T2D susceptibility. PMID- 29969662 TI - Processing apoferritin with the Appion pipeline. AB - The 3DEM map challenge provided an opportunity to test different algorithms and workflows for processing single particle cryo-EM data. We were interested in testing whether we could use the standard Appion workflow with minimal manual intervention to achieve similar or better resolution than other challengers. Another question we were interested in testing was what the influence of particle sorting and elimination would be on the resolution and quality of 3D reconstructions. Since apoferritin is historically a challenging particle for single particle reconstruction and the authors of the original map challenge data used only a fraction of the particles present in the dataset, we focused on the apoferritin dataset for our entry. We submitted a 3.7 A map from 25,844 particles and a 3.6 A map from 53,334 particles and after assessment were among the best of the apoferritin maps that were submitted. Here we present the details of our reconstruction strategy and compare our strategy to that of another high-scoring apoferritin map. Altogether, our results suggest that for a relatively conformationally homogeneous particle like apoferritin, including as many particles as possible after elimination of junk leads to the highest resolution, and the choice of parameters for custom mask creation can lead to subtle but significant changes in the resolution of 3D reconstructions. PMID- 29969663 TI - Chronic tearing induced by apremilast. PMID- 29969664 TI - The association between decreased hand grip strength and hip fracture in older people: A systematic review. AB - Hip fractures are a global concern, resulting in poor outcomes and high health care costs. They mostly affect people >80 years. Hip fractures are influenced by various (modifiable) risk factors. Emerging evidence suggests hand grip strength (HGS) to be one of several useful tools to identify hip fracture risk. This is the first systematic review that aims to assess the evidence underlying the relationship between hip fracture incidence and HGS. Eleven studies were selected for this review (six case-control and five cohort studies), comprising 21,197 participants. Where reported, HGS was significantly decreased in individuals with a hip fracture near the time of injury as compared to controls (p < 0.001); HGS was associated with increased hip fracture risk in all included studies. Meta analysis was not possible. All studies included in this systematic review confirmed a relationship between decreased HGS and hip fracture incidence. We were not able to quantify the strength of this relationship, due to the heterogeneity of the included studies. HGS merits further investigation as a useful tool for identifying individuals that might be at elevated risk for sustaining a hip fracture. PMID- 29969665 TI - Curcumin loaded selenium nanoparticles synergize the anticancer potential of doxorubicin contained in self-assembled, cell receptor targeted nanoparticles. AB - Doxorubicin (DOX) has been extensively used to treat a wide range of cancers in free and nanotized form. Nanotization of DOX has alleviated its toxicity and efflux-mediated resistance. However, frequent upregulation of anti-apoptotic pathways, chemotherapy-enhanced inflammation, and epithelial-mesenchymal transition (EMT), present additional aspects of cellular DOX resistance. Nanoparticle-mediated combination therapy of DOX with additional anticancer agents is expected to offer greater therapeutic benefit by alleviating the overall drug resistance. We synthesized CD44-targeted DOX loaded nanoparticles (PSHA-DOXNPs) and evaluated their anticancer efficacy in combination with curcumin loaded selenium nanoparticles (Se-Cur NPs), previously developed by our group (Kumari et al., 2017). Combination of these nanoparticles (NPs) increased ROS level, decreased mitochondrial membrane potential, induced cell cycle arrest and apoptosis in HCT116 cells. This combination decreased the expressions of NFkappaB, Phospho-NFkappaB, EMT-metastasis-associated proteins (Snail, Vimentin, N-cadherin, CD44, MMP-2 and MMP-9), autophagy-associated proteins (Beclin-1 and LC-3BII), as well as anti-apoptotic protein Bcl-2, increased the expression of pro-apoptotic protein Bax, and increased cyt c release, which indicated decrease in inflammation, metastasis, and autophagy with increase in apoptosis. Moreover, the combination of NPs decreased tumor burden and increased survival of Ehrlich's ascites carcinoma (EAC)-bearing mice. PMID- 29969666 TI - Serotonin-1A receptor dependent modulation of pain and reward for improving therapy of chronic pain. AB - Chronic pain conditions such as low back pain and osteoarthritis are the most prominent causes of disability worldwide. Morphine and other opioid drugs are the gold standard treatment for severe pain, including surgical pain, but the use of these drugs for chronic pain is limited largely because long term use of these drugs is associated with drug abuse and hyperalgesia which produces a negative impact on the treatment. Non-addictive treatments for chronic pain are, therefore, highly needed. Commonly used opioid drugs activate mu opioid receptors, resulting in an inhibition of tonic activity of nociceptive neurons. The rewarding effects of opioid drugs are also mediated via activation of mu opioid receptors and inhibition of GABA mediated control of the activity of dopamineregic neurons. Enhanced glutamate release and greater activity of NMDA glutamate receptors is linked to the hyperalgesic effects of opioid drugs. Evidence suggests that activation of serotonin (5-hydroxytryptamine; 5-HT)-1 A receptors modulates dopamine neurotransmission to inhibit rewarding effects of drugs of abuse. Activation of these receptors inhibits glutamate release from the sensory neurons to reduce pain transmission. To help develop strategies for improving therapeutics in chronic pain, and draw research interest in the synthesis of non-addictive opioid drugs which do not predispose to hyperalgesia, the present article concerns the potential mechanism involved in 5-HT-1 A receptor mediated inhibition of pain and reward. PMID- 29969667 TI - Synthesis of thiolated, PEGylated and POZylated silica nanoparticles and evaluation of their retention on rat intestinal mucosa in vitro. AB - In this study, we synthesised thiolated silica nanoparticles using 3 mercaptopropyltrimethoxysilane and functionalised them with either 5 kDa methoxy polyethylene glycol maleimide (PEG) or 5 kDa alkyne-terminated poly(2-ethyl-2 oxazoline) (POZ). The main objectives of this study are to investigate the effects of pH on the size and xi-potential of these nanoparticles and evaluate their mucoadhesive properties ex vivo using rat intestinal mucosa. The sizes of thiolated, PEGylated and POZylated silica nanoparticles were 53 +/- 1, 68 +/- 1 and 59 +/- 1 nm, respectively. The size of both thiolated and POZylated nanoparticles significantly increased at pH <= 2, whereas no size change was observed at pH 2.5-9 for both these two types of nanoparticles. On the other hand, the size of PEGylated nanoparticles did not change over the studied pH range (1.5-9). Moreover, thiolated nanoparticles were more mucoadhesive in the rat small intestine than both PEGylated and POZylated nanoparticles. After 12 cycles of washing (with a total of 20 mL of phosphate buffer solution pH 6.8), a significantly greater amount of thiolated nanoparticles remained on the intestinal mucosa than FITC-dextran (non-mucoadhesive polymer, p < 0.005) and both PEGylated and POZylated nanoparticles (p < 0.05 both). However, both PEGylated and POZylated nanoparticles showed similar retention to FITC-dextran (p > 0.1 for both). Thus, this study indicates that thiolated nanoparticles are mucoadhesive, whereas PEGylated and POZylated nanoparticles are non-mucoadhesive in the ex vivo rat intestinal mucosa model. Each of these nanoparticles has potential applications in mucosal drug delivery. PMID- 29969669 TI - Right filter-selection for phase separation in equilibrium solubility measurement. PMID- 29969668 TI - Lyophilized tablets for focal delivery of fluconazole and itraconazole through vaginal mucosa, rational design and in vitro evaluation. AB - The present work deals with the rational design and in vitro evaluation of vaginal tablets for focal delivery of fluconazole (FLZ) and itraconazol (ITZ). Drug loaded liposomes with and without d-alpha-tocopheryl polyethylene glycol 1000 succinate (vit E TPGS) were prepared by direct sonication of the components and mixed with albumin to obtain albusomes. Tablets were obtained by direct compression of the lyophilized cake. The influence of vit E TPGS on size, zeta potential and entrapment efficiency (EE%) of liposomes and albusomes was evaluated. Tablet swelling and drug release were studied by in vitro assays. Vit E TPGS neither affected the zeta potential nor the EE% of liposomes and albusomes, but affected the liposomes size and the tablet disintegration time. A rapid erosion was observed for the tablets with the highest content of vitamin, while a slow swelling for those lacking the vitamin (swelling index = 57.76 +/- 13.51%). A faster drug release profile was obtained for the former compared to the latter. The in vitro assay showed that FLZ diffused and solved in the vaginal fluid simulant while ITZ remained into the albusomes, which slowly released ITZ albumin complex and ITZ-loaded liposomes, both suitable carriers for drug transport to deeper vaginal endothelium. PMID- 29969670 TI - Bacterial expression, purification and biophysical characterization of the smallest plant reticulon isoform, RTNLB13. AB - Reticulons are a large family of integral membrane proteins that are ubiquitous in eukaryotes and play a key role in functional remodelling of the endoplasmic reticulum membrane. The reticulon family is especially large in plants, with the Arabidopsis thaliana genome containing twenty-one isoforms. Reticulons vary in length but all contain a conserved C-terminal reticulon homology domain (RHD) that associates with membranes. An understanding of the structure and membrane interactions of RHDs is key to unlocking their mechanism of function, however no three-dimensional structure has been solved. We believe that this is, in part, due to difficulties in obtaining reticulon proteins in yields sufficient for structural study. To address this, we report here the first bacterial overexpression, purification, and biophysical investigation of a reticulon protein from plants, the RTNLB13 protein from A. thaliana. RTNLB13 is the smallest plant reticulon and is made up of a single RHD. We used circular dichroism, SDS-PAGE and analytical ultracentrifugation to reveal that RTNLB13 is 45% alpha-helical in a number of detergent environments, monomeric at low concentrations, and capable of self-association at higher concentrations. We used solution-state NMR to screen the effect of detergent type on the fold of isotopically-enriched RTNLB13, and found that ~60% of the expected protein peaks were broadened due to slow dynamics. This broadening points toward a large network of protein-membrane interactions throughout the sequence. We have interpreted our results in light of current literature and suggest a preliminary description of RTNLB13 structure and topology. PMID- 29969671 TI - RtxA like protein contributes to infection of Francisella novicida in silkworm and human macrophage THP-1. AB - Tularemia is a zoonosis caused by CDC-declared Tier 1 threat agent Francisella tularensis. F. tularensis subsp. novicida (F. novicida) is virulent in mice but non-pathogenic in immunocompetent humans and serves as a potential surrogate organism. In a recent study, we established a silkworm (Bombyx mori) model of infection for F. novicida. Francisella secretes its virulence factors through various mechanisms that modify the intracellular environment to ensure its replication and survival. To identify new pathogenic factors, we focused on the type I secretory system (T1SS) of Francisella. In silico analysis revealed a RtxA (Repeats-in-toxin) like protein in the Francisella genome. The characteristics of RtxA like protein were investigated using mutant analysis. Firstly, the role of rtxA in silkworms was investigated by infecting them with F. novicida strains into the hemocoel. The rtxA mutant failed to kill the silkworms, whereas F. novicida wild-type (WT) strain killed silkworms within 3-7 days post infection. The arrested growth of the mutant strain in silkworms was observed using a whole body CFU count assay. We also investigated the growth characteristics of the rtxA mutant in hemocytes, one of the primary multiplication sites of Francisella within silkworms. Interrupted growth of the rtxA mutant with significantly reduced cytotoxicity was observed in hemocytes via confocal microscopy. Next, we analyzed the effect of rtxA in human monocyte cell line THP-1. The mutant strain showed significantly decreased growth and reduced cytotoxicity compared with its parental strain in THP-1 cells. This study newly identified RtxA like protein of F. novicida as an important lethal pathogenic factor in silkworm and mammalian cells. PMID- 29969674 TI - Ventricular fibromas in children: Surgical resection can be a cure to lethal arrhythmias. PMID- 29969672 TI - A transcriptomic analysis of black cohosh: Actein alters cholesterol biosynthesis pathways and synergizes with simvastatin. AB - Previous studies indicate that the herb black cohosh (Actaea racemosa L.) and the triterpene glycoside actein inhibit the growth of human breast cancer cells and activate stress-associated responses. This study assessed the transcriptomic effects of black cohosh and actein on rat liver tissue, using Ingenuity and ToxFX analyses. Sprague-Dawley rats were treated with an extract of black cohosh enriched in triterpene glycosides (27%) for 24 h or actein for 6 and 24 h, at 35.7 mg/kg, and liver tissue collected for gene expression analysis. Ingenuity analysis indicates the top canonical pathways are, for black cohosh, RAR Activation, and, for actein, Superpathway of Cholesterol Biosynthesis, at 24 h. Actein alters the expression of cholesterol biosynthetic genes, but does not inhibit HMG-CoA reductase activity. Black cohosh and actein inhibited the growth of human breast and colon cancer cells and synergized with the statin simvastatin. Combinations of black cohosh with certain classes of statins could enhance their activity, as well as toxic, such as inflammatory liver, side effects. Transcriptomic analysis indicates black cohosh and actein warrant further study to prevent and treat cancer and lipid disorders. This study lays the basis for an approach to characterize the mode of action and toxicity of herbal medicines. PMID- 29969673 TI - Investigating the risk-benefit balance of substituting red and processed meat with fish in a Danish diet. AB - Danish dietary guidelines recommend the Danish population to increase the consumption of fish while decreasing the consumption of red and processed meat to prevent nutrition-related diseases. However, the presence of contaminants in these foods may affect the overall risk-benefit balance of such substitution. We performed a quantitative risk-benefit assessment on substituting red and processed meat with fish in a Danish diet. We modeled the substitution among Danish adults based on data from a Danish dietary survey and compared four alternative scenarios based on varying chemical and nutrient exposures to the current consumption. We quantified the overall health impact of the substitutions in terms of Disability-Adjusted Life Years (DALYs). Approximately 150 DALYs/100,000 individuals could be averted each year if Danish adults consumed 350 g of fish/week (fatty or mix of fatty and lean) while decreasing the consumption of red and processed meat. A lower beneficial impact was observed when consumption of fish was restricted to lean fish (80 DALYs/100,000 averted), and a marked health loss (180 DALYs/100,000) was estimated when consumption was restricted to tuna. Our results show an overall beneficial effect of the substitution if the consumption of large predatory fish is low and at least half is fatty fish. PMID- 29969675 TI - Seasonal variation in the risk of ischemic stroke in patients with atrial fibrillation: A nationwide cohort study. AB - BACKGROUND: Several cardiovascular diseases exhibit seasonal variations, but data about cold temperature and risk of ischemic stroke in patients with atrial fibrillation (AF) are limited. OBJECTIVE: The purpose of this study was to investigate the risk of ischemic stroke in different seasons, testing the hypothesis that the cold weather season would increase the risk of stroke in AF. METHODS: This study used the National Health Insurance Research Database in Taiwan. From 2000 to 2012, a total of 289,559 AF patients were enrolled, and 34,991 experienced ischemic stroke after mean follow-up of 3 years. The relationship between risk of ischemic stroke and temperatures was analyzed. RESULTS: The highest incidence of ischemic stroke was observed in winter, which was the coldest season, with an incidence rate of 0.33 per 100 person-months. Compared with the summer period, the risk of ischemic stroke increased by 10% in spring (incidence rate ratio [IRR] 1.10; 95% confidence interval [CI] 1.07-1.13) and by 19% in winter (IRR 1.19; 95% CI 1.15-1.22) but did not differ significantly between summer and autumn (IRR 1.00; 95% CI 0.97-1.03). Compared with the days with an average temperature of 30 degrees C, the risk of ischemic stroke for days with an average temperature <20 degrees C significantly increased. Lower 7-, 10-, or 14-day average temperatures were significantly associated with an increased risk of ischemic stroke in the case-crossover analysis. CONCLUSION: In this nationwide study, a seasonal variation of incidence of ischemic stroke in AF patients was observed, with an increased risk of stroke on days with an average temperature <20 degrees C. AF-related stroke may be influenced by environmental interactions. PMID- 29969676 TI - Dietary advanced glycation end products and their relevance for human health. AB - Due to their bioactivity and harmful potential, advanced glycation end products (AGEs) are discussed to affect human health. AGEs are compounds formed endogenously in the human body andexogenously, especially, in foods while thermal processing. In contrast to endogenous AGEs, dietary AGEs are formed in much higher extent. However, their risk potential is also depending on absorption, distribution, metabolism and elimination. For over 10 years an intense debate on the risk of dietary AGEs on human health is going on. On the one hand, studies provided evidence that dietary AGEs contribute to clinical outcomes. On the other hand, human studies failed to observe any association. Because it was not possible to draw a final conclusion, the call for new interdisciplinary approaches arose. In this review, we will give an overview on the current state of scientific knowledge in this field. In particular, we focus on (I) the occurrence of AGEs in foods and the daily uptake of AGEs, (II) contribution to endogenous levels and (III) the effect on health-/disease-related biomarkers in humans. PMID- 29969677 TI - Inhibiting ABCG2 could potentially enhance the efficacy of hypericin-mediated photodynamic therapy in spheroidal cell models of colorectal cancer. AB - BACKGROUND: Photodynamic Therapy (PDT) is an attractive modality for treating solid cancers. This study evaluates the efficacy of Hypericin-PDT as a cytotoxic therapy in colorectal cancer (CRC), using 2D cell cultures and 3D multicellular tumour spheroids. METHODS: Spheroids were generated through forced-floating and agitation-based techniques. 2D and spheroid models of HT29 and HCT116 CRC cells were incubated with Hypericin (0-200 nM) for 16 h. Cultures were irradiated with light (1 J/cm2) and cytotoxicity assessed using Propidium Iodide fluorescence. Expression of ABCG2 protein was assessed by immunoassays in 2D and spheroid cultures. The effect of ABCG2 inhibition, using 10 MUM Ko143, on cytotoxicity following Hypericin-PDT was evaluated. RESULTS: Hypericin-PDT produced a significant reduction in HT29 (p < 0.0001) and HCT116 (p < 0.0001) cell viability in 2D cultures, with negligible non-phototoxicity. Spheroids were more resistant than 2D cultures to Hypericin-PDT (HT29: p = 0.003, HCT116: p = 0.006) and had a greater expression of ABCG2. Inhibition of ABCG2 in spheroids with Ko143 resulted in an enhanced Hypericin-PDT effect compared to Hypericin-PDT alone (HT29: p = 0.04, HCT116: p = 0.01). CONCLUSIONS: Hypericin-PDT has reduced efficacy in CRC spheroids as compared to 2D cultures, which may be attributable through upregulation in ABCG2. The clinical efficacy of Hypericin-PDT may be enhanced by ABCG2 inhibition. PMID- 29969678 TI - Evaluation of targeted curcumin (CUR) loaded PLGA nanoparticles for in vitro photodynamic therapy on human glioblastoma cell line. AB - In this study, antibody-conjugated biodegradable polymeric nanoparticles were developed to enhance the photodaynamic efficiency of curcumin (CUR) on glioblastoma tumor cells. Poly (D, l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) were synthesized and stabilized by polyvinyl alcohol (PVA). Poly(ethylene alt-maleic anhydride) (PEMA) was used to provide carboxyl groups on the surface of NPs. The CUR or FITC (fluorescein isothiocyanate) was encapsulated in PLGA NPs using the nanoprecipitation method. The carboxylic groups on the surface of the PLGA NPs were covalently conjugated to the amino groups of a monoclonal antibody against EGFRvIII (A-EGFRvIII-f). The prepared NPs were fully characterized by Zetasizer, scanning electron microscope (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared (FTIR), and then entrapment efficiency (EE), drug loading efficiency (DLE), CUR release, cell internalization, intrinsic cytotoxicity, and phototoxicity were evaluated. Furthermore, the effect of monoclonal antibody (MAb) on the tyrosine phosphorylation of EGFRvIII after photodynamic therapy (PDT) was assessed. The immunoreactivity of the antibody in MAb-PLGA NPs was preserved during the process of conjugation. The selective cellular internalization of MAb-PLGA NPs (FITC or CUR loaded) into the DKMG/EGFRvIII cells (EGFRvIII overexpressed human glioblastoma cell line) in comparison with DK-MGlow (human glioblastoma cell line with low level of EGFRvIII) was also confirmed. MAb-CUR-PLGA NPs were able to show more effective photodynamic toxicity (56% vs. 24%) on the DKMG/EGFRvIII cells compared to CUR PLGA NPs. These results suggest that the anti-EGFRvIII MAb-CUR-PLGA NPs have potential of targeted drug delivery system for PDT in the overexpressed EGFRvIII tumor cells. PMID- 29969679 TI - Oxidative stress and genotoxic effect of deltamethrin exposure on the Chinese mitten crab, Eriocheir sinensis. AB - The oxidative stress and genotoxic effect of deltamethrin on the Chinese mitten crab Eriocheir sinensis were assessed using several commonly used biomarkers in this study. The results showed that the 48 h and 96 h LC50 values of deltamethrin to E. sinensis were 2.319 and 1.164 MUg/L, respectively, and the safe concentration was 0.293 MUg/L. According to these results, deltamethrin was applied at concentrations of 1/16, 1/8, 1/4, 1/2 and 1/1 96 h LC50 for 8 d in an exposure experiment. The activity of superoxide dismutase (SOD) increased remarkably at 1 d, but decreased at 4 d in concentration group of 1/4, 1/2 and 1/1 LC50, whereas catalase (CAT) activity decreased during the exposure. The total antioxidant capacity (T-AOC) at the concentrations of 1/4, 1/8 and 1/16 LC50 increased significantly at 1 d or 2 d respectively, whereas it decreased gradually until the end of the experiment under the concentrations above 1/4 LC50. The oxidative stress products malondialdehyde (MDA) and hydrogen peroxide (H2O2) in serum increased significantly at each concentration except H2O2 at concentration of 1/16 LC50. Additionally, the micronucleus (MN) frequency of haemocytes increased at the concentrations of 1/4, 1/2 and 1/1 LC50 throughout the exposure, similar trend was observed in the comet ratio and percentage of tail-DNA (%DNA) in haemocytes. These results revealed that deltamethrin had a prominent toxic effect on E. sinensis based on antioxidative response inhibition and genotoxicity that was possibly due to lipid peroxidation (LPO) induced by oxidative products, and the accumulation of peroxide, even under a sublethal concentration. PMID- 29969681 TI - Non-febrile spontaneous neck pain in a patient with diabetes. PMID- 29969680 TI - Zebrafish (Danio rerio): A valuable tool for predicting the metabolism of xenobiotics in humans? AB - Zebrafish has become a popular model organism in several lines of biological research sharing physiological, morphological and histological similarities with mammals. In fact, many human cytochrome P450 (CYP) enzymes have direct orthologs in zebrafish, suggesting that zebrafish xenobiotic metabolic profiles may be similar to those in mammals. The focus of the review is to analyse the studies that have evaluated the metabolite production in zebrafish over the years, either of the drugs themselves or xenobiotics in general (environmental pollutants, natural products, etc.), bringing a vision of how these works were performed and comparing, where possible, with human metabolism. Early studies that observed metabolic production by zebrafish focused on environmental toxicology, and in recent years the main focus has been on toxicity screening of pharmaceuticals and drug candidates. Nevertheless, there is still a lack of standardization of the model and the knowledge of the extent of similarity with human metabolism. Zebrafish screenings are performed at different life stages, typically being carried out in adult fish through in vivo assays, followed by early larval stages and embryos. Studies comparing metabolism at the different zebrafish life stages are also common. As with any non-human model, the zebrafish presents similarities and differences in relation to the profile of generated metabolites compared to that observed in humans. Although more studies are still needed to assess the degree to which zebrafish metabolism can be compared to human metabolism, the facts presented indicate that the zebrafish is an excellent potential model for assessing xenobiotic metabolism. PMID- 29969682 TI - 3-Hydroxycarlactone, a Novel Product of the Strigolactone Biosynthesis Core Pathway. PMID- 29969683 TI - Brassinosteroid Signaling Recruits Histone 3 Lysine-27 Demethylation Activity to FLOWERING LOCUS C Chromatin to Inhibit the Floral Transition in Arabidopsis. AB - The steroid hormone brassinosteroid (BR) plays a broad role in plant growth and development. As the retarded growth in BR-insensitive and BR-deficient mutants causes a strong delay in days to flowering, BR signaling has been thought to promote the floral transition in Arabidopsis. In this study, using a developmental measure of flowering time, we show that BR signaling inhibits the floral transition and promotes vegetative growth in the Arabidopsis accessions Columbia and Enkheim-2. We found that BR signaling promotes the expression of the potent floral repressor FLOWERING LOCUS C (FLC) and three FLC homologs to inhibit flowering. In the presence of BR, the transcription factor BRASSINAZOLE RESISTANT1 (BZR1), together with BES1-INTERACTING MYC-like proteins (BIMs), specifically binds a BR- responsive element in the first intron of FLC and further recruits a histone 3 lysine 27 (H3K27) demethylase to downregulate levels of the repressive H3K27 trimethylation mark and thus antagonize Polycomb silencing at FLC, leading to its activation. Taken together, our findings demonstrate that BR signaling inhibits the floral transition in Arabidopsis by a novel molecular mechanism in which BR signals are transduced into FLC activation and consequent floral repression. PMID- 29969684 TI - Human pharmacological approaches to TRP-ion-channel-based analgesic drug development. AB - The discovery of novel analgesic drug targets is an active research topic owing to insufficient treatment options for persisting pain. Modulators of temperature sensing transient receptor potential ion channels (thermoTRPs), in particular TRPV1, TRPV2, TRPM8 and TRPA1, have reached clinical development. This requires access for TRP channels and the effects of specific modulators in humans. This is currently possible via (i) the study of TRP channel function in human-derived cell lines, (ii) immunohistochemical visualization of TRP channel expression in human tissues, (iii) human experimental pain models employing sensitization by means of topical application of TRP channel activators including capsaicin (TRPV1), menthol (TRPM8), mustard oil and cinnamaldehyde (TRPA1), and (iv) the study of phenotypic consequences of human TRP gene variants. PMID- 29969685 TI - Multidisciplinary Approach in Large-sized Submucosal Myoma: Hysteroscopic Myomectomy after Uterine Artery Embolization. AB - STUDY OBJECTIVE: To evaluate the safety and effectiveness of hysteroscopic myomectomy after uterine artery embolization (UAE) for the treatment of large sized submucosal myomas with deep intramural invasion that are difficult to treat with 1-step hysteroscopy. DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: An academic university hospital. PATIENTS: Eight premenopausal patients with symptomatic submucosal myomas with intramural invasion. INTERVENTIONS: All of the patients after bilateral UAE underwent subsequent hysteroscopic operation 3 to 15 months after UAE. MEASUREMENTS AND MAIN RESULTS: A total of 8 patients who had a large-sized submucosal myoma with deep myometrial invasion were included. The average volume of the submucosal myomas was 87.7+/-39.9 cm3 as confirmed by magnetic resonance imaging, and the average patient age was 37.6 years. The mean volume reduction of the submucosal myomas was 83.3+/-16.4% after UAE, and no immediate complications were observed. One-step hysteroscopic myomectomy after UAE was successfully performed in all patients. Leiomyomas with hyaline degeneration were pathologically confirmed. All women showed improved symptoms, and there was no evidence of recurrence 1 year later. One patient conceived naturally and delivered a full-term baby. CONCLUSION: In premenopausal women with large-sized symptomatic submucosal myomas with deep myometrial invasion, hysteroscopic myomectomy after UAE is very effective and safe. PMID- 29969686 TI - Drug-Induced Anaphylaxis Documented in Electronic Health Records. AB - BACKGROUND: Although drugs represent a common cause of anaphylaxis, few large studies of drug-induced anaphylaxis have been performed. OBJECTIVE: To describe the epidemiology and validity of reported drug-induced anaphylaxis in the electronic health records (EHRs) of a large United States health care system. METHODS: Using EHR drug allergy data from 1995 to 2013, we determined the population prevalence of anaphylaxis including anaphylaxis prevalence over time, and the most commonly implicated drugs/drug classes reported to cause anaphylaxis. Patient risk factors for drug-induced anaphylaxis were assessed using a logistic regression model. Serum tryptase and allergist visits were used to assess the validity and follow-up of EHR-reported anaphylaxis. RESULTS: Among 1,756,481 patients, 19,836 (1.1%) reported drug-induced anaphylaxis; penicillins (45.9 per 10,000), sulfonamide antibiotics (15.1 per 10,000), and nonsteroidal anti-inflammatory drugs (NSAIDs) (13.0 per 10,000) were most commonly implicated. Patients with white race (odds ratio [OR] 2.38, 95% CI 2.27-2.49), female sex (OR 2.20, 95% CI 2.13-2.28), systemic mastocytosis (OR 4.60, 95% CI 2.66-7.94), Sjogren's syndrome (OR 1.94, 95% CI 1.47-2.56), and asthma (OR 1.50, 95% CI 1.43 1.59) had an increased odds of drug-induced anaphylaxis. Serum tryptase was performed in 135 (<1%) anaphylaxis cases and 1,587 patients (8.0%) saw an allergist for follow-up. CONCLUSIONS: EHR-reported anaphylaxis occurred in approximately 1% of patients, most commonly from penicillins, sulfonamide antibiotics, and NSAIDs. Females, whites, and patients with mastocytosis, Sjogren's syndrome, and asthma had increased odds of reporting drug-induced anaphylaxis. The low observed frequency of tryptase testing and specialist evaluation emphasize the importance of educating providers on anaphylaxis management. PMID- 29969687 TI - Endothelial cell-induced cytoglobin expression in vascular smooth muscle cells contributes to modulation of nitric oxide. AB - Cytoglobin is a widely expressed heme protein that binds oxygen, carbon monoxide and nitric oxide. Recent examination of cytoglobin in the vasculature indicates that it contributes to nitric oxide availability, which is central to normal blood vessel function through regulation of smooth muscle cell tone and physiological response. Given the potential implications of cytoglobin in vascular function, we examined how cytoglobin might be uniquely regulated in vascular smooth muscle cells. Our data demonstrate that endothelial cells can increase the expression of cytoglobin in vascular smooth muscle cells, and the induction of cytoglobin is cell contact-dependent. We show that Notch signaling is necessary for endothelial cell-induced cytoglobin expression and Notch2 and Notch3 are sufficient to drive its expression in aortic smooth muscle cells. We further reveal that in cytoglobin-depleted smooth muscle cells there is increased cellular nitric oxide. These data demonstrate that, in addition to being the main producer of vascular nitric oxide, endothelial cells facilitate the ability of smooth muscle cells to metabolize nitric oxide through upregulation of cytoglobin. Our results reveal a novel mechanism by which Notch signaling contributes to vascular function through regulation of a gene that controls nitric oxide levels. PMID- 29969688 TI - Attenuation of murine acute lung injury by PF-573,228, an inhibitor of focal adhesion kinase. AB - Acute lung injury (ALI) is characterized by endothelial barrier disruption resulting in increased vascular permeability. As focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, is involved in endothelial cell (EC) barrier regulation, we hypothesized that FAK inhibition could attenuate agonist induced EC barrier disruption relevant to ALI. Human lung EC were pretreated with one of three pharmacologic FAK inhibitors, PF-573,228 (PF-228, 10 MUM), PF 562,271 (PF-271, 5 MUM) or NVP-TAE226 (TAE226, 5 MUM) for 30 min prior to treatment with thrombin (1 U/ml, 30 min). Western blotting confirmed attenuated thrombin-induced FAK phosphorylation associated with all three inhibitors. Subsequently, EC were pretreated with either PF-228 (10 MUM), TAE226 (5 MUM) or PF-271 (5 MUM) for 30 min prior to thrombin stimulation (1 U/ml) followed by measurements of barrier integrity by transendothelial electrical resistance (TER). Separately, EC grown in transwell inserts prior to thrombin (1 U/ml) with measurements of FITC-dextran flux after 30 min confirmed a significant attenuation of thrombin-induced EC barrier disruption by PF-228 alone. Finally, in a murine ALI model induced by LPS (1.25 mg/ml, IT), rescue treatment with PF 228 was associated with significantly reduced lung injury. Our findings PF-228, currently being studied in clinical trials, may serve as a novel and effective therapeutic agent for ALI. PMID- 29969689 TI - Oxytocin levels in the saliva of preterm infant twins during Kangaroo care. AB - BACKGROUND AND PURPOSE: To investigate whether Kangaroo care (KC) influences the salivary oxytocin (OT) concentration in preterm infants, and which correlates affect the OT response. METHODS: Eleven twin pairs participated in a study in which we collected saliva using cotton swabs twice a day, once during KC and once during baseline conditions (lying in bed or incubator). The total study duration was five days. The saliva of twin siblings were pooled to obtain vials with sufficient volumes of either saliva collected during KC or at baseline. OT levels were measured using a radio-immuno assay. The infants' state of comfort and parent-infant interaction were examined using previously developed Likert-scales, amongst other correlates such as the KC duration, gestational age and birth weight. RESULTS: During KC, OT was lower compared to baseline (mean 1.39 pg/ml (SD 0.58 pg/ml) versus 2.40 pg/ml (SD 1.64 pg/ml), p = 0.03). Comfort at baseline and parent-infant interaction seemed to influence OT responses. CONCLUSION: The OT concentration in the pooled saliva of preterm infant twins decreased during KC. This response of the OT system might be explained by stress during baseline. PMID- 29969690 TI - Nail microbial colonization following hand disinfection: a qualitative pilot study. AB - Effective hand hygiene among healthcare workers is one of the basic principles of preventing nosocomial infections. The aim of the study was a qualitative examination of microbial colonization of nails following hand hygiene. The results were stratified by nail length: short versus long and the presence of a varnish coating: natural versus varnished. The presence of potentially pathogenic micro-organisms was correlated with nail length (odds ratio: 7.1; 95% confidence interval: 1.83-27.39; P < 0.001) and the presence of ultraviolet (UV)-cured nail polish (7.2; 1.25-40.91; P < 0.05). There is a high probability of ineffective hand hygiene when keeping long nails and when UV-cured nail polish is present on them. PMID- 29969691 TI - Point-prevalence survey of carbapenemase-producing Enterobacteriaceae and vancomycin-resistant enterococci in adult inpatients in a university teaching hospital in the UK. AB - Infections with carbapenemase-producing Enterobacteriaceae (CPE) and vancomycin resistant enterococci (VRE) are associated with increased morbidity and mortality, but the carriage rates of CRE and VRE among hospital inpatients are unknown. A point-prevalence survey was conducted to determine CPE and VRE carriage rates in hospitalized adults. Eight hundred and eighteen of 960 (85.2%) adult inpatients were invited to participate in the study. Of these, 595 patients (72.7%) consented and provided specimens. Of 540 samples tested, none were positive for CPE. One hundred and thirty of 540 (24.1%) samples were VRE positive, and 34 of 40 (85%) of wards had cases. Universal screening for CPE may not be cost-effective in low-prevalence settings, but targeted screening of high risk patients should continue. The optimal screening strategy for VRE remains to be determined, as universal screening and isolation is not feasible in the study setting. PMID- 29969693 TI - Potentiation of the leishmanicidal activity of nelfinavir in combination with miltefosine or amphotericin B. AB - The present work assesses the effect in vitro of combining the antiretroviral drug nelfinavir (NFV), a drug used against HIV but also a strong in vitro inhibitor of the growth of Leishmania promastigotes and amastigotes, with amphotericin B or miltefosine on different strains of Leishmania infantum. The isobolograms revealed a synergistic effect for both combinations, with a fractional inhibitory concentration index (?FIC) <0.5. The ?FIC values obtained with reference strain MCAN/ES/98/LLM-724 were 0.25 +/- 0.1 (95% CI: 0.178-0.322) for the combination NFV+AMB and 0.48 +/- 0.2 (95% CI: 0.377-0.573) for the combination NFV+MTF. The effect of NFV on visceral leishmaniasis induced by L. infantum in BALB/c mice was also examined, and the results confirmed a leishmanicidal effect when administered alone, with approximately 60% (P<0.05) reductions in the liver and spleen parasite burdens. This is the first time this has been reported in an in vivo model. A significant reduction in the liver (77%; P<0.01) and spleen (76%; P<0.01) parasite burdens was also observed for NFV+MTF compared with those obtained when these drugs were used alone. This indicates that such combinations may be useful treatment options in patients with visceral leishmaniasis who are also infected with HIV. PMID- 29969692 TI - Predictors of outcome in patients with severe sepsis or septic shock due to extended-spectrum beta-lactamase-producing Enterobacteriaceae. AB - PURPOSE: There are few data in the literature regarding sepsis or septic shock due to extended-spectrum beta-lactamases (ESBL)-producing Enterobacteriaceae (E). The aim of this study was to assess predictors of outcome in septic patients with bloodstream infection (BSI) caused by ESBL-E. METHODS: Patients with severe sepsis or septic shock and BSI due to ESBL-E were selected from the INCREMENT database. The primary endpoint of the study was the evaluation of predictors of outcome after 30 days from development of severe sepsis or septic shock due to ESBL-E infection. Three cohorts were created for analysis: global, empirical therapy and targeted-therapy cohorts. RESULTS: 367 septic patients were analysed. Overall mortality was 43.9% at 30 days. Escherichia coli (62.4%) and Klebsiella pneumoniae (27.2%) were the most frequent isolates. beta-lactam/beta-lactamase inhibitor (BLBLI) combinations were the most empirically used drug (43.6%), followed by carbapenems (29.4%). Empirical therapy was active in vitro in 249 (67.8%) patients, and escalation of antibiotic therapy was reported in 287 (78.2%) patients. Cox regression analysis showed that age, Charlson Comorbidity Index, McCabe classification, Pitt bacteremia score, abdominal source of infection and escalation of antibiotic therapy were independently associated with 30-day mortality. No differences in survival were reported in patients treated with BLBLI combinations or carbapenems in empirical or definitive therapy. CONCLUSIONS: BSI due to ESBL-E in patients who developed severe sepsis or septic shock was associated with high 30-day mortality. Comorbidities, severity scores, source of infection and antibiotic therapy escalation were important determinants of unfavorable outcome. PMID- 29969694 TI - A novel prognostic biomarker for pancreatic ductal adenocarcinoma: hsa_circ_0001649. AB - Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with increasing incidence worldwide. Accumulating evidence indicated that circular RNAs (circRNAs) behave as a novel class of transcription products during multiple cancer processes. Specifically, hsa_circ_0001649 has been reported to be down regulated in several cancers. However, its clinical significance and functional roles in PDAC is still unknown. RT-qPCR was carried out to measure the expression of hsa_circ_0001649 in PDAC tissue samples and cell lines. Additionally, the correlation between hsa_circ_0001649 expression and clinicopathological features was analyzed. The prognostic role of hsa_circ_0001649 was explored by Cox regression analysis. The potential effects of hsa_circ_0001649 in PDAC cells were evaluated in vitro including cell proliferation, colony-forming ability and apoptosis. As a result, hsa_circ_0001649 was abnormally decreased in PDAC tissues and cells, and this down-regulation was correlated with tumor stage and differentiation grade in PDAC patients. Hsa_circ_0001649 could serve as an independent prognostic factor for PDAC patients after surgery. What's more, increased hsa_circ_0001649 caused tumor suppressive effects via reducing cell proliferation, colony-forming ability and promoting cell apoptosis in PANC1 and BxPC3 cells. Collectively, the results illustrated that hsa_circ_0001649 may play a tumor suppressor role in PDAC and offer a potential therapeutic target for treating this fatal disease. PMID- 29969695 TI - Hypermethylated CD36 gene affected the progression of lung cancer. AB - OBJECTIVE: Our study aimed to explore the relationship between CD36 methylation and the development of lung cancer and investigate the effect of combine treatment of Decitabine and Chidamide in lung cancer. METHODS: The differentially expression genes in tumor samples and normal samples were determined by microarray analysis. Weighted gene co-expression network analysis (WGCNA) was utilized to analyze gene expression data of lung cancer and the hub genes were screened in the modules. Methylation-specific PCR (MSP) was conducted to detect the methylation level of CD36 in lung cancer cells. QRT-PCR analysis and western blotting were performed to explore the relative mRNA expression and protein level. MTT assays, wound healing assay, Transwell assays and flow cytometry were conducted to clarify the cell proliferation, migration, invasion and cell cycle of lung carcinoma cell lines in vitro respectively. By xenograft and immunohistochemistry, the effect of co-treatment of Decitabine and Chidamide was further verified in vivo. RESULTS: The heatmap displayed that the top 20 differential mRNA-expression gene in lung cancer tissues and normal tissues in which CD36 was low expressed in the tumor samples and high expressed in the normal samples. By WGCNA, CD36 was selected to be the hub gene in the brown module. And then CD36 was confirmed to be differential expressed and hypermethylated in lung cancer through qRT-PCR and western blotting. CD36 inhibited the lung cancer cell proliferation, promoted cell apoptosis, blocked cell cycle at G0/G1 phase, and inhibited cell migration. What's more, we found that Decitabine (DCTB) and Chidamide (CDM) co-treatment induced de-methylation and re-expression of silenced CD36 by conducting the vivo experiments. DCTB + CDM co-treatment synergistically suppressed tumor growth. CONCLUSION: Our results showed that the high methylation of CD36 in lung cancer played an important role in the procession of lung cancer and Decitabine joint Chidamide had obvious effect of inhibiting the growth of lung tumor. PMID- 29969697 TI - Genome-wide transcriptome profiling provides insights into panicle development of rice (Oryza sativa L.). AB - Panicle architecture is an important component of agronomic trait in rice, which is also a key ingredient that could influence yield and quality of rice. In the panicle growth and development process, there are a series of complicated molecular and cellular events which are regulated by many interlinking genes. In this study, to explore the potential mechanism and identify genes and pathways involved in the formation of rice panicle, we compared the transcriptional profile of rice panicles (NIL-GW8 and NIL-gw8Amol) at three different stages of panicle development: In5 (formation of higher-order branches), In6 (differentiation of glumes) and In7 (differentiation of floral organs). A range of 40.5 to 54.1 million clean reads was aligned to 31,209 genes in our RNA-Seq analysis. In addition, we investigated transcriptomic changes between the two rice lines during different stages. A total of 726, 1121 and 2584 differentially expressed genes (DEGs) were identified at stages 1, 2 and 3, respectively. Based on an impact analysis of the DEGs, we hypothesize that MADS-box gene family, cytochrome P450 (CYP) and pentatricopeptide repeat (PPR) protein and various transcription factors may be involved in regulation of panicle development. Further, we also explored the functional properties of DEGs by gene ontology analysis, and the results showed that different numbers of DEGs genes were associated with 53 GO groups. In KEGG pathway enrichment analysis, many DEGs related to biosynthesis of secondary metabolites and plant hormone signal transduction, suggesting their important roles during panicle development. This study provides the first examination of changes in gene expression between different panicle development stages in rice. Our results of transcriptomic characterization provide important information to elucidate the complex molecular and cellular events about the panicle formation in rice or other cereal crops. Also, the findings will be helpful for the further identification of the genes related to panicle development. PMID- 29969696 TI - Hsa-miR-497 as a new regulator in TGFbeta signaling pathway and cardiac differentiation process. AB - Cardiosphere-derived cells (CDCs) contain cardiac stem cell subpopulations and are introduced as useful source for cardiac differentiation and therapy. Furthermore, research has highlighted miRNAs important role in various biological processes and cardiogenesis. Here, we intended to investigate the effect of hsa miR-497 (miR-497) on TGFbeta signaling pathway genes expression during the process of CDCs differentiation to cardiomyocytes. CDCs were successfully differentiated to the cardiac-like cells. In this study, we found that after cardiac differentiation induction, miR-497 expression was significantly decreased. Computational miRNA target prediction analyses revealed that TGFbeta signaling pathway is a possible target of miR-497. Therefore, miR-497 was overexpressed in CDCs before the induction of differentiation. TGFbeta1, TGFbetaR1, TGFbetaR2, and SMAD3 genes expression level was decreased after miR 497 overexpression. Also, immunocytochemistry and cell morphology analysis indicated that miR-497 overexpression affecting cardiac differentiation process. Finally, direct interaction of miR-497 with 3'-UTR sequence of TGFbetaR1 was supported through dual luciferase assay, consistent with miR-497 reported negative effect on SMAD3 expression. Accordingly, here a model of miR-497 involvement in regulation of TGFbeta signaling pathway is introduced in which, side branches of TGFbeta signaling pathway downregulate miR-497 to ensure upregulation of TGFbetaR1 and TGFbetaR2 and finally stronger TGFbeta signaling. PMID- 29969698 TI - The use of a tympanoplasty blade for tumor extirpation of the auricle. PMID- 29969699 TI - Choosing the right biologic for psoriatic patients may be in the cards. PMID- 29969700 TI - Ixekizumab provides superior efficacy compared with ustekinumab over 52 weeks of treatment: Results from IXORA-S, a phase 3 study. AB - BACKGROUND: Biologics targeting interleukin 17A (IL-17A) allow for rapid clearance of psoriatic plaques, with a clinically favorable safety profile. OBJECTIVES: To compare the safety and efficacy of ixekizumab, an IL-17A antagonist, with the safety and efficacy of the IL-12/23 inhibitor ustekinumab through 52 weeks of treatment in the head-to-head trial IXORA-S. METHODS: Patients were randomized to ixekizumab (n = 136) or ustekinumab (n = 166) and dosed per the approved labels. After 1 year, efficacy was assessed via improvements in Psoriasis Area and Severity Index (PASI) score (with PASI 90 indicating a 90% or greater improvement from baseline PASI score) and a static Physician's Global Assessment (sPGA) response of either 0 or 0 or 1, with dropouts counted as nonresponders. Safety analyses included treatment-emergent adverse events (AEs). RESULTS: At week 52, significantly more ixekizumab-treated patients (P < .01) reported PASI 90 (104 [76.5%]), an sPGA response of 0 (72 [52.9%]), or an sPGA response of 0 or 1 (110 [82.1%]) responses than did ustekinumab-treated patients (PASI 90, 98 [59.0%]; sPGA response of 0, 60 [36.1%]; and sPGA response of 0 or 1, 108 [65.1%]). Treatment-emergent AEs, serious AEs, and discontinuation rates were not different between the treatment groups. Injection site reactions occurred more frequently in the ixekizumab treated group (ixekizumab, 22 [16.3%]; ustekinumab, 2 [1.2%]) (P < .001). LIMITATIONS: This study was not designed to compare safety end points related to rare events. CONCLUSIONS: Compared with ustekinumab, ixekizumab showed superior efficacy and comparable safety outcomes through 52 weeks of treatment. PMID- 29969701 TI - Natural history of disease activity and damage in patients with cutaneous lupus erythematosus. AB - BACKGROUND: Long-term studies characterizing disease course of cutaneous lupus erythematosus (CLE) patients on standard-of-care treatments are lacking. OBJECTIVE: We characterized and compared disease course of CLE patients using Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). METHODS: In total, 83 CLE patients with CLASI scores collected from >=3 study visits within 2 years had disease activity and damage trends calculated by average change scores (ACS). Trends were classified as improved (ACS <=-3), worsened (ACS >=3), or stable (-3 < ACS < 3). Linear regression models compared CLASI trends between groups. RESULTS: Most patients (72.73%) with initial CLASI activity (CLASI-A) scores >9 (N = 33) had improved disease activity versus 14.00% of those with initial CLASI-A scores <=9 (N = 50). Linear regression analyses showed significant improvement in CLASI-A scores in patients of minority races (P < .05), with baseline CLASI-A scores >9 (P < .0001), baseline CLASI damage (CLASI D) scores >=10 (P = .0001), and CLE disease duration <=1 year (P = .01). Of 28 patients with baseline CLASI-D scores >=10, 35.71% had improvements in damage, while 5.26% of patients with initial CLASI-D scores of 5-9 (N = 19) and 0% with initial CLASI-D scores <5 (N = 36) (P = .0005) had improvements. LIMITATIONS: Limitations include small sample size. CONCLUSION: Baseline CLASI-A score >9, minority race, and short disease duration predict CLE disease activity improvement. A baseline CLASI-D score >=10 is associated with disease damage improvement. PMID- 29969702 TI - Ovine plasma dipalmitoylphosphatidylcholine does not predict decompression bubbling. AB - Decompression illness (DCI) is the main risk associated with scuba diving. Some divers ("bubblers") are more sensitive to DCI than others ("non-bubblers"). We found that there are active hydrophobic spots (AHS) on the luminal aspect of ovine blood vessels, which contain the surfactant dipalmitoylphosphatidylcholine (DPPC). DPPC leaks from the lung into the plasma, settling on the blood vessel to create AHS. These are the main source of gas micronuclei from which bubbles develop after decompression. A correlation between bubbling ovine blood vessels and the animal's plasma DPPC might lead to the development of a blood test for vulnerability to DCI. Samples from ovine blood vessels were stretched on microscope slides, placed anaerobically in saline at the bottom of a Pyrex bowl, and exposed to high pressure. Automated photography was used after decompression to reveal AHS by visualising their bubble production. Phospholipids were extracted from the AHS and plasma for determination of DPPC. Bubbling was unrelated to the concentration of DPPC in the plasma (2.15 +/- 0.87 MUg/ml). Bubble production from the AHS (n = 130) as a function of their DPPC content yielded two groups, one unrelated to DPPC and the other which demonstrated increased bubbling with elevation of DPPC. We suggest this may be related to alternate layering with hydrophobic and hydrophilic phospholipids. This study reinforces the connection between DPPC and DCI. However, a blood test for diver vulnerability to decompression stress is not recommended. PMID- 29969703 TI - No evidence in support of a prodromal respiratory control signature in the TgF344 AD rat model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative condition disturbing major brain networks, including those pivotal to the motor control of breathing. The aim of this study was to examine respiratory control in the TgF344-AD transgenic rat model of AD. At 8-11 months of age, basal minute ventilation and ventilatory responsiveness to chemostimulation were equivalent in conscious wild type (WT) and TgF344-AD rats. Under urethane anesthesia, basal diaphragm and genioglossus EMG activities were similar in WT and TgF344-AD rats. The duration of phenylbiguanide-induced apnoea was significantly shorter in TgF344-AD rats compared with WT. Following bilateral cervical vagotomy, diaphragm and genioglossus EMG responsiveness to chemostimulation were intact in TgF344-AD rats. Amyloid precursor protein C-terminal fragments were elevated in the TgF344 AD brainstem, in the absence of amyloid-beta accumulation or alterations in tau phosphorylation. Brainstem pro-inflammatory cytokine concentrations were not increased in TgF344-AD rats. We conclude that neural control of breathing is preserved in TgF344-AD rats at this stage of the disease. PMID- 29969704 TI - Astrocyte networks modulate respiration - sniffing glue. AB - The role of astrocytes in the modulation of breathing has emerged. Within the two major respiratory control centers, the inspiration generating preBotzinger Complex and the chemosensitive parafacial respiratory group/retrotrapezoid nucleus, rhythmically active astrocytes have been discovered. These are connected in glial subnetworks that intermingle with the neuronal network. Furthermore, astrocytes modify overall respiratory network behavior through gliotransmitter release, especially during hypoxic and hypercapnic stress. Here, we review some recent discoveries regarding astrocyte-neuronal interactions on a cellular as well as neural network level including the novel gliotransmitter PGE2. PMID- 29969706 TI - Generation of a novel Streptococcus agalactiae ghost vaccine and examination of its immunogenicity against virulent challenge in tilapia. AB - Streptococcus agalactiae (S. agalactiae) is a gram-positive pathogen that causes a wide range of infections in fish and other animals including humans. Bacterial ghosts (BGs) are nonliving, empty cell envelopes and are well represented as novel vaccine candidates. In this study, we examined the immunogenicity and protective efficacy of S. agalactiae ghosts (SAG) against a virulent challenge in tilapia. Nonliving SAG was generated by a culture with Penicillin and Streptolysin, and then treated with the MIC of sodium hydroxide. The formation of a transmembrane lysis tunnel structure in SAG was visualized by electron microscopy. To investigate the SAG as a vaccine candidate, fish were divided into three groups, A (SAG immunized), B [Formalin-inactivated S. agalactiae (FSA) immunized] and C (phosphate-buffered saline, PBS-immunized control). The IgM antibody responses were significantly stronger in the SAG-immunized group than in FSA-immunized group, which was higher than in the non-immunized control group (P < 0.05). Moreover, phagocytic activity (percent phagocytes, PP) was significantly higher (p < 0.05) in the SAG-immunized group than in FSA-immunized group, which was higher than in the non-immunized control group (P < 0.05). In addition, non specific immune immunity, such as lysozyme and superoxide dismutase activities, in the SAG-immunized fish showed significantly higher activities than FSA immunized fish and the control group fish (P < 0.05). Also, fish immunized with SAG and FSA showed significantly higher (p < 0.05) gene expression of IL-1beta, TNF-alpha, IFN-gamma and TGF-beta in the head kidney and spleen than fish treated with PBS during the whole observed period. In addition, fish immunized with SAG showed significantly higher gene expression of L-1beta, TNF-alpha, and TGF-beta in the spleen than in the FSA-immunized fish. Although there was no significant (P > 0.05) difference of survival rate (SR) or relative percent survival (RPS) between SAG and FSA immunized groups, they were all significantly more protected against the S. agalactiae challenge (SR: 86.67%, RPS: 76.395) and (SR: 80.00%, RPS: 67.50%) respectively, compared to the PBS-treated group (SR: 33.33%). These results suggest that immunization with SAG induces immune responses and provides protection against a virulent S. agalactiae challenge. PMID- 29969705 TI - Thoracoabdominal asynchrony and paradoxical motion in middle stage amyotrophic lateral sclerosis. AB - AIM: To assess thoracoabdominal asynchrony (TAA) and the presence of paradoxical motion in middle stage amyotrophic lateral sclerosis (ALS) and its relationships with chest wall tidal volume (VT,CW), breathing pattern and cough peak flow (CPF). METHODS: Phase angle (theta) between upper (RCp) and lower ribcage (RCa) and abdomen (AB), as well as percentage of inspiratory time for the lower ribcage (IPRCa) and abdomen (IPAB) moving in opposite directions were quantified using optoelectronic plethysmography in 12 ALS patients during quiet breathing and coughing. Paradoxical motion of the compartments was based on threshold values of theta and IP, obtained in twelve age and sex matched healthy persons. RESULTS: During quiet breathing, significantly higher RCa and AB theta (p < .05), IPRCa (p = 0.001) and IPAB (p < 0.05) were observed in ALS patients as compared to controls. In ALS patients, correlations between RCa and AB theta with forced vital capacity (FVC) (r=-0.773, p < 0.01), vital capacity (r=-0.663, p < 0.05) and inspiratory capacity (IC) (r=-0.754, p < 0.01), as well as between RCp and RCa theta with FVC (r=-0.608, p < 0.05) and CPF (r=-0.601, p < 0.05) were found. During coughing, correlations between RCp and AB theta with CPF (r=-0.590, p < 0.05), IC (r=-0.748, p < 0.01) and VT,CW (r=-0.608, p < 0.05), as well as between RCa and AB theta with CPF (r=-0.670, p < 0.05), IC (r=-0.713, p < 0.05) and peak expiratory flow (r=-0.727, p < 0.05) were also observed in ALS patients. ALS patients with paradoxical motion presented lower vital capacity and FVC%pred (p < 0.05) compared to those without paradoxical motion. CONCLUSIONS: Middle stage ALS patients exhibit TAA and paradoxical motion during quiet spontaneous breathing and coughing. In addition, diaphragmatic weakness (i.e. decrease in excursion of the RCa and AB compartments) was observed earlier in the lower ribcage rather than the abdominal compartment in this population. PMID- 29969707 TI - Time-course study of the protection induced by an interferon-inducible DNA vaccine against viral haemorrhagic septicaemia in rainbow trout. AB - The highly effective DNA vaccines against diseases caused by fish rhabdoviruses in farmed fish consist of a DNA plasmid vector encoding the viral glycoprotein under the control of a constitutive cytomegalovirus promoter (CMV). Among others, attempts to improve efficacy and safety of these DNA vaccines have focused on regulatory elements of plasmid vectors, which play a major role in controlling expression levels of vaccine antigens. Depending on the context, use of a fish derived promoter with minimal activity in mammalian cells could be preferable. Another aspect related to the CMV promoter is that constitutive expression of the vaccine antigen may lead to rapid elimination of antigen expressing cells in the fish and thereby potentially reduce the long-term effects of the vaccine. In this study, we compared DNA vaccines with the interferon-inducible Mx promoter from rainbow trout and the CMV promoter, respectively. Plasmid constructs encoding the enhanced green fluorescent protein (EGFP) were used for the in vitro analysis, whereas DNA vaccines encoding the glycoprotein (G) of the viral haemorrhagic septicaemia virus (VHSV) were applied for the in vivo examination. The in vitro analysis showed that while the DNA vaccine with the CMV promoter constitutively drove the expression of EGFP in both fish and human cell lines, the DNA vaccine with the Mx promoter inducibly enhanced the expression of EGFP in the fish cell line. To address the impact on protection, a time-course model was followed as suggested by Kurath et al. (2006), where vaccinated fish were challenged with VHSV at 2, 8 and 78 weeks post-vaccination (wpv). The DNA vaccine with the CMV promoter protected at all times, while vaccination with the DNA vaccine containing the Mx promoter only protected the fish at 8 wpv. However, following induction with Poly (I:C) one week before the challenge, high protection was also evident at 2 wpv. In conclusion, the results revealed a more fish host dependent activity of the trout Mx promoter compared to the traditionally used cross species-active CMV promoter, but improvements will be needed for its application in DNA vaccines to ensure long term protection. PMID- 29969708 TI - Edaravone, a cytoprotective drug, enhances transgene expression mediated by lipoplexes in HepG2 cells and mice. AB - A requirement of gene therapy is efficient nucleic acid delivery. However, the application of cationic liposomes to gene therapy is restricted by their inefficient transfection capacity, which may be caused by cytotoxicity. This cytotoxicity is highly dependent on cationic lipid-induced reactive oxygen species (ROS). Here, to provide cellular protection, we used edaravone, an efficacious anti-oxidative drug, to scavenge ROS during transfection using cationic liposome/plasmid DNA complexes (lipoplexes). Both free edaravone and edaravone-loaded liposomes (EDLPs) enhanced transgene expression in the human hepatoma cell line, HepG2, while EDLPs decreased the effective dose of edaravone. The cellular protective effect of edaravone was found to decrease the cytotoxicity of cationic liposomes. Edaravone was also effective in the commercial product, Lipofectamine(r) 3000, which may expand the application of edaravone to promote transfection efficiency. Compared with free edaravone, EDLPs also showed superior transgene expression in mice. Our findings will promote the development of efficient and safe gene therapy. PMID- 29969709 TI - Low molecular-weight hyaluronan as a cryoprotectant for the storage of microencapsulated cells. AB - The low-temperature storage of therapeutic cell-based products plays a crucial role in their clinical translation for the treatment of diverse diseases. Although dimethylsulfoxide (DMSO) is the most successful cryoprotectant in slow freezing of microencapsulated cells, it has shown adverse effects after cryopreserved cell-based products implantation. Therefore, the search of alternative non-toxic cryoprotectants for encapsulated cells is continuously investigated to move from bench to the clinic. In this work, we investigated the low molecular-weight hyaluronan (low MW-HA), a natural non-toxic and non-sulfated glycosaminoglycan, as an alternative non-permeant cryoprotectant for the slow freezing cryopreservation of encapsulated cells. Cryopreservation with low MW-HA provided similar metabolic activity, cell dead and early apoptotic cell percentage and membrane integrity after thawing, than encapsulated cells stored with either DMSO 10% or Cryostor 10. However, the beneficial outcomes with low MW HA were not comparable to DMSO with some encapsulated cell types, such as the human insulin secreting cell line, 1.1B4, maybe explained by the different expression of the CD44 surface receptor. Altogether, we can conclude that low MW HA represents a non-toxic natural alternative cryoprotectant to DMSO for the cryopreservation of encapsulated cells. PMID- 29969710 TI - Preparation of spray dried submicron particles: Part B - Particle recovery by electrostatic precipitation. AB - The low bioavailability of poorly water-soluble drugs is currently one of the major focuses of pharmaceutical research. One strategy currently being investigated to overcome this limitation is to decrease the particle size of the active pharmaceutical ingredients (API). An innovative process for this is spray drying with spray conditioning, which can produce submicron particles. One challenge resulting from this process is the recovery of these dispersed particles from a gas flow. Electrostatic precipitation is a common technique for air purification purposes, but an adapted electrostatic precipitator (ESP) design is necessary to achieve high collection efficiencies. The ESP design in this work uses the precipitation method of Penney filters which separates charging and collection into two stages. The ESP dimensions depend on various assumptions and simplifications. Several experiments were conducted to assess the performance of the ESP and characterize its behaviour in long-term tests. The crucial parameters in the charging process are the residence time as well as the operating voltage. These constraints were examined to enhance the collection efficiency. Based on these tests it was possible to determine a suitable charging length as well as the dimensions of the collection stage. In conclusion, an ESP customized for collecting particles in the range of 0.1-1 um was designed, built and tested, and collection efficiencies higher than 99% were achieved for submicron particle size distributions. For a robust process continuous cleaning of the charging stage is necessary. PMID- 29969711 TI - All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance. AB - The term "disease" conjures a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic and pharmacodynamic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. This knowledge, however, applies less so in the context of drug absorption and distribution for orally administered dosage forms. Here, we revisit and re evaluate the influence of a portfolio of gastrointestinal diseases and surgical effects on the functionality of the gastrointestinal tract, their implications for drug delivery and attempt to uncover significant links for clinical practice. PMID- 29969712 TI - Development and characterization of gemcitabine hydrochloride loaded lipid polymer hybrid nanoparticles (LPHNs) using central composite design. AB - Lipid polymer hybrid nanoparticles (LPHNs) combine the characteristics and beneficial properties of both polymeric nanoparticles and liposomes. The objective of this study was to design and optimize gemcitabine hydrochloride loaded LPHNs based on the central composite design approach. PLGA 50:50/PLGA 65:35 mass ratio (w/w), soya phosphatidylcholine (SPC)/polymer mass ratio (%, w/w) and amount of DSPE-PEG were chosen as the investigated independent variables. The LPHNs were prepared with modified double emulsion solvent evaporation method and characterized by testing their particle size, encapsulation efficiency, and cumulative release. The composition of optimal formulation was determined as 1,5 (w/w) PLGA 50:50/PLGA 65:35 mass ratio, 30% (w/w) SPC/polymer mass ratio and 15 mg DSPE-PEG. The results showed that the optimal formulation gemcitabine hydrochloride loaded LPHNs had encapsulation efficiency of 45,2%, particle size of 237 nm and cumulative release of 62,3% at the end of 24 h. The morphology of LPHNs was found to be spherical by transmission electron microscopy (TEM) observation. Stability studies showed that LPHNs were physically stable until 12 months at 4 degrees C and 9 months at 25 degrees C/60% RH. The results suggest that the LPHNs can be an effective drug delivery system for hydrophilic active pharmaceutical ingredient. PMID- 29969713 TI - Self-microemulsifying tablets prepared by direct compression for improved resveratrol delivery. AB - The purpose of this study was to develop self-microemulsifying (SME-) tablets to improve resveratrol solubility whilst delivering resveratrol in a preferred tablet dosage form. Resveratrol was dissolved in liquid self-microemulsifying drug delivery system (SMEDDS) (10% w/w) and solidified through adsorption on several different solid carriers. Two ranges of synthetic amorphous silica (Sylysia(r) 290, 350, 470, 580; Syloid(r) 244FP, AL-1FP) as well as granulated magnesium aluminometasilicate (Neusilin(r) US2) were screened for their SMEDDS adsorbent capacity. The most efficient carrier from every range was chosen for further SME-tablet development. To counteract the high ratio of liquid in SME tablets, additional dry binders (microcrystalline cellulose, copovidone) were added to the tableting mixture, as well as superdisintegrant (croscarmellose sodium) and lubricant (magnesium stearate). Finally, approx. 600 mg tablets were directly pressed using 12 mm flat face punch, containing 41.75% SMEDDS. Overall, all tablets exhibited sufficient hardness (>50 N), although it was negatively affected by higher compression force. Tablets with Neusilin(r) US2 proved to have highest hardness, as granulated structure of Neusilin(r) US2 provided best compaction properties needed for successful direct compression of tablets. All prepared SME tablet formulations disintegrated in under 10 min and formed microemulsions (droplet size < 100 nm) upon dilution with water, with Neusilin(r) US2 tablets exhibiting the lowest droplet size (<30 nm). While conventional dissolution test indicated incomplete resveratrol release from solid carriers in both pH 1.2 and 6.8 media, no difference fatty acid amount titrated during fasted state in vitro lipolysis between liquid and solid SMEDDS was observed. Moreover, accelerated stability tests confirmed over 90% of trans-resveratrol remained in solid SMEDDS following 90 days at 40 degrees C, with no crystallization of resveratrol observed during that time. To sum up, through adsorption on solid carriers, in particular Neusilin(r) US2, SMEDDS was successfully transformed into a directly compressible mixture and tableted without the loss of its self microemulsifying ability. PMID- 29969714 TI - Dr. Jekyll and Mr. Hyde: Oxidizable phenol-generated reactive oxygen species enhance sulforaphane's antioxidant response element activation, even as they suppress Nrf2 protein accumulation. AB - The transcription factor Nrf2 is a master regulator of antioxidant and cytoprotective genes, binding to antioxidant response elements (AREs) in their promoter regions. Due to the therapeutic role of the Nrf2/ARE system in oxidative homeostasis, its activation has been investigated in many pre-clinical and clinical trials for common chronic diseases. One of the most promising Nrf2 activators is sulforaphane, the subject of over 50 clinical trials. In this work, we examine the effect of reactive oxygen species (ROS) on sulforaphane's Nrf2/ARE activation in the non-tumorigenic keratinocyte cell line HaCaT, with the non arylating oxidizable phenol, 2,5-di-tert-butylhydroquinone (dtBHQ), as the source of ROS. We find that, in combination with 2.5 uM sulforaphane, dtBHQ markedly enhances ARE-regulated gene expression, including expression of the cytoprotective proteins aldo-keto reductase family 1 member C1 (AKR1C1) and heme oxygenase-1 (HO-1). Additionally, sulforaphane's therapeutic window is widened by 12.5 uM dtBHQ. Our data suggest that H2O2 generated by dtBHQ oxidation is responsible for these effects, as shown by inclusion of catalase and by co treatment with sulforaphane and H2O2. While sulforaphane treatment causes Nrf2 protein to accumulate as expected, interestingly, dtBHQ and H2O2 appear to act on targets downstream of Nrf2 protein accumulation to enhance sulforaphane's ARE regulated gene expression. Inclusion of dtBHQ or H2O2 with sulforaphane does not increase Nrf2 protein levels, and catalase has little effect on Nrf2 protein levels in the presence of sulforaphane and dtBHQ. Surprisingly, dtBHQ suppresses Nrf2 protein synthesis. Inclusion of a superoxide dismutase mimetic with sulforaphane and dtBHQ partly rescues Nrf2 suppression and significantly further increases sulforaphane's efficacy for ARE-reporter expression. Thus, there is a "Dr. Jekyll and Mr. Hyde" effect of ROS: ROS enhance sulforaphane's ARE-regulated gene expression even as they also inhibit Nrf2 protein synthesis. This unexpected finding reveals the degree to which targets in the ARE pathway downstream of Nrf2 protein accumulation contribute to gene expression. The results presented here provide a model system for significant enhancement of sulforaphane's potency with small molecule co-treatment. PMID- 29969715 TI - Increased TFAM binding to mtDNA damage hot spots is associated with mtDNA loss in aged rat heart. AB - The well-known age-related mitochondrial dysfunction deeply affects heart because of the tissue's large dependence on mitochondrial ATP provision. Our study revealed in aged rat heart a significant 25% decrease in mtDNA relative content, a significant 29% increase in the 4.8 Kb mtDNA deletion relative content, and a significant inverse correlation between such contents as well as a significant 38% decrease in TFAM protein amount. The TFAM-binding activity to specific mtDNA regions increased at those encompassing the mtDNA replication origins, D-loop and Ori-L. The same mtDNA regions were screened for different kinds of oxidative damage, namely Single Strand Breaks (SSBs), Double Strand Breaks (DSBs), abasic sites (AP sites) and oxidized bases as 7,8-dihydro-8-oxoguanine (8oxoG). A marked increase in the relative content of mtDNA strand damage (SSBs, DSBs and AP sites) was found in the D-loop and Ori-L regions in the aged animals, unveiling for the first time in vivo an age-related, non-stochastic accumulation of oxidative lesions in these two regions that appear as hot spots of mtDNA damage. The use of Formamidopyrimidine glycosylase (Fpg) demonstrated also a significant age-related accumulation of oxidized purines particularly in the D-loop and Ori-L regions. The detected increased binding of TFAM to the mtDNA damage hot spots in aged heart suggests a link between TFAM binding to mtDNA and loss of mitochondrial genome likely through hindrance of repair processes. PMID- 29969716 TI - Plasma lipid peroxidation biomarkers for early and non-invasive Alzheimer Disease detection. AB - INTRODUCTION: Alzheimer Disease (AD) standard diagnosis is based on evaluations and biomarkers that are non-specific, expensive, or requires invasive sampling. Therefore, an early, and non-invasive diagnosis is required. As regards molecular mechanisms, recent research has shown that lipid peroxidation plays an important role. METHODS: Well-defined participants groups were recruited. Lipid peroxidation compounds were determined in plasma using a validated analytical method. Statistical studies consisted of an elastic-net-penalized logistic regression adjustment. RESULTS: The regression model fitted to the data included six variables (lipid peroxidation biomarkers) as potential predictors of early AD. This model achieved an apparent area under the receiver operating characteristics (AUC-ROCs) of 0.883 and a bootstrap-validated AUC-ROC of 0.817. Calibration of the model showed very low deviations from real probabilities. CONCLUSION: A satisfactory early diagnostic model has been obtained from plasma levels of 6 lipid peroxidation compounds, indicating the individual probability of suffering from early AD. PMID- 29969717 TI - Nox4 in renal diseases: An update. AB - Reactive oxygen species derived from NADPH oxidase contribute to a wide variety of renal diseases. Nox4, the major NADPH isoform in kidney, produces mainly H2O2 that regulates physiological functions. Nox4 contributes to redox processes involved in diabetic nephropathy, acute kidney injury, obstructive nephropathy, hypertensive nephropathy, renal cell carcinoma and other renal diseases by activating multiple signaling pathways. Although Nox4 is found in a variety of cell types, including epithelial cells, podocytes, mesangial cells, endothelial cells and fibroblasts, its role is not clear and even controversial. In some conditions, Nox4 protects cells by promoting cell survival in response to harmful stimuli. In other scenarios it induces cell apoptosis, inflammation or fibrogenesis. This functional variability may be attributed to distinct cell types, subcellular localization, molecular concentrations, disease type or stage, and other factors yet unexplored. In this setting, we reviewed the function and mechanism of Nox4 in renal diseases, highlighted the contradictions in Nox4 literature, and discussed promising therapeutic strategies targeting Nox4 in the treatment of certain types of renal diseases. PMID- 29969718 TI - IRE1alpha aggravates ischemia reperfusion injury of fatty liver by regulating phenotypic transformation of kupffer cells. AB - Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all. This study evaluates whether ER-stress of KCs is activated in fatty liver and accelerate IRI of fatty livers. ER-stress of KCs was activated in fatty liver, especially the IRE1alpha signal pathway. KCs with activated ER-stress secreted more proinflammatory cytokine to induce its M1-phenotypic shift in fatty liver, resulting in more severe IRI. Also, activated ER-stress of BMDMs in vitro by tunicamycin can induce its pro-inflammatory shift and can be reduced by 4-PBA, an ER-stress inhibitor. Knockdown of IRE1alpha could regulate the STAT1 and STAT6 pathway of macrophage to inhibit the M1-type polarization and promote M2 phenotypic shift. Furthermore, transfusion of IRE1alpha-knockdown KCs significantly reduced the liver IRI as well as the ROS of HFD feeding mice. Altogether, these data demonstrated that IRE1alpha of KCs may be a potential target to reduce the fatty liver associated IRI in liver transplantation. PMID- 29969719 TI - Transferrin and transferrin receptors update. AB - In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1 can mediate cellular uptake of both Tf and H-ferritin, an iron storage protein. New World arenaviruses, which cause hemorrhagic fever, and Plasmodium vivax use TfR1 for entry into host cells. Human TfR2, another receptor for Tf, is predominantly expressed in hepatocytes and erythroid precursors, and holo-Tf dramatically upregulates its expression. TfR2 forms a complex with hemochromatosis protein, HFE, and serves as a component of the iron sensing machinery in hepatocytes. Defects in TfR2 cause systemic iron overload, hemochromatosis, through down-regulation of hepcidin. In erythroid cells, TfR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis. TfR2 facilitates iron transport from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Administration of apo-Tf, which scavenges free iron, has been explored for various clinical conditions including atransferrinemia, iron overload, and tissue ischemia. Apo-Tf has also been shown to ameliorate anemia in animal models of beta-thalassemia. In this review, I provide an update and summary on our knowledge of mammalian Tf and its receptors. PMID- 29969720 TI - Combined median and ulnar nerve palsy complicating distal radius fractures. AB - BACKGROUND: Fractures of the distal radius only rarely give rise to complications in the immediate postoperative period. Combined median and ulnar nerve palsy is a complication that can be missed by the surgeon. MATERIALS AND METHODS: Three cases diagnosed early after surgery are reported here. The patients were 15, 16, and 30 years of age, respectively. None had preoperative neurological deficits. The youngest patient was injured during sports and the other 2 patients during traffic accidents. All 3 patients had a displaced fracture of the distal radius combined with a fracture of the distal fourth of the ulna or ulnar styloid process and were treated by anterior plate fixation. Operative times were 47, 62, and 120minutes, respectively. Compartment syndrome was ruled out based on low pain intensity and absence of forearm tightness to palpation. RESULTS: The electrophysiological study performed 1 month post-injury in all 3 patients showed severe impairments of both median and ulnar nerve function. Median and ulnar nerve release surgery was performed in the 15-year-old 6 weeks post-injury. No nerve damage or fibrosis was seen during the procedure. All patients recovered fully within 3 months and had normal findings from follow-up electrophysiology testing after 6 months. DISCUSSION: Combined median and ulnar nerve palsy has rarely been reported and is among the rare complications of distal radial fractures that can develop in the event of a high-energy trauma and/or major displacement. Both previously published data and our experience indicate that surgical nerve release is unnecessary. Clinical recovery within 3 months is the rule. LEVEL OF EVIDENCE: IV, case-reports. PMID- 29969721 TI - Surgeon's and patient's radiation exposure during percutaneous thoraco-lumbar pedicle screw fixation: A prospective multicenter study of 100 cases. AB - HYPOTHESIS: Percutaneous pedicle screw fixations (PPSF) are increasingly used in spine surgery, minimizing morbidity through less muscle breakdown but at the cost of intraoperative fluoroscopic guidance that generates high radiation exposure. Few studies have been conducted to measure them accurately. MATERIAL AND METHODS: The objective of our study is to quantify, during a PPSF carried out in different experimented centers respecting current radiation protection recommendations, this irradiation at the level of the surgeon and the patient. We have prospectively included 100 FPVP procedures for which we have collected radiation doses from the main operator. For each procedure, the doses of whole-body radiation, lens and extremities were measured. RESULTS: Our results show a mean whole body, extremity and lens exposure dose per procedure reaching 1.7+/ 2.8MUSv, 204.7+/-260.9MUSv and 30.5+/-25.9MUSv, respectively. According to these values, the exposure of the surgeon's extremities and lens will exceed the annual limit allowed by the International Commission on Radiological Protection (ICRP) after 2440 and 4840 procedures respectively. CONCLUSION: Recent European guidelines will reduce the maximum annual exposure dose from 150 to 20mSv. The number of surgical procedures to not reach the eye threshold, according to our results, should not exceed 645 procedures per year. Pending the democratization of neuronavigation systems, the use of conventional fluoroscopy exposes the eyes in the first place. Therefore they must be protected by leaded glasses. LEVEL OF PROOF: IV, case series. PMID- 29969722 TI - Is reverse total shoulder arthroplasty more effective than hemiarthroplasty for treating displaced proximal humerus fractures in older adults? A systematic review and meta-analysis. AB - INTRODUCTION: The indications for surgical treatment of displaced proximal humerus fractures in older patients have gradually changed in the past 10 years: fewer hemiarthroplasty (HA) procedures but more reverse shoulder arthroplasty (RSA) procedures are being done. The aim of this study was to determine the clinical and radiological outcomes, the complications, reoperations and revisions of RSA and to compare them with those of HA. MATERIAL AND METHODS: A systematic review of the literature published between January 2006 and February 2016 was carried out to identify studies reporting or comparing results of HA and RSA for proximal humerus fractures in patients above 65 years of age. These studies were classified based on their quality and level of evidence. Of the 67 studies that were identified and reviewed, 22 were chosen for the analysis. RESULTS: The functional outcome (Constant score) after RSA is significantly better and more reproducible that the one obtained after HA. RSA provides significantly better active range of motion in forward flexion and abduction than HA. Conversely, active internal and external rotation are worse after RSA than HA. Reattachment of the tuberosities around the RSA improves the rotation ability. Even if the tuberosities do not heal, the functional outcomes are satisfactory after RSA but not HA due to a major functional deficit. The tuberosity healing rate around the RSA does not decline with age, contrary to HA where age is a negative factor. The overall complication rate is higher after RSA than HA; however the reoperation rate is equal. The revision rate for implant change is higher after HA. CONCLUSION: Compared to HA, RSA provides more reproducible function with better recovery of active forward flexion and abduction, even when the tuberosities are not reattached or do not heal properly. The poor rotation ability can be improved by reinserting the tuberosities. While the complication rate after RSA is higher than after HA, the reoperation rate is equal, and the revision rate is lower. LEVEL OF EVIDENCE: IV, Systematic review of literature. PMID- 29969723 TI - Fatigue in type 1 diabetes, prevalence, predictors and comparison with the background population. AB - AIM: Fatigue is scarcely studied in type 1 diabetes (T1D), and the aims were to investigate its prevalence compared to the background population, potential associations, and to validate the Fatigue Questionnaire (FQ) in type 1 diabetes. METHODS: Persons with T1D were recruited from three outpatient clinics in Norway. Fatigue was measured using the FQ, and FQ data from the Norwegian background population were used for comparison. Socio-demographic and clinical variables were obtained by self-report, clinical investigation, medical records and laboratory tests. RESULTS: Of 332 eligible patients, 288 (87%) were included. Mean age was 44.65/44.95 years (SD 13.34/13.38) for females/males, respectively. Total fatigue (TF) was 15.31 (SD 5.51) compared to 12.2 (SD 4.0) in the background population (p < 0.001). HADS >= 8, current menstruation, increased leukocytes and sleep problems were associated with increased TF. Chronic fatigue (CF) was reported in 26.4% compared to 11% in the background population (p < 0.001). HADS >= 8, increased time since diagnosis and decreased sleep quality were associated with CF. The validity, internal consistency and repeatability of the FQ was confirmed. CONCLUSIONS: Fatigue was more common in T1D than in the background population, and associated with increased anxiety, depression and sleep problems. The FQ demonstrated satisfactory psychometric properties. PMID- 29969724 TI - Evidence for the utility of antenatal HbA1c to predict early postpartum diabetes after gestational diabetes in South Africa. AB - Aim To evaluate antenatal HbA1c at diagnosis and in the 4 weeks preceding delivery to predict early postpartum diabetes mellitus (DM) in women with Gestational Diabetes Mellitus (GDM). Methods Seventy-eight women with GDM were prospectively assessed. The ability of HbA1c at GDM diagnosis (t1) and in the 4 weeks preceding delivery (t2) to predict DM 6-12 weeks after delivery was investigated. Glucose assessment was performed between November 1, 2015, and November 1, 2016 at Tygerberg Hospital (TH), Cape Town, South Africa (SA). Individuals with known pre-existing diabetes were excluded. Results HbA1c of 6.2% (44 mmol/mol) and 6.5% (48 mmol/mol) at t1 predicted DM with sensitivities of 95% and 90% and specificities of 62% and 70% respectively. At t2 the best cut-off for HbA1c, in accordance with t1, was also 6.2% (44 mmol/mol; sensitivity 92%, specificity 56%). Nineteen of the 29 women with suspected pre-gestational DM had HbA1c levels >= 6.5% (48 mmol/mol) at t1. The increased risk for postpartum DM with HbA1c >= 6.2% (44 mmol/mol) was four-fold (OR 3.97 CI 2.08-7.59p < 0.001) at t1 and five-fold (OR 5.08 CI 1.60-16.25 p = 0.006) at t2. Conclusion HbA1c lower than 6.5% (48 mmol/mol) predicts postpartum DM in women with GDM. HbA1c can serve as instrument to improve postpartum follow-up. PMID- 29969725 TI - The relationship between circulating adiponectin, ADIPOQ variants and incident cardiovascular disease in type 2 diabetes: The Fremantle Diabetes Study. AB - AIMS: To investigate the relationship between serum adiponectin, ADIPOQ variants and haplotypes, and cardiovascular disease (CVD) in type 2 diabetes (T2D). METHODS: Baseline data including serum total adiponectin and 21 ADIPOQ polymorphisms were available for 1076 participants (mean age 64.0 years, 49.4% males) in a community-based cohort followed for an average of 12 years. RESULTS: During 8843 patient-years of follow-up for coronary heart disease (CHD), 13,494 patient-years for ischaemic stroke (IS) and 12,028 patient-years for heart failure (HF), 40.4%, 11.8% and 31.9% of patients experienced a first episode of CHD, IS or HF, respectively. In Cox regression after adjustment for the most parsimonious models, loge(serum adiponectin) and the ADIPOQ variant rs12495941 were inversely associated with incident CHD (hazard ratio [95% confidence interval] 0.79 [0.65-0.98] and 0.64 [0.44-0.94], respectively), while rs1648707 was positively associated with incident IS (2.05 [1.37-3.06]; all P <= 0.028). In males, rs9860747 and rs17366568 predicted CHD (0.22 [0.05-0.92] and 1.50 [1.01 2.20]; P <= 0.042), while rs1648707 and rs1063537 predicted IS (2.36 [1.32-4.23] and 2.09 [1.17-3.72]; P <= 0.012). In females, rs10937273 predicted CHD via an interaction with serum adiponectin (0.43 [0.21-0.91]; P = 0.027), while rs864265 predicted IS (0.43 [0.21-0.88], P = 0.021). The associations between ADIPOQ variants and outcomes were supported by haplotype block analysis. Neither serum adiponectin nor ADIPOQ variants predicted HF. CONCLUSIONS: Serum total adiponectin and gender-specific ADIPOQ variants predict CHD and IS, but not HF, independently of other risk factors in community-based patients with T2D. In contrast to some previous studies, there was no relationship between a high serum total adiponectin and CVD. PMID- 29969726 TI - Establishing a Research Agenda on Mobile Health Technologies and Later-Life Pain Using an Evidence-Based Consensus Workshop Approach. AB - The rapid growth of mobile health (mHealth) devices holds substantial potential for improving care and care outcomes in all patient populations, including older adults with pain. However, existing research reflects a substantial gap in knowledge about how to design, evaluate, and disseminate devices to optimally address the many challenges associated with managing pain in older persons. Given these knowledge gaps, we sought to develop a set of practice-based research priorities to facilitate innovation in this field. We employed the Cornell Research-Practice Consensus Workshop Model, an evidence-based approach to generating research priorities. Sixty participants attended the conference, where stakeholder groups included older adults with pain and their caregivers, behavioral and social scientists, healthcare providers, pain experts, and specialists in mHealth and health policy. Participants generated 13 recommendations classified into 2 categories: 1) implications for designing research on mHealth among older adults (eg, conduct research on ways to enhance accessibility of mHealth tools among diverse groups of older adults with pain, expand research on mHealth sensing applications), and 2) implementation of mHealth technology into practice and associated regulatory issues (eg, promote research on ways to initiate/sustain patient behavior change, expand research on mHealth cybersecurity and privacy issues). PERSPECTIVE: This report highlights a set of research priorities in the area of mHealth and later-life pain derived from the joint perspectives of researchers and key stakeholder groups. Addressing these priorities could help to improve the quality of care delivered to older adults with pain. PMID- 29969727 TI - Effective PEI-mediated delivery of CRISPR-Cas9 complex for targeted gene therapy. AB - The-state-of-art CRISPR/Cas9 is one of the most powerful among the approaches being developed to rescue fundamental causes of gene-based inheritable diseases. Several strategies for delivering such genome editing materials have been developed, but the safety, efficacy over time, cost of production, and gene size limitations are still under debate and must be addressed to further improve applications. In this study, we evaluated branched forms of the polyethylenimine (PEI) - branched PEI 25 kDa (BPEI-25K) - and found that it could efficiently deliver CRISPR/Cas9 plasmids. Plasmid DNA expressing both guide RNA and Cas9 to target the Slc26a4 locus was successfully delivered into Neuro2a cells and meditated genome editing within the targeted locus. Our results demonstrated that BPEI-25K is a promising non-viral vector to deliver the CRISPR/Cas9 system in vitro to mediate targeted gene therapy, and these findings contribute to an understanding of CRISPR/Cas9 delivery that may enable development of successful in vivo techniques. PMID- 29969728 TI - Virulence-associated genes and molecular characteristics of non-O1/non-O139 Vibrio cholerae isolated from hepatitis B cirrhosis patients in China. AB - OBJECTIVES: We aimed to report virulence-associated genes and molecular characteristics of non-O1/non-O139 Vibrio cholerae isolated from hepatitis B cirrhosis patients in China. METHODS: Patient clinical data including course of disease, laboratory tests, antibiotic treatment and outcomes were collected. Antimicrobial susceptibility testing was performed and virulence-associated genes were detected by PCR. Genetic relatedness among non-O1/non-O139 V. cholerae strains was investigated by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: All three strains in this study harbored pathogenicity related genes like rtxA, rtxC, toxR, hapA, hlyA and ompW whereas they lacked ctxA, ctxB, tcpA, ompU and zot genes. None of them showed resistance to any antibiotic detected. A new allele of gyrB was submitted to the MLST database and designated as 97. Two novel sequence types (ST518 and ST519) and ST271 were identified by multilocus sequence typing (MLST). PFGE indicated considerable diversity among three non-O1/non-O139 V. cholerae strains. CONCLUSIONS: Three sporadic cases highlight that non-O1/non-O139 V. cholerae can cause opportunistic invasiveness infection in cirrhosis patients. Pathogenicity may be related to virulence-associated genes. Timely detection and antibiotic therapy should be paid more attention to in clinic. PMID- 29969729 TI - Jingshu Keli attenuates cervical spinal nerve ligation-induced allodynia in rats through inhibition of spinal microglia and Stat3 activation. AB - BACKGROUND CONTEXT: Cervical radicular pain resulting from mechanical compression of a spinal nerve secondary to spinal degenerative alternations negatively impacts patients' quality of life. Jingshu Keli (JSKL), a traditional Chinese medicine formula with multiple active compounds, has been prescribed for pain management in patients with cervical radiculopathy for decades. Two major components of JSKL, ferulic acid and cinnamaldehyde, were identified to have anti inflammation effect via inhibiting activation of Stat3. PURPOSE: To investigate the efficacy of JSKL by investigating its mechanism in attenuating cervical radiculopathy-induced mechanical allodynia via modulation activation of spinal microglia and phosphorylation of signal transducer and activator of transcription 3 (Stat3). STUDY DESIGN: An in vivo animal experiment. METHODS: Cervical radiculopathy of rats was established by C7 spinal nerve ligation (SNL) with 6-0 silk suture. The effect of postoperational daily gavage of JSKL on mechanical allodynia of rats was tested on day 3, 7, and 14 after surgery. Furthermore, spinal glial cells activation and phosphorylation of Stat3 (p-Stat3) were tested with immunofluorescence imaging and Western blot. RESULT: The JSKL significantly inhibited SNL-induced allodynia as well as microglia activation in the spinal cord on day 7 and 14 after surgery. Moreover, expression of p-Stat3 was decreased in rats with SNL and JSKL treatment in comparison with rats with SNL and vehicle treatment. CONCLUSIONS: The JSKL attenuated SNL-induced mechanical allodynia in rats. This analgesic effect might be explained by the suppression of activations of spinal microglia as well as p-Stat3. Our study provides experimental evidence for JSKL as an alternative approach to manage refractory pain in patients with cervical radiculopathy. PMID- 29969730 TI - Responsiveness of the Patient-Reported Outcomes Measurement Information System (PROMIS), Neck Disability Index (NDI) and Oswestry Disability Index (ODI) instruments in patients with spinal disorders. AB - BACKGROUND CONTEXT: The Patient-Reported Outcomes Information System (PROMIS) instruments are an important advancement in the use of PROs, but need to be evaluated with longitudinal data to determine whether they are responsive to change in specific clinical populations. PURPOSE: The purpose of this study was to assess the responsiveness of the PROMIS Physical Function (PF), PROMIS Pain Interference (PI), Neck Disability Index (NDI), and the Oswestry Disability Index (ODI). STUDY DESIGN/SETTING: This study entailed prospective data collection from consecutive patients aged 18 and older, visiting a university-based orthopaedic spine clinic between October 2013 and January 2017. PATIENT SAMPLE: A total of 763 participants in the sample had a mean age of 58 (SD = 15) years and the sample was 50.2% male and 92.8% Caucasian. OUTCOME MEASURES: The PROMIS PF and PROMIS PI Computerized Adaptive Tests along with either the NDI or ODI instruments were administered on tablet computers before clinic visits. Global rating of change questions relating to pain and function levels was also administered. METHODS: Baseline scores were compared with follow-up scores at four different time-points from 3-months to 6-months and beyond. Patient demographics, mean scores, paired-sample t tests, Standardized Response Mean (SRM), and Effect Size (ES) were analyzed to determine instrument responsiveness. This project was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number U01AR067138 and the authors have no conflicts of interest to disclose. RESULTS: The PROMIS instruments were strongly correlated with each other as well as with the NDI and ODI. Responsiveness was significant on all four instruments at every time-point assessed (paired sample t tests ranged from p < .001 to p = .049). SRM's were large and over 0.94 for every instrument at every time-point. Cohen's d ES were large and over 0.96 for all at all time-points, except for the NDI which had ES ranging from 0.74 to 0.83. This study showed large effect sizes and responsiveness of the PROMIS PF, PROMIS PI, NDI and ODI in a population of orthopaedic patients with spine pathologies. CONCLUSION: This study demonstrates strong responsiveness of the PROMIS PF and PROMIS PI in a spine clinic population. PMID- 29969731 TI - Three-dimensional microstructural reconstruction of the ovine intervertebral disc using ultrahigh field MRI. AB - BACKGROUND: The intervertebral disc (IVD) is a complex organ that acts as a flexible coupling between two adjacent vertebral bodies and must therefore accommodate compression, bending, and torsion. It consists of three main components, which are elegantly structured to allow this: the annulus fibrosus (AF), the nucleus pulposus (NP), and the end-plates (EP). PURPOSE: Thus far, it has not been possible to examine the microarchitecture of the disc directly in three dimensions in its unaltered state and thus knowledge of the overall architecture of the disc has been inferred from a range of imaging sources, or by using destructive methods. STUDY DESIGN: A nondestructive ultrahigh field Magnetic Resonance Imaging (MRI) of 11.7 T was used together with image analysis to visualize the ovine IVDs. METHODS: Three-dimensional image stacks from eight IVDs harvested from sheep, half of which were 4 to 5 years old and the others approximately 2 years old were reconstructed and examined, and their microstructure were imaged. The overall structure of the disc, including the average of 14 AF lamellae (9-28), NP, and EP was then visualized with particular attention given to integrating elements as radial translamellar cross-links, AF NP transition zone EP-AF integration and EP-NP insertion nodes (ie the connecting junctions between the EP and NP). Moreover, collagen fiber orientation was determined at different depths and locations throughout the annulus. RESULTS: It was found that there was a clearer demarcation in the AF-NP transition zone of the younger discs compared with the older ones. This difference was reflected in the visibility of AF-NP and EP-AF integration. It was also possible to view the fiber architecture of the AF-NP integration in greater depth than was possible previously with histological techniques. These fibers were mainly observed in the younger discs and their length was measured to be of 2.6 +/- 0.2 mm. CONCLUSIONS: The present results provide a substantial advance in visualization of the three dimensional architecture of an intact IVD and the integration of its components. PMID- 29969732 TI - Can the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio be beneficial in predicting lymph node metastasis and promising prognostic markers of gastric cancer patients? Tumor maker retrospective study. AB - BACKGROUD: Inflammation can promote tumor growth, invasion, angiogenesis and even metastasis. Inflammatory markers have prognostic value in some malignancies. The aim of the present study was to examine whether neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) served as sensitive serum markers for predicting lymph node metastasis and prognostic factors in gastric cancer (GC) patients. METHODS: 904 consecutive patients who underwent radical total or subtotal gastrectomy between 2010 and 2011, were included in this study. The clinical utility of the NLR and PLR was evaluated by receiver operating characteristic (ROC) curves,Kaplan-Meier curves and Cox regression analyses were used to calculate the overall survival (OS) characteristics. RESULTS: We determined the cutoff values of NLR and PLR was 2.0 and 160 respectively according to the ROC curve. Both the NLR and PLR were significantly associated with LN (lymph node) metastasis, and high NLR and PLR groups were significantly associated with poor overall survival. Additionally, NLR and TNM stage were independent prognostic factors for overall survival, however, PLR had limited value. CONCLUSIONS: NLR and PLR levels may be valuable indexes for lymph node metastasis. Although both the PLR and NLR may have prognostic value of gastric cancer patients, NLR is better to predict overall survival than PLR. PMID- 29969733 TI - Lessons Learned From My Mentors: The 2018 Miller-Sarkin Award Recipient Speech. PMID- 29969734 TI - Clinical Outcome of Minimally Invasive Decompression Without Discectomy in Contained Foraminal Disc Herniation: A Single-Center Study. AB - BACKGROUND: Foraminal disc herniation is rare. When conservative treatment fails, it is often treated with discectomy via a paraspinal or Wiltse approach. In contained foraminal disc herniation, more symptoms arise from the foraminal compression of the exiting nerve root, including the dorsal root ganglion, than from the herniation itself. We aimed to evaluate the benefits of stand-alone decompression without discectomy for patients with contained foraminal disc herniation. METHODS: This study included 17 patients with unilateral single-level foraminal disc herniation (14 women and 3 men; mean age, 62.8 +/- 14.6 years, range, 37-86 years). Disc herniation was confirmed as contained by preoperative magnetic resonance imaging and/or computed tomography and by intraoperative exploration. All patients underwent thorough decompression without discectomy, via a paraspinal approach. Pain was evaluated preoperatively and at 3 and 12 months postoperatively using a visual analog scale (VAS). The Oswestry Disability Index (ODI) and Macnab criteria were used to evaluate final outcomes. RESULTS: The most commonly affected level was L5-S1. All 17 patients showed significant improvements in VAS and ODI scores at 3 and 12 months postoperatively. According to the Macnab criteria, outcome results were excellent in 13 patients and good in 4. The mean duration of follow-up was 18.4 +/- 2.4 months, with no recurrences or lumbar instability at the final follow-up. CONCLUSIONS: Stand-alone decompression without discectomy is an effective method for relieving symptoms and preserving the disc in contained foraminal disc herniation. A minimally invasive approach with thorough decompression techniques yields good results. PMID- 29969735 TI - Imaging-Ambiguous Lesions of Meckel's Cave-Utility of Endoscopic Endonasal Transpterygoid Biopsy. AB - INTRODUCTION: Meckel's cave is a dural-lined cavity in the middle fossa skull base in which lies the Gasserian ganglion, a potential site for tumors and inflammatory lesions. A variety of lesions can be predominantly isolated to Meckel's cave, including extension from head and neck cancers, other malignant tumors, as well as benign lesions. Clinical presentation and imaging findings are often insufficient to establish a diagnosis. Hence, histologic confirmation is required to determine the appropriate treatment strategy. Several surgical approaches have been used to reach this deep-seated area, often with significant morbidity and prolonged recovery. Given advancements in endoscopy and greater facility with the technique, the endoscopic endonasal approach has been used increasingly to reach lesions in the region. METHODS: A single-institution, retrospective chart review over a 10-year period was performed to identify and describe patients with pathologically differing but imaging-similar lesions with their epicenter in Meckel's cave. RESULTS: Of a total of 21 cases of lesions in Meckel's cave approached by an endoscopic endonasal transpterygoid approach, we present 6 patients with imaging-ambiguous lesions involving Meckel's cave that were biopsied via the extended endoscopic endonasal approach. Among this diverse group, pathology included B-cell lymphoma, squamous cell carcinoma, adenocarcinoma, malignant schwannoma, benign schwannoma, and neurosarcoidosis. CONCLUSIONS: We explore not only the relevance of this approach in the armamentarium of the modern skull-base surgeon but also its limitations and conclude that the endoscopic endonasal approach provides a safe and relatively direct, minimally invasive corridor to many lesions of Meckel's cave. PMID- 29969736 TI - Repeat Radiosurgery Treatment After Cavernous Malformation Radiosurgery. AB - OBJECTIVE: Of cavernous malformations (CMs) treated with radiosurgery (RS), 5% bleed after 2-year initial latency period. This rate is similar to failure rate of RS for other pathologies, which often require repeat RS for favorable outcome. The aim of this pilot study was to define failure of CM RS and to assess safety of second RS. METHODS: Retrospective analysis was performed of 7 of 345 CMs retreated with RS; 6 CMs were deep-seated, and 1 was superficial. Median time between the 2 treatments was 8 years (range, 3-16 years), and median follow-up time after second RS was 3 years (range, 1-9 years). RESULTS: Following the 2 year latency period after RS, 6% of deep-seated and 5% of hemispheric CMs, and 6% of deep-seated and 2% of hemispheric lesions caused transient neurologic deficits without hemorrhage. A second treatment was indicated for rebleed in 5 cases and for recurrent transient neurologic deficits in 2 cases. Prescribed dose was 15 Gy (range, 12-20 Gy) at first treatment and 12 Gy (range, 12-18 Gy) at second treatment. Target volumes were 692 mm3 (range, 54-2400 mm3) and 935 mm3 (range, 150-1550 mm3) at first and second treatments, respectively, and treatment volumes were 811 mm3 (range, 79-2500 mm3) and 962 mm3 (range, 194-1750 mm3), respectively. Differences in treatment parameters were not significant. Reason for failure was inaccurate target definition in only 2 cases. There were no bleeds, morbidity, or mortality after second RS. CONCLUSIONS: Second RS applied to previously treated CMs is safe and may be effective. Further investigations are needed to verify these findings and assess long-term benefit of second RS. PMID- 29969737 TI - Application of Fibrin Rich in Leukocytes and Platelets in the Reconstruction of Endoscopic Approaches to the Skull Base. AB - BACKGROUND: The objective of this work is to report the feasibility and results of an institutional protocol for the application of an innovative biologically active hemoderivative autologous material, denominated leukocyte- and platelet rich fibrin (L-PRF), in the reconstruction of endoscopic approaches to the sellar region. METHODS: L-PRF membranes were produced from centrifuged autologous venous blood. They were used for the reconstruction of transsphenoidal endoscopic approaches to the sellar region in 12 patients. The trophism of the mucosa was monitored during the first 30 days by means of fiberoptic endoscopic controls on the second and seventh postoperative days. Follow-up was performed to rule out complications up to 30 postoperatively days. RESULTS: The product obtained bore the characteristics of the original descriptions of L-PRF. Standardized preparation of L-PRF membranes promoted early regeneration of the sphenoid sinus mucosa to close endoscopic approaches to the sellar region. No complications within the first 30 postsurgical days were reported. CONCLUSIONS: L-PRF membranes offer characteristics that are superior to other techniques and products, mainly because of their role as biological promoters of tissue regeneration, their low economic cost, and immediate availability. However, it would be necessary to confirm these results in studies involving more patients. PMID- 29969738 TI - Recurring Thalamic Symptoms Due to Intracranial Dural Arteriovenous Fistula: Report of Unusual Case and Treatment Outcome. AB - BACKGROUND: Initial clinical presentation of dural arteriovenous fistula (DAVF) with predominantly thalamic symptoms is rare and has not been reported until now. CASE DESCRIPTION: A young child presenting with complaints of tinnitus and mild right hemiparesis was evaluated with an initial magnetic resonance imaging, which revealed a Borden type 2 DAVF in the right transverse sinus with retrograde venous drainage and cortical venous reflux. Flow-related small aneurysms were also noted in the left basal vein of Rosenthal (BVR). Two days later, his motor power deteriorated and he developed right hemisensory loss and severe thalamic pain. Aphasia was atypical and mimicked the transcortical type. Repeat imaging revealed expanding thrombosed aneurysm of BVR with mass effect and edema on thalamocapsular region. Initial antiedema measures reversed the neurologic deficits; however, they recurred, necessitating an urgent endovascular intervention. Angiogram revealed an extensive high-flow DAVF in the right transverse-sigmoid sinus and torcula with preferential retrograde venous drainage into deep veins and left BVR. He underwent staged embolization of DAVF, resulting in significant obliteration of shunt. Neurologic deficits improved in the postoperative period, and the patient remained clinically asymptomatic at 6 months of follow-up. CONCLUSIONS: DAVF presenting with recurrent predominantly thalamic symptoms is rare. Atypical transcortical aphasia rather than fluent aphasia is an unusual clinical manifestation of thalamic pathology and could result from the involvement of specific thalamic nuclei. Preferential high flow into BVR in the presence of venous anomalies could potentially induce architectural weakness of the venous wall and precipitate aneurysm formation. Embolization of the DAVF can potentially reverse this unusual neurologic condition. PMID- 29969739 TI - What Is the Best Timing of Repeated CT Scan in Mild Head Trauma with an Initially Positive CT Scan? AB - BACKGROUND: Mild traumatic brain injury (MTBI) is among the most common causes of emergency admission. Current guidelines have clearly evidenced risk factors and neurologic signs that should suggest computed tomography (CT) of the head at admission and indications for the first repeated CT scan. However, the role and frequency of further repeated CT scans after an initially positive scan are still unclear. METHODS: We retrospectively analyzed 222 patients admitted in our hospital for clinical observation after an MTBI and a positive initial scan. Repeated CT scans were categorized according to timing from the first scan. All the scans were evaluated for the presence of posttraumatic lesions. We classified the data in 3 groups according to the timing of CT scans: A (CT scans at t0-t12 t24), B (t0-t12-t48), and C (t0-t24-t48). Differences in worsening or stability of posttraumatic lesions were compared by the chi2 test. RESULTS: 146 CT scans were performed at t12, 81 at t24, and 143 at t48. The initial CT scan was positive for epidural hematoma in 17 cases, subdural hematoma in 106, subdural hygroma in 10, intracerebral contusion in 110, subarachnoid hemorrhage in 109, and intraventricular hemorrhage in 12. None of the posttraumatic lesions showed significant worsening or at the first or second CT scan in any of the 3 groups. CONCLUSIONS: The treatment of patients in clinically stable condition with an MTBI and posttraumatic intracranial lesions at initial CT scan has been shown to minimally benefit from repeated CT scans. Given neurologic stability, a control scan can be safely delayed up to 48 hours to avoid unnecessary scans. PMID- 29969740 TI - Compression of Thoracic Spinal Cord with Decreased Cerebrospinal Fluid Space After Implantation of Paddle Lead Spinal Cord Stimulation at T9: A Three Dimensional Myelographic Computed Tomography Study. AB - OBJECTIVES: To investigate the extent of spinal cord compression and cerebrospinal fluid (CSF) space after T9 paddle lead spinal cord stimulation (SCS) using three-dimensional myelographic computed tomography scans. METHODS: Preoperative and postoperative three-dimensional myelographic computed tomography scans were performed in 15 patients with paddle lead SCS at T9 for neuropathic back and leg pain. Four axial levels between each row of the electrodes were selected and the cross-sectional areas of thecal sac and spinal cord, the width of anterior and posterior CSF space, and contact angle of the lead within T9 spinal canal were measured with 12-month pain relief assessment. RESULTS: The cross-sectional areas of thecal sac and spinal cord under each contact of paddle leads decreased significantly (23.89 +/- 11.48% and 9.45 +/- 4.80%; P < 0.05, respectively). The width of posterior CSF space decreased by 38.65 +/- 20.97% and that of anterior CSF space showed a greater reduction by 59.09 +/- 18.39% (P < 0.05). We achieved a mean pain relief of 45.49 +/- 13.73% at 12-month follow-up and found a significant correlation with percentage reduction in the area of the spinal cord. CONCLUSIONS: Significant reduction in the cross-sectional area of spinal cord and anterior CSF space as well as thecal sac and posterior CSF space resulted in deformation of the spinal cord under paddle leads at T9 within 7 postoperative days. Close approximation to the dorsal column and the mass effect of paddle leads may determine the clinical outcome of paddle lead SCS and also raise safety concerns. PMID- 29969741 TI - Laser-Assisted Excision of Coil Mass While Clipping Recurrent Intracranial Aneurysms After Prior Endovascular Coiling: Our Initial Experience. AB - BACKGROUND: Excision of coil mass during clipping of recurrent or residual aneurysms after prior endovascular coiling is challenging. We evaluated the use of the carbon dioxide laser for safe and effective removal of coils during aneurysm surgery. Two cases are presented. CASE DESCRIPTION: The first patient was a 56-year-old man with a previously coiled ruptured anterior communicating artery aneurysm. Angiography at 3-year follow-up showed recurrent aneurysm, which could not be coiled again owing to technical reasons. An aneurysm clip could not be safely applied owing to the weight of the coil mass compromising the parent vessel lumen. Laser-assisted coil mass resection was performed before permanent clip application. Intraoperative cerebral angiography showed complete obliteration of the aneurysm. The second patient was a 69-year-old woman with a previously coiled unruptured middle cerebral artery aneurysm. Angiography at 2 year follow-up showed recurrence of the aneurysm, which could not be coiled again owing to technical reasons. Laser-assisted coil mass resection was performed before the aneurysm was safely clipped. Intraoperative angiography showed complete obliteration of the aneurysm. No complications occurred using the carbon dioxide laser. At 1-year follow-up, both patients were asymptomatic with no evidence of aneurysmal recurrence. CONCLUSIONS: Excision of coil mass is required while treating recurrent and/or residual intracranial aneurysms that were previously treated by endovascular technique. The use of carbon dioxide laser assistance while retrieving these coils is safe and effective. PMID- 29969742 TI - Pedicle Screw with Cement Augmentation in Unilateral Transforaminal Lumbar Interbody Fusion: A 2-Year Follow-Up Study. AB - OBJECTIVE: To evaluate safety and efficacy of pedicle screw with polymethyl methacrylate (PMMA) augmentation in unilateral transforaminal lumbar interbody fusion (uTLIF) in osteoporotic patients. METHODS: We randomly divided 50 osteoporotic patients with degenerative lumbar diseases diagnosed between February 2014 and November 2015 into 2 groups. One group underwent standard uTLIF, and the other group underwent uTLIF with PMMA augmentation. All patients were scheduled to attend a series of regular follow-up evaluations. Oswestry Disability Index, Japanese Orthopaedic Association score, visual analog scale score, lumbar lordotic angle, segmental lordotic angle, and disc space height (DSH) at each follow-up were collected and analyzed. RESULTS: The 2-year follow up was completed by 24 patients in the uTLIF group and 23 patients in the PMMA group. Oswestry Disability Index, Japanese Orthopaedic Association score, and visual analog scale score showed significant improvements after surgery in both groups, with no significant difference between groups. DSH in the uTLIF group was 8.7 +/- 2.3 mm and in the PMMA group was 10.7 +/- 1.6 mm. Fusion rate in the uTLIF group was 19/24 and in the PMMA group was 21/23. DSH and fusion rate in the PMMA group were higher than those in the uTLIF group. No severe complications were observed after PMMA injection. CONCLUSIONS: Pedicle screw with PMMA augmentation can increase fixation stability and reduce DSH loss in uTLIF. Moreover, PMMA in the vertebral body did not impede the interbody fusion ability in uTLIF. PMID- 29969743 TI - Monitoring of the Effect of Cerebral Autoregulation on Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: To detect cerebral autoregulation (CA) in patients with aneurysmal subarachnoid hemorrhage (aSAH) by near-infrared spectroscopy and to assess its association with delayed cerebral ischemia (DCI). METHODS: From January to August 2017, 81 patients (average age 53.25 +/- 10.27 years) were studied. Near-infrared spectroscopy was used to monitor CA, and associated factors were evaluated. Monitoring of CA was carried out at 5 time points (preoperative day 1 and postoperative days 1, 2, 3, and 7). Patients were sorted into 2 groups according to whether DCI occurred (DCI group and non-DCI group). The relationship between CA and DCI in patients with aSAH was analyzed. RESULTS: Among 81 patients, CA trended toward being impaired in patients with aSAH with a poorer grade. DCI occurred in 39 of 51 (48.15%) patients with impaired CA. DCI occurred in 6 of 30 (7.4%) patients with intact CA. CONCLUSIONS: Impaired CA monitored by near infrared spectroscopy was shown in patients with aSAH before and after surgical intervention. Older age, smoking, hypertension, and especially impaired CA are independent risk factors for patients with DCI. PMID- 29969745 TI - A Reliable Nomogram Model to Predict the Recurrence of Chronic Subdural Hematoma After Burr Hole Surgery. AB - OBJECTIVE: We established a reliable nomogram model to predict the recurrence of chronic subdural hematoma (CSDH) after burr hole surgery. METHODS: We retrospectively analyzed 514 patients who were treated in our hospital between January 2010 and November 2017 and included 231 patients in this study. We used univariate and binary logistic regression analysis to identify the significantly related predictors for recurrence. Subsequently, we established the nomogram model using these predictors and validated it. RESULTS: The total rate of recurrence after initial surgery for CSDH was 14.29% (33/231) during the following 3 months. We found that preoperative hematoma volume (greater than 121 mL), postoperative residual cavity volume (greater than 72 mL), computed tomography scan imaging type (hyper- and mixed-density type), and age (older than 65 years of age) were significantly related to recurrence. We used 50% recurrence rate as the classification cutoff, with the corresponding points of 252 to validate the nomogram model. The accuracy of predicting the recurrence of CSDH calculated by the binary logistic regression model was 91.7%. The sensitivity and specificity of the nomogram were 87.88% and 84.85%, respectively. CONCLUSIONS: This nomogram model had a high precision to predict the recurrence of CSDH. It needs more external and prospective validation in the future. We expect this model could be used in different neurosurgical problems as well. PMID- 29969744 TI - Effectiveness of Dural Sealants in Prevention of Cerebrospinal Fluid Leakage After Craniotomy: A Systematic Review. AB - OBJECTIVE: Cerebrospinal fluid (CSF) leakage is one of the most challenging complications in neurosurgery. We sought to evaluate the efficacy of dural sealants in preventing CSF leakage after cranial surgery. METHODS: A literature search was performed in the PubMed, Embase, and Cochrane databases. The inclusion criteria were defined to include articles describing regular cranial procedures combined with the use of any dural sealant reporting CSF leakage. The primary outcome was CSF leakage (pseudomeningocele formation or incisional CSF leakage), secondary outcomes were pseudomeningocele formation, incisional CSF leakage, and surgical-site infection. RESULTS: Twenty articles were included. Ten of these were comparative studies (sealant vs. no sealant) including 3 randomized controlled trials. In the 20 articles, a total of 3682 surgical procedures were reported. The number of CSF leakages in general did not differ between the sealant group (8.2%) and control group (8.4%), risk ratio (RR) 0.84 (0.50-1.42), I2 = 56%. Exclusion of non-randomized controlled trials did not alter the results. Meta-analyses for secondary outcomes showed no difference between number of incisional CSF leakage, RR 0.30 (0.05-1.59), I2 = 38%. Also, no difference was found in the pseudomeningocele formation, RR 1.50 (0.43-5.17), I2 = 0%. Surgical site infection was seen less in the sealant group (1.0%) compared with the control group (5.6%), RR 0.25 (0.13-0.48), I2 = 0%. CONCLUSIONS: This systematic review showed that dural sealants did not reduce the number of CSF leaks in general, the number of incisional CSF leaks alone, or the number of pseudomeningocele formations alone. However, dural sealants reduced the risk of surgical-site infection. PMID- 29969747 TI - From Conversation to Transformation: Mens' Perspective on Strange Nuances of Neurosurgical Practice for Women in India. AB - BACKGROUND: In India, men outnumber women in neurosurgery by a wide margin. At the graduation party of our woman colleague, we recalled the experiences of the past few years. It led to a transforming experience for the authors, who have hitherto only held the "mens' perspective." METHODS: Societal pressures of marriage, profession, family, and culture on women in India emerge readily in this conversational piece. A comparison with "obstetrics and gynecology" in which women dominate is drawn to better describe the idiosyncrasies of Indian society. The meaning of discrimination and equality is examined in terms of neurosurgical training for women. RESULTS: At present, the price of becoming a doctor in India is the youth of the kid and uncertainties in the career because of gruesome competition at each level, without any incentives. CONCLUSIONS: Conversation itself is one of the greatest forces for changing the situation and how this conversation can be taken forward to transform a "culture of discrimination" to a "culture of acceptance." PMID- 29969748 TI - Reply to Author. PMID- 29969746 TI - Prognostic Factors in Clival Chordomas: An Integrated Analysis of 347 Patients. AB - OBJECTIVE: To investigate prognostic factors of clival chordoma using the largest patient set to date. METHODS: Appropriate studies were identified per search criteria, data satisfying criteria were extracted, and survival analysis was performed to investigate prognostic factors of clival chordoma. RESULTS: A total of 347 patients from the literature cohort met our inclusion criteria. Of 346 cases in which extent of resection was reported, gross total resection (GTR), subtotal resection, and biopsy were achieved in 118 (34.1%), 205 (59.2%), and 21 (6.1%) cases, respectively. Two (0.6%) subjects did not undergo surgery. Of 185 cases in which surgical approach was reported, 56 (30.3%) underwent an endoscopic transoral approach, 17 (9.2%) microscopic transsphenoidal, 45 (24.3%) endoscopic or microscopic, 45 (24.3%) craniotomy, and 22 (11.9%) other approaches. There was no significant difference in GTR rates of different surgical approaches (P = 0.101). Median follow-up was 46.6 months. The 5- and 10-year rates for progression-free survival (PFS) were 59.2% and 47.9%, respectively. The 5- and 10 year rates for overall survival (OS) were 77.3% and 63.9%, respectively. On multivariate analysis for both PFS and OS, GTR demonstrated significantly improved outcomes when compared with subtotal resection (hazard ratio 0.45, 95% confidence interval 0.22-0.90, P = 0.025 for PFS; hazard ratio 0.20, confidence interval 0.06-0.65, P = 0.008 for OS). CONCLUSIONS: GTR rates were comparable in different surgical approaches. GTR was a significant predictor of longer PFS and OS in clival chordoma. PMID- 29969749 TI - Cytomegalovirus Infection Among Cord Blood Allogeneic Transplantation Recipients: Low Incidence of Cytomegalovirus Events without High-Dose Valacyclovir Prophylaxis. PMID- 29969750 TI - Higher sympathetic activity as a risk factor for skeletal deterioration in pheochromocytoma. AB - Despite the potential biological importance of sympathetic activity in human bone metabolism, its effects on bone microarchitecture, a key determinant of bone quality, has not been thoroughly studied. In the present study, we investigated the lumbar spine trabecular bone score (TBS) as an indicator of skeletal deterioration in pheochromocytoma. Among 620 consecutive patients with newly diagnosed adrenal incidentaloma, 29 with histologically confirmed pheochromocytoma (a catecholamine-secreting neuroendocrine tumor) and 266 with nonfunctional adrenal incidentaloma were defined as cases and controls, respectively. After adjustment for confounders, subjects with pheochromocytoma had 2.9% lower lumbar spine TBS than those without pheochromocytoma (P = 0.038). Moreover, urinary normetanephrine level, but not urinary metanephrine level, was inversely correlated with lumbar spine TBS (P = 0.009). Subjects in the highest urinary normetanephrine quartile showed markedly lower lumbar spine TBS than those in the lowest quartile (P = 0.018), in a dose-response manner across increasing urinary normetanephrine quartile categories (P for trend = 0.021). Consistent with the results of previous studies, subjects with pheochromocytoma had significantly lower bone mass at the lumbar spine and higher serum level of C terminal telopeptide of type I collagen than controls (P = 0.013 and 0.002, respectively). These findings provide clinical evidence that catecholamine excess and the resultant sympathetic overstimulation in pheochromocytoma may contribute to bone fragility, especially in the trabecular bone, through a weak microarchitecture in addition to a lower bone mass and increased bone resorption, and support the possibility of pheochromocytoma as a secondary cause of osteoporosis. PMID- 29969752 TI - Absence of fosfomycin resistance in gastrointestinal Escherichia coli following fosfomycin therapy. PMID- 29969751 TI - Micafungin use in a UK tertiary referral hospital. AB - OBJECTIVES: Here we sought to describe the real-life usage of micafungin in a UK tertiary referral hospital. METHODS: A prospective, non-interventional, observational surveillance study was performed. RESULTS: Micafungin was commenced in 174 courses involving 148 patients to treat invasive candidiasis and candidaemia (132 courses) and aspergillosis in situations where alternatives such as voriconazole or liposomal amphotericin B could not be used (42 courses). Fungal infection was defined as proven as per European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) guidelines in 84 courses (48.3%). Micafungin was well tolerated; 10 patients (6.8%) developed a rise in alanine aminotransferase (ALT) and only 1 patient stopped therapy due to this. Therapy was rationalised to fluconazole in 77 courses (44.3%). There were no differences in intensive care unit admission or deaths when comparing all 174 courses where patients received micafungin for Aspergillus and Candida infection, respectively [49% vs. 42% (P=0.82) and 24% vs. 15% (P=0.186)]. One patient developed disseminated mucormycosis and four patients had recurrent candidaemia (attributed to poor source control) while receiving micafungin. CONCLUSIONS: Micafungin was clinically effective for the treatment of invasive Candida and Aspergillus infections, and usage did not increase the risk of liver dysfunction even in patients with abnormal ALT at baseline. PMID- 29969753 TI - Antimicrobial resistance among Helicobacter pylori isolates in Alaska, 2000-2016. AB - OBJECTIVES: Alaska Natives experience a high burden of Helicobacter pylori infection and concomitant high rates of gastric cancer. Additionally, the prevalence of antimicrobial-resistant H. pylori has been shown to be high in Alaska. In this study, antimicrobial resistance over time among sentinel surveillance isolates was evaluated and risk factors for carrying antimicrobial resistant H. pylori were assessed. METHODS: Through Alaska's H. pylori sentinel surveillance system, antral and fundal biopsies from Alaska Native patients undergoing esophagogastroduodenoscopy for clinical indications during 2000-2016 were collected and cultured. For positive cultures, minimum inhibitory concentrations (MICs) of metronidazole, amoxicillin, clarithromycin, tetracycline and levofloxacin were determined. RESULTS: A total of 800 H. pylori isolates obtained from 763 patients were tested. Resistance to metronidazole was most common (342/800; 42.8%), followed clarithromycin (238/800; 29.8%), both clarithromycin and metronidazole (128/800; 16.0%) and levofloxacin (113/800; 14.1%). Low proportions of isolates were resistant to amoxicillin and tetracycline. Levofloxacin resistance increased between 2000 and 2016 (P<0.001), but resistance to other antimicrobials did not change over time. Metronidazole and clarithromycin resistance were more common among women (P<0.001 for both), whilst levofloxacin resistance was more common among those with an urban residence (P=0.003). Metronidazole and levofloxacin resistance were more common among older patients (P<0.05). CONCLUSION: Between 2000 and 2016, a large percentage of H. pylori isolates received by the Alaska Sentinel Surveillance System demonstrated resistance to common antimicrobials. The surveillance system provides valuable information for clinicians to make informed treatment choices for patient with H. pylori. PMID- 29969754 TI - Specifications of Computerized Provider Order Entry and Clinical Decision Support Systems for Cancer Patients Undergoing Chemotherapy: A Systematic Review. AB - OBJECTIVE: Chemotherapy medication errors are catastrophic. The prescription phase in the chemotherapy process plays a key role in the creation of medication errors, and therefore the use of computerized physician order entry (CPOE) and clinical decision support system (CDS) systems is recommended to reduce chemotherapy medication errors. The purpose of this study was to carry out a systematic review on the specifications of the CPOE and CDS systems for chemotherapy prescription. MATERIALS AND METHODS: A systematic review on articles published in English up to September 22, 2017, using the 3 databases PubMed, Embase, and Medline was conducted. Those articles that focused on the specifications of CPOE and CDSS in chemotherapy prescription were included in this review. FINDINGS: Of the 2,471 articles identified, 58 articles met the inclusion criteria and were included in this study. Specifications related to chemotherapy CPOE systems were categorized into the following 6 groups: automation and facilitation of the chemotherapy prescription phase, hospital workflow support, documentation and reporting, drug safety, information security, and system communications. The specifications of chemotherapy CDSS were also divided into 4 categories: embedding chemotherapy protocols, automated dose calculations and adjustment, providing alerts/reminders at the time of prescribing, and guiding or asking the user to complete the important prescription parameters. In 12 articles, the chemotherapy prescription CDSS were designed and evaluated independently of the CPOE; 45 articles provided prescription chemotherapy CDSS as part of the CPOE system, and in 1 article CPOE was introduced with no CDSS. CONCLUSION: In complicated settings such as chemotherapy, simplification of the processes is more imperative. The use of chemotherapy CPOE, which includes specifications for helping the medical staff with their workload, encourages the professionals to use such systems and increases the likelihood for success of these systems. PMID- 29969755 TI - Circ-ANAPC7 is Upregulated in Acute Myeloid Leukemia and Appears to Target the MiR-181 Family. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) are a family of novel non-coding RNAs associated with various diseases, especially cancer. Recent studies have demonstrated that circRNAs participate in pathogenesis mainly by acting as microRNA (miRNA) sponges. The expression profile of circRNAs in acute myeloid leukemia (AML) has rarely been reported. METHODS: Profiles of circRNAs were analyzed using an Arraystar human circRNA microarray with 5 bone marrow samples from patients with newly diagnosed AML and 5 from patients with iron-deficiency anemia. Quantitative reverse transcription PCR was used to validate the expression pattern of circRNAs. Furthermore, circRNA-miRNA network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied. RESULTS: CircRNA microarray analysis revealed that 698 circRNAs were differentially expressed in AML patients, with 282 circRNAs found to be upregulated and 416 to be downregulated. Quantitative reverse transcription PCR showed that circ-ANAPC7 was significantly upregulated in AML. Bioinformatics analysis predicted that circ-ANAPC7 acts as a sponge for the miR-181 family, KEGG analysis revealed that it is associated with cancer-related pathways, and GO analysis indicated that most of its target genes are involved in biological processes. CONCLUSIONS: These findings show that circ-ANAPC7 is a promising biomarker for AML, and that it might participate in AML pathogenesis by acting as a sponge for the miR-181 family. PMID- 29969756 TI - Bushenshugan Formula Attenuates the Development of Lung Cancer by Inhibiting Epithelial-Mesenchymal Transition. AB - BACKGROUND/AIMS: BushenShugan Formula (BSF) is a traditional Chinese medicine that has therapeutic effects on middle- and late-stage lung adenocarcinoma in clinical application. It was reported that Bushen Chinese medicine suppressed the onset of pre-metastatic niches in a murine model of spontaneous lung metastasis. However, the mechanisms of BSF on human lung adenocarcinoma remain unknown. METHODS: Cell proliferation was determined by CCK8 and colony formation. Cell apoptosis and cell cycle were detected by flow cytometry. Cancer stem cells properties were examined by spheroid body formation. The migration and invasion abilities were analyzed by wound healing assay and transwell invasion assay. The mRNA expressions were determined by qRT-PCR. Western blotting analysis showed the protein levels. RESULTS: BSF was shown to inhibit the proliferation of A549 cells in time- and concentration-dependent manners. Colony formation assays also indicated the antiproliferative effect of BSF against A549 cells. Cellular mechanistic studies demonstrated that BSF arrested the cell cycle in G2/M phase and induced apoptosis. Importantly, BSF could inhibit the epithelial-mesenchymal transition(EMT) of A549 cells through PI3K/AKT/NF-kappaB pathway. CONCLUSIONS: BSF effectively inhibited tumour growth, suggesting that it is a promising anticancer treatment for further clinical development. PMID- 29969757 TI - Influence of Timing of Initiation and Volume of Processed Plasma on the Outcome of Septic Shock Patients Treated with Coupled Plasma Filtration and Adsorption. AB - BACKGROUND: The extracorporeal removal of mediators is a rescue strategy for septic shock patients, which is still under investigation. Several techniques are available: coupled plasma filtration and adsorption (CPFA) combines plasma processing with renal replacement therapy. METHODS: The study aimed to elucidate the role of both timing of initiation and intensity of treatment on the outcome, for which we retrospectively studied 52 patients. We collected the overall pre CPFA time interval, starting from the first episode of hypotension in the wards and the volume of processed plasma (Vp), which we used as a proxy for intensity of treatment. RESULTS: Timing of initiation did not significantly differ between survivors and non-survivors (25 vs. 27 h), while the Vp did (0.25 vs. 0.17 L/kg/session, p < 0.05). The significance of Vp was confirmed by a multiple logistic regression model. CONCLUSION: Our study confirms that intensity of CPFA, but not its timing of initiation, correlates with survival of septic shock patients. PMID- 29969759 TI - A Simple and Cheap Hospitalization Risk Assessment Tool for Use in Hemodialysis Patients. AB - OBJECTIVE: To develop a simple, objective, cheap scoring tool incorporating nutritional parameters and other variables to predict hospitalization and mortality among hemodialysis patients - a tool that could be utilized in low resource countries. METHODS: The following variables were scored according to severity into 0, 1, 2 or 3: BMI, functional capacity, HD vintage in years, serum albumin, serum ferritin, and the number of comorbid conditions (diabetes mellitus, hypertension, ischemic heart disease, cerebrovascular disease). This tool was evaluated on our regular hemodialysis patients who were followed up for 24 months (June 2015 till July 2017). In our study population, the maximum score recorded was 12; accordingly, a score of 6 was used to differentiate between a low-risk group (score < 6) or a high-risk group (score >=6). The 2 groups were compared (using the Chi square test) for possible differences in mortality and hospitalization rates during the follow-up period. RESULTS: One hundred and forty adult hemodialysis patients were monitored over 2 years; 83 were males and 57 females; 59% of the patients had diabetes mellitus. Twenty-nine patients (30.7%) were found to be in the high-risk group and 111 (79.3%) in the low-risk group. The high-risk patients were almost one and a half times more likely to be hospitalized for vascular access issues than the low-risk group (p = 0.056) and 3 times more likely to be hospitalized for non-vascular access issues than the low risk group (p = 0.0001). The mortality rate in the high-risk group was 3.1 times that in the low-risk group, but this was not statistically significant. CONCLUSION: Using a simple and cheap assessment tool in hemodialysis patients, we have identified patients at high risk for hospitalization rates and mortality. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=490544. PMID- 29969758 TI - Emerging Role of Exosomes in the Joint Diseases. AB - Exosomes are a subset of small, membrane-bound extracellular vesicles that are important for communication among cells. They originate from the cell membrane during endocytic internalization, and are stable in biological fluids, including blood and synovial fluids. Increasing knowledge is emerging about exosomes in joint diseases, including osteoarthritis, rheumatoid arthritis, osteonecrosis of the femoral head, and others. Exosomes in synovial fluid can lead to inflammation, degeneration of cartilage, and destruction of joints. Exosomes in blood have diagnostic value in the early disease stage or for complicated conditions of joint diseases. Exosomes from stem cells could delay diseases and repair joints. For a comprehensive understanding about the emerging role of exosomes in joint diseases, we introduced the isolation and verification of exosomes from synovial fluid, reviewed the physiological and pathological effects of exosomes on joints, and discussed the diagnostic value and therapeutic potential of exosomes in joint diseases. In the future, immunologically active exosomes and engineered exosomes will of interest in the joint diseases. Challenges in the field of exosomes in joint-disease research include complex and expensive isolation, detection of contributing molecular, effectiveness and safety evaluation. In summary, challenges remain, but the field of exosomes in joint diseases has potential, including in mechanisms, diagnoses and therapies. PMID- 29969760 TI - Nrf2 Pathway in Age-Related Neurological Disorders: Insights into MicroRNAs. AB - A general hallmark of neurological diseases is the loss of redox homeostasis that triggers oxidative damages to biomolecules compromising neuronal function. Under physiological conditions the steady-state concentrations of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are finely regulated for proper cellular functions. Reduced surveillance of endogenous antioxidant defenses and/or increased ROS/RNS production leads to oxidative stress with consequent alteration of physiological processes. Neuronal cells are particularly susceptible to ROS/RNS due to their biochemical composition. Overwhelming evidences indicate that nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-linked pathways are involved in protective mechanisms against oxidative stress by regulating antioxidant and phase II detoxifying genes. As such, Nrf2 deregulation has been linked to both aging and pathogenesis of many human chronic diseases, including neurodegenerative ones such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nrf2 activity is tightly regulated by a fine balance between positive and negative modulators. A better understanding of the regulatory mechanisms underlying Nrf2 activity could help to develop novel therapeutic interventions to prevent, slow down or possibly reverse various pathological states. To this end, microRNAs (miRs) are attractive candidates because they are linked to intracellular redox status being regulated and, post transcriptionally, regulating key components of ROS/RNS pathways, including Nrf2. PMID- 29969761 TI - Early Screening for Posttraumatic Stress Disorder in Inpatient Detoxification and Motivation Treatment: Results and Consequences. AB - AIMS: Posttraumatic stress disorder (PTSD) is a significant comorbidity in substance use disorders (SUDs). While most studies have addressed trauma/PTSD in abstinent patients, little is known about trauma/PTSD in early detoxification treatment. The current study therefore addresses the systematic evaluation of trauma/PTSD in early inpatient detoxification. METHODS: A cross-sectional survey was accomplished in three German-speaking clinics (n = 134) specialized in inpatient detoxification and motivation treatment. All measures are based on self report using trauma-specific questionnaires and measures for general psychopathological burden. RESULTS: Participation rate was 60.1% and patients did not show clinically obvious psychological distress during or after assessment. DSM-IV traumatic events were reported by 66.4%. Of the total sample, 38.1% screened positive for PTSD, and 14.9% screened positive for subsyndromal PTSD. PTSD patients reported significantly more childhood adversities and significantly higher scores in depression and -general psychopathology compared to subsyndromal PTSD and SUD-only patients. CONCLUSIONS: Early and systematic evaluation of PTSD in SUD inpatient detoxification treatment is largely safe and yields important information for individual treatment. The high PTSD-rate and the high symptom load in SUD patients during inpatient detoxification treatment highlight the need for a more stringent address of trauma/PTSD in early SUD treatment. PMID- 29969762 TI - In Vitro Study of Endotoxin Adsorption by a Polymyxin B-Immobilized Fiber Column. AB - BACKGROUND: Polymyxin B-immobilized fiber (PMX-F) columns are used as therapeutic interventions for septic shock. The clinical efficacy has been reported for 2-h applications, but their ability to adsorb endotoxin over longer treatments has not been fully elucidated. We hypothesized that PMX-F columns are capable of endotoxin removal for more than 2 h. METHOD: We designed closed circuits incorporating either a PMX-F column with an 8.5-mL priming volume (PMX-01R) or a sham-control column, and used inactivated fetal bovine serum as the circulating perfusate. Endotoxin was continuously injected at a fixed rate for 24 h, and perfusate endotoxin concentrations were measured at fixed time points. PMX-01R endotoxin adsorption was calculated from the difference in the endotoxin concentrations. RESULTS: PMX-01R endotoxin adsorption increased continuously in a virtually linear manner. CONCLUSIONS: The PMX-01R column showed sustained endotoxin adsorption for at least 24 h. This indicated that PMX-F columns would be capable of clinical endotoxin removal for 24 h. PMID- 29969763 TI - The Trajectories of the Number of Pain Sites and Their Associated Factors in Older Adults: Results from the Korean Longitudinal Study of Ageing. AB - BACKGROUND: The aging of the population will result in an increase in demand for pain management. Pain adversely affects physical and mental functioning in older adults and accounts for a considerable proportion of all medical expenses. OBJECTIVES: This study was performed to investigate the patterns of changes in the trajectories of the number of pain sites in older adults and the factors that affect these patterns according to gender. METHODS: Data were extracted for subjects that participated in the Korean Longitudinal Study of Ageing from 2006 to 2014. The study population consisted of 2,839 individuals (1,190 men and 1,649 women) >=60 years old. A group-based trajectory model was used to determine the optimal number of subgroups and the trajectories of the number of pain sites according to gender. A multinomial regression analysis was conducted to identify factors that affect the probability of inclusion in each trajectory group. RESULTS: The trajectories of the number of pain sites were consistent in both genders. Almost all women had one or more pain symptom, and a greater number of pain sites than men. Older age, longest-duration occupation requiring manual labor, lack of physical activity, depressive symptoms, and poor self-rated health were associated with a greater number of pain sites in both genders. A lower level of education, married status, and experience of injury were associated with the number of pain sites in men but not in women, while household income and chronic diseases were associated with the number of pain sites only in women. CONCLUSIONS: The pain status at the early stage is predictive of future pain. In this study, we identified gender differences in the trends of the number of pain sites and associated factors. Further comprehensive studies on pain intensity and duration are required. PMID- 29969764 TI - Impact of Insufficient Response with an Increase in Tumor Number in Predicting Transcatheter Arterial Chemoembolization Refractoriness for Hepatocellular Carcinoma. AB - AIM: In Japan, transcatheter arterial chemoembolization (TACE) refractoriness for hepatocellular carcinoma has been defined as an insufficient therapeutic effect after >=2 procedures. Insufficient TACE for intrahepatic lesions is defined as the presence of > 50% viable lesions (ineffective) or an increase in their number (progressive). This study aimed to examine the possibility of earlier evaluation of TACE refractoriness. METHODS: Patients who underwent TACE for hepatocellular carcinomas > 3 cm in size or with > 3 nodules at our hospital between 2010 and 2014 were analyzed. The cases assessed as TACE insufficient for the first time were divided into 2 groups: the "either" group, evaluated as either "ineffective" or "progressive," and the "both" group, that is, both "ineffective" and "progressive." RESULTS: The study participants included 40 of 212 consecutive patients who underwent TACE, divided into the either (n = 23) and both (n = 17) groups. Seventeen of 23 (73.9%) patients in the either group and all 17 (100%) in the both group had TACE refractoriness (p = 0.0295). CONCLUSIONS: Patients with both "ineffective" and "progressive" lesions are extremely likely to be TACE refractory at a significantly higher frequency than are those with either condition. Thus, when both of these factors are observed, switching to other therapies should be considered. PMID- 29969765 TI - Maternal Folate Intake and Risk of Childhood Brain and Spinal Cord Tumors: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Many epidemiological studies have investigated the effect of maternal diet and prenatal multivitamin supplementation on pediatric cancer risk. Childhood brain and spinal cord tumors (CBSCT) have been attributed to different possible risk factors. METHODS: We conducted a systematic review and meta analysis on maternal folate intake before and during pregnancy and the risk of CBSCT. We systematically reviewed publications obtained by searching the Insitute for Scientific Information Web of Knowledge and PubMed literature databases. We extracted the risk estimate of the highest and the lowest reported categories of intake from each study and conducted a meta-analysis using a random-effects model. RESULTS: The results of the pooled analysis of all 10 studies, 1 cohort and 9 case-control studies, indicated that maternal folate intake was inversely associated with CBSCT risk (OR 0.77; 95% CI 0.67-0.88, p < 0.001; I2 = 51.22%, p = 0.001). Separate analyses on the basis of the source of folate (folic acid supplementation, dietary folate) and in relation to the timing of exposure (before pregnancy, during pregnancy) found that folic acid supplementation was associated with an approximately 23% reduction in -CBSCT risk (OR 0.77, 95% CI 0.66-0.90, p = 0.001; I2 = 53.18%, p = 0.001) and consumption during pregnancy was associated with an approximately 20% reduction in CBSCT risk (OR 0.80, 95% CI 0.67-0.97, p = 0.020; I2 = 62.48%, p < 0.001). CONCLUSIONS: Maternal consumption of folic acid is associated with a reduced risk of CBSCT. Further investigations are necessary to increase the reliability of the results and estimate the relationship between dose-response and the best outcome. PMID- 29969767 TI - Imaging Features of Varicella Zoster Virus Cranial Multiple Mononeuropathies. PMID- 29969766 TI - Host MICA Polymorphism as a Potential Predictive Marker in Response to Chemotherapy for Colorectal Liver Metastases. AB - BACKGROUND: Understanding the genetic background of a tumor is important to better stratify patient prognosis and select optimal treatment. For colorectal liver metastases (CLM), however, clinically available biomarkers remain limited. METHODS: After a comprehensive sequencing of 578 cancer-related genes in 10 patients exhibiting very good/poor responses to chemotherapy, the A5.1 variant of the MICA gene was selected as a potential biomarker for CLM. The clinical relevance of MICA A5.1 was then investigated in 58 patients who underwent CLM resection after chemotherapy. RESULTS: The A5.1 variant was observed in 16 (27.6%) patients examined using direct DNA sequencing, and a very high concordance rate (56/58, 96.6%) for the MICA variant was confirmed between tumor tissues and normal liver parenchyma. A multivariate analysis of 38 patients with no history of treatment with anti-EGFR antibodies confirmed that MICA A5.1 was significantly correlated with an optimal CT morphologic response (OR 11.67; 95% CI 2.08-65.60; p = 0.005) and tended to be correlated with a tumor viability of < 20% after chemotherapy (OR 5.91; 95% CI 0.97-36.02; p = 0.054). MICA A5.1 was also associated with a decreased risk of progression after CLM resection. CONCLUSION: The MICA A5.1 polymorphism was associated with a better CT morphologic response to chemotherapy and a reduced risk of relapse after CLM resection. Given the high concordance rate in MICA variants between normal liver tissue and CLM, the genetic background of the host could be a new biomarker for CLM. PMID- 29969769 TI - Is Human Sebum the Source of Skin Follicular Ultraviolet-Induced Red Fluorescence? A Cellular to Histological Study. AB - BACKGROUND: The ultraviolet-induced red fluorescence (UVRF) from human skin follicles was suggested to be a result of Propionibacterium acnes and was used for the monitoring of acne. More recent studies suggested that the UVRF may be more related to sebum rather than to microorganisms. OBJECTIVE: To clarify whether human sebum or follicular microorganisms are the source of UVRF. METHODS: We examined the fluorescence of human-derived SZ95 sebocytes, human sebaceous glands, sebum extracted from the sebaceous glands, and bacteria isolated from human hair follicles under ultraviolet light. RESULTS: SZ95 sebocytes, human sebaceous glands, and sebum do not emit UVRF. Two types of UVRF peaking at about 635 nm and at about 620 nm were detected in P. acnes and Staphylococcus epidermidis, respectively. This is the first report that S. epidermidis emits UVRF when it is anaerobically cultured and then exposed to air. CONCLUSION: Human follicular UVRF is emitted by resident bacteria, not by sebum. Therefore, UVRF may be used to monitor certain species of skin microorganisms. PMID- 29969768 TI - Applying Regional Citrate Anticoagulation in Continuous Renal Replacement Therapy for Acute Kidney Injury Patients with Acute Liver Dysfunction: a Retrospective Observational Study. AB - BACKGROUND/AIMS: Continuous renal replacement therapy (CRRT) is a treatment for acute kidney injury (AKI) patients. It has become a controversy about whether patients with liver dysfunction should perform CRRT with regional citrate anticoagulation (RCA). METHODS: This retrospective observational study enrolled 145 AKI patients (275 CRRT sessions) who received CRRT with RCA and had no history of chronic liver disease. Circuit survival time, blood pressure, trans membrane pressure (TMP), acid-base and electrolyte status were recorded and analyzed. The severity of liver dysfunction was determined by total bilirubin (TBil) and international normalized ratio (INR), while the accumulation degree of citrates was quantified by total/ ionized calcium (tCa/iCa) raito. RESULTS: Our results showed that there was no correlation of tCa/iCa ratio with TBil or INR. And tCa/iCa ratio was not related to the disturbances of pH, lactates, sodium, magnesium, blood pressure or TMP despite that high tCa/iCa ratios might be related to the decrease of circuit survival time. TBil did not correlate with the above indexes, except for lactates levels. INR did not correlate with the above indexes except for lactates levels and blood pressure. In addition, neither was TBil, INR, nor tCa/iCa ratio, related with fatal outcomes (22.76% of the patients). CONCLUSION: The present study demonstrated that, with proper monitoring and adjustment of citrates and calcium infusion, applying RCA in CRRT is reasonably safe for AKI patients with acute liver dysfunction, as long as circuit time stays below roughly 50 hours. PMID- 29969770 TI - Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501). AB - BACKGROUND: The incidences of metastatic brain tumors from malignant melanomas have increased and survival has been prolonged by novel molecular targeted agents and immunotherapy. However, malignant melanomas are uncommon in Asian populations. OBJECTIVES: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in Japanese melanoma patients with brain metastases treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 177 patients with 1,500 tumors who underwent GKRS for brain metastases from malignant melanomas. This study was conducted by the Japanese Leksell Gamma Knife Society (JLGK1501). RESULTS: Six and 12 months after GKRS, the cumulative incidences of local tumor recurrence were 9.2 and 13.8%. Intratumoral hemorrhage (p < 0.0001) and larger tumor volume (p = 0.001) in GKRS were associated with significantly poorer local control outcomes. The use of immune checkpoint inhibitors before GKRS was significantly associated with symptomatic adverse events (p = 0.037). The median overall survival time after the initial GKRS was 7.3 months. Lower Karnofsky performance status scores (p = 0.016), uncontrolled primary cancer (p < 0.0001), and multiple brain metastases (p = 0.014) significantly influenced unfavorable overall survival outcomes. The cumulative incidences of neurological death 6 and 12 months after GKRS were 9.7 and 17.4%, those of neurological deterioration were 14.2 and 19.6%, and those of new tumor appearance were 34.5 and 40.5%. CONCLUSIONS: The results of the present multicenter study suggest that GKRS is a relatively effective and safe modality for control of tumor progression in Japanese patients with brain metastases from malignant melanomas. PMID- 29969771 TI - Radiographic Imaging Does Not Reliably Predict Macroscopic Extranodal Extension in Human Papilloma Virus-Associated Oropharyngeal Cancer. AB - BACKGROUND: Radiographic concern for lymphatic extranodal extension (ENE) impacts upfront management decisions for patients with human papilloma virus (HPV) oropharyngeal squamous cell carcinoma (OPSCC). Therefore, we set out to evaluate the accuracy of preoperative contrast-enhanced computed tomography (CECT) to predict major ENE (> 2 mm). METHODS: Twenty-seven consecutive patients with HPV associated OPSCC who presented at our institutional multidisciplinary tumor board were staged radiographically with positron emission tomography (PET/CT) and CECT, and underwent primary transoral robotic resection and neck dissection. CECT imaging results were correlated with pathologic ENE (pENE). RESULTS: CECT specificity for all pENE was 69 and 75% for radiologist 1 and 2, respectively. For pENE > 2 mm, the sensitivities were 88 and 100%, but specificities were 52.6 and 63.2%. Positive predictive values (PPV) were 43.8 and 53.3%; negative predictive values were 90.9 and 100%. On logistic regression analysis, only size >=3 cm (OR 4.7-5.4, p < 0.02, 95% CI 1.3-44.0) demonstrated significant correlation with major ENE > 2 mm. CONCLUSIONS: Preoperative imaging for HPV associated OPSCC had a PPV for pENE > 2 mm of 44-55%, based on any interruption in the capsule or invasion into the perinodal fat. The PPV is low and equipoise in treatment decision making for patients with HPV-associated OPSCC may require other imaging characteristics. PMID- 29969772 TI - Erratum. PMID- 29969773 TI - SLCO1B1 c.521T>C Genotyping in the Austrian Population Using 2 Commercial Real Time Polymerase Chain Reaction Assays: An Implementation Study. AB - Statin-induced myopathy is reported to be significantly associated with the SCLO1B1 c.521T>C polymorphism. To date, SLCO1B1 c.521T>C epidemiologic data for the Austrian population is still lacking. Therefore, this study aimed at assessing the genotype and allele frequencies of the SLCO1B1 c.521T>C variant in Austria and evaluating the clinical performance of 2 commercial real-time polymerase chain reaction (PCR) assays. Genomic DNA isolated from 181 healthy individuals was analyzed for the SLCO1B1 c.521T>C polymorphism in a comparative manner using the SLCO1B1 c.521T>C RealFastTM Assay and the BioPro SLCO1B1 Genotyping real-time PCR Kit. A total of 10 (5.5%) and 44 (24.3%) out of 181 individuals were SLCO1B1 c.521T>C C/C-homo- and -C/T-heterozygotes, the genotypes indicative of high and increased risk of statin-induced myopathy, respectively. The SLCO1B1 c.521C allele frequency rate was 17.7%. In conclusion, the genetic predisposition of elevated statin-induced myopathy risk in the Austrian population is frequent. Both real-time PCR assays under investigation here are reliable and robust SLCO1B1 c.521T>C genotyping tools in clinical routine. PMID- 29969774 TI - Topical Eugenol Successfully Treats Experimental Candida albicans-Induced Keratitis. AB - PURPOSE: To determine the efficacy of eugenol for the treatment of Candida keratitis in an experimental model. METHODS: The in vitro antifungal activity of eugenol and fluconazole was tested against C. albicans strains via the microbroth dilution method. An experimental model of Candida albicans keratitis was used. Rabbits were classified into those that received no treatment (control; group 1) and those that started eugenol treatment immediately (group 2) or after 4 days (group 3) of keratitis induction (n = 12-16 rabbits/group). The 2 treatment groups were assigned to 50 MUL of 4 mg/mL eugenol drops hourly for 15 days, while the control group received saline. Corneal penetration of eugenol was measured using HPLC, and corneal toxicity was evaluated clinically and histopathologically. RESULTS: The in vitro minimum inhibitory concentrations of eugenol and fluconazole against C. albicans were 2 and > 0.4 mg/mL, respectively. A 4-mg/mL preparation of eugenol in propylene glycol was the maximum nontoxic dose on rabbit corneas as suggested by clinical and histopathologic findings. At least 75% of all eugenol-treated eyes recovered from keratitis, with improvement in the remaining 25% of the eyes compared to controls. CONCLUSIONS: Eugenol can act as a natural, safe, and effective treatment for fungal keratitis, regardless of whether treatment is started immediately or after 4 days of keratitis induction. PMID- 29969775 TI - Atypical Glandular Cells: Interobserver Variability according to Clinical Management. AB - OBJECTIVE: The 2014 Bethesda System diagnostic criteria for atypical glandular cells (AGC) aids in classification of atypical cells in cervical cytology. There is limited literature regarding reproducibility and interobserver variability in the application of the 2014 AGC criteria. Our aim is to assess the interobserver variability of AGC with a focus on how diagnostic categories link with guideline driven management. STUDY DESIGN: Three observers re-reviewed 51 previously diagnosed AGC Papanicolaou tests. The diagnoses were categorized as follows: (1) according to guideline-specified management, and (2) as glandular vs. squamous lesions. The kappa statistic was used to evaluate interobserver agreement. RESULTS: The interobserver variability per guideline management by weighted 2 observer kappa ranged from 0.009 to 0.530, with half of the interobserver pairings meeting the threshold for at least fair-moderate agreement. For categorization as glandular, squamous, or both, unweighted kappa yielded at best fair interobserver agreement (kappa = 0.250) in 1 pairing, with low kappa scores in the remainder of reviewer pairs (range 0.015-0.152). CONCLUSIONS: There is significant interobserver variability in the diagnosis of AGC. The AGC cases when divided by clinical management had fair-moderate interobserver agreement, suggesting that diagnostic variability likely has a real effect on patient care. This diagnostic uncertainty should be understood by cytologists and clinicians. PMID- 29969777 TI - Erratum: Zhou et al. Clinical Utility of Serum Cystatin C in Predicting Diabetic Nephropathy Among Patients with Diabetes Mellitus: a Meta-Analysis. PMID- 29969778 TI - Current Guidelines for Obesity Prevention in Childhood and Adolescence. AB - OBJECTIVE: Current guidelines for prevention of obesity in childhood and adolescence are discussed. METHODS: A literature search was performed in Medline via PubMed, and appropriate studies were analyzed. RESULTS: Programs to prevent childhood obesity have so far remained mainly school-based and effects have been limited. Analyses by age group show that prevention programs have the best results in younger children (<12 years). Evidence-based recommendations for pre school- and early school-aged children indicate the need for interventions that address parents and teachers alike. During adolescence, school-based interventions proved most effective when adolescents were addressed directly. To date, obesity prevention programs have mainly focused on behavior-oriented prevention. Recommendations for community- or environment-based prevention have been suggested by the German Alliance of Noncommunicable Diseases and include a minimum of 1 h of physical activity at school, promotion of healthy food choices by taxing unhealthy foods, mandatory standards for meals at kindergartens and schools as well as a ban on unhealthy food advertisement aimed at children. CONCLUSION: Behavior-oriented prevention programs showed only limited long-term effects. Certain groups at risk for the development of obesity are not reached effectively by current programs. Although universally valid conclusions cannot be drawn given the heterogeneity of available studies, clearly combining behavior based programs with community-based prevention to counteract an 'obesogenic environment' is crucial for sustainable success of future obesity prevention programs. PMID- 29969779 TI - A Novel Mutation of SLC19A2 in a Chinese Zhuang Ethnic Family with Thiamine Responsive Megaloblastic Anemia. AB - BACKGROUND/AIMS: Thiamine-responsive megaloblastic anemia syndrome is a rare autosomal recessive disorder resulting from mutations in SLC19A2, and is mainly characterized by megaloblastic anemia, diabetes, and progressive sensorineural hearing loss. METHODS: We study a Chinese Zhuang ethnicity family with thiamine responsive megaloblastic anemia. The proband of the study presented with anemia and diabetes, similar to his late brother, as well as visual impairment. All clinical manifestations were corrected with thiamine (30 mg/d) supplementation for 1-3 months, except for visual impairment, which was irreversible. The presence of mutations in all exons and the flanking sequences of the SLC19A2 gene were analyzed in this family based on the proband's and his brother's clinical data. Computer analysis and prediction of the protein conformation of mutant THTR 1. The relative concentration of thiamine pyrophosphate in the proband's whole blood before and after initiation of thiamine supplement was measured by high performance liquid chromatography (HPLC). RESULTS: Gene sequencing showed a homozygous mutation in exon 6 of the SLC19A2 gene (c.1409insT) in the proband. His parents and sister were diagnosed as heterozygous carriers of the c.1409insT mutation. Computer simulation showed that the mutations caused a change in protein conformation. HPLC results suggested that the relative concentration of thiamine pyrophosphate in the proband's whole blood after thiamine supplement was significantly different (P=0.016) from that at baseline. CONCLUSIONS: This novel homozygous mutation (c.1409insT) caused the onset of thiamine-responsive megaloblastic anemia in the proband. PMID- 29969780 TI - Quality of Care in Ulcerative Colitis: A Modified Delphi Panel Approach. AB - OBJECTIVES: To establish clinical consensus on important and relevant quality-of care (QoC) attributes in ulcerative colitis (UC) treatment that may improve treatment outcomes and guide best practices. METHODS: Thirty-eight QoC attributes were identified in a literature review. Sixteen European-based experts were selected based on their contributions to UC guidelines, publications, and patient care. A 3-round, modified Delphi panel was conducted including an interview round, and 2 web-based rounds to reach consensus and finalize a QoC attribute list. RESULTS: The draft QoC attribute list derived from a literature review and Round 1, expert interviews, comprised 63 attributes. In Rounds 2 and 3, the QoC attributes frequently rated as critically important were diagnosis (n = 15, 93.8%), treatment adherence (n = 15, 93.8%), and access to care/treatment (Round 2: n = 14, 87.5%; Round 3: n = 15, 93.8%). The final QoC attribute list consisted of 61 attributes across 20 domains, with the most attributes reported in the "treatment goals" domain (n = 9). CONCLUSION: QoC is a complex and evolving concept that can improve outcomes while maximizing healthcare resources. Limited time and resources hamper clinicians' ability to openly and empathetically communicate with patients; novel technology may help to offer solutions. PMID- 29969782 TI - Predictors of High-Risk Adenoma Occurrence at Surveillance Colonoscopy in Patients Who Undergo Colorectal Adenoma Removal. AB - OBJECTIVES: Surveillance colonoscopy is recommended after polypectomy because adenoma recurrence is common. The aim of this study was to evaluate the predictors of high-risk adenoma occurrence at surveillance colonoscopy in patients who undergo colorectal adenoma removal and to clarify the association between age and recurrent colorectal adenoma. METHODS: This retrospective study included 563 patients who had colorectal adenomas at baseline colonoscopy and who underwent surveillance colonoscopy. The risk factors for recurrent adenoma were evaluated and the 5-year cumulative incidence rates of overall and high-risk adenoma were compared according to age group. RESULTS: During a mean follow-up period of 3.1 years, 305 (54.2%) patients had overall adenoma recurrence, and 80 (14.2%) patients had high-risk adenoma at surveillance colonoscopy. In a multivariate analysis, old age (>=60 years) and presence of multiple adenomas (3 or more) were significantly associated with high-risk adenoma (p = 0.002 and p = 0.006 respectively). The 5-year cumulative incidence rates of high-risk adenoma were 7.4, 16.7, and 24.1% in the < 50, 50-59, and >=60 years group respectively (p < 0.001). CONCLUSIONS: Old age (>=60 years) and presence of multiple adenomas (3 or more) were strongly associated with the occurrence of high-risk adenoma at surveillance colonoscopy. The 5-year cumulative incidence of high-grade adenoma was significantly high in the old age group. PMID- 29969781 TI - MicroRNA-500a Promotes the Progression of Hepatocellular Carcinoma by Post Transcriptionally Targeting BID. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is one of the most common human malignant diseases in the world, and the mechanisms underlying HCC carcinogenesis and progression need further investigation. MicroRNAs play important roles in the development of cancer, and miR-500a is suggested to be deregulated in some types of cancer. However, the underlying molecular mechanisms of miR-500a in HCC remain unknown. METHODS: The expression of miR-500a in HCC was analyzed in The Cancer Genome Atlas (TCGA) database and examined in 33 pairs of HCC tissues and matched nontumor tissues. The correlation between miR-500a expression and prognosis of HCC patients was analyzed from the survival data in TCGA. The mechanism of miR 500a upregulation in HCC was detected using chromatin immunoprecipitation quantitative real-time PCR. The roles of miR-500a in HCC development were examined using a cell counting kit-8 assay in vitro and growth of transplanted tumors in nude mice in vivo. Apoptosis of HCC was detected using Annexin V/propidium iodide staining. The expression of BH3-interacting death agonist (BID) protein was examined using western blot analysis. RESULTS: miR-500a expression was upregulated in HCC tissues, and high miR-500a expression was significantly correlated with the poor prognosis of HCC patients. Histone modifications in the promoter region of miR-500a may be responsible for its increased expression. Inhibition of miR-500a in HCC cell lines significantly promoted apoptosis, as well as inhibiting the proliferation of HCC cells and growth of transplanted tumors in nude mice. miR-500a directly targeted the 3' untranslated region of BID mRNA, and inhibition of miR-500a-promoted apoptosis was almost completely abolished by the administration of ABT-199 via the BID mitochondria pathway. CONCLUSION: Our results suggest that histone modifications in the promoter region of miR-500a may be responsible for the increased expression of miR-500a in HCC, which promotes cancer progression by targeting BID, indicating that miR-500a may be a potential prognostic predictor and therapeutic target for HCC patients. PMID- 29969783 TI - Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury. AB - BACKGROUND/AIMS: Peptidyl-prolyl cis-trans isomerase FKBP25 is a member of the FK506-binding proteins family which has peptidyl-prolyl cis/trans isomerase domain. The biological function and pathophysiologic role of FKBP25 remain elusive. METHODS: The spatio-temporal changes in expression of endothelial FKBP25 upon oxygen-glucose deprivation (OGD) treatment were examined by Western blot and immunofluorescence. The immunoprecipitation and fluorescence resonance energy transfer (FRET) were used to address the interacting proteins with FKBP25. RESULTS: In the present study, nuclear translocation of FKBP25 was observed following OGD in cultured endothelial cells. Intriguingly, FKBP25 nuclear translocation was further validated in peroxynitrite (ONOO-)-treated endothelial cells. Coimmunoprecipitation and FRET data indicated that FKBP25 translocated into the nucleus, in which it interacted with 60S ribosomal protein L7a, while overexpression FKBP25 protect endothelial cells against OGD injury. CONCLUSION: Our findings reveal that the nuclear import of FKBP25 and binding with 60S ribosomal protein L7a are protective stress responses to ischemia/nitrosaive stress injury. PMID- 29969784 TI - Executive Impairments in Binge Drinking: Evidence for a Specific Performance Monitoring Difficulty during Alcohol-Related Processing. AB - This study evaluated inhibition and performance-monitoring abilities through the explicit processing of alcohol cues. Twenty-two binge drinkers (BD) and 22 control participants performed a speeded Go/No-Go task using pictures of alcohol and soft cans as Go and No-Go targets. This task measures inhibitory control and performance monitoring (i.e., task adjustment through errors and feedback processing) during the explicit processing of alcohol cues. Groups did not significantly differ regarding inhibition abilities. However, BD had poorer performance-monitoring abilities, reflected by a difficulty to adjust after errors, especially when these errors were related to alcohol cues. These findings suggest that the explicit processing of alcohol cues negatively impacts cognitive abilities among BD. PMID- 29969785 TI - Adenine-Induced Chronic Renal Failure in Rats: A Model of Chronic Renocardiac Syndrome with Left Ventricular Diastolic Dysfunction but Preserved Ejection Fraction. AB - BACKGROUND/AIMS: Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Rats with adenine-induced chronic renal failure (ACRF) develop severe renal insufficiency and metabolic abnormalities that closely resemble those in patients with uremia. The aim of the present study was to determine left ventricular (LV) morphology and function in rats with ACRF. METHODS: Male Sprague-Dawley rats received either chow containing adenine or were pair-fed an identical diet without adenine (controls, C). After 9-13 weeks animals were anesthetized with isoflurane and cardiac function was assessed both by echocardiography and by LV catheterization. RESULTS: Rats with ACRF showed increases in serum creatinine (323+/-107 vs. 33+/-5 uM, P< 0.05), mean arterial pressure (115+/-6 vs. 106+/-7 mmHg, P< 0.05) and LV weight (3.4+/-0.3 vs. 2.5+/ 0.2 mg/kg, P< 0.05) vs. controls. Rats with ACRF had reduced early diastolic tissue Doppler velocities in the LV, enlarged left atrial diameter (4.8+/-0.8 vs. 3.5+/-0.4 mm, P< 0.05) and elevated LV end-diastolic pressure (15+/-5 vs. 8+/-1 mmHg, P< 0.01). Cardiac output was increased in ACRF rats (211+/-66 vs. 149+/-24 ml/min, P< 0.05) and systolic function preserved. In the LV of ACRF rats there were statistically significant (P< 0.05) increases in cardiomyocyte diameter, proliferation and apoptosis, while there was no difference between groups in fibrosis. CONCLUSION: Rats with ACRF develop LV hypertrophy and diastolic dysfunction while systolic performance was preserved. There was an increased hypertrophy and apoptosis of cardiomyocytes in the LV of ACRF rats. The cardiac abnormalities in ACRF rats resemble those in patients with CKD in which heart failure with preserved ejection fraction is common. Hence, this experimental model is well suited for studying pathophysiological mechanisms in chronic renocardiac syndromes. PMID- 29969786 TI - Future Trends and the Economic Burden of Dementia in Manitoba: Comparison with the Rest of Canada and the World. AB - Dementia is a growing public health concern in Canada. This epidemic is linked to huge human and economic costs. The number of Manitobans (65+) with dementia in 2045 (47,021), representing 2.58% of the Manitoban population, will be 2.3 times that of the year 2015 (20,235). The number of cases of dementia in Manitoba grew by 20.7% from 2015 to 2025, 68.16% from 2015 to 2035 and at an alarming rate of 125% from 2015 to 2045. Importantly, the total economic burden of dementia in Manitoba is close to one billion USD and is expected to grow more than 28 billion USD during the year 2038. The focus of this review is to compare dementia rates and the financial burden of dementia in Manitoba with the rest of Canada and the world from 2012 to 2048. PMID- 29969787 TI - Identification of a Broad-Spectrum Peptidoglycan Hydrolase Associated with the Particle of Xanthomonas oryzae Phage Xop411. AB - Virion-associated peptidoglycan hydrolases (VAPGH) in bacteriophages are potential antimicrobials. Xop411 is a syphophage infecting the Gram-negative Xanthomonas oryzae pv. oryzae that causes bacterial leaf blight in rice plants. The Xop411 gp21 protein was identified here as a peptidoglycan glycohydrolase by Western blotting and zymogram assay, and localized to the phage tail by immunogold-labelling electron microscopy. This protein showed an apparent molecular mass of 17 kDa in SDS-polyacrylamide gels, larger than that calculated from the amino acid sequence, 15 kDa with 130 residues. The recombinant gp21 expressed in Escherichia coli formed inclusion bodies, which gained enzyme activity after in-gel renaturation. In contrast, the secreted recombinant protein (s-gp21His) expressed in Pichia pastoris was soluble and enzymatically active. Plate assays showed that s-gp21His was capable of killing 3 species of Xanthomonas, a genus containing 27 closely related plant pathogenic species, as well as the opportunistic Pseudomonas aeruginosa and Stenotrophomonas maltophilia causing nosocomial infections. These results indicate that the Xop411 gp21 has possible wide applications as an antimicrobial against xanthomonads and at least 2 opportunistic bacteria. Several other VAPGH from Xanthomonas phages were also identified by bioinformatic analysis, with 1 being confirmed by Western blotting. PMID- 29969788 TI - Unique Francisella Phosphatidylethanolamine Acts as a Potent Anti-Inflammatory Lipid. AB - Virulent Francisella tularensis subsp. tularensis (Ftt) is a dynamic, intracellular, bacterial pathogen. Its ability to evade and rapidly suppress host inflammatory responses is considered a key element for its profound virulence. We previously established that Ftt lipids play a role in inhibiting inflammation, but we did not determine the lipid species mediating this process. Here, we show that a unique, abundant, phosphatidylethanolamine (PE), present in Francisella, contributes to driving the suppression of inflammatory responses in human and mouse cells. Acyl chain lengths of this PE, C24: 0 and C10: 0, were key to the suppressive capabilities of Francisella PE. Addition of synthetic PE 24: 0-10: 0 resulted in the accumulation of PE in host cells for up to 24 h of incubation, and recapitulated the inhibition of inflammatory responses observed with native Ftt PE. Importantly, this novel PE significantly inhibited inflammatory responses driven by a medically and globally important flavivirus, dengue fever virus. Thus, targeting these lipids and/or the pathways that they manipulate represents a new strategy to combat immunosuppression engendered by Ftt, but they also show promise as a novel therapeutic intervention for significant viral infections. PMID- 29969789 TI - Samantha Adams Festschrift: The Dot at the End of the Funnel-TILT Remembers Samantha Adams. PMID- 29969790 TI - Samantha Adams Festschrift: Coming of Age-Samantha Adam's Career at Erasmus University Rotterdam. PMID- 29969791 TI - Samantha Adams Festschrift: Sam Adams and the Social Construction of Technology and Health-Implications for Biomedical Informatics. PMID- 29969793 TI - Samantha Adams Festschrift: Keeping Close Tabs-In Memoriam Samantha Adams. PMID- 29969794 TI - Samantha Adams Festschrift: How to be a Student and How to Mentor Students-A Remembrance of Dr. Samantha Adams, Who Did These and Everything Else So Well. PMID- 29969792 TI - Samantha Adams Festschrift: Adamsian Discourse-The Patient, and Everything Else. PMID- 29969795 TI - [Influence of a Migration Background on the Implementation of Breastfeeding and Premature Weaning]. AB - QUESTIONS: Current studies on breastfeeding behavior that adequately consider migration aspects are not available from Germany. The following research questions should be answered with the help of a prospective study: What factors influence the probability of (premature) weaning and actual breastfeeding duration? What roles do migration background (MB) and generation play? Do observed effects persist after controlling for education, parity, etc.? PATIENT COHORT AND METHODOLOGY: In a one-year study in 3 Berlin maternity hospitals, women were interviewed on socio-demografic details and migration aspects on admission to the delivery room. On the 2nd / 3rd day postpartum, another standardized interview was conducted that included questions on the beginning of breastfeeding and planned breastfeeding period. Six months postpartum, a sub cohort was interviewed by telephone or other means about the actual breastfeeding period. Nursing behavior was analyzed using multivariate regression models. A Cox regression was used to analyze actual breastfeeding duration and possible influencing factors. RESULTS: The pre-partum group included 7,100 women (57.9% with a migrant background), 6,884 women were interviewed on the maternity ward, and 605 women were in the sub-cohort questioned six months postpartum. 55.9% of first-generation migrant women, 32.9% of 2nd / 3rd-generation migrant women, and 52.9% of women with no MB were still breastfeeding 6 months postpartum (p<0.001). In the adjusted regression model, women with a migrant background were more likely to start breastfeeding than women with no MB. Cox's regression analysis examined the likelihood of breastfeeding within 6 months: The adjusted model showed no effect of migration status. CONCLUSION: The migration background factor has only a small influence on breastfeeding behavior. Possible differences should take the migration generation into account. PMID- 29969796 TI - A pneumatosis intestinalis case diagnosed with water-immersion technique. PMID- 29969798 TI - Self-expandable covered metallic stent as a conduit for pancreatic stone extraction. PMID- 29969797 TI - Endoscopic transluminal water irrigation for duodenal diverticulitis. PMID- 29969799 TI - Successful endoscopic lithotripsy using a new digital cholangioscope through an overtube placed by an enteroscope. PMID- 29969801 TI - Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer. PMID- 29969800 TI - Narrow-band imaging detects synchronous oropharyngeal squamous carcinoma during treatment of an early esophageal squamous cell carcinoma. PMID- 29969802 TI - Successful closure of a chronic vesicorectal fistula after radical prostatectomy with an over-the-scope clip. PMID- 29969803 TI - Endoscopic full-thickness resection for diagnosis of Hirschsprung's disease. PMID- 29969804 TI - Successful endoscopic removal of fractured guidewire fragments from a peripheral bile duct using a biliary stent delivery system and biopsy forceps. PMID- 29969805 TI - Endoscopic ultrasound-guided angiotherapy in refractory gastrointestinal bleeding from large isolated gastric varices: a same-session combined approach. PMID- 29969806 TI - Caroli's disease associated with biliary papillomatosis and cholangiolithiasis. PMID- 29969807 TI - Prospective comparative study of endoscopic submucosal dissection and gastrectomy for early neoplastic lesions including patients' perspectives. AB - BACKGROUND: There are no prospective studies comparing endoscopic submucosal dissection (ESD) and gastrectomy, especially evaluating patient-reported outcomes. Our aim was to compare the safety and impact on quality of life (QoL) of ESD and gastrectomy in patients with early gastric neoplasia. METHODS: This prospective study included consecutive patients presenting with early gastric neoplasia in a tertiary center from January 2015 to August 2016. Data collection included curative resection, adverse events (AEs), and patient-reported outcomes (questionnaires: EORTC QLQ-C30, EORTC STO-22, EQ-5D-5 L, and Assessment of Survivor Concerns) before and after interventions (after 1 month, 3 - 6 months, and 1 year). RESULTS: 254 patients with early lesions were included: 153 managed by ESD and 101 by gastrectomy, the former being significantly older and with less advanced lesions. Mean procedural time and length of stay were significantly higher in the surgery group (164 vs. 72 minutes and 16.3 vs. 3.5 days; P < 0.001). Complete resection was higher in the surgical group (99 % vs. 90 %; P = 0.02); ESD was curative in 79 % of patients. Severe AEs and surgical re intervention were significantly more frequent in the gastrectomy group (21.8 % vs. 7.8 % and 11 % vs. 1 %, respectively). Endoscopic treatment was associated with a positive impact on global health-related QoL at 1 year (net difference + 9.9; P = 0.006), role function and symptom scales (fatigue, pain, appetite, eating restrictions, dysphagia, and body image). Concerns about recurrence did not differ between the groups. CONCLUSIONS: In patients with early gastric neoplasia, ESD is safer and is associated with a positive impact on health related QoL when compared with gastrectomy, without increasing fear of recurrence and new lesions. PMID- 29969808 TI - Comparison of endoscopic papillary large balloon dilation with or without endoscopic sphincterotomy for the treatment of large bile duct stones. AB - BACKGROUND: Endoscopic papillary large balloon dilation (EPLBD) without prior endoscopic sphincterotomy (EST) produces excellent outcomes for the treatment of large common bile duct (CBD) stones. However, it remains unclear how the outcomes of EPLBD alone compare with those of EPLBD with EST. In this study, we assessed the safety and therapeutic outcomes of EPLBD with vs. without EST for the removal of large bile duct stones. METHODS: This prospective, multicenter study was conducted on 200 patients with bile duct stones of >= 10 mm in diameter. Patients were randomly assigned to an EPLBD alone group (n = 100) or an EPLBD with EST group (n = 100). These two groups were compared with respect to overall procedure related adverse events, overall stone removal success rate, number of endoscopic sessions required for complete stone removal, need for mechanical lithotripsy, and total procedure time. RESULTS: The incidence of adverse events was not significantly different between the groups (EPLBD alone vs. EPLBD with EST: overall adverse events 6 % vs. 4 %, P = 0.75; pancreatitis 1 % vs. 3 %, P = 0.62). Overall success (P = 0.35), initial success (P = 0.28), and the need for mechanical lithotripsy (P = 0.39) were also similar between groups. Median total procedure time tended to be greater in the EPLBD alone group (20.5 minutes) than in the EPLBD with EST group (18 minutes; P = 0.08). CONCLUSION: The therapeutic outcomes and adverse events of EPLBD alone for the removal of large bile duct stones were comparable to those of EPLBD with EST. PMID- 29969809 TI - [The Current S2e Guideline for Hallux valgus - Evidence-based Guideline Development Using Meta-analysis]. AB - The hallux valgus deformity is untreated usually regarded as progressive deformity that does not necessarily lead to pain and suffering for the patient. Prevention primary: foot conforming footwear to avoid bruising and to avoid a forced progression of pathology. Functional stabilization of the foot by means of gymnastics or physiotherapy instructions. Secondary: orthotic and/or insoles to improve the functional stabilization. Tertiary: consistent adapted postoperative treatment, which is based on the operation procedure. The indication for initiation of a therapeutic measure is based on the suffering of the patient, age and presence of arthritis in the MTP-I-joint. More patient-specific pathologies may affect the initiation of treatment also. In the first stage of outpatient consultation and physiotherapy are at the forefront, additive analgesic or anti inflammatory medication. Manual therapies, physiotherapy, orthotics or orthopedic measures adopted in view of the existing pathology and suffering pressure. In stage 2 of outpatient or inpatient surgical treatment therapeutic measures are indicated when symptomatic hallux valgus surgical therapy should be oriented on the severity of the pathology and the postoperative mobilization possibilities of the patient and other patient-specific criteria. PMID- 29969810 TI - Reliability, Validity, and Responsiveness of the Chinese Version of the Knee Injury and Osteoarthritis Outcome Score (KOOS) in Patients with Anterior Cruciate Ligament Reconstruction in Mainland China. AB - OBJECTIVE: The aim of this study was to perform a cross-cultural adaption of the KOOS into Chinese and to evaluate its psychometric properties in patients with anterior cruciate ligament reconstruction (ACL reconstruction) in mainland China. DESIGN: A cross-sectional study. SETTING: Patients completed the Chinese version of the KOOS and the SF-36 questionnaire three times. We evaluated the reliability, checked the validity, and assessed the responsiveness. PARTICIPANTS: A total of 42 patients who had undergone ACL reconstruction. MAIN OUTCOME MEASURES: The results of the questionnaire survey. RESULTS: The Chinese version of the KOOS was well accepted, with ideal test-retest reliability and internal consistency. The test-retest reliability was significant, with high ICC values ranging from 0.888 to 0.941. Additionally, we found that the internal consistency was adequate, with Cronbach's alpha coefficient ranging from 0.740 to 0.975. All a priori hypotheses were supported by a high correlation between the KOOS and SF 36. Furthermore, responsiveness was demonstrated since the ES and SRM between subscales following ACL reconstruction was found in the expected pattern. CONCLUSIONS: The Chinese version of the KOOS showed psychometric properties demonstrating acceptable reliability and validity similar to the original version. We conclude that the Chinese version is a reliable and valid instrument for research and clinical assessments of ACL reconstruction patients in mainland China. PMID- 29969811 TI - [Transoral Spine Surgery - an Update]. AB - Even though in recent years the number of transoral spinal interventions has decreased in Europe and North America - mainly because of the progress in the drug therapy of rheumatism, there are still pathologies that can only be addressed by a transoral approach. The classical transoral approach can be expanded in collaboration with oral-maxillofacial surgery and ear, nose and throat surgery, but this is rarely necessary. The transoral approach is now mainly used for resection of pathological tissue. Additional stabilisation is often necessary and is performed in Europe and North America via a posterior approach, due to the lack of availability of anterior plate systems. Anterior plate systems are still used in India and China. In these countries, the numbers of transoral operations are generally still increasing. Today the indications for transoral spinal surgery consist mainly of infections and tumours, and more rarely of trauma and congenital malformations of the craniocervical junction. The numbers of surgical interventions for these indications has remained constant in recent years. The most recent advancement is the use of endoscopes and transnasal access. With these techniques, additional alternatives and supplements are available for further reducing the morbidity of transoral surgery. Despite the low number of cases, surgical therapy of the corresponding pathologies can be offered to patients with a calculable risk. PMID- 29969812 TI - [Be Searching for Happiness - An Excursus to Some Scientific Basics]. AB - Starting with the fairy-tale "Hans in luck" some scientific basics of social economy, neurobiology, psychology, psychiatry, and philosophy in the context of happiness are elucidated and from a personal point of view assigned to a moral, an aesthetic, an intellectual, and a spiritual dimension as fundamental principles of the human living together. PMID- 29969813 TI - [Can Happiness be "Produced"?] AB - Psychiatry und psychotherapy aim at relieving their patients from mental diseases and disturbances and at enabling them to feel happier than they would do otherwise. Thus, part of their raison d'etre depends on the chance to achieve happiness by a systematic effort. A "pursuit of happiness" along this line has repeatedly met with skepticism. The contribution discusses for arguments against the possibility to produce happiness - in oneself or others - by making it an explicit objective: the "happiness paradox", the irreducible subjectivity of happiness, the variability of happiness, and the theory that the ability to feel happy is completely genetically determined. PMID- 29969814 TI - [Happiness in Spite of Mental Disease?] AB - The title's mode "in spite of" suggests that being mentally ill is an obstacle to happiness. Indeed, mental disorders usually tend to preclude happiness. This is at least partly due to the psycho-social consequences of such a disease. There are many hurdles for people with mental illness that exclude them from the sources of happiness. However, on the one hand we have to realize that happiness may not be the most important thing in life, and on the other hand, one may still become happy not only in spite of but even because of being mentally ill. The article closes with an illustrative tale about an unexpected visit by happiness. PMID- 29969815 TI - [Misfortune with Health - Fortune in Illness]. AB - Health and illness in modern societies are often understood as moral or normative categories. The author proposes an anthropological, not mutually excluding concept. A case study shows that even a severe illness with shortened life expectation and -quality can provide new possibilities and confer fulfilment and happiness for the people affected on condition that they and their caregivers have an open-minded attitude ("serendipity"), sense of coherence, empowerment and orientation towards "recovery" as a new concept of healthiness at their disposal. The challenges for mental health services are being discussed. PMID- 29969816 TI - [Appropriation or Alienation? The Need of Sense and the Provocative Question on a "Successful Psychosis"]. AB - Are mental disorders on the rise, or rather the willingness to disclose them and ask for help? Is humanity becoming increasingly ill or is illness becoming more and more human? Which perspective on mental disorders, especially psychosis, helps the patient to integrate their own experience, and others to avoid social distance? Can psychiatry learn and eventually teach to view these distinct human characteristics not only as pathologic foreignness and abnormality, but also from an anthropological perspective, as a profoundly human expression that exists on a continuum? What value can categories such as purpose and happiness have in this context? The paper introduces the example of Hamburg as city of contradictions with high levels of sickness absence, but simultaneously top scores in the happiness index. Then follows an attempt to outline which perspective on mental illness and which therapeutic stance might be helpful, so that illness and happiness are no longer seen as mutually exclusive. The final case history asks the provocative question if there can be a "successful psychosis". PMID- 29969817 TI - [The Ultimate Disaster? Dementia between Personal Experience and Social Representation]. AB - Dementia is widely regarded as one of the greatest threats to a good and dignified life in old age, a condition so terrifying that even death appears preferable. This contribution is dedicated to a critical discussion of the corresponding conceptions of dementia. It first provides an overview on the existing knowledge on the wellbeing and quality of life of people with dementia. Against this backdrop, it explores the reasons for the negative assessment of dementia in the public sphere. In doing so, it examines prevalent interpretations of dementia in light of widespread societal views and values. PMID- 29969818 TI - [Luck in Forensic Psychiatry]. AB - Luck in forensic psychiatry may mean a fair treatment for the affected person, safety for the society and satisfying work for the clinician. There has been great progress in forensic psychiatry. A high quality forensic treatment consists of a professional attitude, which preserves the personal integrity and identity. The principles of RNR (Risk-Need-Responsivity) are essential. There are very promising treatment approaches like the "Good lives model" or the "Community Reinforcement Approach" (CRA-Concept), which consider the personal aims and the pursuit of happiness of the patient as a starting point and resource. The most recent legislative changes will probably cause a shorter duration of stay in forensic clinics and will require a more intense and well connected aftercare. The risk of a relapse is not a matter of luck. It can be calculated and reduced. However, further research is needed to improve effectiveness of the follow-up care. PMID- 29969819 TI - [Ethical Reflections on Parenthood of Mentally Ill Patients]. AB - Ethical aspects towards the parenthood of mentally ill patients will be discussed in the German health care system. The "concept of an ethical therapist" offers new perspectives for solutions concerning the individual level. Structural and systemic problems require institutional and political configurations. The "ethical compass of psychiatric parenthood" points the dimensions of autonomy, heteronomy, egoism, and public spirit. Reductions of psycho-social burden, an age dependent differentiated prevention und early external assessment contribute to successful parenthood of mentally ill patients. PMID- 29969820 TI - [Dimensions of Luck and Happiness in Psychiatric Nursing]. AB - OBJECTIVE: The purpose of this article is to discuss various aspects of the concepts of luck and happiness within the field of psychiatric nursing. METHODS: Personal factors, work characteristics and work environment were included and combined with case studies from a local hospital. RESULTS: Fortune and happiness of psychiatric and mental health nurses are influenced by contextual factors and individual experiences with patients. CONCLUSION: Fortune and happiness are important factors for nursing situations and outcomes of care. They also affect the number and the quality of the workforce in psychiatric nursing. PMID- 29969821 TI - [The Happiness of Being a Psychotherapist]. AB - Professional work enables people to become conscious of their self-efficiency, to develop self-confidence and to have feelings of belongingness. How far does psychotherapy as a profession satisfy these desiderata? Psychotherapists are able to make others happier than they would otherwise be, but this does not seem to be sufficient for them to find satisfaction in their work. On average, psychotherapists seem to be fairly satisfied with their job. There are, however, great individual differences partly correlated with therapy efficacy. Dissatisfied psychotherapists should make an effort to overcome their difficulties by supervision and continued training, both in their own and in their patients' interest. PMID- 29969822 TI - [Happiness - A Philosophical Road Map]. AB - The interdisciplinary studies included in the special issue of the Psychiatrische Praxis "On Happiness" tackle that topic from various, diverse directions. It is the aim of this concluding contribution to provide some orientation from a philosophical perspective, sketching themes and problems that one might encounter in an investigation of happiness. The survey is guided by four fundamental questions: What is happiness? How to become happy? How important is it to be happy? And how is happiness related to ethics? PMID- 29969823 TI - [Treatment of HPV-associated Anal Lesions in HIV-positive Patients - Comparison of Surgical Treatment and Topical Therapy with Imiquimod]. AB - OBJECTIVES: In HIV+-patients, routine proctological assessment is warranted due to the high incidence of human papilloma virus (HPV) infection-related anogenital lesions, such as Condylomata acuminata (C. ac.), anal intraepithelial dysplasia (AIN) and anal cancer. For C. ac. and AIN, surgical resection and topical therapy with imiquimod have been discussed as treatment options. BACKGROUND: In this study, we contrasted surgical resection and topical imiquimod therapy of HPV associated anal lesions in HIV+-patients, with a focus on healing rates and clinical outcome. We also analysed whether a synergistic treatment effect was detectable. METHODS: This was a retrospective analysis of 97 HIV+ patients who underwent proctological evaluation and treatment over a 10-year period (11/2004 - 11/2015) at our centre. Initial success of surgical treatment, topical imiquimod therapy and the combination of the two strategies were compared. RESULTS: In 53/97 patients (54%), HPV-associated anal disease was diagnosed upon the first visit. In approx. 50% of the patients, the HIV infection was adequately controlled (52 patients with viral load < 40 copies [53.6%]) under cART. The mean age was 41.0 +/- 11.6 years. In 7/53 patients with macroscopic C. ac., low-grade and in 18/53 patients high-grade AIN were additionally confirmed. Success rates of surgical resection, imiquimod treatment and the combination of the two were compared. Complete remission of C. ac. and AIN four weeks after treatment was considered a therapeutic success. For C. ac., success rates with imiquimod were 5/25 (20.0%) vs. surgery* 30/57 (52.6%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 7/15 (46.7%). For AIN, success rates with imiquimod were 4/24 (16.7%) vs. surgery* 47/83 (56.7%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 9/21 (42.8%). In 7/92 (13%) of surgical treatments, complications were reported: four minor and two significant bleeding episodes and one perianal thrombosis. No side effects of imiquimod were documented besides skin irritation. CONCLUSION: Surgery is more effective than topical imiquimod as initial therapy of HPV-related anogenital disease in HIV+-patients. A synergistic effect could not be demonstrated. On this basis, we recommend surgical treatment of C. ac. and AIN in HIV+-patients as first line treatment. PMID- 29969824 TI - [The Federal Participation Law as Chance for a Network Related Community Psychiatry]. PMID- 29969825 TI - [University - Asylum - Military Hospital: Heidelberg Psychiatrist Hans W. Gruhle (1880 - 1958) in Wuerttemberg, 1935 - 1945]. AB - Heidelberg psychiatrist Hans Walther Gruhle (1880 - 1958) faced a harsh interruption of his academic career, when National Socialist authorities put into doubt his reliability in respect to their political goals in 1934. Holding a senior position at Heidelberg's psychiatric university clinic, Gruhle had been transmitted to the state-run mental asylums of Zwiefalten and Weissenau, both geographically located in Southern Wuerttemberg. In function and spatial perspective, Gruhle thus came close to forced sterilization and so-called central euthanasia, initiated by the National Socialist health administration in late 1939. From 1940 however, Gruhle found himself delegated to the military hospital at Winnenden, near Stuttgart, where he continued to be in charge until 1945. Seemingly in accord with the visions of the French Army Forces and their medical branch, Gruhle became an advisor of the French Army after the end of WW II. Sources of Baden-Wuerttemberg State Archives as well as sources from the archives of the regional mental asylums are presented here, in order to re-construct biography and functional aspects of a German psychiatrist during war time. PMID- 29969826 TI - The impact of everolimus in reducing cytomegalovirus events in kidney transplant recipients on steroid-avoidance strategy: 3-year follow-up of a randomized clinical trial. AB - There is no evidence of whether everolimus (EVR) reduces cytomegalovirus (CMV) events in patients receiving steroid-free regimens. Besides, studies evaluating a tacrolimus (TAC) and EVR regimen are limited to 1-year follow-up. In this single center prospective randomized trial, the incidence of CMV and 3-year efficacy and safety outcomes of EVR were compared to those of mycophenolate sodium (MPS) in a steroid-free regimen based on low-exposure TAC. Both groups received rabbit anti thymocyte globulin (r-ATG) induction (6 mg/kg) and the steroids were withdrawn at day 7. Maintenance immunosuppression consisted of TAC (4-7 ng/ml until month 3 and 2-4 ng/ml thereafter) plus EVR (3-8 ng/ml) in the EVR group (n = 59); and TAC (4-7 ng/ml during all follow-up) plus MPS (1440 mg) in the MPS group (n = 56). The EVR group presented with a lower incidence of CMV events (18.6% vs. 50%, P = 0.001). No differences were observed in biopsy-proven acute rejection (6.8% vs. 3.6%, P = 0.680),graft loss (0.0% vs. 1.8%, P = 0.487),death (6.8% vs. 1.8%, P = 0.365), or estimated glomerular filtration rate at 36 months (61.1 +/- 25.4 vs. 66.3 +/- 24 ml/min/1.73 m2 , P = 0.369). A higher proportion of patients discontinued MPS treatment (8.5% vs. 26.8%, P = 0.013) for safety issues. In conclusion, EVR was associated with lower rates of CMV events in patients induced with standard dose r-ATG and a maintenance steroid-free regimen based on TAC. This regimen effectively prevented acute rejection and demonstrated a more favorable safety profile. (ClinicalTrials.gov:NCT02084446). PMID- 29969827 TI - Atopic dermatitis: the skin barrier and beyond. AB - BACKGROUND: Atopic dermatitis is the most common chronic inflammatory skin disorder, affecting up to 20% of children and 10% of adults in industrialized countries. This highly debilitating condition poses a considerable burden to both the individual and society at large. The pathophysiology of atopic dermatitis is complex, encompassing both genetic and environmental risk factors. METHODS: This is a narrative review based on a systematic literature search. CONCLUSIONS: Dysregulation of innate and adaptive immunity plays a key role; however, recent epidemiological, genetic and molecular research has focused interest on skin barrier dysfunction as a common precursor and pathological feature. Current understanding of the aetiology of atopic dermatitis highlights disruption of the epidermal barrier leading to increased permeability of the epidermis, pathological inflammation in the skin, and percutaneous sensitization to allergens. Thus, most novel treatment strategies seek to target specific aspects of the skin barrier or cutaneous inflammation. Several studies have also shown promise in preventing atopic dermatitis, such as the early use of emollients in high-risk infants. This may have broader implications in terms of halting the progression to atopic comorbidities including food allergy, hay fever and asthma. PMID- 29969828 TI - Development of death education training content for adult cancer patients: A mixed methods study. AB - AIMS AND OBJECTIVES: The aim of this mixed methods study was to develop science based content for a systematic death education training system based on the needs of adult cancer patients. The study contained two parts: survey development and Delphi survey. First, a small sample test was conducted to check the reliability and validity of the questionnaire. Next, this questionnaire was applied to investigate adult cancer patients' needs for death education. Then, we invited experts in the fields of nursing management, clinical medicine, clinical nursing and psychological care to carry out two rounds of Delphi consultations to revise the training content. BACKGROUND: Death education is often combined with hospice care, which is based on a clear 6-month survival period. However, the survival of adult cancer patients has improved with improved cancer diagnoses and treatments, and death education should be initiated before the dying stage. At the same time, patients' needs for medical information become increasingly important in daily clinical practice. Therefore, a death education programme based on adult cancer patients' needs was developed to help these patients reflect on the meanings of life and death. DESIGN: A mixed methods study. METHODS: During the survey development period (from April 2017-September 2017), a small sample test (n = 150) was conducted to verify the reliability and validity of the questionnaire on death education needs of adult cancer patients. This questionnaire was developed based on a literature review and discussion among the study group. Next, 324 adults with cancer, recruited from a three-level cancer hospital in Tianjin, China, were surveyed to analyse their needs for death education, using the questionnaire that had been tested in the pretest period. Finally, a Delphi survey was conducted from October 2017-January 2018. A panel of experts (n = 23) recruited from major hospitals, nursing schools and universities in China in the fields of clinical nursing, nursing management, clinical medicine and psychological care took part in the study to revise the training contents based on the investigation results. RESULTS: The reliability and validity of results based on the small sample test revealed that the Cronbach's alpha coefficient and the half-degree of reliability of the questionnaire were 0.924 and 0.951, respectively. This demonstrated that the questionnaire had high reliability. The KMO was 0.756 and the Bartlett Test of Sphericity showed p < 0.001, indicating that the factor analysis was justified in the sample. Eight components with eigenvalues greater than one were retained by the factor analysis. The investigation of the patients' needs for death education showed that the overall score of patients' needs was 3.60 +/- 0.709 points (needs were measured on a scale from 1-5, where 5 indicates high needs), and there were high demands for education regarding "cancer patient life reviews," "death-related ethical issues" and "to leave peacefully." Data from expert panel members were collected in two rounds over a 4-month period, and consensus was achieved in the second Delphi round. The final death education contents of adult cancer patients contained four sections: cancer, death, psychology and practice. These were divided into 54 teaching topics to be included in 14 courses. CONCLUSIONS: The adult cancer patient death education training content devised in this study is science-based, practical and can be used as a guide for clinical nurses to provide high-quality care to adult cancer patients. RELEVANCE TO CLINICAL PRACTICE: Nurses could become more involved in providing death education to adult cancer patients and their families. Further research is needed to explore the applicability of the training content and to develop the content according to changing times and patients' needs. PMID- 29969829 TI - "Heart disease never entered my head": Women's understanding of coronary heart disease risk factors. AB - AIMS AND OBJECTIVES: This study investigated experiences of women with a primary diagnosis of ACS (NSTEMI & Unstable Angina). The study explored how women interpreted their risk for coronary heart disease (CHD) and how this influenced their treatment-seeking decisions. BACKGROUND: Efforts to reduce the incidence of cardiovascular disease, the number one killer of women, require aggressive risk factor modification, risk assessment and evidence-based treatments. CHD is largely preventable; however, despite the availability of evidence on prevention and risk factor reduction, it appears that misunderstandings persist. DESIGN: A naturalistic case study design guided this study. METHODS: Thirty women participated (n = 30); a within-case analysis was followed by a cross-case analysis. Data collection included participant diaries and face-to-face interviews. Data were analysed using modified analytic induction which allowed the emergence of theoretical insights. RESULTS: This article provides insight into women's perception of risk for CHD, particularly in relation to smoking. The findings provide a platform for a wider discourse on women's interpretation of their risk for CHD and their treatment-seeking decisions. The data reflect the ongoing misunderstanding that CHD affects men more than women. CONCLUSIONS: More focus is needed on risk factor management and CHD symptom presentation in women. An emphasis on the chronic disease aspect of CHD may promote a timely focus on secondary prevention and the follow-up needed through patient education and empowerment. RELEVANCE TO CLINICAL PRACTICE: This study demonstrates that primary and secondary prevention education initiatives are needed for CHD risk factor management and symptom interpretation. The implications of smoking on cardiovascular health need further dissemination. Efforts to support smoking cessation need to be strengthened and widely accessible. Primary care can have a key role to play in managing CHD risk and supporting women with positive risk factors. PMID- 29969830 TI - Inherited or acquired modifiers of iron status may dramatically affect the phenotype in dehydrated hereditary stomatocytosis. AB - Severe iron overload is frequent in dehydrated hereditary stomatocytosis (DHSt) despite well-compensated hemolysis and no or little transfusion requirement. We investigated 4 patients with proven DHSt, in whom the degree of hemolysis was closely related to iron status. Genetic modifiers increasing iron stores (HFE:pCys282Tyr, HAMP:c-153C>T mutations) were accompanied with high liver iron concentrations and increased hemolysis, whereas therapeutic phlebotomies alleviated the hemolytic phenotype. There were no manifestations of hemolysis in one patient with low iron stores. Hemolysis reappeared when iron supplementation was given. The search for genetic or acquired modifiers of iron status and the modulation of iron stores may help in the management of these patients. PMID- 29969831 TI - Genetic analysis: Wnt and other pathways in nonsyndromic tooth agenesis. AB - Tooth agenesis (TA) is one of the most common developmental anomalies that affects the number of teeth. An extensive analysis of publicly accessible databases revealed 15 causative genes responsible for nonsyndromic TA, along with their signaling pathways in Wnt/beta-catenin, TGF-beta/BMP, and Eda/Edar/NF kappaB. However, genotype-phenotype correlation analysis showed that most of the causal genes are also responsible for syndromic TA or other conditions. In a total of 198 different mutations of the 15 genes responsible for nonsyndromic TA, 182 mutations (91.9%) are derived from seven genes (AXIN2, EDA, LRP6, MSX1, PAX9, WNT10A, and WNT10B) compared with the remaining 16 mutations (8.1%) identified in the remaining eight genes (BMP4, DKK1, EDAR, EDARADD, GREM2, KREMEN1, LTBP3, and SMOC2). Furthermore, specificity analysis in terms of the ratio of nonsyndromic TA mutations versus syndromic mutations in each of the aforementioned seven genes showed a 98.2% specificity rate in PAX9, 58.9% in WNT10A, 56.6% in MSX1, 41.2% in WNT10B, 31.4% in LRP6, 23.8% in AXIN2%, and 8.4% in EDA. These findings underscore an important role of the Wnt and Wnt-associated pathways in the genetic etiology of this heterozygous disease and shed new lights on the discovery of novel molecular mechanisms associated with tooth agenesis. PMID- 29969832 TI - Initiatives aimed at retaining ethnically diverse student nurses in undergraduate programmes: An integrative review. AB - AIMS AND OBJECTIVES: To identify initiatives aimed at retaining ethnically diverse students in Bachelor/Baccalaureate undergraduate nursing programmes. The review focused on identifying strategies attempting to address this issue. BACKGROUND: There is a recognised shortage of ethnically diverse registered nurses (RN) worldwide. Multiple strategies have been implemented internationally to create a more linguistically and culturally diverse RN workforce. Governments have invested significant resources into these strategies, but the outcomes have been variable. If a future RN workforce is to be representative of their populations, then effective evidence-based interventions are required. DESIGN: An integrative review of the literature published from January 2006-December 2015. METHOD: CINAHL, PubMed, ProQuest, ERIC and Cochrane databases were searched using the key terms student nurse, attrition and retention to identify papers. The CASP tools were used to evaluate relevant studies for rigour (Critical Appraisal Skills Programme [CASP], 2017). Seventeen papers were identified for inclusion. The findings from these studies were analysed using thematic analysis. RESULTS: Four themes emerged from the analysis: prediction, recruitment and retention, single approach and multiple approaches. CONCLUSIONS: Many factors affect the processes of retaining ethnically diverse student nurses in a Bachelor/Baccalaureate undergraduate programme. Programme single approaches appear to be limiting; however, implementation of a broad range of strategies across the continuum from recruitment to graduation is likely to be a more appropriate solution to achieving higher graduation rates amongst ethnically diverse students. RELEVANCE TO CLINICAL PRACTICE: Supporting the recruitment and retention of ethnically diverse students assists in greater numbers of RNs graduating and provides a more linguistically and culturally diverse workforce representative of their population. PMID- 29969833 TI - Hypertension: a new treatment for an old disease? Targeting the immune system. AB - Arterial hypertension represents a serious public health problem, being a major cause of morbidity and mortality worldwide. The availability of many antihypertensive therapeutic strategies still fails to adequately treat around 20% of hypertensive patients, who are considered resistant to conventional treatment. In the pathogenesis of hypertension, immune system mechanisms are activated and both the innate and adaptive immune responses play a crucial role. However, what, when and how the immune system is triggered during hypertension development is still largely undefined. In this context, this review highlights scientific advances in the manipulation of the immune system in order to attenuate hypertension and end-organ damage. Here, we discuss the potential use of immunosuppressants and immunomodulators as pharmacological tools to control the activation of the immune system, by non-specific and specific mechanisms, to treat hypertension and improve end-organ damage. Nevertheless, more clinical trials should be performed with these drugs to establish their therapeutic efficacy, safety and risk-benefit ratio in hypertensive conditions. PMID- 29969835 TI - Free fatty acid receptor 4 agonists induce lysophosphatidic acid receptor 1 (LPA1 ) desensitization independent of LPA1 internalization and heterodimerization. AB - The crosstalk between the free fatty acid receptor FFA4 and the lysophosphatidic acid receptor LPA1 seems to be of pathophysiological importance. We explored this crosstalk employing co-expression of fluorescent protein-tagged receptors. FFA4 activation induces functional desensitization of LPA1 receptors and phosphorylation of both receptors. LPA1 activation induces phosphorylation of LPA1 , but not of FFA4, and induces internalization of both receptors into heterogeneous types of vesicles. Docosahexaenoic acid (DHA) induces internalization of FFA4 but not of LPA1 . Fatty acid-induced FFA4-LPA1 interaction was observed using Forster resonance energy transfer and co immunoprecipitation. Such interaction took place after desensitization was already established. Data indicate that FFA4 activation induces LPA1 desensitization in an internalization-independent process and that complex cellular processes participate in the crosstalk of these receptors. PMID- 29969834 TI - A Bayesian framework for health economic evaluation in studies with missing data. AB - Health economics studies with missing data are increasingly using approaches such as multiple imputation that assume that the data are "missing at random." This assumption is often questionable, as-even given the observed data-the probability that data are missing may reflect the true, unobserved outcomes, such as the patients' true health status. In these cases, methodological guidelines recommend sensitivity analyses to recognise data may be "missing not at random" (MNAR), and call for the development of practical, accessible approaches for exploring the robustness of conclusions to MNAR assumptions. Little attention has been paid to the problem that data may be MNAR in health economics in general and in cost effectiveness analyses (CEA) in particular. In this paper, we propose a Bayesian framework for CEA where outcome or cost data are missing. Our framework includes a practical, accessible approach to sensitivity analysis that allows the analyst to draw on expert opinion. We illustrate the framework in a CEA comparing an endovascular strategy with open repair for patients with ruptured abdominal aortic aneurysm, and provide software tools to implement this approach. PMID- 29969836 TI - Molecular insights into paediatric breast fibroepithelial tumours. AB - AIMS: This study aims to examine the molecular genetics of paediatric breast fibroepithelial tumours through the targeted sequencing of 50 genes. METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues of fibroepithelial tumours diagnosed in a cohort of patients aged 18 years and below were subjected to next generation sequencing using the Haloplex Target Enrichment System. Twenty-five conventional and 17 juvenile fibroadenomas were studied, with MED12 mutations found in 53.8 and 35% of the tumours, respectively. There was also one benign fibroepithelial neoplasm with hybrid features of juvenile papillomatosis and infarcted benign phyllodes tumour-like areas. Most tumours did not have mutations in well-known cancer driver genes, none harboured TERT promoter mutations, while 25.6% (11 of 43) showed no mutations. Metachronous and synchronous tumours were found to have mutational heterogeneity with some containing mutations in MED12; other genes or no mutations were detected at all. Four of eight giant fibroadenomas (size 5 cm or larger) had no mutations detected, suggesting that there are other molecular mechanisms driving their growth. Tumours with MED12 mutations incidentally had a significantly higher stromal mitotic count compared with those without. CONCLUSION: While paediatric fibroepithelial lesions can have cellular stroma potentially raising concern for phyllodes tumour, their lack of TERT promoter and cancer driver mutations is reassuring. The absence of mutations in a significant proportion of tumours, especially the giant fibroadenomas, warrants investigation of pathogenetic mechanisms beyond those involving the 50 genes. PMID- 29969837 TI - Real-time dynamic torque values and axial forces during preparation of straight root canals using three different endodontic motors and hand preparation. AB - AIM: To assess the real-time dynamic torque values and axial forces during preparation of straight root canals using three different endodontic motors and hand preparation. METHODOLOGY: Sixty maxillary incisors were divided into four homogeneous groups (n = 15). After glide path establishment (size 20) the root canals were prepared to an apical size 40 using the rotary NiTi system F6 SkyTaper. Motors (DentaPort ZX OTR, EndoPilot and VDW.silver) were set to 'auto torque-reverse' mode and DentaPort ZX was set to its specific OTR mode (optimum torque reverse). One group served as a control using manual balanced-force canal preparation with K-Flexofiles. Teeth were embedded in resin and fixed in a multi component sensor measuring axial and torsional load during active instrumentation with 50 Hz. Preparation time was also recorded. Data were statistically analysed using the Kruskal-Wallis test. RESULTS: The maximum axial forces (peak) and both peaks of dynamic clockwise and counter-clockwise torque did not differ significantly when using the three different motors despite different gear ratios and pre-settings. Only the VDW.silver motor exceeded the torque values during the use of 30 instruments (3.3%). The Morita OTR motor exceeded the maximum intrinsic torque set at 1.0 Ncm in approximately 53% of cases. The larger tapered F6 SkyTaper instruments (size 20, .06 taper and size 30, .06 taper) created significantly higher torque values (P < 0.0001). Manual instrumentation created significantly lower torque levels and higher axial values compared to rotary instrumentation (P < 0.0001) and was significantly more time consuming (P < 0.0001). CONCLUSIONS: Manual preparation was associated with significantly lower torque peaks compared to rotary instrumentation. The three motors remained well within the safety torque values of the instruments. PMID- 29969838 TI - Attenuation profile matching: An accurate and scan parameter-robust measurement method for small airway dimensions in low-dose CT scans. AB - PURPOSE: The dimensions of small airways with an internal diameter of less than 2 3 mm are important biomarkers for the evaluation of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The resolution limitations of CT systems, however, have remained a barrier to be of use for determining the small airway dimensions. We present a novel approach, called the attenuation profile matching (APM) method, which allows for the accurate determination of the small airway dimension while being robust to varying CT scan parameters. METHOD: For generating the synthetic attenuation profiles of an airway, we acquired and employed the point spread functions of a CT system by calculating its convolution with numerical airway models with varying wall thicknesses. The dimensions of a given airway were determined as per the numerical model yielding minimum error between the measured and the synthetic attenuation profiles across the airway. RESULTS: In a phantom study with airway tubes, the APM method proved to be highly accurate in determining airway wall dimensions. The measurement error for the smallest tube (0.6 mm thickness, 3 mm diameter) was merely 0.02 mm (3.3%) in wall thickness and 0.17 mm (5.6%) in lumen diameter. In a pilot clinical test, the APM method was able to distinguish the airway wall thicknesses of COPD cases (1.16 +/- 0.23 mm) from those of normal subjects (0.6 +/- 0.18 mm), while the measurements using the full width at half maximum method substantially overlapped (1.45 +/- 0.32 mm vs. 1.28 +/- 0.30 mm, respectively) and were barely distinguishable from each other. CONCLUSION: Our proposed APM method has the potential to overcome the resolution limitations of current CT systems and accurately determine the small airway dimensions in COPD patients. PMID- 29969839 TI - Postauthorization Changes to Specific Obligations of Conditionally Authorized Medicines in the European Union: A Retrospective Cohort Study. AB - When medicines are granted a Conditional Marketing Authorisation (CMA) in Europe, specific obligations are requested to obtain comprehensive data on benefits and risks. We performed a retrospective cohort study to characterize obligations, examine changes to their description and due dates after initial authorization, determine timing of data submission relative to due dates, and identify drug related, procedure-related, and obligation-related factors associated with change. We identified 69 obligations for 26 medicines conditionally authorized between 2006 and 2016. We found 39 changes to 27 obligations (39% of obligations), of which four substantially changed the obligation. For 55% of obligations, data submission was delayed. Eleven factors were associated with change, including the use of CMA as a rescue option. The results are potentially indicative of a continuous search by regulators to reduce uncertainties. Submission delays impact public health negatively by prolonging exposure of patients to unknown risks, particularly when the level of uncertainty is high. PMID- 29969840 TI - Building A Longitudinal Cohort From 9-1-1 to 1-Year Using Existing Data Sources, Probabilistic Linkage, and Multiple Imputation: A Validation Study. AB - OBJECTIVE: The objective was to describe and validate construction of a population-based, longitudinal cohort of injured older adults from 9-1-1 call to 1-year follow-up using existing data sources, probabilistic linkage, and multiple imputation. METHODS: This was a descriptive cohort study conducted in seven counties in Oregon and Washington from January 1, 2011, through December 31, 2011, with follow-up through December 31, 2012. The primary cohort included all injured adults >= 65 years served by 44 emergency medical services (EMS) agencies. We used nine existing databases to assemble the cohort, including EMS data, two state trauma registries, two state discharge databases, two state vital statistics databases, the Oregon Physician Order for Life-Sustaining Treatment registry, and Medicare claims data. We matched data files using probabilistic linkage and handled missing values with multiple imputation. We independently validated data processes using 1,350 randomly sampled records for probabilistic linkage and 3,140 randomly sampled records for variables created from existing data sources. RESULTS: There were 15,649 injured older adults in the primary cohort, with 13,661 (87.3%) total matched records and 9,337 (59.7%) matches to the index ED/hospital visit. The sensitivity of linkage was 99.9% (95% confidence interval [CI] = 99.3%-100%) for any match and 98.3% (95% CI = 96.2%-99.4%) for index event matches. The specificity of linkage was 95.7% (95% CI = 93.7%-97.2%) for any match and 100% (95% CI = 99.2%-100%) for index event matches. Name, date of birth, home zip code, age, and hospital had the highest yield for linkage. Patients with matched records tended to be higher acuity than unmatched patients, suggesting selection bias if unmatched patients were excluded. Compared to hand abstracted values, the sensitivity of electronically derived variables ranged from 18.2% (abdominal-pelvic Abbreviated Injury Scale score >= 3) to 97.4% (in hospital mortality), with specificity of 88.0% to 99.8%. CONCLUSIONS: A population-based emergency care cohort with long-term outcomes can be constructed from existing data sources with high accuracy and reasonable validity of resulting variables. PMID- 29969841 TI - Anti-rheumatic medication and salivary MMP-8, a biomarker for periodontal disease. AB - OBJECTIVE: To investigate the impact of anti-rheumatic medications on salivary matrix metalloproteinase (MMP)-8 levels and MMP-8/TIMP (tissue inhibitor of MMPs) 1 ratio in patients with rheumatoid arthritis (RA) and periodontal findings during a 1-year follow-up. MATERIALS AND METHODS: Salivary MMP-8 was measured by an immunofluorometric assay and TIMP-1 by an enzyme-linked immunosorbent assay of 53 patients with early untreated RA (ERA), naive to synthetic disease modifying anti-rheumatic drugs (DMARDs), of 28 patients with chronic RA (CRA), candidates for biologic DMARDs and of 43 age- and sex-matched controls. Periodontal health was evaluated by bleeding on probing (BOP), pocket depth (PD), and periodontal inflammatory burden index (PIBI). Examinations were conducted twice for RA patients and once for controls. RESULTS: Salivary MMP-8 level and MMP-8/TIMP-1 ratio associated positively with PIBI in patients with chronic RA (MMP-8: p < 0.001 at baseline, p = 0.002 after follow-up; MMP-8/TIMP-1 ratio p < 0.001, p = 0.003, respectively) and in controls (MMP-8: p = 0.010, MMP-8/TIMP-1 ratio: p = 0.010). Salivary MMP-8 levels were highest at the early stage of RA. The used DMARDs, synthetic or biologic, did not affect salivary MMP-8 concentrations. CONCLUSIONS: The use of synthetic or biologic DMARDs did not affect salivary MMP 8 levels in RA patients regardless the duration of RA. PMID- 29969842 TI - Environmental tobacco smoke exposure during pregnancy has limited effect on infant birthweight and umbilical vein endothelial nitric oxide synthase. AB - INTRODUCTION: Women who smoke, deliver significantly smaller infants. These infants have reduced levels of the vasodilator endothelial nitric oxide synthase (eNOS) levels in the umbilical vessels, which may reduce fetal growth. Serum cotinine, the degradation product of nicotine, can be used to determine the level of tobacco exposure. Newborns of environmental smokers are suggested to be smaller and shorter in weight, length, and head circumference. eNOS levels have not yet been studied in these infants. We investigated the existence of a relation between maternal environmental tobacco smoke exposure, eNOS activity, concentration, and birthweight. MATERIAL AND METHODS: We included 263 healthy singleton pregnancies categorized into three groups according to measured cotinine levels: 175 nonsmokers, 38 smokers, and 50 environmental smokers. Cotinine was quantified by mass spectrometry with a detection limit of .2 ng/mL; eNOS activity and concentration were measured in endothelial cells (ECs) of the umbilical vein. RESULTS: Infants born to environmental smokers had similar weights to infants born to nonsmokers (47 g heavier, P = .48). Cotinine concentrations were .06/.09/.12 ng/mL (quartiles) in infants born to nonsmokers, .27/.37/.81 ng/mL in infants born to women exposed to environmental tobacco smoke, and 43.0/63.8/108.1 ng/mL in infants born to smokers. The eNOS concentration was 1.65 +/- .92 ng/106 ECs (mean +/- SD) in nonsmokers and 1.71 +/ 1.00 ng/106 ECs in environmental smokers. The eNOS activity was 52.0 +/- 20.6 pmol l-citrulline/min/106 ECs in nonsmokers and 48.7 +/- 19.8 pmol l citrulline/min/106 ECs in environmental smokers. CONCLUSIONS: Infants born to environmental smokers, as judged by umbilical serum cotinine levels close to .2 ng/mL, are not associated with lower birthweight or reduced eNOS activity, or concentration in the fetal vascular bed. PMID- 29969843 TI - Cariogenic microbiome and microbiota of the early primary dentition: A contemporary overview. AB - Recent advances in the field of molecular microbiology provide an unprecedented opportunity to decipher the vast diversity of the oral microbiome in health and disease. Here, we provide a contemporary overview of the oral microbiome and the microbiota of early childhood caries (ECC) with particular reference to newer analytical techniques. A MEDLINE search revealed a total of 20 metagenomic studies describing cariogenic microbiomes of ECC, 10 of which also detailed the healthy microbiomes. In addition, seven studies on site-specific microbiomes, focusing on acidogenic and aciduric microbiota of deep-dentinal lesions, were also reviewed. These studies evaluated plaque and saliva of children aged 1.5-11 years, in cohorts of 12-485 individuals. These studies reveal a very rich and diverse microbial communities, with hundreds of different phylotypes and microbial species, including novel species and phyla such as Scardovia wiggsiae, Slackia exigua, Granulicatella elegans, Firmicutes in the plaque biofilms of children with ECC. On the contrary, bacteria such as Streptococcus cristatus, S. gordonii, S. sanguinis, Corynebacterium matruchotii, and Neisseria flavescens were common in plaque biofilm of noncarious, healthy, tooth surfaces in subjects with caries. The review illustrates the immense complexity and the diversity of the human oral microbiota of the cariogenic plaque microbiome in ECC, and the daunting prospect of its demystification. PMID- 29969844 TI - Periprostatic Fat Adipokines Expression Correlated with Prostate Cancer Aggressiveness in Men Undergoing Radical Prostatectomy for Clinically Localised Disease. AB - OBJECTIVES: To investigate relationship between periprostatic adipose tissue (PPAT) adipokines expression and PCa aggressiveness using both pathological features of radical prostatectomy (RP) and multiparametric MRI parameters. PATIENTS AND METHODS: Sixty-nine men were recruited to assess immunohistochemical expression of TNFalpha- and VEGF of periprostatic fat of radical prostate specimens. Percent immunopositivity was quantified on scanned slides using Aperio Positive Pixel Count algorithm for PPAT TNFalpha, VEGF and androgen receptors. Periprostatic fat volume (PFV) was segmented on contiguous T1 -weighted axial MRI slices from the level of the prostate base to apex. PFV was normalised to prostate volume (PV) to account for variations in PV (NPFV=PFV/PV). MRI quantitative values (Kep , Ktrans, and ADC) were measured from PCa primary lesion using OleaSphere software. Patients were stratified into three groups according to RP GS: <=6, 7(3+4) and 7(4+3) or more. RESULTS: The mean rank of VEGF and TNFalpha were significantly different between the groups [H(2)= 11.038, p=0.004] and [H(2)=13.086, p=0.001], respectively. Patients with stage pT3 had higher TNFalpha (18.2+/-8.95) positivity than patients with stage pT2 (13.27+/-10.66), t (67) =-2.03, p=0.047. TNFalpha expression significantly correlated with Ktrans (rho=0.327, p=0.023). TNFalpha (p=0.043) and VEGF (p= 0.02) correlates with high grade PCa (GS>=7) in radical prostatectomy specimens and correlated significantly with upgradation of Gleason score from biopsy to radical prostatectomy histology. CONCLUSIONS: Expression level of TNFalpha and VEGF on immunostaining significantly correlated with aggressivity of PCa. As biomarkers, these suggest the risk of having high-grade PCa in men undergoing RP. This article is protected by copyright. All rights reserved. PMID- 29969846 TI - Tropical Medicine & International Health. PMID- 29969847 TI - Paraffinoma induced bilateral preauricular cheek skin defects. AB - "Paraffinoma" is a well-recognized complication of paraffin oil injection into various body parts for an aesthetic purpose. After a variable latency phase, paraffinoma can present as a wide range of clinical symptoms. This paper is a case report of surgical excision of the paraffinoma and subsequent reconstruction of the associated skin defect on bilateral preauricular cheeks, manifesting 50 years after a primary injection. PMID- 29969848 TI - Changing Concept of the Prevalence of Eosinophilic Esophagitis: Visible and Hidden Patients. PMID- 29969845 TI - Peyer's patches-derived CD11b+ B cells recruit regulatory T cells through CXCL9 in dextran sulphate sodium-induced colitis. AB - Regulatory T (Treg) cells play an essential role in the maintenance of intestinal homeostasis. In Peyer's patches (PPs), which comprise the most important IgA induction site in the gut-associated lymphoid tissue, Treg cells promote IgA isotype switching. However, the mechanisms underlying their entry into PPs and isotype switching facilitation in activated B cells remain unknown. This study, based on the dextran sulphate sodium (DSS)-induced colitis model, revealed that Treg cells are significantly increased in PPs, along with CD11b+ B-cell induction. Immunofluorescence staining showed that infiltrated Treg cells were located around CD11b+ B cells and produced transforming growth factor-beta, thereby inducing IgA+ B cells. Furthermore, in vivo and in vitro studies revealed that CD11b+ B cells in PPs had the capacity to recruit Treg cells into PPs rather than promoting their proliferation. Finally, we found that Treg cell recruitment was mediated by the chemokine CXCL9 derived from CD11b+ B cells in PPs. These findings demonstrate that CD11b+ B cells induced in PPs during colitis actively recruit Treg cells to accomplish IgA isotype switch in a CXCL9-dependent manner. PMID- 29969850 TI - Predicting Working Memory Capacity in Older Subjects Using Quantitative Electroencephalography. AB - Objective: We utilized a spectral and network analysis technique with an integrated support vector classification algorithm for the automated detection of cognitive capacity using resting state electroencephalogram (EEG) signals. Methods: An eyes-closed resting EEG was recorded in 158 older subjects, and spectral EEG parameters in seven frequency bands, as well as functional brain network parameters were, calculated. In the feature extraction stage, the statistical power of the spectral and network parameters was calculated for the low-, moderate-, and high-performance groups. Afterward, the highly-powered features were selected as input into a support vector machine classifier with two discrete outputs: low- or high-performance groups. The classifier was then trained using a training set and the performance of the classification process was evaluated using a test set. Results: The performance of the Support Vector Machine was evaluated using a 5-fold cross-validation and area under the curve values of 70.15% and 74.06% were achieved for the letter numbering task and the spatial span task. Conclusion: In this study, reliable results for classification accuracy and specificity were achieved. These findings provide an example of a novel method for parameter analysis, feature extraction, training, and testing the cognitive function of elderly subjects based on a quantitative EEG signal. PMID- 29969849 TI - Prevalence and Risk Factors of Abusive Behaviors in the Caregivers of People with Dementia in Korea. AB - Objective: We investigated the prevalence and risk factors of physically abusive behaviors (PhAB) and psychologically abusive behaviors (PsAB) towards people with dementia (PWD) in family caregivers, and compared their prevalences between East Asian and Western countries. Methods: We estimated the prevalence and risk factors of PhAB and PsAB in 467 Korean pairs of community-dwelling PWD and their primary family caregivers. We evaluated abusive behaviors using the Modified Conflict Tactics Scale. In addition, we compared the prevalence of abusive behaviors between Asian and Western countries through a meta-analysis on 12 studies including the current one. Results: More than a half of the caregivers reported PsAB and about one out of seven caregivers admitted PhAB within past three months. PsAB and PhAB were slightly more prevalent in East Asian countries than in Western countries. Non-Alzheimer type and moderate to severe behavioral and psychological symptoms of dementia were associated with the risk of PhAB but not with the risk of PsAB. Severe care burden and low income were associated with the risk of PhAB and PsAB. Conclusion: PhAB and PsAB were as prevalent in the family caregivers of PWD in Asian countries including Korea as in Western countries. Prevention strategies should be implemented according to the type of abusive behaviors. PMID- 29969851 TI - Physical Activity of Patients with Chronic Schizophrenia and Related Clinical Factors. AB - Objective: This study aimed to investigate clinical factors contributing to the low physical activity (PA) of patients with chronic schizophrenia. Methods: PA was measured in 50 outpatients with chronic schizophrenia using the International Physical Activity Questionnaire Short Form (IPAQ-SF). Psychopathology, psychosocial functioning, and extrapyramidal symptoms were assessed using the 18 item-Brief Psychiatric Rating Scale (BPRS-18), Global Assessment of Functioning (GAF), and Drug-Induced Extrapyramidal Symptom Scale (DIEPSS), respectively. We examined differences in these clinical variables between "inactive," "minimally active," and "health enhancing physical activity" groups. Linear regression analysis was used to examine the clinical factors explaining low PA levels in patients with schizophrenia. Results: Subjects spent an average of 130.18+/ 238.89 min/wk on moderate/vigorous-intensity PA and only 26% of them met the recommended PA guideline of 150 minutes of at least moderate PA per week. The inactive group showed significantly higher BPRS-18 and DIEPSS scores, and a lower GAF score than the other groups. Linear regression analysis showed that DIEPSS scores independently explained the amount of total PA (p=0.001) and time spent being sedentary (p=0.028). Conclusion: This study provides preliminary evidence that extrapyramidal symptoms could be a major impediment to the PA of patients with schizophrenia. PMID- 29969852 TI - Detecting Manic State of Bipolar Disorder Based on Support Vector Machine and Gaussian Mixture Model Using Spontaneous Speech. AB - Objective: This study was aimed to compare the accuracy of Support Vector Machine (SVM) and Gaussian Mixture Model (GMM) in the detection of manic state of bipolar disorders (BD) of single patients and multiple patients. Methods: 21 hospitalized BD patients (14 females, average age 34.5+/-15.3) were recruited after admission. Spontaneous speech was collected through a preloaded smartphone. Firstly, speech features [pitch, formants, mel-frequency cepstrum coefficients (MFCC), linear prediction cepstral coefficient (LPCC), gamma-tone frequency cepstral coefficients (GFCC) etc.] were preprocessed and extracted. Then, speech features were selected using the features of between-class variance and within-class variance. The manic state of patients was then detected by SVM and GMM methods. Results: LPCC demonstrated the best discrimination efficiency. The accuracy of manic state detection for single patients was much better using SVM method than GMM method. The detection accuracy for multiple patients was higher using GMM method than SVM method. Conclusion: SVM provided an appropriate tool for detecting manic state for single patients, whereas GMM worked better for multiple patients' manic state detection. Both of them could help doctors and patients for better diagnosis and mood state monitoring in different situations. PMID- 29969853 TI - Which Provocation Test Will Be Added to Routine High-resolution Manometry Protocol in Unexplained Dysphagia? PMID- 29969854 TI - Is High-resolution Anorectal Pressure Topography More Useful Than Wave Manometry in Dyssynergic Defecation? PMID- 29969856 TI - Chronic Cough Is Associated With Long Breaks in Esophageal Peristaltic Integrity on High-resolution Manometry. AB - Background/Aims: Breaks in the peristaltic contour on esophageal high-resolution manometry (HRM) may be associated with bolus retention in the esophagus. We evaluated the relationship between peristaltic breaks and esophageal symptoms, reflux exposure, and symptom outcomes in a prospective patient cohort. Methods: Two hundred and eighteen patients (53.2 +/- 0.9 years, 68.3% female) undergoing both pH-impedance testing and HRM over a 5-year period were prospectively evaluated. Demographics, symptom presentation, acid exposure time, symptom association probability, and symptom burden scores were collected. Outcomes were assessed on follow-up using changes in symptom scores. Presence of long breaks (>= 5 cm) on HRM was assessed by a blinded author. Relationships between breaks, reflux parameters, presenting symptoms, and outcomes were assessed. Results: Patients with long breaks were more likely to have cough as a presenting symptom than those without (43.4% vs 28.6%, P = 0.024); statistical differences were not demonstrated with other symptoms (P >= 0.3). Numbers of swallows with long breaks were higher in patients with cough compared to those without (2.4 +/- 0.3 vs 1.6 +/- 0.2, P = 0.021); differences were not found with other symptoms (P >= 0.4). Long breaks were not associated with age, gender, race, reflux burden, symptom association, or changes in symptom metrics (P >= 0.1 for all comparisons). Among patients with cough, the presence of long breaks predicted suboptimal symptom improvement with antireflux therapy (P = 0.018); this difference did not hold true for other symptoms (P >= 0.2). Conclusions: Long breaks in esophageal peristaltic integrity are associated with cough. The presence of long breaks is associated with suboptimal benefit from antireflux therapy. PMID- 29969857 TI - Abnormal Bolus Reflux Is Associated With Poor Pulmonary Outcome in Patients With Idiopathic Pulmonary Fibrosis. AB - Background/Aims: Gastroesophageal reflux (GER) is postulated to play a role in idiopathic pulmonary fibrosis (IPF). However, the value of objective GER measures in predicting IPF disease progression is unclear. We aim to evaluate the association between objective GER measures on multichannel intraluminal impedance and pH (MII-pH) testing and development of poor pulmonary outcomes within 1 year in prelung transplant IPF patients. Methods: This was a retrospective cohort study of adults with IPF who underwent pre-lung transplant evaluation with MII-pH off proton pump inhibitors (PPI) at a tertiary care center from June 2008 to November 2015. Patients were followed for 1 year from time of MII-pH for poor pulmonary outcomes, defined by hospitalization for respiratory exacerbation or death. Univariate, multivariate and time-to-event analyses were performed to assess associations between baseline GER parameters on MII-pH and poor outcomes. Results: Eighty-four subjects (mean age 61.1 years, 64.3% male) were included. Subjects with increased bolus exposure time (BET) had a higher incidence of 1 year poor pulmonary outcome vs normal BET (45.7% vs 15.2%, P = 0.006). Increased BET remained an independent predictor of poor outcome after controlling for age, gender, body mass index, smoking, lung disease severity, and PPI use (OR, 4.18; P = 0.030). Increased BET was also predictive of decreased time to poor pulmonary outcome (hazard ratio [HR], 4.88; P = 0.007). Subgroup analyses showed that increased BET remained independently associated with time to pulmonary hospitalization (HR, 4.00; P = 0.020), with a trend for 1-year mortality (HR, 2.19; P = 0.380). Conclusion: Increased BET on MII-pH is an independent predictor of poor pulmonary outcome over 1 year in IPF patients. PMID- 29969859 TI - 200 mL Rapid Drink Challenge During High-resolution Manometry Best Predicts Objective Esophagogastric Junction Obstruction and Correlates With Symptom Severity. AB - Background/Aims: Single swallow integrated relaxation pressure (IRP) on high resolution manometry (HRM) does not always accurately predict esophagogastric outflow obstruction on timed barium esophagogram (TBE). Furthermore, neither single swallow IRP or TBE is reliable in predicting symptoms, particularly after treatment with dilatation or myotomy. A 200 mL rapid drink challenge (RDC) has been proposed as an adjunctive test during HRM. This serves as a "stress-test" to the esophagogastric junction, and may yield clinically useful parameters. We aim to assess HRM parameters during RDC, and their ability to predict outflow obstruction on TBE in patients with dysphagia, and to correlate with symptoms in patients' achalasia. Methods: Thirty patients with dysphagia were recruited. All underwent standard single swallow HRM analysis, 200 mL RDC, then TBE. RDC parameters, including esophagogastric pressure gradient, IRP, and RDC duration were evaluated. Multiple regression analysis was performed to assess the best predictive parameter for obstruction on TBE. A further 21 patients with achalasia were evaluated with Eckhardt score, single swallow HRM, RDC, and TBE. Parameter correlation with Eckhardt score was evaluated. Results: Mean IRP during RDC was the best HRM parameter at predicting outflow obstruction on TBE. This performed much better in untreated patients (sensitivity 100% and specificity 85.5%) than in previously treated patients (sensitivity 50% and specificity 66%). In patients with achalasia, mean IRP during RDC was the only parameter that correlated with symptom score. Conclusion: Mean IRP during RDC appears to be a clinically useful "stress test" to the esophagogastric junction during HRM. PMID- 29969858 TI - Esophagography in Patients With Esophageal Achalasia Diagnosed With High resolution Esophageal Manometry. AB - Background/Aims: High-resolution esophageal manometry (HREM) is considered to be the gold standard for the diagnosis of achalasia. However, the Japan Esophageal Society recommends that esophagography is also accurate in either diagnosing or excluding the disorder. Accordingly, we compared the efficacy of esophagography and HREM in diagnosing achalasia patients with upper gastrointestinal symptoms. Methods: HREM was performed in 126 patients with dysphagia. The final diagnosis of achalasia was done using HREM. Demographic data, symptoms, quality of life (QOL) were also obtained. We assessed the patients who were not able to be diagnosed by esophagography and compared the diagnostic values for esophagography with HREM-based achalasia diagnosis as the gold standard. Results: A total of 48 cases of patients with achalasia, including 21 men and 27 women (mean age, 48.4 +/- 19.6 years), were included in the study. Two patients were excluded. Of the remaining 46 patients, 36 (78.3%) patients were diagnosed as having achalasia by esophagography. The diagnostic sensitivity, specificity, and accuracy of esophagography were 78.3%, 88.0%, and 83.0%, respectively. Patients with type III achalasia had significantly lower physical QOL score than those with type I or II achalasia. Although the mental QOL score in patients with type III achalasia tended to decrease compared with that in patients with type I and II achalasia, the difference was not statistically significant. Conclusions: Diagnosing esophageal achalasia by using esophagography alone has limited yield. Therefore, HREM should be used in patients with dysphagia and in whom achalasia cannot be diagnosed using EGD or esophagography. PMID- 29969860 TI - Effects of the Administration of Probiotics on Fecal Microbiota Diversity and Composition in Healthy Individuals. AB - Background/Aims: Probiotics are expected to modify the composition of gut microbiota. We aimed to investigate the changes in the composition and diversity of gut microbiota by the administration of probiotics in healthy individuals. Methods: Twelve healthy volunteers with age range of 30-42 years provided baseline fecal samples. Subsequently, they took commercially available probiotic capsules (a mixture for Bifidobacterium, Lactobacillus, and Enterococcus) for 4 weeks. Fecal samples were collected at 4 weeks of administration and 2 weeks after the stop of administration. Fecal microbiota was analyzed via 16S ribosomal RNA gene sequencing. Results: The mean Shannon index was not significantly altered by the 4-week administration of probiotics (4.365 vs 4.556, P > 0.05). The proportion of Bacteroidetes, Actinobacteria, Firmicutes , and Proteobacteria was not significantly changed by the 4-week administration of probiotics. At the genus level, the proportions of Lactobacillus (2.138% vs 2.773%, P = 0.028) and Enterococcus (0.022% vs 2.758%, P = 0.004) significantly increased 4 weeks after the administration of probiotics, but reduced 2 weeks after the stop of administration (2.773% vs 3.292%, P = 0.064 and 2.758% vs 0.001%, P = 0.001). Conclusions: The diversity of fecal microbiota is not significantly affected by 4 weeks of probiotics administration. The proportion of fecal microbiota at the genus level is significantly altered by the administration of probiotics. However, this effect does not seem to last long, probably because of homeostasis or dietary influence. PMID- 29969855 TI - Role of Gut Microbiota-Gut Hormone Axis in the Pathophysiology of Functional Gastrointestinal Disorders. AB - Gut microbiota exert a pivotal influence on various functions including gastrointestinal (GI) motility, metabolism, nutrition, immunity, and the neuroendocrine system in the host. These effects are mediated by not only short chain fatty acids produced by microbiota but also gut hormones and inflammatory signaling by enteroendocrine and immune cells under the influence of the microbiota. GI motility is orchestrated by the enteric nervous system and hormonal networks, and disturbance of GI motility plays an important role in the pathophysiology of functional gastrointestinal disorders (FGIDs). In this context, microbiota-associated mediators are considered to act on specific receptors, thus affecting the enteric nervous system and, subsequently, GI motility. Thus, the pathophysiology of FGIDs is based on alterations of the gut microbiota/gut hormone axis, which have crucial effects on GI motility. PMID- 29969862 TI - Response to Treatment of Helicobacter pylori-associated Dyspepsia: Eradication of Helicobacter pylori or Correction of Gastric or Intestinal Dysbiosis? PMID- 29969861 TI - Relation of Enteric alpha-Synuclein to Gastrointestinal Dysfunction in Patients With Parkinson's Disease and in Neurologically Intact Subjects. AB - Background/Aims: alpha-Synucleinopathy in the brain is the neuropathological hallmark of Parkinson's disease (PD). However, the functional impact of alpha synucleinopathy in the enteric nervous system remains unknown. We aim to evaluate the association between gastrointestinal (GI) dysfunction and alpha-synuclein (alphaSYN) pathology in the stomach and colon of PD patients and controls, as well as to investigate the association between the alphaSYN pathology in GI tract and future PD risk. Methods: A total of 35 PD patients and 52 neurologically intact subjects were enrolled in this study. Endoscopic biopsies were performed, and then immunohistochemical staining for alphaSYN was performed. All subjects completed the validated Rome III questionnaire for the assessment of GI symptoms. The association between GI symptoms and the alphaSYN pathology in GI mucosa was evaluated. Incident PD cases were assessed during a median follow-up of 46 months. Results: The proportion of self-reported constipation and functional constipation through the Rome III questionnaire was significantly higher in PD patients than in controls (P < 0.001 and P = 0.015). However, no significant association was found between the alphaSYN pathology in the stomach and colon mucosa and constipation, as well as other GI symptoms including dyspepsia symptoms and abdominal discomfort or pain, regardless of the presence or absence of clinical PD (P > 0.05). No incident PD cases were diagnosed during study period. Conclusions: Our present study suggests that the deposition of alphaSYN in the mucosal enteric nervous system may not be reflected by functional impairment of the affected segment of the gut. PMID- 29969863 TI - Rumination Syndrome: Unknown Pathology Easy to Diagnose With High-resolution Impedance Manometry. PMID- 29969864 TI - Factors Determining the Inter-observer Variability and Diagnostic Accuracy of High-resolution Manometry for Esophageal Motility Disorders. AB - The figure 6 should have been presented as follows. PMID- 29969865 TI - Effects of Germanium (Ge) on the silica spicules of the marine sponge Suberites domuncula: Transformation of spicule type. AB - Germanium (Ge), in the form of germanic acid, at a Ge/Si molar ratio of 1.0 inhibits gemmule development and silica deposition in the marine demosponge Suberites domuncula. Lower Ge/Si ratios inhibit the growth in length of the silica spicules (tylostyles) producing short structures, but with relatively normal morphology and close to normal width; spherical protuberances occasionally occur on these spicules. A few of the short spicules possess completely round rather than pointed tips. Many of the latter develop when Ge is added (pulsed) to growing animals, thus inducing a change in spicule type. These results indicate that the growth in length of the axial filament is more sensitive to Ge inhibition than is silica deposition and that pointed spicule tips normally develop because the growth of the axial filament at the spicule tip is more rapid than silica deposition. Newly formed spicules initiate silica deposition at the spicule head but the absence of Ge-induced bulbs as in freshwater spicules (oxeas) leaves open the question of whether there is a silicification center(s) present in Suberites tylostyles. The morphogenesis of freshwater oxeas and of marine tyolstyles appears fundamentally different-bidirectional growth in the former and unidirectional growth in the latter. X-ray analysis demonstrate relatively uniform Ge incorporation into the silica spicules with considerable variation from spicule to spicule in the incorporated level. Increased silicic acid concentration induces the formation of siliceous spheres, suggesting that the axial filament becomes prematurely encased in silica. PMID- 29969866 TI - Body mass and natural diet as determinants of the number and volume of adipocytes in eutherian mammals. AB - Total dissection of a randomly collected sample of 202 adult and subadult eutherian mammals, combined with site-specific adipocyte volume determination, shows that the number of adipocytes in the body is proportional to (Body Mass)0.74 for predominantly carnivorous species and to (Body Mass)0.78 for mainly herbivorous, nonruminant mammals. Adipocyte expansion or shrinkage, not proliferation or depletion of adipocyte number, is the principal mechanism of adipose tissue enlargement and reduction. Therefore, the adipocytes of large mammals are larger than those of smaller specimens of similar dietary habits and fatness. We suggest that the presence of more numerous, smaller adipocytes in smaller mammals is related to their higher mass-specific metabolic rate. The adipose tissue of mammals with a predominantly carnivorous diet contains 4.6 times as many adipocytes as that of herbivorous nonruminants of similar body mass; but nonruminant herbivores are not necessarily fatter because the adipocytes of carnivorous mammals are proportionately smaller than those of nonruminant herbivores. We suggest that a carbohydrate-based energy metabolism is associated with fewer, relatively larger adipocytes and that when lipids and proteins form the major dietary energy source, adipose tissue consists of a greater number of smaller adipocytes. PMID- 29969867 TI - Autolysis and heterolysis of the epidermal cells in anuran tadpole tail regression. AB - Autolysis and heterolysis of the degenerating epidermis of the tail fin of Rana japonica tadpoles during spontaneous metamorphosis were observed by transmission and scanning electron microscopy. In the early climactic stages of metamorphosis (st. 19-20), the outermost epidermal cells developed vacuoles that were acid phosphatase positive and showed apparent breakdown of the cell membrane. The cells shrunk, perhaps due to the rupture of the cell membrane, and sloughed off without typical cornification. As tail resorption proceeded, autolysis of the epidermal cells spread towards the inner layers, in which some epidermal cells lost desmosomal junctions. They also displayed atrophic figures with condensed cytoplasm, breakdown of the cell membrane, and pycnotic nuclei. Lymphocytes, neutrophils and macrophages were already present in the basal layers of the premetamorphic epidermis (st. 10). Based on ultrastructural observation, blood cells could be distinguished from autolysing epidermal cells. Only a few blood cells were found in the early climactic stages of metamorphosis (st. 19-20), but the number of the blood cells, especially macrophages, greatly increased during the final stages of metamorphosis (st. 23-24). During the final stages, many macrophages were observed to phagocytose the autolysing epidermal cells by projecting slender pseudopodia into the inner epidermis. Macrophages also were observed to pass through the degraded basal lamella. These results suggest that not only autophagy but also heterophagy of the epidermal cells by the macrophages is a major process in the regression of the tail fin epidermis. PMID- 29969868 TI - Electron microscopy of the medial cortex in the lizard Psammodromus algirus. AB - The medial cortex of Psammodromus presents a three-layer organization. Most of the cell bodies are localized in a compact lamina, the cellular layer. Two plexiform layers, superficial and deep, enclose the cellular layer. The most external portion of the superficial plexiform layer is formed by a limiting glial sheet consisting of tanycytic processes that reach the surface of the cortex. Astrocytes are localized close to the glial sheet. There are two types of axon terminals within the superficial plexiform layer: type S with spheric vesicles and type F with pleomorphic vesicles. Large solitary neurons are present at middle levels of the layer. In the cellular layer there are three neuronal types: large neurons with dispersed chromatin, neurons of medium size with chromatin clumps, and electron-dense neurons. Protoplasmic astrocytes are found superficially in this layer. In the deep plexiform layer numerous neuronal cell bodies are visible, and three types can be distinguished: horizontal fusiform cells, globous neurons with indented nuclei, and electron-dense neurons. Protoplasmic astrocytes are present throughout this layer. Oligodendrocytes are more frequent in the inner third of the layer, often related to fibers of a thick fascicle running in contact with the ependyma, the alveus. The ependyma is formed by a single row of prismatic cells bordering the lateral ventricle. PMID- 29969869 TI - Cellular structure of adipose tissue in birds. AB - In a randomly collected sample of 91 wild and captive birds, in which there is no significant correlation between fatness and body mass, the total number of adipocytes is proportional to (Body Mass)0.68 . The adipose tissue of larger birds consists of proportionately fewer adipocytes; therefore, the adipocytes of larger birds are larger, in relation to the fatness of the specimens, than those of the smaller species. The cellularity of the adipose tissue of predominantly carnivorous birds does not differ from that of mainly herbivorous species. The adipocytes in the abdominal cavity and around the thigh are on average 29% larger than those in the superficial and clavicular depots; however, these site-specific differences were variable and were statistically insignificant in many of the specimens. The size of the adipocyte complement is highly variable even among specimens of a single species and similar body mass, suggesting that in birds the number as well as the volume of adipocytes might increase or decrease as the adipose tissue expands or shrinks. PMID- 29969870 TI - External features of the developing embryo of the stonefly, Kamimuria tibialis (pictet) (plecoptera, perlidae). AB - External features of the egg, developing embryo, and first instar nymph of Kamimuria tibialis are described. The embryonic development from the germ disc to the full-grown embryo is divided into 12 stages. The saclike embryonic rudiment is formed by the bending and folding of the germ disc. The embryo first elongates at the egg surface and then sinks into the yolk due to caudal flexure. In the head, four paired protocerebral lobes differentiate and the fourth lobes are thought to be the rudiments of preantennal ganglia. The columnar serosal cells appear at the posterior pole of the egg and they disappear before katatrepsis. The coniform chloride cells occur at the hind margins of the first nine abdominal segments in the full-grown embryo and first instar nymph. Amnion formation in K. tibialis is very similar to that of Allonarcys proteus and the Isoptera. It is proposed that the immersed type of growth pattern of embryos is divided into two subtypes in hemimetabolous insects; one is in the Palaeoptera and Paraneoptera, and the other is in the Plecoptera, Orthoptera, Notoptera, Isoptera, Embioptera, and the blattarian, Periplaneta americana. PMID- 29969871 TI - Development and rudimentation of the peripheral olfactory system in the harbor porpoise Phocoena phocoena (Mammalia: Cetacea). AB - Serial sections of 13 embryos and fetuses of the harbor porpoise from 10 mm crown rump length up to 167 mm total length were studied. Unlike the adult animals, ontogenetic stages of 18-27 mm crown-rump length still show a typical mammalian olfactory bulb. The olfactory bulb primordium is penetrated by olfactory nerve fibers, the latter passing through the cribriform plate. However, the olfactory bulb anlage is gradually reduced in later stages, its placodal component being largely uncoupled from the telencephalon. As a ganglionlike structure, the remains of the placodal component stay in contact with the nasal septum and mucosa via thin bundles of nerve fibers. The ganglion and plexus can be traced within the meninges until the adult stage of the porpoise. There is strong evidence that they represent the material of the terminalis system, which cannot be distinguished from the olfactory system in earlier stages. A vomeronasal organ could not be detected in the embryonal and fetal material investigated. PMID- 29969872 TI - Architecture of a lamellicorn flagellum (Phyllopertha horticola, scarabaeidae, coleoptera, insecta). AB - The distal three of the seven flagellar segments of the scarabaeid beetle Phyllopertha horticola are lamelliform, gathered into a club, and possess five sensillar fields that are packed with sensilla placodea. The most proximal surface of the club bears only hair-shaped sensilla. On the inner four sensillar fields a narrow central elongated zone houses pit organs and cavities with sunken sensilla placodea and other sensilla. The most distal, fifth sensillar field is smooth. The sensilla placodea seem to be of several types. The only distinct difference between the sexes is the shorter and more rounded lamellae of the female. The total count of sensilla placodea in males outnumbers that of the females by about 60%. PMID- 29969873 TI - Developmental events of the pectoral muscle in rainbow trout larvae (Salmo gairdneri). AB - Skeletal muscles of developing pectoral fins in rainbow trout larvae (Salmo gairdneri) were analyzed by electron microscopy. Large, branched mitochondria were dominant structures in developing myotubes. Mitochondria were associated with the tubular system (T and SR). New mitochondria arose from old ones when the latter extruded whorls of paired membranes surrounding a nonmembranous core. The core was comprised in part of a dense material, presumably, DNA. The developing muscles were characterized by two sets of caveolae which provided the major contributions to the tubular system. Large caveolae gave rise to elements traditionally designated as SR tubules but which later lost their exterior connections. Small caveolae gave rise to small diameter tubules that appear to be analogous to T tubules, which maintained connections with the exterior. Both tubular elements abutted mitochondria. The two elements ran parallel to each other and intersected with each other to form junctions. Each set of elements possessed intratubular junctions. PMID- 29969874 TI - Distribution of myofiber types in thigh muscles of chickens. AB - The composition of myofiber types varies within thigh muscles of chickens. The present study was designed to determine whether or not myofiber types were distributed uniformly across the diameter of the thigh muscles of chickens. Cross sections from middle portions of muscles were used histochemically to examine differences in distribution and composition of myofiber types in the muscles. Myofibers that reacted moderately (M) or strongly (S) for myosin adenosine triphosphatase (ATPase) after preincubation at pH 4.3 were classified as type I. Type I myofibers reacted weakly (W), moderately (M), or strongly (S) for ATPase after preincubation at pH 10.6; these type I myofibers were subclassified into four types (ISW , ISM , ISS , and IMM ). Myofibers that reacted negatively for acid-stable ATPase and strongly for alkali-stable ATPase were classified into two types: type IIA, with strong NADH tetrazolium reductase (NADH-TR), and type IIB, with weak NADH-TR activity. The M. pubo-ischio-femoralis pars lateralis had numerous type IIA myofibers and very few type ISM myofibers, whereas the pars medialis had many type IMM myofibers and few type ISS and IIA myofibers. The type I group of myofibers did not exceed about 50% in the other muscles, which had one to three types of type ISW , ISM , and ISS myofibers. The Mm. femorotibiales had more type ISW , and ISM myofibers in the deep regions near the femur than in the superficial regions. The M. iliotibialis cranialis, M. iliofibularis, and M. flexor cruris medialis had more type ISW , ISM , or ISS myofibers in the medial regions than in the lateral regions. A few type ISW myofibers were scattered in the cranial part of M. iliotibialis and in the M. ambiens. The M. flexor cruris lateralis pars pelvica had type IIA and IIB myofibers exclusively. All the muscles had type IIA myofibers. Type IIB myofibers existed in the muscles except the M. puboischio-femoralis. Type IIA and IIB myofibers differed in proportion in different muscles and in their different regions. The type I group of myofibers was generally concentrated more in the deep regions near the femur and in the medial regions than in the superficial and lateral regions of the thigh muscles. The distribution of type IIA myofibers resembled that of type I group. Type IIB myofibers showed a distribution opposite to that of type I group and IIA myofibers. The spatial distribution of myofiber types within individual muscles can account for the various locomotory and postural requirements of the thigh. PMID- 29969875 TI - Delayed puberty versus hypogonadism: a challenge for the pediatrician. AB - Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty (DP), is mainly found in males, and is characterized by short stature and delayed skeletal maturation. A family history of the subject comprising the timing of puberty in the parents and physical examination may provide clues regarding the cause of DP. Delayed onset of puberty is rarely considered a disease in either sex. In fact, DP usually represents a common normal variant in pubertal timing, with favorable outcomes for final height and future reproductive capacity. In adolescents with CDGP, a linear growth delay occurs until immediately before the start of puberty, then the growth rate rapidly increases. Bone age is often delayed. CDGP is a diagnosis of exclusion; therefore, alternative causes of DP should be considered. Functional hypogonadotropic hypogonadism may be observed in patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions including celiac disease, inflammatory bowel diseases, kidney insufficiency, and anorexia nervosa. Permanent hypogonadotropic hypogonadism (pHH) showing low serum value of testosterone or estradiol and blunted follicle-stimulating hormones (FSH) and luteinizing hormones (LH) levels may be due to abnormalities in the central nervous system. Therefore, magnetic resonance imaging is necessary to exclude morphological abnormalities and neoplasia. Moreover, pHH may be isolated, as observed in Kallmann syndrome, or associated with other hormone deficiencies, as found in panhypopituitarism. Baseline or gonadotropin-releasing hormone pituitary stimulated gonadotropin level is not sufficient to easily differentiate CDGP from pHH. Low serum testosterone in male patients and low estradiol values in female patients, associated with high serum FSH and LH levels, suggest a diagnosis of hypergonadotropic hypogonadism. A genetic analysis can reveal a chromosomal abnormality (e.g., Turner syndrome or Klinefelter syndrome). In cases where the adolescent with CDGP is experiencing psychological difficulties, treatment should be recommended. PMID- 29969877 TI - Fertility preservation in pediatric and young adult female cancer patients. AB - As the 5-year survival rate increases up to 80% in pediatric cancer patients, the number of women patients with reduced gonadal function by chemotherapy and radiotherapy increases. The gonadal toxicity of pediatric patients varies highly according to the chemotherapeutic agent and the type of radiotherapy. Although American Society of Clinical Oncology published the guideline for fertility preservation, additional scientific and ethical concerns should be considered for clinical practice. In addition, only the experimental method can be applied for the prepubertal patients in contrast to the postpubertal patients. In this review, we will discuss some options for preserving fertility among women's quality of life issues. PMID- 29969876 TI - Fat and bone in children - where are we now? AB - The risk of fracture secondary to low-impact trauma is greater in obese children, suggesting obese children are at risk of skeletal fragility. However, despite this finding, there is a lack of agreement about the impact of excessive adiposity on skeletal development. The combination of poor diet, sedentary lifestyle, greater force generated on impact through falls, and greater propensity to falls may in part explain the increased risk of fracture in obese children. To date, evidence suggests that in early childhood years, obesity confers a structural advantage to the developing skeleton. However, in time, this relationship attenuates and then reverses, such that there is a critical period during skeletal development when obesity has a detrimental effect on skeletal structure and strength. Fat mass may be important to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Evidence from studies examining bone microstructure suggests skeletal adaption to excessive load fails, and bone strength is relatively diminished in relation to body size in obese children. Mechanisms that may explain these changes include changes in the hormonal environment, particularly in relation to alterations in adipokines and fat distribution. Given the concomitant rise in the prevalence of childhood obesity and fractures, as well as adult osteoporosis, further work is required to understand the relationship between obesity and skeletal development. PMID- 29969878 TI - Etiological trends in male central precocious puberty. AB - PURPOSE: In the present study, the etiological trends in male central precocious puberty (CPP) were examined, and annual distribution was evaluated. METHODS: Seventy-one male CPP subjects who started puberty before 9 years of age were included in this study. All individuals were diagnosed as having CPP at Samsung Medical Center between 2001 and 2016. Chronological age at puberty onset, diagnosis of CPP, bone age, weight (kg), height (cm), puberty stage, brain magnetic resonance imaging findings, testosterone level, basal gonadotropin level, and gonadotropin level after gonadotropin releasing hormone stimulation were analyzed. RESULTS: The 71 patients were divided into 2 groups: idiopathic (group I) and organic (group II) when the lesion was identified as associated with the central nervous system (CNS) or when the patient received chemotherapy for non-CNS tumors before CPP diagnosis, respectively. Forty-four cases (62%) were idiopathic, and 27 (38%) were organic. The proportion of idiopathic CPP was higher than that of organic CPP during the study period. In 51.9% of organic cases, puberty started before 8 years of age, whereas it started after that age in 93.2% of the idiopathic cases. CONCLUSION: In the present study, among all male CPP cases, 62% were idiopathic. The probability of idiopathic CPP prevalence was higher in males when the puberty onset was after 8 years of age with no history of cranial radiotherapy or chemotherapy. PMID- 29969879 TI - Visceral fat thickness and its associations with pubertal and metabolic parameters among girls with precocious puberty. AB - PURPOSE: This study aimed to investigate associations of central obesity with sexual maturation and metabolic parameters in Korean girls with precocious puberty. METHODS: This retrospective study evaluated data from 72 girls under 8 years of age with a chief complaint of early breast development. The patients were categorized as central precocious puberty (CPP) subjects or non-CPP subjects based on their gonadotropin-releasing hormone stimulation test results. Visceral fat thickness (VFT) was measured using ultrasonography and defined as the distance from the linea alba to the aorta. Patient anthropometric, metabolic, and hormonal parameters were also evaluated. RESULTS: Increased VFT was correlated with an earlier onset of thelarche among all study subjects (r=-0.307, P=0.034). Overweight CPP subjects showed higher insulin resistance than normal weight CPP subjects. Insulin resistance was not significantly different between overweight and normal weight non-CPP subjects. VFT was not significantly different between CPP and non-CPP subjects (2.22+/-0.79 cm vs. 2.74+/-1.47 cm, P=0.169). However, overweight and obese CPP subjects (body mass index percentile>85%) had lower VFT than non-CPP obese subjects. CONCLUSION: Central obesity, defined using ultrasonography-measured VFT, might be associated with early pubertal development in Korean girls. However, VFT was not higher in CPP than non-CPP patients and was not significantly correlated with insulin resistance. Further longitudinal studies with a larger cohort are needed. PMID- 29969880 TI - Thyroid dysfunction in patients with childhood-onset medulloblastoma or primitive neuroectodermal tumor. AB - PURPOSE: We investigated the clinical characteristics of patients who developed thyroid dysfunction and evaluated the risk factors for hypothyroidism following radiotherapy and chemotherapy in pediatric patients with medulloblastoma or primitive neuroectodermal tumor (PNET). METHODS: The medical records of 66 patients (42 males) treated for medulloblastoma (n=56) or PNET (n=10) in childhood between January 2000 and December 2014 at Seoul National University Children's Hospital were retrospectively reviewed. A total of 21 patients (18 high-risk medulloblastoma and 3 PNET) underwent high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR). RESULTS: During the median 7.6 years of follow-up, 49 patients (74%) developed transient (n=12) or permanent (n=37) hypothyroidism at a median 3.8 years of follow-up (2.9-4.6 years). Younger age (<5 years) at radiation exposure (P=0.014 vs. >=9 years) and HDCT (P=0.042) were significantly predictive for hypothyroidism based on log-rank test. However, sex, type of tumor, and dose of craniospinal irradiation (less vs. more than 23.4 Gy) were not significant predictors. Cox proportional hazard model showed that both younger age (<5 years) at radiation exposure (hazard ratio [HR], 3.1; vs. >=9 years; P=0.004) and HDCT (HR, 2.4; P=0.010) were significant predictors of hypothyroidism. CONCLUSION: Three-quarters of patients with pediatric medulloblastoma or PNET showed thyroid dysfunction, and over half had permanent thyroid dysfunction. Thus, frequent monitoring of thyroid function is mandatory in all patients treated for medulloblastoma or PNET, especially, in very young patients and/or high-risk patients recommended for HDCT/ASCR. PMID- 29969881 TI - Cancer in thyroid nodules with fine-needle aspiration in Korean pediatric populations. AB - PURPOSE: To determine the prevalence and clinical findings of benign thyroid nodules and cancer in Korean pediatric patients with thyroid nodules. METHODS: We investigated the medical records of 134 patients aged younger than 18 years who had a goiter, thyroid nodule, thyroid mass, or thyroid cancer who underwent fine needle aspiration biopsy (FNAB). RESULTS: The study population included 113 females (84.3%) and 21 males (13.7%); the mean patient age was 16.1+/-2.3 years (range, 8-18 years). Of the 134 patients, 24 (18.0%) were finally diagnosed with thyroid cancer, of which 20 (83.3%) were papillary cancer and 4 (16.7%) were follicular cancer. No patient was exposed to radiation. FNAB revealed malignant cancer in 21 of the patients; 3 were initially reported as having benign tumors by FNAB, but were later diagnosed with follicular cancer. An additional 13 patients were suspected to have malignant tumors by FNAB, with a final diagnosis of nodular hyperplasia. Cystic nodules were more common in the benign group. The percentages of cervical lymphadenopathy and irregular nodular margins were higher in the malignant group compared to the benign group. Cervical lymphadenopathy and FNAB malignant findings were highly suggestive of malignant nodules. CONCLUSION: Thyroid cancer prevalence in a Korean pediatric population is comparable to reported estimates of worldwide thyroid cancer prevalence. In this population, cancer predominates on the right thyroid lobe. Papillary thyroid cancers are dominant in the Korean pediatric population but are less prevalent than in Korean adults. As expected, FNAB was highly accurate in predicting malignant nodules. PMID- 29969882 TI - Association Kikuchi disease with Hashimoto thyroiditis: a case report and literature review. AB - Kikuchi-Fujimoto disease (KFD) is a benign and self-limited disease characterized by fever and lymphadenopathy. The etiology of KFD is unknown, but an autoimmune cause has been suggested. Hashimoto thyroiditis is the most common autoimmune thyroid disorder in children and is known to be associated with other autoimmune diseases. Only a few cases of Hashimoto thyroiditis associated with KFD have been documented. We report a case of a 16-year-old girl who was first diagnosed with KFD and developed Hashimoto thyroiditis 2 years and 6 months later during her follow-up period. Physicians of patients with KFD should consider the possibility of autoimmune diseases like Hashimoto's thyroiditis. PMID- 29969883 TI - Respiratory failure in a diabetic ketoacidosis patient with severe hypophosphatemia. AB - Phosphate is essential in regulating human metabolic processes, and severe hypophosphatemia can induce neurologic and hematological complications and result in respiratory failure and cardiac dysfunction. Therefore, correction of severe hypophosphatemia can be pivotal in the management of diabetic ketoacidosis (DKA). We report the case of a 14-year-old female who was diagnosed with type 1 diabetes and referred to our institute for treatment of DKA. Although the patient received fluid and continuous insulin administration according to the current DKA treatment protocol, generalized tonic seizures and cardiac arrest developed. After cardiopulmonary resuscitation, the patient recovered and was stable. Within 16 hours after DKA treatment, the patient developed respiratory failure with severe hypophosphatemia that required mechanical ventilation. Concurrent neurologic evaluation revealed no specific abnormalities. The patient recovered without any complications after correcting the hypophosphatemia. We suggest vigilant monitoring of the phosphate level in DKA patients and active replacement when required. PMID- 29969884 TI - De novo a novel variant of CaSR gene in a neonate with congenital hypoparathyroidism. AB - Autosomal-dominant hypocalcemia with hypercalciuria (ADHH) is a genetic disease characterized by hypoparathyroidism with hypercalciuria. Most patients with ADHH have calcium-sensing receptor (CaSR) gene mutations. The CaSR gene controls parathyroid secretions, and mutations in this gene can be detected via changes in serum calcium level. The activating mutation of the CaSR gene results in familial or sporadic ADHH. Most activating mutations of the CaSR gene are reportedly de novo missense mutations. This is the first case report of a novel activating variant of the CaSR gene in a neonate with congenital hypoparathyroidism with hypomagnesemia and hypercalciuria. We also report the 3-month follow-up management of the patient. PMID- 29969885 TI - Characterization and evaluation of liver fibrosis grade in patients with chronic hepatitis B virus infection and normal transaminases. AB - Backgrounds/Aims: The objective of our study was to determine the epidemiological, laboratory, and serological characteristics of patients with chronic hepatitis B virus (HBV) infection and normal transaminases. The study also aimed to evaluate liver damage by measuring the liver fibrosis (LF) grade and to identify possible factors associated with the presence of fibrosis. Methods: A retrospective observational study was conducted in patients with chronic HBV infection and classified as inactive carriers or immune-tolerant. Epidemiological variables of age, sex, immigrant, alcohol consumption, and body mass index (BMI), as well as virological variables (HBV DNA) and transaminase level were collected throughout the follow-up. The LF grade was evaluated by transient elastography. The cutoff value for significant fibrosis (SF) was liver stiffness >=7.9 kPa. Results: A total of 214 patients were included in the analysis, and 62% of them had a BMI >=25 kg/m2 . During follow-up, 4% of patients showed transaminase elevation (<1.5 times normal). Most patients had a viral DNA level <2,000 IU/mL (83%). Data on LF were available in 160 patients; of these, 14% had SF, 9% F3, and 6% F4. The variables associated with the presence of SF were transaminase alteration during follow-up, as 23% of patients with SF had elevated transaminases versus 3% of patients without SF (P<0.005), and BMI, as the vast majority of patients with SF (88%) had a BMI >=25 kg/m2 versus 56% of patients without SF (P<0.05). Conclusions: In patients with chronic HBV infection and normal transaminases, liver damage does not seem to be related to DNA levels, alcohol consumption, or immigrant status. SF seems to be associated with transaminase alteration during follow-up and elevated BMI. It is therefore recommended to measure LF grade with validated non-invasive methods in such patients. PMID- 29969886 TI - Is irrational use of intralipid emulsion justified in amlodipine toxicity. PMID- 29969887 TI - Amitriptyline inhibits MAPK/ERK, CREB pathway and proinflammatory cytokines through A3AR activation in rat neuropathic pain models. AB - Background: The pain relief properties of tricyclic antidepressants can be attributed to several actions. Recent observations suggest that adenosine is involved in the antinociceptive effect of amitriptyline. The A3 adenosine receptor (A3AR) is the only adenosine subtype to be overexpressed in inflammatory and cancer cells. This study was carried out to investigate the role of A3AR in the anti-nociceptive effect of amitriptyline. Methods: Spinal nerve-ligated neuropathic pain was induced by ligating the L5 and L6 spinal nerves of male Sprague Dawley rat. Neuropathic rats were randomly assigned to one of the three groups (8 per group): a neuropathic pain with normal saline group, a neuropathic pain with amitriptyline group, and a neuropathic pain with amitriptyline and MRS group. Amitriptyline or saline were administered intraperitoneally and MRS-1191, an A3AR antagonist in amitriptyline and MRS group, was injected subcutaneously immediately before amitriptyline administration. ERK 1/2, CREB proteins, and proinflammatory cytokines were assessed by immunoblotting or RT-PCR. Results: Amitryptyline increased the mechanical withdrawal threshold of a neuropathic rats. pERK 1/2 and pCREB proteins, and proinflammatory cytokines produced by spinal nerve ligation were significantly reduced by amitriptyline administration. However, the use of MRS-1191 before amitriptyline not only reduced the threshold of mechanical allodynia, but also increased signaling proteins and proinflammatory cytokines, which were reduced by amitriptyline. Conclusions: The results of this study suggest that the anti-nociceptive effect of amitriptyline is in the suppression of ERK 1/2 and CREB signaling proteins, and in the alleviation of the inflammatory response through the activation of A3AR. PMID- 29969888 TI - Association between perioperative cholesterol level and analgesia after video assisted thoracoscopic surgery. AB - Background: Cholesterol plays an important role in the action of opioid analgesics, but its association with postoperative pain has not been clarified. Our study examined the association of pre- and postoperative total serum cholesterol (TSC) level changes with postoperative pain outcomes in patients with non-small cell lung cancer (NSCLC) who underwent lobectomy via video-assisted thoracoscopic surgery (VATS). Methods: We retrospectively reviewed medical records of patients with NSCLC who underwent VATS lobectomy at a single tertiary care hospital. We sought to determine the association between preoperative TSC, TSC on postoperative day (POD) 0-1, and pre- and postoperative changes in TSC by comparing numeric rating scale (NRS) scores on POD 0, 1 and 2 and total morphine equivalent consumption on POD 0-2. Multivariate linear regression analyses were used, and P < 0.05 was considered statistically significant. Results: A total of 1,720 patients with NSCLC who underwent VATS lobectomy were included in the analysis. The change in TSC, preoperative TSC, and postoperative TSC showed no associations with morphine equivalent consumption on POD 0-2 (P > 0.05). In addition, the changes in TSC, preoperative TSC, and postoperative TSC were not associated with postoperative NRS pain score on POD 0, 1 and 2 (P > 0.05). Conclusions: Our results indicated that no significant association was observed between pre- and postoperative TSC level and postoperative pain outcome (opioid consumption on POD 0-2, NRS pain score on POD 0, 1 and 2) after VATS lobectomy of the lung. PMID- 29969889 TI - Does pediatric anesthesia cause brain damage? - Addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data. AB - Anesthesia facilitates surgery in millions of young children every year. Structural brain abnormalities and functional impairment observed in animals have created substantial concerns among clinicians, parents, and government regulators. Clinical studies seemed ambivalent; it remains unclear whether differential species effects exist towards anesthetic exposure. The current literature search and analysis attempts to unify the available clinical and animal studies, which currently comprise of > 530 in vivo animal studies and > 30 clinical studies. The prevalence of abnormalities was lowest for exposures < 1 hour, in both animals and humans, while studies with injurious findings increased in frequency with exposure time. Importantly, no exposure time, anesthetic technique, or age during exposure was clearly identifiable to be entirely devoid of any adverse outcomes. Moreover, the age dependence of maximum injury clearly identified in animal studies, combined with the heterogeneity in age in most human studies, may impede the discovery of a specific human neurological phenotype. In summary, animal and human research studies identify a growing prevalence of injurious findings with increasing exposure times. However, the existing lack of definitive data regarding safe exposure durations, unaffected ages, and non-injurious anesthetic techniques precludes any evidence-based recommendations for drastically changing current clinical anesthesia management. Animal studies focusing on brain maturational states more applicable to clinical practice, as well as clinical studies focusing on prolonged exposures during distinct developmental windows of vulnerability, are urgently needed to improve the safety of perioperative care for thousands of young children requiring life saving and quality of life-improving procedures daily. PMID- 29969891 TI - Dynamics of Speech Perception in the Auditory-Visual Mode: An Empirical Evidence for the Management of Auditory Neuropathy Spectrum Disorders. AB - BACKGROUND AND OBJECTIVES: The present study probed into the relative and combined contribution of auditory and visual modalities in the speech perception of individuals with auditory neuropathy spectrum disorders (ANSD). Specifically, the identification scores of consonantvowel (CV) syllables, visual enhancement (VE), and auditory enhancement in different signal to noise ratios (SNRs) were compared with that of the control group. Subjects and. METHODS: The study used a repeated measure standard group comparison research design. Two groups of individuals in the age range of 16 to 35 years participated in the study. The clinical group included 35 participants diagnosed as ANSD, while the control group had 35 age and gender matched individuals with typical auditory abilities. The participants were assessed for CV syllable identification in auditory only (A), visual only (V), and auditory-visual (AV) modalities. The syllables were presented in quiet and at 0 dB SNR. RESULTS: The speech identification score was maximum in AV condition followed by A-condition and least in V condition. This was true in both the groups. The individuals with ANSD were able to make better use of visual cues than the control group, as evident in the VE score. CONCLUSIONS: The dynamics of speech perception in the AV mode is different between ANSD and control. There is definite benefit of auditory as well as visual cues to individuals with ANSD, suggesting the need to facilitate both the modalities as part of the audiological rehabilitation. Future studies can focus on independently facilitating the two modalities and testing the benefits in the AV mode of speech perception in individuals with ANSD. PMID- 29969893 TI - Polarized Luminescence of Anisotropic LaPO4:Eu Nanocrystal Polymorphs. AB - Lanthanide elements exhibit highly appealing spectroscopic properties that are extensively used for phosphor applications. Their luminescence contains precise information on the internal structure of the host materials. Especially, the polarization behavior of the transition sublevel peaks is a fingerprint of the crystal phase, symmetry, and defects. However, this unique feature is poorly explored in current research on lanthanide nanophosphors. We here report on a detailed investigation of the evolution of Eu3+ luminescence during the thermally induced phase transition of LaPO4 nanocrystal hosts. By means of c-axis-aligned nanocrystal assemblies, we demonstrate a dramatic change of the emission polarization feature corresponding to the distinct Eu3+ site symmetries in different LaPO4 polymorphs. We also show that changes of the nanocrystal structure can be identified by this spectroscopic method, with a much higher sensitivity than the X-ray diffraction analysis. This new insight into the nanostructure-luminescence relationship, associated with the unprecedented polarization characterizations, provides a new methodology to investigate phase transitions in nanomaterials. It also suggests a novel function of lanthanide emitters as orientation-sensing nanoprobes for innovative applications such as in bioimaging or microfluidics. PMID- 29969894 TI - Fabrication of a Double-Cross-Linked Interpenetrating Polymeric Network (IPN) Hydrogel Surface Modified with Polydopamine to Modulate the Osteogenic Differentiation of Adipose-Derived Stem Cells. AB - Hydrogel surface properties can be modified to form bioactive interfaces to modulate the osteogenic differentiation of stem cells. In this work, a hydrogel made of gelatin methacrylamide (GelMA) and alginate was designed and tested as a scaffold to control stem-cell osteogenic differentiation. The hydrogel's surface was treated with polydopamine (pDA) to create an adhesive layer for the adsorption of the osteoinductive drug dexamethasone (Dex). The presence of the pDA coating enhanced Dex adsorption and retention over 21 days. This effect resulted in a delay in the osteogenic differentiation of hASCs cultured on the hydrogel treated with a pDA layer. PMID- 29969892 TI - Protective Effect and Mechanism of Theanine on Lipopolysaccharide-Induced Inflammation and Acute Liver Injury in Mice. AB - Theanine, a unique bioactive constituent from tea ( Camellia sinensis) leaves, is widely used as a functional ingredient and dietary supplement. To evaluate the anti-inflammatory and hepatoprotective effects of theanine and its molecular mechanism, the lipopolysaccharide (LPS)-induced inflammation mouse model was employed in this study. The survival rate of mice in the theanine-treated group increased significantly compared with that of LPS-only group mice. Furthermore, ICR male mice were randomly divided into three or four groups: control, LPS (LPS treatment only), LPS + theanine (20 mg/kg/day), and theanine (theanine treatment only). The results showed that compared with the LPS group, the liver damage and oxidative stress of the theanine-treated group decreased significantly, based on plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, hepatic total superoxide dismutase (T-SOD), and malondialdehyde (MDA) levels, and histological scores and apoptosis [terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining and caspase-3 activity] in the liver tissues. Furthermore, compared with no treatment, pretreatment with theanine significantly decreased the release of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, inhibited the expression of several inflammatory factors (including IL-1beta, TNF-alpha, and IL 6), and increased the IL-10/interferon (IFN)-gamma ratio in the hepatic tissues. In the LPS-induced inflammation model, theanine inhibited the expression of proinflammatory mediators involved in the nuclear factor-kappa B (NF-kappaB) pathway, such as inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-3 (MMP-3), and attenuated the phosphorylation of NF-kappaB in the hepatic tissues. Moreover, theanine suppressed the acute-phase response (elevated nitric oxide and C-reactive protein levels). Furthermore, theanine suppressed the LPS-induced inflammatory state by normalizing hypothalamic pituitary-adrenal (HPA) axis hyperactivity. Taken together, the results suggest that theanine potentially ameliorates LPS-induced inflammation and acute liver injury; molecular mechanism of action may involve normalization of HPA axis hyperactivity and inactivation of the NF-kappaB signaling pathway. PMID- 29969890 TI - Cervical plexus block. AB - Cervical plexus blocks (CPBs) have been used in various head and neck surgeries to provide adequate anesthesia and/or analgesia; however, the block is performed in a narrow space in the region of the neck that contains many sensitive structures, multiple fascial layers, and complicated innervation. Since the intermediate CPB was introduced in addition to superficial and deep CPBs in 2004, there has been some confusion regarding the nomenclature and definition of CPBs, particularly the intermediate CPB. Additionally, as the role of ultrasound in the head and neck region has expanded, CPBs can be performed more safely and accurately under ultrasound guidance. In this review, the authors will describe the methods, including ultrasound-guided techniques, and clinical applications of conventional deep and superficial CPBs; in addition, the authors will discuss the controversial issues regarding intermediate CPBs, including nomenclature and associated potential adverse effects that may often be neglected, focusing on the anatomy of the cervical fascial layers and cervical plexus. Finally, the authors will attempt to refine the classification of CPB methods based on the target compartments, which can be easily identified under ultrasound guidance, with consideration of the effects of each method of CPB. PMID- 29969895 TI - Deep Oxidation of NO by a Hybrid System of Plasma-N-Type Semiconductors: High Energy Electron-Activated "Pseudo Photocatalysis" Behavior. AB - A "pseudo photocatalysis" process, being initiated between plasma and N-type semiconductors in the absence of light, was investigated for NO removal for the first time via dynamic probing of reaction processes by FT-IR spectra. It was demonstrated that N-type semiconductor catalysts could be activated to produce electron-hole (e--h+) pairs by the collision of high-energy electrons (e*) from plasma. Due to the synergy of plasma and N-type semiconductors, major changes were noted in the conversion pathways and products. NO can be directly converted to NO2- and NO3- instead of toxic NO2, owing to the formation of O2- and .OH present in catalysts. New species like O3 or .O may be generated from the interaction between catalyst-induced species and radicals in plasma at a higher SIE, leading to deep oxidation of existing NO2 to N2O5. Experiments with added trapping agents confirmed the contribution of e- and h+ from catalysts. A series of possible reactions were proposed to describe reaction pathways and the mechanism of this synergistic effect. We established a novel system and realized an e*-activated "pseudo photocatalysis" behavior, facilitating the deep degradation of NO. We expect that this new strategy would provide a new idea for in-depth analysis of plasma-activated catalysis phenomenon. PMID- 29969896 TI - Syntheses, Spectroscopic Properties, and Computational Study of ( E, Z)-Ethenyl and Ethynyl-Linked BODIPYs. AB - A series of ( E, Z)-ethenyl- and ethynyl-linked boron dipyrromethene (BODIPY) dimers were synthesized in 23-34% yields by condensation of pyrroles with the corresponding bis-benzaldehydes, followed by oxidation and boron complexation. The BODIPY dimers were characterized by 1H, 13C, and 11B NMR spectroscopy, high resolution mass spectrometry, and, in the cases of 1b, 2, and 3, by X-ray crystallography. The spectroscopic properties for this series of dimers were investigated in tetrahydrofuran solutions, and very similar absorption and emission profiles were observed for all dimers. Density functional theory calculations show minimal conjugation between the two BODIPY units in the dimers, as a result of the large dihedral angle between the BODIPYs and the linker. The ( E)-ethenyl-linked dimer 1a showed the highest fluorescence quantum yield of all dimers investigated in this study. PMID- 29969897 TI - Enhancing the Electrochemiluminescence of Luminol by Chemically Modifying the Reaction Microenvironment. AB - As one of the most efficient and commonly used electrochemiluminescence (ECL) reagents, luminol has been paid much attention by the analysts due to its low excitation potential, simple dissolved oxygen-based coreactant ECL reaction requirement, and the widely analytical applications. However, the ECL performances of luminol on most electrode materials suffered from the lower ECL quantum yield, which limited its analytical applications. Herein, it was first found that, compared to that of the bare gold electrode, the ECL quantum yield of luminol on the 1,6-hexanedithiol hydrophobic pinhole film modified gold electrode was 3 times increased. This higher ECL quantum yield of luminol was related to the hydrophobic microenvironment on the surface of the modified electrode, which was formed from the hydrophobic carbon chains on the basis of their supramolecular interaction. On the basis of this new finding as well as the cap effect of gold nanoparticle to these pinhole gates, a highly sensitive ECL sensing scheme for microRNA was also developed. PMID- 29969898 TI - Obtaining Multiple Coproducts from Red Grape Pomace via Anthocyanin Extraction and Biogas Production. AB - Red grape pomace (RGP), a byproduct of red wine production, is an abundant food processing waste stream in California, rich in both anthocyanins, a class of red blue pigments, and lignocellulose. Extraction of anthocyanins and biofuel production from RGP have been investigated independently, but no research has examined employing both strategies together for maximal valorization. In this study, anthocyanins were most effectively extracted from RGP at 80 degrees C. Convection- and vacuum-oven drying of the pomace were found to decrease anthocyanin yield, whereas lyophilization did not significantly affect yield. Fermentable sugars were successfully separated from the crude extract via solid phase extraction. Ionic liquid pretreatment of RGP was determined to be a nonviable option for application to anaerobic digestion. Extraction reduced biomethane output, but supplementation with the aqueous fraction of the extract mitigated much of this difference, indicating sequential extraction and fractionation of anthocyanins from RGP can minimize the impact on biofuel yields. PMID- 29969900 TI - Asymmetric Total Synthesis and Absolute Configuration Determination of (-) Verrupyrroloindoline. AB - The first asymmetric total synthesis of (-)-verrupyrroloindoline (20% overall yield in 6 steps) is described. The short approach was enabled by Buchwald's Cu(II)-catalyzed asymmetric conjugate reduction, DMDO-triggered one-pot four-step tandem reaction, and the first amide-selective Ir-catalyzed direct reduction of beta-carboethoxy tertiary lactam. Along with the total synthesis, the absolute configuration of natural verrupyrroloindoline was determined as 7 R,10 R,11 R. PMID- 29969899 TI - Daily Consumption of Bilberry ( Vaccinium myrtillus L.) Extracts Increases the Absorption Rate of Anthocyanins in Rats. AB - The effects of daily consumption of anthocyanins on bioavailability has remained unclear. In this study, we evaluated whether daily consumption affects the absorption rate of anthocyanins in rats when consumed during the active and sleep phase. Eighty rats were randomly divided into two groups. The first group consumed AIN-93G control diets, and the second group consumed AIN-93G diets containing 1% bilberry extract for 2 weeks. After 12 h fast, anthocyanins were not detected in plasma of rats. Bilberry extract (500 mg/kg body weight) was then orally administered at the beginning of the diurnal light period (ZT0, sleep phase) or at the end of the diurnal light period (ZT12, active phase). Blood concentrations of anthocyanins peaked 1 h after administration in both groups. Maximum blood concentration in rats that consumed bilberry extract daily (852 nM) was higher than that in control rats (630 nM) when the extract was administered at ZT0 but not at ZT12. Daily consumption of anthocyanins increases their absorption rate, but this effect is limited to the beginning of the sleep phase. PMID- 29969901 TI - Dynamics of Ferrofluid Drops on Magnetically Patterned Surfaces. AB - The motion of liquid drops on solid surfaces is attracting a lot of attention because of its fundamental implications and wide technological applications. In this article, we present a comprehensive experimental study of the interaction between gravity-driven ferrofluid drops on very slippery oil-impregnated surfaces and a patterned magnetic field. The drop speed can be accurately tuned by the magnetic interaction, and more interestingly, drops are found to undergo a stick slip motion whose contrast and phase can be easily tuned by changing either the strength of the magnetic field or the ferrofluid concentration. This motion is the result of the periodic modulation of the external magnetic field and can be accurately analyzed because the intrinsic pinning due to chemical defects is negligible on oil-impregnated surfaces. PMID- 29969902 TI - Anomer Preferences for Glucuronic and Galacturonic Acid and Derivatives and Influence of Electron-Withdrawing Substituents. AB - Equilibrium anomeric ratios are reported for pyranoses (hemiacetals) of glucuronic and galacturonic acid and their derivatives. These are compared to related gluco- and galactopyranoses and to deoxyfluorogluco- and deoxyfluorogalactopyranoses. An association between axial anomer stability and the sum of 1H NMR downfield chemical shifts for protons H-3 and H-5 was observed in D2O with gluco- and galactopyranoses as reference compounds. When compared to 2-hydroxytetrahydropyran in water, introduction of three OAc substituents and one carboxylic acid substituent leads to an increase in stability of the axial anomer by 0.89-1.05 kcal/mol. This is interpreted as the electron-withdrawing substituents causing a reduction in the steric (gauche) interaction and an increase in favourable Coulombic interaction between CH groups of the pyranose and the anomeric group through substituent deshielding effects. Anomer preferences for galacturonic acid and its derivatives were more sensitive to solvent polarity compared to other pyranoses, and this may be linked to the electrostatic potential and reduced stabilization of the equatorial anomeric OH group due to reduced hydrogen bonding. The latter is more notable in nonpolar chloroform. Analysis of crystal structures combined with molecular dynamics indicated there are conformational distinctions between galacturonic acid and glucuronic acid that could influence properties. PMID- 29969903 TI - Micro- and Nanomotors as Active Environmental Microcleaners and Sensors. AB - The quest to provide clean water to the entire population has led to a tremendous boost in the development of environmental nanotechnology. Toward this end, micro/nanomotors are emerging as attractive tools to improve the removal of various pollutants. The micro/nanomotors either are designed with functional materials in their structure or are modified to target pollutants. The active motion of these motors improves the mixing and mass transfer, greatly enhancing the rate of various remediation processes. Their motion can also be used as an indicator of the presence of a pollutant for sensing purposes. In this Perspective, we discuss different chemical aspects of micromotors mediated environmental cleanup and sensing strategies along with their scalability, reuse, and cost associated challenges. PMID- 29969904 TI - Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of Chemoselectivity by Organophotocatalysis and Dual Organocatalysis. AB - The catalytic and chemoselective oxidation of cinnamaldehyde derivatives having a C?C bond and formyl group was studied by using two organocatalysts. The visible light-induced catalysis using rhodamine 6G as an organophotocatalyst promoted the methoxyhydroxylation of the C?C bond in a chemoselective manner. In contrast, the cooperation between rhodamine 6G and N-heterocyclic carbene (NHC) allowed the oxidative esterification of formyl group. PMID- 29969905 TI - Morus alba Leaf Bioactives Modulate Peroxisome Proliferator Activated Receptor gamma in the Kidney of Diabetic Rat and Impart Beneficial Effect. AB - Peroxisome proliferator activated receptor gamma (PPARgamma) is a ligand activated nuclear receptor that can be activated or repressed by several exogenous and endogenous ligands and acts by modulating genes that regulate lipid, glucose, and insulin homeostasis. In kidney, PPARgamma is involved in normal kidney development and other physiological functions. In our earlier report, we showed that feeding Morus alba leaves to experimental diabetic rats ameliorated diabetic nephropathy and significantly decreased microalbuminuria. In this paper, we have attempted to look into the molecular mechanism involving PPARgamma modulation by mulberry leaf bioactive compounds by in vitro and in vivo methods and its impact on key inflammatory markers. In vitro assay by TR-FRET suggested that mulberry leaf extracts can serve as a putative modulator of PPARgamma. High glucose conditions in vitro and in vivo increased PPARgamma levels, which were ameliorated by mulberry leaves or their extracts. Interestingly, PPARgamma was significantly phosphorylated at Ser112 by upstream kinases ERK42/44 in kidney of diabetic animals on feeding mulberry leaves. In vitro studies using MDCK cell line revealed that increased Ser112 phosphorylation was observed when cells were treated with bound phenolic acid rich extract but not with free phenolic acid rich extracts. HPLC analysis and bioassay-guided activity revealed that coumaric acid was the bioactive molecule within bound phenolic acid rich extract that was responsible for increased ERK42/44-mediated phosphorylation at Ser112. Furthermore, mulberry leaf bioactive compounds showed beneficial effect on the tested inflammatory markers. PMID- 29969906 TI - Dr. Mathilde Krim: A Scientist and Her Fellowship Legacy. AB - On January 15, 2018, the world lost Dr. Mathilde Krim, a woman who changed the life of every person who has ever worked in HIV research. Variously remembered as a humanitarian, a socialite, a philanthropist, and a political activist, Dr. Krim was first and foremost a scientist. We highlight her pioneering research in fetal sex determination, as well as her activism during the unfolding AIDS epidemic, which culminated in the cofounding of amfAR, the Foundation for AIDS Research. Finally, we provide an analysis of the award named in honor of her inspirational leadership, the Mathilde Krim Fellowships in Basic Biomedical Research, which aims to catapult the careers of exceptional, early-stage researchers in the HIV/AIDS field. We follow applicants through the two-tier application process and dissect what defines a successful applicant at each stage. Through the Krim Fellowships, we hope to ensure that a new generation of HIV scientists can realize amfAR's goal of ending the AIDS epidemic. PMID- 29969907 TI - Sex Differences in the Neuropsychiatric Symptoms of Patients With Alzheimer's Disease. AB - The aim of this study was to describe sex differences in neuropsychiatric symptoms (NPSs) in patients with Alzheimer's disease (AD). Baseline scores on the Cohen-Mansfield Agitation Inventory, Neurobehavioral Rating Scale-Agitation subscale, and the Neuropsychiatric Inventory from patients with AD enrolled in a multicenter trial of citalopram for the treatment of agitation were analyzed. We found not only that patients with AD having agitation were likely to exhibit many other NPSs but also that the women in this study were more likely to exhibit a broader range of NPS than were the men. These results suggest greater heterogeneity in the clinical presentation of women compared to men, and thus in the potential targets for treatment in these patients. Further characterization of sex differences in NPS can inform future efforts aimed at establishing subtypes of patients for whom various treatment approaches will be most appropriate. PMID- 29969908 TI - The Dietary Approaches to Stop Hypertension (DASH)-Style Diet and an Alternative Mediterranean Diet are Differently Associated with Serum Inflammatory Markers in Female Adults. AB - BACKGROUND: Studies on the association between a priori dietary patterns and serum highly sensitive C-reactive protein (hs-CRP) have led to inconsistent results, and we are not aware of any study on interleukin 17A (IL-17A) as an inflammatory marker associated with autoimmune diseases. OBJECTIVE: The present study aimed to investigate the association between Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean dietary patterns with circulating hs CRP and IL-17A levels. METHODS: In this cross-sectional study, female teachers (aged 20-50 years) who lived in Yazd, Iran, were randomly selected from elementary, guidance, and high schools from September 2015 to February 2016. Anthropometric data, as well as general information and dietary food intakes, were gathered, and each participant gave 1 blood sample. Participants were categorized into tertiles based on the DASH and the Mediterranean diet calculated scores. The associations between the dietary patterns and serum hs-CRP and IL-17A levels were assessed in the crude and multivariable models. In total, 320 female teachers aged 40.38 (8.08) years were included. RESULTS: The DASH diet was associated with lower serum hs-CRP levels in the crude ( P = .05) and the fully adjusted models ( P = .02), while it was not significantly associated with IL-17A levels. The participants with the highest adherence to the Mediterranean diet had significantly lower circulating IL-17A levels ( P = .04) even controlling for all confounders ( P = .02); however, there was not a significant relationship between this diet and hs-CRP levels. CONCLUSIONS: The DASH and the Mediterranean dietary patterns might be differently associated with inflammatory markers. Further prospective studies are recommended to confirm our results. PMID- 29969909 TI - The Association Between Smoking Cessation Period and Metabolic Syndrome in Korean Men. AB - The association between smoking cessation period and metabolic syndrome (MS) is currently unknown. We studied 6032 men aged >19 years who participated in the Korean National Health and Nutrition Examination Surveys between 2010 and 2012. The risk of MS according to the amount of smoking and duration of smoking cessation was examined, and adjusted for age, amount of alcohol consumed, physical activity, body mass index, income, and education levels. Compared with never-smokers, there was a significant increase in the risk of MS among current smokers >10 pack-years and former smokers with a history of pack-years >30. The odds ratio for MS increased with smoking amount in both current and former smokers. But the risk of MS in former smokers was no longer significant after 20 years of smoking cessation adjusted for past smoking amount. Thus, to prevent MS, current smokers should quit smoking early and former smokers should continue quitting. PMID- 29969910 TI - Impulsivity predicts illness severity in long-term course of bipolar disorder: A prospective approach. AB - BACKGROUND: Bipolar disorder is a common, severe and chronic mental illness. Despite this, predictors of illness severity remain poorly understood. Impulsivity is reported to be associated with bipolar disorder and aggravating comorbidities. This study therefore sought to examine the predictive value of impulsivity for determining illness severity in euthymic bipolar disorder patients. METHODS: Baseline trait impulsivity of 120 bipolar euthymic patients (81 bipolar disorder I [68%], 80 female [67%]) and 51 healthy controls was assessed using Barratt Impulsiveness Scale 11. The impact of impulsivity on illness severity (measured with morbidity index) was prospectively tested in 97 patients with sufficient follow-up data (average observation time: 54.4 weeks), using linear regression analysis. RESULTS: Barratt Impulsiveness Scale 11 total (beta = 0.01; p < 0.01) and in particular Barratt Impulsiveness Scale 11 attentional subscale scores (beta = 0.04; p < 0.001) predicted illness severity in bipolar disorder, while controlling for other clinical variables. Only age at onset persisted as an additional, but less influential predictor. Barratt Impulsiveness Scale 11 total scores and Barratt Impulsiveness Scale 11 attentional subscale scores were significantly higher in euthymic patients compared to controls. This was not observed for the motor or non-planning subscale scores. LIMITATIONS: The average year-long observation time might not be long enough to account for the chronic course of bipolar disorder. CONCLUSION: Trait impulsivity and particularly attentional impulsivity in euthymic bipolar patients can be strong predictors of illness severity in bipolar disorder. Future studies should explore impulsivity as a risk assessment for morbidity and as a therapeutic target in bipolar disorder patients. PMID- 29969911 TI - Gangrene of the Glans Penis in a Diabetic Patient Due to Calcific Arteriopathy. PMID- 29969913 TI - Kentucky's Smoking Cessation Quitline: Annual Estimated Return on Investment to Employers. AB - PURPOSE: State-based smoking cessation telephone quitlines offer a cost-effective method of providing tobacco treatment at no cost to participants. The study objective was to assess the annual return on investment (ROI) to employers if they were to bear the entire responsibility from the Kentucky quitline. DESIGN: A retrospective design was used to estimate the annual ROI to employers from the Kentucky quitline. SETTING: The telephone quitline (1-800-QUIT-NOW) provided intake and follow-up data for all Kentucky participants who enrolled in the program from 2012 to 2014. PARTICIPANTS: All individuals aged 18+ who enrolled in the Kentucky quitline from 2012 to 2014. MEASURES: Successful tobacco cessation was assessed from follow-up surveys that took place after individuals completed the program. Cost savings to employers associated with tobacco cessation were gleaned from a published meta-analysis. The Kentucky quitline provided estimates for annual program expenses. ANALYSIS: The annual ROI was calculated as the difference between estimated annual cost savings due to smoking cessation and annual program expenses. RESULTS: From 2012 to 2014, 5425 individuals were enrolled in the quitline. The annual ROI to employers was estimated to be $998 680, with an ROI ratio of 6.2:1. CONCLUSIONS: Employers may receive a substantial ROI if they were to fund the Kentucky quitline. Study results may be used as evidence to support cost-sharing partnerships between public health agencies and employers to sustain funding for telephone quitlines. PMID- 29969912 TI - Two-Dimensional Versus Three-Dimensional Laparoscopic Systems in Urology: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Laparoscopy is widely used in the urological field. This systematic review and a meta-analysis were conducted to assess the clinical and surgical efficacy of the three-dimensional (3D) laparoscopic system in comparison with two dimensional (2D) laparoscopy for treatment of different urological conditions. METHODS: Following guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses, a systematic literature search in Web of Science, PubMed, Cochrane Library, and EMBase was carried out to identify relevant studies published up to May 2018. Articles published in the English language of both randomized and observational studies comparing 3D and 2D laparoscopic systems in urological surgeries were included. Level of evidence and quality assessments of all included studies were conducted. Interested data were extracted for comparison and meta-analysis. RESULTS: Our literature search generated 17 studies comparing 3D and 2D laparoscopic systems in different urological surgeries. Of these, 13 studies containing 548 and 449 patients operated on with 2D and 3D laparoscopic systems, respectively, were included for meta-analysis. These 13 studies were divided into three groups according to surgical type. Group 1: Partial nephrectomy (PN); operative time (p = 0.19), estimated blood loss (EBL) (p = 0.51), dissecting time (p = 0.58), and suturing time (p = 0.28) were not statistically significant between 2D and 3D laparoscopic systems. However, warm ischemia time during PN was significantly shorter during 3D laparoscopy (p < 0.00001). Group 2: Pyeloplasty; this procedure showed no significant difference between the two systems. Group 3: Radical prostatectomy (RP); shorter operative time (p < 0.0001) and lower EBL (p = 0.001) were associated with the 3D laparoscopic system. CONCLUSION: Three-dimensional laparoscopy mainly improves the depth of perception, leading to better visibility, which is important for some complex urological surgeries such as PN, pyeloplasty, and RP. Based on our findings, 3D laparoscopy seems to provide better clinical and surgical outcomes in some urological procedures compared with conventional 2D laparoscopy. PMID- 29969914 TI - Postoperative imatinib in patients with intermediate risk gastrointestinal stromal tumor. AB - AIM: To determine whether imatinib adjuvant treatment improved recurrence-free survival (RFS) in gastrointestinal stromal tumor (GIST) with intermediate risk. MATERIALS & METHODS: Patients who had undergone complete tumor resection with intermediate risk were enrolled. RESULTS: A total of 99 patients received imatinib adjuvant therapy and 93 patients only received observation. The RFS in patients who received adjuvant therapy was superior to RFS in control group (p = 0.004). GIST with location of intestine or rectum and GIST with exon 11 deletion mutation had longer RFS. CONCLUSION: Adjuvant imatinib improves RFS of GIST with intermediate risk of recurrence, particularly in GIST with intestinal and rectal location or c-kit gene exon 11 deletion mutation. PMID- 29969915 TI - Apparent metabolisable energy and amino acid digestibility of microalgae Spirulina platensis as an ingredient in broiler chicken diets. AB - 1. This work investigates the apparent metabolisable energy (AME), its nitrogen corrected form (AMEn) and amino acid (AA) digestibility coefficients of the microalgae Spirulina platensis as an ingredient in broiler chicken diets. 2. One group of birds was fed with a basal control diet (BD), and another was fed with a test diet composed of the BD with the addition of the microalgae at a proportion of 200 g/kg. AME and AMEn were assessed by total excreta collection and indigestibility analysis using acid-insoluble ash (AIA) as a marker. 3. The microalgae comprised 888.0 g/kg dry matter (DM), 18.42 MJ/kg gross energy, 514.7 g/kg crude protein, 9.9 g/kg ether extract, 10.6 g/kg crude fibre, 94.4 g/kg ash, 3.1 g/kg Ca and 11.0 g/kg P. 4. The values obtained for AME (13.48 MJ/kg DM) and AMEn (11.72 MJ/kg DM) were higher (p < 0.01) than those obtained using the AIA method (9.39-8.29 MJ/kg DM). The microalgae ileal digestibility coefficients were 0.80 +/- 0.04 and 0.78 +/- 0.04 for essential and non-essential AA, respectively. 5. Overall, the metabolisable energy content and digestibility of AA for S. platensis indicated that the microalgae are potentially an alternative nutrient source for broilers. The AIA method underestimated AME and AMEn in comparison to the total excreta collection method. PMID- 29969916 TI - A simplified 10-step Tai-chi programme to enable people with dementia to improve their motor performance: a feasibility study. AB - OBJECTIVE:: To evaluate the feasibility and preliminary effects of a simplified 10-step Tai-chi programme to improve the motor performance of people with dementia. DESIGN:: A two-arm, single-blinded cluster randomized controlled trial, registered with ClinicalTrials.gov (NCT03341091). SETTING:: Community health centres. PARTICIPANTS:: Twenty-six dyads of people with dementia and their family caregivers were recruited, with mean (SD) ages of 82.2 (7.43) and 51.3 (18.97), respectively. INTERVENTIONS:: The experimental group underwent a 16 week 10-step simplified Tai-chi training programme, with additional measures to enhance engagement. The control group joined recreational activities organized by the centres. MAIN OUTCOME MEASURE(S):: The feasibility assessment included recruitment, attrition, adherence to, and engagement in the Tai-chi programme. The preliminary effects were assessed by the participants' performance in mobility tests. RESULTS:: Preliminary feasibility was established, with an acceptable recruitment rate of 58% (26 out of 45 assessed dyads) and a high attendance rate of 81% (25.88 out of 32 Tai-chi sessions). There was positive engagement in the training sessions, and no adverse incidents. However, five participants withdrew from the Tai-chi group, for a high attrition rate of 38%, and the mean home practice time decreased between weeks 8 and 16. In most of the motor performance tests, a slight but insignificant improvement was observed in the Tai-chi group compared to the control group. CONCLUSION:: A tailored Tai-chi programme for people with dementia using a dyadic approach has been found to be feasible. However, stronger support must be provided to family caregivers to improve the participants' sustained participation. PMID- 29969917 TI - SMYD3 promoter hypomethylation is associated with the risk of colorectal cancer. AB - AIM: SMYD3 encodes histone lysine methyltransferase. The goal of our study was to investigate the association between SMYD3 methylation and colorectal cancer (CRC). MATERIALS & METHODS: SMYD3 methylation was measured by quantitative methylation-specific PCR method in 117 pairs of CRC tumor and para-tumor tissues. RESULTS: Significantly lower SMYD3 methylation was observed in CRC tumor tissues than para-tumor tissues (p = 0.002). Further subgroup analysis by clinical features showed that significantly lower SMYD3 methylation were only observed in the CRC patients with tumors of moderately and well differentiation, positive lymph node metastasis, and stage III + IV. CONCLUSION: Our work reported for the first time that SMYD3 promoter hypomethylation was associated with CRC. PMID- 29969918 TI - Validation Master Plans: Progress of Implementation in the Pharmaceutical Industry. AB - BACKGROUND: Some international regulatory agencies require that companies develop a validation master plan (VMP) to govern their validation activities, but such a plan is not an explicit requirement of US regulations. This paper examines the progress that US pharmaceutical companies have made to implement VMPs for drug products manufactured and produced in accordance with the US FDA Good Manufacturing Practice for Finished Pharmaceuticals. METHODS: A survey instrument was developed using an established framework with a focus on behavior and capability and disseminated electronically to midlevel and senior regulatory and quality professionals concentrated in the US. RESULTS: Responses from 42 senior regulatory professionals showed that VMPs are incorporated into the quality systems of most companies but approaches to implementation differ. Small companies typically employ centralized VMPs whereas larger companies commonly decentralize their VMPs. Companies of all sizes most commonly use paper rather than electronic tools to organize and track validations including validations of equipment. CONCLUSION: The fact that VMPs are commonly used even when they are not mandated suggests that the VMP is becoming an industry standard and may suggest that global standards are playing a significant role in the quality approaches of US-based companies. PMID- 29969919 TI - Gender-Related Differences in Antiplatelet Therapy and Impact on 1-Year Clinical Outcome in Patients Presenting With ACS: The START ANTIPLATELET Registry. AB - We investigated whether gender influences antiplatelet treatment in patients with acute coronary syndrome (ACS). The primary end point was major adverse cardiac and cerebrovascular events (MACCEs), a composite of death, myocardial infarction (MI), stroke, or target vessel revascularization. The coprimary end point was net adverse cardiac and cerebrovascular events (NACEs), based on MACCE plus major bleeding. From January 2014 to December 2016, 840 consecutive patients with ACS who completed 1-year follow-up were enrolled, 625 (74%) males and 215 (26%) females. Percutaneous coronary interventions (PCI) and drug-eluting stents (DES) were more often used in males (PCI: 532 [87%] vs 168 [80%], P = .02 and DES 474 [76%] vs 143 [66%], P = .01). Males were more often treated with dual antiplatelet therapy (DAPT; 94% vs 88%, P = .01). In DAPT, ticagrelor was the most prevalent strategy, regardless of gender (47% vs 49%, P = .68); clopidogrel was preferred in women (42% vs 33%, P = .04); and prasugrel was preferred in men (11% vs 17%, P = .04). At multivariate analysis, MACCE and NACE were similar between genders. Therefore, although P2Y12 inhibitor choice in DAPT might be influenced by gender, a DAPT choice, tailored by balancing the ischemic/bleeding risk, has a similar clinical outcome irrespective of gender. PMID- 29969920 TI - Adherence barriers to inhaled medicines in Japanese older patients with asthma evaluated using the "Adherence Starts with Knowledge 20" (ASK-20) questionnaire. AB - OBJECTIVE: We investigated adherence barriers to inhaled medicines among older compared to younger adults with asthma in Japan. METHODS: Adherence barriers to inhaled medicines were evaluated in 251 Japanese older (n = 138) and younger (n = 113) adults with asthma using the self-reporting "Adherence Starts with Knowledge 20" (ASK-20) questionnaire. RESULTS: There were fewer older adults with poor adherence to inhaled medicines than younger adults. The ASK-20 questionnaire revealed (odds ratio [95% confidence interval]) item Q11 ("My doctor/nurse and I work together to make decisions"; 2.94 [1.31, 6.61]; p < 0.05) as an independent adherence barrier to inhaled medicines among older adults, whereas younger adults reported item Q3 ("My use of alcohol gets in the way of taking my medicines"; 3.91 [1.02 to 15.1]; p < 0.05) and item Q16 ("Taken a medicine more or less often than prescribed? "; 2.31 [1.32 to 4.06]; p < 0.05) as barriers. Older adults with poor adherence identified item Q1 ("I just forget to take my inhaled medicines some of the time"; 4.43 [1.77, 11.1]; p < 0.05) as a barrier, although the total ASK-20 scores and total barrier counts were significantly higher in older (both, p < 0.05) and younger (both, p < 0.05) adults with poor adherence than in those with good adherence. CONCLUSION: Older Japanese patients had better adherence to inhaled medicines than younger patients. Barriers were different between older and younger adults. These results will help personalize education for inhaled medicines in Japanese asthmatics. PMID- 29969921 TI - Physical Activity Among Adolescents in India: A Qualitative Study of Barriers and Enablers. AB - Inadequate physical activity (PA) levels are reported in Indian youth, with lowest levels among adolescents, particularly girls. We aimed to identify barriers to and enablers of PA among school children in New Delhi and examine potential differences by gender and school type (government vs. private). A total of 174 students (private school students = 88, 47% girls; government school students = 86, 48% girls) aged 12 to 16 years from two Delhi schools participated in 16 focus group discussions (FGDs) conducted by bilingual moderators. We conducted FGDs separately for girls and boys, for students in Grades VIII and IX, and for private and government schools. We conducted FGDs among government school students in Hindi and translated the transcriptions to English for analysis. We coded transcriptions using a combination of inductive and deductive approaches, guided by the "youth physical activity promotion model." We identified various personal, social, and environmental barriers and enablers. Personal barriers: Private school girls cited body image-related negative consequences of PA participation. Social barriers: Girls from both schools faced more social censure for participating in PA. Environmental barriers: Reduced opportunity for PA in schools was commonly reported across all participants. Personal enablers: All participants reported perceived health benefits of PA. Social enablers: Several participants mentioned active parents and sports role models as motivators for increasing PA. Few environmental enablers were identified. This study highlights the need for further investment in physical activity within schools and for gender-sensitive policies for encouraging PA participation among adolescents in India. PMID- 29969922 TI - Personalized therapy when tackling nonalcoholic fatty liver disease: a focus on sex, genes, and drugs. AB - INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world. It describes a term for a group of hepatic diseases including steatosis, fibrosis, and cirrhosis that can finally lead to hepatocellular carcinoma. There are many factors influencing NAFLD initiation and progression, such as obesity, dyslipidemia, insulin resistance, genetic factors, and hormonal changes. However, there is also lean-NAFLD which is not associated with obesity. NAFLD is considered to be a sexually dimorphic disease. In most cases, men have a higher prevalence for the disease compared to premenopausal women. Areas covered: In this review, we first summarize the NAFLD disease epidemiology, pathology, and diagnosis. We describe NAFLD progression with the focus on sexual and genetic differences for disease development and pharmacological treatment. Personalized treatment for multifactorial NAFLD is discussed in consideration of different factors, including genetics, gender and sex. Expert opinion: The livers of female and male NAFLD patients have different metabolic capacities which influence the metabolism of all drugs applied to such patients. This aspect is not yet sufficiently taken into account. The liver computational models might quicken the pace toward assessing personalized disease progression and treatment options. PMID- 29969923 TI - Autophagy in normal tissues of camel (Camelus dromedarius) with focus on immunoexpression of LC3 and LC3B. AB - Autophagy is a highly regulated intracellular pathway for degradation and recycling of cytoplasmic protein aggregates and entire organelles. The autophagic pathway is stimulated by nutrient starvation, which prompted us to study the desert camel. Various organs of the camel undergo ecological and physiological stress due to food and water deprivation, dehydration and long exposure to solar radiation. We investigated the immunohistochemical expression of specific biomarkers of autophagy under normal conditions as a baseline for later work on stressed individuals. The autophagy-specific biomarkers, microtubule-associated protein1 light chain 3 (LC3), and its cleaved variant, LC3B, were strongly expressed in the cytosol of all tissues examined. The cytosolic immunoreactivity of LC3 was relatively weak, diffuse and vacuolar, while that of LC3B was stronger, punctate and at lower levels. LC3 appears to be associated with the autophagosomal membranes, either free or lysosome-bounded. LC3B is specific for the autophagosome-lysosome complexes and their degraded, granular contents. Autophagy was strongly expressed in CNS neurons and intestinal neural elements, which suggests a protective function for the nervous system. Autophagic markers also were seen in deformed immune-competent cells with fragmented nuclei in lymph nodes, spleen and gut-associated lymphoid tissue (GALT), which suggests a "suicidal" activity of eliminating unneeded cells. Autophagy, as measured by LC3 and LC3B expression, may participate in a general regulatory mechanism in tissues of the desert camel. PMID- 29969924 TI - Asthma symptoms, interactive physical play and behavioral and academic outcomes in urban children with persistent asthma. AB - OBJECTIVES: Asthma may lead to reduced participation in interactive physical play (IPP). Urban youth with asthma are also at risk for behavioral and academic difficulties. Exploring associations between asthma, IPP and socio-emotional and academic outcomes in children with asthma is important. Study objectives are to: (1) describe IPP participation among school children with persistent asthma; (2) determine if IPP varies with asthma severity (3) determine independent associations of both asthma severity and IPP with socio-emotional and academic outcomes. METHODS: We analyzed data from children with persistent asthma enrolled in the SB-TEAM trial (Rochester, NY). Caregiver surveys assessed asthma severity, IPP participation (gym >=3 days/week, running at recess, sports team participation), socio-emotional and academic outcomes. Bivariate and regression analyses assessed relationships between variables. RESULTS: Of 324 children in the study (59% Black, 31% Hispanic, mean age 7.9), 53% participated in any IPP at school. Compared to those with mild persistent asthma, fewer children with moderate-severe asthma had no limitation in gym (44% vs. 58%, p < .01), and fewer ran at recess (29% vs. 42%, p < .01) or engaged in any IPP (48% vs. 58%, p = .046). Asthma severity was not associated with socio-emotional or academic outcomes. However, children participating in IPP had better positive peer social and task orientation skills, were less shy/anxious, and more likely to meet academic standards (all p < .05). Results were consistent in multivariable analyses. CONCLUSIONS: Urban children with moderate-severe asthma partake in less IPP, which is associated with socio-emotional and academic outcomes. Further efforts are needed to optimize asthmatic children's participation in IPP. PMID- 29969925 TI - Diagnosis and management of laryngotracheal stenosis. AB - INTRODUCTION: Laryngotracheal stenosis comprises a broad spectrum of congenital and acquired conditions that commonly cause pediatric airway obstruction. Although the majority of these conditions were historically managed with endoscopic dilations, the introduction of operative procedures such as laryngotracheoplasty, cricotracheal resection, and slide tracheoplasty changed the treatment paradigm. The gradual evolution of endoscopic technology enabled surgeons to perform certain procedures endoscopically that were previously only able to be performed in an open fashion. Areas covered: This review highlights the important aspects of the diagnosis, workup, and surgical treatment of pediatric laryngotracheal stenosis. Important articles describing research and techniques within pediatric airway reconstruction are summarized and included in the review. Expert commentary: The importance of the multidisciplinary concept of treating laryngotracheal stenosis is evidenced by the establishment of aerodigestive centers internationally. In order to continue successfully treating complex cases of laryngotracheal stenosis, further airway research is needed. The application and feasibility of tracheal transplantation and replacement is likely the next frontier in the treatment of laryngotracheal stenosis. PMID- 29969926 TI - Filarial tropical pulmonary eosinophilia: a condition masquerading asthma, a series of 12 cases. AB - INTRODUCTION: Tropical pulmonary eosinophilia (TPE) is a form of occult filariasis, clinically characterized by paroxysmal cough, wheezing and dyspnea which is often misdiagnosed and treated as asthma. These manifestations result from a host immune response to trapped antigens of the microfilarial parasites Wuchereria bancrofti or Brugia malayi in the pulmonary microcirculation. CASE STUDY: We describe three rare presentations of TPE (cor pumonale, cystic lung disease and respiratory distress mimicking acute severe asthma) in our series of 12 cases. All cases were from filaria endemic areas and presented with cough, wheezing and dyspnea, either alone or in combination. Subsequent work-up revealed peripheral eosinophilia, raised serum IgE levels and positive serum filarial antibody and/or antigen in all the cases. RESULTS: All patients were treated with diethylcarbamazine (DEC), while few required inhaled/systemic corticosteroid. Prompt improvement in clinical symptoms with a decrease in eosinophil count was seen in all. Two cases relapsed requiring a second course of DEC. Long-term outcome was good, however, there was a persistence of restrictive lung function and echocardiographic feature of pulmonary hypertension in the patients with cystic lung disease and cor pulmonale, respectively. CONCLUSION: TPE should always be considered in patients from filaria endemic areas presenting with cough, dyspnea or wheezing. High eosinophil count (>3 * 109 cells) with raised IgE level (>1000 IU/mL) in such cases should alert the physician to look for TPE. Early diagnosis and treatment can prevent disease progression and complications. PMID- 29969927 TI - The impact of asthma on quality of life and anxiety: a pilot study. AB - INTRODUCTION: Asthmatic patients are at risk for psychiatric symptoms. The objective of this study is to test the hypothesis that asthmatics have worse quality of life and anxiety scores in relation to a control group. METHODS: This study is a cross-sectional study in which quality of life and anxiety scores were compared in a sample of 102 individuals, 51 asthmatics and 51 non-asthmatics. Quality of life and anxiety scores were quantified using validated questionnaires. The differences between the averages and the correlations between the total score for quality of life and anxiety were compared with t-tests and Pearson's correlation tests, respectively. The odds ratio compared the prevalence of moderate and severe anxiety between the groups. RESULTS: The asthma group had higher average anxiety (p < 0.001) and lower averages in all areas of quality of life: physical functioning, physical role functioning, bodily pain, general health, vitality, social functioning, emotional role functioning and mental health (p < 0.05 for all variables). There was a significant and inverse correlation between the total score for quality of life and anxiety scores but only in the asthma group (r = -0.71). CONCLUSIONS: Asthmatics have worse indicators of quality of life and anxiety, even though the symptoms of asthma are under clinical control. Moreover, the inverse correlation between the quality of life and the average anxiety scores in the asthma group suggests that the pulmonary inflammatory process of asthma may be related to the pathophysiology of emotional commitment in that group. PMID- 29969928 TI - Susceptibility to Exacerbations in Black Adults with Asthma. AB - OBJECTIVE: Exacerbations account for much of the morbidity in asthma. In a large intervention study, we sought to test the hypothesis that a Black adult exacerbation-prone phenotype - a group of Black people with asthma who are at high risk of repeat exacerbation within one year - exists in asthma independent of clinical control. METHODS: We analyzed exacerbation risk factors in 536 self identified Black Americans with asthma eligible for, or on, Step 3 NAEPP therapy who participated in a randomized 6-18 month trial of tiotropium versus long acting beta agonist as add-on therapy to inhaled corticosteroids. Exacerbations were defined as events treated by oral or systemic corticosteroids. Clinical control was assessed by a validated asthma control questionnaire (ACQ5). RESULTS: Exacerbations became more likely with loss of clinical control. The mean baseline ACQs for exacerbators and non-exacerbators were 2.41 and 1.91 respectively (p < 0.001). The strongest independent factor associated with exacerbations across all ACQ levels was an exacerbation in the preceding year (adjusted OR 3.26; P < 0.001). The severity of prior exacerbations did not correlate with the likelihood of a future exacerbation. Lower baseline FEV1/FVC was also associated with increased risk of exacerbations. CONCLUSIONS: Even though exacerbations increase with loss of clinical control, an exacerbation susceptibility phenotype exists in Black adults with asthma, independent of clinical control. This phenotype requires precision therapeutic targeting. PMID- 29969930 TI - Process Evaluation and Lessons Learned From Engaging Local Policymakers in the B'More Healthy Communities for Kids Trial. AB - Partnerships linking researchers to the policymaking process can be effective in increasing communication and supporting health policy. However, these policy partnerships rarely conduct process evaluation. The Policy Working Group (Policy WG) was the policy-level intervention of the multilevel B'More Healthy Communities for Kids (BHCK) trial. The group sought to align interests of local policymakers, inform local food and nutrition policy, introduce policymakers to a new simulation modeling, and sustain intervention levels of BHCK. We conducted an evaluation on the Policy WG between July 2013 and May 2016. We evaluated process indicators for reach, dose-delivered, and fidelity and developed a SWOT (strengths, weaknesses, opportunities, and threats) analysis. The policy intervention was implemented with high reach and dose-delivered. Fidelity measures improved from moderate to nearly high over time. The number of health related issues on policymakers' agenda increased from 50% in the first 2 years to 150% of the high standard in Year 3. SWOT analysis integrated a stakeholder feedback survey to consider areas of strength, weakness, opportunity, and threats. Although the fidelity of the modeling was low at 37% of the high standard, stakeholders indicated that the simulation modeling should be a primary purpose for policy intervention. Results demonstrate that process evaluation and SWOT analysis is useful for tracking the progress of policy interventions in multilevel trials and can be used to monitor the progress of building partnerships with policymakers. PMID- 29969929 TI - Synthesis, biological evaluation, and molecular modelling studies of potent human neutrophil elastase (HNE) inhibitors. AB - We report the synthesis and biological evaluation of a new series of 3- or 4 (substituted)phenylisoxazolones as HNE inhibitors. Due to tautomerism of the isoxazolone nucleus, two isomers were obtained as final compounds (2-NCO and 5 OCO) and the 2-NCO derivatives were the most potent with IC50 values in the nanomolar range (20-70 nM). Kinetic experiments indicated that 2-NCO 7d and 5-OCO 8d are both competitive HNE inhibitors. Molecular modelling on 7d and 8d suggests for the latter a more crowded region about the site of the nucleophilic attack, which could explain its lowered activity. In addition molecular dynamics (MD) simulations showed that the isomer 8d appears more prone to form H-bond interactions which, however, keep the reactive sites quite distant for the attack by Ser195. By contrast the amide 7d appears more mobile within the active pocket, since it makes single H-bond interactions affording a favourable orientation for the nucleophilic attack. PMID- 29969931 TI - Lipoxin A4 attenuates LPS-induced acute lung injury via activation of the ACE2 Ang-(1-7)-Mas axis. AB - Previous studies have reported that lipoxin A4 (LXA4) and the angiotensin I converting enzyme 2 (ACE2), angiotensin-(1-7) [Ang-(1-7)], and its receptor Mas [ACE2-Ang-(1-7)-Mas] axis play important protective roles in acute lung injury (ALI). However, there is still no direct evidence of LXA4-mediated protection via the ACE2-Ang-(1-7)-Mas axis during ALI. This work was performed using an LPS induced ALI mouse model and the data indicated the following. First, the animal model was established successfully and LXA4 ameliorated LPS-induced ALI. Second, LXA4 could increase the concentration and activity of ACE2 and the levels of Ang (1-7) and Mas markedly. Third, LXA4 decreased the levels of TNF-alpha, IL-1beta, and reactive oxygen species while increasing IL-10 levels. Fourth, LXA4 inhibited the activation of the NF-kappaB signal pathway and repressed the degradation of inhibitor of NF-kappaB, the phosphorylation of NF-kappaB, and the translocation of NF-kappaB. Finally, and more importantly, BOC-2 (LXA4 receptor inhibitor), MLN 4760 (ACE2 inhibitor), and A779 (Mas receptor antagonist) were found to reverse all of the effects of LXA4. Our data provide evidence that LXA4 protects the lung from ALI through regulation of the ACE2-Ang-(1-7)-Mas axis. PMID- 29969933 TI - Childhood Socioeconomic Status and Later Life Cognition: Evidence From the Wisconsin Longitudinal Study. AB - OBJECTIVES: This study examined childhood socioeconomic status (SES) as a predictor of later life cognition and the extent to which midlife SES accounts for associations. METHODS: Data came from 5,074 participants in the Wisconsin Longitudinal Study. Measures from adolescence included parents' educational attainment, father's occupational status, and household income. Memory and language/executive function were assessed at ages 65 and 72 years. RESULTS: Global childhood SES was a stronger predictor of baseline levels of language/executive function than baseline memory. Associations involving parents' education were reduced in size and by statistical significance when accounting for participants' midlife SES, whereas associations involving parental income and occupational status became statistically nonsignificant. We found no associations between childhood SES and change in cognition. DISCUSSION: Findings contribute to growing evidence that socioeconomic differences in childhood have potential consequences for later life cognition, particularly in terms of the disparate levels of cognition with which people enter later life. PMID- 29969934 TI - Specialization of CDK1 and cyclin B paralog functions in a coenocystic mode of oogenic meiosis. AB - Oogenesis in the urochordate, Oikopleura dioica, occurs in a large coenocyst in which vitellogenesis precedes oocyte selection in order to adapt oocyte production to nutrient conditions. The animal has expanded Cyclin-Dependant Kinase 1 (CDK1) and Cyclin B paralog complements, with several expressed during oogenesis. Here, we addressed functional redundancy and specialization of CDK1 and cyclin B paralogs during oogenesis and early embryogenesis through spatiotemporal analyses and knockdown assays. CDK1a translocated from organizing centres (OCs) to selected meiotic nuclei at the beginning of the P4 phase of oogenesis, and its knockdown impaired vitellogenesis, nurse nuclear dumping, and entry of nurse nuclei into apoptosis. CDK1d-Cyclin Ba translocated from OCs to selected meiotic nuclei in P4, drove meiosis resumption and promoted nuclear envelope breakdown (NEBD). CDK1d-Cyclin Ba was also involved in histone H3S28 phosphorylation on centromeres and meiotic spindle assembly through regulating Aurora B localization to centromeres during prometaphase I. In other studied species, Cyclin B3 commonly promotes anaphase entry, but we found O. dioica Cyclin B3a to be non-essential for anaphase entry during oogenic meiosis. Instead, Cyclin B3a contributed to meiotic spindle assembly though its loss could be compensated by Cyclin Ba. PMID- 29969932 TI - PTENalpha regulates mitophagy and maintains mitochondrial quality control. AB - : PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTENalpha, the first identified PTEN isoform, regulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTENalpha-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTENalpha-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion. Mitochondrial clearance by mitophagy is also impaired in PTENalpha-deficient cardiomyocytes. In addition, we found PTENalpha physically interacts with the E3 ubiquitin ligase PRKN, which is an important mediator of mitophagy. PTENalpha binds PRKN through the membrane binding helix in its N-terminus, and promotes PRKN mitochondrial translocation through enhancing PRKN self-association in a phosphatase-independent manner. Loss of PTENalpha compromises mitochondrial translocation of PRKN and resultant mitophagy following mitochondrial depolarization. We propose that PTENalpha functions as a mitochondrial quality controller that maintains mitochondrial function and cardiac homeostasis. ABBREVIATIONS: BECN1 beclin 1; CCCP carbonyl cyanide m-chlorophenylhydrazone; FBXO7 F-box protein 7; FS fraction shortening; HSPA1L heat shock protein family A (Hsp70) member 1 like; HW: BW heart weight:body weight ratio; I-R ischemia reperfusion; ISO isoprenaline; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MBH membrane binding helix; MFN1 mitofusin 1; MFN2 mitofusin 2; Nam nicotinamide; TMRM tetramethylrhodamine ethyl ester; WGA wheat germ agglutinin. PMID- 29969935 TI - Efficacy and Harms of Pharmacological Interventions for Neurobehavioral Symptoms in Post-Traumatic Amnesia after Traumatic Brain Injury: A Systematic Review. AB - Many individuals in post-traumatic amnesia (PTA) following traumatic brain injury (TBI) experience neurobehavioral symptoms (NBS) in addition to disorientation and amnesia. These symptoms are associated with low rehabilitation engagement, self inflicted harm, and risk of violence. The aim of this systematic review was to evaluate the efficacy and harms of pharmacological interventions for NBS in PTA following TBI in adults. Studies in English published before December 2017 were reviewed. Six databases were searched, with additional hand searching of key journals, clinical trials registries, and international drug regulators. Evidence quality was assessed using Joanna Briggs Institute Critical Appraisal Instruments. Thirteen studies were identified: three randomized controlled trials (RCTs), three cohort studies, and seven case series. In the RCTs, neither amantadine nor sertraline reduced NBS. Less rigorous studies reported reduced NBS in patients administered haloperidol, ziprasidone, carbamazepine, amitriptyline, desipramine, and varied neuroleptics. There is a paucity of well-designed, adequately powered and controlled studies of pharmacological interventions for NBS in PTA. More research is needed to provide evidence-based treatment recommendations and improve care. PMID- 29969936 TI - Bilateral Motor Cortex Plasticity in Individuals With Chronic Stroke, Induced by Paired Associative Stimulation. AB - BACKGROUND: In the chronic phase after stroke, cortical excitability differs between the cerebral hemispheres; the magnitude of this asymmetry depends on degree of motor impairment. It is unclear whether these asymmetries also affect capacity for plasticity in corticospinal tract excitability or whether hemispheric differences in plasticity are related to chronic sensorimotor impairment. METHODS: Response to paired associative stimulation (PAS) was assessed bilaterally in 22 individuals with chronic hemiparesis. Corticospinal excitability was measured as the area under the motor-evoked potential (MEP) recruitment curve (AUC) at baseline, 5 minutes, and 30 minutes post-PAS. Percentage change in contralesional AUC was calculated and correlated with paretic motor and somatosensory impairment scores. RESULTS: PAS induced a significant increase in AUC in the contralesional hemisphere ( P = .041); in the ipsilesional hemisphere, there was no significant effect of PAS ( P = .073). Contralesional AUC showed significantly greater change in individuals without an ipsilesional MEP ( P = .029). Percentage change in contralesional AUC between baseline and 5 m post-PAS correlated significantly with FM score ( r = -0.443; P = .039) and monofilament thresholds ( r = 0.444, P = .044). DISCUSSION: There are differential responses to PAS within each cerebral hemisphere. Contralesional plasticity was increased in individuals with more severe hemiparesis, indicated by both the absence of an ipsilesional MEP and a greater degree of motor and somatosensory impairment. These data support a body of research showing compensatory changes in the contralesional hemisphere after stroke; new therapies for individuals with chronic stroke could exploit contralesional plasticity to help restore function. PMID- 29969937 TI - Bioengineered surgical repair of a chronic oronasal fistula in a cat using autologous platelet-rich fibrin and bone marrow with a tailored 3D printed implant. AB - Clinical summary: A tissue engineering approach was used to aid the surgical repair of a chronic oronasal fistula (ONF) in a 13-year-old cat. A three dimensional (3D) printed mesh, tailored to the size and shape of the ONF, was created to support a soft tissue flap used to close the defect; and also to provide a matrix for mesenchymal stromal cells present in bone marrow aspirate and bioactive cytokines and growth factors present in platelet-rich fibrin harvested from the patient. A CT scan at day 75 after surgery revealed the formation of new tissue in the defect and the healing process was complete at follow-up 6 months after surgery. Relevance and novel information: Complications are frequently reported following surgical repair of ONFs and include dehiscence of the palatal suture line, flap necrosis due to damage to the greater palatine artery and maxillary osteomyelitis, mainly due to chronic infection and bone lysis. The case described here demonstrates how input from a multidisciplinary team and the use of a biomaterial, processed by sophisticated technologies, can create a precision regenerative medicine strategy adapted to the patient's clinical needs; this provided a novel therapeutic solution for an otherwise hard to treat clinical problem. PMID- 29969938 TI - Towards a biomarker model for cognitive improvement: No change in memory-related prefrontal engagement following a negative cognitive remediation trial in bipolar disorder. AB - BACKGROUND: Cognitive deficits are prevalent in bipolar disorder during remission but effective cognition treatments are lacking due to insufficient insight into the neurobiological targets of cognitive improvement. Emerging data suggest that dorsal prefrontal cortex target engagement is a key neurocircuitry biomarker of pro-cognitive treatment effects. AIMS: In this randomized controlled functional magnetic resonance imaging study, we test this hypothesis by investigating the effects of an ineffective cognitive remediation intervention on dorsal prefrontal response during strategic memory encoding and working memory engagement. METHODS: Bipolar disorder patients in partial remission with subjective cognitive difficulties were randomized to receive 12-week group-based cognitive remediation ( n = 13) or to continue their standard treatment ( n = 14). The patients performed a strategic episodic picture encoding task and a spatial n-back working memory task under functional magnetic resonance imaging at baseline and following cognitive remediation or standard treatment. RESULTS: The right dorsolateral prefrontal cortex was commonly activated by both strategic memory tasks across all patients. The task-related prefrontal engagement was not altered by cognitive remediation relative to standard treatment. The dorsolateral prefrontal cortex response was not significantly associated with recall accuracy or working memory performance. CONCLUSIONS: As hypothesized, no task-related change in prefrontal activity was observed in a negative cognitive remediation trial in remitted bipolar disorder patients. By complementing previous findings linking cognitive improvement with increased dorsolateral prefrontal cortex engagement, our negative findings provide additional validity evidence to the dorsal prefrontal target engagement biomarker model of cognitive improvement by strengthening the proposed causality between modulation of dorsolateral prefrontal cortex engagement and pro-cognitive effects. PMID- 29969939 TI - High Resolution Computed Tomography Atlas of the Porcine Temporal Bone and Skull Base: Anatomical Correlates for Traumatic Brain Injury Research. AB - Brain injuries are a significant cause of morbidity and mortality worldwide. Auditory and vestibular dysfunction may occur following trauma to the temporal bone (TB), including the lateral skull base. The porcine model is a commonly used large animal model for investigating brain injury. Reports detailing porcine TB anatomy based on high resolution computed tomography (HRCT) imaging, however, are limited. Herein, we employ HRCT to evaluate and describe the bony anatomy of the porcine TB and lateral skull base. High-resolution multi-detector and cone beam CT were used to image porcine TBs (n = 16). TBs were analyzed for major anatomical structures and compared to human species. Porcine temporal bone anatomy was readily identifiable by HRCT. Although some variability exists, the ossicular chain, vestibule, cochlea, course of the facial nerve, and skull base are similar to those of humans. Major differences included position of the external auditory canal and mastoid, as well as presence of the petrous carotid canal. Study findings may serve as an atlas to evaluate the porcine middle and inner ear, as well as lateral skull base injuries for future porcine brain injury models or other studies that require CT-based analysis. PMID- 29969940 TI - Behavioral remodeling of normal and cancerous epithelial cell lines with differing invasion potential induced by substrate elastic modulus. AB - The micro-environment of cancer cells in the body is mechanically stiffer than that of normal cells. We cultured three breast cell lines of MCF10A-normal, MCF7 noninvasive, and MDA-MB-231-invasive on PDMS substrates with different elastic moduli and different cellular features were examined.Effects of substrate stiffness on cell behavior were evident among all cell lines. Cancerous cells were more sensitive to substrate stiffness for cell behaviors related to cell motility and migration which are necessary for invasion. The invasive cancerous cells were the most motile on substrates with moderate stiffness followed by non invasive cancerous cells. Gene markers alterations were generally according to the analyzed cell movement parameters. Results suggest that alterations in matrix stiffness may be related to cancer disease and progression. PMID- 29969941 TI - Sudden death due to an invasive mole in a young primigravida: Precipitous presentation masquerading the natural manner. AB - Pulmonary metastasis is a well-known complication of an invasive mole. However, sudden death due to haemoptysis resulting from a metastatic invasive mole is extremely rare. We report the sudden unexpected death of an 18-year-old primigravida following a molar pregnancy. The death event was complicated within a few days of presentation by a clinically unsuspected mole invading the lung vasculature with associated widespread metastatic calcifications in the liver and brain. Death was due to haemorrhagic shock as a result of massive haemoptysis resulting from the invasive mole metastasising to the pulmonary vasculature. This was substantiated with a post-mortem computed tomography and gross and histopathological findings at autopsy. This case highlights the need for a high index of suspicion about potentially life-threatening pulmonary metastasis in women with trophoblastic diseases. PMID- 29969942 TI - Insufficient autophagy: a novel autophagic flux scenario uncovered by impaired liver TFEB-mediated lysosomal biogenesis from chronic alcohol-drinking mice. AB - Macroautophagy/autophagy is a dynamic process, and newly synthesized autophagosomes need to fuse with lysosomes to complete the full process, which is referred to as autophagic degradation or autophagic flux. Therefore, the proper number and function of lysosomes are critical for accomplishing autophagic flux. In a recent study, we found that chronic ethanol consumption impairs TFEB (transcription factor EB) function, which leads to decreased lysosomal biogenesis resulting in hepatic steatosis and liver injury in mice. Interestingly, using the autophagic flux assay recommended by the autophagy guidelines, we discovered a novel autophagic flux scenario, which we termed insufficient autophagy. Insufficient autophagy is a scenario in which cells have a decreased number of lysosomes resulting in the accumulation of early autophagosomes. Insufficient autophagy is marked by a partially increased autophagic flux, but the process cannot reach its full degradative capacity due to the lack of a sufficient number of lysosomes. Our work demonstrated that pharmacological or genetic activation of TFEB-mediated lysosomal biogenesis enhances autophagic flux coupled with mitochondrial biogenesis in protecting against ethanol-induced liver injury. Overall, these findings not only identified the steps in which chronic ethanol impairs autophagic flux, but also discovered insufficient autophagy as a novel previously unappreciated autophagic flux scenario. PMID- 29969943 TI - Variation in Candidate Traumatic Brain Injury Biomarker Genes Are Associated with Gross Neurological Outcomes after Severe Traumatic Brain Injury. AB - Diagnostic and prognostic biomarkers of traumatic brain injury (TBI) are actively being pursued; potential candidates include glial fibrillary acid protein (GFAP), S100 calcium-binding protein B (S100B), and ubiquitin C-terminal hydrolase L1 (UCHL1), two of which the United States Food and Drug Administration (FDA) recently approved for marketing of blood tests for adult concussion. The relationship between biomarker-encoding genes and TBI outcomes remains unknown. This pilot study explores variation in 18 single nucleotide polymorphisms (SNPs) in biomarker-encoding genes as predictors of neurological outcome in a population of adults with severe TBI. Participants (n = 305) were assessed using the Glasgow Outcome Scale (GOS) at 3, 6, 12, and 24 months post-injury. Multivariate logistical regression was used to calculate the odds ratio (OR) and determine the odds of having a lower score on the GOS ( = 1-2 vs. 3-5) based on variant allele presence, while controlling for confounders. Possession of the variant allele of one S100B SNP (rs1051169) was associated with higher scores on the GOS at 3 months (OR = 0.39; p = 0.04), 6 months (OR = 0.34; p = 0.02), 12 months (OR = 0.32; p = 0.02), and 24 months (OR = 0.30; p = 0.02) post-severe TBI. The relationship among these polymorphisms, protein levels, and biomarker utility, merits examination. These findings represent a novel contribution to the evidence that can inform future studies aimed at enhancing interpretation of biomarker data, identifying novel biomarkers, and ultimately harnessing this information to improve clinical outcomes and personalize care. PMID- 29969944 TI - Rocaglamide enhances NK cell-mediated killing of non-small cell lung cancer cells by inhibiting autophagy. AB - Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing. In addition, we further identified that the target of RocA was ULK1 (unc-51 like autophagy activating kinase 1) that is required for autophagy initiation. Using firefly luciferase containing the 5' untranslated region of ULK1, we found that RocA inhibited the protein translation of ULK1 in a sequence-specific manner. Taken together, RocA could block autophagic immune resistance to NK cell-mediated killing, and our data suggested that RocA was a promising therapeutic candidate in NK cell-based cancer immunotherapy. PMID- 29969946 TI - A Darker Side of Hope: Harmony-Focused Hope Decreases Collective Action Intentions Among the Disadvantaged. AB - Hope is viewed as a positive emotion associated with the motivation to change existing conditions. As such, it is highly relevant for social change, particularly when considering disadvantaged groups. We propose that, in the context of unequal intergroup relations, hope may actually undermine motivation for change among disadvantaged group members. Specifically, we distinguish between hope targeted at harmony with the outgroup and hope targeted at social equality between groups. Drawing on insights regarding the consequences of positive intergroup interactions, we predict that hope for harmony with the outgroup can undermine the constructive tension that motivates the disadvantaged toward equality. Across four studies, involving different intergroup contexts, hope for harmony was negatively associated with disadvantaged group members' motivation for collective action. We further found that high identifiers from the disadvantaged group were immune to this effect. We discuss theoretical and practical implications for the role of hope in social change. PMID- 29969945 TI - Specific autophagy and ESCRT components participate in the unconventional secretion of CFTR. AB - The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (DeltaF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRDeltaF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR. In mammalian cells, we found that autophagic pathways were modulated by conditions that also stimulate unconventional secretion, namely ER stress and an ER-to-Golgi transport blockade. Additionally, we found that knockdown of early autophagy components, ATG5 and ATG7, and treatment with pharmacological autophagy inhibitors, wortmannin and 3-methyladenine, abolished the unconventional secretion of CFTR that had been stimulated by ER stress and an ER-to-Golgi blockade. Interestingly, immunoelectron microscopy revealed that GORASP2/GRASP55, which mediates unconventional CFTR trafficking, is present in multivesicular bodies (MVB) and autophagosomal structures under ER stress conditions. A custom small-interfering RNA screen of mammalian ESCRT proteins that mediate MVB biogenesis showed that silencing of some ESCRTs, including MVB12B, inhibited unconventional CFTRDeltaF508 secretion. Furthermore, MVB12B overexpression partially rescued cell-surface expression and Cl- channel function of CFTRDeltaF508. Taken together, these results suggest that components involved in early autophagosome formation and the ESCRT/MVB pathway play a key role in the stress-induced unconventional secretion of CFTR. PMID- 29969948 TI - Parents' prenatal joint attachment representations and early caregiving: the indirect role of prenatal marital affect. AB - This research examined couples' marital affect as a mediator between the couples' combined attachment representations (assessed prenatally) and each of their caregiving quality at 8 months postpartum. We followed 125 couples pregnant with their first child over the transition to parenthood. Prenatally, the Adult Attachment Interview was administered and marital interactions were observed. Parents were categorized in joint attachment pairs: secure/secure, secure mother/insecure father, secure father/insecure mother, and insecure/insecure. Caregiving in dyadic parent-infant interactions was observed at home, 8 months postpartum. Results indicated the secure/secure pairing displayed the most positive marital affect overall and predicted higher sensitivity in both mothers and fathers compared to parents in secure mother/insecure father pairs. Indirect effects indicate marital affect mediated the relations between joint attachment pairs and caregiving. Findings suggest that joint attachment pairs relate to prenatal marital quality, which in turn spills over to predict each parent's later caregiving quality. PMID- 29969947 TI - Intravital Monitoring of Vasculature After Targeted Gene Therapy Alone or Combined With Tumor Irradiation. AB - Vascular-targeted therapies exhibit radiosensitizing effects by remodeling tumor vasculature, thus facilitating the increased oxygenation of the remaining tumor tissue. To examine these phenomena, the effects of antiendoglin gene therapy alone and in combination with irradiation were monitored for 5 consecutive days on a murine mammary adenocarcinoma (TS/A) tumor model growing in a dorsal window chamber. The vascularization of the tumors was assessed by the determination of the tumor vascular area and by measurement of tumor perfusion by using laser Doppler flowmetry to provide insight into intratumoral gene electrotransfer effects. The changes in the vascular area after this specific therapy correlated with laser Doppler measurements, indicating that either of the methods can be used to demonstrate the induced changes in the vascularization and perfusion of tumors. Gene electrotransfer with an endothelial-specific promoter resulted in a vascular-targeted effect on tumor vasculature within the first 24 hours and did not restore within 5 days. The combination with the irradiation did not result in a more pronounced vascular effect, and irradiation alone only abrogated the formation of new vessels and prevented an increase in the tumor perfusion over time. The results indicate that tumors grown in a dorsal window chamber facilitate intravital measurements of the vascularization of tumors and blood perfusion, enabling the monitoring of the antiangiogenic or vascular disruptive effects of different therapies. PMID- 29969949 TI - "Eavesdropping on Happiness" Revisited: A Pooled, Multisample Replication of the Association Between Life Satisfaction and Observed Daily Conversation Quantity and Quality. AB - In the present study, we aimed to replicate and extend findings by Mehl, Vazire, Holleran, and Clark (2010) that individuals with higher well-being tend to spend less time alone and more time interacting with others (e.g., greater conversation quantity) and engage in less small talk and more substantive conversations (e.g., greater conversation quality). To test the robustness of these effects in a larger and more diverse sample, we used Bayesian integrative data analysis to pool data on subjective life satisfaction and observed daily conversations from three heterogeneous adult samples, in addition to the original sample ( N = 486). We found moderate associations between life satisfaction and amount of alone time, conversation time, and substantive conversations, but no reliable association with small talk. Personality did not substantially moderate these associations. The failure to replicate the original small-talk effect is theoretically and practically important, as it has garnered considerable scientific and lay interest. PMID- 29969950 TI - Midterm results of the cylindrical fully porous-coated uncemented femoral stem in revision patients with Paprosky I-IIIA femoral defects. AB - INTRODUCTION: The aim of this study was to analyze the survival of the Echelon(r) femoral stems in revision hip surgeries in patients with Paprosky I-IIIA femoral defects. PATIENTS AND METHODS: Sixty-six patients (70 hips) who underwent revision hip surgery with at least 3 years of follow-up data were included in the study between 2000 and 2013. The mean patient age was 64.5 (32-83) years, and the mean follow-up period was 93 (45-206) months. The reasons for revision were aseptic loosening in 55 (78.6%) patients, periprosthetic joint infection in 9 (12.9%) patients, periprosthetic fracture in 4 (5.7%) patients, and stem fracture in 2 (2.9%) patients. The preoperative and postoperative follow-up X-rays and functional scores were evaluated. RESULTS: Five patients died in an average of 70 (45-86) months after surgery due to non-related diseases. We encountered sciatic nerve palsy in two patients and early hip dislocation in two patients, whereas 54 patients were able to walk without any assistive device. The remaining 12 patients required an assistive device to walk. The mean Harris hip score significantly increased from 34 (7-63) preoperatively to 72 (43-96) postoperatively. Aseptic loosening was observed in one patient. The survival of the porous-coated anatomical uncemented femoral stem was 98.4% over 10 years. CONCLUSION: This study showed that good clinical outcomes and survival can be obtained when using porous-coated anatomical uncemented femoral stems. PMID- 29969951 TI - Biovalorization of glucose in four culture media and effect of the nitrogen source on fermentative alcohols production by Escherichia coli. AB - Glucose is one of the most abundant monosaccharides and the easiest carbon source to be consumed by bacteria. In this study, four culture media (LB, M9, M63 and MOPS) were supplemented with glucose at three different concentrations (4, 12.5 and 25 g/L) in the presence of a genetically modified strain of Escherichia coli with the purpose of selecting the most suitable culture medium to obtain ABD (acetoin (A) and 2,3-butanediol (2,3-BD)). The selected medium was M9, the cheapest culture medium, since the ABD yields obtained fermenting 12.5 and 25 g/L of glucose in M9 culture medium at 37 degrees C, atmospheric pressure, initial pH 6.5, 100 rpm and 10% (v/v) of inoculum were similar compared to the ABD yields obtained using M63 and LB culture media. The influence of nitrogen on ABD yield was tested adding sodium nitrate (NaNO3) or urea ((NH2)2CO) to M9 culture medium at three different nitrogen concentrations (2.5, 5.0 and 7.0 g N/L). Adding urea (7.0 g N/L) to M9 supplemented with 25 g/L of glucose improved by 23% the ABD yield at 96 h compared to M9 without urea, reaching a value of 27.2% (g ABD/g glucose). In contrast, the use of NaNO3 had no significant effect on the ABD yield. PMID- 29969952 TI - Transmural migration of azygous vein Hem-O-lok clip causing food bolus 3 months following uneventful minimally invasive oesophagectomy. AB - BACKGROUND: Hem-o-lok clips are widely deployed in various laparoscopic and robotic operations. Their migration is not very common and majority of reported cases are limited to biliary, prostatic and vesico-urethral cases. METHODS: Herein, we would like to report the first case of transmural migration of Hem-o lok clip from azygous vein stump following totally minimally invasive two-stage oesophagectomy for squamous cell carcinoma of the distal oesophagus, into the gastric conduit 3-months following uneventful discharge. The patient presented with 5-days history of worsening dysphagia. RESULTS: The subsequent gastroscopy revealed normal gastric conduit with two Hem-o-lok clips containing the azygous vein stump within its lumen at the level of the oesophago-gastric anastomosis, propagating a food bolus obstruction. The foreign body was successfully removed and the patient was discharged the same day without any complications at 5 months follow up. CONCLUSION: Hem-o-lok clip migration trends to be a well-established event. However, their mechanism and exact incidence remains elusive to this date. To the best of our knowledge, their migration in oesophageal cancer surgery has not been reported. PMID- 29969953 TI - Transcultural Modifications of a Japanese Language Group Prenatal Care Program for Transcultural Adaptation. AB - INTRODUCTION: The CenteringPregnancy model has been demonstrated to improve birth outcomes for certain cultural and ethnic groups, but the literature lacks examples on how to modify their guidelines for socioculturally isolated women. Our aim is to examine the modifications we made to the CenteringPregnancy group prenatal care for Japanese women and to examine the implications for transcultural modification. METHODS: Using a descriptive case study design, we examined the cultural fit and modifications of our Japanese prenatal group approach. We report the aspects that do not require modifications and the transcultural modifications that are needed. Based on this descriptive case, we discuss the lessons learned for making transcultural modifications that may apply to other cultural groups. RESULTS: Many aspects of the CenteringPregnancy were readily adopted. We made 10 substantive transcultural modifications and articulate considerations for transcultural modifications. DISCUSSION/CONCLUSION: This research illustrates transcultural considerations for modifying the CenteringPregnancy model and provides implications for use in other isolated populations of pregnant women. PMID- 29969954 TI - Examination of the Interproximal Wear Mechanism: Facet Morphology and Surface Texture Analysis. AB - Dentition is considered a dynamic system with forces that directly affect dental treatment stability and success. Understanding the biomechanical forces that influence tooth alignment is essential for both planning and performing dental treatments, as well as for anthropological and evolutionary studies. While there is currently an abundance of research on the mechanics of dental wear at the occlusal surface, the mechanics of interproximal dental wear is largely unexplored. The fretting mechanism, a wear process resulting from small-amplitude cyclic motion of 2 solid contacting surfaces, was refuted as a possible mechanism for occlusal wear but has never been considered for interproximal wear. Therefore, the aim of the current study was to reveal the biomechanical process of the interproximal wear and to explore whether the fretting mechanism could be associated with this process. Premolar teeth with interproximal wear facets were examined by 3-dimensional surface texture analysis using a high-resolution confocal disc-scanning measuring system. The unique texture topography of 3 areas in the proximal surface of each tooth was analyzed by applying 3D dental surface texture analysis. Each area showed unique texture characteristics, presenting statistically significant differences between the inner area of the facet and its margins or the surface outside the facets borders. Based on these results, we concluded that fretting is a key mechanism involved in interproximal wear. PMID- 29969955 TI - Activity of Streptococcus mutans VicR Is Modulated by Antisense RNA. AB - The VicRK 2-component system of Streptococcus mutans regulates genes associated with cell wall biogenesis and biofilm formation. A putative RNase III-encoding gene ( rnc) is located downstream from the vicRKX operon. The goals of this study were to investigate the potential role of VicR in the regulation of adjacent downstream genes and evaluate transcription levels of vicR during planktonic and biofilm growth. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to investigate whether vicRKX and adjacent downstream genes were cotranscribed. Binding of purified recombinant VicR protein to promoter regions of vicR, rnc, and syfA genes was confirmed by electrophoretic mobility shift assay and by chromatin immunoprecipitation analyses. VicR antisense (AS vicR) RNA was detected by Northern blotting and qRT-PCR assays. AS vicR overexpression mutants were constructed, and the biofilm biomass was determined by crystal violet microtiter assay. Adjacent downstream genes rnc, smc, syfA, smu.1511, and syfB were cotranscribed with vicRKX. The predicted promoter regions of vicR, rnc, and syfA genes were directly regulated by VicR. An AS vicR RNA transcript was detected upstream of the rnc gene. Expression of the AS vicR RNA transcript was elevated in planktonic cultures and repressed during biofilm growth. In addition, Western blot data showed that expression of the VicR protein decreased by 35% in planktonic as compared with biofilm cultures. Furthermore, we show that overexpression of AS vicR led to a reduction in biofilm formation. The downstream genes rnc, smc, syfA, smu.1511, and syfB are cotranscribed with vicRKX. VicR is autophosphorylated, and rnc and syfA are directly regulated by VicR. Expression of VicR protein correlated inversely with different levels of AS vicR RNA transcript and growth conditions. The biofilm biomass decreased in the AS vicR overexpression mutant. These data suggest a role for the AS vicR RNA transcript in posttranscriptional regulation of VicR protein production in S. mutans. PMID- 29969956 TI - Reversible cerebral vasoconstriction complicated with brain infarction immediately after carotid artery stenting. AB - Reversible cerebral vasoconstriction is a very rare complication after carotid artery stenting (CAS). It has been reported to occur more than several hours after CAS and to have a good clinical course. A 73-year-old man underwent CAS for a high-grade symptomatic stenosis of his left carotid artery. Immediately after CAS, he had consciousness disturbance and right hemiparesis. We first suspected hyperperfusion syndrome, but antihypertensive therapy exacerbated his symptoms. On repeated postoperative angiography, the middle cerebral artery (MCA) appeared to become progressively narrower. Perfusion computed tomography indicated hypoperfusion in the left MCA territory, so we diagnosed the patient with ischemic symptoms due to hypoperfusion associated with MCA vasoconstriction. Although these findings were temporary, right weakness and cognitive dysfunction lingered and caused severe disability. As vasoconstriction after CAS may result in a poor outcome, it must be promptly distinguished and treated accordingly. PMID- 29969958 TI - Successful recanalization using the Embolus Retriever with Interlinked Cage for acute stroke due to calcified cerebral emboli. AB - Mechanical thrombectomy is a safe and effective treatment in patients with acute ischemic stroke caused by large vessel occlusions. However, in rare cases, the procedure may be challenging due to the composition of the embolus. We describe a case of a mechanical thrombectomy with the Embolus Retriever with Interlinked Cage (ERIC) device in a patient with an acute ischemic stroke due to calcified cerebral emboli in the middle cerebral artery. The procedure was done after a failed recanalization attempt with manual aspiration thrombectomy. An 82-year-old woman presented to the emergency department with a sudden onset of right-sided weakness. A computed tomographic angiography showed left middle cerebral (M1 branch) calcified emboli. After the administration of an intravenous thrombolytic agent, the patient was transferred to the angiographic suite for a mechanical thrombectomy. After failure to recanalize the vessel with manual aspiration thrombectomy, successful recanalization was achieved via mechanical thrombectomy using the ERIC device. Mechanical thrombectomy with an ERIC device can be a useful option in cases of acute ischemic stroke caused by calcified cerebral emboli. PMID- 29969957 TI - Early reappearance of disappeared ruptured small aneurysm with concomitant vertebral artery dissection. AB - Thrombosis of a previously ruptured intracranial aneurysm is a frequent event and it most commonly occurs in large or giant aneurysms. We present a dynamic short term follow-up and management of thrombosis in a ruptured small posterior inferior cerebellar artery aneurysm with concomitant vertebral artery dissection (VAD). Clinical and radiological follow-up findings and reviewed literature on thrombosis of small ruptured aneurysms are the focus of this presentation. Early reappearance of a disappeared ruptured small cerebral aneurysm with a concomitant VAD may be attributed to the controlled ovarian hyperstimulation phase of in vitro fertilization and prolonged use of oral contraceptive pills. PMID- 29969960 TI - Duplication of the vertebral artery: A series of four cases. AB - INTRODUCTION: Duplication of the vertebral artery (VA) is a rare vascular variant, with less than 50 reported cases in the literature. CASE SERIES: We present four cases of VA duplication and discuss the imaging findings, which highlight the rarely seen VA duplication. DISCUSSION: VA duplication is generally considered to be an incidental finding. The VA is formed from the fusion of the longitudinal anastomoses that link the cervical intersegmental arteries, during the 32-40-day stage. The duplication of the VA is a clinically relevant finding for planning of head and neck surgery and neuro-interventional procedures. PMID- 29969959 TI - The influence of coccygeal dynamic patterns on ganglion impar block treatment results in chronic coccygodynia. AB - Objective Ganglion impar block (GIB) can be performed in patients with chronic coccygodynia who do not respond to conservative treatments. We investigated the effect of coccygeal dynamic patterns on the treatment outcome in patients with chronic coccygodynia treated with GIB. Materials and methods We retrospectively analyzed the data for patients diagnosed with chronic coccygodynia who underwent GIB only once by a transsacrococcygeal method under fluoroscopy guidance in our Pain Medicine Clinic. Patients were assessed with standard and dynamic coccyx radiographs and classified according to coccygeal mobility. Pain scores were assessed with a numerical rating scale (NRS) before and after the intervention (at 1 hour and 4, 12 and 24 weeks). A 50% or more reduction in the NRS score was accepted as significant pain relief. Results Of the 37 patients included in the study, 14 had normal coccyx (Group I) and 23 had immobile coccyx (Group II) based on the radiological evaluation. The NRS scores were significantly reduced in both groups on each follow-up visit but there was no significant difference between the two groups in terms of pre- and post-intervention NRS scores. Significant pain relief was achieved in 42.9% and 61.9% of patients in Group I and II at the last examination, respectively. Conclusion GIB administered by transsacrococcygeal method in patients with chronic coccygodynia is a safe and alternative treatment approach with reduced pain scores and low complication rates. In patients with chronic coccygodynia, having a normal or immobile coccyx does not appear to affect treatment outcomes. PMID- 29969961 TI - [Ultramarathon with Type 1 Diabetes]. AB - Ultramarathon with Type 1 Diabetes Abstract. We report the case of a 63-year-old runner with type 1 diabetes mellitus requiring insulin since the age of 21. At the age of 32, he ran his first marathon, and at the age of 34 the first ultramarathon. So far, he has finished more than 90 marathons and ultramarathons. Thanks to an insulin pump and continuous glucose monitoring, he has so far completed 48 24-h-runs with an average distance of 133 km. The analysis of running volume and HbA1c values showed a significant increase in monthly exercise volume, a significant decrease in HbA1c values over the years, and a significant correlation between monthly running kilometers and HbA1c values. PMID- 29969963 TI - ? PMID- 29969962 TI - ? PMID- 29969964 TI - [CME Sonography 82/Answers: Fever, Shivering Fit]. PMID- 29969965 TI - ? PMID- 29969966 TI - ? PMID- 29969967 TI - [CME Answers: "Adrenal Insufficiency" Praxis No. 13]. PMID- 29969968 TI - ? AB - People with a positive body image are more content with their body, reflect their society's beauty ideals more critically, have the ability to care for their body and are better protected from depression. Adolescence represents a particularly critical period relating to the development of the body image. The results of 1023 adolescents between the age of 13 and 16 years are unambiguous: In both analyzed language parts of the country, the positive body image correlates significantly positive with mental health and significantly negative with the influence by the media. For the future it is recommended to develop target-group specific and gender-specific awareness and communication measures, particularly by including social media, as well as associated means to strengthen adolescents' mental health. PMID- 29969969 TI - [Biomarkers of Smoking - Which Cut-Off Values Should be Used?] AB - Biomarkers of Smoking - Which Cut-Off Values Should be Used? Abstract. Verification of smoking status by means of biomarkers is important for treatment decisions of patients with smoking-related diseases. Cotinine is currently the best biomarker to document nicotine consumption. A low cost alternative method to determine smoking status is by measurement of carboxyhemoglobin (CO-Hb) in the exhaled breath. The main disadvantage of CO-Hb is the short half-life. The appropriate cut-off value for active nicotine consumption in Switzerland is 50 ng/ml or higher cotinine in the urine or 10 ng/ml and 12 ng/ml in serum and saliva, respectively. CO-Hb levels greater than 2 % indicate smoking with high probability, levels above 3 % with very high probability. PMID- 29969970 TI - [CME ECG 61: Management of Premature Ventricular Contractions]. PMID- 29969971 TI - [CME: Multiple Myeloma - a Review]. AB - CME: Multiple Myeloma - a Review Abstract. Multiple myeloma accounts for 1 % of all malignancies, and its incidence increases with age. Both the symptoms and the course of the disease are heterogeneous. While some patients experience unspecific complaints, e.g. malaise or lethargy, others might present with emergency situations like hypercalcemia, spinal cord compression or hyperviscosity, so that an urgent therapy initiation is crucial. The aim of this article is to review the most common initial symptoms, typical emergencies, as well as diagnostics and therapy of multiple myeloma. PMID- 29969972 TI - [A Rare Cause of an Angioedema-Like Habitus]. AB - A Rare Cause of an Angioedema-Like Habitus Abstract. We report about a 69-year old patient arriving at the emergency room with suspected allergic reaction grade III due to a pronounced facial swelling, dyspnea and dizziness. However, the cause was a bilateral pneumothorax with massive soft-tissue emphysema. On the one side it was due to a spontaneous secondary genesis in the context of a chronic pulmonary disease, on the other side it was due to a traumatic serial rib fracture. PMID- 29969973 TI - [An Endurance Athlete with Calf Pain - Probably Musculoskeletal?] AB - An Endurance Athlete with Calf Pain - Probably Musculoskeletal? Abstract. Deep vein thromboses are frequent and account for one third of all cardiovascular diseases. But undoubtedly patients often present risk factors. To assume a deep vein thrombosis in an endurance athlete with pain in the calf, therefore seems unreasonable. The positive D-dimer and the side differences of the calf diameter was the key for the correct diagnosis. The treatment with Heparin improved clinical symptoms within 5 days and the patient became free of pain. The additionally conducted ultrasound showed no more hints for a thromboembolic process. PMID- 29969974 TI - The development of a global Midwifery Education Accreditation Programme. AB - BACKGROUND: Many countries are responding to the global shortage of midwives by increasing the student intake to their midwifery schools. At the same time, attention must be paid to the quality of education being provided, so that quality of midwifery care can be assured. Methods of assuring quality of education include accreditation schemes, but capacity to implement such schemes is weak in many countries. OBJECTIVE: This paper describes the process of developing and pilot testing the International Confederation of Midwives' Midwifery Education Accreditation Programme (ICM MEAP), based on global standards for midwifery education, and discusses the potential contribution it can make to building capacity and improving quality of care for mothers and their newborns. METHODS: A review of relevant global, regional and national standards and tools informed the development of a set of assessment criteria (which was validated during an international consultation exercise) and a process for applying these criteria to midwifery schools. The process was pilot tested in two countries: Comoros and Trinidad and Tobago. RESULTS: The assessment criteria and accreditation process were found to be appropriate in both country contexts, but both were refined after the pilot to make them more user-friendly. CONCLUSION: The ICM MEAP has the potential to contribute to improving health outcomes for women and newborns by building institutional capacity for the provision of high quality midwifery education and thus improved quality of midwifery care, via improved accountability for the quality of midwifery education. PMID- 29969975 TI - Beyond bus fare: deconstructing prenatal care travel among low-income urban mothers through a mix methods GIS study. AB - OBJECTIVE: Guided by critical theory, this study illustrates the value of interpretative mapping to deconstruct bus travel to publicly funded prenatal care in a city marked by health and social inequities. METHODS: This mixed methods study used GIS maps based on 61,305 births to study the known barrier of transportation to prenatal care among urban mothers most at risk for preterm birth. RESULTS: Among 350 census tracts, 36 census tracts had preterm rates between 25 -36.9%. Modeling travel time for the case vignette for routine prenatal care took 21 visits to different geographically located facilities. This burden increased to 32 visits if the case vignette was high-risk. CONCLUSIONS: Interpretative GIS mapping is an important tool to ground truth spatially linked data into real world meanings. Promoting optimal health requires innovative and feasible approaches that take into consideration daily maternal functioning as pregnant mothers care for their children and themselves. PMID- 29969977 TI - Characteristics associated with lack of HIV testing during pregnancy and delivery in 36 U.S. states, 2004-2013. AB - The Centers for Disease Control and Prevention and the American Congress of Obstetricians and Gynecologists recommend universal prenatal HIV testing to prevent perinatal HIV transmission in the U.S.; since the 1990s perinatal HIV transmission has declined. In 2006, 74% of women with a recent live birth reported testing for HIV prenatally or at delivery. We used Pregnancy Risk Assessment Monitoring System data from 36 states and New York City from 2004 to 2013 (N = 387,424) to assess characteristics associated with lack of self reported testing and state-to-state variability in these associations. Overall, 75.2% (95% confidence interval [CI] 75.0-75.5) of women with a recent live birth reported an HIV test. There were significant differences in testing prevalence by state, ranging from 91.8% (95% CI 91.0-92.6) in New York to 42.3% (95% CI 41.7 43.5) in Utah. In adjusted analysis, characteristics associated with no reported testing included being married, white, non-Hispanic, multiparous, not smoking during pregnancy, and having neither Medicaid nor Special Supplemental Nutritional Program for Women, Infants, and Children. White married women were 57% (adjusted prevalence ratio [aPR] 1.57, 95% CI 1.52-1.63) more likely to report no test compared to white unmarried women. Multiparous married women were 57% (aPR 1.57, 95% CI 1.51-1.64) more likely to report no test compared to multiparous unmarried women. Women who were married, white, non-Hispanic, and multiparous women were 23% less likely to be tested than other women combined. Marital status was significantly associated with lower prevalence of testing in 35 of the 37 reporting areas, and race was significant in 30 of 35 states with race information. The prevalence of reported HIV testing during pregnancy or at delivery remains below 80%. Opportunities exist to increase HIV testing among pregnant women, particularly among certain subpopulations. PMID- 29969979 TI - Can letter position encoding be modified by visual perceptual elements? AB - A plethora of studies has revealed that letter position coding is relatively flexible during word recognition (e.g., the transposed-letter [TL] pseudoword CHOLOCATE is frequently misread as CHOCOLATE). A plausible explanation of this phenomenon is that letter identity and location are not perfectly bound as a consequence of the limitations of the visual system. Thus, a complete characterization of letter position coding requires an examination of how letter position coding can be modulated by visual perceptual elements. Here we conducted three lexical decision experiments with TL and replacement-letter pseudowords that manipulated the visual characteristics of the stimuli. In Experiment 1, each syllable was presented either in a different colour or monochromatically (e.g., [Formula: see text] vs. [Formula: see text]) with the transposition occurring across syllables. In Experiment 2, the critical letters had a consistent contrast or not (e.g., [Formula: see text] vs. [Formula: see text]). In Experiment 3, the stimuli were presented either simultaneously or serially, letter by letter (i.e., as occurs in braille reading). Results showed that whereas colouring differently each syllable only produced a small nonsignificant reduction of the TL effect, the other two manipulations-presenting the two critical letters with an altered contrast and presenting the letters one at a time-reduced, but did not eliminate, the magnitude of the TL effect relative to the regular format. Although these findings are consistent with models that postulate an early perceptual locus of the TL effect, the robustness of the TL effect suggests that letter position coding also has an orthographic abstract component. PMID- 29969978 TI - Molecular screening for Neisseria gonorrhoeae antimicrobial resistance markers in Nigerian men who have sex with men and transgender women. AB - Antimicrobial-resistant Neisseria gonorrhoeae (NG) is a global public health issue that threatens effectiveness of current treatments of NG. Increased use of nucleic acid amplification tests (NAATs) in lieu of cultures makes obtaining clinical isolates for susceptibility testing difficult and samples collected in commercial transport buffer for NAATs do not preserve viable organism, while molecular methods of assessing antibiotic susceptibility do not require viable organism. We evaluated 243 NG-positive samples in Aptima transport media including urine, oral, and rectal swabs from Nigerian men who have sex with men for markers to penicillinase-producing NG, ciprofloxacin ( GyrA and ParC mutations), and extended spectrum cephalosporins (ESCs, PenA mosaic [allele X], PonA, mtrR, PorB mutations) by real-time PCR. NG DNA was recovered in 75% (183/243) of samples. Of these, 93% (171/183) were positive for at least one resistance marker. We observed a prevalence of dual resistance markers to penicillin and ciprofloxacin at 46.2% (79/171). Six percent of samples (10/171) tested positive for the PenA mosaic (allele X) ESC marker. These data indicate that antibiotic-resistant NG is common in Nigeria. Laboratory and clinical capacity building in Nigeria should include development of methods to culture NG and determine antimicrobial susceptibility. PMID- 29969980 TI - The soft explosive model of placental mammal evolution. AB - BACKGROUND: Recent molecular dating estimates for placental mammals echo fossil inferences for an explosive interordinal diversification, but typically place this event some 10-20 million years earlier than the Paleocene fossils, among apparently more "primitive" mammal faunas. RESULTS: However, current models of molecular evolution do not adequately account for parallel rate changes, and result in dramatic divergence underestimates for large, long-lived mammals such as whales and hominids. Calibrating among these taxa shifts the rate model errors deeper in the tree, inflating interordinal divergence estimates. We employ simulations based on empirical rate variation, which show that this "error-shift inflation" can explain previous molecular dating overestimates relative to fossil inferences. Molecular dating accuracy is substantially improved in the simulations by focusing on calibrations for taxa that retain plesiomorphic life history characteristics. Applying this strategy to the empirical data favours the soft explosive model of placental evolution, in line with traditional palaeontological interpretations - a few Cretaceous placental lineages give rise to a rapid interordinal diversification following the 66 Ma Cretaceous-Paleogene boundary mass extinction. CONCLUSIONS: Our soft explosive model for the diversification of placental mammals brings into agreement previously incongruous molecular, fossil, and ancestral life history estimates, and closely aligns with a growing consensus for a similar model for bird evolution. We show that recent criticism of the soft explosive model relies on ignoring both experimental controls and statistical confidence, as well as misrepresentation, and inconsistent interpretations of morphological phylogeny. More generally, we suggest that the evolutionary properties of adaptive radiations may leave current molecular dating methods susceptible to overestimating the timing of major diversification events. PMID- 29969981 TI - SimCAL: a flexible tool to compute biochemical reaction similarity. AB - BACKGROUND: Computation of reaction similarity is a pre-requisite for several bioinformatics applications including enzyme identification for specific biochemical reactions, enzyme classification and mining for specific inhibitors. Reaction similarity is often assessed at either two levels: (i) comparison across all the constituent substrates and products of a reaction, reaction level similarity, (ii) comparison at the transformation center with various degrees of neighborhood, transformation level similarity. Existing reaction similarity computation tools are designed for specific applications and use different features and similarity measures. A single system integrating these diverse features enables comparison of the impact of different molecular properties on similarity score computation. RESULTS: To address these requirements, we present SimCAL, an integrated system to calculate reaction similarity with novel features and capability to perform comparative assessment. SimCAL provides reaction similarity computation at both whole reaction level and transformation level. Novel physicochemical features such as stereochemistry, mass, volume and charge are included in computing reaction fingerprint. Users can choose from four different fingerprint types and nine molecular similarity measures. Further, a comparative assessment of these features is also enabled. The performance of SimCAL is assessed on 3,688,122 reaction pairs with Enzyme Commission (EC) number from MetaCyc and achieved an area under the curve (AUC) of > 0.9. In addition, SimCAL results showed strong correlation with state-of-the-art EC-BLAST and molecular signature based reaction similarity methods. CONCLUSIONS: SimCAL is developed in java and is available as a standalone tool, with intuitive, user friendly graphical interface and also as a console application. With its customizable feature selection and similarity calculations, it is expected to cater a wide audience interested in studying and analyzing biochemical reactions and metabolic networks. PMID- 29969982 TI - Genome sequence and effectorome of Moniliophthora perniciosa and Moniliophthora roreri subpopulations. AB - BACKGROUND: The hemibiotrophic pathogens Moniliophthora perniciosa (witches' broom disease) and Moniliophthora roreri (frosty pod rot disease) are among the most important pathogens of cacao. Moniliophthora perniciosa has a broad host range and infects a variety of meristematic tissues in cacao plants, whereas M. roreri infects only pods of Theobroma and Herrania genera. Comparative pathogenomics of these fungi is essential to understand Moniliophthora infection strategies, therefore the detection and in silico functional characterization of effector candidates are important steps to gain insight on their pathogenicity. RESULTS: Candidate secreted effector proteins repertoire were predicted using the genomes of five representative isolates of M. perniciosa subpopulations (three from cacao and two from solanaceous hosts), and one representative isolate of M. roreri from Peru. Many putative effectors candidates were identified in M. perniciosa: 157 and 134 in cacao isolates from Bahia, Brazil; 109 in cacao isolate from Ecuador, 92 and 80 in wild solanaceous isolates from Minas Gerais (Lobeira) and Bahia (Caicara), Brazil; respectively. Moniliophthora roreri showed the highest number of effector candidates, a total of 243. A set of eight core effectors were shared among all Moniliophthora isolates, while others were shared either between the wild solanaceous isolates or among cacao isolates. Mostly, candidate effectors of M. perniciosa were shared among the isolates, whereas in M. roreri nearly 50% were exclusive to the specie. In addition, a large number of cell wall-degrading enzymes characteristic of hemibiotrophic fungi were found. From these, we highlighted the proteins involved in cell wall modification, an enzymatic arsenal that allows the plant pathogens to inhabit environments with oxidative stress, which promotes degradation of plant compounds and facilitates infection. CONCLUSIONS: The present work reports six genomes and provides a database of the putative effectorome of Moniliophthora, a first step towards the understanding of the functional basis of fungal pathogenicity. PMID- 29969983 TI - Genomic variations and association study of agronomic traits in flax. AB - BACKGROUND: Flax (Linum usitatissimum. L) is an ancient oilseed and natural fiber crop. It could be divided into three categories by use, namely oil flax, fiber flax and oil-fiber dual purpose (OF). Cultivated flax is widely used in the food and textile industry. It is of great significance to elucidate the genetic characteristics of flax collections for accelerating the process of breeding improvement in this dual purpose crop. With the development of next-generation sequencing, we can use new methods, such as SLAF-seq (specific-locus amplified fragment sequencing), to decode unknown genomes of species. In this study, a high through sequencing of flax collections using SLAF-seq was conducted. The evolutionary tendency was defined and candidate genes associated with agronomic traits of flax species were identified by Genome-Wide Association Studying (GWAS). RESULTS: A flax collection consisting of 224 varieties were sequenced by SLAF-seq. In total, 346,639 SLAF tags were developed from all accessions, with an average sequencing depth of 7.19 for each accession. A total of 584,987 SNPs (single nucleotide polymorphism) with an MAF > 0.05 were identified from these SLAFs. The population structure division and phylogenetic analysis indicated a strong divergence among three kinds of flax groups. The genome-wide variation uncovered that oil flax had the highest genetic diversity and was considered to be the ancestor of fiber flax and oil-fiber flax. Sixteen associated peak SNPs for six traits were obtained by GWAS of oil-related traits using EMMAX (efficient mixed-model association eXpedited). Candidate genes and their related pathway were evaluated. A new GWAS was developed for fiber properties using the GLM (General linear model) model and a number of loci were identified. CONCLUSIONS: To our knowledge, this is the first study on discovery multiple loci for important agronomic traits of flax species using GWAS strategy. These results will provide the highest possibility of incorporating both high fiber and good oil traits in a single variety. PMID- 29969985 TI - QTLs and eQTLs mapping related to citrandarins' resistance to citrus gummosis disease. AB - BACKGROUND: Phytophthora nicotianae Breda de Haan (Phytophthora parasitica Dastur) causes severe damage to citrus crops worldwide. A population of citrandarins was created from the cross between the susceptible parent Citrus sunki Hort. Ex Tan. and the resistant parent Poncirus trifoliata (L.) Raf. cv. Rubidoux, both parents and two reference rootstocks (Rangpur lime and Swingle citrumelo) were grafted in a greenhouse on Rangpur lime. Inoculations were performed at 10 cm and 15 cm above the grafting region and the resulting lesions were evaluated by measuring the lesion length 60 days after inoculation. As control, non-inoculated plants of each genotype were used. In addition, we evaluated the expression of 19 candidate genes involved in citrus defense response 48 h after pathogen infection by quantitative Real-Time PCR (qPCR). We mapped genomic regions of Quantitative Trait Loci (QTLs) and Expression Quantitative Trait Loci (eQTLs) associated with resistance to P. parasitica in the linkage groups (LGs) of the previously constructed maps of C. sunki and P. trifoliata. RESULTS: We found disease severity differences among the generated hybrids, with lesion lengths varying from 1.15 to 11.13 mm. The heritability of the character was 65%. These results indicate that there is a great possibility of success in the selection of resistant hybrids within this experiment. The analysis of gene expression profile demonstrated a great variation of responses regarding the activation of plant defense pathways, indicating that citrandarins have several defense strategies to control oomycete infection. The information of the phenotypic and gene expression data made possible to detect genomic regions associated with resistance. Three QTLs and 84 eQTLs were detected in the linkage map of P. trifoliata, while one QTL and 110 eQTLs were detected in C. sunki. CONCLUSIONS: This is the first study to use eQTLs mapping in the Phytophthora citrus interaction. Our results from the QTLs and eQTLs mapping allow us to conclude that the resistance of some citrandarins to the infection by P. parasitica is due to a favorable combination of QTLs and eQTLs transmitted by both parents. PMID- 29969984 TI - Asymmetric expression patterns reveal a strong maternal effect and dosage compensation in polyploid hybrid fish. AB - BACKGROUND: Hybridization and polyploidization are regarded as the major driving forces in plant speciation, diversification, and ecological adaptation. Our knowledge regarding the mechanisms of duplicated-gene regulation following genomic merging or doubling is primarily derived from plants and is sparse for vertebrates. RESULTS: We successfully obtained an F1 generation (including allodiploid hybrids and triploid hybrids) from female Megalobrama amblycephala Yih (BSB, 2n = 48) * male Xenocypri davidi Bleeker (YB, 2n = 48). The duplicated gene expression patterns of the two types of hybrids were explored using RNA-Seq data. In total, 5.44 * 108 (69.32 GB) clean reads and 499,631 assembled unigenes were obtained from the testis transcriptomes. The sequence similarity analysis of 4265 orthologs revealed that the merged genomes were dominantly expressed in different ploidy hybrids. The differentially expressed genes in the two types of hybrids were asymmetric compared with those in both parents. Furthermore, the genome-wide expression level dominance (ELD) was biased toward the maternal BSB genome in both the allodiploid and triploid hybrids. In addition, the dosage compensation mechanisms that reduced the triploid expression levels to the diploid state were determined in the triploid hybrids. CONCLUSIONS: Our results indicate that divergent genomes undergo strong interactions and domination in allopolyploid offspring. Genomic merger has a greater effect on the gene expression patterns than genomic doubling. The various expression mechanisms (including maternal effect and dosage compensation) in different ploidy hybrids suggest that the initial genomic merger and doubling play important roles in polyploidy adaptation and evolution. PMID- 29969986 TI - Trimodal distribution of arylamine N-acetyltransferase 1 mRNA in breast cancer tumors: association with overall survival and drug resistance. AB - BACKGROUND: Arylamine N-acetyltransferase 1 (NAT1) is a drug metabolizing enzyme that has been associated with cancer cell proliferation in vitro and with survival in vivo. NAT1 expression has been associated with the estrogen receptor and it has been proposed as a prognostic marker for estrogen receptor positive cancers. However, little is known about the distribution of NAT1 mRNA across an entire patient population or its effects on outcomes. To address this, gene expression data from breast cancer patient cohorts were investigated to identify sub-populations based on the level of NAT1 expression. Patient survival and drug response was examined to determine whether NAT1 mRNA levels influenced any of these parameters. RESULTS: NAT1 expression showed a trimodal distribution in breast cancer samples (n = 1980) but not in tumor tissue from ovarian, prostate, cervical or colorectal cancers. In breast cancer, NAT1 mRNA in each sub population correlated with a separate set of genes suggesting different mechanisms of NAT1 gene regulation. Kaplan-Meier plots showed significantly better survival in patients with highest NAT1 mRNA compared to those with intermediate or low expression. While NAT1 expression was elevated in estrogen receptor-positive patients, it did not appear to be dependent on estrogen receptor expression. Overall survival was analyzed in patients receiving no treatment, hormone therapy or chemotherapy. NAT1 expression correlated strongly with survival in the first 5 years in those patients receiving chemotherapy but did not influence survival in the other two groups. This suggests that low NAT1 expression is associated with chemo-resistance. The sensitivity of NAT1 mRNA levels as a single parameter to identify non-responders to chemotherapy was 0.58 at a log(2) < 6.5. CONCLUSIONS: NAT1 mRNA can be used to segregate breast cancer patients into sub-populations that demonstrate different overall survival. Moreover, low NAT1 expression shows a distinct poor response to chemotherapy. Analysis of NAT1 expression may be useful for identifying specific individuals who would benefit from alternative therapy or drug combinations. However, additional information is required to increase the sensitivity of identifying non responders. PMID- 29969988 TI - H4K20me3 co-localizes with activating histone modifications at transcriptionally dynamic regions in embryonic stem cells. AB - BACKGROUND: Bivalent chromatin domains consisting of the activating histone 3 lysine 4 trimethylation (H3K4me3) and repressive histone 3 lysine 27 trimethylation (H3K27me3) histone modifications are enriched at developmental genes that are repressed in embryonic stem cells but active during differentiation. However, it is unknown whether another repressive histone modification, histone 4 lysine 20 trimethylation (H4K20me3), co-localizes with activating histone marks in ES cells. RESULTS: Here, we describe the previously uncharacterized coupling of the repressive H4K20me3 heterochromatin mark with the activating histone modifications H3K4me3 and histone 3 lysine 36 trimethylation (H3K36me3), and transcriptional machinery (RNA polymerase II; RNAPII), in ES cells. These newly described bivalent domains consisting of H3K4me3/H4K20me3 are predominantly located in intergenic regions and near transcriptional start sites of active genes, while H3K36me3/H4K20me3 are located in intergenic regions and within gene body regions of active genes. Global sequential ChIP, also termed reChIP-Seq, confirmed the simultaneous presence of H3K4me3 and H4K20me3 at the same genomic regions in ES cells. Genes containing H3K4me3/H4K20me3 exhibit decreased RNAPII pausing and are poised for deactivation of RNAPII binding during differentiation relative to H3K4me3 marked genes. An evaluation of transcription factor (TF) binding motif enrichment revealed that DNA sequence may play a role in shaping the landscape of these novel bivalent domains. Moreover, H3K4me3/H4K20me3 and H3K36me3/H4K20me3 bound regions are enriched with repetitive LINE and LTR elements. CONCLUSIONS: Overall, these findings highlight a previously undescribed subnetwork of ES cell transcriptional circuitry that utilizes dual marking of the repressive H4K20me3 mark with activating histone modifications. PMID- 29969987 TI - Phylogeography and genetics of the globally invasive snail Physa acuta Draparnaud 1805, and its potential to serve as an intermediate host to larval digenetic trematodes. AB - BACKGROUND: Physa acuta is a globally invasive freshwater snail native to North America. Prior studies have led to conflicting views of how P. acuta populations are connected and genetic diversity is partitioned globally. This study aims to characterize phylogeographic and population genetic structure within the native range of P. acuta, elucidate its invasion history and assess global patterns of genetic diversity. Further, using meta-analytic methods, we test the 'Enemy Release hypothesis' within the P. acuta - digenetic trematode system. The 'Enemy Release hypothesis' refers to the loss of native parasites following establishment of their host within an invasive range. Population genetic data is combined with surveys of trematode infections to map range-wide trematode species richness associated with P. acuta, and to identify relevant host-population parameters important in modeling host-parasite invasion. RESULTS: Phylogenetic analyses using mtDNA uncovered two major clades (A & B). Clade A occurs globally while clade B was only recovered from the Western USA. All invasive populations sampled grouped within Clade A, where multiple independent source populations were identified from across North America. Significant population genetic structure was found within the native range of P. acuta, with some evidence for contemporary geographic barriers between western and eastern populations. Mito nuclear discordance was found suggesting historical isolation with secondary contact between the two mitochondrial clades. Trematode species richness was found to differ significantly between native and invasive populations, in concordance with the 'Enemy-Release hypothesis'. Further, our data suggests a positive relationship between nucleotide diversity of invasive populations and trematode prevalence and richness. CONCLUSIONS: This study includes a wider geographic sampling of P. acuta within its native range that provides insight into phylogeographic and population genetic structure, range-wide genetic diversity and estimation of the invasion history. Meta-analysis of P. acuta - trematode surveys globally is consistent with the 'Enemy-Release hypothesis'. Additionally, results from this study suggest that host demographic parameters, namely genetic diversity as a proxy for population size, may play an essential role in how parasite communities assemble within invasive host populations. This knowledge can be used to begin to construct a framework to model host-parasite invasion dynamics over time. PMID- 29969989 TI - Whole-exome sequencing identifies R1279X of MYH6 gene to be associated with congenital heart disease. AB - BACKGROUND: Myosin VI, encoded by MYH6, is expressed dominantly in human cardiac atria and plays consequential roles in cardiac muscle contraction and comprising the cardiac muscle thick filament. It has been reported that the mutations in the MYH6 gene associated with sinus venosus atrial septal defect (ASD type III), hypertrophic (HCM) and dilated (DCM) cardiomyopathies. METHODS: Two patients in an Iranian family have been identified who affected to Congenital Heart Disease (CHD). The male patient, besides CHD, shows that the thyroglossal sinus, refractive errors of the eye and mitral stenosis. The first symptoms emerged at the birth and diagnosis based on clinical features was made at about 5 years. The family had a history of ASD. For recognizing mutated gene (s), whole exome sequencing (WES) was performed for the male patient and variants were analyzed by autosomal dominant inheritance mode. RESULTS: Eventually, by several filtering processes, a mutation in MYH6 gene (NM_002471.3), c.3835C > T; R1279X, was identified as the most likely disease-susceptibility variant and then confirmed by Sanger sequencing in the family. The mutation frequency was checked out in the local databases. This mutation results in the elimination of the 660 amino acids in the C-terminal of Myosin VI protein, including the vital parts of the coiled coil structure of the tail domain. CONCLUSIONS: Our study represents the first case of Sinus venosus defect caused directly by MYH6 stop codon mutation. Our data indicate that by increase haploinsufficiency of myosin VI, c.3835C > T mutation with reduced penetrance could be associated with CHD. PMID- 29969990 TI - Effectiveness of a comprehensive interactive eHealth intervention on patient reported and clinical outcomes in patients with an implantable cardioverter defibrillator [ACQUIRE-ICD trial]: study protocol of a national Danish randomised controlled trial. AB - BACKGROUND: In Denmark and other countries, there has been a shift in the management of patients with an implantable cardioverter defibrillator (ICD) with remote device monitoring largely replacing in-hospital visits. Less patient-nurse and patient-physician interaction may lead to gaps in patients' quality of care and impede patients' adaptation to living successfully with the ICD. A comprehensive eHealth intervention that include goal-setting, monitoring of symptoms of depression, anxiety, and quality of life, psychological treatment, information provision, supportive tools, online dialogues with nursing staff and access to an online community network, may help fill these gaps and be particularly beneficial to patients who suffer from anxiety and depression. This study will evaluate the effectiveness of the ACQUIRE-ICD care innovation, a comprehensive and interactive eHealth intervention, on patient-reported and clinical outcomes. METHODS: The ACQUIRE-ICD study is a multicenter, prospective, two-arm, unblinded randomised controlled superiority trial that will enroll 478 patients implanted with a first-time ICD or ICD with cardiac synchronisation therapy (CRT-D) from the six implanting centers in Denmark. The trial will evaluate the clinical effectiveness and cost-effectiveness of the ACQUIRE-ICD care innovation, as add-on to usual care compared with usual care alone. The primary endpoint, device acceptance, assessed with the Florida Patient Acceptance Survey, is evaluated at 12 months' post implant. Secondary endpoints, evaluated at 12 and 24 months' post implant, include patient-reported outcomes, return to work, time to first ICD therapy and first hospitalisation, mortality and cost effectiveness. DISCUSSION: The effectiveness of a comprehensive and interactive eHealth intervention that relies on patient-centred and personalised tools offered via a web-based platform targeted to patients with an ICD has not been assessed so far. The ACQUIRE-ICD care innovation promotes and facilitates that patients become active participants in the management of their disease, and as such addresses the need for a more patient-centered disease-management approach. If the care innovation proves to be beneficial to patients, it may not only increase patient empowerment and quality of life but also free up time for clinicians to care for more patients. TRIAL REGISTRATION: The trial has been registered on https://clinicaltrials.gov/ct2/show/NCT02976961 on November 30, 2016 with registration number [ NCT02976961 ]. PMID- 29969991 TI - Limitations of alignment-free tools in total RNA-seq quantification. AB - BACKGROUND: Alignment-free RNA quantification tools have significantly increased the speed of RNA-seq analysis. However, it is unclear whether these state-of-the art RNA-seq analysis pipelines can quantify small RNAs as accurately as they do with long RNAs in the context of total RNA quantification. RESULT: We comprehensively tested and compared four RNA-seq pipelines for accuracy of gene quantification and fold-change estimation. We used a novel total RNA benchmarking dataset in which small non-coding RNAs are highly represented along with other long RNAs. The four RNA-seq pipelines consisted of two commonly-used alignment free pipelines and two variants of alignment-based pipelines. We found that all pipelines showed high accuracy for quantifying the expression of long and highly abundant genes. However, alignment-free pipelines showed systematically poorer performance in quantifying lowly-abundant and small RNAs. CONCLUSION: We have shown that alignment-free and traditional alignment-based quantification methods perform similarly for common gene targets, such as protein-coding genes. However, we have identified a potential pitfall in analyzing and quantifying lowly expressed genes and small RNAs with alignment-free pipelines, especially when these small RNAs contain biological variations. PMID- 29969992 TI - Identifying drug substances of screening tool for older persons' appropriate prescriptions for Japanese. AB - BACKGROUND: In 2015, the Japan Geriatric Society (JGS) updated "the Guidelines for Medical Treatment and its Safety in the elderly," accompanied with the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP J): "drugs to be prescribed with special caution" and "drugs to consider starting." The JGS proposed the STOPP-J to contribute to improving prescribing quality; however, each decision should be carefully based on medical knowledge. The STOPP-J shows examples of commonly prescribed drug substances, but not all relevant drugs. This research aimed to identify substances using such coding, as a standardized classification system would support medication monitoring and pharmacoepidemiologic research using such health-related information. METHODS: A voluntary team of three physicians and two pharmacists identified possible approved medicines based on the STOPP-J, and matched certain drug substances to the Anatomical Therapeutic Chemical Classification (ATC) and the Japanese price list as of 2017 February. Injectables and externally used drugs were excluded, except for self-injecting insulin, since the STOPP-J guidelines are intended to cover medicines used chronically for more than one month. Some vaccines are not available in the Japanese price list since they not reimbursed through the national health insurance. RESULTS: The ATC 5th level was not available for 39 of the 235 identified substances, resulting in their classification at the ATC 4th level. Furthermore, among 26 combinations, 10 products were matched directly to the ATC 5th level of the exact substances, and others were linked to the ATC representing the combination or divided into multiple substances for classification if the combination was not listed in the ATC. CONCLUSION: This initial work demonstrates the challenge of matching ATC codes and the Japan standard commodity classification codes corresponding to STOPP-J substances. Since coding facilitates database analysis, the proposed drug list could be applied to research using large databases to examine prescribing patterns in patients older than 75 years or who are frail. Since ATC is not available for some substances, Japanese medicines need the process to be registered in the ATC for an effective screening tool to be developed for STOPP-J. PMID- 29969993 TI - Estimating causal effects of time-dependent exposures on a binary endpoint in a high-dimensional setting. AB - BACKGROUND: Recently, the intervention calculus when the DAG is absent (IDA) method was developed to estimate lower bounds of causal effects from observational high-dimensional data. Originally it was introduced to assess the effect of baseline biomarkers which do not vary over time. However, in many clinical settings, measurements of biomarkers are repeated at fixed time points during treatment and, therefore, this method needs to be extended. The purpose of this paper is to extend the first step of the IDA, the Peter Clarks (PC) algorithm, to a time-dependent exposure in the context of a binary outcome. METHODS: We generalised the so-called "PC-algorithm" to take into account the chronological order of repeated measurements of the exposure and proposed to apply the IDA with our new version, the chronologically ordered PC-algorithm (COPC-algorithm). The extension includes Firth's correction. A simulation study has been performed before applying the method for estimating causal effects of time-dependent immunological biomarkers on toxicity, death and progression in patients with metastatic melanoma. RESULTS: The simulation study showed that the completed partially directed acyclic graphs (CPDAGs) obtained using COPC algorithm were structurally closer to the true CPDAG than CPDAGs obtained using PC-algorithm. Also, causal effects were more accurate when they were estimated based on CPDAGs obtained using COPC-algorithm. Moreover, CPDAGs obtained by COPC algorithm allowed removing non-chronological arrows with a variable measured at a time t pointing to a variable measured at a time t' where t' < t. Bidirected edges were less present in CPDAGs obtained with the COPC-algorithm, supporting the fact that there was less variability in causal effects estimated from these CPDAGs. In the example, a threshold of the per-comparison error rate of 0.5% led to the selection of an interpretable set of biomarkers. CONCLUSIONS: The COPC algorithm provided CPDAGs that keep the chronological structure present in the data and thus allowed to estimate lower bounds of the causal effect of time dependent immunological biomarkers on early toxicity, premature death and progression. PMID- 29969994 TI - Children with cyclic vomiting syndrome: phenotypes, disease burden and mitochondrial DNA analysis. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) is characterized by repeated, stereotypical vomiting episodes. It is possibly associated with mitochondrial DNA (mtDNA) variants. We examined the phenotype, disease burden, treatment and performed mtDNA analysis in pediatric CVS. METHODS: This retrospective study included 42 children with CVS in a tertiary care center. Information regarding medical history, clinical features, laboratory tests, and treatment were collected. mtDNA sequencing was performed among 13 patients. RESULTS: Mean age of onset among patients was 4.0+/-3.4 years, and mean age at diagnosis was 6.7+/-4.2 years. CVS episodes in onset and features were stereotypic. Recognizable prodromes were reported in 54.8% patients. Neuroimaging showed previously unknown intracranial abnormalities. Gastrointestinal infection was found in four patients. Mean duration of hospitalization was 7.0+/-2.4 days, and mean hospitalization cost was 10,891 RMB. Sequencing showed that 4/13 patients had C16519T mtDNA polymorphism, and 2/13 patients had G3010A mtDNA polymorphism. CONCLUSIONS: Cyclic vomiting syndrome is a disabling disorder, which causes huge disease burdens to the patients and their families. Early clinical suspicion and prompt diagnosis are crucial. mtDNA polymorphisms were found in some patients, but they were not significantly associated with pediatric CVS. PMID- 29969995 TI - Automated closed-loop management of body temperature using forced-air blankets: preliminary feasibility study in a porcine model. AB - BACKGROUND: Management of a patient's body temperature is an important aspect of care that should be addressed by targeted temperature management (TTM). Often, non-invasive methods like forced-air blankets are used. Especially in the operating room this management may be a subsidiary and repetitive task requiring constant observation of the patient's body temperature and adaption using the limited set of available settings. Thus, automation of TTM is a feasible target to improve patient outcome and reduce caregiver workload. METHODS: A Philips IntelliVue MP 50 patient monitor with an arterial PiCCO catheter system was used to measure patient blood temperature. Thermal management was performed with a 3M Bair Hugger 755 warming unit with forced air blankets. The warming unit was extended by a computer interface to allow for remote and automated control. A proposed closed-loop algorithm reads the measured temperature and performs automated control of the 3M Bair Hugger. Evaluation was performed in an experimental intensive care setting for animal studies. Two fully automated trials are compared with two manual and two uncontrolled trials in the same study setting using six female pigs for prolonged observation times of up to 90 hours in each trial. RESULTS: The developed system and proposed algorithm allow more precise temperature management by keeping a set target temperature within a range of +/- 0.5 degrees C in 88% of the observation time and within a range of +/- 1.0 degrees C at all times. The proposed algorithm yielded better performance than did manual control or uncontrolled trials. It was able to adapt to individual patient needs as it is more dynamic than look-up table approaches with fixed settings for various temperatures. CONCLUSIONS: Closed-loop TTM using non invasive forced-air warming blankets was successfully tested in a porcine study with the proposed hardware interface and control algorithm. This automation can be beneficial for patient outcome and can reduce caregiver workload and patient risk in clinical settings. As temperature readings are most often available, existing devices like the 3M Bair Hugger can easily be expanded. However, even if clinical application is feasible, open questions regarding approval and certification of such automated systems within the current legal situation still need to be answered. PMID- 29969996 TI - Telmisartan protects chronic intermittent hypoxic mice via modulating cardiac renin-angiotensin system activity. AB - BACKGROUND: To explore the effects of chronic intermittent hypoxia (CIH), which mimics sleep apnea syndrome, on the cardiac renin angiotensin system (RAS), and to investigate the cardiac protection of an angiotensin receptor blocker (ARB)telmisartan (TERT) against CIH. METHODS: 32 healthy male C57B6J mice were randomly divided into CIH, ARB, blank and air control groups. CIH lasted for 12 weeks. Cardiac angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE 2) and angiotensin II (Ang II) were evaluated by immunohistochemistry. Myocardial apoptosis were assessed by TUNEL assay and myocardial cell ultrastructure were observed under transmission electron microscope. RESULTS: Cardiac ACE expression was higher in the CIH group than in blank and air control groups, which was decreased with TERT treatment. TERT treatment elevated the expression of cardiac ACE 2 and Ang II compared with CIH group. Myocardial cell and capillary endothelial cell apoptosis, mitochondrial injury were most severe in CIH groups, which were mitigated with TERT treatment. CONCLUSIONS: CIH changes the expression of cardiac ACE, ACE2 and Ang II, which may cause myocardial damage. TERT protects mice from CIH-linked cardiac damage via modulating the activity of RAS in the hearts. PMID- 29969997 TI - Multimorbidity patterns with K-means nonhierarchical cluster analysis. AB - BACKGROUND: The purpose of this study was to ascertain multimorbidity patterns using a non-hierarchical cluster analysis in adult primary patients with multimorbidity attended in primary care centers in Catalonia. METHODS: Cross sectional study using electronic health records from 523,656 patients, aged 45-64 years in 274 primary health care teams in 2010 in Catalonia, Spain. Data were provided by the Information System for the Development of Research in Primary Care (SIDIAP), a population database. Diagnoses were extracted using 241 blocks of diseases (International Classification of Diseases, version 10). Multimorbidity patterns were identified using two steps: 1) multiple correspondence analysis and 2) k-means clustering. Analysis was stratified by sex. RESULTS: The 408,994 patients who met multimorbidity criteria were included in the analysis (mean age, 54.2 years [Standard deviation, SD: 5.8], 53.3% women). Six multimorbidity patterns were obtained for each sex; the three most prevalent included 68% of the women and 66% of the men, respectively. The top cluster included coincident diseases in both men and women: Metabolic disorders, Hypertensive diseases, Mental and behavioural disorders due to psychoactive substance use, Other dorsopathies, and Other soft tissue disorders. CONCLUSION: Non-hierarchical cluster analysis identified multimorbidity patterns consistent with clinical practice, identifying phenotypic subgroups of patients. PMID- 29969998 TI - Prevalence of rheumatic heart disease in Zambian school children. AB - BACKGROUND: The large global burden of rheumatic heart disease (RHD) has come to light in recent years following robust epidemiologic studies. As an operational research component of a broad program aimed at primary and secondary prevention of RHD, we sought to determine the current prevalence of RHD in the country's capital, Lusaka, using a modern imaging-based screening methodology. In addition, we wished to evaluate the practicality of training local radiographers in echocardiography screening methods. METHODS: Echocardiography was conducted on a random sample of students in 15 schools utilizing a previously validated, abbreviated screening protocol. Through a task-shifting scheme, and in the spirit of capacity-building to enhance local diagnostic and research skills, general radiographers based at Lusaka University Teaching Hospital (UTH) were newly trained to use portable echocardiography devices. Students deemed as screen positive were referred for comprehensive echocardiography and clinical examination at UTH. Cardiac abnormalities were classified according to standard World Heart Federation criteria. RESULTS: Of 1102 students that were consented and screened, 53 students were referred for confirmatory echocardiography. Three students had definite RHD, 10 had borderline RHD, 29 were normal, and 11 students were lost to follow-up. The rates of definite, borderline, and total RHD were 2.7 per 1000, 9.1 per 1000, and 11.8 per 1000, respectively. Anterior mitral valve leaflet thickening and chordal thickening were the most common morphological defects. The pairwise kappa test showed fair agreement between the local radiographers and an echocardiographer quality assurance specialist. CONCLUSION: The prevalence of asymptomatic RHD in urban communities in Zambia is within the range of results reported in other sub-Saharan African countries using the WHF criteria. Task-shifting local radiographers to conduct echocardiography was feasible. The results of this study will be used to inform ongoing efforts in Zambia to control and eventually eliminate RHD. TRIAL REGISTRATION: The study was registered on clinicaltrials.gov ( #NCT02661763 ). PMID- 29969999 TI - Expanding laparoscopic pancreaticoduodenectomy to pancreatic-head and periampullary malignancy: major findings based on systematic review and meta analysis. AB - BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) remains to be established as a safe and effective alternative to open pancreaticoduodenectomy (OPD) for pancreatic-head and periampullary malignancy. The purpose of this meta-analysis was to compare LPD with OPD for these malignancies regarding short-term surgical and long-term survival outcomes. METHODS: A literature search was conducted before March 2018 to identify comparative studies in regard to outcomes of both LPD and OPD for the treatment of pancreatic-head and periampullary malignancies. Morbidity, postoperative pancreatic fistula (POPF), mortality, operative time, estimated blood loss, hospitalization, retrieved lymph nodes, and survival outcomes were compared. RESULTS: Among eleven identified studies, 1196 underwent LPD, and 8247 were operated through OPD. The pooled data showed that LPD was associated with less morbidity (OR = 0.57, 95%CI: 0.41~ 0.78, P < 0.01), less blood loss (WMD = - 372.96 ml, 95% CI, - 507.83~ - 238.09 ml, P < 0.01), shorter hospital stays (WMD = - 197.49 ml, 95% CI, - 304.62~ - 90.37 ml, P < 0.01), and comparable POPF (OR = 0.85, 95%CI: 0.59~ 1.24, P = 0.40), and overall survival (HR = 1.03, 95%CI: 0.93~ 1.14, P = 0.54) compared to OPD. Operative time was longer in LPD (WMD = 87.68 min; 95%CI: 27.05~ 148.32, P < 0.01), whereas R0 rate tended to be higher in LPD (OR = 1.17; 95%CI: 1.00~ 1.37, P = 0.05) and there tended to be more retrieved lymph nodes in LPD (WMD = 1.15, 95%CI: -0.16~ 2.47, P = 0.08), but these differences failed to reach statistical significance. CONCLUSIONS: LPD can be performed as safe and effective as OPD for pancreatic head and periampullary malignancy with respect to both surgical and oncological outcomes. LPD is associated with less intraoperative blood loss and postoperative morbidity and may serve as a promising alternative to OPD in selected individuals in the future. PMID- 29970000 TI - Correction for retest effects across repeated measures of cognitive functioning: a longitudinal cohort study of postoperative delirium. AB - BACKGROUND: Few studies have compared methods to correct for retest effects or practice effects in settings where an acute event could influence test performance, such as major surgery. Our goal in this study was to evaluate the use of different methods to correct for the effects of practice or retest on repeated test administration in the context of an observational study of older adults undergoing elective surgery. METHODS: In a cohort of older surgical patients (N = 560) and a non-surgical comparison group (N = 118), we compared changes on repeated cognitive testing using a summary measure of general cognitive performance (GCP) between patients who developed post-operative delirium and those who did not. Surgical patients were evaluated pre-operatively and at 1, 2, 6, 12, and 18 months following surgery. Inferences from linear mixed effects models using four approaches were compared: 1) no retest correction, 2) mean-difference correction, 3) predicted-difference correction, and 4) model based correction. RESULTS: Using Approaches 1 or 4, which use uncorrected data, both surgical groups appeared to improve or remain stable after surgery. In contrast, Approaches 2 and 3, which dissociate retest and surgery effects by using retest-adjusted GCP scores, revealed an acute decline in performance in both surgical groups followed by a recovery to baseline. Relative differences between delirium groups were generally consistent across all approaches: the delirium group showed greater short- and longer-term decline compared to the group without delirium, although differences were attenuated after 2 months. Standard errors and model fit were also highly consistent across approaches. CONCLUSION: All four approaches would lead to nearly identical inferences regarding relative mean differences between groups experiencing a key post operative outcome (delirium) but produced qualitatively different impressions of absolute performance differences following surgery. Each of the four retest correction approaches analyzed in this study has strengths and weakness that should be evaluated in the context of future studies. Retest correction is critical for interpretation of absolute cognitive performance measured over time and, consequently, for advancing our understanding of the effects of exposures such as surgery, hospitalization, acute illness, and delirium. PMID- 29970001 TI - Plant organelle RNA editing and its specificity factors: enhancements of analyses and new database features in PREPACT 3.0. AB - BACKGROUND: Gene expression in plant chloroplasts and mitochondria is affected by RNA editing. Numerous C-to-U conversions, accompanied by reverse U-to-C exchanges in some plant clades, alter the genetic information encoded in the organelle genomes. Predicting and analyzing RNA editing, which ranges from only few sites in some species to thousands in other taxa, is bioinformatically demanding. RESULTS: Here, we present major enhancements and extensions of PREPACT, a WWW based service for analysing, predicting and cataloguing plant-type RNA editing. New features in PREPACT's core include direct GenBank accession query input and options to restrict searches to candidate U-to-C editing or to sites where editing has been documented previously in the references. The reference database has been extended by 20 new organelle editomes. PREPACT 3.0 features new modules "EdiFacts" and "TargetScan". EdiFacts integrates information on pentatricopeptide repeat (PPR) proteins characterized as site-specific RNA editing factors. PREPACT's editome references connect into EdiFacts, linking editing events to specific co-factors where known. TargetScan allows position-weighted querying for sequence motifs in the organelle references, optionally restricted to coding regions or sequences around editing sites, or in queries uploaded by the user. TargetScan is mainly intended to evaluate and further refine the proposed PPR-RNA recognition code but may be handy for other tasks as well. We present an analysis for the immediate sequence environment of more than 15,000 documented editing sites finding strong and different bias in the editome data sets. CONCLUSIONS: We exemplarily present the novel features of PREPACT 3.0 aimed to enhance the analyses of plant-type RNA editing, including its new modules EdiFacts integrating information on characterized editing factors and TargetScan aimed to analyse RNA editing site recognition specificities. PMID- 29970002 TI - HapCHAT: adaptive haplotype assembly for efficiently leveraging high coverage in long reads. AB - BACKGROUND: Haplotype assembly is the process of assigning the different alleles of the variants covered by mapped sequencing reads to the two haplotypes of the genome of a human individual. Long reads, which are nowadays cheaper to produce and more widely available than ever before, have been used to reduce the fragmentation of the assembled haplotypes since their ability to span several variants along the genome. These long reads are also characterized by a high error rate, an issue which may be mitigated, however, with larger sets of reads, when this error rate is uniform across genome positions. Unfortunately, current state-of-the-art dynamic programming approaches designed for long reads deal only with limited coverages. RESULTS: Here, we propose a new method for assembling haplotypes which combines and extends the features of previous approaches to deal with long reads and higher coverages. In particular, our algorithm is able to dynamically adapt the estimated number of errors at each variant site, while minimizing the total number of error corrections necessary for finding a feasible solution. This allows our method to significantly reduce the required computational resources, allowing to consider datasets composed of higher coverages. The algorithm has been implemented in a freely available tool, HapCHAT: Haplotype Assembly Coverage Handling by Adapting Thresholds. An experimental analysis on sequencing reads with up to 60 * coverage reveals improvements in accuracy and recall achieved by considering a higher coverage with lower runtimes. CONCLUSIONS: Our method leverages the long-range information of sequencing reads that allows to obtain assembled haplotypes fragmented in a lower number of unphased haplotype blocks. At the same time, our method is also able to deal with higher coverages to better correct the errors in the original reads and to obtain more accurate haplotypes as a result. AVAILABILITY: HapCHAT is available at http://hapchat.algolab.eu under the GNU Public License (GPL). PMID- 29970003 TI - Prediction of RNA-protein sequence and structure binding preferences using deep convolutional and recurrent neural networks. AB - BACKGROUND: RNA regulation is significantly dependent on its binding protein partner, known as the RNA-binding proteins (RBPs). Unfortunately, the binding preferences for most RBPs are still not well characterized. Interdependencies between sequence and secondary structure specificities is challenging for both predicting RBP binding sites and accurate sequence and structure motifs detection. RESULTS: In this study, we propose a deep learning-based method, iDeepS, to simultaneously identify the binding sequence and structure motifs from RNA sequences using convolutional neural networks (CNNs) and a bidirectional long short term memory network (BLSTM). We first perform one-hot encoding for both the sequence and predicted secondary structure, to enable subsequent convolution operations. To reveal the hidden binding knowledge from the observed sequences, the CNNs are applied to learn the abstract features. Considering the close relationship between sequence and predicted structures, we use the BLSTM to capture possible long range dependencies between binding sequence and structure motifs identified by the CNNs. Finally, the learned weighted representations are fed into a classification layer to predict the RBP binding sites. We evaluated iDeepS on verified RBP binding sites derived from large-scale representative CLIP seq datasets. The results demonstrate that iDeepS can reliably predict the RBP binding sites on RNAs, and outperforms the state-of-the-art methods. An important advantage compared to other methods is that iDeepS can automatically extract both binding sequence and structure motifs, which will improve our understanding of the mechanisms of binding specificities of RBPs. CONCLUSION: Our study shows that the iDeepS method identifies the sequence and structure motifs to accurately predict RBP binding sites. iDeepS is available at https://github.com/xypan1232/iDeepS . PMID- 29970004 TI - BROCKMAN: deciphering variance in epigenomic regulators by k-mer factorization. AB - BACKGROUND: Variation in chromatin organization across single cells can help shed important light on the mechanisms controlling gene expression, but scale, noise, and sparsity pose significant challenges for interpretation of single cell chromatin data. Here, we develop BROCKMAN (Brockman Representation Of Chromatin by K-mers in Mark-Associated Nucleotides), an approach to infer variation in transcription factor (TF) activity across samples through unsupervised analysis of the variation in DNA sequences associated with an epigenomic mark. RESULTS: BROCKMAN represents each sample as a vector of epigenomic-mark-associated DNA word frequencies, and decomposes the resulting matrix to find hidden structure in the data, followed by unsupervised grouping of samples and identification of the TFs that distinguish groups. Applied to single cell ATAC-seq, BROCKMAN readily distinguished cell types, treatments, batch effects, experimental artifacts, and cycling cells. We show that each variable component in the k-mer landscape reflects a set of co-varying TFs, which are often known to physically interact. For example, in K562 cells, AP-1 TFs were central determinant of variability in chromatin accessibility through their variable expression levels and diverse interactions with other TFs. We provide a theoretical basis for why cooperative TF binding - and any associated epigenomic mark - is inherently more variable than non-cooperative binding. CONCLUSIONS: BROCKMAN and related approaches will help gain a mechanistic understanding of the trans determinants of chromatin variability between cells, treatments, and individuals. PMID- 29970006 TI - A case report of myocarditis combined with hepatitis caused by herpes simplex virus. AB - BACKGROUND: Viral myocarditis presents with various symptoms, including fatal arrhythmia and cardiogenic shock, and may develop into chronic myocarditis and dilated cardiomyopathy in some patients. We report a case of viral myocarditis and hepatitis caused by herpes simplex virus. CASE PRESENTATION: A 20-year-old woman was admitted to our hospital with fever, fatigue, and anorexia. The initial investigation showed elevated liver enzyme levels and elevated creatine phosphokinase, and computed tomography showed diffuse swelling and internal heterogeneous image in the liver. These findings were consistent with acute hepatitis; therefore, we performed a liver biopsy, which showed parenchymal necrosis and lymphocytic infiltration. The night that the liver biopsy was performed, blood pressure gradually decreased and revealed cardiogenic shock. Electrocardiography showed diffuse ST-segment elevation, and echocardiography showed a dilated, spherical ventricle with reduced systolic function and pericardial effusion. An endomyocardial biopsy revealed lymphocyte infiltration of the myocardium, confirming acute myocarditis. After a few days, tests for immunoglobin M and immunoglobin G antibodies against herpes simplex virus were positive. CONCLUSIONS: We presented a rare case of myocarditis combined with hepatitis that was caused by herpes simplex virus. Acute myocarditis can occur concurrently with hepatitis, pancreatitis, nephritis, and encephalitis; thus, determining the presence of other infectious lesions is necessary to provide appropriate treatment for the patient. PMID- 29970005 TI - Medication review versus usual care to improve drug therapies in older inpatients not admitted to geriatric wards: a quasi-experimental study (RASP-IGCT). AB - BACKGROUND: Interdisciplinary geriatric consultation teams (IGCT) are regularly requested to provide comprehensive geriatric assessments in older inpatients. Our primary aim was to evaluate whether medication reviews increased the number of IGCT-provided drug-related recommendations. Secondary aims were to reduce the number of potentially inappropriate medications (PIMs), and to identify the acceptance rate of and determinants for the number of recommendations. METHODS: A before-after study was performed in older inpatients not admitted to acute geriatric wards. The before cohort received usual care (UC); the after cohort was subjected to the intervention (I), consisting of a systematic medication review, based on but not limited to the RASP (Rationalization of Home Medication by an Adjusted STOPP in Older Patients) list. The primary outcome measure was the number of IGCT-provided drug-related recommendations. Age, sex, Charlson Comorbidity Index, creatinine clearance and serum creatinine were ascertained upon enrolment. Following variables were determined on admission and at discharge: number of drugs and number as well as type of RASP-identified PIMs. Acceptance by ward-based physicians was also determined. Poisson regression was performed to identify determinants for the primary outcome measure. RESULTS: Fifty-nine participants were enrolled (nUC = 29; nI = 30). The intervention increased the number of drug-related recommendations from a median of 0 (IQR: 0 1) to 8 (IQR: 6.75-10) (p < 0.001). The median number of accepted recommendations differed significantly as well (UC vs. I: 0.0 (0.0-0.5) vs. 3.0 (0.0-5.3); p < 0.001). In the intervention cohort, patients were discharged with fewer drugs compared to admission (UC vs. I: 108.5%, IQR: 100.0-135.8% vs. 92%, IQR: 80.5 103.5%; p = 0.002). More RASP PIMs were discontinued in the intervention cohort, with a mean difference of 1.49 RASP PIMs (95% confidence interval (CI): 0.70, 2.23; p < 0.001). Regression analysis identified two determinants: allocation to the intervention cohort with an incidence rate ratio (IRR) of 14.1 (95% CI: 8.30, 23.8) and the number of preadmission drugs with an IRR of 1.06 (95% CI: 1.03, 1.09). CONCLUSIONS: A structured medication review as part of usual IGCT care may contribute to an increased detection of drug-related problems and help to further reduce polypharmacy in older inpatients, not admitted to acute geriatric care wards. TRIAL REGISTRATION: NCT02165618 , retrospectively registered June 17, 2014. PMID- 29970007 TI - Pain perception of older adults in nursing home and home care settings: evidence from China. AB - BACKGROUND: In the past decade, the number of long-term care (LTC) services for older adults in China has grown annually by an average of 10%. Older adults, their family members, and policymakers in China are concerned about patient outcomes in different care settings because older adults who have a similar functional status and LTC needs may choose either nursing home care or home care. The aim of this study was to compare pain perception in nursing home care and home care settings for physically dependent older adults in China. METHODS: Multi stage sampling method was used to recruit respondents aged 65 and older from Yichang City, China, in 2015. The researchers employed a two-step analytical strategy-zero-inflated ordered probit regression followed by propensity score matching method-to model the effect of contrasting residence types on pain perception. RESULTS: Zero-inflated ordered probit regression analysis with participants unmatched (n = 484) showed that compared with older adults who received home care, those who received nursing home care did not have more severe pain (beta = 0.088, SE = 0.196, p = 0.655). After propensity-score matching, the research found that older adults in the home care group perceived less pain compared with the nursing home group (beta = 0.489, SE = 0.169, p = 0.004). CONCLUSIONS: The older adults who received home care perceived significantly less pain than the nursing home residents. The pain of older adults may differ based on the type of LTC services and therapy intensity they received, and home care might lead to less pain and better comfort than nursing home care. PMID- 29970008 TI - Expanding the role of clinical pharmacists on interdisciplinary primary care teams for chronic pain and opioid management. AB - BACKGROUND: Facilitating appropriate and safe prescribing of opioid medications for chronic pain management in primary care is a pressing public health concern. Interdisciplinary team-based models of primary care are exploring the expansion of clinical pharmacist roles to support disease management for chronic conditions, e.g. pain. Our study aims to 1) identify roles clinical pharmacists can assume in primary care team based chronic pain care processes and 2) understand the barriers to assuming these expanded roles. METHODS: Setting: Veterans Health Administration (VA) has implemented an interdisciplinary team based model for primary care which includes clinical pharmacists. DESIGN: We employed an inductive two part qualitative approach including focus groups and semi-structured interviews with key informants. PARTICIPANTS: 60 members of VA primary care teams in two states participated in nine preliminary interdisciplinary focus groups where a semi-structured interview guide elucidated provider experiences with screening for and managing chronic pain. To follow up on emergent themes relating to clinical pharmacist roles, an additional 14 primary care providers and clinical pharmacists were interviewed individually. We evaluated focus group and interview transcripts using the method of constant comparison and produced mutually agreed upon themes. RESULTS: Clinical pharmacists were identified by primary care providers as playing a central role with the ongoing management of opioid therapy including review of the state prescription drug monitoring program, managing laboratory screening, providing medication education, promoting naloxone use, and opioid tapering. Specific barriers to clinical pharmacists role expansion around pain care include: limitations of scopes of practice, insufficient institutional support (low staffing, dedicated time, insufficient training, lack of interdisciplinary leadership support), and challenges and opportunities for disseminating clinical pharmacists' expanded roles. CONCLUSIONS: Expanding the role of the clinical pharmacist to collaborate with providers around primary care based chronic pain management is a promising strategy for improving pain management on an interdisciplinary primary care team. However, expanded roles have to be balanced with competing responsibilities relating to other conditions. Interdisciplinary leadership is needed to facilitate training, resources, adequate staffing, as well as to prepare both clinical pharmacists and the providers they support, about expanded clinical pharmacists' scopes of practice and capabilities. PMID- 29970009 TI - Assessment of the Feasibility of automated, real-time clinical decision support in the emergency department using electronic health record data. AB - BACKGROUND: The use of big data and machine learning within clinical decision support systems (CDSSs) has the potential to transform medicine through better prognosis, diagnosis and automation of tasks. Real-time application of machine learning algorithms, however, is dependent on data being present and entered prior to, or at the point of, CDSS deployment. Our aim was to determine the feasibility of automating CDSSs within electronic health records (EHRs) by investigating the timing, data categorization, and completeness of documentation of their individual components of two common Clinical Decision Rules (CDRs) in the Emergency Department. METHODS: The CURB-65 severity score and HEART score were randomly selected from a list of the top emergency medicine CDRs. Emergency department (ED) visits with ICD-9 codes applicable to our CDRs were eligible. The charts were reviewed to determine the categorization components of the CDRs as structured and/or unstructured, median times of documentation, portion of charts with all data components documented as structured data, portion of charts with all structured CDR components documented before ED departure. A kappa score was calculated for interrater reliability. RESULTS: The components of the CDRs were mainly documented as structured data for the CURB-65 severity score and HEART score. In the CURB-65 group, 26.8% of charts had all components documented as structured data, and 67.8% in the HEART score. Documentation of some CDR components often occurred late for both CDRs. Only 21 and 11% of patients had all CDR components documented as structured data prior to ED departure for the CURB 65 and HEART score groups, respectively. The interrater reliability for the CURB 65 score review was 0.75 and 0.65 for the HEART score. CONCLUSION: Our study found that EHRs may be unable to automatically calculate popular CDRs-such as the CURB-65 severity score and HEART score-due to missing components and late data entry. PMID- 29970010 TI - Concurrent validity and reliability of the Community Balance and Mobility scale in young-older adults. AB - BACKGROUND: With the growing number of young-older adults (baby-boomers), there is an increasing demand for assessment tools specific for this population, which are able to detect subtle balance and mobility deficits. Various balance and mobility tests already exist, but suffer from ceiling effects in higher functioning older adults. A reliable and valid challenging balance and mobility test is critical to determine a young-older adult's balance and mobility performance and to timely initiate preventive interventions. The aim was to evaluate the concurrent validity, inter- and intrarater reliability, internal consistency, and ceiling effects of a challenging balance and mobility scale, the Community Balance and Mobility Scale (CBM), in young-older adults aged 60 to 70 years. METHODS: Fifty-one participants aged 66.4 +/- 2.7 years (range, 60-70 years) were assessed with the CBM. The Fullerton Advanced Balance scale (FAB), 3 Meter Tandem Walk (3MTW), 8-level balance scale, Timed-Up-and-Go (TUG), and 7-m habitual gait speed were used to estimate concurrent validity, examined by Spearman correlation coefficient (rho). Inter- and intrarater reliability were calculated as Intra-class-correlations (ICC), and internal consistency by Cronbach alpha and item-total correlations (rho). Ceiling effects were determined by obtaining the percentage of participants reaching the highest possible score. RESULTS: The CBM significantly correlated with the FAB (rho = 0.75; p < .001), 3MTW errors (rho = - 0.61; p < .001), 3MTW time (rho = - 0.35; p = .05), the 8 level balance scale (rho = 0.35; p < .05), the TUG (rho = - 0.42; p < .01), and 7 m habitual gait speed (rho = 0.46, p < .001). Inter- (ICC2,k = 0.97), intrarater reliability (ICC3,k = 1.00) were excellent, and internal consistency (alpha = 0.88; rho = 0.28-0.81) was good to satisfactory. The CBM did not show ceiling effects in contrast to other scales. CONCLUSIONS: Concurrent validity of the CBM was good when compared to the FAB and moderate to good when compared to other measures of balance and mobility. Based on this study, the CBM can be recommended to measure balance and mobility performance in the specific population of young older adults. TRIAL REGISTRATION: Trial number: ISRCTN37750605 . (Registered on 21/04/2016). PMID- 29970011 TI - The inflammatory response and neuronal injury in Streptococcus suis meningitis. AB - BACKGROUND: Many of the currently used models of bacterial meningitis have limitations due to direct inoculation of pathogens into the cerebrospinal fluid or brain and a relatively insensitive assessment of long-term sequelae. The present study evaluates the utility of a Streptococcus (S.) suis intranasal infection model for the investigation of experimental therapies in meningitis. METHODS: We examined the brains of 10 piglets with S. suis meningitis as well as 14 control piglets by histology, immunohistochemistry and in-situ tailing for morphological alterations in the hippocampal dentate gyrus and microglial activation in the neocortex. RESULTS: In piglets with meningitis, the density of apoptotic neurons was significantly higher than in control piglets. Moreover, scoring of microglial morphology revealed a significant activation of these cells during meningitis. The slight increase in the density of dividing cells, young neurons and microglia observed in piglets suffering from meningitis was not statistically significant, probably because of the short time frame between onset of clinical signs and organ sampling. CONCLUSIONS: The morphological changes found during S. suis meningitis are in accordance with abnormalities in other animal models and human autopsy cases. Therefore, the pig should be considered as a model for evaluating effects of experimental therapeutic approaches on neurological function in bacterial meningitis. PMID- 29970013 TI - Tuberculous pneumonia-induced severe ARDS complicated with DIC in a female child: a case of successful treatment. AB - BACKGROUND: Tuberculous (TB) pneumonia can induce acute respiratory distress syndrome (ARDS). Although TB pneumonia is one of the causes of disease and death among children worldwide, the literature on TB pneumonia-induced ARDS is limited. We report herein on the successful treatment of a two-year-old female child with TB pneumonia-induced severe ARDS complicated with disseminated intravascular coagulation (DIC). CASE PRESENTATION: A two-year-old Vietnamese female child with sustained fever and cough for 20 days was transferred to our hospital. She had severe dyspnea and a chest X-ray showed bilateral infiltration without findings of heart failure. After tracheal intubation, her oxygenation index (OI) and PaO2/FiO2 (PF) ratio were 29 and 60 mmHg, respectively. Mycobacterium tuberculosis was detected by real-time polymerase chain reaction (rPCR) assay of tracheal lavage fluid. She was diagnosed as having severe ARDS that developed from TB pneumonia. Anti-tuberculous therapy and cardiopulmonary support were started. However, her respiratory condition deteriorated despite treatment with high-frequency oscillating ventilation (HFO), vasopressor support, and 1 g/kg of immunoglobulin. On the third day after admission, her International Society on Thrombosis and Hemostasis DIC score had increased to 5. Recombinant human soluble thrombomodulin (rTM) was administered to treat the DIC. After the administration of rTM was completed, OI gradually decreased, after which the mechanical ventilation mode was changed from HFO to synchronized intermittent mandatory ventilation. The DIC score also gradually decreased. Plasma levels of soluble receptor for advanced glycan end products (sRAGE) and high mobility group box 1 (HMGB-1), which are reported to be associated with ARDS severity, also decreased. In addition, inflammatory biomarkers, including interferon-gamma (IFN-gamma) and interleukin-6 (IL-6), decreased after the administration of rTM. Although severe ARDS (P/F ratio ? 100 mmHg) continued for 19 days, the patient's OI and P/F ratio improved gradually, and she was extubated on the 27th day after admission. The severe ARDS with DIC was successfully treated, and she was discharged from hospital on day 33 post-admission. CONCLUSIONS: We successfully treated a female child suffering from TB pneumonia-induced severe ARDS complicated with DIC using multimodal interventions. (338/350). PMID- 29970012 TI - Does discovery of differentially culturable M tuberculosis really demand a new treatment paradigm? Longitudinal analysis of DNA clearance from sputum. AB - BACKGROUND: According to the traditional tuberculosis (TB) treatment paradigm, the initial doses of treatment rapidly kill most Mycobacterium tuberculosis (Mtb) bacilli in sputum, yet many more months of daily treatment are required to eliminate a small, residual subpopulation of drug-tolerant bacilli. This paradigm has recently been challenged following the discovery that up to 90% of Mtb bacilli in sputum are culturable only with growth-factor supplementation. These "differentially culturable" bacilli are hypothesized to be more drug-tolerant than routinely culturable bacilli. This hypothesis implies an alternative paradigm in which TB treatment does not rapidly reduce the total Mtb population but only the small, routinely culturable subpopulation. To evaluate these competing paradigms, we developed a culture-independent method for quantifying the viable fraction of Mtb bacilli in sputum during treatment. METHODS: We used GeneXpert MTB/RIF to quantify Mtb DNA in sputa collected longitudinally from Ugandan adults taking standard 4-drug treatment for drug-susceptible pulmonary TB. We modeled GeneXpert cycle thresholds over time using nonlinear mixed-effects regression. We adjusted these models for clearance of DNA from killed-but-not-yet degraded bacilli, assuming clearance half-lives ranging from 0 to 1.25 days. We used a convolution integral to quantify DNA from viable bacilli only, and converted cycle thresholds to Mtb genomic equivalents. We replicated our results in a South African cohort. RESULTS: We enrolled 41 TB patients in Uganda. Assuming a DNA-clearance half-life of 0 days, genomic equivalents of viable sputum bacilli decreased by 0.22 log/day until 8.8 days, then by 0.07 log/day afterwards. Assuming a DNA-clearance half-life of 1.25 days, genomic equivalents of viable bacilli decreased by 0.36 log/day until 5.0 days, then by 0.06 log/day afterwards. By day 7, viable Mtb had decreased by 97.2-98.8%. We found similar results for 19 TB patients in South Africa. DISCUSSION: Using a culture independent method, we found that TB treatment rapidly eliminates most viable Mtb in sputum. These findings are incompatible with the hypothesis that differentially culturable bacilli are drug-tolerant. CONCLUSIONS: A culture independent method for measuring viable Mtb in sputum during treatment corroborates the traditional TB treatment paradigm in which a rapid bactericidal phase precedes slow, elimination of a small, residual bacillary subpopulation. PMID- 29970014 TI - Structured reporting of x-rays for atraumatic shoulder pain: advantages over free text? AB - BACKGROUND: To analyse structured and free text reports of shoulder X-ray examinations evaluating the quality of reports and potential contributions to clinical decision-making. METHODS: We acquired both standard free text and structured reports of 31 patients with a painful shoulder without history of previous trauma who received X-ray exams. A template was created for the structured report based on the template ID 0000154 (Shoulder X-ray) from radreport.org using online software with clickable decision trees with concomitant generation of structured semantic reports. All reports were evaluated regarding overall quality and key features: content, information extraction and clinical relevance. RESULTS: Two experienced orthopaedic surgeons reviewed and rated structured and free text reports of 31 patients independently. The structured reports achieved significantly higher median ratings in all key features evaluated (P < 0.001), including facilitation of information extraction (P < 0.001) and better contribution to subsequent clinical decision-making (P < 0.001). The overall quality of structured reports was significantly higher than in free text report (P < 0.001). CONCLUSIONS: A comprehensive structured template may be a useful tool to assist in clinical decision-making and is, thus, recommended for the reporting of degenerative changes regarding X-ray examinations of the shoulder. PMID- 29970015 TI - Case report: a thiazide diuretic to treat polyuria induced by tolvaptan. AB - BACKGROUND: Currently, the vasopressin V2 receptor antagonist tolvaptan is the only available treatment for autosomal dominant polycystic kidney disease (ADPKD), but there are tolerability issues due to aquaretic side-effects such as polyuria. A possible strategy to ameliorate these side-effects may be addition of a thiazide diuretic, this is an established treatment in nephrogenic diabetes insipidus, a condition where vasopressin V2 receptor function is absent. CASE PRESENTATION: We describe a 46-year-old male ADPKD-patient, who was prescribed tolvaptan, which caused polyuria of around 5 l per day. Hydrochlorothiazide was added to treat hypertension, which resulted in a marked decrease in urine production. While using tolvaptan, rate of eGFR decline was - 1.35 mL/min/1.73m2 per year, whereas after hydrochlorothiazide was initiated this was - 3.97 mL/minute/1.73m2 per year. CONCLUSIONS: This case report indicates that while addition of hydrochlorothiazide may improve tolerability of vasopressin V2 receptor antagonists, co-prescription should only be used with great scrutiny as it may decrease tolvaptan effect on rate of ADPKD disease progression. PMID- 29970017 TI - Late presentation to HIV/AIDS care at the Douala general hospital, Cameroon: its associated factors, and consequences. AB - BACKGROUND: The introduction of anti-retroviral treatment (ART) has significantly reduced mortality and morbidity associated with HIV/AIDS. While treatment at early stages of the disease is related to a better prognosis, late presentation (LP) to care is harmful to the infected person, the society and is more costly. We aimed to describe late presentation to HIV care, its associated factors and consequences in patients followed up in a tertiary hospital in Cameroon. METHODS: We retrospectively assessed patients' files between 1996 and 2014 at the Douala general hospital (DGH) HIV treatment centre. Late presentation (LP) to HIV care was defined as a CD4+ T cell count< 350 cells/mm3 or advanced clinical stages of the disease (WHO stages 3/4) at first presentation for care. We used logistic regression to study factors associated with late presentation and assessed occurrence of opportunistic infections and mortality at 3, 6 and 12 months after presentation to care. RESULTS: Of 1866 files studied, mean age was 40 (SD: 10) years, median CD4+ T cell count was 147 (IQR: 63-270) cells/mm3, 58.2% were at HIV clinical stages 3 and 4. The prevalence of late presentation to HIV care was 89.7% (95% CI: 88.2-91.0%) and remained above 80% from 1996 to 2014. Circumstances of diagnosis: prevention of mother to child transmission program/blood donation (OR = 0.16, 95% CI 0.10-0.29), having a positive partner (OR = 0.16, 95%CI = 0.10-0.26), and routine screening (OR = 0.13, 95%CI = 0.10 0.19) reduced the odds of presenting late compared to clinical suspicion. Students had lower odds of presenting late compared to people who had an employment (OR = 0.50, 95%CI = 0.26-0.98). Calendar time OR = 1.64, 95% CI = 1.08 2.48 for >=2010 vs. < 2005) increased the odds of late presentation. Mortality and opportunistic infections prevalence remained significantly higher in late presenters at 3, 6 and 12 months than in early presenters. CONCLUSION: Late presentation to HIV care is very high at the DGH and is related to poor outcome. More screening and sensitization campaigns should be carried out in the population to diagnose the disease at an earlier stage. PMID- 29970016 TI - Left ventricular hypertrophy in experimental chronic kidney disease is associated with reduced expression of cardiac Kruppel-like factor 15. AB - BACKGROUND: Left ventricular hypertrophy (LVH) increases the risk of death in chronic kidney disease (CKD). The transcription factor Kruppel-like factor 15 (KLF15) is expressed in the heart and regulates cardiac remodelling through inhibition of hypertrophy and fibrosis. It is unknown if KLF15 expression is changed in CKD induced LVH, or whether expression is modulated by blood pressure reduction using angiotensin converting enzyme (ACE) inhibition. METHODS: CKD was induced in Sprague-Dawley rats by subtotal nephrectomy (STNx), and rats received vehicle (n = 10) or ACE inhibition (ramipril, 1 mg/kg/day, n = 10) for 4 weeks. Control, sham-operated rats (n = 9) received vehicle. Cardiac structure and function and expression of KLF15 were assessed. RESULTS: STNx caused impaired kidney function (P < 0.001), hypertension (P < 0.01), LVH (P < 0.001) and fibrosis (P < 0.05). LVH was associated with increased gene expression of hypertrophic markers, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP, P < 0.01) and connective tissue growth factor (CTGF) (P < 0.05). Cardiac KLF15 mRNA and protein expression were reduced (P < 0.05) in STNx and levels of the transcription regulator, GATA binding protein 4 were increased (P < 0.05). Ramipril reduced blood pressure (P < 0.001), LVH (P < 0.001) and fibrosis (P < 0.05), and increased cardiac KLF15 gene (P < 0.05) and protein levels (P < 0.01). This was associated with reduced ANP, BNP and CTGF mRNA (all P < 0.05). CONCLUSION: This is the first evidence that loss of cardiac KLF15 in CKD induced LVH is associated with unchecked trophic and fibrotic signalling, and that ACE inhibition ameliorates loss of cardiac KLF15. PMID- 29970018 TI - Measurement of area difference ratio of Photoplethysmographic pulse wave in patients with pre-eclampsia. AB - BACKGROUND: Preeclampsia (PE) is associated with an increase in maternal arterial stiffness, which may be reflected by photoplethysmography (PPG) of the pulse wave. The aim of this study was to investigate area difference ratio (ADR), a novel parameter derived from PPG, in women with and without preeclampsia. METHODS: Patients with and without preeclampsia in the third trimester were enrolled. All patients had photoplethysmography of the pulse wave assessed. ADR was compared between the two groups. RESULTS: Seventy-two patients in the third trimester of gestation, of which 36 had preeclampsia and 36 did not, were enrolled. The ADR was lower in the preeclampsia group vs. the non-preeclampsia group (0.725 [IQR 0.681-0.779] vs. 0.752 [IQR 0.717-0.910], P < 0.01). CONCLUSIONS: Measuring the ADR through analyzing PPG of the pulse wave may be a useful diagnostic tool in patients with preeclampsia. PMID- 29970019 TI - Cerclage is associated with the increased risk of preterm birth in women who had cervical conization. AB - BACKGROUND: The aim of this study was to determine the effect of cerclage in women who underwent cervical conization. METHODS: Study data were collected from the Korea National Health Insurance Claims Database of the Health Insurance Review and Assessment Service for 2009-2013. Women who had a conization in 2009 and a subsequent first delivery between 2009 and 2013 in Korea were enrolled. RESULTS: Among the women who had conization in 2009, 1075 women had their first delivery between 2009 and 2013. A cerclage was placed in 161 of the women who were treated by conization. The rate of preterm birth was higher in the women who were treated with cerclage following a conization compared with those without cerclage (10.56 vs 4.27, p < 0.01, respectively). The multivariate regression analysis revealed that the women who were treated cerclage following a conization had an increased risk of preterm delivery compared with women without cerclage (odds ratio (OR), 2.6, 95% confidence interval (CI), 1.4-4.9). CONCLUSION: Our study showed that cerclage associated with an increased risk of preterm birth and preterm premature rupture of membranes in women who underwent conization. Further studies are required to clarify the mechanism by which cerclage affects the risk of preterm birth. PMID- 29970020 TI - Group B streptococcal colonization in mothers and infants in western China: prevalences and risk factors. AB - BACKGROUND: The epidemiology of maternal and infant Group B streptococcus (GBS) colonization is poorly understood in China. The aim of this study is to explore the prevalence and risk factors associated with maternal and infant GBS colonization in Western China. METHODS: From January 2017 to June 2017, a prospective study was conducted to estimate the maternal and infant GBS colonization rate by maternal rectovaginal and infant nasopharynx, ear canal and umbilical swab culture. Patient demographics, clinical characteristics and outcomes were collected. Chi-square and logistic regression analyses were used to examine the risk factors associated with GBS colonization of mothers and infants. RESULTS: The GBS colonization rate in mothers and infants was 6.1 and 0.7%, respectively. The vertical transmission rate was 7.6%. The early onset GBS infection rate was 0.58 per 1000 live births and mortality was 0.29 per 1000 live births. Age younger than 40 years (p = 0.040) and minority ethnic status (p = 0.049) were associated with higher GBS colonization rate in pregnant women. Positive GBS status in the mother prior to delivery (p < 0.001) as well as longer duration of membrane rupture (>=12 h) (p < 0.001) and longer labor (>=4 h) (p < 0.001) were all significant risk factors for GBS colonization in infants. Compared to infants without GBS colonization, infants colonized with GBS were more likely to have had a temperature of >=38 degrees C (p < 0.001), developed early onset infection (EOD) (p < 0.001), and been prescribed antibiotics (p < 0.001). Furthermore, infants with GBS were more likely to have been admitted to neonatal intensive unit (NICU) (p < 0.001) with a longer hospital length of stay (LOS) (p < 0.001). CONCLUSIONS: Maternal GBS colonization, longer duration of membrane rupture and labor were all major risk factors associated with GBS colonization in Chinese infants. Infant GBS colonization was associated with increased risk of EOD and NICU admission as well as longer LOS. PMID- 29970021 TI - FOXA1 and AR in invasive breast cancer: new findings on their co-expression and impact on prognosis in ER-positive patients. AB - BACKGROUND: The role of forkhead-box A1 (FOXA1) and Androgen receptor (AR) in breast cancer (BC) has been extensively studied. However, the prognostic role of their co-expression in Estrogen receptor positive (ER+) BC has not been investigated so far. The aim of the present study was thus to assess the co expression (protein and mRNA) of FOXA1 and AR in BC patients, in order to evaluate their prognostic impact according to ER status. METHODS: Immunohistochemical expression of AR and FOXA1 was evaluated on 479 consecutive BC, with complete clinical-pathological and follow up data. Fresh-frozen tissues from 65 cases were available. The expression of AR and FOXA1 with ER was validated using mRNA analyses. Survival and Cox proportional hazard analyses were used to evaluate the relationship between FOXA1, AR and prognosis. RESULTS: Expression of ER, AR and FOXA1 was observed in 78, 60 and 85% of cases respectively. Most AR+ cases (97%) were also FOXA1+. The level of FOXA1 mRNA positively correlated with level of both AR mRNA (r = 0.8975; P < 0.001) and ER mRNA (r = 0.7326; P < 0.001). In ER+ BC, FOXA1 was associated with a good prognosis independently of AR expression in the three subgroups analyzed (FOXA1+/AR+; FOXA1+/AR-; FOXA1-/AR-). Multivariate analyses confirmed that FOXA1 may provide more information than AR in Disease-Free Interval (DFI) of ER+ BC patients. CONCLUSION: Our results suggest that in BC the expression of FOXA1 is directly related to the expression of AR. Despite that, FOXA1 is found as superior predicting marker of recurrences compared to AR in ER+ BC patients. PMID- 29970022 TI - Improvements to the gastric cancer tumor-node-metastasis staging system based on computer-aided unsupervised clustering. AB - BACKGROUND: The Union for International Cancer Control (UICC) tumor-node metastasis (TNM) classification is a key gastric cancer prognosis system. This study aimed to create a new TNM system to provide a reference for the clinical diagnosis and treatment of gastric cancer. METHODS: A review of gastric cancer patients' records was conducted in The First Hospital of China Medical University and the Liaoning Cancer Hospital and Institute. Based on patients' prognoses data, computer-aided unsupervised clustering was performed for all possible TNM staging situations to create a new staging division system. RESULTS: The primary outcome measure was 5-year survival, analyzed according to TNM classifications. Computer-aided unsupervised clustering for all TNM staging situations was used to create TNM division criteria that were more consistent with clinical situations. Furthermore, unsupervised clustering for the number of lymph node metastasis in the N stage led to the formulation of a classification method that differs from the existing N stage criteria, and unsupervised clustering for tumor size provided an additional reference for prognosis estimates. CONCLUSIONS: Finally, we developed a TNM staging system based on the computer-aided unsupervised clustering method; this system was more in line with clinical prognosis data when compared with the 7th edition of UICC gastric cancer TNM classification. PMID- 29970024 TI - Antibiotic resistance and molecular characterization of the hydrogen sulfide negative phenotype among diverse Salmonella serovars in China. AB - BACKGROUND: Among 2179 Salmonella isolates obtained during national surveillance for salmonellosis in China from 2005 to 2013, we identified 46 non-H2S-producing strains originating from different sources. METHODS: The isolates were characterized in terms of antibiotic resistance and genetic variability by pulsed field gel electrophoresis and multilocus sequence typing. Mutation in the phs operon, which may account for the non-H2S-producing phenotype of the isolated Salmonella strains, was performed in this study. RESULTS: Among isolated non-H2S producing Salmonella strains, more than 50% were recovered from diarrhea patients, of which H2S-negative S. Gallinarum, S. Typhimurium, S. Choleraesuis and S. Paratyphi A isolates constituted 76%. H2S-negative isolates exhibited a high rate of resistance to ticarcillin, ampicillin, and tetracycline, and eight of them had the multidrug resistance phenotype. Most H2S-negative Salmonella isolates had similar pulsed-field gel electrophoresis profiles and the same sequence type as H2S-positive strains, indicating a close origin, but carried mutations in the phsA gene, which may account for the non-H2S-producing phenotype. CONCLUSIONS: Our data indicate that multiple H2S-negative strains have emerged and persist in China, emphasizing the necessity to implement efficient surveillance measures for controlling dissemination of these atypical Salmonella strains. PMID- 29970025 TI - Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma. AB - BACKGROUND: Anti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure. METHODS: This was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS). RESULTS: Seventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3-3.9; p = 0.003) and 2.5 (95%CI:1.3 4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid death (<=3 months) was significantly higher in BRAF-mutated patients (55.2% vs. 20.0%, p = 0.014). DISCUSSION: This is the largest series of unselected patients treated in real life with anti-PD-1 as second-or-higher line of treatment. Anti-PD-1 was less effective in BRAF-mutated cases as a majority of patients presented aggressive tumor evolution after BRAFi discontinuation. These data are consistent with previous studies suggesting a negative impact of BRAFi prior to immunotherapy. PMID- 29970026 TI - Prediction of pre-eclampsia and its subtypes in high-risk cohort: hyperglycosylated human chorionic gonadotropin in multivariate models. AB - BACKGROUND: The proportion of hyperglycosylated human chorionic gonadotropin (hCG h) to total human chorionic gonadotropin (%hCG-h) during the first trimester is a promising biomarker for prediction of early-onset pre-eclampsia. We wanted to evaluate the performance of clinical risk factors, mean arterial pressure (MAP), %hCG-h, hCGbeta, pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and mean pulsatility index of the uterine artery (Uta-PI) in the first trimester in predicting pre-eclampsia (PE) and its subtypes early-onset, late-onset, severe and non-severe PE in a high-risk cohort. METHODS: We studied a subcohort of 257 high-risk women in the prospectively collected Prediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction (PREDO) cohort. Multivariate logistic regression was used to construct the prediction models. The first model included background variables and MAP. Additionally, biomarkers were included in the second model and mean Uta-PI was included in the third model. All variables that improved the model fit were included at each step. The area under the curve (AUC) was determined for all models. RESULTS: We found that lower levels of serum PlGF concentration were associated with early-onset PE, whereas lower %hCG-h was associated with the late-onset PE. Serum PlGF was lower and hCGbeta higher in severe PE, while %hCG-h and serum PAPP-A were lower in non severe PE. By using multivariate regression analyses the best prediction for all PE was achieved with the third model: AUC was 0.66, and sensitivity 36% at 90% specificity. Third model also gave the highest prediction accuracy for late onset, severe and non-severe PE: AUC 0.66 with 32% sensitivity, AUC 0.65, 24% sensitivity and AUC 0.60, 22% sensitivity at 90% specificity, respectively. The best prediction for early-onset PE was achieved using the second model: AUC 0.68 and 20% sensitivity at 90% specificity. CONCLUSIONS: Although the multivariate models did not meet the requirements to be clinically useful screening tools, our results indicate that the biomarker profile in women with risk factors for PE is different according to the subtype of PE. The heterogeneous nature of PE results in difficulty to find new, clinically useful biomarkers for prediction of PE in early pregnancy in high-risk cohorts. TRIAL REGISTRATION: International Standard Randomised Controlled Trial number ISRCTN14030412 , Date of registration 6/09/2007, retrospectively registered. PMID- 29970027 TI - Age and sex differences in emergency department visits of nursing home residents: a systematic review. AB - BACKGROUND: Nursing home residents (NHRs) are often transferred to emergency departments (EDs). A great proportion of ED visits is considered inappropriate. There is evidence that male NHRs are more often hospitalised, but this is less clear for ED visits. It is unclear, which influence age has on ED visits. We aimed to study the epidemiology of ED visits in NHRs focusing on age- and sex specific differences. METHODS: A systematic review was carried out based on articles found in MEDLINE (via PubMed), CINAHL and Scopus. Articles published on or before Aug 31, 2017 were eligible. Two reviewers independently identified articles for inclusion. The quality of studies was assessed by the Joanna Briggs Institute critical appraisal tool for prevalence studies. RESULTS: Out of 1192 references, we found seven studies meeting our inclusion criteria. Six studies were conducted in the USA or Canada. Overall, 29-62% of NHRs had at least one ED visit over the course of 1 year. Most studies assessing the influence of sex found that male residents visited EDs more frequently. All but one of the five studies with multivariable analyses reported a statistically significant positive association (with odds or rate ratios of 1.05-1.38). All studies assessed the influence of age. There was no clear pattern with some studies showing no association between ED visits and age and other studies reporting decreasing ED visits with increasing age or increasing proportions followed by a decrease in the highest age group. Studies used 85+ or 86+ years as the highest age category. Hospital admission rate ranged from 36.4 to 48.7%. There was no study reporting stratified analyses by age and sex. Only one study reported main diagnoses leading to ED visits stratified by sex. CONCLUSION: Male NHRs visit EDs more often than females, but there is no evidence on reasons. The association with age is unclear. Any future study on acute care of NHRs should assess the influence of age and sex. These studies should include large sample sizes to provide a more differentiated age categorisation. TRIAL REGISTRATION: PROSPERO CRD42017074845 . PMID- 29970028 TI - The effects of pre-existing dementia on surgical outcomes in emergent and nonemergent general surgical procedures: assessing differences in surgical risk with dementia. AB - BACKGROUND: The aim was to assess the morbidity and in-hospital mortality that occur in surgical patients with pre-existing dementia compared with those outcomes in non-dementia patients following emergent and nonemergent general surgical operations. METHODS: A total of 120 patients with dementia were matched for sex and type of surgery with 120 patients who did not have dementia, taken from a cohort of 15,295 patients undergoing surgery, in order to assess differences in surgical risk with dementia. Patient information was examined, including sex, body mass index (BMI), prevalence of individual comorbidities at admission, and several other variables that may be associated with postoperative outcomes as potential confounders. RESULTS: Patients with dementia tended to have a higher overall complication burden compared to those without. This was evidenced by a higher average number of complications per patient (3.30 vs 2.36) and a higher average score on the comprehensive complication index (48.61 vs 37.60), values that were statistically significant for a difference between the two groups. The overall in-hospital mortality in patients with dementia was 28.3% (34 deaths out of 120 patients). During the same period, at our hospital, the overall in-hospital mortality in the control group was 20% (24 deaths out of 120 patients). Patient groups with and without dementia each had 3 and 5 associated risk factors for morbidity and 9 and 12 risk factors for mortality, respectively. CONCLUSIONS: Patients with pre-existing dementia have a greater than average risk of early death after surgery, and their incidence of fatal complications is higher than that of surgical patients without dementia. PMID- 29970023 TI - Community Assessment of COPD Health Care (COACH) study: a clinical audit on primary care performance variability in COPD care. AB - BACKGROUND: A thorough evaluation of the adequacy of clinical practice in a designated health care setting and temporal context is key for clinical care improvement. This study aimed to perform a clinical audit of primary care to evaluate clinical care delivered to patients with COPD in routine clinical practice. METHODS: The Community Assessment of COPD Health Care (COACH) study was an observational, multicenter, nationwide, non-interventional, retrospective, clinical audit of randomly selected primary care centers in Spain. Two different databases were built: the resources and organization database and the clinical database. From January 1, 2015 to December 31, 2016 consecutive clinical cases of COPD in each participating primary care center (PCC) were audited. For descriptive purposes, we collected data regarding the age at diagnosis of COPD and the age at audit, gender, the setting of the PCC (rural/urban), and comorbidities for each patient. Two guidelines widely and uniformly used in Spain were carefully reviewed to establish a benchmark of adequacy for the audited cases. Clinical performance was analyzed at the patient, center, and regional levels. The degree of adequacy was categorized as excellent (> 80%), good (60 80%), adequate (40-59%), inadequate (20-39%), and highly inadequate (< 20%). RESULTS: During the study 4307 cases from 63 primary care centers in 6 regions of the country were audited. Most evaluated parameters were judged to fall in the inadequate performance category. A correct diagnosis based on previous exposure plus spirometric obstruction was made in an average of 17.6% of cases, ranging from 9.8 to 23.3% depending on the region. During the audited visit, only 67 (1.6%) patients had current post-bronchodilator obstructive spirometry; 184 (4.3%) patients had current post-bronchodilator obstructive spirometry during either the audited or initial diagnostic visit. Evaluation of dyspnea was performed in 11.1% of cases. Regarding treatment, 33.6% received no maintenance inhaled therapies (ranging from 31.3% in GOLD A to 7.0% in GOLD D). The two most frequently registered items were exacerbations in the previous year (81.4%) and influenza vaccination (87.7%). CONCLUSIONS: The results of this audit revealed a large variability in clinical performance across centers, which was not fully attributable to the severity of the disease. PMID- 29970030 TI - Effect of different delivery modes on the short-term strength of the pelvic floor muscle in Chinese primipara. AB - BACKGROUND: To investigate the effect of different delivery modes and related obstetric factors on the short-term strength of the pelvic floor muscle after delivery in Chinese primipara. METHODS: A total of 4769 healthy Chinese primiparas at postpartum 6-8 weeks were interviewed. According to the difference of delivery mode, the selected primiparas were divided into 2 groups, including cesarean delivery group containing 2020 and vaginal delivery group containing 2749. All the vaginal deliveries were further divided into 3 groups, including episiotomy group containing 2279, perineal laceration group containing 398, and forceps assisted group containing72. The scales of their pelvic floor muscle (PFM) strengths were examined by specially trained personnel using digital palpation (Modified Oxford scale:0-5 grade). According to participants' willingness, if the PFM strength was weak (0 or 1 grade), at-home PFM training would be recommended and an electrical stimulation combined with biofeedback therapy would be conducted for them in hospital. Twelve weeks after delivery, the PFM strength would be measured again. For statistical analysis, t-test, one-way variance analysis, Chi-square analysis, Kruskal-Wallis test H, Mann-Whitney U test and Wilcoxon test were carried out. RESULTS: The PFM strength in cesarean delivery group was higher than in vaginal delivery group (p < 0.05). Among 3 vaginal delivery groups, the PFM strength in perineal laceration group was the highest (p < 0.05); however, there was no difference in PFM strength between episiotomy group and forceps assisted group (p>0.05). After accepting PFM training at home and therapy in hospital, 305 women showed increased PFM strength (p < 0.05). CONCLUSIONS: Vaginal delivery is an independent risk factor causing the damage of PFM, and episiotomy may cause injury of PFM. Through PFM training at home and therapy in hospital, those damage will resume as soon as possible in the short-time period after delivery. PMID- 29970029 TI - Mothers' reproductive and medical history misinformation practices as strategies against healthcare providers' domination and humiliation in maternal care decision-making interactions: an ethnographic study in Southern Ghana. AB - BACKGROUND: Pregnant women can misinform or withhold their reproductive and medical information from providers when they interact with them during care decision-making interactions, although, the information clients reveal or withhold while seeking care plays a critical role in the quality of care provided. This study explored 'how' and 'why' pregnant women in Ghana control their past obstetric and reproductive information as they interact with providers at their first antenatal visit, and how this influences providers' decision making at the time and in subsequent care encounters. METHODS: This research was a case-study of two public hospitals in southern Ghana, using participant observation, conversations, interviews and focus group discussions with antenatal, delivery, and post-natal clients and providers over a 22-month period. The Ghana Health Service Ethical Review Committee gave ethical approval for the study (Ethical approval number: GHS-ERC: 03/01/12). Data analysis was conducted according to grounded theory. RESULTS: Many of the women in this study selectively controlled the reproductive, obstetric and social history information they shared with their provider at their first visit. They believed that telling a complete history might cause providers to verbally abuse them and they would be regarded in a negative light. Examples of the information controlled included concealing the actual number of children or self-induced abortions. The women adopted this behaviour as a resistance strategy to mitigate providers' disrespectful treatment through verbal abuses and questioning women's practices that contradicted providers' biomedical ideologies. Secondly, they utilised this strategy to evade public humiliation because of inadequate privacy in the hospitals. The withheld information affected quality of care decision-making and care provision processes and outcomes, since misinformed providers were unaware of particular women's risk profile. CONCLUSION: Many mothers in this study withhold or misinform providers about their obstetric, reproductive and social information as a way to avoid receiving disrespectful maternal care and protect their privacy. Improving provider client relationship skills, empowering clients and providing adequate infrastructure to ensure privacy and confidentiality in hospitals, are critical to the provision of respectful maternal care. PMID- 29970032 TI - Minimal change disease associated with anti-PD1 immunotherapy: a case report. AB - BACKGROUND: Oncologic immunotherapy is a form of therapy intended to reactivate the immune response to tumor cells using agents that modulate immune checkpoints, such as programmed cell death protein 1 and its ligand (PD-1/PD-L), and cytotoxic T-lymphocyte-associated antigen 4. Along with activation of the immune system to tumors, immune-mediated kidney side effects have been reported, most of which are cases of interstitial nephritis. Glomerular disease, however, appears rare. CASE PRESENTATION: Herein, we describe a patient with nephrotic syndrome related to treatment with an anti-PD1 antibody for Hodgkin lymphoma. Following the third dose of anti-PD1 antibody, the patient developed massive proteinuria and nephrotic syndrome. Kidney biopsy showed diffuse podocyte foot process effacement upon electron microscopy, which was consistent with minimal change disease. Corticosteroid treatment yielded full and rapid remission of nephrotic syndrome in 1 month. CONCLUSION: The present case suggests an association between anti-PD1 therapeutic immune activation and the development of nephrotic syndrome. Given the increasing prevalence of oncologic immunotherapy, patients should be routinely monitored for kidney side effects associated with these agents. PMID- 29970031 TI - Mutant p53 gain of function induces HER2 over-expression in cancer cells. AB - BACKGROUND: HER2 over-expression is related with a poor prognosis in patients with invasive breast cancer tumors. Clinical associations have reported that somatic mutations of p53 more frequently detected in cases of sporadic breast cancer of the HER2 subtypes, besides a high percentage of HER2-amplifying tumors carry germline mutations of p53. The mechanisms responsible for the acquisition of oncogenic functions of p53 mutant proteins (mtp53), known as Gain of Function (GOF), over HER2 expression have not been reported. The objective of this study was to evaluate a possible relationship between p53 mutants and HER2 regulation. METHODS: HER2 expression (transcription and protein), as well as HER2 protein stabilization have been evaluated after inducing or silencing of p53 mutants' expression in cell lines. Finally, we evaluated the interaction of the p53 mutants over the HER2 receptor promoter. RESULTS: Higher HER2 expression in cell lines harboring endogenous mtp53 compared with wt or null expression of p53 cell lines. Transfection of p53 mutants (R248Q and R273C) in cell lines increased the expression of HER2. Silencing of p53 mutants, decrease HER2 expression. The p53 mutants R248Q and R273C significantly increase the luciferase activity on the HER2 promoter, and both mutants also promote acetylation of H3 and H4 histones binding in it. CONCLUSIONS: These findings show for the first time that p53 mutants induce over-expression of HER2 at transcriptional level of the HER2 protein. Our results could have clinical implications in breast cancer and other types of cancer where HER2 is over-expressed and used as a therapy target. PMID- 29970033 TI - Effect of early and intensive nutrition care, delivered via telephone or mobile application, on quality of life in people with upper gastrointestinal cancer: study protocol of a randomised controlled trial. AB - BACKGROUND: A major challenge for those living with cancers of the upper gastrointestinal tract (oesophagus, stomach and pancreas), is the impact of the disease and treatment on nutritional status and quality of life. People with cancer and malnutrition have a greater risk of morbidity and mortality. Nutrition intervention is recommended to commence immediately in those who are malnourished or at risk of malnutrition. Novel cost-effective approaches that can deliver early, pre-hospital nutrition intervention before usual hospital dietetic service is commenced are needed. Linking clinicians and patients via mobile health (mHealth) and wireless technologies is a contemporary solution not yet tested for delivery of nutrition therapy to people with cancer. The aim of this study is to commence nutrition intervention earlier than usual care and evaluate the effects of using the telephone or mHealth for intervention delivery. It is hypothesised that participants allocated to receive the early and intensive pre-hospital dietetic service will have more quality-adjusted life years lived compared with control participants. This study will also demonstrate the feasibility and effectiveness of mHealth for the nutrition management of patients at home undergoing cancer treatment. METHODS: This study is a prospective three-group randomised controlled trial, with a concurrent economic evaluation. The 18 week intervention is provided in addition to usual care and is delivered by two different modes, via telephone (group 1) or via mHealth (group 2), The control group receives usual care alone (group 3). The intervention is an individually tailored, symptom-directed nutritional behavioural management program led by a dietitian. Participants will have at least fortnightly reviews. The primary outcome is quality adjusted life years lived and secondary outcomes include markers of nutritional status. Outcomes will be measured at three, six and 12 months follow up. DISCUSSION: The findings will provide evidence of a strategy to implement early and intensive nutrition intervention outside the hospital setting that can favourably impact on quality of life and nutritional status. This patient-centred approach is relevant to current health service provision and challenges the current reactive delivery model of care. TRIAL REGISTRATION: 27th January 2017 Australian and New Zealand Clinical Trial Registry ( ACTRN12617000152325 ). PMID- 29970034 TI - Familial risks in and between stone diseases: sialolithiasis, urolithiasis and cholelithiasis in the population of Sweden. AB - BACKGROUND: According to the literature the three stone diseases, sialolithiasis (SL), urolithiasis (UL) and cholelithiasis (CL) share comorbidities. We assess familial and spouse risks between these stone disease and compare them to familial risks for concordant (same) stone disease. METHODS: Study population including familiar relationships was obtained from the Swedish Multigeneration Register and stone disease patients were identified from nation-wide medical records. Standardized incidence ratios (SIRs) were calculated for 0-83 year old offspring when their first-degree relatives were diagnosed with stone disease and the rates were compared to individuals without a family history of stone disease. Numbers of offspring with SL were 7906, for UL they were 170,757 and for CL they were 204,369. RESULTS: SIRs for concordant familial risks were 2.06 for SL, 1.94 for UL and 1.82 for CL. SIRs for SL and UL were slightly higher for women than for men. Familial risks between stone diseases were modest. The highest risk of 1.17 was for UL when family members were diagnosed with CL, or vice versa. The SIR for UL was 1.15 when family members were diagnosed with SL. Familial risks among spouses were increased only for UL-CL pairs (1.10). CONCLUSIONS: Familial risks for concordant SL were 2.06 and marginally lower for the other diseases. Familial risks between stone diseases were low but higher than risks between spouses. The data show that familial clustering is unique to each individual stone disease which would imply distinct disease mechanisms. The results cast doubt on the reported comorbidities between these diseases. PMID- 29970036 TI - Aberrant Promoter Methylation of YAP Gene and its Subsequent Downregulation in Indian Breast Cancer Patients. AB - BACKGROUND: YAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. Despite various studies, the role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. Therefore in the present study we aimed to investigate YAP at DNA, mRNA and protein level and also attempted to correlate our molecular findings with various clinicopathological variables of the patients. METHODS: The study comprised of a total 137 genetically unrelated women with sporadic breast cancer cases and normal adjacent tissues not infiltrated with tumor. Mutation of YAP gene was analyzed by automated DNA sequencing. YAP promoter methylation was studied using MS-PCR. Expression at mRNA and protein level was studied using qPCR and IHC respectively. RESULTS: In our study YAP mRNA expression was found to be 8.65 +/- 6.17 fold downregulated in 67.15% cases. The expression of YAP when analyzed at the protein level by IHC was found to be absent in 78.83% cases. Results from MS-PCR analysis showed that YAP promoter methylation plays an important role in declining the expression of YAP protein. The absence of YAP protein coincided with 86.60% methylated cases thereby showing a very strong correlation (p = 0.001). We also investigated YAP mutation at the major check point sites in the Hippo pathway and observed no mutation. A significant association was observed on correlating mRNA expression with clinical stages (p = 0.038) and protein expression with ER status (p = 0.018) among Indian breast cancer patients. CONCLUSION: The expression of YAP was found to be downregulated in response to aberrant promoter methylation. The downregulation of YAP are consistent with previous studies suggesting it to have a tumor suppressive role in breast cancer. We did not observe any mutation at the major check point sites in the Hippo pathway. PMID- 29970037 TI - Co-infection with hepatitis B virus among tuberculosis patients is associated with poor outcomes during anti-tuberculosis treatment. AB - BACKGROUND: Tuberculosis (TB) and chronic Hepatitis B virus (HBV) infection are common in China. Fist-line anti-TB medications often produce drug-induced liver injury (DILI). This study sought to investigate whether TB patients with chronic HBV co-infection are more susceptible to liver failure and poor outcomes during anti-TB treatment. METHODS: Eighty-four TB patients developed DILI during anti-TB treatment and were enrolled, including 58 with chronic HBV co-infection (TB-HBV group) and 26 with TB mono-infection (TB group). Clinical data and demographic characteristics were reviewed. The severity of DILI and incidences of liver failure and death were compared. Risk factors of clinical outcomes were defined. RESULTS: The patterns of DILI were similar in both groups. Compared with patients in the TB group, patients in the TB-HBV group who did not receive anti-HBV therapy before anti-TB treatment were more susceptible to Grade-4 severity of DILI (36.2% vs. 7.7%, P = 0.005), liver failure (67.2% vs. 38.5%, P = 0.013) and poor outcomes (37.9% vs. 7.7%, P = 0.005). Age > 50 years (48.1% vs. 22.6%, P = 0.049), cirrhosis (50.0% vs. 15.4%, P = 0.046) and total bilirubin > 20 mg/dl (51.6% vs. 14.8%, P = 0.005) were independent risk factors for the rate of death in the TB-HBV group, and HBV DNA > 20,000 IU/ml had borderline significance (44.1% vs. 20.8%, P = 0.081). In the TB-HBV group, nucleos(t)ide analogues as rescue therapy were not able to reduce short-term death (33.3% vs. 36.8%, P = 0.659) once liver failure had occurred. CONCLUSIONS: Patients on anti-TB therapy with chronic HBV co-infection are more susceptible to developing liver failure and having poor outcomes during anti-TB treatment. Regular monitoring of liver function and HBV DNA level is mandatory. Anti-HBV treatment should be considered in those with high viral levels before anti-TB treatment. PMID- 29970035 TI - Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. AB - BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) and osteosarcoma (OSC) is very effective: the vast majority of patients recover and survive for decades. However, they still need to face serious adverse effects of chemotherapy. One of these is cardiotoxicity which may lead to progressive heart failure in the long term. Cardiotoxicity is contributed mainly to the use of anthracyclines and might have genetic risk factors. Our goal was to test the association between left ventricular function and genetic variations of candidate genes. METHODS: Echocardiography data from medical records of 622 pediatric ALL and 39 OSC patients were collected from the period 1989-2015. Fractional shortening (FS) and ejection fraction (EF) were determined, 70 single nucleotide polymorphisms (SNPs) in 26 genes were genotyped. Multivariate logistic regression and multi-adjusted general linear model were performed to investigate the influence of genetic polymorphisms on the left ventricular parameters. Bayesian network based Bayesian multilevel analysis of relevance (BN-BMLA) method was applied to test for the potential interaction of the studied cofactors and SNPs. RESULTS: Our results indicate that variations in ABCC2, CYP3A5, NQO1, SLC22A6 and SLC28A3 genes might influence the left ventricular parameters. CYP3A5 rs4646450 TT was 17% among ALL cases with FS lower than 28, and 3% in ALL patients without pathological FS (p = 5.60E-03; OR = 6.94 (1.76-27.39)). SLC28A3 rs7853758 AA was 12% in ALL cases population, while only 1% among controls (p = 6.50E-03; OR = 11.56 (1.98-67.45)). Patients with ABCC2 rs3740066 GG genotype had lower FS during the acute phase of therapy and 5-10 years after treatment (p = 7.38E-03, p = 7.11E-04, respectively). NQO1 rs1043470 rare T allele was associated with lower left ventricular function in the acute phase and 5-10 years after the diagnosis (p = 4.28E-03 and 5.82E-03, respectively), and SLC22A6 gene rs6591722 AA genotype was associated with lower mean FS (p = 1.71E-03), 5-10 years after the diagnosis. CONCLUSIONS: Genetic variants in transporters and metabolic enzymes might modulate the individual risk to cardiac toxicity after chemotherapy. PMID- 29970038 TI - Optimal profile limits for maternal mortality rate (MMR) in South Sudan. AB - BACKGROUND: Reducing Maternal Mortality Rate (MMR) is considered by the international community as one of the eight Millennium Development Goals. Based on previous studies, Skilled Assistant at Birth (SAB), General Fertility Rate (GFR) and Gross Domestic Product (GDP) have been identified as the most significant predictors of MMR in South Sudan. This paper aims for the first time to develop profile limits for the MMR in terms of significant predictors SAB, GFR, and GDP. The paper provides the optimal values of SAB and GFR for a given MMR level. METHODS: Logarithmic multi- regression model is used to model MMR in terms of SAB, GFR and GDP. Data from 1986 to 2015 collected from Juba Teaching Hospital was used to develop the model for predicting MMR. Optimization procedures are deployed to attain the optimal level of SAB and GFR for a given MMR level. MATLAB was used to conduct the optimization procedures. The optimized values were then used to develop lower and upper profile limits for yearly MMR, SAB and GFR. RESULTS: The statistical analysis shows that increasing SAB by 1.22% per year would decrease MMR by 1.4% (95% CI (0.4-5%)) decreasing GFR by 1.22% per year would decrease MMR by 1.8% (95% CI (0.5-6.26%)). The results also indicate that to achieve the UN recommended MMR levels of minimum 70 and maximum 140 by 2030, the government should simultaneously reduce GFR from the current value of 175 to 97 and 75, increase SAB from the current value of 19 to 50 and 76. CONCLUSIONS: This study for the first time has deployed optimization procedures to develop lower and upper yearly profile limits for maternal mortality rate targeting the UN recommended lower and upper MMR levels by 2030. The MMR profile limits have been accompanied by the profile limits for optimal yearly values of SAB and GFR levels. Having the optimal level of predictors that significantly influence the maternal mortality rate can effectively aid the government and international organizations to make informed evidence-based decisions on resources allocation and intervention plans to reduce the risk of maternal death. PMID- 29970039 TI - Evaluation of the effectiveness of combined femtosecond laser-assisted cataract surgery and femtosecond laser astigmatic keratotomy in improving post-operative visual outcomes. AB - BACKGROUND: To determine postoperative refractive and visual outcomes and astigmatic changes after femtosecond laser astigmatic keratotomy in femtosecond laser-assisted cataract surgery (FLACS). METHODS: This was a prospective interventional case series. Patients with age-related cataract and corneal astigmatism (1.0-3.0D) were treated with FLACS and femtosecond laser astigmatic keratotomy (FSAK). All patients underwent examinations before and 3 months after surgery; visual acuity, subjective and objective refraction, and corneal astigmatism were evaluated and recorded for all patients by using an OPD-Scan III topographer. Vector analysis of astigmatic changes was performed by using the Alpins vector method. RESULTS: Twenty-five patients were included in the study. Postoperatively, refractive and corneal astigmatism were both reduced significantly (P < 0.05), concurrent with improved uncorrected distance visual acuity and corrected distance visual acuity. The rate of spectacle use was significantly reduced at 3 months postoperatively (P = 0.001). The mean magnitude of the target-induced astigmatism vector (1.40 +/- 0.37D) was slightly higher than the mean magnitude of the surgically induced astigmatism vector (1.22 +/- 0.46D). The magnitude of error (- 0.18 +/- 0.36D), as well as the correction index (0.88 +/- 0.29), demonstrated slight undercorrection. The angle of error was 0.85 +/- 13.69 degrees , which was close to zero. CONCLUSIONS: Combined femtosecond laser-assisted cataract surgery and astigmatic keratotomy may be an effective approach to manage preoperative astigmatism in cataract surgery, although slight undercorrection may exist during short-term follow-up. TRIAL REGISTRATION: ChiCTR-TRC-14004977. PMID- 29970040 TI - Kaposi's sarcoma of the conjunctiva and the eyelid leads to the diagnosis of human immunodeficiency virus infection - a case report. AB - BACKGROUND: The purpose of this case report is to describe a conjunctiva and eyelid Kaposi's sarcoma (KS) as the initial manifestation of acquired immunodeficiency syndrome (AIDS), which led to the diagnosis of HIV infection. There are only 3 reported cases of ocular KS as an initial manifestation of HIV infection. CASE PRESENTATION: A 32-year old white man presented to our department with a 1 month history of eye redness. The patient had an enlarged violet coloured mass on the right superior eyelid which had evolved over the course of 1 week. There was also a mobile bulbar conjunctival lesion with a bright red colour, approximately 5 mm * 5 mm, in the superior temporal quadrant of his left eye. The lesions looked like a chalazion and a subconjunctival haemorrhage, respectivly. Presumed KS diagnosis was confirmed with HIV-1 positive testing and histopathology from tissue biopsy. The patient's CD4 count was 23/mm3 and viral RNA load 427,000/ml. Further systemic evaluation showed a diffuse sarcoma. CONCLUSION: This case report demonstrates the importance of recognizing the ocular manifestations of AIDS in establishing the correct diagnosis of KS and subsequently diagnosing occult HIV infection. Although ocular KS as the initial manifestation of HIV-AIDS is an extremely rare event, a proper diagnosis may contribute to prompt management with personal and social relevance. PMID- 29970041 TI - Social differences in diagnosed depression among adolescents in a Swedish population based cohort. AB - BACKGROUND: Population based research regarding social differences in diagnosed depression in adolescence is sparse. In this study unique material containing in and outpatient data was used to determine if low social position in childhood increases the risk of diagnosed depression in adolescence. To further examine this association, gender differences and interactions were explored. METHODS: The study population was extracted from the Stockholm Youth Cohort (SYC), a register based cohort containing psychiatric care for all young people in Stockholm County and information about social position. For the purpose of this study, all in the SYC who turned 13 years old during 2001-2007, in total 169,262 adolescents, were followed up in 2005-2011 for diagnoses of depression until age 18. Associations were estimated with Cox regression models and presented as Hazard Ratios (HR). RESULTS: The risk of diagnosed depression was higher for adolescents with parents with low education (HR = 1.1, CI = 1.0-1.2) and medium education (HR = 1.1, CI = 1.1-1.2) compared to high as well as for those with lower household income (for example, medium low, HR = 1.2, CI = 1.1-1.3) and for those with parents who received an unemployment benefit (HR = 1.3, CI = 1.2-1.4). No differences were found for those with the lowest household income compared to those with the highest level. Adolescents with parents born outside the Nordic countries had a lower risk of diagnosed depression (HR = 0.7, CI = 0.6-0.7). An interaction effect was found between gender and parental education. CONCLUSIONS: Social differences were found but the magnitude was modest and gender differences small. PMID- 29970042 TI - Adolescent childbearing trends and sub-national variations in Ethiopia: a pooled analysis of data from six surveys. AB - BACKGROUND: Ethiopia houses the second largest population of female adolescents in Africa. Adolescent childbearing can have detrimental effect to the health and wellbeing of women and their offspring. This study examined trends, sub-national variations and determinants of early childbearing (i.e. childbearing before age 20) in Ethiopia. METHODS: Data from the 2000-2011 Ethiopia Demographic and Health Surveys and from the 2014-2016 Performance Monitoring and Accountability surveys were pooled for this analysis. Based on the year the women reached puberty, five different cohorts were reconstructed that date back to the early 1970s. Kaplan Meier methodology was used to estimate the cumulative probability of early childbearing and a Cox proportional hazard regression model to examine the associated factors. RESULTS: The cumulative probability of early childbearing declined by approximately two-fifth in the past four decades, from 57.6 to 35.3%. The occurrence of early childbearing varies substantially by region. In the most recent period, it ranged from 9.6% in Addis Ababa to 59% in Benishangul-Gumuz. Early childbearing risk was reduced by 95% for women who did not marry before the age of 20 years compared to those who married before the age of 18 years. For adolescents who married at the age of 18 and 19 years, early childbearing risk decreased by 60 and 78%, respectively. During the same period, there was a parallel decline in the cumulative probability of early marriage (i.e., before the legal age of 18 years) from 55.3 to 28.7%. Compared with adolescents with no education, those with elementary and secondary or higher education had a 50 and 82% lower risk of early childbearing, respectively. CONCLUSIONS: Early childbearing declined in Ethiopia, largely driven by a parallel reduction in early marriage. However, a large portion of adolescents are still facing early childbearing, and the situation is more dismal in some regions than others. A further reduction in early childbearing is warranted by enforcing the law on the minimum marriage age and expanding secondary and higher education for females. These efforts should give greater emphasis to regions where early childbearing is markedly high. PMID- 29970043 TI - Household environment and symptoms of childhood acute respiratory tract infections in Nigeria, 2003-2013: a decade of progress and stagnation. AB - BACKGROUND: Acute respiratory infections (ARIs) remains a disease of public health importance in Nigeria. Though, previous studies have identified factors associated with childhood ARI symptoms, the progress made in reducing the burden of this major childhood morbidity in the past decade in Nigeria has not been quantified. Therefore, this study describes the trends in the prevalence and factors associated with ARI symptoms among under-five (U5) children in Nigeria between years 2003 and 2013. METHODS: A retrospective cross-sectional analysis of nationally representative data from the Nigeria Demographic and Health Surveys (NDHS) for years 2003, 2008 and 2013 was done. The study sample included women of reproductive age who had U5 children presenting with a cough accompanied with short rapid breaths in the last 2 weeks prior data collection. Data were analysed using complementary log regression model. RESULTS: Prevalence of ARI symptoms were 10.3, 4.6 and 3.8% for years 2003, 2008 and 2013 respectively. The use of unclean cooking fuel was not associated with ARI symptom in 2003 and 2008, but in 2013 (OR = 2.50, CI: 1.16-5.42). Living in houses built with poor quality materials was associated with higher risk of ARI symptoms in 2008 (OR = 1.34, CI: 1.11-1.61) and 2013 (OR = 1.59, CI: 1.32-1.93). Higher risk of ARI symptoms was also associated with younger child's age, Northern regions and household wealth quintile between 2003 and 2013. CONCLUSIONS: Though there has been a significant progress in the reduction of the prevalence of ARI symptoms between 2003 and 2013, the same could not be said of household environmental risk factors. Interventions to reduce the contributory effects of these factors to the occurrence of ARI symptoms should be instituted by government and other relevant stakeholders. PMID- 29970044 TI - The impact of participatory budgeting on health and wellbeing: a scoping review of evaluations. AB - BACKGROUND: Participatory budgeting (PB), citizens deliberating among themselves and with officials to decide how to allocate funds for public goods, has been increasingly implemented across Europe and worldwide. While PB is recommended as good practice by the World Bank and the United Nations, with potential to improve health and wellbeing, it is unclear what evaluations have been conducted on the impact of PB on health and wellbeing. METHODS: For this scoping review, we searched 21 databases with no restrictions on publication date or language. The search term 'participatory budget' was used as the relevant global label for the intervention of interest. Studies were included if they reported original analysis of health, social, political, or economic and budgetary outcomes of PB. We examined the study design, analysis, outcomes and location of included articles. Findings are reported narratively. RESULTS: From 1458 identified references, 37 studies were included. The majority of evaluations (n = 24) were of PB in South America, seven were in Europe. Most evaluations were case studies (n = 23) conducting ethnography and surveys, focussing on political outcomes such as participation in PB or impacts on political activities. All of the quantitative observational studies analysing population level data, except one in Russia, were conducted in South America. CONCLUSION: Despite increasing interest in PB, evaluations applying robust methods to analyse health and wellbeing outcomes are scarce, particularly beyond Brazil. Therefore, implementation of PB schemes should be accompanied by rigorous qualitative and quantitative evaluation to identify impacts and the processes by which they are realised. PMID- 29970045 TI - Total and regional bone mineral and tissue composition in female adolescent athletes: comparison between volleyball players and swimmers. AB - BACKGROUND: Exploring the osteogenic effect of different bone-loading sports is particular relevant to understand the interaction between skeletal muscle and bone health during growth. This study aimed to compare total and regional bone and soft-tissue composition between female adolescent swimmers (n=20, 15.71+/ 0.93 years) and volleyball players (n=26, 16.20+/-0.77 years). METHODS: Dietary intake was obtained using food frequency questionnaires. Body size was given by stature, sitting height, and body mass. Six skinfolds were measured. Bone mineral content (BMC) and density (BMD), lean soft tissue, and fat tissue were assessed using dual-energy X-ray absorptiometry. Pearson's product moment correlation coefficients were calculated to examine the relationships among variables, by type of sport. Comparisons between swimmers and volleyball players were performed using student t-tests for independent samples and multivariate analysis of covariance (controlling for age, training history and body size). RESULTS: Swimmers (BMC: 2328+/-338 g) and volleyball players (BMC: 2656+/-470 g) exceeded respectively by 2.1 and 2.8 standard deviation scores the average of international standards for whole body BMC of healthy adolescents. Years of training in swimmers were positively related to the upper limbs BMC (r=+0.49, p<0.05). In volleyball players, years of training correlated significantly with lower limbs BMD (r=+0.43, p<0.05). After adjustments for potential confounders, moderate differences (ES-r=0.32) between swimmers and volleyball players were noted in BMD at the lower limbs (volleyball players: +0.098 g?cm-2, +7.8%). CONCLUSIONS: Youth female athletes who participate in high-intensity weight loading activities such as volleyball exhibit moderately higher levels of BMD at the lower limbs compared to non-loading sports such as swimming. PMID- 29970047 TI - Magnitude of opportunistic diseases and their predictors among adult people living with HIV enrolled in care: national level cross sectional study, Ethiopia. AB - BACKGROUND: Opportunistic diseases cause morbidity and mortality among human immunodeficiency virus (HIV) infected persons. There is dearth of evidence on the magnitude and predictors of opportunistic diseases among PLHIV in Ethiopia. This study was conducted to determine the magnitude and predictors of opportunistic diseases among adults enrolled in the national HIV/AIDS care and treatment services and generate information for program planning and medicine quantification in the country. METHODS: A health facility-based cross-sectional study was conducted. Probability proportional to size and random sampling methods were employed to select health facilities and medical records of adult HIV infected patients respectively. A total of 7826 medical records were reviewed from 60 health facilities nationwide. Socio-demographic and clinical data including diagnosis of opportunistic diseases were collected from the medical records. Period prevalence of opportunistic diseases over one year period was determined. Bivariate and multivariate logistic regression was used to measure associations between independent variables and the dependent variable, occurrence of opportunistic diseases. RESULTS: Of the total of 7826 study participants, 3748 (47.9%) were from hospitals and 4078 were from health centers. The majority (61.8%) were female. The median age was 32 years with interquartile range (IQR) of 27-40. The median duration of stay in HIV care was 56 (IQR = 28-80) months; 7429 (94.9%) were on antiretroviral treatment. A total of 1665 cases of opportunistic diseases were recorded with an overall prevalence estimated at 21.3% (95% confidence interval (CI): 20.36, 22.18%). Skin diseases (4.1%), diarrhea (4.1%), bacterial pneumonia (3.6%), recurrent upper respiratory tract infections (3.1%) and tuberculosis (2.7%) were the leading opportunistic diseases. Isoniazid preventive therapy coverage among eligible patients was 24.8%. Persons with a CD4 count < 200 cells/mm3 [adjusted odds ratio (AOR) 1.80, 95% CI: 1.45, 2.23]; and who were bed ridden or ambulatory functional status [AOR (95% CI) = 3.19 (2.32, 4.39)] were independent predictors of diagnosis of opportunistic diseases. CONCLUSION: Opportunistic diseases were found to be pervasive among HIV infected adults in Ethiopia. Proactive identification and management, and prevention of opportunistic diseases should be strengthened especially among females, ambulatory or bed-ridden, and patients with low CD4 cell count. PMID- 29970046 TI - Statewide dissemination and implementation of physical activity standards in afterschool programs: two-year results. AB - BACKGROUND: In 2015, YMCA afterschool programs (ASPs) across South Carolina, USA pledged to achieve the YMCA physical activity standard calling for all children to accumulate 30 min of moderate-to-vigorous physical activity (MVPA) while attending their ASPs. This study presents the final two-year outcomes from the dissemination and implementation efforts associated with achieving this MVPA standard. METHODS: Twenty ASPs were sampled from all South Carolina YMCA-operated ASPs (N = 97) and visited at baseline (2015) and first (2016) and second year (2017) follow-up. All ASPs were provided training to increase MVPA during the program by extending the scheduled time for activity opportunities and modifying commonly played games to increase MVPA. The RE-AIM framework was used to evaluate the statewide intervention. Accelerometer-derived MVPA was the primary outcome. Intent-to-treat (ITT) models were conducted summer 2017. Programs were also classified, based on changes in MVPA from 2015 to 2016 and 2016-2017, into one of three categories: gain, maintain, or lost. Implementation, within the three groups, was evaluated via direct observation and document review. RESULTS: Adoption during the first year was 45% of staff attending training, with this increasing to 67% of staff during the second year. ITT models indicated no increase in the odds of accumulating 30 min of MVPA after the first year for either boys (odds ratio [OR] 1.06, 95CI 0.86-1.31) or girls (OR 1.14, 95CI 0.87 1.50), whereas an increase in the odds was observed during the second year for boys (OR 1.31, 95CI 1.04-1.64) and girls (OR 1.50 95CI 1.01-1.80). Programs that lost MVPA (avg. - 5 to - 7.5 min/d MVPA) elected to modify their program in a greater number of non-supportive ways (e.g., reduce time for activity opportunities, less time spent outdoors), whereas ASPs that gained MVPA (avg. + 5.5 to + 10.1 min MVPA) elected to modify their program in more supportive ways. CONCLUSIONS: The statewide study demonstrated minimal improvements in overall MVPA. However, child MVPA was dramatically influenced by ASPs who elected to modify their daily program in more supportive than non-supportive ways, with no one program modifying their program consistently across the multi-year initiative. These findings have important implications for organizations seeking to achieve the MVPA standard. TRIAL REGISTRATION: Clinical Trial Registration: NCT02394717 . PMID- 29970048 TI - Movement behaviours are associated with lung function in middle-aged and older adults: a cross-sectional analysis of the Canadian longitudinal study on aging. AB - BACKGROUND: Physical activity has been shown to attenuate the age-associated decline in lung function; however, there is little research evaluating different movement behaviours as potential correlates of lung function. Modifiable determinants need to be identified, as the prevalence of chronic respiratory disease is on the rise. The purpose of this study was to investigate associations of self-reported movement behaviours (i.e., sitting time, walking, different intensities of physical activity, and strengthening activities), with lung function in middle-aged and older adults without a respiratory disease, according to their smoking history. METHODS: Data from participants of the Canadian Longitudinal Study on Aging were used for analysis (n = 16,839). Lung function was assessed using spirometry. A modified version of the Physical Activity Scale for the Elderly was used to assess sitting time and physical activity levels. Smoking status was classified as non-smoking, < 10 pack years smoking, and 10 or more pack years of smoking. The association between movement behaviours and lung function was assessed using hierarchical linear regression models with all covariates (age, sex, smoking status, body mass index, education, retirement status, and sleep duration) entered into block 1, and all movement behaviours entered into block 2. RESULTS: All movement behaviours were associated with Forced Expiratory Volume in 1 s (FEV1) and Forced Vital Capacity (FVC) % predicted in crude and adjusted models, regardless of smoking status. Sitting time was negatively associated with both FEV1%pred (beta: -0.094, CI: -0.140, - 0.047) and FVC%pred (beta: -0.087, CI: -0.128, -0.045) among those who never smoked, and strength activity was positively associated with both FEV1%pred (beta: 0.272, CI: 0.048, 0.496) and FVC%pred (beta: 0.253, CI: 0.063,0.442) among those who smoked < 10 pack years, as well as with FVC%pred among those who smoked 10 or more pack years (beta: 0.309, CI: 0.064, 0.554). CONCLUSIONS: This is the first study to assess the association of different movement behaviours with lung function among middle-aged and older adults without a respiratory disease. These findings indicate that movement behaviours are correlates of lung function, and that they may be modifiable determinants of the age-associated decline in lung function. PMID- 29970050 TI - Reproducibility of domain-specific physical activity over two seasons in children. AB - BACKGROUND: Knowledge of the reproducibility of domain-specific accelerometer determined physical activity (PA) estimates are a prerequisite to conduct high quality epidemiological studies. The aim of this study was to determine the reproducibility of objectively measured PA level in children during school hours, afternoon hours, weekdays, weekend days, and total leisure time over two different seasons. METHODS: Six hundred seventy six children from the Active Smarter Kids study conducted in Sogn og Fjordane, Norway, were monitored for 7 days by accelerometry (ActiGraph GT3X+) during January-February and April-May 2015. Reproducibility was estimated week-by-week using intra-class correlation (ICC) and Bland-Altman plots with 95% limits of agreement (LoA). RESULTS: When controlling for season, reliability (ICC) was 0.51-0.66 for a 7-day week, 0.55 0.64 for weekdays, 0.11-0.43 for weekend days, 0.57-0.63 for school hours, 0.42 0.53 for afternoon hours, and 0.42-0.61 for total leisure time. LoA across models approximated a factor of 1.3-2.5 standard deviations of the sample PA levels. 3-6 weeks of monitoring were required to achieve a reliability of 0.80 across all domains but weekend days, which required 5-32 weeks. CONCLUSION: Reproducibility of PA during leisure time and weekend days were lower than for school hours and weekdays, and estimates were lower when analyzed using a week-by-week approach over different seasons compared to previous studies relying on a single short monitoring period. To avoid type 2-errors, researchers should consider increasing the monitoring period beyond a single 7-day period in future studies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT021324947 . Registered on 7 April 2014. PMID- 29970049 TI - Longitudinal study of adolescent tobacco use and tobacco control policies in India. AB - BACKGROUND: This project will use a multilevel longitudinal cohort study design to assess whether changes in Community Tobacco Environmental (CTE) factors, measured as community compliance with tobacco control policies and community density of tobacco vendors and tobacco advertisements, are associated with adolescent tobacco use in urban India. India's tobacco control policies regulate secondhand smoke exposure, access to tobacco products and exposure to tobacco marketing. Research data about the association between community level compliance with tobacco control policies and youth tobacco use are largely unavailable, and are needed to inform policy enforcement, implementation and development. METHODS: The geographic scope will include Mumbai and Kolkata, India. The study protocol calls for an annual comprehensive longitudinal population-based tobacco use risk and protective factors survey in a cohort of 1820 adolescents ages 12-14 years (and their parent) from baseline (Wave 1) to 36-month follow-up (Wave 4). Geographic Information Systems data collection will be used to map tobacco vendors, tobacco advertisements, availability of e-cigarettes, COTPA defined public places, and compliance with tobacco sale, point-of-sale and smoke-free laws. Finally, we will estimate the longitudinal associations between CTE factors and adolescent tobacco use, and assess whether the associations are moderated by family level factors, and mediated by individual level factors. DISCUSSION: India experiences a high burden of disease and mortality from tobacco use. To address this burden, significant long-term prevention and control activities need to include the joint impact of policy, community and family factors on adolescent tobacco use onset. The findings from this study can be used to guide the development and implementation of future tobacco control policy designed to minimize adolescent tobacco use. PMID- 29970052 TI - A skill to be worked at: using social learning theory to explore the process of learning from role models in clinical settings. AB - BACKGROUND: Role modelling is widely accepted as being a highly influential teaching and learning method in medical education but little attention is given to understanding how students learn from role models. This study focuses on role modelling as an active, dynamic process, involving observational learning and aims to explore the process involved, including strategies that learners and medical teachers use to support this. METHODS: To gain insight into medical students' and clinical teachers' understanding of learning through role modelling, a qualitative, interpretative methodology was adopted, using one-to one semi-structured interviews. Six final year medical students and five clinical teachers were purposefully sampled and interviewed. Interviews were audio recorded and transcribed. The data were then analysed using open and axial coding before codes were combined to develop broader themes. RESULTS: Students could identify ways in which they learnt from role models but acknowledged that this was complex and haphazard. They described selectively and consciously paying attention, using retention strategies, reproducing observed behaviour and being motivated to imitate. Students evidenced the powerful impact of direct and vicarious reinforcement. Clinical teachers reported using strategies to help students learn, but these were not always consciously or consistently applied or informed by teachers' understanding of their students' cognitive processing. CONCLUSION: Findings illustrate in what ways the process of learning from role models in clinical settings is challenging. They also support the relevancy and usefulness of Bandura's four stage social learning model for understanding this process and informing recommendations to make learning from role modelling more systematic and effective. PMID- 29970051 TI - The prevalence of edentulism and their related factors in Indonesia, 2014/15. AB - BACKGROUND: Little information exists about the loss of all one's teeth (edentulism) among older adults in Indonesia. The aim of this study was to investigate the prevalence of edentulism and associated factors among older adults in Indonesia. METHOD: This study examines the self-reported prevalence of edentulism and associated factors among older adults (50 years and older) in a cross-sectional national study using the Indonesia Family Life Survey IFLS-5, 2014/15. The community-based study uses a multi-stage stratified sampling design to interview and assess household members, with a household response rate of over 90%. RESULTS: The overall prevalence of edentulism was 7.2, 29.8% in 80 years and older and 11.8% in those with no formal education. In adjusted Poisson regression analysis, older age, living in five major island groups and having functional disability were associated with edentulism. In addition, among men, having quit and current tobacco use and among women, having low social capital were associated with edentulism. Further, in adjusted analysis, among men, edentulism was positively associated with hypertension and negatively associated with diabetes, and among women, edentulism was associated with functional disability. CONCLUSIONS: Results suggest that overall and/or among men or women that older age, living in five major island groups, having functional disability, tobacco quitters and users and those with low social capital was associated with edentulism. The identified associated factors of edentulism may be utilized in oral health programmes targeting older adults in Indonesia. PMID- 29970053 TI - A community-based cluster randomised controlled trial in rural Bangladesh to evaluate the impact of the use of iron-folic acid supplements early in pregnancy on the risk of neonatal mortality: the Shonjibon trial. AB - BACKGROUND: Iron-deficiency is the most common nutritional deficiency globally. Due to the high iron requirements for pregnancy, it is highly prevalent and severe in pregnant women. There is strong evidence that maternal iron deficiency anaemia increases the risk of adverse perinatal outcomes. However, most of the evidence is from observational epidemiological studies except for a very few randomised controlled trials. IFA supplements have also been found to reduce the preterm delivery rate and neonatal mortality attributable to prematurity and birth asphyxia. These results combined indicate that IFA supplements in populations of iron-deficient pregnant women could lead to a decrease in the number of neonatal deaths mediated by reduced rates of preterm delivery. In this paper, we describe the protocol of a community-based cluster randomised controlled trial that aims to evaluate the impact of maternal antenatal IFA supplements on perinatal outcomes. METHODS/DESIGN: The effect of the early use of iron-folic acid supplements on neonatal mortality will be examined using a community based, cluster randomised controlled trial in five districts with 30,000 live births. In intervention clusters trained BRAC village volunteers will identify pregnant women & provide iron-folic acid supplements. Groundwater iron levels will be measured in all study households using a validated test kit. The analysis will follow the intention to treat principle. We will compare neonatal mortality rates & their 95% confidence intervals adjusted for clustering between treatment groups in each groundwater iron-level group. Cox proportional hazards mixed models will be used for mortality outcomes & will include groundwater iron level as an interaction term in the mortality model. DISCUSSION: This paper aims to describe the study protocol of a community based randomised controlled trial evaluating the impact of the use of iron-folic acid supplements early in pregnancy on the risk of neonatal mortality. This study is critical because it will determine if antenatal IFA supplements commenced in the first trimester of pregnancy, rather than later, will significantly reduce neonatal deaths in the first month of life, and if this approach is cost-effective. TRIAL REGISTRATION: This trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) on 31 May 2012. The registration ID is ACTRN12612000588897 . PMID- 29970054 TI - The effect of nurse empowerment educational program on patient safety culture: a randomized controlled trial. AB - BACKGROUND: The complexity of patients' condition and treatment processes in intensive care units (ICUs) predisposes patients to more hazardous events. Effective patient safety culture is related to lowering the rate of patients' complications and fewer adverse events. The present study aimed to determine the effect of empowering nurses and supervisors through an educational program on patient safety culture in adult ICUs. METHODS: A randomized controlled trial was conducted during April-September 2015 in 6 adult ICUs at Namazi Hospital, Shiraz, Iran. A total of 60 nurses and 20 supervisors were selected through proportional stratified sampling and census, respectively, and randomly assigned to the experimental and control groups. The intervention consisted of a two-day workshop, hanging posters, and distributing pamphlets that covered topics such as patient safety, patient safety culture, speak up about safety issues, and the skills of Team Strategies and Tools to Enhance Performance and Patient Safety. Data were collected through a hospital survey on patient safety culture. Eventually, 61 participants completed the study. Data were analyzed using descriptive statistics, independent-samples t-test, paired-samples t-test, and Chi-square test. P < 0.05 was considered statistically significant. RESULTS: In the experimental group, the total post-test mean scores of the patient safety culture (3.46 +/- 0.26) was significantly higher than that of the control group (2.84 +/- 0.37, P < 0.001). It was also higher than that of the pre-test (2.91 +/ 0.4, P < 0.001). Additionally, significant improvements were observed in 5 out of 12 dimensions in the experimental group. However, dimensions such as non punitive response to errors and the events reported did not improve significantly. CONCLUSION: Empowering nurses and supervisors could improve the overall patient safety culture. Nonetheless, additional actions are required to improve areas such as reporting the events and non-punitive response to errors. TRIAL REGISTRATION: IRCT2015053122494N1 . Date registered: March 2, 2016. PMID- 29970055 TI - Nm23-H1 is involved in the repair of ionizing radiation-induced DNA double-strand breaks in the A549 lung cancer cell line. AB - BACKGROUND: Although originally identified as a putative metastasis suppressor, increasing studies have confirmed a possible role for Nm23-H1 in DNA repair, through the base excision repair and nucleotide excision repair pathways. In this study, we explored whether Nm23-H1 was also involved in double-strand break repair (DSBR). METHODS AND RESULTS: We constructed a stable A549-shNm23-H1 cell line with doxycycline-regulated expression of Nm23-H1, and a A549-nNm23-H1 cell line that over expressed a nucleus-localized version of Nm23-H1. Results from both lines confirmed that Nm23-H1 participated in the repair of double-strand breaks induced by X-rays, using Comet and gamma-H2AX foci assays. Subsequent studies showed that Nm23-H1 activated the phosphorylation of checkpoint-related proteins including ATM serine/threonine kinase (on S1981), tumor protein p53 (on S15), and checkpoint kinase 2 (Chk2) (on T68). We also detected interactions between Nm23-H1 and the MRE11-RAD50-NBS1 (MRN) complex, as well as Ku80. Moreover, NBS1 and Ku80 levels were comparably higher in Nm23-H1 overexpressing cells than in control cells (t = 14.462, p < 0.001 and t = 5.347, p = 0.006, respectively). As Ku80 is the keystone of the non-homologous end joining (NHEJ) pathway, we speculate that Nm23-H1 promotes DSBR through NHEJ. CONCLUSIONS: The results indicate that Nm23-H1 participates in multiple steps of DSBR. PMID- 29970056 TI - A novel in vivo method to evaluate trueness of digital impressions. AB - BACKGROUND: Intraoral scanners are devices for capturing digital impressions in dentistry. Until now, several in vitro studies have assessed the trueness of digital impressions, but in vivo studies are missing. Therefore, the purpose of this study was to introduce a new method to assess trueness of intraoral scanners and digital impressions in an in vivo clinical set-up. METHODS: A digital impression using an intraoral scanner (Trios(r) 3 Cart wired, 3Shape, Copenhagen, Denmark) and a conventional alginate impression (Cavex Impressional(r), Cavex, Haarlem, the Netherlands) as clinical reference were made for two patients assigned for full mouth extraction. A total of 30 teeth were collected upon surgery after impressions making. The gypsum model created from conventional impression and extracted teeth were then scanned in a lab scanner (Activity 885(r), SmartOptics, Bochum, Germany). Digital model of the intraoral scanner (DM), digital model of the conventional gypsum cast (CM) and those of the extracted natural teeth (NT) were imported to a reverse engineering software (3 matic(r), Materialise, Leuven, Belgium) in which the three models were registered then DM and CM were compared to their corresponding teeth in NT by distance map calculations. RESULTS: DM had statistically insignificant better trueness when compared to CM for total dataset (p = 0.15), statistically insignificant better trueness for CM when mandibular arches analyzed alone (p = 0.56), while a significantly better DM trueness (p = 0.013) was found when only maxillary arches were compared. CONCLUSIONS: Our results show that digital impression technique is clinically as good as or better than the current reference standard for study models of orthognathic surgery patients. PMID- 29970057 TI - The increasing prevalence of myopia and high myopia among high school students in Fenghua city, eastern China: a 15-year population-based survey. AB - BACKGROUND: Myopia is the leading cause of preventable blindness in children and young adults. Multiple epidemiological studies have confirmed a high prevalence of myopia in Asian countries. However, fewer longitudinal studies have been performed to evaluate the secular changes in the prevalence of myopia, especially high myopia in China. In the present study, we investigated trends in the prevalence of myopia among high school students in Fenghua city, eastern China, from 2001 to 2015. METHODS: This was a population-based, retrospective study. Data were collected among 43,858 third-year high school students. Noncycloplegic autorefraction was used to determine refractive error, which was defined as low myopia, moderate myopia, high myopia and very high myopia according to the spherical equivalent from the worse eye of each participant. The prevalence of myopia was calculated and the annual percentage change (APC) was used to quantify the time trends. All analyses were conducted using the SPSS, Stata and Graphpad Prism software. RESULTS: From 2001 to 2015, the prevalence of overall myopia increased from 79.5% to 87.7% (APC =0.59%), with a significant increase of moderate myopia (38.8% to 45.7%, APC = 0.78%), high myopia (7.9% to 16.6%, APC = 5.48%) and very high myopia (0.08% to 0.92%, APC = 14.59%), while the prevalence of low myopia decreased from 32.7% to 24.4% (APC = - 1.73%). High myopia and very high myopia contributed the major part of the increasing trend of myopia prevalence (contribution rate 27.00% and 69.07%, respectively). CONCLUSIONS: During the 15-year period, there was a remarkable increase in the prevalence of high and very high myopia among high school students, which might become a serious public health problem in China for the next few decades. PMID- 29970058 TI - Relationship between body image and weight status in east Asian countries: comparison between South Korea and Taiwan. AB - BACKGROUND: There are many studies examining the relationship between body image and weight status that compare Western and Asian countries. One limitation of these past studies was assuming that all Asian countries are a homogeneous group. To fill the gap in the literature, this study examined the relationship between body image and weight status between participants from two Asian countries. METHODS: This study utilized data from the 2010 module of the East Asian Social Survey from South Korea (n = 1576) and Taiwan (n = 2199), which contained questions related to body image. Body image was originally measured using a five point Likert-type question, which was collapsed into three categories for the analysis. Weight status was derived from body mass index scores, which were calculated using self-reported weight and height. A set of multinomial logistic regression analyses were used to investigate the relationship between body image and weight status, stratified by country. RESULTS: A significant relationship between body image and weight status after controlling for relevant covariates was reaffirmed in this study in the South Korean and Taiwanese. Results indicated that the relationship between body image and weight status of the Taiwanese sample was similar to the relationship in the South Korean sample. However, the results from a further analysis showed that the strength of the relationship across the two Asian countries appeared to be different. CONCLUSIONS: The weight over-perception was more evident in South Korea than in Taiwan. Females were more vulnerable to societal pressures for thinness and the misperception of the ideal body than males. Interventions to improve distorted body image perception were needed in both countries. PMID- 29970059 TI - Calcifediol (25-hydroxyvitamin D) improvement and calcium-phosphate metabolism of alendronate sodium/vitamin D3 combination in Chinese women with postmenopausal osteoporosis: a post hoc efficacy analysis and safety reappraisal. AB - BACKGROUND: Vitamin D (VD) insufficiency or deficiency is a frequent comorbidity in Chinese women with postmenopausal osteoporosis (PMO). The present study aimed to investigate 25-hydroxyvitamin D [25(OH) D] improvement and calcium-phosphate metabolism in Chinese PMO patients treated with 70 mg of alendronate sodium and 5600 IU of vitamin D3 (ALN/D5600). METHODS: Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders. RESULTS: Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%). CONCLUSION: Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 MUg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage. PMID- 29970060 TI - Factors related to fertility desire among female sex workers living with HIV in the Dominican Republic. AB - BACKGROUND: Female sex workers living with HIV are at increased risk for negative health outcomes and multiple levels of stigma. However, there is limited research on female sex workers living with HIV and even less focused on reproductive health. METHODS: We analyzed data using logistic regression from a cohort of 247 female sex workers of reproductive age living with HIV in Santo Domingo, Dominican Republic to assess factors associated with fertility desire. RESULTS: Most participants had children (93.1%; mean: 2.8; range: 1,8) and 28.3% reported fertility desire. Bivariate regression analysis uncovered that participants who desired children were less likely to report being on antiretroviral treatment and more likely to have a detectable viral load. Multivariate regression results showed participants who desired more children were: less likely to be older, have higher levels of HIV-related internalized stigma, have a history of pregnancy loss, have fewer children and have a perception that their partner has negative feelings about pregnancy. CONCLUSIONS: Individual and interpersonal characteristics were found to be associated with fertility desire in this study. Additional in-depth research is needed to understand how the role of stigma, partner dynamics and reproductive history as it relates to fertility desire, in order to ensure the reproductive health and wellbeing of this population. PMID- 29970061 TI - IgG4-related ophthalmic disease involving extraocular muscles: case series. AB - BACKGROUND: To elucidate the clinical features of strabismus associated with IgG4 related ophthalmic disease (IgG4-ROD). All of the four patients with IgG4-ROD showed marked enlargement of the extraocular muscles, however, two patients showed orthotropia with full ductions and versions. One patient showed a small angle of exotropia and hypertropia of less than 5 prism diopters. One remaining patient showed orthotropia, full ductions and versions despite marked enlargement of the extraocular muscles, then developed hypertropia up to 35 prism diopters with activation of inflammation, which promptly improved after treatment with oral steroids. CONCLUSIONS: IgG4-ROD usually shows normal ocular motility despite extraocular muscle enlargement, which is the key distinguishing feature from other orbital inflammatory diseases. Active flare-up with increased serum IgG4 levels may produce a large angle of eye deviation, but mostly respond well to steroid treatment. PMID- 29970062 TI - 10-hydroxy-2-decenoic acid of royal jelly exhibits bactericide and anti inflammatory activity in human colon cancer cells. AB - BACKGROUND: Royal jelly (RJ), the exclusive food for the larva of queen honeybee, is regarded as the novel supplement to promote human health. The function of RJ may be attributed to its major and unique fatty acid, 10-hydroxy-2-decenoic acid (10-HDA). The current study investigated the anti-inflammory function of 10-HDA on human colon cancer cells, WiDr, as well as its effect on the growth of pathogenic bacterium. METHODS: The pro-inflammatory cytokines, receptor antagonist cytokine (IL-1ra) and nuclear factor-kappa B (NF-kappaB) in WiDr cells was analyzed by Enzyme-linked immunosorbent assay (ELISA) or western blot. The growth inhibition of 10-HDA on bacterium was evaluated by determination of minimal inhibitory concentrations (MIC) and minimal bactericide concentrations (MBC). RESULTS: The production of pro-inflammatory cytokines, Interleukin (IL)-8, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) in WiDr cells was modulated by 10-HDA. IL-8 were dramatically declined by 10-HDA at 3 mM, while IL-1beta and TNF-alpha were significantly decreased. 10-HDA increased IL-1ra in a dose manner. NF-kappaB pathway is primarily in response to prototypical pro-inflammatory cytokines, and NF-kappaB was reduced after 10-HDA treatment. 10-HDA acted as potent bactericide against animal- or human-specific pathogens, including Staphylococcus aureus, Streptococcus alactolyticus, Staphylococcus intermedius B, Staphylococcus xylosus, Salmonella cholearasuis, Vibro parahaemolyticus and Escherichia coli (hemolytic). CONCLUSIONS: The current study showed that in vitro 10-HDA from RJ exhibited anti-inflammatory activity in WiDr cells, as well as anti-bacterial activity against animal pathogens. 10-HDA showed its potential as anti-imflammtory agent and bactericide to benefit human gastrointestinal tract. PMID- 29970063 TI - Evaluating a community-based cervical cancer screening strategy in Western Kenya: a descriptive study. AB - BACKGROUND: The incidence of cervical cancer in Kenya is among the highest in the world. Few Kenyan women are able to access screening, thus fueling the high cervical cancer burden. Self-collected human papilloma Virus (HPV) tests, administered during community-health campaigns in rural areas may be a way to expand access to screening. METHODS: In December 2015, we carried out a four-day community health campaign (CHC) to educate participants about cervical cancer prevention and offer self-administered HPV screening. Community enumeration, outreach and mobilization preceded the CHC. Samples were sent to Migori County Hospital for HPV DNA testing using careHPV Test Kits. Women were notified of results through their choice of short message service (SMS), phone call, home visit or clinic visit. HPV positive women were referred for cryotherapy following a screen-and-treat strategy. RESULTS: Door-to-door enumeration identified approximately 870 eligible women in Ngodhe Community in Migori County. Among the 267 women attending the campaign, 255 women enrolled and collected samples: 243 tests were successfully resulted and 12 were indeterminate. Of the 243 resulted tests, 47 (19%) were positive for HPV, with young age being the only significant predictor of positivity. In multivariate analysis, each additional year of age conferred about a 4% decrease in the odds of testing positive (95% CI 0.1 to 7%, p = 0.046). Just over three-quarters of all women (195/255), were notified of their results. Those who were unable to be reached were more likely to prefer receiving results from clinic (54/60, 90%) and were less likely to have mobile phones (24/60, 73%). Although 76% of HPV positive women were notified of their results, just half (51%) of those testing positive presented for treatment. HPV positive women who successfully accessed the treatment facility did not differ from their non-presenting counterparts by demographics, health history, desired route of notification or access to a mobile phone. CONCLUSION: Nearly a third of eligible women in Ngodhe Community attended the CHC and were screened for cervical cancer. Nearly all women who attended the CHC underwent cervical cancer screening by self-collected HPV tests. Three-quarters of all participants received results, but just half of HPV positive participants presented for treatment in a timely fashion, suggesting that linkage to treatment remains a major challenge. TRIAL REGISTRATION: NCT02124252 , Registered 25 April 2014. PMID- 29970064 TI - Antibacterial interactions, anti-inflammatory and cytotoxic effects of four medicinal plant species. AB - BACKGROUND: The constant emergence of antibiotic resistant species and the adverse side effects of synthetic drugs are threatening the efficacy of the drugs that are currently in use. This study was aimed at investigating the possible antibacterial interactions, anti-inflammatory and cytotoxic effects of selected medicinal plants based on their traditional usage. METHODS: The acetone extracts of four plant species were assessed independently and in combination for antibacterial activity using microdilution assay and the sum of the fractional inhibitory concentration (FIC) was calculated. The ability of Dombeya rotundifolia and Schkuhria pinnata extracts to inhibit the production of reactive oxygen species (ROS) in LPS induced RAW 264.7 macrophage cells was evaluated using Dichloro-dihydro-fluorescein diacetate (H2DCF-DA) assay to determine anti inflammatory potential and the toxicity on African green monkey kidney (Vero) cells was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: The antibacterial efficacies of the different combinations of Schkuhria pinnata (A), Commelina africana (B), Dombeya rotundifolia (C) and Elephantorrhiza elephantina (D) plants varied from combination to combination. Synergistic effects were only exhibited against P. aeruginosa, while the antagonistic effects were only observed against E. coli. Both S. pinnata and D. rotundifolia demonstrated anti-inflammatory potential by inhibiting the production of ROS in a dose dependant manner. The cytotoxicity of the plants (LC50 values) ranged from < 25.0 to 466.1 MUg/mL. S pinnata extract was the most toxic with the lowest LC50 value of < 25.0 MUg/mL. CONCLUSIONS: The synergistic interaction observed indicates that combinational therapy may improve biological activity. This report highlights the anti-inflammatory potential of S. pinnata and D. rotundifolia; which could be exploited in the search for anti inflammatory agents. However, the cytotoxicity of S. pinnata highlights the importance of using this plant with caution. PMID- 29970065 TI - Chemical composition, antioxidant, antimicrobial and Antiproliferative activities of essential oil of Mentha spicata L. (Lamiaceae) from Algerian Saharan atlas. AB - BACKGROUND: Mentha spicata (M. spicata) is a member of Lamiaceae that spreads mainly in the temperate and sub-temperate zones of the world. It is considered as a rich source of essential oils, which is widely used in pharmaceutical industries and food production. The objectives of the current study were to evaluate chemical composition, antioxidant, antimicrobial and antiproliferative activities associated with the essential oil of M. spicata cultivated in Algerian Saharan Atlas. METHODS: The aerial parts of M. spicata were subjected to hydrodistillation to produce the oil. Chemical identification of the oil composition was conducted by GC and GC-MS analyses. The antioxidant activity of the hydrodistilled oil was studied using DPPH, ABTS radical scavenging and ferric reducing power assay. Antimicrobial potential was characterized against two microorganisms, signifying Gram positive, and Gram negative bacteria, and one Candida species. The microdilution method was employed to determine the minimum inhibitory concentration (MIC). The oil's antiproliferative effects against three human tumor cell lines were also investigated using the MTT assay, and the toxic doses that yielded 50% reduction of cell viability (LD50) were reported. RESULTS: Chemical analysis of the essential oil composition revealed 44 unique compounds with oxygenated monoterpenes (67.2%), followed by monoterpene hydrocarbons (20.8%), as the most abundant chemical components. Essential oil of M. spicata demonstrated moderate antioxidant activities as well as moderate to weak antimicrobial activities with best susceptibility observed for Gram positive bacteria towards the oil. In addition, anticancer activities that are associated with the oil against three human cancer cell lines were observed with LD50 values of 324 MUg/mL, 279 MUg/mL, 975 MUg/mL against T47D, HCT-116 and MCF-7 cell lines, respectively. CONCLUSION: The results suggest that M. spicata essential oil may have potential value as a bioactive oil, for nutraceutical and medical applications, with its antioxidant, antimicrobial and antiproliferative activities. PMID- 29970066 TI - Asthma exacerbations in a subtropical area and the role of respiratory viruses: a cross-sectional study. AB - BACKGROUND: Multiple factors are involved in asthma exacerbations, including environmental exposure and viral infections. We aimed to assess the association between severe asthma exacerbations, acute respiratory viral infections and other potential risk factors. METHODS: Asthmatic children aged 4-14 years were enrolled for a period of 12 months and divided into two groups: those with exacerbated asthma (group 1) and non-exacerbated asthma (group 2). Clinical data were obtained and nasopharyngeal samples were collected through nasopharyngeal aspirate or swab and analysed via indirect fluorescent immunoassays to detect influenza A and B viruses, parainfluenza 1-3, adenovirus and respiratory syncytial virus. Rhinovirus was detected via molecular assays. Potential risk factors for asthma exacerbation were identified in univariate and multivariate analyses. RESULTS: In 153 children (group 1: 92; group 2: 61), median age 7 and 8 years, respectively, the rate of virus detection was 87.7%. There was no difference between groups regarding the frequency of virus detection (p = 0.68); however, group 1 showed a lower frequency (19.2%) of inhaled corticosteroid use (91.4%, p < 0.01) and evidence of inadequate disease control. In the multivariate analysis, the occurrence of three or more visits to the emergency room in the past 12 months (IRR = 1.40; p = 0.04) and nonadherence to inhaled corticosteroid (IRR = 4.87; p < 0.01) were the only factors associated with exacerbation. CONCLUSION: Our results suggest an association between asthma exacerbations, poor disease control and nonadherence to asthma medication, suggesting that viruses may not be the only culprits for asthma exacerbations in this population. PMID- 29970067 TI - Femtosecond laser-assisted cataract surgery with implantation of a diffractive trifocal intraocular lens after laser in situ keratomileusis: a case report. AB - BACKGROUND: We report for the first time, a case of femtosecond laser-assisted cataract surgery (FLACS) with implantation of a diffractive trifocal intraocular lens (IOL) after laser in situ keratomileusis (LASIK). CASE PRESENTATION: A 60 year-old man underwent FLACS uneventfully 15 years after myopic LASIK. An AT Lisa tri 839MP IOL was implanted with the expectation of spectacle independence. The Haigis-L formula was chosen for calculation of the IOL power and it provided reliable results. Three months postoperatively, the uncorrected visual acuities were 0.00 logMAR for distance, 0.10 logMAR for intermediate, and 0.10 logMAR for near. CONCLUSIONS: This case suggested that FLACS presents a feasible surgical technique for post-LASIK eyes and that implantation of trifocal IOL can achieve good visual performance in strictly selected cases after myopic LASIK. PMID- 29970068 TI - Educating speech-language pathologists working in early intervention on environmental health. AB - BACKGROUND: The goals of this study were (1) to determine early intervention (EI) Speech-Language Pathologists' (SLPs) level of training and knowledge on environmental toxicants and their effect on infant and child development; and (2) to examine the effectiveness of a continuing education (CE) event designed to enhance the knowledge of EI SLPs on environmental toxicants and their effects on child development. METHODS: A survey was launched via Qualtrics and posted on the American Speech-Language Hearing Association's Early Intervention Community page to assess environmental health knowledge of SLPs. Results from this survey were used to create an environmental health CE event targeted towards EI SLPs. Attendees were given a pre- and post-test to assess the effectiveness of our program. RESULTS: One hundred and fifty-eight participants completed the online survey and a majority (61%, n = 97) of participants reported some level of dissatisfaction with their previous training in regards to environmental exposures. Fifty-six percent (n = 89) of the participants also reported feeling unprepared to be a health advocate regarding environmental exposure concerns within their community. Forty-eight people (26 SLPs and 22 SLP master's students) attended the CE event. Paired t-tests revealed significant improvements from the pre- to the post- test results among all attendees. CONCLUSIONS: These findings suggest that SLPs who work in EI feel undertrained and unprepared to advocate for environmental health to the families they serve. This study reveals that CE is one way by which to increase the knowledge base of SLPs on environmental health. PMID- 29970069 TI - Verbal and non-verbal communication skills including empathy during history taking of undergraduate medical students. AB - BACKGROUND: Verbal and non-verbal aspects of communication as well as empathy are known to have an important impact on the medical encounter. The aim of the study was to analyze how well final year undergraduate medical students use skills of verbal and non-verbal communication during history-taking and whether these aspects of communication correlate with empathy and gender. METHODS: During a three steps performance assessment simulating the first day of a resident 30 medical final year students took histories of five simulated patients resulting in 150 videos of physician-patient encounters. These videos were analyzed by external rating with a newly developed observation scale for the verbal and non verbal communication and with the validated CARE-questionnaire for empathy. One way ANOVA, t-tests and bivariate correlations were used for statistical analyses. RESULTS: Female students showed signicantly higher scores for verbal communication in the case of a female patient with abdominal pain (p < 0.05), while male students started the conversations significantly more often with an open question (p < 0.05) and interrupted the patients significantly later in two cases than female students (p < 0.05). The number of W-questions asked by all students was significantly higher in the case of the female patient with abdominal pain (p < 0.05) and this patient was interrupted after the beginning of the interview significantly earlier than the patients in the other four cases (p < 0.001). Female students reached significantly higher scores for non-verbal communication in two cases (p < 0.05) and showed significantly more empathy than male students in the case of the female patient with abdominal pain (p < 0.05). In general, non-verbal communication correlated significantly with verbal communication and with empathy while verbal communication showed no significant correlation with empathy. CONCLUSIONS: Undergraduate medical students display differentiated communication behaviour with respect to verbal and non-verbal aspects of communication and empathy in a performance assessment and special differences could be detected between male and female students. These results suggest that explicit communication training and feedback might be necessary to raise students' awareness for the different aspects of communication and their interaction. PMID- 29970071 TI - Impact of universal home visits on maternal and infant outcomes in Bauchi state, Nigeria: protocol of a cluster randomized controlled trial. AB - BACKGROUND: Maternal mortality in Nigeria is one of the highest in the world. Access to antenatal care is limited and the quality of services is poor in much of the country. Previous research in Bauchi State found associations between maternal morbidity and domestic violence, heavy work in pregnancy, lack of knowledge about danger signs, and lack of spousal communication about pregnancy and childbirth. This cluster randomized controlled stepped-wedge trial will test the impact of universal home visits to pregnant women and their partners, and the added value of video edutainment. METHODS: The trial will take place in six wards of Toro Local Government Area in Bauchi State, Nigeria, randomly allocated into three waves of two wards each. Home visits will begin in wave 1 wards immediately; in wave 2 wards after one year; and in wave 3 wards after a further year. In each wave, one ward, randomly allocated, will receive video edutainment during the home visits. Female home visitors will contact all households in their catchment areas of about 300 households, register all pregnant women, and visit them every two months during pregnancy, after delivery and one year later. They will use android handsets to collect information on pregnancy progress, send this to a central server, and discuss with the women the evidence about household factors associated with higher maternal risks, using video clips in the edutainment wards. Male home visitors will contact the partners of the pregnant women and discuss with them the same evidence. We will compare outcomes between wave 1 and wave 2 wards at about one year, between wave 2 and wave 3 wards at about two years, and finally between wards with and without added edutainment. Primary outcomes will be complications in pregnancy and delivery, and child health at one year. Secondary outcomes include knowledge and attitudes, use of health services, knowledge of danger signs, and household care of pregnant women. DISCUSSION: Demonstrating an impact of home visits and understanding potential mechanisms could have important implications for reducing maternal morbidity and mortality in other settings with poor access to quality antenatal care services. TRIAL REGISTRATION: Registration number: ISRCTN82954580 . Registry: ISRCTN. Date of registration: 11 August 2017. Retrospectively registered. PMID- 29970070 TI - Short linear motifs in intrinsically disordered regions modulate HOG signaling capacity. AB - BACKGROUND: The effort to characterize intrinsically disordered regions of signaling proteins is rapidly expanding. An important class of disordered interaction modules are ubiquitous and functionally diverse elements known as short linear motifs (SLiMs). RESULTS: To further examine the role of SLiMs in signal transduction, we used a previously devised bioinformatics method to predict evolutionarily conserved SLiMs within a well-characterized pathway in S. cerevisiae. Using a single cell, reporter-based flow cytometry assay in conjunction with a fluorescent reporter driven by a pathway-specific promoter, we quantitatively assessed pathway output via systematic deletions of individual motifs. We found that, when deleted, 34% (10/29) of predicted SLiMs displayed a significant decrease in pathway output, providing evidence that these motifs play a role in signal transduction. Assuming that mutations in SLiMs have quantitative effects on mechanisms of signaling, we show that perturbations of parameters in a previously published stochastic model of HOG signaling could reproduce the quantitative effects of 4 out of 7 mutations in previously unknown SLiMs. CONCLUSIONS: Our study suggests that, even in well-characterized pathways, large numbers of functional elements remain undiscovered, and that challenges remain for application of systems biology models to interpret the effects of mutations in signaling pathways. PMID- 29970072 TI - Reducing antibiotic use for uncomplicated urinary tract infection in general practice by treatment with uva-ursi (REGATTA) - a double-blind, randomized, controlled comparative effectiveness trial. AB - BACKGROUND: Uncomplicated urinary tract infections (UTI) are common in general practice and usually treated with antibiotics. This contributes to increasing resistance rates of uropathogenic bacteria. A previous trial showed a reduction of antibiotic use in women with UTI by initial symptomatic treatment with ibuprofen. However, this treatment strategy is not suitable for all women equally. Arctostaphylos uva-ursi (UU, bearberry extract arbutin) is a potential alternative treatment. This study aims at investigating whether an initial treatment with UU in women with UTI can reduce antibiotic use without significantly increasing the symptom burden or rate of complications. METHODS: This is a double-blind, randomized, and controlled comparative effectiveness trial. Women between 18 and 75 years with suspected UTI and at least two of the symptoms dysuria, urgency, frequency or lower abdominal pain will be assessed for eligibility in general practice and enrolled into the trial. Participants will receive either a defined daily dose of 3 * 2 arbutin 105 mg for 5 days (intervention) or fosfomycin 3 g once (control). Antibiotic therapy will be provided in the intervention group only if needed, i.e. for women with worsening or persistent symptoms. Two co-primary outcomes are the number of all antibiotic courses regardless of the medical indication from day 0-28, and the symptom burden, defined as a weighted sum of the daily total symptom scores from day 0-7. The trial result is considered positive if superiority of initial treatment with UU is demonstrated with reference to the co-primary outcome number of antibiotic courses and non-inferiority of initial treatment with UU with reference to the co primary outcome symptom burden. DISCUSSION: The trial's aim is to investigate whether initial treatment with UU is a safe and effective alternative treatment strategy in women with UTI. In that case, the results might change the existing treatment strategy in general practice by promoting delayed prescription of antibiotics and a reduction of antibiotic use in primary care. TRIAL REGISTRATION: EudraCT: 2016-000477-21 . Clinical trials.gov: NCT03151603 (registered: 10 May 2017). PMID- 29970073 TI - An integrated oral health program for rural residential aged care facilities: a mixed methods comparative study. AB - BACKGROUND: People in residential aged care facilities (RACF) are at very high risk of developing complex oral diseases and dental problems. A multidisciplinary approach incorporating oral health professionals and RACF staff is important for improving and sustaining oral health in RACFs. However, difficulties exist with access to oral health services for RACFs, particularly those in regional and rural areas. This study investigated the impact and experience of an integrated oral health program utilising tele-dentistry and Oral Health Therapists (OHT) in RACFs in a rural setting within Australia. METHODS: A mixed method comparison study was undertaken. Two hundred fifty-two clinical audits were completed across nine facilities with and without access to the integrated oral health program. Twenty-seven oral health quality of life surveys were completed with eligible residents. One focus group discussions (FGD) and eight interviews were completed with RACF staff. Thematic analysis was conducted on the transcribed FGDs and IDIs. Quantitative data were analysed using descriptive statistics. RESULTS: Audits showed an improved compliance to Australian Aged Care Quality Accreditation Standards for oral health in the facilities with access to the integrated program compared to those without the program. Thematic analysis revealed that facilities with the integrated program reported improvements in importance placed on OH, better access to OH services and training, and decreased disruption of residents, particularly those with high care needs. CONCLUSIONS: The integrated oral health program incorporating OHTs and tele-dentistry shows potential to improve the oral health outcomes of residents of RACFs. Improvements for managing oral health of residents with high care needs were observed. RACFs without easy access to an oral health service will also likely benefit from the increased support and training opportunities that the program enables. PMID- 29970074 TI - Estimating the distribution of morbidity and mortality of childhood diarrhea, measles, and pneumonia by wealth group in low- and middle-income countries. AB - BACKGROUND: Equitable access to vaccines has been suggested as a priority for low and middle-income countries (LMICs). However, it is unclear whether providing equitable access is enough to ensure health equity. Furthermore, disaggregated data on health outcomes and benefits gained across population subgroups are often unavailable. This paper develops a model to estimate the distribution of childhood disease cases and deaths across socioeconomic groups, and the potential benefits of three vaccine programs in LMICs. METHODS: For each country and for three diseases (diarrhea, measles, pneumonia), we estimated the distributions of cases and deaths that would occur across wealth quintiles in the absence of any immunization or treatment programs, using both the prevalence and relative risk of a set of risk and prognostic factors. Building on these baseline estimates, we examined what might be the impact of three vaccines (first dose of measles, pneumococcal conjugate, and rotavirus vaccines), under five scenarios based on different sets of quintile-specific immunization coverage and disease treatment utilization rates. RESULTS: Due to higher prevalence of risk factors among the poor, disproportionately more disease cases and deaths would occur among the two lowest wealth quintiles for all three diseases when vaccines or treatment are unavailable. Country-specific context, including how the baseline risks, immunization coverage, and treatment utilization are currently distributed across quintiles, affects how different policies translate into changes in cases and deaths distribution. CONCLUSIONS: Our study highlights several factors that would substantially contribute to the unequal distribution of childhood diseases, and finds that merely ensuring equal access to vaccines will not reduce the health outcomes gap across wealth quintiles. Such information can inform policies and planning of programs that aim to improve equitable delivery of healthcare services. PMID- 29970076 TI - Predictor of multidrug resistant tuberculosis in southwestern part of Ethiopia: a case control study. AB - BACKGROUND: Curable disease tuberculosis is becoming incurable or difficult to treat due to drug resistance. Multi drug resistance tuberculosis is a major health problem for less developed countries. Development of drug resistance is mainly as result of man related factors and poor lifestyle. Identifying predictors of drug resistance and working on them is the important way of reducing the expansion in high burden countries. Ethiopia is one of TB, TB/HIV, and multi-drug resistant tuberculosis (MDR-TB) high burden country globally. This study was aimed to assess predictor of MDR-TB in southwest part of Ethiopia. METHODS: Unmatched case control study was conducted in case to control ratio of 1:1.2 in southwest part of Ethiopia. The cases were recruited from confirmed MDR TB patient enrolled on second line treatment in Shenen Gibe Hospital (MDR-TB treatment center of the prefecture) and the controls were recruited from previously TB patients who cured or patient with smear negative at the end of treatment month during the study period in the same area. The data was collected by structured questionnaire by interview and logistic regression analyses were used to identify predictors of MDR-TB. Odds ratios with 95% CI were computed to determine the predictors. RESULT: From the total 132 participants about 45% of them were cases. None disclosed tuberculosis infected to relatives [AOR = 3.4, 95% CI (1.2-9.8)], insufficient instruction on how to take anti-TB drug [AOR = 4.7, 95% CI (1.4-14.6)], contact history with MDR-TB [AOR = 8.5, 95% CI (2.9 25.5)], interruption of first-line anti-TB treatment for at list 1 day [AOR = 7.9, 95% CI (2.5-24.9)], and having alcohol drinking habits [AOR = 5.1, 95% CI (1.4-18.7)] were identified predictors for MDR-TB infection in study area. CONCLUSION: TB infection disclosure status, insufficient instruction on drug usage, contact history with MDR-TB, interruption of first-line anti-TB drugs, and alcohol drinking habits were identified predictor of MDR-TB case. Therefore, early detection and proper treatment of drug susceptible TB, strengthening directly observed treatment, short-course on daily bases, community involvement, and supporting the patient to intervene identified factors is paramount. PMID- 29970077 TI - Assessing food system vulnerabilities: a fault tree modeling approach. AB - BACKGROUND: Food system function is vulnerable to disruption from a variety of sources. Disruption of the processes required for food provision may result in decreases in food security in affected communities. Currently, there are few tools that quantitatively predict or analyze food system vulnerabilities to contribute to food system resilience analysis. This work presents a prototype version of one such tool, a fault tree, which can be used conceptually and for future modeling work. Fault tree analysis is an engineering tool used to illustrate basic and intermediate factors that can cause overall system failures. METHODS: The fault tree defines food system functioning as food security at the community level and maps the components of the food system onto three main tenets of food security - accessibility, availability, and acceptability. Subtrees were populated using a top down approach guided by expertise, extant literature, and 36 stakeholder interviews. RESULTS: The food system is complex, requiring 12 subtrees to elaborate potential failures. Subtrees comprising accessibility include physical accessibility of the vending point and economic accessibility among community members. Food availability depends on the functioning of the food supply chain, or, in the case of individuals who rely on donated food, the food donation system. The food supply chain includes processing, wholesale operations, distribution systems, and retail center subtrees. Elements of acceptability include the medical appropriateness, nutritional adequacy, and cultural acceptability of food. Case studies of the effects of Winter Storm Jonas of 2016 and the 2013-2017 California drought in Baltimore City illustrate the utility of the fault tree model. CONCLUSION: FTA of potential routes to food system failure provides a tool that allows for consideration of the entirety of the food system; has potential to provide a quantitative assessment of food system failure and recovery; and is able to capture short-term and long-term hazards in a single framework. This systems modeling approach highlights an extensive list of vulnerability points throughout the food system, and underscores the message that reducing food system vulnerabilities requires action at all levels to protect communities from the risks of short-term and long-term threats to food security. PMID- 29970075 TI - Schwannoma of the colon and rectum: a systematic literature review. AB - BACKGROUND: Schwannomas of the colon and rectum are rare among gastrointestinal schwannomas. They are usually discovered incidentally as a submucosal mass on routine colonoscopy and diagnosed on pathologic examination of the operative specimen. Little information exists on the diagnosis and management of this rare entity. The aim of this study is to report a case of cecal schwannoma and the results of a systematic review of colorectal schwannoma in the literature. MAIN BODY: PubMed, Scopus, and Cochrane database searches were performed for case reports and case series of colonic and rectal schwannoma. Ninety-five patients with colonic or rectal schwannoma from 70 articles were included. Median age was 61.5 years (59% female). Presentation was asymptomatic (28%), rectorrhagia (23.2%), or abdominal pain (15.8%). Schwannoma occurred in the left and sigmoid colon in 36.8%, in the cecum and right colon in 30.5%, and in the rectum in 21.1%. Median tumor size was 3 cm and 56.2% of patients who underwent preoperative colonoscopy had a typical smooth submucosal mass. At pathology, 97.9, 13.7, and 5.3% of schwannomas stained positive for S100, vimentin, and GFAP, respectively. The median mitotic index was 1/50. CONCLUSIONS: Colorectal schwannoma is a very rare subtype of gastrointestinal schwannoma which occurs in the elderly, almost equally in men and women. Schwannoma should be included in the differential diagnosis of a submucosal lesion along with gastrointestinal stromal tumor, neuro-endocrine tumors, and leiomyoma-leiomyosarcoma. Definitive diagnosis is based on immunohistochemistry of the operative specimen. Rarely malignant, surgery is the mainstay of treatment. PMID- 29970078 TI - Physicians' preferences for bone metastases treatments in France, Germany and the United Kingdom. AB - BACKGROUND: Several bone-targeted agents (BTAs) are available for preventing skeletal-related events (SREs), but they vary in terms of efficacy, safety and mode of administration. This study assessed data on European physicians' treatment preferences for preventing SREs in patients with bone metastases from solid tumours. METHODS: Physicians completed a web-based discrete-choice experiment survey of 10 choices between pairs of profiles of hypothetical BTAs for a putative patient. Each profile included five attributes within a pre defined range (primarily based on existing BTAs' prescribing information): time (months) until the first SRE; time (months) until worsening of pain; annual risk of osteonecrosis of the jaw (ONJ); annual risk of renal impairment; and mode of administration. Choice questions were developed using an experimental design with known statistical properties. A separate main-effects random parameters logit model was estimated for each country and provided the relative preference for the treatment attributes in the study. RESULTS: A total of 191 physicians in France, 192 physicians in Germany, and 197 physicians in the United Kingdom completed the survey. In France and the United Kingdom, time until the first SRE and risk of renal impairment were the most important attributes; in Germany, time until the first SRE and delay in worsening of pain were the most important. In all countries, a 120-min infusion every 4 weeks was the least preferred mode of administration (p < 0.05) and the annual risk of ONJ was judged to be the least important attribute. CONCLUSIONS: When making treatment decisions regarding the choice of BTA, delaying the onset of SREs/worsening of pain and reducing the risk of renal impairment are the primary objectives for physicians. PMID- 29970079 TI - A comparative study on the frequency of simulation-based training and assessment of non-technical skills in the Norwegian ground ambulance services and helicopter emergency medical services. AB - BACKGROUND: Inadequate non-technical skills (NTSs) among employees in the Norwegian prehospital emergency medical services (EMSs) are a risk for patient and operational safety. Simulation-based training and assessment is promising with respect to improving NTSs. The frequency of simulation-based training in and assessment of NTSs among crewmembers in the Norwegian helicopter emergency medical service (HEMS) has gained increased attention over recent years, whereas there has been much less focus on the Norwegian ground emergency medical service (GEMS). The aim of the study was to compare and document the frequencies of simulation-based training in and assessment of seven NTSs between the Norwegian HEMS and GEMS, conditional on workplace and occupation. METHOD: A comparative study of the results from cross-sectional questionnaires responded to by employees in the Norwegian prehospital EMSs in 2016 regarding training in and assessment of NTSs during 2015, with a focus on the Norwegian GEMS and HEMS. Professional groups of interest are: pilots, HEMS crew members (HCMs), physicians, paramedics, emergency medical technicians (EMTs), EMT apprentices, nurses and nurses with an EMT licence. RESULTS: The frequency of simulation-based training in and assessment of seven generic NTSs was statistically significantly greater for HEMS than for GEMS during 2015. Compared with pilots and HCMs, other health care providers in GEMS and HEMS undergo statistically significantly less frequent simulation-based training in and assessment of NTSs. Physicians working in the HEMS appear to be undergoing training and assessment more frequently than the rest of the health trust employees. The study indicates a tendency for lesser focus on the assessment of NTSs compared to simulation-based training. CONCLUSION: HEMS has become superior to GEMS, in terms of frequency of training in and assessment of NTSs. The low frequency of training in and assessment of NTSs in GEMS suggests that there is a great potential to learn from HEMS and to strengthen the focus on NTSs. Increased frequency of assessment of NTSs in both HEMS and GEMS is called for. PMID- 29970080 TI - Screening for vitamin D deficiency in a tropical area: results of a sun exposure questionnaire. AB - BACKGROUND: Vitamin D deficiency is pandemic while resources available to measure 25-hydroxyvitamin D (25OHD) are limited. The present study aimed to verify whether sun exposure measured by a structured questionnaire could predict serum 25OHD concentrations in healthy Caucasian individuals living in a tropical area. METHODS: A cross-sectional study was carried out in subjects living in the greater Sao Paulo area, Brazil. Two groups of 50 young (20 to 40 years old) and 50 older (60 to 80 years old) subjects (N = 200) answered a structured questionnaire on sun exposure and had blood samples drawn for serum 25OHD concentration measurement during both summer and winter. Anthropometric data were also recorded. Correlation between the questionnaire variables (duration of sun exposure, amount of exposed skin, total sun exposure score - TSES and other data) and serum 25OHD concentration was evaluated. RESULTS: Mean serum 25OHD concentration was 17.60 +/- 7.3 ng/mL with no difference between age groups (p = 0.293). TSES weakly correlated with serum 25OHD levels (r = 0.264; p < 0.001). Separate analyzes by age groups demonstrated that TSES correlated significantly with serum 25OHD concentration only in the older subjects during summer (r = 0.322; p = 0.023). Using linear regression analyses, TSES and body mass index (BMI) were significantly associated with serum 25OHD levels. On the other hand, Receiver operating characteristic (ROC) analysis for TSES showed no significance as a screening tool for vitamin D deficiency (p = 0.172). CONCLUSION: Sun exposure questionnaire associated with BMI correlates with serum 25OHD concentration with very low accuracy. The use of the questionnaire does not discriminate between vitamin D sufficient and deficient individuals. PMID- 29970081 TI - Peptides derived from the integrin beta cytoplasmic tails inhibit angiogenesis. AB - BACKGROUND: Integrins are essential regulators of angiogenesis. However, the antiangiogenic potential of peptides derived from the integrin cytoplasmic tails (CT) remains mostly undetermined. METHODS: Here we designed a panel of membrane penetrating peptides (termed as mbetaCTPs), each comprising a C-terminal NxxY motif from one of the conserved integrin beta CTs, and evaluated their antiangiogenic ability using both in vitro and in vivo approaches. RESULTS: We found that mbeta3CTP, mbeta5CTP and mbeta6CTP, derived respectively from the integrin beta3, beta5 and beta6 CTs, but not others, exhibit antiangiogenic ability. Interestingly, we observed that the integrin beta3, beta5 and beta6 CTs but not others are able to interact with beta3-endonexin. In addition, the antiangiogenic core in mbeta3CTP is identical to a previously identified beta3 endonexin binding region in the integrin beta3 CT, indicating that the antiangiogenic mbetaCTPs may function via their binding to beta3-endonexin. Consistently, knockdown of endogenous beta3-endonexin in HUVECs significantly suppresses tube formation, suggesting that beta3-endonexin is proangiogenic. However, neither treatment with the antiangiogenic mbetaCTPs nor knockdown of endogenous beta3-endonexin affects integrin-mediated HUVEC adhesion and migration, indicating that their antiangiogenic effect may not rely on directly regulating integrin activity. Importantly, both treatment with the antiangiogenic mbetaCTPs and knockdown of endogenous beta3-endonexin in HUVECs inhibit VEGF expression and cell proliferation, thereby providing mechanistic explanations for the functional consequences. CONCLUSION: Our results suggest that the antiangiogenic mbetaCTPs can interact with beta3-endonexin in vascular endothelial cells and suppress its function in regulating VEGF expression and cell proliferation, thus disclosing a unique pathway that may be useful for developing novel antiangiogenic strategies. PMID- 29970082 TI - Engineering de novo anthocyanin production in Saccharomyces cerevisiae. AB - BACKGROUND: Anthocyanins are polyphenolic pigments which provide pink to blue colours in fruits and flowers. There is an increasing demand for anthocyanins, as food colorants and as health-promoting substances. Plant production of anthocyanins is often seasonal and cannot always meet demand due to low productivity and the complexity of the plant extracts. Therefore, a system of on demand supply is useful. While a number of other (simpler) plant polyphenols have been successfully produced in the yeast Saccharomyces cerevisiae, production of anthocyanins has not yet been reported. RESULTS: Saccharomyces cerevisiae was engineered to produce pelargonidin 3-O-glucoside starting from glucose. Specific anthocyanin biosynthetic genes from Arabidopsis thaliana and Gerbera hybrida were introduced in a S. cerevisiae strain producing naringenin, the flavonoid precursor of anthocyanins. Upon culturing, pelargonidin and its 3-O-glucoside were detected inside the yeast cells, albeit at low concentrations. A number of related intermediates and side-products were much more abundant and were secreted into the culture medium. To optimize titers of pelargonidin 3-O-glucoside further, biosynthetic genes were stably integrated into the yeast genome, and formation of a major side-product, phloretic acid, was prevented by engineering the yeast chassis. Further engineering, by removing two glucosidases which are known to degrade pelargonidin 3-O-glucoside, did not result in higher yields of glycosylated pelargonidin. In aerated, pH controlled batch reactors, intracellular pelargonidin accumulation reached 0.01 umol/gCDW, while kaempferol and dihydrokaempferol were effectively exported to reach extracellular concentration of 20 uM [5 mg/L] and 150 uM [44 mg/L], respectively. CONCLUSION: The results reported in this study demonstrate the proof-of-concept that S. cerevisiae is capable of de novo production of the anthocyanin pelargonidin 3-O glucoside. Furthermore, while current conversion efficiencies are low, a number of clear bottlenecks have already been identified which, when overcome, have huge potential to enhance anthocyanin production efficiency. These results bode very well for the development of fermentation-based production systems for specific and individual anthocyanin molecules. Such systems have both great scientific value for identifying and characterising anthocyanin decorating enzymes as well as significant commercial potential for the production of, on-demand, pure bioactive compounds to be used in the food, health and even pharma industries. PMID- 29970083 TI - Impact of immunization against OxLDL on the pulmonary response to cigarette smoke exposure in mice. AB - BACKGROUND: Cigarette smoke exposure can affect pulmonary lipid homeostasis and cause a progressive increase in pulmonary antibodies against oxidized low-density lipoproteins (OxLDL). Similarly, increased anti-OxLDL antibodies are observed in atherosclerosis, a pathology also tightly associated with smoking and lipid homeostasis disruption. Several immunization strategies against oxidized lipid species to help with their clearance have been shown to reduce the formation of atherosclerotic lesions. Since oxidized lipids are generated during cigarette smoke exposure, we investigated the impact of a prophylactic immunization protocol against OxLDL on the pulmonary effects of cigarette smoke exposure in mice. METHODS: Mice were immunized systemically with a mixture of human OxLDL (antigen source) and AddaVax (adjuvant) or PBS alone prior to the initiation of acute (2 week) or sub-chronic (8 weeks) cigarette smoke exposure protocols. Anti OxLDL antibodies were measured in the bronchoalveolar lavage (BAL) fluid and serum by direct ELISA. Pulmonary impacts of cigarette smoke exposure and OxLDL immunization were assessed by measuring BAL inflammatory cells, lung functions, and changes in lung structure and gene levels of matrix/matrix-related genes. RESULTS: Immunization to OxLDL led to a marked increase in circulating and pulmonary antibodies against OxLDL that persisted during cigarette smoke exposure. OxLDL immunization did not exacerbate or reduce the inflammatory response following acute or sub-chronic exposure to cigarette smoke. OxLDL immunization alone had effects similar to cigarette smoke exposure on lung functions but OxLDL immunization and cigarette smoke exposure had no additive effects on these parameters. No obvious changes in lung histology, airspace or levels of matrix and matrix-related genes were caused by OxLDL immunization compared to vehicle treatment. CONCLUSIONS: Overall, this study shows for the first time that a prophylactic immunization protocol against OxLDL can potentially have detrimental effects lung functions, without having additive effects over cigarette smoke exposure. This work sheds light on a complex dynamic between anti-OxLDL antibodies and the pulmonary response to cigarette smoke exposure. PMID- 29970084 TI - Cattle transhumance and agropastoral nomadic herding practices in Central Cameroon. AB - BACKGROUND: In sub-Saharan Africa, livestock transhumance represents a key adaptation strategy to environmental variability. In this context, seasonal livestock transhumance also plays an important role in driving the dynamics of multiple livestock infectious diseases. In Cameroon, cattle transhumance is a common practice during the dry season across all the main livestock production zones. Currently, the little recorded information of the migratory routes, grazing locations and nomadic herding practices adopted by pastoralists, limits our understanding of pastoral cattle movements in the country. GPS-tracking technology in combination with a questionnaire based-survey were used to study a limited pool of 10 cattle herds from the Adamawa Region of Cameroon during their seasonal migration, between October 2014 and May 2015. The data were used to analyse the trajectories and movement patterns, and to characterize the key animal health aspects related to this seasonal migration in Cameroon. RESULTS: Several administrative Regions of the country were visited by the transhumant herds over more than 6 months. Herds travelled between 53 and 170 km to their transhumance grazing areas adopting different strategies, some travelling directly to their destination areas while others having multiple resting periods and grazing areas. Despite their limitations, these are among the first detailed data available on transhumance in Cameroon. These reports highlight key livestock health issues and the potential for multiple types of interactions between transhumant herds and other domestic and wild animals, as well as with the formal livestock trading system. CONCLUSION: Overall, these findings provide useful insights into transhumance patterns and into the related animal health implications recorded in Cameroon. This knowledge could better inform evidence based approaches for designing infectious diseases surveillance and control measures and help driving further studies to improve the understanding of risks associated with livestock movements in the region. PMID- 29970085 TI - EU health systems classification: a new proposal from EURO-HEALTHY. AB - BACKGROUND: In accordance the WHO framework of health system functions and by using the indicators collected within the EURO-HEALTHY project, this work aims to contribute to the discussion on the classification of EU health systems. METHODS: Three methods were used in this article: factor analysis, cluster analysis and descriptive analysis; data were mainly collected from the WHO and Eurostat databases. RESULTS: The most relevant result is the proposed classification of health systems into the following clusters: Austria-Germany, Central and Northern Countries, Southern Countries, Eastern Countries 'A' and Eastern Countries 'B'. CONCLUSIONS: The proposed typology contributes to the discussion about how to classify health systems; the typology of EU health systems allows comparisons of characteristics and health system performance across clusters and policy assessment and policy recommendation within each cluster. PMID- 29970086 TI - Fascin induces melanoma tumorigenesis and stemness through regulating the Hippo pathway. AB - BACKGROUND: Fascin is a F-actin bundling protein and its overexpression is correlated with poor prognosis and increases metastatic potential in a number of cancers. But underlying function and mechanism of fascin on tumorigenesis in melanoma remain elusive. METHODS: The melanoma cell lines WM793 and WM39 were employed for the soft agar and sphere formation assay. Quantitative RT-PCR and Western blot were performed for identifying the gene expression at mRNA and protein levels, respectively. Co-IP and in vitro GST pulldown experiments were used to test the interaction between fascin and MST2. RESULTS: Fascin regulates tumorigenesis and cancer cell stemness in melanoma through inhibition of the Hippo pathway kinase MST2 and the activation of transcription factor TAZ. Our data showed that fascin interacts with the kinase domain of MST2 to inhibit its homodimer formation and kinase activity. Depletion of fascin led to increase of p LATS level and decrease of TAZ, but not YAP. We also demonstrated that fascin regulates melanoma tumorigenesis independent of its actin-bundling activity. CONCLUSIONS: Fascin is a new regulator of the MST2-LATS-TAZ pathway and plays a critical role in melanoma tumorigenesis. Inhibition of fascin reduces melanoma tumorigenesis and stemness, and thus fascin could be a potential therapeutic target for this malignancy. PMID- 29970087 TI - Decentralizing the delivery of HIV pre-exposure prophylaxis (PrEP) through family physicians and sexual health clinic nurses: a dissemination and implementation study protocol. AB - BACKGROUND: Gay, bisexual and other men who have sex with men (gbMSM) in Canada continue to experience high rates of incident HIV. Pre-exposure prophylaxis (PrEP, the regular use of anti-HIV medication) reduces HIV acquisition and could reduce incidence. However, there are too few physicians with expertise in HIV care to meet the projected demand for PrEP. To meet demand and achieve greater public health impact, PrEP delivery could be 'decentralized' by incorporating it into front-line prevention services provided by family physicians (FPs) and sexual health clinic nurses. METHODS: This PrEP decentralization project will use two strategies. The first is an innovative knowledge dissemination approach called 'Patient-Initiated CME' (PICME), which aims to empower individuals to connect their family doctors with online, evidence-based, continuing medical education (CME) on PrEP. After learning about the project through community agencies or social/sexual networking applications, gbMSM interested in PrEP will use a uniquely coded card to access an online information module that includes coaching on how to discuss their HIV risk with their FP. They can provide their physician a link to the accredited CME module using the same card. The second strategy involves a pilot implementation program, in which gbMSM who do not have a FP may bring the card to designated sexual health clinics where trained nurses can deliver PrEP under a medical directive. These approaches will be evaluated through quantitative and qualitative methods, including: questionnaires administered to patients and physicians at baseline and at six months; focus groups with patients, FPs, and sexual health clinic staff; and review of sexual health clinic charts. The primary objective is to quantify the uptake of PrEP achieved using each decentralization strategy. Secondary objectives include a) characterizing barriers and facilitators to PrEP uptake for each strategy, b) assessing fidelity to core components of PrEP delivery within each strategy, c) measuring patient-reported outcomes including satisfaction with clinician-patient relationships, and d) conducting a preliminary costing analysis. DISCUSSION: This study will assess the feasibility of a novel strategy for disseminating knowledge about evidence-based clinical interventions, and inform future strategies for scale-up of an underutilized HIV prevention tool. PMID- 29970088 TI - Improving health equity: changes in self-assessed health across income groups in China. AB - BACKGROUND: Beginning in 2010, China has endeavoured to expand health coverage and provide residents with fair access to primary health care with the intention of improving health equity. This study aims to measure changes in income-related health inequity in China between 2010 and 2014. METHODS: Data were extracted from the nationally representative annual survey of the China Family Panel Studies in 2010 and 2014 with a first wave of 31,743 respondents and a second wave of 32,006 respondents over age 15. In both years, subjects were stratified into the following five categories of income: poorest 20%, lower 20%, medium 20%, higher 20% and richest 20%. The concentration curve and index was used to compare the distribution of health status in income quintiles, and a logistic model was used to examine the relationship between health and socioeconomic indicators with self assessed health as the primary outcome of interest. RESULTS: Income was significantly associated with self-assessed health in China. The concentration curve was above the line of equality in both years, while the self-assessed health line in 2014 was closer to the equality line. The concentration index (CIN) displayed the similar result of decreasing inequality, with the CIN in 2014 (- 0.157) closer to zero (the line of equality) than that of 2010 (- 0.167). In 2010, there was a decreasing trend of people reporting poor health from the poorest to the richest, while in 2014, there was no significant difference between the poorest and lower 20% or between the higher 20% and the medium 20%. The odds ratio of the prevalence of self-reporting poor health between the poorest and richest increased from 0.555 (95% CI: 0.484-0.636) in 2010 to 0.598 (95% CI: 0.513-0.696) in 2014. CONCLUSIONS: From 2010 to 2014, the self-assessed health gap between income groups in China decreased, and health equity improved. However, health differences remain. In order to achieve better health for all, China should further strengthen the role of primary care in reducing health inequity. PMID- 29970089 TI - Prevalence and determinants of contraceptive utilization among married women at Dabat Health and Demographic Surveillance System site, northwest Ethiopia. AB - BACKGROUND: Despite the enormous benefits of family planning services, the contraceptive utilization still remains low in Sub-Saharan Africa. There is regional variation in modern contraceptive utilization in Ethiopia. Therefore, this study was aimed to determine the prevalence of modern contraceptive utilization and determinants in Dabat demographic and health surveillance system site, northwest Ethiopia. METHODS: A re-census was carried out in Dabat Health and Demographic Surveillance System (HDSS) site from October to December 2014. Data of 8271 married women collected in the re-census was used. The outcome variable was current utilization of any modern contraceptive methods whereas socio demographic and economic variables were the potential determinants considered. Bi-variable and multivariable binary logistic regression along with odds ratio and 95% confidence interval were used to describe the strength of association. RESULTS: Prevalence of modern contraceptive utilization among married women in Dabat DHSS site was found to be 32.5% (95%CI: 31.5, 33.5%). After adjusting for covariates; the odds of using modern contraceptive were 2.35 times, 1.91 times, and 1.39 times higher among women of secondary and above educational level, urban residents, and women having six and above living children, respectively. CONCLUSION: Modern contraceptive utilization was found to be very low. Effort has to be applied to improve women's educational level that increases their understanding of reproductive health issues. It is also important to give special emphasis for rural residents, those aged 20-40 years, and those with six or more living children while serving for modern contraceptive methods. PMID- 29970090 TI - Effect of an organised screening program on socioeconomic inequalities in mammography practice, knowledge and attitudes. AB - BACKGROUND: Breast cancer stands as the leading cause of cancer related mortality in women worldwide. Mammography screening has the potential to improve prognosis by reducing stage at diagnosis. Socioeconomic inequalities in mammography cancer screening have been widely reported. The influence of organised programs on socioeconomic disparities regarding mammography screening is to date unclear. We aimed to investigate the impact of an organised regional screening program on socioeconomic inequalities in terms of the uptake, knowledge and attitudes towards mammography screening. METHODS: Data were obtained from two cross sectional surveys of women 50 to 69 years old conducted in 1998 and 2012, before and after the implementation of an organised breast cancer screening program in Geneva, Switzerland. Socioeconomic status was measured by monthly household income and education level. Logistic and linear regression multivariable models were used to investigate the evolution of socioeconomic gradients between 1998 and 2012 in terms of uptake, knowledge and attitudes towards mammography screening. RESULTS: In 1998, before the implementation of an organised screening program, 44% of women from the lowest education category reported mammography practice conforming to recommendations versus 63% of the more educated participants. This socioeconomic gradient was no longer present in 2012 where reported mammography practice at guideline-recommended frequency were 83 and 82% in the lowest and highest education level categories respectively (change in education gradient over time, p = 0.018). The difference in mammography practice in agreement with recommendations between the lowest and the highest income category went from 27 percentage points in 1998 to 14 percentage points in 2012 (change in income gradient over time, p = 0.10). The socioeconomic gradient in negative attitudes towards mammography screening persisted in 2012 but was reduced compared to 1998. We did not observe a reduction in the socioeconomic disparities in knowledge regarding mammography screening over this period. CONCLUSIONS: This study suggests that mammography screening programs may lessen socioeconomic inequities in mammography practice. Such programs should feature adapted communication tools to reach women of lower socioeconomic status to attempt to further reduce socioeconomic gradients in mammography screening. PMID- 29970091 TI - Metabolic engineering of Escherichia coli for the synthesis of polyhydroxyalkanoates using acetate as a main carbon source. AB - BACKGROUND: High production cost of bioplastics polyhydroxyalkanoates (PHA) is a major obstacle to replace traditional petro-based plastics. To address the challenges, strategies towards upstream metabolic engineering and downstream fermentation optimizations have been continuously pursued. Given that the feedstocks especially carbon sources account up to a large portion of the production cost, it is of great importance to explore low cost substrates to manufacture PHA economically. RESULTS: Escherichia coli was metabolically engineered to synthesize poly-3-hydroxybutyrate (P3HB), poly(3-hydroxybutyrate-co 4-hydroxybutyrate) (P3HB4HB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) using acetate as a main carbon source. Overexpression of phosphotransacetylase/acetate kinase pathway was shown to be an effective strategy for improving acetate assimilation and biopolymer production. The recombinant strain overexpressing phosphotransacetylase/acetate kinase and P3HB synthesis operon produced 1.27 g/L P3HB when grown on minimal medium supplemented with 10 g/L yeast extract and 5 g/L acetate in shake flask cultures. Further introduction succinate semialdehyde dehydrogenase, 4-hydroxybutyrate dehydrogenase, and CoA transferase lead to the accumulation of P3HB4HB, reaching a titer of 1.71 g/L with a 4-hydroxybutyrate monomer content of 5.79 mol%. When 1 g/L of alpha-ketoglutarate or citrate was added to the medium, P3HB4HB titer increased to 1.99 and 2.15 g/L, respectively. To achieve PHBV synthesis, acetate and propionate were simultaneously supplied and propionyl-CoA transferase was overexpressed to provide 3-hydroxyvalerate precursor. The resulting strain produced 0.33 g/L PHBV with a 3-hydroxyvalerate monomer content of 6.58 mol%. Further overexpression of propionate permease improved PHBV titer and 3 hydroxyvalerate monomer content to 1.09 g/L and 10.37 mol%, respectively. CONCLUSIONS: The application of acetate as carbon source for microbial fermentation could reduce the consumption of food and agro-based renewable bioresources for biorefineries. Our proposed metabolic engineering strategies illustrate the feasibility for producing polyhydroxyalkanoates using acetate as a main carbon source. Overall, as an abundant and renewable resource, acetate would be developed into a cost-effective feedstock to achieve low cost production of chemicals, materials, and biofuels. PMID- 29970092 TI - Physical activity counseling in primary care and family medicine residency training: a systematic review. AB - BACKGROUND: Physical inactivity is a global public health challenge. Physical activity (PA) promotion in healthcare delivery systems is effective to reduce physical inactivity. A primary care setting provides an appropriate environment for PA counseling since it is a primary contact with primary care or family physicians encounter the majority of the population. Lack of knowledge and inadequate training in PA counseling is one of the most important barriers to PA promotion. The purpose of this systematic review was to evaluate PA counseling training in primary care residency programs. METHODS: The authors systematically searched PubMed, Web of Science, Scopus and The Cochrane Library for articles published in English from 2000 to 2017. Articles regarding PA counseling in primary care residency training were extracted and outcomes assessed for this systematic review. RESULTS: Based on the initial review, 378 articles were excluded (362 articles excluded based on titles and abstracts and 16 articles excluded based on full texts). Four articles were included in this review, addressed PA counseling curricula in primary care residency training. All studies included PA counseling training as part of obesity and healthy lifestyle training. The training improved knowledge among primary care residents, but may not necessarily result in better attitudes or self-efficacy, which could be improved by elective rotations that focus on improved attitudes, self-efficacy, and professional norms for PA counseling. Brief training in counseling did not improve quality nor increase the rate of counseling. CONCLUSIONS: This systematic review demonstrates a lack of evidence due to a small number of included studies. The heterogeneous outcomes from the minimal programs are needed to carefully interpret. However, this review sheds light on the importance of training in PA counseling in primary care residency programs. The development of training in PA counseling should focus on an approach that improves attitudes and the self efficacy of primary care residents. Elective rotations, where residents voluntarily choose their subject, may provide the appropriate training period for PA counseling. Policymakers and academics should play an active role in the implementation of PA counseling as an essential competency for primary care physicians. PMID- 29970093 TI - Like parent, like child? Dietary resemblance in families. AB - BACKGROUND: Studies investigating dietary resemblance between parents and their children have gained mixed results, and the resemblance seems to vary across nutrients, foods, dietary-assessment tools used, and parent-child pairs. We investigated parent-child dietary resemblance using a novel approach in applying statistical analysis, which allowed the comparison of 'whole-diet' between parents and their children. Additionally, we sought to establish whether sociodemographic factors or family meals were associated with dietary resemblance and whether parent-child dietary resemblance was dependent on the parent providing food consumption data on behalf of the child (father or mother, "the respondent"). METHODS: The DAGIS study investigated health behaviors among Finnish preschoolers using a cross-sectional design. One parent filled in a food frequency questionnaire (FFQ) measuring the child's food consumption outside preschool hours during the last week. In addition, we instructed both parents or legal guardians, should the child have two, to fill in a similar FFQ regarding their own food use. Parents also reported their educational level, the number of children living in the same household, and the number of family meals. As a measure of dietary resemblance between a parent and a child, we computed Spearman correlations ranging mostly from no resemblance (0) to complete resemblance (+ 1) between parent-child pairs over the 'whole-diet' (excluding preschool hours). These resemblance measures were further investigated using linear mixed models. RESULTS: We obtained 665 father-child and 798 mother-child resemblance measures. Mother-child resemblance was on average 0.57 and stronger than father-child resemblance (0.50, p < 0.0001), which was explained by a parent-respondent interaction: the diet of the child resembled more the diet of the parent who provided food consumption data for the child. In univariate models, father- and mother-reported number of family meals were positively associated with father child and mother-child resemblances. Mother-reported number of family meals was positively associated with mother-child resemblance in a full model. CONCLUSIONS: The diet of the child seems to resemble more the diet of the parent responsible for the reporting of food consumption. Studies should report who provided the food consumption data for the child and take this into account in analyses, since reporter-bias can influence the results. PMID- 29970094 TI - Cytotoxic properties of the anthraquinone derivatives isolated from the roots of Rubia philippinensis. AB - BACKGROUND: Cancer is one of the most frequently occurring diseases and is the second leading cause of death worldwide. In this study, anthraquinone derivatives (Compounds 1-5) were evaluated for their anti-cancer potential against various skin and breast cancer cell lines to assess whether these anthraquinone derivatives may serve as a lead for the augmentation of anti-cancer drug. METHODS: Anthraquinone derivatives, 2-methyl-1,3,6-trihydroxy-9,10-anthraquinone 3-O-(6'-O-acetyl)-alpha-rhamnosyl(1 -> 2)-beta-glucoside (Comp 1), 2-methyl-1,3,6 trihydroxy-9,10-anthraquinone (Comp 2), and alizarin (Comp 3) were isolated from the dichloromethane fraction of the roots of Rubia philippinensis., whereas ethyl acetate fraction yielded xanthopurpurin (Comp 4) and lucidin-omega-methyl ether (Comp 5). Structures of all the isolated compounds were determined by spectral data analysis. All isolated compounds (Comp 1-5) were assessed for cytotoxicity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against four different cancer cell lines, i.e. human melanoma (SK-MEL-5), murine melanoma (B16F10), and human breast adenocarcinoma (MCF7 and MDA-MB-231). RESULTS: Significant activity of the compounds 4 and 5 was observed against the breast cancer cell line MDA-MB-231 with IC50 values of 14.65 +/- 1.45 and 13.03 +/- 0.33 MUM, respectively. Encouragingly, IC50 values of 67.89 +/- 1.02 and 79.01 +/- 0.03 MUM against normal kidney epithelial cells (MDCK) were also obtained for compounds 4 and 5, respectively, which indicated very low toxicity and favorable selectivity indices for compounds 4 and 5 in the range of 1.85 to 3.95 and 2.11 to 6.06 against skin cancer cell lines (SK-MEL-5, and B16F10), and breast cancer cell lines (MCF7 and MDA-MB-231), respectively. CONCLUSION: Our results suggested that the compounds 4 (xanthopurpurin) and 5 (lucidin-omega methyl ether) showed high selective toxicity towards breast cancer cells at lower concentrations without showing toxicity towards normal cells, thus could be of potential as new lead molecules in cancer treatment. PMID- 29970095 TI - Trend in primary caesarean delivery: a five-year experience in ABRUZZO, ITALY. AB - BACKGROUND: Primary caesarean section (PCS) rate is one of the main indicators of quality of care suggested by the Italian Government. Hospital rankings are usually based on it, therefore lower rates reflect more appropriate clinical practice. The aim of this study is to describe a five-year trend of PCS rate in Abruzzo region from 2009 to 2013 and to examine the medical indications for this mode of delivery. METHODS: Forty-five thousand one hundred forty-nine deliveries occurring from 2009 to 2013 were collected from all hospital discharge records (HDR) and analyzed. Among them we found 12,542 PCS. Odds ratios (ORs) with 95% confidence interval (95% CI) were estimated using logistic regression methods to evaluate the relationship between maternal risk factors and PCS in hospital over 1000 delivery/yrs. RESULTS: The five-year PCS rate was 28.9%, with a decreasing trend from 31.4% in 2009 to 26.1% in 2013. Vasto Civil Hospital shows the lowest PCS rate (17.9% in 2013) among hospitals with a maximum of 1000 deliveries per year, while Pescara Civil Hospital shows the lowest PCS rate (25.4% in 2013) among hospitals with over 1000 deliveries per year. Women with major risk factors for cesarean section delivered more frequently in maternity units over 1000 delivery/yrs. Logistic regression analyses showed as diabetes, hypertension, twin pregnancy, fetal distress and preterm delivery were significant risk factors to deliver in unit over 1000 delivery/yrs. The most frequent (overall 66.6%) discharge diagnosis recorded in Hospital discharge records (HDR) is "Caesarean Delivery Without Indication". 7.3% of PCS made in Abruzzo concerns women living in other Italian regions. 11.4% of PCS contains one of the indications to caesarean section (CS) that the Italian Guidelines consider appropriate. CONCLUSIONS: During the analyzed period, Abruzzo showed a decreasing, but still too high, PCS rate, compared to the limits fixed by the Italian Ministry of Health. Considering the limitation of this study, based on administrative data that are poor in clinical information, it is not possible to define the appropriateness of all caesarean sections. PMID- 29970096 TI - Computer-aided prediction of antigen presenting cell modulators for designing peptide-based vaccine adjuvants. AB - BACKGROUND: Evidences in literature strongly advocate the potential of immunomodulatory peptides for use as vaccine adjuvants. All the mechanisms of vaccine adjuvants ensuing immunostimulatory effects directly or indirectly stimulate antigen presenting cells (APCs). While numerous methods have been developed in the past for predicting B cell and T-cell epitopes; no method is available for predicting the peptides that can modulate the APCs. METHODS: We named the peptides that can activate APCs as A-cell epitopes and developed methods for their prediction in this study. A dataset of experimentally validated A-cell epitopes was collected and compiled from various resources. To predict A cell epitopes, we developed support vector machine-based machine learning models using different sequence-based features. RESULTS: A hybrid model developed on a combination of sequence-based features (dipeptide composition and motif occurrence), achieved the highest accuracy of 95.71% with Matthews correlation coefficient (MCC) value of 0.91 on the training dataset. We also evaluated the hybrid models on an independent dataset and achieved a comparable accuracy of 95.00% with MCC 0.90. CONCLUSION: The models developed in this study were implemented in a web-based platform VaxinPAD to predict and design immunomodulatory peptides or A-cell epitopes. This web server available at http://webs.iiitd.edu.in/raghava/vaxinpad/ will facilitate researchers in designing peptide-based vaccine adjuvants. PMID- 29970097 TI - Modeled exposure to tetrachloroethylene-contaminated drinking water and the risk of placenta-related stillbirths: a case-control study from Massachusetts and Rhode Island. AB - BACKGROUND: Residents of Massachusetts and Rhode Island were exposed to tetrachloroethylene (PCE)-contaminated drinking water from 1968 through the early 1990s when the solvent was used to apply a vinyl liner to drinking water mains to address taste and odor problems. Few studies have examined the risk of fetal death among women exposed to solvent-contaminated drinking water. Two previous investigations found moderate increases in the risk of stillbirth among highly exposed women; however, these results were based on a small number of cases. The present case-control study was undertaken to examine further this association with a large number of stillbirths. METHODS: Cases were comprised of stillborn infants delivered between 1968 and 1995 to mothers who resided in 28 Massachusetts and Rhode Island cities and towns with some affected water mains (N = 296). Cases were included if the cause of death was placental abruption and/or placental insufficiency. Controls were randomly selected live-born infants who were delivered in the same time period and geographic area (N = 783). Data on confounding variables were gathered from vital records and questionnaires. PCE exposure was estimated using a leaching and transport model integrated into water system software. RESULTS: Mothers with any PCE exposure had a 1.7-fold increase in the adjusted odds of placenta-related stillbirth (95% CI: 1.2-2.4). The adjusted odds ratio (OR) increased as a woman's exposure level increased: in comparison to unexposed mothers, ORs were 1.5 (95% CI: 1.0-2.3) for low exposure (> 0-median), 1.7 (95% CI: 1.1-2.5) for moderate exposure (>median-90th percentile) and 1.9 (95% CI: 1.1-3.2) for high exposure (>90th percentile) (p value for trend = 0.02). A similar pattern was observed when PCE exposure was dichotomized at 40 MUg/L, the suggested action guideline for remediation (OR = 1.5, 95% CI: 1.1-2.2 and OR = 2.6, 95% CI: 1.4-4.8, respectively, for PCE exposure <=40 MUg/L and > 40 MUg/L) (p value for trend = .003). CONCLUSIONS: We observed a linear dose-dependent increase in the odds of stillbirth due to placental abruption and placental insufficiency with prenatal exposure to PCE contaminated drinking water. Because PCE remains a common drinking water contaminant, these findings highlight the importance of considering pregnant women when monitoring, regulating and remediating drinking water supplies. PMID- 29970098 TI - Mental health service users' experiences of psychiatric re-hospitalisation - an explorative focus group study in six European countries. AB - BACKGROUND: Psychiatric re-hospitalisation is considered costly and disruptive to individuals. The perspective of the mental health service user is largely unexplored in literature. The purpose of our study was to explore service users' experiences of psychiatric re-hospitalisation across six countries in Europe. METHOD: Eight focus groups were conducted in Romania, Slovenia, Finland, Italy, Austria and Norway. RESULTS: A total of 55 service users participated in the study. All participants had been in receipt of mental health services for at least 1 year, and had experienced more than one psychiatric hospitalisation. The experience of re-hospitalisation was considered: (1) less traumatising than the first hospitalisation, (2) to be necessary, and a relief, (3) occurring by default and without progress, (4) part of the recovery process. CONCLUSIONS: Psychiatric re-hospitalisation was considered inevitable by the study participants, in both positive and negative terms. Striking similarities in service user experiences were found across all of the six countries, the first experience of psychiatric hospitalisation emerging as especially significant. Findings indicate the need for further action in order to develop more recovery and person-centred approaches within hospital care. For psychiatric inpatient care to be a positive part of the recovery process, further knowledge on what therapeutic action during the hospital stay would be beneficial, such as therapy, activities and integration with other services. PMID- 29970099 TI - Reticuloendotheliosis virus and avian leukosis virus subgroup J synergistically increase the accumulation of exosomal miRNAs. AB - BACKGROUND: Co-infection with avian leukosis virus subgroup J and reticuloendotheliosis virus induces synergistic pathogenic effects and increases mortality. However, the role of exosomal miRNAs in the molecular mechanism of the synergistic infection of the two viruses remains unknown. RESULTS: In this study, exosomal RNAs from CEF cells infected with ALV-J, REV or both at the optimal synergistic infection time were analysed by Illumina RNA deep sequencing. A total of 54 (23 upregulated and 31 downregulated) and 16 (7 upregulated and 9 downregulated) miRNAs were identified by comparing co-infection with two viruses, single-infected ALV-J and REV, respectively. Moreover, five key miRNAs, including miR-184-3p, miR-146a-3p, miR-146a-5p, miR-3538 and miR-155, were validated in both exosomes and CEF cells by qRT-PCR. GO annotation and KEGG pathway analysis of the miRNA target genes showed that the five differentially expressed miRNAs participated in virus-vector interaction, oxidative phosphorylation, energy metabolism and cell growth. CONCLUSIONS: We demonstrated that REV and ALV-J synergistically increased the accumulation of exosomal miRNAs, which sheds light on the synergistic molecular mechanism of ALV-J and REV. PMID- 29970100 TI - Positive surgical margin is associated with biochemical recurrence risk following radical prostatectomy: a meta-analysis from high-quality retrospective cohort studies. AB - BACKGROUND AND PURPOSE: Although numerous studies have shown that positive surgical margin (PSM) is linked to biochemical recurrence (BCR) in prostate cancer (PCa), the research results have been inconsistent. This study aimed to explore the association between PSM and BCR in patients with PCa following radical prostatectomy (RP). MATERIALS AND METHODS: In accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA), PubMed, EMBASE and Wan Fang databases were searched for eligible studies from inception to November 2017. The Newcastle-Ottawa Scale was used to assess the risk of bias of the included studies. Meta-analysis was performed by using Stata 12.0. Combined hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models. RESULTS: Ultimately, 41 retrospective cohort studies of high quality that met the eligibility criteria, comprising 37,928 patients (94 3294 per study), were included in this meta-analysis. The results showed that PSM was associated with higher BCR risk in both univariate analysis (pooled HR = 1.56; 95% CI 1.46, 1.66; p < 0.001) and multivariate analysis (pooled HR = 1.35; 95% CI 1.27, 1.43; p < 0.001). Moreover, no potential publication bias was observed among the included studies in univariate analysis (p-Begg = 0.971) and multivariate analysis (p-Begg = 0.401). CONCLUSIONS: Our meta-analysis demonstrated that PSM is associated with a higher risk of BCR in PCa following RP and could serve as an independent prognostic factor in patients with PCa. PMID- 29970101 TI - Epstein-Barr virus- and cytomegalovirus-specific immune response in patients with brain cancer. AB - BACKGROUND: Patients with brain tumor or pancreatic cancer exhibit the poorest prognosis, while immune fitness and cellular immune exhaustion impacts their survival immensely. This work identifies differences in the immune reactivity to the common human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) between patients with brain tumor in comparison to those with pancreatic cancer and healthy individuals. METHODS: We characterized the humoral and cellular immune responses of patients with brain tumor or pancreatic cancer to cytomegalovirus structural protein pp65 (CMV-pp65) as well as Epstein-Barr nuclear antigen-1 (EBNA-1) by whole-blood assay and ELISA. RESULTS: Anti-CMV-pp65 plasma immunoglobulin gamma (IgG) titers were significantly lower in patients with brain tumor compared to healthy donors and patients with pancreatic cancer. Among the responding patients with GBM, those with a weak anti-CMV IgG response also had a decreased median overall survival (p = 0.017, 667 vs 419 days) while patients with brain tumor showed a generally suppressed anti-CMV immune reactivity. Patients with brain tumor exhibited a significantly lower interferon gamma (IFNgamma) response to EBNA-1 and CMV-pp65 compared to patients with pancreatic cancer or healthy donors. This antigen-specific response was further amplified in patients with brain tumor upon conditioning of whole blood with IL 2/IL-15/IL-21. Exclusively in this setting, among the responding patients with GBM, those exhibiting a EBV-specific cellular immune response above the median also displayed an increased median overall survival pattern compared to weak responders (753 vs 370 days, p < 0.001). CONCLUSIONS: This report provides (i) a fast and easy assay using common viral antigens and cytokine stimulation to screen for immune fitness/exhaustion of patients with brain tumor in comparison to pancreatic cancer and healthy individuals and (ii) EBV/CMV-induced IFNgamma production as a potential marker of survival in patients with brain tumor. PMID- 29970102 TI - CD8+ T cells specific for conserved, cross-reactive Gag epitopes with strong ability to suppress HIV-1 replication. AB - BACKGROUND: Development of AIDS vaccines for effective prevention of circulating HIV-1 is required, but no trial has demonstrated definitive effects on the prevention. Several recent T-cell vaccine trials showed no protection against HIV 1 acquisition although the vaccines induced HIV-1-specific T-cell responses, suggesting that the vaccine-induced T cells have insufficient capacities to suppress HIV-1 replication and/or cross-recognize circulating HIV-1. Therefore, it is necessary to develop T-cell vaccines that elicit T cells recognizing shared protective epitopes with strong ability to suppress HIV-1. We recently designed T cell mosaic vaccine immunogens tHIVconsvX composed of 6 conserved Gag and Pol regions and demonstrated that the T-cell responses to peptides derived from the vaccine immunogens were significantly associated with lower plasma viral load (pVL) and higher CD4+ T-cell count (CD4 count) in HIV-1-infected, treatment-naive Japanese individuals. However, it remains unknown T cells of which specificities have the ability to suppress HIV-1 replication. In the present study, we sought to identify more T cells specific for protective Gag epitopes in the vaccine immunogens, and analyze their abilities to suppress HIV-1 replication and recognize epitope variants in circulating HIV-1. RESULTS: We determined 17 optimal Gag epitopes and their HLA restriction, and found that T-cell responses to 9 were associated significantly with lower pVL and/or higher CD4 count. T cells recognizing 5 of these Gag peptides remained associated with good clinical outcome in 221 HIV-1-infected individuals even when comparing responders and non responders with the same restricting HLA alleles. Although it was known previously that T cells specific for 3 of these protective epitopes had strong abilities to suppress HIV-1 replication in vivo, here we demonstrated equivalent abilities for the 2 novel epitopes. Furthermore, T cells against all 5 Gag epitopes cross-recognized variants in majority of circulating HIV-1. CONCLUSIONS: We demonstrated that T cells specific for 5 Gag conserved epitopes in the tHIVconsvX have ability to suppress replication of circulating HIV-1 in HIV-1 infected individuals. Therefore, the tHIVconsvX vaccines have the right specificity to contribute to prevention of HIV-1 infection and eradication of latently infected cells following HIV-1 reactivation. PMID- 29970103 TI - Meta-analysis of the potential role of extracorporeal shockwave therapy in osteonecrosis of the femoral head. AB - BACKGROUND: We aimed to evaluate the role of extracorporeal shockwave therapy (ESWT) in improving osteonecrosis of the femoral head (ONFH). METHODS: We searched studies focusing on the role of ESWT in ONFH using PubMed, Embase, the Cochrane Library, WanFang, VIP, and CNKI databases updated up to July 28, 2017, without language restriction. Standardized mean difference (SMD) values and 95% confidence intervals (95% CIs) were pooled to compare the pain score and Harris hip score for ESWT treatment and other treatment strategies. RESULTS: Four articles, including 230 ONFH patients, were eligible for the meta-analysis. No significant differences were found in the pain score (SMD = - 1.0104; 95% CI - 2.3279-0.3071) and Harris hip score (SMD = 0.3717; 95% CI - 0.3125-1.0559) between the two groups before treatment. After treatment, significant differences were found between the experimental and control groups in the pain score (SMD = - 2.1148; 95% CI - 3.2332-0.9965) and Harris hip score (SMD = 2.1377; 95% CI 1.2875 2.9880). There were no significant differences in pain score before and after treatment between the two groups (SMD = - 0.7353; 95% CI - 2.1272-0.6566), but significant differences were found in the Harris hip score (SMD = 1.2969; 95% CI 0.7171-1.8767). CONCLUSION: For patients at an early stage, ESWT may be safe and effective for relief of pain and improvement of motor function. PMID- 29970104 TI - Distribution of enteropathogenic Yersinia spp. and Salmonella spp. in the Swedish wild boar population, and assessment of risk factors that may affect their prevalence. AB - BACKGROUND: Pure Eurasian wild boars and/or hybrids with domestic pigs are present in the wild on most continents. These wild pigs have been demonstrated to carry a large number of zoonotic and epizootic pathogens such as Salmonella spp., Yersinia enterocolitica and Y. pseudotuberculosis. Wild boar populations throughout Europe are growing and more and more wild boar meat is being consumed, the majority within the homes of hunters without having passed a veterinary inspection. The aim of this study was to investigate if factors such as population density, level of artificial feeding, time since establishment of a given population, and the handling of animal by-products from slaughtered animals could influence the presence of these pathogens in the wild boar. RESULTS: In total, 90 wild boars from 30 different populations in Sweden were sampled and analysed using a protocol combining pre-cultivation and PCR-detection. The results showed that 27% of the sampled wild boars were positive for Salmonella spp., 31% were positive for Y. enterocolitica and 22% were positive for Y. pseudotuberculosis. In 80% of the sampled populations, at least one wild boar was positive for one of these enteropathogens and in total, 60% of the animals carried at least one of the investigated enteropathogens. The presumptive risk factors were analysed using a case-control approach, however, no significant associations were found. CONCLUSION: Human enteropathogens are commonly carried by wild boars, mainly in the tonsils, and can thus constitute a risk for contamination of the carcass and meat during slaughter. Based on the present results, the effect of reducing population densities and number of artificial feeding places might be limited. PMID- 29970105 TI - Proton versus photon deep inspiration breath hold technique in patients with hodgkin lymphoma and mediastinal radiation : A PLANNING COMPARISON OF DEEP INSPIRATION BREATH HOLD INTENSITY MODULATION RADIOTHERAPY AND INTENSITY MODULATED PROTON THERAPY. AB - BACKGROUND: The benefits of proton therapy in the treatment of patients with Hodgkin lymphoma (HL) are controversially discussed. Therefore we compared intensitiy modulated proton therapy (IMPT) with intensity modulated radiotherapy (IMRT), in the form of volumetric modulated arc therapy (VMAT) in patients with Hodgkin lymphoma (HL), through a comparative treatment planning study. METHODS: Radiation plans for 21 patients with Hodgkin Lymphoma (HL) were computed for IMPT and deep inspiration breath hold (DIBH) VMAT. Plans were optimized and computed assuming deep inspiration breath holding conditions. Dosimetric comparison on standard metrics from dose volume histograms was performed to appraise the relative merits of the two techniques, while proton plan robustness was assessed by re-computing the dose distribution of each plan by varying the Hounsfield Units to stopping power calibration by applying a +/- 3 and 4% error. RESULTS: DIBH-VMAT and IMPT both provided excellent coverage, conformity and heterogeneity of the clinical target volume (CTV) and planning target volume (PTV). IMPT reduced mean doses to the breasts, lungs, heart and normal tissue by 38-83%. IMPT significantly reduced mean doses to the heart to < 5 Gy despite bulky mediastinal disease and decreased breast doses in female patients to < 1 Gy. Despite the simulated 3 and 4% miscalibration errors, no remarkable or measurable impact was observed on the organs at risk (OARs). CONCLUSIONS: This is the first comparison between DIBH-VMAT and IMPT in HL treatment. We could demonstrate statistically significant decreases in all dose/volume metrics of the OARs. Regardless of the planning paradigm used, range uncertainties can substantially under dose the PTV, while perhaps not leading to clinically significant deterioration of CTV coverage. With the geometry applied no impact was observed for OARs, suggesting IMPT as a superior technique for potentially reducing future health risks for HL patients. PMID- 29970106 TI - International norms and the politics of sexuality education in Nigeria. AB - BACKGROUND: Proponents have promoted sexuality education as a means of empowering adolescents, yet it has been thwarted in many low and middle-income countries. Nigeria represents an exception. Despite social opposition, the government in 1999 unexpectedly approved sexuality education policy. Since then, implementation has advanced, although efficacy has differed across states. We draw on theory concerning international norm diffusion to understand Nigerian policy development. RESULTS: We find that a confluence of international and national norms and interests shaped policy outcomes, including concern over HIV/AIDS. A central dynamic was an alliance of domestic NGOs and international donors pressing the Nigerian government to act. CONCLUSIONS: We argue that theory on international norms can be applied to understand policy dynamics across a variety of health and population areas, finding value in approaches that integrate rather than juxtapose consideration of (1) international and national influences; (2) long and short-term perspectives on policy change; and (3) norms and interests. PMID- 29970107 TI - A municipality-based vocational rehabilitation programme for occupationally marginalized citizens: a study protocol for a mixed methods study. AB - BACKGROUND: In 2013 vocational rehabilitation programmes (VRP) were given official and legal approval under Danish law to assist occupationally marginalized citizens in gaining general life skills, building their work ability, and increasing their chances of entering the work force. The project's aim is to develop a detailed understanding of the health, psychosocial and work circumstances of participating citizens, and of the important processes and mechanisms underlying the potential effects of participating in the VRP. METHODS: This study uses an exploratory mixed methods approach with sequential use of quantitative and qualitative methods. Participants are citizens assigned to an individually tailored VRP in the municipality of Sonderborg, Denmark. The quantitative part of the study consists of a longitudinal survey in which participants complete questionnaires at baseline and at follow-up one year later. Variables include demographic and personal characteristics, the latter ascertained through validated questionnaires on well-being, physical activity, interpersonal problems, general health, work ability, kinesiophobia, self efficacy, depression and anxiety. The qualitative part of the study consists of semi-structured interviews and observations that explore experiences related to VRP. Participants will be recruited and data collected from questionnaires, interviews and observations in the period February 2016 - March 2018. DISCUSSION: This research will assemble a unique corpus of knowledge about the characteristics, experiences and outcomes of occupationally marginalized citizens participating in a VRP. It will identify potential enablers and barriers to a successful outcome, and ultimately this knowledge will help inform the future design of individually tailored VRP's. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02641704 , date of registration December 29, 2015. PMID- 29970108 TI - 6-minute walk test as a measure of disease progression and fatigability in a cohort of individuals with RYR1-related myopathies. AB - BACKGROUND: RYR1-related Myopathies (RYR1-RM) comprise a group of rare neuromuscular diseases (NMDs) occurring in approximately 1/90000 people in the US pediatric population. RYR1-RM result from pathogenic mutations in the ryanodine receptor isoform-1 (RYR1) gene where consequent RyR1 protein calcium dysregulation leads to impaired excitation-contraction coupling, oxidative and nitrosative stress, and mitochondrial depletion. These physiological deficits perpetuate RyR1 dysfunction causing further muscle injury, muscle weakness, and muscle fatigue. Muscle weakness and fatigue are two primary complaints in patients with RYR1-RM and are major symptoms that limit the ability of individuals to perform activities of daily living. The six-minute walk test (6MWT) is an endurance test with high reliability and validity used to measure walking capacity, disease progression, and more recently, fatigability in NMDs with limited results in RYR1-RM. Therefore, the purpose of our study is to objectively assess disease progression and fatigability in RYR1-RM affected individuals using the 6MWT. We hypothesized that 6MWT distance and fatigability would not change significantly between 0 and 6-month visits in RYR1-RM patients, given the clinically reported stable or slowly progressive nature of the disease. We also hypothesized participants would show fatigability during the 6MWT, given muscle weakness and fatigue are the two primary complaints of affected individuals. RESULTS: As expected, paired t-test analyses revealed no significant difference between total distance traveled (p = .608) or percent change in speed (p = .141) at 0-months compared with the 6-month visit. Fatigability was observed given the decline in speed between the first and last minute of the 6MWT at the 6 month time point (p <= .0005,). Although this decline was not significant at baseline, a significant decline in speed from the 1st minute did occur at minutes 2, 3, and 4 during the baseline visit. CONCLUSION: In this RYR1-RM cohort, the 6MWT showed disease stability over a 6-month period but revealed fatigability during the test. Given these results, the 6MWT may be a promising endpoint for evaluating fatigability and therapeutic efficacy in the 6-month treatment phase of our current n-acetylcysteine trial in this population. Improvement post intervention could be attributed to the intervention rather than variability in disease progression. TRIAL REGISTRATION: Clinical Trials.gov, NCT02362425 , Registered 13 February 2015-Prospectively registered. PMID- 29970109 TI - Teriflunomide attenuates neuroinflammation-related neural damage in mice carrying human PLP1 mutations. AB - BACKGROUND: Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome. METHODS: We applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry. RESULTS: Preventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset. CONCLUSIONS: We identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking. PMID- 29970110 TI - Kawasaki Disease in the neonate: case report and literature review. AB - BACKGROUND: Kawasaki Disease (KD), the leading cause of acquired heart disease in children in the developed world, is extremely rare in neonates. We present a case of incomplete KD in a neonate and a review of the literature on neonatal KD. CASE PRESENTATION: A previously healthy full term 15 day old Caucasian male with an unremarkable antenatal and perinatal history, presented on Day 2 of illness with fever, rash, irritability, and poor feeding. Examination revealed fever (39.6C), tachycardia, tachypnea, extreme irritability, and a generalized maculopapular rash, but was otherwise normal. His complete blood count, CRP and ESR were normal. Empiric intravenous antibiotics and acyclovir resulted in no improvement. On day 4, he had ongoing fever and developed recurrent apnea, required supplemental oxygen, and was transferred to the pediatric intensive care unit. On day 6, he developed bilateral non-purulent conjunctivitis, palmar erythema, bilateral non-pitting edema and erythema of his feet, and arthritis. His full septic work-up and viral studies were negative. On Day 7 he was treated with intravenous immunoglobulin, and over the next 48 h his symptoms including extremity edema resolved, he no longer required supplemental oxygen, and fever did not recur. On day 9 of illness he had marked thrombocytosis. Subsequently, he developed distal extremity desquamation. Repeated echocardiograms excluded the presence of coronary artery aneurysms (CAA). CONCLUSIONS: We believe this to be a rare case of incomplete KD in a neonate, in which timely IVIG administration led to resolution of the acute illness and may have prevented CAA. A comprehensive English-language medical literature review of KD presenting in the neonatal period revealed only fifteen case reports. Cases often presented with incomplete KD, and a number had atypical laboratory features including a normal CRP in the acute phase, similar to what was seen in our patient. This case and our literature review should increase awareness that KD can rarely occur in neonates, often presenting atypically. Recognizing KD in a neonate enables appropriate treatment that can result in resolution of symptoms and may decrease the risk of cardiac complications. PMID- 29970112 TI - Diet quality is inversely associated with obesity in Chinese adults with type 2 diabetes. AB - BACKGROUND: Diet quality has been linked to obesity, but this relationship remains unclear in individuals with type 2 diabetes (T2D). The aim of this study is to examine the association between diet quality and obesity in Chinese adults with T2D. METHODS: Between April and November 2016, a total of 211 Chinese T2D adults who underwent assessment of diabetes-related treatment goals and metabolic control were recruited into two groups based on their body mass index (BMI): obese group (BMI >=30 kg/m2) and non-obese group (BMI = 18.5-24.9 kg/m2). Diet quality indices including Alternate Healthy Eating Index-2010 (AHEI-2010), Diet Quality Index-International (DQI-I), and Dietary Approach to Stop Hypertension (DASH) score, were derived from a validated food frequency questionnaire. RESULTS: Obese T2D patients had significantly lower AHEI-2010 (P < 0.001), DQI-I (P < 0.001), and DASH total scores (P = 0.044) than their non-obese counterparts, independent of age and sex. They also had higher total energy (P < 0.001), protein percentage of energy (P = 0.023), and meat, poultry and organ meat (P < 0.001), but lower vegetable (P = 0.014) intakes. Our multivariate logistic regression analyses demonstrated that the AHEI-2010, but not DQI-I and DASH, total score had an inverse association with obesity, independent of sociodemographics, anti-diabetic medication use, physical activity level and total energy intake (odds ratio [OR] per standard deviation (1-SD) increase: 0.95, 95% confidence interval [CI]: 0.91-0.99, P = 0.020). This association remained significant after further adjustment for glycemic control. Inverse associations were also found between obesity and multivariate-adjusted component scores, including AHEI-2010 red/processed meat (OR per 1-SD: 0.71, 95% CI: 0.51 0.99, P = 0.044), DQI-I variety (OR per 1-SD: 0.63, 95% CI: 0.46-0.86, P = 0.004), and DASH red/processed meat (OR per 1-SD: 0.57, 95% CI: 0.38-0.84, P = 0.005). CONCLUSIONS: Better diet quality, as characterized by higher AHEI-2010 scores, was associated with lower odds of obesity in Chinese adults with T2D. Dietary patterns reflecting high consumption of plant-based foods and low consumption of animal-based, high-fat, and processed foods may be imperative to optimize nutritional guidance for obesity management in this population. PMID- 29970111 TI - Postoperative (chemo) radiation in patients with squamous cell cancers of the head and neck - clinical results from the cohort of the clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer". AB - BACKGROUND: Postoperative (chemo) radiation improves tumor control and survival in high-risk patients with head and neck squamous cell carcinoma based on established risk factors. The clinical cooperation group "Personalized Radiotherapy in Head and Neck Cancer" focuses on the identification and validation of new biomarkers, which are aimed at eventually stratifying and personalizing the therapy concept. Hence, we reviewed all patients with head and neck squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx, treated with postoperative (chemo) radiation from 06/2008 until 06/2015 at the Department of Radiation Oncology in the University Hospital, LMU Munich. Here we report the clinical results of the cohort, laying the foundation for further research within the framework of a clinical cooperation group. METHODS: Patient data were retrospectively (until 2013) and prospectively (from 2013) collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors. RESULTS: We identified 302 patients (median follow-up 45 months, average age 60.7 years), having received postoperative (chemo)radiation (median 64 Gy). Chemotherapy was added in 58% of cases, mostly Cisplatin/5- Fluorouracil in concordance with the ARO 96-3 study. The 3-year overall survival, local, locoregional and distant failure estimates were 70.5, 9.7, 12.2 and 13.5%, respectively. Human papillomavirus-associated oropharyngeal cancer was associated with a significant improved overall survival, locoregional, distant and overall tumor control rates in multivariate analysis. Additionally, in multivariate analysis, for local failure, resection status and perineural invasion, for locoregional and distant failure extracapsular extension and for overall survival the presence of nodal disease were significant adverse factors. Moreover, 138 patients have been treated in concordance with the ARO 96 3 protocol, corroborating the results of this study. CONCLUSIONS: Our cohort represents a large unselected cohort of patients with head and neck squamous cell carcinoma treated with postoperative (chemo)radiation. Tumor control rates and survival rates are consistent with the results of previously reported data. PMID- 29970113 TI - Changes in plasma levels of perfluoroalkyl substances (PFASs) are related to increase in carotid intima-media thickness over 10 years - a longitudinal study. AB - BACKGROUND: It has previously been reported that the environmental contaminants perfluoroalkyl substances (PFASs) are linked to atherosclerosis in cross sectional studies. Since cross-sectional studies could be subject to reverse causation, the purpose of this study was to analyze if the longitudinal changes in PFASs during a 10-year follow-up were related to the change in carotid artery intima-media thickness (IMT, ultrasound) during the same period. METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 1016 individuals were investigated at age 70; 826 of them were reinvestigated at age 75 and 602 at age 80 years. Eight different PFASs were measured in plasma by ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and IMT was measured at all three time points. Random-effects mixed regression models were used to examine the associations over time. RESULTS: IMT increased 0.058 mm during the 10-year period (p < 0.0001). Following adjustment for baseline values of PFASs (age 70) and sex, the changes in plasma levels of 6 of the 8 measured PFASs were significantly related to the change in IMT over the 10 year follow-up period in a positive fashion (p < 0.0062 using Bonferroni correction for 8 tests). Further adjustment for traditional cardiovascular (CV) risk factors (HDL and LDL cholesterol, smoking, systolic blood pressure, statin use, fasting glucose and serum triglycerides) affected these relationships only marginally. CONCLUSION: The change in plasma levels of several PFASs during 10 years was positively related to increase in IMT seen during the same period, giving prospective evidence that PFASs might interfere with the atherosclerotic process. PMID- 29970115 TI - Novel oncogene COPS3 interacts with Beclin1 and Raf-1 to regulate metastasis of osteosarcoma through autophagy. AB - BACKGROUND: Expression of COP9 signalosome subunit 3 (COPS3), an oncogene overexpressed in osteosarcoma, has been demonstrated to be significantly correlated with tumor metastasis. However, the underlying mechanism by which COPS3 promotes metastasis of osteosarcoma and its role in autophagy remain unknown. METHODS: The expression of COPS3 was detected in primary osteosarcoma tissues and matching lung metastasis tissues by immunohistochemistry (IHC). The effect of COPS3 on the metastasis of osteosarcoma cells was investigated by transwell, wound healing assays and animal studies. Indicated proteins was analyzed by western blotting when COPS3 was knockdown or overexpressed. The COPS3 Interacting protein was determined by immunoprecipitation assay. The relationship between COPS3 and autophagy was detected by western blotting and immunofluorescence. RESULTS: We found that knockdown of COPS3 significantly reduced the lung metastasis of osteosarcoma cells in a mouse model, coinciding with downregulation of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling. The silencing of COPS3 also inhibited the epithelial-mesenchymal transition (EMT) through the 90 kDa ribosomal S6 kinases (RSK), a family of signal transduction proteins downstream of MEK/ERK. Reciprocal immunoprecipitation assays revealed that COPS3 directly interacts with Raf-1, an upstream regulator of MEK/ERK. Surprisingly, Beclin1, an important autophagic protein, appeared in the COPS3-immunoprecipitates, along with the autophagic markers LC3-I and LC3-II. Loss of COPS3 completely inhibited H2O2 induced autophagic flux and reduced Beclin1 expression. Additionally, autophagy inhibitor or silencing of Beclin1 both decreased cell metastasis. CONCLUSIONS: Taken together, these data reveal a novel function of COPS3 in the regulation of autophagy and highlight the relationship between autophagy and metastasis in osteosarcoma cells. PMID- 29970114 TI - Ingested engineered nanomaterials: state of science in nanotoxicity testing and future research needs. AB - BACKGROUND: Engineered nanomaterials (ENM) are used extensively in food products to fulfill a number of roles, including enhancement of color and texture, for nutritional fortification, enhanced bioavailability, improved barrier properties of packaging, and enhanced food preservation. Safety assessment of ingested engineered nanomaterials (iENM) has gained interest in the nanotoxicology community in recent years. A variety of test systems and approaches have been used for such evaluations, with in vitro monoculture cell models being the most common test systems, owing to their low cost and ease-of-use. The goal of this review is to systematically assess the current state of science in toxicological testing of iENM, with particular emphasis on model test systems, their physiological relevance, methodological strengths and challenges, realistic doses (ranges and rates), and then to identify future research needs and priorities based on these assessments. METHODS: Extensive searches were conducted in Google Scholar, PubMed and Web of Science to identify peer-reviewed literature on safety assessment of iENM over the last decade, using keywords such as "nanoparticle", "food", "toxicity", and combinations thereof. Relevant literature was assessed based on a set of criteria that included the relevance of nanomaterials tested; ENM physicochemical and morphological characterization; dispersion and dosimetry in an in vitro system; dose ranges employed, the rationale and dose realism; dissolution behavior of iENM; endpoints tested, and the main findings of each study. Observations were entered into an excel spreadsheet, transferred to Origin, from where summary statistics were calculated to assess patterns, trends, and research gaps. RESULTS: A total of 650 peer-reviewed publications were identified from 2007 to 2017, of which 39 were deemed relevant. Only 21% of the studies used food grade nanomaterials for testing; adequate physicochemical and morphological characterization was performed in 53% of the studies. All in vitro studies lacked dosimetry and 60% of them did not provide a rationale for the doses tested and their relevance. Only 12% of the studies attempted to consider the dissolution kinetics of nanomaterials. Moreover, only 1 study attempted to prepare and characterize standardized nanoparticle dispersions. CONCLUSION: We identified 5 clusters of factors deemed relevant to nanotoxicology of food-grade iENM: (i) using food-grade nanomaterials for toxicity testing; (ii) performing comprehensive physicochemical and morphological characterization of iENM in the dry state, (iii) establishing standard NP dispersions and their characterization in cell culture medium, (iv) employing realistic dose ranges and standardized in vitro dosimetry models, and (v) investigating dissolution kinetics and biotransformation behavior of iENM in synthetic media representative of the gastrointestinal (GI) tract fluids, including analyses in a fasted state and in the presence of a food matrix. We discussed how these factors, when not considered thoughtfully, could influence the results and generalizability of in vitro and in vivo testing. We conclude with a set of recommendations to guide future iENM toxicity studies and to develop/adopt more relevant in vitro model systems representative of in vivo animal and human iENM exposure scenarios. PMID- 29970117 TI - Social and physical environmental correlates of independent mobility in children: a systematic review taking sex/gender differences into account. AB - BACKGROUND: Children's independent mobility (CIM) is an important contributor to physical activity and health in children. However, in the last 20 years CIM has significantly decreased. To develop effective intervention programs to promote CIM, the impact of the environment on CIM must be identified. This review seeks to provide an overview of sex/gender-specific socio-ecological correlates of CIM. METHODS: A systematic literature search of five databases (PubMed, PsycInfo, Scopus, Medline, Web of Science) was conducted with a priori defined eligibility criteria and identified 1838 potential articles published between January 1990 and November 2017. Two independent reviewers screened the literature and identified and rated methodological quality of the studies. Related factors of CIM were summarized separately for CIM license (parental permission to travel independently) and CIM destination (destinations to which a child travels independently), and separately for boys and girls using a semi-quantitative method. RESULTS: Twenty-seven peer-reviewed journal articles were identified which examined the relationship between the social and physical environment and CIM. Only seven studies reported results divided by sex/gender. Most associations between the environment and CIM were found in the expected direction (positive or negative) or not associated at all. The social environment seemed to be more influential for ensuring CIM than the physical environment. Neighborhood safety, fear of crime and stranger, parental support, and perception of traffic were important social environmental factors influencing CIM, while car ownership, distance, and neighborhood design were relevant physical environmental attributes. Few studies examined sex/gender-related environmental correlates of independent mobility, and those findings were inconsistent. CONCLUSION: The findings of this systematic review serve as suggestions for intervention programs to increase CIM and to identify future directions in research. To establish a robust comprehension of the impact of the social and physical environment on CIM, further sex/gender-sensitive studies using comparable measurements for CIM and environmental correlates are needed. PMID- 29970118 TI - From health for all to universal health coverage: Alma Ata is still relevant. AB - With increasing adoption of universal health coverage (UHC), the health for all agenda is resurgent around the world. However, after a promising start the first time in 1978, the health for all agenda fizzled over the next decade. This commentary discusses the origin of the health for all agenda in the 1970s and the influence of global politico-economic forces in shaping that agenda, its demise and the resurgence in the form of UHC in the twenty-first century. We discuss UHC's focus on finances and the increasing role of market economy in health care, and the opportunities and risks UHC poses. We conclude by saying that UHC's greater focus on finances is prudent, but in order to achieve its promise, UHC needs to regulate the market based provision of healthcare, and incorporate more of the people and community centered ethos of its earlier iteration from 40 years ago. PMID- 29970116 TI - Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation. AB - BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC) tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation. PMID- 29970119 TI - Dynamic hip kinematics during squatting before and after total hip arthroplasty. AB - BACKGROUND: The difference in in vivo kinematics before and after total hip arthroplasty (THA) for the same subjects and the clearance between the liner and neck during squatting have been unclear. The purpose of the present study was to clarify (1) the changes in the in vivo kinematics between prosthetic hips and osteoarthritis hips of the same subjects and (2) the extent of the liner-to-neck clearance during squatting under weight-bearing conditions. METHODS: This study consisted of 10 patients who underwent unilateral THA for symptomatic osteoarthritis. Using a flat-panel X-ray detector, we obtained continuous radiographs during squatting. We analyzed the hip joint's movements using three dimensional-to-two-dimensional model-to-image registration techniques. We also quantified the minimum distance at maximum flexion and extension, and the minimum angle at maximum flexion between the liner and stem neck. RESULTS: The maximum hip flexion angles post-THA (80.7 degrees [range, 69.4-98.6 degrees ]) changed significantly compared with the pre-THA values (71.7 degrees [range, 55.2 degrees -91.2 degrees ]). The pelvic tilt angle (posterior +, anterior-) at the maximum hip flexion post-THA (10.4 degrees [range, - 6.7 degrees to 26.9 degrees ]) was significantly smaller than that at pre-THA (16.6 degrees [range, 3 degrees to 40.3 degrees ]). The minimum anterior and posterior liner-to-neck distances averaged 10.9 and 8.0 mm, respectively, which was a significant difference. The minimum liner-to-neck angle at maximum flexion averaged 34.7 degrees (range, 20.7 degrees -46.3 degrees ). No liner-to-neck contact occurred in any of the hips. CONCLUSION: THA increased the range of hip joint motion and the pelvis tilted anteriorly more after than before THA, with sufficient liner-to neck clearance during squatting. These data may be beneficial for advising patients after THA regarding postoperative activity restrictions in daily life. PMID- 29970121 TI - Surgical repair of massive dilatation of the right atrium with tricuspid regurgitation. AB - BACKGROUND: Massive dilatation of the right atrium with tricuspid regurgitation is frequently diagnosed by accidental recognition of an enlarged cardiac silhouette during routine chest radiography. Although some patients are asymptomatic, enlargement of the right atrium can cause secondary tricuspid regurgitation due to dilatation of the tricuspid annulus, associated with arrhythmias and thrombus formation leading to pulmonary embolism, stroke, and, rarely, sudden death due to left ventricular compression. CASE PRESENTATION: A 76 year-old woman was followed up due to atrial fibrillation and tricuspid regurgitation for 8 years. A follow-up echocardiogram showed progressive dilatation of the right atrium. Because of the development of shortness of breath, right atrial plication and tricuspid valve repair were performed. Tricuspid annuloplasty was performed on the beating heart with the use of a 28-mm Carpentier-Edwards Physio tricuspid annuloplasty ring. Plication of the enlarged right atrium was performed at the interatrial septum, the free right atrium wall including the appendage, and the space between the inferior vena cava and the tricuspid ring. Closure of the left atrial appendage was performed from outside to prevent left atrial thrombus formation. Postoperative X-ray and computed tomography showed reduced cardiac silhouette and right atrial volume. The patient was discharged uneventfully and returned for follow-up visits with improved symptoms. CONCLUSIONS: An adult case of massive dilatation of the right atrium of unknown etiology is reported. The patient's symptoms were relieved by our operative procedure. PMID- 29970120 TI - Roles and mechanisms of leptin in osteogenic stimulation in cervical ossification of the posterior longitudinal ligament. AB - BACKGROUND: Hyperleptinemia is a common feature of obese people, and leptin, an adipocyte-derived cytokine, is believed to be an important factor in the pathogenesis of cervical ossification of the posterior longitudinal ligament(C OPLL). So this research was to identify the relation between the serum leptin and bone metabolic markers and how the leptin induced osteogenic effect in C-OPLL. METHODS: Sixty-four samples were selected to determine the concentration of leptin, insulin, and alkaline phosphatase. And the association of leptin with these factors was also examined. We also evaluate the effect of leptin on the development of C-OPLL and further explored the possible underlying mechanism in vitro. RESULTS: We found that serum leptin concentrations were higher in females than in males. Serum leptin and ALP concentrations were increased significantly in C-OPLL females compared to non-OPLL females. In OPLL subjects, the serum leptin concentration corrected for body mass index correlated negatively with the ALP concentrations. In C-OPLL cells, leptin treatment led to a significant increase in mRNA expressions of ALP and OCN and formation of mineralized nodule. Our experiments reported here that osteogenic effect of leptin in C-OPLL cells could be mediated via ERK1/2, p38 MAPK, and/or JNK signaling pathways. CONCLUSIONS: From this research, we got that leptin treatment led to a significant increase in mRNA expressions of ALP and OCN and formation of mineralized nodule. And the osteogenic effect of leptin in C-OPLL cells could be mediated via ERK1/2, p38 MAPK, and/or JNK signaling pathways. PMID- 29970122 TI - Long non-coding RNA-SNHG7 acts as a target of miR-34a to increase GALNT7 level and regulate PI3K/Akt/mTOR pathway in colorectal cancer progression. AB - BACKGROUND: Colorectal cancer (CRC) arises in a multistep molecular network process, which is from either discrete genetic perturbation or epigenetic dysregulation. The long non-coding RNAs (lncRNAs), emerging as key molecules in human malignancy, has become one of the hot topics in RNA biology. Aberrant O glycosylation is a well-described hallmark of many cancers. GALNT7 acts as a glycosyltransferase in protein O-glycosylation, involving in the occurrence and development of CRC. METHODS: The microarrays were used to survey the lncRNA and mRNA expression profiles of primary CRC cell line SW480 and metastatic CRC cell line SW620. Cell proliferation, migration, invasion, and apoptosis were assayed. Xenograft mouse models were used to determine the role of lncRNA-SNHG7 in CRC in vivo. In addition, CNC analysis and competing endogenous analysis were used to detect differential SNHG7 and relational miRNAs expression in CRC cell lines. RESULTS: SNHG7 expression showed a high fold (SW620/SW480) in CRC microarrays. The CRC patients with high expression of SNHG7 had a significantly poor prognosis. Furthermore, SNHG7 promoted CRC cell proliferation, metastasis, mediated cell cycle, and inhibited apoptosis. SNHG7 and GALNT7 were observed for co-expression by CNC analysis, and a negative correlation of SNHG7 and miR-34a were found by competing endogenous RNA (ceRNA) analysis. Further results indicated that SNHG7 facilitated the proliferation and metastasis as a competing endogenous RNA to regulate GALNT7 expression by sponging miR-34a in CRC cell lines. SNHG7 also played the oncogenic role in regulating PI3K/Akt/mTOR pathway by competing endogenous miR-34a and GALNT7. CONCLUSION: The CRC-related SNHG7 and miR-34a might be implicated in CRC progression via GALNT7, suggesting the potential usage of SNHG7/miR-34a/GALNT7 axis in CRC treatment. PMID- 29970124 TI - The application value of MRI in the diagnosis of subclinical inflammation in patients with rheumatoid arthritis in remission. AB - BACKGROUND: To explore the value of MRI in the diagnosis of subclinical inflammation in patients with early rheumatoid arthritis (RA) in remission and to predict the radiographic progression. METHODS: A total of 76 of 156 patients with early RA in remission at 1 year and with available magnetic resonance imaging (MRI) data at baseline and at 12 months were included. Complete clinical and laboratory evaluations were conducted for the patients. MRI images were assessed according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) system. Progression of bone erosions was defined as an increase of 1 or more units in annual RAMRIS score for erosions compared to baseline. RESULTS: At 1 year, the majority of patients with RA in sustained remission showed some inflammatory activity on MRI (43.4% synovitis, 39.5% bone marrow edema (BME), and 9.2% tenosynovitis), and 25 of the 76 patients (32.9%) showed MRI progression of bone erosions. A significant difference was observed in MRI BME and bone erosion at 1 year, with higher mean score in patients with progression compared to non progression of erosions (BME, 4.8 +/- 3.6 vs 3.1 +/- 2.1, P = 0.01; bone erosion, 13.5 +/- 9.6 vs 4.4 +/- 3.6, P < 0.001). CONCLUSION: Persistent subclinical inflammations were shown in patients with sustained remission; BME in MRI may be a strong predictor of future radiographic progression of bone erosions in patients with persistent clinical remission. PMID- 29970125 TI - Amyloidosis due to TTR mutations in Mexico with 4 distincts genotypes in the index cases. PMID- 29970123 TI - DNMT1 regulates expression of MHC class I in post-mitotic neurons. AB - Major Histocompability Complex I (MHC-I) molecules present cellularly derived peptides to the adaptive immune system. Generally MHC-I is not expressed on healthy post-mitotic neurons in the central nervous system, but it is known to increase upon immune activation such as viral infections and also during neurodegenerative processes. MHC-I expression is known to be regulated by the DNA methyltransferase DNMT1 in non-neuronal cells. Interestingly DNMT1 expression is high in neurons despite these being non-dividing. This suggests a role for DNMT1 in neurons beyond the classical re-methylation of DNA after cell division. We thus investigated whether DNMT1 regulates MHC-I in post-mitotic neurons. For this we used primary cultures of mouse cerebellar granule neurons (CGNs). Our results showed that knockdown of DNMT1 in CGNs caused upregulation of some, but not all subtypes of MHC-I genes. This effect was synergistically enhanced by subsequent IFNgamma treatment. Overall MHC-I protein level was not affected by knockdown of DNMT1 in CGNs. Instead our results show that the relative MHC-I expression levels among the different MHC subtypes is regulated by DNMT1 activity. In conclusion, we show that while the mouse H2-D1/L alleles are suppressed in neurons by DNMT1 activity under normal circumstances, the H2-K1 allele is not. This finding is particularly important in two instances. One: in the context of CNS autoimmunity with epitope presentation by specific MHC-I subtypes where this allele specific regulation might become important; and two: in amyotropic lateral sclerosis (ALS) where H2-K but not H2-D protects motor neurons from ALS astrocyte-induced toxicity in a mouse model of ALS. PMID- 29970126 TI - Correction to: miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy. AB - The original article [1] contains a spelling error in the authorship; the authors would like to note the correct spelling of the second author, Jiajia Xi. PMID- 29970127 TI - CPNE1 is a target of miR-335-5p and plays an important role in the pathogenesis of non-small cell lung cancer. AB - BACKGROUND: Despite advances in diagnosis and treatment, the survival of non small cell lung cancer (NSCLC) patients remains poor. There is therefore a strong need to identify potential molecular targets for the treatment of NSCLC. In the present study, we investigated the function of CPNE1 in the regulation of cell growth, migration and invasion. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression of CPNE1 and miR-335-5p. Western blot and immunohistochemical assays were used to investigate the levels of CPNE1 and other proteins. Flow cytometry was used to determine cell cycle stage and apoptosis. CCK-8 and clonogenic assays were used to investigate cell proliferation. Wound healing, migration and invasion assays were used to investigate the motility of cells. A lung carcinoma xenograft mouse model was used to investigate the in vivo effects of CPNE1 overexpression. RESULTS: We observed that knockdown of CPNE1 and increased expression of miR-335-5p inhibits cell proliferation and motility in NSCLC cells, and found that CPNE1 was a target of miR-335-5p. In addition, our data indicated that CPNE1 inhibition could improve the clinical effects of EGFR tyrosine kinase inhibitors. CONCLUSIONS: The present results indicate that CPNE1 may be a promising molecular target in the treatment of NSCLC. PMID- 29970129 TI - Treatment of cardiac synovial sarcoma: experience of two cases. AB - BACKGROUND: Primary heart sarcomas are exceedingly rare tumors. Among primary cardiac sarcomas, synovial sarcoma is one of the rarest, involving cardiac cavities or pericardium. CASE PRESENTATION: Two cases of synovial sarcoma are presented with the clinical course and therapy. Both cases were treated with surgery and chemo/radiotherapy. Interestingly, one of the patient, a 52-year-old male with an intracardiac synovial sarcoma, undergone a SynCardia total artificial heart implantation, but died for multiple pulmonary metastases waiting for transplantation. CONCLUSION: Complete surgical resection of cardiac synovial sarcoma is the gold standard of therapy, though rarely possible. Although guidelines for the treatment are not well established, due to limited number of cases reported, chemotherapy and radiotherapy are frequently administered and seem to prolong mean patient's survival. Cardiac transplantation could be considered in selected cases. PMID- 29970130 TI - Acute pain in the prehospital setting: a register-based study of 41.241 patients. AB - BACKGROUND: Acute pain is a frequent symptom, but little is known about the frequency and causes of acute pain in the prehospital population. The objectives of this study were to investigate the frequency of moderate to severe pain among prehospital patients and the underlying causes according to primary hospital diagnose codes. METHODS: This was a register-based study on 41.241 patients transported by ambulance. Information on moderate to severe pain [Numeric Rating Scale (NRS, 0-10) > 3 or moderate pain or higher on 4-point likert scale] was extracted from a national electronic prehospital patient record. Patient information was merged with primary hospital diagnose codes based on the 10th version of the International Classification of Diseases (ICD-10) to investigate underlying causes of pain. RESULTS: 11.430 patients (27.7%) reported moderate to severe pain during ambulance transport. As a measure of opioid demanding acute pain, 3.275 of 41.241 patients (7.9%) were treated with intravenous fentanyl. Underlying causes of pain were heterogenic according to ICD-10 chapters with injuries being the largest group of patients with moderate to severe pain (XIX: 42.8% of 8.041 patients), followed by non-specific diagnoses (XVIII: 28.5% of 7.101 patients and XXI: 31.6% of 5.148 patients), diseases of the circulatory system (IX: 22.1% of 4.812 patients) and other (20.3% of 16.139 miscellaneous patients). DISCUSSION: Due to the high frequency of moderate to severe pain affecting a wide range of patients, more attention on acute pain is necessary. Whether ambulance personnel have sufficient options for treating various pain conditions might be a subject of future evaluation. Non-specific diagnoses accounted for surprisingly many patients with moderate to severe pain, of which many were treated with intravenous fentanyl. This may be substance of further investigation. CONCLUSIONS: Moderate to severe pain is a highly frequent and probably underestimated symptom among patients transported by ambulance. Underlying causes of pain are heterogenic as described by primary hospital diagnose codes. More focus on the treatment of acute pain is needed. PMID- 29970128 TI - Plasmodium and intestinal parasite perturbations of the infected host's inflammatory responses: a systematic review. AB - Co-infection of malaria and intestinal parasites is widespread in sub-Saharan Africa and causes severe disease especially among the poorest populations. It has been shown that an intestinal parasite (helminth), mixed intestinal helminth or Plasmodium parasite infection in a human induces a wide range of cytokine responses, including anti-inflammatory, pro-inflammatory as well as regulatory cytokines. Although immunological interactions have been suggested to occur during a concurrent infection of helminths and Plasmodium parasites, different conclusions have been drawn on the influence this co-infection has on cytokine production. This review briefly discusses patterns of selected cytokine (IL-6, IL 8, IL-10, TNF-alpha and INF-gamma) responses associated with infections caused by Plasmodium, intestinal parasites as well as a Plasmodium-helminth co-infection. PMID- 29970131 TI - Long non-coding RNA UFC1 promotes gastric cancer progression by regulating miR 498/Lin28b. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have emerged as important regulators of human cancers. However, the functional roles of lncRNAs and the mechanisms responsible for their aberrant expression in gastric cancer (GC) have not been well characterized. METHODS: In this study, we examined the expression of lncRNA UFC1 in GC by qRT-PCR and explored its correlation with clinicopathological parameters. In vitro cell functional assays and in vivo animal studies were performed to determine the roles of UFC1 in GC progression. RESULTS: UFC1 was elevated and predicted poorer prognosis in GC. UFC1 knockdown inhibited while UFC1 overexpression promoted GC cell proliferation, migration, and invasion. UFC1 bound to miR-498 to antagonize its tumor suppressive effect on Lin28b. Suppression of Lin28b by miR-498 could be rescued by UFC1 overexpression, whereas Lin28b overexpression partially rescued UFC1 knockdown-mediated inhibition of GC cell function. Lin28b expression was increased in GC and suggested a co expression pattern with UFC1. CONCLUSIONS: UFC1 has a promoting role in GC progression, at least in part, by acting as a miR-498 sponge and derepressing Lin28b expression, which would provide a novel biomarker for GC diagnosis and prognosis and offer a potential target for GC therapy. PMID- 29970132 TI - Profile of the 2016 dengue outbreak in Nepal. AB - OBJECTIVE: The objective of this study was to obtain clinical, virological and demographic data detailing the 2016 dengue outbreak in Nepal. RESULTS: Dengue disease was first reported in Nepal in 2004 and several major outbreaks have occurred since then, with a significant impact on public health. An outbreak of dengue fever occurred in Nepal during June to November 2016, with a peak number of cases reported in September. 1473 patients with laboratory confirmed DENV infections visited or were admitted to hospitals during this period. The most common clinical symptoms included fever, headache, joint pain and thrombocytopenia. Serotyping of 75 serum samples from patients having fever for less than 4 days was carried out with a dengue virus (DENV) serotype-specific RT PCR strategy. Our results indicate that the dengue outbreak in Nepal during 2016 was caused predominantly, if not exclusively, by DENV-1, representing a shift in the prevailing serotype from DENV-2, the dominant serotype characterizing the 2013 dengue epidemic in Nepal. Hopefully, this report will assist Nepalese public health agencies in developing improved dengue-related programs including mosquito vector control, DENV surveillance, and diagnosis and treatment of dengue fever patients, in order to reduce the impact of future dengue epidemics. PMID- 29970133 TI - Competitive suppression of dengue virus replication occurs in chikungunya and dengue co-infected Mexican infants. AB - BACKGROUND: Co-circulation of dengue virus (DENV) and chikungunya virus (CHIKV) is increasing worldwide but information on the viral dynamics and immune response to DENV-CHIKV co-infection, particularly in young infants, is scant. METHODS: Blood samples were collected from 24 patients, aged 2 months to 82 years, during a CHIKV outbreak in Mexico. DENV and CHIKV were identified by RT-PCR; ELISA was used to detect IgM and IgG antibodies. CHIKV PCR products were cloned, sequenced and subjected to BLAST analysis. To address serological findings, HMEC-1 and Vero cells were inoculated with DENV-1, DENV-2 and CHIKV alone and in combination (DENV-2-CHIKV and DENV-1-CHIKV); viral titers were measured at 24, 48 and 72 h. RESULTS: Nine patients (38%) presented co-infection, of who eight were children. None of the patients presented severe illness. Sequence analysis showed that the circulating CHIKV virus belonged to the Asian lineage. Seroconversion to both viruses was only observed in the four patients five years or older, while the five infants under two years of age only seroconverted to CHIKV. Viral titers in the CHIKV mono-infected cells were greater than in the DENV-1 and DENV-2 mono infected cells. Furthermore, we observed significantly increased CHIKV progeny and reduction of DENV progeny in the co-infected cells. CONCLUSIONS: In our population, DENV-CHIKV co-infection was not associated with increased clinical severity. Our in vitro assay findings strongly suggest that the lack of DENV IgG conversion in the co-infected infants is due to suppression of DENV replication by the Asian lineage CHIKV. The presence of maternal antibody and immature immune responses in the young infants may also play a role. PMID- 29970134 TI - A foodborne acute gastroenteritis outbreak caused by GII.P16-GII.2 norovirus in a boarding high school, Beijing, China: a case-control study. AB - OBJECTIVE: In December 2017, an acute gastroenteritis outbreak involving 61 students occurred in a boarding high school in Beijing, China. We conducted an outbreak investigation immediately in order to determine the cause of this outbreak and provide effective control measures. RESULTS: The laboratory inspection showed that this outbreak was caused by GII.P16-GII.2 norovirus. Risk factor analysis indicated that the lunch provided by Cafeteria 1 on Dec 12 might be the risk factor of the outbreak with an odds ratio (OR) of 3.800 (95% confidence interval [CI] 1.089-13.258). Additionally, a tray line server of Cafeteria 1 was found to have gastro-enteral symptoms recently. Based on the clinical symptoms and epidemiology investigation, the symptomatic server was considered to be the possible source of infection. PMID- 29970135 TI - A single topical fluralaner application to cats and to dogs controls fleas for 12 weeks in a simulated home environment. AB - BACKGROUND: Fluralaner (Bravecto(r), Merck Animal Health, Madison, NJ, USA) is a novel isoxazoline that provides up to 12 weeks flea and tick control when administered orally to dogs. Two assessor-blinded studies, one in dogs, the other in cats evaluated the sustained efficacy of a topical fluralaner formulation against fleas in a simulated home environment (SHE). METHODS: Animals were ranked and blocked into groups of two using flea counts completed 24 hours following Ctenocephalides felis infestations placed on dogs on Day -64, and on cats on Day 36. Within blocks animals were randomized to a treatment group, 10 animals per group, one group to receive fluralaner spot-on (minimum dose rate for dogs, 25 mg/kg; for cats, 40 mg/kg), the other to be a sham-treated control. Animals were then placed into their SHE, one animal per pen or cage and then infested with 100 C. felis at weekly intervals. Dogs were infested from Day -56 through -21 and cats on Days -28 and -21. Fleas were counted and removed from each dog and cat on Day -1. Study animals were then held in clean pens/cages until treatment on Day 0. One day later, after treatment, all animals were returned to their home environment (SHE). Additional 50-flea challenges were placed on each animal on Days 22, 50 and 78. Fleas were counted and replaced on all animals on Day 1 and weekly thereafter for 12 weeks. RESULTS: Arithmetic mean counts in control-group animals exceeded 10 fleas at all post-treatment assessments except on Days 1, 7 and 14. All control-group animals remained infested at each assessment from Day or 28 through Day 84, thereby validating the challenge methodology. Fluralaner efficacy was 100% on all occasions except for 2 fleas found on 1 dog on Day 1, and 3 fleas on 1 dog on Day 14. One flea was recovered from 1 fluralaner treated cat on Day 1. There were no treatment-related adverse events. CONCLUSION: A single application of a topical formulation of fluralaner is well tolerated and highly effective in the prevention of flea infestations of dogs and cats throughout the 12 weeks following treatment. PMID- 29970136 TI - 17p13.3 genomic rearrangement in a Chinese family with split-hand/foot malformation with long bone deficiency: report of a complicated duplication with marked variation in phenotype. AB - BACKGROUND: Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication. METHODS: A four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members. RESULTS: No mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family. CONCLUSIONS: The present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify underlying genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement. PMID- 29970137 TI - Correction to: DamID profiling of dynamic Polycomb-binding sites in Drosophila imaginal disc development and tumorigenesis. AB - Unfortunately, the original version of this article contained a typographical error in one of the author names. The name of the author Alexey Pindyurin was incorrectly spelt as Alexey Pinduyrin. The correct spelling is included here and has been updated in the original article. PMID- 29970138 TI - 17beta-estradiol upregulates IL6 expression through the ERbeta pathway to promote lung adenocarcinoma progression. AB - BACKGROUND: In non-small cell lung cancer (NSCLC), estrogen (E2) significantly promotes NSCLC cell growth via estrogen receptor beta (ERbeta). Discovery and elucidation of the mechanism underlying estrogen-promoted NSCLC progression is critical for effective preventive interventions. IL6 has been demonstrated to be involved in the development, progression and metastasis in several cancers and IL6 overexpression is associated with poor prognosis in NSCLC. However, the exact role played by IL6 in estrogen-promoted NSCLC progress remain unknown. Here, we evaluated the expression and biological effects of IL6 in NSCLC cells when treated with E2 and explored the underlying mechanism of IL6 in E2-promoted NSCLC progression. METHODS: Expression of ERbeta/IL6 in 289 lung cancer samples was assessed by immunohistochemistry. Matched samples of metastatic lymph node and primary tumor tissues were used to quantify the expression of ERbeta/IL6 by western blot. Expression levels of IL6 in NSCLC cells were quantified by western blotting, ELISA, and immunofluorescence staining. The effects of IL6 stimulated by E2 on cell malignancy were evaluated using CCK8, colony formation, wound healing and transwell. Furthermore, overexpression and knockdown ERbeta constructs were constructed to measure the expression of IL6. The effects of IL6 stimulated by E2 on tumor growth were evaluated using a urethane-induced adenocarcinoma model. In addition, a xenograft mouse model was used to observe differences in ERbeta subtype tumor growth with respect to IL6 expression. RESULTS: IL6/ERbeta expression were significantly increased in lung cancer. Higher IL6/ERbeta expression was associated with decreased differentiation or increased metastasis. IL6 was an independent prognostic factor for overall survival (OS), higher IL6 expression was associated with decreased OS. Furthermore, ERbeta regulates IL6 expression via MAPK/ERK and PI3K/AKT pathways when stimulated by E2 and promotes cell malignancy in vitro and induced tumor growth in vivo. Finally we confirm that ERbeta isolation 1/5 is essential for E2 promotion of IL6 expression, while ERbeta2 not. CONCLUSIONS: Our findings demonstrate that E2 stimulates IL6 expression to promote lung adenocarcinoma progression through the ERbeta pathway. We also clarify the difference in each ERbeta subtype for E2 promoting IL6 expression, suggesting that ERbeta/IL6 might be potential targets for prognostic assessment and therapeutic intervention in lung cancer. PMID- 29970139 TI - Training with Hybrid Assistive Limb for walking function after total knee arthroplasty. AB - BACKGROUND: The Hybrid Assistive Limb (HAL, CYBERDYNE) is a wearable robot that provides assistance to patients while walking, standing, and performing leg movements based on the intended movement of the wearer. We aimed to assess the effect of HAL training on the walking ability, range of motion (ROM), and muscle strength of patients after total knee arthroplasty (TKA) for osteoarthritis and rheumatoid arthritis, and to compare the functional status after HAL training to the conventional training methods after surgery. METHODS: Nine patients (10 knees) underwent HAL training (mean age 74.1 +/- 5.7 years; height 150.4 +/- 6.5 cm; weight 61.2 +/- 8.9 kg), whereas 10 patients (11 knees) underwent conventional rehabilitation (mean age 78.4 +/- 8.0 years; height 150.5 +/- 10.0 cm; weight 59.1 +/- 9.8 kg). Patients underwent HAL training during 10 to 12 (average 14.4 min a session) sessions over a 4-week period, 1 week after TKA. There was no significant difference in the total physical therapy time including HAL training between the HAL and control groups. Gait speed, step length, ROM, and muscle strength were evaluated. RESULTS: The nine patients completed the HAL training sessions without adverse events. The walking speed and step length in the self-selected walking speed condition, and the walking speed in the maximum walking speed condition were greater in the HAL group than in the control group at 4 and 8 weeks (P < 0.05). The step length in the maximum walking speed condition was greater in the HAL group than in the control group at 2, 4, and 8 weeks (P < 0.05). The extension lag and knee pain were lower in the HAL group than in the control group at 2 weeks (P < 0.05). The muscle strength of knee extension in the HAL group was greater than that in the control group at 8 weeks (P < 0.05). CONCLUSION: HAL training after TKA can improve the walking ability, ROM, and muscle strength compared to conventional physical therapy for up to 8 weeks after TKA. Since the recovery of walking ability was earlier in the HAL group than in the control group and adverse events were not observed in this pilot study, HAL training after TKA can be considered a safe and effective rehabilitation intervention. TRIAL REGISTRATION: UMIN, UMIN000017623 . Registered 19 May 2015. PMID- 29970140 TI - Fulminant hepatitis due to very severe sinusoidal obstruction syndrome (SOS/VOD) after autologous peripheral stem cell transplantation: a case report. AB - BACKGROUND: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (SOS/VOD), is a potentially fatal complication of allogeneic or autologous hematopoietic stem cell transplantation. A plethora of transplant and patient-related risk factors predispose to SOS/VOD and should be taken into account for prognosis assessment as well as for adequate therapeutic intervention. CASE PRESENTATION: We describe the case of a mantle cell lymphoma patient who developed a fulminant hepatitis following oxaliplatin-containing intensive chemotherapy and autologous transplantation. This clinical manifestation was secondary to a very severe SOS/VOD. The patient did not exhibit the usual risk factors and presented a non-classical form with major cytolysis, thus puzzling SOS/VOD diagnosis in this context. CONCLUSION: SOS has been previously reported after oxaliplatin-based chemotherapy regimens for colorectal cancers, in particular in patients with colorectal liver metastases. We therefore suspected a potential relationship with oxaliplatin-based regimen as a driver of SOS/VOD in a non-susceptible lymphoma patient. With regards to this case, clinicians and especially intensivists should be aware of this atypical presentation. PMID- 29970141 TI - Canine babesiosis treatment rates in South African veterinary clinics between 2011 and 2016. AB - BACKGROUND: South African veterinarians report the perception of a multi-year decline in the number of dogs presenting with clinical babesiosis, a common and serious disease of dogs in the country. This study tested this observation through analysis of veterinary hospital medical records from 2011 through 2016. METHODS: Medical records were collected from 44 participating South African veterinary hospitals. The collected medical records were searched to enumerate the number of Babesia-specific medication treatments administered to dogs at all participating hospitals. A healthcare use rate was calculated for canine babesiosis treatment for each calendar year from 2011 to 2016. The healthcare use rate numerator was the total number of canine babesiosis treatments and the denominator was the total dog visits to all participating veterinary practices over the same period. RESULTS: There were 2.6 million dog visits to 44 participating veterinary practices between 2011 and 2016. The number of canine babesiosis treatments for each year in chronological order starting with 2011 was: 2957; 2679; 2456; 2746; 2272; and 1592. South African regions with the highest number of canine babesiosis treatments were Gauteng, Free State and Mpumalanga. The overall calculated healthcare use rate for canine babesiosis treatment declined 72% over the study period from 1.18% in 2011 to 0.33% in 2016. The steepest decline of 31% was observed between 2015 and 2016. CONCLUSIONS: South African veterinary practices saw a decline in canine babesiosis treatment administration from 2011 to 2016 with the steepest decline beginning in 2015. PMID- 29970143 TI - Screening for biomarkers reflecting the progression of Babesia microti infection. AB - BACKGROUND: Babesiosis is caused by the invasion of erythrocytes by parasites of the Babesia spp. Babesia microti is one of the primary causative agents of human babesiosis. To better understand the status of the disease, discovering key biomarkers of the different infection stages is crucial. RESULTS: This study investigated B. microti infection in the mouse model from 0 to 270 days post infection (dpi), using blood smears, PCR assays and ELISA. PCR assays showed a higher sensitivity when compared to microscopic examination. Specific IgG antibodies could be detected from 7 days to 270 dpi. Two-dimensional electrophoresis was combined with western blotting and mass spectrometric analysis to screen for specific reactive antigens during both the peak parasitaemia period (7 dpi) and IgG antibody response peak period (30 dpi) by the infected mice plasma. The 87 positive reactive proteins were identified and then expressed with the wheat germ cell-free system. Protein microarrays of all 87 targeted proteins were produced and hybridized with the serial plasma of infected mice model. Based on the antigen reaction profile during the infection procedure, 6 antigens were selected and expressed in Escherichia coli. Due to an early response to IgM, lower immunoreactivity levels of IgG after two months and higher immunoreactivity level IgG during nine months, four recombinant proteins were selected for further characterization, namely rBm2D97(CCF75281.1), rBm2D33(CCF74637.1), rBm2D41(CCF75408.1) and rBm7(CCF73510.1). The diagnostic efficacy of the four recombinant protein candidates was evaluated in a clinical setting using babesiosis patient plasma. The rBm2D33 showed the highest sensitivity with a positive rate of 62.5%. Additional characterization of the two candidate proteins using a mouse vaccination assay, demonstrated that rBm2D41 could reduce peak parasitaemia by 37.4%, indicating its efficacy in preventing severe babesiosis. CONCLUSIONS: The detection technologies of microscopic examination, PCR assays and antibody tests showed different sensitivities and accuracy during the different stages of B. microti infection. Antibody detection has a unique significance for B. microti infection in the asymptomatic stages. Using immunoreactivity profiles, biomarkers for disease progression were identified and represent useful information for future the diagnosis and vaccine development for this serious disease of public health significance. PMID- 29970142 TI - Effects of a 6-week, whole-body vibration strength-training on depression symptoms, endocrinological and neurobiological parameters in adolescent inpatients experiencing a major depressive episode (the "Balancing Vibrations Study"): study protocol for a randomized placebo-controlled trial. AB - BACKGROUND: Moderate to vigorous endurance and strength-training exercise was suggested as a treatment option for major depression. However, there is little evidence to support this suggestion in adolescent patients. The present study investigates the effects of a whole-body vibration strength-training intervention on symptoms in medication-naive adolescent inpatients experiencing a major depressive episode. Potential underlying endocrinological and neurobiological mechanisms are explored. METHODS/DESIGN: A double-blinded randomized controlled trial is conducted at the University Hospital of Cologne in Germany, comparing a 6-week, whole-body vibration strength-training with a 6-week placebo intervention, as add-on therapy to inpatient treatment as usual. Forty-one subjects (13-18 years of age) will be included in each of the two groups. The study is powered to detect (alpha = .05, beta = .2) a medium effect size difference between the two groups (d = .5) in terms of patients' change in the Children's Depression Rating Scale raw-score, from baseline until the end of the intervention. As secondary endpoints, the effects of exercise treatment on patients' cortisol awakening response as well as on brain-derived neurotrophic factor, insulin-like growth factor 1 and inflammatory markers (tumor necrosis factor-alpha, interleukin-6 and C-reactive protein) serum levels will be assessed. DISCUSSION: This study will provide evidence on the effectiveness of whole-body vibration strength-training as an add-on therapy in adolescent inpatients experiencing a major depressive episode. After completion of data collection, the present study will be the largest randomized controlled trial so far to investigate the effectiveness of an exercise intervention in inpatient adolescents suffering from a major depressive episode. Moreover, the present study may help to determine the underlying mechanisms of potential anti depressant effects of exercise in depressed adolescent inpatients. TRIAL REGISTRATION: DRKS.de, German Clinical Trials Register (DRKS), Identifier: DRKS00011772 . Registered on 20 March 2017. PMID- 29970144 TI - Effect of noisy galvanic vestibular stimulation in community-dwelling elderly people: a randomised controlled trial. AB - BACKGROUND: Balance disorders are a risk factor for falls in the elderly. Although noisy galvanic vestibular stimulation (nGVS) has been reported to improve balance in young people, randomised control trials targeting community dwelling elderly people have not been conducted to date. We aimed to assess the influence of nGVS on COP sway in the open-eye standing posture among community dwelling elderly people in a randomised controlled trial. METHODS: A randomised controlled trial of 32 community-dwelling elderly people randomly assigned to control (sham stimulation) and an nGVS groups. All participants underwent centre of pressure (COP) sway measurements while standing with open eyes at baseline and during stimulation. The control group underwent sham stimulation and the nGVS group underwent noise stimulation (0.4 mA; 0.1-640 Hz). RESULTS: In the nGVS group, sway path length, mediolateral mean velocity and anteroposterior mean velocity decreased during stimulation compared with baseline (P < 0.01). The effect of nGVS was large in participants with a high COP sway path length at baseline, but there was no significant difference in COP sway in the control group. CONCLUSIONS: We conclude that nGVS decreases the COP sway path length and mean velocity of community-dwelling elderly people when standing with open eyes. This suggests that nGVS could be effective for treating balance dysfunction in the elderly. PMID- 29970145 TI - Predicting environmentally suitable areas for Anopheles superpictus Grassi (s.l.), Anopheles maculipennis Meigen (s.l.) and Anopheles sacharovi Favre (Diptera: Culicidae) in Iran. AB - BACKGROUND: Malaria is an important mosquito-borne disease, transmitted to humans by Anopheles mosquitoes. The aim of this study was to gather all records of three main malaria vectors in Iran during the last decades, and to predict the current distribution and the environmental suitability for these species across the country. METHODS: All published documents on An. superpictus Grassi (s.l.), An. maculipennis Meigen (s.l.) and An. sacharovi Favre during 1970-2016 in Iran were obtained from different online data bases and academic libraries. A database was created in ArcMap 10.3. Ecology of these species was analyzed and the ecological niches were predicted using MaxEnt model. RESULTS: Anopheles superpictus (s.l.) is the most widespread malaria vector in Iran, and exists in both malaria endemic and non-endemic areas. Whereas An. maculipennis (s.l.) is reported from the northern and northwestern parts, Anopheles sacharovi is mostly found in the northwestern Iran, although there are some reports of this species in the western, southwestern and eastern parts. The area under receiver operating characteristic (ROC) curve (AUC) for training and testing data was calculated as 0.869 and 0.828, 0.939 and 0.915, and 0.921 and 0.979, for An. superpictus (s.l.), An. maculipennis (s.l.) and An. sacharovi, respectively. Jackknife test showed the environmental variable with highest gain in the predicting power of the model when used in isolation was annual precipitation for An. superpictus (s.l.) and An. maculipennis (s.l.), and precipitation of the driest quarter for An. sacharovi. CONCLUSIONS: Despite this range, global warming may increase the potential risk for malaria transmission in some cleared-up areas, where these proven vectors are active. Mapping and prediction of spatial/temporal distribution of these vectors will be beneficial for decision makers to be aware of malaria transmission risk, especially in the western parts of the country. PMID- 29970146 TI - Mechanical circulatory support as bridge therapy for heart transplant: case series report. AB - BACKGROUND: Mechanical circulatory support (MCS) represents an effective urgent therapy for patients with cardiac arrest or end-stage cardiac failure. However, its use in developing countries as a bridge therapy remains controversial due to costs and limited duration. This study presents five patients who underwent MSC as bridge therapy for heart transplantation in a developing country. CASE PRESENTATION: We present five patients who underwent MCS as bridge therapy for heart transplant between 2010 and 2015 at Fundacion Cardioinfantil-Instituto de Cardiologia. Four were male, median age was 36 (23-50) years. One patient had an ischemic cardiomyopathy, one a lymphocytic myocarditis, two had electrical storms (recurrent ventricular tachycardia) and one an ischemic cardiomyopathy with an electrical storm. Extracorporeal life support (ECLS) was used in three patients, left ventricular assistance in one, and double ventricular assistance in one (Levitronix(r) Centrimag(r)). Median assistance time was 8 (2.5-13) days. Due to the inability of cardiopulmonary bypass weaning, two patients required ECLS after transplant. One patient died in the intensive care unit due to type I graft rejection. Endpoints assessed were 30-day mortality, duration of bridge therapy and complications related to MCS. Patients that died on ECLS, or were successfully weaned off ECLS were not included in this study. CONCLUSIONS: MCS is often the only option of support for critically ill patients waiting for a heart transplant and could be considered as a short-term bridge therapy. PMID- 29970147 TI - Evaluating the effectiveness of trematocides against Fasciola gigantica and amphistomes infections in cattle, using faecal egg count reduction tests in Iringa Rural and Arumeru Districts, Tanzania. AB - BACKGROUND: Fasciolosis, caused by the liver fluke Fasciola gigantica, and paramphistomosis are widespread in cattle in Tanzania, and the use of trematocides is encouraged by the Government livestock extension officers. However, reduced efficacy of oxyclozanide against Fasciola gigantica and amphistomes (rumen flukes), and albendazole against F. gigantica, has been reported in some regions. This study was conducted to assess the efficacy of different trematocides against F. gigantica and amphistome infections in cattle at Iringa Rural and Arumeru Districts. METHODS: Cattle found with concurrent infection of F. gigantica and amphistomes were randomly grouped into six experimental groups. One control group was left untreated while five treatment groups were treated with one of five trematocides that include: albendazole, nitroxynil, oxyclozanide, closantel and triclabendazole. Post-treatment faecal sample collection was done on the day of treatment and again at 7, 14 and 28 days, from each cattle. The samples were processed by Flukefinder(r) method to recover and identify eggs. Assessment of the efficacy of the trematocides against F. gigantica and amphistomes was conducted using faecal egg count reduction (FECR) tests. RESULTS: The findings of the present study in both districts indicate that nitroxynil, oxyclozanide, closantel and triclabendazole are effective against patent F. gigantica infection, as the calculated FECR% for each trematocide was 100% by day 14 post-treatment. However, albendazole found to have reduced efficacy of against F. gigantica, as FECR% was 49% in Arumeru District and 89% in Iringa Rural District by day 14 post-treatment. Oxyclozanide was the only trematocide found to be effective against amphistomes with FECR of 99%. CONCLUSIONS: Albendazole had reduced efficacy against F. gigantica in cattle in Arumeru and Iringa Rural Districts, Tanzania. The reduced efficacy was prominent in Arumeru, where cattle are commonly treated with anthelmintics, than in Iringa Rural, where cattle are seldom treated. PMID- 29970148 TI - A critically ill patient after a colchicine overdose below the lethal dose: a case report. AB - BACKGROUND: Although 0.8 mg/kg is considered a lethal dose of colchicine, fatal cases of patients who followed a critical disease course after an intake below this lethal dose have been reported. CASE PRESENTATION: An 18-year-old Japanese woman who had taken an overdose of prescription colchicine (15 mg; 0.2 mg/kg) was brought to our emergency out-patient department. Although her colchicine intake was below 0.8 mg/kg (considered the lethal dose), she reached a critical state and underwent three phases characterizing colchicine poisoning (gastrointestinal symptoms, multiple organ failure, and recovery). Her condition was critical, with a Sequential Organ Failure Assessment score of a maximum of 14. CONCLUSIONS: Patients might reach a critical stage after colchicine ingestion at a non-lethal dose. Thus, it might be necessary to review which dose of colchicine should be considered lethal. PMID- 29970149 TI - Assessment of vector competence of UK mosquitoes for Usutu virus of African origin. AB - BACKGROUND: Usutu virus (USUV) is an emerging zoonotic virus originally from sub Saharan Africa. It has been introduced into Europe on multiple occasions, causing substantial mortality within the Eurasian blackbird (Turdus merula) population. It is transmitted by the mosquito species Culex pipiens in Europe and Africa. Vector competence studies indicate that European strains of USUV are readily transmitted by indigenous Cx. pipiens. However, there is limited information on the ability of an African strain to infect European mosquitoes. METHODS: We evaluated the ability of African strain SAAR-1776 to infect two lines of Cx. pipiens colonised within the United Kingdom (UK). Mosquitoes were fed blood meals containing this virus and maintained at 25 degrees C for up to 21 days. Individual mosquitoes were tested for the presence of virus in the body, legs and an expectorate saliva sample. Changes to the consensus of the virus genome were monitored in samples derived from infected mosquitoes using amplicon based next generation sequencing. RESULTS: Infection, dissemination and the presence of virus in saliva in one mosquito line was observed, but no evidence for dissemination in the second mosquito line. This suggests a strong barrier to infection in UK Cx. pipiens for this strain of USUV. When comparing the genome of input virus within the blood meal with USUV recovered from an infected mosquito, we observed limited changes in the consensus genome sequence. CONCLUSIONS: The evaluation of vector competence of UK populations of Cx. pipiens for Usutu virus suggests a limited susceptibility to infection with USUV strain SAAR-1776 of African origin. However, within a single mosquito there was complete dissemination and expectoration of USUV, indicating that infection, and potentially transmission, is possible. Sequence changes were observed that may represent early adaption to the mosquito host and could reflect the early events of USUV establishment in European mosquito populations. PMID- 29970150 TI - Dietary practice and associated factors among type 2 diabetic patients in Felege Hiwot Regional Referral Hospital, Bahir Dar, Ethiopia. AB - OBJECTIVE: Even if patient's dietary practice is a gold standard measure to manage type 2 diabetes, there is a limited study in the area. Therefore, the objective of this study was to assess dietary practice and associated factors among type 2 diabetic patients. RESULT: The study revealed that only 35.9% of the patients had good dietary practice. Attending above primary education [AOR = 1.9, 95% CI (1.1, 3.2)], having family support [AOR = 2.6, 95% CI (1.6, 4.2)], and receiving nutrition education [AOR = 2.5, 95% CI (1.5, 4.2)] were independent predictors for good dietary practice. Thus, the findings indicate the need to improve a method of nutrition education both for the patients and their families. Moreover, the government needs to improve literacy rate of citizens. PMID- 29970151 TI - The pattern of color change in small mammal museum specimens: is it independent of storage histories given museum-specific conditions? AB - OBJECTIVE: Determination of color and evaluating its variation form the basis for a broad range of research questions. For studies on taxonomy, systematics, etc., resorting to mammal specimens in museum collections has a number of advantages over using field specimens. However, if museum specimens are to be for studying color, they should accurately represent the color of live animals, or we should understand how they differ. Basically, this study addresses this question: How does coat color vary when dealing with specimens of Akodon budini (Budin's grass mouse, Thomas 1918), stored in one museum collection for different periods of time? RESULTS: We measured color values through a spectroradiometer and a diffuse illumination cabin and used the reflectance values in the form of CIELab tri stimulus values, considering CIE standard illuminant A. We observed that there is a relationship between specimen storage antiquity and pelage color and it seems that it is general for at least a number of small mammals and this could indicate a universal phenomenon across several mammal species and across several storage conditions. Our results, as others, emphasize the importance of considering storage time, among other circumstances, in research studies using mammal skins and where color is of importance. PMID- 29970152 TI - TMEM106B haplotypes have distinct gene expression patterns in aged brain. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) inherited as one of two common haplotypes at the transmembrane protein 106B (TMEM106B) locus are associated with the risk of multiple neurodegenerative diseases, including frontotemporal lobar degeneration with pathological inclusions of TDP-43. Among the associated variants, rs3173615 (encoding p.T185S) is the only coding variant; however, non coding variants may also contribute to disease risk. It has been reported that the risk haplotype is associated with higher levels of TMEM106B and increased levels of TMEM106B cause cytotoxicity; however, the precise mechanism through which TMEM106B haplotypes contribute to neurodegeneration is unclear. METHODS: We utilized RNA sequencing data derived from temporal cortex (TCX) and cerebellum (CER) from 312 North American Caucasian subjects neuropathologically diagnosed with Alzheimer's disease, progressive supranuclear palsy, pathological aging or normal controls to analyze transcriptome signatures associated with the risk (TT) and protective (SS) TMEM106B haplotypes. In cohorts matched for disease phenotype, we used Analysis of Variance (ANOVA) to identify differentially expressed genes and Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene networks associated with the risk and protective TMEM106B haplotypes. RESULTS: A total of 110 TCX and 116 CER samples were included in the analyses. When comparing TT to SS carriers, we detected 593 differentially expressed genes in TCX and 7 in CER. Gene co-expression network analyses further showed that in both TCX and CER the SS haplotype was positively correlated with gene networks involved in synaptic transmission, whereas the TT haplotype was positively correlated with gene networks enriched for immune response. Gene expression patterns of 5 cell-type-specific markers revealed significantly reduced expression of the neuronal marker and relative increases in all other cell markers in TT as compared to SS carriers in TCX with a similar but non significant trend in CER. CONCLUSIONS: By comparing the common TMEM106B risk and protective haplotypes we identified significant and partly conserved transcriptional differences across TCX and CER and striking changes in cell-type composition, especially in TCX. These findings illustrate the profound effect of TMEM106B haplotypes on brain health and highlight the importance to better understand TMEM106B's function and dysfunction in the context of neurodegenerative diseases. PMID- 29970153 TI - Impact of partially and fully closed eaves on house entry rates by mosquitoes. AB - BACKGROUND: Most people infected with malaria acquire the infection indoors from mosquito vectors that entered the house through open eaves, windows and doors. Structural house improvement (e.g. closed eaves and screened windows) is an established method of reducing mosquito entry. It could be complementary to other interventions such as insecticide-treated bed nets (ITNs) for malaria control because it covers and protects all individuals in a house equally. However, when implemented at a large scale, house improvement may not be employed optimally. It is therefore critical to assess whether partial house improvement will have any effect on mosquito house entry. We investigated the effect of partial and complete eave closure on the house-entry rates of malaria vectors and other mosquitoes in southern Malawi. METHODS: The study was conducted for 25 nights in May-June 2016. Twenty-five traditional houses were modified according to five treatments: fully closed eaves, three different levels of partially closed eaves, and open eaves. All houses had fully screened windows and closed doors. Host seeking mosquitoes were sampled inside these houses using Centers for Disease Control and Prevention (CDC) light traps. The effect of open eaves versus partial or complete eave closure on the number of mosquitoes trapped inside the house was estimated using a generalized linear mixed model fitted with Poisson distribution and a log-link function. RESULTS: House entry by malaria vectors was 14-times higher in houses with fully open eaves compared to houses with fully closed eaves adjusting for wall-type, number of people that slept in the house the previous night, cooking locations and presence of livestock. Houses with four small openings had 9 times more malaria vectors compared to houses with fully closed eaves. The catches of culicine mosquitoes caught in houses with fully closed eaves were not different from those caught in houses with the other treatments. CONCLUSIONS: Closed eaves resulted in fewer malaria vectors in houses, with differences depending on the degree of eave closure. The ability of malaria vectors to locate any remaining entry points on improved houses, as demonstrated here, suggests that quality control must be an important component of implementing house improvement as an intervention.The lack of effect on culicine mosquitoes in this study could reduce acceptance of house improvement, as implemented here, by household residents due to continued nuisance biting. This limitation could be addressed through community engagement (e.g. encouraging people to close their doors early in the evenings) or improved designs. PMID- 29970154 TI - A constrained SSU-rRNA phylogeny reveals the unsequenced diversity of photosynthetic Cyanobacteria (Oxyphotobacteria). AB - OBJECTIVE: Cyanobacteria are an ancient phylum of prokaryotes that contain the class Oxyphotobacteria. This group has been extensively studied by phylogenomics notably because it is widely accepted that Cyanobacteria were responsible for the spread of photosynthesis to the eukaryotic domain. The aim of this study was to evaluate the fraction of the oxyphotobacterial diversity for which sequenced genomes are available for genomic studies. For this, we built a phylogenomic constrained SSU rRNA (16S) tree to pinpoint unexploited clusters of Oxyphotobacteria that should be targeted for future genome sequencing, so as to improve our understanding of Oxyphotobacteria evolution. RESULTS: We show that only a little fraction of the oxyphotobacterial diversity has been sequenced so far. Indeed 31 rRNA clusters of the 60 composing the photosynthetic Cyanobacteria have a fraction of sequenced genomes < 1%. This fraction remains low (min = 1%, median = 11.1%, IQR = 7.3%) within the remaining "sequenced" clusters that already contain some representative genomes. The "unsequenced" clusters are scattered across the whole Oxyphotobacteria tree, at the exception of very basal clades. Yet, these clades still feature some (sub)clusters without any representative genome. This last result is especially important, as these basal clades are prime candidate for plastid emergence. PMID- 29970155 TI - Acupoint herbal plaster for patients with primary dysmenorrhea: study protocol for a randomized controlled trial. AB - BACKGROUND: Primary dysmenorrhea (PD), is one of main gynecological complaints in women of child-bearing age. Common medications for PD do not always achieve satisfactory outcome of pain relief. Hence, both health professionals and patients are seeking help from complementary and alternative medicine. The acupoint herbal plaster (AHP), which appears to be a safe and effective way to alleviate menstrual pain, as well as to improve other PD-related symptoms. Despite similar clinical studies for this condition in the past, no high-quality methodology-based clinical trial has been reported to date. The current study aims to assess the efficacy of the AHP compared with the acupoint placebo plaster (APP) and being placed on a waiting-list control group in patients with primary dysmenorrhea. METHODS/DESIGN: This study is a randomized, single-center, placebo controlled clinical trial. A total of 180 women with PD will be included and randomly allocated to the AHP, APP and waiting-list (WL) groups in a 1:1:1 ratio. Patients in the AHP group will be provided with herbal plasters (Shaofuzhuyu decoction) on various acupoints: Shenque (CV8), Guanyuan (CV4), Qihai (CV5), Ciliao (BL32) and Zigong (EX-CA1). Women in the APP group will receive placebo plasters on the same acupoints, and no intervention will be given to the WL group until completion of the study. The primary outcome will be pain intensity reduction measured by a Visual Analog Scale (VAS), with other outcome measurements including the Cox Menstrual Symptom Scale (CMSS), the 12-Item Short Form Health Survey (SF-12) and the Participant Global Impression of Change (PGIC). All assessments will be performed at baseline, each menstrual cycle during the treatment course and the follow-up course. Any adverse events will be recorded throughout the study. DISCUSSION: This is the first study to compare the changes in menstrual pain after three different interventions: the active intervention (AHP), the placebo intervention (APP), and a period of no intervention (WL). This three-arm randomized controlled trial (RCT) aims to investigate the relative contributions of the specific (AHP vs. APP) and non specific (APP vs. WL) effects to the overall clinical effects of the active AHP on women with PDM. The scientific and rigorous methodology design of this trial should gather good evidence to assess the curative effects and safety of the AHP on PD. Moreover, the results of this study may provide evidence-based references for the treatment of menstrual pain in future. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-TRC-16008701. Registered on 22 July 2016. PMID- 29970156 TI - Acceptability of the method of administration of a patient-reported outcome measure (PROM) with stroke survivors, a randomised controlled trial protocol. AB - BACKGROUND: UK-wide national clinical guidelines promote routine 6-month post stroke follow-up assessment. However, as part of this 6-month assessment little information is gathered from the patient's perspective. The means of collecting this patient-centred information might be served best by a patient-reported outcome measure (PROM) at the 6-month assessment time point. Currently, four different methods of 6-month follow-up assessment occur; the most common being face-to-face interview followed by telephone interview, postal questionnaire and online questionnaire. Therefore, this study will investigate if the acceptability of telephone, online or postal administration of a PROM at the 6-month post-stoke time point is not inferior to face-to-face administration. METHODS/DESIGN: A UK multicentre, blinded (analyst and researcher), pragmatic, non-inferiority study, with 80% power using a 2.5% non-inferiority margin was designed to compare the acceptability of three modes of administration (telephone interview, postal questionnaire and online questionnaire) compared with face-to-face interview administration of a PROM. We plan to approach and randomise a minimum of 808 potentially eligible participants, 202 participants per group. DISCUSSION: The aim of this ongoing research is to understand if there is a difference between face-to-face administration and the other three methods of administering a PROM as a patient-centred supplement to the 6-month review for stroke survivors. In utilising a pragmatic design, it is believed that this study will offer UK wide generalisable results, of the acceptability of the methods under investigation, to inform clinicians and commissioners of stroke services. TRIALS REGISTRATION: ClinicalTrials.gov: NCT03177161 . Registered on 6 June 2017. PMID- 29970157 TI - Induction of immune response in chickens primed in ovo with an inactivated H9N2 avian influenza virus vaccine. AB - OBJECTIVE: Infection of chickens with low pathogenic avian influenza virus, such as H9N2 virus, culminates in decreased egg production and increased mortality and morbidity if co-infection with other respiratory pathogens occurs. We have previously observed the induction of antibody- and cell-mediated immune responses after intramuscular administration of an H9N2 beta-propiolactone inactivated virus vaccine to chickens. Given the fact that in ovo vaccination represents a practical option for vaccination against H9N2 AIV in chickens, in the current study, we set out to characterize immune responses in chickens against a beta propiolactone inactivated H9N2 virus vaccine after primary vaccination in ovo on embryonic day 18, and secondary intramuscular vaccination on day 14 post-hatch. We also included the Toll-like receptor 21 ligand, CpG ODN 2007, and an oil emulsion adjuvant, AddaVaxTM, as adjuvants for the vaccines. RESULTS: Antibody mediated immune responses were observed after administering the secondary intramuscular vaccine. Cell-mediated immune responses were observed in chickens that received the beta-propiolactone inactivated H9N2 virus combined with AddaVaxTM. Our results demonstrate that adaptive immune responses can be induced in chickens after a primary in ovo vaccination and secondary intramuscular vaccination. PMID- 29970159 TI - Modes of mechanical ventilation vary between hospitals and intensive care units within a university healthcare system: a retrospective observational study. AB - OBJECTIVE: As evidence-based guidance to aid clinicians with mechanical ventilation mode selection is scant, we sought to characterize the epidemiology thereof within a university healthcare system and hypothesized that nonconforming approaches could be readily identified. We conducted an exploratory retrospective observational database study of routinely recorded mechanical ventilation parameters between January 1, 2010 and December 31, 2016 from 12 intensive care units. Mode epoch count proportions were examined using Chi squared and Fisher exact tests as appropriate on an inter-unit basis with outlier detection for two test cases via post hoc pairwise analyses of a binomial regression model. RESULTS: Final analysis included 559,734 mode epoch values. Significant heterogeneity was demonstrated between individual units (P < 0.05 for all comparisons). One unit demonstrated heightened utilization of high-frequency oscillatory ventilation, and three units demonstrated frequent synchronized intermittent mandatory ventilation utilization. Assist control ventilation was the most commonly recorded mode (51%), followed by adaptive support ventilation (23.1%). Volume-controlled modes were about twice as common as pressure controlled modes (64.4% versus 35.6%). Our methodology provides a means by which to characterize the epidemiology of mechanical ventilation approaches and identify nonconforming practices. The observed variability warrants further clinical study about contributors and the impact on relevant outcomes. PMID- 29970160 TI - How can the risk of ovarian retorsion be reduced? AB - BACKGROUND: In the current treatment of idiopathic ovarian torsion, the use of oophorectomy has declined in favor of preserving the ovary. This approach brings with it the question of how to reduce the possibility of retorsion of the detorsioned ovary. The aim of this study was to analyze how retorsion can be prevented. METHODS: Five patients (a 30-day-old Caucasian girl, a 55-day-old Caucasian girl, an 8-year-old Caucasian girl, a 10-year-old Caucasian girl, and a 16-year-old Caucasian girl) who underwent surgery due to non-neoplastic ovarian torsion were retrospectively analyzed for diagnosis and treatment in terms of reducing the possibility of retorsion. RESULTS: In all patients, a precise diagnosis of idiopathic unilateral ovarian torsion was made during laparotomy, and the patients underwent different procedures. The ovary was found to be autoamputated in one patient, and two patients underwent salpingo-oophorectomies due to adnexal necrosis. The ovaries were detorsioned in the remaining two patients. During the operations, patients were evaluated regarding the prevention of retorsion of the ipsilateral and/or contralateral ovary; cyst drainage, cystectomy, ligament fixation, and/or oophoropexy were performed. The median follow-up period of the patients was 2 years (range 1.5-6 years), and they continue to be followed uneventfully. CONCLUSIONS: To date, there is no standard approach to protect the ovary from retorsion in patients who undergo surgery due to torsion. The surgical procedure should be tailored on a case-by-case basis. PMID- 29970161 TI - Coping strategies among nurses in South-west Ethiopia: descriptive, institution based cross-sectional study. AB - OBJECTIVE: This study aimed to describe coping strategies for job stress among nurses working in Jimma Zone public hospitals, South-west Ethiopia. The study conducted from March to April 2014 through census using English version structured self-administered questionnaire. RESULT: This study indicated percentage mean overall score of 65.07% for adaptive coping approach and 56.86% for a maladaptive approach. Nurses mostly used coping strategy were; just concentrating on what they have to do, make a plan of action and following it, developing coworker/peer support, and having a close friend to tell. While, coping strategy that least used among nurses were; do not want to come to work when stressed, directly expressing anger on family or friends, trying to feel better by taking drinks like tea, coffee, soft drinks more than usual and accept the situation because there is nothing to do. In summary, an adaptive approach was dominant style; social support and plan-full problem solving were the most preferred strategies. While escape-avoidance coping strategy least used. Further researches need to be conducted to explore its predictors. PMID- 29970158 TI - Tumor matrix remodeling and novel immunotherapies: the promise of matrix-derived immune biomarkers. AB - Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy. PMID- 29970162 TI - Adolescent deliveries in rural Cameroon: comparison of delivery outcomes between primipara and multipara adolescents. AB - OBJECTIVE: Adolescent pregnancies are high risk and deliveries in this age group are usually associated with adverse outcomes. The perception that multiparous adolescents have better delivery outcomes than primiparous counterparts is not uncommon. We sought to determine if multiparous adolescents were precluded from having adverse delivery outcomes when compared to primiparous adolescents. The data used for the analysis is a side product from a published project aimed at mapping the epidemiology of adolescent deliveries in the Oku health district. RESULTS: From an 8-year (2009-2016) retrospective register analysis of data from two primary healthcare facilities in the Oku health district-a rural area in Cameroon, the prevalence of multiparous adolescent deliveries was 21.5% (78/363). After multivariable analyses, and adjusting for age, sex of baby, gestational age, marital status and HIV status, primiparous adolescents were more likely to have low birth weight infants (LBW) (OR: 3.2; 95% CI 1.1, 9.7; p = 0.04) when compared with multiparous adolescents. Though primiparous adolescents were more likely to have LBW infants than multiparous adolescents, this group of mothers are generally ill-equipped to handle pregnancies and adolescent-friendly programs are necessary to decrease the associated burden. PMID- 29970163 TI - Sero-prevalence of hepatitis B virus infection and associated factors among health care workers and medical waste handlers in primary hospitals of North-west Ethiopia. AB - OBJECTIVE: The aim of this cross-sectional study was to determined the sero prevalence of HBV infection and associated factors among health care workers and medical waste handlers in primary hospitals of North-west Ethiopia. RESULTS: A total of 388 study participants were included in this study. Of which, 268 (69%) were health care workers and 120 (31%) were medical waste handlers. Males accounted 54.9% and the mean age for all study participants was 28.3 (standard deviation = 6.9). Hepatitis B virus surface antigen (HBsAg) was detected in 2.6% health care workers and 2.5% medical waste handlers and the overall hepatitis B virus infection was 10 (2.6%). High rate of hepatitis B virus infection was detected in single participants and those in the age group of 30-40 years were more infected (6.6%). History of contact with HBV infected case (8.3%) (AOR = 6.8, 95% CI = 1.6-28.5, P = 0.009) and history of jaundice (15.4%) (AOR = 10.5, 95% CI = 2.1-12.2, P = 0.03) were statistically associated factors for HBV infection. More than half (54.4%) of the study participants did not take training on infection and 9 (4.3%) of them were positive for HBsAg (COR = 1.3, 95% CI = 0.0.02-1.02, P = 0.052). PMID- 29970165 TI - Interactions between life expectancy and the incidence and mortality rates of cancer in China: a population-based cluster analysis. AB - BACKGROUND: The relationship between cancer and life expectancy is well established in both developed and developing countries. China is a vast country with significant geographical differences in population structure and healthcare, and thus provides a unique opportunity to analyze the complex relationship between life expectancy and cancer incidence and mortality rates. METHODS: Cancer data were extracted for a total of 255 units (cities or counties) from the 2013 National Central Cancer Registry. Life expectancy data at the unit level were obtained from the National Centers for Disease Control and Prevention. Linear regression analysis was used to analyze the relationship between life expectancy and crude incidence and mortality rates of cancer. In a separate analysis, life expectancy was rated as low (< 76.0 years), middle (76-80 years), or high (> 80 years). RESULTS: Overall, the cancer incidence and mortality rates positively correlated with life expectancy in both sexes (R at 0.37 and 0.50, P < 0.001). The correlation was significant for the following cancers: lung, colorectal, prostate, bladder and pancreas, as well as for lymphoma in men (R 0.36-0.58, P < 0.001), lung, breast, colorectal, thyroid, uterus, and ovary in women (R 0.18 0.51, P < 0.001). We failed to observe an association between upper gastrointestinal cancer and life expectancy. The number of cities/counties with low, middle and high life expectancy levels were 110, 101 and 44, respectively. The highest age-standardized cancer incidence rate was observed in areas with a high life expectancy level (192.83/100,000). The highest age-standardized mortality rate was in areas with the lowest life expectancy (118.44/100,000). Cancers of the stomach, liver and esophagus are major cancer types in areas with low and middle life expectancy. In contrast, areas with high life expectancy had high incidence and mortality rates of colorectal cancer, breast cancer in women and prostate cancer in men. CONCLUSIONS: Longer life expectancy is associated with higher overall cancer incidence and mortality in China. The cancer pattern also varies substantially across areas with different life expectancy levels. Life expectancy levels must be considered when developing strategies to prevent and treat cancers. PMID- 29970164 TI - Expression profiling of Trypanosoma congolense genes during development in the tsetse fly vector Glossina morsitans morsitans. AB - BACKGROUND: The tsetse transmitted parasitic flagellate Trypanosoma congolense causes animal African trypanosomosis (AAT) across sub-Saharan Africa. AAT negatively impacts agricultural, economic, nutritional and subsequently, health status of the affected populace. The molecular mechanisms that underlie T. congolense's developmental program within tsetse are largely unknown due to considerable challenges with obtaining sufficient parasite cells to perform molecular studies. METHODS: In this study, we used RNA-seq to profile T. congolense gene expression during development in two distinct tsetse tissues, the cardia and proboscis. Indirect immunofluorescent antibody test (IFA) and confocal laser scanning microscope was used to localize the expression of a putative protein encoded by the hypothetical protein (TcIL3000_0_02370). RESULTS: Consistent with current knowledge, genes coding several variant surface glycoproteins (including metacyclic specific VSGs), and the surface coat protein, congolense epimastigote specific protein, were upregulated in parasites in the proboscis (PB-parasites). Additionally, our results indicate that parasites in tsetse's cardia (C-parasites) and PB employ oxidative phosphorylation and amino acid metabolism for energy. Several genes upregulated in C-parasites encoded receptor-type adenylate cyclases, surface carboxylate transporter family proteins (or PADs), transport proteins, RNA-binding proteins and procyclin isoforms. Gene ontology analysis of products of genes upregulated in C-parasites showed enrichment of terms broadly associated with nucleotides, microtubules, cell membrane and its components, cell signaling, quorum sensing and several transport activities, suggesting that the parasites colonizing the cardia may monitor their environment and regulate their density and movement in this tissue. Additionally, cell surface protein (CSP) encoding genes associated with the Fam50 'GARP', 'iii' and 'i' subfamilies were also significantly upregulated in C-parasites, suggesting that they are important for the long non-dividing trypomastigotes to colonize tsetse's cardia. The putative products of genes that were upregulated in PB-parasites were linked to nucleosomes, cytoplasm and membrane-bound organelles, which suggest that parasites in this niche undergo cell division in line with prior findings. Most of the CSPs upregulated in PB-parasites were hypothetical, thus requiring further functional characterization. Expression of one such hypothetical protein (TcIL3000_0_02370) was analyzed using immunofluorescence and confocal laser scanning microscopy, which together revealed preferential expression of this protein on the entire surface coat of T. congolense parasite stages that colonize G. m. morsitans' proboscis. CONCLUSION: Collectively, our results provide insight into T. congolense gene expression profiles in distinct niches within the tsetse vector. Our results show that the hypothetical protein TcIL3000_0_02370, is expressed on the entire surface of the trypanosomes inhabiting tsetse's proboscis. We discuss our results in terms of their relevance to disease transmission processes. PMID- 29970167 TI - Prevalence of self-medication practice among health sciences students in Kermanshah, Iran. AB - BACKGROUND: The possibility of self-medication is higher in health sciences students than other students because of easy access to drug information resources and relatively sufficient familiarity with various kinds of drugs. The current study was aimed to determine the prevalence of self-medication and its related factors among the health sciences students. METHODS: A total of 250 health sciences students were included in this cross-sectional study via random sampling. Data were collected by a researcher-made self-medication questionnaire. The collected data were analyzed by SPSS-20 software using descriptive and inferential statistics (chi-square test). RESULTS: The prevalence of self medication was 89.6%. Prior experience about the illness, non-seriousness of the illness and availability of drugs were the most prevalent reasons for self medication. The most commonly used medications included common cold drugs, analgesics and antibiotics. The most frequently used medications were cold pill, acetaminophen pill and amoxicillin capsule. Most students obtained their pharmaceutical information from the pharmacist physician and online sources. Self medication did not show a significant difference in terms of variables such as age, gender, marital status, insurance status and residence. CONCLUSION: Given the high prevalence of self-medication among the health sciences students, training courses about the self-medication risks, more supervision over prohibition of over-the-counter drugs and adequate facilities for students' access to medical services are suggested to be provided. PMID- 29970168 TI - Understanding the implementation and efficacy of a home-based strength and balance fall prevention intervention in people aged 50 years or over with vision impairment: a process evaluation protocol. AB - BACKGROUND: A nested process evaluation, within a randomised controlled trial, will explore relationships between program outcomes and quality of intervention implementation of the Lifestyle-Integrated Functional Exercise Program in older people with vision impairment. The Lifestyle-Integrated Functional Exercise Program is a home-based strength and balance program that has been shown to reduce falls in high risk populations. A pilot study showed positive trends in improvements in physical function in older people with vision impairment after participation in the program. The program will be delivered by Orientation and Mobility Specialists, who are experienced in working with people with vision impairment. METHODS: The process evaluation has a mixed methods design. This includes quantitative (fidelity checklist score, number of completed sessions, survey data and a habit formation scale), as well as qualitative (open responses from program staff and semi-structured interviews with study participants) data. Process evaluation measures include program adherence (fidelity), complete delivery (dose delivered), participant receipt (dose received) and participant enactment. Using the Behaviour Change Wheel, a logic model was built to explain the intended inputs, outputs, outcomes and relationships to the behaviour change techniques in the Lifestyle-Integrated Functional Exercise Program in older people with vision impairment. DISCUSSION: The findings of the process evaluation will inform the provision of fall prevention programs in older people with vision impairment by Orientation and Mobility Specialists. To date, there are no proven falls prevention programs which aim to improve physical function and reduce falls in older people with vision impairment. This process evaluation will contribute new knowledge about the implementation of a strength and balance program in this population. TRIAL REGISTRATION: ACTRN12616001186448 . Registered 29 August 2016. PMID- 29970169 TI - Errors in the Hematology Laboratory at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. AB - OBJECTIVE: The objective of this study was to determine the magnitude of pre analytical, analytical and post-analytical laboratory errors in hematology tests. RESULTS: A total of 2606 hematology requests were studied. Out of the total, 562 (21.6%) pre-analytic, 14 (0.5%) analytical and 168 (6.4%) post-analytical errors were recorded which contribute a total frequency of 75.5, 1.9 and 22.6%, respectively. The name of the physician requesting the test was not provided on 2215 (85%) of request forms and 1827 (70.1%) of the request forms were unaccompanied with proper clinical details of the patient. Essential information required on the request forms was often missed. Close communication between clinicians and laboratory personnel is the key to improve laboratory quality in general. PMID- 29970166 TI - Chinese expert consensus on echelons treatment of pelvic fractures in modern war. AB - The characteristics and treatment of pelvic fractures vary between general conditions and modern war. An expert consensus has been reached based on pelvic injury epidemiology and the concepts of battlefield treatment combined with the existing levels of military medical care in modern warfare. According to this consensus, first aid, emergency treatment and early treatment of pelvic fractures are introduced in three separate levels. In Level I facilities, simple triage and rapid treatment following the principles of advanced trauma life support are recommended to evaluate combat casualties during the first-aid stage. Re evaluation, further immobilization and fixation, and hemostasis are recommended at Level II facilities. At Level III facilities, the main components of damage control surgery are recommended, including comprehensive hemostasis, a proper resuscitation strategy, the treatment of concurrent visceral and blood vessel damage, and battlefield intensive care. The grading standard for evidence evaluation and recommendation was used to reach this expert consensus. PMID- 29970171 TI - A novel method of inducing thrombosis in target arteries using coronary stents for therapeutic occlusion. AB - OBJECTIVES: Peripheral artery embolizations are often required for therapeutic purposes. The therapeutic embolizations are usually performed using embolization particles and coils. These procedures are also associated with complications. Coils and their delivery cables, and the expertise are not always available in all catheterization centers. Hence, a novel, simple controlled technique for arterial closure would be useful in emergency settings. RESULTS: Following is a report of seven cases where embolization was performed successfully on an emergency basis after stenting using coronary stents for better closure of the target artery. Six patients underwent bronchial artery embolization for recurrent massive hemoptysis, and one another patient had pseudoaneurysm following percutaneous nephrolithotomy, and presented with hematuria and persistent and increasing blood discharge in drainage catheter. The stents were deployed in the target artery using 6F Judkin's diagnostic catheter over the 014 wires, which are easily available in all cardiac catheterization laboratories. This is a novel method to establish a metal platform inside the target arteries using coronary stents for better closure of the target arteries in combination with embolization techniques. The procedures were performed as lifesaving measures when small coils and the delivery cables were not available at the time of the procedures. PMID- 29970172 TI - Estimating program coverage in the treatment of severe acute malnutrition: a comparative analysis of the validity and operational feasibility of two methods. AB - BACKGROUND: Many health programs can assess coverage using standardized cluster survey methods, but estimating the coverage of nutrition programs presents a special challenge due to low disease prevalence. Used since 2012, the Semi Quantitative Evaluation of Access and Coverage (SQUEAC) employs both qualitative and quantitative methods to identify key barriers to access and estimate coverage of therapeutic feeding programs. While the tool has been increasingly used in programs, the validity of certain methodological elements has been the subject of debate. METHODS: We conducted a study comparing a SQUEAC conjugate Bayesian analysis to a two-stage cluster survey estimating the coverage of a therapeutic feeding program in Niger in 2016. RESULTS: We found that the coverage estimate from the conjugate Bayesian analysis was sensitive to the prior estimation. With the exception of prior estimates produced by an external support team, all prior estimates resulted in a conflict with the likelihood result, excluding interpretation of the final coverage estimate. Allowing for increased uncertainty around the prior estimate did not materially affect conclusions. CONCLUSION: SQUEAC is a demanding analytical method requiring both qualitative and quantitative data collection and synthesis to identify program barriers and estimate coverage. If the necessary technical capacity is not available to objectively specify an accurate prior for a conjugate Bayesian analysis, alternatives, such as a two-stage cluster survey or a larger likelihood survey, may be considered to ensure valid coverage estimation. TRIAL REGISTRATION: NCT03280082 . Retrospectively registered on September 12, 2017. PMID- 29970170 TI - The utility of measuring the apparent diffusion coefficient for peritumoral zone in assessing infiltration depth of endometrial cancer. AB - BACKGROUND: The invasion depth of endometrial cancer is one of the most important prognosis factors. The aim of the current study was to investigate the diagnostic value of the apparent diffusion coefficient (ADC) of the peritumoral zone for assessing the infiltration depth of endometrial cancer. METHODS: An institutional review board approved this prospective study, and all study participants provided informed consent. A total of 58 patients (mean age 54 +/- 8.3 years, range 34-69 years) with endometrial cancer were prospectively enrolled. Two radiologists assessed all preoperative magnetic resonance images with T1, T2, and diffusion weighted imaging, and determined the location of the deepest invasion of the tumor. The peritumoral zone was defined as a 5-mm-thick zone surrounding and adjacent to the cancerous endometrium. The mean ADC (ADCm) values of the tumor and the peritumoral zone were measured. Sensitivity, specificity, positive and negative predictive values, and the area under the receiver operating characteristic curve (Az) were calculated for visual inspection, and an ADC cutoff value for the peri-endometrial zone was determined for predicting the myometrial invasion depth. RESULTS: The ADCm values of tumors and peritumoral zones were 0.83 * 10- 3 mm2/sec and 1.06 * 10- 3 mm2/sec, respectively. There was no significant difference between the ADCm values of the tumors in the superficial and deep myometrial invasion groups (P > 0.05). However, the ADCm value at the peritumoral zone in the deep myometrial invasion group (1.23 * 10- 3 mm2/sec) significantly differed from that in the superficial myometrial invasion group (0.99 * 10- 3 mm2/sec) (p = 0.005). In assessments of deep myometrial invasion, the sensitivity, specificity, negative predictive value, and positive predictive value were 0.58, 0.93, 0.84, and 0.77, respectively, for the ADCm cutoff value of the peritumoral zone, and 0.71, 0.80, 0.87, and 0.60. respectively, for visual inspection. The accuracy of myometrial invasion depth assessment using the ADCm cutoff value and visual inspection were 83 and 78%, respectively. The Az for both was 0.76. CONCLUSION: ADCm at the peritumoral zone can predict deep myometrial invasion of endometrial cancer. This value can therefore enhance confidence in preoperative endometrial cancer evaluation, and when tailoring surgical approaches. PMID- 29970173 TI - The experience of breastfeeding infants affected by congenital diaphragmatic hernia or esophageal atresia. AB - BACKGROUND: Newborns with congenital diaphragmatic hernia (CDH) and esophageal atresia (EA) might experience breastfeeding difficulties. The aim of this study was to detect the prevalence of breastfeeding in newborns with CDH and EA at different time points. METHODS: We performed an epidemiological study and retrospective survey on the prevalence of breastfeeding in CDH and EA affected newborns. We identified 40 CDH and 25 EA newborns who were fed through breastfeeding procedures according to WHO categorized definitions, and compared the breastfeeding procedures at the beginning of hospitalization and at three months of life. RESULTS: Although all the mothers attempted breastfeeding after birth, only 44 (67.7%) were still breastfeeding at the time of discharge. Exclusive breastfeeding was successful for only 19 (29%) mothers. The rate of exclusive breastfeeding at three months of life did not differ statistically from discharge and between the two groups of study. CONCLUSION: A large percentage of mothers of children with CDH and EA who breastfed at the beginning of hospitalization did not continue at three months. It would be important to increase the breastfeeding rate in CDH and EA affected newborns by following specific steps for vulnerable infants and sustaining breastfeeding after discharge. PMID- 29970174 TI - Development of in vitro enteroids derived from bovine small intestinal crypts. AB - Cattle are an economically important domestic animal species. In vitro 2D cultures of intestinal epithelial cells or epithelial cell lines have been widely used to study cell function and host-pathogen interactions in the bovine intestine. However, these cultures lack the cellular diversity encountered in the intestinal epithelium, and the physiological relevance of monocultures of transformed cell lines is uncertain. Little is also known of the factors that influence cell differentiation and homeostasis in the bovine intestinal epithelium, and few cell-specific markers that can distinguish the different intestinal epithelial cell lineages have been reported. Here we describe a simple and reliable procedure to establish in vitro 3D enteroid, or "mini gut", cultures from bovine small intestinal (ileal) crypts. These enteroids contained a continuous central lumen lined with a single layer of polarized enterocytes, bound by tight junctions with abundant microvilli on their apical surfaces. Histological and transcriptional analyses suggested that the enteroids comprised a mixed population of intestinal epithelial cell lineages including intestinal stem cells, enterocytes, Paneth cells, goblet cells and enteroendocrine cells. We show that bovine enteroids can be successfully maintained long-term through multiple serial passages without observable changes to their growth characteristics, morphology or transcriptome. Furthermore, the bovine enteroids can be cryopreserved and viable cultures recovered from frozen stocks. Our data suggest that these 3D bovine enteroid cultures represent a novel, physiologically relevant and tractable in vitro system in which epithelial cell differentiation and function, and host-pathogen interactions in the bovine small intestine can be studied. PMID- 29970175 TI - The volatilome - investigation of volatile organic metabolites (VOM) as potential tumor markers in patients with head and neck squamous cell carcinoma (HNSCC). AB - BACKGROUND: Different organisms such as bacteria, molds and humans produce and release a relative unknown class of metabolites which are responsible for the individual olfactory pattern. These volatile organic metabolites (VOM) represent a kind of biosignature that reflects the sum of all multifactorial influences, including genetics, environmental factors, nutritional and disease status. As a result of pathological processes the individual body odor can be influenced by newly produced or altered compositions of the VOM. Until now, human VOM have been detected in various body media, such as on the skin, in the exhaled air as well as in body fluids such as saliva, mother's milk, sweat, blood and urine. METHODS: In this retrospective case-control study urinary VOM of 53 therapy-naive patients with head and neck squamous cell carcinoma (HNSCC) and 82 healthy controls were semi-quantified by headspace solid-phase micro extraction (SPME) gas chromatography (GC) mass spectrometry (MS). At first, the procedure was optimized in respect to the extraction parameters. By using Student's t-test significant differences in the VOM pattern with the corresponding p-values were obtained. For multivariate metabolite pattern recognition the hierarchical cluster analysis by Ward was applied, followed by the supervised partial least squares-discriminant analysis (PLS-DA). RESULTS: In total 81 VOMs could identified in the urine samples of all study participants, of which 25 were significantly increased and of which were 10 significantly reduced in HNSCC-patients compared to the controls. In addition, the multivariate statistics confirmed that on the basis of the renal excreted pattern of the volatile metabolites a high discrimination can be carried out between patients with a tumor in the head and neck region and controls. The substance group of the saturated, unbranched aldehydes makes a substantial contribution in this context. CONCLUSIONS: The systematic pattern analysis of urinary VOMs appears to have potential clinical application as a diagnostic tool for cancer, especially HNSCC. PMID- 29970176 TI - Whole-exome sequencing identifies novel pathogenic mutations and putative phenotype-influencing variants in Polish limb-girdle muscular dystrophy patients. AB - BACKGROUND: Limb girdle muscular dystrophies (LGMD) are a group of heterogeneous hereditary myopathies with similar clinical symptoms. Disease onset and progression are highly variable, with an elusive genetic background, and around 50% cases lacking molecular diagnosis. METHODS: Whole exome sequencing (WES) was performed in 73 patients with clinically diagnosed LGMD. A filtering strategy aimed at identification of variants related to the disease included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of genes expressed in muscle, analysis of the disease-associated interactome and copy number variants analysis. RESULTS: Genetic diagnosis was possible in 68.5% of cases. On average, 36.3 rare variants in genes associated with various muscle diseases per patient were found that could relate to the clinical phenotype. The putative causative mutations were mostly in LGMD-associated genes, but also in genes not included in the current LGMD classification (DMD, COL6A2, and COL6A3). In three patients, mutations in two genes were suggested as the joint cause of the disease (CAPN3+MYH7, COL6A3+CACNA1S, DYSF+MYH7). Moreover, a variety of phenotype-influencing variants were postulated, including in patients with an identified already known primary pathogenic mutation. CONCLUSIONS: We hypothesize that LGMD could be better described as oligogenic disorders in which dominant clinical presentation can result from the combined effect of mutations in a set of genes. In this view, the inter- and intrafamilial variability could reflect a specific genetic background and the presence of sets of phenotype-influencing or co-causative mutations in genes that either interact with the known LGMD associated genes or are a part of the same pathways or structures. PMID- 29970178 TI - Image set for deep learning: field images of maize annotated with disease symptoms. AB - OBJECTIVES: Automated detection and quantification of plant diseases would enable more rapid gains in plant breeding and faster scouting of farmers' fields. However, it is difficult for a simple algorithm to distinguish between the target disease and other sources of dead plant tissue in a typical field, especially given the many variations in lighting and orientation. Training a machine learning algorithm to accurately detect a given disease from images taken in the field requires a massive amount of human-generated training data. DATA DESCRIPTION: This data set contains images of maize (Zea mays L.) leaves taken in three ways: by a hand-held camera, with a camera mounted on a boom, and with a camera mounted on a small unmanned aircraft system (sUAS, commonly known as a drone). Lesions of northern leaf blight (NLB), a common foliar disease of maize, were annotated in each image by one of two human experts. The three data sets together contain 18,222 images annotated with 105,705 NLB lesions, making this the largest publicly available image set annotated for a single plant disease. PMID- 29970177 TI - Human osteoblasts exhibit sexual dimorphism in their response to estrogen on microstructured titanium surfaces. AB - BACKGROUND: Osseointegration is dependent on the implant surface, surrounding bone quality, and the systemic host environment, which can differ in male and female patients. Titanium (Ti) implants with microstructured surfaces exhibit greater pullout strength when compared to smooth-surfaced implants and exhibit enhanced osteogenic cellular responses in vitro. Previous studies showed that 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] has a greater effect on rat osteoblast differentiation on microstructured Ti compared to smooth Ti surfaces and tissue culture polystyrene (TCPS). The stimulatory effect of 17beta-estradiol (E2) on differentiation is observed in female osteoblasts on micro-rough Ti, but it is not known if male osteoblasts behave similarly in response to E2 and microtopography. This study assessed whether human male and female osteoblasts exhibit sex-specific differences in response to E2 and 1alpha,25(OH)2D3 when cultured on microstructured Ti surfaces. METHODS: Osteoblasts from three male and three female human donors were cultured on Ti discs with varying surface profiles: a smooth pretreatment (PT), a coarse grit-blasted/acid-etched (SLA), and an SLA surface having undergone modification in a nitrogen environment and stored in saline to maintain hydrophilicity (modSLA). Cells cultured on these surfaces were treated with E2 or 1alpha,25(OH)2D3. RESULTS: Male and female human osteoblasts responded similarly to microstructure although there were donor specific differences; cell number decreased, and osteocalcin (OCN), osteoprotegerin (OPG), and latent and active transforming growth factor 1 increased on SLA and modSLA compared to TCPS. Female osteoblasts had higher alkaline phosphatase activity and OCN production than male counterparts but produced less OPG. Both sexes responded similarly to 1alpha,25(OH)2D3. E2 treatment reduced cell number and increased osteoblast differentiation and factor production only in female cells. CONCLUSIONS: Male and female human osteoblasts respond similarly to microstructure and 1alpha,25(OH)2D3 but exhibit sexual dimorphism in substrate-dependent responses to E2. E2 affected female osteoblasts, suggesting that signaling is sex-specific and surface-dependent. Donor osteoblasts varied in response, demonstrating the need to test multiple donors when examining human samples. Understanding how male and female cells respond to orthopedic biomaterials will enable greater predictability post implantation as well as therapies that are more patient-specific. PMID- 29970179 TI - Fasciola hepatica induces Foxp3 T cell, proinflammatory and regulatory cytokine overexpression in liver from infected sheep during early stages of infection. AB - The expression of T regulatory cells (Foxp3), regulatory (interleukin [IL]-10 and transforming growth factor beta [TGF-beta]) and proinflammatory (tumor necrosis factor alpha [TNF-alpha] and interleukin [IL]-1beta) cytokines was quantified using real time polymerase chain reaction (qRT-PCR) in the liver of sheep during early stages of infection with Fasciola hepatica (1, 3, 9, and 18 days post infection [dpi]). Portal fibrosis was also evaluated by Masson's trichrome stain as well as the number of Foxp3+ cells by immunohistochemistry. Animals were divided into three groups: (a) group 1 was immunized with recombinant cathepsin L1 from F. hepatica (FhCL1) in Montanide adjuvant and infected; (b) group 2 was uniquely infected with F. hepatica; and (c) group 3 was the control group, unimmunized and uninfected. An overexpression of regulatory cytokines of groups 1 and 2 was found in all time points tested in comparison with group 3, particularly at 18 dpi. A significant increase of the number of Foxp3+ lymphocytes in groups 1 and 2 was found at 9 and 18 dpi relative to group 3. A progressive increase in portal fibrosis was found in groups 1 and 2 in comparison with group 3. In this regard, group 1 showed smaller areas of fibrosis than group 2. There was a significant positive correlation between Foxp3 and IL-10 expression (by immunohistochemistry and qRT-PCR) just as between portal fibrosis and TGF-beta gene expression. The expression of proinflammatory cytokines increased gradually during the experience. These findings suggest the induction of a regulatory phenotype by the parasite that would allow its survival at early stages of the disease when it is more vulnerable. PMID- 29970180 TI - Immunohistochemical over expression of p53 in head and neck Squamous cell carcinoma: clinical and prognostic significance. AB - OBJECTIVE: Immunohistochemical over expression of p53 is considered as a marker of poor prognosis in many cancers. Therefore, we aimed to evaluate immunohistochemical overexpression of p53 in 121 cases of head and neck Squamous cell carcinoma and its association with various clinicopathologic features and survival. RESULTS: Total 66.1% (80 cases) expressed positive p53 expression, 34% (29 cases) revealed no p53 expression, while focal positive p53 expression was noted in 9.9% (12 Cases). Moreover, high p53 expression (> 70%) was noted in 26.4% (32 cases), while 19% (23 cases) showed 51-70% p53 expression. On the basis of intensity of p53 staining; strong p53 expression was noted in 39.7% (48 cases), while 24.8% (30 cases) and 10.7% (13 cases) revealed intermediate and weak p53 expression respectively. Significant association of p53 intensity of expression with extranodal extension and higher tumor grade (grades II and III) was noted. p53 is useful prognostic biomarker in head and neck Squamous cell carcinoma and therefore we suggest that more large scale studies are needed to evaluate its prognostic significance in our population. PMID- 29970181 TI - Capacity gaps in health facilities for case management of intestinal schistosomiasis and soil-transmitted helminthiasis in Burundi. AB - BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis (STH) are endemic diseases in Burundi. STH control is integrated into health facilities (HF) across the country, but schistosomiasis control is not. The present study aimed to assess the capacity of HF for integrating intestinal schistosomiasis case management into their routine activities. In addition, the current capacity for HF-based STH case management was evaluated. METHODS: A random cluster survey was carried out in July 2014, in 65 HF located in Schistosoma mansoni and STH endemic areas. Data were collected by semi-quantitative questionnaires. Staff with different functions at the HF were interviewed (managers, care providers, heads of laboratory and pharmacy and data clerks). Data pertaining to knowledge of intestinal schistosomiasis and STH symptoms, human and material resources and availability and costs of diagnostic tests and treatment were collected. FINDINGS: Less than half of the 65 care providers mentioned one or more major symptoms of intestinal schistosomiasis (abdominal pain 43.1%, bloody diarrhoea 13.9% and bloody stool 7.7%). Few staff members (15.7%) received higher education, and less than 10% were trained in-job on intestinal schistosomiasis case management. Clinical guidelines and laboratory protocols for intestinal schistosomiasis diagnosis and treatment were available in one third of the HF. Diagnosis was performed by direct smear only. Praziquantel was not available in any of the HF. The results for STH were similar, except that major symptoms were more known and cited (abdominal pain 69.2% and diarrhoea 60%). Clinical guidelines were available in 61.5% of HF, and albendazole or mebendazole was available in all HF. CONCLUSIONS: The current capacity of HF for intestinal schistosomiasis and STH detection and management is inadequate. Treatment was not available for schistosomiasis. These issues need to be addressed to create an enabling environment for successful integration of intestinal schistosomiasis and STH case management into HF routine activities in Burundi for better control of these diseases. PMID- 29970182 TI - Stable isotope informed genome-resolved metagenomics reveals that Saccharibacteria utilize microbially-processed plant-derived carbon. AB - BACKGROUND: The transformation of plant photosynthate into soil organic carbon and its recycling to CO2 by soil microorganisms is one of the central components of the terrestrial carbon cycle. There are currently large knowledge gaps related to which soil-associated microorganisms take up plant carbon in the rhizosphere and the fate of that carbon. RESULTS: We conducted an experiment in which common wild oats (Avena fatua) were grown in a 13CO2 atmosphere and the rhizosphere and non-rhizosphere soil was sampled for genomic analyses. Density gradient centrifugation of DNA extracted from soil samples enabled distinction of microbes that did and did not incorporate the 13C into their DNA. A 1.45-Mbp genome of a Saccharibacteria (TM7) was identified and, despite the microbial complexity of rhizosphere soil, curated to completion. The genome lacks many biosynthetic pathways, including genes required to synthesize DNA de novo. Rather, it requires externally derived nucleotides for DNA and RNA synthesis. Given this, we conclude that rhizosphere-associated Saccharibacteria recycle DNA from bacteria that live off plant exudates and/or phage that acquired 13C because they preyed upon these bacteria and/or directly from the labeled plant DNA. Isotopic labeling indicates that the population was replicating during the 6-week period of plant growth. Interestingly, the genome is ~ 30% larger than other complete Saccharibacteria genomes from non-soil environments, largely due to more genes for complex carbon utilization and amino acid metabolism. Given the ability to degrade cellulose, hemicellulose, pectin, starch, and 1,3-beta-glucan, we predict that this Saccharibacteria generates energy by fermentation of soil necromass and plant root exudates to acetate and lactate. The genome also encodes a linear electron transport chain featuring a terminal oxidase, suggesting that this Saccharibacteria may respire aerobically. The genome encodes a hydrolase that could breakdown salicylic acid, a plant defense signaling molecule, and genes to interconvert a variety of isoprenoids, including the plant hormone zeatin. CONCLUSIONS: Rhizosphere Saccharibacteria likely depend on other bacteria for basic cellular building blocks. We propose that isotopically labeled CO2 is incorporated into plant-derived carbon and then into the DNA of rhizosphere organisms capable of nucleotide synthesis, and the nucleotides are recycled into Saccharibacterial genomes. PMID- 29970183 TI - Canine respiratory coronavirus employs caveolin-1-mediated pathway for internalization to HRT-18G cells. AB - Canine respiratory coronavirus (CRCoV), identified in 2003, is a member of the Coronaviridae family. The virus is a betacoronavirus and a close relative of human coronavirus OC43 and bovine coronavirus. Here, we examined entry of CRCoV into human rectal tumor cells (HRT-18G cell line) by analyzing co-localization of single virus particles with cellular markers in the presence or absence of chemical inhibitors of pathways potentially involved in virus entry. We also targeted these pathways using siRNA. The results show that the virus hijacks caveolin-dependent endocytosis to enter cells via endocytic internalization. PMID- 29970184 TI - Effect of Linagliptin and Voglibose on metabolic profile in patients with Type 2 Diabetes: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control by promoting GLP1-mediated glucose-dependent insulin secretion and suppression of glucagon. Sitagliptin and vildagliptin have been shown to improve insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, these patients had uncontrolled blood glucose at inclusion; therefore, the improvement in insulin sensitivity observed in these studies could be attributed to the drug per se and/or reduction in glucotoxicity. This study examines the effect of linagliptin on insulin sensitivity and beta-cell function in patients with well controlled T2DM. METHODS: Thirty patients with T2DM of duration <=5 years, and having HbA1c < 7.5% were randomized to receive linagliptin, voglibose or placebo (n = 10 each), and were followed up for 6 months. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretory response was measured by basal (M0) and postprandial (M1) beta-cell function, and area under curve (AUC) for C-peptide during mixed meal tolerance test. RESULTS: The median HbA1c of the study subjects at inclusion was 6.9% and there was no significant difference among the groups in terms of age, duration of diabetes, body mass index (BMI), HbA1c, insulin sensitivity, AUC of C-peptide and M0 and M1 at baseline. At the end of the study, there was a modest reduction in HbA1c (- 0.2%) in the linagliptin group, and a significant decrease (- 0.8%) in the voglibose group, as compared to placebo (p = 0.038). However, there were no significant differences in insulin sensitivity, M0 and M1 and AUC of C-peptide, within, or among the groups. CONCLUSION: Linagliptin modestly improves glycemic profile in patients with well controlled T2DM; however, it may not have an effect on insulin sensitivity in these patients. TRIAL REGISTRATION: Retrospectively Registered in Clinicaltrials.gov (ID number, NCT02097342 ). Registered: March 27, 2014. PMID- 29970185 TI - Azithromycin enhances anticancer activity of TRAIL by inhibiting autophagy and up regulating the protein levels of DR4/5 in colon cancer cells in vitro and in vivo. AB - BACKGROUND: Azithromycin is a member of macrolide antibiotics, and has been reported to inhibit the proliferation of cancer cells. However, the underlying mechanisms are not been fully elucidated. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) selectively targets tumor cells without damaging healthy cells. In the present study, we examined whether azithromycin is synergistic with TRAIL, and if so, the underlying mechanisms in colon cancers. METHODS: HCT-116, SW480, SW620 and DiFi cells were treated with azithromycin, purified TRAIL, or their combination. A sulforhoddamine B assay was used to examine cell survival. Apoptosis was examined using annexin V-FITC/PI staining, and autophagy was observed by acridine orange staining. Western blot analysis was used to detect protein expression levels. In mechanistic experiments, siRNAs were used to knockdown death receptors (DR4, DR5) and LC-3B. The anticancer effect of azithromycin and TRAIL was also examined in BALB/c nude mice carrying HCT-116 xenografts. RESULTS: Azithromycin decreased the proliferation of HCT-116 and SW480 cells in a dose-dependent manner. Combination of azithromycin and TRAIL inhibited tumor growth in a manner that could not be explained by additive effects. Azithromycin increased the expressions of DR4, DR5, p62 and LC-3B proteins and potentiated induction of apoptosis by TRAIL. Knockdown of DR4 and DR5 with siRNAs increased cell survival rate and decreased the expression of cleaved-PARP induced by the combination of azithromycin and TRAIL. LC-3B siRNA and CQ potentiated the anti-proliferation activity of TRAIL alone, and increased the expressions of DR4 and DR5. CONCLUSION: The synergistic antitumor effect of azithromycin and TRAIL mainly relies on the up-regulations of DR4 and DR5, which in turn result from LC-3B-involved autophagy inhibition. PMID- 29970187 TI - In preschool children, physical activity during school time can significantly increase by intensifying locomotor activities during physical education classes. AB - OBJECTIVES: After categorizing preschool children into "active and low active" according to their moderate and vigorous physical activity (MVPA) in PE classes (PE), we compared these two groups within each sex and by sex in: (a) % MVPA and MVPA minutes accrued from each fundamental motor skill (FMS) during PE and (b) % MVPA during school time. RESULTS: 532 children (mean age 5.2 years, 50% girls) were selected from a nationwide program which provides 3 weekly PE. Children wore accelerometers during one school day which included PE. We recorded the type and duration of each activity indicated by the teacher, classifying each one into the corresponding FMS, extracting its MVPA minutes from the accelerometer software. Children were categorized into active and low active. Comparisons used T-tests. In PE, active children accumulate 40 and 36 percentage points (pp) more MVPA minutes (boys and girls respectively), while during school time, 4 pp more in each sex. Girls are significantly less active. Just considering locomotion, active boys and girls accumulate 11 more MVPA minutes during PE. Active boys surpass the MVPA guideline for PE, while active girls almost reach it. Low active children (especially girls) should intensify locomotor activities during PE. PMID- 29970186 TI - Global phosphoproteomics of CCR5-tropic HIV-1 signaling reveals reprogramming of cellular protein production pathways and identifies p70-S6K1 and MK2 as HIV responsive kinases required for optimal infection of CD4+ T cells. AB - BACKGROUND: Viral reprogramming of host cells enhances replication and is initiated by viral interaction with the cell surface. Upon human immunodeficiency virus (HIV) binding to CD4+ T cells, a signal transduction cascade is initiated that reorganizes the actin cytoskeleton, activates transcription factors, and alters mRNA splicing pathways. METHODS: We used a quantitative mass spectrometry based phosphoproteomic approach to investigate signal transduction cascades initiated by CCR5-tropic HIV, which accounts for virtually all transmitted viruses and the vast majority of viruses worldwide. RESULTS: CCR5-HIV signaling induced significant reprogramming of the actin cytoskeleton and mRNA splicing pathways, as previously described. In addition, CCR5-HIV signaling induced profound changes to the mRNA transcription, processing, translation, and post translational modifications pathways, indicating that virtually every stage of protein production is affected. Furthermore, we identified two kinases regulated by CCR5-HIV signaling-p70-S6K1 (RPS6KB1) and MK2 (MAPKAPK2)-that were also required for optimal HIV infection of CD4+ T cells. These kinases regulate protein translation and cytoskeletal architecture, respectively, reinforcing the importance of these pathways in viral replication. Additionally, we found that blockade of CCR5 signaling by maraviroc had relatively modest effects on CCR5-HIV signaling, in agreement with reports that signaling by CCR5 is dispensable for HIV infection but in contrast to the critical effects of CXCR4 on cortical actin reorganization. CONCLUSIONS: These results demonstrate that CCR5-tropic HIV induces significant reprogramming of host CD4+ T cell protein production pathways and identifies two novel kinases induced upon viral binding to the cell surface that are critical for HIV replication in host cells. PMID- 29970189 TI - Comparison of topical tofacitinib and 0.1% hypochlorous acid in a murine atopic dermatitis model. AB - BACKGROUND: Topical administration of PR022, 0.05% hypochlorous acid (HOCl) in gel has been demonstrated to be beneficial in a chronic murine atopic dermatitis model. In a follow up study we tested a higher concentration (0.1%) of PR022 HOCl gel in comparison to the Janus kinase inhibitor tofacitinib, both of which are currently in clinical phase studies for treatment of human atopic dermatitis. METHODS: The effect of topically administered HOCl (0.1%) in gel was compared to a topical formulation of tofacitinib (0.5%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice as well as itch behaviour. NC/Nga mice were sensitized with house dust mite allergen. After reaching visible lesions, mice were treated either topically with HOCl or tofacitinib or gel vehicle for 17 days. After termination of the study, dorsal root ganglia were isolated for ex vivo stimulation and skin samples were taken for cytokine determination in inflamed skin. RESULTS: When administered onto lesional skin of NC/Nga mice, both HOCl and tofacitinib reduced lesions and scratching behaviour. The reduced inflammatory response by HOCl and tofacitinib treatment was demonstrated by diminished inflammatory cytokines in affected skin tissue from NC/Nga mice. Dorsal root ganglia neurons re-stimulated with a range of mediators of itch showed a reduced response compared to the vehicle control mice, when isolated from tofacitinib or HOCl treated mice. CONCLUSIONS: These data indicate a similar beneficial potential of topical high dose PR022 HOCl (0.1%) in gel and tofacitinib, in a translational murine model of atopic dermatitis. PMID- 29970188 TI - Chronic restraint stress induces hippocampal memory deficits by impairing insulin signaling. AB - Chronic stress is a psychologically significant factor that impairs learning and memory in the hippocampus. Insulin signaling is important for the development and cognitive function of the hippocampus. However, the relation between chronic stress and insulin signaling at the molecular level is poorly understood. Here, we show that chronic stress impairs insulin signaling in vitro and in vivo, and thereby induces deficits in hippocampal spatial working memory and neurobehavior. Corticosterone treatment of mouse hippocampal neurons in vitro caused neurotoxicity with an increase in the markers of autophagy but not apoptosis. Corticosterone treatment impaired insulin signaling from early time points. As an in vivo model of stress, mice were subjected to chronic restraint stress. The chronic restraint stress group showed downregulated insulin signaling and suffered deficits in spatial working memory and nesting behavior. Intranasal insulin delivery restored insulin signaling and rescued hippocampal deficits. Our data suggest that psychological stress impairs insulin signaling and results in hippocampal deficits, and these effects can be prevented by intranasal insulin delivery. PMID- 29970190 TI - Student performance on the Test of Scientific Literacy Skills (TOSLS) does not change with assignment of a low-stakes grade. AB - OBJECTIVE: Response-validated multiple-choice assessments are used in college courses to assess student learning gains. The ability of a test to accurately reflect student learning gains is highly dependent on the students' effort. Within our institution, lackluster student effort is common on response-validated multiple-choice concept assessments that are not included as a portion of the semester grade but are used to inform curricular changes. Thus, we set out to determine whether increasing testing stakes by assigning a grade on student performance had an effect on student score and self-reported effort. The Test of Scientific Literacy Skills (TOSLS) is a response-validated multiple-choice assessment used to measure scientific literacy in undergraduates. We administered the TOSLS to students enrolled in a general education Biology course, both during the first 2 weeks (pretest) and the last 2 weeks (posttest) of the course. RESULTS: Self-reported effort and TOSLS performance were significantly correlated in the ungraded cohort. This relationship did not exist in the graded sections. Our data indicate that assigning a low-stakes grade has no significant effect on mean student performance or self-reported effort on the TOSLS within our general education course. PMID- 29970192 TI - Efficacy of a Salmonella live vaccine for turkeys in different age groups and antibody response of vaccinated and non-vaccinated turkeys. AB - OBJECTIVE: Human Salmonellosis continues to be one of the most important foodborne zoonoses worldwide, although a decrease in case numbers has been noted in recent years. It is a foodborne zoonotic infection most commonly associated with the consumption of raw egg products but also with meat consumption including the consumption of poultry products. Turkey flocks in Europe have been reported to be affected by Salmonella infection, too. The present study examines the efficacy of a newly licensed Salmonella life vaccine in reducing infections with the Salmonella serovars Typhimurium and Enteritidis in turkeys. Turkeys were vaccinated the first day of life and at the age of 6 and 16 weeks. Groups of birds which had received different numbers of vaccinations were then submitted to challenge trials with either SE or ST. RESULTS: In vaccinated birds Salmonella counts in liver and spleen and, less effectively, in caecum were reduced compared to unvaccinated birds. In several groups serum antibody-titers were statistically significantly higher in vaccinated turkeys than in non-vaccinated ones at day seven post infection, but only in one out of six groups at day 14 post infection. PMID- 29970191 TI - Downregulated miR-98-5p promotes PDAC proliferation and metastasis by reversely regulating MAP4K4. AB - BACKGROUND: The aberrant expression of microRNAs (miRNAs) has emerged as important hallmarks of cancer. However, the molecular mechanisms underlying the differences of miRNA expression remain unclear. Many studies have reported that miR-98-5p plays vital functions in the development and progression of multiple cancers. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: The expression of miR-98-5p and its specific target gene were determined in human PDAC specimens and cell lines by miRNA qRT-PCR, qRT-PCR and western blot. The effects of miR-98-5p depletion or ectopic expression on PDAC proliferation, migration and invasion were evaluated in vitro using CCK-8 proliferation assays, colony formation assays, wound healing assays and transwell assays. Furthermore, the in vivo effects were investigated using the mouse subcutaneous xenotransplantation and pancreatic tail xenotransplantation models. Luciferase reporter assays were employed to identify interactions between miR-98 5p and its specific target gene. RESULTS: MiR-98-5p expression was significantly lower in cancerous tissues and associated with tumor size, TNM stage, lymph node metastasis and survival. Notably, a series of gain- and loss-of-function assays elucidated that miR-98-5p suppressed PDAC cell proliferation, migration and invasion both in vitro and in vivo. Luciferase reporter assays, western blot and qRT-PCR revealed MAP4K4 to be a direct target of miR-98-5p. The effects of ectopic miR-98-5p were rescued by MAP4K4 overexpression. In contrast, the effects of miR-98-5p depletion were impaired by MAP4K4 knockdown. Furthermore, miR-98-5p suppressed the MAPK/ERK signaling pathway through downregulation of MAP4K4. In addition, the expression level of miR-98-5p was negatively correlated with MAP4K4 expression in PDAC tissues and cell lines. CONCLUSIONS: These results suggest that downregulation of miR-98-5p promotes tumor development by downregulation of MAP4K4 and inhibition of the downstream MAPK/ERK signaling, thus, highlighting the potential of miR-98-5p as a therapeutic target for PDAC. PMID- 29970193 TI - The splenic response to stroke: from rodents to stroke subjects. AB - BACKGROUND: Stroke is the fifth leading cause of death and the leading cause of long-term disability in the USA, costing $40.2 billion in direct and indirect costs. Globally, stroke is the second leading cause of death and has a higher prevalence in lower- and middle-income countries compared to high-income countries. The role of the spleen in stroke has been studied in rodent models of stroke and is seen as a major contributor to increased secondary neural injury after stroke. Splenectomy 2 weeks prior to ischemic and hemorrhagic stroke in mice and rats shows decreased infarct volumes. Additionally, the spleen decreases in size following stroke in rodents. Pro-inflammatory mediators are also increased in the spleen and subsequently the brain after stroke. These data in preclinical models of stroke have led stroke neurologists to look at the splenic response in stroke subjects. The outcomes of these studies suggest the spleen is responding in a similar manner in stroke subjects as it is in animal models of stroke. CONCLUSION: Animal models demonstrating the detrimental role of the spleen in stroke are providing strong evidence of how the spleen is responding during stroke in human subjects. This indicates treatments targeting the splenic immune response in animals could provide useful targets and treatments for stroke subjects. PMID- 29970194 TI - Comparative analysis of miRNA profile in human dendritic cells infected with respiratory syncytial virus and human metapneumovirus. AB - OBJECTIVE: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are responsible for respiratory diseases, mostly in children. Despite the clinical and epidemiological similarities between these two pneumoviruses, they elicit different immune responses. This work aims to further our understanding of the differential immune response induced by these respiratory viruses by determining the changes of small non-coding RNAs (miRNAs), which regulate gene expression and are involved in numerous cellular processes including the immune system. RESULTS: In the present study, we analyzed the expression of miRNA transcripts of human dendritic cells infected with RSV or HMPV by high throughput sequencing using Illumina sequencing technology. Further validation of miRNA expression by quantitative polymerase chain reaction indicated that HMPV infection up-regulated the expression of 2 miRNAs (hsa-miR-182-5p and hsa-miR-4634), while RSV infection induced significant expression of 3 miRNAs (hsa-miR-4448, hsa-miR-30a-5p and hsa miR-4634). The predominant miRNA induced by both viruses was hsa-miR-4634. PMID- 29970195 TI - The 678 Hz acoustic immittance probe tone: a more definitive indicator of PET than the traditional 226 Hz method. AB - BACKGROUND: The accurate diagnosis of Eustachian tube (ET) dysfunction can be very difficult. Our aim is to determine whether a 678 Hz probe tone is a more accurate indicator of Patulous ET (PET) than the 226 Hz probe tone when used in compliance over time (COT) testing. METHODS: Twenty subjects (11 normal ET ears and 7 PET ears) were individually seated in an examination room and connected to a GSI TympStar Middle Ear Analyzer. The order of probe tone frequency (678 or 226 Hz) was randomized. Baseline "testing" COT recordings for each ear undergoing testing were completed. Subjects were instructed to occlude their contralateral nostril and to breathe forcefully in and out through their ipsilateral nostril until the test had run to completion. This process was repeated with the probe tone that had not been previously run. For the control group, each subject had one random ear tested. For the experimental group, only the affected ear(s) was tested. Wilcoxon rank rum tests were performed to determine statistical significance. RESULTS: The baseline COT measurements for the control group and PET group were similar, 0.86 mL (SD = 0.34) and 0.74 (SD = 0.33) respectively. Comparing the 226 Hz tone between groups revealed that PET patients had a median COT difference 0.19 mL higher than healthy ET patients, and for the 678 Hz tone, PET patients had a median COT difference of 0.57 mL higher than healthy ET patients. Both were deemed to be statistically significant (p = 0.002, p = 0.004 respectively). The was a statistically significant median COT difference between the 678 Hz and 226 Hz of 0.61 mL (p = 0.034) for the PET group, while the same comparison for the control group of 0.05 mL was not significant (p = 0.262), suggesting that the 678 Hz tone yields a larger response for PET than the 226 Hz tone, and no difference for the control group, thus making it less prone to artifact noise interference. CONCLUSION: The 678 Hz probe tone is a more reliable indicator of ET patency, and should be preferably used over the 226 Hz tone for future COT testing. PMID- 29970197 TI - Metformin or insulin: logical treatment in women with gestational diabetes in the Middle East, our experience. AB - OBJECTIVE: The debate still continues about the preferred modality of treatment of gestational diabetes requiring pharmacological treatment. Insulin was previously considered as the gold standard, but the National Institute of Health and Care Excellence now recommend metformin as the first line drug of choice. The pharmacological management of gestational diabetes mellitus in the Middle East with its high risk population has not been widely published. We aim to evaluate the safety and efficacy of using metformin in comparison to insulin, in our group of patients, and to study key associated morbidities. RESULTS: A total of 291 women registered in the clinic during the study period. One hundred and twenty one (121) were women with gestational diabetes Mellitus requiring medical therapy. Among them, 107 delivered at term. Ninety (84%) women received metformin. Additional insulin was required in 32% of these patients. There was a significant difference in the birth weight of babies in the metformin with insulin group of 207 g (p value 0.04) in favour of metformin. There was no significant difference in maternal or neonatal morbidities between the groups. Metformin was thus found to be a safe, practical and cost effective medication to be offered to our population. PMID- 29970198 TI - The impact of the number of tuberculin skin test reactors and infection confirmation on the risk of future bovine tuberculosis incidents; a Northern Ireland perspective. AB - Currently policies enabling cattle herds to regain Official Tuberculosis Free (OTF) status after a bovine tuberculosis (bTB) herd incident vary between individual parts of the British Isles from requiring only one negative single comparative intradermal tuberculin test (SCITT) herd test when bTB infection is not confirmed to needing two consecutively negative SCITT herd tests after disclosure of two or more reactors, irrespective of bTB confirmation. This study used Kaplan-Meier curves and univariable and multivariable Cox Proportional Hazard models to evaluate the effect of the number of SCITT reactors and bTB confirmation on the risk of future bTB herd incident utilising data extracted from the national animal health database in Northern Ireland. Based on multivariable analyses the risk of a future bTB herd incident was positively associated with the number of SCITT reactors identified during the incident period (hazard ratio = 1.861 in incidents >5 SCITT reactors compared to incidents with only one SCITT reactor; P < 0.001), but not with bTB confirmation. These findings suggest that the probability of residual bTB infection in a herd increases with an increasing number of SCITT reactors disclosed during a bTB herd incident. It was concluded that bTB herd incidents with multiple SCITT reactors should be subjected to stricter control measures irrespective of bTB infection confirmation status. PMID- 29970196 TI - 3-O-acetyl-11-keto-beta-boswellic acid exerts anti-tumor effects in glioblastoma by arresting cell cycle at G2/M phase. AB - BACKGROUND: Glioblastoma (GBM) is the most common, malignant, and lethal primary brain tumor in adults accounting for about 50% of all gliomas. Up to now, the chemotherapy approaches for GBM were limited. 3-O-acetyl-11-keto-beta-boswellic acid (AKBA), the major active ingredient of the gum resin from Boswellia serrata and Boswellia carteri Birdw., was reported to inhibit the growth of many types of cancer cells; however, the underlying mechanism of its anticancer effects are still unclear. METHODS: The effects of AKBA on cell viability and its cytotoxicity were determined using CCK8 and LDH kits respectively. The EdU-DNA synthesis assay was used to evaluate inhibition of cell proliferation by AKBA. The role of AKBA in glioblastoma cell functions such as migration/invasion, and colony formation was evaluated using transwell chambers and soft agar, respectively. Flow cytometry and western blotting were used to detect AKBA induced apoptosis. Potential mechanisms of AKBA action were explored by RNA sequencing and the identified hub genes were validated by real-time quantitative PCR and western blotting. Finally, the in vivo anti-tumor activity of AKBA was evaluated against a human glioblastoma cell line, U87-MG, in a xenograft mouse model. RESULTS: AKBA inhibited cell proliferation, caused the release of LDH, decreased DNA synthesis, and inhibited the migration, invasion, and colony formation of U251 and U87-MG human glioblastoma cell lines. AKBA increased apoptosis as well as the activity of caspase 3/7 and the protein expression of cleaved-caspase 3 and cleaved PARP, while decreasing mitochondrial membrane potential. RNA-sequencing analyses showed that AKBA suppressed the expression of pRB, FOXM1, Aurora A, PLK1, CDC25C, p-CDK1, cyclinB1, Aurora B, and TOP2A while increasing the expression of p21 and GADD45A. These findings were validated by qRT-PCR and western blotting. The data are consistent with a mechanism in which AKBA arrested the cell cycle in glioblastoma cells at the G2/M phase by regulating the p21/FOXM1/cyclin B1 pathway, inhibited mitosis by downregulating the Aurora B/TOP2A pathway, and induced mitochondrial-dependent apoptosis. Oral administration of AKBA (100 mg/kg) significantly suppressed the tumorigenicity of U87-MG cells in a xenograft mouse model. CONCLUSIONS: Taken together, these results suggest that AKBA (molecular weight, 512.7 Da) might be a promising chemotherapy drug in the treatment of GBM. PMID- 29970200 TI - Viral and bacterial co-infection in hospitalised children with refractory Mycoplasma pneumoniae pneumonia. AB - To investigate the impact of viral and bacterial co-infection in hospitalised children with Mycoplasma pneumoniae pneumonia (RMPP). Retrospective analysis of 396 children with RMPP in our hospital admitted between 1 January 2011 and 31 December 2016 was performed. Nasal aspirate samples were collected for pathogen detection and clinical data were collected. We analysed clinical characteristics, lung imaging characteristics and pathogenic species among these children. Of the 396 RMPP cases, 107 (27.02%) had co-infection with other pathogen, with Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus being the most common bacteria of infection and human bocavirus (HBoV), human rhinovirus, respiratory syncytial virus being the most common viruses of infection. Children with co-infection were younger than that with single infection (P = 0.010). Children with both virus and bacteria co-infection had been the youngest (P = 0.040). Children with co-infection had a longer fever process, higher leukocyte count, higher C-reactive protein compared with single infection (P < 0.05). Children with co-infection had a higher percentage of pnemothorax and diffuse large area of inflammation in chest X-ray manifestation compared with children with single infection (P < 0.05). S. pneumonia and HBoV was the leading cause of co-infection in RMPP. Co-infections led to more disease severity in children with RMPP compared with single infections. PMID- 29970201 TI - Drumming-associated anthrax incidents: exposures to low levels of indoor environmental contamination. AB - Two fatal drumming-related inhalational anthrax incidents occurred in 2006 and 2008 in the UK. One individual was a drum maker and drummer from the Scottish Borders, most likely infected whilst playing a goat-skin drum contaminated with Bacillus anthracis spores; the second, a drummer and drum maker from East London, likely became infected whilst working with contaminated animal hides.We have collated epidemiological and environmental data from these incidents and reviewed them alongside three similar contemporaneous incidents in the USA. Sampling operations recovered the causative agent from drums and drum skins and from residences and communal buildings at low levels. From these data, we have considered the nature of the exposures and the number of other individuals likely to have been exposed, either to the primary infection events or to subsequent prolonged environmental contamination (or both).Despite many individual exposures to widespread low-level spore contamination in private residences and in work spaces for extended periods of time (at least 1 year in one instance), only one other individual acquired an infection (cutaneous). Whilst recognising the difficulty in making definitive inferences from these incidents to specific residual contamination levels, and by extending the risk to public health, we believe it may be useful to reflect on these findings when considering future incident management risk assessments and decisions in similar incidents that result in low-level indoor contamination. PMID- 29970202 TI - Barriers and Facilitators to Injection Safety in Ambulatory Care Settings. AB - OBJECTIVEIdentify factors referred to as barriers and facilitators that can prevent or assist safe injection practices in ambulatory care settings to guide quality improvement.DESIGNIn this mixed-methods study, we utilized observations and interviews.SETTINGThis study was conducted at ambulatory clinics at a midwestern academic medical center from May through August 2017. Sites included a variety of clinical settings that performed intramuscular, intradermal, intravenous, or intra-articular injections.PARTICIPANTS AND INTERVENTIONSDirect observations of injections and interviews of ambulatory care staff were conducted. An observation checklist was created, including standards of injection safety from nationally recognized guidelines. Interview questions were developed using the System Engineering Initiative for Patient Safety (SEIPS) model. Interviews were recorded, transcribed, and then coded by 2 investigators.RESULTSIn total, 106 observations and 36 interviews were completed at 21 clinics. Injection safety standards with the lowest adherence included using needleless access devices to prepare injections (33%) and the proper use of multidose vials (<80%). Of 819 coded interview segments, 461 (56.3%) were considered facilitators of safe injection practices. The most commonly identified barriers were patient movement during administration, feeling rushed, and inadequate staffing. The most commonly identified facilitators were availability of supplies, experience in the practice area, and availability of safety needles and prefilled syringes.CONCLUSIONSPerceived barriers and facilitators to infection control elements of injection safety are interconnected with SEIPS elements of persons, organizations, technologies, tasks, and environment. Direct observations demonstrated that knowledge of safety injection standards does not necessarily translate to best practices and may not match self-reported data.Infect Control Hosp Epidemiol 2018;39:841-848. PMID- 29970199 TI - Quantifying TB transmission: a systematic review of reproduction number and serial interval estimates for tuberculosis. AB - Tuberculosis (TB) is the leading global infectious cause of death. Understanding TB transmission is critical to creating policies and monitoring the disease with the end goal of TB elimination. To our knowledge, there has been no systematic review of key transmission parameters for TB. We carried out a systematic review of the published literature to identify studies estimating either of the two key TB transmission parameters: the serial interval (SI) and the reproductive number. We identified five publications that estimated the SI and 56 publications that estimated the reproductive number. The SI estimates from four studies were: 0.57, 1.42, 1.44 and 1.65 years; the fifth paper presented age-specific estimates ranging from 20 to 30 years (for infants <1 year old) to <5 years (for adults). The reproductive number estimates ranged from 0.24 in the Netherlands (during 1933-2007) to 4.3 in China in 2012. We found a limited number of publications and many high TB burden settings were not represented. Certain features of TB dynamics, such as slow transmission, complicated parameter estimation, require novel methods. Additional efforts to estimate these parameters for TB are needed so that we can monitor and evaluate interventions designed to achieve TB elimination. PMID- 29970204 TI - Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants - CORRIGENDUM. PMID- 29970203 TI - Do Periarticular Joint Injections Present an Increase in Infection Risk? - CORRIGENDUM. PMID- 29970205 TI - Outbreak of Hepatitis A Virus Infection Among Adult Patients of a Mental Hospital Los Angeles County, 2017 - CORRECTION. PMID- 29970206 TI - Improved Outcomes When Antibiotic Prescribing Guidelines Are Followed by Healthcare Providers: A Colombian Example to Encourage Adherence in Hospital Settings - CORRIGENDUM. PMID- 29970207 TI - Human Factors and Systems Engineering: The Future of Infection Prevention? PMID- 29970208 TI - Clinical Characteristics of the 2013 Haiyan Typhoon Victims Presenting to the Belgian First Aid and Support Team. AB - OBJECTIVE: In 2013, the Philippines was struck by typhoon Haiyan, which damaged local hospitals and disrupted health care. The Belgian First Aid and Support Team erected a field hospital and water purification unit in Palo. This study aims to describe the diagnoses encountered and treatment provided. METHODS: In this cross sectional study, medical records of 1267 field hospital patients were reviewed for gender, age, complaints, diagnoses, and management and referral information. RESULTS: Almost 28% of the patients suffered from injury, but most presented with nonsurgical diseases (64%), particularly of respiratory (31%), dermatological (11%), and digestive (8%) origin. Only 53% presented with disaster-related pathology, and 59% showed signs of infection. Patients needed wound care (47%), pain relief (33%), or antibiotics (29%); 9% needed procedures, 8% needed fluid therapy, and 5% needed psychological support. Children under 5 years of age were more at risk for infections (OR, 18.8; CI, 10.6-33.3) and injuries (OR, 10.3; CI, 6.3-16.8). Males were more prone to injuries than females (OR, 2.1; CI, 1.6-2.6). CONCLUSIONS: One week after the acute phase of a typhoon, respiratory, dermatological, and digestive problems emerge to the prejudice of trauma. Only 53% of patients presented with disaster-related conditions. Young children are more at risk for injury and infectious diseases. These trends should be anticipated when composing Emergency Medical Teams and medical resources to be sent to disaster sites. (Disaster Med Public Health Preparedness. 2018;page 1 of 14). PMID- 29970209 TI - A label survey to identify ingredients potentially containing GM organisms to estimate intake exposure in Brazil. AB - OBJECTIVE: To identify ingredients from products and by-products derived from GM crops in packaged food products and to analyse the presence of these ingredients in the foods most commonly consumed by the Brazilian population. DESIGN: Cross sectional study. SETTING: A search of the scientific literature to identify the use of products and by-products derived from GM crops in foods in Brazil and a study of food labels in a supermarket belonging to one of the ten largest supermarket chains in Brazil. SUBJECTS: To identify the ingredients present in packaged food products and their nomenclatures, the labels of all packaged food products available for sale in a supermarket were analysed. Subsequently, the presence of potential GM ingredients in the foods most commonly consumed by the Brazilian population was analysed. RESULTS: A total of twenty-eight GM crops' by products with applications in the food industry (from soyabeans, corn, cotton and a yeast) were identified. Such by-products are presented as food ingredients or additives on food labels with 101 distinct nomenclatures. Most of the variety (63.8 %) and the quantity (64.5 %) of the foods most commonly consumed by Brazilians may contain a least one GM ingredient. CONCLUSIONS: The presence of at least one potential GM ingredient was observed in more than half of the variety of foods most commonly consumed by the Brazilian population. Such ingredients were identified with distinct nomenclatures and incomplete descriptions, which may make it difficult to identify potential GM foods and confuse consumers when making food choices. PMID- 29970210 TI - Through the eyes of others - the social experiences of people with dementia: a systematic literature review and synthesis. AB - : ABSTRACTBackground:Psychosocial models suggest that the lived experience of dementia is affected by interpersonal factors such as the ways in which others view, talk about, and behave toward the person with dementia. This review aimed to illuminate how informal, everyday interpersonal relationships are experienced by people with dementia within their social contexts. METHOD: A systematic review of qualitative literature published between 1989 and May 2016 was conducted, utilizing the electronic databases PsycINFO, MEDLINE, and CINAHL-Complete. This was followed by a critical interpretative synthesis to understand how people with dementia perceive the attitudes, views, and reactions of other people toward them, and the subjective impact that these have. RESULTS: Four major themes were derived from the findings of the 23 included studies: being treated as an "other" rather than "one of us"; being treated as "lesser" rather than a full, valued member of society; the impact of others' responses; and strategies to manage the responses of others. Thus, people with dementia can feel outcast and relegated, or indeed feel included and valued by others. These experiences impact upon emotional and psychological well-being, and are actively interpreted and managed by people with dementia. CONCLUSION: Experiences such as loss and diminishing identity have previously been understood as a direct result of dementia, with little consideration of interpersonal influences. This review notes that people with dementia actively engage with others, whose responses can foster or undermine social well-being. This dynamic relational aspect may contribute to emerging understandings of social health in dementia. PMID- 29970211 TI - Effects of active psychosocial stimulation on social interactions of people with dementia living in a nursing home: a comparative study - ERRATUM. PMID- 29970212 TI - Social health in dementia care: harnessing an applied research agenda. AB - The notion of social health (Huber et al., 2011) as applied to dementia care research was introduced to redress the balance of empirical studies that tended to focus on biomedical, cognitive, and functional status in dementia (Vernooij Dassen and Jeon, 2016). The introduction of social health has followed the zeitgeist of campaigners for a better life for those living with dementia, with initiatives to improve the social images of dementia (Alzheimers.org, 2017). Examples from social research in dementia to examine friendships and the social environments of people with dementia exist (Medeiros et al., 2012), but introduction of the paradigm of social health in dementia (Vernooij-Dassen and Jeon, 2016) has harnessed a growing research agenda (de Vugt and Droes, 2017). This paradigm provides an umbrella concept to study how social aspects influence the dynamic balance between opportunities and limitations in dementia. Social health goes beyond the neuropathology of dementia, to understand how people, their social networks and wider society with its norms, interact with the condition (Vernooij-Dassen and Jeon, 2016). It is not far removed from the ideas of Tom Kitwood, the pioneer of person-centered dementia care, who noted that "personhood is a standing or status that is bestowed upon one human being, by others, in the context of relationship and social being" (Kitwood, 1997). The INTERDEM (Early detection and timely INTERvention in DEMentia, www.interdem.org) psychosocial research agenda aspired to improve knowledge about social inclusion and reciprocal relationships for people with dementia (Moniz-Cook et al., 2011). The concept of social health (Vernooij-Dassen and Jeon, 2016) with its dimensions for dementia research (Droes et al., 2017) has begun to develop this knowledge base. PMID- 29970213 TI - Soil characteristics influencing the spatial distribution of melioidosis in Far North Queensland, Australia. AB - The environmental bacterium, Burkholderia pseudomallei, is responsible for the potentially fatal disease melioidosis. Factors responsible for the temporospatial distribution of cases are incompletely understood, although a combination of rainfall, groundwater levels and the physicochemical properties of soil are important. The distribution of culture-positive cases of melioidosis from 1996 to 2016 in Far North Queensland, Australia, was investigated to determine the association with different soil types and landforms in Cairns, the region's largest city. Cases were clustered on alluvial fan landforms of strongly bleached gradational textured and yellow massive gradational textured soils indicating these soils are more suitable for B. pseudomallei and risk of melioidosis infection is higher in these areas, cases were less frequent on other soil types on alluvial fan landforms (despite comparable population density) and beach ridges. This indicates that the combination of these soils might be more suitable for B. pseudomallei, increasing the risk of disease in these locations. Sociodemographic characterisics of the population in cluster locations were considered. Knowledge of local soil characteristics may help predict cases of melioidosis and inform public health strategies to prevent the disease. Because melioidosis case clusters were identified, testing for the presence of B. pseudomallei across the study area is a useful target of future research. PMID- 29970214 TI - Diagnosis of brain abscess: a challenge that Magnetic Resonance can help us win! PMID- 29970215 TI - Comparison of Aqueous and Alcohol-based Agents for Presurgical Skin Preparation Methods in Mice. AB - Preparing the skin of rodents for surgery often involves multiple applications of antiseptic agents. However, fewer applications may achieve the same antiseptic outcome. We evaluated the antimicrobial efficacy and effects on intraoperative body temperature of various surgical scrub agents, including novel waterless alcohol-based (WAB) options. Prior to ventral laparotomy, female C57BL/6 mice were treated with 0.9% saline (control); 70% ethanol; 10% povidone-iodine alternated with saline or 70% ethanol; 2% chlorhexidine digluconate alternated with saline or 70% ethanol; or 1 of 3 WAB products-commercial surgical scrub A, commercial surgical scrub B, or a common commercial hand sanitizer. Core temperatures were recorded, and aerobic culture swabs were collected from the surgical site at multiple time points. Intraoperative temperature trajectories for animals treated with scrub B, 10% povidone-iodine with saline, or hand sanitizer did not differ from saline (control). Temperature trajectories of mice treated with other scrub agents did differ significantly from saline. Bacteria were not detected at the operative site after 3 scrubs of 70% ethanol or 10% povidone-iodine alternated with ethanol, 2 scrubs of scrub A or B, 1 scrub of hand sanitizer, and both 1 and 3 scrubs of 2% chlorhexidine alternated with ethanol. Scrub B and 2% chlorhexidine-ethanol demonstrated prolonged antibacterial efficacy. Histology of corresponding haired skin sections revealed no differences in postoperative healing between groups, and no postoperative infections occurred. These results indicate that various novel WAB disinfectants, particularly scrub B (61% ethanol and 1% chlorhexidine gluconate), mitigate intraoperative temperature effects associated with several traditional agents and combinations. Furthermore, reduction of skin bacterial load without adverse effects on healing was seen with fewer than triplicate applications of most tested agents. Ultimately effective skin preparation can be achieved by using only 1 or 2 applications of scrub, thus rendering the triplicate skin-prep method unnecessary in laboratory mice. PMID- 29970216 TI - Long Noncoding RNA NEAT1 Promotes Growth and Metastasis of Cholangiocarcinoma Cells. AB - Long noncoding RNAs (lncRNAs) are known to play important roles in cancers. However, little is known about lncRNAs in cholangiocarcinoma (CCA), a cholangiocyte malignancy with poor prognosis. We investigated the role of nuclear paraspeckle assembly transcript 1 (NEAT1) lncRNA in promoting CCA. qRT-PCR analysis of patient samples showed that NEAT1 expression was higher in CCA tumors than in matched adjacent nontumor tissue. NEAT1 levels were also higher in CCA cell lines than in a normal biliary epithelium cell line (HIBEpic). NEAT1 knockdown in CCA cell lines using shNEAT1 reduced cell proliferation and colony formation in CCK-8 and colony formation assays, respectively. CCA cells transfected with shNEAT1 also exhibited reduced metastasis and invasiveness in Transwell assays. NEAT1 knockdown cells produced smaller tumors, demonstrating that NEAT1 promotes tumor growth in vivo. Silencing of NEAT1 increased E-cadherin expression in vitro, and E-cadherin expression was inversely correlated with NEAT1 expression in CCA tissue samples. RIP and ChIP assays suggest that NEAT1 is recruited to the E-cadherin promoter by EZH2 (enhancer of zeste homolog 2), where it represses E-cadherin expression. These findings indicate that NEAT1 exerts oncogenic effects in CCA. We postulate that NEAT1 is a potentially useful diagnostic and therapeutic target for CCA. PMID- 29970217 TI - Use of an ingredient-based analysis to investigate a national outbreak of Escherichia coli O157, United Kingdom, July 2016. AB - Public Health England was alerted to a national outbreak of Shiga toxin-producing Escherichia coli O157 PT34 in July 2016. Early investigations suggested that the likely source was a salad item consumed outside of the home. A number of cases reported consuming meals at a staff canteen (Venue A) and a garden cafe (Venue B). Both venues shared a common salad supplier. An investigation was undertaken to measure associations between salad items and illness using an 'ingredient based analysis'. A retrospective case-control study was conducted using an online questionnaire to collect information on menu items consumed at each venue. Chefs at both venues were interviewed to identify ingredients contained within each menu item. Both venues were pooled together for multivariable analysis measuring associations at the ingredient level. Among 203 responses, 24 cases were identified (13 confirmed, two probable and nine possible). Case onsets ranged between 7 and 25 June 2016. Multivariable analysis identified strong evidence that only baby mixed-leaf salad from the common supplier was a vehicle of infection (adjusted odds ratio = 13.1; 95% confidence interval: 1.6-106.5). Identifying the specific salad ingredient associated with illness was made possible by using an ingredient-based analysis. We recommend the increased use of ingredient-based analyses. PMID- 29970218 TI - In the national epidemiological bulletins - a selection from recent issues. PMID- 29970219 TI - Spatio-temporal patterns of highly pathogenic avian influenza virus subtype H5N8 spread, France, 2016 to 2017. AB - IntroductionFrance is one of Europe's foremost poultry producers and the world's fifth largest producer of poultry meat. In November 2016, highly pathogenic avian influenza (HPAI) virus subtype H5N8 emerged in poultry in the country. As of 23 March 2017, a total of 484 confirmed outbreaks were reported, with consequences on animal health and socio-economic impacts for producers. Methods: We examined the spatio-temporal distribution of outbreaks that occurred in France between November 2016 and March 2017, using the space-time K-function and space-time permutation model of the scan statistic test. Results: Most outbreaks affected duck flocks in south-west France. A significant space-time interaction of outbreaks was present at the beginning of the epidemic within a window of 8 km and 13 days. This interaction disappeared towards the epidemic end. Five spatio temporal outbreak clusters were identified in the main poultry producing areas, moving sequentially from east to west. The average spread rate of the epidemic front wave was estimated to be 5.5 km/week. It increased from February 2017 and was negatively associated with the duck holding density. Conclusion: HPAI-H5N8 infections varied over time and space in France. Intense transmission events occurred at the early stages of the epidemic, followed by long-range jumps in the disease spread towards its end. Findings support strict control strategies in poultry production as well as the maintenance of high biosecurity standards for poultry holdings. Factors and mechanisms driving HPAI spread need to be further investigated. PMID- 29970221 TI - Vision Outcomes Following Anti-Vascular Endothelial Growth Factor Treatment of Diabetic Macular Edema in Clinical Practice. PMID- 29970222 TI - Three dimensional characterisation of chromatography bead internal structure using X-ray computed tomography and focused ion beam microscopy. AB - X-ray computed tomography (CT) and focused ion beam (FIB) microscopy were used to generate three dimensional representations of chromatography beads for quantitative analysis of important physical characteristics including tortuosity factor. Critical-point dried agarose, cellulose and ceramic beads were examined using both methods before digital reconstruction and geometry based analysis for comparison between techniques and materials examined. X-ray 'nano' CT attained a pixel size of 63 nm and 32 nm for respective large field of view and high resolution modes. FIB improved upon this to a 15 nm pixel size for the more rigid ceramic beads but required compromises for the softer agarose and cellulose materials, especially during physical sectioning that was not required for X-ray CT. Digital processing of raw slices was performed using software to produce 3D representations of bead geometry. Porosity, tortuosity factor, surface area to volume ratio and pore diameter were evaluated for each technique and material, with overall averaged simulated tortuosity factors of 1.36, 1.37 and 1.51 for agarose, cellulose and ceramic volumes respectively. Results were compared to existing literature values acquired using established imaging and non-imaging techniques to demonstrate the capability of tomographic approaches used here. PMID- 29970223 TI - Usefulness of Reflectance Confocal Microscopy For in Vivo Diagnosis of Sebomatricomas. PMID- 29970224 TI - Frontal Tumor that Increased in Size with the Valsalva Maneuver. PMID- 29970225 TI - Measurement of the Psychological Impact of Psoriasis on Patients Receiving Systemic Treatment. AB - BACKGROUND AND OBJECTIVES: The negative impact of psoriasis on patient quality of life can be as important as the physical consequences of the disease. We could assume that clearance of the disease would also lead to an improvement in its psychosocial impact. The present study assesses the psychological state of patients with psoriasis receiving systemic treatment in a psoriasis unit, especially those with mild or no disease involvement. METHODS: We performed a cross-sectional, observational, noninterventional epidemiological study of 2 cohorts (cases and controls). The patients self-completed demographic data and 4 questionnaires (Rosenberg Self-Esteem Scale, Skindex-29, HADS, and COPE-28 questionnaire) at a single visit. RESULTS: We recruited 111 patients diagnosed with psoriasis and 109 control patients. In self-esteem, the mean and standard deviation (SD) score was 33.5 (4.8) for the psoriasis group and 33.3 (6.7) for the control group, with no significant differences. In the Skindex-29, the mean score for the psoriasis group was almost 3 times higher than that of the control group (30 vs. 11). Significant differences were found in the HADS scores of both groups (12.7 vs. 9.0, P<.001). The mean HADS-A scores were 8.0 (4.78) for the psoriasis group compared with 5.7 (3.8) for the control group (P<.001). In the case of HADS-D, the scores were 4.7 (3.9) compared with 3.2 (3.1) (P<.004), respectively. CONCLUSIONS: Our findings indicate that it is necessary to assess the psychological state of patients with psoriasis, because psychological effects persist even in cases where the disease is almost totally controlled. PMID- 29970226 TI - Stewart-Bluefarb Syndrome: Case Report and Review of the Literature. PMID- 29970227 TI - Variability of facial movements in relation to sexual dimorphism and age: three dimensional geometric morphometric study. AB - The aim of this study was to introduce suitable imaging technique and analytical methods for a detailed description of the facial movements in relation to sexual dimorphism and age in adult individuals. Removing of size factor from the analysis, we hypothesised that there will be no significant intersexual difference in facial mobility. We assume facial movements to be more pronounced in the older age category due to increasing the facial surface. We have compared five facial movements - raising eyebrows, closing eyes, pursing of the lips, inflating of the cheeks and smile - in relation to neutral expression of the human face. The material sample comprised three-dimensional facial surface models of healthy adult individuals of the Czech nationality (63 females, 58 males). Methods of geometric morphometry and multivariate statistics were used. Local tissue motion due to facial movements was expressed using colour-coded maps. The movement showing significant intersexual difference was inflating of the cheeks. Ageing in both sexes has significantly influenced the facial mobility on average after 50 years of age. Changes related to senescence have occurred in eye closing, smile and inflating of the cheeks. An enlarged facial surface has been noted in the group of individuals belonging to the older age category, what is probably the result of increased manifestation of skin folds and wrinkles. This is related to the loss of skin elasticity and overall weakening of the underlying muscles, especially in the infraorbital and cheeks area. PMID- 29970228 TI - Development and validation of a computational model for understanding the effects of an upright birthing position on the female pelvis. AB - Upright, natural birthing positions, such as squatting, are associated with several clinical benefits, yet recumbent positions are still most common during delivery in most health centres. The biomechanics of birth positioning are not yet fully understood; therefore, our objectives were to develop and validate a computational model that could determine pelvic kinematics under loading conditions resulting from an upright birthing position. A three-dimensional model of the pelvic region was created from MRI scans of a non-pregnant subject. Bones were designated rigid segments with sacroiliac and pubic symphysis joint motion constrained only by contact surfaces and ligaments modeled as non-linear spring elements. Actuating torques at the lumbosacral and hip joints were defined based on motion analyses of squatting. The model was validated by comparing simulation results with data from the literature and in vivo MRI data from three subjects in a kneel-squat position. Good agreement was found between clinical pelvimetry measurements from the squat simulation and MRI data. Differences between simulation predictions were within one standard deviation of mean MRI kneel-squat results for all clinical measurements except one: the predicted increase in bispinous diameter was approximately 1.5 standard deviations less than that of the mean MRI results and still well within physiologic limits according to data in the literature. This model can, therefore, be used to provide further insight into the biomechanics of certain upright birthing positions, such as squatting. PMID- 29970229 TI - Site specificity of mechanical and structural properties of human fascia lata and their gender differences: A cadaveric study. AB - The whole thigh muscles are covered with the fascia lata, which could have morphological and mechanical features that match the underlying muscles' functions. In this study, we investigated the morphological and elastic properties of the human fascia lata taken from four (anterior, medial, lateral, and posterior) sites on the thigh of 17 legs of 12 cadavers (6 males and 6 females, 75-92 years). The thickness of the fascia lata was determined with a caliper. The interwoven collagen fiber's directions were measured and classified into longitudinal, transverse, and diagonal in two opposing directions, relative to the thigh. Tensile strength test along the longitudinal and transverse directions was performed, and the stiffness, Young's modulus, and hysteresis were determined. Fascia lata at the lateral site (0.8 +/- 0.2 mm) was significantly thicker compared to other sites (0.2-0.3 mm). Fiber's directions showed substantial variability among sites, and longitudinally directed fibers were higher in proportion (28-32%) than those in other directions (20-27%) at all sites except for the posterior site. The stiffness and Young's modulus in the longitudinal direction (20-283 N/mm; 71.6-275.9 MPa, highest at the lateral site) were significantly higher than in the transverse direction (3-16 N/mm; 3.2-41.9 MPa, lowest at the lateral site). At the medial site, the proportion of the transversely directed fibers was higher in females than males, with higher stiffness and Young's modulus thereof. The present study shows that the fascia lata possesses site- and gender-dependence of the morphological characteristics and elastic properties. PMID- 29970230 TI - Coronary artery bypass as a transplant process. PMID- 29970231 TI - Successful use of a ventricular assist device in a neonate with hypoplastic left heart syndrome with right ventricular dysfunction. PMID- 29970232 TI - Single-Cell Imaging Approaches for Studying Small-RNA-Induced Gene Regulation. AB - RNA interference (RNAi) is a process by which gene expression is downregulated by small interfering RNAs or microRNAs. The quantification of the RNAi efficiency can be performed at both the messenger RNA (mRNA) and the protein level, which is required to assess the potency of small interfering RNAs or microRNAs. Recently, we employed a single-cell mRNA imaging method to study RNAi in which we visualized individual mRNA targets with high precision while resolving the cellular localization and cell-to-cell heterogeneity in addition to RNAi efficiency. In this Biophysical Perspective, we highlight our recent work on quantitative analysis of the RNAi pathway and point out some important future directions. Alongside, we discuss about several single-cell imaging techniques that can be applied to study RNAi. The single-cell imaging techniques discussed here are widely applicable to other gene regulation processes such as the CRISPR CAS system. PMID- 29970233 TI - Pleistocene animal communities of a 1.5 million-year-old lake margin grassland and their relationship to Homo erectus paleoecology. AB - The ecological and selective forces that sparked the emergence of Homo's adaptive strategy remain poorly understood. New fossil and archaeological finds call into question previous interpretations of the grade shift that drove our ancestors' evolutionary split from the australopiths. Furthermore, issues of taphonomy and scale have limited reconstructions of the hominin habitats and faunal communities that define the environmental context of these behavioral changes. The multiple ~1.5 Ma track surfaces from the Okote Member of the Koobi Fora Formation at East Turkana provide unique windows for examining hominin interactions with the paleoenvironment and associated faunas at high spatiotemporal resolution. These surfaces preserve the tracks of many animals, including cf. Homo erectus. Here, we examine the structure of the animal community that inhabited this landscape, considering effects of preservation bias by comparing the composition of the track assemblage to a skeletal assemblage from the same time and place. We find that the track and skeletal assemblages are similar in their representation of the vertebrate paleocommunity, with comparable levels of taxonomic richness and diversity. Evenness (equitability of the number of individuals per taxon) differs between the two assemblages due to the very different circumstances of body fossil versus track preservation. Both samples represent diverse groups of taxa including numerous water-dependent species, consistent with geological interpretations of the track site environments. Comparisons of these assemblages also show a pattern of non-random hominin association with a marginal lacustrine habitat relative to other vertebrates in the track assemblage. This evidence is consistent with behavior that included access to aquatic foods and possibly hunting by H. erectus in lake margins/edaphic grasslands. Such behaviors may signal the emergence of the adaptative strategies that define our genus. PMID- 29970234 TI - Antimicrobial photodynamic active biomaterials for periodontal regeneration. AB - OBJECTIVE: Biomaterials for periodontal regeneration may have insufficient mechanical and antimicrobial properties or are difficult to apply under clinical conditions. The aim of the present study was to develop a polymeric bone grafting material of suitable physical appearance and antimicrobial photodynamic activity. METHODS: Two light curable biomaterials based on urethane dimethacrylate (BioM1) and a tri-armed oligoester-urethane methacrylate (BioM2) that additionally contained a mixture of beta-tricalcium phosphate microparticles and 20wt% photosensitizer mTHPC (PS) were fabricated and analyzed by their compressive strength, flexural strength and modulus of elasticity. Cytotoxicity was observed by incubating eluates and in direct-contact to MC3T3-E1 cells. Antimicrobial activity was ascertained on Porphyromonas gingivalis and Enterococcus faecalis upon illumination with laser light (652nm, 1*100J/cm2, 2*100J/cm2). RESULTS: The compressive strength, flexural strength and elastic modulus were, respectively, 311.73MPa, 22.81MPa and 318.85MPa for BioM1+PS and 742.37MPa, 7.58MPa and 406.23MPa for BioM2+PS. Both materials did not show any cytotoxic behavior. Single laser-illumination (652nm) caused total suppression of P. gingivalis (BioM2+PS), while repeated irradiation reduced E. faecalis by 3.7 (BioM1+PS) and 3.1 (BioM2+PS) log-counts. SIGNIFICANCE: Both materials show excellent mechanical and cytocompatible properties. In addition, irradiation with 652nm induced significant bacterial suppression. The manufactured biomaterials might enable a more efficient cure of periodontal bone lesions. Due to the mechanical properties functional stability might be increased. Further, the materials are antimicrobial upon illumination with light that enables a trans-mucosal eradication of residual pathogens. PMID- 29970235 TI - Novel vaccines: Technology and development. AB - The development and widespread use of vaccines, which are defined by the World Health Organization as "biological preparations that improve immunity to a particular disease," represents one of the most significant strides in medicine. Vaccination was first applied to reduce mortality and morbidity from infectious diseases. The World Health Organization estimates that vaccines prevent 2 to 3 million human deaths annually, and these numbers would increase by at least 6 million if all children received the recommended vaccination schedule. However, the origins of allergen immunotherapy share the same intellectual paradigm, and subsequent innovations in vaccine technology have been applied beyond the prevention of infection, including in the treatment of cancer and allergic diseases. This review will focus on how new and more rational approaches to vaccine development use novel biotechnology, target new mechanisms, and shape the immune system response, with an emphasis on discoveries that have direct translational relevance to the treatment of allergic diseases. PMID- 29970236 TI - [Monitoring of coagulation by intraoperative thromboelastometry of liver transplantation in a patient using warfarin - case report]. AB - INTRODUCTION: Advanced hepatic disease may - in addition to the widely recognized hemorrhagic complications - occur with thrombotic events. We describe the case of a cirrhotic patient taking warfarin and whose coagulation management during liver transplantation was guided by thromboelastometry (ROTEM(r)). CASE REPORT: A 56 year-old male patient diagnosed with alcohol cirrhosis using warfarin (2.5mg.day 1) for partial portal vein thrombosis with the International Normalized Ratio (INR) of 2.14. At the beginning of surgery, the ROTEM(r) parameters were all normal. In the anhepatic phase, EXTEM and INTEM remained normal, but FIBTEM showed reduction of amplitude after 10min and maximum clot firmness. Finally, in the neohepatic phase, there was a slight alteration in the hypocoagulability of most of the parameters of the EXTEM, INTEM and FIBTEM, besides a notable correction of the Coagulation Time (CT) in HEPTEM compared to the CT of the INTEM. Therefore, the patient did not receive any transfusion of blood products during surgery and in the postoperative period, being discharged on the 8th postoperative day. DISCUSSION: Coagulation deficit resulting from cirrhosis distorts INR as a parameter of anticoagulation adequacy and as a determinant of the need for blood transfusion. Thus, thromboelastometry can provide important information for patient management. PMID- 29970237 TI - Clinician-centered Outcomes Assessment of Retreatment and Endodontic Microsurgery Using Cone-beam Computed Tomographic Volumetric Analysis. AB - INTRODUCTION: Outcomes assessment of retreatment and endodontic microsurgery (EMS) are traditionally based on clinical findings and radiographs. The purpose of this study was to assess the volumetric change of periapical radiolucencies (PARLs) by cone-beam computed tomographic (CBCT)-based analysis in retreatment and EMS cases. METHODS: For 68 retreatment and 57 EMS cases, preoperative and recall clinical data, periapical (PA) radiographs, and CBCT imaging were retrospectively obtained. Specialized software was used by 2 board-certified endodontists for volumetric analysis of PARLs. For EMS and retreatment, clinical outcomes were determined by combining clinical data with CBCT-generated volumetric analysis (PA radiographs not used). Additionally, comparisons of percent volume reduction for EMS and retreatment were performed. Examiner interpretations of outcomes assessment using PA radiography and CBCT imaging were compared. RESULTS: In teeth with or without a preoperative PARL, EMS resulted in a statistically significant difference in complete healing (49/57 [86.0%]) versus retreatment (28/68 [41.2%], P < .0001). EMS resulted in a statistically significant difference in combined complete healing and reductive healing (54/57 [94.7%]) versus retreatment (56/68 [82.4%], P < .05). Of 46 recalls in which CBCT imaging detected a PARL, PA radiography detected 30 (a 35% false-negative rate). Of the 79 recall studies in which CBCT imaging did not detect a PARL, PA radiography did detect PARL in 13 (a 16.5% false-positive rate). CONCLUSIONS: In this CBCT and clinical data-based outcomes assessment, EMS resulted in a greater mean volumetric reduction and a higher healing rate compared with retreatment. Postoperative CBCT imaging is more sensitive and specific than PA radiography in assessing PARL and has demonstrable usefulness in outcomes assessment. PMID- 29970239 TI - Status of the Epicardial Coronary Arteries in Non-ST Elevation Acute Coronary Syndrome in Patients with Mechanical Prosthetic Heart Valves (from the TROIA-ACS Trial). AB - Coronary thromboembolism (CE) is a rare cause of prosthetic valve derived complications. This study investigates the diagnosis and treatment strategies for non-ST elevation acute coronary syndrome (NSTEACS) in patients with prosthetic heart valves. Forty-eight NSTEACS patients with prosthetic heart valves (mitral:27; aortic:14; mitral+aortic:7) were included in this study. All patients underwent transthoracic and transesophageal echocardiographic examination and coronary angiography. Normal coronary angiographic findings, or visible trombus in one of the coronary arteries, international normalized ratio <2, concomitant prosthetic valve thrombosis (PVT) and absence of multivessel atherosclerotic disease favored CE rather than atherothrombosis. Thrombolytic therapy (TT) with low-dose slow-infusion of tissue type plasminogen activator was used in patients with suspected CE and/or PVT. Coronary angiography demonstrated normal coronary arteries in 26 patients, CE in 16 patients and coronary atherosclerosis in 6 patients. Transesophageal echocardiography revealed obstructive PVT in 9 and nonobstructive PVT in 28 patients whereas 11 patients had normally functioning prostheses. TT was administered to 24 patients with PVT and/or CE. In these patients, TT was successful in 19 patients, partially successful in 4 patients and failed in 1 patient. In conclusion, NSTEACS in patients with prosthetic heart valves is more likely to be associated with PVT derived CE rather than atherosclerosis. TT with low-dose slow infusion of type plasminogen activator has proved its efficacy and safety in patients with CE and/or PVT. PMID- 29970238 TI - Usefulness of the Addition of Renal Function to the CHA2DS2-VASc Score as a Predictor of Thromboembolism and Mortality in Patients Without Atrial Fibrillation. AB - Research is conflicting whether kidney function should be incorporated in thromboembolism risk prediction. Our published data showed that the CHA2DS2-VASc score predicts thromboembolism and mortality in those without atrial fibrillation. We used the Rochester Epidemiology Project medical records system to retrospectively evaluate whether adding renal impairment (1 point) to the CHA2DS2-VASc score (-R) enhances the score's prediction of mortality, thromboembolism, and atrial fibrillation in patients without atrial fibrillation. We identified patients that had an implantable cardiac monitoring device placed from January 1, 2004 to December 31, 2013, which was defined as the start date. Follow-up was through March 7, 2016. An implantable device was required to discern the absence of atrial fibrillation. Renal impairment was defined as chronic kidney disease stage 3 or greater. The population (n = 1,606) had a mean age of 69.8 years and median follow-up of 4.8 years. Baseline renal impairment was predictive of mortality (hazard ratio [HR] 2.06, 95% confidence interval [CI] 1.64 to 2.60, p <0.001), thromboembolism (HR 1.34, 95% CI 0.96 to 1.87, p = 0.09), and atrial fibrillation (HR 1.31, 95% CI 0.98 to 1.74, p = 0.07). Lower glomerular filtration rate correlated significantly with mortality. Increasing CHA2DS2-VASc-R score correlated significantly with mortality, thromboembolism, and incident atrial fibrillation. The addition of renal impairment to the CHA2DS2 VASc score improved the C-statistics for thromboembolism and survival from 0.72 to 0.73 (p = 0.01) and 0.70 to 0.72 (p <0.001). Adding renal impairment to the CHA2DS2-VASc score improves the score's prediction of thromboembolism and mortality in a population without atrial fibrillation, although the incremental benefit appears mild. PMID- 29970240 TI - Comparison of Outcomes in DeBakey Type AI Versus AII Aortic Dissection. AB - The DeBakey classification divides type A acute aortic dissection (AAD) into type I and type II; the latter limited to the ascending aorta. We endeavored to examine differences in DeBakey groups in a contemporary registry. We divided 1,872 patients with noniatrogenic AAD from the International Registry of Acute Aortic Dissection into type I (n = 1691, 90.3%) and type II (n = 181, 9.7%). Patients with type II AAD were older. On presentation, patients with type I AAD reported more back and abdominal pain and were more likely to have pulse deficit. Intramural hematoma was more frequent in type II AAD. Most patients with both types were treated surgically. Lower rates of renal failure, coma, mesenteric and limb ischemia were noted in those with type II AAD. In-hospital death was less frequent (16.6% vs 22.5%) after type II AAD, a trend that did not reach significance. There was no difference in the incidence of new dissection, rapid aortic growth, late aortic intervention or survival at 5 years. In conclusion, AAD limited to the ascending aorta (DeBakey type II) appears to be associated with improved clinical outcomes compared with dissection that extend to the aortic arch or beyond. Although fewer dissection-related complications were noted in patients presenting with type II AAD, as was a trend toward reduced in hospital mortality, 5-year survival and descending aortic sequelae are not reduced in this contemporary report from International Registry of Acute Aortic Dissection. PMID- 29970241 TI - Disparities in receipt of follow-up care instructions among female adult cancer survivors: Results from a national survey. AB - OBJECTIVE: To evaluate predictors of receipt of follow-up instructions at completion of cancer treatment among women with breast and gynecologic cancers (cervical, endometrial, ovarian) in the United States, and determine if the factors differ by cancer type. METHODS: We designed a cross-sectional study using data from the "Cancer Survivorship" module of the 2016 Behavioral Risk Factor Surveillance System (BRFSS). We created logistic regression models to determine characteristics associated with receipt of follow-up care instructions, and stratified by models by cancer type to evaluate differences in factors. RESULTS: Our sample included 954 (66%) and 492 (34%) women with breast and gynecologic cancers respectively. Even after adjustment, women treated for gynecologic cancer had 63% lower odds [0.37 (0.25-0.55)] of receiving follow-up instructions compared to women with breast cancer. Among breast cancer patients, those with an income <$25,000 per year had lower odds of receiving follow-up instructions [0.53(0.31-0.92)], while patients with high BMI (BMI >=30 kg/m2) had higher odds of receiving follow-up instructions [1.91 (1.15-3.18)]. Among gynecologic cancer patients, those diagnosed 51-75 years had higher odds of receiving follow-up instructions compared to those diagnosed <=50 years [2.54 (1.13-5.70)]. CONCLUSION: In our study, gynecologic cancer patients less frequently received follow-up instructions compared to breast cancer patients. Receipt of follow-up instructions also differed by demographic and lifestyle factors. The results provide evidence for the need of public health initiatives to increase the frequency of follow-up instructions for gynecologic cancer patients, which can potentially increase the rate of follow-up and improve long-term outcomes. PMID- 29970242 TI - Apparent diffusion coefficient values obtained by unenhanced MRI predicts disease specific survival in bladder cancer. AB - AIM: To assess the ability of apparent diffusion coefficient (ADC) measurements obtained by MRI to predict disease-specific survival (DSS) in patients with bladder cancer and compare it with established clinico-pathological prognostic factors. MATERIAL AND METHODS: The ethical review board approved this cross sectional study. Patients with suspected bladder cancer receiving diagnostic 3 T diffusion-weighted imaging (DWI) of the bladder before transurethral resection of the bladder (TUR-B) or radical cystectomy were evaluated prospectively. Two independent radiologists measured ADC values in bladder cancer lesions in regions of interest. Associations between ADC values and pathological features with DSS were tested statistically. A combined model was established using artificial neuronal network (ANN) methodology. RESULTS: A total of 51 patients (median age 69 years, range 41-89 years) were included. Three patients were lost to follow up, leaving 48 patients for survival analysis. Seven patients died during the 795 months studied. ADC showed significant potential to predict DSS (p<0.05). Except for grading, all pathological features as assessed by TUR-B could predict DSS (p<0.05, respectively). The combined ANN classifier showed the highest accuracy to predict DSS (0.889, 95% confidence interval: 0.732-1, p=0.001) compared to all single parameters. ADC was the second important predictor of the ANN. CONCLUSIONS: ADC measurements obtained by unenhanced MRI predicts DSS in bladder cancer patients. A combined classifier including ADC and clinico-pathological information showed high accuracy to identify patients at high risk for disease related death. PMID- 29970243 TI - Straight-to-test faecal tagging CT colonography for exclusion of colon cancer in symptomatic patients under the English 2-week-wait cancer investigation pathway: a service review. AB - AIM: To present the initial 12 months of data of a straight-to-test (STT) computed tomography colonography (CTC) protocol as the first-line investigation for change in bowel habit (CIBH) and iron deficiency anaemia (IDA) in patients over 60 referred directly from primary care. MATERIALS AND METHODS: In 12 months, 1,792 STT CTC for IDA and CIBH were performed. No colonoscopies were performed as the primary investigation in this cohort. Data from this cohort were gathered prospectively. RESULTS: The colorectal cancer (CRC) detection rate was 4.9% and polyp detection rate was 13.5%. The CRC rate increased related to age (p=0.001), the CRC detection rate was 2.6% in patients aged 60-69 years, compared to 4.9%, 7.4%, and 11.4% in the 70-79, 80-89, and >90 years age groups. The CRC rate was higher in patients with IDA compared to CIBH (6.8% versus 3.9%, p=0.017). There were significantly more left-sided cancers (p=0.0165). Non-colonic cancers were found in 4.3% of patients and 6.8% had incidental findings that required further investigation and 11.9% had a new, potentially significant, incidental finding. CONCLUSION: These results are comparable to colonoscopy in terms of diagnostic accuracy and similar to those of CTC in published multicentre trials. This exciting model of care within radiology enables earlier testing, reduces waiting times, with fewer outpatient appointments, and results in good clinician and patient satisfaction. PMID- 29970244 TI - Breast cancer Ki67 expression prediction by DCE-MRI radiomics features. AB - AIM: To investigate whether quantitative radiomics features extracted from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are associated with Ki67 expression of breast cancer. MATERIALS AND METHODS: This institutional review board-approved retrospective study comprised 377 Chinese women who were diagnosed with invasive breast cancer in 2015. This cohort included 53 low-Ki67 expression (Ki67 proliferation index less than 14%) and 324 cases with high-Ki67 expression (Ki67 proliferation index more than 14%). A binary-classification of low-versus high- Ki67 expression was performed. A set of 56 quantitative radiomics features, including morphological, greyscale statistic, and texture features, were extracted from the segmented lesion area. Three machine learning classification methods, including naive Bayes, k-nearest neighbour and support vector machine, were employed for the classification and the least absolute shrink age and selection operator (LASSO) method was used to select most predictive features set for the classifiers. Classification performance was evaluated by the area under receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. RESULES: The model that used naive Bayes classification method achieved the best performance than the other two methods, yielding 0.773 AUC, 0.757 accuracy, 0.777 sensitivity and 0.769 specificity. Three most predictive features, i.e., contrast, entropy and line likeness, were selected by the LASSO method and showed a statistical significance (p<0.05) in the classification. CONCLUSION: The present study showed that quantitative radiomics imaging features of breast tumour extracted from DCE-MRI are associated with breast cancer Ki67 expression. Future larger studies are needed in order to further evaluate the findings. PMID- 29970245 TI - Cerebrovascular manifestations in neurosarcoidosis: how common are they and does perivascular enhancement matter? AB - AIM: To determine the occurrence of ischaemic and haemorrhagic events in patients with neurosarcoidosis at presentation and follow-up and to evaluate its association with perivascular enhancement. MATERIALS AND METHODS: The MRI findings in patients with neurosarcoidosis who presented to our institute from 2002-2017 were retrospectively reviewed, with emphasis on cerebrovascular events. A chi-squared test was used to evaluate the statistical association with presence of perivascular enhancement. RESULTS: A total of 49 patients (32 females and 17 males) were analysed. Ischaemic events were noted in four patients at presentation while parenchymal haemorrhages occurred in three patients. The combined occurrence of cerebrovascular events (CVEs) at presentation was 14%. On follow-up, three additional patients developed ischaemic infarcts, of which, one patient had parenchymal haemorrhage at presentation. Additionally, one patient also developed new parenchymal haemorrhages. In total, 10 patients in current cohort developed CVEs, either at presentation or on follow-up. Perivascular enhancement was seen in 50% of patients with cerebrovascular events and 18% of patients with neurosarcoidosis, but no CVEs. This was statistically significant (p<0.05). CONCLUSION: CVEs in patients with neurosarcoidosis are more common than previously reported and appear to be significantly related to the presence of perivascular enhancement on imaging. PMID- 29970246 TI - Apparent diffusion coefficient measurement in luminal breast cancer: will tumour shrinkage patterns affect its efficacy of evaluating the pathological response? AB - AIM: To determine which region of interest (ROI) placement method of apparent diffusion coefficient (ADC) measurement has the best performance for predicting pathological complete response (PCR) at two cycles of neoadjuvant chemotherapy (NAC) according to different tumour shrinkage patterns of luminal breast cancer and to assess the evaluative accuracy of ADC value combined with other clinicopathological indicators. MATERIALS AND METHODS: Sixty-one patients who underwent NAC for histopathologically confirmed breast cancer were enrolled in this retrospective study. The ADC values of different shrinkage patterns (concentric shrinkage, nest or dendritic shrinkage, and mixed shrinkage) for tumours shown by diffusion-weighted imaging (DWI) were measured independently using three ROI placement methods (single-round, three-round, and freehand). Intraclass correlation coefficients (ICCs) were used to assess the interobserver variability in the ADC values. Multivariate logistic regression analysis was performed to identify the independent predictors of PCR. RESULTS: The best placement method found was single-round ROI in all the patients (AUC=0.863). When analysed separately, the effectiveness results differed: the single-round method was optimal for concentrically shrinking tumours (AUC=0.970); the freehand method was optimal for nest or dendritically shrinking tumours (AUC=0.714); and the three-round method was optimal for mixed shrinking tumours (AUC=0.975). Multivariate logistic analysis showed that oestrogen receptor (ER), DeltaADC% and tumour diameter reduction (DeltaD%) were independent factors in evaluating the PCR. CONCLUSION: The methods for measuring ADC values vary across different shrinkage patterns of luminal tumours. DeltaADC%, ER and DeltaD% were independent factors for evaluating the PCR. PMID- 29970247 TI - Evaluation of a computer-aided detection (CAD)-enhanced 2D synthetic mammogram: comparison with standard synthetic 2D mammograms and conventional 2D digital mammography. AB - AIM: To evaluate the diagnostic performance of computer-aided detection (CAD) enhanced synthetic mammograms in comparison with standard synthetic mammograms and full-field digital mammography (FFDM). MATERIALS AND METHODS: A CAD-enhanced synthetic mammogram, a standard synthetic mammogram, and FFDM were available in 68 breast-screening cases recalled for soft-tissue abnormalities (masses, parenchymal deformities, and asymmetric densities). Two radiologists, blinded to image type and final assessment outcome, retrospectively read oblique and craniocaudal projections for each type of mammogram. The resulting 204 pairs of 2D images were presented in random order and scored on a five-point scale (1, normal to 5, malignant) without access to the Digital breast tomosynthesis (DBT) slices. Receiver operating characteristic (ROC) curve analysis was performed. RESULTS: There were 34 biopsy-proven malignancies and 34 normal/benign cases. Diagnostic accuracy was significantly improved for the CAD-enhanced synthetic mammogram compared to the standard synthetic mammogram (area under the ROC curve [AUC]=0.846 and AUC=0.683 respectively, p=0.004) and compared to the conventional 2D FFDM (AUC=0.724, p=0.027). The CAD-enhanced synthetic mammogram had the highest diagnostic accuracy for all soft-tissue abnormalities, and for malignant lesions sensitivity was not affected by tumour size. For all 68 cases, there was an average of 3.2 areas enhanced per image. For the 34 cancer cases, 97.4% of lesions were correctly enhanced, with 2.1 false areas enhanced per image. CONCLUSIONS: CAD enhancement significantly improves performance of synthetic 2D mammograms and also exhibits improved diagnostic accuracy compared to conventional 2D FFDM. PMID- 29970248 TI - Descriptive study of ultrasound images of the upper airway obtained after insertion of laryngeal mask. AB - OBJECTIVE: To evaluate clinical usefulness of ultrasound images of the upper airway in order to check correct laryngeal mask placement. MATERIAL AND METHODS: A prospective observational study was conducted on patients scheduled for abdominal surgery under general anaesthesia, in whom the patency of the upper airway was ensured using an Ambu(r)AuraGainTM laryngeal mask. An ultrasound scan was performed of the upper-airway in the cranio-caudal direction and with longitudinal scans in the anterior midline and parasagittal axis, in three moments: before, after inserting and after removing the mask. All recorded images were evaluated in a second time by a radiologist-expert in upper airway ultrasound. Subsequently, the ultrasound data were related to the clinical difficulty of the insertion and presence of air leaks. RESULTS: Data was collected from 30 patients (20 females and 10 males) being operated on for abdominal hysterectomy (15), eventroplasty (6), uterine myomectomy (3), and umbilical (4) and inguinal herniorrhaphy (2). The blind insertion of the masks did not present difficulties in 24 (80%) patients. Air leakage was detected in 8 (26.7%) patients, which was moderate in 7 cases and severe in one of them. The ultrasound findings confirmed good mask placement in 22 (73.3%) patients. Anatomical airway changes after laryngeal mask extraction were only observed in 3 (12%) patients, all of them minor. There was a statistically significant association (P<.05) between difficulty in inserting the device and the level of air leakage. CONCLUSIONS: Upper airway ultrasound is a useful diagnostic method to evaluate laryngeal mask placement. Laryngeal oedema was not observed after removal of the device. PMID- 29970249 TI - Parent reported long-term quality of life outcomes in children after congenital diaphragmatic hernia repair. AB - PURPOSE: The aim of this study was to determine long-term outcomes for congenital diaphragmatic hernia (CDH) patients including quality of life (QoL), symptom burden, reoperation rates, and health status. METHODS: A chart review and phone QoL survey were performed for patients who underwent CDH repair between 2007 and 2014 at a tertiary free-standing children's hospital. Comprehensive outcomes were collected including subsequent operations and health status. Associations with QoL were tested using Wilcoxon Rank-Sum tests and Pearson correlation coefficients. RESULTS: Of 102 CDH patients identified, 46 (45.1%) patient guardians agreed to participate with mean patient age of 5.8 (SD, 2.2) years at time of follow-up. Median PedsQLTM and PedsQLTM Gastrointestinal scores were 91.8 (IQR, 84.8-95.8) and 95.8 (IQR, 93.0-98.2), out of 100. Thoracoscopic repair was associated with higher PedsQLTM scores while defects with an intrathoracic stomach were associated with increased gas and bloating. No difference in QoL was found when comparing defect side, patch vs primary repair, prenatal diagnosis, extracorporeal membrane oxygenation, or recurrence. Older age weakly correlated with worse school functioning and heartburn. CONCLUSION: Children with CDH have reassuring QoL scores. Given the correlation between older age and poor school function, longer follow-up of patients with CDH may be warranted. LEVEL OF EVIDENCE: III (Retrospective comparative study). PMID- 29970250 TI - Potentially harmful microalgae and algal blooms in the Red Sea: Current knowledge and research needs. AB - Harmful algal blooms (HABs) have increased throughout the world's coastal oceans during the last century mostly due to water eutrophication and climate change. These blooms are often accompanied by extreme extensive negative impacts to fisheries, coastal resources, public health and local economies. However, limited studies have reported HAB events in Red Sea coastal waters. This article reviews potentially harmful microalgae in the Red Sea, based on available published information during the last 3 decades. Five harmful algal blooms were recorded in the Red Sea; of which 3 blooms are formed by dinoflagellates (Noctiluca scintillans, Pyrodinuium bahamense, Protoperidinium quinquecorne), one by raphidophytes (Heterosigma akashiwo) and one by cyanobacteria (Trichodesmium erythraeum). Additionally, mangrove swamps in the Red Sea were occupied by cyanobacterial mats, which contain microcystin and saxitoxin-producing species. The existing data in this review could be a catalyst for the establishment of monitoring and management program for HABs and their toxins in Red Sea coastal waters. This review also identifies current research gaps and suggests future research directions. PMID- 29970251 TI - Research gaps of coral ecology in a changing world. AB - Coral reefs have long inspired marine ecologists and conservationists around the world due to their ecological and socioeconomic importance. Much knowledge on the anthropogenic impacts on coral species has been accumulated, but relevant research gaps on coral ecology remain underappreciated in human-modified seascapes. In this review we assessed 110 studies on coral responses to five major human disturbances- acidification, climate change, overfishing, pollution and non-regulated tourism -to identify geographic and theoretical gaps in coral ecology and help to guide further researches on the topic. We searched for papers in Web of Science published from 2000 to 2016 and classified them according to the ocean, ecoregion, human threat, level of biological organization, study approach, method of data collection, depth of data collected, and type of coral response. Most studies were carried out in the Indo-Pacific and Caribbean (36.3 and 31.9%, respectively) and used observational approach (60%) with scuba diving (36.3%) to assess the impact of ocean warming (55.4%) on coral communities (58.2%). Only 37 of the 141 global ecoregions that contain coral reefs were studied. All studies were restricted to shallow waters (0.5-27 m depth) and reported negative responses of corals to human disturbance. Our results reinforce the notion that corals are sensitive to anthropogenic changes. They reveal the scarcity of information on coral responses to pollution, tourism, overfishing and acidification, particularly in mesophotic ecosystems (>30 m depth) and in ecoregions outside the Indo-Pacific and Caribbean. Experimental studies at the individual and population levels should be also encouraged. PMID- 29970252 TI - Clear cell sarcoma of the gastrointestinal tract and malignant gastrointestinal neuroectodermal tumour: distinct or related entities? A review. AB - Clear cell sarcoma is an uncommon sarcoma which rarely occurs as a primary tumour in the gastrointestinal tract (CCS-GIT). It shares common molecular genetic abnormalities with the more recently described entity, malignant gastrointestinal neuroectodermal tumour (GNET) but is distinguished by its morphological and immunohistochemical findings. The exact nosological relationship between these tumours continues to be debated. In this review, we present two cases of these rare neoplasms from our files and perform a statistical comparison of all published cases to determine if significant differences exist in their clinicopathological features and biological behaviour. Thirteen cases of CCS-GIT and 58 of GNET were included. CCS-GIT occurred more commonly in males (84.6% vs 46.6%, p = 0.01) and in an older age group (median 57 vs 33 years, p < 0.01). There was no significant difference in their location in the gastrointestinal tract, median tumour size and proportion of cases with an EWSR1-ATF1 vs EWSR1 CREB1 fusion. Median survival for CCS-GIT was 13.5 months and for GNET, 9.5 months (p = 0.78). There was no significant difference in the Kaplan-Meier survival curves for either time to first metastasis (p = 0.88) or overall survival (p = 0.18), including after controlling for tumour size using regression models. Our analysis confirms that aside from morphological variations between these tumours, they also exhibit epidemiological and clinical differences. Despite the prevalent perception that GNET is associated with a more aggressive clinical course, our findings indicate that there is no significant difference in their biological behaviour, although both clearly share a bleak prognosis. Further experience is awaited to determine optimal treatment strategies and whether CCS-GIT and GNET would differ in their response to various therapies. PMID- 29970253 TI - Leptin and its receptor: can they help to differentiate chromophobe renal cell carcinoma from renal oncocytoma? AB - One of the challenges in differentiating chromophobe renal cell carcinoma (chRCC) from benign renal oncocytoma (RO) is overlapping morphology between the two subtypes. The aim of this study was to investigate the usefulness of expression of leptin (Ob) and its receptor (ObR) in discriminating chRCC from RO. Sections from paraffin-embedded, formalin-fixed tumour nephrectomy specimens of 45 patients, made up of 30 chRCC (15 eosinophilic variant and 15 non-eosinophilic variant) and 15 RO, were used in this study. Samples (30) of clear cell RCC (ccRCC), the most common histological subtype, were used to verify staining patterns found by others in our cohort of Australasian patients. Matched morphologically normal non-cancer kidney tissues were included for each specimen. Sections were batch-immunostained using antibodies against Ob and ObR. Stained sections were digitally scanned using Aperio ImageScope, and the expression pattern of Ob and ObR was studied. In this cohort, male to female ratio was 2:1; median age was 64 (45-88 years); and median tumour size was 3.8 cm (range 1.2-18 cm). There were 47 (62.7%) T1, seven T2, 20 T3 and one T4 stage RCC. Two patients with ccRCC presented with metastases. Nuclear expression of Ob was significantly higher in RO compared with chRCC. The increased nuclear expression of Ob in RO compared with chRCC may be a useful aid in the difficult histological differentiation of RO from chRCC, especially eosinophilic variants of chRCC. PMID- 29970254 TI - Concentrating non-dilute urine before protein electrophoresis for the detection of monoclonal free light chains is unnecessary and wasteful. PMID- 29970255 TI - Performance of LDL-C calculated with Martin's formula compared to the Friedewald equation in familial combined hyperlipidemia. AB - BACKGROUND AND AIMS: A novel method to estimate low density lipoprotein cholesterol (LDL-C) has been proposed by Martin et al. This may permit a more accurate estimation of cardiovascular risk, however, external validation is needed. Here, the performance of LDL-C using this new method (LDL-N) is compared with LDL-C estimated with Friedewald equation (LDL-F) in familial combined hyperlipidemia (FCHL), a common primary dyslipidemia in which apolipoprotein B containing particle composition is abnormal and interferes with LDL-C estimation. METHODS: A total of 410 FCHL subjects were included. LDL-C was estimated with both the Friedewald equation (LDL-F) and the novel formula (LDL-N). Apolipoprotein B levels and non- HDL-C were recorded. The correlation and concordance between LDL-F and LDL-N and both Apolipoprotein B and non-HDL-C levels were calculated. Analysis stratifying for triglyceride tertiles and FCHL lipid phenotypes was also carried out. RESULTS: The correlations between LDL-N and Apo B and non-HDL-C were rho = 0.777 (95%CI 0.718-0.825) and rho = 0.735 (95%CI 0.648-0.816), respectively. The corresponding correlations for LDL-F were rho = 0.551(95%CI 0.454-0.637) and rho = 0.394 (95%CI 0.253-0.537), respectively. In mixed dyslipidemia or isolated hypertriglyceridemia, these correlations were significantly better using LDL-N. With respect to concordance, LDL-N performed significantly better than LDL-F when considering apoB <90 mg/dL (kappaLDL-N = 0.495 vs. kappaLDL-F = 0.165) and non-HDL-C <130 (kappaLDL-N = 0.724 vs. kappaLDL F = 0.253). CONCLUSIONS: In FCHL, LDL-C estimation using Martin's formula showed greater correlation and concordance with non-HDL-C and Apo B compared with the Friedewald equation. PMID- 29970256 TI - Ultrasound carotid plaque features, cardiovascular disease risk factors and events: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND AIMS: It is not known if ultrasound carotid plaque features are associated with cardiovascular disease (CVD) risk factors or if they predict future CVD events. METHODS: We measured total carotid plaque area (TPA) and grayscale plaque features (grayscale median, black areas, and discrete white areas) by B-mode carotid ultrasound among 2205 participants who participated in the first (baseline) visit of the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine relationships between ultrasound plaque features and CVD risk factors at baseline. Cox proportional hazards models were used to assess if TPA, grayscale features, and carotid plaque score (number of arterial segments with a plaque) could predict incident coronary heart disease and cerebrovascular disease events over a mean follow-up of 13.3 years. RESULTS: Participants were mean (standard deviation [SD]) 65.4 (9.6) years, 49% male, 39% White, 11% Chinese, 28% Black, and 22% Hispanic. Mean TPA 27.7 (24.7) mm2, but no grayscale plaque features, was associated with CVD risk factors. In fully adjusted models, TPA but no grayscale features predicted incident coronary heart disease (CHD) events (HR 1.23; 95%CI 1.11-1.36; p<0.001), however, C-statistics for CHD were similar to carotid plaque score but less than for coronary artery calcium (CAC) scoring. Neither TPA nor grayscale features independently predicted cerebrovascular events. CONCLUSIONS: In middle-aged adults free of known cardiovascular disease, TPA but not grayscale plaque features was associated with CVD risk factors and predicted incident CHD events. For CHD, prediction indices for TPA were similar to carotid plaque score but less than for CAC. PMID- 29970257 TI - Effect of dietary cation-anion difference on acid-base status and dry matter intake in dry pregnant cows. AB - The objective was to determine if the reduction in dry matter (DM) intake of acidogenic diets is mediated by inclusion of acidogenic products, content of salts containing Cl, or changes in acid-base status. The hypothesis was that a decrease in intake is mediated by metabolic acidosis. Ten primigravid Holstein cows at 148 +/- 8 d of gestation were used in a duplicated 5 * 5 Latin square design. The dietary cation-anion difference (DCAD) of diets and acid-base status of cows were manipulated by incorporating an acidogenic product or by adding salts containing Cl, Na, and K to the diets. Treatments were a base diet (T1; 1.42% K, 0.04% Na, 0.26% Cl; DCAD = 196 mEq/kg); the base diet with added 1% NaCl and 1% KCl (T2; 1.83% K, 0.42% Na, 1.23% Cl; DCAD = 194 mEq/kg); the base diet with added 7.5% acidogenic product, 1.5% NaHCO3, and 1% K2CO3 (T3; 1.71% K, 0.54% Na, 0.89% Cl; DCAD = 192 mEq/kg); the base diet with added 7.5% acidogenic product (T4; 1.29% K, 0.13% Na, 0.91% Cl; DCAD = -114 mEq/kg); and the base diet with 7.5% acidogenic product, 1% NaCl, and 1% KCl (T5; 1.78% K, 0.53% Na, 2.03% Cl; DCAD = -113 mEq/kg). Periods lasted 14 d with the last 7 d used for data collection. Feeding behavior was evaluated for 12 h in the last 2 d of each period. Reducing the DCAD by feeding an acidogenic product reduced blood pH (T1 = 7.450 vs. T2 = 7.436 vs. T3 = 7.435 vs. T4 = 7.420 vs. T5 = 7.416) and induced a compensated metabolic acidosis with a reduction in bicarbonate, base excess, and partial pressure of CO2 in blood, and reduced pH and strong ion difference in urine. Reducing the DCAD reduced DM intake 0.6 kg/d (T1 = 10.3 vs. T4 = 9.7 kg/d), which was caused by the change in acid-base status (T2 + T3 = 10.2 vs. T4 + T5 = 9.6 kg/d) because counteracting the acidifying action of the acidogenic product by adding salts with strong cations to the diet prevented the decline in intake. The decline in intake caused by metabolic acidosis also was observed when adjusted for body weight (T2 + T3 = 1.75 vs. T4 + T5 = 1.66% BW). Altering the acid-base status with acidogenic diets reduced eating (T2 + T3 = 6.7 vs. T4 + T5 = 5.9 bouts/12 h) and chewing (T2 + T3 = 14.6 vs. T4 + T5 = 13.5 bouts/12 h) bouts, and extended meal duration (T2 + T3 = 19.8 vs. T4 + T5 = 22.0 min/meal) and intermeal interval (T2 + T3 = 92.0 vs. T4 + T5 = 107.7 min). Results indicate that reducing the DCAD induced a compensated metabolic acidosis and reduced DM intake, but correcting the metabolic acidosis prevented the decline in DM intake in dry cows. The decrease in DM intake in diets with negative DCAD was mediated by metabolic acidosis and not by addition of acidogenic product or salts containing Cl. PMID- 29970258 TI - Characterization and identification of surface crystals on smear-ripened cheese by polarized light microscopy. AB - Surface crystallization and radial demineralization of Ca, P, and Mg occur in smear-ripened cheese. Furthermore, crystals of ikaite, struvite, calcite, and brushite have been identified in cheese smears by powder X-ray diffractometry (PXRD), and ikaite and struvite exist in smears as single crystals. Polarized light microscopy (PLM) is a simple, inexpensive, and well-established method in geology to detect and identify single crystals. However, use of PLM to identify cheese crystals has not been reported previously. The specific objectives of this research were (1) to identify crystals in cheese smears using selected PLM criteria; (2) to compare identification by PLM against PXRD; and (3) to develop and evaluate a novel treatment for smear material to improve crystal analyses by both PLM and PXRD. Duplicate wheels of 4 cheeses produced by different manufacturers were obtained from retail sources. Scrapings of surface smears were prepared and analyzed by PLM and PXRD by previously described methods. Crystals were categorized by PLM based on angle of extinction (AE), birefringence behavior under crossed polarizers and quartz filters, and size and shape (circularity) by image analysis. Crystals observed by PLM fell almost exclusively into 2 readily differentiated groups based on birefringence behavior and estimated angle of extinction. Group 1 (n = 18) were highly birefringent with AE = 88-92 degrees , whereas group 2 (n = 28) had no birefringence with AE = 13-26 degrees . Group 2 crystals were significantly larger and more circular than group 1 crystals. Group 1 and 2 were identified as struvite and ikaite, respectively, based on known birefringence and AE characteristics. Struvite was identified in all 4 cheeses by PLM but in only 3 cheeses by PXRD. Ikaite was identified in 3 cheeses by PLM but in only 2 cheeses by PXRD. These discrepancies occurred because the smear scrapings from 1 cheese contained excessive amorphous matter that caused extreme background noise, potentially obscuring diffractogram peaks that may have been present. To minimize noise, smear scrapings were dispersed in aqueous NaOH (pH 10) before analyses, which resulted in consistent results by PXRD and PLM. The method also rendered high-quality images by PLM. Data suggest that PLM may offer a simple and inexpensive means to identify struvite, ikaite, and possibly other single crystals in cheese smears. PMID- 29970259 TI - Fully automated, multi-criterial planning for Volumetric Modulated Arc Therapy - An international multi-center validation for prostate cancer. AB - BACKGROUND AND PURPOSE: Reported plan quality improvements with autoplanning of radiotherapy of the prostate and seminal vesicles are poor. A system for automated multi-criterial planning has been validated for this treatment in a large international multi-center study. The system is configured with training plans using a mechanism that strives for quality improvements relative to those plans. MATERIAL AND METHODS: Each of the four participating centers included thirty manually generated clinical Volumetric Modulated Arc Therapy prostate plans (manVMAT). Ten plans were used for autoplanning training. The other twenty were compared with an automatically generated plan (autoVMAT). Plan evaluations considered dosimetric plan parameters and blinded side-by-side plan comparisons by clinicians. RESULTS: With equivalent Planning Target Volume (PTV) V95%, D2%, D98%, and dose homogeneity autoVMAT was overall superior for rectum with median differences of 3.4 Gy (p < 0.001) in Dmean, 4.0% (p < 0.001) in V60Gy, and 1.5% (p = 0.001) in V75Gy, and for bladder Dmean (0.9 Gy, p < 0.001). Also the clinicians' plan comparisons pointed at an overall preference for autoVMAT. Advantages of autoVMAT were highly treatment center- and patient-specific with overall ranges for differences in rectum Dmean and V60Gy of [-4,12] Gy and [ 2,15]%, respectively. CONCLUSION: Observed advantages of autoplanning were clinically relevant and larger than reported in the literature. The latter is likely related to the multi-criterial nature of the applied autoplanning algorithm, with for each center a dedicated configuration that aims at plan improvements relative to its (clinical) training plans. Large variations among patients in differences between manVMAT and autoVMAT point at inconsistencies in manual planning. PMID- 29970260 TI - Novel Therapeutic Targets for Managing Dyslipidemia. AB - Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in developed nations. Therapeutic modulation of dyslipidemia by inhibiting 3'-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is standard practice throughout the world. However, based on findings from Mendelian studies and genetic sequencing in prospective longitudinal cohorts from around the world, novel therapeutic targets regulating lipid and lipoprotein metabolism, such as apoprotein C3, angiopoietin-like proteins 3 and 4, and lipoprotein(a), have been identified. These targets may provide additional avenues to prevent and treat atherosclerotic disease. We therefore review these novel molecular targets by addressing available Mendelian and observational data, therapeutic agents in development, and early outcomes results. PMID- 29970261 TI - Ahmed glaucoma drainage implant surgery in the management of refractory uveitic glaucoma: Long-term follow up. AB - OBJECTIVE: To examine the long-term efficacy, safety and complications of Ahmed glaucoma drainage implant surgery in patients with refractory uveitic glaucoma. METHODS: Retrospective review of consecutive cases of patients with refractory uveitic glaucoma who underwent Ahmed glaucoma drainage implant surgery between 2004-2014. Demographic characteristics of the study population, visual acuity, intraocular pressure (IOP), number of antiglaucoma medications and operative and postoperative complications were recorded. Complete success was defined as IOP>=5 and <=18mmHg without any medication, as qualified success if IOP<=18mmHg with one or more medications. Patients with less than 12 months of follow-up were excluded. RESULTS: 21 patients (26 eyes) were included. The mean postoperative follow-up was 53.5+/-31 months. Eight eyes (30%) had at least one previously failed glaucoma surgery. IOP was reduced from a mean of 30.0mmHg to 14.0mmHg at the last follow-up visit (P<.001). The number of IOP-lowering medications was reduced from a median of 2.9 preoperatively to 1.1 at the last follow-up (P<.001). Overall, 7 eyes (27%) were classified as complete success, 13 eyes (50%) were considered as qualified success, and 6 eyes (23%) met the criteria for failure. The most common postoperative complication was hypertensive phase in 12 eyes (46%). Kaplan-Meier life-table analysis showed a cumulative probability of success after Ahmed glaucoma valve implantation of 65% at 84 months. CONCLUSIONS: Ahmed glaucoma drainage implant surgery may be considered a long-term effective and safety surgical option for patients with refractory uveitic glaucoma. PMID- 29970263 TI - Postoperative temporomandibular dysfunction in patients with fractures of the zygomatic complex: a prospective follow-up study. AB - The aim of this prospective follow-up study was to clarify the incidence and characteristics of dysfunction of the temporomandibular joint (TMJ) in patients treated surgically for fractures of the zygomatic complex. Patients were evaluated on presentation and six months after injury to assess the function of the masticatory system using the Helkimo index, which incorporates two complementary subindices: the subjective symptomatic (anamnestic) index (Ai) and the objective clinical dysfunction index (Di). Forty-five patients (12 women and 33 men, mean (range) age 44 (21-83)years) completed the study. Six patients developed subjective symptoms of dysfunction of the TMJ during follow-up, in four of whom they were severe. Clinical findings were noted in 38 patients but without significant association with subjective symptoms. Dysfunction of the TMJ is common six months after surgical treatment of a fracture of the zygomatic complex, and patients with such fractures should be evaluated for temporomandibular dysfunction during follow-up and referred for treatment when necessary. PMID- 29970262 TI - Surgical guide and CAD/CAM prebent titanium plate for sagittal split ramus osteotomy in the correction of mandibular prognathism. AB - This study was designed to introduce and evaluate the clinical use of a surgical guide and a CAD/CAM prebent titanium plate for sagittal split ramus osteotomy (SSRO) in the correction of mandibular prognathism. We studied 14 patients who had been diagnosed, and treated by bilateral SSRO with the guide, during the period July 2015-January 2016. Surface deviations of distal segments from simulation until the end of the operation were measured on a coloured map. Deviations of position and orientation of the condyle and proximal segment from before to after operation, and those from simulation until the end of the operation, were measured with a 3-dimensional vector. All patients were followed up for at least a year. The coloured map showed that the mean (SD) distances were 0.40 (0.25)mm between the simulated and postoperative distal segments. The 3 dimensional vector showed that the mean values of mediolateral, anteroposterior, and superior-inferior translations of the condyles were less than 1mm (p<0.02) from before the operation until the end, and from simulation to the end of the operation, and the mean value of pitching for proximal segments was less than 1 degrees (p<0.02) from simulation to the end of the operation. At the one year follow-up, the occlusions were stable. Based on accurate diagnosis and simulation, this guide takes the distal segment precisely to its planned position, and the condyle and proximal segment are well-controlled. This is a useful tool, which is comparatively easy to make and operate. PMID- 29970264 TI - Selfless Triage. PMID- 29970265 TI - Subclinical T cell-mediated liver transplant rejection: The jury is still out. PMID- 29970266 TI - Transcultural adaptation and validation of the Spanish-language version of ACTIVLIM in adults with inherited myopathies using the Rasch model. AB - INTRODUCTION: ACTIVLIM is an instrument for the measurement of activity limitations in patients with neuromuscular disorders. The aim of this study is to establish a transcultural adaptation and psychometric validation of the Spanish language version of ACTIVLIM in a sample of Spanish patients with inherited myopathies. PATIENTS AND METHOD: A Spanish-language version of ACTIVLIM was developed using the translation/back translation method. The questionnaire was administered to 135 patients with inherited myopathies. The psychometric properties of the questionnaire were assessed using the Rasch model. Floor and ceiling effects were estimated. Unidimensionality was evaluated with a principal component analysis of the residuals of the model, and using infit and outfit statistics. We estimated reliability with the person separation reliability index and invariance with differential item functioning. External construct validity was tested through correlation with the Brooke scale, the Vignos scale, the Functional Independence Measure scale, and floor-to-stand time. Test-retest reliability was evaluated with the intraclass correlation coefficient and differential item functioning. RESULTS: The psychometric analysis of the Spanish language version of ACTIVLIM demonstrated that floor effect was absent, although a modest ceiling effect was identified. The instrument displayed unidimensionality, good internal consistency, external construct validity, and good test-retest reliability. CONCLUSION: The Spanish-language version of ACTIVLIM is a valid and reliable measurement nstrument for assessing activity limitations in patients with inherited myopathies. PMID- 29970267 TI - Higher than ... or lower than ....? Evidence for the validity of the extrapolation of laboratory toxicity test results to predict the effects of chemicals and ionising radiation in the field. AB - Single species laboratory tests and associated species sensitivity distributions (SSDs) that utilise the resulting data can make a key contribution to efforts to prospective hazard assessments for pesticides, biocides, metals and ionising radiation for research and regulatory risk assessment. An assumption that underlies the single species based toxicity testing approach when combined in SSD models is that the assessments of sensitivities to chemical and ionising radiation measured across a range of species in the laboratory can inform on the likely effects on communities present in the field. Potential issues with the validity of this assumption were already recognised by Van Straalen and Denneman (1989) in their landmark paper on the SSD methodology. In this work, they identified eight major factors that could potentially compromise the extrapolation of laboratory toxicity data to the field. Factors covered a range of issues related to differences in chemistry (e.g. bioavailability, mixtures); environmental conditions (optimal, variable), ecological (compensatory, time scale) and population genetic structure (adaptation, meta-population dynamics). This paper outlines the evidence pertaining to the influence of these different factors on toxicity in the laboratory as compared to the field focussing especially on terrestrial ecosystems. Through radiological and ecotoxicological research, evidence of the influence of each factor on the translation of observed toxicity from the laboratory to field is available in all cases. The importance of some factors, such as differences in chemical bioavailability between laboratory tests and the field and the ubiquity of exposure to mixtures is clearly established and has some relevance to radiological protection. However, other factors such as the differences in test conditions (optimal vs sub-optimal) and the development of tolerance may be relevant on a case by case basis. When SSDs generated from laboratory tests have been used to predict chemical and ionising radiation effects in the field, results have indicated that they may often seem to under-predict impacts, although this may also be due to other factors such as the effects of other non-chemical stressors also affecting communities at polluted sites. A better understanding of the main factors affecting this extrapolation can help to reduce uncertainty during risk assessment. PMID- 29970268 TI - Is cardiovascular magnetic resonance measurement of diffuse fibrosis ready for clinical use in the systemic RV? PMID- 29970269 TI - ABCA3 Deficiency in a Newborn with Respiratory Failure. PMID- 29970270 TI - Early diagnosis of atrial fibrillation using a E-health application. PMID- 29970271 TI - Shark Related Injuries: A Case Series of Emergency Department Patients. AB - INTRODUCTION: Shark-related-injuries (SRIs) are not thoroughly evaluated in the medical literature given their rare occurrence. Previous studies involve the utilization of large-independent databases and have demonstrated that shark attacks appear to be increasing, even though mortality of SRIs has decreased from 51% in 1958 to 8.3% in 2001. METHODS: We performed a retrospective chart review on patients presenting to 10 emergency departments (ED) in southeastern Virginia from February 22, 2008 through December 31, 2016. We used a free-text search feature to identify patients documented to have the word "shark" in the record. We reported descriptive statistics for patient demographics, disposition, mortality, time of injury, body injury location, activity during injury, injury severity score (ISS), antibiotic use, and if the patient was in the International Shark Attack File(ISAF) or the Global Shark Attack File(GSAF). RESULTS: We identified 11 patients. Most patients were male (81.8%) and Caucasian (90.9%) with a mean age of 35 years old (SD = 13.4, range17-55). Most patients (72.7%) arrived to the ED by private vehicle. Seventy-eight percent of patients were safely discharged from the ED. There were no deaths. There was a bimodal distribution of the time of injury around noon and early evening. Only 1 of our patients was present in the GSAF and 4 were present in the ISAF. CONCLUSION: Most SRIs can be safely evaluated, treated, and discharged from the ED. Utilization of large databases for shark related research may underestimate its prevalence in the US. Further research is needed into the care of SRIs in the ED. PMID- 29970272 TI - Machine learning approaches for predicting disposition of asthma and COPD exacerbations in the ED. AB - OBJECTIVE: The prediction of emergency department (ED) disposition at triage remains challenging. Machine learning approaches may enhance prediction. We compared the performance of several machine learning approaches for predicting two clinical outcomes (critical care and hospitalization) among ED patients with asthma or COPD exacerbation. METHODS: Using the 2007-2015 National Hospital and Ambulatory Medical Care Survey (NHAMCS) ED data, we identified adults with asthma or COPD exacerbation. In the training set (70% random sample), using routinely available triage data as predictors (e.g., demographics, arrival mode, vital signs, chief complaint, comorbidities), we derived four machine learning-based models: Lasso regression, random forest, boosting, and deep neural network. In the test set (the remaining 30% of sample), we compared their prediction ability against traditional logistic regression with Emergency Severity Index (ESI, reference model). RESULTS: Of 3206 eligible ED visits, corresponding to weighted estimates of 13.9 million visits, 4% had critical care outcome and 26% had hospitalization outcome. For the critical care prediction, the best performing approach- boosting - achieved the highest discriminative ability (C-statistics 0.80 vs. 0.68), reclassification improvement (net reclassification improvement [NRI] 53%, P = 0.002), and sensitivity (0.79 vs. 0.53) over the reference model. For the hospitalization prediction, random forest provided the highest discriminative ability (C-statistics 0.83 vs. 0.64) reclassification improvement (NRI 92%, P < 0.001), and sensitivity (0.75 vs. 0.33). Results were generally consistent across the asthma and COPD subgroups. CONCLUSIONS: Based on nationally representative ED data, machine learning approaches improved the ability to predict disposition of patients with asthma or COPD exacerbation. PMID- 29970273 TI - Observer reproducibility of breast strain elastography in data acquisition and interpretation: A methodological issue. PMID- 29970274 TI - Complex endovascular aneurysm repair is associated with higher perioperative mortality but not late mortality compared with infrarenal endovascular aneurysm repair among octogenarians. AB - OBJECTIVE: As our collective experience with complex endovascular aneurysm repair (EVAR) has grown, an increasing number of older patients are being offered endovascular repair of juxtarenal aneurysms. Outcomes after complex EVAR in this older subpopulation are not well-described. We sought to specifically evaluate clinical outcomes after complex EVAR compared with infrarenal EVAR in a cohort of octogenarians. METHODS: A single-center retrospective review was conducted using a database of consecutive patients treated with elective EVAR for abdominal aortic aneurysms (AAAs) between 2009 and 2015. Only patients 80 years of age or older were included. Patients in the complex EVAR group were treated with either snorkel/chimney or fenestrated techniques, whereas infrarenal EVAR consisted of aneurysm repair without renal or visceral involvement. Relevant demographic, anatomic, and device variables, and clinical outcomes were collected. RESULTS: There were 103 patients (68 infrarenal, 35 complex) treated within the study period with a mean follow-up of 21 months. A total of 75 branch grafts were placed (59 renal, 11 celiac, 5 superior mesenteric artery) in the complex group, with a target vessel patency of 98.2% at latest follow-up. Patients undergoing complex EVAR were more likely to be male (82.8% vs 60.2%; P = .02) and have a higher prevalence of renal insufficiency (71.4% vs 44.2%; P = .008). The 30-day mortality was significantly greater in patients treated with complex EVAR (8.6% vs 0%; P = .03). There were no differences in major adverse events (P = .795) or late reintervention (P = .232) between groups. Interestingly, sac growth of more than 10 mm was noted to be more frequent with infrarenal EVAR (17.6% vs 2.8%; P = .039). However, both type IA (5.7% infrarenal; 4.9% complex) and type II endoleaks (32.3% infrarenal; 25.7% complex) were found to be equally common in both groups. Complex EVAR was not associated with increased all-cause mortality at latest follow-up (P = .322). Multivariable Cox modeling demonstrated that AAAs greater than 75 mm in diameter (hazard ratio; 4.9; 95% confidence interval, 4.6 48.2) and renal insufficiency (hazard ratio, 3.71; 95% confidence interval, 1.17 11.6) were the only independent risk factors of late death. CONCLUSIONS: Complex EVAR is associated with greater perioperative mortality compared with infrarenal EVAR among octogenarians. However, late outcomes, including the need for reintervention and all-cause mortality, are not significantly different. Larger aneurysms and chronic kidney disease portends greater risk of late death after EVAR, regardless of AAA complexity. These patient-related factors should be considered when offering endovascular treatment to older patients. PMID- 29970275 TI - Corrigendum to "Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia" [Clin. Neurol. Neurosurg. 168 (May) (2018) 60-63]. PMID- 29970276 TI - Estradiol-17beta and testosterone levels during the annual reproductive cycle of in Mytilus coruscus. AB - The aim of the study was to examine seasonal variations in the estradiol-17beta (E2) and testosterone (T) levels in the gonad of Mytilus coruscus in relation to the reproductive cycle. M. coruscus individuals were obtained from March 2012 to February 2013 and gonadal tissue was studied by histological analysis and transmission electron microscopy. Histological data revealed that gametogenesis occurs from autumn to winter (i.e., from September to January) when the water temperature is lower than the rest of the year, and spawning occurs in spring (i.e., March onwards). In this study, we used enzyme-linked immunosorbent assay (ELISA) to measure the estradiol (E2) and testosterone (T) concentrations in Mytilus coruscus. The E2 level ranged from 109.59 to 412.31 pg/g wet weight and from 81.45 to 356.05 pg/g wet weight throughout the year. Furthermore, there was a positive correlation between the E2 level and mean oocyte diameter during the study period, indicating that E2 plays a role in sexual maturation in M. coruscus females and males. Thus, E2 and T may be endogenous modulators in sex determination and in the development and maturation of M. coruscus. PMID- 29970280 TI - Diagnostic approach to fetal microcephaly. AB - : Microcephaly in utero is conventionally defined as a fetal head circumference (HC) 3SD below the mean for gestational age according to Jeanty et al.'s reference range. Prediction of microcephaly at birth (micB) based on conventional prenatal biometry is associated with a high percentage of false positive diagnoses and as a result, in countries in which it is an option, termination of pregnancy may be offered in cases that would have culminated in birth of a normocephalic child. A false negative diagnosis is rarer, but may lead to the birth of a symptomatic microcephalic child. In this review we present the results of our recent studies aimed at improvement of accurate prenatal detection of microcephaly including: (1), application of two new reference ranges for fetal HC in cases with a prenatal diagnosis of microcephaly based on the conventional reference; (2) assessment whether integration of additional parameters (stricter fetal HC cut-offs, small-for-gestational age (SGA), decreased HC/abdominal circumference and HC/femur length ratios, presence of associated malformations and family history) can improve prediction; (3), estimation of the difference between Z-scores of prenatal HC and the corresponding occipitofrontal circumference (OFC) at birth in order to propose an adjustment for better prediction of the actual OFC deviation at birth; (4), assessment whether micB diagnosis can be improved by accurate detection of false positive Fmic cases whose small HC is due to an acrocephalic-like head deformation by applying a new reference range of a vertical measurement of the fetal head: foramen magnum-to cranium distance (FCD). The conventional and new reference ranges for fetal HC, all result in considerable over-diagnosis of fetal microcephaly (ranging from 43% to 33%). The use of the new references does not significantly improve micB prediction compared with the conventional one, whilst integrating additional parameters results in a better positive predictive value (PPV), but an increase in false negatives. The degree of Fmic severity is significantly over-estimated compared to the corresponding micB. The difference between the postnatal OFC deviation from the mean and the prenatal HC ranges from -0.74 SD to -1.95 SD for various fetal HC references. Application of the reference range for vertical cranial dimensions enables exclusion of fetuses with a small HC associated with a vertical cranial deformity without missing those with actual micB. Combining the fetal HC with the developed FCD criteria raised the PPV of micB to 78%. CONCLUSIONS: Prediction of micB can be improved by integrating additional parameters and by application of the FCD criteria, however the correct diagnosis of Fmic remains challenging. An algorithm for evaluation of fetal microcephaly is provided. PMID- 29970281 TI - A brother and sister with intellectual disability and characteristic neuroimaging findings. AB - Leukoencephalopathy with brain calcifications and cysts (LCC) is a genetic white matter disorder, which involves the brain small blood vessels. In the absence of extra-neurological symptoms, LCC has a pathognomonic radiological phenotype. Recently, biallelic mutations in the SNORD118 gene, which is a non-protein coding gene, were discovered to cause LCC. We present here two siblings with developmental delay and a typical MRI pattern, who were diagnosed with LCC. The mutations in the SNORD118 gene were initially missed with whole exome sequencing (WES), but recognition of the MRI patterns of both children raised the suspicion of LCC and led to a genetically proven diagnosis after re-evaluation of the WES data. PMID- 29970283 TI - Analysis of lead and cadmium in cereal products and duplicate diets of a small group of selected Brisbane children for estimation of daily metal exposure. AB - Exposure to toxic metals such as lead (Pb) and cadmium (Cd) from foods is a concern for young children. The aims of the study were to analyse the levels of Pb and Cd in breakfast cereals, rice products and diets of selected children, and to estimate the daily intakes of Pb and Cd in these children. The samples (n = 82) of ready-to-eat breakfast cereals and rice products (n = 36) were collected and obtained from various markets in Brisbane, Australia. The samples for a duplicate diet study were collected for 3 consecutive days from normal healthy children (n = 15). The analysis was performed using ICP-MS after microwave digestion. The levels of Pb and Cd found in breakfast cereals and rice products ranged from <0.01 to 0.25 mg/kg for Pb and <0.01 to 0.11 mg/kg for Cd. The estimated daily intakes of Pb and Cd in children varied widely and ranged from 0.90 to 11.7 (5.6 +/- 3.5 MUg/day) for Pb and 0.98 to 9.5 (4.0 +/- 2.2 MUg/day) for Cd. The study shows low intakes of Pb and Cd in children. PMID- 29970284 TI - Accuracy of 3D reproduction of natural head position using three different manual reorientation methods compared to 3D software. AB - PURPOSE: The aim of this study was to analyze the positional differences of three dimensional (3D) natural head positions (NHPs) reproduced by three different manual reorientation methods without special software by the Pose from Orthography and Scaling with ITerations (POSIT) method. METHODS: Five ceramic markers were attached to each of 12 patients' faces, and frontal and lateral photographs in the NHP and 3D computed tomography (CT) were taken. The 3D surface model was reoriented for the NHP reproduction by four different methods: the POSIT method (standard method), the location of the markers (A), the soft tissue landmarks (B) on the photographs, and manual correction without photographs (C). On each 3D surface model, the location of the skull was evaluated three dimensionally. RESULTS: Differences between reproduced NHPs in each of the four different methods were statistically significant (p < 0.0001). Compared to the POSIT method, the accuracy of the other reproducing methods was lower. The A and B methods showed a similar accuracy to each other, while the C method presented the most inaccurate NHP. CONCLUSION: If 3D NHP reproduction using special software is impossible, reproducing NHP with photographs may be used as an alternative method, but its application should be clinically limited. PMID- 29970285 TI - Dental consequences of pterygomaxillary dysjunction during fronto-facial monobloc advancement with internal distraction for Crouzon syndrome. AB - Crouzon syndrome is a syndromic faciocraniosynostosis that can be associated with severe fronto-facial retrusion leading to major functional impairments: extreme exorbitism may be vision-threatening and severe respiration impairment can be life-threatening. The procedure of choice for the primary correction of this retrusion is fronto-facial monobloc advancement (FFMBA) with internal or external distraction. FFMBA involves pterygomaxillary dysjunction (PMD), using either a superior or an intra-oral approach. This step is at risk of damaging the germs of the decidual and permanent molars. Here we considered a series of 15 patients with Crouzon syndrome who benefited from FFMBA performed by the same surgeon, using a superior approach through the infra-temporal fossa for PMD. Based on pre operative, early post-operative and late post-operative CT-scans, we recorded missing teeth, morphological dental anomalies and the Nolla stage for the first and second permanent maxillary molars. We showed that early FFMBA has significant dental consequences, and that these dental effects are correlated with an early age at surgery. Although the indications of early FFMBA in Crouzon syndrome with severe functional repercussions are not questionable, our results should be compared to dental outcomes of FFMBA performed with an intra-oral PMD. PMID- 29970286 TI - Non-invasive imaging techniques and assessment of carotid vasa vasorum neovascularization: Promises and pitfalls. AB - Carotid adventitia vasa vasorum neovascularization (VVn) is associated with the initial stages of arteriosclerosis and with the formation of unstable plaque. However, techniques to accurately quantify that neovascularization in a standard, fast, non-invasive, and efficient way are still lacking. The development of such techniques holds the promise of enabling wide, inexpensive, and safe screening programs that could stratify patients and help in personalized preventive cardiovascular medicine. In this paper, we review the recent scientific literature pertaining to imaging techniques that could set the stage for the development of standard methods for quantitative assessment of atherosclerotic plaque and carotid VVn. We present and discuss the alternative imaging techniques being used in clinical practice and we review the computational developments that are contributing to speed up image analysis and interpretation. We conclude that one of the greatest upcoming challenges will be the use of machine learning techniques to develop automated methods that assist in the interpretation of images to stratify patients according to their risk. PMID- 29970282 TI - Actin-Based Cell Protrusion in a 3D Matrix. AB - Cell migration controls developmental processes (gastrulation and tissue patterning), tissue homeostasis (wound repair and inflammatory responses), and the pathobiology of diseases (cancer metastasis and inflammation). Understanding how cells move in physiologically relevant environments is of major importance, and the molecular machinery behind cell movement has been well studied on 2D substrates, beginning over half a century ago. Studies over the past decade have begun to reveal the mechanisms that control cell motility within 3D microenvironments - some similar to, and some highly divergent from those found in 2D. In this review we focus on migration and invasion of cells powered by actin, including formation of actin-rich protrusions at the leading edge, and the mechanisms that control nuclear movement in cells moving in a 3D matrix. PMID- 29970287 TI - Editorial commentary: To pace, or not to pace in vasovagal syncope? PMID- 29970289 TI - "Other" tags for "Self"-generated speech in patients with auditory verbal hallucinations, an fMRI study. PMID- 29970288 TI - Development of a relative potency test using ELISA for human rabies vaccines. AB - The NIH potency test for human rabies vaccines has disadvantages for use, especially in developing countries where rabies is endemic and prophylaxis needs ample, rapid, and reliable vaccine supplies. In China, 60-75 million doses of human rabies vaccines are administered each year. Vaccine quality control is of paramount importance, as is the release of potency-validated vaccines. We intended to design an alternative to the NIH in vivo method, and developed a relative potency test using an ELISA. Using Pearson's correlation analysis, we found a close relationship between the rabies vaccine glycoprotein content in vitro and the potency values in vivo. We suggest the relative potency test developed here as a simplified method for human rabies vaccine quality control in China and a possible alternative to the NIH method. PMID- 29970290 TI - Complete spontaneous regression of a metastatic melanoma of the mandible: a case report and follow-up recommendations. AB - Regression of metastatic melanoma is very rare and occurs in only 0.23% of cases. Metastasis to the oral cavity is particularly uncommon and accounts for only 1-3% of all oral malignancies. This report presents a case of spontaneous and complete regression of a metastatic melanoma in the mandibular ramus. The patient remains asymptomatic more than 2 years after diagnosis. The patient was followed up regularly. It is recommended that further surveillance imaging be performed in asymptomatic patients following discussion with the surgical and oncological teams. This type of surveillance, together with new systemic treatments, is advocated due to its potential to increase long-term survival even after relapse. PMID- 29970292 TI - Keratinophilic fungi from the vicinity of salt pan soils of Sambhar lake Rajasthan (India). AB - Forty soil samples were collected from seven sites in the vicinity of Sambhar lake Rajasthan, India and screened for the presence of keratinophilic fungi using hair baiting techniques for isolation. Seventeen isolates were recovered and identified. The cultures were identified by recognition of their macro- and micro morphological features. Their identification was confirmed by BLAST using ITS1 5.8S-ITS2 rDNA region and sequences have been deposited in NCBI data base. A total of 34 species belonging to 29 genera were isolated. Among the dermatophytes and related keratinophilic fungi Chrysosporium indicum was predominant followed by Ctenomyces serratus, C. tropicum, Keratinophyton durus, Auxarthron conjugatum, Gymnascella dankaliensis, Gymnoascoideus petalosporus and Uncinocarpus reesii. Twenty-six species belonging to 22 genera represented other species. Our study indicates that keratinophilic fungi and species are found in the soils at the vicinity of the Sambhar Lake, and human activities can be the potential source of pathogenic fungi. PMID- 29970291 TI - Piperlongumine inhibits neuroinflammation via regulating NF-kappaB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells. AB - Inflammatory processes in the central nervous system are feature among biological reactions to harmful stimuli such as pathogens and damaged cells. In resting conditions, microglia are involved in immune surveillance and brain homeostasis. However, the activation of abnormal microglia can be detrimental to neurons, even resulting in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease. Therefore, normalization of microglial activation is considered a promising strategy for developing drugs that can treat or prevent inflammation-related brain diseases. In the present study, we investigated the effects of piperlongumine, an active component of Piper longum, on lipopolysaccharide (LPS)-induced neuroinflammation using BV2 microglial cells. We found that piperlongumine significantly inhibited the production of nitric oxide and prostaglandin E2 induced by LPS. Piperlongumine also reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 as well as proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6. Piperlongumine exerted its anti-neuroinflammatory effects by suppressing the nuclear factor kappa B signaling pathway. These findings suggest that piperlongumine could be a candidate agent for the treatment of inflammation related neurodegenerative diseases. PMID- 29970293 TI - GRAND(ER) ROUNDS: Expanding the universe of topics and speakers in a pathology department seminar series. AB - This article reports on a unique pathology department seminar series that included talks on social science and humanities topics in addition to traditional biomedical subjects. The goals, achievements, and potential of such a series are addressed via review of selected speakers and topics. PMID- 29970294 TI - The mayo clinic model of clinical integration. AB - The multi-campus Academic Health Center (AHC) of the future will need to be system-based and committed to clinical integration to continue to meet institutional goals and serve the needs of its patients. The key tactics we describe to accomplish this are. PMID- 29970295 TI - Minimally-invasive temporary gastric stimulation: A pilot study to predict the outcome of electronic gastric stimulation with the EnterraTM system. AB - INTRODUCTION: Gastroparesis (GP) is defined as delayed gastric emptying (GE) without any obstruction of the pylorus. It can be divided into idiopathic, diabetic, post surgical and rare causes. Electronic gastric stimulation (EGS) - Enterra MedtronicTM - is a part of GP therapy. Although its positive impact has been reported in open label trials, randomized controlled trials failed in demonstrating a positive outcome. The aim of this pilot study was to establish a reliable prediction for permanent gastric stimulation. PATIENTS AND PROCEDURE: 6 female patients underwent laparoscopic implantation of 2 temporary electrodes. The EnterraTM system was connected and taped to the skin. Baseline and postoperative gastroparesis cardinal symptom index (GCSI), a validated index for GP therapy, was assessed. Response to EGS was defined as a 50% decrease of baseline GCSI. RESULTS: 4 of 6 patients responded to temporary EGS. 3 of 4 responders underwent permanent implantation. 1 non-responder received a permanent EnterraTM at another institution. After a median follow up time of 9months the responder group GCSI remained low, whereas the non-responder GCSI had increased. Moreover, the health care system was saved ? 30,678.03 by this test stimulation concept. CONCLUSION: Laparoscopic implantation of a temporary EGS system predicts the outcome of permanent gastric stimulation and is cost-saving. PMID- 29970296 TI - Drug Administration to the Wrong Nursing Home Residents Reported to the Quebec Poison Center: A Retrospective Study. AB - OBJECTIVE: This study examined the association between the administration of drugs to the wrong nursing home residents with a need for hospital treatment or as an indicator of mortality. DESIGN: A retrospective observational study of medical records from February 1, 2016, to January 31, 2017. SETTING: Calls made to the Quebec Poison Center. PARTICIPANTS: Nursing home residents aged >=65 years. INTERVENTION(S): Medication administered to the wrong resident. MAIN OUTCOME MEASURE(S): Death, hospital referral and treatment, number of drugs or type of drug classes. RESULTS: Of the 6282 calls received by the Quebec Poison Center concerning medication errors, 494 cases were included in the retrospective study. Half of the patients (51%) received at least 5 different drugs that were not prescribed for them. Most patients (82%) were asymptomatic at the time of the call to the poison center; however, a third (34%) of the exposures were considered potentially toxic and were treated at the hospital. The most prominent drug classes involved include antihypertensives, antiarrhythmics, and antipsychotics. In particular, almost a quarter (23%) of cases of clozapine maladministration resulted in moderate or severe effects. No deaths were reported. CONCLUSIONS/IMPLICATIONS: Medication errors in nursing homes are prevalent. The medical provider and probably the poison control center should be consulted as soon as possible when people are aware of administration of medication to the wrong patient, which is considered a medical emergency until proven otherwise. Public policies should seek for better surveillance and prompt intervention. Research should be undertaken to limit errors of drug administration to the wrong nursing home residents. PMID- 29970297 TI - Quercetin in collagen-induced arthritis. Some comments. PMID- 29970298 TI - Low-dose-rate brachytherapy for prostate cancer in renal transplant recipients. AB - PURPOSE: Prostate cancer (PCa) is the most common malignancy among men and one of the most common neoplasms affecting renal transplant recipients (RTRs). The available treatments for localized PCa among the general population (GP), surgery and external beam radiotherapy, carry a risk of damage to the transplanted kidney, the ureters, and the bladder and therefore tend to be avoided by most groups. The objective of this study was to assess the efficacy and feasibility of low-dose-rate brachytherapy (LDR-BT) for PCa in RTRs. METHODS AND MATERIALS: We carried out a retrospective review on all RTRs diagnosed of PCa who had undergone LDR-BT at our institution between 2000 and 2015. Nine patients met these criteria, but 1 did not fulfill the followup. Hence, we analyzed 8 patients. We reviewed all clinical data for PCa and graft function in these patients and compared the results with the GP. RESULTS: Mean baseline prostate-specific antigen was 6.8 +/- 1.9 ng/mL. All PCa had a Gleason score of 6 and were classified as low risk according the Europe Association of Urology guidelines. Mean followup after seed implantation was 48 +/- 12.8 months. All 8 patients remain free of prostate-specific antigen failure. Five-year progression-free survival, cancer-specific survival, and overall survival rates were 100%, 100%, and 62.5%. There was no specific toxicity associated with LDR-BT, and there were no acute adverse events affecting the graft. CONCLUSIONS: LDR-BT is a feasible and acceptable treatment for localized PCa in RTRs. Oncological outcomes are similar to the GP, and there is minimal toxicity to the renal graft. PMID- 29970299 TI - Hepatitis B vaccination coverage among health-care workers in Africa: A systematic review and meta-analysis. AB - OBJECTIVE: To estimate full hepatitis B vaccination coverage (uptake of >=3 doses of vaccine) among health-care workers (HCWs) in Africa. METHODS: We systematically searched the PubMed(r), Embase(r), CINAHL and Psych-Info databases for studies published from January 2010 to October 2017 that reported full hepatitis B vaccination coverage among HCWs in Africa. A random effects meta analysis was conducted to determine pooled estimates of full vaccination coverage. RESULTS: Of the 331 articles identified, 35 studies from 15 African countries met the inclusion criteria and were included in the review. The estimated full hepatitis B vaccination coverage was 24.7% (95% CI: 17.3-32.0). Regional coverage was highest in northern Africa (62.1%, 95% CI: 42.5-81.7) and lowest in central Africa (13.4%, 95% CI: 4.5-22.3). Doctors were more likely (OR: 2.6, 95% CI: 1.8-3.7) to be fully vaccinated than Nurses with estimated pooled estimates of 52.4% (95% CI: 31.1-73.8) and 26.3% (95% CI: 9.7-42.9), respectively. Also, HCWs with 10 or more years of experience were more likely to be vaccinated than those with less than 10 years of experience (OR: 2.2, 95% CI: 1.5-3.3). The common reasons identified for non-vaccination of HCWs were unavailability of vaccine 50.5% (95% CI: 26.5-74.4), busy work schedule 37.5% (95% CI: 12.6-62.4) and cost of vaccination 18.4% (95% CI: 7.1-29.7). CONCLUSION: The evidence available suggests that many HCWs in Africa are at risk of Hepatitis B infection as only a quarter of them were fully vaccinated against Hepatitis B virus. This study highlights the need for all African governments to establish and implement hepatitis B vaccination policies for HCWs. PMID- 29970300 TI - Midwives' perceptions of vaccines and their role as vaccinators: The emergence of a new immunization corps. AB - BACKGROUND: In France, midwives have recently been authorized to administer various vaccines to women (including pregnant women), newborns, and their family members. This is expected to enhance vaccine coverage. However, the French high level of vaccine hesitancy is also observed in some healthcare workers. We thus aimed to determine the perceptions of French midwives concerning vaccines. METHODS: We distributed an anonymous online questionnaire between September and December 2017, targeting midwives who were still in training or working in the public or private sector. RESULTS: A total of 917 questionnaires were analyzed (median age 26 years). Almost half of participants (44.5%) were students. On a scale of 0-100, the median perception of the usefulness, safety, and trust of vaccinations were 92, 80, and 85, respectively. The mean scores of students were significantly higher for each perception, whereas in professional midwives, age and perceptions were negatively correlated. When asked whether there were scientific, philosophical, or religious arguments not to vaccinate, 83.2%, 69.8%, and 77.8% of participants disagreed, respectively. The vast majority (91.6%) was very or mostly favorable to the pertussis vaccine after delivery, but only around half (51.5%) to the influenza vaccine during pregnancy; those favorable to the pertussis vaccine were younger. A high proportion of participants (88.3%) considered that midwives were in a good position to vaccinate, with this proportion being even higher among students. CONCLUSIONS: These results suggest that the recent authorization regarding vaccine administration will result in better vaccine coverage of pregnant women and their families by midwives. The better perceptions of younger participants are also encouraging. However, the level of trust in vaccinations (only 80.1%) and the low number of participants favorable to the influenza vaccine during pregnancy suggest that initial and continuous training should be reinforced. PMID- 29970302 TI - Flagellin-deficient outer membrane vesicles as adjuvant induce cross-protection of Salmonella Typhimurium outer membrane proteins against infection by heterologous Salmonella serotypes. AB - Salmonella enteric serovar infections result in high morbidity and mortality worldwide. Cross-protective vaccines are an effective strategy in controlling salmonellosis caused by multiple serotypes. In our previous study, outer membrane vesicles (OMVs) derived from flagellin-deficient Salmonella Typhimurium (S. Typhimurium) were proven effective in mediating cross-protection against infection by multiple Salmonella serotypes; OMVs also exhibit potent adjuvant effects. In this study, we further investigated the adjuvant capacities of flagellin-deficient S. Typhimurium OMVs. Our finding showed that outer membrane proteins (OMPs) in combination with flagellin-deficient S. Typhimurium OMVs could function as adjuvants and invoke stronger humoral, cellular, mucosal, and cross protective immune responses compared to conventional aluminum (alum). Furthermore, as an adjuvant, OMVs could induce significantly higher cellular immune responses and display enhanced cross-protection for OMPs against wild-type virulent Salmonella Choleraesuis and Salmonella Enteritidis challenge. In summary, OMVs function as a potent adjuvant with the capability of conferring greater cross-protection against infection by multiple Salmonella serotypes, and may be of great value as an effective vaccine adjuvant in enteric diseases. PMID- 29970301 TI - Advancing practice for back pain through stratified care (STarT Back). AB - BACKGROUND: Low back pain (LBP) is common, however research comparing the effectiveness of different treatments over the last two decades conclude either no or small differences in the average effects of different treatments. One suggestion to explain this is that patients are not all the same and important subgroups exist that might require different treatment approaches. Stratified care for LBP involves identifying subgroups of patients and then delivering appropriate matched treatments. Research has shown that stratified care for LBP in primary care can improve clinical outcomes, reduce costs and increase the efficiency of health-care delivery in the UK. The challenge now is to replicate and evaluate this approach in other countries health care systems and to support services to implement it in routine clinical care. RESULTS: The STarT Back approach to stratified care has been tested in the National Health Service, within the UK, it reduces unnecessary overtreatment in patients who have a good prognosis (those at low risk) yet increases the likelihood of appropriate healthcare and associated improved outcomes for those who are at risk of persistent disabling pain. The approach is cost-effective in the UK healthcare setting and has been recommended in recent guidelines and implemented as part of new LBP clinical pathways of care. This approach has subsequently generated international interest, a replication study is currently underway in Denmark, however, some lessons have already been learnt. There are potential obstacles to implementing stratified care in low-and-middle-income settings and in other high income settings outside of the UK, however, implementation science literature can inform the development of innovations and efforts to support implementation of stratified care. CONCLUSIONS: The STarT Back approach to stratified care for LBP is a promising method to advance practice that has demonstrated clinical and cost effectiveness in the UK. Over time, further evidence for both the effectiveness and the adaptations needed to test and implement the STarT Back stratified care approach in other countries is needed. PMID- 29970303 TI - Antimicrobial Stewardship: What We All Just Need to Know. AB - CONTEXT: Microbial resistance to antibiotics is increasing while antimicrobials are limited. Responsible use is necessary. OBJECTIVE: Describe the present acquisitions of antimicrobial stewardship programmes (ASPs) in general and in urology. EVIDENCE SYNTHESIS: Well-designed ASPs have an impact on reducing treatment duration, shortening intravenous treatment in favour of oral targeted therapy, and reducing the total antibiotic prescription. Moreover, the hospital length of stay can potentially be reduced without hazard for the patient. CONCLUSIONS: It is recommended to set up an ASP for education and feedback as standard in urological practice. The exact design of the ASP should be tailored to regional prerequisites. PMID- 29970304 TI - Corrigendum to "Sealing or infiltrating proximal carious lesions" [J. Dent. 74 (2018) 15-22]. PMID- 29970305 TI - An extremely rare case of primary malignancy in giant cell tumor of bone, arising in the right femur and harboring H3F3A mutation. AB - We experienced a case of primary malignancy in giant cell tumor of bone (GCTB), arising in the right femur and harboring H3F3A mutation. A 27-year-old Japanese male without any prior disease history complained of pain in his right hip joint and right lower limb. Radiological images revealed an osteolytic and multicystic lesion existing mainly at the proximal epiphysis of the right femur. Preoperative clinical diagnosis was GCTB, although irregular marginal sclerosis was an atypical radiographic finding for conventional GCTBs. Biopsy sample from the lesion revealed the coexistence of typical GCTB and undifferentiated high-grade round cell sarcoma. Despite of the wide local resection of the tumor with preoperative and postoperative chemotherapy, the patient died of multiple distant metastases of the tumor 9 months after the surgery. Since heterozygous H3F3A c. 103G>T (p. Gly34Trp) mutation was detected not only in the biopsy sample from the primary site with typical GCTB and high-grade sarcoma components but also in the resected material from the metastatic site with only pure high-grade sarcoma component, the tumor was considered originally derived from conventional GCTB and acquire malignant transformation to high-grade sarcoma. Thus, this is an extremely rare case of primary malignancy in GCTB and the first case report of primary malignancy in GCTB proved the presence of H3F3A mutation even in the sarcoma component. PMID- 29970306 TI - Subcellular localization and expression of E-cadherin and SNAIL are relevant since early stages of oral carcinogenesis. AB - The biological process of epithelial-to-mesenchymal transition (EMT) has been studied in oral squamous cell carcinoma (OSCC) metastasis, but it is rarely evaluated at several stages of oral carcinogenesis. This study aimed to analyze the presence of SNAIL and E-cadherin proteins, markers of EMT, in the development and progression of OSCC, evaluating excised specimens of potentially malignant lesions (oral leukoplakia with and without dysplasia-OL and OLD, respectively), tumor tissues (OSCC), metastatic lymph nodes (LN), and normal oral mucosa (NOM) by immunohistochemistry, considering subcellular localization. Additionally, SNAIL and E-cadherin transcripts were evaluated in vitro by qPCR, using SCC-9 cell line in comparison to human keratinocytes (HPEC). There was a significant increase in nuclear expression of SNAIL from NOM to OLD followed by a noticeable decrease in nuclear expression accompanied by increased cytoplasmic expression in OSCC (p<0.05). The E-cadherin cytoplasmic expression was remarkable and statistically significant higher in OSCC and LN, both compared to NOM (p< 0.0001), OL (p<0.01) and OLD (p< 0.0001 and p<0.001, respectively). In vitro, E cadherin and SNAIL transcripts were lower in SCC-9 compared to HPEC cells, although only the decrease of E-cadherin was statistically significant (p<0.05). Regarding the association of E-cadherin and SNAIL expression with the clinical findings, the analysis revealed an association between the cytoplasmic expression of SNAIL and the invasion pattern (p=0.05) in OSCC. The increased nuclear SNAIL expression may be characteristic of OLD, and the presence of E-cadherin in cell cytoplasm a marker of transformation to malignancy of potentially malignant oral leukoplakias into OSCC. PMID- 29970308 TI - Design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors with bicyclic isoxazoline carboxamides as the P3 ligand. AB - We describe the design, synthesis, X-ray studies, and biological evaluation of novel BACE1 inhibitors containing bicyclic isoxazoline carboxamides as the P3 ligand in combination with methyl cysteine, methylsulfonylalanine and Boc-amino alanine as P2 ligands. Inhibitor 3a displayed a BACE1 Ki value of 10.9 nM and EC50 of 343 nM. The X-ray structure of 3a bound to the active site of BACE1 was determined at 2.85 A resolution. The structure revealed that the major molecular interactions between BACE1 and the bicyclic tetrahydrofuranyl isoxazoline heterocycle are van der Waals in nature. PMID- 29970307 TI - Increased number of arginase 1-positive cells in the stroma of carcinomas compared to precursor lesions and nonneoplastic tissues. AB - Arginase 1 (Arg1) is involved in dampening the response of antitumor T lymphocytes. Arg1 expression has been reported in a variety of cancer cell lines and tumor-associated myeloid-derived cells. However, its examination in situ in tumor microenvironment is poorly investigated. We examined the Arg1-positive cells in tumor microenvironment of gastric carcinomas (GCs), colorectal carcinomas (CRCs) and prostate carcinomas (PCs), and analyzed their clinicopathological significance. Immunohistochemical staining for Arg1 was done in 60 GCs, 38 gastric adenomas, 40 CRCs, 10 colonic adenomas, 36 PCs, and 15 benign prostatic hyperplasia (BPH). Arg1 expression was predominantly localized in tumor microenvironment and the stroma of nonneoplastic tissues. Cells with Arg1 expression were mostly leukocytes, morphologically resembling polymorphonuclear neutrophils, and showed CD15 expression. Arg1 expression was focally expressed in cancer cells of 6 PCs, but not in those of GCs and CRCs. Arg1-positive cells were significantly more infiltrated in tumors than adenomas and nonneoplastic tissues, such as BPH, intestinal metaplasia and adjacent tissues. There were no significant findings between them and clinicopathological parameters, except for the relationship to gender and tumor differentiation in CRCs. These findings suggest that Arg1-positive cells in tumor microenvironment is involved in the occurrence of GCs, CRCs, and PCs. More expansive studies are necessary to better elucidate their clinicopathological significance in carcinomas. PMID- 29970309 TI - Highly selective anthraquinone-chalcone hybrids as potential antileukemia agents. AB - A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway. Treatment of K562 cells with each of these four compounds caused decrease in the expression levels of MMP2, MMP9, and VEGF, suggesting their anti-invasive, antimetastatic and antiangiogenic properties. The compounds 6g and 6v downregulated expression levels of miR-155 in K562 cells, while compounds 6e and 6u upregulated miR-155 levels in treated cells, in comparison with control cells. The structure-based 3-D QSAR models for 6f, 6e, 6i and 6l describe pro-apoptotic activity against caspase-3. PMID- 29970310 TI - Establishing a Europe-wide foundation for high quality midwifery education: The role of the European Midwives Association (EMA). AB - A cornerstone of European policy involves freedom of movement of individuals between member countries, which applies equally to those who use and provide maternity care. To promote and support safe, high quality maternity care, minimum standards for midwifery education and practice have been published, including Directives EEC/80/154 and EEC/80/155 which support the recognition of professional qualifications. These Directives established a minimum standard for midwifery education, including the duration and content of theoretical and practical education. Annex V of the Directives established a framework of professional activities to define and guide the scope of midwifery practice in EU member countries. The Directives were updated in 2013, with the European Midwives Association (EMA) an important partner in this process. While the degree of implementation of the Directives at individual country level varies, EMA has an ongoing role in ensuring, promoting and advancing high quality midwifery education and practice throughout the EU. PMID- 29970311 TI - Funding Support and Principal Investigator Leadership of Oncology Clinical Trials Using Radiation Therapy. AB - PURPOSE: Sources of funding and principal investigator (PI) leadership for clinical trials using radiation therapy (RT) are not well characterized but are important mediators of innovation, particularly because funding for trials from the National Institutes of Health (NIH) has decreased and industry funding has increased. We sought to determine characteristics of trials using RT that are associated with industry funding, NIH funding, and radiation oncologist (RO) PI leadership. METHODS AND MATERIALS: www.ClinicalTrials.gov was queried for all open, interventional trials that administered RT. Logistic regression was used to identify associations between trial characteristics, receipt of funding type (NIH, industry, or other), and PI leadership. RESULTS: The authors identified 1469 oncology trials, of which 41% were based in the United States, 56% were based internationally, and 3% were based in the United States and internationally. Of these, 22% were RT monotherapy, 53% were bimodality (40% RT + drug, 13% RT + surgery), and 24% were trimodality. Although ROs led 60% of all trials, industry-sponsored trials were significantly less likely to have RO PIs (35% RO vs 65% non-RO PI; adjusted odds ratio [aOR], 0.45; 95% confidence interval [CI], 0.28-0.73), to fund trials that did not incorporate drug therapy (aOR, 0.19; 95% CI, 0.10-0.35), or to fund phase III trials (aOR, 0.25; 95% CI, 0.11-0.60) because industry-sponsored trials favored smaller phase I trials. NIH funded trials were not associated with PI type and, although not statistically significant, favored larger phase III trials (unadjusted OR, 2.06; 95% CI, 0.99 4.29). ROs were less likely to lead trials incorporating drug therapy (aOR, 0.30; 95% CI, 0.22-0.41). CONCLUSIONS: ROs are less likely than other specialties to lead trials that use RT in combination with drug therapy or surgery and more likely to lead trials supported by nonindustry, non-NIH funding. This suggests a need for ROs to lead multimodality trials and to consider opportunities to interact with industry. As NIH resources decrease, alternative funding is needed to support innovation, particularly in in RT-alone trials. PMID- 29970312 TI - Radiologic Response and Disease Control of Recurrent Intracranial Meningiomas Treated With Reirradiation. AB - PURPOSE: To evaluate the clinical outcomes of reirradiation of recurrent meningiomas and factors related to patient selection and treatment modality. METHODS AND MATERIALS: Recurrent meningioma patients who failed prior stereotactic radiosurgery (SRS) or fractionated external beam radiation therapy (EBRT) received reirradiation using either SRS or EBRT. Complete response (CR), partial response (PR), and progression after reirradiation were evaluated using the MacDonald criteria. Local control (LC), progression-free survival (PFS), and overall survival (OS) after reirradiation were analyzed using the Kaplan-Meier method. Logistic and Cox regression analyses were performed to identify factors associated with reirradiation modality and PFS, respectively. RESULTS: Forty three patients (14 grade 1/unknown, 29 grade 2/3) were reirradiated with SRS (67%) or EBRT (33%). Median time from initial SRS/EBRT to reirradiation was 60 months (range, 7.5-202); median tumor volume at the time of reirradiation was 4.8 cm3 (range, 0.14-64). After a median radiologic follow-up of 19.4 months, the response rate (CR + PR) was 8% for grade 1 and 20% for grade 2/3 meningiomas. After 2 years, LC was 78%, PFS was 63%, and OS was 80%. Larger tumor volume and prior SRS were associated with reirradiation using EBRT. Reirradiated grade 2/3 meningiomas had significantly worse PFS than grade 1 (2-year PFS: 50% vs 92%, respectively; P = .02) but not LC (P = .11) or OS (P = .39). On multivariable analysis, worse PFS was significantly associated with grade 2/3 histology (hazard ratio, 3.92; 95% confidence interval, 1.33-11.6) as well as worse Karnofsky Performance Scale score but not reirradiation dose, volume, and modality. Grades 3 to 4 radiation necrosis developed in 4 patients (10%). CONCLUSIONS: Reirradiation of recurrent meningiomas appears to be feasible with promising clinical outcomes and an acceptable toxicity profile. PMID- 29970313 TI - Predicting Late Fecal Incontinence Risk After Radiation Therapy for Prostate Cancer: New Insights From External Independent Validation. AB - PURPOSE: This study aimed to validate a previously published predictive model for late fecal incontinence (FI) in a contemporary population of prostate cancer patients treated with radical radiation therapy. METHODS AND MATERIALS: The validation included patients treated with intensity-modulated radiation therapy (IMRT) (2010-2014). Prescribed dose range was 65-80 Gy, including conventional and moderate hypo-fractionated treatments. Rectal toxicity was scored using LENT/SOMA, a minimum 2-year follow up was considered. We chose to validate the model published by Rancati et al for predicting chronic FI, developed on a 3 dimensional conformal radiation therapy (3DCRT) population. It considered a longitudinal endpoint defined as the average toxicity grade during the follow up. This continuous endpoint was dichotomized using a cut-off value of mean FI grade >1. The model included mean rectal dose (Dmean), previous diseases of the colon (COLO) and previous abdominal surgery (SURG). Doses were corrected to 2 Gy/fraction using the linear-quadratic model and applying alpha/beta ratio = 4.8 Gy. RESULTS: 228 patients constituted the validation population. A mean FI grade >1 was scored in 25 patients (11%). Logistic regression confirmed risk factors reported in the literature, with similar odds ratios (ORs) for Dmean (1.04 +/- 0.03 vs 1.06 +/- 0.04) and SURG (1.9 +/- 1.7 vs 1.6 +/- 1.45); COLO was not confirmed. Consequently, the predictive models including Dmean/Dmean + SURG were evaluated using calibration plots. Both showed a clear discriminative trend, but the absolute observed toxicity rates were underestimated (ie, absolute predicted rates were always lower than corresponding absolute observed rates). This result was consistent with an unexpected effect of hypofractionation (OR = 2.20, conventional = 8.1% vs hypofractionated = 17.4%) beyond the standard correction using linear-quadratic model. Nevertheless, the FI rate in the conventionally treated group was almost double the rate observed in the previously studied cohort (4.3% vs 8.1%). CONCLUSIONS: The study confirms previously published results indicating that abdominal surgery and rectal mean dose are risk factors for late FI. Calibration plots highlight a possible role of hypofractionation beyond linear-quadratic correction. PMID- 29970314 TI - Model-Interpolated Gating for Magnetic Resonance Image-Guided Radiation Therapy. AB - PURPOSE: To develop and validate a technique for radiation therapy gating using slow (<=1 frame per second) magnetic resonance imaging (MRI) and a motion model. Proposed uses of the technique include radiation therapy gating using T2-weighted images and conducting additional imaging studies during gated treatments. METHODS AND MATERIALS: The technique uses a physiologically guided breathing motion model to interpolate deformed target position between 2-dimensional (2D) MRI images acquired every 1 to 3 seconds. The model is parameterized by a 1-dimensional respiratory bellows surrogate and is continuously updated with the most recently acquired 2D images. A phantom and 8 volunteers were imaged with a 0.35T MRI guided radiation therapy system. A balanced steady-state free precession sequence with a 2D frame rate of 3 frames per second was used to evaluate the technique. The accuracy and beam-on positive predictive value (PPV) of the model-based gating decisions were evaluated using the gating decisions derived from imaging as a ground truth. A T2-weighted gating offline proof-of-concept study using a half-Fourier, single-shot, turbo-spin echo sequence is reported. RESULTS: Model interpolated gating accuracy, beam-on PPV, and median absolute distances between model and image-tracked target centroids were, on average, 98.3%, 98.4%, and 0.33 mm, respectively, in the balanced steady-state free precession phantom studies and 93.7%, 92.1%, and 0.86 mm, respectively, in the volunteer studies. T2 model interpolated gating in 6 volunteers yielded an average accuracy and PPV of 94.3% and 92.5%, respectively, and the mean absolute median distance between modeled and imaged target centroids was 0.86 mm. CONCLUSIONS: This work demonstrates the concept of model-interpolated gating for MRI-guided radiation therapy. The technique was found to be potentially sufficiently accurate for clinical use. Further development is needed to accommodate out-of-plane motion and the use of an internal MR-based respiratory surrogate. PMID- 29970315 TI - Radiologic-Pathologic Correlation of Extranodal Extension in Patients With Squamous Cell Carcinoma of the Oral Cavity: Implications for Future Editions of the TNM Classification. AB - PURPOSE: To evaluate the accuracy and prognostication of the presence of radiologic extranodal extension (rENE) versus pathologic extranodal extension (pENE) in patients with oral cavity squamous cell carcinoma (OSCC). METHODS AND MATERIALS: A retrospective review was conducted for all newly diagnosed OSCC patients who underwent neck dissection in our institution from 2010 to 2015 with available records of preoperative computed tomography or magnetic resonance imaging. Two head and neck neuroradiologists reviewed the presence of rENE (defined as ill-defined lymph node borders) on imaging independently, being blinded regarding the pathology report. The impact of the imaging-surgery interval, imaging modalities, and intrarater and interrater concordance of rENE was assessed. The diagnostic accuracy of rENE versus pENE was evaluated. Overall survival (OS) was compared between those with and without rENE. Multivariate analysis evaluated the prognostic value of rENE. RESULTS: Among the 508 patients, rENE and pENE were identified in 57 and 121 cases, respectively. The diagnostic accuracy of rENE versus pENE was identical (73%) for cases with the imaging surgery interval <=4 weeks (n = 276) and 4 to 8 weeks (n = 207) but lower (48%) for those >8 weeks (n = 25). Computed tomography displayed higher accuracy on rENE assessment versus magnetic resonance imaging (80% vs 63%, P = .011). Interrater and intrarater concordance (n = 93) was good (kappa = 0.79) and excellent (kappa = 0.94), respectively. Excluding the 25 cases with a >8 weeks imaging-surgery interval, the sensitivity, specificity, positive predictive value, and negative predictive value of rENE versus pENE in the remaining 483 cases were 52%, 96%, 93%, and 66%, respectively. Patients with rENE (n = 55) had inferior OS versus those without rENE (n = 202), and both had lower OS than node negative (n = 226) patients (3-year OS: 31% vs 68% vs 81%, P < .001). Multivariate analysis, adjusted for age, T category, N category, and performance status, confirmed the prognostic value of rENE for OS (hazard ratio 3.3, 95% confidence interval 2.4-5.3, P < .001). CONCLUSIONS: This large cohort study shows a high specificity but low sensitivity of rENE for pENE. Similar to pENE, the presence of rENE is associated with reduced survival in OSCC. PMID- 29970316 TI - Dose Effect in Adjuvant Radiation Therapy for the Treatment of Resected Keloids. AB - PURPOSE: Surgical excision of keloids can result in an insidious cycle of tissue injury and repeat keloid formation unless combined with adjuvant therapy to halt this cycle. We present our results of postoperative radiation therapy for keloids with various dose regimens. METHODS AND MATERIALS: A retrospective review of 124 patients with 250 keloid lesions treated with postoperative radiation therapy was analyzed. In this institutional review board-approved study, 125 keloids were treated to 20 Gy in 5 fractions and 125 keloids were treated to 12 to 16 Gy in 3 to 4 fractions. Local failure was defined as redevelopment of any clinically apparent keloid at the treated site. The median age was 34 years (14-84 years). Keloids were located on the ear (34%), neck/shoulder (19%), abdomen (13%), chest (10%), face (9%), breast (7%), extremities (4%), and back (3%). Median keloid size was 4 cm (0.5-20 cm). RESULTS: At a median follow-up of 40 months, the recurrence rate for all lesions was 5.6%. Lesions treated to 20 Gy had a recurrence rate of 1.6% compared with 9.6% with <20 Gy and an odds ratio of 0.16 (P = .02). Upon univariate and multivariate analysis there were no differences in recurrence rate with respect to location, race, gender, age, previously treated lesions, and presence of multiple keloids. The lone predictor for improved control rate was the dose of 20 Gy in 5 fractions compared with less than that. Control rate for lesions treated to a biologically equivalent dose2 of 35 to 36 Gy2, 48 to 52.5 Gy2, and 60 to 72 Gy2 were 10% (P = .007), 8.9% (P = .16), and 1.6% (P = .02), respectively. CONCLUSIONS: Surgical excision followed by immediate adjuvant radiation therapy for keloids provides excellent local control and cosmesis. Treatment with a biologically equivalent dose2 > 60 (20 Gy in 5 fractions) yielded superior local control over lower dose regimens. PMID- 29970317 TI - Intraoperative Tumor Bed Boost With Electrons in Breast Cancer of Clinical Stages I Through III: Updated 10-Year Results. AB - PURPOSE: To assess retrospectively the role of an anticipated intraoperative tumor electron radiation therapy (IOERT) as a bed boost during breast-conserving surgery followed by conventional whole breast irradiation (WBI). METHODS AND MATERIALS: An unselected cohort of 770 breast cancer patients of all risk types was analyzed in terms of local control (LC) and survival outcome. Patients were treated by breast-conserving surgery, IOERT of 10 Gy, and WBI to total median doses of 54 Gy (range, 1.6-2). Patients were retrospectively analyzed for LC, locoregional control, metastasis-free survival (MFS), overall survival (OS), and breast cancer-specific survival (BCSS). RESULTS: After a median follow-up of 121 months (range, 4-200), 21 (2.7%) in-breast recurrences (IBRs) were observed, 107 patients (14%) died and 106 (14%) developed metastases. Ten-year rates of LC, locoregional control, MFS, OS, and BCSS amounted to 97.2%, 96.5%, 86%, 85.7%, and 93.2 %, respectively. In multivariate analysis, HER2+ and triple-negative breast cancer subtype (TN) turned out to be significant negative predictors for IBRs (hazard ratios, 15.02 and 12.87, respectively; P < .05). Sorted by subtypes, 10 year LC rates were observed in 98.7% (range, 96.7%-99.5%) (luminal A), 98% (range, 94%-99.3%) (luminal B), 87.9% (range, 66.2%-96%) (HER2+), and 89% (range, 76.9%-94.9%) (TN), respectively. CONCLUSIONS: After 10 years, boost IOERT maintains high LC rates in any risk setting. PMID- 29970318 TI - Personalized Anatomic Eye Model From T1-Weighted Volume Interpolated Gradient Echo Magnetic Resonance Imaging of Patients With Uveal Melanoma. AB - PURPOSE: We present a 3-dimensional patient-specific eye model from magnetic resonance imaging (MRI) for proton therapy treatment planning of uveal melanoma (UM). During MRI acquisition of UM patients, the point fixation can be difficult and, together with physiological blinking, can introduce motion artifacts in the images, thus challenging the model creation. Furthermore, the unclear boundary of the small objects (eg, lens, optic nerve) near the muscle or of the tumors with hemorrhage and tantalum clips can limit model accuracy. METHODS AND MATERIALS: A dataset of 37 subjects, including 30 healthy eyes of volunteers and 7 eyes of UM patients, was investigated. In our previous work, active shape model was successfully applied to retinoblastoma eye segmentation in T1-weighted 3T MRI. Here, we evaluate this method in a more challenging setting, based on 1.5T MRI acquisition and different datasets of awake adult eyes with UM. The lens and cornea together with the sclera, vitreous humor, and optic nerve were automatically segmented and validated against manual delineations of a senior ocular radiation oncologist, in terms of the Dice similarity coefficient and Hausdorff distance. RESULTS: Leave-one-out cross validation (mixing both volunteers and UM patients) yielded median Dice similarity coefficient values (respective of Hausdorff distance) of 94.5% (1.64 mm) for the sclera, 92.2% (1.73 mm) for the vitreous humor, 88.3% (1.09 mm) for the lens, and 81.9% (1.86 mm) for the optic nerve. The average computation time for an eye was 10 seconds. CONCLUSIONS: To our knowledge, our work is the first attempt to automatically segment adult eyes, including patients with UM. Our results show that automated active shape model segmentation can succeed in the presence of motion, tumors, and tantalum clips. These results are promising for inclusion in clinical practice. PMID- 29970319 TI - The effect of acute oral phosphatidic acid ingestion on myofibrillar protein synthesis and intracellular signaling in older males. AB - BACKGROUND: Age-related muscle loss (sarcopenia) may be driven by a diminished myofibrillar protein synthesis (MyoPS) response to anabolic stimuli (i.e. exercise and nutrition). Oral phosphatidic acid (PA) ingestion has been reported to stimulate resting muscle protein synthesis in rodents, and enhance resistance training-induced muscle remodelling in young humans. PURPOSE: This study examined the effects of acute oral PA ingestion on resting and exercise-induced MyoPS rates in older individuals. METHODS: Sixteen older males performed a bout of unilateral leg resistance exercise followed by oral ingestion of 750 mg of soy derived PA or a rice-flour placebo (PL) over 60 min post-exercise. A primed continuous infusion of l-[ring-13C6]-phenylalanine with serial muscle biopsies was used to determine MyoPS at rest and between 0-150 and 150-300 min post exercise. RESULTS: Plasma [PA] concentrations were elevated above basal values from 180 to 300 min post-exercise in PA only (P = 0.02). Exercise increased MyoPS rates above basal values between 150 and 300 min post-exercise in PL (P = 0.001), but not PA (P = 0.83). Phosphorylation of p70S6K, rpS6, 4E-BP1 and Akt was elevated above basal levels in the exercised leg over 150-300 min post-exercise for PL only (P = 0.018, 0.007, 0.011 and 0.002, respectively), and were significantly greater than PA (P < 0.01 for all proteins). The effects of oral PA ingestion on proteolytic signaling markers were equivocal. CONCLUSIONS: Acute oral phosphatidic acid ingestion appears to interfere with resistance exercise induced intramuscular anabolic signaling and MyoPS in older males and, therefore, may not be a viable treatment to counteract sarcopenia. Clinicaltials.gov registration no: NCT03446924. PMID- 29970320 TI - Handgrip strength and lean mass are independently related to brain atrophy among alcoholics. AB - BACKGROUND: In neurodegenerative disorders or in normal aging humans a relationship between muscle mass and/or performance and brain volume was observed, that is not dependent on age or other confounding factors. The aim of the present study is to analyse the relationship between lean mass and handgrip strength in alcoholics, who frequently show brain and muscle atrophy. METHODS: It was included 101 male patients aged 58.35 +/- 11.59 years, and 44 controls, all of them workers of our hospital, drinkers of less than 20 g ethanol/day, of similar age. Patients and controls underwent dominant handgrip assessment with a Collins' dynamometer, whole body composition analysis by densitometry, and brain computed tomography (CT) examination, with further calculation of several indices indicative of brain atrophy. MAIN RESULTS: 1) Brain atrophy is a very common finding among alcoholics, both among cirrhotics and non-cirrhotics. 2) Alcoholics show a marked reduction in handgrip strength, and also in lean mass, especially at the arms and legs -but not in the trunk, even if patients with ascites were excluded.3) There is a relationship between reduced lean mass and brain atrophy, and a close correlation between handgrip strength and brain atrophy, that is independent of age and liver function. 4) Total fat amount is not different among alcoholics and controls, but there are marked differences in fat distribution: alcoholics show less fat in arms, but more fat in trunk, so that if we calculate the peripheral fat/trunk fat index, marked differences were observed among alcoholics and controls. Neither total fat nor fat distribution were related to brain atrophy. CONCLUSION: among alcoholics, as in other neurodegenerative conditions, there is a relationship between reduced lean mass and brain atrophy, and a close correlation between handgrip strength and brain atrophy, that is independent of age, duration of ethanol consumption and liver function. PMID- 29970321 TI - Selection of Oral Anticoagulants in Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Anticoagulant therapy is indicated for management of ischemic stroke patients with nonvalvular atrial fibrillation. We retrospectively investigated how oral anticoagulants were selected for ischemic stroke patients with nonvalvular atrial fibrillation. METHODS: This study included 297 stroke patients with nonvalvular atrial fibrillation admitted to our hospital between September 2014 and December 2017, and who were subsequently transferred to other institutions or discharged home. Baseline clinical characteristics were compared between patients prescribed warfarin and those prescribed direct-acting oral anticoagulants. RESULTS: In total, 280 of 297 (94.3%) patients received oral anticoagulant therapy, including 36 with warfarin, while 244 received direct oral anticoagulants. Age, percentage of heart failure, CHADS2 score before stroke onset, percentage of treatment with warfarin on admission, percentage of feeding tube at hospital discharge, and modified Rankin Scale at hospital discharge were significantly higher in the warfarin group versus the direct oral anticoagulants group, while creatinine clearance was significantly higher in the direct oral anticoagulant group. By multiple logistic regression, taking warfarin at admission and higher modified Rankin Scale at hospital discharge were associated with warfarin selection, while higher creatinine clearance was associated with direct oral anticoagulant selection (warfarin: odds ratio [OR] 7.10 [95% confidence interval {CI} 2.83-17.81]; modified Rankin Scale at hospital discharge: [OR] 1.47 [95% {CI} 1.06-2.04]; creatinine clearance: [OR] .97 [95% {CI} .95-.99]). CONCLUSIONS: Selection of oral anticoagulants in acute ischemic stroke patients with nonvalvular atrial fibrillation was influenced by warfarin use at admission, clinical severity at hospital discharge, and renal function. PMID- 29970323 TI - Modern Interdisciplinary and Interhospital Acute Stroke Therapy-What Patients Think About It and What They Really Understand. AB - BACKGROUND: Access to reperfusion therapies in patients with large vessel occluding acute ischemic stroke demands process reorganization and optimization. Neurovascular networks are being built up to provide 24/7 endovascular stroke therapy service. In times of an increasingly complex stroke rescue chain little is known about patients' and their relatives' treatment awareness. METHODS: All patients, who received any kind of acute reperfusion treatment between January and August 2017 in the university hospital Aachen, and their proxies, were included in the survey. Patients were either primarily or secondarily transferred. RESULTS: For all questions regarding stroke treatment patients and their caregivers provided concurring answers. 40% of both patients and caregivers did not understand the treatment that was performed. Finally, patients who perceived on their own that stroke detection was delayed had significantly longer onset to door times than patients who did not have this impression. CONCLUSIONS: This study showed that patients' and proxies' answers correlated significantly. In case of patients' unavailability extrapolation of treatment satisfaction from answers by proxies might be permitted. High percentages of patients and caregivers do not understand relevant information, possibly due to limits of communication in an emergency setting or deficits in communication during the hospital stay. More emphasis should be laid on providing further information during the hospital stay. PMID- 29970322 TI - Comparison of Premortem Magnetic Resonance Imaging and Postmortem Autopsy Findings of a Cortical Microinfarct. AB - An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3 tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination. PMID- 29970324 TI - Prevalence of Radiographic Morphology of Femoroacetabular Impingement in Indian Population: A Multicenter Study. AB - BACKGROUND: Femoroacetabular impingement (FAI) is an overlooked entity in India, as primary osteoarthritis of hip is uncommon in Indian population. The purpose of this study is to find out the prevalence of radiographic morphology of FAI in young asymptomatic population in India. METHODS: This is a multicenter, cross sectional study. Radiographs of 500 young asymptomatic volunteers were taken from 10 centers across India. Suboptimal imaging lead to exclusion of 48 radiographs. Crossover sign, ischial spine sign, and posterior wall sign were included in "acetabular rotation abnormalities (R)," lateral center-edge angle and acetabular index were included in "acetabular overcoverage abnormalities (O)" while pistol grip deformity and alpha angle in "femoral abnormalities (F)." Furthermore, all the hips were divided into 4 types: normal hips (N); type I hip with single abnormality (R/O/F); type II with combination of any 2 (RO/RF/OF), and type III with all 3 abnormalities. RESULTS: Sixty-eight percent of 904 hips had at least 1 type of abnormality with 47.5% hips having signs of pincer impingement, 7.9% with signs of cam impingement, and 10.8% with mixed signs. Type I.R hips (32%) were the most common hips followed by type I.O hips (18%) and type I.F (8%). Males had higher percentage of abnormalities (1.5 times) compared to females. Interobserver reliability was 0.55 to 0.81 for all the parameters. Power of study was 0.98. CONCLUSION: Radiographic morphology of FAI exists with high prevalence in young asymptomatic Indian population similar to other ethnicities except for low prevalence of cam morphology. Long-term follow-up of this cohort will reveal the natural history of these morphologies. PMID- 29970325 TI - Comparing the 30-Day Risk of Venous Thromboembolism and Bleeding in Simultaneous Bilateral vs Unilateral Total Knee Arthroplasty. AB - BACKGROUND: Simultaneous bilateral total knee arthroplasty (SBTKA) may offer certain benefits; however, its overall safety is still disputed. This study aimed at comparing the risk of thromboembolism and bleeding in patients who underwent SBTKA vs unilateral total knee arthroplasty (TKA). METHODS: The American College of Surgeons National Surgical Quality Improvement Program database from 2008 to 2015 was used to investigate the short-term postoperative complications and their risk factors following SBTKA as compared to unilateral TKA. Demographics, comorbidities, and 30-day outcomes were analyzed. Complications with an increased incidence following SBTKA were stratified to identify subgroups of patients at high risk. RESULTS: A total of 155,022 patients were identified, of which 150,581 underwent unilateral TKA and 4441 underwent SBTKA. The SBTKA group was found to be at a higher risk of venous thromboembolism (VTE), bleeding, and composite morbidity. Stratification analysis revealed that SBTKA subgroups at higher risk of VTE include patients of black or Asian origin, obese patients, and those who underwent anesthesia other than general or spinal/epidural. SBTKA subgroups at higher risk of bleeding include patients older than 85 years, those with race other than white, underweight and obese patients, and patients who underwent anesthesia other than spinal/epidural. Although none of the subgroups were protected from bleeding, patients who underwent spinal/epidural anesthesia had a lower risk of bleeding compared to other types of anesthesia. CONCLUSION: SBTKA confers an increased risk of postoperative VTE, bleeding, and composite morbidity at 30 days, with no increase in mortality. PMID- 29970326 TI - Does the Preoperative Varus Deformity Influence the Survival of Postoperative Neutral-Aligned TKAs? An Analysis With a Minimum 5-Year Follow-Up. AB - BACKGROUND: Postoperative neutral alignment may be an important factor for longevity of total knee arthroplasty (TKA). In knees with severe varus deformity, greater soft tissue release and bone resection were required to achieve neutral alignment. We investigated the relationship between the severity of preoperative varus deformity and longevity of neutral-aligned TKAs. METHODS: Of the 723 knees in patients who underwent primary TKA for varus-type osteoarthritis between November 1998 and June 2009, 496 knees aligned neutrally (the postoperative mechanical hip-knee-ankle [HKA] axis angle ranged between -3 degrees and 3 degrees ) and followed up for at least 5 years were included in the study. The mean follow-up period was 9.28 years. Patients were divided into 4 groups based on their preoperative HKAs: mild (0 degrees < HKA <= 5 degrees , n = 79), moderate (5 degrees < HKA <= 10 degrees , n = 204), severe (10 degrees < HKA <= 15 degrees , n = 149), and very severe (HKA > 15 degrees , n = 64) groups. Failure was defined as need for revisional TKA for mechanical reason. Survival was analyzed by Kaplan-Meier method and log-rank test. RESULTS: The overall failure rate was 2.02% (10 of 496 prostheses). The cumulative survival rates of neutral-aligned TKAs at 10 years were 97.4% (95% confidence interval [CI], 93.9% 100%), 99.0% (95% CI, 97.6%-100%), 97.8% (95% CI, 95.4%-100%), and 96.9% (95% CI, 92.6%-100%) in mild, moderate, severe, and very severe varus groups, respectively. There were no significant differences between group survival rates (P = .395). CONCLUSION: The severity of preoperative varus deformity did not affect survival rates of neutral-aligned TKAs over 10 years. PMID- 29970327 TI - Femoral-Acetabular Mating: The Effect of Femoral and Combined Anteversion on Cross-Linked Polyethylene Wear. AB - BACKGROUND: Cross-linked polyethylene (XLPE) has generally low rates of wear and osteolysis at 10 years, but component position may become important with longer follow-up. At 5-13 years, neither acetabular component lateral opening angle nor version were significantly correlated to wear. In the present study, we analyzed the effects of femoral anteversion and combined anteversion on XLPE wear. METHODS: Forty-two well-functioning primary total hip arthroplasties in 36 patients, performed by a single surgeon via a posterior approach, were followed for a minimum of 5 years (mean, 7.1 years; range, 5.0-10.3). All hips had a modular, XLPE liner with a >=36-mm bearing. Femoral anteversion was measured on the modified Budin view. Wear was measured on radiographs using a validated, computer-assisted, edge-detection-based algorithm. The mean lateral opening angle was 40.4 degrees (range, 22.6 degrees -50.3 degrees ). The mean acetabular version was 19.1 degrees (range, 11.3 degrees -27.5 degrees ). Neither of these variables was significantly correlated to wear. Effects of femoral anteversion and combined anteversion on XLPE wear were assessed using linear and polynomial regression analysis. RESULTS: Femoral anteversion (mean, 18.4 degrees ; range, 6.8 degrees -30.7 degrees ) was significantly correlated to linear wear (mean, 0.06 mm/y; range, 0-0.16), showing an inverse parabolic relationship with the least wear occurring at 18.2 degrees (P = .02). Combined anteversion (mean, 37.2 degrees ; range, 21.8 degrees -54.3 degrees ) showed a similar significant relationship with the least wear at 38.1 degrees (P < .001). Based on regression, combined anteversion between 24.6 degrees and 50.4 degrees resulted in linear wear rates less than 0.1 mm/y. CONCLUSION: To the authors' knowledge, this is the first study to identify femoral anteversion as an independent factor influencing XLPE wear, with least wear occurring around 18 degrees . At 5-10 years, average linear wear of XLPE is below 0.1 mm/y over a 25 degrees -50 degrees range of combined anteversion, with the least wear around 38 degrees . Femoral-acetabular mating is a product of both components. Femoral component version and combined anteversion had a greater effect on wear than acetabular component lateral opening angle. Additional studies are warranted, but these results indicate that the sensitivity of wear studies is increased with version assessments. PMID- 29970328 TI - Efficacy and safety of adjunctive drug-coated balloon therapy in endovascular treatment of common femoral artery disease. AB - BACKGROUND: Surgical endarterectomy with or without patch angioplasty has been considered the gold standard for treatment of symptomatic common femoral artery (CFA) disease. Surgical risks include wound infection, hematoma and lymph leak in approximately 17% of patients. Endovascular therapy has less procedure-related morbidity and mortality. Endovascular approaches achieve patency rates of 60% to 90% at 1 and 2 years utilizing atherectomy and balloon angioplasty. CFA stenting has been limited due to concerns of stent kinking, thrombosis and restenosis. Combined directional atherectomy with drug-coated balloon to treat CFA disease in patients with Rutherford II/III patients has been studied recently. We sought to study the safety and outcomes of adjunct drug-coated balloon (DCB) therapy in symptomatic CFA disease patients, including critical limb ischemia (Rutherford IV), after achieving procedural success. OBJECTIVE: To evaluate the additive efficacy of drug coated balloon in treating CFA disease. METHODS: Using retrospective single center data, we analyzed the outcomes of patients who underwent CFA interventions. In this non-randomized study, all patients from December 2010 to December 2014 with CFA disease underwent atherectomy (orbital, plaque excision or both) with adjunctive scoring balloon angioplasty (Ath/PTA). After December 2014, patients treated with combination atherectomy and DCB, (Ath/DCB), underwent final drug delivery to the vessel wall with drug-coated balloon. Distal embolic protection devices were used in the majority of patients. Primary efficacy endpoint was 1-year primary patency and freedom from clinically driven target lesion revascularization (CD-TLR). Patency of vessels was assessed at 12-month interval using duplex ultrasound. RESULTS: Seventy de novo common femoral artery stenotic lesions were treated in both groups. Mean age was 69 in (Ath/PTA) group and 72 in Ath/DCB group. Patients in each group had similar risk factor profiles including diabetes mellitus, hypertension, smoking, coronary artery disease, myocardial infarction, prior coronary revascularization, congestive heart failure, cerebrovascular accidents and chronic kidney disease. The Ath/DCB group had more advanced disease presentation by Rutherford classification (intermittent claudication in 61% and critical limb ischemia in 39% versus intermittent claudication in 76% and chronic limb ischemia in 24%) when compared with the Ath/PTA group. Primary efficacy endpoint was met in 85% and 94% (p = 0.26) in the Ath/PTA and Ath/DCB groups respectively. All patients had run-off angiography at the end of procedure to ensure patency. CONCLUSION: Adjunctive drug-coated balloon therapy does not increase the primary patency rate when compared with atherectomy and scoring balloon angioplasty alone at 1-year in common femoral artery disease treatment. PMID- 29970329 TI - A first time repair of pseudoaneurysm of the ascending aorta with a Valiant Navion Evo thoracic endograft(r). AB - We describe the first case of an endovascular repair for a pseudoaneurysm of the ascending aorta using the Valiant Navion EVO(r) low-profile thoracic endograft from MedtronicTM. A successful outcome from a potentially fatal condition in a severely compromised patient was achieved. PMID- 29970330 TI - From the Wave Equation to Biomolecular Structure and Dynamics. AB - The multiscale models for complex chemical systems constitute a powerful computational tool to describe biomolecular structure and dynamics, including enzymatic reactions. Here, the development of this method is presented as a miraculous chain of events, involving astoundingly lucky encounters of brilliant minds such as Planck, Schrodinger, Pauling, Karplus, Levitt, and Warshel. PMID- 29970331 TI - Risk of Traumatic Brain Injury Among Children, Adolescents, and Young Adults With Attention-Deficit Hyperactivity Disorder in Taiwan. AB - PURPOSE: Previous studies suggested that patients with attention-deficit hyperactivity disorder (ADHD) were prone to health-risk behaviors and accidents. However, the relationship of ADHD with the risk of traumatic brain injury (TBI) remained uncertain. METHODS: Using the Taiwan National Health Insurance Research Database, 72,181 children (aged 3-11 years), adolescents (12-17 years), and young adults (18-29 years) with ADHD and 72,181 age-/sex-matched controls were enrolled between 2001 and 2009, and followed up to the end of 2011 in our study. Those who developed any TBI during the follow-up period were identified. RESULTS: Children, adolescents, and young adults with ADHD had a higher incidence of developing any TBI (9.8% vs. 2.2%, p < .001), such as skull fracture (.2% vs. .1%, p < .001) and concussion (4.3% vs. 1.0%, p < .001), than the controls did. Cox regression analysis with the adjustment of demographic data, psychiatric comorbidities, and ADHD medications showed that ADHD was related to an increased risk of subsequent TBI (hazard ratio: 4.57, 95% confidence interval: 4.31-4.85), and indicated that long-term use of ADHD medication was associated with a reduced likelihood of subsequent TBI (hazard ratio: .93, 95% confidence interval: .87-.99). CONCLUSIONS: Patients with ADHD had an increased risk of developing any TBI compared with the controls. Long-term use of ADHD medications would reduce this risk. Our findings suggested that the public health government and clinicians should pay more attention to the TBI risk among patients with ADHD, and further indicated the importance of the optimal treatment for ADHD. PMID- 29970332 TI - Longitudinal Evaluation of Syndemic Risk Dyads in a Cohort of Young Pregnant Couples. AB - PURPOSE: The burden of syndemics-which are clusters of overlapping risk factors that adversely impact health-has been previously evaluated among high-risk individuals, yet little is known regarding syndemics within the relationship context. METHODS: We evaluated concordant and discordant syndemic profiles among 296 pregnant couples and their actor-partner effects longitudinally from pregnancy to 1-year postpartum. RESULTS: Syndemic score and severity were correlated across all time points for men and women. There was a significant difference in syndemic score (betaMen-Women = .2736, p = <.0001) and severity (betaMen-Women = .4282, p = <.0001) during pregnancy. For actor effects, we found score (betaT1-T2 = .273, p = .002; betaT2-T3 = .300, p = .005) and severity (betaT1-T2 = .253, p = .004; betaT2-T3 = .418, p = .001) were significantly associated across all time points for women. For men, only syndemic score predicted subsequent score at later time points (betaT1-T2 = .393, p = <.001; betaT2-T3 = .421, p = <.001). Severity was not significantly associated across time (betaT1-T2 = .043, p = .566; betaT2-T3 = .172, p = .066). For partner effects, we found women's syndemic risk to influence men's syndemic risk, while men had no significant effect on women's syndemic risk. CONCLUSIONS: Pregnancy provides an opportunity to reduce syndemic burden among men and women. Couples based prevention programs may serve to reduce syndemic risk for both partners, particularly during the postpartum period. PMID- 29970334 TI - Is distal hypospadias repair mostly a cosmetic operation? PMID- 29970333 TI - Use of Mind-Body Therapies Among Young Adults Aged 18-24 Years: Findings From the 2012 National Health Interview Survey. AB - PURPOSE: To investigate the prevalence, patterns, and satisfaction of use of mind body therapies (MBTs) in a nationally representative sample of young adults (ages 18-24 years). METHODS: Young adults interviewed in the 2012 National Health Interview Survey were analyzed (n = 3,286). Individual types (e.g., mindfulness) and a combined measure of use of any MBT were assessed. Reasons for and satisfaction with use was also investigated. Design-based F tests and logistic regression were used; all analyses were weighted and stratified by gender. RESULTS: Overall, 14.6% of young adults used MBT in the past year (9.6% of men and 19.1% of women, p < .001). Among men, higher levels of education, greater numbers of health conditions, and healthy behaviors were associated with greater odds of MBT use. Among women, Latina and black women had lower odds of use (vs. white). Higher education, greater mental distress, and greater numbers of health conditions and healthy behaviors were associated with greater odds of use. While both men and women reported stress reduction and general wellness as top reasons for use, men also reported the use to improve athletic performance. CONCLUSIONS: Young adulthood is a critical period in the life course when individuals are establishing lifestyle and health behaviors that can be enduring. Because stress is a persistent problem, and many MBTs can be helpful with management of stress and anxiety, young adult may be underutilizing these modalities. Public health and educational strategies for greater engagement in MBT among young adults are warranted. PMID- 29970335 TI - Closed Incision Negative Pressure Therapy Reduces Surgical Site Infections in Vascular Surgery: A Prospective Randomised Trial (AIMS Trial). AB - BACKGROUND: Surgical site infections (SSIs) of the groin remain a crucial problem in vascular surgery, prompting great interest in preventative techniques, such as closed incision negative pressure therapy (ciNPT). This prospective randomised study aimed to assess the potential benefits of ciNPT application after groin incisions for vascular surgery. METHOD: The study included 204 patients who underwent vascular surgery for peripheral artery disease (PAD) at two sites between July 2015 and May 2017. These patients received post-operative treatment with ciNPT (intervention group) or standard wound dressings (control group). After exclusion, 188 patients were assessed for SSIs using the Szilagyi classification. RESULTS: The mean patient age was 66.6 +/- 9.4 years (range 43-85 years), and 70% were male (n = 132). Regarding PAD stage, 52% were stage IIB, 28% stage III, and 19% stage IV. Among the patients, 45% (n = 85) had had a previous groin incision. Bacterial swabs were performed in each case of suspected SSI (22.8% [43/188]), while 76.7% (33/188) were negative, there were 5% [5/98] positive swabs in the intervention group and 5.5% [5/90] in the control group). Antibiotics were given to 13.2% of the intervention group, and 31.1% of the control group (p = .004). The control group experienced more frequent SSIs (33.3%; 30/90) than the intervention group (13.2%; 13/98; p = .0015; absolute risk difference -20.1 per 100; 95% CI -31.9 to 8.2). This difference was based on an increased rate of Szilagyi I SSI in the control group (24.6% vs. 8.1%, p = .0012). CONCLUSION: The results confirmed a reduced superficial SSI rate after vascular surgical groin incision using ciNPT compared with standard wound dressings. PMID- 29970336 TI - Rapid rare ABO blood typing using a single PCR based on a multiplex SNaPshot reaction. AB - BACKGROUND: ABO subgroups would be considered when discrepancies in ABO grouping occur. Serological methods including adsorption-elution test, salivary ABH inhibition test, and anti-A1 (lectin) saline method could be used. However, these serological methods are laboring and obscure. Therefore, reliable and affordable method to assess the ABO subgroups is of particular interest. METHODS: To solve this problem, the multiplex SNaPshot-based assays were designed to determine rare A and B subgroups. Primers used as probes for determination of rare ABO blood groups known in Taiwanese population were designed. Many ABO subtype samples were used to validate the accuracy and reproducibility of our SNaPshot panel. RESULTS: A panel of primer probes were successfully designed in determining 8 SNP sites (261, 539, 838, 820, 745, 664, IVS6 +5, and 829 in exon 6 and 7) for A phenotype and 6 SNP sites (261, 796, IVS3 +5, 247, 523, and 502 in exon 2, 6 and 7 and intron 3) for B phenotype. SNaPshot analysis for defining blood group A alleles (A1, A2, A3, Am and Ael) and blood group B alleles (B1, B3, Bw and Bel) was therefore available. CONCLUSIONS: SNaPshot analysis could be used in reference laboratories for typing known rare subgroups of A and B without DNA cloning and traditional sequencing. Moreover, this method would help to construct databases of genotyped blood donors, and it potentially plays a role in determining fetal maternal ABO incompatibility. PMID- 29970337 TI - Leprosy manifesting as nasal obstruction and epistaxis. PMID- 29970338 TI - Inflammation-induced metabolic derangements or adaptation: An immunometabolic perspective. AB - Inflammatory mediators have a well-established role in mediating metabolic disturbances. Chronic low-grade inflammation is implicated in the pathogenesis of obesity and the development of metabolic syndrome. This phenomenon is even more pronounced in severe inflammatory states such as in critically ill patients where hyperglycaemia invariably manifests. Similarly, though inflammatory mediators have a well-established role in promoting bone resorption, the adaptive function of this process remains unknown. Here we review emerging evidence from the field of immunometabolism suggesting that these two processes serve a common goal, namely, to sustain the rapid proliferation of immune cells during an infection. Activated immune cells exhibit an increased demand for glucose which not only provides energy, but also glycolytic intermediates which are fluxed into biosynthetic processes. Similarly, phosphate liberated from bone is consumed during the phosphorylation of glycolytic intermediates, which plays a critical role in the synthesis of nucleotides and phospholipids. Taken together, these considerations suggest that metabolic alterations induced by inflammatory mediators do not manifest as an inability to maintain homeostatic levels of metabolites but represent an adaptive shift in the homeostatic set point during an infection. PMID- 29970339 TI - Plant Immunity: From Signaling to Epigenetic Control of Defense. AB - Pathogen recognition by plants results in the activation of signaling pathways that induce defense reactions. There is growing evidence indicating that epigenetic mechanisms directly participate in plant immune memory. Here, we discuss current knowledge of diverse epigenomic processes and elements, such as noncoding RNAs, DNA and RNA methylation, histone post-translational modifications, and chromatin remodeling, that have been associated with the regulation of immune responses in plants. Furthermore, we discuss the currently limited evidence of transgenerational inheritance of pathogen-induced defense priming, together with its potentials, challenges, and limitations for crop improvement and biotechnological applications. PMID- 29970340 TI - Noncommunicable Diseases in Low- and Middle-Income Countries: A Strategic Approach to Develop a Global Implementation Research Workforce. AB - Globally, most of the burden from noncommunicable disease is now evident in low- and middle-income countries (LMICs). At the same time, many effective noncommunicable disease interventions are now available and recommended for implementation and scale-up across LMIC health systems-yet are not being widely implemented. Understanding optimal and sustainable implementation strategies for these interventions within the LMIC context will need locally led and conducted implementation research- a research capacity which currently is lacking. The National Institutes of Health institutes, centers, and offices work with the Fogarty International Center to support biomedical research and research training across the globe. The National Heart, Lung, and Blood Institutes' Center for Translation Research and Implementation Science has a strategic focus on implementation research in global health. The Center for Translation Research and Implementation Science is considering strategies for developing research capacity and skill sets to conduct this priority research along with National Institutes of Health institutes and centers and other key global institutions that highly value implementation research. Short-term and medium-term strategies will be needed along with building on current efforts and investments and considering new efforts to address gaps. Developing and sustaining this research workforce will present many challenges and require much effort, but the returns could be transformative in advancing the prevention, treatment, and control of noncommunicable diseases within LMICs. PMID- 29970341 TI - Questionnaires and checklists for central auditory processing screening used in Brazil: a systematic review. AB - INTRODUCTION: The action of listening involves a complex interaction between the peripheral and central auditory systems. Central auditory processing disorder can be described as any problem in one or more auditory abilities. Literature reports that behavioral questionnaires and checklists can be applied to screen individuals at risk for central auditory processing disorder. OBJECTIVE: To identify and analyze in the national literature questionnaires and checklists for the screening of central auditory processing available in Brazil for the Portuguese language. METHODS: The research was carried out in electronic databases and "gray literature". The search strategy was: "questionnaires OR surveys and questionnaires AND auditory OR hearing tests OR auditory perception AND Brazil". The research was carried out between June and August of 2017. Study selection followed inclusion and exclusion criteria. The criteria adopted included Brazilian studies, without date and design restriction, that were carried out, translated, adapted and/or validated to Brazilian Portuguese or European Portuguese, as tools for central auditory processing screening. International studies that were not adapted to the Portuguese language were excluded, as well as the ones that were not available in full. RESULTS: A total of 3664 publications were found and seven articles were selected for this systematic review, according to the established criteria. CONCLUSIONS: There is scarce national literature for central auditory processing screening and the only tool validated to Brazilian Portuguese, published as a monograph, is the auditory processing domains questionnaire. It is suggested that new studies with greater methodological stringency related to the processes of tool adaptation and validation be developed and published in the usual scientific databases, aiming at greater diffusion and clinical applicability. PMID- 29970342 TI - Molecular Markers and Prognosis of Myelofibrosis in the Genomic Era: A Meta analysis. AB - Molecular markers are important in guiding treatment and predicting outcome in the genomic era. Meta-analysis of molecular markers in myelofibrosis through a search of PubMed and Medline through October 31, 2017 was performed. Markers with more than 3 studies that compared overall survival (OS) and leukemia-free survival (LFS) were analyzed. A total of 16 studies were included. Hazard ratios (HRs) for OS were as follows: IDH 2.65 (95% confidence interval [CI], 1.66-4.21), SRSF2 2.12 (95% CI, 1.18-3.79), high-risk myeloma 2.11 (95% CI, 1.70-2.61), ASXL1 1.92 (95% CI, 1.60-2.32), EZH2 1.88 (95% CI, 1.32-2.67), JAK2 1.41 (95% CI, 1.04 1.93) in the univariate analysis and 1.49 (95% CI, 0.42-5.30) in the multivariate analysis. LFS of JAK2 and SRSF2 had HRs of 1.81 (95% CI, 0.42-5.30) and 0.36 (95% CI, 0.02-6.48), respectively. In conclusion, mutations in IDH, SRSF2, and ASXL1 had worse prognosis in OS with HRs around 2. JAK2 and SRSF2 mutation were not associated with increased leukemia transformation. The adverse effect of triple negative, which was often compared with CALR mutation, needs to be explored. PMID- 29970343 TI - A review of the safety of common aesthetic procedures during pregnancy. PMID- 29970344 TI - Chances and limitations of a low-cost mobile 3D scanner for breast imaging in comparison to an established 3D photogrammetric system. AB - BACKGROUND: In search of new possibilities in 3D surface imaging, several nonmedical scanning systems have been assessed for their implementation in plastic surgery. The aim of this study was to compare a new affordable 3D imaging consumer product with an established medical 3D imaging system for objective 3D breast imaging. METHOD: We compared a low-cost mobile, handheld scanner against an established medical 3D surface imaging system. Forty-two female patients who underwent different types of breast surgery were captured in a 3D view with both devices. Digital breast measurement, volume measurement, and breast surface-to surface analysis were done using Mirror software. Repeatability was assessed by repeated 3D scans of the torso and surface-to-surface analysis. RESULTS: Digital breast measurement showed low differences with good-to-excellent correlation between both devices. Mean breast volume difference was small (-5.11 +/- 32.10 mL) within the 95% limits of agreement. Surface-to-surface analysis yielded a higher surface deviation in the lower breast quadrants (1.62 +/- 0.80 mm root mean square [RMS] error and 1.81 +/- 0.88 mm RMS error) than in the upper breast quadrants. Repeatability was satisfactory with a mean of 0.636 +/- 0.279 mm RMS error. CONCLUSION: Affordable mobile surface scanners may offer new perspectives in the future for 3D breast imaging. Although surface acquisition was sufficient for breast measurements in comparison to an established system, the lack of appropriate medical software for patient consultation next to moderate texture quality needs to be improved for wider acceptance in plastic surgery. PMID- 29970345 TI - Propeller TAP flap breast reconstruction: A simplified surgical technique. PMID- 29970346 TI - Should planned/desired pregnancy be considered an absolute contraindication to breast reconstruction with free abdominal Flaps? A retrospective case series and systematic review. AB - BACKGROUND: Autologous breast reconstruction is considered by many to be the gold standard reconstructive modality following mastectomy. Despite the advantages of autologous reconstruction, however, surgeons have been cautious in recommending this approach to patients who desire to become pregnant postoperatively because of concerns related to abdominal wall morbidity. While intuitive, this approach does not appear to be based on robust data. Hence, the authors examined the clinical outcome in patients who became pregnant following autologous breast reconstruction. METHODS: Patients who underwent autologous breast reconstruction with free abdominal flaps that required an incision in the anterior rectus sheath were identified. Of them, patients who became pregnant post reconstruction were included for subsequent analysis. Of particular interest were any peripartal and postpartal complications that could be attributed to the preceding abdominal flap harvest. Additionally, a systematic review of the literature was performed. RESULTS: We identified five patients who met inclusion criteria. All five patients underwent bilateral breast reconstruction with free muscle-sparing transverse rectus abdominis musculocutaneous (MS-TRAM) flaps. None of the patients had any preexisting abdominal wall morbidity. All five patients proceeded to full-term pregnancy and successfully delivered newborns, four of which were delivered by normal vaginal delivery and one by cesarean section. No abdominal wall complications were noted during pregnancy, delivery, or postpartum. CONCLUSION: Contemporary data do not support the notion that breast reconstruction with free abdominal flaps is contraindicated in the setting of desired or planned pregnancy. PMID- 29970347 TI - A proteomic insight into the MSP1 and flg22 induced signaling in Oryza sativa leaves. AB - : Previously, we reported a novel Magnaporthe oryzae- secreted protein MSP1, which triggers cell death and pathogen-associated molecular pattern (PAMP) triggered immune (PTI) responses in rice. To investigate the MSP1 induced defense response in rice at the protein level, we employed a label-free quantitative proteomic approach, in parallel with flg22 treatment, which is a well-known elicitor. Exogenous application of MSP1 to rice leaves induced an oxidative burst, MAPK3/6 activation, and activation of pathogenesis-related genes (DUF26, PBZ, and PR-10). MaxQuant based label free proteome analysis led to the identification of 4167 protein groups of which 433 showed significant differences in response to MSP1 and/or flg22 treatment. Functional annotation of the differential proteins showed that majority of the proteins related to primary, secondary, and lipid metabolism were decreased, while proteins associated mainly with the stress response, post-translational modification and signaling were increased in abundance. Moreover, several peroxidases and receptor kinases were induced by both the elicitors, highlighting their involvement in MSP1 and flg22 induced signaling in rice. Taken together, the results reported here contribute to our understanding of MSP1 and flg22 triggered immune responses at the proteome level, thereby increasing our overall understanding of PTI signaling in rice. BIOLOGICAL SIGNIFICANCE: MSP1 is a M. oryzae secreted protein, which triggers defense responses in rice. Previous reports have shown that MSP1 is required for the pathogenicity of rice blast fungus, however, the exact mechanism of its action and its downstream targets in rice are currently unknown. Identification of the downstream targets is required in order to understand the MSP1 induced signaling in rice. Moreover, key proteins identified could also serve as potential candidates for the generation of disease resistance crops by modulating stress signaling pathways. Therefore, here we employed, for the first time, a label-free quantitative proteomic approach to investigate the MSP1 induced signaling in rice together with flg22. Functional annotation of the differential proteins showed that majority of the proteins related to primary, secondary, and lipid metabolism were decreased, while proteins related to the defense response, signaling and ROS detoxification were majorly increased. Thus, as an elicitor, recombinant MSP1 proteins could be utilized to inducing broad pathogen resistance in crops by priming the local immune responses. PMID- 29970348 TI - Myocarditis as a Form of Presentation of an Inflammatory Autoimmune Myopathy Associated With Anti-signal Recognition Particle Antibodies. PMID- 29970349 TI - Sudden Cardiac Death Risk Prediction: The Role of Cardiac Magnetic Resonance Imaging. AB - Sudden cardiac death (SCD) accounts for more than 4 million global deaths per year. While it is most commonly caused by coronary artery disease, a final common pathway of ventricular arrhythmias is shared by different etiologies. The most effective primary and secondary prevention strategy is an implantable cardioverter-defibrillator (ICD). The decision to implant an ICD for primary prevention is largely based on a left ventricular ejection fraction <= 35%, but this criterion in isolation is neither sensitive nor specific. Novel imaging parameters hold promise to improve ICD candidate selection. Cardiac magnetic resonance (CMR) imaging is a powerful and versatile technique, with the ability to comprehensively assess cardiac structure and function. A range of variables based on CMR techniques (late gadolinium enhancement, T1 mapping, T2* relaxometry, deformation imaging) have been associated with ventricular arrhythmias and SCD risk. The role of CMR in the estimation of ventricular arrhythmias and SCD risk in coronary artery disease, nonischemic cardiomyopathies, cardiac transplant, iron-overload cardiomyopathy and valvular heart disease is reviewed in this article. Prospective, randomized trials and standardization of CMR techniques are required before its routine use can be recommended for guiding SCD prevention strategies. PMID- 29970350 TI - Beneficial effects of the commercial lactic acid bacteria product, Vigiis 101, on gastric mucosa and intestinal bacterial flora in rats. AB - BACKGROUND: Gastric mucosal integrity is maintained through achieving a balance between potentially detrimental and protective factors. This study aimed to evaluate the effects of Vigiis 101 powder, a product consisting of dried Lactobacillus paracasei subsp. paracasei NTU 101 bacteria, on intestinal bacterial flora and acute damage to the gastric mucosa induced by pylorus ligation. METHOD: Acute gastric injury were induced by pylorus ligation. Rats were orally treated with the vehicle or 0.15, 0.30, 1.50 g/kg (0.5-, 1-, and 5-x) Vigiis 101 for 8 weeks. We analyzed the intestinal microflora, short-chain fatty acids, antioxidant enzyme levels and gastric lesion. RESULTS: Daily treatment of rats with Vigiis 101 increased the levels of beneficial Bifidobacterium spp. and Lactobacillus spp., and reduced those of detrimental Clostridium perfringens and Enterobacteriaceae. Vigiis 101 treatment also markedly reduced gastric lesion areas by between 1.7 and 11.4%, and significantly increased the levels of the short-chain fatty acids (SCFAs): acetic acid, propionic acid, and butyric acid in cecal samples by 45-86%, 127-158%, and 20-211%, respectively, compared to non treated controls. In the gastric mucosa of rats treated with Vigiis 101, the activity of superoxide dismutase and levels of prostaglandin E2 (PGE2) were enhanced, and the activity of lipid peroxidase reduced, relative to controls. CONCLUSION: The up-regulation of PGE2 and SCFAs in the gastric mucosa is likely to stimulate mucus secretion and increase transmucosal resistance, thereby contributing to Vigiis 101-mediated protection from gastric mucosal lesions induced by pylorus ligation. PMID- 29970351 TI - The regulation of normal and neoplastic hematopoiesis is dependent on microenvironmental cells. AB - Each day the adult human produces 4 * 1011 red blood cells, 1 * 1011 white blood cells and 1 * 1011 platelets, levels of production which can increase 10-20 fold in times of heightened demand. Hematopoiesis, or the formation of the ten different types of blood and marrow cells, is a complex process involving hematopoietic stem cells (HSCs), cytokine growth factors and cell surface adhesion molecules, and both specific and ubiquitous transcription factors. The marrow micro-environmental niche is defined as the site at which HSCs reside and are nurtured, receiving the signals that lead to their survival, replication and/or differentiation. Using microscopic, biochemical and molecular methods many different cells and the signals responsible for niche function have been identified. Early studies suggested two distinct anatomical sites for the niche, perivascular and periosteal, but the preponderance of evidence now favors the former. Within the "vascular niche" much evidence exists for important contributions by vascular endothelial cells (ECs), CXCL12-abundant reticular (CAR) cells and mesenchymal stromal cells, through their elaboration of chemokines, cytokines and cell surface adhesion molecules. In a series of studies we have found, and will present the evidence that megakaryocytes (MKs), the precursors of blood platelets, must be added to this list. In addition to normal blood cell development, numerous studies have implicated the perivascular niche as contributing to the pathogenesis of a variety of hematological malignancies. Our laboratory focuses on the Ph (Crane et al., 2017)-negative myeloproliferative neoplasms (MPNs), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). These diseases are characterized by clonal expansion of HSCs and one or more mature blood cell types, hypermetabolism, a propensity to disorders of hemostasis (thrombosis > bleeding) and in some, evolution to acute leukemia. While a variety of therapies can control the abnormal expansion of the progeny of the malignant HSC, the only curative therapy is myeloablation with conditioning therapy or immunological means, followed by allogeneic stem cell transplantation (SCT), a procedure that is often inadequate due to relapse of the malignant clone. While the three disorders were postulated by Dameshek in the 1950s to be related to one another, proof came in 2005 when an acquired mutation in the signaling kinase Janus kinase 2 (Jak2V617F) was identified in virtually all patients with PV, and ~50% of patients with ET and PMF. Since that time a number of other mutations have been identified that account for the "Jak2V617F negative" MPNs, including the thrombopoietin receptor, c-MPL, other mutations of Jak2, calreticulin and a variety of epigenetic modifier genes (e.g. TET2). Using a cell-specific Cre recombinase and SCT techniques we can introduce Jak2V617F into murine megakaryocytes and platelets, hematopoietic stem cells, and endothelial cells, alone or in combination, in order to probe the role of the mutant kinase in various cells on several aspects of the MPNs. Using these tools we have found that the expression of Jak2V617F in HSCs and ECs drives a MPN characterized by neutrophilia, thrombocytosis and splenomegaly, eventually evolving into myelosclerosis. Somewhat surprisingly, we found that Jak2V617F bearing ECs were required for many features of the MPN, such as enhancing the growth of Jak2V617F-bearing HSCs over that of wild type HSCs, its characteristic radioresistance, and a hemostatic defect. Altogether, our studies suggest that the malignant vascular niche is a critical element in the pathogenesis of MPNs, and a more thorough understanding of the molecular basis for these findings could lead to improved treatment for patients with these disorders. PMID- 29970352 TI - Corrigendum to 'Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib: Patient focused outcome results from the randomised phase III REACH study' [Eur J Canc 81 (2017) 17-25]. PMID- 29970353 TI - Will SPYRAL HTN-ON MED change my practice? SPYRAL HTN-ON MED: a prospective, randomised, sham-controlled trial on renal denervation in the presence of antihypertensive medications. PMID- 29970354 TI - Will SPYRAL HTN-OFF MED change my practice? SPYRAL HTN-OFF MED: a prospective, randomised, sham-controlled trial on renal denervation in the absence of antihypertensive medications. PMID- 29970356 TI - A Novel mHealth Approach for a Patient-Centered Medication and Health Management System in Taiwan: Pilot Study. AB - BACKGROUND: Mobile health (mHealth) apps have recently demonstrated the potential to engage and empower people to improve their own health. Although the availability of health-related apps is increasing, their adoption rate in Taiwan is exceptionally low mainly due to the preponderance of Western culture-based app designs that are challenging for non-English-speaking individuals. To our knowledge, no mHealth app is available in Taiwan that is culturally tailored for Chinese-speaking users and that applies a patient-centered approach to self manage medication and health. OBJECTIVE: The purpose of this study was to design and deploy a culturally tailored mHealth system that could be easily integrated into current clinical practice and to evaluate how this mHealth system could support the continuity of patient care in Taiwan. METHODS: An mHealth information system and a mobile app were designed. To promote the best patient experience, a Quick Response (QR) code system was developed to enable efficient registration of personal medication information through the mobile app. The app also supported notifications for drug utilization, refills, and symptom checks. Patients were encouraged to record medication use, symptoms, and self-assessments in the app during their treatment period. Evaluation of the novel mHealth system was conducted from August 1, 2016 to December 31, 2016 at MacKay Memorial Hospital, Taipei, Taiwan. Population data and app usage statistics were analyzed. RESULTS: During the 5-month implementation period, a total of 25,909 users downloaded the app with an overall 7-day retention rate of 15.4% (SD 3.9). Young male adults (range 25-44 years) were the predominant user population. Patients' feedback on app usability and design, QR code system as drug input method, medication reminders, and linking family or friends into care networks was generally positive. Physicians showed great interest in utilizing patient-generated data in their care process, and the positive medication adherence rate was the most highly valued component of this system. CONCLUSIONS: This pilot study demonstrated the value of a novel mHealth approach for individualized medication and health management in Taiwan. The mHealth system shows the potential to optimize personalized care into existing clinical services and may help hospitals and health authorities perform continuous quality improvement and policy development. PMID- 29970355 TI - Traditional and Web-Based Technologies to Improve Partner Notification Following Syphilis Diagnosis Among Men Who Have Sex With Men in Lima, Peru: Pilot Randomized Controlled Trial. AB - BACKGROUND: Patient-initiated partner notification (PN) following the diagnosis of a sexually transmitted infection is a critical component of disease control in men who have sex with men (MSM) sexual networks. Both printed and internet-based technologies offer potential tools to enhance traditional partner notification approaches among MSM in resource-limited settings. OBJECTIVE: This randomized controlled trial aimed to evaluate the effect of 2 different PN technologies on notification outcomes following syphilis diagnosis among MSM in Peru: a Web-based notification system and patient-delivered partner referral cards. METHODS: During 2012-2014, we screened 1625 MSM from Lima, Peru, for syphilis infection and enrolled 370 MSM with symptomatic primary or secondary syphilis (n=58) or asymptomatic latent syphilis diagnosed by serology (rapid plasma reagin, RPR, and Microhemagglutination assay for Treponema pallidum antibody; n=312). Prior to enrollment, potential participants used a computer-based self-interviewing system to enumerate their recent sexual partnerships and provide details of their 3 most recent partners. Eligible participants were randomly assigned to one of 4 intervention arms: (1) counseling and patient-initiated Web-based PN (n=95), (2) counseling with Web-based partner notification and partner referral cards (n=84), (3) counseling and partner referral cards (n=97), and (4) simple partner notification counseling (control; n=94). Self-reported partner notification was assessed after 14 days among 354 participants who returned for the follow-up assessment. RESULTS: The median age of enrolled participants was 27 (interquartile range, IQR 23-34) years, with a median of 2 partners (IQR 1-5) reported in the past month. Compared with those who received only counseling (arm 4), MSM provided with access to Web-based partner notification (arms 1 and 2) or printed partner referral cards (arms 2 and 3) were more likely to have notified one or more of their sexual partners (odds ratio, OR, 2.18, 95% CI 1.30-3.66; P=.003 and OR 1.68, 95% CI 1.01-2.79; P=.045, respectively). The proportion of partners notified was also higher in both Web-based partner notification (241/421, 57.2%; P<.001) and referral card (240/467, 51.4%; P=.006) arms than in the control arm (82/232, 35.3%). CONCLUSIONS: Both new Web-based technologies and traditional printed materials support patient-directed notification and improve self-reported outcomes among MSM with syphilis. Additional research is needed to refine the use of these partner notification tools in specific partnership contexts. TRIAL REGISTRATION: ClinicalTrials.gov NCT01720641; https://clinicaltrials.gov/ct2/show/NCT01720641 (Archived by WebCite at http://www.webcitation.org/70A89rJL4). PMID- 29970357 TI - An mHealth Intervention for Persons with Diabetes Type 2 Based on Acceptance and Commitment Therapy Principles: Examining Treatment Fidelity. AB - BACKGROUND: Web-based interventions are becoming an alternative of treatment aimed to support behavioral changes and several advantages over traditional treatments are reported. New ways of delivering an intervention may result in new challenges regarding monitoring of treatment fidelity (TF) which is essential to ensure internal and external validity. Despite the importance of the theme, only a few studies in this field are reported. OBJECTIVE: To examine TF of a mobile phone delivered intervention based on Acceptance and Commitment Therapy (ACT) with electronic diaries and written situational feedback for persons with diabetes mellitus type 2, the recommendations from the Behavior Change Consortium (BCC) established by The National Institutes of Health (NHI) were applied. To analyze fidelity, they recommend 5 areas to be investigated (1) design of the study, (2) provider training, (3) delivery of treatment, (4) receipt of treatment, and (5) enactment of treatment. In the current study, these areas were examined based on the analysis of therapists' adherence to the treatment protocol and participants' and therapists' experience with the intervention. METHODS: To investigate the therapists' adherence to the treatment protocol, a total of 251 written feedback text messages were divided into text segments. Qualitative thematic analyses were then performed to examine how ACT and other therapeutic processes were used in the feedback by the therapists. For the therapists' and participants' experience analysis, participants answered a self-reported questionnaire and participated in 2 interviews. The therapists continuously reported their experiences to the researcher responsible for the project. RESULTS: The results show high adherence to the TF strategies 20/21 (95%) applicable items of the fidelity checklist recommended by NHI BCC were identified in the present study. Measured provider skill acquisition post-training was the only item absent in the fidelity checklist. The results also show high therapists' adherence to the treatment protocol. All ACT processes (values, committed action, acceptance, contact with the present moment, self as context and cognitive defusion) were found in the coded text segments of the feedback in addition to communication and motivation strategies. For 336/730 (46%) of total possible text segments coded independently by 2 researchers, the interrater reliability measured by Cohen's kappa was .85. The evaluation of participants' and therapists' experience with the intervention was generally positive. CONCLUSIONS: Based on the analyses of therapists' adherence to the treatment protocol grounded by ACT-principles and participants' and therapists' experience with the intervention, the 5 areas of TF recommended by NHI BCC were analyzed indicating a high level of TF. These results ensure an appropriate level of internal and external validity of the study and reliable intervention results and facilitate a precise replication of this intervention concept. Web-based psychological interventions to support people with chronic conditions are becoming increasingly more common. This study supports the results from a previous study which indicated that ACT could be reliably delivered in a written web-based format. TRIAL REGISTRATION: ClinicalTrials.gov NCT01297049; https://clinicaltrials.gov/ct2/show/NCT01297049 (Archived by WebCite at http://www.webcitation.org/70WC4Cm4T). PMID- 29970358 TI - Impact of Internet-Based Interventions on Caregiver Mental Health: Systematic Review and Meta-Analysis. AB - BACKGROUND: The health of informal caregivers of adults with chronic conditions is increasingly vital since caregivers comprise a large proportion of supportive care to family members living in the community. Due to efficiency and reach, internet-based interventions for informal caregivers have the potential to mitigate the negative mental health outcomes associated with caregiving. OBJECTIVE: The objective of this systematic review and meta-analysis was to examine the impact of internet-based interventions on caregiver mental health outcomes and the impact of different types of internet-based intervention programs. METHODS: MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane, and AgeLine databases were searched for randomized controlled trials or controlled clinical trials published from January 1995 to April 2017 that compared internet-based intervention programs with no or minimal internet-based interventions for caregivers of adults with at least 1 chronic condition. The inclusion criteria were studies that included (1) adult informal caregivers (aged 18 years or older) of adults living in the community with a chronic condition; (2) an internet-based intervention program to deliver education, support, or monitoring to informal caregivers; and (3) outcomes of mental health. Title and abstract and full-text screening were completed in duplicate. Data were extracted by a single reviewer and verified by a second reviewer, and risk of bias assessments were completed accordingly. Where possible, data for mental health outcomes were meta-analyzed. RESULTS: The search yielded 7923 unique citations of which 290 studies were screened at full-text. Of those, 13 studies met the inclusion criteria; 11 were randomized controlled trials, 1 study was a controlled clinical trial, and 1 study comprised both study designs. Beneficial effects of any internet-based intervention program resulted in a mean decrease of 0.48 points (95% CI -0.75 to 0.22) for stress and distress and a mean decrease of 0.40 points (95% CI -0.58 to -0.22) for anxiety among caregivers. For studies that examined internet-based information and education plus professional psychosocial support, the meta analysis results showed small to medium beneficial effect sizes of the intervention for the mental health outcomes of depression (-0.34; 95% CI -0.63 to -0.05) and anxiety (-0.36; 95% CI -0.66 to -0.07). Some suggestion of a beneficial effect on overall health for the use of information and education plus combined peer and professional support was also shown (1.25; 95% CI 0.24 to 2.25). Overall, many studies were of poor quality and were rated at high risk of bias. CONCLUSIONS: The review found evidence for the benefit of internet-based intervention programs on mental health for caregivers of adults living with a chronic condition, particularly for the outcomes of caregiver depression, stress and distress, and anxiety. The types of interventions that predominated as efficacious included information and education with or without professional psychological support, and, to a lesser extent, with combined peer and psychological support. Further high-quality research is needed to inform the effectiveness of interactive, dynamic, and multicomponent internet-based interventions. TRIAL REGISTRATION: PROSPERO CRD42017075436; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=75436 (Archived by WebCite at http://www.webcitation.org/709M3tDvn). PMID- 29970361 TI - Sixty seconds on . . . GP chatbot. PMID- 29970359 TI - A New Online Mental Health Training Program for Workplace Managers: Pre-Post Pilot Study Assessing Feasibility, Usability, and Possible Effectiveness. AB - BACKGROUND: Mental health has become the leading cause of sickness absence in high-income countries. Managers can play an important role in establishing mentally healthy workplaces and coordinating their organization's response to a mentally ill worker. OBJECTIVE: This pilot study aims to evaluate the feasibility, usability, and likely effectiveness of a newly developed online training program for managers called HeadCoach. HeadCoach aims to build managers' confidence in supporting the mental health needs of staff and promote managerial behavior most likely to result in a more mentally healthy workplace. METHODS: In total, 66 managers from two organizations were invited to participate in this pre post pilot study of HeadCoach, which was made available to managers to complete at their own pace over a 4-week period. Data were collected at baseline and post intervention via an online research platform. The difference in mean scores for each outcome between these two time points was calculated using paired samples t tests. RESULTS: Of all the invited managers, 59.1% (39/66) participated in the trial, with complete pre-post data available for 56.4% (22/39) of the participants. The majority of respondents reported positive engagement with the program. During the study period, managers' knowledge regarding their role in managing mental health issues (P=.01) and their confidence in communicating with employees regarding mental illness (P<.001) significantly increased. In addition, a significant increase was observed from the baseline in managers' self-reported actions to use strategies to prevent and decrease stress among their team members (P=.02). CONCLUSIONS: Although caution is needed due to the absence of a control group, preliminary results of this study suggest that HeadCoach could be a feasible, acceptable, and efficient method of training managers in best workplace practices to help support the mental health needs of their staff. PMID- 29970362 TI - Period poverty: five minutes with . . . Eleanor Wilson. PMID- 29970360 TI - Identifying Barriers and Facilitators of 13 mHealth Projects in North America and Africa: Protocol for a 5-Year Implementation Science Study. AB - BACKGROUND: Although many mHealth interventions have shown efficacy in research, few have been effectively implemented and sustained in real-world health system settings. Despite this programmatic gap, there is limited conclusive evidence identifying the factors that affect the implementation and successful integration of mHealth into a health system. OBJECTIVE: The aim of this study is to examine the individual, organizational, and external level factors associated with the effective implementation of WelTel, an mHealth intervention designed to support outpatient medication adherence and engagement in care in Africa and North America. METHODS: We will adopt the Consolidated Framework for Implementation Research (CFIR) constructs for evaluation of mHealth implementation including a scoring and monitoring system. We will apply the adapted tool to identify facilitators and barriers to implementation of the WelTel mHealth intervention in order to determine how the technology platform is perceived, diffused, adapted, and used by different mHealth project teams and health system actors in Africa and North America. We will use a mixed-methods approach to quantitatively test whether the factors identified in the CFIR framework are associated with the successful uptake of the mHealth intervention toward implementation goals. We will triangulate these data through interviews and focus group discussion with project stakeholders, exploring factors associated with successful implementation and sustainment of these interventions. RESULTS: The development of the customized CFIR is finalized and currently is in pilot testing. The initial results of the use of the tool in those 13 implementations will be available in 2019. Continuous conference and peer- reviewed publications will be published in the coming years. CONCLUSIONS: The results of this study will provide an in-depth understanding of individual, organizational, and external level factors that influence the successful implementation of mHealth in different health systems and geographic contexts over time. Via the tool's unique scoring system connected to qualitative descriptors, these data will inform the most critical implementation targets and contribute to the tailoring of strategies that will assist the health system in overcoming barriers to implementation, and ultimately, improve treatment adherence and engagement in care. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9633. PMID- 29970363 TI - Buffer or Suffer: Redesigning Heart Failure Postdischarge Clinic Using Queuing Theory. PMID- 29970364 TI - Cystathionine gamma Lyase Sulfhydrates the RNA Binding Protein HuR to Preserve Endothelial Cell Function and Delay Atherogenesis. AB - Background -Hydrogen sulfide (H2S), generated by cystathionine gamma lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and pro-atherogenic conditions. Methods Endothelial cell CSE knock out mice were generated and lung endothelial cells were studied in vitro (gene expression, protein sulfhydration and monocyte adhesion). Mice were crossed onto the ApoE-/- background and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, H2S bioavailability and amino acid profiling were also performed using human material. Results -The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein HuR. CSE expression was upregulated in mice following partial carotid artery ligation as well as in atheromas from human subjects. Despite the increase in CSE protein, circulating and intra-plaque H2S levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely due to increased IL-1beta. Consistent with the loss of H2S, HuR sulfhydration was attenuated in atherosclerosis, and resulted in the stabilization of HuR-target mRNAs e.g. CD62E and cathepsin S, both of which are linked with endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed upon treatment with a H2S donor. Finally, in mice and humans, plasma levels of the CSE substrate; L-cystathionine, negatively correlated with vascular reactivity and H2S levels indicating its potential use as a biomarker for vascular disease. Conclusions -The constitutive S-sulfhydration of HuR (on Cys13) by CSE-derived H2S prevents its homo-dimerization and activity which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation the beneficial actions of CSE-derived H2S are lost due to the phosphorylation and inhibition of the enzyme. PMID- 29970366 TI - Inorganic phosphate as a potential risk factor for chronic disease. PMID- 29970365 TI - MMP (Matrix Metalloprotease)-9-Producing Monocytes Enable T Cells to Invade the Vessel Wall and Cause Vasculitis. AB - RATIONALE: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. OBJECTIVE: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent. METHODS AND RESULTS: The tissue transcriptome of GCA-affected temporal arteries contained high amounts of MMP-9 transcripts, and immunostaining for pro-MMP-9 localized the enzyme to wall-infiltrating macrophages. MMP-2 and MMP-9 transcripts were also abundant in monocytes and monocyte-derived macrophages from patients with GCA. Patient-derived monocytes outperformed healthy monocytes in passing through engineered basement membranes. GCA CD (cluster of differentiation) 4+ T cells required MMP-9-producing monocytes to penetrate through matrix built from type IV collagen. In vivo functions of MMP-9 were tested in a human artery-SCID (severe combined immunodeficiency) chimera model by blocking enzyme activity with a highly specific monoclonal antibody or by injecting rMMP-9 (recombinant MMP-9). Inhibiting MMP-9 activity profoundly suppressed vascular injury, decreased the density of inflammatory infiltrates ( P<0.001), reduced intramural neoangiogenesis ( P<0.001), and prevented intimal layer hyperplasia ( P<0.001). rMMP-9 amplified all domains of vasculitic activity, promoted assembly of T-cell infiltrates ( P<0.05), intensified formation of new microvessels ( P<0.001), and worsened intimal thickening ( P<0.001). Systemic delivery of N-acetyl-proline-glycine-proline-a matrikine produced by MMP-9-mediated gelatinolysis-had limited vasculitogenic effects. CONCLUSIONS: In large vessel vasculitis, MMP-9 controls the access of monocytes and T cells to the vascular wall. T cells depend on MMP-9-producing monocytes to pass through collagen IV-containing basement membrane. Invasion of vasculitogenic T cells and monocytes, formation of neoangiogenic networks, and neointimal growth all require the enzymatic activity of MMP-9, identifying this protease as a potential therapeutic target to restore the immunoprivilege of the arterial wall in large vessel vasculitis. PMID- 29970367 TI - Anticonvulsants in the treatment of low back pain and lumbar radicular pain: a systematic review and meta-analysis. AB - BACKGROUND: The use of anticonvulsants (e.g., gabapentin, pregabalin) to treat low back pain has increased substantially in recent years despite limited supporting evidence. We aimed to determine the efficacy and tolerability of anticonvulsants in the treatment of low back pain and lumbar radicular pain compared with placebo. METHODS: A search was conducted in 5 databases for studies comparing an anticonvulsant to placebo in patients with nonspecific low back pain, sciatica or neurogenic claudication of any duration. The outcomes were self reported pain, disability and adverse events. Risk of bias was assessed using the Physiotherapy Evidence Database (PEDro) scale, and quality of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Data were pooled and treatment effects were quantified using mean differences for continuous and risk ratios for dichotomous outcomes. RESULTS: Nine trials compared topiramate, gabapentin or pregabalin to placebo in 859 unique participants. Fourteen of 15 comparisons found anticonvulsants were not effective to reduce pain or disability in low back pain or lumbar radicular pain; for example, there was high-quality evidence of no effect of gabapentinoids versus placebo on chronic low back pain in the short term (pooled mean difference [MD] -0.0, 95% confidence interval [CI] -0.8 to 0.7) or for lumbar radicular pain in the immediate term (pooled MD -0.1, 95% CI -0.7 to 0.5). The lack of efficacy is accompanied by increased risk of adverse events from use of gabapentinoids, for which the level of evidence is high. INTERPRETATION: There is moderate- to high-quality evidence that anticonvulsants are ineffective for treatment of low back pain or lumbar radicular pain. There is high-quality evidence that gabapentinoids have a higher risk for adverse events. PROTOCOL REGISTRATION: PROSPERO-CRD42016046363. PMID- 29970369 TI - Prepubertal vulvovaginitis. PMID- 29970368 TI - Care of community-dwelling older adults with dementia and their caregivers. PMID- 29970370 TI - Perirenal soft tissue infiltration from immunoglobulin G4-related disease. PMID- 29970371 TI - Reducing food insecurity and improving health with a basic income guarantee. PMID- 29970372 TI - Investing appropriately to alleviate child poverty in Canada. PMID- 29970373 TI - Inequity a root cause of poor health among Indigenous peoples. PMID- 29970374 TI - Mediterranean diets and metabolic syndrome status in the PREDIMED randomized trial. PMID- 29970375 TI - Medical school admission requirements lock out many Indigenous students. PMID- 29970376 TI - CMA phasing out annual General Council meeting. PMID- 29970377 TI - Physician health charter calls on health systems, organizations to share responsibility for burnout. PMID- 29970378 TI - Migrant children in US were given range of psychotropic drugs to control behaviour, lawsuits allege. PMID- 29970379 TI - Impact of Ventricular Morphology on Fiber Stress and Strain in Fontan Patients. AB - BACKGROUND: Right ventricular (RV) morphology has been associated with adverse clinical outcomes in Fontan patients. The impact of RV versus left ventricular morphology on ventricular stress and strain in single ventricles is not well known. METHODS AND RESULTS: Cardiac magnetic resonance examinations in 193 patients with the Fontan circulation were retrospectively analyzed. Ventricular mass, volume, global circumferential and longitudinal strain, and global average end-systolic fiber stress were calculated using previously published methods. Compared with left ventricular morphology, RV morphology (48%) was associated with higher ventricular end-diastolic volume (110 mL/BSA1.3 versus 84 mL/BSA1.3, P<0.001), lower mass-to-volume ratio (0.46 versus 0.57, P<0.001), higher global average end-systolic fiber stress (23 kPa versus 20 kPa, P=0.002), worse global circumferential strain (-21% versus -24%, P<0.001), and higher prevalence of greater than or equal to moderate atrioventricular valve regurgitation (25% versus 6%, P<0.001). Ejection fraction and global longitudinal strain were similar between the groups. Death or listing for heart transplantation occurred in 24 (12%) with a median follow-up of 6.2 years. On univariate analysis, RV morphology, ventricular dilatation, and worse global circumferential strain were associated with this composite outcome. CONCLUSIONS: In comparison to Fontan patients with a dominant left ventricle, those with a dominant RV have higher fiber stress, a higher rate of ventricular dilatation, lower circumferential fiber shortening, and similar longitudinal shortening. RV morphology, ventricular dilation, and worse circumferential strain are associated with death or heart transplantation. The difference in myofiber architecture may contribute to suboptimal adaptation of the RV as a systemic ventricle. PMID- 29970380 TI - Caseous Calcification of the Mitral Annulus With Atrial and Ventricular Fistulization. PMID- 29970381 TI - High-Risk Plaque Regression and Stabilization: Hybrid Noninvasive Morphological and Hemodynamic Assessment. PMID- 29970382 TI - Stress in the Single Ventricle: Old Concepts, New Tools. PMID- 29970383 TI - David Oliver: Are we rushing patients home before they're ready? PMID- 29970385 TI - Transitioning From "Sick Kid" to Community Health Worker: Building Better Bridges to Adult Care. PMID- 29970386 TI - Health of Infants After ART-Treated, Subfertile, and Fertile Deliveries. AB - OBJECTIVES: To assess the risk of adverse health outcomes for infants after assisted reproductive technology (ART)-treated and subfertile as compared with fertile deliveries. METHODS: Live-born singleton infants >=23 weeks' gestational age (GA) born in Massachusetts between July 1, 2004, and December 31, 2010, were analyzed by linking a clinical ART database with state vital records. chi2 tests were used to compare the outcomes of fertile (those without ART treatment or other indicators of infertility), subfertile (indicators of infertility, no ART), and ART-treated (linked to ART deliveries) mothers, stratified by GA. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated by using multivariate logistic regression within each GA stratum, controlling for maternal sociodemographic and health characteristics. RESULTS: Compared with infants of fertile mothers (n = 336 705), infants born to subfertile (n = 5043) or ART treated (n = 8375) mothers were more likely to be preterm (aOR 1.39 [95% CI 1.26 1.54] and aOR 1.72 [95% CI 1.60-1.85], respectively) and have respiratory and gastrointestinal and/or nutritional conditions (aOR range: 1.12-1.18). When stratified by GA, infants of subfertile or ART-treated mothers were at greater risk for congenital malformations and infectious diseases as well as cardiovascular and respiratory conditions (aOR range: 1.30-2.61; 95% CI range: 1.02-4.59). Compared with infants born to subfertile mothers, infants born to ART treated mothers were at lower risk for being small for GA and having congenital malformations and cardiovascular conditions and at higher risk for infectious disease conditions. CONCLUSIONS: Compared with infants born to fertile mothers, infants of subfertile and ART-treated mothers are at greater risk for adverse health outcomes at birth beyond prematurity. The occurrence and magnitude of these risks vary by GA and organ systems. PMID- 29970388 TI - Disseminated coccidioidomycosis. PMID- 29970387 TI - Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63+/-0.74) was significantly increased (p=0.037) compared with the preconception year (0.50+/-0.71) as well as the postabortion mean number of new Gd+ lesions (0.77+/-1.40 vs 0.39+/-1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly. PMID- 29970389 TI - Randomised, prospective clinical trial of platelet-rich plasma injection in the management of severe dry eye. AB - BACKGROUND: To evaluate the effectiveness of platelet-rich plasma (PRP) injections in the treatment of severe dry eye. METHODS: This prospective, intervention study included patients with severe dry eye who had been diagnosed with Sjogren syndrome. Patients were divided into two groups. The intervention group received PRP (n=15) injections on days 0, 30, 60 and 90, as well as hyaluronic acid five times per day. The comparison group received hyaluronic acid (n=15) five times per day. Subjects were measured at baseline and at 30, 60 and 90 days. The primary outcome measures were changes in corneal staining according to the Oxford classification, results of the Schirmer test and tear break-up time (TBUT). The secondary outcome measures were changes in the Ocular Surface Disease Index (OSDI) and treatment compliance. RESULTS: All subjects completed the study. The intervention group showed improvements in all primary outcome measures when compared with the control group, including a reduction in corneal staining (p<0.001), increase in the mean Schirmer value from 5.6+/-0.7 to 9.0+/-1.1 mm, and an increase in TBUT from 4.0+/-0.4 to 6.4+/-0.4 s at day 90. An improvement in subjective OSDI values was also found. CONCLUSION: PRP injection is safe and effective in improving tear parameters as well as subjective parameters, and was found to be superior to hyaluronic acid alone in the management of patients with severe dry eye. This represent a novel alternative treatment for severe dry eye. TRIAL REGISTRATION NUMBER: NCT02257957. PMID- 29970390 TI - Impact of car transport availability and drive time on eye examination uptake among adults aged >=60 years: a record linkage study. AB - AIM: To examine associations between uptake of free primary eye care, service availability (density of optometric practices) and service accessibility (household car access and drive time to nearest provider) after accounting for socioeconomic status and other individual, household and area factors. METHODS: We constructed a cohort of 294 870 community-dwelling adults aged 60 years, drawing contextual information from the 2011 Northern Ireland Census. Minimum drive times to the nearest optometry practice (1-19 min) and number of practices were derived for 890 geographical areas. The primary outcome was attendance at one or more publicly funded eye examinations to which all cohort members were entitled between 2009 and 2014. We used multiple log-binomial regression to estimate associations between eye care uptake, car ownership and drive time. RESULTS: Eye examination uptake was 60.0%. 23.7% of the cohort had no car access, and these individuals had lower uptake than car owners (unadjusted risk ratio (RR) of uptake=0.86 (0.86, 0.87)). Among non-car owners, uptake decreased with drive time (longest vs shortest: RR=0.92 (0.88, 0.97)) with the largest decrease at 4 min drive time (approximately 1.5 miles). This pattern was weaker among car owners. These associations were independent of service availability, which was not associated with uptake. CONCLUSION: Both drive time and household car access were associated with eye care use, adjusting for individual, household and area factors. Policies to improve uptake should target those with no car access, especially those beyond walking distance from the nearest eye care provider. PMID- 29970384 TI - Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features. AB - Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent. PMID- 29970391 TI - Allogeneic transplantation using TLI-ATG conditioning for Hodgkin lymphoma after failure of autologous transplantation. PMID- 29970393 TI - Selection of men for investigation of possible testicular cancer in primary care: a large case-control study using electronic patient records. AB - BACKGROUND: Testicular cancer incidence has risen over the last two decades and is expected to continue to rise. There are no primary care studies on the clinical features of testicular cancer, with recent National Institute for Health and Care Excellence (NICE) guidance based solely upon clinical consensus. AIM: To identify clinical features of testicular cancer and to quantify their risk in primary care patients, with the aim of improving the selection of patients for investigation. DESIGN AND SETTING: A matched case-control study in males aged >=17 years, using Clinical Practice Research Datalink records. METHOD: Putative clinical features of testicular cancer were identified and analysed using conditional logistic regression. Positive predictive values (PPVs) were calculated for those aged <50 years. RESULTS: In all, 1398 cases were available, diagnosed between 2000 and 2012, with 4956 age-, sex-, and practice-matched controls. Nine features were independently associated with testicular cancer, the top three being testicular swelling (odds ratio [OR] 280, 95% confidence interval [CI] = 110 to 690), testicular lump (OR 270, 95% CI = 100 to 740), and scrotal swelling (OR 170, 95% CI = 35 to 800). The highest PPV for 17-49-year-olds was testicular lump, at 2.5% (95% CI = 1.1 to 5.6). Combining testicular lump with testicular swelling or testicular pain produced PPVs of 17% and 10%, respectively. CONCLUSION: Testicular enlargement carries a risk of cancer of 2.5% - close to the current 3% threshold in UK referral guidance. Contrary to traditional teaching, painful testicular enlargement may signify cancer. Some initial hydrocele diagnoses appear to be wrong, with missed cancers, suggesting an ultrasound may be useful when a hydrocele diagnosis is uncertain. These results support the existing NICE guidelines, and help to characterise when an ultrasound should be considered in symptomatic men. PMID- 29970392 TI - Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells. AB - CD38 is a transmembrane exoenzyme that is associated with poor prognosis in chronic lymphocytic leukemia (CLL). High CD38 levels in CLL cells are linked to increased cell migration, but the molecular basis is unknown. CD38 produces nicotinic acid adenine dinucleotide phosphate and adenosine 5'-diphosphate ribose, both of which can act to increase intracellular Ca2+ levels. Here we show that CD38 expression increases basal intracellular Ca2+ levels and stimulates CLL cell migration both with and without chemokine stimulation. We find that CD38 acts via intracellular Ca2+ to increase the activity of the Ras family GTPase Rap1, which is in turn regulated by the Ca2+-sensitive Rap1 guanine-nucleotide exchange factor RasGRP2. Both Rap1 and RasGRP2 are required for CLL cell migration, and RasGRP2 is polarized in primary CLL cells with high CD38 levels. These results indicate that CD38 promotes RasGRP2/Rap1-mediated CLL cell adhesion and migration by increasing intracellular Ca2+ levels. PMID- 29970394 TI - Impact of a single eGFR and eGFR-estimating equation on chronic kidney disease reclassification: a cohort study in primary care. AB - BACKGROUND: Chronic kidney disease (CKD) is diagnosed using the estimated glomerular filtration rate (eGFR) and the urinary albumin:creatinine ratio (ACR). The eGFR is calculated from serum creatinine levels using the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. AIM: To compare the performance of one versus two eGFR/ACR measurements, and the impact of equation choice, on CKD diagnosis and classification. DESIGN AND SETTING: Cohort study in primary care in the Thames Valley region of the UK. METHOD: Data were from 485 participants aged >60 years in the Oxford Renal Cohort Study with at least two eGFR tests. The proportion of study participants diagnosed and classified into different CKD stages using one and two positive tests were compared. Prevalence of CKD diagnosis and classification by CKD stage were compared when eGFR was calculated using MDRD and CKD-EPI equations. RESULTS: Participants included in the analysis had a mean age of 72.1 (+/-6.8) years and 57.0% were female. Use of a single screening test overestimated the proportion of people with CKD by around 25% no matter which equation was used, compared with the use of two tests. The mean eGFR was 1.4 ml/min/1.73 m2 (95% CI = 1.1 to 1.6) higher using the CKD-EPI equation compared with the MDRD equation. More patients were diagnosed with CKD when using the MDRD equation, compared with the CKD-EPI equation, once (64% versus 63%, respectively) and twice (39% versus 38%, respectively), and 16 individuals, all of who had CKD stages 2 or 3A with MDRD, were reclassified as having a normal urinary ACR when using the CKD-EPI equation. CONCLUSION: Current guidance to use two eGFR measures to diagnose CKD remains appropriate in an older primary care population to avoid overdiagnosis. A change from MDRD to CKD-EPI equation could result in one in 12 patients with a CKD diagnosis with MDRD no longer having a diagnosis of CKD. PMID- 29970395 TI - Measles: is it still a threat? PMID- 29970396 TI - Hypertension referrals from community pharmacy to general practice: multivariate logistic regression analysis of 131 419 patients. AB - BACKGROUND: The burden of hypertension in primary care is high, and alternative models of care, such as pharmacist management, have shown promise. However, data describing outcomes from routine consultations between pharmacists and patients with hypertension are lacking. AIM: To identify factors associated with referral of patients from pharmacies to general practice within the first 2 weeks of starting a new antihypertensive medication. DESIGN AND SETTING: Multivariate logistic regression conducted on data from community pharmacies in England. METHOD: Data were obtained from the New Medicine Service between 2011 and 2012. Analyses were conducted on 131 419 patients. In all, 15 predictors were included in the model, grouped into three categories: patient-reported factors, demographic factors, and medication-related factors. RESULTS: Mean patient age was 65 years (+/-13 years), and 85% of patients were of white ethnicity. A total of 5895 (4.5%) patients were referred by a pharmacist to a GP within the first 2 weeks of starting a new antihypertensive medication. Patients reporting side effects (adjusted odds ratio [OR] 11.60, 95% confidence interval [CI] = 10.85 to 12.41) were most likely to be referred. Prescriptions for alpha-blockers were associated with referral (adjusted OR 1.28, 95% CI = 1.12 to 1.47), whereas patients receiving angiotensin-II receptor blockers were less likely to be referred (adjusted OR 0.89, 95% CI = 0.80 to 0.99). CONCLUSION: Most patients were followed up by pharmacists without the need for referral. Patient-reported side effects, medication-related concerns, and the medication class prescribed influenced referral. These data are reassuring, in that additional pharmacist involvement does not increase medical workload appreciably, and support further development of pharmacist-led hypertension interventions. PMID- 29970397 TI - Variation in anticoagulation for atrial fibrillation between English clinical commissioning groups: an observational study. AB - BACKGROUND: Despite improvement in anticoagulation for atrial fibrillation (AF), substantial variation in anticoagulation persists between clinical commissioning groups (CCGs) and regions in England. AIM: To identify reasons for variation between English CCGs in anticoagulation for AF. DESIGN AND SETTING: A 4-year observational study from 2012/2013 to 2015/2016, of the national Quality and Outcomes Framework. METHOD: Multiple regression and Pearson's correlation coefficients were used to analyse anticoagulation for AF in relation to older age, Index of Multiple Deprivation, prescription of non-vitamin K antagonist oral anticoagulants (NOACs), and exception reporting, as well as stroke hospital admission and mortality. RESULTS: The proportion of eligible patients in England prescribed anticoagulants for AF without exceptions for clinical complexity or patient dissent increased from 65.1% in 2012/2013 to 77.9% in 2015/2016. In 2015, 290 920 additional eligible people were anticoagulated in association with use of the CHA2DS2VASc rather than CHADS2 score. From 2012 to 2015, exception reporting almost halved from 20% to 10.2%. Variation in CCG anticoagulation was not associated with deprivation or NOAC use. There was a strong negative association between exception reporting representing patient complexity and anticoagulation performance, accounting for 57% of the variation in anticoagulation without exceptions (multiple regression coefficient = -0.81; 95% confidence intervals = 0.92 to -0.71; P<0.001). CONCLUSION: Anticoagulation for AF has improved substantially in England in association with considerable increases in the eligible population as a result of decreased exception reporting and the use of the CHA2DS2VASc score. There is still substantial room for improvement in most CCGs because, even allowing for exceptions, nine out of 10 CCGs failed to achieve 90% anticoagulation. PMID- 29970399 TI - Clinical Characteristics and Health Outcomes of Neonates Reporting to the Emergency Department With Hypothermia. AB - OBJECTIVES: Although hypothermia has long been considered a sign of serious bacterial infection (SBI) in neonates, there is a lack of medical literature on this topic, and little is known about the prevalence of serious infection in these patients. Our primary objective was to assess the prevalence and type of serious infection in neonates with hypothermia. Our secondary objective was to describe the prevalence and type of significant pathology overall in this cohort. METHODS: We examined neonates (<=28 days old) evaluated in the emergency department and/or admitted to the hospital with hypothermia over a 3-year period. Demographics and relevant clinical data were extracted from the medical record. Fisher's exact test was used to determine differences in the prevalence of clinical and demographic characteristics in patients with and without a diagnosis of serious infection. RESULTS: Sixty-eight neonates met inclusion criteria, and 63 (93%) were admitted. Of those admitted to the hospital, 5 (7.9%) had a diagnosis of serious infection, including SBI (n = 4) and disseminated herpes simplex virus (n = 1). The types of SBI included urinary tract infection, septicemia, and meningitis. Eighty percent and 60% of neonates with hypothermia and diagnosed with serious infection had a temperature <=34.4 degrees C and ill appearance, respectively. Significant pathology was found in 9 (14.3%) patients and included both infectious and noninfectious diagnoses. CONCLUSIONS: Neonates presenting with hypothermia have a substantial risk for SBI or other significant pathology. This population merits further investigation; a multicenter prospective study should be conducted to better understand associations between risk factors and outcomes. PMID- 29970400 TI - Genes, smoking, and organic solvent exposure: An alarming cocktail for MS risk. PMID- 29970398 TI - Optimising Genomic Selection in Wheat: Effect of Marker Density, Population Size and Population Structure on Prediction Accuracy. AB - Genomic selection applied to plant breeding enables earlier estimates of a line's performance and significant reductions in generation interval. Several factors affecting prediction accuracy should be well understood if breeders are to harness genomic selection to its full potential. We used a panel of 10,375 bread wheat (Triticum aestivum) lines genotyped with 18,101 SNP markers to investigate the effect and interaction of training set size, population structure and marker density on genomic prediction accuracy. Through assessing the effect of training set size we showed the rate at which prediction accuracy increases is slower beyond approximately 2,000 lines. The structure of the panel was assessed via principal component analysis and K-means clustering, and its effect on prediction accuracy was examined through a novel cross-validation analysis according to the K-means clusters and breeding cohorts. Here we showed that accuracy can be improved by increasing the diversity within the training set, particularly when relatedness between training and validation sets is low. The breeding cohort analysis revealed that traits with higher selection pressure (lower allelic diversity) can be more accurately predicted by including several previous cohorts in the training set. The effect of marker density and its interaction with population structure was assessed for marker subsets containing between 100 and 17,181 markers. This analysis showed that response to increased marker density is largest when using a diverse training set to predict between poorly related material. These findings represent a significant resource for plant breeders and contribute to the collective knowledge on the optimal structure of calibration panels for genomic prediction. PMID- 29970401 TI - IgLON5: A case with predominant cerebellar tau deposits and leptomeningeal inflammation. PMID- 29970402 TI - Validating the targets for neurostimulation in essential tremor. PMID- 29970403 TI - Cholesterol levels, statins, and spontaneous intracerebral hemorrhage: An interesting but complicated story. PMID- 29970404 TI - DBS of the PSA and the VIM in essential tremor: A randomized, double-blind, crossover trial. AB - OBJECTIVE: To evaluate deep brain stimulation (DBS) of the posterior subthalamic area (PSA) in essential tremor (ET) and compare it to the ventral intermediate nucleus of the thalamus (VIM) in terms of stimulation efficacy, efficiency, and side effects. METHODS: DBS leads were implanted such that contacts were placed in the VIM, on the intercommissural line, and in the PSA. Thirteen patients with ET entered a randomized, double-blind crossover phase and completed a 1-year follow up. RESULTS: PSA-DBS significantly reduced tremor severity and improved quality of life. There were no relevant differences in quality and frequency of stimulation side effects between VIM and PSA, with a tendency toward greater tremor improvement with PSA stimulation. Clinical benefit was achieved at significantly lower stimulation amplitudes in the PSA. The majority of patients remained with PSA-DBS after 1 year. CONCLUSION: In accordance with previous retrospective investigations, our prospective data suggest that PSA-DBS is at least equally effective as but possibly more efficient than VIM-DBS. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with essential tremor, PSA-DBS is not significantly different from VIM DBS in suppressing tremor, but clinical benefit from PSA-DBS is attained at lower stimulation amplitudes. PMID- 29970405 TI - Association of statin use with spontaneous intracerebral hemorrhage: A cohort study. AB - OBJECTIVE: To examine the association between statin exposure in a dose-dependent manner and intracerebral hemorrhage (ICH) in a large nationwide study. METHODS: The computerized database of the largest health care provider in Israel was used to identify diagnosed ICH among new users of statins, who started statin treatment between 2005 and 2010. We assessed a dose-response relationship between ICH and statins, using the average atorvastatin equivalent daily dose (AAEDD). Multivariable Cox proportional hazard regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio of ICH. RESULTS: Of the 345,531 included patients, 1,304 were diagnosed with ICH during a median follow-up of 9.5 years (interquartile range 7.6-11.0). Overall, 75.3% of patients had AAEDD <10 mg/d, 19.0% had AAEDD 0-19.9 mg/d, and 5.7% had AAEDD >=20 mg/d. The corresponding proportions were 81.0%, 15.0%, 4.0% among ICH cases, and 75.3%, 19.0%, 5.7% among non-ICH cases. Compared to those with AAEDD <10 mg/d (reference), the adjusted hazard ratio (HR) for ICH was 0.68 (95% confidence interval [CI] 0.58-0.79) in those with AAEDD 10-19.9 mg/d, and 0.62 (0.47-0.81) in those with AAEDD >=20 mg/d. Compared to the lowest baseline total cholesterol quartile, the adjusted HR for ICH was 0.71 (95% CI 0.62-0.82), 0.55 (0.47-0.64), and 0.57 (0.49-0.67) in those in the second, third, and highest quartiles, respectively. The results were similar and robust among highly persistent statin users and after controlling for the change in cholesterol level. CONCLUSIONS: This study confirms that the risk of ICH decreases with increasing cholesterol levels, but suggests that statin use might be associated with decreased risk of ICH. PMID- 29970406 TI - Organic solvents and MS susceptibility: Interaction with MS risk HLA genes. AB - OBJECTIVE: We hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes. METHODS: Using a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction. RESULTS: Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2 1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB1*15, and absence of HLA-A*02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure. CONCLUSION: The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS. PMID- 29970407 TI - Implementation and optimization of molecular rapid diagnostic tests for bloodstream infections. AB - PURPOSE: The implementation and optimization of molecular rapid diagnostic tests (mRDTs) as an antimicrobial stewardship intervention for patients with bloodstream infections (BSIs) are reviewed. SUMMARY: All U.S. acute care hospitals accredited by the Joint Commission are required to implement an antimicrobial stewardship program (ASP). Of the many interventions available to ASPs, mRDTs have demonstrated consistent, meaningful results on antimicrobial optimization and patient outcomes. Even among infectious diseases and antimicrobial stewardship-trained pharmacists, significant knowledge and familiarity gaps exist regarding available mRDTs and how best to implement and optimize them. Given the paucity of infectious diseases and/or antimicrobial stewardship-trained pharmacists, the mandates for establishing ASPs will require non-infectious diseases/antimicrobial stewardship-trained pharmacists to implement stewardship interventions, which may include mRDTs, within their institution. Optimization of mRDTs requires adequate diagnostic stewardship, specifically evaluating how mRDT implementation may decrease costs and assist in meeting antimicrobial stewardship regulatory requirements. Knowledge of how these technologies will augment existing microbiology and antimicrobial stewardship workflow is essential. Finally, selecting the right mRDT necessitates familiarity with the instrument's capabilities and with the institutional antibiogram. CONCLUSION: mRDTs have demonstrated the ability to be one of the most powerful antimicrobial stewardship interventions. Pharmacists required to implement an ASP in their institution should consider mRDTs as standard of care for patients with BSIs. PMID- 29970409 TI - More real-world trials are needed to establish if web-based physical activity interventions are effective. PMID- 29970408 TI - Predicted lean body mass, fat mass, and all cause and cause specific mortality in men: prospective US cohort study. AB - OBJECTIVE: To investigate the association of predicted lean body mass, fat mass, and body mass index (BMI) with all cause and cause specific mortality in men. DESIGN: Prospective cohort study. SETTING: Health professionals in the United States PARTICIPANTS: 38 006 men (aged 40-75 years) from the Health Professionals Follow-up Study, followed up for death (1987-2012). MAIN OUTCOME MEASURES: All cause and cause specific mortality. RESULTS: Using validated anthropometric prediction equations previously developed from the National Health and Nutrition Examination Survey, lean body mass and fat mass were estimated for all participants. During a mean of 21.4 years of follow-up, 12 356 deaths were identified. A J shaped association was consistently observed between BMI and all cause mortality. Multivariable adjusted Cox models including predicted fat mass and lean body mass showed a strong positive monotonic association between predicted fat mass and all cause mortality. Compared with those in the lowest fifth of predicted fat mass, men in the highest fifth had a hazard ratio of 1.35 (95% confidence interval 1.26 to 1.46) for mortality from all causes. In contrast, a U shaped association was found between predicted lean body mass and all cause mortality. Compared with those in the lowest fifth of predicted lean body mass, men in the second to fourth fifths had 8-10% lower risk of mortality from all causes. In the restricted cubic spline models, the risk of all cause mortality was relatively flat until 21 kg of predicted fat mass and increased rapidly afterwards, with a hazard ratio of 1.22 (1.18 to 1.26) per standard deviation. For predicted lean body mass, a large reduction of the risk was seen within the lower range until 56 kg, with a hazard ratio of 0.87 (0.82 to 0.92) per standard deviation, which increased thereafter (P for non-linearity <0.001). For cause specific mortality, men in the highest fifth of predicted fat mass had hazard ratios of 1.67 (1.47 to 1.89) for cardiovascular disease, 1.24 (1.09 to 1.43) for cancer, and 1.26 (0.97 to 1.64) for respiratory disease. On the other hand, a U shaped association was found between predicted lean body mass and mortality from cardiovascular disease and cancer. However, a strong inverse association existed between predicted lean body mass and mortality from respiratory disease (P for trend <0.001). CONCLUSIONS: The shape of the association between BMI and mortality was determined by the relation between two body components (lean body mass and fat mass) and mortality. This finding suggests that the "obesity paradox" controversy may be largely explained by low lean body mass, rather than low fat mass, in the lower range of BMI. PMID- 29970410 TI - Calnexin revealed as an ether-a-go-go chaperone by getting mutant worms up and going. AB - The role of ion channels in cell excitability was first revealed in a series of voltage clamp experiments by Hodgkin and Huxley in the 1950s. However, it was not until the 1970s that patch-clamp recording ushered in a revolution that allowed physiologists to witness how ion channels flicker open and closed at angstrom scale and with microsecond resolution. The unexpectedly tight seal made by the patch pipette in the whole-cell configuration later allowed molecular biologists to suck up the insides of identified cells to unveil their unique molecular contents. By refining these techniques, researchers have scrutinized the surface and contents of excitable cells in detail over the past few decades. However, these powerful approaches do not discern which molecules are responsible for the dynamic control of the genesis, abundance, and subcellular localization of ion channels. In this dark territory, teams of unknown and poorly understood molecules guide specific ion channels through translation, folding, and modification, and then they shuttle them toward and away from distinct membrane domains via different subcellular routes. A central challenge in understanding these processes is the likelihood that these diverse regulatory molecules may be specific to ion channel subtypes, cell types, and circumstance. In work described in this issue, Bai et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812025) begin to shed light on the biogenesis of UNC-103, a K+ channel found in Caenorhabditis elegans. PMID- 29970411 TI - No voltage change at skeletal muscle SR membrane during Ca2+ release-just Mermaids on acid. AB - Calcium ions control multiple physiological functions by binding to extracellular and intracellular targets. One of the best-studied Ca2+-dependent functions is contraction of smooth and striated muscle tissue, which results from Ca2+ ligation to calmodulin and troponin C, respectively. Ca2+ signaling typically involves flux of the ion across membranes via specifically gated channel proteins. Because calcium ions are charged, they possess the ability to generate changes in the respective transmembrane voltage. Ca2+-dependent voltage alterations of the surface membrane are easily measured using microelectrodes. A well-known example is the characteristic plateau phase of the action potential in cardiac ventricular cells that results from the opening of voltage-gated L-type Ca2+ channels. Ca2+ ions are also released from intracellular storage compartments in many cells, but these membranes are not accessible to direct voltage recording with microelectrodes. In muscle, for example, release of Ca2+ from the sarcoplasmic reticulum (SR) to the myoplasm constitutes a flux that is considerably larger than the entry flux from the extracellular space. Whether this flux is accompanied by a voltage change across the SR membrane is an obvious question of mechanistic importance and has been the subject of many investigations. Because the tiny spaces enclosed by the SR membrane are inaccessible to microelectrodes, alternative methods have to be applied. In a study by Sanchez et al. (2018. J. Gen. Physiol. https://doi.org/10.1085/jgp.201812035) in this issue, modern confocal light microscopy and genetically encoded voltage probes targeted to the SR were applied in a new approach to search for changes in the membrane potential of the SR during Ca2+ release. PMID- 29970412 TI - Heat-resistant action potentials require TTX-resistant sodium channels NaV1.8 and NaV1.9. AB - Damage-sensing nociceptors in the skin provide an indispensable protective function thanks to their specialized ability to detect and transmit hot temperatures that would block or inflict irreversible damage in other mammalian neurons. Here we show that the exceptional capacity of skin C-fiber nociceptors to encode noxiously hot temperatures depends on two tetrodotoxin (TTX)-resistant sodium channel alpha-subunits: NaV1.8 and NaV1.9. We demonstrate that NaV1.9, which is commonly considered an amplifier of subthreshold depolarizations at 20 degrees C, undergoes a large gain of function when temperatures rise to the pain threshold. We also show that this gain of function renders NaV1.9 capable of generating action potentials with a clear inflection point and positive overshoot. In the skin, heat-resistant nociceptors appear as two distinct types with unique and possibly specialized features: one is blocked by TTX and relies on NaV1.9, and the second type is insensitive to TTX and composed of both NaV1.8 and NaV1.9. Independent of rapidly gated TTX-sensitive NaV channels that form the action potential at pain threshold, NaV1.8 is required in all heat-resistant nociceptors to encode temperatures higher than ~46 degrees C, whereas NaV1.9 is crucial for shaping the action potential upstroke and keeping the NaV1.8 voltage threshold within reach. PMID- 29970413 TI - Protein Carbonylation and Glycation in Legume Nodules. AB - Nitrogen fixation is an agronomically and environmentally important process catalyzed by bacterial nitrogenase within legume root nodules. These unique symbiotic organs have high metabolic rates and produce large amounts of reactive oxygen species that may modify proteins irreversibly. Here, we examined two types of oxidative posttranslational modifications of nodule proteins: carbonylation, which occurs by direct oxidation of certain amino acids or by interaction with reactive aldehydes arising from cell membrane lipid peroxides; and glycation, which results from the reaction of lysine and arginine residues with reducing sugars or their autooxidation products. We used a strategy based on the enrichment of carbonylated peptides by affinity chromatography followed by liquid chromatography-tandem mass spectrometry to identify 369 oxidized proteins in bean (Phaseolus vulgaris) nodules. Of these, 238 corresponded to plant proteins and 131 to bacterial proteins. Lipid peroxidation products induced most carbonylation sites. This study also revealed that carbonylation has major effects on two key nodule proteins. Metal-catalyzed oxidation caused the inactivation of malate dehydrogenase and the aggregation of leghemoglobin. In addition, numerous glycated proteins were identified in vivo, including three key nodule proteins: sucrose synthase, glutamine synthetase, and glutamate synthase. Label-free quantification identified 10 plant proteins and 18 bacterial proteins as age specifically glycated. Overall, our results suggest that the selective carbonylation or glycation of crucial proteins involved in nitrogen metabolism, transcriptional regulation, and signaling may constitute a mechanism to control cell metabolism and nodule senescence. PMID- 29970414 TI - Adiposity-Mortality Relationships in Type 2 Diabetes, Coronary Heart Disease, and Cancer Subgroups in the UK Biobank, and Their Modification by Smoking. AB - OBJECTIVE: The obesity paradox in which overweight/obesity is associated with mortality benefits is believed to be explained by confounding and reverse causality rather than by a genuine clinical benefit of excess body weight. We aimed to gain deeper insights into the paradox through analyzing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, with coronary heart disease (CHD), with cancer, and by smoking status; and adjusting for several confounders. RESEARCH DESIGN AND METHODS: We studied the general UK Biobank population (N = 502,631) along with three subgroups of people with type 2 diabetes (n = 23,842), CHD (n = 24,268), and cancer (n = 45,790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage, and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation index, education, and disease history. RESULTS: For BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted hazard ratio for obese vs. normal BMI 0.78 [95% CI 0.65, 0.95]) but not among those with CHD (1.00 [0.86, 1.17]). The obesity paradox was pronounced in current smokers, absent in never smokers, and more pronounced in men than in women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationship. CONCLUSIONS: The obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of subgroup analyses and statistical adjustments are consistent with reverse causality and confounding. PMID- 29970416 TI - Counting the fish eaten rather than the fish caught. PMID- 29970415 TI - Genetic selection of athletic success in sport-hunting dogs. AB - Modern dogs are distinguished among domesticated species by the vast breadth of phenotypic variation produced by strong and consistent human-driven selective pressure. The resulting breeds reflect the development of closed populations with well-defined physical and behavioral attributes. The sport-hunting dog group has long been employed in assistance to hunters, reflecting strong behavioral pressures to locate and pursue quarry over great distances and variable terrain. Comparison of whole-genome sequence data between sport-hunting and terrier breeds, groups at the ends of a continuum in both form and function, reveals that genes underlying cardiovascular, muscular, and neuronal functions are under strong selection in sport-hunting breeds, including ADRB1, TRPM3, RYR3, UTRN, ASIC3, and ROBO1 We also identified an allele of TRPM3 that was significantly associated with increased racing speed in Whippets, accounting for 11.6% of the total variance in racing performance. Finally, we observed a significant association of ROBO1 with breed-specific accomplishments in competitive obstacle course events. These results provide strong evidence that sport-hunting breeds have been adapted to their occupations by improved endurance, cardiac function, blood flow, and cognitive performance, demonstrating how strong behavioral selection alters physiology to create breeds with distinct capabilities. PMID- 29970417 TI - Tailoring crop nutrition to fight weeds. PMID- 29970418 TI - Local structure can identify and quantify influential global spreaders in large scale social networks. AB - Measuring and optimizing the influence of nodes in big-data online social networks are important for many practical applications, such as the viral marketing and the adoption of new products. As the viral spreading on a social network is a global process, it is commonly believed that measuring the influence of nodes inevitably requires the knowledge of the entire network. Using percolation theory, we show that the spreading process displays a nucleation behavior: Once a piece of information spreads from the seeds to more than a small characteristic number of nodes, it reaches a point of no return and will quickly reach the percolation cluster, regardless of the entire network structure; otherwise the spreading will be contained locally. Thus, we find that, without the knowledge of the entire network, any node's global influence can be accurately measured using this characteristic number, which is independent of the network size. This motivates an efficient algorithm with constant time complexity on the long-standing problem of best seed spreaders selection, with performance remarkably close to the true optimum. PMID- 29970419 TI - Linking glucose metabolism to the stringent response through the PTS. PMID- 29970420 TI - Universal folding pathways of polyhedron nets. AB - Low-dimensional objects such as molecular strands, ladders, and sheets have intrinsic features that affect their propensity to fold into 3D objects. Understanding this relationship remains a challenge for de novo design of functional structures. Using molecular dynamics simulations, we investigate the refolding of the 24 possible 2D unfoldings ("nets") of the three simplest Platonic shapes and demonstrate that attributes of a net's topology-net compactness and leaves on the cutting graph-correlate with thermodynamic folding propensity. To explain these correlations we exhaustively enumerate the pathways followed by nets during folding and identify a crossover temperature [Formula: see text] below which nets fold via nonnative contacts (bonds must break before the net can fold completely) and above which nets fold via native contacts (newly formed bonds are also present in the folded structure). Folding above [Formula: see text] shows a universal balance between reduction of entropy via the elimination of internal degrees of freedom when bonds are formed and gain in potential energy via local, cooperative edge binding. Exploiting this universality, we devised a numerical method to efficiently compute all high temperature folding pathways for any net, allowing us to predict, among the combined 86,760 nets for the remaining Platonic solids, those with highest folding propensity. Our results provide a general heuristic for the design of 2D objects to stochastically fold into target 3D geometries and suggest a mechanism by which geometry and folding propensity are related above [Formula: see text], where native bonds dominate folding. PMID- 29970421 TI - Shedding some blue light on alternative promoter usage in plants. PMID- 29970422 TI - Convergent beam electron holography for analysis of van der Waals heterostructures. AB - The van der Waals heterostructures, which explore the synergetic properties of 2D materials when assembled into 3D stacks, have already brought to life a number of exciting phenomena and electronic devices. Still, the interaction between the layers in such assembly, possible surface reconstruction, and intrinsic and extrinsic defects are very difficult to characterize by any method, because of the single-atomic nature of the crystals involved. Here we present a convergent beam electron holographic technique which allows imaging of the stacking order in such heterostructures. Based on the interference of electron waves scattered on different crystals in the stack, this approach allows one to reconstruct the relative rotation, stretching, and out-of-plane corrugation of the layers with atomic precision. Being holographic in nature, our approach allows extraction of quantitative information about the 3D structure of the typical defects from a single image covering thousands of square nanometers. Furthermore, qualitative information about the defects in the stack can be extracted from the convergent diffraction patterns even without reconstruction, simply by comparing the patterns in different diffraction spots. We expect that convergent beam electron holography will be widely used to study the properties of van der Waals heterostructures. PMID- 29970423 TI - Ferroelectric domain wall dynamics characterized with X-ray photon correlation spectroscopy. AB - Technologically important properties of ferroic materials are determined by their intricate response to external stimuli. This response is driven by distortions of the crystal structure and/or by domain wall motion. Experimental separation of these two mechanisms is a challenging problem which has not been solved so far. Here, we apply X-ray photon correlation spectroscopy (XPCS) to extract the contribution of domain wall dynamics to the overall response. Furthermore, we show how to distinguish the dynamics related to the passing of domain walls through the periodic (Peierls) potential of the crystal lattice and through the random potential caused by lattice defects (pinning centers). The approach involves the statistical analysis of correlations between X-ray speckle patterns produced by the interference of coherent synchrotron X-rays scattered from different nanosize volumes of the crystal and identification of Poisson-type contribution to the statistics. We find such a contribution in the thermally driven response of the monoclinic phase of a ferroelectric PbZr0.55Ti0.45O3 crystal and calculate the number of domain wall jumps in the studied microvolume. PMID- 29970425 TI - Paleoclimatic changes are the most probable causes of the rainforest crises 2,600 y ago in Central Africa. PMID- 29970424 TI - Reply to Giresse et al.: No evidence for climate variability during the late Holocene rainforest crisis in Western Central Africa. PMID- 29970427 TI - Discrepant Cytogenetic and Interphase Fluorescence In Situ Hybridization (I-FISH) Results from Bone Marrow Specimens of Patients with Hematologic Neoplasms. AB - Conventional cytogenetic and routine I-FISH (interphase fluorescence in-situ hybridization) studies periodically present discrepant results on the same sample calling into question their validity. Generally it is expected that these tests confirm each other, otherwise there is concern that they may represent laboratory error. We present data showing that these discrepant results are rarely due to laboratory error, and that M-FISH (metaphase fluorescence in-situ hybridization) can usually reconcile them by identifying the nature of these differences. This report includes 32 bone marrow (BM) samples from patients with hematologic neoplasms that showed incongruent cytogenetic/I-FISH results. M-FISH was selectively applied for further clarification of these discrepancies when deemed necessary. This study evaluated BM samples in our laboratory (Integrated Oncology, Phoenix, AZ) that represented 5 major categories of hematologic disorders (MDS/AML, MPN, NHL, CLL, & PCN). Five general categories of these cases were identified: 1) laboratory error (clerical), 2) limited resolution of testing methods, 3) cellular response to culture/preparative conditions, 4) cytogenetic bi-clonality and 5) failed hybridizations due to cover-slipping. Our results suggest that the majority of discrepant results are related to the intrinsic nature of the malignant cells (and how they respond to their growth environment) evaluated by these two testing methods. PMID- 29970428 TI - New Onset Iron Deficiency Anemia in Chronic Therapeutic Plasma Exchange Patients. AB - Iron deficiency has been recognized as a complication of whole blood and red blood cell apheresis donation; however, the effect of chronic therapeutic plasma exchange (TPE) on patient iron status is largely unknown. We performed a retrospective review of all patients undergoing chronic TPE (at least 1 TPE every 2 weeks for 1 month with a minimum of 8 TPE treatments) with 5% albumin at our institution from 2011 to 2016. After review of serum iron level and iron saturation status, six out of ten (60%) of the patients who meet the study criteria were found to develop iron deficiency anemia (IDA). This data supports the notion that chronic TPE, especially when combined with additional risk factors, can increase the risk of IDA. PMID- 29970429 TI - Blood Transfusion Indicators Following Trauma in the Non-Massively Bleeding Patient. AB - BACKGROUND: Establishing transfusion guidelines during trauma resuscitation is challenging. Our objective was to evaluate indications for transfusion in trauma patients who emergently received <=2 units of red blood cells (RBC) during the first hour of resuscitation. METHODS: A single center retrospective study included non-massively bleeding trauma patients stratified into 2 groups: 1) with a clinical indication for transfusion and 2) with no indication for transfusion. Admission vital signs (VS), injury severity score (ISS), shock index, and laboratory values were compared between the two groups using the Wilcoxon rank sum test. RESULTS: Among 111 non-massively bleeding trauma patients, 40 presented no indication for transfusion. All patients presented similar ISS and VS. The 71 patients presenting with an indication for transfusion had higher bicarbonate (22.6 vs 20.8) and lower lactate levels (4.7 v 6.6) (p<0.05). CONCLUSION: Lactate and bicarbonate blood levels may be potential indicators for RBC transfusion need during trauma resuscitation in non-massively bleeding patients. PMID- 29970430 TI - Major Discrepancies of HCV Viral Loads Determined by Real Time Polymerase Chain Reaction Caused by Use of Collection Tubes that Differ Only with the Presence or Absence of Serum Separator. AB - BACKGROUND: For viral load (VL) analysis of hepatitis C virus (HCV) by Real Time PCR, approved collection tubes were lavender top (LTT) and plasma processing (PPT) tubes, that differ in that PPTs include plasma separator. Using a Real Time PCR method, we investigated how the results correlated for the two tube types. METHODS: The plasma fractions of blood samples from each of 202 patients were collected in LTT and PPT tubes at the same time and were assayed for HCV VL by the Abbott m2000 Real Time PCR System; the results were analyzed statistically. RESULTS: VLs for 103 samples for both tubes were negative. Positive results were obtained for another 79 tube pairs, including six with VLs for LTTs but values below linearity for the corresponding PPTs. For the 73 samples for which quantitative results were obtained for both tube types, VLs were statistically higher in LTTs (means 1,817,821.8 in LTTs and 1,083,669.1 in PPTs, p=0.006, alpha=0.05) using the paired t-test and confirmed by the Chi Square and McNemars tests. CONCLUSIONS: VLs in LTTs are significantly higher and more sensitive than in PPTs, suggesting the necessity of standardization of collection tubes for HCV VLs. PMID- 29970431 TI - Rapid, Reliable, and Inexpensive HLA-B*58:01 Detection Method Using DNA Binding Dye-based Duplex Allele-specific Melting Curve Analysis. AB - BACKGROUND: Allopurinol is the most commonly used drug for the treatment of gout and also one of the most common causes of severe cutaneous adverse reactions (SCARs). Human leukocyte antigen-B*58:01 (HLA-B*58:01) is strongly associated with allopurinol-induced SCARs. The aim of the present study was to develop and validate a rapid and economic screening method for HLA-B*58:01. METHODS: The accuracy of duplex allele-specific melting curve analysis using DNA-binding dye for HLA-B*58:01 was evaluated in 150 blood samples with sequence-based typing (SBT) as the reference method. RESULTS: Fifty HLA-B*58:01-positive and 100 negative results obtained by duplex allele-specific melting curve analysis were completely in agreement with the SBT results. CONCLUSION: Duplex allele-specific melting curve analysis is a rapid, reliable and inexpensive assay that is appropriate for screening for the HLA-B*58:01 allele. PMID- 29970433 TI - Second-trimester Maternal Serum Screening Biomarkers in the Risk Assessment for Preeclampsia. AB - To evaluate the predictive value of second-trimester maternal serum screening biomarkers for preeclampsia, we analyzed the second-trimester serum prenatal screening data of pregnant women, and identified preeclampsia diagnosis by hospitalization records. 198 cases who developed preeclampsia and 1171 healthy controls were included in this study. In 15~20 gestational weeks, the cases who developed into preeclampsia had lower serum levels of uE3, uE3 MoM, but higher AFP MoM than controls, while no difference on AFP, fbeta-hCG, and fbeta-hCG MoM were found. A higher level of uE3 MoM was associated with a lower risk of preeclampsia (OR=0.35, 95% CI:0.19-0.65, P=0.0009). In addition, threshold effect was observed between preeclampsia and the MoM value of AFP and fbeta-hCG, the risk of preeclampsia increased when the AFP MoM>=1.43(OR=1.93, 95% CI:1.20-3.11, P=0.0064), or fbeta-hCG MoM>=2.31(OR=2.59, 95% CI:1.46-4.59, P=0.0012). PMID- 29970432 TI - Red Blood Cell Distribution Width in Rheumatoid Arthritis, Ankylosing Spondylitis and Osteoarthritis: True Inflammatory Index or Effect of Anemia? AB - OBJECTIVE: To date, there have been no studies systematically comparing red blood cell distribution width (RDW) among rheumatoid arthritis (RA), ankylosing spondylitis (AS) and osteoarthritis (OA). Therefore, this study aimed to make comparisons and to explore whether erythrocytopenia and hemoglobin (Hb) reduction could influence RDW level and its association with conventional inflammatory or immune markers in RA, AS and OA. METHODS: A total of 222 patients with RA, 150 with AS, 78 with OA and 126 healthy controls (HC) were enrolled. Clinical and laboratory data of all subjects were extracted from electronically stored medical records. RESULTS: Increased RDW level was found only in RA patients and showed significant diagnostic value for RA. It was much higher in those with erythrocytopenia and Hb reduction. However, those without Hb reduction did not show significant difference of RDW from HC. RDW positively correlated with CRP and ESR respectively in RA and OA patients. However, when the patients were divided into Hb reduction and non-Hb reduction groups, the correlations became insignificant. CONCLUSIONS: RDW level is increased only in RA patients, but not in those with AS and OA. However, increased RDW and its association with CRP may be mainly due to Hb reduction. Therefore, whether RDW could be used as useful inflammatory index for RA, AS and OA remains to be evaluated. PMID- 29970434 TI - Effect of Cytokines and Hyperthermia on Phagocytosis and Phosphatidylserine Externalization: Implication for the Pathophysiology of Hemophagocytic Syndrome. AB - OBJECTIVE: An aberrant production of inflammatory cytokines, with resultant febrile response, is a cardinal finding of hemophagocytic syndrome. A role of inflammatory cytokines on phagocytosis and clearance of apoptotic cells or particles has been shown, but effects of cytokines or hyperthermia on phagocytosis of viable blood cells were not fully understood. We examined effects of cytokines and hyperthermia on phagocytosis, and externalization of phosphatidylserine on the surface of phagocytosed blood cells, to clarify the pathophysiology of hemophagocytic syndrome. METHODS: THP-1 macrophage cells were incubated with non-opsonized and opsonized sheep erythrocytes (SE) in the presence of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN gamma), macrophage-colony stimulating factor (M-CSF), interleukin (IL)-6, IL-10 or IL-18, and phagocytic activity was analyzed. Co-operative effect between cytokines was also examined. In addition, SE were incubated at 37 or 39 degrees C, and phagocytic activity was analyzed. After treatment of SE with cytokine or hyperthermia, phosphatidylserine expression of the cell surface was analyzed by detecting Annexin V-positive cells. RESULTS: IL-6, IL-10 and IL-18 significantly increased phagocytosis of non-opsonized SE, but IFN-gamma suppressed it. Phagocytosis of opsonized SE was significantly increased by any of the cytokines. IFN-gamma suppressed and IL-10 enhanced phagocytic activity induced by other cytokines in non-opsonized SE, while in opsonized SE, both cytokines co-operated with other cytokines to enhance phagocytosis. Incubation of SE at a high temperature (39 degrees C) resulted in increased phagocytic activity, as compared to SE incubated at 37 degrees C. Cytokines and a high temperature did not increase the number of Annexin V-positive SE. CONCLUSIONS: IL-6, IL-10 and IL-18 can augment phagocytosis of viable blood cells, whether cells are opsonized or not. Hyperthermia also enhances phagocytosis. These in vitro data suggest that therapy for targeting cytokine (IL-6, IL-10 or IL-18) by using biologics or small molecule drugs may be beneficial for the treatment of hemophagocytic syndrome. Unlike the case of apoptotic cells, phagocytosis of viable blood cells seems to be mediated via phosphatidylserine-independent manner. PMID- 29970435 TI - Cloning and Purification of Per a 4, a Gene Encoding a Periplaneta Americana Allergen, and Preparation of Its Monoclonal Antibodies. AB - OBJECTIVE: To clone, express, purify the Per a 4 gene encoding an allergen of Periplaneta Americana and prepare monoclonal antibodies against the recombinant allergen. METHODS: The total RNA was extracted from P. Americana, and the target gene was amplified by RT-PCR and cloned into pMD18-T vector. After being confirmed by nucleotide sequencing, the gene was then inserted into pGEX-3X to construct the express vector pGEX-3X-Per a 4. Further, the pGEX-3X-Per a 4 was transformed into E. coli BL21 (DE3), and induced for expression by IPTG. By affinity chromatography, the recombinant allergen was purified and identified by SDS-PAGE and Western blotting. The BALB/c mouse was immunized with the recombinant allergen to prepare the specific monoclonal antibodies, which was then identified by co-immunoprecipitatin and western blotting. RESULTS: The full length cDNA encoding Per a 4 of P. Americana was obtained with 552 bp in length, which had 99.4% similarity with the reference sequence (GenBank AY792948). The constructed vector pGEX-3X-Per a 4 was transformed in E. coli BL21 (DE3), expressed with the induction of IPTG. By SDS-PAGE, a band of about 49 KD was present. Further, the western-blotting showed that the prepared monoclonal antibodies can bind the serum antibodies in patients allergic to P. Americana. CONCLUSIONS: Both the recombinant allergen Per a 4 and its monoclonal antibodies were obtained. PMID- 29970436 TI - Prediction of CD16+ Monocyte in Acute Rejection after Liver Transplantation. AB - BACKGROUND: CD16+ monocytes have recently shown the ability to inhibit the proliferation of CD4+CD25+Foxp3+ T cells (Tregs). The inhibitory role of Tregs in acute rejection has been described in patients with liver transplantation. However, the role of CD16+ monocytes in the development of allograft rejection after liver transplantation remains unknown. METHODS: Forty-five liver transplant recipients, including 25 acute rejection diagnosed by liver biopsy and clinical symptoms and 20 stable allograft liver function recipients, were collected from January 2007 to September 2015 at our hospitals. To assay the frequencies of CD16+ monocytes and Tregs in blood samples, flow cytometry was performed. RESULTS: Compared with the stable allograft liver function recipients, a significant increase in CD16+ monocytes (19.45+/-5.25% vs 7.17+/-1.69%, P<0.001) and decreased Tregs (1.74+/-0.59% vs 5.53+/-2.18%, P<0.001) was observed among recipients with acute rejection. CD16+ monocytes were positively correlated with RAI (rejection activity index) (R2=0.84, P<0.001), but negatively correlated with the frequency of Tregs (R2=0.86, P<0.001). CONCLUSIONS: Based on our data, we concluded that CD16+ monocytes might be responsible for the development of acute allograft rejection after liver transplantation, which may be associated with inhibition of Treg cells. PMID- 29970437 TI - Associations between Single Nucleotide Polymorphisms in the Mitochondrial DNA D Loop Region and Outcome of Gastroenteropancreatic Neuroendocrine Neoplasm. AB - Accumulation of single-nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) of mitochondrial DNA (mtDNA) may be associated with cancer risk and disease outcome. We evaluated the predictive value of these SNPs for GEP-NEN outcome. Three SNP sites of nucleotides 16257C/A, 150C/T and 151C/Tdel were identified for statistically significant prediction of postoperative survival in GEP-NEN by univariate analysis with log-rank test. In addition, the minor haplotype of nucleotides 16257A in the hypervariable segment 1(HV1) region of the D-loop was identified for their association with lower survival rate of GEP-NEN (relative risk, 3.390; 95% CI, 1.071~10.729; p=0.038) by multivariate analysis with COX hazards model. The analysis of genetic polymorphisms in the mitochondrial D-loop can help identify patient subgroups with a high risk of GEP NEN outcome. PMID- 29970438 TI - Collagen Triple Helix Repeat Containing 1 Expression in Osteosarcoma: A New Predictor of Prognosis. AB - BACKGROUND: Some studies have demonstrated that the collagen triple helix repeat containing 1 (CTHRC1) protein is abnormally expressed in multiple human solid tumors. We assessed the expression of CTHRC1 in osteosarcoma. METHODS: The CTHRC1 expression status was examined by immunohistochemistry and quantitative real-time polymerase chain reaction. Then, we analyzed the relationship between CTHRC1 expression and clinicopathological characteristics in osteosarcoma patients. RESULTS: The expression rate of CTHRC1 protein in osteosarcoma was significantly higher than that in adjacent normal tissues. The high expression of CTHRC1 was strongly correlated with the differentiation, recurrence rate, chemotherapy response, and metastasis in patients with osteosarcoma. The survival analysis suggested that high expression of CTHRC1 in osteosarcoma patients correlates with a shorter survival time. Cox regression analysis demonstrated that the prognosis of osteosarcoma patients was closely associated with CTHRC1. CONCLUSIONS: The high CTHRC1 expression indicates the poor prognosis of osteosarcoma patients. PMID- 29970439 TI - Effects of Carnosine and Vitamin E on Nucleobindin 2 (NUCB2)/nesfatin-1, Ghrelin, Adropin, and Irisin in Experimentally Induced Ovarian Torsion. AB - INTRODUCTION: Delay in the diagnosis of ovarian torsion leads to serious histopathological changes and many problems, including infertility. Various agents have been investigated to minimize detorsion-associated potential injury. This study was performed to study the effects of carnosine and vitamin E on tissue and serum expression of Nucleobindin 2 (NUCB2)/nesfatin-1, ghrelin, adropin, and irisin to determine whether they have protective effects in cases of ovarian torsion. MATERIAL AND METHOD: Seventy-eight rats were allocated evenly into 13 groups. All rats, excluding those in the control and sham groups and Groups (G) III, IV, and V, were subjected to ovarian torsion for 12 hours. The groups were designated as follows: G-I (control), G-II (sham), G-III (vitamin E), G-IV (carnosine), G-V (carnosine + vitamin E), G-VI (torsion), G-VII (torsion + detorsion), G-VIII (torsion + vitamin E), G-IX (torsion + carnosine), G-X (torsion + carnosine + vitamin E), G-XI (torsion + detorsion + vitamin E), G-XII (torsion + detorsion + carnosine), and G-XIII (torsion + detorsion + carnosine + vitamin E). Serum levels of NUCB2/nesfatin-1, ghrelin, adropin, and irisin were measured by ELISA. Immunohistochemical methods were used to measure the expression of these hormones in ovarian tissue. RESULTS: The levels of NUCB2/nesfatin-1 immunoreactivity were increased in G-VII, G-XI, and G-XII (p<0.05). The immunoreactivity of ghrelin was significantly decreased in G-VI, G IX, G-XI, and G-XII. However, adropin immunoreactivity did not differ significantly between the groups (p>0.05). The level of irisin immunoreactivity was decreased in G-VI, G-VII, and G-VIII (p<0.05). The serum levels of NUCB2/nesfatin-1, ghrelin, adropin, and irisin paralleled the tissue immunohistochemical results. CONCLUSION: Carnosine and vitamin E protected the ovaries from ischemia-reperfusion injury in ovarian torsion. These antioxidants, especially carnosine, may be useful for the treatment of ovarian torsion. PMID- 29970440 TI - Mechanisms of Resistance in Clinical Isolates of Enterobacter cloacae that Are Less Susceptible to Cefepime than to Ceftazidime. AB - Thirty-two Enterobacter cloacae strains that are less susceptible to cefepime than to ceftazidime were collected. This unique phenotype of 8 strains was confirmed using the agar dilution method. OXA1, OXA10, OXA31 and OXA35 were detected in 3, 2, 3, and 2 strains, respectively, whereas all strains were negative for PSE-1 genes. OXA genes were also identified in the plasmid DNA of 5 strains, but only 2 strains were positive in a conjugation experiment. The acrA, acrB and tolC genes were identified in 4, 4 and 6 strains, respectively. Decreased expression of the acrA mRNA and overexpression of the acrB and tolC mRNAs were observed using real-time RT-PCR. Most of the bacteria (n=7) stably expressed the marA gene, which is a regulatory gene in the AcrAB-TolC multidrug efflux system, whereas all strains were negative for ramA. The acrA, acrB, tolC, acrR and marA genes were similar to the genes in reference strains in GenBank, with nucleotide homologies of 96%, 98%, 98%, 98% and 100%, respectively. In conclusion, the mechanism of resistance of Enterobacter cloacae with less susceptibility to cefepime than to ceftazidime is associated with the overexpression of AcrAB-TolC and the production of OXA1, XA10, OXA31 and OXA35. PMID- 29970441 TI - Association between Biofilm Formation and Antimicrobial Resistance in Carbapenem Resistant Pseudomonas Aeruginosa. AB - Recently, carbapenem resistance in P. aeruginosa is an increasingly important problem globally. Biofilm formation is a well-known pathogenic mechanism of P. aeruginosa, and the gene, pslA, plays an important role in its primary stages. We studied the association between biofilm formation and pslA in carbapenem resistant P. aeruginosa isolates, along with antimicrobial resistance and the prevalence of metallo-beta-lactamase (MBL) genes, based on the presence of pslA 82 carbapenem-resistant P. aeruginosa isolates were collected from a tertiary hospital in Daejeon, Korea, between March 2008 and June 2014. Minimum inhibitory concentrations (MICs) of nine antimicrobial agents were determined using the agar dilution method. Biofilm formation was measured by microtiter plate assay. PCR and sequencing were used to identify pslA and the MBL gene. 76 (92.7%) carbapenem resistant isolates were biofilm producers. These biofilm producers showed higher levels of amikacin, ceftazidime, and cefepime resistance than non-producers. pslA was detected in 71 (93.4%) biofilm-producing isolates and these results were statically significant (p<0.01). 11 isolates carrying pslA and blaIMP-6 were extremely resistant to all antimicrobials tested. In this study, biofilm formation was significantly associated with pslA Furthermore, the coexistence of pslA and the MBL gene in carbapenem-resistant isolates likely contributed to the increase in antimicrobial resistance. PMID- 29970442 TI - Bilateral Wilms'Tumor in Trisomy 18 Syndrome: Case Report and Critical Review of the Literature. AB - We present a patient with trisomy 18 syndrome and bilateral Wilms' tumor representing the second case of the literature. Physicians should remain alert to the possibility of WT in patients with trisomy 18 who may survive beyond infancy. In this event, it may be essential to consider periodic abdominal ultrasound for screening purposes. A critical review of the literature is presented. PMID- 29970443 TI - ADAMTS13 Testing Methodologies and Thrombotic Thrombocytopenic Purpura (TTP): Conflicting Results Can Pose a Clinical Dilemma. AB - ADAMTS13 testing plays a critical role in confirming the clinical diagnosis of acquired idiopathic thrombotic thrombocytopenic purpura (TTP) and distinguishing it from other forms of thrombotic microangiopathies (TMA). Serial measurements of ADAMTS13 activity and inhibitor levels are also helpful in determining response to treatment and/or subsequent relapses. Numerous ADAMTS13 assays have been developed recently, including some with rapid turnaround times. Despite the good inter-assay correlation of different ADAMTS13 methodologies in published case studies, discrepancies have been shown to occur. Here we present a case where discrepant results were obtained using two different assays, posing a clinical treatment dilemma. PMID- 29970444 TI - Prolonged Activated Partial Thromboplastin Time and False-Positive Results for Fibrinogen and Fibrin Degradation Products in a B-Cell Lymphoma Patient. AB - We report a unique case of a B-cell lymphoma patient in whom IgM monoclonal gammopathy resulted in a prolonged activated partial thromboplastin time (APTT) and false-positive results for fibrinogen and fibrin degradation products (FDPs). An 86-year-old man was referred to our hospital for further examination of abnormal cells in his peripheral blood. Laboratory data upon admission revealed an elevation of monoclonal IgM, presence of FDPs and marked prolongation of APTT (>180 s). Bone marrow examination revealed a predominant involvement of B lymphoma cells. In vitro examination revealed that IgM isolated from the patient's plasma had resulted in false-positive results for FDPs and APTT. Neither hemorrhagic nor thrombotic tendency was observed in this patient, suggesting that the abnormal coagulation data were due to interference by elevated monoclonal IgM levels. PMID- 29970445 TI - Paratesticular Fibrous Pseudotumor: A New Entity of IgG4-Related Disease? AB - INTRODUCTION: Paratesticular fibrous pseudotumor (PFP) represents a benign tumor like lesion confined to intrascrotal, paratesticular areas. Due to its rarity, only less than 200 cases have been reported to date, of which both pathogenesis and clinical management are little understood. Recently, PFP has been postulated to be among the spectrum of so-called immunoglobulin G4-related diseases (IgG4 RD). Here we describe a case of PFP focusing on the clinical, morphological features and the utility of immunohistochemistry to support the theory that PFP might be a potential member of IgG4-RD family. CASE PRESENTATION: A 41-year-old man presented with a slowly growing, right intrascrotal mass An MRI scan revealed a diffuse-proliferative nodular mass around the paratesticular area. The patient underwent right orchiectomy and a diffuse multinodular tumor with testicular compression was discovered without intratesticular infiltration. Postoperatively, the patient has been well for 2 years up to the recent follow up. On histological examination, the lesion consisted of hyalinized fibrotic tissue with storiform patterns. There were scattered germinal centers; lymphocytic vasculitis was also noted. The immunoglobulin G4 staining showed infiltration of positive plasma cells with highest count 52 per high-power field, whereas the mixed Kappa and Lambda immunoglobulin light chain expression indicated the polyclonality of the plasma cell population. CONCLUSIONS: The morphological and immunohistochemical features in our case support the theory of PFP being part of IgG4-RD. Familiarity to this tumor-like lesion is crucial, since it may respond to corticosteroid therapy, which may save patients from more aggressive surgical procedures. PMID- 29970447 TI - Abstracts of Presentations at the Association of Clinical Scientists 138th Meeting Houston, TX, May 16-19, 2018. PMID- 29970446 TI - Loss of the Thioretinaco Ozonide Oxygen Adenosine Triphosphate Complex from Mitochondria Produces Mitochondrial Dysfunction and Carcinogenesis. AB - The active site of oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis is proposed to consist of thioretinaco, a complex of two molecules of thioretinamide with cobalamin, oxidized to the disulfonium derivative, thioretinaco ozonide, and complexed with oxygen, nicotinamide adenine dinucleotide, inorganic phosphate and ATP. Reduction of the active site complex by electrons from mitochondrial electron transport complexes releases ATP from binding to the active site, producing nicotinamide riboside and hydroperoxide and generating a membrane potential from proton transport to the active site. Opening of the mitochondrial permeability transition pore from decreased mitochondrial melatonin leads to loss of the active site complex from mitochondrial membranes, as observed in aging and dementia. Loss of the active site complex from mitochondria also results from opening of the permeability transition pore and from decomposition of the disulfonium active site by electrophilic carcinogens, oncogenic viruses and microbes which cause depletion of adenosyl methionine because of increased biosynthesis of polyamines, and by free radical oxygen species generated by ionizing radiation, and by catecholamines. Thus the loss of thioretinaco ozonide from mitochondria produces the impaired oxidative phosphorylation, oxidative stress, calcium influx, apoptosis, aerobic glycolysis, and mitochondrial dysfunction that are observed in chemical carcinogenesis, microbial carcinogenesis, traumatic brain injury, aging and dementia. PMID- 29970449 TI - Correction: PI(4,5)P2 forms dynamic cortical structures and directs actin distribution as well as polarity in Caenorhabditis elegans embryos (doi: 10.1242/dev.164988). PMID- 29970448 TI - Is there a causal link between intracellular Na elevation and metabolic remodelling in cardiac hypertrophy? AB - Alterations in excitation-contraction coupling and elevated intracellular sodium (Nai) are hallmarks of pathological cardiac remodelling that underline contractile dysfunction. In addition, changes in cardiac metabolism are observed in cardiac hypertrophy and heart failure (HF) that lead to a mismatch in ATP supply and demand, contributing to poor prognosis. A link between Nai and altered metabolism has been proposed but is not well understood. Many mitochondrial enzymes are stimulated by mitochondrial calcium (Camito) during contraction, thereby sustaining production of reducing equivalents to maintain ATP supply. This stimulation is thought to be perturbed when cytosolic Nai is high due to increased Camito efflux, potentially compromising ATPmito production and leading to metabolic dysregulation. Increased Nai has been previously shown to affect Camito; however, whether Nai elevation plays a causative role in energetic mismatching in the hypertrophied and failing heart remains unknown. In this review, we discuss the relationship between elevated Nai, NaK ATPase dysregulation and the metabolic phenotype in the contexts of pathological hypertrophy and HF and their link to metabolic flexibility, capacity (reserve) and efficiency that are governed by intracellular ion homeostasis. The development of non-invasive analytical techniques using nuclear magnetic resonance able to probe metabolism in situ in the functioning heart will enable a better understanding of the underlying mechanisms of Nai overload in cardiac pathophysiology. They will lead to novel insights that help to explain the metabolic contribution towards these diseases, the incomplete rescue observed with current therapies and a rationale for future energy-targeted therapies. PMID- 29970451 TI - Switching roles for DNA and histone methylation depend on evolutionary ages of human endogenous retroviruses. AB - We provide a comprehensive genomic and epigenomic map of the more than 500,000 endogenous retroviruses (ERVs) and fragments that populate the intergenic regions of the human genome. The repressive epigenetic marks associated with the ERVs, particularly long terminal repeats (LTRs), show a remarkable switch in silencing mechanisms, depending on the evolutionary age of the LTRs. Young LTRs tend to be CpG rich and are mainly suppressed by DNA methylation, whereas intermediate age LTRs are associated predominantly with histone modifications, particularly histone H3 lysine 9 (H3K9) methylation. Young LTRs can be reactivated by treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) alone, but their level of expression is much increased by 5-aza-CdR treatment plus knockdown of one of several H3K9 methyltransferases or of the H3K27 methyltransferase EZH2. The removal of cytosine methylation led to rapid, widespread increases in H3K9me3 in the LTRs. Intermediate age LTRs had lower CpG densities and were not up-regulated by 5-aza-CdR treatment, but they were sensitive to knockdown of H3K9 methyltransferases. Unlike the situation in embryonic stem cells, the polycomb repressive complex (PRC2) has a minor role in LTR suppression by itself and is only a player after removal of cytosine methylation in the analyzed cancer cell line. Up-regulation of LTRs and induction of "viral mimicry" is rapidly becoming of interest for predicting cancer patient response to epigenetic therapies. Understanding the mechanism for LTR suppression is of major importance in order to improve patient treatment strategies. PMID- 29970450 TI - Immune signatures correlate with L1 retrotransposition in gastrointestinal cancers. AB - Long interspersed nuclear element-1 (LINE-1 or L1) retrotransposons are normally suppressed in somatic tissues mainly due to DNA methylation and antiviral defense. However, the mechanism to suppress L1s may be disrupted in cancers, thus allowing L1s to act as insertional mutagens and cause genomic rearrangement and instability. Whereas the frequency of somatic L1 insertions varies greatly among individual tumors, much remains to be learned about underlying genetic, cellular, or environmental factors. Here, we report multiple correlates of L1 activity in stomach, colorectal, and esophageal tumors through an integrative analysis of cancer whole-genome and matched RNA-sequencing profiles. Clinical indicators of tumor progression, such as tumor grade and patient age, showed positive association. A potential L1 expression suppressor, TP53, was mutated in tumors with frequent L1 insertions. We characterized the effects of somatic L1 insertions on mRNA splicing and expression, and demonstrated an increased risk of gene disruption in retrotransposition-prone cancers. In particular, we found that a cancer-specific L1 insertion in an exon of MOV10, a key L1 suppressor, caused exon skipping and decreased expression of the affected allele due to nonsense mediated decay in a tumor with a high L1 insertion load. Importantly, tumors with high immune activity, for example, those associated with Epstein-Barr virus infection or microsatellite instability, tended to carry a low number of L1 insertions in genomes with high expression levels of L1 suppressors such as APOBEC3s and SAMHD1 Our results indicate that cancer immunity may contribute to genome stability by suppressing L1 retrotransposition in gastrointestinal cancers. PMID- 29970453 TI - Gosport: will justice ever be served? PMID- 29970454 TI - India's unofficial medical watchdog shows its teeth. PMID- 29970452 TI - Massive variation of short tandem repeats with functional consequences across strains of Arabidopsis thaliana. AB - Short tandem repeat (STR) mutations may comprise more than half of the mutations in eukaryotic coding DNA, yet STR variation is rarely examined as a contributor to complex traits. We assessed this contribution across a collection of 96 strains of Arabidopsis thaliana, genotyping 2046 STR loci each, using highly parallel STR sequencing with molecular inversion probes. We found that 95% of examined STRs are polymorphic, with a median of six alleles per STR across these strains. STR expansions (large copy number increases) are found in most strains, several of which have evident functional effects. These include three of six intronic STR expansions we found to be associated with intron retention. Coding STRs were depleted of variation relative to noncoding STRs, and we detected a total of 56 coding STRs (11%) showing low variation consistent with the action of purifying selection. In contrast, some STRs show hypervariable patterns consistent with diversifying selection. Finally, we detected 133 novel STR phenotype associations under stringent criteria, most of which could not be detected with SNPs alone, and validated some with follow-up experiments. Our results support the conclusion that STRs constitute a large, unascertained reservoir of functionally relevant genomic variation. PMID- 29970455 TI - Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Chronic inflammation induced by chronic hepatitis B virus (HBV) infection increases the risk of hepatocellular carcinoma (HCC). However, little is known about the immune landscape of HBV-related HCC and its influence on the design of effective cancer immunotherapeutics. METHODS: We interrogated the immune microenvironments of HBV-related HCC and non-viral-related HCC using immunohistochemistry and cytometry by time-of-flight (CyTOF). On identifying unique immune subsets enriched in HBV-related HCC, we further interrogated their phenotypes and functions using next-generation sequencing (NGS) and in vitro T cell proliferation assays. RESULTS: In-depth interrogation of the immune landscapes showed that regulatory T cells (TREG) and CD8+ resident memory T cells (TRM) were enriched in HBV-related HCC, whereas Tim-3+CD8+ T cells and CD244+ natural killer cells were enriched in non-viral-related HCC. NGS of isolated TREG and TRM from HBV-related HCC and non-viral-related HCC identified distinct functional signatures associated with T-cell receptor signalling, T-cell costimulation, antigen presentation and programmed cell death protein 1 (PD-1) signalling. TREG and TRM from HBV-related HCC expressed more PD-1 and were functionally more suppressive and exhausted than those from non-virus-related HCC. Furthermore, immunosuppression by PD-1+ TREG could be reversed with anti-PD 1 blockade. Using multiplexed tissue immunofluorescence, we further demonstrated that TREG and TRM contributed to overall patient survival: TREG were associated with a poor prognosis and TRM were associated with a good prognosis in HCC. CONCLUSION: We have shown that the HBV-related HCC microenvironment is more immunosuppressive and exhausted than the non-viral-related HCC microenvironment. Such in-depth understanding has important implications in disease management and appropriate application of immunotherapeutics. PMID- 29970456 TI - Knowledge and attitudes of Australian general practitioners towards medicinal cannabis: a cross-sectional survey. AB - OBJECTIVES: To examine the knowledge and attitudes of Australian general practitioners (GP) towards medicinal cannabis, including patient demand, GP perceptions of therapeutic effects and potential harms, perceived knowledge and willingness to prescribe. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional survey completed by 640 GPs (response rate=37%) attending multiple-topic educational seminars in five major Australian cities between August and November 2017. MAIN OUTCOME MEASURES: Number of patients enquiring about medicinal cannabis, perceived knowledge of GPs, conditions where GPs perceived it to be beneficial, willingness to prescribe, preferred models of access, perceived adverse effects and safety relative to other prescription drugs. RESULTS: The majority of GPs (61.5%) reported one or more patient enquiries about medicinal cannabis in the last three months. Most felt that their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. Over half (56.5%) supported availability on prescription, with the preferred access model involving trained GPs prescribing independently of specialists. Support for use of medicinal cannabis was condition-specific, with strong support for use in cancer pain, palliative care and epilepsy, and much lower support for use in depression and anxiety. CONCLUSIONS: The majority of GPs are supportive or neutral with regards to medicinal cannabis use. Our results highlight the need for improved training of GPs around medicinal cannabis, and the discrepancy between GP-preferred models of access and the current specialist led models. PMID- 29970459 TI - Boost funding for social care to achieve integration with health, says watchdog. PMID- 29970457 TI - Proteomic Profiling of Microtubule Self-organization in M-phase. AB - Microtubules (MTs) and associated proteins can self-organize into complex structures such as the bipolar spindle, a process in which RanGTP plays a major role. Addition of RanGTP to M-phase Xenopus egg extracts promotes the nucleation and self-organization of MTs into asters and bipolar-like structures in the absence of centrosomes or chromosomes. We show here that the complex proteome of these RanGTP-induced MT assemblies is similar to that of mitotic spindles. Using proteomic profiling we show that MT self-organization in the M-phase cytoplasm involves the non-linear and non-stoichiometric recruitment of proteins from specific functional groups. Our study provides for the first time a temporal understanding of the protein dynamics driving MT self-organization in M-phase. PMID- 29970458 TI - A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells. AB - Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition. PMID- 29970460 TI - Restricted Localization of Photosynthetic Intracytoplasmic Membranes (ICMs) in Multiple Genera of Purple Nonsulfur Bacteria. AB - In bacteria and eukaryotes alike, proper cellular physiology relies on robust subcellular organization. For the phototrophic purple nonsulfur bacteria (PNSB), this organization entails the use of a light-harvesting, membrane-bound compartment known as the intracytoplasmic membrane (ICM). Here we show that ICMs are spatially and temporally localized in diverse patterns among PNSB. We visualized ICMs in live cells of 14 PNSB species across nine genera by exploiting the natural autofluorescence of the photosynthetic pigment bacteriochlorophyll (BChl). We then quantitatively characterized ICM localization using automated computational analysis of BChl fluorescence patterns within single cells across the population. We revealed that while many PNSB elaborate ICMs along the entirety of the cell, species across as least two genera restrict ICMs to discrete, nonrandom sites near cell poles in a manner coordinated with cell growth and division. Phylogenetic and phenotypic comparisons established that ICM localization and ICM architecture are not strictly interdependent and that neither trait fully correlates with the evolutionary relatedness of the species. The natural diversity of ICM localization revealed herein has implications for both the evolution of phototrophic organisms and their light-harvesting compartments and the mechanisms underpinning spatial organization of bacterial compartments.IMPORTANCE Many bacteria organize their cellular space by constructing subcellular compartments that are arranged in specific, physiologically relevant patterns. The purple nonsulfur bacteria (PNSB) utilize a membrane-bound compartment known as the intracytoplasmic membrane (ICM) to harvest light for photosynthesis. It was previously unknown whether ICM localization within cells is systematic or irregular and if ICM localization is conserved among PNSB. Here we surveyed ICM localization in diverse PNSB and show that ICMs are spatially organized in species-specific patterns. Most strikingly, several PNSB resolutely restrict ICMs to regions near the cell poles, leaving much of the cell devoid of light-harvesting machinery. Our results demonstrate that bacteria of a common lifestyle utilize unequal portions of their intracellular space to harvest light, despite light harvesting being a process that is intuitively influenced by surface area. Our findings therefore raise fundamental questions about ICM biology and evolution. PMID- 29970461 TI - RIG-I Detects Kaposi's Sarcoma-Associated Herpesvirus Transcripts in a RNA Polymerase III-Independent Manner. AB - Retinoic acid-inducible gene I (RIG-I) is a cytosolic pathogen recognition receptor that initiates the innate immune response against many RNA viruses. We previously showed that RIG-I restricts Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation (J. A. West et al., J Virol 88:5778-5787, 2014, https://doi.org/10.1128/JVI.03226-13). In this study, we report that KSHV stimulates the RIG-I signaling pathway in a RNA polymerase (Pol) III-independent manner and subsequently induces type I interferon (IFN) responses. Knockdown or inhibition of RNA Pol III had no effect on beta interferon (IFN-beta) induction by KSHV. By using high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation (HITS-CLIP) approach, we identified multiple KSHV regions that give rise to RNA fragments binding to RIG-I, such as ORF810420-10496, Repeat region (LIR1)119059-119204, and ORF2543561-43650 The sequence dissimilarity between these fragments suggests that RIG-I detects a particular structure rather than a specific sequence motif. Synthesized ORF810420-10496 RNA stimulated RIG-I dependent but RNA Pol III-independent IFN-beta signaling. In summary, several KSHV RNAs are sensed by RIG-I in a RNA Pol III-independent manner.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Innate immune responses against viral infections, especially the induction of type I interferon, are critical for limiting the replication of viruses. Retinoic acid inducible gene I (RIG-I), a cytosolic RNA helicase sensor, plays a significant role in the induction of type I interferon responses following viral infection. Here, we identified multiple RNA regions in KSHV as potential virus ligands that bind to RIG-I and stimulate RIG-I-dependent but RNA Pol III-independent IFN-beta signaling. Our results expand the role of RIG-I by providing an example of a DNA virus activating a canonical RNA-sensing pathway. PMID- 29970462 TI - The Integrative Conjugative Element (ICE) of Mycoplasma agalactiae: Key Elements Involved in Horizontal Dissemination and Influence of Coresident ICEs. AB - The discovery of integrative conjugative elements (ICEs) in wall-less mycoplasmas and the demonstration of their role in massive gene flows within and across species have shed new light on the evolution of these minimal bacteria. Of these, the ICE of the ruminant pathogen Mycoplasma agalactiae (ICEA) represents a prototype and belongs to a new clade of the Mutator-like superfamily that has no preferential insertion site and often occurs as multiple chromosomal copies. Here, functional genomics and mating experiments were combined to address ICEA functions and define the minimal ICEA chassis conferring conjugative properties to M. agalactiae Data further indicated a complex interaction among coresident ICEAs, since the minimal ICEA structure was influenced by the occurrence of additional ICEA copies that can trans-complement conjugation-deficient ICEAs. However, this cooperative behavior was limited to the CDS14 surface lipoprotein, which is constitutively expressed by coresident ICEAs, and did not extend to other ICEA proteins, including the cis-acting DDE recombinase and components of the mating channel whose expression was detected only sporadically. Remarkably, conjugation-deficient mutants containing a single ICEA copy knocked out in cds14 can be complemented by neighboring cells expressing CDS14. This result, together with those revealing the conservation of CDS14 functions in closely related species, may suggest a way for mycoplasma ICEs to extend their interaction outside their chromosomal environment. Overall, this report provides a first model of conjugative transfer in mycoplasmas and offers valuable insights into understanding horizontal gene transfer in this highly adaptive and diverse group of minimal bacteria.IMPORTANCE Integrative conjugative elements (ICEs) are self transmissible mobile genetic elements that are key mediators of horizontal gene flow in bacteria. Recently, a new category of ICEs was identified that confer conjugative properties to mycoplasmas, a highly adaptive and diverse group of wall-less bacteria with reduced genomes. Unlike classical ICEs, these mobile elements have no preferential insertion specificity, and multiple mycoplasma ICE copies can be found randomly integrated into the host chromosome. Here, the prototype ICE of Mycoplasma agalactiae was used to define the minimal conjugative machinery and to propose the first model of ICE transfer in mycoplasmas. This model unveils the complex interactions taking place among coresident ICEs and suggests a way for these elements to extend their influence outside their chromosomal environment. These data pave the way for future studies aiming at deciphering chromosomal transfer, an unconventional mechanism of DNA swapping that has been recently associated with mycoplasma ICEs. PMID- 29970463 TI - Viral Entry Properties Required for Fitness in Humans Are Lost through Rapid Genomic Change during Viral Isolation. AB - Human parainfluenza viruses cause a large burden of human respiratory illness. While much research relies upon viruses grown in cultured immortalized cells, human parainfluenza virus 3 (HPIV-3) evolves in culture. Cultured viruses differ in their properties compared to clinical strains. We present a genome-wide survey of HPIV-3 adaptations to culture using metagenomic next-generation sequencing of matched pairs of clinical samples and primary culture isolates (zero passage virus). Nonsynonymous changes arose during primary viral isolation, almost entirely in the genes encoding the two surface glycoproteins-the receptor binding protein hemagglutinin-neuraminidase (HN) or the fusion protein (F). We recovered genomes from 95 HPIV-3 primary culture isolates and 23 HPIV-3 strains directly from clinical samples. HN mutations arising during primary viral isolation resulted in substitutions at HN's dimerization/F-interaction site, a site critical for activation of viral fusion. Alterations in HN dimer interface residues known to favor infection in culture occurred within 4 days (H552 and N556). A novel cluster of residues at a different face of the HN dimer interface emerged (P241 and R242) and imply a role in HPIV-3-mediated fusion. Functional characterization of these culture-associated HN mutations in a clinical isolate background revealed acquisition of the fusogenic phenotype associated with cultured HPIV-3; the HN-F complex showed enhanced fusion and decreased receptor cleaving activity. These results utilize a method for identifying genome-wide changes associated with brief adaptation to culture to highlight the notion that even brief exposure to immortalized cells may affect key viral properties and underscore the balance of features of the HN-F complex required for fitness by circulating viruses.IMPORTANCE Human parainfluenza virus 3 is an important cause of morbidity and mortality among infants, the immunocompromised, and the elderly. Using deep genomic sequencing of HPIV-3-positive clinical material and its subsequent viral isolate, we discover a number of known and novel coding mutations in the main HPIV-3 attachment protein HN during brief exposure to immortalized cells. These mutations significantly alter function of the fusion complex, increasing fusion promotion by HN as well as generally decreasing neuraminidase activity and increasing HN-receptor engagement. These results show that viruses may evolve rapidly in culture even during primary isolation of the virus and before the first passage and reveal features of fitness for humans that are obscured by rapid adaptation to laboratory conditions. PMID- 29970464 TI - The Actinomyosin Motor Drives Malaria Parasite Red Blood Cell Invasion but Not Egress. AB - Apicomplexa are obligate intracellular parasites that actively invade, replicate within, and egress from host cells. The parasite actinomyosin-based molecular motor complex (often referred to as the glideosome) is considered an important mediator of parasite motility and virulence. Mature intracellular parasites often become motile just prior to egress from their host cells, and in some genera, this motility is important for successful egress as well as for subsequent invasion of new host cells. To determine whether actinomyosin-based motility is important in the red blood cell egress and invasion activities of the malaria parasite, we have used a conditional genetic approach to delete GAP45, a primary component of the glideosome, in asexual blood stages of Plasmodium falciparum Our results confirm the essential nature of GAP45 for invasion but show that P. falciparum does not require a functional motor complex to undergo egress from the red blood cell. Malarial egress therefore differs fundamentally from induced egress in the related apicomplexan Toxoplasma gondiiIMPORTANCE Clinical malaria results from cycles of replication of single-celled parasites of the genus Plasmodium in red blood cells. Intracellular parasite replication is followed by a highly regulated, protease-dependent process called egress, in which rupture of the bounding membranes allows explosive release of daughter merozoites which rapidly invade fresh red cells. A parasite actinomyosin-based molecular motor (the glideosome) has been proposed to provide the mechanical force to drive invasion. Studies of the related parasite Toxoplasma gondii have shown that induced egress requires parasite motility, mediated by a functional glideosome. However, whether the glideosome has a similar essential role in egress of malaria merozoites from red blood cells is unknown. Here, we show that although a functional glideosome is required for red blood cell invasion by Plasmodium falciparum merozoites, it is not required for egress. These findings place further emphasis on the key role of the protease cascade in malarial egress. PMID- 29970465 TI - Heterogeneous and Flexible Transmission of mcr-1 in Hospital-Associated Escherichia coli. AB - The recent emergence of a transferable colistin resistance mechanism, MCR-1, has gained global attention because of its threat to clinical treatment of infections caused by multidrug-resistant Gram-negative bacteria. However, the possible transmission route of mcr-1 among Enterobacteriaceae species in clinical settings is largely unknown. Here, we present a comprehensive genomic analysis of Escherichia coli isolates collected in a hospital in Hangzhou, China. We found that mcr-1-carrying isolates from clinical infections and feces of inpatients and healthy volunteers were genetically diverse and were not closely related phylogenetically, suggesting that clonal expansion is not involved in the spread of mcr-1 The mcr-1 gene was found on either chromosomes or plasmids, but in most of the E. coli isolates, mcr-1 was carried on plasmids. The genetic context of the plasmids showed considerable diversity as evidenced by the different functional insertion sequence (IS) elements, toxin-antitoxin (TA) systems, heavy metal resistance determinants, and Rep proteins of broad-host-range plasmids. Additionally, the genomic analysis revealed nosocomial transmission of mcr-1 and the coexistence of mcr-1 with other genes encoding beta-lactamases and fluoroquinolone resistance in the E. coli isolates. These findings indicate that mcr-1 is heterogeneously disseminated in both commensal and pathogenic strains of E. coli, suggest the high flexibility of this gene in its association with diverse genetic backgrounds of the hosts, and provide new insights into the genome epidemiology of mcr-1 among hospital-associated E. coli strains.IMPORTANCE Colistin represents one of the very few available drugs for treating infections caused by extensively multidrug-resistant Gram-negative bacteria. The recently emergent mcr-1 colistin resistance gene threatens the clinical utility of colistin and has gained global attention. How mcr-1 spreads in hospital settings remains unknown and was investigated by whole-genome sequencing of mcr-1-carrying Escherichia coli in this study. The findings revealed extraordinary flexibility of mcr-1 in its spread among genetically diverse E. coli hosts and plasmids, nosocomial transmission of mcr-1-carrying E. coli, and the continuous emergence of novel Inc types of plasmids carrying mcr-1 and new mcr-1 variants. Additionally, mcr-1 was found to be frequently associated with other genes encoding beta-lactams and fluoroquinolone resistance. These findings provide important information on the transmission and epidemiology of mcr-1 and are of significant public health importance as the information is expected to facilitate the control of this significant antibiotic resistance threat. PMID- 29970466 TI - Neutralization Mechanisms of Two Highly Potent Antibodies against Human Enterovirus 71. AB - Despite significant advances in health care, outbreaks of infections by enteroviruses (EVs) continue to plague the Asia-Pacific region every year. Enterovirus 71 (EV71) causes hand-foot-and-mouth disease (HFMD), for which there are currently no therapeutics. Here, we report two new antibodies, A9 and D6, that potently neutralize EV71. A9 exhibited a 50% neutralizing concentration (neut50) value of 0.1 nM against EV71, which was 10-fold lower than that observed for D6. Investigation into the mechanisms of neutralization revealed that binding of A9 to EV71 blocks receptor binding but also destabilizes and damages the virus capsid structure. In contrast, D6 destabilizes the capsid only slightly but interferes more potently with the attachment of the virus to the host cells. Cryo electron microscopy (cryo-EM) structures of A9 and D6 bound with EV71 shed light on the locations and nature of the epitopes recognized by the two antibodies. Although some regions of the epitopes recognized by the two antibodies overlap, there are differences that give rise to dissimilarities in potency as well as in the mechanisms of neutralization. Interestingly, the overlapping regions of the epitopes encompass the site that the virus uses to bind SCARB2, explaining the reason for the observed blocking of the virus-receptor interaction by the two antibodies. We also identified structural elements that might play roles in modulating the stability of the EV71 particles, including particle integrity. The molecular features of the A9 and D6 epitopes unveiled in this study open up new avenues for rationally designing antiviral drugs.IMPORTANCE During the course of viral infections, the human body produces neutralizing antibodies which play a defining role in clearing the virus. From this study, we report two new, highly potent neutralizing antibodies, A9 and D6, against enterovirus 71 (EV71), the causative agent of HFMD. Both antibodies prevent the virus from entering the host cell, a step that is important for establishing a successful infection. A9 destabilizes and damages the virus capsid that forms an outer protective covering around the genome of the virus, while also interfering with virus attachment to the host cells. In contrast, D6 only prevents binding of the virus to its receptor(s). The mechanism of neutralization of A9 is unique and has not been observed before for neutralizing antibodies targeting EVs. The two antibodies that we are reporting in this study have potential to be developed into much needed therapeutic interventions for treatment of HFMD, outbreaks of which are reported every year in the Asia-Pacific region. PMID- 29970467 TI - Errors during Gene Expression: Single-Cell Heterogeneity, Stress Resistance, and Microbe-Host Interactions. AB - Gene expression has been considered a highly accurate process, and deviation from such fidelity has been shown previously to be detrimental for the cell. More recently, increasing evidence has supported the notion that the accuracy of gene expression is indeed flexibly variable. The levels of errors during gene expression differ from condition to condition and even from cell to cell within genetically identical populations grown under the same conditions. The different levels of errors resulting from inaccurate gene expression are now known to play key roles in regulating microbial stress responses and host interactions. This minireview summarizes the recent development in understanding the level, regulation, and physiological impact of errors during gene expression. PMID- 29970468 TI - Type 2 NADH Dehydrogenase Is the Only Point of Entry for Electrons into the Streptococcus agalactiae Respiratory Chain and Is a Potential Drug Target. AB - The opportunistic pathogen Streptococcus agalactiae is the major cause of meningitis and sepsis in a newborn's first week, as well as a considerable cause of pneumonia, urinary tract infections, and sepsis in immunocompromised adults. This pathogen respires aerobically if heme and quinone are available in the environment, and a functional respiratory chain is required for full virulence. Remarkably, it is shown here that the entire respiratory chain of S. agalactiae consists of only two enzymes, a type 2 NADH dehydrogenase (NDH-2) and a cytochrome bd oxygen reductase. There are no respiratory dehydrogenases other than NDH-2 to feed electrons into the respiratory chain, and there is only one respiratory oxygen reductase to reduce oxygen to water. Although S. agalactiae grows well in vitro by fermentative metabolism, it is shown here that the absence of NDH-2 results in attenuated virulence, as observed by reduced colonization in heart and kidney in a mouse model of systemic infection. The lack of NDH-2 in mammalian mitochondria and its important role for virulence suggest this enzyme may be a potential drug target. For this reason, in this study, S. agalactiae NDH 2 was purified and biochemically characterized, and the isolated enzyme was used to screen for inhibitors from libraries of FDA-approved drugs. Zafirlukast was identified to successfully inhibit both NDH-2 activity and aerobic respiration in intact cells. This compound may be useful as a laboratory tool to inhibit respiration in S. agalactiae and, since it has few side effects, it might be considered a lead compound for therapeutics development.IMPORTANCES. agalactiae is part of the human intestinal microbiota and is present in the vagina of ~30% of healthy women. Although a commensal, it is also the leading cause of septicemia and meningitis in neonates and immunocompromised adults. This organism can aerobically respire, but only using external sources of heme and quinone, required to have a functional electron transport chain. Although bacteria usually have a branched respiratory chain with multiple dehydrogenases and terminal oxygen reductases, here we establish that S. agalactiae utilizes only one type 2 NADH dehydrogenase (NDH-2) and one cytochrome bd oxygen reductase to perform respiration. NADH-dependent respiration plays a critical role in the pathogen in maintaining NADH/NAD+ redox balance in the cell, optimizing ATP production, and tolerating oxygen. In summary, we demonstrate the essential role of NDH-2 in respiration and its contribution to S. agalactiae virulence and propose it as a potential drug target. PMID- 29970469 TI - The Escherichia coli Type III Secretion System 2 Has a Global Effect on Cell Surface. AB - Many strains of Escherichia coli carry a 29,250-bp ETT2 pathogenicity island (PAI), which includes genes predicted to encode type III secretion system (T3SS) components. Because it is similar to the Salmonella pathogenicity island 1 (SPI 1) system, encoding a T3SS in Salmonella enterica, it was assumed that ETT2 also encodes a secretion system injecting effectors into host cells. This assumption was checked in E. coli serotype O2-associated with urinary tract infections and septicemia-which has an intact ETT2 gene cluster, in contrast to most strains in which this cluster carries deletions and mutations. A proteomic search did not reveal any putative secreted effector. Instead, the majority of the secreted proteins were identified as flagellar proteins. A deletion of the ETT2 gene cluster significantly reduced the secretion of flagellar proteins, resulting in reduced motility. There was also a significant reduction in the transcriptional level of flagellar genes, indicating that ETT2 affects the synthesis, rather than secretion, of flagellar proteins. The ETT2 deletion also resulted in additional major changes in secretion of fimbrial proteins and cell surface proteins, resulting in relative resistance to detergents and hydrophobic antibiotics (novobiocin), secretion of large amounts of outer membrane vesicles (OMVs), and altered multicellular behavior. Most important, the ETT2 deletion mutants were sensitive to serum. These major changes indicate that the ETT2 gene cluster has a global effect on cell surface and physiology, which is especially important for pathogenicity, as it contributes to the ability of the bacteria to survive serum and cause sepsis.IMPORTANCE Drug-resistant extraintestinal pathogenic E. coli (ExPEC) strains are major pathogens, especially in hospital- and community acquired infections. They are the major cause of urinary tract infections and are often involved in septicemia with high mortality. ExPEC strains are characterized by broad-spectrum antibiotic resistance, and development of a vaccine is not trivial because the ExPEC strains include a large number of serotypes. It is therefore important to understand the virulence factors that are involved in pathogenicity of ExPEC and identify new targets for development of antibacterial drugs or vaccines. Such a target could be ETT2, a unique type III secretion system present (complete or in parts) in many ExPEC strains. Here, we show that this system has a major effect on the bacterial surface-it affects sensitivity to drugs, motility, and secretion of extracellular proteins and outer membrane vesicles. Most importantly, this system is important for serum resistance, a prerequisite for septicemia. PMID- 29970470 TI - Avian Influenza Virus PB1 Gene in H3N2 Viruses Evolved in Humans To Reduce Interferon Inhibition by Skewing Codon Usage toward Interferon-Altered tRNA Pools. AB - Influenza A viruses cause an annual contagious respiratory disease in humans and are responsible for periodic high-mortality human pandemics. Pandemic influenza A viruses usually result from the reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the synonymous codons of the avian influenza virus PB1 gene of the 1968 H3N2 pandemic virus. We generated recombinant H3N2 viruses differing only in codon usage of PB1 mRNA and demonstrated that codon usage of the PB1 mRNA of recent H3N2 virus isolates enhances replication in interferon (IFN)-treated human cells without affecting replication in untreated cells, thereby partially alleviating the interferon induced antiviral state. High-throughput sequencing of tRNA pools explains the reduced inhibition of replication by interferon: the levels of some tRNAs differ between interferon-treated and untreated human cells, and evolution of the codon usage of H3N2 PB1 mRNA is skewed toward interferon-altered human tRNA pools. Consequently, the avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells. Our results indicate that the change in tRNA availabilities resulting from interferon treatment is a previously unknown aspect of the antiviral action of interferon, which has been partially overcome by human-adapted H3N2 viruses.IMPORTANCE Pandemic influenza A viruses that cause high human mortality usually result from reassortment of gene segments between human and avian influenza viruses. These avian influenza virus gene segments need to adapt to humans. Here we focus on the human adaptation of the avian influenza virus PB1 gene that was incorporated into the 1968 H3N2 pandemic virus. We demonstrate that the coding sequence of the PB1 mRNA of modern H3N2 viruses enhances replication in human cells in which interferon has activated a potent antiviral state. Reduced interferon inhibition results from evolution of PB1 mRNA codons skewed toward the pools of tRNAs in interferon-treated human cells, which, as shown here, differ significantly from the tRNA pools in untreated human cells. Consequently, avian influenza virus-derived PB1 mRNAs of modern H3N2 viruses have acquired codon usages that better reflect tRNA availabilities in IFN-treated cells and are translated more efficiently. PMID- 29970472 TI - Warm birthday wishes for NHS. PMID- 29970471 TI - Energy Conservation via Hydrogen Cycling in the Methanogenic Archaeon Methanosarcina barkeri. AB - Energy conservation via hydrogen cycling, which generates proton motive force by intracellular H2 production coupled to extracellular consumption, has been controversial since it was first proposed in 1981. It was hypothesized that the methanogenic archaeon Methanosarcina barkeri is capable of energy conservation via H2 cycling, based on genetic data that suggest that H2 is a preferred, but nonessential, intermediate in the electron transport chain of this organism. Here, we characterize a series of hydrogenase mutants to provide direct evidence of H2 cycling. M. barkeri produces H2 during growth on methanol, a phenotype that is lost upon mutation of the cytoplasmic hydrogenase encoded by frhADGB, although low levels of H2, attributable to the Ech hydrogenase, accumulate during stationary phase. In contrast, mutations that conditionally inactivate the extracellular Vht hydrogenase are lethal when expression of the vhtGACD operon is repressed. Under these conditions, H2 accumulates, with concomitant cessation of methane production and subsequent cell lysis, suggesting that the inability to recapture extracellular H2 is responsible for the lethal phenotype. Consistent with this interpretation, double mutants that lack both Vht and Frh are viable. Thus, when intracellular hydrogen production is abrogated, loss of extracellular H2 consumption is no longer lethal. The common occurrence of both intracellular and extracellular hydrogenases in anaerobic microorganisms suggests that this unusual mechanism of energy conservation may be widespread in nature.IMPORTANCE ATP is required by all living organisms to facilitate essential endergonic reactions required for growth and maintenance. Although synthesis of ATP by substrate-level phosphorylation is widespread and significant, most ATP is made via the enzyme ATP synthase, which is energized by transmembrane chemiosmotic gradients. Therefore, establishing this gradient across the membrane is of central importance to sustaining life. Experimental validation of H2 cycling adds to a short list of mechanisms for generating a transmembrane electrochemical gradient that is likely to be widespread, especially among anaerobic microorganisms. PMID- 29970473 TI - Eosinophils suppress Th1 responses and restrict bacterially induced gastrointestinal inflammation. AB - Eosinophils are predominantly known for their contribution to allergy. Here, we have examined the function and regulation of gastrointestinal eosinophils in the steady-state and during infection with Helicobacter pylori or Citrobacter rodentium We find that eosinophils are recruited to sites of infection, directly encounter live bacteria, and activate a signature transcriptional program; this applies also to human gastrointestinal eosinophils in humanized mice. The genetic or anti-IL-5-mediated depletion of eosinophils results in improved control of the infection, increased inflammation, and more pronounced Th1 responses. Eosinophils control Th1 responses via the IFN-gamma-dependent up-regulation of PD-L1. Furthermore, we find that the conditional loss of IFN-gammaR in eosinophils phenocopies the effects of eosinophil depletion. Eosinophils further possess bactericidal properties that require their degranulation and the deployment of extracellular traps. Our results highlight two novel functions of this elusive cell type and link it to gastrointestinal homeostasis and anti-bacterial defense. PMID- 29970475 TI - Simultaneous recordings of action potentials and calcium transients from human induced pluripotent stem cell derived cardiomyocytes. AB - Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) offer a unique in vitro platform to study cardiac diseases, as they recapitulate many disease phenotypes. The membrane potential (Vm) and intracellular calcium (Ca2+) transient (CaT) are usually investigated separately, because incorporating different techniques to acquire both aspects concurrently is challenging. In this study, we recorded Vm and CaT simultaneously to understand the interrelation between these parameters in hiPSC-CMs. For this, we used a conventional patch clamp technique to record Vm, and synchronized this with a Ca2+ imaging system to acquire CaT from same hiPSC-CMs. Our results revealed that the CaT at 90% decay (CaT90) was longer than action potential (AP) duration at 90% repolarization (APD90). In addition, there was also a strong positive correlation between the different parameters of CaT and AP. The majority of delayed after depolarizations (DADs) observed in the Vm recording were also characterized by elevations in the intracellular Ca2+ level, but in some cases no abnormalities were observed in CaT. However, simultaneous fluctuations in CaT were always observed during early after depolarizations (EADs) in Vm In summary, simultaneous recording of Vm and CaT broadens the understanding of the interrelation between Vm and CaT and could be used to elucidate the mechanisms underlying arrhythmia in cardiac disease condition. PMID- 29970474 TI - Inhibition of CRTH2-mediated Th2 activation attenuates pulmonary hypertension in mice. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3+CD4+ T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2+/+ bone marrow reconstitution and CRTH2+/+ CD4+ T cell adoptive transfer deteriorated hypoxia + ovalbumin-induced PAH in CRTH2-/- mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH. PMID- 29970476 TI - Epigenetic modifications by polyphenolic compounds alter gene expression in the hippocampus. AB - In this study, we developed an experimental protocol leveraging enhanced reduced representation bisulphite sequencing to investigate methylation and gene expression patterns in the hippocampus in response to polyphenolic compounds. We report that the administration of a standardized bioavailable polyphenolic preparation (BDPP) differentially influences methylated cytosine patterns in introns, UTR and exons in hippocampal genes. We subsequently established that dietary BDPP-mediated changes in methylation influenced the transcriptional pattern of select genes that are involved in synaptic plasticity. In addition, we showed dietary BDPP mediated changes in the transcriptional pattern of genes associated with epigenetic modifications, including members of the DNA methyl transferase family (DNMTs) and the Ten-eleven translocation methylcytosine dioxygenases family (TETs). We then identified the specific brain bioavailable polyphenols effective in regulating the transcription of DNMTs, TETs and a subset of differentially methylated synaptic plasticity-associated genes. The study implicates the regulation of gene expression in the hippocampus by epigenetic mechanisms as a novel therapeutic target for dietary polyphenols. PMID- 29970477 TI - The STK35 locus contributes to normal gametogenesis and encodes a lncRNA responsive to oxidative stress. AB - Serine/threonine kinase 35 (STK35) is a recently identified human kinase with an autophosphorylation function, linked functionally to actin stress fibers, cell cycle progression and survival. STK35 has previously been shown to be highly expressed in human testis, and we demonstrated its regulation by nuclear localized importin alpha2 in HeLa cells. The present study identifies progressive expression from the STK35 locus of two coding mRNA isoforms and one long non coding RNA (lncRNA) in mouse testis during spermatogenesis, indicating their tightly controlled synthesis. Additionally, lncRNA transcripts are increased by exposure to oxidative stress in mouse GC-1 germ cell line. STK35 knockout (KO) mice lacking all three RNAs are born at sub-Mendelian frequency, and adults manifest both male and female germline deficiency. KO males exhibit no or partial spermatogenesis in most testis tubule cross-sections; KO ovaries are smaller and contain fewer follicles. Eyes of KO mice display phenotypes ranging from gross deformity to mild goniodysgenesis or iridocorneal angle malformation, to overtly normal. These findings demonstrate the tight regulation of transcription from the STK35 locus and its central importance to fertility, eye development and cell responses to oxidative stress. PMID- 29970478 TI - Impact of ambient temperature on energy cost and economical speed during level walking in healthy young males. AB - We measured oxygen consumption and carbon dioxide output during walking [per unit distance (Cw) values] for 14 healthy young human males at seven speeds from 0.67 to 1.67 m s-1 (4 min per stage) in thermoneutral (23 degrees C), cool (13 degrees C), and hot (33 degrees C) environments. The Cw at faster gait speeds in the 33 degrees C trial was slightly higher compared to those in the 23 degrees C and 13 degrees C trials. We found the speed at which the young males walked had a significant effect on the Cw values (P<0.05), but the different environmental temperatures showed no significant effect (P>0.05). Economical speed (ES) which can minimize the Cw in each individual was calculated from a U-shaped relationship. We found a significantly slower ES at 33 degrees C [1.265 (0.060) m s-1 mean (s.d.)] compared to 23 degrees C [1.349 (0.077) m s-1] and 13 degrees C [1.356 (0.078) m s-1, P<0.05, respectively] with no differences between 23 degrees C and 13 degrees C (P>0.05). Heart rate and mean skin temperature responses in the 33 degrees C condition increased throughout the walking trial compared to 23 degrees C and 13 degrees C (all P<0.05). These results suggest that an acutely hot environment slowed the ES by ~7%, but an acutely cool environment did not affect the Cw and ES. PMID- 29970479 TI - Increased expression of serum periostin and YKL40 in children with severe asthma and asthma exacerbation. AB - Children with severe asthma or acute asthma exacerbation may encounter difficulties in performing pulmonary function tests. In this situation, serum biomarkers can play a great role in evaluation of such patients. The aim of this study was to estimate the serum levels of human chitinase-3-like protein 1 (YKL40) and periostin in a group of Egyptian children with asthma during acute asthma exacerbation and in stable asthmatics compared with healthy control, and to correlate these findings with the severity of asthma. This cross-sectional study enrolled 120 childrenwith asthma with different degrees of asthma severity, according to the Global Initiative for Asthma guidelines, along with 60 age matched and sex-matched healthy control. A complete blood count and an estimation of serum periostin and YKL40 levels were performed for all cases and control. Individual and mean values of periostin and YKL40 were significantly higher during acute asthma exacerbations, p<0.001. A highly significant relation between serum levels of periostin and YKL40 and asthma severity, p value for each was <0.001. Absolute eosinophil count was significantly correlated with the serum periostin levels in stable asthmatic group (p=0.01) only. There was significantly positive correlation (P<0.001) between both markers in stable asthmatic group. Spearman's correlation coefficient shows a statistically significant positive correlation between both markers and patient's age and duration of asthma, p value for each was 0.001. These findings highlight the importance of periostin and YKL40 as serum biomarkers for assessment of asthma severity and acute asthma exacerbations in children with asthma. PMID- 29970481 TI - Inhibition of Parp1 by BMN673 Effectively Sensitizes Cells to Radiotherapy by Upsetting the Balance of Repair Pathways Processing DNA Double-Strand Breaks. AB - Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 MUmol/L) or AG14361 (0.4 MUmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 MUmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (~1 hour) and at pharmacologically achievable concentrations in vivo BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. Mol Cancer Ther; 17(10); 2206-16. (c)2018 AACR. PMID- 29970480 TI - Efficacy of the MDM2 Inhibitor SAR405838 in Glioblastoma Is Limited by Poor Distribution Across the Blood-Brain Barrier. AB - Controversy exists surrounding whether heterogeneous disruption of the blood brain barrier (BBB), as seen in glioblastoma (GBM), leads to adequate drug delivery sufficient for efficacy in GBM. This question is especially important when using potent, targeted agents that have a poor penetration across an intact BBB. Efficacy of the murine double minute-2 (MDM2) inhibitor SAR405838 was tested in patient-derived xenograft (PDX) models of GBM. In vitro efficacy of SAR405838 was evaluated in PDX models with varying MDM2 expression and those with high (GBM108) and low (GBM102) expression were evaluated for flank and orthotopic efficacy. BBB permeability, evaluated using TexasRed-3 kDa dextran, was significantly increased in GBM108 through VEGFA overexpression. Drug delivery, MRI, and orthotopic survival were compared between BBB-intact (GBM108-vector) and BBB-disrupted (GBM108-VEGFA) models. MDM2-amplified PDX lines with high MDM2 expression were sensitive to SAR405838 in comparison with MDM2 control lines in both in vitro and heterotopic models. In contrast with profound efficacy observed in flank xenografts, SAR405838 was ineffective in orthotopic tumors. Although both GBM108-vector and GBM108-VEGFA readily imaged on MRI following gadolinium contrast administration, GBM108-VEGFA tumors had a significantly enhanced drug and gadolinium accumulation, as determined by MALDI-MSI. Enhanced drug delivery in GBM108-VEGFA translated into a marked improvement in orthotopic efficacy. This study clearly shows that limited drug distribution across a partially intact BBB may limit the efficacy of targeted agents in GBM. Brain penetration of targeted agents is a critical consideration in any precision medicine strategy for GBM. Mol Cancer Ther; 17(9); 1893-901. (c)2018 AACR. PMID- 29970482 TI - Role of EphB3 Receptor in Mediating Head and Neck Tumor Growth, Cell Migration, and Response to PI3K Inhibitor. AB - Eph proteins have emerged as critical drivers affecting tumor growth and progression in human malignancies. Our The Cancer Genome Atlas (TCGA) data analysis showed that EphB3, a receptor tyrosine kinase, is frequently coamplified with PIK3CA in head and neck squamous cell carcinoma (HNSCC). We therefore hypothesized that EphB3 amplification plays a protumorigenic role in HNSCC and that EphB3 and PIK3CA are cooperating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported, because EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival. This is correlated with an increase in prosurvival proteins, S6 and BcL-XL, in the EphB3 shRNA tumors treated with BKM120 compared with controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo To explain these results, we examined EphB3 phosphorylation levels in HNSCC at baseline. Although total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion protein resulted in decreased HNSCC migration and cell growth, and enhanced response to BKM120 in vitro These data collectively indicate that progression of HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit tumor growth and enhance sensitivity to PI3K inhibitors in HNSCC. Mol Cancer Ther; 17(9); 2049-59. (c)2018 AACR. PMID- 29970483 TI - A Chemosensitivity Study of Colorectal Cancer Using Xenografts of Patient-Derived Tumor-Initiating Cells. AB - Current genomic and gene expression analyses provide versatile tools to improve cancer chemotherapy. However, it is still difficult to predict whether each patient responds to a particular regimen or not. To predict chemosensitivity in each patient with colorectal cancer, we developed an evaluation method using the primary tumor-initiating cells (TIC, aka cancer stem cells) xenografted in nude mice subcutaneously (patient-derived spheroid xenografts; PDSX). Simultaneously, we also prepared the conventional patient-derived xenografts (PDX) from the same patients' tumors and compared the dosing results with those of PDSXs. We further compared the chemosensitivities of PDSXs with those of 7 patients who had been given regimens such as FOLFOX and FOLFIRI to treat their metastatic lesions. As per the results, the PDSX method provided much more precise and predictable tumor growth with less variance than conventional PDX, although both retained the epithelial characteristics of the primary tumors. Likewise, drug-dosing tests showed essentially the same results in PDXs and PDSXs, with stronger statistical power in PDSXs. Notably, the cancer chemosensitivity in each patient was precisely reflected in that of the PDSX mice along the clinical course until the resistance emerged at the terminal stage. This "paraclinical" xenograft trials using PDSXs may help selection of chemotherapy regimens efficacious for each patient, and, more importantly, avoiding inefficient ones by which the patient can lose precious time and QOL. Furthermore, the PDSX method may be employed for evaluations of off-label uses of cancer chemotherapeutics and compassionate uses of yet-unapproved new drugs in personalized therapies. Mol Cancer Ther; 17(10); 2187-96. (c)2018 AACR. PMID- 29970485 TI - Adopting new technology shouldn't create extra work. PMID- 29970484 TI - Drug-Sensitivity Screening and Genomic Characterization of 45 HPV-Negative Head and Neck Carcinoma Cell Lines for Novel Biomarkers of Drug Efficacy. AB - There is an unmet need for effective targeted therapies for patients with advanced head and neck squamous cell carcinoma (HNSCC). We correlated gene expression, gene copy numbers, and point mutations in 45 human papillomavirus negative HNSCC cell lines with the sensitivity to 220 anticancer drugs to discover predictive associations to genetic alterations. The drug response profiles revealed diverse efficacy of the tested drugs across the cell lines. Several genomic abnormalities and gene expression differences were associated with response to mTOR, MEK, and EGFR inhibitors. NOTCH1 and FAT1 were the most commonly mutated genes after TP53 and also showed some association with response to MEK and/or EGFR inhibitors. MYC amplification and FAM83H overexpression associated with sensitivity to EGFR inhibitors, and PTPRD deletion with poor sensitivity to MEK inhibitors. The connection between high FAM83H expression and responsiveness to the EGFR inhibitor erlotinib was validated by gene silencing and from the data set at the Cancer Cell Line Encyclopedia. The data provide several novel genomic alterations that associated to the efficacy of targeted drugs in HNSCC. These findings require further validation in experimental models and clinical series. Mol Cancer Ther; 17(9); 2060-71. (c)2018 AACR. PMID- 29970486 TI - Applications and advances of CRISPR-Cas9 in cancer immunotherapy. AB - Immunotherapy has emerged as one of the most promising therapeutic strategies in cancer. The clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (CRISPR-Cas9) system, as an RNA-guided genome editing technology, is triggering a revolutionary change in cancer immunotherapy. With its versatility and ease of use, CRISPR-Cas9 can be implemented to fuel the production of therapeutic immune cells, such as construction of chimeric antigen receptor T (CAR-T) cells and programmed cell death protein 1 knockout. Therefore, CRISPR-Cas9 technology holds great promise in cancer immunotherapy. In this review, we will introduce the origin, development and mechanism of CRISPR-Cas9. Also, we will focus on its various applications in cancer immunotherapy, especially CAR-T cell-based immunotherapy, and discuss the potential challenges it faces. PMID- 29970487 TI - Comprehensive overview of the pharmacogenetic diversity in Ashkenazi Jews. AB - BACKGROUND: Adverse drug reactions are a major concern in drug development and clinical therapy. Genetic polymorphisms in genes involved in drug metabolism and transport are major determinants of treatment efficacy and adverse reactions, and constitute important biomarkers for drug dosing, efficacy and safety. Importantly, human populations and subgroups differ substantially in their pharmacogenetic variability profiles, with important consequences for personalised medicine strategies and precision public health approaches. Despite their long migration history, Ashkenazi Jews constitute a rather isolated population with a unique genetic signature that is distinctly different from other populations. OBJECTIVE: To provide a comprehensive overview of the pharmacogenetic profile in Ashkenazim. METHODS: We analysed next-generation sequencing data from 5076 Ashkenazim individuals and used sequence data from 117 425 non-Jewish individuals as reference. RESULTS: We derived frequencies of 164 alleles in 17 clinically relevant pharmacogenes and derived profiles of putative functional consequences, providing the most comprehensive data set of Jewish pharmacogenetic diversity published to date. Furthermore, we detected 127 variants with an aggregated frequency of 20.7% that were specifically found in Ashkenazim, of which 55 variants were putatively deleterious (aggregated frequency of 9.4%). CONCLUSION: The revealed pattern of pharmacogenetic variability in Ashkenazi Jews is distinctly different from other populations and is expected to translate into unique functional consequences, especially for the metabolism of CYP2A6, CYP2C9, NAT2 and VKORC1 substrates. We anticipate that the presented data will serve as a powerful resource for the guidance of pharmacogenetic treatment decisions and the optimisation of population-specific genotyping strategies in the Ashkenazi diaspora. PMID- 29970490 TI - Non-invasive prenatal testing: public and doctors should be consulted, says BMA. PMID- 29970488 TI - Genetic obesity: next-generation sequencing results of 1230 patients with obesity. AB - BACKGROUND: Obesity is a global and severe health problem. Due to genetic heterogeneity, the identification of genetic defects in patients with obesity can be time consuming and costly. Therefore, we developed a custom diagnostic targeted next-generation sequencing (NGS)-based analysis to simultaneously identify mutations in 52 obesity-related genes. The aim of this study was to assess the diagnostic yield of this approach in patients with suspected genetic obesity. METHODS: DNA of 1230 patients with obesity (median BMI adults 43.6 kg/m2; median body mass index-SD children +3.4 SD) was analysed in the genome diagnostics section of the Department of Genetics of the UMC Utrecht (The Netherlands) by targeted analysis of 52 obesity-related genes. RESULTS: In 48 patients pathogenic mutations confirming the clinical diagnosis were detected. The majority of these were observed in the MC4R gene (18/48). In an additional 67 patients a probable pathogenic mutation was identified, necessitating further analysis to confirm the clinical relevance. CONCLUSIONS: NGS-based gene panel analysis in patients with obesity led to a definitive diagnosis of a genetic obesity disorder in 3.9% of obese probands, and a possible diagnosis in an additional 5.4% of obese probands. The highest yield was achieved in a selected paediatric subgroup, establishing a definitive diagnosis in 12 out of 164 children with severe early onset obesity (7.3%). These findings give a realistic insight in the diagnostic yield of genetic testing for patients with obesity and could help these patients to receive (future) personalised treatment. PMID- 29970491 TI - Linking histone methylation, transcription rates, and stem cell robustness. PMID- 29970489 TI - Condensin Depletion Causes Genome Decompaction Without Altering the Level of Global Gene Expression in Saccharomyces cerevisiae. AB - Condensins are broadly conserved chromosome organizers that function in chromatin compaction and transcriptional regulation, but to what extent these two functions are linked has remained unclear. Here, we analyzed the effect of condensin inactivation on genome compaction and global gene expression in the yeast Saccharomyces cerevisiae by performing spike-in-controlled genome-wide chromosome conformation capture (3C-seq) and mRNA-sequencing analysis. 3C-seq analysis shows that acute condensin inactivation leads to a global decrease in close-range intrachromosomal interactions as well as more specific losses of interchromosomal tRNA gene clustering. In addition, a condensin-rich interaction domain between the ribosomal DNA and the centromere on chromosome XII is lost upon condensin inactivation. Unexpectedly, these large-scale changes in chromosome architecture are not associated with global changes in mRNA levels. Our data suggest that the global transcriptional program of proliferating S. cerevisiae is resistant to condensin inactivation and the associated profound changes in genome organization. PMID- 29970492 TI - Complication free survival long-term after hemopoietic cell transplantation in thalassemia. PMID- 29970493 TI - Still a role for second-line chemoimmunotherapy in chronic lymphocytic leukemia? PMID- 29970494 TI - Immune failure, infection and survival in chronic lymphocytic leukemia. PMID- 29970495 TI - Immune failure, infection and survival in chronic lymphocytic leukemia in Denmark. PMID- 29970496 TI - News Feature: The carbon detectives. PMID- 29970498 TI - Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC. AB - Immunotherapy with monoclonal antibodies against programmed cell death (PD-1), such as nivolumab and pembrolizumab, has significantly improved the survival of patients with metastatic non-small cell lung cancer (NSCLC). In order to determine the subset of patients that can benefit most from these therapies, biomarkers such as programmed death ligand-1 (PD-L1) have been proposed. However, the predictive and prognostic role of the use of PD-L1 is controversial. Anti-PD L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability and tumour heterogeneity. Additionally, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Moreover PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as epidermal growth factor receptor (EGFR), echinoderm microtubule associated protein-like 4 (EML4) fusion with anaplastic lymphoma kinase (ALK), and Kirsten rat sarcoma viral oncogene homolog (KRAS). Preclinical studies have shown the potential role of targeted therapy in immune escape mechanisms in NSCLC cells. This review summarizes current literature data on the heterogeneity of PD L1 expression and the relationship with such factors and with clinicopathological features of NSCLC. PMID- 29970499 TI - Lung Cancer Stem Cells and Cancer Stem Cell-targeting Natural Compounds. AB - The novel information regarding molecular and translational research have created a paradigm shift in the understanding of lung cancer biology, revealing the more precise target for anti-cancer drug discovery. Lung cancer is a leading cause of cancer death worldwide accounting for approximately 1 in 5 of all cancer-related deaths. The most important causes of death in such a cancer involves the treatment failure as well as the spreading of cancer cells to distant sites which the cancer stem cell (CSC) within the tumor is accepted as a key driver. CSC is a rare special population of cancer cells exhibiting high tumorigenic properties together with self-renewal and differentiation capability. CSC is not only linked with high tumor-initiating activity, but is also implicated in chemotherapeutic resistance, metastasis, epithelial to mesenchymal transition, and recurrence. Thereafter, novel therapeutic strategies targeting these CSCs are considered in order to improve long-term clinical outcome. Here, we provide sufficient data regarding the biology of CSC in lung cancer, known CSC markers and cellular signals, and promising compounds targeting the stem cell signals in lung cancer that may benefit the development of novel anti-cancer treatment. PMID- 29970500 TI - Severe Defects in the Macrophage Barrier to Gut Microflora in Inflammatory Bowel Disease and Colon Cancer. AB - The continuity of the subepithelial band of lamina propria-indigenous macrophages (SBLP-M) discourages commensal gut bacteria from invading the host. In this Review we analyzed the impact of a disintegrating SBLP-M in inflammatory bowel disease (IBD), which results in microbiota inflow, inadequate immune responses and IBD-associated colon cancer. In previous work, we analyzed endoscopic biopsies taken from normal-looking descending colon in 247 patients with IBD, and 167 from control patients without IBD. Sections immunostained for cluster of differentiation 68 (CD68) protein showed no inflammatory changes. In IBD, the band of CD68+ SBLP-M was fragmented or minute in 59% (47/80) and absent in 9% (7/80). In contrast, only 31% (51/167) of the biopsies from control patients had a fragmented/minute band of CD68+ SBLP-M and this band was not absent in any (p<0.05). The finding that the band of CD68+ SBLP-M was fragmented to totally lost in IBD suggests a long-lasting defect in the barrier against the gut microbiome in IBD. The lack of ongoing inflammation in colonic biopsies should rule-out the participation of bone marrow-derived inflammation-elicited macrophages in loss of the barrier. Today, it is widely accepted that dysbiosis and inappropriate immune response to microbial flora play a pivotal role in the pathogenesis and development of IBD-associated colon cancer. Based on present knowledge, it is submitted that defects in the SBLP-M barrier in IBD encourage the trespassing of the gut microflora into the host, thereby destabilizing host immunity. These events in concert may play the ultimate pivotal role in the evolution of colon cancer in patients with IBD. PMID- 29970501 TI - The Role of Histone Deacetylase Inhibitors in Uveal Melanoma: Current Evidence. AB - Uveal melanoma is the most common intraocular malignancy in adults, representing approximately 3% of all melanoma cases. Despite progress in chemotherapy, radiation and surgical treatment options, the prognosis and survival rates remain poor. Acetylation of histone proteins causes transcription of genes involved in cell growth, DNA replication and progression of cell cycle. Overexpression of histone deacetylases occurs in a wide spectrum of malignancies. Histone deacetylase inhibitors block the action of histone deacetylases, leading to inhibition of tumor cell proliferation. This article reviewed the potential therapeutic effects of histone deacetylase inhibitors on uveal melanoma. MEDLINE database was used under the key words/phrases: histone deacetylase, inhibitors, uveal melanoma and targeted therapies for uveal melanoma. A total of 47, English articles, not only referring to uveal melanoma, published up to February 2018 were used. Valproic acid, trichostatin A, tenovin-6, depsipeptide, panobinostat (LBH-589), vorinostat (suberanilohydroxamic acid) entinostat (MS-275), quisinostat, NaB, JSL-1, MC1568 and MC1575 are histone deacetylase inhibitors that have demonstrated promising antitumor effects against uveal melanoma. Histone deacetylase inhibitors represent a promising therapeutic approach for the treatment of uveal melanoma. PMID- 29970502 TI - Contribution of Computed Tomographic Angiography to Pretreatment Planning of Radio-embolization of Liver Tumors. AB - Transarterial radio-embolization (TARE) using yttrium-90 microspheres is a promising method based on the brachytherapeutic effect of radionuclide with beta minus decay dissolved in solid microparticles applied directly to tumor-supplying arteries. This treatment is complex, as well as logistically and technically extremely demanding and must be planned in detail. The visualization of the vascular supply of the liver and the possible parasitic supply of the tumor is essential not only for indication of the procedure and correct identification of the arteries to which the microspheres will be applied, but also for prevention of non-target deposition of radioactive material. This review addresses the use of computed tomographic angiography in the preparatory phase of TARE. PMID- 29970503 TI - High ANXA7 Potentiates Eucalyptol Toxicity in Hormone-refractory Prostate Cancer. AB - BACKGROUND/AIM: Our studies showed that ANXA7 is a novel tumor suppressor gene that is lost in various aggressive forms of prostate cancer. However, little is known about the role of ANXA7 in the anticancer drug treatment towards different cancers. MATERIALS AND METHODS: The expression of ANXA7 was measured in the 60 cancer cell lines of the NCI-60 ADS project and correlated with the enhanced sensitivity to over 30,000 natural and synthetic compounds. RESULTS: Eucalyptol showed a high positive correlation with ANXA7 expression and castration-resistant prostate cancer cell death occurred very effectively in response to the combination of eucalyptol and overexpressed wt-ANXA7 than either agent alone. The synergistic effects of ANXA7 and eucalyptol resulted in concordant changes in gene expression profiles particularly of Ras family members, MDM4, NF-KB and VEGF. CONCLUSION: Overexpression of ANXA7 enhances eucalyptol cytotoxicity in prostate cancer cell lines. PMID- 29970504 TI - Hydrogen Sulfide Is Increased in Oral Squamous Cell Carcinoma Compared to Adjacent Benign Oral Mucosae. AB - BACKGROUND/AIM: Hydrogen sulfide (H2S) and the enzymes that synthesize it, cystathionine-b-synthase, cystathionine gamma-lyase, and 3-mercaptopyruvate, are increased in different human malignancies. Due to its short half-life, H2S concentrations have not been directly measured in a human malignancy. Here we directly measured in vivo H2S levels within oral squamous cell carcinoma (OSCC). PATIENTS AND METHODS: Punch biopsies of OSCC and benign mucosae from 15 patients were analyzed by HPLC, western blotting, and tissue microarray analyses. RESULTS: H2S concentrations were significantly higher in OSCC compared to adjacent benign oral mucosae. Western blot and tissue microarray studies revealed significantly increased cystathionine-b-synthase, cystathionine gamma-lyase, and 3 mercaptopyruvate, phopho-Stat3, mitoNEET, hTERT, and MAPK protein levels in OSCC. CONCLUSION: H2S concentrations and the enzymes that synthesize it are significantly increased in OSCC. Here, for the first time H2S concentrations within a living human malignancy were measured and compared to adjacent counterpart benign tissue. PMID- 29970505 TI - Analysis of Anticancer Activity and Chemical Sensitization Effects of Dendropanax morbifera and Commersonia bartramia Extracts. AB - BACKGROUND/AIM: Dendropanax morbifera (DM) and Commersonia bartramia (CB) are possible candidates for immunotherapy. In this study, the cytotoxicity and chemical sensitization of DM and CB extracts on gynecologic and colon cancers were evaluated. MATERIALS AND METHODS: The malignant cell lines were cultured and analyzed for cytotoxicity and chemical sensitization. A mouse model was also constructed to make the condition similar to in vivo. Reverse transcription polymerase chain reaction was conducted to determine alterations in drug resistant genes. RESULTS: The extracts from DM and CB showed specific cytotoxicity to malignant cell lines. DM increased chemical sensitivity to cervical and ovarian cancer, while CB showed improved sensitization to endometrial cancer. The effects of the extracts were confirmed using a mouse model. The extracts induced differences in the expression levels of a number of genes related to drug resistance. CONCLUSION: DM and CB extracts could be novel agents for immunotherapy and chemical sensitization in gynecologic and colon cancers. PMID- 29970506 TI - Immunohistochemical Study of Mitosis-regulatory Proteins in Gastroenteropancreatic Neuroendocrine Neoplasms. AB - BACKGROUND/AIM: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous tumors. Therapeutic targets remain to be identified and apart from the proliferation marker Ki-67, useful prognostic markers are rare. Mitotic proteins, such as forkheadbox protein M1 (FOXM1), survivin and aurora kinases, play a role in GEP-NEN progression. In this study, immunohistochemistry was used to analyze how this protein network is expressed in different subgroups of GEP-NENs and determine potential expression patterns that could be useful as tumor markers. MATERIALS AND METHODS: Tumor tissues from 75 patients were studied immunohistochemically with antibodies against aurora B, survivin and FOXM1. The expression pattern was correlated with clinicopathological data such as tumor grading, metastatic state and prognosis. RESULTS: The immunohistochemical analysis of nuclear aurora kinase B revealed a positive correlation with nuclear survivin and FOXM1 staining patterns. Furthermore, aurora B was positively related to grading and tumor size and negatively to differentiation and functionality. CONCLUSION: The expression of aurora kinase B is associated with differentiation, progression and the aggressiveness of GEP-NENs. In the context of tumor progression, aurora B is strongly associated with markers of the mitosis regulatory network, survivin, FOXM1 and Ki-67. A shift of the intracellular localization of aurora B might be useful for the subclassification of intermediate-grade intestinal NET and NEC (20%=2.33) were independent predictors of poorly differentiated HCC. Recurrence-free and overall survival were comparable despite these significant predictors. CONCLUSION: The preoperative status of two or three positive tumor markers and high NLR facilitated selecting HCC patients with poorly differentiated disease, which will assist making therapeutic decisions for HCC patients. PMID- 29970536 TI - EpCAM as a Predictive Marker of Tumor Recurrence and Survival in Patients Who Underwent Surgical Resection for Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Epithelial cell adhesion molecule (EpCAM) is expressed in hepatic progenitor cells and hepatocellular carcinoma (HCC), and is considered a marker of liver cancer stem cells. MATERIALS AND METHODS: A total of 262 patients were enrolled who had undergone surgical resection for HCC, with immunohistochemical staining results for EpCAM. The immunohistochemical expression of EpCAM and other stemness-related markers was evaluated as prognosticators of tumor recurrence and survival in patients who underwent surgical resection for HCC. RESULTS: A multivariate Cox regression analysis showed that tumor size [hazard ratio (HR)=2.26, p=0.005], intrahepatic metastasis (HR=2.31, p=0.011), and EpCAM positivity (HR=1.74, p=0.038) were associated with tumor recurrence. In a Kaplan Meier survival analysis, patients with EpCAM-positive tumors had a significantly higher tumor recurrence rate and a reduced overall survival compared to those with EpCAM-negative tumors. CONCLUSION: Immunohistochemical expression of EpCAM was identified as a poor prognosticator of recurrence and survival after surgical resection in patients with HCC. PMID- 29970537 TI - DNA from Human Polyomaviruses, MWPyV, HPyV6, HPyV7, HPyV9 and HPyV12 in Cutaneous T-cell Lymphomas. AB - BACKGROUND/AIM: The etiopathogenesis of mycosis fungoides and Sezary syndrome remains obscure. Different viruses have been proposed to have a role in the etiopathogenesis of cutaneous T-cell lymphomas (CTCL). In the present study, the presence of five recently discovered human polyomaviruses 6 (HPyV6), human polyomaviruses 7 (HPyV7), human polyomaviruses 9 (HPyV9), human polyomaviruses 12 (HPyV12), and Malawi polyomavirus (MWPyV), have been analyzed in 55 CTCL in order to confirm the skin tropism and the possible pathological association of these new polyomaviruses. MATERIALS AND METHODS: Human polyomaviruses DNA were amplified from skin lesions were recovered from a total of 55 patients (32 males and 23 females, average age 63+/-15 years) affected by CTCL. RESULTS: When assayed for the presence of 5 different HPyVs, (HPyV6, HPyV7, HPyV9, MWPyV, and HPyV12) HPyV9, HPyV10 and HPyV12 DNA sequences were not found in any skin specimens. HPyV6 and 7 DNA was detected in 1/55 (1.8%) of skin specimens. CONCLUSION: The low-level presence of HPyV6 and HPyV7 DNA, and lack of detection of polyomaviruses HPyV9, MWPyV and HPyV12 in our series do not support a significant role of these HPyVs subtypes in the etiopathogenesis of skin cancers. PMID- 29970538 TI - Prognostic and Predictive Factors for Anti-androgen Withdrawal in Castration resistant Prostate Cancer. AB - BACKGROUND/AIM: We aimed to identify prognostic and predictive factors for anti androgen withdrawal syndrome (AWS) to help guide decisions on anti-androgen withdrawal in castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: This study included 95 patients with prostate cancer which progressed to CRPC despite primary androgen-deprivation therapy (ADT). AWS was defined as >50% prostate-specific antigen decline after anti-androgen withdrawal. Associations between AWS, and clinicopathological factors and prognosis were investigated. RESULTS: Among the 95 patients, 84 (88.4%) underwent anti-androgen withdrawal, among whom AWS was recognized in nine (10.8%). Gleason score and response duration to primary ADT were predictors of AWS. Long duration of response to primary ADT was also associated with better progression-free survival [hazard ratio (HR)=0.021, 95% confidence interval (CI)=0.0025-0.14, p<0.0001] and overall survival (HR=0.0042, 95% CI=0.0001-0.089, p<0.0001). Age (HR=7.19, 95% CI=1.08 54.27, p=0.041) and radiological/clinical progression (HR=3.14, 95% CI=1.35-6.43, p=0.010) were associated with worse overall survival. Intriguingly, radiological/clinical progression was associated with the differential effect of anti-androgen withdrawal on overall survival (interaction p=0.031). CONCLUSION: Patients who suffer radiological/clinical progression are unsuitable candidates for anti-androgen withdrawal. PMID- 29970539 TI - Pathological High-risk Renal Cell Carcinoma: Trends in Clinical Characteristics Over 25 Years. AB - BACKGROUND/AIM: The incidence of renal cell carcinoma (RCC) has been increasing mainly due to the increase in the incidental detection of small renal masses. The aim of this study was to verify whether the trend towards early diagnosis changed the clinical characteristics of pathologically-defined high-risk RCC patients over the last decades. PATIENTS AND METHODS: A total of 741 patients with pathologically-confirmed high-risk RCC (pT1-4, and/or pN1 and/or Fuhrman grade 3 4 and/or all M1 patients) treated with radical (RN) or partial nephrectomy (PN) at a single tertiary referral center between 1987 and 2011 were included in the study. The temporal trends of pre-operative clinical and tumor characteristics were assessed relying on the lowess smoother weighted function with corresponding 95% confidence interval. Estimated annual percentage changes (EAPC) were evaluated using a log linear regression model. RESULTS: The median age of patients increased from 57.5 to 67.3 years between 1987 and 2011 (EAPC 4.9%, p=0.002). Body mass index and gender rates remained stable during the study period. A constant trend towards patients with one or more comorbidity was observed. Moreover, the proportion of asymptomatic patients at diagnosis and of clinical T1 increased by 41.1 and 19.8%, respectively (all p<=0.007). The clinical tumor size dropped from 8.4 to 6.2 cm (EAPC -1.2%, p=0.001). This trend was accompanied by a clinically-relevant increase by 15.3% in the rate of patients without clinical metastases (p=0.07). Conversely, the rate of clinical lymphadenopathies remained stable over time. Finally, the rate of PNs performed increased by 23.3% (p<0.001). CONCLUSION: Over the years, pathologically confirmed high-risk RCC patients are older, mostly asymptomatic, with smaller cancers, with a higher rate of tumors localized to the kidney and with a decreased rate of metastatic disease at diagnosis. These trends can explain the increasing number of PNs performed despite the presence of a high-risk cancer profile. PMID- 29970540 TI - Single-source Dual-energy CT as a Part of 18F-FDG PET/CT: Direct Comparison of Iodine-related and Metabolic Parameters in Non-small Cell Lung Cancer. AB - Aim: The aim of the study was to assess possible correlation of fluorogeoxyglucose (FDG) uptake and iodine-related attenuation values derived from positron-emission tomography/computed tomography (PET/CT) using single source dual-energy CT scan (DE-CT) in non-small cell lung cancer (NSCLC). Materials and Methods: Forty-eight patients with histologically-proven NSCLC underwent 18 F-FDG-PET/CT within their staging process. PET/CT included single source DE-CT in late post-contrast phase. Direct comparison of PET and DE-related values was performed. A sub-study regarding different histological types and various thresholds for quantification of volume metabolic values was also performed. Results: A strong correlation was found of metabolic tumor volume and total lesion glycolysis with total iodine content using Pearson correlation analysis (r=0.965-0.983; p<0.0001) with various thresholds for FDG lesion segmentation. The strongest correlations with iodine content were reached using 10% threshold for segmentation. Only a weak correlation was found between iodine content and the maximal standard uptake value. A significant difference between adenocarcinomas and other histological subtypes was found for selected parameters of metabolic PET and DE-CT data. Conclusion: Our study demonstrated a strong correlation of the iodine content calculated from single-source DE-CT with volumetric FDG parameters in NSCLC. without a significant effect of the threshold value for FDG lesion segmentation. PMID- 29970542 TI - Low-dose High-resolution 18F-FDG-PET/CT Using Time-of-flight and Point-spread Function Reconstructions: A Role in the Detection of Breast Carcinoma Axillary Lymph Node Metastases. AB - AIM: to evaluate the performance of N-staging assessment in clinically-proven T1 breast carcinoma by high-resolution 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography (18F-FDG-PET/CT) using time-of-flight with point spread function reconstruction. PATIENTS AND METHODS: In 30 women with clinically proven T1 breast carcinoma, imaging before surgery was performed using 18F-FDG PET/CT. The results of PET/CT in detection of lymph node metastases were compared with those obtained after pathological investigation of axillary biopsy. A four ring PET subsystem with image reconstruction using time-of-flight and point spread function was used with the radiopharmaceutical dose reduction to 2.5 MBq/kg. RESULTS: Axillary lymph node metastasis was confirmed by histology in 13 patients, but metastasis was suspected based on PET/CT in 12 of those patients, the absence of metastasis was surgically confirmed in 17 women, 15 of which were suspected based on PET/CT. The sensitivity for detection of axillary lymph node metastasis was 93.3%, with a specificity of 88.2% in the whole patient cohort. Additionally, distant metastatic spread was found in 13.3% of patients. CONCLUSION: The reconstruction of PET images with time-of-flight and point-spread function enabled the improvement of diagnostic performance in N-staging of breast carcinoma, even when the dose of radiopharmaceutical was reduced to 2.5 MBq/kg. PMID- 29970541 TI - 18F-Fluorocholine PET/MRI in Restaging of Prostatic Carcinoma in Relation to PSA Level and Detection of Active Disease. AB - AIM: To evaluate our own experience with 18F- fluoromethylcholine-(FCH)-positron emission tomography combined with magnetic resonance imaging (PET/MRI) in restaging of patients with prostatic carcinoma and elevated serum prostate specific antigen (PSA) level. PATIENTS AND METHODS: The analysis was performed on a sample of 100 male patients who underwent 18F-FCH-PET/MRI, with a mean age of 63.2 years (range=47-78 years). The imaging was performed using an integrated PET/MRI hybrid system after intravenous application of 18F-FCH at a dose of 1.25 MBq/kg. The number and sites of pathological accumulation of FCH related to local recurrence, nodal spread and skeletal metastases were compared to corresponding MRI findings; furthermore, the relation of PSA level and presence of FCH accumulation in tumorous tissue was assessed; finally we correlated the findings of different sites of metastatic involvement. RESULTS: In patients with a PSA level up to 2 ng/ml, accumulation in tumorous tissue of local recurrence or metastases was found in 83.33% in cases of biochemical relapse, and in patients with PSA level above 5 ng/ml in 100% of cases. In general, we found any finding explained rise of PSA level in 94% of patients. CONCLUSION: 18F-FCH-PET/MRI using an integrated system with 1,25 MBq/kg dosing of FCH is a valuable tool in evaluation of restaging in patients with prostatic carcinoma, with high detection rate even in those with a low serum PSA level. PMID- 29970543 TI - Tumor-related Perfusion Changes in White Matter Adjacent to Brain Tumors: Pharmacodynamic Analysis of Dynamic 3T Magnetic Resonance Imaging. AB - BACKGROUND/AIM: To verify perfusion differences in white matter adjacent to glioblastomas and metastatic tumors in dynamic contrast-enhanced (DCE) 3T magnetic resonance imaging (MRI) using gradient echo (GRE) T1 techniques. MATERIALS AND METHODS: A retrospective comparative study was carried out on adults with glioblastoma (n=67) and brain metastases (n=31). In each patient, conventional 3T-MRI and DCE-MRI with 25 acquisitions of GRE-T1 were performed. The initial area under the contrast-uptake curve (iAUC) and transfer constant (Ktrans) in peritumoral regions of the white matter were evaluated using T1 pharmacodynamic modeling software. RESULTS: Statistically significantly higher relative iAUC (p<0.001) and Ktrans (p<0.01) values were recorded for peritumoral white matter near glioblastomas compared to that near metastases: 2.29 (SD=1.11) and 2.12 (SD=1.05) vs. 0.96 (SD=0.31) and 1.18 (SD=0.35), respectively. CONCLUSION: In comparison to Ktrans, the iAUC obtained by DCE-MRI is more suitable for assessing glioblastomas because it better reflects pharmacokinetic peritumoral changes. Increased iAUC in white matter near to tumor generally indicates glioblastoma, however, a low level does not exclude it. PMID- 29970544 TI - Hybrid Imaging PET/CT with Application of 18F-Fluorothymidine in Patients with Head and Neck Carcinoma Undergoing Radiotherapy. AB - AIM: To introduce the possible benefits of the positron-emission tomography (PET)/computed tomography (CT) with 18F-3'-deoxy-3'-fluorothymidine (18F-FLT) in patients with orofacial carcinomas and its impact to patient management. MATERIALS AND METHODS: Thirty-six patients with orofacial squamous cell carcinomas underwent 18F-FLT-PET/CT during radiotherapy. Examinations were performed after administration of 18F-FLT (1.8 MBq/kg) including full-diagnostic CT. Analysis of the radiotherapy effect was performed with possible prospect of repeated and focused irradiation. RESULTS: Complete absence of 18F-FLT uptake was found in 20 patients, thus complete response to radiotherapy was reported. Persistence of focal 18F-FLT uptake was observed in 16 patients; in 11 patients, the measured activity was only mild. In five patients, a higher level of 18F-FLT uptake was measured and additional irradiation was performed in defined regions. Repeated follow-up proved complete regression 18F-FLT uptake. CONCLUSION: It was possible to assess the effect of radiotherapy with the use of 18F-FLT-PET/CT and findings are suitable for radiation dose-escalation planning. PMID- 29970546 TI - Antidiabetic Medication, Statins and the Risk and Prognosis of Non-endometrioid Endometrial Cancer in Women with Type 2 Diabetes. AB - AIM: To determine the incidence and prognosis of non-endometrioid endometrial cancer (EC) in relation to the use of metformin, other antidiabetic medication (ADM) and statins in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In order to analyze the incidence and prognosis of non-endometrioid EC, two cohorts were obtained from a nationwide diabetes database (FinDM); 57 non endometrioid ECs were observed in a cohort of 92,366 women with newly-diagnosed T2D during the follow-up (1996 to 2011) to assess the incidence, and a retrospective cohort of 105 women with T2D diagnosed with non-endometrioid EC (1998 to 2011) was used to estimate cumulative mortality from EC and other causes of death. Hazard ratios (HRs) with 95% confidence intervals (CIs) for EC incidence were estimated in the full-cohort analysis and in the nested case control analysis, matched for age and duration of T2D. Cumulative mortality was estimated by using the Aalen-Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models regarding the pre-diagnostic use of different forms of ADM and statins. RESULTS: In the nested case-control analysis, the use of metformin was not associated with the risk of non-endometrioid EC (HR=1.09, 95% CI=0.59-2.00), whereas statin use was associated with a lower risk (HR=0.47, 95% CI=0.26-0.84). The results from the full-cohort analysis supported these findings. Mortality from non-endometrioid EC was not different between users of metformin and other types of oral ADM (HR=1.56, 95% CI=0.40-6.07) but was observed to be lower in statin users (HR=0.41, 95% CI=0.20-0.82). CONCLUSION: Our findings were inconclusive regarding the association of metformin with the risk and prognosis of non-endometrioid EC. However, statin use was associated with a lower incidence and mortality from this disease. PMID- 29970545 TI - The Impact of Immune Interaction on the Metastatic Infiltration of Colorectal Carcinoma to Lymph Nodes. AB - BACKGROUND/AIM: Tumour-infiltrating lymphocytes (TILs) and Granzyme B play crucial roles in immune reactions against colorectal carcinoma (CRCa). The inhibitor of Granzyme B is Serpin B9. The aim of this study was to evaluate the effect of immunohistological parameters of TILs on the prognosis of CRCa and presence of lymph node metastasis. PATIENTS AND METHODS: A total of 152 patients who underwent surgery for CRCa were analyzed, including 63 patients in cohort stage II, according to the Union for International Cancer Control (UICC), and 89 patients in cohort UICC stage III. The TIL pattern was classified as peritumoural (PTL), intratumoural (ITL), intrastromal (ISL) or Crohn-like, and immunohistological staining of TIL and cancer cells was also performed. RESULTS: A significantly higher density of CD8+ and CD4+ TILs was observed in the UICC II group, and significantly higher densities of CD4+ TILs were observed in the UICC II group in all distinguished patterns. In the same cohort, higher numbers of CD57+ cells and FoxP3+ TILs and Granzyme B levels were observed. In cohort UICC III, there was a higher density of ISL, PTL CD8+, CD25+ TILs and cancer cells showed staining for Serpin B9. CD57, Granzyme B and CD8 were demonstrated as positive prognostic factors of overall survival, and CD57 and CD4+ TILs were demonstrated as positive prognostic factors of recurrence. CONCLUSION: TILs and CD57 are promising prognostic factors of CRCa. The association of Serpin B9 with lymph node metastasis reveals a potential mechanism for tumour resistance to immune reaction. PMID- 29970547 TI - Significance of De Ritis (Aspartate Transaminase/Alanine Transaminase) Ratio as a Significant Prognostic But Not Predictive Biomarker in Japanese Patients with Metastatic Castration-resistant Prostate Cancer Treated with Cabazitaxel. AB - BACKGROUND/AIM: To date, there have not been any established biomarkers predicting the efficacy of cabazitaxel in patients with metastatic castration resistant prostate cancer (mCRPC). The objective of this study was to evaluate the significance of the aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT) ratio (De Ritis ratio) as a biomarker for mCRPC patients receiving cabazitaxel. PATIENTS AND METHODS: This study included 74 consecutive docetaxel-refractory mCRPC patients treated with cabazitaxel. It assessed the impact of the pretreatment De Ritis ratio, in addition to conventional clinicopathological parameters, on the oncological outcomes in these patients. RESULTS: After treatment with cabazitaxel, 22 (29.7%) of the 74 patients achieved a prostate-specific antigen (PSA) response; however, there was no significant difference in the PSA response rate between patients with a low De Ritis ratio (<1.35) and those with a high ratio (>=1.35). In this series, the median periods of PSA progression-free survival (PFS) and overall survival (OS) after the introduction of cabazitaxel were 4.2 and 14.7 months, respectively. No significant difference was noted in PSA PFS between the low and high De Ritis ratio groups, whereas OS in the high De Ritis ratio group was significantly poorer compared with that in the low De Ritis ratio group. Univariate analysis showed the significant impact of the De Ritis ratio on OS, but not PFS, in these 74 patients. Furthermore, the De Ritis ratio, in addition to the performance status and lactate dehydrogenase level, was shown to be independently associated with OS on multivariate analysis. CONCLUSION: Assessment of the De Ritis ratio may provide useful prognostic, but not predictive, information on cabazitaxel therapy in mCRPC patients. PMID- 29970548 TI - Efficacy-safety of Facilitated Subcutaneous Immunoglobulin in Immunodeficiency Due to Hematological Malignancies. A Single-Center Retrospective Analysis. AB - BACKGROUND/AIM: Hematological malignancies are frequently complicated by secondary immunodeficiency (SID). Immunoglobulin replacement with intravenous gamma globulins (IVIg) reduces infection incidence, antibiotics' need and hospitalization days in these patients. Facilitated subcutaneous immunoglobulin replacement (fSCIg) has been studied in primary immunodeficiency patients and is equally efficacious with several advantages (self-administration, same bioavailability, long infusion intervals, fewer adverse drug reactions). fSCIg has been less extensively studied in SID. We present our retrospective single center data of fSCIg administration to hematological patients with SID, focusing on efficacy and safety issues. PATIENTS AND METHODS: Overall, 33 hematological patients with hypogammaglobulinemia were treated with fSCIg according to ESMO 2015 guidelines, between mid-October 2015 and mid-January 2018 in our Department. RESULTS: The infection rate was very low (18.1%). Shorter infusion intervals further reduced it. ADRs were rare (9%) and mild (grade 1). fSCIg managed to reduce the everyday nursery/hospital burden of our tertiary hospital. CONCLUSION: fSCIg compares favorably to IVIg replacement in SID patients. PMID- 29970549 TI - Neoadjuvant Radiotherapy with Capecitabine Plus Bevacizumab for Locally Advanced Lower Rectal Cancer: Results of a Single-institute Phase II Study. AB - BACKGROUND/AIM: A single-arm phase II clinical trial was conducted to evaluate the safety and efficacy of adding bevacizumab to standard capecitabine-based neoadjuvant chemoradiotherapy (CRT) for the treatment of locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Twenty-five patients were enrolled. Patients received capecitabine-based CRT for 5 weeks and 3 days. Bevacizumab was administered every 2 weeks during CRT. Within 6-10 weeks after completion of CRT, surgery was performed. RESULTS: With regard to CRT-related acute toxicities, most of the adverse events were limited to grade 1. A pathological complete response was obtained in four (16%) patients. In total, six patients (24%) developed postoperative complications. Six out of five (83%) patients healed without the need for surgical intervention. CONCLUSION: Although acute toxicity during CRT with bevacizumab was minimal and postoperative complications do not seem to increase, the addition of bevacizumab apparently offers no clinically-significant benefit for patients with LARC. PMID- 29970550 TI - A Tool to Predict the Probability of Intracerebral Recurrence or New Cerebral Metastases After Whole-brain Irradiation in Patients with Head-and-Neck Cancer. AB - BACKGROUND/AIM: Patients with metastatic head-and-neck cancer require individual therapies facilitated by prognostic tools. A tool to estimate the risk of recurrent or new cerebral metastases following whole-brain irradiation (WBI) is presented. PATIENTS AND METHODS: Age, gender, performance status, cancer site, number of cerebral lesions, extracerebral metastases, and time between cancer diagnosis and treatment of cerebral metastases were evaluated for intracerebral control in 23 patients. For characteristics showing a trend (p<0.07), points for these characteristics were created by dividing 6-month intracerebral control rates by 10. Patient scores were obtained by adding these points. RESULTS: Better intracerebral control was significantly associated with oropharyngeal and laryngeal cancer (p=0.014). Absence of extra-cerebral metastases (p=0.069) and longer time between cancer diagnosis and treatment of cerebral metastases (p=0.053) showed trends. Three groups were identified, namely with 3-11, 13-18 and 20-24 points. Six-month intracerebral control rates were 0%, 50% and 100% (p=0.003), respectively, for these groups. CONCLUSION: A new tool was created to predict intracerebral control following WBI and should contribute to personalization of treatment for patients with cerebral metastases of head-and neck cancer. PMID- 29970551 TI - Unusual Papillary Squamous Cell Carcinoma of the Tip of Tongue Presenting in a Patient Status Post Heart Transplant. AB - Oral papillary squamous cell carcinoma (PSCC) is an unusual variant of squamous cell carcinoma with a better prognosis. The most common location of PSCC in the oral cavity is the gingiva and buccal mucosa, and it is exceedingly rare in the tongue. Herein, we present a case of PSCC in an 85-year-old male with a history of heart transplant and long-term use of immunosuppression medication. A verrucous pedunculated mass measuring 3.5 cm in the greatest dimension was present on the tip of tongue and a partial glossectomy was performed. Histological diagnosis was well differentiated PSCC with focal and minimal stalk invasion. No vascular nor perineural invasion was identified. Based on the current WHO and AJCC oral cancer staging system, the tumor stage was T2N0M0. The tumor cells were focally positive for p16, but in situ hybridization was negative for low-risk HPV (types 6 and 11) and high-risk HPV (types 16, 18, 31, 33 and 51). To the best of our knowledge, this is the first documented case of PSCC present on the tip of tongue in patients with long-term immune suppression. The pathogenesis, stage and prognosis of this entity are discussed. More case studies with long-term follow up are needed to achieve an accurate tumor stage and definite prognosis. PMID- 29970552 TI - Long-term Outcomes of Radiotherapy Regimen of 72 Gy in 30 Fractions for Prostate Cancer. AB - BACKGROUND/AIM: The long-term efficacy and safety of moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) in prostate cancer remains uncertain. This study aimed to evaluate MH-IMRT regimen of 72 Gy in 30 fractions in patients with prostate cancer. PATIENTS AND METHODS: The outcomes of 412 consecutive prostate cancer patients, who received MH-IMRT between May 2007 and December 2012, were retrospectively reviewed. The median patient age was 70.9 (range=50-84) years. Late gastrointestinal (GI) and genitourinary (GU) toxicity rates were evaluated according to the CTCAE ver. 3.0. The overall survival, biochemical relapse-free survival rate (bRFS), late GI toxicity, and GU toxicity rates were analyzed with the Kaplan-Meier method. RESULTS: The median follow-up was 71.5 (range, 1.4-124.8) months. The 5-year bRFS rate was 93.2%. The 5-year grade >=2 late GI and GU toxicity rates were 3.3% and 4.5%, respectively. CONCLUSION: MH-IMRT regimen of 72 Gy in 30 fractions was effective and safe for prostate cancer patients. PMID- 29970553 TI - Skin Reaction to Cetuximab as a Criterion for Treatment Selection in Head and Neck Cancer. AB - BACKGROUND/AIM: It can be hypothesized that in patients with locally advanced head and neck cancer and prominent cetuximab (CMb)-induced skin rash, immunoradiotherapy would result in a survival advantage over chemoradiotherapy with cisplatin (CP). PATIENTS AND METHODS: After a loading dose of CMb, one weekly cycle of CMb and CP concurrently with RT, patients who developed a grade >=2 rash proceeded with immunoradiotherapy, and those with a grade 0-1 rash had chemoradiotherapy. RESULTS: A grade 3-4 allergic reaction to CMb developed in 11/39 (28.2%) patients and further recruitment was stopped. These patients proceeded treatment with CP. In early assessment of skin rash 10/28 patients qualified for chemoradiotherapy and 18/28 patients for immunoradiotherapy. There was no difference in survival between the two groups. CONCLUSION: Rate of serious CMb-induced hypersensitivity reactions was unacceptably high. Even though immunoradiotherapy was administered only to the prognostically most favorable group of patients, it resulted in no advantage over chemoradiotherapy. PMID- 29970554 TI - Prevalence of High-risk HPV in Postmenopausal Women with Benign Cervical Cytology - A Population-based Cohort Study. AB - AIM: To compare the clinical performance of human papillomavirus (HPV) mRNA and DNA assays in postmenopausal women. MATERIALS AND METHODS: A total of 5,925 postmenopausal women were tested with cytology and the Luminex HPV DNA assay. High risk-HPV-positive women with benign cytology underwent a complimentary HPV mRNA assay (APTIMA). Both assays and the cytological testing were repeated after 12 months. RESULTS: A total of 334 women were found to be high-risk HPV-positive; 272 out of these women met the inclusion criteria. At follow-up, 25 (9.2%) out of the 272 included women had cytological abnormalities. HPV mRNA assay at follow-up had a sensitivity of 84% (95% confidence interval=63.9-95.4%) and a specificity of 60.2% (95% confidence interval=53.7-66.3%; p=0.0003) to detect these lesions. Corresponding values for the HPV DNA assay were 88% (95% confidence interval=68.8 97.4%) and 43.5% (95% confidence interval=37.2-49.4%). CONCLUSION: The HPV mRNA assay offers a comparable sensitivity but a higher specificity than the HPV DNA assay in detecting precancerous cervical lesions. PMID- 29970557 TI - Structure-associated Functional Control of TX-1877 Series by Glyco-conjugation. AB - BACKGROUND/AIM: Sugar molecules are often used as a tool to structurally modify chemical compounds. The features of synthesized sugar-conjugated TX-1877 derivatives were herein examined. MATERIALS AND METHODS: The molecular stabilities (reactivity) and hydrophobicities of sugar (e.g., monosaccharide and tetra-O-acetylated monosaccharide)-conjugated TXs were analyzed using a molecular simulation (e.g. molecular mechanics (MM) and molecular orbital (MO) analysis). RESULTS: The hydrophobicities of TX-1877 derivatives were increased by tetra-O acetylation, and TX-2244 exhibited the most potent radiosensitizing activity (enhancement ratio: ER=2.30). CONCLUSION: The conformations and hydrophobicities of chemical compounds may be controlled by adding monosaccharide- and tetra-O acetyl-conjugated sugars to TX-1877. PMID- 29970556 TI - Application of iNKT Cell-targeted Active Immunotherapy in Cancer Treatment. AB - In tumor immunity, invariant natural killer T (iNKT) cells play a pivotal role as a link between the innate and adaptive immune systems. With a precisely regulated activation mechanism, iNKT cells have the ability to respond quickly to antigenic stimulation and rapidly produce cytokines and chemokines, and subsequently an effective antitumor immune response. The development of iNKT cell-targeted active immunotherapy enables, not only an antitumor immune response through innate and acquired immunity, but also the conversion of an immunosuppressive into an immunogenic microenvironment. This review is focused on the activation mechanism and the role of iNKT cells after therapeutic active immunization. The therapeutic strategy targeting iNKT cells is expected to be applied to clinical practice in combination with surgery and chemotherapy. PMID- 29970558 TI - Growth Suppression of Human Colorectal Cancer Cells with Mutated KRAS by 3-Deaza cytarabine in 3D Floating Culture. AB - BACKGROUND/AIM: During screening for compounds that selectively suppress growth of human colorectal cancer (CRC) spheroids with mutant (mt) KRAS, the uridine analogue, 5-bromouridine (BrUrd) was identified and its derivatives were explored. MATERIALS AND METHODS: DNA incorporation in two-dimensional (2D) and three-dimensional floating (3DF) cultures was examined with the uridine analogue, 5-ethynyl-2'-deoxyuridine (EdU). The area of HKe3 CRC spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in 3DF culture with 11 BrUrd derivatives. RESULTS: EdU was strongly incorporated into newly-synthesized DNA from HKe3-mtKRAS cells compared to HKe3-wtKRAS in 2D and 3DF culture. 3-Deaza-cytarabine, which has properties of BrUrd and cytidine, was the most effective inhibitor of HKe3-mtKRAS spheroids with the least toxicity to HKe3-wtKRAS. Growth suppression of 3-deaza-cytarabine was stronger than cytarabine in 2D culture, and toxicity was lower than gemcitabine in long-term 3DF culture. CONCLUSION: 3-Deaza-cytarabine exhibits properties useful for the treatment of CRC patients with mtKRAS. PMID- 29970559 TI - Activated EphA2 Processing by MT1-MMP Is Involved in Malignant Transformation of Ovarian Tumours In Vivo. AB - BACKGROUND/AIM: Erythropoietin-producing hepatocellular receptor-2 (EphA2) is overexpressed in ovarian cancer. The N-terminals of EphA2 are processed by membrane-type 1 matrix metalloproteinase (MT1-MMP) and can subsequently induce ligand-independent signal activation to promote motility, invasion, and metastasis. The aim of this study was to investigate whether EphA2 processing occurs in benign, borderline, and malignant ovarian tumours. MATERIALS AND METHODS: Overall 107 ovarian epithelial carcinomas (OECs; 47 serous, 24 endometrioid, 16 mucinous, and 20 clear cell), 54 ovarian borderline tumours (OBTs; 12 serous, 42 mucinous), and 45 adenomas (15 serous, 17 mucinous, and 13 endometriotic cysts) were evaluated. Expression and processing of EphA2 were semi quantitatively analyzed. EphA2 processing was also investigated by immunoblotting. RESULTS: EphA2 and MT1-MMP co-expression were detected. N terminal EphA2 levels were significantly lower than those of C-terminal EphA2 in OECs and OBTs, but not in adenomas. Immunoblotting revealed processed fragments in OEC and OBTs. CONCLUSION: EphA2 processing by MT1-MMP is associated with malignant transformation in ovarian tumours. PMID- 29970560 TI - Visualizing Energy Charge in Breast Carcinoma Tissues by MALDI Mass-spectrometry Imaging Profiles of Low-molecular-weight Metabolites. AB - BACKGROUND/AIM: Metabolomics is widely used for biomarker discovery, but conventional mass-spectrometry extraction procedures lose the spatial localization of metabolites. In this study, we directly analyzed breast carcinoma tissues embedded in frozen tissue microarrays (fTMAs) using MALDI mass spectrometry imaging (MALDI-MSI). MATERIALS AND METHODS: A total of 119 breast tissues (84 carcinoma and 35 normal) were used. MSI data were extracted from each tissue. RESULTS: Overall, 185 of 1,915 peaks which were commonly detected in 60% of target areas were subjected to further analysis. One hundred and fifty-two peaks of carcinoma showed significantly higher intensity than normal. Comparing metabolite profiles from carcinoma and normal tissues, energy charge (EC) and the sum of adenosine phosphate compound (AXP) indicated significantly higher intensities in cancerous tissues than normal. But comparisons of EC and AXP among lymph node metastasis, tumor size and tumor subtypes indicated no significant differences. CONCLUSION: Breast carcinoma tissues had higher EC and AXP values than normal. MALDI-MSI could be a tool for characterizing breast carcinoma. PMID- 29970561 TI - Catumaxomab with Activated T-cells Efficiently Lyses Chemoresistant EpCAM positive Triple-negative Breast Cancer Cell Lines. AB - BACKGROUND/AIM: Epithelial cell adhesion molecule (EpCAM) is expressed in various types of cancer, including breast cancer, and is correlated with metastasis, invasion, therapeutic resistance and prognosis. Moreover, several cell surface markers, such as CD44 and EpCAM, are molecular targets on cancer stem-like cells of breast cancer. The aim of this study was to investigate whether catumaxomab, a clinical-grade bispecific antibody that binds to both EpCAM on tumor cells and CD3 on T-cells, combined with activated T-cells can eliminate chemoresistant triple-negative breast cancer (TNBC) cells in vitro. MATERIALS AND METHODS: First, a cell line (MUK-BC1) was established from human breast carcinoma cells derived from a patient with chemoresistant and disseminated breast cancer. These EpCAM-positive TNBC cells were almost completely resistant to various drug mediated cytotoxicities up to a concentration of 10 MUg/ml. RESULTS: Pre treatment with catumaxomab and subsequent addition of interleukin-2/OKT3 activated autologous T-cells eliminated EpCAM-positive TNBC cells. CONCLUSION: Catumaxomab combined with activated T-cells may be a potent therapeutic modality to overcome chemoresistant EpCAM-positive TNBC cells. PMID- 29970563 TI - Evaluation of a Hypertensive Rat Model Using Peripheral Blood Neutrophil Activity, Phagocytic Activity and Oxidized LDL Evaluation. AB - BACKGROUND/AIM: A system is being developed that can be used to easily evaluate the health condition of an individual with the help of trace amounts of a blood sample by focusing on xenobiotics. The system is called "Multimodal homeostasis evaluation system" (measurement of neutrophil activity, phagocytic activity of phagocytes and quantification of oxidized LDL (OxLDL)). To elucidate the possibility of using this system as an evaluation system for the health condition of an individual, clearly explaining the changes in various diseases is essential. In this study, evaluations were carried out using hypertensive model animals. MATERIALS AND METHODS: Spontaneously hypertensive model rats SHR/NCrlCrlj and control rats WKY/NCrlCrlj were raised for 10 weeks from 6 to 16 weeks of age and their blood pressure was measured over time. Blood neutrophil activity (superoxide anion (O2*-) generation and myeloperoxidase (MPO) activity) and phagocytic activity of phagocytes was measured by our developed apparatus (a simple prototype device under development). OxLDL was measured by an ELISA kit, and biochemical markers were measured using the blood sample. RESULTS: Compared to WKY rats of the control group, systolic blood pressure, diastolic blood pressure, and mean blood pressure of SHR rats increased significantly with age. In SHR rats, there was a significant elevation in O2*- generation and MPO activity of neutrophils, alanine aminotransferase and triglycerides of blood, while phagocytic activity, OxLDL, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol and total-bilirubin decreased. CONCLUSION: In the hypertensive model, biochemical markers were found to have a relationship with O2*- generation, MPO activity, phagocytic activity of phagocytes, and OxLDL. This system is expected to be useful for clinical monitoring of hypertension diseases. PMID- 29970562 TI - Inhibition of Survivin by Adenovirus Vector Enhanced Paclitaxel-induced Apoptosis in Breast Cancer Cells. AB - BACKGROUND/AIM: Survivin expression has been shown to be associated with cancer progression, poor prognosis, and drug resistance. The aim of this study was to examine whether survivin knock-down could enhance paclitaxel-induced apoptosis in breast cancer cells in vitro. MATERIALS AND METHODS: MCF-7 cells were infected with an siRNA-expressing adenovirus vector against survivin (Adv-siSurv) or Renilla luciferase as a control (Adv-siRL). After treatment with paclitaxel, cells were analyzed by apoptotic, cell cycle and immunoblotting assays. RESULTS: Of cells treated with paclitaxel alone, only 20.2+/-2.08% showed apoptotic features. An increase in the paclitaxel dose was associated with increased survivin expression. In contrast, Adv-siSurv infection resulted in a marked increase in apoptotic cell death in paclitaxel-treated MCF-7 cells (49.9+/ 7.70%). The percentage of cells in the G2M phase was lower (23.9+/-1.64%) in Adv siSurv-infected cells than that of Adv-siRL-treated cells (40.0+/-2.43%). Adv siSurv infection reduced survivin, procaspase-9, and procaspase-3 levels in paclitaxel-treated MCF-7 cells. CONCLUSION: Loss of survivin expression enhanced paclitaxel-induced apoptosis in MCF-7 breast cancer cells in vitro. PMID- 29970564 TI - Phagocytic Activation of Macrophages with Serum MAF Depends on Engulfment Efficiency and Not Migratory Activity. AB - BACKGROUND/AIM: Serum-derived macrophage activating factor (serum MAF) is known to increase the phagocytic activity of macrophages and potentially plays a role in activating cancer immunity. In order to reveal the contributing factors for phagocytic activation, the migratory activity and the efficiency of engulfment was analyzed. MATERIALS AND METHODS: THP-1 macrophages were induced by 12-O tetradecanoyl-13-acetate (TPA). The migratory activity and efficiency of engulfment were analyzed by time-lapse imaging and suspension assay, respectively. RESULTS: While the distance of migration did not change before and after activation with serum MAF, the efficiency of beads internalisation was significantly increased. CONCLUSION: Phagocytic activation of serum-MAF-treated macrophages was caused by increasing the efficiency of engulfment. This study contributes to the knowledge about the activation of the immune system through phagocytic activation of macrophages. PMID- 29970565 TI - Concentration-dependent Activation of Inflammatory/Anti-inflammatory Functions of Macrophages by Hydrolyzed Whey Protein. AB - BACKGROUND/AIM: Whey protein is a mixture of globulins isolated from whey and mainly composed of beta-lactoglobulin, alpha-lactoalbumin, and lactoferrin. In this study, whey protein was hydrolyzed using various proteases, and the macrophage activation was evaluated. MATERIALS AND METHODS: Hydrolyzed whey protein was prepared using various proteases to evaluate phagocytic activity and cytokine productivity. RESULTS: The results of SDS-PAGE and gel permeation chromatography (GPC) analysis indicated that the molecular weight of whey protein was reduced using various proteases. The hydrolyzed whey protein showed a concentration-dependent induction of macrophage phagocytic activity. In addition, the hydrolyzed whey protein significantly enhanced the production of the inflammatory cytokine, TNF-alpha. Production of the anti-inflammatory cytokine, IL-10, was not observed at concentrations up to 1 MUg, but significant production was confirmed at 100 MUg. CONCLUSION: Hydrolyzed whey protein can induce the phagocytic activity of macrophages and activation of the inflammatory/anti inflammatory functions of the macrophages depends on the concentration of the hydrolyzed whey protein. PMID- 29970566 TI - Global Liver Gene Expression Analysis on a Murine Hepatic Steatosis Model Treated with Mulberry (Morus alba L.) Leaf Powder. AB - BACKGROUND/AIM: Mulberry (Morus alba L.) leaves (ML) contain many functional components, such as 1-deoxynojirimycin, flavonoids (rutin, quercetin, kaempferol). It is well known that 1-deoxynojirimycin functions to suppress increases in blood glucose level by alpha-glucosidase inhibitory activity. Thus, the molecular mechanism underlying the protective and therapeutic effects of ML supplementation was investigated on a mouse model of high-calorie diet (Western diet: WD)-induced hepatic steatosis (HS). MATERIALS AND METHODS: The C57BL/6J mouse was used for the HS model. The mice were divided into three groups: control (normal diet: ND), WD, and WD + 1% ML groups. The WD group was fed a high-calorie (high carbohydrate and high fat) diet for 12 weeks to develop HS. At week 12, all mice were sacrificed, blood was collected for biochemical tests, and the liver was obtained for histological examination and RNA sequencing (RNA-Seq). RESULTS: Liver weight, plasma triglycerides (TG), alanine aminotransferase (ALT), and alanine aminotransferase (AST) levels of both ML groups were significantly lower than those of the WD group. On histological examination of the liver, the area of fatty deposits was found to be suppressed by ML administration. In the gene expression analysis of the liver of WD- versus ML-fed mice by RNA-Seq, 722/45,706 genes exhibited a significant change in expression (corrected p-value<0.05). Gene network analysis of these genes showed that genes related to liver inflammation were inactivated and those related to regeneration of liver were activated in the ML group. CONCLUSION: ML functions to suppress HS in WD-fed mice and regulates genes related to inflammation and regeneration of liver cells. PMID- 29970567 TI - Radiosensitizing Effect of 5-Aminolevulinic Acid and Protoporphyrin IX on Carbon ion Beam Irradiation. AB - BACKGROUND/AIM: Carbon-ion beam is one of the most advanced radiations used for cancer treatment. However, there are tumors that are difficult to suppress with carbon-ion beam alone, thus necessitating development of drugs that can enhance its therapeutic effect. In this regard, the radiosensitizing effect of 5 aminolevulinic acid (ALA) and protoporphyrin IX (PpIX), that is a metabolic intermediate of ALA, on carbon-ion beam was investigated. MATERIALS AND METHODS: Radiosensitizing activity, mitochondrial ROS and DNA double-strand break production of ALA and PpIX were evaluated by irradiation with 1.0 or 1.5-Gy carbon-ion beam to mouse mammary EMT6 tumor cells. RESULTS: Combination of carbon ion beam and ALA or PpIX showed a significant enhancement of its cytotoxic activity through a significant increase in ROS production in mitochondria. Furthermore, the combined activity of carbon-ion beam and ALA resulted in a significant increase in DNA double-strand breakage. CONCLUSION: ALA selectively accumulates in the mitochondria and PpIX synthesized from ALA reacts with carbon ion beam to produce ROS that exert antitumor activity. PMID- 29970568 TI - Construction of Anti-HER2 Recombinants as Targeting Modules for a Drug-delivery System Against HER2-positive Cells. AB - BACKGROUND/AIM: Recombinant antibodies have been investigated and used in applications such as targeting modules of drug-delivery systems (DDS) against cancers. This study aimed to prepare recombinant antibodies against HER2, containing sortase A (SrtA) recognition sequence, that are applicable as targeting modules in DDS after linkage with the drug-carrier containing oligoglycine-acceptor peptide by SrtA transpeptidation. MATERIALS AND METHODS: The recombinant trastuzumab fragment antibodies (scFvs and Fab) with the SrtA recognition motif (LPXTG) at their C-terminal were constructed and expressed in Escherichia coli and Chinese hamster ovary (CHO) cells, respectively. The reactivity of the purified recombinant antibodies towards HER2-expressing cells was also evaluated via immunofluorescent staining. RESULTS: Fab demonstrated higher yield and purity and better reactivity towards HER2-expressing cells (HCT 15 and HeLa) when compared to scFvs. CONCLUSION: The CHO expression system possesses superior yield and purity when compared to the E. coli expression system with respect to the preparation of recombinant antibodies applicable in targeting modules for DDS (DDS-TM). Moreover, a Fab variant prepared in this study demonstrated the potential to be a DDS-TM against HER2-expressing cancer cells. PMID- 29970569 TI - Possible Application of Ascites-infiltrating Gamma-delta T Cells for Adoptive Immunotherapy. AB - BACKGROUND/AIM: Malignant ascites contain many tumour-infiltrating lymphocytes. gammadelta T cells with antitumour activity have attracted attention as effector cells in cancer immunotherapy. Vdelta2+ T cells were cultured from peripheral blood mononuclear cells (PBMCs) and ascites-infiltrating lymphocytes (AILs) to compare the differences in response to 2-methyl-3-butenyl-1-pyrophosphate (2M3B1 PP) and zoledronate (Zol) as antigens in vitro. MATERIALS AND METHODS: To expand Vdelta2+ T cells from PBMCs and AILs from 29 patients with cancer, these cells were cultured and subjected to analysis. RESULTS: The proliferation rate of Vdelta2+ T cells was higher in both PBMCs and AILs when cultured with Zol than with 2M3B1-PP. Although Vdelta2+ T cells show a higher rate of expansion in AILs compared to PBMCs, the number of mixed tumour cells in ascites was decreased when cultured with Zol. CONCLUSION: Vdelta2+ T cells in AILs are cytotoxic to tumour cells in ascites and may be considered in adoptive immunotherapy. PMID- 29970571 TI - Dewaxed Brown Rice Feed Improves Fatty Liver in Obese and Diabetic Model Mice. AB - BACKGROUND/AIM: Dewaxed brown rice has macrophage activation ability via TLR4 and contains a high amount of lipopolysaccharides (LPS). It is expected that dewaxed brown rice can help prevent lifestyle diseases. In this study, the anti-obesity effect of dewaxed brown rice was investigated using obese and diabetic model mice. MATERIALS AND METHODS: Dewaxed brown rice and white rice were polished and powdered by Toyo Rice Co. Diet pellets were prepared (AIN-93) with 50% dewaxed brown rice or white rice powder and fed to type II diabetic model KK-Ay mice for 10 weeks. Weight and fasting blood glucose were measured every week, and whole blood and liver was collected on the final day for the evaluation of biochemical data. RESULTS: A 20% reduction in body weight was found in the dewaxed brown rice feed and white rice feed groups compared to the normal feed group. Fasting blood glucose increased in the normal-diet group, but on the other hand, the blood glucose in the white rice and the dewaxed brown rice feed group was almost constant. Dewaxed brown rice feed group of plasma ALT and AST, liver TG and T-CHO were significantly lower than that of the control and the white rice feed group. CONCLUSION: Dewaxed brown rice feed has an anti-obesity effect to suppress increasing body weight, fasting blood glucose, and an effect of suppressing fatty liver. PMID- 29970570 TI - Immunosuppression Induced by Perioperative Peritonitis Promotes Lung Metastasis. AB - BACKGROUND/AIM: Perioperative intra-abdominal infection has been reported as a risk factor for metastasis. The aim of this study was to investigate the mechanism by which peritonitis induces immunosuppression in the lung, which in turn promotes lung metastasis. MATERIALS AND METHODS: C57BL/6 mice were intravenously administered B16F10 melanoma cells to induce lung metastasis and subsequently subjected to cecal ligation and puncture (CLP) to induce peritonitis or sham surgery. The number of lung metastatic nodules was evaluated. Cell fractions in lungs and serum cytokines after CLP were investigated. RESULTS: CLP mice showed an increased number of lung metastases compared to sham-treated mice. The fraction and number of natural killer (NK) cells in lungs of CLP mice were significantly reduced in early post-CLP phase. Myeloid-derived suppressor cells (MDSCs) in lungs were significantly decreased in CLP mice. Serum IL-6 and TNF levels were significantly elevated in CLP mice. CONCLUSION: Peritonitis promoted lung metastasis in a murine model, which may be attributable to the impact of NK cells and MDSCs in the lungs. PMID- 29970573 TI - Prognostic Factors for Pancreatic Cancer Patients Treated with Immune-cell Therapy. AB - BACKGROUND/AIM: The past 17 years, immune-cell therapy has been administered to 990 patients with advanced or recurrent pancreatic adenocarcinoma and 50 patients with curatively resected pancreatic adenocarcinoma. MATERIALS AND METHODS: The correlation between overall survival (OS) and various factors including sex, age, performance status (PS), distant metastasis, chemotherapy, radiotherapy, and type of immune-cell therapy were evaluated by univariate and multivariate analyses. RESULTS: The median OS of advanced or recurrent pancreatic cancer was 5.8 months, and the prognosis was improved in pancreatic cancer patients who received immune cell therapy with PS scores of 0-1 [hazard risk (HR)=0.56; 95% confidence interval (CI)=0.46-0.68; p<0.0001], chemotherapy (HR=0.68; 95%CI=0.54-0.87; p=0.002), or radiotherapy (HR=0.76; 95%CI=0.63-0.93; p=0.006). Multivariate analysis demonstrated that distant metastasis indicated a poor prognosis for pancreatic cancer patients that were administered immune-cell therapy (HR=1.62; 95%CI=1.37-1.93; p<0.0001). Additionally, the combined immune-cell therapy with alphabeta T cell and dendritic cell (DC) vaccine provided a survival benefit in advanced or recurrent pancreatic cancer patients (HR=0.69; 95%CI=0.57-0.83; p<0.0001). CONCLUSION: A survival benefit could be potentially obtained with better PS by the combination of alphabeta T cell therapy, DC vaccine therapy, and chemotherapy at an early stage in pancreatic cancer. PMID- 29970574 TI - Seizures and Tumor Progression in Glioma Patients with Uncontrollable Epilepsy Treated with Perampanel. AB - BACKGROUND/AIM: Excessive extracellular glutamate activates AMPA-type glutamate receptors (AMPA receptors) and induces seizures. Antagonistic activation of AMPA receptors inhibits epilepsy and glioma growth in in vitro and in vivo studies. This study was conducted to evaluate the clinical impacts of perampanel (PER), a novel AMPA receptor antagonist, on seizures and tumor progression in glioma patients with uncontrollable epilepsy. PATIENTS AND METHODS: Twelve glioma patients with uncontrollable epilepsy were treated with PER. Seizure response, PER concentration, and tumor volume were assessed. RESULTS: Obvious seizure control was observed in 10 analyzed patients (100%) and 6 patients (60%) became seizure-free. Median plasma concentrations of PER were 296 ng/ml in those with 4 mg/day PER treatment and 518 ng/ml in those with 8 mg/day PER treatment. High intensity lesions in fluid-attenuated inversion recovery of magnetic resonance imaging (MRI) were volumetrically assessed to analyze tumor size. Volume reduction was detected within 6 months in correlation with increased plasma levels of PER. CONCLUSION: PER treatment was effective in uncontrollable epilepsy with gliomas. MRI images showed the inhibition of tumor growth. PMID- 29970572 TI - Association of Serum HB-EGF Value and Response to Chemotherapy in Patients with Recurrent Ovarian Cancer. AB - BACKGROUND/AIM: Many anticancer agents including molecularly-targeted drugs have been developed for ovarian cancer. However, the prognosis of recurrent ovarian cancer remains extremely poor. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is reported as a rational target for ovarian cancer therapy. Moreover, serum HB-EGF expression is recognized as a biomarker in patients with primary ovarian cancer. MATERIALS AND METHODS: We analysed serum samples with recurrent ovarian cancer at the Fukuoka University Hospital from April 2009 to March 2014. To assess the clinical significance of serum HB-EGF in recurrent ovarian cancer, the association between serum HB-EGF levels and prognosis in patients with recurrent ovarian cancer was examined using ELISA. RESULTS: Patients with high serum HB-EGF expression showed a significantly poor response to second-line chemotherapeutic agents compared with patients with low HB-EGF levels. CONCLUSION: HB-EGF expression in serum may be a potential therapeutic indicator for novel HB-EGF-targeted therapy in recurrent ovarian cancer. PMID- 29970576 TI - Improvement in Protracted Wound Healing by Topical Cream Containing Lipopolysaccharide Derived from Pantoea agglomerans. AB - BACKGROUND/AIM: The wound-healing effect of lipopolysaccharide (LPS) reportedly results from its ability to induce the removal of foreign bodies, anti inflammatory function, and tissue-repair function. We reported the improvement of patients with protracted wound healing after the dermal administration of topical cream containing LPS derived from Pantoea agglomerans, which is a symbiotic bacterium present in wheat and confirmed as safe. PATIENTS AND METHODS: Topical cream with LPS was applied on four patients who showed protracted wound healing, after their informed consent. The wound was evaluated on the basis of the change in the approximate wound volume calculated from the width, length, and depth of the wound. RESULTS: Case 1: A 76-year-old man developed infection at the puncture site after endovascular laser treatment of the right lower extremity varicose veins and suffered protracted wound healing. The wound was treated with gentamicin application containing LPS, and shrank in two weeks. Case 2: A 72-year old man developed a wound infection and had purulent drainage one week after endovascular laser treatment of the left lower extremity varicose veins. The wound was closed in one month using gentamicin application containing LPS. Case 3: A 67-year-old woman with protracted wound healing developed infection in the right inguinal region after the surgical treatment of acute aortic dissection and experienced complete wound dehiscence. The wound shrank one week after gauze packing with LPS and was temporarily sutured. The wound was completely closed in two weeks with gentamicin application containing LPS. Case 4: An 86-year-old woman with protracted wound healing became bedridden after cerebral infarction and developed pressure ulcers in the sacral area. The ulcer disappeared in four months with LPS-containing sugar and povidone-iodine application twice a day. There were no adverse effects from LPS application in any of these patients. CONCLUSION: In diabetes, one cause of protracted wound healing is the low innate immune function, such as the phagocytic activity of macrophages. LPS is expected to promote healing by improving innate immunity, and its beneficial effect of promoting wound healing was clearly demonstrated in the present cases. The topical application of LPS is clinically effective for wound healing and is considered a potentially novel treatment method. PMID- 29970575 TI - Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer. AB - BACKGROUND/AIM: TAS-102 has led to a significant improvement in overall survival (OS) and progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC). Neutropenia is the most common adverse event and an important factor impacting chemotherapy continuation. In this retrospective study, factors associated with grade >=3 neutropenia, that is frequently observed in TAS-102 treated patients, were examined. PATIENTS AND METHODS: The medical records of 41 patients with CRC who received TAS-102 between October 2014 and June 2017 at the Fukuoka University Hospital were retrospectively reviewed. Response rate, PFS, OS, and adverse events were analyzed using KRAS mutation, administration method, concomitant drug administration, neutrophil-to-lymphocyte ratio (NLR), and Onodera's prognostic nutritional index (Onodera's index) as a stratification factors. RESULTS: Both PFS and OS were significantly higher with TAS-102 plus bevacizumab combination therapy. Biweekly administration (7.1%) was associated with significantly less neutropenia compared to normal administration (44.4%). DCR with biweekly administration was better than that with normal administration, although without statistical significance. No significant difference was observed in OS rates between the biweekly and normal administration regimens; however, the biweekly regimen was associated with significantly prolonged PFS. By multivariate analysis, a significant difference was noted in the Onodera's index for OS and in the administration method and NLR for PFS. CONCLUSION: Biweekly administration without a change in the drug dose intensity was associated with reduced neutropenia in patients with mCRC. The effects and adverse events of TAS-102 were associated with concomitant drug administration, administration method, and nutritional status. PMID- 29970582 TI - Medical needs of adolescent refugees resettling in Western Australia. AB - OBJECTIVE: To investigate the medical needs and socioeconomic determinants of health among adolescent refugees resettling in Western Australia. DESIGN: Comprehensive medical and socioeconomic health data of resettling adolescent refugees aged 12 years and above attending a Refugee Health Service over a 1-year period were analysed. RESULTS: Medical records of 122 adolescents, median (range) age of 14 (12-17) years, were reviewed. Socioeconomic vulnerabilities included dependence on government financial support (50%), housing issues (27%) and child protection service involvement (11%). Medical concerns included non-communicable disorders (85%), infectious diseases (81%), nutrition/growth (71%) and physical symptoms of non-organic origin (43%). One quarter (27%) of female adolescents had sexual/reproductive health issues. A median (range) of 5 (2-12) health concerns were identified for each adolescent with 49% requiring referral to subspecialty services. CONCLUSION: Resettling adolescent refugees are socioeconomically vulnerable with a range of medical issues that frequently require additional subspecialty health referrals. PMID- 29970581 TI - Functional outcome in contemporary children and young adults with tetralogy of Fallot after repair. AB - OBJECTIVE: Functional outcome measures are of growing importance in the aftercare of patients with congenital heart disease. This study addresses the functional status with regard to exercise capacity, health-related physical fitness (HRPF) and arterial stiffness in a recent cohort of children, adolescents and young adults with tetralogy of Fallot (ToF) after repair. DESIGN: Single-centre, uncontrolled and prospective cohort study. SETTING: Outpatient department of the German Heart Centre Munich; July 2014-January 2018. PATIENTS: One hundred and six patients with ToF after repair (13.5+/-3.7 years, 40 females) were included. Data were compared with a recent cohort of healthy controls (HCs) (n=1700, 12.8+/-2.6 years, 833 females). MAIN OUTCOME MEASURES: Patients underwent a symptom-limited cardiopulmonary exercise test, performed an HRPF test (FitnessGram) and had an assessment of their arterial stiffness (Mobil-O-Graph). RESULTS: Compared with HC, patients with ToF showed lower predicted [Formula: see text]O2 peak (ToF: 80.4% +/- 16.8% vs HC: 102.6% +/- 18.1%, p<0.001), impaired ventilatory efficiency (ToF: 29.6 +/- 3.6 vs HC: 27.4 +/- 2.9, p<0.001), chronotropic incompetence (ToF: 167 +/- 17 bpm vs HC: 190 +/- 17 bpm, p<0.001) and reduced HRPF (ToF z-score: -0.65 +/- 0.87 vs HC z-score: 0.03 +/- 0.65, p<0.001). Surrogates of arterial stiffness, central and peripheral systolic blood pressure, did not differ between the two groups. CONCLUSIONS: Contemporary children, adolescents and young adults with ToF still have functional limitations. How impaired HRPF and limited exercise capacity interact and how they can be modified needs to be evaluated in further intervention studies. PMID- 29970583 TI - Emollient bath additives for eczema add no benefit. PMID- 29970577 TI - Efficacy and Safety of Bi-weekly Pegfilgrastim for Dose-dense Chemotherapy induced Neutropenia in Breast Cancer Patients. AB - BACKGROUND/AIM: The dose-dense doxorubicin and cyclophosphamide (ddAC) for patients with HER-2-negative breast cancer is recommended by the National Comprehensive Cancer Network guideline in US. However, there are little data on serum G-CSF concentrations in patients undergoing bi-weekly dose-dense therapy with pegfilgrastim. The objective of this study was to compare the serum G-CSF concentrations in patients receiving pegfilgrastim in bi- or tri-weekly regimens. PATIENTS AND METHODS: This study included 26 patients who received ddAC or docetaxel and cyclophosphamide (TC) for primary breast cancer. Serum G-CSF concentrations were measured by ELISA. RESULTS: Serum G-CSF concentrations peaked in the second week of ddAC cases and in the ninth week of TC cases. Neutrophils gradually increased until the sixth week in ddAC cases, while they were slightly decreased during the first three weeks in TC cases. Treatments were completed without febrile neutropenia or treatment delays. CONCLUSION: Primary prophylactic pegfilgrastim administrations increased serum G-CSF concentrations, helping to maintain the absolute neutrophil counts that are required to undergo chemotherapy. The treatment of ddAC with 3.6 mg pegfilgrastim is completely safe for female Japanese patients. PMID- 29970584 TI - Non-research payments to physicians associated with more opioid prescriptions in the USA. PMID- 29970585 TI - Exercise for people with hip and knee osteoarthritis. PMID- 29970586 TI - European Medicines Agency reviews dosing errors with methotrexate. PMID- 29970587 TI - Recent opioid use associated with increased risk of falls in older people. PMID- 29970588 TI - Impact of screening on chlamydia infections. PMID- 29970589 TI - Little evidence that antidepressants are effective for insomnia. PMID- 29970590 TI - Subcutaneous fat necrosis in a neonate. PMID- 29970591 TI - Fifteen-minute consultation: Management of the upper limb in unilateral cerebral palsy. AB - Children with unilateral cerebral palsy (UCP) have complex health, education and social care needs. Delayed gross motor milestones are the most common presenting feature, and much of the early management focuses on gross motor skills and lower limb management. In later childhood, adolescence and adulthood, upper limb function has significant impact on activity, participation and independence. There is clear pathophysiological rationale and emerging clinical evidence that earlier intervention to improve upper limb function is beneficial. Whereas most children with UCP are managed in secondary care, it is recommended that the assessment and delivery of specialist intervention for the upper limb occurs at a regional centre. PMID- 29970593 TI - FAST education campaign did not improve response to minor strokes. PMID- 29970592 TI - Supplementation in hypophosphataemic rickets: the bare bones of management. PMID- 29970594 TI - Correction: Subarachnoid gadolinium following angiography-induced cortical blindness. PMID- 29970595 TI - Central cause of positioning vertigo. PMID- 29970596 TI - The m6A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5'-3' exoribonuclease XRN1. AB - N6-methyladenosine (m6A) modifications in RNAs play important roles in regulating many different aspects of gene expression. While m6As can have direct effects on the structure, maturation, or translation of mRNAs, such modifications can also influence the fate of RNAs via proteins termed "readers" that specifically recognize and bind modified nucleotides. Several YTH domain-containing proteins have been identified as m6A readers that regulate the splicing, translation, or stability of specific mRNAs. In contrast to the other YTH domain-containing proteins, YTHDC2 has several defined domains and here, we have analyzed the contribution of these domains to the RNA and protein interactions of YTHDC2. The YTH domain of YTHDC2 preferentially binds m6A-containing RNAs via a conserved hydrophobic pocket, whereas the ankyrin repeats mediate an RNA-independent interaction with the 5'-3' exoribonuclease XRN1. We show that the YTH and R3H domains contribute to the binding of YTHDC2 to cellular RNAs, and using crosslinking and analysis of cDNA (CRAC), we reveal that YTHDC2 interacts with the small ribosomal subunit in close proximity to the mRNA entry/exit sites. YTHDC2 was recently found to promote a "fast-track" expression program for specific mRNAs, and our data suggest that YTHDC2 accomplishes this by recruitment of the RNA degradation machinery to regulate the stability of m6A-containing mRNAs and by utilizing its distinct RNA-binding domains to bridge interactions between m6A-containing mRNAs and the ribosomes to facilitate their efficient translation. PMID- 29970598 TI - Effects of social network diversity on mortality, cognition and physical function in the elderly: a longitudinal analysis of the Chicago Health and Aging Project (CHAP). AB - BACKGROUND: Having a larger social network has been shown to have beneficial effects on health and survival in adults, but few studies have evaluated the role of network diversity, in addition to network size. We explore whether social network diversity is associated with mortality, cognition and physical function among older black and white adults. METHODS: Data are obtained from the Chicago Health and Aging Project, a longitudinal, population-based study of adults aged 65 years and older at baseline. Using Cox proportional hazards regression, we estimate the hazard of mortality by network diversity (n=6497). The association between network diversity and cognition (n=6560) and physical function (n=6561) is determined using generalised estimating equations. Models were adjusted for age, gender, race, socioeconomic status, marital status and health-related variables. RESULTS: In fully adjusted models, elderly with more diverse social networks had a lower risk of mortality (HR=0.93, p<0.01) compared with elderly with less diverse networks. Increased diversity in social networks was also associated with higher global cognitive function (coefficient=0.11, p<0.001) and higher physical function (coefficient=0.53, p<0.001). CONCLUSIONS: Social networks are particularly important for older adults as they face the greatest threats to health and depend on network relationships, more than younger individuals, to meet their needs. Increasing diversity, and not just increasing size, of social networks may be essential for improving health and survival among older adults. PMID- 29970600 TI - Evolution of human, chicken, alligator, frog, and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity. AB - Although multiple steroid ligands of the glucocorticoid, mineralocorticoid, and progestin families bind to and regulate the activity of mineralocorticoid receptors (MRs), the responses to these ligands differ across species. To understand how the different domains of MRs contribute to the ligand-induced activation or inhibition of MR activity, we studied the response to eight steroids (aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone, and spironolactone) of human, chicken, alligator, frog, and zebrafish full-length MRs and truncated MRs, which lacked the N-terminal domain (NTD) and DNA binding domain (DBD). Compared to full length MRs, some truncated MRs were not activated by the steroids, and others required higher steroid concentrations for activation. Progesterone, 19 norprogesterone, and spironolactone did not activate full-length or truncated human, alligator, or frog MRs. However, at 10 nM, these steroids activated full length chicken and zebrafish MRs, whereas at 100 nM, these steroids had little activity for truncated chicken MRs, but they retained activity for truncated zebrafish MRs. This suggests that regulation of the activation of the chicken MR by progestin resides in the NTD-DBD and that of the zebrafish MR resides in the hinge-LBD. Zebrafish and chicken MRs contain a serine corresponding to Ser810 in human MR, which is required for the antagonist activity of progesterone for human MR, suggesting a previously uncharacterized mechanism of regulation of progestin activation of chicken and zebrafish MRs. These findings suggest that progesterone may be a physiological activator of chicken and zebrafish MRs. PMID- 29970597 TI - Queuosine modification protects cognate tRNAs against ribonuclease cleavage. AB - Eukaryotic transfer RNAs (tRNA) contain on average 13 modifications that perform a wide range of roles in translation and in the generation of tRNA fragments that regulate gene expression. Queuosine (Q) modification occurs in the wobble anticodon position of tRNAs for amino acids His, Asn, Tyr, and Asp. In eukaryotes, Q modification is fully dependent on diet or on gut microbiome in multicellular organisms. Despite decades of study, cellular roles of Q modification remain to be fully elucidated. Here we show that in human cells, Q modification specifically protects its cognate tRNAHis and tRNAAsn against cleavage by ribonucleases. We generated cell lines that contain completely depleted or fully Q-modified tRNAs. Using these resources, we found that Q modification significantly reduces angiogenin cleavage of its cognate tRNAs in vitro. Q modification does not change the cellular abundance of the cognate full length tRNAs, but alters the cellular content of their fragments in vivo in the absence and presence of stress. Our results provide a new biological aspect of Q modification and a mechanism of how Q modification alters small RNA pools in human cells. PMID- 29970601 TI - Proteomic analysis of S-nitrosylated nuclear proteins in rat cortical neurons. AB - Neurons modulate gene expression in response to extrinsic signals to enable brain development, cognition, and learning and to process stimuli that regulate systemic physiological functions. This signal-to-gene communication is facilitated by posttranslational modifications such as S-nitrosylation, the covalent attachment of a nitric oxide (NO) moiety to cysteine thiols. In the cerebral cortex, S-nitrosylation of histone deacetylase 2 (HDAC2) is required for gene transcription during neuronal development, but few other nuclear targets of S-nitrosylation have been identified to date. We used S-nitrosothiol resin assisted capture on NO donor-treated nuclear extracts from rat cortical neurons and identified 614 S-nitrosylated nuclear proteins. Of these, 131 proteins have not previously been shown to be S-nitrosylated in any system, and 555 are previously unidentified targets of S-nitrosylation in neurons. The sites of S nitrosylation were identified for 59% of the targets, and motifs containing single lysines were found at 33% of these sites. In addition, lysine motifs were necessary for promoting the S-nitrosylation of HDAC2 and methyl-CpG binding protein 3 (MBD3). Moreover, S-nitrosylation of the histone-binding protein RBBP7 was necessary for dendritogenesis of cortical neurons in culture. Together, our findings characterize S-nitrosylated nuclear proteins in neurons and identify S nitrosylation motifs that may be shared with other targets of NO signaling. PMID- 29970599 TI - Diabetes, plasma glucose and incidence of colorectal cancer in Chinese adults: a prospective study of 0.5 million people. AB - BACKGROUND: Diabetes is associated with higher risk of colorectal cancer (CRC). Uncertainty remains about the relevance of duration of diabetes and about the association of blood glucose with CRC risk among individuals without diabetes. METHODS: The prospective China Kadoorie Biobank recruited 512 713 participants in 2004-2008 from 10 diverse areas in China. After 10 years of follow-up, 3024 incident cases of CRC (1745 colon, 1716 rectal) were recorded among 510 136 participants without prior cancer at baseline. Cox regression was used to estimate adjusted HRs for CRC associated with diabetes (previously diagnosed or screen-detected) and, among those without previously diagnosed diabetes, with levels of random plasma glucose (RPG). RESULTS: Overall 5.8% of participants had diabetes at baseline. Individuals with diabetes had an adjusted HR of 1.18 (95% CI 1.04 to 1.33) for CRC, with similar risk for colon and rectal cancer (1.19 [1.01 to 1.39] vs 1.14 [0.96 to 1.35]). The HRs decreased with longer duration of diabetes (p for trend 0.03). Among those without previously diagnosed diabetes, RPG was positively associated with CRC, with adjusted HRs per 1 mmol/L higher baseline RPG of 1.04 (1.02 to 1.05) for CRC, again similar for colon and rectal cancer (1.03 [1.01to 1.05] and 1.04 [1.02 to 1.06], respectively). The associations of diabetes and RPG appeared stronger in men than in women, but the differences were non-significant (p for heterogeneity 0.3 and 0.2). DISCUSSION: Among Chinese adults, diabetes and higher blood glucose levels among those without known diabetes are associated with higher risk of CRC. PMID- 29970602 TI - Tomosyn functions as a PKCdelta-regulated fusion clamp in mast cell degranulation. AB - Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fcepsilon receptor (FcepsilonRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcepsilonRI-stimulated degranulation of mast cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and threonine residues, dissociated from the SNARE protein syntaxin 4 (STX4), and associated with STX3. We identified PKCdelta as the major kinase required for tomosyn-1 threonine phosphorylation and for regulation of the interaction with STXs. Incubation with high IgE concentrations increased tomosyn-1 abundance in cultured mast cells. Similarly, in basophils from allergic patients with high amounts of serum IgE, the abundance of tomosyn-1 was increased as compared to that in patients with normal IgE concentrations. Our findings identified tomosyn-1 as an inhibitor of mast cell degranulation that required PKCdelta to switch its interaction with STX partners during fusion. We suggest that the IgE-mediated increase in tomosyn-1 abundance in allergic patients may represent a counterregulatory mechanism to limit disease development. PMID- 29970603 TI - Inhibition of the acetyltransferase NAT10 normalizes progeric and aging cells by rebalancing the Transportin-1 nuclear import pathway. AB - Hutchinson-Gilford progeria syndrome (HGPS) is an incurable premature aging disease. Identifying deregulated biological processes in HGPS might thus help define novel therapeutic strategies. Fibroblasts from HGPS patients display defects in nucleocytoplasmic shuttling of the GTP-bound form of the small GTPase Ran (RanGTP), which leads to abnormal transport of proteins into the nucleus. We report that microtubule stabilization in HGPS cells sequestered the nonclassical nuclear import protein Transportin-1 (TNPO1) in the cytoplasm, thus affecting the nuclear localization of its cargo, including the nuclear pore protein NUP153. Consequently, nuclear Ran, nuclear anchorage of the nucleoporin TPR, and chromatin organization were disrupted, deregulating gene expression and inducing senescence. Inhibiting N-acetyltransferase 10 (NAT10) ameliorated HGPS phenotypes by rebalancing the nuclear to cytoplasmic ratio of TNPO1. This restored nuclear pore complex integrity and nuclear Ran localization, thereby correcting HGPS cellular phenotypes. We observed a similar mechanism in cells from healthy aged individuals. This study identifies a nuclear import pathway affected in aging and underscores the potential for NAT10 inhibition as a possible therapeutic strategy for HGPS and perhaps also for pathologies associated with normal aging. PMID- 29970604 TI - Nuclear import pathway key to rescuing dominant progerin phenotypes. AB - In this issue of Science Signaling, Larrieu et al show that an acetyltransferase inhibitor that rescues many dominant nuclear phenotypes caused by progerin, a truncated form of lamin A, does so by releasing the specialized nuclear import receptor TNPO1 from sequestration by microtubules. This release enables TNPO1 dependent import of specific cargoes, including the nuclear pore protein Nup153 and the heterogeneous nuclear ribonucleoprotein hnRNPA1, thus restoring the functionality of nuclear pore complexes, rebalancing the nucleocytoplasmic Ran gradient, and normalizing gene expression. PMID- 29970605 TI - A case of suspected illegal abortion: how clinicians may assist the forensic pathologist. AB - Abortion may be performed in a safe or unsafe manner, the latter being a frequent and dangerous event. It can also be performed in countries where abortion is legally recognised but, for various reasons, may be undertaken in an illegal environment. We present a case of a possible illegal abortion. A woman presented to the hospital with a dead fetus, saying that she was the victim of a car accident. Forensic and gynaecological examination of the woman were carried out, along with an autopsy of the fetus. It was discovered that the woman had performed a clandestine abortion. The differential diagnosis between illegal abortion and miscarriage represents a complicated issue and requires both clinical and forensic support. The gynaecologist may be of assistance to the forensic pathologist in confirming whether an illegal abortion has been performed. PMID- 29970606 TI - Mesonephric adenocarcinoma of the vagina masquerading as a suburethral cyst. AB - Mesonephric adenocarcinoma (MA) of the vagina is an extremely rare tumour of the female genital tract. There are currently 22 reported cases in the published literature. Consequently, its pathophysiology and disease progression remain poorly understood.A 63-year-old woman presented with a history of a swelling in her vagina. Two-dimensional pelvic floor ultrasound and MRI demonstrated a multiloculated cyst with no malignant features. Initial workup provided a working diagnosis of a suburethral cyst. The diagnosis of MA was made on histology after excision of the cyst. Subsequent postoperative investigation showed no spread of the disease. The patient completed a course of prophylactic brachytherapy to prevent the possibility of any recurrence of disease. Due to its rarity, it remains difficult to diagnose MA of the vagina even on histological analysis. We would therefore recommend a low threshold to excise or perform tissue biopsy of unspecified vaginal masses. PMID- 29970608 TI - Unexpected cause of fever in a patient with untreated HIV. AB - We report a case of a 27-year-old man with a history of untreated HIV who presented with fever, rash and leg cramps. Initial suspicion was high for an infectious process; however, after an exhaustive evaluation, thyrotoxicosis was revealed as the aetiology of his symptoms. Recent intravenous contrast administration complicated his workup to determine the exact cause of hyperthyroidism. Differentiation between spontaneously resolving thyroiditis and autonomous hyperfunction was paramount in the setting of existing neutropenia and the need for judicious use of antithyroid therapy. The inability to enlist a nuclear scan in the setting of recent iodinated contrast administration prompted alternative testing, including thyroid antibodies and thyroid ultrasound. In this case, we will discuss the diagnostic challenges of thyrotoxicosis in a complex patient, the sequelae of iodine contrast administration, effects of iodine on the thyroid and the predictive value of other available tests. PMID- 29970607 TI - Synchronous MALT lymphoma of the colon and stomach and regression after eradication of Strongyloides stercoralis and Helicobacter pylori. AB - Mucosa-associated lymphoid tissue (MALT) is vital for host immunological surveillance against pathogens. MALT lymphoma, also known as extranodal marginal zone B cell lymphoma, is a non-Hodgkin's lymphoma subtype that predominantly arises in the gastrointestinal tract. Chronic Helicobacter pylori (H. pylori) infection is a common cause of gastric MALT lymphoma, although other infections are reported in association with extragastric MALT lymphomas. To our knowledge, here we report the first case of synchronous MALT lymphomas of the colon and stomach in the presence of Strongyloides stercoralis and H. pylori infections that resolved after eradication of both organisms. PMID- 29970609 TI - A case of deadly panniculitis. AB - While the majority of panniculitides are benign in nature, there are rare instances when panniculitis presents as the initial sign of a complex disease state. We describe a case of panniculitis initially diagnosed as lupus profundus that was challenged when features of haemophagocytic lymphohistiocytosis became apparent. We illustrate how some key clinical features and newer investigations can help differentiate between benign and malignant panniculitis. PMID- 29970611 TI - Testicular cancer: symptoms for urgent referral are identified. PMID- 29970610 TI - Undiagnosed Chilaiditi syndrome presenting with pericarditis in a patient with congenital anomalies. PMID- 29970612 TI - NHS must make urgent plans for no-deal Brexit, MPs hear. PMID- 29970613 TI - A politics of the senses: the political role of the King's-Evil in Richard Wiseman's Severall Chirurgicall Treatises. AB - Written by Richard Wiseman, sergeant-surgeon to King Charles II of England, 'A Treatise on the King's-Evil' within his magnum opus Severall Chirurgicall Treatises (1676), acts as a proto-case series which explores the treatment and cure of 91 patients with the King's-Evil. Working within the confines of the English monarch's ability to cure the disease with their miraculous (or thaumaturgic) touch, Wiseman simultaneously elevates and extends the potential to heal to biomedicine. Wiseman's work on the King's-Evil provides an interesting window through which the political expediency of the monarch's thaumaturgic touch may be explored. The dependence of the thaumaturgic touch on liturgy, theatricality and its inherent political economy in Restoration England allowed Wiseman to appropriate the traditionally monarchical role of healer as his own, by drawing attention to a medical ritual of healing that was as reliant, just as the theatrical ritual of monarchical thaumaturgy was, on symbolic binaries of healer-healed, head-body and touch-sight. PMID- 29970614 TI - Pyruvate dehydrogenase complex deficiency is linked to regulatory loop disorder in the alphaV138M variant of human pyruvate dehydrogenase. AB - The pyruvate dehydrogenase multienzyme complex (PDHc) connects glycolysis to the tricarboxylic acid cycle by producing acetyl-CoA via the decarboxylation of pyruvate. Because of its pivotal role in glucose metabolism, this complex is closely regulated in mammals by reversible phosphorylation, the modulation of which is of interest in treating cancer, diabetes, and obesity. Mutations such as that leading to the alphaV138M variant in pyruvate dehydrogenase, the pyruvate decarboxylating PDHc E1 component, can result in PDHc deficiency, an inborn error of metabolism that results in an array of symptoms such as lactic acidosis, progressive cognitive and neuromuscular deficits, and even death in infancy or childhood. Here we present an analysis of two X-ray crystal structures at 2.7-A resolution, the first of the disease-associated human alphaV138M E1 variant and the second of human wildtype (WT) E1 with a bound adduct of its coenzyme thiamin diphosphate and the substrate analogue acetylphosphinate. The structures provide support for the role of regulatory loop disorder in E1 inactivation, and the alphaV138M variant structure also reveals that altered coenzyme binding can result in such disorder even in the absence of phosphorylation. Specifically, both E1 phosphorylation at alphaSer-264 and the alphaV138M substitution result in disordered loops that are not optimally oriented or available to efficiently bind the lipoyl domain of PDHc E2. Combined with an analysis of alphaV138M activity, these results underscore the general connection between regulatory loop disorder and loss of E1 catalytic efficiency. PMID- 29970615 TI - An oxanthroquinone derivative that disrupts RAS plasma membrane localization inhibits cancer cell growth. AB - Oncogenic RAS proteins are commonly expressed in human cancer. To be functional, RAS proteins must undergo post-translational modification and localize to the plasma membrane (PM). Therefore, compounds that prevent RAS PM targeting have potential as putative RAS inhibitors. Here we examine the mechanism of action of oxanthroquinone G01 (G01), a recently described inhibitor of KRAS PM localization. We show that G01 mislocalizes HRAS and KRAS from the PM with similar potency and disrupts the spatial organization of RAS proteins remaining on the PM. G01 also inhibited recycling of epidermal growth factor receptor and transferrin receptor, but did not impair internalization of cholera toxin, indicating suppression of recycling endosome function. In searching for the mechanism of impaired endosomal recycling we observed that G01 also enhanced cellular sphingomyelin (SM) and ceramide levels and disrupted the localization of several lipid and cholesterol reporters, suggesting that the G01 molecular target may involve SM metabolism. Indeed, G01 exhibited potent synergy with other compounds that target SM metabolism in KRAS localization assays. Furthermore, G01 significantly abrogated RAS-RAF-MAPK signaling in Madin-Darby canine kidney (MDCK) cells expressing constitutively activated, oncogenic mutant RASG12V. G01 also inhibited the proliferation of RAS-less mouse embryo fibroblasts expressing oncogenic mutant KRASG12V or KRASG12D but not RAS-less mouse embryo fibroblasts expressing oncogenic mutant BRAFV600E. Consistent with these effects, G01 selectively inhibited the proliferation of KRAS-transformed pancreatic, colon, and endometrial cancer cells. Taken together, these results suggest that G01 should undergo further evaluation as a potential anti-RAS therapeutic. PMID- 29970616 TI - Region-specific proteolysis differentially modulates type 2 and type 3 inositol 1,4,5-trisphosphate receptor activity in models of acute pancreatitis. AB - Fine-tuning of the activity of inositol 1,4,5-trisphosphate receptors (IP3R) by a diverse array of regulatory inputs results in intracellular Ca2+ signals with distinct characteristics. These events allow the activation of specific downstream effectors. We reported previously that region-specific proteolysis represents a novel regulatory event for type 1 IP3R (R1). Specifically, caspase fragmented R1 display a marked increase in single-channel open probability. More importantly, the distinct characteristics of the Ca2+ signals elicited via fragmented R1 can activate alternate downstream effectors. In this report, we expand these studies to investigate whether all IP3R subtypes are regulated by proteolysis. We now show that type 2 and type 3 IP3R (R2 and R3, respectively) are proteolytically cleaved in rodent models of acute pancreatitis. Surprisingly, fragmented IP3R retained tetrameric architecture, remained embedded in endoplasmic reticulum membranes and were not functionally disabled. Proteolysis was associated with a marked attenuation of the frequency of Ca2+ signals in pancreatic lobules. Consistent with these data, expression of DNAs encoding complementary R2 and R3 peptides mimicking fragmented receptors at particular sites, resulted in a significant decrease in the frequency of agonist-stimulated Ca2+ oscillations. Further, proteolysis of R2 resulted in a marked decrease in single-channel open probability. Taken together, proteolytic fragmentation modulates R2 and R3 activity in a region-specific manner, and this event may contribute to the altered Ca2+ signals in pancreatic acinar cells during acute pancreatitis. PMID- 29970618 TI - Effect of routing paradigm on patient-centered outcomes in acute ischemic stroke. AB - OBJECTIVE: To compare performance of routing paradigms for patients with acute ischemic stroke using clinical outcomes. METHODS: We simulated different routing paradigms in a system comprising one primary stroke center (PSC) and onecomprehensive stroke center (CSC), separated by distances representative of urban, suburban, and rural environments. In the Nearest Center paradigm, patients are initially sent to the nearest center, while in CSC First, patients are sent to the CSC. In Rhode Island and Distributive paradigms, patients with Field Assessment Stroke Triage for Emergency Destination (FAST-ED) score >=4 are sent to the CSC, while others are sent to the nearest center or PSC, respectively. Performance and efficiency were compared using rates of good clinical outcome determined by type and timing of treatment using clinical trial data and number needed to bypass (NNB). RESULTS: Good clinical outcome was achieved in 43.67% of patients in Nearest Center and 44.62% in CSC First, Rhode Island, and Distributive in an urban setting; 42.79% in Nearest Center and 43.97% in CSC First and Rhode Island in a suburban setting; and 39.76% in Nearest Center, 41.73% in CSC First, and 41.59% in Rhode Island in a rural setting. In all settings, the NNB was considerably higher for CSC First than for Rhode Island or Distributive. CONCLUSION: Routing paradigms that allow bypass of nearer hospitals for thrombectomy-capable centers improve population-level patient outcomes. Differences are more pronounced with increasing distance between hospitals; therefore, the choice of model may have greater effect in rural settings. Selective bypass, as implemented in Rhode Island and Distributive paradigms, improves system efficiency with minimal effect on outcomes. PMID- 29970617 TI - Larger ACE 68 aspiration catheter increases first-pass efficacy of ADAPT technique. AB - PURPOSE: To report the efficacy of A Direct Aspiration first-Pass Thrombectomy (ADAPT) technique with larger-bore ACE aspiration catheters as first-line treatment for anterior circulation emergent large vessel occlusions (ELVOs), and assess for the presence of a first-pass effect with ADAPT. METHODS: We retrospectively reviewed 152 consecutive patients with anterior circulation ELVOs treated with the ADAPT technique as first-line treatment using ACE60, 64, or 68 at our institution. Baseline characteristics, procedural variables, and modified Rankin Scale (mRS) at 90 days were recorded. RESULTS: Fifty-seven patients were treated with ACE60 (37.5%), 35 with ACE64 (23%), and 60 with ACE68 (39.5%). Median groin puncture to reperfusion time was 30 min with ACE60, 26 min with ACE64, and 19.5 min with ACE68. Successful reperfusion after the first ADAPT pass was 33% with ACE60 and 53% with ACE68 (P=0.04). The stent-retriever rescue rate was 26% with ACE60, 3% with ACE64, and 10% with ACE68 (P=0.004). In multivariate logistic regression analysis, use of the ACE68 aspiration catheter was an independent predictor of successful reperfusion after the first ADAPT pass (P=0.016, OR1.67, 95% CI 1.1 to 2.54), and successful reperfusion after the first ADAPT pass was an independent predictor of good clinical outcome at 90 days (P=0.0004, OR6.2, 95% CI 2.27 to 16.8). CONCLUSION: Use of the larger-bore ACE 68 aspiration catheter was associated with shorter groin puncture to reperfusion time, higher rate of successful reperfusion after the first ADAPT pass, and lower rate of stent-retriever rescue. Further, a first-pass effect was demonstrated in our ADAPT patient cohort. PMID- 29970619 TI - Long term follow-up of endovascular management of spinal cord arteriovenous malformations with emphasis on particle embolization. AB - OBJECTIVE: To determine long term safety and efficacy of endovascular treatment of spinal cord arteriovenous malformations (AVMs), with calibrated particle embolization as a firstline approach. METHODS: We reviewed clinical and imaging data of consecutive patients who underwent endovascular treatment for both nidal and fistulous type spinal cord AVMs in our center, from 1990 to 2015. Outcome at the last follow-up was assessed by an independent observer. RESULTS: Embolization of spinal cord AVMs was performed in 61 patients, including 46 (75%) with particles (exclusively in 29 patients), 30 (49%) with cyanoacrylate, and 6 (10%) with combined surgical treatments. Particle embolizations were iterative in 33 patients (median number of sessions 5 (range 3-6)). Neurological deterioration after treatment occurred in 5 patients (cyanoacrylate=4, surgery=1, particles=0; P<0.001). At a median follow-up of 6 years (range 3-13 years), angiographic cure was obtained in 11/61 (18%) patients (nidal type=6/53 (11%), fistulous type=5/8 (63%)). In progressive forms, neurological improvement occurred in 16/28 (57%) patients, stabilized in 9/28 (31%), and worsened in 3/28 (12%). In hemorrhagic forms, the rebleeding rate was 4/14 patient years without standard treatment, 0/322 patient years in partial iterative treatment, and 0/15 patient years in angiographically cured lesions (P=0.001). CONCLUSION: Our study suggests that particle embolization as a firstline therapy to treat spinal cord AVMs is safe and offers long term efficacy, especially for those with small, distal, and multiple shunts. Partial occlusion of the AVM may be sufficient to prevent rebleeding, without the potential risks of complete occlusion. Particle calibration and injection technique, 'one by one', are critical to safety. Cyanoacrylate embolization or surgery remains necessary if particle embolization fails to occlude large shunts. PMID- 29970620 TI - Transient in-stent stenosis: a common finding after flow diverter implantation. AB - BACKGROUND AND PURPOSE: In recent years, implantation of flow diverters has emerged as an option for the endovascular treatment of intracranial aneurysms. One complication of treatment with flow diverters is the occurrence of in-stent stenosis, which has been reported to be partially reversible. The purpose of our study was to assess the incidence and dynamics of in-stent stenosis on angiographic short term and long term follow-up after treatment with flow diverters. METHODS: A retrospective review of our prospectively maintained database identified all patients with intracranial internal carotid artery (ICA) aneurysms treated by flow diverters at our institution between 2014 and 2017. Clinical charts, procedural data, and angiographic results were reviewed. RESULTS: 18 patients were included. The mean short term follow-up was 92+/-19 days and mean long term follow-up was 449+/-120 days after treatment. No neurologic complications were observed. There was no procedure related mortality. Long term angiographic results showed complete occlusion in 83.3%, neck remnants in 11.1%, and incomplete occlusion in 5.5% of cases. In-stent stenosis was observed in all cases. Mean stenosis improved significantly from 30% on short term follow-up to 12% on long-term follow-up (P<0.0001). CONCLUSION: In-stent stenosis is a common finding on short term follow-up after the treatment with flow diverters but improves over time. PMID- 29970621 TI - Prognosis of asymptomatic intracranial hemorrhage after endovascular treatment. AB - OBJECTIVE: Asymptomatic intracranial hemorrhage (aSICH) is a common phenomenon after endovascular treatment of acute ischemic stroke, but its prognostic impacts remain unclear. This study evaluated functional outcomes of thrombectomy in patients with and without aSICH. METHODS: Patients with acute ischemic stroke due to large artery occlusion in the anterior circulation who were treated with thrombectomy were enrolled in 21 centers. According to CT scans performed within 72 hours of endovascular procedures, patients with aSICH or without intracranial hemorrhage were included while patients with symptomatic intracranial hemorrhage (SICH) were excluded. Baseline data and functional outcomes were compared between patients with aSICH and those without intracranial hemorrhage. Logistic regression analysis was applied to evaluate the impacts of aSICH on functional outcomes. RESULTS: Of the 632 patients with endovascular treatment, 101 (16.0%) were classified as having SICH, 212 (33.5%) as having aSICH, and 319 (50.5%) as being without intracranial hemorrhage. Patients with aSICH after endovascular treatment had a lower ratio of excellent outcome (mRS 0-1, OR 0.53; 95% CI 0.33 to 0.84, P=0.007) than those without intracranial hemorrhage. There were no significant differences concerning favorable outcome (mRS 0-2, OR 0.76; 95% CI 0.50 to 1.14, P=0.185) or mortality (OR 0.64; 95% CI 0.38 to 1.09, P=0.101) between patients with aSICH and those without intracranial hemorrhage. CONCLUSIONS: In an Asian population, aSICH after thrombectomy may decrease the likelihood of an excellent functional outcome but does not influence a favorable outcome and mortality in patients with ischemic stroke due to large artery occlusion in the anterior circulation. PMID- 29970622 TI - Psychotic due to bath salts and methamphetamines: emergency cesarean section under general anesthesia. AB - The use of "bath salts" or other new psychoactive substances, otherwise known as "legal highs", is increasing. Illicit drug use during pregnancy is not uncommon. Nevertheless, literature reporting bath salts and their effect on pregnancy is scant. Besides, there seems to be no literature about bath salts and conduct of general anesthesia. This case report describes a general anesthetic for the surgical delivery of an infant to a woman under the acute influence of bath salts and methamphetamines. PMID- 29970623 TI - Emerging pathways of communication between the heart and non-cardiac organs. AB - The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis - a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart. PMID- 29970624 TI - Emerging trends in pediatric dentistry. PMID- 29970625 TI - Pattern of dental caries in 3-6-year-old children using decayed, missing, filled surface index and hierarchical caries pattern system: A descriptive study. AB - Background and Objectives: The dental caries status of a population group with permanent dentition is traditionally described using decayed, missing, and filled teeth or surface (DMFT or DMFS) index, and the corresponding index for the primary dentition is dmft or dmfs. dmf value alone has certain limitations; therefore, additional measures to describe dental caries are important. Poulsen and Horowitz in 1997 described a hierarchical method to determine the severity of dental caries. Aim of the Study: The aim of the study was to determine the pattern of dental caries in 3-6-year-old children using Poulsen and Horowitz hierarchical system and to assess the usefulness of this system. Methodology: Data were collected from 500, 3-6-year-old children. Dmfs was recorded according to World Health Organization criteria 2013. On the basis of the caries recordings, the dmfs score of each child was calculated and each child was assigned to one of the six zones of increasing caries severity, ranging from 0 (caries free) to 5 (most severe). Statistical Analysis Used: The collected data were tabulated and analyzed using Student's t-test, ANOVA, and Pearson's correlation coefficient. Results: The overall mean dmfs for the study population was 9.10. The distribution of children according to the severity zones of Poulsen and Horowitz indicates a very low percentage (17.8%) of caries-free children and also a high percentage of children with caries in severity zone 2 (33.4%) and 4 (18.6%). Conclusion: The Poulsen and Horowitz model gives broader aspect for the assessment of severity of dental caries in 3-6-year-old children. PMID- 29970626 TI - Dental erosion in schoolchildren and associated factors: A cross-sectional study. AB - Context: Throughout life, the teeth are exposed to different types of wear, including dental erosion, which is characterized by the loss of surface mineralized tissue due to a chemical process without bacterial involvement and strongly influenced by eating habits. Aim: The aim of this study to evaluate the prevalence of dental erosion in schoolchildren and associated factors. Setting and Design: This is a cross-sectional study. Material and Methods: The study was conducted at a public and private school in the city of Sao Luis (MA), Brazil, involving a sample of 239 children aged 6-10 years. Data were collected through a questionnaire and clinical examination. Dental erosion was evaluated using the Basic Erosive Wear Examination. Statistical Analysis: Data analysis involved descriptive statistics, Pearson's Chi-square test, the linear trend Chi-square test, and Fisher's exact test, with the level of significance set to 5%. Results: The male sex accounted for 50.2% of the sample and the female sex accounted for 49.8%; 62.8% attended the public school and 37.2% attended the private school. The prevalence of dental erosion was 11.7%, with the highest prevalence among 9 year-olds (46.4%). Dental erosion was significantly associated with age (P = 0.009) and type of school (P < 0.001). Conclusion: The present findings underscore the need for strategies to prevent or arrest the erosive process through local actions involving schoolchildren, parents/caregivers, and teachers. PMID- 29970627 TI - Oral health awareness in school-going children and its significance to parent's education level. AB - Background: The oral health imparts a major impact on one's quality of life. Since last decades, there is an increase in the prevalence of dental afflictions which can be avoided by the knowledge of simple preventive measures. Aim: The aim of this study was to assess the oral health status of children and to analyze its association with the education level of their parents. Materials and Methods: Two randomly schools were selected and all the children from 5-15 years willing to participate in the present cross-sectional study were assessed for oral health status using the World Health Organization for the oral health awareness in children, 2004. Both child and parents were directly interviewed to avoid any bias in understanding the questionnaire. Statistical Package for the Social Sciences (16.0) was used for data analysis. Chi-square/Fisher's exact test was used to compare the dichotomous variables. Results: A total of 210 (133 males and 77 females) children were assessed along with their parents for the awareness of child's oral health condition. Totally 134 (63.3%) children were of age group 5 10 years, while 76 (36.7%) children were of age group 11-15 years. Children with uneducated parents have often experienced toothache, brushes once a daily and frequently visits the dentist for toothache compared to children of educated parents, and this association was observed to be statistically significant (<0.001). Conclusion: The oral health status of children was average. However, education level and awareness of parents regarding oral health preventive measures play a key role in determining the oral health of children. PMID- 29970628 TI - Oral manifestations of gastroesophageal reflux disease in children: A preliminary observational study. AB - Aims: This study aimed to document the prevalence of oral manifestations seen among pediatric gastroesophageal reflux disease (GERD) patients in Chennai, Tamil Nadu, India. Methodology: This study was performed at various children's hospitals in Chennai. Fifty-one GERD patients who were assessed by endoscopy and 24 h pH-metry, 31 (60.78%) males and 20 (39.21%) females, aged 2-12 years (mean age, 7.43 years), comprised the study group. All patients answered a detailed frequency questionnaire related to regurgitation and acidic foods and participated in a clinical dental examination. Statistical Analysis Used: Data were analyzed using the SPSS statistical software package version 19. Results: Among the GERD patients, 42 (82.35%) had dental erosion. A total of 668 (57.98%) deciduous teeth and 484 (42.02%) permanent teeth were examined, of which dental erosion was detected in 248 (21.52%) and 171 (14.84%) teeth, respectively. The most commonly affected primary tooth was the occlusal surface of the maxillary posteriors and commonly affected permanent tooth was occlusal surface of the mandibular molars. Conclusions: There may be a positive correlation between GERD and dental erosion. According to this study, presence of erosion, especially in posterior teeth, could be a key to diagnose GERD and refer the child to the gastroenterologist. PMID- 29970629 TI - Salivary interleukin-6 levels in children with early childhood caries and ventricular septal defect. AB - Background: The efficacy of dental treatment on the levels of inflammatory markers in ventricular septal defect (VSD) has not been fully explored. Aims: The aim of this study was to assess the level of salivary interleukin-6 (IL-6) in children with early childhood caries (ECC) and VSD and to compare its levels before and after comprehensive full mouth rehabilitation. Methods: Saliva samples were collected from children with ECC and VSD before dental treatment and 1-month posttreatment. The salivary IL-6 levels were analyzed using the enzyme-linked immunosorbent assay method. Gingival index (GI) was also timely recorded during the study period. Oral health awareness sessions were conducted for children and their parents. The Fisher's Least Significant Difference test was used for intergroup comparison of salivary IL-6 levels, while the paired t-test compared the values of GI before and after treatment. Results: The mean salivary IL-6 levels 1 month after treatment had reduced (P < 0.000). There was a reduction in GI score (P = 0.002). Conclusions: When children having VSD and ECC are dentally rehabilitated and followed up periodically, the level of IL-6 is minimized, hence improving the quality of life of the affected children. PMID- 29970630 TI - Effect of crude apple extract on the cariogenic factors of Streptococcus mutans: An in vitro study. AB - Objective: The aim was to assess the effects of crude extract of whole apple on the cariogenic properties of Streptococcus mutans by evaluating (1) its growth, (2) its adherence property, and (3) changes caused by acid produced by S. mutans in the presence of sucrose (in vitro). Study Design: Kashmiri Apples (sourced from the local market) were used for the study. Whole apple extracts including the skin were used to obtain undiluted crude apple extract. The growth of S. mutans in the presence of the crude apple extract was evaluated by agar diffusion test as well as direct contact inhibition test. The effects of the crude extract on the adherence of S. mutans was assessed by modified O'Toole method in which the viable cell counts of S. mutans which remained adherent on the microtitre plate were calculated. The effects of the test materials on pH changes caused by S. mutans in the presence of sucrose were assessed using pH meter. Results: Crude extract of the whole apple showed no significant inhibitory effect on the growth of S. mutans while a significant inhibitory activity on the adherence of S. mutans was observed. Furthermore, the significant inhibitory effect on the pH drop was recorded, although pH remained below the critical value of 5.5 at all times. Conclusion: Crude whole apple extract has considerable anti-cariogenic effect on S. mutans and hence can be used as a natural alternative which can aid in the prevention of dental caries. PMID- 29970632 TI - Root canal morphology of primary molars by clearing technique: An in vitro study. AB - Objective: The objective of the study was to study root canal morphology of primary molars by clearing technique and to observe for any variations. Materials and Methods: One hundred and twenty extracted primary molars were divided into four groups (n = 30); Group I = maxillary first, Group II = maxillary second, Group III = mandibular first, and Group IV = mandibular second. The samples were subjected to decalcification, clearing, and dye penetration. The data regarding the root canal morphology of each sample were tabulated based on the number of root canals, curvature of the root canal, and root canal configuration. Descriptive statistics were applied. Results: According to Vertucci's root canal configuration in Group I, mesiobuccal root exhibited 93.10% Type I, 6.90% Type II, and 6.90% Type IV; distobuccal root had 95.65% Type I and 4.35% Type IV; and palatal roots had 100% Type I canal configuration. In Group II, mesiobuccal root showed 90% Type I and 10% Type IV; distobuccal root had 100% Type I; palatal root exhibited 96.30% Type I and 3.70% Type III. In Group III, mesial root showed 20% Type I, 6.67% Type III, and 73.33% Type IV and distal root had 76.67% Type I and 23.33% Type IV. In Group IV, mesial root exhibited 100% Type IV and distal root had 43.33% Type I and 65.67% Type IV canal anatomy. Conclusion: Vertucci's Type I root canal configurations were most frequently observed. PMID- 29970631 TI - Comparative evaluation of the antimicrobial susceptibility and cytotoxicity of husk extract of Cocos nucifera and chlorhexidine as irrigating solutions against Enterococcus Faecalis, Prevotella Intermedia and Porphyromonas Gingivalis - An in vitro study. AB - Aim and Background: The aim of the present study is to evaluate and compare the antimicrobial susceptibility and cytotoxicity of Cocos nucifera and chlorhexidine (CHX) as irrigating solutions against Enterococcus faecalis, Prevotella intermedia, and Porphyromonas gingivalis. Materials and Methods: The ethanolic extract of husk of C. nucifera was prepared. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the extract were determined using the serial broth dilution method and its cytotoxicity was evaluated against human periodontal fibroblasts using 3-(4,5-dimethyl-thiazole-2-yl)-2,5-diphenyl tetrazolium bromide assay. Antibacterial susceptibility for two irrigating solutions, namely 2% CHX gluconate irrigant (Group I) and 1.5% C. nucifera husk irrigant (Group II), was tested against P. gingivalis, P. intermedia, and E. faecalis. Results: The MIC and MBC of C. nucifera husk extract for P. gingivalis were 468.75 MUg/ml and 1562.5 MUg/ml, for P. intermedia were 48.8 MUg/ml and 1875 MUg/ml, and for E. faecalis were 1562.5 MUg/ml and 3750 MUg/ml, respectively. The extract was nontoxic to the human periodontal fibroblast. Both the materials have shown similar antibacterial susceptibility and no difference was observed at baseline, 10, 30, and 60 min using two-way repeated measures of ANOVA. However, a statistically significant difference was observed between different time points for P. gingivalis and P. intermedia using Bonferroni multiple comparison test (f = 826.1390, P <= 0.05). Conclusion: 1.5% of ethanolic husk extract of C. nucifera has a significant antibacterial action against polymicrobial dental biofilm and its activity is comparable to that of 2% CHX which validates its use as a future irrigating solution for overcoming bacterial resistance with synthetic agents. PMID- 29970633 TI - Surface remineralization potential of nano-hydroxyapatite, sodium monofluorophosphate, and amine fluoride containing dentifrices on primary and permanent enamel surfaces: An in vitro study. AB - Background: Organic amine fluorides and nano-hydroxyapatite dentifrices have shown remineralization potential in various studies. However, there is a lack of direct comparison between amine fluoride and nano-hydroxyapatite with conventional inorganic fluorides as sodium monofluorophosphate. Aim: The aim of the study is to evaluate remineralizing efficacy of the three dentifrices on both primary and permanent enamel surfaces. Methods: Enamel sections were obtained from 40 sound molars - 20 primary and 20 permanent molars. Five enamel slabs were prepared from these extracted molars stored in artificial saliva, wherein one slab acted as control, second as demineralized (negative control), and other three slabs were brushed with sodium monofluorophosphate, amine fluoride, and nano-hydroxyapatite dentifrices, respectively, twice daily for 21 days. Scanning electron microscopy- Energy dispersive spectroscopy (SEM-EDS) analysis for surface morphology and calcium and phosphorus content and Vickers surface microhardness (SMH) values were evaluated at baseline, after demineralization, and postapplication of the experimental agents. Results: Highly significant changes in calcium phosphorus ratio and SMH values were seen in enamel slabs treated with nano-hydroxyapatite and amine fluoride dentifrice as compared to sodium monofluorophosphate in both primary and permanent teeth. Surface morphology of enamel slabs treated with amine fluoride most closely resembled natural enamel morphology, while sodium monofluorophosphate-treated surfaces showed globular pattern of remineralization. Deposition of a separate highly mineralized layer over existing surface was seen in nano-hydroxyapatite-treated surfaces. Conclusions: Nano-hydroxyapatite exhibited highest remineralization potential in terms of mineral gain followed by amine fluoride and sodium monofluorophosphate dentifrice. PMID- 29970634 TI - Assessment of the effect of parental presence in dental operatory on the behavior of children aged 4-7 years. AB - Background: Child presents a unique challenge to accept a dental treatment, and such a challenge gets modified by the presence or the absence of a parent in the operatory. Many dentists have reportedly and controversially used parental separation anxiety as a tool to control behavior of an uncooperative child and also to deliver quality dental treatment in young children. But is the parental separation beneficial for dentist to gain child cooperation? Aims and Objectives: The objective is to evaluate the influence of parental presence or absence in the operating room on child's behavior during dental procedure on children of 4 years and above. Materials and Methods: The study was carried out on 30 children of 4-7 years of age group, 16 (4-6 years) preschoolers, and 14 (6-7 years) early schoolers. Two consecutive restorative procedures were carried out. On a first visit, parents were present and on a second visit, separation of parents was done. Behavior rating was done by commonly used Frankel's Behavior Rating Scale. Results: Chi-square test was performed for the statistical analysis. There was no significant difference found in the child's behavior by the presence or absence of parents in the perception of dental treatment in the dental operatory. In contrast to that there was a significant increase in cooperative behavior of some children due to other factors influencing the behavior of the child with a Chi square value = 35.296, P < 0.001. Conclusion: Parents can be excluded from the dental operatory to eliminate many behavior-related problems during the course of treatment. PMID- 29970635 TI - Zinc oxide eugenol and Endoflas pulpectomy in primary molars: 24-month clinical and radiographic evaluation. AB - Context: Despite modern advancement in material and technical aspect, management of infected primary molars is of prime concern in pediatric endodontics. An effective root canal material plays the major role in achieving the fluid impervious seal by defending against variant microflora and maintaining the tooth in function for longer duration. Aims: This study aims to evaluate and compare the success of endoflas as root canal filling material in infected primary molars with zinc oxide eugenol (ZOE). Materials and Methods: Primary molars with necrotic pulp in healthy, cooperative children were selected. Ethical clearance and informed consent was obtained. Standardized pulpectomy procedure was done and root canals were filled with either ZOE or endoflas. Further follow-up with clinical and radiographic evaluation was carried at 0, 3, 6, 12, and 24 months. The findings obtained were statistically analyzed using Chi-square test. Results: Endoflas showed acceptable results as root canal filling material in primary molars even at 2-year follow-up, though overfilling of root canals led to low success rate compared to teeth with combined optimal and under fillings. There was no significant difference between the two materials (P > 0.05). Conclusions: Endoflas could be a potential alternative to ZOE for preserving infected primary molars. PMID- 29970636 TI - A bite out of anxiety: Evaluation of animal-assisted activity on anxiety in children attending a pediatric dental outpatient unit. AB - Background: Anxiety control has been one of the key factors that shows that success of a pediatric dental practice. Animal- Aassisted therapy has shown to have many health benefits, which has brought the animal species closer to our homes with an establishment of a relationship. Aims and Objectives: The purpose of this study was to compare a Anxiety levels of patients scheduled to visit a Private private Ppediatric dDental Hhealth- Ccare Ffacility in Chennai and Ccompare the levels when exposed to animal-assisted activityAAA at the waiting area and in the oOperating area. This study being a first of its kind in the Dental dental Environment environment consisted of 20 children (9 Malemales, 11 Femalefemales), aged 4--11 years, attending a private dental care facility in Chennai. Results: Results showed that a 15- min exposure in the waiting area has reduced the level of anxiety and also showed no increase in anxiety among the subjectsparticipants. Conclusion: Thus, Pet pet Ttherapy has shown to be a promising method of Anxiety anxiety control, a key to a successful dental practice. PMID- 29970637 TI - Development and evaluation of new clinical methods of age estimation in children based on the eruption status of primary teeth. AB - Background: Age estimation methods in the permanent dentition are numerous in number and well established and evaluated. However, there exists a dearth of methods available for the estimation of age based on the eruption status of primary teeth, despite various studies displaying greater accuracy using such methods. Aim: The purpose of this study was to develop the methods of age estimation based on the eruption status of primary teeth and based on previous methods developed for permanent teeth and to assess the accuracy of the methods in a clinical situation. Materials and Methods: A total of 50 children were randomly selected between the age group of 6 and 38 months for the assessment of primary tooth emergence in the oral cavity. New methods of age estimation (triangles and regression equations) were developed for used in the Indian population. Results: Data were analyzed using receiver operating characteristics curve and intraclass correlation coefficient. Our results conducted in a validation sample of 30 children suggested high levels of accuracy using the new methods, with greater accuracy displayed using the regressive equation (0.928) as compared to the new triangle of age estimation (0.897). Conclusion: Such methods of age estimation will be of unparalleled importance in rural setups, which cannot afford the luxury of panoramic radiography. PMID- 29970638 TI - A clinical trial comparing antimicrobial efficacy of "essential oil of Ocimum sanctum" with triple antibiotic paste as an intracanal medicament in primary molars. AB - Objectives: To evaluate the aerobic and anaerobic antimicrobial efficacy of Ocimum Sanctum (Tulsi) essential oil and compare it with that of triple antibiotic paste (TAP) by collecting microbiological samples from the root canals of primary molars. Study Design: Forty children were selected for the study and were randomly divided into two groups of twenty each, namely, TAP group and O. sanctum group (basil). Six intracanal samples were collected for every patient, comprising of two each after access opening, irrigation and after 3 days of intracanal medicament placement. These samples were cultured in aerobic and anaerobic environment and later colony-forming units (CFUs) were counted and intragroup as well as intergroup comparison was done. Results: Analysis of the results showed that there was a statistically significant reduction in CFUs after using essential oil of O. sanctum as an intracanal medicament. Saline use also leads to a statistically significant reduction in CFUs irrespective of the intracanal medicament used. TAP showed better antibiotic properties in comparison with that of O. sanctum. Conclusion: Antibiotic use is often associated with the adverse effects and development of resistance due to injudicious use. O. sanctum can be used in cases of long-standing infection owing to its antimicrobial efficacy and anti-inflammatory potential as an intracanal medicament in primary teeth. PMID- 29970639 TI - A randomized controlled clinical trial to evaluate and compare three chairside techniques of veneering stainless steel crowns. AB - Background: With the increasing patient demands of esthetics in paediatric dentistry, pre-veneered stainless steel crowns (SSCs) have been made available commercially. However, they suffer from technique sensitivity, limited ability to crimp and associated higher costs. Aim: The present study was planned to clinically evaluate and compare the success of preformed SSCs in which esthetic modification was done using three different techniques of composite veneering. Materials and Methods: A total of 60 primary molars selected from patients between the age group of 4-9 years were randomly divided into three groups having 20 samples each: Group A (composite veneering done using the open face technique), Group B (composite veneering done after sand-blasting SSCs), and Group C (composite veneering done after preparing retentive grooves on SSCs). The patients were evaluated at 1, 3, 6, and 9 months as per evaluation criteria. Statistical Analysis: Kruskal-Wallis and ANOVA were used to compare means among three groups at different time intervals. Results: All 60 SSCs were retained at the end of the study, thereby demonstrating 100% success of SSCs. Open window technique of veneering significantly showed maximum retention of composite veneers; therefore, highest level of parental satisfaction. Overall, the most common fracture was of adhesive type seen at the metal composite interface. Conclusions: All the three techniques used provide a chairside and easy method for esthetic modification of the SSCs. The open window is the most successful of the three methods of veneering and may be clinically useful technique for dental practitioners and pediatric dentists. PMID- 29970640 TI - Early treatment of pseudo-class III malocclusion with modified swallowing occlusal contact intercept appliance (S.O.C.I.A.). AB - Aims: The aim of the present work was to evaluate the dentoskeletal effects of swallowing occlusal contact intercept appliance (SOCIA) III in pseudo Class III malocclusion treatment. Materials and Methods: Thirty-six patients (mean age: 9.46 years old) with pseudo-Class III malocclusion and 22 pseudo-Class III untreated controls (mean age: 8.7 years old) were selected and examined. All patients presented with a cervical stage CS2, CS3, or CS4. Patients with CS5 were not enrolled in the study. Cephalometric analysis was performed before phase 1 treatment (T1) and immediately following phase 2 treatment (T2). Statistical Analysis: Paired t-test and independent t-test. Results: SOCIA III had skeletal and dental effects. The main effects of SOCIA III were on the midface with an effective increase of the sagittal growth (cranial base P < 0.001, anterior cranial base (ACB) P < 0.001, and maxilla growth P < 0.001) and vertical growth (anterior facial height P < 0.001). The effects of SOCIA on the mandible were a control of mandibular postrotation (P = 0.82) and the sagittal growth (P < 0.007). At the end of the treatment, a normal overjet was achieved (P < 0.001). Conclusions: The SOCIA III effects are resumed as follow: (a) an effective maxillary sagittal increase on the sagittal plane; (b) a vertical mandibular control; (c) a resolution of overjet; (d) no increase of overbite; (e) a stimulation of ACB growth. PMID- 29970641 TI - Dentin dysplasia type 1 - clinical management dilemmas: A case report of first generation sufferers. AB - Dentine Dysplasia is a rare genetic condition. The treatment options and dilemmas associated with the condition remain undiscovered so far. This article highlights the variations in traits and challenges faced in the treatment of the cases. PMID- 29970642 TI - Aberrant root formation - An unreported complication of dental trauma. AB - Trauma and infection to immature teeth can result in a number of complications. Discontinuity in the formation of root is one such complication which has never been documented before. In the following article, a case report of this aberrancy which was observed in the root of a permanent central incisor, subsequent to a traumatic injury is discussed. In spite of this discontinuity, complete root formation and vital pulp were noted in the tooth. Since such a case has not been reported in literature till date, this complication is described and the possible cause of its occurrence is discussed in this article. PMID- 29970643 TI - Arrested root growth and concomitant failure of eruption of a developing tooth following open reduction and internal fixation of a pediatric mandibular fracture. AB - Mandible is one of the commonly fractured bone in children during maxillofacial trauma. These factures are usually managed conservatively but sometimes require open reduction and internal fixation (ORIF). Management of mandibular fracture in children is influenced by the presence of developing permanent tooth buds, minimal anchorage from primary teeth and facial growth and development. Although, there have been technical and material advancements with ORIF, it is still associated with complications related to growth and damage to developing teeth. This case report describes a case of mandibular parasymphyseal fracture managed successfully with open reduction and internal fixation using a miniplate and a consequent cessation of root growth and eruption failure of a mandibular canine present in the fixation area. PMID- 29970644 TI - A valuable guideline for thermal ablation of primary and metastatic lung tumors. PMID- 29970645 TI - Angiogenesis and apatinib: Can be used for the patients with non-gastic cancer? PMID- 29970647 TI - Long noncoding RNAs in cervical cancer. AB - This is a review about long noncoding RNAs (lncRNAs) and cervical cancer, especially the crucial regulating role played by lncRNAs on cervical cancer. LncRNAs are a big family with popular investigation in the last years. LncRNAs, as its noncoding proteins, once were considered to be useless RNAs without much more concern. However, much more attention was paid with the unique relationships between lncRNAs and disease. Especially, lncRNAs were evaluated and found its modifying and regulating functions in the process of cancer development. In this review, we summarize the characteristics of certain lncRNAs which are crucial for cervical cancer, find their mechanisms, and provide more possible direction for following evaluations including the point for target treatment. PMID- 29970646 TI - Expert consensus workshop report: Guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition). AB - Although surgical resection with curative intent is the main therapy for both primary and metastatic lung tumors, about 80% of lung cancers cannot be removed by surgery. Because most patients with unresectable lung cancer only receive limited benefits from traditional radiotherapy and chemotherapy, many novel local treatment modalities have emerged including local ablation therapy. The Minimally Invasive Treatment of Lung Cancer Branch, Professional Committee of Minimally Invasive Treatment of Cancer of the Chinese Anti-Cancer Association and Committee on Tumor Ablations, Chinese College of Interventionalists have organized multidisciplinary experts to develop guidelines for this treatment modality. These guidelines aim at standardizing thermal ablation procedures, describing the indications for candidates, assessing outcomes, and preventing postablation complications. PMID- 29970648 TI - Efficacy and safety of computed tomography-guided 125I brachytherapy for lymph node metastatic from hepatocellular carcinoma. AB - Purpose: A survival benefit may be associated with the positive control of extrahepatic lymph node metastasis (LNM) of hepatocellular carcinoma (HCC). However, no standard treatment exists. The aim of this study was to evaluate the safety and efficacy of iodine-125 (125I) brachytherapy (BT) of LNM of HCC, especially in patients with multiple lymph nodules or repeated lymph node recurrence. Materials and Methods: From June 2007 to July 2016, clinical and imaging data of 22 patients were collected at our center. According to the treatment planning system, 37 BT targets were treated by seed implantation with computed tomography (CT)-guidance. The radioactive treatment-related adverse events and surgical complications were recorded. The BT target therapeutic response was evaluated by the RECIST. The median survival time and rates were evaluated by the Kaplan-Meier method. Results: Twenty-two patients were enrolled (median age: 48 years; 90.9% males), and 58 lymph node areas were diagnosed as metastatic. The incidence of LNM was high in porta hepatis (33.9%) and right para aortic nodes (14.2%), and lower incidence rates were observed in other areas. The median imaging follow-up time was 12 months (inter-quartile range 5.5-20.5), the complete response was 29, the partial response was 5, the stable disease was 2, the progressive disease was 1, and the local response rate was 91.8%. The median survival time from the beginning of BT was 25 months. The 1, 2, and 3-year overall survival rates were 64.3%, 43.4%, and 27.1%, respectively, and the 5-year overall survival rate from the time of HCC diagnosis was 31.1%. No BT-induced acute morbidity according to the Radiation Therapy Oncology Group criteria was reported. After 5.5 months, one patient diagnosed with a duodenal ulcer underwent gastroduodenoscopy. The surgical complications included mild pancreatitis in 3 patients and stomach bleeding and pneumothorax in 1 patient. Conclusion: CT guided 125I BT treatment of LNM of HCC presented good local control rates and controllable complications. It is a safe and effective palliative treatment for patients with LNM of HCC. Further study is needed to evaluate its long-term safety and efficacy. PMID- 29970649 TI - Effects of Spica prunellae on caspase-3-associated proliferation and apoptosis in human lung cancer cells in vitro. AB - Purpose: This study aimed to explore the molecular mechanisms underlying the effects of Spica prunellae on proliferation and apoptosis of lung cancer cells in vitro. Materials and Methods: The cell viability was determined with the CCK8 assay and the apoptosis was examined by flow cytometry. Western blotting was applied to detect the protein level of caspase-3 expression. Results: It was observed that Spica prunellae could promote the apoptosis and inhibit the proliferation of A549 in vitro. The analysis of Western blotting showed that the expression level of proapoptosis protein caspase-3 was generally unchanged, whereas the level of activated caspase-3 was significantly increased. Conclusion: The results indicated that the growth of lung cancer cells A549 might be inhibited with Spica prunellae through activating the proapoptotic protein caspase-3 and inducing cellular apoptotic pathway. PMID- 29970650 TI - Computed tomography-guided percutaneous microwave ablation for treatment of peripheral ground-glass opacity-Lung adenocarcinoma: A pilot study. AB - Purpose: The purpose of the study is to retrospectively evaluate the safety and efficacy of microwave ablation (MWA) for the treatment of ground-glass opacity (GGO)-lung adenocarcinoma. Materials and Methods: From December 2013 to June 2017, a total of 51 patients (22 males and 29 females, mean age of 69.4 +/- 10.1 years) were included in this study, with 51 lung adenocarcinoma lesions showing GGO (mean long-axis diameter of 18.7 +/- 6.05 mm). They received a total of 52 sessions of percutaneous computed tomography-guided (CT-guided) MWA. First, lung adenocarcinoma with GGO was histologically defined by needle biopsy under the guidance of CT. Second, the efficacy of CT-guided MWA was analyzed, including the feasibility, safety, 3 years local progression-free survival (LPFS), 3 years disease-specific survival, and 3 years overall survival (OS). Final, complications after MWA were also summarized. Results: The technical success rate was 100%, without MWA procedure-related death. At the median follow-up period (27.02, range: 7-45 months), the rates of 3 years LPFS, cancer-specific survival, and OS were 98%, 100%, and 96%, respectively. The complications after MWA included pneumothorax (48.1%, 25/52), hemoptysis (28.8%, 14/52), pleural effusion (23.1%, 12/52), and pulmonary infection (7.7%, 4/52). Conclusions: CT-guided percutaneous MWA was a feasible, safe, and effective therapeutic approach for treating GGO-lung adenocarcinoma. PMID- 29970651 TI - Conversion chemotherapy with capecitabine and oxaliplatin for colorectal cancer with potentially resectable liver metastases: A phase II, open-label, single-arm study. AB - Aim: The aim of this is study is to assess the efficacy and safety of conversion capecitabine plus oxaliplatin (XELOX) in Chinese patients with potentially resectable colorectal liver metastases (CLMs). Patients and Methods: Thirty patients (median age 57.5 years) with potentially resectable CLMs were treated with XELOX in a single-arm, open-label, nonrandomized, multicenter clinical trial. Results: The objective response rate in the 30 patients was 40% (95% confidence interval: 22.7%-59.4%), and the rate of conversion to resectable CLMs was 43.3%. Patients who underwent liver resection (n = 11) had a longer median progression-free survival and overall survival than those who did not. XELOX showed an acceptable safety profile. Conclusion: XELOX may effectively convert potentially resectable CLM into resectable CLM, providing survival benefits with a favorable safety profile. Clinical Trials.gov identifier: NCT 00997685. PMID- 29970652 TI - Distribution of human papillomavirus genotypes and its relationship to clinicopathology in invasive cervical carcinoma in Zhejiang Province, China. AB - Aims: This study aims to investigate the prevalence of human papillomavirus (HPV) genotypes and analyze the relationship of HPV infectious status to clinicopathologic characteristics of invasive cervical carcinoma (ICC) in Zhejiang Province. Materials and Methods: All consecutive patients diagnosed with the International Federation of Gynecology and Obstetrics stage IA to IV ICC, treated at our institutions between January 2007 and December 2008 were enrolled. The associations between the clinicopathologic parameters and the HPV status were assessed by the Pearson Chi-square test. Results: Out of 1169 patients, 1072 (91.70%) patients had detectable HPV, the HPV-positive rate seemed to be higher as the severity of pathology increased and preferred to squamous cell carcinoma (SCC). HPV-16/-58/-18/-52 was the most prevalent types found in Zhejiang Province. HPV-16 was preferred to SCC (P = 0.049), while HPV-58 seemed to be more likely in non-SCC (P = 1.18E-6), deep stromal invasion (DSI)-positive (P = 0.001), lymphovascular space invasion (LVSI)-positive (P = 4.84E-6), and lymph node metastasis (LNM)-positive (P = 7.98E-4). HPV-52 was more common in surgery patients who were beyond 35 years old (P = 0.02), as well as in DSI-positive (P = 0.014) patients. However, there were no significant differences regarding HPV-58 to any clinicopathologic parameters. Conclusions: HPV-16/-18/-58/-52 was the most commonly identified types in Zhejiang Province, which contributed for vaccine development. Furthermore, HPV-16 was preferred to SCC, while HPV-58 seemed to be more likely in non-SCC, DSI-positive, LVSI-positive, and LNM-positive patients, and HPV-52 was more common in surgery patients who were beyond 35 years old, as well as in DSI-positive patients. PMID- 29970653 TI - Lack of association between the distribution of ABO blood groups and nasopharyngeal carcinoma in a population of Southern China. AB - Objectives: Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. The ABO blood group antigens are chemical constituents on the surface of red blood cells and various epithelial cells. Several studies have described the association of ABO blood types with multiple types of human cancer. In this study, we aimed to investigate the relationship between the incidence of NPC and ABO blood groups. Materials and Methods: We retrospectively analyzed the files of 1136 pathologically confirmed patients with NPC and 1024 cancer-free healthy controls, including the information of serologically determined blood group. The distribution of blood groups between patients with NPC and the control group was determined. The Chi-square test was applied to assess the distribution of age, gender, smoking, family history, and ABO blood groups between the NPC and the controls. Pearson's correlation was performed to evaluate the correlation between ABO blood groups and clinical stages. Results: There was no significant difference in age, smoking, family history, and ABO blood group between patients with NPC and the control group (P > 0.05). ABO blood groups were also not associated with NPC stages (P = 0.506). However, the proportion of males with NPC was higher than that of control group (P < 0.01). Conclusion: The blood group types were not associated with increased risk of NPC and NPC stages in a population of Southern China. PMID- 29970654 TI - Comparison of the short-term clinical outcome between open and minimally invasive esophagectomy by comprehensive complication index. AB - Objective: Esophagectomies are associated with high mortality and various complications. Previous studies reported on the short-term outcomes were heterogeneous and inconsistent in comparing minimally invasive esophagectomy (MIE) with traditional open esophagectomy (OE). The objective of this study is to compare the short-term outcomes between MIE and OE calculated using Comprehensive Complication Index (CCI) which incorporates all complication severities. Materials and Methods: We did expertise-based randomized controlled trial from September 2014 to October 2015. A total of 144 patients with resectable cancer were randomly selected to be treated by OE or MIE. The CCI was calculated using the Clavien-Dindo classification grade of all postoperative complications collected. Demographic characteristics, preoperative clinical assessment, postoperative complications, and CCI of patients were compared between both groups. Results: Among the 144 patients included in this study, 97 underwent OE and 47 underwent MIE. Demographics, preoperative clinical assessment, and inpatient mortality in both cohorts were almost identical. Eighty-four patients (86.6%) of OE group and 26 patients (55.3%) of MIE group suffered from complications. A significant difference was observed in blood transfusion (P = 0.04), moderate and severe pain (P < 0.01), and diarrhea (P = 0.03) between two groups. There was an obvious statistical significance of CCI between OE and MIE groups (P = 0.036). Conclusions: The CCI is a promising scoring system that could be used to assess the severity of complications after esophagectomy. MIE could improve the short-term outcomes by reducing some mild and moderate complications. PMID- 29970655 TI - The diagnostic value of multi-slice spiral computed tomography in patients with renal carcinoma. AB - Objective: This study was aimed to investigate the characteristics of multi-slice spiral computed tomography (CT) image in kidney cancer patients and its clinical value in staging diagnosis of kidney cancer. Materials and Methods: This study included 57 patients who were confirmed as kidney cancer through postoperative pathological examination; they were diagnosed within February 2014 and December 2016 in our hospital. The data obtained from multi-slice spiral CT plain scan and contrast-enhanced CT of these patients was retrospectively analyzed. Moreover, we determined the characteristics of multi-slice spiral CT image for kidney cancer and analyzed their consistency with pathological staging. Results: CT plain scan showed that kidney lumps were mostly found in the prominent renal contour or renal parenchyma, and they were round-like or round in shape. Among the 57 included patients, the tumors of 43 cases showed regular edges, and 14 showed irregular edges. Among the 14 cases, 10 patients had tumors with lobulated edges and 5 with spinous tumor edge. Among all the 57 patients, CT plain scan showed there were 5 cases with slightly higher density, 24 cases with mixed density, 28 cases with equal density or slightly lower density. The range of tumor diameter was 2.1-12.6 cm; the tumor diameter was smaller than 3 cm in 11 cases, 3-7 cm in 34 cases, and larger than 7 cm in 12 cases. In terms of contrast enhancement, the arterial phase was obviously enhanced in 31 cases, moderately and irregularly enhanced in 18 cases, and slightly enhanced in 8 cases. Moreover, the renal parenchymal scan showed a rapid decline in the enhancement and a further decline in the enhancement of renal pelvic tumor; the three stages of enhancement could be expressed in terms of fast forwardness and fast backwardness. A total of 33, 4, 9, and 11 cases were classified as postoperative pathological Stage I, II, III, and IV, respectively; 35, 5, 7, and 10 cases were classified as CT scan Stage I, II, III, and IV, respectively; and 34, 5, 8, and 10 cases were classified as contrast-enhanced CT scan Stage I, II, III, and IV, respectively. No significant difference was observed in the frequency of CT scan, the enhanced stage and pathological stage (P > 0.05). Conclusion: CT image of kidney cancer revealed the morphological and enhanced features of this tumor. The consistency between CT stage and pathological stage was high; thus, this method can be applied as a forecasting method for pathological staging. PMID- 29970656 TI - The features and prognostic impact of extracranial metastases in patients with epidermal growth factor receptor-mutant lung adenocarcinoma. AB - Aims: We have previously demonstrated that brain metastases were more common among patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma. However, the association of EGFR mutation and extracranial metastases (ECM) remains inconclusive. In this study, we explored the potential association between EGFR mutation and the risk of ECM. Patients and Methods: Between March 2007 and December 2014, 234 patients were analyzed for the potential association between EGFR mutation and ECM. Statistical Analysis Used: Multivariate Cox regression analysis. Results: There were no associations between the EGFR mutation and metastases in different organs, except for bone. The frequency of EGFR mutation was statistically higher for patients with bone metastases (BMs) at the initial diagnosis (P = 0.039) and at the last follow-up (P = 0.018) as compared to those with wild-type EGFR. In multivariate logistic regression analysis, EGFR mutation significantly increased the risk of BM at the initial diagnosis (P = 0.036). Among those patients without BM at initial diagnosis, 1- and 2-year accumulative rates of subsequent BM were significantly higher in patients with EGFR-mutant disease (P = 0.026). EGFR mutation was an independent risk factor for subsequent BM (P < 0.05). In addition, patients with finial BM and EGFR-mutant disease had longer median survival as compared to those with wild-type disease (P = 0.020). Conclusions: Only BM in patients with ECM was significantly correlated with EGFR mutation during their disease course. EGFR mutation was an independent predictive and prognostic factor for developing BM, which was also a positive predictive factor for overall survival of patients who developed BM. PMID- 29970658 TI - Effect of low-frequency rotary magnetic fields on advanced gastric cancer: Survival and palliation of general symptoms. AB - Objective: The tumor inhibition by magnetic fields (MFs) has been reported in many in vivo and in vitro studies, while clinical trials have been rare. This report aimed to evaluate the improvement of survival and general symptoms in advanced cancer patients treated with MFs. Subjects and Methods: In this study, we investigated 21 patients with advanced gastric cancer (AGC) treated with 420 r/min, 0.4-T low-frequency rotary MFs. The treatment area encompassed the primary tumor sites, metastatic sites, and metastatic lymph nodes. In addition, the patients were treated 2 h per day, 5 days per week for 6-12 weeks. The toxicity pilot human study was approved by the competent ethical committee. Toxicity and side effects were assessed according to the WHO criteria. The changes of general symptoms were analyzed during low-frequency rotary MFs treatment and 2 weeks after the end of therapy. Electrocardiogram, chest X-ray, physical examination, blood cell count and complete blood chemistry, biochemical, and kidney function tests were performed before and after the end of the treatment. All 21 patients were followed up by outpatient service or telephone interview. Results: Our results demonstrated that low-frequency rotary MFs improved abdominal pain in 9/21 (42.9%), nausea/vomiting in 4/21 (19.0%), weight loss in 11/21 (52.4%), ongoing blood loss in 2/21 (9.5%), physical strength in 5/21 (23.8%), and sleep quality in 4/21 (19.0%) patients. No severe toxicity and side effect were observed in our trial. The median survival time was 8.0 months (95% confidence interval, 5.190-10.810). The 1-year survival rate was 25.8%. Conclusion: Low frequency rotary MFs may prolong survival and improve general symptom of AGC patients, as an effective, well-tolerated, and safe treatment choice. PMID- 29970657 TI - A meta-analysis of adoptive immunotherapy in postoperative hepatocellular carcinoma. AB - Background: Adoptive immunotherapy (AIT) has been adopted as an adjuvant treatment for hepatocellular carcinoma (HCC) patients after curative therapy. However, the outcomes of AIT remain controversial. Purpose: The purpose of this study is to analyze the safety and efficacy of AIT with the recurrence rate and mortality. Materials and Methods: We identified eight randomized controlled trials (RCTs) that adopted AIT to HCC after curative treatments. A meta-analysis was carried out to assess the recurrence rate and mortality. Results: Eight RCTs with 964 patients were included in the study. The overall analysis showed that AIT treatment can not only decrease the 1-year (risk ratio [RR] =0.59, 95% confidence interval [95% CI] = 0.48-0.72, P < 0.00001), 2-year (RR = 0.69, 95% CI = 0.60-0.79, P < 0.00001), and 3-year (RR = 0.82, 95% CI = 0.74-091, P = 0.0001) recurrence, but also decrease the 1-year (RR = 0.43, 95% CI = 0.30-0.62, P = 0.00001), 2-year (RR = 0.56, 95% CI = 0.46-0.74, P < 0.00001), and 3-year (RR = 0.85, 95% CI = 0.73-0.99, P = 0.03) mortality. The results also indicate that the group of lymphokine-activated killer (LAK) cells showed lower pooled RR values compared to the group of cytokine-induced killer cells among every subgroups. However, the AIT treatment failed to affect the 5-year recurrence rate and mortality (P > 0.05). Conclusions: This review provides available evidences that AIT, especially the treatment of LAK, can be used to decrease the early recurrence and mortality of postoperative HCC but may not the long term. PMID- 29970659 TI - Relationship between Vitamin D receptor gene polymorphism and renal cell carcinoma susceptibility. AB - Aim of Study: Results on the association of Vitamin D receptor (VDR) gene polymorphism with renal cell carcinoma (RCC) susceptibility from the present reports are still debating. This meta-analysis was conducted to assess the association of VDR ApaI (rs7975232), BsmI (rs1544410), TaqI (rs731236), and Fok1 (rs2228570) gene polymorphisms with RCC risk. Materials and Methods: The association studies were recruited from PubMed on May 1, 2016, and eligible reports were extracted and data were synthesized using meta-analysis method. Result: Six investigations were included into this meta-analysis for the relationship between VDR gene polymorphism and RCC susceptibility. In this meta analysis, the ApaI A allele, AA genotype, aa genotype, and Fok1 FF genotype were associated with RCC susceptibility in Asians. However, VDR BsmI and TaqI gene polymorphisms were not associated with the RCC risk in Asians, Caucasians, and overall populations. Furthermore, Fok1 gene polymorphism was not associated with the RCC risk in Caucasians and overall populations. Conclusion: ApaI gene polymorphism and Fok1 FF genotype were associated with RCC susceptibility in Asians. PMID- 29970660 TI - Investigating the risk factors of hepatocellular carcinoma and survival analysis for cirrhosis after transjugular intrahepatic portosystemic shunt in treating portal hypertension. AB - Objective: This study aimed to explore the risk factors of hepatocellular carcinoma (HCC) and survival analysis for cirrhosis after transjugular intrahepatic portosystemic shunt (TIPS) in treating portal hypertension. Materials and Methods: A retrospective database review was performed, including 106 patients (33 females and 73 males; aged 26-68 years with mean age of 55.3 +/- 9.1 years) who received TIPS for treating recurrent gastroesophageal variceal bleeding or refractory ascites with portal hypertension. All the patients were recruited from the Interventional Oncology Department at Beijing Ditan Hospital between October 2008 and December 2011. The TIPS was successfully performed on all involved patients by puncturing at the right branch of portal vein via right hepatic vein. After TIPS, the patients were consecutively followed up at the outpatient clinic. The patients were examined by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen every 3 months for 3 years, for detecting the occurrence of malignant nodules and early HCC. The post-TIPS medical database was reviewed with univariate and multivariate analysis to identify the risk factors for new nodules retrospectively. Results: The overall incidence of HCC was 38.7% (41/106). The multivariate analysis showed that an increased odds ratios (OR) of HCC was observed in the complication of portal hypertension (OR, 0.396; 95% confidence interval [CI], 0.171-0.918; P = 0.031) and preoperative cirrhosis classification (OR, 0.060; 95% CI, 0.021-0.175; P = 0.000). P < 0.05was considered statistically significant. After TIPS, the cumulative probabilities of survival time for patients with cirrhosis at 1, 2, and 3 years were 100%, 68%, and 61%, respectively (log rank test, P = 0.18). The cumulative incidence of new nodules was significantly lower among patients with refractory ascites than those with upper gastrointestinal hemorrhage. Specifically, the survival rates of patients with upper gastrointestinal hemorrhage at years 1, 2, and 3 were 100%, 65%, and 51%, respectively, compared to 100%, 88%, and 85% corresponding to patients with refractory ascites (P = 0.009). The cumulative incidence of HCC was significantly lower in cirrhosis patients with CT identified grade III than those with grade IV. At years 1, 2, and 3, the survival rates of cirrhosis patients with CT identified grade IV were 96%, 22%, and 20%, respectively, compared to 100%, 98%, and 90% in controls (P = 0.012). Conclusions: The identification of clinical variables associated with increased risks of HCC may be useful for selecting appropriate candidates for TIPS. Results suggested that the patients with cirrhosis of CT identified grade IV and with upper gastrointestinal hemorrhage might be relevant to increased odds of HCC after TIPS. PMID- 29970661 TI - A differential expression network method identifies ankylosing spondylitis related genes. AB - Background: The exact pathogenic mechanism of ankylosing spondylitis (AS) is still unclear. Objective: we aimed to screen key genes associated with AS using differential expression network (DEN), and further to reveal the molecular mechanism of AS. Materials and Methods: First, the gene expression data of AS were recruited and preprocessed. Meanwhile, differentially expressed genes (DEGs) were identified. Then, the DEN including the differential interactions and the nondifferential interactions were constructed, and the hub genes were determined according to degree centrality analysis of nodes. Finally, pathway enrichment analysis was conducted on these genes contained in the DEN to further to determine the importance of the hub genes. Results: A total of 20,102 genes were obtained and 145 DEGs which including 99 upregulated genes and 46 downregulated genes were identified. Then, a DEN which contained 434 differential interactions and 2 nondifferential interactions were constructed. In the following, four hub genes which were USP7, hepatoma-derived growth factor, EP300, and split hand/foot malformation type 1 (SHFM1) were screened out. None of them was DEGs. Finally, the hub genes of EP300 and SHFM1 were enriched in the pathways of prostate cancer and adherens junction and proteasome pathway, respectively. Conclusions: Compared to the traditional differential genes methods, DEN is a more useful and comprehensive method to conduct on the AS. We predict that these genes (such as EP300 and SHFM1) could be chosen as novel predictive markers for AS. PMID- 29970662 TI - Post-transcriptional regulation DPC4 gene by miR-190 in colorectal cancer cells. AB - Objective: The objective of this study is to elucidate the regulation of the DPC4 gene by miR-190 in colorectal cancer (CRC) cells. The present study was undertaken to determine whether the DPC4 gene is a target gene of miRNA-190, identify target motifs and to elucidate the mechanism of regulation of DPC4 by miRNA-190. Materials and Methods: MiR-190 and DPC4 expression were measured in five different CRC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The regulation of DPC4 by miR-190 was evaluated by qRT-PCR, Western blotting, and luciferase reporter assays in the human CRC cell line HT-29 after treatment with miR-190 mimics and inhibitors. Results: The DPC4 mRNA, miR-, and DPC4 protein expression levels were highest in LS174T cells while lowest in SW480 and SW620 cells. The DPC4/miR-190 ratio in the HT-29 cancer cell line was the largest. MiR-190 expression increased dramatically after treatment with miR-190 mimics and decreased significantly after treatment with miR-190 inhibitors. DPC4 protein expression decreased in the miR-190 mimics transfection group when compared to the negative control (N.C.) group and increased in the miR 190 inhibitor groups when compared to the inhibitor plus N.C. group. MiR-190 inhibits the relative luciferase activity of psiCHECK-2TM vector-3'UTR compared to the N.C. group, while miR-190 had no obvious effect on the relative luciferase activity of the psiCHECK-2TM vector-3'UTRmut and psiCHECK-2TM vector transfected cells. Conclusions: The DPC4 gene might be the target gene of miR-190, which may negatively regulate the DPC4 gene in human CRC cells by translational suppression rather than mRNA degradation. PMID- 29970663 TI - Promotion of Insulin-like growth factor II in cell proliferation and epithelial mesenchymal transition in hepatocellular carcinoma. AB - Aim: This study aims to investigate the involvement of insulin-like growth factor II (IGF-II) in human hepatocellular carcinoma (HCC) proliferation and metastasis. Materials and Methods: The effects of IGF-II on cell proliferation, cell cycle, apoptosis, cell migration, and invasion in HCC Huh7 cells were investigated in the study. Results: IGF-II promoted cell proliferation and colony formation, suppressed cell apoptosis in Huh7 cells by promoting cell cycle progression, induced epithelial-mesenchymal transition (EMT) phenotypes, and enhanced the metastatic potential of HCC in vitro. Conclusion: Our results revealed that IGF II promotes cell proliferation and EMT in HCC cells. PMID- 29970664 TI - Promoter methylation of human mutL homolog 1 and colorectal cancer risk: A meta analysis. AB - Aims: Several studies suggested that promoter methylation of human mutL homolog 1 (hMLH1) was associated with the risk of colorectal cancer (CRC). However, other studies did not indicate the same results. To derive a more comprehensive estimation of the association between hMLH1 methylation and CRC risk, we conducted a meta-analysis. Materials and Methods: We searched in the PubMed, EMBASE, and WanFang Medicine databases. The strength of the associations was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Results: A total of 47 studies with 4296 cases and 2827 controls were included. A statistically significant association between hMLH1 methylation and CRC risk was found (OR = 9.25; 95% CI, 5.65-15.53; P < 0.001). The heterogeneity was significant (P < 0.001). In the subgroup analysis of race, Asian and Caucasian with hMLH1 methylation had increased CRC risk (OR = 12.19; 95% CI, 7.02-23.42; P < 0.001 and OR = 6.38; 95% CI, 2.17-19.64; P < 0.001). In the subgroup analysis of sample source, only the sample from tissue showed increased CRC risk (OR = 10.46; 95% CI, 6.12-17.90; P < 0.001). The Egger's test did not find publication bias (P = 0.176). Conclusions: In conclusion, this meta-analysis suggested that hMLH1 methylation was associated with an increased CRC risk. PMID- 29970666 TI - Expression level of long noncoding RNA H19 in plasma of patients with nonsmall cell lung cancer and its clinical significance. AB - Objective: This study was aimed to explore the expression level of long noncoding RNA H19 in the plasma of patients with nonsmall cell lung cancer (NSCLC) and its clinical significance. Methods: A total of 66 NSCLC patients (case group) and 31 patients with benign lung disease (control group) admitted from February 2015 to February 2017 were included in this study. Real-time polymerase chain reaction assay was applied to examine the relative expression level of long noncoding RNA H19 in the plasma of the two groups. The relationship between H19 expression and clinical, pathological features was explored. Receiver-operating characteristic (ROC) curve was applied to evaluate the clinical value of plasma H19 as a tumor marker in the auxiliary diagnosis of NSCLC. Results: The relative expression levels of plasma H19 inpatients from NSCLC group and benign lung disease group were 5.62 +/- 2.02 (DeltaCt) and 7.74 +/- 2.75 (DeltaCt), respectively. The NSCLC group presented with significantly higher levels than that of the benign disease group (P < 0.05). According to the median of relative expression level of 5.54, the plasma H19 of NSCLC patients was classified into low expression group >=5.54 (n = 34) and high expression group <5.52 (n = 32). The relationship between the patients' clinical, pathological features, and the expression level of H19 was analyzed. The expression of H19 was not significantly correlated with the gender, age, clinical staging, tumor diameter, and pathological type of the patients (Pall > 0.05). With the serum H19 as a diagnosis reference, the diagnostic sensitivity of NSCLC was 67.74%, and the specificity was 63.08%. The area under the ROC curve was 0.73, and the diagnostic cutoff value was 6.62. Conclusion: Plasma level of H19 in NSCLC patients was significantly increased, which could be applied as a serological marker for the auxiliary diagnosis of NSCLC. PMID- 29970665 TI - Expression of fascin_1 protein in cancer tissues of patients with nonsmall cell lung cancer and its relevance to patients' clinicopathologic features and prognosis. AB - Objective: The aim of this study is to explore the expression of Fascin_1 protein in cancer tissues of patients with nonsmall cell lung cancer (NSCLC) and its relevance to patients' clinicopathologic features and prognosis. Methods: Retrospective analysis was performed on 81 patients with NSCLC who were admitted to our hospital and received surgical treatment from February 2012 to March 2016. To analyze the correlation of Fascin_1 protein expression in cancer tissues with the clinicopathologic features and prognosis of the patients, the immuno histochemical method was applied to examine Fascin_1 protein expression in cancer and normal paracarcinoma tissues of the included 81 NSCLC patients. Results: Fascin_1 protein was diffused in cancer tissues, and cancer cells surrounding the carcinoma lesions were strongly stained. The protein was mainly located on the cytoplast or membrane of positive cells and manifested as a focal or diffuse brown granular distribution. The negative, weakly positive, and strongly positive expression rates in cancer tissues were 23.5% (19/81), 35.8% (29/81), and 40.7% (33/81), respectively. The negative, weakly positive, and strongly positive expression rates in paracarcinoma tissues were 71.6% (58/81), 12.3% (10/81), and 16% (13/81), respectively. The difference was statistically significant (P < 0.05), and the positive expression rate of Fascin_1 in cancer tissues was significantly higher than that of in paracarcinoma tissues (P < 0.05). The positive expression of Fascin_1 in cancer tissues was significantly correlated with the neoplasm stage (P < 0.05) and mediastinal lymph node metastases (P < 0.05); however, it was not relevant to the patients' age, gender, tumor size, pathological type, tumor grading, or pleural effusion (P > 0.05). The median survival times for patients with positive Fascin_1 and negative Fascin_1 expression in cancer tissues were 26 and 44 months, respectively, indicating that the median survival time of the Fascin_1-positive group was significantly lower than that of in the Fascin_1-negative group (heart rate = 2.74, 95% confidence interval: 1.32-6.87, P < 0.05). Conclusions: Fascin_1 protein expression in NSCLC tissues and normal paracarcinoma issues were different. Fascin_1 expression in cancer tissues was related to the poor prognosis of NSCLC patients. PMID- 29970667 TI - Urine PCA3 mRNA level in diagnostic of prostate cancer. AB - Objective: The objective of this study is to evaluate the diagnostic effects of urine PCA3 mRNA level in patients with prostate cancer (PC). Methods: Twenty four patients with pathologically confirmed PC, 40 patients with benign prostatic hyperplasia (BPH), and 13 patients with urolithiasis were recruited in this study. The urine level of PCA3 mRNA was determined with real-time polymerase chain reaction and compared among the three groups. With the reference parameter of urine PCA3 mRNA, the diagnostic sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. Results: The mRNA level in urine of PC, BPH and urolithiasis were 60.2 +/- 32.2, 17.1 +/- 12.9, and 6.2 +/- 3.1, respectively, indicating that mRNA level in PC was significantly higher than that of in other two groups (P < 0.05). The AUC was 0.90 while the sensitivity and specificity were 87.5% and 79.2% with the cutoff value of 33.86. Conclusion: The urine PCA3 mRNA could be a biomarker for diagnosing patients with PC. PMID- 29970668 TI - Increased expression of epidermal growth factor-like domain-containing protein 7 is predictive of poor prognosis in patients with hepatocellular carcinoma. AB - Objective: Epidermal growth factor-like domain-containing protein 7 (EGFL7) is an endothelial cell-derived secreted factor that regulates vascular tube formation. In human cancer, the specificity of expression is lost as EGFL7 has been detected in tumor cells, in addition to endothelial cells. This study evaluated the intricate relationship between hypoxia-inducible factor 1-alpha (HIF-1alpha) and EGFL7 under both hyperoxia and hypoxia states. Materials and Methods: In the present study, immunohistochemical staining and ELISA were applied to examine the relative level of EGFL7 in 182 cases of hepatocellular carcinoma (HCC) formalin fixed and paraffin-embedded tissues and 110 cases of HCC serum samples. Quantitative polymerase chain reaction and Western blotting were applied to verify the correlation between serum EGFL7 level and anoxic microenvironment. Immunohistochemical staining was performed to determine the correlation between EGFL7 and HIF1-alpha. Results: The correlations between EGFL7 expression and patients' age, tumor size, gender, N-stage, history of cirrhosis, M-stage, history of hepatitis C, and history of hepatitis B were statistically insignificant (P = 0.28, 0.34, 0.71, 0.15, 0.8, 0.2, 0.052, and 0.14, respectively). High level of EGFL7 was significantly correlated with overall survival as well as disease-free survival in 182 HCC patients (P = 0.0016 and P < 0.001, respectively). The correlations between serum EGFL7 and vascular invasion and extrahepatic metastasis were statistically significant (P < 0.0001). Among the 35 HIF1-alpha-positive HCC patients, 69% were medium positive and 31% were strong positive. EGFL7 protein expression level was oxygen dependent in HCC line (P < 0.05). Conclusions: EGFL7 was found to be a potential predictor for HCC survival and metastasis state; EGFL7 may be a promising biomarker and therapeutic target in human HCC. PMID- 29970669 TI - Association between leptin level and renal cell carcinoma susceptibility and progression: A meta-analysis. AB - Objectives: It is well-documented that obesity participated in the development of renal cell carcinoma (RCC). Leptin is closely associated with obesity. This study is aimed to investigate the relationship between leptin level and RCC susceptibility and progression. Methods: A meta-analysis was conducted to explore the association between leptin level and RCC susceptibility and progression. The studies were retrieved from electronic databases during January 1990-September 2017 with keywords. The qualified studies were screened with inclusion and exclusion criteria. A random effects model was applied to calculate the pooled standard mean differences and the corresponding confidence intervals. Results: Ten studies were finally included in this meta-analysis. The serum leptin level in male RCC was significantly lower than that of in female RCC in overall populations, Asians, and Caucasians while no marked difference was noted between genders in the plasma samples. Plasma leptin level in Stage I-II RCC was significantly higher than that in the Stage III-IV. In addition, no significant difference was observed between following parameters, including RCC and non-RCC, clear and non-clear RCC, Grade I-II and Grade III-IV RCC, M0 and M1 RCC, N0 and N1 RCC, and size <4 cm and size >4 cm RCC. No evidence of publication bias was observed. Conclusions: Our findings indicated that serum leptin level was lower in men with RCC than in women with RCC. Leptin level may not be related to the risk and progression of RCC. However, more studies should be performed in the future. PMID- 29970670 TI - ATP7B rs9535826 is associated with gastrointestinal toxicity of platinum-based chemotherapy in nonsmall cell lung cancer patients. AB - Aims: Platinum-based chemotherapy is considered as the first-line treatment for nonsmall cell lung cancer (NSCLC) patients. However, platinum resistance and toxicity are major obstacles to its clinical applications. The two P-type ATPases ATP7A and ATP7B have been identified to play an essential role in the transport of platinum. Their genetic polymorphisms may affect the treatment outcome and toxicity of platinum. In this study, we aimed to investigate the association of ATP7A and ATP7B genetic polymorphisms with clinical outcome and toxicity of platinum-based chemotherapy in NSCLC patients. Subjects and Methods: Four hundred and twenty-seven NSCLC patients were enrolled. All patients have accepted platinum-based chemotherapy for at least two cycles. ATP7A (rs2227291 and rs6622665) and ATP7B (rs1061472 and rs9535826) polymorphisms were genotyped by allele-specific matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Chemotherapeutic response, overall survival time, and hematological and gastrointestinal toxicity were recorded and their associations with genetic factors were evaluated. Results: ATP7A rs2227291 and rs6622665 deviated from Hardy-Weinberg equilibrium. Therefore, the two single-nucleotide polymorphisms were not taken into consideration. For ATP7B polymorphism, ATP7B rs9535826 was associated with gastrointestinal toxicity, and the GG genotype showed lower gastrointestinal toxicity (odds ratio = 0.30; 95% confidence interval = 0.10 0.90; P = 0.031). Conclusion: The genotypes of ATP7B gene may be novel and significant biomarkers for predicting the gastrointestinal toxicity of platinum based chemotherapy in NSCLC patients. PMID- 29970671 TI - Clinical application of electrocardiogram-guided tip positioning in peripheral inserted central catheters placement. AB - Objective: The objective of the study was to perform the control study between the electrocardiogram (ECG)-guided tip positioning and traditional radiological confirmation method in peripherally inserted central catheters (PICC) placement; the accuracy and applicability of ECG-guided tip positioning were investigated. It aimed to expand the scope of PICC applications. Methods: From March 2016 to August 2017, 101 cases of patient with tumor admitted to the hospital were included in this study. The control study was performed before and after PICC placement. The tip positioning of PICC placement was performed under the guidance of bedside ECG system. The X-ray confirmation was applied for confirmation. Several parameters were observed, including positioning accuracy, success rate of primary catheterization, incidence of ectopic catheter, average catheterization time, and incidence of complications. Results: Position accuracy was 100%. The success rate of primary catheterization was 99%. The incidence of ectopic catheter was 1%. Average catheterization time was (49.59 +/- 21.45) min. Incidence of postoperative complications within 1 week was 4%. Conclusion: ECG guided PICC tip positioning was safe and accurate. Success rate of catheterization could be improved. ECG-guided PICC tip positioning can be applied as an alternative approach for patients with P-wave fluctuations. PMID- 29970672 TI - Expression of CD133 protein in osteosarcoma and its relationship with the clinicopathological features and prognosis. AB - Objective: The objective of this study is to evaluate the association between expression of CD133 protein and the clinicopathological features of patients with osteosarcoma. Methods: This study retrospectively analyzed 28 cases of osteosarcoma in our hospital from 2007 to 2016, as well as 21 cases of osteochondroma in the same period as control group. The expression of CD133 protein in paraffin specimens of two groups of patients was detected with immunohistochemistry SP assay. Results: CD133-positive staining was observed in the cytoplasm or cell membrane. The positive rate of CD133 protein expression in osteosarcoma tissue was significantly higher than that of in osteochondroma (60.7% vs. 19.0%), with statistically significant difference (P < 0.01). The patients of osteosarcoma were followed up for 11-94 months, and the median survival time was 47 months. During follow-up period, there were 16 cases of lung, spine, or retroperitoneal metastasis. At the end of the follow-up, 15 cases were dead and 13 cases were still alive. Distant metastasis and Enneking staging were significantly correlated with CD133-positive expression in osteosarcoma patients (P < 0.05), and the proportion of CD133-positive expression was high in both distant metastasis and Enneking staging. The median disease-free survival time was 21 and 32 months for CD133-positive and CD133-negative expression patients with osteosarcoma, respectively, with statistically significant difference (P < 0.05). However, the median survival time of the CD133-positive and CD133-negative expression groups was 46 and 49 months, without statistically significant difference (P > 0.05). Conclusion: The expression of CD133 protein in patients with osteosarcoma was significantly high and related to the distant metastasis, which may be a potential prediction biomarker for poor prognosis of osteosarcoma patients. PMID- 29970674 TI - Republished: Identifying key genes in retinoblastoma by comparing classifications of several kinds of significant genes. AB - [This corrects the article DOI: 10.4103/0973-1482.180678]. PMID- 29970673 TI - Using 18F-fluorodeoxyglucose positron emission tomography/computed tomography to estimate the length of gross tumor and involvement of lymph nodes in esophagogastric junction carcinoma. AB - Objective: To determine the optimal approach for estimating the length of gross tumor and involvement of the lymph nodes with 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in esophagogastric junction carcinoma (EGJC). The result was verified with pathologic examination. Materials and Methods: Twenty patients with diagnosed and untreated EGJC were enrolled. The length of the gross tumor was measured using different approaches with PET/CT: Standardized uptake value (SUV) 1.5-5.5 in intervals of 1.0 and 10% 50% of maximum SUV (SUVmax) on 18F-FDG PET/CT in intervals of 10%. The results were expressed as L1.0-L5.0, and L10%-L50%, respectively. The pathological length of gross tumor (Lpath) was calculated based on the shrinkage ratio of primary tumor. The measurable lymph nodes were measured on PET/CT preoperatively, labeled during operation, and examined for pathology. Results: Lpath was 6.87 +/- 2.25 cm, L30% and L2.5 were 6.61 +/- 1.76 cm and 7.56 +/- 1.89 cm, respectively. L30% was closer to Lpath than other % SUVmax, L2.5 was closer to Lpath than other absolute SUV thresholds. The diagnostic performance of 18F-FDG PET/CT for lymph nodes was best at the cutoff SUV of 2.7, providing sensitivity of 70% and a specificity of 83.7% for detecting lymph node metastases. Conclusions: The tumor length with 30% SUVmax as the threshold was closest to the actual pathological length of EGJC. The diagnostic efficiency of 18F-FDG PET/CT was best at the cutoff SUVmax of 2.7 for detecting lymph node metastases in EGJC. PMID- 29970675 TI - Triptolide: A new star for treating human malignancies. AB - In recent years, cancer has become the most common human disease worldwide, and great attentions have been paid to clarifying the carcinogenesis and identifying new effective antitumor therapy. Although great progress has been made in this research field, human malignant diseases could still not be radically cured. Thunder god vine is a herbal medicine, which has proved to exert efficient antitumor activity in various human cancers such as lung cancer, pancreatic cancer, and colon cancer. In vivo and in vitro experiments showed that thunder god vine extract triptolide could inhibit tumor cell proliferation, cell migration, and cell invasion. Here, we overviewed the functional role of triptolide in human malignancies and its promising therapeutic potential in treating such deadly diseases. PMID- 29970676 TI - The effect of TGF-beta signaling on regulating proliferation of uterine leiomyoma cell via ERalpha signaling activated by bisphenol A, octylphenol and nonylphenol in vitro. AB - Objectives: To study the transforming growth factor beta (TGF-beta) signaling pathway in interactions with estrogen receptor alpha (ERalpha) signaling pathway mediating the growth of human uterine leiomyoma (UL) activated by phenolic environmental estrogens (EEs). Methods: The subcultured UL cells were used to determine the validation of TGF-beta3 for the viability of human UL cells using CCK-8 assay, mRNA expressions of ERalpha, and c-fos by quantitative reverse transcription polymerase chain reaction method, and expressions of p-Smad3, SnoN, and c-fos proteins by Western blot assay in each treatment group. Results: Compared with each of EEs or TGF-beta3 treatment, slightly decrease in the proliferation rate of UL was detected in the coexistence of each EE with TGF beta3. Interestingly, mRNA expressions of ERalpha and c-fos reduced in the setting of coexistence of TGF-beta3 and EEs. Somehow, the expression of p-Smad3 and c-fos proteins significantly decreased in each of E2, bisphenol A (BPA), nonylphenol (NP), and octylphenol (OP) group, as well as the expression of SnoN protein significantly reduced only in BPA and NP groups, followed by TGF-beta3 treatment. With the overlaid action of ICI 182,780, the expression of p-Smad3 protein significantly increased in OP group, but slightly increased in E2, BPA, NP, and OP groups. However, compared with the control group, the expression of SnoN and c-fos proteins significantly decreased in the same setting. Conclusion: Both ERalpha signaling pathway and TGF-beta signaling pathway have different roles in governing UL cell proliferation. The phenolic EEs can be a promoter to the proliferation of UL cells, which is mediated by ERalpha signaling pathway and cross-talked with TGF-beta signaling pathway. PMID- 29970677 TI - Myeloperoxidase -463 G/A polymorphism is associated with lung cancer risk: A meta analysis with 7420 cases and 9132 controls. AB - Aims: Several studies evaluated the association between myeloperoxidase (MPO) 463 G/A polymorphism and the risk of lung cancer. However, the results were not stable. Materials and Methods: Online electronic databases (PubMed, EMBASE, and Wanfang database) were searched. The strength of association between the MPO -463 G/A polymorphism and lung cancer risk was assessed by calculating odds ratios (OR) with 95% confidence interval (CI). Results: A total of 22 studies with 7420 cases and 9132 controls on the association between MPO -463 G/A polymorphism and lung cancer risk were included for this meta-analysis. MPO -463 G/A polymorphism was associated with a significantly decreased risk of lung cancer (OR = 0.91; 95% CI: 0.85-0.98; I 2 = 25%). In the race subgroup analysis, Asians with MPO -463 G/A polymorphism had decreased lung cancer risk (OR = 0.81; 95% CI: 0.70-0.93; I 2 = 0%). However, Caucasians did not show significant result (OR = 0.93; 95% CI: 0.86-1.02; I 2 = 36%). In the subgroup analysis according to source of control, both population-based studies and hospital-based studies were marginally significantly associated with decreased risk of lung cancer (OR = 0.90; 95% CI: 0.82-1.00; I 2 = 41% and OR = 0.91; 95% CI: 0.82-1.01; I 2 = 0%). Conclusion: The present meta-analysis suggested that the MPO -463 G/A polymorphism carriers had a protective role in lung cancer. PMID- 29970678 TI - The total number of lymph nodes harvested from pathological T3N0 rectal cancer patients: Prognostic significance and potential indication for postoperative radiotherapy. AB - Background: Lymph node status is important in staging colorectal cancer. The use of combination treatment for pathological T3N0 (pT3N0) rectal cancer patients has been controversial. We aimed to explore the prognostic significance of the total number of lymph nodes harvested from pT3N0 rectal cancer patients. Methods: Between June 2004 and November 2011, 289 pT3N0 rectal cancer patients who received total mesorectal excision (TME) with or without postoperative chemotherapy were retrospectively reviewed. The main independent variable was the total number of harvested lymph nodes, and the endpoints included local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS). Results: The patients had a median of 13 lymph nodes harvested. When compared with patients who had < 12 lymph nodes harvested, patients who had >=12 lymph nodes harvested had higher 5-year LRFS (84.7% vs. 98.0%, P < 0.001), DFS (71.4% vs. 86.8%, P < 0.001), and OS (77.6% vs. 94.9%, P < 0.001) rates. Multivariate analysis demonstrated that the patients who had >=12 lymph nodes harvested had a significantly lower risks of local relapse (hazard ratio [HR], 0.099; P < 0.001), treatment failure (HR: 0.291; P < 0.001), and death (HR: 0.231; P < 0.001) when compared with patients who had <12 lymph nodes harvested. Conclusions: The number of lymph nodes harvested was independently associated with local relapse, treatment failure, and OS rates in pT3N0 rectal cancer patients who received initial TME with or without postoperative chemotherapy. Postoperative radiotherapy should not be omitted for pT3N0 rectal cancer patients who had <12 lymph nodes harvested. PMID- 29970679 TI - Expression of microRNAs-106b in nonsmall cell lung cancer. AB - Aim: To explore the expression of microRNA-106b (miRNA-106b) in nonsmall cell lung cancer (NSCLC). Settings and Design: miRNAs are short regulatory RNAs that negatively modulate gene expression at the posttranscriptional level, and are deeply involved in the pathogenesis of several types of cancer. miRNA-106b has been shown to play an oncogenic role in tumor progression. The expression of miRNA-106b is detected in this study. Subjects and Methods: Quantitative reverse transcription polymerase chain reaction and Northern blotting were used to detect the expression level of miRNA-106b in 200 NSCLC samples. Statistical Analysis Used: All statistical analyses were performed using SPSS 16.0 software. Results were statistically evaluated using the Kruskal-Wallis test and Mann-Whitney U test. Survival curves were estimated by the Kaplan-Meier method and P < 0.05 was considered to be statistically significant. Results: miRNA-106b expression is increased in NSCLC tissues. Statistical analysis showed that overexpression of miRNA-106b was strongly associated with lymph node metastasis, stage of tumor node metastasis classification, and poor prognosis. Moreover, there was a significant difference in the miRNA-106b expression levels between smoking and nonsmoking patients. Multivariate Cox regression analysis showed that miRNA-106b was an independent prognostic factor for NSCLC patients. Conclusions: These data suggest that aberrantly expressed miRNA-106b may contribute to the development of NSCLC. PMID- 29970680 TI - Association between polymorphisms of interleukin-17A G197A and interleukin-17F A7488G and risk of colorectal cancer. AB - Background: Interleukin (IL)-17A and IL-17F are inflammatory cytokines mainly produced by T helper 17 cells. IL-17A is known to be protumorigenic while IL-17F has a protective role in cancer. A number of studies have been conducted to determine the association between polymorphisms of IL-17AG197A (rs2275913) and IL 17FA7488G (rs763780) and risk of cancers. No studies have yet to be conducted to genotype the IL-17AG197A polymorphism in colorectal cancer (CRC). Objective: To assess the association of IL-17AG197A and IL-17FA7488G polymorphisms with CRC risk. Materials and Methods: We performed the genotyping by polymerase chain reaction-restriction fragment length polymorphism method on blood samples from 80 healthy individuals and paraffin-embedded tumor tissues from 70 CRC patients. Results: Our study showed that IL-17A197AA genotype was significantly associated with an increased CRC risk with odds ratios of 6.08 (95% confidence interval [CI]: 2.25-16.42, P < 0.001) and 2.80 (95% CI: 1.23-6.35, P = 0.014), in comparison with GG and AG genotypes, respectively. However, IL-17FA7488G polymorphism was not significantly associated with CRC risk (P = 0.102). No significant association of IL-17AG197A and IL-17FA7488G polymorphisms with patient and tumor variables was found. Conclusion: This report from Malaysia shows the relationship of IL-17A197AA genotype with susceptibility to CRC. PMID- 29970681 TI - Peroxisome proliferators-activated receptor gamma polymorphisms and colorectal cancer risk. AB - Aims: Several studies evaluated the association between peroxisome proliferators activated receptor gamma (PPARgamma) Pro12Ala (rs1801282), and His477His (rs3856806) polymorphisms and the risk of colorectal cancer (CRC). However, the results were not stable. Materials and Methods: We searched databases containing PubMed and EMBASE. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the associations. Results: A significantly decreased CRC risk was found for PPARgamma Pro12Ala polymorphism (OR = 0.88, 95% CI 0.83-0.94, P < 0.0001). In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.89, 95% CI 0.83 0.95, P = 0.0003) but not in Asian population (OR = 0.76, 95% CI 0.57-1.02, P = 0.07). In the subgroup analysis by CRC location, significantly decreased risks were found in rectal cancer (OR = 0.88, 95% CI 0.77-1.00, P = 0.05) and colon cancer (OR = 0.82, 95% CI 0.73-0.92, P = 0.0008). In addition, a significantly decreased CRC risk was also detected for PPARgamma His477His polymorphism (OR = 0.66, 95% CI 0.44-1.00, P = 0.05). In the subgroup analysis by race, a significantly decreased risk was found in the Caucasian population (OR = 0.43, 95% CI 0.26-0.69, P = 0.0006) but not in Asian population (OR = 0.95, 95% CI 0.73 1.25, P = 0.72). Conclusions: PPARgamma Pro12Ala and His477His polymorphisms might be associated with susceptibility of CRC. PMID- 29970682 TI - Human epidermal growth factor receptor 2 expressions and Janus-activated kinase/signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 pathway may be associated with clinicopathological features and prognosis of gastric cancer. AB - Objective: Our study aims to investigate the expression of human epidermal growth factor receptor 2 (HER-2), Janus-activated kinase/signal transducer, and activator of transcription 3-suppressor of cytokine signaling 3 (JAK/STAT3-SOCS3) pathway in gastric cancer (GC) and its relationship with clinicopathological features and prognosis of GC. Materials and Methods: A total of 105 GC patients who underwent surgical resection were enrolled for our study, and corresponding 60 normal tissues adjacent to carcinoma (>10 cm from the carcinoma tissues) as control groups. Spearman correlation analysis was applied for correlation analysis among HER-2, STAT3, and SOCS3. Kaplan-Meier method and Cox proportional hazard model were applied for investigating the associations among HER-2, STAT3 and SOCS3 expressions and prognosis of GC patients. Results: The expressions of HER-2 and STAT3 in GC tissues were increased, but SOCS3 expression showed an evident decrease with the change of depth of invasion, lymph node metastasis (LNM), and tumor node metastasis staging (all P < 0.05). The result of Spearman correlation analysis showed a positive correlation between HER-2 and STAT3 (r = 0.216, P < 0.05), while a negative correlation was observed between STAT3 and SOCS3 (r = -0.237, P < 0.05). Kaplan-Meier analysis results showed that the survival time of HER-2 and STAT3 negative group were both higher than their positive group (both P < 0.001), nevertheless, the survival time of SOCS3 negative group was lower than positive group (P < 0.001). Cox regression multivariate analysis indicated HER-2, STAT3, SOCS3, LNM, and depth of invasion were independent prognostic factors influenced the prognosis of GC (all P < 0.001). Conclusion: Our study revealed that HER-2 may participates in the development, invasion and metastasis of GC by affecting the JAK/STAT3 pathway. HER-2, STAT3, and SOCS3 serve as reference indexes for the prognosis of GC patients. PMID- 29970683 TI - Ultrasonography is valuable in evaluation of papillary thyroid microcarcinoma based on 5 mm tumor size. AB - Introduction: Fine-needle aspiration was once done in suspected malignant thyroid nodules more than 5 mm in diameter. Five millimeter has been applied in many studies as the cut off tumor size in recent years. In this study, we would like to analyze the clinicopathological and ultrasonographic features of papillary thyroid microcarcinoma (PTMC) <=5 mm and >5 mm with the aim of finding out the diagnostic value of ultrasonography. Subjects and Methods: A total of 291 patients from January 2012 to October 2014 who underwent an ultrasound examination and were postoperatively diagnosed as PTMC were enrolled in the study. The patients were divided into Group A (<=5 mm) and Group B (>5 mm, <=10 mm) based on diameter. The clinicopathological and ultrasonographic features of the two groups were statistically analyzed. Results: In total, 291 thyroid tumors were analyzed in 291 patients. In patients who were identified with multiple tumors, the largest nodule in size was used for analysis. PTMC >5 mm in diameter were found with a higher incidence of lymph node metastasis and advanced tumor node-metastasis (TNM) Stage (III/IV) with a significant difference, also with a larger part of multiple tumors compared to PTMC <5 mm. Of all the ultrasonographic features studied, calcification and peripheral halo were more significantly correlated with PTMC >5 mm. The presence of vascularity and blood supply were both associated with the tumor size. Conclusion: Larger tumor size of PTMC is more likely to involve in lymph node metastasis and advanced TNM stage. Correlation of tumor size with calcification, peripheral halo, vascularity, and blood supply do exist in PTMC. Ultrasound is of great value in the evaluation of PTMC. PMID- 29970684 TI - Synergistic effect of thymoquinone and melatonin against breast cancer implanted in mice. AB - Aim: To test the anticancer potential of a combination of thymoquinone (TQ) and melatonin (MLT) against breast cancer implanted in mice. Materials and Methods: The antiproliferative activity of TQ, MLT, and their combination was tested against mouse epithelial breast cancer cell line (EMT6/P) using 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The combination index (CI) was calculated using isobolographic method. Balb/C mice were transplanted with EMT6/P cell line and in vivo antitumor activity was assessed for TQ, MLT, and their combination. Changes in tumor size were measured for each treatment. Histological examination of tumor sections was performed using standard hematoxylin/eosin staining protocol and TUNEL colorimetric assay was used to test the apoptosis induction ability for all treatments. Immunohistochemical staining was used to detect vascular endothelial growth factor (VEGF) expression in tumor section and ELISA was used to measure serum levels of interferon gamma (INF-gamma) and interleukin-4. Serum levels of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were used as biomarkers of hepatotoxicity of the combination therapy. Results: Synergistic anticancer effect was observed between TQ and MLT with CI value of 0.552. The combination of TQ and MLT caused a significant decrease in tumor size with a percentage cure of 60%. The combination therapy induced extensive necrosis, increased apoptosis rate, and decreased VEGF expression in tumor sections. Serum levels of INF-gamma were increased in mice treated with combination therapy and AST and ALT levels were close to their normal values. Conclusions: The combination TQ and MLT act synergistically to inhibit breast cancer implanted in mice. The anticancer effect of this combination is mediated by induction of apoptosis, angiogenesis inhibition, and activation of T helper 1 anticancer immune response. PMID- 29970685 TI - The detection and significance of T cells in nasopharyngeal carcinoma patients. AB - Aim of Study: Nasopharyngeal carcinoma (NPC) is by far the most common malignant tumor of the nasopharynx and is suggested to be related to immune system dysfunction. T cells play a central role in the cell-mediated immunity. However, how the T cells vary during the NPC treatment is still unclear. Materials and Methods: We divided the NPC patients into previously untreated, partial remission, complete remission, and relapse groups. Healthy controls were those without any autoimmune diseases, cancer, or recent infection. We used flow cytometry to detect the changes in T cell subsets. Results: We found the quantity (%) of CD4+ CD25+ CD127low/- Treg regulatory T cells and CD8+ CD28- T cells were obviously increased in NPC previously untreated, partial remission, and relapse groups. There was no difference in these two subsets between complete remission groups and healthy controls. In addition, the quantity (%) of CD3+ CD4+ and CD8+ CD28+ effector T cells were reduced in NPC previously untreated, partial remission, and relapse groups. There was no difference in these two subsets between complete remission groups and healthy controls. Conclusions: Our research determines the changes of T cell subsets in different stages of NPC. PMID- 29970687 TI - The more potential performance of nidogen 2 methylation by tissue or plasma DNA over brichoalveolar lavage DNA in diagnosis of nonsmall cell lung cancer. AB - Background: Nonsmall cell lung cancer (NSCLC) is one of the leading incidence and mortality of malignant tumors worldwide. While aberrant DNA methylation is a frequent event occurred during NSCLC carcinogenesis and development, therefore holding the potential to predict the process of tumor development. This study aims to explore the feasibility of gene nidogen 2 (NID2) as the diagnostic biomarker for NSCLC. Materials and Methods: Quantitative methylation specific polymerase chain reaction of NID2 has been done among the following sample panels: For tissue methylation evaluation, we collected 96 cases of NSCLC versus 18 cases of noncancerous lung lesions (NCLLs); 46 from the 96 NSCLC patients also provided DNA of bronchoalveolar lavage (BAL) and plasma sample, the methylation status of which are assessed against 12 cases of NCLL for BAL and 30 cases of NCLL for plasma samples, respectively. Results: The methylation rate of NID2 in NSCLC versus NCLL is evaluated as: In tissue 59.40% versus 16.67%, (P = 0.0001); in BAL 30.43% versus 16.67% (P = 0.1640); in plasma 45.65% versus 20.00% (P = 0.0191). Conclusions: Our study revealed the frequent occurrence of aberrant NID2 methylation in NSCLC and peripheral blood, which might be useful as a biomarker to predict NSCLC or to screen the high-risk population for NSCLC. PMID- 29970686 TI - Clinical evaluation of potential usefulness of serum lactate dehydrogenase level in follow-up of small cell lung cancer. AB - Background: Lactate formation is upregulated in tumor cells by lactate dehydrogenase (LDH). High serum LDH level is linked to many malignancies with poorer survival, but tumor LDH has not been well investigated in small cell lung cancer (SCLC). Patients and Methods: The study was performed in 120 cases of SCLC confirmed by pathological examination. The evaluation of treatment response to chemotherapy was based on response evaluation criteria in solid tumors criteria. The serum LDH levels were determined at diagnosis and follow-up visits. The distribution and differences in LDH change and the chemotherapeutic response rate was evaluated by using chi 2 tests. Receiver operating characteristic curves were calculated to select the cut-off level of an increase in LDH indicating significant progression. The correlation of time of serum LDH normalization, time to-progression (TTP), and overall survival (OS) were analyzed by Pearson correlation. Influence of increasing LDH on survival was calculated using the Kaplan-Meier method. Results: At diagnosis, significant differences in LDH levels were found between the groups with limited or extensive. In contrast to the limited-stage group, the extensive-stage group showed significantly decreased the level of LDH after the first-line chemotherapy. In patients whose diseases progressed, LDH levels were significantly higher in the last 1-month period preceding progression compared with the level at the progression. In the follow up, we found that prolonging periods of serum LDH normalization were co-related to TTP and OS significantly. An increase in LDH by at least 51.5 U/L was found to be associated to a significantly higher probability of disease progression, and patients with initial increased LDH had a significantly reduced probability of survival. Conclusions: LDH is validated for its potential usefulness as markers for monitoring treatment response in SCLC and also suitable for discriminating between disease and disease-free periods. PMID- 29970688 TI - Keratinocyte growth factor binding to fibroblast growth factor receptor 2-IIIb promotes epithelial ovarian cancer cell proliferation and invasion. AB - Aim of Study: To analyze the function of keratinocyte growth factor (KGF) and it ligand fibroblast growth factor receptor 2-IIIb (FGFR2-IIIb) in the epithelial ovarian cancer (EOC) progression. Materials and Methods: In this study, the protein KGF and corresponding ligand FGFR2-IIIb expression were detected in both normal epithelial ovarian tissues and in EOC tissues. Seventy-one ovarian tumor tissues were examined for KGF and FGFR2-IIIb expression by immunohistochemistry; seven normal epithelial ovarian tissues as control were examined. By using a monoclonal antibody to inhibit KGF activation, we tested KGF-induced EOC cells invasion ability. By means of Western blot, we tested extracellular signal regulated kinase (ERK), phosphorylation ERK, myosin light chain (MLC), and phosphorylation MLC with or without KGF protein. Results: We found that the expression FGFR2-IIIb increased in EOC cells and tissues comparing with its normal counterpart, and the expression of KGF protein decreased or undetectable in human EOC cells and tissues comparing with its normal part. The effect of KGF in promoting EOC cell invasion was blocked by an FGFR2-IIIb antibody. We further discovered that KGF upregulated ERK and MLC phosphorylation in the highly invasive ovarian cancer cell line HO8910PM. Therefore, regarding the highly invasive ovarian cancer cells, we speculated that KGF might promote proliferation and invasion through the ERK-MLC pathway. Conclusions: These results suggest that KGF might play an important role in the progression of ovarian cancer and could be an attractive target for ovarian cancer therapy. PMID- 29970689 TI - Extent of breast cancer type 1 promoter methylation correlates with clinicopathological features in breast cancers. AB - Aim of Study: The current meta-analysis investigated the correlation between breast cancer type 1 (BRCA1) promoter methylation and the clinicopathological features of breast cancer (BC). Materials and Methods: An electronic literature search was performed to identify and select cohort studies, by employing stringent inclusion and exclusion criteria, for data relevant to promoter methylation of BRCA1 and BC. Statistical analysis of the extracted data was performed using comprehensive meta-analysis 2.0 software (CMA 2.0) (Biostat Inc., Englewood, New Jersey, USA). Results: A total of 125 published studies were retrieved from the literature search, and finally, 18 cohort studies meeting our inclusion criteria were incorporated into our meta-analysis. The 18 studies contained a total of 3213 BC patients. Meta-analysis results revealed that BRCA1 promoter methylation in BC patients with high and moderately differentiated tumors (I-II) was significantly lower than patients with poorly-differentiation tumors (III) (odds ratio [OR] =0.450, 95% confidence interval [95% CI] =0.241 0.838, P = 0.012). BRCA1 promoter methylation in BC patients with lymph node (LN) metastasis was significantly higher than patients without LN metastasis (OR = 2.244, 95% CI = 1.278-3.940, P = 0.005). The results of ethnicity-based subgroup analysis showed a significant difference in histological grade of BC on Asians, LN metastasis of BC in Asians and Caucasians, subtypes of BC in Caucasians, and age at diagnosis of BC patients in Caucasians (all P < 0.05). Conclusions: Our meta-analysis revealed that BRCA1 promoter methylation status is linked to tumor grade and LN metastasis of BC. PMID- 29970691 TI - Breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1, may be associated with clinicopathological features of breast cancer. AB - Objective: We aim to investigate whether the breast cancer metastasis suppressor gene, breast cancer metastasis suppressor 1 (BRMS1), is correlated with clinicopathological features of breast cancer or not. Materials and Methods: Following a stringent inclusion and exclusion criteria, case-control studies related to the association between BRMS1 and breast cancer were selected from articles retrieved by electronic database searches. All statistical analyses were performed by Stata version 12.0 (Stata Corp, College Station, TX, USA). Results: A total of 12 studies were ultimately included in this meta-analysis. Results of our meta-analysis suggested that BRMS1 protein in breast cancer tissues was significantly lower compared with normal breast tissues (odds ratio [OR] =0.08, 95% confidence interval [CI] =0.04-0.15, P < 0.001). The BRMS1 protein in metastatic breast cancer tissue was lower than that in nonmetastatic breast cancer tissue (OR = 0.20, 95% CI = 0.13-0.29, P < 0.001), and BRMS1 protein in tumor-node-metastasis (TNM) stages 1, 2 was found to be higher than TNM stages 3, 4 (OR = 4.62, 95% CI = 2.77-7.70, P < 0.001). With respect to breast cancer types, BRMS1 protein in all the three major types of breast cancer was lower than the normal tissues. We also found strong correlations between BRMS1 mRNA levels and TNM stage and tumor size. Conclusion: Our meta-analysis results showed that reduced BRMS1 expression level was significantly associated with clinicopathological features of breast cancer, suggesting that loss of expression or reduced levels of BRMS1 might be a strong indicator of the metastatic capacity of breast cancer, with poor prognosis. PMID- 29970690 TI - Serum paraoxonase and arylesterase can be useful markers to predict neoadjuvant chemotherapy requirement in patients with breast cancer. AB - Aim: The aims of this study are to evaluate the serum levels of paraoxonase (PON) and arylesterase (ARE) in breast cancer (BC) patients; to determine their relationship with chemotherapy requirements in BC; and to find a cut-off value to assess subjects with a higher risk of BC. Subjects and Methods: A total of 40 BC patients and 33 age-matched healthy women were included in this study. Beside other biochemical parameters, participants' serum PON and ARE levels were determined and analyzed. Results: Serum PON and ARE levels were found decreased in sera of the patients (96.44 +/- 21 and 159.75 +/- 15.75 U/L, respectively)compared to controls (158.39 +/- 23.04 and 239.33 +/- 32.98 U/L, respectively) (P = 0.001 for both). Subgroup analysis of the BC patients revealed that both serum PON and ARE levels were lower in patients who needed neoadjuvant chemotherapy (NAC), compared to those who did not (P = 0.024 and 0.02, respectively). We determined a cut-off value of PON according to the receiver operating characteristic curve analysis as 131.2 U/L (sensitivity 97.5% and specificity 93.9%). Conclusion: BC patients have lower serum PON and ARE levels than healthy controls. Also, serum ARE levels (but not PON) were negatively correlated with body mass index in BC patients. Both serum PON and ARE levels were lower in patients who needed NAC than in patients who did not need such therapy. PMID- 29970692 TI - Relationship between angiotensin-converting enzyme insertion/deletion gene polymorphism and prostate cancer susceptibility. AB - Background and Objective: Investigations on the relationship between angiotensin converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and prostate cancer risk are conflicting. This meta-analysis was conducted to assess the relationship between ACE I/D gene polymorphism and prostate cancer risk. Materials and Methods: Reports were identified from PubMed, Cochrane Library, and China Biological Medicine (CBM)-disc (CBM database) on December 30, 2014, and eligible studies were recruited. Results: ACE I/D gene polymorphism was not associated with prostate cancer risk for overall populations in this meta analysis (D allele: Odds ratio [OR] =1.56, 95% confidence interval [95% CI]: 1.00 2.46, P = 0.05; DD genotype: OR = 1.74, 95% CI: 0.95-3.20, P = 0.07; II genotype: OR = 0.67, 95% CI: 0.39-1.15, P = 0.15). Furthermore, the association of ACE I/D gene polymorphism with colorectal cancer risk was not found for the Caucasians. Interestingly, ACE I/D gene polymorphism was associated with prostate cancer risk for the Asian population and Latino population. Conclusions: There was an association between ACE I/D gene polymorphism and prostate cancer risk for the Asians and Latino population in this meta-analysis. However, more investigations should be performed to confirm this relationship. PMID- 29970693 TI - Promoter methylation of WNT inhibitory factor-1 may be associated with the pathogenesis of multiple human tumors. AB - Aim: We investigated the association of WNT inhibitory factor-1 (WIF-1) gene methylation with the pathogenesis of multiple human tumors, using a meta-analysis based approach. Materials and Methods: Electronic databases and manual search was additionally employed to retrieve relevant published literature. The cohort studies relating to tumor and WIF-1 were screened based on predefined selection criteria, and all extracted data from the selected studies were analyzed through STATA software. Results: Sixteen studies were finally enrolled in our study involved 1112 tumor samples and 612 adjacent normal samples. The study result showed that WIF-1 gene methylations in tumor tissues were significantly higher compared with adjacent/normal tissues. The result of subgroup analysis on ethnicity revealed that in the Caucasians, Asians, and Africans, the methylation status of WIF-1 gene in tumor tissues was higher than adjacent/normal tissues. Further subgroup analysis on disease types revealed that WIF-1 gene methylation status is a widespread phenomenon that is, observed in tumor tissues of patients with multiple human tumors compared with that in adjacent/normal tissues. Interestingly, there was no significant difference in WIF-1 gene methylation between tumor tissues among patients with lung cancer, gastric cancer, astrocytoma, and adjacent/normal tissues, indicating the WIF-1 gene methylation not a general nonspecific phenomenon. Conclusion: WIF-1 gene methylation in tumor tissues was significantly more frequent as compared to that in adjacent normal tissues, indicating that WIF-1 gene methylation may be an important event in the pathogenesis of multiple human tumors. PMID- 29970694 TI - Longan flower proanthocyanidins induce apoptosis in HT-29 colorectal carcinoma spheroids. AB - Aim of Study: Proanthocyanidin-rich longan flower extract (LFP) has been previously shown to inhibit the proliferation and anchorage-independent growth in soft agar of two colorectal carcinoma (CRC) cells in vitro. In this report, we further examined the effects of LFP in a CRC spheroid model. Materials and Methods: A liquid-overlay assay employing HT-29 spheroids was used to evaluate the effects of LFP on cancer cell tumorigenesis, viability, and apoptosis. Associated effects on signaling path ways (epidermal growth factor receptor [EGFR], Akt) and apoptotic regulators were measured using Western blot. Results: Treatment with LFP up to 200 MUg/ml inhibited tumor growth in a dose-dependent manner and induced prominent apoptosis as measured by annexin V staining. Cells treated with LFP showed decreased EGFR and Akt phosphorylation with decreased expression of B-cell lymphoma 2. Conclusion: The ability of LFP to induce apoptosis in CRC spheroids warrants further investigation of its composition and identification of tumor-active components. PMID- 29970695 TI - Gemstone spectral imaging dual-energy computed tomography for differentiation of renal cell carcinoma and minimal-fat renal angiomyolipoma. AB - Purpose: To investigate the values of gemstone spectral imaging (GSI)-dual-energy computed tomography (DECT) in differentiation of renal cell carcinoma (RCC) and minimal-fat renal angiomyolipoma (MF-RAML). Patients and Methods: Twenty-one patients with ischemic RCC and 19 patients with MF-RAML were enrolled in this study. GSI was performed on them, and the spectrum signs were analyzed. Results: I(H2O), H2O(I), I(fat), and fat(I) concentrations, normalized I concentration, and effective atomic number of corticomedullary phase and parenchymal phase in enhanced GSI-DECT in ischemic RCC group were all significantly lower than those in MF-RAML group (P < 0.05). CT value and absolute slope rate of spectral attenuation curve in two phases in ischemic RCC group were also significantly lower than those in MF-RAML group (P < 0.05). Conclusion: GSI-DECT has provided a new idea and method for differential diagnosis of ischemic RCC and MF-RAML, with high-clinical values. PMID- 29970696 TI - Diagnostic value of CYFRA 21-1 and carcinoembryonic antigen in diagnosis of operable lung cancer from benign lung disease. AB - Background: Lung cancer is sometimes difficult to differentiate from benign lung diseases with nodular shadow in imaging scan. In these cases, exploratory operation is needed for the patients with highly suspected malignant disease. Therefore, there is an urgent demand to differentiate the benign lung disease from malignant lung nodules rather than invasive method. Aim: We evaluated the diagnostic value of two tumor markers in distinguishing operable lung cancer from benign lung disease. Materials and Methods: The serum levels of carcinoembryonic antigen (CEA) and CYFRA 21-1 were retrospectively analyzed in 236 lung cancer patients and 44 patients with benign lung disease. These benign lung diseases were presented with evidence of a high likelihood of having lung cancer. After surgical operation, diagnosis of lung cancer and benign lung disease were confirmed by histological examination. Results: We found that the average level of tumor marker in operable lung cancer patients was higher than those in patients with benign lung disease. CYFRA 21-1 sensitivity and specificity for lung cancer diagnosis was 37.3% and 90.9%, respectively, while that for CEA was 22.0% and 90.9%. The combined value for the sensitivity and specificity of these two tumor markers was 47.5% and 81.8%, respectively. Conclusion: Our results indicate that the combination of these two tumor markers resulted in higher sensitivity compared to use CYFRA 21-1 or CEA along. Given its lower sensitivity and higher specificity, positive CYFRA 21-1 or positive CEA strongly supports lung cancer in patients with nodular shadow in imaging scan. PMID- 29970697 TI - Role of taurine upregulated gene 1 as a predictor of poor outcome in osteosarcoma. AB - Aims: Previous studies have found that long noncoding RNA taurine upregulated gene 1 (TUG1) can regulate osteosarcoma cells apoptosis and proliferation; the aim of this study was to investigate the clinical significance of TUG1 in osteosarcoma. Subjects and Methods: The expression of TUG1 was detected by real time and quantitative polymerase chain reaction assay in 94 pairs of tumor tissues and corresponding noncancerous bone tissues of osteosarcoma patients. Its correlations with clinicopathologic features were analyzed, and the significance of TUG1 as a prognostic factor was determined. Results: This study shows that the expression of TUG1 in osteosarcoma tissues was significantly higher than that in adjacent normal bone tissues. Upregulation of TUG1 was significantly correlated with the larger tumor size and advanced tumor-node-metastases stage of osteosarcoma patients. Kaplan-Meier curve showed a decreased overall survival time of osteosarcoma patients with high TUG1 expression. Moreover, univariate and multivariate analyses suggested that low-expression level of TUG1 was an independent poor prognostic indicator for osteosarcoma patients. Conclusions: In conclusion, our data support TUG1 as a potential prognostic predictor and gene therapy target with its high expression in tumor tissues and its association with carcinogenesis and progression in osteosarcoma. PMID- 29970698 TI - Patterns of care of nonsmall cell lung cancer patients in China and implications for survival. AB - Purpose: We reported the patterns of care for a cohort of Chinese patients with nonsmall cell lung cancer (NSCLC) and examined the characteristics of those patients who did not receive cancer-specific treatment. Materials and Methods: This was a prospective cohort study. The study population was patients with first primary NSCLC diagnosed and admitted to Hebei Cancer Hospital in Hebei Province in China from January 2004 to December 2005. Logistic regression was used to examine factors associated with no cancer-specific treatment. Cox proportional hazard regression was used to examine the effects of cancer treatment on survival. Results: Of 579 NSCLC patients included in the study, 73.4% were male, 84.3% died by the end of the study after 7 years follow-up, 40.1% were diagnosed at a late stage of disease, and 33.7% had unknown disease stage. Over half (50.8%) of the patients received palliative care, 23.8% for curative care, and 25.4% did not receive any cancer-specific treatment. The probability of not receiving cancer-specific treatment was significantly higher for those who diagnosed at older age (odds ratio [OR] =3.01, 95% confidence interval [95% CI]: 1.79-5.06), had unknown stage at diagnosis (OR = 2.77, 95% CI: 1.41-5.47), or had unclassified histological type (OR = 3.48, 95% CI: 1.94-6.21). After adjusted for other factors, patients received anti-cancer treatment had significantly lower risk of dying from NSCLC P < 0.0001) compared with patients who did not receive any cancer-specific treatment. Conclusions: Despite the benefits of anti-cancer treatments confirmed in this study, over a quarter patients did not receive any such treatment. Finding the reasons for the patients who did not receive cancer specific treatment may improve the quality of patient care in this population. PMID- 29970699 TI - Positron imaging for verification of irradiation field during radiotherapy. AB - Aim of Study: The present study was designed to investigate the application of positron images from photonuclear reactions to verify the location of targeted radiation in vivo. Materials and Methods: The phantom study was conducted with distilled water, porcine muscle, porcine adipose tissue, and graphite; these subjects were irradiated separately with 50 MV photons generated by an MM50 Racetrack Microtron. The positron emission activity was measured using a Geiger counter, and the radioactive decay curves for each of the irradiated materials were then established. The positron emission tomography (PET) images of the three tissue models were also achieved using the same radiation conditions. The in vivo PET imaging study was also conducted in tumor-bearing rabbits. Results: Our results demonstrated that the PET imaging could be used to verify the position of the irradiation field in vivo. The dose distribution images of photonuclear reactions of 11 C and 15 O were uniform, using 2-Gy 50 MV photons. Conclusions: The factors influencing the half-life of radiation activity in various tissues were different from the first order kinetic reaction in physics. PMID- 29970700 TI - A modified method by differential adhesion and serum-free culture medium for enrichment of cancer stem cells. AB - Objective: In this study, we showed a modified method for the isolation of cancer stem cells (CSCs) using a combination of differential adhesion method and serum free culture medium (SFM) method. Materials and Methods: Trypsin-sensitive cells and trypsin-resistant cells were isolated from MB49, EJ, and SK-OV-3 cells using a combination of differential adhesion method and SFM method. The CSCs markers expression of trypsin-resistant cells was verified by the flow cytometry, the Western blotting, and the quantitative polymerase chain reaction. Functional comparisons were verified by the resistance to chemotherapy assay, the transwell assay, and the tumor xenograft formation assay. Results: Trypsin-resistant cells were isolated successfully. They were identified with high expression of CSCs markers and possessed higher resistance to chemotherapy, greater migration in vitro and stronger tumorigenic abilities in vivo. Conclusion: Trypsin-resistant cells showed specific CSCs characterizations. They were able to be isolated successfully with a modified method by a combination of differential adhesion method and SFM method. PMID- 29970701 TI - Retrospective analysis on the efficacy of sunitinib/sorafenib in combination with dendritic cells-cytokine-induced killer in metastasis renal cell carcinoma after radical nephrectomy. AB - Objective: Sunitinib/sorafenib (SU/SO), dendritic cells (DCs), or DC-cytokine induced killer (CIK) could significantly prolong progression-free survival (PFS), 3-year overall survival (OS), or 5-year OS for patients with metastatic renal cell carcinoma (mRCC). We retrospectively analyzed the clinical efficacy between SU/SO combined with DC-CIK and SU/SO monotherapy in treating renal cell carcinoma (RCC) patients with metastasis after radical nephrectomy. Materials and Methods: All patients (n = 34) with postoperative mRCC in our hospital from January 2009 to January 2014 were received either SU/SO monotherapy (Group 1, n = 15) or in combination with DC-CIK (Group 2, n = 19). A retrospective study was based on the primary endpoint (PFS) and secondary endpoint (OS). Results: At a median follow up of 19.5 months, in Group 2, as compared with in Group 1, the median PFS was significantly longer (28.0 vs. 11.0 months, P = 0.03). Moreover, the 3-year OS was higher (57.1% vs. 28.6%). The cases of progressive diseases (PDs) and deaths were less in Group 2 than that in Group 1 (PD: 8 vs. 9, deaths: 3 vs. 5); however, the cases of stable diseases were more (11 vs. 6). In addition, the 3 year OS was higher in SU + DC-CIK group than that in SO + DC-CIK group (63.36% vs. 50%). There was no significant difference for PFS between SO + DC-CIK group and SU single agent group. Conclusions: SU/SO with DC-CIK could significantly prolong the median PFS, improve the 3-year OS rate, prolong the 3-year OS. It is likely to be a new approach for mRCC after radical nephrectomy. PMID- 29970702 TI - Serum B7 homologous body 4 for the diagnosis of ovarian cancer in Chinese Han women: A meta-analysis. AB - Objective: The aim of this study is to investigate the clinical value of serum B7 homologous body 4 (B7-H4) protein detection for the diagnosis of ovarian cancer (OC) in Chinese Han women by pooling published data. Methods: A systematic literature search was conducted in Cochrane Library, PubMed, EMBASE, Wanfang, and China National Knowledge Infrastructure databases. The bivariate model was utilized to calculate the pooled estimates. Publication bias was assessed by using funnel plots and Deek's test. Results: After the review, ten publications were found to meet our inclusion criteria. The overall diagnostic sensitivity and specificity of B7-H4 in OC were 0.782 (95% confidence interval [CI]: 0.732-0.825) and 0.870 (95% CI: 0.804-0.916), respectively. The area under summary receiver operating characteristic curves was 0.86 (95% CI: 0.83-0.89). No significant publication bias was observed in the included studies. Conclusion: Serum B7-H4 detection, either alone or in combination with carbohydrate antigen 125, has an acceptable value in the diagnosis of OC. PMID- 29970703 TI - Low molecular weight heparin in treating patients with lung cancer received chemotherapy: A meta-analysis. AB - Objective: To systematically review the efficacy and safety of low molecular weight heparin (LMWH) in treating patients with lung cancer received chemotherapy. Materials and Methods: Databases including PubMed, The Cochrane Library, Excerpt Medica Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, VIP, and Wanfang Data were searched for the randomized controlled trials (RCTs) about LMWH in treating patients with lung cancer received chemotherapy from the establishment to May 31, 2015. According to the inclusion and exclusion criteria, two reviewers independently screened literature, extracted data, and assessed quality of the included studies. Meta analysis was then performed by using Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) software. Results: A total of eight RCTs involving 952 patients were finally included. Meta-analysis showed that compared with the control group, LMWH significantly improved the 1- and 2-year overall survival (OS) rates of the patients with lung cancer received chemotherapy (risk ratio [RR] =1.65, 95% confidence interval [95% CI] [1.20-2.26], P = 0.002; RR = 2.63, 95% CI [1.40 4.94], P = 0.003, respectively), and significantly reduced the incidence of venous thromboembolism (VTE) (RR = 0.40, 95% CI [0.23-0.69], P = 0.001), not significantly increased the incidence of major bleeding events and thrombocytopenia (RR = 1.29, 95% CI [0.57-2.96], P = 0.54; RR = 0.86, 95% CI [0.69-1.07], P = 0.18, respectively), and not significantly improved the overall response rate (RR = 1.24, 95% CI [0.98-1.57], P = 0.07). Conclusion: LMWH improves the 1- and 2-year OS rates of the patients with lung cancer received chemotherapy and reduces the incidence of VTE, not increase the incidence of major bleeding events and thrombocytopenia. These show that there is a certain effect of LMWH, and the security is good. PMID- 29970704 TI - Study on early diagnosis of epithelial ovarian cancer by analysis of plasma septin-9 and clusterin level. AB - Background and Aim: To investigate the value of peripheral blood plasma levels of septin-9 and clusterin protein in the diagnosis of epithelial ovarian cancer (EOC). Materials and Methods: The peripheral blood plasma samples were obtained from 137 EOC patients, 12 borderline ovarian tumor patients, 10 benign ovarian tumor patients, 41 benign pelvic lesion patients, and 58 healthy women. The peripheral plasma septin-9 and clusterin proteins levels were measured by enzyme linked immunosorbent assay. The power of test was evaluated with the area under the receiver operating characteristic curve (ROC) (AUC). Results: The mean levels of plasma septin-9 and clusterin in EOC patients were significantly higher than that in healthy women (P = 0.002, P = 0.021). The mean levels of plasma septin-9 in benign pelvic lesion patients were significantly higher than that in healthy women (P = 0.007). The mean levels of plasma septin-9 in epithelial ovarian carcinoma patients with tumor family history or distant metastases were significantly higher than that of patients without (P = 0.040, P = 0.025). The AUC of septin-9 protein was 0.712, when the optimal cut-off point was 0.28, the sensitivity and diagnostic specificity were 82.5% and 50.0%, respectively; the AUC of clusterin was 0.636, and when the optimal cut-off point was 87.96 ng/ml, the sensitivity and diagnostic specificity was 71.5% and 41.4%, respectively. Conclusion: The plasma levels of septin-9 and clusterin in ovarian cancer patients were abnormally elevated, which might be used as potential candidates of peripheral blood tumor biomarkers for early diagnosis of EOC and septin-9 might be related to distal metastases of EOC. The septin-9 might play the promotion role, which protein level relates to not only the distal metastases but also the prognosis of EOC. Due to the limit of sample volume, further enlargement of the sample size and set up of the follow-up system is in need to in-depth study the relationship between plasma protein concentration with the distal metastases, and further explore its correlation with the prognosis of EOC. PMID- 29970706 TI - Clinical efficiency of repeated pulmonary metastasectomy in sarcoma patients with recurrent pulmonary metastasis: A meta-analysis. AB - Introduction: Recurrent pulmonary metastasis is common in sarcoma patients following the first pulmonary metastasectomy. Repeated pulmonary metastasectomy (RPM) may be a possible treatment method, but it has several unfavorable aspects. The clinical efficiency of RPM has not been established, as previous studies have reached inconsistent results. Materials and Methods: Comprehensively literature searches were conducted in PubMed, Web of Science, Embase, and Cochrane Library. All eligible articles were included according to inclusion criteria. Then, a meta analysis was conducted to clarify the clinical efficiency of RPM. Results: A total of 9 articles with 464 patients were included. We found that sarcoma patients with recurrent pulmonary metastasis that underwent RPM had significantly better overall survival (hazard ratio = 0.59; 95% confidence interval, 0.44-0.81; P = 0.001). No significant publication bias was found. Sensitivity analysis showed the results were stable. Conclusion: Selected sarcoma patients with recurrent pulmonary metastasis following the first pulmonary metastasectomy could still benefit from RPM, despite its unfavorable aspects. PMID- 29970705 TI - Evaluation of the relationship of erythrocyte membrane Na+/K+-ATPase enzyme activity and tumor response to chemoradiotherapy in patients diagnosed with locally advanced nonsmall cell lung cancer and glioblastoma multiforme. AB - Context: Radiotherapy is the commonly used therapeutic modality for inoperable cancer types. We investigated chemoradiotherapy (CRT) effects on the Na +/K + ATPase enzyme. Aims: The aim of the present study was to determine the usefulness of Na +/K +-ATPase enzyme as a prognostic factor and as a potential target for increasing the CRT response of nonsmall cell lung cancer (NSCLC) and glioblastoma multiforme (GBM). Settings and Design: We prospectively evaluated 30 patients (all were treated with CRT) and 20 healthy controls. Subjects and Methods: Blood samples were taken before and after the completion of CRT from the patients and once from the control group. Erythrocyte membranes were isolated and Na +/K + ATPase enzyme activities were measured. Statistical Analysis Used: The statistical significance was calculated using the one-way analysis of variance test and the Tukey's test. Results: Na +/K +-ATPase activity levels were increased in the patient groups before completion of CRT CRT, when compared to the control group. A significant decrease in Na +/K +-ATPase activity was noted in the patient groups after the completion of CRT when compared to before CRT, but the activity remained higher than in the control group. No relationship was noted between survival and Na +/K +-ATPase activity in NSCLC and GBM patients. Conclusion: Levels of Na +/K +-ATPase activity were initially high in patients with NSCLC and GBM, and decreased after the completion of CRT. This supports a linkage between the altered activity of Na +/K +-ATPase and the treatment effects of CRT. The observed change in Na +/K +-ATPase activity in cancer patients receiving CRT suggests that targeting this enzyme could represent a novel mean of combatting NSCLC and GBM. PMID- 29970707 TI - Association of CYP3A5*3 polymorphisms and prostate cancer risk: A meta-analysis. AB - Aim of Study: The CYP3A5*3 allele (A6986G transition in intron 3) is the major member of cytochrome P450 subfamily, which plays a pivotal role in exogenous carcinogens of liver. Variation of the CYP3A5*3 (rs776746 A > G) can lead to oxidation and inactivation of testosterone, which may result in individual susceptibility to prostate cancer. Methods: All eligible published studies about association between CYP3A5*3 polymorphisms and prostate cancer risk were searched in PubMed, Embase, Web of Science, and Cochrane Library, for the period up to August 2015. Odds ratios (ORs) together with 95% confidence intervals (95% CIs) were used to access the strength of the association. Results: Six case-control studies including 2522 cancer patients and 2444 healthy controls were finally included. The meta-analysis results suggested that CYP3A5*3 polymorphisms were significantly associated with an increased risk of prostate cancer under two genetic models (GG + AG vs. AA: OR = 1.53, 95% CI = 1.23-1.90, P = 0.000; GG vs. AA: OR = 1.46, 95% CI = 1.14-1.87, P = 0.000). Further subgroup analysis according to ethnicity indicated that CYP3A5*3 polymorphism may increase the risks of prostate cancer among African (G allele vs. A allele: OR = 1.34, 95% CI = 1.14-1.57, P = 0.000; GG + AG vs. AA: OR = 1.606, 95% CI = 1.27-2.04, P = 0.000). Sensitivity analysis indicated a reliable result and publication bias suggested no strong publication bias under the genetic models. Conclusion: Our data support that the CYP3A5*3 polymorphism may be associated with increased risk of prostate cancer, particularly in African populations. Large and well-designed studies are needed to validate this association. PMID- 29970708 TI - Does serum alkaline phosphatase level really indicate the prognosis in patients with osteosarcoma? A meta-analysis. AB - Objective: Osteosarcoma is the most common malignant bone tumor that occurs in children and adolescents. Various studies have investigated the role of serum alkaline phosphatase (ALP) level in patients with osteosarcoma but report conflicting findings. Thus, a meta-analysis to assess its prognostic value more precisely is conducted. Materials and Methods: Pooled hazard ratio (HR) with 95% confidence intervals (CIs) of overall survival (OS) was used to assess the prognostic role of serum ALP level. Eleven studies published between 1993 and 2013 with a total of 1336 osteosarcoma patients were included. Results: Overall, the pooled HR for all 11 eligible studies evaluating high ALP level on OS was 1.60 (95% CI: 1.38-1.86). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Begg's (0.553) and Egger's (0.382) test also did not suggest evidence for publication bias. Conclusion: This meta-analysis suggests that high serum ALP level is obviously associated with lower OS rate in patients with osteosarcoma, and it is an effective biomarker of prognosis. PMID- 29970709 TI - Modulation of the gamma-secretase activity as a therapy against human hepatocellular carcinoma. AB - Objective: Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. The discovery of new therapies against HCC is highly dependable on finding molecules which play essential roles in cancer development. The objective of this study was to evaluate the activity of gamma secretase (gamma-secretase), and the antitumor effects of a gamma-secretase inhibitor (GSI) in HCC. Methods: The expression of presenilin 1 (PS1), a core component of gamma-secretase, was examined by Western blot. Activity of gamma-secretase was measured by a luciferase-based reporter system, and cancer cells were transfected either with PS1 dominant negative mutant (PS1D385A) or treated with GSI. Results: Expression of PS1 was increased in HCC tissue and several HCC cell lines, which were accompanied by elevated gamma-secretase activity. Cell colony formation and cell proliferation were decreased upon treatment with GSI but not with PS1D385A transfection. Conclusion: GSIs may be appealing candidates for the development of new therapies against HCC. PMID- 29970710 TI - Imbalance of T-helper 1/T-helper 2 cytokines and impaired glucose tolerance among patient with acute coronary syndrome. AB - Purpose: The balance between T helper (Th) cells Th1- and Th2-related cytokines plays a key role in the clinical process of acute coronary syndrome (ACS) and type 2 diabetes mellitus (T2DM) or impaired glucose tolerance (IGT). The objective of this study was to assess the status of Th1/Th2 cytokines in patients with ACS and T2D or IGT. Methods: A total of 201 ACS patients were enrolled in the study. All ACS patients were divided into three groups: Group I-patients with normal glucose tolerance (NGT), Group II-patients with IGT and Group III-patients with T2D. We measured circulating Th1/Th2-type cytokines (interleukin [IL]-4, IL 13, interferon-gamma [IFN-gamma], and tumor-necrosis factor-alpha [TNF-alpha]) using enzyme-linked immunosorbent assay and calculated the ratio of Th1/Th2. Results: Significant elevations in serum levels of IL-4, IL-13, IFN-gamma, and TNF-alpha were found in ACS-T2D and ACS-IGT groups compared to that in both ACS NGT group and healthy individuals. Higher serum levels of IL-4, IL-13, and TNF alpha were found in ACS-NGT group than that in the control group. Furthermore, IL 4 and IFN-gamma concentrations were significantly higher in ACS-T2D patients than in ACS-IGT patients. IFN-gamma/IL-4, IFN-gamma/IL-13, and TNF-alpha/IL-4 ratios as markers of Th1/Th2 ratio were significantly higher for the ACS-T2D group and ACS-IGT group as compared to that in the ACS-NGT group and control group (P < 0.05). Conclusion: Shifts in the balance of Th1/Th2 toward a predominance of Th1 may represent more severe inflammatory status in ACS patients with type T2D or IGT. PMID- 29970711 TI - Clinical significance and association of GSTP1 hypermethylation with hepatocellular carcinoma: A meta-analysis. AB - Objective: To quantitatively investigate the effect of GSTP1 hypermethylation on hepatocellular carcinoma (HCC) using a meta-analysis of available case-control studies. Materials and Methods: Previous studies have primarily evaluated the incidence of GSTP1 hypermethylation in HCC and corresponding control groups, and compared the incidence of GSTP1 hypermethylation in tumor tissues, pericancer liver tissues, normal liver issues, and nontumor liver tissues with that in other diseases. Data regarding publication information, study characteristics, and incidence of GSTP1 hypermethylation in both groups were collected from these studies and summarized. Eleven studies, including 546 cases of HCC and 575 nontumor cases, were identified for meta-analysis. Results: Statistically significant odds ratios (ORs) of GSTP1 hypermethylation were obtained from tumor tissues and nontumorous liver tissues of HCC patients (OR 2.63, 95% confidence interval [CI]: 1.77-3.89%, P < 0.0001), tumor tissues of HCC patients, healthy liver tissues of patients with other diseases (OR 7.29, 95% CI: 2.87-18.51%, P < 0.0001), tumor tissues of HCC patients, and liver tissues of patients with nontumorous liver diseases (OR 2.13, 95% CI: 1.10-4.13%, P < 0.05). The pooled analysis showed significantly increased ORs of GSTP1 hypermethylation (OR 2.21, 95% CI: 1.01-4.84%, P < 0.05) from HCC tissues and cirrhotic tissues. Conclusions: The results of this meta-analysis suggest that GSTP1 hypermethylation induces the inactivation of GSTP1 gene, plays an important role in hepatocarcinogenesis, and is associated with an increased risk of HCC. PMID- 29970712 TI - MiR-499 rs3746444 polymorphism and hepatocellular carcinoma risk: A meta analysis. AB - Aims: Several studies suggested that miR-499 rs3746444 polymorphism was associated with the risk of hepatocellular carcinoma (HCC). However, other studies did not confirm the result. To derive a more comprehensive estimation of the association between miR-499 rs3746444 polymorphism and HCC risk, we conducted a meta-analysis. Materials and Methods: PUBMED, COCHRANE, and WEB OF SCIENCE databases were retrieved for the association studies focused on the relationship between miR-499 rs3746444 polymorphism and the risk of HCC. The strength of the associations between miR-499 rs3746444 polymorphism and the risk of HCC was measured by odds ratios (ORs) with 95% confidence intervals (CIs). Results: A statistically significant association between miR-499 rs3746444 polymorphism and the risk of HCC was fond (OR = 1.26; 95% CI, 1.04-1.52; P = 0.02). In the subgroup analysis of race, Asian population with miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.29; 95% CI, 1.03-1.62; P = 0.03). In the subgroup analysis of hepatitis virus status, patients with HBV and miR-499 rs3746444 polymorphism showed increased HCC risk (OR = 1.38; 95% CI, 1.17-1.64; P = 0.0002). In the subgroup analysis of source of control, both hospital- and population-based studies found significant results (OR = 1.46; 95% CI, 1.12-1.90; P = 0.005; OR = 1.19; 95% CI, 1.01-1.40; P = 0.04). Conclusions: This meta analysis suggested that mir-499 rs3746444 polymorphism was associated with an increased HCC risk. PMID- 29970714 TI - Association between Kruppel like factor 6 intervening sequence 1-27 G > A and cancer susceptibility: A meta-analysis. AB - Background/Objective: It has been reported that Kruppel like factor 6 intervening sequence (KLF6 IVS) 1-27 G > A might be associated with cancer susceptibility. Here, we conducted a meta-analysis to summarize and clarify this association. Materials and Methods/Main Results: A systematic search of studies on the association between KLF6 IVS 1-27 G > A, and cancer susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. Seven articles were included in our meta-analysis. Overall and in prostate cancer, population-based subgroup overall and Caucasian subgroup overall, no evidence was found for the association between KLF6 IVS 1-27 G > A polymorphism and cancer susceptibility in any genetic model and the results showed stability in sensitivity analyses. Conclusions: KLF6 IVS 1-27 G > A may not be associated with cancer susceptibility, especially the susceptibility of unselected prostate cancer. However, there was insufficient data to fully confirm the association between KLF6 IVS 1-27 G > A and familial prostate cancer, sporadic prostate cancer, gastric cancer, and cancers from different ethnicity, and the results should be interpreted with caution. PMID- 29970713 TI - The expression of insulin receptor substrate 1 and estrogen receptor as prognostic factor on breast cancer patient. AB - Background: Insulin receptor substrate 1 (IRS-1) has been known to be an associated factor with breast cancer progression. However, there has been little study with respect to the relationship between the expression of IRS-1 and breast cancer prognosis in clinical practice. In this study, we evaluated the impact of the estrogen receptor (ER) and IRS-1 on the recurrence and survival of breast cancer patients. Methods: We analyzed the pathologic finding of 376 tissue samples from breast cancer patients who received proper treatment between January 1990 and December 2006 using the tissue microarray. We measured the expression of ER and IRS-1 by immunohistochemistry staining and analyzed the difference of recurrence and survival rate in each subgroup of ER and IRS-1. Results: Our results show that there is a significant difference of disease-free survival (DFS) according to ER and IRS-1 subgroups with both univariate and multivariate analyses. Specifically, ER-positive and IRS-1-positive breast cancer samples showed improved DFS compared to ER-positive and IRS-1-negative breast cancer (adjusted hazard ratio: 2.17; 95% confidence interval: 1.15-4.09; P = 0.01). There was a difference of overall survival according to ER and IRS-1 subgroups by univariate analysis (P = 0.01), but not by multivariate analysis (P = 0.36). Conclusion: ER and IRS-1 subgroups appear to be critical factors for the prediction of breast cancer recurrence. In particular, we suggest that the patients who have ER-positive and IRS-1-negative breast cancer undergo more aggressive treatment because they have poorer prognoses. PMID- 29970715 TI - Anti-tumor effects of phenolic alkaloids of menispermum dauricum on gastric cancer in vivo and in vitro. AB - Aim: This study was conducted to investigate the anti-tumor effects of the Chinese traditional herb phenolic alkaloids of menispermum dauricum (PAMD) on gastric cancer both in vitro and in vivo. Materials and Methods: Cell apoptosis was detected in cultured SGC-7901 cells after administration of a different dose of PAMD. Gastric cancer model was established by single i.p. injection of SGC 7901 cells in the mice (n = 60). Then, animals were received high dose (20 mg/kg), medial dose (10 mg/kg), and low dose (5 mg/kg) of PAMD. Mice received 5 floxuridine was set as positive controls and received normal saline was as blank controls. Effects of PAMD on tumor growth were evaluated by tumor inhibition rate. Tumor tissues were collected from mice and detected for the expression of several genes P53, B-cell CLL/lymphoma 2 (BCL-2), BCL-2-associated X protein (BAX), CASPASE-3, K-RAS by real-time polymerase chain reaction, and Western blot. In addition, tumor cell changes were observed under transmission electron microscopy. Results: The apoptosis index in PAMD at high- and medial-dose group was significantly higher than that in blank control group (P < 0.01). PAMD at different dose could significantly decrease the tumor weight compared to the blank control group (P < 0.01). In addition, PAMD could obviously increase BAX and caspase-3 expression as well as decrease K-RAS expression when compared to the blank control treatment (P < 0.01). Furthermore, PAMD could induce tumor cell morphology changes. Conclusions: PAMD could suppress gastric tumor growth in vivo, possibly through increasing the expression of pro-apoptotic genes expression then leading to cell apoptosis and inhibiting oncogenic K-RAS expression. PMID- 29970716 TI - Clinical outcome of 30 patients with bone marrow metastases. AB - Objective: Cancer patients with bone marrow metastases are rare and dismal. The study was to identify the clinical features and prognostic factors in cancer patients with bone marrow metastases. Patients and Methods: A total of 30 patients with bone marrow metastases were reviewed between September 2007 and September 2013. Bone marrow metastases were identified by bone marrow aspiration. Results: The median age was 56.5 years (range, 8-85 years). The two most common primary tumor sites were the stomach (7, 23.3%), breast (5, 16.7%). Bone metastases (27, 90.0%) were the most common concurrent metastases. The most common cause for bone marrow aspiration was anemia and thrombocytopenia (10, 33.3%). The median survival time was 3 months (range, 0.5-82 months). Patients with good performance status (n = 19) had a longer median survival time than patients with poor performance status (n = 11) (8 months vs. 1 months, P = 0.041). Patients with primary unknown origin (n = 5) had a significantly shorter overall survival time than patients with known origin (n = 25) (1 month vs. 6 months = 0.010). The median survival time was 9 months in the systemic therapy group (n = 21) and 1 month in the best supportive care group (n = 9) (P = 0.000). Conclusion: To make primary origin clear and start systemic antitumor therapy is beneficial for patients with bone marrow metastases. PMID- 29970717 TI - CCND1 rs9344 polymorphism is associated with the risk of hepatocellular carcinoma in Caucasian population. AB - Aims: Some studies investigated the association between CCND1 rs9344 polymorphism and hepatocellular carcinoma (HCC) risk. However, the results were inconclusive. Thus, we did a meta-analysis to determine this relationship. Materials and Methods: Relevant studies were systematically searched using the PubMed, CNKI, and EMBASE databases. The strength of the association was calculated with the odds ratio (OR) and respective 95% confidence intervals (Cis). Results: We investigated the association between CCND1 rs9344 polymorphism and HCC risk in the dominant models. The result of this meta-analysis showed that CCND1 rs9344 polymorphism did not significantly associated with HCC risk (OR = 1.09; 95% CI 0.88-1.34). In the stratified analysis by ethnicity, we found that this polymorphism was significantly associated with HCC risk in Caucasians (OR = 1.55; 95% CI, 1.05-2.29). However, we did not find any significant association between this polymorphism and HCC risk in Asians (OR = 0.91; 95% CI, 0.71-1.18). Conclusions: This meta-analysis suggested that CCND1 rs9344 polymorphism might be associated with the risk of HCC among Caucasians. PMID- 29970718 TI - Baicalein and Ly294002 induces liver cancer cells apoptosis via regulating phosphatidyl inositol 3-kinase/Akt signaling pathway. AB - Aim: The aim of this study is to investigate the mechanism of baicalein in inducing human liver cell line SMMC-7721 apoptosis. Materials and Methods: Twenty micromoles baicalein or 10 MUM LY294002 was adopted to treat SMMC-7721 cells. Cell proliferation was tested by cell counting kit-8 assay. Cell cycle was determined by flow cytometry and cyclin D1 expression. Cell apoptosis was detected by annexin V/propidium iodide double staining. Phosphatidyl inositol 3 kinase (PI3K)/Akt signaling pathway was assessed by real-time polymerase chain reaction and Western blot. Results: Baicalein suppressed liver cancer cell SMMC 7721 proliferation and induced cell apoptosis together with LY294002. Baicalein blocked cell cycle in G0-G1 phase and downregulated cyclin D1 level. Baicalein and LY294002 significantly suppressed PI3K/Akt signaling pathway-related molecule activity at both mRNA and protein levels (P < 0.05). Conclusion: Baicalein can inhibit liver cancer cell proliferation and promote cell apoptosis by affecting PI3K/Akt signaling pathway together with LY294002. PMID- 29970719 TI - Association of cytotoxic T-lymphocyte antigen 4 rs231775 gene polymorphism with colorectal cancer risk. AB - Aim of the Study: Results on the relationship between cytotoxic T-lymphocyte antigen 4 (CTLA4) +49A/G (rs231775) gene polymorphism and colorectal cancer risk are still debated. This meta-analysis was performed to assess the association between CTLA4 +49A/G and colorectal cancer risk. Materials and Methods: The relevant studies were searched from PubMed, Cochrane Library, and China Biological Medicine Database-disc, and eligible investigations were included and synthesized using meta-analysis method. Results: Eleven studies were recruited into this meta-analysis for the association of CTLA4 A/G gene polymorphism and colorectal cancer risk, consisting of 1802 colorectal cancer patients and 2939 controls. G allele was a risk factor for the colorectal cancer risk, and AA genotype might be a protective factor against colorectal cancer risk in overall populations (G allele: Odds ratio [OR] = 1.19, 95% confidence interval [CI]: 1.03 1.38, P = 0.02; AA genotype: OR = 0.63, 95% CI: 0.47-0.84, P = 0.002). However, the GG genotype was not associated with colorectal cancer risk in overall populations. Conclusion: The association between CTLA4 G allele/AA genotype and colorectal cancer risk was found in this meta-analysis. PMID- 29970720 TI - Primary pulmonary epithelioid angiosarcoma: A case report and literature review. AB - Primary pulmonary epithelioid angiosarcoma is an extremely rare malignancy. Herein, we report the case of an elderly Chinese patient with primary pulmonary epithelioid angiosarcoma. The 72-year-old man presented with a 1-month history of persistent hemoptysis and left chest pain and weight loss of 3 kg. A chest computed tomography (CT) scan revealed two masses (maximum size 3.0 cm * 2.0 cm and 0.8 cm * 0.5 cm) in right lower lobe. We performed a left thoracotomy for tumor resection. Pathological examination showed that there was a significant amount of hemorrhage, fibrinous exudates, degeneration, and necrosis. With immunohistochemical analysis, tumor cells had strong expression of CD34, FLI-1, vimentin. Morphological and immunohistochemical findings supported the diagnosis of epithelioid angiosarcoma. PMID- 29970722 TI - Surgical treatment of esophageal carcinoma after distal partial gastrectomy: Case report and literature review. AB - The objective of the study was to highlight the significance of surgical treatment for esophageal carcinoma after distal gastrectomy and provide suitable surgical options. A patient with esophageal carcinoma and previous distal partial gastrectomy was treated by replacing the esophagus with remnant stomach and moving the spleen into the thoracic cavity. We then systematically reviewed the literature on the treatment of such conditions. Postoperative recovery went well. During the 2-year follow-up, the patient did not complain any discomfort and had no signs of metastasis or recurrence. For esophageal carcinoma patients who have undergone distal gastrectomy, surgery should remain an option. For patients whose carcinoma is in the lower part of the esophagus or who are frail but had an early diagnosis, surgery to replace the esophagus with remnant stomach and relocation of the spleen into the thoracic cavity should be considered. PMID- 29970721 TI - Ventricular bigeminal rhythm associated with trastuzumab: A potential cardiac side effect. AB - Cardiac side effects of targeted chemotherapy agents are getting more and more important topic nowadays. However, the studies on this topic are limited. Because multiple agent chemotherapy is not a common treatment option, it is hard to establish controlled study groups (as before chemotherapy and after chemotherapy); further, cancer, itself, may cause cardiac side effects and uncertainty of the symptoms may be associated with previous clinical situation before chemotherapy. For all that, we may get information to a certain degree about the side effects of these agents by analyzing case reports. These side effects have a broad spectrum from asymptomatic rhythm alterations to acute cardiac death. In this case report, we aim to discuss asymptomatic ventricular bigeminal rhythm, which is proved by electrocardiography, of our patient during treated by trastuzumab. PMID- 29970723 TI - Recurrent fibrosarcoma of maxillary sinus involving the cranial base: A rare case. AB - Adult fibrosarcoma (FS) of the maxillary sinus and the cranial base is a rare soft tissue sarcoma which is clinically characterized by a high frequency of local repeated recurrence if not excised widely. At present, the standard treatment option for FS is surgical resection. Here, we report a case of a 46 year-old male with a 5 months history recurrent FS of the maxillary sinus. The patient possessed an enormous mass in the right maxillofacial region extending to the cranial base, as observed by computed tomography. Histologically, the lessions were composed of hypercellular cells with heterogenous groups. The recurrence and pathologically heterogenous groups of FS lead to therapeutic complexities. Due to the challenging anatomy in head and neck region, it is crucial to define the lesion areas and weigh the balance between life quality and functional reconstruction. PMID- 29970724 TI - Cervical mass as the initial manifestation of occult papillary thyroid carcinoma: Report of three cases. AB - Occult thyroid carcinoma is mostly discovered by autopsy or by other causes of thyroid surgery. To the best of our knowledge, there have been only a few reports concerning the situation that cervical mass was the initial manifestation of occult papillary thyroid carcinoma. The three patients in our report were all admitted to hospital because of the masses on their necks. Although pathology reports showed the nodal presence of thyroid cancer, we did not find the primary tumor on the same side of thyroid. We reported the clinical data of patients, including chief complaint, ultrasonography, computed tomography, and pathology results. We attempt to raise awareness regarding this particular disease and as a reference for clinical diagnosis and treatment. Examinations are needed to confirm the diagnosis for occult cancer of the thyroid. Surgical procedure is the major treatment method at present. PMID- 29970725 TI - Prevention of severe acute kidney injury by implementation of care bundles: Some progress but still a lot of work ahead. AB - Routine health data, dating from 1990 to 2015, show a dramatic rise in the incidence of acute kidney injury (AKI) in the general population and an apparent increase in acute dialysis (AKI-D) prompting calls for improvement of care in AKI patients. Recent reports suggest flattening of population-based AKI occurrence rates or declining frequencies of AKI or AKI-D in subgroups of high-risk patients with known onset of AKI. These temporal changes in AKI occurrence relate at least in part to the widespread implementation of AKI prevention care bundles. Nevertheless, AKI frequencies and AKI morbidity and mortality remain high. Incorporation of real-time electronic alerts and the use of novel biomarkers in high-risk patients or patients with known onset of AKI may result in further reductions of AKI incidences by early recognition of AKI and by timely conservative management of AKI. There is an urgent need for further treatment options of established AKI. PMID- 29970726 TI - Improvement in dialysis-related adverse events with use of body composition monitoring. AB - This study aims to utilize body composition monitor (BCM) device to achieve euvolemic status in problematic dialysis patients and to evaluate its clinical outcome. One hundred and five hemodialysis (HD) patients were enrolled based on difficulty in achieving dry weight. The reasons for enrollment in the study were (a) recurrent intradialytic hypotension, (b) intradialytic hypertension, (c) intradialytic muscle cramps, or (d) the presence of comorbid conditions that make clinical assessment of dry weight difficult (e.g., cirrhosis of liver, heart failure, severe malnutrition, or morbid obesity). Following initial assessment of hydration status using BCM device, dry weight for each patient was adjusted accordingly (upward, downward, or unchanged). The patients were, thereafter, monitored over a 15-week period for possible resultant change in the clinical and hemodynamic parameters. Forty-two patients were monitored due to hypertension, 18 due to hypotension, 10 due to hypotension and cramps, and 35 due to comorbid conditions that make clinical assessment of dry weight difficult. At the conclusion of study period, there was improvement in the monitored parameters. Hypertension improved in 79% of the patient with hypertension, hypotension in 90%, and hypotension with cramps in 90%. In the comorbid group, BCM monitoring provided better insight to clinical problem management in 80% cases. Overall quality of BCM assessments was 96.1%. In the hypertension group, mean blood pressure decreased by 10.9 mm Hg in the whole group (P = 0.0006), the drop was 3 mm Hg in the patients dialyzing with HD (P = 0.0006) and 8.6 mm Hg in those on hemodiafiltration (HDF) (P = 0.08). In the comorbid conditions group, the mean blood pressure rose by 22.5 mm Hg in the whole group (P 0.00001), 21.5 mm Hg in the patients dialyzing with HD (P = 0.00001) and 21.5 mm Hg in those on HDF (P = 0.0004). BCM monitoring together with clinical assessment is a useful tool which when appropriately applied reduces the incidence of dialysis-related complications. PMID- 29970727 TI - Correlation and discrepancy of phospholipase A2 receptor staining in membranous nephropathy in paraffin-embedded kidney biopsies. AB - Distinguishing primary from secondary forms of membranous nephropathy (MN) in paraffin-embedded kidney biopsies is challenging. Previous studies have measured the accuracy, sensitivity, and specificity of phospholipase A2 receptor (PLA2R) on MN. However, due to the absence of a gold standard method for diagnosis, further studies are necessary. Here, we measure the correlation and discrepancy of PLA2R on MN in paraffin-embedded kidney biopsies by correlating PLA2R findings with immunofluorescence (IF), light microscopy (LM), and electron microscopy (EM) results. A total of 116 kidney biopsies were investigated including 87 MN and 29 nonmembranous kidney diseases. PLA2R was examined by indirect IF assay. A total of 79 MN cases were subjected to PLA2R staining and histopathological analyses. The remaining eight cases were excluded due to the lack of the glomeruli in the sections. The correlation and discrepancy between PLA2R and IF findings were seen in 65.45% and 34.55%, respectively. PLA2R and EM findings showed a 65.52% correlation and 34.48% discrepancy. LM features and PLA2R findings showed a correlation of 58.44% and discrepancy of 41.56%. Overall correlation between histopathology and PLA2R was seen in 65.82% and 34.18% showed discordant cases. All 29 non-membranous MN cases were negative for PLA2R. Staining for PLA2R could be a useful adjunctive tool in the stratification of cases of MN. The findings of this study strongly recommend the use of PLA2R IF staining method as a routine test for all MN cases. PMID- 29970728 TI - Fibroblast growth factor-23 as a predictor biomarker of acute kidney injury after cardiac surgery. AB - Renal ischemia/reperfusion injury is a major cause of acute kidney injury (AKI). The lack of early biomarkers for predicting AKI has hampered our ability to initiate preventive and therapeutic measures in an opportune way. Fibroblast growth factor 23 (FGF-23) is elevated in chronic kidney disease, but data on FGF 23 in humans with AKI are limited. Herein, we tested whether FGF-23 levels rise early in the course of AKI following cardiac surgery. We prospectively evaluated eighty adult patients who underwent cardiac surgery. Patients were divided into two groups (AKI and non-AKI group) on the basis of whether they developed postoperative AKI within 24 h after surgery. Plasma FGF-23 levels were measured before surgery and 24 h after surgery. The primary outcome was AKI diagnosed using the AKI Network criteria. Forty-five patients (56.2.5%) developed AKI after surgery. Plasma FGF-23 increased significantly from a mean of 26.8 +/- 2.47 ng/mL at baseline to 341.7 +/- 38.1 ng/mL 24 h after cardiopulmonary bypass. Univariate analysis showed a significant correlation between AKI and the following: percent change in plasma FGF-23, postoperative serum level of creatinine, FGF-23, and neutrophil gelatinase-associated lipocalin. Receiver operating characteristic curve analysis revealed that, for percent change in plasma FGF-23 concentrations at 24 h, the area under the curve was 0.9, sensitivity was 100%, and specificity was 97.1%. Plasma FGF-23 percent change is more valid compared with FGF-23 before or after procedure in the prediction of AKI and represents a novel and highly predictive early biomarker for AKI after cardiac surgery. PMID- 29970729 TI - Evaluation of blood pressure in children with idiopathic overactive bladder syndrome. AB - Children with an overactive bladder generally exhibit frequency, urgency, and urge incontinence. Often, a child will squat to try to prevent urinary incontinence. The bladder in these children is not anatomically and is functionally, smaller than normal and exhibits strong uncontrolled contractions. The aim of this study was to the evaluation of blood pressure (BP) in children with idiopathic overactive bladder syndrome. In this case-control study, we selected 110 children with overactive bladder as cases and 220 children without overactive bladder as controls. Children with overactive bladder and healthy children without overactive bladder were enrolled, and their BP was measured in children. P <0.05 was considered statistically significant in our comparisons. The mean age of the children was 8.8 +/- 1.70 and 8.53 +/- 2.44 years in overactive bladder and control group, respectively. The mean systolic and diastolic BP were a significant difference between case and control groups (P = 0.001). Systolic and diastolic BP were significantly higher in children with overactive bladder. PMID- 29970730 TI - Combined use of Vitamins E and C improve nephrotoxicity induced by colistin in rats. AB - This study was performed to investigate the protective effect of combined use of Vitamins E and C on colistin-induced tubular damage in rat. Animals were treated with sterile saline, colistin methanesulfonate (CMS), CMS + Vitamin E + Vitamin C, and Vitamin E + vitamin C, respectively, for seven days. Thereafter, animals were sacrificed and the urine N-acetyl-b-D-glucosaminidase (NAG) and gamma glutamyl transferase (GGT) levels, plasma level of creatinine (Cr), vitamin E and vitamin C, and renal tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as renal histology were performed. CMS induced acute tubular necrosis, increased the NAG, GGT, and MDA levels, and reduced the Vitamin E, Vitamin C, SOD, CAT, and GPx activities. Co-treatment with vitamins E and C restored all biochemical parameters cited above and improved the histopathological damage. Tubular damage induced by colistin is at least partly due to oxidative stress. Nephroprotective effect of Vitamins E and C is partially mediated through its antioxidant properties, and the higher protection by the combination of these vitamins is related to its synergistic effects. PMID- 29970731 TI - Nigella sativa prevented liver and renal tissue damage in lipopolysaccharide treated rats. AB - Liver and renal dysfunction accompanying with the tissues' oxidative damage has been reported to occur during Inflammation. Nigella sativa has been well known for its antioxidant and anti-inflammatory effects. The aim of this study was to investigate preventive effects of N. sativa on liver and renal tissue damage in lipopolysaccharide (LPS) -treated rats. The rats were divided into five groups: (1) control; (2) LPS (1 mg/kg, IP, for 10 days), (3-5) N. sativa hydroethanolic extract (100, 200, or 400 mg/kg) before LPS. Compared to LPS group, treatment by the extract decreased alondialdehyde, nitric oxide (NO) metabolites, and interleukin-6 while increased thiol content and superoxide dismutase and catalase activities in both renal and liver tissues. N. sativa extract also decreased serum aspartate aminotransferase, alanine aminotrans-ferase, and alkaline phosphatase concentration, while it increased serum protein and albumin compared with LPS group. In LPS group, serum blood urea nitrogen and creatinine were higher than control group. The extract reversed the negative effects of LPS. The results demonstrated that the N. sativa prevented liver and renal tissue damage in LPS-treated rats. It is suggested that the effects are due to its antioxidant and anti-inflammatory effects. PMID- 29970732 TI - Prevalence of cardiac arrhythmia and risk factors in chronic kidney disease patients. AB - Chronic kidney disease (CKD) patients have a high risk for cardiac arrhythmia. This study aimed to investigate the prevalence of cardiac arrhythmia in CKD patients and to evaluate the relationship between arrhythmia and biochemical and echocardiographic parameters. CKD patients between 18 and 80 years of age were enrolled from the nephrology outpatient clinic. Physical examination, complete blood count, urinalysis biochemical analysis, electrocardiogram, echocardiogram, and 24-h Holter electrocardiogram were performed. Patients with and without cardiac arrhythmia were compared regarding their characteristics, laboratory findings, and echocardiographic parameters. Risk factors for cardiac arrhythmia were also evaluated. The carotid intima-media thickness was measured using Doppler ultrasonography. In our study involving 59 patients, 44 (74%) had atrial arrhythmia (AA) and 40 (68%) had ventricular arrhythmia (VA). Atrial and/or VA were diagnosed in 46 patients (78%), of whom six (10.2%) had AA, two (3.4%) had VA and 38 (64.4%) had AA plus VA. Atrial fibrillation (AF) was present in two patients (3.4%) in the form of paroxysmal AF. Risk factors for AA were low calcium level and posterior wall thickness, while factors associated with VA were age, triglyceride level, leukocyte count, and nonusage of angiotensin 2 receptor blockers. Risk factors for AA and/or VA included increased platelet count, age, and leukocyte count. AA and/or VA were found in as high as 78% of CKD patients. Further studies evaluating course of the disease from early stages are needed to identify risk factors. PMID- 29970733 TI - Pulmonary function tests and plasma nitric oxide levels in pediatric hemodialysis. AB - The relationships between the lungs and the kidneys are clinically important; however, the impact of nitric oxide (NO) on respiratory function in renal patients is less known. The aim of this study is to evaluate pulmonary function tests (PFTs), NO level and their correlation in children on treatment with hemodialysis (HD) for the end-stage renal disease. This study was performed among 20 patients on regular HD and 20 controls. Participants were subjected to clinical examination, and pulmonary function evaluation was performed using spirometry. The following parameters were obtained as follows: forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), Tuffenau index (FEV1/%FVC), (FEF25%-75%), and peak expiratory flow. Spirometry was carried out before and after HD sessions, and at the same time of clinical assessments, blood samples were taken to measure arterial-blood gas (ABG) and NO levels. There was the statistically significant difference between patient and control groups regarding NO and all PFTs except FEV1/FVC. There was no statistically significant correlation between NO and biological parameters in both cases and controls, but there was negative although the statistically not significant correlation between the PFTs, ABG, and duration of dialysis in the case group. There was statistically significant negative correlation between NO and some PFTs in case group; also the effect of dialysis on pulmonary functions tests and NO levels were only on the FVC of patients which significantly improved. Postdialysis blood gases remained normal among children on HD. NO may be involved in the deterioration of pulmonary function, and therefore, we feel that it can be used as a marker of clinical deterioration. PMID- 29970734 TI - The pathological evaluation of nonneoplastic kidney disorder in tumor nephrectomy specimens. AB - Renal cell carcinoma (RCC) comprises 2%-3% of all visceral and 80%-85% of all adult kidney malignancies. Nephrectomy is the treatment of choice for renal tumors. The accurate pathological evaluation of nonneoplastic renal parenchyma in nephrectomy specimens is important for subsequent management. Eighty-two patients with RCC who underwent surgery at Imam Khomeini Hospital, Urmia, Iran, from April 2006 to February 2015 were studied. Paraffin blocks of the hospital archives were stained by hematoxylin and eosin (H and E) and periodic acid-Schiff staining. Microscopic examination was performed on nontumoral portions that were in the farthest possible distance from the tumor. Out of total 82 cases, 24 (29.3%) had normal renal parenchyma and 58 (70.7%) had pathological changes in renal parenchyma. The most frequent pathological findings were vascular sclerosis with parenchymal scarring and pyelonephritis. Other findings include focal and diffuse mesangial hypercellularity, eight; focal segmental glome-rulonephritis, five; membranoproliferative glomerulonephritis, three; and membranous glome rulonephritis, two. Parenchymal scarring and vascular change included 36% of clear cell type, 41% of papillary type, and 53.8% of chromophobe type. Although there is not any statistical relation between the gender of patients and pathological findings, there was an obvious correlation between age and pathological findings. Before the age of 55 years, vascular sclerosis with parenchymal scarring and glomerular diseases and then chronic pyelonephritis are more prevalent.Evaluation of pathological changes in nonneo-plastic renal parenchyma is an essential step in recognizing patients at risk of accelerated functional failure of the single remaining kidney, particularly in patients with a background of chronic vascular injury associated with diabetes or hypertension. PMID- 29970735 TI - Evaluation of interleukin-18 in children with steroid-sensitive nephrotic syndrome before and after using levamisole. AB - Levamisole is often discussed as the first alternative to steroids. It is an antihelminthic drug that has been used for steroid-sensitive nephrotic syndrome (SSNS) for more than 20 years. Interleukin (IL)-18, a member of the IL-1 cytokine superfamily, is recognized as an important regulator of immune responses. The aim of the study was to investigate the IL-18 levels in serum from children with SSNS during relapse and remission after using levamisole or three months in a trial to test the efficacy of its action in reducing frequency of relapses in SSNS. This study was done on 23 children with frequently relapsing SSNS treated with levamisole besides steroids, then followed up three months; 16 males and seven females (mean age: 7.96 years and median 8 years). Clinical and laboratory assessments were done before starting therapy and after three months including cumulative dose of steroids and serum IL-18. We found that IL-18 level showed a significant elevation after three months of levamisole therapy compared to its level before initiation of levamisole therapy, with no relapses in these three months, no reported side effect, and significant reduction of cumulative dose of steroids. Levamisole effectiveness in reduction of relapses of SSNS may be due to resetting of the type 1/type 2 imbalance, proved by induction of IL 18 may be useful in the therapy. PMID- 29970736 TI - Drug-induced acute interstitial nephritis: Prospective randomized trial comparing oral steroids and high-dose intravenous pulse steroid therapy in guiding the treatment of this condition. AB - The most important aspect of treating drug-induced acute interstitial nephritis (AIN) is timely discontinuation of the offending drug. Steroids, oral as well as intravenous (IV), are used in the treatment of drug-induced AIN. The present study was undertaken to compare the efficacy of oral prednisolone versus IV suprapharmacological doses of corticosteroids in the treatment of drug-induced AIN. This prospective randomized controlled study included drug-induced AIN diagnosed on histopathology over a period of two years. Patients were randomized to oral prednisolone (Group A) 1 mg/kg for two weeks or pulse methylprednisolone (Group B) 30 mg/kg for three days (maximum 1 g) followed by oral prednisolone 1 mg/kg for two weeks, tapered over two weeks. Response was reported as complete remission (CR) [improvement in estimated glomerular filtration rate (eGFR) to >=60 mL/min/1.73 m2], partial remission (PR) (improvement but eGFR <60 mL/min/1.73 m2), or nonresponders to steroids (no CR/PR). Steroid therapy was instituted to 31 biopsy-proven AIN cases (Group A - 16 and Group B - 15). Drugs implicated in the causation of AIN included pantoprazole, diclofenac, rifampicin, naproxen, aspirin, imipenem, piroxicam, cefixime, lornoxicam, Chinese herbs, etoricoxib, ciprofloxacin, and phenytoin. There was no difference in the baseline parameters between the two groups. At the end of follow-up, 58.06% achieved CR and 41.93% achieved PR. In Group A, nine (56.2%) achieved CR and seven (43.7%) achieved PR. In Group B, nine (60%) achieved CR and six (40%) achieved PR. There was no significant difference between the two groups. Pulses of high doses of corticosteroids have a significant but transient anti-inflammatory effect. Both oral and IV suprapharmacological doses of corticosteroids are equally effective in the treatment of drug-induced AIN, if used early. PMID- 29970737 TI - Prediction of cardiovascular disease risk using framingham risk score among office workers, Iran, 2017. AB - Cardiovascular diseases (CVDs) are leading cause of morbidity and mortality and early identification of risk factors can help reduce mortality from them. The aim of this study was to determine the risk of CVD based on the Framingham Risk Score (FRS) among office workers, Yasuj City, Southwestern Iran. In this descriptive study, 180 workers aged 30-74 years old free of cardiovascular disease were recruited by single-stage stratified cluster sampling from the office of Yasuj City. Analysis showed that 163 workers (90.5%) were at low risk, 12 people (6.6%) at moderate risk, and five people (2.9%) at high 10-year risk of CVD. Mean of FRS and 10-year prediction of CVD risk was significantly higher among male workers than females. Subjects with normal body mass index than overweight and obese people had only significantly lower FRS (P <0.001), but 10-year risk of CVD did not differ among groups. Participants with Master of Science and above educational degree and subjects with normal waist-to-hip ratio had only significantly lower 10-year risk of CVD (P < 0.001). Nonsmokers, whose with systolic blood pressure <140 mm Hg, total cholesterol <240 mg/dL, normal total cholesterol/high-density lipoprotein-cholesterol (HDL-C), and abnormal HDL-C had significantly lower both FRS and 10-year CVD risk (P <0.01). This population based study will health care policy makers develop targeted strategies to develop individual and community-based health care promotion programs. PMID- 29970738 TI - Determinants of patency of arteriovenous fistula in hemodialysis patients. AB - The arteriovenous fistula (AVF) is the vascular access of the first choice for hemodialysis (HD). Studies on patency of AVF and its affecting factors reveal a high risk for access failure. The aim of this study was to assess the primary and secondary AVF patency and their determinant factors. It was a retrospective, descriptive study conducted in the HD facility of the Nephrology Department in Rabta University Hospital. We included AVF created before December 2009 in end stage renal disease (ESRD) patients. The end of the follow-up was fixed in December 2013. We included 126 AVFs created in 111 patients; 22.5% were aged >65 years, 39.6% were diabetic, 68.5% were hypertensive, and 26.1% had peripheral vascular disease. The primary patency rates were 78% at one year and 42% at five years. The secondary patency rates were 80% at one year and 69% at five years. Multivariate analysis revealed that the factors affecting the primary patency of AVF were: the use of jugular catheter for longer than three months (odds ratio (OR):1.91, P = 0.044) and a C-reactive protein >5 mg/L (OR: 1.7, P = 0.049). Aging (>65 years) (OR: 2.46, P = 0.042), referral time to a nephrologist <6 months before onset of ESRD (OR: 2.87, P = 0.015), absence of an antiplatelet therapy (OR: 4.47, P = 0.005), and serum phosphorus <45 mg/L (OR: 2.07, P = 0.045) were the significant impairing risk factors for secondary AVF patency. Our study suggests that early referral and creation of AVF and maturation before ESRD as well as its adequate monitoring are essential for maintaining patency. PMID- 29970739 TI - Crescentic infection related glomerulonephritis in adult and its outcome. AB - The epidemiology of infection-related glomerulonephritis (IRGN) is changing in recent times both in developed and developing nations. Although published studies showed renal outcome in adult IRGN was not as benign as in children, literature regarding clinical profile and outcome of crescentic form of adult IRGN is scarce; hence, we aimed to study the clinical profile of crescentic IRGN. We conducted a retrospective observational study in patients with crescentic IRGN in adults at the Department of Nephrology, Madras medical college, Chennai between 2009 and 2014. A total of 47 patients were included with a mean follow-up of 9.9 +/- 4.2 months. The mean age was 42 +/- 13.5 years. About 19.1% of patients had diabetes. The skin was the most common site of infection (38.3%) with methicillin resistant Staphylococcus acareas (MRSA) as the most common organism. Hypocomplementemia was present in 100% in our study. Hemodialysis (HD) was required in 53.2% of patients and oral steroids were given in 78.7%. Complete renal recovery was seen only in 25.5%, progression to chronic kidney disease in 40.4%, seven patients reached end-stage renal disease, and nine patients died during follow-up. On univariate analysis, MRSA infection, the unidentified source of infection, nonisolation of organisms presence of interstitial fibrosis and tubular atrophy in renal biopsy and requirement of HD were found to be significant risk factors for poor renal outcome. In our study, crescentic form of IRGN is associated with poor renal outcome. PMID- 29970740 TI - Who is sleeping more efficient? Patients on peritoneal dialysis or hemodialysis. AB - Sleep disorder, a common complaint among patients with the end-stage renal disease can affect most aspects of life. Therefore, we aimed to compare sleep quality of patients with peritoneal dialysis (PD) and hemodialysis (HD). This cross-sectional study was conducted on patients on dialysis who were referred to three major centers of Shiraz. The Pittsburgh Sleep Quality Index (PSQI) was used to compare sleep quality between patients on PD and HD. We also assessed some baseline characteristics to find out if they were independent predictors of sleep quality. Spearman correlation coefficients, one and two sample t-test, Chi square, or Fisher's exact test were used to analyze the data. P <0.05 was considered statistically significant. The Statistical Package for Social Sciences version 18.0 for Windows was used for data analyzing. A total of 144 patients including 63 (43.8%) men and 81 (56.2%) women with the mean age of 54.4 +/- 11.8 years completed the questionnaire survey. The total PSQI score showed that 77 (54.6%) of all patients had sleep disturbances without statistical difference between genders (P >0.05). On the other hand, the prevalence of sleep disturbance in HD patients (70.1%) was significantly higher than PD patients (35.9%), (P <0.001). HD patients had a higher rate of poor sleep quality than PD patients. Further studies are necessary to investigate the causes of poor quality of sleep in these patients and also to investigate methods to improve sleep quality in this population. PMID- 29970741 TI - Early initiation of angiotensin-converting enzyme inhibitors in postrenal transplant period: A study from a state-run tertiary care center. AB - Angiotensin-converting enzyme inhibitors (ACEi) comprise a drug class, which are potent antihypertensives with renoprotective effects but are grossly underutilized in renal transplant recipients. These drugs have been reported to cause elevated potassium and creatinine levels in some renal transplant patients. There have been no reports of prospective studies on use of ACEi in renal transplant patients in the early post-transplant period. The purpose of this study is to assess the safety of an ACEi, when started in the early post transplant period. In this prospective observational study, we reviewed 78 kidney transplant recipients during the period of January 2012 to March 2017 at our institution. Sixty-four patients were initiated on ACEi therapy within a month of transplantation, while 14 were initiated after one-month post-transplant; the latter was classified as late initiation group. Patients were enrolled when they met the following criteria: declining serum creatinine, improving urine output, and serum potassium <5.5 mEq/L. Exclusion criteria included anaphylaxis to ACEi, use of ACEi or angiotensin receptor blocker for the treatment of post-transplant erythrocytosis, and serum potassium >5.5 mEq/L. Sixty-four patients were studied, 53 (83%) were male and 11 (17%) were female. Mean age was 32 +/- 15 years (12 56). Minimum duration of follow-up was six months. For each patient, hemoglobin, serum creatinine, and potassium levels were tested at the beginning of ACEi and at the end of the first, third, and the sixth month. The average potassium and hemoglobin levels did not differ significantly between the groups and were within the normal clinical ranges. While incidence of graft failure did not differ, death with functioning graft was lower in the ACEi group. ACEi can successfully be used in postrenal transplant with beneficial long-term impact on renal function. However, here is a need for further randomized controlled studies to validate this observation. PMID- 29970742 TI - Histopathological study of nephrotic syndrome in adults: A Moroccan report. AB - The reported causes of nephrotic syndrome (NS) varies between different countries. In this retrospective study, we aimed to evaluate the underlying causes of NS in adult patients who underwent renal biopsy in a region of Morocco and we also determined the distribution of histopathological diagnoses with regard to the age subgroups and genders from January 2007 to December 2016. Patients were divided into four groups according to age at the time of renal biopsy. A total of the 257 patients with NS were included in this study. The mean age of the patients was 40.9 +/- 16.7 years; male gender was preponderant (61.9%). One hundred and sixty-six (64.6 %) and 81 (35.4%) patients were diagnosed as primary and secondary glomerulonephritis, respectively. The most common diagnosis in NS was membranous nephropathy (MN) (22.2%), followed by minimal change disease (MCD) (20.6%), and lupus nephritis (LN) (13.6%). Among the patients aged 15-30, 31-45, 46-60, and >61 years, the most common cause of NS was MCD (32.1%), MN (29.6 %), MN (26.1%), and amyloidosis (AM) (28.2%), respectively. The proportion of patients with MCD and LN decreased in parallel with patient age and the proportion of patients with renal AM increased in parallel with patient age. Among the female patients aged 15-30 and 31-45 years, LN was the leading cause of NS (41.5 and 36.7%, respectively). Among the male patients aged 15-30 years, MCD was the leading cause of NS (43.2%). Our study over 10 years represents an important data of regional variations of glomerular diseases presenting with adult-onset NS. PMID- 29970743 TI - Albuminuria status and patterns of dyslipidemia among type 2 diabetes black patients managed at a tertiary health-care hospital: A Post hoc analysis. AB - Cardiovascular disease (CVD) risk in type 2 diabetes mellitus (T2DM) increases with the development of albuminuria and is related in part to dyslipidemia. The present analysis assessed lipid profile and patterns of dyslipidemia in T2DM patients according to albuminuria status. This was a post hoc analysis of data from 181 T2DM patients seen at a tertiary health-care hospital and enrolled in a cross-sectional study of albuminuria status. Abnormal albuminuria was defined as microalbuminuria [albumin to creatinine ratio (ACR) 30-299.9 mg/g] or macro albuminuria (ACR >=300 mg/g). Atherogenic dyslipidemia was defined as triglycerides (TGs) >=150 mg/dL and/or high-density lipoprotein-cholesterol (HDL c) <40 mg/dL in men and <50 mg/dL in women using international consensus criteria. High levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), HDL-c, non-HDL-c, TG, and low level of HDL-c were defined according to 2012 American Association of Clinical Endocrinologists' guidelines. Comparisons between T2DM patients with and without abnormal albuminuria were done using Chi-square test, Student's t-test, or two-sample t-test with equal variance and Mann-Whitney test as appropriate. P< 0.05 defined the level of statistical significance. Of the 181 T2DM patients, 93 (51%) had abnormal albuminuria with 32% and 19% having microalbuminuria and macro-albuminuria, respectively. Average TC, HDL-c, HDL-c, non-HDL-c, and TG levels were 171 +/- 41, 111 +/- 36, 38 +/- 16, 133 +/- 38, and 98 (45-234) mg/dL, respectively. These values were significantly lower for TC (P = 0.047), LDL-c (P = 0.030), and non-HDL-c (P = 0.05) in comparison with patients with normal albuminuria. Low HDL-c (64.5%) and high TG (9.7%) were, respectively, the most and less frequent patterns of isolated dyslipidemia in patients with abnormal albuminuria. Atherogenic dyslipidemia with mainly low HDL-c levels is common in T2DM patients with abnormal albuminuria and could contribute to CVD and renal disease progression. PMID- 29970744 TI - A six-year survey of the spectrum of renal disorders on native kidney biopsy results in Central Iran and a review of literature. AB - Native kidney biopsy reports in previous studies that are mostly originated in Western countries show various results in different parts of the world. In this study, we aimed to determine the prevalence of renal biopsy disorders in Iran and compare it with that of other studies in the world. This cross-sectional study evaluated consecutive native kidney biopsies performed in four centers in Isfahan, Iran, from 2009 to 2014. We also reviewed other relevant studies in Iran and the world. Overall, 1547 renal biopsies were reviewed; 493 cases were excluded (transplant or re-biopsy cases) and 1054 cases (43.3% female) were included in our study with a mean (+/-standard deviation) age of 33.1 (+/-18.5) years. The first three most prevalent diagnoses were focal and segmental glomerulosclerosis (FSGS) (24.8%), minimal change disease (MCD) (14.2%), and membranous glomerulonephritis (MGN) (9.6%). IgA nephropathy (IgAN) was more prevalent among men, whereas lupus nephritis had a higher prevalence among women. In three out of six previous studies conducted in Iran, the most prevalent pathological diagnosis was MGN; in two others, MCD predominated; and in the third study, FSGS had the highest prevalence. In Europe and Western Pacific Region, IgAN was by far the most prevalent GN, while studies in other parts of the world show conflicting results. The most prevalent diagnosis in our study was FSGS, which was consistent with previous studies in Iran, which seems to have an increasing prevalence. It is recommended that having a national registry is crucial to determine the current status and for better planning and management of renal disorders. PMID- 29970745 TI - Knowledge and attitude toward organ donation among health-care professionals in a rural town in India. AB - Organ shortage is the greatest challenge facing the field of organ transplantation today. We aimed to study the attitude and knowledge toward organ donation among health-care professionals (HCPs) in rural India. The study was conducted in a rural town in Konkan region of Maharashtra in India. A questionnaire testing knowledge and attitude about various aspects of organ donation was distributed to HCPs. One hundred percent of the respondents were aware about organ donation. Nearly 40.6% and 21.9% believed that a healthy person and a cardiac dead person can be donors, respectively. Fifty percent believed that a brain dead person can be a donor and 3.1% clearly stated as to be having no idea regarding the health status of a donor. Almost 37.5% were ready to believe a heart beating person declared as "brain dead" as dead. Nearly 15.6% were ready to accept a brain dead person as "legally" dead. Highest awareness was observed regarding eye donation, i.e., 87.5%. High awareness was also observed regarding liver, kidney, heart, skin, and body donations, i.e., 78.1%, 65.6%, 37.5%, 31.3%, and 25.0%, respectively. Awareness regarding organ donation of other tissues and organs was poor. Nearly 46.9% HCPs stated that they felt need for an educational session on organ donation. Awareness regarding concept of organ donation among HCPs in rural India is high. Awareness regarding details of organ donation needs further awareness drives. There is a lack of understanding regarding various aspects of brain death and its importance in organ donation. PMID- 29970746 TI - Primary IgA nephropathy in the Kashmiri population. AB - IgA nephropathy (IgAN) remains one of the most common glomerular lesions, which has a striking geographic distribution and is the most common form of primary glomerular disease in Asia. However, the exact prevalence or clinicopathological spectrum of IgAN in India is not well documented. This retrospective study analyzed the presentation in 126 patients of primary IgAN out of 298 native kidney biopsies (42.28%) performed over a period of three years (2013-2015). The patients were followed up for three months. This is the second highest prevalence recorded in the world after Japan. Among the clinical features of our cohort, the mean age was 31 years, with a male-to-female ratio of 2:1, with the highest incidence observed in the third decade of life in both sexes. The majority of our patients (47%) presented with renal failure with a mean serum creatinine value of 3.1 mg/dL and with burnt out morphology on histo-pathology; 72.2% of patients were hypertensive at presentation. On histopathology, Haas class V (35.5%) had the highest frequency followed by class IV (25.8%). The Oxford MEST score was not applicable in 36 patients because of advanced sclerosis (>50%). In the remaining ninety patients, majority had tubular atrophy and interstitial fibrosis of varying degrees. At three months of follow-up, the patients who had presented with renal failure (47.6%), settled in chronic kidney disease stage III (25.4%) followed by stage IV (18.6%) and stage V (11.8%). Our study in Kashmir suggests that IgAN is more common in the younger age group, with a significant number of patients presenting with advanced renal failure and, on morphology, showing a burnt out disease, with many developing end-stage renal disease. Studies evaluating the underlying factors can have immense importance in dealing with the disease. PMID- 29970747 TI - Pediatric acute kidney injury in North India: A prospective hospital-based study. AB - The conducted study aimed to determine the incidence and clinical profile of acute kidney injury (AKI) in hospitalized patients using the AKI Network (AKIN) criteria. This prospective observational study was conducted at the Pediatric ward and pediatric Intensive Care Unit of a tertiary level teaching hospital in North India. The participants were 763 consecutive patients aged three months to 12 years from January 2014 to October 2015 and were assessed for eligibility. Of these, 163 patients were excluded from the study. Main outcome measure was incidence of AKI based on the AKIN criteria. Factors associated with AKI were analyzed. A total of 600 patients (141 critically ill and 459 noncritically ill) were enrolled. The incidence of AKI was 25.2% (n = 151); it was significantly higher among critically ill (53.2%) than non-critically ill patients (16.6%), P <0.001. Most patients with AKI were in Stage 1 (n = 99; 65.6%). Ten patients (6.6%) required dialysis (peritoneal dialysis n = 8; hemodialysis n = 2). Patient with AKI had significantly higher median (interquartile range) PIM-2 score, 22.6 (5-61.7), longer hospital stay (10 vs. 7 days), and mortality rate (28.5% vs. 3.6%); P <0.001. Nephrotoxic drugs [hazard ratio (HR): 5.5, 95% confidence interval (CI): 2.6-11.4; P = 0.001]; hypovolemia (HR: 1.7, 95% CI: 1-2.7; P = 0.035); sepsis (HR 2.3, 95% CI: 1.1-5); and mechanical ventilation (HR: 3.3, 95% CI: 1.6-6.8) were independent predictors for AKI. AKI was an independent risk factor for mortality and risk increased with increasing stage of AKI. Mortality was significantly higher in Stage 3 AKI (n = 14; 60.9%); P <0.001. Independent predictors for mortality in AKI were acidosis (HR: 3.6; 95% CI 1.5-8.6), mechanical ventilation (HR: 34; 95% CI 9.3-123), shock (HR: 19.7; 95% CI 2-194), and sepsis (HR: 3; 95% CI 1-8). The incidence of AKI is high among pediatric patients admitted to this center, including among noncritically ill children. AKI is associated with significantly increased morbidity and mortality. PMID- 29970748 TI - A case report of successful renal transplantation in an ABO incompatible patient with a preformed donor-specific antibody and negative CDC human leukocyte antigens crossmatch. AB - ABO incompatibility and preformed antibodies against the human leukocyte antigen (HLA) are two impermissible barriers to a successful renal transplantation, especially in highly sensitized patient population. With the availability of effective desensitization regimens, good patient and graft outcomes have been reported. As transfusion medicine specialists we report our experience, where patient presented with dual histocompatibility barriers i.e. ABO incompatibility along with preformed donor-specific antibodies (DSA) and negative complement dependent lymphocytotoxicity (CDC) HLA crossmatch. The desensitization strategy followed for our patient included rituximab (375 mg/m2), bortezomib (1.3 mg/m2) and eleven pre-transplant therapeutic plasma exchange (TPE) followed by intravenous immunoglobulin (100 mg/kg per TPE session). Anti-B titer of 1:1 and negative Luminex crossmatch (LumXm) class II DSA (less than 1000 mean fluorescence intensity; MFI), was achieved prior to renal transplantation. Fifteen months post-transplant, patient is doing well with serum creatinine level of 0.8 mg/dL with repeat LumXm class II DSA negative (891 MFI). The desensitization regimen followed proved to be effective in our case. PMID- 29970749 TI - Recurrence of membranous nephropathy three weeks' postrenal transplant: A surprise in store. AB - Membranous nephropathy (MN) may occur in the transplanted kidney, either as recurrent disease in patients who had MN as the cause of end-stage renal disease (ESRD) in the native kidney or de novo, in patients who had another cause of ESRD initially. The reported incidence of recurrent MN ranges between 10% and 45%. Clinical manifestations of recurrent MN are typically observed 13-15 months after transplantation, although they may be observed much earlier (within weeks). Our patient had a recurrence in three weeks. Recurrent disease can lead to loss of the allograft. PMID- 29970750 TI - Genitourinary melioidosis in a Bangladeshi farmer with IgA nephropathy complicated by steroid-induced diabetes mellitus. AB - Melioidosis is an emerging infectious disease in many countries including Bangladesh. Genitourinary infection due to Burkholderia pseudomallei is a well recognized manifestation although less commonly reported in Asia than Australia. Here, we report case history of a 38-year-old Bangladeshi farmer, diagnosed with IgA nephropathy and on oral prednisolone, who presented with features of urinary tract infection. Diagnostic workup confirmed genitourinary infection due to B. pseudomallei and diabetes mellitus. He was treated with ceftazidime followed by the combination of co-trimoxazole and doxycycline. After two-year follow-up, he was free of symptoms with no recurrence of melioidosis. In the context of growing evidence of melioidosis endemicity in Bangladesh, physicians should be aware and include melioidosis as differential in appropriate clinical scenario. Melioidosis may cause urinary tract infections and should be suspected in high-risk groups like farmers and in the presence of risk factors such as diabetes mellitus and other immunosuppressive conditions. PMID- 29970751 TI - Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection? AB - Renal involvement is the most common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. While membranous nephropathy is the most frequent, the association with focal segmental glomerulosclerosis (FSGS) is not as strong, and only a few cases have been described in the literature. In particular, the tip variant FSGS is extremely rare and to our knowledge has not previously been described in association with chronic HBV infection. The management of such cases can be challenging. Immunosuppression may lead to enhanced viral replication and flare-up of the hepatic disease. Antiviral treatment has been reported to induce remission in hepatitis B-associated glomerulonephritis in a few cases. However, their use is primarily restricted to the treatment of associated liver disease, and the current guidelines do not provide specific recommendations on HBV-mediated kidney disease in the absence of hepatic involvement. We describe a case of nephrotic syndrome due to secondary tip variant FSGS in a patient with chronic HBV infection who went into complete remission with antiviral therapy alone and present an argument for the use of oral antiviral agents as the primary treatment option for FSGS-related nephrotic syndrome in chronic HBV-infected patients without progressive liver disease. PMID- 29970752 TI - Multiple tuberculomas invading the central nervous system as a paradoxical reaction in a kidney transplantation recipient. AB - A paradoxical reaction during anti-tuberculosis (anti-TB) therapy is commonly reported in patients with human immunodeficiency virus (HIV). However, a similar reaction to anti-TB therapy can also occur in patients without HIV, especially in patients who have undergone solid organ transplantation. A 65-year-old woman who underwent kidney transplantation six months prior presented to our emergency room with progressive paraparesis. She had been diagnosed with drug-susceptible miliary TB and had undergone two weeks of treatment with anti-TB medication. Magnetic resonance imaging showed a spinal intramedullary mass and multiple intracranial nodules. The etiology of the lesions was confirmed as Mycobacterium tuberculosis. We report a paradoxical reaction of spinal intramedullary and multiple intracranial tuberculomas in a patient with miliary TB who had received appropriate treatment for more than two weeks. PMID- 29970753 TI - A patient with polycystic kidney disease, hepatic cysts and atrial myxoma. AB - With the development of renal replacement therapy, cardiovascular complications have become the major cause of death in patients with polycystic kidney disease (PKD). Atrial myxoma is a cardiac abnormality that has been rarely reported with PKD. The presence of atrial myxomas is not free of complication as it can cause cardiac outflow obstruction and embolic manifestations ending up in death. Here, we report a case of a 44-year-old female who presented with PKD associated with atrial myxoma. A 44-year-old female presented to the emergency department unconscious with a history of sudden onset of dizziness and palpitation. An urgent electrocardiogram was done and showed supraventricular tachycardia. The patient was sedated and emergency synchronized direct current shock was delivered. She started to regain her conscious and her vital signs started to stabilize. Past medical history revealed our female had left atrial mass discovered 10 months earlier and was surgically excised one month before admission. Histological examination showed this mass was myxoma. Blood investigations at the time of admission showed deranged kidney functions. Urine analysis showed uric acid crystals and microscopic hematuria. Abdominal ultrasound showed bilateral polycystic kidneys, two hepatic right lobe cysts, and bilateral multiple renal stones. Cardiac abnormalities are serious complications that could be associated with PKD and are a major cause of death in this population. Atrial myxomas are a rare association with this condition. Further studies to identify other gene loci in PKD may provide an explanation for the associated cardiac abnormalities. PMID- 29970754 TI - Poststreptococcal glomerulonephritis with atypical hemolytic uremic syndrome: An unusual presentation. AB - A 14-year-old female presented with oliguric dialysis requiring kidney injury due to acute poststreptococcal glomerulonephritis (PSGN) with hypertension strongly suggestive of atypical hemolytic uremic syndrome (aHUS) with microangiopathic hemolytic anemia and elevated factor H antibody levels. Renal biopsy revealed crescentic glomerulonephritis with typical subepithelial, intramembranous and mesangial electron-dense deposits (humps) on electron microscopy. She was treated with glucocorticoids following which she recovered, remained dialysis free and her Factor H antibody levels and depressed complement 3 levels normalized. PSGN associated HUS has rarely been described, with this patient being the 11th case reported, to the best of our knowledge. This case is unique as we describe the course and management of the first patient with PSGN-associated HUS in the era of eculizumab, without eculizumab, and plasmapheresis. This patient presented with clinical and histological features of PSGN as well as anemia and thrombocytopenia consistent with aHUS. Given that these diseases are both mediated through the alternate complement pathway, it is tempting to speculate that blockade of the terminal complement pathway through the use of eculizumab might improve outcomes. Temporally, the hematological parameters in our patient seemed to improve soon after treatment was initiated; however, none of the prior cases in the literature experienced any long-term hematological issues, suggesting that supportive management can be a reasonable alternative. PMID- 29970756 TI - Anemia and ferritin in hemodialysis: A new insight for evaluation of managing system. PMID- 29970755 TI - Acquired cystic kidney disease and renal tumor. AB - Immunosuppression is a well-known risk factor for malignancy. Renal transplant patients are at high risk for cancer in the native kidneys especially in the presence of acquired cystic disease. We report a case highlighting the importance of screening for renal malignancy in renal transplant patients. PMID- 29970757 TI - Kidney cysticercosis, cysticercosis related kidney disease and cysticercosis in patients with underlying renal problem: A Rare but important tropical renal infection. PMID- 29970758 TI - Filgrastim-related acute kidney injury in a male renal transplant recipient. PMID- 29970759 TI - Acute kidney injury due to mothball poisoning: Indian pediatric cases. PMID- 29970760 TI - Having rs1042636C677T calcium-sensing receptor polymorphism: Increased or decreased risk for nephrolithiasis? PMID- 29970761 TI - Comparison of anemia and ferritin level between patients on hemodialysis and peritoneal dialysis. PMID- 29970762 TI - Interleukin-6 -174G/C polymorphism and end-stage renal disease: Is there any role? PMID- 29970763 TI - Transplant recipients with cytomegalovirus and BK polyomavirus coinfection nephropathy. PMID- 29970764 TI - Economic burden of asthma in India. PMID- 29970765 TI - Factors influencing severity of community-acquired pneumonia. AB - Introduction: Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality in India. There is a need to understand the risk factors associated with severity of CAP in our population. This study was part of the international global initiative for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia study to evaluate MRSA. Methods: A total of 100 consecutive cases of pneumonia admitted to the Department of Pulmonary Medicine in a tertiary care hospital were recruited in the study during March-July 2015. The severity of pneumonia was assessed based on the CURB-65 score. Individuals with pneumonia and CURB-65 score >2 were compared with subjects with CURB-65 score <=2. Individuals were also evaluated for the causative organism and its resistance pattern with specific reference to the presence of MRSA. Results: Mean age of patients was 54.03 years, 66% were men. Patients were managed either in the intensive care unit (42%) or wards/high dependency unit (58%), 22% needed noninvasive ventilation and 18% needed mechanical ventilation within 24 h of admission. On multivariate analysis, prior respiratory infection (within last 1 year), obesity (body mass index >30), and alcoholism, old age (>60 years) were independently associated risk factors for severe pneumonia. There were no cases of MRSA. In 34% of cases, organisms could be identified. Most common organisms were Klebsiella (8%), influenza (8%), and Pseudomonas (5%). Conclusion: Prior respiratory infection, obesity, alcoholism, and old age (>60 years) were observed to be important risk factors for severe CAP. Prospective studies should evaluate effect of weight reduction and cessation of alcohol consumption on recurrences of pneumonia in this population and on the severity of pneumonia. PMID- 29970766 TI - Patient characteristics and outcome of end-stage lung diseases referred for lung transplantation in North India. AB - Objective: Most countries worldwide have transplant registries for patients with end-stage lung diseases (ESLD) requiring lung transplantation. There is no such lung transplant registry in India. Herein, we describe the demographic profile and clinical outcomes among patients referred for lung transplantation at a tertiary care center in North India. Materials and Methods: This was a prospective, observational study of consecutive patients with chronic respiratory diseases who were referred for lung transplantation between July 2013 and December 2016. Patients were evaluated using standard criteria for listing for lung transplantation. Results: Of the 176 patients assessed for lung transplantation, 167 were included in the study. The mean (standard deviation [SD]) age of the study population (52.1% females) was 53.2 (14.7) years. Interstitial lung disease (ILD, 46.7%), chronic obstructive pulmonary disease (COPD, 25.7%), and bronchiectasis (10.2%) were the most common diseases in this population. The median (interquartile range, IQR) survival was worst for patients with bronchiolitis (78.5 [9-208] days) and idiopathic pulmonary fibrosis (IPF, 93.5 [19-239] days) and best for patients with idiopathic pulmonary arterial hypertension (757 [340-876] days) and COPD (578 [184-763] days). Only 13% of the patients expressed willingness for lung transplantation. Patients willing for transplantation died earlier than those unwilling (median [IQR], 102 [36-224] days vs. 310 [41-713] days, P < 0.001). Conclusion: ILD was the most common cause of ESLD in patients referred for lung transplantation. The waitlist mortality was highest for patients with bronchiolitis and IPF. Despite having ESLD, very few patients were willing for lung transplantation. Patients willing for lung transplantation died earlier than those who were unwilling. PMID- 29970767 TI - Evaluation of Xpert(r)Mycobacterium tuberculosis/rifampin in sputum-smear negative and sputum-scarce patients with pulmonary tuberculosis using bronchoalveolar lavage fluid. AB - Context: Sputum smear-negative and sputum-scarce pulmonary tuberculosis (PTB) is a diagnostic challenge. Xpert(r) Mycobacterium tuberculosis/rifampin (MTB/RIF) provides a rapid diagnosis on high-quality biological specimen obtained by bronchoscopy. Aims: The aim of this study is to evaluate Xpert(r) MTB/RIF on bronchoalveolar lavage (BAL) fluid in sputum smear-negative and sputum-scarce PTB patients. Settings: Tertiary care hospital in India. Design: This was prospective observational study. Materials and Methods: Between January 2015 and November 2016, we prospectively recruited sputum-smear negative and sputum-scarce patients under evaluation for PTB and performed BAL. Sensitivity, specificity, positive, and negative predictive values were calculated for the diagnosis of PTB on BAL fluid for acid-fast bacilli smear and Xpert(r) MTB/RIF using liquid culture as the reference standard and compared to the final diagnosis based on composite reference standard. Sensitivity, specificity, and predictive values were calculated with 95% class intervals. McNemar's test was used for comparison of sensitivities. Results: Of the 60 patients included, 52 (88.3%) had a final diagnosis of PTB and 16 (26.7%) were culture confirmed. Xpert(r) MTB/RIF had a sensitivity and specificity of 81% (54%-96%) and 73% (56%-85%) in culture confirmed cases; 46% (32%-60%) and 100% (63%-100%) for the final diagnosis; 32% (17%-51%) and 100% (54%-100%) in culture negative cases, respectively. Culture had a sensitivity of 32% (20%-47%) for the final diagnosis. Conclusions: In sputum smear-negative and sputum-scarce patients with clinico-radiological features of PTB Xpert(r) MTB/RIF has good sensitivity for diagnosis on BAL fluid. It is useful even when cultures are negative. PMID- 29970768 TI - Obstructive Sleep Apnea in a rural population in South India: Feasibility of health care workers to administer level III sleep study. AB - Objectives: To estimate the occurrence of obstructive sleep apnea (OSA) and its risk factors in a rural Indian population using screening questionnaire and Level III sleep study. To determine the feasibility to train community health workers to administer Level III sleep study in the high-risk population. Materials and Methods: The study was conducted from seven villages with adult population of 2247, in Mugalur, near Bengaluru, from January to April 2014. Berlin questionnaire was used to screen 321 participants chosen by stratified random sampling. A total of 26 out of 321 patients underwent Level III sleep study at home, administered by the health workers, who were trained in three sessions to hook up the machine. Data were verified by a certified sleep physician. Results: The mean age was 39.43 +/- 15.6 years with the M:F ratio of 0.98:1. Prevalence of risk of OSA by Berlin questionnaire was 8.72% (95% confidence interval [CI] 5.63, 11.81) in the total population, 7.4% in males and 11.7% in females. Older age (odds ratio [OR] 3.97; CI 1.63, 9.6), hypertension (OR 11; CI 4.3, 28.2), obesity (OR 2.35; CI 1, 5.5), and higher Mallampati score (OR 3.78; CI 1.7, 8.4) were significantly associated with high risk of OSA (P = 0.0001-0.04). Twenty-six patients underwent Level III sleep study and OSA was diagnosed in 12 patients. The mean apnea-hypopnea index (AHI) of this group was 9.7/h. The prevalence of OSA by AHI criteria was 3.74%. Conclusions: OSA is underdiagnosed in rural populations, although risk factors are present. Training community health workers to administer Level III sleep study is a feasible and cost-effective strategy. PMID- 29970769 TI - Impact of introducing light-emitting diode fluorescence microscopy services for diagnosis of pulmonary tuberculosis under Revised National Tuberculosis Control Program India. AB - Context: Light-emitting diode fluorescence microscopy (LED-FM) has been recommended by the WHO and the Government of India over the conventional bright field microscopy using Ziehl-Neelsen (ZN) staining for the diagnosis of sputum smear-positive tuberculosis (TB) suspects. Aim: The aim of this study was to assess the effectiveness of LED-FM in detecting TB cases. Setting and Design: This retrospective cohort study was carried out in December 2016 using secondary data of the years 2011-2012 from designated microscopy centers (DMCs) at Chandigarh, India. Methodology: Two peripheral DMCs where conventional ZN microscopy was used were taken as controls comparable to two peripheral DMCs which used LED-FM services in programmatic settings. The record of all suspected TB patients who underwent sputum smear examination pre- and post-LED-FM introduction was compared for measuring smear-positive cases, conformational grading, and time taken to read per slide examined. Chi-square was applied to access the statistical significance. Results: Out of total 8850 cases registered after the inception of LED-FM microscopy services, case detection rate was 13.3%, with significant decrease in case detection rate at tertiary level DMCs, there was significant increase in case detection rate at peripheral DMCs operating with LED-FM in contrast to ZN microscopy which was used previously. Scanty grade smear increased significantly by 9.0%. The time taken per slide examination decreased by 57.1% (from 7 min on an average to 3 min on an average) after LED-FM was used. Conclusion: LED-FM is easy to use, takes lesser time to examine slides, and has longer self-life. It also eases laboatory technician's task in reporting scanty grade positives which use to be challenging previously. The results of this study provide enough evidences to scale up the installation process and usage of LED-FM at DMCs for TB diagnosis in Indian settings. PMID- 29970770 TI - Economic burden of asthma among patients visiting a private hospital in South India. AB - Background: The presence of asthma is associated with a socioeconomic burden due to both direct and indirect cost. Aim: This study aims to estimate the economic burden of asthma in terms of direct and indirect cost as also determine if the proper control and adherence to medication would result in reduced cost. Materials and Methods: Direct cost was calculated in terms of medications, doctors visit, investigations, and hospitalizations. Indirect cost was calculated in terms of lost wages, termed as absenteeism. Asthma control was assessed using the asthma control test questionnaire. Results: A total of 120 patients were included; 69 males and 51 females. The mean annual direct cost for asthma treatment was ?18,737/year. The mean annual cost due to medications, doctor's visit, investigations, and hospitalization was ?7,427, ?2089/year, ?1103/year, and ?62,500/year, respectively. An asthma patient lost an average of 17 working days/year. The mean annual indirect cost for an asthma patient was ?25,358, whereas, for the caregivers was ?19,971. About 47.5% of patients had well controlled asthma and 52.5% of patients had uncontrolled asthma. The mean annual direct cost among controlled and uncontrolled asthma patients were ?13,010 and ?23,918, respectively. Fifty-seven percent of patients were compliant with medication. The mean annual direct cost among compliant and non-compliant patients was ?14,401 and ?24,407, respectively. Percentage of hospitalization was less among the compliant group (6%) when compared with noncompliant group (17%). Conclusion: Asthma is not only associated with patient-specific impairment but also a significant economic burden to the family and society. Loss of productivity is another underappreciated source of economic loss. PMID- 29970771 TI - Prolonged stay predictors in patients admitted with chronic obstructive pulmonary disease acute exacerbation. AB - Objectives: The study aimed to identify the factors related to prolonged stay in those patients admitted with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) to our hospital. Methods: We conducted a retrospective study by reviewing the medical records of all patients admitted with AECOPD to the University Hospital Complex of Santiago de Compostela in 2007 and 2008. To identify variables independently associated with length of stay, we conducted a logistic regression including those variables which proved to be significant in the univariate analysis. Results: Six hundred and sixty-one patients were assessed; 76.6% were male and the mean age was 74.5 years (standard deviation [SD]: 11.48). The mean stay was 11.9 days (SD: 8) and 24% of all patients required prolonged stay. Factors associated with prolonged mean stay in multivariate analysis were admission to the Intensive Care Unit (odds ratio [OR], 14.7), hospitalization by internal medicine (OR, 2.1), and use of noninvasive mechanical ventilation (OR, 1.75). Conclusions: Prolonged stay in AECOPD is primarily related to the unit patients are admitted to, and to the need for more intensive care. PMID- 29970774 TI - Allergic bronchopulmonary aspergillosis presenting as nephrotic syndrome due to secondary amyloidosis: Case report and systematic review of the literature. AB - Allergic bronchopulmonary aspergillosis (ABPA) is a complex inflammatory lung disorder complicating bronchial asthma and cystic fibrosis. Although the condition responds to treatment with glucocorticoids and antifungal drugs, lack of timely recognition, and inadequate treatment of ABPA can lead to progressive lung damage. Uncommonly, long standing inflammation and bronchiectasis can also lead to the development of secondary amyloidosis. Herein, we report a case of ABPA, which presented as nephrotic syndrome and progressed rapidly to end-stage renal disease. PMID- 29970773 TI - Use of autologous blood patch for prolonged air leak in spontaneous pneumothoraces in the adolescent population. AB - Instillation of an autologous blood patch for prolonged air leak (PAL) in chest tube system has been studied and determined to be a safe and effective treatment plan for adults. The current recommended treatment guidelines for a PAL in adolescent secondary to a spontaneous pneumothorax are surgical intervention. This paper serves as documentation of two case reports with successful treatment of PALs with autologous blood patch in two adolescent patients. PMID- 29970772 TI - Chronic obstructive pulmonary disease and the hallmarks of aging. AB - Aging is characterized by progressive deterioration of physiological integrity, decline in homeostasis, and degeneration of the tissues that occurs after the reproductive phase of life is complete, leading to impaired function. This deterioration is an important risk factor for chronic lung pathologies such as chronic obstructive pulmonary disease (COPD). COPD is a disease that develops gradually. Emphysematous changes in the lung take years to develop after exposure to cigarette smoke; hence, the vast majority of patients are elderly. There has been a dramatic increase in the life expectancy of the general population, resulting in an increased burden of chronic lung diseases. There is growing evidence that molecular mechanisms involved in aging may also play a role in COPD pathogenesis. Recently, the nine hallmarks of aging were identified. In this article, we will review the nine hallmarks of aging and how each hallmark contributes to the pathogenesis of COPD. PMID- 29970775 TI - Management of cardiac tamponade during catheter-directed thrombolysis of saddle pulmonary embolism: A clinical dilemma. AB - Catheter-directed thrombolysis (CDT) for the treatment of acute pulmonary embolism (PE) has gained popularity in recent years, but potential complications during the procedure and their management are not frequently discussed in the literature. In this case report, we describe the clinical dilemma regarding the postoperative anticoagulation management of a 60-year-old male who developed cardiac perforation during a CDT of an acute saddle PE. Early resumption of systemic heparin in such cases may help in clot resolution; however, it can worsen the hemopericardium. On the other hand, delaying restarting heparin may help in healing of the cardiac perforation but can lead to clot propagation. As the chest tube output was minimal initially, anticoagulation was started, which, however, led to disastrous outcome. With limited published medical literature to help guide such a complex situation, it may be prudent to carefully weigh the risks and benefits of resuming systemic heparin versus delaying it for 1-2 days to allow for definitive resolution of the cardiac perforation. PMID- 29970776 TI - Broncholithiasis presenting with lithoptysis. AB - Broncholithiasis is defined as calcified or ossified material in the bronchial lumen. The most frequently seen symptoms are a non-productive cough and hemoptysis. Occasionally, broncholytic expectoration can be seen, which is known as lithoptysis. As this is not a common finding, a case diagnosed with lithoptysis is presented here. PMID- 29970777 TI - Autologous blood patch pleurodesis: An effective but underused method. PMID- 29970778 TI - A 44-year-old man with hemoptysis. AB - A 44-year-old man with background history of diffuse cutaneous systemic sclerosis and dilated cardiomyopathy receiving immunosuppressive medications, presented with a 2-month history of cough and streaky hemoptysis. Clinicoradiological features were consistent with an endotracheal mass. Subsequently, the patient developed nodular skin lesions and the tracheal mass increased in size causing central airway obstruction. This clinicopathologic conference discusses the clinical and radiological differential diagnoses of such a clinical presentation and their management options. PMID- 29970779 TI - Pulmonary mass with a classical sign on computed tomography scan. PMID- 29970780 TI - Monitoring whole-lung lavage using lung ultrasound: The changing phases of the lung. AB - Lung ultrasound (LUS) has been proven to yield valuable information for lung and pleural pathology. It is well validated for assessing extravascular lung water. It can also be used to monitor stages of controlled lung de-aeration in whole lung lavage (WLL) which is the treatment for Pulmonary Alveolar Protienosis (PAP),characterized by abnormal surfactant in the alveoli affecting gas exchange .LUS can help decide the point of termination of lung flooding. A 55 year old lady with biopsy proven pulmonary alveolar proteinosis presented with respiratory failure. WLL was planned. LUS was used to study the stages of lung flooding as previously described for ARDS model.6 areas screened based on six areas that are normally examined like upper zone, mid zone and lower zone showed alveolar interstitial pattern. One lung ventilation (OLV) was done and isolation of lavage lung was confirmed which was seen as lung collapse (lung pulse) on LUS. Saline infusion resulted in increase in B lines followed by tissue like pattern with fluid bronchogram on LUS(alveolar flooding) in all the areas. During the lavage of the second lung, appearance of alveolar flooding pattern resulted in termination of saline infusion. The use of LUS in monitoring WLL reduced amount of saline used for lavage, pick up complications like pleural effusion and spillage. PMID- 29970781 TI - A rare case of horseshoe lung with scimitar syndrome and persistent left superior vena cava. PMID- 29970782 TI - A progressive granulomatous disease mimicking tuberculosis. PMID- 29970783 TI - Sustained response to low-dose nifedipine in a patient with idiopathic pulmonary arterial hypertension. PMID- 29970784 TI - Granulomatous-lymphocytic interstitial lung disease at the emergency department: Think about it! PMID- 29970785 TI - Beaded pulmonary artery sign. PMID- 29970787 TI - Pneumomediastinum resulting in procedure failure during computed tomography guided biopsy of anterior mediastinal lesion in two children. PMID- 29970786 TI - Lipid-poor adrenal adenoma versus metastasis in lung cancer: Diagnosis by "comparative enhancement" at multiphasic MR imaging. PMID- 29970788 TI - Klinefelter syndrome and bronchial asthma: Is there any relationship between the low testosterone levels and asthma exacerbations? PMID- 29970789 TI - Thymoma metastasis: Differential diagnosis of pleural nodules and masses. PMID- 29970790 TI - The Antioxidant Gallic Acid Inhibits Aflatoxin Formation in Aspergillus flavus by Modulating Transcription Factors FarB and CreA. AB - Aflatoxin biosynthesis is correlated with oxidative stress and is proposed to function as a secondary defense mechanism to redundant intracellular reactive oxygen species (ROS). We find that the antioxidant gallic acid inhibits aflatoxin formation and growth in Aspergillus flavus in a dose-dependent manner. Global expression analysis (RNA-Seq) of gallic acid-treated A. flavus showed that 0.8% (w/v) gallic acid revealed two possible routes of aflatoxin inhibition. Gallic acid significantly inhibited the expression of farB, encoding a transcription factor that participates in peroxisomal fatty acid β-oxidation, a fundamental contributor to aflatoxin production. Secondly, the carbon repression regulator encoding gene, creA, was significantly down regulated by gallic acid treatment. CreA is necessary for aflatoxin synthesis, and aflatoxin biosynthesis genes were significantly downregulated in ?creA mutants. In addition, the results of antioxidant enzyme activities and the lipid oxidation levels coupled with RNA Seq data of antioxidant genes indicated that gallic acid may reduce oxidative stress through the glutathione- and thioredoxin-dependent systems in A. flavus. PMID- 29970791 TI - The Presence of Toxic and Non-Toxic Cyanobacteria in the Sediments of the Limpopo River Basin: Implications for Human Health. AB - The presence of harmful algal blooms (HABs) and cyanotoxins in drinking water sources poses a great threat to human health. The current study employed molecular techniques to determine the occurrence of non-toxic and toxic cyanobacteria species in the Limpopo River basin based on the phylogenetic analysis of the 16S rRNA gene. Bottom sediment samples were collected from selected rivers: Limpopo, Crocodile, Mokolo, Mogalakwena, Nzhelele, Lephalale, Sand Rivers (South Africa); Notwane (Botswana); and Shashe River and Mzingwane River (Zimbabwe). A physical-chemical analysis of the bottom sediments showed the availability of nutrients, nitrates and phosphates, in excess of 0.5 mg/L, in most of the river sediments, while alkalinity, pH and salinity were in excess of 500 mg/L. The FlowCam showed the dominant cyanobacteria species that were identified from the sediment samples, and these were the Microcystis species, followed by Raphidiopsis raciborskii, Phormidium and Planktothrix species. The latter species were also confirmed by molecular techniques. Nevertheless, two samples showed an amplification of the cylindrospermopsin polyketide synthetase gene (S3 and S9), while the other two samples showed an amplification for the microcystin/nodularin synthetase genes (S8 and S13). Thus, these findings may imply the presence of toxic cyanobacteria species in the studied river sediments. The presence of cyanobacteria may be hazardous to humans because rural communities and farmers abstract water from the Limpopo river catchment for human consumption, livestock and wildlife watering and irrigation. PMID- 29970793 TI - The Need to Introduce Simulation-Based Teaching in Pharmacy Education in Saudi Arabia. AB - Pharmacists worldwide, including Saudi Arabia, are now increasingly expected to play a more patient-centred role. The transition of pharmacists from a dispensing role to a more patient-centred clinical role requires the adoption of innovative learning techniques in pharmacy teaching and learning to transform the future pharmacy workforce. One such innovation in pharmacy education is simulation-based pharmacy teaching. The use of simulation in pharmacy education allows pharmacy students to not only improve their clinical knowledge and skills, but also serves as a tool to improve their critical thinking that is a pre-requisite in sound clinical decision-making. Given the importance of patient-oriented teaching in pharmacy education, the majority of institutions offering pharmacy education in the developed countries have successfully integrated simulation-based teaching in their respective curricula to meet both patient and practice needs. However, most of the universities offering undergraduate pharmacy programs in the developing world, including Saudi Arabia, have limited application of patient-focused teaching in their respective programs. This article aims to highlight the importance of introducing simulation-based teaching in pharmacy education in Saudi Arabia. PMID- 29970792 TI - Enrichment Preferences of FIV-Infected and Uninfected Laboratory-Housed Cats. AB - Environmental enrichment is critical for alleviating stress in laboratory felines. However, there is a paucity of information about suitable enrichment for cats. This study aimed to determine preferred enrichment options of individually housed, castrated male domestic short hair cats (Felis catus) used in a longitudinal study of the effects of chronic feline immunodeficiency virus (FIV) infection, and to determine if the FIV status of the cats affected enrichment preferences. Preference testing was performed with two types of grooming brushes, three different interactive play options, including a laser, ball, and petting interaction with a familiar investigator, and two types of toenail conditioning objects. We found that cats elected to be brushed, preferred social interaction and play with the laser to the ball, and preferred to scratch on an inclined-box toenail conditioning object compared to a horizontal, circular toenail conditioning object. There were individual preferences for enrichment opportunities. There were no differences in preferences between FIV-infected and sham-infected cats. These enrichment preferences may be used to advise laboratory animal facilities and researchers about how to best accommodate the behavioral needs of laboratory cats. PMID- 29970795 TI - Is It a Good Time to Be a Pharmacist in the US? AB - The labor market for pharmacists in the United States has seen significant dynamics over the past couple of decades in both demand and supply. The purpose of this brief editorial is to discuss some key concerns for pharmacists in the current labor market and over the next decade. A key issue in evaluating how pharmacists will fare in moving forward into expanded clinical roles and functions will be the degree to which they expand their professional autonomy. PMID- 29970794 TI - Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1. AB - Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 μM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases. PMID- 29970796 TI - Tunable Silver-Functionalized Porous Frameworks for Antibacterial Applications. AB - Healthcare-associated infections and the rise of drug-resistant bacteria pose significant challenges to existing antibiotic therapies. Silver nanocomposites are a promising solution to the current crisis, however their therapeutic application requires improved understanding of underpinning structure-function relationships. A family of chemically and structurally modified mesoporous SBA-15 silicas were synthesized as porous host matrices to tune the physicochemical properties of silver nanoparticles. Physicochemical characterization by transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), X-ray absorption near-edge spectroscopy (XANES) and porosimetry demonstrate that functionalization by a titania monolayer and the incorporation of macroporosity both increase silver nanoparticle dispersion throughout the silica matrix, thereby promoting Ag2CO3 formation and the release of ionic silver in simulated tissue fluid. The Ag2CO3 concentration within functionalized porous architectures is a strong predictor for antibacterial efficacy against a broad spectrum of pathogens, including C. difficile and methicillin-resistant Staphylococcus aureus (MRSA). PMID- 29970798 TI - Laser-Ablated ZnO Nanoparticles and Their Photocatalytic Activity toward Organic Pollutants. AB - This work aimed to prepare nanostructures of ZnO with various lasers, testing them as photocatalysts, and comparing their morphology and activity in the degradation of organic pollutants in aqueous media. ZnO nanospheres (ns-ZnO) and ZnO nanorods (ms-ZnO) were prepared via the laser ablation of a Zn metal plate in water using nanosecond- and millisecond-pulsed lasers, respectively. The obtained materials were characterized using a set of optical, structural, and surface science techniques, such as UV-vis spectroscopy, X-ray diffraction (XRD), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). Under visible-light irradiation, both nanostructures were found to be catalytically active toward the oxidation of methylene blue, which was used as a model compound. The ZnO nanorods fabricated with the millisecond laser showed better photocatalytic performance than their spherically shaped counterparts obtained by means of the nanosecond laser, which could be assigned to a larger number of defects on the ms-ZnO surface. PMID- 29970797 TI - Neighborhood Disorder and Obesity-Related Outcomes among Women in Chicago. AB - Neighborhood psychosocial stressors like crime and physical disorder may influence obesity-related outcomes through chronic stress or through adverse effects on health behaviors. Google Street View imagery provides a low-cost, reliable method for auditing neighborhood physical disorder, but few studies have examined associations of Street View-derived physical disorder scores with health outcomes. We used Google Street View to audit measures of physical disorder for residential census blocks from 225 women aged 18-44 enrolled from 4 Chicago neighborhoods. Latent neighborhood physical disorder scores were estimated using an item response theory model and aggregated to the block group level. Block group level physical disorder scores and rates of police-recorded crime and 311 calls for service requests were linked to participants based on home addresses. Associations were estimated for 6 obesity-related outcomes: body mass index, obesity, total moderate-to-vigorous physical activity, and weekly consumption of sugar-sweetened beverages, fast food, and snacks. Hierarchical regression models estimated cross-sectional associations adjusting for individual sociodemographics and neighborhood poverty. Higher neighborhood physical disorder was associated with greater odds of obesity (OR: 1.43, 95% CI: 1.01, 2.02). Living in a neighborhood with a higher crime rate was associated with an increase in weekly snack consumption of 3.06 (95% CI: 1.59, 4.54). PMID- 29970799 TI - Leptospirosis Health Intervention Module Effect on Knowledge, Attitude, Belief, and Practice among Wet Market Workers in Northeastern Malaysia: An Intervention Study. AB - Leptospirosis is an infectious disease which can be prevented by increasing awareness and promoting preventive health behaviours among high risk groups including wet market workers. Thus, the aim of this study was to determine the effectiveness of Leptospirosis Health Intervention Program (LHIP) in improving knowledge, attitude, belief and practice towards leptospirosis among wet market workers in Kelantan. This intervention study was conducted in two main wet markets in Kelantan involving 116 participants in each control and intervention groups. The health education intervention was based on Leptospirosis Health Intervention Module. The knowledge, attitude, belief and practice scores were measured before and six weeks after the intervention to examine the effect of the program. The results showed that knowledge (p < 0.001), attitude (p = 0.001), belief (p < 0.001) and practice (p < 0.001) scores changes were significantly higher in the intervention group compared to the control group. The adjusted mean differences were 12.93 (95% CI: 8.47, 17.39) for knowledge, 5.55 (95% CI: 2.28, 8.81) for attitude, 7.21 (95% CI: 3.43, 10.99) for belief and 7.35 (95% CI: 3.64, 11.05) for practice scores. Leptospirosis Health Intervention Program was an effective health educational tools to improve awareness and preventive behaviours among risk groups such as wet market workers. PMID- 29970800 TI - Effect of Helmert Transformation Parameters and Weight Matrix on Seasonal Signals in GNSS Coordinate Time Series. AB - Seasonal signals caused by the Earth’s surface mass redistribution can be detected by Global Navigation Satellite Systems (GNSS). The authors analyze the effect of Helmert transformation parameters and weight matrices, as well as the additional draconic signals on seasonal signals, in the GNSS coordinate time series. Moreover, the contribution of environmental loading models to the GNSS position series is assessed. Position time series of 647 global stations, with spans of 2-21 years are collected to generate six cumulative solutions using different parameters estimated in a deterministic model, as well as weight matrices. Comparison among the different solutions indicates that Helmert transformation parameters and weight matrices can result in a root mean square of 0.1 mm and 0.3 mm for seasonal signals, respectively. Compared to the displacements obtained from environmental loading models, seasonal signals estimated with the Helmert parameters and full weight matrices considered seems to have the best agreement with the results of the loading model. Meanwhile, the additional draconic signals are not effective to be parameterized in the deterministic model with an observation time span less than 15 years, marginally. There are 62%, 72% and 90% of 647 stations with weight root mean squares (WRMS) reduced by removing the loading-model-induced changes from the GNSS residual series for the east, north and vertical components, respectively. Finally, to obtain a velocity estimation with a bias of less than 0.1 mm/yr induced by seasonal signals, the position series with a time span greater than seven years is suggested. PMID- 29970801 TI - Measurement of Urinary Bladder Pressure: A Comparison of Methods. AB - Pressure is an essential parameter for the normal function of almost all organs in the human body. Measurement of pressure is therefore highly important in clinical practice and medical research. In clinical practice, pressures are often measured indirectly through a fluid line where the pressure is transmitted from the organ of interest to a remote, externally localized transducer. This method has several limitations and is prone to artefacts from movements. Results from an in vitro bench study comparing the characteristics of two different sensor systems for bladder assessment are presented; a new cystometry system using a MEMS-based in-target organ sensor was compared with a conventional system using water-filled lines connected to external transducers. Robustness to measurement errors due to patient movement was investigated through response to forced vibrations. While the new cystometry system detected real changes in applied pressure for excitation frequencies ranging from 5 Hz to 25 Hz, such small and high-frequency stimuli were not transmitted through the water-filled line connected to the external transducer. The new sensor system worked well after a resilient test at frequencies up to 70 Hz. The in-target organ sensor system will offer new possibilities for long-term monitoring of in vivo pressure in general. This opens up the possibility for future personalized medical treatment and renders possible new health services and, thereby, an increased patient empowerment and quality of life. PMID- 29970803 TI - Functional Analysis of Promoters of Genes in Lipid Metabolism and Their Transcriptional Response to STAT3 under Leptin Signals. AB - We characterized the promoters of target genes of the signal transducer and activator of transcription 3, STAT3 (carnitine palmitoyltransferase I, CPT Iα1b, acetyl-CoA carboxylase alpha, ACCα; fatty acid synthase, FAS; and peroxisome proliferator-activated receptor gamma, PPARγ) in a teleost Pelteobagrus fulvidraco. Binding sites of STAT3 were predicted on these promoters, indicating that STAT3 probably mediated their transcriptional activities. Leptin had no effect on the activity of ACCα and PPARγ promoters, but increased CPT Iα1b promoter activity and decreased FAS promoter activity. The −979/−997 STAT3 binding site of CPT Iα1b and the −794/−812 STAT3 binding site of FAS were functional binding loci responsible for leptin-induced transcriptional activation. The study provided direct evidence that STAT3 regulated the expression of CPT Iα1b and FAS at the transcription level, and determined the STAT3 response element on promoters of CPT Iα1b and FAS under leptin signal. PMID- 29970802 TI - Interplay between Oxidative Stress and Platelet Activation in Coronary Thrombus of STEMI Patients. AB - BACKGROUND: Platelet activation and oxidative stress seem to play a key role in coronary thrombus formation and are associated with thrombus burden in ST elevation myocardial infarction (STEMI). However, the interplay between oxidative stress and platelet activation has not been fully elucidated. MATERIALS AND METHODS: For 32 patients with STEMI undergoing primary percutaneous coronary intervention (PPCI) and 10 patients with stable angina (SA) and oxidative stress, as assessed by NADPH isoform 2 activity (soluble Nox2-derived peptide, sNox2-dp), levels of oxidized low-density lipoproteins (oxLDLs) and platelet activation markers such as soluble CD40 Ligand (sCD40L) and soluble P-selectin (sP-selectin) were measured in the retrieved material (coronary thrombi plus blood waste) of STEMI patients and in intracoronary blood of SA patients, respectively, and in peripheral blood samples of both groups. RESULTS: In aspirated thrombi and blood waste of STEMI patients we found higher serum levels of sNox2-dp, oxLDLs, sCD40L, and sP-selectin, as compared to the intracoronary blood samples of SA patients. Moreover, in thrombi and blood waste of STEMI patients, a direct correlation between markers of oxidative stress and of platelet activation was found. Also, in STEMI patients a progressive increase of oxidative stress and platelet activation markers was observed according to the thrombus score burden. STEMI patients showed higher peripheral blood Nox2 activity and oxLDL levels as compared to SA patients. CONCLUSION: This study shows a close relationship between oxidative stress and platelet activation in the intracoronary blood waste and aspirated thrombi of STEMI patients, suggesting a role of oxidative stress in promoting thrombus formation and growth. PMID- 29970804 TI - An Optical Fiber Refractive Index Sensor Based on the Hybrid Mode of Tamm and Surface Plasmon Polaritons. AB - A novel high performance optical fiber refractive index (RI) sensor based on the hybrid transverse magnetic (TM) mode of Tamm plasmon polariton (TPP) and surface plasmon polariton (SPP) is proposed. The structure of the sensor is a multi-mode optical fiber with a one dimensional photonic crystal (1 DPC)/metal multi-films outer coated on its fiber core. A simulation study of the proposed sensor is carried out with the geometrical optical model to investigate the performance of the designed sensor with respect to the center wavelength, bilayer period and the thickness of silver layer. Because the lights transmitted in the fiber sensor have much larger incident angles than those in the prism based sensors, the center wavelength of the 1 DPC should shift to longer wavelength. When the coupling between TM-TPP and SPP is stronger, the sensor exhibits better performance because the electromagnetic field of the TPP-SPP hybrid mode is enhanced more in the analyte. Compared to most conventional fiber surface plasmon resonance sensors, the figure of merit of the proposed sensor is much higher while the sensitivity is comparable. The idea of utilizing TPP-SPP hybrid mode for RI sensing in the solid-core optical fiber structure presented in this paper could contribute to the study of the fiber RI sensor based on TPP. PMID- 29970806 TI - Mycotoxin Biosensor Based on Optical Planar Waveguide. AB - The research aim of this work is to develop a simple and highly sensitive optical biosensor for detection of mycotoxins. This sensor is built on a planar waveguide operating on the polarization interferometry principle, i.e., detecting a phase shift between p- and s-components of polarized light developed during the binding of analyte molecules. The operation of the proposed sensor is similar to that of a Mach-Zehnder interferometer, while its design is much simpler and it does not require splitting the waveguide into two arms. The refractive index sensitivity of the polarization interferometer sensor was in the range of 5200 radians per refractive index unit (RIU). Several tests were conducted to detect ochratoxin A (OTA) at different concentrations in direct immunoassay with specific antibodies immobilized in the sensing window. The lowest concentration of OTA of 0.01 ng/mL caused a phase shift of nearly one period. The results obtained prove high sensitivity of the sensors, which are capable of detecting even lower concentrations of mycotoxins at the ppt (part-per-trillion) level. PMID- 29970805 TI - Venom Ontogeny in the Mexican Lance-Headed Rattlesnake (Crotalus polystictus). AB - As trophic adaptations, rattlesnake venoms can vary in composition depending on several intrinsic and extrinsic factors. Ontogenetic changes in venom composition have been documented for numerous species, but little is known of the potential age-related changes in many rattlesnake species found in México. In the current study, venom samples collected from adult and neonate Crotalus polystictus from Estado de México were subjected to enzymatic and electrophoretic analyses, toxicity assays (LD50), and MALDI-TOF mass spectrometry, and a pooled sample of adult venom was analyzed by shotgun proteomics. Electrophoretic profiles of adult males and females were quite similar, and only minor sex-based variation was noted. However, distinct differences were observed between venoms from adult females and their neonate offspring. Several prominent bands, including P-I and P-III snake venom metalloproteinases (SVMPs) and disintegrins (confirmed by MS/MS) were present in adult venoms and absent/greatly reduced in neonate venoms. Age-dependent differences in SVMP, kallikrein-like, phospholipase A2 (PLA2), and L-amino acid oxidase (LAAO) activity levels were confirmed by enzymatic activity assays, and like many other rattlesnake species, venoms from adult snakes have higher SVMP activity than neonate venoms. Conversely, PLA2 activity was approximately 2.5 × greater in venoms from neonates, likely contributing to the increased toxicity (neonate venom LD50 = 4.5 μg/g) towards non-Swiss albino mice when compared to adult venoms (LD50 = 5.5 μg/g). Thrombin-like (TLE) and phosphodiesterase activities did not vary significantly with age. A significant effect of sex (between adult male and adult female venoms) was also observed for SVMP, TLE, and LAAO activities. Analysis of pooled adult venom by LC-MS/MS identified 14 toxin protein families, dominated by bradykinin-inhibitory peptides, SVMPs (P-I, P-II and P-III), disintegrins, PLA2s, C-type-lectins, CRiSPs, serine proteinases, and LAAOs (96% of total venom proteins). Neonate and adult C. polystictus in this population consume almost exclusively mammals, suggesting that age-based differences in composition are related to physical differences in prey (e.g., surface-to-volume ratio differences) rather than taxonomic differences between prey. Venoms from adult C. polystictus fit a Type I pattern (high SVMP activity, lower toxicity), which is characteristic of many larger-bodied rattlesnakes of North America. PMID- 29970807 TI - Wireless Passive Ultra High Frequency RFID Antenna Sensor for Surface Crack Monitoring and Quantitative Analysis. AB - An exponential increase in large-scale infrastructure facilitates the development of wireless passive sensors for permanent installation and in-service health monitoring. Due to their wireless, passive and cost-effective characteristics, ultra-high frequency (UHF) radio frequency identification (RFID) tag antenna based sensors are receiving increasing attention for structural health monitoring (SHM). This paper uses a circular patch antenna sensor with an open rectangular window for crack monitoring. The sensing mechanism is quantitatively studied in conjunction with a mode analysis, which can uncover the intrinsic principle for turning an antenna into a crack sensor. The robustness of the feature is examined when the variation of crack position associated with an aluminum sample and the antenna sensor is considered. The experimental results demonstrate a reasonable sensitivity and resolution for crack characterization. PMID- 29970809 TI - Present and Future Therapy of Cryptococcus Infections. AB - Cryptococcal infections burden the immunocompromised population with unacceptably high morbidity and mortality. This population includes HIV-infected individuals and those undergoing organ transplants, as well as seemingly immunocompetent patients (non-HIV, non-transplant). These groups are difficult to manage with the current therapeutic options and strategies, particularly in resource-limited settings. New trials aimed at providing the best treatment strategies for resource-limited countries that will reduce costs and adverse reactions have focused on decreasing the length of therapy and using more readily accessible antifungal agents such as fluconazole. Furthermore, the emergence of antifungal resistance poses another challenge for successful treatment and may require the development of new agents for improved management. This review will discuss the principles of management, current and future antifungal agents, as well as emerging techniques and future directions of care for this deadly infection. PMID- 29970808 TI - beta-glucan Salecan Improves Exercise Performance and Displays Anti-Fatigue Effects through Regulating Energy Metabolism and Oxidative Stress in Mice. AB - Fatigue induced by prolonged exercise not only leads to the decrease of exercise capacity, but also might be the cause of many diseases. In consideration of the side effects of pharmacological drugs, dietary supplements seem to be a better choice to ameliorate exercise-induced fatigue. The present study aimed to investigate the anti-fatigue effect of Salecan, a novel water-soluble β glucan, during exercise and explore the underlying mechanisms. Male Institute of Cancer Research (ICR) mice were divided into five groups, including the Rest group and the other four Swim-groups treated with Salecan at 0, 25, 50, and 100 mg/kg/day for four weeks. Salecan treatment markedly increased the exhaustive swimming time of mice in the forced swimming test. Exercise fatigue and injury related biochemical biomarkers including lactate, blood urea nitrogen (BUN), creatinine kinase (CK), alanine transaminase (ALT), and aspartate transaminase (AST) were ameliorated by Salecan. Salecan reversed the decreased serum glucose levels and glycogen contents caused by exercise. In addition, Salecan improved oxidative stress induced by exercise through regulating Nrf2/HO-1/Trx signaling pathway. Thus, the beneficial effects of Salecan against fatigue may be due to its positive effects on energy metabolism and antioxidation defence. Our results suggest that Salecan could be a novel potential candidate for anti-fatigue dietary supplements. PMID- 29970810 TI - Effect of Suspended Particulate Matter on the Accumulation of Dissolved Diarrhetic Shellfish Toxins by Mussels (Mytilus galloprovincialis) under Laboratory Conditions. AB - In recent years, detection of trace amounts of dissolved lipophilic phycotoxins in coastal waters has been possible using solid phase adsorption toxin tracking (SPATT) samplers. To explore the contribution of dissolved diarrhetic shellfish toxins (DST) to the accumulation of toxins by cultivated bivalves, mussels (Mytilus galloprovincialis) were exposed to different concentrations of purified okadaic acid (OA) and dinophysistoxin-1 (DTX1) in filtered (0.45 µm) seawater for 96 h. Accumulation and esterification of DST by mussels under different experimental conditions, including with and without the addition of the food microalga Isochrysis galbana, and with the addition of different size fractions of suspended particulate matter (SPM) (<75 µm, 75-150 µm, 150-250 µm) were compared. Results showed that mussels accumulated similar amounts of OA and DTX1 from seawater with or without food microalgae present, and slightly lower amounts when SPM particles were added. Mussels preferentially accumulated OA over DTX1 in all treatments. The efficiency of the mussel’s accumulation of OA and DTX1 from seawater spiked with low concentrations of toxins was higher than that in seawater with high toxin levels. A large proportion of OA (86-94%) and DTX1 (65-82%) was esterified to DTX3 by mussels in all treatments. The proportion of I. galbana cells cleared by mussels was markedly inhibited by dissolved OA and DTX1 (OA 9.2 µg L−1, DTX1 13.2 µg L−1) in seawater. Distribution of total OA and DTX1 accumulated in the mussel tissues ranked in all treatments as follows: digestive gland > gills > mantle > residual tissues. However, the percentage of total DST in the digestive gland of mussels in filtered seawater (67%) was higher than with the addition of SPM particles (75-150 µm) (51%), whereas the gills showed the opposite trend in filtered seawater with (27%) and without (14.4%) SPM particles. Results presented here will improve our understanding of the mechanisms of DST accumulation by bivalves in marine aquaculture environments. PMID- 29970812 TI - Purification and Characterization of Native and Vaccine Candidate Mutant Enterotoxigenic Escherichia coli Heat-Stable Toxins. AB - Enterotoxigenic Escherichia coli (ETEC), which secretes the heat-stable toxin (ST) is among the four most important enteropathogens that cause moderate-to severe diarrhea in children in low- and middle-income countries. ST is an intestinal molecular antagonist causing diarrhea and hence an attractive vaccine target. A non-toxic and safe ST vaccine should include one or more detoxifying mutations, and rigorous characterization of such mutants requires structurally intact peptides. To this end, we established a system for purification of ST and ST mutants by fusing the sequence encoding the mature ST peptide to the disulfide isomerase DsbC. A Tobacco Etch Virus protease cleavage site facilitates the proteolytic release of free ST with no additional residues. The purified ST peptides have the expected molecular masses, the correct number of disulfide bridges, and have biological activities and antigenic properties comparable to ST isolated from ETEC. We also show that free DsbC can assist in refolding denatured and misfolded ST in vitro. Finally, we demonstrate that the purification system can be used to produce ST mutants with an intact neutralizing epitope, that two single mutations, L9S and A14T, reduce toxicity more than 100-fold, and that the L9S/A14T double mutant has no measurable residual toxicity. PMID- 29970813 TI - Effect of a Synthetic Nano-CaO-Al2O3-SiO2-H2O Gel on the Early-Stage Shrinkage Performance of Alkali-Activated Slag Mortars. AB - The relatively high shrinkage of the alkali-activated slag (AAS) has restricted its application as a widely-used building material. This research attempts to study the effect of a hydrothermally synthesized C-A-S-H gel, which has a similar composition to that of the main AAS product, on the shrinkage performance of the AAS. The C-A-S-H nano-particles were mixed into AAS mortars in a proportion ranging from 1 wt % to 5 wt % using two different methods, and the drying and autogenous shrinkage ratio of modified AAS mortars were measured at various ages. The effect of C-A-S-H on their microstructures was also characterized. Results obtained indicated that the addition of C-A-S-H gel to AAS mortars had reduced their drying and autogenous shrinkage, with the addition of 3 wt % reaching the maximum reduction. However, the added amount was not directly proportional to the decrease of shrinkage; the proportion of early-stage drying shrinkage of AAS mortars was greater than that of autogenous shrinkage; the dispersion method was slightly better than the dry mixing method in both shrinkage reduction. MIP results suggested that the addition of C-A-S-H gel had reduced the total porosity and the average pore size of AAS mortars, optimized their pore structure distribution, and significantly reduced the volume of mesopores (<0.05 µm) which resulted in high shrinkage, while the adding method had no significant effect on the pore size distribution of AAS mortars. SEM results showed that the addition of C-A-S-H gel can reduce the crack width of mortars, obtain a dense and uniform matrix structure, increase the density, and effectively suppress both shrinkage deformation of the system, whereas the adding method has no obvious effect on the crack width of the mortar. This research provides a novel approach of the AAS shrinkage reduction and structure refinement, shedding lights on nano material modification of the AAS. PMID- 29970811 TI - Loneliness and Diurnal Salivary Cortisol in Emerging Adults. AB - This study aimed to examine the relationship between trait loneliness and diurnal rhythms of salivary cortisol. Fifty-One Chinese undergraduates provided six saliva samples on a weekday at immediately, 0.5, 3, 6, and 12 h after waking, and at bedtime. Saliva collection times were monitored using electronic devices (MEMS TrackCaps). Participants were also administered a questionnaire consisting of scales measuring, trait loneliness, depression, and demographics. Relationships between loneliness and the cortisol awakening response (CAR), diurnal slope (DS), and area under the curve with respect to ground (AUCG) were examined using multiple regression analyses. Results showed that a higher loneliness score was associated with an attenuated CAR, a large AUCG, and a steeper DS, with the effects of compliance, waking time, and depression being controlled. As a blunted CAR and a higher diurnal cortisol level have been shown to be associated with poorer health in prior studies, increased attention to the mechanisms translating loneliness into disease endpoints via elevated cortisol is warranted. PMID- 29970814 TI - A 10-Bit 300 kS/s Reference-Voltage Regulator Free SAR ADC for Wireless-Powered Implantable Medical Devices. AB - This paper presents a reference-voltage regulator free successive-approximation register analog-to-digital converters (SAR ADC) with self-timed pre-charging for wireless-powered implantable medical devices. Assisted by a self-timed pre charging technique, the proposed SAR ADC eliminates the need for a power-hungry reference-voltage regulator and area-consuming decoupling capacitor while maintaining insensitivity to the supply voltage fluctuation. Fabricated with a 0.18-µm complementary metal-oxide-semiconductor (CMOS) technology, the proposed SAR ADC achieves a Signal To Noise And Distortion Ratio (SNDR) of 53.32 dB operating at 0.8 V with a supply voltage fluctuation of 50 mVpp and consumes a total power of 2.72 µW at a sampling rate of 300 kS/s. Including the self timed pre-charging circuits, the total figure-of-merit (FOM) is 23.9 fJ/conversion-step and the total area occupied is 0.105 mm2. PMID- 29970815 TI - Effect of Red Ginseng Extract on the Pharmacokinetics and Efficacy of Metformin in Streptozotocin-Induced Diabetic Rats. AB - The purpose of this study was to investigate the effect of red ginseng extract on the pharmacokinetics (PK) and efficacy of metformin in streptozotocin-induced diabetic rats. The diabetes mellitus rat model was established by intraperitoneally administering multiple doses of streptozotocin (30 mg/kg, twice on day 1 and 8), and diabetic rats received metformin 50 mg/kg with or without single or multiple administration of Korean red ginseng extract (RGE, 2 g/kg/day, once or for 1 week). RGE administration did not affect the plasma concentration and renal excretion of metformin. Further, diabetic rats were administered metformin (50 mg/kg) and RGE (2 g/kg) alone or concomitantly for 5 weeks, and both regimens decreased the fasting blood glucose and glycated hemoglobin (Hb A1c) levels. Furthermore, fasting blood glucose levels were reduced by metformin or RGE administered alone but recovered to the control level following co administration, suggesting that the effect was additive. However, triglyceride and free fatty acid levels were not different with metformin and RGE treatment alone or in combination. Biochemical parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol levels were not different among the three treatment groups. In conclusion, RGE and metformin showed an additive effect in glycemic control. However, the co administration of RGE and metformin did not cause PK interactions or affect biochemical parameters including the free fatty acid, triglyceride, AST, ALT, or cholesterol levels. PMID- 29970816 TI - Optimisation of the Microwave-Assisted Ethanol Extraction of Saponins from Gac (Momordica cochinchinensis Spreng.) Seeds. AB - BACKGROUND: Gac (Momordica cochinchinensis Spreng.) seeds contain saponins that are reportedly medicinal. It was hypothesised that the extraction of saponins from powdered Gac seed kernels could be optimised using microwave-assisted extraction (MAE) with ethanol as the extraction solvent. The aim was to determine an appropriate ethanol concentration, ratio of solvent to seed powder and microwave power and time for extraction. Whether or not defatting the Gac seed powder had an impact on the extraction of saponins, was also determined. RESULTS: A four-fold higher total saponin content (TSC) was obtained in extracts from full fat Gac seed kernel powder than from defatted powder (100 vs. 26 mg aescin equivalents (AE) per gram of Gac seeds). The optimal parameters for the extraction of saponins were a ratio of 30 mL of 100% absolute ethanol per g of full-fat Gac seed kernel powder with the microwave set at 360 W for three irradiation cycles of 10 s power ON and 15 s power OFF per cycle. CONCLUSIONS: Gac seed saponins could be efficiently extracted using MAE. Full-fat powder of the seed kernels is recommended to be used for a better yield of saponins. The optimised MAE conditions are recommended for the extraction of enriched saponins from Gac seeds for potential application in the nutraceutical and pharmaceutical industries. PMID- 29970817 TI - The Expression of CARK1 or RCAR11 Driven by Synthetic Promoters Increases Drought Tolerance in Arabidopsis thaliana. AB - Drought stress hinders plant growth and development, and abscisic acid (ABA) stimulates plants to respond to drought. Here, to increase plant tolerance to drought, we designed three synthetic promoters (Ap, Dp, ANDp) to determine transcription activity and drought stress resistance in plants resulting from combinations of (1) synthetic promoters and (2) the functional genes CARK1 (cytosolic ABA receptor kinase 1) and RCAR11 (regulatory components of ABA receptor 11). Transient expression of eGFP and the dual-luciferase assay demonstrated that the basal transcriptional activities of Ap and ANDp were present at low levels under normal conditions, while the synthetic promoters were apparently induced upon either treatment of exogenous ABA or co-transformation with effector DREB2A (dehydration-responsive element binding protein 2A). Analysis of the transgenic plants (Ap:CARK1, Dp:CARK1, ANDp:CARK1, and Dp:RCAR11 Ap:CARK1) showed that the synthetic promoters Ap, Dp, and ANDp increased the expression of exogenous genes in transgenic plants upon treatment of ABA or d mannitol. ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 transgenic plants were sensitive to ABA and d-mannitol during cotyledon greening and root growth. A drought tolerance assay revealed that ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 exhibited a higher survival rate than others upon drought stress. These results indicate that the combinations ANDp:CARK1 and Dp:RCAR11-Ap:CARK1 can be used to generate drought stress resistance in plants. PMID- 29970818 TI - Optimal Polygon Decomposition for UAV Survey Coverage Path Planning in Wind. AB - In this paper, a new method for planning coverage paths for fixed-wing Unmanned Aerial Vehicle (UAV) aerial surveys is proposed. Instead of the more generic coverage path planning techniques presented in previous literature, this method specifically concentrates on decreasing flight time of fixed-wing aircraft surveys. This is achieved threefold: by the addition of wind to the survey flight time model, accounting for the fact fixed-wing aircraft are not constrained to flight within the polygon of the region of interest, and an intelligent method for decomposing the region into convex polygons conducive to quick flight times. It is shown that wind can make a huge difference to survey time, and that flying perpendicular can confer a flight time advantage. Small UAVs, which have very slow airspeeds, can very easily be flying in wind, which is 50% of their airspeed. This is why the technique is shown to be so effective, due to the fact that ignoring wind for small, slow, fixed-wing aircraft is a considerable oversight. Comparing this method to previous techniques using a Monte Carlo simulation on randomised polygons shows a significant reduction in flight time. PMID- 29970819 TI - Transcription Factor ETS-1 and Reactive Oxygen Species: Role in Vascular and Renal Injury. AB - The E26 avian erythroblastosis virus transcription factor-1 (ETS-1) is a member of the ETS family and regulates the expression of a variety of genes including growth factors, chemokines and adhesion molecules. Although ETS-1 was discovered as an oncogene, several lines of research show that it is up-regulated by angiotensin II (Ang II) both in the vasculature and the glomerulus. While reactive oxygen species (ROS) are required for Ang II-induced ETS-1 expression, ETS-1 also regulates the expression of p47phox, which is one of the subunits of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and a major source of ROS in the kidney and vasculature. Thus, there appears to be a positive feedback between ETS-1 and ROS. ETS-1 is also upregulated in the kidneys of rats with salt sensitive hypertension and plays a major role in the development of end-organ injury in this animal model. Activation of the renin angiotensin system is required for the increased ETS-1 expression in these rats, and blockade of ETS-1 or haplodeficiency reduces the severity of kidney injury in these rats. In summary, ETS-1 plays a major role in the development of vascular and renal injury and is a potential target for the development of novel therapeutic strategies to ameliorate end-organ injury in hypertension. PMID- 29970822 TI - Application of Struvite-MAP Crystallization Reactor for Treating Cattle Manure Anaerobic Digested Slurry: Nitrogen and Phosphorus Recovery and Crystal Fertilizer Efficiency in Plant Trials. AB - Recycling and reusing the nutrient resources from anaerobic digested slurry is very promising for environmental pollution control and agriculture sustainable development. We focus here on nitrogen and phosphorus recycling in treating cattle manure anaerobic digested slurry by a magnesium ammonium phosphate (struvite-MAP) crystallization process and examine the impact of MAP precipitation on plant growth. The MAP crystallization process was studied by a combination of Design-Expert 8.0.6 software, mathematical modeling, and experiments. The influence of Mg/P, N/P and pH on nitrogen (N) and phosphorus (P) recovery was investigated. Then, the fertilizing efficiency of the MAP precipitate on the growth of three vegetables (water spinach (Swamp cabbage), amaranth and Brassica parachinensis) was also evaluated. The results showed that more than 89% of N and 99% of P could be recovered at pH = 10 with molar ratios of Mg/P = 1.6 and N/P = 1.2. Compared with the control pots and potassium chloridepots, the fresh weight, dry weight and average height of swamp cabbage in the MAP pots were obviously enhanced without burning effects. The results showed that MAP precipitation can promote the development of plants, which is promising for its use as a slow-release fertilizer for agricultural production. PMID- 29970821 TI - Risk of Metabolic Syndrome among Middle-Aged Koreans from Rural and Urban Areas. AB - Metabolic syndrome (MetS) is a common global health problem. This study aims to assess nutrient intake and risk of MetS in middle-aged Koreans based in residential areas. Participants were 161,326 (142,137 in urban and 19,189 in rural) subjects enrolled in the Korea Genome and Epidemiology Study. The prevalence of MetS was much higher in rural (39.8%) than that in urban (22.5%) subjects (p < 0.001). The rural residents showed significantly higher blood pressure (p < 0.001), serum triglyceride levels (p < 0.001), and LDL (Low density lipoprotein)-cholesterol level (p < 0.001), as well as the odds ratio (OR) for MetS (OR = 1.65, 95% CI: 1.59-1.71), compared to urban residents. The rural subjects showed a higher consumption of carbohydrate and sodium compared to the urban subjects (p < 0.001). After adjusting for potential confounders, subjects in the highest quartile of carbohydrate intake had higher OR for MetS (OR = 1.23, 95% CI: 1.15-1.32) and those in the highest quartile of sodium intake had a higher chance of having MetS (OR = 1.11, 95% CI: 1.07-1.16) than did those in the lowest quartiles. Our results suggested that the higher consumption of carbohydrate and sodium in rural residents might be associated with the increased risk of MetS in this population. PMID- 29970820 TI - The Effects of Birth Year, Age and Sex on Hemagglutination Inhibition Antibody Responses to Influenza Vaccination. AB - The first exposure to influenza is thought to impact subsequent immune responses later in life. The consequences of this can be seen during influenza epidemics and pandemics with differences in morbidity and mortality for different birth cohorts. There is a need for better understanding of how vaccine responses are affected by early exposures to influenza viruses. In this analysis of hemagglutination inhibition (HI) antibody responses in two cohorts of military personnel we noticed differences related to age, sex, prior vaccination, deployment and birth year. These data suggest that HI antibody production, in response to influenza vaccination, is affected by these factors. The magnitude of this antibody response is associated with, among other factors, the influenza strain that circulated following birth. PMID- 29970823 TI - Automatic Annotation of Unlabeled Data from Smartphone-Based Motion and Location Sensors. AB - Automatic data annotation eliminates most of the challenges we faced due to the manual methods of annotating sensor data. It significantly improves users’ experience during sensing activities since their active involvement in the labeling process is reduced. An unsupervised learning technique such as clustering can be used to automatically annotate sensor data. However, the lingering issue with clustering is the validation of generated clusters. In this paper, we adopted the k-means clustering algorithm for annotating unlabeled sensor data for the purpose of detecting sensitive location information of mobile crowd sensing users. Furthermore, we proposed a cluster validation index for the k-means algorithm, which is based on Multiple Pair-Frequency. Thereafter, we trained three classifiers (Support Vector Machine, K-Nearest Neighbor, and Naïve Bayes) using cluster labels generated from the k-means clustering algorithm. The accuracy, precision, and recall of these classifiers were evaluated during the classification of “non-sensitive” and “sensitive” data from motion and location sensors. Very high accuracy scores were recorded from Support Vector Machine and K-Nearest Neighbor classifiers while a fairly high accuracy score was recorded from the Naïve Bayes classifier. With the hybridized machine learning (unsupervised and supervised) technique presented in this paper, unlabeled sensor data was automatically annotated and then classified. PMID- 29970824 TI - Design and Implementation of a Central-Controllable and Secure Multicast System Based on Universal Identifier Network. AB - With the rapid increase of network users and services, the breadth and depth of Internet have greatly changed. The mismatch between current network requirements and original network architecture design has spurred the evolution or revolution of Internet to remedy this gap. Lots of research projects on future network architecture have been launched, in which Universal Identifier Network (UIN) architecture that is based on the identifier/location separation, access/core separation and control/forwarding separation can provide better mobility, security and reliability. On the other hand, the demand of group communication has increased due to the fine-grained network services and successive booming of new applications such as IoT (Internet of Things). Most of current multicast schemes are based on the open group model with open group membership (multicast only care the multicast group state, not the group member) and open access to send/receive multicast data, which are beneficial to multicast routing for its simplification. However, the open group membership makes the group member management difficult to be realized, and open access may result in lots of security vulnerabilities such as Denial of service (DoS), eavesdropping and masquerading, which make deployment more difficult. Therefore, in this paper we propose a Central-Controllable and Secure Multicast (CCSM) system based on the UIN architecture, and redesign the multicast service procedures including registration, join/leave, multicast routing construction and update with objective to achieve better mobility support, security, scalability and controllable. More specifically, we design a new group management scheme to perform the multicast members join/leave with authentication and a central controllable multicast routing scheme to provide a secure way to set up multicast entries on routers. The CCSM inherits the characteristics of UIN in terms of mobility and security, and it can provide the centralized multicast routing computation and distributes the multicast routing into forwarders. We compare CCSM with Protocol Independent Multicast-Sparse Mode (PIM-SM), and the results show that CCSM reduces the multicast join delay, and performs better than PIM-SM in term of reconstruction cost under low multicast density. PMID- 29970825 TI - Monitoring and Simulating Environmental Asbestos Dispersion from a Textile Factory. AB - Although workplace asbestos concentrations (AC) have been reported several times, the past environmental AC are relatively poorly studied. Due to the harmful effects of the asbestos industry, production has moved from early industrialized countries (Japan), to late industrialized countries (Korea), and finally to industrializing countries (Indonesia). The purpose of this study was to determine current occupational exposure levels and evaluate neighborhood environmental exposure levels in an Indonesian asbestos textile factory through collaboration among three generation of industrialized countries. Asbestos concentrations were measured inside and outside of the factory and compared with simulated data. ACs in the factory were similar to those of 1980s and 1990s levels in the Korean factory that transferred the machines. Environmental ACs were dispersed according to wind direction. There were no significant differences between monitored and simulated data, and correlation coefficients between downwind, upwind, and middle wind directions were high, with some statistical significance. This study can be used to estimate past environmental ACs to understand the causality of asbestos related diseases. Because of the small sample size and specific weather conditions, a large-scale study of various asbestos exposure sources, including asbestos cement factories, shipyards, and mines, and various atmospheric conditions is required. PMID- 29970826 TI - Deterministic Propagation Modeling for Intelligent Vehicle Communication in Smart Cities. AB - Vehicular Ad Hoc Networks (VANETs) are envisaged to be a critical building block of Smart Cities and Intelligent Transportation System (ITS) where applications for pollution, congestion reduction, vehicle mobility improvement, accident prevention and safer roads are some of the VANETs expected benefits towards Intelligent Vehicle Communications. Although there is a significant research effort in Vehicle-to-Infrastructure (V2I) and Vehicle-to-Vehicle (V2V) communication radio channel characterization, the use of a deterministic approach as a complement of theoretical and empirical models is required to understand more accurately the propagation phenomena in urban environments. In this work, a deterministic computational tool based on an in-house 3D Ray-Launching algorithm is used to represent and analyze large-scale and small-scale urban radio propagation phenomena, including vehicle movement effects on each of the multipath components. In addition, network parameters such as throughput, packet loss and jitter, have been obtained by means of a set of experimental measurements for different V2I and V2V links. Results show the impact of factors such as distance, frequency, location of antenna transmitters (TX), obstacles and vehicle speed. These results are useful for radio-planning Wireless Sensor Networks (WSNs) designers and deployment of urban Road Side Units (RSUs). PMID- 29970828 TI - Red (635 nm), Near-Infrared (808 nm) and Violet-Blue (405 nm) Photobiomodulation Potentiality on Human Osteoblasts and Mesenchymal Stromal Cells: A Morphological and Molecular In Vitro Study. AB - Photobiomodulation (PBM) has been used for bone regenerative purposes in different fields of medicine and dentistry, but contradictory results demand a skeptical look for its potential benefits. This in vitro study compared PBM potentiality by red (635 +/- 5 nm) or near-infrared (NIR, 808 +/- 10 nm) diode lasers and violet-blue (405 +/- 5 nm) light-emitting diode operating in a continuous wave with a 0.4 J/cm2 energy density, on human osteoblast and mesenchymal stromal cell (hMSC) viability, proliferation, adhesion and osteogenic differentiation. PBM treatments did not alter viability (PI/Syto16 and MTS assays). Confocal immunofluorescence and RT-PCR analyses indicated that red PBM (i) on both cell types increased vinculin-rich clusters, osteogenic markers expression (Runx-2, alkaline phosphatase, osteopontin) and mineralized bone-like nodule structure deposition and (ii) on hMSCs induced stress fiber formation and upregulated the expression of proliferation marker Ki67. Interestingly, osteoblast responses to red light were mediated by Akt signaling activation, which seems to positively modulate reactive oxygen species levels. Violet-blue light-irradiated cells behaved essentially as untreated ones and NIR irradiated ones displayed modifications of cytoskeleton assembly, Runx-2 expression and mineralization pattern. Although within the limitations of an in vitro experimentation, this study may suggest PBM with 635 nm laser as potential effective option for promoting/improving bone regeneration. PMID- 29970829 TI - Characterization and Dynamic Shift of Microbial Communities during Start-Up, Overloading and Steady-State in an Anaerobic Membrane Bioreactor. AB - A lab-scale anaerobic membrane bioreactor (AnMBR) with a side stream tubular membrane was developed to treat synthetic domestic sewage to evaluate its performance and the dynamic shift of bacterial and archaeal communities during the start-up, steady-state, overloading and recovery periods of operation at mesophilic temperatures. During the start-up period, the bacterial and archaeal communities changed drastically, and Proteobacteria and Bacteroidetes predominated. During the steady-state period, the AnMBR exhibited excellent COD removal above 91%, and COD of the effluent was below 50 mg/L. High-throughput sequencing analysis results revealed that bacterial and archaeal communities shifted significantly from the start-up to the steady-state period, and that the Proteobacteria phylum predominated on days 140, 162 and 190, and the archaea community hydrogenotrophic methanogen genus Methanolinea (1.5-6.64%) predominated over the aceticlastic methanogen genus Methanothrix (1.35-3.07%). During the overloading period, significant changes occurred in microbial community on day 210, e.g., the phyla Bacteroidetes (30%), Proteobacteria (23%) and Firmicutes (18%) predominated and the archaeal community was completely suppressed, and Methanobrevibacter (0.7%) was the only methanogen genus that emerged in the overloading period. After a shock loading period, the microbial communities exhibited significant changes within the ranks of methanogens and shifted to dominance of the aceticlastic methanogen pathway. In addition, the TVFAs to alkalinity ratio in this study was suitable as an indicator of monitoring performance in the AnMBR operation. PMID- 29970830 TI - Phenotypic Characterization of the c.1679+1643G>T (1811+1643G>T) Mutation in Hispanic Cystic Fibrosis Patients. AB - Cystic fibrosis (CF) is the most common fatal genetic diseases in the United States in Caucasians. More than 2000 genetic mutations have been described and CF is now known to affect other races. The incidence of CF in individuals of Hispanic descent is estimated to be 1:9200. An uncommon mutation, 1811+1643G>T, was recently reported. We report four patients with the 1811+1643G>T mutation (homozygous or heterozygous) and describe their clinical features and compare them to the remainder of our Hispanic cohort group. The homozygous patients had a more severe phenotype compared to the Hispanic cohort in the following areas: their pancreatic status, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), chronic Pseudomonas aeruginosa (PA) colonization, pulmonary exacerbations requiring oral and intravenous antibiotics, and hospitalization rate. These preliminary findings suggest that future studies investigating the clinical trajectory with a larger cohort of patients homozygous for the 1811+1643G>T mutation are needed. PMID- 29970831 TI - Activating Childcare Environments for All Children: the Importance of Children's Individual Needs. AB - Characteristics of the physical childcare environment are associated with children’s sedentary behavior (SB) and physical activity (PA) levels. This study examines whether these associations are moderated by child characteristics. A total of 152 1- to 3-year-old children from 22 Dutch childcare centers participated in the study. Trained research assistants observed the physical childcare environment, using the Environment and Policy Assessment Observation (EPAO) protocol. Child characteristics (age, gender, temperament and weight status) were assessed using parental questionnaires. Child SB and PA was assessed using Actigraph GT3X+ accelerometers. Linear regression analyses including interaction terms were used to examine moderation of associations between the childcare environment and child SB and PA. Natural elements and portable outdoor equipment were associated with less SB and more PA. In addition, older children, boys and heavier children were less sedentary and more active, while more use of childcare and an anxious temperament were associated with more SB. There were various interactions between environmental factors and child characteristics. Specific physical elements (e.g., natural elements) were especially beneficial for vulnerable children (i.e., anxious, overactive, depressive/withdrawn, overweight). The current study shows the importance of the physical childcare environment in lowering SB and promoting PA in very young children in general, and vulnerable children specifically. Moderation by child characteristics shows the urgency of shaping childcare centers that promote PA in all children, increasing equity in PA promotion in childcare. PMID- 29970827 TI - Recent Insights on Alzheimer's Disease Originating from Yeast Models. AB - In this review article, yeast model-based research advances regarding the role of Amyloid-β (Aβ), Tau and frameshift Ubiquitin UBB+1 in Alzheimer’s disease (AD) are discussed. Despite having limitations with regard to intercellular and cognitive AD aspects, these models have clearly shown their added value as complementary models for the study of the molecular aspects of these proteins, including their interplay with AD-related cellular processes such as mitochondrial dysfunction and altered proteostasis. Moreover, these yeast models have also shown their importance in translational research, e.g., in compound screenings and for AD diagnostics development. In addition to well established Saccharomyces cerevisiae models, new upcoming Schizosaccharomyces pombe, Candida glabrata and Kluyveromyces lactis yeast models for Aβ and Tau are briefly described. Finally, traditional and more innovative research methodologies, e.g., for studying protein oligomerization/aggregation, are highlighted. PMID- 29970832 TI - Application of Fraser's "Practical" Ethic in Veterinary Practice, and Its Compatibility with a "One Welfare" Framework. AB - Ethically challenging situations are common in veterinary practice, and they may be a source of moral stress, which may in turn impact the welfare of veterinarians. Despite recognition of the importance of ethical reasoning, some veterinary students may struggle to apply theoretical ethical frameworks. Fraser developed a “practical” ethic consisting of four principles that can be applied to ethically challenging situations. We apply Fraser’s “practical” ethic to three cases that veterinarians may encounter: animal hoarding, animal neglect, and treatment of wildlife. We argue that Fraser’s “practical” ethic is consistent with a One Welfare framework, and may have increasing currency for veterinarians in the light of the World Animal Health Organisation’s Global Animal Welfare Strategy. Both Fraser’s “practical” ethic and a One Welfare framework require veterinarians to consider the impacts of animal ethics decisions on a broader scale than most other ethical frameworks have prepared them for. We discuss the strengths and limitations of Fraser’s “practical” ethic when applied in veterinary contexts and recommend additional support and training to enable veterinarians to effectively apply these frameworks in real-world settings. PMID- 29970835 TI - Differential Ultra-Wideband Microwave Imaging: Principle Application Challenges. AB - Wideband microwave imaging is of interest wherever optical opaque scenarios need to be analyzed, as these waves can penetrate biological tissues, many building materials, or industrial materials. One of the challenges of microwave imaging is the computation of the image from the measurement data because of the need to solve extensive inverse scattering problems due to the sometimes complicated wave propagation. The inversion problem simplifies if only spatially limited objects—point objects, in the simplest case—with temporally variable scattering properties are of interest. Differential imaging uses this time variance by observing the scenario under test over a certain time interval. Such problems exist in medical diagnostics, in the search for surviving earthquake victims, monitoring of the vitality of persons, detection of wood pests, control of industrial processes, and much more. This paper gives an overview of imaging methods for point-like targets and discusses the impact of target variations onto the radar data. Because the target variations are very weak in many applications, a major issue of differential imaging concerns the suppression of random effects by appropriate data processing and concepts of radar hardware. The paper introduces related methods and approaches, and some applications illustrate their performance. PMID- 29970833 TI - Hybrid Molecules Composed of 2,4-Diamino-1,3,5-triazines and 2-Imino-Coumarins and Coumarins. Synthesis and Cytotoxic Properties. AB - A series of 2-imino-2H-chromen-3-yl-1,3,5-triazine compounds 5-12, which are namely hybrids of 2,4-diamino-1,3,5-triazines and 2-imino-coumarins, was synthesized by reacting 2-(4,6-diamine-1,3,5-triazin-2-yl)acetonitriles 1-4 with 2-hydroxybenzaldehydes. After this, upon heating in aqueous DMF, 2-imino-2H chromen-3-yl-1,3,5-triazines 10 and 12 were converted into the corresponding 2H chromen-3-yl-1,3,5-triazines 13 and 14, which are essentially hybrids of 2,4 diamino-1,3,5-triazines and coumarins. The in vitro anticancer activity of the newly prepared compounds was evaluated against five human cancer cell lines: DAN G, A-427, LCLC-103H, SISO and RT-4. The greatest cytotoxic activity displayed 4 [7-(diethylamino)-2-imino-2H-chromen-3-yl]-6-(4-phenylpiperazin-1-yl)-1,3,5 triazin-2-amine (11, IC50 in the range of 1.51-2.60 μM). PMID- 29970834 TI - Improved General and Oral Health in Diabetic Patients by an Okinawan-Based Nordic Diet: A Pilot Study. AB - Periodontal disease, periodontitis as well as the preceding gingivitis, has been associated with both obesity and diabetes. Studies have shown that diet changes can lead to a lower incidence of such inflammation. The aim of the present case series over four weeks was to study the effects on medical and dental conditions in patients with type 2 diabetes of the consumption of the Okinawan-based Nordic Diet (OBND®). Medical and dental examinations were performed to estimate the general health and gingivitis/periodontitis. Serum cytokine levels were assessed using Luminex technology. Eight of ten study participants completed the study. All participants lost weight (p = 0.012). Six out of seven that were treated with insulin could reduce their insulin intake after two weeks with OBND®. The reduction was about 16 units which corresponds to a 34% relative reduction compared to the starting point (range 15-63%). Fasting blood glucose values fell (p = 0.035). Hemoglobin A1c (HbA1c) (p = 0.01), triglycerides (p = 0.05), and low density lipoprotein (LDL) (p = 0.05) were also reduced. Bleeding on probing changed from ~28% before any dietary changes to ~13% after two weeks with OBND® (p = 0.01). The reduction in gingival bleeding was as substantial as might be expected from one session of professional tooth cleaning. Markers of inflammation were also reduced. The OBND® thus showed significant promise in alleviating the impact of diabetes on dental as well as general health. PMID- 29970836 TI - Specificities and Efficiencies of Primers Targeting Candidatus Phylum Saccharibacteria in Activated Sludge. AB - Candidatus Saccharibacteria is a well-described candidate phylum that has not been successfully isolated. Nevertheless, its presence was suggested by 16S rRNA gene sequencing data, and it is frequently detected in natural environments and activated sludge. Because pure culture representatives of Candidatus Saccharibacteria are lacking, the specificity of primers for the determination of their abundance and diversity should be carefully evaluated. In this study, eight Candidatus Saccharibacteria-specific primers were selected from previous studies and evaluated for their coverage against a public database, annealing temperature of the combined primer sets, as well as their utilization to determine the detection frequencies and phylogenetic diversity by cloning analysis, and in quantification by quantitative polymerase chain reaction (PCR). Among the eight primers, four primers (TM7314F, TM7580F, TM7-910R, and TM7-1177R) showed high coverage. Cloning analysis showed that four primer sets (TM7314F and TM7-910R, TM7314F and TM7-1177R, TM7580F and TM7-910R, and TM7580F and TM7-1177R) yielded high detection frequencies for Candidatus Saccharibacteria in activated sludge from a wastewater treatment plant in Higashihiroshima City, Japan. Quantitative PCR results indicated that the primer set containing TM7314F and TM7-910R was superior for the specific detection of Candidatus Saccharibacteria in activated sludge. PMID- 29970838 TI - Development of iGrow: A Curriculum for Youth/Adult Dyads to Increase Gardening Skills, Culinary Competence, and Family Meal Time for Youths and Their Adult Caregivers. AB - This manuscript describes the development of a “learn by actively participating” curriculum for youth and their adult caregivers (dyad pair) to increase gardening skills, culinary competence, and family meal time. The curriculum was developed by integrating “iCook 4-H” and Junior Masters Gardener “Health and Nutrition from the Garden”, and “Essential Elements of 4-H Youth Development” curriculums with additional resources for gardening activities from the USDA’s My Plate and garden-based recipes. Expert reviewers (n = 11) provided feedback on the curriculum content, session structure, dosage, age appropriateness, and balance of the three focused areas. Seven family dyads (n = 14) participated in focus groups about understanding of need, interest, barriers, and potential engagement. A 10-week curriculum was developed and named: iGrow. The curriculum is a hands on, active learning program delivered through five, two-hour sessions using a family dyad model. Three main focus areas included gardening, culinary skills, and family conversation/interaction that all focused on togetherness. For the final iGrow curriculum, expert-level content review and feedback from focus group dyad pairs was used to revise the curriculum which further enhanced the approach and balance of the curriculum content. Focus group feedback supported appropriateness, dosage and learning objectives, and content depth. This curriculum has been developed to provide knowledge of gardening and culinary skills with the goal of increased consumption of fruit and vegetables. PMID- 29970839 TI - A Compact Low-Power LoRa IoT Sensor Node with Extended Dynamic Range for Channel Measurements. AB - As sub-GHz wireless Internet of Things (IoT) sensor networks set the stage for long-range, low-data-rate communication, wireless technologies such as LoRa and SigFox receive a lot of attention. They aim to offer a reliable means of communication for an extensive amount of monitoring and management applications. Recently, several studies have been conducted on their performance, but none of these feature a high dynamic range in terms of channel measurement. In this contribution an autonomous, low-power, LoRa-compatible wireless sensor node is presented. The main uses for this node are situated in LoRa channel characterization and link performance analysis. By applying stepped attenuators controlled by a dynamic attenuation adjustment algorithm, this node provides a dynamic range that is significantly larger than what is provided by commercially available LoRa modules. The node was calibrated in order to obtain accurate measurements of the received signal power in dBm. In this paper, both the hardware design as well as some verification measurements are discussed, unveiling various LoRa-related research applications and opportunities. PMID- 29970840 TI - Forecasting of Cereal Yields in a Semi-arid Area Using the Simple Algorithm for Yield Estimation (SAFY) Agro-Meteorological Model Combined with Optical SPOT/HRV Images. AB - In semi-arid areas characterized by frequent drought events, there is often a strong need for an operational grain yield forecasting system, to help decision makers with the planning of annual imports. However, monitoring the crop canopy and production capacity of plants, especially for cereals, can be challenging. In this paper, a new approach to yield estimation by combining data from the Simple Algorithm for Yield estimation (SAFY) agro-meteorological model with optical SPOT/ High Visible Resolution (HRV) satellite data is proposed. Grain yields are then statistically estimated as a function of Leaf Area Index (LAI) during the maximum growth period between 25 March and 5 April. The LAI is retrieved from the SAFY model, and calibrated using SPOT/HRV data. This study is based on the analysis of a rich database, which was acquired over a period of two years (2010 2011, 2012-2013) at the Merguellil site in central Tunisia (North Africa) from more than 60 test fields and 20 optical satellite SPOT/HRV images. The validation and calibration of this methodology is presented, on the basis of two subsets of observations derived from the experimental database. Finally, an inversion technique is applied to estimate the overall yield of the entire studied site. PMID- 29970837 TI - Protective Effects of a Lipid Extract from Hard-Shelled Mussel (Mytilus coruscus) on Intestinal Integrity after Lipopolysaccharide Challenge in Mice. AB - This study investigated the protective effects of a lipid extract from hard shelled mussel (HMLE) on intestinal integrity and the underlying mechanisms after a lipopolysaccharide (LPS) challenge in mice by using a 3 × 2 factorial design. Mice received olive oil, fish oil, and HMLE (n = 12 per group) by using gastric gavage for six weeks, respectively. Then half the mice in each group was injected intraperitoneally with LPS and the other half with phosphate buffered saline. Four hours after injection, mice were sacrificed and samples were collected. n-3 PUFAs were significantly enriched in erythrocytes following fish oil and HMLE supplementation. Both fish oil and HMLE improved intestinal morphology by restoring the ileac villus height and barrier function, which is indicated by decreased colonic myeloperoxidase activity and increased diamine oxidase activity as well as enhanced mRNA expression of intestinal tight junction proteins known as occludin and claudin-1 when compared with olive oil. In addition, both fish oil and HMLE increased colon production and the expression of anti-inflammatory cytokine, IL-10, while they inhibited the abnormal production and expression of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 relative to the olive oil. Lastly, in comparison with olive oil, both fish oil and HMLE downregulated the TLR-4 signaling pathway by reducing the expression of two key molecules in this pathway, which are called TLR-4 and MyD88. These results suggest that HMLE had a protective effect on intestinal integrity after the LPS challenge, which was equivalent to that of fish oil. This effect might be associated with the regulation of inflammatory mediators and the inhibition of the TLR-4 signaling pathway. PMID- 29970841 TI - Synthesis, Characterization, and Sensitivity of a CL-20/PNCB Spherical Composite for Security. AB - Highly energetic materials have received significant attention, particularly 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20). However, the application of this material was limited due to its high sensitivity. It is well known that the shape, size, and structure of energetic materials (EMs) significantly influence their sensitivity. At present, there are several ways to reduce the sensitivity of CL-20, such as spheroidization, ultrafine processing, and composite technology. However, only one or two of the abovementioned methods have been reported in the literature, and the obtained sensitivity effect was unsatisfactory. Thus, we tried to further reduce the sensitivity of CL-20 by combining the above three methods. The as-prepared composite was precipitated from the interface between two solutions of water and ethyl acetate, and the composite was insensitive compared with other reported CL-20-based EMs. The H50 value for the composite ranged up to 63 cm. This approach opens new prospects for greatly reducing the sensitivity of high Ems. PMID- 29970842 TI - Rapid Determination of Saponins in the Honey-Fried Processing of Rhizoma Cimicifugae by Near Infrared Diffuse Reflectance Spectroscopy. AB - OBJECTIVE: A model of Near Infrared Diffuse Reflectance Spectroscopy (NIR-DRS) was established for the first time to determine the content of Shengmaxinside I in the honey-fried processing of Rhizoma Cimicifugae. METHODS: Shengmaxinside I content was determined by high-performance liquid chromatography (HPLC), and the data of the honey-fried processing of Rhizoma Cimicifugae samples from different batches of different origins by NIR-DRS were collected by TQ Analyst 8.0. Partial Least Squares (PLS) analysis was used to establish a near-infrared quantitative model. RESULTS: The determination coefficient R2 was 0.9878. The Cross-Validation Root Mean Square Error (RMSECV) was 0.0193%, validating the model with a validation set. The Root Mean Square Error of Prediction (RMSEP) was 0.1064%. The ratio of the standard deviation for the validation samples to the standard error of prediction (RPD) was 5.5130. CONCLUSION: This method is convenient and efficient, and the experimentally established model has good prediction ability, and can be used for the rapid determination of Shengmaxinside I content in the honey-fried processing of Rhizoma Cimicifugae. PMID- 29970844 TI - Accurate Calibration of Multi-LiDAR-Multi-Camera Systems. AB - As autonomous driving attracts more and more attention these days, the algorithms and sensors used for machine perception become popular in research, as well. This paper investigates the extrinsic calibration of two frequently-applied sensors: the camera and Light Detection and Ranging (LiDAR). The calibration can be done with the help of ordinary boxes. It contains an iterative refinement step, which is proven to converge to the box in the LiDAR point cloud, and can be used for system calibration containing multiple LiDARs and cameras. For that purpose, a bundle adjustment-like minimization is also presented. The accuracy of the method is evaluated on both synthetic and real-world data, outperforming the state-of the-art techniques. The method is general in the sense that it is both LiDAR and camera-type independent, and only the intrinsic camera parameters have to be known. Finally, a method for determining the 2D bounding box of the car chassis from LiDAR point clouds is also presented in order to determine the car body border with respect to the calibrated sensors. PMID- 29970843 TI - Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases. AB - The endogenous ouabain (EO) is a steroid hormone secreted by the adrenal gland with cardio-tonic effects. In this article, we have reviewed and summarized the most recent reports about EO, particularly with regard to how it may interact with specific genetic backgrounds. We have focused our attention on the EO’s potential pathogenic role in several diseases, including renal failure, essential hypertension and heart failure. Notably, these reports have demonstrated that EO acts as a pro-hypertrophic and growth-promoting hormone, which might lead to a cardiac remodeling affecting cardiovascular functions and structures. In addition, a possible role of EO in the development of acute kidney injury has been hypothesized. During the last decays, many important improvements permitted a deeper understanding of EO’s metabolisms and functions, including the characteristics of its receptor and the effects of its activation. Such progresses indicated that EO has significant implications in the pathogenesis of many common diseases. The patho-physiological role of EO in the development of hypertension and other cardiac and renal complications have laid the basis for the development of a new selective compound that could selectively modulate the genetic and molecular mechanisms involved in EO’s action. It is evident that the knowledge of EO has incredibly increased; however, many important areas remain to be further investigated. PMID- 29970845 TI - Tracking Cell Recruitment and Behavior within the Tumor Microenvironment Using Advanced Intravital Imaging Approaches. AB - Recent advances in imaging technology have made it possible to track cellular recruitment and behavior within the vasculature of living animals in real-time. Using approaches such as resonant scanning confocal and multiphoton intravital microscopy (IVM), we are now able to observe cells within the intact tumor microenvironment of a mouse. We are able to follow these cells for extended periods of time (hours) and can characterize how specific cell types (T cells, neutrophils, monocytes) interact with the tumor vasculature and cancer cells. This approach provides greater insight into specific cellular behaviors and cell cell interactions than conventional techniques such as histology and flow cytometry. In this report, we describe the surgical preparation of animals to expose the tumor and both resonant scanning confocal and multiphoton imaging approaches used to track leukocyte recruitment, adhesion, and behavior within the tumor microenvironment. We present techniques for the measurement and quantification of leukocyte behavior within the bloodstream and tumor interstitium. The use of IVM to study leukocyte behavior within the tumor microenvironment provides key information not attainable with other approaches, that will help shape the development of better, more effective anticancer drugs and therapeutic approaches. PMID- 29970846 TI - Development of a Modular Board for EEG Signal Acquisition. AB - The increased popularity of brain-computer interfaces (BCIs) has created a new demand for miniaturized and low-cost electroencephalogram (EEG) acquisition devices for entertainment, rehabilitation, and scientific needs. The lack of scientific analysis for such system design, modularity, and unified validation tends to suppress progress in this field and limit supply for new low-cost device availability. To eliminate this problem, this paper presents the design and evaluation of a compact, modular, battery powered, conventional EEG signal acquisition board based on an ADS1298 analog front-end chip. The introduction of this novel, vertically stackable board allows the EEG scaling problem to be solved by effectively reconfiguring hardware for small or more demanding applications. The ability to capture 16 to 64 EEG channels at sample rates from 250 Hz to 1000 Hz and to transfer raw EEG signal over a Bluetooth or Wi-Fi interface was implemented. Furthermore, simple but effective assessment techniques were used for system evaluation. While conducted tests confirm the validity of the system against official datasheet specifications and for real world applications, the proposed quality verification methods can be further employed for analyzing other similar EEG devices in the future. With 6.59 microvolts peak-to-peak input referred noise and a −97 dB common mode rejection ratio in 0-70 Hz band, the proposed design can be qualified as a low cost precision cEEG research device. PMID- 29970847 TI - Effect of Using Different Kinds and Ratios of Vegetable Oils on Ice Cream Quality Characteristics. AB - The aim of this study was to develop ice cream products using different types of oils, a sensory ballot to focus on the textural attributes of new ice cream products, evaluate physicochemical properties of these products and physical measurements. Milkfat, hazelnut oil and olive oil were mixed at different concentrations for a total of 12% fat. Control sample contains 12% milk fat while the other formulations contain different proportion of milk fat, hazelnut oil and olive oil as the fat content. The combination of the different proportion of milk fat, hazelnut oil and olive oil are given as % milk fat, % hazelnut oil and % olive oil respectively; 12:0:0, 0:12:0, 0:0:12, 6:6:0, 6:0:6, 0:6:6, 4:4:4. The pH, free acidity, total solid ingredient, b* value and volume increase rate were statistically significant (p < 0.05). Sensory analysis results showed that: samples were 50% hazelnut oil-50% olive oil had the highest color and appearance scores. On the other hand, the highest score in body and texture scores were belongs to the sample of used 50% milk fat-50% hazelnut oil and 50% milk fat-50% olive oil, 50% milk fat-50% olive oil the most preferred ones in total quality criterions. PMID- 29970848 TI - Development of a Strategic Tool for Shared Decision-Making in the Use of Antidepressants among Patients with Major Depressive Disorder: A Focus Group Study. AB - Shared decision-making (SDM) has been recognized as an important tool in the mental health field and considered as a crucial component of patient-centered care. Therefore, the purpose of this study was to develop a strategic tool towards the promotion and implementation of SDM in the use of antidepressants among patients with major depressive disorder. Nineteen doctors and 11 major depressive disorder patients who are involved in psychiatric outpatient clinic appointments were purposively selected and recruited to participate in one of six focus groups in a large teaching hospital in Malaysia. Focus groups were transcribed verbatim and analyzed using a thematic approach to identify current views on providing information needed for SDM practice towards its implementation in near future. Patients’ and doctors’ views were organized into six major themes, which are; summary of treatment options, correct ways of taking medication, potential side effects of treatments related to patients, sharing of case study related to the treatment options, cost of treatment options, and input from pharmacist. The information may be included in the SDM tool which can be useful to inform further research efforts and developments that contribute towards the successful implementation of SDM into clinical practice. PMID- 29970849 TI - Synthesis, Structure-Activity Relationships and In Vitro Toxicity Profile of Lactose-Based Fatty Acid Monoesters as Possible Drug Permeability Enhancers. AB - Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship between their structure and biological effect. Using tensiometric measurements the critical micelle concentrations (CMCs) of the surfactants were determined and demonstrate that increasing hydrophobic chain length reduces surfactant CMC. In vitro testing on Caco-2 intestinal and Calu-3 airway epithelia revealed that cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, is presented for most of the surfactants at concentrations greater than their CMCs. Further biological study demonstrates that application of cytotoxic concentrations of the surfactants is associated with depolarizing mitochondrial membrane potential, increasing nuclear membrane permeability and activation of effector caspases. It is, therefore, proposed that when applied at cytotoxic levels, the surfactants are inducing apoptosis in both cell lines tested. Importantly, through the culture of epithelial monolayers on Transwell® supports, the surfactants demonstrate the ability to reversibly modulate transepithelial electrical resistance (TEER), and thus open tight junctions, at non-toxic concentrations, emphasizing their potential application as safe permeability enhancers in vivo. PMID- 29970851 TI - Continuous Flow Alcoholysis of Dialkyl H-Phosphonates with Aliphatic Alcohols. AB - The continuous flow alcoholysis of dialkyl H-phosphonates by aliphatic alcohols in the absence of a catalyst was elaborated using a microwave (MW) reactor equipped with a flow cell. By the precise control of the reaction conditions, the synthesis could be fine-tuned towards dialkyl H-phosphonates with two different and with two identical alkyl groups. In contrast to the "traditional" batch alcoholysis, flow approaches required shorter reaction times, and the products became available at a larger scale. PMID- 29970850 TI - Radiation Pneumonitis: Old Problem, New Tricks. AB - Radiation therapy is a major treatment modality for management of non-small cell lung cancer. Radiation pneumonitis is a dose limiting toxicity of radiotherapy, affecting its therapeutic ratio. This review presents patient and treatment related factors associated with the development of radiation pneumonitis. Research focusing on reducing the incidence of radiation pneumonitis by using information about lung ventilation, imaging-based biomarkers as well as normal tissue complication models is discussed. Recent advances in our understanding of molecular mechanisms underlying lung injury has led to the development of several targeted interventions, which are also explored in this review. PMID- 29970852 TI - Maternal Biomarkers of Acetaminophen Use and Offspring Attention Deficit Hyperactivity Disorder. AB - Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. We sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. This report analyzed 1180 children enrolled at birth and followed prospectively as part of the Boston Birth Cohort, including 188 with ADHD diagnosis based on electronic medical record review. Maternal biomarkers of acetaminophen intake were measured in plasma samples obtained within 1-3 days postpartum. Odds ratios for having ADHD diagnosis or other developmental disorders were estimated using multinomial logistic regression models, adjusting for pertinent covariables. Compared to neurotypical children, we observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose-responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. In the stratified analyses, differential point estimates of the associations were observed across some strata of covariates. However, these differences were not statistically significant. Maternal acetaminophen biomarkers were specifically associated with increased risk of ADHD diagnosis in offspring. Additional clinical and mechanistic investigations are warranted. PMID- 29970853 TI - Fluorinated Metal Phthalocyanines: Interplay between Fluorination Degree, Films Orientation, and Ammonia Sensing Properties. AB - In this work, the sensor response of MPcFx (M = Cu, Co, Zn; x = 0, 4, 16) films toward gaseous NH3 (10-50 ppm) was studied by a chemiresistive method and compared to that of unsubstituted MPc films to reveal the effects of central metals and F-substituents on the sensing properties. A combination of atomic force microscopy and X-ray diffraction techniques have been used to elucidate the structural features of thin MPcFx films deposited by organic molecular beam deposition. It has been shown that the sensor response of MPcF4 films to ammonia is noticeably higher than that of MPc films, which is in good correlation with the values of binding energy between the metal phthalocyanine and NH3 molecules, as calculated by the density functional theory (DFT) method. At the same time, in contrast to the DFT calculations, MPcF16 demonstrated the lesser sensor response compared with MPcF4, which appeared to be connected with the different structure and morphology of their films. The ZnPcF4 films were shown to exhibit a sensitivity to ammonia up to concentrations as low as 0.1 ppm, and can be used for the selective detection of ammonia in the presence of some reducing gases and volatile organic compounds. Moreover, the ZnPcF4 films can be used for the detection of NH3 in the gas mixture simulating exhaled air (N2 76%, O2 16%, H2O 5%, and CO2 3%). PMID- 29970855 TI - Preparation of CaCO3-TiO2 Composite Particles and Their Pigment Properties. AB - CaCO3-TiO2 composite particles were prepared with calcium carbonate (CaCO3) and TiO2 in stirred mill according the wet grinding method. The pigment properties, morphology, and structure of CaCO3-TiO2 composite particles and the interaction behaviors between CaCO3 and TiO2 particles were explored. In the CaCO3-TiO2 composite particles, TiO2 is uniformly coated on the surface of CaCO3 and the firm combination between CaCO3 and TiO2 particles is induced by the dehydration reaction of surface hydroxyl groups. CaCO3-TiO2 composite particles have similar pigment properties to pure TiO2. The hiding power, oil absorption, whiteness and ultraviolet light absorption of composite particles are close to those of pure TiO2. The application performance of CaCO3-TiO2 composite particles in the paint is consonant with their pigment properties. The contrast ratio of the exterior paint containing CaCO3-TiO2 composite particles is equivalent to that of the paint containing the same proportion of pure TiO2. PMID- 29970856 TI - Light-Weight Integration and Interoperation of Localization Systems in IoT. AB - As the ideas and technologies behind the Internet of Things (IoT) take root, a vast array of new possibilities and applications is emerging with the significantly increased number of devices connected to the Internet. Moreover, we are also witnessing the fast emergence of location-based services with an abundant number of localization technologies and solutions with varying capabilities and limitations. We believe that, at this moment in time, the successful integration of these two diverse technologies is mutually beneficial and even essential for both fields. IoT is one of the major fields that can benefit from localization services, and so, the integration of localization systems in the IoT ecosystem would enable numerous new IoT applications. Further, the use of standardized IoT architectures, interaction and information models will permit multiple localization systems to communicate and interoperate with each other in order to obtain better context information and resolve positioning errors or conflicts. Therefore, in this work, we investigate the semantic interoperation and integration of positioning systems in order to obtain the full potential of the localization ecosystem in the context of IoT. Additionally, we also validate the proposed design by means of an industrial case study, which targets fully-automated warehouses utilizing location-aware and interconnected IoT products and systems. PMID- 29970854 TI - Isoflavones Production and Possible Mechanism of Their Exudation in Genista tinctoria L. Suspension Culture after Treatment with Vanadium Compounds. AB - The family Fabaceae traditionally serves as a food and herbal remedies source. Certain plants serve for treatment of menopausal symptoms based on a presence of typical secondary metabolites, isoflavones. Beside soybean and clovers, other plants or cultures in vitro can produce these molecules. A cultivation in vitro can be enhanced by elicitation that stimulates metabolites biosynthesis via stress reaction. Vanadium compounds have been already described as potential elicitors, and the aim of this study was to determine the impact of NH4VO3 and VOSO4 solutions on isoflavones production in Genista tinctoria L. cell cultures. The significant increase of isoflavones content, such as genistin, genistein, or formononetin, was measured in a nutrient medium or dry mass after NH4VO3 treatment for 24 or 48 h. The possible transport mechanism of isoflavones release as a result of elicitation was further evaluated. An incubation with different transport inhibitors prior to elicitation took effect on isoflavones content in the medium. However, there was a non-ended result for particular metabolites such as genistein and daidzein, where ATP-binding cassette (ABC) or, alternatively, multidrug and toxin extrusion (MATE) proteins can participate. Possible elicitation by some inhibitors was discussed as a result of their pleiotropic effect. Despite this outcome, the determination of the transport mechanism is an important step for identification of the specific transporter. PMID- 29970857 TI - Quantitative Proteomic Analysis Provides Insights into Rice Defense Mechanisms against Magnaporthe oryzae. AB - Blast disease is one of the major rice diseases, and causes nearly 30% annual yield loss worldwide. Resistance genes that have been cloned, however, are effective only against specific strains. In cultivation practice, broad-spectrum resistance to various strains is highly valuable, and requires researchers to investigate the basal defense responses that are effective for diverse types of pathogens. In this study, we took a quantitative proteomic approach and identified 634 rice proteins responsive to infections by both Magnaporthe oryzae strains Guy11 and JS153. These two strains have distinct pathogenesis mechanisms. Therefore, the common responding proteins represent conserved basal defense to a broad spectrum of blast pathogens. Gene ontology analysis indicates that the “responding to stimulus” biological process is explicitly enriched, among which the proteins responding to oxidative stress and biotic stress are the most prominent. These analyses led to the discoveries of OsPRX59 and OsPRX62 that are robust callose inducers, and OsHSP81 that is capable of inducing both ROS production and callose deposition. The identified rice proteins and biological processes may represent a conserved rice innate immune machinery that is of great value for breeding broad-spectrum resistant rice in the future. PMID- 29970858 TI - Multi-Focus Image Fusion Method for Vision Sensor Systems via Dictionary Learning with Guided Filter. AB - Vision sensor systems (VSS) are widely deployed in surveillance, traffic and industrial contexts. A large number of images can be obtained via VSS. Because of the limitations of vision sensors, it is difficult to obtain an all-focused image. This causes difficulties in analyzing and understanding the image. In this paper, a novel multi-focus image fusion method (SRGF) is proposed. The proposed method uses sparse coding to classify the focused regions and defocused regions to obtain the focus feature maps. Then, a guided filter (GF) is used to calculate the score maps. An initial decision map can be obtained by comparing the score maps. After that, consistency verification is performed, and the initial decision map is further refined by the guided filter to obtain the final decision map. By performing experiments, our method can obtain satisfying fusion results. This demonstrates that the proposed method is competitive with the existing state-of the-art fusion methods. PMID- 29970859 TI - Buspirone Nanovesicular Nasal System for Non-Hormonal Hot Flushes Treatment. AB - The aim of this work was to design and characterize a new nanovesicular nasal delivery system (NDS) containing buspirone, and investigate its efficiency in an animal model for the treatment of hot flushes. The presence of multilamellar vesicles with a mean size distribution of 370 nm was evidenced by transition electron microscopy (TEM), cryo-scanning electron microscopy (Cryo-SEM), and dynamic light scattering (DLS) tests. Pharmacodynamic evaluation of the nasal treatment efficacy with the new system was carried out in ovariectomized (OVX) rat—an animal model for hot flushes—and compared with other treatments. We found that the nasal administration of a buspirone NDS resulted in a significant reduction in tail skin temperature (TST). This effect was not observed in the control buspirone-treated groups. Buspirone levels in the plasma and brain of nasally-treated normal rats were quantified and compared with those of rats that had received oral administration by a LC-MS/MS assay. A significantly higher bioavailability was achieved with the new treatment relative to an oral administration of the same drug dose. No pathological changes in the nasal cavity were observed following sub-chronic nasal administration of buspirone NDS. In conclusion, the data of our investigation show that buspirone in the new nanovesicular nasal carrier could be considered for further studies for the development of a treatment for the hot flushes ailment. PMID- 29970860 TI - Special Issue "Fungal Burden in Different Countries". AB - Adults and children living in many countries face a combined burden of infectious diseasesincluding fungal infections (for example, tinea capitis, recurrent vulvo vaginal thrush, chronicpulmonary aspergillosis, candidemia) [...]. PMID- 29970862 TI - Children's Environmental Health Indicators for Pacific Island Countries. AB - Healthy environments support the wellbeing of children and the environment thus play a cardinal role in the future of Pacific Island Countries (PICs). Children are more vulnerable and at risk to environmental hazards than adults because they breathe, drink, and eat much more relative to body weight, resulting in greater exposures in the different environments in which children find themselves every day. We examine the role that children’s environmental health indicators (CEHI) can play for PICs to highlight priorities and we prioritise actions to improve children’s environmental health and thus achieve their ‘Healthy Islands’ vision. We conducted a systematic search of relevant documented and publicly available Pacific Island Country information on children’s environmental health indicators using the general Internet, as well as databases such as PubMed, Google Scholar, relevant UN agencies, as well as regional databases. Information on CEHI was available—mainly in grey literature—but not specifically aimed at PICs. Likewise, similar observations were made for peer-reviewed literature. From this review, we compiled summaries and a framework to propose the requirements as well as provide a foundation for the development of CEHI for PICs. CEHI development for PICs should ideally be a multi-sectoral endeavour within each PIC as well as for the region. This can be achieved through public, private, and academic sector initiatives to draw in all sectors of government as well as the relevant UN agencies and regional PIC-representative organisations. PMID- 29970861 TI - Smart Vest for Respiratory Rate Monitoring of COPD Patients Based on Non-Contact Capacitive Sensing. AB - In this paper, a first approach to the design of a portable device for non contact monitoring of respiratory rate by capacitive sensing is presented. The sensing system is integrated into a smart vest for an untethered, low-cost and comfortable breathing monitoring of Chronic Obstructive Pulmonary Disease (COPD) patients during the rest period between respiratory rehabilitation exercises at home. To provide an extensible solution to the remote monitoring using this sensor and other devices, the design and preliminary development of an e-Health platform based on the Internet of Medical Things (IoMT) paradigm is also presented. In order to validate the proposed solution, two quasi-experimental studies have been developed, comparing the estimations with respect to the golden standard. In a first study with healthy subjects, the mean value of the respiratory rate error, the standard deviation of the error and the correlation coefficient were 0.01 breaths per minute (bpm), 0.97 bpm and 0.995 (p < 0.00001), respectively. In a second study with COPD patients, the values were −0.14 bpm, 0.28 bpm and 0.9988 (p < 0.0000001), respectively. The results for the rest period show the technical and functional feasibility of the prototype and serve as a preliminary validation of the device for respiratory rate monitoring of patients with COPD. PMID- 29970863 TI - Platinum Complexes Can Bind to Telomeres by Coordination. AB - It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13 times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly. PMID- 29970864 TI - Simultaneous Measurement of Curvature, Strain and Temperature Using a Twin-Core Photonic Crystal Fiber-Based Sensor. AB - A novel twin-core photonic crystal fiber-based sensor for simultaneous measurement of curvature, strain and temperature is proposed. The fiber sensor is constructed by splicing the homemade twin-core photonic crystal fiber between two segments of single mode fiber. Affected by the coupling between two cores, the transmission spectrum of the fiber sensor has different wavelength responses to curvature, strain, and temperature. The maximal sensitivities to curvature, strain and temperature are 10.89 nm/m-1, 1.24 pm/MUepsilon and 73.9 pm/ degrees C, respectively. Simultaneous measurement of curvature, strain and temperature can be achieved by monitoring the wavelength shifts of selected valleys in the transmission spectrum. Contrast experiment based on traditional twin-core fiber is carried out. Experimental results demonstrate that twin-core photonic crystal fiber-based sensor has higher sensitivity and better linearity than traditional twin-core fiber-based sensor. PMID- 29970865 TI - Chalcone Derivatives Enhance ATP-Binding Cassette Transporters A1 in Human THP-1 Macrophages. AB - Atherosclerosis is a process of imbalanced lipid metabolism in the vascular walls. The underlying pathology mainly involves the deposition of oxidized lipids in the endothelium and the accumulation of cholesterol in macrophages. Macrophages export excessive cholesterol (cholesterol efflux) through ATP-binding cassette transporter A1 (ABCA1) to counter the progression of atherosclerosis. We synthesized novel chalcone derivatives and assessed their effects and the underlying mechanisms on ABCA1 expression in macrophages. Human THP-1 macrophages were treated with synthetic chalcone derivatives for 24 h. In Western blot and flow cytometry analyses, a chalcone derivative, (E)-1-(3,4-diisopropoxyphenyl)-3 (4-isopropoxy-3-methoxyphenyl)prop- 2-en-1-one (1m), was observed to significantly enhance ABCA1 protein expression in THP-1 cells (10 µM, 24 h). Levels of mRNA of ABCA1 and liver X receptor alpha (LXRα) were quantified using a real-time quantitative polymerase chain reaction technique and were found to be significantly increased after treatment with the novel chalcone derivative 1m. Several microRNAs, including miR155, miR758, miR10b, miR145, miR33, and miR106b, which functionally inhibit ABCA1 expression were suppressed after treatment with 1m. Collectively, 1m increases ABCA1 expression in human THP 1 macrophages. The mechanisms involve the activation of the LXRα-ABCA1 pathway and suppression of certain microRNAs that regulate ABCA1 expression. PMID- 29970866 TI - Nonviral Gene Therapy for Cancer: A Review. AB - Although the development of effective viral vectors put gene therapy on the road to commercialization, nonviral vectors show promise for practical use because of their relative safety and lower cost. A significant barrier to the use of nonviral vectors, however, is that they have not yet proven effective. This apparent lack of interest can be attributed to the problem of the low gene transfer efficiency associated with nonviral vectors. The efficiency of gene transfer via nonviral vectors has been reported to be 1/10th to 1/1000th that of viral vectors. Despite the fact that new gene transfer methods and nonviral vectors have been developed, no significant improvements in gene transfer efficiency have been achieved. Nevertheless, some notable progress has been made. In this review, we discuss studies that report good results using nonviral vectors in vivo in animal models, with a particular focus on studies aimed at in vivo gene therapy to treat cancer, as this disease has attracted the interest of researchers developing nonviral vectors. We describe the conditions in which nonviral vectors work more efficiently for gene therapy and discuss how the goals might differ for nonviral versus viral vector development and use. PMID- 29970867 TI - Combining Targeted Metabolites Analysis and Transcriptomics to Reveal Chemical Composition Difference and Underlying Transcriptional Regulation in Maca (Lepidium Meyenii Walp.) Ecotypes. AB - Maca (Lepidium meyenii Walp.) is a traditional Andean crop with great potential for various sanitarian and medical functions, which is attracting increased research attention. The majority of previous Maca studies were focused on biochemistry and pharmacodynamics, while the genetic basis of its unique characteristics lagged due to a lack of genome information. The authors perform gas chromatography-mass spectrometry (GC/MS) analysis in the hypocotyls of three Maca ecotypes and identify 79 compounds. Among them, 62 compounds have distinct profiles among Maca ecotypes. To reveal the underlying regulatory mechanism of the chemical composition differences, de novo transcriptome sequencing is performed and the transcription profiles of three Maca ecotypes are comparatively analyzed. Functional analysis indicates several key pathways, including “starch and sucrose metabolism,” “phenylpropanoid biosynthesis,” “phenylalanine metabolism” and “plant pathogen interaction,” are involved in regulating the chemical compositions of Maca. Combining metabolomics and transcriptomics analysis indicates transcription factors such as MYB and WRKY and mediators such as protein kinase and bifunctional inhibitors might be critical regulators of chemical composition in Maca. The transcriptome reference genome and differentially expressed genes (DEGs) obtained in this study might serve as an initial step to illustrate the genetic differences in nutrient component, secondary metabolites content, medicinal function and stress resistance in Maca. PMID- 29970868 TI - miRNAs in Insects Infected by Animal and Plant Viruses. AB - Viruses vectored by insects cause severe medical and agricultural burdens. The process of virus infection of insects regulates and is regulated by a complex interplay of biomolecules including the small, non-coding microRNAs (miRNAs). Considered an anomaly upon its discovery only around 25 years ago, miRNAs as a class have challenged the molecular central dogma which essentially typifies RNAs as just intermediaries in the flow of information from DNA to protein. miRNAs are now known to be common modulators or fine-tuners of gene expression. While recent years has seen an increased emphasis on understanding the role of miRNAs in host virus associations, existing literature on the interaction between insects and their arthropod-borne viruses (arboviruses) is largely restricted to miRNA abundance profiling. Here we analyse the commonalities and contrasts between miRNA abundance profiles with different host-arbovirus combinations and outline a suggested pipeline and criteria for functional analysis of the contribution of miRNAs to the insect vector-virus interaction. Finally, we discuss the potential use of the model organism, Drosophila melanogaster, in complementing research on the role of miRNAs in insect vector-virus interaction. PMID- 29970870 TI - Children's Environmental Health Indicators in Context of the Sustainable Development Goals for Small Island Developing States. AB - The unique environmental vulnerability of small island developing states (SIDS) is likely to impact negatively on children's health. Children's environmental health indicators (CEHI) are standardized measures that can be used to assess the environmental exposures and their resulting health outcomes in children. This study sought to utilize the United Nations (UN) global Sustainable Development Goals (SDGs), with their associated targets and indicators, as a framework for a CEHI proposal for SIDS. Exposure-side indicators were taken from key themes from the 2012 Rio+20 UN Conference on Sustainable Development, and health-side indicators were selected based on the most significant contributors to the burden of disease in children. The multiple-exposures-multiple-effect (MEME) framework was then used to show the relationships between environmental exposures and children's health outcomes. The framework was populated with available data from the World Bank's DataBank. Whilst there was some data available at a population level, major gaps in both exposure-side and health-side indicators were revealed. In order to progress children's environmental health in SIDS, a further piece of work is required to propose a fully prioritized set of exposure-side and health side CEHIs; based on, but not exclusively linked to, the SDGs. PMID- 29970869 TI - Protective Effect of Pure Sour Cherry Anthocyanin Extract on Cytokine-Induced Inflammatory Caco-2 Monolayers. AB - Anthocyanins have several beneficial effects, especially on inflammatory and oxidative conditions. The pro-inflammatory cytokines, tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), induce damage in the intestinal barrier and participate in the pathogenesis of chronic bowel diseases. A number of fruits have high anthocyanin contents with strong biological activity which can support protective actions. Sour cherry (Prunus cerassus) is one of the richest fruits in anthocyanins; especially it has high content of cyanidins. The aim of this study was to test the biological effects of a pure sour cherry anthocyanin extract under inflammatory conditions on the intestinal barrier. Caco 2 monolayers were stimulated with 50 ng/mL TNF-α and 25 ng/mL IL-1β, and the protective effects of the anthocyanin extract were examined. We demonstrated the safety of 500, 50, 5 and 0.5 µM anthocyanin extracts through cell impedance measurements. The 50 µM anthocyanin extract inhibited the cytokine-induced Caco-2 permeability and the nuclear translocation of NF-κB p65 subunits. The extract significantly reduced the release of IL 6 and IL-8 production in intestinal cells and glutathione peroxidase activity stimulated by cytokines. We demonstrated, for the first time, the beneficial effects of pure sour cherry anthocyanin extract on inflammatory Caco-2 monolayers, indicating that this substance could be protective in inflammatory bowel diseases and is an excellent raw material for further applications and formulations. PMID- 29970871 TI - Application of Millifluidics to Encapsulate and Support Viable Human Mesenchymal Stem Cells in a Polysaccharide Hydrogel. AB - Human adipose-derived stromal cells (hASCs) are widely known for their immunomodulatory and anti-inflammatory properties. This study proposes a method to protect cells during and after their injection by encapsulation in a hydrogel using a droplet millifluidics technique. A biocompatible, self-hardening biomaterial composed of silanized-hydroxypropylmethylcellulose (Si-HPMC) hydrogel was used and dispersed in an oil continuous phase. Spherical particles with a mean diameter of 200 MUm could be obtained in a reproducible manner. The viability of the encapsulated hASCs in the Si-HPMC particles was 70% after 14 days in vitro, confirming that the Si-HPMC particles supported the diffusion of nutrients, vitamins, and glucose essential for survival of the encapsulated hASCs. The combination of droplet millifluidics and biomaterials is therefore a very promising method for the development of new cellular microenvironments, with the potential for applications in biomedical engineering. PMID- 29970873 TI - Comparison of Data Preprocessing Approaches for Applying Deep Learning to Human Activity Recognition in the Context of Industry 4.0. AB - According to the Industry 4.0 paradigm, all objects in a factory, including people, are equipped with communication capabilities and integrated into cyber physical systems (CPS). Human activity recognition (HAR) based on wearable sensors provides a method to connect people to CPS. Deep learning has shown surpassing performance in HAR. Data preprocessing is an important part of deep learning projects and takes up a large part of the whole analytical pipeline. Data segmentation and data transformation are two critical steps of data preprocessing. This study analyzes the impact of segmentation methods on deep learning model performance, and compares four data transformation approaches. An experiment with HAR based on acceleration data from multiple wearable devices was conducted. The multichannel method, which treats the data for the three axes as three overlapped color channels, produced the best performance. The highest overall recognition accuracy achieved was 97.20% for eight daily activities, based on the data from seven wearable sensors, which outperformed most of the other machine learning techniques. Moreover, the multichannel approach was applied to three public datasets and produced satisfying results for multi-source acceleration data. The proposed method can help better analyze workers’ activities and help to integrate people into CPS. PMID- 29970872 TI - Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid. AB - 5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4 hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4 enamide derivatives with lengths varying from about 15-20 A were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 MUMU and 165 MUMU. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds. PMID- 29970874 TI - Microcystin Content in Phytoplankton and in Small Fish from Eutrophic Nyanza Gulf, Lake Victoria, Kenya. AB - The human health risks posed by exposure to cyanobacterial toxins such as microcystin (MC) through water and fish consumption remain poorly described. During the last two decades, coastal regions of Lake Victoria such as Nyanza Gulf (Kisumu Bay) have shown severe signs of eutrophication with blooms formed by Microcystis producing MC. In this study, the spatial variability in MC concentration in Kisumu Bay was investigated which was mostly caused by Microcystis buoyancy and wind drifting. Small fish (<6 cm) mainly composed of Rastrineobola argentea were examined for MC content by means of biological methods such as ELISA and protein phosphatase inhibition assay (PPIA) and partly by chemical-analytical methods such as LC-MS/MS. Overall, the MC content in small fish was related to the MC content observed in the seston. When comparing the MC content in the seston in relation to dry weight with the MC content in small fish the latter was found three orders of magnitude decreased. On average, the ELISA determined MC contents exceeded the PPIA-determined MC contents by a factor of 8.2 +/- 0.5 (SE) while the MC contents as determined by LC-MS/MS were close to the detection limit. Using PPIA, the MC content varied from 25-109 (mean 62 +/- 7) ng/g fish dry weight in Kisumu Bay vs. 14 +/- 0.8 ng MC/g in the more open water of L. Victoria at Rusinga channel. Drying the fish under the sun showed little effect on MC content, although increased humidity might indirectly favor photocatalyzed MC degradation. PMID- 29970875 TI - Effect of Breviscapine on Recovery of Viable Myocardium and Left Ventricular Remodeling in Chronic Total Occlusion Patients After Revascularization: Rationale and Design for a Randomized Controlled Trial. AB - BACKGROUND How to speed the recovery of viable myocardium in chronic total occlusion (CTO) patients after revascularization is still an unsolved problem. Breviscapine is widely used in cardiovascular diseases. However, there has been no study focused on the effect of breviscapine on viable myocardium recovery and left ventricular remodeling after CTO revascularization. MATERIAL AND METHODS We propose to recruit 78 consecutive coronary artery disease (CAD) patients with CTO during a period of 12 months. They will be randomly assigned to receive either breviscapine (40 mg) or placebo in the following 12 months. Blood tests, electrocardiogram, and Major Adverse Cardiac Events (MACE) will be collected at baseline and the follow-up visits at 1, 3, 6, 9, and 12 months. Low-dose dobutamine MRI will be applied for the assessment of viable myocardium, microcirculation perfusion, and left ventricular remodeling, and the concentrations of angiogenic cytokine, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) will be investigated at baseline and at 1- and 12-month follow-up. The recovery of viable myocardium after revascularization in CTO patients was the primary endpoint. Improvement of microcirculation perfusion, left ventricular remodeling, peripheral concentrations of VEGF and bFGF as well as MACE will be the secondary endpoints. RESULTS Breviscapine treatment obviously improve the recovery of viable myocardium, myocardial microcirculation perfusion, and left ventricular remodeling after revascularization in CTO patients, and reduce the occurrence of MACE. We also will determine if breviscapine increases the peripheral blood angiogenic cytokine concentrations of VEGF and bFGF. CONCLUSIONS This study will aim to demonstrate the effect of breviscapine on the recovery of viable myocardium and left ventricular remodeling in CTO patients after revascularization. PMID- 29970876 TI - Nivolumab Immunotherapy in Malignant Mesothelioma: A Case Report Highlighting a New Opportunity for Exceptional Outcomes. AB - BACKGROUND Malignant pleural mesothelioma (MPM) is a highly lethal cancer with a median survival of ~12 months even with aggressive intervention. Frontline therapy relies on systemic cisplatin and pemetrexed chemotherapy and has a response rate of ~35-41%; currently, there are no US Food and Drug Administration approved second-line therapies for MPM. Herein, we present a patient with MPM who experienced rapid disease progression after standard therapy but who had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. CASE REPORT A 68-year-old male with a history of work-related asbestos exposure was diagnosed with MPM. He was treated with primary resection followed by systemic chemotherapy with cisplatin and pemetrexed. When chemotherapy failed, he was switched to immunotherapy with nivolumab and achieved an exceptional response. CONCLUSIONS We report the first case of a patient with MPM who experienced rapid disease progression after standard therapy but had an exceptional and sustained response to immune checkpoint inhibition with single agent nivolumab. As outcomes with traditional chemotherapy regimens remain disappointing, there is a substantial need for new approaches to MPM; our case highlights a new therapeutic opportunity even in the face of aggressive disease. Indeed, a new era of investigation utilizing immunotherapy for mesothelioma is beginning, with much anticipation. PMID- 29970877 TI - Pyruvate kinase M2 isoform deletion in cone photoreceptors results in age-related cone degeneration. AB - The tumor form of pyruvate kinase M2 has been suggested to promote cellular anabolism by redirecting the metabolism to cause accumulation of glycolytic intermediates and increasing flux through the pentose phosphate pathway, which is a metabolic pathway parallel to glycolysis. Both rod and cone photoreceptors express the tumor form of pyruvate kinase M2. Recent studies from our laboratory show that PKM2 is functionally important for rod photoreceptor structure, function, and viability. However, the functional role of PKM2 in cones is not known. In this study, we conditionally deleted PKM2 in cones (cone-cre PKM2-KO) and found that loss of PKM2 results in the upregulation of PKM1 and a significant loss of cone function and cone degeneration in an age-dependent manner. Gene expression studies on cone-cre PKM2-KO show decreased expression of genes regulating glycolysis, PPP shunt, and fatty acid biosynthesis. Consistent with these observations, cones lacking PKM2 have significantly shorter cone outer segments than cones with PKM2. Our studies clearly suggest that PKM2 is essential for the anabolic process in cones to keep them alive for normal functioning and to support cone structure. PMID- 29970878 TI - Knockdown of Yin Yang 1 enhances anticancer effects of cisplatin through protein phosphatase 2A-mediated T308 dephosphorylation of AKT. AB - Cisplatin is still one of the first-line drugs for chemotherapy of head and neck squamous cell carcinoma (HNSCC) and shows a survival advantage for HNSCC. However, a substantial proportion of HNSCC eventually becomes resistance to cisplatin and the underlying mechanisms remain to be fully understood. Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications and also plays a role in chemotherapy resistance. Here, we reported that knockdown of YY1 by lentivirus-mediated short hairpin RNA or tetracycline inducible short hairpin RNA enhanced cisplatin-induced apoptosis and inhibition of cell proliferation, migration and invasion in the HNSCC cell lines, and inhibition of the xenograft tumor growth. The underlying mechanisms were revealed that knockdown of YY1 downregulated both S473 and T308 phosphorylation of AKT (protein kinase B), which was mainly responsible for cisplatin resistance, whereas overexpression of YY1 upregulated both S473 and T308 phosphorylation. Cisplatin upregulated YY1 mRNA and protein expression and both S473 and T308 phosphorylation of AKT. In the presence of cisplatin, knockdown of YY1 not only blocked cisplatin-induced increase in S473 and T308 phosphorylation of AKT, but still downregulated T308 phosphorylation. Moreover, protein phosphatase 2A (PP2A) antagonist, okadaic acid, upregulated T308, but not S473, phosphorylation, and simultaneously abolished YY1 knockdown-mediated enhancement of cisplatin-induced inhibition of cell proliferation. In addition, knockdown of YY1 promoted PP2A activity through upregulating mRNA and protein expressions of PP2A catalytic subunit alpha (PPP2CA) through the binding of YY1 in the promoter of PPP2CA. Conversely, activating PP2A by forskolin also promoted YY1 degradation and subsequently inhibited T308 phosphorylation. These results suggested that knockdown of YY1 enhanced anticancer effects of cisplatin through PP2A mediating T308 dephosphorylation of AKT, and that targeting YY1 or PP2A would enhance the efficiency of cisplatin chemotherapy in treatment of HNSCC. PMID- 29970879 TI - Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting beta-catenin nuclear translocation. AB - Epithelial-mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of beta-catenin in this process is elusive. We identified that LIM domain kinase (LIMK)2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain- and loss-of function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1-S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of beta-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via beta-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy. PMID- 29970880 TI - Consequences of blunting the mevalonate pathway in cancer identified by a pluri omics approach. AB - We have previously shown that the combination of statins and taxanes was a powerful trigger of HGT-1 human gastric cancer cells' apoptosis1. Importantly, several genes involved in the "Central carbon metabolism pathway in cancer", as reported in the Kyoto Encyclopedia of Genes and Genomes, were either up- (ACLY, ERBB2, GCK, MYC, PGM, PKFB2, SLC1A5, SLC7A5, SLC16A3,) or down- (IDH, MDH1, OGDH, P53, PDK) regulated in response to the drug association. In the present study, we conducted non-targeted metabolomics and lipidomics analyses by complementary methods and cross-platform initiatives, namely mass spectrometry (GC-MS, LC-MS) and nuclear magnetic resonance (NMR), to analyze the changes resulting from these treatments. We identified several altered biochemical pathways involved in the anabolism and disposition of amino acids, sugars, and lipids. Using the Cytoscape environment with, as an input, the identified biochemical marker changes, we distinguished the functional links between pathways. Finally, looking at the overlap between metabolomics/lipidomics and transcriptome changes, we identified correlations between gene expression modifications and changes in metabolites/lipids. Among the metabolites commonly detected by all types of platforms, glutamine was the most induced (6-7-fold), pointing to an important metabolic adaptation of cancer cells. Taken together, our results demonstrated that combining robust biochemical and molecular approaches was efficient to identify both altered metabolic pathways and overlapping gene expression alterations in human gastric cancer cells engaging into apoptosis following blunting the cholesterol synthesis pathway. PMID- 29970881 TI - Delta133p53alpha, a natural p53 isoform, contributes to conditional reprogramming and long-term proliferation of primary epithelial cells. AB - We previously developed the technique of conditional reprogramming (CR), which allows primary epithelial cells from fresh or cryopreserved specimens to be propagated long-term in vitro, while maintaining their genetic stability and differentiation potential. This method requires a combination of irradiated fibroblast feeder cells and a Rho-associated kinase (ROCK) inhibitor. In the present study, we demonstrate increased levels of full-length p53 and its natural isoform, Delta133p53alpha, in conditionally reprogrammed epithelial cells from primary prostate, foreskin, ectocervical, and mammary tissues. Increased Delta133p53alpha expression is critical for CR since cell proliferation is rapidly inhibited following siRNA knockdown of endogenous Delta133p53alpha. Importantly, overexpression of Delta133p53alpha consistently delays the onset of cellular senescence of primary cells when cultured under non-CR conditions in normal keratinocyte growth medium (KGM). More significantly, the combination of Delta133p53alpha overexpression and ROCK inhibitor, without feeder cells, enables primary epithelial cells to be propagated long-term in vitro. We also show that Delta133p53alpha overexpression induces hTERT expression and telomerase activity and that siRNA knockdown of hTERT causes rapid inhibition of cell proliferation, indicating a critical role of hTERT for mediating the effects of Delta133p53alpha. Altogether, these data demonstrate a functional and regulatory link between p53 pathways and hTERT expression during the conditional reprogramming of primary epithelial cells. PMID- 29970882 TI - The novel long noncoding RNA u50535 promotes colorectal cancer growth and metastasis by regulating CCL20. AB - Long noncoding RNAs (lncRNAs) have been emerging as master regulators of tumor growth and metastasis, but the functions and underlying mechanisms of lncRNAs in colorectal cancer (CRC) still need to be clarified. Here, we found a novel lncRNA u50535, which was greatly overexpressed in CRC tissues and was associated with poor prognosis in CRC patients. Function studies showed that u50535 was an oncogene in CRC both in vitro and in vivo. In mechanism, through RNA sequencing and rescue assay, we found that u50535 activates CCL20 signaling to promote cell proliferation and migration in CRC. Taken together, these findings suggest that u50535 can promote CRC growth and metastasis and may serve as a potential biomarker in CRC. PMID- 29970883 TI - Dynamic strain determination using fibre-optic cables allows imaging of seismological and structural features. AB - Natural hazard prediction and efficient crust exploration require dense seismic observations both in time and space. Seismological techniques provide ground motion data, whose accuracy depends on sensor characteristics and spatial distribution. Here we demonstrate that dynamic strain determination is possible with conventional fibre-optic cables deployed for telecommunication. Extending recently distributed acoustic sensing (DAS) studies, we present high resolution spatially un-aliased broadband strain data. We recorded seismic signals from natural and man-made sources with 4-m spacing along a 15-km-long fibre-optic cable layout on Reykjanes Peninsula, SW-Iceland. We identify with unprecedented resolution structural features such as normal faults and volcanic dykes in the Reykjanes Oblique Rift, allowing us to infer new dynamic fault processes. Conventional seismometer recordings, acquired simultaneously, validate the spectral amplitude DAS response between 0.1 and 100 Hz bandwidth. We suggest that the networks of fibre-optic telecommunication lines worldwide could be used as seismometers opening a new window for Earth hazard assessment and exploration. PMID- 29970884 TI - An antisense RNA capable of modulating the expression of the tumor suppressor microRNA-34a. AB - The microRNA-34a is a well-studied tumor suppressor microRNA (miRNA) and a direct downstream target of TP53 with roles in several pathways associated with oncogenesis, such as proliferation, cellular growth, and differentiation. Due to its broad tumor suppressive activity, it is not surprising that miR34a expression is altered in a wide variety of solid tumors and hematological malignancies. However, the mechanisms by which miR34a is regulated in these cancers is largely unknown. In this study, we find that a long noncoding RNA transcribed antisense to the miR34a host gene, is critical for miR34a expression and mediation of its cellular functions in multiple types of human cancer. We name this long noncoding RNA lncTAM34a, and characterize its ability to facilitate miR34a expression under different types of cellular stress in both TP53-deficient and wild-type settings. PMID- 29970885 TI - Can we conclude a potential therapeutic action for Parkinson's disease by using postmortem tissue and a preclinical model based on an exogenous neurotoxin? PMID- 29970886 TI - Publisher Correction: IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29970887 TI - Inflammation rewires the brain. PMID- 29970888 TI - Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions. AB - Excess adiposity is a risk factor for several cancers of the gastrointestinal system, specifically oesophageal adenocarcinoma and colorectal, small intestine, pancreatic, liver, gallbladder and stomach cancers. With the increasing prevalence of obesity in nearly all regions of the world, this relationship could represent a growing source of cancers of the digestive system. Experimental and molecular epidemiological studies indicate important roles for alterations in insulin signalling, adipose tissue-derived inflammation and sex hormone pathways in mediating the association between adiposity and gastrointestinal cancer. The intestinal microbiome, gut hormones and non alcoholic fatty liver disease (NAFLD) also have possible roles. However, important gaps remain in our knowledge. For instance, our understanding of how adiposity throughout the life course is related to the risk of gastrointestinal cancer development and of how obesity influences gastrointestinal cancer prognosis and survival is limited. Nonetheless, the increasing use of state-of-the-art analytical methods (such as omics technologies, Mendelian randomization and MRI) in large-scale epidemiological studies offers exciting opportunities to advance our understanding of the complex relationship between adiposity and gastrointestinal cancers. Here, we examine the epidemiology of associations between obesity and gastrointestinal cancer, explore potential mechanisms underlying these relationships and highlight important unanswered research questions. PMID- 29970889 TI - Elucidating the genetic basis of social interaction and isolation. AB - The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study participants, we perform genome wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P < 5 * 10-8) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation. PMID- 29970891 TI - Emergence of a novel mobile colistin resistance gene, mcr-8, in NDM-producing Klebsiella pneumoniae. AB - The rapid increase in carbapenem resistance among gram-negative bacteria has renewed focus on the importance of polymyxin antibiotics (colistin or polymyxin E). However, the recent emergence of plasmid-mediated colistin resistance determinants (mcr-1, -2, -3, -4, -5, -6, and -7), especially mcr-1, in carbapenem resistant Enterobacteriaceae is a serious threat to global health. Here, we characterized a novel mobile colistin resistance gene, mcr-8, located on a transferrable 95,983-bp IncFII-type plasmid in Klebsiella pneumoniae. The deduced amino-acid sequence of MCR-8 showed 31.08%, 30.26%, 39.96%, 37.85%, 33.51%, 30.43%, and 37.46% identity to MCR-1, MCR-2, MCR-3, MCR-4, MCR-5, MCR-6, and MCR 7, respectively. Functional cloning indicated that the acquisition of the single mcr-8 gene significantly increased resistance to colistin in both Escherichia coli and K. pneumoniae. Notably, the coexistence of mcr-8 and the carbapenemase encoding gene blaNDM was confirmed in K. pneumoniae isolates of livestock origin. Moreover, BLASTn analysis of mcr-8 revealed that this gene was present in a colistin- and carbapenem-resistant K. pneumoniae strain isolated from the sputum of a patient with pneumonia syndrome in the respiratory intensive care unit of a Chinese hospital in 2016. These findings indicated that mcr-8 has existed for some time and has disseminated among K. pneumoniae of both animal and human origin, further increasing the public health burden of antimicrobial resistance. PMID- 29970890 TI - Novel ADAM-17 inhibitor ZLDI-8 enhances the in vitro and in vivo chemotherapeutic effects of Sorafenib on hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the greatest life threats for Chinese people, and the prognosis of this malignancy is poor due to the strong chemotherapy resistance in patients. Notch pathway components mediate cell survival and epithelial-mesenchymal transition (EMT), and also participate in the induction of multi-drug resistance (MDR). In the present study, we demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of HCC cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. ZLDI-8 treatment enhanced the effect of Sorafenib on inhibiting tumor growth in nude HCC bearing mice model. These results suggest that ZLDI-8 can be a promising therapeutic agent to enhance Sorafenib's anti-tumor effect and to overcome the MDR of HCC patients. PMID- 29970893 TI - Transparent and flexible fingerprint sensor array with multiplexed detection of tactile pressure and skin temperature. AB - We developed a transparent and flexible, capacitive fingerprint sensor array with multiplexed, simultaneous detection of tactile pressure and finger skin temperature for mobile smart devices. In our approach, networks of hybrid nanostructures using ultra-long metal nanofibers and finer nanowires were formed as transparent, flexible electrodes of a multifunctional sensor array. These sensors exhibited excellent optoelectronic properties and outstanding reliability against mechanical bending. This fingerprint sensor array has a high resolution with good transparency. This sensor offers a capacitance variation ~17 times better than the variation for the same sensor pattern using conventional ITO electrodes. This sensor with the hybrid electrode also operates at high frequencies with negligible degradation in its performance against various noise signals from mobile devices. Furthermore, this fingerprint sensor array can be integrated with all transparent forms of tactile pressure sensors and skin temperature sensors, to enable the detection of a finger pressing on the display. PMID- 29970892 TI - PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer. AB - Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5+ CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA mutation/LGR5+ expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA mutation/LGR5+ expression was a potential biomarker for monitoring chemotherapy resistance in CRC. PMID- 29970895 TI - Single-dose testosterone administration increases men's preference for status goods. AB - In modern human cultures where social hierarchies are ubiquitous, people typically signal their hierarchical position through consumption of positional goods-goods that convey one's social position, such as luxury products. Building on animal research and early correlational human studies linking the sex steroid hormone testosterone with hierarchical social interactions, we investigate the influence of testosterone on men's preferences for positional goods. Using a placebo-controlled experiment (N = 243) to measure individuals' desire for status brands and products, we find that administering testosterone increases men's preference for status brands, compared to brands of similar perceived quality but lower perceived status. Furthermore, testosterone increases positive attitudes toward positional goods when they are described as status-enhancing, but not when they are described as power-enhancing or high in quality. Our results provide novel causal evidence for the biological roots of men's preferences for status, bridging decades of animal behavioral studies with contemporary consumer research. PMID- 29970896 TI - Dexmedetomidine for conscious sedation with colorectal endoscopic submucosal dissection: a prospective double-blind randomized controlled study. AB - OBJECTIVE: Conscious sedation for colorectal endoscopic submucosal dissection (ESD) has not been standardized, and there are no studies of sedation for colorectal ESD. METHODS: We conducted a prospective double-blind randomized controlled trial to clarify the usefulness of DEX during colorectal ESD. In total 80 patients with colorectal ESD from April 2016 to May 2017 were assigned to the placebo group or the DEX group (40 cases each). The primary outcome was patient satisfaction (visual analogue scale: VAS). Secondary outcomes were evaluated for 13 factors, including patient pain level (VAS), endoscopist satisfaction (VAS), objective patient pain level viewed from the endoscopist's perspective (VAS), rate of patient response, rate of side effects, etc., from the patient's and endoscopist's perspectives. RESULTS: Patient satisfaction was 8.4 and 9.1 (P = 0.018) in the placebo group and the DEX group, respectively. Secondary outcomes of patient pain level, endoscopist satisfaction, objective patient pain level from the endoscopist's perspective for the placebo and DEX groups were 1.2 and 0.4 (P = 0.045), 8.2 and 9.3 (P < 0.001), and 1.2 and 0.5 (P = 0.002), respectively. All of these were significantly positive results (more comfortable and less pain) in the DEX group. The rate of a patient response was 100% in all cases. The side effects (hypoxia/bradycardia/hypotension) were 0%/0%/0% and 7.5%/7.5%/5% (P = 0.030). However, these rates were less than the reported side effect occurrence rate, and no additional medication was needed. CONCLUSION: DEX enables conscious sedation, and is useful not only for patient and endoscopist satisfaction but also for pain relief. DEX is an effective sedation method for colorectal ESD. PMID- 29970897 TI - Complex consisting of antisense DNA and beta-glucan promotes internalization into cell through Dectin-1 and hybridizes with target mRNA in cytosol. AB - Antisense oligonucleotides (AS-ODNs) hybridize with specific mRNAs, resulting in interference with the splicing mechanism or the regulation of protein translation. We previously demonstrated that the beta-glucan schizophyllan (SPG) can form a complex with AS-ODNs with attached dA40 (AS-ODNs/SPG), and this complex can be incorporated into cells, such as macrophages and dendritic cells, expressing the beta-glucan receptor Dectin-1. We have achieved efficient gene silencing in animal models, but the uptake mechanism and intracellular distribution are unclear. In this study, we prepared the complex consisting of SPG and AS-ODNs (AS014) for Y-box binding protein-1 (YB-1). After treatment with endocytosis inhibitor Pitstop 2 and small interfering RNA targeting Dectin-1, we found that AS014/SPG complexes are incorporated into cells by Dectin-1-mediated endocytosis and inhibit cell growth in a Dectin-1 expression level-dependent manner. After treatment with AS014/SPG complexes, we separated the cell lysate into endosomal and cytoplasmic components by ultracentrifugation and directly determined the distribution of AS014 by reverse transcription PCR using AS014 ODNs as a template or a reverse transcription primer. In the cytoplasm, AS014 clearly hybridized with YB-1 mRNAs. This is the first demonstration of the distinct distribution of the complex in cells. These results could facilitate the clinical application of the complex. PMID- 29970894 TI - Therapeutic effect of dental pulp stem cell transplantation on a rat model of radioactivity-induced esophageal injury. AB - Dental pulp stem cell (DPSC) transplantation has been demonstrated to promote the regeneration and repair of tissues and organs and is a potentially effective treatment for radioactive esophageal injury. In this study, to explore the therapeutic effects of DPSCs on acute radiation-induced esophageal injury, DPSCs were cultured and transplanted into rats with acute radioactive esophageal injuries induced by radioactive 125I seeds in vivo. In the injured esophagus, PKH26-labeled DPSCs co-localized with PCNA, CK14, CD71, and integrin alpha6, and the expression levels of these four makers of esophageal stem cells were significantly increased. After DPSC transplantation, the injured esophagus exhibited a greater thickness. In addition, the esophageal function and inflammation recovered faster. The results demonstrated that transplanted DPSCs, which trans-differentiated into esophageal stem cells in vivo, could repair the damaged esophageal tissue. PMID- 29970898 TI - To catch a quake. AB - A revolution in seismic detection technology is underway, capturing unprecedented observations of earthquakes and their impacts. These sensor innovations provide real-time ground shaking observations that could improve emergency response following damaging earthquakes and may advance our understanding of the physics of earthquake ruptures. PMID- 29970900 TI - Author Correction: Investigation on the interface between Li10GeP2S12 electrolyte and carbon conductive agents in all-solid-state lithium battery. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29970899 TI - Epigenetic silencing of tumor suppressor gene CDKN1A by oncogenic long non-coding RNA SNHG1 in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is the as the most frequently observed biliary tract malignancy, which has low survival rate in addition to constrained treatment options; nevertheless, the fundamental molecular phenomenon underlying malignant progression of CCA is quite ambiguous. Recently long non-coding RNAs (lncRNAs) have been found to have significant regulatory functions in several human cancers. Herein, we have figured out that lncRNA SNHG1, with substantially enhanced expression in CCA, is capable of acting as the oncogenic molecule of CCA. As revealed by our data, SNHG1 knockdown extensively inhibited CCA cell migration as well as proliferation in vitro and in vivo. In addition, in accordance with the findings of the RNA-Seq analysis, SNHG1 knockdown exhibited a significant impact on the target genes that were linked to cell migration and regulation of cell proliferation, in addition to the apoptotic phenomenon. In a mechanistic manner, we also showed that SNHG1 bound to the histone methyltransferase enhancer of the zeste homolog 2 (EZH2, which is regarded as the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is an extremely conserved protein complex regulating gene expression with the help of methylating lysine 27 on histone H3), specifying the histone alteration pattern on the target genes, including CDKN1A, and, as a result, altered the CCA cell biology. These data verified a major function of the epigenetic regulation of SNHG1 in CCA oncogenesis, in addition to its likely function as a target for CCA interruption. PMID- 29970901 TI - MiR-133b targets Sox9 to control pathogenesis and metastasis of breast cancer. AB - The miR-133b, a commonly recognized muscle-specific miRNA, was reported to be deregulated in many kinds of cancers. However, its potential roles in tumorigenesis remain greatly elusive. Herein, we demonstrate that miR-133b is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. Ectopic expression of miR-133b suppresses clonogenic ability and metastasis-relevant traits in vitro, as well as carcinogenesis and pulmonary metastasis in vivo. Further studies have identified Sox9, c-MET, and WAVE2 as direct targets of miR-133b, in which Sox9 contributes to all miR-133b-endowed effects including cell proliferation, colony formation, as well as cell migration and invasion in vitro. Moreover, re-expression of Sox9 reverses miR-133b-mediated metastasis suppression in vivo. Taken together, these findings highlight an important role for miR-133b in the regulation of tumorigenesis and metastatic potential of breast cancer and suggest a potential application of miR-133b in cancer treatment. PMID- 29970902 TI - Identification of microR-106b as a prognostic biomarker of p53-like bladder cancers by ActMiR. AB - Bladder cancers can be categorized into subtypes according to gene expression patterns. P53-like muscle-invasive bladder cancers are generally resistant to cisplatin-based chemotherapy, but exhibit heterogeneous clinical outcomes with a prognosis intermediate to that of the luminal and basal subtypes. The optimal approach to p53-like tumors remains poorly defined and better means to risk stratify such tumors and identification of novel therapeutic targets is urgently needed. MicroRNAs (miRNAs) play a key role in cancer, both in tumorigenesis and tumor progression. In the past few years, miRNA expression signatures have been reported as prognostic biomarkers in different tumor types including bladder cancer. However, miRNA's expression does not always correlate well with its activity. We previously developed ActMiR, a computational method for explicitly inferring miRNA activities. We applied ActMiR to The Cancer Genome Atlas (TCGA) bladder cancer data set and identified the activities of miR-106b-5p and miR-532 3p as potential prognostic markers of the p53-like subtype, and validated them in three independent bladder cancer data sets. Especially, higher miR-106b-5p activity was consistently associated with better survival in these data sets. Furthermore, we experimentally validated causal relationships between miR-106-5p and its predicted target genes in p53-like cell line HT1197. HT1197 cells treated with the miR-106b-5p-specific inhibitor were more invasive while cells treated with the miR-106b-5p-specific mimic were less invasive than corresponding controls. Altogether, our results suggest that miR-106b-5p activity can categorize p53-like bladder tumors into more and less-favorable prognostic groups, which provides critical information for personalizing treatment option for p53-like bladder cancers. PMID- 29970903 TI - Synergistic anti-angiogenic treatment effects by dual FGFR1 and VEGFR1 inhibition in FGFR1-amplified breast cancer. AB - FGFR1 amplification has been found in 15% of patients with breast cancer and has been postulated as a promising marker to predict response against FGFR inhibitors. However, early phase clinical trials of selective FGFR inhibitors demonstrated only limited efficacy in FGFR1-amplified breast cancer patients. We found that BGJ398, an FGFR inhibitor, effectively inhibited phosphorylation of FGFR1 and MEK/ERK signaling in FGFR1-amplified breast cancer without affecting tumor cell proliferation. However, FGFR1 knockout inhibited tumor angiogenesis in vivo. We unraveled that FGFR1 regulates the secretion of the proangiogenic vascular endothelial growth factor (VEGF) in a MAPK-dependent manner. We further found that FGF-FGFR1 signaling induces an autocrine activation of VEGF-VEGFR1 pathway that again amplifies VEGF secretion via VEGF-VEGFR1-AKT signaling. Targeting both VEGFR1 and FGFR1 resulted in synergistic anti-angiogenic treatment effects in vivo. We thus postulate synergistic treatment effects in FGFR1/VEGFR1 positive breast cancer patients by dual targeting of FGFR and VEGFR. PMID- 29970905 TI - Hypertriglyceridemia is associated with impaired fasting glucose in normal-weight children. AB - BACKGROUND: Previous studies have suggested that elevated triglyceride levels may precede the appearance of glucose metabolic disturbances in adults; nonetheless, this hypothesis has not been tested in children. Hence, we evaluated whether hypertriglyceridemia is associated with impaired fasting glucose (IFG) in normal weight children. METHODS: Normal-weight healthy children aged 7-15 years were enrolled in a population-based cross-sectional population study and allocated into groups with and without hypertriglyceridemia. Hypertriglyceridemia was defined by serum triglyceride levels >=100 and >=130 mg/dL for children aged 7-9 and 10-15 years, respectively, and IFG by fasting plasma glucose levels >=100 and <126 mg/dL. RESULTS: A total of 1453 children with average age of 11.3 +/- 2.4 years were enrolled in the study and allocated into the groups with (n = 172) and without (n = 1281) hypertriglyceridemia. In the overall population, the prevalence of hypertriglyceridemia and IFG was 11.8% and 11.2%, respectively. The logistic regression analysis adjusted by age, gender, BMI, waist circumference, and insulin levels showed that hypertriglyceridemia is associated with IFG in children aged 10-15 years (odds ratio (OR) = 1.67; 95% confidence interval (CI): 1.02-2.77, p = 0.04) but not in those aged 7-9 years (OR = 1.48; 95% CI: 0.39 5.58, p = 0.55). CONCLUSION: Hypertriglyceridemia is associated with IFG in normal-weight children aged 10-15 years, but not in those aged 7-9 years. PMID- 29970904 TI - Hypoxia-induced LncRNA-BX111 promotes metastasis and progression of pancreatic cancer through regulating ZEB1 transcription. AB - The contribution of long noncoding RNAs (lncRNAs) to pancreatic cancer progression and the regulatory mechanisms of their expression are attractive areas. In the present study, the overexpression of lncRNA-BX111887 (BX111) in pancreatic cancer tissues was detected by microarray and further validated in a cohort of pancreatic cancer tissues. We further demonstrated that knockdown or overexpression of BX111 dramatically repressed or enhanced proliferation and invasion of pancreatic cancer cells. Mechanically, BX111 activated transcription of ZEB1, a key regulator for epithelia-mesenchymal transition (EMT), via recruiting transcriptional factor Y-box protein (YB1) to its promoter region. Moreover, we revealed that BX111 transcription was induced by hypoxia-inducible factor (HIF-1alpha) in response to hypoxia. In addition, BX111 contributed to the hypoxia-induced EMT of pancreatic cells by regulating expression of ZEB1 and its downstream proteins E-cadherin and MMP2. Coincidence with in vitro results, BX111 depletion effectively inhibited growth and metastasis of xenograft tumor in vivo. The clinical samples of pancreatic cancer further confirmed a positive association between BX111 and ZEB1. Moreover, high BX111 expression was correlated with late TNM stage, lymphatic invasion and distant metastasis, as well as short overall survival time in patients. Taken together, our findings implicate a hypoxia-induced lncRNA contributes to metastasis and progression of pancreatic cancer, and suggest BX111 might be applied as a potential biomarker and therapeutic target for pancreatic cancer. PMID- 29970907 TI - Neuroendocrine cells amplify asthma. PMID- 29970906 TI - SOX17 restrains proliferation and tumor formation by down-regulating activity of the Wnt/beta-catenin signaling pathway via trans-suppressing beta-catenin in cervical cancer. AB - The SRY-box containing gene 17 (SOX17) is considered as a regulator in stemness maintenance and a suppressor in some malignant tumors. However, the biological function and molecular mechanism of SOX17 in the process of initiation and progression of cervical cancer remain obscure. In this study, immunohistochemistry showed that the expression of SOX17 was high in the normal cervix, moderate in the high-grade squamous intraepithelial lesion, and low in the cervical cancer. SOX17 inhibited the proliferation and viability of cervical cancer cells in vitro as well as tumor formation in vivo. Additionally, SOX17 induced the cell cycle arrest at the transition from the G0/G1 phase to the S phase. The TOP/ FOP-Flash reporter assay and Western blotting showed SOX17 inhibited the activity of the Wnt/beta-catenin signaling pathway in cervical cancer. Further, firefly luciferase reporter assay and quantitative chromatin immunoprecipitation (qChIP) assays confirmed that SOX17 trans-suppressed the expression of beta-catenin by directly binding to the specific region of the beta catenin promoter. Together, our data demonstrated that SOX17 restrained the proliferation and tumor formation by down-regulating the activity of the Wnt/beta catenin signaling pathway via trans-suppression of beta-catenin in cervical cancer. PMID- 29970909 TI - The role of engram cells in the systems consolidation of memory. AB - What happens to memories as days, weeks and years go by has long been a fundamental question in neuroscience and psychology. For decades, researchers have attempted to identify the brain regions in which memory is formed and to follow its changes across time. The theory of systems consolidation of memory (SCM) suggests that changes in circuitry and brain networks are required for the maintenance of a memory with time. Various mechanisms by which such changes may take place have been hypothesized. Recently, several studies have provided insight into the brain networks driving SCM through the characterization of memory engram cells, their biochemical and physiological changes and the circuits in which they operate. In this Review, we place these findings in the context of the field and describe how they have led to a revamped understanding of SCM in the brain. PMID- 29970908 TI - FOXP3 inhibits angiogenesis by downregulating VEGF in breast cancer. AB - Forkhead box P3 (FOXP3), an X-linked tumor suppressor gene, plays an important role in breast cancer. However, the biological functions of FOXP3 in breast cancer angiogenesis remain unclear. Here we found that the clinical expression of nuclear FOXP3 was inversely correlated with breast cancer angiogenesis. Moreover, the animal study demonstrated that FOXP3 significantly reduced the microvascular density of MDA-MB-231 tumors transplanted in mice. The cytological experiments showed that the supernatant from FOXP3-overexpressing cells exhibited a diminished ability to stimulate tube formation and sprouting in HUVECs in vitro. In addition, expression of vascular endothelial growth factor (VEGF) was downregulated by FOXP3 in breast cancer cell lines. Luciferase reporter assays and chromatin immunoprecipitation assays demonstrated that FOXP3 can directly interact with the VEGF promoter via specific forkhead-binding motifs to suppress its transcription. Importantly, the inhibitory effects of FOXP3 in the supernatant on tube formation and sprouting in HUVECs could be reversed by adding VEGF in vitro. Nuclear FOXP3 expression was inversely correlated with VEGF expression in clinical breast cancer tissues, and FOXP3 downregulation and VEGF upregulation were both correlated with reduced survival in breast cancer data sets in the Kaplan-Meier plotter. Taken together, our data demonstrate that FOXP3 suppresses breast cancer angiogenesis by downregulating VEGF expression. PMID- 29970911 TI - Ded-Mek. PMID- 29970910 TI - LncRNA KCNQ1OT1 regulates proliferation and cisplatin resistance in tongue cancer via miR-211-5p mediated Ezrin/Fak/Src signaling. AB - Numerous findings have demonstrated that long noncoding RNA (lncRNA) dysregulation plays a key role in many human neoplasms, including tongue squamous cell carcinoma (TSCC), yet the potential mechanisms of lncRNAs in chemo resistance remain elusive. Our research showed that the lncRNA KCNQ1OT1 was upregulated in chemo-insensitive TSCC tissues compared with chemo-sensitive TSCC specimens. Meanwhile, high KCNQ1OT1 expression was closely correlated with poor prognosis. Furthermore, KCNQ1OT1 promoted TSCC proliferation and conferred TSCC resistance to cisplatin-induced apoptosis in vitro and in vivo. Using online database analysis, we predicted that the lncRNA KCNQ1OT1 facilitates tumor growth and chemo-resistance by acting as a competing endogenous RNA (ceRNA) to modulate the expression of miR-211-5p. And miR-211-5p upregulation significantly impaired TSCC proliferation and resumed TSCC chemo-sensitivity, which is contrary to the function of lncRNA KCNQ1OT1. Luciferase experiments confirmed that miR-211-5p harbor binding sites for the 3'-UTRof Ezrin mRNA, and Ezrin/Fak/Src signaling was activated in cisplatin-resistant TSCC cells. Finally, miR-211-5p inhibition in sh KCNQ1OT1-expressing TSCC cells rescued the suppressed cell proliferation and cisplatin resistance induced by KCNQ1OT1 knockdown. In summary, our study has elucidated the role of the oncogenic lncRNA KCNQ1OT1 in TSCC growth and chemo resistance, which may serve as a new target for TSCC therapy. PMID- 29970912 TI - Europe's biggest research fund cracks down on 'ethics dumping'. PMID- 29970913 TI - Isolation of a Yersinia enterocolitica biotype 1B strain in France, and evaluation of its genetic relatedness to other European and North American biotype 1B strains. PMID- 29970914 TI - Dispute between physicians and family on surgical treatment for an infant with ultra short gut syndrome: the perspective of an Ethics Committee. PMID- 29970916 TI - Pre-conception susceptibility to endocrine disruptors. PMID- 29970915 TI - Thin is required for cell death in the Drosophila abdominal muscles by targeting DIAP1. AB - In holometabolous insects, developmentally controlled programmed cell death (PCD) is a conserved process that destroys a subset of larval tissues for the eventual creation of new adult structures. This process of histolysis is relatively well studied in salivary gland and midgut tissues, while knowledge concerning larval muscle destruction is limited. Here, we have examined the histolysis of a group of Drosophila larval abdominal muscles called the dorsal external oblique muscles (DEOMs). Previous studies have defined apoptosis as the primary mediator of DEOM breakdown, whose timing is controlled by ecdysone signaling. However, very little is known about other factors that contribute to DEOM destruction. In this paper, we examine the role of thin (tn), which encodes for the Drosophila homolog of mammalian TRIM32, in the regulation of DEOM histolysis. We find that loss of Tn blocks DEOM degradation independent of ecdysone signaling. Instead, tn genetically functions in a pathway with the death-associated inhibitor of apoptosis (DIAP1), Dronc, and death-associated APAF1-related killer (Dark) to regulate apoptosis. Importantly, blocking Tn results in the absence of active Caspase-3 immunostaining, upregulation of DIAP1 protein levels, and inhibition of Dronc activation. DIAP1 and Dronc mRNA levels are not altered in tn mutants, showing that Tn acts post-transcriptionally on DIAP1 to regulate apoptosis. Herein, we also find that the RING domain of Tn is required for DEOM histolysis as loss of this domain results in higher DIAP1 levels. Together, our results suggest that the direct control of DIAP1 levels, likely through the E3 ubiquitin ligase activity of Tn, provides a mechanism to regulate caspase activity and to facilitate muscle cell death. PMID- 29970917 TI - Amino acids - lifesaver or killer in patients with diabetes? PMID- 29970919 TI - Reinforcing the social compromise of accelerated approval. PMID- 29970918 TI - Emergence and spread of carbapenem-resistant Acinetobacter baumannii international clones II and III in Lima, Peru. AB - Carbapenem-resistant Acinetobacter baumannii is the top-ranked pathogen in the World Health Organization priority list of antibiotic-resistant bacteria. It emerged as a global pathogen due to the successful expansion of a few epidemic lineages, or international clones (ICs), producing acquired class D carbapenemases (OXA-type). During the past decade, however, reports regarding IC I isolates in Latin America are scarce and are non-existent for IC-II and IC-III isolates. This study evaluates the molecular mechanisms of carbapenem resistance and the epidemiology of 80 non-duplicate clinical samples of A. baumannii collected from February 2014 through April 2016 at two tertiary care hospitals in Lima. Almost all isolates were carbapenem-resistant (97.5%), and susceptibility only remained high for colistin (95%). Pulsed-field gel electrophoresis showed two main clusters spread between both hospitals: cluster D containing 51 isolates (63.8%) associated with sequence type 2 (ST2) and carrying OXA-72, and cluster F containing 13 isolates (16.3%) associated with ST79 and also carrying OXA-72. ST2 and ST79 were endemic in at least one of the hospitals. ST1 and ST3 OXA-23 producing isolates were also identified. They accounted for sporadic hospital isolates. Interestingly, two isolates carried the novel OXA-253 variant of OXA 143 together with an upstream novel insertion sequence (ISAba47). While the predominant A. baumannii lineages in Latin America are linked to ST79, ST25, ST15, and ST1 producing OXA-23 enzymes, we report the emergence of highly resistant ST2 (IC-II) isolates in Peru producing OXA-72 and the first identification of ST3 isolates (IC-III) in Latin America, both considered a serious threat to public health worldwide. PMID- 29970920 TI - Quality of life in the subacute period following a cervical traumatic spinal cord injury based on the initial severity of the injury: a prospective cohort study. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVES: To evaluate the relationship between quality of life (QOL) after a traumatic spinal cord injury (TSCI) and acute predictors, with a particular emphasis on the initial severity of the neurological injury. Secondarily, to compare the QOL after a TSCI with the general population. SETTING: A single Level-1 SCI-trauma centre. METHODS: A cohort of 119 individuals admitted after a cervical TSCI between April 2010 and September 2016 was studied. QOL was assessed using the SF-36v2 questionnaire 6-12 months following the injury, and compared to the general population. The relationship between the initial severity of the neurological injury and the SF 36 summary scores was assessed using linear multivariable regression analyses. RESULTS: Individuals sustaining less severe neurological injury (grade D) exhibited higher PCS than individuals with grades A, B or C injury. Individuals with initial grade A injury showed increased MCS than individuals with incomplete grade B, C or D injury, with 42.9% scoring higher than the general population. The initial grade was significantly associated with chronic PCS and MCS. CONCLUSIONS: The initial severity of the neurological injury after a cervical TSCI may be used to estimate QOL in the subacute period following the injury. Individuals with complete tetraplegia may report good mental QOL despite severe physical impairment. Our findings could help clinicians to determine realistic expectations for patients in terms of QOL, and optimize the rehabilitation plan based on the initial evaluation after a TSCI. PMID- 29970922 TI - THE INTERPLAY OF THE TWO HEMISPHERES OF THE BRAIN IN PSYCHOANALYSIS. AB - Several authors have written intriguingly about the right and left hemispheres of the brain. Each hemisphere perceives the world differently, impacting that which it looks upon and reinforcing our particular world view. Notably, the left hemisphere, has always been assumed to be the dominant hemisphere, but only because it has language and is so adept at formulating arguments. The detached mode of the left hemisphere, while useful and necessary to get distance, is no more real than the engaged, imaginative approach of the right hemisphere. Having written about self-sufficiency as a defense against feeling alone and helpless, I now consider these rational, problem solving, answer generating, and planning activities as products of the left hemisphere. The approach that I am suggesting is of calling our patients' attention to how their left hemisphere overpowers the new, more uncertain voice of the right hemisphere just after it speaks in a session. PMID- 29970923 TI - HAROLD SEARLES: LIFELONG WORK OF A MASTER CLINICIAN. AB - Harold F. Searles was one of the most gifted and innovative clinicians of psychoanalysis. His clinical work arouses interest on its own merit, as well as for the ways in which it shaped his highly innovative thinking. We can only imagine what special processes were developing in Searles's inner world under the everlasting impact of his experience with psychotic patients and from his life in general. Searles focused extensively on how the psychotic individuals' mental distortions impacted their capacity to form personal relationships in general, and the role of the analyst and countertransference in treatment. This unique viewpoint helped him sustain a creative commitment to psychotic patients, regarded by many as unsuitable for psychoanalysis. PMID- 29970924 TI - Capsular serovars of virulent Capnocytophaga canimorsus are shared by the closely related species C. canis and C. cynodegmi. AB - Capnocytophaga canimorsus is a dog oral commensal bacterium that causes rare but life-threatening generalized infections in humans who have been in contact with its animal hosts. Two other dog commensals, Capnocytophaga canis and Capnocytophaga cynodegmi, cause rare, mild local infections. To date, nine capsular serovars have been described in C. canimorsus. Here, we serotyped 112 strains of Capnocytophaga spp. isolated from human infections. The C. canimorsus strains (86 of 96, 89.6%) belonged to serovars A, B, or C with relative frequencies of approximately 30% for each serovar. The high prevalence of the A, B, and C serovars in strains isolated from humans, compared to the previously described low prevalence of these serovars among dog isolates (7.6%), confirms that these three serovars are more virulent to humans than other serovars and suggests that the low incidence of disease may be linked to the low prevalence of the A, B, and C serovars in dogs. We serotyped six strains of C. canis and ten strains of C. cynodegmi and, surprisingly, found one C. canis and three C. cynodegmi strains to be of capsular serovar B. This observation prompted us to test 34 dog-isolated C. canis and 16 dog-isolated C. cynodegmi strains. We found four C. canis strains belonging to serovar A and one belonging to serovar F. In contrast, no dog-isolated C. cynodegmi strain could be typed with the available antisera. This work demonstrates that virulence-associated capsular polysaccharides (A, B, and C) are not specific to the C. canimorsus species. PMID- 29970925 TI - Growth characteristics in individuals with osteogenesis imperfecta in North America: results from a multicenter study. AB - PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was 4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves. PMID- 29970926 TI - Normative and conceptual ELSI research: what it is, and why it's important. AB - The Ethical, Legal, and Social Implications (ELSI) Research Program of the National Human Genome Research Institute sponsors research examining ethical, legal, and social issues arising in the context of genetics/genomics. The ELSI Program endorses an understanding of research not as the sole province of empirical study, but instead as systematic study or inquiry, of which there are many types and methods. ELSI research employs both empirical and nonempirical methods. Because the latter remain relatively unfamiliar to biomedical and translational scientists, this paper seeks to elucidate the relationship between empirical and nonempirical methods in ELSI research. It pays particular attention to the research questions and methods of normative and conceptual research, which examine questions of value and meaning, respectively. To illustrate the distinct but interrelated roles of empirical and nonempirical methods in ELSI research, including normative and conceptual research, the paper demonstrates how a range of methods may be employed both to examine the evolution of the concept of incidental findings (including the recent step toward terming them 'secondary findings'), and to address the normative question of how genomic researchers and clinicians should manage incidental such findings. PMID- 29970927 TI - Incidental or secondary findings: an integrative and patient-inclusive approach to the current debate. AB - Incidental or secondary findings (ISFs) in whole exome or whole genome sequencing have been widely debated in recent literature. The American College of Medical Genetics and Genomics' recommendations on diagnostic ISFs have strongly catalyzed the discussion, resulting in worldwide reactions and a variety of international guidelines. This article will outline how propositions on levels of terminology, policy, and underlying values are still internationally criticized and adjusted. Unsolved questions regarding ISFs include a suitable terminology, adequate counseling or informed consent procedures, opt-out possibilities, reporting ISFs to (parents of) minors and values regarding professional duty, patient autonomy, and actionability. These questions will be characterized as intrinsically related and reciprocally maintained and hence, symptomatic, single-level reflections will be marked as ineffective. Instead, a level-integrative approach of the debate that explicitly acknowledges this interaction and considers a balance between internationally significant and case-specific solutions, will be advocated. Second, the inclusion of a patient perspective will be strongly encouraged to complement the professional preponderance in the current debate. The examination of lived patient experiences, a qualitative focus on the subjective meaning of ISFs, and a contextualization of meaning processes will be suggested as specific concretizations. This integrative and inclusive approach aims for a more comprehensive understanding of ISFs, a consideration of all relevant stakeholders' perspective and, ultimately, an effective health-care policy. PMID- 29970928 TI - Multi-level genomic analyses suggest new genetic variants involved in human memory. AB - Development of high-throughput genotyping platforms provides an opportunity to identify new genetic elements related to complex cognitive functions. Taking advantage of multi-level genomic analysis, here we studied the genetic basis of human short-term (STM, n = 1623) and long-term (LTM, n = 1522) memory functions. Heritability estimation based on single nucleotide polymorphism showed moderate (61%, standard error 35%) heritability of short-term memory but almost zero heritability of long-term memory. We further performed a two-step genome-wide association study, but failed to find any SNPs that could pass genome-wide significance and survive replication at the same time. However, suggestive significance for rs7011450 was found in the shared component of the two STM tasks. Further inspections on its nearby gene zinc finger and at-hook domain containing and SNPs around this gene showed suggestive association with STM. In LTM, a polymorphism within branched chain amino acid transaminase 2 showed suggestive significance in the discovery cohort and has been replicated in another independent population of 1862. Furthermore, we performed a pathway analysis based on the current genomic data and found pathways including mTOR signaling and axon guidance significantly associated with STM capacity. These findings warrant further replication in other larger populations. PMID- 29970930 TI - Note from the New Editor in Chief. PMID- 29970931 TI - Refusing to Examine Extremely Premature Newborns. PMID- 29970929 TI - Iron-Nicarbazin derived platinum group metal-free electrocatalyst in scalable size air-breathing cathodes for microbial fuel cells. AB - In this work, a platinum group metal-free (PGM-free) catalyst based on iron as transitional metal and Nicarbazin (NCB) as low cost organic precursor was synthesized using Sacrificial Support Method (SSM). The catalyst was then incorporated into a large area air-breathing cathode fabricated by pressing with a large diameter pellet die. The electrochemical tests in abiotic conditions revealed that after a couple of weeks of successful operation, the electrode experienced drop in performances in reason of electrolyte leakage, which was not an issue with the smaller electrodes. A decrease in the hydrophobic properties over time and a consequent cathode flooding was suspected to be the cause. On the other side, in the present work, for the first time, it was demonstrated the proof of principle and provided initial guidance for manufacturing MFC electrodes with large geometric areas. The tests in MFCs showed a maximum power density of 1.85 W m-2. The MFCs performances due to the addition of Fe-NCB were much higher compared to the iron-free material. A numerical model using Nernst-Monod and Butler-Volmer equations were used to predict the effect of electrolyte solution conductivity and distance anode-cathode on the overall MFC power output. Considering the existing conditions, the higher overall power predicted was 3.6 mW at 22.2 S m-1 and at inter-electrode distance of 1 cm. PMID- 29970932 TI - Use of Aborted Fetal Tissue in Vaccines and Medical Research Obscures the Value of All Human Life. AB - This opinion addresses the licitness, quasi-benefits, and consequences of using aborted fetal tissue in vaccines and in medical research. The Catholic Church permits temporary use of vaccines generated using aborted fetal tissue to protect children from preventable diseases until alternative vaccines that do not use aborted fetal tissue are available. In medical research, cell lines that were generated from elective abortions should be avoided and alternative cell lines of licit origin utilized. The association between in utero Zika virus infections and microcephaly has increased the demand for fetal tissue to establish causality and to understand disease progression. These studies require extensive oversight as they could directly encourage elective abortions. The consequence of the use of fetal tissue from elective abortions is desensitization of beneficiaries to the original illicit act of abortion thereby obscuring the value of all human life and potentially leading to scandal. Summary: The use of fetal tissue from elective abortions is commonplace in the pharmaceutical industry and in medical research. This opinion addresses the licitness, quasi-benefits, and consequences of using fetal tissue from elective abortions in vaccines and in medical research. All people of good conscience have the responsibility to voice opposition to the use of fetal tissue from elective abortions in order to promote development of alternatives, affirm the value of all human life and limit scandal. PMID- 29970933 TI - Jesus the Divine Physician. AB - During his earthly life, Jesus was very active in his ministry of healing. He cured the blind, opened the ears of the deaf, and brought the dead back to life. The early Church Fathers gave our Lord the title of "the Divine Physician." However, Jesus did not cure all disease and sickness once and for all. Instead he asked us to have faith, to renounce sin, with its concomitant morbidity and mortality, and to believe in him. Jesus came to give us a life that will never end, not even with death. The Church and her members have the ongoing task of continuing his healing work in the world of today. PMID- 29970934 TI - It Is Who We Become. PMID- 29970935 TI - Self-Monitoring of Fertility Hormones: A New Era for Natural Family Planning? AB - Natural family planning (NFP) methods have served many generations well, and in particular, the symptothermal or symptohormonal methods. The comparison of daily mucus and temperature records for individual cycles with daily hormone measurements, which is now possible, shows that some of the assumptions underlying NFP may not be completely accurate. The various methods are inadvertently depending on an element of chance, which, of course, cannot be known by the NFP user. However, it is statistically inevitable that such errors will result eventually in an unexpected pregnancy, and these discrepancies are the likely reason for the method failures. Further research and integration of home hormone measurements with NFP symptoms are needed. Summary: Traditional NFP methods, based on the observations of temperature, mucus, and luteinizing hormone, can work well. However, these data are sometimes difficult to interpret, and significant changes in the variables are sometimes "missing" from some cycles. Changes in these variables are elicited by the estrogen and progesterone released from the ovaries. It follows that the direct measures of events in the ovaries are the levels of estrogen and progesterone or their derivatives in blood or urine. Measurements of urinary derivatives of estrogen and progesterone can be used to monitor the ovaries directly and are clearer indicators than traditional NFP methods. PMID- 29970936 TI - Generation, Gestation, and Birth: An Important Element in the Embryo Adoption Debate. AB - Those who consider embryo adoption/rescue a licit means to save the lives of cryopreserved and abandoned embryos often have recourse to an analogy between gestation and wet nursing, claiming that since procreation is complete at the moment of conception, there is no moral difference between gestating another person's child and wet nursing another person's child. The claim that procreation terminates at conception is evaluated in light of the thought of St. Thomas, and a determination of the moral means of ordering oneself to the good of the species by means of procreation is made in accordance with the natural law reasoning advocated by that saint. Summary: The Catholic Church teaches that procreation must be the fruit of the marriage act. Some moral theologians consider procreation to be complete at the moment of conception and so conclude that the impregnation of a woman by means of embryo transfer does not violate the principle that procreation must be the fruit of marriage. Others, however, consider procreation to include gestation and birth. This article advances reasons why the latter view should be preferred and what this entails for the ethics of embryo adoption or rescue. PMID- 29970937 TI - Infant Male Circumcision: A Catholic Theological and Bioethical Analysis. AB - Infant male circumcision (IMC) has become controversial among Catholics, and many have criticized the practice of routine IMC, still widely performed in the United States. Others have gone further, claiming that circumcision has been condemned explicitly by the Church and criticizing IMC as "mutilation" and, hence, prohibited implicitly by Catholic moral principles. However, closer examination of the Catholic tradition shows that the Church regards IMC as having been a means of grace under the Old Covenant and, more importantly, in the flesh of Jesus. This positive theological account of IMC cannot be evaded by invoking a supposed historical distinction between milah (a token cut) and periah (the complete removal of the foreskin). The Church has never condemned IMC as mutilation, and while IMC carries some risk, there is no evidence that it inflicts per se disabling mutilation. A reasonable body of medical opinion regards IMC as conferring net health benefits. Summary: This paper concerns the ethics of infant male circumcision especially, though not only, as this is practiced within contemporary Judaism. This topic is examined from a Catholic ethical and theological perspective. It is found that the Church has never sought to restrict Jews from practicing circumcision and has never condemned circumcision as "mutilation." Current evidence suggests that infant male circumcision confers net health benefits. Catholic theology since the Second Vatican Council has increasingly emphasized that God's covenant with the Jewish people remains valid. It has never been revoked. This covenant includes infant male circumcision. PMID- 29970938 TI - Contemporary Medical Students' Perceptions of the Hippocratic Oath. AB - Background: The Hippocratic Oath is a standard of medical ethics. Oath adaptations are common. Objective: Evaluate students' perceptions regarding the oath. Design: Survey of University of California, Los Angeles (UCLA) Medical School graduating students regarding the oath's relevance, content, and application, and whether a choice of version should be provided. Results: Forty two of the fifty-three students (79 percent) considered the original oath relevant. Most (53 percent) disagreed that the oath in its original form be used, and most preferred a modified oath. More agreed (40 percent) than disagreed (28 percent) on providing a choice of version of the oath. The mean of correct answers as to the original oath's contents was 68 percent. Euthanasia and abortion prohibitions were recognized by 68 percent and 62 percent, respectively. Increased knowledge of the original's contents correlated with decreased desire that it be used (p = .02). Recognition of euthanasia/abortion prohibitions was significantly better for those in disagreement than in agreement that the original be used. Those who disagreed that a choice of oath versions be provided had significantly better knowledge of the original's euthanasia/abortion prohibitions than those who agreed. However, those who felt strongly that a choice should or should not be given each had a 100 percent accuracy of identifying euthanasia/abortion prohibitions. Conclusions: Most students preferred an adapted oath to the original. Increased student knowledge of the original oath's contents, including reference to euthanasia/abortion, significantly correlated with decreased desire to use it. Given the original's importance in medical ethics, this is concerning. A subset of students, however, affirmed the original's value and desired its use. Improved education in the Hippocratic oath is important, given modern medicine's complex moral issues. Summary: The Hippocratic oath is a standard of medical ethics. Oath adaptations eliminating the original's prohibitions of abortion/euthanasia are common. Most medical students who were questioned preferred the adapted oath to the original. Only two-thirds recognized the original's prohibitions of abortion/euthanasia. Those who knew of the original oath's prohibitions also had a decreased desire that it be used. Students disagreeing that a choice of versions of the oath be provided had better knowledge of these prohibitions. This is concerning, given the original oath's importance in medical ethics including at the 1945-1949 Nuremberg trials. Nonetheless, a subset of students affirmed the original Hippocratic oath's importance, desiring its use. PMID- 29970939 TI - Current Medical Research: Winter/Spring 2017. PMID- 29970941 TI - Titles Received. PMID- 29970940 TI - Special issue in Commemoration of the 50th Anniversary of Humanae vitae. PMID- 29970943 TI - Additive yield response of chickpea (Cicer arietinum L.) to rhizobium inoculation and phosphorus fertilizer across smallholder farms in Ethiopia. AB - The impacts of rhizobium inoculation on growth and yield of chickpea have mainly been tested in experiments conducted in greenhouses or on research stations. We report the response of the crop to inoculation (I) and phosphorus fertilizer (P) application across a large number of smallholder's farms over four regions of Ethiopia, covering diverse soil fertility and agro-ecological conditions. Increased grain yields due to the soil fertility treatments was evident for 99% target farmers. On average, I and P increased grain yield by 21% and 25% respectively, while the combined application of I and P resulted in a 38% increase. However, observed grain yields on control plots and responses to the treatments on individual farms varied greatly, and relative yield responses (%; yield of P and/I minus control yield, divided by control yield) ranged from 3% to 138%. With the exception of a few extremely poorly yielding locations, average responses to P and I were high across a wide range of control yields, indicating the possibility of boosting chickpea productivity for smallholders with P fertilizer and inoculant technology. Variation in response to rhizobium inoculation was mostly independent of agro-ecology and soil type although it was found to be low on a number of farms with extremely high N contents (%). Assuming that a relative yield increase of 10% due to treatment effects is required to be visible, 71%, 73% and 92% of the farmers observed a yield benefit by applying P, I, and P + I, respectively. The results are discussed with respect to the additive benefits of P fertilizers and rhizobial inoculation and their implications for wide scale promotion of inoculant technology to smallholders. PMID- 29970942 TI - Differential regulation of volatile emission from Eucalyptus globulus leaves upon single and combined ozone and wounding treatments through recovery and relationships with ozone uptake. AB - Both ozone and wounding constitute two key abiotic stress factors, but their interactive effects on plant constitutive and stress-elicited volatile (VOC) emissions are poorly understood. Furthermore, the information on time-dependent modifications in VOC release during recovery from a combined stress is very limited. We studied the modifications in photosynthetic characteristics and constitutive and stress-induced volatile emissions in response to single and combined applications of acute ozone (4, 5, and 6 ppm) and wounding treatments through recovery (0.5-75 h) in a constitutive isoprene and mono- and sesquiterpene emitter Eucalyptus globulus. Overall, the photosynthetic characteristics were surprisingly resistant to all ozone and wounding treatments. Constitutive isoprene emissions were strongly upregulated by ozone and combined ozone and wounding treatments and remained high through recovery phase, but wounding applied alone reduced isoprene emission. All stress treatments enhanced emissions of lipoxygenase pathway volatiles (LOX), mono- and sesquiterpenes, saturated aldehydes (C7-C10), benzenoids, and geranylgeranyl diphosphate (GGDP) pathway volatiles. Once elicited, GGDP volatile, saturated aldehyde and benzenoid emissions remained high through the recovery period. In contrast, LOX emissions, and total mono- and sesquiterpene emissions decreased through recovery period. However, secondary rises in total sesquiterpene emissions at 75 h and in total monoterpenes at 25-50 h were observed. Overall, acute ozone and wounding treatments synergistically altered gas exchange characteristics and stress volatile emissions. Through the treatments and recovery period, stomatal ozone uptake rate and volatile emission rates were poorly correlated, reflecting possible ozone-scavenging effect of volatiles and thus, reduction of effective ozone dose and elicitation of induced defense by the acute ozone concentrations applied. These results underscore the important role of interactive stresses on both constitutive and induced volatile emission responses. PMID- 29970944 TI - Reducing spatial variability of soybean response to rhizobia inoculants in farms of variable soil fertility in Siaya County of western Kenya. AB - Soybean grain yields in sub-Saharan Africa have remained at approximately 50% below those attained in South America despite numerous efforts. A study was conducted in Siaya County (western Kenya) involving 107 farms with soils of different fertility status. The main objective was to test combinations of two inoculants (Legumefix and Biofix) and nutrient sources (Minjingu and Sympal) to raise soybean grain yields. Inoculation used Legumefix or Biofix with and without Minjingu or Sympal in a factorial design. There was soil acidity and a widespread deficiency of potassium, nitrogen, and phosphorus. Inoculation and nutrient source led to increases in nodulation and nodule occupancy. For grain yields the response varied from nil in some sites to high increases in others. Highest grain yields (3000-4000 kg ha-1) were obtained with Legumefix + Sympal (12% of the farmers testing it). The formulation of the nutrient source was important to meet other nutrient deficiencies in most of the soils. Farmers using Legumefix + Sympal require yield increases of 35% for profitability (Value cost ratio of 3) while farmers using Minjingu + inoculant require a yield increase of at least 68%. Inoculants used alone were most profitable but this is advisable only when farmers are too resource constrained to afford fertilizer. For sustainable yields Legumefix + Sympal or Biofix + Sympal were recommended. PMID- 29970946 TI - Sustainable intensification through rotations with grain legumes in Sub-Saharan Africa: A review. AB - We conducted a systematic review of literature on the residual effects of grain legumes in cereal-based systems of sub-Saharan Africa (SSA) to quantify the magnitude and variability of rotational effects, to explore the importance of environmental and management factors in determining variability and to evaluate the evidence of the different mechanisms that explain rotational effects. We retrieved 44 unique publications providing 199 observations comparing continuous cereal performance with that of a grain legume-cereal rotation. The overall mean yield increase of 0.49 t grain ha-1, equal to an increase of 41% of the continuous cereal yield, is highly significant, but the variability in residual effects is large. Effects were more pronounced in southern Africa, the highlands of East Africa and the Guinea savannah, and less in the humid forest/derived savannah of West Africa and the Sudano-Sahelian zone. Maize showed stronger yield responses after a legume than millet and sorghum. Agro-ecological zone and cereal type were however confounded. All grain legume types significantly improved cereal yields, with stronger residual effects observed after soybean and groundnut than after cowpea. Fertiliser N application to cereals reduces the residual effects of legumes, but the response at 60-120 kg N ha-1 still equalled 0.32 t ha-1 or 59% of the response when no N is applied. The sustained benefits with large N applications indicate the importance of non-N effects. While mechanisms for improved soil P availability after grain legumes have been studied in some detail, it remains uncertain how important these are in farmers' fields. Grain legumes are unlikely to have a major influence on the availability of nutrients other than N and P, or on soil pH. Beneficial impacts of grain legumes on soil organic matter content can occur if legumes contribute to a greater overall cropping productivity, but studies generally report no such impacts. Evidence of impacts of grain legumes on weeds is limited to striga. Studies on the impacts on nematode pressure in cereals are inconclusive, probably because legumes act as a host for some of the key nematode genera that harm maize. The impact on the pressure of other pests and diseases in cereals is probably important, but evidence on this from SSA is lacking. Future research on N2 fixation by grain legumes and residual N benefits should focus on explaining the wide variability observed among sites. There is a clear need for more detailed mechanistic studies to assess the occurrence and relevance of non-N effects of grain legumes, particularly in relation to common pests and diseases in cereals. PMID- 29970947 TI - Farmers' use and adaptation of improved climbing bean production practices in the highlands of Uganda. AB - Climbing beans offer potential for sustainable intensification of agriculture, but their cultivation constitutes a relatively complex technology consisting of multiple components or practices. We studied uptake of improved climbing bean production practices (improved variety, input use and management practices) through co-designed demonstrations and farmer-managed adaptation trials with 374 smallholder farmers in eastern and southwestern Uganda. A sub-set of these farmers was monitored one to three seasons after introduction. About 70% of the farmers re-planted climbing beans one season after the adaptation trial, with significant differences between eastern (50%) and southwestern Uganda (80-90%). Only 1% of the farmers used all of the improved practices and 99% adapted the technology. On average, farmers used half of the practices in different combinations, and all farmers used at least one of the practices. Yield variability of the trials was large and on average, trial plots did not yield more than farmers' own climbing bean plots. Yet, achieved yields did not influence whether farmers continued to cultivate climbing bean in the subsequent season. Uptake of climbing beans varied with household characteristics: poorer farmers cultivated climbing beans more often but used fewer of the best-bet practices; male farmers generally used more practices than female farmers. Planting by poorer farmers resulted in adaptations such as growing climbing beans without fertilizer and with fewer and shorter stakes. Other relationships were often inconsistent and farmers changed practices from season to season. The diversity of farmer responses complicates the development of recommendation domains and warrants the development of a basket of options from which farmers can choose. Our study shows how adoption of technologies consisting of multiple components is a complicated process that is hard to capture through the measurement of an adoption rate at a single point in time. PMID- 29970945 TI - Cowpea (Vigna unguiculata L. Walp) hosts several widespread bradyrhizobial root nodule symbionts across contrasting agro-ecological production areas in Kenya. AB - Cowpea (Vigna unguiculata L. Walp.) is an important African food legume suitable for dry regions. It is the main legume in two contrasting agro-ecological regions of Kenya as an important component of crop rotations because of its relative tolerance to unpredictable drought events. This study was carried out in an effort to establish a collection of bacterial root nodule symbionts and determine their relationship to physicochemical soil parameters as well as any geographical distributional patterns. Bradyrhizobium spp. were found to be widespread in this study and several different types could be identified at each site. Unique but rare symbionts were recovered from the nodules of plants sampled in a drier in land region, where there were also overall more different bradyrhizobia found. Plants raised in soil from uncultivated sites with a natural vegetation cover tended to also associate with more different bradyrizobia. The occurrence and abundance of different bradyrhizobia correlated with differences in soil texture and pH, but did neither with the agro-ecological origin, nor the origin from cultivated (n = 15) or uncultivated (n = 5) sites. The analytical method, protein profiling of isolated strains by Matrix-Assisted Laser Desorption Ionization Time of-Flight Mass Spectrometry (MALDI-TOF MS), provided higher resolution than 16S rRNA gene sequencing and was applied in this study for the first time to isolates recovered directly from field-collected cowpea root nodules. The method thus seems suitable for screening isolate collections on the presence of different groups, which, provided an appropriate reference database, can also be assigned to known species. PMID- 29970948 TI - N2-fixation and N contribution by grain legumes under different soil fertility status and cropping systems in the Guinea savanna of northern Ghana. AB - Continuous cereal-based cropping has led to a rapid decline in soil fertility in the Guinea savanna agro-ecological zone of northern Ghana with corresponding low crop yields. We evaluated the effects of cropping system and soil fertility status on grain yields and N2-fixation by grain legumes and net N contribution to soil fertility improvement in contrasting sites in this agro-ecological zone. Maize was intercropped with cowpea, soybean and groundnut within a row, with a maize stand alternated with two equally spaced cowpea or groundnut stands and in the maize-soybean system, four equally spaced soybean stands. These intercrops were compared with sole crops of maize, cowpea, soybean and groundnut in fertile and poorly fertile fields at sites in the southern (SGS) and the northern (NGS) Guinea savanna. The proportion of N derived from N2-fixation (%Ndfa) was comparable between intercrops and sole crops. However, the amount of N2-fixed was significantly larger in sole crops due to a greater biomass accumulation. Legumes in poorly fertile fields had significantly smaller shoot delta15N enrichment ( 2.8 to +0.70/00) and a larger %Ndfa (55-94%) than those in fertile fields (-0.8 to +2.20/00; 23-85%). The N2-fixed however was larger in fertile fields (16-145 kg N ha-1) than in poorly fertile fields (15-123 kg N ha-1) due to greater shoot dry matter and N yields. The legumes grown in the NGS obtained more of their N requirements from atmospheric N2-fixation (73-88%) than legumes grown in the SGS (41-69%). The partial soil N balance (in kg ha-1) was comparable between intercrops (-14 to 21) and sole legumes (-8 to 23) but smaller than that of sole maize receiving N fertiliser (+7 to +34). With other N inputs (aerial deposition) and outputs (leaching and gaseous losses) unaccounted for, there is uncertainty surrounding the actual amount of soil N balances of the cropping systems, indicating that partial N balances are not reliable indicators of the sustainability of cropping systems. Nevertheless, the systems with legumes seem more attractive due to several non-N benefits. Our results suggest that soybean could be targeted in the SGS and cowpea in the NGS for greater productivity while groundnut is suited to both environments. Grain legumes grown in poorly fertile fields contributed more net N to the soil but growing legumes in fertile fields seems more lucrative due to greater grain and stover yields and non-N benefits. PMID- 29970949 TI - Soyabean response to rhizobium inoculation across sub-Saharan Africa: Patterns of variation and the role of promiscuity. AB - Improving bacterial nitrogen fixation in grain legumes is central to sustainable intensification of agriculture in sub-Saharan Africa. In the case of soyabean, two main approaches have been pursued: first, promiscuous varieties were developed to form effective symbiosis with locally abundant nitrogen fixing bacteria. Second, inoculation with elite bacterial strains is being promoted. Analyses of the success of these approaches in tropical smallholder systems are scarce. It is unclear how current promiscuous and non-promiscuous soyabean varieties perform in inoculated and uninoculated fields, and the extent of variation in inoculation response across regions and environmental conditions remains to be determined. We present an analysis of on-farm yields and inoculation responses across ten countries in Sub Saharan Africa, including both promiscuous and non-promiscuous varieties. By combining data from a core set of replicated on-farm trials with that from a large number of farmer-managed try outs, we study the potential for inoculation to increase yields in both variety types and evaluate the magnitude and variability of response. Average yields were estimated to be 1343 and 1227 kg/ha with and without inoculation respectively. Inoculation response varied widely between trials and locations, with no clear spatial patterns at larger scales and without evidence that this variation could be explained by yield constraints or environmental conditions. On average, specific varieties had similar uninoculated yields, while responding more strongly to inoculation. Side-by side comparisons revealed that stronger responses were observed at sites where promiscuous varieties had superior uninoculated yields, suggesting the availability of compatible, effective bacteria as a yield limiting factor and as a determinant of the magnitude of inoculation response. PMID- 29970950 TI - Benefits of inoculation, P fertilizer and manure on yields of common bean and soybean also increase yield of subsequent maize. AB - Common bean and soybean yield poorly on smallholder farms in Rwanda. We evaluated the benefits of inoculation combined with P fertilizer and manure on yields of common bean and soybean in three agro-ecological zones (AEZs), and their residual effects on a subsequent maize crop. In the first season, the treatments included inoculum, three rates of manure, and two rates of P fertilizer, with nine replications (three per AEZ). Both legumes responded well to inoculation if applied together with manure and P fertilizer. Grain yields varied from 1.0 t ha 1 to 1.7 t ha-1 in unamended control plots to 4.8 t ha-1 for common bean and 3.8 t ha-1 for soybean in inoculated plots with both P and manure addition. The response of common bean and soybean to inputs varied greatly between AEZs. In the AEZ with low and erratic rainfall (Bugesera), yields of both legumes and maize were low and maize after soybean failed to yield any grain due to drought. In this regard, early maturing legume varieties are advised in regions of low rainfall. Responses of maize to an input applied to the legumes strongly increased when other inputs were applied together to the legume. This allowed greater maize yields which ranged from 0.8 t ha-1 in control plots to 6.5 t ha-1 in treatments previously inoculated with P and manure added for maize grown after common bean and from 1.9 t ha-1 in control plots to 5.3 t ha-1 for maize grown after soybean. The amount of N2-fixed measured using the 15N-natural abundance method differed between the two legumes and varied between 15 and 198 kg N2 ha-1 for common bean and between 15 and 186 kg N2 ha-1 for soybean and differed enormously among treatments and AEZs. Application of inputs to the legumes also resulted in enhanced N and P uptake of the subsequent maize. The use of inoculum combined with manure and P fertilizer is a good option for smallholder farmers growing common bean and soybean in rotation with maize. We observed strong effects of environment and call for care when targeting crops and technologies for sustainable crop production. PMID- 29970951 TI - Feasibility of transference of inoculation-related technologies: A case study of evaluation of soybean rhizobial strains under the agro-climatic conditions of Brazil and Mozambique. AB - The soybean-Bradyrhizobium symbiosis can be very effective in fixing nitrogen and supply nearly all plant's demand on this nutrient, obviating the need for N fertilizers. Brazil has been investing in research and use of inoculants for soybean for decades and with the expansion of the crop in African countries, the feasibility of transference of biological nitrogen fixation (BNF) technologies between the continents should be investigated. We evaluated the performance of five strains (four Brazilian and one North American) in the 2013/2014 and 2014/2015 crop seasons in Brazil (four sites) and Mozambique (five sites). The experimental areas were located in relatively similar agro-climatic regions and had soybean nodulating rhizobial population ranging from ? 10 to 2 * 105 cells g 1 soil. The treatments were: (1) NI, non-inoculated control with no N-fertilizer; (2) NI + N, non-inoculated control with 200 kg of N ha-1; and inoculated with (3) Bradyrhizobium japonicum SEMIA 5079; (4) B. diazoefficiens SEMIA 5080; (5) B. elkanii SEMIA 587; (6) B. elkanii SEMIA 5019; (7) B. diazoefficiens USDA 110; (8) SEMIA 5079 + 5080 (only tested in Brazil). The best inoculation treatments across locations and crop seasons in Brazil were SEMIA 5079 + 5080, SEMIA 5079 and USDA 110, with average grain yield gains of 4-5% in relation to the non-inoculated treatment. SEMIA 5079, SEMIA 5080, SEMIA 5019 and USDA 110 were the best strains in Mozambique, with average 20-29% grain yield gains over the non-inoculated treatment. Moreover, the four best performing strains in Mozambique resulted in similar or better yields than the non-inoculated + N treatment, confirming the BNF as an alternative to N-fertilizers. The results also confirm the feasibility to transfer soybean inoculation technologies between countries, speeding up the establishment of sustainable cropping systems. PMID- 29970952 TI - Understanding variability in the benefits of N2-fixation in soybean-maize rotations on smallholder farmers' fields in Malawi. AB - Soybean production can contribute to the nitrogen economy of smallholder farming systems, but our understanding of factors explaining variability in nitrogen fixation and rotational benefits across farms and regions is limited. Biological nitrogen fixation (BNF) was quantified with the natural abundance method in 150 farmer-managed soybean plots under different varieties and inputs in Dowa, Mchinji and Salima districts of Malawi. Soybean yielded on average 1.2 t ha-1 grain and the above-ground biomass at mid pod filling (R5.5) was 2.8 t ha-1 and contained in total 63 kg ha-1 nitrogen derived from the atmosphere (Ndfa). Locally sourced varieties obtained a larger %Ndfa (65%) than the 'improved' variety Nasoko (53%). The %Ndfa was positively associated with soil sand content, sowing date, plant population and biomass accumulation, but it was not affected by inoculation with rhizobia or the combination of inoculation and NPK fertiliser application. Quantities of N2 fixed differed between regions and years, and was enhanced by applying inoculant and fertiliser together, leading to more biomass accumulation and larger grain yields. Soil available P and exchangeable K contents also increased the total amount of N2 fixed. In a related trial, continuous maize yields were compared with maize following soybean in 53 farmer managed fields. Average yield in continuous maize was 2.5 t ha-1, while maize after soybean produced 3.5 t ha-1 (139% of continuous maize). Farmers with higher maize yields, who applied external nutrient inputs, and with a larger value of household assets achieved greater yield responses to rotation with soybean. A relative yield increase of more than 10% was observed on 59, 90 and 77% of the fields in Dowa, Mchinji and Salima respectively. We conclude that fields of soybean and maize that receive adequate nutrient inputs and good management to ensure good yields benefit most in terms of quantities of N2 fixed by the legume and the yield response of the following maize crop. The results suggest that the promotion of soybean-maize rotations should be done through an integrated approach including the promotion of appropriate soil and crop management techniques. Furthermore, they suggest that wealthier households are more likely to apply adequate nutrient inputs and good crop management practices and are likely to receive larger maize yield responses to the incorporation of soybean. PMID- 29970953 TI - Unintended effects of a targeted maternal and child nutrition intervention on household expenditures, labor income, and the nutritional status of non-targeted siblings in Ghana. AB - It is common for health and nutrition interventions to target specific household members and for evaluations of their effects to focus exclusively on those members. However, if a targeted intervention changes a household's utility maximization problem or influences decision-making, households might respond to the intervention in unintended ways with the potential to affect the wellbeing of non-targeted members. Using panel data from a randomized controlled nutrition trial in Ghana, we evaluate household behavioral responses to the provision of small-quantity lipid-based nutrient supplements (SQ-LNS) to mothers and their infants to prevent undernutrition. We find that targeted supplementation with SQ LNS had a positive effect on household expenditures on food, including some nutrient-rich food groups, as well as on non-food goods and services. We also find a positive impact on labor income, particularly among fathers. We then explore intrahousehold spillover effects on the nutritional status of non targeted young children in the household. We find evidence that the targeted provision of SQ-LNS led to higher height-for-age z-scores among non-targeted children in the LNS group compared to the non-LNS group, though only among those with relatively taller mothers, which is an indicator of a child's growth potential. These findings support existing evidence and suggest that unintended behavioral responses and spillover are a real possibility in the context of nutrition interventions targeting nutritionally-vulnerable household members. Thoughtfully considering this possibility in the design, analyses, and evaluation of targeted nutrition interventions may provide a more complete picture of overall effects. PMID- 29970954 TI - New modalities for managing drought risk in rainfed agriculture: Evidence from a discrete choice experiment in Odisha, India. AB - Droughts have historically had large impacts on agricultural production in rainfed agricultural systems. Scientists and policymakers have proposed various strategies for managing risks, with limited success. In this study we consider two such strategies, specifically drought tolerant rice and weather index insurance. While neither drought tolerant cultivars nor weather index insurance products are perfect solutions for adequately managing drought risk in and of themselves, there is scope to exploit the benefits of each and bundle them into a complementary risk management product, specifically through proper index calibration and an optimized insurance design. In this study, we explore preferences for such a complementary risk management product using discrete choice experiments in Odisha, India. We are able to estimate the added value that farmers perceive in the bundled product above and beyond the value associated with each of the independent products. We also show that valuations are very sensitive to the basis risk implied by the insurance product, with farmers less enthusiastic about risk management products that leave significant risks uninsured. PMID- 29970955 TI - Intravitreal aflibercept for exudative age-related macular degeneration with good visual acuity: 2-year results of a prospective study. AB - Purpose: We report the 2-year outcomes of intravitreal aflibercept (IVA) for exudative age-related macular degeneration (AMD) with good visual acuity (VA) and examine the baseline factors associated with good visual outcome. Materials and methods: This multicenter, prospective study evaluated 39 eyes (39 AMD patients) enrolled from August 2013 to August 2014 at 12 and 24 months. Only patients with initial best-corrected VA (BCVA) >0.3 logarithm of the minimum angle of resolution (20/40 Snellen) were eligible. Three consecutive monthly IVA injections were followed by 2 monthly injections for 12 months. Thereafter, patients received injections on a treat- and-extend regimen for up to 24 months. Outcome measures included BCVA and central macular thickness (CMT) at 12 and 24 months. Post hoc analysis, BCVA, and CMT were evaluated by AMD types (typical AMD [tAMD], type 1, and type 2 polypoidal choroidal vasculopathy [PCV]). Baseline characteristics and BCVA associations were evaluated with linear regression analysis and Student's t-test. Results: Mean age was 69 years and 26 of 39 eyes were male. tAMD, type 1 and type 2 PCV occurred in 18, 12, and 9 eyes, respectively. Baseline mean BCVA was 0.097 logarithm of the minimum angle of resolution (20/25 Snellen) and showed significant improvement to 0.058 (20/22 Snellen, P=0.03) at 12 months and 0.066 (20/23) at 24 months. CMT improved significantly from 320 (99) um (mean [SD]) to 250 (93) um (P=0.002) at 12 months and 240 (93) um (P=0.0005) at 24 months. BCVA and CMT were not significantly different among the three groups. Only subretinal hemorrhage (SRH) was significantly associated with improved BCVA. BCVA change from baseline was -0.12 with SRH and -0.011 without SRH (P=0.017) at 12 months. Conclusion: IVA showed good efficacy for exudative AMD with good VA at 24 months. tAMD and type 1 and 2 PCV showed similar prognosis. Baseline SRH predicted favorable long-term vision in AMD with good VA. PMID- 29970956 TI - Short-versus long-term dual antiplatelet therapy after second-generation drug eluting stent implantation: a systematic review and meta-analysis of randomized controlled trials. AB - Background: The optimal dual antiplatelet therapy (DAPT) duration after second generation drug-eluting stent (DES) implantation remains unclear. We aim to evaluate the efficacy and safety of short-term (<=6 months) and long-term (>=12 months) DAPT after second-generation DES implantation. Methods: Randomized controlled trials (RCTs) were searched in PubMed, the Cochrane Library, the Embase and ClinicalTrials.gov in the English language. The endpoints included all cause mortality, cardiac death, non-cardiac death, myocardial infarction (MI), stent thrombosis (ST), stroke, all bleeding, and major bleeding. The effect estimate was expressed by using the hazard ratio (HR) with 95% CI and random effect models. Results: Seven RCTs with 13,571 patients were included in this study. In terms of survival endpoints, there was no significant difference in all cause mortality (HR: 0.91; 95% CI: 0.71-1.17), cardiac death (HR: 0.93; 95% CI: 0.67-1.29), and non-cardiac death (HR: 0.89; 95% CI: 0.62-1.28) in the 2 groups. Moreover, there was no significant difference in ischemic outcomes, including MI (HR: 1.15; 95% CI: 0.91-1.45), ST (HR: 1.11; 95% CI: 0.75-1.66), and stroke (HR: 0.85; 95% CI: 0.53-1.35) in the 2 groups. In terms of bleeding endpoints, there was no significant difference in all bleeding (HR: 0.81; 95% CI: 0.64-1.04) and major bleeding (HR: 0.82; 95% CI: 0.49-1.36) in the 2 groups. The subgroup analysis showed that the proportion of patients with acute coronary syndrome was not associated with the benefit of long-term versus short-term DAPT. Conclusion: Short-term DAPT is not inferior to long-term DAPT in patients implanted with second-generation DES. PMID- 29970957 TI - Sevoflurane anesthesia during pregnancy in mice induces hearing impairment in the offspring. AB - Introduction: Exposure to gamma-aminobutyric acid-mimetics and N-methyl-D aspartate-receptor antagonists during pregnancy may lead to hearing loss and long term behavioral abnormalities in the offspring. The purpose of this study was to explore the association between prenatal exposure to sevoflurane (SEV) anesthesia and hearing impairment in mice. Materials and methods: On gestational day 15, pregnant Kunming mice were exposed for 2 hours to 2.5% SEV plus 100% oxygen (anesthesia group) or 100% oxygen alone (control group). Results: During auditory brainstem response testing on P30, offspring of the anesthesia group mice exhibited higher hearing thresholds at 8, 16, 24, and 32 kHz; longer peak latency of wave II at all four frequencies; and longer interpeak latencies from waves II to V at 16, 24, and 32 kHz, compared to the control offspring. Caspase-3, iNOS, and COX-2 activation occurred in the fetal cochlea of the anesthesia group. Mitochondrial swelling was observed in the anesthesia group offspring at P1 and P15. Conclusion: Our results suggest that SEV exposure during pregnancy may cause detrimental effects on the developing auditory system. PMID- 29970958 TI - Salidroside ameliorates autophagy and activation of hepatic stellate cells in mice via NF-kappaB and TGF-beta1/Smad3 pathways. AB - Purpose: Liver fibrosis is commonly seen and a necessary stage in chronic liver disease. The aim of this study was to explore the effect of salidroside on liver fibrosis in mice and its potential mechanisms. Materials and methods: Two mouse liver fibrosis models were established by intraperitoneal injection of carbon tetrachloride (CCl4) for 8 weeks and bile duct ligation for 14 days. Salidroside was injected intraperitoneally at doses of 10 and 20 mg/kg once a day. Gene and protein expression levels were determined by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, Western blot, immunohistochemistry, and immunofluorescence. Results: Salidroside inhibited the production of extracellular matrix (ECM) and regulated the balance between MMP2 and TIMP1 and, therefore, alleviated liver fibrosis in the two fibrosis models. Salidroside reduced the production of transforming growth factor (TGF)-beta1 in Kupffer cells and hepatic stellate cells (HSCs) via the nuclear factor-kappaB signaling pathway and, therefore, inhibited the activation of HSCs and autophagy by downregulation of the TGF-beta1/Smad3 signaling pathway. Conclusion: Salidroside can effectively attenuate liver fibrosis by inhibiting the activation of HSCs in mice. PMID- 29970959 TI - Additive effect of oral LDD175 to tamsulosin and finasteride in a benign prostate hyperplasia rat model. AB - Objective: We investigated the benefits of the BKCa agonist 4-chloro-7 trifluoromethyl-10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acid (LDD175) combined with tamsulosin and finasteride, in a benign prostatic hyperplasia (BPH) rat model. Materials and methods: Castration was performed by bilateral orchiectomy under ketamine anesthesia. A rat model of BPH was established by daily intramuscular administration of testosterone propionate plus 17beta estradiol for 8 weeks. Model rats were administered combinations of 20 mg/kg LDD175, 0.01 mg/kg tamsulosin and 1 mg/kg finasteride once daily by oral gavage for 4 weeks from week 6 to 9 post-surgery. Intraurethral pressure induced by electrostimulation of the hypogastric nerve was measured at the end of administration. Body and genitourinary organ weights were recorded, serums were assayed for hormone concentrations, and tissues were subjected to histopathology, and analyses of alpha1-adrenoceptor mRNA and protein expression levels after treatment. Results: Combined LDD175, tamsulosin, and finasteride significantly decreased prostatic index, serum hormone levels, epithelial thickness, and prostate expression of alpha1-adrenoceptors in BPH model rats. The 3-drug combination was more effective than any other combination or LDD175 alone. Conclusion: These results suggest that LDD175 addition to tamsulosin and finasteride may be beneficial for the treatment of BPH patients who do not respond to tamsulosin plus finasteride. PMID- 29970960 TI - Relationship between beliefs about medicines, adherence to treatment, and disease activity in patients with rheumatoid arthritis under subcutaneous anti-TNFalpha therapy. AB - Objective: In patients with rheumatoid arthritis (RA), nonadherence to treatment is often related to patients' beliefs and concerns regarding their medication. This study aimed to analyze the correlations regarding patients' medication beliefs, medication adherence, and objective measures of disease activity and safety in patients with RA established on subcutaneous (SC) anti-tumor necrosis factor alpha (TNFalpha) therapy. Methods: This Phase IV, noninterventional, non drug-specific study enrolled patients with RA being treated with stable-dose SC anti-TNFalpha (adalimumab, etanercept, golimumab, and certolizumab pegol). At initial visit and 6 and 12 months later, patients completed the Beliefs about Medicines Questionnaire-Specific section, assessing perceptions of personal need for anti-TNFalpha therapy (anti-TNFalpha-Necessity) and concerns (anti-TNFalpha Concerns), Medication Adherence Rating Scale (MARS), mean Disease Activity Score in 28 joints (DAS28), and other scales. Longitudinal data were analyzed by linear mixed models. Results: A total of 460 patients were included. At initial visit, anti-TNFalpha-Necessity beliefs were high (mean +/- SD: 4.3 +/- 0.55) vs anti TNFalpha-Concerns (2.8 +/- 0.78). Medication adherence (MARS) was high (4.8 +/- 0.39). All scores remained stable over the 1-year follow-up period. Anti-TNFalpha Necessity beliefs and anti-TNFalpha-Concerns were not related to each other, but strongly correlated with medication adherence. While concerns worsened with disease activity, clinical status, and low quality of life, necessity beliefs remained unaffected. Conclusion: In patients with RA established on stable-dose SC anti-TNFalpha, anti-TNFalpha-Necessity beliefs persistently outweighed anti TNFalpha-Concerns, but both correlated with adherence. These findings may be of use in subsequent studies looking to predict adherence in patients starting treatment with SC anti-TNFalpha. PMID- 29970961 TI - Role of accelerated aging in limb muscle wasting of patients with COPD. AB - Purpose: Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD. Patients and methods: The levels of phosphorylated H2AX (gammaH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPDL), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16ink4a, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured. Results: We observed a decrease in gammaH2AX expression in COPDL, which occurred in association with a tendency to increase in CDKN2A/p16ink4a, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPDL. Conclusion: These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPDL. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation. PMID- 29970962 TI - Pioglitazone use in patients with diabetes and risk of bladder cancer: a systematic review and meta-analysis. AB - Pioglitazone has been reported to increase the risk of bladder cancer but the conclusions of published clinical studies are confusing. We conducted a systematic review and meta-analysis of all eligible randomized controlled trial (RCT) studies and observational studies, in order to identify a more precise relationship between pioglitazone and risk of bladder cancer. We searched for publications up to January 24, 2018, in PubMed, EMBASE, Scopus, Web of Science, Cochrane register, and Chinese National Knowledge Infrastructure databases, and the references of the retrieved articles and relevant reviews were also checked. Relative risk and 95% confidence interval (CI) were used to assess this correlation. A dose-related meta-analysis was performed as well. Data on RCT studies showed a null association between pioglitazone and bladder cancer. The pooled RR estimates of the 12 included studies illustrated that pioglitazone is associated with a 14% increased risk of bladder cancer (95% CI 1.03-1.26). No evidence of publication bias was detected. In the dose effect analysis, patients who used a higher dose of pioglitazone had an increased risk of bladder cancer. In conclusion, this meta-analysis indicated that pioglitazone is associated with an increased risk of bladder cancer. Further research should be conducted to confirm our findings and reveal the potential biological mechanisms. PMID- 29970963 TI - The homogeneous and heterogeneous risk factors for the morbidity and prognosis of bone metastasis in patients with prostate cancer. AB - Purpose: Using the Surveillance, Epidemiology, and End Results database (SEER) to assess the incidence and risk factors of morbidity and prognosis for bone metastases in initial metastatic prostate cancer. Patients and methods: The records of 249,331 prostate cancer patients in the SEER database, diagnosed between 2010 and 2014, were obtained were obtained to investigate the risk factors for developing bone metastasis, and the records of 9925 of them who registered before 2013 were retrieved (with at least 1 year follow up) to explore the prognostic factors for bone metastasis. Multivariate logistic and Cox regression were used to identify risk factors and prognostic factors for bone metastases, respectively. Results: In total, 12,794 patients (5.1%) were diagnosed with bone metastases at the initial diagnosis. Older age, unmarried status, lymph node metastasis, poor tumor differentiation grade (Gleason grade), metastases at lung, brain, and liver were all positively associated with risk for the morbidity and prognosis of bone metastasis in prostate cancer. Black race and higher T stage were positively associated with bone metastasis development; however, they were not associated with a prognosis of bone metastasis. Conclusion: The incidence of bone metastasis in prostate cancer was approximately 5% with poor survival. The prostate cancer has homogeneous and heterogeneous risk factors for incidence and prognosis of bone metastasis, which may provide potential guidelines for the screening and preventive treatment for the bone metastasis of prostate cancer. PMID- 29970964 TI - Decreased expression of TRPV1 in renal cell carcinoma: association with tumor Fuhrman grades and histopathological subtypes. AB - Purpose: The aim of this study was to investigate whether the expression of the ligand-gated Ca2+ channel transient receptor potential vanilloid type-1 (TRPV1) in primary human renal cell carcinoma (RCC) is associated with clinicopathological features. Patients and methods: Fresh and frozen primary tumor and normal peritumoral kidney tissues from 127 patients diagnosed with RCC were analyzed for TRPV1 expression by quantitative reverse transcription polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry. Results: Quantitative RT-PCR revealed that TRPV1 was decreased 3.20-fold in RCC tissue vs normal peritumoral kidney tissue (p=0.012). Significantly different TRPV1 mRNA expression was detected in RCC tissues of different Fuhrman grades and histopathological subtypes (F=4.282, p=0.015 and F=5.205, p=0.014, respectively). Decreased TRPV1 expression was correlated with RCC histopathological subtype (R= 0.554, p=0.003) and Fuhrman grade (R=-0.525, p=0.006). Western blot analysis of TRPV1 protein expression showed similar results. Immunohistochemical analysis showed strong expression of TRPV1 in kidney tubules but demonstrated weak or no immunostaining in RCC tissues. Conclusion: TRPV1 expression was decreased in RCC, which was significantly associated with tumor Fuhrman grades and histopathological subtypes. It seems to suggest that TRPV1 expression may be a valuable tool to predict the extent of RCC progression. PMID- 29970966 TI - Cervical lymph node metastases in salivary gland adenoid cystic carcinoma: a systematic review and meta-analysis. AB - Background: The purpose of this research was to determine whether neck dissection is necessary for the adenoid cystic carcinoma (ACC) of head and neck. Materials and methods: This article screened the abstract and full-text papers that investigated salivary gland primary ACC of head and neck. Two independent reviewers searched for articles published before October 2017 in three databases (Web of Science, PubMed, and Ovid), having no limits in date and language. Statistical data were analyzed statistically by Review Manager 5.3. Results: In total, 18 studies involving 2993 patients were included in the analysis. Of the 2993 patients, 473 patients had cervical lymph node metastasis, with a merge frequency of 16% (95% CI: 13-19). Among included articles, only 4 involved cervical lymph node occult metastases, with a merge frequency of 14% (95% CI: 9 20). There were 5 articles containing minor salivary glands (MiSGs) involving 370 patients of which 92 patients had cervical lymph node metastases and the merge frequency was 25% (95% CI: 11-38). Moreover, there were 4 studies on major salivary glands involving 904 patients of which 158 patients had cervical lymph node metastases and the merge frequency was 17% (95% CI: 15-20). Conclusion: Elective neck dissection is unnecessary for all patients with salivary gland ACC of head and neck. Moreover, compared with major salivary glands, MiSGs have a higher cervical lymph node metastases rate in ACC. The overall cervical lymph node metastases rate of MiSGs is 25%, which is enough to attract our attention. Therefore, we suggest that neck dissection might be applied to ACC of MiSGs. PMID- 29970965 TI - Cancer risk assessment in modern radiotherapy workflow with medical big data. AB - Modern radiotherapy (RT) is being enriched by big digital data and intensive technology. Multimodality image registration, intelligence-guided planning, real time tracking, image-guided RT (IGRT), and automatic follow-up surveys are the products of the digital era. Enormous digital data are created in the process of treatment, including benefits and risks. Generally, decision making in RT tries to balance these two aspects, which is based on the archival and retrieving of data from various platforms. However, modern risk-based analysis shows that many errors that occur in radiation oncology are due to failures in workflow. These errors can lead to imbalance between benefits and risks. In addition, the exact mechanism and dose-response relationship for radiation-induced malignancy are not well understood. The cancer risk in modern RT workflow continues to be a problem. Therefore, in this review, we develop risk assessments based on our current knowledge of IGRT and provide strategies for cancer risk reduction. Artificial intelligence (AI) such as machine learning is also discussed because big data are transforming RT via AI. PMID- 29970968 TI - Macular ganglion cell complex measurement in bilateral retrobulbar optic neuropathy without a relative afferent pupillary defect. AB - Purpose: This study aimed to demonstrate the clinical usefulness of measuring the macular ganglion cell complex (GCC) for the early detection of axonal loss in eyes with bilateral retrobulbar optic neuropathies. Patients and methods: We retrospectively reviewed the medical records of three patients with bilateral toxic, ischemic, or infiltrative retrobulbar optic neuropathy. Results: No relative afferent pupillary defect was detected in any patients. The results of the fundus examinations were unremarkable at the initial presentation except for slight optic disk pallor in the right eye of Case 3. Magnetic resonance imaging showed no abnormal findings in Cases 1 and 2. Measurement of the macular GCC clarified the presence of axonal loss in all three cases with diagnostic uncertainty. Although reduction in the macular GCC thickness was not observed initially in Case 2, it became evident later when both optic disks still appeared normal. Conclusion: A reduction in the macular GCC thickness seemed to precede the appearance of optic disk pallor and occurs regardless of toxic, ischemic, or infiltrative retrobulbar optic neuropathy. The current case series suggested that measurement of the macular GCC facilitated early differentiation between bilateral retrobulbar optic neuropathy and nonorganic visual loss, which can otherwise be challenging in some cases. PMID- 29970967 TI - The prognostic value and clinicopathological features of sarcomatoid differentiation in patients with renal cell carcinoma: a systematic review and meta-analysis. AB - Background and purpose: Numerous studies have demonstrated that sarcomatoid differentiation is linked to the risk of renal cell carcinoma (RCC). However, its actual clinicopathological impact remains inconclusive. Therefore, we undertook a meta-analysis to evaluate the pathologic and prognostic impacts of sarcomatoid differentiation in patients with RCC by assessing cancer-specific survival, overall survival, recurrence-free survival, progression-free survival, and cancer specific mortality. Materials and methods: In accordance with the preferred reporting items for systematic reviews and meta-analysis statement, relevant studies were collected systematically from PubMed, Embase, and Web of Science to identify relevant studies published prior to January 2018. The pooled effects (hazard ratios, odds ratios, and standard mean differences) and 95% confidence intervals were calculated to investigate the association of sarcomatoid differentiation with cancer prognosis and clinicopathological features. Results: Thirty-five studies (N=11,261 patients [n=59-1,437 per study]) on RCC were included in this meta-analysis. Overall, the pooled analysis suggested that sarcomatoid differentiation was significantly associated with unfavorable cancer specific survival (HR=1.46, 95% CI: 1.26-1.70, p<0.001), overall survival (HR=1.59, 95% CI: 1.42-1.78, p<0.001), progression-free survival (HR=1.61, 95% CI: 1.35-1.91, p<0.001), recurrence-free survival (HR=1.60, 95% CI: 1.29-1.99, p<0.001), and cancer-specific mortality (HR=2.36, 95% CI: 1.64-3.41, p<0.001) in patients with RCC. Moreover, sarcomatoid differentiation was closely correlated with TNM stage (III/IV vs I/II: OR=1.84, 95% CI: 1.12-3.03, p=0.017), Fuhrman grade (III/IV vs I/II: OR=8.37, 95% CI: 2.92-24.00, p<0.001), lymph node involvement (N1 vs N0: OR=1.88, 95% CI: 1.08-3.28, p=0.026), and pathological types (clear cell RCC-only vs mixed type: OR=0.48, 95% CI: 0.29-0.80, p=0.005), but was not related to gender (male vs female, OR=0.86, 95% CI: 0.58-1.28, p=0.464) and average age (SMD=-0.02, 95% CI: -0.20-0.17, p=0.868). Conclusion: This study suggests that sarcomatoid differentiation in histopathology is associated with poor clinical outcome and advanced clinicopathological features in RCC and could serve as a poor prognostic factor for RCC patients. PMID- 29970969 TI - Are adolescent elite athletes less psychologically distressed than controls? A cross-sectional study of 966 Norwegian adolescents. AB - Introduction: Psychological distress is increasing among adolescents and clusters with other mental health problems such as eating problems. The aim of this study was to investigate the prevalence of psychological distress among young elite athletes and age-matched controls and whether prevalence figures may be attributed to perfectionism and eating problems. Methods: First-year athletes from all Norwegian elite sport high schools (n=711) and 500 students from randomly selected ordinary high schools were eligible for this cross-sectional study. In total, 611 athletes and 355 student controls provided self-report data about psychological distress, perfectionism, and eating problems (ie, body dissatisfaction and a drive for thinness), as well as their physical training/activity. Results: A significantly higher proportion of controls scored above the cutoff point for marked psychological distress. Physical activity above the recommended levels for this age group predicted psychological distress among the controls, while the opposite was found in the student elite athlete sample. In both samples, perfectionistic concerns, ie, concern over mistakes, predicted overall psychological distress. However, among elite athletes, perfectionistic concerns were particularly associated with clinically significant psychological distress. Moreover, the impact of eating problems was negligible. Conclusion: Results from this study highlight the need to target the maladaptive perfectionistic concerns to prevent psychological distress among young athletes as well as among their age-matched nonathlete counterparts. PMID- 29970970 TI - Biochemical changes in stored donor units: implications on the efficacy of blood transfusion. AB - Background: Blood transfusion with allogeneic blood products is a common medical intervention to treat anemia or prepare patients for surgical procedures. Generally, the blood units are secured and stored prior to expected transfusion. During storage, a number of biochemical changes occur (generally known as storage lesion), which can affect the efficacy of blood transfusion. The aim of the study was to evaluate the biochemical changes that occur in blood units during storage and to project the impact of these changes on transfusion. Methods: The study protocol was approved by the Faculty of Medicine Research Ethics committee of Mbarara University of Science and Technology. A total of 200 blood recipients were categorized into two study arms: group I received fresh blood (n=100) and group II received old blood (n=100), who were formally consented and recruited consecutively. A total of 2 mL of venous blood was collected from each participant in EDTA tubes before transfusion (for pre-transfusion hemoglobin [Hb] estimation) and after transfusion (for post-transfusion Hb estimation). Each crossmatched unit was sampled to collect plasma for pH, lactate and potassium assays. Data were analyzed with STATA version 12.0. Results: A total of 200 blood transfusion recipients aged 1-60 years were enrolled in the study. Up to 60% of the participants were females. The pH of the stored blood dropped from 7.4 to 7.2 in the first 3 days to ~7.0 by day 11 and to <7.0 by day 35 (p=0.03). The average rise in lactate level was 25 g/dL in blood stored for 0 to 11 days and 32.4 g/dL in blood stored for 21-35 days. The highest increase was encountered in blood stored beyond 28 days: 40-57 g/dL by 35 days (p=0.001). Potassium levels equally increased from ~4.6 mmol/L in the first 5 days of storage to ~14.3 mmol/L by 11 days. From the third week of blood storage and beyond, there was exponential increase in potassium levels, with the highest record in blood units stored from 30 to 35 days (p=0.068). Conclusion: Whole blood stored for >14 days has reduced efficacy with increased markers of red cell storage lesion such as increased potassium level, lactate and fall in pH. These lesions increase the length of hospital stay. PMID- 29970971 TI - Joint versus separate inpatient rehabilitation treatment for patients with alcohol use disorder or drug use disorder: an observational study. AB - Background: In many national treatment systems, patients with alcohol use disorders (AUD) and those with drug use disorders (DUD) are treated separately, while other systems provide joint treatment for both kinds of substance use disorders (SUDs). Regarding long-term rehabilitation treatment of DUD and AUD patients, there is however a lack of empirical studies on the comparison between a separate versus joint treatment modality. Methods: Data were gathered from 2 rehabilitation units located in small towns from the same German region. One unit provided treatment to a mixed group of AUD and DUD patients, while the other unit treated the 2 groups separately. Staffing, funding, and treatment programs were otherwise similar between facilities. Data were gathered from standardized routine documentation and standardized interviews. In order to understand correlates of premature treatment termination, a logistic regression analysis was performed, with treatment modality and type of SUD as main predictors, and a range of patient characteristics as covariates. Results: Patients (N=319) were diagnosed with AUD (48%), DUD (34%), or AUD plus DUD (18%). Patients in joint treatment showed a higher prevalence of lapses during treatment than those in separate treatment (26% versus 12%; p=0.009), but there was no significant difference in the prevalence of premature terminations (38% versus 44%, p=0.26). Treatment modality and interaction between modality and type of SUD was not significantly associated with premature termination. Joint treatment completers showed higher satisfaction with treatment than separate treatment completers (p<0.001). Conclusion: We found no evidence here for a difference between treatment modalities in terms of premature termination rate. Satisfaction level was higher in those who completed joint treatment compared to separate treatment. PMID- 29970972 TI - "Zero Suicide" - A model for reducing suicide in United States behavioral healthcare. AB - Suicide is a serious public health concern in the US, especially for those served in outpatient behavioral health. Over the past decade, there has been a dramatic increase in US suicide rates, and a significant proportion of those dying by or attempting suicide were treated in outpatient behavioral healthcare within the prior year. In response, the US Action Alliance released the National Strategy for Suicide Prevention in 2012, a key tenet of which is the "Zero Suicide" (ZS) model. ZS provides resources for administrators and providers to create a systematic approach to quality improvement for suicide prevention in healthcare systems via seven essential elements (Lead, Train, Identify, Engage, Treat, Transition, Improve). In this paper, we describe the ZS model, as well as our operationalization of the model in an NIMH-funded study in ~170 free-standing New York State outpatient behavioral health clinics, serving >80,000 patients. This study is the largest implementation and evaluation of the ZS approach ever conducted in outpatient behavioral health. Evaluation of ZS implementation in "real-world" clinical settings will provide crucial insight regarding broader dissemination and inform how to best adopt empirically-supported care for suicidal patients in outpatient behavioral health, thereby reducing tragic and preventable loss of life. PMID- 29970973 TI - Geostatistical Analysis Methods for Estimation of Environmental Data Homogeneity. AB - The methodology for assessing the spatial homogeneity of ecosystems with the possibility of subsequent zoning of territories in terms of the degree of disturbance of the environment is considered in the study. The degree of pollution of the water body was reconstructed on the basis of hydrochemical monitoring data and information on the level of the technogenic load in one year. As a result, the greatest environmental stress zones were isolated and correct zoning using geostatistical analysis techniques was proved. Mathematical algorithm computing system was implemented in an object-oriented programming C #. A software application has been obtained that allows quickly assessing the scale and spatial localization of pollution during the initial analysis of the environmental situation. PMID- 29970974 TI - ASHP-PPAG Guidelines for Providing Pediatric Pharmacy Services in Hospitals and Health Systems. PMID- 29970976 TI - Effect of Nursing Education on Optimization of Medication Reconciliation in the Pediatric Emergency Department. AB - OBJECTIVE: This study was conducted to evaluate the impact of education on optimizing medication histories in a single-center pediatric emergency department. METHODS: This was a prospective, 2-phase study of 200 patients ages 21 years and younger who presented to the pediatric emergency department in January and February 2017. In phase I of the study, 100 patients were interviewed by both a nurse and a pharmacist. Between phases I and II, the pharmacist educated each nurse and disseminated standardized education materials. In phase II, 100 additional patients were interviewed by both a nurse and a pharmacist. Discrepancies were quantified in both phases of the study. The primary outcome was the distribution of total discrepancies in medications identified. Total discrepancies were defined as a composite of medication name, dose, route, frequency, and time of last dose. RESULTS: A total of 200 medication histories were collected over phases I and II. In phase I (n = 79), the pharmacist identified 185 medications, 88 of which were also identified by the nurse. In phase II (n = 82), the pharmacist identified 180 medications, 95 of which were also identified by the nurse. The distribution of discrepancies per patient and per medication was significantly reduced in regard to dose, route, and frequency documentation. CONCLUSION: Although improvement was observed, barriers beyond a knowledge deficit exist to limit accuracy of medication histories collected by nurses. PMID- 29970975 TI - Pain Management in Pediatric Chronic Kidney Disease. AB - Pain is a common problem in children with chronic kidney disease (CKD); however, limited data exist regarding its management. Although most pain is managed pharmacologically, in some instances non-pharmacologic management can aid in safely ameliorating discomfort. Because of the accumulation of toxic metabolites, many common pain medications have adverse effects on kidney function or altered pharmacokinetics in the setting of CKD. Decreased clearance impacts safe dosing of analgesics. The pain management of patients on renal replacement therapy requires an understanding of drug clearance due to the different modalities of dialysis. This educational review highlights pain medications that are safe, albeit often with adjusted dosing, as well as drugs best avoided in the management of pediatric kidney disease. Acetaminophen should be used as a first line therapy for pain management in children with CKD. Opioids may be added to control moderate to severe pain. Although data are currently lacking, buprenorphine holds promise as a potentially useful drug for the treatment of pain in pediatric patients with CKD. The addition of adjuvant pain medications and non-pharmacologic therapies maybe also be helpful. Despite these options, pain often remains difficult to treat in children with CKD. PMID- 29970977 TI - Characterization of the Clinical Outcomes With Cefepime in a Neonatal Intensive Care Unit: A Retrospective Cohort Study. AB - OBJECTIVES: The objective of this study was to characterize clinical outcomes when cefepime was used in a neonatal intensive care population. METHODS: Data were extracted from the medical records of all full-term (40 weeks gestational age) patients up to 2 months of age and preterm patients up to 48 weeks postmenstrual age admitted to the neonatal intensive care unit (NICU) at a freestanding children's hospital between January 1, 2010, and December 31, 2013, who received at least 48 hours of cefepime. The primary outcome measure was a positive clinical response as defined by a normalization of white blood cell count and/or culture clearance. RESULTS: Final analysis included 74 patients. Clinical response was evaluable in 43.2% (32 of 74) of courses. Of these, positive clinical response was observed in 81.3% (26 of 32). Overall patient mortality was 16.2% (12 of 74). Adverse effects (AEs) occurred in 14.9% (11 of 74) of courses. CONCLUSIONS: Cefepime can be used safely with reasonable clinical response in a NICU population, but additional studies are needed to further determine cefepime-associated clinical outcomes. PMID- 29970978 TI - General Anesthesia With Dexmedetomidine and Remifentanil in a Neonate During Oracotomy and Resection of a Congenital Cystic Adenomatoid Malformation. AB - Based on animal data, concern has been expressed regarding the potential deleterious neurocognitive effects of general anesthesia during infancy and early life. Although there are no definitive data to prove this effect, the neonatal period has been suggested to be the most vulnerable period. While various inhaled and intravenous anesthetic agents have been implicated, dexmedetomidine and the opioids may be devoid of such effects. However, there are limited data regarding the combination of these agents during neonatal surgery and anesthesia. We present the use of these agents in combination with epidural anesthesia for postoperative analgesia in a 1-day-old neonate during thoracotomy and excision of a congental cystic adenomatoid malformation. Previous reports of the use of this unique combination of agents are reviewed and their role in this scenario discussed. PMID- 29970979 TI - Angioedema Associated With Nebulized Recombinant Human DNase in a Preterm Infant: Case Report. AB - Pulmonary atelectasis leads to difficulties in weaning of the neonates from mechanical ventilation. The management of persistent atelectasis in neonates constitutes a common challenge for physicians. Several reports suggested Recombinant human DNase (rhDNase) as a beneficial therapy for neonates with persistent atelectasis by reducing mucous viscosity. No adverse effect associated with rhDNase treatment was reported in neonates. Herein, we report probable adverse reactions associated with rhDNase use in a preterm infant. Therefore, we suggest that clinicians must be aware of this reaction in neonates and should carefully follow up these infants for the development of adverse reactions. We think that more clinical experience and data are needed to define its tolerability and adverse effect profile in neonates. PMID- 29970980 TI - Dosing for Fentanyl Infusion in Obese Children: Just Because It's What We Have Always Done Doesn't Mean It Is Right. PMID- 29970981 TI - Pediatric News. PMID- 29970982 TI - HMG-CoA Reductase Inhibitors Relieve Endoplasmic Reticulum Stress by Autophagy Inhibition in Rats With Permanent Brain Ischemia. AB - Exploring and expanding the indications of common clinical drugs, such as statins, is important to improve the prognosis of patients with permanent cerebral infarction. It has been suggested that reversing the defects in cellular autophagy and ER stress with statin therapy may be a potential treatment option for reducing ischemic damage. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO) by electrocoagulation surgery. Atorvastatin (ATV, 10 mg/kg/day) or vehicle was administered intraperitoneally. Rats were divided into the vehicle-treated (SHAM), ATV pretreatment for MCAO (AMCAO), and 3 methyladenine (3MA) combined with ATV pretreatment (3MAMCAO) groups. Magnetic resonance imaging, as well as immunohistochemical and Western blot assessments, were performed 24 h after MCAO. Each ATV-treated group demonstrated significant reductions in infarct volume compared with that in the vehicle-treated group at 24 h after MCAO, which was associated with autophagy reduction and ER stress attenuation in neurons and neovascularization. Next, Western blotting was used to detect the levels of the autophagy-related proteins LC3B and P62 and of ER stress pathway proteins. However, 3MA significantly partially inhibited the ER stress pathway via limiting the autophagic flux in the AMCAO group. In conclusion, our results imply that the neuroprotective function of ATV depends on autophagic activity to diminish ER stress-related cell apoptosis in rats with PMCAO and suggest that compounds that inhibit autophagic activity might reduce the neuroprotective effect of ATV after brain ischemia. PMID- 29970984 TI - Non-linear ICA Analysis of Resting-State fMRI in Mild Cognitive Impairment. AB - Compared to linear independent component analysis (ICA), non-linear ICA is more suitable for the decomposition of mixed components. Existing studies of functional magnetic resonance imaging (fMRI) data by using linear ICA assume that the brain's mixed signals, which are caused by the activity of brain, are formed through the linear combination of source signals. But the application of the non linear combination of source signals is more suitable for the mixed signals of brain. For this reason, we investigated statistical differences in resting state networks (RSNs) on 32 healthy controls (HC) and 38 mild cognitive impairment (MCI) patients using post-nonlinear ICA. Post-nonlinear ICA is one of the non linear ICA methods. Firstly, the fMRI data of all subjects was preprocessed. The second step was to extract independent components (ICs) of fMRI data of all subjects. In the third step, we calculated the correlation coefficient between ICs and RSN templates, and selected ICs of the largest spatial correlation coefficient. The ICs represent the corresponding RSNs. After finding out the eight RSNs of MCI group and HC group, one sample t-tests were performed. Finally, in order to compare the differences of RSNs between MCI and HC groups, the two sample t-tests were carried out. We found that the functional connectivity (FC) of RSNs in MCI patients was abnormal. Compared with HC, MCI patients showed the increased and decreased FC in default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), somato-motor network (SMN), visual network(VN), MCI patients displayed the specifically decreased FC in auditory network (AN), self-referential network (SRN). The FC of core network (CN) did not reveal significant group difference. The results indicate that the abnormal FC in RSNs is selective in MCI patients. PMID- 29970985 TI - Sirt3 Ameliorates Oxidative Stress and Mitochondrial Dysfunction After Intracerebral Hemorrhage in Diabetic Rats. AB - Aim: Sirtuin3 (sirt3) plays a pivotal role in improving oxidative stress and mitochondrial dysfunction which directly induced neuronal apoptosis after intracerebral hemorrhage (ICH). Reactive oxygen species (ROS) is also a critical activator in triggering NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasomes activation which can regulate inflammatory responses in brain. Moreover, hyperglycemia can aggravate the ICH-induced damage. Hence, this study was designed to investigate the mechanisms of neuroprotection of sirt3 in hyperglycemic ICH. Methods: ICH model was established by autologous blood injection. Hyperglycemia was induced by intraperitoneal injection with streptozotocin. Honokiol (HKL, a pharmacological agonist of sirt3) was injected intraperitoneally at doses of 2.5, 5, or 10 mg/kg. Sirt3 small interfering RNA transfection was implemented through intracerebroventricular injection. The expression of sirt3 and its downstream signaling molecules were detected using Western blotting or immunofluorescence staining. Morphological changes of mitochondria were detected by electron microscopy. SH-SY5Y cells were incubated with 10 MUM oxyhemoglobin for 48 h to establish an in vitro ICH model, and then JC-1 staining was used to determine mitochondrial membrane potential (Deltapsim). Results: Hyperglycemia could suppress sirt3 expression after ICH when compared with non-diabetic rats. Sirt3 protein expression was decreased to the minimum at 24 h in perihematoma tissues. Electron microscope analysis indicated that hyperglycemic ICH induced extensive mitochondrial vacuolization. HKL attenuated ROS accumulation, adenosine triphosphate reduction, and Deltapsim through Sirt3 superoxide dismutase 2 (SOD2) and Sirt3-NRF1-TFAM pathway. Sirt3 knockdown could exacerbate the neuronal apoptosis and reverse the positive effects of HKL. Sirt3 activation could decrease NLRP3 and interleukin-1beta levels through deacetylating SOD2 and scavenging ROS. Conclusion: HKL protects against hyperglycemic ICH-induced neuronal injury via a sirt3-dependent manner. PMID- 29970983 TI - Common Defects of Spine Dynamics and Circuit Function in Neurodevelopmental Disorders: A Systematic Review of Findings From in Vivo Optical Imaging of Mouse Models. AB - In vivo optical imaging is a powerful tool for revealing brain structure and function at both the circuit and cellular levels. Here, we provide a systematic review of findings obtained from in vivo imaging studies of mouse models of neurodevelopmental disorders, including the monogenic disorders fragile X syndrome, Rett syndrome, and Angelman syndrome, which are caused by genetic abnormalities of FMR1, MECP2, and UBE3A, as well as disorders caused by copy number variations (15q11-13 duplication and 22q11.2 deletion) and BTBR mice as an inbred strain model of autism spectrum disorder (ASD). Most studies visualize the structural and functional responsiveness of cerebral cortical neurons to sensory stimuli and the developmental and experience-dependent changes in these responses as a model of brain functions affected by these disorders. The optical imaging techniques include two-photon microscopy of fluorescently labeled dendritic spines or neurons loaded with fluorescent calcium indicators and macroscopic imaging of cortical activity using calcium indicators, voltage-sensitive dyes or intrinsic optical signals. Studies have revealed alterations in the density, stability, and turnover of dendritic spines, aberrant cortical sensory responses, impaired inhibitory function, and concomitant failure of circuit maturation as common causes for neurological deficits. Mechanistic hypotheses derived from in vivo imaging also provide new directions for therapeutic interventions. For instance, it was recently demonstrated that early postnatal administration of a selective serotonin reuptake inhibitor (SSRI) restores impaired cortical inhibitory function and ameliorates the aberrant social behaviors in a mouse model of ASD. We discuss the potential use of SSRIs for treating ASDs in light of these findings. PMID- 29970986 TI - Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism. AB - Mutations in the SHANK family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of SHANK with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models. To investigate the phylogenetic conservation of phenotypes resultant of Shank2 loss-of-function in a translationally relevant animal model, we generated and characterized a novel transgenic rat with a targeted mutation of the Shank2 gene, enabling an evaluation of gene-associated phenotypes, the elucidation of complex behavioral phenotypes, and the characterization of potential translational biomarkers. The Shank2 loss-of-function mutation resulted in a notable phenotype of hyperactivity encompassing hypermotivation, increased locomotion, and repetitive behaviors. Mutant rats also expressed deficits in social behavior throughout development and in the acquisition of operant tasks. The hyperactive phenotype was associated with an upregulation of mGluR1 expression, increased dendritic branching, and enhanced long-term depression (LTD) in the striatum but opposing morphological and cellular alterations in the hippocampus (HP). Administration of the mGluR1 antagonist JNJ16259685 selectively normalized the expression of striatally mediated repetitive behaviors and physiology but had no effect on social deficits. Finally, Shank2 mutant animals also exhibited alterations in electroencephalography (EEG) spectral power and event-related potentials, which may serve as translatable EEG biomarkers of synaptopathic alterations. Our results show a novel hypermotivation phenotype that is unique to the rat model of Shank2 dysfunction, in addition to the traditional hyperactive and repetitive behaviors observed in mouse models. The hypermotivated and hyperactive phenotype is associated with striatal dysfunction, which should be explored further as a targetable mechanism for impairment in ASD. PMID- 29970987 TI - Shank2 Deletion in Parvalbumin Neurons Leads to Moderate Hyperactivity, Enhanced Self-Grooming and Suppressed Seizure Susceptibility in Mice. AB - Shank2 is an abundant postsynaptic scaffolding protein implicated in neurodevelopmental and psychiatric disorders, including autism spectrum disorders (ASD). Deletion of Shank2 in mice has been shown to induce social deficits, repetitive behaviors, and hyperactivity, but the identity of the cell types that contribute to these phenotypes has remained unclear. Here, we report a conditional mouse line with a Shank2 deletion restricted to parvalbumin (PV) positive neurons (Pv-Cre;Shank2fl/fl mice). These mice display moderate hyperactivity in both novel and familiar environments and enhanced self-grooming in novel, but not familiar, environments. In contrast, they showed normal levels of social interaction, anxiety-like behavior, and learning and memory. Basal brain rhythms in Pv-Cre;Shank2fl/fl mice, measured by electroencephalography, were normal, but susceptibility to pentylenetetrazole (PTZ)-induced seizures was decreased. These results suggest that Shank2 deletion in PV-positive neurons leads to hyperactivity, enhanced self-grooming and suppressed brain excitation. PMID- 29970989 TI - Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models. AB - Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The SHANK3 gene (and to a lesser degree SHANK2) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the CONTACTIN 4 gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both SHANKs and CNTN4 affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (Shank2-/-), Shank3 (Shank3alphabeta-/-), and Cntn4 (Cntn4-/-) as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the alpha1 subunit of the GABAA receptor was analyzed for inhibitory synaptic transmission. We found that both Shank2-/- and Shank3alphabeta-/- mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions-especially in the striatum and thalamus-when compared to wildtype controls. Interestingly, even though Cntn4-/- mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, Cntn4-/- mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions. PMID- 29970988 TI - Fas Ligand Gene (Faslg) Plays an Important Role in Nerve Degeneration and Regeneration After Rat Sciatic Nerve Injury. AB - Wallerian degeneration (WD) is associated with changes in the expression levels of a large number of genes. However, the effects of these up- or down-regulated genes are poorly understood. We have reported some key factors that are differentially regulated during WD in our previous research. Here, we explored the roles of Fas ligand gene (Faslg) in WD after rat sciatic nerve injury. The data showed that Faslg was up-regulated in injured nerves. Expression changed of Faslg in Schwann cells (SCs) resulted in alterations in the release of related factors. Silencing or overexpression of Faslg affected SC proliferation, migration, and apoptosis through beta-catenin, nuclear factor-kappaB (NF-kappaB), and caspase-3 pathways in vivo and in vitro. Our data suggest that Faslg is a key regulatory gene that affects nerve repair and regeneration in peripheral nerve injury. This study sheds new light on the effects of Faslg on peripheral nerve degeneration and/or regeneration. PMID- 29970990 TI - A Guide to Single-Cell Transcriptomics in Adult Rodent Brain: The Medium Spiny Neuron Transcriptome Revisited. AB - Recent advances in single-cell technologies are paving the way to a comprehensive understanding of the cellular complexity in the brain. Protocols for single-cell transcriptomics combine a variety of sophisticated methods for the purpose of isolating the heavily interconnected and heterogeneous neuronal cell types in a relatively intact and healthy state. The emphasis of single-cell transcriptome studies has thus far been on comparing library generation and sequencing techniques that enable measurement of the minute amounts of starting material from a single cell. However, in order for data to be comparable, standardized cell isolation techniques are essential. Here, we analyzed and simplified methods for the different steps critically involved in single-cell isolation from brain. These include enzymatic digestion, tissue trituration, improved methods for efficient fluorescence-activated cell sorting in samples containing high degree of debris from the neuropil, and finally, highly region-specific cellular labeling compatible with use of stereotaxic coordinates. The methods are exemplified using medium spiny neurons (MSN) from dorsomedial striatum, a cell type that is clinically relevant for disorders of the basal ganglia, including psychiatric and neurodegenerative diseases. We present single-cell RNA sequencing (scRNA-Seq) data from D1 and D2 dopamine receptor expressing MSN subtypes. We illustrate the need for single-cell resolution by comparing to available population-based gene expression data of striatal MSN subtypes. Our findings contribute toward standardizing important steps of single-cell isolation from adult brain tissue to increase comparability of data. Furthermore, our data redefine the transcriptome of MSNs at unprecedented resolution by confirming established marker genes, resolving inconsistencies from previous gene expression studies, and identifying novel subtype-specific marker genes in this important cell type. PMID- 29970991 TI - Transformation of Feature Selectivity From Membrane Potential to Spikes in the Mouse Superior Colliculus. AB - Neurons in the visual system display varying degrees of selectivity for stimulus features such as orientation and direction. Such feature selectivity is generated and processed by intricate circuit and synaptic mechanisms. A key factor in this process is the input-output transformation from membrane potential (Vm) to spikes in individual neurons. Here, we use in vivo whole-cell recording to study Vm-to spike transformation of visual feature selectivity in the superficial neurons of the mouse superior colliculus (SC). As expected from the spike threshold effect, direction and orientation selectivity increase from Vm to spike responses. The degree of this increase is highly variable, and interestingly, it is correlated with the receptive field size of the recorded neurons. We find that the relationships between Vm and spike rate and between Vm dynamics and spike initiation are also correlated with receptive field size, which likely contribute to the observed input-output transformation of feature selectivity. Together, our findings provide useful information for understanding information processing and visual transformation in the mouse SC. PMID- 29970992 TI - Identification of Functional Cell Groups in the Abducens Nucleus of Monkey and Human by Perineuronal Nets and Choline Acetyltransferase Immunolabeling. AB - The abducens nucleus (nVI) contains several functional cell groups: motoneurons of the singly-innervated twitch muscle fibers (SIF) and those of the multiply innervated muscle fibers (MIF) of the lateral rectus muscle (LR), internuclear neurons (INTs) projecting to the contralateral oculomotor nucleus (nIII) and paramedian tract-neurons (PMT) that receive input from premotor neurons of the oculomotor system and project to the floccular region. In monkey, these cell populations can be delineated by their chemical signature. For correlative clinico-pathological studies the identification of the homologous cell groups in the human nVI are required. In this study, we plotted the distribution of these populations in monkey nVI by combined tract-tracing and immunohistochemical staining facilitating the identification of homologous cell groups in man. Paraffin sections of two Rhesus monkeys fixed with 4% paraformaldhehyde and immunostained with antibodies directed against choline acetyltransferase (ChAT) as marker enzyme for cholinergic neurons and chondroitin sulfate proteoglycan (CSPG) to detect perineuronal nets (PNs) revealed four neuron populations in nVI with different chemical signatures: ChAT-positive and CSPG-positive SIF motoneurons, ChAT-positive, but CSPG-negative MIF motoneurons, and ChAT-negative neurons with prominent PNs that were considered as INTs. This was confirmed by combined immunofluorescence labeling of cholera toxin subunit B (CTB) or wheat germ agglutinin (WGA) and ChAT or CSPG in nVI sections from cases with tracer injections into nIII. In the rostral part of nVI and at its medial border, populations of ChAT-negative groups with weak CSPG-staining, but with strong acetylcholinesterase (AChE) activity, were identified as PMT cell groups by correlating them with the location of anterograde tracer labeling from INTs in nIII. Applying ChAT- and CSPG-immunostaining as well as AChE staining to human brainstem sections four neuron groups with the same chemical signature as those in monkey could be identified in and around the nVI in human. In conclusion, the distribution of nVI neuron populations was identified in human based on findings in monkey utilizing their markers for cholinergic neurons and their different ensheathment by PNs of the extracellular matrix. PMID- 29970994 TI - Using tDCS as an Add-On Treatment Prior to FES Therapy in Improving Upper Limb Function in Severe Chronic Stroke Patients: A Randomized Controlled Study. AB - : Background: Upper limb function recovery is of vital importance for stroke patients. However, it is difficult to get ideal recovery, especially for patients with severe chronic stroke. As the first randomized controlled long-term trial combining bilateral transcranial direct current stimulation (tDCS) and functional electrical stimulation (FES) therapy, this study examined the efficacy of a novel protocol that included applying tDCS as an add-on treatment prior to FES therapy over the course of a 4-week program. Methods: Thirty subjects with severe chronic stroke were randomized to either Group A (active tDCS+FES) (N = 15) or Group B (sham tDCS+FES) (N = 15). Five assessments including 3 behavioral outcome measurement scales [the Fugl-Meyer scale (cFMA), the Wolf motor function test (WMFT) and the modified Ashworth scale (MAS)], the surface electromyography (sEMG) evaluation and the transcranial magnetic stimulation (TMS) assessment were performed to evaluate subjects before and after the overall therapy. Results: In Group A, the combined protocol was well tolerated by all patients and induced significant improvements in upper extremity motor abilities in terms of the assessments of cFMA [t(14) = -5.658, p < 0.05], WMFT [t(14) = -3.746, p < 0.05], MAS [t(14) = 5.236, p < 0.05], sEMG and TMS. The results of between-group comparisons showed there was a significant difference between Group A and Group B in terms of the assessments of cFMA [t(28) = 2.223, p < 0.05], WMFT [t(28) = 2.152, p < 0.05] and sEMG [F(1, 196) = 0.918, p < 0.05]. Conclusion: The proposed protocol can facilitate improvements in upper extremity motor abilities in severe chronic stroke patients and is more beneficial than the protocol with FES therapy alone. Our results showed efficacy of the new paradigm with combined intervention in both the central nervous system and the peripheral nervous system. TRIAL REGISTRATION: ChiCTR-ICR-15006108. PMID- 29970993 TI - Event-Related Potentials in Relation to Risk-Taking: A Systematic Review. AB - Event-related potentials (ERPs) have been used to investigate neural mechanisms underlying risk-related decisions over the last 16 years. We aimed to systematically evaluate associations between risk-taking and ERP components elicited during decisions and following feedback. A total of 79 articles identified from PsychINFO and PubMed databases met the inclusion criteria. Selected articles assessed early ERP components (feedback-related negativity/FRN, error-related negativity/ERN, and medial frontal negativity/MFN) and the mid latency P3 component, all using gambling paradigms that involved selecting between choices of varying risk (e.g., Iowa Gambling Task, Balloon Analogue Risk Task, and two-choice gambling tasks). The P3 component was consistently enhanced to the selection of risky options and when positive feedback (as compared to negative feedback) was provided. Also consistently, the early negative components were found to be larger following feedback indicating monetary losses as compared to gains. In the majority of studies reviewed here, risk was conceptualized in the context of simple economical decisions in gambling tasks. As such, this narrow concept of risk might not capture the diversity of risky decisions made in other areas of everyday experience, for example, social, health, and recreational risk-related decisions. It therefore remains to be seen whether the risk sensitivity of the ERP components reviewed here generalizes to other domains of life. PMID- 29970996 TI - Classification of Alzheimer's Disease by Combination of Convolutional and Recurrent Neural Networks Using FDG-PET Images. AB - Alzheimer's disease (AD) is an irreversible brain degenerative disorder affecting people aged older than 65 years. Currently, there is no effective cure for AD, but its progression can be delayed with some treatments. Accurate and early diagnosis of AD is vital for the patient care and development of future treatment. Fluorodeoxyglucose positrons emission tomography (FDG-PET) is a functional molecular imaging modality, which proves to be powerful to help understand the anatomical and neural changes of brain related to AD. Most existing methods extract the handcrafted features from images, and then design a classifier to distinguish AD from other groups. These methods highly depends on the preprocessing of brain images, including image rigid registration and segmentation. Motivated by the success of deep learning in image classification, this paper proposes a new classification framework based on combination of 2D convolutional neural networks (CNN) and recurrent neural networks (RNNs), which learns the intra-slice and inter-slice features for classification after decomposition of the 3D PET image into a sequence of 2D slices. The 2D CNNs are built to capture the features of image slices while the gated recurrent unit (GRU) of RNN is cascaded to learn and integrate the inter-slice features for image classification. No rigid registration and segmentation are required for PET images. Our method is evaluated on the baseline FDG-PET images acquired from 339 subjects including 93 AD patients, 146 mild cognitive impairments (MCI) and 100 normal controls (NC) from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Experimental results show that the proposed method achieves an area under receiver operating characteristic curve (AUC) of 95.3% for AD vs. NC classification and 83.9% for MCI vs. NC classification, demonstrating the promising classification performance. PMID- 29970995 TI - Local and Widespread Slow Waves in Stable NREM Sleep: Evidence for Distinct Regulation Mechanisms. AB - Previous work showed that two types of slow waves are temporally dissociated during the transition to sleep: widespread, large and steep slow waves predominate early in the falling asleep period (type I), while smaller, more circumscribed slow waves become more prevalent later (type II). Here, we studied the possible occurrence of these two types of slow waves in stable non-REM (NREM) sleep and explored potential differences in their regulation. A heuristic approach based on slow wave synchronization efficiency was developed and applied to high-density electroencephalographic (EEG) recordings collected during consolidated NREM sleep to identify the potential type I and type II slow waves. Slow waves with characteristics compatible with those previously described for type I and type II were identified in stable NREM sleep. Importantly, these slow waves underwent opposite changes across the night, with only type II slow waves displaying a clear homeostatic regulation. In addition, we showed that the occurrence of type I slow waves was often followed by larger type II slow waves, whereas the occurrence of type II slow waves was usually followed by smaller type I waves. Finally, type II slow waves were associated with a relative increase in spindle activity, while type I slow waves triggered periods of high-frequency activity. Our results provide evidence for the existence of two distinct slow wave synchronization processes that underlie two different types of slow waves. These slow waves may have different functional roles and mark partially distinct "micro-states" of the sleeping brain. PMID- 29970998 TI - Alcohol Consumption and Subclinical Findings on Cognitive Function, Biochemical Indexes, and Cortical Anatomy in Cognitively Normal Aging Han Chinese Population. AB - Background: Binge drinking of alcohol is associated with brain damage, but less is known about relationship of light-to-moderate alcohol consumption with cognitive function, biochemical indexes, and cortical anatomy. Previous findings have debated on whether light-to-moderate drinking has any health benefits. We investigated cortical thickness and its association with alcohol consumption and cognitive functions in a non-dementia aging Han Chinese population. Methods: 940 non-dementia aging subjects were included in our study (alcohol n = 149; non alcohol n = 791). Among them, 572 received blood biochemical tests including liver function and lipid metabolism (alcohol n = 100; non-alcohol n = 472) and 141 had brain magnetic resonance imaging (alcohol n = 27; non-alcohol n = 114). The Beijing version of the Montreal Cognitive Assessment and the Chinese version of the neuropsychological test battery were used to assess cognitive functions. Results: There was no significant difference in cognitive functions between alcohol and non-alcohol groups in the overall database. Similarly, there was no significant difference in liver function and lipid metabolism between two groups in the sub-database. The left superiortemporal gyrus was one of age sensitive regions and alcohol consumption was significantly associated with thinner cortex of the left superiotemporal cluster in the sub-database. Conclusion: Alcohol consumption was not significantly associated with better or worse cognitive function and biochemical indexes abnormality, however, significantly associated with thinner cortex of the left superiortemporal gyrus in cognitively normal aging Han Chinese population. PMID- 29970997 TI - Oxytocin as a Modulator of Synaptic Plasticity: Implications for Neurodevelopmental Disorders. AB - The neuropeptide oxytocin (OXT) is a crucial mediator of parturition and milk ejection and a major modulator of various social behaviors, including social recognition, aggression and parenting. In the past decade, there has been significant excitement around the possible use of OXT to treat behavioral deficits in neurodevelopmental disorders, including autism spectrum disorder (ASD). Yet, despite the fast move to clinical trials with OXT, little attention has been paid to the possibility that the OXT system in the brain is perturbed in these disorders and to what extent such perturbations may contribute to social behavior deficits. Large-scale whole-exome sequencing studies in subjects with ASD, along with biochemical and electrophysiological studies in animal models of the disorder, indicate several risk genes that play an essential role in brain synapses, suggesting that deficits in synaptic activity and plasticity underlie the pathophysiology in a considerable portion of these cases. OXT has been repeatedly shown, both in vitro and in vivo, to modify synaptic properties and plasticity and to modulate neural activity in circuits that regulate social behavior. Together, these findings led us to hypothesize that failure of the OXT system during early development, as a direct or indirect consequence of genetic mutations, may impact social behavior by altering synaptic activity and plasticity. In this article, we review the evidence that support our hypothesis. PMID- 29970999 TI - Efficacy and Safety of Cyclosporine in Acute Myocardial Infarction: A Systematic Review and Meta-Analysis. AB - There are various studies that have addressed the use of Cyclosporine among patients with acute myocardial infarction (AMI). However, to date there is hardly any concise and systematically structured evidence that debate on the efficacy and safety of Cyclosporine in AMI patients. The aim of this review is to systematically summarize the overall evidence from published trials, and to conduct a meta-analysis in order to determine the efficacy and safety of Cyclosporine vs. placebo or control among patients with AMI. All randomized control trial (RCT) published in English language from January 2000 to August 2017 were included for the systematic review and meta-analysis. A total of six RCTs met the inclusion and were hence included in the systematic review and meta analysis. Based on the performed meta-analysis, no significant difference was found between Cyclosporine and placebo in terms of left ventricular ejection fraction (LVEF) improvement (mean difference 1.88; 95% CI -0.99 to 4.74; P = 0.2), mortality rate (OR 1.01; 95% Cl 0.60 to 1.67, P = 0.98) and recurrent MI occurrence (OR 0.65; 95% Cl 0.29 to 1.45, P = 0.29), with no evidence of heterogeneity, when given to patients with AMI. Cyclosporine also did not significantly lessen the rate of rehospitalisation in AMI patients when compared to placebo (OR 0.91; 95% Cl 0.58 to 1.42, P = 0.68), with moderate heterogeneity (I2 = 46%). There was also no significant improvement in heart failure events between Cyclosporine and placebo in AMI patients (OR 0.63; 95% Cl 0.31 to 1.29, P = 0.21; I2 = 80%). No serious adverse events were reported in Cyclosporine group across all studies suggesting that Cyclosporine is well tolerated when given to patients with AMI. The use of Cyclosporine in this group of patients, however, did not result in better clinical outcomes vs. placebo at improving LVEF, mortality rate, recurrent MI, rehospitalisation and heart failure event. PMID- 29971000 TI - A Controlled Fermented Samjunghwan Herbal Formula Ameliorates Non-alcoholic Hepatosteatosis in HepG2 Cells and OLETF Rats. AB - Hepatosteatosis (HS), a clinical feature of fatty liver with the excessive intracellular accumulation of triglyceride in hepatocytes, is manifested by perturbation of the maintenance of liver lipid homeostasis. Samjunghwan (SJH) is an herbal formula used mostly in Korean traditional medicine that is effective against a number of metabolic diseases, including obesity. Herbal drugs, enriched with numerous bioactive substances, possess health-protective benefits. Meanwhile, fermented herbal products enriched with probiotics are known to improve metabolic processes. Additionally, current lines of evidence indicate that probiotics-derived metabolites, termed as postbiotics, produce the same beneficial effects as their precursors. Herein, the anti-HS effects of 5-weeks naturally fermented SJH (FSJH) was investigated with FSJH-mixed chow diet in vivo using Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats as animal models of HS and controls, respectively. In parallel, the anti-HS effects of postbiotic-metabolites of three bacterial strains [Lactobacillus brevis (LBB), Lactococcus lactis (LCL) and Lactobacillus plantarum (LBP)] isolated from FSJH were also evaluated in vitro using the FFAs-induced HepG2 cells. Feeding OLETF rats with FSJH-diet effectively reduced body, liver, and visceral adipose tissue (VAT) weights, produced marked hypolipidemic effects on serum and hepatic lipid parameters, decreased serum AST and ALT levels, and upregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR gene expressions levels. Additionally, exposure of FFAs-induced HepG2 cells to postbiotic metabolic media (PMM) of bacterial strains also produced marked hypolipidemic effects on intracellular lipid contents and significantly unregulated the HMGCOR, SREBP, and ACC, and downregulated the AMPK and LDLR genes expressions levels. Overall, our results indicate that FSJH enriched with fermented metabolites could be an effective anti-HS formulation. PMID- 29971001 TI - Integrated Network Pharmacology and Metabolomics Analysis of the Therapeutic Effects of Zi Dian Fang on Immune Thrombocytopenic Purpura. AB - Current hormone-based treatments for immune thrombocytopenic purpura (ITP) are associated with potentially serious adverse reactions. Zi Dian Fang (ZDF) is a multi-target Traditional Chinese Medicine (TCM) used to treat both the symptoms and root causes of ITP, with fewer side effects than hormone-based treatments. This study analysis of the therapeutic effects of ZDF on ITP from three aspects: platelet proliferation, immunoregulation, and inflammation. After detection of 52 chemical constituents of ZDF by UPLC-Q-TOF/MS, The main targets and pathways affected by ZDF were screened by network pharmacology and verified by Western blot and ELISA. Meanwhile, metabolomics analysis were applied to a mouse model of ITP to identify and screen endogenous terminal metabolites differentially regulated by ZDF. Integrated network pharmacology and metabolomics analysis of the therapeutic effects of ZDF on ITP may be as follows: ZDF counteracts ITP symptoms mainly by inhibiting Ras/MAPKs (Ras/Mitogen-activated protein kinases) pathway, and the expression of upstream protein (Ras) and downstream protein (p ERK, p-JNK, p-p38) were inhibited, which affects the content of effect index associated with proliferation (Thrombopoietin, TPO; Granulocyte-macrophage colony stimulating factor, GM-CSF), inflammation (Tumor necrosis factor-alpha, TNF alpha; Interleukin-6, IL-6), immune (Interleukin-2, IL-2; Interferon-gamma, IFN gamma; Interleukin-4, IL-4), so that the body's arginine, Delta12-prostaglandin j2 (Delta12-PGJ2), 9-cis-Retinoic Acid, sphingosine-1-phosphate (S1P), oleic acid amide and other 12 endogenous metabolites significantly changes. Considering the established safety profile, the present study suggests ZDF may be a useful alternative to hormone-based therapies for the treatment of ITP. PMID- 29971002 TI - A 42-Markers Pharmacokinetic Study Reveals Interactions of Berberine and Glycyrrhizic Acid in the Anti-diabetic Chinese Medicine Formula Gegen-Qinlian Decoction. AB - Herbal medicines are commonly used as compound formulas in clinical practice to achieve optimal therapeutic effects. However, the combination mechanisms usually lack solid evidence. In this study, we report synergistic interactions through altering pharmacokinetics in Gegen-Qinlian Decoction (GQD), an anti-diabetic Chinese medicine formula. A multi-component pharmacokinetic study of GQD and the single herbs was conducted by simultaneously monitoring 42 major bioactive compounds (markers) in rats plasma using LC/MS/MS within 30 min. GQD could remarkably improve the plasma concentrations of berberine (BER) and other alkaloids in Huang-Lian by at least 30%, and glycyrrhizic acid (GLY) from Gan-Cao played a major role. A Caco-2 cell monolayer test indicated that GLY improved the permeability of BER by inhibiting P-glycoprotein. Although GLY alone did not show observable effects, the co-administration of GLY (ig, 50 or 80 mg/kg) could improve the anti-diabetic effects of berberine (ig, 50 mg/kg) in db/db mice in a dose-dependent manner. The blood glucose decreased by 46.9%, whereas the insulin level increased by 40.8% compared to the control group. This is one of the most systematic studies on the pharmacokinetics of Chinese medicine formulas, and the results demonstrate the significance of pharmacokinetic study in elucidating the combination mechanisms of compound formulas. PMID- 29971003 TI - Inhibition of Inflammation, Suppression of Matrix Metalloproteinases, Induction of Neurogenesis, and Antioxidant Property Make Bryostatin-1 a Therapeutic Choice for Multiple Sclerosis. AB - Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and myelin damage. Pro-inflammatory cytokines, oxidative stress, high level of matrix metalloproteinases (MMPs) activity and blood-brain barrier (BBB) damage, immune-mediated destruction of myelin and neuron loss are involved in the pathogenesis of MS. The currently approved treatments for MS include injectable drugs (interferon-beta and glatiramer acetate), oral drugs (fingolimod), and monoclonal antibodies (natalizumab). The mentioned therapeutic choices are mostly focused on the inhibition of inflammation. Therefore, the search for a multi-target therapeutic choice remains unchallenged. It seems that a drug with anti-inflammatory, oxidative stress inhibitory, reduction of MMPs activity, and neurogenesis stimulatory properties may be effective for treatment of MS. In this regard, Bryostatin-1 as a macrolide and marine natural product has been selected as a therapeutic choice. Studies indicate that Bryostatin-1 has anti-inflammatory and antioxidant properties and decreases MMPs level and BBB damage. Furthermore, Bryostatin-1 has a neuroprotective effect and promotes neurogenesis and differentiation of oligodendrocyte progenitor stem cells as a critical step for remyelination/myelogenesis. Based on these properties, we hypothesized here that Bryostatin-1 is an effective treatment in MS. PMID- 29971004 TI - PATs and SNATs: Amino Acid Sensors in Disguise. AB - Solute Carriers (SLCs) are involved in the transport of substances across lipid bilayers, including nutrients like amino acids. Amino acids increase the activity of the microenvironmental sensor mechanistic Target of Rapamycin Complex 1 (mTORC1) to promote cellular growth and anabolic processes. They can be brought in to cells by a wide range of SLCs including the closely related Proton-assisted Amino acid Transporter (PAT or SLC36) and Sodium-coupled Neutral Amino acid Transporter (SNAT or SLC38) families. More than a decade ago, the first evidence emerged that members of the PAT family can act as amino acid-stimulated receptors, or so-called "transceptors," connecting amino acids to mTORC1 activation. Since then, further studies in human cell models have suggested that other PAT and SNAT family members, which share significant homology within their transmembrane domains, can act as transceptors. A paradigm shift has also led to the PATs and SNATs at the surface of multiple intracellular compartments being linked to the recruitment and activation of different pools of mTORC1. Much focus has been on late endosomes and lysosomes as mTORC1 regulatory hubs, but more recently a Golgi-localized PAT was shown to be required for mTORC1 activation. PATs and SNATs can also traffic between the cell surface and intracellular compartments, with regulation of this movement providing a means of controlling their mTORC1 regulatory activity. These emerging features of PAT and SNAT amino acid sensors, including the transceptor mechanism, have implications for the pharmacological inhibition of mTORC1 and new therapeutic interventions. PMID- 29971005 TI - Bevacizumab Diminishes Inflammation in an Acute Endotoxin-Induced Uveitis Model. AB - Introduction: Uveitis is an eye disease characterized by inflammation of the uvea and an early and exhaustive diagnosis is essential for its treatment. The aim of our study is to assess the potential toxicity and anti-inflammatory efficacy of Bevacizumab in an experimental uveitis model by subcutaneously injecting lipopolysaccharide into Lewis rats and to clarify its mechanism. Material and Methods: Blood-aqueous barrier integrity was assessed 24 h after endotoxin induced uveitis (EIU) by analyzing two parameters: cell count and protein concentration in aqueous humors. Histopathology of all eye structures was also studied. Enzyme-linked immunosorbent analyses of the aqueous humor samples were performed in order to calculate the diverse chemokine and cytokine protein levels and oxidative stress-related markers were also evaluated. Results: The aqueous humor's cellular content significantly increased in the group treated with only Bevacizumab, but it had no effect on retina histopathological grading. Nevertheless, the inflammation noted in ocular structures when administering Bevacizumab with endotoxin was mostly prevented since aqueous humor cell content considerably lowered, and concomitantly with a sharp drop in uveal, vitreous, and retina histopathological grading. The values of the multi-faceted cytokine IL-2 also significantly decreased (p < 0.05 vs. endotoxin group), and the protective IL-6 and IL-10 cytokines values rose with related anti-oxidant system recovery (p < 0.05 vs. endotoxin group). Concurrently, some related M1 macrophage chemokines substantially increased, e.g., GRO/KC, a chemokine that also displays any kind of protective role. Conclusion: All these results revealed that 24 h after being administered, Bevacizumab treatment in EIU significantly prevented inflammation in various eye structures and correct results in efficacy vs. toxicity balance were obtained. PMID- 29971006 TI - The Modulatory Properties of Li-Ru-Kang Treatment on Hyperplasia of Mammary Glands Using an Integrated Approach. AB - Background: Li-Ru-Kang (LRK) has been used in the treatment of hyperplasia of mammary glands (HMG) for several decades and can effectively improve clinical symptoms. This study aims to investigate the mechanism by which LRK intervenes in HMG based on an integrated approach that combines metabolomics and network pharmacology analyses. Methods: The effects of LRK on HMG induced by estrogen progesterone in rats were evaluated by analyzing the morphological and pathological characteristics of breast tissues. Moreover, UPLC-QTOF/MS was performed to explore specific metabolites potentially affecting the pathological process of HMG and the effects of LRK. Pathway analysis was conducted with a combination of metabolomics and network pharmacology analyses to illustrate the pathways and network of LRK-treated HMG. Results: Li-Ru-Kang significantly improved the morphological and pathological characteristics of breast tissues. Metabolomics analyses showed that the therapeutic effect of LRK was mainly associated with the regulation of 10 metabolites, including prostaglandin E2, phosphatidylcholine, leukotriene B4, and phosphatidylserine. Pathway analysis indicated that the metabolites were related to arachidonic acid metabolism, glycerophospholipid metabolism and linoleic acid metabolism. Moreover, principal component analysis showed that the metabolites in the model group were clearly classified, whereas the metabolites in the LRK group were between those in the normal and model groups but closer to those in the normal group. This finding indicated that these metabolites may be responsible for the effects of LRK. The therapeutic effect of LRK on HMG was possibly related to the regulation of 10 specific metabolites. In addition, we further verified the expression of protein kinase C alpha (PKCalpha), a key target predicted by network pharmacology analysis, and showed that LRK could significantly improve the expression of PKCalpha. Conclusion: Our study successfully explained the modulatory properties of LRK treatment on HMG using metabolomics and network pharmacology analyses. This systematic method can provide methodological support for further understanding the complex mechanism underlying HMG and possible traditional Chinese medicine (TCM) active ingredients for the treatment of HMG. PMID- 29971008 TI - Logical Modeling and Analysis of Cellular Regulatory Networks With GINsim 3.0. AB - The logical formalism is well adapted to model large cellular networks, in particular when detailed kinetic data are scarce. This tutorial focuses on this well-established qualitative framework. Relying on GINsim (release 3.0), a software implementing this formalism, we guide the reader step by step toward the definition, the analysis and the simulation of a four-node model of the mammalian p53-Mdm2 network. PMID- 29971007 TI - Biomarkers for Pulmonary Vascular Remodeling in Systemic Sclerosis: A Pathophysiological Approach. AB - Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc) associated with high morbidity and mortality. There are several biomarkers of SSc-PAH, reflecting endothelial physiology, inflammation, immune activation, extracellular matrix, metabolic changes, or cardiac involvement. Biomarkers associated with diagnosis, disease severity and progression have been identified, however, very few have been tested in a prospective setting. Some antinuclear antibodies such as nucleosome antibodies (NUC), anti-centromere antibodies (CENP-A/B) and anti-U3-ribonucleoprotein (anti-U3-RNP) are associated with PAH while anti-U1-ribonucleoprotein (anti-U1-RNP) is associated with a reduced PAH risk. Anti-endothelin receptor and angiotensin-1 receptor antibodies might be good markers of SSc-PAH and progression of pulmonary vasculopathy. Regarding the markers reflecting immune activation and inflammation, there are many inconsistent results. CXCL-4 was associated with SSc progression including PAH and lung fibrosis. Growth differentiation factor (GDF)-15 was associated with PAH and mortality but is not specific for SSc. Among the metabolites, kynurenine was identified as diagnostic marker for PAH, however, its pathologic role in the disease is unclear. Endostatin, an angiostatic factor, was associated with heart failure and poor prognosis. Established heart related markers, such as N-terminal fragment of A-type natriuretic peptide/brain natriuretic peptide (NT-proANP, NT proBNP) or troponin I/T are elevated in SSc-PAH but are not specific for the right ventricle and may be increased to the same extent in left heart disease. Taken together, there is no universal specific biomarker for SSc-PAH, however, there is a pattern of markers that is strongly associated with a risk of vascular complications in SSc patients. Further comprehensive, multicenter and prospective studies are warranted to develop reliable algorithms for detection and prognosis of SSc-PAH. PMID- 29971009 TI - The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks. AB - Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users' learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualization of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to the software tools GINsim, BioLQM, Pint, MaBoSS, and Cell Collective, for the modeling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses. PMID- 29971010 TI - Dental Findings in Patients With Non-surgical Hypoparathyroidism and Pseudohypoparathyroidism: A Systematic Review. AB - Background: Dental aberrations have been mentioned in relation to non-surgical hypoparathyroidism (Ns-HypoPT) and pseudohypoparathyroidism (PHP). However, a systematic review of dental characteristics have not been performed. The present systematic review describes the dental findings in patients with Ns-HypoPT and PHP. Methods: Studies on Ns-HypoPT and PHP reporting dental features were eligible. A systematic literature search was conducted using four bibliographic databases (Web of Science, Scopus, Pubmed, and Embase) and was limited to studies written in English. Reviews, meta-analyses and letters were excluded. Both the research and reporting of results were based on PRISMA (preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Results: Of 88 studies included, nine were cross-sectional, one was a prospective cohort study, 26 were case series, and 52 were case reports. The most frequently reported findings in patients with Ns-HypoPT were enamel opacities, enamel hypoplasia, hypodontia, and eruption disturbances. In patients with PHP, enamel hypoplasia, eruption disturbance, and deviation of the root morphology were the most frequently reported findings. Conclusion: An association between enamel hypoplasia and Ns HypoPT and PHP is likely. The results should, however, be interpreted cautiously due to the limited number of high-quality studies. The present review confirms the need of further well-designed studies, such as large-scale studies, e.g., multicenter studies, to conclude on the reported associations between Ns HypoPT/PHP and enamel hypoplasia. PMID- 29971011 TI - Osteoarthritis-Like Changes in Bardet-Biedl Syndrome Mutant Ciliopathy Mice (Bbs1M390R/M390R): Evidence for a Role of Primary Cilia in Cartilage Homeostasis and Regulation of Inflammation. AB - Osteoarthritis (OA) is a debilitating inflammation related disease characterized by joint pain and effusion, loss of mobility, and deformity that may result in functional joint failure and significant impact on quality of life. Once thought of as a simple "wear and tear" disease, it is now widely recognized that OA has a considerable metabolic component and is related to chronic inflammation. Defects associated with primary cilia have been shown to be cause OA-like changes in Bardet-Biedl mice. We examined the role of dysfunctional primary cilia in OA in mice through the regulation of the previously identified degradative and pro inflammatory molecular pathways common to OA. We observed an increase in the presence of pro-inflammatory markers TGFbeta-1 and HTRA1 as well as cartilage destructive protease MMP-13 but a decrease in DDR-2. We observed a morphological difference in cartilage thickness in Bbs1 M390R/M390R mice compared to wild type (WT). We did not observe any difference in OARSI or Mankin scores between WT and Bbs1M390R/M390R mice. Primary cilia appear to be involved in the upregulation of biomarkers, including pro-inflammatory markers common to OA. PMID- 29971012 TI - Validation of Patient-Specific Cerebral Blood Flow Simulation Using Transcranial Doppler Measurements. AB - We present a validation study comparing results from a patient-specific lattice Boltzmann simulation to transcranial Doppler (TCD) velocity measurements in four different planes of the middle cerebral artery (MCA). As part of the study, we compared simulations using a Newtonian and a Carreau-Yasuda rheology model. We also investigated the viability of using downscaled velocities to reduce the required resolution. Simulations with unscaled velocities predict the maximum flow velocity with an error of less than 9%, independent of the rheology model chosen. The accuracy of the simulation predictions worsens considerably when simulations are run at reduced velocity, as is for example the case when inflow velocities from healthy individuals are used on a vascular model of a stroke patient. Our results demonstrate the importance of using directly measured and patient-specific inflow velocities when simulating blood flow in MCAs. We conclude that localized TCD measurements together with predictive simulations can be used to obtain flow estimates with high fidelity over a larger region, and reduce the need for more invasive flow measurement procedures. PMID- 29971013 TI - Exploring the Potential Roles of Band 3 and Aquaporin-1 in Blood CO2 Transport Inspired by Comparative Studies of Glycophorin B-A-B Hybrid Protein GP.Mur. AB - The Cl-/HCO3- exchanger band 3 is functionally relevant to blood CO2 transport. Band 3 is the most abundant membrane protein in human red blood cells (RBCs). Our understanding of its physiological functions mainly came from clinical cases associated with band 3 mutations. Severe reduction in band 3 expression affects blood HCO3-/CO2 metabolism. What could happen physiologically if band 3 expression is elevated instead? In some areas of Southeast Asia, about 1-10% of the populations express GP.Mur, a glycophorin B-A-B hybrid membrane protein important in the field of transfusion medicine. GP.Mur functions to promote band 3 expression, and GP.Mur red cells can be deemed as a naturally occurred model for higher band 3 expression. This review first compares the functional consequences of band 3 at different levels, and suggests a critical role of band 3 in postnatal CO2 respiration. The second part of the review explores the transport of water, which is the other substrate for intra-erythrocytic CO2/HCO3- conversion (an essential step in blood CO2 transport). Despite that water is considered unlimited physiologically, it is unclear whether water channel aquaporin-1 (AQP1) abundantly expressed in RBCs is functionally involved in CO2 transport. Research in this area is complicated by the fact that the H2O/CO2 transporting function of AQP1 is replaceable by other erythrocyte channels/transporters (e.g., UT-B/GLUT1 for H2O; RhAG for CO2). Recently, using carbonic anhydrase II (CAII)-filled erythrocyte vesicles, AQP1 has been demonstrated to transport water for the CAII-mediated reaction, CO2(g) + H2O ? HCO3-(aq) + H+(aq). AQP1 is structurally associated with some population of band 3 complexes on the erythrocyte membrane in an osmotically responsive fashion. The current findings reveal transient interaction among components within the band 3 central, CO2-transport metabolon (AQP1, band 3, CAII and deoxygenated hemoglobin). Their dynamic interaction is envisioned to facilitate blood CO2 respiration, in the presence of constantly changing osmotic and hemodynamic stresses during circulation. PMID- 29971014 TI - Specific Binding Protein ABCC1 Is Associated With Cry2Ab Toxicity in Helicoverpa armigera. AB - A pyramid strategy combining the crystal (Cry) 1A and 2A toxins in Bacillus thuringiensis (Bt) crops are active against many species of insects and nematode larvae. It has been widely used to delay pest adaption to genetically modified plants and broaden the insecticidal spectrum in many countries. Unfortunately, Cry2A can also bind with the specific receptor proteins of Cry1A. ATP-binding cassette (ABC) transporters can interact with Cry1A toxins as receptors in the insect midgut, and ABC transporter mutations result in resistance to Bt proteins. However, there is limited knowledge of the ABC transporters that specifically bind to Cry2Ab. Here, we cloned the ABCC1 gene in Helicoverpa armigera, which expressed at all larval stages and in nine different tissues. Expression levels were particularly high in fifth-instar larvae and Malpighian tubules. The two heterologously expressed HaABCC1 transmembrane domain peptides could specifically bind to Cry2Ab with high affinity levels. Moreover, transfecting HaABCC1 into the Spodoptera frugiperda nine insect cell significantly increased its mortality when exposed to Cry2Ab in vitro, and silencing HaABCC1 in H. armigera by RNA interference significantly reduced the mortality of larvae exposed to Cry2Ab in vivo. Altogether current results suggest that HaABCC1 serves as a functional receptor for Cry2Ab. PMID- 29971016 TI - The Association Between Endurance Training and Heart Rate Variability: The Confounding Role of Heart Rate. AB - Heart rate variability (HRV) is a widely used marker of cardiac autonomic nervous activity (CANA). Changes in HRV with exercise training have often been interpreted as increases in vagal activity. HRV is strongly associated with heart rate, which in turn, is associated with heart size. There is strong evidence from basic studies that lower heart rate in response to exercise training is caused by morphological and electrical remodeling of the heart. In a cross-sectional study in participants of a 10 mile race, we investigated the influence of endurance exercise on HRV parameters independently of heart size and heart rate. One hundred-and-seventy-two runners (52 females and 120 males) ranging from novice runners with a first participation to an endurance event to highly trained runners, with up to 15 h of training per week, were included in the analysis. R-R intervals were recorded by electrocardiography over 24 h. Left ventricular end diastolic volume indexed to body surface area (LVEDVI) was assessed by transthoracic echocardiography and peak oxygen consumption (VO2peak) by cardiopulmonary exercise testing. Exercise was quantified by VO2peak, training volume, and race performance. HRV was determined during deep sleep. HRV markers of vagal activity were moderately associated with exercise variables (standardized beta = 0.28-0.40, all p < 0.01). These associations disappeared when controlling for heart rate and LVEDVI. Due to the intrinsic association between heart rate and HRV, conclusions based on HRV parameters do not necessarily reflect differences in CANA. Based on current evidence, we discourage the use of HRV as a marker of CANA when measuring the effect of chronic exercise. PMID- 29971015 TI - Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility. AB - Purpose: Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle. Methods: In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Results: We found that the HCN channel blocker ZD7288 (50 MUM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18beta-glycyrrhetic acid suggesting that HCN channels are located within the gap junction interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288. Conclusion: These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy. PMID- 29971017 TI - Synergistic Effects of Nano-ZnO and Low pH of Sea Water on the Physiological Energetics of the Thick Shell Mussel Mytilus coruscus. AB - In order to investigate the ecotoxicological effects of nano-ZnO particles and seawater acidification on marine bivalves, the thick shell mussels, Mytilus coruscus were subjected to joint treatments with different nano-ZnO concentrations (0 [control], 2.5 [medium] and 10 mg L-1 [high]) under two pH levels (7.7 [low]and 8.1 [control]) for 14 days. The results showed that respiration rate (RR), absorption efficiency (AE), clearance rate (CR), O:N ratio and scope for growth (SFG) were significantly reduced with nano-ZnO concentration increase, but ammonium excretion rate (ER) was increased. Low pH significantly reduced CR, RR, SFG, and O:N ratio of the mussels especially under high nano-ZnO conditions, and significantly increased ER. Principal component analysis (PCA) showed consistent relationships among most tested parameters, especially among SFG, RR, O:N ratio and CR under the normal pH and 0 nano-ZnO conditions. Therefore, seawater acidification and nano-ZnO interactively impact the ecophysiological responses of mussels and cause more severe effects when they appear concurrently. PMID- 29971018 TI - The Impact of Variational Primary Collaterals on Cerebral Autoregulation. AB - The influence of the anterior and posterior communicating artery (ACoA and PCoA) on dynamic cerebral autoregulation (dCA) is largely unknown. In this study, we aimed to test whether substantial differences in collateral anatomy were associated with differences in dCA in two common types of stenosis according to digital subtraction angiography (DSA): either isolated basal artery and/or bilateral vertebral arteries severe stenosis/occlusion (group 1; group 1A: with bilateral PCoAs; and group 1B: without bilateral PCoAs), or isolated unilateral internal carotid artery severe stenosis/occlusion (group 2; group 2A: without ACoA and with PCoA; group 2B: with ACoA and without PCoAs; and group 2C: without both ACoA and PCoA). The dCA was calculated by transfer function analysis (a mathematical model), and was evaluated in middle cerebral artery (MCA) and/or posterior cerebral artery (PCA). Of a total of 231 non-acute phase ischemic stroke patients who received both dCA assessment and DSA in our lab between 2014 and 2017, 51 patients met inclusion criteria based on the presence or absence of ACoA or PCoA, including 21 patients in the group 1, and 30 patients in the group 2. There were no significant differences in gender, age, and mean blood pressure between group 1A and group 1B, and among group 2A, group 2B, and group 2C. In group 1, the PCA phase difference values (autoregulatory parameter) were significantly higher in the subgroup with patent PCoAs, compared to those without. In group 2, the MCA phase difference values were higher in the subgroup with patent ACoA, compared to those without. This pilot study found that the cross-flow of the ACoA/PCoA to the affected area compensates for compromised dCA in the affected area, which suggests an important role of the ACoA/PCoA in stabilizing cerebral blood flow. PMID- 29971020 TI - Periodicity: A Characteristic of Heart Rate Variability Modified by the Type of Mechanical Ventilation After Acute Lung Injury. AB - We present a novel approach to quantify heart rate variability (HRV) and the results of applying this approach to synthetic and original data sets. Our approach evaluates the periodicity of heart rate by calculating the transform of Relative Shannon Entropy, the maximum value of the RR interval periodogram, and the maximum, mean values, and sample entropy of the autocorrelation function. Synthetic data were generated using a Van der Pol oscillator; and the original data were electrocardiogram (ECG) recordings from anesthetized rats after acute lung injury while on biologically variable (BVV) or continuous mechanical ventilation (CMV). Analysis of the synthetic data revealed that our measures were correlated highly to the bandwidth of the oscillator and assessed periodicity. Then, applying these analytical tools to the ECGs determined that the heart rate (HR) of BVV group had less periodicity and higher variability than the HR of the CMV group. Quantifying periodicity effectively identified a readily apparent difference in HRV during BVV and CMV that was not identified by power spectral density measures during BVV and CMV. Cardiorespiratory coupling is the probable mechanism for HRV increasing during BVV and becoming periodic during CMV. Thus, the absence or presence of periodicity in ventilation determined HRV, and this mechanism is distinctly different from the cardiorespiratory uncoupling that accounts for the loss of HRV during sepsis. PMID- 29971019 TI - Vitamin C in Cancer: A Metabolomics Perspective. AB - There is an ongoing interest in cellular antioxidants and oxidants as well as cellular mechanisms underlying their effects. Several reports suggest that vitamin C (L-ascorbic acid) functions as a pro-oxidant with selective toxicity against specific types of tumor cells. In addition, reduced glutathione plays an emerging role in reducing oxidative stress due to xenobiotic toxins such as metals and oxidants associated with diseases such as cancer, cardiovascular disease, and stroke. High-dose intravenous vitamin C and intravenous glutathione have been used as complementary, alternative, and adjuvant medicines. Here, we review the molecular mechanisms underlying the regulation of oxidation/reduction systems, focusing on the altered metabolomics profile in cancer cells following treatment with pharmacological vitamin C. This review focuses on the role of vitamin C in energy metabolism in terms of adenosine triphosphate, cysteine, and reduced glutathione levels, affecting cancer cell death. PMID- 29971021 TI - A Systematic Review of Amenable Resilience Factors That Moderate and/or Mediate the Relationship Between Childhood Adversity and Mental Health in Young People. AB - Background: Up to half of Western children and adolescents experience at least one type of childhood adversity. Individuals with a history of childhood adversity have an increased risk of psychopathology. Resilience enhancing factors reduce the risk of psychopathology following childhood adversity. A comprehensive overview of empirically supported resilience factors is critically important for interventions aimed to increase resilience in young people. Moreover, such an overview may aid the development of novel resilience theories. Therefore, we conducted the first systematic review of social, emotional, cognitive and/or behavioral resilience factors after childhood adversity. Methods: We systematically searched Web of Science, PsycINFO, and Scopus (e.g., including MEDLINE) for English, Dutch, and German literature. We included cohort studies that examined whether a resilience factor was a moderator and/or a mediator for the relationship between childhood adversity and psychopathology in young people (mean age 13-24). Therefore, studies were included if the resilience factor was assessed prior to psychopathology, and childhood adversity was assessed no later than the resilience factor. Study data extraction was based on the STROBE report and study quality was assessed with an adapted version of Downs and Black's scale. The preregistered protocol can be found at: http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016051978. Results: The search identified 1969 studies, of which 22 were included (eight nationalities, study sample n range: 59-6780). We found empirical support for 13 of 25 individual-level (e.g., high self-esteem, low rumination), six of 12 family level (e.g., high family cohesion, high parental involvement), and one of five community-level resilience factors (i.e., high social support), to benefit mental health in young people exposed to childhood adversity. Single vs. multiple resilience factor models supported the notion that resilience factors should not be studied in isolation, and that interrelations between resilience factors should be taken into account when predicting psychopathology after childhood adversity. Conclusions: Interventions that improve individual, family, and/or social support resilience factors may reduce the risk of psychopathology following childhood adversity. Future research should scrutinize whether resilience factors function as a complex interrelated system that benefits mental health resilience after childhood adversity. PMID- 29971022 TI - Anxiety and Extraversion in Lupus-Related Atherosclerosis. AB - Objectives: Patients with systemic lupus erythematosus (SLE) are characterized by increased cardiovascular disease (CVD) risk as well as heightened rates of psychological distress. Since a link between psychological issues and CV morbidity has been previously suggested, the influence of psychological burden on subclinical atherosclerosis in SLE patients was investigated. Methods: 71 SLE patients were assessed for the presence of subclinical atherosclerosis-defined either as carotid and/or femoral plaque formation or arterial wall thickening [Intima Media Thickness (IMT) levels > 0.90 mm by Doppler ultrasound]; personality traits, anxiety and depression, sleeping habits and fatigue levels were also evaluated by specific questionnaires including Eysenck Personality Questionnaire Scale, State-Trait Anxiety Inventory (STAI), Zung Depression Scale, Athens Insomnia Scale and Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F). Disease related clinical and laboratory features and traditional risk factors for atherosclerosis were documented. Univariate and multivariate analysis were performed. Results: SLE patients with arterial wall thickening displayed higher STAI anxiety scores (either as a current state or as a personality trait) compared to those without (49.8 +/- 5.6 vs. 46.9 +/- 5.4, p value: 0.03 and 49.2 +/- 4.4 vs. 45.7 +/- 6.8, p-value: 0.009, respectively). In a multivariate model, trait anxiety and extraversion personality scores were found to be independently associated with arterial wall thickening and plaque formation, respectively [OR95%(CI):1.2(1.0-1.5) and 0.7(0.6-1.0), respectively], following adjustment for potential confounders. No other associations were detected. Conclusions: Anxiety and extraversion personality traits have been independently associated with subclinical atherosclerosis in lupus patients, implying psychoneuroimmunological interactions as contributors in SLE related atherosclerosis. PMID- 29971023 TI - Freudarwin: Evolutionary Thinking as a Root of Psychoanalysis. AB - This essay synthesizes the place of biological evolutionism in the early history of psychoanalysis, and shows the implicit significance of German Darwinism in Sigmund Freud's whole psychoanalytical works. In particular, Freud, together with Sandor Ferenczi (1873-1933), applied to mental disorders hypotheses inspired by August Pauly's (1850-1914) psychological Lamarckism and Ernst Heckel (1834-1919) theory of recapitulation. Both of these theories rested upon the principle of inheritance of acquired characteristics, and were disproved by biological discoveries during the interwar period. However, despite these scientific progresses, Freud never gave up his idea of inherited unconscious memories, and we try here to sketch out what would have cost him a renunciation to such outdated biological principles. Notwithstanding, Sigmund Freud was the first to elaborate on evolutionary causes of mental syndromes, which makes of him the forerunner of current neo-Darwinian psychopathology, with few continuators to date within the psychoanalytic field. Nowadays, the extended neo-Darwinian synthesis and affective neuroscience may pave the way for a rational Darwinian approach to human mental disorders, which would take into account the whole neurological and psychological evolution of species, and be centered on emotions and their vicissitudes. PMID- 29971024 TI - Time and Narrative: An Investigation of Storytelling Abilities in Children With Autism Spectrum Disorder. AB - This study analyzed the relation between mental time travel (MTT) and the ability to produce a storytelling focusing on global coherence, which is one of the most notable characteristics of narrative discourse. As global coherence is strictly tied to the temporal sequence of the events narrated in a story, we hypothesized that the construction of coherent narratives would rely on the ability to mentally navigate in time. To test such a hypothesis, we investigated the relation between one component of MTT-namely, episodic future thinking (EFT)-and narrative production skills by comparing the narratives uttered by 66 children with high-functioning autism spectrum disorder (ASD) with those produced by 66 children with typical development. EFT was assessed by administering a task with minimal narrative demands, whereas storytelling production skills were assessed by administering two narrative production tasks that required children to generate future or past episodes with respect to the target stimuli. The results showed that EFT skills were impaired only in a subgroup of children with ASD and that such subgroup performed significantly worse on the narrative production task than ASD participants with high EFT skills and participants with typical development. The practical and theoretical implications of these findings are discussed. PMID- 29971025 TI - The Effect of Parental Involvement and Socioeconomic Status on Junior School Students' Academic Achievement and School Behavior in China. AB - A survey was conducted on 19,487 Chinese junior school students to elucidate the moderating role of socioeconomic status (SES) in the relationship between parental involvement (i.e., home-based involvement and academic socialization) and junior school students' performance in school (i.e., academic achievement and school behavior). The data includes 10,042 males and 9,445 females (mean age = 14.52, SD = 1.24). It was taken from the 2013-2014 Chinese Educational Panel Survey (CEPS), that was administrated by the National Survey Research Center at Renmin University of China. The results demonstrate that SES negatively moderates both the relationship between academic socialization and academic achievement, and the relationship between home-based involvement and school behavior. Findings imply that parental involvement activities are highly beneficial for junior school students in families with low SES. Academic socialization is generally associated with academic success, whereas home-based involvement closely relates to school behavior. Future home-based interventions can be developed to promote parental involvement activities in low-SES families. The results also showed important implications for the development of family education in China. PMID- 29971026 TI - Counting and Number Line Trainings in Kindergarten: Effects on Arithmetic Performance and Number Sense. AB - Children's early numerical capacities form the building blocks for later arithmetic proficiency. Linear number placements and counting skills are indicative of mapping, as an important precursor to arithmetic skills, and have been suggested to be of vital importance to arithmetic development. The current study investigated whether fostering mapping skills is more efficient through a counting or a number line training program. Effects of both programs were compared through a quasi-experimental design, and moderation effects of age and socio-economic status (SES) were investigated. Ninety kindergartners were divided into three conditions: a counting, a number line, and a control condition. Pretests and posttests included an arithmetic (addition) task and a battery of number sense tasks (comparison, number lines, and counting). Results showed significantly greater gains in arithmetic, counting, and symbolic number lines in the counting training group than in the control group. The number line training group did not make significantly greater gains than the control group. Training gains were moderated by age, but not SES. We concluded that counting training improved numerical capacities effectively, whereas no such improvements could be found for the number line training. This suggests that only a counting approach is effective for fostering number sense and early arithmetic skills in kindergarten. Future research should elaborate on the parameters of training programs and the consequences of variation in these parameters. PMID- 29971027 TI - Breaking Away From the Male Stereotype of a Specialist: Gendered Language Affects Performance in a Thinking Task. AB - This experimental online-survey study investigated if different written language forms in German have an effect on male bias in thinking. We used answers to the specialist riddle as an indicator for male bias in mental representations of expertise. The difficulty of this thinking task lies in the fact that a gender unspecified specialist is often automatically assumed to be a man due to gender stereotypes. We expected that reading a text in gender-fair language before processing the specialist riddle helps readers achieve control over automatically activated gender stereotypes and thus facilitates the restructuring and reinterpretation of the problem, which is necessary to reach the conclusion that the specialist is a woman. We randomly assigned 517 native German speakers (68% women) to reading a text on expertise written either in gender-fair language or in masculine generics. Subsequently, participants were asked to solve the specialist riddle. The results show that reading a text in gender-fair language before processing the riddle led to higher rates of answers indicating that the specialist is a women compared to reading a text in masculine generics (44% vs. 33%) in women and men regardless of their self-stereotyping concerning agency and communion. The findings indicate that reading even a very short text in gender fair language can help people break their gender-stereotype habit and thus reduce male bias in thinking. Our research emphasizes the importance of using gender fair language in German-language texts for reducing gender stereotypes. PMID- 29971028 TI - An ERP Investigation of L2-L1 Translation Priming in Adult Learners. AB - A longstanding debate centers around how beginning adult bilinguals process words in their second language (L2). Do they access the meaning of the L2 words directly or do they first activate the native language (L1) translation equivalents in order to access meaning? To address this question, we used ERPs to investigate how newly learned L2 words influence processing of their L1 translation equivalents. We taught participants the meanings of 80 novel L2 (pseudo)words by presenting them with pictures of familiar objects. After 3 days of learning, participants were tested in a backward translation priming paradigm with a short (140 ms) stimulus onset asynchrony. L1 targets preceded by their L2 translations elicited faster responses and smaller amplitude negativities than the same L1 targets preceded by unrelated L2 words. The bulk of the ERP translation priming effect occurred within the N400 window (350-550 ms), suggesting that the new L2 words were automatically activating their semantic representations. A weaker priming effect in the preceding window (200-350 ms) was found at anterior sites, providing some evidence that the forms of the L1 translation equivalents had also been activated. These results have implications for models of L2 processing at the earliest stages of learning. PMID- 29971029 TI - The Movement-Image Compatibility Effect: Embodiment Theory Interpretations of Motor Resonance With Digitized Photographs, Drawings, and Paintings. AB - To evoke the impression of movement in the "immobile" image is one of the central motivations of the visual art, and the activating effect of images has been discussed in art psychology already some 100 years ago. However, this topic has up to now been largely neglected by the researchers in cognitive psychology and neuroscience. This study investigates - from an interdisciplinary perspective - the formation of lateralized instances of motion when an observer perceives movement in an image. A first step was to identify images that evoke a perception of movement in a certain direction and to give this a rating. Reaction times leading to the engagement of a joystick following the presentation of images are used to evidence the postulated movement occasioned by the perception of movement in an image. Where the required direction of joystick moves matched the expected perception of movement direction in the image, significantly shorter reaction times were recorded. The experiment was able to prove a "movement-image compatibility effect" in observers of images. Based on this, the paper revisits and brings up to date the theses on motor sensory response to images which were developed in art psychology at the beginning of the 20th century. It furthermore contributes an embodiment theory interpretation to the prevalent representational explanation of compatibility effects. PMID- 29971030 TI - Measuring Women's Empowerment in Sub-Saharan Africa: Exploratory and Confirmatory Factor Analyses of the Demographic and Health Surveys. AB - Background: Women's status and empowerment influence health, nutrition, and socioeconomic status of women and their children. Despite its benefits, however, research on women's empowerment in Sub-Saharan Africa (SSA) is limited in scope and geography. Empowerment is variably defined and data for comparison across regions is often limited. The objective of the current study was to identify domains of empowerment from a widely available data source, Demographic and Health Surveys, across multiple regions in SSA. Methods: Demographic and Health Surveys from nineteen countries representing four African regions were used for the analysis. A total of 26 indicators across different dimensions (economic, socio-cultural, education, and health) were used to characterize women's empowerment. Pooled data from all countries were randomly divided into two datasets-one for exploratory factor analysis (EFA) and the other for Confirmatory Factor Analysis (CFA)-to verify the factor structure hypothesized during EFA. Results: Four factors including attitudes toward violence, labor force participation, education, and access to healthcare were found to define women's empowerment in Central, Southern, and West Africa. However, in East Africa, only three factors were relevant: attitudes toward violence, access to healthcare ranking, and labor force participation. There was limited evidence to support household decision-making, life course, or legal status domains as components of women's empowerment. Conclusion: This foremost study advances scholarship on women's empowerment by providing a validated measure of women's empowerment for researchers and other stakeholders in health and development. PMID- 29971032 TI - Editorial: Investigating Grammar in Autism Spectrum Disorders. PMID- 29971031 TI - Omega-6:3 Ratio More Than Absolute Lipid Level in Diet Affects Associative Learning in Honey Bees. AB - Floral pollen is a major source of honey bee nutrition that provides them with micro- and macro-nutrients, including proteins, fatty acids, vitamins, and minerals. Different pollens vary in composition, including in the essential fatty acids, alpha-linolenic acid (omega-3) and linoleic acid (omega-6). Monocultures, prevalent in modern agriculture, may expose honey bee colonies to unbalanced omega-6:3 diets. The importance of omega-3 in the diet for adequate learning and cognitive function, with a focus on suitable omega-6:3 ratio, is well documented in mammals. We have recently shown, for the first time in invertebrates, the importance of omega-3 in diets for associative learning ability in honey bees. In the current work, we examine the effect of the absolute amount of omega-3 in diet compared to the omega-6:3 ratio on honey bee associative learning. We fed newly emerged bees for 1 week on different artificial diets, which had lipid concentration of 1, 2, 4, or 8%, with omega-6:3 ratios of 0.3, 1, or 5, respectively. We then tested the bees in a proboscis-extension response olfactory conditioning assay. We found that both omega-6:3 ratio and total lipid concentration affected learning. The most detrimental diet for learning was that with a high omega-6:3 ratio of 5, regardless of the absolute amount of omega-3 in the diet. Bees fed an omega-6:3 ratio of 1, with 4% total lipid concentration achieved the best performance. Our results with honey bees are consistent with those found in mammals. Best cognitive performance is achieved by a diet that is sufficiently rich in essential fatty acids, but as long as the omega-6:3 ratio is not high. PMID- 29971033 TI - Chop and Change: A Commentary and Demonstration of Classical vs. Modern Measurement Models for Interpreting Latent-Stability of Occupational-Future Time Perspective. AB - This commentary article was initially motivated by an empirical paper published in the journal of Work, Aging, and Retirement that reported support for stability (non-decreasing) future time perspectives (FTP) over two repeated-measurements. That is, empirical evidence supporting the temporal stability of an adapted measure (occupational-FTP [O-FTP]) serves as guiding framework for demonstrating limitations of classical test theory (CTT) and modern psychometrics' (IRT) enabling extension for stronger substantive inferences from response data. The focal authors' quantitative attention to study design and statistical analysis is commendable. In this commentary, I aim to complement their efforts from a measurement perspective. This is accomplished through four sections. In the first section, I summarize some well-known limitations to CTT measurement models for assessing change. Then, I briefly introduce item response theory (IRT) as an alternative test theory. In the second section, Chop, I review the empirical evidence for FTP and O-FTP's latent-factor structure. Then, I bring evidence from modern psychometric methods to bear on O-FTP, specifically, a model-comparisons approach was adopted for comparing relative fit of 1-factor, 2-factor, and bifactor solutions in cross-sectional data (N = 511). Findings supported retention of the bifactor solution. In the third section, Change, I extend the bifactor model to two-wave FTP data over approximately 2 years (N = 620) as an instructive application for assessing temporal stability. The fourth section concludes with a brief discussion of substantive implications and meaningful interpretation of (O)-FTP scores over time. PMID- 29971034 TI - Concurrent IDH1 and SMARCB1 Mutations in Pediatric Medulloblastoma: A Case Report. AB - Isocitrate Dehydrogenase-1 (IDH1) is a driver gene in several cancers including brain tumors such as low-grade and high-grade gliomas. Mutations of SMARCB1 were described in atypical teratoid rhabdoid tumors and to date have not been associated with the pathogenesis of medulloblastoma. We report concurrent IDH1 and SMARCB1 mutations in a medulloblastoma patient. We searched the catalog of somatic mutations in cancer (COSMIC) database and other mutation databases and to our knowledge- this is the first reported case of medulloblastoma harboring both mutations together. Our patient is a 13-year-old male presenting with headache and vomiting at diagnosis. MRI revealed left cerebellar expansive lesion with no evidence of metastasis. A histopathological diagnosis of desmoplastic/nodular medulloblastoma was made after complete resection of the tumor. Immunophenotypic characterization and methylation profiling suggested a medulloblastoma with SHH activation. Next generation sequencing of a panel of 400 genes revealed heterozygous somatic IDH1(p.R132C), SMARCB1(p.R201Q), and CDH11(p.L625T) mutations. The patient was treated according to the HIT-SIOP PNET 4 protocol. He is in complete remission more than 2 years after diagnosis. In conclusion, increasing use of high throughput sequencing will certainly increase the frequency with which rare mutations or mutation combinations are identified. The exact frequency of this mutation combination and whether it has any particular therapeutic implications or prognostic relevance requires further investigation. PMID- 29971035 TI - Clinical Staging of Amyotrophic Lateral Sclerosis in Chinese Patients. AB - Objective: It is important to explore the utility of clinical staging systems in the management of amyotrophic lateral sclerosis (ALS). Our aim was to assess the validity of King's College in a Chinese ALS cohort, by evaluating the duration and informativeness of each stage and examining the association between stage and prognosis. Methods: From May 2008 to December 2016, patients with a likely diagnosis of ALS were registered. We prospectively assessed the progression of the patients through the stages and calculated the duration of each stage. Results: The median duration in Stage 1 was 12.00 months, Stage 2 7.50 months, Stage 3 6.50 months, and Stage 4 4.10 months. Subset analysis revealed that the spinal-onset and early-onset patients had a longer median time in Stage 1 compared to bulbar-onset and late-onset patients, respectively. Riluzole treatment extended the durations of Stages 1 and 2, and the effect was maintained in patients with long-term use of riluzole (>6 months). Patients who initiated long-term riluzole therapy early, in Stage 1 or 2, had a longer Stage 2. Patients who received percutaneous gastrostomy endoscopy (PEG) or non-invasive positive pressure ventilation (NIPPV) showed longer durations of Stage 4. The differences in survival time measured from each stage to death or censor date were significant. Conclusions: We validated the King's College staging system in a Chinese population, and showed this system to be useful in clinical practice. Patients with bulbar-onset or an age of onset>45 years tended to have rapidly progressing ALS. Riluzole may be more effective when initiated in an early disease stage and continued long-term. PEG and NIPPV treatments can extend disease duration of Stage 4. PMID- 29971036 TI - Alterations of Both Dendrite Morphology and Weaker Electrical Responsiveness in the Cortex of Hip Area Occur Before Rearrangement of the Motor Map in Neonatal White Matter Injury Model. AB - Hypoxia-ischemia (H-I) in rats at postnatal day 3 causes disorganization of oligodendrocyte development in layers II/III of the sensorimotor cortex without apparent neuronal loss, and shows mild hindlimb dysfunction with imbalanced motor coordination. However, the mechanisms by which mild motor dysfunction is induced without loss of cortical neurons are currently unclear. To reveal the mechanisms underlying mild motor dysfunction in neonatal H-I model, electrical responsiveness and dendrite morphology in the sensorimotor cortex were investigated at 10 weeks of age. Responses to intracortical microstimulation (ICMS) revealed that the cortical motor map was significantly changed in this model. The cortical area related to hip joint movement was reduced, and the area related to trunk movement was increased. Sholl analysis in Golgi staining revealed that layer I-III neurons on the H-I side had more dendrite branches compared with the contralateral side. To investigate whether changes in the motor map and morphology appeared at earlier stages, ICMS and Sholl analysis were also performed at 5 weeks of age. The minimal ICMS current to evoke twitches of the hip area was higher on the H-I side, while the motor map was unchanged. Golgi staining revealed more dendrite branches in layer I-III neurons on the H-I side. These results revealed that alterations of both dendrite morphology and ICMS threshold of the hip area occurred before the rearrangement of the motor map in the neonatal H-I model. They also suggest that altered dendritic morphology and altered ICMS responsiveness may be related to mild motor dysfunction in this model. PMID- 29971037 TI - Chronic Traumatic Encephalopathy in Professional American Football Players: Where Are We Now? AB - Repetitive head trauma provides a favorable milieu for the onset of inflammatory and neurodegenerative processes. The result of long-lasting head trauma is chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, military personnel, and more recently, in American football players. CTE is a chronic neurodegenerative disease with hallmarks of hyperphosphorylated tau (p-tau) aggregates and intercellular lesions of neurofibrillary tangles. The criteria for CTE diagnosis requires at least 1-2 focal perivascular lesions of p tau in the cerebral cortex, at the depth of the sulci. These pathognomonic lesions aggregate within neurons and glial cells such as astrocytes, and cell processes within the vicinity of small blood vessels. CTE presents in a distinct topographical distribution pattern compared to other tauopathies such as AD and other age-related astrogliopathies. CTE also has an insidious onset, years after repetitive head trauma. The disease course of CTE is characterized by cognitive dysfunction, behavioral changes, and can progress to altered motor function with parkinsonian-like manifestations in later stages. This short review aims to summarize CTE in professional football, epidemiology, diagnosis based on neuroanatomical abnormalities, cognitive degeneration, and adverse mental health effects, as well as gaps in the literature and future directions in diagnostics, therapeutics, and preventive measures. PMID- 29971038 TI - Extended Erythropoietin Treatment Prevents Chronic Executive Functional and Microstructural Deficits Following Early Severe Traumatic Brain Injury in Rats. AB - Survivors of infant traumatic brain injury (TBI) are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose * 6d) to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12) controlled-cortical impact (CCI) model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI). Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI. PMID- 29971040 TI - Interferons in Traumatic Brain and Spinal Cord Injury: Current Evidence for Translational Application. AB - This review article provides a general perspective of the experimental and clinical work surrounding the role of type-I, type-II, and type-III interferons (IFNs) in the pathophysiology of brain and spinal cord injury. Since IFNs are themselves well-known therapeutic targets (as well as pharmacological agents), and anti-IFNs monoclonal antibodies are being tested in clinical trials, it is timely to review the basis for the repurposing of these agents for the treatment of brain and spinal cord traumatic injury. Experimental evidence suggests that IFN-alpha may play a detrimental role in brain trauma, enhancing the pro inflammatory response while keeping in check astrocyte proliferation; converging evidence from genetic models and neutralization by monoclonal antibodies suggests that limiting IFN-alpha actions in acute trauma may be a suitable therapeutic strategy. Effects of IFN-beta administration in spinal cord and brain trauma have been reported but remain unclear or limited in effect. Despite the involvement in the inflammatory response, the role of IFN-gamma remains controversial: although IFN-gamma appears to improve the outcome of traumatic spinal cord injury, genetic models have produced either beneficial or detrimental results. IFNs may display opposing actions on the injured CNS relative to the concentration at which they are released and strictly dependent on whether the IFN or their receptors are targeted either via administration of neutralizing antibodies or through genetic deletion of either the mediator or its receptor. To date, IFN-alpha appears to most promising target for drug repurposing, and monoclonal antibodies anti IFN alpha or its receptor may find appropriate use in the treatment of acute brain or spinal cord injury. PMID- 29971042 TI - Next-Generation Sequencing of Cerebrospinal Fluid for the Diagnosis of Neurocysticercosis. AB - Background: Neurocysticercosis (NCC) is the most common helminthic infection of the central nervous system (CNS). The diagnosis of NCC is sometimes challenging due to its heterogenous clinical manifestations and the variable sensitivity and specificity of neuroimaging and serological tests. Methods: Next-generation sequencing (NGS) of cerebrospinal fluid (CSF) was used to detect pathogens in patients with clinically suspected CNS infections. A series of patients diagnosed with NCC is reviewed here. Results: Using NGS of CSF, four patients were diagnosed with NCC. The reads corresponding to Taenia solium ranged from 478 to 117,362, with genomic coverage of 0.0564-11.15%. Reads corresponding to T. solium were not found in non-template controls and far exceeded those of the background microorganisms in patients with NCC, facilitating the interpretation of the NGS results. Conclusions: This case series demonstrates that NGS of CSF is promising in the diagnosis of NCC in difficult to diagnose cases. Larger studies are needed in the future. PMID- 29971041 TI - Atrial Cardiopathy and Sympatho-Vagal Imbalance in Cryptogenic Stroke: Pathogenic Mechanisms and Effects on Electrocardiographic Markers. AB - Recently, atrial cardiopathy has emerged as possible pathogenic mechanism in cryptogenic stroke and many electrocardiographic (ECG) markers have been proposed in order to detect an altered atrial substrate at an early stage. The autonomic nervous system (ANS) plays a well-known role in determining significant and heterogeneous electrophysiological changes of atrial cardiomyocytes, that promote atrial fibrillation episodes in cardioembolic stroke. Conversely, the role of ANS in atrial cardiopathy and cryptogenic stroke is less known, as well as ANS effects on ECG markers of atrial dysfunction. In this paper, we review the evidence linking ANS dysfunction and atrial cardiopathy as a possible pathogenic factor in cryptogenic stroke. PMID- 29971039 TI - On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease. AB - Significant advances have been made uncovering the factors that render neurons vulnerable in Parkinson's disease (PD). However, the critical pathogenic events leading to cell loss remain poorly understood, complicating the development of disease-modifying interventions. Given that the cardinal motor symptoms and pathology of PD involve the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc), a majority of the work in the PD field has focused on this specific neuronal population. PD however, is not a disease of DA neurons exclusively: pathology, most notably in the form of Lewy bodies and neurites, has been reported in multiple regions of the central and peripheral nervous system, including for example the locus coeruleus, the dorsal raphe nucleus and the dorsal motor nucleus of the vagus. Cell and/or terminal loss of these additional nuclei is likely to contribute to some of the other symptoms of PD and, most notably to the non-motor features. However, exactly which regions show actual, well-documented, cell loss is presently unclear. In this review we will first examine the strength of the evidence describing the regions of cell loss in idiopathic PD, as well as the order in which this loss occurs. Secondly, we will discuss the neurochemical, morphological and physiological characteristics that render SNc DA neurons vulnerable, and will examine the evidence for these characteristics being shared across PD-affected neuronal populations. The insights raised by focusing on the underpinnings of the selective vulnerability of neurons in PD might be helpful to facilitate the development of new disease modifying strategies and improve animal models of the disease. PMID- 29971043 TI - Expanding the Potential Therapeutic Options for Remote Ischemic Preconditioning: Use in Multiple Sclerosis. PMID- 29971044 TI - The Role of Semaphorin 4D in Bone Remodeling and Cancer Metastasis. AB - Semaphorin 4D (Sema4D; CD100) is a transmembrane homodimer 150-kDa glycoprotein member of the Semaphorin family. Semaphorins were first identified as chemorepellants that guide neural axon growth. Sema4D also possesses immune regulatory activity. Recent data suggest other Sema4D functions: inactivation of platelets, stimulation of angiogenesis, and regulation of bone formation. Sema4D is a coupling factor expressed on osteoclasts that inhibits osteoblast differentiation. Blocking Sema4D may, therefore, be anabolic for bone. Sema4D and its receptor Plexin-B1 are commonly dysregulated in cancers, suggesting roles in cancer progression, invasion, tumor angiogenesis, and skeletal metastasis. This review focuses on Sema4D in bone and cancer biology and the molecular pathways involved, particularly Sema4D-Plexin-B1 signaling crosstalk between cancer cells and the bone marrow microenvironment-pertinent areas since a humanized Sema4D neutralizing antibody is now in early phase clinical trials in cancers and neurological disorders. PMID- 29971045 TI - Identification of a New Antimicrobial Resistance Gene Provides Fresh Insights Into Pleuromutilin Resistance in Brachyspira hyodysenteriae, Aetiological Agent of Swine Dysentery. AB - Brachyspira hyodysenteriae is the aetiological agent of swine dysentery, a globally distributed disease that causes profound economic loss, impedes the free trade and movement of animals, and has significant impact on pig health. Infection is generally treated with antibiotics of which pleuromutilins, such as tiamulin, are widely used for this purpose, but reports of resistance worldwide threaten continued effective control. In Brachyspira hyodysenteriae pleuromutilin resistance has been associated with mutations in chromosomal genes encoding ribosome-associated functions, however the dynamics of resistance acquisition are poorly understood, compromising stewardship efforts to preserve pleuromutilin effectiveness. In this study we undertook whole genome sequencing (WGS) and phenotypic susceptibility testing of 34 UK field isolates and 3 control strains to investigate pleuromutilin resistance in Brachyspira hyodysenteriae. Genome wide association studies identified a new pleuromutilin resistance gene, tva(A) (tiamulin valnemulin antibiotic resistance), encoding a predicted ABC-F transporter. In vitro culture of isolates in the presence of inhibitory or sub inhibitory concentrations of tiamulin showed that tva(A) confers reduced pleuromutilin susceptibility that does not lead to clinical resistance but facilitates the development of higher-level resistance via mutations in genes encoding ribosome-associated functions. Genome sequencing of antibiotic-exposed isolates identified both new and previously described mutations in chromosomal genes associated with reduced pleuromutilin susceptibility, including the 23S rRNA gene and rplC, which encodes the L3 ribosomal protein. Interesting three antibiotic-exposed isolates harboured mutations in fusA, encoding Elongation Factor G, a gene not previously associated with pleuromutilin resistance. A longitudinal molecular epidemiological examination of two episodes of swine dysentery at the same farm indicated that tva(A) contributed to development of tiamulin resistance in vivo in a manner consistent with that seen experimentally in vitro. The in vitro studies further showed that tva(A) broadened the mutant selection window and raised the mutant prevention concentration above reported in vivo antibiotic concentrations obtained when administered at certain doses. We show how the identification and characterisation of tva(A), a new marker for pleuromutilin resistance, provides evidence to inform treatment regimes and reduce the development of resistance to this class of highly important antimicrobial agents. PMID- 29971046 TI - The Fecal Microbiota in the Domestic Cat (Felis catus) Is Influenced by Interactions Between Age and Diet; A Five Year Longitudinal Study. AB - In humans, aging is associated with changes in the gastrointestinal microbiota; these changes may contribute to the age-related increase in incidence of many chronic diseases, including Type 2 diabetes. The life expectancies of cats are increasing, and they are also exhibiting the same types of diseases. While there are some studies investigating the impacts of diets on gastrointestinal microbiota in young cats, the impacts of aging in older cats has not been explored. We followed a cohort of related kittens, maintained on two commercial diets (kibbled and canned) from weaning (8 weeks) to 5 years of age (260 weeks). We hypothesized that the long-term feeding of specific diet formats would (a) lead to microbial composition changes due to aging, (b) impact body composition, and (c) affect insulin sensitivity in the aging cat. We observed that both diet and age affected fecal microbial composition, and while age correlated with changes in body composition, diet had no effect on body composition. Similarly insulin sensitivity was not affected by age nor diet. 16S rRNA sequencing found unclassified Peptostreptococcaceae were prominent across all ages averaging 21.3% of gene sequence reads and were higher in cats fed canned diets (average of 25.7% of gene sequence reads, vs. 17.0% for kibble-fed cats). Age-related effects on body composition and insulin sensitivity may become apparent as the cats grow older; this study will continue to assess these parameters. PMID- 29971049 TI - Whole-Cell MALDI-TOF MS Versus 16S rRNA Gene Analysis for Identification and Dereplication of Recurrent Bacterial Isolates. AB - Many ecological experiments are based on the extraction and downstream analyses of microorganisms from different environmental samples. Due to its high throughput, cost-effectiveness and rapid performance, Matrix Assisted Laser Desorption/Ionization Mass Spectrometry with Time-of-Flight detector (MALDI-TOF MS), which has been proposed as a promising tool for bacterial identification and classification, could be advantageously used for dereplication of recurrent bacterial isolates. In this study, we compared whole-cell MALDI-TOF MS-based analyses of 49 bacterial cultures to two well-established bacterial identification and classification methods based on nearly complete 16S rRNA gene sequence analyses: a phylotype-based approach, using a closest type strain assignment, and a sequence similarity-based approach involving a 98.65% sequence similarity threshold, which has been found to best delineate bacterial species. Culture classification using reference-based MALDI-TOF MS was comparable to that yielded by phylotype assignment up to the genus level. At the species level, agreement between 16S rRNA gene analysis and MALDI-TOF MS was found to be limited, potentially indicating that spectral reference databases need to be improved. We also evaluated the mass spectral similarity technique for species level delineation which can be used independently of reference databases. We established optimal mass spectral similarity thresholds which group MALDI-TOF mass spectra of common environmental isolates analogically to phylotype- and sequence similarity-based approaches. When using a mass spectrum similarity approach, we recommend a mass range of 4-10 kDa for analysis, which is populated with stable mass signals and contains the majority of phylotype-determining peaks. We show that a cosine similarity (CS) threshold of 0.79 differentiate mass spectra analogously to 98.65% species-level delineation sequence similarity threshold, with corresponding precision and recall values of 0.70 and 0.73, respectively. When matched to species-level phylotype assignment, an optimal CS threshold of 0.92 was calculated, with associated precision and recall values of 0.83 and 0.64, respectively. Overall, our research indicates that a similarity based MALDI-TOF MS approach can be routinely used for efficient dereplication of isolates for downstream analyses, with minimal loss of unique organisms. In addition, MALDI-TOF MS analysis has further improvement potential unlike 16S rRNA gene analysis, whose methodological limits have reached a plateau. PMID- 29971047 TI - Comparison of Database Search Methods for the Detection of Legionella pneumophila in Water Samples Using Metagenomic Analysis. AB - Metagenomic analysis has become a powerful tool to analyze bacterial communities in environmental samples. However, the detection of a specific bacterial species using metagenomic analysis remains difficult due to false positive detections of sequences shared between different bacterial species. In this study, 16S rRNA amplicon and shotgun metagenomic analyses were conducted on samples collected along a stream and ponds in the campus of Hokkaido University. We compared different database search methods for bacterial detection by focusing on Legionella pneumophila. In this study, we used L. pneumophila-specific nested PCR as a gold standard to evaluate the results of the metagenomic analysis. Comparison with the results from L. pneumophila-specific nested PCR indicated that a blastn search of shotgun reads against the NCBI-NT database led to false positive results and had problems with specificity. We also found that a blastn search of shotgun reads against a database of the catalase-peroxidase (katB) gene detected L. pneumophila with the highest area under the receiver operating characteristic curve among the tested search methods; indicating that a blastn search against the katB gene database had better diagnostic ability than searches against other databases. Our results suggest that sequence searches targeting long genes specifically associated with the bacterial species of interest is a prerequisite to detecting the bacterial species in environmental samples using metagenomic analyses. PMID- 29971048 TI - Reductive Debromination of Polybrominated Diphenyl Ethers - Microbes, Processes and Dehalogenases. AB - Extensive utilization of polybrominated diphenyl ethers (PBDEs) as flame retardants since the 1960s in a variety of commercial products has resulted in ubiquitous environmental distribution of commercial PBDE mixtures. Dangers posed to biological populations became apparent after the discovery of elevated levels of PBDEs in biota, most notably in human breast milk and tissues. Environmental persistence of PBDEs results in significant transboundary displacement, threatening fragile ecosystems globally. Despite efforts to curtail usage of PBDEs, public concern remains about the effects of legacy PBDEs contamination and continued discharge of PBDEs in regions lacking restrictions on usage and manufacture. Among available technologies for remediation of PBDEs such as ex situ soil washing, electrokinetic degradation, and biodegradation, this review focuses on bioremediation by microbes under anaerobic conditions. Bioremediation is generally preferred as it is less disruptive to contaminated ecosystems, is cost-effective, and can be implemented at sites that may be inaccessible to more traditional ex-situ methods. The aims of this review are to (1) summarize current knowledge of anaerobic microbes that debrominate PBDEs and their associated synergistic partnerships with non-dehalogenating microbes; (2) explore current understandings of the metabolic reductive debromination of PBDE congeners; (3) discuss recent discoveries on dehalogenase genes involved in debromination of PBDEs. PMID- 29971050 TI - NADH-Mediated Gene Expression in Streptococcus pneumoniae and Role of Rex as a Transcriptional Repressor of the Rex-Regulon. AB - Nicotinamide adenine dinucleotides (NAD(H)) play a vital role in various biological processes, including keeping the cellular redox balance. In this study, we investigate the regulatory responses of Streptococcus pneumoniae D39 to NADH and characterize the role of the Rex protein as a transcriptional repressor of the gapN, fba, pncB, adhB2, gap, and adhE genes. Transcriptomic analysis was used to observe the response of S. pneumoniae D39 to NADH. Our microarray studies revealed elevated expression of various genes/operons involved in transport and biosynthesis of niacin (gapN, fba, pncB, adhB2, gap, and adhE). Promoter lacZ fusion assays and microarray studies with the rex mutant revealed the role of Rex as a transcriptional repressor of gapN, fba, pncB, adhB2, gap, and adhE involved in niacin uptake and biosynthesis, in the presence of NADH. We predict the operator site (5'-TTGTKAWAAWWTTCACAA-3') of Rex in the regulatory regions of Rex regulated genes that was subsequently validated by promoter mutational experiments. PMID- 29971051 TI - Genomics-Based Insights Into the Biosynthesis and Unusually High Accumulation of Free Fatty Acids by Streptomyces sp. NP10. AB - Streptomyces sp. NP10 was previously shown to synthesize large amounts of free fatty acids (FFAs). In this work, we report the first insights into the biosynthesis of these fatty acids (FAs) gained after genome sequencing and identification of the genes involved. Analysis of the Streptomyces sp. NP10 draft genome revealed that it is closely related to several strains of Streptomyces griseus. Comparative analyses of secondary metabolite biosynthetic gene clusters, as well as those presumably involved in FA biosynthesis, allowed identification of an unusual cluster C12-2, which could be identified in only one other S. griseus-related streptomycete. To prove the involvement of identified cluster in FFA biosynthesis, one of its three ketosynthase genes was insertionally inactivated to generate mutant strain mNP10. Accumulation of FFAs in mNP10 was almost completely abolished, reaching less than 0.01% compared to the wild-type strain. Cloning and transfer of the C12-2 cluster to the mNP10 mutant partially restored FFA production, albeit to a low level. The discovery of this rare FFA biosynthesis cluster opens possibilities for detailed characterization of the roles of individual genes and their products in the biosynthesis of FFAs in NP10. PMID- 29971052 TI - Comparative Assessment of the Bioremedial Potentials of Potato Resistant Starch Based Microencapsulated and Non-encapsulated Lactobacillus plantarum to Alleviate the Effects of Chronic Lead Toxicity. AB - Lead (Pb) is a well-recognized and potent heavy metal with non-biodegradable nature and can induce the oxidative stress, degenerative damages in tissues, and neural disorders. Certain lactic acid bacterial strains retain the potential to mitigate the lethal effects of Pb. The present work was carried out to assess the Pb bio-sorption and tolerance capabilities of Lactobacillus plantarum spp. Furthermore, potato resistant starch (PRS)-based microencapsulated and non encapsulated L. plantarum KLDS 1.0344 was utilized for bioremediation against induced chronic Pb toxicity in mice. The experimental mice were divided into two main groups (Pb exposed and non-Pb exposed) and, each group was subsequently divided into three sub groups. The Pb exposed group was exposed to 100 mg/L Pb(NO3)2 via drinking water, and non-Pb exposed group was supplied with plain drinking water during 7 weeks prolonged in vivo study. The accumulation of Pb in blood, feces, renal, and hepatic tissues and its pathological damages were analyzed. The effect of Pb toxicity on the antioxidant enzyme capabilities in blood, serum, as well as, on levels of essential elements in tissues was also calculated. Moreover, KLDS 1.0344 displayed remarkable Pb binding capacity 72.34% and Pb tolerance (680 mg/L). Oral administration of both non- and PRS- encapsulated KLDS 1.0344 significantly provided protection against induced chronic Pb toxicity by increasing fecal Pb levels (445.65 +/- 22.28 MUg/g) and decreasing Pb in the blood up to 137.63 +/- 2.43 MUg/L, respectively. KLDS 1.0344 microencapsulated with PRS also relieved the renal and hepatic pathological damages and improved the antioxidant index by inhibiting changes in concentrations of glutathione peroxidase, glutathione, superoxide dismutase, malondialdehyde, and activated oxygen species, which were affected by the Pb exposure. Overall, our results suggested that L. plantarum KLDS 1.0344 either in free or encapsulated forms hold the potentiality to deliver a dietetic stratagem against Pb lethality. PMID- 29971053 TI - Phospholipolysis Caused by Different Types of Bacterial Phospholipases During Cold Storage of Bovine Raw Milk Is Prevented by N2 Gas Flushing. AB - Cold storage aims to preserve the quality and safety of raw milk from farms to dairies; unfortunately, low temperatures also promote the growth of psychrotrophic bacteria, some of which produce heat-stable enzymes that cause spoilage of milk or dairy products. Previously, N2 gas flushing of raw milk has demonstrated significant potential as a method to hinder bacterial growth at both laboratory and pilot plant scales. Using a mass spectrometry-based lipidomics approach, we examined the impact of cold storage [at 6 degrees C for up to 7 days, the control condition (C)], on the relative amounts of major phospholipids (phosphatidylethanolamine/PE, phosphatidylcholine/PC, phosphatidylserine/PS, phosphatidylinositol/PI, and sphingomyelin/SM) in three bovine raw milk samples, and compared it to the condition that received additional N2 gas flushing (N). As expected, bacterial growth was hindered by the N2-based treatment (over 4 log units lower at day 7) compared to the non-treated control condition. At the end of the cold storage period, the control condition (C7) revealed higher hydrolysis of PC, SM, PE, and PS (the major species reached 27.2, 26.7, 34.6, and 9.9 MUM, respectively), compared to the N2-flushed samples (N7) (the major species reached 55.6, 35.9, 54.0, and 18.8 MUM, respectively). C7 samples also exhibited a three fold higher phosphatidic acid (PA) content (6.8 MUM) and a five-fold higher content (17.3 MUM) of lysophospholipids (LPE, LPC, LPS, and LPI) whereas both lysophospholipids and PA remained at their initial levels for 7 days in N7 samples. Taking into consideration the significant phospholipid losses in the controls, the lipid profiling results together with the microbiological data suggest a major role of phospholipase (PLase) C (PLC) in phospholipolysis during cold storage. However, the experimental data also indicate that bacterial sphingomyelinase C, together with PLases PLD and PLA contributed to the degradation of phospholipids present in raw milk as well, and potential contributions from PLB activity cannot be excluded. Altogether, this lipidomics study highlights the beneficial effects of N2 flushing treatment on the quality and safety of raw milk through its ability to effectively hinder phospholipolysis during cold storage. PMID- 29971055 TI - Expression of Hemolysin Is Regulated Under the Collective Actions of HapR, Fur, and HlyU in Vibrio cholerae El Tor Serogroup O1. AB - The biotype El Tor of serogroup O1 and most of the non-O1/non-O139 strains of Vibrio cholerae can produce an extracellular pore-forming toxin known as cholera hemolysin (HlyA). Expression of HlyA has been previously reported to be regulated by the quorum sensing (QS) and the regulatory proteins HlyU and Fur, but lacks the direct evidence for their binding to the promoter of hlyA. In the present work, we showed that the QS regulator HapR, along with Fur and HlyU, regulates the transcription of hlyA in V. cholerae El Tor biotype. At the late mid logarithmic growth phase, HapR binds to the three promoters of fur, hlyU, and hlyA to repress their transcription. At the early mid-logarithmic growth phase, Fur binds to the promoters of hlyU and hlyA to repress their transcription; meanwhile, HlyU binds to the promoter of hlyA to activate its transcription, but it manifests direct inhibition of its own gene. The highest transcriptional level of hlyA occurs at an OD600 value of around 0.6-0.7, which may be due to the subtle regulation of HapR, Fur, and HlyU. The complex regulation of HapR, Fur, and HlyU on hlyA would be beneficial to the invasion and pathogenesis of V. cholerae during the different infection stages. PMID- 29971056 TI - A Novel Process for Cadaverine Bio-Production Using a Consortium of Two Engineered Escherichia coli. AB - Bio-production of cadaverine from cheap carbon sources for synthesizing bio-based polyamides is becoming more common. Here, a novel fermentation process for cadaverine bio-production from glucose was implemented by using a microbial consortium of two engineered Escherichia coli strains to relieve the toxic effect of cadaverine on fermentation efficiency. To achieve controllable growth of strains in the microbial consortium, two engineered E. coli strains grown separately on different carbon sources were first constructed. The strains were, an L-lysine-producing E. coli NT1004 with glucose as carbon source, and a cadaverine-producing E. coli CAD03 with glucose metabolism deficiency generated by modifying the PTSGlc system with CRISPR-Cas9 technology and inactivating cadaverine degradation pathways. Co-culturing these two engineered E. coli strains with a mixture of glucose and glycerol led to successful production of cadaverine. After optimizing cultivation conditions, a cadaverine titer of 28.5 g/L was achieved with a multi-stage constant-speed feeding strategy. PMID- 29971054 TI - The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis. AB - Leishmaniasis is a vector-borne infectious disease caused by different species of protozoa from the Leishmania genus. Classically, the disease can be classified into two main clinical forms: Visceral (VL) and Tegumentary (TL) leishmaniasis. TL is a skin/mucosal granulomatous disease that manifests mainly as cutaneous localized or disseminated ulcers, papules diffusely distributed, mucosal lesions or atypical lesions. Once the etiology of the infection is confirmed, treatment can take place, and different drugs can be administered. It has already been shown that, even when the scar is clinically evident, inflammation is still present in the native tissue, and the decrease of the inflammatory process occurs slowly during the 1st years after clinical healing. The maintenance of residual parasites in the scar tissue is also well documented. Therefore, it is no longer a surprise that, under some circumstances, therapeutic failure and/or lesion reactivation occurs. All over the years, an impressive amount of data on relapses, treatment resistance and lesion reactivation after healing has been collected, and several factors have been pointed out as having a role in the process. Different factors such as Leishmania species, parasite variability, Leishmania RNA virus 1, parasite load, parasite persistence, age, nutritional status, gender, co-morbidities, co-infection, pregnancy, immunosuppression, lesion duration, number and localization of lesions, drug metabolism, irregular treatment and individual host cellular immune response were described and discussed in the present review. Unfortunately, despite this amount of information, a conclusive understanding remains under construction. In addition, multifactorial influence cannot be discarded. In this context, knowing why leishmaniasis has been difficult to treat and control can help the development of new approaches, such as drugs and immunotherapy in order to improve healing maintenance. In this sense, we would like to highlight some of the findings that may influence the course of Leishmania infection and the therapeutic response, with an emphasis on TL. PMID- 29971057 TI - Integrated Multi-Omic Analysis of Mycobacterium tuberculosis H37Ra Redefines Virulence Attributes. AB - H37Ra is a virulence attenuated strain of Mycobacterium tuberculosis widely employed as a model to investigate virulence mechanisms. Comparative high throughput studies have earlier correlated its avirulence to the presence of specific mutations or absence of certain proteins. However, a recent sequencing study of H37Ra, has disproved several genomic differences earlier reported to be associated with virulence. This warrants further investigations on the H37Ra proteome as well. In this study, we carried out an integrated analysis of the genome, transcriptome, and proteome of H37Ra. In addition to confirming single nucleotide variations (SNVs) and insertion-deletions that were reported earlier, our study provides novel insights into the mutation spectrum in the promoter regions of 7 genes. We also provide transcriptional and proteomic evidence for 3,900 genes representing ~80% of the total predicted gene count including 408 proteins that have not been identified previously. We identified 9 genes whose coding potential was hitherto reported to be absent in H37Ra. These include 2 putative virulence factors belonging to ESAT-6 like family of proteins. Furthermore, proteogenomic analysis enabled us to identify 63 novel proteins coding genes and correct 25 existing gene models in H37Ra genome. A majority of these were found to be conserved in the virulent strain H37Rv as well as in other mycobacterial species suggesting that the differences in the virulent and avirulent strains of M. tuberculosis are not entirely dependent on the expression of certain proteins or their absence but may possibly be ascertained to functional changes. PMID- 29971058 TI - Isolation of Low-Abundant Bacteroidales in the Human Intestine and the Analysis of Their Differential Utilization Based on Plant-Derived Polysaccharides. AB - Bacteroidales are the most abundant Gram-negative bacteria flourished in the human intestine with great underlying benefits to be discovered and developed as the next-generation probiotics. However, the traditional isolation method limits the mining of low-abundant species. In this study, modified selective medium was established using xylan as the sole carbohydrate source to enrich low-abundant species such as Prevotella copri and Bacteroides xylanisolvens from healthy human fecal samples. The growth rate, transcriptomics, and metabolomics profiles of the enriched low-abundant species were then evaluated. The considerable upregulated genes encoding xylan-associated hydrolysis and transportation, along with the increased xylose production detected in the culture of the enriched Bacteroidales strains based on xylan, were considered as positive proof of the feasibility of the modified methodology. PMID- 29971059 TI - Differences Between Indigenous Yeast Populations in Spontaneously Fermenting Musts From V. vinifera L. and V. labrusca L. Grapes Harvested in the Same Geographic Location. AB - Yeast communities associated with Vitis vinifera L. ecosystems have been widely characterized. Less is known, however, about yeast communities present in grapes and fermenting musts from Vitis non-vinifera ecosystems. Moreover, there are no comparative studies concerning yeast communities in grapes from V. vinifera L. and non-vinifera Vitis species in vineyards from a shared terroir. In this work, we have used a culture-dependent strategy, phenotypic analyses, and molecular genotyping, to study the most representative yeast species present in spontaneously fermenting musts of grapes harvested from neighboring V. vinifera L. (cv. Malbec) and V. labrusca L. (cv. Isabella) vineyards. Phenotypic analyses of H2S production, ethanol tolerance and carbon utilization, on randomly selected strains of each Hanseniaspora uvarum, Starmerella bacillaris and Saccharomyces cerevisiae strains, as well as microsatellite genotyping of S. cerevisiae isolates from each the Malbec and Isabella grape musts, suggest that V. vinifera L. and V. labrusca L. ecosystems could harbor different yeast strain populations. Thus, microbial communities in exotic Vitis species may offer opportunities to look for unique yeast strains that could not be present in conventional V. vinifera L. ecosystems. PMID- 29971060 TI - Stimulation of the Internal Ribosome Entry Site (IRES)-Dependent Translation of Enterovirus 71 by DDX3X RNA Helicase and Viral 2A and 3C Proteases. AB - The translation of enterovirus 71 (EV71) is mediated by an internal ribosome entry site (IRES)-dependent manner. EV71 IRES comprises five highly structured domains (domains II-VI) in the 5'-untranslated region of the viral mRNA. A conserved AUG triplet residing in domain VI is proposed to be the ribosome entry site. It is thus envisaged that the highly structured conformation of domain VI may actually reduce the accessibility of the AUG triplet to the ribosome. This study identified a DEAD-box family RNA helicase, DDX3X, that positively regulated the EV71 IRES-dependent translation. The helicase activity of DDX3X was required for the stimulation of EV71 IRES activity; however, DDX3X was no longer important for the IRES activity when the secondary structure of domain VI was destabilized. DDX3X interacted with the truncated eIF4G which bound specifically to domain V. Thus, we proposed that DDX3X might bind to domain VI or a region nearby via the interaction with the truncated eIF4G, and subsequently unwound the secondary structure of domain VI to facilitate ribosome entry. Additionally, we demonstrated that the viral 2Apro and 3Cpro enhanced the IRES-dependent translation via their protease activities. Together, these results indicate that DDX3X is an important RNA helicase involved in EV71 IRES-dependent translation and that IRES translation is enhanced by viral infection, partly mediated by viral protease activity. PMID- 29971062 TI - 3-Hydroxyphthalic Anhydride- Modified Rabbit Anti-PAP IgG as a Potential Bifunctional HIV-1 Entry Inhibitor. AB - Several studies have reported that amyloid fibrils in human semen formed from a naturally occurring peptide fragment of prostatic acidic phosphatase (PAP248 286), known as semen-derived enhancer of viral infection (SEVI), could dramatically enhance human immunodeficiency virus type 1 (HIV-1) infection. Accordingly, SEVI might serve as a novel target for new antiviral drugs or microbicide candidates for the prevention of sexually transmitted HIV. Theoretically, a special anti-PAP or anti-SEVI antibody could reduce the enhancement of viral infection by blocking the binding of HIV and SEVI fibrils. Here, 3-hydroxyphthalic anhydride modified anti-PAP248-286 antibody, named HP API, exhibited broad-spectrum and highly effective anti-HIV-1 activities on different subtypes and tropism. By using time-of-addition, cell-cell fusion and a single-cycle HIV-1 infection assays, we demonstrated that HP-API is an HIV-1 entry/fusion inhibitor. Mechanism studies suggest that HP-API inhibited HIV-1 entry/fusion by targeting both HIV-1 gp120 envelop and CD4 receptor on the host cell specifically. It is noteworthy that HP-API abrogated the formation of SEVI fibrils and partially interfered with SEVI-mediated enhancement of HIV-1 infection. Based on these findings, HP-API could be considered a bifunctional HIV 1 entry/fusion inhibitor with high potential. PMID- 29971061 TI - Standardized Preparation for Fecal Microbiota Transplantation in Pigs. AB - The intestine of pigs harbors a mass of microorganisms which are essential for intestinal homeostasis and host health. Intestinal microbial disorders induce enteric inflammation and metabolic dysfunction, thereby causing adverse effects on the growth and health of pigs. In the human medicine, fecal microbiota transplantation (FMT), which engrafts the fecal microbiota from a healthy donor into a patient recipient, has shown efficacy in intestinal microbiota restoration. In addition, it has been used widely in therapy for human gastrointestinal diseases, including Clostridium difficile infection, inflammatory bowel diseases, and irritable bowel syndrome. Given that pigs share many similarities with humans, in terms of anatomy, nutritional physiology, and intestinal microbial compositions, FMT may also be used to restore the normal intestinal microbiota of pigs. However, feasible procedures for performing FMT in pigs remains unclear. Here, we summarize a standardized preparation for FMT in pigs by combining the standard methodology for human FMT with pig production. The key issues include the donor selection, fecal material preparation, fecal material transfer, stool bank establishment, and the safety for porcine FMT. Optimal donors should be selected to ensure the efficacy of porcine FMT and reduce the risks of transmitting infectious diseases to recipients during FMT. Preparing for fresh fecal material is highly recommended. Alternatively, frozen fecal suspension can also be prepared as an optimal choice because it is convenient and has similar efficacy. Oral administration of fecal suspension could be an optimal method for porcine fecal material transfer. Furthermore, the dilution ratio of fecal materials and the frequency of fecal material transfer could be adjusted according to practical situations in the pig industry. To meet the potential large-scale requirement in the pig industry, it is important to establish a stool bank to make porcine FMT readily available. Future studies should also focus on providing more robust safety data on FMT to improve the safety and tolerability of the recipient pigs. This standardized preparation for porcine FMT can facilitate the development of microbial targeted therapies and improve the intestinal health of pigs. PMID- 29971064 TI - Beneficial Effect of Fluoxetine and Sertraline on Chronic Stress-Induced Tumor Growth and Cell Dissemination in a Mouse Model of Lymphoma: Crucial Role of Antitumor Immunity. AB - Clinical data and experimental studies have suggested a relationship between psychosocial factors and cancer prognosis. Both, stress effects on the immune system and on tumor biology were analyzed independently. However, there are few studies regarding the stress influence on the interplay between the immune system and tumor biology. Moreover, antidepressants have been used in patients with cancer to alleviate mood disorders. Nevertheless, there is contradictory evidence about their action on cancer prognosis. In this context, we investigated the effect of chronic stress on tumor progression taking into account both its influence on the immune system and on tumor biology. Furthermore, we analyzed the action of selective serotonin reuptake inhibitors, fluoxetine and sertraline, in these effects. For this purpose, C57BL/6J mice submitted or not to a chronic stress model and treated or not with fluoxetine or sertraline were subcutaneously inoculated with EL4 cells to develop solid tumors. Our results indicated that chronic stress leads to an increase in both tumor growth and tumor cell dissemination. The analysis of cell cycle regulatory proteins showed that stress induced an increase in the mRNA levels of cyclins A2, D1, and D3 and a decrease in mRNA levels of cell cycle inhibitors p15, p16, p21, p27, stimulating cell cycle progression. Moreover, an augment of mRNA levels of metalloproteases (MMP-2 and MMP-9), a decrease of inhibitors of metalloproteases mRNA levels (TIMP 1, 2, and 3), and an increase in migration ability were found in tumors from stressed animals. In addition, a significant decrease of antitumor immune response in animals under stress was found. Adoptive lymphoid cell transfer experiments indicated that the reduced immune response in stressed animals influenced both the tumor growth and the metastatic capacity of tumor cells. Finally, we found an important beneficious effect of fluoxetine or sertraline treatment on cancer progression. Our results emphasize the crucial role of the immune system in tumor progression under stress situations. Although a direct effect of stress and drug treatment on tumor biology could not be ruled out, the beneficial effect of fluoxetine and sertraline appears to be mainly due to a restoration of antitumor immune response. PMID- 29971065 TI - Prostaglandin E2 Stimulates the Expansion of Regulatory Hematopoietic Stem and Progenitor Cells in Type 1 Diabetes. AB - Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only "experimental therapy" that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, ex vivo modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human in vitro autoimmune assays, PG modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes. PMID- 29971066 TI - Pathogenic Role of Complement in Antiphospholipid Syndrome and Therapeutic Implications. AB - Antiphospholipid syndrome (APS) is an acquired autoimmune disease characterized by thromboembolic events, pregnancy morbidity, and the presence of antiphospholipid (aPL) antibodies. There is sound evidence that aPL act as pathogenic autoantibodies being responsible for vascular clots and miscarriages. However, the exact mechanisms involved in the clinical manifestations of the syndrome are still a matter of investigation. In particular, while vascular thrombosis is apparently not associated with inflammation, the pathogenesis of miscarriages can be explained only in part by the aPL-mediated hypercoagulable state and additional non-thrombotic effects, including placental inflammation, have been described. Despite this difference, evidence obtained from animal models and studies in APS patients support the conclusion that complement activation is a common denominator in both vascular and obstetric APS. Tissue bound aPL rather than circulating aPL-beta2 glycoprotein I immune complexes seem to be responsible for the activation of the classical and the alternative complement pathways. The critical role of complement is supported by the finding that complement-deficient animals are protected from the pathogenic effect of passively infused aPL and similar results have been obtained blocking complement activation. Moreover, elevated levels of complement activation products in the absence of abnormalities in regulatory molecules have been found in the plasma of APS patients, strongly suggesting that the activation of complement cascade is the result of aPL binding to the target antigen rather than of a defective regulation. Placental complement deposits represent a further marker of complement activation both in animals and in patients, and there is also some suggestive evidence that complement activation products are deposited in the affected vessels. The aim of this review is to analyze the state of the art of complement involvement in the pathogenesis of APS in order to provide insights into the role of this system as predictive biomarker for the clinical manifestations and as therapeutic target. PMID- 29971067 TI - T Cell Hierarchy in the Pathogenesis of Psoriasis and Associated Cardiovascular Comorbidities. AB - The key role of T cells in the pathogenesis of cutaneous psoriasis has been well described in the last decade and the knowledge of the relative role of the different subsets of T cells in psoriasis pathogenesis has considerably evolved. Now, it is clear that IL-17A-producing T cells, including Th17/Tc17, have a central role in the pathogenesis of cutaneous psoriasis and therapies blocking the IL-17A pathway show high clinical efficacy. By contrast, the contribution of IFNgamma-producing T cells has progressively become less clear because of the lack of efficacy of anti-IFNgamma antibodies in clinical studies. In parallel, the role of CD8+ T cells specific for self-antigens has been revived and increasing evidence now indicates that in psoriatic skin the majority CD8+ T cells are present in the form of epidermal tissue-resident memory T cells. In the last years it also emerged the possibility of a contribution of T cell recirculation in the pathogenesis of psoriasis and its systemic manifestations. The aim of this review is to define a hierarchy for the different subsets of T cells in the T cell-mediated inflammatory cascade in psoriatic skin. This analysis will possibly help to distinguish the subsets that initiate the disease, those involved in the establishment of the self-sustaining amplification loop that leads to the cutaneous clinical manifestations and finally the subsets that act as downstream players in established lesions. Specific T cell subpopulations finally will be considered for their possible role in propagating inflammation at distant sites and for representing a link with systemic inflammation and cardiovascular comorbidities. PMID- 29971068 TI - Latent Mycobacterium tuberculosis Infection Is Associated With a Higher Frequency of Mucosal-Associated Invariant T and Invariant Natural Killer T Cells. AB - Increasing drug resistance and the lack of an effective vaccine are the main factors contributing to Mycobacterium tuberculosis (Mtb) being a major cause of death globally. Despite intensive research efforts, it is not well understood why some individuals control Mtb infection and some others develop active disease. HIV-1 infection is associated with an increased incidence of active tuberculosis, even in virally suppressed individuals. Mucosal-associated invariant T (MAIT) and invariant natural killer T (iNKT) cells are innate T cells that can recognize Mtb infected cells. Contradicting results regarding the frequency of MAIT cells in latent Mtb infection have been reported. In this confirmatory study, we investigated the frequency, phenotype, and IFNgamma production of MAIT and iNKT cells in subjects with latent or active Mtb infection. We found that the frequency of both cell types was increased in subjects with latent Mtb infection compared with uninfected individuals or subjects with active infection. We found no change in the expression of HLA-DR, PD-1, and CCR6, as well as the production of IFNgamma by MAIT and iNKT cells, among subjects with latent Mtb infection or uninfected controls. The proportion of CD4- CD8+ MAIT cells in individuals with latent Mtb infection was, however, increased. HIV-1 infection was associated with a loss of MAIT and iNKT cells, and the residual cells had elevated expression of the exhaustion marker PD-1. Altogether, the results suggest a role for MAIT and iNKT cells in immunity against Mtb and show a deleterious impact of HIV-1 infection on those cells. PMID- 29971063 TI - Role of Optineurin in the Mitochondrial Dysfunction: Potential Implications in Neurodegenerative Diseases and Cancer. AB - Optineurin (Optn) is a 577 aa protein encoded by the Optn gene. Mutations of Optn are associated with normal tension glaucoma and amyotrophic lateral sclerosis, and its gene has also been linked to the development of Paget's disease of bone and Crohn's disease. Optn is involved in diverse cellular functions, including NF kappaB regulation, membrane trafficking, exocytosis, vesicle transport, reorganization of actin and microtubules, cell cycle control, and autophagy. Besides its role in xenophagy and autophagy of aggregates, Optn has been identified as a primary autophagy receptor, among the five adaptors that translocate to mitochondria during mitophagy. Mitophagy is a selective macroautophagy process during which irreparable mitochondria are degraded, preventing accumulation of defective mitochondria and limiting the release of reactive oxygen species and proapoptotic factors. Mitochondrial quality control via mitophagy is central to the health of cells. One of the important surveillance pathways of mitochondrial health is the recently defined signal transduction pathway involving the mitochondrial PTEN-induced putative kinase 1 (PINK1) protein and the cytosolic RING-between-RING ubiquitin ligase Parkin. Both of these proteins, when mutated, have been identified in certain forms of Parkinson's disease. By targeting ubiquitinated mitochondria to autophagosomes through its association with autophagy related proteins, Optn is responsible for a critical step in mitophagy. This review reports recent discoveries on the role of Optn in mitophagy and provides insight into its link with neurodegenerative diseases. We will also discuss the involvement of Optn in other pathologies in which mitophagy dysfunctions are involved including cancer. PMID- 29971069 TI - Role of Hepatitis C Virus Envelope Glycoprotein E1 in Virus Entry and Assembly. AB - Hepatitis C virus (HCV) glycoproteins E1 and E2 form a heterodimer to constitute viral envelope proteins, which play an essential role in virus entry. E1 does not directly interact with host receptors, and its functions in viral entry are exerted mostly through its interaction with E2 that directly binds the receptors. HCV enters the host cell via receptor-mediated endocytosis during which the fusion of viral and host endosomal membranes occurs to release viral genome to cytoplasm. A putative fusion peptide in E1 has been proposed to participate in membrane fusion, but its exact role and underlying molecular mechanisms remain to be deciphered. Recently solved crystal structures of the E2 ectodomains and N terminal of E1 fail to reveal a classical fusion-like structure in HCV envelope glycoproteins. In addition, accumulating evidence suggests that E1 also plays an important role in virus assembly. In this mini-review, we summarize current knowledge on HCV E1 including its structure and biological functions in virus entry, fusion, and assembly, which may provide clues for developing HCV vaccines and more effective antivirals. PMID- 29971070 TI - Immune Curbing of Cancer Stem Cells by CTLs Directed to NANOG. AB - Cancer stem cells (CSCs) have been identified as the source of tumor growth and disease recurrence. Eradication of CSCs is thus essential to achieve durable responses, but CSCs are resistant to current anti-tumor therapies. Novel therapeutic approaches that specifically target CSCs will, therefore, be crucial to improve patient outcome. Immunotherapies, which boost the body's own immune system to eliminate cancerous cells, could be an alternative approach to target CSCs. Vaccines of dendritic cells (DCs) loaded with tumor antigens can evoke highly specific anti-tumor T cell responses. Importantly, DC vaccination also promotes immunological memory formation, paving the way for long-term cancer control. Here, we propose a DC vaccination that specifically targets CSCs. DCs loaded with NANOG peptides, a protein required for maintaining stem cell properties, could evoke a potent anti-tumor immune response against CSCs. We hypothesize that the resulting immunological memory will also control newly formed CSCs, thereby preventing disease recurrence. PMID- 29971071 TI - Molecular Characterization of Magnesium Chelatase in Soybean [Glycine max (L.) Merr.]. AB - Soybean (Glycine max) seed yields rely on the efficiency of photosynthesis, which is poorly understood in soybean. Chlorophyll, the major light harvesting pigment, is crucial for chloroplast biogenesis and photosynthesis. Magnesium chelatase catalyzes the insertion of Mg2+ into protoporphyrin IX in the first committed and key regulatory step of chlorophyll biosynthesis. It consists of three types of subunits, ChlI, ChlD, and ChlH. To gain a better knowledge of chlorophyll biosynthesis in soybean, we analyzed soybean Mg-chelatase subunits and their encoding genes. Soybean genome harbors 4 GmChlI genes, 2 GmChlD genes, and 3 GmChlH genes, likely evolved from two rounds of gene duplication events. The qRT PCR analysis revealed that GmChlI, GmChlD, and GmChlH genes predominantly expressed in photosynthetic tissues, but the expression levels among paralogs are different. In silicon promoter analyses revealed these genes harbor different cis regulatory elements in their promoter regions, suggesting they could differentially respond to various environmental and developmental signals. Subcellular localization analyses illustrated that GmChlI, GmChlD, and GmChlH isoforms are all localized in chloroplast, consistent with their functions. Yeast two hybrid and bimolecular fluorescence complementation (BiFC) assays showed each isoform has a potential to be assembled into the Mg-chelatase holocomplex. We expressed each GmChlI, GmChlD, and GmChlH isoform in Arabidopsis corresponding mutants, and results showed that 4 GmChlI and 2 GmChlD isoforms and GmChlH1 could rescue the severe phenotype of Arabidopsis mutants, indicating that they maintain normal biochemical functions in vivo. However, GmChlH2 and GmChlH3 could not completely rescue the chlorotic phenotype of Arabidopsis gun5-2 mutant, suggesting that the functions of these two proteins could be different from GmChlH1. Considering the differences shown on primary sequences, biochemical functions, and gene expression profiles, we conclude that the paralogs of each soybean Mg-chelatase subunit have diverged more or less during evolution. Soybean could have developed a complex regulatory mechanism to control chlorophyll content to adapt to different developmental and environmental situations. PMID- 29971072 TI - Sulfur and Calcium Simultaneously Regulate Photosynthetic Performance and Nitrogen Metabolism Status in As-Challenged Brassica juncea L. Seedlings. AB - In the present study, the role of sulfur (K2SO4: S; 60 mg S kg-1 sand) and/or calcium (CaCl2: Ca; 250 mg Ca kg-1 sand) applied alone as well as in combination on growth, photosynthetic performance, indices of chlorophyll a fluorescence, nitrogen metabolism, and protein and carbohydrate contents of Indian mustard (Brassica juncea L.) seedlings in the absence and presence of arsenic (Na2HAsO4.7H2O: As1; 15 mg As kg-1 sand and As2; 30 mg As kg-1 sand) stress was analyzed. Arsenic with its rising concentration negatively affected the fresh weight, root/shoot ratio, leaf area, photosynthetic pigments content, photosynthetic oxygen yield, and chlorophyll a fluorescence parameters: the O-J, J-I and I-P rise, QA- kinetic parameters, i.e., PhiP0, Psi0, PhiE0, and PIABS, along with Fv/F0 and Area while increased the energy flux parameters, i.e., ABS/RC, TR0/RC, ET0/RC, and DI0/RC along with F0/Fv and Sm due to higher As/S and As/Ca ratio in test seedlings; however, exogenous application of S and Ca and their combined effect notably counteracted on As induced toxicity on growth and other important growth regulating processes. Moreover, inorganic nitrogen contents, i.e., nitrate (NO3-) and nitrite (NO2-) and the activities of nitrate assimilating enzymes, viz., nitrate reductase (NR) and nitrite reductase (NiR) and ammonia assimilating enzymes, viz., glutamine synthetase (GS) and glutamate synthase (GOGAT) along with protein and carbohydrate contents were severely affected with As toxicity; while under similar condition, ammonium (NH4+) content and glutamate dehydrogenase (GDH) activity in both root and leaves showed reverse trend. Furthermore, S and Ca supplementation alone and also in combination to As stressed seedlings ameliorated these parameters except NH4+ content and GDH activity, which showed an obvious reduction under similar conditions. These findings point out that exogenous application of S and/or Ca particularly S+Ca more favorably regulated the photosynthesis, contents of protein, carbohydrate and inorganic nitrogen, and the activities of nitrate and ammonia assimilating enzymes, which might be linked with the mitigation of As stress. Our results suggest that exogenous application of S+Ca more efficiently defends Brassica seedlings by declining As accumulation in root and shoot tissues and by maintaining the photosynthesis and nitrogen metabolism as well. PMID- 29971073 TI - Coping With Metal Toxicity - Cues From Halophytes. AB - Being the native flora of saline soil, halophytes are well studied for their salt tolerance and adaptation mechanism at the physiological, biochemical, molecular and metabolomic levels. However, these saline habitats are getting contaminated due to various anthropogenic activities like urban waste, agricultural runoff, mining, industrial waste that are rich in toxic metals and metalloids. These toxic metals impose detrimental effects on growth and development of most plant species. Halophytes by virtue of their tolerance to salinity also show high tolerance to heavy metals which is attributed to the enhanced root to shoot metal translocation and bioavailability. Halophytes rapidly uptake toxic ions from the root and transport them toward aerial parts by using different transporters which are involved in metal tolerance and homeostasis. A number of defense related physiological and biochemical strategies are known to be crucial for metal detoxification in halophytes however; there is paucity of information on the molecular regulators. Understanding of the phenomenon of cross-tolerance of salinity with other abiotic stresses in halophytes could very well boost their potential use in phytoremediation. In this article, we present an overview of heavy metal tolerance in case of halophytes, associated mechanisms and cross tolerance of salinity with other abiotic stresses. PMID- 29971074 TI - Subunit Interaction Differences Between the Replication Factor C Complexes in Arabidopsis and Rice. AB - Replication factor C (RFC) is a multisubunit complex that opens the sliding clamp and loads it onto the DNA chain in an ATP-dependent manner and is thus critical for high-speed DNA synthesis. In yeast (Saccharomyces cerevisiae) and humans, biochemical studies and structural analysis revealed interaction patterns between the subunits and architectures of the clamp loaders. Mutations of ScRFC1/2/3/4/5 lead to loss of cell viability and defective replication. However, the functions of RFC subunits in higher plants are unclear, except for AtRFC1/3/4, and the interaction and arrangement of the subunits have not been studied. Here, we identified rfc2-1/+, rfc3-2/+, and rfc5-1/+ mutants in Arabidopsis, and found that embryos and endosperm arrested at the 2/4-celled embryo proper stage and 6-8 nuclei stages, respectively. Subcellular localization analysis revealed that AtRFC1 and OsRFC1/4/5 proteins were localized in the nucleus, while AtRFC2/3/4/5 and OsRFC2/3 proteins were present both in the nucleus and cytoplasm. By using yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) techniques, we demonstrated the interactions of Arabidopsis and rice (Oryza sativa) RFC subunits, and proposed arrangements of the five subunits within the RFC complex, which were AtRFC5-AtRFC4-AtRFC3/2-AtRFC2/3-AtRFC1 and OsRFC5-OsRFC2 OsRFC3-OsRFC4-OsRFC1, respectively. In addition, AtRFC1 could interact with AtRFC2/3/4/5 in the presence of other subunits, while OsRFC1 directly interacted with the other four subunits. To further characterize the regions required for complex formation, truncated RFC proteins of the subunits were created. The results showed that C-termini of the RFC subunits are required for complex formation. Our studies indicate that the localization and interactions of RFCs in Arabidopsis and rice are distinctly discrepant. PMID- 29971076 TI - Phenotypic Description of Theobroma cacao L. for Yield and Vigor Traits From 34 Hybrid Families in Costa Rica Based on the Genetic Basis of the Parental Population. AB - A comprehensive understanding of the genetic basis of target traits in any crop is critical to design breeding strategies for the development and release of new improved varieties. In this study, 34 cacao families were evaluated for vigor and yield related traits over the course of 6 years in Costa Rica. Linear mixed models provided the variance components for the partitioning of additive and non additive effects. Heritabilities of yield over time ranged from 0.085 to 0.576, from 0.127 to 0.399 for vigor, and 0.141 to 0.146 for disease resistance traits. Significant (p < 0.001) general combining abilities were observed for ICS-43 and LcTeen-37 with negative effect on average yield (-0.674, -0.690), respectively. Specific combining abilities for yield had significant (p < 0.001) positive effect from the cross GU-154-L x UF-273 Type 2 (0.703) and strong negative interaction between ICS-43 and LF-1 (-0.975). A weighted index was used to select the top performers while providing the corresponding genetic gains. At an 1% selection intensity, yield component gains ranged from 17.8 to 331.9%. Agronomic traits such as branch angle, trunk diameter and jorquette height had lower genetic gains and lower heritabilities. In addition, the parents in this study were genotyped with a 96-SNP marker off-typing set and a significant positive correlation of 0.39 (p = 0.019) was found between genetic distance and specific combining abilities for yield. Preliminary comparison of clonal parents vs. seedlings yield in the family with the highest SCA suggest for the first time presence of heterobeltiosis in cacao. PMID- 29971075 TI - Cytoskeleton in the Parasitic Plant Cuscuta During Germination and Prehaustorium Formation. AB - Although cytoskeleton is a driving force for cell division and growth in higher plants, there is little evidence about its components in parasitic angiosperms. Microtubules and actin filaments in cells of shoot apical meristem and root-like structure of stem holoparasites European (C. europaea L.) and Eastern (C. monogyna Vahl.) dodders, as well as in prehaustorium, the specific organ adapted to parasitism, were visualized for the first time by immunolabeling and fluorescence microscopy. The significance of cytoskeletal elements during germination and prehaustorium formation was addressed by treatments with taxol, oryzalin, latrunculin B, cytochalasin B/D, jasplakinolide, and 2,3-butanedione monoxime. In shoot apical meristem many dividing cells were observed, in contrast to root-like structure, devoid of cell divisions. Cortical microtubules were oriented transversely and/or obliquely, while actin filaments were randomly distributed in cells of both organs. Furthermore, longitudinal cortical microtubules were present in digitate cells of prehaustorium, and transverse arrays were found in its file cells. Long and short random actin filaments were also observed in prehaustorium cells. Thus, it was shown that the cytoskeleton in dodder shoot cells is organized in a similar way to non-parasitic dicots, while cytoskeletal organization has some peculiarities in quickly senescing root-like structure and prehaustorium. PMID- 29971077 TI - Physical Mapping of a Novel Locus Conferring Leaf Rust Resistance on the Long Arm of Agropyron cristatum Chromosome 2P. AB - Wheat leaf rust is one of the most common wheat diseases worldwide and can cause up to 40% wheat yield loss. To combat the growth and spread of leaf rust disease, continual exploration and identification of new and effective resistance genes are needed. Here, we report for the first time a locus conferring leaf rust resistance located on the long arm of Agropyron cristatum chromosome 2P in Triticum aestivum-A. cristatum 2P translocation lines. This study used 50 leaf rust races, including two Chinese major dominant leaf rust races, named by THT and PHT, and other 48 different leaf rust races collected from 11 provinces, 1autonomous region and 1 municipality of China to test the resistance to T. aestivum-A. cristatum 2P chromosome translocation lines and their backcross populations, the results indicated that the novel leaf rust resistance locus was immune or nearly immune to all tested leaf rust races. Four long arm translocation lines with different breakpoints of A. cristatum chromosome 2PL and their backcross populations were tested with leaf rust race THT at the seedling and adult stages and genotyped with 2P-specific STS markers. The results showed that the novel leaf rust resistance locus of the T. aestivum-A. cristatum 2P translocation lines was located in the chromosomal bin FL 0.66-0.86 of 2PL. Therefore, T. aestivum-A. cristatum 2P chromosome translocation lines conferring leaf rust resistance locus could provide a novel disease-resistance resource for future wheat breeding programs. PMID- 29971078 TI - Proteomic Profiling and Epitope Analysis of the Complex alpha-, gamma-, and omega Gliadin Families in a Commercial Bread Wheat. AB - Wheat gliadins are a complex group of proteins that contribute to the functional properties of wheat flour doughs and contain epitopes that are relevant for celiac disease (CD) and wheat-dependent exercise-induced anaphylaxis (WDEIA). In this study, we extracted ethanol-soluble gliadin fractions from flour of the Korean bread wheat cultivar Keumkang. Proteins were separated by 2-dimensional gel electrophoresis (2-DE) using a pI range of 6-11 in the first dimension and subjected to tandem mass spectrometry. alpha-, gamma-, and omega-gliadins were identified as the predominant proteins in 31, 28, and one 2-DE spot, respectively. An additional six omega-gliadins were identified in a separate experiment in which a pI range of 3-11 was used for protein separation. We analyzed the composition of CD- and WDEIA-relevant epitopes in the gliadin sequences from Keumkang flour, demonstrating the immunogenic potential of this cultivar. Detailed knowledge about the complement of gliadins accumulated in Keumkang flour provides the background necessary to devise either breeding or biotechnology strategies to improve the functional properties and reduce the adverse health effects of the flour. PMID- 29971079 TI - The CYP71AZ P450 Subfamily: A Driving Factor for the Diversification of Coumarin Biosynthesis in Apiaceous Plants. AB - The production of coumarins and furanocoumarins (FCs) in higher plants is widely considered a model illustration of the adaptation of plants to their environment. In this report, we show that the multiplication of cytochrome P450 variants within the CYP71AZ subfamily has contributed to the diversification of these molecules. Multiple copies of genes encoding this enzyme family are found in Apiaceae, and their phylogenetic analysis suggests that they have different functions within these plants. CYP71AZ1 from Ammi majus and CYP71AZ3, 4, and 6 from Pastinaca sativa were functionally characterized. While CYP71AZ3 merely hydroxylated esculetin, the other enzymes accepted both simple coumarins and FCs. Superimposing in silico models of these enzymes led to the identification of different conformations of three regions in the enzyme active site. These sequences were subsequently utilized to mutate CYP71AZ4 to resemble CYP71AZ3. The swapping of these regions lead to significantly modified substrate specificity. Simultaneous mutations of all three regions shifted the specificity of CYP71AZ4 to that of CYP71AZ3, exclusively accepting esculetin. This approach may explain the evolution of this cytochrome P450 family regarding the appearance of FCs in parsnip and possibly in the Apiaceae. PMID- 29971080 TI - The Role of Malic Enzyme on Promoting Total Lipid and Fatty Acid Production in Phaeodactylum tricornutum. AB - To verify the function of malic enzyme (ME1), the ME1 gene was endogenously overexpressed in Phaeodactylum tricornutum. Overexpression of ME1 increased neutral and total lipid content and significantly increased saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) in transformants, which varied between 23.19 and 25.32% in SFAs and between 49.02 and 54.04% in PUFAs, respectively. Additionally, increased ME1 activity was accompanied by elevated NADPH content in all three transformants, indicating that increased ME1 activity produced additional NADPH comparing with that of WT. These results indicated that ME1 activity is NADP-dependent and plays an important role in the NADPH levels required for lipid synthesis and fatty acid desaturation in P. tricornutum. Furthermore, our findings suggested that overexpression of endogenous ME1 represents a valid method for boosting neutral-lipid yield in diatom. PMID- 29971081 TI - Overexpression of Artemisia annua Cinnamyl Alcohol Dehydrogenase Increases Lignin and Coumarin and Reduces Artemisinin and Other Sesquiterpenes. AB - Artemisia annua is the only medicinal crop that produces artemisinin for malarial treatment. Herein, we describe the cloning of a cinnamyl alcohol dehydrogenase (AaCAD) from an inbred self-pollinating (SP) A. annua cultivar and its effects on lignin and artemisinin production. A recombinant AaCAD was purified via heterogeneous expression. Enzyme assays showed that the recombinant AaCAD converted p-coumaryl, coniferyl, and sinapyl aldehydes to their corresponding alcohols, which are key intermediates involved in the biosynthesis of lignin. Km, Vmax, and Vmax/Km values were calculated for all three substrates. To characterize its function in planta, AaCAD was overexpressed in SP plants. Quantification using acetyl bromide (AcBr) showed significantly higher lignin contents in transgenics compared with wild-type (WT) plants. Moreover, GC-MS based profiling revealed a significant increase in coumarin contents in transgenic plants. By contrast, HPLC-MS analysis showed significantly reduced artemisinin contents in transgenics compared with WT plants. Furthermore, GC-MS analysis revealed a decrease in the contents of arteannuin B and six other sesquiterpenes in transgenic plants. Confocal microscopy analysis showed the cytosolic localization of AaCAD. These data demonstrate that AaCAD plays a dual pathway function in the cytosol, in which it positively enhances lignin formation but negatively controls artemisinin formation. Based on these data, crosstalk between these two pathways mediated by AaCAD catalysis is discussed to understand the metabolic control of artemisinin biosynthesis in plants for high production. PMID- 29971083 TI - The atroviolacea Gene Encodes an R3-MYB Protein Repressing Anthocyanin Synthesis in Tomato Plants. AB - The anthocyanin biosynthetic pathway is well characterized in plants. However, in tomato (Solanum lycopersicum L.) an exhaustive knowledge of its regulation is still lacking. Tomato mutants showing higher levels of anthocyanins in fruits or vegetative tissues, such as Anthocyanin fruit (Aft) or atroviolacea (atv), have been extensively exploited in the attempt to clarify the process. Nevertheless, only candidate genes have been proposed as responsible for such phenotypes. The recessive atv mutation likely represents an allelic variant of a gene introgressed in tomato from wild Solanum species. We performed genome sequencing of atv/atv plants followed by candidate gene analysis, and identified a mutated gene encoding an R3-MYB protein. When overexpressed, this protein abolished anthocyanin production in tomato seedlings and plants, by silencing key regulators and biosynthetic genes of the pathway. The functional analysis of the protein clearly showed that it can negatively interfere with the activation of the anthocyanin biosynthetic pathway mediated by the endogenous MYB-bHLH-WDR (MBW) complexes. In particular, this R3-MYB protein can directly bind the bHLH factors which are part of the MBW complexes, therefore acting as a competitive inhibitor. The R3-MYB protein here described is therefore involved in a feedback mechanism that dampens the production of anthocyanins once activated by endogenous or exogenous stimuli. The atv mutation causes the production of a truncated version of the R3-MYB factor that cannot retain the full potential to inhibit the MBW complexes, thus leading to a constitutively higher production of anthocyanins. PMID- 29971084 TI - The Greenish Flower Phenotype of Habenaria radiata (Orchidaceae) Is Caused by a Mutation in the SEPALLATA-Like MADS-Box Gene HrSEP-1. AB - In Arabidopsis thaliana, the E-class SEPALLATA (SEP) genes are generally expressed across all floral whorls. These genes play fundamental roles in floral organ fate determination during development by interacting with other MADS-box gene products, such as those from A-, B-, and C-class genes. However, the function of SEP genes in orchid remains obscure. Here, we analyzed a mutant orchid cultivar with greenish flowers in Habenaria radiata and found that this phenotype is caused by the absence of SEP function. Wild type H. radiata flowers contain a column and two perianth whorls consisting of three greenish sepals, two white petals, and a lip (labellum). By contrast, the flowers of H. radiata cultivar 'Ryokusei' appear greenish, with three normal sepals in whorl 1, two greenish petals and a lip in whorl 2, and several sepaloid organs and a ventral column in whorls 3 and 4. We isolated two SEP-like genes (HrSEP-1 and HrSEP-2) and two AGAMOUS-like genes (HrAG-1 and HrAG-2) from wild type H. radiata and compared their expression in the wild type vs. the mutant cultivar. HrAG-1 and HrAG-2 were expressed in the column in the wild type, whereas these genes were expressed in the ventral column and in sepaloid organs that had been converted from a column in 'Ryokusei.' HrSEP-1 and HrSEP-2 were expressed in all floral organs in the wild type. However, in the mutant cultivar, HrSEP-2 was expressed in all floral organs, while HrSEP-1 expression was not detected. Thus, we analyzed the genomic structures of HrSEP-1 in the wild type and 'Ryokusei' and identified a retrotransposon-like element in its first exon in 'Ryokusei.' Yeast two-hybrid assays demonstrated that HrSEP-1 interacts with HrDEF, HrAG-1, and HrAG-2. These results indicate that the mutant phenotype of 'Ryokusei' flowers is caused by the loss of function of HrSEP-1. Therefore, this gene plays an important role in column, lip, and petal development in H. radiata flowers. PMID- 29971086 TI - Development of an Artificial Neural Network as a Tool for Predicting the Targeted Phenolic Profile of Grapevine (Vitis vinifera) Foliar Wastes. AB - High performance liquid chromatography data related to the concentrations of 12 phenolic compounds in vegetative parts, measured at four sampling times were processed for developing prediction models, based on the cultivar, grapevine organ, growth stage, total flavonoid content (TFC), total reducing capacity (TRC), and total antioxidant activity (TAA). 12 Artificial neural network (ANN) models were developed with 79 input variables and different number of neurons in the hidden layer, for the prediction of 12 phenolics. The results confirmed that the developed ANN-models (R2 = 0.90 - 0.97) outperform the stepwise regression models (R2 = 0.05 - 0.78). Moreover, the sensitivity of the model outputs against each input variable was computed by using ANN and it was revealed that the key determinant of phenolic concentration was the source organ of the grapevine. The ANN prediction technique represents a promising approach to predict targeted phenolic levels in vegetative parts of the grapevine. PMID- 29971082 TI - Tackling Plant Meiosis: From Model Research to Crop Improvement. AB - Genetic engineering and traditional plant breeding, which harnesses the natural genetic variation that arises during meiosis, will have key roles to improve crop varieties and thus deliver Food Security in the future. Meiosis, a specialized cell division producing haploid gametes to maintain somatic diploidy following their fusion, assures genetic variation by regulated genetic exchange through homologous recombination. However, meiotic recombination events are restricted in their total number and their distribution along chromosomes limiting allelic variations in breeding programs. Thus, modifying the number and distribution of meiotic recombination events has great potential to improve and accelerate plant breeding. In recent years much progress has been made in understanding meiotic progression and recombination in plants. Many genes and factors involved in these processes have been identified primarily in Arabidopsis thaliana but also more recently in crops such as Brassica, rice, barley, maize, or wheat. These advances put researchers in the position to translate acquired knowledge to various crops likely improving and accelerating breeding programs. However, although fundamental aspects of meiotic progression and recombination are conserved between species, differences in genome size and organization (due to repetitive DNA content and ploidy level) exist, particularly among plants, that likely account for differences in meiotic progression and recombination patterns found between species. Thus, tools and approaches are needed to better understand differences and similarities in meiotic progression and recombination among plants, to study fundamental aspects of meiosis in a variety of plants including crops and non-model species, and to transfer knowledge into crop species. In this article, we provide an overview of tools and approaches available to study plant meiosis, highlight new techniques, give examples of areas of future research and review distinct aspects of meiosis in non-model species. PMID- 29971085 TI - Divergent Secondary Metabolites and Habitat Filtering Both Contribute to Tree Species Coexistence in the Peruvian Amazon. AB - Little is known about the mechanisms promoting or limiting the coexistence of functionally divergent species in hyperdiverse tropical tree genera. Density dependent enemy attacks have been proposed to be a major driver for the local coexistence of chemically divergent congeneric species. At the same time, we expect local soil conditions to favor the coexistence of species sharing similar functional traits related to resource use strategies, while environmental heterogeneity would promote the diversity of these traits at both local and large spatial scales. To test how these traits mediate species coexistence, we used functional trait data for 29 species from the tree genus Protium (Burseraceae), collected in 19 plots (2 ha each) in the Peruvian Amazon. We characterized the presence-absence of 189 plant secondary metabolites (SM) for 27 of these species, and 14 functional traits associated with resource use strategies (RUT) for 16 species. Based on these data, we found that SM were significantly more dissimilar than null expectations for species co-occurring within plots, whereas RUT were significantly more similar. These results were consistent with the hypothesis that density-dependent enemy attacks contribute to the local coexistence of congeneric species displaying divergent chemical defenses, whereas local habitat conditions filter species with similar RUT. Using measurements of nine soil properties in each plot, we also found a significant turnover of RUT traits with increasing dissimilarity of soil texture and nutrient availabilities, providing support for the hypothesis that soil heterogeneity maintains functional diversity at larger spatial scales (from 500 m up to ca. 200 km) in Protium communities. Our study provides new evidence suggesting that density-dependent enemy attacks and soil heterogeneity both contribute to maintaining high species richness in diverse tropical forests. PMID- 29971087 TI - Evidence for the Involvement of Fatty Acid Biosynthesis and Degradation in the Formation of Insect Sex Pheromone-Mimicking Chiloglottones in Sexually Deceptive Chiloglottis Orchids. AB - Hundreds of orchid species secure pollination by sexually luring specific male insects as pollinators by chemical and morphological mimicry. Yet, the biochemical pathways involved in the synthesis of the insect sex pheromone mimicking volatiles in these sexually deceptive plants remain poorly understood. Here, we explore the biochemical pathways linked to the chemical mimicry of female sex pheromones (chiloglottones) employed by the Australian sexually deceptive Chiloglottis orchids to lure their male pollinator. By strategically exploiting the transcriptomes of chiloglottone 1-producing Chiloglottis trapeziformis at distinct floral tissues and at key floral developmental stages, we identified two key transcriptional trends linked to the stage- and tissue dependent distribution profiles of chiloglottone in the flower: (i) developmental upregulation of fatty acid biosynthesis and beta-oxidation genes such as KETOACYL ACP SYNTHASE, FATTY ACYL-ACP THIOESTERASE, and ACYL-COA OXIDASE during the transition from young to mature buds and flowers and (ii) the tissue-specific induction of fatty acid pathway genes in the callus (the insectiform odor producing structure on the labellum of the flower) compared to the labellum remains (non-odor-producing) regardless of development stage of the flower. Enzyme inhibition experiments targeting KETOACYL-ACP SYNTHASE activity alone in three chiloglottone-producing species (C. trapeziformis, C. valida, and C. aff. valida) significantly inhibited chiloglottone biosynthesis up to 88.4% compared to the controls. These findings highlight the role of coordinated (developmental stage- and tissue-dependent) fatty acid gene expression and enzyme activities for chiloglottone production in Chiloglottis orchids. PMID- 29971088 TI - Janus-Faced Nature of Light in the Cold Acclimation Processes of Maize. AB - Exposure of plants to low temperature in the light may induce photoinhibitory stress symptoms, including oxidative damage. However, it is also known that light is a critical factor for the development of frost hardiness in cold tolerant plants. In the present work the effects of light during the cold acclimation period were studied in chilling-sensitive maize plants. Before exposure to chilling temperature at 5 degrees C, plants were cold acclimated at non-lethal temperature (15 degrees C) under different light conditions. Although exposure to relatively high light intensities during cold acclimation caused various stress symptoms, it also enhanced the effectiveness of acclimation processes to a subsequent severe cold stress. It seems that the photoinhibition induced by low temperature is a necessary evil for cold acclimation processes in plants. Greater accumulations of soluble sugars were also detected during hardening at relatively high light intensity. Certain stress responses were light-dependent not only in the leaves, but also in the roots. The comparison of the gene expression profiles based on a microarray study demonstrated that the light intensity is at least as important a factor as the temperature during the cold acclimation period. Differentially expressed genes were mainly involved in most of assimilation and metabolic pathways, namely photosynthetic light capture via the modification of chlorophyll biosynthesis and the dark reactions, carboxylic acid metabolism, cellular amino acid, porphyrin or glutathione metabolic processes, ribosome biogenesis and translation. Results revealed complex regulation mechanisms and interactions between cold and light signalling processes. PMID- 29971089 TI - High Fructose Intake During Pregnancy in Rats Influences the Maternal Microbiome and Gut Development in the Offspring. AB - Studies in pregnant women indicate the maternal microbiome changes during pregnancy so as to benefit the mother and fetus. In contrast, disruption of the maternal microbiota around birth can compromise normal bacterial colonisation of the infant's gastrointestinal tract. This may then inhibit development of the gut so as to increase susceptibility to inflammation and reduce barrier function. The impact of modulating fructose intake on the maternal microbiome through pregnancy is unknown, therefore we examined the effect of fructose supplementation on the maternal microbiome together with the immediate and next generation effects in the offspring. Wistar rat dams were divided into control and fructose fed groups that received 10% fructose in their drinking water from 8 weeks of age and throughout pregnancy (10-13 weeks). Maternal fecal and blood samples were collected pre-mating (9 weeks) and during early (gestational day 4-7) and late pregnancy (gestational day 19-21). We show supplementation of the maternal diet with fructose appears to significantly modulate the maternal microbiome, with a significant reduction in Lactobacillus and Bacteroides. In offspring maintained on this diet up to pregnancy and term there was a reduction in gene expression of markers of gut barrier function that could adversely affect its function. An exacerbated insulin response to pregnancy, reduced birth weight, but increased fat mass was also observed in these offspring. In conclusion dietary supplementation with fructose modulates the maternal microbiome in ways that could adversely affect fetal growth and later gut development. PMID- 29971090 TI - Differential Integration of Transcriptome and Proteome Identifies Pan-Cancer Prognostic Biomarkers. AB - High-throughput analysis of the transcriptome and proteome individually are used to interrogate complex oncogenic processes in cancer. However, an outstanding challenge is how to combine these complementary, yet partially disparate data sources to accurately identify tumor-specific gene products and clinical biomarkers. Here, we introduce inteGREAT for robust and scalable differential integration of high-throughput measurements. With inteGREAT, each data source is represented as a co-expression network, which is analyzed to characterize the local and global structure of each node across networks. inteGREAT scores the degree by which the topology of each gene in both transcriptome and proteome networks are conserved within a tumor type, yet different from other normal or malignant cells. We demonstrated the high performance of inteGREAT based on several analyses: deconvolving synthetic networks, rediscovering known diagnostic biomarkers, establishing relationships between tumor lineages, and elucidating putative prognostic biomarkers which we experimentally validated. Furthermore, we introduce the application of a clumpiness measure to quantitatively describe tumor lineage similarity. Together, inteGREAT not only infers functional and clinical insights from the integration of transcriptomic and proteomic data sources in cancer, but also can be readily applied to other heterogeneous high throughput data sources. inteGREAT is open source and available to download from https://github.com/faryabib/inteGREAT. PMID- 29971091 TI - Editorial: The Least Cost Path From Landscape Genetics to Landscape Genomics: Challenges and Opportunities to Explore NGS Data in a Spatially Explicit Context. PMID- 29971092 TI - Quantitative Evaluation of Toxic Polyglycine Biosynthesis and Aggregation in Cell Models Expressing Expanded CGG Repeats. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by expanded CGG (CGGexp) trinucleotides in the 5'UTR of the FMR1 gene encoding fragile X mental retardation protein (FMRP). The patients, with the number of the repeats ranging from 55 to 200, show specific manifestation of clinical symptoms that include intention tremor, gait ataxia, cognitive deficits, and brain atrophy. Accumulation of toxic polyglycine (FMRpolyG), a by-product of the CGGexp repeat-associated non-ATG (RAN) translation, is considered to be one of the main factors triggering neurodegenerative processes in FXTAS patients. Nevertheless, the nature of the FMRpolyG-induced cell damage, especially in the context of its soluble and inclusion-associated forms, is still elusive. Targeting either biosynthesis, cellular stability or aggregation capacity of toxic FMRpolyG could be considered as a potential therapeutic strategy for FXTAS. Therefore, we tested a variety of quantitative methods based on forced expression of genetic constructs carrying CGGexp repeats in the context of the FMR1 5'UTR fused to GFP, mCherry or Firefly luciferase gene in or out of frame to the polyglycine encoding sequence. We show that FMRpolyG translation either from native or an AUG-induced start codon as well as the translation yield of the FMRP open reading frame equivalent located downstream of the CGGexp element can be effectively estimated using fluorescence microscopy, flow cytometry or luciferase assay. We also quantitatively estimated soluble fraction and insoluble form of FMRpolyG aggregated in foci using an electrophoretic separation of cell lysates and fluorescence microscopy, respectively. Importantly, we show that dependent on a fusion tag, FMRpolyG has a different potential for aggregate formation. Our established protocols enable sensitive tracking of FMRP and FMRpolyG quantitative and qualitative changes after treatment with potential therapeutic agents for FXTAS. Furthermore, they can be modified for application to other RAN translation- and aggregation-related diseases. PMID- 29971093 TI - Genetic Architecture of Feeding Behavior and Feed Efficiency in a Duroc Pig Population. AB - Increasing feed efficiency is a major goal of breeders as it can reduce production cost and energy consumption. However, the genetic architecture of feeding behavior and feed efficiency traits remains elusive. To investigate the genetic architecture of feed efficiency in pigs, three feeding behavior traits (daily feed intake, number of daily visits to feeder, and duration of each visit) and two feed efficiency traits (feed conversion ratio and residual feed intake) were considered. We performed genome-wide association studies (GWASs) of the five traits using a population of 1,008 Duroc pigs genotyped with an Illumina Porcine SNP50K BeadChip. A total of 9 genome-wide (P < 1.54E-06) and 35 suggestive (P < 3.08E-05) single nucleotide polymorphisms (SNPs) were detected. Two pleiotropic quantitative trait loci (QTLs) on SSC 1 and SSC 7 were found to affect more than one trait. Markers WU_10.2_7_18377044 and DRGA0001676 are two key SNPs for these two pleiotropic QTLs. Marker WU_10.2_7_18377044 on SSC 7 contributed 2.16 and 2.37% of the observed phenotypic variance for DFI and RFI, respectively. The other SNP DRGA0001676 on SSC 1 explained 3.22 and 5.46% of the observed phenotypic variance for FCR and RFI, respectively. Finally, functions of candidate genes and gene set enrichment analysis indicate that most of the significant pathways are associated with hormonal and digestive gland secretion during feeding. This study advances our understanding of the genetic mechanisms of feeding behavior and feed efficiency traits and provide an opportunity for increasing feeding efficiency using marker-assisted selection or genomic selection in pigs. PMID- 29971095 TI - Instant Feedback Rapid Prototyping for GPU-Accelerated Computation, Manipulation, and Visualization of Multidimensional Data. AB - Objective: We have created an open-source application and framework for rapid GPU accelerated prototyping, targeting image analysis, including volumetric images such as CT or MRI data. Methods: A visual graph editor enables the design of processing pipelines without programming. Run-time compiled compute shaders enable prototyping of complex operations in a matter of minutes. Results: GPU acceleration increases processing the speed by at least an order of magnitude when compared to traditional multithreaded CPU-based implementations, while offering the flexibility of scripted implementations. Conclusion: Our framework enables real-time, intuition-guided accelerated algorithm and method development, supported by built-in scriptable visualization. Significance: This is, to our knowledge, the first tool for medical data analysis that provides both high performance and rapid prototyping. As such, it has the potential to act as a force multiplier for further research, enabling handling of high-resolution datasets while providing quasi-instant feedback and visualization of results. PMID- 29971094 TI - Editorial: Metal Biology Takes Flight: The Study of Metal Homeostasis and Detoxification in Insects. PMID- 29971096 TI - Estimation of the Craniectomy Surface Area by Using Postoperative Images. AB - Decompressive craniectomy (DC) is a neurosurgical procedure performed to relieve the intracranial pressure engendered by brain swelling. However, no easy and accurate method exists for determining the craniectomy surface area. In this study, we implemented and compared three methods of estimating the craniectomy surface area for evaluating the decompressive effort. We collected 118 sets of preoperative and postoperative brain computed tomography images from patients who underwent craniectomy procedures between April 2009 and April 2011. The surface area associated with each craniectomy was estimated using the marching cube and quasi-Monte Carlo methods. The surface area was also estimated using a simple AC method, in which the area is calculated by multiplying the craniectomy length (A) by its height (C). The estimated surface area ranged from 9.46 to 205.32 cm2, with a median of 134.80 cm2. The root-mean-square deviation (RMSD) between the marching cube and quasi-Monte Carlo methods was 7.53 cm2. Furthermore, the RMSD was 14.45 cm2 between the marching cube and AC methods and 12.70 cm2 between the quasi-Monte Carlo and AC methods. Paired t-tests indicated no statistically significant difference between these methods. The marching cube and quasi-Monte Carlo methods yield similar results. The results calculated using the AC method are also clinically acceptable for estimating the DC surface area. Our results can facilitate additional studies on the association of decompressive effort with the effect of craniectomy. PMID- 29971097 TI - Prevalence and Risk Factors Associated with Injurious Falls among Community Dwelling Older Adults in Indonesia. AB - Objective: To assess the prevalence and health correlates of fall-related injury in a national population-based community-dwelling sample of older Indonesians. Methods: Participants were 6698 older adults, 50 years and older (median age 58.0 years, IQR=11.0, and age range of 50-101 years), who took part in in the Indonesia Family Life Survey (IFLS-5) in 2014-15. They provided information about sociodemographic, various health variables, including a falling down and received treatment history in the last two years. Results: Overall, 12.8% had one or more fall-related injuries in the past two years, 14.0% among women and 11.5% among men, 7.6% had a single fall, and 5.2% multiple fall-related injuries in the past two years. In multivariable logistic regression models, having two or more chronic conditions, urinary problems, and functional disability was independently associated with multiple fall-related injuries in the past two years in both sexes. Sex-specific risk factors were former tobacco use, having or having had a cataract, sleep disturbance, and sleep impairment in men and poorer economic background, depression symptoms, and low cognitive functioning in women. Conclusion: A significant proportion of older adults in Indonesia have fall related injury. Several homogenous between the sexes and sex-specific risk factors for fall-related injury were identified that can help in designing fall prevention strategies. PMID- 29971098 TI - Patient- and Caregiver-Related Factors Associated with Caregiver Assessed Global Deterioration Scale Scoring in Demented Patients. AB - Background: Informant-based rating scales are widely used in dementia but patients' and caregivers' features influence the final scoring. We aimed to evaluate the role of patient- and caregiver-related factors in a caregiver rated Global Deterioration Scale (GDS) score in a sample of Greek patients with dementia. Methods: We included 194 patients with dementia and 194 caregivers/family relatives; Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Katz Index of Activities of Daily Living (K IADL) were administered to (a) patients and Center for Epidemiologic Studies Depression (CES-D) Scale; Zarit Burden Interview (ZBI) to (b) caregivers. Participants' demographics and patients' and caregivers' characteristics were entered into a 3-block regression analysis. Results: The final model explained 55% of the total variance of the caregiver assessed GDS score. The following variables significantly contributed to the final model: MMSE (beta=-0.524); K IADL (beta=-0.264); ZBI (beta=0.145). Conclusion: We herein confirm the contribution of patients' cognitive and functional status and caregivers' burden in caregiver rated GDS scoring irrespective of demographic-related characteristics. PMID- 29971099 TI - Predictors of Mortality in Scrub Typhus Infection Requiring Intensive Care Admission in Tertiary Healthcare Centre of Nepal. AB - Introduction: This study aimed to explore the predictors of mortality from scrub typhus infection in patients requiring intensive care unit (ICU) admission. Materials and Methods: A retrospective study was conducted on 120 patients with serum ELISA IgM positive for scrub typhus (optical density >= 0.5) admitted at the medical ICU of Chitwan Medical College Teaching Hospital between April 2016 and September 2017. Data was extracted from patient medical records and electronic database of the hospital. The outcome measurement was mortality (Yes/No) due to the infection. A multivariate binary logistic regression analysis (p < 0.10) using potential variables from bivariate analysis (p < 0.25) was adjusted to predict the mortality. Results: The mortality rate was 20% (24/120). Factors associated with mortality, as found using bivariate analysis, were heart rate > 100/minute (p < 0.001), systolic blood pressure < 90 mmHg (p = 0.025), diastolic blood pressure < 60 mmHg (p = 0.032), serum creatinine > 1.4 mg/dl (p < 0.001), acute kidney injury requiring dialysis (p = 0.029), acute respiratory distress syndrome (p < 0.001), and shock requiring vasopressor (p < 0.001). Regression analysis showed age (odds ratio [OR] = 1.063; 95% CI = 1.010-1.118; p = 0.019) and serum creatinine (OR = 1.063; 95% CI = 1.010-1.118; p = 0.019) as significant predictors of poor outcome. Conclusion: Older age and high serum creatinine were found to be independent predictors of poor outcome in patients with scrub typhus admitted in medical ICU. PMID- 29971100 TI - Pregnancy Ketonemia and Development of the Fetal Central Nervous System. AB - Glucose is the major source of energy for the human brain which in turn uses ketone bodies as a supplement for energy deficit in glucose cell deficiency conditions. Pregnancy complicated by gestational diabetes is a condition associated with significantly increased risk of ketonemia development. The data available proves a changing influence of ketones on the central nervous system during fetal life and in adults as well. Ketone bodies freely pass through the placenta. They can affect fetal growth and organ damage development, especially the central nervous system. As agreed in the current recommendation of the diabetes associations, it is not obligatory for the attending doctor to conduct a routine inspection of ketone bodies during diabetes treatment in pregnancy. This article is a literature review of ketones' effect on the central nervous system and an attempt to initiate discussion whether we should consider including ketonemia assessment into the standard care package for pregnant women with diabetes and begin some research on the explanation of its influence on fetal development. PMID- 29971101 TI - Adipokines in Semen: Physiopathology and Effects on Spermatozoas. AB - Adipokines are secreted by adipose tissue and could be the link between obesity and infertility. Different studies investigated the involvement of adipokines in reproductive functions but only a few have looked into the male part. This review assesses adipokine functions on male reproductive parameters. Adiponectin seems to have a positive effect on sperm parameters, whereas other adipokines such as resistin or chemerin would have a rather deleterious effect on spermatogenesis. Semen parameters seem to be impacted when resistin and chemerin are increased: indeed, there is a decrease of sperm motility. Sperm morphology is improved when adiponectin is increased. The most studied adipokine, leptin, has a dual effect with a positive effect on sperm at physiological levels and a negative one for high seminal concentrations. Many semen parameters and fertility itself are disturbed according to semen adipokine levels, even if it is not the only interfering element. Taken together, adipokines are found in human and animal semen and most of them or their receptors are expressed in male genital tract. Although the pathophysiological role of adipokines in semen is not clearly elucidated, the adipokines could influence sperm functionality and could be potential biomarkers of male fertility. PMID- 29971103 TI - Diagnostic Values of Free Triiodothyronine and Free Thyroxine and the Ratio of Free Triiodothyronine to Free Thyroxine in Thyrotoxicosis. AB - Background: The results of previous studies on the usefulness of free triiodothyronine (FT3) to free thyroxine (FT4) are controversial. We investigated the usefulness of FT3, FT4, and FT3/FT4 ratio in differentiating Graves' disease (GD) from destructive thyroiditis. Methods: A total of 126 patients with untreated GD, 36 with painless thyroiditis, 18 with painful subacute thyroiditis, and 63 healthy controls, were recruited. The levels of FT3 and FT4 and the FT3/FT4 ratios for the different etiologies of thyrotoxicosis were evaluated separately by receiver operating characteristic (ROC) curve analysis. The expression levels of type 1 and type 2 deiodinase (DIO1 and DIO2) in thyroid tissues were also investigated. Results: The optimal cut-off values were 7.215 pmol/L for FT3, 21.71 pmol/L for FT4, and 0.4056 for the FT3/FT4 ratio. The specificity and positive predictive value of the FT3/FT4 ratio were highest for values > 0.4056. DIO1 mRNA expression was significantly higher in the thyroid tissue of patients with GD (P = 0.013). Conclusions: We demonstrated that the FT3/FT4 ratio was useful in differentiating GD from destructive thyroiditis. In addition, a relatively high expression of type 1 deiodinase in the thyroid might be responsible for the high FT3/FT4 ratio in patients with GD. PMID- 29971104 TI - Complex Karyotype in Hematological Diseases: A 6-Year Single Centre Study from Pakistan. AB - Background: Most of the hematological disorders are heterogenous with regard to morphology, immunophenotype, and genetic rearrangements. Multiple recurrent chromosomal aberrations have been identified by conventional cytogenetic analysis, which is now widely recognized as one of the most important diagnostic and prognostic determinants in these patients. Though rarer, complex karyotype has been associated with worst prognosis. Materials and Methods: A total of 1185 bone marrow or peripheral blood cytogenetics samples were taken with different hematological diseases. They included both benign and malignant disease entities. In each case, cells were cultured and conventional cytogenetic analysis was performed. Results: Among 1185 subjects, 41 (3.4%) patients possessed complex cytogenetic abnormalities. Out of these 41, 33 (80%) were males. The mean age was 37 years (median age 39 years). Myelodysplastic syndromes had the most numbers of complex karyotypes (8%), followed by acute myeloid leukemia (7%) and acute lymphoblastic leukemia (4%). Also we found few patients with acute promyelocytic leukemia, aplastic anemia , chronic myeloid leukemia, and diffuse large B cell Lymphoma possessing complex karyotype. Frequencies of different cytogenetic abnormalities were assessed with respect to disease as well as independently. Trisomy 21 was the most common chromosomal abnormality found in 28% of patients. Conclusion: Complex karyotype was most frequently associated with myelodysplastic syndromes and acute myeloid leukemia. Trisomy 21 and deletion 5q were the commonest cytogenetic abnormalities found. We also assessed complex karyotype in benign diseases and detected one patient of aplastic anemia with complex karyotype. This is the first study highlighting the presence of complex karyotypes in hematological disorders in our region. PMID- 29971102 TI - Role of Lipotoxicity and Contribution of the Renin-Angiotensin System in the Development of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes' size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS. PMID- 29971105 TI - Epimutation and Cancer: Carcinogenesis Viewed as Error-Prone Inheritance of Epigenetic Information. AB - The epimutation concept, that is, malignancy is a result of deranged patterns of gene expression due to defective epigenetic control, proposes that in the majority of adult cancers the primary (initiating) lesion adversely affects the mechanism of vertical transmission of the epigenetic pattern existing in the stem cells of differentiated tissue. Such an error-prone mechanism will result in deviant gene expression capable of accumulation at each mitosis of the affected stem cell clone. It is argued that a proportion of these proliferation products will express combinations of genes which endow them with malignant properties, such as the ability to transgress tissue boundaries and migrate to distant locations. Since the likelihood of this occurrence is dependent on the proliferation of cells manifesting the defective epigenetic transmission, the theory predicts that cancer incidence will be strongly influenced by factors regulating the turnover rate of the stem cells of the tissue in question. Evidence relating to this stipulation is examined. In addition, it would be anticipated on the basis of the selection of genes involved that the susceptibility to malignant transformation will vary according to the tissue of origin and this is also discussed. PMID- 29971106 TI - Effect of Thermocycling, Teeth, and Polymerization Methods on Bond Strength Teeth Denture Base. AB - Objective: To evaluate the shear bond strength between different artificial teeth and denture base polymerized by two polymerization methods submitted to thermocycling. Materials and Methods: Two acrylic resins were selected according to the polymerization method (water-bath and microwave), and four different artificial teeth (Biotone, Dentsply; Trilux, Vipi Dent; Premium 8, Heraeus Kulzer; Soluut PX, Yamahachi) were also tested. The polymerization of the acrylic resin was performed by using conventional cycle (8 h at 74 degrees C) in water bath and using two cycles (20 min at 270 W + 5 min at 360 W) by the microwave method. The shear bond strength was evaluated after 24 h of water storage at 37 degrees C (immediately) and after the thermocycling test (5,000 cycles, 5-55 degrees C). The shear bond strength (n=10) was performed using a universal testing machine (Instron 4411) at a crosshead speed of 1.0 mm/min. Modes of failures were classified as cohesive and adhesive. The data (MPa) were statistically analyzed by three-way ANOVA, and the mean values were compared by the Tukey test (alpha = 0.05). Results: In general, the polymerization by microwave showed the highest shear bond strength values, and Trilux artificial teeth had the lowest bond strength values (p < 0.05). Thermocycling did not affect the shear bond strength (p < 0.05). There was a predominance of cohesive failures for all groups. Conclusions: The chemical composition of the artificial teeth affects the bond strength, and the microwave method is preferable to perform the acrylic resin polymerization. PMID- 29971107 TI - Three-Dimensional Accuracy of Digital Impression versus Conventional Method: Effect of Implant Angulation and Connection Type. AB - Purpose: The aim of this in vitro study was to compare the accuracy of different implant impression techniques of the maxillary full arch with tilted implants of two connection types. Materials and Methods: Two maxillary edentulous acrylic resin models with two different implant connections (internal or external) served as a reference model. Each model had two anterior straight and two posterior angulated implants. Ninety impressions were made using an intraoral scanner (Trios 3Shape) with scan bodies for digital impression (groups DII and DIE), a custom open tray with additional silicone for the conventional direct group (groups CDI and CDE), and a custom closed tray with additional silicone for the conventional indirect group (groups CII and CIE) from both internal and external models, respectively. A coordinate-measuring machine (CMM) was used to measure linear and angular displacement for conventional specimens. For digital groups, an optical CMM was used to scan the reference model. STL data sets from the digital specimen were superimposed on STL reference data sets to assess angular and linear deviations. Data were analyzed with three-way ANOVA and t-test at alpha=0.05. Results: There were significant angular and linear distortion differences among three impression groups (P < 0.001), angular distortion differences between internal and external connections (P < 0.001), and between straight and tilted implants for either linear (P < 0.001) or angular (P=0.002) distortion. The type of the connection and implant angle did not have any effect on linear and angular distortion of the digital technique (p > 0.05). Minimum angular and linear distortion was seen for tilted implants in DII and DIE groups (0.36 degrees +/- 0.37 and 0.16 +/- 0.1 mm). Conclusion: Impression techniques (digital versus conventional) affected the transfer accuracy. Digital techniques demonstrated superior outcome in comparison with conventional methods, and the direct technique was better than the indirect conventional technique. Connection type and implant angulation were other factors that influenced accuracy. However, when digital impression was applied, accuracy was not affected by the type of connection and angulation. PMID- 29971108 TI - Secondary Bleedings in Oral Surgery Emergency Service: A Cross-Sectional Study. AB - Introduction: Bleeding after dental surgery is still a common cause for emergency presentation in patients using anticoagulants. Our aim was to analyze pertinent characteristic features on the one hand and to bare existing problems in handling on the other. Materials and Methods: The study included 76 patients. We documented basic data, anticoagulant medication, type of surgery, and tooth socket sutures in respective patients. Results: The vast majority of patients took a coumarin derivative (41) and acetylsalicylic acid (27). Nine (12%) of the patients had to be hospitalized due to ongoing bleeding despite local haemostyptic steps and/or circulatory dysregulation. Most patients could be successfully treated in outpatient settings. No statistically significant correlation between bleeding, level of INR value, number of extracted teeth, and sewed alveoli could be shown. Sixty-five percent of cases with tooth extractions did not have suture of tooth sockets. Eighty-seven percent of the patients denied being informed about possible self-treatment options by their surgeon/dentist, and none of the patients got presurgical-fabricated bandage plate(s). Conclusions: Patients taking coumarin derivative currently, furthermore, represent the biggest anticoagulant after-bleeding group in dentoalveolar surgery. The major part of after-bleedings (90%) can be handled in an outpatient setting with simplest surgical interventions. Unfortunately, the biggest part of the patient collective got no suture, no prefabricated dental bandage plate(s), and no explanation by their dentist how to handle in case of after-bleeding. Therefore, dental practitioners should furthermore get enlightenment on how to prevent after-bleeding situations. PMID- 29971109 TI - Impact of Malocclusions on the Oral Health-Related Quality of Life of Early Adolescents in Ndola, Zambia. AB - The study aimed to assess the prevalence of malocclusions and its impact on oral health-related quality of life (OHRQoL) among early adolescents in Ndola, Zambia. It used a random sample of 384 primary school children aged 12-14 years. The Child Oral Health Impact Profile-Short Form 19 (COHIP-SF19) was used to assess OHRQoL, and the Dental Aesthetic Index (DAI) was used to examine dentofacial anomalies. The chi-square test was used to study whether there was a statistically significant association between variables and multivariate logistic regression for the influence of sociodemographic and malocclusions on OHRQoL. Statistical significance was set at p < 0.05. Participants' sociodemographics were 53.6% female, 41.7% aged 13 years, and 43.5% from grade six. The overall reported impact on OHRQoL was 11.7%, which was significant (p < 0.001) by age and sex, and higher in females than males. The overall prevalence of malocclusions was 27.9%, which was significant (p=0.005) by sex, and higher in males than females. Children with malocclusions reported significant (p < 0.001) negative oral health impact compared to the children without malocclusions. Spacing, diastema, and crowding were most prevalent malocclusions that showed clear inverse association with OHRQoL. The study findings provide indications that malocclusions are negatively associated with OHRQoL among Zambian early adolescents. PMID- 29971110 TI - The Efficacy of Graphene Foams for Culturing Mesenchymal Stem Cells and Their Differentiation into Dopaminergic Neurons. AB - The implantation of stem cells in vivo is the ideal approach for the restoration of normal life functions, such as replenishing the decreasing levels of affected dopaminergic (DA) neurons during neurodegenerative disease conditions. However, combining stem cells with biomaterial scaffolds provides a promising strategy for engineering tissues or cellular delivery for directed stem cell differentiation as a means of replacing diseased/damaged tissues. In this study, mouse mesenchymal stem cells (MSCs) were differentiated into DA neurons using sonic hedgehog, fibroblast growth factor, basic fibroblast growth factor, and brain derived neurotrophic factor, while they were cultured within collagen-coated 3D graphene foams (GF). The differentiation into DA neurons within the collagen coated GF and controls (collagen gels, plastic) was confirmed using beta-III tubulin, tyrosine hydroxylase (TH), and NeuN positive immunostaining. Enhanced expression of beta-III tubulin, TH, and NeuN and an increase in the average neurite extension length were observed when cells were differentiated within collagen-coated GF in comparison with collagen gels. Furthermore, these graphene based scaffolds were not cytotoxic as MSC seemed to retain viability and proliferated substantially during in vitro culture. In summary, these results suggest the utility of 3D graphene foams towards the differentiation of DA neurons from MSC, which is an important step for neural tissue engineering applications. PMID- 29971111 TI - Noncoding RNAs and Stem Cell Function and Therapy. PMID- 29971112 TI - Early Infant Feeding Practices as Possible Risk Factors for Immunoglobulin E Mediated Food Allergies in Kuwait. AB - Objective: Early feeding and infant exposures have been suggested as potential risk factors for immunoglobulin E- (IgE-) mediated food allergy (FA). We aimed to evaluate the association between IgE-mediated FA in children and early exposures including the child's nutritional status, breastfeeding and its duration, the age at which the solid food was first introduced, antibiotic exposure during the first year of life, and the child's vitamin D status during infancy. Design: A case-control study. Setting and Subjects: Children aged 0-13 years were recruited from pediatric allergy and immunology clinics (PAICs) located at major government hospitals in Kuwait (total FA cases: n = 100; boys = 67%), and healthy controls (n = 100, boys 55%) were recruited from various vaccination units at primary healthcare centers. Results: Cow's milk allergy was the most common type of FA. FA status was independently associated with the early exposures of exclusive breastfeeding (aOR = 15.55 (3.26-74.19), p = 0.001), vitamin D deficiency or insufficiency during infancy (aOR = 5.42 (1.92-15.30), p = 0.001), and antibiotic exposure during the first year of life (aOR = 5.00 (1.58-15.84), p = 0.006). Conclusions: FA is highly prevalent among children in Kuwait, and our data indicate that early nutrition-related and antibiotic exposures are associated with FA risk. PMID- 29971113 TI - Diarrhea Prevalence and Sociodemographic Factors among Under-Five Children in Rural Areas of North Gondar Zone, Northwest Ethiopia. AB - Background: Diarrheal disease remains one of the principal causes of morbidity and mortality in infants and children in developing countries, including Ethiopia. Risk factors for diarrhea vary by settings and have important implications for developing intervention strategies to reduce the burden of the disease. Thus, the aim of this study was to assess diarrhea prevalence and sociodemographic factors among under-five children in rural areas of North Gondar Zone. Methods: A community-based cross-sectional study was conducted from April to June 2016 among 736 randomly selected households with one child under five years old. A structured questionnaire was used for collecting information on sociodemographic characteristics and diarrheal occurrence. Data was analyzed using SPSS version 20. The bivariate and multivariable logistic regression analysis were used to determine the association between risk factors and diarrheal occurrence, and a p value < 0.05 was taken as statistically significant. Results: A total of 736 under-five children and their respondents were enrolled during the study period. Almost all respondents were biological mothers 96.4% (709/736), married 94.2% (693/736), and house wives 86% (632/736). The overall prevalence of diarrheal disease among under-five children was 22.1% (163/743). Of these, children with age group of less than one year old, 7.7 % (57/736), were commonly infected with diarrheal diseases. Children less than or equal to one year [AOR=1.82, 95% CI= (1.39, 4.63)], guardians [AOR=4.37, 95% CI= (1.73, 11.1)], and children with no breast feeding practice [AOR=3.13, 95% CI= (1.62, 6.03)] were the major risk factors for the occurrence of diarrhea. Conclusion: Childhood diarrhea remains an important health concern in the study area. Occurrence of diarrhea was statistically associated with child age less than or equal to one year, educational status of mother/guardians, and breast feeding. To minimize the magnitude childhood diarrhea, various designing and implementing strategies, such as health education, child care, breast feeding, and weaning practice, integrated with the existing national health extension are quite essential. PMID- 29971114 TI - Investigating Youth Sport Coach Perspectives of an Asthma Education Module. AB - Physical activity can reduce symptoms and improve wellbeing in people who have asthma, and organized sport is one way for children and youth with asthma to engage in exercise. While asthmatic youth may experience a number of barriers to sport participation, healthy physical and social sport environments supported by coaches can help asthmatic youth athletes maintain long-term engagement in activity. This paper reports results of an assessment of an online coach education tool related to air quality, physical activity, and allergic disease (e.g., asthma). Focus groups with youth team sport coaches in southern Ontario (n = 12 participants) were conducted to explore how users experience the module and short- and medium-term outcomes of implementation. Although coaches perceive the module as relevant, it is considered less valuable in certain contexts (e.g., indoor environments) or when compared with other coach education (e.g., tactical). Although broad asthma management behaviours (e.g., athlete medical forms) were recognized, specific module-identified prevention and management techniques (e.g., the Air Quality Health Index) were less frequently described. Ensuring environment and health coach education emphasizes athlete performance while reducing risk is critical to promoting module application and providing safe and enjoyable youth team sport spaces. PMID- 29971115 TI - Carboxyhaemoglobin Levels among Traders Exposed to Vehicular Emissions in Three Motor Parks in Ibadan, Nigeria. AB - Carbon monoxide (CO) remains a leading cause of work-related chemical poisoning. Vehicular emissions are the primary daily ambient source of CO in urban Nigerian motor parks, where there have been few human exposure studies. Using a cross sectional comparative design, we assessed carboxyhaemoglobin levels (% COHb), a biomarker of CO exposure, among traders at three motor parks (AMP, IMP, and NMP) and other traders (nonmotor park workers) in Ibadan, Nigeria, using a noninvasive pulse CO-dosimeter (Rad 57). Ninety-three traders were proportionally allocated between motor parks; 93 other traders were selected based on specific study inclusion criteria. Mean ages of motor park traders and other traders were comparable, 37.8 +/- 11.1 and 38.7 +/- 9.6, respectively. Mean % COHb for traders (range 3-22) at AMP, IMP, and NMP was 11.2 +/- 3.8, 11.6 +/- 3.1, and 12.2 +/- 3.3, respectively, while mean % COHb for other traders was about three times lower, 4.1 +/- 1.7 (range 2-8). Overall, mean % COHb for motor park traders, 11.7 +/- 3.3, was also significantly higher than for other traders (p < 0.05). Nevertheless, mean % COHb for both groups exceeded the current World Health Organization guideline, 2.5%. This study suggested that motor park traders have higher % COHb and thus are highly susceptible to exposure and more vulnerable to known risks of adverse health effects from exposure to CO. PMID- 29971116 TI - Minimum Intracanal Dressing Time of Triple Antibiotic Paste to Eliminate Enterococcus Faecalis (ATCC 29212) and Determination of Minimum Inhibitory Concentration and Minimum Bactericidal Concentration: An Ex Vivo Study. AB - Objectives: Enterococcus faecalis (E. faecalis) is the most commonly isolated microorganism from teeth with postoperative infection. Triple antibiotic paste (TAP) has the ability to eradicate microorganisms from the root canal system when used as an intracanal medicament. The aim of this study was to determine the minimum duration of application of TAP required for elimination of E. faecalis from the root canal system and its minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) in an ex-vivo model. Materials and Methods: Root canals of 34 extracted human single canal teeth were inoculated with E. Faecalis after instrumentation, and then 4 g of TAP (ciprofloxacin, metronidazole and doxycycline) was mixed with 4.5 mL of saline and applied as intracanal medicament. The teeth were sectioned longitudinally and dentin chips were collected and evaluated to determine the count of bacterial colonies. Micro dilution broth test was used to assess the MIC and MBC of TAP. Data were analyzed using SPSS version 22 via the Wilcoxon signed rank test. Results: After seven days of application of TAP as intracanal medicament, E. faecalis was eliminated from the dentinal tubules of the apical half of root canal up to 400 MU depth. The MIC and MBC of TAP in its original concentration were both found to be 16 MUg/mL. Conclusions: The original concentration of TAP was found to be 5*104 times its MIC. Considering the risk of coronal discoloration of teeth following the use of TAP, application of its lower concentrations is recommended. PMID- 29971117 TI - Evaluation of the Effect of Buccolingual and Apicocoronal Positions of Dental Implants on Stress and Strain in Alveolar Bone by Finite Element Analysis. AB - Objectives: The position of dental implants in the alveolar bone can affect the surrounding bone from biomechanical and biological aspects. The purpose of this study was to evaluate the effect of implant position on stress and strain distribution in the surrounding bone by using finite element analysis (FEA). Materials and Methods: Thirteen computerized models of a 3.8-mm-diameter XiVE implant with the abutment and crown of a mandibular second premolar in a mandibular bone segment were designed. In the reference model, the implant was placed at the center of the alveolar ridge with its crest module located above the alveolar crest. In the other models, the implants were positioned buccally, lingually, coronally or apically by 0.5, 1 or 1.5mm. By using the ANSYS software program, a 100-N load was applied to the buccal cusp parallel to and at a 30 degree angle relative to the longitudinal axis of the fixture. The models were analyzed in terms of the distribution of stress and strain in the bone. Results: The different implant positions induced nonlinear stress and strain changes in the bone. The central, 1.5-mm apical, and 1.5-mm coronal implant positions induced high amounts of stress and strain under off-axial loads. Conclusions: Within the limitations of this study, the results showed that the stress and strain in the bone around the implant undergo small nonlinear changes with buccolingual and apicocoronal shifting of the implant and can be affected by the configuration of the implant in contact with the bone. PMID- 29971119 TI - Effect of Nd:YAG and Diode Lasers on Apical Seal of Root Canals Filled with AH Plus and Mineral Trioxide Aggregate-Based Sealers. AB - Objectives: Laser irradiation, as an adjunct to root canal preparation, may increase the success rate of endodontic treatments. This study aimed to assess the effect of neodymium-doped yttrium aluminum garnet (Nd:YAG) and diode lasers on the apical seal of the root canals filled with AH Plus(r) and mineral trioxide aggregate (MTA)-based sealers. Materials and Methods: This in-vitro experimental study was conducted on 96 single-rooted, single-canal extracted human teeth with closed apices. The root canals were prepared by using ProTaper(r) rotary instruments and were randomly divided into six groups (n=16): 940-nm diode laser and AH Plus(r) sealer (group 1), Nd:YAG laser and AH Plus(r) sealer (group 2), AH Plus(r) sealer (group 3), 940-nm diode laser and MTA-based sealer (group 4), Nd:YAG laser and MTA-based sealer (group 5), MTA-based sealer (group 6), as well as positive and negative control groups. A bacterial leakage model was used for microleakage assessment. Qualitative assessment was done by using a scanning electron microscope (SEM). Data were analyzed by two-way analysis of variance (ANOVA) at the significance level of 0.05. Results: There were statistically significant differences between the experimental and control groups (P=0.002). The laser-treated groups showed a lower apical microleakage compared to the non laser-treated groups, although the difference was not statistically significant (P>0.05). No significant differences were noted between the two lasers in terms of the apical microleakage, irrespective of the type of sealer (P>0.05). Conclusions: Laser irradiation, as an adjunct to root canal preparation, has no significant effect on the level of apical microleakage. PMID- 29971118 TI - Radiographic Comparison of Bovine Bone Substitute Alone Versus Bovine Bone Substitute and Simvastatin for Human Maxillary Sinus Augmentation. AB - Objectives: The aim of this study was to compare the efficacy of bovine bone substitute (Compact Bone B. (r)) alone versus bovine bone substitute and simvastatin for human maxillary sinus augmentation. Materials and Methods: This study was conducted on 16 sinuses in eight patients. Radiographic assessments were done preoperatively (T0), immediately (T1) and at nine months after sinus grafting (T2). Alveolar bone height and density were assessed on cone beam computed tomography (CBCT) scans using Planmeca RomexisTM Imaging Software 2.2. Results: The change in alveolar bone height and density between T0, T1 and T2 was significant in both groups. Alveolar bone height (h0, h1, h2) and vertical height of the grafted bone (g1, g2) in three lines (anterior, middle and posterior) were not significantly different between groups. The grafted bone height shrinkage (%) in the anterior, middle and posterior limits of the augmented area were not significantly different between groups. The existing alveolar and grafted bone density increased significantly in both groups between T1 and T2, except for the existing alveolar bone density in the control group. There were no statistically significant differences between the alveolar bone density values obtained in TI and T2 between groups, except for the existing alveolar bone density at T1. Conclusions: This study did not show any significant positive effect for simvastatin in maxillary sinus augmentation based on radiographic examination. PMID- 29971120 TI - Modified Pedicle Grafting: A Novel Noninvasive Technique for Soft Tissue Augmentation Around Maxillary Dental Implants. AB - Objectives: This study sought to assess the efficacy of modified pedicle grafting as a noninvasive technique for soft tissue augmentation around maxillary dental implants. Materials and Methods: This descriptive study was conducted on eight patients who met the inclusion criteria. Prior to the second-stage surgery for exposing the implants, the buccal keratinized mucosa width, vestibular depth, and mucosal thickness around the implants were measured. The same parameters were measured six months after the second-stage surgery and were compared with the baseline values. Also, the color match of the graft with the adjacent gingival and mucosal tissues was evaluated. Results: Forty-seven maxillary implants were evaluated. The minimum and maximum gains of keratinized mucosal width were respectively equal to 0mm and 7mm, with a mean of 4.31+/-1.19mm. The mean vestibular depth around the implants was 9.47+/-1.75mm (ranging from 5mm to 12mm) six months after the surgery. At the beginning of the study, a thin mucosa surrounded the implants, but after six months, the peri-implant keratinized mucosa width increased. The color match of the graft with the adjacent gingival and mucosal tissues was excellent based on the periodontists' opinion. Conclusions: Modified pedicle grafting is a safe and predictable technique for soft tissue augmentation around maxillary implants. This technique is reliable for increasing the width of keratinized mucosa in fully and partially edentulous patients with a shallow vestibular depth. The stability of the pedicle flap is achieved by fixing the flap to the tissue around the healing abutment. PMID- 29971121 TI - Bite Force of 3-6-Year-Old Children After Unilateral Extraction of Primary Teeth. AB - Objectives: This study aimed to assess the bite force of 3-6-year-old children in primary dentition period after unilateral extraction of a primary first molar (D) and its correlation with the height, weight, gender, type of occlusion, and temporomandibular disorders (TMDs). Materials and Methods: Twenty children between the ages of 3 and 6 years with a unilaterally extracted D comprised our case group, and 29 age-matched children with no extracted teeth comprised the control group. The maximum bite force at the site of posterior teeth was measured using a bite force measuring device with a 0.2-mm thickness and 3-cm diameter, attached to a strain-gage sensor. Each child bit the sensor with maximum force for 3 seconds, and this was repeated three times at 10-minute intervals. The mean value was calculated. Data were analyzed using SPSS 18 software program via generalized estimating equation (GEE). Results: the bite force on the side of extraction was significantly lower than that on the contralateral side (P<0.05). Also, the bite force was significantly correlated with the height, gender, and age, but the correlations between the bite force and weight, type of occlusion and side of the jaw were not significant (P>0.05). Conclusions: Extraction of primary first molars decreases the bite force on the respective side of the jaw. PMID- 29971122 TI - Shear Bond Strength of Rebonded Ceramic Brackets Using Four Different Methods of Adhesive Removal. AB - Objectives: Rebonding of isolated brackets is an economic option that can be conducted using available in-office or commercial recycling methods. Nowadays, lasers are known as an efficient modality for composite removal, but there is not much information available about using lasers for removal of adhesive remnants from the ceramic bracket base. Materials and Methods: Fifty human premolar teeth were divided into five groups. Samples in all groups were bonded to ceramic brackets. Brackets in four groups were debonded and the remaining adhesive was removed by Er:YAG laser, Er;Cr:YSGG laser, sandblasting or direct flame. After removing adhesives from the tooth surfaces by carbide bur, the recycled brackets were bonded again. in the control group, new ceramic brackets were bonded. Finally, all brackets were debonded by universal testing machine and their shear bond strength (SBS) was measured. The adhesive remnant index (ARI) was calculated under a stereomicroscope at *10 magnification. Data were analyzed using oneway ANOVA and Tukey's test. Results: SRS values showed no significant difference among the five groups (P=0.568). The highest SRS was noted in the control group (7.46+/-1.4 MPa), followed by Er:YAG laser group (7.40+/-1.24 Mpa) and the lowest was noted in the flame group (6.32+/-2.3 Mpa). ARI scores indicated that most of the adhesive remained on the tooth surface in all groups. Conclusions: Recycling of ceramic brackets with Er:YAG laser is an efficient in-office method which causes the least damage to the bracket base. However, all methods of bracket recycling showed acceptable SBS. PMID- 29971123 TI - A New Method of Treatment of Temporomandibular Joint Ankylosis with Osteodistraction Using the Sh-Device: A Case Report. AB - This case report presents a 16-year-old boy with bilateral temporomandibular joint (TMJ) bony ankylosis due to trauma. The patient had undergone several unsuccessful therapeutic surgeries and was experiencing reduced mouth opening, difficulty in eating and speaking, poor oral hygiene, snoring, and depression. Bilateral gap arthroplasty and distraction osteogenesis (DO) were performed. After the surgery, we were able to move the osteodistractors forward and prevent the upward and backward movement of the proximal mandibular segment with the use of our custom-made Sh-device, which allowed bone growth and soft-tissue matching. The mandibular deficiency was treated, and the patient's sleep quality significantly improved after three months. The physical, orthodontic and speech therapies were continued. The facial asymmetry, difficulty in sleeping, eating and speaking, and low self-esteem were completely resolved. At the 8-year follow up, the patient's condition was satisfactory. The Sh-device can be used as a contemporary treatment modality for TMJ ankylosis. PMID- 29971124 TI - Comparative Evaluation of the Effect of Different Post and Core Materials on Stress Distribution in Radicular Dentin by Three-Dimensional Finite Element Analysis. AB - Objectives: The aim of this study was to investigate the stress distribution of different post and core materials in radicular dentin by three-dimensional finite element analysis (3D FEA). Materials and Methods: Twelve 3D models of a maxillary central incisor were simulated in the ANSYS 5.4 software program. The models were divided into three groups; the first group included: 1-Gold post and core and 2 Nickel-chromium (Ni-Cr) post and core restored with metal-ceramic restorations (MCRs). The second group included: 1-Stainless steel post, 2-Titanium post, 3 Carbon fiber post, 4-Glass fiber post, and 5-Quartz fiber post with composite cores and MCRs. The third group included: 1-Zirconia post and core, 2-Zirconia post, 3-Carbon fiber post, 4-Glass fiber post, and 5-Quartz fiber post; the last four models had composite cores restored with all-ceramic restorations (ACRs). Each specimen was subjected to a compressive load at a 45-degree angle relative to its longitudinal axis at a constant intensity of 100 N. The models were analyzed with regard to the stress distribution in dentin. Results: Two stress concentration sites were detected in the models. The first group showed the lowest stress levels in the cervical region, while the stress levels detected in the second group were higher than those in the first group and lower than those found in the third group. Fiber-reinforced posts induced a higher stress concentration between the middle and cervical thirds of the root compared to other posts. Conclusions: According to the results, since cast posts induce lower stresses in dentin, they are recommended for clinical use. Fiber-reinforced posts and ACRs caused the maximum stresses in dentin. PMID- 29971125 TI - Intranasal Premedication Effect of Dexmedetomidine Versus Midazolam on the Behavior of 2-6-Year-Old Uncooperative Children in Dental Clinic. AB - Objectives: The aim of this study was to compare the intranasal premedication effect of newly introduced dexmedetomidine (DEX) versus midazolam on the behavior of uncooperative children in the dental clinic. Materials and Methods: This crossover double-blind clinical trial was conducted on 20 uncooperative children aged 2-6 years who required at least two similar dental treatment visits. The subjects were randomly given 1 MUg/kg of DEX and 0.5 mg/kg of midazolam via the intranasal route. For the sedation protocol in the two groups, 0.25 mg/kg of atropine in combination with 0.5 mg/kg of midazolam added to 1-2 mg/kg of ketamine were used 30 minutes after premedication and transferring the patient to the operating room. Dental treatments were carried out by a pediatric dentist blinded to the type of the administered premedication. The sedative efficacy (overall success rate) of the agents was assessed by two independent pediatric dentists based on the Houpt scale. Data analyses were carried out according to Wilcoxon signed-rank test and paired t-test. Results: There were no significant differences in the premedication efficacy of intranasal DEX and midazolam according to the Houpt scale (P>0.05). Conclusions: Intranasal midazolam and DEX are satisfactory and effective premedication regimens for uncooperative children. PMID- 29971126 TI - Efficacy of Octacalcium Phosphate and Octacalcium Phosphate/Gelatin Composite on the Repair of Critical-Sized Calvarial Defects in Rats. AB - Objectives: The healing of bone defects in the craniofacial region is an important clinical issue. We aimed to compare the effects of octacalcium phosphate (OCP) and the combination of OCP/gelatin (OCP/Gel) on calvarial bone regeneration in rats. Materials and Methods: In this study, 72 male Sprague Dawley rats were randomly assigned to the OCP (n=24), OCP/Gel (n=24), and control groups (n=24). Lesions with a diameter of 9 mm were created in the parietal bone and were filled with 9-mg OCP and OCP/Gel disks. In the control group, no substance was implanted in the defect. Sampling was performed on days 10, 14, 21, and 28 after the implantation. After tissue processing, 5-MUm sections were prepared and stained by hematoxylin and eosin (H&E) stain. The sections were studied, and the volume fraction of the newly formed bone was assessed by Kruskal Wallis test at a significance level of 0.05. Results: In the experimental groups, new bone formation was detected at the margins of the defects 10 days after the implantation. With the progression of the healing process, the newly formed bone covered greater areas of the defects and developed a more mature structure. In the control group, the defects were primarily filled with a dense connective tissue with small islands of new bone. The results of histomorphometric assessments showed that the volume of the newly formed bone in the experimental groups had a significant statistical difference with that in the control group (P<0.001). Conclusions: The OCP/Gel composite can be useful in the healing process of calvarial bone defects. PMID- 29971127 TI - Effect of Selected Luting Agents on the Retention of CAD/CAM Zirconia Crowns Under Cyclic Environmental Pressure. AB - Objectives: The aim of this study was to evaluate the retention strength of zirconia crowns luted with two types of resin cement under environmental pressure changes. Materials and Methods: Thirty zirconia crowns were fabricated by using computer-aided design/computer-aided manufacturing (CAD/CAM) system and were cemented by Panavia F2.0 (PAN), hand-mixed RelyX Unicem (UNH), or auto-mix RelyX Unicem Aplicap (UNA) cements on the corresponding extracted human molars. The samples were randomly divided into three groups according to the cement type. After 3000 thermal cycles, the cemented crowns were subjected to 24 pressure cycles (0 to 5 atmospheres). The retention force (N) of the specimens was measured in a universal testing machine. To normalize the retentive force, the recorded force was divided by the surface area of each tooth for measuring the retentive strength (MPa). The mean retention strengths (and forces) of the groups were compared by using one-way analysis of variance (ANOVA) and Tukey's honest significant difference (HSD) test (alpha=0.05). The failure modes were also examined by using a stereomicroscope. Results: The retention values related to the evaluated resin cements were significantly different; the UNA group showed the highest retention strength (6.45+/-0.35 MPa) followed by the UNH (4.99+/-0.47 MPa) and PAN (4.45+/-0.39 MPa, P<0.001) groups. The adhesive failure mode was predominant in all the groups. Conclusions: The choice of resin cements and their mixing methods, which lead to differences in porosity, may affect the retention strength of zirconia crowns. PMID- 29971128 TI - Comparative Evaluation of Retentive Properties of Two Compatible Ball Attachments in Mandibular Implant-Retained Overdentures: An In Vitro Study. AB - Objectives: The retentive properties of implant-retained overdentures (IRO) may be influenced by the type of attachments. The aim of this research was to compare the retention of two dental implant systems with compatible ball attachments, namely Straumann(r) system (SS) and Rhein83 SRL system (RS) after fatigue testing. Materials and Methods: Two laboratory models consisting of two parallel Straumann(r) fixtures at a distance of 22 mm were prepared. Five pairs of each systems' ball attachments were examined (n=5). The samples were soaked in artificial saliva. The retention strength values (RSV) were recorded before the fatigue test and after 1100, 2200, 3300, 4400, and 5500 insertion and removal cycles at a speed of 51 mm/minute with a 50-N load cell in a universal testing machine. The data were analyzed by repeated measures analysis of variance (ANOVA) followed by independent sample t-test with Bonferroni corrections. Results: There was a decrease in the RSV in both systems after 5500 cycles of insertion and removal. There was a significant statistical difference between the RSV of the normal Sphero Block of the RS (17.52+/-0.68 N) and that of the Spare Lamella retention inserts of the SS (19.72+/-0.74 N, P=0.001). Conclusions: Although the RSVs of the RS and SS were almost similar before the fatigue test, as the number of insertion and removal cycles increased, the RSV decreased more significantly in the RS compared to the SS. PMID- 29971129 TI - Evaluation of Microhardness of Mineral Trioxide Aggregate After Immediate Placement of Different Coronal Restorations: An In Vitro Study. AB - Objectives: The purpose of this research was to evaluate the effect of immediate placement of different restorative materials in comparison with a temporary restoration on the surface microhardness of mineral trioxide aggregate (MTA). Materials and Methods: Access cavities were prepared in 40 extracted human molars, and a 3-mm layer of MTA was placed in the pulp chamber. The samples were divided into eight groups (n=5). Ten minutes after the MTA placement, two groups were restored with Zonalin temporary restoration, while the other six groups were restored with glass-ionomer cement (GIC), resin-modified glass-ionomer (RMGI), or resin-based composite. In each group, the Vickers microhardness (VMH) of MTA was determined after 7 and 21 days. Data were entered into SPSS 17 software program and were analyzed by two-way analysis of variance (ANOVA). The significance level was set at 5%. Results: The type of restorative materials had a statistically significant effect on the microhardness of MTA (P=0.002). However, the microhardness of MTA was neither significantly influenced by the timing of final restoration (P=0.246) nor by the time-material interaction (P=0.116). Conclusions: Based on the results of the present study and by considering the limitations of laboratory studies, it is recommended to postpone the placement of final restorations until the underlying MTA is completely set. Otherwise, in the clinical conditions in which early covering of MTA is recommended, sufficient moist-curing and hydration should be guaranteed by selecting a restorative material with the lowest hydrophilic interaction energy. PMID- 29971130 TI - Evaluation of the Prevalence of Mucous Retention Pseudocyst and its Correlation with the Associated Risk Factors Using Panoramic Radiography and Cone-Beam Computed Tomography. AB - Objectives: Mucous retention pseudocyst (MRP) of the maxillary sinus is an incidental finding on radiographs. The radiographs taken for dental purposes provide an opportunity for dentists to recognize asymptomatic maxillary sinus anomalies. The purpose of this study was to determine the prevalence of MRP on panoramic and cone-beam computed tomography (CBCT) views and to evaluate the associated risk factors. Materials and Methods: In this study, 710 panoramic radiographs and 90 CBCT scans were examined with regard to the presence of MRP in the maxillary sinus during 2014-15. The MRP prevalence and some associated risk factors such as age, gender, season, smoking, allergy, asthma, chronic sinusitis, nasal polyp, mucosal thickening, and post-nasal drip (PND) were evaluated. Results: The frequency of MRP was 2.4% on the 710 evaluated panoramic images and 43.3% on the 90 evaluated CBCT views. The frequency of MRP on the panoramic and CBCT views was higher in males than in females. There was a significant association between smoking and MRP on panoramic images (P=0.02) and CBCT views (P<0.001). There was a significant association between PND and MRP on CBCT views (P=0.02). The highest frequency of MRP was seen in spring (P=0.04) according to panoramic radiographs and in spring and summer (P=0.001) according to CBCT views. Conclusions: The occurrence of MRP had a significant association with smoking and PND, and the highest frequency of MRP was detected in spring and summer. Also, CBCT scanning detects MRP more accurately than panoramic radiography. PMID- 29971131 TI - Comparison of Short and Standard Implants in the Posterior Mandible: A 3D Analysis Using Finite Element Method. AB - Objectives: This study aimed to analyze functional stresses around short and long implant-supported prostheses with different crown heights. Materials and Methods: Four three-dimensional (3D) models were designed with SolidWorks 2015. In models 1 (control) and 2, three dental implants (second premolar 4.1*8 mm, molars: 4.8*8 mm) were placed. In models 3 and 4, three dental implants (second premolar 4.1*4 mm, molars: 4.8*4) were placed. Residual bone height was 10 mm in groups 1 and 2 (grafted bone) models and 6 mm in groups 3 and 4. The crown heights were modeled at 11.5 mm for groups 1 to 3, and 15 mm for group 4. The applied oblique force was 220 N to simulate chewing movements. The maximum von Mises and principal stresses on the implants and the supporting tissues were compared using the 3D finite element method. Results: In all models, the highest stress value was seen within the most coronal part of bone (crestal bone), which was cortical or grafted bone. The highest stress values in the bone supporting the implant neck were seen in the premolar region of each model, especially in model 4 (291.16 MPa). The lowest stress values were demonstrated in the molar region of model 3 (48.066 MPa). The model 2 implants showed the highest von Mises stress concentrated at their neck (424.44 MPa). Conclusions: In atrophic posterior mandible with increased crown height space, short implants with wider diameter seem to be a more feasible approach compared to grafting methods. PMID- 29971132 TI - The Scatter Search Based Algorithm for Beam Angle Optimization in Intensity Modulated Radiation Therapy. AB - This article introduces a new framework for beam angle optimization (BAO) in intensity-modulated radiation therapy (IMRT) using the Scatter Search Based Algorithm. The potential benefits of plans employing the coplanar optimized beam sets are also examined. In the proposed beam angle selection algorithm, the problem is solved in two steps. Initially, the gantry angles are selected using the Scatter Search Based Algorithm, which is a global optimization method. Then, for each beam configuration, the intensity profile is calculated by the conjugate gradient method to score each beam angle set chosen. A simulated phantom case with obvious optimal beam angles was used to benchmark the validity of the presented algorithm. Two clinical cases (TG-119 phantom and prostate cases) were examined to prepare a dose volume histogram (DVH) and determine the dose distribution to evaluate efficiency of the algorithm. A clinical plan with the optimized beam configuration was compared with an equiangular plan to determine the efficiency of the proposed algorithm. The BAO plans yielded significant improvements in the DVHs and dose distributions compared to the equispaced coplanar beams for each case. The proposed algorithm showed its potential to effectively select the beam direction for IMRT inverse planning at different tumor sites. PMID- 29971133 TI - The Modelling of Hand, Foot, and Mouth Disease in Contaminated Environments in Bangkok, Thailand. AB - Hand, foot, and mouth disease (HFMD) has spread widely in a continuing endemic in Thailand. There are no specific vaccines or antiviral treatments available that specifically target HFMD. Indirect transmission via free-living viruses from the environment may influence HFMD infections because the virus can survive for long periods in the environment. In this study, a new mathematical model is proposed to investigate the effect of indirect transmission from contaminated environments and the impact of asymptomatic individuals. By fitting our model to reported data on hospitalized individuals of HFMD endemic in Bangkok, Thailand, 2016, the basic reproduction number was estimated as 1.441, which suggests that the disease will remain under current conditions. Numerical simulations show that the direct transmission from asymptomatic individuals and indirect transmission via free living viruses are important factors which contribute to new HFMD infections. Sensitivity analysis indicates that the basic reproduction number is sensitive to the transmission rate of asymptomatic and symptomatic subgroups and indirect transmission. Our findings suggest that cleaning the environment frequently and healthcare precautions which include the reduction of direct transmission rates should be promoted as effective control strategies for preventing the HFMD spread. PMID- 29971134 TI - Modelling Optimal Control of In-Host HIV Dynamics Using Different Control Strategies. AB - HIV is one of the major causes of deaths, especially in Sub-Saharan Africa. In this paper, an in vivo deterministic model of differential equations is presented and analyzed for HIV dynamics. Optimal control theory is applied to investigate the key roles played by the various HIV treatment strategies. In particular, we establish the optimal strategies for controlling the infection using three treatment regimes as the system control variables. We have applied Pontryagin's Maximum Principle in characterizing the optimality control, which then has been solved numerically by applying the Runge-Kutta forth-order scheme. The numerical results indicate that an optimal controlled treatment strategy would ensure significant reduction in viral load and also in HIV transmission. It is also evident from the results that protease inhibitor plays a key role in virus suppression; this is not to underscore the benefits accrued when all the three drug regimes are used in combination. PMID- 29971135 TI - Hypoxia exposure induced cisplatin resistance partially via activating p53 and hypoxia inducible factor-1alpha in non-small cell lung cancer A549 cells. AB - Lung cancer is one of the most frequently occurring and fatal cancer types worldwide. Cisplatin is widely used for chemotherapy of non-small cell lung cancer (NSCLC). However, the use of cisplatin has been met with the challenge of chemoresistance as a result of hypoxia, which is common in adult solid tumors and is a principal cause of a poor patient outcome. In the present study, the effects of hypoxia on the response of the NSCLC A549 cell line to the clinically relevant cytotoxic cisplatin were evaluated via regulating hypoxia inducible facor-1alpha (HIF-1alpha) and p53. Hypoxia exposure upregulated the expression levels of HIF 1alpha and p53, and promoted glycolysis in A549 cells, which was attenuated by HIF-1alpha knockdown by siRNA introduction, indicating the critical roles of HIF 1alpha in regulating glycolysis under hypoxic conditions. HIF-1alpha-knockdown also sensitized A549 cells to cisplatin in hypoxia-exposed, but not in normoxia exposed A549 cells, suggesting that hypoxia-induced cisplatin resistance partially contributes toward the upregulation of HIF-1alpha by hypoxia exposure. The present study also determined that hypoxia-upregulated p53 activated its downstream target gene p21 transcriptionally and blocked the cell cycle at the G1 G0 phase, thereby leading to inhibition of cell proliferation. As a result, activated p53 desensitized A549 cells to cisplatin potentially through increasing the non-proliferation status of A549 cells and therefore minimizing the influence of cisplatin. Taken together, these results identified the exact effects of HIF 1alpha and p53 induced by hypoxia and potentially elucidated their protective effects on A549 cells against cisplatin. PMID- 29971136 TI - Biochanin A Reduces Inflammatory Injury and Neuronal Apoptosis following Subarachnoid Hemorrhage via Suppression of the TLRs/TIRAP/MyD88/NF-kappaB Pathway. AB - Inflammatory injury and neuronal apoptosis participate in the period of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Suppression of inflammation has recently been shown to reduce neuronal death and neurobehavioral dysfunction post SAH. Biochanin A (BCA), a natural bioactive isoflavonoid, has been confirmed to emerge the anti-inflammatory pharmacological function. This original study was aimed at evaluating and identifying the neuroprotective role of BCA and the underlying molecular mechanism in an experimental Sprague-Dawley rat SAH model. Neurobehavioral function was evaluated via the modified water maze test and modified Garcia neurologic score system. Thus, we confirmed that BCA markedly decreased the activated level of TLRs/TIRAP/MyD88/NF-kappaB pathway and the production of cytokines. BCA also significantly ameliorated neuronal apoptosis which correlated with the improvement of neurobehavioral dysfunction post SAH. These results indicated that BCA may provide neuroprotection against EBI through the inhibition of inflammatory injury and neuronal apoptosis partially via the TLRs/TIRAP/MyD88/NF-kappaB signal pathway. PMID- 29971137 TI - Neural Basis of Depression Related to a Dominant Right Hemisphere: A Resting State fMRI Study. AB - Background: In the past, studies on the lateralization of the left and right hemispheres of the brain suggested that depression is dominated by the right hemisphere of the brain, but the neural basis of this theory remains unclear. Method: Functional magnetic resonance imaging of the brain was performed in 22 depressive patients and 15 healthy controls. The differences in the mean values of the regional homogeneity (ReHo) of two groups were compared, and the low frequency amplitudes of these differential brain regions were compared. Results: The results show that compared with healthy subjects, depressive patients had increased ReHo values in the right superior temporal gyrus, right middle temporal gyrus, left inferior temporal gyrus, left middle temporal gyrus, right middle frontal gyrus, triangular part of the right inferior frontal gyrus, orbital part of the right inferior frontal gyrus, right superior occipital gyrus, right middle occipital gyrus, bilateral anterior cingulate, and paracingulate gyri; reduced ReHo values were seen in the right fusiform gyrus, left middle occipital gyrus, left lingual gyrus, and left inferior parietal except in the supramarginal and angular gyri. Conclusions: The results show that regional homogeneity mainly occurs in the right brain, and the overall performance of the brain is such that right hemisphere synchronization is enhanced while left hemisphere synchronization is weakened. ReHo abnormalities in the resting state can predict abnormalities in individual neurological activities that reflect changes in the structure and function of the brain; abnormalities shown with this indicator are the neuronal basis for the phenomenon that the right hemisphere of the brain has a dominant effect on depression. PMID- 29971138 TI - Risk Factors for the Progression of Mild Cognitive Impairment in Different Types of Neurodegenerative Disorders. AB - Objective: Mild cognitive impairment (MCI) is a transitional state between normal aging and early dementia. It has a heterogeneous etiology and clinical course. This study aimed to examine the factors associated with the progression of MCI in different types of dementia disorders. Method: A retrospective, longitudinal, observational study of outpatients with MCI was conducted at a medical center in northern Taiwan. Patient medical records were reviewed, and risk factors were analyzed by multivariate analysis. Results: Among 279 patients with MCI, 163 (58.4%), 68 (24.4%), and 48 (17.2%) were diagnosed with Alzheimer's disease, vascular cognitive impairment, and Lewy body diseases, respectively. During the observation period, 37.2% of patients progressed to dementia. Older age and a higher Clinical Dementia Rating Scale-Sum of Boxes were associated with the risk of progression. Hyperlipidemia was associated with a decreased risk. Converters were more likely to receive an antidementia prescription. Conclusion: Our study suggests the importance of comprehensive clinical profiling, risk factor assessment, and detailed drug history evaluations in improving our understanding and management of dementia subtypes. PMID- 29971139 TI - Sleep Quality and Emotion Regulation Interact to Predict Anxiety in Veterans with PTSD. AB - Posttraumatic stress disorder (PTSD) is a debilitating and common consequence of military service. PTSD is associated with increased incidence of mood disturbances (e.g., anxiety). Additionally, veterans with PTSD often have poor quality sleep and poor emotion regulation ability. We sought to assess whether such sleep and emotion regulation deficits contribute to mood disturbances. In 144 veterans, using a double moderation model, we tested the relationship between PTSD and anxiety and examined whether sleep quality and emotion regulation interact to moderate this relationship. We found that PTSD predicts higher anxiety in veterans with poor and average sleep quality who utilize maladaptive emotion regulation strategies. However, there was no relationship between PTSD and anxiety in individuals with good sleep quality, regardless of emotion regulation. Similarly, there was no relationship between PTSD and anxiety in individuals with better emotion regulation, regardless of sleep quality. Results were unchanged when controlling for history of traumatic brain injury (TBI), despite the fact that those with both PTSD and TBI had the poorest emotion regulation overall. Taken together, these results suggest that good-quality sleep may be protective against poor emotion regulation in veterans with PTSD. Sleep may therefore be a target for therapeutic intervention in veterans with PTSD and heightened anxiety. PMID- 29971140 TI - Metabolic Risk Factors of Alzheimer's Disease, Dementia with Lewy Bodies, and Normal Elderly: A Population-Based Study. AB - Background: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) share many risk factors. Evidence suggests that metabolic risk factors are important to AD; however, their association with DLB is unclear. The risk of cardiovascular diseases (CVD) associated with AD and DLB is also uncertain. Thus, this nationwide, population-based study was designed to evaluate the metabolic and CVD risks in AD and DLB. Materials and Methods: Data were obtained from the Taiwan National Health Insurance Research Database. AD patients, DLB patients, and normal control (NC) individuals from 1996 to 2013 were enrolled for risk assessment. Results: In total, 7544 NC individuals, 1324 AD patients, and 562 DLB patients were enrolled. Participants with one or more metabolic risk factors had significantly higher odds of AD or DLB. No significant differences in metabolic risk factors were observed between DLB and AD patients. AD patients had a lower risk of CVD (aHR = 0.67, 95% CI = 0.59-0.76, p value < 0.001) and coronary artery disease (CAD) (aHR = 0.59, 95% CI = 0.51-0.69, p value < 0.001) than NC. DLB patients had a higher risk of ischemic stroke (aHR = 2.27, 95% CI = 1.68-3.06, p value < 0.001) than NC. Conclusion: Metabolic risk factors are important in AD and DLB. Patients with AD might have a lower risk of CAD and ischemic strokes. Patients with DLB might have a higher risk of ischemic stroke. PMID- 29971141 TI - Standardised Neuropsychological Assessment for the Selection of Patients Undergoing DBS for Parkinson's Disease. AB - DBS is an increasingly offered advanced treatment for Parkinson's disease (PD). Neuropsychological assessment is considered to be an important part of the screening for selection of candidates for this treatment. However, no standardised screening procedure currently exists. In this study, we examined the use of our standardised neuropsychological assessment for the evaluation of surgical candidates and to identify risk factors for subsequent decline in cognition and mood. A total of 40 patients were assessed before and after DBS. Evaluation of mood and case notes review was also undertaken. Before DBS, patients with PD demonstrated frequent impairments in intellectual functioning, memory, attention, and executive function, as well as high rates of mood disorder. Post-DBS, there was a general decline in verbal fluency only, and in one patient, we documented an immediate and irreversible global cognitive decline, which was associated with older age and more encompassing cognitive deficits at baseline. Case note review revealed that a high proportion of patients developed mood disorder, which was associated with higher levels of depression at baseline and greater reduction in levodopa medication. We conclude that our neuropsychological assessment is suitable for the screening of candidates and can identify baseline risk factors, which requires careful consideration before and after surgery. PMID- 29971142 TI - Sinomenine hydrochloride inhibits cell survival in human hepatoma Huh7 cells. AB - The present study aimed to investigate the effect of sinomenine hydrochloride (SIN) on cell survival/proliferation in the human hepatoma cell line Huh7, as well as determine the underlying mechanisms. Three different doses of SIN, 140, 280 and 560 uM, were tested. Cellular apoptosis and cell cycle distribution were analyzed by flow cytometry. Western blotting was used to determine protein levels of the apoptosis-associated regulators, cleaved caspase 3, B-cell lymphoma-2 (Bcl 2)-associated X protein (Bax), Bcl-2 homologous antagonist/killer (Bak) and Bcl extra large (Bcl-xl), as well as the cell cycle-related regulators, p21 and p27. It was observed that the three doses of SIN were able to suppress Huh7 cell survival/proliferation, and efficiently induce cellular apoptosis as well as multiphase cell cycle arrest. Mechanistically, SIN treatment upregulated the levels of the pro-apoptotic regulators, cleaved caspase 3 and Bax, and downregulated the level of anti-apoptotic Bcl-xl. Additionally, SIN treatment also increased the protein levels of p21 and p27, as two regulators functioning to slow cell cycle progression. Taken together, the present studied indicated SIN to be a promising compound for the treatment of hepatocellular carcinoma, based on its apparent effect in modulating cell apoptosis and the cell cycle in Huh7 cells in vitro. PMID- 29971143 TI - Achieving better health for people with intellectual disability: the power of policy. AB - : People with intellectual disability have high mental and physical healthcare needs, which must be addressed on individual, local and national levels. Policy interventions informed by research and stakeholder views and extending beyond a focus on health are needed to reduce inequities in this group. Declaration of interest: None. PMID- 29971144 TI - Prevalence, factors and reasons associated with missed first appointments among out-patients with schizophrenia at the Federal Neuro-Psychiatric Hospital, Benin City. AB - Background: Non-attendance to clinic appointments is associated with poorer treatment outcomes. There is a dearth of information about missed first clinic appointments among patients with schizophrenia in Nigeria. Aims: To determine the prevalence, correlates and reasons for missed first appointment among out patients with schizophrenia at the Federal Neuro-Psychiatric Hospital, Benin City, Nigeria. Method: A cross-sectional descriptive study among 275 out-patients with schizophrenia, using the Mini International Neuro-Psychiatric Interview and the Brief Psychiatric Rating Scale. Results: The prevalence of missed first appointment was 31%. Higher BPRS score was associated with missing the appointment. The main reasons for missed appointments were: forgetting the appointment date and patient's refusal to come to the clinic. Conclusions: Missed first out-patient clinic appointment is common among patients with schizophrenia at the study site, forgetting appointment dates being a common reason. Among other recommendations, methods of reminding patients and caregivers of appointment dates at the study location may need to be explored. Declaration of interest: None. PMID- 29971145 TI - Assessing the readability of the self-reported Strengths and Difficulties Questionnaire. AB - : The Strengths and Difficulties Questionnaire (SDQ) is one of the most widely used measures in child and adolescent mental health in clinical practice, community-based screening and research. Assessing the readability of such questionnaires is important as young people may not comprehend items above their reading ability when self-reporting. Analyses of readability in the present study indicate that the self-report SDQ might not be suitable for young people with a reading age below 13-14 years and highlight differences in readability between subscales. The findings suggest a need for caution in using the SDQ as a self report measure for children below the age of 13, and highlight considerations of readability in measure development, selection and interpretation. Declaration of interest: None. PMID- 29971147 TI - Erratum: A symptom-based approach to treatment of psychosis in autism spectrum disorder in October 2017-ERRATUM. AB - [This corrects the article DOI: 10.1192/bjo.2017.2.]. PMID- 29971146 TI - Preconception prediction of expectant fathers' mental health: 20-year cohort study from adolescence. AB - : We examined prospective associations between men's common mental disorders in the decades prior to offspring conception and subsequent paternal antenatal mental health problems. Data came from a prospective intergenerational cohort study which assessed common mental disorder nine times from age 14 to 29 years, and in the third trimester of subsequent pregnancies to age 35 years (N = 295 pregnancies to 214 men). Men with histories of adolescent and young adult common mental disorders were over four times more likely to experience antenatal mental health problems. Future research identifying modifiable perinatal factors that counteract preconception risk would provide further targets for intervention. Declaration of interest: None. PMID- 29971149 TI - The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis. AB - Background: Antineuronal antibodies are associated with psychosis, although their clinical significance in first episode of psychosis (FEP) is undetermined. Aims: To examine all patients admitted for treatment of FEP for antineuronal antibodies and describe clinical presentations and treatment outcomes in those who were antibody positive. Method: Individuals admitted for FEP to six mental health units in Queensland, Australia, were prospectively tested for serum antineuronal antibodies. Antibody-positive patients were referred for neurological and immunological assessment and therapy. Results: Of 113 consenting participants, six had antineuronal antibodies (anti-N-methyl-D-aspartate receptor antibodies [n = 4], voltage-gated potassium channel antibodies [n = 1] and antibodies against uncharacterised antigen [n = 1]). Five received immunotherapy, which prompted resolution of psychosis in four. Conclusions: A small subgroup of patients admitted to hospital with FEP have antineuronal antibodies detectable in serum and are responsive to immunotherapy. Early diagnosis and treatment is critical to optimise recovery. Declaration of interest: None. PMID- 29971148 TI - Neuroticism and suicide in a general population cohort: results from the UK Biobank Project. AB - Background: Neuroticism has often been linked to suicidal thoughts and behaviour. Aims: To examine whether neuroticism is associated with suicide deaths after adjusting for known risks. Method: UK Biobank participants (n = 389 365) were assessed for neuroticism as well as social, demographic and health-related variables at study entry and followed for up to 10 years. Suicide risk was modelled using Cox regression stratified by gender. Results: Neuroticism increased the risk of suicide in both men (hazard ratio (HR) = 1.15, 95% CI 1.09 1.22) and women (HR = 1.16, 95% CI 1.06-1.27). In a subsample who were assessed for mood disorders, neuroticism remained a significant predictor for women (HR 1.25, 95% CI 1.03-1.51) but not for men. Conclusions: Screening and therapeutic interventions for neuroticism may be important for early suicide prevention. Declaration of interest: None. PMID- 29971150 TI - Qualitative exploration of the effect of a television soap opera storyline on women with experience of postpartum psychosis. AB - Background: Postpartum psychosis has recently been the focus of an in-depth storyline on a British television soap opera watched by millions of viewers. Aims: This research explored how the storyline and concomitant increase in public awareness of postpartum psychosis have been received by women who have recovered from the condition. Method: Nine semistructured, one-to-one interviews were conducted with women who had experienced postpartum psychosis. Thematic analysis consistent with Braun and Clarke's six-step approach was used to generate themes from the data. Results: Public exposure provided by the postpartum psychosis portrayal was deemed highly valuable, and its mixed reception encompassed potentially therapeutic benefits in addition to harms. Conclusions: Public awareness of postpartum psychosis strongly affects women who have experienced postpartum psychosis. This research highlights the complexity of using television drama for public education and may enable mental health organisations to better focus future practices of raising postpartum psychosis awareness. Declaration of interest: GB is chair of action on Postpartum Psychosis. JH is director of action on Postpartum Psychosis. IJ is a trustee of action on Postpartum Psychosis and was a consultant to the BBC (television company) on the EastEnders storyline. CD is a trustee of action on Postpartum Psychosis, a trustee of BIPOLAR UK, vice chair of the Maternal Mental Health Alliance, and was a consultant to the BBC (television company) on the EastEnders storyline. PMID- 29971151 TI - Mental health in UK Biobank: development, implementation and results from an online questionnaire completed by 157 366 participants. AB - Background: UK Biobank is a well-characterised cohort of over 500 000 participants that offers unique opportunities to investigate multiple diseases and risk factors. Aims: An online mental health questionnaire completed by UK Biobank participants was expected to expand the potential for research into mental disorders. Method: An expert working group designed the questionnaire, using established measures where possible, and consulting with a patient group regarding acceptability. Case definitions were defined using operational criteria for lifetime depression, mania, anxiety disorder, psychotic-like experiences and self-harm, as well as current post-traumatic stress and alcohol use disorders. Results: 157 366 completed online questionnaires were available by August 2017. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status than the general population across a range of indicators. Thirty-five per cent (55 750) of participants had at least one defined syndrome, of which lifetime depression was the most common at 24% (37 434). There was extensive comorbidity among the syndromes. Mental disorders were associated with high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation. Conclusions: The questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed owing to selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health. Declaration of interest: G.B. received grants from the National Institute for Health Research during the study; and support from Illumina Ltd. and the European Commission outside the submitted work. B.C. received grants from the Scottish Executive Chief Scientist Office and from The Dr Mortimer and Theresa Sackler Foundation during the study. C.S. received grants from the Medical Research Council and Wellcome Trust during the study, and is the Chief Scientist for UK Biobank. M.H. received grants from the Innovative Medicines Initiative via the RADAR-CNS programme and personal fees as an expert witness outside the submitted work. PMID- 29971152 TI - Temporal order of cancers and mental disorders in an adult population. AB - Background: Population-based examination of comorbidity is an emerging field of study. Aims: The purpose of the present population level study is to expand our understanding of how cancer and mental illness are temporally associated. Method: A sample of 83 648 056 physician billing records for 664 838 (56% female) unique individuals over the age of 18 was stratified on ages 19-49 years and 50+ years, with temporal order of mental disorder and cancer forming the basis of comparison. Results: Mental disorders preceded cancers for both genders within each age strata. The full range of cancers and mental disorders preceding or following each pivot ICD class are described in terms of frequency of diagnosis and duration in days, with specific examples illustrated. Conclusions: The temporal comorbidity between specific cancers and mental disorders may be useful in screening or clinical planning and may represent indicators of disease mechanism that warrant further screening or investigation. Declaration of interest: None. PMID- 29971153 TI - Internet-delivered cognitive behavioural therapy for young children with obsessive-compulsive disorder: development and initial evaluation of the BIP OCD Junior programme. AB - Background: Internet-delivered cognitive behavioural therapy (ICBT) is a promising approach for increasing access to evidence-based treatments. Aims: To develop and evaluate the feasibility and preliminary efficacy of an ICBT programme for young children with obsessive-compulsive disorder (OCD), named BIP OCD Junior. Method: Eleven children aged 7-11 years were enrolled in a 12-week open trial of parent- and therapist-guided ICBT for OCD. The primary outcome measure was the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Results: There was a significant improvement in OCD symptoms post-treatment, with a large within-group effect size on the CY-BOCS (Cohen's d = 1.86, 95% CI 0.83 to 2.86). Results were maintained at 3-month follow-up. Both children and parents rated the treatment as credible and were highly satisfied with the intervention. Conclusions: BIP OCD Junior is a feasible and credible treatment option for young children with OCD. Randomised controlled trials are needed to further establish its efficacy and cost-effectiveness relative to gold standard face-to-face CBT. Declaration of interest: None. PMID- 29971154 TI - Shared decision-making with involuntary hospital patients: a qualitative study of barriers and facilitators. AB - Background: Last year, there were more than 63 622 involuntary admissions to psychiatric hospitals in England. One of the core principles stipulated in the code of practice for care under the Mental Health Act is involving involuntary patients in care decisions. Aims: Identifying barriers and facilitators to shared decision-making with involuntary patients. Method: Focus groups and individual interviews with patients and clinicians who have experience with involuntary hospital treatment were carried out. Data were subjected to thematic analysis. Results: Twenty-two patients and 16 clinicians participated. Barriers identified included challenges in communication, and noisy and busy wards making one-to-one meetings difficult. Patient involvement was identified as easier if initiated early after admission and if the whole clinical team was on board. Carers' presence helped decision-making through providing additional information and comfort. Conclusions: The barriers and facilitators identified can inform changes in the practice of involuntary care to increase patient involvement. Declaration of interest: None. PMID- 29971156 TI - Cost-effectiveness of cognitive-behavioural therapy for sleep disorder added to usual care in patients with schizophrenia: the BEST study. AB - Background: Sleep problems are pervasive in people with schizophrenia, but there are no clinical guidelines for their treatment. The Better Sleep Trial (BEST) concluded that suitably adapted cognitive-behavioural therapy (CBT) is likely to be highly effective, although its cost-effectiveness is unknown. Aims: To assess the potential cost-effectiveness of CBT for sleep disorders in patients with schizophrenia. Method: An economic evaluation of the BEST study with a 6-month time horizon was used to establish the cost-effectiveness of CBT plus usual care in terms of costs per quality-adjusted life year (QALY) gained. Uncertainty was displayed on cost-effectiveness planes and acceptability curves. Value of information analysis was performed to estimate the benefits of obtaining further evidence. Results: On average, the treatment led to a 0.035 QALY gain (95% CI 0.016 to 0.084), and L1524 (95% CI -10 529 to 4736) and L1227 (95% CI -10 395 to 5361) lower costs from National Health Service and societal perspectives, respectively. The estimated value of collecting more information about the effects of the CBT on costs and QALYs was approximately L87 million. Conclusions: CBT for insomnia in people with schizophrenia is effective and potentially cost effective. A larger trial is needed to provide clear evidence about its cost effectiveness. Relevance: Patients with schizophrenia have multiple complex health needs, as well as very high rates of depression, suicidal ideation and poor physical health. The results of this study showed that treating pervasive sleep problems in this patient group with cognitive-behavioural therapy (CBT) is very likely to improve patient quality of life in the short term. Clinicians most commonly use hypnotic medication to treat sleeping disorders. This study indicates that CBT may be an effective and cost-effective intervention in this patient group. This alternative would also be aligned with patient preferences for psychological and behavioural-type therapy. Declaration of interest: None. PMID- 29971155 TI - Mother and Baby Units matter: improved outcomes for both. AB - Background: Mother and Baby Units (MBUs) are usually preferred by patients and clinicians. Current provision is limited, although expansion is in progress. To ensure successful investment in services, outcome measurement is vital. Aims: To describe maternal outcomes, mother-infant outcomes and their relationship in one MBU. Method: Paired maternal Brief Psychiatric Rating Scale (BPRS) scores, Health of the Nation Outcome Scales (HoNOS) scores and Crittenden CARE-Index (CCI) mother-infant interaction data were collected at admission and discharge. Results: There were significant improvements in BPRS (n = 152), HoNOS (n = 141) and CCI (n = 62) scores across diagnostic groups. Maternal BPRS scores and mother infant interaction scores were unrelated. Improvement in maternal HoNOS scores was associated with improved maternal sensitivity and reduction in maternal unresponsiveness and infant passiveness. Conclusions: Positive outcomes were achieved for mothers and babies across all diagnostic groups. Reduction in maternal symptoms, as measured by BPRS, does not necessarily confer improvement in mother-infant interaction. MBU treatment should focus on both maternal symptoms and mother-infant interaction. Declaration of interest: None. PMID- 29971158 TI - A randomised controlled trial to evaluate the plaque removal efficacy of sodium bicarbonate dentifrices in a single brushing clinical model. AB - Objective: To evaluate plaque removal efficacy of dentifrices containing sodium bicarbonate (NaHCO3) compared with a non-NaHCO3 dentifrice after a single-timed brushing. Materials and methods: A randomised, controlled, examiner-blinded, four period, crossover study in 56 adults with a mean whole-mouth plaque index of >=2.00 (six site modification of Turesky modification of Quigley-Hein Plaque Index [TPI]). Subjects brushed once for one timed minute with a 67% NaHCO3 dentifrice with herbs; a 67% NaHCO3 dentifrice without herbs; a 62% NaHCO3 dentifrice with herbs; or a non-NaHCO3 dentifrice without herbs. All contained 923 p.p.m. fluoride as sodium fluoride. Pre- and post-brushing plaque assessments were performed. Results: Mean TPI score decreased from pre- to post-brushing with all treatments. There were statistically significantly greater reductions in plaque for NaHCO3 dentifrices compared to non-NaHCO3 (p < 0.0001 for all) with no significant differences between NaHCO3-containing dentifrices. A post hoc analysis of plaque removal from different oral areas showed statistically significant differences in favour of the NaHCO3 dentifrices over the non-NaHCO3 dentifrice for almost all surfaces. No adverse events were reported. Discussion and conclusion: Plaque removal was significantly greater with NaHCO3-containing dentifrices compared with a non-NaHCO3 dentifrice after a single, timed brushing. There was no effect of herbal tinctures. This study was registered at ClincalTrials.org: NCT03285984. PMID- 29971157 TI - Bipolar disorder, comorbid anxiety disorders, gynecomastia and dental pain: case analysis with literature review. AB - : Bipolar disorder with comorbid anxiety disorders frequently requires rational polypharmacy, including use of serotonergic psychotropics. These may result in adverse effects, influencing adherence, complicating treatment and confounding diagnoses. Serotonergic non-adherence is associated with discontinuation syndromes. In this complex case with an on/off/on/off design, both dose-dependent buspirone-induced gynecomastia and buspirone discontinuation syndrome with dental pain are reported. Clinicians and patients should consider these findings to maximise treatment adherence, minimise any unnecessary interventions and address unusual adverse effects. Since patients may not voluntarily disclose specific adverse effects and often do not acknowledge non-adherence, clinician-directed questions are required. This case further emphasises the importance of medication and symptom timelines to guide determination of causation for adverse effects. Although findings from this case cannot be generalised, they suggest the need for continued clinician and patient education, as well as the benefit from detailed case reports. Declaration of interest: None. PMID- 29971159 TI - Designing a Cocreated Intervention with African American Older Adults for Hypertension Self-Management. AB - Hypertension is a lifelong disease that requires self-management. Additionally, there are disparities in hypertension self-management that disproportionately affect African Americans. Interventions designed in collaboration with older adults have the potential to improve hypertension self-management. The purpose of this design paper is to describe the process in which African American older adults and nurse researchers cocreated an intervention to address stress in the self-management of hypertension. A semistructured interview guide was used to elicit feedback on self-management behaviors to cocreate an intervention with the participants. Participants provided constant iterative feedback on the design used for the intervention. Participants prioritized the content and mode of delivery. African American older adults with hypertension (N = 31; 87% women) participated in two focus group sessions. The primary stressors identified by the group that influenced their blood pressure self-management were as follows: (a) measuring blood pressure and using home blood pressure monitors; (b) difficulty communicating with family and friends; (c) sleep management and pain at night; and (d) healthy eating. Based on the participants' feedback, we created four biweekly (2-hour) group sessions that incorporated their suggestions and addressed their concerns. Health care providers can use this technique to engage African American older adults in participant-centered hypertension self management. PMID- 29971160 TI - Comparative Evaluation of Adiposity Indices as Predictors of Hypertension among Brazilian Adults. AB - Purpose: To compare several anthropometric indices in the prediction of hypertension among adults. Methods: This is a cross-sectional study. Five hundred and eighteen adult men and women (40.9 +/- 10.5 years; 1.62 +/- .09 m; 72.3 +/- 15.6 kg) volunteered to participate and underwent blood pressure and anthropometric measures. Anthropometric assessments were used to calculate body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to stature ratio (WSR), body adiposity index (BAI), and conicity index (C). Comparisons between men and women were carried out by independent t-test and chi square test. Cut-off points for each adiposity index to predict hypertension were obtained using Receiver Operating Characteristic (ROC) curve analyses. The significance level was set at P <= .05. Results: All adiposity indices regarding both genders showed significant odds ratios, except BAI (odds ratio: 1.534; CI: 0.916-2.571) for women. In men, WHR and WSR were considered as more balanced indices regarding their sensitivity (AUC: 73.8 and 71.4, respectively) and specificity (AUC: 77.6 and 73.1, respectively). In women, WHR and WSR presented areas under the ROC curves higher than C index (P = .007) and BAI (P = .03), respectively. Conclusion: Indices that consider abdominal adiposity such as WC, WHR, and WSR have a stronger relationship with hypertension compared to others. PMID- 29971161 TI - Association between HDL Cholesterol Levels and the Consumption of Vitamin A in Metabolically Healthy Obese Lebanese: A Cross-Sectional Study among Adults in Lebanon. AB - Objectives: Previous studies show the association between vitamin A and elevation of plasma triglyceride concentrations. However, limited information exists on the association between vitamin A and plasma HDL cholesterol concentrations. The aim of this study is to investigate the association between plasma HDL cholesterol levels and vitamin A intake in 57 metabolically healthy obese (MHO) Lebanese. Methods: Out of the 112 adult obese participants who had completed anthropometric and biochemical data, 57 (22 males and 35 females) aged 18-62 years old are metabolically healthy and their data are included in this study. A valid semiquantitative food frequency questionnaire (SQFFQ) was used to test vitamin A intake among other antioxidants. The participants were recruited from the database of three dietary clinics across Lebanon. Results: Pearson's correlation coefficient was used to measure the strength of the relationship between vitamin A and plasma HDL cholesterol levels. There was a significant positive correlation (P value = 0.0225) between vitamin A consumption and HDL cholesterol serum levels in obese participants; when vitamin A levels decrease, HDL levels decrease more in female than in male participants. Conclusion: The association between dietary vitamin A, a powerful antioxidant, and high HDL levels is shown in MHO but should be further exploited in future studies. PMID- 29971162 TI - Elective "True Day Case" Laparoscopic Inguinal Hernia Repair in a District General Hospital: Lessons Learned from 1000 Consecutive Cases. AB - Introduction: Laparoscopic inguinal hernia repair (LIHR) is ideal for day case surgery. It is recommended that at least 70% should be day cases as a measure of cost-effectiveness. The aims of this study were to (i) assess the rate of true day case (TDC) surgery and (ii) identify predictors associated with unexpected overnight stay (UOS). Methods: Data was collected prospectively on 1000 consecutive elective LIHR performed in a District General Hospital (DGH) over a 7 year period. Data was collected on baseline patient demographics, ASA grade, and intraoperative details. A multivariate analysis was performed in order to identify predictors of UOS. Results: 1000 patients (927 males) underwent elective LIHR. Mean age was 57.3+/-15.2 years. 915 patients were planned as day case procedures. 822/915 day cases (89.8%) were discharged on the same day and 93 (10.2%) stayed overnight unexpectedly. Patient age, duration of procedure, and patient slot in the operating list were found to be independent predictors (p<0.05) of UOS. Conclusion: Our results demonstrate that LIHR is a "true" day case procedure in a DGH. Although some factors associated with UOS cannot be altered, careful patient selection and operating list planning are of paramount importance in order to minimise the burden on healthcare resources. PMID- 29971163 TI - Burden of Depression among Working-Age Adults with Rheumatoid Arthritis. AB - Objective: This study estimated the excess clinical, humanistic, and economic burden associated with depression among working-age adults with Rheumatoid Arthritis (RA). Methods: A retrospective cross-sectional study was conducted among working-age (18 to 64 years) RA patients with depression (N = 647) and without depression (N = 2,015) using data from the nationally representative Medical Expenditure Panel Survey for the years 2009, 2011, 2013, and 2015. Results: Overall, 25.8% had depression. In adjusted analyses, adults with RA and depression compared to those without depression were significantly more likely to have pain interference with normal work (severe pain: AOR = 2.22; 95% CI = 1.55, 3.18), functional limitations (AOR = 2.17; 95% CI = 1.61, 2.94), and lower mental health HRQoL scores. Adults with RA and depression had significantly higher annual healthcare expenditures ($14,752 versus 10,541, p < .001) and out-of pocket spending burden. Adults with RA and depression were more likely to be unemployed and among employed adults, those with depression had a significantly higher number of missed work days annually and higher lost annual wages due to missed work days. Conclusions: This study highlights the importance of effectively managing depression in routine clinical practice of RA patients to reduce pain and functional limitations, improve quality of life, and lower direct and indirect healthcare costs. PMID- 29971164 TI - The Etiological Spectrum of Febrile Encephalopathy in Adult Patients: A Cross Sectional Study from a Developing Country. AB - The profile of febrile encephalopathy varies based on different demographic and geographical characteristics of the study population. This retrospective, cross sectional study was conducted to evaluate the etiological spectrum of febrile encephalopathy in hospitalized adult patients. A total of 293 patients with the mean age of 49.7 +/- 23 were evaluated of whom 77.1% presented with encephalopathy syndrome. The most common diagnosis in patients with clinical syndromes suggestive of central nervous system (CNS) infection was sepsis associated encephalopathy (SAE) (22.9%), followed by bacterial meningitis (14%) and neurotuberculosis (9.9%). The comparison between the elderly and young adults showed that, in the young adults, bacterial meningitis and neurotuberculosis, and in the elderly SAE, are among the most common causes of clinical syndromes suggestive of CNS infection including febrile encephalopathy in our region. Moreover, we illustrated an upward trend for the proportion of diagnosing CNS infections among those who underwent diagnostic LP, from 40.4% in 2011 to 70% in 2015, that could be indicative of an increasing threshold for performing LP at least in our center in recent years. Whether these changes have been associated with increasing the rate of diagnostic errors or not needs to be evaluated in future studies. PMID- 29971165 TI - Equestrian Injury Presentations to a Regional Trauma Centre in Ireland. AB - Background: The Irish Equestrian industry provides over 12,500 full time job equivalents contributing in excess of ?454 million to the Irish economy annually. For such an important industry there is a paucity of information relating to equestrian injuries. Aims: The aim of this study was to determine the demographics, characteristics, and outcomes of equestrian related injuries presenting to the emergency department of a regional trauma centre in Ireland over the course of one year. Methods: Retrospective analysis of all 30,700 presentations to the emergency department (ED) of the Midland Regional Hospital (MRH) Tullamore in 2013 was performed to identify equestrian related presentations. Patient demographics, mechanism of injury, radiology results, management, and follow-up data were collected and analysed using Microsoft Excel software. Results: A total of 149 equestrian related presentations were identified during the study period. There were significantly more females involved in equestrian injuries than males (58% versus 42%). Falling from a horse contributed to significantly more presentations and admissions than any other cause. 36% of presentations were associated with a radiological abnormality. Types of injuries identified included skeletal fractures (27.5%), joint dislocation/subluxation (5%), concussion (12.5%), and splenic laceration/intraperitoneal haemorrhage (1%). Admission or transfer to tertiary care was required for 18% of equestrian injuries. Only 43% of presentations were discharged back to primary care from the emergency department. Conclusion: This study identifies a high incidence of morbidities associated with equestrian presentations. In addition we recognised populations at risk of specific injuries and described high-risk mechanisms of injury. PMID- 29971166 TI - Acute Whole Body Vibration Decreases the Glucose Levels in Elderly Diabetic Women. AB - Type II diabetes (TIIDM) is characterized by high levels of blood glucose followed by excessive insulin release so that the target cells become less sensitive, developing insulin resistance and maintaining hyperglycemic levels. Physical activity is the strongest element to prevent and to manage the TIIDM, and the majority of patients do not remain in regularly active levels, because the premature fatigue in these patients decreases the adherence to the training. Contrastingly, the whole body vibration (WBV) training may improve the glucose metabolism in diabetic patients, reducing the peripheral blood sugar, decreasing the physical discomfort and perceived exertion. Therefore, the purpose of the study was to determine the effect of an acute WBV session as therapy to promote fasting decreases in insulin levels in peripheral blood in TIIDM when compared to healthy elderly. For this, fifteen healthy elderly women and fourteen diabetic elderly women, all sedentary, were allocated in diabetic or control groups, and we made an acute whole body session composed of 10 bouts lasting 2 minutes each one, separated by a 30-second rest period. The WBV was executed in a triaxial platform MY3 Power Plate(r) at 35 hertz and has been chosen a peak-to-peak displacement of 4 millimeters. After the protocol, both groups decreased the glycemic levels and increased lactate production in relation to the basal levels and when compared diabetic and control, where the most important results have been shown in diabetic women. This study revealed that WBV training in TIIDM has had significant beneficial effects on the control of glucose levels, still in an acute session. So that, the complete training probably will show better results about glycemic control and this finding could be especially important when prescribing exercise for elderly who are unable or unwilling to use traditional loads or who show poor exercise compliance. PMID- 29971167 TI - Minimally Invasive Plate Osteosynthesis for Proximal Humerus Fractures: A Retrospective Study Describing Principles and Advantages of the Technique. AB - Background: The aim of this study was to evaluate the clinical and radiographic results after minimally invasive plate osteosynthesis (MIPO) for proximal humerus fractures. Potential advantages of this approach include the easier exposure of the greater tuberosity and the limited surgical dissection around the fracture site. Materials and Methods: From October 2011 to March 2016, thirty-nine patients (32 women, 7 men) with a mean age of 64.9 years (range: 48-80) were surgically treated with the MIPO technique for proximal humeral fractures. According to Neer classification, there were 12 two-part, 24 three-part, and 2 four-part fractures and 1 two-part fracture-dislocation; the AO/OTA system was also used to categorize the fractures. The Constant-Murley (CMS) and the Oxford Shoulder (OSS) Scores were used to evaluate shoulder function. Results: Thirty four patients were available for clinical and radiographic evaluation at a mean follow-up of 31.8 months (range: 12-54 months). All fractures healed and no postoperative complications occurred. Full recovery of pretrauma activities was reported by 27 patients, while 7 patients presented mild functional limitations. The mean absolute CMS was 75.2 (range: 55-95), the mean normalized CMS was 90.5 (range: 69-107), and the mean OSS was 43.7 (range: 31-48). The only statistically significant correlation was found between the female gender and lower absolute CMS and OSS. Radiographic evaluation revealed varus malunion in 4 cases and valgus malunion in 1 case, while incomplete greater tuberosity reduction was detected in 4 cases. All malunions were related to inadequate reduction at time of surgery and not to secondary displacement. Conclusions: MIPO for proximal humeral fractures is an effective and safe surgical procedure. The limited tissue dissection allows minimizing the incidence of nonunion, avascular necrosis, and infection. The technique is not easy, requires experience to achieve mastery, and should be reserved for selected fracture patterns. In our experience, the main advantage of this approach consists in the direct access to the greater tuberosity, thus facilitating its anatomic reduction and fixation. PMID- 29971168 TI - Hemodynamic Response to Massive Bleeding in a Patient with Congenital Insensitivity to Pain with Anhidrosis. AB - A patient with congenital insensitivity to pain with anhidrosis (CIPA) underwent revision of total hip arthroplasty under general anesthesia with only propofol. During surgery, neither elevation of stress hormones nor hemodynamic changes associated with pain occurred; however, when blood was rapidly lost, compensatory tachycardia was observed. Although patients with CIPA are complicated with autonomic disturbance due to dysfunction of postganglionic sympathetic fibers, this compensatory response indicated that the adrenal glands in patients with CIPA secrete catecholamine as part of a compensatory response during bleeding under general anesthesia. PMID- 29971169 TI - Dislodged Bonded Molar Tube into Wound during Orthognathic Surgery. AB - Introduction: Dislodgement of orthodontic appliance into operation wounds may occur while performing orthognathic surgery. Its occurrence is commonly associated with bonded upper molar tube. Case Report: A 25-year-old gentleman presented with recurrent upper right vestibular abscess three months following a bimaxillary orthognathic surgery. A bonded molar orthodontic tube had dislodged into the wound during the operation. The clinical presentation initially mimics an odontogenic infection until our investigations revealed that it originated from the dislodged appliance. The abscess was drained, the wound site was explored, and the molar tube and neighbouring rigid fixation plates and screws were removed. The patient recovered well following the procedure. Conclusion: Dislodged metal orthodontic appliance in oral wound acts as a foreign body that may exert allergic reactions, infection, or inflammation. Pre- and postoperative intraoral examination of fixed orthodontic appliances including its count should be recorded in orthognathic surgery protocol. PMID- 29971170 TI - A Rare Extraskeletal Osteosarcoma Appearing After 55 Years on a Large Stage 3 Burn Scar. AB - It is widely accepted that chronic burn wounds may lead to the development of various malignant skin tumors. Deep stage 3 burned areas may facilitate deeper carcinogenesis. Deep tissues are probably less subject to severe insult than is the epithelial layer during physical insult, suggesting that soft tissues transform to a lesser extent during the late stages of tumoral development as in an immunocompromised district with altered local immune defense with both cellular and humoral defense affected. Most authors claim that tumors are almost squamous cell carcinomas, although other types of malignancies such as basal cell carcinoma and, to a lesser extent, melanoma can also be seen. However, malignant transformation of cutaneous soft tissue in a burn insult area has rarely been described. Similarly, burn-induced tumors of histiocytic origin have been reported in few cases and osteosarcoma only in two case reports. Here, we report a patient case suffering from severe large stage 3 burn after-effects on the leg. Fifty-five years after the injury, this patient developed a large extraosseous osteosarcoma on the scar. PMID- 29971171 TI - Isolated Polycystic Liver Disease: An Unusual Cause of Recurrent Variceal Bleed. AB - Isolated polycystic liver disease is a rare disorder. Majority of the patients with isolated polycystic liver disease are asymptomatic with incidental detection of liver cysts on imaging studies done for other purposes. Minority of patients develop symptoms which are mostly secondary to enlarging cysts size and hepatomegaly. Rarely, these patients develop portal hypertension and can present with its clinical manifestations and consequences in the form acute variceal bleeding or recurrent ascites. We present a rare case of 67-year-old female patient with significant history of polycystic liver disease who presented to the hospital with recurrent hematemesis and melena. She underwent esophagogastroduodenoscopy which showed multiple large esophageal varices requiring banding. PMID- 29971172 TI - Duodenal Pyloric Gland Adenoma in a 59-Year-Old Asian Male. AB - Pyloric gland adenomas (PGAs) are rare precancerous tumors typically arising from the stomach. Even more rarely do they arise in extragastric sites such as the duodenum and gallbladder. The identification of PGAs is important because they possess a risk of developing into invasive adenocarcinoma. This case report describes a 59-year-old male who presented to our office for a follow-up of a nonspecific duodenal lesion. Endoscopic ultrasound and pathology revealed a PGA with low grade dysplasia and some areas of focal high grade dysplasia. It is important that gastroenterologists are aware of these lesions and their risk of malignant transformation. More studies are needed to describe the long-term behavior of pyloric gland adenomas and to recommend appropriate endoscopic surveillance of these lesions. PMID- 29971173 TI - Candida glabrata: A Unique Cause of Necrotizing Urethritis. AB - Necrotizing urethritis is a rare malady with only one other case reported in the literature found to be due to an infectious cause. We report a case of necrotizing urethritis caused by Candida glabrata and review all relevant literature to date. The patient is a 56-year-old man with a past medical history significant for poorly controlled insulin-dependent type 2 diabetes mellitus and incomplete bladder emptying who presented to the University Medical Center with perineal pain, fever, and urinary retention. Cross-sectional imaging showed emphysematous changes in the bulb of the corpus spongiosum. After admission, his fever and leukocytosis persisted, and his physical exam worsened with intravenous antibiotics alone. Subsequently, the patient underwent cystourethroscopy with incision and debridement of the corpus spongiosum. Postoperatively, he improved clinically and his spongiosum wound and urine grew Candida glabrata. To our knowledge, we report the first case of necrotizing urethritis caused by Candida glabrata. PMID- 29971174 TI - Corrigendum to "Community-Acquired Cavitary Pseudomonas Pneumonia Linked to Use of a Home Humidifier". AB - [This corrects the article DOI: 10.1155/2017/5474916.]. PMID- 29971175 TI - Recurrence of Primary Vascular Leiomyosarcoma Five Years after Initial Diagnosis in the Lower Extremity. AB - Primary leiomyosarcomas of vascular origin are rare tumors. They frequently arise within the inferior vena cava; however, the peripheral vein was also affected. To date, only a few hundred cases have been reported in the world literature. Although it is an extremely aggressive tumor, the symptoms may be unspecific, especially in the lower extremities. In this report, we present a case of primary vascular leiomyosarcoma, arising from the short saphenous vein, with symptoms mimicking thrombus in the initial diagnosis. The diagnosis of leiomyosarcomas was confirmed by standard H&E staining and immunohistochemical staining. Recurrence of the tumor has been observed five years after surgical treatment. Due to its rarity, experience in the management of this type of tumor is limited. The mainstay of treatment for these tumors is complete surgical resection. The purpose of the presented case is to discuss the clinicopathological features and management options of this tumor, under the light of the most recent literatures. PMID- 29971176 TI - Camptocormia in an Adolescent: A Case Report and Review of the Literature. AB - Camptocormia, or bent-spine syndrome, is an entity with a long history and many etiologies. We discuss below both the history of this diagnosis in light of a rare case of psychogenic camptocormia and the recent changes in nosology regarding this disorder. PMID- 29971177 TI - Parotid Oncocytoma as a Manifestation of Birt-Hogg-Dube Syndrome. AB - Birt-Hogg-Dube syndrome (BHD) is a rare autosomal dominant disease characterized by skin fibrofolliculomas, pulmonary cysts, spontaneous pneumothoraces, and renal cancers. Oncocytomas are benign epithelial tumors that are also rare. Recently, there have been a few case reports of BHD with a parotid oncocytoma that appears to have a BHD phenotype. Here we document the eighth known case and describe the magnetic resonance imaging features of the parotid oncocytoma, which mimicked Warthin's tumor. Radiologists should be aware of the association between these rare disorders. PMID- 29971179 TI - An Ulcerated Ileal Gastrointestinal Stromal Tumor Disguised as Acute Appendicitis. AB - Background: Gastrointestinal stromal tumor (GIST) of the ileum is not a common differential to consider in the management of acute right iliac fossa (RIF) pain and tenderness. Finding of a normal-looking appendix intraoperatively should arouse the surgeon to explore further and look for other unanticipated pathologies. We present a case, clinically diagnosed as acute appendicitis and intraoperatively found to be an ulcerated ileal GIST. Case Presentation: A 28 year-old female without previous comorbidities presented to the emergency unit with sudden pain around the umbilicus that later migrated and localized to the RIF for one day. There was associated intermittent fever and anorexia without urinary symptoms. Abdominal examination revealed guarding and rebound tenderness at RIF. Examination by 2 senior surgeons at different points of time, the same day, made a clinical diagnosis of acute appendicitis. Ultrasonogram (USG) was inconclusive. At laparotomy through Lanz incision, the appendix was found to be normal and no other pathology was identified on walking bowel up to 3 ft proximal to ileocecal junction (ICJ). Just when closure was thought of, an ulcerated lesion could be seen through the medial aspect of the incision. On further exploration, a 7 * 5 cm ulcerated lesion arising from the antimesenteric border of the ileum was noted with localized interloop hemoperitoneum and inflammatory exudates. Ileal segmental resection anastomosis was done with peritoneal toileting. The lesion was subsequently reported to be an ulcerated malignant GIST. Conclusion: The commonest cause of RIF pain with localized peritonitis is an acutely inflamed appendix. Dilemma arises when the appendix is found to look normal. Further exploration is indicted to not miss other findings. PMID- 29971178 TI - Aortic Aneurysm as a Complication of Granulomatosis with Polyangiitis Successfully Treated with Prednisolone and Cyclophosphamide: A Case Report and Review of the Literature. AB - A 57-year-old Japanese man was admitted to the hospital with back pain and fever, multiple lung nodules, and abdominal aortic aneurysm (AAA). Laboratory tests performed at admission showed an increased proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA) level. Video-associated thoracoscopic lung biopsy was performed; pathologic examination showed granulation tissue with necrosis and multinucleated giant cells. The diagnosis of granulomatosis with polyangiitis (GPA) was confirmed on the basis of the clinical presentation, laboratory findings, and lung biopsy. All symptoms were ameliorated, and the serum level of PR3-ANCA declined following treatment with prednisolone and cyclophosphamide. Although the association of GPA with AAA is rare, GPA may be included among the large vessel vasculitides that can give rise to aortic aneurysm. PMID- 29971180 TI - Unexpected Liver Embryonal Sarcoma in the Adult: Diagnosis and Treatment. AB - Undifferentiated embryonal sarcoma of the liver is a malignancy with poor prognosis observed more frequently in children between 6 and 10 years old and very rarely found in adults. We present a case of embryonal sarcoma of the liver in a 60-year-old woman without significant medical history who presented to our attention with constitutional symptoms. Preoperative assessments did not show alterations in blood chemistry or tumor markers. Imaging studies showed a huge mass lying in the right abdominal quadrants, strictly adherent to the liver. The tumor was partially cystic with a thickened wall, sporadic contrast enhancement, and solid component. The patient underwent excision of the mass with associated liver bisegmentectomy S5-S6. Postoperative course was uneventful. The definitive histological diagnosis revealed the presence of embryonal sarcoma of the liver. We describe the clinical, histopathological, and therapeutic options adopted in the multimodal treatment of this disease. PMID- 29971181 TI - Postpartum urinary retention: Evaluation of risk factors. AB - Objective: Postpartum urinary retention means the absence of spontaneous micturition more than 6 hours after birth or when residual volume after urination is less than 150 cc. If neglected, postpartum urinary retention may result in bladder denervation and detrusor muscle weakness requiring intermittent catheterization or permanent micturition dysfunction. Our goal was to identify the possible risk factors for postpartum urinary retention. Materials and Methods: Five hundred sixty female subjects were included in this retrospective study. All data obtained including variables such as age, parity, body mass index, duration of labor, prepartum bladder catheterization were compared between female subjects with and without postpartum urinary retention. Results: Among the 560 patients recruited to our study, 124 (22.1%) had postpartum urinary retention. Third stage duration, time from birth to the first void, and number of peripartum micturitions were found to be potential risk factors for postpartum urinary retention. Different than other studies, our study revealed a correlation between peripartum catheterization and postpartum urinary retention. There were no statistically significant differences between patients with and without postpartum urinary retention in terms of other variables. Conclusion: In this study, a correlation between peripartum catheterization and postpartum urinary retention was found. There are studies that reported the possible risk factors related to the occurrence of postpartum urinary retention. More studies should be conducted to investigate long-term results with larger populations. PMID- 29971182 TI - Evaluation of the diabetes in pregnancy study group of India criteria and Carpenter-Coustan criteria in the diagnosis of gestational diabetes mellitus. AB - Objective: Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance that is diagnosed for the first time during pregnancy. This prospective study was undertaken to validate the single-step non-fasting 75 gm Diabetes in Pregnancy Study Group of India (DIPSI) criteria of GDM in Indian patients in comparison with the two-step fasting 100 gm glucose challenge through the Carpenter Coustan criteria (CCC). Materials and Methods: Two hundred patients underwent comparative testing using the DIPSI criteria and CCC. Plasma venous blood glucose levels were estimated using the hexokinase method; values >=140 mg/dL at 2 hours were considered positive according to the DIPSI criteria. Any two values from >=95 mg/dL for fasting, >=180 mg/dL at 1 hour, >=155 mg/dL at 2 hours, and >=140 mg/dL at 3 hours were considered positive with the CCC. Results: The mean age and body mass index were 24.26+/-3.75 years and 20.7+/-3.07 kg/m2. The sensitivity, specificity, and positive and negative predictive values of the DIPSI guidelines were found as 100%, 97.14%, 83.87%, and 100%, respectively. The positive and negative likelihood ratios were 35.8 and zero. Diagnostic accuracy was found as 97.56%. Conclusion: DIPSI having high sensitivity, specificity, negative predictive value and diagnostic accuracy. DIPSI offers simplicity, feasibility, convenience, and repeatability while economizing universal screening and diagnosis of GDM on a mass-scale. The DIPSI procedure has the potential to be applied to the entire obstetric population, in the implementation of public health programs to diagnose GDM in the community, thus reaching the needs of the developing world. PMID- 29971183 TI - Visfatin as a predictor for growth of fetus and infant. AB - Objective: Visfatin is an adipocytokine that functions as an enzyme and a growth factor to investigate the relationship between serum visfatin and the fetus's anthropometric markers up to a year after birth. Materials and Methods: Forty-one eligible pregnant women in their first trimester were divided and matched in terms of body mass index (BMI) before pregnancy into normal and higher than normal BMI groups, A and B. Serum visfatin levels were measured during 6-12 and 15-20 weeks of gestation using ELISA. Results: The infants were followed up for a mean duration of 10.19+/-2.83 months. In group A, there was a strong positive relationship between birth head circumference and the first (p1=0.054, r1=0.580) and second trimester visfatin levels (p2=0.051, r2=0.530). In group B, second trimester visfatin levels correlated negatively with birth length (p=0.015, r= 0.523) and infant's head circumference (p2=0.050, r2=-0.392). In a separate study on group B, visfatin levels in the first and second trimesters showed a significant negative correlation with infant's weight. A significant correlation was observed between the first and second trimesters visfatin level with infant's height in both groups, such that this relationship was positive in group A and negative in group B. Linear regression analysis revealed that first and second trimester visfatin levels were significant independent predictors of infant's weight in group B and infant's height in both groups. Second trimester visfatin level was a significant predictor of birth height in group B. Conclusion: Maternal serum visfatin level shows a relationship with fetal and infant anthropometric indicators, with different effects in the two groups, suggesting visfatin dysfunction in the overweight group before pregnancy. PMID- 29971184 TI - Investigation of the embryotoxic and teratogenic effect of Hypericum perforatum in pregnant rats. AB - Objective: Hypericum perforatum (HP) is a herbal product used in the treatment of depression, but its harm on the fetus has not been established. This study investigated the effects of HP according to fetal clinical, morphologic, and histologic findings. Study design is an animal study. Materials and Methods: Fifty-four 4-5-month-old female Wistar rats were divided into three groups: control, 100 mg/kg HP, and 300 mg/kg HP. HP treatment using drinking water was started one week before mating and ended with the delivery of pups. Results: HP exposure before conception diminished the pregnancy rate and decreased the fetal number; during pregnancy it tended to increase the duration of gestation, and deteriorated the fetal development as determined using body weight. It also damaged liver and kidney tissues, most probably due to oxidative stress, as supported through inducible nitric oxide synthase antibody staining findings at both doses. Conclusion: HP should not be recommended to women who would like to be pregnant or are pregnant because it can be harmful for both fetal and maternal health. PMID- 29971185 TI - Diagnostic value of neutrophil to lymphocyte ratio in differentiation of ruptured ovarian cysts and adnexal torsion. AB - Objective: Ovarian cyst rupture and adnexal torsion (AT) differential diagnosis is important for early surgical intervention of AT for preserving ovarian function. The aim of this study was to evaluate the diagnostic value of preoperative the neutrophil-to-lymphocyte ratio (NLR) in patients with adnexal torsion and ovarian cyst rupture. Materials and Methods: Data of 80 patients who underwent surgery between 2012 and 2017 for ovarian cyst rupture, adnexal torsion, and unruptured ovarian cyst were analyzed. Patients were categorized as adnexal torsion (n=35), ovarian cyst rupture (n=20), unruptured ovarian cyst (n=25) groups. Preoperative NLR were compared among the three groups of the patients. Results: The adnexal torsion group had a median NLR of 8.0 (range, 4.0 14.1), the ovarian cyst rupture group had a median of NLR 7.5 (range, 3.7-11.5), and median NLR of the unruptured ovarian cyst group was 2.2 (range,1.8-2.7). The NLR was found to have a difference that reached statistical significance among the three groups (p<0.001). When the groups were individually compared, there was no significant difference between the ovarian cyst rupture and adnexal torsion groups (p=0.372), but there was a significant difference between the unruptured ovarian cyst and adnexal torsion groups (p<0.001). Conclusion: NLR may be useful in the differential diagnosis of unruptured ovarian cyst from adnexal torsion, but it has no diagnostic value for the differentiation of ovarian cyst rupture and adnexal torsion. PMID- 29971186 TI - Retrospective analysis of mature cystic teratomas in a single center and review of the literature. AB - Objective: The aim af this study is to evaluate patients with mature cystic teratomas (MCT) with regard to the view of updated knowledge using our retrospective findings. Materials and Methods: This was a retrospective study and included a total of 306 patients from 2013 through 2017 at the Istanbul Zeynep Kamil Women and Children's Diseases Training and Research Hospital. Results: The mean age of the patients was 34.03+/-11.98 years. Thirty (9.8%) patients were postmenopausal. Torsion was detected in 17 (5.6%) patients. There was a statistically significant relationship between MCT and CA 19-9 levels in our series (p<0.01) but no statistically significant correlation was found with other markers. Conclusion: The possibility of malignancy at postmenopausal ages and in large MCT should not be forgotten. It should be kept in mind that MCT can be seen in unexpected places. PMID- 29971187 TI - Incidence of suspicious axillary lymph node involvement in fluorine-18 fluoro-D glucose positron emission tomography/computed tomography in gynecologic cancers. AB - Objective: There is scarce information about axillary lymph node involvement in gynecologic cancers. We analyzed the incidence of suspicious axillary lymph nodes in gynecologic cancers. Materials and Methods: We retrospectively analyzed the positron emission tomography/computed tomography findings of 251 patients with endometrial, cervical, and ovarian cancer. There is no cut-off value documented for axillary metastases from gynecologic cancers; therefore we adopted the cut off standardized uptake values (SUVs) proclaimed in breast cancer. Results: A total of 251 patients records were available for analysis; 40 patients (15.9%) with suspicious axillary lymph nodes were included in the study. Twenty-one and a half percent (n=20/93) of patients with endometrium cancer, 14.1% (n=14/99) of patients with ovarian cancer, and 10% (n=6/59) of those with cervical cancer had suspicious axillary lymph nodes. Patients with an maximum SUV (SUVmax) uptake higher than 3 underwent axillary lymph node biopsy. None of them was found to have axillary metastases of gynecologic cancers in the pathologic evaluation. In one patient with endometrial cancer, an obscure breast ductal carcinoma was diagnosed, another patient with endometrial cancer was found to have follicular lymphoma. The third patient with endometrial cancer had no malignancy in axillary lymph node biopsy, but had Hurthle cell neoplasia in a thyroid biopsy; the patient did not accept any surgical or medical treatment for endometrial cancer and died 23 months later. There were three (7.5%) metachronous cancers out of 40 gynecologic cancers; two patients were explained above, the third patient with endometrium cancer, who was not histopathologically evaluated although the axillary SUVmax was <3, had rectosigmoid cancer and glioblastoma metachronously. Conclusion: Our study shows that an important ratio (14-21%) of patients with gynecologic cancer has suspicious axillary lymph nodes. Increased SUVmax, particularly above 3, might be used as an indication for axillary biopsy and may help to identify secondary metastatic cancer. PMID- 29971188 TI - A mini-review of aesthetic gynecology and leading gynecology associations' approaches to this issue. AB - Aesthetic gynecology has seen increasing patient and physician demand. Although this typically falls in the reign of obstetrics and gynecology, plastic surgeons and cosmetic surgeons have also developed great interest in this field. Currently, few if any obstetrics and gynecology residency or fellowship programs teach this subject matter though inroads have taken place in plastic surgery and cosmetic surgery training programs that had the foresight to include specific training in this field. Currently, many surgeons start by first training in various established certification and preceptorship programs based in the United States and the United Kingdom. New programs worldwide in 2016-2017 have also been launched to offer certification training to interested physicians in both surgical and non-surgical treatments. A steady flow of certificate programs continues to evolve in Turkey, the Middle East, Spain, and South America, as a second wave of experts emerge. We present a review of surgical and non-surgical techniques of what is presently called "aesthetic gynecology" and the approaches of prominent gynecologic societies regarding this relatively new subspecialty. PMID- 29971190 TI - Anatomic structure of the internal iliac artery and its educative dissection for peripartum and pelvic hemorrhage. AB - The abdominal aorta is divided into two parts (right and left) at the level of the fourth-fifth lumbar vertebra and called the common iliac artery. Anterior to the sacroiliac joint, common iliac arteries are divided into external and internal iliac arteries. The external iliac artery supplies the lower limb, and the internal iliac artery is the major vascular supply of the pelvis. Internal iliac artery is divided into anterior and posterior trunk. The anterior trunk supplies the pelvis, visceral organs, and the posterior trunk supplies pelvic parietal structures. The broad ligament envelopes the uterus anteriorly and posteriorly with its sheets and continues as the pelvic peritoneum at the lateral side of the pelvic wall. After cutting the pelvic peritoneum, the retroperitoneal area is visualized and the internal iliac artery with other great vessels of the abdomen can be noted. PMID- 29971191 TI - External iliac artery thrombosis after hypogastric artery ligation and pelvic packing for placenta previa percreta. AB - Placenta previa percreta is a serious pregnancy condition that may cause massive bleeding. Life-threatening hemorrhage is commonly managed via cesarean hysterectomy or vascular ligations in order to preserve fertility. We present a case of bilateral external iliac artery thrombosis after pelvic compression and uterine devascularization due to placenta previa percreta. The patient had cesarean section due to ultrasonography and magnetic resonance imaging-diagnosed placenta previa percreta, and stated that she preferred a conservative approach rather than hysterectomy in a case of massive bleeding. Spontaneous hemorrhage was recognized during the operation. Pelvic compression and bilateral uterine and internal iliac artery ligations were performed. The left external iliac artery was accidentally held and bonded as the left internal iliac artery, which was turned loose within a minute after distinguishing the vessels. Emergency angiography that was applied because of patient's leg pain showed bilateral external iliac artery thrombosis. Angioplasty was performed by a cardiologist for bilateral occlusions. Placenta invasion abnormalities may be managed by pelvic compression or vascular ligations, which have their own serious complications that the surgeon must manage immediately. PMID- 29971192 TI - Diagnostic sign of intra uterine extra amniotic adhesions with 4D ultrasonography: Sheet on string. PMID- 29971189 TI - Oocyte in vitro maturation: A sytematic review. AB - In vitro maturation (IVM) is one of the most controversial aspects of assisted reproductive technology. Although it has been studied extensively, it is still not a conventional treatment option and is accepted as an alternative treatment. However, studies have shown that IVM can be used in almost all areas where in vitro fertilization (IVF) is used and it has a strong place in fertility protection and Ovarian Hyperstimulation syndrome management. The aim of this systematic review was to address all aspects of the current knowledge of IVM treatment together with the evolution of IVM and IVF. PMID- 29971193 TI - Bilateral Facial Spasm Following Guillain-Barre Syndrome. AB - Background: We report a patient who developed lower facial muscle spasm at rest and bilateral facial synkinesis several months after treatment of Guillain-Barre syndrome (GBS); this finding, to our knowledge, is hitherto unreported. Phenomenology Shown: Bilateral synkinesis, facial muscles spasm at rest, bilateral postparalytic facial syndrome. Educational Value: Aberrant regeneration of nerve fibers post GBS, resulting in facial muscles spasm at rest, bilateral synkinesis. PMID- 29971195 TI - A Treatable Rare Cause of Progressive Ataxia and Palatal Tremor. AB - Background: Cerebrotendinous xanthomatosis is a rare autosomal recessive neurometabolic disorder characterized by chronic diarrhea, tendon xanthomas, juvenile cataracts, and neurological symptoms. Case Report: An adult patient with cerebrotendinous xanthomatosis exhibited ataxia and palatal tremor in the absence of tendon xanthomas and cataracts. Discussion: The importance of this case resides on the fact that cerebrotendinous xanthomatosis should be considered as a possible etiology of the syndrome of progressive ataxia with palatal tremor, even in the absence of tendon xanthomas and cataracts. Early diagnosis is critical to the institution of specific treatment with chenodeoxycholic acid. PMID- 29971196 TI - Hemifacial Spasm in Mucopolysaccharidosis Type VI (Maroteaux-Lamy Syndrome). AB - Background: Hemifacial spasms are involuntary contractions of the muscles of one side of the face. Case Report: Here, we report a 5-year-old female patient with a significant past medical history, including mucopolysaccharidosis type VI, who also presented with hemifacial spasms. Further investigations showed narrowing of skull foramina and hydrocephalus, but no compression of the facial nerve. Carbamazepine was given to the patient, which caused cessation of the spasms. Discussion: Currently, there is no literature discussing the relationship between hemifacial spasms and mucopolysaccharidosis type VI; we have proposed that mucopolysaccharide deposits or dural thickening may contribute to nerve irritation. PMID- 29971194 TI - Conditions Associated with Essential Tremor in Veterans: A Potential Role for Chronic Stress. AB - Background: Increased depression, hearing loss, dementia, alcoholism, and mortality in essential tremor patients remain unexplained. We investigated whether conditions associated with tremor are linked to chronic stress. Methods: The FY2013 Veterans Affairs database was queried for 38 selected dual diagnosis combinations in 5,854,223 veterans aged 21-95 years. Results: Post-traumatic stress disorder, anxiety, and depression were the most common psychiatric diagnoses in tremor patients, with the odds ratio exceeding 2 in all 15-year cohorts. Depending on age, patients with essential tremor were more likely than those without to have obsessive-compulsive disorder, bipolar illness, schizophrenia, use tobacco and abuse alcohol, have hypertension, obesity, hyperlipidemia, diabetes, vitamin D deficiency, coronary and cerebrovascular diseases, congestive heart failure, stroke, asthma, hypothyroidism, irritable bowel syndrome, renal insufficiency, alcoholic liver disease, hearing loss, glaucoma, macular degeneration, migraine, epilepsy, idiopathic polyneuropathy, history of head trauma, and 'Alzheimer's dementia. In contrast, lung and colorectal cancer, amyotrophic lateral sclerosis, psychostimulant abuse, and rheumatoid arthritis were not more common. Discussion: Post-traumatic stress disorder, anxiety, and depression, strongly associated with essential tremor, are known risk factors for poor health habits, tobacco use and alcohol abuse; collectively these are risk factors for vascular disease, with further negative health consequences for multiple organ systems. As essential tremor is associated with all these conditions, we propose that chronic stress is not only responsible for the conditions associated with tremor but in some cases itself directly and indirectly induces essential tremor, so that tremor and poor health share a common cause. PMID- 29971197 TI - Deep Brain Stimulation Management of Essential Tremor with Dystonic Features. AB - Clinical Vignette: A 64-year-old female with essential tremor (ET) presents for evaluation of deep brain stimulation (DBS) candidacy. Examination revealed subtle dystonic features as well as a disabling postural-action tremor. Clinical Dilemma: Can dystonia occur in the setting of the diagnosis of ET and can its presence alter DBS target selection? Clinical Solution: Unilateral DBS implantation of the ventralis intermedius (Vim) led to improvement in both tremor and dystonic posturing. Gap in Knowledge: Case reports of DBS in dystonic tremor suggest Vim, globus pallidus internus (GPi), and subthalamic targets may all be effective, to varying degrees, in improving both tremor and dystonia. More rigorous studies are needed to identify the optimal target(s). Expert Commentary: This case underscores the limited evidence available to guide a clinician's choice of DBS targets in patients with ET and dystonia. The severity of the dystonia and the presence of more generalized dystonia may alter the thinking about optimal targeting. Vim, GPi, and subthalamic targets appear potentially acceptable options, though Vim is usually the first target attempted when postural-action tremor is the chief complaint. Occasionally, a second rescue DBS lead may be necessary. PMID- 29971198 TI - Abnormal Vertical Eye Movements as a Clue for Diagnosis of Niemann-Pick Type C. AB - Background: Adult-onset Niemann-Pick Type C is a rare neurogenetic lysosomal disorder, whose diagnosis is often delayed and missed because of its heterogeneous clinical presentations and rarity as well as the lack of awareness of characteristic eye findings among neurologists. Phenomenology Shown: Impaired smooth pursuits, saccades, and optokinetic nystagmus in the vertical direction, with relatively normal eye movements in the horizontal direction, and ataxia features on finger chase testing, tandem walking, and gait ataxia. Educational Value: Impairment of vertical eye movements in combination with ataxia, cognitive impairment, and/or psychiatric symptoms in an adult patient should always raise clinical suspicion of Niemann-Pick Type C. PMID- 29971199 TI - Rockin' Yourself Asleep. AB - Background: Sleep-related rhythmic movement disorder occurs frequently in childhood with a minority of patients having persistent symptoms in adolescence. Phenomenology Shown: We describe a 14-year-old female showing a typical example of head banging at onset of sleep. Educational Value: Sleep-related rhythmic movement disorder usually has a benign and self-limiting nature and medication might only be warranted in cases of severe sleep disruption or frequent injuries. PMID- 29971200 TI - Tardive Akathisia with Asymmetric and Upper-body Presentation: Report of Two Cases and Literature Review. AB - Background: Akathisia is an inner urge to move a body area with an objective motor component of restlessness. Tardive akathisia (TA) is usually bilateral with a predominant lower-body presentation. We report two patients with an asymmetrical predominantly upper-body involvement. Case Report: Two young men with history of psychiatric problems and neuroleptic use revealed atypical TA, characterized by asymmetrical and predominantly upper-body involvement. Their main manifestations were rubbing the face, mostly with one hand, accompanied by an inner sensation of restlessness. Discussion: Our patients are proof that TA can present with asymmetrical and upper-body involvement even with normal brain imaging. PMID- 29971202 TI - Corrigendum: Digitizing Tablet and Fahn-Tolosa-Marin Ratings of Archimedes Spirals have Comparable Minimum Detectable Change in Essential Tremor. AB - [This corrects the article DOI: 10.7916/D89S20H7.]. PMID- 29971201 TI - Dystonia is a Common Phenotypic Feature of MEGDEL Syndrome. AB - In Response To: Giron C, Roze E, Degos, B, Meneret A, Jardel C, Lannuzel A, et al. Adult-onset generalized dystonia as the main manifestation of MEGDEL syndrome. Tremor Other Hyperkinet Mov. 2018; 8. doi: 10.7916/D8VM5VBQ. PMID- 29971203 TI - Why do we need regional chronic kidney disease-mineral bone disorders guidelines? PMID- 29971204 TI - Atrial fibrillation and chronic kidney disease: A bad combination. PMID- 29971205 TI - Pathology identifies glomerular treatment targets in diabetic nephropathy. AB - The development of the glomerular injury in diabetic nephropathy involves interactions between podocytes, endothelium, and the mesangium. Loss of podocytes is an early and critical step in the development of diabetic nephropathy, and analysis of structural lesions within the mesangium such as mesangiolysis implicate the loss of podocytes as a key mediating event. The BTBR ob/ob mouse has proved a useful tool to demonstrate that restoration of podocyte density, once thought to be an absolute barrier to glomerular repair, can be achieved with replacement of the hormone leptin that is constitutively absent in these mice. Restoration of podocyte density is associated with reversal of the structural lesions of morphologically advanced diabetic glomerular injury in this model. This finding, in conjunction with the demonstration in human diabetic patients with morphologically advanced diabetic nephropathy and with long-standing functioning pancreatic transplants of ten years duration that their diabetic nephropathy can be reversed, suggests that restoration of podocyte number and density is an appropriate target for the development of new therapeutics for diabetic nephropathy. PMID- 29971206 TI - Hemodialysis as a life-sustaining treatment at the end of life. AB - The Act on Decisions on Life-Sustaining Treatment for Patients in Hospice and Palliative Care or at the End of Life came into effect on February 4th, 2018, in South Korea. Based on the Act, all Koreans over the age of 19 years can decide whether to refuse life-sustaining treatments at the end of life via advance directive or physician orders. Hemodialysis is one of the options designated in the Act as a life-sustaining treatment that can be withheld or withdrawn near death. However, hemodialysis has unique features. So, it is not easy to determine the best candidates for withholding/withdrawing hemodialysis at the end of life. Thus, it is necessary to investigate the meaning and implications of hemodialysis at the end of life with ethical consideration of futility and withholding or withdrawal of intervention. PMID- 29971207 TI - Epidemiology of continuous renal replacement therapy in Korea: Results from the National Health Insurance Service claims database from 2005 to 2016. AB - Background: Continuous renal replacement therapy (CRRT) is an important treatment modality for severe acute kidney injury. As such, the epidemiology of CRRT in Korea needs further investigation. Methods: We conducted a nationwide, population based study analyzing the claims data from National Health Insurance Service of Korea. All index intensive care unit admission cases of CRRT in government designated tertiary referral hospitals in Korea from 2005 to 2016 were included. Patients with a history of renal replacement therapy or who were under 20 years old were not considered. In addition to baseline and treatment characteristics, patient outcomes, including all-cause mortality and renal survival rates, were investigated. We stratified the study patients according to 3-year time periods and major regions of the nation. Results: We included 37,337 patients who received CRRT in Korea. The overall use of CRRT increased over time, and more than 80% of cases of acute renal replacement therapy were CRRT after 2014. Seoul was the region in which the majority of CRRT (45.0%) was performed. The clinical characteristics of CRRT patients were significantly different among time intervals and regions. Both all-cause mortality and renal survival rates after CRRT were prominently improved in the recent time periods (P < 0.001). Conclusion: CRRT is a widely used treatment strategy for severe acute kidney injury in Korea. The prognosis of CRRT patients has improved compared to the past. This epidemiological study of CRRT in Korea revealed notable trends with regard to time period and geographic region. PMID- 29971208 TI - Concurrent renal dysfunction with ischemic heart disease is an important determinant for cardiac and cerebrovascular mortality in patients on chronic digoxin therapy for atrial fibrillation. AB - Background: Major adverse cardiac and cerebrovascular events (MACCEs) are main concerns in patients with atrial fibrillation (AF); however, factors affecting MACCEs remain inconclusive in AF patients chronically treated with digoxin. We investigated the major clinical determinants for fatal MACCEs in AF patients treated with digoxin over a 10-year follow-up period. Methods: We analyzed a retrospective cohort of 1,480 AF patients at Eulji University Hospital, Daejeon, South Korea from March 2004 to August 2015. Among this population, 402 consecutive patients receiving chronic digoxin therapy were selected for the study. Data for electrocardiography, medication history, laboratory values including the serum digoxin concentration (SDC) and fatal MACCEs were collected. All data were divided and compared between groups based on the occurrence of MACCEs. Results: The overall incidence of fatal MACCEs among the 402 digoxin treated AF patients (age, 68 +/- 11 years; male, 40.3%) was 12.1%. These fatalities resulted from heart failure (46.1%), fatal stroke (26.9%), fatal myocardial infarction (15.3%) and sudden cardiac death (5.7%). A higher prevalence of diabetes, pre-existing ischemic heart disease (IHD), lower estimated glomerular filtration rate (eGFR), higher SDC, and junctional bradycardia were more frequently observed in patients with MACCEs compared to those without MACCEs. Multivariable analysis showed that an eGFR of <= 60 mL/min/1.73 m2 and pre-existing IHD had a hazard ratio of 3.35 and a confidence interval of 1.64-6.87 (P < 0.001) for fatal MACCEs. Conclusion: Chronic kidney disease stage III-V with pre-existing IHD is significantly associated with increased cardiac and cerebrovascular mortality in AF patients with chronic digoxin use. PMID- 29971209 TI - Uremic pruritus and associated factors in hemodialysis patients: A multi-center study. AB - Background: Uremic pruritus is a common and disturbing problem in hemodialysis patients. Although its pathogenesis is not completely understood, it is thought to be multifactorial. The aim of this study was to identify risk factors of uremic pruritus in hemodialysis patients. Methods: A total of 249 patients from four dialysis centers were included in this study. Data were collected using a questionnaire, the visual analogue scale, and the Hospital Anxiety and Depression Scale. We investigated whether socio-demographic and biochemical parameters were correlated to uremic pruritus. Results: Pruritus was present in 53.4% of the hemodialysis patients. The mean visual analogue scale severity was 6.47 +/- 1.56. Patients with white blood cell (WBC) counts > 6.7 * 103/MUL had 1.73 times (95% confidence interval [CI], 1.360-2.888; P = 0.036) more pruritus than did those with WBC counts < 6.7 * 103/MUL. Patients with dry skin were 0.2 times (95% CI, 0.070-0.182; P = 0.028) more likely to suffer from very severe pruritus than were those with normal skin. Conclusion: Uremic pruritus remains a serious problem in dialysis patients. The WBC level and presence of dry skin are thought to be among its causes. Therefore, data regarding the possible risk factors of uremic pruritus must be followed closely in patients at risk. PMID- 29971211 TI - Stabilization of serum alkaline phosphatase in hemodialysis patients by implementation of local chronic kidney disease-mineral bone disorder management strategy: A quality improvement study. AB - Background: The aim of this study is to narrow the gap between global guidelines and local practices, we recently established domestic recommendations by adapting the international guidelines for management of chronic kidney disease-mineral bone disorder (CKD-MBD) in patients on maintenance hemodialysis (MHD). This study was undertaken to determine whether application of this guideline adaptation was associated with improved serum mineral profiles in patients with CKD-MBD. Methods: A total of 355 patients on MHD were enrolled from seven dialysis units. After adhering to our strategy for one year, serum phosphorus, calcium, intact parathyroid hormone (iPTH), and alkaline phosphatase (AP) levels were compared with the baseline. The endpoint was improvement in the proportion of patients with serum mineral levels at target recommendations. Results: The median serum phosphorus level and proportion of patients with serum phosphorus within the target range were not changed. Although the median serum calcium level was significantly increased, the proportion of patients with serum calcium within the target range was not significantly affected. The proportion of patients with serum iPTH at the target level was not altered, although the median serum iPTH was significantly decreased. However, both median serum AP and the proportion of patients with serum AP at the target level (70.4% vs. 89.6%, P < 0.001) were improved. Conclusion: In our patients with MHD, serum mineral profiles were altered and the serum AP level stabilized after implementing our recommendations. Long-term follow-up evaluations are necessary to determine whether uremic bone disease and cardiovascular calcifications are affected by these recommendations. PMID- 29971210 TI - Obesity may be erythropoietin dose-saving in hemodialysis patients. AB - Background: In dialysis patients, the obesity-survival paradox still requires an explanation. Anemia and high doses of erythropoiesis-stimulating agents (ESAs) are associated with worse outcomes in the hemodialysis (HD) population. In the present study, we explored the relation between obesity and anemia control in a sample of maintenance HD patients in Egypt. Methods: This multicenter observational study included 733 patients on maintenance HD from 9 hemodialysis centers in Egypt. Clinical and laboratory data as well as average doses of ESAs and parenteral iron were recorded. The erythropoietin resistance index (ERI) was calculated. Results: Obesity, defined as a body mass index (BMI) >= 30 kg/m2, was present in 22.6% of the studied population. The target hemoglobin level (10.0 11.5 g/dL) was achieved in 27.3% of non-obese and 25.3% of obese patients, with no significant difference. The median serum ferritin and the values of transferrin saturation index did not differ significantly between these two groups. The weekly ESA dose was significantly lower in obese than in non-obese patients (P = 0.0001). A trend toward higher ESA doses and ERI values was observed in patients with lower BMIs (P < 0.0001). Multiple linear regression revealed that the BMI and urea reduction ratio were the strongest predictors of the ERI. Conclusion: Our study adds more evidence to obesity-associated advantages in HD patients. BMI may determine ESA response, with better responses observed in patients with higher BMIs. PMID- 29971212 TI - Long-term prognosis of BK virus-associated nephropathy in kidney transplant recipients. AB - Background: The long-term prognosis of BK virus-associated nephropathy (BKVAN) in kidney transplant recipients (KTRs) is uncertain. We evaluated the long-term prognosis in KTRs with BKVAN and the clinical significance of BKVAN on post transplant clinical outcome. Methods: We retrospectively analyzed the medical records of 582 patients who underwent kidney transplant (KT) between 2001 and 2014. We divided the patients into a BKVAN group (15 patients) diagnosed by allograft biopsy and a control group (356 patients). Results: The incidence of BKVAN was 4.0%, and the mean follow-up duration was 93.1 +/- 52.3 months. Median time from KT to BKVAN diagnosis was 5.9 months (interquartile range [IQR], 4.4 8.7). In the BKVAN group, 9 (60.0%) KTRs with combined acute rejection progressed to graft failure, and the median time from BKVAN diagnosis to graft failure was 36.2 months (IQR, 9.7-65.5). Death-censored graft survival rate and patient survival rate in the BKVAN group were significantly lower than those in the control group. BKVAN and rejection were independent risk factors for graft failure. In the subgroup analysis, death-censored graft survival rate of KTRs with BKVAN with acute rejection was significantly worst in comparison with similar patients without BKVAN regardless of acute rejection (P < 0.001). Conclusion: The long-term prognosis of BKVAN with acute rejection was very poor because of graft failure caused by inadequate treatment for acute rejection considering BKVAN. Therefore, we should carefully monitor the allograft status of KTRs through regular surveillance tests after treatment for BKVAN with acute rejection. PMID- 29971213 TI - A case of microscopic polyangiitis presenting with acute spinal subdural hemorrhage. AB - This report describes a case of a 62-year-old woman with microscopic polyangiitis (MPA) who developed acute spinal subdural hemorrhage. MPA was confirmed by positive autoantibodies to myeloperoxidase and focal segmental necrotizing and pauci-immune crescentic glomerulonephritis on renal biopsy. She did not recover from paraplegia due to acute spinal subdural hemorrhage, despite decompression operation and aggressive immunosuppression. Although spontaneous spinal hemorrhage in MPA patients is very rare, the prognosis for such patients is poor. Considering the possibility of ongoing vasculitis activity in extra-renal organs, clinicians should be very cautious to attenuate the strength of immunosuppressant drugs, even in patients with chronic or irreversible renal pathology. PMID- 29971214 TI - Obturator hernia in autosomal dominant polycystic kidney disease. PMID- 29971215 TI - Erratum: Association of serum uric acid level with coronary artery stenosis severity in Korean end-stage renal disease patients [Volume 36, Issue 3, September 2017, Pages 282-289]. AB - [This corrects the article on p. 282 in vol. 36, PMID: 28904880.]. PMID- 29971216 TI - Predictors of Colorectal Cancer Screening in Two Underserved U.S. Populations: A Parallel Analysis. AB - Background: Despite declining colorectal cancer (CRC) incidence and mortality rates in the U.S., significant geographic and racial disparities in CRC death rates remain. Differences in guideline-concordant CRC screening rates may explain some of these disparities. We aim to assess individual and neighborhood-level predictors of guideline-concordant CRC screening within two cohorts of individuals located within CRC mortality geographic hotspot regions in the U.S. Methods: A total of 36,901 participants from the Southern Community Cohort Study and 4,491 participants from the Ohio Appalachia CRC screening study were included in this study. Self-reported date of last CRC screening was used to determine if the participant was within guidelines for screening. Logistic regression models were utilized to determine the association of individual-level predictors, neighborhood deprivation, and residence in hotspot regions on the odds of being within guidelines for CRC screening. Results: Lower household income, lack of health insurance, and being a smoker were each associated with lower odds of being within guidelines for CRC screening in both cohorts. Area-level associations were less evident, although up to 15% lower guideline adherence was associated with residence in neighborhoods of greater deprivation and in the Lower Mississippi Delta, one of the identified CRC mortality hotspots. Conclusion: These results reveal the adverse effects of lower area-level and individual socioeconomic status on adherence to CRC guideline screening. PMID- 29971217 TI - Genomic Comparison Among Global Isolates of L. interrogans Serovars Copenhageni and Icterohaemorrhagiae Identified Natural Genetic Variation Caused by an Indel. AB - Leptospirosis is a worldwide zoonosis, responsible for more than 1 million cases and 60,000 deaths every year. Among the 13 pathogenic species of the genus Leptospira, serovars belonging to L. interrogans serogroup Icterohaemorrhagiae are considered to be the most virulent strains, and responsible for majority of the reported severe cases. Serovars Copenhageni and Icterohaemorrhagiae are major representatives of this serogroup and despite their public health relevance, little is known regarding the genetic differences between these two serovars. In this study, we analyzed the genome sequences of 67 isolates belonging to L. interrogans serovars Copenhageni and Icterohaemorrhagiae to investigate the influence of spatial and temporal variations on DNA sequence diversity. Out of the 1072 SNPs identified, 276 were in non-coding regions and 796 in coding regions. Indel analyses identified 258 indels, out of which 191 were found in coding regions and 67 in non-coding regions. Our phylogenetic analyses based on SNP dataset revealed that both serovars are closely related but showed distinct spatial clustering. However, likelihood ratio test of the indel data statistically confirmed the presence of a frameshift mutation within a homopolymeric tract of lic12008 gene (related to LPS biosynthesis) in all the L. interrogans serovar Icterohaemorrhagiae strains but not in the Copenhageni strains. Therefore, this internal indel identified can genetically distinguish L. interrogans serovar Copenhageni from serovar Icterohaemorrhagiae with high discriminatory power. To our knowledge, this is the first study to identify global sequence variations (SNPs and Indels) in L. interrogans serovars Copenhageni and Icterohaemorrhagiae. PMID- 29971218 TI - From Host Heme To Iron: The Expanding Spectrum of Heme Degrading Enzymes Used by Pathogenic Bacteria. AB - Iron is an essential nutrient for many bacteria. Since the metal is highly sequestered in host tissues, bound predominantly to heme, pathogenic bacteria often take advantage of heme uptake and degradation mechanisms to acquire iron during infection. The most common mechanism of releasing iron from heme is through oxidative degradation by heme oxygenases (HOs). In addition, an increasing number of proteins that belong to two distinct structural families have been implicated in aerobic heme catabolism. Finally, an enzyme that degrades heme anaerobically was recently uncovered, further expanding the mechanisms for bacterial heme degradation. In this analysis, we cover the spectrum and recent advances in heme degradation by infectious bacteria. We briefly explain heme oxidation by the two groups of recognized HOs to ground readers before focusing on two new types of proteins that are reported to be involved in utilization of heme iron. We discuss the structure and enzymatic function of proteins representing these groups, their biological context, and how they are regulated to provide a more complete look at their cellular role. PMID- 29971219 TI - Life and Death of mRNA Molecules in Entamoeba histolytica. AB - In eukaryotic cells, the life cycle of mRNA molecules is modulated in response to environmental signals and cell-cell communication in order to support cellular homeostasis. Capping, splicing and polyadenylation in the nucleus lead to the formation of transcripts that are suitable for translation in cytoplasm, until mRNA decay occurs in P-bodies. Although pre-mRNA processing and degradation mechanisms have usually been studied separately, they occur simultaneously and in a coordinated manner through protein-protein interactions, maintaining the integrity of gene expression. In the past few years, the availability of the genome sequence of Entamoeba histolytica, the protozoan parasite responsible for human amoebiasis, coupled to the development of the so-called "omics" technologies provided new opportunities for the study of mRNA processing and turnover in this pathogen. Here, we review the current knowledge about the molecular basis for splicing, 3' end formation and mRNA degradation in amoeba, which suggest the conservation of events related to mRNA life throughout evolution. We also present the functional characterization of some key proteins and describe some interactions that indicate the relevance of cooperative regulatory events for gene expression in this human parasite. PMID- 29971220 TI - Association Between Gut Microbiota and Helicobacter pylori-Related Gastric Lesions in a High-Risk Population of Gastric Cancer. AB - Eradication of Helicobacter pylori has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and H. pylori-related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were Bacteroidetes, Firmicutes, and Proteobacteria with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current H. pylori infection compared with negative subjects. As for the differential bacteria, the average relative abundance of Bacteroidetes was found to significantly decrease from H. pylori negative (66.16%) to past infection group (33.01%, p = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, p = 0.027). For Firmicutes and Proteobacteria, the average relative abundances showed elevated trends in the past H. pylori infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, p = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, p = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both p < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria, may be involved in the process of H. pylori-related gastric lesion progression and provide hints for future evaluation of microbial changes after H. pylori eradication. PMID- 29971222 TI - Growth Failure and Excessive Weight Gain in a 10 Year Old Male With Obesity: Approach to Diagnosis, Management, and Treatment of Acquired Hypothyroidism. AB - We report the case of a 10 year old male with severe obesity who presented with a 2 year history of significant growth failure and excessive weight gain that was subsequently diagnosed with serum negative Hashimoto's thyroiditis and acquired hypothyroidism. Initial investigations revealed a markedly elevated thyroid stimulating hormone (TSH) concentration >100 uIU/mL and an undetectable free thyroxine with total thyroxine 0.56 ug/dL. Thyroid antibodies were negative, however ultrasound findings were consistent with Hashimoto's thyroiditis. After treatment with levothyroxine supplementation, he had significant weight loss and marked improvement in his growth velocity. This case emphasizes the need to recognize excessive weight gain and growth failure as an initial presentation of Hashimoto's thyroiditis and highlights management and approach to treatment. Diagnosis and treatment is vital as prolonged undiagnosed hypothyroidism can result in incomplete catch up growth and compromised final adult height. PMID- 29971221 TI - Colony and Single Cell Level Analysis of the Heterogeneous Response of Cryptococcus neoformans to Fluconazole. AB - Cryptococcus neoformans is a human fungal pathogen that can cause fatal meningitis in immunocompromised individuals. Fluconazole (FLC) is a fungistatic drug administered to treat cryptococcosis. When exposed to the inhibitory concentration of FLC, C. neoformans exhibits heteroresistance where a small subpopulation of cells develops into FLC-resistant colonies. FLC-resistant cells are aneuploids with regard to specific beneficial chromosomal regions. Factors underlying the potential for only certain C. neoformans cells in a genetically isogenic population to become FLC-resistant are unknown. In this study, we systematically examine the heterogeneous response of C. neoformans to FLC at a colony and individual cell level. We find that the heterogeneity in response to FLC is reflected by variable diminishment of the ergosterol at the plasma membrane. A population of C. neoformans spread on a semi-solid medium displays two types of outcomes following FLC exposure. The first outcome is colonies consisting of non-resistant cells (survivors). The size of colonies consisting of survivors ranges from a few cells to visible colonies, which reflects intrinsic phenotypic heterogeneity of the C. neoformans population. The second outcome is FLC-resistant cells forming colonies of sizes significantly larger as compared to colonies made of survivors. We propose a model that describes how a distribution of these types of cellular responses within a population changes depending on FLC concentration and factors that influence the rate of cellular growth including temperature, media type, growth phase, and the age of cells. Our findings highlight a complex nature of the response to a fungistatic drug and provide insights that may help to optimize FLC therapy. PMID- 29971224 TI - Short-Term Evaluation of Left Ventricular Mass and Function in Children With Growth Hormone Deficiency After Replacement Treatment. AB - Background: Our study was designed to assess the effects of GHD on nutritional and metabolic parameters, brain natriuretic peptide (BNP) levels, and left ventricular mass (LVM) in prepubertal children and after short-term GH replacement therapy. Materials and Methods: This prospective study enrolled 81 children. We compared 40 GHD children (16 males and 24 females) to 41 healthy children (control group) (18 males and 23 females). All subjects were at Tanner Stage I (aged 7-11 years). At the baseline, a blood sample was drawn and echocardiographic images were obtained. These tests were repeated on the GHD subjects after 6 months of GH replacement therapy. Body surface, weight, size, blood pressure, heart rate, glucose, insulin, HOMA-IR, HOMA-beta, QUICKI, cholesterol, HDLc, LDLc, triglycerides, IGF1, and IGFBP3 were measured. Indexed LVM, diastolic and systolic diameter (dD-sD), diastolic and systolic LV function, isovolumic relaxation time, right ventricle function, and BNP levels were obtained through echocardiography. These parameters were correlated to growth factors. Data were analyzed using Student's t-test or U-Mann-Whitney-test and Pearson's correlation, considering p < 0.05 to be significant. Results: Indexed LVM was smaller in GHD patients than in controls, whereas diastolic and systolic functions, BNP, metabolic, and nutritional profiles were similar. After treatment, nutritional and metabolic profiles significantly improved, though diastolic and systolic functions did not seem to have changed. There was a significant increase in LVM. Indexed LVM was similar to that of controls. Significant correlations were obtained between LVM-IGF1 and sD-IGFBP3. Conclusions: GHD in childhood is associated with a lower indexed LVM. In the short-term, GH increases the indexed LVM, while maintaining normal systolic and diastolic functions, BNP, and an improved lipid profile. PMID- 29971225 TI - Community Management of Acute Malnutrition (CMAM) in Odisha, India: A Multi Stakeholder Perspective. AB - India remains home to nearly one-third of the world's children with severe and acute malnutrition (SAM). The present study looks at the function and implementation of a Community Management of Severe Acute Malnutrition (CMAM) programme for treatment of children with SAM in Odisha, an Indian state. A cross sectional study design using qualitative techniques with direct observation of process and infrastructure was adopted to explore the views of stakeholders on the programme implementation. The study focuses on Kandhamal, a district in Odisha, and was conducted during June-August, 2015. Of the district and community level stakeholders involved in CMAM programme, 49 were selected as study participants using purposive sampling. In-depth interviews were conducted to obtain relevant information. Data was analyzed using data analysis software, atlas.ti version 7. The analysis demonstrated the overall acceptability, feasibility and economic viability of the programme. Additionally, the study identified several enablers (such as good response from child, village leadership involvement, multisectoral participation etc.) and barriers (such as limited awareness, increased work load, irregular staff payment etc.) linked to programme implementation. Interactions with beneficiaries and stakeholders also provided the real picture on the ground. The study emphasizes the need for stakeholders to work responsibly and in unison, and need for beneficiaries to accept, participate and contribute to the programme. In view of maximum impact, the study recommends that CMAM programmes be implemented with existing primary healthcare facilities. The study also outlines future scope for policy-level interventions and support to ensure sustainability of this healthcare delivery model. PMID- 29971223 TI - Difficult vs. Severe Asthma: Definition and Limits of Asthma Control in the Pediatric Population. AB - Evaluating the degree of disease control is pivotal when assessing a patient with asthma. Asthma control is defined as the degree to which manifestations of the disease are reduced or removed by therapy. Two domains of asthma control are identified in the guidelines: symptom control and future risk of poor asthma outcomes, including asthma attacks, accelerated decline in lung function, or treatment-related side effects. Over the past decade, the definition and the tools of asthma control have been substantially implemented so that the majority of children with asthma have their disease well controlled with standard therapies. However, a small subset of asthmatic children still requires maximal therapy to achieve or maintain symptom control and experience considerable morbidity. Childhood uncontrolled asthma is a heterogeneous group and represents a clinical and therapeutic challenge requiring a multidisciplinary systematic assessment. The identification of the factors that may contribute to the gain or loss of control in asthma is essential in differentiating children with difficult to-treat asthma from those with severe asthma that is resistant to traditional therapies. The aim of this review is to focus on current concept of asthma control, describing monitoring tools currently used to assess asthma control in clinical practice and research, and evaluating comorbidities and modifiable and non-modifiable factors associated with uncontrolled asthma in children, with particular reference to severe asthma. PMID- 29971227 TI - Health Complaints Associated With Poor Rental Housing Conditions in Arkansas: The Only State Without a Landlord's Implied Warranty of Habitability. AB - This is a review of an existing article that surveyed the perceived health of renters' in Arkansas. As a first in the field of public health it was able to provide ground-level insight through tenant interviews about housing and health in the state. This review illuminates how the state's sociopolitical characteristics may affect marginalized Arkansas renters. Marginalized renters may include persons living below the poverty line, people of color, and women who are the head of household. This article seeks to elucidate how the upstream factor, habitability law, may impact tenant health in the state. With a novel public health approach, the article contributes to the existing housing and health literature with its invaluable insight of stakeholders' perspectives relating to how habitability law may impact their health outcomes. Now is an opportune time for public health practitioners, researchers, and policymakers to facilitate incremental change to include landlords in their state public health system. Such inclusion may improve housing while promoting, improving, and protecting health outcomes for Arkansas renters. PMID- 29971226 TI - Cultural Diversity and Mental Health: Considerations for Policy and Practice. AB - The purpose of this paper is to explore some of the key considerations that lie at the intersection of cultural diversity and mental health. Mental health providers and professionals across the world have to work with clients that are often from cultures other than their own. The differences in cultures have a range of implications for mental health practice, ranging from the ways that people view health and illness, to treatment seeking patterns, the nature of the therapeutic relationship and issues of racism and discrimination. This paper will excavate some of these considerations with a view to raising possible ways in which mental health systems and professionals can engage across cultures more equitably and sustainably. PMID- 29971229 TI - Ultrafine Particle Recovery Using Thin Permeable Films. AB - The selective recovery of ultrafine, <10 MUm, particles remains a significant challenge in the minerals industry. Indeed, these particles often report to tailings impoundments, resulting in under-utilization of mined resources and the need for tailings dams. Recently, a technique has been developed offering the potential to selectively recover particles down to <1 MUm in size. This technique, originally inspired by oil agglomeration, uses a high internal-phase water in oil emulsion as a binder to selectively agglomerate hydrophobic particles. Due to the significant concentration of the dispersed aqueous phase, ~95%, the continuous organic phase forms a network of very thin, permeable films, estimated to be 60 nm thick. These are stabilized by an emulsifier. In the high shear field of the agglomeration process, the binder is fragmented into smaller hydrophobic portions, delivering its thin film coating to the adhering hydrophobic particles. Permeation of water across the thin films eliminates the viscous hydrodynamic resistance, permitting sub-micron particle recovery to occur at rates similar to those for particles considerably larger in size. This recovery occurs within seconds under intense mixing. In this study, a model system consisting of magnetite, with a Sauter mean diameter of 11.4 MUm, was agglomerated using the water in oil emulsion binder. The binder, which contained the emulsifier sorbitan monooleate, appeared to also act as a collector for the magnetite, thus no separate particle conditioning step was required. Curiously, however, the binder requirements were higher than expected. Further investigations concerning the stability of the binder revealed that the magnetite particles were causing rapid binder degradation. Therefore, prior to agglomeration using the binder, the particles were conditioned with sorbitan monooleate to render them hydrophobic. This pre-conditioning led to significant reductions in the binder dosage required to achieve agglomeration. Moreover, the resulting dosage matched that predicted by a model silica system for the same specific hydrophobic surface area, thus allowing a model to be validated based on the required binder dosage for a known hydrophobic surface area. Examination of binder stability in the presence of conditioned magnetite revealed that the now hydrophobic particles stabilized the binder. PMID- 29971228 TI - Phenotypic Heterogeneity in Dementia: A Challenge for Epidemiology and Biomarker Studies. AB - Dementia can result from a number of distinct diseases with differing etiology and pathophysiology. Even within the same disease, there is considerable phenotypic heterogeneity with varying symptoms and disease trajectories. Dementia diagnosis is thus very complex, time-consuming, and expensive and can only be made definitively post-mortem with histopathological confirmation. These inherent difficulties combined with the overlap of some symptoms and even neuropathological features, present a challenging problem for research in the field. This has likely hampered progress in epidemiological studies of risk factors and preventative interventions, as well as genetic and biomarker research. Resource limitations in large epidemiologically studies mean that limited diagnostic criteria are often used, which can result in phenotypically heterogeneous disease states being grouped together, potentially resulting in misclassification bias. When biomarkers are identified for etiologically heterogeneous diseases, they will have low specificity for any utility in clinical practice, even if their sensitivity is high. We highlight several challenges in in the field which must be addressed for the success of future genetic and biomarker studies, and may be key to the development of the most effective treatments. As a step toward achieving this goal, defining the dementia as a biological construct based on the presence of specific pathological features, rather than clinical symptoms, will enable more precise predictive models. It has the potential to lead to the discovery of novel genetic variants, as well as the identification of individuals at heightened risk of the disease, even prior to the appearance of clinical symptoms. PMID- 29971230 TI - Tailoring the Wettability of Colloidal Particles for Pickering Emulsions via Surface Modification and Roughness. AB - Pickering emulsions are water or oil droplets that are stabilized by colloidal particles and have been intensely studied since the late 90s. The surfactant-free nature of these emulsions has little adverse effects such as irritancy and contamination of environment and typically exhibit enhanced stability compared to surfactant-stabilized emulsions. Therefore, they offer promising applications in cosmetics, food science, controlled release, and the manufacturing of microcapsules and porous materials. The wettability of the colloidal particles is the main parameter determining the formation and stability of Pickering emulsions. Tailoring the wettability by surface chemistry or surface roughness offers considerable scope for the design of a variety of hybrid nanoparticles that may serve as novel efficient Pickering emulsion stabilizers. In this review, we will discuss the recent advances in the development of surface modification of nanoparticles. PMID- 29971231 TI - Conformational Sampling of Small Molecules With iCon: Performance Assessment in Comparison With OMEGA. AB - Herein we present the algorithm and performance assessment of our newly developed conformer generator iCon that was implemented in LigandScout 4.0. Two data sets of high-quality X-ray structures of drug-like small molecules originating from the Protein Data Bank (200 ligands) and the Cambridge Structural Database (481 molecules) were used to validate iCon's performance in the reproduction of experimental conformations. OpenEye's conformer generator OMEGA was subjected to the same evaluation and served as a reference software in this analysis. We tested several setting patterns in order to identify the most suitable and efficient ones for conformational sampling with iCon; equivalent settings were also tested on OMEGA in order to compare the results obtained from the two programs and better assess iCon's performance. Overall, this study proved that iCon is able to generate reliable representative conformational ensembles of drug like small molecules, yielding results comparable to those showed by OMEGA, and thus is ready to serve as a valuable tool for computer-aided drug design. PMID- 29971232 TI - Large Magnetic Polyoxometalates Containing the Cobalt Cubane '[CoIIICo 3II (OH)3(H2O)6-m(PW9O34)]3-' (m = 3 or 5) as a Subunit. AB - A synthetic procedure is presented to construct new magnetic polyoxometalates (POMs) containing one or two subunits of '[CoIIICo 3II (OH)3(H2O)6-m(PW9O34)]3-' (m = 3 or 5). The substitution of the water ligands present in these subunits by oxo or hydroxo ligands belonging to other POM fragments, gives rise to four, larger POM anions: [Co7(OH)6(H2O)6(PW9O34)2]9- (2), [Co7(OH)6(H2O)4(PW9O34)2] n9n (2'), [Co11(OH)5(H2O)5(W6O24)(PW9O34)3]22- (3) and [{Co4(OH)3(H2O)(PW9O34)}2{K?(H2W12O41)2}{Co(H2O)4}2]17- (4). The crystal structures, magnetic characterization and stabilities in aqueous solutions of these POM derivatives are also presented. PMID- 29971234 TI - The Transcriptomic Analysis of Circulating Immune Cells in a Celiac Family Unveils Further Insights Into Disease Pathogenesis. AB - Celiac disease (CD), the most common chronic enteropathy worldwide, is triggered and sustained by a dysregulated immune response to dietary gluten in genetically susceptible individuals. Up to date either the role of environmental factors and the pathways leading to mucosal damage have been only partially unraveled. Therefore, we seized the unique opportunity to study a naturally-occurring experimental model of a family composed of both parents suffering from CD (one on a gluten-free diet) and two non-celiac daughters. The control group consisted in four unrelated cases, two celiac and two non-celiac subjects, all matching with family members for both disease status and genetic susceptibility. In this privileged setting, we sought to investigate gene expression in peripheral blood mononuclear cells (PBMCs), a population known to mirror the immune response state within the gut. To this purpose, PBMCs were obtained from the four biopsied proven CD patients and the four non-celiac cases. Each group included two family members and two unrelated control subjects. After RNA purification and cDNA synthesis, each sample underwent a microarray screen on a whole-transcriptome scale, and the hybridization results were visualized by hierarchical clustering. Differentially expressed genes (DEG) were partitioned into clusters displaying comparable regulations among samples. These clusters were subjected to both functional and pathway analysis by using the Kyoto Encyclopedia of Genes and Genomes. Interestingly, on a global gene expression level, the family members clustered together, regardless of their disease status. A relevant fraction of DEG belonged to a limited number of pathways, and could be differentiated based on disease status: active CD vs. treated CD and CD vs. controls. These pathways were mainly involved in immune function regulation, cell-cell junctions, protein targeting and degradation, exosome trafficking, and signal transduction. Worth of noting, a small group of genes mapping on the male-specific region of the Y chromosome, and previously linked to cardiovascular risk, was found to be strongly upregulated in the active CD case belonging to the family, who suddenly died of a heart attack. Our results provide novel information on CD pathogenesis and may be useful in identifying new therapeutic tools and risk factors associated with this condition. PMID- 29971235 TI - A Systematic Review of Epidemiology and Risk Factors Associated With Chinese Inflammatory Bowel Disease. AB - Background: Recent epidemiological data have revealed a dramatically rising prevalence and incidence of inflammatory bowel diseases (IBDs) in Mainland China, a rapidly growing industrialized region, over the last two decades. Objectives: We performed a systematic review to investigate the changing trends in the incidence of IBD in Mainland China and summarized the recent findings in risk factors associated with Chinese IBD. Methods: Relevant references were obtained from an electronic database search via MEDLINE and EMBASE (for English literatures), the China Academic Journals Full-text Database (CJFD) and the China Science Periodical Database (CSPD) in Wanfang Data (for Chinese literatures). Results: Total 1,584 abstracts in Chinese and 171 abstracts in English were collected. Eight full-text with epidemiological data, 25 with risk factor data in Chinese and 7 full-text with epidemiological data, 12 with risk factor data in English were finally identified and included for analysis. Data from included epidemiological studies has showed a striking increase in the incidence rate of IBD in Mainland China over time, and current incidence rates for IBD, UC, and CD were 1.80 (IBD), 1.33 (UC), and 0.46/1,000,000 (CD), though it varies among regions and ethnic minority populations. In addition, several risk factors including environmental factors, diet, intestinal infectious agents, hygiene, stress, and lifestyle have been reported to be associated with the increased incidence of Chinese IBD. Conclusion: This systematic review revealed an increased incidence of IBD in Mainland China. Although it is still lower than that in the Western world, however, China has a huge population; therefore, the total number of IBD patients might not be so little as previously thought and the disease burden of IBD in China is likely underestimated. HIGHLIGHTS Recent epidemiological data have revealed a dramatically rising prevalence and incidence of inflammatory bowel diseases (IBD) in Mainland China, a rapidly growing industrialized region, over the last two decades.This systematic review based on recent epidemiological data has revealed a striking increase in the incidence rate of IBD in Mainland China, though it varies among regions and ethnic minority populations.Several potential risk factors of IBD including environmental factors, diet, intestinal infectious agents, hygiene, stress, and lifestyle have been reported to be associated with the increased incidence of Chinese IBD.This systematic review on epidemiologic and risk factor studies has expanded understanding of the occurrence, distribution, geographic variance and risk factors of Chinese IBD and will provide clinicians important information in understanding current status of IBD in Mainland China. PMID- 29971233 TI - Kinase and Phosphatase Cross-Talk at the Kinetochore. AB - Multiple kinases and phosphatases act on the kinetochore to control chromosome segregation: Aurora B, Mps1, Bub1, Plk1, Cdk1, PP1, and PP2A-B56, have all been shown to regulate both kinetochore-microtubule attachments and the spindle assembly checkpoint. Given that so many kinases and phosphatases converge onto two key mitotic processes, it is perhaps not surprising to learn that they are, quite literally, entangled in cross-talk. Inhibition of any one of these enzymes produces secondary effects on all the others, which results in a complicated picture that is very difficult to interpret. This review aims to clarify this picture by first collating the direct effects of each enzyme into one overarching schematic of regulation at the Knl1/Mis12/Ndc80 (KMN) network (a major signaling hub at the outer kinetochore). This schematic will then be used to discuss the implications of the cross-talk that connects these enzymes; both in terms of why it may be needed to produce the right type of kinetochore signals and why it nevertheless complicates our interpretations about which enzymes control what processes. Finally, some general experimental approaches will be discussed that could help to characterize kinetochore signaling by dissociating the direct from indirect effect of kinase or phosphatase inhibition in vivo. Together, this review should provide a framework to help understand how a network of kinases and phosphatases cooperate to regulate two key mitotic processes. PMID- 29971236 TI - Functional Mechanism of the Efflux Pumps Transcription Regulators From Pseudomonas aeruginosa Based on 3D Structures. AB - Bacterial antibiotic resistance is a worldwide health problem that deserves important research attention in order to develop new therapeutic strategies. Recently, the World Health Organization (WHO) classified Pseudomonas aeruginosa as one of the priority bacteria for which new antibiotics are urgently needed. In this opportunistic pathogen, antibiotics efflux is one of the most prevalent mechanisms where the drug is efficiently expulsed through the cell-wall. This resistance mechanism is highly correlated to the expression level of efflux pumps of the resistance-nodulation-cell division (RND) family, which is finely tuned by gene regulators. Thus, it is worthwhile considering the efflux pump regulators of P. aeruginosa as promising therapeutical targets alternative. Several families of regulators have been identified, including activators and repressors that control the genetic expression of the pumps in response to an extracellular signal, such as the presence of the antibiotic or other environmental modifications. In this review, based on different crystallographic structures solved from archetypal bacteria, we will first focus on the molecular mechanism of the regulator families involved in the RND efflux pump expression in P. aeruginosa, which are TetR, LysR, MarR, AraC, and the two-components system (TCS). Finally, the regulators of known structure from P. aeruginosa will be presented. PMID- 29971238 TI - Transcatheter Aortic Valve Replacement and Concomitant Mitral Regurgitation. AB - Mitral regurgitation frequently coexists in patients with severe aortic stenosis. Patients with moderate to severe mitral regurgitation at the time of transcatheter aortic valve replacement are at increased risk of future adverse events. Whether concomitant mitral regurgitation is independently associated with worse outcomes after TAVR remains a matter of debate. The optimal therapeutic strategy in these patients-TAVR with evidence-based heart failure therapy, combined TAVR and transcatheter mitral valve intervention, or staged transcatheter therapies-is ill-defined, and guideline-based recommendations in patients at increased risk for open heart surgery are lacking. Hence, a thorough evaluation of the aortic and mitral valve anatomy and function, along with an in depth assessment of the patients' baseline risk profile, provides the basis for an individualized treatment approach. The aim of this review is therefore to give an overview of the current literature on mitral regurgitation in TAVR, focusing on different diagnostic and therapeutic strategies and optimal clinical decision making. PMID- 29971239 TI - Indexed Left Atrial Adipose Tissue Area Is Associated With Severity of Atrial Fibrillation and Atrial Fibrillation Recurrence Among Patients Undergoing Catheter Ablation. AB - Background: Epicardial adipose tissue (EAT) has been associated with adverse left atrial (LA) remodeling and atrial fibrillation (AF) outcomes, possibly because of paracrine signaling. Objectives: We examined factors associated with a novel measure of EAT i.e., indexed LAEAT (iLAEAT) and its prognostic significance after catheter ablation (CA) of atrial fibrillation (AF). Methods: We performed a retrospective analysis of 274 participants with AF referred for CA. LAEAT area was measured from a single pre-ablation CT image and indexed to body surface area (BSA) to calculate iLAEAT. Clinical, echocardiographic data and 1-year AF recurrence rates after CA were compared across tertiles of iLAEAT. We performed logistic regression analysis adjusting for factors associated with AF to examine relations between iLAEAT and AF recurrence. Results: Mean age of participants was 61 +/- 10 years, 136 (49%) were women, mean BMI was 32 +/- 9 kg/m2 and 85 (31%) had persistent AF. Mean iLAEAT was 0.82 +/- 0.53 cm2/m2. Over 12-months, 109 (40%) had AF recurrence. Participants in the highest iLAEAT tertile were older, had higher CHA2DS2VASC scores, more likely to be male, have greater LA volume, and were more likely to have persistent (vs. paroxysmal) type AF than participants in the lowest iLAEAT tertile (p for all < 0.05). In regression analyses, iLAEAT was associated with higher odds of AF recurrence (OR = 2.93; 95% CI 1.34-6.43). Conclusions: iLAEAT can quantify LA adipose tissue burden using standard CT images. It is strongly associated with AF risk factors and outcomes, supporting the hypothesis that EAT plays a role in the pathophysiology of AF. PMID- 29971237 TI - Actionable Metabolic Pathways in Heart Failure and Cancer-Lessons From Cancer Cell Metabolism. AB - Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit. PMID- 29971240 TI - Characterization of the Temporal Trends in the Rate of Cattle Carcass Condemnations in the US and Dynamic Modeling of the Condemnation Reasons in California With a Seasonal Component. AB - Based on the 2016 National Cattlemen's Beef Association statistics, the cattle inventory in the US reached 93.5 million head, from which 30.5 million were commercial slaughter in 2016. California ranked fourth among all the US states that raise cattle and calves, with 5.15 million head and approximately 1.18 million slaughtered animals per year. Approximately 0.5% of cattle carcasses in the US are condemned each year, which has an important economic impact on cattle producers.In this study, we first described and compared the temporal trends of cattle carcass condemnations in all the US states from Jan-2005 to Dec-2014. Then, we focused on the condemnation reasons with a seasonal component in California and used dynamic harmonic regression (DHR) models both to model (from Jan-2005 to Dec-2011) and predict (from Jan-2012 to Dec-2014) the carcass condemnations rate in different time horizons (3 to 12 months).Data consisted of daily reports of 35 condemnation reasons per cattle type reported in 684 federally inspected slaughterhouses in the US from Jan-2005 to Dec-2014 and the monthly slaughtered animals per cattle type per states. Almost 1.5 million carcasses were condemned in the US during the 10 year study period (Jan 2005-Dec 2014), and around 40% were associated with three condemnation reasons: malignant lymphoma, septicemia and pneumonia. In California, emaciation, eosinophilic myositis and malignant lymphoma were the only condemnation reasons presenting seasonality and, therefore, the only ones selected to be modeled using DHRs. The DHR models for Jan-2005 to Dec-2011 were able to correctly model the dynamics of the emaciation, malignant lymphoma and eosinophilic myositis condemnation rates with coefficient of determination ( Rt2 ) of 0.98, 0.87 and 0.78, respectively. The DHR models for Jan-2012 to Dec-2014 were able to predict the rate of condemned carcasses 3 month ahead of time with mean relative prediction error of 33, 11, and 38%, respectively. The systematic analysis of carcass condemnations and slaughter data in a more real-time fashion could be used to identify changes in carcass condemnation trends and more timely support the implementation of prevention and mitigation strategies that reduce the number of carcass condemnations in the US. PMID- 29971242 TI - Treatment of Retained Fetal Membranes in the Mare-A Practitioner Survey. AB - Retained fetal membranes (RFM) is a common post-partum problem in mares for which the treatment is highly variable. The aim of this study was (i) to investigate the different treatments used by equine practitioners for RFM and (ii) to determine if there is a difference between treatments used by reproductive specialists and general equine practitioners. Information regarding treatment of RFM was sought from veterinary practitioners via a survey and this was compared to recommendations in the current literature. The survey was sent out to equine veterinarians and mixed practitioners with a high equine case load. Most treatments of RFM were in line with current recommendations, while some obsolete practices are still routinely performed by a small number of practitioners. Treatment recommendations for RFM have changed over the last few decades, but there are no universally accepted guidelines. The vast variety of treatments reported by practitioners in the present survey reflect this lack of guidance. More extensive research is needed in this area to establish evidence-based, uniformly agreed upon protocols. PMID- 29971241 TI - Inhibition of Rumen Methanogenesis and Ruminant Productivity: A Meta-Analysis. AB - Methane (CH4) formed in the rumen and released to the atmosphere constitutes an energy inefficiency to ruminant production. Redirecting energy in CH4 to fermentation products with a nutritional value to the host animal could increase ruminant productivity and stimulate the adoption of CH4-suppressing strategies. The hypothesis of this research was that inhibiting CH4 formation in the rumen is associated with greater ruminant productivity. The primary objective of this meta analysis was to evaluate how inhibiting rumen methanogenesis relates with the efficiencies of milk production and growth and fattening. A systematic review of peer-reviewed studies in which rumen methanogenesis was inhibited with chemical compounds was conducted. Experiments were clustered based on research center, year of publication, experimental design, feeding regime, type of animal, production response, inhibitor of CH4 production, and method of CH4 measurement. Response variables were regressed against the random experiment effect nested in its cluster, the random effect of the cluster, the linear and quadratic effects of CH4 production, and the random interaction between CH4 production and the experiment nested in the cluster. When applicable, responses were adjusted by intake of different nutrients included as regressors. Inhibiting rumen methanogenesis tended to associate positively with milk production efficiency, although the relationship was influenced by individual experiments. Likewise, a positive relationship between methanogenesis inhibition and growth and fattening efficiency depended on the inclusion and weighting of individual experiments. Inhibiting rumen methanogenesis negatively associated with dry matter intake. Interpretation of the effects of inhibiting methanogenesis on productivity is limited by the availability of experiments simultaneously reporting energy losses in feces, H2, urine and heat production, as well as net energy partition. It is concluded that inhibiting rumen methanogenesis has not consistently translated into greater animal productivity, and more animal performance experiments are necessary to better characterize the relationships between animal productivity and methanogenesis inhibition in the rumen. A more complete understanding of changes in the flows of nutrients caused by inhibiting rumen methanogenesis and their effect on intake also seems necessary to effectively re-channel energy gained from CH4 suppression toward consistent gains in productivity. PMID- 29971243 TI - Phylogenetic Analysis of ORF Viruses From Five Contagious Ecthyma Outbreaks in Argentinian Goats. AB - Orf virus (ORFV) is the etiological agent of Contagious Ecthyma (CE) disease that mainly affects sheep, goats, wild ruminants, and humans with a worldwide distribution. To date, only two strains from Argentinian sheep have been characterized at the molecular level and there is little information on ORFV strains circulating in Argentina. Here we describe and analyze five outbreaks of CE in goats in three geographic regions of the country: Northwest, Center, and Southwest. The phylogenetic analysis based on four molecular markers of ORFV (orf011 partial sequence and orf020, orf109, and orf127 complete sequence genes) revealed that there are different strains circulating in Argentina and pointed out the importance of knowing the health status of animals traded between farms. PMID- 29971244 TI - Risk of Immune-Related Pancreatitis in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors: Systematic Assessment with Meta-Analysis. AB - We performed a systematic review and meta-analysis to determine the risk of immune-related pancreatitis associated with the treatment by immune checkpoint inhibitors (ICIs) for solid tumors. Eligible studies were selected from multiple databases including phase II/III randomized controlled trials (RCTs) with ICIs in solid tumor patients. The data were analyzed with Stata version 12.0 software. After excluding ineligible studies, a total of 15 clinical trials were considered eligible for the meta-analysis, which included 9099 patients. Compared with chemotherapy or placebo, the risk ratio (RR) for all-grade lipase elevation after CTLA-4 inhibitor treatment was 1.05 (95% confidence interval (CI): 1.01-2.24, p = 0.047). However, the risk for pancreatitis after ICI treatment in any subgroup was not significantly higher than that after control therapy. In addition, compared with ipilimumab/nivolumab alone, the RR for all-grade and high-grade lipase elevation under combination treatment of nivolumab and ipilimumab was 6.43 (95% CI: 1.43-28.99, p = 0.015) and 6.44 (95% CI: 1.39-29.79, p = 0.017), respectively, and the RR for all-grade amylase elevation under combination treatment was 6.08 (95% CI: 1.51-24.44, p = 0.011). Our meta-analysis has demonstrated that both CTLA-4 inhibitors alone and combination treatment of nivolumab and ipilimumab could increase the risk of amylase or lipase elevation, but not significantly increase the risk of pancreatitis when compared with controls. PMID- 29971245 TI - Risk factors for mortality and effect of correct fluid prescription in children with diarrhoea and dehydration without severe acute malnutrition admitted to Kenyan hospitals: an observational, association study. AB - Background: Diarrhoea causes many deaths in children younger than 5 years and identification of risk factors for death is considered a global priority. The effectiveness of currently recommended fluid management for dehydration in routine settings has also not been examined. Methods: For this observational, association study, we analysed prospective clinical data on admission, immediate treatment, and discharge of children age 1-59 months with diarrhoea and dehydration, which were routinely collected from 13 Kenyan hospitals. We analysed participants with full datasets using multivariable mixed-effects logistic regression to assess risk factors for in-hospital death and effect of correct rehydration on early mortality (within 2 days). Findings: Between Oct 1, 2013, and Dec 1, 2016, 8562 children with diarrhoea and dehydration were admitted to hospital and eligible for inclusion in this analysis. Overall mortality was 9% (759 of 8562 participants) and case fatality was directly correlated with severity. Most children (7184 [84%] of 8562) with diarrhoea and dehydration had at least one additional diagnosis (comorbidity). Age of 12 months or younger (adjusted odds ratio [AOR] 1.71, 95% CI 1.42-2.06), female sex (1.41, 1.19-1.66), diarrhoea duration of more than 14 days (2.10, 1.42-3.12), abnormal respiratory signs (3.62, 2.95-4.44), abnormal circulatory signs (2.29, 1.89-2.77), pallor (2.15, 1.76-2.62), use of intravenous fluid (proxy for severity; 1.68, 1.41 2.00), and abnormal neurological signs (3.07, 2.54-3.70) were independently associated with in-hospital mortality across hospitals. Signs of dehydration alone were not associated with in-hospital deaths (AOR 1.08, 0.87-1.35). Correct fluid prescription significantly reduced the risk of early mortality (within 2 days) in all subgroups: abnormal respiratory signs (AOR 1.23, 0.68-2.24), abnormal circulatory signs (0.95, 0.53-1.73), pallor (1.70, 0.95-3.02), dehydration signs only (1.50, 0.79-2.88), and abnormal neurological signs (0.86, 0.51-1.48). Interpretation: Children at risk of in-hospital death are those with complex presentations rather than uncomplicated dehydration, and the prescription of recommended rehydration guidelines reduces risk of death. Strategies to optimise the delivery of recommended guidance should be accompanied by studies on the management of dehydration in children with comorbidities, the vulnerability of young girls, and the delivery of immediate care. Funding: The Wellcome Trust. PMID- 29971247 TI - Using Automated Live Cell Imaging to Reveal Early Changes during Human Motor Neuron Degeneration. AB - Human neurons expressing mutations associated with neurodegenerative disease are becoming more widely available. Hence, developing assays capable of accurately detecting changes that occur early in the disease process and identifying therapeutics able to slow these changes should become ever more important. Using automated live-cell imaging, we studied human motor neurons in the process of dying following neurotrophic factor withdrawal. We tracked different neuronal features, including cell body size, neurite length, and number of nodes. In particular, measuring the number of nodes in individual neurons proved to be an accurate predictor of relative health. Importantly, intermediate phenotypes were defined and could be used to distinguish between agents that could fully restore neurons and neurites and those only capable of maintaining neuronal cell bodies. Application of live-cell imaging to disease modeling has the potential to uncover new classes of therapeutic molecules that intervene early in disease progression. PMID- 29971246 TI - Age-Related Declines in Prefrontal Cortical Expression of Metabotropic Glutamate Receptors that Support Working Memory. AB - Glutamate signaling is essential for the persistent neural activity in prefrontal cortex (PFC) that enables working memory. Metabotropic glutamate receptors (mGluRs) are a diverse class of proteins that modulate excitatory neurotransmission via both presynaptic regulation of extracellular glutamate levels and postsynaptic modulation of ion channels on dendritic spines. This receptor class is of significant therapeutic interest for treatment of cognitive disorders associated with glutamate dysregulation. Working memory impairment and cortical hypoexcitability are both associated with advanced aging. Whether aging modifies PFC mGluR expression, and the extent to which any such alterations are regionally or subtype specific, however, is unknown. Moreover, it is unclear whether specific mGluRs in PFC are critical for working memory, and thus, whether altered mGluR expression in aging or disease is sufficient to play a causative role in working memory decline. Experiments in the current study first evaluated the effects of age on medial PFC (mPFC) mGluR expression using biochemical and molecular approaches in rats. Of the eight mGluRs examined, only mGluR5, mGluR3, and mGluR4 were significantly reduced in the aged PFC. The reductions in mGluR3 and mGluR5 (but not mGluR4) were observed in both mRNA and protein and were selectively localized to the prelimbic (PrL), but not infralimbic (IL), subregion of mPFC. Finally, pharmacological blockade of mGluR5 or mGluR2/3 using selective antagonists directed to PrL significantly impaired working memory without influencing non-mnemonic aspects of task performance. Together, these data implicate attenuated expression of PFC mGluR5 and mGluR3 in the impaired working memory associated with advanced ages. PMID- 29971248 TI - Optogenetic Study of Anterior BNST and Basomedial Amygdala Projections to the Ventromedial Hypothalamus. AB - The basomedial amygdala (BM) influences the ventromedial nucleus of the hypothalamus (VMH) through direct glutamatergic projections as well as indirectly, through the anterior part of the bed nucleus of the stria terminalis (BNSTa). However, BM and BNSTa axons end in a segregated fashion in VMH. BM projects to the core of VMH, where VMH's projection cells are located, whereas BNSTa projects to the shell of VMH, where GABAergic cells that inhibit core neurons are concentrated. However, the consequences of this dual regulation of VMH by BM and BNSTa are unknown. To study this question, we recorded the responses of VMH's shell and core neurons to the optogenetic activation of BM or BNSTa inputs in transgenic mice that selectively express Cre-recombinase in glutamatergic or GABAergic neurons. Glutamatergic BM inputs fired most core neurons but elicited no response in GABAergic shell neurons. Following BM infusions of AAV-EF1alpha-DIO-hChR2-mCherry in Vgat-ires-Cre-Ai6 mice, no anterograde labeling was observed in the VMH, suggesting that GABAergic BM neurons do not project to the VMH. In contrast, BNSTa sent mostly GABAergic projections that inhibited both shell and core neurons. However, BNSTa-evoked IPSPs had a higher amplitude in shell neurons. Since we also found that activation of GABAergic shell neurons causes an inhibition of core neurons, these results suggest that depending on the firing rate of shell neurons, BNSTa inputs could elicit a net inhibition or disinhibition of core neurons. Thus, the dual regulation of VMH by BM and BNSTa imparts flexibility to this regulator of defensive and social behaviors. PMID- 29971249 TI - Dynamic Interactions between Emotion Perception and Action Preparation for Reacting to Social Threat: A Combined cTBS-fMRI Study. AB - Expressions of emotion are powerful triggers for situation-appropriate responses by the observer. Of particular interest regarding the preparation of such adaptive actions are parietal and premotor cortices, given their potential for interaction with the amygdala (AMG), which is known to play a crucial role in the processing of affective information and in motor response. We set out to disentangle the respective roles of the inferior parietal lobule (IPL) and ventral premotor cortex (PMv) in humans in the processing of emotional body expressions by assessing remote effects of continuous theta burst stimulation (cTBS) in the action network and in AMG. Participants were presented with blocks of short videos showing either angry or neutral whole-body actions. The experiment consisted of three fMRI sessions: two sessions were preceded by stimulation of either right IPL (rIPL) or right PMv (rPMv); and a third session assessed baseline activity. Interestingly, whereas at baseline the left AMG did not differentiate between neutral and angry body postures, a significant difference between these conditions emerged after stimulation of either rIPL or rPMv, with much larger responses to angry than to neutral stimuli. In addition, the effects of cTBS stimulation and emotion were also observed in two other action-relevant areas, the supplementary motor area and the superior parietal cortex. Together, these results show how areas involved in action and emotion perception and in action preparation interact dynamically. PMID- 29971250 TI - Editorial: Gender Bias in Publishing: Double-Blind Reviewing as a Solution? PMID- 29971251 TI - Systemic and Intra-Habenular Activation of the Orphan G Protein-Coupled Receptor GPR139 Decreases Compulsive-Like Alcohol Drinking and Hyperalgesia in Alcohol Dependent Rats. AB - GPR139 is an orphan G protein-coupled receptor (GPCR) that is expressed mainly in the brain, with the highest expression in the medial habenula. The modulation of GPR139 receptor function has been hypothesized to be beneficial in the treatment of some mental disorders, but behavioral studies have not yet provided causal evidence of the role of GPR139 in brain dysfunction. Because of the high expression of GPR139 in the habenula, a critical brain region in addiction, we hypothesized that GPR139 may play role in alcohol dependence. Thus, we tested the effect of GPR139 receptor activation using the selective, brain-penetrant receptor agonist JNJ-63533054 on addiction-like behaviors in alcohol-dependent male rats. Systemic administration of JNJ-63533054 (30 mg/kg but not 10 mg/kg, p.o.) reversed the escalation of alcohol self-administration in alcohol-dependent rats, without affecting water or saccharin intake in dependent rats or alcohol intake in nondependent rats. Moreover, systemic JNJ-63533054 administration decreased withdrawal-induced hyperalgesia, without affecting somatic signs of alcohol withdrawal. Further analysis demonstrated that JNJ-63533054 was effective only in a subgroup of dependent rats that exhibited compulsive-like alcohol drinking. Finally, site-specific microinjection of JNJ-63533054 in the habenula but not interpeduncular nucleus (IPN) reduced both alcohol self-administration and withdrawal-induced hyperalgesia in dependent rats. These results provide robust preclinical evidence that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals, suggest that GPR139 may be a novel target for the treatment of alcohol use disorder, and demonstrate that GPR139 is functionally relevant in regulating mammalian behavior. PMID- 29971253 TI - Transvesicoscopic Bipolar Sealing of Vesicovaginal Fistula. AB - Introduction: Vesicovaginal fistula (VVF) is a problem that physically and psychologically debilitates the patient. Options for treatment of VVF include transabdominal, transvaginal, transvesical, laparoscopic, and robotic repair or minimally invasive methods such as fulguration. We describe a novel minimally invasive technique: transvesicoscopic bipolar sealing of the vesicovaginal fistula (TBSF). Case Presentation: We carried out the transvesicoscopic sealing of VVF with 5 mm of diameter on a 46-year-old woman, who had a failed conservative treatment with a Foley catheter placement. The patient was informed about the modified surgical procedure before operation. The fistula tract was sealed by using an electrothermal bipolar vessel sealer through a 5-mm transvesical ports. The patient was discharged on the first postoperative day and was on anticholinergic medications after the operation. The patient remained dry after the removal of the catheter at the third postoperative week. Conclusion: In select cases of VVF, TBSF may be effectively used for closure of the fistula tract. PMID- 29971252 TI - Chronometry on Spike-LFP Responses Reveals the Functional Neural Circuitry of Early Auditory Cortex Underlying Sound Processing and Discrimination. AB - Animals and humans rapidly detect specific features of sounds, but the time courses of the underlying neural response for different stimulus categories is largely unknown. Furthermore, the intricate functional organization of auditory information processing pathways is poorly understood. Here, we computed neuronal response latencies from simultaneously recorded spike trains and local field potentials (LFPs) along the first two stages of cortical sound processing, primary auditory cortex (A1) and lateral belt (LB), of awake, behaving macaques. Two types of response latencies were measured for spike trains as well as LFPs: (1) onset latency, time-locked to onset of external auditory stimuli; and (2) selection latency, time taken from stimulus onset to a selective response to a specific stimulus category. Trial-by-trial LFP onset latencies predominantly reflecting synaptic input arrival typically preceded spike onset latencies, assumed to be representative of neuronal output indicating that both areas may receive input environmental signals and relay the information to the next stage. In A1, simple sounds, such as pure tones (PTs), yielded shorter spike onset latencies compared to complex sounds, such as monkey vocalizations ("Coos"). This trend was reversed in LB, indicating a hierarchical functional organization of auditory cortex in the macaque. LFP selection latencies in A1 were always shorter than those in LB for both PT and Coo reflecting the serial arrival of stimulus specific information in these areas. Thus, chronometry on spike-LFP signals revealed some of the effective neural circuitry underlying complex sound discrimination. PMID- 29971254 TI - Lateral cavo-caval shunt: an alternative veno-venous bypass in liver surgery. AB - When inferior vena cava (IVC) resection is mandatory during liver surgery, use of a veno-venous bypass (VVB) is usually required despite its specific related adverse events. We describe a safe and alternative technique which allows both derivation of the portal and the caval blood flow by performing a lateral cavo caval shunt using a prosthetic graft. PMID- 29971256 TI - A good response to glucocorticoid for sub-acute liver failure: a case report. AB - Liver failure is a severe clinical syndrome presenting with coagulation dysfunction, jaundice, hepatic encephalopathy, and ascites. It often has a dismal prognosis. The role of glucocorticoid for the treatment of liver failure is unclear. In this paper, we reported that a female patient with sub-acute liver failure had a good response to glucocorticoid. PMID- 29971257 TI - Endoscopic resection or surgical management for nonampullary duodenal neoplasms? PMID- 29971255 TI - Microenvironment and tumor cells: two targets for new molecular therapies of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC), is one of the most frequent human cancer and is characterized by a high mortality rate. The aggressiveness appears strictly related to the liver pathological background on which cancer develops. Inflammation and the consequent fibro/cirrhosis, derived from chronic injuries of several origins (viral, toxic and metabolic) and observable in almost all oncological patients, represents the most powerful risk factor for HCC and, at the same time, an important obstacle to the efficacy of systemic therapy. Multiple microenvironmental cues, indeed, play a pivotal role in the pathogenesis, evolution and recurrence of HCC as well as in the resistance to standard therapies observed in most of patients. The identification of altered pathways in cancer cells and of microenvironmental changes, strictly connected in pathogenic feedback loop, may permit to plan new therapeutic approaches targeting tumor cells and their permissive microenvironment, simultaneously. PMID- 29971258 TI - Differential diagnosis of gastrointestinal stromal tumor by histopathology and immunohistochemistry. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract. GISTs account for approximately 80% of the clinically relevant GI mesenchymal tumors. Although most GISTs show spindle cell morphology, 10-15% of GISTs show pure epithelioid configuration. Therefore, not only spindle cell tumors but also epithelioid cell ones developing in the GI tract are subject to the differential diagnoses of GISTs. GISTs are basically positive for KIT, a receptor tyrosine kinase (RTK) encoded by protooncogene c kit, by immunohistochemistry, but approximately 5% of GISTs are only weakly or barely positive for KIT. Since almost all spindle cell type GISTs are strongly and diffusely positive for KIT regardless of different genetic subtypes, diagnosis of the spindle cell type GISTs is not difficult. On the other hand, epithelioid cell type GISTs show different staining patterns of KIT in different genetic backgrounds. Approximately half of the epithelioid cell type GISTs with platelet-derived growth factor receptor alpha (PDGFRA) gene mutation might show weak or undetectable staining of KIT. On the other hand, almost all GISTs are negative for desmin, which is a positive marker for mature smooth muscle cells, and S100 protein, which is a Schwann cell marker. Smooth muscle tumors such as leiomyomas and leiomyosarcomas, which usually show the spindle cell morphology, consist of approximately 10% of the clinically relevant GI mesenchymal tumors and are almost positive for desmin and negative for KIT and S100 protein. Schwannomas which nearly always show the spindle cell pattern, comprise up to 5% of the GI mesenchymal tumors, and almost all of them are positive for S100 protein and negative for KIT and desmin. Thus, most GI mesenchymal tumors are differentially diagnosed by immunohistochemistry (IHC) of KIT, desmin and S100 protein. However, mesenchymal tumors such as desmoids, solitary fibrous tumors (SFTs), inflammatory myofibroblastic tumors (IMTs), perivascular epithelioid cell tumors (PEComas), inflammatory fibroid polyps (IFPs), rarely develop in the GI tract, and have to be correctly diagnosed through detection of specific immunohistochemical markers and/or unique genetic aberrations. PMID- 29971260 TI - Improving the mucosal visualization at gastroscopy: a systematic review and meta analysis of randomized, controlled trials reporting the role of Simethicone +/- N acetylcysteine. AB - Background: The objective of this article is to study the role of Simethicone +/- N-acetylcysteine in improving the mucosal visualization during oesophago-gastro duodenoscopy (OGD). Methods: The data retrieved from the published randomized controlled trials (RCTs) reporting the role of Simethicone +/- N-acetylcysteine during OGD was analysed using the principles of meta-analysis. The summated outcome of continuous variables was expressed as standardized mean difference (SMD) and dichotomous data was presented in odds ratio (OR). Results: Three RCTs on 654 patients reported OGD with and without pre-procedure oral administration of Simethicone +/- N-acetylcysteine evaluating visibility as good or excellent in number during the procedure. In the random effects model analysis using the statistical software Review Manager 5.3, the use of Simethicone +/- N acetylcysteine was associated with improved (OR, 0.43; 95% CI, 0.28, 0.68; z=3.65; P=0.0003) mucosal visibility. Four RCTs on 364 patients reported OGD with and without pre-procedure oral administration of Simethicone +/- N-acetylcysteine evaluating visibility score in study group. In the random effects model analysis using the statistical software Review Manager 5.3, the use of Simethicone +/- N acetylcysteine was associated with improved (SMD, -1.66; 95% CI, -1.93, -1.40; z=12.25; P=0.00001) mucosal visibility score compared to no-Simethicone group. Conclusions: The findings of current study on 1,099 patients successfully demonstrate that the pre-procedure oral administration of Simethicone +/- N acetylcysteine improves mucosal visualization and mucosal visualization score during OGD. PMID- 29971259 TI - Does "July effect" exist in colonoscopies performed at teaching hospitals? AB - Background: To compare the outcomes of the colonoscopies between the early (July September) and the later (April-June) academic year at the urban-teaching hospitals. Methods: Our study cluster was derived from the National Inpatient Sample (NIS) database for the years 2010-2014. International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) procedure codes were used to identify the adult patients who underwent inpatient colonoscopy at urban teaching hospitals. Post-colonoscopy outcomes and the complications were recognized using ICD-9 CM codes among any of the secondary diagnoses. Categorical and continuous variables were assessed using Pearson's Chi-square and Student's t test respectively. Odds of complications during the early vs. later academic year was also evaluated by the two-way hierarchical logistic regression analysis. Results: A total of 124,155 (weighted n=617,907) colonoscopy procedures were performed at the urban teaching hospitals in the US from 2010 to 2014. Out of these, 61,272 (weighted n=304,946) and 62,883 (weighted n=312,961) procedures were performed during early (July to September) and later (April to June) academic months, respectively. There was no significant difference in the all cause mortality (1.4% vs. 1.4%, P=0.208), and the complications such as colonic perforations (3.1% vs. 3.2%, P=0.229) and postoperative infections (0.6% vs. 0.6%, P=0.733) between the two groups. Similarly, the splenic rupture (0.0% vs. 0.0%, P=0.180) was equally infrequent in both the groups. Bleeding/hematoma following colonoscopy (0.9% vs. 0.8%, P=0.004) was marginally higher during the later academic months. There were no statistically distinctions in terms of length of stay (LOS) (days) (7.3+/-9.1 vs. 7.3+/-9.1, P=0.918), total hospitalization charges ($60,549.41 vs. $59,918.56, P=0.311) and discharge of patients to other facilities between the early and the later academic months. Colonoscopy performed during the early academic months was not found to be a significant independent predictor for post-colonoscopy complications such as colon perforation (OR =0.99, 95% CI: 0.93-1.06, P=0.760), postoperative bleeding/hematoma (OR =0.92, 95% CI: 0.81-1.04, P=0.196) and postoperative infection (OR =0.99, 95% CI: 0.84-1.15, P=0.850). Conclusions: There was no "July effect" on the outcomes of colonoscopies between the early vs. the later academic months. PMID- 29971262 TI - Vitamin D: a brief overview of its importance and role in inflammatory bowel disease. AB - Vitamin D has traditionally been known for its regulation of bone metabolism and homeostasis, but emerging evidence suggests that it also has a broad function in immune regulation, and inflammatory bowel disease (IBD). The etiology of IBD is thought to be multifactorial but stems in part due to the deregulation of the immune response to environmental factors in the setting of a pre-existing genetic disposition. Vitamin D, based on its mechanistic role at the cellular level in T cell trafficking, had been postulated to have a direct effect on the immune system, This alludes to the fact that vitamin D may have the ability to not only potentiate the IBD phenotype, but also in doing so, its supplementation may serve a therapeutic role in amelioration of the diseased state. We review in this article the current literature as it pertains to the basic mechanism of Vitamin D, its role in the pathogenicity of IBD, how it regulates our immune system, interpretation and accuracy of obtaining levels, and the role there may be in supplementation in IBD. PMID- 29971261 TI - Meta-analysis of randomized controlled trials only exploring the role of single incision laparoscopic surgery versus conventional multiport laparoscopic surgery for colorectal resections. AB - Background: The objective of this article is to evaluate the surgical outcomes in patients undergoing single incision laparoscopic surgery (SILS) versus conventional multi-incision laparoscopic surgery (MILS) for colorectal resections. Methods: The data retrieved from the published randomized controlled trials (RCTs) reporting the surgical outcomes in patients undergoing SILS versus MILS for colorectal resections was analysed using the principles of meta analysis. The combined outcome of dichotomous data was represented as risk ratio (RR) and continuous data was shown as standardized mean difference (SMD). Results: Five RCTs on 525 patients reported the colorectal resections by SILS versus MILS technique. In the random effects model analysis using the statistical software Review Manager 5.3, the operation time (SMD, 0.20; 95% CI, -0.11 to 0.52; z=1.28; P=0.20), length of in-patient stay (SMD, -0.18; 95% CI, -0.51 to 0.14; z=1.10; P=0.27) and lymph node harvesting (SMD, 0.09; 95% CI, -0.14 to 0.33; z=0.76; P=0.45) were comparable between both techniques. Furthermore, post operative complications (RR, 1.00; 95% CI, 0.65-1.54; z=0.02; P=0.99), post operative mortality, surgical site infection rate (RR, 3.00; 95% CI, 0.13-70.92; z=0.68; P=0.50), anastomotic leak rate (RR, 0.43; 95% CI, 0.11-1.63; z=1.24; P=0.21), conversion rate (P=0.13) and re-operation rate (P=0.43) were also statistically similar following SILS and MILS. Conclusions: SILS failed to demonstrate any superiority over MILS for colorectal resections in all post operative surgical outcomes. PMID- 29971264 TI - Announcement: New Deputy Editors of the Journal of Cardiovascular Imaging. PMID- 29971263 TI - Antihypertensive Treatment in Severe Aortic Stenosis. AB - Previously, antihypertensive treatment in severe aortic stenosis was considered a relative contraindication. However, recent studies have shown that antihypertensive treatment may be safe and even beneficial in terms of reducing the progression of left ventricular pressure overload and even retarding the progression of valvular aortic stenosis. To date, no randomized clinical trials have been performed and no definite treatment guideline exist for the proper antihypertensive regimens. Antihypertensive treatment with beta-blockers has generally been avoided in patients with severe aortic stenosis (AS) due to the concerns for inducing left ventricular dysfunction and hemodynamic compromise in the presence of severe outflow tract obstruction. Although it remains unclear whether antihypertensive treatment with a beta-blocker is associated with increased risk of cardiovascular events in patients with AS, recent studies have shown that the use of beta-blockers may be safe and may even be beneficial. Renin angiotensin system (RAS) are upregulated in AS and have been shown to be involved in valve calcification and progression in both experimental models and in human trials. As such, theoretically, RAS inhibition would have benefit in retarding the progression of valvular stenosis as well as have benefit in left ventricle remodeling. Recent clinical studies are indeed showing that use of RAS inhibition may be beneficial in patients with AS. Future clinical trials to establish the ideal target blood pressure and antihypertensive regimens in severe AS is essential. PMID- 29971265 TI - Utility of D-shaped Left Ventricle and Mitral E/E' in Patients with Pulmonary Hypertension. PMID- 29971266 TI - Issues on Estimated Pulmonary Artery Pressure in Liver Transplant Candidates. PMID- 29971267 TI - Epicardial Fat Thickness, Free Fatty Acid Can Predict Acute Ischemic Stroke in Patients with Atrial Fibrillation? PMID- 29971268 TI - Epicardial Fat Thickness and Free Fatty Acid Level are Predictors of Acute Ischemic Stroke with Atrial Fibrillation. AB - BACKGROUND: Increased epicardial fat is known to be associated with the presence and chronicity of atrial fibrillation (AF). Free fatty acids (FFAs) are major components of epicardial fat; however, their potential association with AF in ischemic stroke has not been investigated. We aimed to assess the performance of echocardiographic epicardial fat thickness (EFT) and plasma FFA level in identifying patients with ischemic stroke and AF. METHODS: We enrolled a total of 214 consecutive patients (mean age, 66.8 +/- 12.3 years; 39.7% women) diagnosed with acute ischemic stroke between March 2011 and June 2014. The patients were divided into two groups: ischemic stroke with AF (n = 35, 16.4%) and ischemic stroke without AF (n = 179, 83.6%). RESULTS: The ischemic stroke with AF group showed significantly higher serum FFA level (1379.7 +/- 717.5 vs. 757.8 +/- 520.5 uEq/L, p < 0.0001) and EFT (6.5 +/- 1.2 vs. 5.3 +/- 1.2 mm, p < 0.001) than the group without AF. Multivariable logistic regression analysis demonstrated that age (odds ratio [OR], 1.112), serum FFA level (OR, 1.002), and EFT (OR, 1.740) were independently associated with the ischemic stroke group with AF. EFT and FFA significantly improved the goodness-of-fit and discriminability of the simple regression model including age as a covariate (log likelihood difference, 21.35; p < 0.001; c-index difference, 17.9%; p < 0.001). CONCLUSIONS: High EFT and serum FFA level were associated with ischemic stroke in patients with AF. Echocardiographic EFT and serum FFA level can play a significant role in identifying ischemic stroke with AF. PMID- 29971269 TI - Correlation between Echocardiographic Pulmonary Artery Pressure Estimates and Right Heart Catheterization Measurement in Liver Transplant Candidates. AB - BACKGROUND: Patients undergoing liver transplant have worse outcomes in the presence of pulmonary hypertension. Correlation between echocardiography and catheterization derived pressures in this population is not well studied. Our study's aim is to show the relationship between pulmonary artery systolic pressure derived from transthoracic echo (ePASP) with pulmonary artery systolic pressure measured during right heart catheterization (cPASP). METHODS: Single center retrospective study, patients being evaluated for liver transplant (n = 31) who had an interpretable Doppler signal for ePASP and had right heart catheterization (RHC) measurements within 3 months constituted the study group. Control group (n = 49) consisted of patients who did not have liver disease. RESULTS: There was modest correlation between ePASP and cPASP (R = 0.58, p < 0.001) in LT candidates (n = 31) compared with the control group (R = 0.74, p < 0.001, n = 49). The 95% limits of agreement by Bland-Altman analysis ranged from +33.6 mmHg to -21.7 mmHg. Using receiver operating characteristic analysis, ePASP cut-off > 47 mmHg was 59% sensitive and 78% specific to diagnose pulmonary artery (PA) hypertension (mean PA pressure > 25 mmHg) in the LT candidates, while a similar cutoff performed well in the control group (cutoff > 43 mmHg, n = 47, 91% sensitive, 100% specific). CONCLUSIONS: Compared with other disease states, ePASP correlates modestly with cPASP in patients with advanced liver disease. A higher ePASP cutoff should be used to screen for pulmonary hypertension. A multi-center prospective study with simultaneous transthoracic echocardiography and RHC measurements is required to determine the best cut-off in this population. PMID- 29971270 TI - E/E' and D-shaped Left Ventricle Severity in Patients with Increased Pulmonary Artery Pressure. AB - BACKGROUND: D-shaped left ventricle (D-LV) is an interesting echocardiographic finding in pulmonary hypertension (PH) and is the result of structural distortion of the interventricular septum. The eccentricity index (EI) is a quantitative measure used to evaluate the severity of D-LV in patients with increased pulmonary artery pressure (PAP). However, D-LV and EIs have rarely been studied in terms of their association with hemodynamic factors. METHODS: A total of 526 patients with a maximal tricuspid regurgitation velocity (VmaxTR) > 2.8 m/s on echocardiography identified between January 2012 and December 2017 were enrolled. After exclusion, a total of 289 patients were analyzed. The association between D LV and hemodynamic factors were analyzed using logistic regression. Furthermore, factors that impacted the severity of the D-LV, as defined by EIs, were also analyzed using the multiple linear regression model. RESULTS: In the multivariate logistic regression model, higher pulmonary artery pressure (PAP, p = 0.001), lower tricuspid annular plane systolic excursion (TAPSE, p = 0.048), and E/E' (p = 0.017) were found to be significant risk factors for the presence of D-LV. Additional analysis with age and body mass index added to independent variables, PAP (p = 0.008), TAPSE (p = 0.028), and age (p < 0.001) were significant risk factors for the presence of D-LV. In patients with D-LV, only E/E' was independently associated with EIs (R2 = 0.666, p < 0.001). CONCLUSIONS: In patients with increased PAP, D-LV is associated with PAP, TAPSE, E/E', and age. EIs are associated with left ventricular filling pressure, represented as E/E'. PMID- 29971271 TI - Cardiac and Pericardial 18F-FDG Uptake on Oncologic PET/CT: Comparison with Echocardiographic Findings. AB - BACKGROUND: Interpretation of cardiac uptake on 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is often confounded by intense physiological FDG uptake and numerous benign conditions. The aim of the study was to describe the echocardiographic features in concordance with cardiac and pericardial 18F-FDG uptake on whole-body oncology PET/CT. METHODS: We enrolled 43 consecutive patients (34 solid tumors, 8 lymphomas and 1 leukemia) who were newly diagnosed with non-cardiac malignancy showing incidental cardiac or pericardial 18F-FDG uptake on PET/CT and underwent transthoracic Doppler echocardiography (TTE) within 1 month of PET/CT. The maximum standardized uptake (SUVmax) of all lesions was measured. RESULTS: Fifty-six 18F-FDG uptake lesions (32 pericardium, 7 myocardium, 9 cardiac chambers and 8 great vessels) were found, and pericardial effusion was the most common echocardiographic finding (22/43, 51.2%) among study population. Pericardial FDG uptake was shown as pericardial effusion (68.8%), intrapericardial echogenic materials (31.3%), pericardial thickening (28.1%), hyperechogenicity of myopericardium (18.8%), and restricted sliding movement or constrictive pericarditis (15.6%) on TTE. Lesions with regional wall motion abnormality (p = 0.004) or constrictive pericarditis (p = 0.021) had significantly higher mean SUVmax than those without. Myocardial FDG uptake demonstrated pericardial effusion (57.1%), regional wall motion abnormality (57.1%), and increased myocardial wall thickness (42.9%). All cardiac chamber FDG uptakes showed intracardiac mass on TTE. CONCLUSIONS: Cardiac or pericardial 18F-FDG uptake on oncology PET/CT shows characteristic echocardiographic features according to which heart sites are involved. PMID- 29971272 TI - A Case of Unroofed Coronary Sinus with Coronary Sinus Orifice Atresia: Use of Multimodality Imaging. PMID- 29971273 TI - Photoredox-promoted alkyl radical addition/semipinacol rearrangement sequences of alkenylcyclobutanols: rapid access to cyclic ketones. AB - Two photo-catalytic tandem alkyl radical addition/semipinacol rearrangement reactions of cycloalkanol-substituted styrenes with N-acyloxyphthalimides and O acyl oximes have been documented. These protocols provide efficient access to functionalized cyclic ketones, and feature mild conditions (i.e., visible light irradiation, redox neutral and room temperature), broad substrate scope and excellent functional group tolerance. PMID- 29971274 TI - Re-designing the alpha-synuclein tetramer. AB - A computationally re-designed molecular loop optimizes helical packing of alpha synuclein monomers to seal the aggregation-resistant low-weight tetramer, a key target for Parkinson's disease. Helical monomers are pushed into active conformations during supramolecular assembly, and familial missense mutations double the energy barrier to tetramerization, preserving the pool of potentially amyloidogenic monomers. PMID- 29971275 TI - Unusual high-temperature reversible phase transition containing dielectric and nonlinear optical switches in host-guest supramolecular crown ether clathrates. AB - A novel high-temperature dielectric and quadratic nonlinear optical switching material, 3,4-difluoroanilinium 18-crown-6 perchlorate, was synthesized. It exhibits two successive structural phase transitions at 347 K and 240 K, respectively. Gradually increased SHG-active characteristics are also identified. PMID- 29971276 TI - A robust 3D host for sodium metal anodes with excellent machinability and cycling stability. AB - This study demonstrates a robust and ultra-stable sodium infiltrated Fe2O3 coated carbon textile (SFCT) anode with excellent machinability. The obtained SFCT anode overcomes the disadvantage of Na electrodes, which is not easily processable, and exhibits more flat voltage profiles, lower stripping/plating overpotential, and better cycling stability in an additive-free carbonate-based electrolyte compared with bare Na electrodes. PMID- 29971278 TI - A novel, fast and sensitive supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) method for analysis of arachidonic acid metabolites. AB - The development of a rapid, sensitive and reliable method for the quantification of bioactive arachidonic acid metabolites (AA-metabolites) in biological samples is quite challenging due to the minute concentration, short half-life and their structural complexity arising from different isomers. In this study, a simple, fast and environmentally friendly supercritical fluid chromatography-tandem mass spectrometry (SFC-MS/MS) method was developed and validated for simultaneous measurement of five (PGD2, PGE2, PGF2alpha, 6KetoPGF1alpha and LTB4) AA metabolites in biological samples. These analytes were extracted by protein precipitation followed by separation and quantification. The analysis was completed within 3 minutes. The matrix matched linear calibration ranged from 0.5 100 ng mL-1 (r2 >= 0.995), whilst, the limit of quantification of PGD2, PGE2, PGF2alpha, and LTB4 was 0.5 ng mL-1 and was 2.5 ng mL-1 for 6KetoPGF1alpha. The interday and intraday precisions of the method were less than 15% while the accuracy of most of the analytes varied between 83 and 109%. Finally, as a proof of concept, the method was successfully applied for the determination of eicosanoids in human samples, which expands the possibility to explore physiological states, disease phenotypes, and novel biomarkers. PMID- 29971277 TI - Directed assembly of fullerene on modified Au(111) electrodes. AB - Here we show a conceptual approach to realize the scanning tunneling microscopy based induced-assembly of fullerene (C60) molecules on top of a buffer organic adlayer at room temperature in a solution environment. The realization of spatially-defined C60 assembly is attributed to the modulation of substrate molecular interactions with the assistance of a buffer layer. PMID- 29971279 TI - Mixed annihilation electrogenerated chemiluminescence of iridium(iii) complexes. AB - Previously reported annihilation ECL of mixtures of metal complexes have generally comprised Ir(ppy)3 or a close analogue as a higher energy donor/emitter (green/blue light) and [Ru(bpy)3]2+ or its derivative as a lower energy acceptor/emitter (red light). In contrast, here we examine Ir(ppy)3 as the lower energy acceptor/emitter, by combining it with a second Ir(iii) complex: [Ir(df ppy)2(ptb)]+ (where ptb = 1-benzyl-1,2,3-triazol-4-ylpyridine). The application of potentials sufficient to attain the first single-electron oxidation and reduction products can be exploited to detect Ir(ppy)3 at orders of magnitude lower concentration, or enhance its maximum emission intensity at high concentration far beyond that achievable through conventional annihilation ECL of Ir(ppy)3 involving comproportionation. Moreover, under certain conditions, the colour of the emission can be selected through the applied electrochemical potentials. We have also prepared a novel Ir(iii) complex with a sufficiently low reduction potential that the reaction between its reduced form and Ir(ppy)3+ cannot populate the excited state of either luminophore. This enabled, for the first time, the exclusive formation of either excited state through the application of higher cathodic or anodic potentials, but in both cases, the ECL was greatly diminished by parasitic dark reactions. PMID- 29971280 TI - An electron compensation mechanism for the polymorphism of boron monolayers. AB - Boron monolayers have been increasingly attractive, while it is still a challenge to understand their structural stabilities, due to electron deficiency and multi center bonds. In this work, we propose the average electron compensation (AEC) mechanism for boron monolayers based on high-throughput first-principles calculations. It is found that the AEC parameter (lambda) tends to be zero for the stable free-standing boron monolayers. In addition, this mechanism can quantitatively describe the stability of boron monolayers on various metal substrates, providing direct suggestions for experimentalists to synthesize various boron monolayers for practical applications. PMID- 29971282 TI - Switchable ferroelectric photovoltaic effects in epitaxial h-RFeO3 thin films. AB - Ferroelectric photovoltaics (FPVs) have drawn much attention owing to their high stability, environmental safety, and anomalously high photovoltages, coupled with reversibly switchable photovoltaic responses. However, FPVs suffer from extremely low photocurrents, which is primarily due to their wide band gaps. Here, we present a new class of FPVs by demonstrating switchable ferroelectric photovoltaic effects and narrow band-gap properties using hexagonal ferrite (h RFeO3) thin films, where R denotes rare-earth ions. FPVs with narrow band gaps suggest their potential applicability as photovoltaic and optoelectronic devices. The h-RFeO3 films further exhibit reasonably large ferroelectric polarizations (4.7-8.5 MUC cm-2), which possibly reduces a rapid recombination rate of the photo-generated electron-hole pairs. The power conversion efficiency (PCE) of h RFeO3 thin-film devices is sensitive to the magnitude of polarization. In the case of the h-TmFeO3 (h-TFO) thin film, the measured PCE is twice as large as that of the BiFeO3 thin film, a prototypic FPV. The effect of electrical fatigue on FPV responses has been further investigated. This work thus demonstrates a new class of FPVs towards high-efficiency solar cell and optoelectronic applications. PMID- 29971283 TI - Highly responsive hydrazine sensors based on donor-acceptor perylene diimides: impact of electron-donating groups. AB - Three high-performance hydrazine sensing devices have been developed based on donor-acceptor perylenediimides (PDIs) with strongly electron-donating piperidinyl (PDI-PY), pyrrolidinyl (PDI-PI) and n-hexylamino (PDI-HE) as substituents at the perylene core. These PDI devices, compared with reported PDI molecules, displayed 1-2 orders of magnitude higher sensitivity, short response/recovery time and a lower detection limit towards hydrazine vapour. Experimental results demonstrated that PDI-HE possessed the most excellent sensing performance due to its larger electron density and well-defined crystalline structure with a smaller pi-pi distance of 3.55 A, yet, poor crystalline structure, weak pi-pi orbital overlap as well as a larger interplanar spacing of 3.62 A led to the poorest sensing performance of PDI-PY devices. This study clearly reveals that electron-donating substituents can remarkably improve the sensing performance of PDI devices by increasing the density of electrons, meanwhile, the steric hindrance of electron-donating groups can modulate the sensing performance by influencing the crystalline structure, pi-pi overlap and pi-pi distance. The excellent sensing performance makes donor-acceptor perylenes one of the candidates with the most potential for fabrication of highly efficient PDI sensing devices. PMID- 29971284 TI - Epitaxial growth and physical properties of 2D materials beyond graphene: from monatomic materials to binary compounds. AB - The discovery of graphene opened a door for manufacturing and investigating two dimensional (2D) materials. After more than ten years of development, 2D materials have become one of the most important topics in materials research, with dozens of new materials having been synthesized experimentally and even more predicted theoretically. In this review, we provide a comprehensive overview of the fabrication of 2D materials based on epitaxial growth in an ultra-high vacuum (UHV) experimental environment and the investigation of their physical and chemical properties. In particular, we focus on techniques like intercalation, templated molecular adsorption, and direct selenization and tellurization of metal substrates. We discuss progress in fabrication methods of monatomic and binary 2D materials and highlight their interesting and quite unusual physical properties. Finally, we assess future directions of research in this field, where breakthroughs can be expected, and indicate where investments in additional research might be most rewarding scientifically. PMID- 29971281 TI - Controllable self-assembled plasmonic vesicle-based three-dimensional SERS platform for picomolar detection of hydrophobic contaminants. AB - Hydrophobic contaminants in food and the environment seriously threaten human health. The ultrasensitive detection of these pollutants can minimize their damage. However, current ultrasensitive sensing strategies are limited to solid substrate-based surface-enhanced Raman spectroscopy (SERS) detection. Herein, we report a controllable and reproducible solution-based SERS detection platform for the direct and ultrasensitive detection of hydrophobic contaminants by using self assembled three-dimensional plasmonic vesicles. To this end, amphiphilic gold nanoparticles (AuNPs) tethered with linear block copolymer (BCP) of polystyrene-b poly (ethylene oxide) (PS-b-PEO) were designed, which display dual functions for improving detection sensitivity, including serving as building blocks for the construction of plasmonic vesicles to yield large numbers of hot-spots for SERS enhancement, and providing hydrophobic PS layers to enrich and concentrate target hydrophobic molecules for direct SERS detection with hydrophobic interaction. By modulating the AuNP size and the length of BCP chains, the ultrahigh detection sensitivity, down to the picomolar level, was obtained via using 80 nm AuNPs tethered with BCP of PEO45-b-PS900-SH. In addition, the proposed method exhibits excellent reproducibility, universality, practicability, as well as multiplexing detection capacity in actual contaminant-spiked soil samples. Briefly, the designed self-assembled plasmonic vesicle-based SERS platform provides an ideal generic methodology for the ultrasensitive detection of hydrophobic contaminants that can greatly accelerate on-site testing in food and environmental monitoring. PMID- 29971285 TI - Porous CaFe2O4 as a promising lithium ion battery anode: a trade-off between high capacity and long-term stability. AB - Metal oxides are considered as attractive candidates as anode materials for lithium ion batteries (LIBs) due to their high capacities compared to commercialized graphite. However, fast capacity fading, which is caused by inherent large volume expansions and agglomeration of active particles upon cycling, is a great challenge. Herein, we propose the design of porous CaFe2O4 electrode material to address the above issue. Compared to pristine iron oxides, CaFe2O4 exhibits a distinct trade-off in terms of high capacity and long-term stability, which is beneficial to the potential practical applications. Such a trade-off effect is attributed to the synergistic effect between the porous structure and the in situ formed CaO nanograins during charging/discharging processes. This work provides an effective strategy in achieving anode materials with high capacity and long-term stability for next-generation LIBs. PMID- 29971286 TI - Inhibition of the prototropic tautomerism in chrysazine by p-sulfonatocalixarene hosts. AB - This study explores the interesting effect of p-sulfonatocalix[n]arene hosts (SCXn) on the excited-state tautomeric equilibrium of Chrysazine (CZ), a model antitumour drug molecule. Detailed photophysical investigations reveal that conversion of CZ from its more dipolar, excited normal form (N*) to the less dipolar, tautomeric form (T*) is hindered in SCXn-CZ host-guest complexes, which is quite unexpected considering the nonpolar cavity of the hosts. The atypical effect of SCXn is proposed to arise due to the partial inclusion or external binding of CZ with the hosts, which facilitates H-bonding interactions between CZ and the sulfonate groups present at the portals of the hosts. The intermolecular H-bonding subsequently leads to weakening of the pre-existing intramolecular H bond network within CZ, and thus hinders the tautomerizaion process. Our results suggest that rather than the binding affinity, it is the orientation of CZ in the SCXn-CZ complexes, and its proximity to the portals of the host that plays a predominant role in influencing the tautomeric equilibrium. These observations are supported by quantum chemical calculations. Thermodynamic studies validate that SCXn-CZ interaction is essentially enthalpy driven and accompanied by small entropy loss, which is consistent with the binding mechanisms. PMID- 29971288 TI - Carbenium ion formation by fragmentation of electrochemically generated oxonium ions. AB - Fragmentation of electrochemically generated oxonium ions can be exploited to form carbenium ions at a low oxidation potential in the presence of a nucleophile. The application of this concept is demonstrated for the allylation of carbenium ions generated by the anodic oxidation of stannylmethylethers. PMID- 29971287 TI - Boosting water oxidation electrocatalysts with surface engineered amorphous cobalt hydroxide nanoflakes. AB - Enriching dominant active intermediates is most pivotal in developing efficient non-noble oxygen evolution reaction (OER) electrocatalysts for water oxidation. Herein, we report surface-engineered amorphous cobalt hydroxide nanoflakes on nickel foam as highly active electrocatalysts for boosting water oxidation by a new repeatedly switching current-polarity strategy. It is discovered that sulfur introduction can simultaneously increase the Co3+/Co2+ ratio to generate more targeted OOH* intermediates and regulate the surface electronic structure to greatly boost its intrinsic activity. The density functional theory (DFT) calculations further confirm the reduction of the free energy of the OOH* intermediates. Consequently, our Co(OH)xS electrocatalyst exhibits an ultralow overpotential of 283 and 365 mV at 100 and 1000 mA cm-2 in alkaline media, respectively, and its turnover frequency (TOF) is more than 4 times higher than the corresponding Co(OH)x catalysts. This heteroatom triggered surface engineering may open up avenues to explore other efficient non-noble metal electrocatalysts for water oxidation. PMID- 29971289 TI - Secondary dialkylammonium salt/crown ether [2]pseudorotaxanes as nanostructured platforms for proton transport. AB - Multivalent secondary dialkylammonium salt/crown ether [2]pseudorotaxane, supramolecular polymer networks have been obtained by mixing surfactant encapsulated clusters with dibenzo[24]crown-8 groups and star polymers end functionalized with dibenzylammonium ions. This induces remarkable enhancements and rational control of proton conductivity of the supramolecular networks. PMID- 29971290 TI - Protein-protein interactions of human glyoxalase II: findings of a reliable docking protocol. AB - Glyoxalase II (GlxII) is an antioxidant glutathione-dependent enzyme, which catalyzes the hydrolysis of S-d-lactoylglutathione to form d-lactic acid and glutathione (GSH). The last product is the most important thiol reducing agent present in all eukaryotic cells that have mitochondria and chloroplasts. It is generally known that GSH plays a crucial role not only in the cellular redox state but also in various cellular processes. One of them is protein S glutathionylation, a process that can occur through an oxidation reaction of proteins' thiol groups by GSH. Changes in protein S-glutathionylation have been associated with a range of human diseases such as diabetes, cardiovascular and pulmonary diseases, neurodegenerative diseases and cancer. Within a major project aimed at elucidating the role of GlxII in the mechanism of S-glutathionylation, a reliable computational protocol consisting of a protein-protein docking approach followed by atomistic Molecular Dynamics (MD) simulations was developed and it was applied to the prediction of molecular associations between human GlxII (in the presence and absence of GSH) and some proteins that are known to be S glutathionylated in vitro, such as actin, malate dehydrogenase (MDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The computational results show a high propensity of GlxII to interact with actin and MDH through its active site and a high stability of the GlxII-protein systems when GSH is present. Moreover, close proximities of GSH with actin and MDH cysteine residues have been found, suggesting that GlxII could be able to perform protein S-glutathionylation by using the GSH molecule present in its catalytic site. PMID- 29971291 TI - Reliable and computationally affordable prediction of the energy gap of (TiO2)n (10 <= n <= 563) nanoparticles from density functional theory. AB - The optical gap (Ogap) of a set of (TiO2)n nanoclusters and nanoparticles with n = 10-563 and different morphologies such as spherical, octahedral, lamellar, or tubular finite structures is investigated based on a relativistic all-electron description along with a numerical atomic centered orbital basis set. Two different functionals are used, PBE and PBEx, the former corresponds to a standard implementation of the generalized gradient approximation (GGA) and the latter to a hybrid functional with 12.5% of Fock exchange which reproduces the band gap of bulk TiO2 anatase and rutile. It is shown that the inclusion of exchange Fock in the PBE functional promotes a systematic energy gap opening of 1.25 eV relative to the PBE values. Remarkably, a linear correlation is found between PBEx and PBE Ogap calculated values with concomitant similar correlations for the HOMO and LUMO orbital energies. However, it appears that PBEx induces a larger downshift on the HOMO orbital than the upshift observed on the LUMO one. The fact that the PBEx hybrid functional was shown to reproduce the experimental energy gaps of stoichiometric and reduced TiO2 bulk phases leads to a suitable and practical way to successfully estimate Ogap of TiO2 nanoparticles containing up to thousands of atoms with PBEx precision from computationally affordable PBE calculations. PMID- 29971292 TI - Visible light driven water splitting through an innovative Cu-treated-delta-MnO2 nanostructure: probing enhanced activity and mechanistic insights. AB - In this study, we have fabricated nanostructured thin films of delta-MnO2 on FTO glass substrates by a facile, room-temperature and low cost chemical bath deposition method. A copper treatment procedure in the synthesis steps results in a film of Cu-delta-MnO2, which displays significant photoactivity when used as a photocathode for hydrogen evolution reaction, with a photocurrent of 3.59 mA cm-2 (at 0 V vs. RHE) in a mild acidic solution. Furthermore, the electrodes also display significant electrocatalytic activity towards water oxidation reaching up to 10 mA cm-2 (at only 1.67 V vs. RHE). The Cu-delta-MnO2 film has been thoroughly characterized via various physicochemical, optical and electrochemical techniques, and an attempt has been made to explain the conductivity mechanism. It is suggested that Cu treatment enhances the photoactivity of delta-MnO2 films through a series of surface dominated processes, which facilitate reduced recombination and enhanced hole consumption at the interface of the electrode and electrolyte. These results establish birnessite-based manganese dioxides as suitable candidates for electrodes in water splitting cells and pave the way for atomic-level engineering of earth abundant materials to reach the ultimate goal of low-cost, sustainable generation of hydrogen. PMID- 29971293 TI - A robust two-dimensional zirconium-based luminescent coordination polymer built on a V-shaped dicarboxylate ligand for vapor phase sensing of volatile organic compounds. AB - We report herein a new two-dimensional zirconium-based luminescent coordination polymer Zr6(sdba)4(MU3-O)4(MU3-OH)4(HCOO)2(OH)2(H2O)2 (1) [sdba = 4,4' sulfonyldibenzoate] exhibiting selective fluorescence responses towards a variety of volatile organic compounds upon exposure in the vapor phase. Having a unique two-dimensional signal response towards aromatic molecules, including but not limited to nitroaromatic explosives, it is capable of identifying a diverse set of analytes. In addition, compound 1 shows its remarkably high sensitivity toward acetone vapors. PMID- 29971294 TI - Defining the conditional basis of silicon phthalocyanine near-IR ligand exchange. AB - Bond cleavage reactions initiated by long-wavelength light are needed to extend the scope of the caged-uncaged paradigm into complex physiological settings. Axially unsymmetrical silicon phthalocyanines (SiPcs) undergo efficient release of phenol ligands in a reaction contingent on three factors - near-IR light (690 nm), hypoxia, and a thiol reductant. These studies detail efforts to define the mechanistic basis for this unique conditionally-dependent bond cleavage reaction. Spectroscopic studies provide evidence for the formation of a key phthalocyanine radical anion intermediate formed from the triplet state in a reductant-dependent manner. Computational chemistry studies indicate that phenol ligand solvolysis proceeds through a heptacoordinate silicon transition state and that this solvolytic process is favored following SiPc radical anion formation. These results provide insight regarding the central role that radical anion intermediates formed through photoinduced electron transfer with biological reductants can play in long-wavelength uncaging reactions. PMID- 29971295 TI - The contact mechanics challenge: tribology meets soft matter. AB - In the fall of 2015, Martin Muser suggested a Contact Mechanics Challenge for the Tribology community. The challenge was an ambitious effort to compare a wide variety of theoretical and computational contact-mechanics approaches, and involved researchers voluntarily tackling the same hypothetical contact problem. The result is an impressive collection of innovative approaches - including a surprise experimental effort - that highlight the continuing importance of surface contact mechanics and the challenges of solving these large-scale problems. Here, we describe how the Contact Mechanics Challenge also reveals exciting opportunities for the Soft Matter community to engage intensely with classical and emerging problems in tribology, surface science, and contact mechanics. PMID- 29971296 TI - Ultrathin nanosheet-assembled [Ni3(OH)2(PTA)2(H2O)4].2H2O hierarchical flowers for high-performance electrocatalysis of glucose oxidation reactions. AB - Ultrathin two-dimensional (2D) metal-organic framework (MOF) nanosheets have been regarded as very promising electrocatalysts, although more efforts need to be devoted to improve their electrocatalytic activity. Here, we have developed ultrathin 2D nanosheet-assembled [Ni3(OH)2(PTA)2(H2O)4].2H2O (Ni-MOF, PTA = p benzenedicarboxylic acid) hierarchical flowers, which demonstrate superior electrocatalytic activity and excellent stability for the glucose oxidation reaction (GOR). The ultrathin 2D nanosheet-assembled flower-like nanostructure can provide interconnected open pores, accounting for its high electrocatalytic performance. Additionally, most of the ultrathin 2D nanosheets are in close contact with each other, making the ultrathin 2D nanosheets more stable. Furthermore, the electrocatalytic activity of the Ni-MOF flowers can be adjusted by doping Zn into the framework. PMID- 29971297 TI - New insights into the electrochemistry of magnesium molybdate hierarchical architectures for high performance sodium devices. AB - Magnesium molybdate (MgMoO4), which possesses synergistic features combining both hierarchical plate-like nanomaterials and porous architectures, has been successfully synthesized through a facile combustion synthesis at a low temperature. The hierarchical architecture is characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), scanning transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS) analyses. The as-obtained MgMoO4 nanoplates showed a porous structure with a pore-size distribution ranging from 50 to 70 nm. This porosity provides an electron transport pathway and enhanced surface reaction kinetics. The binding energies measured for Mg 2p, Mo 3d, 3p and O 1s are consistent with the literature, and with the metal ions being present as M(ii) and M(vi) states, respectively. This indicates that the oxidation states of the metal cations are as expected. The electrochemical behaviour of MgMoO4 was investigated using aqueous (NaOH) and non aqueous solvents (NaClO4 in EC : DMC : FEC) for supercapacitor and battery applications. The sodium-ion capacitor involves ion absorption and insertion into the MgMoO4 electrodes resulting in superior power and energy densities. However, the cycling stability was found to be stable only for an aqueous system. The formation of a solid electrolyte surface layer restricted the reversible capacity of the MgMoO4 in the sodium-battery. Nevertheless, it does offer some promise as an anode material for storing energy with high rate performance and excellent capacity retention. Detailed comparative analyses of various electrolytes in storage devices such as hybrid sodium-ion capacitors and sodium-ion batteries are vital for the integration of hierarchical structured materials into practical applications. The reaction mechanisms are postulated. PMID- 29971298 TI - Self-assembled heteropolyacid on nitrogen-enriched carbon nanofiber for vanadium flow batteries. AB - A novel polyoxometalate-based electrode was developed by incorporating phosphotungstic acid (PWA) in nylon-6,6 nanofiber, followed by carbonization. The developed PWA-carbon nanofiber (PWA-CNF) showed the characteristics of the dual scale porosity of micro- and mesoporous substrate with surface area of around 684 m2 g-1. The compound exhibited excellent stability in vanadium electrolyte and battery cycling. Evaluation of electrocatalytic properties toward V2+/V3+ and VO2+/VO2+ redox couples indicated promising advantages in electron transfer kinetics and increasing energy efficiency, particularly for the VO2+/VO2+ couple. Moreover, the developed electrode exhibited substantially improved energy efficiency (14% higher than that of pristine carbon felt) in the single cell vanadium redox flow battery. This outstanding performance was attributed to high surface area and abundant oxygen-containing linkages in the developed electrode. PMID- 29971299 TI - Controllable spherical aggregation of monodisperse carbon nanodots. AB - Monodisperse carbon nanodots (MCNDs) having an identical composition, structure, shape and size possess identical chemical and physical properties, making them highly promising for various technical and medical applications. Herein, we report a facile and effective route to obtain monodisperse carbon nanodots 3.5 +/ 0.9 nm in size by thermal decomposition of organosilane within the pores of monodisperse mesoporous silica particles with subsequent removal of the silica template. Structural studies demonstrated that the MCNDs we synthesized consist of ~7-10 defective graphene layers that are misoriented with respect to each other and contain various oxygen-containing functional groups. It was demonstrated that, owing to their identical size and chemical composition, the MCNDs are formed via coagulation primary aggregates ~10-30 nm in size, which are, in turn, combined into secondary porous spherical aggregates ~100-200 nm in diameter. The processes of coagulation of MCNDs and peptization of their hierarchical aggregates are fully reversible and can be controlled by varying the MCND concentration or the pH value of the hydrosols. Submicrometer spherical aggregates of MCNDs are not disintegrated as the hydrosol is dried. The thus obtained porous spherical aggregates of MCNDs are promising for drug delivery as a self-disassembling container for medicinal preparations. PMID- 29971300 TI - Three-dimensional angiography fused with CT/MRI for multimodal imaging of nanoparticles based on Ba4Yb3F17:Lu3+,Gd3+ . AB - Designing nanosized multi-modality contrast agents for high-resolution imaging is challenging since most agents are only useful for single-mode imaging. In this work, we successfully synthesized biocompatible polyethylene glycol (PEG-) and l glutamine (GLN-) modified Ba4Yb3F17:Lu3+,Gd3+ nanoparticles (LNPs@PEG@GLN) that can be employed as a multi-modality contrast agent. Fluorescence dye-modified LNPs@PEG@GLN nanoparticles can be used for computed tomography (CT), magnetic resonance imaging (MRI), and fluorescence imaging (FI). They display high X-ray absorption, outstanding T2-weighted imaging capability, and good fluorescence uptake. Furthermore, LNPs@PEG@GLN enhances contrast efficiencies for different imaging modalities in vivo. Interestingly, LNPs@PEG@GLN is a promising agent for CT angiography. These nanoparticles could be a promising contrast agent for multi modality imaging and diagnosing vascular diseases. PMID- 29971301 TI - Reactive two-component monolayers template bottom-up assembly of nanoparticle arrays on HOPG. AB - Two triphenyleneethynylene derivatives, 1OH and 2, self-assemble a patterned monolayer (ML) at the solution-graphite (HOPG) interface. The four molecule unit cell of the ML, (1OH1OH22), spans 19 nm and contains adjacent columns of 1OH molecules spaced by 4.7 nm. Following ML assembly, a disulfide is appended to the alcohol group on each 1OH molecule and used to capture 2.0 nm gold nanoparticles (AuNP). The patterned monolayer directs bottom-up assembly of a 5 nm/19 nm double pitch AuNP pattern. PMID- 29971302 TI - Ca2+, redox, and thermoresponsive supramolecular hydrogel with programmed quadruple shape memory effect. AB - A new shape memory hydrogel, which can be programmed with quadruple geometries when stimuli are applied sequentially, is presented. With a new redox-responsive stimulus coupled with two other common regulation mechanisms, this hydrogel shows multiple shape memory behaviours, which is promising for various applications, especially drug delivery. PMID- 29971303 TI - 1,8-Diamidocarbazoles: an easily tuneable family of fluorescent anion sensors and transporters. AB - The synthesis, structure and anion recognition properties of an extensive, rationally designed series of bisamide derivatives of 1,8-diaminocarbazole and 1,8-diamino-3,6-dichlorocarbazole are described. Despite simple structures and the presence of only three hydrogen bond donors, such compounds are remarkably strong and selective receptors for oxyanions in DMSO + 0.5%H2O. Owing to their carbazole fluorophore, they are also sensitive turn-on fluorescent sensors for H2PO4- and AcO-, with a more than 15-fold increase in fluorescence intensity upon binding. Despite relatively weak chloride affinity, some of the diamidocarbazoles have also been shown, for the first time, to be very active chloride transporters through lipid bilayers. The binding, sensing and transport properties of these receptors can be easily modulated by the usually overlooked variations in the length and degree of branching of their alkyl side arms. Overall, this study demonstrates that the 1,8-diamidocarbazole binding unit is a very promising and synthetically versatile platform for the development of fluorescent sensors and transporters for anions. PMID- 29971304 TI - Water-resistant PEDOT:PSS hole transport layers by incorporating a photo crosslinking agent for high-performance perovskite and polymer solar cells. AB - We demonstrated a water-resistant PEDOT:PSS HTL by incorporating a photo crosslinking agent into a PEDOT:PSS film. A crosslinking system was successfully formed inside the PEDOT:PSS film by simple and fast photo-polymerization of PCDSA monomers. Combination of the crosslinking system and MeOH surface treatment simultaneously improved the device efficiency and stability of both perovskite and polymer solar cells. The crosslinking system inside PEDOT:PSS changed its intrinsic water-soluble characteristic into a water-resistant property, thus preventing water penetration into the PEDOT:PSS film. In addition, MeOH treatment improved the surface conductivity and reduced the surface roughness of the PEDOT:PSS film by removing surface residues of PDAs and insulating PSS parts. PMID- 29971305 TI - Optical properties of bimetallic compositional heterodimers. AB - Many important applications of nanometer-sized metal objects arise from the light induced interactions between their component structures. Here, we demonstrate through state-of-the-art quantum mechanical simulations, the optical response of bimetallic heterodimers (two closely adjacent nanoparticles) composed of Al and Na nanoparticles. We calculate the optical response using time-dependent density functional theory. We found that Al-Na bimetallic heterodimers show rich optical features, strongly depending on the size heterogeneity and interparticle gap distances. In particular, we observe remarkable optical field enhancements and creation of new low-energy absorption peaks with respect to the single Al and Na nanoparticles. We believe that our results may influence the design of future nanoparticle-based optical nanoantenna. PMID- 29971306 TI - Resistance of water transport in carbon nanotube membranes. AB - Carbon nanotube (CNT) membranes have long been considered as next-generation membranes due to superfast water transport inside tubes. However, a large pressure loss occurs at the pore mouth, and consequently water transport through the whole tubes is significantly retarded. To find out the reason behind this, we conduct systematic non-equilibrium molecular dynamics (NEMD) simulations on water transport through CNT membranes with various tube diameters and lengths. The whole transport resistance is contributed by the interfacial and interior parts, and the interfacial contribution plays a dominating role in short tubes and only can be ignored when the tube length reaches a scale of several micrometers. With regard to the origin of the interfacial resistance, the hydrogen bonding rearrangement (HBR) effect accounts for at least 45%, and the rest is attributed to the geometrical or steric crowding of water molecules near the pore mouth. To reduce the dominant interfacial resistance, we change the shape of the pore mouth from plate to hourglass by mimicking the aquaporin water channels. The interfacial resistance is thus decreased by >27%. It is also found that the reduction is originated from the optimized HBR rather than the subdued steric crowding of water molecules near the pore mouth. PMID- 29971307 TI - Genome-wide survey of remote homologues for protein domain superfamilies of known structure reveals unequal distribution across structural classes. AB - Domains are the basic building blocks of proteins which can combine to give rise to different domain architectures. Annotation of domains in a sequence is the first step towards understanding the biological function. Since there are a limited number of folds and evolutionarily related proteins have a similar structure, function can be inferred through remote homology. Computational sequence searches were performed for remote homologues on genomes of around ~160 000 different organisms, starting from nearly 11 000 superfamily queries of known structure. Case studies revealed that most of the associated domains are involved in the same biological process. Using all the proteins predicted to have at least one structural domain, a coverage of 61% of Pfam families was achieved which is higher than the existing methods (43.36% by SIFTS). Taxonomic analysis of the proteins revealed 493 superfamilies in all the major kingdoms of life and a few lateral gene transfers between viruses and cellular organisms. The distribution of remote homologues across different classes, folds and superfamilies was studied and reveals that sequences are unequally distributed across structural classes. Finally, domain architectures were computed for the homologues and these data were compiled for each superfamily and organism. PMID- 29971308 TI - G4-quartet hydrogels from 5'-hydrazino-guanosine for the non-covalent and covalent remediation of contaminants from water. AB - The creation of supramolecular hydrogels from relatively simple building blocks demonstrates the power of molecular self-assembly to make functional materials. G4-quartet hydrogels are appealing for a number of applications, including the environmental remediation of pollutants in water. We find that the guanosine analog, 5'-deoxy-5'-hydrazinoguanosine (HG 2) self-assembles into a self-standing hydrogel in the presence of stoichiometric amounts (0.25 equiv.) of KCl. The higher water solubility of HG 2 (14.5 mM), compared to that of the parent compound G 1 (2.1 mM), likely contributes to its enhanced gelation. The structural basis for this HG 2.KCl hydrogel, confirmed by PXRD, IR and CD, is the G4.K+ quartet, which forms extended 1D ion-channel assemblies that entangle to give a stable and long-lived hydrogel. We also find that adding KCl to a saturated solution of HG 2 triggers the generation of colloidal G4.K+ assemblies in situ that selectively and efficiently binds the anionic dye naphthol blue black (NBB) over a cationic dye. In addition to this non-covalent electrostatic binding of anions, the nucleophilic 5'-hydrazino group in the HG 2.KCl hydrogel HG 2 enables the efficient absorption of propionaldehyde from both the gas phase and from water solution via the formation of covalent hydrazone linkages with the gel matrix. PMID- 29971309 TI - Two-dimensional metal-organic framework nanosheets: synthesis and applications. AB - Two-dimensional (2D) metal-organic framework (MOF) nanosheets are attracting increasing research attention due to their unique properties originating from their ultrathin thickness, large surface area and high surface-to-volume atom ratios. Many great advances have been made in the synthesis and application of 2D MOF nanosheets over the past few years. In this review, we summarize the recent advances in the synthesis of 2D MOF nanosheets by using top-down methods, e.g. sonication exfoliation, mechanical exfoliation, Li-intercalation exfoliation and chemical exfoliation, and bottom-up methods, i.e. interfacial synthesis, three layer synthesis, surfactant-assisted synthesis, modulated synthesis, and sonication synthesis. In addition, the recent progress in 2D MOF nanosheet-based nanocomposites is also briefly introduced. The potential applications of 2D MOF nanosheets in gas separation, energy conversion and storage, catalysis, sensors and biomedicine are discussed. Finally, we give our personal insights into the challenges and opportunities for the future research of 2D MOF nanosheets and their composites. PMID- 29971310 TI - Effect of fullerene acceptor on the performance of solar cells based on PffBT4T 2OD. AB - We have studied bulk-heterojunction (BHJ) solar cells composed of the polymer PffBT4T-2OD as electron donor and three different electron accepting fullerenes, namely PC71BM, PC61BM and indene-C60-bis-adduct (ICBA) in order to understand the impact of different fullerenes on the morphology and efficiency of the corresponding photovoltaic devices. Despite PffBT4T-2OD:ICBA devices being characterised by higher values of Voc, they display the lowest power conversion efficiency (PCE) due to their lower Jsc and FF values. We find that although all blend films have similar morphologies, X-ray scattering indicates a reduced degree of order within the fullerene domains in the ICBA-based film. Due to the high LUMO level of ICBA, the corresponding blends are characterised by a lower initial exciton dissociation and this associated with the reduced ordering within the ICBA domains results in increased geminate recombination of the photogenerated electrons in the fullerene-rich domains and a consequently reduced PCE of the corresponding devices. PMID- 29971311 TI - Chirality transfer from organic ligands to silver nanostructures via chiral polarisation of the electric field. AB - Water-soluble ligand protected optically active silver nanostructures were synthesised in a one-step reduction and capping process mediated by thiol containing biomolecules. The synthesis was performed successfully with d- and l cysteine and l-glutathione. The chiroptical properties of the obtained nanostructures were investigated by circular dichroism spectroscopy in the ultraviolet and visible wavelength range. They exhibit a g-value of up to 0.7%, which is about one order of magnitude larger compared to particles prepared by citrate reduction followed by a ligand exchange reaction. The structure and composition of the prepared materials were characterised by transmission electron microscopy, energy-dispersive X-ray and X-ray photoelectron spectroscopy. Although these structures do not have a chiral geometry, they show mirror image g values when capped with d- and l-cysteine. This indicates that the underlying chirality transfer mechanism is based on an electric field polarisation process. PMID- 29971312 TI - Scalable solid-state synthesis of coralline-like nanostructured Co@CoNC electrocatalyst for Zn-air batteries. AB - A facile and scalable solid-state synthesis strategy is developed to produce hierarchical coralline-like nanostructured electrocatalysts with cobalt nanoparticles and Co-NX sites for efficient oxygen reduction reaction, opening up an avenue for the mass production of non-precious metal catalysts for metal-air batteries and fuel cells, etc. PMID- 29971314 TI - Valley-selective circular dichroism and high carrier mobility of graphene-like BC6N. AB - The two-dimensional (2D) hybrid structures of boron nitride (BN) and graphene with properties superior to the individuals are long desired. In this work, we demonstrate theoretically that this goal can be reached in a new graphene-like borocarbonitride (g-BC6N) whose domain has been synthesized in recent experiments. It has a direct band gap of 1.833 eV and a high carrier mobility comparable to that of black phosphorene. The inversion symmetry breaking in g BC6N leads to a pair of inequivalent valleys with opposite Berry curvatures in the vicinities of the vertices (K and K') of the Brillouin zone. The coexistence of valley-selective circular dichroism and high carrier mobility in g-BNC6 is beneficial to realize the valley Hall effect. We also propose a tight-binding (TB) model to describe the intrinsic features of this type of lattice, revealing a new class of 2D valleytronic materials. PMID- 29971313 TI - Application of Q2MM to predictions in stereoselective synthesis. AB - Quantum-Guided Molecular Mechanics (Q2MM) can be used to derive transition state force fields (TSFFs) that allow the fast and accurate predictions of stereoselectivity for a wide range of catalytic enantioselective reactions. The basic ideas behind the derivation of TSFFs using Q2MM are discussed and the steps involved in obtaining a TSFF using the Q2MM code, publically available at github.com/q2mm, are shown. The applicability for a range of reactions, including several non-standard applications of Q2MM, is demonstrated. Future developments of the method are also discussed. PMID- 29971315 TI - Preparation of Sb nanoparticles in molten salt and their potassium storage performance and mechanism. AB - Sb nanoparticles with a size of 55 nm are fabricated via the reduction of SbCl3 by metallic Al in the molten salt of SbCl3 at 80 degrees C. In situ XRD patterns and ex situ Raman spectra show that the potassium storage mechanism is an alloying-type with the formation of a cubic K3Sb phase when fully potassiated and an amorphous phase when fully depotassiated. As an anode for potassium-ion batteries, Sb nanoparticles coated with graphene could deliver a reversible capacity of 381 mA h g-1 at 100 mA g-1, and maintain a capacity of 210 mA h g-1 at 500 mA g-1 for 200 cycles. PMID- 29971316 TI - Structural investigations of SnS1-xSex solid solution synthesized from chalcogeno carboxylate complexes of organo-tin by colloidal and solvent-less routes. AB - Tin chalcogenides are important semiconducting materials due to their non-toxic nature, cost effectiveness and layered structure. In this study, a facile synthetic route has been employed for the synthesis of a bis(selenobenzoato)dibutyltin(iv) complex, and used along with the bis(thiobenzoato)dibutyltin(iv) complex, as single source precursors, to prepare binary tin chalcogenides and their solid solution (SnS1-xSex) in the entire range. The synthesis of the solid solution was carried out by colloidal and melt methods. The comparative analysis of the solid solution obtained from both routes indicates that the colloidal method provides superior control over composition. The UV-Vis-NIR analysis showed a gradual change in the band gap, while moving from SnS to SnSe. PMID- 29971317 TI - Plant extracts as green reductants for the synthesis of silver nanoparticles: lessons from chemical synthesis. AB - The increasing use of silver (Ag) nanoparticles (NPs) in daily-life applications, electronics, or catalysis calls for green and cost-efficient synthetic methods. Ag NPs are used especially in biomedicine because of their antibacterial, antifungal, or anticancer properties. Chemical synthesis allows tuning the particle morphology, size, and crystallinity, but requires toxic and hazardous chemicals. Bioinspired synthetic protocols have shown promise to minimize environmental impact, but biological protocols for the synthesis of Ag NPs lack control on the morphology and crystallinity. This review briefly compiles the chemical synthesis of Ag NPs and contrasts it with "green" protocols based on lessons learnt from chemical synthesis. The synthesis of Ag NPs with different plant extracts and the associated phytomolecules, their chemical and biological effects, and their effect on particle synthesis are described and put into perspective to improve green protocols. The surface functionalization of Ag NPs by phytomolecules and the mechanisms of their biomedical applications are summarized. PMID- 29971319 TI - Investigating the Role of Micronutrients in Brain Development and Psychiatric Disorders via Magnetic Resonance Imaging. PMID- 29971318 TI - Potential Underuse of the Sentinel Lymph Node Biopsy for High-Risk Squamous Cell Carcinoma of the Skin. PMID- 29971320 TI - The Carbohydrate-Insulin Model of Obesity Is Difficult to Reconcile With Current Evidence. PMID- 29971321 TI - Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas. AB - Importance: Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs. Objective: To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. Design, Setting, and Participants: A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Main Outcomes and Measures: Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine. Results: All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up. Conclusions and Relevance: This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery. PMID- 29971323 TI - Expanding Access to Magnetic Resonance Imaging for Patients With Cardiac Rhythm Devices. PMID- 29971322 TI - Association of Future Orientation With Violence Perpetration Among Male Youths in Low-Resource Neighborhoods. PMID- 29971326 TI - Data Sharing-The Time Has (Not Yet?) Come. PMID- 29971324 TI - Association of APOL1 With Heart Failure With Preserved Ejection Fraction in Postmenopausal African American Women. AB - Importance: APOL1 genotypes are associated with kidney diseases in African American individuals and may influence cardiovascular disease and mortality risk, but findings have been inconsistent. Objective: To discern whether high-risk APOL1 genotypes are associated with cardiovascular disease and stroke in postmenopausal African American women, who are at high risk for these outcomes. Design, Setting, and Participants: The Women's Health Initiative is a prospective cohort that enrolled 161 838 postmenopausal women into clinical trials and an observational study between 1993 and 1998. This study includes 11 137 African American women participants who had a clinical event from enrollment to June 2014. Data analyses were completed from January 2017 to August 2017. Exposures: The variants of APOL1 were genotyped or imputed from whole-exome sequencing. Main Outcomes and Measures: Incident coronary heart disease, stroke and heart failure subtypes, and overall and cause-specific mortality were adjudicated from hospital records and death certificates. Estimated incidence rates were determined for each outcome and hazard ratios (HR) and 95% CIs for the associations of APOL1 groups with outcomes. Results: The mean (SD) age of participants was 61.7 (7.1) years. Carriers of high-risk APOL1 variants (n = 1370; 12.3%) had higher prevalence of hypertension, use of cholesterol-lowering medications, and reduced estimated glomerular filtration rate (eGFR). After a mean (SD) of 11.0 (3.6) years, carriers of high-risk APOL1 variants had a higher incidence rate of hospitalized heart failure with preserved ejection fraction (HFpEF) than low-risk carriers did but showed no differences for other outcomes. In adjusted models, there was a significant 58% increased hazard of hospitalized HFpEF (HR, 1.58 [95% CI, 1.03-2.41]) among carriers of high-risk APOL1 variants compared with carriers of low-risk APOL1 variants. The association with HFpEF was attenuated (HR = 1.50 [95% CI, 0.98-2.30]) and no longer significant when adjusting for baseline eGFR. Conclusions and Relevance: Status as a carrier of a high-risk APOL1 genotype was associated with HFpEF hospitalization among postmenopausal women, which is partly accounted for by baseline kidney function. These findings do not support an association of high-risk APOL1 genotypes with coronary heart disease, stroke, or mortality in postmenopausal African American women. PMID- 29971327 TI - Different Population and End Point Definitions in Reproduction Analysis Based on Shared Data. PMID- 29971325 TI - Association of Out-of-Pocket Annual Health Expenditures With Financial Hardship in Low-Income Adults With Atherosclerotic Cardiovascular Disease in the United States. AB - Importance: Health insurance is effective in preventing financial hardship from unexpected major health care events. However, it is also essential to assess whether vulnerable patients, particularly those from low-income families, are adequately protected from longitudinal health care costs for common chronic conditions such as atherosclerotic cardiovascular disease (ASCVD). Objective: To examine the annual burden of total out-of-pocket health expenses among low-income families that included a member with ASCVD. Design, Setting, and Participants: In this cross-sectional study of the Medical Expenditure Panel Survey from January 2006 through December 2015, all families with 1 or more members with ASCVD were identified. Families were classified as low income if they had an income under 200% of the federal poverty limit. Analyses began December 2017. Main Outcomes and Measures: Total annual inflation-adjusted out-of-pocket expenses, inclusive of insurance premiums, for all patients with ASCVD. We compared these expenses against annual family incomes. Out-of-pocket expenses of more than 20% and more than 40% of family income defined high and catastrophic financial burden, respectively. Results: We identified 22 521 adults with ASCVD, represented in 20 600 families in the Medical Expenditure Panel Survey. They correspond to an annual estimated 23 million or 9.9% of US adults with a mean (SE) age of 65 (0.2) years and included 10.9 million women (47.1%). They were represented in 21 million or 15% of US families. Of these, 8.2 million families (39%) were low income. The mean annual family income was $57 143 (95% CI, $55 377-$58 909), and the mean out-of-pocket expense was $4415 (95% CI, $3735-$3976). While financial burden from health expenses decreased throughout the study, even in 2014 and 2015, low-income families had 3-fold higher odds than mid/high-income families of high financial burden (21.4% vs 7.6%; OR, 3.31; 95% CI, 2.55-4.31) and 9-fold higher odds of catastrophic financial burden (9.8% vs 1.2%; OR, 9.35; 95% CI, 5.39-16.20), representing nearly 2 million low-income families nationally. Further, even among the insured, 1.6 million low-income families (21.8%) experienced high financial burden and 721 000 low-income families (9.8%) experienced catastrophic out-of-pocket health care expenses in 2014 and 2015. Conclusions and Relevance: One in 4 low-income families with a member with ASCVD, including those with insurance coverage, experience a high financial burden, and 1 in 10 experience a catastrophic financial burden due to cumulative out-of pocket health care expenses. To alleviate economic disparities, policy interventions must extend focus to improving not only access, but also quality of coverage, particularly for low-income families. PMID- 29971328 TI - Potential Underuse of the Sentinel Lymph Node Biopsy for High-Risk Squamous Cell Carcinoma of the Skin-Reply. PMID- 29971329 TI - Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths. AB - Importance: Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence. Objective: To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths. Design, Setting, and Participants: A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout +/-3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018. Exposures: United States mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997. Main Outcomes and Measures: Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms. Results: The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (beta = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (beta = -1.59 to -1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years). Conclusions and Relevance: The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths. PMID- 29971331 TI - Dupilumab Treatment of Very Severe Refractory Atopic Hand Eczema. PMID- 29971330 TI - Use of Machine Learning to Determine Deviance in Neuroanatomical Maturity Associated With Future Psychosis in Youths at Clinically High Risk. AB - Importance: Altered neurodevelopmental trajectories are thought to reflect heterogeneity in the pathophysiologic characteristics of schizophrenia, but whether neural indicators of these trajectories are associated with future psychosis is unclear. Objective: To investigate distinct neuroanatomical markers that can differentiate aberrant neurodevelopmental trajectories among clinically high-risk (CHR) individuals. Design, Setting, and Participants: In this prospective longitudinal multicenter study, a neuroanatomical-based age prediction model was developed using a supervised machine learning technique with T1-weighted magnetic resonance imaging scans of 953 healthy controls 3 to 21 years of age from the Pediatric Imaging, Neurocognition, and Genetics (PING) study and then applied to scans of 275 CHR individuals (including 39 who developed psychosis) and 109 healthy controls 12 to 21 years of age from the North American Prodrome Longitudinal Study 2 (NAPLS 2) for external validation and clinical application. Scans from NAPLS 2 were collected from January 15, 2010, to April 30, 2012. Main Outcomes and Measures: Discrepancy between neuroanatomical-based predicted age (hereafter referred to as brain age) and chronological age. Results: The PING-derived model (460 females and 493 males; age range, 3-21 years) accurately estimated the chronological ages of the 109 healthy controls in the NAPLS 2 (43 females and 66 males; age range, 12-21 years), providing evidence of independent external validation. The 275 CHR individuals in the NAPLS 2 (111 females and 164 males; age range, 12-21 years) showed a significantly greater mean (SD) gap between model-predicted age and chronological age (0.64 [2.16] years) compared with healthy controls (P = .008). This outcome was significantly moderated by chronological age, with brain age systematically overestimating the ages of CHR individuals who developed psychosis at ages 12 to 17 years but not the brain ages of those aged 18 to 21 years. Greater brain age deviation was associated with a higher risk for developing psychosis (F = 3.70; P = .01) and a pattern of stably poor functioning over time, but only among younger CHR adolescents. Previously reported evidence of accelerated reduction in cortical thickness among CHR individuals who developed psychosis was found to apply only to those who were 18 years of age or older. Conclusions and Relevance: These results are consistent with the view that neuroanatomical markers of schizophrenia may help to explain some of the heterogeneity of this disorder, particularly with respect to early vs later age of onset of psychosis, with younger and older individuals having differing intercepts and trajectories in structural brain parameters as a function of age. The results also suggest that baseline neuroanatomical measures are likely to be useful in estimating onset of psychosis, especially (or only) among CHR individuals with an earlier age of onset of prodromal symptoms. PMID- 29971332 TI - Finding Means to Fulfill the Societal and Academic Imperative for Open Data Access and Sharing. PMID- 29971333 TI - The Future of JAMA Dermatology. PMID- 29971334 TI - An Annular Eruption in a Young Child. PMID- 29971336 TI - Naturalistic Speech-Generating Device Interventions for Children With Complex Communication Needs: A Systematic Review of Single-Subject Studies. AB - Purpose: This article presents a systematic review that aimed to synthesize single-subject-design studies that have examined naturalistic interventions for teaching the expressive use of speech-generating devices (SGDs) to children with complex communication needs. Specifically, this review describes what intervention strategies are most commonly applied in studies with positive effects and minimal methodological flaws and examines the populations and outcomes for which these strategies have been effective. Method: A systematic approach was used to qualitatively code variables of interest to this review. Results were summarized via both visual analysis and effect size methods, and a certainty of evidence methodology was adopted to describe the quality of the evidence. Results: Thirty-two unique studies met inclusion criteria, with 19 having consistent positive results and meeting minimum requirements for certainty of evidence. Although studies used a variety of titles to describe intervention packages (e.g., milieu teaching, interaction strategies), certain strategies were common across studies. These included (a) creating and capturing communication opportunities via methods such as time delay and questioning; (b) providing feedback via methods such as reinforcement of requests, praise, or expansions; (c) prompting (verbal, physical, gestural); (d) modeling; and (e) training communication partners. Conclusions: Findings regarding these intervention components help to provide practical guidelines for naturalistic SGD intervention. Limitations of the current body of research (e.g., need to include more home-based studies and more intermediate to advanced SGDs, need to critically analyze the most critical intervention components) provide suggestions for future research. Supplemental Material: https://doi.org/10.23641/asha.6615332. PMID- 29971335 TI - Assessing Biological and Methodological Aspects of Brain Volume Loss in Multiple Sclerosis. AB - Importance: Before using brain volume loss (BVL) as a marker of therapeutic response in multiple sclerosis (MS), certain biological and methodological issues must be clarified. Objectives: To assess the dynamics of BVL as MS progresses and to evaluate the repeatability and exchangeability of BVL estimates with Jacobian Integration (JI) and Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL) (specifically, the Structural Image Evaluation, Using Normalisation, of Atrophy-Cross-Sectional [SIENA-X] tool or FMRIB's Integrated Registration and Segmentation Tool [FIRST]). Design, Setting, and Participants: A cohort of patients who had either clinically isolated syndrome or MS was enrolled from February 2011 through October 2015. All underwent a series of annual magnetic resonance imaging (MRI) scans. Images from 2 cohorts of healthy volunteers were used to evaluate short-term repeatability of the MRI measurements (n = 34) and annual BVL (n = 20). Data analysis occurred from January to May 2017. Main Outcomes and Measures: The goodness of fit of different models to the dynamics of BVL throughout the MS disease course was assessed. The short-term test-retest error was used as a measure of JI and FSL repeatability. The correlations (R2) of the changes quantified in the brain using JI and FSL, together with the accuracy of the annual BVL cutoffs to discriminate patients with MS from healthy volunteers, were used to measure compatibility of imaging methods. Results: A total of 140 patients with clinically isolated syndrome or MS were enrolled, including 95 women (67.9%); the group had a median (interquartile range) age of 40.7 (33.6-48.1) years. Patients underwent 4 MRI scans with a median (interquartile range) interscan period of 364 (351-379) days. The 34 healthy volunteers (of whom 18 [53%] were women; median [IQR] age, 33.5 [26.2 42.5] years) and 20 healthy volunteers (of whom 10 [50%] were women; median [IQR] age, 33.0 [28.7-39.2] years) underwent 2 MRI scans within a median (IQR) of 24.5 (0.0-74.5) days and 384.5 (366.3-407.8) days for the short-term and long-term MRI follow-up, respectively. The BVL rates were higher in the first 5 years after MS onset (R2 = 0.65 for whole-brain volume change and R2 = 0.52 for gray matter volume change) with a direct association with steroids (beta = 0.280; P = .02) and an inverse association with age at MS onset, particularly in the first 5 years (beta = 0.015; P = .047). The reproducibility of FSL (SIENA) and JI was similar for whole-brain volume loss, while JI gave more precise, less biased estimates for specific brain regions than FSL (SIENA-X and FIRST). The correlation between whole-brain volume loss using JI and FSL was high (R2 = 0.92), but the same correlations were poor for specific brain regions. The area under curve of the whole-brain volume change to discriminate between patients with MS and healthy volunteers was similar, although the thresholds and accuracy index were distinct for JI and FSL. Conclusions and Relevance: The proposed BVL threshold of less than 0.4% per year as a marker of therapeutic efficiency should be reconsidered because of the different dynamics of BVL as MS progresses and because of the limited reproducibility and variability of estimates using different imaging methods. PMID- 29971338 TI - Effects of Second Language Proficiency and Linguistic Uncertainty on Recognition of Speech in Native and Nonnative Competing Speech. AB - Purpose: The purpose of this study was to investigate the effects of 2nd language proficiency and linguistic uncertainty on performance and listening effort in mixed language contexts. Method: Thirteen native speakers of Dutch with varying degrees of fluency in English listened to and repeated sentences produced in both Dutch and English and presented in the presence of single-talker competing speech in both Dutch and English. Target and masker language combinations were presented in both blocked and mixed (unpredictable) conditions. In the blocked condition, in each block of trials the target-masker language combination remained constant, and the listeners were informed of both prior to beginning the block. In the mixed condition, target and masker language varied randomly from trial to trial. All listeners participated in all conditions. Performance was assessed in terms of speech reception thresholds, whereas listening effort was quantified in terms of pupil dilation. Results: Performance (speech reception thresholds) and listening effort (pupil dilation) were both affected by 2nd language proficiency (English test score) and target and masker language: Performance was better in blocked as compared to mixed conditions, with Dutch as compared to English targets, and with English as compared to Dutch maskers. English proficiency was correlated with listening performance. Listeners also exhibited greater peak pupil dilation in mixed as compared to blocked conditions for trials with Dutch maskers, whereas pupil dilation during preparation for speaking was higher for English targets as compared to Dutch ones in almost all conditions. Conclusions: Both listener's proficiency in a 2nd language and uncertainty about the target language on a given trial play a significant role in how bilingual listeners attend to speech in the presence of competing speech in different languages, but precise effects also depend on which language is serving as target and which as masker. PMID- 29971337 TI - Marijuana Use, Respiratory Symptoms, and Pulmonary Function: A Systematic Review and Meta-analysis. AB - Background: The health effects of smoking marijuana are not well-understood. Purpose: To examine the association between marijuana use and respiratory symptoms, pulmonary function, and obstructive lung disease among adolescents and adults. Data Sources: PubMed, Embase, PsycINFO, MEDLINE, and the Cochrane Library from 1 January 1973 to 30 April 2018. Study Selection: Observational and interventional studies published in English that reported pulmonary outcomes of adolescents and adults who used marijuana. Data Extraction: Four reviewers independently extracted study characteristics and assessed risk of bias. Three reviewers assessed strength of evidence. Studies of similar design with low or moderate risk of bias and sufficient data were pooled. Data Synthesis: Twenty-two studies were included. A pooled analysis of 2 prospective studies showed that marijuana use was associated with an increased risk for cough (risk ratio [RR], 2.04 [95% CI, 1.02 to 4.06]) and sputum production (RR, 3.84 [CI, 1.62 to 9.07]). Pooled analysis of cross-sectional studies (1 low and 3 moderate risk of bias) showed that marijuana use was associated with cough (RR, 4.37 [CI, 1.71 to 11.19]), sputum production (RR, 3.40 [CI, 1.99 to 5.79]), wheezing (RR, 2.83 [CI, 1.89 to 4.23]), and dyspnea (RR, 1.56 [CI, 1.33 to 1.83]). Data on pulmonary function and obstructive lung disease were insufficient. Limitation: Few studies were at low risk of bias, marijuana exposure was limited in the population studied, cohorts were young overall, assessment of marijuana exposure was not uniform, and study designs varied. Conclusion: Low-strength evidence suggests that smoking marijuana is associated with cough, sputum production, and wheezing. Evidence on the association between marijuana use and obstructive lung disease and pulmonary function is insufficient. Primary Funding Source: None. (PROSPERO: CRD42017059224). PMID- 29971339 TI - FDA Regulation of Mobile Medical Apps. PMID- 29971340 TI - Questionable Assumptions Provided in Nonoperative Treatment of Appendicitis Survey. PMID- 29971341 TI - Moving From Hope to Hard Work in Data Sharing. PMID- 29971342 TI - Forward and Backward Masking of Consonants in School-Age Children and Adults. AB - Purpose: This experiment sought to determine whether children's increased susceptibility to nonsimultaneous masking, particularly backward masking, is evident for speech stimuli. Method: Five- to 9-year-olds and adults with normal hearing heard nonsense consonant-vowel-consonant targets. In Experiments 1 and 2, those targets were presented between two 250-ms segments of 70-dB-SPL speech shaped noise, at either -30 dB signal-to-noise ratio (Experiment 1) or at the listener's word recognition threshold (Experiment 2). In Experiment 3, the target was presented in steady speech-shaped noise at listener threshold. For all experiments, percent correct was estimated for initial and final consonants. Results: In the nonsimultaneous noise conditions, child-adult differences were larger for the final consonant than the initial consonant whether listeners were tested at -30 dB signal-to-noise ratio (Experiment 1) or at their individual word recognition threshold (Experiment 2). Children were not particularly susceptible to backward masking relative to adults when tested in a steady masker (Experiment 3). Conclusions: Child-adult differences were greater for backward than forward masking for speech in a nonsimultaneous noise masker, as observed in previous psychophysical studies using tonal stimuli. Children's greater susceptibility to nonsimultaneous masking, and backward masking in particular, could play a role in their limited ability to benefit from masker envelope modulation when recognizing masked speech. PMID- 29971343 TI - Audiology Faculty Author Impact Metrics as a Function of Institution. AB - Purpose: The purpose of this study was to develop a method for the assessment of audiology author impact as a function of institution and compare these results to a recent college ranking of audiology graduate programs. Method: Scopus author impact metrics (i.e., number of documents, number of citations, and h index) from a previous study (Stuart, Faucette, & Thomas, 2017) were generated for 79 accredited graduate programs in audiology in the United States and Canada. Author impact metrics were summed to represent the total institution output, and median values were calculated to reflect a measure of central tendency of individual faculty performance. Results: Three hundred and seventy-nine audiology faculty members were identified and of those 86.0% (n = 326) were found in Scopus. Database presence increased with increasing rank (p = .003). Scopus index values were positively skewed. The total summed number of documents, citations, and h indices were positively correlated with the total number of faculty in the institutions and with the summed number of coauthors (p < .001). The median number of documents, citations, and h indices were not significantly correlated with the total number of faculty in the institutions but were positively correlated with the median number of coauthors (p < .001). In general, indices were higher for research/doctoral versus nonresearch universities. Higher college program rankings were statistically related with better Scopus index values. Conclusion: These institutional metrics may be used to serve as a benchmark for institutional production, attracting students, hiring faculty, and assessing allocation of institutional funding. PMID- 29971344 TI - Association of Attending Surgeon With Variation in the Receipt of Genetic Testing After Diagnosis of Breast Cancer. AB - Importance: Genetic testing after diagnosis of breast cancer is common, but little is known about the influence of the surgeon on the variation in testing. Objectives: To quantify and explain the association of attending surgeon with rates of genetic testing after diagnosis of breast cancer. Design, Setting, and Participants: This population-based study identified 7810 women with stages 0 to II breast cancer treated between July 1, 2013, and August 31, 2015, through the Surveillance, Epidemiology, and End Results registries for the state of Georgia, as well as Los Angeles County, California. Surveys were sent approximately 2 months after surgery. Also surveyed were 488 attending surgeons identified by the patients. Main Outcomes and Measures: The study examined the association of surgeon with variation in the receipt of genetic testing using information from patient and surgeon surveys merged to Surveillance, Epidemiology, and End Results and genetic testing data obtained from 4 laboratories. Results: In total, 5080 women (69.6%) of 7303 who were eligible (mean [SD] age, 61.4 [0.8] years) and 377 surgeons (77.3%) of 488 (mean [SD] age, 53.8 [10.7] years) responded to the survey. Approximately one-third (34.5% [1350 of 3910] of patients had an elevated risk of mutation carriage, and 27.0% (1056 of 3910) overall had genetic testing. Surgeons had practiced a mean (SE) of 20.9 (0.6) years, and 28.9% (107 of 370) treated more than 50 cases of new breast cancer per year. The odds of a patient receiving genetic testing increased more than 2-fold (odds ratio, 2.48; 95% CI, 1.85-3.31) if she saw a surgeon with an approach 1 SD above that of a surgeon with the mean test rate. Approximately one-third (34.1%) of the surgeon variation was explained by patient volume and surgeon attitudes about genetic testing and counseling. If a patient with higher pretest risk saw a surgeon at the 5th percentile of the surgeon distribution, she would have a 26.3% (95% CI, 21.9% 31.2%) probability of testing compared with 72.3% (95% CI, 66.7%-77.2%) if she saw a surgeon at the 95th percentile. Conclusions and Relevance: In this study, the attending surgeon was associated with the receipt of genetic testing after a breast cancer diagnosis. Variation in surgeon attitudes about genetic testing and counseling may explain a substantial amount of this association. PMID- 29971345 TI - Questionable Assumptions Provided in Nonoperative Treatment of Appendicitis Survey-Reply. PMID- 29971346 TI - Does Speaker Race Affect the Assessment of Children's Speech Accuracy? A Comparison of Speech-Language Pathologists and Clinically Untrained Listeners. AB - Purpose: Some pronunciation patterns that are normal in 1 dialect might represent an error in another dialect (i.e., [koupsilonl] for cold, which is typical in African American English [AAE] but an error in many other dialects of English). This study examined whether trained speech-language pathologists and untrained listeners accommodate for presumed speaker dialect when rating children's productions of words. This study also explored whether effects of presumed race on perceived speech accuracy are mediated by individuals' knowledge and beliefs about AAE and their implicit attitudes about race. Method: Multiple groups of listeners rated the accuracy of a set of children's productions of words that have a distinct pronunciation in AAE. These were presented in 1 of 3 conditions: paired with no visual stimulus (to assess baseline accuracy) or paired with either African American children's faces (to suggest that the speaker uses AAE) or European American children's faces (to suggest that the speaker does not use AAE). Listeners also completed a set of measures of knowledge and attitudes about AAE and race, taken from previous studies. Results: Individuals in both groups rated children's productions more accurately when they were presented with African American children's faces than when paired with European American faces. The magnitude of this effect was generally similar across the 2 groups and was generally strongest for words that had been judged in the baseline condition to contain an error. None of the individual-differences measures predicted ratings. Conclusions: Assumptions about speaker attributes affect individuals' assessment of children's production accuracy. These effects are robust across trained and untrained listeners and cannot be predicted by existing measures of knowledge and attitudes about AAE and race. PMID- 29971347 TI - Visual recency bias is explained by a mixture model of internal representations. AB - Human bias towards more recent events is a common and well-studied phenomenon. Recent studies in visual perception have shown that this recency bias persists even when past events contain no information about the future. Reasons for this suboptimal behavior are not well understood and the internal model that leads people to exhibit recency bias is unknown. Here we use a well-known orientation estimation task to frame the human recency bias in terms of incremental Bayesian inference. We show that the only Bayesian model capable of explaining the recency bias relies on a weighted mixture of past states. Furthermore, we suggest that this mixture model is a consequence of participants' failure to infer a model for data in visual short-term memory, and reflects the nature of the internal representations used in the task. PMID- 29971348 TI - Revisiting individual differences in the time course of binocular rivalry. AB - Simultaneously showing an observer two incompatible displays, one to each eye, causes binocular rivalry, during which the observer regularly switches between perceiving one eye's display and perceiving the other. Observers differ in the rate of this perceptual cycle, and these individual differences have been reported to correlate with differences in the perceptual switch rate for other bistable perception phenomena. Identifying which psychological or neural factors explain this variability can help clarify the mechanisms underlying binocular rivalry and of bistable perception generally. Motivated by the prominent theory that perceptual switches during binocular rivalry are brought about by neural adaptation, we investigated whether perceptual switch rates are correlated with the strength of neural adaptation, indexed by visual aftereffects. We found no compelling evidence for such correlations. Moreover, we did not corroborate previous findings that switch rates are correlated between binocular rivalry and other forms of bistable perception. This latter nonreplication prompted us to perform a meta-analysis of existing research into correlations among forms of bistable perception, which revealed that evidence for such correlations is much weaker than is generally believed. By showing no common factor linking individual differences in binocular rivalry and in our other paradigms, these results fit well with other work that has shown such common factors to be rare among visual phenomena generally. PMID- 29971349 TI - Attention alters spatial resolution by modulating second-order processing. AB - Endogenous and exogenous visuospatial attention both alter spatial resolution, but they operate via distinct mechanisms. In texture segmentation tasks, exogenous attention inflexibly increases resolution even when detrimental for the task at hand and does so by modulating second-order processing. Endogenous attention is more flexible and modulates resolution to benefit performance according to task demands, but it is unknown whether it also operates at the second-order level. To answer this question, we measured performance on a second order texture segmentation task while independently manipulating endogenous and exogenous attention. Observers discriminated a second-order texture target at several eccentricities. We found that endogenous attention improved performance uniformly across eccentricity, suggesting a flexible mechanism that can increase or decrease resolution based on task demands. In contrast, exogenous attention improved performance in the periphery but impaired it at central retinal locations, consistent with an inflexible resolution enhancement. Our results reveal that endogenous and exogenous attention both alter spatial resolution by differentially modulating second-order processing. PMID- 29971352 TI - Onychomadesis Following a Fish Pedicure. PMID- 29971351 TI - Different Population and End Point Definitions in Reproduction Analysis Based on Shared Data-Reply. PMID- 29971350 TI - Serial dependence in the perception of visual variance. AB - The recent history of perceptual experience has been shown to influence subsequent perception. Classically, this dependence on perceptual history has been examined in sensory-adaptation paradigms, wherein prolonged exposure to a particular stimulus (e.g., a vertically oriented grating) produces changes in perception of subsequently presented stimuli (e.g., the tilt aftereffect). More recently, several studies have investigated the influence of shorter perceptual exposure with effects, referred to as serial dependence, being described for a variety of low- and high-level perceptual dimensions. In this study, we examined serial dependence in the processing of dispersion statistics, namely variance-a key descriptor of the environment and indicative of the precision and reliability of ensemble representations. We found two opposite serial dependences operating at different timescales, and likely originating at different processing levels: A positive, Bayesian-like bias was driven by the most recent exposures, dependent on feature-specific decision making and appearing only when high confidence was placed in that decision; and a longer lasting negative bias-akin to an adaptation aftereffect-becoming manifest as the positive bias declined. Both effects were independent of spatial presentation location and the similarity of other close traits, such as mean direction of the visual variance stimulus. These findings suggest that visual variance processing occurs in high-level areas but is also subject to a combination of multilevel mechanisms balancing perceptual stability and sensitivity, as with many different perceptual dimensions. PMID- 29971353 TI - Caring for Patients With Neurological Impairment: Conversations Between a Pediatrician and Geriatrician. PMID- 29971355 TI - Selenium Toxicity Associated With Reversible Leukoencephalopathy and Cortical Blindness. PMID- 29971354 TI - Association of Inadequately Controlled Disease and Disease Severity With Patient Reported Disease Burden in Adults With Atopic Dermatitis. AB - Importance: Real-world data are limited on the patient-reported burden of adult atopic dermatitis (AD). Objective: To characterize the patient-reported burden of AD with regard to impact of disease severity and inadequate control in adults from clinical settings. Design, Setting, and Participants: In this cross sectional study using data from 6 academic medical centers in the United States collected by a self-administered internet-based questionnaire, 1519 adult patients with AD were stratified by AD severity as mild or moderate/severe using the Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). Patients with moderate/severe disease using systemic immunomodulators/phototherapy were further stratified as having adequate or inadequate disease control. Strata were compared for all outcomes. Main Outcomes and Measures: Outcomes included validated measures and stand-alone questions assessing itch (pruritus numerical rating scale; PO-SCORAD itch visual analog scale), pain (numerical rating scale), sleep (PO-SCORAD sleep visual analog scale; sleep interference with function), anxiety and depression (Hospital Anxiety and Depression Scale), and health-related quality of life (Dermatology Life Quality Index). Results: Among the 1519 adult patients with AD, relative to mild AD (n = 689, 64% women; mean [SD] age, 46.5 [18.0] years), patients with moderate/severe AD (n = 830, 66.8% women; mean [SD] age, 45.1 [16.9] years) reported more severe itching and pain, greater adverse effects on sleep, higher prevalence of anxiety and depression (417 [50.2%] vs 188 [27.3%]), and greater health-related quality-of-life impairment. The 103 patients with moderate/severe AD with inadequate disease control despite treatment with systemic immunomodulators or phototherapy (55.7%) reported higher burdens of itch and sleeping symptoms vs patients with controlled disease including more days per week with itchy skin (5.7 vs 2.7) and higher proportions with itch duration greater than half a day (190 [22.8%] vs 20 [2.9%]). Sleep symptoms included trouble sleeping (3.9 vs 1.1 on the PO-SCORAD VAS), longer sleep latency (38.8 vs 21.6 minutes), more frequent sleep disturbances (2.6 vs 0.4 nights in past week), and greater need for over-the-counter sleep medications (324 [39%] vs 145 [21%]). Conclusions and Relevance: Inadequate disease control was common among patients with moderate/severe AD, and was associated with a higher patient-reported burden than patients with controlled disease. Regardless of disease control, the burden of moderate/severe AD was higher than mild AD, suggesting a need for more effective therapies for moderate/severe disease. PMID- 29971356 TI - Maternal Responsiveness to Gestures in Children With Down Syndrome. AB - Purpose: This study compared gesture use in young children with Down syndrome (DS) and typical development (TD) as well as how mothers respond to child gestures based on child age and diagnosis. Method: Twenty-two mother-child dyads with DS and 22 mother-child dyads with TD participated. The child participants were between 22 and 63 months and were matched on chronological age. We coded child gesture use and whether mothers recoded child gestures (i.e., provided a verbal translation) during naturalistic interactions. Results: The children with DS used more gestures than peers with TD. After controlling for expressive language ability, the two groups were not significantly different on child gesture use. Regardless of child diagnosis, mothers recoded approximately the same percentage of child gestures. There was a significant interaction between child diagnosis and child age when predicting the percentage of maternal gesture recodes; mothers of children with DS did not demonstrate differences in the percentage of maternal gesture recodes based on child age, but there was a negative relationship between the percentage of maternal gesture recodes and child age for the children with TD. Conclusions: Young children with DS gesture more than chronological age-matched children with TD, therefore providing numerous opportunities for caregivers to recode child gestures and support language development. Early intervention should focus on increasing parent responsiveness to child gestures earlier in life in order to provide additional word-learning opportunities for children with DS. PMID- 29971358 TI - Incorrect Numbers of Adverse Events Reported. PMID- 29971357 TI - Association of Patient Frailty With Increased Risk of Complications After Adrenalectomy. PMID- 29971360 TI - Jacqueline Kennedy Onassis Reservoir, Central Park, New York City. PMID- 29971361 TI - Web-Based Platform vs Genetic Counselors in Educating Patients About Carrier Results From Exome Sequencing. PMID- 29971362 TI - Correlates and Outcomes of Physician Burnout. PMID- 29971363 TI - Regulation of Cosmetics. PMID- 29971364 TI - Ethical Issues Related to Breastfeeding for US Physicians Who Are Mothers. PMID- 29971365 TI - Standardization of Continuous Renal Replacement Therapy. PMID- 29971366 TI - Web-Based Platform vs Genetic Counselors in Educating Patients About Carrier Results From Exome Sequencing-Reply. PMID- 29971367 TI - Correlates and Outcomes of Physician Burnout-Reply. PMID- 29971368 TI - Ethical Issues Related to Breastfeeding for US Physicians Who are Mothers-Reply. PMID- 29971371 TI - Clarifications in Abstract and Key Points. PMID- 29971369 TI - Standardization of Continuous Renal Replacement Therapy-Reply. PMID- 29971373 TI - Typo in In-Text Citation. PMID- 29971372 TI - Incorrect Corresponding Author Email Address and Error in the Strengths and Limitations Section. PMID- 29971376 TI - Musical Chairs: Using Wheelchair Ballroom Dance in Disability Education. PMID- 29971377 TI - New Genetic Links to Depression May Pave the Way for Novel Treatment Strategies. PMID- 29971378 TI - Incorrect Name and Degrees Listed for an Author. PMID- 29971379 TI - Replacing the Pap Test With Screening Based on Human Papillomavirus Assays. PMID- 29971381 TI - New Relief for Ulcerative Colitis. PMID- 29971382 TI - First Artificial Iris Ok'd. PMID- 29971380 TI - US Department of Justice Investigations of Implantable Cardioverter Defibrillators and Quality Improvement in Health Care. PMID- 29971383 TI - Diagnosing Fractures With AI. PMID- 29971384 TI - Odds Ratios-Current Best Practice and Use. PMID- 29971385 TI - Management of Patients With Acute Lower Gastrointestinal Tract Bleeding. PMID- 29971387 TI - Housing as a Step to Better Health. PMID- 29971388 TI - The Sin of Treating Symptoms. PMID- 29971389 TI - Conflicts of Interest in Nutrition Research. PMID- 29971390 TI - Conflicts of Interest in Nutrition Research. PMID- 29971391 TI - Moral Dilemmas for Physicians Treating Terminal Patients. PMID- 29971392 TI - Professional Football Participation and Mortality. PMID- 29971393 TI - Professional Football Participation and Mortality. PMID- 29971394 TI - Conflict of Interest in Nutrition Research-Reply. PMID- 29971395 TI - Moral Dilemmas for Physicians Treating Terminal Patients-Reply. PMID- 29971396 TI - Professional Football Participation and Mortality-Reply. PMID- 29971397 TI - Effect of Screening With Primary Cervical HPV Testing vs Cytology Testing on High grade Cervical Intraepithelial Neoplasia at 48 Months: The HPV FOCAL Randomized Clinical Trial. AB - Importance: There is limited information about the relative effectiveness of cervical cancer screening with primary human papillomavirus (HPV) testing alone compared with cytology in North American populations. Objective: To evaluate histologically confirmed cumulative incident cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+) detected up to and including 48 months by primary HPV testing alone (intervention) or liquid-based cytology (control). Design, Setting, and Participants: Randomized clinical trial conducted in an organized Cervical Cancer Screening Program in Canada. Participants were recruited through 224 collaborating clinicians from January 2008 to May 2012, with follow-up through December 2016. Women aged 25 to 65 years with no history of CIN2+ in the past 5 years, no history of invasive cervical cancer, or no history of hysterectomy; who have not received a Papanicolaou test within the past 12 months; and who were not receiving immunosuppressive therapy were eligible. Interventions: A total of 19 009 women were randomized to the intervention (n = 9552) and control (n = 9457) groups. Women in the intervention group received HPV testing; those whose results were negative returned at 48 months. Women in the control group received liquid-based cytology (LBC) testing; those whose results were negative returned at 24 months for LBC. Women in the control group who were negative at 24 months returned at 48 months. At 48-month exit, both groups received HPV and LBC co-testing. Main Outcomes and Measures: The primary outcome was the cumulative incidence of CIN3+ 48 months following randomization. The cumulative incidence of CIN2+ was a secondary outcome. Results: Among 19 009 women who were randomized (mean age, 45 years [10th-90th percentile, 30-59]), 16 374 (8296 [86.9%] in the intervention group and 8078 [85.4%] in the control group) completed the study. At 48 months, significantly fewer CIN3+ and CIN2+ were detected in the intervention vs control group. The CIN3+ incidence rate was 2.3/1000 (95% CI, 1.5-3.5) in the intervention group and 5.5/1000 (95% CI, 4.2 7.2) in the control group. The CIN3+ risk ratio was 0.42 (95% CI, 0.25-0.69). The CIN2+ incidence rate at 48 months was 5.0/1000 (95% CI, 3.8-6.7) in the intervention group and 10.6/1000 (95% CI, 8.7-12.9) in the control group. The CIN2+ risk ratio was 0.47 (95% CI, 0.34-0.67). Baseline HPV-negative women had a significantly lower cumulative incidence of CIN3+ at 48 months than cytology negative women (CIN3+ incidence rate, 1.4/1000 [95% CI, 0.8-2.4]; CIN3+ risk ratio, 0.25 [95% CI, 0.13-0.48]). Conclusions and Relevance: Among women undergoing cervical cancer screening, the use of primary HPV testing compared with cytology testing resulted in a significantly lower likelihood of CIN3+ at 48 months. Further research is needed to understand long-term clinical outcomes as well as cost-effectiveness. Trial Registration: isrctn.org Identifier: ISRCTN79347302. PMID- 29971398 TI - Association of the US Department of Justice Investigation of Implantable Cardioverter-Defibrillators and Devices Not Meeting the Medicare National Coverage Determination, 2007-2015. AB - Importance: The US Department of Justice (DOJ) conducted an investigation into implantable cardioverter-defibrillators (ICDs) not meeting the Centers for Medicare & Medicaid Services National Coverage Determination (NCD) criteria. Objective: To examine changes in the proportion of initial primary prevention ICDs that did not meet NCD criteria following the announcement of the DOJ investigation at hospitals that reached settlements (settlement hospitals) and those that did not (nonsettlement hospitals). Design, Setting, and Participants: Multicenter, longitudinal, serial cross-sectional analysis of 300 151 initial primary prevention ICDs among Medicare beneficiaries from January 1, 2007, through December 31, 2015, at 1809 US hospitals in the National Cardiovascular Data Registry (NCDR) ICD Registry, of which 452 hospitals (with 99 591 primary prevention ICDs) reached settlements with the DOJ. Exposures: The DOJ investigation announcement in 2010. Main Outcomes and Measures: Proportion of initial primary prevention ICDs not meeting NCD criteria. Results: In January 2007, the proportion of initial ICDs not meeting NCD criteria was 25.8% (95% CI, 24.7% to 26.8%) at settlement hospitals and 22.8% (95% CI, 22.1% to 23.5%) at nonsettlement hospitals (P < .001). Over the study period, there was a 62.7% (95% CI, 59.2% to 66.1%) relative decrease and 16.1% (95% CI, 14.8% to 17.5%) absolute decrease in the proportion of ICDs not meeting NCD criteria at settlement hospitals compared with a 53.2% (95% CI, 50.4% to 56.0%) relative decrease and 12.1% (95% CI, 11.2% to 13.0%) absolute decrease in proportion at nonsettlement hospitals (P < .001 for both; P for interaction < .001). Trends significantly differed between hospital groups only in the period following the announcement of the DOJ investigation (January 2010-June 2011) [corrected], with larger and more rapid decreases at settlement hospitals (P for interaction = .01). Over the study period, there was a 32.8% (95% CI, 29.9% to 35.7%) relative decrease and a 1703 ICDs (95% CI, 1520 to 1886) absolute decrease in the volume of primary prevention ICDs implanted at settlement hospitals compared with a 17.4% (95% CI, 14.8% to 20.0%) relative decrease and a 1495 ICDs (95% CI, 1249 to 1741) absolute decrease in volume at nonsettlement hospitals (P < .001 for both; P for interaction < .001), with more modest decreases or slight increases in secondary prevention ICD volume. These patterns were similar when examining ICD utilization among non Medicare beneficiaries. Conclusions and Relevance: From 2007 through 2015, the volume of primary prevention implantable cardioverter-defibrillators and the proportion of devices not meeting the Centers for Medicare & Medicaid Services National Coverage Determination criteria decreased at all hospitals with substantially larger decreases at hospitals that reached settlements in the US Department of Justice investigation. These patterns extended to implantable cardioverter-defibrillators placed in non-Medicare beneficiaries, which were not the focus of the US Department of Justice investigation. PMID- 29971399 TI - Endocarditis. PMID- 29971401 TI - A 30-Mile-per-Hour Headwind. PMID- 29971402 TI - Management Considerations in Infective Endocarditis: A Review. AB - Importance: Infective endocarditis occurs in approximately 15 of 100 000 people in the United States and has increased in incidence. Clinicians must make treatment decisions with respect to prophylaxis, surgical management, specific antibiotics, and the length of treatment in the setting of emerging, sometimes inconclusive clinical research findings. Observations: Community-associated infective endocarditis remains the predominant form of the disease; however, health care accounts for one-third of cases in high-income countries. As medical interventions are increasingly performed on older patients, the disease incidence from cardiac implanted electronic devices is also increasing. In addition, younger patients involved with intravenous drug use has increased in the past decade and with it the proportion of US hospitalization has increased to more than 10%. These epidemiological factors have led to Staphylococcus aureus being the most common cause in high-income countries, accounting for up to 40% of cases. The mainstays of diagnosis are still echocardiography and blood cultures. Adjunctive imaging such as cardiac computed tomographic and nuclear imaging can improve the sensitivity for diagnosis when echocardiography is not conclusive. Serological studies, histopathology, and polymerase chain reaction assays have distinct roles in the diagnosis of infective endocarditis when blood culture have tested negative with the highest yield obtained from serological studies. Increasing antibiotic resistance, particularly to S aureus, has led to a need for different antibiotic treatment options such as newer antibiotics and combination therapy regimens. Surgery can confer a survival benefit to patients with major complications; however, the decision to pursue surgery must balance the risks and benefits of operations in these frequently high-risk patients. Conclusions and Relevance: The epidemiology and management of infective endocarditis are continually changing. Guidelines provide specific recommendations about management; however, careful attention to individual patient characteristics, pathogen, and risk of sequela must be considered when making therapeutic decisions. PMID- 29971404 TI - Reviving the FDA's Authority to Publicly Explain Why New Drug Applications Are Approved or Rejected. PMID- 29971405 TI - Recurrent Renal Cysts in a Transplanted Kidney. PMID- 29971407 TI - High Blood Pressure During Pregnancy and Development of Risk Factors for Cardiovascular Disease. PMID- 29971408 TI - Error in Figures. PMID- 29971406 TI - The Carbohydrate-Insulin Model of Obesity: Beyond "Calories In, Calories Out". AB - Despite intensive research, the causes of the obesity epidemic remain incompletely understood and conventional calorie-restricted diets continue to lack long-term efficacy. According to the carbohydrate-insulin model (CIM) of obesity, recent increases in the consumption of processed, high-glycemic-load carbohydrates produce hormonal changes that promote calorie deposition in adipose tissue, exacerbate hunger, and lower energy expenditure. Basic and genetic research provides mechanistic evidence in support of the CIM. In animals, dietary composition has been clearly demonstrated to affect metabolism and body composition, independently of calorie intake, consistent with CIM predictions. Meta-analyses of behavioral trials report greater weight loss with reduced glycemic load vs low-fat diets, though these studies characteristically suffer from poor long-term compliance. Feeding studies have lacked the rigor and duration to test the CIM, but the longest such studies tend to show metabolic advantages for low-glycemic load vs low-fat diets. Beyond the type and amount of carbohydrate consumed, the CIM provides a conceptual framework for understanding how many dietary and nondietary exposures might alter hormones, metabolism, and adipocyte biology in ways that could predispose to obesity. Pending definitive studies, the principles of a low-glycemic load diet offer a practical alternative to the conventional focus on dietary fat and calorie restriction. PMID- 29971412 TI - Web Exclusive. Annals Graphic Medicine - Finding the Funny: Everything. PMID- 29971411 TI - Isorhythmic Atrioventricular Dissociation and the Purloined P Wave After Transcatheter Aortic Valve Replacement. PMID- 29971413 TI - Associations Between Gun Shows and Firearm Deaths and Injuries. PMID- 29971414 TI - Associations Between Gun Shows and Firearm Deaths and Injuries. PMID- 29971415 TI - Associations Between Gun Shows and Firearm Deaths and Injuries. PMID- 29971416 TI - Associations Between Gun Shows and Firearm Deaths and Injuries. PMID- 29971417 TI - Firearm-Related Injury and Death. PMID- 29971418 TI - Comparison of Five Major Guidelines for Statin Use in Primary Prevention. PMID- 29971419 TI - Comparison of Five Major Guidelines for Statin Use in Primary Prevention. PMID- 29971420 TI - Comparison of Five Major Guidelines for Statin Use in Primary Prevention. PMID- 29971421 TI - Correction: Transfusion-Transmitted Plasmodium falciparum in a Patient With Sickle Cell Hemoglobinopathy. PMID- 29971422 TI - Emergency Room. PMID- 29971423 TI - Autopsy. PMID- 29971424 TI - The Box. PMID- 29971425 TI - Concussion. AB - Concussions are a common injury for which patients often present first to primary care physicians. They can affect the day-to-day function of patients in school and work, as well as in sports and recreational activities. Recognizing common physical signs and symptoms after injury facilitates timely diagnosis and treatment, permitting initiation of an active management approach to recovery while preventing secondary injury. For persons with persistent symptoms, active rehabilitation may be utilized, with the goal of returning patients to full function. PMID- 29971426 TI - Annals for Educators - 3 July 2018. PMID- 29971427 TI - Effectiveness of Live Attenuated vs Inactivated Influenza Vaccines in Children During the 2012-2013 Through 2015-2016 Influenza Seasons in Alberta, Canada: A Canadian Immunization Research Network (CIRN) Study. AB - Importance: Recent observational studies report conflicting results regarding the effectiveness of live attenuated influenza vaccine (LAIV), particularly against influenza A(H1N1)pdm09. Objective: To compare the effectiveness of LAIV and inactivated influenza vaccine (IIV) against laboratory-confirmed influenza. Design, Setting, and Participants: A test-negative study to estimate influenza vaccine effectiveness (VE) using population-based, linked, individual-level laboratory, health administrative, and immunization data. Data were obtained from 10 169 children and adolescents aged 2 to 17 years (children) who were tested for influenza in inpatient or outpatient settings during periods when influenza was circulating based on a threshold level of 5% weekly test positivity for the province during the 4 influenza seasons spanning from November 11, 2012, to April 30, 2016, in Alberta, Canada. Logistic regression was used to estimate VE by vaccine type, influenza season, and influenza type and subtype. The relative effectiveness of each vaccine type was assessed by comparing the odds of laboratory-confirmed influenza infection for LAIV recipients with that for IIV recipients. Exposures: The primary exposure was receipt of LAIV or IIV before testing for influenza. Main Outcomes and Measures: The primary outcome was influenza case status as determined by reverse-transcriptase polymerase chain reaction testing. Results: A total of 10 779 respiratory specimens (from 10 169 children) collected and tested for influenza during the 4 influenza seasons were included, with 53.4% from males; the mean (SD) age was 7.0 (4.6) years. Across the 4 influenza seasons, 3161 children tested positive for influenza. Combining the 4 influenza seasons, the adjusted VE against influenza A(H1N1)pdm09 was 69% (95% CI, 56%-78%) for LAIV compared with 79% (95% CI, 70%-86%) for IIV. Vaccine effectiveness against influenza A(H3N2) was 36% (95% CI, 14%-53%) for LAIV and 43% (95% CI, 22%-59%) for IIV. Against influenza B, VE was 74% (95% CI, 62%-82%) for LAIV and 56% (95% CI, 41%-66%) for IIV. There were no significant differences in the odds of influenza infection for LAIV recipients compared with IIV recipients except for influenza B during the 2015-2016 season, when LAIV recipients had lower odds of infection than IIV recipients (odds ratio, 0.36; 95% CI, 0.17-0.76). Conclusions and Relevance: There was no evidence to support the lack of effectiveness of LAIV against influenza A(H1N1)pdm09. These results support administration of either vaccine type in this age group. PMID- 29971428 TI - Association of Maternal Diabetes With Neonatal Outcomes of Very Preterm and Very Low-Birth-Weight Infants: An International Cohort Study. AB - Importance: Diabetes in pregnancy is associated with a 2-times to 3-times higher rate of very preterm birth than in women without diabetes. Very preterm infants are at high risk of death and severe morbidity. The association of maternal diabetes with these risks is unclear. Objective: To determine the associations between maternal diabetes and in-hospital mortality, as well as neonatal morbidity in very preterm infants with a birth weight of less than 1500 g. Design, Setting, Participants: This retrospective cohort study was conducted at 7 national networks in high-income countries that are part of the International Neonatal Network for Evaluating Outcomes in Neonates and used prospectively collected data on 76 360 very preterm, singleton infants without malformations born between January 1, 2007, and December 31, 2015, at 24 to 31 weeks' gestation with birth weights of less than 1500 g, 3280 (4.3%) of whom were born to diabetic mothers. Exposures: Any type of diabetes during pregnancy. Main Outcomes and Measures: The primary outcome was in-hospital mortality. The secondary outcomes were severe neonatal morbidities, including intraventricular hemorrhages of grade 3 to 4, cystic periventricular leukomalacia, retinopathy of prematurity needing treatment and bronchopulmonary dysplasia, and other morbidities, including respiratory distress, treated patent ductus arteriosus, and necrotizing enterocolitis. Odds ratios (ORs) with 95% confidence intervals were estimated, adjusted for potential confounders, and stratified by gestational age (GA), sex, and network. Results: The mean (SD) birth weight of offspring born to mothers with diabetes was significantly higher at 1081 (262) g than in offspring born to mothers without diabetes (mean [SD] birth weight, 1027 [270] g). Mothers with diabetes were older and had more hypertensive disorders, antenatal steroid treatments, and deliveries by cesarean delivery than mothers without diabetes. Infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. In-hospital mortality (6.6% vs 8.3%) and the composite of mortality and severe morbidity (31.6% vs 40.6%) were lower in infants of mothers with diabetes. However, in adjusted analyses, no significant differences in in hospital mortality (adjusted OR, 1.16 (95% CI, 0.97-1.39) or the composite of mortality and severe morbidity (adjusted OR, 0.99 (95% CI, 0.88-1.10) were observed. With few exceptions, outcomes of infants born to mothers with and without diabetes were similar regardless of infant sex, GA, or country of birth. Conclusions and Relevance: In high-resource settings, maternal diabetes is not associated with an increased risk of in-hospital mortality or severe morbidity in very preterm infants with a birth weight of fewer than 1500 g. PMID- 29971430 TI - Consideration of Population-Based BRCA Testing as a Strategy to Reduce Disparities in Genetic Counseling Referrals: The Importance of Stating (and Proving) the Obvious. PMID- 29971431 TI - Less Is More in Colorectal Cancer Posttreatment Surveillance. PMID- 29971432 TI - Prescription to Over-the-Counter Switch of Metronidazole and Azelaic Acid for Treatment of Rosacea. PMID- 29971429 TI - Association Between Preoperative Proteinuria and Postoperative Acute Kidney Injury and Readmission. AB - Importance: Proteinuria indicates renal dysfunction and is a risk factor for morbidity among medical patients, but less is understood among surgical populations. There is a paucity of studies investigating how preoperative proteinuria is associated with surgical outcomes, including postoperative acute kidney injury (AKI) and readmission. Objective: To assess preoperative urine protein levels as a biomarker for adverse surgical outcomes. Design, Setting, and Participants: A retrospective, population-based study was conducted in a cohort of patients with and without known preoperative renal dysfunction undergoing elective inpatient surgery performed at 119 Veterans Affairs facilities from October 1, 2007, to September 30, 2014. Data analysis was conducted from April 4 to December 1, 2016. Preoperative dialysis, septic, cardiac, ophthalmology, transplantation, and urologic cases were excluded. Exposures: Preoperative proteinuria as assessed by urinalysis using the closest value within 6 months of surgery: negative (0 mg/dL), trace (15-29 mg/dL), 1+ (30-100 mg/dL), 2+ (101-300 mg/dL), 3+ (301-1000 mg/dL), and 4+ (>1000 mg/dL). Main Outcomes and Measures: Primary outcome was postoperative predischarge AKI and 30-day postdischarge unplanned readmission. Secondary outcomes included any 30-day postoperative outcome. Results: Of 346 676 surgeries, 153 767 met inclusion criteria, with the majority including orthopedic (37%), general (29%), and vascular procedures (14%). Evidence of proteinuria was shown in 43.8% of the population (trace: 20.6%, 1+: 16.0%, 2+: 5.5%, 3+: 1.6%) with 20.4%, 14.9%, 4.3%, and 0.9%, respectively, of the patients having a normal preoperative estimated glomerular filtration rate (eGFR). In unadjusted analysis, preoperative proteinuria was significantly associated with postoperative AKI (negative: 8.6%, trace: 12%, 1+: 14.5%, 2+: 21.2%, 3+: 27.6%; P < .001) and readmission (9.3%, 11.3%, 13.3%, 15.8%, 17.5%, respectively, P < .001). After adjustment, preoperative proteinuria was associated with postoperative AKI in a dose-dependent relationship (trace: odds ratio [OR], 1.2; 95% CI, 1.1-1.3, to 3+: OR, 2.0; 95% CI, 1.8-2.2) and 30 day unplanned readmission (trace: OR, 1.0; 95% CI, 1.0-1.1, to 3+: OR, 1.3; 95% CI, 1.1-1.4). Preoperative proteinuria was associated with AKI independent of eGFR. Conclusions and Relevance: Proteinuria was associated with postoperative AKI and 30-day unplanned readmission independent of preoperative eGFR. Simple urine assessment for proteinuria may identify patients at higher risk of AKI and readmission to guide perioperative management. PMID- 29971433 TI - Medical Attention Seeking After Transient Ischemic Attack and Minor Stroke Before and After the UK Face, Arm, Speech, Time (FAST) Public Education Campaign: Results From the Oxford Vascular Study. AB - Importance: Risk of major stroke is high during the hours and days after transient ischemic attack (TIA) and minor stroke but is substantially reduced by urgent medical treatment. Public education campaigns have improved the response after major stroke, but their association with behavior after TIA and minor stroke is uncertain. The number of potentially preventable early recurrent strokes in patients who delay or fail to seek medical attention is unknown. Objective: To investigate the association of public education with delays and failure in seeking medical attention after TIA and minor stroke. Design, Setting, and Participants: Prospective population-based study of all patients with TIA or stroke who sought medical attention between April 1, 2002, and March 31, 2014, registered at 9 general practices in Oxfordshire, United Kingdom. Data analysis took place from July 1, 2013, to March 2, 2015. Exposures: Face, Arm, Speech, Time (FAST) public education campaign in the United Kingdom. Main Outcomes and Measures: Number of early recurrent strokes in patients who delayed or failed to seek medical attention, as well as the odds of seeking urgent attention after TIA and minor stroke before vs after initiation of the public education campaign. Results: Among 2243 consecutive patients with first TIA or stroke (mean [SD] age, 73.6 [13.4] years; 1126 [50.2%] female; 96.3% of white race/ethnicity), 1656 (73.8%) had a minor stroke or TIA. After the FAST campaign, patients with major stroke more often sought medical attention within 3 hours (odds ratio [OR], 2.56; 95% CI, 1.11-5.90; P = .03). For TIA and minor stroke, there was no improvement in use of emergency medical services (OR, 0.79; 95% CI, 0.50-1.23; P for interaction = .03 vs major stroke) or time to first seeking medical attention within 24 hours (OR, 0.75; 95% CI, 0.48-1.19; P for interaction = .006 vs major stroke). Patient perception of symptoms after TIA and minor stroke was associated with more urgent behavior, but correct perception declined after the FAST campaign (from 37.3% [289 of 774] to 27.6% [178 of 645]; OR, 0.64; 95% CI, 0.51 0.80; P < .001). One hundred eighty-eight patients had a stroke within 90 days of their initial TIA or stroke, of whom 93 (49.5%) followed unheeded TIAs for which no medical attention was sought, similar before and after the FAST campaign (43 of 538 [8.0%] before vs 50 of 615 [8.1%] after, P = .93). Conclusions and Relevance: This study suggests that in contrast to major stroke, extensive FAST based public education has not improved the response to TIA and minor stroke in the United Kingdom, emphasizing the need for campaigns that are tailored to transient and less severe symptoms. PMID- 29971434 TI - Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine Metabolism: Findings From the UK Biobank. AB - Importance: Prospective cohorts in North America, Europe, and Asia show consistent inverse associations between coffee drinking and mortality, including deaths from cardiovascular disease and some cancers. However, concerns about coffee, particularly among people with common genetic polymorphisms affecting caffeine metabolism and among those drinking more than 5 cups per day, remain. Objective: To evaluate associations of coffee drinking with mortality by genetic caffeine metabolism score. Design, Setting, and Participants: The UK Biobank is a population-based study that invited approximately 9.2 million individuals from across the United Kingdom to participate. We used baseline demographic, lifestyle, and genetic data form the UK Biobank cohort, with follow-up beginning in 2006 and ending in 2016, to estimate hazard ratios (HRs) for coffee intake and mortality, using multivariable-adjusted Cox proportional hazards models. We investigated potential effect modification by caffeine metabolism, defined by a genetic score of previously identified polymorphisms in AHR, CYP1A2, CYP2A6, and POR that have an effect on caffeine metabolism. Of the 502 641 participants who consented with baseline data, we included those who were not pregnant and had complete data on coffee intake and smoking status (n = 498 134). Exposures: Total, ground, instant, and decaffeinated coffee intake. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: The mean age of the participants was 57 years (range, 38-73 years); 271 019 (54%) were female, and 387 494 (78%) were coffee drinkers. Over 10 years of follow-up, 14 225 deaths occurred. Coffee drinking was inversely associated with all-cause mortality. Using non-coffee drinkers as the reference group, HRs for drinking less than 1, 1, 2 to 3, 4 to 5, 6 to 7, and 8 or more cups per day were 0.94 (95% CI, 0.88 1.01), 0.92 (95% CI, 0.87-0.97), 0.88 (95% CI, 0.84-0.93), 0.88 (95% CI, 0.83 0.93), 0.84 (95% CI, 0.77-0.92), and 0.86 (95% CI, 0.77-0.95), respectively. Similar associations were observed for instant, ground, and decaffeinated coffee, across common causes of death, and regardless of genetic caffeine metabolism score. For example, the HRs for 6 or more cups per day ranged from 0.70 (95% CI, 0.53-0.94) to 0.92 (95% CI, 0.78-1.10), with no evidence of effect modification across strata of caffeine metabolism score (P = .17 for heterogeneity). Conclusions and Relevance: Coffee drinking was inversely associated with mortality, including among those drinking 8 or more cups per day and those with genetic polymorphisms indicating slower or faster caffeine metabolism. These findings suggest the importance of noncaffeine constituents in the coffee mortality association and provide further reassurance that coffee drinking can be a part of a healthy diet. PMID- 29971435 TI - Women's Cardiovascular Health After a Hypertensive Disorder of Pregnancy. PMID- 29971436 TI - A Multicenter Study of Patient-Reported Infectious and Noninfectious Complications Associated With Indwelling Urethral Catheters. AB - Importance: Indwelling urethral catheters (ie, Foley catheters) are important in caring for certain hospitalized patients but can also cause complications in patients. Objective: To determine the incidence of infectious and noninfectious patient-reported complications associated with the indwelling urethral catheter. Design, Setting, and Participants: A prospective cohort study of consecutive patients with placement of a new indwelling urethral catheter while hospitalized at 1 of 4 US hospitals in 2 states. The study was conducted from August 26, 2015, to August 18, 2017. Participants were evaluated at baseline and contacted at 14 days and 30 days after insertion of the catheter about complications associated with the indwelling urethral catheter and how catheterization affected their social activities or activities of daily living. Exposures: Indwelling urethral catheter placement during hospitalization. Patients were enrolled within 3 days of catheter insertion and followed up for 30 days after catheter placement, whether the catheter remained in or was removed from the patient. Main Outcomes and Measures: Infectious and noninfectious complications associated with an indwelling urethral catheter as well as how the catheter affected patient social activities or activities of daily living. Results: Of 2967 eligible patients, 2227 (75.1%) agreed to participate at 1 of 4 study sites; 2076 total patients were evaluated. Of these, 71.4% were male; mean (SD) age was 60.8 (13.4) years. Most patients (1653 of 2076 [79.6%]) had short-term catheters placed for surgical procedures. During the 30 days after urethral catheter insertion, 1184 of 2076 patients (57.0%; 95% CI, 54.9%-59.2%) reported at least 1 complication due to the indwelling urethral catheter. Infectious complications were reported by 219 of 2076 patients (10.5%; 95% CI, 9.3%-12.0%), whereas noninfectious complications (eg, pain or discomfort, blood in the urine, or sense of urinary urgency) occurred in 1150 patients (55.4%; 95% CI, 53.2%-57.6%) (P < .001). Women were more likely to report an infectious complication (92 of 594 [15.5%] women vs 127 of 1482 [8.6%] men; P < .001), while men were more likely to report a noninfectious complication (869 of 1482 [58.6%] men vs 281 of 594 [47.3%] women; P < .001). Restrictions in activities of daily living (49 of 124 patients [39.5%]) or social activity (54 of 124 [43.9%]) were commonly reported by the patients who had catheters still in place; sexual problems were reported by 99 of 2034 patients (4.9%) after their catheter was removed. Conclusions and Relevance: Noninfectious complications of urethral catheters affect a substantial number of patients, underscoring the importance of avoiding urethral catheterization whenever possible. Given the high incidence of these patient-reported complications, urethral catheter-associated noninfectious complications should be a focus of surveillance and prevention efforts. PMID- 29971437 TI - Hypertensive Disorders of Pregnancy and Maternal Cardiovascular Disease Risk Factor Development: An Observational Cohort Study. AB - Background: Women with a history of hypertensive disorders of pregnancy (HDP) are nearly twice as likely to develop cardiovascular disease (CVD) as those who are normotensive during pregnancy. However, the emergence of CVD risk factors after HDP is less well-understood. Objective: To identify associations between HDP and maternal CVD risk factors and chart the trajectory of risk factor development after pregnancy. Design: Observational cohort study. Setting: United States. Participants: 58 671 parous NHS II (Nurses' Health Study II) participants who did not have CVD or risk factors of interest at baseline. Measurements: Women were followed for self-reported physician diagnosis of chronic hypertension and hypercholesterolemia and confirmed type 2 diabetes mellitus (T2DM) from their first birth through 2013; mean follow-up ranged from 25 to 32 years across these end points. Multivariable Cox proportional hazards models estimated hazard ratios (HRs) and 95% CIs, with adjustment for prepregnancy confounders. Results: Compared with women who were normotensive during pregnancy, those with gestational hypertension (2.9%) or preeclampsia (6.3%) in their first pregnancy had increased rates of chronic hypertension (HRs, 2.8 [95% CI, 2.6 to 3.0] and 2.2 [CI, 2.1 to 2.3], respectively), T2DM (HRs, 1.7 [CI, 1.4 to 1.9] and 1.8 [CI, 1.6 to 1.9], respectively), and hypercholesterolemia (HRs, 1.4 [CI, 1.3 to 1.5] and 1.3 [CI, 1.3 to 1.4], respectively). Although these women were more likely to develop CVD risk factors throughout follow-up, the relative risk for chronic hypertension was strongest within 5 years after their first birth. Recurrence of HDP further elevated risks for all end points. Limitation: Participants self reported HDP. Conclusion: Women with HDP in their first pregnancy had increased rates of chronic hypertension, T2DM, and hypercholesterolemia that persisted for several decades. These women may benefit from lifestyle intervention and early screening to reduce lifetime risk for CVD. Primary Funding Source: National Institutes of Health. PMID- 29971438 TI - Cone Vision Changes in the Enhanced S-Cone Syndrome Caused by NR2E3 Gene Mutations. AB - Purpose: To determine the progression of cone vision loss in patients with recessive disease from NR2E3 gene mutations. Methods: Patients with NR2E3 mutations (n = 37) were studied as a retrospective observational case series clinically and with chromatic static perimetry. Patients were investigated cross sectionally, and a subset was followed longitudinally. Results: Patients showed a range of visual acuities; there was no clear relationship to age. With kinetic perimetry (V4e target), a full field could be retained over many years. Other patients showed progression from a full field, with or without pericentral scotomas, to a small central island. Three patterns of S-cone function were defined, based on percentage of hypersensitive S-cone loci in the field. From occupying most of the visual field, hyperfunctioning S-cone loci could diminish in percent, remaining largely in the periphery. Normal S-cone functioning then dominates, followed by the appearance of an annular region of abnormal S-cone loci approximately 10 degrees to 40 degrees from the fovea. Overall, S-cone sensitivity declined 2.6 times faster than L/M-cone sensitivity. Conclusions: Murine proof-of-concept studies suggest that clinical trials of patients with NR2E3 mutations may be forthcoming. Patterns of S-cone hyperfunction across the field would serve as a means to categorize patients as entry criteria or cohort selection in clinical trials. S-cone perimetry can be measured in the clinic and would be the logical efficacy monitor for therapeutic strategies. Given further understanding of the natural history of the disease, targeting the annular region of S-cone dysfunction for a focal therapy or for monitoring in a retina-wide intervention warrants consideration. PMID- 29971439 TI - The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants. AB - Purpose: To assess the occurrence and the disease expression of the common p.Asn1868Ile variant in patients with Stargardt disease (STGD1) harboring known, monoallelic causal ABCA4 variants. Methods: The coding and noncoding regions of ABCA4 were sequenced in 67 and 63 STGD1 probands respectively, harboring monoallelic ABCA4 variants. In case p.Asn1868Ile was detected, segregation analysis was performed whenever possible. Probands and affected siblings harboring p.Asn1868Ile without additional variants in cis were clinically evaluated retrospectively. Two asymptomatic siblings carrying the same ABCA4 variants as their probands were clinically examined. The penetrance of p.Asn1868Ile was calculated using allele frequency data of ABCA4 variants in non Finnish European individuals. Results: The p.Asn1868Ile variant was found in cis with known variants in 14/67 probands. In 27/67 probands, we identified p.Asn1868Ile without additional variants in cis, in combination with known, mainly severe ABCA4 variants. In 23/27 probands, the trans configuration was established. Among 27 probands and 6/7 STGD1 siblings carrying p.Asn1868Ile, 42% manifested late-onset disease (>44 years). We additionally identified four asymptomatic relatives carrying a combination of a severe variant and p.Asn1868Ile; ophthalmologic examination in two persons did not reveal STGD1. Based on ABCA4 allele frequency data, we conservatively estimated the penetrance of p.Asn1868Ile, when present in trans with a severe variant, to be below 5%. Conclusions: A significant fraction of genetically unexplained STGD1 cases carries p.Asn1868Ile as a second variant. Our findings suggest exceptional differences in disease expression or even nonpenetrance of this ABCA4 variant, pointing toward an important role for genetic or environmental modifiers in STGD1. PMID- 29971440 TI - Influence of the Water-Drinking Test on Intraocular Pressure, Schlemm's Canal, and Autonomic Nervous System Activity. AB - Purpose: To assess changes in Schlemm's canal (SC), intraocular pressure (IOP), and autonomic nervous system activity in healthy individuals after performing the water-drinking test (WDT). Methods: The SC area (SCAR), trabecular meshwork (TM) thickness, IOP, high frequency (HF) of heart rate variability (HRV), heart rate (HR), and systolic (SBP) and diastolic blood pressure (DBP) were measured in 22 young healthy participants before and after the WDT, which involved drinking a 1 liter water load in 5 minutes.The SC and TM profiles were captured using a Spectralis optical coherence tomography device (anterior segment module). HF was recorded using Kubios HRV Premium software to evaluate parasympathetic nervous system activity. Results: Compared with baseline values, IOP increased significantly (14.9 +/- 2.7 mm Hg vs. 18.4 +/- 3.3 mm Hg; P < 0.001), whereas HF (1587 +/- 930 ms2 vs. 2193 +/- 863 ms2; P < 0.001), mean SCAR (6521 +/- 1360 MUm2 vs. 5180 +/- 1455 MUm2; P < 0.001), and HR (69 +/- 9.7 beats/min vs. 63 +/- 8.9 beats/min; P < 0.001) values decreased significantly by 15 minutes after water loading. Least significant difference pairwise comparison revealed significant fluctuations of all parameters (SCAR, IOP, HF, and HR) at 15 minutes and their recovery at 30-minutes post-WDT. TM thickness, SBP, and DBP post-WDT did not differ significantly. The increase in IOP (r = -0.4047; P = 0.010) and HF (r = 0.386; P = 0.014) correlated significantly with the decrease in SCAR. Conclusions: The WDT may cause parasympathetic nervous system stimulation, leading to the collapse of SC, which leads to increased IOP. PMID- 29971441 TI - Effect of Nitric Oxide on Acanthamoeba castellanii. AB - Purpose: Acanthamoeba keratitis is a well-known intractable corneal infectious disease. We investigated the anti-Acanthamoeba effect of exogenous nitric oxide (NO). Methods: Acanthamoeba castellanii was axenically cultured and exposed to various concentrations of NO donors, such as sodium nitrite, sodium nitroprusside (SNP), and NO-releasing silica nanoparticles (coated in branched polyethylene imine, size:100 nm), for 1 to 7 days (sodium nitrite and SNP: 0, 0.1, 1, 10, 100, and 1000 MUM; silica nanoparticles: 0, 6.25, 12.5, 25, 50, and 100 MUg/mL). Human corneal epithelial cells (HCECs) were cultured and exposed to sodium nitrite, SNP (0, 0.1, 1, 10, 100, and 1000 MUM), and silica nanoparticles for 1, 2, and 3 days. Results: Sodium nitrite and SNP showed a dose-dependent inhibitory effect on A. castellanii viability. A more prominent inhibitory effect was observed with SNP (less than 10% of organisms survived at 7-day culture with 1000 MUM) compared with sodium nitrite. However, more cytotoxicity on HCEC was observed with SNP. NO releasing silica nanoparticles were successfully internalized into the amoebic cytoplasm and accumulated in large vacuoles. Although blank silica nanoparticles had no inhibitory effect on A. castellanii viability, NO-releasing silica nanoparticles showed a dose-dependent amoebicidal effect. Furthermore, no cystic transformation of A. castellanii was observed under a phase contrast microscope or transmission electron microscope after exogenous NO treatment. Conclusions: Our results demonstrated the anti-Acanthamoeba effect of exogenous NO. This finding suggests that NO-releasing drug platforms, including nano-carriers, can be a promising therapeutic strategy for Acanthamoeba keratitis. PMID- 29971443 TI - Does Glaucoma Alter Eye Movements When Viewing Images of Natural Scenes? A Between-Eye Study. AB - Purpose: To investigate whether glaucoma produces measurable changes in eye movements. Methods: Fifteen glaucoma patients with asymmetric vision loss (difference in mean deviation [MD] > 6 dB between eyes) were asked to monocularly view 120 images of natural scenes, presented sequentially on a computer monitor. Each image was viewed twice-once each with the better and worse eye. Patients' eye movements were recorded with an Eyelink 1000 eye-tracker. Eye-movement parameters were computed and compared within participants (better eye versus worse eye). These parameters included a novel measure: saccadic reversal rate (SRR), as well as more traditional metrics such as saccade amplitude, fixation counts, fixation duration, and spread of fixation locations (bivariate contour ellipse area [BCEA]). In addition, the associations of these parameters with clinical measures of vision were investigated. Results: In the worse eye, saccade amplitude?(?def?upalpha{?unicode[Times]{x3B1}}?)?(?def?upbeta{?unicode[Times]{x3B }}?)?(?def?upgamma{?unicode[Times]{x3B3}}?)?(?def?updelta{?unicode[Times]{x3B4}}? ?(?def?upvarepsilon{?unicode[Times]{x3B5}}?)?(?def?upzeta{?unicode[Times]{x3B6}}? ?(?def?upeta{?unicode[Times]{x3B7}}?)?(?def?uptheta{?unicode[Times]{x3B8}}?)?(?de ?upiota{?unicode[Times]{x3B9}}?)?(?def?upkappa{?unicode[Times]{x3BA}}?)?(?def?upl mbda{?unicode[Times]{x3BB}}?)?(?def?upmu{?unicode[Times]{x3BC}}?)?(?def?upnu{?uni ode[Times]{x3BD}}?)?(?def?upxi{?unicode[Times]{x3BE}}?)?(?def?upomicron{?unicode[ imes]{x3BF}}?)?(?def?uppi{?unicode[Times]{x3C0}}?)?(?def?uprho{?unicode[Times]{x3 1}}?)?(?def?upsigma{?unicode[Times]{x3C3}}?)?(?def?uptau{?unicode[Times]{x3C4}}?) 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There was a significant correlation between the intereye difference in BCEA, and differences in MD values (?({?rm{Spearman^{?prime} s}}? r = 0.65;P = 0.01?)), while differences in SRR were associated with differences in visual acuity (?({?rm{Spearman^{?prime} s}}? r = 0.64;P = 0.01?)). Furthermore, between-eye differences in BCEA were a significant predictor of between-eye differences in MD: for every 1-dB difference in MD, BCEA reduced by 6.2% (95% confidence interval, 1.6%-10.3%). Conclusions: Eye movements are altered by visual field loss, and these changes are related to changes in clinical measures. Eye movements recorded while passively viewing images could potentially be used as biomarkers for visual field damage. PMID- 29971442 TI - Comparing Clinical Perimetry and Population Receptive Field Measures in Patients with Choroideremia. AB - Purpose: Choroideremia (CHM) is an X-linked recessive form of hereditary retinal degeneration, which, at advanced stages, leaves only small central islands of preserved retinal tissue. Unlike many other retinal diseases, the spared tissue in CHM supports excellent central vision and stable fixation. Such spared topography in CHM presents an ideal platform to explore the relationship between preserved central retinal structure and the retinotopic organization of visual cortex by using functional magnetic resonance imaging (fMRI). Methods: fMRI was conducted in four participants with CHM and four healthy control participants while they viewed drifting contrast pattern stimuli monocularly. A single ~3 minute fMRI run was collected for each eye separately. fMRI data were analyzed using the population receptive field (pRF) modeling approach. Participants also underwent ophthalmic evaluations of visual acuity and static automatic perimetry. Results: The spatial distribution and strength of pRF estimates correlated positively and significantly with clinical outcome measures in most participants with CHM. Importantly, the positive relationship between clinical and pRF measurements increased with increasing disease progression. A less consistent relationship was observed for control participants. Conclusions: Although reflecting only a small sample size, clinical evaluations of visual function in participants with CHM were well characterized by the spatial distribution and strength of pRF estimates by using a single ~3-minute fMRI experiment. fMRI data analyzed with pRF modeling may be an efficient and objective outcome measure to complement current ophthalmic evaluations. Specifically, pRF modeling may be a feasible approach for evaluating the impact of interventions to restore visual function. PMID- 29971444 TI - Prediction of Individual Disease Conversion in Early AMD Using Artificial Intelligence. AB - Purpose: While millions of individuals show early age-related macular degeneration (AMD) signs, yet have excellent vision, the risk of progression to advanced AMD with legal blindness is highly variable. We suggest means of artificial intelligence to individually predict AMD progression. Methods: In eyes with intermediate AMD, progression to the neovascular type with choroidal neovascularization (CNV) or the dry type with geographic atrophy (GA) was diagnosed based on standardized monthly optical coherence tomography (OCT) images by independent graders. We obtained automated volumetric segmentation of outer neurosensory layers and retinal pigment epithelium, drusen, and hyperreflective foci by spectral domain-OCT image analysis. Using imaging, demographic, and genetic input features, we developed and validated a machine learning-based predictive model assessing the risk of conversion to advanced AMD. Results: Of a total of 495 eyes, 159 eyes (32%) had converted to advanced AMD within 2 years, 114 eyes progressed to CNV, and 45 to GA. Our predictive model differentiated converting versus nonconverting eyes with a performance of 0.68 and 0.80 for CNV and GA, respectively. The most critical quantitative features for progression were outer retinal thickness, hyperreflective foci, and drusen area. The features for conversion showed pathognomonic patterns that were distinctly different for the neovascular and the atrophic pathways. Predictive hallmarks for CNV were mostly drusen-centric, while GA markers were associated with neurosensory retina and age. Conclusions: Artificial intelligence with automated analysis of imaging biomarkers allows personalized prediction of AMD progression. Moreover, pathways of progression may be specific in respect to the neovascular/atrophic type. PMID- 29971445 TI - Hyperosmotic Stress-Induced TRPM2 Channel Activation Stimulates NLRP3 Inflammasome Activity in Primary Human Corneal Epithelial Cells. AB - Purpose: The purpose of this study was to determine whether either a hyperosmotic or oxidative stress induces NLRP3 inflammasome activation and increases in bioactive IL-1beta secretion through transient receptor potential melastatin 2 (TRPM2) activation in primary human corneal epithelial cells (PHCECs). Methods: Real-time PCR, Western blots, and immunofluorescent staining were used to evaluate TRPM2 and NLRP3, ASC, caspase-1, and IL-1beta mRNA and protein expression levels, respectively. A CCK-8 assay evaluated cell viability. Hyperosmotic 500 mOsm and oxidative 0.5 mM H2O2 stresses were imposed. TRPM2 expression was inhibited with a TRPM2 inhibitor, 20 MUM N-(p-amylcinnamoyl) anthranilic acid (ACA), or TRPM2 siRNA knockdown. Results: In the hypertonic medium, TRPM2, NLRP3, ASC, caspase-1, and IL-1beta gene and protein expression levels rose after 4 hours (P <= 0.043), whereas ACA preincubation suppressed these rises (P <= 0.044). Similarly, H2O2 upregulated TRPM2 protein expression by 80%, and induced both NLRP3 inflammasome activation and increased bioactive IL 1beta secretion (P <= 0.036), whereas ACA pretreatment suppressed these effects (P <= 0.029). TRPM2 siRNA transfection reduced TRPM2 gene expression by 70% (P = 0.018) in this hyperosmotic medium and inhibited the increases in NLRP3, caspase 1, and IL-1beta gene (P <= 0.028) and protein expression (P <= 0.037). Conclusions: TRPM2 activation by either a hyperosmotic or oxidative stress contributes to mediating increases in NLRP3 inflammasome activity and bioactive IL-1beta expression because inhibiting TRPM2 activation or its expression blunted both of these responses in PHCECs. This association points to the possibility that TRPM2 is a viable target to suppress hyperosmotic-induced corneal epithelial inflammation. PMID- 29971446 TI - Activation of Dendritic Cells in Dry Eye Mouse Model. AB - Purpose: The immune system plays a major role in the pathogenesis of dry eye diseases (DED), and dendritic cells (DCs) are known to be important initiators of acquired immunity. Thus, the purpose of this study was to determine the contribution of DCs to the development of DED. Methods: Mouse dry eye model was induced by subcutaneous injections of scopolamine and was euthanized at the baseline, and 2, 4, and 7 days postinjection. The activation of the DCs was determined by the mixed leukocyte reaction (MLR), and the number of activated CD86+ DCs in the lymph nodes was determined by flow cytometry. Upregulation of cytokines in the culture supernatant of MLR was determined by ELISA. Results: Significantly increased superficial corneal punctate lesions and decreased number of goblet cells in the conjunctiva were observed in scopolamine-injected mice. The number of activated CD86+ DCs was significantly increased in the cervical lymph nodes but not in the inguinal lymph nodes of the dry eye mice. The stimulatory activity of the DCs derived from the cervical lymph nodes of dry eye mice was significantly higher than that of control mice, and upregulations of IL 17, IL-2, and IL-4 were observed in the culture supernatant of MLR. These results indicate that the DCs of the cervical lymph nodes were activated by the scopolamine injections. Conclusions: Our results indicate that DCs in our dry eye model were sufficiently activated to stimulate the T cells that participate in the onset and progression of DED. PMID- 29971447 TI - Ultra-Wide-Field Fluorescein Angiography-Guided Normalization of Ischemic Index Calculation in Eyes With Retinal Vein Occlusion. AB - Purpose: The purpose of this study was to compare the use of central and montaged ultra-wide-field fluorescein angiography (UWFFA) images for calculating the area of nonperfusion (NP) and ischemic index (ISI) in patients with retinal vein occlusion (RVO) and macular edema (ME) and to correlate these measurements with best-corrected visual acuity (BCVA) and central macular thickness (CMT). Methods: Thirty eyes of 30 RVO patients with recurrent ME were enrolled. Baseline UWFA images were sent to the Doheny Image Reading Center for quantitative analysis by certified graders. The association between ISI from the various zones and BCVA and CMT was examined by Spearman rank correlation and compared. Generalized linear models (GLMs) were used to analyze associations between BCVA and disease status. Results: The NP area and ISI for central and montaged images were not significantly different for any retinal zone. A modest but statistically significant negative linear correlation was observed between BCVA and ISI, ranging from r = -0.3825 in the perimacular area (PMA) to r = -0.584 in the far peripheral area (FPA). On GLM analysis, both PMA (beta = -1.059; 95% confidence interval: -1.74 to -0.378) and FPA (beta = -0.505; 95% confidence interval: 0.988 to -0.021) were significant independent predictors of BCVA. We found no correlation between ISI from the various zones and CMT in this cohort. Conclusions: Montaging of UWFFA images may not be required to adequately quantify and represent areas of NP in eyes with RVO. NP in both the PMA and peripheral retina appear relevant to visual function, highlighting the importance of evaluating the retinal periphery in these individuals. PMID- 29971448 TI - Oxidative Stress Suppresses Cellular Autophagy in Corneal Epithelium. AB - Purpose: Oxidative stress is a major pathogenesis of certain ocular surface diseases. This study investigated the association of oxidative stress and cellular autophagy in corneal epithelium. Methods: We applied hydrogen peroxide (H2O2) to induce oxidative damage to cultured human corneal epithelial (HCE) cells and rat corneas. Cell viability, Western blotting of caspase 8, and TUNEL staining were conducted to measure the cellular injury. The production of reactive oxygen species (ROS) was measured and the levels of the following marker and key factors of ROS were also measured to detect oxidative stress: 3 nitrotyrosine, nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), superoxide dismutase, catalase, and glutathione S-transferase P. The following key factors of autophagy were measured: LC3, beclin 1, Atg 12, and P62. We also applied an agonist of autophagy, rapamycin, in the experiment. Results: Cellular injury and oxidant damage were induced after exposure to H2O2 in HCE cells and rat corneas, such as increases of cell death and production of ROS; upregulation of a ROS generation enzyme, NOX4; and downregulation of degradation factors of ROS, superoxide dismutase, catalase, and glutathione S-transferase P. However, the process of cellular autophagy was suppressed by the measurements of LC3, beclin 1, Atg 12, and P62. Furthermore, application of rapamycin antagonized the cellular and oxidant injury induced by H2O2 but increased the level of autophagy in HCE cells. Conclusions: The oxidative stress of corneal epithelium is associated with the inhibition of cellular autophagy. PMID- 29971449 TI - [The value of human milk for preterm infants-overview and practical aspects]. AB - Over the last decades the immense benefit of human milk on the nutrition of preterm infants has become increasingly evident. Research has confirmed that human milk has significant advantages for the preterm infant in terms of host defense, gastrointestinal development and maturation, neurological development, reduction of necrotizing enterocolitis, retinopathy of prematurity and chronic lung disease as well as mental and physical benefits for the mother. Computing these factors into a health-cost-benefit equation, positive economic consequences for a national public health system were demonstrated.Therefore, international feeding guidelines recommend human milk to be the first choice for preterm infants, the primary source being the infant's mother. The first alternative is milk from an established donor milk bank. To meet the unique nutritional demands of preterm infants and to avoid postnatal growth restriction, human milk must be fortified with additional micro- and macronutrients. Concerns about microbial colonization and contamination and hygienic aspects concerning milk handling need to be addressed when feeding human milk to preterm infants.Early initiation and maintenance of lactation is challenging for mothers of preterm infants and their caregivers. Providing lactation support from educated staff, optimal nursing environments, and the positive attitude of an experienced NICU (neonatal intensive care unit) team will contribute to successful lactation and breastfeeding even beyond discharge of the infant. PMID- 29971450 TI - [Operating upon the Bloodless Heart : A History of Surgical Time between Craft, Machines and Organisms, 1900-1950]. AB - Up until now time has rarely been considered in the historiography of surgery. However, the emergence of modern operating procedures is based significantly on establishing controlled relations of time by adjusting organic, technological and organizational processes. Early cardiac surgery in particular faced a crucial time problem: excluding the heart from the circulatory system long enough to operate inside its bloodless chambers. This problem can be traced back to the early 20th century, when surgeons such as Ludwig Rehn (1849-1930), Friedrich Trendelenburg (1844-1924), and Alexis Carrel (1873-1944) experimented with occlusions of the great vessels. Throughout the first half of the century, various attempts were made to prolong the possible time of circulatory arrest. In this regard, Arthur W. Meyer (1885-1934) in Berlin developed surgical craft procedures, John H. Gibbon Jr. (1903-1973) worked on constructing a heart-lung machine in Boston/Philadelphia, and Wilfred G. Bigelow in Toronto experimented with lowering the temperature of the body. Meticulous scrutiny of these developments illustrates how heterogeneous periods, rhythms, and paces had to be harmonized in order to gain decisive minutes or even seconds. Therefore, major developments on the way to open heart surgery can be described as a history of surgical time. PMID- 29971451 TI - Use of benzodiazepines and cardiovascular mortality in a cohort of women aged over 50 years. AB - PURPOSE: To assess the association between use of benzodiazepines (including the Z-drugs zopiclone and zolpidem) and cardiovascular mortality in women aged over 50 years. METHODS: We used data from the E3N cohort. Data self-reported in biennial questionnaires was matched with drug reimbursement and vital status/causes of death data. In Cox models, exposure to benzodiazepines was fitted using time-varying variables, the reference category being women with no benzodiazepine delivery since January 2004. RESULTS: Among 85,353 women born 1925 1950 and followed between 2004 and 2011, 506 cardiovascular deaths occurred. Exposure to benzodiazepines was associated with increased cardiovascular mortality when hazard ratios (HRs) were adjusted only for age (HRever use 1.65; 95% CI 1.39, 1.97), but not when further adjusted for antidepressant use (HRever use 1.15; 95% CI 0.94, 1.40), nor in the multivariable model (HRever use 0.93; 95% CI 0.75, 1.16). Exposure to hypnotic benzodiazepines remained associated with increased cardiovascular mortality (HRever use 1.23; 95% CI 1.01, 1.51), but with no consistent trend across duration/dose or time since last use, while exposure to anxiolytic benzodiazepines was not (HRever use 0.83; 95% CI 0.67, 1.02). CONCLUSION: In our study, adjustment for antidepressant use strongly attenuated any benzodiazepine-cardiovascular mortality association. Whether the modest association observed with hypnotic benzodiazepines is due to residual confounding deserves further investigation. PMID- 29971452 TI - [Impact of anamnestic information and neurological deficits on the detection rate of secondary headaches]. AB - PURPOSE: Headaches are a very common symptom and imaging is important to rule out symptomatic causes. For clinical differentiation between primary and secondary headaches an exact anamnesis and neurological examination are important. The aim of this study is therefore to identify anamnestic and neurological information that is associated with secondary headaches. Moreover, this study gives an overview of the causes and differential diagnoses of secondary headaches. METHODS: We performed a retrospective analysis of 239 patients >=18 years with headaches who had undergone computed tomography or magnetic resonance imaging. The impact of basic characteristics such as age and gender as well as anamnestic (pain intensity, thromboembolic risk profile) and clinical information (neurological deficit, papilledema, reduced vigilance) was tested by chi2 test at the significance level p < 0.05. RESULTS: In all, 27 of the included patients (11.3%) showed intracranial pathologies that required treatment. The most frequent pathologies were intracranial hypertension (9 patients), cerebral mass lesions (7 patients) and thrombosis of the cranial sinus/veins (3 patients). There was a significant association of a pathologic imaging finding and neurological deficits (p = 0.001) and a papilledema (p < 0.001). Reduced vigilance, pain intensity and thromboembolic risk factors as well as age and gender showed no significant association. CONCLUSIONS: A neurological deficit and especially papilledema are hints towards secondary headaches and should result in computed tomography or magnetic resonance imaging. Other factors such as reduced vigilance, pain intensity, age and gender have no relevant impact on the occurrence of intracranial pathologies. PMID- 29971453 TI - [Innovations in personalized medicine : Molecular characterization of liquid biopsy-fake or fact?] AB - The molecular characterization of biomarkers will be fundamental for personalized medicine. New therapeutic targets have been identified in urological tumors (mainly in prostate cancer) and are currently being investigated in clinical trials. Tissue biopsies are associated with high costs, morbidity of the biopsy sample, and only allow analysis of a point-shaped part of the tumor. The liquid biopsy of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) are noninvasive ways to detect specific changes in the tumor. There are still a few challenges to overcome, e. g., the stability and origin of the CTCs and cfDNA. The detection methods are not yet standardized which makes quality management more difficult. The main applications of liquid biopsy have led to a boom in the field of molecular diagnostics, which does not always have to do with the extended understanding of the individual analytes, but much more on the better sensitivity of the technologies. Despite the tremendous progress made in recent years in the field of liquid biopsy, this has not led to clinical implementation. There is still a lack of validated treatment guidelines in which the results of liquid biopsies can be integrated. PMID- 29971454 TI - Changes in sensorimotor network activation after botulinum toxin type A injections in patients with cervical dystonia: a functional MRI study. AB - Botulinum toxin type A (BoNT) is considered an effective therapeutic option in cervical dystonia (CD). The pathophysiology of CD and other focal dystonias has not yet been fully explained. Results from neurophysiological and imaging studies suggest a significant involvement of the basal ganglia and thalamus, and functional abnormalities in premotor and primary sensorimotor cortical areas are considered a crucial factor in the development of focal dystonias. Twelve BoNT naive patients with CD were examined with functional MRI during a skilled hand motor task; the examination was repeated 4 weeks after the first BoNT injection to the dystonic neck muscles. Twelve age- and gender-matched healthy controls were examined using the same functional MRI paradigm without BoNT injection. In BoNT-naive patients with CD, BoNT treatment was associated with a significant increase of activation in finger movement-induced fMRI activation of several brain areas, especially in the bilateral primary and secondary somatosensory cortex, bilateral superior and inferior parietal lobule, bilateral SMA and premotor cortex, predominantly contralateral primary motor cortex, bilateral anterior cingulate cortex, ipsilateral thalamus, insula, putamen, and in the central part of cerebellum, close to the vermis. The results of the study support observations that the BoNT effect may have a correlate in the central nervous system level, and this effect may not be limited to cortical and subcortical representations of the treated muscles. The results show that abnormalities in sensorimotor activation extend beyond circuits controlling the affected body parts in CD even the first BoNT injection is associated with changes in sensorimotor activation. The differences in activation between patients with CD after treatment and healthy controls at baseline were no longer present. PMID- 29971455 TI - The association of cortisol and adrenal androgen with trabecular bone score in patients with adrenal incidentaloma with and without autonomous cortisol secretion. AB - : Despite ethnic differences in cortisol sensitivity, only one study in Caucasians has assessed trabecular bone score (TBS) in patients with subclinical hypercortisolism (SH). We showed that both subtle cortisol excess and reduced adrenal androgen may contribute to impaired bone quality in Asian women with SH. INTRODUCTION: One study in Caucasians has assessed trabecular bone score (TBS), an index of bone microstructure, in adrenal incidentaloma (AI) patients with subclinical hypercortisolism (SH). There are ethnic differences in cortisol sensitivities between Caucasian and Asian populations. We investigated the associations of cortisol and the adrenal androgen dehydroepiandrosterone-sulfate (DHEA-S) with TBS in AI patients with SH, adrenal Cushing's syndrome (CS), and nonfunctional AI (NFAI). METHODS: We measured TBS, cortisol levels after the overnight 1 mg dexamethasone suppression test (1 mg DST), and cortisol/DHEA-S in 61 patients with SH (30 men; 31 women), 19 with adrenal CS (4 men; 15 women), and 355 with NFAI (213 men; 142 women). RESULTS: After adjusting for confounders, the serum cortisol level after 1 mg DST was inversely correlated with TBS in men (beta = -0.133, P = 0.045) and women (beta = - 0.140, P = 0.048). Higher cortisol/DHEA-S ratio was associated with lower TBS in women (beta = - 0.252, P < 0.001), but not men. This inverse association of cortisol/DHEA-S ratio in women remained statistically significant after adjusting for the serum cortisol level after 1 mg DST (beta = - 0.221, P = 0.008). Compared with women with NFAI, women with SH had 2.2% lower TBS (P = 0.040). Deteriorated bone microstructure (TBS < 1.230) was associated with the serum cortisol level after 1 mg DST (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.04-4.53) and cortisol/DHEA-S ratio (OR, 2.05; 95% CI, 1.03-4.08). CONCLUSIONS: Subtle cortisol excess in both genders and reduced DHEA-S, especially in women, may contribute to impaired bone quality in Asian patients with SH. PMID- 29971456 TI - Correction to: The effect of magnesium on early osseointegration in osteoporotic bone: a histological and gene expression investigation. AB - This article was originally published under a CC BY-NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 29971458 TI - [Influence of enhanced capacity for degradation of misfolded proteins on tumorigenesis]. PMID- 29971457 TI - Sodium valproate ameliorates memory impairment and reduces the elevated levels of apoptotic caspases in the hippocampus of diabetic mice. AB - Learning and memory deficits appear in chronic diabetes and valproic acid has been proved to be beneficial in neurodegenerative diseases. Hence, the current study investigated the effectiveness of chronic valproate treatment for diabetes induced memory impairment and increased levels of hippocampal apoptotic caspases. This study was conducted in adult male C57B15/J mice. Diabetes, which was induced by alloxan (150 mg/kg; i.p.), was confirmed when fasting blood sugar (FBS) was > 200 mg/dl. Sodium valproate (100 mg/kg; i.p.) was administrated to the diabetic and non-diabetic groups, every 72 h for 2 months. Next, all groups were evaluated for memory performance using the radial maze and shuttle box. After FBS measurement, animals were killed and the hippocampus was extracted and prepared for ELISA to assess caspase levels. Diabetic animals had significantly high FBS and memory impairment 2 months after the alloxan injection. Hippocampal levels of caspases 3, 6, and 8 were significantly higher in the diabetic group than in the control group. However, valproate treatment of diabetic animals significantly improved memory performance in both the radial maze and shuttle box and reduced the elevated levels of hippocampal apoptotic caspases, in comparison with diabetic animals. Chronic administration of valproate seems to have beneficial effects on diabetic neuropathy. PMID- 29971459 TI - [Perioperative management for CRS and HIPEC : Anesthesiological aspects]. AB - Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are therapeutic options for the treatment of intra-abdominal neoplasms. Following the resection of all visible tumor areas by CRS, microscopic tumor areas are treated with HIPEC. This procedure increases the quality of life and survival. The CRS with HIPEC is a complex surgical procedure in which the mainly younger and often otherwise healthy patients undergo several pathophysiological changes during the operation. The main concern of the anesthesiologist is the massive volume loss, volume shift and metabolic alterations. Patients with a high comorbidity should undergo preoperative optimization to reduce the perioperative morbidity and mortality especially by protracted interventions. PMID- 29971460 TI - [Technical aspects of laparoscopic liver surgery : Transfer from open to laparoscopic liver surgery]. AB - BACKGROUND: Laparoscopic surgery has become the standard for most visceral surgery procedures in many hospitals. Now, liver resections are also being increasingly carried out laparoscopically. The advantages of the laparoscopic technique have been demonstrated in numerous case series and in a recent randomized controlled trial. AIMS: The aim of this review article is to present the available techniques for laparoscopic liver surgery (LLS). METHODS: The technical variations reported in the literature as well as the own experience with LLS are reported. RESULTS: Optimal patient and trocar positions are crucial for successful LLS and they are chosen according to the planned type of liver surgery: the literature offers several options in particular for surgery of the cranial and dorsal liver segments. As for open liver surgery, a restrictive volume management and the application of the Pringle maneuver are helpful to reduce intraoperative blood loss in LLS. In addition, several dissection techniques have been adopted from open liver surgery. The Cavitron Ultrasound Surgical Aspirator (CUSATM) is particularly suitable for parenchymal dissection close to major vascular structures, since it guarantees a meticulous parenchymal dissection with minimal vascular injuries. CONCLUSION: The developments of minimally invasive surgery nowadays allow complex liver resections, which can mostly be performed comparable to open liver surgery. Hopefully, minimally invasive liver surgery will further develop in Germany in the near future, since it offers several advantages over open liver surgery. PMID- 29971461 TI - Is the 3,4-methylendioxypyrovalerone/mephedrone combination responsible for enhanced stimulant effects? A rat study with investigation of the effect/concentration relationships. AB - RATIONALE: The use of synthetic cathinones as recreational drugs frequently sold in combination has been increasing exponentially. However, the consequences of combining cathinones on the resulting stimulant effects and the pharmacokinetics have been poorly investigated. OBJECTIVE AND METHODS: To study 3,4 methylenedioxypyrovalerone (MDPV; 3 mg/kg) and mephedrone (4-MMC; 30 mg/kg) induced effects on rat locomotor activity and pharmacokinetics, administered alone or in combination by the intragastric route. The pharmacokinetic parameters were determined using non-compartmental analysis and the relationships between the locomotor activity and drug concentrations using sigmoidal Emax modeling. RESULTS: Locomotor activity significantly increased during the first hour post administration with the MDPV/4-MMC combination in comparison to MDPV (p < 0.001) and 4-MMC (p < 0.01) alone. The pharmacokinetic profile of MDPV, but not 4-MMC, was significantly modified with the combination resulting in decreases in Cmax (16.4 +/- 5.5 versus 62.2 +/- 14.2 MUg/L, p < 0.05) and AUC0 -> infinity (708 +/- 91 versus 3316 +/- 682 MUg/L/min, p < 0.01) and increases in V/F (582.6 +/- 136.8 versus 115.9 +/- 42.7 L/kg, p < 0.05) and Cl/F (4.6 +/- 0.7 versus 1.2 +/- 0.4 L/kg/min, p < 0.01) in comparison to MDPV alone. The sigmoidal Emax model fitted the observed data well; MDPV being markedly more potent than 4-MMC (EC50, 0.043 versus 0.7 MUmol/L). The enhancing factor representing the MDPV contribution to the alteration in the relationships between locomotor activity and 4-MMC concentrations was 0.3. CONCLUSION: An MDPV/4-MMC combination results in enhanced stimulant effects in the rat, despite significant reduction in MDPV bioavailability. Enhanced effects could be explained by increased MDPV distribution and/or possible complementation at the brain dopaminergic targets. However, the exact consequences of the MDPV/4-MMC combination in humans remain to be clarified. PMID- 29971462 TI - Discrimination, Bullying and Harassment in Surgery: A Systematic Review and Meta analysis. AB - BACKGROUND: In 2015, the public media in Australia reported a series of life stories of victims who had been subjected to inappropriate behaviors in their surgical careers, bringing the profession into disrepute. Currently, limited data are available in the medical literature on discrimination, bullying and harassment (DBH) in surgery. This significant information gap prompted a systematic review to compile relevant information about DBH in surgical practice and training, in particular, its prevalence and impact. METHODS: A literature search was conducted using the MEDLINE, EMBASE and PubMed databases (May 1929 October 2017). Studies identified were appraised with standard selection criteria. Data points were extracted, and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Eight studies, comprising 5934 participants, were examined. Discrimination occurred in a pooled estimate of 22.4% [95% Confidence Interval (CI) = 14.0-33.9%]. One of the papers reported the prevalence of bullying using two methods including Revised Negative Acts Questionnaire and a definition by Einarsen. Pooled estimate of incidence rate was thus 37.7% (95% CI = 34.0-41.5%) and 40.3% (95% CI = 34.7-46.2%), respectively. In terms of harassment, pooled prevalence was 31.2% (95% CI = 10.0-65.0%). CONCLUSIONS: DBH is a significant issue in surgery. The true incidence of these issues may remain underestimated. Actions are being taken by professional bodies to create a positive culture in surgery. The effectiveness of these strategies is yet to be determined. More studies are warranted to investigate the magnitude of these issues given their psychological impact, and more importantly to monitor the effectiveness of current measures. PMID- 29971463 TI - What Patients Look for When Browsing Online for Pancreatic Cancer: The Bait Behind the Byte. AB - BACKGROUND: Suitability is a patient-centered metric defined as how appropriately health information is targeted to specific populations to increase knowledge. However, suitability is most commonly evaluated exclusively by healthcare professionals without collaboration from intended audiences. Suitability (as rated by intended audiences), accuracy and readability have not been evaluated on websites discussing pancreatic cancer. METHODS: Ten healthy volunteers evaluated fifty pancreatic cancer websites using the suitability assessment of materials (SAM instrument) for the materials' overall suitability. Readability and accuracy were correlated. RESULTS: Ten recruited volunteers (ages 23-63, 50% female) found websites to be on average "adequate" or "superior" in suitability. Surgery, radiotherapy and nonprofit websites had higher suitability scores as compared to counterparts (p <= 0.03). There was no correlation between readability and accuracy levels and suitability scores (p >= 0.3). Presence of visual aids was associated with better suitability scores after controlling for website quality (p <= 0.01). CONCLUSION: Suitability of websites discussing pancreatic cancer treatments as rated by lay audiences differed based on therapy type and website affiliation, and was independent of readability level and accuracy of information. Nonprofit affiliation websites focusing on surgery or radiotherapy were most suitable. Online information should be assessed for suitability by target populations, in addition to readability level and accuracy, to ensure information reaches the intended audience. PMID- 29971464 TI - Immunotherapy with cancer peptides in combination with intravesical bacillus Calmette-Guerin for patients with non-muscle invasive bladder cancer. AB - PURPOSE: A phase I study using two peptide vaccines derived from M phase phosphoprotein 1 (MPHOSPH1) and DEP domain containing 1 (DEPDC1) demonstrated promising results for the treatment of advanced bladder cancer. Therefore, we further tested the ability of these peptides to prevent recurrence after transurethral resection of the bladder tumor in patients with non-muscle invasive bladder cancer (NMIBC). MATERIALS AND METHODS: 127 patients were enrolled in a multicenter, non-randomized phase II clinical trial. The primary endpoint was recurrence-free survival (RFS) rate, and secondary endpoints were safety and immunological response. HLA-A24-restricted peptides were subcutaneously administered in addition to intravesical BCG therapy. The exploratory endpoint evaluated differences of RFS rate between HLA-A*2402-positive (A24(+)) and negative (A24(-)) groups. RESULTS: A 2-year RFS rate in all patients was 74.0%. The RFS rate in the A24(+) group (n = 75) and in the A24(-) group (n = 52) were 76.0 and 71.2%, respectively. This vaccine therapy was well-tolerated and feasible. MPHOSPH1 and DEPDC1 peptide-specific cytotoxic T lymphocyte responses were observed in 75.8 and 77.5% of the A24(+) group, respectively. Patients having both peptide-specific CTL responses showed significantly better RFS than patients without CTL response (P = 0.014). In the A24(+) group, patients who had positive reaction at the injection sites (RAI) had significantly lower rates of recurrence than RAI-negative patients (P = 0.0019). CONCLUSIONS: Cancer peptide vaccines in combination with intravesical BCG therapy demonstrated good immunogenicity and safety, and may provide benefit for preventing recurrence of NMIBC. PMID- 29971466 TI - Short-term effects of Finnish sauna bathing on blood-based markers of cardiovascular function in non-naive sauna users. AB - Emerging evidence suggests that sauna bathing is associated with reduced risk of cardiovascular and all-cause mortality events. However, the biochemical pathways by which sauna bathing might confer its effects on cardiovascular function are not certain. We aimed to study the acute effects of Finnish sauna bathing on various blood-based cardiovascular biomarkers. The study included 102 non-naive sauna users (54% male) with mean age of 51.9 years, who had at least one cardiovascular risk factor. Participants underwent a 30-min single sauna session (mean temperature, 73 degrees C). Biochemical profiling was conducted before, immediately after sauna and 30-min post-sauna. Overall median N-terminal pro-B type natriuretic peptide (NT-proBNP) level (n = 20 participants) was 46.0 ng/L before sauna exposure, which increased to 50.5 ng/l immediately after sauna (median change, + 12.00%; p < 0.001) and remained persistent at 30-min post-sauna (median change from pre-sauna to post-30-min sauna, + 13.93%; p < 0.001). The changes were more evident in males compared with females. There were no significant changes in overall levels of high sensitivity C-reactive protein, creatine kinase, high sensitivity troponin I, and creatine kinase-MBm. However, levels of creatine kinase increased in males (median change immediately after sauna, + 2.99%; p = 0.024). Levels of NT-proBNP increased after sauna exposure. The increase in levels of creatine kinase was more evident in males. Long-term interventional studies are warranted to evaluate if these biomarkers are involved in pathways underlying the associations of sauna bathing with cardiovascular outcomes. PMID- 29971465 TI - Potentiation of PD-L1 blockade with a potency-matched dual cytokine-antibody fusion protein leads to cancer eradication in BALB/c-derived tumors but not in other mouse strains. AB - We have recently described a novel therapeutic antibody product (IL2-F8-TNFmut), featuring the simultaneous fusion of murine IL2 and of a TNF mutant with scFv(F8), an antibody specific to the alternatively-spliced extra domain A of fibronectin (EDA). Here, we report on the in vivo characterization of the anti cancer activity of IL2-F8-TNFmut in four immunocompetent murine models of cancer, CT26, WEHI-164, F9 teratocarcinoma and Lewis lung carcinoma (LLC), using the product alone or in combination with a monoclonal antibody specific to murine PD L1. All four models exhibited a strong expression of EDA-fibronectin, which was confined to vascular structures for F9 tumors, while the other three malignancies exhibited a more stromal pattern of staining. A complete and long-lasting tumor eradication of CT26 and WEHI-164 tumors was observed in BALB/c mice when IL2-F8 TNFmut was used in combination with PD-L1 blockade. The combination treatment led to improved tumor growth inhibition in 129/SvEv mice bearing murine teratocarcinoma or in C57BL/6 mice bearing murine LLC, but those cancer cures were difficult to achieve in those models. A microscopic analysis of tumor sections, obtained 24 h after pharmacological treatment, revealed that the PD-L1 antibody had homogenously reached tumor cells in vivo and that the combination of PD-L1 blockade with IL2-F8-TNFmut stimulated an influx of NK cells and of T cells into the neoplastic mass. These data indicate that potency-matched dual-cytokine fusion proteins may be ideally suited to potentiate the therapeutic activity of immune check-point inhibitors. PMID- 29971467 TI - A phase 1 study of ADI-PEG 20 and modified FOLFOX6 in patients with advanced hepatocellular carcinoma and other gastrointestinal malignancies. AB - PURPOSE: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS: This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m2 (Cohort 2 and RP2D expansion). RESULTS: Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m2 weekly with mFOLFOX6. The most common any grade adverse events (AEs) were thrombocytopenia, neutropenia, leukopenia, anemia, and fatigue. Among the 23 HCC patients, the most frequent treatment-related Grade >= 3 AEs were neutropenia (47.8%), thrombocytopenia (34.7%), leukopenia (21.7%), anemia (21.7%), and lymphopenia (17.4%). The ORR for this group was 21% (95% CI 7.5 43.7). Median PFS and OS were 7.3 and 14.5 months, respectively. Arginine levels were depleted with therapy despite the emergence of low levels of anti-ADI-PEG 20 antibodies. Arginine depletion at 4 and 8 weeks and archival tumoral argininosuccinate synthetase-1 levels did not correlate with response. CONCLUSIONS: Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m2 weekly shows an acceptable safety profile and favorable efficacy compared to historic controls. Further evaluation of this combination is warranted in advanced HCC patients. PMID- 29971468 TI - An Internet-based survey to evaluate the comfort and need for further pubovaginal sling training. AB - INTRODUCTION AND HYPOTHESIS: The pubovaginal sling (PVS) dates to the 1940s as an efficacious surgical treatment for stress urinary incontinence (SUI). Recently, it has been replaced by the midurethral sling (MUS). Since 2008, international regulatory agencies increased regulation and issued warnings on vaginal mesh for repair of pelvic organ prolapse (POP), which has led to increased scrutiny of the MUS. Thus, the need for surgical comfort with PVS is resurfacing. We sought to evaluate the surgical practice patterns among international urogynecologists for the treatment of SUI and identify whether a need and interest for more training exists. METHODS: We developed a short, Internet-based survey for members of the International Urogynecological Association (IUGA). Descriptive analyses, binomial and multivariate logistic regressions were calculated to determine significant associations. RESULTS: Among 556 members who responded to the survey, 72% did not offer PVS in practice. Among those who did, there was as significant relationship between offering PVS and practicing in the United States, board-certification in urogynecology, PVS exposure in training, increasing number of PVS performed during training, and comfort with PVS. Members interested in further PVS training were younger, less comfortable with PVS, performed fewer PVS, or had no exposure in training. CONCLUSION: Most IUGA members do not offer PVS in clinical practice. As would be expected, members who performed more PVS in training and were more comfortable with PVS were likely to offer it to patients. Our results highlight a learning gap, especially among younger providers who are not comfortable with PVS and desire further training in this procedure. PMID- 29971469 TI - Vitamin E as alternative local treatment in genitourinary syndrome of menopause: a randomized controlled trial. AB - INTRODUCTION AND HYPOTHESIS: Genitourinary syndrome of menopause is a major health concern in postmenopausal women. This study was aimed at comparing the effect of a vitamin E vaginal suppository with that of conjugated estrogen vaginal cream on sexual function in postmenopausal women with genitourinary syndrome of menopause. METHODS: This survey was carried out on 52 postmenopausal women aged 40-65 years who had been referred to gynecology clinics in Mashhad city, during 2013-2014. Keeping beta = 0.1, the power was calculated to be 90%. The patients were randomly divided into two groups: vitamin E vaginal suppository and conjugated estrogen vaginal cream. Participants used the medications for 12 weeks. They were visited at the 4th, 8th, and 12th weeks. Validated Abbreviated Sexual Function Questionnaire (ASFQ), as the primary outcome measure, and a demographic information questionnaire, were used to collect data at each visit. Data were analyzed using SPSS and p < 0.05 was considered statistically significant. RESULTS: Mean overall scores of the ASFQ were increased significantly in both groups during the course of the study, compared with baseline (p < 0.001). However, the mean ASFQ scores of the two treatments did not differ significantly. CONCLUSION: Improved scores of ASFQ after the 12th week showed that the treatment was successful in both groups. Therefore, a vitamin E vaginal suppository may be an alternative to vaginal estrogen in relieving the symptoms of vaginal atrophy in postmenopausal women, especially those not able to use hormone therapy or have low compliance. PMID- 29971470 TI - Safety of laparoscopic sacrocolpopexy with concurrent rectopexy: peri-operative morbidity in a nationwide cohort. AB - INTRODUCTION AND HYPOTHESIS: Rectopexy and sacrocolpopexy can be performed concurrently to treat rectal and vaginal prolapse. We hypothesized that concurrent procedures might be associated with more complications than rectopexy and sacrocolpopexy alone. METHODS: Patients undergoing laparoscopic sacrocolpopexy or rectopexy, or concurrent laparoscopic sacrocolpopexy and rectopexy were identified in the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database from 2013 to 2016. Preoperative characteristics, operative time, and 30-day post-operative complications were compared between groups. Complications were those defined by the ACS Risk Calculator. Descriptive tests and regression methods were utilized for group comparisons. Significance was set at p < 0.05. RESULTS: We identified 7,232 laparoscopic sacrocolpopexy, 1,560 laparoscopic rectopexy, and 123 concurrent laparoscopic sacrocolpopexy and rectopexy cases. Patients undergoing concurrent procedures were more commonly white, non-Hispanic, non-diabetic, and smokers. Operative time was longest for concurrent procedures, followed by sacrocolpopexy and rectopexy (p < 0.0001). Patients undergoing isolated rectopexy were more commonly >= American Society of Anesthesiologists class 3 (p < 0.0001). Rates of any complication for colpopexy, rectopexy, and concurrent procedures did not differ (6.18%, 7.63%, 8.94%; p = 0.058). Serious complication rates for colpopexy, rectopexy, and concurrent procedures did not differ (5.52%, 6.35%, 8.13%; p = 0.222). Odds of experiencing any complication were higher comparing rectopexy with colpopexy alone (adjusted odds ratio = 1.252, 95% CI 1.002-1.565). Comparing all groups, rectopexy had the highest mortality, reoperation, and transfusion rates (all p < 0.05). Concurrent procedures had the highest surgical site and urinary tract infection rates (all p < 0.05). CONCLUSIONS: Complications were low for all three procedures. Concurrent repair may be appropriate in well selected patients. PMID- 29971471 TI - Development of an X-specific marker and identification of YY individuals in spinach. AB - Spinach is a popular vegetable native to central and western Asia. It is dioecious with a pair of nascent sex chromosomes. The difficulties of working with the non-recombining sex determination region of XY individuals have hindered the progress toward sequencing sex chromosomes of most dioecious species. Here we present important advances toward characterizing the non-recombining sex chromosomes in spinach. Of nearly 400 spinach accessions screened, we identified a single accession of spinach in which androdioecious XY individuals segregate YY spinach. The male and female genomes of the spinach cultivar Shami and USDA accession PI 664497 were sequenced at 12-17 * coverage. X-specific sequences were identified by comparing the depth of coverage differences between male and female alignments to a female draft genome. YY individuals were used as a negative control to validate X-specific markers found by depth of coverage analysis. Of 19 possible X chromosome sequences found by depth of coverage analysis, one was verified to be X-specific by a PCR-based marker, SpoX, which amplified genomic DNA from XX and XY, but not YY templates. Androdioecious XY individuals of accession PI 217425 (Cornell #9) were used to develop inbred lines, and at S7 generation, all XY individuals were androdioecious and all YY individuals were pure male. The sex reversal of the XY mutant to hermaphrodite is strong evidence that the sex chromosomes in spinach have a two-gene sex determination system. These results are crucial towards sequencing the X and Y chromosomes to advance sex chromosome research in spinach. PMID- 29971472 TI - Identification of powdery mildew resistance QTL in strawberry (Fragaria * ananassa). AB - Key Message Powdery mildew resistance in two strawberry mapping populations is controlled by both stable and transient novel QTL of moderate effect. Some low transferability of QTL across wider germplasm was observed. The obligate biotrophic fungus Podosphaera aphanis is the causative agent of powdery mildew on cultivated strawberry (Fragaria * ananassa). Genotypes from two bi-parental mapping populations 'Emily' * 'Fenella' and 'Redgauntlet' * 'Hapil' were phenotyped for powdery mildew disease severity in a series of field trials. Here, we report multiple QTL associated with resistance to powdery mildew, identified in ten phenotyping events conducted across different years and locations. Six QTL show a level of stable resistance across multiple phenotyping events; however, many other QTL were represented in a single phenotyping event and therefore must be considered transient. Subsequent screening of identified QTL across a validation set determined whether identified QTL remained closely linked to the associated resistance gene in the wider germplasm. Furthermore, a preliminary association analysis identified a novel conserved locus for further investigation. Our data suggest that resistance is highly complex and that multiple, primarily additive, sources of quantitative resistance to powdery mildew exist across strawberry germplasm. Utilisation of the reported markers in marker-assisted breeding or genomic selection would lead to improved powdery mildew-resistant strawberry cultivars, particularly where the studied parents, progeny and close pedigree material are included in breeding germplasm. PMID- 29971473 TI - The soybean experiment '1000 Gardens': a case study of citizen science for research, education, and beyond. AB - KEY MESSAGE: Citizen science, an approach that includes normal citizens in scientific research, holds great potential also for plant sciences and breeding and can be a powerful research tool to complement traditional approaches. Citizen science is an approach that includes normal citizens in scientific research, but has so far not been exploited by the various disciplines in plant sciences. Moreover, global threats challenge human well-being and science can provide solutions, but needs to leave the ivory tower in the mind of the broader public. In 2016, we performed the '1000 Gardens-the soybean experiment' citizen science project, that aimed at finding citizens in Germany who would grow soybean lines in their own gardens and evaluate them for a range of traits related to adaptation and agronomic performance. Here, we describe details of this project, i.e. the recruitment, performance, and compliance of the citizen scientists. A total of 2492 citizen scientists volunteered for the project, but through the high media coverage a much broader audience than just the participants was reached. Our 1000 Gardens project was successful in collecting a scientifically unique data set with heritabilities ranging up to 0.60 for maturity date or 0.69 for plant height. Our results suggest that the citizen science approach holds great potential also for plant sciences and can be a powerful research tool to complement traditional approaches. Our project was also successful in raising public awareness about the importance of plant breeding and in communicating key messages on the manifold benefits of legumes for a sustainable agriculture to a broader public. Thus, citizen science appears as a promising avenue to demonstrate the value of breeding and science to the general public by including normal citizens in scientific research. PMID- 29971474 TI - [Microscope-integrated intraoperative optical coherence tomography in examination of pediatric patients under anesthesia]. AB - BACKGROUND: The therapeutic principle of examinations of children under general anaesthesia using microscope-integrated optical coherence tomography (MI-OCT) is presented. The aim was to assess novel indications as well as limitations for MI OCT to enhance ophthalmological examinations of neonates and children under general anesthesia. METHODS: The study was based on a review of the literature from google.scholar.com and PubMed and our own data from a prospective study (Department for Ophthalmology, University of Cologne) of 14 children with anterior and posterior segment anomalies undergoing examinations under anesthesia. Patients were examined using a commercially available MI-OCT device. The study analyzed the general feasibility of MI-OCT for ophthalmological examination of children under general anesthesia for the anterior and posterior eye segments and the benefits of indications and intraoperative findings. RESULTS: The MI-OCT significantly enriched the examinations of children under general anesthesia and delivered additional information not visible with the surgical microscope. Even in situations with a limited anterior chamber view MI OCT enabled estimation of distances, such as corneal thickness. In addition to influencing therapeutic decisions, in 12/14 children MI-OCT also enabled examination of the thickness of the nerve fibre layer of the optic nerve disc and the retina. CONCLUSION: The data presented here underline the benefit of the intraoperative MI-OCT in ophthalmological examinations of children under general anesthesia. In particular MI-OCT enables examinations of children with corneal opacification, if an ophthalmological examination under general anesthesia becomes necessary. PMID- 29971476 TI - Construction and characterization of the GFAT gene as a novel selection marker in Aspergillus nidulans. AB - Glutamine:fructose-6-phosphate aminotransferase (GFAT) catalyzes the formation of glucosamine-6-phosphate, and its gene is one of the genes essential for microbes. Using the GFAT-encoding gene can prevent the use of a drug-resistant gene as a selection marker in a bacterial system. Another unique property of the GFAT selection marker is that no particular compound is prohibited or required for creating a selective stress for a yeast. Filamentous fungi are major producers of industrial enzymes. However, there has been no report on the construction and application of the GFAT gene as a selection marker in filamentous fungi. To develop a new selection marker, the GFAT-encoding gene gfaA was deleted from the genome of the filamentous fungus Aspergillus nidulans, and the gfat gene of the straw mushroom Volvariella volvacea was used as the selection marker to mediate the transformation and overexpression of a thermostable bacterial laccase in A. nidulans. The GFAT-deficient strain A. nidulans ?gfaA was not able to grow in the culture medium containing 0.5% yeast extract unless about 20 mM glucosamine was used to supplement to the medium. The gfat gene was amplified and inserted into the integration vector pAL5 and autonomous replication vector Prg3-AMA1-NotI for A. nidulans to generate the gfat vectors pALG and pAMAG, respectively. Using these gfat vectors, the laccase gene lcs from a hyperthermophilic bacterium was overexpressed intra- and extracellularly in A. nidulans ?gfaA. Therefore, recombinant filamentous fungi can be constructed with gfat vectors, which can be maintained stably in host cells with the naturally occurred selective stress of a medium, forage, pulp, animal gut, wastewater, or soil. PMID- 29971475 TI - Two direct gene targets contribute to Clp-dependent regulation of type IV pilus mediated twitching motility in Lysobacter enzymogenes OH11. AB - Lysobacter enzymogenes is an agriculturally important Gram-negative bacterium that employs a multitude of antifungal mechanisms to inhibit and infect filamentous fungal pathogens, through secretion of antifungal antibiotic HSAF (heat-stable antifungal factor), formation of T4P (type IV pilus)-mediated twitching motility, and production of extracellular chitinase. Interestingly, all such key antifungal factors seem to be controlled by Clp, a master regulator in L. enzymogenes; however, the underlying mechanisms are poorly understood. Here, employing strain OH11 as a working model, we show that Clp plays a dual role in controlling OH11 twitching motility. It controls transcription of pilA, a major T4P structure pilin gene, via directly binding to its promoter region, as well as regulates the gene transcription of pilMONOPQ operon, whose products were essential for T4P assembly, by directly binding to a similar promoter sequence. We also truncated the Clp-binding region of the pilA promoter fragment down to 41 bp to identify the potential Clp-binding sequence. In addition, the Clp recognized pilM promoter motif of the L. enzymogenes strains is similarly conserved as the pilA promoter, both with a conserved 5'-GTG and a conserved CAC 3', spaced by ten highly variable nucleotides. Thus, this study identified two direct and previously uncharacterized gene targets of Clp contributing to its regulation in the L. enzymogenes twitching motility. Overall, our findings further elucidate the molecular genetics of Clp-dependent twitching motility in Lysobacter. PMID- 29971477 TI - Quality, safety and efficacy profiling of ginseng adventitious roots produced in vitro. AB - Ginseng (Panax ginseng C. A. Meyer, Family Araliaceae) is one of the major medicinal and nutraceutical plants, which is native to oriental region. It is used worldwide as a popular herbal medicine because of its pharmacological effects like anti-oxidative, anti aging, anti-cancer, adaptogenic, and other health-improving activities. Chief components of ginseng identified till date are ginsenosides, a group of saponins with triterpenoid structure. Ginseng is cultivated under controlled conditions, and for harvesting of fully grown roots of the plant, the cultivation takes long duration of about 5-7 years and cultivated ginseng roots are inferior in quality and ginsenoside content. Wild Mountain ginseng is superior in quality and ginsenoside content but is scarce in nature. Therefore, for obtaining the useful compounds of this plant at commercial scale, cell and organ cultures especially adventitious roots have been established by using superior clones of wild mountain ginseng, ginseng biomass is produced by applying large scale bioreactors. In this paper, an effort has been made to shed light on the scientific literature and to decipher the evidences for quality, safety, and efficacy of ginseng adventitious roots produced from in vitro cultures. PMID- 29971478 TI - ? PMID- 29971479 TI - The central nervous system manifestations of localized craniofacial scleroderma: a study of 10 cases and literature review. AB - BACKGROUND: Localized craniofacial scleroderma is a rare pediatric disease that involves a spectrum of discoloration, fibrosis and hemiatrophy of the face and scalp. Children with localized craniofacial scleroderma may have neurological symptoms, and in this context often undergo diagnostic imaging of the brain. OBJECTIVE: To catalogue neuroimaging abnormalities in patients with localized craniofacial scleroderma treated at our institution, review their clinical courses and compare this data with prior studies. MATERIALS AND METHODS: Following Institutional Review Board approval, an imaging database search identified 10 patients with localized craniofacial scleroderma and neuroimaging abnormalities treated at our institution. Neuroimaging exams and the electronic medical record were reviewed for each case. RESULTS: The most common indications for neuroimaging were headache or seizure (80% of cases). The most common neuroimaging abnormalities were T2-hyperintense, subcortical white matter lesions ipsilateral to the cutaneous lesion (90% of cases) on magnetic resonance imaging (MRI). Calcifications or blood products (50%), cysts (40%) and abnormal enhancement (20%) were also observed. A positron emission tomography (PET) scan obtained for a single case demonstrated diminished 18F-fluorodeoxyglucose (FDG) avidity corresponding to the dominant focus of signal abnormality on MRI. Progressive neuroimaging abnormalities were present in 30% of cases. There was no consistent relationship between changes in neurological symptoms following treatment and neuroimaging findings. CONCLUSION: Our results are similar to previously published data. In the absence of new or worsening neurological symptoms, the role of neuroimaging for follow-up of localized craniofacial scleroderma is unclear. Knowledge of intracranial neuroimaging abnormalities that are commonly associated with localized craniofacial scleroderma helps to distinguish these lesions from others that have similar appearance. PMID- 29971481 TI - Two stirred-tank bioreactors in series enable continuous production of alcohols from carbon monoxide with Clostridium carboxidivorans. AB - Microbial batch production of alcohols by fermentation of CO-rich gases with Clostridia is limited by low volumetric productivities due to the need for formation of organic acids first (acidogenic phase) followed by re-consumption of the acids to form alcohols (solventogenic phase). Continuous autotrophic production of alcohols was made possible with C. carboxidivorans by use of two continuously operated stirred-tank bioreactors in series without cell retention. The pH in the first reactor was controlled to pH 6.0 for continuous growth of the cells. Steady-state concentrations of 3.0 g L-1 acetate and 0.1 g L-1 butyrate were measured at a mean hydraulic residence time of 8.3 h. The pH in the second reactor was controlled to pH 5.0 for enhancing continuous formation of alcohols resulting in steady-state concentrations of 6.1 g L-1 ethanol, 0.7 g L-1 butanol, and 0.1 g L-1 hexanol at a mean hydraulic residence time of 12.5 h. Continuous formation of alcohols from CO was already observed in the first stirred-tank reactor parallel to the formation of acids, whereas re-consumption of acids as well as de-novo syntheses of alcohols from CO was shown in the second stirred tank reactor. Thus, high final alcohol-to-acid ratios of 3.9 gethanol gacetate-1 and 4.4 gbutanol gbutyrate-1 were achieved in the continuous syngas-fermentation process with C. carboxidivorans. PMID- 29971480 TI - Impaired healing of cornea incision injury in a TRPV1-deficient mouse. AB - The present study attempts to elucidate the role of TRPV1 cation channel receptor on primary repair in an incision-wounded mouse cornea in vivo. Previous study revealed that blocking TRPV1 suppressed myofibroblast formation and expression of transforming growth factor beta1 (TGFbeta1) in cultured keratocytes or ocular fibroblasts. Male C57BL/6 (wild-type; WT) mice and male C57BL/6 Trpv1-null (KO) mice incurred a full-thickness incision injury (1.8 mm in length, limbus to limbus) in the central cornea of one eye with a surgical blade under general and topical anesthesia. The injury was not sutured. On days 0, 5, and 10, the eyes were enucleated, processed for histology, immunohistochemistry, and real-time RT PCR gene expression analysis to evaluate the effects of the loss of TRPV1 on primary healing. Electron microscopy observation was also performed to know the effect of the loss of TRPV1 on ultrastructure of keratocytes. The results showed that the loss of Trpv1 gene delayed closure of corneal stromal incision with hindered myofibroblast transdifferentiation along with declines in the expression of collagen Ia1 and TGFbeta1. Inflammatory cell infiltration was not affected by the loss of TRPV1. Ultrastructurally endoplasmic reticulum of TRPV1-null keratocytes was more extensively dilated as compared with WT keratocytes, suggesting an impairment of protein secretion by TRPV1-gene knockout. These results indicate that injury-related TRPV1 signal is involved in healing of stromal incision injury in a mouse cornea by selectively stimulating TGFbeta induced granulation tissue formation. PMID- 29971482 TI - A soft sensor based on online biomass measurements for the glucose estimation and control of fed-batch cultures of Bacillus thuringiensis. AB - On bioprocess engineering, experimental measurements are always a costly part of the modeling effort; therefore, there is a constant need to develop cheaper, simpler, and more efficient methodologies to exploit the information available. The aim of the present work was to develop a soft sensor with the capacity to perform reliable substrate predictions and control in microbial cultures of the fed-batch type, using mainly microbial growth data. This objective was achieved using dielectric spectroscopy technology for online monitoring of microbial growth and hybrid neural networks for online prediction of substrate concentration. The glucose estimator was integrated to a fuzzy logic controller to control the substrate concentration in a fed-batch experiment. Dielectric spectroscopy is a technology sensitive to the air volume fraction in the culture media and the turbulence generated by the agitation; however, the introduction of a polynomial function for the calibration of the permittivity signal allowed biomass estimations with an approximation error of 2%. The methodology presented in this work was successfully implemented for the glucose prediction and control of a fed-batch culture of Bacillus thuringiensis with an approximation error of 6%. PMID- 29971483 TI - Pediatric spinal infections-a review of non-tuberculous infections. AB - Pediatric spinal infection includes spinal epidural abscess, spondylodiscitis and intradural (extramedullary and intramedullary) spinal infections. However, these entities are extremely rare and no clear guidelines exist for their management. Pertinent literature was searched and a detailed narrative review of this topic is presented. PMID- 29971484 TI - CLAVATA1-type receptor-like kinase CsCLAVATA1 is a putative candidate gene for dwarf mutation in cucumber. AB - Dwarf mutations have played vital roles in elucidating the regulatory molecular mechanisms of plant height. In this study, we identified a mutant named Csdw, whose mutagenesis was induced by ethyl methyl sulfonate in cucumber, and this mutant exhibited a dwarf phenotype with a reduced internode length because of the reduction of cell division in the main stem. The dwarf phenotype of Csdw could be partially rescued through GA3 application, and endogenous GA3 levels from the stem of Csdw decreased distinctly. Genetic analysis showed that Csdw was attributed to a recessive gene. The MutMap and Kompetitive Allele Specific PCR genotyping results revealed that Csa3G872760 (CsCLAVATA1), encoding a CLAVATA1 type receptor-like kinase, was a putative candidate gene for dwarf mutation in cucumber. The expression of CsCLAVATA1 in the stem of Csdw was lower than that of wild-type plants. Therefore, CsCLAVATA1 could regulate the dwarf phenotype in cucumber. PMID- 29971485 TI - Detection and genomic characterization of new avian-like hepatitis E virus in a sparrow in the United States. AB - Hepatitis E virus (HEV) is a nonenveloped, positive-sense, single-stranded RNA virus that has been detected in a wide variety of animals. In 2017, an avian-like HEV was identified in sparrow feces sampled from around a pig farm in the midwestern United States. Sequence analysis revealed that the sparrow isolate represents a novel HEV that is distantly related to chicken and little egret HEVs. PMID- 29971486 TI - Hepatitis C virus serologic relapse after treatment with direct-acting antivirals is dependent on viral RNA levels in peripheral blood mononuclear cells and the grade of liver cirrhosis. AB - The disappearance of hepatitis C virus (HCV) from serum and tissues for 12 weeks after the end of treatment (EOT) with direct-acting antivirals (DAAs) is known as a "sustained virologic response" (SVR) and occurs more frequently in non cirrhotic patients than in cirrhotic patients. In this study, we evaluated the outcome of HCV treatment with sofosbuvir (SOF) plus ledipasvir (LDV) at both EOT and 12 weeks after EOT in patients with and without hepatic cirrhosis to address the relationship of serologic relapse to persistent infection of PBMCs and the frequency of hepatic encephalopathy and hepatocellular carcinoma (HCC) after treatment. Seventy-five patients with post-HCV liver cirrhosis were assigned to one of three groups (A, B, and C), each of which included 25 patients and corresponded to the patients' Child-Turcotte-Pugh (CTP) classification. All of the patients received a daily dose of SOF (400 mg) plus LDV (90 mg) for 24 weeks and were tested using HCV single-strand reverse transcription (SRT) and PCR analysis of PBMCs at both EOT and 12 weeks after EOT. Fourteen (18.7%) out of 75 patients (all study populations) had intra-PBMC HCV RNA, but only nine of them (64.3%) developed HCV RNA serum relapse (seroconversion) 12 weeks after EOT (P < 0.001). Encephalopathy was significantly higher in group C at EOT and 12 weeks after EOT (P < 0.05). Development of HCC was observed in decompensated patients of group C (2 out of 5 = 40.0%) 12 weeks post-EOT (P = 0.03). In conclusion, detection of HCV RNA within PBMCs at the EOT provides an indication of potential relapse after 12 weeks. Moreover, development of encephalopathy and HCC after HCV eradication by SOF plus LDV therapy is perhaps a future warning for post treatment hepatic decompensation in cirrhotic patients. PMID- 29971487 TI - A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment. AB - Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment. PMID- 29971488 TI - Robotic-assisted total mesorectal excision (TME) for rectal cancer results in a significantly higher quality of TME specimen compared to the laparoscopic approach-report of a single-center experience. AB - AIM: Robotic surgery allows for a better visualization and more precise dissection especially in the narrow male pelvis and mid and lower third of the rectum. However, superiority to laparoscopic TME has yet to be proven. We therefore analyzed short-term outcomes of laparoscopic and robotic low anterior rectal resection for rectal cancer. PATIENTS AND METHODS: From 2011 to 2016, 44 robotic (RTME) and 41 laparoscopic (LTME) low anterior rectal resection with total mesorectal excision were performed at a single institution. Specimen quality was assessed and reported by an independent pathologist following international guidelines. RESULTS: The groups did not differ significantly regarding gender, age, ASA stage, BMI, and distance of the lower tumor margin from the anal verge. More patients in the RTME group underwent preoperative chemoradiation (43.2 vs. 19.5%, p = 0.019). The quality of the TME specimen was significantly better in the RTME group (complete/nearly complete/incomplete for RTME 97/0/3% and for LTME 78/17/5%, p = 0.03). The conversion rate tended to be lower in the RTME group (7 vs. 17%, p = 0.143). There was no difference in CRM positivity between the groups. CONCLUSION: Robotic surgery is safe and can improve the quality of TME for rectal cancer compared to laparoscopy. Any effect on long-term survival remains to be established. PMID- 29971489 TI - [Children of mentally ill parents : Also a topic in the context of child protection]. AB - BACKGROUND: Severe mental illness in parents increases the risk of neglect, physical and sexual abuse (adverse childhood experiences, ACE) of children. OBJECTIVE: Presentation of the current situation of child protection issues in psychiatric care in Germany and the derivation of needs and potential solution strategies. MATERIAL AND METHODS: Based on a selective literature search, the needs and the current situation in Germany are presented and potential solution strategies are pointed out. The analysis is supplemented by a descriptive evaluation of specific consultation requests to the medical child protection hotline, which were descriptively evaluated and served as a starting point for the selective literature search. RESULTS: Despite the well-known comprehensive influence of mental illnesses of parents on their children, psychiatric patients have not yet been systematically registered regarding whether they have to care for underage children. There is a lack of systematic and comprehensive support for families at risk. Of all calls to the project medical child protection hotline, calls from the field of adult psychiatry and psychosomatics make up by far the highest proportion from the field of adult medicine. CONCLUSION: An increased awareness of child protection issues is necessary in the field of adult psychiatric treatment. Systematic counselling services for acute cases and also networking and structured cooperation with other medical fields, such as child and youth psychiatry, pediatrics and child and youth welfare should be addressed. PMID- 29971490 TI - [Rationality and freedom in medicine: the case of electroconvulsive therapy]. AB - There are no rational reasons why electroconvulsive therapy (ECT) should not be subject to the same criteria in its clinical application as any other treatment in medicine. Associations referring to historical events and their presentation in the media do not provide convincing arguments against the clinical use of ECT. In order to offer ECT to patients, scientifically solid evidence with respect to its clinical results must be available. As this scientific evidence is clearly given, ECT must be offered to the patients. A well-informed, reflected medicine must not withhold an effective treatment like ECT from the patients and medicine should not be influenced by associations but only by scientific evidence, even though the exact mechanisms of action of ECT are not known in detail. The image of ECT has clearly improved during the last decades thereby increasing the hope that unjustified arguments against ECT will lose their impact. PMID- 29971491 TI - Preventing vertical virus infections: the role of serologic screening of pregnant women. AB - Several virus infections affect the pregnancy itself as well as the foetal development (rubella, PVB19, VZV, HSV, HCMV, HBV, HIV). Prevention can be established by vaccination or an assessment of the immunity status as well as by chemotherapy. The following review provides an update to current aspects focusing on the role of serologic screening. PMID- 29971492 TI - Increased active phase atrial contraction is related to marathon runner performance. AB - PURPOSE: Left atrial (LA) contraction is essential for left ventricular (LV) filling during exertion. We sought to evaluate the relationship of LA contraction and exercise capacity in trained athletes. METHODS: Sixteen male marathon runners were recruited and allocated into two groups according to their previous training status (>= or < 100 km peer week). All subjects underwent a baseline cardiopulmonary test to evaluate maximal aerobic capacity and a transthoracic echocardiography previous and immediate post-marathon. LA contractile function evaluation was accomplished by measuring the negative deformation of the post P wave strain curve (LASa). LASa change was defined as LASa pre-marathon minus LASa immediate post-marathon. RESULTS: Mean age was 39 +/- 6 years. LA volume index (39 +/- 13 vs. 31 +/- 5 mL/m2, p = 0.04), LV mass index (91 +/- 21 vs. 73 +/- 12 g/m2, p = 0.04), VO2 max (59 +/- 3 vs. 50 +/- 8 mL/kg/min, p = 0.036) were higher in more intensive trained group and marathon time was lower (185 +/- 14 vs. 219 +/- 24 min, p = 0.017). An increase in LASa after immediate post-marathon was observed in both groups, which was significantly greater in the highly trained group (18.9 +/- 5.8 vs. 6.3 +/- 3.5%, p < 0.003). Maximum VO2 measured previous to the marathon was inversely related to marathon time and directly correlated to LASa change (rho = 0.744, p = 0.001, rho = 0.546, p = 0.028, respectively). CONCLUSIONS: Athletes with more intensive training load have larger LV mass and LA size. An increase in LA contraction was seen post-marathon, which was significantly greater in the highly trained group. This increase in the LA contraction was related to the maximum VO2 measured previous to the marathon and to performance in a highly demanding test. PMID- 29971493 TI - Oct-4 and CD44 in epithelial stem cells like of benign odontogenic lesions. AB - Benign epithelial odontogenic lesions are great clinical importance entities that develop in the jaws from the tissues that form teeth. It has been shown that benign and malignant tumors are present in a large number of tumor stem cells, which has great implications in the development of these lesions. Oct-4 and CD44 have been demonstrated as important markers for tumoral stem cells. The aim of this study was investigate the presence of stem cell markers Oct-4 and CD44 in benign epithelial odontogenic lesions. Twenty odontogenic keratocysts (OKC), 20 ameloblastomas (AMB) of the solid/multicystic type and 20 adenomatoid odontogenic tumors (AOT) were retrospectively analyzed for immunohistochemical detection of Oct-4 and CD44 in their epithelial component. All cases were positive for the two markers, with the majority exhibiting a high expression. Analysis of the expression of Oct-4 revealed no statistically significant differences (p = 0.406) between the lesions studied. Regarding CD44, there was a significant difference between the cases of AMB and AOT in relation with OKC, with the latter presenting a greater labelling (p = 0.034). No statistically significant correlation between Oct-4 and CD44 was observed in the lesions. In our findings, the presence of stem cell-like phenotype at various sites of the epithelial component of the odontogenic lesions was identified, suggesting its possible participation in histogenesis and differentiation without, however, exerting influence on the aggressiveness of the lesions. PMID- 29971494 TI - Cochlear implantation in children with CHARGE syndrome: a report of eight cases. AB - OBJECTIVE: To report neuroradiologic findings, surgical strategies and clinical and audiological results in a series of children with CHARGE syndrome (CS) who had been evaluated for cochlear implantation (CI). STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral university hospital. PATIENTS: Eight profoundly deafened children with CS were included. Routine audiometric measurements, speech perception categories and speech intelligibility ratings were performed pre- and post-operatively. Neuroradiological and intraoperative findings, surgical planning, and post-operative complications were analyzed. RESULTS: Six children were profoundly deaf from birth and 2 had progressive hearing loss to profound levels. Cochlear nerve deficiency (CND) was noted in 5 out of the 6 patients with congenital sensorineural hearing loss (SNHL). Seven children underwent CI. Surgery was performed using standard transmastoid facial recess approach in 3 ears, subtotal petrosectomy in 3, and transmastoid single slit labyrinthotomy in one. Temporary facial palsy occurred in one patient. In the group of patients with congenital SNHL, 2 children benefitted from CI and developed spoken language; the remaining 3 children obtained improved access to environmental sounds and used signs and gestures as their main mode of communication. The two patients with progressive SNHL had preoperative verbal language and continued to use verbal language after CI. CONCLUSIONS: The constant presence of temporal bone anomalies in children with CS requires surgical expertise in performing non-standard approaches for safe and effective CI. Patients with progressive SNHL and normal cochlear nerves had satisfactory results with CI. Limited benefits have been observed in presence of CND. PMID- 29971496 TI - Impaired finger dexterity and nigrostriatal dopamine loss in Parkinson's disease. AB - Impaired finger dexterity occurs in Parkinson's disease (PD) and has been considered a limb-kinetic apraxia associated with primary sensory cortical dysfunction. To study the role of nigrostriatal dopamine loss and elementary parkinsonian motor deficits in impaired finger dexterity of PD. Thirty-two right handed untreated PD patients and 30 right-handed healthy controls were included. All patients underwent [18F] FP-CIT positron emission tomography studies. We examined the associations among unilateral coin rotation (CR) score, Unified Parkinson's Disease Rating Scale (UPDRS) subscores for bradykinesia and rigidity of the corresponding arm, and contralateral regional striatal dopamine transporter (DAT) uptake. We also measured the effect of oral levodopa dose on CR scores and UPDRS subscores. PD patients performed worse than controls on the CR task. Unilateral arm UPDRS bradykinesia scores were associated with DAT uptake in the contralateral putamen. The left CR score was associated with left arm bradykinesia and rigidity scores and DAT uptake in the right posterior putamen, whereas no such associations were found for the right CR score. There was a significant effect of handedness on the association of putamen DAT uptake with CR scores, but not with UPDRS subscores. An oral levodopa challenge improved CR scores and UPDRS subscores on both sides. Impaired finger dexterity in PD is related to elementary parkinsonian motor deficits and nigrostriatal dopamine loss. Impaired dominant hand dexterity associated with nigrostriatal dopamine loss seems to be compensated to some extent by the dominant cerebral cortex specialized for controlling precise finger movements. PMID- 29971497 TI - Thoraco-esophageal fistula during percutaneous tracheostomy. PMID- 29971495 TI - Levodopa-induced dyskinesia: clinical features, incidence, and risk factors. AB - Symptoms of Parkinson's disease have been controlled with levodopa for many years; however, motor complications consisting of wearing off of medication effect and dyskinesias tend to occur within a few years of starting levodopa. Motor complications can begin a few months after taking levodopa, with the average time to onset estimated to be 6.5 years. Dyskinesias can be troublesome and require intervention. Levodopa-induced dyskinesia can be composed of a variety of movement disorders including chorea, dystonia, ballism, myoclonus, and akathisia. Based on the clinical pattern, the most common dyskinesia is chorea and choreoathetosis. The clinical manifestations can be divided into three main categories based on their clinical movement patterns and the temporal correlation between the occurrence of dyskinesia and the levodopa dosing: on or peak-dose dyskinesias, biphasic dyskinesias, and Off dyskinesias. Severe cases of dyskinesia have been reported, with the extreme being dyskinesia-hyperpyrexia syndrome. The prevalence of LID has been reported in many studies, but the reported incidence varies. The rate of LID development is from 3 to 94%. The prevalence of LID mainly depends on age at onset, disease duration, and severity, and duration of levodopa therapy. Some of the risk factors for the development of dyskinesia are modifiable. Modifiable risk factors include levodopa dose and body weight. Non-modifiable risk factors include age, gender, duration of disease, clinical subtype, disease progression, disease severity, and genetic factors. PMID- 29971498 TI - A genetic variant located in the miR-532-5p-binding site of TGFBR1 is associated with the colorectal cancer risk. AB - BACKGROUND: Genome-wide association studies have identified genes in the transforming growth factor-beta (TGFbeta) signaling pathway that are responsible for regulating carcinogenesis. METHODS: We searched for single-nucleotide polymorphisms (SNPs) located within 3'-untranslated regions (3'-UTRs) that might affect the ability of miRNAs to bind genes in the TGFbeta pathway for further analysis. We used TaqMan technology to genotype these SNPs in a population-based case-control study of 1147 colorectal cancer patients and 1203 matched controls in a Chinese population. RESULTS: The rs1590 variant of TGFBR1 exhibited a significant association with colorectal cancer risk. Compared with individuals carrying the rs1590 TT genotype, individuals carrying the GT/GG genotypes had a decreased risk of colorectal cancer [odd ratio (OR) = 0.82, 95% confidence interval (CI) = 0.68-0.97], which was more evident among older individuals with a family history of cancer. Luciferase assays confirmed that the rs1590 T allele altered the capacity of miR-532-5p to bind TGFBR1. CONCLUSIONS: Based on these findings, the rs1590 variant in the 3'-UTR of TGFBR1 may contribute to the susceptibility to colorectal cancer, predominantly by altering miR-532-5p binding. PMID- 29971499 TI - Examination of 2-methacryloyloxyethyl phosphorylcholine polymer coated acrylic resin denture base material: surface characteristics and Candida albicans adhesion. AB - The aim of this study is to evaluate the effects of 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer coating with various concentrations onto acrylic resin denture base material on surface characteristics such as contact angle and surface roughness and on Candida albicans adhesion which is the major factor of denture stomatitis. Specimens, prepared from heat-polymerized acrylic denture base material, were divided into control and three test groups, randomly. Surfaces of the specimens in test groups were coated with poly(MPC) (PMPC) by graft polymerization of MPC in different concentrations (0.25 mol/L; 0.50 mol/L and 0.75 mol/L), while no surface treatment was applied to the control group. Contact angles and surface roughness were examined, and chemical composition of the surfaces was analyzed by Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy (FTIR) to verify the presence of PMPC coatings. Then, specimens were incubated with C. albicans for 18 h and the number of adhered cells was determined. Upon PMPC coating, the contact angle values statistically decreased, but no difference was found in surface roughness values. A statistically significant decrease was observed in C. albicans adhesion in parallel with the increase in the MPC polymer concentration. There was no significant difference between 0.50 mol/L and 0.75 mol/L groups in terms of adhesion. These findings indicated that graft polymerization of MPC on acrylic denture base material reduces the adhesion of C. albicans, and may be evaluated as a coating for prevention of denture stomatitis. PMID- 29971500 TI - Development of a Virosomal RSV Vaccine Containing 3D-PHAD(r) Adjuvant: Formulation, Composition, and Long-Term Stability. AB - PURPOSE: Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD(r) adjuvant. METHODS: Virosomes were initially formed by contacting a lipid film containing 3D-PHAD(r) with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO. RESULTS: Virosomes formed from lipid films contained the membrane glycoproteins G and F, at similar F to G ratios but lower concentrations than in virus, and the added lipids, but only a fraction of the 3D-PHAD(r). By single particle tracking (SPT), the virosome size distribution resembled that seen by cryo-electron microscopy, but dynamic light scattering showed much larger particles. These differences were caused by small virosome aggregates. Measured by SPT, virosomes were stable for 300 days. 3DPHAD (r) incorporation in virosomes could be enhanced by providing the adjuvant from DCPC solubilized stock, but also by adding DMSO dissolved adjuvant to pre-formed virosomes. Virosomes with 0.1 mg/mg of 3D-PHAD(r)/viral protein from DMSO induced antibody titers similar to those by virosomes containing 0.2 mg/mg of DCPC-solubilized 3D-PHAD(r). CONCLUSIONS: Stable 3D-PHAD(r) adjuvanted RSV virosomes can be formulated. PMID- 29971501 TI - Targeting the mitochondrial VDAC in hepatocellular carcinoma using a polyclonal antibody-conjugated to a nitrosyl ruthenium complex. AB - The rational design of anti-cancer agents includes a new approach based on ruthenium complexes that can act as nitric oxide (NO) donor agents against specific cellular targets. One of the most studied classes of those compounds is based on bis(bipyridine) ruthenium fragment and its derivative species. In this work, we present the chemical and cytotoxicity properties against the liver hepatocellular carcinoma cell line HepG2 of cis-[RuII(NO+)Cl(dcbpy)2]2- conjugated to a polyclonal antibody IgG (anti-VDAC) recognizing a cell surface marker. UV-visible bands of the ruthenium complex were assigned with the aid of density functional theory, which also allowed estimation of the structures that explain the biological effects of the ruthenium complex-IgG conjugate. The interaction of cis-[RuII(NO+)Cl(dcbpy)2]3- with mitochondria was evaluated due to the potential of these organelles as anti-cancer targets, and considering they interact with the anti-VDAC antibody. The cytotoxicity of cis [RuII(NO+)Cl(dcbpy)2]3--anti-VDAC antibody was up to 80% greater in comparison to the free cis-[RuII(NO+)Cl(dcbpy)2]3- complex. We suggest that this effect is due to site-specific interaction of the complex followed by NO release. PMID- 29971502 TI - Coarse taxonomy (tolerance-value averaging) biases Hilsenhoff's family-level biotic index. AB - Hilsenhoff's family-level index (FBI) combines information about the relative abundances of taxa and their tolerances to pollution. Versions of this index are used extensively in North America to assess water quality. When faced with constraints on time, money, or expertise, bioassessment practitioners have been tempted to calculate a version of the FBI with very coarse (e.g., order-level) taxonomy. Such an approach requires a degree of within-taxon averaging of tolerance values and raises questions about the degree to which accuracy is compromised and bias is introduced. Data from thousands of streams in Ontario (Canada) demonstrated that such tolerance-value averaging produces index scores and associated water-quality classifications that are not equivalent to those calculated with the standard family-level taxonomic precision. Two methods were used in an attempt to correct the order-level FBI scores to equivalence with the family-level index: (1) tolerance scores for the orders included in the calculation were calculated as abundance-weighted means of the scores of their component families, and (2) order-level FBI scores were estimated as predicted values from a polynomial regression of the two versions of the index. The use of abundance-weighted mean tolerance scores greatly improved the accuracy of the order-level index, and the regression-based correction reduced bias by equalizing the distribution of errors across the range of observed FBI values. Nonetheless, equivalence of scores was not demonstrated, and water quality was misclassified in 12 to 80% of cases. Practitioners are discouraged from the practice of tolerance-value averaging and are advised to adhere to the standard family-level FBI. PMID- 29971503 TI - Hip and spine bone mineral density are greater in master sprinters, but not endurance runners compared with non-athletic controls. AB - : We examined bone density in older athletes and controls. Sprinters had greater hip and spine bone density than endurance athletes and controls, whereas values were similar in the latter two groups. These results could not be explained by differences in impact, muscle size or power between sprint and endurance athletes. PURPOSE: We examined the relationship between prolonged participation in regular sprint or endurance running and skeletal health at key clinical sites in older age, and the factors responsible for any associations which we observed. METHODS: We recruited 38 master sprint runners (28 males, 10 females, mean age 71 +/- 7 years), 149 master endurance runners (111 males, 38 females, mean age 70 +/ 6 years) and 59 non-athletic controls (29 males, 30 females, mean age 74 +/- 5 years). Dual X-ray absorptiometry was used to assess hip and spine bone mineral density (BMD), body composition (lean and fat mass), whilst jump power was assessed with jumping mechanography. In athletes, vertical impacts were recorded over 7 days from a waist-worn accelerometer, and details of starting age, age graded performance and training hours were recorded. RESULTS: In ANOVA models adjusted for sex, age, height, body composition, and jump power, sprinter hip BMD was 10 and 14% greater than that of endurance runners and controls respectively. Sprinter spine BMD was also greater than that of both endurance runners and controls. There were no differences in hip or spine BMD between endurance runners and controls. Stepwise regression showed only discipline (sprint/endurance), sex, and age as predictors of athlete spine BMD, whilst these variables and starting age were predictive of hip BMD. CONCLUSIONS: Regular running is associated with greater BMD at the fracture-prone hip and spine sites in master sprinters but not endurance runners. These benefits cannot be explained by indicators of mechanical loading measured in this study including vertical impacts, body composition or muscular output. PMID- 29971505 TI - Structure and stability of propellane-like E[Formula: see text]. AB - Propellane-like structures are an important building block for group-14 compounds. Therefore, in the present work, we study theoretically various such structures of the form E[Formula: see text] starting with the pure molecules for which E = E' = E" = C, Si, Ge, or Sn. Subsequently, we study the systems with E ? E' = E" and finally, we consider some selected cases molecules for which E, E', and E" all are different. Special emphasis is put on identifying structural trends for the molecules with at least two different group-14 elements. The resulting scheme is, we believe, generally valid for group-14 based systems with more than one type of group-14 elements. PMID- 29971504 TI - Genetic variability and physiological traits of Saccharomyces cerevisiae strains isolated from "Vale dos Vinhedos" vineyards reflect agricultural practices and history of this Brazilian wet subtropical area. AB - Vale dos Vinhedos appellation of origin has a very recent history as industrial wine making region. In this study we investigated the genetic and phenotypic variability of Saccharomyces cerevisiae strains isolated from South-Brazilian vineyards in order to evaluate strain fermentation aptitude and copper and sulphites tolerance. Merlot grape bunches were collected from three vineyards and yeast isolation was performed after single bunch fermentation. High genotypic variability was found and most of the genotypes revealed to be vine-specific. No industrial strain dissemination was present in the sampled vineyards, although it has been wildly reported in traditional winemaking countries. From the phenotypic traits analysis these Brazilian native strains showed good fermentation performances, good tolerance to sulphites and, in particular, a high copper tolerance level. Copper is the most important metal in the formulation of fungicides against downy mildew (Plasmopara viticola), one of the most harmful disease of the vines, and other fungal pests. The high tolerance to copper suggests an environmental adaptation to the strong use of copper-based fungicides, requested by the wet subtropical climate. PMID- 29971506 TI - The role of dissolved oxygen content as a modulator of microbial polyhydroxyalkanoate synthesis. AB - Polyhydroxyalkanoates (PHAs) are a diverse class of bio-polymers synthesized by bacteria, usually during imbalanced growth conditions. Optimizing PHA productivity is highly dependent on the bioreactor oxygen transfer rate (OTR), which is an important consideration for process performance and economics, particularly with increasing scale. Relatively few in-depth studies are available regarding the effect of OTR and dissolved oxygen content (DOC) on PHA formation, synthesis rates, composition, and characteristics. This review examines past research studies on the effect of low DOC environments on production of short chain length (scl-) PHAs, synthesized by both pure and mixed cultures, in order to identify opportunities and gaps concerning the effect of DOC on production of medium-chain length (mcl-) PHAs, an area that has not been studied in detail. The literature indicates that production of scl-PHA (a reductive process) acts as an electron sink allowing cells to maintain balanced redox state at low DOC. Conversely, production of mcl-PHA via fatty acid de novo synthesis (also a reductive process) does not occur to any significant extent in low DOC environments, while mcl-PHA synthesis from fatty acids (an oxidative process) can be promoted in low DOC environments. The monomer composition, molecular mass, as well as physical and thermal properties of the polymer can change in response to OTR, but further research in this area is required for both scl- and mcl-PHAs. Process design and management of bioreactor OTR in PHA production might therefore be directed by the final application of the polymer rather than cost considerations. PMID- 29971507 TI - Correction to: Consensus on best practice standards for Fracture Liaison Service in the Asia-Pacific region. AB - In this article the name of the sixth author, E. Michael Lewiecki was rendered incorrectly. The publisher regrets this error and apologizes for the inconvenience caused. PMID- 29971509 TI - Relationship between spinal sagittal alignment and acetabular coverage: a patient matched control study. AB - INTRODUCTION: The significance of the relationship between the spine and hip joints has been frequently discussed. However, the relationship between acetabular coverage and spinal sagittal alignment has not been fully elucidated as previous studies did not adequately control for factors that might affect the spinopelvic alignment. The aim of this study was to elucidate the impact of acetabular coverage on spinal sagittal alignment by comparing patient groups matched on sex, age, and the presence of hip and anterior impingement pain. MATERIALS AND METHODS: We prospectively enrolled 30 women undergoing periacetabular osteotomy (PAO) for developmental dysplasia of the hip (DDH) and 30 women undergoing hip arthroscopic surgery (HAS) for labral tears. The lateral centre edge angle was measured on hip radiographs. In addition, the sagittal vertical axis, pelvic tilt, pelvic incidence, sacral slope (SS), and lumbar lordosis (LL) were measured on preoperative plain radiographs of the whole spine to assess the sagittal spinal alignment. Clinical and radiologic data were compared between the two groups (PAO vs. HAS). RESULTS: The patient groups did not differ in age and body mass index. The mean SS was significantly greater in the PAO group (41.6 degrees +/- 1.6 degrees ) than in the HAS group (35.3 degrees +/- 1.5 degrees ; P = 0.0039). Additionally, the mean LL was significantly greater in the PAO group (54.5 degrees +/- 2.0 degrees ) than in the HAS group (45.1 degrees +/- 1.9 degrees ; P = 0.0015). CONCLUSIONS: The SS and LL were greater in patients with DDH than in patients with hip pain, but without DDH. Patients with DDH might show lumbar hyperlordosis to rotate the pelvis anteriorly, increasing the anterosuperior acetabular coverage. PMID- 29971508 TI - Biomechanical and morphological stability of acellular scaffolds for tissue engineered heart valves depends on different storage conditions. AB - Currently available bioprosthetic heart valves have been successfully used clinically; however, they have several limitations. Alternatively, tissue engineering techniques can be used. However, there are limited data concerning the impact of storage conditions of scaffolds on their biomechanics and morphology. The aim of this study was to determine the effect of different storage conditions on the biomechanics and morphology of pulmonary valve dedicated for the acellular scaffold preparation to achieve optimal conditions to obtain stable heart valve prostheses. Scaffold can then be used for the construction of tissue-engineered heart valve, for this reason evaluation of these parameters can determine the success of the clinical application this type of bioprosthesis. Pulmonary heart valves were collected from adult porcines. Materials were divided into five groups depending on the storage conditions. Biomechanical tests were performed, both the static tensile test, and examination of viscoelastic properties. Extracellular matrix morphology was evaluated using transmission electron microscopy and immunohistochemistry. Tissue stored at 4 degrees C exhibited a higher modulus of elasticity than the control (native) and fresh acellular, which indicated the stiffening of the tissue and changes of the viscoelastic properties. Such changes were not observed in the radial direction. Percent strain was not significantly different in the study groups. The storage conditions affected the acellularization efficiency and tissue morphology. To the best of our knowledge, this study is the first that attributes the mechanical properties of pulmonary valve tissue to the biomechanical changes in the collagen network due to different storage conditions. Storage conditions of scaffolds for tissue-engineered heart valves may have a significant impact on the haemodynamic and clinical effects of the used bioprostheses. PMID- 29971510 TI - Effect of drug amlodipine on the charged lipid bilayer cell membranes DMPS and DMPS + DMPC: a molecular dynamics simulation study. AB - In this work, the effects of the anti-hypertensive drug amlodipine in native and PEGylated forms on the malfunctioning of negatively charged lipid bilayer cell membranes constructed from DMPS or DMPS + DMPC were studied by molecular dynamics simulation. The obtained results indicate that amlodipine alone aggregates and as a result its diffusion into the membrane is retarded. In addition, due to their large size aggregates of the drug can damage the cell, rupturing the cell membrane. It is shown that PEGylation of amlodipine prevents this aggregation and facilitates its diffusion into the lipid membrane. The interaction of the drug with negatively charged membranes in the presence of an aqueous solution of NaCl, as the medium, is investigated and its effects on the membrane are considered by evaluating the structural properties of the membrane such as area per lipid, thickness, lipid chain order and electrostatic potential difference between bulk solution and lipid bilayer surface. The effect of these parameters on the diffusion of the drug into the cell is critically examined and discussed. PMID- 29971511 TI - Zn-containing polymer nanogels promote cervical dentin remineralization. AB - OBJECTIVE: Nanogels designing for effective treatment of eroded cervical dentin lesions. MATERIALS AND METHODS: Polymethylmetacrylate-based nanoparticles (NPs) were doxycycline (D), calcium, or zinc loaded. They were applied on eroded cervical dentin. Treated surfaces were characterized morphologically by atomic force and scanning electron microscopy, mechanically probed by a nanoindenter to test nanohardness and Young's modulus, and chemically analyzed by Raman spectroscopy at 24 h and 7 days of storage. Data were submitted to ANOVA and Student-Newman-Keuls multiple comparisons tests. RESULTS: Dentin treated with Zn NPs attained the highest nanomechanical properties, mineralization, and crystallinity among groups. Nanoroughness was lower in Zn-treated surfaces in comparison to dentin treated with undoped gels. Dentin treated with Ca-NPs created the minimal calcification at the surface and showed the lowest Young's modulus at peritubular dentin. Intertubular dentin appeared remineralized. Dentinal tubules were empty in samples treated with D-NPs, partially occluded in cervical dentin treated with undoped NPs and Ca-NPs, and mineral covered when specimens were treated with Zn-NPs. CONCLUSIONS: Zn-loaded NPs permit functional remineralization of eroded cervical dentin. Based on the tested nanomechanical and chemical properties, Zn-based nanogels are suitable for dentin remineralization. CLINICAL RELEVANCE: The ability of zinc-loaded nanogels to promote dentin mineralization may offer new strategies for regeneration of eroded cervical dentin and effective treatment of dentin hypersensitivity. PMID- 29971512 TI - The Mucosal Scarring Index: reliability of a new composite index for assessing scarring following oral surgery. AB - OBJECTIVES: A critical and uniform assessment of mucosal scarring following oral surgery is needed to refine surgical decision-making. For that purpose, the Mucosal Scarring Index (MSI) was developed. MATERIALS AND METHODS: The MSI is a composite index based on five parameters: width, height/contour, color, suture marks, and overall appearance. Each parameter is assessed with a 0-1-2 score, yielding a MSI score ranging from 0 (no scar) to 10 (most extreme scar). Five periodontists, 5 prosthodontists, and 5 orthodontists assessed scarring using the new index on the basis of 30 clinical photographs of post-surgical sites. Cases had been carefully selected making sure that the complete spectrum of the index would be represented in the analysis. Duplicate evaluation was performed with a 2 h interval and in random order of cases. RESULTS: On a total of 450 assessments, the mean MSI amounted to 4.91 (SD 3.087) with no significant differences between scores given by periodontists (mean 4.65; SD 3.054), orthodontists (mean 5.04; SD 3.301), or prosthodontists (mean 4.81; SD 2.842) (p = 0.548). The MSI appeared a highly reliable index given excellent inter- as well as intra-examiner agreement (ICC > 0.9; p < 0.001). Clinicians agreed most on 'overall appearance' (kappa = 0.582; p < 0.001) and least on 'suture marks' (kappa = 0.352; p < 0.001). CONCLUSION: The MSI is an effective, easy-to-use, and reliable composite index to assess mucosal scarring following oral surgical procedures. CLINICAL RELEVANCE: The MSI can be used as an adjunct to other indices in the esthetic evaluation of oral surgical procedures. PMID- 29971514 TI - Disentangling the role of TRPM4 in hippocampus-dependent plasticity and learning: an electrophysiological, behavioral and FMRI approach. AB - Hippocampal long-term potentiation (LTP) has been extensively studied as a cellular model of learning and memory. Recently, we described a central function of the Transient Receptor Potential M4 (TRPM4) channel in hippocampal LTP in mice in vitro. Here, we used Trpm4 knock-out (Trpm4-/-) rats to scrutinize TRPM4's role in the intact brain in vivo. After having confirmed the previous in vitro findings in mice, we studied hippocampal synaptic plasticity by chronic recordings in freely moving rats, hippocampus-dependent learning by a behavioral battery and hippocampal-cortical connectivity by fMRI. The electrophysiological investigation supports an involvement of TRPM4 in LTP depending on the induction protocol. Moreover, an exhaustive analysis of the LTP kinetics point to mechanistic changes in LTP by trpm4 deletion. General behavior as measured by open field test, light-dark box and elevated plus maze was inconspicuous in Trpm4 /- rats. However, they showed a distinct deficit in spatial working and reference memory associated to the Barnes maze and T-maze test, respectively. In contrast, performance of the Trpm4-/- in the Morris water maze was unaltered. Finally, fMRI investigation of the effects of a strong LTP induction manifested BOLD responses in the ipsilateral and contralateral hippocampus and the prefrontal cortex of both groups. Yet, the initial BOLD response in the stimulated hippocampal area of Trpm4-/- was significantly enhanced compared to WT rats. Our findings at the cellular, behavioral and system level point to a relevant role for TRPM4 in specific types of hippocampal synaptic plasticity and learning but not in hippocampal-prefrontal interaction. PMID- 29971515 TI - Intraoperative diagnosis with abnormal branching of the left A8 pulmonary artery from the left main pulmonary artery. AB - BACKGROUND: Safety is of vital importance for lung resection. The dissection of pulmonary vessels is associated with vascular injury and bleeding, and identification of the vessels is necessary. The most common abnormal branching pattern of the left pulmonary artery is the mediastinal lingular artery. However, a mediastinal basal pulmonary artery is very rare. A case of abnormal branching from the left pulmonary artery to S8 which was diagnosed intraoperatively, and, thus, its dissection was avoided, is reported. CASE PRESENTATION: A 76-year-old woman with rheumatoid arthritis was diagnosed with left upper lung adenocarcinoma and visited our hospital. Contrast CT was not performed due to renal dysfunction, and abnormal branching of the left pulmonary artery was not identified. Video assisted thoracoscopic left upper lobectomy and lymphadenectomy were performed. After the upper pulmonary vein was dissected and tissue around it was detached carefully, a pulmonary mediastinal branch from the left main pulmonary artery was identified descending between the upper pulmonary vein and upper bronchus. It was possible to separate the interlobar fissure safely and preserve A8. On retrospective examination, non-contrast CT showed A8. CONCLUSIONS: Although preoperative identification of left pulmonary mediastinal branches was difficult by non-contrast CT, a careful surgical procedure preserved the left pulmonary mediastinal A8. PMID- 29971513 TI - Survival of dental implants placed in autogenous bone grafts and bone flaps in head and neck oncology patients: a systematic review. AB - Using implants to retain prostheses as part of the oral rehabilitation of head and neck cancer patients is an increasingly common treatment modality, particularly in transported bone which is used to reconstruct defects following oncological surgical resection. The aim of this systematic review is to evaluate the survival of dental implants placed into autogenous bone grafts and flaps, in head and neck cancer patients. MEDLINE, EMBASE, CENTRAL and Science Direct databases were searched (1980-August 2017) for studies evaluating intra-oral implant placement into autogenous bone grafts and flaps in H&N cancer patients. Twenty articles were included reporting on 1905 implants placed into autogenous bone in head and neck cancer patients. Implant survival varied from 54 to 100% within the studies with 11 studies reporting implant survival of over 90%. In conclusion, intra-oral implant survival in autogenous bone grafts in head and neck oncology patients is promising, however inconsistencies in data reporting and in outcome definitions precludes formal meta-analysis. PMID- 29971516 TI - Disease surveillance data sharing for public health: the next ethical frontiers. AB - In the recent years, we have been witnessing a digital revolution in public and global health creating unprecedented opportunities for epidemic intelligence and public health emergencies. However, these opportunities created a double edge sword as access to data, quality monitoring and assurance, as well as governance and regulation frameworks for data privacy are lagging behind technological achievements.In this paper we identify three ethical challenges: sharing data across various early warning tools to support risk assessment. Secondly, define the challenges to be addressed by the legal frameworks for public health data sharing to unlock the potential of population-level datasets for research with no impact on citizens privacy. The third challenge lies with stricter regulation of the IT industry with regards to manipulating user data - such an initiative, GDPR, comes to force in the EU in May 2018. PMID- 29971517 TI - Non-invasive kinetic modelling of PET tracers with radiometabolites using a constrained simultaneous estimation method: evaluation with 11C-SB201745. AB - BACKGROUND: Kinetic analysis of dynamic PET data requires an accurate knowledge of available PET tracer concentration within blood plasma over time, known as the arterial input function (AIF). The gold standard method used to measure the AIF requires serial arterial blood sampling over the course of the PET scan, which is an invasive procedure and makes this method less practical in clinical settings. Traditional image-derived methods are limited to specific tracers and are not accurate if metabolites are present in the plasma. RESULTS: In this work, we utilise an image-derived whole blood curve measurement to reduce the computational complexity of the simultaneous estimation method (SIME), which is capable of estimating the AIF directly from tissue time activity curves (TACs). This method was applied to data obtained from a serotonin receptor study (11C SB207145) and estimated parameter results are compared to results obtained using the original SIME and gold standard AIFs derived from arterial samples. Reproducibility of the method was assessed using test-retest data. It was shown that the incorporation of image-derived information increased the accuracy of total volume of distribution (V T) estimates, averaged across all regions, by 40% and non-displaceable binding potential (BP ND) estimates by 16% compared to the original SIME. Particular improvements were observed in K1 parameter estimates. BP ND estimates, based on the proposed method and the gold standard arterial sample-derived AIF, were not significantly different (P=0.7). CONCLUSIONS: The results of this work indicate that the proposed method with prior AIF information obtained from a partial volume corrected image-derived whole blood curve, and modelled parent fraction, has the potential to be used as an alternative non invasive method to perform kinetic analysis of tracers with metabolite products. PMID- 29971518 TI - Photobiomodulation therapy reduces viral load and cell death in ZIKV-infected glioblastoma cell line. PMID- 29971519 TI - Fear avoidance and self-efficacy at 4 weeks after ACL reconstruction are associated with early impairment resolution and readiness for advanced rehabilitation. AB - PURPOSE: To examine the association of fear avoidance and self-efficacy psychological factors within 4 weeks after anterior cruciate ligament (ACL) reconstruction with knee impairment resolution and readiness for advanced rehabilitation at 12 weeks post-surgery. METHODS: Seventy-five patients participated. Data collection included demographics; questionnaires on fear avoidance (Pain Catastrophizing Scale, PCS; shortened Tampa Scale for Kinesiophobia, TSK-11) and self-efficacy (modified Self-Efficacy for Rehabilitation Outcome Scale, SER; Knee Activity Self-Efficacy, KASE) at 1, 4, and 12 weeks post-surgery; and knee impairment measures (pain intensity, range of motion, and quadriceps symmetry index) at 12 weeks post-surgery. Readiness for advanced rehabilitation (READY or NOT READY) was determined by knee impairment resolution criteria; demographics and questionnaire scores were compared between groups. Questionnaire scores at 1 and 4 weeks post-surgery and the change between time points were examined for association with knee impairment measures and group assignment. RESULTS: READY included 32 patients; NOT READY included 43 patients. Questionnaire scores improved in both groups over time. Significant correlations across groups were: PCS scores at 1 and 4 weeks post-surgery with pain intensity at 12 weeks post-surgery (r = 0.24 and 0.29, respectively) and KASE score 4 weeks post-surgery with range of motion deficit at 12 weeks post-surgery (r = - 0.26). Contact injury was more prevalent in READY. After accounting for mechanism of injury, higher TSK-11 and fear of re-injury subscale scores at 4 weeks post surgery increased the odds of NOT READY assignment at 12 weeks post-surgery (odds ratios 1.10 and 1.31, respectively). CONCLUSIONS: Lower pain catastrophizing and higher knee activity self-efficacy levels 4 weeks after ACL reconstruction were associated with better knee impairment resolution at 12 weeks post-surgery, whereas lower kinesiophobia at 4 weeks post-surgery increased the odds of meeting advanced rehabilitation criteria at 12 weeks post-surgery. The clinical implication of these findings is that measuring pain catastrophizing, knee activity self-efficacy and kinesiophobia at 4 weeks post-surgery may improve prediction of patients at risk for delayed rehabilitation progression 12 weeks post-surgery. LEVEL OF EVIDENCE: III. PMID- 29971520 TI - Surveying the management of Achilles tendon ruptures in the Netherlands: lack of consensus and need for treatment guidelines. AB - PURPOSE: This study aimed to describe and analyse usual care of Achilles tendon ruptures (ATRs) by orthopaedic surgeons and trauma surgeons in the Netherlands. METHODS: A nationwide online survey of ATR management was sent to all consultant orthopaedic and trauma surgeons in the Netherlands, requesting participation of those involved in ATR management. Data on individual characteristics and the entire ATR management (from diagnosis to rehabilitation) were gathered. Consensus was defined as >= 70% agreement on an answer. RESULTS: A total of 91 responses (70 orthopaedic surgeons and 21 trauma surgeons) were analysed. There was consensus on the importance of the physical examination in terms of diagnosis (> 90%) and a lack of consensus on diagnostic imaging (ultrasound/MRI). There was consensus that non-surgical treatment is preferred for sedentary and systemically diseased patients and surgery for patients who are younger and athletic and present with larger tendon gap sizes. There was consensus on most of the non surgical methods used: initial immobilisation in plaster cast with the foot in equinus position (90%) and its gradual regression (82%) every 2 weeks (85%). Only length of immobilisation lacked consensus. Surgery was generally preferred, but there was a lack of consensus on the entire followed protocol. Orthopaedic and trauma surgeons differed significantly on their surgical (p = 0.001) and suturing techniques (p = 0.002) and methods of postoperative immobilisation (p < 0.001). Orthopaedic surgeons employed open repair and Bunnell sutures more often, whereas trauma surgeons used minimally invasive approaches and bone anchors. Rehabilitation methods and advised time until weight-bearing and return to sport varied. Orthopaedic surgeons advised a significantly longer time until return to sport after both non-surgical treatment (p = 0.001) and surgery (p = 0.002) than trauma surgeons. CONCLUSION: This is the first study to describe the entire ATR management. The results show a lack of consensus and wide variation in management of ATRs in the Netherlands. This study shows that especially the methods of the perioperative and rehabilitation phases were inconclusive and differed between orthopaedic and trauma surgeons. Further research into optimal ATR management regimens is recommended. In addition, to achieve uniformity in management more multidisciplinary collaboration between Dutch and international surgeons treating ATRs is needed. LEVEL OF EVIDENCE: Cross-sectional survey, Level V. PMID- 29971521 TI - R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome. AB - TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking. PMID- 29971522 TI - The effect of a coix seed oil injection on cancer pain relief. AB - BACKGROUND: Pain is one of the most commonly reported symptoms in patients with advanced cancer, but is still less than optimally treated. The effect of traditional Chinese medicine in cancer pain treatment is nowadays getting more and more attention. OBJECTIVE: To investigate the effect of a coix seed oil injection on cancer pain relief in a cancer center in a tertiary hospital in China. METHODS: Patients in the treatment group received a coix seed oil injection for 2 weeks, while patients in the control group received equivalent 0.9% saline. The numeric rating scale was used to assess the pain level. The Quality of Life Questionnaire-Core 30 was used to assess life quality. The adverse drug reactions during the treatment process were observed. RESULTS: Patients in the coix seed treatment group had significantly superior efficacy on pain control over those in the control group. Coix seed therapy significantly improved patients' scores reflecting by the Quality of Life Questionnaire-Core 30 (QLQ-C30) scale. In addition, the occurrence of adverse reactions such as constipation and nausea in the treatment group was significantly lower than that in the control group. CONCLUSION: The coix seed oil injection effectively reduced the pain level of cancer patients, significantly improved their life quality, and had no obvious adverse effects. PMID- 29971523 TI - Nuclear dynamics in the homothallic ascomycete Sordaria fimicola. AB - BACKGROUND: The coprophilous ascomycete Sordaria fimicola usually reproduces sexually. Sexual differentiation in S. fimicola is accompanied by cellular and morphological changes, followed by multicellular tissue development to complete the sexual cycle. Although the morphological features of the sexual reproductive structure in S. fimicola have been well characterized, little is known about the nuclear dynamics and organization during these processes. Therefore, in this study, we successfully developed an Agrobacterium-mediated protoplast transformation protocol and generated histone H2B-mCherry-labeled S. fimicola strains. The life cycle of S. fimicola begins with germination of the ascospore and ends with the formation and discharge of new ascospores from the mature black sexual fruiting bodies, the so-called perithecia. The nuclear dynamics of the fluorescently labeled strains were examined during ascospore germination, hyphal elongation, and hyphal fusion using fluorescent microscopy. RESULTS: Live imaging revealed that the nuclei in the germlings and fusion hyphae during the pre contact interaction are located adjacent to the tip. CONCLUSIONS: This is the first report of the application of a fluorescence labeling technique in S. fimicola. This application will help researchers gain a better understanding of nuclear distribution and investigate the protein-protein interaction networks during fruiting body formation for advanced molecular genetic studies in S. fimicola. PMID- 29971524 TI - Neurological sciences impact factor 2017 is increased to 2.285: a comment from the Editor in Chief. PMID- 29971525 TI - Aggressive immunosuppression in Susac's syndrome: 10 years of follow-up. PMID- 29971526 TI - Modulation of brain kisspeptin expression after bisphenol-A exposure in a teleost fish, Catla catla. AB - Endocrine-disrupting chemicals (EDCs) affect the neuroendocrine system which in turn influences the reproductive regulation. Neuronal genes disrupted by EDCs are the gonadotropin-releasing hormone (gnrh2), the Kiss/GPR54 system that regulates gonadotropin release and cyp19b gene encoding brain aromatase. In the present study, pubertal Catla catla expected to spawn for first the time in the coming season were exposed to graded concentration of bisphenol-A (10, 100, 1000 MUg/l) for 14 days. Messenger RNA (mRNA) levels of neuroendocrine genes, i.e., kisspeptins and their receptors, gonadotropin-releasing hormone type II and brain aromatase were studied after 14 days exposure. Results showed that bisphenol-A (BPA) strongly upregulated expression of kiss1, kiss2, gpr54a, and gnrh2 in fish exposed to 10 MUg/l BPA. Fish exposed to 1000 MUg/l BPA, expression of kiss1 and gnrh2 were comparable to control while kiss2 mRNA increased compared to controls. Brain aromatase (cyp19b) mRNA expression increased in fish exposed to both 10 and 1000 MUg/l BPA. These results indicate that BPA exposure can disrupt organization of the kisspeptin signaling pathways. This neuroendocrine disruption may be the underlying mechanism by which a suite of reproductive abnormalities are induced. PMID- 29971527 TI - Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo controlled study. AB - AIMS/HYPOTHESIS: The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non alcoholic fatty liver disease (NAFLD). METHODS: This randomised placebo controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). RESULTS: Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m2 (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, -15%; dapagliflozin, -13%; OM-3CA + dapagliflozin, -21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, -24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase (gamma-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in gamma-GT correlated with changes in liver PDFF (rho = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. CONCLUSIONS/INTERPRETATION: Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02279407 FUNDING: The study was funded by AstraZeneca. PMID- 29971528 TI - Dietary manganese and type 2 diabetes mellitus: two prospective cohort studies in China. AB - AIMS/HYPOTHESIS: The association between dietary Mn and type 2 diabetes is unclear. We aimed to elucidate whether dietary Mn is associated with type 2 diabetes, to investigate whether this association is independent of dietary total antioxidant capacity (TAC) and to explore the underlying mechanisms in their association. METHODS: Two prospective cohorts of 3350 and 7133 Chinese adults (20 74 years old) were enrolled including, respectively, 244 and 578 individuals newly diagnosed with type 2 diabetes, with mean values of 4.2 and 5.3 years of follow-up. Cox's proportional-hazards regression and linear regression were performed to investigate the association between dietary Mn and type 2 diabetes (diagnosed by OGTT) or HbAlc and to analyse the joint association between dietary Mn and TAC. Restricted cubic spline (RCS) regression was applied to the non linear association between dietary Mn and incidence of type 2 diabetes. Mediation analysis was applied to explore potential mediators in their association in a subgroup of 500 participants. RESULTS: Dietary Mn intakes were 4.58 +/- 1.04 and 4.61 +/- 1.08 (mean +/- SD) mg/day in the two cohorts. Dietary Mn was inversely associated with type 2 diabetes incidence and HbAlc concentration in both cohorts (ptrend < 0.01 and <0.01 for type 2 diabetes, and ptrend < 0.01 and =0.02 for HbAlc, respectively, in each cohort) independent of TAC, adjusted for age, sex, BMI, tobacco use, alcohol consumption, physical activity, diabetes inheritance, total energy, carbohydrate, total fatty acids, fibre, calcium, Mg, hypertension, hyperlipidaemia, and impaired glucose tolerance or FBG (all at baseline). Their inverse association was stronger in the presence of diets with high, compared with low, TAC. In RCS, intakes of >6.01 and 6.10-6.97 mg/day were associated with a significantly lower type 2 diabetes incidence in the two respective cohorts. Mediation analysis showed that high plasma Mn and low oxidative stress (increased Mn superoxide dismutase and decreased 8-hydroxydeoxyguanosine) contributed to the association between dietary Mn and both type 2 diabetes and HbAlc. CONCLUSIONS/INTERPRETATION: Dietary Mn was inversely associated with type 2 diabetes independently of TAC. In addition, this association was stronger in a high- rather than low-TAC diet. Plasma Mn and oxidative stress were mediators in the association between dietary Mn and type 2 diabetes. Future studies on absolute Mn intake should be conducted to study the potential non-linearity and optimal levels of dietary Mn and type 2 diabetes. PMID- 29971529 TI - Bioengineered human pseudoislets form efficiently from donated tissue, compare favourably with native islets in vitro and restore normoglycaemia in mice. AB - AIMS/HYPOTHESIS: Islet transplantation is a treatment option that can help individuals with type 1 diabetes become insulin independent, but inefficient oxygen and nutrient delivery can hamper islet survival and engraftment due to the size of the islets and loss of the native microvasculature. We hypothesised that size-controlled pseudoislets engineered via centrifugal-forced-aggregation (CFA PI) in a platform we previously developed would compare favourably with native islets, even after taking into account cell loss during the process. METHODS: Human islets were dissociated and reaggregated into uniform, size-controlled CFA PI in our microwell system. Their performance was assessed in vitro and in vivo over a range of sizes, and compared with that of unmodified native islets, as well as islet cell clusters formed by a conventional spontaneous aggregation approach (in which dissociated islet cells are cultured on ultra-low-attachment plates). In vitro studies included assays for membrane integrity, apoptosis, glucose-stimulated insulin secretion assay and total DNA content. In vivo efficacy was determined by transplantation under the kidney capsule of streptozotocin-treated Rag1-/- mice, with non-fasting blood glucose monitoring three times per week and IPGTT at day 60 for glucose response. A recovery nephrectomy, removing the graft, was conducted to confirm efficacy after completing the IPGTT. Architecture and composition were analysed by histological assessment via insulin, glucagon, pancreatic polypeptide, somatostatin, CD31 and von Willebrand factor staining. RESULTS: CFA-PI exhibit markedly increased uniformity over native islets, as well as substantially improved glucose stimulated insulin secretion (8.8-fold to 11.1-fold, even after taking cell loss into account) and hypoxia tolerance. In vivo, CFA-PI function similarly to (and potentially better than) native islets in reversing hyperglycaemia (55.6% for CFA PI vs 20.0% for native islets at 500 islet equivalents [IEQ], and 77.8% for CFA PI vs 55.6% for native islets at 1000 IEQ), and significantly better than spontaneously aggregated control cells (55.6% for CFA-PI vs 0% for spontaneous aggregation at 500 IEQ, and 77.8% CFA-PI vs 33.4% for spontaneous aggregation at 1000 IEQ; p < 0.05). Glucose clearance in the CFA-PI groups was improved over that in the native islet groups (CFA-PI 18.1 mmol/l vs native islets 29.7 mmol/l at 60 min; p < 0.05) to the point where they were comparable with the non transplanted naive normoglycaemic control mice at a low IEQ of 500 IEQ (17.2 mmol/l at 60 min). CONCLUSIONS/INTERPRETATION: The ability to efficiently reformat dissociated islet cells into engineered pseudoislets with improved properties has high potential for both research and therapeutic applications. PMID- 29971530 TI - Molecular dynamics simulations suggest why the A2058G mutation in 23S RNA results in bacterial resistance against clindamycin. AB - Clindamycin, a lincosamide antibiotic, binds to 23S ribosomal RNA and inhibits protein synthesis. The A2058G mutation in 23S RNA results in bacterial resistance to clindamycin. To understand the influence of this mutation on short-range interactions of clindamycin with 23S RNA, we carried out full-atom molecular dynamics simulations of a ribosome fragment containing clindamycin binding site. We compared the dynamical behavior of this fragment simulated with and without the A2058G mutation. Molecular dynamics simulations suggest that clindamycin in the native ribosomal binding site is more internally flexible than in the A2058G mutant. Only in the native ribosome fragment did we observe intramolecular conformational change of clindamycin around its C7-N1-C10-C11 dihedral. In the mutant, G2058 makes more stable hydrogen bonds with clindamycin hindering its conformational freedom in the ribosome-bound state. Clindamycin binding site is located in the entrance to the tunnel through which the newly synthesized polypeptide leaves the ribosome. We observed that in the native ribosome fragment, clindamycin blocks the passage in the tunnel entrance, whereas in the mutated fragment the aperture is undisturbed due to a different mode of binding of clindamycin in the mutant. Restricted conformational freedom of clindamycin in a position not blocking the tunnel entrance in the A2058G mutant could explain the molecular mechanism of bacterial resistance against clindamycin occurring in this mutant. PMID- 29971531 TI - Molecular subtype predicts incidence and prognosis of brain metastasis from breast cancer in SEER database. AB - PURPOSE: To evaluate the impact of molecular subtype on incidence and prognosis of brain metastasis from breast cancer. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 18 registry was used to select breast cancer patients from 2010 to 2014. Molecular subtypes were classified as luminal A (hormone receptor [HR]+/human epidermal growth factor receptor 2 [HER2]-), luminal B (HR+/HER2+), HER2 (HR-/HER2+), or triple negative breast cancer (TNBC) (HR-/HER2-). The incidence and prognosis of brain metastasis was evaluated according to molecular subtype. RESULTS: Among the 206913 breast cancer patients, the HER2 subtype showed the highest incidence of brain metastasis (1.0%). HER2 and TNBC with multiple extracranial metastases (bone, liver, and lung) showed a high incidence of brain metastasis (28.0 and 30.8%, respectively). Median survival of luminal A, luminal B, HER2, and TNBC in brain metastasis was 12, 23, 10, and 6 months (p < 0.001), and in brain metastasis without visceral metastasis was 14, 34, 17, and 8 months (p < 0.001). On multivariate analysis, the order of subtype by favorable prognosis was luminal B, luminal A, HER2, and TNBC in all brain metastasis, while for brain metastasis patients without visceral metastasis, the order was luminal B, HER2, luminal A, and TNBC. CONCLUSIONS: Molecular subtype and visceral metastasis should be considered for prediction of prognosis for patients with brain metastasis. The patients with HER2 and TNBC cancer subtypes having visceral metastasis, close surveillance could contribute to early detection of brain metastasis and may putatively lead to improved quality of life and survival. PMID- 29971534 TI - What Justifies Judgments of Inauthenticity? AB - The notion of authenticity, i.e., being "genuine," "real," or "true to oneself," is sometimes held as critical to a person's autonomy, so that inauthenticity prevents the person from making autonomous decisions or leading an autonomous life. It has been pointed out that authenticity is difficult to observe in others. Therefore, judgments of inauthenticity have been found inadequate to underpin paternalistic interventions, among other things. This article delineates what justifies judgments of inauthenticity. It is argued that for persons who wish to live according to the prevailing social and moral standards and desires that are seriously undesirable according to those standards, it is justified to judge that a desire is inauthentic to the extent that it is due to causal factors that are alien to the person and to the extent that it deviates from the person's practical identity. The article contributes to a tradition of thinking about authenticity which is known mainly from Frankfurt and Dworkin, and bridges the gap between theoretical ideals of authenticity and real authenticity-related problems in practical biomedical settings. PMID- 29971532 TI - Cell growth potential drives ferroptosis susceptibility in rhabdomyosarcoma and myoblast cell lines. AB - PURPOSE: Ferroptosis is a programmed form of iron-dependent cell death caused by lipid hydroperoxide accumulation, which can be prevented by glutathione peroxidase 4 (GPx4) activity. Here we investigated the effects of ferroptosis inducers called erastin and RSL3, which act by glutathione depletion and GPx4 inactivation, respectively, on muscle-derived cell lines of embryonal and alveolar rhabdomyosarcoma (RMS), and mouse normal skeletal C2C12 myoblasts. METHODS: Myogenic lines were exposed to stepwise increasing concentrations of ferroptosis inducers either alone or in combination with iron supplementation, iron chelating agents (bathophenanthrolinedisulfonic acid, BPS), antioxidant molecules (glutathione, N-acetylcysteine), lipid peroxidation inhibitors (ferrostatin-1), and chemotherapeutic agents (doxorubicin and actinomycin D). Drug susceptibility was quantified by measuring cell viability, proliferation and differentiation via neutral red assay, crystal violet assay and Giemsa staining, respectively. The detection of lipid hydroperoxide and protein levels was performed by immunofluorescence and Western blot analysis, respectively. RESULTS: Erastin and RSL3 increased lipid hydroperoxide levels preferentially in the embryonal U57810 and myoblast C2C12 lines, leading to ferroptosis that was accentuated by iron supplementation or prevented by co-treatment with BPS, glutathione, N-acetylcysteine and ferrostatin-1. The inhibition of extracellular regulated kinases (ERK) pathway prevented ferroptosis in U57810 and C2C12 cells, whereas its increased activation in the embryonal RD cells mediated by caveolin-1 (Cav-1) overexpression led to augmented ferroptosis susceptibility. Finally, we observed the combination of erastin or RSL3 with chemotherapeutic doxorubicin and actinomycin D agents to be effective in increasing cell death in all RMS lines. CONCLUSIONS: Erastin and RSL3 trigger ferroptosis in highly proliferating myogenic lines through a ERK pathway-dependent fashion. PMID- 29971535 TI - [Orbital neoplasia causing proptosis]. PMID- 29971536 TI - [Systematic literature search in PubMed : A short introduction]. AB - In order to identify current (and relevant) evidence for a specific clinical question within the unmanageable amount of information available, solid skills in performing a systematic literature search are essential. An efficient approach is to search a biomedical database containing relevant literature citations of study reports. In this article, we explain step by step how to perform a systematic literature search via PubMed (MEDLINE) by means of an example research question in the field of ophthalmology. First, we demonstrate how to translate the clinical problem into a well-framed and searchable research question, how to identify relevant search terms and how to conduct a text word search and a search with keywords in MeSH terms. We then show how to limit the number of search results if the search yields too many irrelevant hits and how to increase the number in the case of too few citations. Finally, we summarize all essential principles that guide a literature search via PubMed. PMID- 29971533 TI - Autophagy-regulating microRNAs: potential targets for improving radiotherapy. AB - BACKGROUND: Radiotherapy (RT) is one of the most important therapeutic strategies against cancer. However, resistance of cancer cells to radiation remains a major challenge for RT. Thus, novel strategies to overcome cancer cell radioresistance are urgent. Macroautophagy (hereafter referred to as autophagy) is a biological process by which damaged cell components can be removed and accordingly represent a cytoprotective mechanism. Because radiation-induced autophagy is associated with either cell death or radioresistance of cancer cells, a deeper understanding of the autophagy mechanism triggered by radiation will expedite a development of strategies improving the efficacy of RT. MicroRNAs (miRNAs) are involved in many biological processes. Mounting evidence indicates that many miRNAs are involved in regulation of the autophagic process induced by radiation insult, but the underlying mechanisms remain obscure. Therefore, a deep understanding of the mechanisms of miRNAs in regulating autophagy and radioresistance will provide a new perspective for RT against cancer. METHODS: We summarized the recent pertinent literature from various electronic databases, including PubMed. We reviewed the radiation-induced autophagy response and its association of the role, function and regulation of miRNAs, and discussed the feasibility of targeting autophagy-related miRNAs to improve the efficacy of RT. CONCLUSION: The beneficial or harmful effect of autophagy may depend on the types of cancer and stress. The cytoprotective role of autophagy plays a dominant role in cancer RT. For most tumor cells, reducing radiation-induced autophagy can improve the efficacy of RT. MiRNAs have been confirmed to take part in the autophagy regulatory network of cancer RT, the autophagy-regulating miRNAs therefore could be developed as potential targets for improving RT. PMID- 29971537 TI - [Hearing preservation in children with electric-acoustic stimulation after cochlear implantation : Outcome after electrode insertion with minimal insertion trauma (German version)]. AB - BACKGROUND: Cochlear implantation in patients with functional residual low frequency hearing is performed according to an established hearing-preserving surgical technique in order to cause minimal trauma of inner ear structures. Due to the increasing number of cochlear implants in children, the preservation of residual hearing is becoming increasingly important in this patient collective. OBJECTIVES: Short- and mid-term hearing preservation outcome in pediatric patients is investigated. MATERIALS AND METHODS: A group of 9 children (12 ears) between 5 and 12 years of age were examined after hearing-assisted cochlear implantation with respect to the pure tone audiometric thresholds. Retrospectively, short-term hearing preservation (up to 3 months after surgery) was examined. In a subgroup of 5 children, mid-term hearing preservation (7.5 to 16 months after surgery) was also analyzed. The mean values of hearing preserved (HL%) and hearing loss (HL) due to electrode insertion were calculated as measured values. RESULTS: In the whole group, the mean values of the preoperative PTAlow were 29.8 dB and the short-term postoperative PTAlow 42.6 dB. The mean value of the HL% was 73.6%, corresponding to an HL of 9.4 dB. In the subgroup, the mean PTAlow postoperatively was 46.0 dB in the mid-term and the HL% at 80.7% with a HL of 6.6 dB. CONCLUSIONS: The results in children are consistent with the results in adults. Electric-acoustic stimulation (EAS) should be used in the treatment of children with existing low-frequency residual hearing, as good residual hearing preservation can also be achieved in children after implantation. PMID- 29971539 TI - [Dementia in hospital, practice and outpatient treatment-a challenge for continuous qualification, education and interdisciplinary cooperation]. PMID- 29971538 TI - 'Hepworth hitch': parastomal hernia prevention by simple modifications of operative techniques. PMID- 29971544 TI - Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study. AB - Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50 mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1 mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFkappaB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis. PMID- 29971545 TI - When task sharing reduces interference: evidence for division-of-labour in Stroop like tasks. AB - Performing a task with another person may either enhance or reduce the interference produced by task-irrelevant information. In three experiments, we employed the joint version of a Stroop-like task (i.e., the picture-word interference-PWI-task) to investigate some of the task features that seem to be critical in determining the effect of task-irrelevant information when the task is shared between two individuals. Participants were asked to perform a PWI task, which required to name a picture while ignoring a distractor word, first individually (in a baseline block of trials) and then co-acting with an alleged partner. Results showed that, compared to the baseline and to a condition in which participants continued to perform the PWI task individually, the belief of co-acting with another individual who was thought to be in charge of the distractor words suppressed the semantic interference effect when these words were in case alternation letters (e.g., "mOuSe"). Conversely, the semantic interference effect persisted when the co-actor was thought to be in charge of the same task as the participant, that is, the co-actor was thought to respond to the pictures. These results are accounted for by assuming that, when the participant knows that another person is in charge of the task-irrelevant information, a division-of-labour between participant and co-actor can be established. Such a division-of-labour may provide the participant with a strategy to oppose the semantic interference effect. Our findings, therefore, suggest that sharing a task with another person in charge of potentially interfering information can enable people to filter out this information from their own task representation. PMID- 29971543 TI - Maresin 1 attenuates pro-inflammatory reactions and ER stress in HUVECs via PPARalpha-mediated pathway. AB - The current study was designed to investigate the therapeutic effects of Maresin 1 (MAR1) on atherosclerotic response. Human monocytes THP-1 and human umbilical vein endothelial cells (HUVECs) were used to investigate the effects of MAR1 on lipopolysaccharide (LPS)-induced inflammation and apoptosis. In this study, we found that MAR1 induces peroxisome proliferator-activated receptor alpha (PPARalpha) expression. We also demonstrated that MAR1 suppresses atherosclerotic reactions caused by LPS treatment via a PPARalpha-dependent pathway. MAR1 treatment inhibited LPS-induced phosphorylation of nuclear factor kappa B (NF kappaB) and secretion of pro-inflammatory cytokines in HUVECs and THP-1 cells. In HUVEC cells, expression of adhesion molecules and LPS-stimulated adhesion of THP 1 cells to the endothelium were significantly decreased after MAR1 treatment. Furthermore, LPS-induced endoplasmic reticulum (ER) stress and cell apoptosis was significantly decreased after MAR1 treatment of HUVECs. MAR1 also led to a dose dependent increase in oxygen-regulated protein 150 (ORP150) expression which is responsible for the inhibition of ER stress. Notably, all of the pro atherosclerotic effects were completely abrogated by treatment with small interfering (si) RNA targeting PPARalpha. In conclusion, MAR1 ameliorates LPS induced atherosclerotic reactions via PPARalpha-mediated suppression of inflammation and ER stress. PMID- 29971546 TI - Leptomeningeal recurrence after long-term alectinib therapy for non-small cell lung cancer harboring an EML4-ALK fusion protein. AB - The recent approval of anaplastic lymphoma kinase (ALK) inhibitors for the treatment of ALK-rearranged non-small cell lung cancer (NSCLC) has dramatically transformed cancer therapy. However, leptomeningeal metastases (LM) are frequent and often devastating complications of ALK-rearranged NSCLC, and treatment against LM remains challenging. Herein we report a case of a 19-year-old male diagnosed with ALK-rearranged NSCLC with LM. He experienced heavy treatment before introduction of alectinib therapy, which continued for approximately 5.5 years with marked efficacy. However, he experienced recurrence of a bulbar metastasis after discontinuation of alectinib. Reintroduction of standard-dose alectinib therapy resolved the lesion again. Our findings suggest that ALK tyrosine kinase inhibitor therapy should be continued in patients showing a long term complete response, unless intolerable toxicities are present, and that rechallenge treatment with alectinib may represent a therapeutic option for central nervous system metastases. PMID- 29971547 TI - Molecular cloning, identification of GSTs family in sunflower and their regulatory roles in biotic and abiotic stress. AB - Glutathione-S-transferase (GST) genes exist widely in plants and play major role in metabolic detoxification of exogenous chemical substances and oxidative stress. In this study, 14 sunflower GST genes (HaGSTs) were identified based on the sunflower transcriptome database that we had constructed. Full-length cDNA of 14 HaGTSs were isolated from total RNA by reverse transcription PCR (RT-PCR). Sunflower was received biotic stress (Sclerotinia sclerotiorum) and abiotic stress (NaCl, low-temperature, drought and wound). GST activity was measured by using the universal substrate. The results showed that most of the HaGSTs were up regulated after NaCl and PEG6000-induced stresses, while a few HaGSTs were up regulated after S. sclerotiorum, hypothermia and wound-induced stressed, and there was correlation between the changes of GST activity and the expression of HaGSTs, indicating that HaGSTs may play regulatory role in the biotic and abiotic stress responses. 14 HaGSTs from sunflower were identified, and the expression of HaGSTs were tissue-specific and played regulatory roles in both stress and abiotic stress. PMID- 29971549 TI - [Universities and medicine]. AB - History of universities with special emphasis on medicine as part of universities is presented as a short survey. Particular attention is thereby focused on the development of university based medical schools in Austria, especially in the city of Vienna. The importance of Abraham Flexner for both the US and european medical schools is recognized. The Bologna-system of european curriculum design is mentioned as well as the development of non-public universities in Austria. Finally the peculiarity of the development of medical schools in Austria within the past twenty years is addressed. Digressions on Humboldt's vision of university and on lectures as an essential didactic item in universities are integrated within the text. PMID- 29971548 TI - Theoretical models to predict the inhibitory effect of ligands of sphingosine kinase 1 using QTAIM calculations and hydrogen bond dynamic propensity analysis. AB - We report here the results of two theoretical models to predict the inhibitory effect of inhibitors of sphingosine kinase 1 that stand on different computational basis. The active site of SphK1 is a complex system and the ligands under the study possess a significant conformational flexibility; therefore for our study we performed extended simulations and proper clusterization process. The two theoretical approaches used here, hydrogen bond dynamics propensity analysis and Quantum Theory of Atoms in Molecules (QTAIM) calculations, exhibit excellent correlations with the experimental data. In the case of the hydrogen bond dynamics propensity analysis, it is remarkable that a rather simple methodology with low computational requirements yields results in excellent accord with experimental data. In turn QTAIM calculations are much more computational demanding and are also more complex and tedious for data analysis than the hydrogen bond dynamic propensity analysis. However, this greater computational effort is justified because the QTAIM study, in addition to giving an excellent correlation with the experimental data, also gives us valuable information about which parts or functional groups of the different ligands are those that should be replaced in order to improve the interactions and thereby to increase the affinity for SphK1. Our results indicate that both approaches can be very useful in order to predict the inhibiting effect of new compounds before they are synthesized. PMID- 29971550 TI - Erythrocyte fouling on micro-engineered membranes. AB - Crossflow microfiltration of plasma from blood through microsieves in a microchannel is potentially useful in many biomedical applications, including clinically as a wearable water removal device under development by the authors. We report experiments that correlate filtration rates, transmembrane pressures (TMP) and shear rates during filtration through a microscopically high channel bounded by a low intrinsic resistance photolithographically-produced porous semiconductor membrane. These experiments allowed observation of erythrocyte behavior at the filtering surface and showed how their unique deformability properties dominated filtration resistance. At low filtration rates (corresponding to low TMP), they rolled along the filter surface, but at higher filtration rates (corresponding to higher TMP), they anchored themselves to the filter membrane, forming a self-assembled, incomplete monolayer. The incompleteness of the layer was an essential feature of the monolayer's ability to support sustainable filtration. Maximum steady-state filtration flux was a function of wall shear rate, as predicted by conventional crossflow filtration theory, but, contrary to theories based on convective diffusion, showed weak dependence of filtration on erythrocyte concentration. Post-filtration scanning electron micrographs revealed significant capture and deformation of erythrocytes in all filter pores in the range 0.25 to 2 MUm diameter. We report filtration rates through these filters and describe a largely unrecognized mechanism that allows stable filtration in the presence of substantial cell layers. PMID- 29971551 TI - Efficient Production of 2,6-Difluorobenzamide by Recombinant Escherichia coli Expressing the Aurantimonas manganoxydans Nitrile Hydratase. AB - 2,6-Difluorobenzamide is an important intermediate with many applications in pesticide industries. Through screening a library of recombinant nitrile hydratases, the nitrile hydratase from Aurantimonas manganoxydans ATCC BAA-1229 was selected for production of 2,6-difluorobenzamide from 2,6 difluorobenzonitrile. Key parameters of the biocatalytic process, including temperature, pH, substrate loading, and substrate feeding mode, were optimized. Finally, 314 g/L of 2,6-difluorobenzamide was produced in a simple batch process within 11 h without formation of any by-product in an economical non-buffer system and similar result was obtained when scaled up to 30 L. This study constitutes the first report of 2,6-difluorobenzamide significant production using a recombinant Escherichia coli-based biocatalyst. PMID- 29971552 TI - Suicide risk assessment: examining transitions in suicidal behaviors among pregnant women in Peru. AB - The goals of this research were to characterize suicidal behavior among a cohort of pregnant Peruvian women and identify risk factors for transitions between behaviors. The World Health Organization Composite International Diagnostic Interview suicide questionnaire was employed to assess suicidal behavior. Discrete-time survival analysis was used to study the cumulative age-of-onset distribution. The hazard function was calculated to assess the risk of onset of each suicidal behavior. Among 2062 participants, suicidal behaviors were endorsed by 22.6% of participants; 22.4% reported a lifetime history of suicidal ideation, 7.2% reported a history of planning, and 6.0% reported attempting suicide. Childhood abuse was most strongly associated with suicidal behavior, accounting for a 2.57-fold increased odds of suicidal ideation, nearly 3-fold increased odds of suicide planning, and 2.43-fold increased odds of suicide attempt. This study identified the highest prevalence of suicidal behavior in a population of pregnant women outside the USA. Diverse populations of pregnant women and their patterns of suicidal behavior transition must be further studied. The association between trauma and suicidal behavior indicates the importance of trauma-informed care for pregnant women. PMID- 29971553 TI - Postnatal depressive symptoms in women with and without antenatal depressive symptoms: results from a prospective cohort study. AB - Evidence exists that the risk factors for depression in the antenatal and postnatal period may differ, but only a handful of studies looked at depression longitudinally. The aims of this study were (1) to estimate the prevalence of postnatal depressive symptoms in Kuwait where data about postnatal depression are scarce and identify its determinants and (2) to compare these risk factors between women who had experienced antenatal depressive symptoms and those that did not. Data collected in the TRansgenerational Assessment of Children's Environmental Risk (TRACER) Study in Kuwait were used in this analysis. The sample was restricted to the 1348 women who answered the Edinburgh Postnatal Depression Scale (EPDS) both antenatally and postnatally. The prevalence of postnatal depressive symptoms, defined by an EPDS score >= 10, was 11.7%. Overall, antenatal depressive symptoms were the strongest determinant of postnatal depressive symptoms. Multivariable logistic regression analysis showed that in women with depressive symptoms in pregnancy, having a lower household income was the most significant risk factor for postnatal depressive symptoms. Among women without antenatal depressive symptoms, those who had lower income, were Kuwaitis, experienced other problems in pregnancy such as perceived stress, PTSD symptoms and social isolation, and those who delivered a boy had higher odds of postnatal depressive symptoms. Antenatal depressive symptoms and other psychosocial characteristics can predict postnatal depressive symptoms. Therefore, maternal mental health issues should be detected during the antenatal period and support should be provided in order to lower the risk of postnatal depression and its sequelae. PMID- 29971554 TI - Correction to: PTSD and gender: could gender differences in war trauma types, symptom clusters and risk factors predict gender differences in PTSD prevalence? AB - AbstractThe female-male ratio in the prevalence of post-traumatic stress disorder (PTSD) is approximately 2:1. Gender differences in experienced trauma types, PTSD symptom clusters, and PTSD risk factors are unclear. We aimed to address this gap using a cross-sectional design. A sample of 991 civilians (522 women, 469 men) from South Lebanon was randomly selected in 2007, after the 2006 war. Trauma types were grouped into disaster and accident, loss, chronic disease, non malignant disease, and violence. PTSD symptom clusters involved re-experiencing, avoidance, negative cognitions and mood, and arousal. These were assessed using parts I and IVof the Arabic version of the Harvard Trauma Questionnaire (HTQ). Risk factors were assessed using data from a social support and life events questionnaire in multiple regression models. Females were twice as likely as males to score above PTSD threshold (24.3 vs. 10.4%, p ? 0.001). Total scores on all trauma types were similar across genders. Females scored higher on all symptom clusters (p < 0.001). Social support, social life events, witnessed traumas, and domestic violence significantly were associated with PTSD in both genders. Social support, social life events, witnessed traumas and domestic violence were significantly associated with PTSD in both genders. Conversely, gender difference in experienced traumas was not statistically significant. These findings accentuate the need to re-consider the role of gender in the assessment and treatment of PTSD. PMID- 29971557 TI - The influence of seasonal variations on in vitro fertilization and fresh/frozen embryo transfer: a retrospective study. AB - PURPOSE: To evaluate whether seasonal variations can affect the outcomes of in vitro fertilization (IVF) and embryo transfer (ET). METHODS: The data of 2868 IVF ET cycles over 5 years from patients treated for fallopian tube factors, oligospermia, and asthenospermia were collected retrospectively. The cycles were divided into four seasonal groups based on the day of ET. All cycles were performed using the gonadotropin-releasing hormone agonist and antagonist protocols. The ovarian response, embryo quality, and pregnancy outcomes were compared among groups. In addition, 4106 frozen embryo transfer (FET) cycles performed during the same period were analyzed, and the pregnancy outcomes were compared among the four seasonal groups. RESULTS: The total dose of gonadotropin in the winter group (2106.04 +/- 705.57 IU) was higher than the doses in the spring and summer groups (1994.06 +/- 674.95, 2009.07 +/- 742.26 IU, P < 0.05). The numbers of total oocytes, matured oocytes, fertilizations, cleavages, and high-quality embryos were comparable among seasonal groups (P > 0.05). Significant differences were not observed among seasonal groups in ET or FET for the implantation rate, clinical pregnancy rate, live birth rate, and miscarriage rate (P > 0.05). CONCLUSION: Seasonal variations have little influence on the outcomes of IVF-ET and FET. IVF-ET or FET treatment can be performed during any season. PMID- 29971555 TI - Diagnosis of congenital and acquired focal lesions in the neck, abdomen, and pelvis with contrast-enhanced ultrasound: a pictorial essay. AB - : Contrast-enhanced ultrasound (CEUS) is a versatile imaging modality that improves the diagnostic potential of conventional ultrasound. It allows for portable imaging at the bedside. In this paper, we illustrate how CEUS can be used in evaluating several focal lesions in the pediatric population, including liver hemangioma, telangiectasias, splenic hamartomas, and bladder lesions. We describe the ultrasound findings and contrast enhancement patterns associated with these lesions. Findings are correlated with MRI, CT, and/or pathology when available. This paper demonstrates the value of CEUS in improving characterization of many focal lesions in the pediatric population. CONCLUSION: CEUS is a valuable bedside technique for use in the pediatric population to evaluate focal lesions in various organs, and will allow for safe, more efficient diagnostic imaging. What is Known: * CEUS offers many advantages over CT and MRI and is underutilized in the United States. * It is only FDA approved for vesicoureteral reflux and liver in the pediatric population. However, off label uses are well described. What is New: * This pictorial essay describes ultrasound findings and contrast enhancement patterns associated with liver hemangioma, liver telangiectasia, splenic hamartoma, hemorrhagic ovarian cyst, urachal remnant, spinning top urethras, and kaposiform hemangioendothelioma. * We demonstrate the utility of CEUS in expanding the diagnostic potential of conventional ultrasound. PMID- 29971556 TI - Impact of external cooling with icepacks on 68Ga-PSMA uptake in salivary glands. AB - BACKGROUND: External cooling of the salivary glands is advised to prevent xerostomia in lutetium-177-PSMA treatment for advanced prostate cancer. Since evidence addressing this subject is sparse, this study aims to determine impact of icepacks application on uptake in salivary glands. Eighty-nine patients referred for gallium-68-PSMA PET/CT for (re)staging of prostate cancer were prospectively included. Twenty-four patients were scanned with unilateral (solely left-sided) icepacks; 20 with bilateral icepacks; 45 without icepacks. Icepacks were applied approximately 30 minutes prior to tracer injection. PET/CT acquisition started 1 hour postinjection. Radiotracer uptake was measured in the parotid- and submandibular glands. RESULTS: When comparing the intervention group with the control group, uptake in the left parotid gland significantly differed: SUVmax: 11.07 +/- 3.53 versus 12.95 +/- 4.16; p = 0.02. SUVpeak: 9.91 +/- 3.14 versus 11.45 +/- 3.61; p = 0.04. SUVmax and SUVpeak were reduced with 14.52% and 13.45%. All other SUV values did not significantly differ. Patients with bilateral icepacks showed no significant differences in PSMA uptake compared to the control group (all: p > 0.05). Intra-patient analysis revealed some significant differences in SUVmax and SUVpeak between the cooled and non-cooled parotid gland (SUVmax: 11.12 +/- 3.71 versus 12.69 +/- 3.75; p = 0.00. SUVpeak: 9.93 +/- 3.32 versus 11.25 +/- 3.25; p = 0.00). CONCLUSIONS: Impact of icepacks on PSMA uptake seems to be limited to the parotid glands. As clinical relevance of these findings is debatable, structural application of icepacks in the setting of lutetium-177 PSMA therapy needs careful consideration. PMID- 29971558 TI - Extraparenchymal ovarian and testicular Leydig cells: ectopic/heterotopic or orthotopic? AB - PURPOSE: We are conducting a prospective study trying to determine, in both sexes, the frequency of appearance of ectopic Leydig cells, their preferred location, their relationship with nerve structures and the possible causes of their appearance. METHODS: We have studied 86 cases that were removed according to different clinical indications for pathological study: uterine leyomiomas (n = 12), ovarian cystadenoma (n = 4), endometrial hyperplasia (n = 8), endometrial carcinoma (n = 12), cervical carcinoma (n = 4), seminoma (n = 4), fallopian tube ligatures (n = 24), vasectomies (n = 8), nonspecific orchiepididymitis (n = 2), and unknown (n = 8). RESULTS: We have observed ectopic Leydig cells in 13/86 cases (15.11%), 9/72 in the female samples (12.50%) and 4/14 in male samples (28.57%). The most frequent location was the mesosalpinx (4 of 13: 30.76%). CONCLUSIONS: These high figures lead us to believe that the ectopia of Leydig cells is not really a pathologic entity, but a finding related to specific functions yet to be determined. PMID- 29971559 TI - Incidence and risk factors for gestational diabetes mellitus in twin versus singleton pregnancies. AB - OBJECTIVE: To compare the incidence and risk factors for gestational diabetes mellitus (GDM) between women with twin and singleton pregnancies. METHODS: Retrospective study of all women who had a twin or singleton birth in Ontario (2012-2016). Risk ratios (RR) and 95% CIs for GDM (stratified by type of treatment) were adjusted for relevant confounding variables. Multivariable Poisson regression analysis was used to identify risk factors for GDM in twin and singleton gestations. RESULTS: Of 270,843 women who met inclusion criteria, 266,942 (98.6%) and 3901 (1.4%) had a singleton and a twin pregnancy, respectively. Women with twins had a significantly higher risk for overall GDM (aRR = 1.13, 95% CI 1.01-1.28) and diet-treated GDM (aRR = 1.20, 95% CI 1.01 1.42) while the association with insulin-treated GDM was not significant (aRR = 1.07, 95% CI 0.89-1.28). Maternal age >= 35 years, non-Caucasian ethnicity and BMI > 30 kg/m2 were independent risk factors for GDM among women with twins and singletons, and the magnitude of the association of these factors with GDM was similar. CONCLUSIONS: Women with twins are at increased risk of GDM, mainly due to a higher rate of diet-treated GDM. Despite higher baseline risk of GDM in women with twins, the effect of known risk factors for GDM is similar to that observed in singletons. PMID- 29971560 TI - An effect of maternal nifedipine therapy on fetoplacental blood flow: a prospective study. AB - PURPOSE: The aim of this study is to assess the effects of maternal nifedipine administration on placental and fetal blood flow. METHODS: A total of 29 patients with preterm labor diagnosis admitted to the tertiary care center, Zeynep Kamil Hospital, were evaluated. Before and 24-48 h after administration of oral nifedipine, Doppler ultrasound scan was carried out to measure fetal middle cerebral artery, ductus venosus, umbilical artery, and maternal uterine artery blood flow. RESULTS: After 24 and 48 h of therapy, there were no changes in mean PI and RI in the umbilical arteries and ductus venosus (p > 0.05). Fetal middle cerebral artery and maternal uterine artery PI and RI values showed a significant reduction 24-48 h after oral nifedipine therapy (p < 0.05). CONCLUSIONS: Our study showed that 24 and 48 h after oral nifedipine therapy, there is a significant increase in fetal MCA and maternal uterine artery blood flow, while fetal umbilical artery and ductus venosus Doppler values do not change. PMID- 29971561 TI - A prospective study on the predictive value of DNA methylation in cervical intraepithelial neoplasia prognosis. AB - PURPOSE: To study the predictive value of the DNA methylation levels of JAM3, SOX1, SLIT2, C13ORF18, and TERT in the cervical intraepithelial neoplasia prognosis. METHOD: In the present study, 139 cases were collected and followed up for 24 months. The DNA methylation levels of JAM3, SOX1, SLIT2, C13ORF18, and TERT were tested from their exfoliated cells. One-way ANOVA, receiver operating characteristic (ROC) curve analyses were conducted to analyze the data. RESULTS: The DNA methylation of the five genes was associated with prognosis of CIN. The levels of methylation increased as the progression of lesion for the prognosis. For CIN1, difference between DNA methylation of JAM3, SOX1, SLIT2, and C13ORF18 had significance statistically (P < 0.001). Sensitivity (95.2%) and specificity (93.1%) of JAM3 were the highest compared with other genes for the prognosis of CIN1. In addition, for CIN2/3, DNA methylation of JAM3, SOX1, SLIT2, TERT, and C13ORF18 had difference statistically (P < 0.001). JAM3 were also the highest in sensitivity (95.2%) and specificity (93.1%) compared with other genes for the prognosis of CIN2/3. CONCLUSIONS: Our data suggest for the first time that DNA methylation levels are associated with prognosis of CIN significantly. DNA methylation levels of some genes, especially JAM3, may serve as markers for the prediction of the CIN prognosis, including CIN1 nature prognosis and CIN2/3 after treatment. PMID- 29971562 TI - Is surgical resection useful in elderly newly diagnosed glioblastoma patients? Outcome evaluation and prognostic factors assessment. AB - ASTRACT: BACKGROUND: The incidence of glioblastoma among elderly patients is constantly increasing. The value of radiation therapy and concurrent/adjuvant chemotherapy has been widely assessed. So far, the role of surgery has not been thoroughly investigated. The study aimed to evaluate safety and impact of several entities of surgical resection on outcome of elderly patients with newly diagnosed glioblastoma treated by a multimodal approach. METHODS: Patients >= 65 years, underwent surgery were included. The extent of surgical resection (EOR) was defined as complete resection (CR = 100%), gross total resection (GTR = 90 99%), sub-total resection (STR = 78-90%), partial resection (PR = 30-78%), and biopsy. After surgery, all patients received adjuvant radiotherapy (60/2 Gy fraction) with concomitant/adjuvant temozolomide chemotherapy. RESULTS: From March 2004 to December 2015, 178 elderly with a median age of 71 years (range 65 83 years) were treated. CR was obtained in 8 (4.5%), GTR in 63 (35.4%), STR in 46 (25.8%), PR in 16 (9.0%), and biopsy in 45 (25.3%). RT was started in all patients, concurrent/adjuvant CHT in 149 (83.7%) and 132 (74.2%). The median follow-up time was 12.2 months (range 0.4-50.4 months). The median, 1- and 2-year progression-free survival was 8.9 months (95%CI 7.8-100 months), 32.0 +/- 3.5%, and 12.9 +/- 2.6%. The median, 1- and 2-year overall survival were 12.2 (95%CI 11.3-13.1 months), 51.1 +/- 3.7%, and 16.3 +/- 2.9%. Tumor location, extent of resection, and neurological status after surgery statistically affected survival (p ? 0.01). CONCLUSION: Maximal surgical resection is safe and feasible in elderly patients with influence on survival. A preoperative evaluation has to be carried out. PMID- 29971563 TI - Incidence and morphometry of caroticoclinoid foramina in Greek dry human skulls. AB - BACKGROUND: Ossification of the caroticoclinoid ligament (CCL) and formation of a caroticoclinoid foramen (CCF) may impose significant risk to neurosurgeons by impeding mobilization of the cavernous segment of the internal carotid artery. Although safe surgical access to the clinoidal space is related to understanding the CCF anatomical and ethnic variants, there remains a paucity of studies of the morphology and bony relationships. The current study provides a systematic morphological and morphometric analysis of the CCF, the ossification of the CCL extending between the anterior and middle clinoid processes, and their relations in a Greek population. MATERIALS AND METHODS: The incidence of unilateral and bilateral CCF, types (complete, incomplete, and contact) of ossified CCLs, and foramina diameter according to side and gender were determined in 76 Greek adult dry skulls. Findings were correlated with the morphology of optic strut (OS) (presulcal, sulcal, postsulcal, and asymmetric). RESULTS: A CCF was detected in 74% of the specimens. The majority of skulls (51.4%) had bilateral CCF, whereas 22.3% of the skulls had unilateral foramina. Incomplete CCF were observed in 69.3%, complete in 19.8%, and contact type in 10.9%. The mean CCF diameter was 0.55 +/- 0.07 cm on the left and 0.54 +/- 0.08 cm on the right side. Side symmetry existed, although there were no significant differences according to gender. The CCF were more prominent in skulls with a sulcal type of OS. CONCLUSIONS: The results of the present study augment the current knowledge on the morphology of key anatomical landmarks, CCF, and CCL ossification in the sellar area, indicating population differences. A significant side asymmetry in caroticoclinoid osseous bridging and foramina is highlighted. These findings are necessary for a safe surgical access to the clinoidal area. PMID- 29971564 TI - Correction to: Reply to the letter "Cardiac autonomic evaluation in breast cancer patients: role of cytokines and heart rate recovery". AB - Unfortunately, errors occurred in the original article. PMID- 29971565 TI - Effect of Vanadium Supplementation on Production Performance, Nutrient Utilization, Plasma Mineral Concentration, and Mineral Balance in Lactating Goats. AB - Vanadium (V) has not been elucidated as an essential mineral in ruminants, though in lower organisms and rat model, its role is well known as insulin-a mimetic agent for catalyzing enzymatic activities. The objective of this study was to determine the effect of V supplementation on production performance, milk composition, and mineral profile in lactating goats. Twenty-four crossbred goats (body weight 34.83 +/- 0.25 kg) were blocked in four groups and randomly assigned to four treatment groups (n = 6) on body weight and milk yield basis. All the animals were kept on similar feeding regimen except that different treatment groups were supplemented with 0, 2, 4, and 6 ppm inorganic V/kg DM. Feed intake, milk yield, milk composition, nutrient utilization, minerals in plasma and milk, and their balance studies post vanadium supplementation were observed during the 150-day experimental period. V supplementation did not change dry matter intake (DMI), milk yield, and composition during the experimental period. Calcium levels in plasma were improved (P < 0.05) on vanadium supplementation. Nutrient digestibility remained similar among goats fed on basal or V-supplemented diets. Blood and milk V concentration showed a positive correlation with supplemental V levels but no difference was observed in levels of other minerals. The results of present findings indicated that up to the supplemented level, dietary inorganic V does not affect the production and mineral profile in milk and plasma. PMID- 29971567 TI - The predominance and clustering of Clostridioides (Clostridium) difficile PCR ribotype 001 isolates in three hospitals in Eastern Slovakia, 2017. AB - This study aimed to implement a toxigenic culture as an optional third diagnostic step for glutamate dehydrogenase (GDH)-positive and toxin A/B-negative diarrheal stool samples into a diagnostic algorithm for Clostridioides (Clostridium) difficile infection (CDI), and to characterise C. difficile isolates for epidemiological purposes. During the 5-month study, 481 diarrhoeal stool samples from three Slovak hospitals were investigated and 66 non-duplicated GDH-positive stool samples were found. Of them, 36 were also toxin A/B-positive. Twenty-three GDH-positive and toxin A/B-negative stool samples were shown subsequently to be positive following toxigenic culture (TC). Molecular characterisation of C. difficile isolates showed the predominance of PCR ribotype (RT) 001 (n = 37, 56.1%) and the occurrence of RT 176 (n = 3, 4.5%). C. difficile RT 001 isolates clustered to eight clonal complexes (CCs) using multiple-locus variable-number tandem repeats analysis (MLVA). Interestingly, one third of RT 001 isolates clustering in these CCs were cultured from toxin A/B-negative stool samples. Our observations highlight the need of use multiple step diagnostic algorithm in CDI diagnosis in order to detect all CDI cases and to avoid the spread of C. difficile in healthcare settings. PMID- 29971568 TI - Antihypertensive effect of azilsartan versus olmesartan in patients with essential hypertension: a meta-analysis. AB - OBJECTIVE: The comparison of antihypertensive effects between azilsartan and olmesartan in patients with essential hypertension has been investigated in several studies. The results were not consistent. We performed this meta-analysis determining the antihypertensive effect of azilsartan versus olmesartan in patients with essential hypertension. METHODS: Pubmed, Web of Science, and Cochrane Central were searched for all published randomized studies comparing the antihypertensive effects between azilsartan and olmesartan in patients with essential hypertension. RESULTS: The antihypertensive effects were assessed in 1402 patients included in five trials. The reduction of office systolic blood pressure treated with azilsartan was greater than olmesartan (weighted mean differences (WMD) - 2.15 (95% confidence interval (CI), - 3.78, - 0.53) mm Hg, p < 0.01). There was no significant difference in reduction of office diastolic blood pressure between azilsartan and olmesartan (WMD - 0.99 (95% CI, - 2.06, 0.08) mm Hg, p > 0.05). The reduction of office systolic blood pressure treated with azilsartan was greater than olmesartan at same dose for both drugs (WMD - 2.24 (95% CI, - 4.03, - 0.44) mm Hg, p < 0.05), whereas there was no significant difference in reduction of office diastolic blood pressure between azilsartan and olmesartan (WMD - 0.55 (95% CI, - 1.76, 0.66) mm Hg, p > 0.05). CONCLUSIONS: This meta-analysis provides the evidence that the reduction of office systolic blood pressure treated with azilsartan was greater than olmesartan in patients with essential hypertension. These findings suggest the importance of strict designed randomized controlled trials in determining antihypertensive effects of angiotensin II receptor blockers in clinical practice. PMID- 29971566 TI - Patient's satisfaction at 2 years after groin hernia repair: any difference according to the technique? AB - BACKGROUND: Long-term patient's satisfaction after groin hernia repair is rarely studied in the literature. The aim of this study was to compare the four main techniques of inguinal hernia repair in terms of patient's satisfaction and quality of life at the 2-year follow-up in a prospective registry. METHODS: From September 2011 to March 2014, consecutive patients underwent groin hernia repair and were prospectively included in the Club Hernie registry, which also consisted of expert surgeons in parietal repair. The data on patient demographics, clinical presentation, initial workup, operative technique, postoperative course, clinical follow-up, and quality of life at 2 years (2Y-FU) were recorded. RESULTS: Overall, 5670 patients were included in the study: 1092 undergoing Lichtenstein's technique, 1259 for trans-inguinal preperitoneal technique (TIPP), 1414 for totally extraperitoneal approach (TEP) and 1905 for transabdominal preperitoneal approach (TAPP). The patients undergoing Lichtenstein's technique were significantly older, with more inguinoscrotal hernias and co-morbidities than those undergoing other techniques. A total of 83% patients had a complete 2Y-FU. The patient's satisfaction at 2Y-FU was similar between the different techniques. In the univariate and multivariate analyses, pain on postoperative day 1 was the only independent prognostic factor of the patient's satisfaction at 2Y-FU. CONCLUSION: In this large series, no statistical differences were found between the four studied techniques regarding the 2Y-Fu results and patients' satisfaction. Provided the technique has been done properly (expert surgeon) the results and the patients' satisfaction are fair and equivalent among the four studied techniques. In a multivariate analysis, the only factor predictive of bad late results was severe pain at D1. PMID- 29971569 TI - Self- and informant-rated apathy in patients with childhood-onset craniopharyngioma. AB - INTRODUCTION: The current study aimed to assess whether childhood-onset craniopharyngioma patients suffer from symptoms of apathy, as assessed by patients themselves and their close others. We further analyzed whether apathy scores are related to symptoms of depression. METHODS: Childhood-onset craniopharyngioma patients (n = 35, 16 female, median age = 22) and matched healthy controls (n = 35, 19 female, median age = 21) were asked to complete self ratings of the Apathy Evaluation Scale, whereas informant-ratings were obtained from their close others. Depression was assessed by self-ratings using the German version of the Center for Epidemiological Studies Depression Scale. As primary outcome measures, self- and informant-rated apathy scores were compared between patients and healthy controls. As secondary outcome measures, differences between self- and informant-rated apathy within the single groups and associations between apathy and depression were analyzed. RESULTS: Compared to healthy controls, patients displayed significantly higher apathy levels in informant ratings (medianpatients = 18, mediancontrols = 12, p = .021), but not in self ratings (medianpatients = 11, mediancontrols =12, p = .68). In patients, there was a significant discrepancy between self- and informant-rated apathy and self rated apathy was related to symptoms of depression. CONCLUSIONS: This is the first study to show that childhood-onset craniopharyngioma patients may be at high risk for apathy. Noteworthy, apathy levels in the patient group were judged to be high by their close others but not by the patients themselves, indicating that many patients were not fully aware of their impairments. As apathy is associated with numerous adverse outcomes affecting everyday life and vocational opportunities, future investigations are needed to identify specific risk factors for apathy. Clinical Trial Registration No: NCT00258453. PMID- 29971570 TI - Colorimetric determination of ofloxacin using unmodified aptamers and the aggregation of gold nanoparticles. AB - A colorimetric method is presented for the determination of the antibiotic ofloxacin (OFL) in aqueous solution. It is based on the use of an aptamer and gold nanoparticles (AuNPs). In the absence of OFL, the AuNPs are wrapped by the aptamer and maintain dispersed even at the high NaCl concentrations. The solution with colloidally dispersed AuNPs remains red and has an absorption peak at 520 nm. In the presence of OFL, it will bind to the aptamer which is then released from the AuNPs. Hence, AuNPs will aggregate in the salt solution, and color gradually turns to blue, with a new absorption peak at 650 nm. This convenient and specific colorimetric assay for OFL has a linear response in the 20 to 400 nM OFL concentration range and a 3.4 nM detection limit. The method has a large application potential for OFL detection in environmental and biological samples. Graphical abstract Schematic of a sensitive and simple colorimetric aptasensor for ofloxacin (OFL) detection in tap water and synthesic urine. The assay is based on the salt-induced aggregation of gold nanoparticles which results in a color change from red to purple. PMID- 29971572 TI - Targeting the enzymes involved in arachidonic acid metabolism to improve radiotherapy. AB - During radiotherapy, an inflammatory response might be induced by activating various enzymes involved in membrane lipid metabolism. The eicosanoid pathway associated with cytosolic phospholipase A2 (cPLA2), cyclooxygenases (COXs), and lipoxygenases (LOXs) can be induced by radiation, and many lipid metabolites might contribute to cancer-associated inflammation, cell proliferation, and cell survival in cancer. The lipid metabolites are also involved in the establishment of the tumor-associated microenvironment through promotion of angiogenesis and formation of vascular network. These biological activities of lipid metabolites are responsible for malignant progression with the acquisition of radioresistance, leading to unsatisfactory outcome of cancer radiotherapy. Many efforts have been made to identify the mechanisms associated with bioactive lipid metabolites and radiation signaling that lead to radioresistance and to develop potent radiosensitizers to improve therapeutic efficacy. Beneficial outcomes would be achieved by targeting the enzymes, such as cPLA2, COXs, and LOXs, responsible for arachidonic acid metabolism and cancer-associated inflammation during cancer radiotherapy. The current study demonstrated a brief review for the radioresistant effects of bioactive lipid metabolites and their enzymes in cancer and the radiosensitizing effects of inhibitors for the enzymes on cancer therapy. PMID- 29971571 TI - Modelling of the cathodic and anodic photocurrents from Rhodobacter sphaeroides reaction centres immobilized on titanium dioxide. AB - As one of a number of new technologies for the harnessing of solar energy, there is interest in the development of photoelectrochemical cells based on reaction centres (RCs) from photosynthetic organisms such as the bacterium Rhodobacter (Rba.) sphaeroides. The cell architecture explored in this report is similar to that of a dye-sensitized solar cell but with delivery of electrons to a mesoporous layer of TiO2 by natural pigment-protein complexes rather than an artificial dye. Rba. sphaeroides RCs were bound to the deposited TiO2 via an engineered extramembrane peptide tag. Using TMPD (N,N,N',N'-tetramethyl-p phenylenediamine) as an electrolyte, these biohybrid photoactive electrodes produced an output that was the net product of cathodic and anodic photocurrents. To explain the observed photocurrents, a kinetic model is proposed that includes (1) an anodic current attributed to injection of electrons from the triplet state of the RC primary electron donor (PT) to the TiO2 conduction band, (2) a cathodic current attributed to reduction of the photooxidized RC primary electron donor (P+) by surface states of the TiO2 and (3) transient cathodic and anodic current spikes due to oxidation/reduction of TMPD/TMPD+ at the conductive glass (FTO) substrate. This model explains the origin of the photocurrent spikes that appear in this system after turning illumination on or off, the reason for the appearance of net positive or negative stable photocurrents depending on experimental conditions, and the overall efficiency of the constructed cell. The model may be a used as a guide for improvement of the photocurrent efficiency of the presented system as well as, after appropriate adjustments, other biohybrid photoelectrodes. PMID- 29971573 TI - Omega-3 polyunsaturated fatty acids as adjuvant therapy of colorectal cancer. AB - The majority of evidence linking anti-colorectal cancer (CRC) activity with omega 3 polyunsaturated fatty acids (O3FAs) has focussed on decreased CRC risk (prevention). More recently, preclinical data and human observational studies have begun to make the case for adjuvant treatment of advanced CRC. Herein, we review latest data regarding the effect of O3FAs on post-diagnosis CRC outcomes, including mechanistic preclinical data, evidence that O3FAs have beneficial effects on efficacy and tolerability of CRC chemotherapy, and human epidemiological data linking dietary O3FA intake with CRC outcomes. We also highlight ongoing randomised controlled trials of O3FAs with CRC endpoints and discuss critical gaps in the evidence base, which include limited understanding of the effects of O3FAs on the tumour microenvironment, the host immune response to CRC, and the intestinal microbiome. PMID- 29971574 TI - Effects of physicochemical parameters on volatile sulphur compound formation from L-methionine catabolism by non-growing cells of Kluyveromyces lactis. AB - The present study investigated for the first time the effects of various physicochemical parameters on the production of volatile sulphur compounds (VSCs) by non-growing cells of Kluyveromyces lactis supplemented with L-methionine. The results showed that the production of VSCs positively correlated with the cell biomass, but it seemed that no clear relationship with L-methionine concentration existed. Temperature and pH significantly affected the formation of VSCs with more production at 30 degrees C and pH 5, respectively. Nitrogen supplementation (in the form of diammonium phosphate, DAP) repressed the production of VSCs. It is interesting to note that DAP and yeast extract supplementation induced the production of methional, but not Mn2+ supplementation. The presence of Mn2+ improved the production of methionol and dimethyl disulphide, but inhibited the formation of S-methyl thioacetate. The study indicated that optimization of physicochemical conditions and media composition would be crucial for producing L methionine-derived VSC bioflavor. PMID- 29971576 TI - Nitro derivatives of triazetidine: potential high energy density materials. AB - In a continuing effort to evaluate the properties of new possible high energy density materials, we have calculated the optimized geometries and thermodynamic properties of a series of nitro derivatives of triazetidine, c-CH2(NH)3. After evaluating approximately 50 different levels of NO2 substitution and conformations, we predict that several nitrotriazetidine compounds show some significantly desirable HEDM properties. Graphical abstract The triazetidine molecule, the parent structure for a series of new hypothetical high energy densitymaterials with various NO2 content. PMID- 29971575 TI - Cardiovascular Autonomic Dysfunction in Patients with Cancer. AB - PURPOSE OF REVIEW: Elucidating the mechanisms that contribute to adverse cardiovascular (CV) outcomes and reduce quality of life among patients with cancer is paramount. Cancer, certain cancer drugs, radiation therapy, cancer associated lifestyle disturbances, and cancer-independent comorbidities combine to predispose oncology patients to autonomic dysfunction (AD). This review will explore the assessment, etiology, and clinical implications of AD in cancer patients and will speculate on therapeutic and research opportunities. RECENT FINDINGS: AD is particularly prevalent among patients with advanced cancer, but studies suggest increased prevalence across the entire continuum of cancer survivors compared to cancer-free controls. Data on cancer therapy-induced injury to the autonomic nervous system are limited to small studies. AD has been reported after cranial, neck, and mediastinal radiation therapy. Although AD has been shown to confer increased risk of adverse CV outcomes in cancer-free patients, the prognostic relevance of AD in oncology patients is less well investigated. Markers of AD including elevated resting heart rate (HR), reduced HR variability, and abnormal HR recovery have been associated with shorter survival times in various cancer cohorts. Furthermore, AD has been implicated in the etiology of cancer-related fatigue and exercise limitation. Multiple risk factors predispose oncology patients to AD, which is associated with adverse outcomes, including increased mortality, exercise limitation, and fatigue among this cohort. The contribution of AD to overall morbidity and mortality in cancer survivors has largely been overlooked to date. Further investigation is necessary to better understand cancer-treatment specific autonomic injury and to evaluate the role of various pharmacological and non-pharmacological interventions with potential to tackle the sympathovagal imbalance observed in cancer survivors. PMID- 29971577 TI - Exploring Racial Differences in Patient Centeredness of Care (PCC) During Breast Cancer (BC) Chemotherapy Clinical Visits. AB - OBJECTIVES: The communication patterns between clinician and patient, described as the patient centeredness of care (PCC), may be a critically important etiology of breast cancer (BC) racial disparity. The purpose of this prospective, comparative pilot study was to qualitatively explore and code for PCC during the clinical visit of women undergoing BC chemotherapy and compare by race. METHODS: Age-matched Black and White women were recruited. Audio recordings of clinical visits conducted prior to any cycle (except first) chemotherapy infusion were obtained and transcribed. Transcripts were blindly reviewed by three independent coders assigning PCC scores, ranging from 1 to 5, with lower scores indicating better PCC. Consensus was reached among reviewers via discussion. RESULTS: Dyads consisted of five Black (mean age 47) and five White (mean age 45) women undergoing BC chemotherapy. Twenty-four recordings were analyzed, 13 White and 11 Black. For all 22 PCC items, the mean scores were worse for Black women with significant differences (compared by chi-square analysis) noted for 6/22 items (27%). CONCLUSIONS: Qualitatively exploring clinician and patient communication patterns during the chemotherapy clinical visits informs the understanding of racial differences for symptom assessment, reporting, and management. These pilot findings inform future research exploring racial disparity in cancer treatment dose intensity. PMID- 29971578 TI - Physiotherapists' Adoption of a Theory-Based Skills Training Program in Guiding People with Rheumatoid Arthritis to Health-Enhancing Physical Activity. AB - PURPOSE: To describe physiotherapists' (PTs') adoption of a theory-based skills training program preparing them to guide people with rheumatoid arthritis (RA) to health-enhancing physical activity (HEPA) within a 1-year intervention trial. METHOD: This was a longitudinal case study. Ten female PTs (age 25-59), delivering the HEPA intervention, participated. Data were collected on five occasions over a 19-month period: once before the training course, once after 4 course days, twice during the HEPA intervention and once after the HEPA intervention. Knowledge on about physical activity (score 0-6) and behavior change techniques (BCTs) (score 0-18), fear-avoidance beliefs (score 8-48) and self-efficacy to guide behavior change (score 9-54) were assessed with a questionnaire. Structured logbooks were used to register PTs' self-reported guiding behavior. Criteria for PTs' adherence to the protocol were pre-set. RESULTS: PTs' knowledge on about BCTs and their self-efficacy increased significantly (p < 0.05) from median 9 to 13 and from median 38 to 46.5, respectively. Knowledge on about physical activity was high and fear-avoidance beliefs were low before the education (median 6 and 13.5, respectively) and did not change over time. Two out of ten PTs fulfilled the pre-set criteria for adherence throughout the intervention. CONCLUSION: The results suggest that a theory-based skills training program improves PTs' knowledge on about behavior change techniques and their self-efficacy to guide people with RA to HEPA. PTs' adherence to the protocol was not complete but the clinical relevance of the adherence criteria need to be validated against observed PT behavior and patient outcomes. PMID- 29971580 TI - Pre-operative embolisation of spinal tumours: neither neglect the neighbour nor blindly follow the gold standard. AB - A large variety of vertebral tumours undergoes transarterial embolisation (TAE) prior to surgery. However, the subsequent intra-operative blood loss is unpredictable. This retrospective analysis, aims to determine the impact of various factors that may potentially influence the estimated intra-operative blood loss (EBL) in these patients. The study included 56 consecutive patients with spinal tumours who underwent pre-operative TAE. Demographic information, treatment history, tumour type, MRI characteristics, angiographic appearance, embolisation technique and surgical invasiveness were correlated with EBL using univariate and multivariate analysis. Mean EBL was 1317 mls. On univariate analysis, haematological/primary tumours, MRI hypervascularity and selective embolisation were significantly (P < 0.05) associated with increased EBL. A total angiographic devascularisation and embolisation of additional segments above and/or below the involved level were significantly associated with decreased EBL. There was no significant association with hypervascular angiographic appearance or surgical invasiveness. MRI and angiographic hypervascularity were not entirely concordant, especially for the category of moderately vascularised metastases. After multivariate analysis, MRI hypervascularity (1434 vs. 929 mls, P = 0.018) and embolisation of additional segments (1082 vs. 1607 mls, P = 0.003) remained significantly correlated with EBL. In conclusion, during pre-operative TAE of spinal tumours, routine angiographic interrogation of additional levels above and below the involved segment should be made, with a low threshold for embolising them, if safely performable. Compared to angiographic gold standard, MRI hypervascularity is probably a better predictor of EBL. PMID- 29971579 TI - A reproductive and developmental screening study of the fungal toxin ochratoxin A in Fischer rats. AB - The presence of the mycotoxin ochratoxin A (OTA) in cereal grains is due to the growth of toxigenic Penicillium mold on stored crops. Human exposure to OTA is higher in infants, toddlers, and children than in adolescents and adults, based on exposure assessments of ng OTA consumed/kg body weight/day. Ochratoxin A is nephrotoxic and teratogenic in animals, but its effects on juveniles exposed during the reproduction and development period have not been studied. To address this, Fischer rats were exposed to 0, 0.16, 0.4, 1.0, or 2.5 mg OTA/kg diet throughout breeding, gestation, and lactation and its adverse effects were assessed in adult rats and their offspring on postnatal day (PND) 21. There were no effects on implantation but post-implantation fetotoxicity was observed in the 2.5 mg/kg dose group, corresponding to a calculated dose of 167.0 MUg/kg bw/day in dams. Adverse effects on body and kidney weights and on clinical parameters indicative of renal toxicity were significant in adult rats exposed to 1.0 mg OTA/kg diet (55.2 and 73.3 MUg/kg bw/day in adult males and females, respectively) and in PND21 rats at the 0.4 mg/kg dose (33.9 MUg/kg bw/day in dams), suggesting that weanling rats were more sensitive to OTA than adults. Overall, nephrotoxicity was the primary effect of OTA in weanling rats exposed throughout gestation and lactation at sub-fetotoxic concentrations in diet. PMID- 29971581 TI - Influence of Drain Placement on Postoperative Pain Following Laparoscopic Roux-en Y Gastric Bypass for Morbid Obesity: Randomized Controlled Trial. AB - BACKGROUND: There is currently no evidence to support the routine use of an abdominal drain following laparoscopic Roux-en-Y gastric bypass (RYGB). Our aim was to investigate drain use in laparoscopic RYGB and its effects on postoperative pain. METHODS: Sixty-six patients were randomly divided into two groups as no-drain (n = 36) and with-drain (n = 30). Intraoperative (time, blood loss, complications) and postoperative outcomes (morbidities, pain scores, hospital stay) were compared. RESULTS: Demographics of both groups were comparable. Three patients in the no-drain group required a drain (8.3%). Median visual analog scale scores for days 1-3 for with-drain and no-drain groups were 4.5 (2-9) vs. 3 (0-8) (p = 0.02), 3 (0-7) vs. 2 (0-7) (p = 0.10), and 2 (0-7) vs. 0 (0-4) (p = 0.0004), respectively. There was no difference between the groups in terms of complications and length of hospital stay. CONCLUSION: Drain use increased the postoperative pain following laparoscopic RYGB. Drain placement following laparoscopic RYGB should be selective instead of a routine application. PMID- 29971582 TI - Correction to: Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis. AB - The family name of the corresponding author on this article was incorrectly spelled as "El Hakem Matraiah". The correct spelling should have been "El Hakem Metraiah". This is now presented correctly in this article. PMID- 29971584 TI - Oral cyclophosphamide in treatment of patients with refractory idiopathic inflammatory myopathies: a retrospective observational study. AB - To describe the use of oral cyclophosphamide (PO CYC) in a single center longitudinal cohort of patients with idiopathic inflammatory myopathies (IIM). Patients using PO CYC were identified through a retrospective chart review of a myositis cohort at a single academic center. PO CYC dose, duration, adverse events, and disease activity measures before and after CYC were analyzed. Disease activity measures included muscle enzymes, manual muscle testing (MMT8), 100-mm visual analog scale (VAS), and 1-4 Likert scale for physician global assessment. Fourteen patients were treated with PO CYC within the cohort between 2008 and 2017; 9 dermatomyositis (DM), 3 polymyositis (PM), and 2 with immune-mediated necrotizing myopathy (IMNM). Age was 51.1 (40-72) years and the cumulative dose of PO CYC was 41 (2-131) grams over duration of 12.4 (0.5-43) months, mean (range) for all. All patients had severe refractory IIM, 10 (72%) with ILD, 3 (21%) with cardiac involvement and 4 (29%) were dependent in most activities of daily living. Median number of prior failed therapies was 4.5 (range 3-6) including intravenous CYC in 5 patients. Disease activity measures significantly improved following CYC use and concomitant daily prednisone dose decreased. The most common adverse events during CYC therapy were infections. We report the first cohort study of PO CYC use in IIM patients with severe, treatment refractory disease. Further trials are needed to verify these results as well as to evaluate long-term safety outcomes. PMID- 29971583 TI - Women who had appendectomy have increased risk of systemic lupus erythematosus: a nationwide cohort study. AB - The appendix is involved in immune function, and an appendectomy may alter the immune system. Studies evaluating the relationship between previous appendectomy and the risk of systemic lupus erythematosus (SLE) are lacking. This nationwide cohort study investigated the incidence and risk of SLE in patients who underwent appendectomy. Patients aged > 20 years who received appendectomy from 2000 to 2011 were identified from the National Health Insurance Research Database and assigned to the appendectomy cohort. Patients without appendectomy were randomly selected from the NHIRD and assigned to the control cohort; they were frequency matched to each study patient at a 4:1 ratio by sex, age, and index year. All patients were followed until SLE diagnosis, withdrawal from the National Health Insurance program, or the end of 2011. We used Cox models to estimate the hazard ratio (HR) and 95% confidence interval (CI) to compare the risk of SLE between the appendectomy and control cohorts. From 23.74 million people in the cohort, 80,582 patients undergoing appendectomy and 323,850 patients without appendectomy were followed for 723,438 and 2,931,737 person-years, respectively. The appendectomy cohort had a 2.04-fold higher risk of SLE than the control cohort (adjusted HR = 2.04, 95% CI = 1.52-2.76). Women aged <= 49 years who underwent appendectomy had a 2.27-fold higher risk of SLE than the corresponding controls (adjusted HR = 2.27, 95% CI = 1.62-3.19). Women aged <= 49 years who underwent appendectomy have a significantly higher risk of SLE. PMID- 29971585 TI - Prevalence and factors associated with disturbed sleep in outpatients with ankylosing spondylitis. AB - Sleep disturbance is prevalent among patients with ankylosing spondylitis (AS) and is considered a multifactorial issue. The study was designed to investigate sleep disturbance and its associated factors in AS outpatients in Southwest China. Patients were recruited by convenience sampling in this cross-sectional study. The Pittsburgh Sleep Quality Index (PSQI), the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), the Bath AS Patient Global Score (BAS-G), and the Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality, disease activity, function status, global well-being, depression, and anxiety. Spearman's correlation, t test, ANOVA, and multiple linear regression analysis were used to explore the associated factors of sleep disturbance. Of the 281 outpatients included in the study, 190 (67.6%) patients had sleep disturbance. The married patients, the patients with extra-spinal manifestation, depression and anxiety, longer duration of diagnostic delay, higher disease activity, worse functional status and global well-being, high level of pain, and fatigue, had poorer sleep quality (P < 0.05). Multiple linear regression analysis revealed age (beta = 0.087, P = 0.102), BAS-G (beta = 0.181, P = 0.003), fatigue (beta = 0.170, P = 0.002), anxiety (beta = 0.151, P = 0.002) and nocturnal back pain (beta = 0.192, P = 0.001), extra-spinal manifestation (beta = 0.120, P = 0.012), and duration of diagnostic delay (beta = 0.174, P = 0.001) were the contributors to PSQI. Sleep disturbance is common in AS patients in Southwest China. It may be useful to keep regular exercise, strengthen the management of pain, relieve anxiety, and prevent and treat extra-spinal manifestation for improving sleep quality. PMID- 29971586 TI - Adaption to stress via Pbs2 during Metarhizium rileyi conidia and microsclerotia development. AB - The high osmolarity glycerol (HOG) pathway plays important role in Metarhizium rileyi microsclerotia (MS) development. To investigate how M. rileyi transduce growth stress and regulate MS development via mitogen-activated protein kinase kinase (MAPKK) Pbs2, phenotypic characterization of the yeast Pbs2 homolog were performed. Expression of pbs2 peaked when MS formation occurred day 3 in liquid amended medium. Compared with wild-type and complemented strains, deletion mutant of pbs2 (Deltapbs2) delayed dimorphic switch and vegetative growth, displayed sensitivities to various stress, and significantly reduced conidial (98%) and MS (40%) yields. Furthermore, transcription analysis showed that other genes of HOG signaling pathway were down-regulated in Deltapbs2 mutants. Insect bioassays revealed that Deltapbs2 mutants had decreased virulence levels in topical (24%) and injection (53%) bioassays. This study confirmed that Pbs2 play important roles in colony morphology, conidiation, stresses response and MS development in M. rileyi. PMID- 29971588 TI - Commonalities in the Association of Behavioral Activation and Behavioral Inhibition with Problem Gambling and Alcohol Use in Young Adult College Students. AB - In a previous study of young adult college students (age 18-25), we found an association among 157 past year gamblers between gambling severity as measured by the Problem Gambling Severity Index and negative affect as measured by the total score on the 21-item Depression Anxiety and Depression Scales. An inverse association between the behavioral activation system reward responsiveness scale and gambling severity was found, as was an inverse association between reward and negative affect. In addition, an association between the behavioral inhibition system scale and negative affect was observed. Theoretical models such as Shaffer's Syndrome Addiction model posit that problem behaviors are expressions of a common underlying etiology. In the current paper, we present results from the previous database regarding the severity of alcohol use among 286 past year drinkers as measured by the Alcohol Use Disorders Identification Test. As with gambling severity, reward responsiveness was inversely associated with alcohol use severity both directly and indirectly through negative affect. Severity was also directly associated with the BAS fun seeking scale. As previously found, negative affect was associated with inhibition. Among 125 students engaging in each behavior, scores for each severity index were also correlated. These findings suggest that a reward oriented coping approach may be protective against both more severe gambling and alcohol use problems. An inhibitory or escapist approach may lead to more severe problems. They also suggest that behaviors are co-occurring in a significant number of students, and levels of severity in one behavior are associated with levels in the other. It is hoped these results can inform future research and interventions. PMID- 29971589 TI - Gambling Disorder in Male Violent Offenders in the Prison System: Psychiatric and Substance-Related Comorbidity. AB - Gambling disorder is an addiction that can cause major suffering, and some populations seem to be more vulnerable than others. Offender populations have a remarkably high prevalence of gambling problems and they are also over represented in a number of diagnoses related to gambling disorder, like substance use disorders and antisocial personality disorder. Yet, there are few studies investigating gambling disorder prevalence and related psychiatric comorbidity in this group. This study aims to investigate the prevalence of, and association between, gambling disorder and other psychiatric diagnoses in a sample of young, male violent offenders. Two hundred and sixty-four male offenders, all serving sentences for violent crimes (recruited between 2010 and 2012) participated in this study and went through comprehensive psychiatric evaluation, including assessment for Diagnostic and Statistical Manual of Mental Disorders 4th Edition criteria. Sixteen percent of the participants met criteria for gambling disorder. Antisocial personality disorder, cannabis, cocaine and anabolic steroids abuse were significantly more common among participants with gambling disorder. The gambling disorder group also showed significantly lower educational attainment. Cocaine abuse and failure to graduate elementary and middle school in expected time were independently associated with gambling disorder in a regression analysis. This study confirms the previously described high prevalence of gambling disorder in offenders. The psychiatric comorbidity was high and the problems had started early, with lower educational attainment in the gambling disorder group. The findings stress the importance of increased awareness of gambling problems among convicted offenders and of gambling research on young people with delinquent behavior. There is a need of more research to investigate this further, in order to develop preventive strategies and treatment. PMID- 29971587 TI - PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects. AB - BACKGROUND: Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression. RESULTS: TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04 1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001-1.21), though these comparisons missed the corrected threshold for statistical significance (alpha = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers. CONCLUSIONS: This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects. PMID- 29971590 TI - Editorial: Therapy-induced metastasis. AB - The idea for this Special Issue originated from our recent review in Nature Reviews Clinical Oncology entitled "Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?" Martin et al. (Nat Rev Clin Oncol 14:32-44, 2017). While preparing this review, it became evident that an overwhelming number of preclinical and clinical papers were implicating the involvement of all the major and indispensable cancer treatment modalities in causing increased numbers of tumour cells in circulation (CTCs), and potentially increased risk of distant metastasis. This led to our decision to expand the topic by addressing some of the issues associated with therapy-induced tumour progression. Here, we present papers from ten research groups who give a comprehensive coverage of the biological processes and clinical procedures that can lead to enhanced metastasis and/or tumour recurrence. Our authors provide evidence that all the common therapies, including radiotherapy, chemotherapy, fine needle biopsies, surgical procedures and anaesthesia have the potential to contribute to tumour progression. PMID- 29971591 TI - Subtypes of pediatric acute respiratory distress syndrome have different predictors of mortality. AB - PURPOSE: Acute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS. METHODS: This was a single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests. RESULTS: Direct ARDS had lower severity of illness (p < 0.001) but worse oxygenation (p < 0.001), relative to indirect. Predictors of mortality were similar for direct and indirect ARDS. When comparing infectious and non infectious ARDS, infectious ARDS had lower severity of illness (p < 0.001), worse oxygenation (p = 0.014), and lower mortality (p = 0.013). In multivariable analysis, immunocompromised status demonstrated effect modification between infectious and non-infectious ARDS (p = 0.005 for interaction), with no association with mortality in non-infectious ARDS. CONCLUSIONS: In children, direct and indirect ARDS have distinct clinical characteristics, but similar outcomes and similar predictors of mortality. In contrast, infectious and non infectious ARDS demonstrate heterogeneity of clinical characteristics, mortality, and predictors of mortality, with traditional predictors of ARDS mortality only applicable to infectious ARDS. PMID- 29971593 TI - Terlipressin versus norepinephrine as infusion in patients with septic shock: a multicentre, randomised, double-blinded trial. AB - PURPOSE: Recent clinical data suggest that terlipressin, a vasopressin analogue, may be more beneficial in septic shock patients than catecholamines. However, terlipressin's effect on mortality is unknown. We set out to ascertain the efficacy and safety of continuous terlipressin infusion compared with norepinephrine (NE) in patients with septic shock. METHODS: In this multicentre, randomised, double-blinded trial, patients with septic shock recruited from 21 intensive care units in 11 provinces of China were randomised (1:1) to receive either terlipressin (20-160 ug/h with maximum infusion rate of 4 mg/day) or NE (4 30 ug/min) before open-label vasopressors. The primary endpoint was mortality 28 days after the start of infusion. Primary efficacy endpoint analysis and safety analysis were performed on the data from a modified intention-to-treat population. RESULTS: Between 1 January 2013 and 28 February 2016, 617 patients were randomised (312 to the terlipressin group, 305 to the NE group). The modified intention-to-treat population comprised 526 (85.3%) patients (260 in the terlipressin group and 266 in the NE group). There was no significant difference in 28-day mortality rate between the terlipressin group (40%) and the NE group (38%) (odds ratio 0.93 [95% CI 0.55-1.56]; p = 0.80). Change in SOFA score on day 7 was similar between the two groups: - 7 (IQR - 11 to 3) in the terlipressin group and - 6 (IQR - 10 to 5) in the NE group. There was no difference between the groups in the number of days alive and free of vasopressors. Overall, serious adverse events were more common in the terlipressin group than in the NE group (30% vs 12%; p < 0.001). CONCLUSIONS: In this multicentre, randomised, double blinded trial, we observed no difference in mortality between terlipressin and NE infusion in patients with septic shock. Patients in the terlipressin group had a higher number of serious adverse events. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov: ID NCT01697410. PMID- 29971595 TI - Opposing pupil responses to offered and anticipated reward values. AB - Previous studies have shown that the pupils dilate more in anticipation of larger rewards. This finding raises the possibility of a more general association between reward amount and pupil size. We tested this idea by characterizing macaque pupil responses to offered rewards during evaluation and comparison in a binary choice task. To control attention, we made use of a design in which offers occurred in sequence. By looking at pupil responses after choice but before reward, we confirmed the previously observed positive association between pupil size and anticipated reward values. Surprisingly, however, we find that pupil size is negatively correlated with the value of offered gambles before choice, during both evaluation and comparison stages of the task. These results demonstrate a functional distinction between offered and anticipated rewards and present evidence against a narrow version of the simulation hypothesis; the idea that we represent offers by reactivating states associated with anticipating them. They also suggest that pupil size is correlated with relative, not absolute, values of offers, suggestive of an accept-reject model of comparison. PMID- 29971596 TI - Association Between High-Dose Spironolactone and Decongestion in Patients with Acute Heart Failure: An Observational Retrospective Study. AB - BACKGROUND: Acute congestive heart failure (ACHF) is a state of severe, secondary hyperaldosteronism. Relief of congestion has prognostic implications. Our aim was to assess associations between high-dose spironolactone and (1) decongestion and (2) safety in patients with ACHF. METHODS: The charts of 20 patients who were hospitalized with ACHF and received high doses of spironolactone (75-300 mg daily, group A) on top of standard of care (SOC) treatment were retrospectively studied and compared with the ones of 20 matched patients who received SOC treatment alone (group B). RESULTS: The two groups were similar as per their baseline characteristics. Mean daily spironolactone dose was 143 +/- 56 in group A vs. 25 +/- 25 mg in group B (P < 0.001). Patients of group A demonstrated significantly greater daily urine output (median [25th, 75th percentile] 2.9 [2.3, 3.9] vs. 2.2 [1.9, 2.5] L/day, P = 0.009), daily weight loss (1.1 [0.9, 1.7] vs. 0.4 [0.2, 1.2] kg/day, P = 0.005) and total body weight loss (10.5 [7.3, 13.8] vs. 3.8 [3.0, 6.0] kg, P < 0.001) compared with patients of group B. There were no differences in incidence of renal dysfunction, hypokalemia and hyperkalemia. CONCLUSION: In patients with ACHF, administration of high doses of spironolactone on top of SOC treatment appears safe and is associated with greater decongestion than SOC alone. PMID- 29971597 TI - Successful laparoscopic resection for cap polyposis: case report, literature review. AB - BACKGROUND: Cap polyposis is a rare gastrointestinal disease with endoscopically and pathologically distinctive features. Its exact etiology has not been fully elucidated. In a few cases, there was recurrence after inadequate treatment. Efficacy of Helicobacter pylori eradication therapy, however, has been shown in some published research. CASE PRESENTATION: A 70-year-old female patient developed intermittent mucous diarrhea with loss of body weight and visited a physician. Total colonoscopy showed multiple sessile polyps which were partially coadunated from the rectum to the sigmoid colon. Histopathological finding was tubular adenoma with mild atypia. The patient stayed for observation. Worsening symptoms following protein-losing enteropathy demanded surgical treatment because malignancy could not be ruled out. Laparoscopic resection was performed, and the surgical specimens revealed that the polypoid lesion mainly consisted of mild adenomatous glands which were covered with purulent granulation tissues. We made final diagnosis of cap polyposis and saw rapid improvement of her symptoms. Long term observation is required after surgery. CONCLUSIONS: We reported a case of successful laparoscopic resection of cap polyposis with protein-losing enteropathy (170 words). PMID- 29971592 TI - Surviving sepsis campaign: research priorities for sepsis and septic shock. AB - OBJECTIVE: To identify research priorities in the management, epidemiology, outcome and underlying causes of sepsis and septic shock. DESIGN: A consensus committee of 16 international experts representing the European Society of Intensive Care Medicine and Society of Critical Care Medicine was convened at the annual meetings of both societies. Subgroups had teleconference and electronic based discussion. The entire committee iteratively developed the entire document and recommendations. METHODS: Each committee member independently gave their top five priorities for sepsis research. A total of 88 suggestions (ESM 1 - supplemental table 1) were grouped into categories by the committee co-chairs, leading to the formation of seven subgroups: infection, fluids and vasoactive agents, adjunctive therapy, administration/epidemiology, scoring/identification, post-intensive care unit, and basic/translational science. Each subgroup had teleconferences to go over each priority followed by formal voting within each subgroup. The entire committee also voted on top priorities across all subgroups except for basic/translational science. RESULTS: The Surviving Sepsis Research Committee provides 26 priorities for sepsis and septic shock. Of these, the top six clinical priorities were identified and include the following questions: (1) can targeted/personalized/precision medicine approaches determine which therapies will work for which patients at which times?; (2) what are ideal endpoints for volume resuscitation and how should volume resuscitation be titrated?; (3) should rapid diagnostic tests be implemented in clinical practice?; (4) should empiric antibiotic combination therapy be used in sepsis or septic shock?; (5) what are the predictors of sepsis long-term morbidity and mortality?; and (6) what information identifies organ dysfunction? CONCLUSIONS: While the Surviving Sepsis Campaign guidelines give multiple recommendations on the treatment of sepsis, significant knowledge gaps remain, both in bedside issues directly applicable to clinicians, as well as understanding the fundamental mechanisms underlying the development and progression of sepsis. The priorities identified represent a roadmap for research in sepsis and septic shock. PMID- 29971598 TI - Beware the bright basilar artery: an early and specific CT sign of acute basilar artery thrombosis. PMID- 29971594 TI - Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners. AB - PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 * 10-6), 5q23.2 (p = 2.5 * 10-6), 1q21.3 (p = 3.2 * 10-6), 10p13 (p = 1.3 * 10-5) and 12p12.1 (p = 7.1 * 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism. PMID- 29971599 TI - Daylight saving time, circadian rhythms, and cardiovascular health. AB - Very recently, the European Parliament, called to decide on possible abolition of the Daylight Saving Time (DST), approved a resolution calling the scientific community to conduct a more in-depth evaluation. The question is based on disruption of body's circadian rhythms. We review here the relationship between DST and cardiovascular health. The available evidence suggests the existence of an association between DST and a modest increase of occurrence of acute myocardial infarction, especially in the first week after the spring shift. Possible mechanisms include sleep deprivation, circadian misalignment and environmental conditions. The role of gender and individual preference in circadian rhythms (chronotype) will need further assessment. PMID- 29971600 TI - Gene therapy strategies in the treatment of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is an inherited myocardial disease with an estimated prevalence of 1:200 caused by mutations in sarcomeric proteins. It is associated with hypertrophy of the left ventricle, increased interstitial fibrosis, and diastolic dysfunction for heterozygous mutation carriers. Carriers of double heterozygous, compound heterozygous, and homozygous mutations often display more severe forms of cardiomyopathies, ultimately leading to premature death. So far, there is no curative treatment against HCM, as current therapies are focused on symptoms relief by pharmacological intervention and not on the cause of HCM. In the last decade, several strategies have been developed to remove genetic defects, including genome editing, exon skipping, allele-specific silencing, spliceosome-mediated RNA trans-splicing, and gene replacement. Most of these technologies have already been tested for efficacy and efficiency in animal or human-induced pluripotent stem cell models of HCM with promising results. We will summarize recent technological advances and their implication as gene therapy options in HCM with a special focus on treating MYBPC3 mutations and its potential for being a successful bench to bedside example. PMID- 29971601 TI - Correction to: Cardiospecific deletion of alphaE-catenin leads to heart failure and lethality in mice. AB - The original version of this article unfortunately contained a mistake. The published paper presented an incorrect version of Table 1. The corrected Table is given here. PMID- 29971603 TI - Re. Re. Dabigatran overdose: a case report of acute hepatitis. Extracorporeal treatment and review of the literature. PMID- 29971602 TI - Clinical characteristics of pediatric patients with myeloid sarcoma without bone marrow involvement in Japan. AB - Myeloid sarcoma (MS) is a rare neoplastic condition that is often described in association with acute myeloid leukemia (AML). MS in childhood has received little attention, particularly in Japan. We carried out a nationwide retrospective analysis of Japanese children diagnosed with MS without bone marrow involvement. Inclusion criteria were diagnosis of MS at younger than 20 years of age between January 1, 2000 and December 31, 2013. There was a predominance of males (8:2), and the median age at MS diagnosis was 4 years. Sites of involvement varied and included skin (n = 3), head and/or neck (n = 2), and multiple sites (n = 2). Karyotypes were evaluated in seven patients, with one individual carrying t(8;21) and t(9;11). Four patients developed bone marrow involvement 2-55 months after diagnosis of MS. All patients received chemotherapy for de novo AML and two individuals received HSCT in first remission. Seven of ten patients survived for 50-152 months (median, 93 months) without disease after initial chemotherapy. This retrospective study confirmed that pediatric MS without bone marrow involvement in Japan is a very rare disease. MS patients responded favorably to therapies for de novo AML, and HSCT in first remission was not indicated for all patients. PMID- 29971604 TI - TCF7L2 gene variants predispose to the development of type 2 diabetes mellitus among individuals with metabolic syndrome. AB - INTRODUCTION: Transcription factor 7-like 2 (TCF7L2) gene variants rs12255372 and rs7903146 have been consistently shown to raise genetic risk for type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the possible role of these variants in the development of impaired glucose metabolism (IGM), including impaired fasting glucose (IFG) or T2DM, in patients with metabolic syndrome (MS). PATIENTS AND METHODS: The study population consisted of 228 patients with MS who were divided into two groups. The first group consisted of 148 patients with MS and IGM [39M/109F, 59.8 +/- 14.6 (mean +/- SD) years] and the second group of 80 patients with MS and normoglycemia (NGM) (16M/64F, 56.1 +/- 15.8 years). The diagnosis of MS was based on the criteria proposed by the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) Scientific Statement. Anthropometric parameters including BMI and waist circumference were recorded and blood samples were obtained after overnight fasting for biochemical tests. The rs12255372 and rs7903146 TCF7L2 polymorphisms were genotyped in peripheral blood leucocytes. RESULTS: Analysis of the distribution of the TCF7L2 polymorphic alleles revealed that the frequency of the T allele of the TCF7L2 variant rs12255372 was 38.2% in the study population, while the frequency of the T allele of the TCF7L2 rs7903146 variant was 35.3%. The T allele of the rs12255372 variant was more frequently present in patients with MS and IGM (48.3%) compared to patients with MS and NGM (19.4%, p < 0.001). Also, the T allele of rs7903146 was more frequently present in patients with MS and IGM (44.6%) compared to patients with MS and NGM (18.1%, p < 0.001). Logistic regression analysis followed and revealed that the presence of the T allele for both rs12255372 and rs7903146 TCF7L2 gene variants is a very powerful predictor of the presence of glucose disorders, increasing the risk more than fourfold in patients with MS and after adjustment for potential confounders, such as age, gender, BMI, and waist circumference (TCF7L2 rs12255372: Exp(B) 4.917, p < 0.001 and TCF7L2 rs7903146: Exp(B) 5.460, p < 0.001). CONCLUSION: The presence of the rs12255372 and rs7903146 TCF7L2 gene variants plays an important role in the development of T2DM among individuals with MS. These findings support the notion that among subjects with MS, those who finally develop T2DM have a genetic predisposition to beta-cell dysfunction. PMID- 29971605 TI - Management of acromegaly: an exploratory survey of physicians from the Middle East and North Africa. AB - BACKGROUND: Worldwide variations exist in the diagnosis and management of patients with acromegaly. For such a rare condition, the knowledge and perception of physicians would most likely direct the care of patients. However, the adherence of physicians in non-Western regions to guidelines for the diagnosis and management of acromegaly has not been previously ascertained. METHODS: An online survey was conducted to assess the perceptions and practice of physicians regarding acromegaly diagnosis and management as per international guidelines. An electronic questionnaire containing key questions was mailed, initially to physicians in Saudi Arabia (KSA) and later to other countries in the Middle East and North Africa (MENA) region. Additional questions were included to ensure the relevance of the respondents' replies. The responses were captured and summarized anonymously. Descriptive comparisons were made with two similar international and national surveys from other regions. RESULTS: Two hundred forty-seven doctors responded to the survey. Of these, 155 (64.5%) fulfilled the inclusion criteria and, in particular, confirmed having treated acromegaly patients in the previous 12 months, and they constituted the basis of this study. The three most common referring specialties for patients were internists (44; 28.4%), neurosurgeons (46; 29.6%), and family medicine physicians (42; 27.1%), respectively. The combination of growth hormone (GH) nadir during the oral glucose tolerance test (OGTT) and elevated insulin-like growth factor-1 (IGF-1) levels was used by 99 physicians (63.9%) to diagnose acromegaly. The main determinant for treatment choice was tumor mass characteristics confirmed by 117 respondents (75.5%) with neurosurgery as first treatment choice confirmed by 124 respondents (80%). Combined measurement of IGF-1 and GH levels after OGTT at 3 months after surgery was the most widely used criterion for assessment of surgical outcomes, confirmed by 82 physicians (52.9%). The biggest barriers to optimal management of acromegaly as perceived by 38.1% and 35.5% of the respondents were high cost of medications and lack of physicians' awareness, respectively. CONCLUSIONS: The majority of the surveyed physicians reported variable adherence to the international acromegaly guidelines. Clearly, higher awareness is needed among physicians for early diagnosis and timely referral for specialist management. PMID- 29971606 TI - "I Am Uncertain About What My Uncertainty Even Is": Men's Uncertainty and Information Management of Their BRCA-Related Cancer Risks. AB - Men with a germline pathogenic BRCA1 or BRCA2 variant have increased risks for developing breast, pancreatic, prostate, and melanoma cancers, but little is known about how they understand and manage their cancer risks. This study examines how men with BRCA-related cancer risks manage uncertainty and information about their risks. Twenty-five men who were either a BRCA carrier or have a BRCA-positive first-degree family member that put the participant at 50% chance of also being a BRCA carrier were interviewed for this study. Using uncertainty management theory as a theoretical framework, this study demonstrates that men manage uncertainty by seeking information from female family members, websites, and healthcare providers, and are under-informed about their cancer risks. Further, in handling their information, men prefer information about cancer risk percentages and screening recommendations in the form of lists presented to them via websites, printed literature, proactive healthcare providers, and an identifiable male spokesperson. Finally, men used BRCA-related cancer risk information to make decisions about whether or not to engage in screening and prevention, manage their BRCA-related cancer risks, and overall family well-being-yet often at the expense of their own individual risks. Implications for genetic counseling and family conversations are discussed. PMID- 29971607 TI - Health Risk Assessment for Local Residents from the South China Sea Based on Mercury Concentrations in Marine Fish. AB - The offshore area of the South China Sea is an important fishing ground in China. We used a food frequency questionnaire to determine marine fish consumption by local residents, and we detected mercury concentrations in commonly consumed marine fish species. In total, 127.9 g/day of the marine fish consumed was identified in 178 local residents. THg and MeHg concentrations in 209 samples of 22 fish species ranged from 11.3 to 215.0 ug/kg wt and 2.0 to 160.0 ug/kg wt, respectively. The mean MeHg exposure from marine fish to local residents was 0.099 ug/kg bw, accounting for 43.0% of the provisional tolerated weekly intake (PTWI) (1.6 ug/kg bw/week), suggesting a low health risk. However, a potentially high health risk (202.2% of PTWI) was identified in those with 97.5% MeHg exposure. PMID- 29971608 TI - Correction to: Organochlorine Chemical Residues in Northern Cardinal (Cardinalis cardinalis) Eggs from Greater Washington, DC USA. AB - The original version of this article contained a mistake. Author name in the text citation and reference in section should be Maldonado et al (2016), it was incorrectly spelled as Maldinado et al (2015). PMID- 29971610 TI - Colorimetric determination of the pesticide chlorothalonil based on the aggregation of gold nanoparticles. AB - A method is described for the determination of the pesticide chlorothalonil (CLT). It is based on the finding that citrate-capped gold nanoparticles (AuNPs) undergo aggregation on exposure to chlorothalonil. This is accompanied by a visually detectable color change from wine red to blue. The effect is due to the interaction of the cyano group of chlorothalonil with gold nanoparticles. The assay may also be performed by using a spectrometer. The ratio of absorbances at 700 nm and 520 nm (A700/A520) linearly drops in the 5 to 100 ng.mL-1 CLT concentration range, with a 3.6 ng.mL-1 detection limit. This is below the Chinese guideline value for cucumber. The method is rather simple and does not require any modification of the AuNPs or the utilization of antibody. It was successfully applied to the determination of CLT in (spiked) cucumber samples. Recoveries ranged from 80.4 to 97.4%, and the analytical results compared well with those obtained by HPLC. Graphical abstract Schematic of the assay. The strong interaction of the cyano group of acetamiprid with gold nanoparticles (AuNPs) via Au-N bond induces the aggregation of gold nanoparticles, and this is accompanied by a color change from red to purple. PMID- 29971609 TI - Autoimmune Hepatitis in the Elderly: Diagnosis and Pharmacologic Management. AB - Autoimmune hepatitis (AIH) may present as acute or chronic hepatitis in the elderly. Advanced hepatic fibrosis and cirrhosis are common on first presentation in this population. In this review, we discuss the presentation, approach to diagnosis and management of AIH in the elderly. As polypharmacy is common in the elderly, careful medication use history is essential for detecting drug-induced AIH-like hepatitis. Steroid-sparing or minimizing therapeutic regimens are preferred to treat AIH in the elderly. For the purpose of induction, budesonide or lower dose prednisone in combination with azathioprine (AZA) regimens are preferred over high-dose prednisone monotherapy due to the higher risk of side effects of the later in the elderly. The goal of maintenance therapy should be to achieve full biochemical and histologic remission. Bone density monitoring and interventions to prevent steroid-related bone disease should be implemented throughout the course of the disease. Liver transplantation should be considered in the elderly patient with liver failure or early hepatocellular carcinoma if there are no significant comorbidities or compromise in functional status. PMID- 29971611 TI - The effects of inhaled multi-walled carbon nanotubes on blood pressure and cardiac function. AB - BACKGROUND: Heart rate variability (HRV) as a marker reflects the activity of the autonomic nervous system. The prognostic significance of HRV for cardiovascular disease has been reported in clinical and epidemiological studies. Our laboratory has reported alterations in rat heart rate variability (HRV) due to increasing activity of both sympathetic and parasympathetic nervous system after pulmonary exposure to multi-walled carbon nanotubes (MWCNTs). This suggests that pulmonary inhalation of engineered nanoparticles (ENs) may lead to functional changes in the cardiovascular system. The present study further investigated the effects of inhaled MWCNTs on the cardiovascular system and evaluated the correlation between the alterations in HRV and changes in cardiovascular function. METHODS: Male Sprague-Dawley rats were pre-implanted with a telemetry device and exposed by inhalation to MWCNTs for 5 h at a concentration of 5 mg/m3. The electrocardiogram (EKG) and blood pressure were recorded in real time by the telemetry system at pre-exposure, during exposure, and 1 and 7 days post-exposure. In vivo cardiac functional performance in response to dobutamine was determined by a computerized pressure-volume loop system. RESULTS: Inhalation of MWCNTs significantly increased both systolic and diastolic blood pressure and decreased heart rate in awake freely moving rat. Additionally, inhalation of MWCNTs also reduced cardiac stroke work, stroke volume, and output in response to dobutamine in anesthetized rats. CONCLUSIONS: Inhalation of MWCNTs altered cardiovascular performance, which was associated with MWCNT exposure-induced alterations in the sympathetic and parasympathetic nervous system. These findings suggest the need to further investigate the cardiovascular effects of inhaled MWCNTs. PMID- 29971613 TI - The Use of Antibiograms in Orthopedic Surgery. AB - PURPOSE OF REVIEW: Organism identification and antibiotic selection remain a critical component of periprosthetic joint infection (PJI) treatment. Prior to organism identification and/or the availability of antibiotic sensitivities, empiric antibiotics are routinely started. A basic understanding of a region or institutions antibiogram is paramount for selection of an empiric treatment regimen. Evolving antibiogram results and regional antibiotic resistance are important to follow as this may change antibiotic selection in some patient populations. RECENT FINDINGS: The Clinical Laboratory and Standards Institute (CLSI) has created guidelines and standards for the creation and maintenance of antibiograms that should be followed by institutions. The infecting organism during PJI may be different in acute vs chronic infections and empiric therapy may change depending on the timing. Antibiotic prophylaxis for major procedures in certain patient populations should be critically evaluated based on regional and national antibiogram results. The CLSI guides recommendations and antibiotic resistance testing techniques and should be consulted when creating an antibiogram. The local and regional antibiogram should be consulted prior to administration of empiric and prophylactic antibiotics. PMID- 29971612 TI - The Effect of Left Ventricular Assist Device Therapy on Cardiac Biomarkers: Implications for the Identification of Myocardial Recovery. AB - PURPOSE OF REVIEW: Left ventricular assist device (LVAD) therapy serves as mainstay therapy for bridge to transplantation and destination therapy. Evidence is now mounting on the role of LVAD therapy as bridge to recovery. In the current review, we will summarize the data on biomarkers of myocardial recovery following LVAD implantation. RECENT FINDINGS: Myocardial recovery can occur spontaneously, following pharmacological intervention and in the setting of mechanical circulatory support such as LVAD. Several biomarkers such as B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), ST2, etc. have been identified and are being used to guide medical therapy in heart failure (HF) patients. However, recent data raised concern that those biomarkers may not be helpful in managing heart failure patients in general, and as such questioned their use in the advanced heart failure population. At this point, the use of biomarker to identify patients with myocardial recovery during LVAD support has not been established, and LVAD explantation remains a decision driven by echocardiographic and hemodynamics improvement. HF biomarkers in monitoring myocardial and neurohormonal activation response to mechanical unloading and medical therapy could be valuable. However, at this time, there is inadequate evidence to select a single or a set of HF biomarkers to reliably identify patients bridged to recovery for LVAD explantation. PMID- 29971614 TI - Patients' views about parathyroid transplantation for post-thyroidectomy hypoparathyroidism. AB - BACKGROUND: Permanent hypoparathyroidism (hypoPT) represents the most common postoperative complication associated with total thyroidectomy. Current treatment relies on high-dose calcium and/or vitamin D supplementation, but often this is insufficient and some patients remain symptomatic. Parathyroid allotransplantation is a new therapeutic option described recently in the literature. This study aims to investigate the patients' acceptability of parathyroid transplantation as a potential new treatment for hypoPT. METHOD: Online survey of members of HypoParaUK, a support group for individuals affected by hypoPT. RESULTS: Responses were received from 252 hypoPT patients. Majority declared to experience severe symptoms despite regular medical treatment. On a severity scale of 0-5, symptoms that were most troublesome were fatigue (3.8), low sense of well-being (3.5), and numbness/tingling (2.9). On a scale of 0-10, on average, their current quality of life (QoL) was 5 +/- 3 and they expected this would improve to 7 +/- 2 with correction of their hypoPT. Forty-four percent of patients were extremely interested in a potential technique involving intramuscular injection of parathyroid cell suspension compared to just 14% who were interested in the more invasive procedure of implantation of a parathyroid allograft into the forearm. The main concerns expressed were related to the possible need for immunosuppressive therapy. CONCLUSION: Patients with severe symptomatic hypoPT seem interested to consider participation in a clinical trial exploring the feasibility and success rate of parathyroid transplantation. PMID- 29971615 TI - An efficient and facile synthesis of new tetracyclic fused pyrazolo[4,3 c][1,2,4]triazino[4,5-a]quinolin-4(5H)-ones. AB - Reaction of amidrazones 1a-1i with (1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H pyrazol-4-ylidene)propanedinitrile (2) in ethyl acetate solution in one-step reaction led to the formation of unprecedented pyrazolo[4,3-c][1,2,4]triazino[4,5 a]quinolin-4(5H)-ones 3a-3g along with pyrazolo[4,3-c][1,2,4]triazino[4,5 a]quinolin-12b-oles 3h-3m in moderate to excellent yields. These novel heterocycles were formed via a Michael addition reaction followed by intramolecular cyclization via a dearomatization process. PMID- 29971616 TI - Structural modification on rupestonic acid leads to highly potent inhibitors against influenza virus. AB - Influenza viruses are responsible for seasonal epidemics and occasional pandemics, which cause significant morbidity and mortality. Although several drugs (adamantanes and neuraminidase inhibitors) are available in the market, the worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs. Artemisia rupestris L. is a folk medicine used to treat cold. In this paper, we structurally modified rupestonic acid, a bioactive component of A. rupestris, to synthesize a series of 2-substituted rupestonic acid methyl esters (3a-3o). Their structures were fully characterized by 1H NMR, 13C NMR, HRMS spectra. Among them, compounds 3b and 3c exhibited potent activities against influenza H1N1 with micromolar IC50 values and might serve as new lead compounds for the treatment of influenza. PMID- 29971617 TI - QEX: target-specific druglikeness filter enhances ligand-based virtual screening. AB - Druglikeness is a useful concept for screening drug candidate compounds. We developed QEX, which is a new druglikeness index specific to individual targets. QEX is an improvement of the quantitative estimate of druglikeness (QED) method, which is a popular quantitative evaluation method of druglikeness proposed by Bickerton et al. QEX models the physicochemical properties of compounds that act on each target protein based on the concept of QED modeling physicochemical properties from information on US Food and Drug Administration-approved drugs. The result of the evaluation of PubChem assay data revealed that QEX showed better performance than the original QED did (the area under the curve value of the receiver operating characteristic curve improved by 0.069-0.236). We also present the c-Src inhibitor filtering results of the QEX constructed using Src family kinase inhibitors as a case study. QEX distinguished the inhibitors and non-inhibitors better than QED did. QEX works efficiently even when datasets of inactive compounds are unavailable. If both active and inactive compounds are present, QEX can be used as an initial filter to enhance the screening ability of conventional ligand-based virtual screenings. PMID- 29971619 TI - Functional Polymorphism Located in the microRNA Binding Site of the Insulin Receptor (INSR) Gene Confers Risk for Type 2 Diabetes Mellitus in the Bangladeshi Population. AB - Bangladesh has the second largest number of adults with diabetes in South Asia. Compelling evidence suggest that miRNAs contribute to the etiology of Type 2 diabetes mellitus (T2DM) by regulating many aspects of glucose homeostasis. Hence, we hypothesized that genetic polymorphisms in the diabetes-related miRNA target-binding sites could be associated with the risk of T2DM in Bangladesh. The reference Single nucleotide polymorphism (SNP) data from the Insulin Receptor (INSR) gene were downloaded from the ENSEMBL genome browser release 88 and further analyzed in silico for identifying SNPs with deleterious effect and clinical relationships. Further, case-control study using the microRNA-binding site polymorphism rs1366600 (T > C) located at the 3' UTR of the INSR gene was carried out in 217 T2DM patients and 237 healthy controls from Bangladesh. Genotyping was performed using the real time PCR based allele discrimination method. The results showed that the minor allele 'C' is associated with increased risk of T2DM [Odds ratio (OR) 1.87; 95% confidence intervals (CI) 1.28-2.74; P = 0.0010]. When we dissected our analysis to include the dominant model (CC + TC genotype against the TT genotype), we found that the CC and TC genotypes were associated with increased risk of T2DM in Bangladeshi population (OR 2.01; 95% CI 1.31-3.07; P = 0.0012). However, in recessive model (CC vs TT + TC); the effect was not statistically significant (OR 2.23; 95% CI 0.66-7.51; P = 0.1848). Stratification of our data based on the gender of the cases and controls showed similar degree of risk association with respect to different genotypes and alleles. Our study showed that the miRNA binding site polymorphism rs1366600 located at the 3'-UTR region of the INSR gene is associated with increased risk of T2DM in Bangladeshi individuals. PMID- 29971618 TI - The impact of heart, lung and diaphragmatic ultrasound on prediction of failed extubation from mechanical ventilation in critically ill patients: a prospective observational pilot study. AB - BACKGROUND: Failed extubation from mechanical ventilation in critically ill patients is multifactorial, complex and not well understood. We aimed to identify whether combined transthoracic echocardiography, lung and diaphragmatic ultrasound can predict extubation failure in critically ill patients. RESULTS: Fifty-three participants who were intubated > 48 h and deemed by the treating intensivist ready for extubation underwent a 60-min pre-extubation weaning trial (pressure support <= 10 cmH2O and positive end expiratory pressure 5 cmH2O). Prior to extubation, data collected included ultrasound assessment of left ventricular ejection fraction, left atrial area, early diastolic trans-mitral flow velocity wave (E), early diastolic trans-mitral flow velocity wave/late diastolic trans-mitral flow velocity wave (E/A), early diastolic trans-mitral flow velocity wave/early diastolic mitral annulus velocity (E/E'), interatrial septal motion, lung loss of aeration score and diaphragm movement. At the end of the weaning trial, the rapid shallow breathing index and serum B-type natriuretic peptide concentration were measured. Success and failure of weaning was assessed by defined criteria. Decision to extubate was at the discretion of the treating intensivist. Failure of extubation was defined as re-intubation, non-invasive ventilation or death within 48 h after extubation. Of 53 extubated participants, 11 failed extubation. Failed extubation was associated with diabetes, ischaemic heart disease, higher E/E' (OR 1.27, 95% CI 1.05-1.54), left atrial area (OR 1.14, CI 1.02-1.28), fixed rightward curvature of the interatrial septum (OR 12.95, CI 2.73-61.41), and higher loss of aeration score of anterior and lateral regions of the lungs (OR 1.41, CI 1.01-1.82). CONCLUSIONS: Failed extubation in mechanically ventilated patients is more prevalent if markers of left ventricular diastolic dysfunction and loss of lung aeration are present. PMID- 29971620 TI - Poly-L-gamma-glutamic acid production by recombinant Bacillus subtilis without pgsA gene. AB - Poly-gamma-glutamic acid (PGA) is a promising bio-based polymer that shares many functions with poly (acrylic acid) and its derivatives. Thus, technologies for efficient production and molecular size control of PGA are required to expand the application of this useful biopolymer. In Bacillus strains, PGA is synthesized by the PgsBCA protein complex, which is encoded by the pgsBCA gene operon, otherwise is known as ywsC and ywtAB operons and/or capBCA operon. Hence, we investigated responsible components of the PgsBCA complex in B. subtilis for over-production of PGA. In particular, we constructed genomic pgsBCA gene-deletion mutants of B. subtilis. And also, we assembled high copy-number plasmids harboring sigmaA dependent promoter, leading to high-level expression of all combinations of pgsBCA, pgsBC, pgsBA, pgsCA, pgsB, pgsC, and/or pgsA genes. Subsequently, PGA production of the transformed B. subtilis mutant was determined in batch fermentation using medium supplemented with L-glutamate. PGA production by the transformants introduced with pgsBC genes (lacking the genomic pgsBCA genes) was 26.0 +/- 3.0 g L-1, and the enantiomeric ratio of D- and L-glutamic acid (D/L ratio) in the produced PGA was 5/95. In contrast, D/L-ratio of produced PGA by the transformants introduced with pgsBCA genes (control strains) was 75/25. In conclusion, B. subtilis without pgsA gene could over-produce PGA with an L-rich enantiomeric ratio. PMID- 29971621 TI - Present clinical practices of stereotactic irradiation for metastatic brain tumors in Japan: results of questionnaire survey of the Japanese Radiation Oncology Study Group (JROSG) working subgroup for neurological tumors. AB - BACKGROUND: To determine the current practice of stereotactic irradiation (STI) for brain metastases in Japan by a questionnaire survey. METHODS: A questionnaire was distributed to 313 institutions performing STI with one of the following machines: Gamma Knife (GK), CyberKnife (CK), Novalis (Nov), or other linear accelerator (LINAC)-based systems (OLS). The participation was voluntary. RESULTS: There were 163 responding institutions. The total number of STI treatments between April 2013 and March 2014 was 10,684. Stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT) were performed in 8624 (80.7%) and 2060 (19.3%) cases, respectively. Whole-brain radiation therapy (WBRT) was performed for a total of 3515 cases. For a case model of a 1.5-cm solitary brain metastasis in a non-eloquent area, the most common GTV-PTV margin was 2 mm (22 of 114 institutions), and an institutional standard fraction was 1 (75 of 114 institutions). The doses for the model case also varied from 13.0 to 26.0 Gy (Median 20 Gy) when converted to SRS (alpha/beta = 10). A prescription point was at the PTV margin the most. The median dose constraints which were converted to SRS (alpha/beta = 3) to organs at risk were 12.2, 12.7, and 13.7 Gy for optic nerves, cavernous sinus, and brainstem, respectively. CONCLUSIONS: STI for brain metastases in current practice varied significantly among institutions. These different strategies relied mostly on the type of treatment machine used. It is thus necessary to establish a common guideline to express dose prescriptions and plan qualities for different STI machines. PMID- 29971623 TI - Association of wrist circumference with cardio-metabolic risk factors: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: The association of Wrist Circumference (WrC) with cardio metabolic risk factors is still contradictory. We aimed to systematically review the association of WrC with cardio-metabolic diseases among the general populations. METHODS: We systematically searched electronic databases such as PubMed/Medline, Web of Sciences, and Scopus without language restriction until March 2017. Observational studies that examined the association of WrC with any cardio-metabolic risk factors were included. Pooled association of WrC with metabolic syndrome (MetS) was estimated using a random-effect model, and heterogeneity among studies was assessed by I2 index and Q test. RESULTS: A total of 14 papers including cohort study (n = 9), cross-sectional study (n = 4), and case-control study (n = 1) met the criteria and included. The eligible papers have been examined the association of WrC with any cardiovascular disorders (n = 8), metabolic syndrome (n = 4), insulin resistance (IR) (n = 5), diabetes mellitus (n = 2), impaired glucose tolerance (n = 1), cardio-metabolic risk factors (n = 2) and obesity/overweight (n = 1). In the whole population (both adults and pediatric population), high WrC increased the risk of MetS by 33% (Pooled OR = 1.33; 95% CI 1.20, 1.48; I2 = 60.2%, p = 0.04), while the pooled OR in adult populations was 1.27 (95% CI 1.15-1.41; I2: 32.8%, p = 0.21). Qualitative synthesis showed that associations of WrC with other cardio-metabolic risk factors are conflicting. CONCLUSION: High WrC increased the risk of MetS and other cardio-metabolic risk factors. However, due to limited studies, particularly in children, results should be declared with great caution. Further cohort studies are needed to clarify whether WrC is a suitable anthropometric index to predict cardio-metabolic disorders in adult and children populations in different societies. LEVEL OF EVIDENCE: Level 1, systematic review and meta analysis. PMID- 29971622 TI - Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan. AB - BACKGROUND: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). METHODS: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. RESULTS: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3 76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. CONCLUSIONS: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence. PMID- 29971624 TI - Granulomatous mastitis: etiology, imaging, pathology, treatment, and clinical findings. AB - PURPOSE: To outline the demographics, clinical presentation, imaging features, and treatment modalities observed among a series of patients diagnosed with biopsy-proven granulomatous mastitis (GM). METHOD: Following approval by institutional review board, retrospective chart review was performed on patients with biopsy-proven granulomatous mastitis at our institution in the period from January 2013 until October 2017. RESULTS: A total of 90 patients were identified: 87 women and 3 men. The mean age was 35 years, mostly women in their reproductive age. In our study, patients with GM were more likely to be Hispanic compared to the general population. Sixty-three percent of patients were within 5 years of previous pregnancy. Painful palpable mass-like lesion was the most common physical finding. Breast ultrasound (US) was performed in all patients, and most commonly showed a hypoechoic irregular-shaped mass. Mammography (MG) showed asymmetry or irregular mass as the main finding. Definitive diagnosis was obtained by imaging-guided core needle biopsies in 94.4%. Conservative management was preferred, and only one patient underwent surgery. CONCLUSION: Although clinical and radiological findings of patients with GM may mimic those of breast carcinoma, our study showed that women of childbearing age, especially among Hispanic ethnicity with a recent history of pregnancy or high prolactin level and newly tender mass-like lesion, in addition to new focal asymmetry on mammogram and heterogeneous hypoechoic irregular-shaped mass on ultrasound exam, should raise concern for GM. Non-invasive approach and clinical follow-up were the preferred treatment method. PMID- 29971625 TI - Effectiveness of neo-adjuvant systemic therapy with trastuzumab for basal HER2 type breast cancer: results from retrospective cohort study of Japan Breast Cancer Research Group (JBCRG)-C03. AB - PURPOSE: While human epidermal growth factor receptor 2 (HER2) target therapies have significantly improved the prognosis of patients with HER2-enriched breast cancer, differing clinical benefits and gene expression analyses suggest a divergent HER2 subgroup. We aimed to investigate whether the basal HER2 subtype of breast cancer has distinguished characteristics. METHODS: We performed a substudy by using data from a retrospective multi-institutional cohort of JBCRG C03. Between 2001 and 2011, we identified 184 eligible patients who received concurrent neo-adjuvant chemotherapy (NAC) with trastuzumab for hormone receptor negative and HER2-positive breast cancer. We defined basal HER2 subtype breast cancer as HER2-positive, ER/PgR-negative, and basal markers (EGFR, CK14 or CK5/6) positive by immunohistochemistrical evaluation. The pathologic complete response (pCR) and disease-free survival (DFS) rates were compared between the two subtypes. RESULTS: A total of 127 (69.0%) patients achieved pCR after NAC and 29 (15.8%) patients experienced events of DFS within a 42 month median follow-up period (interquartile range 26-58 months). Although the basal HER2 subtype was related with poor DFS (3 year DFS: non-basal HER2, 95.0%; basal HER2, 86.9%; adjusted HR 3.4; 95% CI 1.2-14.5), neither the subtype (pCR: non-basal HER2, 75%; basal HER2, 66.7%; adjusted OR 0.60; 95% CI 0.27-1.28) nor the degree of expression of basal markers was significantly related with the pCR rate. CONCLUSION: Basal HER2 phenotype showed poor DFS, but equivalent pCR rate after concurrent neo-adjuvant chemotherapy with trastuzumab. A different treatment approach to basal-HER2 type is needed even for cases that achieved adequate clinical response after NAC. PMID- 29971626 TI - Endocrine therapy use in the twenty-first century: usage rates and temporal trends illustrate opportunities for improvement for South Carolina Medicaid women. AB - PURPOSE: This study examines endocrine therapy (ET) non-initiation, non adherence, and duration by age, race, temporal trend for South Carolina Medicaid enrolled women diagnosed with estrogen receptor-positive breast cancer between 2000 and 2014 (N = 3830). METHODS: Age, race, relative risk, and median duration of ET use were compared. Temporal trends in ET non-initiation, non-adherence, and duration were observed using linear and logistic regression models, controlling for age and race. RESULTS: Fifty-three percent of women in the sample did not initiate ET, with highest non-initiation rates among African Americans and survivors under age 50. Of those who did initiate ET, 42% were non-adherent with a median ET usage duration of 37 months. Twenty-one percent of initiators continued taking ET for 5 years or more. There was no change in the odds of ET non-initiation from 2000 to 2004 (OR 1.02, p = 0.67). The odds of ET non initiation decreased from 2005 to 2009 (OR 0.81, p < 0.001) but then increased from 2010 to 2014 (OR 1.08, p = 0.002). There was no change in the odds of ET non adherence from 2000 to 2006 (OR 1.02, p = 0.53), but from 2007 to 2012, the odds of ET non-adherence decreased each year (OR 0.93, p = 0.02). The average ET usage duration was increasing from 2000 to 2006 (beta = 2.74, p < 0.001) but decreasing from 2006 to 2012 (beta = - 1.46, p < 0.001). CONCLUSIONS: This study provides a realistic picture of the challenges associated with ET usage among South Carolina Medicaid breast cancer patients. It particularly highlights small improvements over time in ET usage rates, indicating more opportunities for improvement in ET initiation, adherence, and duration among younger women of lower socio-economic status. PMID- 29971627 TI - Protein N-glycosylation alteration and glycolysis inhibition both contribute to the antiproliferative action of 2-deoxyglucose in breast cancer cells. AB - PURPOSE: Cancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2 Deoxyglucose (2-DG) is used in this context due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N linked glycosylation interference. METHODS AND RESULTS: 2-Deoxyglucose behaved as an anticancer agent with a similar efficiency on cell number decrease between the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 breast cancer cells. It also interfered with the N-linked glycosylation process in both cell lines as illustrated by the migration profile of the lysosomal-associated membrane protein 2 and calumenin. These results are reinforced by the appearance of an abnormal Man7GlcNAc2 structure both on lipid-linked oligosaccharides and N-linked glycoproteins of 2-DG incubated MDA-MB-231 cells. Besides, 2-DG-induced a transient endoplasmic reticulum stress that was more sustained in MDA-MB-231 cells. Both changes were abrogated by mannose. 2-DG, even in the presence of mannose, decreased glycolysis in both cell lines. Mannose partially reversed the effects of 2-DG on cell numbers with N-linked glycosylation interference accounting for 37 and 47% of 2-DG anti-cancerous effects in MDA-MB-231 and MCF-7 cells, respectively. CONCLUSION: N-linked glycosylation interference and glycolysis disruption both contribute to the anticancer properties of 2-DG in breast cancer cells. PMID- 29971628 TI - Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the elongation factor 2 kinase (eEF-2K) signaling axis in triple-negative breast cancer. AB - BACKGROUND/PURPOSE: Triple-negative breast cancer (TNBC) is the most aggressive and chemoresistant subtype of breast cancer. Therefore, new molecular targets and treatments need to be developed to improve poor patient prognosis and survival. We have previously shown that eukaryotic elongation factor 2 kinase (eEF-2K) is highly expressed in TNBC cells, is associated with poor patient survival and prognosis, and promotes cell proliferation, migration, and invasion. In vivo targeting of eEF-2K significantly reduces the tumor growth of orthotopic TNBC xenograft mouse models, suggesting that eEF-2K may serve as a potential novel therapeutic target. METHODS/RESULTS: In the current study, we identified thymoquinone (TQ), an active ingredient of Nigella sativa, as a potential safe and effective eEF-2K inhibitor in TNBC. We demonstrated for the first time that TQ inhibits the protein and mRNA expression of eEF-2K, as well as the clinically relevant downstream targets, including Src/FAK and Akt, and induces the tumor suppressor miR-603, in response to NF-kB inhibition. This effect was associated with a significant decrease in the proliferation, colony formation, migration, and invasion of TNBC cells. Furthermore, systemic in vivo injection of TQ (20 and 100 mg/kg) significantly reduced the growth of MDA-MB-231 tumors and inhibited the eEF-2K expression in an orthotopic tumor model in mice. CONCLUSION: Our study provides first evidence that TQ treatment inhibits cell proliferation, migration/invasion, and tumor growth, in part through the inhibition of eEF-2K signaling in TNBC. Thus, our findings suggest that systemic TQ treatment may be used as a targeted therapeutic strategy for the inhibition of eEF-2K in TNBC tumor growth and progression. PMID- 29971630 TI - The effect of short-term health promotion intervention on motor function in community-dwelling older adults. AB - BACKGROUND: Slow walking speed as one indicator of physical frailty has been found to be associated with deterioration of the health status. Although many reports have shown that exercise training improves motor function, it is unclear whether a group-based and short-term health promotion intervention will improve motor function in older adults. AIMS: This study aimed to examine the effectiveness of a short-term health promotion intervention on motor function in community-dwelling older adults. METHODS: A 6-month middle-term and moderate intensity programme (MTMIP) and a 6-week short-term high-intensity programme (STHIP) were conducted. There were 28 and 29 subjects selected for the MTMIP and STHIP, respectively. The difference in motor function test outcomes was compared by assessment of comfortable walking speed, maximal walking speed, a sit-to-stand test (STS), and a timed up-and-go test (TUG). RESULTS: Comfortable walking speed, maximum walking speed, STS and TUG were significantly improved at end of the programme in the STHIP group (p = 0.02, p = 0.03, p < 0.001 and p = 0.002). Multiple regression analysis revealed that implementation of STHIP had a significant effect on end-of-programme comfortable walking speed (beta = 0.19, p = 0.006, 95% CI 0.06 to 0.32). DISCUSSION: It was assumed that the training content of the STHIP, with its emphasis on high intensity and physical performance, was the main factor in improved walking speed. CONCLUSIONS: Our results demonstrated the effectiveness of STHIP on motor function. These findings could help support development of more effective intervention methods in community-dwelling older adults. PMID- 29971629 TI - Synthesis of Au@Ag core-shell nanostructures with a poly(3,4-dihydroxy-L phenylalanine) interlayer for surface-enhanced Raman scattering imaging of epithelial cells. AB - Poly(3,4-dihydroxy-L-phenylalanine) (polyDOPA) is a stable and biocompatible reducing agent. A versatile strategy is described here for the synthesis of core shell Au@Ag nanostructures containing a polyDOPA interlayer. The latter provides abundant sites for deposition of nanocomposites, to immobilize molecules and to grow shells. The Au@polyDOPA@Ag nanoparticles are shown to generate strong and stable surface-enhanced Raman spectroscopy (SERS) signals compared to bare AuNPs and bare AgNPs. Folic acid was then immobilized on Au@polyDOPA@Ag nanoparticles and then applied to SERS imaging of human lung adenocarcinoma cell line A549 by the specific recognition of the folic acid receptor. The folic acid-conjugated SERS tags were promising to be nanoplatforms for imaging of cancer cells. Graphical abstract An Au@Ag core-shell nanostructures SERS nanotag with a polyDOPA interlayer was fabricated and then applied to SERS imaging of epithelial cells. (DOPA: 3,4-Dihydroxy-[L-phenylalanine]; FA: folic acid; 4-MBA: 4 mercaptobenzoic acid). PMID- 29971631 TI - CD44v9 as a poor prognostic factor of triple-negative breast cancer treated with neoadjuvant chemotherapy. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard therapeutic strategy for triple-negative breast cancer (TNBC). TNBC patients with residual disease after NAC have a significantly worse survival than those with pathological complete response (pCR); however, there is no apparent prognostic factor for non pCR patients. Cancer stemness or epithelial-mesenchymal transition (EMT) might influence the sensitivity to chemotherapy. PATIENTS AND METHODS: Forty-eight patients with TNBC who were treated with NAC were available were included in this study. The expressions of stemness marker CD44v9, EMT marker vimentin and BRCA1, and basal phenotype were evaluated with immunohistochemistry. The relationships between the expression of these proteins and the pCR rate and the prognosis, especially in the patients with residual tumors, were investigated. RESULTS: Among the 48 patients, pCR was achieved in 14 cases. High nuclear grade and basal phenotype in the pre-NAC samples were significantly correlated with pCR (p = 0.0458 and 0.0343). There were no significant relationships between the pCR rate and the expression of CD44v9, vimentin, or BRCA1. Achieving pCR was significantly correlated with longer distant metastasis-free survival (DMFS) (p = 0.0206). High CD44v9 expression was significantly associated with shorter DMFS (p = 0.0291). Among the patients in whom pCR was not achieved, high grade in the residual tumor cells, poor pathological response and high CD44v9 expression in the pre-treatment CNB samples were significantly correlated with a poor DMFS (p = 0.0433, 0.0406 and p = 0.0333). In addition, high grade in the residual tumor cells was significantly associated with high CD44v9 expression in the pre-treatment CNB (p = 0.0389). CONCLUSIONS: High CD44v9 expression in pre-NAC samples was associated with poor prognosis in TNBC patients treated with NAC, especially for those in whom pCR was not achieved. PMID- 29971633 TI - Robust Identification of Rich-Club Organization in Weighted and Dense Structural Connectomes. AB - The human brain is a complex network, in which some brain regions, denoted as 'hub' regions, play critically important roles. Some of these hubs are highly interconnected forming a rich-club organization, which has been identified based on the degree metric from structural connectomes constructed using diffusion tensor imaging (DTI)-based fiber tractography. However, given the limitations of DTI, the yielded structural connectomes are largely compromised, possibly affecting the characterization of rich-club organizations. Recent progress in diffusion MRI and fiber tractography now enable more reliable but also very dense structural connectomes to be achieved. However, while the existing rich-club analysis method is based on weighted networks, it is essentially built upon degree metric and, therefore, not suitable for identifying rich-club organizations from such dense networks, as it yields nodes with indistinguishably high degrees. Therefore, we propose a novel method, i.e. Rich-club organization Identification using Combined H-degree and Effective strength to h-degree Ratio (RICHER), to identify rich-club organizations from dense weighted networks. Overall, it is shown that more robust rich-club organizations can be achieved using our proposed framework (i.e., state-of-the-art fiber tractography approaches and our proposed RICHER method) in comparison to the previous method focusing on weighted networks based on degree, i.e., RC-degree. Furthermore, by simulating network attacks in 3 ways, i.e., attack to non-rich-club/non-rich-club edges (NRC2NRC), rich-club/non-rich-club edges (RC2NRC), and rich-club/rich-club edges (RC2RC), brain network damage consequences have been evaluated in terms of global efficiency (GE) reductions. As expected, significant GE reductions have been detected using our proposed framework among conditions, i.e., NRC2NRC < RC2NRC, NRC2NRC < RC2RC and RC2NRC < RC2RC, which however have not been detected otherwise. PMID- 29971632 TI - Preeclampsia and Related Cardiovascular Risk: Common Genetic Background. AB - PURPOSE OF REVIEW: Preeclampsia (PE) is a hypertensive disorder exclusive for pregnancy. It affects women all over the world and poses a great threat to life, both for mother and child. No definitive treatment exists and placenta delivery comprises the only known cure for PE. One of the most severe complications observed in preeclamptic women is the occurrence of cardiovascular diseases (CVDs) later in life. RECENT FINDINGS: Both PE and CVDs share some of their pathogenic pathways and gene variations. Thus far, a number of publications have examined those relationships; however, almost all of them focus only on common risk factors. The precise pathomechanism and genetic basis of PE and its associated cardiovascular complications remain unknown. Therefore, the aim of this review is to unify and clarify the current state of knowledge and provide direction for future studies, especially those regarding the genetic aspect. PMID- 29971634 TI - Efficient Mapping of the Motor Cortex with Navigated Biphasic Paired-Pulse Transcranial Magnetic Stimulation. AB - Navigated transcranial magnetic stimulation (nTMS) can be applied to locate cortical muscle representations. Usually, single TMS pulses are targeted to the motor cortex with the help of neuronavigation and by measuring motor evoked potential (MEP) amplitudes from the peripheral muscles. The efficacy of single pulse TMS to induce MEPs has been shown to increase by applying facilitatory paired-pulse TMS (ppTMS). Therefore, the aim was to study whether the facilitatory ppTMS could enable more efficient motor mapping. Biphasic single pulse TMS and ppTMS with inter-stimulus intervals (ISIs) of 1.4 and 2.8 ms were applied to measure resting motor thresholds (rMTs) as a percentage of the maximal stimulator output and to determine the cortical representation areas of the right first dorsal interosseous muscle in healthy volunteers. The areas, shapes, hotspots, and center of gravities (CoGs) of the representations were calculated. Biphasic ppTMS with ISI of 1.4 ms resulted in lower rMTs than those obtained with the other protocols (p = 0.001). With ISI of 2.8 ms, rMT was lower than with single-pulse TMS (p = 0.032). The ppTMS mapping was thus performed with lower intensity than when using single-pulse TMS. The areas, shapes, hotspots, and CoGs of the muscle representations were in agreement. Hence, biphasic ppTMS has potential in the mapping of cortical hand representations in healthy individuals as an alternative for single-pulses, but with lower stimulation intensity by utilizing cortical facilitatory mechanism. This could improve application of nTMS in subjects with low motor tract excitability. PMID- 29971635 TI - Workforce Configurations to Provide High-Quality, Comprehensive Primary Care: a Mixed-Method Exploration of Staffing for Four Types of Primary Care Practices. AB - BACKGROUND: Broad consensus exists about the value and principles of primary care; however, little is known about the workforce configurations required to deliver it. OBJECTIVE: The aim of this study was to explore the team configurations and associated costs required to deliver high-quality, comprehensive primary care. METHODS: We used a mixed-method and consensus building process to develop staffing models based on data from 73 exemplary practices, findings from 8 site visits, and input from an expert panel. We first defined high-quality, comprehensive primary care and explicated the specific functions needed to deliver it. We translated the functions into full-time equivalent staffing requirements for a practice serving a panel of 10,000 adults and then revised the models to reflect the divergent needs of practices serving older adults, patients with higher social needs, and a rural community. Finally, we estimated the labor and overhead costs associated with each model. RESULTS: A primary care practice needs a mix of 37 team members, including 8 primary care providers (PCPs), at a cost of $45 per patient per month (PPPM), to provide comprehensive primary care to a panel of 10,000 actively managed adults. A practice requires a team of 52 staff (including 12 PCPs) at $64 PPPM to care for a panel of 10,000 adults with a high proportion of older patients, and 50 staff (with 10 PCPs) at $56 PPPM for a panel of 10,000 with high social needs. In rural areas, a practice needs 22 team members (with 4 PCPs) at $46 PPPM to serve a panel of 5000 adults. CONCLUSIONS: Our estimates provide health care decision makers with needed guideposts for considering primary care staffing and financing and inform broader discussions on primary care innovations and the necessary resources to provide high-quality, comprehensive primary care in the USA. PMID- 29971636 TI - Assessment of Implantable Cardioverter-Defibrillator Used in Heart Failure with Reduced Ejection Fraction as Primary Prevention in an Underserved Population. PMID- 29971637 TI - Identifying barriers to cancer survivors sharing their survivorship care plans with their healthcare provider. AB - PURPOSE: To understand what factors influence whether a cancer survivor will share their survivorship care plan (SCP) with their healthcare provider (HCP). METHODS: We used data from 3231 cancer survivors who utilized the OncoLink SCP resource between 2009 and 2016. Random forest and stepwise regression were used to identify predictors of SCP satisfaction and barriers to survivors sharing their care plans with their HCPs. RESULTS: Eighty-seven percent of users rated their satisfaction with their SCP as good or better; however, only 70% of survivors planned to share their SCP with their HCP. The most commonly reported reason for not sharing was a feeling that their HCP would not care. Self-reported satisfaction with their SCP was strongest predictor of whether a survivor would share their SCP. Gender, cancer status, number of chemotherapies received, and who was managing their healthcare were all associated with self-reported survivor satisfaction with their SCP. CONCLUSIONS: Survivor satisfaction with SCPs was high, but there was a disconnect in the number of satisfied survivors and the number of survivors planning to share their SCP with their HCP. To bridge this gap, additional prompts that HCPs are expecting this information should be added to the care plans. IMPLICATIONS FOR CANCER SURVIVORS: One of the primary functions of survivorship care plans is to improve communication between survivor and healthcare provider. While survivors are overwhelmingly satisfied with their SCP, additional steps are necessary to get survivors to share their SCP with their HCP. PMID- 29971638 TI - Correction to: Veteran Coffee Socials: A Community-Building Strategy for Enhancing Community Reintegration of Veterans. AB - The original version of this article unfortunately contained a mistake in co author name and his affiliation. The author name should be Anthony Russo instead it was published as Antony Russo and his affiliation has been corrected. PMID- 29971639 TI - G protein-coupled receptor LGR6 is an independent risk factor for colon adenocarcinoma. AB - LGR6 is a member of the G protein-coupled receptor family that plays a tumor suppressive role in colon cancer. However, the relationship between LGR6 expression in patients and clinicopathological factors remains unclear. This study aimed to clarify whether the expression level of LGR6 is correlated with colon adenocarcinoma progression. Immunohistochemistry was used to detect LGR6 expression in colon adenoma tissues (n = 21), colon adenocarcinoma tissues (n = 156), and adjacent normal tissues (n = 124). The expression levels of LGR6 in colon adenoma and adenocarcinoma were significantly higher than those in normal colon epithelial tissues (P < 0.001). Low LGR6 expression predicted a short overall survival in patients with colon adenocarcinoma (log-rank test, P = 0.016). Univariate and multivariate survival analyses showed that, in addition to N and M classification, LGR6 expression served as an independent prognostic factor. Thus, low expression of LGR6 can be used as an independent prognostic parameter in patients with colon adenocarcinoma. PMID- 29971640 TI - Dental stem cell and dental tissue regeneration. AB - The teeth are highly differentiated chewing organs formed by the development of tooth germ tissue located in the jaw and consist of the enamel, dentin, cementum, pulp, and periodontal tissue. Moreover, the teeth have a complicated regulatory mechanism, special histologic origin, diverse structure, and important function in mastication, articulation, and aesthetics. These characteristics, to a certain extent, greatly complicate the research in tooth regeneration. Recently, new ideas for tooth and tissue regeneration have begun to appear with rapid developments in the theories and technologies in tissue engineering. Numerous types of stem cells have been isolated from dental tissue, such as dental pulp stem cells (DPSCs), stem cells isolated from human pulp of exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAPs), and dental follicle cells (DFCs). All these cells can regenerate the tissue of tooth. This review outlines the cell types and strategies of stem cell therapy applied in tooth regeneration, in order to provide theoretical basis for clinical treatments. PMID- 29971641 TI - Fluorescent reporter transgenic mice for in vivo live imaging of angiogenesis and lymphangiogenesis. AB - The study of lymphangiogenesis is an emerging science that has revealed the lymphatic system as a central player in many pathological conditions including cancer metastasis, lymphedema, and organ graft rejection. A thorough understanding of the mechanisms of lymphatic growth will play a key role in the development of therapeutic strategies against these conditions. Despite the known potential of this field, the study of lymphatics has historically lagged behind that of hemangiogenesis. Until recently, significant strides in lymphatic studies were impeded by a lack of lymphatic-specific markers and suitable experimental models compared to those of the more immediately visible blood vasculature. Lymphangiogenesis has also been shown to be a key phenomenon in developmental biological processes, such as cell proliferation, guided migration, differentiation, and cell-to-cell communication, making lymphatic-specific visualization techniques highly desirable and desperately needed. Imaging modalities including immunohistochemistry and in situ hybridization are limited by the need to sacrifice animal models for tissue harvesting at every experimental time point. Moreover, the processes of mounting and staining harvested tissues may introduce artifacts that can confound results. These traditional methods for investigating lymphatic and blood vasculature are associated with several problems including animal variability (e.g., between mice) when replicating lymphatic growth environments and the cost concerns of prolonged, labor-intensive studies, all of which complicate the study of dynamic lymphatic processes. With the discovery of lymphatic-specific markers, researchers have been able to develop several lymphatic and blood vessel specific, promoter-driven, fluorescent-reporter transgenic mice for visualization of lymphatics in vivo and in vitro. For instance, GFP, mOrange, tdTomato, and other fluorescent proteins can be expressed under control of a lymphatic-specific marker like Prospero-related homeobox 1 (Prox1), which is a highly conserved transcription factor for determining embryonic organogenesis in vertebrates that is implicated in lymphangiogenesis as well as several human cancers. Importantly, Prox1-null mouse embryos develop without lymphatic vessels. In human adults, Prox1 maintains lymphatic endothelial cells and upregulates proteins associated with lymphangiogenesis (e.g., VEGFR-3) and downregulates angiogenesis-associated gene expression (e.g., STAT6). To visualize lymphatic development in the context of angiogenesis, dual fluorescent-transgenic reporters, like Prox1-GFP/Flt1-DsRed mice, have been bred to characterize lymphatic and blood vessels simultaneously in vivo. In this review, we discuss the trends in lymphatic visualization and the potential usage of transgenic breeds in hemangiogenesis and lymphangiogenesis research to understand spatial and temporal correlations between vascular development and pathological progression. PMID- 29971643 TI - The bottleneck of the psychological refractory period effect involves timing of response initiation rather than response selection. AB - The Psychological Refractory Period (PRP) effect is a delay in responding that is assumed to be caused by a bottleneck that prevents preparation of a second action until preparation of the previous action has been completed. The bottleneck is usually attributed to a limitation that prevents concurrent selection of two responses. However, evidence reviewed here challenges this selection interpretation. We propose instead that the bottleneck is due to a process that programs the timing of response initiation, and which must be completed immediately prior to responding. This hypothesis is based on two conclusions from recent developments in research, which includes findings from paradigms that do not involve the PRP. The first conclusion is from studies involving the startle response and single-task simple (precued) reaction time; these studies indicate that programming the timing of response onsets is needed to enable response initiation. This programing takes longer for more complicated timing, and must be delayed until just prior to responding. The second conclusion is from studies of concurrent rhythmic movements demonstrating that the representation of timing is restricted to one temporal frame unless very rapid performance enables parallel timing. These findings reveal limitations that can combine to produce the PRP bottleneck. This interpretation clarifies otherwise puzzling aspects of the PRP effect and indicates that a fundamental restriction concerning response timing may underlie both limitations and the PRP effect that they produce. This restriction might arise because timing is controlled by subcortical neural structures with limited working memory. PMID- 29971642 TI - The Fabrication of Large-Area, Uniform Graphene Nanomeshes for High-Speed, Room Temperature Direct Terahertz Detection. AB - In recent years, graphene nanomesh (GNM), a material with high flexibility and tunable electronic properties, has attracted considerable attention from researchers due to its wide applications in the fields of nanoscience and nanotechnology. Herein, we have processed large-area, uniform arrays of rectangular graphene nanomesh (r-GNM) and circular graphene nanomesh (c-GNM) with different neck widths by electron beam lithography (EBL). The electronic properties of those high-quality GNM samples have been characterized systematically. Electrical measurements illustrated that top-gated field effect transistors with different neck widths of the GNM possessed different Ion/Ioff ratios. In particular, the devices based on r-GNM with a neck width of 30 nm were found to possess the largest Ion/Ioff ratio of ~ 100, and the band gap of the r GNM was estimated to be 0.23 eV, which, to the best of authors' knowledge, is the highest value for graphene ribbons or a GNM with a neck width under 30 nm. Furthermore, the terahertz response of large-area r-GNM devices based on the photoconductive effect was estimated to be 10 mA/W at room temperature. We also explored the practical application of terahertz imaging, showing that the devices can be used in a feasible setting with a response time < 20 ms; this enables accurate and fast imaging of macroscopic samples. PMID- 29971644 TI - Optimal response vigor and choice under non-stationary outcome values. AB - Within a rational framework, a decision-maker selects actions based on the reward maximization principle, which stipulates that they acquire outcomes with the highest value at the lowest cost. Action selection can be divided into two dimensions: selecting an action from various alternatives, and choosing its vigor, i.e., how fast the selected action should be executed. Both of these dimensions depend on the values of outcomes, which are often affected as more outcomes are consumed together with their associated actions. Despite this, previous research has only addressed the computational substrate of optimal actions in the specific condition that the values of outcomes are constant. It is not known what actions are optimal when the values of outcomes are non stationary. Here, based on an optimal control framework, we derive a computational model for optimal actions when outcome values are non-stationary. The results imply that, even when the values of outcomes are changing, the optimal response rate is constant rather than decreasing. This finding shows that, in contrast to previous theories, commonly observed changes in action rate cannot be attributed solely to changes in outcome value. We then prove that this observation can be explained based on uncertainty about temporal horizons; e.g., the session duration. We further show that, when multiple outcomes are available, the model explains probability matching as well as maximization strategies. The model therefore provides a quantitative analysis of optimal action and explicit predictions for future testing. PMID- 29971645 TI - Peripartum Cardiomyopathy and Preeclampsia: Overlapping Diseases of Pregnancy. AB - PURPOSE OF REVIEW: Hypertensive disorders of pregnancy (HDP) often result in cardiac dysfunction and have been variably included as a risk factor for peripartum cardiomyopathy (PPCM). However, there is debate regarding the relationship between the two entities. RECENT FINDINGS: Diastolic dysfunction appears to be more predominant among gravidas with HDP, while systolic dysfunction predominates in PPCM. However, this finding is not consistent in all studies. Recent examinations of mortality and morbidity associated with PPCM in the setting of HDP do not demonstrate a predominant pattern with a mixture of results. Further, right ventricular dysfunction is identified to be a common theme in both populations. From a basic science perspective, there is evidence to demonstrate a predominantly anti-angiogenic milieu in both PPCM and HDP. PPCM and HDP associated cardiomyopathy overlap significantly. As such, unifying theories for their pathophysiology should be investigated. PMID- 29971646 TI - Alzheimer's Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing. AB - The advent of next-generation sequencing has changed genetic diagnostics, allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated FTD and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of AD and FTD and suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarkers testing, AD and FTD can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis and specific etiology of the disease, as well as provide information for the family and determine eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests so they can make an informed decision about testing. PMID- 29971648 TI - Surgical outcomes in 13 patients with bronchopulmonary carcinoid tumors including one recurrent oncocytic carcinoid tumor. AB - INTRODUCTION: Bronchopulmonary carcinoids are low-grade tumors for which the standard treatment is surgical resection. We retrospectively evaluated the surgical outcomes. METHODS: Thirteen patients underwent surgical resection for them at our institution between January 2005 and December 2016. We collected their clinicopathologic data to evaluate surgical outcomes. RESULTS: The 13 patients comprised seven men and six women. Complete resection was performed in all cases. All the tumors were typical carcinoids, including one oncocytic carcinoid which showed highest fluorodeoxyglucose (FDG) uptake (SUVmax 45.7). The 5-year overall survival rates were 100%. The only patient with oncocytic carcinoid developed recurrence of liver metastasis 49 months after the primary lung resection. The metastasis showed low FDG uptake (SUVmax 2.8) and its histology was typical carcinoid and not oncocytic carcinoid. CONCLUSION: Surgical outcomes in our patients were favorable. In oncocytic carcinoid, metastatic site may have a radiologic and histologic appearance different from the primary tumor. PMID- 29971647 TI - Biomarkers and Pharmacogenomics in Kidney Transplantation. AB - This review is focused on present and future biomarkers, along with pharmacogenomics used in clinical practice for kidney transplantation. It aims to highlight biomarkers that could potentially be used to improve kidney transplant early and long-term graft survival, but also potentially patient co-morbidity. Future directions for improving outcomes are discussed, which include immune tolerance and personalising immunosuppression regimens. PMID- 29971650 TI - Interrelationship between late gestational ewe factor and early life lamb factors in semi-arid tropical region. AB - The limitation in feed availability in the semi-arid region during the lean period can result in a variation of the body condition, body weight of pregnant ewe which in turn may affect the lamb birth weight, colostrum immunoglobulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1). Therefore, the present study was initiated to assess the interrelationship between late gestational ewe factor and early life lamb factors in the semi-arid tropical region. For this purpose, 83 Malpura and 45 Avikaline pregnant ewes were selected and their body condition score (BCS) at late gestation, body weight at lambing, and birth weight of lambs was recorded. The BCS of ewes in late gestation had significant (P < 0.001) positive correlation (r2 = 0.465) with the birth weight of lambs. The body weight at lambing was significantly (P < 0.05) higher in single-lamber ewes as compared to twin-bearing ewes. The plasma IGF-1 of lamb increased significantly (P < 0.05) with the increase of BCS of ewe at the late gestation as well as body weight after lambing. The colostrum of twin-lamb producing ewes had higher (P < 0.05) IgG content than single-lamb producing ewes. The concentration of IGF-1 was significantly (P < 0.05) higher in single-born lamb as compared to twin-born lamb. Based on the results of the present study, it is to conclude that higher BCS at late gestation and higher body weight of ewes at lambing is desirable for producing lambs with a higher birth weight having higher growth potential as well as chances of survival. PMID- 29971649 TI - Strategies of the control of an outbreak of leptospiral infection in dairy cattle in Northeastern Brazil. AB - The aim of the present study was to describe the strategies of the control of an outbreak of leptospiral infection in dairy cattle in Maranhao State, Northeastern Brazil. In the period from January to July 2015, 18 (17%) out of 106 cows presented abortion, six (5.7%) stillbirth, and 12 (11.3%) repeated estrus, totaling 24 animals with reproductive problems. The diagnosis of leptospirosis was based on serology (microscopic agglutination test-MAT), bacteriological culture, and polymerase chain reaction (PCR). Antibiotic therapy, vaccination protocols, and changes in management practices were suggested as control measures. Of all animals on the farm (n = 280), 136 (48.6%) were seropositive for at least one serovar of Leptospira sp. No pure leptospiral culture was obtained. Eight of the animals with reproductive problems yielded positive PCR results (vaginal fluid of seven animals and urine and vaginal fluid of one animal). Genetic sequencing of a vaginal fluid/urine PCR-positive sample revealed Leptospira borgpetersenii. One year after the adoption of control measures, no reproductive problems were observed. Thus, leptospirosis probably caused the reproductive failures in the herd, and the control and prevention measures implemented were efficient in controlling the disease. PMID- 29971651 TI - A Qualitative Study of the Acceptability of the Proposed ICD-11 Gender Incongruence of Childhood Diagnosis Among Transgender Adults Who Were Labeled Due to Their Gender Identity Since Childhood. AB - For the forthcoming ICD-11, the ICD-10 category of Gender Identity Disorder of Childhood has been reformulated as Gender Incongruence of Childhood (GIC) and moved out of the mental disorders chapter. Proponents of eliminating the GIC diagnosis altogether claim that it is unnecessary and inherently harmful, although they do not eschew the diagnosis for adolescents and adults. Using a qualitative methodology, this study examined the impact of receiving a diagnosis related to gender identity as a child among transgender people who had had this experience, and evaluated participants' views of the acceptability and usefulness of the ICD-11 GIC proposal. Participants receiving health services at a specialized public clinic for transgender health in Mexico City who had received some form of diagnosis in childhood were referred to participate in a semistructured interview. A sample of 12 transgender people (eight transgender women and four transgender men; ages 18-49) was necessary to reach saturation. Diagnoses received were non-specific rather than formal gender identity diagnoses, were experienced by participants as negative, and were used to justify potentially harmful interventions. However, when participants reviewed the ICD-11 proposals for GIC, all indicated that the category was necessary and important and could have a range of personal, familial, and social benefits. They agreed with its placement in a new chapter on Conditions Related to Sexual Health and endorsed the proposed definition and name of the category. Although this study involved a small and specific sample, the results raise questions about the claim that the diagnosis is inherently harmful and universally deplored by transgender people. PMID- 29971652 TI - An Exploration of the Relations Between Self-Reported Gender Identity and Sexual Orientation in an Online Sample of Cisgender Individuals. AB - The present study explored the relations between self-reported aspects of gender identity and sexual orientation in an online sample of 4756 cisgender English speaking participants (1129 men) using the Multi-Gender Identity Questionnaire and a sexual orientation questionnaire. Participants also labeled their sexual orientation. We found a wide range of gender experiences in the sample, with 38% of the participants feeling also as the "other" gender, 39% wishing they were the "other" gender, and 35% wishing they had the body of the "other" sex. Variability in these measures was very weakly related to sexual orientation, and these relations were gender-specific, being mostly U shaped (or inverted-U shaped) in men and mostly linear asymptotic in women. Thus, in women, feeling-as-a-woman was highest in the exclusively heterosexual group, somewhat lower in the mostly heterosexual group, and lowest in the bisexual, mostly homosexual, and exclusively homosexual groups, which did not differ, and the reverse was true for feeling-as-a-man (i.e., lowest in the exclusively heterosexual group and highest in the bisexual, mostly homosexual, and exclusively homosexual groups). In men, feeling-as-a-man was highest at both ends of the sexual orientation continuum and lowest at its center, and the reverse was true for feeling-as-a-woman. Similar relations were evident also for the other aspects of gender identity. This study adds to a growing body of literature that questions dichotomous conventions within the science of gender and sexuality. Moreover, our results undermine the tight link assumed to exist between sexual and gender identities, and instead posit them as weakly correlated constructs. PMID- 29971653 TI - Does an Autism Spectrum Disorder Care Pathway Improve Care for Children and Adolescents with ASD in Inpatient Psychiatric Units? AB - Youth with autism spectrum disorder (ASD) are psychiatrically hospitalized at high rates. Though specialized psychiatric units are effective, few specialized units exist. The ASD Care Pathway (ASD-CP) was developed as a scalable approach to improving care in general psychiatric units through staff training and a package of autism-specific intervention strategies. An evaluation of the effectiveness of the ASD-CP in a public hospital child psychiatric service compared 18 months (n = 17) versus 18 months (n = 20) post implementation. Average length of hospital stay decreased 40% (22.4-13.4 days) and use of crisis interventions decreased 77% (holds/restraints; 0.65/day to 0.15/day), though each result only approached statistical significance (p = 0.07; 0.057). This study provides preliminary evidence for improved outcomes after implementation of an ASD-CP. PMID- 29971654 TI - Differences of Symptom Distribution Across Adult Age in High Functioning Individuals on the Autism Spectrum Using Subscales of the Autism Spectrum Quotient. AB - Little is known about the distribution of symptoms of Autism Spectrum Disorder (ASD) across the lifespan. In this cross-sectional study, we examined differences between subscales of the Autism Spectrum Quotient (AQ) between different age groups. 654 Subjects referred to an outpatient University Clinic with specialized expertise in ASD were included. Data collection, including self-report and report by spouses, was performed from 2008 to 2014. Results show no significant differences between the different age groups. AQ scores based on self-report corresponded remarkably well with those from their spouses. In conclusion, the main traits of an ASD appear stable between the different age groups. Also, the results show that using the AQ, patients have largely the same appreciation of symptoms as their spouses. PMID- 29971655 TI - Adult Siblings Who Have a Brother or Sister with Autism: Between-Family and Within-Family Variations in Sibling Relationships. AB - Prior research on the sibling relationship in the context of autism spectrum disorder (ASD) has included only one sibling per family. We used multi-level modeling to examine aspects of the sibling relationship in 207 adults who have a brother or sister with ASD from 125 families, investigating variability in sibling relationship quality and pessimism within and between families. We found that there was greater variability in aspects of the sibling relationship with the brother or sister with ASD within families than between families. Sibling individual-level factors were associated with positive affect in the sibling relationship, while family-level factors were associated with the sibling's pessimism about their brother or sister's future. The findings illustrate the unique experiences of siblings within families. PMID- 29971656 TI - Training Physical Therapists in Early ASD Screening. AB - Physical therapists (PTs) are often one of the first professionals to evaluate children at risk. To examine the effect of an early screening training on pediatric PTs': (1) knowledge of autism spectrum disorder (ASD), (2) clinical self-efficacy, and (3) identification of markers. Twenty-six PTs participated in a 2-day "Early ASD Screening" workshop. The ASD Knowledge and Self-Efficacy Questionnaire, and video case study analysis were completed pre- and post training. Changes following training were significant for ASD knowledge related to etiology and learning performance, early signs, risk factors, and clinical self-efficacy. Rating the videoed case study after the training, was significantly more accurate than it was before. Training PTs is important for enhancing early identification of ASD. PMID- 29971657 TI - Brief Report: Learning Language Through Overhearing in Children with ASD. AB - We explored whether children with autism spectrum disorder (ASD) learn new nouns from overheard speech. Thirteen children (4-5 years) with ASD participated in an Addressed condition, in which they were directly taught a novel label (e.g., toma) for one of three novel objects, and an Overheard condition, in which the objects and label were presented in a conversation between two adults. In both conditions, children were then asked to identify the labeled object (e.g., "find the toma"). Children selected the target novel object at rates above chance in the Addressed condition, and of critical importance, they also did so in the Overheard condition. This suggests that, like TD children, children with ASD may learn from language that is not directed to them. PMID- 29971658 TI - An Investigation of Gelotophobia in Individuals with a Diagnosis of High Functioning Autism Spectrum Disorder. AB - Samson et al. (Journal of Autism and Developmental Disorders 41:475-483, 2011) conducted the first empirical investigation examining the fear of being laughed at (gelotophobia) and its prevalence in individuals with high-functioning autism spectrum disorder (hfASD). The present research examined gelotophobia in relation to social functioning, perceived social support, life satisfaction and quality of life (QoL) in individuals with hfASD, including past experiences of bullying and the presence of comorbid psychopathology. Participants were 103 adults with a clinical diagnosis of hfASD and 137 typically developing controls. Individuals with hfASD presented with higher rates of gelotophobia symptomatology in comparison to controls (87.4 vs. 22.6% respectively). It was also found that social functioning, past experiences of bullying, anxiety and life satisfaction were predictors of gelotophobia amongst individuals with hfASD. PMID- 29971659 TI - Emotional Processing in Autism Spectrum Disorders: Effects of Age, Emotional Valence, and Social Engagement on Emotional Language Use. AB - Children with autism spectrum disorders (ASD) show deficits in reporting others' emotions (Lartseva et al. in Front Hum Neurosci 8:991, 2015) and in deriving meaning in social contexts (Klin et al. in Handbook of autism and pervasive developmental disorders, Wiley, Hoboken, 2005). However, researchers often use stimuli that conflate salient emotional and social information. Using a matched pairs design, the impact of emotional and social information on emotional language in pre-school and school-age children, with and without ASD, was assessed with a picture description task comprising rated stimuli from the Pictures with Social Contexts and Emotional Scenes database (Teh et al. in Behav Res Methods, https://doi.org/10.3758/s13428-017-0947-x , 2017). Results showed both groups with ASD produced fewer emotional terms than typically developing children, but the effects were moderated by valence, social engagement, and age. Implications for theory and clinical practice are discussed. PMID- 29971660 TI - Young Adults on the Autism Spectrum: The Struggle for Appropriate Services. AB - In the United States, young adults with an autism spectrum disorder (ASD) lose federally mandated supports upon leaving high school. To arrange adult services, families must prove their young adult's eligibility and find competent service providers. National-level statistics regarding receipt of appropriate adult services are discouraging, but little is known about families' lived experience with regard to services. Therefore, qualitative interviews focused on the search for and satisfaction with adult services were conducted with parents of young adults with ASD, then analyzed using the constant comparative method. Emergent themes included Bureaucracy and Fighting for Access, Staffing Issues, Program Suitability, and "Doing It Yourself." The need to improve service access and delivery is discussed, as are issues facing specific ASD subgroups. PMID- 29971662 TI - Increasing Caregivers' Adherence to an Early-Literacy Intervention Improves the Print Knowledge of Children with Language Impairment. AB - This study investigated the effects of four behavior-change techniques for caregivers implementing a 15-week literacy intervention with their children with language impairment. Techniques include modeling, encouragement, feedback, and rewards. Random assignment within a factorial experimental design was used to determine which behavior-change technique(s) each of the 128 caregivers would receive. Caregivers' adherence was assessed for frequency and dosage of intervention based on submission of logs and tape recordings. Children's print knowledge was assessed at pre- and posttest to assess literacy skills. Results showed that children whose caregivers were rewarded 50 cents per session to implement the intervention made significantly greater gains in print knowledge over the treatment period. Further, these effects were fully mediated by effects of the behavior-change technique on caregivers' adherence to the intervention. PMID- 29971661 TI - Measuring Individual Differences in Cognitive, Affective, and Spontaneous Theory of Mind Among School-Aged Children with Autism Spectrum Disorder. AB - The present study examined individual differences in theory of mind (ToM) among a group of 60 children (7-11 years-old) with autism spectrum disorder (ASD) and average intelligence. Using open-ended and structured tasks to measure affective ToM, cognitive ToM, and spontaneous social attribution, we explored the nature of ToM and assessed whether ToM predicts the phenotypic heterogeneity in ASD through structural equation modeling. Affective ToM uniquely predicted social symptom severity, whereas no ToM types predicted parent reported social functioning. Our findings suggest that differentiating among theoretical components is crucial for future ToM research in ASD, and ToM challenges related to reasoning about others' emotions may be particularly useful in distinguishing children with worse social symptoms of ASD. PMID- 29971663 TI - Social Interactions Between 24-Month-Old Children and Their Older Sibling with Autism Spectrum Disorder: Characteristics and Association with Social Communicative Development. AB - This study compared sibling interactions between 24-month-old children and their older sibling with ASD (high-risk; n = 24) with 24-month-old children and their typically developing older sibling (low-risk; n = 32). First, high-risk sibling pairs showed lower levels of positive behaviour and younger siblings of children with ASD imitated their older sibling less. Second, in the high-risk group positive interactions were positively associated with the youngest child's language abilities. However, this association was no longer significant after controlling for language abilities at 14 months. Third, more total interactions in the high-risk group, both negative and positive, were associated with more ASD characteristics. Thus, early sibling interactions might reveal interesting information in light of the (atypical) developmental trajectories of younger siblings of children with ASD. PMID- 29971664 TI - Resilience of an aquatic macrophyte to an anthropogenically induced environmental stressor in a Ramsar wetland of southern Chile. AB - In mid-2004, anthropogenically induced changes in water quality of the Rio Cruces wetland, a Ramsar site located in southern Chile (ca. 40 degrees S), enhanced the resuspension of iron-enriched sediments, which were subsequently deposited over the most abundant aquatic macrophyte of the wetland (Egeria densa Planch. 1849). This event triggered the formation of brownish, necrotic patches and increased iron contents in the leaves and stems of E. densa, which contributed to a significant demise of the plant within the wetland. In this study, we estimate the recovery time as a proxy for resilience of this macrophyte at organismal and population levels. Macro- and micro-optical characteristics, as well as iron contents in tissues of E. densa, were documented in four time windows (2004, 2008, 2012, and 2014). In addition, the size of the macrophyte population and its spatial occurrence were monitored from 2008 to 2016 across 36 study sites within the wetland. Our results suggest necrotic patches and high iron contents in E. densa persisted at least until 2008. After 2013, a significant increase in the spatial occurrence of E. densa was observed within the wetland, reaching full recovery of the population during 2015. The health of plant tissues and iron contents in leaves and stems showed recovery period close to 4 years, while the recovery of the spatial occurrence of E. densa took approximately 9 years. While the monitoring of plant health was not performed on a strict annual basis, the recovery rates estimated here are slower than those described for other macrophytes. This finding might reflect the long-lasting effects of the disturbance from 2004 and the interaction with biotic processes, such as foraging by waterbirds recolonizing the Rio Cruces wetland. These results show that full recovery of E. densa was achieved through a cascade of effects starting with abiotic factors (water quality) and passing through physiological and individual levels, to finally reach the population level. A key aspect of this response is the invasive nature of the macrophyte, which likely contributed to its recovery as a consequence of improved water quality. Less successful macrophyte species in other systems may not reach the specific population recovery, and become subdominant species instead, or even be eradicated from the wetland either as the result of herbivory or due to competition with other macrophytes. PMID- 29971665 TI - Managing geese with recreational hunters? AB - As many goose populations across the northern Hemisphere continue to rise, the role of hunters to manage these populations is increasingly being considered. We studied recreational goose hunters in Denmark to assess their behavioural and motivational characteristics, willingness to alter their hunting effort, as well as their ability to act as stewards of a rapidly increasing goose population. We identified several behavioural characteristics that typify effective goose hunting practices. We suggest a degree of specialization is necessary to increase goose harvests, as well as mitigating animal welfare issues (e.g. wounding). However, the majority of Danish goose hunters can be considered to be casual participants in this form of hunting. This poses a challenge for wildlife managers wishing to engage recreational hunters to manage highly dynamic wildlife populations, such as geese. If recreational hunters are to be used as a management tool, wildlife managers and hunting organizations will need to consider how best to facilitate skill development, hunting practices and socially legitimate hunting ethics to foster the stewardship role of hunting. We conclude that it is incumbent on wildlife managers to recognize and deal with both internal factors (e.g. skill development) and external influences (e.g. animal welfare concerns). In doing so, potential tensions in the multi-functionality of hunting can be alleviated, maintain hunting as a legitimate and accepted recreational past-time and management tool. PMID- 29971667 TI - Correction to: RF-ablation pattern shaping employing switching channels of dual bipolar needle electrodes: ex vivo results. AB - The original version of this article was published without funding note. The funding note is given below. PMID- 29971666 TI - Modeling Approaches in Cost-Effectiveness Analysis of Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: An Updated Systematic Review and Recommendations for Future Economic Evaluations. AB - BACKGROUND: Numerous cost-effectiveness analyses (CEAs) of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) have been published in the last three decades. Literature reviews of the modeling methods and results from these CEAs have also been published. The last literature review that focused on modeling methods, without country or time horizon in the inclusion criteria, included studies published up to 2012. Since then, new DMTs have become available, and new models and data sources have been used to assess their cost effectiveness. OBJECTIVE: The aim of this systematic review was to provide a detailed and comprehensive description of the relevant aspects of economic models used in CEAs of DMTs for RRMS, to understand how these models have progressed from recommendations provided in past reviews, what new approaches have been developed, what issues remain, and how they could be addressed. METHODS: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), the National Health System (NHS) Economic Evaluations Database, the Health Technology Assessment (HTA) Database, and EconLit were searched for cost-effectiveness studies of DMTs for RRMS that used decision-analytic models, published in English between 1 January 2012 and 24 December 2017. The inclusion criteria were as follows: being a full economic evaluation, a decision-analytic model was used, the target population concerned adult patients with RRMS, and being available in full-text format. Studies were not excluded based on the methodological quality. The background information of the included studies, as well as specific information on the components of the economic models related to the areas of recommendation from previous reviews were extracted. RESULTS: Twenty three studies from ten countries were included. The model structure of these studies has converged over time, characterizing the course of disease progression in terms of changes in disability and the occurrence of relapses over time. Variations were found in model approach; data sources for the natural course of the disease and comparative efficacy between DMTs; number of lines of treatment modeled; long-term efficacy waning and treatment discontinuation assumptions; type of withdrawal; and criteria for selecting adverse events. Main areas for improvement include using long-term time horizons and societal perspective; reporting relevant health outcomes; conducting scenario analyses using different sources of natural history and utility values; and reporting how the model was validated. CONCLUSION: The structure of economic models used in CEAs of DMTs for RRMS has converged over time. However, variation remains in terms of model approach, inputs, and assumptions. Though some recommendations from previous reviews have been incorporated in later models, areas for improvement remain. PMID- 29971669 TI - Mathematical Assessment of the Role of Early Latent Infections and Targeted Control Strategies on Syphilis Transmission Dynamics. AB - A new multi-stage deterministic model for the transmission dynamics of syphilis, which incorporates disease transmission by individuals in the early latent stage of syphilis infection and the reversions of early latent syphilis to the primary and secondary stages, is formulated and rigorously analysed. The model is used to assess the population-level impact of preventive (condom use) and therapeutic measures (treatment using antibiotics) against the spread of the disease in a community. It is shown that the disease-free equilibrium of the model is globally asymptotically stable whenever the associated control reproduction number (denoted by [Formula: see text]) is less than unity. A special case of the model is shown to have a unique and globally-asymptotically stable endemic equilibrium whenever the associated reproduction number (denoted by [Formula: see text]) exceeds unity. Uncertainty and sensitivity analysis of the model, using parameter values and ranges relevant to syphilis transmission dynamics in Nigeria, show that the top three parameters that drive the syphilis infection (with respect to [Formula: see text]) are the disease transmission rate ([Formula: see text]), compliance in condom use (c) and efficacy of condom ([Formula: see text]). Numerical simulations of the model show that the targeted treatment of secondary syphilis cases is more effective than the targeted treatment of individuals in the primary or early latent stage of syphilis infection. PMID- 29971668 TI - Exercise Training Protects Against Aging-Induced Cognitive Dysfunction via Activation of the Hippocampal PGC-1alpha/FNDC5/BDNF Pathway. AB - This study aimed to determine the effect of exercise training on cognitive functioning, and hippocampal PGC-1alpha, FNDC5, BDNF, and other cognition-related gene and protein expression in rats. Rats were divided into 4 groups based on age [3 months (young) vs. 20 months (aged)] and training status (control vs. exercise training). The rats that exercised voluntarily performed exercise training for 90 days, and then all the rats underwent several methods of behavioral assessment. Locomotor activity and spatial memory were lower but anxiety scores were higher in the aged control rats, than in the young control, young exercised, and aged exercised rats (P < 0.05). Hippocampal BDNF, FNDC5, PGC-1alpha, mTOR, ARC, cF-OS, ERK, SIRT, and FOXO expressions were lower, but NF-kappaB expressions were higher in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). Similarly, hippocampal BDNF and FNDC5 protein expression were lower in the aged control rats than in the young control, young exercised, and aged exercised rats (P < 0.05). These findings show that aging induced cognitive dysfunction is associated with a decrease in hippocampal expression of PGC-1alpha, FNDC5, and BDNF, and that exercise training might improve cognitive functioning via activation of these genes and proteins. PMID- 29971670 TI - Preoperative Tumor Markers Independently Predict Survival in Stage III Gastric Cancer Patients: Should We Include Tumor Markers in AJCC Staging? AB - OBJECTIVE: The aim of this study was to determine the prognostic significance of preoperative carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels in patients with resectable gastric cancer (GC). PATIENTS AND METHODS: Patients who underwent a radical resection for GC at the Fujian Medical University Union Hospital between 2007 and 2014 were included in this study. The estimated area under the curve (AUC) was compared to evaluate the discriminatory ability of tumor makers. Additional external validation was performed using a dataset from Sun Yat-sen University Cancer Center. RESULTS: Preoperative CEA/CA19 9 levels were identified as an independent predictor of overall survival (OS) and disease-specific survival (DSS) (both p < 0.05) in the development group. In a subgroup analysis based on TNM stage, preoperative CEA/CA19-9 levels clearly stratified the survival rates for stage III GC (p < 0.05). A multivariate analysis revealed that preoperative CEA/CA19-9 levels were an independent prognostic factor (p < 0.05) in stage III; the AUC of the preoperative CEA/CA19-9 was equivalent to that of T stage. A prediction model (TNMC) for stage III GC was developed by incorporating preoperative CEA/CA19-9 levels into the American Joint Committee on Cancer (AJCC) staging system. The AUC of the TNMC was significantly higher than that of the TNM staging system at 1, 3, and 5 years postoperatively (all p < 0.05), with similar results also being obtained in the external validation set. CONCLUSION: Preoperative CEA/CA19-9 levels are an independent predictor of OS and DSS in stage III GC patients. The inclusion of preoperative CEA/CA19-9 levels in AJCC TNM staging provided an optimal prognosis in stage III GC. PMID- 29971671 TI - Patient-Reported Outcomes for Breast Cancer. AB - Patient-reported outcomes (PROs) provide insight into how patients perceive health and treatment effects, how treatments impact outcomes, and are helpful in determining how disease and surgical interventions impact many aspects of a patients' life. Commonly utilized metrics include survival and disease control, degree of recovery and functional status, access to treatment, treatment-related complications, health-related quality of life, and long-term consequences of therapy. The key to value-based, patient-centered health care is systematically incorporating patient input into the measures that they consider to be the most important outcomes for a particular medical condition while minimizing costs of care. This manuscript reviews the development and validation of multiple available PROs in breast surgical oncology and reconstruction, their impact in improving patient-physician communication and treatment outcome, and potential for impacting reimbursement. The implementation of PROs can be complex and challenging and care must be taken to minimize the potential for survey fatigue by patients and the potential financial burden for implementation, maintenance, and analyses of collected data. Because there is an increased emphasis in providing high-value care for cancer patients, the widespread incorporation of transparent breast-specific PROs stratified by treatments received and disease stage will be essential in delivering exceptional quality care. PMID- 29971672 TI - The Value of a Second Opinion for Breast Cancer Patients Referred to a National Cancer Institute (NCI)-Designated Cancer Center with a Multidisciplinary Breast Tumor Board. AB - BACKGROUND: This study aimed to investigate the changes in diagnosis after a second opinion for breast cancer patients from a multi-disciplinary tumor board (MTB) review at an National Cancer Institute (NCI)-designated cancer center. METHODS: A retrospective study analyzed patients with a breast cancer diagnosed at an outside institution who presented for a second opinion from August 2015 to March 2016 at the Medical University of South Carolina (MUSC). Radiology, pathology, and genetic testing reports from outside institutions were compared with reports generated after an MTB review and subsequent workup at MUSC. The second-opinion cases were categorized based on whether diagnostic variations were present or not. RESULTS: The review included 70 patients seeking second opinions, and 33 (47.1%) of these patients had additional radiologic images. A total of 30 additional biopsies were performed for 25 patients, with new cancers identified in 16 patients. Overall, 16 (22.8%) of the 70 of patients had additional cancers diagnosed. For 14 (20%) of the 70 patients, a second opinion led to a change in pathology interpretation. Genetic testing was performed for 11 patients (15.7%) who met the National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, but none showed a mutation other than a variant of unknown significance. After a complete workup, 30 (42.8%) of the 70 patients had a change in diagnosis as a result of the MTB review. CONCLUSION: A review by an MTB at an NCI designated cancer center changed the diagnosis for 43% of the patients who presented for a second opinion for breast cancer. The study findings support the conclusion that referral for a second opinion is beneficial and has a diagnostic impact for many patients. PMID- 29971673 TI - 'Driving' Rates Down: A Population-Based Study of Opening New Radiation Therapy Centers on the Use of Mastectomy for Breast Cancer. AB - BACKGROUND: Two new cancer centers providing radiation therapy opened in Alberta, Canada, in 2010 and 2013, respectively. We aimed to assess whether opening the new RT centers influenced mastectomy rates for breast cancer. METHOD: Breast cancer patients who underwent surgery from 2004 through 2015 were identified from the Alberta Cancer Registry. Mastectomy rates for 64 predefined health status areas (HSAs) were calculated after adjusting for patient and system factors. Variations in mastectomy rates among the HSAs were quantified using weighted coefficient of variation (CV). Multivariable logistic regressions were performed to determine associations between driving time and mastectomy use in the entire cohort and in subgroups. RESULTS: Of the 21,872 patients, the proportion of patients who lived a <= 60 min drive from the nearest RT center significantly increased from 68.8% (95% CI 67.7-69.9%) to 80.7% (95% CI 79.5-81.9%) during the study period. Concurrently, the crude provincial mastectomy rate decreased from 56.2% (95% CI 55.3-57.1%) to 45.3% (95% CI 44.1-46.5%). However, variation in adjusted mastectomy rates (weighted CV) across the 64 HSAs increased from 9.5 to 14.6. Factors associated with mastectomy included age, larger tumor size, lymph node involvement, higher tumor grade, molecular subtype, lobular histology type, more comorbidities, academic institution, region, earlier period of diagnosis, and longer driving time to the nearest RT center. CONCLUSIONS: Opening new RT centers in previously underserved regions reduced driving times to the nearest center, and was associated with a reduction in mastectomy rates; however, these reductions among regions across the province were not uniform. PMID- 29971674 TI - Cancer Immune Therapy: Prognostic Significance and Implications for Therapy of PD 1 in BCG-Relapsing Bladder Cancer. PMID- 29971675 TI - Why Do Reoperation Rates Vary So Much After Lumpectomy for Breast Cancer? Examining the Reoperation Puzzle at the Massachusetts General Hospital. PMID- 29971676 TI - Joint Statement by the Surgery Journal Editors Group: Adopted by the Annals of Surgical Oncology. PMID- 29971678 TI - Tumor Size and Presence of Metastatic Disease at Diagnosis are Associated with Disease-Specific Survival in Parathyroid Carcinoma. AB - BACKGROUND: The incidence of parathyroid carcinoma is reported to be rising. There is minimal data on prognostic variables associated with cancer-specific survival. The objectives of this study were to evaluate the trends in incidence and assess prognostic factors. METHODS: A retrospective review of the SEER database between 1973 and 2014 was performed, identifying 520 patients with parathyroid carcinoma. Population-adjusted incidence rates were calculated in 4 year intervals. A Cochrane-Armitage test was performed to analyze changes in trend in incidence, tumor size, and extent of disease. Age, year of diagnosis, race, gender, extent of disease, surgical resection, treatment with radiation, tumor size, and lymph node status were assessed using Mantel-Cox log rank test. Multivariate analysis was performed by Cox regression analysis. RESULTS: The incidence of parathyroid carcinoma has been increasing since 1974 from 2 to 11 cases per 10 million people but has since stabilized at 11 cases per 10 million people since 2001. The increasing incidence was attributed to locoregional disease and tumor size < 3 cm. The presence of metastatic disease [hazard ratio (HR) 111.4, 95% confidence interval (CI) 20.6-601.8, p < 0.0001) and tumor size > 3 cm (HR 5.6, 95% CI 1.5-21.2, p = 0.011] were associated with worse cancer specific survival by univariate and multivariate analyses. CONCLUSIONS: The incidence of parathyroid carcinoma has remained stable over the past decade. Tumor size < 3 cm and regional disease have increased in incidence. Patients with metastatic disease and tumors > 3 cm have worse cancer-specific survival. These findings can be incorporated in the development of a staging system for parathyroid carcinoma. PMID- 29971677 TI - Significance of Lymphovascular Space Invasion by the Sarcomatous Component in Uterine Carcinosarcoma. AB - OBJECTIVE: The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS). METHODS: This was a secondary analysis of a prior multicenter retrospective study that examined women with stage I-IV UCS who underwent primary hysterectomy. Archived histopathology slides were reviewed and LVSI was scored as follows: LVSI with a carcinomatous component alone (LVSI-carcinoma; n = 375, 76.8%) or LVSI containing a sarcomatous component with or without a carcinomatous component (LVSI-sarcoma; n = 113, 23.2%). Qualitative metrics of LVSI were correlated to clinicopathological factors and survival outcome. RESULTS: Tumors in the LVSI sarcoma group were more likely to have sarcoma dominance (82.1 vs. 26.4%) heterologous sarcomatous component (51.3 vs. 37.9%), low-grade carcinoma (42.5 vs. 22.4%), and large tumor size (81.0 vs. 70.2%) in the primary tumor site compared with tumors in the LVSI-carcinoma group (all p < 0.05). On multivariate analysis, LVSI-sarcoma was independently associated with decreased progression free survival (5-year rates: 34.9 vs. 40.8%, adjusted hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.36-2.50, p < 0.001), and cause-specific survival (5 year rates: 41.8 vs. 55.9%, adjusted HR 1.95, 95% CI 1.39-2.75, p < 0.001) compared with LVSI-carcinoma. Postoperative radiotherapy for women with LVSI sarcoma had a higher reduction rate of recurrence/progression of disease (54% reduction, p = 0.04) compared with postoperative radiotherapy for women with LVSI carcinoma (26% reduction, p = 0.08). CONCLUSION: In UCS, the presence of a sarcomatous component in LVSI is particularly prevalent when a tumor has sarcoma dominance. Our study suggests that LVSI containing a sarcomatous component may be a predictor of decreased survival for women with UCS. PMID- 29971679 TI - Methylmalonic Acid Levels and their Relation with Cobalamin Supplementation in Spanish Vegetarians. AB - Cobalamin deficiency represents a health issue for vegetarians, especially vegans, if supplements are not consumed. Vitamin B12 serum levels, traditionally used to assess the vitamin B12 status, can be normal under functional deficiency conditions. In this regard, methylmalonic acid (MMA) has proven to be a more specific marker to detect subclinical vitamin B12 deficiency. In this study, we present for the first time the cobalamin status of Spanish vegetarians using both vitamin B12 and MMA markers, and the effects of the plant-based diet and the intake of vitamin B12 supplements. Healthy adults were recruited (n = 103, 52% vegans). Dietary preferences and use of supplements were assessed by questionnaires and serum samples were collected and stored. Vitamin B12 was measured by chemiluminiscence and MMA by liquid chromatography tandem mass spectrometry (LC-MS/MS) using solid phase extraction for sample preparation. Obtained values, median (IQR), were: vitamin B12, 278.9 (160.2) pmol/l and MMA, 140.2 (78.9) nmol/l. No significant differences between lacto-ovo vegetarians and vegans were observed. Considering these two markers, 10% of the participants were mild vitamin B12 deficient. Supplementation (75% of the participants) was associated with higher vitamin B12 (p < 0.001) and lower MMA (p = 0.012). In conclusion, Spanish vegetarians have low risk of vitamin B12 deficiency due to vitamin B12 supplementation and the MMA determination is useful to detect mild deficiency. PMID- 29971680 TI - New genera and species of paramphistomes (Digenea: Paramphistomoidea: Cladorchiidae) parasitic in fishes from the Amazon basin in Peru. AB - Two new genera and three new species of paramphistomoid digeneans are described in the family Cladorchiidae Fischoeder, 1901 from doradid, heptapterid, pimelodid and pseudopimelodid fishes in the Amazon River in Peru. Goeldamphistomum amazonum n. g., n. sp. (type-species) from Goeldiella eques (Muller & Troschel) (type host) and Tenellus trimaculatus (Boulenger), and Goeldamphistomum peruanum n. g., n. sp. from Duopalatinus peruanus Eigenmann & Allen (type-host), Calophysus macropterus (Lichtenstein) and Microglanis sp. are placed in the Dadayiinae Fukui, 1929. Both species have an accessory acetabular sucker, which distinguishes the genus from all taxa previously reported from South American freshwater fishes. They differ from each other primarily in that G. amazonum has a prebifurcal genital pore and oblique, separated testes, the levels of which rarely overlap longitudinally, whereas G. peruanum has a postbifurcal genital pore and testes directly to obliquely tandem. Iquitostrema papillatum n. g., n. sp. (Kalitrematinae Travassos, 1933) from the intestine of Hassar orestis (Steindachner) differs from other members of the subfamily in the combination of a massive acetabulum with a papillate luminal surface and symmetrical testes which overlie the caeca close to the caecal arch. These are the first records of paramphistomes from the five host species studied here. PMID- 29971681 TI - Specialty management differences of syphilis and toxoplasmosis surrounding pregnancy: a prospective cross-sectional study. AB - BACKGROUND: Syphilis and toxoplasmosis are two infectious conditions that can occur during pregnancy. Both these diseases can have ocular manifestations and thus are treated by ophthalmologists and obstetricians. We hypothesized that specialty training would affect the way physicians selected therapy. RESULTS: A total of 209 uveitis specialists and approximately 2500 obstetricians across the USA were surveyed using an online questionnaire distributed via listserv and social media posts. Survey respondents were given a series of clinical vignettes containing case examples of a female patient who was either contemplating pregnancy or in the first trimester and was diagnosed with either syphilis or toxoplasmosis. The questionnaire included a total of four case scenarios with questions relating to the management of these diseases, as well as pregnancy counseling. For the syphilis vignette, a total of 97 physicians responded to the survey questions. Choices of therapy between physician specialty differed significantly (p = 0.0001); however, pregnancy status did not seem to affect therapy choice in syphilis. A total of 96 physicians responded to the survey questions pertaining to the toxoplasmosis vignette. For a non-pregnant patient diagnosed with toxoplasmosis, the differences in therapy choice between specialties were not significant; however, when the patient was pregnant, therapy choice was significantly different between specialties (p = 0.0001). CONCLUSIONS: Differences exist between ophthalmologists and obstetricians concerning the therapy for syphilis and toxoplasmosis during pregnancy. Inter-specialty collaboration is needed to develop consistent criteria to improve the management of these patients. PMID- 29971682 TI - Epidemiology of Granulomatosis with Polyangiitis in Poland, 2011-2015. AB - Granulomatosis with polyangiitis (GPA) is a form of vasculitis that affects small and medium-sized vessels in many organs. The aim of the study was to describe the epidemiology of GPA in Poland in 2011-2015, including the incidence and prevalence rates. The authors conducted a retrospective, population-based study, using hospital discharge records with GPA diagnosis. GPA incidence was estimated on the basis of the data from the Polish hospital morbidity study carried out by the National Institute of Public Health. The final study group consisted of 1491 patients (749 females, 742 males) who were first time hospitalized with the diagnosis of GPA. The average annual incidence of GPA in Poland was 7.7/1,000,000 (95% CI, 4.1-11.4), and the point prevalence at the end of 2015 was 36/1,000,000. A statistically significant decrease in the GPA incidence was noticed in this study. A 1-year survival rate for GPA was 94%. In conclusion, the incidence and prevalence rates of GPA in Poland are similar to that reported in other European countries. The study provides recent epidemiological data on GPA in Poland, which may be useful for comparisons with other geographical regions. PMID- 29971683 TI - Budd-Chiari syndrome has different presentations and disease severity during adolescence. AB - : There are limited data on clinical profile of adolescent patients with Budd Chiari syndrome (BCS). We studied clinical, radiological, thrombophilia profile and treatment outcomes in adolescent patients with BCS. METHODS: Forty-three consecutive patients of BCS with onset of symptoms during adolescence (10-19 years) were enrolled in the study. 129 randomly selected adult patients with BCS and 36 children with BCS formed the two control groups. The clinical history, physical examination, laboratory tests, thrombophilic disorders, radiological features and treatment outcomes of adolescents were compared to adults and children. RESULTS: In adolescents, ascites (25/43 vs. 110/129, p = 0.0004) and thrombophilic disorders (16/43 vs. 93/129 p < 0.0001) were less frequent than adults. More adolescents (14/43) presented with hepatomegaly alone without ascites than adults (9/129, p < 0.001) or children (1/36, p = 0.005). Adolescents had lower Clichy scores [3.75 (1.2)] than adults [4.72 (1.3), p < 0.0001) or children [4.43 (1.7), p = 0.041]. JAK-2 V617F mutation was the most common thrombophilic disorder in adolescents (5/43) and more common than children (0/36, p = 0.043). Response to therapy was better in adolescents (74.4%) than children (52.8%, p = 0.038), but similar to adults (63.56%, p = 0.13). CONCLUSION: During adolescence, patients with BCS present less commonly with ascites and may present with hepatomegaly alone. JAK-2 V617F mutation is the most common thrombophilic disorder during adolescence; though thrombophilic disorders are less common in adolescents than adults. Response to therapy is similar to adults, but better than children. PMID- 29971684 TI - Brain response to food brands correlates with increased intake from branded meals in children: an fMRI study. AB - Food branding is ubiquitous, however, not all children are equally susceptible to its effects. The objectives of this study were to 1) determine whether food brands evoke differential response than non-food brands in brain areas related to motivation and inhibitory control using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) and 2) determine the association between brain response and energy intake at test-meals presented with or without brands. Twenty-eight 7-10 year-old children completed four visits as part of a within-subjects design where they consumed three multi-item test-meals presented with familiar food brands, novel food brand, and no brand. On the fourth visit an fMRI was performed where children passively viewed food brands, non-food brands and control images. A whole-brain analysis was conducted to compare BOLD response between conditions. Pearson's correlations were calculated to determine the association between brain response and meal intake. Relative to non-food brands, food brand images were associated with increased activity in the right lingual gyrus. Relative to control, food and non-food brand images were associated with greater response in bilateral fusiform gyri and decreased response in the cuneus, precuneus, lingual gyrus, and supramarginal gyrus. Less activation in the bilateral fusiform gyrus to both food and non-food brands was associated with greater energy intake of the branded vs unbranded meal. These findings may help explain differences in the susceptibility to the intake-promoting effects of food advertising in children. PMID- 29971685 TI - Altered reward-related neural responses in non-manifesting carriers of the Parkinson disease related LRRK2 mutation. AB - Disturbances in reward processing occur in Parkinson's disease (PD) however it is unclear whether these are solely drug-related. We applied an event-related fMRI gambling task to a group of non-manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene, in order to assess the reward network in an "at risk" population for future development of PD. Sixty-eight non-manifesting participants, 32 of which were non-manifesting non-carriers (NMNC), performed a gambling task which included defined intervals of anticipation and response to both reward and punishment in an fMRI setup. Behavior and cerebral activations were measured using both hypothesis driven and whole brain analysis. NMC demonstrated higher trait anxiety scores (p = 0.04) compared to NMNC. Lower activations were detected among NMC during risky anticipation in the left nucleus accumbens (NAcc) (p = 0.05) and during response to punishment in the right insula (p = 0.02), with higher activations among NMC during safe anticipation in the right insula (p = 0.02). Psycho-Physiological Interaction (PPI) analysis from the NAcc and insula revealed differential connectivity patterns. Whole brain analysis demonstrated divergent between-group activations in distributed cortical regions, bilateral caudate, left midbrain, when participants were required to press the response button upon making their next chosen move. Abnormal neural activity in both the reward and motor networks were detected in NMC indicating involvement of the ventral striatum regardless of medication use in "at risk" individuals for future development of PD. PMID- 29971687 TI - Hippocampal structural and functional integrity in multiple sclerosis patients with or without memory impairment: a multimodal neuroimaging study. AB - The increasing evidence for a pure amnestic-like profile in multiple sclerosis (MS) introduces the role of hippocampal formation in MS episodic memory function. The aim of the present study was to investigate structural and functional hippocampal changes in mildly-disabled MS patients with and without memory impairment. Thirty-one MS patients with or without memory impairment and 16 healthy controls (HC) underwent MRI in a 3.0 T MRI scanner. Patients were categorized as memory preserved (MP) and memory impaired (MI) based on verbal and visual memory scores extracted from the Brief Repeatable Neuropsychological Battery. The acquisition protocol included high-resolution 3D-T1-weighted, diffusion weighted imaging and echo-planar imaging sequences for the analysis of hippocampal gray matter (GM) density, perforant pathway area (PPA) tractography, and hippocampal functional connectivity (FC), respectively. Compared to HC, we found decreased left and bilateral hippocampal GM density in MP and MI patients, respectively, decreased fractional anisotropy and increased radial diffusivity on left PPA in MI patients, and reduced FC in MI between left hippocampus and left superior frontal gyrus, precuneus/posterior cingulated cortex and lateral occipital gyrus/angular gyrus. The only differences between MP and MI were found in FC. Specifically, MP patients showed FC changes between left hippocampus and right temporo-occipital fusiform/lingual gyrus (increased FC) as well as supramarginal gyrus (decreased FC). In conclusion, we highlight the early detection of structural hippocampal changes in MS without neuropsychologically detected memory deficits and decreased hippocampal FC in MS patients with impaired memory performance, when both GM density and PPA integrity are affected. PMID- 29971686 TI - Brain degeneration in Parkinson's disease patients with cognitive decline: a coordinate-based meta-analysis. AB - Cognitive decline in Parkinson's disease (PD) is a common sequela of the disease, with its severity increasing as the neurodegenerative process advances. The present meta-analysis used anisotropic effect size seed-based d mapping software to perform analyses using both functional and structural brain imaging data. The analyses were between PD patients with mild cognitive impairment (PD-MCI) and PD patients with dementia (PDD) compared to PD cognitively unimpaired patients (PD CU) and PD patients without dementia (PD-ND) respectively. Thirty-four studies were found and split into three analyses: 405 PD-MCI patients compared to 559 PD CU patients from 1) 15 studies with structural imaging modalities and 2) eight studies with functional imaging modalities, as well as 178 PDD patients compared to 278 PD-ND patients (which includes both PD-CU and PD-MCI) in 3) 11 studies with structural imaging modalities. Statistical threshold was set to uncorrected p < 0.001. We found several brain regions that differed between PD-MCI and PD-CU patients: the left insula, bilateral dorsolateral prefrontal cortex, left angular gyrus, midcingulate cortex, and right supramarginal gyrus. The brain regions identified in the PD-MCI analyses are associated with the somatosensory network and executive processing. In PDD patients, the bilateral insula and right hippocampus were found as regions of structural atrophy. The insula was found in both structural analyses of PD-MCI and PDD, with unilateral insula involvement in PD-MCI extending to bilateral insula involvement in PDD. The results found both a spectrum of increasing brain atrophy in PD cognitive impairment and supports the existence of sub-typing in PD-MCI. PMID- 29971688 TI - Dyssynergic defecation: The not so hidden partner in constipation. PMID- 29971689 TI - Endoscopic ultrasound-guided thrombin injection for management of visceral artery pseudoaneurysm: A novel approach. AB - Visceral artery pseudoaneurysm is a rare and potentially life-threatening vascular entity with a high mortality rate, conventionally managed with digital subtraction angiography with coil embolization or surgery. However, in cases where angiographic coil embolization is not possible due to technical reasons, computerized tomography (CT)/ultrasonography-guided thrombin injection remains a viable option as described in the literature. In this case series, we intend to highlight the role of endoscopic ultrasound-guided thrombin injection in the management of abdominal visceral artery pseudoaneurysm, which is either inaccessible by endovascular route or have high surgical risk of complication. PMID- 29971690 TI - Special issue: bioremediation of contaminated soil and water: GeoTrop 2017. PMID- 29971691 TI - Refugees and family-reunified immigrants have a high incidence of HIV diagnosis and late presentation compared with Danish born: a nationwide register-based cohort study. AB - PURPOSE: Migrants represent a considerable proportion of HIV diagnoses in Europe and are considered a group at risk of late presentation. This study examined the incidence of HIV diagnoses and the risk of late presentation according to migrant status, ethnic origin and duration of residence. METHODS: We conducted a historically prospective cohort study comprising all adult migrants to Denmark between 1.1.1993 and 31.12.2010 (n = 114.282), matched 1:6 to Danish born by age and sex. HIV diagnoses were retrieved from the National Surveillance Register and differences in incidence were assessed by Cox regression model. Differences in late presentation were assessed by logistic regression. RESULTS: Both refugees (HR = 5.61; 95% CI 4.45-7.07) and family-reunified immigrants (HR = 10.48; 95% CI 8.88-12.36) had higher incidence of HIV diagnoses compared with Danish born and the incidence remained high over time of residence for both groups. Migrants from all regions, except Western Asia and North Africa, had higher incidence than Danish born. Late presentation was more common among refugees (OR = 1.87; 95% CI 1.07-3.26) and family-reunified immigrants (OR = 2.30; 95% CI 1.49-3.55) compared with Danish born. Southeast Asia and Sub-Saharan Africa were the only regions with a higher risk of late presentation. Late presentation was only higher for refugees within 1 year of residence, whereas it remained higher within 10 years of residence for family-reunified immigrants. CONCLUSIONS: This register-based study revealed a higher incidence of HIV diagnoses and late presentation among migrants compared with Danish born and the incidence remained surprisingly high over time. PMID- 29971692 TI - A nationwide passive surveillance on fungal infections shows a low burden of azole resistance in molds and yeasts in Tyrol, Austria. AB - PURPOSE: To determine the burden of antifungal resistance in fungi over the last 10 years. METHODS: Performance of a semi-nationwide surveillance on antifungal resistance. RESULTS: We observed a low frequency of azole resistance in Aspergillus fumigatus, a moderate increase of echinocandin resistance in yeasts, and a stable amphotericin B activity in yeasts and molds. Posaconazole resistance in Aspergillus terreus occurred in a few isolates. CONCLUSION: The burden of resistance in fungi seems to be low in Tyrol, Austria. PMID- 29971693 TI - Are ME/CFS Patient Organizations "Militant"? : Patient Protest in a Medical Controversy. AB - Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a contested illness category. This paper investigates the common claim that patients with ME/CFS-and by extension, ME/CFS patient organizations (POs)-exhibit "militant" social and political tendencies. The paper opens with a history of the protracted scientific disagreement over ME/CFS. We observe that ME/CFS POs, medical doctors, and medical researchers exhibit clear differences in opinion over how to conceptualize this illness. However, we identify a common trope in the discourse over ME/CFS: the claim of "militant" patient activism. Scrutinizing this charge, we find no compelling evidence that the vast majority of patients with ME/CFS, or the POs representing them, have adopted any such militant political policies or behaviours. Instead, we observe key strategic similarities between ME/CFS POs in the United Kingdom and the AIDs activist organizations of the mid-1980s in the United States which sought to engage scientists using the platform of public activism and via scientific publications. Finally, we explore the contours of disagreement between POs and the medical community by drawing on the concept of epistemic injustice. We find that widespread negative stereotyping of patients and the marginalization and exclusion of patient voices by medical authorities provides a better explanation for expressions of frustration among patients with ME/CFS. PMID- 29971695 TI - Investigation into the potential for post-mortem formation of carboxyhemoglobin in bodies retrieved from fires. AB - The forensic investigation of a deceased person retrieved following a fire includes measuring carboxyhemoglobin. A carboxyhemoglobin saturation above 10% is considered indicative of respiration during a fire, implying the person had been alive. This relies on the assumption that carbon monoxide will not diffuse into blood used for toxicological analysis. This project investigated the potential for carbon monoxide to passively diffuse into a body and if carboxyhemoglobin levels could become elevated post-mortem. Stillborn piglets with intact skin were exposed to carbon monoxide. Carboxyhemoglobin formed in the hypostasis of the skin, but carboxyhemoglobin levels in blood from the heart and chest cavities were not significantly elevated. However, defects in the skin over body cavities (producing breaches to replicate cases with stab wounds or heat damage) resulted in cavity blood carboxyhemoglobin levels above 10%. A review of fire death cases in South Australia 2000-2015 was performed to determine the origin of the blood samples used for toxicological analysis and the incidence of cases with breaches of body cavities. This revealed a small number of cases in which blood from the cavities had been analyzed when cavity breaches were present. Thus, there is a potential for significant elevation of carboxyhemoglobin saturation post-mortem in forensic casework involving bodies retrieved from fires. PMID- 29971694 TI - The effectiveness of decontamination procedures used in forensic hair analysis. AB - Hair is a mainstream specimen used in forensic toxicology to determine drug use and exposure. However, the interpretation of an analytical hair result can be complicated by the presence of external drug contamination. Decontamination procedures are included in hair analysis methods to remove external contamination, but the capacity of these washes to completely remove contamination for all drugs is controversial. It is evident that there is no consensus on the most effective decontamination procedure, nor can decontamination procedures consistently remove external drug contamination to less than reportable cut-offs for all analytes. ?9-tetrahydrocannabinol deposited from cannabis smoke is mostly removed by organic solvents, whereas ionizable drugs are more effectively removed by an aqueous wash. Organizations such as the Society of Hair Testing recommend a hair decontamination procedure should include both an organic and aqueous washing step, which is in accordance with the reviewed literature. Studies involving a systematic evaluation of various solvents have shown that the most effective organic solvent was methanol and the most effective aqueous solvent contained sodium dodecyl sulfate detergent. If future systematic studies can demonstrate similar findings, a consensus on the most effective decontamination procedure for forensic hair analysis may be established. PMID- 29971697 TI - Design of Bionic Cochlear Basilar Membrane Acoustic Sensor for Frequency Selectivity Based on Film Triboelectric Nanogenerator. AB - Sensorineural hearing loss tops the list of most suffering disease for the sake of its chronic, spirit pressing, and handicapped features, which can happen to all age groups, from newborns to old folks. Laggard technical design as well as external power dependence of conventional cochlear implant cumbers agonized patients and restrict its wider practical application, driving researchers to seek for fundamental improvement. In this paper, we successfully proposed a novel bionic cochlear basilar membrane acoustic sensor in conjugation with triboelectric nanogenerator. By trapezoidally distributing nine silver electrodes on both two polytetrafluoroethylene membranes, a highly frequency-selective function was fulfilled in this gadget, ranging from 20 to 3000 Hz. It is believed to be more discernable with the increment of electrode numbers, referring to the actual basilar membrane in the cochlear. Besides, the as-made device can be somewhat self-powered via absorption of vibration energy carried by sound, which tremendously facilitates its potential users. As a consequence, the elaborate bionic system provides an innovative perspective tackling the problem of sensorineural hearing loss. PMID- 29971696 TI - Endocrine, Sexual Function, and Infertility Side Effects of Immune Checkpoint Inhibitor Therapy for Genitourinary Cancers. AB - PURPOSE OF REVIEW: Immune checkpoint therapy has grown in prominence in the last few decades and is being increasingly utilized in treatment of advanced cancers. Although information on toxicities of these drugs is forthcoming, not much is known regarding the toxicity profile of these drugs from a sexual function standpoint. We undertook the current review to appraise the literature for endocrine/sexual side effects of anti-PD-1/PD-L1 and anti-CTLA-4 therapy. RECENT FINDINGS: Our review included 32 articles and focused primarily on the programmed death (PD) pathway. We found that endocrine side effects after anti-PD-1/PD-L1 therapy are relatively rare, with hypothyroidism (range < 1 to 40%) and hypophysitis (range < 1 to 10%) being the two most common. None of the studies specifically commented on the infertility or sexual side effects of these drugs. However, two studies evaluating biochemical profiles of patients undergoing therapy with ipilimumab (a CTLA-4 inhibitor) or combination therapy (CTLA-4 + PD 1/PD-L1 inhibitors) noted that about < 1 to ~ 60% of the patients developed hypogonadotropic hypogonadism. None of the studies provided information regarding clinically meaningful sexual health endpoints such as libido, erectile function assessments, or sexual function-related quality of life. Endocrine side effects, although uncommon, are important and unique side effects of immune checkpoint therapy because they are often complex and can be life threatening. While side effects on sexual health may not be life threatening, they are lifestyle limiting. Thus, long-term follow-up, post-marketing surveillance, and future studies will need to elucidate the true rates of endocrine/sexual side effects and the mechanisms underlying them. This will aid in better counseling of the patients, as more of them undergo these novel immune checkpoint inhibitor therapies. PMID- 29971700 TI - What is this image? 2018: Image 2. PMID- 29971698 TI - Is Tamsulosin Linked to Dementia in the Elderly? AB - PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) result from age-related changes in detrusor function and prostatic growth that are driven by alterations in the ratio of circulating androgens and estrogens. Alpha-adrenergic receptor blockers are commonly used to treat LUTS because they influence urethral tone and intra-urethral pressure. Molecular cloning studies have identified three alpha1 adrenergic receptor subtypes (alpha1A, alpha1B, and alpha1D). The alpha1A subtype is predominant in the human prostate but is also present in many parts of the brain that direct cognitive function. Tamsulosin is the most widely used alpha1 adrenergic receptor antagonist with 12.6 million prescriptions filled in 2010 alone. When compared to the other common types of alpha1-adrenergic receptor antagonists (i.e., terazosin, doxazosin, and alfuzosin), tamsulosin is 10- to 38 fold more selective for the alpha1A versus the alpha1B subtype. RECENT FINDINGS: Duan et al. have recently shown that men taking tamsulosin have a higher risk of developing dementia when compared to men taking other alpha-adrenergic antagonists or no alpha-adrenergic antagonists at all (HR 1.17; 95% CI 1.14 1.21). Based upon this retrospective analysis, we believe that tamsulosin, because of its unique affinity for alpha1A-adrenergic receptors, may increase the risk of developing dementia when used for an extended period of time. If these findings are confirmed, they carry significant public health implications for an aging society. PMID- 29971699 TI - Immigration and Acculturation: Impact on Health and Well-Being of Immigrants. AB - Among migrants who arrived in the USA and Europe, communicable diseases such as dermatologic, gastrointestinal, and respiratory infections are frequent; non communicable diseases including chronic diseases such as hypertension and diabetes, and vaccine-preventable diseases are also prevalent. Refugees are often not up to date on routine immunizations and screenings for chronic diseases and cancer. In addition, many immigrants have trauma-related mental health problems, which are often not addressed by the healthcare systems where they reside. Determining the healthcare needs of specific immigration groups should lead to the establishment of evidence-based guidelines for providing screening and healthcare services to immigrant populations, for the benefit of the individuals concerned, as well as the host countries. PMID- 29971701 TI - Places of Persistence: Slavery and the Geography of Intergenerational Mobility in the United States. AB - Intergenerational mobility has remained stable over recent decades in the United States but varies sharply across the country. In this article, I document that areas with more prevalent slavery by the outbreak of the Civil War exhibit substantially less upward mobility today. I find a negative link between prior slavery and contemporary mobility within states, when controlling for a wide range of historical and contemporary factors including income and inequality, focusing on the historical slave states, using a variety of mobility measures, and when exploiting geographical differences in the suitability for cultivating cotton as an instrument for the prevalence of slavery. As a first step to disentangle the underlying channels of persistence, I examine whether any of the five broad factors highlighted by Chetty et al. (2014a) as the most important correlates of upward mobility-family structure, income inequality, school quality, segregation, and social capital-can account for the link between earlier slavery and current mobility. More fragile family structures in areas where slavery was more prevalent, as reflected in lower marriage rates and a larger share of children living in single-parent households, is seemingly the most relevant to understand why it still shapes the geography of opportunity in the United States. PMID- 29971702 TI - Pre-service Teachers and Stress During Microteaching: An Experimental Investigation of the Effectiveness of Relaxation Training with Biofeedback on Psychological and Physiological Indices of Stress. AB - Pre-service teacher stress is an understudied research area, with the majority of research focusing on subjective reports of stress. The present study sought to examine the influence of stress-reduction techniques on both subjective and objective indicators of stress during microteaching in preservice teachers. A sample of 44 preservice teachers were randomly assigned to one of three intervention groups; biofeedback, relaxation, or control. Participants in the biofeedback group received relaxation-assisted biofeedback training designed to teach participants the physiological signs of the stress response using HeartMath monitor, along with the HeartMath Quick Coherence(r) technique. Those in the relaxation group were given training in the HeartMath Quick Coherence relaxation technique, with no biofeedback training. Finally, those in the control group did not receive any relaxation or biofeedback training. Using a repeated-measures design, both psychological and physiological indices of stress were measured before and after students engaged in microteaching approaches. Examination of the psychological ratings identified that feelings of calm increased across time; this showed that participants were more comfortable with the microteaching situation with repeated practice. However, none of the physiological interventions were effective in reducing stress. The present study highlights practice as a useful strategy to reduce stress in microteaching situations and points to the importance of employing evidence-based interventions when attempting to reduce stress. PMID- 29971703 TI - In vitro leishmanicidal effects of the anti-fungal drug natamycin are mediated through disruption of calcium homeostasis and mitochondrial dysfunction. AB - Natamycin, a Food and Drug Administration approved anti-fungal drug, and also used as a food additive was evaluated for anti-leishmanial activity since it is known to specifically bind to ergosterol, which is essential to these parasites but absent in mammals. Promising anti-proliferative activity was observed in both promastigote and amastigote forms of the parasite with IC50 values of 15 and 8 uM respectively and a selective index of 12.5. The ultrastructural effects of natamycin on both forms of the parasite and physiological effects on promastigotes were studied in detail for the first time. Electron microscopic observations in treated cells revealed sub-cellular changes like plasma membrane alterations, accumulation of vesicles in the flagellar pocket and extensive mitochondrial damage. Natamycin treatment in promastigotes resulted in elevation of cytosolic calcium (Ca2+) levels which caused irreversible loss of mitochondrial membrane potential. This resulted in depletion of cellular ATP levels along with ROS generation finally leading to apoptosis-like and necrotic cell death. In view of our observations along with the safety profile of an existing anti-fungal drug, natamycin may be further investigated for repurposing it as a promising drug candidate against Leishmaniasis. PMID- 29971704 TI - Paenibacillus bryophyllum sp. nov., a nitrogen-fixing species isolated from Bryophyllum pinnatum. AB - A nitrogen-fixing, endospore-forming bacterium, designated strain L201T was isolated from the leaves of Bryophyllum pinnatum growing in South China Agricultural University. Phylogenetic analysis of the 16S rRNA gene sequence indicated that strain L201T is affiliated with the genus Paenibacillus, and closely related to Paenibacillus albidus Q4-3T (97.4%), Paenibacillus odorifer DSM 15391T (97.3%) and Paenibacillus borealis DSM 13188T (97.2%). The main fatty acids components was anteiso-C15:0 (48.1%). The predominant isoprenoid quinone was MK-7. The major polar lipids were found to be diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The G+C content of strain L201T was 43.9%. DNA-DNA relatedness between L201T and the reference strain was 29.8%. Biological and biochemical tests, protein patterns, genomic DNA fingerprinting and comparison of cellular fatty acids distinguished strain L201T from the closely related Paenibacillus species. Based on these data, the novel species Paenibacillus bryophyllum sp. nov. is proposed, with the type strain L201T(= KCTC 33951 T = GDMCC 1.1251 T). PMID- 29971705 TI - Electrocardiographic RR Interval Dynamic Analysis to Identify Acute Stroke Patients at High Risk for Atrial Fibrillation Episodes During Stroke Unit Admission. AB - Patients at short-term risk of paroxysmal atrial fibrillation (PAF) often exhibit increased RR interval variability during sinus rhythm. We studied if RR dynamic analysis, applied in the first hours after stroke unit (SU) admission, identified acute ischemic stroke patients at higher risk for subsequent PAF episodes detected within the SU hospitalization. Acute ischemic stroke patients underwent continuous cardiac monitoring (CCM) using standard bedside monitors immediately after SU admission. The CCM tracks from the first 48 h were analyzed using a telemedicine service (SRA clinic, Apoplex Medical, Germany). Based on the RR dynamics, the stroke risk analysis (SRA) algorithm stratified the risk for PAF as follows: low risk for PAF, high risk for PAF, presence of manifest AF. The subsequent presence/absence of PAF during the whole SU hospitalization was ruled out using all available CCMs, standard ECGs, or 24-h Holter ECGs. Two hundred patients (40% females, mean age 71 +/- 16 years) were included. According to the initial SRA analysis, 111 patients (56%) were considered as low risk for PAF, 52 (26%) as high risk while 37 patients (18%) had manifest AF. A low-risk level SRA was associated with a reduced probability for subsequent PAF detection (1/111, 0.9%, 95% CI 0-4.3%) while a high-risk level SRA predicted an increased probability (20/52, 38.5% (95% CI 25-52%). RR dynamic analysis performed in the first hours after ischemic stroke may stratify patients into categories at low or high risk for forthcoming paroxysmal AF episodes detected within the SU hospitalization. PMID- 29971706 TI - Anatomical features and significance of the anterolateral ligament of the knee. AB - BACKGROUND: The anterolateral ligament (ALL) was discovered in 1879. For over 130 years, this anatomical structure did not enjoy much attention, but the situation started to change when a number of researchers described its contribution to the rotational stability of the knee joint. PURPOSE OF THE STUDY: To estimate the occurrence of the ALL and describe the aspects of its anatomy that should be factored into the outcome of stabilizing surgeries of the knee joint. MATERIALS AND METHODS: The study was conducted in 60 knee specimens of 30 unfixed human cadavers. Once the anterolateral ligament was identified, we assessed its relationships with the body of the lateral meniscus, the lateral collateral ligament to which it is attached mainly by connective tissue fibers, and the lateral inferior genicular blood vessels. We also identified ALL attachment points on the lateral epicondyle of the femur and the lateral condyle of the tibia. RESULTS: ALL has been identified in 56.6% of the dissected knee pairs in both knees. ALL was present in 66.7% of female joints (24 of 36 specimens) and in 41.6% of male joints (10 of 24 specimens). The average length of the ALL was 38.5 +/- 4.4 mm. The average width near the joint space was 4.45 +/- 0.85 mm. The attachment point on the lateral epicondyle of the femur varied: it was posterior proximal to the lateral collateral ligament in 64.7% of the dissected knees, anterior to the lateral collateral ligament in 23.5% of cases, and on the popliteus tendon insertion or next to it in 11.8% of cases. The point of the anterolateral ligament's attachment on the lateral condyle of the tibia typically lied halfway between the fibular head and Gerdy's tubercle. CONCLUSION: The best site for a bone tunnel is the region on the lateral epicondyle of the femur, lying posterior and proximal to the origin of the lateral collateral ligament. The identified anatomical pattern in the course of the lateral inferior genicular vessels will help to spare these important blood suppliers in the course of a reconstructive surgery of the anterolateral knee joint region. PMID- 29971707 TI - Outcomes of total knee arthroplasty in the adult Kashin-Beck disease with severe osteoarthritis. AB - PURPOSE: Kashin-Beck disease (KBD) is an endemic osteoarthropathy, and the severe knee pain and functional limitations were seriously affecting the quality of life in patients with end-stage KBD. We retrospectively evaluated the clinical outcomes and the quality of life in KBD patients with total knee arthroplasty (TKA). METHODS: A total of 22 subjects (25 knees) suffered KBD with severe knee pain and underwent primary TKA. Knee pain was measured by visual analogue scale (VAS), and the knee function was evaluated by Knee Society Clinical Rating System Score (KSS). KBD Quality of Life (KBDQOL) was used to evaluate the quality of life in KBD patients before and after TKA. RESULTS: There were no major complications after TKA. The levels of VAS score were obviously deceased in post operation than that in pre-operation. The levels of KSS score were increased in one year after TKA compared with the pre-operative values, and it maintained a higher level on three years after TKA. The average KBDQOL score level of each domain in pre-operation and one and three years after TKA was increased accordingly. The average scores of physical function, activity limitation, support of society, mental health, and general health in one year after TKA were significantly higher than those in pre-operation. CONCLUSIONS: TKA can reduce knee pain, improve knee function, and improve the quality life in KBD patients. KBDQOL questionnaire may be a promising instrument for assessing the quality life in KBD patients. PMID- 29971709 TI - Annual Convention SFCR 2018. PMID- 29971708 TI - Clinical practice guidelines for the management of non-specific low back pain in primary care: an updated overview. AB - OBJECTIVE: The aim of this study was to provide an overview of the recommendations regarding the diagnosis and treatment contained in current clinical practice guidelines for patients with non-specific low back pain in primary care. We also aimed to examine how recommendations have changed since our last overview in 2010. METHOD: The searches for clinical practice guidelines were performed for the period from 2008 to 2017 in electronic databases. Guidelines including information regarding either the diagnosis or treatment of non-specific low back pain, and targeted at a multidisciplinary audience in the primary care setting, were considered eligible. We extracted data regarding recommendations for diagnosis and treatment, and methods for development of guidelines. RESULTS: We identified 15 clinical practice guidelines for the management of low back pain in primary care. For diagnosis of patients with non-specific low back pain, the clinical practice guidelines recommend history taking and physical examination to identify red flags, neurological testing to identify radicular syndrome, use of imaging if serious pathology is suspected (but discourage routine use), and assessment of psychosocial factors. For treatment of patients with acute low back pain, the guidelines recommend reassurance on the favourable prognosis and advice on returning to normal activities, avoiding bed rest, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and weak opioids for short periods. For treatment of patients with chronic low back pain, the guidelines recommend the use of NSAIDs and antidepressants, exercise therapy, and psychosocial interventions. In addition, referral to a specialist is recommended in case of suspicion of specific pathologies or radiculopathy or if there is no improvement after 4 weeks. While there were a few discrepancies across the current clinical practice guidelines, a substantial proportion of recommendations was consistently endorsed. In the current review, we identified some differences compared to the previous overview regarding the recommendations for assessment of psychosocial factors, the use of some medications (e.g., paracetamol) as well as an increasing amount of information regarding the types of exercise, mode of delivery, acupuncture, herbal medicines, and invasive treatments. These slides can be retrieved under Electronic Supplementary Material. PMID- 29971710 TI - Cellular and Nuclear Forces: An Overview. AB - Biological cells sample their surrounding microenvironments using nanoscale force sensors on the cell surfaces. These surface-based force and stress sensors generate physical and chemical responses inside the cell. The inherently well connected cytoskeleton and its physical contacts with the force elements on the nuclear membrane lead these physicochemical responses to cascade all the way inside the cell nucleus, physically altering the nuclear state. These physical alterations of the cell nucleus, through yet-unknown complex steps elicit physical and functional response from the chromatin in the form of altered gene expression profiles. This mechanism of force/stress sensing by the cell and then its nuclear response has been shown to play a vital role in maintaining robust cellular homeostasis, controlling gene expression profiles during developmental phases as well as cell differentiation. Over the last few years, there has been appreciable progress toward identification of the molecular players responsible for force sensing. However, the actual sensing mechanism of cell surface bound force sensors and more importantly cascading of the signals, both physical (via cytosolic force sensing elements such as microtubule and actin framework) and chemical (cascade of biochemical signaling from cell surface to nuclear surface and further to the chromatin), inside the cell is poorly understood. In this chapter, we present a review of the currently known molecular players in cellular as well as nuclear force sensing repertoire and their possible mechanistic aspects. We also introduce various biophysical concepts that are used to describe the force/stress sensing and response of a cell. We hope this will help asking clearer questions and designing pointed experiments for better understanding of the force-dependent design principles of the cell surface, nuclear surface, and gene expression. PMID- 29971711 TI - The Bacterial Flagellar Rotary Motor in Action. AB - The bacterial flagellar motor is one of the few rotary motors in nature. Only ~50 nm in diameter, this transmembrane, ion-driven nanomachine rotates a semirigid helical flagellum at speeds of up to 1300 rps. It is composed of at least 13 different proteins, in different copy numbers, resulting from the coordinated, sequential expression of more than 40 genes. Structural studies have revealed a great deal of information about the structure of the motor, but the in vivo activity has been more elusive. Using a multidisciplinary approach combining molecular biology with single molecule fluorescence microscopy and novel data analysis recent work has obtained quantitative data on the stoichiometry, dynamics, and turnover of components of functioning motors in vivo under physiological conditions. This has shown that it is not a stable rotary machine, but that its structure is highly dynamic and undergoes adaptive remodeling in response to different intracellular and extracellular signals. PMID- 29971713 TI - Using Microfluidics Single Filament Assay to Study Formin Control of Actin Assembly. AB - Formin is a highly processive motor that offers very unique features to control the elongation of actin filaments. When bound to the filament barbed-end, it enhances the addition of profilin-actin from solution to dramatically accelerate actin assembly. The different aspects of formin activity can be explored using single actin filament assays based on the combination of microfluidics with fluorescence microscopy. This chapter describes methods to conduct single filament experiments and explains how to probe formin renucleation as a case study: purification of the proteins, the design, preparation, and assembly of the flow chamber, and how to specifically anchor formins to the surface. PMID- 29971712 TI - Purification and Reconstitution of Ilyobacter tartaricus ATP Synthase. AB - F-type adenosine triphosphate (ATP) synthase is a membrane-bound macromolecular complex, which is responsible for the synthesis of ATP, the universal energy source in living cells. This enzyme uses the proton- or sodium-motive force to power ATP synthesis by a unique rotary mechanism and can also operate in reverse, ATP hydrolysis, to generate ion gradients across membranes. The F1Fo-ATP synthases from bacteria consist of eight different structural subunits, forming a complex of ~550 kDa in size. In the bacterium Ilyobacter tartaricus the ATP synthase has the stoichiometry alpha3beta3gammadeltaepsilonab2c11. This chapter describes a wet-lab working protocol for the purification of several tens of milligrams of pure, heterologously (E. coli-)produced I. tartaricus Na+-driven F1Fo-ATP synthase and its subsequent efficient reconstitution into proteoliposomes. The methods are useful for a broad range of subsequent biochemical and biotechnological applications. PMID- 29971714 TI - Engineering Synthetic Myosin Filaments Using DNA Nanotubes. AB - Throughout the cell, motor proteins work together to drive numerous molecular processes and functions. For example, ensembles of myosin motors collectively transport vesicles and organelles, maintain membrane homeostasis, and drive muscle contraction. Studying these motors in groups has become increasingly important with work demonstrating the emergence of ensemble behavior distinct from individual motor behavior. One powerful technique that has been used in the last decade is DNA nanotechnology, which provides precise control over spacing and organization of patterned motor proteins. Until recently, however, most studies combining DNA nanostructures and molecular motors have been confined to discrete DNA structures with limited attachment points for motor proteins. In this chapter, we describe a new approach for making synthetic motor filaments using DNA nanotubes. We present methods for preparing myosin VI-labeled nanotubes and testing these nanotubes using a general in vitro motility setup. Overall, these nanotubes can easily be used to study other large ensembles of molecular motors, such as muscle myosin or ciliary dynein, both proteins that work in large motor ensembles to drive key cellular functions. PMID- 29971715 TI - Direct Imaging of Walking Myosin V by High-Speed Atomic Force Microscopy. AB - High-speed atomic force microscopy allows for directly observing biological molecules in dynamic action at submolecular and sub-100 ms spatiotemporal resolution, without disturbing their function. This microscopy has recently been applied to various proteins with great success. Here, we describe methods to image myosin V molecules walking on actin filaments with high-speed atomic force microscopy. PMID- 29971716 TI - High-Resolution Single-Molecule Kinesin Assays at kHz Frame Rates. AB - This chapter describes methods for high-speed, unloaded, in vitro single-molecule kinesin tracking experiments. Instructions are presented for constructing a total internal reflection dark-field microscope (TIRDFM) and labeling motors with gold nanoparticles. An AMP-PNP unlocking assay is introduced as a specialized means of capturing processive events in a reduced field of view. Finally, step-finding tools for analyzing high frame-rate tracking data are described. PMID- 29971717 TI - Multicolor Tracking of Molecular Motors at Nanometer Resolution. AB - Molecular motors move processively along cytoskeletal filaments through stepping of their catalytic head domains. Observation of the stepping movement of the heads reveals the mechanism of motor processivity and how they coordinate the cycles of the catalytic heads during processive motility. This chapter will discuss recent developments in simultaneous observation of the stepping motions of the two heads using multicolor single particle tracking microscopy. PMID- 29971718 TI - High-Speed Optical Tweezers for the Study of Single Molecular Motors. AB - Mechanical transitions in molecular motors often occur on a submillisecond time scale and rapidly follow binding of the motor with its cytoskeletal filament. Interactions of nonprocessive molecular motors with their filament can be brief and last for few milliseconds or fraction of milliseconds. The investigation of such rapid events and their load dependence requires specialized single-molecule tools. Ultrafast force-clamp spectroscopy is a constant-force optical tweezers technique that allows probing such rapid mechanical transitions and submillisecond kinetics of biomolecular interactions, which can be particularly valuable for the study of nonprocessive motors, single heads of processive motors, or stepping dynamics of processive motors. Here we describe a step-by step protocol for the application of ultrafast force-clamp spectroscopy to myosin motors. We give indications on optimizing the optical tweezers setup, biological constructs, and data analysis to reach a temporal resolution of few tens of microseconds combined with subnanometer spatial resolution. The protocol can be easily generalized to other families of motor proteins. PMID- 29971720 TI - The Role of Supercoiling in the Motor Activity of RNA Polymerases. AB - RNA polymerase (RNAP) is, in its elongation phase, an emblematic example of a molecular motor whose activity is highly sensitive to DNA supercoiling. After a review of DNA supercoiling basic features, we discuss how supercoiling controls polymerase velocity, while being itself modified by polymerase activity. This coupling is supported by single-molecule measurements. Physical modeling allows us to describe quantitatively how supercoiling and torsional constraints mediate a mechanical coupling between adjacent polymerases. On this basis, we obtain a description that may explain the existence and functioning of RNAP convoys. PMID- 29971719 TI - Determining Stable Single Alpha Helical (SAH) Domain Properties by Circular Dichroism and Atomic Force Microscopy. AB - Stable, single alpha-helical (SAH) domains exist in a number of unconventional myosin isoforms, as well as other proteins. These domains are formed from sequences rich in charged residues (Arg, Lys, and Glu), they can be hundreds of residues long, and in isolation they can tolerate significant changes in pH and salt concentration without loss in helicity. Here we describe methods for the preparation and purification of SAH domains and SAH domain-containing constructs, using the myosin 10 SAH domain as an example. We go on to describe the use of circular dichroism spectroscopy and force spectroscopy with the atomic force microscope for the elucidation of structural and mechanical properties of these unusual helical species. PMID- 29971721 TI - Single-Molecule FRET Analysis of Replicative Helicases. AB - Over the recent years single-molecule fluorescence resonance energy transfer (smFRET) technique has proven to be one of the most powerful tools for revealing mechanistic insights into helicase activities. Here we describe details of single molecule FRET assays for probing DNA unwinding activities as well as functional dynamics by replicative helicases in real time. The ability of smFRET to measure the behavior of biomolecules at a nanometer scale enabled us to address how the leading and lagging strand synthesis are coordinated during DNA replication, to resolve DNA unwinding steps of Bacteriophage T7 helicase, and to observe heterogeneous unwinding patterns modulated by the DNA binding domain of E1 helicase. These single-molecule FRET assays are generally applicable to other replicative and nonreplicative hexameric helicases. PMID- 29971722 TI - Recombinases and Related Proteins in the Context of Homologous Recombination Analyzed by Molecular Microscopy. AB - Transmission electron microscopy (TEM) and atomic force microscopy (AFM) are powerful tools to study the behavior of various actors in homologous recombination including molecular motors such as recombinases and helicases/translocases. Here we present specific approaches developed in terms of sample preparation and imaging methods to contribute to the understanding of homologous recombination process and its regulation focusing on the interplay between recombinases and other related proteins such as mediators or antirecombinase actors.Homologous recombination (HR) is a high-fidelity DNA repair pathway since it uses a homologous DNA as template. Recombinases such as RecA in bacteria, RadA in archaea, and Rad51 in eukaryotes are key proteins in the HR pathway: HR is initiated with formation of an ssDNA overhang on which recombinases polymerize and form a dynamic active nucleoprotein filament able to search for homology and to exchange DNA strand in an ATP-dependent manner. We provide practical methods to analyze presynaptic filament formation on ssDNA, its composition and regulation in presence of mediator partners, antirecombinase activity of translocase, and chromatin remodeling events. PMID- 29971723 TI - DNA Organization and Superesolved Segregation. AB - With single-molecule localization microscopy (SMLM) it is possible to reveal the internal composition, architecture, and dynamics of molecular machines and large cellular complexes. SMLM remains technically challenging, and frequently its implementation requires tailored experimental conditions that depend on the complexity of the subcellular structure of interest. Here, we describe two simple, robust, and high-throughput protocols to study molecular motors and machineries responsible for chromosome transport and organization in bacteria using 2D- and 3D-SMLM. PMID- 29971724 TI - Electrophoretic Analysis of the DNA Supercoiling Activity of DNA Gyrase. AB - Most bacterial cells have a motor enzyme termed DNA gyrase, which is a type-2 topoisomerase that reduces the linking number (Lk) of DNA. The supercoiling energy generated by gyrase is essential to maintain the bacterial chromosome architecture and regulate its DNA transactions. This chapter describes the use of agarose-gel electrophoresis to detect the unconstrained supercoiling of DNA generated by gyrase or other gyrase-like activities. Particular emphasis is made on the preparation of a relaxed plasmid as initial DNA substrate, on the distinction of constrained and unconstrained DNA supercoils, and on the measurement of the DNA supercoiling density achieved by gyrase activity. PMID- 29971725 TI - Single-Molecule Angular Optical Trapping for Studying Transcription Under Torsion. AB - Optical tweezers are flexible and powerful single-molecule tools that have been extensively utilized in biophysical studies. With their ability to stretch and twist DNA, and measure its force and torque simultaneously, they provide excellent opportunities to gain novel insights into the function of protein motors and protein-DNA interactions. Recently, a novel DNA supercoiling assay using an angular optical tweezers (AOT) has been developed to investigate torque generation during transcription. Here, we provide a detailed and practical guide to performing this technique. Using bacterial RNA polymerase (RNAP) as an example, we present protocols for constructing and calibrating an AOT instrument, preparing DNA templates, and acquiring and analyzing real-time data for transcription under DNA supercoiling. While these protocols were initially developed with E. coli RNAP, they can be readily adapted to study other DNA-based motor proteins. PMID- 29971726 TI - Anisotropy-Based Nucleosome Repositioning Assay. AB - Most eukaryotic DNA is tightly packaged into nucleosomes that render these sequences largely inaccessible for transcription or repair. Molecular motors called chromatin remodelers use an ATP-dependent mechanism to relieve the inhibition of these processes by sliding or disassembling the nucleosomes. This allows them to serve an essential role in the regulation of gene expression and genomic integrity. The sliding of nucleosomes along DNA can be studied directly by monitoring the associated changes in the fluorescence anisotropy of fluorophores attached to the ends of the DNA. Nucleosome repositioning can also be monitored indirectly through the ATP hydrolysis of the chromatin remodeler during the sliding reaction. Here we discuss how the kinetic data collected in these experiments can be analyzed by simultaneous global nonlinear least squares (NLLS) analysis using simple sequential "n-step" mechanisms to obtain estimates of the macroscopic rate of nucleosome repositioning and of the stoichiometry of coupling ATP binding and hydrolysis to this reaction. PMID- 29971727 TI - Remodeling and Repositioning of Nucleosomes in Nucleosomal Arrays. AB - ATP-dependent nucleosome remodeling factors sculpt the nucleosomal landscape of eukaryotic chromatin. They deposit or evict nucleosomes or reposition them along DNA in a process termed nucleosome sliding. Remodeling has traditionally been analyzed using mononucleosomes as a model substrate. In vivo, however, nucleosomes form extended arrays with regular spacing. Here, we describe how regularly spaced nucleosome arrays can be reconstituted in vitro and how these arrays can be used to dissect remodeling in the test tube. We outline two assays. The first assay senses various structural changes to a specific nucleosome within the nucleosomal array whereas the second assay is specific toward detecting repositioning of nucleosomes within the array. Both assays exploit changes to the accessibility of DNA to restriction enzymes during the remodeling reaction. PMID- 29971728 TI - Measuring Unzipping and Rezipping of Single Long DNA Molecules with Optical Tweezers. AB - The unwinding of double-stranded DNA is a frequently occurring event during the cellular processes of DNA replication, repair, and transcription. To help further investigate properties of this fundamental process as well as to study proteins acting on unzipped DNA at the single molecule level, we describe a novel method for efficient preparation of long DNA constructs (arbitrary sequences of many kilobasepairs (kbp) in length) that can be forcibly unzipped and manipulated with optical tweezers or other single-molecule manipulation techniques. This method utilizes PCR, a nicking endonuclease, and strand displacement synthesis by the Klenow fragment of DNA polymerase I to introduce labeled nucleotides at appropriate positions to facilitate unzipping of the DNA by application of force. We also describe various optical tweezers measurement modes for measuring DNA unzipping and rezipping. These methods have applications to studying helicases and DNA binding proteins. PMID- 29971729 TI - Single-Molecule Measurements of Motor-Driven Viral DNA Packaging in Bacteriophages Phi29, Lambda, and T4 with Optical Tweezers. AB - Viral DNA packaging is a required step in the assembly of many dsDNA viruses. A molecular motor fueled by ATP hydrolysis packages the viral genome to near crystalline density inside a preformed prohead shell in ~5 min at room temperature. We describe procedures for measuring the packaging of single DNA molecules into single viral proheads with optical tweezers. Three viral packaging systems are described in detail: bacteriophages phi29 (phi29), lambda (lambda), and T4. Two different approaches are described: (1) With phi29 and T4, prohead motor complexes can be preassembled in bulk and packaging can be initiated in the optical tweezers by "feeding" a single DNA molecule to one of the complexes; (2) With phi29 and lambda, packaging can be initiated in bulk then stalled, and a single prohead-motor-DNA complex can then be captured with optical tweezers and restarted. In both cases, the prohead is ultimately attached to one trapped microsphere and the end of the DNA being packaged is attached to a second trapped microsphere such that packaging of the DNA pulls the two microspheres together and the rate of packaging and force generated by the motor is directly measured in real time. These protocols allow for the effect of many experimental parameters on packaging dynamics to be studied such as temperature, ATP concentration, ionic conditions, structural changes to the DNA substrate, and mutations in the motor proteins. Procedures for capturing microspheres with the optical traps and different measurement modes are also described. PMID- 29971730 TI - Methods for Single-Molecule Sensing and Detection Using Bacteriophage Phi29 DNA Packaging Motor. AB - Bacteriophage phi29 DNA packaging motor consists of a dodecameric portal channel protein complex termed connector that allows transportation of genomic dsDNA and a hexameric packaging RNA (pRNA) ring to gear the motor. The elegant design of the portal protein has facilitated its applications for real-time single-molecule detection of biopolymers and chemicals with high sensitivity and selectivity. The robust self-assembly property of the pRNA has enabled biophysical studies of the motor complex to determine the stoichiometry and structure/folding of the pRNA at single-molecule level. This chapter focuses on biophysical and analytical methods for studying the phi29 motor components at the single-molecule level, such as single channel conductance assays of membrane-embedded connectors; single molecule photobleaching (SMPB) assay for determining the stoichiometry of phi29 motor components; fluorescence resonance energy transfer (FRET) assay for determining the structure and folding of pRNA; atomic force microscopy (AFM) for imaging pRNA nanoparticles of various size, shape, and stoichiometry; and bright field microscopy with magnetomechanical system for direct visualization of viral DNA packaging process. The phi29 system with explicit engineering capability has incredible potentials for diverse applications in nanotechnology and nanomedicine including, but not limited to, DNA sequencing, drug delivery to diseased cells, environmental surveillance, and early disease diagnosis. PMID- 29971731 TI - Beliefs About the End of AIDS, Concerns About PrEP Functionality, and Perceptions of HIV Risk as Drivers of PrEP Use in Urban Sexual Minority Men: The P18 Cohort Study. AB - Using cross-sectional data from an ongoing cohort study of young gay, bisexual, and other men who have sex with men (N = 492), we examined the extent to which cognitive factors such as beliefs about the end of AIDS, concerns about the manner in which PrEP works, and perceptions about risk of contracting HIV, are related to PrEP uptake and use. While almost all participants indicted awareness of PrEP, a mere 14% had ever used PrEP. Those with lower concerns about the side effects of PrEP and greater belief that treatment and PrEP would eliminate AIDS were also more likely to have ever used PrEP. Our findings support the ongoing challenges of PrEP uptake as means of curtailing HIV in young sexual minority men, and suggest that beyond the structural factors, consideration must be given to further educating the population as a means of adjusting potentially faulty beliefs, concerns, and perceptions which may influence PrEP utilization. PMID- 29971732 TI - Comparison of Antiretroviral Therapy Adherence Among HIV-Infected Older Adults with Younger Adults in Africa: Systematic Review and Meta-analysis. AB - As access to antiretroviral treatment in low- and middle-income countries improves, the number of older adults (aged >= 50 years) living with HIV is increasing. This study compares the adherence to antiretroviral treatment among older adults to that of younger adults living in Africa. We searched PubMed, Medline, Cochrane CENTRAL, CINAHL, Google Scholar and EMBASE for keywords (HIV, ART, compliance, adherence, age, Africa) on publications from 1st Jan 2000 to 1st March 2016. Eligible studies were pooled for meta-analysis using a random-effects model, with the odds ratio as the primary outcome. Twenty studies were included, among them were five randomised trials and five cohort studies. Overall, we pooled data for 148,819 individuals in two groups (older and younger adults) and found no significant difference in adherence between them [odds ratio (OR) 1.01; 95% CI 0.94-1.09]. Subgroup analyses of studies using medication possession ratio and clinician counts to measure adherence revealed higher proportions of older adults were adherent to medication regimens compared with younger adults (OR 1.06; 95% CI 1.02-1.11). Antiretroviral treatment adherence levels among older and younger adults in Africa are comparable. Further research is required to identify specific barriers to adherence in the aging HIV affected population in Africa which will help in development of interventions to improve their clinical outcomes and quality of life. PMID- 29971733 TI - Fecal Coliform Bacterial Detection to Assess Enema Adherence in HIV Prevention Clinical Studies. AB - Evaluating the efficacy of any HIV prevention strategy is dependent on ensuring and objectively monitoring adherence to the intervention. Medicated rectal enemas are a potential method for providing topical, episodic HIV prophylaxis during receptive anal intercourse. Assessing adherence to recommended enema dosing regimens is essential in evaluating the utility of this strategy. We utilized fecal coliform bacteria on used enema tips as a marker for enema use. Enema tip coliforms were tested by repurposing a microtiter plate-based water quality test designed to detect fecal contamination of water. Coliform detection occurred with 100% sensitivity and specificity when tips were assayed on day of use. The assay performed well post-7 day sample storage at room temperature, yielding a sensitivity of 80% and specificity of 93%. All (n = 64) samples collected in a subset of the DREAM-01 rectal microbicide enema clinical trial tested positive, even when tips were evaluated > 7 days post-reported use. The coliform-based enema tip assay allows monitoring of adherence in interventions involving rectal enemas in a sensitive, specific and inexpensive manner. The test performs well in clinical trial settings. PMID- 29971734 TI - Modelling the Epidemiological Impact and Cost-Effectiveness of PrEP for HIV Transmission in MSM in China. AB - Risk of HIV infection is high in Chinese MSM, with an annual HIV incidence ranging from 3.41 to 13.7/100 person-years. Tenofovir-based PrEP is effective in preventing HIV transmission in MSM. This study evaluates the epidemiological impact and cost-effectiveness of implementing PrEP in Chinese MSM over the next two decades. A compartmental model for HIV was used to forecast the impact of PrEP on number of infections, deaths, and disability-adjusted life years (DALY) averted. We also provide an estimate of the incremental cost-effectiveness ratio (ICER) and the cost per DALY averted of the intervention. Without PrEP, there will be 1.1-3.0 million new infections and 0.7-2.3 million HIV-related deaths in the next two decades. Moderate PrEP coverage (50%) would prevent 0.17-0.32 million new HIV infections. At Truvada's current price in China, daily oral PrEP costs $46,813-52,008 per DALY averted and is not cost-effective; on-demand Truvada reduces ICER to $25,057-27,838 per DALY averted, marginally cost effective; daily generic tenofovir-based regimens further reduce ICER to $3675 8963, wholly cost-effective. The cost of daily oral Truvada PrEP regimen would need to be reduced by half to achieve cost-effectiveness and realize the public health good of preventing hundreds of thousands of HIV infections among MSM in China. PMID- 29971735 TI - Identifying Which Place Characteristics are Associated with the Odds of Recent HIV Testing in a Large Sample of People Who Inject Drugs in 19 US Metropolitan Areas. AB - This exploratory analysis investigates relationships of place characteristics to HIV testing among people who inject drugs (PWID). We used CDC's 2012 National HIV Behavioral Surveillance (NHBS) data among PWID from 19 US metropolitan statistical areas (MSAs); we restricted the analytic sample to PWID self reporting being HIV negative (N = 7477). Administrative data were analyzed to describe the 1. Sociodemographic Composition; 2. Economic disadvantage; 3. Healthcare Service/Law enforcement; and 4. HIV burden of the ZIP codes, counties, and MSAs where PWID lived. Multilevel models tested associations of place characteristics with HIV testing. Fifty-eight percent of PWID reported past-year testing. MSA-level per capita correctional expenditures were positively associated with recent HIV testing among black PWID, but not white PWID. Higher MSA-level household income and imbalanced sex ratios (more women than men) in the MSA were associated with higher odds of testing. HIV screening for PWID is suboptimal (58%) and needs improvement. Identifying place characteristics associated with testing among PWID can strengthen service allocation and interventions in areas of need to increase access to HIV testing. PMID- 29971736 TI - Endogenous arabitol and mannitol improve shelf life of encapsulated Metarhizium brunneum. AB - Successful commercialization of microbial biocontrol agents, such as Metarhizium spp., is often constrained by poor drying survival and shelf life. Here, we hypothesized that culture age would influence endogenous arabitol, erythritol, mannitol and trehalose contents in M. brunneum mycelium and that elevated levels of these compounds would improve drying survival and shelf life of encapsulated mycelium coupled with enhanced fungal virulence against T. molitor larvae. We found that culture age significantly influenced endogenous arabitol and mannitol contents in mycelium with highest concentrations of 0.6 +/- 0.2 and 2.1 +/- 0.2 ug/mg after 72 h, respectively. Drying survival of encapsulated mycelium was independent of culture age and polyol content with 41.1 +/- 4.4 to 55.0 +/- 6.2%. Best shelf life was determined for biomass harvested after 72 h at all investigated storage temperatures with maximum values of 59.5 +/- 3.3% at 5 degrees C followed by 54.5 +/- 1.6% at 18 degrees C and 19.4 +/- 1.3% at 25 degrees C after 6 months. Finally, high fungal virulence against T. molitor larvae of 83.3 +/- 7.6 to 98.0 +/- 1.8% was maintained during storage of encapsulated mycelium for 12 months with larval mortalities being independent of culture age and polyol content. In conclusion, our findings indicate beneficial effects of endogenous polyols in improving shelf life of encapsulated mycelium and this may spur the successful development of microbial biocontrol agents in the future. PMID- 29971737 TI - Novel anelloviruses identified in buccal swabs of Antarctic fur seals. AB - Viral diversity associated with Antarctic wildlife remains poorly studied. Nonetheless, over the past 5 years, there has been a concerted effort using viral metagenomics approaches to identify and characterize viruses associated with Antarctic pinniped and avian species. Here we used a viral metagenomics approach to identify circular DNA viruses in buccal swab samples from Antarctic fur seals (Arctocephalus gazella) breeding on Livingston Island, Antarctica during the 2016/2017 field season. We identified two new lineages of anelloviruses, torque teno Arctocephalus gazella virus (TTAgV)-1 (2083 nts) and -2 (2127-2143 nts), which are most closely related to and cluster with a previously identified anellovirus associated with California sea lions (Zalophus californianus) sharing ~ 60% genome-wide pairwise identity. The ORF1 of TTAgVs share 26-41% amino acid similarity to the ORF1 of other previously identified pinniped-associated anelloviruses. PMID- 29971738 TI - Correction to: Genetic aberrations of the K-ras proto-oncogene in bladder cancer in relation to pesticide exposure. AB - The original publication of this paper contains a mistake. Line 6 in the abstract, line should read "One hundred patients were diagnosed with bladder cancer and two hundred controls attended the outpatient clinic;" PMID- 29971739 TI - Biofilm architecture on different substrates of an Oculatella subterranea (Cyanobacteria) strain isolated from Pompeii archaeological site (Italy). AB - The Cyanobacterium Oculatella subterranea Zammit, Billi, Albertano inhabits hypogea and stone caves and is a pioneer of different stone substrata. In this study, a strain isolated from the House of Marco Castricio (Archaeological Park of Pompeii, Italy) was identified by a polyphasic approach and used for an in vitro colonization test to verify the influence of the substrate on the biofilm architecture. Fine structure of O. subterranea microbial mats was revealed as well as filaments orientation toward light source. This aim has been achieved through confocal laser scanner microscope microscopy and computer image analysis. Moreover, bioreceptivity of five different substrates, commonly retrieved in archaeological sites of Campania, was assessed for O. subterranea. Our results show that the three-dimensional structure of O. subterranea microbial mats is poorly affected by physical and geochemical features of substrates: in fact, the porous architecture of its biofilm was preserved, independently of the materials. On the other hand, the area/perimeter ratio relative to the O. subterranea growth on tuff, brick, and porphyry showed significant differences, indicating dissimilar levels of bioreceptivity of the three substrates. PMID- 29971741 TI - Fate of PAHs in the vicinity of aluminum smelter. AB - Investigation has been carried out in the vicinity of an aluminum smelter located in the industrialized town of Konin. Concentrations of 14 polycyclic aromatic hydrocarbons (PAHs) were determined in grass, spruce needles, and soil collected in the period of the smelter operation and several years after its closing. Significant changes in the quantity of PAHs and their profiles observed in the two measuring periods, stressing the importance of aluminum production with regard to PAH emission. It was confirmed by very high values of the carcinogenic potential (CP) found for PAHs accumulated in grass and soil when compared to the values found in urban and remote sites. PAH ratio rates used as a tool for identifying emission sources showed a pyrogenic origin of PAHs in both periods; the ratios in the period of the smelter running activity were similar to those found in other studies carried out near aluminum smelters. Grass turned out to be a good biomonitor of PAHs similarly to commonly used leaves of various tree species. The use of four age classes of spruce needles, some of which were subjected to emission from the smelter, showed that such approach could serve as an analysis tool for describing retrospective pollution. PMID- 29971740 TI - Evaluation of psychiatric hospital wastewater toxicity: what is its impact on aquatic organisms? AB - The primary source of pharmaceuticals to the aquatic environment is the discharge of wastewater effluents. Pharmaceuticals are a large and diverse group of compounds. Among them, psychotropic substances are particularly interesting to study due to their specific known mode of action. The present study was performed to investigate the effects of wastewater effluents from a psychiatric hospital wastewater treatment plant (WWTP) on several aquatic organisms. All the analyzed pharmaceuticals (10 compounds) were detected in WWTP effluents as well as in the receiving river. Although the environmental concentrations were generally at trace levels (ng L-1 to MUg L-1), induce toxic effects were observed. This study showed the effects of the WWTP effluents on the oogenesis and/or embryogenesis of amphipod crustacean Gammarus fossarum, Japanese fish medaka Oryzias latipes, mollusk Radix peregra, and planarian Schmidtea polychroa. A decrease of the number of oocytes and produced embryos was observed for G. fossarum and S. polychroa. Similarly, the hatching rate of R. peregra was affected by effluents. In the receiving river, the macroinvertebrate community was affected by the wastewater effluents discharge. PMID- 29971742 TI - Microbial fuel cell and membrane bioreactor coupling system: recent trends. AB - Membrane bioreactor (MBR) and microbial fuel cell (MFC) are new technologies based on microbial process. MBR takes separation process as the core to achieve the high efficient separation and enrichment the beneficiation of microbes during the biological treatment. MFC is a novel technology based on electrochemical process to realize the mutual conversion between biomass energy and electric energy, in order to solve the problems of serious membrane fouling and low efficiency of denitrification in membrane bioreactor, the low power generation efficiency, and unavailability of bioelectric energy of MFC. In recent years, MFC MBR coupling system emerged. It can effectively mitigate the membrane fouling and reduce the excess sludge production. Simultaneously, the electricity can be used effectively. The new coupling system has good prospects for development. In this paper, we summarized the research progresses of the two kinds of coupling systems in recent years and analyzed the coupling structure and forms. Based on the above, the future development fields of the MFC-MBR coupling system were prospected. PMID- 29971743 TI - Application of Box-Behnken design and desirability function in the optimization of Cd(II) removal from aqueous solution using poly(o-phenylenediamine)/hydrous zirconium oxide composite: equilibrium modeling, kinetic and thermodynamic studies. AB - In this research work, poly(o-phenylenediamine) was incorporated into the hydrous zirconium oxide matrix to form poly(o-phenylenediamine)/hydrous zirconium oxide composite which is used for the removal of Cd(II) from aqueous solution. The characterization of the material was done based on FTIR, XRD, SEM, and TGA-DTA. The effects of contact time, pH, adsorbent dose, and initial concentration of Cd(II) on the removal of Cd(II) were studied by performing 29 sets of sorption runs using Box-Behnken design combined with response surface methodology (RSM). Various isotherm models were tested to describe the adsorption equilibrium. The adsorption equilibrium data fitted well with Freundlich isotherm model. The maximum adsorption capacity of 66.66 mg g-1 was obtained from Langmuir isotherm. The pseudo-second-order kinetic model described the adsorption kinetics more accurately. Diffusion-based kinetics such as intraparticle diffusion and Bangham's model suggested that both film and intraparticle pore diffusion were involved in the adsorption process. The Elovich model pointed towards the chemisorption. The investigation of desorption and regeneration suggested that the material can be used as an effective sorbent for removal of Cd(II) from aqueous system. PMID- 29971744 TI - Assessment of arsenic removal efficiency by an iron oxide-coated sand filter process. AB - Arsenic is among the most dangerous contaminants which can limit groundwater use for drinking water consumption. Among the most diffused As-removal technologies around the world, adsorptive media systems are usually favored for relatively low cost and simplicity of operation. This study examines the performance of a laboratory-scale iron oxide-coated sand (IOCS) column filter, to remove arsenic (arsenate (As[V]) and arsenite (As[III])) from groundwater. This technology could be adopted in small communities, as it showed consistent removal rates of 99% with an easy-to-operate process. Some considerations about the possible introduction of such technology in developing countries are provided, highlighting the general impacts to human health related to high arsenic concentrations in groundwater. This, among other adsorption processes, could be recommended as a sustainable mean of ensuring good drinking water quality in developing regions, reducing human health impacts. PMID- 29971745 TI - Kinetics, mechanism, and global warming potentials of HFO-1234yf initiated by O3 molecules and NO3 radicals: insights from quantum study. AB - In the present investigation, the oxidation of HFO-1234yf (2,3,3,3 tetrafluoropropene) with O3 molecule and NO3 radical is studied by quantum chemical methods. The possible reaction pathways of the titled molecule with O3 molecule and NO3 radical are analyzed using M06-2X meta-hybrid density functional with the 6-311++G(d,p) basis set. We have further employed a series of single point energy calculations by using a potentially high-level couple cluster method with single and double excitations, including perturbative corrections ((CCSD(T)) at the same basis set. The addition reaction of HFO-1234yf with O3 molecule is initiated by the formation of primary ozonide complex, which leads to the formation of various carbonyl compounds and Criegee intermediates. The calculated energy barriers and thermochemical parameters inferred that decomposition of CH2OO and CF3CFO is slightly more preferred over the formation of CF3CFOO and CH2O. Further, the NO3 radical addition at alpha- and beta-sits of CF3CF?CH2 molecule is analyzed in details. The individual and overall rate constants for each reaction pathways are calculated by using canonical transition state theory over the temperature range of 250-450 K. We have observed that the computed rate constants are in good agreement with the available experimental data. Atmospheric lifetimes and global warming potentials of the HFO-1234yf are also reported in this manuscript. PMID- 29971747 TI - Advanced oxidation of antihypertensives losartan and valsartan by photo-electro Fenton at near-neutral pH using natural organic acids and a dimensional stable anode-gas diffusion electrode (DSA-GDE) system under light emission diode (LED) lighting. AB - In this work photo-electro-Fenton (PEF) processes using a dimensionally stable anode-gas diffusion electrode (DSA-GDE) system under light emission diodes (LED) type radiation were used in the degradation of the angiotensin-II-receptor antagonists (ARA II), valsartan (VAL), and losartan (LOS), which are used in the treatment of hypertension diseases, and are considered among the emerging contaminants (ECs). Organic acids as citric, tartaric, and oxalic acids were used as complexing agents of iron ions in order to maintain the performance of the Fenton reaction at near-neutral pH value. The results show that at 3.42 mA/cm2 after 90 min of electro-Fenton (EF) treatment, degradation of 70% of VAL and 100% of LOS were observed. Total degradation of VAL and LOS was reached with a PEF process at the same time with mineralization of 30%. When citric and tartaric acids were used instead of oxalic acid, similar results were obtained, i.e., total degradation of both compounds, LOS and VAL, after 90 min of treatment. The degradation performance can be attributed to the increase of the initial dissolved iron in the system, facilitating the Fe3+/Fe2+ turnover in the catalytic photo-Fenton reaction and consequently, hydroxyl radical (*OH) production. In addition, the increased photo-activity of the complexes can be associated with their high capability to complex Fe3+ and to promote ligand-to metal charge transfer, which is of key importance to feed Fe2+ to the Fenton process. The results show that the system evaluated was more efficient to eliminate sartan family compounds using LED lighting in comparison with traditional UV-A lamps used in this kind of work. Moreover, three transformation products of VAL degradation and two transformation products of LOS degradation were identified by high-resolution mass spectrometry (HRMS) using hybrid quadrupole-time-of-flight (QTOF) MS and, at the end of the PEF system, the several organic compounds accumulated and no mineralized were effectively treated in a subsequent aerobic biological system. PMID- 29971746 TI - Tamarind seed coat extract restores fluoride-induced hematological and biochemical alterations in rats. AB - Fluoride (F-) is becoming an ineluctable environmental pollutant causing deleterious effects in humans. In the present study, we examined whether tamarind seed coat extract (TSCE) is beneficial against the F--induced systemic toxicity and hematological changes. Wistar rats were randomly grouped as follows: group I served as control; group II intoxicated with sodium fluoride (NaF, 300 ppm) in drinking water; group III was administered through oral intubation with TSCE (100 mg/kg bw); group IV was treated with NaF (300 ppm) in association with TSCE (100 mg/kg bw) for 30 days. The results indicated that F- exposure induced oxidative stress as evidenced by elevated levels of reactive oxygen species and lipid peroxidation in the brain, liver, and kidney. F- administration modulates hematological indices-WBC, RBC, and mean corpuscular volume. Moreover, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acetylcholinesterase, and monoamine oxidase significantly increased on F- exposure. Conversely, delta-aminolevulinic acid dehydratase and glutathione/reduced glutathione ratio were decreased. Activity of antioxidants superoxide dismutase, catalase, glutathione peroxidase, and vitamin C-was also significantly decreased due to F- administration. Treatment with TSCE effectively mitigated the alterations through its antioxidant potential. The data suggested that the TSCE had beneficial effects in alleviating the F--induced toxicity and hence can serve as a promising neutraceutical agent. PMID- 29971748 TI - Switching From Pre-mixed Insulin to Regimens with Insulin Glargine in Type 2 Diabetes: A Prospective, Observational Study of Data From Adriatic Countries. AB - INTRODUCTION: Long-acting insulin analogs such as insulin glargine may offer improved glycemic control in patients with type 2 diabetes (T2D) compared to conventional insulin therapies. The objective of this study was to determine whether switching to insulin glargine had beneficial effects on glycemic control, weight gain, and incidence of hypoglycemia in patients with suboptimally managed T2D. METHODS: This prospective observational study was performed on 1041 patients who were suboptimally controlled on pre-mixed insulin therapy and were switched to an insulin glargine regimen. Clinical markers of glycemic control including glycosylated hemoglobin (HbA1c) < 7% (< 53 mmol/mol) and fasting blood glucose (FBG) levels ranging from 3.9 to 7.2 mmol/L were used for the primary outcome measures. Follow-up assessment of primary outcomes, weight gain, incidence of hypoglycemia, and patient satisfaction with the therapy was performed after three and six months of treatment. RESULTS: Target therapeutic values of HbA1c were achieved in 9.3% and 30.2% of patients, whereas FBG target values were achieved in 25.9% and 52.3% of patients after the third and sixth month of therapy, respectively. Both the HbA1c and FBG targets were reached in 7% and 25.9% of patients at the third and sixth month of therapy, respectively. Switching to insulin glargine decreased the incidence of hypoglycemia from 49.5% to 5.2% after six months of therapy; this decrease was associated with weight loss and was well perceived by the patients. CONCLUSION: Insulin glargine-based regimens are beneficial and safe therapeutic alternatives for T2D patients inadequately controlled with pre-mixed insulin. FUNDING: Sanofi-Aventis Croatia d.o.o., Zagreb, Croatia. PMID- 29971749 TI - Motion onset really does capture attention. AB - Several properties of visual stimuli have been shown to capture attention, one of which is the onset of motion. However, whether motion onset truly captures attention has been debated. It has been argued that motion onset only captured attention in previous studies because properties of the animated motion used in those experiments caused it to be "jerky" (i.e., there were gaps between successive images during animated motion). The present study sought to determine whether natural motion onset captures attention. Additionally, the present study further examined the circumstances under which animated motion onset, the only type of motion onset that can be produced on a computer display, does and does not capture attention. In Experiment 1, participants identified target letters in search arrays containing distinct animated motion types, either accompanied or unaccompanied by a new object. Animated motion onset captured attention, but not when the motion onset was accompanied by a new object, indicating that prior failures to replicate capture by animated motion onset were limited because a new object had always been included in the display. Experiment 2 employed natural motion rather than animated motion and found that participants were fastest at identifying motion-onset targets compared to other target types. These results provide further support for the claim that motion onset captures attention. PMID- 29971750 TI - Dominance of persistence over adaptation in forward masking. AB - Persistence of excitation and neural adaptation are competing theories proposed to explain the mechanisms underlying psychophysical forward masking. Previous research has been directed towards finding models that accurately describe the phenomenon but cannot account for the underlying explanation. The current study was designed to determine which theory best accounts for results obtained from behavioral gap duration adjustment tasks. Thirteen adults adjusted the gap within asymmetrical noise markers to be subjectively equal to the gap within equal intensity-noise markers. The duration of the perceived gap between the asymmetrical markers is expected to vary depending on which theory dominates perception. The persistence of excitation mechanism would lead to longer duration gaps when the second noise marker is lower in intensity than the preceding. Neural adaptation would result in matched gaps that are shorter in duration when the second noise marker was lower in level. The outcome of our data analysis is consistent with the persistence of excitation as a dominant mechanism in forward masking. PMID- 29971751 TI - Impact of spatial grouping on mean size estimation. AB - People represent summary statistics of visual scenes, but it is not fully clear whether such summary statistics are extracted automatically. To determine whether different levels of summary representation (i.e., at the perceptual-group or the entire-display level) may be formed differently, in two experiments we investigated how people extracted summary statistics for displays consisting of spatially segregated groups. Participants were asked to report the mean sizes of either entire sets or perceptual groups in precue and postcue conditions. There was no precueing advantage in the mean size estimations of entire sets. However, when these precues identified target perceptual groups, participants reported the perceptual-group means more accurately than when postcues were used. In the postcue condition, participants were biased toward the entire-set mean even when they were probed to report the perceptual-group mean. There was also greater bias toward the entire-set mean for more erroneous perceptual-group summaries. These findings suggest that ensemble representations are extracted more efficiently for the whole than for the perceptual parts and that ensemble perception is not a uniform process across perceptual groups and entire sets. PMID- 29971752 TI - Enhanced cutaneous wound healing in rats following topical delivery of insulin loaded nanoparticles embedded in poly(vinyl alcohol)-borate hydrogels. AB - Insulin plays an important role in the wound healing process, but its method of delivery to the wound bed and subsequent effect on rate of healing is less well investigated. In this study, we evaluated the therapeutic effectiveness of topical human insulin delivery using a nanoparticulate delivery system suspended in a structured hydrogel vehicle. Poly(lactide-co-glycolide) (PLGA) nanoparticles (NP) of 202.6 nm diameter and loaded with 33.86 MUg insulin per milligram of polymer were formulated using a modified double-emulsion solvent evaporation technique and dispersed in a dilatant hydrogel (poly(vinyl alcohol)-borate). Importantly, this hydrogel formulation was used to achieve ultimate contact with the wound bed. A comparison of wound healing rates following local administration of insulin in the free and nanoencapsulated forms was performed in diabetic and healthy rats. In non-diabetic rats, there was no significant difference between healing observed in control and wounds treated with free insulin (p > 0.05), whereas treatment with insulin encapsulated within PLGA NP showed a significant difference (p < 0.001). In diabetic cohorts, both free insulin and nanoencapsulated insulin induced significant improvement in wound healing when compared to controls, with better percentage wound injury indices observed with the colloidal formulation. At day 10 of the experiment, the difference between percentage wound injury indices of insulin-PLGA NP and free insulin comparing to their controls were 29.15 and 12.16%, respectively. These results support strongly the potential of insulin-loaded colloidal carriers for improved wound healing when delivered using dilatant hydrogel formulations. PMID- 29971753 TI - Environmental sustainability and pollution prevention. PMID- 29971754 TI - Population analysis of Magnaporthe oryzae by using endogenous repetitive DNA sequences and mating-type alleles in different districts of Karnataka, India. AB - Rice is the staple food crop of more than 60% of the population of the world. This crop suffers from blast disease caused by Magnaporthe oryzae. Information on the mating-type allele distribution and diversity of the pathogen population for the state of Karnataka, India is scanty. With this background, a total of 72 isolates of M. oryzae from rice in different districts of Karnataka were examined for identifying sexual mating alleles MAT1, MAT2 and understanding the genetic diversity based on DNA fingerprint of pot2, an inverted repeat transposon. Among 72 isolates, 44 isolates belonged to MAT1 type (male fertile) and 28 isolates were of MAT2 (female fertile) and there were no hermaphrodite isolates. In a given geographical location, only one mating type was identified. Results revealed that the isolates obtained from these regions are not sexually fertile showing predominant asexual reproduction. Hence, genetic variation observed in the pathogen may be mainly because of high copy number of transposons. A high copy number transposon, namely Pot2, was selected in our study to detect genetic diversity of the pathogen. Pot2 rep-PCR DNA fingerprinting profile showed 27 polymorphic bands with bands ranging in size from 0.65 to 4.0 kb and an average of 10 to 14 bands per isolate. Five distinct clusters were formed with two major, two minor, and one outlier. Clusters 4 and 5 are further subdivided into three sub-clusters. Some of the isolates belonging to clusters 3, 4, and 5 are interlinked as these locations are close to one another sharing common geographical parameters and boundaries. This knowledge on the sexual behavior and genetic diversity of M. oryzae is important with respect to breeding for disease resistance. PMID- 29971755 TI - Charge transport in a DNA model with solvent interaction. AB - The charge transport in the modified DNA model is studied by taking into account the factor of solvent and the effect of coupling motions of nucleotides. We report on the presence of the modulational instability (MI) of a plane wave for charge migration in DNA and the generation of soliton-like excitations in DNA nucleotides. By applying the continuum approximation, we show that the original differential-difference equation for the DNA dynamics can be reduced to a set of three coupled nonlinear equations. The linear stability analysis of wave solutions of the coupled systems is performed and the growth rate of instability is found numerically. We also investigate the impact of solvent interaction. The solvent factor introduces a new behavior to the wave patterns, modifying also the intrinsic properties of localized structures. In the numerical simulations, we show that the solitons exists when taking into account the effect of solvent and confirms an highest propagation of localized structures in the systems. The effect of solvent forces introduces a robustness behavior to the formed patterns, reinforcing the idea that the information in the DNA model is confined and concentrated to specific regions for efficiency. We also show that the localized structures can be disappeared with the highest value of solvent factor and thereafter the information within the molecule is not perceptible or not transmitted to another sites. PMID- 29971756 TI - The novel histological evidence of the blood-spleen barrier in duck (Anas platyrhynchos). AB - To identify the existence and composition of the blood-spleen barrier (BSB) in ducks, the microanatomical structures of the duck spleen were investigated by light and transmission electron microscopy, silver staining, enzymatic histochemistry and intravenous injection of ink. The endothelial cells of the sheathed capillaries were cuboidal-shaped and surrounded by an ellipsoid consisting of reticular cells, similar to high endothelial venules (HEVs). After ink injection, carbon particles were initially restricted to the ellipsoid and later trapped in the periellipsoidal lymphatic sheaths (PELS), and then transferred to the periarteriolar lymphatic sheaths (PALS) and splenic nodules over time. Reticular fibers were primarily distributed at the basement membrane of the sheathed capillaries and the periphery of the PELS. Macrophages were primarily distributed at the border between red pulp and PELS. These results suggested that the BSB was present in the ellipsoid and PELS and consisted of the mechanical barrier composed of endothelial cells of the sheathed capillaries, reticular cells and reticular fibers and the biological barrier composed of ellipsoid-associated macrophages. In conclusion, the BSB was identified in the duck spleen for the first time, including cuboidal endothelial cells, ellipsoid associated macrophages, reticular cells and fibers, and resisting circulating pathogen invasions. The study of BSB in ducks provides a theoretical foundation for the structural composition of the avian immune system. PMID- 29971757 TI - [Functional connectivity derived from an electroencephalogram during non-REM sleep in autism spectrum disorders]. AB - AIM: To know the differences in the patterns of functional connectivity, the topological characteristics of the network and the relationship between these latter and the interictal epileptiform anomalies in children with primary and secondary autism spectrum disorder (ASD). PATIENTS AND METHODS: A retrospective study was conducted with 27 children aged between 3 and 13 years diagnosed with ASD. Subjects were submitted to an electroencephalogram in a functional state of spontaneous sleep. Functional connectivity and the properties of the network were analysed using data obtained from the electroencephalogram during the N2 stage of non-REM sleep. The frequency of discharge of the interictal epileptiform activity (FDIEA) was determined and was correlated with the topological properties of the network. RESULTS: Synchronisation was diminished in patients with secondary ASD for the alpha frequency and increased for the theta and delta frequency compared with patients with primary ASD. Local alpha efficiency was higher in patients who presented interictal epileptiform activity. Additionally, in patients with secondary ASD there was a statistically significant positive and negative correlation between FDIEA and the topological properties of the network. CONCLUSIONS: Patients with secondary ASD display patterns of functional connectivity that are weaker for the alpha frequency and stronger for theta and delta than patients with primary ASD. In patients with secondary ASD, the interictal epileptiform activity is related to local and global connectivity of the network for the alpha and beta bands during non-REM sleep. PMID- 29971758 TI - [Review of the novelties from the 2017 ECTRIMS Congress, presented at the 10th Post-ECTRIMS Meeting (II)]. AB - The Post-ECTRIMS Meeting is an emblematic event in the field of multiple sclerosis in Spain. Its chief aim is bring together the country's leading specialist neurologists to analyse the main advances made in multiple sclerosis and to review the most important topics addressed at the ECTRIMS Congress. The tenth Post-ECTRIMS Meeting was held in November 2017. Over the years this event has firmly established itself as an important meeting point where experts from all over the country get together to foster communication, establish synergies and promote and enhance research ultimately aimed at improving the prognosis and quality of life of patients with multiple sclerosis. This second part addresses the different strategies for the management of patients in advanced stages of the disease and the safety of therapy in multiple sclerosis. Likewise, attention is also drawn to the areas that require further scientific and clinical evidence. In this edition, particular importance is given to multiple sclerosis in the paediatric population and ageing in the disease. At the same time emphasis is placed on the need to conduct collaborative studies and to foster greater awareness among specialists regarding the detection and management of the comorbidities in multiple sclerosis. PMID- 29971760 TI - [Bilateral vitreous haemorrhage associated with pontomesencephalic haemorrhage: an extreme case of Terson syndrome]. PMID- 29971759 TI - [Muscular dystrophies in literature, cinema and television]. AB - INTRODUCTION: Muscular dystrophies are inherited disorders, produced by a genetic mutation, with a slow or rapid progression, that basically affect striated muscle tissue. There are several clinical forms, the most frequent being Duchenne's muscular dystrophy and Becker muscular dystrophy. AIM: To analyse how muscular dystrophies have been portrayed in literature, cinema and television. DEVELOPMENT: Muscular dystrophy is a disorder that has been reflected in literature, cinema and television. In some cases it is only mentioned, sometimes it plays a secondary role in the plot, and in others it is the lead character who suffers from the disease. In general, reference is made to Duchenne's disease and, albeit less frequently, to Becker muscular dystrophy, although in some cases the patient is just said to be suffering from muscular dystrophy, without specifying what clinical variety it belongs to. Testimonials, novels, comics, fiction films, documentaries, short films and television programmes have all been produced with the aim of making the disease and its implications more widely known, as well as making the public aware of the need to invest resources in research. CONCLUSIONS: Muscular dystrophy has been portrayed quite realistically in literature, cinema and television, and Duchenne's muscular dystrophy is the clinical variety that has been shown most often. Aspects that have been reflected include its symptoms, progression, prognosis, the role of the family and caregivers, sexuality, palliative care, patients' will to overcome difficulties and the need to raise society's awareness of the condition and to invest more resources in research. PMID- 29971761 TI - [Pisa syndrome associated with codeine]. PMID- 29971763 TI - First report of intersex in a lutjanid: the goldband snapper Pristipomoides multidens. AB - This is the first report of intersex in a lutjanid species, the goldband snapper Pristipomoides multidens, in which the gonads of a male fish contain multifocal oocytes scattered among testicular tissue. The incidence rate of intersex was low (<1.0%), with oocytes observed in the testes of only two of 206 male fish examined. The capacity for P. multidens to develop an intersex condition suggests that future monitoring of this species should include histological analysis of gonads. PMID- 29971764 TI - Changes in nasotracheal tube depth in response to head and neck movement in children. AB - BACKGROUND: A tracheal tube is often inserted via the nasal cavity for dental surgery. The position of the tube tip is important, given that the head position sometimes changes during surgery. Head movement induces changes in the length of the trachea (t-length) and/or the distance between the nare and the vocal cords (n-v-distance). In this study, we investigated the changes in t-length and n-v distance in children undergoing nasotracheal intubation. METHODS: Eighty patients aged 2-8 year undergoing dental surgery were enrolled. After nasotracheal intubation with an uncuffed nasotracheal tube (4.5-6.0 mm), the tube was fixed at the patient's nares. The distance between the tube tip and the first carina was measured using a fibrescope with the angle between the Frankfort plane and horizontal plane set at 110 degrees . The location of the tube in relation to the vocal cords was then checked. These measurements were repeated at angles of 80 degrees (flexion) and 130 degrees (extension). The t-length and n-v-distance were then calculated using these measurements. RESULTS: On flexion, the t-length shortened significantly from 87.5 +/- 10.4 mm to 82.9 +/- 10.7 mm (P = 0.017) and the n-v-distance decreased from 128.1 +/- 10.7 mm to 125.6 +/- 10.4 mm (P = 0.294). On extension, the t-length increased significantly from 87.5 +/- 10.4 mm to 92.7 +/- 10.1 mm (P = 0.007) and the n-v-distance increased from 128.1 +/- 10.7 mm to 129.4 +/- 10.7 mm (P = 0.729). The change in t-length was significantly greater than that in the n-v-distance. CONCLUSION: A change in the position of the tracheal tube tip in the trachea depends mainly on changes in t length during paediatric dental surgery. PMID- 29971762 TI - Selegiline reduces adiposity induced by high-fat, high-sucrose diet in male rats. AB - BACKGROUND AND PURPOSE: Incidence and severity of obesity are increasing worldwide, however, efficient and safe pharmacological treatments are not yet available. Certain MAO inhibitors reduce body weight, although their effects on metabolic parameters have not been investigated. Here, we have assessed effects of a widely used, selective MAO-B inhibitor, selegiline, on metabolic parameters in a rat model of diet-induced obesity. EXPERIMENTAL APPROACH: Male Long-Evans rats were given control (CON) or a high-fat (20%), high-sucrose (15%) diet (HFS) for 25 weeks. From week 16, animals were injected s.c. with 0.25 mg.kg-1 selegiline (CON + S and HFS + S) or vehicle (CON, HFS) once daily. Whole body, subcutaneous and visceral fat was measured by CT, and glucose and insulin tolerance were tested. Expression of glucose transporters and chemokines was assessed by quantitative RT-PCR. KEY RESULTS: Selegiline decreased whole body fat, subcutaneous- and visceral adiposity, measured by CT and epididymal fat weight in the HFS group, compared with HFS placebo animals, without influencing body weight. Oral glucose tolerance and insulin tolerance tests showed impaired glucose homeostasis in HFS and HFS + S groups, although insulin levels in plasma and pancreas were unchanged. HFS induced expression of Srebp-1c, Glut1 and Ccl3 in adipose tissue, which were alleviated by selegiline. CONCLUSIONS AND IMPLICATIONS: Selegiline reduced adiposity, changes in adipose tissue energy metabolism and adipose inflammation induced by HFS diet without affecting the increased body weight, impairment of glucose homeostasis, or behaviour. These results suggest that selegiline could mitigate harmful effects of visceral adiposity. PMID- 29971765 TI - Reply to Letter "Accuracy of POSSUM and Nottingham Hip Fracture Score". PMID- 29971766 TI - A holistic investigation of the ecological correlates of abundance and body size for the endangered White's seahorse Hippocampus whitei. AB - Analysing the associations between the endangered White's seahorse Hippocampus whitei and characteristics of its environment (including habitat, prey and predator variables) in an estuary in New South Wales, Australia, revealed that seahorses had a greater number of significant associations with environmental correlates within a single seagrass bed than among seagrass beds. Predator abundance was negatively correlated with H. whitei abundances among seven seagrass beds (200-6,000 m apart) and no ecological correlate was associated with H. whitei body size distributions. Within the seagrass bed with the greatest number of H. whitei, individuals preferentially selected locations that were deeper, had denser seagrass, more epiphytic prey types and fewer predators. Smaller H. whitei were associated with greater depths within the bed. In this study, each class of ecological correlate (habitat, prey, predators) was found to have at least one significant relationship with H. whitei, depending on the scale, demonstrating that all three are important to H. whitei populations. As such, future studies that evaluate animal populations may benefit from holistic approaches that consider each of these together. For animals that are experiencing dramatic population declines due to habitat destruction, as H. whitei has over the last decade, a better understanding of its relationship to its environment is important to inform conservation action. PMID- 29971767 TI - Reply to "Haematocrit and plasma volume during induction of anaesthesia". PMID- 29971768 TI - Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products - a PEARRL review. AB - OBJECTIVES: In this review, the current biopharmaceutical approaches for evaluation of oral formulation performance in paediatrics are discussed. KEY FINDINGS: The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout its development and growth. Some physiological parameters are yet to be investigated, limiting the use of the existing in vitro biopharmaceutical tools to predict the in vivo performance of paediatric formulations. Meals and frequencies of their administration evolve during childhood and affect oral drug absorption. Furthermore, the establishment of a paediatric Biopharmaceutics Classification System (pBCS), based on the adult Biopharmaceutics Classification System (BCS), requires criteria adjustments. The usefulness of computational simulation and modeling for extrapolation of adult data to paediatrics has been confirmed as a tool for predicting drug formulation performance. Despite the great number of successful physiologically based pharmacokinetic models to simulate drug disposition, the simulation of drug absorption from the GI tract is a complicating issue in paediatric populations. SUMMARY: The biopharmaceutics tools for investigation of oral drug absorption in paediatrics need further development, refinement and validation. A combination of in vitro and in silico methods could compensate for the uncertainties accompanying each method on its own. PMID- 29971769 TI - Protective effect of methylsulfonylmethane in caerulein-induced acute pancreatitis and associated lung injury in mice. AB - OBJECTIVES: In the present study, we have elaborated the anti-inflammatory mechanism of MSM through homing of CD34+ stem cells towards an inflamed region by regulating hydrogen sulfide (H2 S) in an in vivo model of caerulein-induced acute pancreatitis (AP) and associated lung injury. METHODS: Male Swiss mice were treated with hourly intraperitoneal injections of caerulein (50 MUg/kg) for 6 h. MSM (500 mg/kg) was administered intraperitoneally 1 h after the first caerulein injection (therapeutic). The serum amylase activity and myeloperoxidase (MPO) activity in lung and pancreas were measured. The levels of H2 S and interleukin (IL)-1beta, cystathionine-gamma-lyase (CSE) and CD34+ expressions in pancreas and lungs were determined by RT-PCR and ELISA. KEY FINDINGS: Methylsulfonylmethane significantly ameliorated pancreas and lung histopathological changes, decreased serum amylase, MPO activity and inhibited caerulein-induced IL-1beta expression. Furthermore, MSM reduced caerulein-induced H2 S levels by alleviating the expression of CSE in pancreas and lungs and increased CD34 expression and inhibited nuclear factor (NF)-kappaB translocation in caerulein-induced AP and associated lung injury. CONCLUSIONS: These findings indicate that MSM can effectively reduce inflammatory responses and induce the homing of CD34+ cells to the injured tissues. PMID- 29971770 TI - Anesthetic approach to postdural puncture headache in the peripartum period: An Israeli national survey. AB - BACKGROUND: Accidental dural puncture frequency among pregnant women is about 1.5%, while approximately 60% of these women will suffer from post-dural puncture headache (PDPH) that may be debilitating. METHODS: Following IRB approval, we conducted a national survey of the lead anesthesiologist in 23 labor and delivery rooms in Israel. Each survey inquired about medical center annual delivery volume, training program for residents, accidental dural puncture management, processing of information, and PDPH management strategies. RESULTS: Data were collected from all 23 surveyed hospitals. As for methods for PDPH prevention, in most hospitals (87%) a prophylactic epidural blood patch (EBP) is not considered. Injection of epidural normal saline after delivery as a preventive measure is never considered in most (78.3%) hospitals, while four (17.4%) hospitals reported of constitutive use of this technique and one hospital only occasionally. Duration of conservative treatment was 24-48 hours in 95.7% of PDPH cases. CONCLUSION: In this survey, different aspects of treatment and PDPH management were examined. EBP is considered the gold standard in treating PDPH, although prophylactic blood patch is ineffective. We observed a tendency of very low performance of both prophylactic EBP and epidural normal saline administration after delivery in most centers. Most hospitals perform EBP after 24-48 hours of conservative treatment, along with published recommendations that show increased EBP efficiency with this timeframe. In light of the survey information, we aim to reach a uniform literature-based management strategy across Israeli hospitals. PMID- 29971771 TI - Transient reduction in abortion-related lethality after interventions to reduce delays in provision of care at Centre Hospitalier de Libreville, Gabon. PMID- 29971773 TI - Dynamic imaging of multiphase flow through porous media using 4D cumulative reconstruction. AB - This paper introduces an original application on reconstruction strategies for X ray computed microtomography, enabling the observation of time-dependent changes that occur during multiphase flow. In general, by sparsely collecting radiographs, the reconstruction of the object is compromised. Optimizations can be achieved by combining specific characteristics of the dynamics with the acquisition. Herein, the proposed method relies on short random intervals in which no drastic changes occur in the sample to acquire as many radiographs as possible that constitute a reconstructible data set. As these intervals are unpredictable, the method tries to guarantee that the collected radiograph data during these specific intervals are enough to recover useful information about the dynamics. Simulations of a percolating fluid in a digital rock are used to replicate an X-ray computed microtomography experiment to test the proposed method. The results demonstrate the potential of the proposed strategy for imaging multiphase flow in porous media and how data collected during distinct events can be combined to enhance the reconstruction of frames of the percolation process. PMID- 29971772 TI - Geranylgeranyl diphosphate synthase (GGPPS) regulates non-alcoholic fatty liver disease (NAFLD)-fibrosis progression by determining hepatic glucose/fatty acid preference under high-fat diet conditions. AB - Patients with obesity have a high prevalence of non-alcoholic fatty liver disease (NAFLD) and, in parallel, increased susceptibility to fibrosis/cirrhosis/hepatocellular carcinoma (HCC). Herein, we report that a high fat diet (HFD) can augment glycolysis and then accelerate NAFLD-fibrosis progression by downregulating the expression of geranylgeranyl diphosphate synthase (GGPPS), which is a critical enzyme in the mevalonate pathway. Long-term HFD overloading decreases GGPPS expression in mice, which shifts the fuel preference from fatty acids towards glucose. Liver-specific Ggpps deficiency drives the Warburg effect by impairing mitochondrial function, and then induces hepatic inflammation, thus exacerbating fibrosis. Ggpps deficiency also enhances the hyperfarnesylation of liver kinase B1, and promotes metabolic reprogramming by regulating 5'-AMP-activated protein kinase activity. Clinical data further imply that GGPPS expression can predict the stage of NAFLD and recurrence of NAFLD-associated HCC. We conclude that the level of GGPPS is a susceptibility factor for NAFLD-fibrosis progression, and requires more stringent surveillance to ensure early prediction and precision of treatment of NAFLD-related HCC. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29971775 TI - Cardiovascular disease and atopic dermatitis: epidemiological strengths and limitations. PMID- 29971774 TI - Circulating isoflavone and lignan concentrations and prostate cancer risk: a meta analysis of individual participant data from seven prospective studies including 2,828 cases and 5,593 controls. AB - Phytoestrogens may influence prostate cancer development. This study aimed to examine the association between prediagnostic circulating concentrations of isoflavones (genistein, daidzein, equol) and lignans (enterolactone and enterodiol) and the risk of prostate cancer. Individual participant data were available from seven prospective studies (two studies from Japan with 241 cases and 503 controls and five studies from Europe with 2,828 cases and 5,593 controls). Because of the large difference in circulating isoflavone concentrations between Japan and Europe, analyses of the associations of isoflavone concentrations and prostate cancer risk were evaluated separately. Prostate cancer risk by study-specific fourths of circulating concentrations of each phytoestrogen was estimated using multivariable-adjusted conditional logistic regression. In men from Japan, those with high compared to low circulating equol concentrations had a lower risk of prostate cancer (multivariable-adjusted OR for upper quartile [Q4] vs. Q1 = 0.61, 95% confidence interval [CI] = 0.39-0.97), although there was no significant trend (OR per 75 percentile increase = 0.69, 95 CI = 0.46-1.05, ptrend = 0.085); Genistein and daidzein concentrations were not significantly associated with risk (ORs for Q4 vs. Q1 = 0.70, 0.45-1.10 and 0.71, 0.45-1.12, respectively). In men from Europe, circulating concentrations of genistein, daidzein and equol were not associated with risk. Circulating lignan concentrations were not associated with the risk of prostate cancer, overall or by disease aggressiveness or time to diagnosis. There was no strong evidence that prediagnostic circulating concentrations of isoflavones or lignans are associated with prostate cancer risk, although further research is warranted in populations where isoflavone intakes are high. PMID- 29971777 TI - RETRACTION. PMID- 29971776 TI - Teaching behavior technicians to create publication-quality, single-case design graphs in graphpad prism 7. AB - In this investigation, we (a) define the desirable features of publication quality, single-case design graphs based on recommendations in the scholarly literature, (b) suggest GraphPad Prism as a suitable graphing program for creating graphs with those features, and (c) develop and validate a video modeling tutorial designed to train behavior technicians to create such graphs. Our review identified nine commonly recommended features, and Prism facilitated the creation of graphs with those features. We evaluated the effects of a video modeling tutorial on graphing performance in Prism using a multiple-baseline design. All four technicians showed mastery-level graphing accuracy with accompanying increases in efficiency following training, which maintained at follow-up without direct feedback from an expert behavior analyst. Social validity measures found the posttraining graphs to be significantly better than publication quality. We discuss these findings relative to challenges of developing efficient and effective staff-training tutorials. PMID- 29971778 TI - miR-134 targets PDCD7 to reduce E-cadherin expression and enhance oral cancer progression. AB - Oral squamous cell carcinoma (OSCC) is a common malignancy worldwide. This study clarified the oncogenic role of miR-134 in OSCC. Reporter assays, using both wild type and mutant constructs, confirmed that Programmed Cell Death 7 (PDCD7) gene was a potential target of miR-134. The OSCC cells exogenously expressed miR-134 exhibited reduced PDCD7 expression. As expected, exogenous miRZip-134 expression increased PDCD7 expression in the OSCC cells; additionally, PDCD7 expression suppressed the oncogenicity of the OSCC cells. By contrast, PDCD7 knockout through gene editing increased in vitro oncogenicity and neck nodal metastasis in mice, and reduced E-cadherin (E-cad) expression. PDCD7 transactivated E-cad expression via the GC-box in the promoter. Moreover, miR-134-associated cellular transformation and E-cad downregulation was attenuated by PDCD7. Downregulation of both PDCD7 and E-cad and high levels miR-134 expression was observed in OSCC tumor tissues. Activation of the miR-134-PDCD7-E-cad pathogenesis cascade occurred early during the human and murine oral carcinogenesis process. In conclusion, the oncogenic effect of miR-134 in oral carcinoma is mediated by reducing PDCD7 and E-cad expression. PMID- 29971780 TI - Evaluation of circulating EBV microRNA BART2-5p in facilitating early detection and screening of nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is an Epstein-Barr Virus (EBV) associated malignancy which is highly prevalent in Southeast Asia. EBV-related antibodies have been widely used as screening markers for early nasopharyngeal carcinoma (NPC) detection. However, due to its low positive predictive rate, it is essential to develop new biomarkers to facilitate NPC early diagnosis or triage EBV serological high-risk individuals to improve the chance of NPC early detection. BART microRNAs, which are encoded by BamHI region of EBV, were reported to be abundant in NPC and have potential value in early diagnosis of NPC. Here, we quantified circulating level of 17 BART microRNAs in discovery stage based on previous microarray and sequencing data and, in particular, BART 2-5p, the sole candidate whose area under curve (AUC) was higher than 0.8, has been chosen for further study. In validation stage, the sensitivity, specificity and AUC of BART 2-5p was 93.9%, 89.8%, 0.972 (95%CI: 0.954-0.989), respectively, in Cohort 1 constituted by NPC patients and controls from Hong Kong. For validation Cohort 2 consisting of patients and controls from Guangzhou, the sensitivity, specificity and AUC was 94.2%, 83.5%, 0.959 (95%CI: 0.939-0.980), respectively. To evaluate its ability to distinguish preclinical NPC patients, we established a nested case control study with serum samples prospectively collected from 22 NPC patients prior to their clinical diagnosis and 88 matched healthy high-risk controls in a screening trial. The sensitivity and specificity were 90.9% and 54.5%. Collectively, EBV microRNA BART2-5p may be a valuable biomarker for early detection of NPC. PMID- 29971781 TI - Alcohol consumption and risk of multiple myeloma in the NIH-AARP Diet and Health Study. AB - The epidemiologic evidence regarding the relationship between alcohol consumption and multiple myeloma (MM) risk remains limited and inconsistent, although recent studies suggest a potential protective effect. We prospectively investigated the risk of MM in relation to alcohol consumption frequency among 499,292 participants enrolled in the National Institutes of Health (NIH)-AARP Diet and Health Study in 1995-1996. A total of 1,312 MM cases were identified during follow-up through December 2011. Hazard ratios (HR) and 95% confidence intervals (CI) for categories of alcohol consumption relative to those defined as light drinkers (<1 drink/week) were estimated using multivariate Cox proportional hazard models. Overall, increasing frequency of alcohol consumption was inversely associated with MM (p-trend = 0.01), with a statistically significant association among those who consumed 2 drinks per day (HR = 0.70, 95% CI: 0.50, 0.98); similar but not statistically significant associations were observed for greater frequency of alcohol consumption. Among women, risk of MM was reduced among those who consumed less than one drink per day (HR = 0.73, 95% CI: 0.56, 0.97) and associations with greater frequency of alcohol consumption were inverse although not statistically significant. The findings of this large prospective investigation suggest that moderate alcohol consumption may be associated with reduced future risk of MM. PMID- 29971779 TI - Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition. AB - Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, ptrend = 0.40) or UCC (n of cases = 776; 0.91, 0.65-1.26, ptrend = 0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (pheterogeneity > 0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk. PMID- 29971782 TI - Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network. AB - VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF-related molecular mechanisms on breast cancer cells. VEGF-knocked-out MDA-MB-231 cells (231 VEGFKOex3 ) showed rounded morphology and shorter perimeter (1.6-fold, p < 0.0001). The 231 VEGFKOex3 cells also showed impaired cell migration (2.6-fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin-1 overexpressing MDA-MB-231 cells (231 sNRP1 ) exhibited rounded morphology and shorter perimeter (1.3-fold, p < 0.0001). The 231 sNRP1 cells also showed impaired cell migration (1.7-fold, p = 0.003). These changes were similar to that of 231 VEGFKOex3 cells. As MDA-MB-231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP-binding domain regulates the morphology and migration ability of MDA-MB-231 cells. Genome-wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone-receptor-negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer. PMID- 29971783 TI - Fasting and weight-loss restrictive diet practices among 2,700 cancer survivors: results from the NutriNet-Sante cohort. AB - Nutrition is often used by cancer survivors as a lever to take charge of their own health. However, some dietary behaviors are not currently recommended for patients without medical supervision. Our study aimed at evaluating weight-loss restrictive diets and fasting practices among cancer survivors of the NutriNet Sante cohort, as well as related socio-demographic and lifestyle factors. In October 2016, 2,741 cancer survivors had completed a specific questionnaire about their practices. Fasting and non-fasting patients (respectively dieting and non dieting) were compared using logistic regression models. Analyses were weighted according to the age, gender, and cancer location distribution of French cancer cases. 13.8% had already practiced weight-loss restrictive diet as their diagnosis. They were more likely to be women, professionally active, overweight/obese, to use dietary supplements and to have breast cancer (all p < 0.05). 6.0% had already fasted, 3.5% as their diagnosis. They were more likely to be younger, with higher educational level, higher incomes, professionally active, to have a healthy weight, and to use dietary supplements (all p < 0.05). Fasting was associated with the opinion that such practice could improve cancer prognosis (p < 0.0001). Patients who received nutritional information from health care professionals were less likely to practice fasting or weight-loss restrictive diet (0.42[0.27-0.66], p < 0.0001 and 0.49[0.38-0.64], p < 0.0001 respectively). Our study provided original results suggesting that weight-loss restrictive diets are widely practiced by cancer survivors. Fasting was less common in our study though non negligible. Sources of nutritional information received as cancer diagnosis seemed to be a key determinant of these practices. PMID- 29971784 TI - The development of a protocol for diagnosing hand dermatitis from photographic images. AB - BACKGROUND: A hand photography protocol was needed to ascertain the presence and severity of dermatitis in a trial testing the effectiveness of a behaviour change intervention to prevent hand dermatitis in nurses. METHODS: We developed the protocol in 3 stages: (1) we established a procedure for collecting hand photographs; (2) we conducted a stepwise validation process to agree rules for diagnosing and determining the severity of hand dermatitis; and (3) we trained a research nurse to screen out "clear" cases. RESULTS: We developed and trained fieldworkers (n = 97) in a procedure for collecting hand photographs. Study dermatologists established interpretation rules to diagnose and determine the severity of dermatitis from photographs. Prior to the establishment of the rules, interobserver agreement between the 2 dermatologists on the presence or absence of hand dermatitis was moderate (kappa = 0.5). At the final stage of the validation process, the dermatologists agreed on 88% cases from independent assessments, with consensus being reached for the remaining 12% following joint deliberation. Following training, a subgroup analysis of 250 cases screened by the nurse and characterized as "clear" found that 2 (0.8%) "positive" cases were missed. CONCLUSION: We have developed a hand photography protocol that may be used in other studies or in hand dermatitis health surveillance programmes. PMID- 29971786 TI - Rapid bedside rejuvenation of red blood cell with an autologous cell salvage device. AB - BACKGROUND AND OBJECTIVES: During storage, red blood cells (RBCs) undergo physicochemical changes which affect the quality, function, and in vivo survival of transfused packed RBCs (pRBC). Changes include decreased 2,3 diphosphoglycerate (2,3-DPG) levels, decreased ATP, changes in mechanical properties and oxidative injury. RBC rejuvenation is a method used to increase levels of 2,3-DPG and ATP in pRBCs. This process requires incubating the pRBCs with a rejuvenation solution and subsequent washing. Standard blood bank protocols using the COBE 2991 Cell Processor require several hours of preparation. The objective of this study was to verify if a bedside protocol for rejuvenating pRBC and washing with the Sorin Xtra autologous cell salvage system could be used. MATERIALS AND METHODS: Outdated pRBC units were obtained and rejuvenated in a model operating suite using a dry air incubator for 1 h at 37 degrees C. Six units of pRBCs were pre-diluted with saline (1000 ml) and six units were not pre-diluted with saline. All units were washed with normal saline (1000 ml) using an apheresis-design cell salvage device in manual mode and wash volume set to 3000 ml. Samples were collected and analyzed for standard RBC quality parameters at baseline and post-wash. RESULTS: Total pRBC wash efficiency was 94% +/- 12% at a final hematocrit of 67.7 +/- 5.9% while maintaining post wash hemolysis 0.24 +/- 0.12 %. Pre-dilution prior to washing did not confer statistically significant differences in final RBC quality parameters with the notable exceptions of calculated hemolysis and supernatant potassium levels (P < 0.05). The washing process can be completed within 10 min. The post-wash RBC parameters are appropriate for immediate transfusion to patients. PMID- 29971787 TI - Life-threatening arterial haemorrhage following venous occlusion during nephrectomy for renal carcinoma. PMID- 29971785 TI - Encapsulation of Piper aduncum and Piper hispidinervum essential oils in gelatin nanoparticles: a possible sustainable control tool of Aedes aegypti, Tetranychus urticae and Cerataphis lataniae. AB - BACKGROUND: The encapsulated essential oils (EOs) of Piper aduncum L. and Piper hispidinervum C. DC. in gelatin nanoparticles were evaluated against Aedes aegypti Linn., Tetranychus urticae Koch and Cerataphis lataniae Boisd. RESULTS: Encapsulation efficiency of the EOs was measured for absolute concentrations of 500 ug mL-1 (79.2 and 72.7%) and 1000 ug mL-1 (84.5 and 82.2%). The loaded nanoparticles were nearly spherical and well dispersed. The nanoparticles loaded with P. hispidinervum EO had an average size of 100 +/- 2 nm, while the nanoparticles containing P. aduncum EO ranged from 175 +/- 4 to 220 +/- 4 nm. According to zeta potential analysis, the nanoparticles loaded with P. hispidinervum and P. aduncum EOs presented values around -43.5 +/- 3 and -37.5 +/ 2 mV respectively. The controlled release of EOs was described by the anomalous mechanism of Korsmeyer-Peppas. Both encapsulated EOs reached lethal dosages within 24 h of exposure and total mortality of the tested pests. CONCLUSION: The present work successfully developed gelatin-based nanoparticles that served as carriers for the EOs of P. aduncum and P. hispidinervum to be applied as a sustainable control tool of A. aegypti, T. urticae and C. lataniae. The developed loaded nanoparticles presented high encapsulation efficiency and EO concentration release higher than lethal dosages. This indicates that it is feasible to use gelatin-based nanoparticles loaded with P. aduncum and P. hispidinervum EOs to control the tested pests. (c) 2018 Society of Chemical Industry. PMID- 29971788 TI - Repurposing Ionophores as novel antimicrobial agents for the treatment of bovine mastitis caused by Gram-positive pathogens. AB - Increasing reports of multidrug-resistant bacterial infections in animals has created a need for novel antimicrobial agents that do not promote cross resistance to critically important antimicrobial classes used in human medicine. In response to the recent emergence of antimicrobial resistance in several bovine mastitis pathogens, in vitro antimicrobial susceptibility was determined for four polyether ionophores (lasalocid, monensin, narasin and salinomycin) against Staphylococcus spp. and Streptococcus spp. isolated from clinical cases. In addition, erythrocyte haemolysis and WST-1 cell proliferation assays were used to assess in vitro mammalian cell cytotoxicity and biofilm susceptibility testing was performed using the minimum biofilm eradication concentration (MBECTM) biofilm assay. Lasalocid, monensin, narasin and salinomycin exhibited bacteriostatic antimicrobial activity against all pathogens tested, including methicillin-resistant staphylococci, with MIC90 values <16 MUg/ml. Narasin and monensin displayed the least toxicity against mammalian cell lines and all compounds significantly reduced viable cell numbers in a Staphylococcus aureus biofilm. Based on in vitro characterization, all four ionophores offer potentially novel treatments against bovine mastitis but in vivo studies will be essential to determine whether acceptable safety and efficacy is present following intramammary administration. PMID- 29971789 TI - Evaluation of factors associated with retained surgical sponges in veterinary patients: a survey of veterinary practitioners. AB - OBJECTIVES: To evaluate factors that could be associated with retained surgical sponges in veterinary patients. MATERIALS AND METHODS: A survey was distributed to 322 veterinarians attending a national veterinary conference in the UK. The survey included questions about the staff, scheduling, type of surgical procedure, surgical sponges, methods to track surgical sponges and details of clinical cases with retained surgical sponges. RESULTS: The response rate was 64 of 322 (19%). Lack of designated scheduled time for surgical procedures was reported by 30% of respondents and was variable for 31%. More than half of respondents (66%) had two people involved in each surgical procedure. The majority of respondents sterilised their own surgical sponges (91%) and used non radiopaque surgical sponges (56%). Sponges were not counted by 27% of respondents and only occasionally by 20%. Sponge count was not recorded by 70% of respondents. The majority (66%) did not use or have a surgical checklist. Lack of awareness of gossypibomas was reported by 11% of respondents. In all, 27% of respondents were aware of at least one case of retained surgical sponge. Of the 17 cases reported, 14 were small animals. The abdomen was the most common anatomical location for retained surgical sponges and followed elective neutering. CLINICAL SIGNIFICANCE: Despite the low-response rate, our results suggest that methods of surveillance might reduce the incidence of retained surgical sponges. Lack of specifically scheduled time for surgery, few theatre staff and lack of sponge counting and documentation may have contributed to the 17 retained surgical sponge cases reported. PMID- 29971790 TI - Open-source 3D printed sensors for hand strength assessment: Validation of low cost load cell and fabric sensor-based systems. AB - BACKGROUND/AIM: Pinch and grip strength assessment is commonly performed in occupational therapy practice. However, the typically utilised methods are limited to pinch or grip dynamometers and do not readily translate to handling everyday objects. With the advent of consumer-grade 3D printing and low-cost sensor systems, the possibilities for creating customised assessment devices are expanding. As a first step in determining the validity of low-cost sensor systems, their data must be compared to a gold standard. Consequently, this study examined the criterion validity of two such systems for measuring pinch strength, specifically a small load cell and pressure-sensing fabric, with a mechanical pinch gauge. METHODS: A total of 33 participants performed strength tests using a mechanical pinch grip device, which had a plastic 3D printed cover with a pressure-sensing fabric overlaid on it to allow for simultaneous criterion validation, and a small load cell with a plastic 3D printed casing designed for comfortable pinch grip assessment. RESULTS: The simultaneously assessed fabric sensor and mechanical pinch grip device showed excellent absolute (ICC2,k = 0.94) and relative (Pearson's R = 0.90) agreement. Both devices showed similar excellent relative (R > 0.75) agreement with the load cell despite non simultaneous assessment. These findings indicate that 3D printed sensors incorporating a load cell and a pressure-sensing fabric can be used to replicate a pinch grip assessment performed with a mechanical pinch gauge. CONCLUSIONS: This study lays the foundation for these sensor systems to be modified for use as assessment tools during the performance of functional tasks using everyday objects. Additionally, because both systems generate real-time force data they could be used for biofeedback as part of rehabilitation and strengthening programs. To aid uptake and future research using these systems, the 3D print models, step-by-step hardware design and software programs used are provided in an open-source format at www.rehabtools.org/otsensors.html. PMID- 29971791 TI - alpha2delta-1 couples to NMDA receptors in the hypothalamus to sustain sympathetic vasomotor activity in hypertension. AB - KEY POINTS: alpha2delta-1 is upregulated, promoting the interaction with NMDA receptors (NMDARs), in the hypothalamus in a rat model of hypertension. The prevalence of alpha2delta-1-bound NMDARs at synaptic sites in the hypothalamus is increased in hypertensive animals. alpha2delta-1 is essential for the increased presynaptic and postsynaptic NMDAR activity of hypothalamic neurons in hypertension. alpha2delta-1-bound NMDARs in the hypothalamus are critically involved in augmented sympathetic outflow in hypertensive animals. ABSTRACT: Increased glutamate NMDA receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus leads to augmented sympathetic outflow in hypertension. However, the molecular mechanisms underlying this effect remain unclear. alpha2delta-1, previously considered to be a voltage-activated calcium channel subunit, is a newly discovered powerful regulator of NMDARs. In the present study, we determined the role of alpha2delta-1 in regulating synaptic NMDAR activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons in spontaneously hypertensive rats (SHRs). We show that the protein levels of alpha2delta-1 and NMDARs in synaptosomes and the alpha2delta-1-NMDAR complexes in the hypothalamus were substantially higher in SHRs than in normotensive control rats. The basal amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons were significantly increased in SHRs. Strikingly, inhibiting alpha2delta-1 activity with gabapentin or disrupting the alpha2delta-1-NMDAR association with an alpha2delta-1 C-terminus peptide completely normalized the amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons in SHRs. In addition, microinjection of the alpha2delta-1 C-terminus peptide into the PVN substantially reduced arterial blood pressure and renal sympathetic nerve discharges in SHRs. Our findings indicate that alpha2delta-1-bound NMDARs in the PVN are required for the potentiated presynaptic and postsynaptic NMDAR activity of PVN presympathetic neurons and for the elevated sympathetic outflow in hypertension. alpha2delta-1 bound NMDARs may be an opportune target for treating neurogenic hypertension. PMID- 29971793 TI - An unexpected diagnosis in a cat with sudden lameness. PMID- 29971792 TI - Letting Go: Conceptualizing Intervention De-implementation in Public Health and Social Service Settings. AB - The discontinuation of interventions that should be stopped, or de implementation, has emerged as a novel line of inquiry within dissemination and implementation science. As this area grows in human services research, like public health and social work, theory is needed to help guide scientific endeavors. Given the infancy of de-implementation, this conceptual narrative provides a definition and criteria for determining if an intervention should be de-implemented. We identify three criteria for identifying interventions appropriate for de-implementation: (a) interventions that are not effective or harmful, (b) interventions that are not the most effective or efficient to provide, and (c) interventions that are no longer necessary. Detailed, well documented examples illustrate each of the criteria. We describe de implementation frameworks, but also demonstrate how other existing implementation frameworks might be applied to de-implementation research as a supplement. Finally, we conclude with a discussion of de-implementation in the context of other stages of implementation, like sustainability and adoption; next steps for de-implementation research, especially identifying interventions appropriate for de-implementation in a systematic manner; and highlight special ethical considerations to advance the field of de-implementation research. PMID- 29971794 TI - Technical Note: Development of a phantom for dosimetric comparison of murine micro-CT protocols with optically stimulated luminescent dosimeters. AB - PURPOSE: This work aims to evaluate the utility and accuracy of a mouse-like phantom and optically stimulated luminescent dosimeters (OSLDs) in measuring dose delivered to the body and lung of mice undergoing micro-CT imaging. METHODS: A phantom with two cavities for NanoDot OSLDs (Landauer, Inc., Greenwood, IL) was designed and constructed using acrylic to model the mouse body and polyurethane foam to obtain an approximate lung tissue dose. The OSLD dose was compared to ion chamber measurements for the same imaging protocols delivered by a Siemens Inveon micro-CT (Siemens Medical Solutions USA, Inc., Hoffman Estates, IL, USA). A whole body scan, using 80 kV, 0.5 mA and 0.5 mm of aluminum filter, was used to compare results to previously published data. Additionally, dose was measured for the whole body scan without the aluminum filter and two chest protocols (full and half rotation). RESULTS: OSLD dose results agree with chamber measurements within 3%. Average OSLD measurements for the whole body scan without filter were 10.7 +/ 0.7 cGy in the abdomen and 11.2 +/- 0.7 cGy in the lung. For the full rotation chest protocol, the average dose measured in the lung was 65.8 +/- 4.3 cGy and 60.2 +/- 3.9 cGy in the abdomen. Average doses were 41.1 +/- 2.7 cGy in the lung and 38.2 +/- 2.5 cGy in the abdomen for the half rotation chest protocol. The OSLD measurements showed a coefficient of variation under 1.4%. A maximum rotational geometry under-response of 0.86% with respect to exposure at normal incidence to the OSLD was measured. CONCLUSIONS: The doses measured were found to be comparable to other studies for the scanner configuration and protocols chosen. The phantom built for this study was found to give reproducible dose measurements with 4% uncertainty. In this way, a robust and convenient method is established for future dose assessment of micro-CT protocols and interinstitutional comparisons. PMID- 29971795 TI - Factors associated with sleep in family caregivers of individuals with dementia. AB - PURPOSE: The study aimed to identify factors related to family caregivers' sleep. DESIGN AND METHODS: The study used a cross-sectional design with objective and subjective methods to measure sleep in the home setting over a 7-day period. FINDINGS: Findings indicated that poor sleep quality was found in 91.7% of the caregiver participants. Depression, sleep hygiene, burden, and care-recipients' sleep were significant predictors of various dimensions of caregivers' sleep. PRACTICE IMPLICATIONS: Our study suggests that sleep quality for family caregivers of individuals with dementia varies considerably from night to night. Understanding the complex interrelationships among caregivers' sleep and other contributing variables is an important first step toward the development of individualized and effective treatment strategies. PMID- 29971796 TI - Hormonal regulation of oviductal glycoprotein 1 (OVGP1; MUC9) in the rhesus macaque cervix. AB - BACKGROUND: Macaques are outstanding animal models for the development of new contraceptives. In women, progestin-only contraceptives often fail to block ovulation and are believed to act by altering cervix physiology. Herein, we assessed oviductal glycoprotein 1 (OVGP1) in the macaque cervix as a marker for progestogen action. MATERIALS: Rhesus macaques were treated with estradiol (E2 ), E2 plus progesterone (P), and E2 plus levonorgestrel (LNG), a contraceptive progestin. Samples consisted of archived blocks of midcervix mucosa (epithelium and lamina propria) and fresh epithelial cells collected non-invasively by cytobrush. OVGP1 was assayed by quantitative real-time PCR and localized by immunocytochemistry. RESULTS: OVGP1 transcript was maximal after E2 and reduced after treatment with E2 + P (P < .05). LNG also reduced OVGP1 expression (P < .05). OVGP1-specific staining localized to epithelial cells, and transcript was quantifiable in cytobrush collected samples. CONCLUSIONS: OVGP1 expression in cytobrush samples of macaque cervix provides a non-invasive indicator of contraceptive progestin action. PMID- 29971797 TI - Determination of major histocompatibility class I and class II genetic composition of the Caribbean Primate Center specific pathogen-free rhesus macaque (Macaca mulatta) colony based on massively parallel sequencing. AB - BACKGROUND: Knowledge of major histocompatibility complex (MHC) composition and distribution in rhesus macaque colonies is critical for management strategies that maximize the utility of this model for biomedical research. METHODS: Variation within the Mamu-A and Mamu-B (class I) and DRB, DQA/B, and DPA/B (class II) regions of 379 animals from the Caribbean Primate Research Center's (CPRC) specific pathogen free (SPF) colony was examined using massively parallel sequencing. RESULTS: Analyses of the 7 MHC loci revealed a background of Indian origin with high levels of variation despite past genetic bottlenecks. All loci exhibited mutual linkage disequilibria while conforming to Hardy-Weinberg expectations suggesting the achievement of mutation-selection balance. CONCLUSION: The CPRC's SPF colony is a significant resource for research on AIDS and other infectious agents. Characterizing colony-wide MHC variability facilitates the breeding and selection of animals bearing desired haplotypes and increases the investigator's ability to understand the immune responses mounted by these animals. PMID- 29971798 TI - Comparative plasma and interstitial fluid pharmacokinetics and tissue residues of ceftiofur crystalline-free acid in cattle with induced coliform mastitis. AB - Ceftiofur (CEF) is a third-generation cephalosporin that is the most widely used antimicrobial in the dairy industry. Currently, violative meat residues in cull dairy cattle are commonly associated with CEF. One potential cause for violative residues is altered pharmacokinetics of the drug due to disease, which could increase the time needed for the residue to deplete. The objectives of this study were (a) to determine the absolute bioavailability of CEF crystalline-free acid (CFA) in healthy versus diseased cows; (b) to compare the plasma and interstitial fluid pharmacokinetics and plasma protein binding of CEF between healthy dairy cows and those with disease; and (c) to determine the CEF residue profile in tissues of diseased cows. For this trial, disease was induced through intramammary Escherichia coli infusion. Following disease induction and CEF CFA administration, for plasma concentrations, there was not a significant effect of treatment (p = 0.068), but the treatment-by-time interaction (p = 0.005) was significant. There was a significantly greater concentration of CEF in the plasma of the DIS cows at T2 hr (p = 0.002), T8 hr (p < 0.001), T12 hr (p = 0.001), and T16 hr (p = 0.002). For PK parameters in plasma, the slope of the terminal phase of the concentration versus time curve was significantly lower (p = 0.007), terminal half-life was significantly longer (p = 0.014), and apparent volume of distribution during the elimination phase was significantly higher (p = 0.028) diseased group. There was no difference in plasma protein binding of CEF and interstitial fluid pharmacokinetics. None of the cows had kidney CEF residues above the US tolerance level following observation of the drug's withdrawal period, but one cow with a larger apparent volume of distribution and longer terminal half-life had tissue residues slightly below the tolerance. Whereas these findings do not support the hypothesis that severely ill cows need longer withdrawal times, alterations in the terminal half-life suggest that it is theoretically possible. PMID- 29971799 TI - Recent update on methodologies for extraction and analysis of soybean seed proteins. AB - Soybean is one of the best sources of plant protein. Development of improved soybean cultivars through classical breeding and new biotech approaches is important to meet the growing global demand for soybeans. There is a critical need to investigate changes in protein content and profiles to ensure the safety and nutritional quality of new soybean varieties and their food products. A proteomics study begins with an optimal combination of extraction, separation and detection approaches. This review attempts to provide a summary of current updates in the methodologies used for extraction, separation and detection of protein from soybean, the basic foundations for good proteomic research. This information can be effectively used to investigate modifications in protein content and profiles in new varieties of soybeans and other crops. (c) 2018 Society of Chemical Industry. PMID- 29971800 TI - Estimation of functional components of Chinese cabbage leaves grown in a plant factory using diffuse reflectance spectroscopy. AB - BACKGROUND: In recent years, protected crop production using plant factories to produce high-value crops with greater functional components has become more popular in many countries. The quantification of the components, however, is mainly conducted by laboratory analyses, which are both time- and labor consuming. The present study aimed to investigate the potential of a non destructive diffuse reflectance spectroscopy technique for estimating functional components (i.e. glucosinolates, amino acids, sugars and carotenoids) in the leaves of Chinese cabbage grown in a plant factory. RESULTS: From the overall analysis, better estimations were obtained using the partial least square regression procedure. The important wavelengths for each functional component were identified mainly in the ultraviolet-visible regions. Identified wavelengths were 317, 390, 888 and 940 nm for sugars; 520 and 960 nm for amino acids; 385, 860 and 945 nm for glucosinolates; and 454, 472 and 530 nm for carotenoids. CONCLUSION: Optical reflectance spectroscopy shows potential as a tool for the estimation of functional components in the leaves of Chinese cabbage. The results of the present study provide useful information for the design and application of sensors with respect to on-site quantification of the functional components. (c) 2018 Society of Chemical Industry. PMID- 29971801 TI - Errors on a computer task and subclinical symptoms of attention deficit/hyperactivity disorder (ADHD). AB - Previous reports have found increased error rate for children with attention deficit/hyperactivity disorder (ADHD) on response time (RT) computer tasks. Here we attempt the conceptual replication and extension of two studies that examined error rate in a general population of children (N = 203). Study 1 followed Johnstone and Galletta but considered associations between scores on a dimensional measure of ADHD symptoms (rather than comparing those with or without an ADHD diagnosis) and the frequency of commission and omission errors. Study 2 followed Shiels, Tamm & Epstein and examined post-error adjustment in the same group of children as for Study 1. Study 1 did not replicate previous findings of no increase in errors of commission in those with higher ADHD symptoms (Johnstone & Galletta). Instead, we found that younger children with lower ADHD symptoms were more likely to make commission errors, while omission errors did not vary with age. Study 2 replicated the previous finding of less RT slowing in children with more ADHD symptoms, extending this finding to a general population of children. Namely, as ADHD symptoms increase, RT slowing is less likely, putting children with higher ADHD symptoms at risk of additional errors. Overall, we extend previous ADHD research to typically developing children with ADHD symptoms. PMID- 29971802 TI - Dietary inclusion of mushroom (Flammulina velutipes) stem waste on growth performance and immune responses in growing layer hens. AB - BACKGROUND: Medicinal mushrooms contain biologically active substances that can be used as an immune-modulating agent in poultry. The present study aimed to investigate the effects of Flammulina velutipes mushroom waste (FVW) on performance, immune response and serum immunity in growing layer hens. RESULTS: No significant differences (P > 0.05) were observed with respect to average daily feed intake, body weight gain and feed conversion ratio among the experimental groups during the entire study period (1-70 days). Antibody titers against Newcastle disease and infectious bronchitis were higher (P < 0.05) in the FVW fed groups than in the control and antibiotic groups. On day 28, serum immunoglobulin (Ig)A and IgG were higher (P < 0.05) in the 6% FVW group than in the control and antibiotic fed groups. On day 70, serum IgA was higher (P < 0.05) in FVW fed groups than in the control group; IgG was higher (P < 0.05) in the FVW groups than in the control and antibiotic groups. However, IgM was higher (P < 0.05) in both the 4% and 6% FVW groups than in the control and antibiotic groups for both experimental periods. Serum cytokine interleukin (IL)-2 and tumor necrosis factor alpha concentrations were significantly higher (P < 0.05) in both the 4% and 6% FVW grousp than in the control and antibiotic groups; IL-4 was significantly higher (P < 0.05) in the FVW groups than in the control group; and IL-6 was significantly higher (P < 0.05) in the 6% FVW group than in the control and antibiotic groups. CONCLUSION: FVW at the 6% level can be used as a potential phytogenic feed stuff in growing layer hen rations with respect to improving the immune response without affecting normal weight gain. (c) 2018 Society of Chemical Industry. PMID- 29971803 TI - Cytosolic malate and oxaloacetate activate S-type anion channels in Arabidopsis guard cells. AB - Intracellular malate-starch interconversion plays an important role in stomatal movements. We investigated whether malate or oxaloacetate from the cytosolic membrane side regulate anion channels in the plasma membrane of Arabidopsis thaliana guard cells. Physiological concentrations of cytosolic malate have been reported in the range of 0.4-3 mM in leaf cells. Guard cell patch clamp and two electrode oocyte voltage-clamp experiments were pursued. We show that a concentration of 1 mM cytosolic malate greatly activates S-type anion channels in Arabidopsis thaliana guard cells. Interestingly, 1 mM cytosolic oxaloacetate also activates S-type anion channels. Malate activation was abrogated at 10 mM malate and in SLAC1 anion channel mutant alleles. Interestingly, malate activation of S type anion currents was disrupted at below resting cytosolic-free calcium concentrations ([Ca2+ ]cyt ), suggesting a key role for basal [Ca2+ ]cyt signaling. Cytosolic malate was not able to directly activate or enhance SLAC1 mediated anion currents in Xenopus oocytes, whereas in positive controls, cytosolic NaHCO3 enhanced SLAC1 activity, suggesting that malate may not directly modulate SLAC1. Cytosolic malate activation of S-type anion currents was impaired in ost1 and in cpk5/6/11/23 quadruple mutant guard cells. Together these findings show that these cytosolic organic anions function in guard cell 'plasma membrane' ion channel regulation. PMID- 29971805 TI - Secular trends over 40 years of periodontal health and disease in individuals aged 20-80 years in Jonkoping, Sweden: Repeated cross-sectional studies. AB - AIM: To assess trends over 40 years regarding prevalence and severity of periodontitis in a Swedish adult population. MATERIALS AND METHODS: Cross sectional examinations using the same clinical protocol have been repeated every 10 years (1973-2013) in a Swedish city with focus on periodontal disease in adults. Periodontal recordings included all teeth, excluding 3rd molars. Periodontal disease experience was classified (no/minor, moderate and severe). RESULTS: The no/minor group increased from 43% in 1983 to 60% in 2013. There was a non-significant trend for a decrease of the severe group. Over the 40-year period, the number of teeth increased significantly and at the examination 2013, the severe group accounted for this increase. More than 60% of the study population in 2013 had no periodontal pockets (PD) >=6 mm. The number of PD >=4 mm and >=6 mm were unaltered between 2003 and 2013 in all age groups, except for the 20-year old individuals. This group showed a statistically significant increase of >=4 mm PD. CONCLUSIONS: The periodontal health has improved in the population over the 40 years. The number of teeth increased significantly in the population, and in 2013, this increase occurred entirely in the severe group. Finally, there was a trend toward diminished prevalence of severe periodontitis. PMID- 29971806 TI - Cellular immunopathogenesis in primary Toxoplasma gondii infection during pregnancy. AB - Congenital toxoplasmosis is caused by the vertical transmission of infection from mother to foetus through the placenta when a pregnant woman is infected with Toxoplasma gondii (T. gondii). Congenital infection can have serious consequences, such as intrauterine abortion, foetal death and severe neurological, ocular or other organ damage in the foetus. In this review, we focus on recent publications investigating vertical transmission of T. gondii infection, cellular immunopathogenesis and protective immunity in primary toxoplasmosis during pregnancy. PMID- 29971804 TI - An evidence-based systematic review of the off-label uses of lisinopril. AB - AIMS: Lisinopril is an angiotensin-converting-enzyme inhibitor that is largely administered for off-label uses. This study aims to provide a comprehensive review of off-label uses of lisinopril to aid physicians to make evidence-based decisions. METHODS: The following bibliographic databases were searched from inception up to 30 March 2017: PubMed, EMBASE, the Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, Ovid and Proquest. This systematic review sought all randomized trials conducted on adult individuals comparing lisinopril on its off-label uses with alternative drugs or placebos and reported direct or alternative clinical outcomes. Risk of bias assessment by using the Cochrane Collaboration risk-of-bias tool and quality evaluation took place. RESULTS: Included studies demonstrated significant positive effects of lisinopril on proteinuric kidney disease; however, lisinopril caused a slight reduction of glomerular filtration rate (GFR) especially for patients with GFR < 90 ml min-1 . Lisinopril offered better outcomes in comparison to other standard treatments of diabetic nephropathy. Other studies showed positive effects of lisinopril for migraine, prevention of diabetes, myocardial fibrosis, mitral valve regurgitation, cardiomyopathy in patients with Duchenne muscular dystrophy, oligospermia and infertility, and diabetic retinopathy. Conversely, the studies reported that lisinopril was ineffective for five other off-label uses. CONCLUSIONS: The identified studies showed that lisinopril was highly effective for proteinuric kidney disease with a minor but inconsiderable decrease in GFR. Positive effects of lisinopril were demonstrated in seven other off-label uses; however, lisinopril cannot be recommended as the first choice for these until further clinical trials confirm these positive effects. PMID- 29971807 TI - Reliability, validity, and sex differences in a quantitative gag reflex measurement method. AB - A reliable assessment method is required to manage the gag reflex. We tested the inter- and intra-examiner reliability and validity of a quantitative measurement method and evaluated the differences between sexes. This study included 21 healthy adults (10 women, 11 men; mean age, 27.1 +/- 9.9 years). An examiner inserted a standard saliva ejector slowly down the participant's throat to determine the maximum tolerance of the gag reflex; the insertion depth was used as an index of gag reflex. The reflex was measured by one examiner during two sessions (S1 and S3) and by a second examiner during one session (S2) under the same conditions. The galvanic skin response (GSR) and heart rate (HR) were recorded during each session to test the method validity. Data were analysed using the intraclass correlation coefficient (ICC), paired t test, and two-way repeated-measures analysis of variance. The ICC of the gag reflex measurements was 0.91 between S1 and S2, and 0.93 between S1 and S3. The GSR and HR increased significantly after the maximum tolerance of the reflex in S1, S2, and S3 (GSR: P < 0.001, P = 0.004, P = 0.001, respectively; HR: all, P < 0.001). Differences in the measurements according to sex and session were not significant. Our method exhibited excellent inter- and intra-examiner reliability and was unaffected by the participants' sex. Measurement revealed significant autonomic reactivity, which is common for this reflex. Consequently, this method may be used in clinical and laboratory-based applications. PMID- 29971808 TI - Simulation study of misclassification bias in association studies employing partial-mouth protocols. AB - AIM: To simulate the exposure misclassification bias potential in studies of perio-systemic disease associations due to the use of partial-mouth recording (PMR) protocols. METHODS: Using data from 640 participants in the Dental Longitudinal Study, we evaluated distributions of clinical periodontitis parameters to simulate hypothetical outcome probabilities using bootstrap sampling. Logistic regression models were fit using the hypothetical outcome as the dependent variable. Models were run for exposure classifications based on full-mouth recording (FMR) and PMR protocols over 10,000 repetitions. RESULTS: The impact of periodontitis exposure misclassification was dependent on periodontitis severity. Per cent relative bias for simulated ORs of size 1.5, 2 and 4 ranged from 0% to 30% for the effect of severe periodontitis. The magnitude and direction of the bias was dependent on the underlying distribution of the clinical parameters used in the simulation and the size of the association being estimated. Simulated effects of moderate periodontitis were consistently biased towards the null. CONCLUSION: Exposure misclassification bias occurring through the use of PMR protocols may be dependent on the sensitivity of the classification system applied. Using the CDC-AAP case definition, bias in the estimated effects of severe disease was small, on average. Whereas effects of moderate disease were underestimated to a larger degree. PMID- 29971809 TI - Is masticatory performance affected after a unilateral condylar fracture? A cross sectional study. AB - BACKGROUND: Mandibular fractures, especially condylar fractures, are one of the most common facial fractures. Trauma to this region could possibly compromise masticatory performance, which is a vital function for humans. OBJECTIVE: To objectively determine masticatory performance (Mixing Ability Test; MAT) in patients treated for a unilateral condylar fracture, thereby comparing patients in open and closed treatment groups, and assessing whether there is a positive relationship between this performance and subjective mandibular function (Mandibular Functional Impairment Questionnaire; MFIQ). METHODS: Fifty-eight patients were enrolled in a cross-sectional study and examined on an additional appointment at least 1 year after trauma, during which the patients performed the MAT and completed the MFIQ. The Spearman test was used to assess the correlation between the Mixing Ability Index (MAI) and the MFIQ score. A linear regression was used to explore the effects of different factors on the MAI. RESULTS: The correlation between objective masticatory performance and the subjective mandibular function was positive (r = 0.250; P = 0.033). Better masticatory performance was observed in patients who were male, received physiotherapy, had no other mandibular fractures and/or had satisfactory self-perceived occlusion. No significant difference in the MAI was found between the open and closed treatment groups. CONCLUSION: Independent of the chosen treatment, at least 1 year after treatment, individuals who experienced a unilateral fracture of the mandibular condyle exhibit masticatory capacity comparable with that of individuals who have not suffered such injuries. PMID- 29971810 TI - Association between obstructive sleep apnea and alcohol, caffeine and tobacco: A meta-analysis. AB - The aim of this systematic review was to answer the focused question, "Is there an association between obstructive sleep apnea (OSA) and alcohol, caffeine or tobacco use?" Five electronic databases (Cinahl, Literatura Latth American and Caribbean, PubMed, Scopus, Web of Science) and 3 grey literature (Google Academico, ProQuest, OpenGrey) were searched, as well as search on reference list of included papers and contacts with study authors. Observational studies were included. The Meta-Analysis of Statistics Assessment and Review Instrument (MAStARI) tool assessed the potential risk of bias (RoB) among the studies, while the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach determined the level of evidence. Meta-Analysis was performed with RevMan 5.3 software. Among 3,442 identified studies, 14 were included. Eleven studies were classified as moderate RoB and 3 as high RoB. Meta-analysis showed OSA has no association with tobacco and presented a positive association with alcohol. The odds ratio for OSA increased almost 1.33 times (95% confidence interval [CI]; 1.10-1.62) for alcohol users. There was insufficient published data to evaluate whether OSA is associated with caffeine. The overall quality of evidence ranged from low to very low. OSA was associated with the use of alcohol, however there is not enough evidence to confirm the association with tobacco or caffeine. Due to the very low GRADE level of evidence, caution should be applied when considering these findings. PMID- 29971811 TI - Reflectance confocal microscopy features of melanomas on the body and non glabrous chronically sun-damaged skin. AB - BACKGROUND: Melanoma remains a challenge to diagnose, especially when appearing on the background of chronically sun-damaged skin (CSDS). Our goal was to identify and quantify the reflectance confocal microscopy (RCM) features of melanoma on non-facial CSDS. METHODS: Included lesions were biopsy-proven melanomas, from anatomic sites other than the face, neck, scalp and acral skin, with histopathologic finding of solar elastosis in the underlying dermis. All included lesions underwent clinical, dermoscopic and RCM imaging, obtained in a standardized fashion, prior to biopsy. All images were retrospectively analyzed by four observers. RESULTS: We identified 33 melanomas from 33 patients with 63.6% male patients and overall mean age of 72.8 years. The salient RCM features included an atypical honeycomb or disarranged epidermal pattern (81.8%), pagetoid infiltration of the epidermis by both round and/or dendritic melanocytes (100%), focal proliferation of predominantly dendritic melanocytes as sheets (78.8%), foci with non-edged papillae (84.8%), junctional thickening (60.6%), areas of irregular ring or meshwork pattern (78.8%), and underlying thickened collagen bundles (51.5%). CONCLUSION: Non-facial CSDS melanomas share features similar to other melanoma types including pagetoid cells and non-edged papillae. The focal proliferation of dendritic pagetoid cells in sheets is similar to that seen in facial CSDS melanomas. PMID- 29971812 TI - Editorial. PMID- 29971813 TI - Acute tocolysis for uterine tachysystole or suspected fetal distress. AB - BACKGROUND: Uterine tachysystole (more than 5 contractions per 10 minutes in 2 consecutive intervals) is common during labour, particularly with use of labour stimulating agents. Tachysystole may reduce fetal oxygenation by interrupting maternal blood flow to the placenta during contractions. Reducing uterine contractions may improve placental blood flow, improving fetal oxygenation. This review aimed to evaluate the use of tocolytics to reduce or stop uterine contractions for improvement of the condition of the fetus in utero. This new review supersedes an earlier Cochrane Review on the same topic. OBJECTIVES: To assess the effects of the use of acute tocolysis during labour for uterine tachysystole or suspected fetal distress, or both, on fetal, maternal and neonatal outcomes. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (2 February 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating acute tocolysis for uterine tachysystole, intrapartum fetal distress, or both. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. MAIN RESULTS: We included eight studies (734 women), conducted in hospital settings, predominantly in high-income countries (USA, Austria, Uruguay). Two trials were conducted in upper and lower middle-income countries (South Africa, Sri Lanka). The hospital facilities all had the capacity to perform caesarean section. Overall, the studies had a low risk of bias, except for methods to maintain blinding. All of the trials used a selective beta2 (beta2)-adrenergic agonist in one arm, however the drug used varied, as did the comparator. Limited information was available on maternal outcomes.Selective beta2-adrenergic agonist versus no tocolytic agent, whilst awaiting emergency deliveryThere were two stillbirths, both in the no tocolytic control group (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.01 to 4.55; 2 studies, 57 women; low-quality evidence). One had gross hydrocephalus and the second occurred with vaginal delivery after waiting 55 minutes for caesarean section. The decision for caesarean section delivery was an inclusion criterion in both studies so we could not assess this as an outcome under this comparison. Abnormal fetal heart trace is probably lower with tocolytic treatment (RR 0.28, 95% CI 0.08 to 0.95; 2 studies, 43 women; moderate-quality evidence). The effects on the number of babies with Apgar score below seven were uncertain (low-quality evidence).Intravenous (IV) atosiban versus IV hexoprenaline (1 study, 26 women) One infant in the hexoprenaline group required > 24 hours in the neonatal intensive care unit (NICU) following a forceps delivery (RR 0.33, 95% CI 0.01 to 7.50; low-quality evidence). There were no fetal or neonatal mortalities and no Apgar scores below seven. There was one caesarean delivery in the IV hexoprenaline group (RR 0.33, 95% CI 0.01 to 7.50; low-quality evidence), and one case of abnormal fetal heart score in the atosiban group (RR 3.00, 95% CI 0.13 to 67.51; very low-quality evidence).IV fenoterol bromhydrate versus emergency delivery (1 study, 390 women) No data were reported for perinatal death, severe morbidity or fetal or neonatal mortality. IV fenoterol probably increases the risk of caesarean delivery (RR 1.12, 95% CI 1.04 to 1.22; moderate-quality evidence). Fenoterol may have little or no effect on the risk of Apgar scores below seven (RR 1.28, 95% CI 0.35 to 4.68; low-quality evidence).IV hexoprenaline versus no tocolytic agent, whilst awaiting emergency delivery (1 study, 37 women) No data were reported for perinatal death or severe morbidity. There were two fetal deaths in the no tocolytic control group (RR 0.23, 95% CI 0.01 to 4.55; low quality evidence). The rate of caesarean delivery was not reported. There were two babies with Apgar scores below seven in the control group and none in the hexoprenaline group (RR 0.24, 95% CI 0.01 to 4.57; 35 women; low-quality evidence).Subcutaneous terbutaline versus IV magnesium sulphate (1 study, 46 women)No data were reported for perinatal death, severe morbidity or fetal or neonatal mortality. The decision for caesarean section was an inclusion criterion, so we could not assess this. The effects on abnormal fetal heart trace are uncertain (very low-quality evidence).Subcutaneous terbutaline with continuation of oxytocic infusion versus cessation of oxytocic infusion without tocolytic agent (1 study, 28 women) No data were reported for perinatal death, severe morbidity or fetal or neonatal mortality. There may be little or no difference in the rates of caesarean delivery in the subcutaneous terbutaline (8/15) and control groups (4/13) (RR 1.73, 95% CI 0.68 to 4.45; low-quality evidence). There were no cases of Apgar scores below seven or abnormal fetal heart trace.Subcutaneous terbutaline versus no tocolytic agent, whilst awaiting emergency delivery (1 study, 20 women) No data were reported for perinatal death or severe morbidity. There were no fetal or neonatal mortalities. The decision for caesarean section was an inclusion criterion, so we could not assess this. There were two babies with Apgar scores below seven in the control group and none in the terbutaline group (RR 0.17, 95% CI 0.01 to 3.08; low-quality evidence).IV terbutaline versus IV nitroglycerin (1 study, 110 women)No data were reported for perinatal death or severe morbidity or fetal or neonatal mortality. There may be little or no difference in the rates of caesarean delivery between the IV terbutaline (30/57) and control groups (29/53) (RR 0.96, 95% CI 0.68 to 1.36; low quality evidence). There were no cases of Apgar scores below seven. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the effects of tocolytics for uterine tachysystole or suspected fetal distress during labour. The clinical significance for some of the improvements in measures of fetal well being with tocolytics is unclear. The sample sizes were too small to detect effects on neonatal morbidity, mortality or serious adverse effects. The majority of studies are from high-income countries in facilities with access to caesarean section, which may limit the generalisability of the results to lower-resource settings, or settings where caesarean section is not available.Further well designed and adequately powered RCTs are required to evaluate clinically relevant indicators of maternal and neonatal morbidity and mortality. PMID- 29971814 TI - Fluoride intake and urinary fluoride excretion in 4- and 8-year-old children living in urban and rural areas of Southwest Nigeria. AB - OBJECTIVES: To estimate and compare total daily fluoride intake (TDFI), daily urinary fluoride excretion (DUFE), daily fluoride retention (DFR), fractional urinary fluoride excretion (FUFE) and fractional fluoride retention (FFR) in 4- and 8 year-old Nigerians and explore associations between these outcomes to improve understanding of fluoride metabolism. METHODS: Using a cross-sectional observational study, 72 four-year-olds and 72 eight-year-olds were recruited from nursery and primary schools (respectively) in lower and higher water F areas of urban and rural localities in Oyo State, southwest Nigeria. TDFI from diet and toothpaste ingestion was assessed using a validated Food Frequency Questionnaire and visual scale of toothpaste used during toothbrushing. DUFE was measured by collecting a 24-hour urine sample, FUFE estimated as the ratio between DUFE and TDFI, DFR estimated as TDFI-TDFE (where TDFE = DUFE + estimated faecal F excretion (ie TDFI * 10%), and FFR was estimated as [(TDFI-DFR)/TDFI] * 100. Data were analysed using ANOVA with post hoc tests and Student's t tests and strengths of associations between key variables measured. RESULTS: Mean (SD) TDFI, DUFE, DFR, FUFE and FFR were 0.137 (0.169) mg/kg bw/d, 0.032 (0.027) mg/kg bw/d, 0.091 (0.147) mg/kg bw/d, 44% (44%) and 46% (44%), respectively, for 4-year-olds. Corresponding values for 8-year-olds (n = 63) were 0.106 (0.130) mg/kg bw/d, 0.022 (0.017) mg/kg bw/d, 0.073 (0.107) mg/kg bw/d, 36% (30%) and 54% (30%), respectively. Dietary contribution to TDFI was 79% and 75% (respectively), for 4- and 8-year-olds. Mean (SD) TDFI from toothpaste ingestion was 0.021 (0.013) mg/kg bw/d in 4-year-olds, 0.014 (0.010) mg/kg bw/d in 8-year-olds (P = .002) but with no differences between areas. Differences in dietary F intake determined the main differences in F exposure between areas. The positive correlation between TDFI and DUFE was weak for 4-year-olds (r = +.29) and strong for 8-year-olds (r = +.64). A strong positive correlation was observed between TDFI and DFR for both age groups: (r) = +.98 for 4-year-olds and (r) = +.99 for 8-year-olds. CONCLUSION: Fluoride intake in these 4- and 8-year-old Nigerians was much higher than the "optimal range" of 0.05-0.07 mg/kg bw/d in rural, higher F water areas, with diet as the main contributor. F retention was similar in both age groups, with almost half of TDFI retained in the body. In terms of risk vs benefit for fluorosis and dental caries, this finding should be considered when mitigating against excessive fluoride exposure and planning F-based prevention. PMID- 29971815 TI - Therapeutic drug monitoring-guided definition of adherence profiles in resistant hypertension and identification of predictors of poor adherence. AB - AIMS: Arterial hypertension is an important cardiovascular risk factor. A substantial proportion of patients show resistance to antihypertensive treatment but poor adherence to medication regimens is also a significant cause of treatment failure. In this context, therapeutic drug monitoring (TDM) could be useful. The objective of this study was to assess adherence to treatment in patients with resistant hypertension by TDM and to identify parameters that predict nonadherence. METHODS: Liquid chromatography tandem mass spectrometry was used to quantify a wide panel of antihypertensive drugs in human plasma to assess treatment compliance. Associations between TDM-determined adherence profiles, self-reported adherence and other patient-related clinical, anthropometric or demographic features were evaluated as potentially useful pre-TDM predictors of poor adherence. RESULTS: TDM was performed on 50 patients with suspected resistant hypertension: 24% of patients partially complied to treatment and 18% were nonadherent. No concordance was observed with questionnaire results, while nonadherence was associated with high diastolic blood pressure, high heart rate, previous onset of stroke and previous use of invasive treatments, including renal denervation or baroreceptor stimulation. CONCLUSIONS: This evidence highlights the high prevalence of poor adherence in patients with resistant hypertension and the need for caution in using invasive approaches. These preliminary data require validation in a larger cohort, to confirm the need for TDM in routine clinical practice. PMID- 29971816 TI - Response to 'Comment on 'Measuring the impact of medicines regulatory interventions - systematic review and methodological considerations' by Goedecke et al.' PMID- 29971817 TI - Choroidal detachments: what do optometrists need to know? AB - Choroidal detachments occur when there is an accumulation of fluid or blood in the suprachoroidal space, a potential space situated between the choroid and the sclera. They are an uncommon ocular pathology. The most common cause of choroidal detachment is secondary to trabeculectomy; however, there are other causes such as trauma and inflammation. Clinically, choroidal detachments may vary in presentation from asymptomatic, to very poor vision, severe ocular pain, vomiting and nausea. Ocular findings associated with choroidal detachments include serous retinal detachment, secondary angle closure, and a very shallow anterior chamber. Optometrists, as primary eye care providers, need to be aware of the clinical signs and symptoms associated with choroidal detachments and ensure that appropriate and timely management, with a referral to an ophthalmologist, is instigated for optimal visual outcomes. In this review, the pathophysiology, detection, and associated risk factors for choroidal detachments are discussed, and evidence-based management recommendations in an optometric context are provided. The characteristics and management of uveal effusion syndrome are also reviewed, as this can cause idiopathic exudative choroidal detachments distinct from classical choroidal detachment. PMID- 29971818 TI - Molluscum contagiosum arising in a melanocytic congenital nevus. AB - Molluscum contagiosum within a congenital melanocytic nevus has rarely been reported. We report a 6-year-old child with molluscum contagiosum infection arising within an intermediate melanocytic congenital nevus of the thigh, associated with itching and occasional bleeding. Dermoscopy lead to the correct diagnosis, but histologic confirmation with shave biopsy was performed to reassure the parents and allow mechanical removal of the lesions using curettage. PMID- 29971819 TI - Aortic valve replacement in a patient with Sneddon syndrome. PMID- 29971820 TI - Development of a novel reference nomogram for endotracheal intubation in neonatal emergency transport setting. AB - AIM: Neonatal endotracheal intubation is a challenging procedure during transport. The aim of this study was to evaluate the effectiveness of the emergency intubation guidelines followed by our Neonatal Emergency Transport Service (NETS). METHODS: Our transport intubation guidelines follows a weight based nomogram for nasal intubation, and the tube position is clinically verified after intubation, while the postintubation chest X-ray is postponed to Neonatal Intensive Care Unit (NICU) admission. Data on postnatal age, weight and tube insertion depth were obtained from the online NETS clinical database, and the postintubation chest X-ray images were assessed. RESULTS: During the study period, 161 newborn infants were nasally intubated during transport, and received a postintubation radiograph at NICU admission. A total of 130 neonates (80.7%) had the endotracheal tube (ETT) correctly positioned between T1 and T2 vertebrae, while 12 (7.5%) was at C7 vertebrae level and 19 (11.8%) at T3. No patients had ETT tip positioned at T4 vertebrae level or below. No adverse events related to intubation were observed. CONCLUSION: Our intubation procedure showed a good reliability and safety in neonatal critical care transport, although chest X-ray to confirm the tube placement is postponed to NICU arrival. Based on our results, we suggest a revised version of weight-based nomogram for nasal intubation. PMID- 29971822 TI - The complex interplay between gastrointestinal and psychiatric symptoms in irritable bowel syndrome: A longitudinal assessment. AB - AIMS: The aims of this study were to better define the relationship between irritable bowel syndrome (IBS) and psychiatric disorders and to examine the efficacy of paroxetine in the treatment of IBS patients. METHODS: One hundred fifty subjects with diagnosis of IBS (Roma III criteria) and relative sub classification (constipated, diarrhea, and mixed) were assessed for psychopathological features and gastrointestinal symptoms using IBS Symptom Severity Score and were consecutively enrolled. Fifty patients assumed paroxetine for 16 weeks and were longitudinally evaluated. RESULTS: The entire sample had a moderate/severe gastrointestinal symptomatology (IBS-SSS 285.1 +/- 98.6). The IBS subtypes were diarrhea (47.3%), constipated (32%), and mixed (20.7%). Panic disorder was found in 17.4% and major depressive episode in 14.7%. More than 50% of the patients showed "psychopathological features." This group showed more severe gastrointestinal symptoms and worse quality of life than the group without any psychiatric comorbidity (44%). Psychiatric patients also showed a significant impairment of physical state, subjective feeling of well-being, and leisure activities when compared with no psychiatric patients. When the IBS-SSS > 300 group was subgrouped in psychiatric (67.2%) and no psychiatric (32.8%), we found significant differences in all clinician-administered and self-reported scales with more severe psychopathological features in psychiatric group (P < 0.01). Among the patients treated with paroxetine, 34 (68%) completed the longitudinal evaluation showing a significant improvement of both psychiatric and gastrointestinal symptoms. CONCLUSIONS: This study confirms a high presence of psychiatric comorbidities, emphasizing the need for psychiatric screening in all patients with IBS; moreover, the longitudinal evaluation of patients treated with paroxetine showed a significant improvement of both psychiatric and gastrointestinal symptoms. PMID- 29971821 TI - Bias in Mendelian randomization due to assortative mating. AB - Mendelian randomization (MR) has been increasingly used to strengthen causal inference in observational epidemiology. Methodological developments in the field allow detecting and/or adjusting for different potential sources of bias, mainly bias due to horizontal pleiotropy (or "off-target" genetic effects). Another potential source of bias is nonrandom matching between spouses (i.e., assortative mating). In this study, we performed simulations to investigate the bias caused in MR by assortative mating. We found that bias can arise due to either cross trait assortative mating (i.e., assortment on two phenotypes, such as highly educated women selecting taller men) or single-trait assortative mating (i.e., assortment on a single phenotype), even if the exposure and outcome phenotypes are not the phenotypes under assortment. The simulations also indicate that bias due to assortative mating accumulates over generations and that MR methods robust to horizontal pleiotropy are also affected by this bias. Finally, we show that genetic data from mother-father-offspring trios can be used to detect and correct for this bias. PMID- 29971823 TI - Understanding the process of strengthening multi-sectoral efforts for anemia reduction: Qualitative findings from Sierra Leone and Uganda. AB - Anemia is a significant global health problem, and progress to reduce it has been slow. A multi-sectoral, context-specific, and country-led approach is recommended to effectively address anemia, but there is limited documentation of how this has worked in practice. We present key findings and lessons learned from Sierra Leone and Uganda's experiences establishing national-level anemia coordination platforms. A longitudinal collective case study methodology was used, with in depth interviews of National Anemia Working Group members in both countries; data was analyzed to distill the salient lessons learned across countries. Similar factors were identified in the 2 countries. Setting the agenda was an important first step, accomplished by using country-specific anemia-related data and obtaining multi-sectoral commitment. Establishment of a cohesive coordination structure provided an effective platform to prioritize and align anemia activities. Strong, committed leadership and representation of diverse stakeholders was essential to maintain the legitimacy of anemia efforts. The main barriers to the policy-making process included misalignment of sectoral mandates, differences in work cultures, as well as competing priorities and increased staff workload. Sierra Leone and Uganda's experiences contribute to the global evidence base for anemia coordination and planning at the national level, particularly around linking health and non-health sectors and developing multi-sectoral platforms. It remains to be seen how and to what extent resulting policies in Sierra Leone and Uganda will translate to implementation. PMID- 29971824 TI - Left main coronary artery aneurysm presenting with unstable angina. PMID- 29971825 TI - Root surface caries among older Australians. AB - OBJECTIVES: Root caries has increased as a clinical problem in recent decades. However, the use of multiple waves of longitudinal follow-up data in estimating root caries increment has not been previously attempted. The aims of this study were to quantify root caries increment from a longitudinal study of older adults with 4 oral examinations over 11 years and to examine behavioural factors associated with root caries. METHODS: A secondary analysis was undertaken using data collected in 4 waves (baseline, 2-year, 5-year and 11-year) of the South Australian Dental Longitudinal Study which began in 1991/92. The study group consisted of a stratified random sample of people aged 60+ years at baseline. A total of 358 participants with complete oral examinations in all 4 waves were included. The examinations were performed by trained and calibrated dentists. Baseline behavioural risk factors (toothbrushing frequency, flossing frequency, dental visiting pattern, reason for dental visiting and tobacco smoking status) and time in years across the 4 waves were the main exposures. Baseline clinical oral conditions (gingival condition and gingival recession), demographic and socio-economic risk factors served as covariates. Root caries was measured as mean number of untreated root surfaces (root DS) and decayed/filled root surfaces (root DFS) at each wave of examinations. Multivariable multilevel growth model using linear regression analysis was used to get an estimate for root caries increment and associated oral health-related behaviours adjusting for all the covariates. RESULTS: Findings from the multivariable models indicated that the annual increment of root DS and root DFS were 0.07 (SE = 0.01) and 0.11 (SE = 0.02) surfaces, respectively. Irregular brushing (E [SE] = 0.25 [0.12]), visiting the dentist only for problems (E [SE] = 0.30 [0.13]) and smoking (E [SE] = 0.33 [0.12]) were risk factors for the increase in root DS. Irregular flossing and more frequent dental visit were associated with the increase in root DFS. CONCLUSIONS: Root caries increased slowly across time among relatively healthier Australian older adults. Irregular brushing, unfavourable dental visiting and tobacco smoking were risk factors for the increase in untreated root caries, while irregular flossing and more frequent dental visiting were associated with the increase in root DFS. PMID- 29971826 TI - The correlation between conventional echocardiography and two-dimensional speckle strain imaging for evaluating left atrial function in patients with moderate to severe mitral stenosis. AB - AIM: We intended to assess the left atrial deformation parameters, using two dimensional speckle tracking (2DSTE) and transesophageal echocardiography (TEE), and determine the correlation between these two techniques in order to recognize the patients at risk for cardioembolic events. METHOD: Strain and strain rate were measured using 2DSTE among 26 patients in sinus rhythm, with isolated moderate to severe mitral stenosis. Left atrial (LA) volume parameters (maximum, minimum and preatrial contraction) were measured. Among 26 patients, TEE was performed to detect left atrial thrombosis or spontaneous echo contrast. Left atrial appendage velocity (LAAV) was also assessed. RESULTS: A significant correlation was observed between LAAV and the average value of left atrial peak systolic strain (LA-RES) (r = 0.638, P = 0.001). The sensitivity and specificity of mean LA-RES (cutoff = 16.75%) for detecting LAAV < 25 cm/s were 88.9% and 80%, respectively. The sensitivity and specificity of mean LA-RES (cutoff = 18.14%) for detecting LAAV < 25 cm/s and/or dense smoky pattern were 77.8% and 83.3%, respectively, and those of left atrial maximum volume indexed for body surface area(cutoff = 50.75 cc/m2 ), for discriminating LAAV < 25 cm/s and/or dense smoky pattern, were 73.3% and 83.3%, respectively. A meaningful correlation was witnessed between mean LA-RES and left atrial ejection fraction (r = 0.736, P < 0.001), and left atrial expansion index (r = 0.743, P < 0.001). CONCLUSION: The average value of left atrial reservoir function using 2DSTE can be used as a predictive factor for detecting LAAV < 25 cm/s and/or dense SEC and thus recognizing high-risk patients for cardioembolic events with moderate to severe mitral stenosis. In addition, assessment of LA function and LA volume can also be helpful. PMID- 29971827 TI - Inspiratory pre-motor potentials during quiet breathing in ageing and chronic obstructive pulmonary disease. AB - KEY POINTS: A cortical contribution to breathing, as indicated by a Bereitschaftspotential (BP) in averaged electroencephalographic signals, occurs in healthy individuals when external inspiratory loads are applied. Chronic obstructive pulmonary disease (COPD) is a condition where changes in the lung, chest wall and respiratory muscles produce an internal inspiratory load. These changes also occur in normal ageing, although to a lesser extent. In the present study, we determined whether BPs are present during quiet breathing and breathing with an external inspiratory load in COPD compared to age-matched and young healthy controls. We demonstrated that increased age, rather than COPD, is associated with a cortical contribution to quiet breathing. A cortical contribution to inspiratory loading is associated with more severe dyspnoea (i.e. the sensation of breathlessness). We propose that cortical mechanisms may be engaged to defend ventilation in ageing with dyspnoea as a consequence. ABSTRACT: A cortical contribution to breathing is determined by the presence of a Bereitschaftspotential, a low amplitude negativity in the averaged electroencephalographic (EEG) signal, which begins ~1 s before inspiration. It occurs in healthy individuals when external inspiratory loads to breathing are applied. In chronic obstructive pulmonary disease (COPD), changes in the lung, chest wall and respiratory muscles produce an internal inspiratory load. We hypothesized that there would be a cortical contribution to quiet breathing in COPD and that a cortical contribution to breathing with an inspiratory load would be linked to dyspnoea, a major symptom of COPD. EEG activity was analysed in 14 participants with COPD (aged 57-84 years), 16 healthy age-matched (57-87 years) and 15 young (18-26 years) controls during quiet breathing and inspiratory loading. The presence of Bereitschaftspotentials, from ensemble averages of EEG epochs at Cz and FCz, were assessed by blinded assessors. Dyspnoea was rated using the Borg scale. The incidence of a cortical contribution to quiet breathing was significantly greater in participants with COPD (6/14) compared to the young (0/15) (P = 0.004) but not the age-matched controls (6/16) (P = 0.765). A cortical contribution to inspiratory loading was associated with higher Borg ratings (P = 0.007), with no effect of group (P = 0.242). The data show that increased age, rather than COPD, is associated with a cortical contribution to quiet breathing. A cortical contribution to inspiratory loading is associated with more severe dyspnoea. We propose that cortical mechanisms may be engaged to defend ventilation with dyspnoea as a consequence. PMID- 29971828 TI - Sources of morbidity in lorises and pottos in North American zoos: A retrospective review, 1980-2010. AB - Delineating patterns of morbidity can reveal management practices in need of reassessment to improve individual welfare, as well as population health and sustainability. We reviewed medical records from 38 North American zoological institutions for 276 slender lorises, slow lorises, and pottos born between January 1, 1980 and December 31, 2010. This sample included animals identified as 116 Nycticebus pygmaeus, 84 N. coucang, 48 Loris tardigradus tardigradus, 6 L.t. nordicus (now classified as L. lydekkerianus nordicus), and 22 Perodicticus potto. Taxonomy for lorises and pottos is developing, and two of these populations (N. coucang and P. potto) likely included hybrids and/or multiple species. Our focus was to examine trends based on species and age. Across all species, whole body disease events, abnormalities of bloodwork, and dental diseases were the most common sources of morbidity. Other major sources of morbidity varied by species and included trauma, respiratory disease, and ocular disease. A recent upsurge in research has informed feeding practices for slow lorises living in human care, and a similar, evidence-based approach is needed to improve diets for other species. Given the prevalence of trauma in this sample, social needs and reproductive management practices are also important areas for further investigation. Species-level health trends reveal risk factors for individual welfare that can guide husbandry practices in zoos, as well as in sanctuaries caring for the influx of lorises and pottos rescued from the growing wildlife trade. PMID- 29971829 TI - Index serum hyaluronic acid independently and accurately predicts mortality in patients with liver disease. AB - BACKGROUND: Hyaluronic acid is a recognised noninvasive marker of liver fibrosis. However, its prognostic ability has not been extensively studied. AIMS: To investigate the ability of an index serum hyaluronic acid measurement to independently predict transplant-free survival in patients with liver disease of varying aetiology and severity. METHODS: This was a retrospective single-centre cohort study. Serum hyaluronic acid was measured at the discretion of the attending clinicians, in patients attending the liver clinic, to assess disease severity. Patients with a hyaluronic acid measurement between 1995 and 2010 were identified. Patient characteristics at the point of hyaluronic acid measurement were recorded from medical records. Follow-up was from date of index hyaluronic acid measurement to date of death, date of transplant or censor date (July 01, 2015). Primary outcomes were all-cause and liver-related mortality. Kaplan-Meier analysis was used to compare survival in 3 patient groups with hyaluronic acid levels of <100 MUg/L, 100-300 MUg/L and >300 MUg/L. Survival models were constructed using Cox proportional hazard and prediction accuracy was assessed by Harrell's C-statistic. RESULTS: Five hundred and eighty nine patients fulfilled inclusion criteria. Median follow-up was 5.6 years (range 0.1-19.7). Transplant free survival was significantly different between patients with hyaluronic acid <100 MUg/L, 100-300 MUg/L and >300 MUg/L for liver-related as well as all-cause mortality (P < 0.001). Hyaluronic acid level was an independent predictor of survival (liver-related: HR 1.39, 95% CI 1.20-1.60, P < 0.001; all-cause: HR 1.04, 95% CI 1.02-1.06, P = 0.001). The liver-related prediction accuracy of hyaluronic acid was 0.74 (Standard error 0.03). CONCLUSION: Index hyaluronic acid measurement can accurately and independently predict liver-related and all-cause mortality in patients with liver disease. PMID- 29971831 TI - Management of cervical root fracture injury in a patient with epilepsy: Case report with 5-year follow-up. AB - The difficulty in providing stability to the coronal segment makes cervical root fracture one of the most challenging dental traumatic injury. This type of injury is less frequent in children. However, due to their serious consequences and poor prognosis, tooth loss may occur. This report presents the management of a case of cervical root fracture in an 11-year-old patient with epilepsy. The stabilization of the root-fractured tooth with a splint failed due to the recurrent seizures the patient had. Coronal fragment was removed and vital root submergence was performed in order to support the alveolar growth. The natural tooth crown was incorporated into a modified Nance appliance to meet the esthetic and functional requirements of the patient. After 5-year follow-up, this treatment approach has seemed to offer a long-term provisional and satisfactory solution to the consequences of a cervical root fracture injury. PMID- 29971830 TI - Fibroelastoma of the mitral valve apparatus. PMID- 29971832 TI - The Application of Hollow Structured Anodes for Sodium-Ion Batteries: From Simple to Complex Systems. AB - Hollow structures exhibit fascinating and important properties for energy-related applications, such as lithium-ion batteries, supercapacitors, and electrocatalysts. Sodium-ion batteries, as analogs of lithium-ion batteries, are considered as promising devices for large-scale electrical energy storage. Inspired by applications of hollow structures as anodes for lithium-ion batteries, the application of these structures in sodium-ion batteries has attracted great attention in recent years. However, due to the difference in lithium and sodium-ion batteries, there are several issues that need to be addressed toward rational design of hollow structured sodium anodes. Herein, this research news article presents the recent developments in the synthesis of hollow structured anodes for sodium-ion batteries. The main strategies for rational design of materials for sodium-ion batteries are presented to provide an overview and perspectives for the future developments of this research area. PMID- 29971833 TI - New application of direct analysis in real time high-resolution mass spectrometry for the untargeted analysis of fresh and aged secondary organic aerosols generated from monoterpenes. AB - RATIONALE: Secondary organic aerosols (SOAs) represent a significant portion of total atmospheric aerosols. They are generated by the oxidation of volatile organic compounds (VOCs), and particularly biogenic VOCs (BVOCs). The analysis of such samples is usually performed by targeted methods that often require time consuming preparation steps that can induce loss of compounds and/or sample contaminations. METHODS: Recently, untargeted methods using high-resolution mass spectrometry (HRMS) have been successfully employed for a broad characterization of chemicals in SOAs. Herein we propose a new application of the direct analysis in real time (DART) ionization method combined with HRMS to quickly detect several hundred chemicals in SOAs collected on a quartz filter without sample preparation or separation techniques. RESULTS: The reproducibility of measurements was good, with several hundred elemental compositions common to three different replicates. The relative standard deviations of the intensities of the chemical families ranged from 6% to 35%, with sufficient sensitivity to allow the unambiguous detection of 4 ng/mm2 of pinic acid. The presence of oligomers and specific tracers was highlighted by MSn (n <= 4) experiments, an achievement that is difficult to attain with other ultrahigh-resolution mass spectrometers. Contributions of this untargeted DART-HRMS method were illustrated by the analysis of fresh and aged SOAs from different gaseous precursors such as limonene, a beta-pinene/limonene mixture or scots pines emissions. CONCLUSIONS: The results show that it is possible to use DART-HRMS for the identification of tracers of specific aging reactions, or for the identification of aerosols from specific biogenic precursors. PMID- 29971834 TI - Colonoscopy quality requisites for selecting surveillance intervals: A World Endoscopy Organization Delphi Recommendation. AB - BACKGROUND AND AIMS: Different post-polypectomy guidelines underscore the need for high-quality baseline colonoscopy before appropriate surveillance recommendations can be made. Standards for colonoscopy practice have been advocated by gastrointestinal societies. Our aims were to define standards for the procedural practice of colonoscopy in this particular setting of surveillance and to generate a colonoscopy procedural quality checklist that could be implemented in clinical practice. METHODS: This study was based on the Delphi process methodology. The baseline questionnaire included 12 domains and 56 individual statements. A total of three rounds were carried out between September 2015 and March 2016 until consensus or lack of consensus was reached. RESULTS: In total, consensus was reached on 27 statements in nine domains. High levels of agreement and consensus were reached that: (i) colonoscopy should be considered complete only if the whole cecum has been inspected, including the ileocecal valve and the appendiceal orifice (agreement score 4.63; degree of consensus 82%); (ii) quality of the bowel preparation should always be reported (agreement score 4.9, degree of consensus 94%); and (iii) it is preferable to use a segmental validated scale (agreement score 4.36, degree of consensus 86%). Consensus was also reached regarding multiple statements related to documentation of polyps and their resection. Finally, a colonoscopy quality checklist was drafted. CONCLUSION: Consensus on different statements regarding quality of colonoscopy has been reached. Based on this consensus, we propose a colonoscopy quality checklist that would be helpful for post-polypectomy surveillance recommendations. PMID- 29971835 TI - Nanoscale Metal-Organic Frameworks for Therapeutic, Imaging, and Sensing Applications. AB - Nanotechnology has played an important role in drug delivery and biomedical imaging over the past two decades. In particular, nanoscale metal-organic frameworks (nMOFs) are emerging as an important class of biomedically relevant nanomaterials due to their high porosity, multifunctionality, and biocompatibility. The high porosity of nMOFs allows for the encapsulation of exceptionally high payloads of therapeutic and/or imaging cargoes while the building blocks-both ligands and the secondary building units (SBUs)-can be utilized to load drugs and/or imaging agents via covalent attachment. The ligands and SBUs of nMOFs can also be functionalized for surface passivation or active targeting at overexpressed biomarkers. The metal ions or metal clusters on nMOFs also render them viable candidates as contrast agents for magnetic resonance imaging, computed tomography, or other imaging modalities. This review article summarizes recent progress on nMOF designs and their exploration in biomedical areas. First, the therapeutic applications of nMOFs, based on four distinct drug loading strategies, are discussed, followed by a summary of nMOF designs for imaging and biosensing. The review is concluded by exploring the fundamental challenges facing nMOF-based therapeutic, imaging, and biosensing agents. This review hopefully can stimulate interdisciplinary research at the intersection of MOFs and biomedicine. PMID- 29971836 TI - Carboplatin and epirubicin combination therapy for advanced malignant epithelial skin tumors: Retrospective study of six patients. PMID- 29971837 TI - Microbiome analysis of forehead skin in patients with atopic dermatitis and healthy subjects: Implication of Staphylococcus and Corynebacterium. PMID- 29971838 TI - UV-light and dietary vitamin D and their effects on ionized calcium and 25-OH-D plasma concentrations in captive gentoo penguins (Pygoscelis papua). AB - In this study, the effect of ultraviolet (UV) light and dietary vitamin D on calcium metabolism in permanently indoor-housed gentoo penguins (Pygoscelis papua) was investigated. The study consisted of three periods, each completed with blood samples to analyse plasma concentrations of 25-OH-D, 1,25-(OH)2 -D, ionized (iCa) and total calcium (tCa). During the first study period (D), animals were housed under routine conditions without UV-light and fed a diet of different fish species, supplemented with 1,000 IU vitamin D per animal and day. The following study period (Baseline) of 28-day duration consisted of the same diet without any vitamin D supplementation and without UV-light. During the study period (UVB) artificial UV-light was added for 3 weeks. The vitamin D content of fish was measured by high-performance liquid chromatography. It varied between fish species and between facilities, ranging from no measurable content in capelin (Mallotus villosus) to 7,340 IU vitamin D/kg original matter (OM) in herring (Clupea spp). The average dietary vitamin D content was 311 IU/kg OM at facility 1 and 6,325 IU/kg OM at facility 2, resulting in a vitamin D intake per animal and day without supplementation of 130 IU (25.5 IU/kg body weight BW) and 2,454 IU (438.2 IU/kg BW) respectively. The supplementation of vitamin D elevated significantly the plasma concentrations of 25-OH-D by an intraindividual difference of 15 (range -2 to 59) nmol/L and tCa by 0.1 (0.0-0.3) mmol/L only at facility 2. The exposure to UV-light raised the blood concentrations of tCa at facility 2 by 0.15 (0.1-0.2) mmol/L, and of iCa and tCa for females at facility 1 by 0.23 (0.13-0.41) mmol/L and 1.8 (1.1-2.5) mmol/L respectively. No significant influence of the study periods (D) and (UVB) was found for the concentrations of 1,25-(OH)2 -D at both facilities. PMID- 29971840 TI - News & Announcements: American Society for Laser Medicine & Surgery, Inc. PMID- 29971839 TI - Associations of childhood socioeconomic status with mid-life and late-life cognition in Chinese middle-aged and older population based on a 5-year period cohort study. AB - OBJECTIVES: A prospective study was performed to examine the relationship of childhood socioeconomic status (SES) with cognition and the rate of change in a nationally representative sample of community-dwelling middle-aged and older Chinese population. METHODS: This study mainly focused on 3 composite measures of cognitive function, including Telephone Interview of Cognitive Status, word recall, and drawing a figure successfully. Childhood SES was evaluated by parental occupation and education, childhood residence, and self-evaluated financial status. We designed an analysis strategy adding predictors incrementally in different models to examine the changes of effects of childhood SES on cognition by latent growth curve models. RESULTS: Finally, a total of 10 533 respondents were prospectively studied, including 5980 respondents aged 45-59 and 4553 aged 60-90. Cognition in younger cohort showed a curvilinear change, while cognition in older cohort showed a linear decline. After controlling for covariates, middle-aged respondents with higher self-evaluated financial status (beta: -0.22, P < .001), better health status (beta: -0.13, P < .001), higher parental education (beta: 0.17 and 0.10, P < .001), who had lived in city/town before 16 years (beta: 0.69, P < .001), and whose fathers engaged in nonfarming work (beta: 0.43, P < .001) were associated with the better baseline cognition. Similar results were found in older cohort. Additionally, early-life SES was not associated with cognitive decline in both cohorts. CONCLUSIONS: This study indicates that childhood SES is associated with mid-life and late-life baseline cognition, but it is not contributed to cognition decline. Interventions in early life focused on improving childhood SES might have positive impacts on baseline cognition in later-life. PMID- 29971841 TI - The definition of severe systemic lupus erythematosus needs clarification in the next ASFA guidelines. PMID- 29971842 TI - Designing Efficient Energy Funneling Kinetics in Ruddlesden-Popper Perovskites for High-Performance Light-Emitting Diodes. AB - Mixed Ruddlesden-Popper (RP) perovskites are of great interest in light-emitting diodes (LEDs), due to the efficient energy transfer (funneling) from high-bandgap (donor) domains to low-bandgap (acceptor) domains, which leads to enhanced photoluminescence (PL) intensity, long PL lifetime, and high-efficiency LEDs. However, the influence of reduced effective emitter centers in the active emissive film, as well as the implications of electrical injection into the larger bandgap donor material, have not been addressed in the context of an active device. The electrical and optical signatures of the energy cascading mechanisms are critically assessed and modulated in a model RP perovskite series ((C8 H17 NH3 )2 (CH(NH2 )2 )m-1 Pbm Br3m+1 ). Optimized devices demonstrate a current efficiency of 22.9 cd A-1 and 5% external quantum efficiency, more than five times higher than systems where funneling is absent. The signature of nonideal funneling in RP perovskites is revealed by the appearance of donor electroluminescence from the device, followed by a reduction in the LED performance. PMID- 29971844 TI - Men and women with borderline personality disorder resident in Dutch special psychiatric units in prisons: A descriptive and comparative study. AB - BACKGROUND: The overall prevalence of borderline personality disorder is well known, but characteristics of offender patients with the condition are less clear, especially among men. AIM: Describe characteristics of men and women with borderline personality disorder in special psychiatric units in Dutch prisons on three domains: prevalence of child abuse, comorbidity of borderline personality disorder with other disorders, and clinical symptoms. METHODS: One hundred and sixty-seven people were assigned to this study based on a Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnoses retrieved from records. Other DSM-5 diagnoses were also recorded. Two scales, the Dutch Historisch, Klinisch, Toekomst-Revisie and the international Brief Psychiatric Rating Scale-Expanded (BPRS-E) were used to record child abuse and clinical symptoms, respectively. RESULTS: Prevalence rates of child abuse were high, but the men and women did not differ in this respect. The male offender patients were more likely than the women to have a comorbid substance use disorder, whereas the women were more likely to have a comorbid anxiety disorder. Intellectual disability was the most common comorbid Axis II disorder. The women were more likely than the men to have committed a fatal/nearly fatal index offence and showed higher rates of distress or behavioural disturbance on all five BPRS-E factors. CONCLUSIONS: This study provides evidence of the importance of in-depth knowledge of presentations with borderline personality disorder specific to setting. Although we were unable to make direct comparisons with other samples, our figures suggest clinically relevant differences among offender patients from the more widely reported general samples. We also shed light on a sometimes underexposed group of men with borderline personality disorder and their clinical needs. More population-specific intervention and follow-up studies are now indicated. PMID- 29971845 TI - Toward the understanding of human tuberculosis. PMID- 29971843 TI - Methylation of the N-terminal histidine protects a lytic polysaccharide monooxygenase from auto-oxidative inactivation. AB - The catalytically crucial N-terminal histidine (His1) of fungal lytic polysaccharide monooxygenases (LPMOs) is post-translationally modified to carry a methylation. The functional role of this methylation remains unknown. We have carried out an in-depth functional comparison of two variants of a family AA9 LPMO from Thermoascus aurantiacus (TaLPMO9A), one with, and one without the methylation on His1. Various activity assays showed that the two enzyme variants are identical in terms of substrate preferences, cleavage specificities and the ability to activate molecular oxygen. During the course of this work, new functional features of TaLPMO9A were discovered, in particular the ability to cleave xyloglucan, and these features were identical for both variants. Using a variety of techniques, we further found that methylation has minimal effects on the pKa of His1, the affinity for copper and the redox potential of bound copper. The two LPMOs did, however, show clear differences in their resistance against oxidative damage. Studies with added hydrogen peroxide confirmed recent claims that low concentrations of H2 O2 boost LPMO activity, whereas excess H2 O2 leads to LPMO inactivation. The methylated variant of TaLPMO9A, produced in Aspergillus oryzae, was more resistant to excess H2 O2 and showed better process performance when using conditions that promote generation of reactive-oxygen species. LPMOs need to protect themselves from reactive oxygen species generated in their active sites and this study shows that methylation of the fully conserved N-terminal histidine provides such protection. PMID- 29971846 TI - Ion formation in droplet-assisted ionization. AB - RATIONALE: In droplet-assisted ionization (DAI), intact molecular ions are generated from molecules in aerosol droplets by passing the droplets through a temperature-controlled capillary inlet. Ion formation is explored through the effects of analyte mass flow, droplet solvent composition, and capillary temperature on ion signal intensity. METHODS: A Waters SYNAPT G2-S is adapted for DAI by reconfiguring the inlet with a temperature-controlled capillary. Droplets are generated by atomization of a solution containing analyte and then sampled through the inlet. If desired, solvent can be removed from the droplets prior to analysis by sending the aerosol through a series of diffusion dryers. Size distributions of the dried aerosols allow the mass flow of analyte into the inlet to be determined. RESULTS: Analyte signal intensities are orders of magnitude higher from droplets containing a protic solvent (water) than an aprotic solvent (acetonitrile). The highest signal intensities for DAI are obtained with inlet temperatures above 500 degrees C, though the optimum temperature is analyte dependent. At elevated temperatures, droplets are thought to undergo rapid solvent evaporation and bursting to produce ions. The lowest signal intensities are generally obtained in the 100-350 degrees C range, where slow solvent evaporation is thought to inhibit ion formation. As the temperature decreases from 100 degrees C down to 25 degrees C, the signal intensity increases significantly. When 3-nitrobenzonitrile, a common matrix for solid-state matrix assisted ionization (MAI), is added to droplets consisting of 50/50 v/v water and acetonitrile, the matrix enhances ion formation to produce a signal intensity comparable to DAI in 100% water. CONCLUSIONS: The results are consistent with other inlet ionization techniques, suggesting that similar ion formation mechanisms are operative. Optimized ion yields (the combined effects of ionization probability and ion transmission) for DAI are currently in the 10-5 to 10-6 range, which is sufficient for many aerosol applications. PMID- 29971847 TI - Depletion of alphabeta+ T cells for a haploidentical hematopoietic stem cell transplantation in children. AB - A consistent and reproducible depletion technique is crucial for the successful transplantation of an ex vivo depleted graft. Our aim was to evaluate the efficacy of an ex vivo technique for depletion of alphabeta+ T cells using a biotinylated anti-TCRalphabeta monoclonal antibody, which was performed by one clinical nurse specialist. Between 2012 and 2017, 119 depletion procedures from 216 apheresis using the anti-TCRalphabeta monoclonal antibody were performed on 105 pediatric patients. The median log depletion of alphabeta+ T cells was 4.0 (range, 2.5-5.0). The median recovery rates of CD34+ , NK, and gammadelta+ T cells were 90.4%, 74.9%, and 75.9%, respectively. The efficacy of depletion of alphabeta+ T cells significantly improved over time and the duration of the depletion procedure significantly decreased over time. Our study demonstrated that this procedure for depletion of alphabeta+ T cells by skilled staff is highly effective at depleting target cells and obtaining CD34+ progenitor cells. PMID- 29971848 TI - "A body in transformation"-An empirical phenomenological study about fear avoidance beliefs towards physical activity among persons experiencing moderate to-severe rheumatic pain. AB - AIMS AND OBJECTIVES: To gain a better understanding of fear-avoidance beliefs towards physical activity and body awareness in people experiencing moderate-to severe rheumatic pain. BACKGROUND: Rheumatoid arthritis and psoriatic arthritis are long-term conditions with pain as the prominent symptom. Health-promoting physical activity is recommended and can have an analgesic effect. High self rated pain has previously been reported to be associated with increased fear avoidance behaviour in relation to physical activity. Body awareness, which includes attentional focus and awareness of internal body sensations, could be valuable in the nursing care of long-term diseases. DESIGN: Empirical phenomenological. METHODS: An empirical phenomenological psychological method was applied. The interviews took place between autumn 2016-spring 2017 with 11 informants (eight women and three men, age range 44-71 years) who were diagnosed with rheumatoid arthritis (n = 7) or psoriatic arthritis (n = 4), with a disease duration ranging from 3-35 years. The mean visual analogue scale score in the study sample was 60 mm. RESULTS: Three typologies were identified: "My relatively fragile physical status", "I am an active creator" and "Part of something bigger than myself." CONCLUSIONS: The current findings indicated that pain anticipation and fear-avoidance beliefs towards physical activity sometimes affected the behaviour of individuals with long-term rheumatic pain syndromes. People experiencing moderate-to-severe rheumatic pain tended to focus on their fragile physical and emotional state. By adopting a more favourable attitude towards the self, the body could be restored to a state of calm and balance. RELEVANCE TO CLINICAL PRACTICE: The current findings are relevant for healthcare professionals engaged in health-promotion clinical practice. PMID- 29971849 TI - Identifying the Origin and Contribution of Surface Storage in TiO2 (B) Nanotube Electrode by In Situ Dynamic Valence State Monitoring. AB - Fundamental insight into the surface charging mechanism of TiO2 (B) nanomaterials is limited due to the complicated nature of lithiation behavior, as well as the limitations of available characterization tools that can directly probe surface charging process. Here, an in situ approach is reported to monitor the dynamic valence state of TiO2 (B) nanotube electrodes, which utilizes in situ X-ray absorption spectroscopy (XAS) to identify the origin and contribution of surface storage. A real-time correlation is elucidated between the rate-dependent electrode performance and dynamic Ti valence-state change. A continuous Ti valence state change is directly observed through the whole charging/discharging process regardless of charging rates, which proves that along with the well-known non-faradaic reaction, the surface charging process also originates from a faradaic reaction. The quantification of these two surface storage contributions at different charging rates is further realized through in situ dynamic valence state monitoring combined with traditional cyclic voltammetry measurement. The methodology reported here can also be applied to other electrode materials for the real-time probing of valence state change during electrochemical reactions, the quantification of the faradaic and non-faradaic reactions, and the eventual elucidation of electrochemical surface charging mechanisms. PMID- 29971850 TI - A new understanding of the physiology and pathophysiology of colonic motility? AB - BACKGROUND: In recent years, high-resolution manometry has been used in an attempt to gain a greater insight into the physiology/pathophysiology of colonic contractile activity in healthy adults and patients with colonic motility disorders. New colonic motor patterns have been identified and characterized, however, the clinical significance of these findings remains undetermined. PURPOSE: This review will assess the current literature on colonic high resolution manometry and determine if this procedure has advanced our understanding of colonic motility. The limitations, future directions, and the potential of this technique to assess the effects of treatment upon colonic motor patterns will also be discussed. PMID- 29971851 TI - Multiple Pediatric Head Injury Decision Rules but What Should the Clinician Use? PMID- 29971852 TI - Rabs: targets in the plant-pathogen battlefield. PMID- 29971853 TI - Revisiting the impact of radiation therapy on cardiac implantable electronic device (CIED) function. PMID- 29971854 TI - Corticotrophin-releasing factor-mediated effects of DA-9701 in Postoperative Ileus Guinea Pig Model. AB - BACKGROUND: Postoperative ileus (POI) is abdominal surgery-induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA-9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin-releasing factor (CRF) pathways, in a POI model. METHODS: A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA-9701 1, 3, and 10 mg kg-1 . CRF1 receptor antagonist, CP-154 526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c-Fos in the hypothalamus. KEY RESULTS: DA-9701 significantly increased delayed GI transit in POI in a dose dependent manner and decreased plasma ACTH levels at 10 mg kg-1 . CP-154 526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA-9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA-9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA-9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA-9701-pretreated POI than in the untreated POI. CONCLUSIONS AND INFERENCES: The DA-9701-induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway. PMID- 29971855 TI - Chemical Tuning of Zwitterionic Ionic Liquids for Variable Thermophysical Behaviours, Nanostructured Aggregates and Dual-Stimuli Responsiveness. AB - The design and synthesis of a series of zwitterionic ionic liquids (ZILs) to understand the structure-property relationship towards an increase of the thermal stability, a variation of the glass transition temperature, the shape-tuning of nanostructured aggregates and the tuning of the stimuli responsiveness are demonstrated. The substitution reaction of imidazole with various aliphatic and aromatic bromides followed by the reaction of the corresponding substituted imidazoles with bromoalkyl carboxylic acids of varying spacer length produces the ZILs. In aqueous solution, a ZIL molecule either exist in its ionic liquid (substituted imidazolium bromide) form or its zwitterionic (substituted imidazolium alkyl carboxylate) form with an isoelectric point (pI) depending on the pH value of the solution. Upon changing the pH to near or above the pI, the aqueous ZIL solution undergoes transition from a transparent to a turbid phase due to the formation of insoluble hierarchical nanostructured aggregates of various morphologies, such as spheres, tripods, tetrapods, fern-like, flower like, dendrites etc. depending on the pH of the solution and the nature of the alkyl/vinyl/aryl substituents. Upon heating the solution a phase transition occurs from turbid to transparent, exhibiting a distinct reversible upper critical solution temperature (UCST)-type cloud point (Tcp ). It is observed that the cloud point varies with the nature of the substituent, an increase of the concentration of the ZIL as well as with changes of the pH of the solution. PMID- 29971856 TI - Comparison of freeze vacuum drying and conventional drying methods in matrix assisted laser desorption/ionization mass spectrometry analyses of peptides. PMID- 29971857 TI - Manual signing throughout the day: Influence from staff's sign use and type of activity. AB - BACKGROUND: Both individuals with intellectual disabilities (ID) and staff may be more inclined to use manual signs during formal than informal activities. In addition, the sign use of individuals with ID and staff is positively related. It is unclear if activity type and the sign use of staff interact as they shape the sign use of individuals with ID. METHODS: Through non-continuous partial interval coding, we observed frequency of manual sign usage in adults with ID during communicative activities, non-communicative activities and mealtimes in four special schools and 4-day centres. Using loglinear analysis and partial associations, we measured how sign use varied by activity between the people with ID and the staff. RESULTS: When staff used signs, clients and students did not vary their spontaneous signing rate between types of activities. When staff did not use signs, a differential influence appeared according to the type of activity: clients and students were significantly more likely to also refrain from using signs during mealtimes and leisure or work activities such as crafts (84% to 89% of the time) than during communicative activities such as signing sessions (65% of the time). CONCLUSIONS: Reluctance of staff to model sign use seemed to hinder signing implementation by the people with ID. Future studies should take into account various levels of sign prompting and increasing pragmatic functions of individuals' sign use. PMID- 29971858 TI - Imidazole dipeptides can quench toxic 4-oxo-2(E)-nonenal: Molecular mechanism and mass spectrometric characterization of the reaction products. AB - Imidazole dipeptides, such as carnosine (beta-alanyl-l-histidine) and anserine (beta-alanyl-Npi -methyl-l-histidine), are highly localized in excitable tissues, including skeletal muscle and nervous tissue, and play important roles such as scavenging reactive oxygen species and quenching reactive aldehydes. We have demonstrated several reactions between imidazole dipeptides (namely, carnosine, and anserine) and a lipid peroxide-derived reactive aldehyde 4-oxo-2(E)-nonenal. Seven carnosine adducts and two anserine adducts were characterized using liquid chromatography/electrospray ionization-multiple-stage mass spectrometry. Adduct formation occurred between imidazole dipeptides and 4-oxo-2(E)-nonenal mainly through Michael addition, Schiff base formation, and/or Paal-Knorr reaction. The reactions were much more complicated than the reaction with a similar lipid peroxide-derived reactive aldehyde, 4-hydroxy-2(E)-nonenal. PMID- 29971859 TI - High-performance liquid chromatography/electrospray ionisation mass spectrometric characterisation of metabolites produced by Pseudovibrio sp. W64, a marine sponge derived bacterium isolated from Irish waters. AB - RATIONALE: In recent years, metabolites produced by Pseudovibrio species have gained scientific attention due to their potent antimicrobial activity. Recently, we also have assessed the antibacterial activities of Pseudovibrio sp. W64 isolates against Staphylococcus aureus, where only the dominant tropodithietic acid (TDA) was identified. However, characterisation of other metabolites is necessary as these metabolites may also serve as potent antimicrobial agents. METHODS: Liquid chromatography/tandem mass spectrometry (LC/MS/MS), aided by accurate mass measurements, was employed to screen and characterise a range of metabolites produced by Pseudovibrio sp. W64 via assessment of ethyl acetate fractions generated from bacterial cultures. RESULTS: Thirteen metabolites unique to the bacterial culture were detected and their chemical structures were assigned by MS/MS and accurate mass measurements. Among the thirteen metabolites, a methyl ester of TDA, a number of cholic acid derivatives, and amino diols and triols were characterised. CONCLUSIONS: Pseudovibrio sp. W64 produces methylated TDA in addition to TDA, and metabolises lipids and amino acids in the cell culture medium. To the best of our knowledge, this is the first report of methylated TDA, cholic acid and its various analogs, and sphinganine being detected in this Pseudovibrio strain. The data generated may help to better understand the biochemical processes and metabolism of bacterial strains towards discovery of antimicrobial agents from marine sources. PMID- 29971860 TI - Testing the addictive appetite model of binge eating: The importance of craving, coping, and reward enhancement. AB - In the current study, we examine components of the "addictive appetite" model of recurrent binge eating. Specifically, we tested the influence of addictive processes and the influence of emotional regulation processes on recurrent binge eating behaviour. We recruited 79 women in total for the current study: 22 with bulimia nervosa, 26 weight-matched lean comparison women, 15 women with binge eating disorder, and 16 weight-matched overweight/obese comparison women. Participants completed questionnaire assessments of food craving and motivations for eating. Compared with weight-matched comparison women, women with binge-type eating disorders endorse significantly greater levels of food craving, eating for purposes of coping, and eating for purposes of reward enhancement. A cluster analysis revealed that these three traits distinguish women with binge-type eating disorders from weight-matched comparison women. These findings provide support for the addictive appetite model of binge eating behaviour and highlight addictive and emotional regulation processes as potential targets for treatment. PMID- 29971861 TI - TRPM8, ASIC1, and ASIC3 localization and expression in the human oropharynx. AB - BACKGROUND: Oropharyngeal dysphagia (OD) is a prevalent disease with poor prognosis among older people and has no pharmacological treatment. Polymodal sensory receptors like the TRP or ASIC family receptors are potential targets to treat OD. TRPM8 agonists and acidic solutions can improve the swallow response in patients with OD, but little is known about the expression of TRPM8, ASIC1, and ASIC3 in the human oropharynx. The aim of this study was to assess the expression and localization of TRPM8, ASIC1, and ASIC3 in human samples of the oropharynx to lay the basis for new pharmacological treatments for OD. METHODS: Pathology-free samples from oropharyngeal regions innervated by cranial nerves V, IX, and X were obtained during major ENT surgery and processed to obtain mRNA (20 patients) or to be used in immunohistochemical assays (12 patients). TRPM8, ASIC1, and ASIC3 expression and localization were studied with RT-qPCR and fluorescent immunohistochemistry. KEY RESULTS: ASIC3 was expressed in the 3 regions studied with similar levels and was localized on sensory fibers innervating the mucosa below the basal lamina of all studied regions. TRPM8 was also co-localized on the sensory fibers innervating the mucosa below the basal lamina of all studied regions. In contrast, ASIC1 was only found in the nerves innervating the tongue muscular fibers. CONCLUSIONS & INFERENCES: TRPM8 and ASIC3 are found on submucosal sensory nerves in the human oropharynx. Our study lays the basis to use oropharyngeal TRPM8 and ASIC3 receptors as therapeutic targets to develop new active pharmacological treatments for OD patients. PMID- 29971863 TI - When I say ... fairness in selection. PMID- 29971862 TI - Fluorescent Trimethylated Naphthyridine Derivative with an Aminoalkyl Side Chain as the Tightest Non-aminoglycoside Ligand for the Bacterial A-site RNA. AB - The bacterial ribosomal decoding region of the aminoacyl-tRNA site (A-site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well-characterized A-site binding ligands, high off-target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non-aminoglycoside A-site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A-site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A-site (Kd =0.44 MUm; pH 7.0, I=0.06 m, 5 degrees C). Significantly, this ligand shows the tightest binding reported to date among non aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND-C2 -NH2 for high affinity to the A-site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A-site interactions. PMID- 29971864 TI - Interface Engineering for All-Inorganic CsPbI2 Br Perovskite Solar Cells with Efficiency over 14. AB - In this work, a SnO2 /ZnO bilayered electron transporting layer (ETL) aimed to achieve low energy loss and large open-circuit voltage (Voc ) for high-efficiency all-inorganic CsPbI2 Br perovskite solar cells (PVSCs) is introduced. The high quality CsPbI2 Br film with regular crystal grains and full coverage can be realized on the SnO2 /ZnO surface. The higher-lying conduction band minimum of ZnO facilitates desirable cascade energy level alignment between the perovskite and SnO2 /ZnO bilayered ETL with superior electron extraction capability, resulting in a suppressed interfacial trap-assisted recombination with lower charge recombination rate and greater charge extraction efficiency. The as optimized all-inorganic PVSC delivers a high Voc of 1.23 V and power conversion efficiency (PCE) of 14.6%, which is one of the best efficiencies reported for the Cs-based all-inorganic PVSCs to date. More importantly, decent thermal stability with only 20% PCE loss is demonstrated for the SnO2 /ZnO-based CsPbI2 Br PVSCs after being heated at 85 degrees C for 300 h. These findings provide important interface design insights that will be crucial to further improve the efficiency of all-inorganic PVSCs in the future. PMID- 29971866 TI - Toward a parsimonious understanding of suicide: comparing the Three Step Theory to Malhi and colleagues' Integrated Model. PMID- 29971865 TI - Preclinical evaluation of the effects on the gastrointestinal tract of the antineoplastic drug vincristine repeatedly administered to rats. AB - BACKGROUND: Vincristine is a commonly used chemotherapeutic agent. It is associated with undesirable digestive side effects. However, the impact of vincristine on gastrointestinal structure and motility or its long-term effects have not been deeply studied in animal models. This could be useful in order to develop therapeutic or preventive strategies for cancer patients. The aim of this study was to analyze such effects. METHODS: Rats received saline or vincristine (0.1 mg kg-1 , ip) daily for 10 days. Evaluations were performed during treatment and 2-6 weeks after. Somatic mechano-sensitivity was assessed using von Frey hairs. Gastrointestinal motor function was studied by means of radiographic still images and colonic propulsion of fecal pellets using fluoroscopy videos. Histological assessment of the gut morphology and immunohistochemistry for HuC/D and nNOS were performed in whole-mount myenteric plexus preparations. KEY RESULTS: Peripheral sensitivity was increased in animals treated with vincristine and did not subside 2 weeks after treatment finalization. Vincristine treatment inhibited gastrointestinal motility although this was recovered to normal values with time. Damage in the digestive wall after vincristine treatment was greater in the ileum than in the colon. Villi shortening (in ileum) and large inflammatory nodules still remained 2 weeks after treatment finalization. Finally, the proportion of nNOS-immunoreactive neurons was increased with vincristine and continued to be increased 2 weeks after treatment finalization. CONCLUSIONS AND INFERENCES: Vincristine alters gastrointestinal motility, peripheral sensitivity and mucosal architecture. Vincristine-induced neuropathy (somatic and enteric), intestinal mucosa damage and inflammatory infiltrations are relatively long-lasting. PMID- 29971867 TI - Enhancing the Matrix Addressing of Flexible Sensory Arrays by a Highly Nonlinear Threshold Switch. AB - The increasing need for smart systems in healthcare, wearable, and soft robotics is creating demand for low-power sensory circuits that can detect pressure, temperature, strain, and other local variables. Among the most critical requirements, the matrix circuitry to address the individual sensor device must be sensitive, immune to disturbances, and flexible within a high-density sensory array. Here, a strategy is reported to enhance the matrix addressing of a fully integrated flexible sensory array with an improvement of 108 fold in the maximum readout value of impedance by a bidirectional threshold switch. The threshold switch shows high flexibility (bendable to a radius of about 1 mm) and a high nonlinearity of ~1010 by using a nanocontact structure strategy, which is revealed and validated by molecular dynamics simulations and experiments at variable mechanical stress. Such a flexible electronic switch enables a new generation of large-scale flexible and stretchable electronic and optoelectronic systems. PMID- 29971868 TI - The significance of ST-elevation in aVL in anterolateral myocardial infarction: An assessment by cardiac magnetic resonance imaging. AB - BACKGROUND: Anterolateral myocardial infarction (MI) is traditionally defined on the electrocardiogram by ST-elevation (STE) in I, aVL, and the precordial leads. Traditional literature holds STE in lead aVL to be associated with occlusion proximal to the first diagonal branch of the left anterior descending coronary artery. However, concomitant ischemia of the inferior myocardium may theoretically lead to attenuation of STE in aVL. We compared segmental distribution of myocardial area at risk (MaR) in patients with and without STE in aVL. METHODS: We identified patients in the MITOCARE study presenting with a first acute MI and new STE in two contiguous anterior leads from V1 to V6 , with or without aVL STE. Patients underwent cardiac magnetic resonance imaging 3-5 days after acute infarction for quantitative assessment of MaR. RESULTS: A total of 32 patients met inclusion criteria; 13 patients with and 19 without STE in lead aVL. MaR > 20% at the basal anterior segment was seen in 54% of patients with aVL STE, and 11% of those without (p = 0.011). MaR > 20% at the apical inferior segment was seen in 62% and 95% of patients with and without aVL STE, respectively (p = 0.029). The total MaR was not different between groups (44% +/- 10% and 39% +/- 8.3% respectively, p = 0.15). CONCLUSION: Patients with anterior STEMI and concomitant STE in aVL have less MaR in the apical inferior segment and more MaR in the basal anterior segment. PMID- 29971869 TI - Infants' attention bias to faces as an early marker of social development. AB - Infants have a strong tendency to look at faces. We examined individual variations in this attentional bias in 7-month-old infants by using a face distractor competition paradigm and tested in a longitudinal sample whether these variations were associated with outcomes reflecting social behavior at 24 and 48 months of age (i.e., spontaneous helping, emotion understanding, mentalizing, and callous-unemotional traits; N = 100-138). The results showed a robust and distinct attention bias to faces at 7 months, particularly when faces were displaying a fearful expression. This bias declined between 7 and 24 months and there were no significant correlations in attention dwell times between 7 and 24 months of age. Variations in attention to faces at 7 months were not associated with emotion understanding or mentalizing abilities at 48 months of age, but increased attention to faces at 7 months (regardless of facial expression) was related to more frequent helping responses at 24 months and reduced callous unemotional traits at 48 months of age. Thus, while the results fail to associate infants' face bias with later-emerging emotion understanding and mentalizing capacities, they are consistent with a model whereby increased attention to faces in infancy is linked with the development of affective empathy and responsivity to others' needs. PMID- 29971871 TI - Contents: Macromol. Rapid Commun. 1/2016. PMID- 29971872 TI - Strong Support for Macromolecular Rapid Communications. PMID- 29971870 TI - Macromol. Rapid Commun. 1/2016. AB - Back Cover: RAFT polymerization yields reactive block copolymers bearing the pentafluorophenyl ester (PFPA) group, and subsequent Click amidation using 2,2,6,6-tetramethylpiperidine-N-oxyl- (TEMPO-) and imidazolium-functionalized primary amines produces the corresponding functional block copolymers, leading to installation of statistical radical and ionic- sites into the PFPA segment. The monolayered thin film devices fabricated using the obtained block copolymers exhibit repeatable switching (memory) characteristic of electric conductivity (on/off ratio > 103) under a bias voltage. Further details can be found in the article by T. Suga,* K. Aoki, T. Yashiro, and H. Nishide* on page 53. PMID- 29971874 TI - Macromol. Rapid Commun. 21/2015. AB - Back Cover: Tissue scaffolds allowing the behavior of the cells that reside within them to be controlled are of particular interest for tissue engineering. Herein, the preparation of conductive nanofiber-based bone tissue scaffolds are described, made from nonwoven mats of electrospun polycaprolactone with an interpenetrating network of polypyrrole and polystyrenesulfonate. These scaffolds enable the electrical stimulation of human mesenchymal stem cells to enhance their differentiation toward osteogenic outcomes. Further details can be found in the article by J. G. Hardy,* M. K. Villancio-Wolter, R. C. Sukhavasi, D. J. Mouser, D. Aguilar Jr., S. A. Geissler, D. L. Kaplan,* and C. E. Schmidt* on page 1884. PMID- 29971875 TI - Contents: Macromol. Rapid Commun. 21/2015. PMID- 29971877 TI - Advanced Functional Polymers Addressing the Needs of Modern Medicine. PMID- 29971878 TI - Analysis of Molecular Parameters Determining the Antimalarial Activity of Polymer Based Nanomimics. AB - Malaria and other infectious diseases are major global public health problems, which need to be tackled using new technologies to cope with the lack of efficacious vaccines and emerging drug resistance. A recently developed anti infectious concept based on nanomimics tested with Plasmodium falciparum is analyzed for the molecular parameters determining its applicability. Nanomimics nanoscaled polymer-based mimics of host cell membranes-are designed with a reduced number of surface-exposed malaria parasite receptor molecules (heparin), resulting in less potent invasion inhibition as determined in antimalarial assays. In contrast, when shorter receptor molecules are used to form nanomimics, more molecules are needed to obtain nanomimic potency similar to nanomimics with longer receptor molecules. The interaction of heparin on nanomimics with the processed Plasmodium falciparum merozoite surface protein 1-42 (PfMSP142 ) have a high affinity, Kd = 12.1 +/- 1.6 * 10-9 m, as measured by fluorescence cross correlation spectroscopy (FCCS). This detailed characterization of nanomimics and their molecular variants are an important step towards defining and optimizing possible nanomimic therapies for infectious diseases. PMID- 29971879 TI - Technical report: Inter- and intra-rater reliability of regional gastrointestinal transit times measured using the 3D-Transit electromagnet tracking system. AB - BACKGROUND: The 3D-Transit electromagnet tracking system is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit times and motility patterns, based on the anatomical localization of ingestible electromagnetic capsules. Currently, 3D-Transit recordings are manually analyzed to extract GI transit times. As this is a subjective method, there is some inherent variability in the measurements, which may be experience-dependent. We therefore assessed inter- and intra-rater reliability of GI transit times from 3D-Transit recordings. METHODS: Thirty-six 3D-Transit recordings (17 female; median age: 34 years [range: 21-80]) were analyzed twice by 3 raters with varying experience. Each rater manually identified the timestamps when a capsule progressed from antrum to duodenum, and from ileum to right colon. These timestamps, along with the ingestion and expulsion times, were used to determine whole gut (WGTT), gastric emptying (GET), small intestinal (SITT) and colonic (CTT) transit times. Reliability was determined using interclass correlation coefficients (ICCs). KEY RESULTS: For capsule progression timestamps, the most and mid-experienced raters had fair to good inter- and excellent intra-rater reliability (ICCmin-max = 0.61 1.00), whereas the inexperienced rater had poor to fair inter- and poor intra rater reliability (ICCmin-max = 0.28-0.55). GET and SITT reliability between the most and mid-experienced raters was fair (ICCmin-max = 0.61-0.73), while reliability between these raters and the inexperienced rater was poor to fair (ICCmin-max = 0.28-0.55). CTT reliability was excellent between and within all raters (ICCmin-max = 0.92-0.99). CONCLUSIONS & INFERENCES: Inexperienced raters provide the least reliable measurements from 3D-Transit recordings, which confirms requirement for adequate training. Automation may improve the reliability of measurements. PMID- 29971880 TI - Suicidal ideation in patients with coronary heart disease and hypertension: Baseline results from the DEPSCREEN-INFO clinical trial. AB - BACKGROUND: A high proportion of cardiac patients suffers from depression, which is an antecedent for suicidal ideation. This study identifies clinical vulnerabilities for suicidal ideation in cardiac patients. METHODS: The primary outcome of the study was severity of suicidal ideation as measured with the Patient Health Questionnaire (PHQ-9) item No. 9. Covariates were demographics, cardiac characteristics (i.e., Canadian Cardiovascular Society angina rating of chest pain and New York Heart Association rating of shortness of breath), depression (PHQ-8,i.e., PHQ-9 minus item No. 9), anxiety (Generalized Anxiety Disorder-7, GAD-7), somatic symptoms (PHQ-15), illness perception (Brief-Illness Perception Questionnaire), and health-related quality of life (EuroQol-5D, EQ 5D). RESULTS: Data from 1,976 patients were analysed. At least 14% (95% CI [12%, 16%]) of patients indicated suicidal ideations within the last 2 weeks. Bivariate analyses yielded associations between suicidal ideation and higher levels of depression severity, anxiety severity, somatic symptom burden, chest pain, shortness of breath, negative illness perceptions, reduced health-related quality of life, and a higher probability of living alone (all p < 0.001). A multivariable ordinal regression revealed depression severity and anxiety severity to show the highest associations with suicidal ideation (ORPHQ-8 = 1.22, p < 0.001; ORGAD-7 = 1.09, p < 0.001). Having a defibrillator implant was associated with a lower probability of suicidal ideation (OR = 0.27, p = 0.017). CONCLUSIONS: This study identified several clinical vulnerabilities of suicidal ideation. The results stress the importance of screening for suicidal ideation in clinical practice. PMID- 29971881 TI - Cheeky stowaway hitches ride aboard travelling toddler. PMID- 29971882 TI - Opportunistic Immunisation in the Outpatients Department: A Pilot Feasibility Study. PMID- 29971883 TI - Infants less than 2 months old with urinary tract infections. PMID- 29971884 TI - Look at the child, not just the tests. PMID- 29971885 TI - Humiliation by Medical Teachers. PMID- 29971886 TI - Lung function after ventilation of extremely preterm infants. PMID- 29971887 TI - Reply to Humiliation by Medical Teachers. PMID- 29971888 TI - Fever after meningococcal B vaccine. PMID- 29971889 TI - Use of macrolide and beta-lactam combination therapy in paediatric community acquired pneumonia. PMID- 29971890 TI - Midline perineal lesion in a newborn girl. PMID- 29971891 TI - Cheeky stowaway hitches ride aboard travelling toddler. PMID- 29971892 TI - Midline perineal lesion in a newborn girl. PMID- 29971893 TI - Cost-effectiveness analysis of real-time continuous monitoring glucose compared to self-monitoring of blood glucose for diabetes mellitus in Spain. AB - RATIONALE, AIMS AND OBJECTIVES: Self-monitoring of blood glucose (SMBG) is recommended to monitor glycaemic levels. The recent development of real-time continuous glucose monitoring (RT-CGM) enables continuous display of glucose concentration alerting patients in the event of relevant glucose fluctuations, potentially avoiding hypoglycaemic events and reducing long-term complications related to glycosylated haemoglobin (HbA1c) levels. This paper aims to evaluate the cost-effectiveness of RT-CGM compared to SMBG in patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) which should support decision-making on public funding of RT-CGM in Spain. METHODS: We performed a systematic review and meta-analyses on the effectiveness of RT-CGM in the reduction of HbA1c levels and severe hypoglycaemic events. A cost-effectiveness analysis was conducted using a Markov model which simulates the costs and health outcomes of individuals treated under these alternatives for a lifetime horizon from the perspective of the Spanish Health Service. The effectiveness measure was quality-adjusted life years (QALYs). We ran extensive sensitivity analyses, including a probabilistic sensitivity analysis. RESULTS: Real-time continuous glucose monitoring provides a significant reduction of HbA1c for T1DM (13 studies; weighted mean difference (WMD) = -0.23%, 95% CI: -0.35, -0.11) and T2DM (5 studies; WMD = -0.48%, 95% CI: -0.79, -0.17). There were no statistically significant differences in the rate of severe hypoglycaemic events in T1DM (9 studies; OR = 1.16, 95% CI: 0.78, 1.72) or T2DM (no severe hypoglycaemic events were reported in any study). In the base case analysis, RT-CGM led to higher QALYs and health care costs with an estimated incremental cost-effectiveness ratio of ?2 554 723 and ?180 553 per QALY for T1DM and T2DM patients respectively. Sensitivity analyses revealed that the study results were robust. CONCLUSIONS: Real-time continuous glucose monitoring is not a cost-effective technology when compared to SMBG in Spain. PMID- 29971895 TI - Disentangling the complexity of permafrost soil by using high resolution profiling of microbial community composition, key functions and respiration rates. AB - Thawing permafrost can stimulate microbial activity, leading to faster decomposition of formerly preserved organic matter and CO2 release. Detailed knowledge about the vertical distribution of the responsible microbial community that is changing with increasing soil depth is limited. In this study, we determined the microbial community composition from cores sampled in a high Arctic heath at Svalbard, Norway; spanning from the active layer (AL) into the permafrost layer (PL). A special aim has been on identifying a layer of recently thawed soil, the transition zone (TZ), which might provide new insights into the fate of thawing permafrost. A unique sampling strategy allowed us to observe a diverse and gradually shifting microbial community in the AL, a Bacteroidetes dominated community in the TZ and throughout the PL, a community strongly dominated by a single Actinobacteria family (Intrasporangiaceae). The contrasting abundances of these two taxa caused a community difference of about 60%, just within 3 cm from TZ to PL. We incubated subsamples at about 5 degrees C and measured highest CO2 production rates under aerobic incubations, yet contrasting for five different layers and correlating to the microbial community composition. This high resolution strategy provides new insights on how microbial communities are structured in permafrost and a better understanding of how they respond to thaw. PMID- 29971894 TI - Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia. AB - OBJECTIVE: We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large-scale data on Japanese patients with essential thrombocythemia (ET). METHOD: We conducted a study in 352 patients with ET to validate previous prognostic models and search for new prognostic factors. RESULTS: The International Prognostic Score for essential thrombocythemia (IPSET), the conventional risk classification and the International Prognostic Score for thrombosis in essential thrombocythemia (IPSET T) were confirmed to be reproducible in Japanese patients. However, no significant difference was observed between the low-risk and intermediate-risk categories according to the revised IPSET-T, which does not allow direct comparison of the four risk groups. We reevaluated the risk using a modified revised IPSET-T, which was derived from the revised IPSET-T by scoring the factors as follows: one point for age > 60 years, two points for past history of thrombosis, two points for JAK2 gene mutation-positive; total points of 0 = very low risk, 1 = low risk, 2 = intermediate risk, 3 and above = high risk, with significantly different thrombosis-free survival. CONCLUSION: The modified revised IPSET-T has been useful for 4-group stratification to predict a population that requires therapeutic intervention, irrespective of the treatment regimens. PMID- 29971896 TI - Ambiguity preferences for health. AB - In most medical decisions, probabilities are ambiguous and not objectively known. Empirical evidence suggests that people's preferences are affected by ambiguity. Health economic analyses generally ignore ambiguity preferences and assume that they are the same as preferences under risk. We show how health preferences can be measured under ambiguity, and we compare them with health preferences under risk. We assume a general ambiguity model that includes many of the ambiguity models that have been proposed in the literature. For health gains, ambiguity preferences and risk preferences were indeed the same. For health losses, they differed with subjects being more pessimistic in decision under ambiguity. Utility and loss aversion were the same for risk and ambiguity. Our results imply that reducing the clinical ambiguity of health losses has more impact than reducing the ambiguity of health gains, that utilities elicited with known probabilities may not carry over to an ambiguous setting, and that ambiguity aversion may impact value of information analyses if losses are involved. These findings are highly relevant for medical decision making, because most medical interventions involve losses. PMID- 29971897 TI - Envisioning robotic surgery: Surgeons' needs and views on interacting with future technologies and interfaces. AB - BACKGROUND: The development of technology in robotic surgery is typically presented from a technical perspective. This study considers the user perspective as an input to the development of technology by exploring potential solutions within and beyond the field of robotic surgery. METHODS: Advanced technological solution concepts were selected based on a technology review and an ethnographic study. Using a future workshop method, these were rated and discussed by a group of surgeons from three perspectives: enhancing operation outcome, user experience and learning in the operating theatre. RESULTS: Diverse technologies were considered to offer potential for supporting the surgeons' work. User experience and learning could be improved especially via solutions novel to robotic surgery. Robotic surgery technologies currently under development were mainly considered to support a good operation outcome. Suitability for practical work was elaborated upon, and related concerns were identified. CONCLUSIONS: The results can support development of robotic surgery to enhance surgeons' work. PMID- 29971898 TI - Comparison of Lowenstein-Jensen and BACTEC MGIT 960 culture for Mycobacterium tuberculosis in people living with HIV. AB - OBJECTIVES: The aim of the study was to clarify how HIV infection affects tuberculosis liquid and solid culture results in a resource-limited setting. METHODS: We used baseline data from the Study on Outcomes Related to Tuberculosis and HIV Drug Concentrations in Uganda (SOUTH), which included 268 HIV/tuberculosis (TB)-coinfected individuals. Culture results from Lowenstein Jensen (LJ) solid culture and mycobacteria growth indicator tube (MGIT) liquid culture systems and culture-based correlates for bacillary density from the sputum of HIV/TB-coinfected individuals at baseline were analysed. RESULTS: Of 268 participants, 243 had a CD4 cell count available and were included in this analysis; 72.2% of cultures showed growth on solid culture and 82.2% in liquid culture systems (P < 0.015). A higher CD4 cell count was predictive of LJ positivity [adjusted odds ratio (OR) 1.14; 95% confidence interval (CI) 1.03-1.25 per 50 cells/MUL increase; P = 0.008]. The same, but insignificant trend was observed for MGIT positivity (adjusted OR 1.09; 95% CI 0.99-1.211 per 50 cells/MUL increase; P = 0.094). A higher CD4 cell count was associated with a higher LJ colony-forming unit grade (adjusted OR 1.14; 95% CI 1.05-1.25 per 50 cells/MUL increase; P = 0.011) and a shorter time to MGIT positivity [adjusted hazard ratio (HR) 1.08; 95% CI 1.04-1.12 per 50 cells/MUL increase; P < 0.001]. CONCLUSIONS: In a resource-limited setting, the MGIT liquid culture system outperformed LJ solid culture in terms of culture yield and dependence on CD4 cell counts in HIV/TB-coinfected individuals. We therefore suggest considering an adaptation of diagnostic algorithms: when resources allow only one culture method to be performed, we recommend that MGIT liquid culture should be used exclusively in HIV-positive individuals as a first-line culture method, to reduce costs and make TB culture results accessible to more patients in resource-limited settings. PMID- 29971900 TI - Wolbachia modifies thermal preference in Drosophila melanogaster. AB - Environmental variation can have profound and direct effects on fitness, fecundity, and host-symbiont interactions. Replication rates of microbes within arthropod hosts, for example, are correlated with incubation temperature but less is known about the influence of host-symbiont dynamics on environmental preference. Hence, we conducted thermal preference (Tp ) assays and tested if infection status and genetic variation in endosymbiont bacterium Wolbachia affected temperature choice of Drosophila melanogaster. We demonstrate that isogenic flies infected with Wolbachia preferred lower temperatures compared with uninfected Drosophila. Moreover, Tp varied with respect to three investigated Wolbachia variants (wMel, wMelCS, and wMelPop). While uninfected individuals preferred 24.4 degrees C, we found significant shifts of -1.2 degrees C in wMel- and -4 degrees C in flies infected either with wMelCS or wMelPop. We, therefore, postulate that Wolbachia-associated Tp variation within a host species might represent a behavioural accommodation to host-symbiont interactions and trigger behavioural self-medication and bacterial titre regulation by the host. PMID- 29971899 TI - Changes in obese metabolic phenotypes over time and risk of incident chronic kidney disease. AB - AIM: To examine the association between metabolically healthy obese (MHO) phenotype and incident chronic kidney disease (CKD) and study whether changes in metabolic phenotypes over time could affect CKD risk. METHODS: A total of 8589 subjects from the Korean Genome and Epidemiology Study were categorized into four groups based on the presence of obesity and metabolic abnormalities (MA). The primary endpoint was an onset of incident CKD defined as an estimated glomerular filtration rate of <= 60 mL/min/1.73 m2 . Multivariable Cox analysis and time varying Cox analysis were performed to delineate the relationship between obese metabolic phenotypes and incident CKD after adjustment for sociodemographic factors and clinical and laboratory parameters. RESULTS: During a mean follow-up duration of 9.3 years, CKD occurred in 782 (9.1%) participants. In the multivariable Cox model, the hazard ratio (HR) for incident CKD in the MHO, metabolically abnormal non-obese (MANO), and metabolically abnormal obese (MAO) groups was 1.42 (P = 0.002), 1.45 (P < 0.001), and 1.77 (P < 0.001), respectively, compared with the metabolically healthy non-obese (MHNO) group. Time-varying analysis with these four phenotypes as time-varying exposures showed the same results. Furthermore, subjects with persistent MHO through follow-up were at a 2.0-fold increased risk of CKD (P < 0.001). 41.0% of subjects experienced phenotype changes during follow-up. Over the long term, the MHO group had a higher proportion of transition to the MA phenotype and unfavourable metabolic profiles than the MHNO group. Among MHO subjects, those who transitioned to MAO were at a 4.1-fold increased risk of incident CKD than those who regressed to MHNO. In addition, transition to MHO from other groups carried a higher risk of CKD than persistent MHNO. CONCLUSION: MHO subjects are at increased risk for incident CKD. PMID- 29971901 TI - Transient bottom water oxygenation creates a niche for cable bacteria in long term anoxic sediments of the Eastern Gotland Basin. AB - Cable bacteria have been reported in sediments from marine and freshwater locations, but the environmental factors that regulate their growth in natural settings are not well understood. Most prominently, the physiological limit of cable bacteria in terms of oxygen availability remains poorly constrained. In this study, we investigated the presence, activity and diversity of cable bacteria in relation to a natural gradient in bottom water oxygenation in a depth transect of the Eastern Gotland Basin (Baltic Sea). Cable bacteria were identified by FISH at the oxic and transiently oxic sites, but not at the permanently anoxic site. Three species of the candidate genus Electrothrix, i.e. marina, aarhusiensis and communis were found coexisting within one site. The highest filament density (33 m cm-2 ) was associated with a 6.3 mm wide zone depleted in both oxygen and free sulphide, and the presence of an electric field resulting from the electrogenic sulphur oxidizing metabolism of cable bacteria. However, the measured filament densities and metabolic activities remained low overall, suggesting a limited impact of cable bacteria at the basin level. The observed bottom water oxygen levels (< 5 MUM) are the lowest so far reported for cable bacteria, thus expanding their known environmental distribution. PMID- 29971902 TI - Association between computed tomographic characteristics and fractures following stereotactic radiosurgery in dogs with appendicular osteosarcoma. PMID- 29971903 TI - The evolutionary origins of pesticide resistance. AB - Durable crop protection is an essential component of current and future food security. However, the effectiveness of pesticides is threatened by the evolution of resistant pathogens, weeds and insect pests. Pesticides are mostly novel synthetic compounds, and yet target species are often able to evolve resistance soon after a new compound is introduced. Therefore, pesticide resistance provides an interesting case of rapid evolution under strong selective pressures, which can be used to address fundamental questions concerning the evolutionary origins of adaptations to novel conditions. We ask: (i) whether this adaptive potential originates mainly from de novo mutations or from standing variation; (ii) which pre-existing traits could form the basis of resistance adaptations; and (iii) whether recurrence of resistance mechanisms among species results from interbreeding and horizontal gene transfer or from independent parallel evolution. We compare and contrast the three major pesticide groups: insecticides, herbicides and fungicides. Whilst resistance to these three agrochemical classes is to some extent united by the common evolutionary forces at play, there are also important differences. Fungicide resistance appears to evolve, in most cases, by de novo point mutations in the target-site encoding genes; herbicide resistance often evolves through selection of polygenic metabolic resistance from standing variation; and insecticide resistance evolves through a combination of standing variation and de novo mutations in the target site or major metabolic resistance genes. This has practical implications for resistance risk assessment and management, and lessons learnt from pesticide resistance should be applied in the deployment of novel, non-chemical pest control methods. PMID- 29971905 TI - The 87th annual meeting of the American Association of Physical Anthropologists in Austin, Texas. PMID- 29971904 TI - Reproductive tolerance in male primates: Old paradigms and new evidence. AB - Within social groups of primates, males commonly compete over reproduction, but they may also rely on cooperation with other males. Theory suggests that it may be adaptive for male primates to tolerate some reproduction by other males if reproductive tolerance fosters cooperation, particularly that dominant males yield so-called reproductive concessions to subordinates to entice their cooperation. We review four recent studies that claimed to have found evidence for reproductive concessions or similar forms of reproductive tolerance. However, upon critical reevaluation of their results, no study provides conclusive support for reproductive concessions as predicted by theoretical models. Yet two studies demonstrated a form of reproductive tolerance that cannot be explained by any of the existing models, and that seems to have evolved only in multi-male, multi female societies with diverse strategic options for males. Our article provides guidance how to study this form of reproductive tolerance in the absence of a unifying model. PMID- 29971906 TI - Blaise Pascal Medals: A. Corma and P. Samori / Kavli Prize: E. Charpentier, J. Doudna, and V. Siksnys. PMID- 29971907 TI - The accessibility and usability of an Australian web-based self-management programme for people with lower health literacy and joint pain in the UK: A qualitative interview study. PMID- 29971908 TI - Hybrid PbS Quantum-Dot-in-Perovskite for High-Efficiency Perovskite Solar Cell. AB - In this study, a facile and effective approach to synthesize high-quality perovskite-quantum dots (QDs) hybrid film is demonstrated, which dramatically improves the photovoltaic performance of a perovskite solar cell (PSC). Adding PbS QDs into CH3 NH3 PbI3 (MAPbI3 ) precursor to form a QD-in-perovskite structure is found to be beneficial for the crystallization of perovskite, revealed by enlarged grain size, reduced fragmentized grains, enhanced characteristic peak intensity, and large percentage of (220) plane in X-ray diffraction patterns. The hybrid film also shows higher carrier mobility, as evidenced by Hall Effect measurement. By taking all these advantages, the PSC based on MAPbI3 -PbS hybrid film leads to an improvement in power conversion efficiency by 14% compared to that based on pure perovskite, primarily ascribed to higher current density and fill factor (FF). Ultimately, an efficiency reaching up to 18.6% and a FF of over ~0.77 are achieved based on the PSC with hybrid film. Such a simple hybridizing technique opens up a promising method to improve the performance of PSCs, and has strong potential to be applied to prepare other hybrid composite materials. PMID- 29971910 TI - Ag+ -Gated Surface Chemistry of Gold Nanoparticles and Colorimetric Detection of Acetylcholinesterase. AB - Chemical regulation of enzyme-mimic activity of nanomaterials is challenging because it requires a precise understanding of the surface chemistry and mechanism, and rationally designed applications. Herein, Ag+ -gated peroxidase activity is demonstrated by successfully modulating surface chemistry of cetyltrimethylammonium bromide-capped gold nanoparticles (CTAB-AuNPs). A surface blocking effect of long-chain molecules on surfaces of AuNPs that inhibit peroxidase activity of AuNPs is found. Ag+ ions can selectively bind on the surfaces of AuNPs and competitively destroy CTAB membrane forming Ag+ @CTAB-AuNPs complexes to result in enhanced peroxidase activity. Ag+ @CTAB-AuNPs show the highest peroxidase activity compared to similar-sized citrate-capped and ascorbic acid-capped AuNPs. Ag+ @CTAB-AuNPs can potentially develop into analyte responsive systems and exhibit advantages in the optical sensing field. For example, the Ag+ @CTAB-AuNPs system shows an enhanced sensitivity and selectivity for acetylcholinesterase activity sensing compared to other methods. PMID- 29971909 TI - Captopril mitigates splenomegaly and myelofibrosis in the Gata1low murine model of myelofibrosis. AB - Allogeneic stem cell transplantation is currently the only curative therapy for primary myelofibrosis (MF), while the JAK2 inhibitor, ruxolitinib. Has been approved only for palliation. Other therapies are desperately needed to reverse life-threatening MF. However, the cell(s) and cytokine(s) that promote MF remain unclear. Several reports have demonstrated that captopril, an inhibitor of angiotensin-converting enzyme that blocks the production of angiotensin II (Ang II), mitigates fibrosis in heart, lung, skin and kidney. Here, we show that captopril can mitigate the development of MF in the Gata1low mouse model of primary MF. Gata1low mice were treated with 79 mg/kg/d captopril in the drinking water from 10 to 12 months of age. At 13 months of age, bone marrows were examined for fibrosis, megakaryocytosis and collagen expression; spleens were examined for megakaryocytosis, splenomegaly and collagen expression. Treatment of Gata1low mice with captopril in the drinking water was associated with normalization of the bone marrow cellularity; reduced reticulin fibres, splenomegaly and megakaryocytosis; and decreased collagen expression. Our findings suggest that treating with the ACE inhibitors captopril has a significant benefit in overcoming pathological changes associated with MF. PMID- 29971911 TI - Long non-coding RNA FTH1P3 activates paclitaxel resistance in breast cancer through miR-206/ABCB1. AB - Emerging evidence has indicated the important function of long non-coding RNAs (lncRNAs) in tumour chemotherapy resistance. However, the underlying mechanism is still ambiguous. In this study, we investigate the physiopathologic role of lncRNA ferritin heavy chain 1 pseudogene 3 (FTH1P3) on the paclitaxel (PTX) resistance in breast cancer. Results showed that lncRNA FTH1P3 was up-regulated in paclitaxel-resistant breast cancer tissue and cells (MCF-7/PTX and MDA-MB 231/PTX cells) compared with paclitaxel-sensitive tissue and parental cell lines (MCF-7, MDA-MB-231). Gain- and loss-of-function experiments revealed that FTH1P3 silencing decreased the 50% inhibitory concentration (IC50) value of paclitaxel and induced cell cycle arrest at G2/M phase, while FTH1P3-enhanced expression exerted the opposite effects. In vivo, xenograft mice assay showed that FTH1P3 silencing suppressed the tumour growth of paclitaxel-resistant breast cancer cells and ABCB1 protein expression. Bioinformatics tools and luciferase reporter assay validated that FTH1P3 promoted ABCB1 protein expression through targeting miR-206, acting as a miRNA "sponge." In summary, our results reveal the potential regulatory mechanism of FTH1P3 on breast cancer paclitaxel resistance through miR 206/ABCB1, providing a novel insight for the breast cancer chemoresistance. PMID- 29971912 TI - Controlled, Low-Temperature Nanogap Propagation in Graphene Using Femtosecond Laser Patterning. AB - Graphene nanogap systems are promising research tools for molecular electronics, memories, and nanodevices. Here, a way to control the propagation of nanogaps in monolayer graphene during electroburning is demonstrated. A tightly focused femtosecond laser beam is used to induce defects in graphene according to selected patterns. It is shown that, contrary to the pristine graphene devices where nanogap position and shape are uncontrolled, the nanogaps in prepatterned devices propagate along the defect line created by the femtosecond laser. Using passive voltage contrast combined with atomic force microscopy, the reproducibility of the process with a 92% success rate over 26 devices is confirmed. Coupling in situ infrared thermography and finite element analysis yields a real-time estimation of the device temperature during electrical loading. The controlled nanogap formation occurs well below 50 degrees C when the defect density is high enough. In the perspective of graphene-based circuit fabrication, the availability of a cold electroburning process is critical to preserve the full circuit from thermal damage. PMID- 29971913 TI - Strongly Coupled g-C3 N4 Nanosheets-Co3 O4 Quantum Dots as 2D/0D Heterostructure Composite for Peroxymonosulfate Activation. AB - The development of effective approaches for the preparation of 0D quantum dots (QDs)/2D nanosheets (NSs) heterostructures, which have been proven to be favorable for heterogeneous catalysis, is highly desirable but remains a great challenge. Herein, 0D metal oxide nanocrystals-2D ultrathin g-C3 N4 nanosheets (Co3 O4 /CNNS) heterostructures are synthesized via a facile chemical reaction, followed by annealing in air. Ultrafine Co3 O4 QDs (~2.2-3.2 nm) are uniformly and tightly attached on the surface of g-C3 N4 nanosheets. Detailed characterization reveals that the specially designed unique 0D/2D structure is critical to the high photocatalytic performance for the degradation of tetracycline (TC) via peroxymonosulfate (PMS) activation. The optimal catalyst, namely, Co3 O4 /CNNS-1100, exhibits excellent performance and ~98.7% TC can be degraded under visible light irradiation. Moreover, TC degradation is almost completely insusceptible to several real water samples. Meanwhile, other dye pollutants can also be efficiently degraded by the Co3 O4 /CNNS-1100/PMS/vis system. The quenching tests display that that the h+ , ?OH, O2?- , and SO4?- are responsible for TC removal. The improved photocatalytic performance can be attributed to the synergistic effect of the photocatalytic- and chemical processes in the PMS activation. This work gives an insight into the development of multifunctional 0D/2D nanocomposites for further potential applications which are not limited to environmental purification. PMID- 29971914 TI - Risk of amputations associated with SGLT2 inhibitors compared to DPP-4 inhibitors: A propensity-matched cohort study. AB - AIM: To determine the risk of amputations associated with sodium-glucose co transporter-2 inhibitors (SGLT2i) relative to dipeptidyl peptidase-4 inhibitors (DPP4i). MATERIALS AND METHODS: We conducted an active comparator, new user cohort study using data from the Truven Health MarketScan (2009-2015) databases. Patients aged >=18 years newly initiating SGLT2i or DPP4i between April 1, 2013 and March 31, 2015 were included. Patients were matched 1:1 on high dimensional propensity scores and followed until the earliest of any amputation, treatment discontinuation, disenrollment or end of study period (December 31, 2015). Cox proportional hazards models were used to estimate hazard ratios (HR) and robust 95% confidence intervals (CI) for amputation risk. RESULTS: There were 30 216 comparable patients in each arm after matching. Over a median follow-up of 0.6 years, there were 60 amputations (SGLT2i: 36; DPP4i: 24), most at the level of partial foot (75%) and associated with diabetes-related vascular disease (66.7%). The incidence of amputations was higher among SGLT2i patients (1.62 vs. 1.15 per 1000 person-years) with a HR of 1.38 (CI: 0.83-2.31). In subgroup analyses, risk differed by type of SGLT2i: canagliflozin, HR 1.15 (CI: 0.63-2.09); dapagliflozin or empagliflozin, HR 2.25 (CI: 0.78-6.47). CONCLUSION: All SGLT2i had an elevated, though not statistically significant, risk for amputations. PMID- 29971915 TI - Long non-coding RNA AFAP1-AS1/miR-320a/RBPJ axis regulates laryngeal carcinoma cell stemness and chemoresistance. AB - AFAP1-AS1 is a long non-coding RNA that is associated with tumorigenesis and poor prognosis in a variety of cancers. We have been suggested that AFAP1-AS1 increases tumorigenesis in laryngeal carcinoma specifically by enhancing stemness and chemoresistance. We assessed AFAP1-AS1 expression in human laryngeal specimens, paired adjacent normal tissues and human HEp-2 cells. Indeed, we found not only that AFAP1-AS1 was up-regulated in laryngeal carcinoma specimens and cells, but also that stemness-associated genes were overexpressed. Silencing of AFAP1-AS1 promoted HEp-2 cell chemoresistance under cisplatin treatment. Expression of AFAP1-AS1 was increased in drug-resistant Hep-2 cells. We then probed the mechanism of AFAP1-AS1 activity and determined that miR-320a was a potential molecular target of AFAP1-AS1. Luciferase reporter and qRT-PCR assays of AFAP1-AS1 and miR-320a levels in human specimens and cell cultures indicated that AFAP1-AS1 negatively regulates miR-320a. To discover the molecular mechanism of miR-320a, we again used the DIANA Tools algorithm to predict its genetic target, RBPJ. After cloning the 3'-untranslated regions (3'-UTR) of RBPJ into a luciferase reporter, we determined that miR-320a did in fact reduce RBPJ mRNA and protein levels. Ultimately, we determined that AFAP1-AS1 increases RBPJ expression by negatively regulating miR-320a and RBPJ overexpression rescues stemness and chemoresistance inhibited by AFAP1-AS1 silencing. Taken together, these results suggest that AFAP1-AS1 can serve as a prognostic biomarker in laryngeal carcinoma and that miR-320a has the potential to improve standard therapeutic approaches to the disease, especially for cases in which cancer cell stemness and drug resistance present significant barriers to effective treatment. PMID- 29971916 TI - Highly Stable Battery Pack via Insulated, Reinforced, Buckling-Enabled Interconnect Array. AB - This work describes a flexible and stretchable battery pack configuration that exhibits highly stable performance under large deformation up to 100% biaxial stretching. Using stress-enduring printable inks and serpentine interconnects, the new screen-printing route offers an attractive solution for converting rigid battery units into a flexible, stretchable energy storage device. Coin-cell lithium ion batteries are thus assembled onto the island regions of a screen printed, buckling-enabled, polymer-reinforced interconnect "island-bridge" array. Most of the strain on the new energy-storage device is thus accommodated by the stress-enduring serpentine structures, and the array is further reinforced by mechanically strong "backbone" layers. Battery pack arrays are assembled and tested under different deformation levels, demonstrating a highly stable performance (<2.5% change) under all test conditions. A light emitting diode band powered by the battery pack is tested on-body, showing uninterrupted illumination regardless of any degrees of deformation. Moreover, battery-powered devices that are ultrastable under large deformation can be easily fabricated by incorporating different electronics parts such as sensors or integrated circuits on the same platform. Such ability to apply traditionally rigid, bulky lithium ion batteries onto flexible and stretchable printed surfaces holds considerable promise for diverse wearable applications. PMID- 29971917 TI - Leukocytes as a reservoir of circulating oncogenic DNA and regulatory targets of tumor-derived extracellular vesicles. AB - : Essentials Tumor-bearing mice were employed to follow oncogenic HRAS sequences in plasma, and blood cells. Cancer DNA accumulated in leukocytes above levels detected in exosomes, platelets and plasma. Extracellular vesicles and nucleosomes are required for uptake of tumor DNA by leukocytes. Uptake of tumor derived extracellular vesicles by leukocytes triggers coagulant phenotype. SUMMARY: Background Tumor-derived extracellular vesicles (EVs) and free nucleosomes (NSs) carry into the circulation a wealth of cancer-specific, bioactive and poorly understood molecular cargoes, including genomic DNA (gDNA). Objective Here we investigated the distribution of extracellular oncogenic gDNA sequences (HRAS and HER2) in the circulation of tumor-bearing mice. Methods and Results Surprisingly, circulating leukocytes (WBCs), especially neutrophils, contained the highest levels of mutant gDNA, which exceeded the amount of this material recovered from soluble fractions of plasma, circulating EVs, platelets, red blood cells (RBCs) and peripheral organs, as quantified by digital droplet PCR (ddPCR). Tumor excision resulted in disappearance of the WBC-associated gDNA signal within 2-9 days, which is in line with the expected half-life of these cells. EVs and nucleosomes were essential for the uptake of tumor-derived extracellular DNA by neutrophil-like cells and impacted their phenotype. Indeed, the exposure of granulocytic HL-60 cells to EVs from HRAS-driven cancer cells resulted in a selective increase in tissue factor (TF) procoagulant activity and interleukin 8 (IL-8) production. The levels of circulating thrombin-antithrombin complexes (TAT) were markedly elevated in mice harboring HRAS-driven xenografts. Conclusions Myeloid cells may represent a hitherto unrecognized reservoir of cancer-derived, EV/NS-associated oncogenic gDNA in the circulation, and a possible novel platform for liquid biopsy in cancer. In addition, uptake of this material alters the phenotype of myeloid cells, induces procoagulant and proinflammatory activity and may contribute to systemic effects associated with cancer. PMID- 29971918 TI - A feasibility study of intrafractional tumor motion estimation based on 4D-CBCT using diaphragm as surrogate. AB - PURPOSE: To investigate the intrafractional stability of the motion relationship between the diaphragm and tumor, as well as the feasibility of using diaphragm motion to estimate lung tumor motion. METHODS: Eighty-five paired (pre and posttreatment) daily 4D-CBCT images were obtained from 20 lung cancer patients who underwent SBRT. Bony registration was performed between the pre- and post CBCT images to exclude patient body movement. The end-exhalation phase image of the pre-CBCT image was selected as the reference image. Tumor positions were obtained for each phase image using contour-based translational alignments. Diaphragm positions were obtained by translational alignment of its apex position. A linear intrafraction model was constructed using regression analysis performed between the diaphragm and tumor positions manifested on the pretreatment 4D-CBCT images. By applying this model to posttreatment 4D-CBCT images, the tumor positions were estimated from posttreatment 4D-CBCT diaphragm positions and compared with measured values. A receiver operating characteristic (ROC) test was performed to determine a suitable indicator for predicting the estimate accuracy of the linear model. RESULTS: Using the linear model, per-phase position, mean position, and excursion estimation errors were 1.12 +/- 0.99 mm, 0.97 +/- 0.88 mm, and 0.79 +/- 0.67 mm, respectively. Intrafractional per-phase tumor position estimation error, mean position error, and excursion error were within 3 mm 95%, 96%, and 99% of the time, respectively. The residual sum of squares (RSS) determined from pretreatment images achieved the largest prediction power for the tumor position estimation error (discrepancy < 3 mm) with an Area Under ROC Curve (AUC) of 0.92 (P < 0.05). CONCLUSION: Utilizing the relationship between diaphragm and tumor positions on the pretreatment 4D-CBCT image, intrafractional tumor positions were estimated from intrafractional diaphragm positions. The estimation accuracy can be predicted using the RSS obtained from the pretreatment 4D-CBCT image. PMID- 29971919 TI - Reduction of DNA Folding by Ionic Liquids and Its Effects on the Analysis of DNA Protein Interaction Using Solid-State Nanopore. AB - DNA folding is not desirable for solid-state nanopore techniques when analyzing the interaction of a biomolecule with its specific binding sites on DNA since the signal derived from the binding site could be buried by a large signal from the folding of DNA nearby. To resolve the problems associated with DNA folding, ionic liquids (ILs), which are known to interact with DNA through charge-charge and hydrophobic interactions are employed. 1-n-butyl-3-methylimidazolium chloride (C4 mim) is found to be the most effective in lowering the incident of DNA folding during its translocation through solid-state nanopores (4-5 nm diameter). The rate of folding signals from the translocation of DNA-C4 mim is decreased by half in comparison to that from the control bare DNA. The conformational changes of DNA upon complexation with C4 mim are further examined using atomic force microscopy, showing that the entanglement of DNA which is common in bare DNA is not observed when treated with C4 mim. The stretching effect of C4 mim on DNA strands improves the detection accuracy of nanopore for identifying the location of zinc finger protein bound to its specific binding site in DNA by lowering the incident of DNA folding. PMID- 29971920 TI - Wood Derived Composites for High Sensitivity and Wide Linear-Range Pressure Sensing. AB - Natural wood possesses a unique 3D microstructure containing hierarchical interconnected channels along its growth direction. This study reports a facile processing strategy to utilize such structure to fabricate carbon/silicone composite based flexible pressure sensors. The unique contribution of the multichannel structure on the sensor performance is analyzed by comparing the pressure response of the vertically cut and horizontally cut composite structures. The results show that the horizontally cut composite based sensors exhibit much higher sensitivity (10.74 kPa-1 ) and wider linear region (100 kPa, R2 = 99%), due to their rough surface and largely deformable microstructure. Besides, the sensors also show little hysteresis and good cycle stability. The overall outstanding sensing properties of the sensors allow for accurate continuous measurement of human pulse and respiration, benefiting the real-time health signal monitoring and disease diagnoses. PMID- 29971921 TI - Contrasting distributions of bacteriophages and eukaryotic viruses from contaminated coastal sediments. AB - Viruses are ubiquitous, abundant and play an important role in all ecosystems. Here, we advance understanding of coastal sediment viruses by exploring links in the composition and abundance of sediment viromes to environmental stressors and sediment bacterial communities. We collected sediment from contaminated and reference sites in Sydney Harbour and used metagenomics to analyse viral community composition. The proportion of phages at contaminated sites was significantly greater than phages at reference sites, whereas eukaryotic viruses were relatively more abundant at reference sites. We observed shifts in viral and bacterial composition between contaminated and reference sites of a similar magnitude. Models based on sediment characteristics revealed that total organic carbon in the sediments explained most of the environmental stress-related variation in the viral dataset. Our results suggest that the presence of anthropogenic contaminants in coastal sediments could be influencing viral community composition with potential consequences for associated hosts and the environment. PMID- 29971922 TI - Similar long-term efficacy of dual therapy containing raltegravir and a boosted protease inhibitor versus standard triple therapies in pretreated HIV-1-infected patients in a retrospective, real-life cohort of 14 years. AB - OBJECTIVES: Raltegravir is used in many antiretroviral combinations, but its use in treatment-experienced patients without knowledge of baseline resistance is discussed controversially as a number of comparative studies have shown a higher rate of virological failure. However, it has been used frequently for the management of treatment failure, as it was the first integrase inhibitor to become available, and thus offered new options for patients with multiple resistance. The strategic use of raltegravir in this setting is examined in this study. METHODS: In order to examine the efficacy of raltegravir in second and later lines of antiretroviral combinations, data for 740 patients from three clinical cohorts were analysed with a focus on the combinations that were used. These were stratified into the combination of two nonnucleoside reverse transcriptase inhibitors and raltegravir (2NRTIs + RAL), the combination of a boosted protease inhibitor and raltegravir (bPI + RAL), and other raltegravir containing combinations. RESULTS: The overall rate of virological suppression to < 50 HIV-1 RNA copies/mL was 69.5%. Although the baseline rate of virological suppression was higher for 2NRTIs + RAL than for the other strata, the outcomes were similar for all three groups at weeks 24, 48, 72 and 96. CONCLUSIONS: These data indicate that, in a real-life setting, raltegravir can be used with a high virological success rate in treatment-experienced patients, and that the different combinations analysed (2NRTIs + RAL, bPI + RAL and others) show comparable rates of virological suppression. PMID- 29971924 TI - Boron(II) Cations: Interplay between Lewis-Pair-Acceptor and Electron-Donor Properties. AB - Boron(III) cations are widely used as highly Lewis acidic reagents in synthetic chemistry. In contrast, boron(II) cations are extremely rare and their chemistry almost completely unknown. They are both Lewis acids and electron donors, properties that are commonly associated with catalytically active late-transition metal complexes. This double reactivity pattern ensures a rich and diverse chemistry. Herein we report the facile synthesis of several new boron(II) cations starting with a special diborane with two easily exchangeable triflate substituents. By increasing the pi-acceptor character of the neutral sigma-donor reaction partners, first reactions were developed in which the combined Lewis acidity and electron-donor properties of boron(II) cations are applied for the reduction of organic molecules. The results of our study pave the way for applications of these unusual compounds in synthetic chemistry. PMID- 29971925 TI - Medically uncontrolled intraocular pressure in mucopolysaccharidosis type VI. PMID- 29971923 TI - Inference of patient-specific subpathway activities reveals a functional signature associated with the prognosis of patients with breast cancer. AB - Breast cancer is one of the most deadly forms of cancer in women worldwide. Better prediction of breast cancer prognosis is essential for more personalized treatment. In this study, we aimed to infer patient-specific subpathway activities to reveal a functional signature associated with the prognosis of patients with breast cancer. We integrated pathway structure with gene expression data to construct patient-specific subpathway activity profiles using a greedy search algorithm. A four-subpathway prognostic signature was developed in the training set using a random forest supervised classification algorithm and a prognostic score model with the activity profiles. According to the signature, patients were classified into high-risk and low-risk groups with significantly different overall survival in the training set (median survival of 65 vs 106 months, P = 1.82e-13) and test set (median survival of 75 vs 101 months, P = 4.17e-5). Our signature was then applied to five independent breast cancer data sets and showed similar prognostic values, confirming the accuracy and robustness of the subpathway signature. Stratified analysis suggested that the four subpathway signature had prognostic value within subtypes of breast cancer. Our results suggest that the four-subpathway signature may be a useful biomarker for breast cancer prognosis. PMID- 29971926 TI - Practical Guidelines for Shell-Isolated Nanoparticle-Enhanced Raman Spectroscopy of Heterogeneous Catalysts. AB - Shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) has proven to be a useful characterization tool for heterogeneous catalysis research. The advantage of SHINERS lies in studying surface reactions on solid catalysts, including the detection of reactants, intermediates and products, in real time. However, due to the extremely strong local electric fields, minor amounts of contaminants can already have a big impact on the quality and interpretation of the spectroscopic data obtained. Often, a large part of the organic fingerprint region (1100-1700 cm-1 ) is omitted from SHINER spectra as this is not the main region of interest. However, we show that bands in this region are an important indication of the cleanliness of the substrate. In this work, we propose robust synthesis and measurement protocols to obtain clean SHINERS substrates amenable for catalysis research. By cleaning the substrates with various heat and oxidation treatments, featureless Raman spectra can be obtained. Furthermore, very pure gas feeds are required and must be obtained by flushing the gas lines and the reaction chamber beforehand and installing a filter for further cleaning the gas feed. Controlling the laser power to limit substrate and sample degradation is also a crucial aspect of proper measurement protocols. PMID- 29971927 TI - Selection of Secondary Structures of Heterotypic Supramolecular Peptide Assemblies by an Enzymatic Reaction. AB - In a model study to investigate the consequence of reactions of intrinsically disordered regions (IDRs) of proteins in the context of the formation of highly ordered structures, we found that enzymatic reactions control the secondary structures of peptides during assembly. Specifically, phosphorylation of an alpha helix-dominant peptide results in mostly disordered conformations, which become beta-strand-dominant after enzymatic dephosphorylation to regenerate the peptide. In the presence of another peptide largely with a beta-strand conformation, direct coassembly of the peptides results in amorphous aggregates consisting of alpha-helix and beta-strand peptides, but the enzymatically generated peptide coassemblies (from the phosphopeptide) mainly adopt a beta-strand conformation and form ordered structures (e.g., nanofibers). These results indicate that enzymatic dephosphorylation instructs conformationally flexible peptides to adopt thermodynamically favorable conformations in homotypic or heterotypic supramolecular assemblies. PMID- 29971928 TI - Novel surfaces and osseointegration in implant dentistry. AB - Survival, differentiation capability, and activity of cells are strictly related to structural features and the composition of the extracellular matrix, and its variation affects tissue homeostasis. Placement of a dental implant in bone tissue activates a sequence of molecular and cellular events that lead to the apposition of newly-formed bone directly onto the titanium surface. Due to implant's interaction with the mineralized tissue, osseointegration is affected by the surface structure of the implanted material. Surface nanotopography and microtopography can modify the shape and activity of mesenchymal stem cells leading to a higher differentiation rate of these cells into osteogenic lineage with the upregulation of osteoblastic genes. Several approaches for implant surface modification are currently under investigation or have been recently proposed to improve osseointegration. Most surface treatments are aimed at the formation of a thick layer of titanium oxide, at the alteration of surface chemical composition by incorporating bioactive molecules and drugs, and at the creation of a surface topography that is more attractive for osteoblast differentiation, adhesion, and osteogenic activity. Data on the cellular substrate interaction, as well as in vivo studies assessing the response to these novel surfaces, are reviewed in the present study. The application of modern surfaces in dental clinical practice might increase and accelerate implant osseointegration, but could also reduce the occurrence of peri-implant bone loss and favor the re-osseointegration of an affected surface. PMID- 29971929 TI - World congress on insulin resistance, diabetes and cardiovascular disease. PMID- 29971930 TI - Perceptions of Iranian parents towards the paternal role in raising adolescent children. AB - In Iran, as in other nations, adolescence can be a challenging period for both parents and their children. Typically, mothers assume the main role of parenting, which can have a negative impact either directly or indirectly on paternal involvement, or conversely, play a positive role of mediation between fathers and their adolescent children. In the present study, we report on a qualitative study conducted in 2016 that explored the perceptions of Iranian parents toward the paternal role in raising adolescent children. Twenty three mothers and fathers of adolescent children were interviewed to explore their views and experiences with paternal roles in raising adolescent children. Four themes emerged from the data: (i) limited father-child interactions; (ii) mother-led parenting; (iii) father child conflict; and (iv) united front parenting. The findings suggest that mothers maintain a prime role in parenting, but that the involvement of fathers can have a negative or positive impact on adolescent development, depending on the level and quality of that involvement. Strategies need to be explored for how parents can best support one another to engage in the development of adolescent children. PMID- 29971931 TI - N-Formylation of Amines with CO2 and H2 by Using NHC-Iridium Coordination Assemblies as Solid Molecular Catalysts. AB - One of the NHC-iridium coordination assemblies containing 1,5-cyclooctadiene (COD) and iodide ion has been demonstrated as robust, efficient, recyclable solid molecular catalyst for N-formylation of diverse primary and secondary amines with CO2 and H2 under mild reaction conditions. Remarkably, in the case of N,N dimethylformamide production, even at 0.1 mol % catalyst loading under solvent free conditions, the solid catalyst can be readily recovered by simply filtration and reused more than 10 runs without noticeable loss of activity. PMID- 29971932 TI - Monte Carlo simulation of polarization-sensitive second-harmonic generation and propagation in biological tissue. AB - Polarization-sensitive second harmonic generation (p-SHG) is a nonlinear optical microscopy technique that has shown great promise in biomedicine, such as in detecting changes in the collagen ultrastructure of the tumor microenvironment. However, the complex nature of light-tissue interactions and the heterogeneity of biological samples pose challenges in creating an analytical and experimental quantification platform for tissue characterization via p-SHG. We present a Monte Carlo (MC) p-SHG simulation model based on double Stokes-Mueller polarimetry for the investigation of nonlinear light-tissue interaction. The MC model predictions are compared with experimental measurements of second-order nonlinear susceptibility component ratio and degree of polarization (DOP) in rat-tail collagen. The observed trends in the behavior of these parameters as a function of tissue thickness, as well as the overall extent of agreement between MC and experimental results, are discussed. High sensitivities of the susceptibility ratio and DOP are observed for the varying tissue thickness on the incoming fundamental light propagation pathway. PMID- 29971933 TI - Effective Suppression of Lithium Dendrite Growth Using a Flexible Single-Ion Conducting Polymer Electrolyte. AB - A novel single-ion conducting polymer electrolyte (SIPE) membrane with high lithium-ion transference number, good mechanical strength, and excellent ionic conductivity is designed and synthesized by facile coupling of lithium bis(allylmalonato) borate (LiBAMB), pentaerythritol tetrakis (2-mercaptoacetate) (PETMP) and 3,6-dioxa-1,8-octanedithiol (DODT) in an electrospun poly(vinylidienefluoride) (PVDF) supporting membrane via a one-step photoinitiated in situ thiol-ene click reaction. The structure-optimized LiBAMB PETMP-DODT (LPD)@PVDF SIPE shows an outstanding ionic conductivity of 1.32 * 10-3 S cm-1 at 25 degrees C, together with a high lithium-ion transference number of 0.92 and wide electrochemical window up to 6.0 V. The SIPE exhibits high tensile strength of 7.2 MPa and elongation at break of 269%. Due to these superior performances, the SIPE can suppress lithium dendrite growth, which is confirmed by galvanostatic Li plating/stripping cycling test and analysis of morphology of Li metal electrode surface after cycling test. Li|LPD@PVDF|Li symmetric cell maintains an extremely stable and low overpotential without short circuiting over the 1050 h cycle. The Li|LPD@PVDF|LiFePO4 cell shows excellent rate capacity and outstanding cycle performance compared to cells based on a conventional liquid electrolyte (LE) with Celgard separator. The facile approach of the SIPE provides an effective and promising electrolyte for safe, long-life, and high-rate lithium metal batteries. PMID- 29971934 TI - Analyzing the feasibility of discriminating between collagen types I and II using polarization-resolved second harmonic generation. AB - According to previous studies, the nonlinear susceptibility tensor ratio chi33 /chi31 obtained from polarization-resolved second harmonic generation (P-SHG) under the assumption of cylindrical symmetry can be used to distinguish between fibrillar collagen types. Discriminating between collagen fibrils of types I and II is important in tissue engineering of cartilage. However, cartilage has a random organization of collagen fibrils, and the assumption of cylindrical symmetry may be incorrect. In this study, we simulated the P-SHG response from different collagen organizations and demonstrated a possible method to exclude areas where cylindrical symmetry is not fulfilled and where fibrils are located in the imaging plane. The chi33 /chi31 -ratio for collagen type I in tendon and collagen type II in cartilage was estimated to be 1.33 and 1.36, respectively, using this method. These ratios are now much closer than what has been reported previously in the literature, and the larger reported differences between collagen types can be explained by variation in the structural organization. PMID- 29971935 TI - Nurse Perspectives of Maintaining Patient Dignity in Indonesian Clinical Care Settings: A Multicenter Qualitative Study. AB - PURPOSE: Nurses have a professional obligation to maintain patient dignity when providing nursing care. The concept of dignity, however, is dependent on cultural context. The aim of this study was to elicit nurses' perspectives for maintaining patient dignity in Indonesian clinical care settings. DESIGN: A qualitative descriptive study was performed. METHODS: A total of 40 clinical nurse participants were recruited by purposive sampling from six general public hospitals in Eastern Java, Indonesia, including six medical and six surgical units. Data were collected in 2017 using individual face-to-face semistructured interviews. Inductive content analysis was employed. FINDINGS: The interview data revealed nurses considered three main elements were necessary to maintain patient dignity in clinical care: personalized care, which included prioritizing patients and treating as individuals; compassionate care, which included empathizing and providing emotional support; and patient care advocacy, which included protecting patient rights and being a representative for the patient. CONCLUSIONS: This study provided knowledge on how to maintain patient dignity from the cultural perspective of clinical nurses in Indonesia. Our findings highlight the importance of providing dignified care in a manner that is congruent with culture. The nurses in our study considered compassion and beneficence necessary values for providing dignified patient-centered care, which might be qualities that are culturally sensitive for an Indonesian population. CLINICAL RELEVANCE: Strategies should be developed to improve dignity of care for hospitalized patients in Indonesia as well as other cultural settings, which could be incorporated into patient care. These should include improving patients' health literacy to increase patient-centered communication, eliminating mixed-gender wards to enhance patient privacy, and involving family members as partners in health care. PMID- 29971936 TI - Longitudinal Changes in Symptom Cluster Membership in Inflammatory Bowel Disease. AB - PURPOSE: To describe changes in symptom cluster membership over 1 year and to examine which demographic and clinical factors predict changes in symptom cluster membership among adults with inflammatory bowel disease. DESIGN: A retrospective longitudinal study of the Crohn's & Colitis Foundation of America Partners Cohort from 2012 to 2015. METHODS: We measured symptoms of pain interference, fatigue, sleep disturbance, depression, and anxiety. We used latent transition analysis to describe changes in symptom cluster membership (baseline, 6 months, and 12 months) and multinomial regressions to examine factors associated with symptom cluster membership transition. FINDINGS: Four groups were identified (N = 5,296): high symptom burden (32.3%-35.3%), low symptom burden (24.2%-27.1%), physical symptoms (19.0%-20.9%; pain, fatigue, sleep disturbance), and psychological symptoms (20.0%-21.5%; depression, anxiety). The probability of staying in the same group was .814 to .905. Moving from active disease into remission was associated with moving from the high burden to low burden and psychological symptom groups. CONCLUSIONS: Symptom cluster membership was quite stable over 1 year. Research is needed to understand the underlying etiology of symptom clusters better and to develop interventions to reduce symptom burden in this vulnerable population. CLINICAL RELEVANCE: Careful consideration of symptom management options should be done with patients to select options that are effective and potentially target multiple symptoms. PMID- 29971937 TI - Presence of two different bovine hepacivirus clusters in Germany. AB - During the last years, genetic information of hepaciviruses (family Flaviviridae), whose type species is the human hepatitis C virus, was detected in a wide range of primates and non-primate vertebrates. Here, samples collected from 263 German cattle kept in 22 different holdings were analysed for the presence of hepacivirus N (syn. bovine hepacivirus; BovHepV). One hundred eighty six cattle that suffered from unspecific clinical signs such as fever and a reduced milk yield as well as 77 apparently healthy animals were included. A total of 39 cattle (14.8%) tested positive for BovHepV by real-time RT-PCR, but a correlation between clinical signs and virus infection could not be found. From 31 of the virus-positive samples, sequences of the NS3 coding region were generated and from two samples, viral sequences of the complete coding region were produced and compared to further European and African BovHepV sequences. Based on the NS3 genomic region, two distinct German BovHepV clusters were identified which differed between each other up to 20% at the nucleotide level, the diversity within the individual clusters reached up to 10%. Based on the full length sequences, the newly detected virus variants group together with further German and African viruses in a sister relationship to other hepaciviruses from primates and further mammalians, but form distinct clusters within the BovHepV branch. In conclusion, highly diverse hepaciviruses were detected in German cattle further expanding the known phylogenetic diversity of the genus Hepacivirus. PMID- 29971938 TI - Recent advances in cytogenetic characterization of multiple myeloma. AB - The detection of cytogenetic abnormalities in multiple myeloma (MM) has received more importance over last years for risk stratification and the new risk-adapted treatment strategies. Conventional G-banding analysis should be included in a routine procedure for the initial diagnostic workup for patients suspected of MM. However, the detection of chromosomal abnormalities in MM by conventional cytogenetics is limited owing to the low proliferative activity of malignant plasma cells as well as the low number of plasma cells in bone marrow specimens. Fluorescence in situ hybridization (FISH) or microarray-based technologies can overcome some of those drawbacks and detect specific target arrangements as well as chromosomal copy number changes. In this review, we will discuss different cytogenetic approaches and compare their strength and weakness to provide genetic information for risk stratification and prediction of outcome in MM patients. PMID- 29971939 TI - Enantioselective Total Synthesis of Chromanone Lactone Homo- and Heterodimers. AB - A one pot borylation/Suzuki-Miyaura reaction of the 4-bromochromanone lactones 21 and 23, respectively, followed by cleavage of the methyl ether moieties gave the homodimeric chromanone lactones 10 and 11. Reaction of a 1:1 mixture of 21 and 23 under otherwise identical conditions gave a 1:1:2-mixture of the two homodimers 10 and 11 and the heterodimer 12. This is the first example of the preparation of a heterodimeric chromanone lactone. For the enantioselective synthesis of the starting material, phenol 17 was transformed into the chromane 18 using a Wacker type cyclisation with 99 % ee and 80 % yield. PMID- 29971940 TI - Clarifying cognitive control and the controllable connectome. AB - Cognitive control researchers aim to describe the processes that support adaptive cognition to achieve specific goals. Control theorists consider how to influence the state of systems to reach certain user-defined goals. In brain networks, some conceptual and lexical similarities between cognitive control and control theory offer appealing avenues for scientific discovery. However, these opportunities also come with the risk of conceptual confusion. Here, I suggest that each field of inquiry continues to produce novel and distinct insights. Then, I describe opportunities for synergistic research at the intersection of these subdisciplines with a critical stance that reduces the risk of conceptual confusion. Through this exercise, we can observe that both cognitive neuroscience and systems engineering have much to contribute to cognitive control research in human brain networks. This article is categorized under: Neuroscience > Cognition Computer Science > Neural Networks Neuroscience > Clinical Neuroscience. PMID- 29971941 TI - Implications of cardiovascular outcome trials with injectable antidiabetic agents. PMID- 29971942 TI - An Immobilized Enzyme Reactor for Spatiotemporal Control over Reaction Products. AB - This paper describes a microfluidic chip wherein the position and order of two immobilized enzymes affects the type and quantity of reaction products in the flowing fluid. Assembly of the chip is based on a self-assembled monolayer presenting two orthogonal covalent capture ligands that immobilize their respective fusion enzyme. A thiol-tagged substrate is flowed over a region presenting the first enzyme-which generates a product that is efficiently transferred to the second enzyme-and the second enzyme's product binds to an adjacent thiol capture site on the chip. The amount of the three possible reaction products is quantified directly on the chip using self-assembled monolayers for matrix-assisted laser desorption/ionization mass spectrometry, revealing that the same microsystem can be spatiotemporally arranged to produce different products depending on the device design. This work allows for optimizing multistep biochemical transformations in favor of a desired product using a facile reaction and analytical format. PMID- 29971943 TI - TWEAK/Fn14 mediates atrial-derived HL-1 myocytes hypertrophy via JAK2/STAT3 signalling pathway. AB - Atrial myocyte hypertrophy is one of the most important substrates in the development of atrial fibrillation (AF). The TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy in cardiomyopathy. This study therefore investigated the effects of Fn14 on atrial hypertrophy and underlying cellular mechanisms using HL-1 atrial myocytes. In patients with AF, Fn14 protein levels were higher in atrial myocytes from atrial appendages, and expression of TWEAK was increased in peripheral blood mononuclear cells, while TWEAK serum levels were decreased. In vitro, Fn14 expression was up-regulated in response to TWEAK treatment in HL-1 atrial myocytes. TWEAK increased the expression of ANP and Troponin T, and Fn14 knockdown counteracted the effect. Inhibition of JAK2, STAT3 by specific siRNA attenuated TWEAK-induced HL-1 atrial myocytes hypertrophy. In conclusion, TWEAK/Fn14 axis mediates HL-1 atrial myocytes hypertrophy partly through activation of the JAK2/STAT3 pathway. PMID- 29971944 TI - A Dual Carbon-Based Potassium Dual Ion Battery with Robust Comprehensive Performance. AB - Dual carbon-based potassium dual ion batteries (K-DCBs) have recently attracted ever-increasing attention owing to the potential advantages of high performance to-cost ratio, good safety, and environmental friendliness. However, the reported K-DCBs still cannot simultaneously meet the requirements of high capacity, long cycling stability, and low cost, which are necessary for practical applications. In this study, a K-DCB with good comprehensive performance including capacity, cycling stability, medium discharge voltage, and energy density is developed by introducing the optimal cathode and anode materials, i.e., KS6 and natural graphite, respectively. An initial capacity of ~54.6 mAh g-1 and 92.5% capacity retention after 400 cycles can be delivered in a wide voltage window of 2.4-5.4 V at the current density of 100 mA g-1 . A high medium discharge voltage around 4.2 V and an energy density up to 158.3 Wh kg-1 are meanwhile delivered by the K-DCB. In addition, the working mechanism of the devices is understood in detail. It is believed that valuable contributions to the electrochemical performance improvement of the related devices toward practical applications can be provided by this study. PMID- 29971945 TI - In vitro phase I metabolism of three phenethylamines 25D-NBOMe, 25E-NBOMe and 25N NBOMe using microsomal and microbial models. AB - Numerous 2,5-dimethoxy-N-benzylphenethylamines (NBOMe), carrying a variety of lipophilic substituents at the 4-position, are potent agonists at 5 hydroxytryptamine (5HT2A ) receptors and show hallucinogenic effects. The present study investigated the metabolism of 25D-NBOMe, 25E-NBOMe, and 25N-NBOMe using the microsomal model of pooled human liver microsomes (pHLM) and the microbial model of the fungi Cunninghamella elegans (C. elegans). Identification of metabolites was performed using liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS) with a quadrupole time-of-flight (QqToF) instrument. In total, 36 25D-NBOMe phase I metabolites, 26 25E-NBOMe phase I metabolites and 24 25N-NBOMe phase I metabolites were detected and identified in pHLM. Furthermore, 14 metabolites of 25D-NBOMe, 11 25E-NBOMe metabolites, and nine 25N NBOMe metabolites could be found in C. elegans. The main biotransformation steps observed were oxidative deamination, oxidative N-dealkylation also in combination with hydroxylation, oxidative O-demethylation possibly combined with hydroxylation, oxidation of secondary alcohols, mono- and dihydroxylation, oxidation of primary alcohols, and carboxylation of primary alcohols. Additionally, oxidative di-O-demethylation for 25E-NBOMe and reduction of the aromatic nitro group and N-acetylation of the primary aromatic amine for 25N NBOMe took place. The resulting 25N-NBOMe metabolites were unique for NBOMe compounds. For all NBOMes investigated, the corresponding 2,5 dimethoxyphenethylamine (2C-X) metabolite was detected. This study reports for the first time 25X-NBOMe N-oxide metabolites and hydroxylamine metabolites, which were identified for 25D-NBOMe and 25N-NBOMe and all three investigated NBOMes, respectively. C. elegans was capable of generating all main biotransformation steps observed in pHLM and might therefore be an interesting model for further studies of new psychoactive substances (NPS) metabolism. PMID- 29971946 TI - Engaging food service providers to change food service practices in aged care facilities. AB - AIM: The present study describes the impact of a novel education program for food service staff from Australian aged care facilities (ACF) to facilitate improvements in food service practices. The purpose was to explore; (i) the impact of the intervention (ii) barriers and facilitators of the program from food service providers' perspectives and (iii) make program planning and practice recommendations. METHODS: Participants completed pre- and post-program questionnaires, attended two focus groups on program process and impact and 4 months later reported through individual interviews on changes they had implemented. Results were triangulated between the questionnaires, focus groups and interviews and impacts and outcomes identified through directed content analysis. RESULTS: Thirty senior-level chefs and a cook participated from 27 ACF from Victoria, Australia. Participation impacted on the menu, dining experiences and food service practices. All of the participants were enacting changes in their workplace 4 months later as change agents. A focus on skilling the participants as 'change agents', brokering ongoing peer-support and the celebrity and/or expert status of the facilitators were attributed to the success of the intervention. CONCLUSIONS: This novel intervention empowered Victorian food service providers to make positive changes in ACF. Further research is required to measure if these self-reported changes are sustainable and relevant to other facilities and to establish the effect on food experience, satisfaction and well being of residents. PMID- 29971947 TI - Astragaloside IV modulates TGF-beta1-dependent epithelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. AB - Epithelial-mesenchymal transition (EMT) plays an important role in idiopathic pulmonary fibrosis (IPF). Astragaloside IV (ASV), a natural saponin from astragalus membranaceus, has shown anti-fibrotic property in bleomycin (BLM) induced pulmonary fibrosis. The current study was undertaken to determine whether EMT was involved in the beneficial of ASV against BLM-induced pulmonary fibrosis and to elucidate its potential mechanism. As expected, in BLM-induced IPF, ASV exerted protective effects on pulmonary fibrosis and ASV significantly reversed BLM-induced EMT. Intriguing, transforming growth factor-beta1 (TGF-beta1) was found to be up-regulated, whereas Forkhead box O3a (FOXO3a) was hyperphosphorylated and less expressed. However, ASV treatment inhibited increased TGF-beta1 and activated FOXO3a in lung tissues. TGF-beta1 was administered to alveolar epithelial cells A549 to induce EMT in vitro. Meanwhile, stimulation with TGF-beta1-activated phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway and induced FOXO3a hyperphosphorylated and down-regulated. It was found that overexpression of FOXO3a leading to the suppression of TGF beta1-induced EMT. Moreover, ASV treatment, similar with the TGF-beta1 or PI3K/Akt inhibitor, reverted these cellular changes and inhibited EMT in A549 cells. Collectively, the results suggested that ASV significantly inhibited TGF beta1/PI3K/Akt-induced FOXO3a hyperphosphorylation and down-regulation to reverse EMT during the progression of fibrosis. PMID- 29971949 TI - Predictive Models for HOMO and LUMO Energies of N-Donor Heterocycles as Ligands for Lanthanides Separation. AB - Quantum chemical calculations combined with QSPR methodology reveal challenging perspectives for the solution of a number of fundamental and applied problems. In this work, we performed the PM7 and DFT calculations and QSPR modeling of HOMO and LUMO energies for polydentate N-heterocyclic ligands promising for the extraction separation of lanthanides because these values are related to the ligands selectivity in the respect to the target cations. Data for QSPR modeling comprised the PM7 calculated HOMO and LUMO energies of N-donor heterocycles, including several types of both known and virtual undescribed polydentate ligands. Ensemble modeling included various molecular fragments as descriptors and different variable selection techniques to build consensus models (CMs) on a training set of 388 ligands using external cross-validation. CMs were then verified to make predictions for two external test sets: 45 ligands (T1) that were similar to the ligands of the training set, and 1546 structures (T2), which were substantially different from the ligands of the training set. The consensus models predict well in 5-fold cross-validation (RMSEHOMO =0.097 eV, RMSELUMO =0.064 eV), and on the external test sets (T1: RMSEHOMO =0.26 eV, RMSELUMO =0.24 eV; T2: RMSEHOMO =0.26 eV, RMSELUMO =0.17 eV). An analysis of the results reveals that substituents in heteroaromatic rings of the ligands and at the amide nitrogens can deeply influence their metal binding properties. PMID- 29971950 TI - Soil organic carbon sequestration in a changing climate. PMID- 29971948 TI - Signs indicating dementia in Down, Williams and Fragile X syndromes. AB - BACKGROUND: Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups. METHODS: Using the British Present Psychiatric State-learning Disabilities assessment (PPS-LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. The median age of those with FXS (59 years) was higher than of those with DS (50 years) and WS (53 years). RESULTS: Most study participants with DS (80%) and FXS (89%) were or had been moderately or severely intellectually disabled while most participants with WS (73%) were or had been mildly or moderately disabled at adolescent age. The adolescent (premorbid) level of ID did not correlate with the dementia score. The median scores were 11/27, 1/27, and 0/27 in DS, WS, and FXS subgroups, respectively. Dementia that was confirmed by brain imaging, manifested as Alzheimer disease and as moya-moya disease associated vascular dementia in DS and as vascular dementia in WS. CONCLUSIONS: This survey suggests that the risk of dementia varies depending on the cause of ID and that the severity of ID in adolescence does not predict the development of dementia at a later age. Consequently, the ID and dementia should be understood as separate clinical entities that need to be taken into account in the health management of intellectually disabled people. This is important for the arrangement of appropriate and timely interventions, which can be expected to delay the need for institutionalization. PMID- 29971951 TI - Lateral carbon transfer from erosion in noncroplands matters. AB - This study combines two unprecedentedly high resolution (250 * 250 m) maps of soil erosion (inter-rill and rill processes) and soil organic carbon to calculate a global estimate of erosion-induced organic carbon (C) displacement. The results indicate a gross C displacement by soil erosion of 2.5-0.3+0.5 Pg C/year. The greatest share of displaced C (64%) comes from seminatural lands and forests. This suggests that lateral C transfer from erosion in noncroplands may play a more important role than previously assumed. PMID- 29971952 TI - CPAP to diagnose laryngeal clefts by flexible endoscopy in infants. AB - BACKGROUND: Laryngeal clefts (LC) are uncommon but important causes of stridor in infants. Direct laryngoscopy is the recommended method for the detection of LC because LC may be missed by flexible endoscopy. As laryngomalacia by far outnumbers any other cause of stridor in this age group flexible bronchoscopy is usually the preferred method for the evaluation of significant infantile stridor. The aim is to illustrate how the application of CPAP assists the detection of LC during flexible endoscopy. METHOD: Continuous positive airway pressure (CPAP) is applied via endoscopy mask during flexible endoscopy, titrated to open the upper esophageal sphincter, and to spread the inter-arytenoid folds. RESULTS: The application of CPAP of 10-15 cmH2 O resulted in visual unmasking of otherwise obscured LC in four young children assessed for congenital stridor. CONCLUSION: CPAP helps visualize LC by flexible endoscopy obviating transition to direct laryngoscopy and manual exploration. PMID- 29971953 TI - Interferon regulatory factor 5 and nuclear factor kappa-B exhibit cooperating but also divergent roles in the regulation of pro-inflammatory cytokines important for the development of TH1 and TH17 responses. AB - A large body of data demonstrates that interferon regulatory factor 5 (IRF5) and nuclear factor kappa B (NF-kappaB) are the two major transcription factors in classically activated macrophages responsible for the transcriptional control of proinflammatory genes. Although recent evidence suggests that IRF5 interacts with certain members of the nuclear factor kappa B pathway, the extent of cooperation and its implications in disease are ambiguous. Since both pathways are known for their strong contributions in TLR8 signaling we used the human monocytic cell line THP-1.Dual, featuring gene reporters for NF-kappaB and IRFs, to simultaneously study the roles of IRF5 and the NF-kappaB subunit p65 in TLR8 mediated gene reporter activities. Furthermore, we profiled from these cells the proinflammatory cytokines involved in the differentiation of TH1 and TH17 cells. After ablation of IRF5 and/or p65 we activated the resultant cells with the TLR8 agonists R848 or the psoriasis-associated antimicrobial peptide LL-37 complexed with ssRNA and demonstrate that IRF5 deficiency drastically impairs the secretion of IL-1beta, IL-6, IL-12, IL-23 and TNFalpha. In contrast, the lack of p65 impaired only IL-6, IL-12, and IL-23 secretion. Furthermore, we discovered that upon TLR8 stimulation, IRF5 but not NF-kappaB signaling is essential to provide a cytokine milieu supporting TH1 responses. Additionally, we demonstrate that IRF5 and NF-kappaB cooperate to provide a cytokine milieu supporting TH17 responses. Therefore, the distinct role of IRF5 in the intricate signaling network downstream of TLR8 may open new treatment options interfering with but not disrupting NF-kappaB signaling in human diseases. PMID- 29971954 TI - Incubation temperature induced phenotypic plasticity in oviparous reptiles: Where to next? AB - It is now undisputable that incubation temperature induces different phenotypes (sex, body size, body shape, behavior, and locomotion performance) in many if not most oviparous reptiles. These incubation temperature induced differences in phenotype are assumed to result in differential fitness among hatchlings and therefore to play an important role in recruitment of hatchlings and persistence of reptile populations. However, the role of incubation temperature induced differences in hatchling phenotypes in determining hatchling fitness is still under explored and needs more empirical study. This information is especially needed when making predictions on how climate change and its associated nest warming may affect long term persistence of oviparous reptile populations. Curiously, the ontogenetic and physiological mechanisms responsible for incubation temperature induced differences in hatchling reptile locomotion performance are still unknown. In this article, I review the literature on incubation temperature induced differences in hatchling locomotion performance and summarize what is known about this phenomenon and its influence on hatchling fitness. I discuss how the anticipated detrimental effects on hatchling locomotion performance caused by increased nest temperature associated with climate warming could be ameliorated. I also explore the most likely physiological mechanisms underlying incubation temperature induced differences in hatchling locomotion performance and how these mechanisms might be induced. Finally, I highlight current knowledge gaps in our understanding of incubation temperature induced phenotypic plasticity and suggest directions for future research. PMID- 29971955 TI - Severe malnutrition in infants aged <6 months-Outcomes and risk factors in Bangladesh: A prospective cohort study. AB - Severe acute malnutrition (SAM) affects ~4 million infants under 6 months (u6m) worldwide, but evidence underpinning their care is "very low" quality. To inform future research and policy, the objectives of our study were to identify risk factors for infant u6m SAM and describe the clinical and anthropometric outcomes of treatment with current management strategies. We conducted a prospective cohort study in infants u6m in Barisal district, Bangladesh. One group of 77 infants had SAM (weight-for-length Z-score [WLZ] <-3 and/or bipedal oedema); 77 others were "non-SAM" (WLZ >=-2 to <+2, no oedema, mid-upper-arm circumference >=125 mm). All were enrolled at 4-8 weeks of age and followed up at 6 months. Maternal education and satisfaction with breastfeeding were among factors associated with SAM. Duration of exclusive breastfeeding was shorter at enrolment (3.9 +/- 2.1 vs. 5.7 +/- 2.2 weeks, P < 0.0001) and at age 6 months (13.2 +/- 8.9 vs. 17.4 +/- 7.9 weeks; P = 0.003) among SAM infants. Despite referral, only 13 (17%) reported for inpatient care, and at 6 months, 18 (23%) infants with SAM still had SAM, and 3 (3.9%) died. In the non-SAM group, one child developed SAM, and none died. We conclude that current treatment strategies have limited practical effectiveness: poor uptake of inpatient referral being the main reason. World Health Organization recommendations and other intervention strategies of outpatient-focused care for malnourished but clinically stable infants u6m need to be tested. Breastfeeding support is likely central to future treatment strategies but may be insufficient alone. Better case definitions of nutritionally at-risk infants are also needed. PMID- 29971956 TI - Hepatitis C screening in patients with oral lichen planus. PMID- 29971957 TI - Non-Bonding Interactions Enable the Selective Formation of Branched Products in Palladium-Catalyzed Allylic Substitution Reactions. AB - Palladium-catalyzed allylic substitution reactions have become established as an important tool for the construction of carbon-carbon and carbon-heteroatom bonds in modern organic synthesis. However, controlling the regioselectivity of this type of transformation to afford chiral branched products, in addition to controlling the enantioselectivity, is a significant challenge. Excitingly, controlling nonbonding interactions between the substituents on the pi-allyl palladium intermediate and the nucleophile or palladium catalyst has been shown to be effective in achieving this goal. This Focus Review highlights representative advances in this field, according to the mode of non-bonding interaction, including hydrogen-bonding, electrostatic, and coordination interactions. PMID- 29971958 TI - Early interventions in a US military FIRST episode psychosis program. AB - AIM: Naval Medical Center San Diego's Psychiatric Transition Program is a specialized first episode psychosis treatment program that delivers coordinated specialty care to military service members with psychotic disorders. Due to the unique military environment, military service members with first episode psychosis are hypothesized to receive care very early after the emergence of first psychotic symptoms, resulting in significantly reduced duration of untreated psychosis. This study's aim is to calculate the duration of untreated psychosis for patients enrolled in Naval Medical Center San Diego's Psychiatric Transition Program (NMCSD PTP) from 01JUL2014-31DEC2016. METHODS: Patients included in this study had a diagnosis of schizophreniform disorder (13.04%), schizophrenia (43.48%), schizoaffective disorder (8.70%), other specified schizophreniform disorder (30.43%), or brief psychotic disorder (4.35%) upon discharge from military service and NMCSD PTP. Duration of untreated psychosis was defined as the interval from emergence of positive psychotic symptoms to antipsychotic medication initiation. Duration of untreated psychosis was measured through retrospective review of the electronic medical record. A total of 69 subjects in the Naval Medical Center San Diego's Psychiatric Transition Program met inclusion criteria. Mean and median values as well as standard deviations were calculated for all included subjects. RESULTS: The mean duration to scheduled (non-PRN) neuroleptic medication was 37 days (median: 4 days). The mean duration to PRN neuroleptic medication was 21 days (median: 2 days). CONCLUSIONS: These data support our view that the structure of the military and military healthcare system markedly shortens the DUP for military service members who experience first episode psychosis. PMID- 29971959 TI - Prevalence of prediabetes by the fasting plasma glucose and HbA1c screening criteria among the children and adolescents of Shenzhen, China. AB - BACKGROUND: Prediabetes is associated with an increased risk of cardiovascular diseases and all-cause mortality. No research in China has evaluated the prevalence of prediabetes among children and adolescents using the HbA1c criterion or the combined FPG-or-HbA1c diagnostic criterion, and researchers paid no attention to the distributions of blood glucose in Shenzhen, especially for juveniles. METHODS: We conducted a school-based cross-sectional study based on the first-year students from 17 primary, middle, and high schools. Prediabetes was defined as FPG of 5.6-6.9 mmol/L or HbA1c of 5.7%-6.4%. The crude and standardized prevalence of prediabetes with 95% confidence interval (95% CI) was estimated. RESULTS: A total of 7519 participants, aged 6 to 17 years, were included. For all subjects, the crude prevalence (95% CI) of prediabetes was 1.49% (1.21-1.77), 8.72% (8.08-9.36), and 9.80% (9.13-10.47) by the FPG-only, HbA1c-only, and FPG-or-HbA1c criteria, respectively. Based on the 2010 Shenzhen census population, the standardized prevalence was 1.56% (males 1.85%, females 1.19%), 11.05% (males 11.47%, females 10.53%), and 12.19% (males 13.01%, females 11.15%) by the corresponding criteria. The proportion of prediabetes was higher for males than females, and the prevalence decreased with grade for males but increased for females. The association of BMI and prediabetes was U-shaped curve, indicating higher rates of prediabetes for underweight and obesity people. CONCLUSIONS: The blood glucose status of children and adolescents in Shenzhen is worrisome, and the early detection and management of prediabetes are imperative. This article is protected by copyright. All rights reserved. PMID- 29971960 TI - Ni@NiO Nanowires on Nickel Foam Prepared via "Acid Hungry" Strategy: High Supercapacitor Performance and Robust Electrocatalysts for Water Splitting Reaction. AB - Ni/NiO core-shell nanowires on nickel foam (NF) are successfully synthesized using an "acid-hungry" strategy. The 3D electrode with large accessible active sites and improved conductivity, possesses an optimized ionic and electronic transport path during electrochemical processes. High areal capacitance of 1.65 F cm-2 is obtained at an ultrahigh current density of 100 mA cm-2 , which is 19.88 times higher than pristine NF. The direct growth of nanowires makes the present supercapacitor electrode robust for long-term cycling test. By virtue of the favorable hydrogen adsorption energies on Ni0 and OHads energy on NiO or NiOOH, the 3D electrode exhibits high performance in hydrogen evolution reaction with 146 mV at eta10 mA cm-2 and Tafel value of 72 mV dec-1 , and oxygen evolution reaction with 382 mV at eta10 mA cm-2 and Tafel value of 103 mV dec-1 in 1 m KOH. An electrolyzer using 3D electrodes as both anode and cathode can yield a current density of 10 mA cm-2 at 1.71 V, and possesses superior long-term stability to an electrolyzer consisting of Pt/C||Ir/C. The present work develops an effective and low-cost method for the large-scale fabrication of Ni/NiO core-shell nanowires on commercial NF, providing a promising candidate for supercapacitors, fuel cells, and electrocatalysis. PMID- 29971961 TI - 3D follow-up study of facial asymmetry after developmental dysplasia of the hip. AB - OBJECTIVES: To evaluate the change in facial asymmetry among subjects treated for developmental dysplasia of the hip (DDH) from childhood to adolescence. SETTING AND SAMPLE POPULATION: A total of 39 adolescents (26 females and 13 males), born and treated for DDH during 1997-2001, participated in the first examination in 2007 (T1; at the age of 8.2) and in the follow-up in 2016 (T2; at the age of 16.6). MATERIAL AND METHODS: In this longitudinal study, three-dimensional (3D) images were taken using a 3DMD face system based on a stereophotogrammetric method. Facial asymmetry was determined as the average distance (mm) calculated between the original and superimposed mirrored face and the symmetry percentage (%) calculated as the face area where the distance between the original face and the mirrored surface does not exceed 0.5 mm. RESULTS: Results showed increased asymmetry from T1 to T2. The average distance increased for whole face (from 0.51 mm to 0.59 mm, P = .001), upper face (from 0.41 mm to 0.49 mm, P = .005), mid face (from 0.48 mm to 0.57, P = .002) and lower face (from 0.74 mm to 0.85 mm, P = .147). Facial symmetry percentage decreased for whole face from 61.23% to 55.38% (P = .011), for upper face from 69.27% to 62.24% (P = .005) and for mid face from 62.29% to 55.63% (P = .007) and for lower face from 43.37% to 42.19% (P = .66). CONCLUSION: Facial asymmetry increases from childhood to adulthood in subjects treated for DDH. Orthodontic treatment does not eliminate this asymmetric facial growth. PMID- 29971963 TI - Gut microbial diversity in two insectivorous bats: Insights into the effect of different sampling sources. AB - The gut microbiota is now known as a key factor in mammalian physiology and health. Our understanding of the gut microbial communities and their effects on ecology and evolution of their hosts is extremely limited in bats which represent the second largest mammalian order. In the current study, gut microbiota of three sampling sources (small intestine, large intestine, and feces) were characterized in two sympatric and insectivorous bats (Rhinolophus sinicus and Myotis altarium) by high-throughput sequencing of the V3-V4 region of the 16S rRNA gene. Combining with published studies, this work reveals that Gammaproteobacteria may be a dominant class in the whole Chiroptera and Fusobacteria is less observed in bats although it has been proven to be dominant in other mammals. Our results reveal that the sampling source influences alpha diversity of the microbial community in both studied species although no significant variations of beta diversity were observed, which support that fecal samples cannot be used as a proxy of the microbiota in other gut regions in wild animals. PMID- 29971962 TI - Body composition changes differ by gender in stomach, colorectal, and biliary cancer patients with cachexia: Results from a pilot study. AB - Few studies have examined the possibility that cachexia may affect men and women differently. This pilot study assessed gender differences in body composition in stomach, colorectal, and biliary cancer patients with cachexia. A sample of 38 participants (Female: Male = 17:21, mean age 57.4 years) were included if they were undergoing chemotherapy and experienced weight loss of 5% or more over a 6 month period. Bioelectrical impedance analysis (BIA) was applied to measure body composition. Phase angle (PA) and levels of extra-/intracellular water (ECW; ICW) were determined. Data were analyzed first by gender and then compared to age- and gender-matched healthy controls from the NHANES-III dataset. PA was lower (P < .01) in both genders compared with healthy controls, and PA was lower in female patients compared with male patients (P = .03). Male cancer patients with lower PA also had lower ICW levels compared with healthy controls (r = .98, P < .01). For female patients, PA and ICW were negatively correlated (r = .897, P < .01). A lower ECW/ICW ratio was highly correlated (r = .969 for men, r = .639 for women) with increased PA in cancer patients. ICW changes are gender-specific in patients with GI cancer. ECW/ICW ratios and PA may be suitable surrogate markers for gender-specific changes in cell composition and health status. PMID- 29971965 TI - Combined laparoscopic and perineal approach for the management of recurrent tailgut cyst. AB - Tailgut cyst is an uncommon developmental anomaly arising from the embryonic hindgut in the retrorectal space. The patient frequently is asymptomatic or has vague perineal complaints that pose a diagnostic dilemma. Moreover, the patient is often misdiagnosed and therefore mismanaged. MRI is the investigation of choice for diagnosis. After the diagnosis is established, complete surgical excision is required to alleviate patient discomfort and to prevent complications such as infection, malignant transformation, and recurrence. Proper clinical examination and imaging not only establish the accurate diagnosis but also help in determining the best surgical approach for the patient (anterior abdominal, posterior sacral perineal, or combined approach). We hereby report a case of recurrent tailgut cyst managed with a combined anterior laparoscopic and perineal approach. PMID- 29971966 TI - Dealing with effect size multiplicity in systematic reviews and meta-analyses. AB - Systematic reviews often encounter primary studies that report multiple effect sizes based on data from the same participants. These have the potential to introduce statistical dependency into the meta-analytic data set. In this paper, we provide a tutorial on dealing with effect size multiplicity within studies in the context of meta-analyses of intervention and association studies, recommending a three-step approach. The first step is to define the research question and consider the extent to which it mainly reflects interest in mean effect sizes (which we term a convergent approach) or an interest in exploring heterogeneity (which we term a divergent approach). A second step is to identify the types of multiplicities that appear in the initial database of effect sizes relevant to the research question, and we propose a categorization scheme to differentiate them. The third step is to select a strategy for dealing with each type of multiplicity. The researcher can choose between a reductionist meta analytic approach, which is characterized by inclusion of a single effect size per study, and an integrative approach, characterized by inclusion of multiple effect sizes per study. We present an overview of available analysis strategies for dealing with effect size multiplicity within studies and provide recommendations intended to help researchers decide which strategy might be preferable in particular situations. Last, we offer caveats and cautions about addressing the challenges multiplicity poses for systematic reviews and meta analyses. PMID- 29971964 TI - Safety and efficacy of nonvitamin K antagonist oral anticoagulants during catheter ablation of atrial fibrillation: A systematic review and meta-analysis. AB - AIMS: Catheter ablation for atrial fibrillation (AF) is associated with a transitory increase in the risk of both thromboembolic and bleeding events. Evidence on the use of nonvitamin K antagonist oral anticoagulants (NOACs) in patients undergoing AF ablation mostly comes from small observational studies, underpowered to detect differences in clinical outcomes between NOACs and vitamin K antagonists (VKAs) treated patients. This updated meta-analysis aimed to determine the safety and efficacy of periprocedural anticoagulation with NOACs compared with VKAs in AF patients undergoing catheter ablation. METHODS: We searched MEDLINE, Cochrane library, and web sources for randomized and observational studies comparing periprocedural treatment with NOACs and VKAs in patients undergoing AF ablation. The primary safety endpoint was major bleeding events, and the primary efficacy endpoint was thromboembolic events (a composite of systemic thromboembolism, transient ischemic attack, and stroke). RESULTS: A total of 29 studies with 12 644 patients were included in the meta-analysis. Overall, patients on NOACs had a significantly lower risk of major bleeding compared to VKAs either in observational studies (Peto OR 0.68; 95% CI: 0.48 0.95; P = 0.022; I2 = 20%) or in RCTs (Peto OR 0.30; 95% CI: 0.14-0.62; P = 0.001; I2 = 28%). Uninterrupted NOACs reduced the risk of major bleeding when compared to uninterrupted VKAs (Peto OR 0.66; 95% CI: 0.45-0.96; P = 0.028; I2 = 1%), similarly, interrupted NOACs lowered the risk of major bleeding compared to interrupted VKAs (Peto OR 0.29; 95% CI: 0.13-0.66; P = 0.003; I2 = 0%; Pinteraction = 0.076). The rate of thromboembolic complications was very low and did not significantly differ between the study groups either in observational studies (Peto OR 0.91; 95% CI: 0.49-1.67; P = 0.755; I2 = 0%) or in RCTs (Peto OR 0.14; 95% CI: 0.01-1.30; P = 0.083; I2 = 0%). CONCLUSIONS: Use of NOACs compared to VKAs significantly reduced the risk of bleeding in patients with AF ablation. Similarly, the risk of bleeding was lower with uninterrupted NOACs than with uninterrupted VKAs, and with interrupted NOACs than with interrupted VKAs. The rate of thromboembolic complications was extremely low in both study groups without any differences. PMID- 29971967 TI - Psychological Interventions for Runaway and Homeless Youth. AB - PURPOSE: In this review we examined previous studies of psychological interventions for runaway and homeless youth and evaluated the effectiveness of these interventions in terms of mental health outcomes. DESIGN: Literature review. METHODS: A search of various databases, including PubMed, EMBASE, Cochrane Library, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL), was conducted. In this review we systematically described the characteristics of the included studies and interventions, and conducted a narrative synthesis and meta-analyses of the mental health outcomes of the interventions. FINDINGS: Five types of psychological interventions were identified in the included 11 studies: art therapy, cognitive behavioral therapy (CBT)-based interventions, family therapy, motivational interviewing, and strengths-based interventions. The narrative synthesis found positive effects of family therapy on substance use and positive effects of CBT-based interventions on depression. However, according to the meta-analyses, none of the interventions had any significant effects. CONCLUSIONS: Family therapies are likely to be effective in cases of substance use, and CBT-based interventions are likely to be effective in dealing with cases of depression. However, as the quantitative synthesis did not support the effects of any of the psychological interventions on mental health outcomes, further research is needed. CLINICAL RELEVANCE: Nurse led interventions were identified in two studies. Mental health nurses should assess the mental health status of runaway and homeless youth and provide timely and effective interventions. PMID- 29971968 TI - Central obesity indicating a higher prevalence of lower urinary tract symptoms: A case-control matching analysis from a Chinese cross-sectional study in males. AB - Objective The aim of this study was to explore the association between central obesity and lower urinary tract symptoms (LUTS) among men in southern China, and test the hypothesis that central obesity measured by the waist-to-hip ratio (WHR) is a predictor of the severity of LUTS. Methods In all, 4303 men from the Fangchenggang Area Male Healthy and Examination Survey (FAMHES) were included in this study. LUTS were assessed by the International Prostate Symptom Score (IPSS), whereas central obesity was evaluated by the WHR. The association between WHR and LUTS was tested using logistic and Cox regression analyses. Results After screening, 2917 participants were in the study. Univariate analysis indicated significant differences in WHR in the presence of LUTS (P = .012). After stratification by age, logistic regression indicated that LUTS were more frequent in 60-year-old men with a higher WHR (odds ratio [OR] 2.89, 95% confidence interval [CI] 1.21-6.89) compared with participants <40 years old. Cox regression analysis after pairing of 252 LUTS cases and 252 control subjects from the 2917 eligible participants according to age (+/-5 years), indicated that central obesity (WHR >=0.9) may be significantly associated with moderate or severe LUTS (OR 1.95, 95% CI 1.16-3.26). The associations between central obesity and straining (OR 2.44, 95% CI 1.40-4.24) and weak stream (OR 2.37, 95% CI 1.27-4.45) were significant after multivariate adjustment. Conclusions Males with central obesity are at increased risk of LUTS, and increased WHR is associated with worsened straining and weak stream. Further investigations are needed to confirm these associations. PMID- 29971969 TI - Low frequency electrical muscle stimulation and endothelial function in advanced heart failure patients. AB - AIM: Obtain initial estimates of the change in brachial artery endothelial function and maximal oxygen uptake (VO2peak ) with 8 weeks of low-frequency electrical muscle stimulation (LF-EMS) or sham in patients with advanced chronic heart failure. METHODS AND RESULTS: Using a double blind, randomized design, 35 patients with chronic heart failure (New York Heart Association class III-IV) were assigned to 8 weeks (5 * 60 min per week) of either LF-EMS (4 Hz, continuous) or sham (skin level stimulation only) of the quadriceps and hamstrings muscles. Four of the five sessions were at home and one under supervision. Ultrasound images of resting brachial artery diameter and post 5 min occlusion to determine flow-mediated dilation (FMD), a marker of vascular function and peak oxygen uptake (VO2peak ) during cardiopulmonary exercise test, were measured before and after LF-EMS (n = 20) and sham (n = 15) interventions. FMD improved by 2.56% (95% confidence interval: 0.69 to 3.80) with LF-EMS compared with sham (P = 0.07). There were no notable changes in VO2peak . CONCLUSIONS: Improvements in FMD with LF-EMS may have a clinically meaningful effect as higher FMD is associated with better prognosis. This is a preliminary finding, and a larger trial is warranted. PMID- 29971970 TI - Trends in incidence and associated risk factors of suicide mortality in patients with non-small cell lung cancer. AB - Lung cancer patients have an increased risk for committing suicide. But no comprehensive study about the suicide issues among non-small-cell lung cancer (NSCLC) patients has been published. We aimed to estimate the trend of suicide rate and identify the high-risk group of NSCLC patients. Patients diagnosed with primary NSCLC were identified from Surveillance, Epidemiology, and End Results (SEER) database (1973-2013). Suicide mortality rate (SMR) were calculated. Multivariable logistic regression was employed to find out independent risk factors for suicide. Among 495 889 NSCLC patients, 694 (0.14%) of them died from suicide. The suicide mortality rates have significantly decreased (before 1993: 0.21%, 1994-2003: 0.16%, after 2004: 0.09%, P < .001). Male (OR 6.22, 95% CI: 4.96-7.98, P < .001), white (OR 3.89, 95% CI: 2.66-5.97, P < .001), being unmarried (OR 1.43, 95% CI: 1.22-1.67, P < .001), the elderly (60-74 vs <60: OR 1.24, 95% CI: 1.03-1.50, P = .024, >75 vs <60: OR 1.31, 95% CI: 1.05-1.63, P = .018) were independently associated with higher risk of suicide mortality. Surgery (OR: 1.44, 95% CI: 1.19-1.73, P < .001) was also relative with higher risk of suicide. Our study observed significant decrease in suicide mortality among NSCLC patients in US over past decades. Older age, male sex, unmarried status, and surgery were risk factors of committing suicide. Clinicians should be aware of these high-risk groups. PMID- 29971971 TI - 3D printing in medical imaging and healthcare services. AB - Three-dimensional (3D) printing technology has demonstrated a huge potential for the future of medicine. Since its introduction, it has been used in various areas, for example building anatomical models, personalising medical devices and implants, aiding in precision medical interventions and the latest development, 3D bioprinting. This commentary is provided to outline the current use of 3D printing in medical imaging and its future directions for advancing the healthcare services. PMID- 29971972 TI - Evaluation of factors affecting the sense of coherence in women during pregnancy: A prospective pilot study. AB - BACKGROUND: Pregnancy is a special time in the life of a woman, which induces many changes not only in the biological, but also in the biopsychosocial dimension. OBJECTIVES: The aim of the study was to evaluate the factors affecting the sense of coherence (SOC) among women during pregnancy. It was hypothesized that a high SOC will depend on a high level of received support, lack of the risk of mental disorders in the perinatal period and physiological course of pregnancy. MATERIAL AND METHODS: Factographic material was collected by a diagnostic survey method. As a 1st research tool, the Polish adaptation of the Sense of Coherence - Orientation to Life Questionnaire (SOC-29) was used. Another research tool was the Edinburgh Postnatal Depression Scale (EPDS), used here for pregnant women and therefore called Edinburgh Depression Scale (EDS). RESULTS: We analyzed the data of all 200 women with physiological pregnancies and 200 women with complicated pregnancies from whom a complete valid responses were obtained. All women were aged between 18 and 36 years. Significant predictors of low SOC results in the model were: age (odd ratio [OR] = 0.929, 95% confidence interval [CI] 0.870-0.992, p = 0.0280), being multipara (OR = 1.996, 95% CI 1.271-3.135, p = 0.0027), having never/occasionally husband/partner support (OR = 1.978, 95% CI 1.070-3.656, p = 0.0295), and EDS results (OR = 1.312, 95% CI 1.169-1.472, p = 0.0000). CONCLUSIONS: Predisposing factors for the occurrence of a low rate of SOC in pregnant women are: lower age, multiparity, lack of social support, especially from the husband/partner, and the risk of depression during pregnancy. This may result from the fact that a strong SOC develops in the process of socialization, and with age we acquire the ability to accurately assess reality. PMID- 29971973 TI - Age-Specific Cutoff Scores on a T1-Weighted Axial Medial Temporal-Lobe Atrophy Visual Rating Scale in Alzheimer's Disease Using Clinical Research Center for Dementia of South Korea Data. AB - BACKGROUND AND PURPOSE: Visual assessment of medial temporal-lobe atrophy (MTA) has been quick, reliable, and easy to apply in routine clinical practice. However, one of the limitations in visual assessments of MTA is the lack of widely accepted age-adjusted norms and cutoff scores for MTA for a diagnosis of Alzheimer's disease (AD). This study aimed to determine the optimal cutoff score on a T1-weighted axial MTA Visual Rating Scale (VRS) for differentiating patients with AD from cognitively normal elderly people. METHODS: The 3,430 recruited subjects comprising 1,427 with no cognitive impairment (NC) and 2003 AD patients were divided into age ranges of 50-59, 60-69, 70-79, and 80-89 years. Of these, 446 participants (218 in the NC group and 228 in the AD group) were chosen by random sampling for inclusion in this study. Each decade age group included 57 individuals, with the exception of 47 subjects being included in the 80- to 89 year NC group. The scores on the T1-weighted axial MTA VRS were graded by two neurologists. The cutoff values were evaluated from the area under the receiver operating characteristic curve. RESULTS: The optimal axial MTA VRS cutoff score from discriminating AD from NC increased with age: it was >=as >=1, >=2, and >=3 in subjects aged 50-59, 60-69, 70-79, and 80-89 years, respectively (all p<0.001). CONCLUSIONS: These results show that the optimal cutoff score on the axial MTA VRS for diagnosing of AD differed according to the decade age group. This information could be of practical usefulness in the clinical setting. PMID- 29971974 TI - Adverse Events During Perampanel Adjunctive Therapy in Intractable Epilepsy. AB - BACKGROUND AND PURPOSE: Perampanel is the first alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid (AMPA)-receptor antagonist developed to treat epilepsy. The effects of either rapid or slow dose titration on adverse events remain to be elucidated. METHODS: Eighty-five patients received perampanel between March 2016 and August 2016. Patients were divided into two groups according to their dosing schedule: rapid dose titration (2-mg increments at intervals of 1 to 2 weeks) and slow dose titration (2-mg increments at intervals of at least 3 weeks). Seizure frequency and adverse events were analyzed over 3 months. RESULTS: Adverse events were reported by 47 (58%) of the 81 patients analyzed, with 12 (15%) patients discontinuing perampanel due to adverse events. Common adverse events included dizziness (n=30, 37%), aggressive mood and behavior (n=19, 24%), gait disturbance (n=16, 20%), and sleep problems (n=10, 12.4%). The overall adverse events were similar in the slow-titration group (38 of 61 patients) and the rapid-titration group (8 of 20 patients, p=0.081). However, none of the 20 patients in the slow titration group experienced gait disturbance, compared with 16 of the 61 patients in the rapid-titration group (p=0.009), while appetite change was experienced by 4 patients in the slow-titration group but only 1 in the rapid-titration group (p=0.003). No relationship was noted between adverse events and the maximum dose of perampanel (p=0.116). Sex differences were observed, with the response to perampanel being better and the rate of adverse events being higher in females (p=0.015 and p=0.046, respectively). CONCLUSIONS: Slow titration of perampanel may reduce perampanel-related adverse events. PMID- 29971975 TI - Clinical Presentations and Phenotypic Spectrum of Multiple Sclerosis at a University Hospital in Saudi Arabia. AB - BACKGROUND AND PURPOSE: The objective of this study was to determine the frequencies of different clinical presentations and the phenotypic spectrum of multiple sclerosis (MS). METHODS: This cross-sectional study was performed in the Neurology Department of King Fahd Hospital of University Alkhobar in the Kingdom of Saudi Arabia (KSA). Data of 190 MS patients who fulfilled the McDonald criteria were retrieved from medical records and analyzed. RESULTS: The age at disease onset was 26.27+/-8.2 years (mean+/-SD) and disease duration was 6.38+/ 5.10 years. The male-to-female ratio was 1:1.6. Optic neuritis and myelitis were the most-frequent first clinical presentations. Sensory (73.1%), motor (61%), and visual (58.4%) symptoms were the most-frequent established clinical symptoms. Relapsing-remitting multiple sclerosis (RRMS) was present in 75% of the cases. Supratentorial T2-weighted white-matter lesions and deep-gray-matter or juxtacortical lesions were the most-frequent magnetic resonance imaging (MRI) lesions, comprising 28% and 23.7% of all MRI lesions observed in 93.6% and 79.4% of the cases, respectively. The scores on the Expanded Disability Status Scale were within the range of 1.0-5.5 in 82.1% of the patients. There were 145 (76.3%) patients taking interferon beta therapy. CONCLUSIONS: MS presenting in the hospital setting is more common in KSA than reported previously, and the number of diagnosed cases in increasing. It is therefore an emerging and disabling neurological illness in KSA with clinical characteristics not dissimilar to those in other middle eastern countries. A decrease in the frequency of patients with secondary progressive multiple sclerosis (SPMS) indicates either that more new cases of RRMS are being diagnosed or that adequate treatments of RRMS are preventing the evolution to SPMS. Further larger and population-wide epidemiological and clinical studies with the long-term follow-up of MS patients are required to better assess the clinical spectrum of MS in KSA. PMID- 29971976 TI - Effect of Vitamin D Deficiency on the Frequency of Headaches in Migraine. AB - BACKGROUND AND PURPOSE: The risk of vitamin D deficiency varies with the season. The frequency of vitamin D deficiency in migraine patients and its association with migraine are unclear. METHODS: We retrospectively evaluated first-visit migraine patients between January 2016 and May 2017, and investigated the demographics, season, migraine subtypes, frequency, severity, and impact of migraine, psychological and sleep variables, climate factors, and vitamin D levels. The nonfasting serum 25-hydroxyvitamin D concentration was measured to determine the vitamin D level, with deficiency of vitamin D defined as a concentration of <20 ng/mL. RESULTS: In total, 157 patients with migraine aged 37.0+/-8.6 years (mean+/-standard deviation) were analyzed. Their serum level of vitamin D was 15.9+/-7.4 ng/mL. Vitamin D deficiency was present in 77.1% of the patients, and occurred more frequently in spring and winter than in summer and autumn (89.1%, 85.7%, 72.4%, and 61.7%, respectively; p=0.008). In multivariate Poisson regression analysis, monthly headache was 1.203 times (95% confidence interval=1.046-1.383, p=0.009) more frequent in patients with vitamin D deficiency than in those without deficiency after adjusting for demographics, season, migraine subtype, depression, anxiety, and sleep quality. These associations were consistently noted in subgroup analysis of episodic migraine (odds ratio=1.266, p=0.033) and chronic migraine (odds ratio=1.390, p=0.041). CONCLUSIONS: Our study found that a larger number of monthly days with headache was related to vitamin D deficiency among migraineurs. Future studies should attempt to confirm the causal relationship between vitamin D deficiency and migraine. PMID- 29971977 TI - The Etiologies of Chronic Progressive Cerebellar Ataxia in a Korean Population. AB - BACKGROUND AND PURPOSE: The etiologies and frequencies of cerebellar ataxias vary between countries. Our primary aim was to determine the frequency of each diagnostic group of cerebellar ataxia patients in a Korean population. METHODS: We reviewed the medical records of patients who were being followed up between November 1994 and February 2016. We divided patients with cerebellar ataxias into familial and non-familial groups and analyzed the frequency of each etiology. Finally, we categorized patients into genetic, sporadic, secondary, and suspected genetic, but undetermined ataxia. RESULTS: A total of 820 patients were included in the study, among whom 136 (16.6%) familial patients and 684 (83.4%) non familial cases were identified. Genetic diagnoses confirmed 98/136 (72%) familial and 72/684 (11%) nonfamilial patients. The overall etiologies of progressive ataxias comprised 170 (20.7%) genetic, 516 (62.9%) sporadic, 43 (5.2%) secondary, and 91 (11.1%) undetermined ataxia. The most common cause of ataxia was multiple system atrophy (57.3%). In the genetic group, the most common etiology was spinocerebellar ataxia (152/170, 89.4%) and the most common subtype was spinocerebellar ataxia-3.38 of 136 familial and 53 of 684 sporadic cases (91/820, 11.1%) were undetermined ataxia. CONCLUSIONS: This is the largest epidemiological study to analyze the frequencies of various cerebellar ataxias in a Korean population based on the large database of a tertiary hospital movement-disorders clinic in South Korea. These data would be helpful for clinicians in constructing diagnostic strategies and counseling for patients with cerebellar ataxias. PMID- 29971979 TI - Clinical Application of 2017 McDonald Diagnostic Criteria for Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: McDonald criteria for multiple sclerosis diagnosis have been revised over the years, diagnostic procedures have been simplified and earlier diagnosis facilitated. The new 2017 revision introduces other important changes, with a further simplification for the diagnosis. Oligoclonal bands reassume a more relevant role in the workup. METHODS: We describe 3 typical cases of patients admitted for clinically isolated syndrome and illustrate how the application of the new criteria can change the diagnostic approach with respect to the previous criteria. RESULTS: In two of the three cases a diagnosis of multiple sclerosis is now possible. CONCLUSIONS: The new 2017 Multiple Sclerosis criteria may have an important impact in clinical practice with an earlier treatment to avoid the risk of disease dissemination. Their application requires a careful assessment to avoid misdiagnosis and mistreatments. PMID- 29971980 TI - Postoperative Transient Neurologic Dysfunction: A Proposal for Pathophysiology. AB - BACKGROUND AND PURPOSE: Sudden neurological deterioration which cannot be explained by structural change, ischemia or seizure is often observed among neurosurgical patients. We aimed to provide new insight into the pathophysiology of postoperative transient neurologic dysfunction. METHODS: We describe prolonged but fully reversible focal neurologic dysfunction of unknown origin based on the initial evaluation in 8 patients who had received encephalo-duro-arterio synangiosis for moyamoya disease. We performed brain imaging, including diffusion weighted imaging and perfusion magnetic resonance imaging or single photon emission computed tomography, and electroencephalography (EEG) during the episodes and after resolution of the symptoms. RESULTS: The symptoms consisted of dysarthria, hemiparesis, or hemiparesthesia of limbs contralateral to the operated side. These symptoms developed between 12 hours and 8 days after surgery and lasted between 12 hours and 17 days. Structural imaging did not show any significant interval change compared with the immediate postoperative images. Perfusion imaging showed increased cerebral blood flow in the symptomatic hemisphere. EEG revealed low amplitude arrhythmic slowing in the corresponding hemisphere. Follow-up imaging and EEG after recovery did not show any abnormalities. CONCLUSIONS: Transient neurologic dysfunction can occur during the postoperative period of brain surgery. Although this may last more than usual transient ischemic attack or seizure, it eventually resolves regardless of treatment. Based on our observation, we propose that this is the manifestation of the transient cortical depression triggered by mechanical stimulation, analogous to migraine aura associated with cortical spreading depression. PMID- 29971978 TI - Hand Tremor Questionnaire: A Useful Screening Tool for Differentiating Patients with Hand Tremor between Parkinson's Disease and Essential Tremor. AB - BACKGROUND AND PURPOSE: Hand tremor is one of the most frequent symptoms in movement disorders, and differential diagnoses for hand tremor include Parkinson's disease (PD) and essential tremor (ET). However, accurately differentiating between PD and ET in clinical practice remains challenging in patients presenting with hand tremor. We investigated whether a questionnaire based survey could be useful as a screening tool in patients with hand tremor. METHODS: A questionnaire related to hand tremor consisting of 12 items was prospectively applied to patients with PD or ET in three movement-disorder clinics. Each question was analyzed, and a query-based scoring system was evaluated for differentiating hand tremors between PD and ET. RESULTS: This study enrolled 24 patients with PD and 25 patients with ET. Nine of the 12 questions differed significantly between PD and ET: 1 about resting tremor, 4 questions about action tremor, and 4 about asymmetry. A receiver operating characteristics curve analysis revealed that the 9-item questionnaire showed a good discrimination ability, with a sensitivity of 88% and a specificity of 84%. CONCLUSIONS: The developed Hand Tremor Questionnaire might be a good screening tool for hand tremors in patients with PD and ET. PMID- 29971981 TI - Clinical Heterogeneity of Anti-GM2-Ganglioside-Antibody Syndrome. AB - BACKGROUND AND PURPOSE: Antiganglioside antibodies are known to play a pathogenic role in Guillain-Barre syndrome (GBS). Either an immunoglobulin (Ig)G- or IgM type anti-GM2 antibody is detected in rare cases in GBS patients. However, the specific pathogenic role of these antibodies in GBS has not been reported previously. This study aimed to define and characterize the clinical spectrum of GBS with anti-GM2 positivity. METHODS: We reviewed the database of the Dong-A University Neuroimmunology Team, which has collected sera of GBS and its variants from more than 40 general and university-based hospitals in Korea. Detailed information about the involved patients was often obtained and then corrected by the charge doctor applying additional questionnaires. RESULTS: Four patients with acute monophasic peripheral neuropathy or cranial neuropathy with isolated IgM type anti-GM2-antibody positivity were recruited. In addition, IgG-type anti-GM2 antibody was solely detected in the sera of another four patients. The IgM positive group comprised heterogeneous syndromes: two cases of acute motor axonal neuropathy, one of acute inflammatory demyelinating polyneuropathy, and one of isolated facial diplegia. In contrast, all of the cases enrolled in the IgG positive group manifested with dizziness with or without oculomotor palsy due to cranial neuropathy syndrome. CONCLUSIONS: This study has identified that anti-GM2 antibody can be found in various subtypes of GBS and its variants in rare cases. Compared to the clinical heterogeneity of the IgM-positive group, the IgG positive group can be characterized by cranial-dominant GBS variants presenting mainly with oculomotor and vestibular dysfunctions. PMID- 29971982 TI - Mechanical Thrombectomy in Strokes with Large-Vessel Occlusion Beyond 6 Hours: A Pooled Analysis of Randomized Trials. AB - BACKGROUND AND PURPOSE: Mechanical thrombectomy with or without intravenous thrombolysis is indicated in the acute treatment of ischemic strokes caused by an emergent large-vessel occlusion (ELVO) within 6 hours from symptom onset. However, a significant proportion of patients are referred to comprehensive stroke centers beyond this therapeutic time window. This study performed a pooled analysis of data from trials in which mechanical thrombectomy was performed beyond 6 hours from symptom onset. METHODS: We searched for randomized controlled trials that compared mechanical thrombectomy with the best medical treatment beyond 6 hours for ischemic strokes due to ELVO and reported on between 1990 and April 2018. The intervention group comprised patients treated with mechanical thrombectomy. Statistical analysis was conducted while pooling data and analyzing fixed- or random-effects models as appropriate. RESULTS: Four trials involving 518 stroke patients met the eligibility criteria. There were 267 strokes treated with mechanical thrombectomy, with a median time of 10.8 hours between when the patient was last known to be well to randomization. We observed a significant difference between groups concerning the rate of functional independence at 90 days from stroke, with an absolute difference of 27.5% (odds ratio=3.33, 95% CI=1.81-6.12, p<0.001) and good recanalization (odds ratio=13.17, 95% CI=4.17 41.60, p<0.001) favoring the intervention group. CONCLUSIONS: This meta-analysis confirms the efficacy of mechanical thrombectomy in selected ischemic stroke patients beyond 6 hours from symptom onset. The selection is mainly based on the limited core infarct detected by emergent assessment using neuroimaging techniques. PMID- 29971983 TI - Alanyl-tRNA Synthetase 2-Related Dementia with Selective Bilateral Frontal Cystic Leukoencephalopathy. PMID- 29971985 TI - Near-Fatal Statin-Associated Autoimmune Myositis. PMID- 29971984 TI - An Elderly Woman with Reversal of Clinical Presentation Mimicking Rapid-Onset Dystonia-Parkinsonism. PMID- 29971986 TI - Crab Sign in Bilateral Extracranial Vertebral Artery Dissection. PMID- 29971987 TI - The Impact of a National Healthcare System on the Doctor-Patient Relationship in Neurology. PMID- 29971988 TI - Advances in predicting the prognosis of hepatocellular carcinoma recipients after liver transplantation. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors worldwide. Liver transplantation (LT) is known as a curative and therapeutic modality. However, the survival rates of recipients after LT are still not good enough because of tumor recurrence. To improve the survival rates of recipients after LT, identifying predictive factors for prognosis after LT and establishing a model assessing prognosis are very important to HCC patients. There has recently been a lot of clinical and basic research on recurrence and prognosis after LT. Progress has been made, especially in selection criteria for LT recipients and risk factors for predicting prognosis after LT. Hangzhou criteria, in line with China's high current incidence rate of primary liver, are first proposed by Chinese scholars of LT, and are accepted world-wide, and make an important contribution to the development of LT. PMID- 29971989 TI - Depolymerized konjac glucomannan: preparation and application in health care. AB - Konjac glucomannan (KGM) is a water-soluble polysaccharide obtained from the roots and tubers of konjac plants. Recently, a degraded product of KGM, depolymerized KGM (DKGM), has attracted attention because of its low viscosity, improved hydrophily, and favorable physiological functions. In this review, we describe the preparation of DKGM and its prebiotic effects. Other health benefits of DKGM, covering antioxidant and immune activity, are also discussed, as well as its safety. DKGM could be a candidate for use as a tool for the treatment of various diseases, including intestinal flora imbalance, and oxidative- and immune related disorders. PMID- 29971990 TI - Mandatory criteria for the application of variability-based parameters of fluid responsiveness: a prospective study in different groups of ICU patients. AB - BACKGROUND AND OBJECTIVE: Stroke volume variation (SVV) has high sensitivity and specificity in predicting fluid responsiveness. However, sinus rhythm (SR) and controlled mechanical ventilation (CV) are mandatory for their application. Several studies suggest a limited applicability of SVV in intensive care unit (ICU) patients. We hypothesized that the applicability of SVV might be different over time and within certain subgroups of ICU patients. Therefore, we analysed the prevalence of SR and CV in ICU patients during the first 24 h of PiCCO monitoring (primary endpoint) and during the total ICU stay. We also investigated the applicability of SVV in the subgroups of patients with sepsis, cirrhosis, and acute pancreatitis. METHODS: The prevalence of SR and CV was documented immediately before 1241 thermodilution measurements in 88 patients. RESULTS: In all measurements, SVV was applicable in about 24%. However, the applicability of SVV was time-dependent: the prevalence of both SR and CV was higher during the first 24 h compared to measurements thereafter (36.1% vs. 21.9%; P<0.001). Within different subgroups, the applicability during the first 24 h of monitoring ranged between 0% in acute pancreatitis, 25.5% in liver failure, and 48.9% in patients without pancreatitis, liver failure, pneumonia or sepsis. CONCLUSIONS: The applicability of SVV in a predominantly medical ICU is only about 25%-35%. The prevalence of both mandatory criteria decreases over time during the ICU stay. Furthermore, the applicability is particularly low in patients with acute pancreatitis and liver failure. PMID- 29971991 TI - Effect of ultraviolet photofunctionalization of dental titanium implants on osseointegration. AB - OBJECTIVE: The aim of the current study was to evaluate the effect of ultraviolet (UV) photofunctionalization of dental titanium implants with exposure to the oral cavity on osseointegration in an animal model. METHODS: Forty-eight titanium implants (Camlog(r) Conelog(r) 4.3 mmx9.0 mm) were placed epicrestally into the edentulous jaws of three minipigs and implant stability was assessed by measuring the implant stability quotient (ISQ). Prior to implantation half of the implants were photofunctionalized with intense UV-light. After three months, the implants were exposed and ISQ was measured again. After six months of implant exposure, the minipigs were sacrificed and the harvested specimens were analyzed using histomorphometric, light, and fluorescence microscopy. MAIN RESULTS: Forty-two of 48 implants osseointegrated. The overall mean bone-implant contact area (BIC) was (64+/-22)%. No significant differences were found in BIC or ISQ value (multivariate analysis of variance (MANOVA), P>0.05) between implants with and without exposure to UV photofunctionalization. CONCLUSIONS: No significant effects were observed on osseointegration of dental titanium implants nine months after exposure of UV photofunctionalization. PMID- 29971992 TI - A biomechanical case study on the optimal orthodontic force on the maxillary canine tooth based on finite element analysis. AB - Excessive forces may cause root resorption and insufficient forces would introduce no effect in orthodontics. The objective of this study was to investigate the optimal orthodontic forces on a maxillary canine, using hydrostatic stress and logarithmic strain of the periodontal ligament (PDL) as indicators. Finite element models of a maxillary canine and surrounding tissues were developed. Distal translation/tipping forces, labial translation/tipping forces, and extrusion forces ranging from 0 to 300 g (100 g=0.98 N) were applied to the canine, as well as the force moment around the canine long axis ranging from 0 to 300 g.mm. The stress/strain of the PDL was quantified by nonlinear finite element analysis, and an absolute stress range between 0.47 kPa (capillary pressure) and 12.8 kPa (80% of human systolic blood pressure) was considered to be optimal, whereas an absolute strain exceeding 0.24% (80% of peak strain during canine maximal moving velocity) was considered optimal strain. The stress/strain distributions within the PDL were acquired for various canine movements, and the optimal orthodontic forces were calculated. As a result the optimal tipping forces (40-44 g for distal-direction and 28-32 g for labial-direction) were smaller than the translation forces (130-137 g for distal-direction and 110-124 g for labial-direction). In addition, the optimal forces for labial-direction motion (110-124 g for translation and 28-32 g for tipping) were smaller than those for distal-direction motion (130-137 g for translation and 40-44 g for tipping). Compared with previous results, the force interval was smaller than before and was therefore more conducive to the guidance of clinical treatment. The finite element analysis results provide new insights into orthodontic biomechanics and could help to optimize orthodontic treatment plans. PMID- 29971993 TI - Methodology and cohort profile for the Hangzhou Lumbar Spine Study: a study focusing on back health in a Chinese population. AB - Back pain is a worldwide health problem, adding a tremendous burden to modern societies. However, little information on back health is available in China, even though a quarter of the world's population is Chinese. To enhance knowledge in this area, we designed and initiated the Hangzhou Lumbar Spine Study, which is a cross-sectional study of a general sample of mainland Chinese with focusing on disc degeneration, Modic changes, endplate lesions, and back pain. The study consists of a structured questionnaire to measure back pain history and lifetime exposure to suspected risk factors, magnetic resonance imaging of the lumbar spine, bone mineral density study of the spine and hip, and DNA sample analysis. Here we briefly introduce the study methodology, report the test-retest reliability of the questionnaire, and describe the cohort profile to date. Since May 2014, 301 randomly selected subjects (male/female, 122/179; mean age, 51.0 years; range, 20-87 years) have been recruited. Tests-retests of the questionnaire, completed by 40 participants, revealed good reliability. To our knowledge, the Hangzhou Lumbar Spine Study is the first population-based epidemiological study conducted to characterize lumbar spinal phenotypes and back pain, their interaction, and their associations with lifetime environmental exposure, in mainland Chinese. Epidemiological information obtained from a reliable questionnaire, magnetic resonance (MR) imaging data, dual energy X-ray absorptiometry (DXA) measurements, and DNA analysis may serve as a valuable reference for future studies on back health, particularly for mainland Chinese. PMID- 29971994 TI - Stability of a type 2 diabetes rat model induced by high-fat diet feeding with low-dose streptozotocin injection. AB - OBJECTIVE: The present study aims at determining the stability of a popular type 2 diabetes rat model induced by a high-fat diet combined with a low-dose streptozotocin injection. METHODS: Wistar rats were fed with a high-fat diet for 8 weeks followed by a one-time injection of 25 or 35 mg/kg streptozotocin to induce type 2 diabetes. Then the diabetic rats were fed with regular diet/high fat diet for 4 weeks. Changes in biochemical parameters were monitored during the 4 weeks. RESULTS: All the rats developed more severe dyslipidemia and hepatic dysfunction after streptozotocin injection. The features of 35 mg/kg streptozotocin rats more resembled type 1 diabetes with decreased body weight and blood insulin. Rats with 25 mg/kg streptozotocin followed by normal diet feeding showed normalized blood glucose level and pancreatic structure, indicating that normal diet might help recovery from certain symptoms of type 2 diabetes. In comparison, diabetic rats fed with high-fat diet presented decreased but relatively stable blood glucose level, and this was significantly higher than that of the control group (P<0.05). CONCLUSIONS: This model easily recovers with normal diet feeding. A high-fat diet is suggested as the background diet in future pharmacological studies using this model. PMID- 29971996 TI - [Effects of moxibustion at different timings on recovery of gastrointestinal function after laparoscopic surgery]. AB - OBJECTIVE: To evaluate the effect of preoperative and postoperative moxibustion at different timings on the recovery of gastrointestinal function in patients undergoing laparoscopic surgery. METHODS: A total of 108 patients were randomly divided into a preoperative moxibustion group (36 cases), a postoperative moxibustion group (36 cases and 1 dropping), and a control group (36 cases and 1 dropping). Routine care after laparoscopic surgery was received in all three groups. In the preoperative moxibustion group, moxibustion was used at bilateral Zusanli (ST 36) one day before surgery, and 6 h after surgery in the postoperative moxibustion group. The treatment was given 20 min per acupoint. Intervention stopped after the patient's first self-exhaust or defecation. The time of first self-exhaust or defecation, the time of solid food tolerated, the postoperative 1-3 days visual analogue scale (VAS) abdominal pain scores, and adverse reactions during the intervention were recorded. RESULTS: Compared with the postoperative moxibustion group and the control group, the time of first self exhaust or defecation was earlier in the preoperative moxibustion group (both P<0.01); the time of solid food tolerated was earlier in the postoperative moxibustion group (both P<0.01); postoperative 1-3 d VAS scores were lower (P<0.05, P<0.01). The VAS scores in the postoperative moxibustion group were lower than those in the control group (all P<0.05). No adverse reactions occurred in the three groups. CONCLUSION: Preoperative moxibustion can more effectively promote the recovery of gastrointestinal function after laparoscopic surgery and improve the postoperative quality of life. PMID- 29971995 TI - Nucleocapsid protein from porcine epidemic diarrhea virus isolates can antagonize interferon-lambda production by blocking the nuclear factor-kappaB nuclear translocation. AB - Porcine epidemic diarrhea virus (PEDV) is a highly infectious pathogen that can cause severe diseases in pigs and result in enormous economic losses in the worldwide swine industry. Previous studies revealed that PEDV exhibits an obvious capacity for modulating interferon (IFN) signaling or expression. The newly discovered type III IFN, which plays a crucial role in antiviral immunity, has strong antiviral activity against PEDV proliferation in IPEC-J2 cells. In this study, we aimed to investigate the effect of PEDV nucleocapsid (N) protein on type III IFN-lambda. We found that the N proteins of ten PEDV strains isolated between 2013 and 2017 from different local farms shared high nucleotide identities, while the N protein of the CV777 vaccine strain formed a monophyletic branch in the phylogenetic tree. The N protein of the epidemic strain could antagonize type III IFN, but not type I or type II IFN expression induced by polyinosinic-polycytidylic acid (poly(I:C)) in IPEC-J2 cells. Subsequently, we demonstrated that the inhibition of poly(I:C)-induced IFN-lambda3 production by PEDV N protein was dependent on the blocking of nuclear factor-kappaB (NF-kappaB) nuclear translocation. These findings might help increase understanding of the pathogenesis of PEDV and its mechanisms for evading the host immune response. PMID- 29971997 TI - [Effect of auricular intradermal needling combined with erjian (HX6,7i) bloodletting on sleep quality and neuroendocrine level in patients with perimenopausal insomnia]. AB - OBJECTIVE: To compare the effect differences between auricular intradermal needling combined with erjian (HX6,7i) bloodletting and oral administration of western medicine, and to explore the efficacy of neuroendocrine level in patients with perimenopausal insomnia. METHODS: Ninety patients were randomized into an observation group and a control group, 45 cases in each one. In the observation group, auricular intradermal needling combined with erjian (HX6,7i) bloodletting were adopted alternately in the two ears. The auricular points were shen (CO10), xin (CO15), gan (CO12), shenmen (TF4), jiaogan (AH6a), neifenmi (CO18) and erjian (HX6,7i). The treatment was required once 3 days on the auricular points of one side alternatively. Oral administration of estazolam (1mg each day) was applied in the control group for 2 courses, 4 weeks as 1 course, once a day. The scores of Pittsburgh sleep quality index (PSQI), the levels of serum estrogen (E2), 5 hydroxy tryptamine (5-HT) and norepinephrine (NE) were valuated in the two groups before and after treatment. RESULTS: After treatment, the total scores of PSQI reduced in the two groups (both P<0.05), and the improvements of sleeping quality, sleeping time, sleeping difficulty, daytime dysfunction and the total PSQI score in the observation group were superior to those in the control group (all P<0.05). There was no significant difference in serum E2 before and after treatment in the two groups,and between the two groups after treatment (all P>0.05). After treatment, 5-HT contents increased and NE levels decreased in the two groups (all P<0.05), with better results in the observation group (both P<0.05). The total effective rate was 95.6% (43/45) in the observation group, which was higher than 82.2% (37/45) in the control group (P<0.05). CONCLUSION: Auricular intradermal needling combined with erjian (HX6,7i) bloodletting can improve the sleep quality of patients with perimenopausal insomnia, and adjust the neurotransmitter level, which achieves better effect than western medication. PMID- 29971998 TI - [Clinical observation of electroacupuncture combined with auricular point sticking therapy for anal pain of mixed hemorrhoid after external excision and internal ligation]. AB - OBJECTIVE: On the basis of western medication, to investigate the effect of electroacupuncture (EA) combined with auricular point sticking therapy for anal pain of mixed hemorrhoid after external excision and internal ligation,so as to explore the method of improving its effect. METHODS: Ninety patients of mixed hemorrhoids who received external excision and internal ligation were randomly assigned into an EA group, an auricular point sticking group and a combined group, 30 cases in each one. All the treatment was applied 30 min before surgery. Electroacupuncture was used at Xialiao (BL 34) and Changqiang (GV 1) in the EA group, once a day. The auricular points were bilateral shenmen (TF4), pizhixia (AT4), jiaogan (AH6a) and gangmen (HX5) in the auricular point sticking group, pressing 3-6 times every day, once 3-5 min. EA and auricular point sticking therapy were applied in the combined group. When the visual analogue scale (VAS) score was above 6, aminophenol dihydrocodeine was applied in the three groups. The scores of anal pain VAS and limb activity at the 4th, 12th, 24th, 48th, 72th hours after operation were compared among the three groups, as well as the maximum scores of VAS in 24 hours (T24max VAS) of 1-3 days after operation, the total dose of aminophenol dihydrocodeine 72 h after operation. RESULTS: The VAS and limb activity scores at all the time points after operation, the T24max VAS on the 1st, 2nd and 3rd days after operation and the dose of aminophenol dihydrocodeine in the combined group were better than those in the EA and auricular point sticking groups (all P<0.05). The VAS and limb activity scores at 4, 12, 24 h after operation and T24max VAS on the 1st day after operation in the EA group were lower than those in the auricularpoint sticking group (all P<0.05). The VAS and limb activity scores at 48, 72 h after operation, and the T24max VAS on the 2nd and 3rd days in the auricular point sticking group were lower than those in the EA group (all P<0.05). CONCLUSION: EA combined with auricular point sticking therapy are better than simple EA and auricular point sticking therapy for anal pain of mixed hemorrhoid after external excision and internal ligation. The analgesic effect of EA is rapider, and the effect of auricular point sticking therapy is longer. The combination of the two methods own coordination effect. PMID- 29971999 TI - [Effects of intradermal needling combined with tuina on ankle sprain sequelae]. AB - OBJECTIVE: To compare the clinical efficacy differences between intradermal needling combined with tuina and tuina alone on ankle sprain sequelae. METHODS: Ninety patients with chronic ankle sprain were randomly divided into an observation group and a control group, 45 cases in each group. The patients in the control group were treated with conventional tuina. The patients in the observation group were treated with conventional tuina, followed by intradermal needling at ashi point (the most painful tendons node), Shenmai (BL 62)/Zhaohai (KI 6), Jiexi (ST 41)/Zhongfeng (LR 4), Qiuxu (GB 40)/Shangqiu (SP 5) for 24 to 48 hours per treatment; acupoint selection was based on the different side of ankle sprain, and 5 acupoints were selected per treatment, including 2 painful points. The treatment was given twice per week, and totally 8 treatments were given within 4 weeks. The follow-up visit was 12 months. The pain of tendon joints was evaluated by visual analogue scale (VAS); the patient number of severity of ankle pain during walking and running as well as the occurrence and frequency of ankle pain during rest in follow-up visit in the two groups were observed; the satisfaction survey was conducted in the observation group. RESULTS: Compared before treatment, VAS of tendon joints, the patient number of severity of ankle pain during walking and running were improved after treatment in the two groups (all P<0.05), and patient number of the severity of ankle pain during running in the observation group was superior to that in the control group (P<0.05). During follow-up visit, compare with the control group, the occurrence and frequency of ankle pain during rest in the observation group was significantly improved (both P<0.05); the satisfaction in the observation group was significant. CONCLUSION: The intradermal needling combined with tuina could improve the tenderness of tendon joints and pain during walking and running in patients with ankle sprain sequelae; compared with tuina alone, it could reduce the occurrence of ankle pain during rest, which is safe and reliable. PMID- 29972000 TI - [Effects of acupuncture on muscle tension of lower limb in children with spastic cerebral palsy]. AB - OBJECTIVE: To observe the effects of acupuncture at different acupoints in yin meridians and yang meridians on lower limb muscle tension in children with spastic cerebral palsy. METHODS: Ninety children with spastic cerebral palsy aged between 2 to 6 years old were divided into a yin-meridian group, a yang-meridian group and a rehabilitation group, 30 cases in each one. The patients in the rehabilitation group were treated with routine rehabilitation treatment; the patients in the yin-meridian group were treated with routine rehabilitation treatment and acupuncture at Xuehai (SP 10), Yinlingquan (SP 9), Sanyinjiao (SP 6), Taixi (KI 3) and Taichong (LR 3) along yin meridians; the patients in the yang-meridian group were treated with routine rehabilitation treatment and acupuncture at Futu (ST 32), Zusanli (ST 36), Yanglingquan (GB 34), Guangming (GB 37) and Xuanzhong (GB 39) along yang meridians. All the three groups were treated once each other day, 10 times as one course, and totally 20-day treatment was given. Before and after treatment, modified Ashworth scale (MAS), clinical spasm index (CSI) and integrated electromyography (iEMG) of surface electromyogram of gastrocnemius muscle were evaluated. RESULTS: Compared before treatment, the MAS and CSI in the yin-meridian group and yang-meridian group were improved after treatment (P<0.05, P<0.01); the differences before and after treatment in the rehabilitation group were not significant (both P>0.05). After treatment, the differences between the rehabilitation group and yin-meridian group, yang meridian group were significant (P<0.05, P<0.01); the differences of MAS and CSI between the yin-meridian group and yang-meridian group were not significant (both P>0.05). Compared before the treatment, the right-side iEMG and left-side iEMG were reduced in the yin-meridian group and yang-meridian group (all P<0.05); the right-side iEMG was increased in the rehabilitation group (P<0.05). After treatment, the iEMG in the yin-meridian group and yang-meridian group were lower than that in the rehabilitation group (all P<0.05); the differences of iEMG before and after treatment in the yin-meridian group and yang-meridian group were higher than that in the rehabilitation group (all P<0.05); the differences of iEMG between the yin-meridian group and yang-meridian group were not significant (both P>0.05). CONCLUSION: Acupuncture at yin meridians and yang meridians could reduce muscle tension of lower limb and improve limb spasticity in children with spastic cerebral palsy, and the two acupuncture methods have similar clinical curative effect. PMID- 29972001 TI - [Effects of intradermal needling on core muscle stability in children with cerebral palsy: a clinical comparative study]. AB - OBJECTIVE: To observe the effects of rehabilitation training (RT) combined with intradermal needling, RT combined with acupuncture and RT alone on core muscle stability in children with cerebral palsy, and to explore the superior therapy to improve core muscle stability in children with cerebral palsy. METHODS: A total of 120 children with cerebral palsy aged from 2 to 4 years old were randomly divided into a RT and intradermal needling group (group A), a RT and acupuncture group (group B) and a RT group (group C), 40 cases in each one. The patients in the group C were treated with kinesitherapy and core muscle stability training, once a day. Along with identical RT of group C, the patients in the group B were treated with acupuncture (once a day), while the patients in the group A were treated with intradermal needling at Yaoyangguan (GV 3), Mingmen (GV 4), Jiaji (EX-B 2, L2-L5), and 4-week treatment was taken as one course. The integrated electromyography (iEMG) of surface electromyography, root mean square (RMS) and mean power frequency (MPF) of erector spinae muscles, Berg balance scale as well as B area (siting), C area (climbing and kneeling), D area (standing) and E area (walking, running and jumping) of gross motor function measure (GMFM) were compared before and after 3-course treatment. RESULTS: 1 Compared before treatment, the iEMG and RMS of erector spinae muscles in the group A and group B as well as MPF in the group A were all increased after treatment (all P<0.05); after treatment, all the electromyography indexes in the group A were higher than those in the group B and group C (all P<0.05); the RMS in the group B was higher than that in the group C (P<0.05). 2 Compared before treatment, the Berg balance scale was all increased after treatment in the three groups (all P<0.05), and the scale in the group A was higher those that in the group B and group C (both P<0.05). 3 Compared before treatment, the B area and C area of GMFM in the three groups as well as D area in the group A and group B were all improved after treatment (all P<0.05); the B area, C area and D area in the group A and group B were higher than those in the group C (all P<0.05); the B area and C area in the group A were higher than those in the group B (both P<0.05). CONCLUSION: Based on RT, the intradermal needling could better improve core muscle stability and balance-motor ability in children with cerebral palsy, which is superior to regular acupuncture and RT alone. PMID- 29972002 TI - [Comprehensive therapy for senile sensorineural hearing loss: a randomized controlled trial]. AB - OBJECTIVE: To observe the effect differences among the comprehensive therapy, acupuncture and oral mecobalamine for senile sensorineural hearing loss. METHODS: A total of 126 senile sensorineural hearing loss patients were randomized into a comprehensive group, an acupuncture group and a western medication group, 42 cases in each group. After removing and discontinuing cases, 40 cases in each group were included in the analysis. Acupuncture, acupoint injection and auricular point pressing were used in the comprehensive group. Acupuncture for 2 courses was at the affected Tinggong (SI 19), Tinghui (GB 2), Yifeng (TE 17), etc, once every other day, 10 times as a course with one week rest between 2 courses, 3 times a week. Acupuncture as the comprehensive group was applied in the acupuncture group. Mecobalamin tablet was prescribed orally for 2 courses in the western medication group, 3 times a day, 0.5 mg a time, 3 weeks as a course, one week at the interval. Pure tone hearing threshold value and tinnitus grading were observed before and after intervention in the three groups. The clinical effects were compared. RESULTS: After treatment, pure tone hearing threshold value and tinnitus grading were better than those before treatment in the three groups (all P<0.05), with better results in the comprehensive group than those in the other two groups (all P<0.05). The total effective rate of pure tone hearing threshold value was 82.5% (33/40) in the comprehensive group, which was superior to 67.0% (27/40) in the acupuncture group and 62.5% (25/40) in the western medication group (both P<0.05). The total effective rate of tinnitus was 83.3% (30/36) in the comprehensive group, which was superior to 69.7% (23/33) in the acupuncture group and 57.1% (20/35) in the western medication group (both P<0.05). CONCLUSION: The clinical effects of comprehensive therapy on senile sensorineural hearing loss are superior to those of simple acupuncture and oral administration of mecobalamin in terms of pure tone hearing threshold value and tinnitus grading. PMID- 29972003 TI - [Xerophthalmia of qi and yin deficiency treated with jinhuobu needling technique]. AB - OBJECTIVE: To explore the differences in the clinical therapeutic effects on xerophthalmia of qi and yin deficiency between the jinhuobu needling technique (the combined reinforcing technique to induce warm sensation) and the reinforcing needing technique achieved by rotating needle. METHODS: A total of 54 patients of xerophthalmia were randomized into an observation group (28 cases) and a control group (26 cases). In both of the groups, the main acupoints included Cuanzu (BL 2), Sizhukong (TE 23), Taiyang (EX-HN 5) and Fengchi (GB 20); the combined acupoints were Danzhong (CV 17), Sanyinjiao (SP 6), Taixi (KI 3) and Taichong (LR 3). In the observation group, the jinhuobu needling technique was used and in the control group, the reinforcing needing technique achieved by rotating needle was adopted. The treatment was given once every day. 10 treatments made one course and 2 courses were required. Before and after treatment, the score of eye symptoms, tear secretion and the breakup time of tear film were observed in the two groups. The clinical therapeutic effects were compared between the two groups after treatment and in 4-week follow-up after treatment separately. RESULTS: After treatment, the total effective rate was 92.9% (26/28) in the observation group and was 80.8% (21/26) in the control group, without significant difference in comparison (P>0.05). In 4-week follow-up after treatment, the total effective rate was 85.7% (24/28) in the observation group and was 61.5% (16/26) in the control group, indicating the significant difference in comparison (P<0.05). After treatment, the differences were significant in the score of eye symptoms, tear secretion and the breakup time of tear film as compared with those before treatment in the two groups (all P<0.01). After treatment, the improvements of the score of eye symptoms, tear secretion and the breakup time of tear film in the observation group were better remarkably than those in the control group, indicating the significant differences (all P<0.05). CONCLUSION: The jinhuobu needling technique achieves the significant therapeutic effects on xerophthalmia of qi and yin deficiency and the recurrence rate of the disease is low. PMID- 29972004 TI - [Acupoint electrosensitivity and regularity based on bibliometric]. AB - OBJECTIVE: To explore the acupoint electrosensitivity and regularity for assisting the clinical diagnosis and treatment so as to improve the clinical therapeutic effects. METHODS: By means of the computer retrieval (CBMdisc, CNKI, VIP, WanFang, PubMed and EMBASE) and manual retrieval, the relevant literature on acupoint electrosensitivity was reviewed and the modern literature database of acupoint electrosensitivity was established. Using bibliometric, the relations were analyzed among the detected indexes, acupoints, meridians and disorders in the conditions of acupoint electrosensitivity, and the potential regularity was explored. RESULTS: The general detection indexes of acupoint electrosensitivity were resistance, inertia area, volt-ampere area, electric conduction quantity, electric potential, electric current and capacitance. The electrosensitive points included meridian points, auricular points and extraordinary points. Among those points, the electrosensitivity easily occurred at the special points. CONCLUSION: The acupoint electrosensitivity is mainly reflected on the electrical impedance and volt-ampere characteristics. The relative specificity exists between acupoint electrosensitivity and zangfu disorders. In clinical practice, detecting acupoint electrosensitivity may assist the diagnosis and instruct acupoint selection to improve the clinical therapeutic effects. PMID- 29972005 TI - [Comparison of effects of electroacupuncture at "Dachangshu" (BL 25) or "Tianshu" (ST 25) on visceral sensitivity, c-kit and TRPV1 of irritable bowel syndrome rats]. AB - OBJECTIVE: To compare the effects of electroacupuncture (EA) at "Dachangshu" (BL 25) or "Tianshu" (ST 25) for visceral sensitivity, gene expression product c-kit of colonic Cajal interstitial cells (ICC) and capsaicin receptor 1 (TRPV1) of irritable bowel syndrome (IBS) rats, so as to investigate the effect and mechanism differences of EA at the back shu point and the front mu point of large intestine for IBS rats. METHODS: Forty-two Wistar neonatal rats were randomly divided into a blank group (9 rats) and a model group (33 rats). IBS model was established with mother and child separation, acetic acid enema in young rats and colorectal dilatation method. Twenty-seven IBS rats in life were randomly divided into a model control group, a Dachangshu group and a Tianshu group, 9 rats in each group. EA (disperse-dense wave, 2 Hz/100 Hz, 0.1-0.3 mA) for 20 min was used at "Dachangshu" (BL 25) and "Tianshu" (ST 25) respectively in the Dachangshu and Tianshu groups, once every other day, totally 5 times. The rats in the model control group were fixed with soft cloth sleeve for 20 min, without acupuncture. No intervention was used in the blank group. The stool property Bristol grading score was recorded before and after intervention in each group. The visceral sensitivity was evaluated by abdominal withdrawal reflex. The latency until the first systolic wave occurred and the number of systolic wave within 90 s were observed. Immunohistochemical was used to detect the positive expressions of c kit and TRPV1, the ICC colon specific marker. RESULTS: Compared with the blank group, the Bristol score increased,latency period shortened, systolic wave number increased, c-kit and TRPV1 positive expressions increased in the model control group (all P<0.01). Compared with the model control group, the Bristol score decreased, latency period increased, systolic wave number decreased, c-kit and TRPV1 positive expressions decreased after intervention in the Dachangshu and Tianshu groups (P<0.05, P<0.01). Compared with the Dachangshu group, the TRPV1 positive expression decreased after intervention in the Tianshu group (P<0.05). CONCLUSION: EA at "Dachangshu" (BL 25) or "Tianshu"(ST 25) can improve the diarrhea in IBS model rats, reduce the visceral sensitivity, and its mechanism may be related to regulating the expressions of colon c-kit and TRPV1. EA at "Tianshu" (ST 25) is more apparent for TRPV1 than at "Dachangshu" (BL 25). PMID- 29972007 TI - [WANG Leting's academic thoughts on the treatment of stroke]. AB - WANG Leting, known as gold-needle master has its own unique academic system in the treatment of stroke. In view of principle, rule, recipe, acupoint and technique, WANG Leting's academic thoughts were reviewed in the treatment of stroke. In terms of theoretic foundation, treating principles, formula application, rules of acupoint selection and manipulation techniques, the characteristics on the academic thoughts on the treatment of stroke were explained. Professor WANG believes that stroke is caused by deficiency, fire, wind, phlegm, qi and blood. Promoting meridian and collateral circulation, regaining consciousness and cultivating zangfu functions are the treating principles. The acupoint application is characterized as the acupoint selection by stages and the combination of local points with the points in the front and on the back. The penetrating-needling technique and moxibustion are predominated in the treatment. PMID- 29972006 TI - [Study of acupuncture combined with rat nerve growth factor on neurobehavioral ability of cerebral palsy infant rats and its brain tissue growth and metabolism associated proteins]. AB - OBJECTIVE: To study the effects of acupuncture combined with rat nerve growth factor (NGF) on the cerebral palsy infant rats and the proteins which associated with growth, apoptosis and metabolism. METHODS: Seventy infant rats were selected, Fifty infant rats of which were made the cerebral palsy infant model by the ligation of unilateral carotid artery for cerebral ischemia and oxygen deficient environment, then the 30 model rats were randomly divided into a model group, a NGF group and a combined group, 10 rats in each group. Twenty infant rats were used in the sham-operated group and the blank control group, 10 rats in each group. The treatment was not given in the blank control group. The rats in the sham-operated group were cut the neck skin and separated the left carotid artery, and then sutured and disinfected the wound. The intraperitoneal injection of NGF (2000 U*kg-1*d-1) was used in the NGF group. Based on the injection in the NGF group, acupuncture was used in the combined group, once a day, and the acupoints were "Baihui" (GV 20), left "nieI" (extra), "Dazhui" (GV 14), "Jizhong" (extra), "Quchi" (LI 11), "Yongquan" (KI 1), "Hegu" (LI 4), "Zhoujie" (extra) and "Xiqianxue" (extra). The same volume of saline was intraperitoneally injected in the model group for continuous 14 days. Neurobehavioral ability score was evaluated after treatment. TUNEL were conducted to detect the brain cell apoptosis rate and the expressions of apoptosis associated gene Bax, Bcl-2 and Casp3 were detected by PCR. The level of nerve growth associated protein (GAP-43) and energy metabolism-related protein monocarboxylate transporter protien 1(MCT 1) were detected by Western blot. RESULTS: After intervention, the neurobehavioral ability of baby rats in the blank control and sham-operated group was normal, but there was various degrees of abnormity in the model group, NGF group and combined group. The scores of neurobehavioral ability of the combined group and NGF group were better than those of the model control (all P<0.05), and the scores in the combined group was better than those in the NGF group (all P<0.05). The left brain cell apoptosis rate, expressions of Bax and Casp3 in the combined group and NGF group were lower and the expressions of Bcl-2 were higher than those of the model group (all P<0.05), with more obvious results of Bax and Gasp3 in the combined group than those in the NGF group (all P<0.05). The protein levels of GAP-43 and MCT 1 in the combined group and NGF group were higher than those in the model group (all P<0.05), with higher expressions in the combined group compared with those in the NGF group (both P<0.05). CONCLUSION: Acupuncture combined with NGF could improve the neurobehavioral ability of cerebral palsy infant rats, inhibit the nerve cell apoptosis and improve the brain tissue injure and energy metabolism by up-regulating the expressions of GAP-43 and MCT 1. PMID- 29972008 TI - [JIN Bohua's experience in the clinical acupuncture treatment of trigeminal neuralgia with fire needle and filiform needle]. AB - To introduce the experience of JIN Bohua, the capital Chinese medicine master, in the differentiation of acupuncture and the treatment on trigeminal neuralgia with fire needle and filiform needle. Regarding the diagnosis of trigeminal neuralgia, Professor JIN focuses on the coordination of meridian differentiation and zangfu differentiation. For the treatment, the fire needling technique and common filiform needling technique are used in combination. According to meridian differentiation, the acupoints are selected and stimulated with fire needle. In reference to zangfu, qi and blood differentiation, the treatment with filiform needles is applied. "The holistic treatment" and "seeking for the root cause of disorder" are the basic principle to be complied. When treating with filiform needle, Professor JIN emphasizes the needling sequence, meaning stimulating the acupoints in the lower part of the body before those in the upper part of the body, aiming to eliminating the pathogens and strengthening the antipathogenic qi. PMID- 29972009 TI - [Teaching exploration and practice of research experiment of experimental curriculum in Principle and Application of Acupuncture-Moxibustion Equipment]. AB - In order to improve students' ability of performing investigative study, promote practical teaching, optimize teaching philosophy and methods, we integrated the subject frontier dynamics and development achievements and knowledge into teaching content, the teaching exploration and practice of research experiment of experimental curriculum in Principle and Application of Acupuncture-Moxibustion Equipment was performed. The experimental curriculum was used as starting point. Before experimental teaching, the learning of knowledge was completed by theoretical study and key self-study points. During experimental teaching, experimental report and analysis report were completed by group collaboration. After experimental teaching, the research experiment was reported, analyzed and summarized by group discussion and presentation. With innovate, flexible and diverse teaching forms to guide the students to experience the process of "asking questions->conducting experiment->observation->recording->analysis->conclusion >verification of assumptions-discussion->reports", the ability of independent thinking and active investigation was improved; teaching level and teaching effectiveness were promoted. PMID- 29972010 TI - [Essential characteristics and clinical treatment regularity of acupuncture therapy]. AB - As an external therapy, acupuncture has its own essential characteristics and clinical treatment regularity. The nature, the unique view and feasible factor of acupuncture are different totally from those of the internal therapy with Chinese herbal medicine. The thought of the internal therapy does not benefit the essential characteristics of acupuncture clinical practice, named the external therapy is used for either the external disorders or the internal disorders. In macroscopic view, the human body disorder is divided into yang disorder (body surface disorder, somatopathy) and yin disorder (internal disorder, splanchnopathy), which contributes to the general rule of the diagnosis and treatment. The classical meridian system is practical, highly-effective and specific in the treatment guidance for somatopathy in light of the rule as using the external therapy for the external disorder. This system is also important in the treatment for the internal disorder. But, a further study is required to remove the flaws. PMID- 29972011 TI - [Investigation on Qidong in Qidongzeyou in Book of Pulse (Maishu), the bamboo slips of Han Dynasty in Zhangjiashan]. AB - Qidong ( qi change) in Qidongzeyou ((), pulse change indicates the abnormal changes inside body) in the Book of Pulse (Maishu), the Bamboo Slips of Han Dynasty in Zhangjiashan is related to the classical thought on qi and the theory on meridians at early era. The connotation of qidong was explored in views of interdisciplinary perspectives, such as Chinese medicine, philology and qi philosophy in the ancient time. It refers to the pulse changes as mentioned in ancient medical books, indicating the abnormal changes in the body. Before the ancient medical canonization marked as sphygmology, the ancient medical scholar focused on qi monism. Based on the thinking mode as analogy and detecting the root from the phenomenon, it is believed that qidong refers to the imbalance of qi activity inside the body, manifested with the abnormal pulse change at relevant pulse region on the body surface. Accordingly, the disorders inside the body are detected by palpation. PMID- 29972012 TI - [Rules on the combination of acupuncture and herbal medicine for taiyang diseases treated by CHENG Dan-an]. AB - CHENG Dan-an experience was summarized regarding the rules on the combination of acupuncture and herbal medicine for taiyan diseases. Through collecting the materials on the treatment for taiyang diseases with TCM by CHENG Dan-an, the acupoint prescriptions in medical cases were extracted. Using Excel 2010 software, the prescription database was set up. SPSS 23.0 software and Clementine 12.0 software were adopted for the frequency analysis, association rule analysis and cluster analysis. The top 3 high-frequency used acupoints are Zusanli (ST 36), Hegu (LI 4) and Jianshi (PC 5). The top 4 high-frequency used herbs are liquorice, cassia twig, Chinese-date and fresh ginger. The cluster analysis showed that there are 5 combinations with the major acupoints and herbal medicine. The combinations of guizhi tang and the acupoint prescriptions based on the syndrome differentiation as well as banxia xiexin tang and the related acupoint prescriptions play the significant role in the treatment of digestive disorders. The analysis on the rules on the combination of acupuncture and herbal medicine for taiyang diseases treated by CHENG Dan-an provides the approaches to the combination of acupuncture and herbal medicine for the clinical treatment of taiyang diseases, aiming at the mutual improvement of the clinical therapeutic effects. PMID- 29972013 TI - [Acupoint selection pattern of chronic atrophic gastritis based on data mining methods of latent structure model and frequency item set]. AB - OBJECTIVE: To explore the acupoint selection pattern of chronic atrophic gastritis and provide reference for clinical treatment of chronic atrophic gastritis. METHODS: The literature regarding acupuncture for chronic atrophic gastritis published before September 5th of 2016 was searched in the databases of CNKI, CBM, PubMed, etc. The information of symptoms and acupoint selection was extracted to establish medical database of chronic atrophic gastritis. The data mining methods of latent structure model and frequency item set were applied to analyze the acupoint selection pattern of chronic atrophic gastritis. RESULTS: A total of 42 papers were collected in preliminary screening, and 32 papers were included, involving 604 medical cases. The data mining indicated 215 symptoms were involved in medical cases, including 16 high-frequency symptoms (stomach pain, stomach distension and hiccup, etc.), and the latent structure model of chronic atrophic gastritis symptoms was established. Fifty-two acupoints were identified, and high-frequency acupoints included Zusanli (ST 36), Zhongwan (CV 12), Neiguan (PC 6) and Weishu (BL 21), etc. Five frequency item sets of symptom acupoint were identified, including stomach pain+stomach distension+Zusanli (ST 36)+Zhongwan (CV 12), etc. Six frequency item sets of symptom-syndrome-acupoint were identified, including stomach distension+dry mouth+dry defecation+insufficiency of stomach yin+Sanyinjiao (SP 6). CONCLUSION: Acupuncture for chronic atrophic gastritis selected Zusanli (ST 36), Zhongwan (CV 12) and Neiguan (PC 6) as main acupoints, and selected other acupoints based on clinical symptoms. This could provide reference for clinical treatment of chronic atrophic gastritis. PMID- 29972014 TI - [Design of new-style embedded acupoint recognition device]. AB - A new type of embedded acupoint recognition device was developed for acupoint recognition and teaching. Through improving the acupoint electric resistance detection technique of the two-electrode method, combined with mechanical structure design and embedded control technology, the human acupoint database was assembled in the embedded chip with the international symbol, acupoint name, pinyin, location, chart, manuscript and audio information included, a new type of embedded acupoint recognition device was designed. The device was composed of 3 modules, named the acupoint electric resistance detection system, the embedded control system and mechanical system. It achieved skin contact sensation, the collection of electric resistance at the required skin region, the wireless communication, the liquid crystal display (LCD) human-computer interaction and acupoint magnetic head massage. When used, the resistance value of the detected skin is read on LCD to determine whether the detected skin resistance meets the features of low resistance of acupoint and further to identify the acupoint zone. Afterward, the data collected are matched with the human acupoint database to determine the information of acupoint. The control mechanical structure achieves the acupoint pressing and kneading. After verified by many operation staff, it is shown that the device not only improves the recognition speed and precision of acupoint, but also contributes to the acupoint teaching with the human acupoint database displayed on LCD. The achievements benefit the promotion of meridians and acupoints as well as the development of acupuncture devices. PMID- 29972015 TI - [Comparison of the current situation of the randomized controlled trials in the treatment of anxiety with acupuncture at home and abroad]. AB - OBJECTIVE: Through comparing the literature on the randomized controlled trials (RCTs) of acupuncture for anxiety in Chinese and English versions, the participants, the interventions and the outcomes of the therapeutic effect evaluation in acupuncture treatment for anxiety were analyzed so as to provide the references to the high quality clinical research in the future. METHODS: The literature was retrieved on RCTs of acupuncture for anxiety at home and abroad. According to the principles and the methods of the evidence-based medicine, the information on the type of clinical research, participants, interventions and outcomes was extracted and analyzed. RESULTS: A total of 106 valid papers of the Chinese and English versions were collected. In the study at home and abroad, the concepts and recognitions were indistinct among anxiety disorder, anxious emotion and secondary anxiety disorder. The diagnostic criteria were different. Regarding the intervention, the body acupuncture was predominated in the study at home and abroad, focusing on the mind regulation. The acupoints were mainly selected for tranquilizing the mind, promoting the circulation of the governor vessel and removing irritability. Additionally, the auricular acupuncture was often adopted in the treatment of anxious emotion in foreign countries. Regarding the outcomes in the effect evaluation, the scales were not so standardized in the selection and application. The analysis was limited on the factors of the anxiety scales and the survival quality. CONCLUSION: There are the differences in the diagnostic criteria, participant inclusion, intervention and outcomes in the clinical research of anxiety treated with acupuncture at home and abroad. A rigorous design is required in the high quality clinical research for the evaluation on the therapeutic effects of acupuncture on anxiety. PMID- 29972016 TI - Identifying the Rate-Limiting Elementary Steps of Nitrogen Fixation with Single Site Fe Model Complexes. AB - Biomimetic nitrogen fixation provides an attractive alternative for the century old Haber-Bosch process; however, the performance of the currently available molecular biomimetic catalysts is very limited. In this work, we are aiming to understand the catalytic cycle of one of the most promising biomimetic complex families that can be the cornerstone of future computer-aided rational design of biomimetic complexes. We calculate the Gibbs free energy of all elementary reaction steps of homogeneous dinitrogen reduction to NH3 on single-site iron complexes with EPPP tetradentate ligands (E = B, Si). We examine all possible mechanisms and identify the dominant pathways and the critical elementary steps that can be rate-determining in the catalytic cycle of nitrogen fixation. We find that the catalytic mechanism depends on the applied ligand and that the distal pathway observed with E = B is the most favorable route regarding the catalytic performance. Our calculations also reveal the lack of thermodynamic driving force in the last steps of the catalytic cycle that can be responsible for the low catalytic activity of the studied biomimetic catalysts. Our results can serve as a starting point for the rational design of biomimetic complexes, which should focus on establishing a steadily decreasing Gibbs free energy profile, as suggested by the Sabatier principle. PMID- 29972017 TI - Detection and Characterization of Different Brain-Derived Subpopulations of Plasma Exosomes by Surface Plasmon Resonance Imaging. AB - The use of exosomes for diagnostic and disease monitoring purposes is becoming particularly appealing in biomedical research because of the possibility to study directly in biological fluids some of the features related to the organs from which exosomes originate. A paradigmatic example are brain-derived exosomes that can be found in plasma and used as a direct read-out of the status of the central nervous system (CNS). Inspired by recent remarkable development of plasmonic biosensors, we have designed a surface plasmon resonance imaging (SPRi) assay that, taking advantage of the fact that exosome size perfectly fits within the surface plasmon wave depth, allows the detection of multiple exosome subpopulations of neural origin directly in blood. By use of an array of antibodies, exosomes derived from neurons and oligodendrocytes were isolated and detected with good sensitivity. Subsequently, by injecting a second antibody on the immobilized vesicles, we were able to quantify the amount of CD81 and GM1, membrane components of exosomes, on each subpopulation. In this way, we have been able to demonstrate that they are not homogeneously expressed but exhibit a variable abundance according to the exosome cellular origin. These results confirm the extreme variability of exosome composition and demonstrate how SPRi can provide an effective tool for their characterization. Besides, our work paves the road toward more precise clinical studies on the use of exosomes as potential biomarkers of neurodegenerative diseases. PMID- 29972018 TI - Electrical Rectifying and Photosensing Property of Schottky Diode Based on MoS2. AB - Heterojunction based on two-dimensional (2D) layered materials is an emerging topic in the field of nanoelectronics and optoelectronics. Here, molybdenum sulfide (MoS2)-based Schottky diodes were fabricated using the field-effect transistor configuration with asymmetric metal contact structure. Gold and chromium electrodes were employed as drain and source electrodes to form Ohmic and Schottky contact with MoS2, respectively. The devices exhibited electrical rectifying characteristic with the current rectifying ratio exceeding 103 and an ideal factor of 1.5. A physics model of the band diagram was proposed to analyze the gate-tunable rectifying behavior of the device. The dynamic rectification based on the diode circuit was further realized with the operating frequency up to 100 Hz. The devices were also demonstrated to show different sensitivities to the light under external biases in the opposite directions, with the highest photoresponsivity reaching 1.1 * 104 A/W and specific detectivity up to 8.3 * 1012 Jones at a forward drain bias of 10 V. This kind of 2D material-based Schottky diodes have the advantage of simplicity in design and fabrication, as well as superior electrical rectifying and photosensing characteristics, which have great potential for future integrated electronic and optoelectronic applications. PMID- 29972019 TI - Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions Consisting of Five Membered Ring Selective Prins Cyclization and Friedel-Crafts Cyclization. AB - A novel cascade reaction consisting of a five-membered ring selective Prins cyclization and a subsequent Friedel-Crafts cyclization is reported. Treatment of homocinnamyl alcohols and aromatic aldehydes with BF3.OEt2 in CH2Cl2 afforded hydrocyclopentafurans. Also hydrocyclopentafurans underwent the same cascade reaction after its furan ring cleavage upon treatment with BF3.OEt2 at room temperature. Various combinations of hydropentafurans and aromatic aldehydes or indole aldehydes permitted divergent synthesis of diquinane-furans stuck in aromatic rings. PMID- 29972020 TI - Metal-Free All-Carbon Nanohybrid for Ultrasensitive Photoelectrochemical Immunosensing of alpha-Fetoprotein. AB - C60 can accept up to six electrons reversibly and show exceptional light absorption over the entire UV-vis spectrum, making it a potential photoactive probe for photoelectrochemical (PEC) bioassay. However, few successful works have been reported to apply fullerenes in PEC biosensing, partially because of the low electronic conductivity and poor interfacial interactions with targeted biomolecules. Herein, we report the addressing of these two obstacles by coupling high conductive graphite flake (Gr), graphene oxide (GO) with sufficient oxygen containing functional groups, and an alkylated C60 (AC60) into a metal-free all carbon nanohybrid (AC60-Gr-GO) via harnessing delicate noncovalent interactions among them through a facile mechanical grinding. It was revealed that the as obtained AC60-Gr-GO nanohybrid not only showed conspicuous enhancement of photocurrent up to 35 times but also offered rich anchors for bioconjugation. With detection of alpha-fetoprotein as an example, the AC60-Gr-GO based PEC immunosensor demonstrated a broad linear detection range (1 pg.mL-1 to 100 ng.mL 1) and a detection limit as low as 0.54 pg.mL-1, superior/competitive to PEC immunosensors for AFP in previous reports. By a proper reinforcement in conductivity and biointerface engineering, this work may provide a new way to use fullerenes as photoactive materials in more general PEC biosensing. PMID- 29972021 TI - PEGylated Self-Growth MoS2 on a Cotton Cloth Substrate for High-Efficiency Solar Energy Utilization. AB - Solar steam generation, utilizing abundant solar energy and floating photothermal materials, has been considered as one of the most sustainable, efficient ways to solve the problem of water shortage. Here, a new system for solar steam generation is fabricated based on a PEGylated MoS2-cotton cloth (PMoS2-CC). 80.5 90 +/- 3.5% of high-efficiency solar steam generation is achieved under a light density of 1-5 kW m-2 because of the good gas permeability of CC and the hydrophilic property of PMoS2-CC. The self-growth PMoS2-CC provides good photothermal performances in pure water and saline water. The water evaporation rate with PMoS2-CC keeps a stable value after a long-time illumination (4 h) and 32 times cycle tests. Our result provides a way to prepare pure water in the applications for alleviating a scarcity of drinking water. PMID- 29972022 TI - Superhydrophobic Photosensitizers: Airborne 1O2 Killing of an in Vitro Oral Biofilm at the Plastron Interface. AB - Singlet oxygen is a potent agent for the selective killing of a wide range of harmful cells; however, current delivery methods pose significant obstacles to its widespread use as a treatment agent. Limitations include the need for photosensitizer proximity to tissue because of the short (3.5 MUs) lifetime of singlet oxygen in contact with water; the strong optical absorption of the photosensitizer, which limits the penetration depth; and hypoxic environments that restrict the concentration of available oxygen. In this article, we describe a novel superhydrophobic singlet oxygen delivery device for the selective inactivation of bacterial biofilms. The device addresses the current limitations by: immobilizing photosensitizer molecules onto inert silica particles; embedding the photosensitizer-containing particles into the plastron (i.e. the fluid-free space within a superhydrophobic surface between the solid substrate and fluid layer); distributing the particles along an optically transparent substrate such that they can be uniformly illuminated; enabling the penetration of oxygen via the contiguous vapor space defined by the plastron; and stabilizing the superhydrophobic state while avoiding the direct contact of the sensitizer to biomaterials. In this way, singlet oxygen generated on the sensitizer-containing particles can diffuse across the plastron and kill bacteria even deep within the hypoxic periodontal pockets. For the first time, we demonstrate complete biofilm inactivation (>5 log killing) of Porphyromonas gingivalis, a bacterium implicated in periodontal disease using the superhydrophobic singlet oxygen delivery device. The biofilms were cultured on hydroxyapatite disks and exposed to active and control surfaces to assess the killing efficiency as monitored by colony counting and confocal microscopy. Two sensitizer particle types, a silicon phthalocyanine sol-gel and a chlorin e6 derivative covalently bound to fluorinated silica, were evaluated; the biofilm killing efficiency was found to correlate with the amount of singlet oxygen detected in separate trapping studies. Finally, we discuss the applications of such devices in the treatment of periodontitis. PMID- 29972023 TI - Toward Capturing the Exposome: Exposure Biomarker Variability and Coexposure Patterns in the Shared Environment. AB - Many factors affect the variation in the exposome. We examined the influence of shared household and partner's sex in relation to the variation in 128 endocrine disrupting chemical (EDC) exposures among couples. In a cohort comprising of 501 couples trying for pregnancy, we measured 128 (13 chemical classes) persistent and nonpersistent EDCs and estimated 1) sex-specific differences; 2) variance explained by shared household; and 3) Spearman's rank correlation coefficients ( rs) for females, males, and couples' exposures. Sex was correlated with 8 EDCs including per- and polyfluoroalkyl substances (PFASs) ( p < 0.05). Shared household explained 43% and 41% of the total variance for PFASs and blood metals, respectively, but less than 20% for the remaining 11 EDC classes. Coexposure patterns of the exposome were similar between females and males, with within class rs higher for persistent than for nonpersistent chemicals. Median rss of polybrominated compounds and urine metalloids were 0.45 and 0.09, respectively, for females (0.41 and 0.08 for males; 0.21 and 0.04 for couples). Our findings suggest that individual, rather than shared environment, could be a major factor influencing the covariation of the exposome. Understanding the correlations of exposures has important analytical and sampling implications for exposomics research. PMID- 29972024 TI - Multifunctional Activity-Based Protein Profiling of the Developing Lung. AB - Lung diseases and disorders are a leading cause of death among infants. Many of these diseases and disorders are caused by premature birth and underdeveloped lungs. In addition to developmentally related disorders, the lungs are exposed to a variety of environmental contaminants and xenobiotics upon birth that can cause breathing issues and are progenitors of cancer. In order to gain a deeper understanding of the developing lung, we applied an activity-based chemoproteomics approach for the functional characterization of the xenometabolizing cytochrome P450 enzymes, active ATP and nucleotide binding enzymes, and serine hydrolases using a suite of activity-based probes (ABPs). We detected P450 activity primarily in the postnatal lung; using our ATP-ABP, we characterized a wide range of ATPases and other active nucleotide- and nucleic acid-binding enzymes involved in multiple facets of cellular metabolism throughout development. ATP-ABP targets include kinases, phosphatases, NAD- and FAD-dependent enzymes, RNA/DNA helicases, and others. The serine hydrolase targeting probe detected changes in the activities of several proteases during the course of lung development, yielding insights into protein turnover at different stages of development. Select activity-based probe targets were then correlated with RNA in situ hybridization analyses of lung tissue sections. PMID- 29972025 TI - EUROVISCO Guidelines for the Design and Conduct of Clinical Trials Assessing the Disease-Modifying Effect of Knee Viscosupplementation. AB - Objectives Hyaluronic acid viscosupplementation is a commonly used intra articular treatment for osteoarthritis (OA). Some recent preclinical and clinical trials have demonstrated a potential for its disease-modifying effects. The goal of this expert opinion, consensus-driven exercise is to provide guidelines for the design and conduct of clinical trials assessing the disease-modifying effect of viscosupplementation in the knee. Methods The EUROVISCO group constitutes 10 members who had expertise in clinical research methodology in the field of OA and viscosupplementation. They initially drafted issues through an iterative process and had to vote on their degree of agreement on these recommendations. The scores were pooled to generate a median agreement score for each recommendation. Results The document includes 31 recommendations regarding study population, imaging, clinical and biological assessment of disease-modifying effects of viscosupplementation. Agreements were reached on some recommendations. In particular, the experts reached unanimous agreement on double-blind study design, imaging primary outcomes, time interval between 2 radiographs, x-ray procedure standardization, and the combined use of imaging and biological markers. The group did not recommend the use of ultrasonography, computed tomography (CT) scan and CT arthrography as a tool for OA diagnosis or to assess progression over time. Conclusion In summary, the working group identified 31 recommendations that represent the current best practices regarding clinical trials that target the assessment of viscosupplementation disease-modifying effects in patients with knee OA. These recommendations integrate new imaging technologies and soluble biomarkers. PMID- 29972026 TI - Epigenome mapping of human normal purified hepatocytes: personal epigenome variation and genome-epigenome correlation. AB - AIM: The aim of this study was to reveal the epigenome landscape of human normal hepatocytes. MATERIALS & METHODS: Cells purified from partial hepatectomy specimens of Japanese patients were subjected to whole-genome bisulfite sequencing using postbisulfite adaptor tagging, chromatin immunoprecipitation sequencing, RNA sequencing and whole-genome sequencing. RESULTS: CHG and CHH methylations were inversely associated with gene expression. Histone modification profiles of personal differentially methylated regions (pDMRs) differed considerably among samples. pDMRs were observed around the transcription start sites of genes whose expression is reportedly regulated by CpG methylation. pDMRs were frequently observed in the vicinity of single-nucleotide variations and insertions/deletions. CONCLUSION: Genetic variations may induce epigenetic variations, generating individual differences in the phenotypes of normal hepatocytes through variations in expression. PMID- 29972027 TI - Soloist performance of vitrectomy probe in proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the feasibility and outcomes of the sole use of 23g pars plana vitrectomy in cases with diabetic vitreous hemorrhage with vitreoretinal traction. METHODS: Prospective interventional case series involving patients between January 2013 and January 2018. All eyes underwent 23g pars plana vitrectomy with internal tamponade. Intraoperative parameters including ancillary instruments, the methods used for hemostasis and complications were all recorded. Postoperative parameters including anatomic success rate, functional success, and postoperative complications were recorded and analyzed. Patients were followed up for at least 12 months. RESULTS: A total of 68 eyes of 66 patients were included. Intraoperative ancillary instruments were required in 5 (7.4%) eyes. None of the cases required the use of chandelier illumination, endodiathermy, or scissors. Mean best-corrected visual acuity improved significantly from LogMAR 1.67 +/- 0.63 preoperative to 1.22 +/- 0.38 at 1-year follow-up (P = 0.005). Functional success was achieved in 37 (54.4%) eyes at 1-year follow-up. Iatrogenic breaks occurred in 3 (4.4%) eyes, vitreous hemorrhage in 4 (5.9%) eyes, and epiretinal membranes in 3 (4.4%) eyes. Repeated vitrectomy was done in 3 (4.4%) eyes. CONCLUSION: The 23g vitrectomy probe proved to be a safe, effective, and beneficial single tool that could accomplish the diabetic vitrectomy mission exclusively with minimal aid from other instruments in cases with vitreous hemorrhage associated with vitreoretinal traction. PMID- 29972028 TI - Effect of Postoperative Ketorolac Administration on Bone Healing in Ankle Fracture Surgery. AB - BACKGROUND: In an effort to minimize narcotic analgesia and its potential side effects, anti-inflammatory agents offer great potential provided they do not interfere with bone healing. The safety of ketorolac administration after foot and ankle surgery has not been well defined in the current literature. The purpose of this study was to report clinical healing and radiographic outcomes for patients treated with a perioperative ketorolac regimen after open reduction and internal fixation (ORIF) of ankle fractures. METHODS: A retrospective review was performed on all patients that received perioperative ketorolac at the time of lateral malleolar, bimalleolar, and trimalleolar ankle ORIF by a single surgeon between 2010 and 2016 with minimum 4 months follow-up. Patients received 20 tablets of 10 mg ketorolac Q6 hours. Radiographs were evaluated independently by 2 blinded fellowship-trained orthopedic foot and ankle surgeons to assess for radiographic healing. A total of 281 patients were included, with a median age of 51 years and 138 males (47%). Statistical analysis consisted of a linear mixed effects regression. RESULTS: In all, 265/281 (94%) were clinically healed within 12 weeks and 261/281 (92%) were radiographically healed within 12 weeks. Within the group of patients that did not heal within 12 weeks, mean time to clinical healing was 16.9 weeks (range = 14-25 weeks), and mean time to radiographic healing was 17.1 weeks (range = 14-25 weeks). In patients taking ketorolac, there were no cases of nonunion in our series (n = 281) and no significant difference found between fracture patterns and healing or complications ( P = .500). CONCLUSIONS: Perioperative ketorolac use was associated with a high rate of fracture union by 12 weeks. This is the first study to examine the effect of ketorolac on radiographic time to union of ankle fractures. Additional studies are necessary to determine whether ketorolac helps reduce opioid consumption and improve pain following ORIF of ankle fractures. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29972029 TI - Clinical presentation of optic neuritis with autoantibodies anti-myelin oligodendrocyte glycoprotein. AB - PURPOSE: Myelin oligodendrocyte glycoprotein autoantibodies are associated with certain optic neuritis. Little data are known about the specificity of the initial ophthalmologic presentation. METHODS: A monocentric retrospective study (2013-2017) of all patients diagnosed with myelin oligodendrocyte glycoprotein+ optic neuritis in a tertiary ophthalmologic unit was conducted. The primary objective was to define the clinical ophthalmologic description of the first episode. The secondary objective was to evaluate the evolution and final diagnosis. RESULTS: A total of nine patients were included. There was no female predominance (sex ratio f/m = 0.8). At the first optic neuritis episode, the average age was 39.3 years (17-67 years, standard deviation: 18.4). Initial visual acuity was low (+1.07logMAR, standard deviation: 0.77); 5 eyes out of 15 had visual acuity +2logMAR or worse. Optic neuritis was mostly painful (8/9) and bilateral (6/9) but asymmetric. Optic disk swelling was reported in 9/15 eyes and 7/9 patients and was significantly associated with lower visual acuity in the acute phase (+1.46logMAR, standard deviation: 0.67 vs +0.5, standard deviation: 0.55; p = 0.03). After a mean observation period of 3.3 years (0.6-9.4 years, standard deviation: 3.4), median visual acuity was 0.05logMAR. All five patients were followed up for more than 1 year (5.4 years, standard deviation: 3.2) had 3 8 relapses (mean: 4.4, standard deviation: 2.1; annualized relapse rate: 1.2, standard deviation: 0.9). Final diagnosis was chronic relapsing idiopathic optic neuritis (n = 4), clinically isolated optic neuritis (n = 3), and neuromyelitis optica spectrum disorder aquaporin 4- (n = 2). CONCLUSION: Myelin oligodendrocyte glycoprotein+ optic neuritis has an atypical clinical presentation compared with multiple sclerosis and neuromyelitis optica spectrum disorder aquaporin 4+. Its evolution is closer to neuromyelitis optica spectrum disorder aquaporin 4+, with a better visual outcome. PMID- 29972030 TI - Objective and subjective poor mental health indicators among Arab Americans in Michigan: a population-based study. AB - BACKGROUND: Arab Americans are at high risk for poor mental health outcomes and are difficult to study at a population level due to a lack of racial/ethnic identifiers for this population. METHODS: Using data from the standalone 2013 Michigan Arab Behavioral Risk Factor Survey (MI ABRFS) we aimed to understand whether the burden of mental health differed between Arab Americans and non-Arab, non-Hispanic Whites. Two measures of mental health were used: a subjective (number of poor mental health days experienced in the past 30 days) and an objective (being diagnosed with depression) measure. Additionally, we aimed to understand the sociodemographic, stress, and health-related variables associated with the objective and subjective measures of psychopathologies in the Arab American population in Michigan using population-weighted logistic regression models with survey design correction. RESULTS: Arab Americans had increased odds of adverse mental health when compared to non-Arab, non-Hispanic Whites for the subjective measure of number of poor mental health days (OR: 1.62, 95% CI: 1.08, 2.41) and decreased odds of reporting the objective measure of diagnosed depression (OR: 0.54, 95% CI: 0.30, 0.98). Having more than one poor mental health day and being diagnosed with depression among Arab Americans was associated with being female, unmarried, unemployed, and having experienced abuse as a child. DISCUSSION: Combining mental health screenings with primary care check-ups among Arab Americans may be an important step in identifying individuals with mental health needs and extending access to care. PMID- 29972031 TI - A new flavonoid derivative and a new 5-hydroxyanthranilic acid derivative from the sea urchin-derived Streptomyces sp. HDa1. AB - One new flavonoid derivative flavoside A (1), one new 5-hydroxyanthranilic acid derivative crassilin (2), along with the known angucyclinone PD116740 (3) and oxachelin (4), was isolated from the EtOAc extract of the fermentation broth of the sea urchin (Anthocidaris crassispina)-derived actinobacterium, Streptomyces sp. HD01. The structures of these compounds were established on the basis of their HR-ESI-MS and NMR spectroscopic data. All of these compounds were assessed for their antibacterial activity. PMID- 29972032 TI - Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta analysis and Mixed Treatment Comparison of Randomized Trials. AB - BACKGROUND: The comparative effects of droxidopa and midodrine on standing systolic blood pressure (sSBP) and risk of supine hypertension in patients with neurogenic orthostatic hypotension (NOH) are unknown. OBJECTIVE: To perform a Bayesian mixed-treatment comparison meta-analysis of droxidopa and midodrine in the treatment of NOH. METHODS: The PubMed, CENTRAL, and EMBASE databases were searched up to November 16, 2016. Study selection consisted of randomized trials comparing droxidopa or midodrine with placebo and reporting on changes in sSBP and supine hypertension events. Data were pooled to perform a comparison among interventions in a Bayesian fixed-effects model using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled mean changes in sSBP and risk ratios (RRs) for supine hypertension with associated 95% credible intervals (CrIs). RESULTS: Six studies (4 administering droxidopa and 2 administering midodrine) enrolling a total of 783 patients were included for analysis. The mean change from baseline in sSBP was significantly greater for both drugs when compared with placebo (droxidopa 6.2 mm Hg [95% CrI = 2.4-10] and midodrine 17 mm Hg [95% CrI = 11.4-23]). Comparative analysis revealed a significant credible difference between droxidopa and midodrine. The RR for supine hypertension was significantly greater for midodrine, but not droxidopa, when compared with placebo (droxidopa RR = 1.4 [95% CrI = 0.7-2.7] and midodrine RR = 5.1 [95% CrI = 1.6-24]). Conclusion and Relevance: In patients with NOH, both droxidopa and midodrine significantly increase sSBP, the latter to a greater extent. However, midodrine, but not droxidopa, significantly increases risk of supine hypertension. PMID- 29972033 TI - Computerized Adaptive Testing for Patient Reported Outcomes in Ankle Fracture Surgery. AB - BACKGROUND: Advantages of using computerized adaptive testing (CAT) include decreased survey-burden, diminished floor and ceiling effect, and improved ability to detect the minimal clinical significant difference (MCID) among patients. The goal of this study was to compare the legacy patient-reported outcome measures (PROMs) to the Patient-Reported Outcomes Measurement Information System (PROMIS) scores in terms of ability to detect clinically significant changes in patients who have undergone surgery for ankle fractures. METHODS: Patients who underwent osteosynthesis for an unstable ankle fracture between 2013 2016 and completed legacy outcome scores (Foot and Ankle Outcome Score [FAOS], Olerud and Molander Ankle Score [OMAS], and Weber Score) along with the PROMIS Physical Function (PF) and PROMIS Lower Extremity (LE) CATs postoperatively were included. Correlation between the scores at 3-month, 6-month, and 1-year intervals, as well as floor and ceiling effects, in addition to MCIDs were calculated for each instrument. A total of 132 patients were included in the study. RESULTS: There was no observed floor or ceiling effect in either the PROMIS PF or the PROMIS LE scores. Clinically significant changes in the PROMIS LE score were detected in patients between 6-month and 12-month postoperative visits ( P = .0006), whereas the reported OMAS score and Weber scores did not identify a clinically significant difference between patients at their 6-month and 12-month visit. CONCLUSION: The results of this study indicate that the PROMIS LE was superior for evaluating patients following ankle fracture surgery in terms of lower floor and ceiling effects and greater ability to distinguish clinically significant changes in patients between time points following surgery. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 29972035 TI - Fostering Social Connection in the Workplace. PMID- 29972034 TI - New adenine analogues and a pyrrole alkaloid from Selaginella delicatula. AB - Phytochemical study on the n-BuOH extract of Selaginella delicatula lead to the isolation, characterization and structure elucidation of two new adenine analogues, delicatulines A (1) and B (2), one new pyrrole alkaloid (4), and five known compounds (3, 5-8). These new substances all contain an aliphatic chain in their parent nucleus, which were unusual to find in plants. In the present study, they were identified from Selaginellaceae for the first time. The structures and absolute configurations of these new compounds were determined by a combination of NMR and CD spectroscopic analyses. Compounds 1, 3 and 4 were evaluated for their inhibitory activities on HBV surface antigen and HBV DNA in HepAD38 cells. The results showed that these compounds had only weak or no inhibitive effects on HBV. PMID- 29972036 TI - The FACCTs of (Work) Life: How Relationships (and Returns) Are Linked to the Emotional Culture of Companionate Love. PMID- 29972037 TI - Working to Address the Loneliness Epidemic: Perspective-Taking, Presence, and Self-Disclosure. PMID- 29972038 TI - Closing Commentary: Is Technology Making Us More Disconnected? PMID- 29972039 TI - Corrigendum. AB - Corrigendum to ICRP Publication 137: Occupational intakes of radionuclides: Part 3. [Ann. ICRP 46(3/4), 2017]. DOI: 10.1177/0146645317734963 . The following errors have been identified. ICRP apologises for any inconvenience or confusion caused by these errors. [Table: see text][Table: see text][Table: see text][Table: see text]. PMID- 29972040 TI - The bottleneck of cardiac rehabilitation for patients with coronary artery disease: How to overcome. PMID- 29972042 TI - ? PMID- 29972041 TI - Interleukin-18 and the NLR family pyrin domain containing-3 inflammasome in adipose tissue are strongly associated with glucometabolic variables in a cohort of middle-aged men. AB - BACKGROUND: Previous studies have indicated an association between interleukin-18 and glucose. Interleukin-18 becomes active when cleaved by caspase-1, activated by the NLR family pyrin domain containing-3 inflammasome. AIM: To investigate associations between glucometabolic variables and serum levels of interleukin-18 and genetic expression of interleukin-18, caspase-1 and NLR family pyrin domain containing-3 in adipose tissue and circulating leukocytes, and whether these mediators are related to the amount of abdominal adipose tissue . MATERIALS AND METHODS: Fasting blood samples and subcutaneous adipose tissue were collected in a cohort of 103 middle-aged men. Serum levels of interleukin-18 were determined by enzyme-linked immunosorbent assay, gene expression by real-time polymerase chain reaction and insulin sensitivity by glucose clamp. The distribution of abdominal adipose tissue, separated into superficial- and deep subcutaneous, and visceral adipose tissue, was assessed by computed tomography scan. RESULTS: Glucometabolic variables correlated significantly to serum levels of interleukin 18, and to the expression of interleukin-18 and NLR family pyrin domain containing-3 in subcutaneous adipose tissue ( p < 0.05). Significant correlations were further observed between the amount of fat in the different compartments of abdominal adipose tissue and both serum levels of interleukin-18 and genetic expression of interleukin-18 and NLR family pyrin domain containing-3 in adipose tissue. CONCLUSION: The results implicate that the glucometabolic state is of importance for the inflammasome-related inflammation expressed both circulatory and genetically in subcutaneous adipose tissue, the latter highly reflected in the amount of abdominal adipose tissue. PMID- 29972043 TI - ? PMID- 29972044 TI - Protocol for N-of-1 trials proof of concept for rehabilitation of childhood-onset dystonia: Study 1: Protocole des essais de validation a effectif unique pour la readaptation de la dystonie debutant dans l'enfance : Etude 1. AB - BACKGROUND: Hyperkinetic movement disorders (HMD) are a heterogeneous group of neurological conditions among which dystonia is the predominant disorder and dyskinetic cerebral palsy the largest secondary dystonia group. Currently, there are no evidence-based, non-medical management options for childhood HMD. The Cognitive Orientation to daily Occupational Performance (CO-OP) Approach is a task-oriented, performance-based intervention that focuses on participation. PURPOSE: This paper reports the protocol for a proof-of-concept study to assess feasibility and preliminary evidence regarding efficacy of CO-OP for HMD following deep brain stimulation (DBS). METHOD: A series of N-of-1 trials with replications will be conducted with children, ages 6 and 21 years with HMD and DBS as indicated by the Manual Ability Classification System. Ten individualized CO-OP sessions, with multiple baselines before, during, and after, will be completed. The primary outcome measures are the Performance Quality Rating Scale and the Assessment of Motor and Process Skills. Outcome data will be plotted over time for each participant and supplemented with graph statistical analysis and effect size estimates. IMPLICATIONS: A written protocol will be developed based on evidence and feedback incorporating any changes to the CO-OP intervention for children and young people with HMD, as per the Medical Research Council's Framework for Complex Interventions. PMID- 29972046 TI - Protocol for N-of-1 trials with replications across therapists for childhood onset dystonia rehabilitation: Study 2: Protocole des essais a effectif unique avec repetitions par differents ergotherapeutes pour la readaptation de la dystonie debutant dans l'enfance : Etude 2. AB - BACKGROUND: Currently, no evidence-based rehabilitation interventions are available for hyperkinetic movement disorders (HMD), including dyskinetic cerebral palsy (CP). Among these highly heterogeneous disorders, dystonia is the predominant disorder. The Cognitive Orientation to daily Occupational Performance (CO-OP) Approach-a task-oriented, performance-based intervention to enable participation-is currently being evaluated for its potential as an intervention option. PURPOSE: This paper reports the protocol for the second of two studies designed to evaluate the potential of CO-OP to improve functional outcomes for individuals with HMD following deep brain stimulation (DBS). This second study is a systematic replication across multiple treating therapists from multiple centres. METHOD: Systematic replications will be used across centres and treating therapists trained in the CO-OP, using a series of randomized multiple-baseline N of-1 trials. Participants will be ages 6 to 21 years with HMD and DBS as indicated by the Manual Ability Classification System. Data collection will involve multiple data points collected at baseline, during intervention, and after intervention. The intervention will involve occupation-based goal setting followed by 10 individualized CO-OP sessions. The primary outcome measures are the Performance Quality Rating Scale and the Canadian Occupational Performance Measure. Outcome data will be plotted over time for each participant and supplemented with graph statistical analysis and estimate size effect for N-of-1 trials. IMPLICATIONS: The results of this study will help to inform future training procedures and future clinical trials. PMID- 29972048 TI - Not all systematic reviews are created equal. PMID- 29972049 TI - What do we know about technologies for dementia-related wandering? A scoping review: Examen de la portee : Que savons-nous a propos des technologies de gestion de l'errance liee a la demence? AB - BACKGROUND: Occupational therapists use technologies to manage wandering-related risks to promote safety and independence among individuals with dementia living in the community. PURPOSE: The purpose of this review was to examine types of technologies used to manage wandering behaviour. METHOD: Using a modification of Arksey and O'Malley's methodology, we systematically searched peer-reviewed and grey literature on technologies used in home or supportive care environments for persons with dementia at risk for wandering. Data from the studies were analyzed descriptively. FINDINGS: The literature described 83 technologies. Nineteen devices were clinically tested. Interventions ranged from alarm products to mobile locator devices. Benefits included reductions in risk and caregiver burden. IMPLICATIONS: Occupational therapy strategies include technologies to enhance function in persons with dementia. Technologies can also reduce risks of wandering and should be affordable. Ethical issues of the use of technology must be addressed. More research is needed to increase levels of evidence. PMID- 29972050 TI - The Equity Lens for Occupational Therapy: A program development and evaluation tool: L'Equity Lens for Occupational Therapy : un outil pour le developpement et l'evaluation de programme. AB - BACKGROUND: Occupational therapists value the principles of health and health care equity and often face challenges addressing inequities within the systems in which they work. PURPOSE: We present the Equity Lens for Occupational Therapy (ELOT), a framework to provide a practical starting point for reflecting on equity issues and the ways inequities are enacted in daily practice. KEY ISSUES: Building on an existing occupational therapy practice model and well-established program development and evaluation processes, we overlay an equity lens. The lens provides a structured way to critically reflect on occupational therapy programs within their contexts and develop action strategies to prevent or redress inequities. IMPLICATIONS: Taking action on the multiple ways that inequities can be embedded in occupational therapy programs within health and social systems can be a daunting task. The ELOT provides a systematic way to stimulate critical reflection and dialogue, examine practice, focus social advocacy, and take action. PMID- 29972055 TI - Caffeine, gravity, and baroreceptor function: the integration of diet and cardiovascular control. AB - We describe a simple, cost-effective experiment to demonstrate cardiovascular integration of heart rate and blood pressure to accommodate the environmental and dietary factors of gravity and caffeine. Specific learning objectives associated with this include understanding the effects of posture on blood pressure and heart rate, coupled with the role of caffeine in modifying this response. Inclusion of ECG measurements, coupled with heart rate variability analysis, added a demonstration of the contribution made by the autonomic nervous system under these conditions. We clearly demonstrate that the cardiac work, estimated as rate-pressure product, necessary to undertake the transition from supine to standing, is fixed for a given group of subjects. However, the individual contribution of heart rate and systolic pressure to the cardiac workload is subject to the external factors of gravity and caffeine. Such an activity also demonstrates additional benefits, including unstructured teaching opportunities to augment classroom learning associated with integrative physiology and also the discussion of ethical issues with regard to human experimentation. PMID- 29972056 TI - The "African gene" theory: it is time to stop teaching and promoting the slavery hypertension hypothesis. PMID- 29972057 TI - Engagement and higher order skill proficiency of students completing a medical physiology course in three diverse learning environments. AB - The primary aim of this study was to determine whether levels of student engagement, higher order skill proficiency, and knowledge acquisition demonstrated by medical students would differ when completing the same course in three diverse learning environments. Following Institutional Review Board approval, 56 first-year medical students, registered at the same medical school but attending class at three different campus centers, were enrolled in the study. All participants were completing a medical physiology course that utilized the same learning objectives but relied on different faculty incorporating diverse methodologies (percentage of class devoted to active learning strategies), course format (6-wk block vs. 17-wk semester), and student attendance. Students completed a validated survey of student engagement (SSE), a proctored online problem-based assessment of higher order skill proficiency [Collegiate Learning Assessment (CLA+); http://cae.org ], and the National Board of Medical Examiners (NBME) Physiology subject exam. In this limited sample, results indicate no significant differences between campus sites for any of the variables assessed. Levels of engagement were lower than expected compared with published values for graduate students. Higher order skill proficiency assessed by CLA+ was significantly higher than values reported for college seniors nationally. Surprisingly, SSE offered no prediction of performance on CLA+ or NBME, as there were no significant correlations between variables. These data indicate that, although first-year medical students may not perceive themselves as highly engaged, they are adept in using higher order skills and excel in meeting course learning objectives, regardless of learning environment. PMID- 29972058 TI - Peer instruction in a physiology laboratory course in China. AB - Peer instruction has been used extensively in lecture courses; however, there is little evidence of its use in laboratory courses. The purpose of the present study was to describe the implementation of the peer instruction method in a physiology laboratory course in China. Second-year medical students attended a 6 wk physiology laboratory course in the fall semester of the 2016-2017 school year. In the six new physiology laboratory classes, peer instruction strategies were used to substitute for the traditional short, didactic lectures. The effects of peer instruction were measured by in-class quizzes and confidence levels. The students' evaluations of peer instruction were measured by a Likert scale questionnaire. Peer instruction significantly improved the mean score on quizzes (0.53 +/- 0.50 vs. 0.68 +/- 0.47, P < 0.001) and confidence levels (2.36 +/- 0.66 vs. 2.80 +/- 0.45, P < 0.001). Furthermore, for individual incorrect answers, 39.07% changed to correct answers after peer instruction, whereas, for correct answers, 6.61% were changed to an incorrect response. Overall, significantly more students changed their answers from incorrect to correct than from correct to incorrect [chi2: 333.11; degrees of freedom (df): 1; P < 0.001]. Therefore, the positive effects of peer instruction were higher than the negative effects (chi2: 244.55; df: 1; P < 0.001). Moreover, student evaluations of peer instruction were highly positive. In conclusion, the implementation of peer instruction to the physiology laboratory course is an effective strategy to enhance students' performance on in-class quizzes and confidence levels. In addition, the attitude of students toward peer instruction was favorable. PMID- 29972060 TI - Effect of airway narrowing in asthma: active learning through a simple and didactic model. PMID- 29972059 TI - An acid-base "shock and awe" demonstration: the bad breath test. PMID- 29972061 TI - Nurturing interest in science and understanding the role of a scientist by teaching younger students how to apply scientific thinking during daily activities. PMID- 29972063 TI - Best practices in active and student-centered learning in physiology classes. AB - This review article includes our analysis of the literature and our own experiences in using various types of active learning as best practices for evidence-based teaching in physiology. We have evaluated what physiology students should be expected to learn and what are specific challenges to enhancing their learning of physiology principles. We also consider how the instructor should design his or her teaching to improve buy-in from both students and other faculty members. We include a discussion of how the readers can evaluate their teaching approaches for their successes in enhancing student learning of physiology. Thus we have addressed pedagogical improvements specific to student learning of physiology, with additional suggestions from cognitive psychology approaches that can improve physiology teaching and learning. PMID- 29972062 TI - Using a word game to test physiology comprehension. PMID- 29972064 TI - Reflections from Advances editors: how we got to where we did with Advances. PMID- 29972066 TI - Peer teaching beyond the formal medical curriculum. AB - Peer-assisted learning (PAL) is nowadays commonly implemented in medical education. Mostly PAL is utilized to specifically support teaching within one subject or a specific curricular situation. Here, we present a large-scale peer teaching program that aims to address the individual student's learning needs. In addition, it provides a platform for students to participate in academic teaching. A retrospective data analysis was performed to reveal the program's development and acceptance. The program was implemented in 2008/09 with three tutorials conducted by 24 student tutors to support students preparing for reexaminations. Since then, the program has continuously grown. In 2015/16, 140 tutors conducted 52 tutorials, consisting of 2,750 lessons for 1,938 tutees. New tutorial categories were continuously introduced. In 2015/16, these encompassed tutorials that were held concomitantly to the formal curriculum, tutorials that exceeded the contents of the formal curriculum, tutorials for preparation for the state examination, and electives. Evaluations among the tutees revealed that 93.5% of the respondents rated the courses overall as "good" or "excellent" ( n = 13,489) in 2015/16. All elements of the peer teaching program are managed by one academic group. This encompasses the organization of tutorials, the quality management, and the qualification of tutors, including content-related supervision and didactic training. We conclude that the implementation of a large scale peer teaching program can complement the formal curriculum. This might be beneficial for both tutors who can actively train their didactic and content related competencies, and tutees who can autonomously consolidate and expand their knowledge. PMID- 29972065 TI - Multistation exercises: a combination of problem-based learning and team-based learning instructional design for large-enrollment classes. AB - To introduce active learning session for a large group of 250 students, we combined the strengths of problem-based learning and team-based learning to promote a structured active learning strategy with less faculty involvement. For the implementation of this strategy, a case on anemia was selected based on the module already covered in classes. Structured exercises were preplanned on six different concepts that a student should possess for solving the problem. The large group of 250 students was divided into groups of 41 or 42 each. The groups were facilitated by one faculty member for one structured exercise. At the station, the group of 41 or 42 was further broken down into 6 smaller groups comprising 7 students each. After completion of the exercise, students cycled to the next exercise station facilitated by another faculty member. The case was solved in a plenary session. The effectiveness of the method was assessed by comparing the academic performance of the group with other similar groups from the previous year. The intervention group performed significantly better than the nonintervention group on the related item. Quartile subanalysis found that the effect was present in the performance of average and higher quartile groups, but not in the lower quartile group. PMID- 29972067 TI - Preoperative Mental Health Has a Stronger Association with Baseline Self-Assessed Knee Scores than Defect Morphology in Patients Undergoing Cartilage Repair. AB - Objective The purpose of this study was to assess potential correlations between the mental component summary of the Short Form-12 (SF-12 MCS), patient characteristics or lesion morphology, and preoperative self-assessed pain and function scores in patients undergoing autologous chondrocyte implantation (ACI). Design A total of 290 patients underwent ACI for symptomatic cartilage lesions in the knee. One hundred and seventy-eight patients were included in this study as they completed preoperative SF-12, Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. Age, sex, smoker status, body mass index, Worker's Compensation, previous surgeries, concomitant surgeries, number of defects, lesion location in the patella, and total defect size were recorded for each patient. Pearson's correlation and multivariate regression models were used to distinguish associations between these factors and preoperative knee scores. Results The SF 12 MCS showed the strongest bivariate correlation with all KOOS subgroups ( P < 0.001) (except KOOS Symptom; P = 0.557), Tegner ( P = 0.005), Lysholm ( P < 0.001), and IKDC scores ( P < 0.001). In the multivariate regression models, the SF-12 MCS showed the strongest association with all KOOS subgroups ( P < 0.001) (except KOOS Symptom; P = 0.91), Lysholm ( P = 0.001), Tegner ( P = 0.017), and IKDC ( P < 0.001). Conclusion In patients with symptomatic cartilage defects of the knee, preoperative patient mental health has a strong association with self assessed pain and functional knee scores. Further studies are needed to determine if preoperative mental health management can improve preoperative symptoms and postoperative outcomes. PMID- 29972068 TI - In Briefs. PMID- 29972069 TI - Kansas City's Mill Creek Park: A Community Collaboration for Health. PMID- 29972070 TI - Designing for Health: How the Physical Environment Plays a Role in Workplace Wellness. PMID- 29972071 TI - The Role of the Built Environment on Health Across the Life Course: A Call for CollaborACTION. PMID- 29972072 TI - The Art of Health Promotion: linking research to practice. PMID- 29972074 TI - Nutrition Research Special Issue and an Interview With Marion Nestle by Paul Terry. AB - As much as the field of health promotion has benefited mightily in the past decades from Internet abetted access to unlimited health content, our field is also experiencing the best of times and the worst of times. When it comes to our core work of supporting healthy decision-making for individuals, organizations, and communities, the unfettered, voluminous material available has, unimaginably, made facts seem fickle. I am delighted to have Dr Marion Nestle's insights as a preamble to this special issue of the journal. Educating about nutrition and food choices, in particular, has become as much a contest between competing interests and commercial forces, as it has been a discipline guided by credible professionals. I am all in on our Constitution's First Amendment, and having live abroad, I am endlessly smitten with America's robust expression and freedom of speech. But I wonder if our forefathers had seen the Internet coming whether they might have added more stipulations about telling the truth. This special issue of the American Journal of Health Promotion is dedicated to nutrition research where new discoveries, and impassioned scientists like Dr Nestle, provide the light needed to grow fresh knowledge. Exposing both academics and the public to well done studies about how food choices are influenced is ever more crucial in an era of alternative facts about what constitutes healthy eating. PMID- 29972073 TI - Change in US Adult Consumer Knowledge, Attitudes, and Behaviors Related to Sodium Intake and Reduction: SummerStyles 2012 and 2015. AB - PURPOSE: To describe changes in consumer knowledge, attitudes, and behaviors related to sodium reduction from 2012 to 2015. DESIGN: A cross-sectional analysis using 2 online, national research panel surveys. SETTING: United States. PARTICIPANTS: A total of 7796 adults (18+ years). MEASURES: Sodium-related knowledge, attitudes, and behaviors. ANALYSIS: Data were weighted to match the US population survey proportions using 9 factors. Wald chi2 tests were used to examine differences by survey year and hypertensive status. RESULTS: Despite the lack of temporal changes observed in respondent characteristics (mean age: 46 years, 67% were non-Hispanic white, and 26% reported hypertension), some changes were found in the prevalence of sodium-related knowledge, attitudes, and behaviors. The percentage of respondents who recognized processed foods as the major source of sodium increased from 54% in 2012 to 57% in 2015 ( P = .04), as did the percentage of respondents who buy or choose low/reduced sodium foods, from 33% in 2012 to 37% in 2015 ( P = .016). In contrast, the percentage of self reported receipt of health professional advice among persons with hypertension decreased from 59% in 2012 to 45% in 2015 ( P < .0001). Other sodium-related knowledge, attitudes, and behaviors did not change significantly during 2012 to 2015. CONCLUSION: In recent years, some positive changes were observed in sodium related knowledge and behaviors; however, the decrease in reported health professional advice to reduce sodium among respondents with hypertension is a concern. PMID- 29972075 TI - Skin autofluorescence is associated with high-sensitive cardiac troponin T, a circulating cardiac biomarker, in Japanese patients with diabetes: A cross sectional study. AB - The study aims to evaluate the relationship between skin autofluorescence, a marker of advanced glycated end-products accumulation in tissue, and high sensitive cardiac troponin T, a cardiovascular biomarker, in Japanese subjects with diabetes. A total of 145 subjects with diabetes and 32 nondiabetic subjects as control attending the outpatient clinic were examined. Skin autofluorescence was measured using the AGE ReaderTM. Univariate and multivariate regression analyses were used to identify the factors associated with the high-sensitive cardiac troponin T and N-terminal pro-B-type natriuretic peptide values. Skin autofluorescence, high-sensitive cardiac troponin T, and maximum intima-media thickness values were significantly higher in subjects with diabetes than in nondiabetic subjects. Diabetic subjects with skin autofluorescence level?2.47 AU (median value) had higher levels of N-terminal pro-B-type natriuretic peptide ( p = 0.006), high-sensitive cardiac troponin T ( p < 0.0001), pentosidine ( p = 0.011) and maximum intima-media thickness ( p = 0.017) compared to those with skin autofluorescence level <2.47 AU. A multivariate regression analysis using variables that were significantly correlated with high-sensitive cardiac troponin T and N-terminal pro-B-type natriuretic peptide, revealed that estimated glomerular filtration rate (beta = -0.364, p < 0.001) and skin autofluorescence (beta = 0.254, p = 0.0022) were independent determinants of high-sensitive cardiac troponin T, but the variables that were significant in the univariate analysis were no longer predictors for N-terminal pro-B-type natriuretic peptide. Skin autofluorescence measured with the AGE ReaderTM could be an easy and noninvasive surrogate marker for identifying diabetic subjects at high risk for subclinical cardiac injury. PMID- 29972076 TI - Outcomes of Acute Hematogenous Periprosthetic Joint Infection in Total Ankle Arthroplasty Treated With Irrigation, Debridement, and Polyethylene Exchange. AB - BACKGROUND:: Acute hematogenous periprosthetic joint infection (PJI) is defined in the literature as infection diagnosed and treated within 2 to 4 weeks from the onset of symptoms. In total hip and knee arthroplasty, irrigation and debridement (I&D) and polyethylene exchange with component retention has been studied extensively. However, there is minimal literature evaluating this treatment method for PJI in total ankle arthroplasty (TAA). The purpose of this study was to evaluate both the clinical and patient-reported outcomes and survivorship of TAA acute hematogenous PJIs treated with I&D and polyethylene exchange. METHODS:: A single-center, retrospective chart review of prospectively collected data in patients with TAA PJI who subsequently underwent I&D and polyethylene exchange with retention of metal components was conducted. The primary outcome was failure rate of I&D and polyethylene exchange, where failure was defined as subsequent removal of all components and 2-stage revision or arthrodesis. Patient-reported outcomes collected before primary arthroplasty, after primary arthroplasty, and after polyethylene exchange were also analyzed. RESULTS:: We identified 14 patients with acute hematogenous PJI who underwent I&D and polyethylene exchange with retention of metal components. The mean time from primary TAA to symptoms was 43 months (range 1-147 months). The average time from onset of symptoms to I&D and polyethylene exchange was 11.4 +/- 5.6 days. The mean follow-up after this surgery was 2.8 +/- 1.5 years. The long-term failure rate was 54%. The most common bacteria isolated in patients who failed was methicillin-resistant Staphylococcus aureus (MRSA). The most common bacteria isolated in patients who retained their implants was methicillin-sensitive Staphylococcus aureus (MSSA). Visual analog scale (VAS), Short Musculoskeletal Function Assessment (SMFA), Short Form-36 (SF-36), and American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot scale showed significant improvement when compared to preoperative scores in patients who retained their implants both after primary and after I&D and polyethylene exchange. CONCLUSIONS:: I&D and polyethylene exchange with retention of metal components has a long-term survivorship comparable to those reported in the total knee and total hip arthroplasty literature. Patient reported outcomes after I&D and polyethylene exchange were comparable to those collected after primary arthroplasty in those patients who ultimately retained their implants. Two variables in this cohort that were associated with I&D and polyethylene exchange failure include time the patient was symptomatic prior to I&D as well as organism isolated on culture. With a failure rate of 54%, the authors recommend thorough evaluation on a case-by-case basis prior to indicating a patient for single-stage I&D with polyethylene exchange. LEVELS OF EVIDENCE:: Level IV, case series. PMID- 29972077 TI - Pancreas volume in health and disease: a systematic review and meta-analysis. AB - INTRODUCTION: The pancreas plays a central role in metabolism and is involved in the pathogenesis of several diseases. Pancreas volume is a holistic quantitative measure of pancreas size but the clinical relevance of pancreas volumetry is poorly understood. Areas covered: The aim was to systematically review studies in adults that used computed tomography or magnetic resonance imaging to measure pancreas volume in health and disease, to determine normal pancreas volume range, and to quantify changes in pancreas volume that are associated with disease. Expert commentary: The normal pancreas volume range in adults is 71-83 cm3, with no statistically significant difference between men and women. Type 2 diabetes and type 1 diabetes are associated with a progressively reduced pancreas volume. Overweight and obesity are associated with a progressively increased pancreas volume. There is a paucity of studies on pancreas volume in the setting of diseases of the exocrine pancreas, which should become a research priority in the future. PMID- 29972078 TI - The Pattern of Hospital Admissions Prior to Care Home Placement in People With Parkinson's Disease: Evidence of a Period of Crisis for Patients and Carers. AB - OBJECTIVES: We hypothesized that the number and length of hospital admissions in people with Parkinson's disease (PD) would increase immediately prior to admission to a care home relative to those who were able to continue living at home or who died. METHOD: PD patients at Hoehn and Yahr Stages III to V were followed-up over two and a half years with deaths and care home placements recorded. Hospital admissions data were collected over this period. RESULTS: Of 286 patients included in the study, 7.3% entered a care home and 28.3% died. In the final 120 days prior to the study exit point (care home placement, death, or continued living at home), longer hospital stay was significantly associated with care home placement, after adjusting for the competing risk of death. CONCLUSION: Our data provide evidence that, for many people with PD, a period of crisis is reached immediately prior to care home placement. PMID- 29972079 TI - Step-up and step-down treatments for optimal asthma control in children and adolescents. AB - OBJECTIVE: To review therapeutic options for stepwise management of pediatric asthma in the context of this population's unique needs such as potential effects of asthma, treatments, or both on growth and psychosocial development, and caregiver involvement. DATA SOURCES AND STUDY SELECTION: We conducted PubMed searches to identify relevant articles then reviewed resultant articles, guidelines for asthma management in children, and articles from personal files. RESULTS: Stepwise management of asthma, similar to adults, is recommended for children in current global and US guidelines. Treatment may be stepped up or stepped down temporarily or long-term based on response over time. Inhaled corticosteroids remain the recommended treatment for persistent childhood asthma and any potential small effects on growth are considered relatively minor compared with their benefit. Controller medication options for patients <18 years old are limited, especially for Global Initiative for Asthma Steps 2-5. The long acting antimuscarinic antagonist tiotropium (Steps 4/5, patients aged >=12 years) and in certain circumstances (Step 5), anti-immunoglobulin E (aged >=6 years) and interleukin-5 antibodies (aged >=12 years) are newer treatment options. Tiotropium is indicated in the United States and Europe for patients >=6 years old. Stepping down treatment, which is recommended but infrequently practiced, can maintain symptom control and minimize adverse events while substantially reducing costs. Patient education and better monitoring remain important for self management and optimum outcomes. CONCLUSION: A need exists to target individual treatment goals for children with asthma by using step-up and step-down approaches to maximize treatment benefits and minimize potential adverse effects. PMID- 29972080 TI - Does the Health of Adult Child Caregivers Vary by Employment Status in the United States? AB - OBJECTIVE: This study investigates whether the health effects of informal caregiving for aging parents vary by employment status in the United States. Two opposing hypotheses are tested: dual role strain and role enhancement. METHOD: Using national longitudinal data from the U.S. Health and Retirement Study, multivariate regression models predicted self-rated health and mental health among older adult children caregiving for their parents (2009-2012) and noncaregivers. RESULTS: A statistically significant interaction was found between caregiving duration and employment, indicating that employed caregivers had significantly worse health than retired caregivers. Caregiving duration also predicted significantly higher levels of depressive symptoms. DISCUSSION: Our results support the dual role strain hypothesis and suggest that caregiving for a parent up to 4 years is enough to predict significantly worse health among older adult Baby Boomers, especially those in the labor force. The broader implications for public health and workplace policies are discussed. PMID- 29972081 TI - Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse. AB - The purpose of this study was to evaluate the acute effect of a small molecule inhibitor of DGAT-1 on triglycerides (TG) and cholesterol in polygenic type 2 diabetic TallyHo/JngJ (TH) mice. PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice. The concentration of the model compound that produced 50% of maximum lowering of TG level (IC50) in TH mice was not significantly different from that in ICR mice, when estimated using the model-based pharmacokinetic and pharmacodynamic assay, a two-compartmental model and an indirect response model. The clearance of the inhibitor in TH mice was fivefold higher than that in ICR mice, suggesting significantly altered pharmacokinetics. Moreover, the in vitro metabolic elimination kinetic parameters (ke,met), determined using liver microsomes from TH and ICR mice were 1.24 +/- 0.14 and 0.174 +/- 0.116 min-1, respectively. Thus, we report that the differences in the acute effects of the small molecule DAGT-1 inhibitor between TH mice and ICR mice can be attributed to altered pharmacokinetics caused by an altered metabolic rate for the compound in TH mice. PMID- 29972082 TI - Understanding Risk Environments in Permanent Supportive Housing for Formerly Homeless Adults. AB - In this study, we used ethnographic methods and a risk environment framework to consider how contextual factors produce or reduce risk for substance use with a sample of 27 adults who recently moved into permanent supportive housing (PSH). Most apparent was how the social and physical environments interacted, because most participants focused on how having an apartment had dramatically changed their lives and how they interact with others. Specific themes that emerged that also involved economic and policy environments included the following: isolation versus social engagement; becoming one's own caseworker; and engaging in identity work. This study underscores the scarcity yet importance of research that examines the multiple types of environment in which PSH is situated, and suggests that a better understanding of how these environments interact to produce or reduce risk is needed to develop optimal interventions and support services. PMID- 29972084 TI - Current and future therapeutic approaches for the treatment of follicular lymphoma. AB - INTRODUCTION: Recent advances in prognostication as well as management of Follicular Lymphoma (FL) are moving to personalized approach. Areas covered: Prognostic scores as well as consolidated and innovative therapeutic approaches are evaluated according to the various presentation modalities. For asymptomatic, low-tumor burden FL, a 'watch and wait' policy is currently the first-choice approach, although possible alternatives are discussed. Early stage FL may be treated with local radiotherapy although the role of minimal residual disease in possible additional agents should be determined. The first line treatment for symptomatic FL is chemo-immunotherapy followed by two years maintenance therapy with anti-CD20 monoclonal antibodies. A deeper knowledge of FL biology has opened new perspectives regarding the timing of therapy and has offered new targets for the development of novel agents that aim to change the therapeutic scenario of FL management. Expert commentary: The introduction of novel agents could question the incurability of FL and change the therapeutic goal from prolonging the complete remission state to eradicating the disease in young/fit patients, as well as improving quality of life in elderly/unfit patients. In the near future, combining new biologic agents and adoptive cell therapies could help in achieving these aims. PMID- 29972085 TI - Non-strategic ignorance: Considering the potential for a paradigm shift in evidence-based mental health. AB - Randomised controlled trials form a central building block within the prevailing evidence-based mental health paradigm. Both methodology and paradigm have been widely problematised since their emergence in the mid-late twentieth century. We draw on the concept of 'strategic ignorance' to understand why the paradigm still prevails. We present focus group data gathered from 37 participants (service users, public, carers, general practitioners, commissioners) concerning the way they made sense of a randomised controlled trial of psychotherapy for treatment resistant depression. Thematic analysis of the findings revealed an overall critique of randomised controlled trial methods which we refer to as 'non strategic ignorance'. Specifically, participants problematised the construct of depression, unseating the premise of the randomised controlled trial; they were sceptical about the purpose and highlighted its failure to show how therapy works or who might benefit; the randomised controlled trial was seen as inadequate for informing decisions about how to select a therapy. Participants assumed the treatment would be cost-effective given the client group and nature of the therapy, irrespective of any randomised controlled trial findings. Each area of lay ('non-strategic') critique has an analogous form within the methodological expert domain. We argue that 'expert' critiques have generally failed to have paradigmatic impact because they represent strategic ignorance. Yet parallel non strategic critiques have common sense appeal, highlighting the potential power of lay voices. The discussion considers whether the evidence-based mental health paradigm is faced with epistemological problems of such complexity that the conditions exist for a new paradigm in which service user views are central and randomised controlled trials peripheral. PMID- 29972086 TI - Prognostic factor determination mortality of acute glufosinate-poisoned patients. AB - BACKGROUND: Glufosinate-containing herbicide is increasingly used in agriculture. Its poisoning is a worldwide concern. More and more patients are poisoned by glufosinate. The aim of this study was to determine the factors associated with mortality of patients with acute poisoning of glufosinate. METHODS: This was a retrospective cohort study conducted from January 1998 to October 2015. Using a multivariate logistic analysis, data for the total population were retrospectively analyzed to determine the factors associated with mortality. Various variables were compared in survivors and non-survivors. Significant predictive variables, Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system, the Simplified Acute Physiology Score (SAPS) II, and Sequential Organ Failure Assessment (SOFA) score were compared by analyzing receiver operating characteristic (ROC) curves. RESULTS: A total of 253 patients (mean age: 58 years) were enrolled. Of the 253 patients, 219 (86.6%) survived and 34 (13.4%) died. Decreased Glasgow Coma Scale (GCS) and bicarbonate (HCO3-), use of mechanical ventilator, and use of vasopressors (dopamine, dobutamine, norepinephrine) were associated with mortality. The areas under the curve in the ROC curve analysis for the predictive variables, SOFA score, APACHE II scoring system, and SAPS II were 0.952, 0.829, 0.927, and 0.944, respectively. CONCLUSION: Four predictive variables (GCS < 9, HCO3- < 16.0 mmol/L, mechanical ventilator apply, and use of vasopressors) were associated with mortality in the total population of patients with acute poisoning of glufosinate. These predictive variables had good discriminative power for predicting mortality of patients with acute poisoning of glufosinate-containing herbicide compared to APACHE II, SOFA, and SAPS II. PMID- 29972087 TI - Patient preferences for a touch screen tablet-based asthma questionnaire. AB - OBJECTIVE: Assessment of asthma control and provision of asthma action plans are seldom performed in practice, partly due to limited time for physicians to ascertain required information. A patient-facing electronic asthma questionnaire could facilitate information collection. We sought to design a touch-tablet asthma questionnaire for use in the clinic waiting room and to describe patient preferences for the content of such a questionnaire. METHODS: We created a questionnaire prototype based on best evidence and employed rapid-cycle design (semi-structured focus group testing; analysis; corresponding modifications and re-testing) with asthma patients aged >=16 years. We analyzed transcripts using deductive and inductive content analysis. Quantitative measures included Likert scale questions and questionnaire completion times. RESULTS: There were 20 participants across five focus groups (15/20 (75%) female, age 49.1 +/- 15.6 years). Content-related themes included: 1) comprehensibility (language) (how questionnaire language affected ease and accuracy of comprehension) and b) information collection (issues arising during information collection in the following identified subthemes: personal asthma symptoms and triggers; asthma control; asthma medications and contact information). Average questionnaire completion time was 11.7 +/- 5.9 min. Summative Likert scale responses suggested high levels of question comprehension and confidence with responses. CONCLUSIONS: Our analysis provides novel insight about how best to formulate and present asthma-related content in an electronic questionnaire. Such questionnaires might facilitate quality improvement by improving efficiency of data collection, enabling better assessment of asthma control and medication adherence, and personalization of asthma action plans. Future studies should measure real-world uptake of such a questionnaire and impact on care. PMID- 29972088 TI - Does Transcranial Magnetic Stimulation Have an Added Value to Clinical Assessment in Predicting Upper-Limb Function Very Early After Severe Stroke? AB - BACKGROUND: The added prognostic value of transcranial magnetic stimulation (TMS) induced motor-evoked potentials (MEPs) to clinical modeling for the upper limb is still unknown early poststroke. OBJECTIVE: To determine the added prognostic value of TMS of the adductor digiti minimi (TMS-ADM) to the clinical model based on voluntary shoulder abduction (SA) and finger extension (FE) during the first 48 hours and at 11 days after stroke. METHODS: This was a prospective cohort study with 3 logistic regression models, developed to predict upper-limb function at 6 months poststroke. The first model showed the predictive value of SA and FE measured within 48 hours and at 11 days poststroke. The second model included TMS ADM, whereas the third model combined clinical and TMS-ADM information. Differences between derived models were tested with receiver operating characteristic curve analyses. RESULTS: A total of 51 patients with severe, first ever ischemic stroke were included. Within 48 hours, no significant added value of TMS-ADM to clinical modeling was found ( P = .369). Both models suffered from a relatively low negative predictive value within 48 hours poststroke. TMS-ADM combined with SA and FE (SAFE) showed significantly more accuracy than TMS-ADM alone at 11 days poststroke ( P = .039). CONCLUSION: TMS-ADM showed no added value to clinical modeling when measured within first 48 hours poststroke, whereas optimal prediction is achieved by SAFE combined with TMS-ADM at 11 days poststroke. Our findings suggest that accuracy of predicting upper-limb motor function by TMS-ADM is mainly determined by the time of assessment early after stroke onset. PMID- 29972089 TI - Effectiveness of fluticasone furoate/vilanterol versus fluticasone propionate/salmeterol on asthma control in the Salford Lung Study. AB - OBJECTIVE: The Asthma Salford Lung Study demonstrated the effectiveness of initiating once-daily fluticasone furoate/vilanterol (FF/VI) versus continuing usual care in asthma patients in UK primary care [ 1 ]. Here, we report a secondary analysis in a subset of patients with fluticasone propionate/salmeterol (FP/Salm) as their baseline intended maintenance therapy, to evaluate the relative effectiveness of initiating FF/VI versus continuing FP/Salm. METHODS: Adults with symptomatic asthma were randomised to initiate FF/VI 100[200]/25 ug or continue FP/Salm. The Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (AQLQ), Work Productivity and Activity Impairment Asthma questionnaire, severe exacerbations, salbutamol inhaler prescriptions and serious adverse events (SAEs) were recorded throughout the 12-month treatment period. RESULTS: One thousand two hundred and sixty-four patients (FF/VI 646; FP/Salm 618) were included in this subset analysis; 978 had baseline ACT score <20 and were included in the primary effectiveness analysis (PEA) population. At week 24, odds of patients being ACT responders (total score >=20 and/or improvement from baseline >=3) were significantly higher with FF/VI versus FP/Salm (71% vs. 56%; odds ratio 2.03 [95% CI: 1.53, 2.68]; p < 0.001 [PEA]). Significant benefit with FF/VI versus FP/Salm was also observed for AQLQ responders, activity impairment due to asthma, exacerbation rates, and salbutamol inhalers prescribed. No significant between-group differences were observed for impairment while working or work absenteeism due to asthma. CONCLUSIONS: For patients in primary care, initiating FF/VI was significantly better than continuing with FP/Salm for improving asthma control and quality of life, and reducing asthma exacerbations, with no notable difference in SAEs. ClinicalTrials.gov: NCT01706198. PMID- 29972090 TI - Modelling performance and skeletal muscle adaptations with exponential growth functions during resistance training. AB - System theory is classically applied to describe and to predict the effects of training load on performance. The classic models are structured by impulse-type transfer functions, nevertheless, most biological adaptations display exponential growth kinetics. The aim of this study was to propose an extension of the model structure taking into account the exponential nature of skeletal muscle adaptations by using a genetic algorithm. Thus, the conventional impulse-type model was applied in 15 resistance trained rodents and compared with exponential growth-type models. Even if we obtained a significant correlation between actual and modelled performances for all the models, our data indicated that an exponential model is associated with more suitable parameters values, especially the time constants that correspond to the positive response to training. Moreover, positive adaptations predicted with an exponential component showed a strong correlation with the main structural adaptations examined in skeletal muscles, i.e. hypertrophy (R2 = 0.87, 0.96 and 0.99, for type 1, 2A and 2X cross sectional area fibers, respectively) and changes in fiber-type composition (R2 = 0.81 and 0.79, for type 1 and 2A fibers, respectively). Thus, an exponential model succeeds to describe both performance variations with relevant time constants and physiological adaptations that take place during resistance training. PMID- 29972091 TI - Relative Energy Deficiency in Sport: The Tip of an Iceberg. PMID- 29972093 TI - Immunohistochemical Reappraisal Regarding the Frequency of Primary Salivary Gland Follicular Lymphoma. AB - Although it has been described that extranodal marginal zone lymphomas of mucosa associated lymphoid tissue (MALT lymphomas) are the most common type among primary salivary gland lymphomas (SGLs), some studies revealed that the frequency of follicular lymphomas (FLs) was as high as that of MALT lymphomas. However, it has been reported that many of these FLs may have developed in lymph nodes attached to the capsule of the glands or intraglandular lymph nodes. Clinical, histological, immunohistochemical, and cytogenetic features of 11 SGL cases, which were extracted from our surgical pathology file consisting of consecutive pathology cases, were reevaluated to further characterize whether they were actually primary SGLs. There were 3 (27%) cases of FLs, 5 (46%) cases of MALT lymphomas, and 3 (27%) cases of diffuse large B-cell lymphomas. Although all of our FL cases fulfilled the criteria of primary SGL, tumors of several FL cases were surrounded by podoplanin (by D2-40)-positive elongated vessels or linear structures indicative of nodal subcapsular sinuses (open or remnant). This finding would support the aforementioned possibility, and podoplanin staining is necessary before concluding that a FL is a primary SGL. PMID- 29972092 TI - Variability of contribution of vitamin D receptor gene polymorphisms to outcome of HLA-matched sibling allogeneic bone marrow transplantation. AB - Graft-versus-host disease (GVHD) remains one of the major complications of hematopoietic stem cell transplantation (HSCT). Several etiological factors were investigated. Among these, vitamin D and hence its receptor (VDR) gene polymorphisms have gained much interest; however, the results are still controversial. Using PCR-RFLP, we genotyped VDR polymorphisms FokI (rs10735810), ApaI (rs7975232), and Taq1 (rs731236) in 80 patient/donor pairs according to DNA availability. No association was encountered between VDR polymorphisms and GVHD. Neither was there any impact on survival. Only grade II-IV acute GVHD was associated with inferior overall (p = .01), but not disease-free survival. The controversy between our results and the literature may be attributed to marked variability in the relative distribution of VDR genotypes in different populations. Also different environmental factors, including exposure to sun, may ensure vitamin D sufficiency nullifying the impact of VDR polymorphisms. PMID- 29972094 TI - Seasonal changes influence the improvement in asthma symptoms by exercise training in subjects with asthma. AB - OBJECTIVE: To investigate whether patients with moderate-to-severe asthma who commence an exercise training program in winter or summer show differences in exercise capacity, health-related quality of life (HRQoL) and asthma symptoms. METHODS: Forty-two consecutive subjects visiting the outpatient clinic were enrolled in the 17-week rehabilitation program. One group of patients received the intervention from summer to winter (SWG, n = 21), and the other group participated from winter to summer (WSG, n = 21). Before and after the exercise training program, all patients were evaluated by cardiopulmonary exercise test, pulmonary function test, quality of life questionnaire and a daily diary that evaluated clinical asthma symptoms. RESULTS: After the training period, both groups improved similarly in health-related quality of life (HRQoL) and aerobic capacity. The WSG patients had a greater increase that those in the SWG in asthma symptom-free days (p < 0.05). CONCLUSIONS: Our results indicate that seasonal variations affect the improvement in asthma symptoms after an exercise training program but have no effect on health-related quality of life, exercise capacity or pulmonary function. PMID- 29972095 TI - Treatment patterns and related clinical consequences in adults with asthma. AB - OBJECTIVE: A stepwise therapeutic management is recommended for asthma patients by the Global Initiative for Asthma (GINA). Little is known about the recommendations applied in real world settings. This study aims to associate Treatment step with clinical events in patients with mild or severe asthma. METHODS: A retrospective claims database analysis included adult patients with mild (GINA step 1) or severe asthma (GINA step 4). Maximum Treatment Step was measured within the first and second 90-day period after index date (the first date of asthma diagnosis during the inclusion period). Step-down was defined as a Treatment Step change from a higher to lower step, while Step-up was defined as a Treatment Step change from a lower to higher step. The primary outcome was a composite endpoint of asthma-related clinical events, measured at the third 90 day period. RESULTS AND CONCLUSIONS: A total of 6,354 mild-asthma patients and 5,695 severe-asthma patients were included. In mild-asthma, when compared with No Change in Treatment Step, Step-down was associated with a lower risk of future clinical events [adjusted odds ratio (OR) 0.80, 95% confidence interval (95% CI); 0.69-0.94], while Step-up was not associated with a change in clinical events [OR 0.98, 95% CI: 0.77-1.27]. In severe-asthma patients, Step-down was not associated with a change in clinical events [OR 0.94, 95% CI: 0.81-1.10], while Step-up was associated with a higher risk of future clinical events [OR 2.07, 95% CI: 1.29 3.33]. Our findings reassure the appropriateness of stepping-down treatment in mild-asthma patients. Clinicians should closely monitor and/or provide detailed asthma action plans for severe-asthma patients who are stepping-up treatment. PMID- 29972096 TI - Media reporting of suicide and adherence to media guidelines. AB - BACKGROUND: International research consistently shows evidence for an association between sensationalised and detailed media reporting, and suicidal behaviour. AIM: This study examined the quality of media reporting of suicide and adherence to media guidelines in Ireland. METHODS: In accordance with the criteria outlined in the media guidelines for reporting suicide, 243 media articles were screened and analysed for quality of reporting of two high-profile cases of suicide and two cases of suicide that became high profile following a period of intense media coverage that occurred between September 2009 and December 2012. RESULTS: A minority of articles breached the media guidelines in relation to sensationalised language (11.8%), placement of reports on the front page of the newspaper (9.5%), publishing of inappropriate photographs (4.2%) and mention of location of suicide (2.4%), while no articles disclosed the contents of a suicide note. However, in the majority of articles analysed, journalists did not refer to appropriate support services for people vulnerable to, and at risk of suicide (75.8%) or mention wider issues that are related to suicidal behaviour (53.8%). Overemphasis of community grief (48.3%) was also common. Nearly all articles (99.2%) breached at least one guideline and 58.9% of articles breached three or more guidelines. CONCLUSION: Overall, adherence to media guidelines on reporting suicide in Ireland improved in certain key areas from September 2009 until December 2012. Nonetheless, important challenges remain. Increased monitoring by media monitoring agencies, regulators and government departments is required. Implementation should be conducted using a pro-active approach and form part of the curriculum of journalists and editors. The inclusion of guidelines for the reporting of suicidal behaviour in press codes of conduct for journalists warrants consideration. PMID- 29972097 TI - Patient Engagement in Type 2 Diabetes: A Collaborative Community Health Initiative. AB - Purpose The purpose of this study was to describe the effects of an innovative rural community-based, diabetes self-management education and support (DSMES) program on patient behaviors and outcomes. Methods A 12-month pre-post study design with physiological data collection at program initiation, 16 weeks, and 6 and 12 months postenrollment was used for program assessment. The program consisted of an American Diabetes Association-accredited curriculum provided by the hospital and interfaced with a YMCA curriculum promoting lifestyle change. The 28-session program was delivered over a 1-year period. Results The sample size was 115. Participants were primarily white and female, with a mean age of 57 years. Mean body mass index (BMI) at program initiation was 37; mean A1C was 8.5 (69.4 mmol/mol). Significant reductions were obtained in weight, BMI (at 16 weeks), and A1C (at 6 months); these reductions were sustained at 12 months. Medication intake was significantly reduced, and diabetes-related emergency department visits were below national averages. Conclusions Results support the positive impact of a year-long, community-based, healthy behavior, DSMES program on health outcomes and overall costs of care delivery in the rural setting. PMID- 29972098 TI - The theory of masculinity in studies on HIV. A systematic review. AB - This study aimed to describe the methodological characteristics of publications on HIV and masculinity, to identify possible information gaps and determine the main thematic areas. A systematic review was conducted of gender, masculinity, HIV infection and other sexually-transmitted infections in original articles published between 1992 and 2015. Original studies published from Pubmed and Scopus were included. A total of 303 articles were identified, of which 187 were selected. Most of the studies were qualitative and the most widely used technique was the interview. Twenty-nine-point five percent of studies were performed in South Africa, 20.8% in the USA, and 3.2% in Europe. Fifteen percent of the studies were performed in heterosexuals, 12.8% in men who have sex with men, and 60% did not specify the sexual orientation of the population. Eight thematic areas were defined, the most frequent being sexuality and risk behaviours, defined by men's need to demonstrate they were sexually active and a breadwinner. Most studies on HIV and masculinity show a gender bias by not specifying the sexual identity of the population. Studies should consider diversity in sexual and cultural identity in different contexts, including in Europe, to carry out more effective HIV interventions from a masculinity perspective. PMID- 29972099 TI - Co-creation to scale up provision of simplified high-quality comprehensive abortion care in East Central and Southern Africa. AB - Universal access to comprehensive abortion care (CAC) is a reproductive right and is essential to reduce preventable maternal mortality and morbidity. In East Africa, abortion rates are consistently high, and the vast majority of all abortions are unsafe, significantly contributing to unnecessary mortality and morbidity. The current debate article reflects and summarises key action points required to continue to speed the implementation of and expand access to CAC in the East, Central, and Southern African (ECSA) health community. To ensure universal access to quality CAC, a regional platform could facilitate the sharing of best practices and successful examples from the region, which would help to visualise opportunities. Such a platform could also identify innovative ways to secure women's access to quality care within legally restrictive environments and would provide information and capacity building through the sharing of recent scientific evidence, guidelines, and training programmes aimed at increasing women's access to CAC at the lowest effective level in the healthcare system. This type of infrastructure for exchanging information and developing co-creation could be crucial to advancing the Sustainable Development Goals 2030 agenda. PMID- 29972100 TI - Comprehensive Review of Nutrition Components for Occupational Health Nurses-Part 2. AB - This article, the second in a two-part series, reviews and examines the components of clinical nutrition. In Part 2, the authors discuss nutritional components of fats, proteins, vitamins, minerals, and water. A resource guide is provided for the occupational health nurse to assist in the implementation of employee education in the area of healthy nutrition. The intent of the articles is to acquaint and inform the occupational health nurse on the current guidelines for healthy eating so she or he can better appraise their employee population, thus creating a healthier workforce. The information provided is not all inclusive on the topics discussed but it provides a foundation for a better understanding of the requirements for healthy eating. PMID- 29972101 TI - Transglycosylation Activity of Catalytic Domain Mutant of Endo-1,3-beta-glucanase from Cellulosimicrobium cellulans. AB - BACKGROUND: Oligosaccharides are of great value in drug discovery programs which address a wide range of therapeutic strategies in medical specialties. However, owing to difficulties in oligosaccharide synthesis by conventional methods, oligosaccharide assembly using enzymes has been explored. The transglycosylases have been demonstrated to be effective for the oligosaccharide synthesis. Further studies are required to improve the specificity and activity of transglycosylases. There is an additional approach to use mutated glycosidase which transforms into glycosyltransferase with a decreased hydrolytic activity. The substitution of catalytic residue in glycosidase results in the loss of hydrolytic activity. During the reaction with glucanase, reaction of water with the substrate - enzyme intermediate results in the production of a hydrolyzed sugar. When the water molecule is replaced by a competing sugar, a new glycoside linkage is formed as a result of transglycosylation. OBJECTIVE: In this article, we evaluated the transglycosylation activity of endo-1,3-beta-glucanase mutant, E119G, toward laminarioligosaccharides under various pH and temperature conditions, in comparison with those of the wild-type enzyme. We also analyzed the effect of glucose and laminaribiose on the transglycosylation activity. METHOD: In this article, we generated the E119G mutant of endo-1,3-beta-glucanase from Cellulosimicrobium cellulans DK-1. The residue, Glu119, would act as a nucleophile in the reaction and affect the balance between hydrolysis and transglycosylation. The enzymatic activities of wild-type and E119G were estimated by detecting the products obtained from laminarioligosaccharides as substrates. We also analyzed the effect of reaction conditions such as temperature and pH on the enzymatic activity of E119G toward laminaritriose. We further analyzed the enzymatic activity of E119G toward laminaritriose in the presence of glucose or laminaribiose to investigate whether these additional molecules could accelerate the transglycosylation activity. RESULTS: The purified E119G mutant of endo-1,3-beta-glucanase was properly folded, and exhibited the secondary structure, similar to that of wild-type. The E119G mutant exhibited enhanced transglycosylation activity and decreased hydrolytic activity, relative to the wild-type. The hydrolytic as well as transglycosylation activities of E119G decreased with the decrease in temperature, however, the ratio of transglycosylation products increased. The temperature-dependent degree of reduction in hydrolytic activity was higher than that in the transglycosylation activity. The enzymatic activities were similar within the range of pH 4.0 - 7.4, while those at pH 8.0 and 8.5 were slightly decreased. The enzymatic activity of E119G toward laminaritriose in the presence of glucose was ineffective, while the addition of laminaribiose evidently increased the transglycosylation products such as laminaritetraose and laminaripentaose. CONCLUSION: A mutation of catalytic residue, Glu119 to Gly, in endo-1,3-beta-glucanase from Cellulosimicrobium cellulans exhibited transglycosylation activity on laminarioligosaccharides. The combination of laminaribiose and laminaritriose as a substrate enhanced the transglycosylation activity. According to the structural information previously reported, laminaritriose mainly binds to the enzyme at the subsites from -1 to -3 and forms a link with laminaribiose, which transiently binds to the subsites +1 and +2. To increase the amount of transglycosylation product, the reaction was found to be effective at low temperature. PMID- 29972102 TI - New Therapeutic Approaches in the Management of Cardiometabolic Diseases: Bringing the Concepts Together. PMID- 29972103 TI - Appetite reducing herbal drugs from the perspective of Avicenna and Aghili in Iranian Traditional Medicine(Persian medicine). AB - The increasing prevalence of obesity is one of the problems of today's society. Man needs food to continue living, activities, and even the metabolism of food and appetite plays an important role in receiving foods, Appetite and weight reducing synthetic drugs are recommended for some patients with high prices and significant side effects, and limited effectiveness in the treatment of obesity. Given the epidemic of obesity and the lack of satisfaction with synthetic drugs these days, people are more likely to use herbal medicines. complementary medicine has always been considered for the choice of new treatment. This medicine has a long history. Persian Medicine is one of traditional medicine systems This study was a qualitative study on the Books of Canon and the Makhzan Al-Aladvia. Saffron has been introduced in both modern medicine and in Iranian medicine to reduce appetite In the case of Purslane seed and Chio nut ,Figs, Sesame seeds, Camphor, and Solomon's seal, and Opium poppy, which have been appetite suppressant in traditional medicine books, in the books and articles of modern medicine, they have not reduced appetite. Modern medicine has known Gourd as a weight reducing food with the effects on the fat but there is no talk about its appetite effects. According to traditional Iranian medicine, Chio nut causes anorexia due to creating weakness in the stomach. Therefore, it is not advisable for weight loss. More clinical studies to prove the effects of appetite suppressant and weight loss effects of these herbal medicines seem logical. PMID- 29972104 TI - Synthesis and Anticonvulsant Activity of 3-(alkylamino, alkoxy)-1,3,4,5- Tetrahydro-2H-benzo [b] azepine-2-one Derivatives. AB - BACKGROUND & OBJECTIVE: A series of novel 3-Substituted-1,3,4,5-Tetrahydro-2H benzo [b] azepine-2-one Derivatives (4, 5, 7, 10, 12, 5a-j, 8a-e) were synthesized from 1,2,3,4-Tetrahydro-1- naphthalenone. The structures of these compounds were confirmed by IR, 1H NMR, 13C NMR, MASS spectra and elemental analysis. Their anticonvulsant activity was evaluated by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test. Compound 4 showed the maximum anticonvulsant activity against the maximal electroshock test (ED50=26.4, PI =3.2) and against the subcutaneous pentylenetetrazol test (ED50=40.2, PI =2.1). CONCLUSION: Possible structure-activity relationship was discussed. PMID- 29972106 TI - Role of Curcumin in Regulation of TNF-alpha Mediated Brain Inflammatory Responses. AB - BACKGROUND: Inflammation is a protective response of the body system that protects the body from the various kinds of external and internal insults; however, it has been found that most chronic illnesses are caused by dysregulated and excessive inflammation. Inflammation plays a major role in developing neurological diseases. In the brain cytokines, TNF-alpha and TNF-beta are known to mediate inflammation in many diseases. Functions of these cytokines are regulated by the activation of transcription factor NF-kappab. Recent evidence suggest that curcumin has an immense therapeutic potential because of its anti inflammatory and anti-oxidant properties. It has been tested for treating various chronic illnesses associated with the brain. OBJECTIVE: The study aims to elucidate the role of curcumin in alleviating the inflammatory reactions initiated by TNF-alpha and NF-kappab signaling. METHODS: This study is a survey of literature from sources like PubMed central, science direct, medline and available scientific databases to determine how inflammation plays an important role in the development of neurodegenerative diseases and the role of curcumin as an anti-inflammatory agent. Looking into the importance of curcumin in alleviating inflammatory responses, several patents are filed and accepted which are referenced in this article. RESULTS: Neuro-inflammation mediated by TNF-alpha plays a major role in the development of pathologies like Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis etc. Curcumin appears to subside or reduce the inflammatory responses. Thus, it appears to have therapeutic potential for treating various neuroinflammatory diseases. CONCLUSION: Cytokines get upregulated during neurodegenerative diseases as a result of which inflammatory responses are initiated in the brain. Curcumin is reported to have anti-inflammatory properties and thereby its supplementation may help in reducing the inflammation. Future research on this area will further explain the mode of action of curcumin in alleviating neuroinflammation. PMID- 29972105 TI - Neuropsychiatric Aspects in Men with Klinefelter Syndrome. AB - BACKGROUND AND OBJECTIVE: Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy (47,XXY) and cause of male hypergonadotropic hypogonadism. It is characterized by an extreme clinical heterogeneity in presentation, including infertility, hypogonadism, language delay, metabolic comorbidities, and neurocognitive and psychiatric disorders. Since testosterone is known to have organizational, neurotrophic and neuroprotective effects on brain, the condition of primary hypogonadism could play a role. Moreover, given that KS subjects have an additional X, genes on the extra-chromosome could also exert a significant impact. The aim of this narrative review is to analyze the available literature on the relationship between KS and neuropsychiatric disorders. METHODS: To extent to the best of published literature on the topic, it was identified the appropriate keywords and MeSH terms and searched them in Pubmed. Finally, references of original articles and reviews were examined. RESULTS: Both morphological and functional studies focusing on the brain showed that there were important differences in brain structure of KS subjects. Different psychiatric disorders such as Schizophrenia, autism, attention deficit hyperactivity disorder, depression, anxiety, were frequently reported in KS patients according to a broad spectrum of phenotypes. T supplentation (TRT) was not able to improve the psychotic disorders in KS men with or without overt hypogonadism. CONCLUSION: Although the risk of psychosis, depression and autism is increased in subjects with KS, no definitive evidence has been found in studies aiming at identify the relationship between aneuploidy, T deficit and the risk of psychiatric and cognitive disorders in subjects affected by KS. PMID- 29972107 TI - Stability Study of [18F]Fludeoxyglucose and [18F]Fluorocholine in Different Medical Devices for Intravenous Administration. AB - OBJECTIVE: The present study had determine the impact of prolonged storage in a cartridge or syringe on the quality of the [18F]-radiopharmaceuticals used in our center [18F]fludeoxyglucose and [18F]fluorocholine). [18F]-radiopharmaceuticals registered as ready-to-use drugs are prepared in multidose flasks. When the change of packaging must be made extemporaneously for the preparation of patient unit doses in a syringe or cartridge, this is under the responsibility of radiopharmacists. As drug quality in medical devices (syringe or cartridge) is not evaluated during the marketing authorization of such radiopharmaceuticals, an evaluation of drug stability in such devices seems interesting. In addition, if there are difficulties in patient care (placement of the catheter, lack of personal, etc.) or equipment problems (technical issue with the automated dispenser delaying the delivery of the prepared dose), the contact time of [18F] radiopharmaceuticals with the medical devices (cartridge or syringe) increases. METHODS: Appearance, pH, radiochemical purity, sterility and endotoxin tests were made according the current European Pharmacopoeia. Adsorption tests were made according the literature. RESULTS: There was no drug absorption of [18F]fludeoxyglucose or [18F]fluorocholine after 1.5h, which may be related to their hydrophilic nature. No drug radiolysis was observed even after dilution of the radiopharmaceuticals (appearance, pH, and radiochemical purity were unchanged). No impurity from medical devices (cartridge or syringe) was observed, and microbiological aspects remained in specification of the current European Pharmacopoeia. CONCLUSION: These radiopharmaceuticals repackaged in plastic medical devices retained their quality after dispensing and prolonged storage. PMID- 29972108 TI - Estimating the burden on general practitioner services in England from increases in respiratory disease associated with seasonal respiratory pathogen activity. AB - Understanding the burden of respiratory pathogens on health care is key to improving public health emergency response and interventions. In temperate regions, there is a large seasonal rise in influenza and other respiratory pathogens. We have examined the associations between individual pathogens and reported respiratory tract infections to estimate attributable burden. We used multiple linear regression to model the relationship between doctor consultation data and laboratory samples from week 3 2011 until week 37 2015. We fitted separate models for consultation data with in-hours and out-of-hours doctor services, stratified by different age bands. The best fitting all ages models (R2 > 80%) for consultation data resulted in the greatest burden being associated with influenza followed by respiratory syncytial virus (RSV). For models of adult age bands, there were significant associations between consultation data and invasive Streptococcus pneumoniae. There were also smaller numbers of consultations significantly associated with rhinovirus, parainfluenza, and human metapneumovirus. We estimate that a general practice with 10 000 patients would have seen an additional 18 respiratory tract infection consultations per winter week of which six had influenza and four had RSV. Our results are important for the planning of health care services to minimise the impact of winter pressures. *Respiratory pathogen incidence explains over 80% of seasonal variation in respiratory consultation data.*Influenza and RSV are associated with the biggest seasonal rises in respiratory consultation counts.*A third of consultation counts associated with respiratory pathogens were due to influenza. PMID- 29972109 TI - Utility of serial 12-lead electrocardiograms in children with Marfan syndrome. AB - OBJECTIVES: The goal of this study was to assess the utility of serial electrocardiograms in routine follow-up of paediatric Marfan patients. METHODS: Children ?18 years who met the revised Ghent criteria for Marfan syndrome and received a 12-lead electrocardiogram and echocardiogram within a 3-month period were included. Controls were matched by age, body surface area, gender, race, and ethnicity, and consisted of patients assessed in clinic with a normal cardiac evaluation. Demographic, clinical, echocardiographic, and electrocardiographic data were collected. RESULTS: A total of 45 Marfan patients (10.8 [2.4-17.1] years) and 37 controls (12.8 [1.3-17.1] years) were included. Left atrial enlargement and left ventricular hypertrophy were more frequently present on 12 lead electrocardiogram of Marfan patients compared with controls (12 (27%) versus 0 (0%), p<0.001; and 8 (18%) versus 0 (0%), p=0.008, respectively); however, only two patients with left atrial enlargement on 12-lead electrocardiogram were confirmed to have left atrial enlargement by echocardiogram, and one patient had mild left ventricular hypertrophy by echocardiogram, not appreciated on 12-lead electrocardiogram. QTc interval was longer in Marfan patients compared with controls (427+/-16 versus 417+/-22 ms, p=0.03), with four Marfan patients demonstrating borderline prolonged QTc intervals for gender. CONCLUSIONS: While Marfan patients exhibited a higher frequency of left atrial enlargement and left ventricular hypertrophy on 12-lead electrocardiograms compared with controls, these findings were not supported by echocardiography. Serial 12-lead electrocardiograms in routine follow-up of asymptomatic paediatric Marfan patients may be more appropriate for a subgroup of Marfan patients only, specifically those with prolonged QTc interval at their baseline visit. PMID- 29972110 TI - De novo aortopathy and cardiovascular outcomes in paediatric liver transplant recipients. AB - With the increase in long-term survival of post-transplant children, there is a paradigm shift in the emphasis of post-transplant care. We describe de novo cardiovascular abnormalities, which occurred in otherwise asymptomatic paediatric liver transplant recipients, who received liver allografts between 1991 and 2014 at the National University Hospital, Singapore, detected during routine post transplant monitoring. A total of 96 paediatric liver transplants were performed in 90 children. After transplant, 7/90 (7.8%) recipients were identified with new onset aortopathy. Glycogen storage disease type I (42.9% versus 2.4%; p<0.001) and recipient Epstein-Barr virus seropositivity (85.7 versus 31.0%, p=0.004) were significant risk factors for aortopathy on univariate analysis. On multivariate analysis, only glycogen storage disease type I remained as the significant risk factor (odds ratio 51.3 [95% confidence intervals: 1.1-2498.1, p=0.047]). Liver transplant is a double-edged sword that reverses certain cardiopulmonary complications of end-stage liver disease but may induce de novo structural cardiac injury in the form of aortic dilation. PMID- 29972111 TI - Impaired lung function in children and adolescents with Fontan circulation may improve after endurance training. AB - OBJECTIVES: The objective of this research was to study lung function, physical capacity, and effect of endurance training in children and adolescents after Fontan palliation compared with healthy matched controls. METHODS: Fontan patients (n=30) and healthy matched control patients (n=25) performed dynamic and static spirometry, and pulmonary diffusing capacity and maximal oxygen uptake tests, before and after a 12-week endurance training programme and at follow-up after 1 year. RESULTS: Fontan patients had a restrictive lung pattern, reduced pulmonary diffusing capacity (4.27+/-1.16 versus 6.61+/-1.88 mmol/kPa/minute, p<0.001), and a reduced maximal oxygen uptake (35.0+/-5.1 versus 43.7+/-8.4 ml/minute/kg, p<0.001) compared with controls. Patients had air trapping with a higher portion of residual volume of total lung capacity compared with controls (26+/-6 versus 22+/-5%, p<0.05). Vital capacity increased for patients, from 2.80+/-0.97 to 2.91+/-0.95 L, p<0.05, but not for controls after endurance training. The difference in diffusing capacity between patients and controls appeared to be greater with increasing age. CONCLUSIONS: Fontan patients have a restrictive lung pattern, reduced pulmonary diffusing capacity, and reduced maximal oxygen uptake compared with healthy controls. Endurance training may improve vital capacity in Fontan patients. The normal increase in pulmonary diffusing capacity with age and growth was reduced in Fontan patients, which is concerning. Apart from general health effects, exercise may improve lung function in young Fontan patients and should be encouraged. PMID- 29972112 TI - Unusual association between corrected transposition of great arteries and supracardiac total anomalous pulmonary venous connection: a rare combination never reported before. AB - We describe the case of a 52-day-old child who was diagnosed with a rare combination of corrected transposition of great vessels - hypoplastic right ventricle with supracardiac total anomalous pulmonary venous connection. PMID- 29972113 TI - Creation of a defined and stable Fontan fenestration with the new Occlutech Atrial Flow Regulator (AFR(r)). AB - This report describes the first clinical experience with the new Occlutech Atrial Flow Regulator (AFR(r)) device for implementation of a late Fontan fenestration. The AFR(r) device secured a defined diameter of the fenestration without spontaneous re-occlusion of this extra-anatomic perforation. This ensured a permanent clinical improvement of our failing Fontan patient. PMID- 29972114 TI - [Clinical effect of bubble nasal continuous positive airway pressure versus conventional nasal continuous positive airway pressure in respiratory support for preterm infants with neonatal respiratory distress syndrome]. AB - OBJECTIVE: To study the clinical effect and safety of bubble nasal continuous positive airway pressure (BNCPAP) versus conventional nasal continuous positive airway pressure (nCPAP) in respiratory support for preterm infants with neonatal respiratory distress syndrome (NRDS). METHODS: A retrospective analysis was performed for the clinical data of 130 preterm infants with NRDS. Among them, 69 underwent BNCPAP and 61 underwent nCPAP. The two groups were compared in terms of mortality rate, duration of respiratory support, use of pulmonary surfactant (PS), and treatment failure rate, and the incidence rates of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), as well as the changes in blood gas pH, partial pressure of oxygen, and partial pressure of carbon dioxide. The safety was evaluated for both groups. RESULTS: There were no significant differences between the BNCPAP group and the nCPAP group in sex distribution, gestational age, birth weight, Apgar score at 1 and 5 minutes after birth, delivery mode, and the severity of NRDS (P>0.05). No infants in the BNCPAP group died, and one infant in the nCPAP group died; there was no significant difference in the mortality rate between the two groups (P>0.05). There were also no significant differences between the two groups in the duration of noninvasive ventilation, treatment failure rate, the incidence rates of BPD and ROP, and the percentage of infants with a need for use or reuse of PS (P>0.05). After 8-12 hours of ventilation, there were no significant differences between the two groups in the changes in blood gas pH and oxygenation index (P>0.05), while the BNCPAP group had a significantly greater reduction in partial pressure of carbon dioxide than the nCPAP group (P<0.05). There were no significant differences between the two groups in the incidence rates of pneumothorax, nasal septal injury, and nasal mucosal injury (P>0.05). CONCLUSIONS: BNCPAP and nCPAP have similar clinical effect and safety in respiratory support for preterm infants with NRDS. PMID- 29972115 TI - [Follow-up observation of catch-up growth of preterm infants after discharge and risk factors for extrauterine growth retardation]. AB - OBJECTIVE: To investigate the catch-up growth of preterm infants within a corrected age of 6 months and the risk factors for extrauterine growth retardation (EUGR). METHODS: A total of 321 preterm infants who were discharged after treatment in the neonatal intensive care unit and had regular follow-up documents with complete follow-up records were enrolled. According to the Prenatal Health Care Norms in 2015, these infants were divided into low-risk group with 69 infants and high-risk group with 252 infants. The Z-score method was used to evaluate body weight, body length, and head circumference, and the catch-up growth of the preterm infants within a corrected age of 6 months was analyzed. A multivariate logistic regression analysis was performed to identify the risk factors for EUGR at the corrected age of 6 months. RESULTS: The percentage of preterm infants with Z scores of body weight, body length, and head circumference of < -2 (not reach the standard for catch-up growth) in both groups decreased gradually with increasing corrected age. At the corrected age of 6 months, the percentages of preterm infants whose body weight, body length, and head circumference did not reach the standard for catch-up growth in the low-risk group were reduced to 1.4% (1/69), 2.9% (2/69), and 1.4% (1/69) respectively, while in the high-risk group, these percentages were reduced to 1.2% (3/252), 1.6% (4/252), and 3.6% (9/252) respectively. The high-risk group had a significantly higher incidence rate of EUGR at the corrected age of 6 months than the low-risk group (28.2% vs 15.9%, P=0.039). The multivariate logistic regression analysis showed that multiple birth (OR=2.68, P=0.010), low birth weight (<1 000 g: OR=14.84, P<0.001; 1 000-1 499 g: OR=2.85, P=0.005), and intrauterine growth retardation (IUGR) (OR=11.41, P<0.001) were risk factors for EUGR at the corrected age of 6 months, while nutritional enhancement after birth (OR=0.25, P<0.001) reduced the risk of EUGR. CONCLUSIONS: Most preterm infants can achieve catch-up growth at the corrected age of 6 months. High-risk preterm infants have a high incidence rate of EUGR at the corrected age of 6 months. Multiple birth, low birth weight, and IUGR are risk factors for EUGR, while rational nutritional enhancement after birth can reduce the incidence rate of EUGR in preterm infants. PMID- 29972116 TI - [Value of bedside lung ultrasound in the diagnosis of neonatal pneumonia]. AB - OBJECTIVE: To study the value of bedside lung ultrasound in the diagnosis of neonatal pneumonia. METHODS: A total of 49 neonates who were admitted to the Neonatal Intensive Care Unit of Chengdu Women and Children's Central Hospital in March 2017 with respiratory symptoms as the chief complaint were enrolled. Bedside lung ultrasound was performed within 24 hours after admission. A retrospective analysis was performed for their clinical data and lung ultrasound findings. The value of bedside lung ultrasound in the diagnosis of neonatal pneumonia was evaluated. RESULTS: According to the gold standard for the diagnosis of neonatal pneumonia, of all 49 neonates, 44 were diagnosed with pneumonia. According to the criteria for the diagnosis of neonatal pneumonia based on lung ultrasound findings, 38 neonates were diagnosed with pneumonia. In the neonates with respiratory symptoms, lung ultrasound had a sensitivity of 86%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 45% in the diagnosis of neonatal pneumonia. Among the 44 cases of neonatal pneumonia diagnosed by the gold standard, the lung ultrasonic images showed B-lines in all 44 neonates (100%), 75% had pleural line abnormalities, 36% had patchy or local hypoechoic area in the lung, 27% had alveolar-interstitial syndrome, and 20% had air bronchogram. CONCLUSIONS: As a new diagnostic technique in clinical practice, bedside lung ultrasound has a high sensitivity and specificity for the diagnosis of neonatal pneumonia and can thus be used as a tool for the diagnosis of this disease. PMID- 29972117 TI - [Current status of the application of 1H-magnetic resonance spectroscopy in neonates with hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: To investigate the current status of the application of 1H-magnetic resonance spectroscopy (1H-MRS) in neonates with hypoxic-ischemic encephalopathy (HIE), and to describe the trend of research in the field. METHODS: PubMed, EMBASE, and Web of Science were searched for English articles published up to January 10, 2018, with the combination of key words and MeSH terms. The articles were screened according to inclusion and exclusion criteria. Excel 2016, Bicomb 2.0, and VOSviewer1.6.6 were used to analyze the key words, to perform a cluster analysis of hot words, and to plot the knowledge map. RESULTS: A total of 66 articles were included, and 27 high-frequency key words were extracted. The results showed that 1H-MRS was mainly used in four directions of the clinical practice and scientific research on HIE. In clinical practice, 1H-MRS attracted wide attention as a clinical examination for HIE and a tool for prognostic evaluation; in scientific research, 1H-MRS was used in animal experiments and studies associated with mild hypothermia therapy. CONCLUSIONS: As an auxiliary means of magnetic resonance imaging, 1H-MRS plays an important role in investigating the pathogenesis of neonatal HIE, improving existing therapies, and evaluating the prognosis of neonates with HIE. PMID- 29972118 TI - [Association of blood lipids with childhood asthma]. AB - OBJECTIVE: To study the association of blood lipids with the development, clinical stage, allergic condition, and pulmonary function of asthma. METHODS: A total of 56 children with asthma who attended the hospital between October 2016 and March 2017 were enrolled as the asthma group, and 46 children who underwent physical examination as the healthy control group. According to the clinical manifestations, the children with asthma were divided into acute exacerbation group (n=24) and chronic persistent group (n=32). According to the results of skin prick test (SPT) and serum IgE measurement, the children with asthma were divided into non-allergic asthma group (n=16) and allergic asthma group (n=38). Fasting blood lipid levels were measured in both asthma and control groups. Pulmonary function tests were performed for asthmatic children. RESULTS: There were no significant differences in blood lipid levels between the asthma and control groups (P>0.05). The acute exacerbation group had significantly lower serum levels of high-density lipoprotein (HDL) and total cholesterol compared with the control group and the chronic persistent group (P<0.05). The allergic asthma group had a significantly lower serum HDL level than the non-allergic asthma group (P<0.05). In asthmatic children aged 6-13 years, the ratios of the measured values to the predicted values for forced vital capacity, peak expiratory flow, and maximal expiratory flow at 50% of vital capacity had a linear regression relationship with HDL and were positively correlated with HDL (P<0.05). Forced expiratory volume in one second and maximal mid-expiratory flow had a linear regression relationship with both HDL and LDL and were positively correlated with them (P<0.05). CONCLUSIONS: Blood lipids are associated with the clinical stage, allergic condition, and lung function of childhood asthma. This indicates that blood lipids may be involved in several aspects of the pathogenesis of childhood asthma. PMID- 29972119 TI - [Association of vitamin D level with asthma control and pulmonary function in asthmatic children aged 4-12 years]. AB - OBJECTIVE: To study the association of vitamin D level with asthma control and pulmonary function in children with asthma. METHODS: A total of 150 children with asthma were enrolled as observation group, and 55 healthy children were enrolled as control group. According to the level of asthma control, the children were divided into good control group, partial control group, and non-control group. Chemiluminescence microparticle immunoassay was used to measure the serum level of 25-hydroxyvitamin D [25(OH)D] for all groups. According to the level of 25(OH)D, the asthmatic children were divided into normal vitamin D group, vitamin D insufficiency group, and vitamin D deficiency group. Pulmonary function was measured for all asthmatic children. RESULTS: The observation group had a significantly lower serum level of 25(OH)D than the control group (25+/- 7 ng/mL vs 29+/- 4 ng/mL; P<0.05). The normal vitamin D group had the highest asthma control rate, followed by the vitamin D insufficiency group and the vitamin D deficiency group (P<0.05). There was no significant difference in pulmonary function among the three groups (P>0.05). CONCLUSIONS: Asthmatic children have a lower serum level of 25(OH)D than healthy children. The serum level of 25(OH)D is associated with the level of asthma control and has no association with pulmonary function. PMID- 29972120 TI - [Effect of suspension exercise training on motor and balance functions in children with spastic cerebral palsy]. AB - OBJECTIVE: To study the effect of suspension exercise training on motor and balance functions in children with spastic cerebral palsy. METHODS: A total of 97 children with spastic cerebral palsy were randomly divided into an observation group with 49 children and a control group with 48 children. Both groups were given routine rehabilitation training, and the children in the observation group were given suspension exercise training in addition. The scores of the D and E domains of the 88-item version of the Gross Motor Function Measure (GMFM-88) and Berg Balance Scale (BBS) were recorded before treatment and at 1, 3, and 6 months after treatment. Surface electromyography was performed to observe the changes in the root mean square (RMS) of surface electromyogram signals of the adductor muscle and the gastrocnemius muscle. RESULTS: Over the time of treatment, both groups had varying degrees of improvement in the scores of the D and E domains of GMFM-88 and BBS. Compared with the control group, the observation group had significantly greater improvements in D and E functional areas and balance function (P<0.05). Both groups had reductions in the RMS of the surface electromyogram signals of the adductor muscle and the gastrocnemius muscle over the time of treatment, and the observation group had significantly greater reductions than the control group (P<0.05). CONCLUSIONS: Suspension exercise training can effectively improve the motor and balance functions of children with spastic cerebral palsy. PMID- 29972121 TI - [Clinical features and prognosis of children with mature B-cell non-Hodgkin's lymphoma: an analysis of 28 cases]. AB - OBJECTIVE: To study the clinical features and treatment outcome of children with mature B-cell non-Hodgkin's lymphoma (B-NHL). METHODS: A total of 28 previously untreated children with mature B-NHL were enrolled and given the chemotherapy regimen of CCCG-B-NHL-2010. Among them, 20 were given rituximab in addition to chemotherapy. The children were followed up for 31 months (ranged 4-70 months). A retrospective analysis was performed for the clinical features of these children. The Kaplan-Meier method was used for survival analysis. A univariate analysis was performed to investigate the prognostic factors. RESULTS: Among the 28 children, 17 (61%) had Burkitt lymphoma, 8 (29%) had diffuse large B-cell lymphoma (DLBCL), and 3 (11%) had unclassifiable B-cell lymphoma. As for the initial symptom, 13 (46%) had cervical mass, 10 (36%) had maxillofacial mass, 9 (32%) had hepatosplenomegaly, 5 (18%) had abdominal mass, and 5 (18%) had exophthalmos. Of all children, 14 had a lactate dehydrogenase (LDH) level of <500 IU/L, 3 had a level of 500-1 000 IU/L, and 11 had a level of >= 1 000 IU/L. After two courses of chemotherapy, 21 children achieved complete remission and 7 achieved partial remission. At the end of follow-up, 24 achieved continuous complete remission and 4 experienced recurrence. The 2-year event-free survival rate was (85.7+/- 6.6)%. The children with bone marrow infiltration suggested by bone marrow biopsy, serum LDH >=500 IU/L, and bone marrow tumor cells >25% had a low 2-year cumulative survival rate. CONCLUSIONS: The CCCG-B-NHL 2010 chemotherapy regimen combined with rituximab has a satisfactory effect in the treatment of children with B-NHL. Bone marrow infiltration on bone marrow biopsy is associated with poor prognosis. PMID- 29972122 TI - [Association of hypoalbuminemia with acute kidney injury in children after cardiac surgery]. AB - OBJECTIVE: To study whether hypoalbuminemia after pediatric cardiopulmonary bypass (CPB) for cardiac surgery is a risk factor for postoperative acute kidney injury (AKI). METHODS: A retrospective analysis was performed on the clinical data of 1 110 children who underwent CPB surgery between 2012 and 2016. According to the minimum serum albumin within 48 hours postoperatively, these patients were divided into hypoalbuminemia group (<=35 g/L) and normal albumin group (>35 g/L). The two groups were compared in terms of perioperative data and the incidence of AKI. Furthermore, the incidence of AKI was compared again after propensity score matching for the unbalanced factors during the perioperative period. The perioperative risk factors for postoperative AKI were analyzed by logistic regression. RESULTS: The overall incidence rate of postoperative AKI was 13.78% (153/1 110), and the mortality rate was 2.52% (28/1 110). The mortality rate of children with AKI was 13.1% (20/153). The patients with hypoalbuminemia after surgery (<=35 g/L) accounted for 44.50% (494/1 110). Before and after propensity score matching, the hypoalbuminemia group had a significantly higher incidence of AKI than the normal albumin group (P<0.05). The children with AKI had a significantly lower serum albumin level after surgery than those without AKI (P<0.05). The multivariate logistic regression analysis showed albumin <=35 g/L was one of the independent risk factors for postoperative AKI. CONCLUSIONS: Albumin <=35 g/L within 48 hours postoperatively is an independent risk factor for postoperative AKI in children after CPB surgery. PMID- 29972123 TI - [Clinical phenotypes and a genetic analysis of patients with Sotos syndrome]. AB - Three boys aged 7-13 months visited the hospital due to unusual facies (prominent forehead, hypertelorism, or long mandible), motor developmental delay, and mental retardation. As for body length and head circumference, only one patient had a head circumference of >2 SD. Two patients had an advanced bone age, one had electroencephalographic abnormalities, and 3 had enlarged ventricles on head CT. The whole-genome microarray analysis showed the deletion of a copy with a size of 1.75 Mb in the chromosomal region 5q35.2 in one patient, which contained the NSD1 gene. Quantitative real-time PCR was performed for the validation of the region with copy number variation, and the results showed that the copy number of the NSD1 gene in this patient was reduced by half. High-throughput sequencing identified two heterozygous mutations, c.1157T>G and c.1177G>T, in the NSD1 gene in two patients. c.1157T>G mutations had not been reported before, but the bioinformatics analysis showed that this mutation had pathogenicity. All three boys were diagnosed with Sotos syndrome. Sotos syndrome is a congenital overgrowth syndrome with autosomal dominant inheritance; 70%-90% of patients have NSD1 gene mutations, and about 10% of patients have depletion in the 5q35 region (containing the NSD1 gene). PMID- 29972125 TI - [Association of single nucleotide polymorphisms of transcription factors with congenital heart diseases in the Chinese population: a Meta analysis]. AB - OBJECTIVE: To study the association of single nucleotide polymorphisms (SNPs) of transcription factors (NKX2.5, GATA4, TBX5, and FOG2) with congenital heart disease (CHD) in the Chinese population. METHODS: PubMed, Google Scholar, CNKI, Wanfang Data, and Weipu Data were searched for articles on the association of SNPs of target genes with CHD in the Chinese population. If one locus was mentioned in at least two articles, the random or fixed effect model was used to perform a pooled analysis of study results and to calculate the pooled OR and its 95%CI. If a locus was mentioned in only one article, related data were extracted from this article to analyze the association between the SNPs of this locus and CHD. RESULTS: Twenty-three articles were included. The Meta analysis showed that there were significant differences between the CHD and control groups in the genotype and allele frequencies of GATA4 rs1139244 and rs867858 and the genotype frequency of GATA4 rs904018, while there were no significant differences in the SNPs of the other genetic loci between the two groups. The single-article analysis showed that there were significant differences between the two groups in the allele frequencies of NKX2.5 rs118026695/rs703752, GATA4 rs884662/rs12825/rs12458/rs3203358/rs4841588, and TBX5 rs6489956. There were no significant differences in the SNPs of FOG2 locus between the two groups. CONCLUSIONS: The SNPs of some loci in NKX2.5, GATA4, and TBX5 are associated with CHD in the Chinese population, but the association between the SNPs of FOG2 locus and the development of CHD has not been found yet. PMID- 29972124 TI - [Clinical and genetic features of ring chromosome 13 syndrome: an analysis of one case]. AB - A girl aged 5 months was admitted due to developmental delay. Physical examination showed delayed physical development, unusual facies (microcephalus, hypertelorism, low-set ears, wide nasal bridge, and short philtrum), and an absence of the labium minus at one side. The peripheral blood karyotype was 46,XX,r(13)(p11q33)[82]/45,XX,-13[10]/46,XX,r(13;13)(p11q33;p11q33)[8], and array based comparative genomic hybridization showed an 87.5 Mb duplication in 13q11q33.2 region and an 8.2 Mb deletion in 13q33.2q34 region. Fluorescence in situ hybridization showed terminal depletion of the long arm of the ring chromosome 13. The girl was diagnosed with ring 13 syndrome. This syndrome has various clinical phenotypes and is closely associated with the amount and site of the loss of genetic material in chromosomal band and different rates of chimerism. PMID- 29972126 TI - [Psychomotor retardation with neutropenia for more than one year in a toddler]. AB - A boy was admitted at the age of 17 months. He had psychomotor retardation in early infancy. Physical examination revealed microcephalus, unusual facies, and a single palmar crease on his right hand, as well as muscle hypotonia in the extremities and hyperextension of the bilateral shoulder and hip joints. Genetic detection identified two pathogenic compound heterozygous mutations, c.8868-1G>A (splicing) and c.11624_11625del (p.V3875Afs*10), in the VPS13B gene, and thus the boy was diagnosed with Cohen syndrome. Cohen syndrome is a rare autosomal recessive disorder caused by the VPS13B gene mutations and has complex clinical manifestations. Its clinical features include microcephalus, unusual facies, neutropenia, and joint hyperextension. VPS13B gene detection helps to make a confirmed diagnosis. PMID- 29972127 TI - [Effect of LINE1-ORF1p overexpression on the proliferation of nephroblastoma WT_CLS1 cells]. AB - OBJECTIVE: To prepare the LINE1-ORF1p polyclonal antibody, and to study the effect of LINE1-ORF1p on the proliferation of nephroblastoma WT_CLS1 cells. METHODS: A genetic engineering method was used to achieve prokaryotic expression of LINE1-ORF1p, and rabbits were immunized with LINE1-ORF1p to prepare polyclonal antibody. Indirect ELISA was used to evaluate antibody titer, and Western blot and immunohistochemistry were used to evaluate the specific ability of antibody to recognize LINE1-ORF1p. The eukaryotic expression vector pEGFP-N1-LINE1-ORF1 was constructed and used to transfect WT_CLS1 cells. Western blot and qRT-PCR were used to measure the protein and mRNA expression of LINE1-ORF1, respectively, and cell proliferation assay and colony-forming assay were used to evaluate the effect of LINE1-ORF1p on the proliferation of WT_CLS1 cells and the formation of tumor cell clone. RESULTS: The LINE1-ORF1p antibody prepared had a titer of >1:16 000 and could specifically recognize LINE1-ORF1p in cells and tumor tissue. WT_CLS1 cells transfected with pEGFP-N1-LINE1-ORF1 had significant increases in the mRNA and protein expression of LINE1-ORF1 and significantly enhanced cell proliferation ability and colony formation ability (P<0.05). CONCLUSIONS: LINE1 ORF1p can promote the growth of nephroblastoma cells and the formation of tumor cell clone, and may be involved in the pathogenesis of nephroblastoma. PMID- 29972128 TI - [Establishment of cardiac remodeling model in FVB/N mice by intraperitoneal injection of isoproterenol]. AB - OBJECTIVE: To explore the feasibility of intraperitoneal injection of isoproterenol (ISO) to induce cardiac remodeling in FVB/N mice. METHODS: Forty eight FVB/N mice were divided into back subcutaneous saline group (subcutaneous saline group), intraperitoneal saline group, back subcutaneous ISO group (subcutaneous ISO group), and intraperitoneal ISO group according to the route of administration of saline or ISO. ISO (30 MUg/g body weight/day) was given to the subcutaneous ISO group and the intraperitoneal ISO group, twice daily with an interval of 12 hours, for 14 consecutive days. The subcutaneous saline group and the intraperitoneal saline group were injected with an equal volume of saline. The left ventricular end-diastolic posterior wall thickness was measured by echocardiography, and the ratio of heart weight to tibia length was determined. Hematoxylin-eosin staining was used to determine the myocardial fiber diameter. Picric-sirius red staining was used to determine the myocardial collagen deposition area. Quantitative real-time PCR was used to measure the mRNA expression of collagen I. RESULTS: Compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups, the intraperitoneal ISO group had increased sizes of the cardiac cavity and the heart. Compared with the subcutaneous saline and intraperitoneal saline groups, the subcutaneous ISO group showed no significant changes in the gross morphology of the cardiac cavity and the heart. The intraperitoneal ISO group showed significant increases in the ratio of heart weight to tibia length, myocardial fiber diameter, left ventricular end-diastolic posterior wall thickness, myocardial collagen area percentage, and the mRNA expression of collagen I compared with the subcutaneous ISO, subcutaneous saline, and intraperitoneal saline groups (P<0.01). There were no significant differences in the above five indices between the subcutaneous ISO group and the subcutaneous saline and intraperitoneal saline groups (P>0.05). No significant difference in the mortality rate was found between the subcutaneous ISO and intraperitoneal ISO groups (P>0.05). CONCLUSIONS: Intraperitoneal injection of ISO can induce cardiac hypertrophy and fibrosis in FVB/N mice. PMID- 29972130 TI - Georgia: Health System Review. AB - This analysis of the Georgian health system reviews developments in its organization and governance, health financing, health care provision, health reforms and health system performance. Since 2012, political commitment to improving access to health care, to protecting the population from the financial risks of health care costs and to reducing inequalities has led to the introduction of reforms to provide universal health coverage. Considerable progress has been made. Over 90% of the resident population became entitled to a tightly defined package of state-funded benefits in 2013; previously, only 45% of the population had been eligible. The package of services has variable depth of coverage depending on the groups covered, with the lowest income groups enjoying the most comprehensive benefits. To finance the broader coverage, the government increased health spending significantly, although this remains low in international comparisons. Out-of-pocket (OOP) payments have fallen as public spending has increased. Nevertheless, current health expenditure (CHE) is still dominated by OOP payments (57% in 2015), two thirds of which are for outpatient pharmaceuticals. For this reason, in July 2017, the package of benefits was expanded for the most vulnerable households to cover essential medicines for four common chronic conditions. The system has retained extensive infrastructure with strong geographical coverage. Georgia also has a large number of doctors per capita, but an acute shortage of nurses. Incentives in the system for patients and providers favour emergency and inpatient care over primary care. There are also limited financial incentives to improve the quality of care and a lack of disincentives to inhibit poor quality care. Future reform plans focus on ensuring universal access to high-quality medical services, strengthening primary care and public health services, and increasing financial protection. PMID- 29972129 TI - [Effects of bacterial lysates and all trans-retinoic acid on airway inflammation in asthmatic mice]. AB - OBJECTIVE: To observe the effects of bacterial lysates (OM-85BV) and all trans retinoic acid (ATRA) on airway inflammation in asthmatic mice, and to investigate the immunoregulatory mechanism of OM-85BV and ATRA for airway inflammation in asthmatic mice. METHODS: Forty female BALB/c mice were randomly divided into five groups: normal control, model, OM-85BV, ATRA, and OM-85BV+ATRA. A bronchial asthma model was established by intraperitoneal injection of ovalbumin (OVA) for sensitization and aerosol challenge in all mice except those in the normal control group. On days 25-34, before aerosol challenge, the model, OM-85BV, ATRA, and OM-85BV+ATRA groups were given normal saline, OM-85BV, ATRA, and OM-85BV+ATRA respectively by gavage. Normal saline was used instead for sensitization, challenge, and pretreatment before challenge in the normal control group. These mice were anesthetized and dissected at 24-48 hours after the final challenge. Bronchoalveolar lavage fluid (BALF) was collected from the right lung to measure the levels of interleukin-10 (IL-10) and interleukin-17 (IL-17) by ELISA. The left lung was collected to observe histopathological changes by hematoxylin-eosin staining. The relative expression of ROR-gammaT mRNA was measured by quantitative real-time PCR. RESULTS: Compared with the normal control group, the model group showed contraction of the bronchial cavity, increased bronchial secretions, and a large number of infiltrating inflammatory cells around the bronchi and alveolar walls, as well as a significantly reduced level of IL-10 (P<0.05) and significantly increased levels of IL-17 and ROR-gammaT mRNA (P<0.05). Compared with the model group, the OM-85BV, ATRA, and OM-85BV+ATRA groups showed a significant reduction in infiltrating inflammatory cells around the bronchi and alveolar walls; the OM-85BV group showed a significant increase in the level of IL-10 in BALF (P<0.05) and significant reductions in the levels of IL-17 and ROR gammaT mRNA (P<0.05); the ATRA group showed significant reductions in the levels of IL-17 and ROR-gammaT mRNA (P<0.05). Compared with the OM-85BV group, the OM 85BV+ATRA group had significantly increased relative expression of ROR-gammaT mRNA (P<0.05). Compared with the ATRA group, the OM-85BV+ATRA group had significantly increased levels of IL-10 and IL-17 in BALF (P<0.05). CONCLUSIONS: Both OM-85BV and ATRA can reduce respiratory inflammation in asthmatic mice. However, a combination of the two drugs does not have a better effect than them used alone. PMID- 29972132 TI - [Presumed consent for organ donation in Iceland]. PMID- 29972131 TI - Greece: Health System Review. AB - This analysis of the Greek health system reviews developments in its organization and governance, health financing, health care provision, health reforms and health system performance. The economic crisis has had a major impact on Greek society and the health system. Health status indicators such as life expectancy at birth and at age sixtyfive are above the average in the European Union but health inequalities and particular risk factors such as high smoking rates and child obesity persist. The highly centralized health system is a mixed model incorporating both tax-based financing and social health insurance. Historically, a number of enduring structural and operational inadequacies within the health system required addressing, but reform attempts often failed outright or stagnated at the implementation phase. The countrys Economic Adjustment Programme has acted as a catalyst to tackle a large number of wide-ranging reforms in the health sector, aiming not only to reduce public sector spending but also to rectify inequities and inefficiencies. Since 2010, these reforms have included the establishment of a single purchaser for the National Health System, standardizing the benefits package, re-establishing universal coverage and access to health care, significantly reducing pharmaceutical expenditure through demand and supply-side measures, and important changes to procurement and hospital payment systems; all these measures have been undertaken in a context of severe fiscal constraints. A major overhaul of the primary care system is the priority in the period 2018-2021. Several other challenges remain, such as ensuring adequate funding for the health system (and reducing the high levels of out-of pocket spending on health); maintaining universal health coverage and access to needed health services; and strengthening health system planning, coordination and governance. While the preponderance of reforms implemented so far have focused on reducing costs, there is a need to develop this focus into longer-term strategic reforms that enhance efficiency while guaranteeing the delivery of health services and improving the overall quality of care. PMID- 29972133 TI - [Is there lack of ICU beds in Iceland?] PMID- 29972134 TI - [Outcome of coronary artery bypass grafting in women in Iceland]. AB - Introduction The aim of this study was to evaluate the outcome of coronary artery bypass grafting (CABG) in women compared to men, with focus on short-term and long-term complications, 30 day mortality and survival. Materials and methods This was a retrospective study on all CABG patients operated in Iceland between 2001 and 2013. Clinical information was gathered from hospital charts and survival data was obtained from the National Statistics in Iceland. Overall survival was estimated with the Kaplan- Meier method. Logistic and Cox regression analysis were used to identify predictors of operative mortality and long-term survival. Mean follow-up was 6.8 years. Results Of 1755 patients 318 were women (18%). Women were on average four years older than men at the time of operation (69 vs. 65 yrs, p<0.001). Female patients had a higher incidence of hypertension (72 vs. 64%, p=0.009) and their EuroSCOREst was higher (6.1 vs. 4.3, p<0.001). The prevalence of diabetes, dyslipidemia and the extent of coronary artery disease was comparable between groups. The rate of short-term complications, both minor (53% vs. 48%, p=0.07) and major (27% vs. 32%, p=0.2), was similar and operative mortality for women was not statistically different from males (4% vs. 2%, p=0.08). Female gender was neither found to be a predictor of 30-day mortality (OR 0.99; 95%-CI: 0.98-1.01) nor survival (HR 1,08; 95%-OB: 0,82-1,42). Conclusions The number of women that undergo CABG is low and they are four years older than men when operated on. As is the case with men, outcome following CABG in Iceland is very good for women, their overall five-year survival being 87%. PMID- 29972136 TI - [Opioid Induced Pituitary Dysfunction]. AB - A 77-year-old woman with a history of anal squamous cell carcinoma was admitted because of malaise, diarrhea and nausea, in addition to back pain related to a verte- bral compression fracture. During the course of treatment, opioid therapy was initiated, following which the patient became progressively hypotensive and hyponatraemic and respiratory drive progressively decreased. Serum levels of cortisol, TSH and LH were decreased and prolactin slightly elevated, but a Synacthen test and brain MRI turned out normal, suggesting a diagnosis of opioid induced pituitary dysfunction. The patient was given glucocorticoid replacement therapy with good results. Here we present a case of this serious but less well recognised side-effect of opioids. PMID- 29972135 TI - [Perinatal mortality in Iceland 1988-2017]. AB - Introduction Perinatal mortality refers to stillbirth and neonatal death during the first week of life. Recently perinatal mortality rate in Iceland has been among the lowest in the world. The aim of the study was to evaluate how perinatal mortality rate and its causes have changed in Iceland during the last 30 years, particularly to see if it is possible to lower the perinatal mortality rate even more. Cases and methods The study was retrospective and included all infants that were stillborn or died during the first week of life in 1988-2017. Information was obtained from the Icelandic Medical Birth Registry, the annual reports on births in Iceland. A classification focusing on identifying groups of perinatal death that are potentially avoidable was used. An annual percent change was calculated with Poisson regression. Results The perinatal mortality rate declined on average by 3,3% per year in the period based on >=28+0 weeks gestation. The number of infants that died because of congenital anomalies decreased on average by 4,8% per year. The number of growth restricted stillborn singletons after >=28+0 weeks of gestation decreased on average by 3,1% per year. The number of non growth restricted stillborn singletons after >=28+0 weeks of gestation did not decrease significantly. Conclusion Perinatal mortality rate has declined substantially in Iceland during 30 years. Deaths because of congenital anomalies have decreased considerably due to improvement in prenatal diagnosis. Stillbirths associated with growth restriction have decreased but stillbirths that are not associated with growth restriction have not. Thus it is important to emphasize that women seek medical attention when they experience decreased fetal movements. PMID- 29972137 TI - Is cytomegalovirus a risk factor for haemorrhagic cystitis in allogeneic haematopoietic stem cell transplantation recipients? AB - BACKGROUND: Haemorrhagic cystitis (HC) is usually a serious complication in allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients. In this study, our aim was to define risk factors and outcomes for patients with HC in an allo-HSCT setting. METHODS: We retrospectively evaluated 249 allo-HSCTs performed between 2011 and 2016 in our centre. RESULTS: HC was diagnosed in 98 patients (39%) at a median of 119 days (range 5-580) and 91 (93%) of the patients had late onset disease. In univariate analysis, HC was related to cytomegalovirus (CMV) reactivation (P<0.001) and BK viraemia (P<0.001); in multivariate analysis, the presence of CMV reactivation was determined to be an independent risk factor (odds ratio: 22.1; 95% CI 1.73, 282.44; P=0.017). There was no association detected between acute graft versus host disease and patients diagnosed with HC within 100 days of transplant. HC was significantly increased by the presence of myelo-ablative conditioning (odds ratio: 31.28; 95% CI 3.98, 246.87; P=0.001) and BK viraemia (odds ratio: 3.93; 95% Cl 1.10, 14.05; P=0.035) in patients with HC grade II and beyond. Forced hydration was recommended in all patients with grade I HC. Patients with HC and clots were treated with continuous bladder irrigation, and 14 of 44 patients with BK viraemia received cidofovir +/- ribavirin. Eight of these patients (57%) responded to treatment. Refractory HC was detected in 17 patients (17%) and resolved by a variety of procedures. CONCLUSIONS: This study suggests that CMV reactivation is associated with increased risk of HC in multivariate analysis, however, this result is not confirmed in patients with HC grade II and beyond. PMID- 29972138 TI - An easy-to-use baseline scoring system to predict response to peginterferon alfa 2a in patients with chronic hepatitis B in resource-limited settings. AB - BACKGROUND: Approximately one-third of patients have durable responses after finite (48-week) treatment with peginterferon alfa-2a. The ability to identify patients likely to respond would be particularly useful in resource-limited settings. METHODS: Data from 1,363 peginterferon alfa-2a recipients (955 hepatitis B 'e' antigen [HBeAg]-positive and 408 -negative) in six studies were analysed. Baseline scoring systems were developed using generalized additive models and multiple logistic regression analysis to predict virological response (VR; HBV DNA <2,000 IU/ml), alone or combined with alanine aminotransferase (ALT) normalization (CR) at 24 weeks post-treatment. RESULTS: Based on the final models, points were assigned for age >=45 (0) or <45 years (1); male (0) or female (1); hepatitis B surface antigen (HBsAg) >25,000 (0), >7,500-<=25,000 (1), >1,250-<=7,500 (2) or <=1,250 IU/ml (4); HBV DNA >5 (0) or <=5 log10 IU/ml (2) and ALT ratio >1-7 (0) or either <=1 or >7 (1). Higher total scores (range 0-9) indicate higher likelihood of response. VR and CR rates were 28.5% (388/1,363) and 24.4% (332/1,363), respectively, and increased with increasing score: score 0 1 (n=257), VR 14.8%, CR 12.8%; score 2-3 (n=711), VR 23.1%, CR 20.1%; score >=4 (n=395), VR 47.1%, CR 39.5%. CONCLUSIONS: An easy-to-use baseline scoring system for use in settings where HBeAg status and HBV genotypes are unavailable would allow clinicians to identify patients with a low or high chance of achieving a durable post-treatment response to peginterferon alfa-2a. The tool can be used to inform treatment decisions in resource-limited settings. PMID- 29972139 TI - Effect of quantum confinement on lifetime of anharmonic decay of optical phonons in semiconductor nanostructures. AB - The anharmonic decay of phonons underlies many important effects in semiconductors, e.g. hotspot formation, phonon bottleneck and thermal resistivity. In this article, we evaluate the effect of quantum confinement on the anharmonic decay transition probability in a cubic isotropic material. This article focuses on the anharmonic decay of longitudinal optical phonons, generated from hot electrons, are directly related to formation of hotspots in the active region of semiconductor devices. The confinement effect has been realized in double interface heterostructure quantum well (DHSQW) (e.g. AlAs/GaAs/AlAs) and free-standing quantum well (FSQW) (e.g. GaAs) structures as the confined phonon modes have different properties inside the structures. The longitudinal-optical phonon decay rate is reduced for the case of a DHSQW compared to bulk material and for a FSQW the decay rate has a strong dependence on wavevector value of the three phonons involved. PMID- 29972140 TI - Surface enhancement of water at the ionic liquid-gas interface of [HMIM][Cl] under ambient water vapor. AB - The ionic liquid-gas interface of 1-hexyl-3-methyl-imidazolium chloride, [HMIM][Cl], was examined in the presence of water vapor using lab-based ambient pressure x-ray photoelectron spectroscopy (APXPS) at room temperature. The interfacial water uptake was measured quantitatively in the pressure range of high vacuum up to a maximum of 5 Torr (27% RH) and back to high vacuum in a systematic manner. Water mole fractions in the interface determined from APXPS were compared to previously published tandem differential mobility analysis results on [HMIM][Cl] nanodroplets. Our findings show that water constitutes a significantly larger mole fraction at the interface when compared to the bulk. Additionally, the reverse isotherms showed that the uptake of water at the interface of [HMIM][Cl] is a reversible process. PMID- 29972141 TI - Modeling and comparison of alternative approaches for sector duration optimization in a dedicated radiosurgery system. AB - Stereotactic radiosurgery (SRS) is an effective technique to treat brain metastasis for which several inverse planning methods may be appropriate. We compare three different optimization models for segment duration optimization in SRS using Leksell Gamma Knife(r) IconTM (Elekta, Stockholm, Sweden). We investigate (1) a linear programming approach, (2) a piecewise quadratic penalty approach, and (3) an unconstrained convex moment-based penalty approach. We examine the performances of these approaches using anonymized data from 14 previously treated cases. In addition, we investigate the important modeling question of selecting weights for the objective functions where we use a simulated annealing algorithm to determine these weights for each model. The inverse plans obtained via optimization models are compared against each other and against the clinical plans. The three inverse planning models can all yield optimal treatment plans in a reasonable amount of time and the treatment plans obtained by these models meet or exceed clinical guidelines while displaying high conformity. PMID- 29972142 TI - Numerical investigation of cephalopod-inspired locomotion with intermittent bursts. AB - Inspired by recent studies about the fluid dynamics of cephalopods in their escaping swimming mode, we propose a novel design of an underwater propulsion system using a deformable body with pressure chamber, which propels itself in burst-coast cycles through a combined effect of pulsed jet and added-mass related thrust. To investigate the performance of this system we create a free-swimming computational model-the body deformation is prescribed yet the forward motion is driven by hydrodynamic forces. Our focus is on a single bursting cycle, which corresponds to the case that the system rests between bursts. The results can also be applied to the starting stage of a continuous cruising motion. A numerical model using the boundary element method is developed to computationally study the swimming process and the dynamic characteristics of this system. The results show that in the bursting phase its peak speed depends on the size of the body, the deformation time, the amount of volume change during the deformation, and the size of the nozzle where the jet flow is generated. The optimal speed is found to coincide with the critical formation number, indicating that the formation of vortex rings in the wake plays a pivotal role in the dynamics of the system. The dynamics of the system in the coasting phase and the process of refilling the pressure chamber are also studied. PMID- 29972143 TI - Half-metallicity in zigzag phosphorene nanoribbons with magnetic edges. AB - Phosphorene nanoribbons with magnetic edges are potentially attractive for nanoelectronic and spintronic applications. Here, the attention is focused on electronic and magnetic properties of these materials. Using a self-consistent computational method it is shown that, in general, two types of configuration with spontaneous edge magnetization can be responsible for lifting the spin degeneracy, and consequently for the appearance of the half-metallic behavior. Namely, in addition to the well-known configuration with edge states ferromagnetically coupled along each edge and aligned in parallel between the two edges, there is another one (much less explored) with edge states ferromagnetically aligned on only one edge. The ground state magnetic configurations strongly depend on the chemical potential position (electron filling factor), and can be controlled by means of the external perpendicular gate voltage, and by changing the nanoribbon width. It is also shown that the magnetic edge configurations responsible for the half-metallicity can be stabilized with ferromagnetic substrates, due to the proximity effect. PMID- 29972144 TI - A comparative study of physical image quality in digital and synthetic mammography from commercially available mammography systems. AB - We present a comparison between full field digital mammography and synthetic mammography, performed on several mammography systems from four different manufacturers. The analysis is carried out on both the digital and synthetic images of two commercially available mammography phantoms, and focuses on a set of objective metrics that encode the geometrical appearance of imaging features of diagnostic interest. In particular, we measured sizes and contrasts of several clusters of microcalcification specks, shapes and contrasts of circular masses, and the power spectrum of background regions mimicking the heterogeneous texture of the breast parenchyma. Despite the potential issues of tomosynthesis in terms of image blurring, the synthetic images do not highlight any globally significant differences in the rendering of the details of interest, when compared to the original digital mammograms: relative contrasts are generally preserved, as well as the geometry of broad structures. We conclude that, as far as the considered objective metrics are concerned, the image quality of synthetic mammography does not exhibit significant differences with respect to the one of full field digital mammography, for all the considered systems. PMID- 29972145 TI - The race to the bottom: approaching the ideal glass? AB - Key to resolving the scientific challenge of the glass transition is to understand the origin of the massive increase in viscosity of liquids cooled below their melting temperature (avoiding crystallisation). A number of competing and often mutually exclusive theoretical approaches have been advanced to describe this phenomenon. Some posit a bona fide thermodynamic phase to an 'ideal glass', an amorphous state with exceptionally low entropy. Other approaches are built around the concept of the glass transition as a primarily dynamic phenomenon. These fundamentally different interpretations give equally good descriptions of the data available, so it is hard to determine which-if any-is correct. Recently however this situation has begun to change. A consensus has emerged that one powerful means to resolve this longstanding question is to approach the putative thermodynamic transition sufficiently closely, and a number of techniques have emerged to meet this challenge. Here we review the results of some of these new techniques and discuss the implications for the existence-or otherwise-of the thermodynamic transition to an ideal glass. PMID- 29972147 TI - Anatomically plausible models and quality assurance criteria for online mono- and multi-modal medical image registration. AB - Medical imaging is currently employed in the diagnosis, planning, delivery and response monitoring of cancer treatments. Due to physiological motion and/or treatment response, the shape and location of the pathology and organs-at-risk may change over time. Establishing their location within the acquired images is therefore paramount for an accurate treatment delivery and monitoring. A feasible solution for tracking anatomical changes during an image-guided cancer treatment is provided by image registration algorithms. Such methods are, however, often built upon elements originating from the computer vision/graphics domain. Since the original design of such elements did not take into consideration the material properties of particular biological tissues, the anatomical plausibility of the estimated deformations may not be guaranteed. In the current work we adapt two existing variational registration algorithms, namely Horn-Schunck and EVolution, to online soft tissue tracking. This is achieved by enforcing an incompressibility constraint on the estimated deformations during the registration process. The existing and the modified registration methods were comparatively tested against several quality assurance criteria on abdominal in vivo MR and CT data. These criteria included: the Dice similarity coefficient (DSC), the Jaccard index, the target registration error (TRE) and three additional criteria evaluating the anatomical plausibility of the estimated deformations. Results demonstrated that both the original and the modified registration methods have similar registration capabilities in high-contrast areas, with DSC and Jaccard index values predominantly in the 0.8-0.9 range and an average TRE of 1.6-2.0 mm. In contrast-devoid regions of the liver and kidneys, however, the three additional quality assurance criteria have indicated a considerable improvement of the anatomical plausibility of the deformations estimated by the incompressibility-constrained methods. Moreover, the proposed registration models maintain the potential of the original methods for online image-based guidance of cancer treatments. PMID- 29972148 TI - Value of Diffusion-Weighted Imaging Combined with Susceptibility-Weighted Imaging in Differentiating Benign from Malignant Parotid Gland Lesions. AB - BACKGROUND The aim of this study was to investigate the diagnostic value of diffusion-weighted imaging (DWI) in combination with susceptibility-weighted imaging (SWI) for differentiating benign parotid gland lesions from malignant ones. MATERIAL AND METHODS This retrospective study was approved by the Ethics Committee of our hospital. A total of 36 patients (26 benign cases and 10 malignant cases) were confirmed by surgical pathology. The apparent diffusion coefficient (ADC), normalized ADC (ADCNormalized), intratumoral susceptibility signals (ITSS), and morphological characteristics were analyzed with SPSS 19.0 software. RESULTS The mean ADC values of parotid gland lesions was not different between malignant and benign lesions (P=0.07), while the differences between ADCNormalized (P=0.026) and ITSS grading (P=0.014) were statistically significant. Logistic regression analysis identified use of ADCNormalized and ITSS as the only independent predictor of malignant lesions (odds ratio 0.038; 95% confidence interval 0.001~0.988; P=0.011) and (odds ratio 4.867; 95% confidence interval 1.442~16.423; P=0.049), respectively. The optimum threshold of the ADCNormalized values was -0.45%, ITSS grade was 2, the corresponding areas under the receiver operating characteristic curve (AUC) were 0.750 and 0.787 respectively, and the combination of the 2 was 0.846. CONCLUSIONS DWI integrated with SWI can significantly improve the diagnostic efficacy in distinguishing benign from malignant parotid lesions. PMID- 29972149 TI - Corrigendum: Cancer Cell Mitochondria Targeting by Pancratistatin Analogs is Dependent on Functional Complex II and III. AB - This corrects the article DOI: 10.1038/srep42957. PMID- 29972146 TI - Pallidal stimulation in Parkinson disease differentially modulates local and network beta activity. AB - : beta hypersynchrony within the basal ganglia-thalamocortical (BGTC) network has been suggested as a hallmark of Parkinson disease (PD) pathophysiology. Subthalamic nucleus (STN)-DBS has been shown to alter cortical-subcortical synchronization. It is unclear whether this is a generalizable phenomenon of therapeutic stimulation across targets. OBJECTIVES: We aimed to evaluate whether DBS of the globus pallidus internus (GPi) results in cortical-subcortical desynchronization, despite the lack of monosynaptic connections between GPi and sensorimotor cortex. APPROACH: We recorded local field potentials from the GPi and electrocorticographic signals from the ipsilateral sensorimotor cortex, off medications in nine PD patients, undergoing DBS implantation. We analyzed both local oscillatory power and functional connectivity (coherence and debiased weighted phase lag index (dWPLI)) with and without stimulation while subjects were resting with eyes open. MAIN RESULTS: DBS significantly suppressed low beta power within the GPi (-26.98% +/- 15.14%), p < 0.05) without modulation of sensorimotor cortical beta power (low or high). In contrast, stimulation suppressed pallidocortical high beta coherence (-38.89% +/- 6.19%, p = 0.02) and dWPLI (-61.40% +/- 8.75%, p = 0.02). Changes in cortical-subcortical functional connectivity were spatially specific to the motor cortex. SIGNIFICANCE: We highlight the role of DBS in desynchronizing network activity, particularly in the high beta band. The current study of GPi-DBS suggests these network-level effects are not necessarily dependent and potentially may be independent of the hyperdirect pathway. Importantly, these results draw a sharp distinction between the potential significance of low beta oscillations locally within the basal ganglia and high beta oscillations across the BGTC motor circuit. PMID- 29972150 TI - Corrigendum: The neuroprotective action of dexmedetomidine on apoptosis, calcium entry and oxidative stress in cerebral ischemia-induced rats: Contribution of TRPM2 and TRPV1 channels. AB - This corrects the article DOI: 10.1038/srep37196. PMID- 29972151 TI - A lithium ion/oxygen hybrid battery with high energy and high power. AB - A novel lithium ion/oxygen hybrid battery system is proposed that uses the advantages and minimizes the disadvantages of both lithium-ion batteries (LIBs) and lithium-oxygen batteries (LOBs). In it, the LOB-part plays range-extending and high-power output roles, while using the discharge-priority of the LIB-part is suggested to compensate the cycling-life shortcomings of the LOB-part. PMID- 29972152 TI - Surface-initiated atom transfer radical polymerization of cationic corona on iron oxide nanoparticles for magnetic sorting of macrophages. AB - Ovalbumin-incorporated antigen carriers were prepared by surface-initiated atom transfer radical polymerization (SI-ATRP) of iron oxide nanoparticles for magnetic sorting of antigen-presenting cells. Iron oxide nanoparticles were surface-decorated with cationic shells by SI-ATRP, and the primary amines on the surface were further tri-methylated. Surface decoration of the nanoparticles was characterized by Fourier transform infrared spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and transmission electron microscopy with energy-dispersive spectrometry. Ovalbumin-loaded nanoparticles showed higher incorporation in comparison to non-decorated nanoparticles, and the loaded ovalbumin was released faster at low pH than at neutral pH. Ovalbumin loaded nanoparticles were endocytosed by macrophages, and macrophages with nanoparticles were easily harvested by magnetic separation. Magnetically sorted macrophages showed higher release of cytokines including TNF-alpha, MIP-1alpha, and IL-1beta than unsorted macrophages. These results suggest that ovalbumin loaded nanoparticles can potentially increase the efficiency of immune therapy during the antigen-presenting pathway. PMID- 29972153 TI - Self-doped colloidal semiconductor nanocrystals with intraband transitions in steady state. AB - The tunable bandgap energy has been recognized as a prominent feature of the colloidal semiconductor nanocrystal, also called the colloidal quantum dot (CQD). Due to the broken degeneracy caused by the quantum confinement effect, the electronic states of the conduction band (CB) are separated by a few hundred meV. The electronic transition occurring in the conduction band is called the intraband transition and has been regarded as a fast electron relaxation process that cannot be readily observed under steady state. However, recent progress in the studies of intraband transitions allowed the observation of the mid-IR intraband transition in steady state and ambient condition, providing a pathway to exploit the mid-IR electronic transition for various optoelectronic applications. The observation of the steady state intraband transitions has been possible due to the electron filling of the lowest electronic state (1Se) of the conduction band in the semiconductor nanocrystal. Specifically, the nanocrystals are "self-doped" with electrons through chemical synthesis - that is, without the need of adding heterogeneous impurity or applying an electrical potential. In this feature article, we summarize the recent advances in the study on intraband electronic transitions along with the interesting findings on the magnetic and electronic properties of the self-doped colloidal metal chalcogenide semiconductor nanocrystals. The mid-IR intraband transitions of non-toxic nanocrystals, which exclude the toxic mercury and cadmium constituents, are also highlighted, which hold promise for safer applications utilizing the higher quantum states of nanocrystals. PMID- 29972154 TI - A carbonaceous two-dimensional lattice with FeN4 units. AB - A metal-containing carbonaceous two-dimensional lattice was formed on a graphene plane by sublimation, deposition, and pyrolysis of Fe phthalocyanine (Pc). The formation and growth of the FePc-derived pi-conjugated planar system were reflected by its orientation conversion from the perpendicular to horizontal mode and by the N K-edge X-ray absorption near-edge structure. PMID- 29972155 TI - Sustainable hydrophobic terpene-based eutectic solvents for the extraction and separation of metals. AB - Sustainable hydrophobic eutectic solvents, composed of low-priced and biodegradable terpenes and fatty acids, were used for the extraction and separation of Cu(ii) from other transition metals in mildly acidic solutions. Multiple parameters were evaluated for metal extraction and the hydrophobic eutectic solvent was successfully recovered and reused. PMID- 29972156 TI - Towards a sustainable synthesis of amides: chemoselective palladium-catalysed aminocarbonylation of aryl iodides in deep eutectic solvents. AB - A palladium-catalysed aminocarbonylation of (hetero)aryl iodides has, for the first time, been accomplished in deep eutectic solvents as environmentally benign and recyclable media, under mild conditions. The reactions proceeded with a good substrate scope, and a variety of amides have been synthesized in yields up to 98%. PMID- 29972157 TI - Transpeptidation-directed intramolecular bipartite tetracysteine display for sortase activity assay. AB - We developed a label-free method to measure sortase activity by using transpeptidation-directed intramolecular bipartite tetracysteine display. This assay is homogenous with a detection limit of 10.7 ng mL-1, and it can be applied to characterize Sortase A (SrtA)-targeted inhibitors, providing a new approach for anti-virulence drug discovery. PMID- 29972158 TI - Unexpected refacetting of palladium nanoparticles under atmospheric N2 conditions. AB - We demonstrate an unexpected refacetting process of Pd nanoparticles, induced by N2 under atmospheric pressure at elevated temperatures, by in situ TEM observations. The morphology changes, with a notable increase in the fraction of Pd{110} facets, were visualized by atomic-scale TEM images and further explained by theoretical calculations. Firm evidence and rational understanding revealed that the "inert" gas N2 has the ability to modify the structure of metal nanoparticles. This surprising effect should be considered seriously in vast chemical applications that use N2 as a carrier gas or protective atmosphere. PMID- 29972159 TI - Production of dynamic lipid bilayers using the reversible thiol-thioester exchange reaction. AB - Thiol lysolipids undergo thiol-thioester exchange with two phenyl thioester functionalized tails to produce phospholipid structures that assemble into liposomes with differences in exchange rates, temperature sensitivity, permeability, and continued exchange behavior. This in situ formation reaction imparts dynamic characteristics into the membrane for downstream liposome functionalization and mimics native membrane remodeling. PMID- 29972160 TI - Solvation of Al3+ cations in bulk and confined protic ionic liquids: a computational study. AB - Despite the growing interest in the potential electrochemical applications of both aluminium and ionic liquids in batteries, the microstructure of mixtures of trivalent salts and these dense ionic environments is completely unknown. In this work, the solvation of Al3+ cations in highly dense ionic solvents is investigated. For this purpose, molecular dynamics simulations of mixtures of a protic ionic liquid, ethylammonium nitrate (EAN), with aluminium nitrate (Al(NO3)3), both in bulk and confined between graphene walls, are performed. Several structural quantities of the system are calculated for different salt concentrations, such as densities, radial distribution functions, structure factors, coordination numbers and hydrogen bonds for the bulk mixture and ionic density profiles for the confined ones. Moreover, vibrational density of states is calculated for the salt cations, both in bulk and when close to the walls. The results obtained are analyzed and compared to those for mixtures of EAN with monovalent and divalent salts, in order to probe the influence of the salt cation charge on the system's properties. Finally, ab initio density functional theory calculations were performed in order to analyze the structure of the Al3+-ligand complexes, and their predictions for the Raman spectrum are compared both to the corresponding experimental one and the one coming from molecular dynamics simulations. According to our calculations, [Al(NO3)6]3- octahedral complexes do not significantly change the microstructure of the mixtures relative to those of Mg2+-based ones. PMID- 29972161 TI - Effect of environmental parameters on the nano mechanical properties of hyaluronic acid/poly(l-lysine) multilayers. AB - Atomic force microscopy (AFM) was used to determine the mechanical properties as the indentation modulus of native and crosslinked poly(l-lysine) (PLL)/hyaluronic acid (HA) multilayer films by static force measurements. The influence of the surrounding medium on the mechanical properties of the films after preparation is investigated. The indentation modulus of native and crosslinked film was measured at different pH values, ionic strengths and temperatures. The native HA/PLL films, which behave like a physical gel, show the highest values of the indentation modulus for an intermediate pH value and low ionic strength. Any changes in the pH or an increase in the ionic strength/temperature decreases the measured indentation modulus. In contrast, the crosslinked films show an increase by a factor of 80 in the indentation modulus but no response to changes in the pH, ionic strength or temperature; they behave like a chemical gel. The pH, ionic strength and temperature used in this work are close to the in vivo conditions and thus give a fundamental point of view on the nanomechanical response of the PLL/HA films. Furthermore, information about the mechanical properties can be used for the understanding and manipulation of cell adhesion. PMID- 29972163 TI - Relationship between electron-phonon interaction and low-frequency Raman anisotropy in high-mobility organic semiconductors. AB - Recent theoretical studies have shown that charge transport in high-mobility organic semiconductors is limited by low-frequency vibrations because of strong non-local electron-phonon interaction. Here we investigate two high-electron mobility organic semiconductors with similar molecular structures but considerably different crystal packings, TCNQ and F2-TCNQ, and reveal the relationship between the experimental low-frequency Raman spectra and the calculated contributions of various vibrational modes to the electron-phonon interaction. We suggest that the combination of Raman spectroscopy with solid state DFT is a powerful tool for probing electron-phonon interaction and focused search for high-mobility organic semiconductors. PMID- 29972162 TI - Bile acid derivative-based catanionic mixtures: versatile tools for superficial charge modulation of supramolecular lamellae and nanotubes. AB - Self-assembled structures formed by mixtures of cationic and anionic surfactants are interesting tools for applications requiring interactions with charged particles and molecules. Nevertheless, they present instability close to the equimolar composition and poor morphological versatility, which is generally restricted to vesicles and micelles. Against this general trend, we report on bile salt derivative based catanionic mixtures assembling in tubules and lamellae depending on the mixture composition. Electrophoretic mobility measurements prove that the composition also dictates their superficial charge, which can be tuned from negative to positive by increasing the positively charged surfactant fraction in the mixtures. The study of the catanionic aggregates was conducted by means of microscopy and spectroscopy techniques and compared to the self-assembly behaviors of the individual building blocks. This study broadens the so far small array of bile salt derivative catanionic systems, confirming their distinctive behavior in the spectrum of catanionic mixtures. PMID- 29972166 TI - Effects of a Nb nanopin electrode on the resistive random-access memory switching characteristics of NiO thin films. AB - We report the effects of bottom electrode shapes on resistive random-access memory (RRAM) devices composed of Nb (bottom electrode)/NiO (dielectric)/Nb (top electrode) structures. By adopting a nano-fabrication process using an anodic aluminum oxide (AAO) nanotemplate, a well-aligned Nb nanopin array bottom electrode was formed on the surface of a Si substrate. For comparison, a Nb thin film was employed as a different type of bottom electrode. Then, a NiO thin film dielectric was prepared on both the Nb bottom electrodes via a spin coating method, followed by Nb sputtering for the Nb top electrode. Both the RRAM devices with Nb nanopin and thin film bottom electrodes exhibited typical unipolar resistive switching behavior. However, a lower SET/RESET voltage was observed for the Nb nanopin electrode compared to the Nb thin film electrode by virtue of an enhanced electric field induced by the nanopin-shaped electrode. More significantly, on the basis of endurance and retention characteristics, the Nb nanopin electrode played a key role in minimizing the dispersion of the low- and high-resistance state currents and the variation in the SET/RESET voltage by developing more-concise conducting filaments in the conducting path. Therefore, we foresee that this approach can provide an insight into the optimal design of RRAM devices. PMID- 29972167 TI - Dynamic strain in gold nanoparticle supported graphene induced by focused laser irradiation. AB - Graphene on noble-metal nanostructures constitutes an attractive nanocomposite with possible applications in sensors or energy conversion. In this work we study the properties of hybrid graphene/gold nanoparticle structures by Raman spectroscopy and scanning probe methods. The nanoparticles (NPs) were prepared by local annealing of gold thin films using a focused laser beam. The method resulted in a patterned surface, with NPs formed at arbitrarily chosen microscale areas. Graphene grown by chemical vapour deposition was transferred onto the prepared, closely spaced gold NPs. While we found that successive higher intensity (6 mW) laser irradiation increased gradually the doping and the defect concentration in SiO2 supported graphene, the same irradiation procedure did not induce such irreversible effects in the graphene supported by gold NPs. Moreover, the laser irradiation induced a dynamic hydrostatic strain in the graphene on Au NPs, which turned out to be completely reversible. These results can have implications in the development of graphene/plasmonic nanoparticle based high temperature sensors operating in dynamic regimes. PMID- 29972169 TI - High-performance p-type inorganic-organic hybrid thermoelectric thin films. AB - The performance of organic-inorganic hybrid thermoelectric thin films can be dramatically enhanced by optimizing energy filtering and carrier transport states at the organic-inorganic interfaces. In this work, p-type "Sb2Te3/CH3NH3I/Sb2Te3" multilayer thin films were firstly fabricated with varied contents of CH3NH3I, and then an annealing process was used in order to form homogeneous organic inorganic hybrid thin films. The results revealed that the introduced organic component can promote thin film growth and develop a dense nanostructure with improved crystallinity, thus resulting in a significantly increased Seebeck coefficient and a reduced thermal conductivity as a result of the optimized electronic transport characteristics and enhanced effects of phonon scattering. As is expected, the thermoelectric performance of the hybrid-nanocomposite films is enhanced, achieving the maximum ZT value of 1.55 at a temperature of 413 K, which is several times higher than that of the as-fabricated film, thereby suggesting that the proposed strategy can be applied as an efficient method for the preparation of high-performance thermoelectric thin films. PMID- 29972168 TI - Creating capsules with cubanes. AB - A sextuply linked capsule incorporating two Ni(ii) cubane units is formed when Ni(ii) salts are reacted with N-aminoalkyl salicylamidato ligands in a 4 : 3 ratio in methanol. With a short (propyl) alkyl substituent, additional chloride counter ions are included in the cavity by occupation of one apex of each of the linked cubanes, while with a longer (pentyl) substituent, perchlorate and tetrafluoroborate anions are included, probably by H-bonding involving hydroxyl groups on the inner apices of the cubanes, indicating that the cavity can be regarded as suited to binding of hydrophilic units despite the lipophilic character of its links. The dicubane capsules show ferromagnetic behaviour typical of Ni(ii) cubanes in general, with coupling constants dependent upon the nature of the salt-derived counter anions. PMID- 29972170 TI - Single Ag nanoparticle collisions within a dual-electrode micro-gap cell. AB - An adjustable width (between 600 nm and 20 MUm) gap between two Au microelectrodes is used to probe the electrodissolution dynamics of single Ag nanoparticles. One Au microelectrode is used to drive the oxidation and subsequent dissolution of a single Ag nanoparticle, which displays a multi-peak oxidation behavior, while a second Au microelectrode is used to collect the Ag+ that is produced. Careful analysis of the high temporal resolution current-time traces reveals capacitive coupling between electrodes due to the sudden injection of Ag+ ions into the gap between the electrodes. The current-time traces allow measurement of the effect of citrate concentration on the electrodissolution dynamics of a single Ag nanoparticle, which reveals that the presence of 2 mM citrate significantly slows down the release of Ag+. Intriguingly, these experiments also reveal that only a portion (ca. 50%) of the oxidized Ag nanoparticle is released as free Ag+ regardless of citrate concentration. PMID- 29972172 TI - Alkali metal complexes based on bisheterocyclomethanide ligands. AB - A series of new alkali metal complexes containing deprotonated bisheterocyclomethanide were synthesised and structurally as well as spectroscopically characterised. Starting from the neutral bis-(benzoxazol-2 yl)methane ({NCOC6H4}2CH2), the complexes were obtained by facile deprotonation of the methylene bridge with nbutyllithium (nBuLi) or potassium hydride. Each of the resulting complexes [({NCOC6H4}2CH)Li(OEt2)2] (1), [({NCOC6H4}2CH)K(thf)]n (2) and [({NCOC6H4}2CH)K(18-crown-6)]n (3) (n -> infinity) was analysed in the solid state by single crystal X-ray diffraction and in solution by various NMR techniques. All the compounds show a nearly planar ligand with the alkali metal ion chelated by the two ring nitrogen atoms of the conjugated C3N2 moiety. Furthermore, water NMR titration experiments revealed that both compounds 2 and 3 are examples of water-stable reactive organo potassium compounds. Due to their hydrolysis stability, these complexes are under further investigations in deep eutectic solvents. PMID- 29972173 TI - Electric field mediated separation of water-ethanol mixtures in carbon-nanotubes integrated in nanoporous graphene membranes. AB - We investigate the influence of an applied electric field on the separation of a water-ethanol solution inside a carbon nanotube (CNT) using a series of molecular dynamics simulations. The electric field is applied at an angle theta with respect to the axis of the CNT. The study uncovers that with the application of a 'small-angle' electric field (e.g. smaller theta), the water molecules exhibit preferential occupancy inside the CNT, whereas the application of the same electric field at a 'wide-angle' mode (e.g. higher theta) fills the CNT with ethanol molecules in place of water. Remarkably, the direction of the electric field plays a pivotal role because the field exerts a contrasting influence on the behaviours of the water and ethanol molecules. The water dipoles are favourably aligned at small values of theta creating an ordered water structure inside the CNT. Increasing theta disrupts the water dipole orientation and leads to the preferential occupancy of the CNT by ethanol molecules. An in-depth analysis on the simulated systems unveil that, at lower values of theta, multiple layers of water molecules are physically adsorbed near the CNT walls, which is found to diminish as theta is increased. In comparison, at higher magnitudes of theta, the ethanol molecules are preferentially adsorbed inside the CNT. The average interaction energy per ethanol (water) molecule is found to increase (reduce) when theta is monotonically increased, which can be ascribed to the increase (decrease) in the intermolecular hydrogen bonding capacity of the ethanol (water) molecules at larger values of theta. Consequently, inside the CNT, the average occupancy of water molecules decreases and ethanol molecules increases, as theta is monotonically increased, leading to the separation of the ethanol-water mixture. The proposed methodology can convert an equimolar mixture (1 : 1) of ethanol-water into a concentrated one (14 : 1) when the electric field is applied orthogonal to the axis of the CNT. The separation efficiency is found to improve with an increase in the intensity of the externally applied electric field. PMID- 29972174 TI - Disordered peptide chains in an alpha-C-based coarse-grained model. AB - We construct a one-bead-per-residue coarse-grained dynamical model to describe intrinsically disordered proteins at significantly longer timescales than in the all-atom models. In this model, inter-residue contacts form and disappear during the course of the time evolution. The contacts may arise between the sidechains, the backbones or the sidechains and backbones of the interacting residues. The model yields results that are consistent with many all-atom and experimental data on these systems. We demonstrate that the geometrical properties of various homopeptides differ substantially in this model. In particular, the average radius of gyration scales with the sequence length in a residue-dependent manner. PMID- 29972175 TI - Probing ion current in solid-electrolytes at the meso- and nanoscale. AB - We present experimental approaches to probe the ionic conductivity of solid electrolytes at the meso- and nanoscales. Silica ionogel based electrolytes have emerged as an important class of solid electrolytes because they maintain both fluidic and high-conductivity states at the nanoscale, but at the macroscale they are basically solid. Single mesopores in polymer films are shown to serve as templates for cast ionogels. The ionic conductivity of the ionogels was probed by two experimental approaches. In the first approach, the single-pore/ionogel membranes were placed between two chambers of a conductivity cell, in a set-up similar to that used for investigating liquid electrolytes. The second approach involved depositing contacts directly onto the membrane and measuring conductivity without the bulk solution present. Ionic conductivity determined by the two methods was in excellent agreement with macroscopic measurements, which suggested that the electrochemical properties of ionogel based electrolytes are preserved at the mesoscale, and ionogels can be useful in designing meso-scaled energy-storage devices. PMID- 29972177 TI - Graphene-based plastic absorber for total sub-terahertz radiation shielding. AB - Increasing the requirements on telecommunications systems such as the need for higher data rates and connectivity via the Internet of things results in continuously increasing amounts of electromagnetic radiation in ever-higher telecommunications bands (up to terahertz). This can generate unwanted electromagnetic radiation that can affect the operation of electronic devices and human health. Here, we demonstrate that nonconductive and lightweight, graphene based composites can shield more than 99.99% of the electromagnetic energy in the sub-THz range mainly via absorption. This contrasts with state-of-the-art electromagnetic radiation shielding materials that simply redirect the energy of the radiation from a protected area via conduction-based reflection mechanisms. This shifts the problem of electromagnetic pollution from one place to another. We have demonstrated that the proposed composites can be fabricated by industrial compatible methods and are characterized by specific shielding efficiency values that exceed 30 dB cm3 g-1, which is more than those for typical metals used today. Therefore these materials might help to solve the problem of electromagnetic environmental pollution. PMID- 29972178 TI - Enhanced and preferential internalization of lipid nanocapsules into human glioblastoma cells: effect of a surface-functionalizing NFL peptide. AB - Increasing intracellular drug concentration using nanocarriers can be a potential strategy to improve efficacy against glioblastoma (GBM). Here, the fluorescent labelled NFL-TBS.40-63 peptide (fluoNFL) concentration on a lipid nanocapsule (LNC) was studied to enhance nanovector internalization into human GBM cells. LNC surface-functionalization with various fluoNFL concentrations was performed by adsorption. LNC size and surface charge altered gradually with increasing peptide concentration, but their complement protein consumption remained low. Desorption of fluoNFL from the LNC surface was found to be slow. Furthermore, it was observed that the rate and extent of LNC internalization in the U87MG human glioblastoma cells were dependent on the surface-functionalizing fluoNFL concentration. In addition, we showed that the uptake of fluoNFL-functionalized LNCs was preferential towards U87MG cells compared to healthy human astrocytes. The fluoNFL-functionalized LNC internalization into the U87MG cells was energy dependent and occurred possibly by macropinocytosis and clathrin-mediated and caveolin-mediated endocytosis. A new ferrocifen-type molecule (FcTriOH), as a potent anticancer candidate, was then encapsulated in the LNCs and the functionalization improved its in vitro efficacy compared to other tested formulations against U87MG cells. In the preliminary study, on subcutaneous human GBM tumor model in nude mice, a significant reduction of relative tumor volume was observed at one week after the second intravenous injection with FcTriOH loaded LNCs. These results showed that enhancing NFL peptide concentration on the LNC surface is a promising approach for increased and preferential nanocarrier internalization into human GBM cells, and the FcTriOH-loaded LNCs are a promising therapy approach for GBM. PMID- 29972179 TI - Positively charged residues at the channel mouth boost single-file water flow. AB - Water molecules lose two of their four bulk neighbours when entering single-file channels. This process may be sensitive to the presence of positive and negative charges at the channel mouth, since the costs for dehydrating cations and anions differ by a large margin. However, it is not known whether entrance charges affect the single channel water permeability (pf). So far, pf is only known to be governed by H-bond formation between permeating water molecules and wall-lining residues. Here we compare the pf values of five different aquaporin species (AQP1, AQPZ, AQP4 wild type, and two phosphorylation mimicking AQP4 mutants) that offer the same number of hydrogen bond donating and receiving residues in their single-file region but display different entrance charges. The pf measurements were performed with reconstituted lipid vesicles. We assessed (i) the osmotically induced vesicle deflation from the light scattering intensity in a stopped-flow device and (ii) the aquaporin abundance by fluorescence correlation spectroscopy. Substitution of serine at positions 111 and 180 in AQP4 for aspartic acid showed only a marginal effect on pf, suggesting that negative entrance charges are of minor importance. In contrast, the total number of positively charged amino acid side chains at entrances and exits correlates with pf: a total of three, four and seven charges of AQP4, AQPZ, and AQP1 translate into pf values of 1.1, 1.8, and 3.2 * 10-13 cm3 s-1, respectively. Thus, positive interfacial charges boost the pf value of AQP1 to three times the value of AQP4. Nevertheless, the number of hydrogen bond donating and receiving residues in the single-file region remains the major determinant of pf. Their effect on pf may be a hundredfold larger than that of interfacial charges. PMID- 29972180 TI - A novel combined experimental and multiscale theoretical approach to unravel the structure of SiC/SiOx core/shell nanowires for their optimal design. AB - In this work we propose a realistic model of nanometer-thick SiC/SiOx core/shell nanowires (NWs) using a combined first-principles and experimental approach. SiC/SiOx core/shell NWs were first synthesised by a low-cost carbothermal method and their chemical-physical experimental analysis was accomplished by recording X ray absorption near-edge spectra. In particular, the K-edge absorption lineshapes of C, O, and Si are used to validate our computational model of the SiC/SiOx core/shell NW architectures, obtained by a multiscale approach, including molecular dynamics, tight-binding and density functional simulations. Moreover, we present ab initio calculations of the electronic structure of hydrogenated SiC and SiC/SiOx core/shell NWs, studying the modification induced by several different substitutional defects and impurities into both the surface and the interfacial region between the SiC core and the SiOx shell. We find that on the one hand the electron quantum confinement results in a broadening of the band gap, while hydroxyl surface terminations decrease it. This computational investigation shows that our model of SiC/SiOx core/shell NWs is capable to deliver an accurate interpretation of the recorded X-ray absorption near-edge spectra and proves to be a valuable tool towards the optimal design and application of these nanosystems in actual devices. PMID- 29972181 TI - Microneedles integrated with a triboelectric nanogenerator: an electrically active drug delivery system. AB - In this study, a combined system of microneedles and a triboelectric nanogenerator (TENG) has been developed for drug delivery. A triboelectric device, which converts mechanical energy into alternating current (AC), was chosen to replace the electrophoresis (EP) effect. To directly generate triboelectricity from salmon deoxyribonucleic acid (SDNA)-based microneedles, a triboelectric series of SDNA film and chargeable polymers (polyimide and Teflon) was studied. The electrical output of the two charged polymers was compared to find a material that could be highly charged with SDNA. The electrical output was also compared as a function of the concentration of a drug embedded in the SDNA film, and the results confirmed that drug intercalation affected the carrier diffusion. The mechanical strength of the microneedles was assessed by histological analysis of their penetration into porcine cadaver skin. Furthermore, the output voltage of a system incorporating microneedles and TENG in cadaver skin, and in vitro drug release into gelatin were evaluated to examine potential application as an electrically active drug delivery system. The electrical output voltage of this system was ~95 V. The mechanism of triboelectric perturbation to the skin has also been discussed. The system developed in this work is a new, facile approach toward effective drug delivery that replaces the existing EP method and expands the application of TENGs. PMID- 29972182 TI - Protein-protein interactions in AQP regulation - biophysical characterization of AQP0-CaM and AQP2-LIP5 complex formation. AB - Protein-protein interactions play important roles in regulating human aquaporins (AQP) by gating as well as trafficking. While structural and functional studies have provided detailed knowledge of AQP transport mechanisms, selectivity as well as gating by conformational changes of loops or termini, the mechanism behind how protein-protein interactions control AQP-mediated water transport through cellular membranes remains poorly characterized. Here we explore the interaction between two human AQPs and regulatory proteins: the interaction between AQP0 and calmodulin, which mediates AQP0 gating, as well as the interaction between AQP2 and LIP5, which is involved in trafficking. Using microscale thermophoresis (MST) and fluorescence anisotropy, two methods that have the advantage of low sample consumption and detergent compatibility, we show that the interactions can be studied using both full-length AQPs and AQP peptides corresponding to the regulatory protein binding sites. However, full-length AQPs gave better reproducibility between methods and for the first time revealed that AQP0 binds CaM in a cooperative manner, which was not seen in experiments using peptides. Our study highlights that, while peptides are great tools for locating binding sites and pinpointing interacting residues, full-length proteins may give additional insights, such as binding mechanism, allostery and cooperativity, important parameters for understanding protein-protein mediated regulation in the cellular context. Our work provides a platform for further studies of AQP regulation that may be of interest for designing drugs that target AQP complexes as well as the development of artificial bio-mimetic water channels for water purification purposes. PMID- 29972183 TI - Ratiometric photoacoustic nanoprobes for monitoring and imaging of hydrogen sulfide in vivo. AB - Detection and visualization of hydrogen sulphide (H2S) is crucial for understanding its physiological and pathological roles towards human health and diseases, but precisely tracking of H2S in vivo remains challenging due to the limitations of available analytical methods. In this study, we developed a novel ratiometric photoacoustic (PA) nanoprobe for selective detection and imaging of H2S in biological fluids, live cells, brain tissues and animals. The nanoprobe AzHD-LP was fabricated by encapsulation of a newly synthesized H2S-responsive near-infrared (NIR) dye (AzHD) within a liposome (LP). The as-prepared AzHD-LP exhibits a dramatically red-shift response of its absorption peak after reduction reaction of AzHD with H2S: the absorbance of AzHD-LP centered at 600 and 700 nm is decreased and increased, respectively, producing a turn-on ratiometric PA signal in the presence of H2S. Typically, under the excitation of a 532 nm and 700 nm pulsed laser, the selective detection and imaging of H2S was achieved in aqueous solution, living cells and brain tissues of Alzheimer's diseased mice. Moreover, after AzHD-LP conjugated with a tumor-targeting peptide - c(RGDyK) as RGD-AzHD-LP - ratiometric PA mapping of the intratumoral generated H2S in the HCT116 colon tumor-bearing live mice was demonstrated. PMID- 29972184 TI - Cationic poly-l-lysine-encapsulated melanin nanoparticles as efficient photoacoustic agents targeting to glycosaminoglycans for the early diagnosis of articular cartilage degeneration in osteoarthritis. AB - Cartilage degeneration is the hallmark of osteoarthritis (OA) and its early diagnosis is essential for effective cartilage repair. However, until now, there was still a lack of imaging modalities that can accurately detect and evaluate cartilage degeneration in its early stage. Herein, we introduce endogenous melanin nanoparticles (MNPs) encapsulated by poly-l-lysine (PLL) as positively charged contrast agents for the accurate photoacoustic (PA) imaging of cartilage degeneration through its strong electrostatic interaction with anionic glycosaminoglycans (GAGs) in the cartilage. PLL-MNPs presented high PA intensity, photostability and biocompatibility. In vitro PAI studies showed that PLL-MNPs with a zeta potential of +32.5 +/- 9.3 mV had more cartilage uptake and longer retention time than anionic MNPs, and generated a positive relationship with the GAG content in the cartilage. After administration via intra-articular injection in living mouse models, PLL-MNPs exhibited about a two-fold stronger PA signal in a normal joint (with high GAG content) than an OA joint (with low GAG content). Furthermore, the obtained PAI results provided accurate information of the GAG content distribution in the OA knee joint. Consequently, by detecting and analyzing the changes of the GAG content in OA cartilage using PAI, we can clearly distinguish early OA from late OA and monitor the therapeutic efficacy in OA after drug treatment. All PAI results were examined histologically. PMID- 29972186 TI - Engineering two-dimensional gold nanostructures using graphene oxide nanosheets as a template. AB - The rich plasmon resonance modes and local field enhancements of two-dimensional (2D) noble metal nanostructures have boosted their application in distinct areas like catalysis, photonics, medicine and sensing. Here, we develop a unique strategy for the controlled growth of asymmetric 2D gold nanostructures in aqueous media using graphene oxide as a template. By performing mild reduction of gold ions on the surface of Au seeds (~2 nm) attached to graphene oxide nanosheets, the anisotropic growth of 2D gold nanostructures can be carried out through a simple procedure with a tunable control of the final size, shape and thickness, and consequently on their optical properties, without using surfactants. PMID- 29972185 TI - On the stability in alkaline conditions and electrochemical performance of A2BO4 type cathodes for liquid fuel cells. AB - Typical direct liquid fuel cells (DLFCs) use a liquid fuel and O2 as the oxidant. However, for applications where O2 is not available (e.g., space and underwater), the gas has been replaced by H2O2 as a liquid oxidant. This work presents a study of various ceramic disc electrodes with K2NiO4 structure and nominal compositions La2NiO4, La2CuO4, La1.9Pr0.1CuO4, La1.9Sr0.1CuO4, La1.8Ce0.2NiO4, La1.9Pr0.1NiO4, La1.8Pr0.2NiO4 and La1.9Sr0.1NiO4 to assess their stability and activity for the hydrogen peroxide reduction reaction (HPRR) in alkaline media. Stability tests conducted in 2 M NaOH show that Ni and Cu are readily dissolved, as occurs for substituting elements such as Sr, in agreement with calculated Pourbaix diagrams. Such degradation affects the surface of the materials, which is depleted of transition metals. This has consequences for the ORR and HPRR activity due to formation of a La-rich passivation layer on the surface. Only La2CuO4 and La1.8Ce0.2NiO4 display HPRR activity at around -0.25 V vs. RHE. An attempt is made to correlate the composition, chemical stability and electrochemical behaviour of these materials based on known molecular-orbital models proposed for the oxygen reduction reaction. PMID- 29972187 TI - Hydrogen-bonding-directed helical nanofibers in a polythiophene-based all conjugated diblock copolymer. AB - One-dimensional (1D) helical nanofibers were prepared through the self-assembly of an achiral all-conjugated diblock copolymer, poly(3-hexylthiophene)-b-poly[3 (6-hydroxyl)hexylthiophene] (P3HT-b-P3HHT) in an aged pyridine solution. Such helical nanofibers were formed by the pi-pi interaction between planar rigid polythiophene backbones cooperating with the hydrogen-bonding interactions between the polar hydroxyl groups of the side chains of polythiophenes. Intriguingly, the Young's modulus of such helical fibers is as high as ~5.16 GPa, which is about twice that of P3HT films characterized by the peak force quantitative nanomechanical (PF-QNM) method. Furthermore, for the first time, we report that such helical fibers based on all-conjugated polythiophenes exhibited a relatively high field-effect mobility of 0.03472 cm2 V-1 s-1. This work provides a promising approach to craft crystalline helical nanostructures based on polythiophenes possessing both superior mechanical and good charge transport properties, which has great potential for application in other pi-conjugated systems or building blocks for complex superstructures, and mechanical and optoelectronic devices. PMID- 29972188 TI - Characterisation of protein aggregation with the Smoluchowski coagulation approach for use in biopharmaceuticals. AB - Protein aggregation is a field of increasing importance in the biopharmaceutical industry. Aggregated particles decrease the effectiveness of the drug and are associated with other risks, such as increased immunogenicity. This article explores the possibility of using the Smoluchowski coagulation equation and similar models in the prediction of aggregate-particle formation. Three different monoclonal antibodies, exhibiting different aggregation pathways, are analysed. Experimental data are complemented with aggregation dynamics calculated by a coagulation model. Different processes are implemented in the coagulation equation approach, needed to cover the actual phenomena observed in the aggregation of biopharmaceuticals, such as the initial conformational change of the native monomer and reversibility of smaller oligomers. When describing the formation of larger particles, the effect of different aggregation kernel parameters on the corresponding particle size distribution is studied. A significant impact of the aggregate fractal nature on overall particle size distribution is also analysed. More generally, this work is aimed to establish a mesoscopic phenomenological approach for characterisation of protein aggregation phenomena in the context of biopharmaceuticals, capable of covering various aggregate size scales from nanometres to micrometres and reach large time-scales, up to years, as needed for drug development. PMID- 29972189 TI - Gold nanorod-assembled ZnGa2O4:Cr nanofibers for LED-amplified gene silencing in cancer cells. AB - Nanoparticles are now commonly used as non-viral gene vectors for RNA interference (RNAi) in cancer therapy but suffer from low targeting efficiency in situ. Meanwhile, localized drug delivery systems do not offer the effective capability for intracellular gene transportation. We describe here the design and synthesis of a localized therapeutic system, consisting of gold nanorods (Au NRs) loaded with hTERT siRNA assembled on the surface of ZnGa2O4:Cr (ZGOC) nanofibers. This composite system offers the potential for a LED-induced mild photothermal effect which enhances the phagocytosis of Au NRs carrying siRNA and the subsequent release of siRNA in the cytoplasm. Both phenomena amplify the gene silencing effect and consequently offer the potential for a superior therapeutic outcome. PMID- 29972190 TI - Ideal wet two-dimensional foams and emulsions with finite contact angle. AB - We present simulations that show that the equilibrium structure of an ideal two dimensional foam with a finite contact angle develops an inhomogeneity for high liquid fraction phi. In liquid-liquid emulsions this inhomogeneity is known as flocculation. In the case of an ordered foam this requires a perturbation, but in a disordered foam inhomogeneity grows steadily and spontaneously with phi, as demonstrated in our simulations performed with the Surface Evolver. PMID- 29972191 TI - An efficient iodine pentoxide-triggered iodocarbocyclization for the synthesis of iodooxindoles in water. AB - An efficient iodocarbocyclization of alkenes for the synthesis of iodooxindoles has been developed. This reaction proceeds in a chemoselective manner and shows excellent tolerance of various functional groups, including a chemosensitive hydroxymethyl group. Nonmetal inorganic iodine pentoxide was used as both the oxidant and iodine source, making this protocol very practical. On the basis of experimental observations, a plausible electrophilic reaction mechanism was proposed. PMID- 29972192 TI - Impact of "half-crown/two carbonyl"-Ca2+ metal ion interactions of a low molecular weight gelator (LMWG) on its fiber to nanosphere morphology transformation with a gel-to-sol phase transition. AB - We report here a smart functional low molecular weight gelator (LMWG) L, containing an unusual metal ion coordination site, i.e. "half-crown/two carbonyl". The gelator L shows excellent gelation behavior with typical fibrillar morphology in acetonitrile, methanol and ethanol media. Upon Ca2+ ion binding with its "half-crown/two carbonyl" coordination site, the acetonitrile gel of L exhibits a fiber to nanosphere morphology transformation along with a gel-to-sol phase transition as confirmed by microscopic investigation and by direct naked eye visualization, respectively. The mechanism involved in this morphology transformation and gel-to-sol phase transition process was studied thoroughly with the help of computational calculations and various spectroscopic experiments and discussed. PMID- 29972193 TI - Effect of copolymer sequence on structure and relaxation times near a nanoparticle surface. AB - We simulate a simple nanocomposite consisting of a single spherical nanoparticle surrounded by coarse-grained polymer chains. The polymers are composed of two different monomer types that differ only in their interaction strengths with the nanoparticle. We examine the effect of adjusting copolymer sequence on the structure as well as the end-to-end vector autocorrelation, bond vector autocorrelation, and self-intermediate scattering function relaxation times as a function of distance from the nanoparticle surface. We show how the range and magnitude of the interphase of slowed dynamics surrounding the nanoparticle depend strongly on sequence blockiness. We find that, depending on block length, blocky copolymers can have faster or slower dynamics than a random copolymer. Certain blocky copolymer sequences lead to relaxation times near the nanoparticle surface that are slower than those of either homopolymer system. Thus, tuning copolymer sequence could allow for significant control over the nanocomposite behavior. PMID- 29972196 TI - Drying mediated orientation and assembly structure of amphiphilic Janus particles. AB - Amphiphilic Janus particles demonstrate unique assembly structures when dried on a hydrophilic substrate. Particle orientations are influenced by amphiphilicity and Janus balance. A three-stage model is developed to describe the process. Simulation further indicates the dominant force is capillary attraction due to the interface pinning at rough Janus boundaries. PMID- 29972197 TI - A Pb2+ ionic gate with enhanced stability and improved sensitivity based on a 4' aminobenzo-18-crown-6 modified funnel-shaped nanochannel. AB - The existence of heavy ions, such as Pb2+, in the external environment is potentially hazardous as these can be highly toxic to the human body. Inspired by the highly efficient ability of biological ion channels to recognize the metal ion, much effort has been devoted to investigating biomimetic ionic gates based on engineered solid-state conical nanopores/nanochannels. However, the reported system generally displays relatively poor functionality and low stability due to the limited functional region. This article describes an ionic gate with enhanced stability and improved sensitivity based on an emerging advanced funnel-shaped nanochannel system. The ionic gate is developed by anchoring the Pb2+ ion responsive functional molecules, 4'-aminobenzo-18-crown-6 (4-AB18C6), onto the inner surface of a funnel-shaped polyethylene terephthalate (PET) nanochannel. The system can selectively recognize Pb2+ with an ultra-low concentration of down to approximately 10-15 M and displays excellent stability. The Pb2+ ions will form positively charged complexes through specific association with 4-AB18C6, which would screen the negative charge existing on the channel walls, resulting in a decreased ionic current and also an "OFF state". Since the ability of EDTA to associate with Pb2+ is much stronger than that of 4-AB18C6, the nanochannel can also achieve reversible switching upon the alternating addition of Pb2+ ions and EDTA. The switching behaviors of the system were reflected by the good reproducibility of the tunable rectifying effect. The stability of the conical and funnel-shaped nanochannels is also compared using current scanning under constant voltage. The results have shown that the stability of the funnel-shaped nanochannel is much better than that of the conical nanochannel, and this can be ascribed to its much longer critical region. Consequently, the funnel-shaped nanochannels with enhanced stability and improved sensitivity can potentially be applied in ion transportation, sensors, drug release, and energy conversion. PMID- 29972201 TI - Carbon quantum dot-based fluorescent vesicles and chiral hydrogels with biosurfactant and biocompatible small molecule. AB - In recent years, it is heartening to witness that carbon quantum dots (CQDs), a rising star in the family of carbon nanomaterials, have displayed tremendous applications in bioimaging, biosensing, drug delivery, optoelectronics, photovoltaics and photocatalysis. However, the investigations toward self assembly of CQDs are still in their infancy. The participation of CQDs can bring additional functions to supramolecular self-assemblies, with photoluminescent property as the most exciting aspect. Here, we introduce CQDs into two types of classic colloidal systems containing low molecular weight surfactant and gelator to construct fluorescent vesicles and chiral hydrogels. The CQD-based vesicles were constructed through electrostatic interaction between the positively charged CQDs with peripherally substituted imidazolium cations and a negatively-charged biosurfactant, i.e., sodium deoxycholate (NaDC). The chiral hydrogels were prepared by increasing the concentration of NaDC and addition of a tripeptide (glutathione, GSH). It was found that both the hydrogels and corresponding xerogels are highly photoluminescent. A solid sensing system was prepared by coating a uniform layer of the hydrogel onto the silica gel plates by doctor blade technique followed by air-drying, which was then utilized to semiquantitatively detect Cu2+ in aqueous solutions. PMID- 29972202 TI - Effect of mixed surface terminations on the structural and electrochemical properties of two-dimensional Ti3C2T2 and V2CT2 MXenes multilayers. AB - MXenes, a family of layered transition metal carbides and nitrides, have shown great promise for use in emerging electrochemical energy storage devices, including batteries and supercapacitors. MXene surfaces are terminated by mixed O, -F and -OH functional groups as a result of the chemical etching production process. These functional groups are known to be randomly distributed over the surfaces, with limited experimental control over their composition. There is considerable debate regarding the contribution of these functional groups to the properties of the underlying MXene material. For instance, their measured Li or Na capacity is far lower than that predicted by theoretical simulations, which generally assume uniformly terminated surfaces. The extent to which this structural simplification contributes to such discrepancies is unknown. We address this issue by employing first-principles calculations to compare the structural, electronic and electrochemical properties of two common MXenes, namely Ti3C2T2 and V2CT2, with both uniform terminating groups and explicitly mixed terminations. Weighted averages of uniformly-terminated layer properties are found to give excellent approximations to those of more realistic, mixed termination structures. This approximation holds for the lattice parameters, the electronic density of states and the work function. The sodium storage capacity and volume change during sodiation in the interlayer space of these MXenes with mixed surface terminations are also investigated. The redox reaction is shown to be confined to the terminating groups for low concentrations of intercalated Na, with the oxidation state of the metal atoms unaffected until higher concentrations of intercalated Na are achieved. Finally, the average open circuit voltage is shown to be very similar for both Ti3C2T2Na and V2CT2Na with mixed terminations, although it is highly sensitive to the particular composition of the terminating groups. PMID- 29972205 TI - Editorial: Plasma Biomarker for Alzheimer's Disease: Are We Ready Now for Clinical Practice and Drug Trials? PMID- 29972203 TI - Impact of free Nepsilon-carboxymethyllysine, its precursor glyoxal and AGE modified BSA on serotonin release from human parietal cells in culture. AB - Advanced glycation end products (AGEs) are frequently encountered in a western diet, in addition to their formation in vivo. N-Epsilon-carboxymethyllysine (CML), one of the chemically diverse compounds formed in the reaction between reducing carbohydrates and amines, is often used as a marker of advanced glycation, and has been shown to stimulate serotonin release from cells representing the central (SH-SY5Y cells) and the peripheral (Caco-2 cells) serotonin system in vitro. Here, we investigated the effect of glyoxal, free CML, and protein-linked AGE-BSA on serotonin release from human gastric tumour cells, which originate from an adenocarcinoma of the stomach and have recently been shown to be capable of serotonin synthesis and release. Microarray experiments showed both CML and glyoxal to alter genes associated with serotonin receptors. Furthermore, treatment with glyoxal resulted in a small change in RAGE expression while CML did not alter its expression. On a functional level, treatment with 500 MUM CML increased extracellular serotonin content by 341 +/- 241%, while treatment with 1 mg mL-1 AGE-BSA led to a reduction by 49 +/- 11% compared to non treated cells. The CML-induced serotonin release was reduced by the HTR3 antagonist granisetron. Incubation with the RAGE antagonist FPS-ZM1 abolished the effect of AGE-BSA on serotonin release, while no impact on CML-induced serotonin release was observed. Furthermore, treatment with 5 mM CML stimulated proton secretion as a functional outcome measure, assessed using a pH sensitive dye. Taken together, these results indicate a likely HTR3-mediated, RAGE-independent effect of free CML on serotonin release and a RAGE-dependent mechanism for the protein linked AGE-BSA. PMID- 29972206 TI - Editorial: Turning Point towards Blood Biomarker-Guided Targeted Therapy for Precision Medicine in Alzheimer's disease. PMID- 29972207 TI - Editorial: WHO Guidelines on Community-Level Interventions to Manage Declines in Intrinsic Capacity: The Road for Preventing Cognitive Declines in Older Age? PMID- 29972208 TI - Commentary: Fatty acids and Alzheimer's disease: evidence on cognition and cortical beta-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial. PMID- 29972209 TI - What Have We Learned from Expedition III and EPOCH Trials? Perspective of the CTAD Task Force. AB - Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease. Further, the Task Force suggested that a refinement of the amyloid hypothesis may be needed and that other hypotheses should be more fully explored. In addition, they called for improved biomarkers and other outcome assessments to detect the earliest changes in the development of AD. PMID- 29972210 TI - Effects of a Six-Month Multi-Ingredient Nutrition Supplement Intervention of Omega-3 Polyunsaturated Fatty Acids, vitamin D, Resveratrol, and Whey Protein on Cognitive Function in Older Adults: A Randomised, Double-Blind, Controlled Trial. AB - OBJECTIVES: To investigate the impact of a six-month multi-ingredient nutrition supplement intervention (Smartfish(r)), containing omega-3 polyunsaturated fatty acids (PUFAs), vitamin D, resveratrol, and whey protein, on cognitive function in Irish older adults. DESIGN: Double-blind, randomised controlled trial (ClinicalTrials.gov: NCT02001831). A quantitative, mixed-model design was employed in which the dependent variable (cognitive function) was analysed with a between-subjects factor of group (placebo, intervention) and within-subjects factor of testing occasion (baseline, three-months, six-months). SETTING: Community-based intervention including assessments conducted at University College Dublin, Ireland. PARTICIPANTS: Thirty-seven community-dwelling older adults (68-83 years; mean (x)= 75.14 years; standard deviation (SD)= 3.64; 18 males) with normal cognitive function (>24 on the Mini Mental State Examination) were assigned to the placebo (n= 17) or intervention (n= 20) via a block randomisation procedure. INTERVENTION: Daily consumption for six-months of a 200mL liquid juice intervention comprising 3000mg omega-3 PUFAs [1500mg docosahexaenoic acid (DHA) and 1500mg eicosapentaenoic acid (EPA)], 10MUg vitamin D3, 150mg resveratrol and 8g whey protein isolate. The placebo contained 200mL juice only. MEASUREMENTS: A standardised cognitive assessment battery was conducted at baseline and follow-ups. Individual test scores were z-transformed to generate composite scores grouped into cognitive domains: executive function, memory, attention and sensorimotor speed. Motor imagery accuracy and subjective awareness of cognitive failures variables were computed from raw scores. RESULTS: A hierarchical statistical approach was used to analyse the data; first, by examining overall cognitive function, then by domain, and then by individual test scores. Using mixed between-within subjects, analyses of variance (ANOVAs), no significant differences in overall cognitive function or composite cognitive domains were observed between groups over time. The only significant interaction was for Stroop Color-Word Time (p< 0.05). The intervention group demonstrated reduced task completion time at three- and six-month follow-ups, indicating enhanced performance. CONCLUSION: The present nutrition intervention encompassed a multi-ingredient approach targeted towards improving cognitive function, but overall had only a limited beneficial impact in the older adult sample investigated. Future investigations should seek to establish any potential clinical applications of such targeted interventions with longer durations of supplementation, or in populations with defined cognitive deficits. PMID- 29972211 TI - Analysis of the Relationship of Cognitive Impairment and Functional Impairment in Mild Alzheimer's Disease in EXPEDITION 3. AB - BACKGROUND: Clinical progression of Alzheimer's disease is characterized by impairment in cognition and function. OBJECTIVE: To assess the relationship between cognitive and functional impairment in mild Alzheimer's disease. DESIGN: Spearman's rank correlations between cognitive and functional measures were calculated. Autoregressive cross-lagged panel analyses were used to determine the temporal relationship between cognitive and functional decline. SETTING: Post-hoc analysis of clinical trial data. PARTICIPANTS: Placebo-treated patients with mild Alzheimer's disease from the Phase 3 solanezumab study EXPEDITION 3. INTERVENTION: Placebo. MEASUREMENTS: Cognitive and functional measures were assessed at baseline and at six post-baseline time points through Week 80. RESULTS: Correlation between cognitive and functional measures was 0.41 at baseline and 0.65 at Week 80. Autoregressive cross-lagged panel analysis demonstrated that cognitive impairment preceded and predicted subsequent functional decline, but functional scores did not predict cognitive outcomes. CONCLUSIONS: This study supports the hypothesis that functional impairment predictably follows cognitive decline in mild Alzheimer's disease dementia. PMID- 29972212 TI - Detection of Rater Errors on Cognitive Instruments in a Clinical Trial Setting. AB - OBJECTIVES: This study examines errors committed by raters in a clinical trial of a memory enhancement compound. BACKGROUND: Findings of clinical trials are directly dependent on the quality of the data obtained but there is little literature on rates or nature of rater errors on cognitive instruments in a multi site setting. DESIGN: Double-blind placebo-controlled study. SETTING: 21 clinical sites in North America. PARTICIPANTS: Two hundred seventy-five participants. MEASUREMENTS: MMSE, WMS-R Logical Memory I and II, WMS-R Verbal Paired Associates I, WASi Vocabulary, WASi Matrix Reasoning, GDS and MAC-Q. RESULTS: The WMS-R Logical Memory I and II and WASi Vocabulary tests were found to have the greatest number of scoring errors. Few substantive errors were detected on source document review of the MMSE, GDS, MAC-Q and WMS-R Verbal Paired Associates I. Some additional administration and scoring issues were identified during feedback sessions with the raters. CONCLUSIONS: Cognitive measures used in clinical trials are prone to errors which can be detected with proper monitoring. Some instruments are particularly prone to inter-rater variably and should therefore be targets for focused training and ongoing monitoring. Areas in need of further investigation to help inform and optimize quality of clinical trial data are discussed. PMID- 29972214 TI - Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial. AB - BACKGROUND: In several randomized controlled trials (RCT) acetylcholinesterase inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug's efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Abeta 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer's disease (AD). Overall, worsening and disease progression as measured by the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment. PMID- 29972215 TI - An Action Plan to Face the Challenge of Dementia: INTERNATIONAL STATEMENT ON DEMENTIA from IAP for Health. AB - An international committee set up through the IAP for Health met to develop an action plan for dementia. Comprehensive international and national initiatives should move forward with calls for action that include increased public awareness regarding brain health and dementia, support for a broad range of dementia research objectives, and investment in national health care systems to ensure timely competent person-centred care for individuals with dementia. The elements of such action plans should include: 1) Development of national plans including assessment of relevant lifecourse risk and protective factors; 2) Increased investments in national research programs on dementia with approximately 1% of the national annual cost of the disease invested; 3) Allocating funds to support a broad range of biomedical, clinical, and health service and systems research; 4) Institution of risk reduction strategies; 5) Building the required trained workforce (health care workers, teachers, and others) to deal with the dementia crisis; 6) Ensuring that it is possible to live well with dementia; and 7) Ensuring that all have access to prevention programs, care, and supportive living environments. PMID- 29972213 TI - Auraptene in the Peels of Citrus Kawachiensis (Kawachibankan) Contributes to the Preservation of Cognitive Function: A Randomized, Placebo-Controlled, Double Blind Study in Healthy Volunteers. AB - OBJECTIVES: Dementia, which is characterized by a progressive decline in cognitive function, is a major concern in aging societies. Although a number of treatments have been approved, an effective therapy to prevent the disorder is lacking. A supplement that improves cognitive function would benefit patients. The aim of this study was to assess whether auraptene, a citrus coumarin, has a protective effect on cognitive decline. DESIGN: A randomized, placebo-controlled, double-blind study SETTING: Outpatient medical check-up program for cognitive disorders PARTICIPANTS: 84 adult volunteers (they are cognitively normal) met inclusion and exclusion criteria to participate. INTERVENTION: 42 participants received auraptene enriched (containing 6.0 mg/day of auraptene) test juice, and another participants received placebo juice. MEASUREMENTS: 1) Mild Cognitive Impairment (MCI) Screen using the 10-word immediate recall test. 2) The Mini Mental State Examination (MMSE). Cognitive assessment ware carried out baseline and at 24 weeks. RESULTS: Auraptene enriched test juice did not improve cognitive function after 24 weeks compared with baseline data. However, there was a significant difference in the percentage change in cognitive function between the test and placebo orange juice groups (6.3 +/- 18.9 vs. -2.4 +/- 14.8, P < 0.05). Multiple regression analysis demonstrated a significant independent relationship between the percentage change in the 10-word immediate recall test score and test juice consumption including baseline 10-word immediate recall test score in all subjects. CONCLUSION: This is the first study to assess the effectiveness of auraptene in the prevention of cognitive decline. Our results suggest that auraptene is a safe supplement for the prevention of cognitive decline. PMID- 29972216 TI - Methotrexate Exposure and Risk of Cutaneous Malignant Melanoma: No Evidence of a Dose-response Relationship. AB - Methotrexate treatment has been linked with an increased risk of melanoma. However, a possible dose-response relationship with respect to methotrexate exposure and melanoma has not been addressed. The aim of the present study was to investigate whether higher accumulated doses of methotrexate correlate with an increased risk of melanoma, which would further support a possible association. A nationwide retrospective cohort study was conducted. All Swedish patients over 18 years of age who were dispensed methotrexate in the period 2005 to 2014 were registered (n = 101,966) and matched to the cancer registry. A Cox proportional hazards model, testing risk of melanoma vs. total accumulated methotrexate dose, controlled for sex, age group, and time from first to last dispensed prescription of methotrexate, yielded no significant risk dependence on dose, and a hazard ratio of 1.02 (95% CI 0.97-1.08). Overall, no conclusive dose-response relationship was observed between methotrexate exposure and risk of melanoma. PMID- 29972217 TI - Squamous Cell Carcinoma and Multiple Familial Trichoepitheliomas: A Recurrent Association. PMID- 29972218 TI - Wells' Syndrome Associated with Coxsackievirus A6 Infection. PMID- 29972219 TI - Granular IgA Deposits in the Skin of Patients with Coeliac Disease: Is it Always Dermatitis Herpetiformis? AB - Coeliac disease is an immune-mediated enteropathy driven by gluten, which can be associated with dermatitis herpetiformis. The presence of granular IgA deposits, detected by direct immunofluorescence, is the hallmark of dermatitis herpetiformis; nevertheless, IgA deposits have also been demonstrated in healthy skin of patients with coeliac disease. The main objective of this study was to investigate whether IgA deposits could be found in the skin of patients with coeliac disease who have non-dermatitis herpetiformis inflammatory skin diseases. Direct immunofluorescence was performed on perilesional skin biopsies of 6 patients with coeliac disease with non-dermatitis herpetiformis inflammatory skin diseases and, as control, on 12 non-coeliac patients with inflammatory skin diseases. IgA deposits were found in all of the patients with coeliac disease, but were absent in the control group. In conclusion, IgA deposits may be considered an immunopathological marker for coeliac disease; therefore, patients with coeliac disease showing skin manifestations with positive direct immunofluorescence should be investigated carefully in order to make a differential diagnosis between dermatitis herpetiformis and other non-dermatitis herpetiformis inflammatory skin diseases. PMID- 29972220 TI - Overexpression of Androgen, Oestrogen and Progesterone Receptors in Skin Lesions of Becker's Naevus. AB - Becker's naevus is androgen-dependent. The aim of this study was to investigate whether oestrogen and progesterone receptors are involved in this disorder. Immunohistochemistry showed that epidermal expression of androgen receptors, oestrogen receptors (alpha, beta) and progesterone receptors was higher in skin lesions of Becker's naevus than in perilesional and control skin. Androgen receptor overexpression was observed in pilosebaceous glands, while oestrogen and progesterone receptor overexpression was seen in hair follicles, but not in sebaceous glands in skin lesions compared with perilesional skin. Reverse tran scription PCR and Western blot revealed that levels of androgen, oestrogen and progesterone receptors were generally upregulated in skin lesions compared with perilesional and control skin, and their expression was usually higher in perilesional than in control skin. These results suggest that simultaneous overexpression of androgen, oestrogen and progesterone receptors might be implicated in the pathogenesis of Becker's naevus. PMID- 29972221 TI - Safety Profile of Secukinumab in Treatment of Patients with Psoriasis and Concurrent Hepatitis B or C: A Multicentric Prospective Cohort Study. AB - Safety data for secukinumab in patients with psoriasis and viral hepatitis are lacking. The aim of this study is to investigate the risk of reactivation of hepatitis B virus (HBV)/hepatitis C virus (HCV) in patients with psoriasis who are receiving secukinumab therapy. This multicentre study screened 284 patients with psoriasis with available HBV and HCV serological data and 63 patients with concurrent HBV/HCV infection were enrolled. In the absence of antiviral prophylaxis, 7 of 46 (15.2%) patients with HBV exhibited HBV reactivation during secukinumab therapy. The risk of reactivation was significantly higher in HBsAg positive patients, compared with HBsAg-negative/HBcAb-positive patients (24.0% vs. 4.17%, p = 0.047). One of 14 (7.1%) HCV patients showed enhanced replication of HCV with hepatitis. No virus reactivation occurred in patients receiving antiviral prophylaxis. HBsAg-positive and HBsAg-negative/HBcAb-positive psoriasis patients can develop virus reactivation during secukinumab therapy, thus necessitating close monitoring of viral load and considering an antiviral prophylaxis for all HBsAg-positive patients with psoriasis. PMID- 29972222 TI - Melanogenesis Inhibitors. AB - Abnormally high production of melanin or melanogenesis in skin melanocytes results in hyperpigmentation disorders, such as melasma, senile lentigines or freckles. These hyperpigmentary skin disorders can significantly impact an individual's appearance, and may cause emotional and psychological distress and reduced quality of life. A large number of melanogenesis inhibitors have been developed, but most have unwanted side-effects. Further research is needed to better understand the mechanisms of hyperpigmentary skin disorders and to develop potent and safe inhibitors of melanogenesis. This review summarizes the current understanding of melanogenesis regulatory pathways, the potential involvement of the immune system, various drugs in current use, and emerging treatment strategies to suppress melanogenesis. PMID- 29972224 TI - Modulation of Itch by Localized Skin Warming and Cooling. AB - Skin thermal changes modulate itch sensitivity. However, the mechanisms of this modulation are still unclear. Using mouse models of acute and chronic itch, we investigated whether local innocuous thermal stimulation of the skin alters itch sensitivity and if blockade of thermosensitive transient receptor potential (TRP) channels can reduce these changes. Localized thermal changes were achieved by placing a thermal probe in contact with the back skin for 30 s. Warming the skin significantly increased serotonin-evoked scratching and spontaneous scratching in the ovalbumin model of atopic dermatitis but decreased histamine-evoked scratching. These changes were blocked by a TRPV4 antagonist. Cooling the skin significantly increased serotonin-evoked scratching but reduced histamine-evoked scratching. The increase in serotonin-evoked scratching, but not the reduction of histamine-evoked scratching, was blocked by TRPM8 antagonism. Chloroquine-evoked scratching was unaffected by either warming or cooling. Our data indicate that different itch signaling pathways are differentially modulated by skin thermal changes. PMID- 29972223 TI - Antioxidative Phytochemicals Accelerate Epidermal Terminal Differentiation via the AHR-OVOL1 Pathway: Implications for Atopic Dermatitis. AB - Aryl hydrocarbon receptor (AHR) is a chemical sensor that is expressed abundantly in epidermal keratinocytes. Oxidative AHR ligands induce the production of reactive oxygen species. However, antioxidant AHR ligands inhibit reactive oxygen species generation via activation of nuclear factor-erythroid 2-related factor-2, which is a master switch for antioxidative signalling. In addition, AHR signalling accelerates epidermal terminal differentiation, but excessive acceleration by oxidative ligands, such as dioxins, may induce chloracne and inflammation. However, antioxidative phytochemical ligands induce the beneficial acceleration of epidermal differentiation that repairs skin barrier disruption. The upregulated expression of differentiation molecules, such as filaggrin, is mediated via the AHR-OVOL1 axis. This AHR-OVOL1 system is capable of counteracting skin barrier dysfunction in T-helper type 2-shifted inflammation. This article reviews the dynamic and multifaceted role of AHR in epidermal biology and discusses the potential use of antioxidative phytochemical ligands for AHR in inflammatory skin diseases, such as atopic dermatitis. PMID- 29972225 TI - "Promote health, keep the world safe, serve the vulnerable" in the Eastern Mediterranean Region. PMID- 29972226 TI - Pulmonary function tests in Egyptian schoolchildren in rural and urban areas. AB - Background: Previous studies have shown a negative association between urban environments and pulmonary function. Objectives: This longitudinal study examined the effect of an urban environment on pulmonary function tests of children by comparing children from an urban and a rural area in Egypt. The effect of other factors on pulmonary function, including obesity, breastfeeding and parental atopy, was also examined. Methods: Children aged 7-12 years from rural Shibin El Kom and urban Cairo were enrolled in the study. Forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced expiratory rate and peak expiratory flow rate (PEFR) were measured 5 times over a period of 2 years, at 6 monthly intervals. Factorial repeated measures analysis of variance was used to evaluate the differences in the rate of change in FEV1 predicted%, FVC predicted% and PEFR between the children in Cairo and Shibin El-Kom. Generalized linear mixed models were used to analyse factors associated with pulmonary function test results. Results: Generalized linear regression showed that living in Cairo decreased log(FVC), log(FEV1) and log(PEFR). Significant differences were found in the changes occurring between the 2 locations in the last 3 visits; children in Cairo showed a smaller increase in pulmonary function. Conclusions: Differences in pulmonary function in the 2 locations increased significantly with time, indicating a negative effect on lung function of living in urban Cairo. The findings could be used to help in the development of policies in Egypt and other developing countries to improve respiratory health, including promoting breastfeeding and reducing outdoor air pollution. PMID- 29972227 TI - Provincial differences in levels, trends, and determinants of childhood immunization in Pakistan. AB - Background: Efforts to improve immunization rates are urgently needed in Pakistan but national statistics mask important local differences in immunization levels and determinants. Aim: In this study we aimed to determine how similar or different are recent trends and levels of immunization coverage in Pakistan's 4 main provinces [Punjab, Sindh, Khyber Pakhtunkhwa (KPK) and Balochistan], and what factors are associated with complete childhood immunization in each province. Method: We analysed data from the 2006-07 and 2012-13 Pakistan Demographic and Health Surveys. Trends in immunization coverage among children aged 12-23 months were calculated for each province. Bivariate and multivariate analyses were conducted to identify factors associated with complete immunization. Results: The proportion of children completely immunized had risen significantly in Punjab but had fallen significantly in Balochistan. Complete coverage ranged from 16.4% in Balochistan to 65.8% in Punjab (2012-13). Tetanus toxoid injection during pregnancy was a significant predictor of complete immunization everywhere. Other predictors in specific provinces were: urban residence in Balochistan, wealth in Sindh and KPK, mother's education in Punjab and KPK, and distance to the facility in Punjab. Conclusions: Although some strategies to increase immunization coverage are relevant nationwide, programme managers need to seek solutions specific to provincial trends and predictors. This analysis demonstrates that viewing childhood immunization in Pakistan through a provincial lens can help achieve a deeper understanding of the challenges and potential strategies to boost coverage. PMID- 29972228 TI - Patient and caregiver education levels and readmission and mortality rates of congestive heart failure patients. AB - Background: Despite evidence that effective family support improves health behaviour and outcomes, the nature of the correlation between congestive heart failure (CHF) outcome and caregiver contribution has not been well studied. Aim: This single centre pilot study aimed to determine epidemiological correlations between education level and hospital readmission and mortality rates of CHF patients in a nonwestern country population. Methods: The study was performed in King Abdullah Medical City, Makkah, Saudi Arabia from February 2015 to February 2016, and included 167 consecutive patients enrolled in a CHF management registry. Data on the education levels of patients and their caregivers were collected, and patient outcomes in high education level (HEL) and low education level (LEL) groups were compared. Results: Of 167 patients, 101 completed 12 months of follow-up. The mean age was 58 (13.4) years and 80% were men; 87% were Saudi nationals. The HEL group comprised 42 (42%) patients. There were no significant differences in the mortality (3 vs 2%) or readmission rate (18 vs 19%) between the LEL and HEL patients, and 29.6% of LEL patients had caregivers with an LEL. Conclusion: The education levels of CHF patients and caregivers were not correlated with readmission or mortality rates. PMID- 29972229 TI - Assessment of safe injection practices in health facilities in Oman. AB - Background: Unsafe injection practices put patients and providers at risk of infectious and noninfectious adverse events. A 2001 Ministry of Health survey on injection practices in Oman indicated that, while overall standards were good, in some areas there was a need for improvement. Aim: We aimed to evaluate injection safety practices to determine whether facilities meet the requirements for practices, equipment, supplies and waste disposal, and to identify unsafe practices. Methods: We conducted a national cross-sectional survey in 2007 using the World Health Organization tool to evaluate injection safety practices. Using 2-stage cluster sampling, 80 government and 61 private health facilities were randomly selected and evaluated. Results: There was no shortage of injection equipment nor evidence of attempts to sterilize disposable devices. Care providers immediately disposed of the used needle/syringe in sharps containers. Phlebotomy devices were taken from sealed packets in 96% of facilities. In private facilities, 66.3% of the care providers were fully immunized against hepatitis B. Wearing a new pair of gloves for phlebotomy was observed in only 46% of government and 38% of private health facilities. Many health facilities lacked alcohol-based handrub. Conclusions: Many injection safety aspects were satisfactory. However there are still opportunities for improvement. Actions are required to make alcohol-based handrub and appropriate sharps containers available and to provide hepatitis B vaccine and training to health care workers in all facilities. PMID- 29972230 TI - Incidence pattern and spatial analysis of breast cancer in Iranian women: Geographical Information System applications. AB - Background: Breast cancer is the leading cancer in Iranian women, but no studies have yet been conducted on the distribution and pattern of its incidence. Aim: To perform a spatial analysis and determine the incidence pattern of breast cancer in the Islamic Republic of Iran. Methods: This was a cross-sectional, pathology based study of all new female patients with breast cancer registered in the Islamic Republic of Iran in 2011 (n=10 233). Initially, crude incidence rates were calculated for each province and the whole country per 100 000 person-years. Then, a direct standardization method and World Health Organization standard population were used to adjust for age effects on a geographical scale. Stata and Arc GIS software were used to calculate incidence rates and conduct spatial analysis. Results: The mean (standard deviation) age of the patients was 50.9 (12.6) years. The national age-standardized incidence rate for breast cancer in women was 29.88 per 100 000 person-years, with a range of 5-72 in different provinces. The clustering incidence pattern was observed in Mazandaran, Tehran, Alborz, Isfahan and Markazi Provinces (P < 0.01). There was a significant cluster of high incidence of breast cancer in Iranian women. Conclusion: These findings may help to establish etiological hypotheses of cancer causation and identify spatial anomalies in cancer incidence or registration in the Islamic Republic of Iran. Our findings may also aid further research on the possible explanations for these clusters and associations. PMID- 29972231 TI - Factors associated with mental health of high-school students in the Islamic Republic of Iran. AB - Background: Mental disorders of adulthood can be traced to childhood and adolescent disorders so attention to the mental health of young people is important. Objectives: We aimed to determine the mental health status of high school students in Khorramabad and the factors that may affect it. Methods: This cross-sectional study included 1 202 high-school students in Khorramabad in the 2015-2016 academic year. Students were selected using stratified and multistage cluster random sampling. Data were collected on sociodemographic characteristics of the students, and the General Health Questionnaire (GHQ-28) was used to assess symptoms of mental disorders. Logistic regression analysis was used to evaluate the relationship between the presence of symptoms of mental disorder and sociodemographic characteristics. Results: The mean age of the students was 16.1 (SD 0.9) years and 52.7% were girls. Overall, 481 (40%) students (34% of males, 46% of females) had symptoms of mental disorders. Most had mild symptoms; 5% had severe symptoms. Symptoms of anxiety, depression and social impairment were seen in 40%, 33% and 32% of the students respectively; significantly more girls had these symptoms (P < 0.05). Female students, those in higher school grades, and those whose fathers were unemployed and mothers were housewives were significantly more likely to have symptoms of mental disorders (P < 0.05). Conclusions: This study found a high prevalence of symptoms associated with mental disorders in the adolescents in Khorramabad. Counselling centres in schools are needed to offer psychiatric counselling services to students and to implement regular mental health training programmes. PMID- 29972232 TI - Are users of modern and traditional contraceptive methods in Jordan different? AB - Background: The level of current use of modern family planning is the most widely used indicator for evaluating the success of national family planning programmes. Recently the prevalence of traditional methods has increased in Jordan, which may lead to undesired pregnancy. Aims: The main objective of the study was to assess the trends of modern and traditional contraceptive use in Jordan with a focus on examining the differences between the users of each method. Methods: A secondary data analysis of the Jordan 2012 Population and Family Health Survey data was carried out. The survey used a multistage cluster random sample. Bivariate analysis was conducted to identify the difference between modern and traditional contraceptive users. A logistic regression model was used to study significant covariates. Results: Among 10 801 currently married women aged 15-49 years surveyed, 38.8% were not using any contraceptive method, 18.9% used traditional methods, and 42.3% relied on modern contraceptive methods. Logistic regression analysis revealed 4 significant predictors of using modern contraceptive methods: location in Central Region, residence in urban areas, age and parity. Conclusion: Women, particularly those resident in the southern region, should be encouraged to use modern contraceptive methods and this may be achieved by empowering them with more information about sources of these methods that are available to them. Family planning interventions should focus on younger and high parity women as they were more likely to use traditional methods. PMID- 29972233 TI - Occupational lumbar back accidents in the private sector: prevalence and factors associated with their severity and sequelae in central Tunisia. AB - In Tunisia, few studies have been focused on occupational lumbar back accidents. We conducted a descriptive retrospective study of private sector employees in central Tunisia who were victims of lumbar back accidents, reported during a 5 year period from 2010 to 2014, to determine the prevalence and factors associated with their severity and sequelae. Data were collected from the regional centre of the National Health Insurance Fund of Sousse. We identified 293 cases, a prevalence of 14.2% in relation to all occupational accidents reported during this period. More than two thirds of the injured (69.2%) were victims of serious occupational lumbar back accidents and 33.8% of victims reported serious sequelae. After adjustment by binary logistic regression, the occupational category persisted as an associated factor with the severity of occupational lumbar back accidents (P = 0.001, OR = 2.86 [1.50-5.47]). Surgical treatment appeared as an associated factor of severity (P < 0.001, OR = 9.06 [3.09-26.56]) and prominent after effects resulting from these accidents (P < 0.001 OR = 54.72 [18.84-158.93]). Occupational lumbar back accidents are a real health problem. Thus, a preventive strategy should be implemented to reduce their socio-economic consequences. PMID- 29972234 TI - Risk factors for incident shoulder soft tissue rheumatic disorders: a population based case-control study in Lebanon. AB - Background: Soft tissue rheumatic disorders (STRDs) are very common and impact enormously general population, working groups and physiotherapist practices. However, they do not have neither a clear case definition nor objective tests to be accurately diagnosed rendering them neglected with poorly-estimated burden. Shoulder is one of the most frequent sites for STRDs. Aim: The aim of this study was to identify risk factors for shoulder STRDs among Lebanese adults aged >= 15 years. Methods: A case-control study was designed based on data from the Community Oriented Program for Control of Rheumatic Diseases (COPCORD) study conducted in Lebanon in 2009. Cases were defined as those who recently suffered from shoulder pain, tenderness or stiffness with duration not exceeding 12 months (52 cases). These were frequency-matched by age and gender with 208 controls who never experienced any musculoskeletal pain. Results: Area of residence, physical activity, family history and stress-induced sleep difficulty were significantly associated with shoulder STRDs after adjusting for cigarette smoking, job nature and family monthly income. Conclusion: Factors associated with shoulder STRD among the Lebanese population include geographical location, psychosocial factors, physical activity and familial predisposition. Further longitudinal studies are needed to establish a temporal sequence and explore other potential determinants, especially among the working population. PMID- 29972235 TI - How feasible is the life expectancy target in the Saudi Arabian vision for 2030? AB - Background: Over the period 2016-2030, Saudi Arabia seeks to increase life expectancy at birth by 6 years. Aim: The main aim was to analyse the feasibility of this gain using the demographic literature. Methods: The demographic literature on recorded high gains in life expectancy and the determinants of these gains were reviewed. The findings were examined considering the Saudi Arabian context. Results: Explanations covered demographic and behavioural factors, inequalities, health care delivery system, public health provision, health-related policies and advancements in science and technology. However, the crucial factor is the country's position in the "cardiovascular revolution" (which combines smoking prevalence, obesity, lifestyle and related policies). Conclusion: In countries where life expectancy is in the 70s, average yearly gains are less than 0.31 years, much lower that the Saudi Arabian target of 0.43 years. For Saudi Arabia, an average yearly gain of about half this is achievable provided the fundamental drivers of life expectancy are addressed. PMID- 29972236 TI - 'Health Benefits Package': a centerpiece of Universal Health Coverage. PMID- 29972237 TI - Paroxysmal torticollis of infancy: a benign phenomenon? PMID- 29972238 TI - Diversification across biomes in a continental lizard radiation. AB - Ecological opportunity is a powerful driver of evolutionary diversification, and predicts rapid lineage and phenotypic diversification following colonization of competitor-free habitats. Alternatively, topographic or environmental heterogeneity could be key to generating and sustaining diversity. We explore these hypotheses in a widespread lineage of Australian lizards: the Gehyra variegata group. This clade occurs across two biomes: the Australian monsoonal tropics (AMT), where it overlaps a separate, larger bodied clade of Gehyra and is largely restricted to rocks; and in the larger Australian arid zone (AAZ) where it has no congeners and occupies trees and rocks. New phylogenomic data and coalescent analyses of AAZ taxa resolve lineages and their relationships and reveal high diversity in the western AAZ (Pilbara region). The AMT and AAZ radiations represent separate radiations with no difference in speciation rates. Most taxa occur on rocks, with small geographic ranges relative to widespread generalist taxa across the vast central AAZ. Rock-dwelling and generalist taxa differ morphologically, but only the lineage-poor central AAZ taxa have accelerated evolution. This accords with increasing evidence that lineage and morphological diversity are poorly correlated, and suggests environmental heterogeneity and refugial dynamics have been more important than ecological release in elevating lineage diversity. PMID- 29972239 TI - Meta-analysis of the diagnostic accuracy of ultrasound-guided fine-needle aspiration and core needle biopsy in diagnosing axillary lymph node metastasis. AB - BACKGROUND: Axillary lymph node status remains a significant prognostic indicator in breast cancer. Here, the diagnostic accuracy of ultrasound-guided fine-needle aspiration (US-FNA) and ultrasound-guided core needle biopsy (US-CNB) in axillary staging was compared. METHODS: A comprehensive search was undertaken of all published studies comparing the diagnostic accuracy of US-CNB and US-FNA of axillary lymph nodes in breast cancer. Studies were included if raw data were available on the diagnostic performance of both US-FNA and US-CNB, and compared with final histology results. Relevant data were extracted from each study for systematic review. Meta-analysis was performed using a random-effects model. The pooled sensitivity and specificity of US-FNA and US-CNB were obtained using a bivariable model. Summary receiver operating characteristic (ROC) graphs were created to confirm diagnostic accuracy. RESULTS: Data on a total of 1353 patients from six studies met the inclusion criteria and were included in the final analysis. US-CNB was superior to US-FNA in diagnosing axillary nodal metastases: sensitivity 88 (95 per cent c.i. 84 to 91) versus 74 (70 to 78) per cent respectively. Both US-CNB and US-FNA had a high specificity of 100 per cent. Reported complication rates were significantly higher for US-CNB compared with US FNA (7.1 versus 1.3 per cent; P < 0.001). Conversely, the requirement for repeat diagnostic procedures was significantly greater for US-FNA (4.0 versus 0.5 per cent; P < 0.001). CONCLUSION: US-CNB is a superior diagnostic technique to US-FNA for axillary staging in breast cancer. PMID- 29972241 TI - Consumer-resource interactions along urbanization gradients drive natural selection. AB - Urbanization is an important component of global change. Urbanization affects species interactions, but the evolutionary implications are rarely studied. We investigate the evolutionary consequences of a common pattern: the loss of high trophic-level species in urban areas. Using a gall-forming fly, Eurosta solidaginis, and its natural enemies that select for opposite gall sizes, we test for patterns of enemy loss, selection, and local adaptation along five urbanization gradients. Eurosta declined in urban areas, as did predation by birds, which preferentially consume gallmakers that induce large galls. These declines were linked to changes in habitat availability, namely reduced forest cover in urban areas. Conversely, a parasitoid that attacks gallmakers that induce small galls was unaffected by urbanization. Changes in patterns of attack by birds and parasitoids resulted in stronger directional selection, but loss of stabilizing selection in urban areas, a pattern which we suggest may be general. Despite divergent selective regimes, gall size did not very systematically with urbanization, suggesting but not conclusively demonstrating that environmental differences, gene flow, or drift, may have prevented the adaptive divergence of phenotypes. We argue that the evolutionary effects of urbanization will have predictable consequences for patterns of species interactions and natural selection. PMID- 29972240 TI - Maternal obesity has sex-dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring. AB - KEY POINTS: Maternal high-fat diet consumption predisposes to metabolic dysfunction in male and female offspring at young adulthood. Maternal obesity programs non-alcoholic fatty liver disease (NAFLD) in a sex-dependent manner. We demonstrate sex-dependent liver transcriptome profiles in rat offspring of obese mothers. In this study, we focused on pathways related to insulin, glucose and lipid signalling. These results improve understanding of the mechanisms by which a maternal high-fat diet affects the offspring. ABSTRACT: Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA-seq to determine the liver transcriptome of male and female F1 of MO and control-fed mothers. We hypothesized that MO-F1 are predisposed to sex-dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning, all male and female F1 ate a control diet. At PND 110, F1 serum, liver and fat were collected to analyse metabolites, histology and liver differentially expressed genes. Male and female MO-F1 showed increased adiposity index, triglycerides, insulin and homeostatic model assessment vs. C-F1 with similar body weight and glucose serum concentrations. MO-F1 males presented greater physiological and histological NAFLD characteristics than MO-F1 females. RNA-seq revealed 1365 genes significantly changed in male MO-F1 liver and only 70 genes in female MO-F1 compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic processes. Male MO-F1 liver showed the following altered pathways: insulin signalling (22 genes), phospholipase D signalling (14 genes), NAFLD (13 genes) and glycolysis/gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MO-F1 females. In summary, MO programs sex-dependent F1 changes in insulin, glucose and lipid signalling pathways, leading to liver dysfunction and insulin resistance. PMID- 29972242 TI - A pilot study investigating the in vitro efficacy of sucralfate against common veterinary cutaneous pathogens. AB - OBJECTIVE: To determine whether Cicalfate(r) (Avene), a commercially available skin cream, or its active ingredient - sucralfate - demonstrate in vitro antimicrobial effect against common veterinary cutaneous pathogens. MATERIALS AND METHODS: Prospective study assessing in vitro susceptibility of standardised and clinical strains of common veterinary cutaneous pathogens to titrated concentrations of sucralfate in either saline solution (range 0?2 to 200 mg/mL) or in Cicalfate(r) restorative cream solubilised in DMSO (range 0?002 to 1 mg/mL). Minimum inhibitory concentrations were determined by broth dilution in accordance with Clinical and Laboratory Standards Institute guidelines. RESULTS: Both solutions demonstrated in vitro inhibitory effects against strains of Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus pseudintermedius, Escherichia coli and Enterococcus faecalis. Minimum inhibitory concentration ranges for susceptible bacteria tested in Cicalfate(r) solution and sucralfate solution were 0?06 to 0?25 mg/mL and 25 to 50 mg/mL, respectively. Sucralfate solution did not demonstrate antimicrobial effects against laboratory strains of S. aureus and E. faecalis and neither solution demonstrated antimicrobial effects against the clinical strain of P. aeruginosa. For organisms inhibited by sucralfate, Cicalfate(r) solution inhibited growth at lower sucralfate concentrations than sucralfate solution. CLINICAL SIGNIFICANCE: The results of this pilot study suggest that Cicalfate(r) and sucralfate demonstrate in vitro antibacterial activity. Further in vitro and clinical studies are warranted to confirm these observations and determine their clinical utility in the treatment of superficial pyoderma. PMID- 29972243 TI - Validity and reliability of the mixing ability test as masticatory performance outcome in children with spastic cerebral palsy and children with typical development: A pilot study. AB - BACKGROUND: The mixing ability test (MAT) as an outcome measure of masticatory performance is largely used in studies with adults, but not yet with children. OBJECTIVE: This study aimed to test the construct validity and the test-retest reliability of the MAT in children with spastic cerebral palsy (CP) and children with typical development (TD). METHOD: The results of the MAT were correlated with tongue movements, mandible movements, relative muscle contraction and clinical observation measured with ultrasound, 3D kinematics, electromyography (EMG) and relevant items of the mastication observation and evaluation (MOE) instrument, respectively. Moreover, the between-groups effect was tested. Test retest reliability was calculated with an intra-class correlation coefficient (ICC) and standard error of measurement (SEM). RESULTS: Twenty-one children (seven children with spastic CP and 14 children with TD) participated in this study. The MAT scores showed moderate to good correlations with some variables of the tongue movements, horizontal mandible movements and occlusion duration, relative muscle contraction of the left temporalis and all six MOE items (-0.80 < r < 0.49). The MAT scores were significantly higher for children with CP (mean 22.6; SD 2.4) compared to children with TD (mean 19.9; SD 1.9). The test-retest reliability had an ICC of 0.7 and a SEM of 1.16 (+/-5% of the mean score). CONCLUSION: These results indicate that the MAT is suitable and complementary to ultrasound, 3D kinematics, EMG and observation to compare the masticatory performance between children with CP and children with TD, with an acceptable test-retest reliability. PMID- 29972244 TI - Prevalence of bacterial contamination in 50% dextrose vials in varying storage conditions after multiple punctures. AB - OBJECTIVE: To determine the risk of bacterial growth in single use 50% dextrose vials punctured multiple times and stored in various hospital environments. MATERIALS AND METHODS: Three groups of three 50% dextrose vials were stored in our hospital intensive care unit at either ambient light or in a darkened drawer at room temperature or refrigerated at 4 degrees C. One vial in each group was punctured either once, once weekly or once daily for 28 days and samples taken for bacterial culture every 7 days until completion of the project. A fourth group of three vials were inoculated with several species of bacteria and stored in our microbiology laboratory under the environmental conditions described above with cultures performed every 7 days for 28 days. In addition, the water activity of 50% dextrose was determined using commercial laboratory equipment. RESULTS: Scant growth of Escherichia coli and Enterobacter agglomerans was detected in cultures performed on day 7, but not subsequent time points, from the inoculated refrigerated vials. The vial punctured once daily for 28 days and stored under refrigerated conditions showed growth of Bacillus subtilis on day 28. All remaining bottles had no bacterial growth at any time point or environmental condition. The water activity of 50% dextrose was 093 at 24 degrees C and 092 at 4 degrees C. CLINICAL SIGNIFICANCE: Bacterial growth in 50% dextrose vials was uncommon even when inoculated with pathogens. Bacterial growth only occurred in refrigerated storage conditions. The water activity of 50% dextrose is not low enough to inhibit all bacterial and fungal growth. PMID- 29972245 TI - Efficacy of autogenous tooth roots for lateral alveolar ridge augmentation and staged implant placement. A prospective controlled clinical study. AB - OBJECTIVES: To assess and compare the efficacy and safety of autogenous tooth roots (TR) and autogenous bone blocks (AB) for lateral alveolar ridge augmentation and two-stage implant placement. MATERIAL AND METHODS: A total of 30 patients in need of implant therapy and lateral ridge augmentation were allocated to parallel groups receiving either (a) healthy autogenous tooth roots (e.g. retained wisdom or impacted teeth) (n = 15) or (b) cortical autogenous bone blocks harvested from the retromolar area. After 26 weeks of submerged healing, the primary endpoint was defined as the crestal ridge width (mm) (CW26) being sufficient to place an adequately dimensioned titanium implant at the respective sites. RESULTS: Soft tissue healing was uneventful in both groups. CW26 at V isit 6 allowed for a successful implant placement in all patients of both TR (15/15) and AB groups (15/15). Mean CW26 values amounted to 10.06 +/- 1.85 mm (median: 11.0) in the TR and 9.20 +/- 2.09 mm (median: 8.50) in the AB group, respectively. The difference between both groups did not reach statistical significance (p = 0.241). CONCLUSIONS: TR may serve as an alternative graft to support lateral alveolar ridge augmentation and two-stage implant placement. PMID- 29972246 TI - Enhanced identification of maternal hepatitis C virus infection using existing public health surveillance systems. AB - BACKGROUND: Hepatitis C virus (HCV) infection is under-recognized among US adults and children. Prenatal HCV screening may help close the diagnosis gap among women while also identifying at-risk infants. Current surveillance efforts for maternal HCV rely primarily on birth certificate data. We sought a more accurate assessment of HCV prevalence among pregnant women in Ohio by combining existing public health surveillance data. METHODS: Vital Statistics (VS) birth certificate data and Ohio Disease Reporting System (ODRS) HCV case data, both available through the Ohio Department of Health, were linked to determine rates of past or present HCV infection among women giving birth from 2012 to 2015 in Ohio, overall and by county. Among women with available test results, the proportion with present HCV infection indicated by detectable viraemia during pregnancy was calculated. RESULTS: Birth certificate data identified 4695 deliveries to women with past/present HCV infection during the study period. Linkage to ODRS revealed an additional 1778 deliveries to women with past/present infection, including 355 with confirmed viraemia during pregnancy. The prevalence of past/present HCV among pregnant women in Ohio rose from 0.82% in 2012 to 1.54% in 2015. CONCLUSIONS: Maternal HCV infection is under-recognized and increasing in prevalence. Current case identification processes are inadequate in pregnancy, even among women with prior positive HCV testing. Alternative approaches, including enhanced risk factor-based screening or universal prenatal screening in high prevalence settings, are needed to improve rates of HCV recognition among reproductive-aged women and newborns at risk of vertical transmission. PMID- 29972247 TI - Corrigendum. PMID- 29972248 TI - CRAG rocks. PMID- 29972249 TI - Do women experience less diaphragmatic fatigue during inspiratory resistance loading? PMID- 29972250 TI - Stevens-Johnson syndrome/toxic epidermal necrolysis in Jewish and Arab populations. PMID- 29972251 TI - Corrigendum. PMID- 29972252 TI - Spectroscopy and Photodissociation of the Perfluorooctanoate Anion. AB - Perfluorocarbons, a class of fully fluorinated compounds, are highly persistent and toxic pollutants that are receiving increasing attention due to their widespread environmental distribution. In this study, attention was focused on one compound in particular, namely, perfluorooctanoic acid (PFOA). The first investigation of the UV/VUV photochemistry of the PFOA anion in the gas phase by action spectroscopy of selected ions is reported. Two main relaxation channels were identified: photodissociation and photodetachment. Absolute cross sections for the individual observed processes were measured. DFT calculations and natural transition orbital analysis were carried out to help in the interpretation of the experimental results. PMID- 29972253 TI - Iridium-Induced Regioselective B-H and C-C Activations at Azo-Substituted o Carboranes. AB - p-Methoxybenzeneazo-substituted o-carboranes have been synthesized and their reactivity with half-sandwich iridium and rhodium complexes has been investigated in detail. A variety of solvent- and base-dependent, highly site-selective B-H and C-C sigma-bond activations at the C/B cage have been observed. While the use of CH3 OH leads to the formation of metallacarboranes, o-carborane clusters undergo cyclometallation reactions involving B(6)-H, B(4)-H or a rare B(7)-H activation in CH2 Cl2 . The synthesis of a unique pseudo-closo-iridacarborane through a very unconventional metal-mediated Ccage -Ccage activation is described in this contribution. PMID- 29972255 TI - MicroRNA-378 regulates epithelial-mesenchymal transition and metastasis of melanoma by inhibiting FOXN3 expression through the Wnt/beta-catenin pathway. AB - MicroRNAs (miRNAs) participate in the development and progression of melanoma. However, while dysregulation of microRNA-378 (miR-378) has been seen in various cancer types, its clinical importance and function in melanoma is poorly elucidated. In this work, miR-378 expression in melanoma and in adjacent non cancerous tissue was evaluated with quantitative real time polymerase chain reaction (qRT-PCR). A series of assays (wound healing, Transwell and nude mouse subcutaneous tumor model) were used to investigate the implications of abnormal miR-378 regulation on melanoma cell migration and invasion in vitro, and on tumorigenicity in vivo. Prediction and conformation of the miR-378 target gene was undertaken using bioinformatic analysis and luciferase reporter system. Expression of miR-378 was often increased in melanoma, and shown to potentiate its migration, invasion and tumorigenicity. miR-378 acted, at least partially, through inhibition of the potential target FOXN3 and via Wnt/beta-catenin pathway activation. The findings indicate that miR-378 triggers melanoma development and progression. This microRNA could be a novel diagnostic and prognostic biological marker, and provide utility for targeted treatment of melanoma. PMID- 29972254 TI - An ethyl acetate fraction of Artemisia capillaris (ACE-63) induced apoptosis and anti-angiogenesis via inhibition of PI3K/AKT signaling in hepatocellular carcinoma. AB - In cancer treatment, herbal medicines may be a good choice because of the reduced risk of adverse side effects. Artemisia capillaris has been recognized as a promising candidate due to its hepatoprotective effects. Herein, we investigated whether A. capillaris-derived fraction (ACE-63) could inhibit the progression of hepatocellular carcinoma (HCC) and its underlying mechanism. In this study, ACE 63 effectively inhibited the growth and proliferation of HCC cells. ACE-63 induced apoptosis, as observed using Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, which was accompanied with increases in cleaved Poly (ADP-ribose) polymerase (PARP) and caspase-3 in HCC cells. Additionally, the pro-apoptotic effect of ACE-63 was demonstrated by a decrease in the expression of the X-linked inhibitor of apoptosis protein (XIAP) and survivin via a loss of mitochondrial membrane potential. In an ex vivo model, ACE 63 significantly inhibited tumor cell growth and induced apoptosis by increasing the expression of cleaved caspase-3 and DNA fragmentation. In addition, ACE-63 decreased the expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor and inhibited tube formation of human umbilical vein endothelial cells. A mechanistic study revealed that ACE-63 effectively suppressed the PI3K/AKT/mTOR signaling pathways, which were observed as a target signaling by phosphokinase array. Taken together, our findings demonstrate that ACE-63 could not only efficiently induce apoptosis but also inhibit the growth/angiogenesis of human HCC cells by blocking the PI3K/AKT/mTOR signaling pathway, suggesting that ACE-63 may be a new chemotherapeutic candidate against HCC. PMID- 29972257 TI - Suppressed Expression of Cbl-b by NF-kappaB Mediates Icotinib Resistance in EGFR mutant Non-Small-Cell Lung Cancer. AB - Although epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) could greatly improve the prognosis of NSCLC patients harboring activating EGFR mutations, drug resistance still remains a major obstacle to successful treatment. Our previous study found that the EGFR-TKI icotinib could upregulate the expression of Casitas-B-lineage lymphoma protein-B (Cbl-b), an E3 ubiquitin ligase. In the present study, we aimed to clarify the potential role of Cbl-b in the resistance to icotinib, and the underlying mechanisms using EGFR-mutant cell lines. We found that icotinib inhibited the proliferation of mutant-EGFR NSCLC cells (PC9 and HCC827), and upregulated the expression of Cbl-b at both the protein and mRNA levels. Cbl-b knockdown decreased the sensitivity of PC9 and HCC827 cells to icotinib, and partially restored icotinib-inhibited AKT activation in PC9 cells. On the contrary, Cbl-b overexpression could partly reverse the drug resistance in PC9 icotinib-resistant cells (PC9/IcoR). Moreover, overexpressing p65, the main member of transcription factor NF-kappaB family, reversed the icotinib-mediated upregulation of Cbl-b. Collectively, these data suggest that icotinib could upregulate Cbl-b mediated by NF-kappaB inhibition, and Cbl-b contribute to the icotinib sensitivity in EGFR-mutant NSCLC cells. This study highlights that low expression of Cbl-b might be the key obstacles in the efficacy of icotinib therapy. PMID- 29972258 TI - Transport behaviours among older teenagers from semi-rural New Zealand. AB - OBJECTIVE: Transport impacts teenagers by affecting their autonomy and independent access to activities. This manuscript reports descriptive findings of transport behaviours among teenagers in Southland, New Zealand, and discusses the implications of these for public health and policy. METHODS: An online survey was implemented to investigate transport among respondents aged 16 years and older from twelve secondary schools. Two methods of survey distribution were used (in class and at home). Descriptive results were analysed using Stata. RESULTS: Response rate was 71.5% (n=775). The most common forms of transport were as a passenger in a car and walking. Two-thirds of participants had some form of driving licence. Half the sample expressed frustration at being unable to access activities. Significant gender differences existed regarding transport and types of activities accessed. Licence status was associated with physical activity, screen time and transport frustration. CONCLUSIONS: The transport decisions made by teenagers, in aggregate, have implications for policy and infrastructure, and findings provide a foundation for discussions around potential changes to driver education programming, the school uniform policy in New Zealand and further research. Implications for public health: Inquiring about everyday transport habits, outside of the trip to school, and activities accessed provided data about an under-researched group, supporting the ecological approach to transport in the context of public health. PMID- 29972256 TI - Inhibition of CXCR4 regulates epithelial mesenchymal transition of NSCLC via the Hippo-YAP signaling pathway. AB - CXCR4 has been shown to play a key role in the metastasis of non-small cell lung cancer (NSCLC). And CXCR may be associated with the Hippo-Yes kinase-associated protein (YAP) pathway, thus involving in the occurrence and progression of NSCLC. This study aims to investigate the effect of CXCR4 inhibition on epithelial mesenchymal transition (EMT), invasion and migration of NSCLC cells via the Hippo YAP pathway. QRT-PCR and Western blot were employed to detect CXCR4 expression in NSCLC cell lines. A549 and H1299 cells were treated with WZ811 (0, 10, 30, and 50 uM), and A549 cells were also divided into the Control, WZ811, YAP siRNA, and WZ811 + YAP groups. Wound-healing, Transwell assay, immunofluorescent staining, and a luciferase reporter gene assay were performed in this experiment. Compared with human bronchial epithelial (HBE) cells, CXCR4 expression was up-regulated in NSCLC cell lines. WZ811 increased E-cadherin; decreased expression of Twist, vimentin, Snail, p-YAP, CTGF, and BIRC5; blocked GTIIC reporter activity; and reduced migration and invasion of A549 cells, all in a dose-dependent manner. YAP siRNA had a similar effect to WZ811 by inhibiting EMT, invasion and migration of A549 cells. However, compared with A549 cells in the YAP siRNA and WZ811 groups, cells in the WZ811 + YAP group showed a dramatically enhanced EMT phenotype as well as invasion and migration abilities. Inhibition of CXCR4 may reduce EMT, invasion and migration of NSCLC cells, thereby providing a new therapeutic target for NSCLC. PMID- 29972259 TI - Physical activity and body mass shape quality of life trajectories in mid-age women. AB - OBJECTIVE: To determine the combined longitudinal effect of body mass index (BMI) and physical activity (PA) on health-related quality of life (HrQoL), using the SF-6D (SF-36) utility measure. METHODS: Five waves of self-reported data from the 1946-51 cohort (n=5,200; data collection, 2001-2013) of the Australian Longitudinal Study on Women's Health were used. Mixed effect models were employed to address the objective. RESULTS: Women with high PA experienced higher HrQoL regardless of BMI group, however, for those healthy or overweight, there was a very small decline in HrQoL over time. Women reporting no PA levels experienced the lowest baseline mean SF-6D score within each BMI group, with decreasing trajectories over the follow-up period. The rate of decline was greatest in women with obesity. Within each BMI group, there was a large, increasing gap in HrQoL between those who reported no and low PA over time. Women with obesity and high PA experienced similar HrQoL trajectories to women with normal weight or overweight with low PA levels. Overweight women with moderate PA experienced similar HrQoL to those with low PA but normal weight. CONCLUSIONS: PA may mitigate the adverse effect of overweight and obesity on HrQoL at mid-life, at higher activity levels. Implications for public health: PA benefits HrQoL regardless of body mass, with larger gains for those currently not physically active. Moderate to high PA may mitigate the effect of overweight and obesity. PMID- 29972260 TI - Post-Assembly Reactivity of N-Aryl Iminoboronates: Reversible Radical Coupling and Unusual B-N Dynamic Covalent Chemistry. AB - Post-assembly reaction of a dynamic covalent iminoboronate system following addition of Cp2 Co resulted in the formation of a series of new reductively coupled dianionic dimers via C-C bond formation. The dimers formed as a mixture of BN-containing isomeric products: diastereomers rac5 and meso5, with coupled five-membered rings, and enantiomeric rac6, with a fused six-membered ring bicyclic system from C-C bond formation and rearrangement of the B-N bonds. Each isomer was identified using 1 H NMR spectroscopy in combination with single crystal X-ray structure determination. Interestingly, interconversion between the coupled five-membered rings (rac5 ) and fused bicyclic systems (rac6 ) was found to occur through an unprecedented breaking and reforming of the B-N covalent bond. Further, the coupled products could be converted quantitatively back to their iminoboronate precursors with addition of the electron abstractor Ph3 C+ . PMID- 29972261 TI - Frequency-specific alterations of regional homogeneity in subcortical stroke patients with different outcomes in hand function. AB - Emerging evidence has suggested that abnormalities in regional spontaneous brain activity following stroke may be detected by intrinsic low-frequency oscillations (LFO) in resting-state functional MRI (R-fMRI). However, the relationship between hand function outcomes following stroke and local LFO synchronization in different frequency bands is poorly understood. In this study, we performed R fMRI to examine the regional homogeneity (ReHo) at three different frequency bands (slow-5: .01-.027 Hz; slow-4: .027-.08 Hz; and typical band: .01-.1 Hz) in 26 stroke patients with completely paralyzed hands (CPH) and 26 matched patients with partially paralyzed hands (PPH). Compared to the PPH group, decreased ReHo in the bilateral cerebellum posterior lobes and the contralesional cerebellum anterior lobe was observed in the slow-5 band and the slow-4 band in the CPH group, respectively. The mean ReHo values in these regions were positively correlated with the Fugl-Meyer assessment (FMA) scores. In contrast, increased ReHo in the contralesional supplementary motor area and the contralesional superior temporal gyrus was observed in the slow-4 band and the slow-5 band, respectively. The mean ReHo values in these regions were negatively correlated with the FMA scores. Importantly, significant interactions were identified between the frequency bands and the subgroups of patients in the contralesional precentral gyrus and middle frontal gyrus. These findings indicate that frequency dependent R-fMRI patterns may serve as potential biomarkers of the neural substrates associated with hand function outcomes following stroke. PMID- 29972262 TI - The marketing of sugar-sweetened beverages to young people on Facebook. AB - OBJECTIVE: We explored how sugar-sweetened beverages are marketed to Australian young people through sugar-sweetened beverage brand Facebook pages. METHODS: We undertook a content analysis of Facebook posts made by six of the most popular sugar-sweetened beverage Facebook pages in Australia. Data were collected for a six-month period and were quantitatively analysed for descriptive data and explicit marketing techniques and then thematically analysed for implicit marketing messages. RESULTS: There were almost 1.9 million engagements across the six pages over the six-month period. Most posts (70%) included one or more calls to action through which followers were encouraged to do something. Content by sports and energy drink brands were heavily dominated by 'sporting prowess' and 'masculinity' themes while content by Coca-Cola shared the message of 'having fun with friends' and 'happiness'. All pages used outdoor setting scenes. CONCLUSIONS: Sugar-sweetened beverage brands use Facebook to align their marketing with the socio-cultural values and practices likely to be regarded as important by young people. Implications for public health: Our findings provide challenges and opportunities for those in public health advocacy and policy to consider for future obesity-reduction strategies. PMID- 29972263 TI - Sufficient exercise for Australians living with dementia in residential aged care facilities is lacking: an exploration of policy incoherence. PMID- 29972264 TI - Bcl6 knockdown aggravates hypoxia injury in cardiomyocytes via the P38 pathway. AB - B-cell lymphoma 6 (Bcl6) functions as a sequence-specific transcriptional repressor and negative regulator of many signaling proteins. The effects of Bcl6 on cardiomyocyte injury are not clear. This study was designed to determine whether Bcl6 affects hypoxia-induced cardiomyocyte injury and, if so, to identify the underlying mechanism. To meet this aim, cardiomyocytes were exposed to hypoxia and Bcl6 siRNA was used to silence Bcl6 in cardiomyocytes. Bcl6 knockdown under physiological conditions caused increased oxidative stress, apoptosis, and expression of pro-inflammatory cytokines. Increased inflammatory response, oxidative stress, and apoptosis were observed after cells were exposed to hypoxia for 24 h. Bcl6 knockdown aggravated cardiomyocyte injury when exposed to hypoxia. Bcl6 knockdown increased P38 activation without affecting JNK and ERK phosphorylation levels. Treatment with a P38 inhibitor reversed the Bcl6 silencing-induced deteriorating phenotype, as evidenced by reduced inflammatory response, improved oxidative stress response, and increased cell viability. The results indicate that Bcl6 knockdown causes cardiomyocyte injury at baseline conditions and aggravates cardiomyocyte hypoxia injury via activating the P38 pathway. PMID- 29972265 TI - Down-regulation of miR-26 plays essential roles in TGFbeta-induced EMT. AB - Epithelial mesenchymal transformation (EMT) plays fundamental roles in tumor metastasis. MiRNAs function as powerful regulators of EMT. The function and mechanism of miRNAs in EMT of lung cancers remains to be elucidated. Here, we explored the roles and mechanisms of miR-26a in EMT. A cellular EMT model was firstly established by TGFbeta incubation with A549 cells. Compared with control, the expression of miR-26a was down-regulated by 60% in EMT model. Down-regulation of miR-26a was further revealed to increase the expression of mesenchymal markers (N-cadherin, Vimentin, a-Sma and Twist1) and decrease epithelial marker (E cadherin). Consistently, over-expression of miR-26a partially attenuated the regulatory activity of TGFbeta on the expression of EMT markers in A549 cells. These results indicate that down-regulation of miR-26a plays essential functions in TGFbeta-induced EMT. Furthermore, Smad1 and Smad4 were predicted to be potential targets of miR-26a. Over-expression of miR-26a suppressed the luciferase activity of Renilla whose 3' UTR harbors the sequences of Smad1 or Smad4 that might bind to miR-26a, indicating that miR-26a can directly bind to 3' UTR of Smad1 and Smad4. Accordingly, the protein levels of SMAD1 and SMAD4 were significantly suppressed by miR-26a over-expression in A549 cells. Interestingly, the suppressing effects of miR-26a on EMT were totally rescued by over-expression of SMAD1 and SMAD4 in TGFbeta-treated A549 cells. Collectively, down-regulation of miR-26a plays essential roles in TGFbeta-induced EMT, which might provide important implications for the therapeutics of lung cancers. PMID- 29972266 TI - Aggravated intestinal apoptosis by ClC-3 deletion is lethal to mice endotoxemia. AB - Our previous study found that ClC-3 chloride channel functioned differently in the vascular and intestinal inflammation, the loss of ClC-3 reduced vascular inflammation but exacerbated intestinal inflammation. To furtherly clarify the role of ClC-3 chloride channels in systemic inflammation, we used LPS-induced endotoxemia model to investigate the response of wild-type and ClC-3 knockout mice to systemic inflammation. The results showed that in the LPS-induced endotoxemia model, the mortality of mice with ClC-3 deletion was significantly higher than that of wild-type mice. The liver and lung inflammations in mice with ClC-3 deletion were significantly less than those in wild-type mice, and the levels of TNF-alpha and MIP-2 in serum were lower than those of wild-type mice. However, intestinal inflammatory cytokines contents and intestinal permeability were higher than wild-type mice. After transfection of THP-1 cells with ClC-3 siRNA, the contents of TNF-alpha and IL-8 in LPS-induced cell supernatants were significantly decreased. Further experiments revealed that the level of Bax and Cleaved Caspase 3 in intestinal tissue of mice with ClC-3 deletion was significantly increased, while the level of Bcl2 did not change, which indicated that the intestinal apoptosis was increased after LPS-induced mice intestinal integrity destruction. Therefore, the regulation of intestinal tissue integrity by ClC-3 is crucial for maintaining LPS-induced survival in mice with endotoxemia. PMID- 29972267 TI - Clinical subcategorization of minimally conscious state according to resting functional connectivity. AB - Patients in minimally conscious state (MCS) have been subcategorized in MCS plus and MCS minus, based on command-following, intelligible verbalization or intentional communication. We here aimed to better characterize the functional neuroanatomy of MCS based on this clinical subcategorization by means of resting state functional magnetic resonance imaging (fMRI). Resting state fMRI was acquired in 292 MCS patients and a seed-based analysis was conducted on a convenience sample of 10 MCS plus patients, 9 MCS minus patients and 35 healthy subjects. We investigated the left and right frontoparietal networks (FPN), auditory network, default mode network (DMN), thalamocortical connectivity and DMN between-network anticorrelations. We also employed an analysis based on regions of interest (ROI) to examine interhemispheric connectivity and investigated intergroup differences in gray/white matter volume by means of voxel based morphometry. We found a higher connectivity in MCS plus as compared to MCS minus in the left FPN, specifically between the left dorso-lateral prefrontal cortex and left temporo-occipital fusiform cortex. No differences between patient groups were observed in the auditory network, right FPN, DMN, thalamocortical and interhemispheric connectivity, between-network anticorrelations and gray/white matter volume. Our preliminary group-level results suggest that the clinical subcategorization of MCS may involve functional connectivity differences in a language-related executive control network. MCS plus and minus patients are seemingly not differentiated by networks associated to auditory processing, perception of surroundings and internal awareness/self-mentation, nor by interhemispheric integration and structural brain damage. PMID- 29972268 TI - Impacts of tropical forest disturbance on species vital rates. AB - Tropical forests are experiencing enormous threats from deforestation and habitat degradation. Much knowledge of the impacts of these land-use changes on tropical species comes from studies examining patterns of richness and abundance. Demographic vital rates (survival, reproduction, and movement) can also be affected by land-use change in a way that increases species vulnerability to extirpation, but in many cases these impacts may not be manifested in short-term changes in abundance or species richness. We conducted a literature review to assess current knowledge and research effort concerning how land-use change affects species vital rates in tropical forest vertebrates. We found a general paucity of empirical research on demography across taxa and regions, with some biases toward mammals and birds and land-use transitions, including fragmentation and agriculture. There is also considerable between-species variation in demographic responses to land-use change, which could reflect trait-based differences in species sensitivity, complex context dependencies (e.g., between region variation), or inconsistency in methods used in studies. Efforts to improve understanding of anthropogenic impacts on species demography are underway, but there is a need for increased research effort to fill knowledge gaps in understudied tropical regions and taxa. The lack of information on demographic impacts of anthropogenic disturbance makes it difficult to draw definite conclusions about the magnitude of threats to tropical ecosystems under anthropogenic pressures. Thus, determining conservation priorities and improving conservation effectiveness remains a challenge. PMID- 29972269 TI - The health benefits of autonomous vehicles: public awareness and receptivity in Australia. AB - OBJECTIVES: The substantial public health benefits of autonomous vehicles will be optimised once all vehicles operate in autonomous mode. This form of disruptive technology will need to be widely accepted by the community to facilitate the regulatory and behavioural adjustments required to achieve rapid adoption. The aim of this study was to assess: i) receptiveness to autonomous vehicles; ii) the salience of various health benefits (e.g. crash prevention, emission reduction, driving stress reduction, cyclist safety, increased mobility for those unable to drive); and iii) prompted awareness of these health benefits. METHODS: Quantitative and qualitative data were generated via a national online survey of a broad range of Australians aged 16 years and over (n=1,624). RESULTS: There were neutral levels of receptiveness and very low salience of health benefits, but more substantial levels of prompted awareness of positive health outcomes. CONCLUSIONS: These results suggest that the public may be interested in information relating to the individual and societal health benefits of autonomous vehicles, which in turn may increase overall support for this innovation. Implications for public health: Australians are likely to be receptive to autonomous vehicles when provided with information relating to their public health benefits. PMID- 29972270 TI - Age, period and cohort effects on body mass index in New Zealand, 1997-2038. AB - OBJECTIVE: To estimate the effects of age, period and birth cohort on observed trends, and to provide short- to medium-term projections of population BMI in New Zealand. METHODS: Data were obtained from New Zealand national health surveys covering the period 1997 to 2015 (n=76,294 individuals). A Hierarchical Age Period-Cohort (HAPC) model and an Age-Period model with interaction terms were specified for population groups defined by ethnicity and sex. Observed trends were extrapolated to estimate group-specific BMI projections for the period 2015 2038; these were weighted by projected population sizes to calculate population wide BMI projections. RESULTS: Population mean BMI increased from 26.4 kg/m2 (95%CI 26.2-26.5) in 1997 to 28.3 kg/m2 (95%CI 28.2-28.5) in 2015. Both models identified substantial, approximately linear, period trends behind this increase, with no significant cohort effects. Mean BMI was projected to reach 30.6 kg/m2 (95%CI 29.4-31.7; HAPC model) to 30.8 kg/m2 (95%CI 30.2-31.4; Age-Period model) by 2038. CONCLUSIONS: BMI continues to increase in New Zealand. On current trends, population mean BMI will exceed 30 kg/m2 - the clinical cut-off for obesity - by the early 2030s. Implications for public health: Unless prevented by comprehensive public health policy changes, increasing population obesity is likely to result in unfavourable economic and health impacts. PMID- 29972271 TI - Targeting mitochondria with folic acid and vitamin B12 ameliorates nicotine mediated islet cell dysfunction. AB - Nicotine, one of the well-known highly toxic components of cigarette smoke, causes a number of adverse health effects and diseases. Our previous study has shown that nicotine induces reactive oxygen species (ROS) in islet cell and disrupts islet cell mitochondrial membrane potential (DeltaPsim). However, supplementation with folic acid and vitamin B12 were found effective against nicotine induced changes in pancreatic islet cells. But the toxicological effects and underlying mechanisms of nicotine-induced mitochondrial dysfunction is still unknown. In this study, nicotine exposure decreases mitochondrial enzymes (pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, aconitase, malate dehydrogenase) activities by increasing cytosolic Ca2+ level which may contribute to increased mitochondrial ROS production by raising its flow to mitochondria. This in turn produces malondialdehyde and nitric oxide (NO) with a concomitant decrease in the activities of antioxidative enzymes and glutathione levels leading to loss of DeltaPsim. Simultaneously, nicotine induces pancreatic islet cell apoptosis by modulating DeltaPsim via increased cytosolic Ca2+ level, altered Bcl-2, Bax, cytochrome c, caspase-9, PARP expressions which were prevented by the supplementation of folic acid and vitamin B12 . In conclusion, nicotine alters islet cell mitochondrial redox status, apoptotic machinery, and enzymes to cause disruption in the DeltaPsim and supplementation of folic acid and vitamin B12 possibly blunted all these mitochondrial alterations. Therefore, this study may help to determine the pathophysiology of nicotine-mediated islet cell mitochondrial dysfunction. PMID- 29972273 TI - Climate change and us: What nephrologists should know. AB - Global warming poses significant risks to human health and the planet. If allowed to continue unchecked, its consequences will be devastating. While all populations will be effected with time, vulnerable groups, including those with kidney disease, are likely to be at primary risk. This paper summarizes the current state of scientific knowledge relevant to climate change. It discusses the contribution of the health-care system, and particularly dialysis programmes, to greenhouse gas emissions, and pathways that exist for nephrologists to mitigate their environmental impact. PMID- 29972272 TI - Benzyl isothiocyanate inhibits human brain glioblastoma multiforme GBM 8401 cell xenograft tumor in nude mice in vivo. AB - Benzyl isothiocyanate (BITC), a member of isothiocyanates (ITCs), has been shown to induce cell death in many human cancer cells, but there is no further report to show BITC suppresses glioblastoma multiforme cells in vivo. In the present study, we investigate the effects of BITC on the inhibition of GBM 8401/luc2 cell generated tumor on athymic nude mice. We established a luciferase expressing stable clone named as GBM 8401/luc2. Thirty male mice were inoculated subcutaneously with GBM 8401/luc2 cells to generate xenograft tumor mice model. Group I was treated with 110 MUL phosphate-buffered solution plus 10 MUL dimethyl sulfoxide, Group II-III with BITC (5 or 10 MUmol/100 MUL/day, relatively). Mice were given oral treatment of BITC by gavage for 21 days. Results showed that BITC did not affect the body weights. After anesthetized, the photons emitted from mice tumor were detected with Xenogen IVIS imaging system 200 and higher dose of BITC have low total photon flux than that of lower dose of BITC. Results also showed that higher dose of BITC have low total tumor volumes and weights than that of low dose of BITC. Isolated tumors were investigated by immunohistochemical analysis and results showed that BITC at both dose of treatment weakly stained with anti-MCL1 and -XIAP. However, both dose of BITC treatments have strong signals of caspase-3 and Bax. Overall, these data demonstrated that BITC suppressed tumor properties in vivo. Overall, based on these observations, BITC can be used against human glioblastoma multiforme in the future. PMID- 29972274 TI - Corticosteroid therapy for nephrotic syndrome in children. PMID- 29972275 TI - Unexpected Nephrocalcinosis in a Chronic Heavy Cola Drinker. PMID- 29972276 TI - Belatacept for kidney transplant recipients. PMID- 29972277 TI - Altered dietary salt for people with CKD. PMID- 29972278 TI - Feasibility study of a combined lifestyle behaviors and asthma self-management intervention for school-aged children. AB - PURPOSE: The purpose of this study is to test the feasibility of delivering an intervention that combines healthy lifestyle behaviors related to weight management with asthma self-management, the Living Healthy with Asthma intervention, to children who have asthma. METHODS AND DESIGN: Using a mixed design, the feasibility study of the 12-week Living Healthy with Asthma intervention was conducted with a single group of children diagnosed with asthma. Pretest and posttest data were collected on asthma-related (self-management, metered dose inhaler [MDI] skill, asthma severity, quality of life [QOL]), and healthy lifestyle variables (body mass index [BMI], dietary quality). A matched comparison sample was drawn from a separate study that tested the same asthma self-management component (single intervention) used in the feasibility study to determine if the Living Healthy with Asthma intervention worked as well as the single intervention for improving children's asthma self-management. RESULTS: Thirteen school-aged children were enrolled in the feasibility study. There were significant reductions in BMI z-scores (P = 0.007), and improvements in vegetable servings (P = 0.03), MDI skill (P = 0.005), children's QOL (P < 0.001), and parents' QOL (P = 0.03). When comparing the feasibility group with the matched comparison group (n = 13), there were no significant differences in asthma self management, MDI skill, or asthma severity after the interventions. PRACTICE IMPLICATIONS: Findings supported the feasibility of implementing the combined intervention, and it was not inferior to the single intervention-which supports nurses' efforts to help families manage multiple health problems. PMID- 29972280 TI - Proteomic Profile of Daphnia pulex using Data-Independent Acquisition Mass Spectrometry and Ion Mobility Separation. AB - Daphnia pulex is a keystone species for aquatic habitats and an ecological/evolution model organism. Although significant progress has been made on characterizing its genome, the D. pulex proteome remains largely uncharacterized partially due to abnormally high protein degradation during homogenization and emphasis on genomic analysis. In this study, various sample preparation and mass spectrometry acquisition methods are performed for the purpose of improving D. pulex proteome exploration. Benefits for employing both in-gel and in-solution methods of trypsin digestion are observed. Furthermore, acquisition methods employing ion mobility separation greatly increase peptide identification and more than doubled the proteome coverage. Bioinformatic analysis suggests that mitochondrial and hydrolytic activities are enriched in D. pulex compared to closely related invertebrates or Homo sapiens. Also, novel D. pulex proteins possessing putative genome modifying functional domains are identified. Data are available via ProteomeXchange with identifier PXD008455. PMID- 29972279 TI - Robust Ultramicroporous Metal-Organic Frameworks with Benchmark Affinity for Acetylene. AB - Highly selective separation and/or purification of acetylene from various gas mixtures is a relevant and difficult challenge that currently requires costly and energy-intensive chemisorption processes. Two ultramicroporous metal-organic framework physisorbents, NKMOF-1-M (M=Cu or Ni), offer high hydrolytic stability and benchmark selectivity towards acetylene versus several gases at ambient temperature. The performance of NKMOF-1-M is attributed to their exceptional acetylene binding affinity as revealed by modelling and several experimental studies: in situ single-crystal X-ray diffraction, FTIR, and gas mixture breakthrough tests. NKMOF-1-M exhibit better low-pressure uptake than existing physisorbents and possesses the highest selectivities yet reported for C2 H2 /CO2 and C2 H2 /CH4 . The performance of NKMOF-1-M is not driven by the same mechanism as current benchmark physisorbents that rely on pore walls lined by inorganic anions. PMID- 29972281 TI - Effects of isometric, eccentric, or heavy slow resistance exercises on pain and function in individuals with patellar tendinopathy: A systematic review. AB - BACKGROUND AND PURPOSE: The purpose of this study is to evaluate current evidence and provide a review on the effects of isometric, eccentric, or heavy slow resistance (HSR) exercises on pain and function in individuals with patellar tendinopathy (PT). METHODS: Academic journals from CINAHL, Embase, MEDLINE, Scopus, SPORTDiscusTM, and The Cochrane Library were searched from inception to August 2017. Screening of reference lists was also performed. Human interventional studies investigating outcomes of pain and function in PT using either isometric, eccentric, or HSR training exercises were included. The McMaster Critical Review Form-Quantitative Studies was used to assess for risk of bias. Levels of evidence were obtained using the National Health and Medical Research Council (NHMRC) evidence hierarchy. The NHMRC Body of Evidence Framework was utilized to formulate recommendations for clinical practice. Extraction of data was performed by two independent reviewers according to predefined data criterion, data were then tabulated, and a descriptive, qualitative data synthesis was performed. RESULTS: Fifteen studies (3 isometric, 2 HSR, and 10 eccentric) were included for this review. Mean quality score across all studies was 81.6% (range 70% to 93%). Nine studies were of high quality, whereas six studies were of moderate quality. Nine studies were randomized controlled trials, which provided good Level II evidence; four studies were of satisfactory Level III evidence; and two studies were case series (Level IV evidence). CONCLUSIONS: Findings from isometric exercises can be trusted to guide clinical practice (Grade A), whereas eccentric exercises can be trusted to guide clinical practice in most clinical situations (Grade B). It is recommended that HSR exercises should be applied carefully to individual clinical circumstances (Grade C) and interpreted with care. Isometric exercises appear to be more effective during competitive seasons for short-term pain relief, whereas HSR or eccentric exercises are more suitable for long-term pain reduction and improvement in knee function. PMID- 29972283 TI - Epirubicin and long-term heart failure risk in breast cancer survivors. PMID- 29972284 TI - The attribute priming effect in patients with Alzheimer's disease. AB - Experiments with semantic priming (SP) paradigms have documented early hypopriming in patients with AD when concepts are used as primes and attribute concept features as targets, suggesting that concept attributes are vulnerable to damage very early in the disease course. The aims of this study were to confirm early priming reduction in the attribute condition in patients with AD and to determine which of several semantic indexes (such as the level of distinctiveness, correlation or feature dominance of concept features) best predicts the priming effect size in AD. We administered an SP attribute condition paradigm to 20 mildly demented patients with AD and to 10 NCs. We used concept attribute pairs for which normative data of semantic indexes relative to both concept primes (i.e., number, type, mean level of dominance, distinctiveness and correlation of features constituting the concepts) and target features (i.e., level of feature dominance, correlation and distinctiveness) were available. Results showed that compared to NCs, the AD group obtained very reduced priming facilitation. Furthermore, the item regression analyses showed that the priming decrement in the AD group was predicted by the feature dominance of the target in the related pairs; that is, the lower the target feature dominance, the lower the priming effect elicited. These results confirmed hypopriming in the attribute condition from the very early phase of AD and support the view that attributes which are more salient for the identification of a given concept are also those most resistant to semantic memory degradation in AD pathology. PMID- 29972282 TI - Oncofertility-An emerging discipline rather than a special consideration. AB - Originally absent from the oncologist's consult, then placed in a 'quality of life' rubric, oncofertility should now be an essential part of a comprehensive cancer treatment plan in patients of reproductive age, including adolescents and young adults (AYAs). Oncofertility encompasses the endocrine health of the patient, as well as fertility management options. Thus, pubertal transitions in males and females, bone health, and menstrual health are all part of this discipline, enabling practitioners to work in interdisciplinary teams to solve problems in reproductive health. This review provides a summary of the essential considerations required for the assessement of reproductive risk and choice of fertility preservation options as well as considerations for developing oncofertility services for AYAs. PMID- 29972285 TI - Keratinocyte cancers in South Australia: incidence, geographical variability and service trends. AB - OBJECTIVES: To determine the incidence, multiplicity, geographical variability and service trends of keratinocyte cancers (KC) in South Australia (SA). METHODS: Medicare Australia data with a unique identifier were used to assess the number of people treated over years 2010-2014. A maximum of one KC service claim per year was used to determine incidence. Age-standardised rates were estimated as were KC service activity trends. RESULTS: There were 497,581 services to 204,183 SA residents for KC, solar keratoses, locally aggressive skin tumours or suspicious skin lesions. Of these, n=159,137 services were for KC (77,502 people). The five-year (2010-2014) age-standardised rate of KC in SA was 1,466.6 (95%CI 1,458.3-1,474.8) per 100,000. Forty per cent of people had more than one KC removed. Men accounted for more incident cases (59.2%). Age-specific rates showed least variability over time in the youngest age group (15-44 years). For 26 geographical areas, higher age-standardised ratios of KC were seen in coastal and agricultural areas. There was a 59% increase in services for KC from 2000 to 2015. CONCLUSIONS: Age-standardised rates for KC are relatively stable in SA, but regional variations are evident. Services for KC continue to rise. Implications for public health: This is the first systematic report of KC in SA. We demonstrate the utility of using validated Medicare data for assessing KC incidence and trends. PMID- 29972286 TI - Noble-Metal-Free Single-Atom Catalysts CuAl4 O7-9 - for CO Oxidation by O2. AB - The single copper atom doped clusters CuAl4 O7-9 - can catalyze CO oxidation by O2 . The CuAl4 O7-9 - clusters are the first group of experimentally identified noble-metal free single atom catalysts for such a prototypical reaction. The reactions were characterized by mass spectrometry and density functional theory calculations. The CuAl4 O9 CO- is much more reactive than CuAl4 O9 - in the reaction with CO to generate CO2 . One adsorbed CO is crucial to stabilize Cu of CuAl4 O9 - around +I oxidation state and promote the oxidation of another CO. The widely emphasized correlation between the catalytic reactivity of CO oxidation and Cu oxidation state can be understood at the strictly molecular level. The remarkable difference between Cu catalysis and noble-metal catalysis was discussed. PMID- 29972288 TI - Addendum. PMID- 29972287 TI - Community mobilization to modify harmful gender norms and reduce HIV risk: results from a community cluster randomized trial in South Africa. AB - INTRODUCTION: Community mobilization (CM) is increasingly recognized as critical to generating changes in social norms and behaviours needed to achieve reductions in HIV. We conducted a CM intervention to modify negative gender norms, particularly among men, in order to reduce associated HIV risk. METHODS: Twenty two villages in the Agincourt Health and Socio-Demographic Surveillance Site in rural Mpumalanga, South Africa were randomized to either a theory-based, gender transformative, CM intervention or no intervention. Two cross-sectional, population-based surveys were conducted in 2012 (pre-intervention, n = 600 women; n = 581 men) and 2014 (post-intervention, n = 600 women; n = 575 men) among adults ages 18 to 35 years. We used an intent-to-treat (ITT) approach using survey regression cluster-adjusted standard errors to determine the intervention effect by trial arm on gender norms, measured using the Gender Equitable Mens Scale (GEMS), and secondary behavioural outcomes. RESULTS: Among men, there was a significant 2.7 point increase (Beta Coefficient 95% CI: 0.62, 4.78, p = 0.01) in GEMS between those in intervention compared to control communities. We did not observe a significant difference in GEMS scores for women by trial arm. Among men and women in intervention communities, we did not observe significant differences in perpetration of intimate partner violence (IPV), condom use at last sex or hazardous drinking compared to control communities. The number of sex partners in the past 12 months (AOR 0.29, 95% CI 0.11 to 0.77) were significantly lower in women in intervention communities compared to control communities and IPV victimization was lower among women in intervention communities, but the reduction was not statistically significant (AOR 0.53, 95% CI 0.24 to 1.16). CONCLUSION: Community mobilization can reduce negative gender norms among men and has the potential to create environments that are more supportive of preventing IPV and reducing HIV risk behaviour. Nevertheless, we did not observe that changes in attitudes towards gender norms resulted in desired changes in risk behaviours suggesting that more time may be necessary to change behaviour or that the intervention may need to address behaviours more directly. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02129530. PMID- 29972289 TI - Giant adrenal pseudocyst: A rare diagnosis. AB - We present a rare case of giant adrenal pseudocyst as a cause of right upper quadrant (RUQ) pain and highlight the typical multimodality imaging features. The case demonstrates the imaging features associated with giant adrenal pseudocysts to aid accurate and timely diagnosis. Despite the rarity of these lesions they are important to consider as benign lesions can closely mimic malignant ones. Unenhanced and contrast-enhanced CT is the imaging of choice for adrenal cysts. However, MRI can provide more exquisite assessment of cystic, solid and enhancing components. Pseudocysts can be purely cystic, mixed or solid. Classically, adrenal pseudocysts are described as cystic lesions (of homogenous water density) with a fibrous wall and thin internal septations. Mural/septal calcification is commonly demonstrated due to haemorrhage, this is discernible from central/amorphous calcification seen in malignant disease. As in this case, pseudocysts can contain solid components or layering secondary to haemorrhage. The key to differentiating organised haematoma from tumour is the lack of enhancement. If serial imaging is undertaken in these patients rapid changes in the solid components may be seen reflecting resolving haematoma. Adrenal pseudocysts are rare and have a wide differential. Cystic adrenal lesions warrant multimodality assessment as their imaging features aid diagnosis and differentiation from malignant disease. We suggest that MRI plays a complimentary role to CT. CT is superior at demonstrating mural/septal calcification but MRI aids in determining cystic components and differentiating haemorrhage from tumour. PMID- 29972290 TI - Nutritional assessment of patients with end-stage renal disease using the MNA scale. AB - BACKGROUND: Patient malnutrition is a significant problem in the process of rehabilitation and treatment. One of the tools that can reveal the risk of malnutrition is a series of standardized nutritional questionnaires. OBJECTIVES: The aim of the study was to assess the nutritional status of patients with end stage renal disease (ESRD) by means of the minimal nutritional assessment (MNA) scale. MATERIAL AND METHODS: The study group included respondents suffering from ESRD who were patients of the Dialysis Center at the Clinic of Nephrology and Transplantation Medicine at the University Clinical Hospital in Wroclaw. The study was conducted in 47 dialysis patients (22 women and 25 men), mean age 69.68 +/-8.95 years. A standardized MNA scale was used to evaluate the nutritional status of the patients. RESULTS: In the study group, women had a significantly lower score on the MNA scale than men (23.95 vs 25.26 points). Using the MNA scale, the risk of malnutrition was found in 13 patients, while malnutrition was found in 1 patient. Among females, the mean body mass index (BMI) was 27.28, and it was significantly correlated with the MNA score. In males, the mean BMI was 29.61, but it did not correlate with the MNA score. The time spent undergoing renal replacement therapy was 7.63 years for women and 7.24 years for men. This correlated significantly with the MNA score only in the case of men. Significant correlations were established between eating habits and MNA scores in both groups. CONCLUSIONS: The results obtained using the MNA scale showed a significant risk of malnutrition in patients with ESRD. In women only, a low score on the MNA scale significantly correlated with the BMI. The time of renal replacement therapy had a significant impact on the MNA scale only in the case of men. An influence of comorbidities on the MNA scores recorded by men and women was not observed. Major health incidents and other stressful situations significantly affected the nutritional status in men. PMID- 29972291 TI - Effective infection prevention and control: the nurse's role. AB - Healthcare-associated infections and antimicrobial resistance are significant threats to public health. As resistant organisms continue to emerge and evolve, and antimicrobial agents become less effective, infection prevention and control remains a vital aspect of maintaining public health, particularly among vulnerable patient groups such as older people and young children. Because of the increasing complexity of healthcare treatments and interventions, patients are becoming increasingly susceptible to healthcare-associated infections and resistant organisms. This article outlines some of the challenges that nurses may experience in ensuring effective infection prevention and control, and how these can be addressed. PMID- 29972292 TI - Role of nurses in alcohol screening and treatment interventions. AB - Alcohol consumption can be a positive factor in many people's social lives, but for some individuals it may cause associated harm to their health. Alcohol consumption can also place a burden on healthcare services. This article explores the trends of alcohol use, primarily in the UK, and outlines the related health effects. The author reviews the screening and brief interventions that non specialist nurses can use, in partnership with patients, where they have concerns regarding patients' alcohol use and its potentially harmful health effects. PMID- 29972293 TI - Using the Care Excellence Framework to benchmark and improve patient care. AB - Quality is complex and difficult to define, and institutions and organisations often have their own definitions, measurements and assurance processes. The Care Excellence Framework (CEF), developed and used at University Hospitals of North Midlands NHS Trust, is a unique, integrated framework of measurement, clinical observation, patient and staff interviews and benchmarking. It also has an internal accreditation system that provides assurance from ward to board based on the five Care Quality Commission (CQC) domains and reflects CQC standards. The CEF has been established in its existing form since autumn 2016 and has been used in all areas of the organisation. This article provides an overview of the development and use of the CEF in an acute care setting, demonstrates how the framework acts as an internal accreditation system, and shows how it can encourage staff to undertake effective change and transform care from ordinary to excellent. PMID- 29972294 TI - Lithium-Salt-Rich PEO/Li0.3La0.557TiO3 Interpenetrating Composite Electrolyte with Three-Dimensional Ceramic Nano-Backbone for All-Solid-State Lithium-Ion Batteries. AB - Solid electrolytes with high ionic conductivity and good mechanical properties are required for solid-state lithium-ion batteries. In this work, we synthesized composite polymer electrolytes (CPEs) with a three-dimensional (3D) Li0.33La0.557TiO3 (LLTO) network as a nano-backbone in poly(ethylene oxide) matrix by hot-pressing and quenching. Self-standing 3D-CPE membranes were obtained with the support of the LLTO nano-backbone. These membranes had much better thermal stability and enhanced mechanical strength in comparison with solid polymer electrolytes. The influence of lithium (Li) salt concentration on the conductivity of 3D-CPEs was systematically studied, and an ionic conductivity as high as 1.8 * 10-4 S.cm-1 was achieved at room temperature. The electrochemical window of the 3D-CPEs was 4.5 V vs Li/Li+. More importantly, the 3D-CPE membranes could suppress the growth of Li dendrite and reduce polarization; therefore, a symmetric Li|3D-CPE|Li cell with these membranes was cycled at a current density of 0.1 mA.cm-2 for over 800 h. All of the superior properties above made the 3D-CPEs with the LLTO nano-backbone a promising electrolyte candidate for flexible solid-state lithium-ion batteries. PMID- 29972295 TI - Quantitative Analysis of Sex-Hormone-Binding Globulin Glycosylation in Liver Diseases by Liquid Chromatography-Mass Spectrometry Parallel Reaction Monitoring. AB - Sex-hormone-binding globulin (SHBG) is a liver-secreted glycoprotein and a major regulator of steroid distribution. It has been reported that the serum concentration of SHBG changes in liver disease. To explore the involvement of SHBG in liver disease of different etiologies in greater detail, we developed a sensitive and selective liquid chromatography-mass spectrometry parallel reaction monitoring workflow to achieve quantitative analysis of SHBG glycosylation microheterogeneity. The method uses energy-optimized "soft" fragmentation to extract informative Y ions for maximal coverage of glycoforms and their quantitative comparisons. A total of 15 N-glycoforms of two N-glycosites and 3 O glycoforms of 1 O-glycosite of this low-abundance serum protein were simultaneously analyzed in the complex samples. At the same time, we were able to partially resolve linkage isoforms of the fucosylated glycoforms and to identify and quantify SHBG N-glycoforms that were not previously reported. The results show that both core and outer-arm fucosylation of the N-glycoforms increases with liver cirrhosis but that a further increase of fucosylation is not observed with hepatocellular carcinoma (HCC). In contrast, the alpha-2-6 sialylated glycoform of the O-glycopeptide of SHBG increases in liver cirrhosis, and a significant 2 fold further increase is observed in HCC. In general, we do not find a significant contribution of different liver disease etiologies to the observed changes in glycosylation; however, elevation of the newly reported HexNAc(4)Hex(6) N-glycoform is associated with alcoholic liver disease. PMID- 29972296 TI - Toxic Organophosphate Hydrolysis Using Nanofiber-Templated UiO-66-NH2 Metal Organic Framework Polycrystalline Cylinders. AB - Metal organic frameworks (MOFs), the UiO series in particular, have attracted much attention because of the high surface area and ability to capture and decontaminate chemical warfare agents. Much work has been done on incorporating these MOFs into or onto textile materials while retaining the desirable properties of the MOF. Many different techniques have been explored to achieve this. Atomic layer deposition (ALD) of TiO2 followed by solvothermal synthesis of MOF has become one of the most adaptable techniques for growing MOFs on the surface of many different polymer fabric materials. However, little work has been done with using this technique on polymer composite materials. In this work, UiO 66-NH2 was grown onto the surface of poly(methyl methacrylate) (PMMA)/Ti(OH)4 and poly(vinylidene fluoride) (PVDF)/Ti(OH)4 composite fibers by first modifying the surface with ALD of TiO2 (@TiO2) followed by solvothermal synthesis of MOF (@MOF). The catalytic activity of these materials was then evaluated using the simulant paraoxon-methyl (DMNP). These new MOF-functionalized composite fabrics were compared to polyamide-6 (PA-6)@TiO2@MOF- and polypropylene (PP)@TiO2@MOF functionalized fabrics. PMMA/Ti(OH)4@TiO2@MOF fibers resulted in unique hollowed fibers with high surface area of 264 m2/g and fast catalytic activity. The catalytic activity of these samples was found to be related to the active MOF mass fraction on the MOF-functionalized composite fabric, with the hollowed PMMA/Ti(OH)4@TiO2@MOF having the highest weight percent of active MOF and a DMNP t1/2 of 26 min followed by PA-6@TiO2@MOF with 45 min, PVDF/Ti(OH)4@TiO2@MOF with 61 min, and PP@TiO2@MOF with 83 min. PMID- 29972297 TI - Triclinic Off-Stoichiometric Na3.12Mn2.44(P2O7)2/C Cathode Materials for High Energy/Power Sodium-Ion Batteries. AB - The application of sodium-ion batteries (SIBs) requires a suitable cathode material with low cost, nontoxic, high safety, and high energy density, which is still a big challenge; thus, a basic research on exploring new types of materials is imperative. In this work, a manganic pyrophosphate and carbon compound Na3.12Mn2.44(P2O7)2/C has been synthesized through a feasible sol-gel method. Rietveld refinement reveals that Na3.12Mn2.44(P2O7)2 adopts a triclinic structure ( P1 space group), which possesses spacious ion diffusion channels for facile sodium migration. The off-stoichiometric phase is able to offer more reversible Na+, delivering an enhanced reversible capacity of 114 mA h g-1 at 0.1 C, and because of the strong "inductive effect" that (P2O7)4- groups imposing on the Mn3+/Mn2+ redox couple, Na3.12Mn2.44(P2O7)2/C presents high platforms above 3.6 V, contributing a remarkable energy density of 376 W h kg-1, which is among the highest Fe-/Mn-based polyanion-type cathode materials. Furthermore, the off stoichiometric compound also presents satisfactory rate capability and long-cycle stability, with a capacity retention of 75% after 500 cycles at 5 C. Ex situ X ray diffraction demonstrates a single-phase reaction mechanism, and the density functional theory calculations display two one-dimensional sodium migration paths with low energy barriers in Na3.12Mn2.44(P2O7)2, which is vital for the facile sodium storage. We believe that this compound will be a competitive cathode material for large-scale SIBs. PMID- 29972298 TI - Reverse Offset Printing of Semidried Metal Acetylacetonate Layers and Its Application to a Solution-Processed IGZO TFT Fabrication. AB - The submicrometer resolution printing of various metal acetylacetonate complex inks including Fe, V, Mn, Co, Ni, Zn, Zr, Mo, and In was enabled by a robust ink formulation scheme which adopted a ternary solvent system where solubility, surface wettability, and drying as well as absorption behavior on a polydimethylsiloxane sheet were optimized. Hydrogen plasma in heated conditions resulted in bombarded, resistive, or conductive state depending on the temperature and the metal species. With a conductivity-bestowed layer of MoO x and a plasma-protecting layer of ZrO x situated on the top of an IGZO layer, a solution-processed TFT exhibiting an average mobility of 0.17 cm2/(V s) is demonstrated. PMID- 29972299 TI - Aptamer Selection against a Trichomonas vaginalis Adhesion Protein for Diagnostic Applications. AB - Trichomoniasis, caused by Trichomonas vaginalis, is the leading nonviral sexually transmitted infection worldwide. We report the selection of a DNA aptamer against a T. vaginalis adhesion protein, AP65, using a microtiter plate-based in vitro combinatorial chemistry process termed systematic evolution of ligands by exponential enrichment. The enriched library pool was sequenced by next generation sequencing, and several aptamer candidates with high affinity and specificity were identified. The aptamer with the highest affinity and specificity had a KD in the low nanomolar range, as confirmed by three different techniques: surface plasmon resonance, enzyme-linked aptamer assay, and biolayer interferometry. The selected aptamer was demonstrated to have a high specificity to the AP65 protein and to T. vaginalis cells with no cross-reactivity to other enteric and urogenital microorganisms. Current work is focused on the development of inexpensive and easy-to-use aptamer-based diagnostic assays for the reliable and rapid detection of T. vaginalis in vaginal swabs. PMID- 29972300 TI - Selective DOT1L, LSD1, and HDAC Class I Inhibitors Reduce HOXA9 Expression in MLL AF9 Rearranged Leukemia Cells, But Dysregulate the Expression of Many Histone Modifying Enzymes. AB - Mixed lineage leukemia results from chromosomal rearrangements of the gene mixed lineage leukemia (MLL). MLL-AF9 is one such rearrangement that recruits the lysine methyltransferase, human disruptor of telomere silencing 1-like (DOT1L) and lysine specific demethylase 1 (LSD1), resulting in elevated expression of the Homeobox protein A9 (HOXA9), and leukemia. Inhibitors of LSD1 or DOT1L reduce HOXA9 expression, kill MLL-rearranged cells, and may treat leukemia. To quantify their effects on histone modifying enzyme activity and expression in MLL rearranged leukemia, we tested inhibitors of DOT1L (EPZ-5676), LSD1 (GSK2879552), and HDAC (mocetinostat), in the MLL-AF9 cell line MOLM-13. All inhibitors reduced MOLM-13 viability but only mocetinostat induced apoptosis. EPZ-5676 increased total histone lysine dimethylation, which was attributed to a reduction in LSD1 expression, and was indistinguishable from direct LSD1 inhibition by GSK2879552. All compounds directly inhibit, or reduce the expression of, HOXA9, DOT1L and LSD1 by qPCR, increase total histone lysine methylation and acetylation by LC MS/MS, and specifically reduce H3K79Me2 and increase H3K14Ac. Each inhibitor altered the expression of many histone modifying enzymes which may precipitate additional changes in expression. To the extent that this decreases HOXA9 expression it benefits mixed lineage leukemia treatment, all other expression changes are off-target effects. PMID- 29972301 TI - HyPR-MS for Multiplexed Discovery of MALAT1, NEAT1, and NORAD lncRNA Protein Interactomes. AB - RNA-protein interactions are integral to the regulation of gene expression. RNAs have diverse functions and the protein interactomes of individual RNAs vary temporally, spatially, and with physiological context. These factors make the global acquisition of individual RNA-protein interactomes an essential endeavor. Although techniques have been reported for discovery of the protein interactomes of specific RNAs they are largely laborious, costly, and accomplished singly in individual experiments. We developed HyPR-MS for the discovery and analysis of the protein interactomes of multiple RNAs in a single experiment while also reducing design time and improving efficiencies. Presented here is the application of HyPR-MS to simultaneously and selectively isolate the interactomes of lncRNAs MALAT1, NEAT1, and NORAD. Our analysis features the proteins that potentially contribute to both known and previously undiscovered roles of each lncRNA. This platform provides a powerful new multiplexing tool for the efficient and cost-effective elucidation of specific RNA-protein interactomes. PMID- 29972302 TI - Hierarchical Heterostructures of Ultrasmall Fe2O3-Encapsulated MoS2/N-Graphene as an Effective Catalyst for Oxygen Reduction Reaction. AB - In this study, a facile approach has been successfully applied to synthesize a hierarchical three-dimensional architecture of ultrasmall hematite nanoparticles homogeneously encapsulated in MoS2/nitrogen-doped graphene nanosheets, as a novel non-Pt cathodic catalyst for oxygen reduction reaction in fuel cell applications. The intrinsic topological characteristics along with unique physicochemical properties allowed this catalyst to facilitate oxygen adsorption and sped up the reduction kinetics through fast heterogeneous decomposition of oxygen to final products. As a result, the catalyst exhibited outstanding catalytic performance with a high electron-transfer number of 3.91-3.96, which was comparable to that of the Pt/C product. Furthermore, its working stability with a retention of 96.1% after 30 000 s and excellent alcohol tolerance were found to be significantly better than those for the Pt/C product. This hybrid can be considered as a highly potential non-Pt catalyst for practical oxygen reduction reaction application in requirement of low cost, facile production, high catalytic behavior, and excellent stability. PMID- 29972303 TI - Total Synthesis of gamma-Alkylidenebutenolides, Potent Melanogenesis Inhibitors from Thai Medicinal Plant Melodorum fruticosum. AB - A hitherto unreported member of gamma-alkylidenebutenolides in Melodorum fruticosum (Annonaceae), (4 E)-6-benzoyloxy-7-hydroxy-2,4-heptadiene-4-olide, named as isofruticosinol (4) was isolated from the methanol extract of flowers, along with the known related butenolides, namely, the (4 Z)-isomer (3) of 4, melodrinol (1), and its (4 E)-isomer (2). To unambiguously determine the absolute configuration at the C-6 position in these butenolides, the first total syntheses of both enantiomers of 2-4 were achieved over 6-7 steps from commercially available D- or L-ribose (D- and L-5). Using the same protocol, both enantiomers of 1 were also synthesized. Based on chiral HPLC analysis of all synthetic compounds ( S- and R-1-4), all naturally occurring butenolides were assigned as partial racemic mixtures with respect to the chiral center at C-6 (enantiomeric ratio, 6 S/6 R = ~83/17). Furthermore, the melanogenesis inhibitory activities of S- and R-1-4 were evaluated, with all shown to be potent inhibitors with IC50 values in the range 0.29-2.9 MUM, regardless of differences in the stereochemistry at C-6. In particular, S-4 (IC50 = 0.29 MUM) and R-4 (0.39 MUM) showed potent inhibitory activities compared with that of reference standard arbutin (174 MUM). PMID- 29972304 TI - Large Interfacial Magnetostriction in (Co/Ni)4/Pb(Mg1/3Nb2/3)O3-PbTiO3 Multiferroic Heterostructures. AB - The magnetoelastic behavior of multiferroic heterostructures-coupling of magnetic anisotropy or domain dynamics to structural deformations-has been intensively studied for developing materials for energy-efficient, spin-based applications. Here, we report on a large, interface-dominated magnetostriction in (Co/Ni)4/Pb(Mg1/3Nb2/3)O3-PbTiO3 multiferroic heterostructures. Ferromagnetic resonance spectroscopy under voltage-induced strains enabled estimation of the saturation magnetostriction as a function of Ni thickness. The volume and the interface components to the saturation magnetostriction are (6.6 +/- 0.9) * 10-6 and (-2.2 +/- 0.2) * 10-14 m, respectively. Similar to perpendicular magnetic anisotropy in Co/Ni, the large, negative magnetostriction originates from the Co/Ni interfaces. This interfacial functionality delivers an effect over 300% larger than the bulk contribution and can enable low-energy, nanoelectronic devices that combine the tunable magnetic and magnetostrictive properties of Co/Ni multilayers with the ferroelectric properties of Pb(Mg1/3Nb2/3)O3-PbTiO3. PMID- 29972305 TI - Combined Lid Crease and Endoscopic Approach to Lateral Frontal Sinus Disease With Orbital Extension. AB - INTRODUCTION: Functional endoscopic sinus surgery for frontal sinus disease has obviated the need for external approaches. Special circumstances such as acute infection with orbital involvement or significant lateral sinus disease frequently require adjunct access. We describe the clinical outcomes of a combined upper eyelid crease and endoscopic approach for lateral frontal sinus disease with orbital extension. METHODS: A retrospective case series of 7 patients who underwent a combined lid crease approach for frontal sinus disease with orbital extension between April 2012 and October 2016 was performed. All patients had the presence of lateral frontal sinus disease as well as orbital extension as seen on a preoperative computed tomography (CT) scan. Patient demographics, indications for surgery, and perioperative findings were examined. RESULTS: Six of the 7 patients were male. Mean age was 61 years, and the indication for surgery was primarily drainage of mucopyocele and inverting papilloma (IP) in 1 patient. The frontal sinus and orbit were successfully accessed, and the respective pathology was addressed in both locations. No intraoperative or postoperative complications were encountered. There was no postoperative or cosmetic complications. CONCLUSION: The combined lid crease and endoscopic approach is a safe and effective technique for accessing the lateral frontal sinus and orbit. PMID- 29972307 TI - Design of First-Order 121.6 nm Minus Filters. AB - The equivalent parameters function in Macleod software can be used to calculate the equivalent admittance and phase thickness of multilayers, even when the material is both absorbing and dispersive, and the incidence angle is non-zero. We utilized this software to design first-order 121.6 nm minus filters based on a lanthanum trifluoride (LaF3)/magnesium fluoride (MgF2) multilayer; a Gaussian type target curve was also introduced into the design. Minus filters with bandwidths of 10 and 5 nm were obtained and had good visible light suppression and low side-lobe ripples. This designed filter will be fabricated for use in a Lyman-alpha coronagraph and imager installed in the Lyman-Alpha Solar Telescope, which will be launched by China in 2021. PMID- 29972308 TI - Enrichment of protein therapeutics and biomarkers for LC-MS quantification. PMID- 29972306 TI - Ribonucleotide discrimination by translesion synthesis DNA polymerases. AB - The well-being of all living organisms relies on the accurate duplication of their genomes. This is usually achieved by highly elaborate replicase complexes which ensure that this task is accomplished timely and efficiently. However, cells often must resort to the help of various additional "specialized" DNA polymerases that gain access to genomic DNA when replication fork progression is hindered. One such specialized polymerase family consists of the so-called "translesion synthesis" (TLS) polymerases; enzymes that have evolved to replicate damaged DNA. To fulfill their main cellular mission, TLS polymerases often must sacrifice precision when selecting nucleotide substrates. Low base-substitution fidelity is a well-documented inherent property of these enzymes. However, incorrect nucleotide substrates are not only those which do not comply with Watson-Crick base complementarity, but also those whose sugar moiety is incorrect. Does relaxed base-selectivity automatically mean that the TLS polymerases are unable to efficiently discriminate between ribonucleoside triphosphates and deoxyribonucleoside triphosphates that differ by only a single atom? Which strategies do TLS polymerases employ to select suitable nucleotide substrates? In this review, we will collate and summarize data accumulated over the past decade from biochemical and structural studies, which aim to answer these questions. PMID- 29972309 TI - Glu-C, an alternative digestive enzyme for the quantitative LC-MS/MS analysis of an IgG-based antibody biotherapeutic. AB - AIM: LC-MS/MS bottom-up quantitation of proteins has become increasingly popular with trypsin as the most commonly used protease. However, trypsin does not always yield suitable surrogate peptides. An alternative enzyme, Glu-C, was used to generate surrogate peptides for quantifying a bispecific IgG1 biotherapeutic antibody in preclinical matrices. Materials and methods: IgG1 was quantified by pellet digestion using an Acquity UPLC coupled with a Xevo TQ-S mass spectrometer. Results: Two generic LC-MS/MS methods (heavy and light chain) were developed which afforded acceptable precision and accuracy, and an lower limit of quantitation of 1 MUg/ml in three preclinical matrices. A small nonsignificant bias was observed when cynomolgus serum LC-MS/MS results were compared with electrochemiluminescent immunoassay data. CONCLUSION: Glu-C was successfully used as an alternative digestion enzyme for bottom-up quantitation of an IgG1 in matrices from multiple preclinical species, with good agreement with electrochemiluminescent immunoassay data. PMID- 29972310 TI - Efficacy of zofenopril in combination with amlodipine in patients with acute myocardial infarction: a pooled individual patient data analysis of four randomized, double-blind, controlled, prospective studies. AB - OBJECTIVE: In the four SMILE (Survival of Myocardial Infarction Long-Term Evaluation) studies, early administration of zofenopril in acute myocardial infarction (AMI) showed beneficial effects as compared to placebo and other angiotensin converting enzyme inhibitors (ACEIs). This study investigated whether the concomitant administration of the dihydropyridine calcium channel-blocker amlodipine may improve zofenopril efficacy to prevent cardiovascular events in post-AMI patients. METHODS: This was a post-hoc analysis of pooled individual patient data from the four large randomized SMILE studies. The primary endpoint was the 1-year combined occurrence of death or hospitalization for cardiovascular causes. RESULTS: In total, 3488 patients were considered, 303 (8.7%) treated with concomitant amlodipine. Baseline systolic blood pressure and prevalence of metabolic syndrome were higher in amlodipine treated patients. The 1-year occurrence of major cardiovascular outcomes was significantly reduced in patients receiving concomitant treatment with amlodipine (hazard ratio, HR = 0.66; and 95% confidence interval, CI = 0.44-0.98; p = .039). After accounting for treatment with amlodipine, the risk of cardiovascular events was significantly reduced with zofenopril compared to placebo (HR = 0.78; 95% CI = 0.63-0.97; p = .026]. Among ACEI-treated patients, the zofenopril plus amlodipine combination reduced the risk of cardiovascular events by 38%, compared to the combination of other ACEIs plus amlodipine [HR = 0.76; 95% CI = 0.61-0.94); p = .013). The prognostic benefit of concomitant treatment with zofenopril plus amlodipine was independent from blood pressure lowering. CONCLUSIONS: Zofenopril had a positive impact on prognosis in post-AMI patients, compared to other ACEIs. Concomitant administration of amlodipine may help to reduce the risk of cardiovascular events at 1 year. PMID- 29972311 TI - Critical considerations for immunocapture enrichment LC-MS bioanalysis of protein therapeutics and biomarkers. AB - In recent years, immunocapture enrichment coupled with LC-MS technology has seen more applications for the measurement of low abundant protein therapeutics and biomarkers in biological matrices. In this article, several critical considerations for the application of immunocapture enrichment to LC-MS bioanalysis of protein therapeutics and biomarkers, including reagent selection, reagent characterization, designing of capture format, etc. are discussed. All these considerations are critical in developing reliable and robust bioanalytical assays with high assay specificity and sensitivity. Successful examples using the immunocapture LC-MS approach in the quantification of biotherapeutic and low abundant protein biomarkers will also be discussed. PMID- 29972312 TI - Development of an automated, interference-free, 2D-LC-MS/MS assay for quantification of a therapeutic mAb in human sera. AB - AIM: Hybrid LC-MS/MS assays are increasingly used to quantitate proteins in biological matrices. These assays involve analyte enrichment at the protein level. Although suitability has been demonstrated, they are limited by the lack of appropriate affinity reagents and may suffer from interferences caused by binding proteins or antibodies. RESULTS: An online stable isotope standards and capture by anti-peptide antibodies assay was developed, which involves tryptic digestion of a therapeutic monoclonal antibody in human serum to destroy interfering proteins followed by enrichment using high affinity peptide antibodies. The assay was validated and compared with a standard ligand-binding assay currently used for quantification. CONCLUSION: The data show that the stable isotope standards and capture by anti-peptide antibodies-2D-LC-MS/MS assay can be used as an alternative method for measurement of monoclonal antibodies in clinical samples. PMID- 29972313 TI - The fate of abstracts presented at international ophthalmology meetings: 2- and 5 year publication rates. AB - PURPOSE: To investigate the 2- and 5-year publication rates of abstracts presented at major international ophthalmology meetings. METHODS: We analyzed a random selection of 20% of free papers and posters presented at the 2010 meeting of the Association for Research in Vision and Ophthalmology, the American Academy of Ophthalmology, the European Association for Vision and Eye Research, the Asia Pacific Academy of Ophthalmology, and the 2009 European Society of Ophthalmology meeting. The PubMed (MEDLINE) database was searched to identify matching journal articles. Data collection included: topic, geographic origin, presentation type, publication status, and impact factor. A multivariate logistic regression model was used to assess odds of publication and impact factor. RESULTS: Our analysis included 1742 research abstracts. The overall 2- and 5-year publication rates were 33.3% (n = 579) and 47.2% (n = 823), respectively. The highest publication rates were found for Association for Research in Vision and Ophthalmology (36.1% and 51.9%, p < 0.0001), paper presentations (44.5% and 60.5%, p < 0.0001), researches from Oceania (35.8% and 57.1%, p < 0.05) and North America (36.2% and 50.5%, p < 0.05), and Basic science studies (44% and 60.3%, p < 0.01). After adjustments, higher odds of publication were shown by the Association for Research in Vision and Ophthalmology and the American Academy of Ophthalmology meetings (p < 0.0001), papers (p < 0.0001), and Basic science (p < 0.05). The median impact factor was 3.20 (interquartile range = 1.90-3.40). CONCLUSION: Less than half of abstracts presented at the major ophthalmology meetings reach publication within 5 years of their initial presentation. Professionals attending meetings may consider adopting a more critical approach to the preliminary results reported in presented abstracts. Increasing publication rates and reducing potential publication bias is of interest. PMID- 29972314 TI - Spectroscopic and Chemometric Comparison of Local River Sands with the Aggregate Component in Mortars from Ancient Roman Buildings Located in the X Regio Between the Livenza and Tagliamento Rivers, Northeast Italy. AB - A combined spectroscopic-chemometric approach is used to investigate the possible sources of material exploited by the Romans to build four domus and a public thermae complex (I century BC-II century AD) located in the X Regio portion between the rivers Livenza and Tagliamento in northeast Italy. The rounded grain shapes observed in the aggregates recovered from the mortar fragments suggest that the rivers flowing close to the archaeological sites are the most likely sources of material. Coarse-grained sediment samples from nine rivers and streams in this area are examined and their similarities to the aggregate samples evaluated. The diffuse reflection Fourier transform infrared (FT-IR) spectra of the sand samples in the 63-420 um fraction, consisting mainly of carbonates and silicates, are studied and compared in suitable spectral ranges through principal components analysis. As an additional step, the relationship between the most significant scores plots and the composition of the samples is investigated using appropriate descriptive indexes obtained from the spectra. The analysis performed on the river sand spectra alone shows that the samples from the easternmost Lemene and Tagliamento rivers present a behavior distinct from that of the western rivers (Cosa, Livenza, Meduna, Meschio, and Noncello), in agreement with their present location and past history. All the aggregate spectra investigated are compatible with the spectral characteristics of the samples from the Tagliamento and Lemene rivers, except for those from the Torre di Pordenone site, which are more similar to the sand spectra of the western rivers. PMID- 29972315 TI - Calibration-Free Laser-Induced Plasma Analysis of Nanoparticle-Doped Material Using Self-Absorption Correction Methodologies. AB - The qualitative and quantitative analysis of doped nanomaterial containing iron (Fe) and tin (Sn) nanoparticles was investigated using laser-induced breakdown spectroscopy (LIBS). Doped nanoparticles were prepared via co-precipitation and hydrothermal processes. The emission spectra of ablated plasma of doped material revealed the existence of different species in the doped nanomaterial. Simple calibration-free LIBS (CF-LIBS) and internal reference self-absorption correction (IRSAC) CF-LIBS approaches were applied to emission spectra of nanomaterial for quantitative analysis. For both approaches, different spectroscopic parameters such as plasma temperature and electron number density were also determined. Plasma temperature was estimated using a Boltzmann plot and Saha-Boltzmann plot while electron number density was estimated by Stark broadening methods and Saha Boltzmann equations. Results of both calibration-free approaches were compared with a weight percentage method and other recognized techniques such as laser ablation time of flight (LA-TOF) spectroscopy and energy dispersive X-ray (EDX). We concluded that our results provide good agreement with experimental data obtained using LA-TOF spectroscopy and a small deviation from data obtained using the EDX technique. The current work confirms LIBS as a valid analytical approach for quantitative analysis of nanomaterials. PMID- 29972316 TI - Applicability of Femtosecond Laser Electronic Excitation Tagging in Combustion Flow Field Velocity Measurements. AB - Femtosecond laser electronic excitation tagging (FLEET) is a molecular tagging velocimetry technique that can be applied in combustion flow fields, although detailed studies of its application in combustion are still needed. We report the applicability of FLEET in premixed CH4-air flames. We found that FLEET can be applied in all of the combustion areas (e.g., the unburned region, the burned region and the reaction zone). The FLEET signal in the unburned region is significantly higher than that in the burned region. This technique is suitable for both lean and rich CH4-air combustion flow fields and its performance in lean flames is better than that in rich flames. PMID- 29972317 TI - Optical Spectroscopy for Analysis and Monitoring of Metalworking Fluids. AB - For various industrial manufacturing processes, water-based metalworking fluids (MWFs) are of high relevance due to their cooling and lubricating ability. They commonly form oil-in-water emulsions or solutions and hence their composition and stability is crucial for their performance in the metalworking process. To ensure a long service life of the MWF, intense monitoring is obligatory. However, examination techniques which display comprehensive and precise information about the actual state of the cooling lubricant in use are currently not available. The present study aims at testing the suitability of spectroscopic methods in terms of Fourier transform infrared, Raman, and laser-induced fluorescence spectroscopy for analyzing and monitoring MWFs. It is shown that all three techniques are capable of determining the initial composition, i.e., the ratio of water and concentrate. Fourier transform infrared provides the best performance regarding monitoring the state of the fluid over an extended period of time. The spectral signatures show distinct changes during a five-month service life in a technical environment. PMID- 29972318 TI - A Novel Pre-Processing Algorithm Based on the Wavelet Transform for Raman Spectrum. AB - Noise and fluorescent background are two major problems for acquiring Raman spectra from samples, which blur Raman spectra and make Raman detection or imaging difficult. In this paper, a novel algorithm based on wavelet transform that contains denoising and baseline correction is presented to automatically extract Raman signals. For the denoising section, the improved conventional-scale correlation denoising method is proposed. The baseline correction section, which is performed after denoising, basically consists of five aspects: (1) detection of the peak position; (2) approximate second derivative calculation based on continuous wavelet transform is performed using the Haar wavelet function to find peaks and background areas; (3) the threshold is estimated from the peak intensive area for identification of peaks; (4) correction of endpoints, spectral peaks, and peak position; and (5) determine the endpoints of the peak after subtracting the background. We tested this algorithm for simulated and experimental Raman spectra, and a satisfactory denoising effect and a good capability to correct background are observed. It is noteworthy that this algorithm requires few human interventions, which enables automatic denoising and background removal. PMID- 29972319 TI - Validated Approaches for Quantification of Bone Mineral Crystallinity Using Transmission Fourier Transform Infrared (FT-IR), Attenuated Total Reflection (ATR) FT-IR, and Raman Spectroscopy. AB - Bone mineral crystallinity is an important factor determining bone quality and strength. The gold standard method to quantify crystallinity is X-ray diffraction (XRD), but vibrational spectroscopic methods present powerful alternatives to evaluate a greater variety of sample types. We describe original approaches by which transmission Fourier transform infrared (FT-IR), attenuated total reflection (ATR) FT-IR, and Raman spectroscopy can be confidently used to quantify bone mineral crystallinity. We analyzed a range of biological and synthetic apatite nanocrystals (10-25 nm) and found strong correlations between different spectral factors and the XRD determination of crystallinity. We highlight striking differences between FT-IR spectra obtained by transmission and ATR. In particular, we show for the first time the absence of the 1030 cm-1 crystalline apatite peak in ATR FT-IR spectra, which excludes its use for analyzing crystallinity using the traditional 1030/1020 cm-1 ratio. The nu4PO4 splitting ratio was also not adequate to evaluate crystallinity using ATR FT-IR. However, we established original approaches by which ATR FT-IR can be used to determine apatite crystallinity, such as the 1095/1115 and 960/1115 cm-1 peak ratios in the second derivative spectra. Moreover, we found a simple unified approach that can be applied for all three vibrational spectroscopy modalities: evaluation of the nu1PO4 peak position. Our results allow the recommendation of the most reliable analytical methods to estimate bone mineral crystallinity by vibrational spectroscopy, which can be readily implemented in many biomineralization, archeological and orthopedic studies. In particular, we present a step forward in advancing the use of the increasingly utilized ATR FT IR modality for mineral research. PMID- 29972320 TI - Estimation of metabolisable energy and net energy of rice straw and wheat straw for beef cattle by indirect calorimetry. AB - Two experiments were conducted to estimate the metabolisable energy (ME) and net energy (NE) of rice straw and wheat straw for beef cattle. In each experiment, 16 Wandong bulls (Chinese indigenous yellow cattle) were assigned to 4 dietary treatments in a completely randomised design. Four dietary treatments included one corn silage-concentrate basal diet and three test diets in which the basal diet was partly substituted by rice straw (Exp. 1) or wheat straw (Exp. 2) at 100, 300 and 600 g/kg. Total collection of faeces and urine was conducted for 5 consecutive days after a 2-week adaption period, followed by a 4-d period where gas exchange measurements were measured by an open-circuit respiratory cage. Linear regression equations of rice straw- or wheat straw-associated ME and NE contribution in test diets against rice straw or wheat straw substitution amount were developed to predict the ME and NE values of rice straw and wheat straw. These regression equations resulted in ME and NE values (dry matter basis) of 6.76 and 3.42 MJ/kg for rice straw and 6.43 and 3.28 MJ/kg for wheat straw, respectively. The NE and ME requirement for maintenance of Wandong cattle fed a straw-based diet were 357 and 562 kJ.kg-0.75.d-1, respectively. The regression derived ME and NE have lower standard errors and coefficients of variation than those estimated by any single substitution ratio. Our study found that the regression method based on multiple point substitution is more reliable than the substitution method for energy evaluation of feedstuffs for beef cattle. PMID- 29972321 TI - Macrophage M1/M2 polarization in patients with pregnancy-induced hypertension. AB - This study aimed to validate whether macrophage polarization imbalance and abnormal cytokines production occurred in pregnancy-induced hypertension (PIH) patients. PIH women (n = 26) were enrolled and the level of biochemical parameters were determined. The percentage of CD86- and CD163-positive cells, representing M1 and M2 macrophages, were determined by flow cytometry. The concentrations of cytokines (TNF-alpha, IL-1beta, IL-4, IL-13, and IL-10) were determined using enzyme-linked immunosorbent assay kit. THP-1 cells were incubated with 10% serum from PIH and control groups, and then macrophage polarization and cytokines production were analyzed. The levels of high-density lipoprotein cholesterol and apolipoprotein A1 were significantly lower, and the levels of fasting blood glucose, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein a were significantly higher in the PIH group than that in the control group. The PIH group contained a significant higher percentage of CD86-positive cells (M1) and a significant lower percentage of CD163-positive cells (M2), representing higher M1/M2 ratio, than the control group. The PIH group expressed higher concentrations of TNF-alpha and IL-1beta, and expressed lower concentrations of IL-4, IL-10, and IL-13 than the control group. The in vitro experiment also showed macrophage polarization imbalance and abnormal cytokines production in THP-1 cells treated with PIH serum as compared with that treated with control serum. Macrophage polarization imbalance and abnormal cytokines production occurred in PIH patients and in THP-1 cells treated with PIH serum. PMID- 29972323 TI - Quantitation of intact monoclonal antibody in biological samples: comparison of different data processing strategies. AB - AIM: Sample extraction using immuno-affinity capture coupled with LC-high resolution mass spectrometer has recently emerged as a novel approach for the determination of concentrations of large molecules at intact level in biological matrix. METHODOLOGY: In the current work, different data processing strategies for intact protein bioanalysis, deconvoluted mass spectra or extracted ion chromatogram, were applied to quantitate monoclonal antibody in biological samples for comparison of assay performance. CONCLUSION: Both deconvolution and extracted ion chromatogram strategies showed similar selectivity, sensitivity, accuracy and precision. The monkey pharmacokinetics data obtained from both approaches agreed well with each other, and agreed with data obtained from surrogate peptide approach. The pros and cons, and optimal parameters of each approach were discussed. PMID- 29972324 TI - Suicide Risk Assessment. PMID- 29972326 TI - Investigation on the effect of nanoparticle size on the blood-brain tumour barrier permeability by in situ perfusion via internal carotid artery in mice. AB - The blood-brain barrier (BBB) is a limiting factor in nanoparticle drug delivery to the brain, and various attempts have been made to overcome it for efficient drug delivery. Nowadays, it was considered as further issue for brain-drug delivery that the nanoparticle delivered to brain through the BBB reach cancer cells in tumour tissue. In this study, we investigated the effect of nanoparticle size on blood-brain tumour barrier (BBTB) permeation of fluorescence-labelled gold nanoparticles (AuNPs) in a mouse model of orthotopic glioblastoma multiforme (GBM), established by intracranial implantation of luciferase-expressing human glioblastoma U87MG cells. AuNPs sized 10, 50, and 100 nm were perfused into the GBM mice via internal carotid artery (ICA) for 5 min. Immediately after perfusion, the brains were fixed and prepared for LSCM observation. The AuNPs distribution in the normal and tumorous brain tissues was analysed qualitatively and quantitatively. Higher distribution of AuNPs was observed in the tumorous tissue than in the normal tissue. Furthermore, the smallest nanoparticle, 10 nm AuNPs, was widely distributed in the brain tumour tissue, whereas the 50 and 100 nm AuNPs were located near the blood vessels. Therefore, nanoparticle size affected the permeation of nanoparticles from the blood into brain tumour tissue. PMID- 29972322 TI - Void spot assay procedural optimization and software for rapid and objective quantification of rodent voiding function, including overlapping urine spots. AB - Mouse urinary behavior is quantifiable and is used to pinpoint mechanisms of voiding dysfunction and evaluate potential human therapies. Approaches to evaluate mouse urinary function vary widely among laboratories, however, complicating cross-study comparisons. Here, we describe development and multi institutional validation of a new tool for objective, consistent, and rapid analysis of mouse void spot assay (VSA) data. Void Whizzard is a freely available software plugin for FIJI (a distribution of ImageJ) that facilitates VSA image batch processing and data extraction. We describe its features, demonstrate them by evaluating how specific VSA method parameters influence voiding behavior, and establish Void Whizzard as an expedited method for VSA analysis. This study includes control and obese diabetic mice as models of urinary dysfunction to increase rigor and ensure relevance across distinct voiding patterns. In particular, we show that Void Whizzard is an effective tool for quantifying nonconcentric overlapping void spots, which commonly confound analyses. We also show that mouse genetics are consistently more influential than assay design parameters when it comes to VSA outcomes. None of the following procedural modifications to reduce overlapping spots masked these genetic-related differences: reduction of VSA testing duration, water access during the assay period, placement of a wire mesh cage bottom on top of or elevated over the filter paper, treatment of mesh with a hydrophobic spray, and size of wire mesh opening. The Void Whizzard software and rigorous validation of VSA methodological parameters described here advance the goal of standardizing mouse urinary phenotyping for comprehensive urinary phenome analyses. PMID- 29972327 TI - Influence of Community-Level Cultural Beliefs about Autism on Families' and Professionals' Care for Children. AB - This qualitative study aimed to understand how community-level cultural beliefs affect families' and professionals' care for children with autism and developmental delays in immigrant communities, as a first step towards promoting early identification and access to early intervention services. The study was part of the larger New York City (NYC) Korean Community Autism Project, which was designed to identify strategies to increase awareness of autism and reduce delays in treatment seeking within the NYC Korean-American community. Our study elicited early childcare workers' and church leaders' beliefs about autism and developmental disorders and, in particular, early intervention. We also elicited responses to newly developed outreach materials targeting this community. An inductive approach was used to identify concepts and categories associated with autism. Our study confirmed that discomfort, stigma and discrimination are the prevailing community attitudes toward autism and developmental disorders in the Korean-American community. Families' and professionals' understanding of autism and their care for children are affected by these community beliefs. Approaching immigrant communities with general information about child development and education rather than directly talking about autism and developmental disorders is likely to engage more families and professionals in need for diagnostic evaluation and early intervention for autism. PMID- 29972328 TI - An evaluation of the pharmacotherapy for interstitial cystitis. AB - INTRODUCTION: Interstitial cystitis (IC) and bladder pain syndrome (BPS) are chronic conditions that can be debilitating for patients. There is no consensus as to their etiology, and there are many proposed treatment algorithms. Oftentimes multimodal therapy, such as combining behavioral modification and physical therapy alongside pharmacotherapies, will be utilized. With the various treatment options available to patients and providers, there is an ever-growing need to implement evidence-based therapies. Areas covered: The authors explore the different pharmacotherapies as commonly recommended in the American Urological Association (AUA) and European Association of Urology (EAU) multitiered guidelines for IC/BPS treatment as well as other investigational therapies. Pharmacotherapies targeting bladder, pelvic, and/or systemic factors in the overall treatment of IC/BPS are discussed with a particular focus on evidence-based guideline therapies. This article also looks at emerging therapies of interest. Expert opinion: IC/BPS is a syndrome that requires a multimodal approach, including clinical phenotyping and directed therapy based on the patient's symptoms. The AUA and EAU provide guidelines for practitioners to follow, but adequate treatment requires the therapy to be targeted toward the patient's phenotypic domain. PMID- 29972330 TI - Paths of causal influence from prenatal inflammation and preterm gestation to childhood asthma symptoms. AB - INTRODUCTION: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim was to investigate paths of assumed causality leading from foetal inflammatory response syndrome (FIRS) to asthma symptoms in preterms. METHODS: Demographic, antenatal, delivery and outcome data were collected from 262 infants with less than 32 completed weeks of gestational age over a 10-year period in a prospective cohort study. The presence of symptoms of asthma beyond the age of 5 years was the primary outcome measure. The causal effect of FIRS on childhood asthma was tested with three different logistic regression models and two structural equation models (SEM). RESULTS: FIRS (OR = 4.7) and subsequent chronic lung disease of prematurity (OR = 7.7) and early childhood wheezing (OR = 9.5) are the most important risk factors for development of asthma symptoms in children born with less than 32 weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (-0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (-0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW. CONCLUSION: Prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. This influence is mainly related to structural and developmental lung abnormalities initiated in utero as consequences of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis. PMID- 29972329 TI - Evidence from functional ultrasound imaging of enhanced contralesional microvascular response to somatosensory stimulation in acute middle cerebral artery occlusion/reperfusion in rats: A marker of ultra-early network reorganization? AB - Following middle cerebral artery (MCA) stroke, enhanced contralesional evoked responses have been consistently reported both in man and rodents as part of plastic processes thought to influence motor recovery. How early this marker of large-scale network reorganization develops has however been little addressed, yet has clinical relevance for rehabilitation strategies targeting plasticity. Previous work in mice has reported enhanced contralesional responses to unaffected-side forepaw stimulation as early as 45 min after MCA small branch occlusion. Using functional ultrasound imaging (fUSi) in anesthetized rats subjected to distal temporary MCA occlusion (MCAo), we assessed here (i) whether enhanced contralesional responses also occurred with unaffected-side whisker pad stimulation, and if so, how early after MCAo; and (ii) the time course of this abnormal response during occlusion and after reperfusion. We replicate in a more proximal MCA occlusion model the earlier findings of ultra-early enhanced contralesional evoked responses. In addition, we document this phenomenon within minutes after MCAo, and its persistence throughout the entire 90-min occlusion as well as 90-min reperfusion periods studied. These findings suggest that plastic processes may start within minutes following MCAo in rodents. If replicated in man, they might have implications regarding how early plasticity-enhancing therapies can be initiated after stroke. PMID- 29972331 TI - Predictors of prior asthma specialist care among pediatric patients seen in the emergency department for asthma. AB - BACKGROUND: Asthma guidelines recommend specialist care for patients experiencing poor asthma outcomes during emergency department (ED) visits. The prevalence and predictors of asthma specialist care among an ED population seeking pediatric asthma care are unknown. OBJECTIVE: To examine, in an ED population, factors associated with prior asthma specialist use based on parental reports of prior asthma morbidity and asthma care. METHODS: Parents of children ages 0 to 17 years seeking ED asthma care were surveyed regarding socio-demographics, asthma morbidity, asthma management and current asthma specialist care status. We compared prior asthma care and morbidity between those currently cared for by an asthma specialist versus not. Multivariable logistic regression models to predict factors associated with asthma specialist use were adjusted for parent education and insurance type. RESULTS: Of 150 children (62% boys, mean age 4.7 years, 69% Hispanic), 22% reported asthma specialist care, 75% did not see a specialist and for 3% specialist status was unknown. Care was worse for those not seeing a specialist, including under-use of controller medications (24% vs. 64%, p < 0.001) and asthma action plans (20% vs. 62%, p < 0.001). Multivariable logistic regression revealed that lack of recommendation by the primary care physician reduced the odds of specialist care (OR 0.01, 95% CI <0.01, 0.05, p < 0.001). CONCLUSIONS: Asthma specialist care was infrequent among this pediatric ED population, consistent with the sub-optimal chronic asthma care we observed. Prospective trials should further investigate if systematic referral to asthma specialists during/after an ED encounter would improve asthma outcomes. PMID- 29972332 TI - EXPRESS: The Efficacy and Safety of Pulmonary Vasodilators in Patients with Fontan Circulation: a Meta-Analysis of Randomized-Controlled Trials. PMID- 29972333 TI - Senolytic drugs in respiratory medicine: is it an appropriate therapeutic approach? AB - INTRODUCTION: Aging is the major risk factor for most of the chronic diseases. Cellular senescence is one of the main hallmarks of aging. A growing body of evidence implicates accelerated mechanisms of aging, including cellular senescence, in idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) pathogenesis. Senolytics are pharmaceutical agents that eliminate senescent cells, thus blocking tissue degeneration and late life complications and allowing tissue regeneration. Areas covered: The potential use of senolytic drugs in respiratory medicine is examined and discussed. Expert opinion: The promising signal generated by preclinical studies supports proof-of principle clinical studies with senolytic agents in the treatment of IPF, but this signal is not very strong, and furthermore, senolytic drugs could be detrimental in IPF patients. On the other hand, the preclinical evidence that these agents are able to influence the natural history of COPD is still lacking. COPD is a very heterogeneous lung disease presenting different (mixed) phenotypes. Given the difference in underlying pathology of these phenotypes, it can be envisaged that lung aging is more or differently involved in some of these phenotypes than others. Consequently, it will be difficult to determine which COPD patient will benefit from a treatment with senolytics. PMID- 29972334 TI - Rapid glucocorticoid tapering therapy to reduce mortality from pneumocystis pneumonia in patients with rheumatic disease. AB - OBJECTIVE: Pneumocystis pneumonia (PCP) is a serious complication in patients with rheumatic diseases who are receiving immunosuppressive therapy. These patients have a higher mortality from PCP than those with human immunodeficiency virus. We examined factors associated with poor prognosis in patients with rheumatic diseases and evaluated PCP treatment in this population. METHODS: This retrospective, single-center, observational cohort study included 31 patients with rheumatic diseases who were admitted to Juntendo University Hospital for PCP treatment from June 2006 to December 2017. The primary outcome was non-disease specific mortality at discharge. RESULTS: The median age at PCP diagnosis was 64 years. The survival rate was 61.3% (19/31). Twelve patients died, in all cases due to respiratory failure due to PCP. Among variables at PCP diagnosis and those related to PCP treatment, the presence of coexisting pulmonary diseases and greater glucocorticoid dose at PCP diagnosis were associated with higher mortality. The mortality related to biological agents for PCP was low. Rapid tapering of glucocorticoids improved survivability. CONCLUSION: In the treatment of PCP in patients with rheumatic diseases, rapid tapering of glucocorticoids was associated with a higher survival rate than the use of conventional therapy. PMID- 29972335 TI - Sedentary behavior after stroke: A new target for therapeutic intervention. AB - Over the last 10 years, evidence has emerged that too much sedentary time (e.g. time spent sitting down) has adverse effects on health, including an increased risk of cardiovascular disease incidence and mortality. A considerable amount of media attention has been given to the topic. The current UK activity guidelines recommend that all adults should minimize the amount of time spent being sedentary for extended periods. How best to minimize sedentary behavior is a focus of ongoing research. Understanding the impact of sedentary behaviors on the health of people with stroke is vital as they are some of the most sedentary individuals in society. Implementing strategies to encourage regular, short breaks in sedentary behaviors has potential to improve health outcomes after stroke. Intervention work already conducted with adults and older adults suggests that sedentary behaviors can be changed. A research priority is to explore the determinants of sedentary behavior in people with stroke and to develop tailored interventions. PMID- 29972336 TI - Hyaluronated imatinib liposomes with hybrid approach to target CD44 and P-gp overexpressing MDR cancer: an in-vitro, in-vivo and mechanistic investigation. AB - Multi Drug Resistance (MDR) of cancer cells is a constant threat to the clinically used drugs as well as new drug development. In present work, we aimed to assess in-vitro as well as in-vivo efficacy of the developed Imatinib loaded liposomes in MDR cancer. An array of tests was also carried out to comprehensively understand the bio-mechanism that enable these nanocarriers to modulate P-gp activity. Hyaluronic acid coated, Imatinib mesylate containing lipsomes (HA-LIPO-IM) were analysed through in-vitro and in-vivo studies in MDR cancer cells and tumour models. Effect of developed hyaluronated liposomes on various biomolecular mechanisms was also evaluated. Around 3.5 times lower IC50 for HA-LIPO-IM in comparison to drug solution in HT-29 and Colo-320 cells proved the enhanced action of the drug in MDR cells. HA-LIPO formulations were demonstrated to have inhibitory effect on ATPase enzyme. Molecular masking of Imatinib mesylate and CD-44 mediated endocytosis were also found responsible for anti-MDR effect. In-vivo studies revealed the prolonged tumour accumulation and 4 fold increase in tumour regression efficacy of HA-LIPO-IM in comparison to free drug solution. The work demonstrated the target specific accumulation of HA-LIPO IM in CD-44 overexpressing cancer cells through P-gp modulation. PMID- 29972337 TI - Phase analysis in maximal sprinting: an investigation of step-to-step technical changes between the initial acceleration, transition and maximal velocity phases. AB - The aim of this study was to investigate spatiotemporal and kinematic changes between the initial acceleration, transition and maximum velocity phases of a sprint. Sagittal plane kinematics from five experienced sprinters performing 50-m maximal sprints were collected using six HD-video cameras. Following manual digitising, spatiotemporal and kinematic variables at touchdown and toe-off were calculated. The start and end of the transition phase were identified using the step-to-step changes in centre of mass height and segment angles. Mean step-to step changes of spatiotemporal and kinematic variables during each phase were calculated. Firstly, the study showed that if sufficient trials are available, step-to-step changes in shank and trunk angles might provide an appropriate measure to detect sprint phases in applied settings. However, given that changes in centre of mass height represent a more holistic measure, this was used to sub divide the sprints into separate phases. Secondly, during the initial acceleration phase large step-to-step changes in touchdown kinematics were observed compared to the transition phase. At toe-off, step-to-step kinematic changes were consistent across the initial acceleration and transition phases before plateauing during the maximal velocity phase. These results provide coaches and practitioners with valuable insights into key differences between phases in maximal sprinting. PMID- 29972338 TI - Corrigendum. AB - 10th World Research Congress of the European Association for Palliative Care (EAPC). Palliative Medicine, May 2018 32:1_suppl 3-330, doi: 10.1177/0269216318769196. PMID- 29972339 TI - Exploring the barriers and incentive architecture for modifying smoke exposures among asthmatics. AB - BACKGROUND: The socio-structural barriers for reducing secondhand smoke exposure (SHSe) among children with asthma may be insurmountable for low-income caregivers. Health promoting financial incentives (HPFIs) are increasingly being used in the adult population to motivate and sustain tobacco-reduction behaviors. We assessed barriers to SHSe reduction and means to overcome them through the design of an HPFI-based, caregiver-targeted SHSe reduction study. METHODS: Using a mixed-methods design, we conducted semi-structured in-depth interviews among low-income primary caregivers of children with asthma residing in Baltimore City. Quantitative data using an online survey were used to augment interview findings. RESULTS: Home smoking restrictions were a frequently referenced strategy for decreasing SHSe, but interviewees (n = 22) described the complex social pressures that undermine reduction efforts. Caregivers redirected conversations from broadly implemented smoking bans towards targeted reduction strategies among mothers and members of their social network who are active smokers. Participants converged on the notion that sustainable SHSe reduction strategies are realizable only for mothers who are active smokers, possess high self-efficacy and social structures that promote cessation. Survey data (n = 56) clarified the multiple contexts that underlie pediatric SHSe and preferred HPFI architecture that included fixed, recurrent payments contingent on reduced nicotine biomarkers and completion of basic asthma education classes. CONCLUSIONS: Based on the combined analyses, we envision testing a HPFI-based study design whose optimal target population included low-income caregivers and members of their social network where incentives are tied to pediatric biomarkers and asthma education-an integrated approach that has not yet been used in pediatric tobacco studies. PMID- 29972340 TI - Multifaceted activity of N-acetyl-l-cysteine in chronic obstructive pulmonary disease. AB - INTRODUCTION: N-acetyl-l-cysteine (NAC), a derivative of the naturally occurring amino acid l-cysteine, is a mucolytic agent that may also act as an antioxidant by providing cysteine intracellularly for increased production of glutathione. It is also used for the treatment of acetaminophen overdose. Areas covered: The recent international recommendations for the treatment of chronic obstructive pulmonary disease (COPD) report that NAC, because of its mucolytic activity, reduces acute exacerbation of COPD (AECOPD) with a modest improvement in health status. However, NAC is a pleiotropic drug with heterogeneous pharmacologic characteristics that certainly include mucolytic activity, but also has anti infective properties and specific antioxidant and anti-inflammatory effects in the airways. Thus, the mechanisms leading to the protective role of this agent against AECOPD need to be adequately addressed. Expert commentary: The protective effect of NAC against AECOPD seems to be related not only to its well-documented mucolytic activity but also to activation of antioxidant pathways, inhibition of pro-oxidant and inflammatory pathways, and modulation of human bronchial tone. Thus, the dogma that NAC acts prevalently as a mucolytic agent is outdated, and the hypothesis that its anti-inflammatory effect is secondary to the antioxidant activity has been rejected. PMID- 29972342 TI - Adjuvant anti-angiogenic therapy enhances chemotherapeutic uptake in a murine model of head and neck cancer. AB - Intratumoural metabolic demands result in excessive angiogenic cytokine release leading to unorganised vasculature. Resultant fluid dynamics oppose blood flow and drug penetration due to a marked increase in interstitial fluid hydrostatic pressure. It is hypothesised that anti-angiogenic therapy may function to 'prune' vasculature and lead to improved chemotherapeutic penetration. Subcutaneous, OSC19 tumour bearing mice (n = 5/dose/agent) were administered varying doses of an anti-mouse VEGFR2 (DC101) or an anti-mouse VEGFR3 (31C1) -3 d, -1 d, 0 d, +1 d and +3 d prior to 200 ug of cetuximab fluorescently labelled with IRDye800CW. Fluorescence imaging of tumours was performed 10 d post cetuximab-IRDye800CW dose to monitor therapeutic uptake. Co-administration of dual anti-angiogenic agents at 50-50%, 75-25% and 25-75% using optimal dose and time (-1 d 10 mg/kg anti VEGFR2 and -1 d 40 mg/kg anti-VEGFR3) was also evaluated. In order to establish vessel normalisation, NG2 (pericyte marker) and CD31 (endothelial cells) ratios were assessed during immunohistochemical staining of tumour sections. Twenty mg/kg anti-VEGFR3 + 5 mg/kg anti-VEGFR2 significantly (p < .0005) reduced tumour size (-73%) compared to control (59%). The 20 mg/kg anti-VEGFR3 + 5 mg/kg anti VEGFR2 and 30 mg/kg anti-VEGFR3 + 2.5 mg/kg anti-VEGFR2 significantly (p < .0004) improved percent-injected cetuximab-IRDye800CW dose/gram tumour tissue compared to other groups. Adjuvant, dual anti-angiogenic therapy targeting VEGFR2 and VEGFR3 significantly enhances tumour chemotherapeutic uptake compared to control. PMID- 29972343 TI - The palliative care knowledge of nursing home staff: The EU FP7 PACE cross sectional survey in 322 nursing homes in six European countries. AB - BACKGROUND: The provision of high-quality palliative care in nursing homes (NHs) is a major challenge and places demands on the knowledge and skills of the staff. AIM: This study assesses the palliative care knowledge of staff in NHs in Europe. DESIGN: Cross-sectional study using structured survey Setting/participants: Nurses and care assistants working in 322 representative samples of NHs in Belgium, the Netherlands, England, Finland, Poland and Italy. Palliative care knowledge is measured with the Palliative Care Survey. Scores on the scales range between 0 and 1; higher scores indicate more knowledge. RESULTS: A total of 3392 NH-staff were given a questionnaire, and 2275 responded (67%). Knowledge of basic palliative care issues ranged between 0.20 in Poland (95% confidence interval (CI) 0.19; 0.24) and 0.61 in Belgium (95% CI 0.59; 0.63), knowledge of physical aspects that can contribute to pain ranged between 0.81 in Poland (95% CI 0.79; 0.84) and 0.91 in the Netherlands (95% CI 0.89; 0.93), and knowledge of psychological reasons that can contribute to pain ranged between 0.56 in England (95% CI 0.50; 0.62) and 0.87 in Finland (95% CI 0.83; 0.90). Factors associated with knowledge were country, professional role and having undertaken formal training in palliative care. CONCLUSIONS: Knowledge of nurses and care assistants concerning basic palliative care issues appears to be suboptimal in all participating countries, although there is substantial heterogeneity. Education of nursing staff needs to be improved across, but each country may require its own strategy to address the unique and specific knowledge gaps. PMID- 29972344 TI - Oximetry use in obstructive sleep apnea. AB - INTRODUCTION: Overnight oximetry has been proposed as an accessible, simple, and reliable technique for obstructive sleep apnea syndrome (OSAS) diagnosis. From visual inspection to advanced signal processing, several studies have demonstrated the usefulness of oximetry as a screening tool. However, there is still controversy regarding the general application of oximetry as a single screening methodology for OSAS. Areas covered: Currently, high-resolution portable devices combined with pattern recognition-based applications are able to achieve high performance in the detection of this disease. In this review, recent studies involving automated analysis of oximetry by means of advanced signal processing and machine learning algorithms are analyzed. Advantages and limitations are highlighted and novel research lines aimed at improving the screening ability of oximetry are proposed. Expert commentary: Oximetry is a cost effective tool for OSAS screening in patients showing high pretest probability for the disease. Nevertheless, exhaustive analyses are still needed to further assess unattended oximetry monitoring as a single diagnostic test for sleep apnea, particularly in the pediatric population and in populations with significant comorbidities. In the following years, communication technologies and big data analyses will overcome current limitations of simplified sleep testing approaches, changing the detection and management of OSAS. PMID- 29972341 TI - Nutrient limitation affects presynaptic structures through dissociable Bassoon autophagic degradation and impaired vesicle release. AB - Acute mismatch between metabolic requirements of neurons and nutrients/growth factors availability characterizes several neurological conditions such as traumatic brain injury, stroke and hypoglycemia. Although the effects of this mismatch have been investigated at cell biological level, the effects on synaptic structure and function are less clear. Since synaptic activity is the most energy demanding neuronal function and it is directly linked to neuronal networks functionality, we have explored whether nutrient limitation (NL) affects the ultrastructure, function and composition of pre and postsynaptic terminals. We show that upon NL, presynaptic terminals show disorganized vesicle pools and reduced levels of the active zone protein Bassoon (but not of Piccolo). Moreover, NL triggers an impaired vesicle release, which is reversed by re-administration of glucose but not by the blockade of autophagic or proteasomal protein degradation. This reveals a dissociable correlation between presynaptic architecture and vesicle release, since restoring vesicle fusion does not necessarily depend from the rescue of Bassoon levels. Thus, our data show that the presynaptic compartment is highly sensitive to NL and the rescue of presynaptic function requires re-establishment of the metabolic supply rather than preventing local protein degradation. PMID- 29972345 TI - Identification and characterization of a rhamnosyltransferase involved in rutin biosynthesis in Fagopyrum esculentum (common buckwheat). AB - Rutin, a 3-rutinosyl quercetin, is a representative flavonoid distributed in many plant species, and is highlighted for its therapeutic potential. In this study, we purified uridine diphosphate-rhamnose: quercetin 3-O-glucoside 6"-O rhamnosyltransferase and isolated the corresponding cDNA (FeF3G6"RhaT) from seedlings of common buckwheat (Fagopyrum esculentum). The recombinant FeF3G6"RhaT enzyme expressed in Escherichia coli exhibited 6"-O-rhamnosylation activity against flavonol 3-O-glucoside and flavonol 3-O-galactoside as substrates, but showed only faint activity against flavonoid 7-O-glucosides. Tobacco cells expressing FeF3G6"RhaT converted the administered quercetin into rutin, suggesting that FeF3G6"RhaT can function as a rhamnosyltransferase in planta. Quantitative PCR analysis on several organs of common buckwheat revealed that accumulation of FeF3G6"RhaT began during the early developmental stages of rutin accumulating organs, such as flowers, leaves, and cotyledons. These results suggest that FeF3G6"RhaT is involved in rutin biosynthesis in common buckwheat. PMID- 29972347 TI - Clinical outcome and time trends of surgically treated renal cell carcinoma between 1986 and 2010: results from a single centre in Sweden. AB - OBJECTIVE: The aims of this study were to create a cohort of retrospectively collected renal cell carcinoma (RCC) specimens to be used a basis for prognostic molecular studies, and to investigate the outcome and time trends in patients surgically treated for RCC in a single-centre cohort. MATERIALS AND METHODS: Patients undergoing surgery for RCC between 1986 and 2010 were included in the study. Medical records were reviewed, and the diagnostic tissue was re-evaluated according to a modern classification. The change in patient and tumour characteristics over time was analysed. RESULTS: The study included 345 patients. Smaller tumours, as indicated by primary tumour diameter, tumour (T) stage and American Joint Committee on Cancer (AJCC) stage, were found more frequently in later years compared to the early 1990s. No changes in the clinical outcome for the patients were seen among the time periods investigated. Increasing T stage, AJCC stage, primary tumour diameter and decreasing haemoglobin levels were associated with cancer-specific mortality in univariate analysis. A high calcium level was significantly associated with increased cancer-specific mortality (hazard ratio = 4.25, 95% confidence interval 1.36-13.28) in multivariate analysis. CONCLUSIONS: This study on patients who underwent surgery for RCC from 1986 to 2010 at a single institution in Sweden indicates that there has been a change in tumour characteristics of patients diagnosed with RCC over time. It was also shown that calcium levels were an independent prognostic factor for cancer specific mortality in this cohort. This cohort could provide a valuable basis for further molecular studies. PMID- 29972346 TI - Sexuality and childbearing as it is experienced by women living with HIV in Sweden: a lifeworld phenomenological study. AB - The effectiveness of antiretroviral treatment has reduced sexual HIV transmission and mother-to-child-transmission. To optimally support women living with HIV, health care providers need deepened knowledge about HIV, sexuality and childbearing. The aim of this study was to describe the phenomenon sexuality and childbearing as experienced by women living with HIV in Sweden. Data were collected by phenomenon-oriented interviews with 18 HIV-positive women. A reflective lifeworld analysis based on phenomenological philosophy was conducted, describing the meaning structure of the phenomenon. The essence of the phenomenon is that perceptions about HIV and its contagiousness profoundly influence sexual habits and considerations in relation to pregnancy and childbearing. These perceptions are formed in combination with knowledge and interpretations about HIV by the women themselves and by their environments. The essence is further described by its constituents: Risk of transmission imposes demands on responsibility; The contagiousness of HIV limits sexuality and childbearing; Knowledge about HIV transmission provides confident choices and decisions; and To re-create sexuality and childbearing. Although HIV has a low risk of transmission if being well treated, our study shows that HIV-positive women feel more or less contagious, which influences sexuality and decision-making in relation to become pregnant and give birth. PMID- 29972348 TI - Hypervirulent Klebsiella pneumoniae, a 5-year study in a French ICU. AB - PURPOSE: Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a leading cause of severe community-acquired pneumonia, liver abscess and disseminated infection in the Far East. Data regarding the incidence, clinical features and microbiological characteristics related to hvKp infections in the Western world are scarce. METHODOLOGY: The incidence, clinical features and microbiological characteristics of hvKp infections were investigated through a 5-year survey conducted in a single French intensive care unit. K. pneumoniae strains were screened for hypermucoviscosity based on a string test. Multilocus sequence typing and multiplex PCR analysis targeting virulence genes were performed on string test-positive strains. RESULTS: Over a 53-month period, a total of 59 infections due to K. pneumoniae were identified including 26 community-onset infections. Twelve hvKp infections were documented, accounting for 46.1 % of community-acquired K. pneumoniae. Community-acquired pneumonia (n=6), aspiration pneumonia (n=4) and liver abscess (n=2) represented initial sites and mode of infection. Compared to non-hvKp infections, patients with hvKp infections displayed higher rates of multi-organ failure (83.3 % vs 35.7 %; P=0.04), but mortality rates were not different (50 % vs 35 %; P=0.71). Strains K1/ST23 (n=5) and K2/ST86 (n=5) predominated. All hvKp strains displayed wild-type susceptibility. CONCLUSION: hvKp represent a potentially underestimated cause of fatal infections in the Western world. PMID- 29972349 TI - Liver involvement is associated with blood culture positivity and high agglutination titre in patients with brucellosis in Turkey. AB - We investigated the incidence of and risk factors for liver involvement (LI) in patients with brucellosis in Turkey. Diagnosis was established by blood cultures (BCs) or compatible clinical presentation accompanied by serological evidence. Patients received either a combination of doxycycline plus rifampin for 6 weeks or doxycycline for 6 weeks plus streptomycin intramuscularly for the first 2 weeks. Liver function tests, including those for alanine (ALT) and aspartate aminotransferase (AST) levels, were monitored before and at the end of treatment. One hundred and ninety-five patients were included in the study. Seventy patients had elevated transaminases before treatment. Twenty-six patients had a positive BC for brucellosis. In multivariate analysis, BC positivity (OR=2.44, 95 % CI: 1.03-5.78, P=0.043) and serum agglutination titre (SAT) (OR=1.001, 95 % CI: 1.00 1.002, P=0.018) were found to be associated with LI. Serum aminotransferase levels were normalized in all patients with brucellosis. BC positivity and high SAT are independent factors that are associated with LI in patients with brucellosis. PMID- 29972350 TI - A clinical isolate of Escherichia coli co-harbouring mcr-1 and blaNDM-5 in Japan. AB - The mcr-1 gene encodes a phosphoethanolamine transferase, which confers resistance to colistin by transferring phosphoethanolamine to lipid A. This study describes the emergence of a colistin- and carbapenem-resistant clinical isolate of Escherichia coli harbouring mcr-1 and blaNDM-5 genes, located on 90 and 150 Kb plasmids, respectively. The isolate belonged to ST132. This is the first report of a clinical isolate in Japan co-harbouring mcr-1 and blaNDM-5. PMID- 29972351 TI - Timing of ESCRT-III protein recruitment and membrane scission during HIV-1 assembly. AB - The Endosomal Sorting Complexes Required for Transport III (ESCRT-III) proteins are critical for cellular membrane scission processes with topologies inverted relative to clathrin-mediated endocytosis. Some viruses appropriate ESCRT-IIIs for their release. By imaging single assembling viral-like particles of HIV-1, we observed that ESCRT-IIIs and the ATPase VPS4 arrive after most of the virion membrane is bent, linger for tens of seconds, and depart ~20 s before scission. These observations suggest that ESCRT-IIIs are recruited by a combination of membrane curvature and the late domains of the HIV-1 Gag protein. ESCRT-IIIs may pull the neck into a narrower form but must leave to allow scission. If scission does not occur within minutes of ESCRT departure, ESCRT-IIIs and VPS4 are recruited again. This mechanistic insight is likely relevant for other ESCRT dependent scission processes including cell division, endosome tubulation, multivesicular body and nuclear envelope formation, and secretion of exosomes and ectosomes. PMID- 29972352 TI - Multiple inputs ensure yeast cell size homeostasis during cell cycle progression. AB - Coordination of cell growth with division is essential for proper cell function. In budding yeast, although some molecular mechanisms responsible for cell size control during G1 have been elucidated, the mechanism by which cell size homeostasis is established remains to be discovered. Here, we developed a new technique based on quantification of histone levels to monitor cell cycle progression in individual cells with unprecedented accuracy. Our analysis establishes the existence of a mechanism controlling bud size in G2/M that prevents premature onset of anaphase, and controls the overall size variability. While most G1 mutants do not display impaired size homeostasis, mutants in which cyclin B-Cdk regulation is altered display large size variability. Our study thus demonstrates that size homeostasis is not controlled by a G1-specific mechanism alone but is likely to be an emergent property resulting from the integration of several mechanisms that coordinate cell and bud growth with division. PMID- 29972354 TI - Ultrasound-guided hydrodissection for removal of precariously sited contraceptive implants. PMID- 29972355 TI - Sayana Press and a case of likely lipoatrophy. PMID- 29972353 TI - Loss of Atoh1 from neurons regulating hypoxic and hypercapnic chemoresponses causes neonatal respiratory failure in mice. AB - Atoh1-null mice die at birth from respiratory failure, but the precise cause has remained elusive. Loss of Atoh1 from various components of the respiratory circuitry (e.g. the retrotrapezoid nucleus (RTN)) has so far produced at most 50% neonatal lethality. To identify other Atoh1-lineage neurons that contribute to postnatal survival, we examined parabrachial complex neurons derived from the rostral rhombic lip (rRL) and found that they are activated during respiratory chemochallenges. Atoh1-deletion from the rRL does not affect survival, but causes apneas and respiratory depression during hypoxia, likely due to loss of projections to the preBotzinger Complex and RTN. Atoh1 thus promotes the development of the neural circuits governing hypoxic (rRL) and hypercapnic (RTN) chemoresponses, and combined loss of Atoh1 from these regions causes fully penetrant neonatal lethality. This work underscores the importance of modulating respiratory rhythms in response to chemosensory information during early postnatal life. PMID- 29972356 TI - Contraceptive method use among women and its association with age, relationship status and duration: findings from the third British National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - BACKGROUND: One in six pregnancies in Britain are unplanned. An understanding of influences on contraceptive method choice is essential to provision compatible with users' lifestyles. This study describes contraceptive method use by age, and relationship status and duration, among women in Britain. METHODS: Data from women participating in the third British National Survey of Sexual Attitudes and Lifestyles were used to describe contraceptive use grouped as: unreliable method or none; barrier methods; oral/injectable hormonal methods; and long-acting reversible contraception. A total of 4456 women at risk of pregnancy were used to examine associations between contraception use, age, relationship type and duration. Age-stratified odds ratios for contraceptive use by relationship type and duration were estimated using binary logistic regression. RESULTS: Some 26.0% of 16-49-year-olds used hormonal contraception as their usual method. Use of hormonal and barrier methods was highest in the youngest age group and decreased with age; the reverse was true for use of unreliable methods or none. Barrier method use was higher in short-term relationships among younger participants; this was not seen among older respondents. Duration was more strongly associated with usual contraceptive method than relationship type; this pattern was more marked among younger participants. CONCLUSIONS: Asking about relationship status and duration may help providers support women's contraceptive use by considering their priorities and preferences at different life stages. Interactions between relationship characteristics, age and contraception are complex, and bear closer scrutiny both in research and in policy and practice. PMID- 29972357 TI - Contraceptive practices and menstrual patterns in women aged 18-50 years awaiting bariatric surgery. PMID- 29972358 TI - Assessing the relationship between intimate partner violence, externally-decided pregnancy and unintended pregnancies among women in slum communities in Mumbai, India. AB - BACKGROUND: India contends with a high rate of intimate partner violence (IPV), which is associated with unintended pregnancy and reflects low levels of women's decision-making control in relation to their reproductive health. Few studies from South Asia have examined the relationship between pregnancy decision-making, IPV and unintended pregnancy. AIM: This study examined associations between unintended (mistimed and unwanted) pregnancy, women's reports of pregnancy decided externally by husband or in-laws, and IPV, among a sample of married, postpartum women. METHODS: Data from the 'Mechanisms for Relations of Domestic Violence to Poor Maternal and Infant Health in India' study were analysed. Descriptive comparisons between levels of unintended pregnancy were run on all major variables. Unadjusted and adjusted multinomial logistic regression analyses assessed women's reports of having externally-decided pregnancies and IPV victimisation in the year prior to pregnancy as factors in mistimed and unwanted pregnancies. RESULTS: Mistimed and unwanted pregnancies were reported by 12.2% and 7.2% of women, respectively. Externally-decided pregnancies were reported by 8.8% of women. Some 29.4% of women reported experiencing physical and/or sexual IPV in the year prior to pregnancy. Women reporting externally-decided pregnancies were significantly more likely to have had mistimed pregnancies than intended pregnancies, as were women reporting IPV. Neither external pregnancy control nor IPV were associated with unwanted pregnancy. CONCLUSIONS: Women's exclusion from pregnancy decision-making and violence from husbands relate to their ability to time their pregnancies as they wish. The lack of significant association between external decision-making and IPV with unwanted pregnancy may be due to low reporting of unwanted pregnancy. The overall findings highlight the importance of integrating women's involvement in reproductive health decision making and IPV reduction messaging in programming for the women's health sector. PMID- 29972359 TI - The Cardiff postpartum family planning initiative: improving provision of postpartum contraception. PMID- 29972360 TI - Experiences of women in Ireland who accessed abortion by travelling abroad or by using abortion medication at home: a qualitative study. AB - BACKGROUND: The Republic of Ireland has one of the world's most restrictive abortion laws, allowing abortion only to preserve a pregnant woman's life. We examined the impact of the law on women's options for accessing abortion, their decision-making regarding whichpathway to follow, and their experiences with their chosen approach. METHODS: We conducted semi-structured in-depth interviews with 38 women who had either travelled abroad to access abortion in a clinic or had self-managed a medical abortion at home using online telemedicine, between 2010 and 2017. We coded interview transcripts according to an iteratively developed coding guide and performed a thematic analysis to identify key themes. RESULTS: We identified four key themes: (1) self-managing a medical abortion at home using online telemedicine can be a preference over travelling abroad to access abortion services; (2) regardless of the pathway chosen, women experience a lack of pre- and post-abortion support in the Irish healthcare system; (3) feelings of desperation while searching for safe abortion care can lead to considering or attempting dangerous methods; and (4) Irish abortion law and attitudes have impacts beyond physical health considerations, engendering shame and stigma. CONCLUSIONS: Despite the country's restrictive abortion law, women in Ireland do obtain abortions, using methods that are legal and safe elsewhere. However, the law negatively impacts women's ability to discuss their options with their healthcare professionals and to seek follow-up care, and can have serious implications for their physical and emotional health. This study's findings provide evidence to inform public and policy discourse on Ireland's abortion laws. PMID- 29972361 TI - Self-managed abortion in urban Haiti: a mixed-methods study. AB - OBJECTIVE: Although illegal abortion is believed to be widely practised in Haiti, few data exist on such practices. We aimed to learn about illegal abortion access, methods, and perceived barriers to abortion-related care. Additionally, we aimed to identify the proportion of unscheduled antepartum visits to a public hospital that were attributable to unsafe abortion in Cap Haitien, Haiti. STUDY DESIGN: We conducted eight focus groups with women (n=62) and 13 interviews with women's health providers and subsequently administered a survey to pregnant or recently pregnant women (20 weeks of gestation or less) presenting to the hospital from May 2013 to January 2014 (n=255). RESULTS: Among the focus groups, there was widespread knowledge of misoprostol self-managed abortion. Women described use of multiple agents in combination with misoprostol. Men played key roles in abortion decision-making and in accessing misoprostol.Among the 255 pregnant or recently pregnant women surveyed, 61.2% (n=150) reported the current pregnancy was unintended and 30% (n=78) reported attempting an induced abortion. The majority of women used misoprostol either alone or as a part of the medication/herb regimen for their self-managed abortion (85.1%, n=63). CONCLUSIONS: Awareness of methods to induce abortion is high among women in urban Haiti and appears widely practised; yet knowledge of the safest self-managed abortion options remains incomplete. Access to safer abortion services could improve maternal health in Haiti. PMID- 29972362 TI - Where do women and men in Britain obtain contraception? Findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - INTRODUCTION: To estimate the prevalence of use of different sources of contraceptive supplies in Britain and its variation by key demographic and behavioural characteristics. METHODS: Cross-sectional probability sample survey of women and men aged 16-74 years, resident in Britain, interviewed between 2010 and 2012. Analyses reported here were of 4571 women and 3142 men aged 16-44 years who reported having vaginal sex in the past year. Those relying exclusively on sterilisation (including hysterectomy) were excluded. Sources of contraceptive supplies were categorised as: general practice, community clinic, retail and other. Prevalence of use of these sources was estimated, and associated factors examined. RESULTS: Some 87.0% of women and 73.8% of men accessed at least one source of contraceptive supplies in the previous year. Most women (59.1%) used general practice and most men (54.6%) used retail outlets. Community clinics were less commonly used, by 23.0% of women and 21.3% of men, but these users were younger and at greater sexual health risk. These associations were also observed among the 27.3% of women and 30.6% of men who used more than one source category (general practice, community clinic or retail) for contraceptive supplies. CONCLUSIONS: People in Britain use a variety of sources to obtain contraceptive supplies and some sources are more commonly used by those more vulnerable to poorer sexual health. Our findings suggest that national policy changes to increase access to contraceptive methods have had an effect on the diversity of services used. PMID- 29972363 TI - Postabortion long-acting reversible contraception desire in women counselled using Bedsider.org versus standard counselling: a randomised trial. PMID- 29972364 TI - Quality of care and abortion: beyond safety. PMID- 29972365 TI - Moving towards same-day provision of Level 3 care in sexual and reproductive health services. PMID- 29972366 TI - Accidentally-on-purpose: findings from a qualitative study exploring pregnancy intention and long-acting reversible contraceptive use. AB - BACKGROUND: Although it is known that pregnancy intention impacts contraceptive use, there has been little exploration into the relationship between pregnancy intention and long-acting reversible contraception (LARC) non-use in the Australian context. METHODS: Semi-structured telephone interviews with a sample of participants from the Contraceptive Use, Pregnancy Intention and Decisions (CUPID) Study were conducted in 2016. RESULTS: Of the 59 women contacted, 15 participated in an interview. One theme arising from these interviews is reported here. Results from the analysis suggest that women with ambivalent or unclear plans toward pregnancy were less likely to perceive LARC as a suitable method for them. Conversely, women who clearly intended to avoid pregnancy and who had clear plans for future pregnancy valued these methods, and often framed their future plans for pregnancy within the context of their chosen LARC. CONCLUSIONS: Findings presented demonstrated the complex relationship between pregnancy intention and contraceptive use. In particular, this study provided insight into the complex notion of pregnancy ambivalence. Dichotomous definitions of pregnancy as intended or unintended were found to be inadequate in encapsulating actual reproductive experiences. PMID- 29972367 TI - Knowledge, attitudes and practice regarding copper intrauterine contraceptive devices among doctors in Malaysia. AB - BACKGROUND AND OBJECTIVE: Intrauterine contraceptive devices (IUDs) are an important method to reduce unmet need for family planning and for prevention of unintended pregnancy. However, IUD use in Malaysia is still low. Doctors play a major role in influencing IUD uptake among women. This study was designed to evaluate doctors' knowledge, attitudes and perceptions towards IUDs and factors associated with their current practice. METHODS: A questionnaire was mailed to public and private contraceptive providers who practise in Kuala Lumpur, Malaysia. RESULTS: A total of 400 doctors were invited and 240 (60%) of them responded to the survey. Of the respondents, 161 (65.9%) were from the public or government sector and 89 (34.1%) were from the private sector. The knowledge score of doctors was classed as 'average', and correlated well with their previous training level, working position, number of patients seen in a week and number of contraceptive methods available in their facilities. The age, gender, working duration, availability of IUDs in the premises and number of IUD insertions in a month were not statistically associated with the providers' knowledge. The use of IUDs was low, especially among private doctors, and was significantly related to their knowledge of the method. Knowledge scores, perception and practice were significantly lower in the private sector. PMID- 29972368 TI - India needs a policy for couples who lose children after sterilisation. PMID- 29972369 TI - Novel quantitative PCR assay specific for the emerging Perkinsea amphibian pathogen reveals seasonal infection dynamics. AB - Amphibians are suffering from large-scale population declines worldwide, and infectious diseases are a central driving force. Most pathogen-mediated declines are attributed to 2 pathogens, the fungus Batrachochytrium dendrobatidis and iridoviruses in the genus Ranavirus. However, another emerging pathogen within Perkinsea is associated with mass mortality events in anurans throughout the southeastern USA. Molecular resources for detecting amphibian Perkinsea have been limited to general protistan primers that amplify a range of organisms, not all of which are disease agents. Moreover, the only quantitative method available involves histopathology, which is labor intensive, requires destructive sampling, and lacks sensitivity. Here, we developed a novel quantitative (q)PCR assay that is sensitive and specific for amphibian Perkinsea, providing a resource for rapid and reliable pathogen diagnosis. We used histopathology to confirm that qPCR burdens track the severity of Perkinsea infections across multiple anuran tissues. We also sampled 3 natural amphibian communities in Florida, USA, to assess the prevalence and intensity of amphibian Perkinsea infections across species, seasons, tissues, and life stages. Anurans from 2 of 3 sampling locations were infected, totaling 25.1% of all individuals. Infection prevalence varied significantly among locations, seasons, species, and life stages. Infection intensity was significantly higher in larval tissues than adult tissues, and was significantly different across locations, seasons, and species. Understanding relationships between amphibian Perkinsea infection, other pathogens, and biotic and abiotic cofactors will allow us to assess what drives population declines, improving our ability to develop conservation strategies for susceptible species to reduce global amphibian biodiversity loss. PMID- 29972370 TI - Phytogenic feed-additive effects on channel catfish rhamnose-binding lectin levels, and susceptibility to Edwardsiella ictaluri. AB - We investigated the effects of a phytogenic feed additive on disease susceptibility to Edwardsiella ictaluri in channel catfish Ictalurus punctatus and regulation of 6 rhamnose-binding lectin (RBL) genes. Juvenile catfish (n = 250, 13.4 +/- 0.1 g) were allotted to the following treatments: control (floating diet) or EO (floating diet supplemented with essential oils; Digestarom(r) P.E.P. MGE). The fish were fed their respective diets for 6 wk. Following subjection to different feed treatments, all fish were exposed to pathogenic E. ictaluri by bath immersion. Another group of fish were not challenged (non-challenged controls, fed control feed). Mucosal tissue samples were taken to quantify gene expression levels of RBL on Days 1 and 2 post-challenge. After challenge, survival was higher (64.4 vs. 48.0%) in fish fed EO compared to controls (p < 0.05). Relative to non-challenged controls, gill RBL1a mRNA was higher in fish fed EO (p < 0.05) on Day 1 while gill RBL3b was higher in fish fed EO (p < 0.01) on Days 1 and 2, respectively. RBL5a in the skin and proximate small intestine did not change significantly relative to non-challenged fish on Days 1 and 2 of the disease challenge. Results demonstrate that Digestarom(r) P.E.P. MGE improved survival of channel catfish challenged with E. ictaluri. One of the mechanisms through which essential oils may improve survival is through upregulation of RBL1a and RBL3b in the gill. PMID- 29972371 TI - Virulence of the fish pathogen Aeromonas dhakensis: genes involved, characterization and histopathology of experimentally infected hybrid tilapia. AB - Aeromonas dhakensis (Ad) CAIM 1873 growth was evaluated at different conditions and antibiotic susceptibility. Mortality and histopathological damages in hybrid tilapia Oreochromis niloticus * O. mossambicus, and virulence factors caused by Ad bacterial cells and extracellular products (ECPs) were evaluated, and the whole genome was obtained. Ad grew between 0.0 and 5.5% NaCl at a pH of between 4 and 10 and from 4 to 37 degrees C. The lowest minimum inhibitory concentration was found for enrofloxacin (<5 ug ml-1), and bacteria were resistant to erythromycin, amoxicillin and ampicillin. Ad bacterial cells (1.86 * 105 cells g 1) and ECPs (0.462 ug protein fish-1) were highly virulent to challenged hybrid tilapia and caused over 80% mortality at 24 h. The primary clinical sign caused was haemorrhage, and damage was most marked in the spleen, liver, kidney and brain of fish challenged with bacterial cells. To our knowledge, this is the first report that Ad causes pyknotic and karyorrhectic nuclei of erythrocytes in the internal organs of hybrid tilapia, which was the most striking histopathological observation. The virulence of Ad to hybrid tilapia may be primarily related to the activity of haemolysins (hlyA genes) and cytotoxins (aerolysin aerA), along with the production of siderophores and proteases. We also found beta-lactamase, tetracycline and multiple antibiotic resistance genes, as well as adherence, iron acquisition, toxins (aerolysin family, haemolysins) and diverse protease genes. PMID- 29972372 TI - Histopathological alterations in gills of Amazonian shrimp Macrobrachium amazonicum parasitized by isopod Probopyrus bithynis (Bopyridae). AB - The present study describes, for the first time, histopathological alterations in the gills of Macrobrachium amazonicum caused by infestation of Probopyrus bithynis (Isopoda: Bopyridae). In every case (100%), the infestation by P. bithynis was by a single pair of parasites (male and female) and occurred in the right or left side of the branchial chamber; the gill structures were visibly compressed due to the presence of parasites. The gills of M. amazonicum parasitized by P. bithynis exhibited a chronic inflammatory response, with the presence of edema, greater quantities of hemocytes, necrosis, epithelial cell hyperplasia, rupture of the pillar cells at the ends of the gill lamellae, desquamation of the cuticle, lamellar fusion and rupture of the lamellar epithelium. Tissue lesions were found in the histological sections of the gills of the parasitized M. amazonicum. Structural alterations in the branchial chamber of the hosts caused by the presence of P. bithynis can lead to physiological changes that can impair host respiratory performance. Finally, histopathological alterations in the branchial chamber of hosts suggest that P. bithynis feed directly on the gill tissues of this shrimp. PMID- 29972373 TI - Oomycete parasites in freshwater copepods of Patagonia: effects on survival and recruitment. AB - Copepods are hosts to various oomycete parasite species, but the effects of pathogens on copepod populations have rarely been studied. This study aimed to characterize oomycete infection in the freshwater copepod Parabroteas sarsi in a temporary pond in Patagonia (Argentina). A complete hydroperiod was monitored, evaluating environmental variables as influencing factors in the oomycete infections. Laboratory experiments were performed to evaluate the susceptibility of infected copepods to consumption by predators. Although 5 species of copepods were present in the pond, only ovigerous P. sarsi females were parasitized by oomycetes. Two species of oomycetes were always found together: Aphanomyces ovidestruens and Pythium flevoense. Infections were detected at water temperatures >20 degrees C, with a positive relationship between temperature and parasite prevalence. Infection occurred after a decrease in large filter-feeder densities. The pathogens were not lethal to P. sarsi females in the short-term, but did produce mortality of entire egg sacs, thus negatively impacting subsequent recruitment. Mean prevalence of infection in females was 53%, reaching 83% in December. Females have the capacity to release an infected egg sac and generate a new one in a few days. This infection does not affect the susceptibility of P. sarsi to the predator Notonecta vereertbruggheni. The decrease in female abundance registered towards the end of the hydroperiod could be related to a combination of factors that may have a differential effect on female survival, such as increasing temperature, the energy cost of egg sac development and carrying and oomycete infection. PMID- 29972374 TI - Prevalence of the pathogenic crustacean virus Callinectes sapidus reovirus 1 near flow-through blue crab aquaculture in Chesapeake Bay, USA. AB - Understanding the ecology of diseases is important to understanding variability in abundance, and therefore management, of marine animals exploited commercially. The blue crab Callinectes sapidus fills a crucial benthic-pelagic niche in Atlantic estuarine ecosystems and supports large commercial fisheries in both North and South America. In the USA, pre-molt blue crabs are typically held in short-term shedding (ecdysis) facilities to produce soft-shell crabs of increased value. However, mortality rates in these facilities are high and commonly associated with the pathogenic C. sapidus reovirus 1 (CsRV1). To assess whether crab mortalities in these facilities might increase CsRV1 prevalence in wild crab populations, tissue sampled from crabs collected over 2 summers either near to or far from shedding facilities using flow-through water systems were tested by reverse transcription quantitative PCR (RT-qPCR) for the presence of CsRV1 RNA. In support of our hypothesis, PCR data identified the probability of detecting CsRV1 in wild crabs sampled close to shedding facilities to be 78% higher than in crabs sampled from far sites. PCR detections were also 61-72% more probable in male crabs and 21% more likely in male and female crabs over the minimum landing size. As the prevalence at which CsRV1 was detected varied within seasons, among locations and between years, blue crab migration and/or population fluctuations appear to also be involved. PMID- 29972375 TI - Real-time PCR tests to specifically detect IHHNV lineages and an IHHNV EVE integrated in the genome of Penaeus monodon. AB - Infectious hypodermal and hematopoietic necrosis virus (IHHNV) can cause mass mortalities in western blue shrimp Penaeus stylirostris, runt deformity syndrome in Pacific white shrimp P. vannamei and scalloped abdominal shell deformities in black tiger shrimp P. monodon. In P. monodon, however, PCR-based diagnosis of IHHNV can be complicated by the presence of a chromosome-integrated, non replicating endogenous viral element (EVE). To facilitate high-throughput screening of P. monodon for IHHNV infection and/or EVE sequences, here we report real-time PCR tests designed to specifically detect IHHNV Lineage I, II and III but not EVE Type A sequences and vice versa. Using 108 dsDNA copies of plasmid (p)DNA controls containing either IHHNV or EVE-Type A sequences, both tests displayed absolute specificity. The IHHNV-q309 PCR reliably detected down to <=10 copies of pDNA, at which levels a 309F/R PCR amplicon was just detectable, and the presence of an IHHNV-EVE sequence did not significantly impact its sensitivity. The IHHNV-qEVE PCR was similarly sensitive. Testing of batches of P. monodon clinical samples from Vietnam/Malaysia and Australia identified good diagnostic concordance between the IHHNV-q309 and 309F/R PCR tests. As expected for a sequence integrated into host chromosomal DNA, IHHNV-qEVE PCR Ct values were highly uniform among samples from shrimp in which an EVE was present. The highly specific and sensitive IHHNV-q309 and IHHNV-qEVE real-time PCR tests described here should prove useful for selecting broodstock free of IHHNV infection and in maintaining breeding populations of P. monodon specific pathogen free for IHHNV, and if desired, also free of IHHNV-EVE sequences. PMID- 29972376 TI - Non-lethal isolation of the fungal pathogen Batrachochytrium dendrobatidis (Bd) from amphibians. AB - The ability to isolate and purify pathogens is important for the study of infectious disease. A protocol for isolating Batrachochytrium dendrobatidis (Bd), a lethal pathogen of amphibians, has been available for over a decade, but the method relies on sacrificing infected animals. We validated a non-lethal protocol for Bd isolation that uses biopsy punches from toe webbing to collect skin samples from live amphibians in remote field locations. We successfully isolated Bd from the Cascades frog Rana cascadae and found a positive association between Bd infection and probability of Bd growth in culture. Recapture rates of sampled animals suggest that our isolation protocol did not affect frog survival. The ability to collect isolates from live animals will facilitate investigations of the biology of Bd and enhance amphibian conservation efforts. PMID- 29972377 TI - Electron trapping at SiO2/4H-SiC interface probed by transient capacitance measurements and atomic resolution chemical analysis. AB - Studying the electrical and structural properties of the interface of the gate oxide (SiO2) with silicon carbide (4H-SiC) is a fundamental topic, with important implications for understanding and optimising the performances of metal-oxide semiconductor field effect transistor (MOSFETs). In this paper, near interface oxide traps (NIOTs) in lateral 4H-SiC MOSFETs were investigated combining transient gate capacitance measurements (C-t) and state of the art scanning transmission electron microscopy in electron energy loss spectroscopy (STEM-EELS) with sub-nm resolution. The C-t measurements as a function of temperature indicated that the effective NIOTs discharge time is temperature independent and electrons from NIOTs are emitted toward the semiconductor via-tunnelling. The NIOTs discharge time was modelled also taking into account the interface state density in a tunnelling relaxation model and it allowed us to locate traps within a tunnelling distance of up to 1.3 nm from the SiO2/4H-SiC interface. On the other hand, sub-nm resolution STEM-EELS revealed the presence of a non-abrupt (NA) SiO2/4H-SiC interface. The NA interface shows the re-arrangement of the carbon atoms in a sub-stoichiometric SiO x matrix. A mixed sp2/sp3 carbon hybridization in the NA interface region suggests that the interfacial carbon atoms have lost their tetrahedral SiC coordination. PMID- 29972378 TI - Data collection and research with MargheritaTre. AB - OBJECTIVE: MargheritaTre is an electronic health record developed by the Italian Group for the Evaluation of Interventions in Intensive Care Medicine designed to support clinical practice in intensive care units (ICUs) and ensure high-quality data for research purposes. APPROACH: MargheritaTre was developed in collaboration with clinical experts, researchers, and IT specialists. It is currently installed in 40 ICUs and its database contains complete records of more than 65,000 patients. To facilitate data analysis, information is mostly stored in structured or partially structured form. MAIN RESULTS: Data collected with MargheritaTre allow one to conduct research studies on complex clinical problems from manifold perspectives and with different levels of detail, such as epidemiological studies, analyses of the process of care and physiopathological investigations, at both single-organ and organism level. In this paper we describe some of the first projects based on this electronic health record to illustrate its potential for research. SIGNIFICANCE: The MargheritaTre database is a huge and rapidly growing mine of data that will be exploited by our laboratory and shared with other groups to address complex and innovative research and clinical questions. The ultimate aim of these projects is the improvement of the quality of care and patient outcomes, through the development of expert systems integrated in the electronic health record to support clinical practice. PMID- 29972379 TI - Synthesis and growth mechanism of carbon nanotubes growing on carbon fiber surfaces with improved tensile strength. AB - An effective approach has been developed for the catalytic decomposition of acetylene (C2H2) by chemical vapor deposition (CVD), to achieve homogeneous growth of carbon nanotubes (CNTs) on the surfaces of carbon fibers. The morphology of CNTs grown on carbon fiber surfaces was observed by a scanning electron microscope and high-resolution transmission electron microscope, which revealed the uniform coverage of CNTs on the carbon fiber surfaces. The single fiber tensile test demonstrated that the tensile strength of carbon fibers could be increased by more than 12% with the catalytic growth of CNTs on their surface. The reparation of the damage caused during the formation of catalyst nanoparticles, and the cross-link of neighboring graphite crystallites induced by CNTs all occurred during the CVD process, which were considered to be the main reasons for improvement. The growth mechanism model of CNTs formation was established based on the thermodynamics principle and the interface microstructure of CNT-grown carbon fiber, illuminating the detailed mechanism for the growth of CNTs and the change of the shape of catalyst particles. PMID- 29972380 TI - Transmissive structural color filters using vertically coupled aluminum nanohole/nanodisk array with a triangular-lattice. AB - We demonstrate a configuration to generate transmissive structural colors through triangular-lattice square nanohole arrays in aluminum (Al) film with Al nanodisks on the bottom of the nanoholes. By using a simple nanofabrication process, colors covering the entire visible light with different brightness and saturation are achieved by tuning both the period of arrays and the size of nanoholes. The optical behaviors of the structures are systematically investigated by both experimental and theoretical methods. The results indicate that the localized surface plasmon resonance of nanohole arrays plays the key role in the extraordinary transmission and meanwhile the coupling of disks and holes is also of importance for the enhanced transmission. With the wide color gamut, these kinds of vertically coupled Al nanohole/nanodisk arrays show the capabilities for high-resolution full-color printing. Compared to existing transmissive plasmonic color filters, the configuration in this work has the advantages of a simple fabrication process and using cheap aluminum materials. PMID- 29972381 TI - Synthesis of hesperetin-loaded PLGA nanoparticles by two different experimental design methods and biological evaluation of optimized nanoparticles. AB - Hesperetin was effectively encapsulated into poly (d,l-lactic-co-glycolic acid) nanoparticles by using experimental design methods. A seven-factor Plackett Burman design was used in order to determine the major process parameters. A significant linear equation, which shows the effect of each process parameter on encapsulation efficiency was developed, and then the most effective factors were determined. Further investigation and optimization was carried out by applying the three-factor three-level Box-Behnken design. Significant second-order mathematical models were developed by regression analysis of the experimental data for both responses: encapsulation efficiency and nanoparticle size. The two step experimental design allowed the synthesis of the desired nanoparticle formulations with maximum encapsulation efficiency (80.5 +/- 4.9%) and minimum particle size (260.2 +/- 16.5 nm) at optimum process conditions: 0.5% polyvinyl alcohol (PVA) concentration, 5.13 water:organic phase ratio, and 3.59 ml min-1 flow rate of the emulsified solution into 0.1% PVA. Furthermore, the biological activity of these optimized nanoparticles were determined with antimicrobial activity and cytotoxicity studies; results were then compared to the free hesperetin. The cytotoxicity result revealed that hesperetin and hesperetin loaded nanoparticles were biocompatible with normal cell line L929 fibroblast cells up to 184.83 and 190.88 MUg ml-1 for 24 h, and up to 133.24 and 134.80 MUg ml-1 for 48 h, respectively. In the antimicrobial study, the optimized nanoparticle showed inhibition activity (minimal inhibitory concentration (MIC) values were 125 MUg ml-1 for Escherichia coli, and 200 MUg ml-1 for Staphylococcus aureus), while the free hesperetin did not demonstrate activity in both strains (MIC value >200 MUg ml-1). These in vitro results may provide useful information for the investigation of hesperetin-loaded nanoparticles in diagnostic and therapeutic applications. PMID- 29972382 TI - Recent developments in the synthesis and applications of graphene-family materials functionalized with cyclodextrins. AB - The introduction of cyclodextrin species to graphene-family materials (GFMs) constitutes an important area of research, especially in terms of the development of applied nanoscience. The chemistry of cyclodextrins is the so-called host guest chemistry, which has impacted on many fields of research, including catalysis, electrochemistry and nanomedicine. Cyclodextrins are water-soluble and biocompatible supramolecules, and therefore they may introduce new interesting properties to GFMs and may enhance the physicochemical/biological features of native GFMs. The reported methods for the conjugation of cyclodextrins to GFMs utilize either covalent or non-covalent approaches. The recent progress in the applications of GFMs functionalized with cyclodextrins, with the respect to the chemistry and features of these conjugates, is discussed. Special consideration is also given to the recent developments in (i) nanomedicine, (ii) electrochemistry, (iii) adsorption and (iv) catalysis. Examples of these materials are discussed in this work, together with the future outlook on the impact of GFM-cyclodextrin conjugates in the development of applied nanoscience. PMID- 29972383 TI - Correction: Predicting oligomer/polymer compatibility and the impact on nanoscale segregation in thin films. AB - Correction for 'Predicting oligomer/polymer compatibility and the impact on nanoscale segregation in thin films' by Elise F. D. Sabattie et al., Soft Matter, 2017, 13, 3580-3591. PMID- 29972386 TI - Splay-density coupling in semiflexible main-chain nematic polymers with hairpins. AB - A main-chain nematic polymer melt/solution exhibits macroscopic orientational order of main polymer chains, i.e., a preferred (nematic) direction. It has long been known that in such polymeric liquid crystals spatial density/concentration variations and distortions of the nematic direction are coupled, obeying a vectorial continuity constraint whose rigidity increases with chain length. Its vectorial nature precludes the application to flexible chains, where backfolds (hairpins) are present and apolar nematic symmetry is manifest, which has been its puzzling feature from the beginning. We now establish a description of the splay-density coupling in the case of arbitrary backfolding, devising a continuity constraint for the "recovered" polar order of the chain tangents and introducing hairpins as its new type of sources. Performing detailed Monte Carlo simulations of nematic monodomain melts of "soft" worm-like chains with variable length and flexibility, we show via their structure factors that the weakening of the coupling due to the backfolding can be consistently quantified on the macroscopic level. PMID- 29972388 TI - The discovery of a freezing-induced peptide ligation during the total chemical synthesis of human interferon-epsilon. AB - A counterintuitive freezing-induced peptide ligation was discovered during the total synthesis of human interferon-epsilon (hIFN-epsilon) which blocks HIV infection through unique mechanisms. The successful synthesis of hIFN-epsilon (187 amino acids) in this research laid the foundation for related anti-AIDS drug development. Moreover, alanine mutation based on sequence alignment to solve the maldistribution of the ligation site and freezing-induced dominant conformation that facilitates peptide ligation are expected to be helpful for the synthesis of macrobiomolecules. PMID- 29972389 TI - Creating cross-linked lamellar block copolymer supporting layers for biomimetic membranes. AB - The long-standing goal in membrane development is creating materials with superior transport properties, including both high flux and high selectivity. These properties are common in biological membranes, and thus mimicking nature is a promising strategy towards improved membrane design. In previous studies, we have shown that artificial water channels can have excellent water transport abilities that are comparable to biological water channel proteins, aquaporins. In this study, we propose a strategy for incorporation of artificial channels that mimic biological channels into stable polymeric membranes. Specifically, we synthesized an amphiphilic triblock copolymer, poly(isoprene)-block-poly(ethylene oxide)-block-poly(isoprene), which is a high molecular weight synthetic analog of naturally occurring lipids in terms of its self-assembled structure. This polymer was used to build stacked membranes composed of self-assembled lamellae. The resulting membranes resemble layers of natural lipid bilayers in living systems, but with superior mechanical properties suitable for real-world applications. The procedures used to synthesize the triblock copolymer resulted in membranes with increased stability due to the crosslinkability of the hydrophobic domains. Furthermore, the introduction of bridging hydrophilic domains leads to the preservation of the stacked membrane structure when the membrane is in contact with water, something that is challenging for diblock lamellae that tend to swell, and delaminate in aqueous solutions. This new method of membrane fabrication offers a practical model for making channel-based biomimetic membranes, which may lead to technological applications in reverse osmosis, nanofiltration, and ultrafiltration membranes. PMID- 29972390 TI - Selectivity and polarization in water channel membranes: lessons learned from polymeric membranes and CNTs. AB - Water channels are employed by nature to move pure water across cell membranes while selectively rejecting salts. At present, synthetic channels successfully mimic water permeation, yet even the best channels, such as carbon nanotubes (CNTs) and graphene oxide stacks, still fall short of the selectivity target. The present paper analyzes factors that may help to enhance and control salt rejection based on the lessons learned from conventional membranes and CNTs. First, it highlights the importance of raising the ion self-energy (dielectric mechanism), which suggests that having the channels both narrow and surrounded by a low-dielectric environment is key to high selectivity. In contrast, pore charge alone is insufficient, yet it may help to enhance and tune ion rejection, provided that non-mean-field effects enhanced in low-dielectric pores, such as ion association and sorption, especially of H+ and OH- ions, are properly understood and addressed in the channel design. Second, the role of concentration polarization (CP) is analyzed, which shows that the CP level is apparently low in isolated channels or microscopically small membranes. However, the geometry of the diffusion field should change and CP should increase drastically in macroscopic membranes incorporating densely spaced channel arrays. If not properly addressed in membrane design, the increased CP level in scaled-up channel-based membranes may significantly compromise the observed selectivity and require that target of selectivity be re-set to an even more challenging value. These points may help guide the future development of high-performance artificial water channels and their scale-up towards utilization in next-generation water purification membranes. PMID- 29972391 TI - AIRWAY POSITIVE PRESSURE VS. EXERCISES WITH INSPIRATORY LOADING FOCUSED ON PULMONARY AND RESPIRATORY MUSCULAR FUNCTIONS IN THE POSTOPERATIVE PERIOD OF BARIATRIC SURGERY. AB - BACKGROUND: Bariatric surgery can trigger postoperative pulmonary complications due to factors inherent to the procedure, mainly due to diaphragmatic dysfunction. AIM: To evaluate and compare the effects of two levels of positive pressure and exercises with inspiratory load on lung function, inspiratory muscle strength and respiratory muscle resistance, and the prevalence of atelectasis after gastroplasty. METHODS: Clinical, randomized and blind trial, with subjects submitted to bariatric surgery, allocated to two groups: positive pressure group, who received positive pressure at two levels during one hour and conventional respiratory physiotherapy and inspiratory load group, who performed exercises with load linear inspiratory pressure, six sets of 15 repetitions, in addition to conventional respiratory physiotherapy, both of which were applied twice in the immediate postoperative period and three times a day on the first postoperative day. Spirometry was performed for pulmonary function analysis, nasal inspiratory pressure for inspiratory muscle strength and incremental test of respiratory muscle resistance for sustained maximal inspiratory pressure, both preoperatively and on hospital discharge on the second postoperative day. RESULTS: There was no significant difference (p> 0.05) in the expiratory reserve volume and in the tidal volume in the pre and postoperative periods when compared intra and intergroup. There was no significant difference (p>0.05) in the nasal inspiratory pressure and the maximal inspiratory pressure maintained in the inspiratory load group in the intragroup evaluation, but with a significant difference (p<0.05) compared to the positive pressure group. The prevalence of atelectasis was 5% in both groups with no significant difference (p>0.05) between them. CONCLUSION: Both groups, associated with conventional respiratory physiotherapy, preserved expiratory reserve volume and tidal volume and had a low atelectasis rate. The inspiratory loading group still maintained inspiratory muscle strength and resistance of respiratory muscles. PMID- 29972392 TI - INFLUENCE OF SPLENIC IMPLANTS IN THE SUBCUTANEOUS TISSUE ON ASPLENIC ANIMALS SURVIVAL. AB - BACKGROUND: The best site for splenic implant was not defined, mainly evaluating the functionality of the implant. AIM: To evaluate the effects of autogenous splenic implantation on the subcutaneous tissue in the survival of splenectomized rats. METHOD: Twenty-one randomly assigned rats were studied in three groups (n=7): group 1 - manipulation of the abdominal cavity and preservation of the spleen; group 2 - total splenectomy; group 3 - splenectomy and implant of the tissue removed in the subcutaneous. The animals were followed for 90 days postoperatively. RESULTS: There was a higher mortality in groups 2 (p=0.0072) and 3 (p=0.0172) in relation to group 1. There was no difference between groups 2 and 3 (p=0.9817). CONCLUSION: The splenic implant in the subcutaneous is ineffective in the survival of rats submitted to splenectomy. PMID- 29972393 TI - MUSCLE-SPARING VERSUS STANDARD POSTEROLATERAL THORACOTOMY IN NEONATES WITH ESOPHAGEAL ATRESIA. AB - BACKGROUND: The muscle-sparing thoracotomy (MST) has not yet been thoroughly studied and assessed in comparison to the traditional thoracotomy method in newborns. AIM: To compare the outcomes of MST and standard posterolateral thoracotomy (PLT) in newborns. METHODS: Randomized, controlled, double-blind trial on 40 neonates with esophageal atresia, comparing the time of beginning a surgery until seeing the pleura, the duration of hospitalization in the neonatal intensive care unit, the time in ventilator, the time of returning the shoulder function, the time of returning the Moro reflex, and the mortality between the two techniques. RESULTS: The data showed no differences between the two groups in basic information (weight, height, gender, numbers of prematurity neonates and caesarean). The results on the size of the scar in the MST group was significantly lower than in the PLT group. Also, the time of returning the shoulder function in MST group was earlier than in PLT group. There were no significant differences in the duration since the beginning the surgery to see the pleura, the time of being hospitalized in intensive unit, the time that the infant required ventilator, returning time of the Moro reflex in 1st and 3rd months after the operation, and the mortality rates between MST and PLT groups. CONCLUSION: It seems that the advantages of using MST over PLT procedure in neonates include the earlier shoulder function recovery and also superior cosmetic results. PMID- 29972394 TI - THE ROLE OF IMMUNOINFLAMMATORY MARKERS IN THE PROGNOSIS AND RESECTABILITY OF PANCREATIC ADENOCARCINOMA. AB - BACKGROUND: Pancreatic adenocarcinoma has a high mortality rate. A prognostic tool is essential for a better risk stratification. The neutrophil/lymphocyte ratio and adaptations and the platelet/lymphocyte ratio seem promising for this purpose. AIM: Evaluate the prognostic value of neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio, analyze the ideal cutoff values and investigate their utility in predicting resectability. METHODS: Data were collected of patients with pancreatic adenocarcinoma in Hospital de Clinicas de Porto Alegre between 2003 and 2013. The studied ratios were determined by blood count collected at hospital admission and after two cycles of palliative chemotherapy. RESULTS: Basal neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio did not have prognostic impact in survival (p=0.394, p=0.152, p=0.177 respectively). In subgroup analysis of patients submitted to palliative chemotherapy, neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio determined after two cycles of chemotherapy were prognostic for overall survival (p=0.003, p=0.009, p=0.001 respectively). The ideal cutoff values found were 4,11 for neutrophil/lymphocyte ratio (sensitivity 83%, specificity 75%), 2,8 for derived neutrophil/lymphocyte ratio (sensitivity 87%, specificity 62,5%) and 362 for platelet/lymphocyte ratio (sensitivity 91%, specificity 62,5%), Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio were not able to predict resectability (p=0.88; p=0.99; p=0.64 respectively). CONCLUSIONS: Neutrophil/lymphocyte ratio, derived neutrophil/lymphocyte ratio and platelet/lymphocyte ratio are useful as prognostic markers of overall survival in patients with pancreatic adenocarcinoma submitted to palliative chemotherapy. Its use as resectability predictor could not be demonstrated. PMID- 29972395 TI - FOOD INTAKE EVALUATION DURING THE FIRST YEAR OF POSTOPERATIVE OF PATIENTS WITH TYPE 2 DIABETES MELLITUS OR GLYCEMIC ALTERATION SUBMITTED TO ROUX-EN-Y GASTRIC BYPASS. AB - BACKGROUND: : Obesity is one of the main causes of glycemic change. Failure of clinical obesity treatment may lead to an increase in bariatric surgery. Dietary guidance, in conjunction with disabsorptive and hormonal factors resulting from the anatomical and physiological changes provoked by the surgery, is associated with changes in food intake. AIM: To analyze food intake evolution during the first postoperative year of Roux-en-y gastric bypass in patients with type 2 diabetes mellitus or glycemic alteration. METHODS: : This was a longitudinal and retrospective observational study. For food intake evolution analysis, linear regression models with normal errors were adjusted for each of the nutrients. RESULTS: At 12 months, all patients presented improvement in glycemic levels (p<0.05). During the first postoperative year, there was a reduction in energy intake, macronutrients, consumption of alcoholic beverages and soft drinks. Conversely, there was an increase in fiber intake and diet fractionation. It was observed that, despite gastric restrictions, the micronutrient intake specifically recommended for glycemic control was greater up to six months postoperatively. CONCLUSION: There was change in the quantity and quality of food intake. It was the most prevalent glycemic control contributor up to six months postoperatively. At the end of one year, the diet underwent a change, showing a similar tendency to the preoperative food intake pattern. PMID- 29972396 TI - THE COST OF BEING A DOCTOR. PMID- 29972397 TI - ANIMAL MODELS FOR COLORECTAL CANCER. AB - INTRODUCTION: Colorectal cancer is a very frequent sort of neoplasm among the population, with a high mortality rate. It develops from an association of genetic and environmental factors, and it is related to multiple cell signaling pathways. Cell cultures and animal models are used in research to reproduce the process of disease development in humans. Of the existing animal models, the most commonly used are animals with tumors induced by chemical agents and genetically modified animals. OBJECTIVE: To present and synthesize the main animal models of colorectal carcinogenesis used in the research, comparing its advantages and disadvantages. METHOD: This literature review was performed through the search for scientific articles over the last 18 years in PubMed and Science Direct databases, by using keywords such as "animal models", "colorectal carcinogenesis" and "tumor induction". RESULTS: 1,2-dimethylhydrazine and azoxymethane are carcinogenic agents with high specificity for the small and large intestine regions. Therefore, the two substances are widely used. Concerning the genetically modified animal models, there is a larger number of studies concerning mutations of the APC, p53 and K-ras genes. Animals with the APC gene mutation develop colorectal neoplasms, whereas animals with p53 and K-ras genes mutations are able to potentiate the effects of the APC gene mutation as well as the chemical inducers. CONCLUSION: Each animal model has advantages and disadvantages, and some are individually efficient as to the induction of carcinogenesis, and in other cases the association of two forms of induction is the best way to obtain representative results of carcinogenesis in humans. PMID- 29972398 TI - THE USE OF MELD SCORE (MODEL FOR END-STAGE LIVER DISEASE) AND DERIVATIVES IN CARDIAC TRANSPLANTATION. AB - INTRODUCTION: Heart transplantation is still the best therapeutic alternative for the treatment of end-stage heart failure. The use of criteria that consider the complications associated with this procedure can guarantee a better evaluation of the recipient and prepare the team for possible unsatisfactory post-transplant results. The use of the MELD score has been expanded to evaluate cirrhotic patients undergoing various procedures, including cardiac transplantation. OBJECTIVE: To analyze the knowledge on MELD score and its derivatives to the prognosis of patients with end-stage heart failure considered for heart transplantation. METHOD: Was carried out an integrative review of the publications of the last ten years in Pubmed and Lilacs databases, using the descriptors "heart transplantation", "liver disease" and "prognosis". From the total of 111 articles found, six were selected and composed the sample. RESULTS: The MELD-XI score (eXcluding INR) was the most analyzed in the studies due to the exclusion of INR, since many patients with heart failure use anticoagulants, which may alter their value. MELD and derivatives were associated with unsatisfactory results in cardiac transplantation. CONCLUSION: The MELD score can be considered as a good predictor for heart transplantation; however, there are still few studies that make this correlation. PMID- 29972399 TI - PRE- AND POSTOPERATIVE IMAGING METHODS IN COLORECTAL CANCER. AB - INTRODUCTION: Among the screening tests for colorectal cancer, colonoscopy is currently considered the most sensitive and specific technique. However, computed tomography colonography (CTC), magnetic resonance imaging (MRI), and transrectal ultrasonography have gained significant ground in the clinical practice of pre treatment, screening and, more recently, post-treatment and surgical evaluation. OBJECTIVE: To demonstrate the high accuracy of CT and MRI for pre and postoperative colorectal cancer staging. METHODS: Search and analysis of articles in Pubmed, Scielo, Capes Periodicals and American College of Radiology with headings "colorectal cancer" and "colonography". Weew selected 30 articles that contained radiological descriptions, management or statistical data related to this type of neoplasia. The criteria for radiological diagnosis were the American College of Radiology. RESULTS: The great majority of patients with this subgroup of neoplasia is submitted to surgical procedures with the objective of cure or relief, except those with clinical contraindication. CTC colonography is not the most commonly used technique for screening; however, it is widely used for treatment planning, assessment of the abdomen for local complications or presence of metastasis, and post-surgical evaluation. MRI colonography is an alternative diagnostic method to CT, recommended by the American Society of Gastrointestinal Endoscopy. Although there are still no major studies on the use of MRI for screening, the high resolution examination has now shown good results for the American Joint Committee on Cancer TNM classification. CONCLUSION: MRI and CT represent the best means for colorectal neoplasm staging. The use of these methods as screening tools becomes beneficial to decrease complications and discomfort related to colonoscopy. PMID- 29972400 TI - PRE-OPERATIVE BILIARY DRAINAGE IN THE PERIAMPULLARY NEOPLASIA - A SYSTEMATIC REVIEW. AB - INTRODUCTION: Periampular neoplasms represent 5% of all cancers of the gastrointestinal tract with peak incidence in the 7th decade of life. The most common clinical picture is jaundice, weight loss and abdominal pain. Considering that cholestasis is related to postoperative complications, preoperative biliary drainage was developed to improve the postoperative morbidity and mortality of icteric patients with periampular neoplasias, whether resectable or not. OBJECTIVE: To describe the outcome of patients with periampullary tumors undergoing preoperative biliary drainage with pancreatoduodenectomy. METHOD: The search was performed in the Medline/PubMed and Virtual Health Library databases by means of the combination of descriptors of the Medical Subject Headings. Inclusion criteria were clinical trials, cohorts, studies that analyze the morbidity and mortality of preoperative biliary drainage in Portuguese, English and Spanish. Exclusion criteria were studies published more than 10 years ago, experimental studies, systematic reviews and articles with WebQualis C or smaller journal in the area of Medicine I or Medicine III. Of the 196 references found, 46 were obtained for reading with quality assessed through the Checklist Strengthening the Reporting of Observational Studies in Epidemiology. Eight studies were selected for review. RESULTS: A total of 1116 patients with a sample ranging from 48 to 280 patients and a mean age of 48 to 69 years were obtained. Of the eight studies, four observed a higher rate of bleeding in drained patients; three a higher rate of positive bile culture in the intervention group; site and cavitary infection, and biliopancreatic leaks were more common in the drainage group in two studies each. The death outcome and rate of reoperation were observed in larger numbers in the control group in one study each. CONCLUSION: Preoperative intervention leads to a higher rate of infectious complications and bleeding. PMID- 29972401 TI - CURRENT STATUS OF THE MULTIDISCIPLINARY TREATMENT OF GASTRIC ADENOCARCINOMA. AB - BACKGROUND: The complexity of the management of gastric cancer requires a multidisciplinary evaluation of patients with this tumor. Several treatments have been employed, associated to the surgical resection. OBJECTIVE: To review the available therapeutic alternatives for the treatment of gastric adenocarcinoma. METHODS: A review of selected articles on multidisciplinary treatment of gastric adenocarcinoma in the Pubmed and Medline databases between 2000 and 2017 was carried out. The following headings were related: stomach cancer, treatment, chemotherapy and radiotherapy. RESULTS: There are several valid alternatives, with good results for the treatment of gastric cancer: chemoradiotherapy or chemotherapy in the adjuvant scenario; perioperative chemotherapy; and chemoradiotherapy after neoadjuvance with isolated chemotherapy. CONCLUSION: Current evidences suggest that combined multidisciplinary treatment is superior to surgery alone. However, the optimal treatment regimen is not yet established, and depends on a number of factors, especially the type of surgical resection employed. Therefore, the therapeutic decision should be made by a multidisciplinary team, assessing patient's personal characteristics, biology of the tumor, residual disease, risks and side effects. PMID- 29972402 TI - THE IMPORTANCE OF COLONOSCOPY IN INFLAMMATORY BOWEL DISEASES. AB - INTRODUCTION: Endoscopic evaluation, particularly the macroscopic mucosal and histological results of ileocolic biopsies, is essential for the management of inflammatory bowel disease. Endoscopic appearance is not always sufficient to differentiate Crohn's disease and ulcerative colitis, but there are some characteristics that favor one or another diagnosis. Both diseases have an increased incidence of colorectal carcinoma; so, surveillance colonoscopy is important for detecting early neoplastic lesions. OBJECTIVE: To update the importance of endoscopy in the evaluation, diagnosis and prognosis of inflammatory bowel disease. METHOD: Search was done in the scientific literature of the TRIP database, chosen from clinical questions (PICO) with the following descriptors: "inflammatory bowel disease", "endoscopy/colonoscopy", "Crohn's disease", "ulcerative colitis" and "diagnosis/treatment". RESULTS: Endoscopic investigation in patients with chronic colitis is quite accurate for the differential diagnosis between ulcerative colitis and Crohn's disease. Endoscopy is indicated for ulcerative colitis during severe crisis due to its prognostic value. Another accepted indication for endoscopy in inflammatory bowel disease is its use in the screening for dysplastic lesion. CONCLUSION: Ileocolonoscopy allows an accurate diagnosis of Crohn's disease or ulcerative colitis in up to 90% of cases. The healing of the mucosa assessed by endoscopy after treatments despite not being consensus is still the gold-standard in the evaluation of remission of the disease. Colonoscopy is essential for long-term cancer surveillance and in the future the implementation of Confocal Laser Endomicroscopy seems to be very promising in assessing the initial dysplasia. PMID- 29972403 TI - BARIATRIC DIET GUIDE: PLATE MODEL TEMPLATE FOR BARIATRIC SURGERY PATIENTS. AB - BACKGROUND: The Bariatric Plate Model (BPM) may be an adequate form of nutritional guideline after obesity surgery. AIM: Create a food guide, based on the Plate Model for nutritional education of bariatric patients. METHOD: The Plate Model2 was revised from a model initially suggested for dyslipidemic and hypertensive patients to a new objective: adaptation to bariatric patient who needs effective long-term nutritional education. RESULTS: The adaptation of the Plate Model considered protein needs with high biological value, as it is the priority in the BPM, followed by vitamins and minerals and lastly the carbohydrates, especially the whole ones. CONCLUSION: The BPM is a tool that can be effectively used in nutritional education of bariatric patients. PMID- 29972404 TI - EVALUATION OF ESOPHAGEAL ACHALASIA: FROM SYMPTOMS TO THE CHICAGO CLASSIFICATION. AB - INTRODUCTION: The diagnosis of achalasia may be suggested by clinical features but a complete work-up is required not only to confirm the diagnosis but also to grade the disease by severity or clinical subtype. OBJECTIVE: To review the current evaluation of esophageal achalasia and its correct comprehension. METHOD: The literature review was based on papers published on Medline/Pubmed, SciELO and Lilacs, crossing the following headings: "esophageal achalasia"; "deglutition disorders"; "diagnostic techniques", "digestive system"; "endoscopy, digestive system"; "manometry". RESULTS: The diagnosis of achalasia is suggested by clinical features but is not sufficient to distinguish this from other esophageal disease. It must be confirmed by further diagnostic tests, such as esophagogastroduodenoscopy, barium swallow and manometry. Recent advances in diagnostic methods, including high resolution manometry might even help predicting outcome or selected more appropriate procedures to treat the disease. CONCLUSION: A detailed and systematic study of achalasia patients allows not only a correct diagnosis but also contributes to therapeutic decision making and prognosis. PMID- 29972405 TI - PRE-OPERATIVE FASTING: WHY ABBREVIATE? AB - INTRODUCTION: Considering the practice of preoperative fasting based on observations on the gastric emptying delay after induction and the time of this fast is closely linked to organic response to trauma, arise the question about preoperative fasting period necessary to minimize such response and support the professional with clinical and scientific evidence. AIM: To review the aspects related to the abbreviation of preoperative fasting from the metabolic point of view, physiology of gastric emptying, its clinical benefits and the currently recommendations. METHOD: Literature review was based on articles and guidelines published in English and Portuguese, without restriction of time until January 2017, in PubMed, SciELO and Cochrane with the descriptors: surgery, preoperative fasting, carbohydrate. From the universe consulted, 31 articles were selected. RESULTS: The literature suggests that the abbreviation of fasting with beverage added carbohydrates until 2 h before surgery, can bring benefits on glycemic and functional parameters, reduces hospitalization, and does not present aspiration risk of healthy patients undergoing elective surgery. Another nutrient that has been added to the carbohydrate solution and has shown promising results is glutamine. CONCLUSION: The abbreviation of preoperative fasting with enriched beverage with carbohydrates or carbohydrate and glutamine seems to be effective in the care of the surgical patient, optimizing the recovery from of postoperative period. PMID- 29972406 TI - THE ALCOHOL CONSUMPTION IS AMENDED AFTER BARIATRIC SURGERY? AN INTEGRATIVE REVIEW. AB - BACKGROUND: Bariatric surgery has been an alternative when conservative methods of weight loss fail. Patients undergoing bariatric surgery have an increased risk of up to 6.5% of problems related to alcohol. OBJETIVE: To review the literature about the changes on alcohol consumption in this public. METHOD: Database was accessed from June of 2015 to January of 2016 by searching "bariatric surgery" AND "alcoholism", and their Portuguese equivalents. Science Direct, PubMed, Lilacs and Medline, besides manual search, were searched. To be included, the paper should have been published between 2005-2016 and related to bariatric surgery and alcoholism. Theses, dissertations, unpublished papers, case reports and theoretical studies were excluded. In 2005 there was only one review of change in alcohol metabolism in patients undergoing bariatric surgery. There were no publications in 2006. In 2007, only one study was published, and it did not meet the inclusion criteria. In 2010, there was an increase of 13% in publications and of 20% in 2012, reaching 40% in 2013. CONCLUSION: The prevalence and incidence of alcohol consumption in relation to the postoperative time was six months to three years with higher incidence in men. Roux-en-Y gastric bypass showed greater association with increased alcohol consumption during the postoperative period. This and other studies showed that the pattern of alcohol consumption is important to be faced as a problem in bariatric surgery follow-up. PMID- 29972407 TI - NECROTIZING PANCREATITIS: DESCRIPTION OF VIDEOSCOPIC ASSISTED RETROPERITONEAL DEBRIDEMENT (VARD) TECHNIQUE WITH COVERED METALLIC STENT. AB - BACKGROUND: Acute pancreatitis is the third most common gastrointestinal disorder requiring hospitalization in the United States, with annual costs exceeding $2 billions. Severe necrotizing pancreatitis is a life-threatening complication developed in approximately 20% of patients. Its mortality rate range from 15% in patients with sterile necrosis to up 30% in case of infected one associated with multi-organ failure. Less invasive treatment techniques are increasingly being used. These techniques can be performed in a so-called step-up approach. AIM: To present the technique for videoscopic assisted retroperitoneal debridement (Vard technique) with covered metallic stent in necrotizing pancreatitis. METHOD: A guide wire was inserted through the previous catheter that was removed in the next step. Afterwards, the tract was dilated over the guide wire. Then, a partially covered metallic stent was deployed. A 30 degrees laparoscopic camera was inserted and the necrosis removed with forceps through the expanded stent under direct vision. Finally, the stent was removed and a new catheter left in place. RESULT: This technique was used in a 31-year-old man with acute pain in the upper abdomen and diagnosed as acute biliary pancreatitis with infected necrosis. He was treated with percutaneous drains at weeks 3, 6 and 8. Due to partial recovery, a left lateral VARD was performed (incomplete by fixed and adherent tissue) at 8th week. As the patient's inflammatory response was reactivated, a second VARD attempt was performed in three weeks later. Afterwards, patient showed complete clinical and imaging resolution. CONCLUSIONS: Videoassisted retroperitoneal necrosectomy using partially covered metallic stent is a feasible technique for necrotizing pancreatitis. PMID- 29972408 TI - THE CRITICAL VIEW OF SAFETY PREVENTS THE APPEARANCE OF BILIARY INJURIES? ANALYSIS OF A SURVEY. AB - BACKGROUND: The risk of bile duct injury (BDI) during cholecystectomy remains a concern, despite efforts proposed for increasing safety. The Critical View of Safety (CVS) has been adopted promoting to reduce its risk. AIM: To perform a survey to assess the awareness of the CVS, estimating the proportion of surgeons that correctly identified its elements and its relationship with BDI. METHODS: An anonymous online survey was sent to 2096 surgeons inquiring on their common practices during cholecystectomy and their knowledge of the CVS. RESULTS: A total of 446 surgeons responded the survey (21%). The percentage of surgeons that correctly identified the elements of CVS was 21.8% and 24.8% among surgeons claiming to know the CVS. The percentage of surgeons that reported BDI was higher among those that incorrectly identified the elements of the CVS (p=0.03). In the multivariate analysis, career length was the most significant factor related to BDI (p=0.002). CONCLUSIONS: The percentage of surgeons that correctly identified the Critical View of Safety was low, even among those who claimed to know the CVS. The percentage of surgeons that reported BDI was higher among those that incorrectly identified the elements of the CVS. PMID- 29972409 TI - PHARYNGO-ILEO-COLO-ANASTOMOSIS WITH MICRO-VASCULAR BLOOD SUPPLY AUGMENTATION FOR ESOPHAGO-GASTRIC REPLACEMENT DUE TO ESOPHAGO-GASTRIC NECROSIS AFTER CAUSTIC INGESTION. AB - BACKGROUND: Complete esophago-gastric necrosis after caustic ingestion is a challenging surgical scenario for reconstruction of the upper digestive transit. AIM: To present a surgical technique for reconstruction of the upper digestive tract after total esophagectomy and gastrectomy due to esophageal and gastric necrosis. METHOD: The transit was re-established by means of a pharyngo-ileo colic interposition with microsurgical arterial and venous anastomosis for augmentation of blood supply. Colo-duodeno-anastomosis and ileo-transverse colic anastomosis were performed for complete digestive transit reconstruction. RESULT: This procedure was applied in a case of 41 years male attempted suicide by ingesting alkali caustic liquid (concentrated sodium hydroxide). Total necrosis of the esophagus and stomach occurred, which required initially total esophago gastrectomy, closure at the level of the crico-pharyngeal sphincter and jejunostomy for enteral feeding with a highly deteriorated quality of life . The procedure was performed later and there were no major early and late postoperative complications and normal nutritional conditions were re-stablished. CONCLUSION: The procedure is feasible and must be managed by multidisciplinary team in order to re-establish a normal quality of life. PMID- 29972410 TI - Genetic Risk Analysis of Coronary Artery Disease in a Population-based Study in Portugal, Using a Genetic Risk Score of 31 Variants. AB - BACKGROUND: Genetic risk score can quantify individual's predisposition to coronary artery disease; however, its usefulness as an independent risk predictor remains inconclusive. OBJECTIVE: To evaluate the incremental predictive value of a genetic risk score to traditional risk factors associated with coronary disease. METHODS: Thirty-three genetic variants previously associated with coronary disease were analyzed in a case-control population with 2,888 individuals. A multiplicative genetic risk score was calculated and then divided into quartiles, with the 1st quartile as the reference class. Coronary risk was determined by logistic regression analysis. Then, a second logistic regression was performed with traditional risk factors and the last quartile of the genetic risk score. Based on this model, two ROC curves were constructed with and without the genetic score and compared by the Delong test. Statistical significance was considered when p values were less than 0.05. RESULTS: The last quartile of the multiplicative genetic risk score revealed a significant increase in coronary artery disease risk (OR = 2.588; 95% CI: 2.090-3.204; p < 0.0001). The ROC curve based on traditional risk factors estimated an AUC of 0.72, which increased to 0.74 when the genetic risk score was added, revealing a better fit of the model (p < 0.0001). CONCLUSIONS: In conclusion, a multilocus genetic risk score was associated with an increased risk for coronary disease in our population. The usual model of traditional risk factors can be improved by incorporating genetic data. PMID- 29972411 TI - Pioglitazone Induces Cardiomyocyte Apoptosis and Inhibits Cardiomyocyte Hypertrophy Via VEGFR-2 Signaling Pathway. AB - BACKGROUND: Pioglitazone has been widely used as an insulin-sensitizing agent for improving glycemic control in patients with type 2 diabetes mellitus. However, cardiovascular risk and protective effects of pioglitazone remain controversial. OBJECTIVES: In this study, we investigated whether pioglitazone affects cardiomyocyte apoptosis and hypertrophy by regulating the VEGFR-2 signaling pathway. METHODS: Cardiomyocytes were enzymatically isolated from 1- to 3-day-old Sprague-Dawley rat ventricles. Effects of pioglitazone and the VEGFR-2-selective inhibitor apatinib on cardiomyocyte apoptotic rate was determined using flow cytometry, and hypertrophy was evaluated using [3H]-leucine incorporation. The protein expressions of unphosphorylated and phosphorylated VEGFR-2, Akt, P53, and mTOR were determined by Western-Blotting. Analysis of variance (ANOVA) was used to assess the differences between groups. RESULTS: Pioglitazone and VEGFR-2 selective inhibitor apatinib reduced rat cardiomyocyte viability and cardiomyocyte hypertrophy induced by angiotensin II in vitro. Furthermore, in the same in vitro model, pioglitazone and apatinib significantly increased the expression of Bax and phosphorylated P53 and decreased the expression of phosphorylated VEGFR-2, Akt, and mTOR, which promote cardiomyocyte hypertrophy. CONCLUSIONS: These findings indicate that pioglitazone induces cardiomyocyte apoptosis and inhibits cardiomyocyte hypertrophy by modulating the VEGFR-2 signaling pathway. PMID- 29972412 TI - Adropin and Irisin in Patients with Cardiac Cachexia. AB - BACKGROUND: Cardiac cachexia is an important predictive factor of the reduction in survival of patients with heart failure with reduced ejection fraction. OBJECTIVES: The aims of the present study were to evaluate adropin and irisin levels in cachectic and non-cachectic subjects and the relationships between the levels of these proteins and clinical and laboratory parameters in patients with HFrEF. METHODS: The clinical records of patients who were admitted to the cardiology outpatient clinic for heart failure with reduced ejection fraction were screened. Cachectic patients were identified and assigned to the study group (n = 44, mean age, 65.4 +/- 11.2 y; 61.4% men). Heart failure with reduced ejection fraction patients without weight loss were enrolled as the control group (n = 42, mean age, 61.0 +/- 16.5 y; 64.3% men). The serum adropin and irisin levels of all patients were measured. A p-value < 0.05 was considered significant. RESULTS: Serum adropin and irisin levels were significantly higher in the cachexia group than in the controls (Adropin (ng/L); 286.1 (231.3-404.0) vs 213.7 (203.1-251.3); p < 0.001, Irisin (ug/mL); 2.6 (2.2-4.4) vs 2.1 (1.8 2.4); p = 0.001). Serum adropin and irisin levels were positively correlated with brain natriuretic peptide (BNP) levels and New York Heart Association (NYHA) class and negatively correlated with body mass index (BMI) and serum albumin levels (all p values: < 0.001). In a multivariate analysis, adropin was the only independent predictor of cachexia in the heart failure with reduced ejection fraction patients (OR: 1.021; 95% CI: 1.004-1.038; p = 0.017). CONCLUSIONS: The results suggest that adropin and irisin may be novel markers of cardiac cachexia in heart failure with reduced ejection fraction patients. Adropin and irisin are related with the severity of heart failure. PMID- 29972413 TI - Mid- and Longterm Neo-Aortic Valve Regurgitation after Jatene Surgery: Prevalence and Risk Factors. AB - BACKGROUND: Jatene surgery became the surgical procedure of choice to repair transposition of the great arteries (TGA) in neonates and infants. Late complications, mainly related to the pulmonary outflow tract and coronary arteries, are well known. The behavior of the neo-aortic valve is a cause of concern because of its potential for requiring late reoperation. OBJECTIVES: To assess the prevalence and risk factors of neo-aortic valve regurgitation in 127 patients in the late postoperative period of the Jatene surgery. METHODS: Of the 328 survivors of the Jatene surgery at the Biocor Institute from October 1997 to June 2015, all patients undergoing postoperative follow-up were contacted via telephone, 127 being eligible for the study. The patients were divided into two groups, simple TGA and complex TGA groups, with follow-up means of 6.4 +/- 4.7 years and 9.26 +/- 4.22 years, respectively. Echocardiography was performed with adjusted measurements (Z-score) of the neo-aortic annulus, sinus of Valsalva, sinotubular region and ascending aorta, as well as quantification of the neo aortic valve regurgitation grade. RESULTS: The incidence of mild neo-aortic valve regurgitation was 29% in a follow-up of 7.4 +/- 4.7 years. Moderate regurgitation was identified in 24 patients with age mean (+/- standard-deviation) of 9.81 +/- 4.21 years, 19 of whom (79%) in the complex TGA group. Those patients had a higher aortic annulus Z-score. The reoperation rate due to neo-aortic regurgitation associated with aortic dilation was 1.5%, all patients in the complex TGA group. CONCLUSION: This study shows that, despite the low incidence of reoperation after Jatene surgery due to neo-aorta dilation and neo-aortic valve regurgitation, that is a time-dependent phenomenon, which requires strict vigilance of the patients. In this study, one of the major risk factors for neo aortic valve regurgitation was the preoperative pulmonary artery diameter (p < 0.001). PMID- 29972414 TI - Cryptogenic Acute Ischemic Stroke: Assessment of the Performance of a New Continuous Long-Term Monitoring System in the Detection of Atrial Fibrillation. AB - BACKGROUND: Long-term monitoring has been advocated to enhance the detection of atrial fibrillation (AF) in patients with stroke. OBJECTIVE: To evaluate the performance of a new ambulatory monitoring system with mobile data transmission (PoIP) compared with 24-hour Holter. We also aimed to evaluate the incidence of arrhythmias in patients with and without stroke or transient ischemic attack. METHODS: Consecutive patients with and without stroke or TIA, without AF, were matched by propensity score. Participants underwent 24-hour Holter and 7-day PoIP monitoring. RESULTS: We selected 52 of 84 patients (26 with stroke or TIA and 26 controls). Connection and recording times were 156.5 +/- 22.5 and 148.8 +/- 20.8 hours, with a signal loss of 6,8% and 11,4%, respectively. Connection time was longer in ambulatory (164.3 +/- 15.8 h) than in hospitalized patients (148.8 +/- 25.6 h) (p = 0.02), while recording time did not differ between them (153.7 +/- 16.9 and 143.0 +/- 23.3 h). AF episodes were detected in 1 patient with stroke by Holter, and in 7 individuals (1 control and 6 strokes) by PoIP. There was no difference in the incidence of arrhythmias between the groups. CONCLUSIONS: Holter and PoIP performed equally well in the first 24 hours. Data transmission loss (4.5%) occurred by a mismatch between signal transmission (2.5G) and signal reception (3G) protocols in cell phone towers (3G). The incidence of arrhythmias was not different between stroke/TIA and control groups. PMID- 29972416 TI - Tailoring the deep brain stimulation indications in Parkinson's disease. PMID- 29972415 TI - Physical Exercise and Regulation of Intracellular Calcium in Cardiomyocytes of Hypertensive Rats. AB - BACKGROUND: Regulation of intracellular calcium (Ca2+) in cardiomyocytes is altered by hypertension; and aerobic exercise brings benefits to hypertensive individuals. OBJECTIVE: To verify the effects of aerobic exercise training on contractility and intracellular calcium (Ca2+) transients of cardiomyocytes and on the expression of microRNA 214 (miR-214) in the left ventricle of spontaneously hypertensive rats (SHR). METHODS: SHR and normotensive Wistar rats of 16 weeks were divided into 4 groups -sedentary hypertensive (SH); trained hypertensive (TH); sedentary normotensive (SN); and trained normotensive (TN). Animals of the TH and TN groups were subjected to treadmill running program, 5 days/week, 1 hour/day at 60-70% of maximum running velocity for 8 weeks. We adopted a p <= 0.05 as significance level for all comparisons. RESULTS: Exercise training reduced systolic arterial pressure in hypertensive rats. In normotensive rats, exercise training reduced the time to 50% cell relaxation and the time to peak contraction and increased the time to 50% decay of the intracellular Ca2+ transients. In SHR, exercise increased the amplitude and reduced the time to 50% decay of Ca2+ transients. Exercise training increased the expression of miR-214 in hypertensive rats only. CONCLUSION: The aerobic training applied in this study increased the availability of intracellular Ca2+ and accelerated the sequestration of these ions in left ventricular myocytes of hypertensive rats, despite increased expression of miR-214 and maintenance of cell contractility. PMID- 29972417 TI - There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: findings from a systematic review and meta-analysis. AB - OBJECTIVE: Multiple sclerosis (MS) is a complex autoimmune and neurodegenerative disease of the central nervous system. Since MS affects mostly fertile women, pregnancy issues often arise in daily practice. The present study assessed the use of postpartum intravenous immunoglobulin (IVIG) in MS. METHODS: The authors individually searched for records using PubMed, Medline, EMBASE, Cochrane, SciELO, LILACS, and Google Scholar, using the terms "multiple sclerosis" OR "MS" AND "pregnancy" OR "gestation" OR "partum" OR "post-partum" OR "puerperium" AND "immunoglobulin". RESULTS: The initial search returned 321 papers. There were 11 eligible articles selected for the review. In total, 380 patients had received post-natal IVIG to reduce the number of postpartum relapses. The unadjusted number needed to treat was 6.3 for the quantitative and 5.8 for the qualitative analyses. CONCLUSION: The therapeutic effect of IVIG for prevention of postnatal relapses in MS could not clearly be established in this meta-analysis. PMID- 29972418 TI - Prevalence of obesity among stroke patients in five Brazilian cities: a cross sectional study. AB - OBJECTIVE: There is gap in knowledge about obesity prevalence in stroke patients from low- and middle-income countries. Therefore, we aimed to measure the prevalence of overweight and obesity status among patients with incident stroke in Brazil. METHODS: In a cross-sectional study, we measured the body mass index (BMI) of ischemic and hemorrhagic stroke patients. The sample was extracted in 2016, from the cities of Sobral (CE), Sertaozinho (SP), Campo Grande (MS), Joinville (SC) and Canoas (RS). RESULTS: In 1,255 patients with first-ever strokes, 64% (95% CI, 62-67) were overweight and 26% (95%CI, 24-29) were obese. The obesity prevalence ranged from 15% (95%CI, 9-23) in Sobral to 31% (95%CI, 18 45) in Sertaozinho. Physical inactivity ranged from 53% (95%CI, 43-63) in Sobral to 80% (95%CI, 73-85) in Canoas. CONCLUSIONS: The number of overweight patients with incident stroke is higher than the number of patients with stroke and normal BMI. Although similar to other findings in high-income countries, we urgently need better policies for obesity prevention. PMID- 29972419 TI - Neurosyphilis and ocular syphilis clinical and cerebrospinal fluid characteristics: a case series. AB - BACKGROUND: During the first decade of this century, a significant increase in the incidence of syphilis was documented. OBJECTIVE: To study clinical and laboratory characteristics of central nervous system and ocular syphilis. METHODS: A retrospective case series of 13 patients with a clinical and laboratory diagnosis of neurosyphilis and/or ocular syphilis who had been admitted to the Neurology and Neuro-ophthalmology Service of the Hospital de Clinicas, Federal University of Parana. RESULTS: Nine patients had a diagnosis of neurosyphilis and two of them also had ocular syphilis. Four patients had a diagnosis of ocular syphilis alone. Among the patients with a diagnosis of neurosyphilis, six had symptomatic syphilitic meningitis, of whom one manifested as cranial nerve palsy alone, one as cranial nerve palsy plus ocular syphilis, two as transverse myelitis (syphilitic meningomyelitis), one as meningitis worsening the patient's myasthenia gravis symptoms and one as meningitis plus ocular syphilis. Additionally, we diagnosed three patients with meningovascular neurosyphilis. In the univariate analysis, patients without ocular syphilis showed greater levels of total protein and white blood cells in the cerebrospinal fluid than patients with ocular syphilis. CONCLUSION: This Brazilian case series of patients with neurosyphilis and ocular syphilis highlights the wide variability of this disease. A high degree of diagnostic suspicion is necessary when facing neurological and ocular symptoms for rapid diagnosis and appropriate management of patients. PMID- 29972420 TI - Performances on the Timed Up and Go Test and subtasks between fallers and non fallers in older adults with cognitive impairment. AB - This work aimed to compare performances on the Timed Up and Go (TUG) test and its subtasks between faller and non-faller older adults with mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). A prospective study was conducted, with 38 older adults with MCI and 37 with mild AD. Participants underwent an assessment at baseline (the TUG and its subtasks using the Qualisys ProReflex system) and the monitoring of falls at the six-month follow up. After six months, 52.6% participants with MCI and 51.3% with AD fell. In accordance with specific subtasks, total performance on the TUG distinguished fallers from non-fallers with AD, fallers from non-fallers with MCI and non-fallers with MCI from non-fallers with AD. Although no other difference was found in total performances, non-fallers with MCI and fallers with AD differed on the walking forward, turn and turn-to-sit subtasks; and fallers with MCI and non-fallers with AD differed on the turn-to-sit subtask. PMID- 29972421 TI - Painful temporomandibular disorder, sleep bruxism, anxiety symptoms and subjective sleep quality among military firefighters with frequent episodic tension-type headache. A controlled study. AB - OBJECTIVE: To investigate associations of temporomandibular disorders (TMDs), bruxism, anxiety and sleep quality among military firefighters with frequent episodic tension-type headache (FETTH). METHODS: The sample comprised two groups (80 individuals): controls (mean age 35.2 years) and study group (mean age 38.5 years). Headache was diagnosed in accordance with the ICHD-III. The Research Diagnostic Criteria for TMDs were used to classify the TMDs; bruxism was diagnosed in accordance with the International Classification of Sleep Disorders; anxiety was classified using the Beck Anxiety Inventory; and sleep quality was assessed using the Pittsburgh Sleep Quality Index. In the statistical models, we used a significance level of 95%. RESULTS: Associations were found between participants with FETTH and TMDs (p < 0.001) and anxiety (p = 0.002).Poor quality of sleep (p = 0.687) and bruxism (p = 0.670) were not risk factors. CONCLUSION: The study found that TMDs and anxiety among firefighters were associated with FETTH. PMID- 29972422 TI - Genetic variants related to angiogenesis and apoptosis in patients with glioma. AB - BACKGROUND: Glioma, the most common primary malignant brain tumor in adults, is highly aggressive and associated with a poor prognosis. The objectives of this study were to evaluate the association of genetic polymorphisms related to angiogenesis and apoptosis with gliomas, as well as comorbidities, lifestyle, clinical profile, survival and response to treatment (temozolomide [TMZ] and radiotherapy [RT]) in patients with the disease. METHODS: In a total of 303 individuals, genotypes were performed by real-time PCR, and clinical data, lifestyle and comorbidities were obtained from medical records and questionnaires. The significance level was set at 5%. RESULTS: Smoking, alcohol consumption, systemic arterial hypertension, diabetes mellitus and body mass index prevailed among patients, compared to controls (p < 0.05). The heterozygous genotype rs1468727 (T/C) and the homozygous genotype rs2010963 (G/G) (p > 0.05) were observed in both groups. Lifestyle and comorbidities showed independent risk factors for the disease (p < 0.0001, p = 0.0069, p = 0.0394, respectively). Patients with low-grade gliomas had a survival rate of 80.0 +/- 1.7% in three years. For the combination of TMZ+RT, survival was 78.7 +/- 7.6% in 20 months, compared to TMZ only (21.9 +/- 5.1%, p = 0.8711). CONCLUSIONS: Genetic variants were not associated with gliomas. Specific lifestyle habits and comorbidities stood out as independent risk factors for the disease. Low-grade gliomas showed an increase in patient survival with TMZ+RT treatment. PMID- 29972423 TI - Impulse control and related disorders in Parkinson's disease. AB - Neuropsychiatric disorders are common among patients with Parkinson's disease and may appear in any stage of the disease. However, these disorders often go undiagnosed and receive insufficient treatment. Observations in recent years have revealed that dopamine replacement therapy may lead to the development or worsening of conditions, such as gambling disorder, compulsive sexual behavior, compulsive buying and binge eating, in addition to punding and dopamine dysregulation syndrome. The pathophysiology of these disorders seems to be related to abnormal dopaminergic stimulation of the basal regions of the basal ganglia, especially via nigro-mesolimbic pathways. The aim of the present study was to perform a literature review on impulsivity, impulse control disorders and related conditions among patients with Parkinson's disease, with emphasis on their epidemiology, clinical characteristics and treatment. PMID- 29972424 TI - Decisions about deep brain stimulation therapy in Parkinson's disease. AB - Parkinson's disease can be treated surgically in patients who present with motor complications such as fluctuations and dyskinesias, or medically-refractory disabling tremor. In this review, a group of specialists formulated suggestions for a preoperative evaluation protocol after reviewing the literature published up to October 2017. In this protocol, eligibility and ineligibility criteria for surgical treatment were suggested, as well as procedures that should be carried out before the multidisciplinary therapeutic decisions. The review emphasizes the need to establish "DBS teams", with professionals dedicated specifically to this area. Finally, surgical target selection (subthalamic nucleus or globus pallidus internus) is discussed briefly, weighing the pros and cons of each target. PMID- 29972425 TI - Lazarevic-Lasegue sign. AB - Charles Lasegue is reputed to have described the test/sign bearing his name, but he never wrote about it and misinterpreted its mechanism. The purpose of this note is to highlight the work of the Serbian, Laza Lazarevic, who was first to present the original report of this seminal sign in sciatica and provide its appropriate pathophysiological interpretation. PMID- 29972426 TI - Pancake-like gadolinium enhancement in the spinal cord: an image pattern that suggests spondylotic myelopathy. PMID- 29972427 TI - Opisthotonus (arc de cercle) in anti-NMDAR encephalitis. PMID- 29972428 TI - Erratum: Is phrenic nerve conduction affected in patients with difficult-to-treat asthma? AB - [This corrects the article doi: 10.1590/0004-282x20180010]. PMID- 29972429 TI - Mechanisms involved in anti-aging effects of guarana (Paullinia cupana) in Caenorhabditis elegans. AB - Guarana (Paullinia cupana) is habitually ingested by people in the Amazon region and is a key ingredient in various energy drinks consumed worldwide. Extension in longevity and low prevalence of chronic age-related diseases have been associated to habitual intake of guarana. Anti-aging potential of guarana was also demonstrated in Caenorhabditis elegans; however, the mechanisms involved in its effects are not clear. Herein, we investigated the putative pathways that regulate the effects of guarana ethanolic extract (GEE) on lifespan using C. elegans. The major known longevity pathways were analyzed through mutant worms and RT-qPCR assay (DAF-2, DAF-16, SKN-1, SIR-2.1, HSF-1). The possible involvement of purinergic signaling was also investigated. This study demonstrated that GEE acts through antioxidant activity, DAF-16, HSF-1, and SKN-1 pathways, and human adenosine receptor ortholog (ADOR-1) to extend lifespan. GEE also downregulated skn-1, daf-16, sir-2.1 and hsp-16.2 in 9-day-old C. elegans, which might reflect less need to activate these protective genes due to direct antioxidant effects. Our results contribute to the comprehension of guarana effects in vivo, which might be helpful to prevent or treat aging-associated disorders, and also suggest purinergic signaling as a plausible therapeutic target for longevity studies. PMID- 29972430 TI - Establishment of a rat model for uterine leiomyomas based on Western and traditional Chinese medicine theories. AB - Uterine leiomyomas (ULs) are benign monoclonal tumors that arise from the underlying myometrial tissue in the uterus. Effective therapies are still lacking because of poor understanding of the pathophysiology and epidemiology. Hence, it is urgent to establish efficient animal models to screen novel anti-UL therapies. In this study, for the first time, traditional Chinese medicine and Western medicine were combined to establish an animal model of ULs in rats. In order to evaluate the function and value of the novel model, it was compared with other models. The long-term and short-term rat models for ULs were established using progesterone and diethylstilbestrol. Rats in Qi stagnation and blood stasis group were injected with epinephrine hydrochloride and received chronic unpredictable stress for two weeks. Rats in combining disease with syndrome group (CDWSG) received not only epinephrine hydrochloride injection and chronic unpredictable stress but also progesterone and diethylstilbestrol treatment. We analyzed differences in organ coefficient, uterus size, uterine pathology, concentrations of progesterone, estradiol, progesterone receptor, estrogen receptor, expression of desmin, alpha-smooth muscle actin, and vimentin among the five groups. The animal model of ULs was successfully constructed by loading the rats with estrogen and progesterone. The rat model of CDWSG was more stable than other groups and the method was the most efficient. PMID- 29972431 TI - Incentives and barriers to HIV testing among female sex workers in Ceara. AB - OBJECTIVE: Estimating HIV prevalence and describing the incentives and barriers for HIV testing among female sex workers. METHODS: This cross-sectional study recruited 402 women aged 18 years or older, residing in Fortaleza, state of Ceara, Brazil, who reported having had sexual intercourse in exchange for money in last four months. The sample was recruited using Respondent Driven Sampling, between August and November 2010. RESULTS: The 84.1% of the sample tested and the estimated prevalence of HIV infection was 3.8%. The sample was young (25 to 39 years ), single (80.0%), with one to three children (83.6%), had eight or more years of schooling (65.7%), and belonged to social classes D/E (53.1%). The majority worked in fixed locations (bars, motels, hotels, sauna - 88.9%), and prostitution was their only source of income (54.1%). About 25% of the sample did not know where to test in the public health sector and 51.8% either never tested or hadn't tested for over a year or more. The main reported barriers to testing were the perceptions that there was no risk of becoming infected (24.1%), and, alternatively, fear of discrimination if the test was positive (20.5%). Incentives for testing were the greater availability of testing sites (57.0%) and health facilities with alternative schedules (44.2%). CONCLUSIONS: Prevalence for HIV was similar to that found in other Brazilian cities in different regions of the country, although higher than the general female population. Non-traditional venues not associated with the health system and availability of testing in health units during non-commercial hours are factors that encourage testing. Not considering oneself to be at risk, fear of being discriminated against and not knowing testing locations are barriers. PMID- 29972432 TI - Hemovigilance: the experience of transfusion reaction reporting in a Teaching Hospital. AB - OBJECTIVE: To describe the occurrence of immediate transfusion reactions received by the Risk Management Department of Hospital Sao Paulo. METHOD: Cross-sectional and retrospective study which analyzed the notification sheets of transfusion reactions that occurred between May 2002 and December 2016 and were included in the Hemovigilance National System. RESULTS: One thousand five hundred and forty eight transfusion reaction notification sheets were analyzed, all of which concerned immediate reactions associated with packed red blood cells (72.5%). The most frequently reported reaction was febrile non-hemolytic transfusion reaction, and among severe and moderate cases, allergic reaction was the most common. The most frequently reported signs and symptoms were hyperthermia, sudoresis, chills, and skin lesions. No differences were observed regarding gender and age, and 90.7% of reactions occurred in patients with Rh+ factor. CONCLUSION: This study allowed for a better assessment and understanding of transfusion reactions, which will help to improve the quality of blood circulation and provide greater safety of patients undergoing transfusion therapy. PMID- 29972433 TI - The elusive clinical significance of osteocalcin actions in energy metabolism in humans. PMID- 29972434 TI - How deep is our anxiety during treatment of thyroid cancer? PMID- 29972435 TI - An update of genetic basis of PCOS pathogenesis. AB - Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61. PMID- 29972437 TI - UNIFESP Info Plastica - An informative application covering the most frequently performed plastic surgeries worldwide. AB - OBJECTIVES: The objective of this study was to develop a free smartphone application with reliable and useful information for the lay public on the most frequently performed plastic surgeries worldwide. METHODS: The five most frequently performed surgeries worldwide according to ISAPS (International Society of Aesthetic Plastic Surgery) were selected. Information from the websites of the American Society of Plastic Surgeons (ASPS), American Society for Aesthetic Plastic Surgery (ASAPS) and Brazilian Society of Plastic Surgery (SBCP) and from the Outpatient and Hospital Medicine Guide of the Plastic Surgery Division at the Federal University of Sao Paulo (UNIFESP) was used for content assembly. YouTube videos with patients' postoperative testimonials were used for an improved understanding of their real concerns. Printed text was distributed to patients in Brazil's Unified Health Service to improve comprehensibility. Content on each of the five surgeries was presented in the application with the following layout: What is the surgery?; Who are the candidates?; Preparations for surgery; Stages of surgery; Recovery after surgery; Complications; Choice of surgeon; Consultation; What is the cost? and Glossary. All material was delivered to an outsourced company to produce the application software. RESULTS: The result was the creation of an application with extensive content on the most frequently performed plastic surgeries. CONCLUSION: The UNIFESP Info Plastica application is an academically based, free and reliable source of information for the lay public interested in all aspects of the most frequently performed plastic surgeries worldwide. PMID- 29972436 TI - Prophylactic application of laser light restores L-FABP expression in the livers of rats submitted to partial ischemia. AB - OBJECTIVES: The objective of the present study was to evaluate the protective effect of pre-conditioning treatment with laser light on hepatic injury in rats submitted to partial ischemia using mitochondrial function and liver fatty acid binding protein as markers. METHODS: Rats were divided into four groups (n=5): 1) Control, 2) Control + Laser, 3) Partial Ischemia and 4) Partial Ischemia + Laser. Ischemia was induced by clamping the hepatic pedicle of the left and middle lobes of the liver for 60 minutes. Laser light at 660 nm was applied to the liver immediately prior to the induction of ischemia at 22.5 J/cm2, with 30 seconds of illumination at five individual points. The animals were sacrificed after 30 minutes of reperfusion. Blood and liver tissues were collected for analysis of mitochondrial function, determination of malondialdehyde and analysis of fatty acid binding protein expression by Western blot. RESULTS: Mitochondrial function decreased in the Partial Ischemia group, especially during adenosine diphosphate activated respiration (state 3), and the expression of fatty acid binding protein was also reduced. The application of laser light prevented bioenergetic changes and restored the expression of fatty acid binding protein. CONCLUSION: Prophylactic application of laser light to the livers of rats submitted to partial ischemia was found to have a protective effect in the liver, with normalization of both mitochondrial function and fatty acid binding protein tissue expression. PMID- 29972438 TI - Natural history of 39 patients with Achondroplasia. AB - OBJECTIVES: To characterize the natural history of 39 achondroplastic patients diagnosed by clinical, radiological and molecular assessments. METHODS: Observational and retrospective study of 39 patients who were attended at a public tertiary level hospital between 1995 and 2016. RESULTS: Diagnosis was made prenatally in 11 patients, at birth in 9 patients and within the first year of life in 13 patients. The most prevalent clinical findings were short stature, high forehead, trident hands, genu varum and macrocephaly. The most prevalent radiographic findings were rhizomelic shortening of the long bones and narrowing of the interpediculate distance of the caudal spine. There was motor developmental delay in 18 patients and speech delay in 16 patients. The most common clinical intercurrences were middle ear dysfunction, sleep apnea, limb pain and obesity from 2 to 9 years of age. One patient was large for the gestational age but did not develop obesity. One patient developed hydrocephalus at 10 years old. The current age of the patients varies from 15 months to 36 years. The molecular study performed by Sanger sequencing of the common heterozygous mutation 1138G>A in FGFR3 was positive in all patients. Four cases were inherited, and 35 were sporadic (paternal age from 19 to 66 years). CONCLUSIONS: The diagnoses were made early based on clinical and radiographic findings. All cases were confirmed molecularly. Despite presenting a benign course, it is necessary to establish a systematic protocol for the surveillance of these patients due to the common clinical intercurrences. PMID- 29972439 TI - Analysis of cancer perception by elderly people. AB - OBJECTIVE: To evaluate the perception of elderly population about cancer, correlating it with the clinical variables sex, age and past history of cancer. METHODS: The sample was composed of 300 individuals, 174 (58%) women. A questionnaire containing ten questions and based on the Health Information National Trends Survey was used. For statistical analysis, a p value <0.05 was considered significant. RESULTS: Individuals aged 80 years and older were more likely to believe that regular tests can identify cancer in early stages, compared to elderly aged under 80 years (OR: 0.103; CI95%: 0.021-0.499; p=0.005). Elderly subjects with positive history of cancer were more likely to believe that few people survive cancer, compared to those who never had the disease (OR: 0.379; CI95%: 0.167-0.858; p=0.02). All patients with a positive history of cancer believed that early-detected cancer can be cured. CONCLUSION: Aged individuals with >=80 years or older believed in regular exams as a form of early detection of cancer, probably due to the greater frequency of medical instructions. Subjects who had cancer believed that few people survive the disease, perhaps because of the negative experiences they have experienced. Considering the greater presence of fatalistic perceptions, this group constitutes a potential target for educational approaches about cancer. PMID- 29972440 TI - What are the most frequent diagnoses in adolescence? The reality of an Adolescent Medicine Clinic. AB - OBJECTIVE: To characterize the care flow and the primary diagnoses of an Adolescent Medicine Clinic. METHODS: A retrospective descriptive study, with analysis of clinical processes of adolescents (10-18 years) seen at the Adolescent Medicine Clinic, from January 2006 to December 2013. The following variables were analyzed: sex, age, number of visits, referring service and primary diagnoses according to the International Statistical Classification of Diseases and Related Health Problems. As to the variable age, the adolescents were divided into two groups: Group I comprised those aged 10-14 years, and Group II, 15-18 years. RESULTS: A total of 7,692 visits were carried out, in that, 1,659 first visits (22%), with an annual growth rate of 6%. The mean age was 14.2 years, and 55% of patients were female. The group of endocrine, nutritional and metabolic diseases was the most representative in our sample (34%), with obesity being the most frequent diagnosis in both sexes and age groups (23%), with a higher prevalence in males (13% male versus 10% female, p<0.001) and younger adolescents (18% in Group I versus 5% in Group II p<0.001). The group of mental and behavioral disorders was the second most prevalent (32%), affecting mainly females (39% female versus 22% male, p<0.001) and the older age group (39% Group II versus 27% Group I, p<0.001). Social problems were the primary diagnosis in 8% of visits. CONCLUSION: Most diseases diagnosed have a strong behavioral and social component, particularly mental disorders and obesity. This specific type of diagnoses reinforces the need for a global approach for adolescents and specialized adolescent medicine units/clinics. PMID- 29972441 TI - Formulation, implementation and evaluation of a distance course for accreditation in patient safety. AB - OBJECTIVE: To formulate and to implement a virtual learning environment course in patient safety, and to propose ways to estimate the impact of the course in patient safety outcomes. METHODS: The course was part of an accreditation process and involved all employees of a public hospital in Brazil. The whole hospital staff was enrolled in the course. The accreditation team defined the syllabus. The education guidelines were divided into 12 modules related to quality, patient safety and required organizational practices. The assessment was performed at the end of each module through multiple-choice tests. The results were estimated according to occurrence of adverse events. Data were collected after the course, and employees' attitude was surveyed. RESULTS: More than 80% of participants reached up to 70% success on tests after the course; the event-reporting rate increased from 714 (16,264 patients) to 1,401 (10,180 patients). CONCLUSION: Virtual learning environment was a successful tool data. Data on course evaluation is consistent with increase in identification and reporting of adverse events. Although the report increment is not positive per si, it indicates changes in patient safety culture. PMID- 29972442 TI - Current state of multiparameter magnetic resonance imaging of the prostate. AB - Magnetic resonance imaging of the prostate is an imaging method that has shown increasing relevance in urological practice. Due to technological evolution of scanners and the introduction of functional sequences, it has enabled greater accuracy in detection and characterization of prostate tumors. PMID- 29972443 TI - Narrative evaluation strategies as metacognitive task in subjects with schizophrenia. AB - PURPOSE: This study aims to explore the differences in the evaluative component of the narrative structure in subjects diagnosed with schizophrenia compared to subjects diagnosed with affective psychosis. METHODS: The present investigation was descriptive, not experimental and it included the analysis of the narration evaluative components of interviews of 25 individuals with psychiatric diagnosis of chronic schizophrenia and 25 of chronic affective psychosis, matched by age, gender and sociodemographic characteristics. RESULTS: The relationship between diagnosis and type of evaluation showed statistically significant results with a chi square value of 39.880a (p <0.00). It was possible to observe that in the schizophrenia there is a greater inhibition in the elaboration of expressions that imply opinions and that narratives tended to identify facts regardless of how they affected subjects, suggesting a limitation of intersubjective function. CONCLUSION: The diagnostic variable confirms that in schizophrenia there is a functional deterioration in the process of elaborating narrative structures especially in the articulation of the evaluative component. In the case of the affective psychosis group, superficial dysfunctions were manifested, without compromising their performance in the evaluation of narratives. PMID- 29972444 TI - Correlation between sleep profile and behavior in individuals with specific learning disorder. AB - PURPOSE: This study aimed to correlate sleep profile and behavior in individuals with Specific Learning Disorder (SLD). METHODS: The Sleep General Habits Questionnaire, Sleep Diary, and Sleep Disturbance Scale for Children (SDSC) were used in analysis of sleep, whereas the Child Behavior Checklist (CBCL) inventory was used in analysis of behavior. RESULTS: 65.5% of the individuals with SLD presented symptoms of sleep disorders, most frequently wakefulness-sleep transition and sleep disturbance total score, which showed values higher than acceptable. In addition, individuals with SLD presented higher sleep latency than those with typical development. Concerning behavior, 72.4% of the individuals with SLD presented clinical condition of behavior problems. In the control group, none of the participants showed symptoms of sleep or behavior problems. In the SLD group, correlation was observed between behavioral problems and sleep disturbance. CONCLUSION: Individuals with SLD showed high rates of sleep disturbance and behavioral problems. The worse the sleep disturbance, the worse the behavioral aspects in these individuals. PMID- 29972445 TI - Evidence of validity and reliability of a phonological assessment tool. AB - PURPOSE: To present evidence of the validity and reliability of a phonological assessment tool developed to assess the phonological inventory of Brazilian Portuguese. METHODS: The study included 866 children aged between 3 and 8:11 years, divided into three groups: typical, control and clinical. Participants were evaluated using a phonological assessment software, which prompted the spontaneous naming of a series of images. The children's responses were audio recorded and transcribed at the time of the assessment, by the software itself. The Cronbach's alpha coefficient was used to evaluate the internal consistency of the instrument for reliability and validity purposes. Criterion validity was examined by comparing the performance of different groups using Student's t-test for independent samples. Intra- and inter-rater agreement were investigated using Kendall's tau. Results were considered significant at p <= 0.05. RESULTS: The present study provided evidence of validity and reliability (internal consistency) for this phonological assessment tool, confirming the reliability of its items and demonstrating excellent agreement rates between examiners regarding its scoring (intra- and inter-rater reliability). The criterion validity assessment demonstrated that the control group outperformed the clinical group across all phonemes, showing that test scores were successful in identifying children with speech sound disorders (phonological disorders). CONCLUSION: The present findings provide strong evidence of the validity and reliability of this phonological assessment tool. PMID- 29972447 TI - Use of Micro-Computed Tomography for Bone Evaluation in Dentistry. AB - Micro computed tomography (uCT) follows the same principle of computed-tomography used for patients, however providing higher-resolution. Using a non-destructive approach, samples can be scanned, and each section obtained is used to build a volume using tridimensional reconstruction. For bone analysis, it is possible to obtain information about the tissue's microarchitecture and composition. According to the characteristics of the bone sample (e.g. human or animal origin, long or irregular shape, epiphysis or diaphysis region) the pre-scanning parameters must be defined. The resolution (i.e. voxel size) should be chosen taking into account the features that will be evaluated, and the necessity to identify inner structures (e.g. bone channels and osteocyte lacunae). The region of interest should be delimited, and the threshold that defines the bone tissue set in order to proceed with binarization to separate the voxels representing bone from the other structures (channels, resorption areas, and medullary space). Cancellous bone is evaluated by means of the trabeculae characteristics and their connectivity. The cortex is evaluated in relation to the thickness and porosity. Bone mineral density can also be measured, by the amount of hydroxyapatite. Other parameters such as structure-model-index, anisotropy, and fractal dimension can be assessed. In conclusion, intrinsic and extrinsic determinants of bone quality can be assessed by uCT. In dentistry, this method can be used for evaluating bone loss, alterations in bone metabolism, or the effects of using drugs that impair bone remodeling, and also to assess the success rate of bone repair or surgical procedures. PMID- 29972446 TI - Reproducibility assessment of an instrument for measuring the axial force of the tongue. AB - PURPOSE: Evaluate the reproducibility of Forling, a portable instrument for measuring axial tongue force. METHODS: Axial force of the tongue was measured in 49 individuals (30 women and 19 men) aged 18-25 years using the Forling portable instrument. Measurements were performed in three days at intervals of 7+/-2 days. On each day, three 7-second measurements were performed with one-minute intervals between them. The coefficient of variation, Wilcoxon paired test, and intraclass correlation coefficient were used in the statistical analysis of the data. Maximum and mean tongue force values were analyzed, and comparison between them was performed using three approaches: the mean of the three values; the mean of the two highest values; the highest value of each measurement. RESULTS: In the analysis of mean tongue force, the coefficient of variation was considered desirable and the intraclass correlation coefficient was acceptable. Significant differences were observed regarding the maximum value between the second and third days, mean of the two highest values and mean of the three values between the first and second days and the second and third days. In the analysis of maximum tongue force, the coefficient of variation and the intraclass correlation coefficient were acceptable. Significant difference was found only in the comparison between the second and third days. CONCLUSION: Good reproducibility of the data obtained with the use of the Forling portable instrument was observed. PMID- 29972448 TI - Root Morphology and Number of Canals in Mandibular Central and Lateral Incisors Using Cone Beam Computed Tomography. AB - Most failures in endodontic treatment of mandibular incisors are due to the presence of a missed canal specifically the lingual. This investigation aimed to examine the root morphology and number of canals in mandibular incisors using cone beam computed tomography (CBCT). Two hundred and seven patients were assessed in terms of their mandibular central and lateral incisors of CBCT. The inclusion criteria were absence of root resorption, coronal restoration or root filling and clarity and optimal resolution of images. According to the Vertucci's classification, number of roots and canals and type of canal were evaluated by two oral and maxillofacial radiologists. In order to data analysis SPSS version 16 and descriptive statistics were implemented. All mandibular incisors had one root. Most central (84.5%) and lateral (78.2%) incisors had a single canal (p= 0.065). The majority of central (54.5%) and lateral (56.5%) incisors were Vertucci's type I (p= 0.102). Prevalence of one canal in males: central (84.8%), lateral (77.9%) and in females: central (84.2%), lateral (78.5%) (p= 0.518). Prevalence of Vertucci's type I in males: central (52.3%), lateral (45.3%) and in females: central (56.1%), lateral (64.4%) (p=0.188). The prevalence of two canals was 15.5% (central) and 21.8% (lateral) in mandibular incisors. The Vertucci's type I was the most typical kinds of mandibular incisors. Considering the limitations of periapical radiography in determining canal morphology, CBCT can be helpful in case of any concern regarding root canal morphology. PMID- 29972449 TI - Evaluation of Apically Extruded Debris Using Continuous Rotation, Reciprocation, or Adaptive Motion. AB - The aim of this study was to compare the amount of apically extruded debris during root canal instrumentation using ProTaper Next (PTN), Twisted File (TF) Adaptive, and Reciproc instruments. Forty-five extracted human maxillary canines were selected and randomly assigned into 3 groups. The root canals were prepared using PTN instruments with continuous rotation (n=15), TF Adaptive instruments with adaptive motion (n=15), Reciproc instruments with reciprocating motion (n=15). During the preparations, canals were irrigated using distilled water and material extruded apically was collected in pre-weighed Eppendorf tubes. After a 5-day drying period in an incubator, the tubes were weighed and the dry weight of the extruded debris was calculated. Data distributions were assessed via the Shapiro-Wilk test, and groups were compared via the Kruskal-Wallis test. The greatest amount of debris extruded by TF Adaptive and the least by PTN, but the difference was insignificant between groups (p=0.259). All instrumentation systems were associated with debris extrusion. PMID- 29972450 TI - Evaluation of the WaveOne Gold and One Shape New Generation in Reducing Enterococcus faecalis from Root Canal. AB - The aim of this study was to evaluate the WaveOne Gold and One Shape New Generation systems regarding the bacterial removal from root canals infected with Enterococcus faecalis by comparing them to the conventional WaveOne and One Shape systems. Forty-eight distobuccal root canals of maxillary molars sterilized with ethylene oxide were infected with E. faecalis for 21 days, and then root canal initial bacterial sample was collected with paper cones and plated on M enterococcus agar. The specimens were randomly divided into 4 groups according to the instrumentation: WaveOne Gold, One Shape New Generation, WaveOne and One Shape. After instrumentation, samples were collected with use of scraping and paper cones at immediate and 7 days after instrumentation. The bacterial reduction was calculated and then made intragroup analysis by Friedman test and intergroup analysis by Kruskal-Wallis with Dunn's post-hoc test, all at 5% significance. All techniques significantly reduced the number of bacteria in the root canal (p<0.05). WaveOne Gold and One Shape New Generation promoted higher bacterial reduction than WaveOne and One Shape systems (p<0.05), but no significant difference was found between WaveOne Gold and One Shape New Generation or between WaveOne and One Shape (p>0.05). Novel single-file systems promote better bacterial removal than the conventional single-file systems. PMID- 29972451 TI - Effect of Premedication with Anti-inflammatory Drugs on Post-Endodontic Pain: A Randomized Clinical Trial. AB - In spite of advances in root canal therapy and better knowledge of pulpal and periapical inflammation, up 40% of endodontic patients report varying degrees of pain. The aim of this present study was to compare the effect of single preoperative dose of ibuprofen or dexamethasone on post-endodontic pain. Sixty volunteers were divided into three groups (n=20 per group): PL, placebo; IB, 400 mg of ibuprofen; and DE, 8 mg of dexamethasone. The primary outcome was the post endodontic pain intensity measured with a numerical rating scale (4, 8, 12, 24, and 48 h). Secondary outcomes included number of anesthetic cartridges used and consumption of rescue medication. Data were analyzed by one-way ANOVA, chi-square and Kruskal-Wallis tests. There was no significant difference among groups (p>0.05) considering the pain intensity. Only 37% of IB group patients and 28% of DE group patients used some rescue medication. On the other hand, 74% of PL group patients mentioned the consumption of rescue medication; PL group had a statistically significant difference (p<0.05) in comparison with IB and DE groups. The number of anesthetic cartridges used had no statistically significant difference among the groups (p>0.05). Significant differences were not found in the reduction of pain intensity and the number of anesthetic cartridges used. Considering the consumption of rescue medication (secondary outcome), preoperative administration of Ibuprofen or dexamethasone reduces post-endodontic pain and discomfort in comparison with a placebo. Premedication with anti inflammatory drugs drugs could be contributed to control of the post-endodontic pain, mainly in patients more sensible for pain. PMID- 29972452 TI - Polymerization Shrinkage of Bulk Fill Composites and its Correlation with Bond Strength. AB - The present study aimed to evaluates polymerization shrinkage (PS) using microcomputed tomography (MUCT) and microtensile bond strength (MUTBS) in bulk fill composites (BFC) and conventional class I restorations as well as the correlation between these factors. Class I cavities (4 x 5 x 4 mm), factor-C = 4.2, were created in third molars that were free of caries, which were randomly divided in 4 groups (n = 6): XTI (Filtek Supreme XTE: incremental technique); XTB (Filtek Supreme XTE: single fill technique); TBF (Tetric Bulk Fill); and SF (SonicFill). Each tooth was scanned twice in MUCT: T0 was after filling the cavity with composite, and T1 was after light curing. The data were analyzed by subtracting the composite volume for each time (T1 - T0). After 1 week, the teeth were sectioned crosswise in the buccolingual and mesiodistal directions to obtain specimens with approximately 1 mm2 thickness and fixed in a universal testing machine to perform MUTBS. The Kruskal-Wallis and Dunn tests showed a statistically significant difference for shrinkage in uCT among the XTI and XTB and between the SF and XTB. Regarding the MUTBS, all the groups differed from XTB. Bulk fill composites type presents a PS similar to that of the conventional nanoparticulate composite inserted using the incremental technique, but the bond strength was higher for the incremental group, which presented a lower number of pre-test failures when compared to BFC. No correlation was observed between the polymerization shrinkage and bond strength in the studied composites. PMID- 29972453 TI - Effect of Dentin Preparation Mode on the Bond Strength Between Human Dentin and Different Resin Cements. AB - The aim was to evaluate the influence of different dentin preparation mode in the smear layer characteristics (SL), hybrid layer (HL), and microtensile bond strength (uTBS) to dentin with two resin cements. The occlusal dentin of 120 third molars was exposed. The teeth were divided into 4 groups (n=30) according to the dentin preparation mode: 1- fine grain diamond bur; 2- coarse grain diamond bur; 3- multi laminate carbide steel bur; and, 4- ultrasonic CV Dentus diamond bur. Each treated dentin group was divided into 2 sub-groups (n=15) according to the resin cement: (1) RelyX U200 and (2) RelyX ARC. Resin composite blocks were cemented on dentin. After storage at 37o C for 24 h, beams with a cross section area of 1.0 mm2 were obtained, and tested in a universal testing machine at a crosshead speed of 0.5 mm/min. Two additional teeth for each sub group were prepared to analyze the SL and HL on a scanning electron microscopy. According to Kruskal-Wallis test and Dunn tests, there was no significant difference in uTBS among the rotary instruments within each resin cement group. RelyX ARC obtained higher uTBS values compared to RelyX U200 (p<0.05). RelyX ARC formed evident HL, which was not observed for RelyX U200. The dentin mode preparation did not influence the uTBS of the resin cements. The SL was different for all instruments. The cementing agent is more determinant in the hybrid layer formation and bond strength to dentin than the instruments applied on dentin. PMID- 29972454 TI - Can the Application of Multi-Mode Adhesive be a Substitute to Silicatized/Silanized Y-TZP Ceramics? AB - This study evaluated the effectiveness of a multi-mode adhesive (SBU-Scotch Bond Universal/3M) as a substitute for silica coating and silane application on the bonding of zirconia ceramics to resin cement. One-hundred and twenty sintered zirconia ceramic blocks (5 x 5 x 5 mm) were obtained, finished by grounding with silicon carbide paper (#600, #800, #1000 and #1200) and randomly divided into 12 groups (n=10) in accordance with the factors "surface treatment" (ScSi - silicatization + silanization; ScSBU - silicatization + SBU; SBU - SBU without photoactivation and SBUp - SBU photoactivated) and "ceramic" (Lava / 3M ESPE, Ceramill Zirconia / Amann Girrbach and Zirkonzahn / Zirkonzahn). Dual resin cement cylinders (RelyX Ultimate/3M ESPE) were subsequently produced in the center of each block using a silicon matrix (O=2 mm, h=5 mm) and photoactivated for 40 s (1200 mW/cm2). The samples were stored for 30 days in distilled water (37oC) and submitted to shear bond strength test (1 mm/min, 100 KgF). Data (MPa) were analyzed under ANOVA (2 levels) and Tukey test (5%). Complementary analyzes were also performed. ANOVA revealed that only the factor "surface treatment" was significant (p=0.0001). The ScSi treatment (14.28A) promoted statistically higher bond strength values than the other ScSBU (9.03B), SBU (8.47B) and SBUp (7.82B), which were similar to each other (Tukey). Failure analysis revealed that 100% of the failures were mixed. The silica coating followed by the silanization promoted higher bond strength values of resin cement and ceramic, regardless of the zirconia ceramic or SBU. PMID- 29972455 TI - Irradiance and Radiant Exposures Delivered by LED Light-Curing Units Used by a Left and Right-Handed Operator. AB - The combination of the restoration location, the hand preference of the operator using the light-curing unit (LCU), and the design of the LCU all can have an impact on the amount of the light delivered to the restoration. To evaluate the effect of left-handed or right-handed users, the position of the operator (dentist or assistant), and the LCU design on the irradiance, radiant exposure and emission spectrum delivered to the same posterior tooth. Two light emitting diode (LED) LCUs were tested: an angulated monowave LCU Radii-Cal (SDI, Victoria, Australia) and a straight aligned multi-peak LCU Valo Cordless (Ultradent, South Jordan, UT, USA). The irradiance values (mW/cm2), radiant exposure (J/cm2) and emission spectrum were measured using a sensor in maxillary left second molar tooth. The irradiance and radiant exposure were analyzed using three-way ANOVA followed by Tukey test (a=0.05). The emission spectra (nm) were analyzed descriptively. The interaction between LCU design, operator position, and hand preference significantly influenced the irradiance and radiant exposure (P<0.001). In all cases, Valo delivered significantly higher irradiance than Radii-Cal. The handedness and the operator position affected the irradiance and radiant exposure delivered from Valo. Operator position and access affect the irradiance and radiant exposure delivered to the maxillary left second molar. The irradiance and radiant exposure can be greater when a right-hand operator is positioned on the right side of the chair and a left-hand operator is positioned on the left side of the chair. This may result in better resin composite polymerization. PMID- 29972456 TI - Microbial Load After Selective and Complete Caries Removal in Permanent Molars: a Randomized Clinical Trial. AB - The aim of this randomized clinical trial was to compare the remaining microbial load after treatments based on complete and selective caries removal and sealing. Patients with active carious lesions in a permanent molar were randomly allocated into 2 groups: a test group (selective caries removal-SCR; n=18) and a control group (complete caries removal - CCR; n=18). Dentin samples were collected following the excavation and three months after sealing. Streptococcus species, Streptococcus mutans, Lactobacillus species, and total viable microorganisms were cultured to count the viable cells and frequency of species isolation. CCR resulted in significant lower total viable microorganisms counts (p<=0.001), Streptococcus species (p<=0.001) and Lactobacillus species (p<=0.001) initially. However, after sealing, a decrease in total viable microorganisms, Streptococcus species, and Lactobacillus species in the SCR resulted in no difference between the groups after 3 months. In conclusion, selective caries removal is as effective as complete caries removal in reducing dentin bacterial load 3 months after sealing. PMID- 29972457 TI - Comparison Of Full-Mouth Scaling and Quadrant-Wise Scaling in the Treatment of Adult Chronic Periodontitis. AB - In the search for the ideal treatment of periodontal disease various non-surgical techniques should be considered. The objective of this study was to evaluate the efficacy of full-mouth scaling (FMS) by clinical and microbiological parameters. 670 individuals were evaluated with 230 subjects meeting the selection criteria and were divided into two groups; 115 subjects treated with FMS and 115 treated with weekly sessions of scaling and root planning (SRP). The patient population had a mean age of 51.67 years, with moderate chronic periodontitis. Subjects were evaluated prior to treatment (T1) and 90 days after execution of therapy (T2), with regards to: probing depth (PD), clinical attachment level (CAL), plaque index (PI), gingival index (GI), and microbial detection for the presence of Porphyromonas gingivalis (P.g.) and Prevotella intermedia (P.i.) by culture method and confirmed by biochemical tests. Subjects treated in the FMS group also rinsed with 0.12% chlorhexidine mouthwash for seven days following treatment. The results were analyzed using statistical Student's t-test and chi-square test. No statistically significant differences were observed for PD and CAL between T1 and T2 in both groups. For GI and PI significant difference was observed between the groups. For the evaluated microbial parameters was observed reduction of P.g. and P.i., but only for P.g. with a significant reduction in both groups. The full mouth scaling technique with the methodology used in this study provided improved clinical conditions and reduction of P.g. in subjects with moderate periodontitis, optimizing the time spent in the therapeutic execution. PMID- 29972458 TI - Periodontal Condition and Immunological Aspects of Individuals Hospitalized in the Intensive Care Unit. AB - There are few studies on the clinical and immunological periodontal status of intensive care unit (ICU) in-patients. The aim of the present study was to evaluate the periodontal condition among ICU in-patients through clinical and immunological periodontal parameters. From the sample of 373 hospitalized ICU patients, 182 were submitted' to a thorough clinical periodontal and immunological evaluation. Data on bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) were collected and gingival sulcular fluid samples were quantified through ELISA on IL-1, IL-6, and MMP-2 for immunological evaluation. Data was statistically analyzed by Chi-square, Fisher's exact, Mann Whitney tests, and Sperman's correlation and multivariate logistic regression analysis. A high dental plaque index and a high prevalence of periodontitis (48.3%), mostly in moderate and localized chronic form, were observed. Individuals with periodontitis presented higher levels of IL-1 and MMP-2, while individuals with cardiovascular disease (CVD) and individuals with two or more systemic diseases (MSD) presented higher levels of IL-1; diabetes mellitus (DM) and MSD individuals presented higher levels of IL-6. A positive association was found between the severity of periodontitis and CVD (OR 2.2; CI = 1.11-4.42). This study reported a 48.3% of the prevalence of periodontitis in ICU patients and a positive association between the severity of periodontitis and CVD. Additionally, higher levels of IL-1 and MMP-2 were found in individuals with periodontitis, higher levels of IL-6 were found in individuals with DM, and higher levels of IL-1 were found in individuals with CVD. PMID- 29972459 TI - Effects of Diabetes and Hypertension on Oral Mucosa and TGFbeta1 Salivary Levels. AB - : The aim of this study was to investigate salivary levels of TGFbeta1 and proliferation/ maturation of epithelial mucosa cells in diabetic and hypertensive patients. DESIGN: in this cross-sectional study, whole stimulated saliva and oral mucosa exfoliative cytology specimens were collected from 39 patients that were healthy (control, n=10) or presented history of arterial hypertension (HAS, n=9), diabetes mellitus (DM, n=10) or both (DM+HAS, n=10). Salivary flow rate (SFR), TGFbeta1 level in saliva, AgNORs and the epithelial maturation were evaluated. Non-parametric Kruskal-Wallis test, followed by Dunn's multiple comparison post test and the Spearman test correlation analysis were used. SFR showed a significant decreased in DM and DM+HAS (0.47+/-0.11 and 0.64+/-0.43 mL/min) when compared to control (1.4+/-0.38 mL/min). DM+HAS presented the highest value of TGFbeta1 concentration (24.72+/-5.89 pg/mL). It was observed a positive correlation between TGFbeta1 and glycaemia (R=0.6371; p<0.001) and a negative correlation between TGFbeta1 and saliva (R=-0.6162; p<0.001) and glycaemia and SFR (R=-0.5654; P=0.001). AgNORs number and status of maturation of mucosa cells were similar for all conditions. DM and DM+HAS presented the lowest SFR, which correlated with increased TGFbeta1 levels. Despite the higher TGFbeta1 secretion it was not observed changes in the morphology or proliferation of epithelial cells when diabetes or hypertension was present. PMID- 29972460 TI - Orofacial Injuries in Children and Adolescents (2009-2013): A 5-Year Study In Porto, Portugal. AB - The aim of this study was to verify the prevalence of acts of aggression to the head, face and neck towards victims of Physical Violence against Children and Adolescents (PVCA) who were examined at the National Institute of Legal Medicine and Forensic Sciences Delegation North (INMLCF-DN) in Porto, Portugal. A study was carried out on 2,148 complaints of physical aggression against children and adolescents (0 to less than 18 years old) occurred between 2009 and 2013 and which were retrieved from information about violence held on INMLCF-DN data files. Continuous variables were described and the association between them was verified by Chi-square or Fischer's Exact tests with 5% significance level. Within the 5-year timespan, 1,380 cases were identified with clinical relation with physical aggression. Most subjects evaluated were male adolescents and the most affected body region was the face, to which 747 injuries (24.7%) were recorded, with statistically significant association between sex and region (head and face). Victims in 15-17-year-old age group are more susceptible to violence than those in the 0-14-year-old age range. Dentists routinely examine the face, neck and skull, which make them the most appropriate health professionals to identify cases of aggression early. PMID- 29972461 TI - Seroprevalence of Toxoplasma gondii and Toxocara canis in a human rural population of Southern Rio Grande do Sul. AB - Due to the growing population of pets, especially homeless dogs and cats, zoonoses still represent a significant public health problem. Toxoplasma gondii and Toxocara spp. are epidemiologically important zoonotic agents as they are etiological factors of human toxoplasmosis and toxocariasis, respectively. These parasites remain neglected even though they are substantially prevalent in rural areas. The aim of this study was to investigate T. gondii and T. canis seroprevalence and risk factors of seropositivity in a rural population in Pelotas municipality, Brazil. The study participants (n=344) were patients of a Basic Healthcare Unit (BHU) located in Cerrito Alegre. Blood samples were collected and tested for T. gondii antibodies by indirect immunofluorescence and T. canis antibodies by an indirect ELISA that targets an excreted-secreted antigen (TES). T. gondii seropositivity was 53.2%, with higher titers (1:256 - 1:1,024) in individuals who habitually eat pork, beef, or chicken, while T. canis seropositivity was 71.8% and concomitant T. gondii and T. canis seropositivity was 38.3%. Among the seropositivity risk factors assessed, only habitual undercooked meat consumption was significant (p = 0.046; OR = 3.7) for T. gondii and none of them were associated with T. canis seropositivity. Both parasites have a high prevalence in rural areas, which reinforces the need to invest in rural community education and health. PMID- 29972462 TI - The interplay between mutations in cagA, 23S rRNA, gyrA and drug resistance in Helicobacter pylori. AB - In this study, we evaluated the mutations of Helicobacter pylori associated with resistance to clarithromycin and levofloxacin. Furthermore, based on the proposed interaction between antimicrobial resistance and pathogenicity, we correlated the mutation profiles of the strains with the presence of the pathogenicity gene cagA. We analyzed 80 gastric biopsy specimens from H. pylori-infected patients for point mutations in the 23S rRNA gene region and in the gyrA gene, which are related to clarithromycin and levofloxacin resistance, respectively, and investigated the presence of the cagA gene in these strains. We observed that in the assayed biopsies, 8.7% (7/80) had mutations in the 23S rRNA gene region at positions 2143 and 2142, while 22.5% (18/80) had mutations in gyrA at codons 87 and 91. Moreover, absence of the CagA-EPIYA pathogenicity factor was observed in 68% (17/25) of resistant samples. The knowledge of the local profile of antimicrobial resistance and the complex interplay involving resistance and pathogenicity can contribute to an appropriate clinical approach. PMID- 29972465 TI - ERRATUM: Pathology and pathogenesis of human leptospirosis: a commented review. PMID- 29972464 TI - Factors associated with the development of physical disabilities in Hansen's disease. AB - Hansen's disease is probably the human disease that causes more damage. The aim of this study was to investigate the association between the occurrence of the association of grade 1 and 2 physical disabilities in Hansen's disease, as well as implications of joint analysis and strength of association with independent demographic and clinical variables. This is a quantitative, descriptive, retrospective, population-based and documentary study developed from 2009 to 2014 in a Hansen's disease reference center in Joao Pessoa, PB. It involved 414 medical records, the diagnosis and discharge data on socio-demographic, clinical and simplified neurological evaluation variables. Data were analyzed using descriptive (absolute frequency and percentage) and inferential (Chi-Square and Prevalence Ratio (PR) statistics techniques. Both in the diagnosis and discharge, low education level, multibacillary classification and presence of affected nerves were statistically associated to the development of disabilities (p <0.05). The gender showed association only at discharge (p <0.05). Male gender, low education level, multibacillary classification and presence of affected nerves were identified as factors associated with the development of disabilities, and the individuals were more likely to develop disabilities at discharge. There is a need for development of surveillance actions for the population group identified for the detection and early treatment of the disease. Higher chances of developing disabilities in the discharge period makes the promotion of guidelines that standardize the care of these individuals imperative. PMID- 29972463 TI - Focal persistence of soil-transmitted helminthiases in impoverished areas in the State of Piaui, Northeastern Brazil. AB - This study aims to describe the prevalence, distribution, and factors associated with soil-transmitted helminthiases (STHs) in rural localities in Piaui, Brazil. Two cross-sectional surveys (n=605 subjects; 172 families) were carried out in order to obtain socio-demographic, anthropometric, spatial and parasitological data. Parasites were evaluated using Kato-Katz and centrifugal sedimentation techniques. Eggs were measured to assess infection with zoonotic Strongylida parasites. Kernel maps were constructed with Q-GIS. The prevalence of hookworm infection was 12.4% (75/605). Other helminthes found were Trichuris trichiura (n=1; 0.2%) and Hymenolepis nana (n=1; 0.2%). The hookworm positivity rate was significantly lower among subjects who had used albendazole when compared with individuals who had not used anthelmintics or had used antiprotozoal drugs in the last 6 months (8/134 [6.0%] vs. 59/415 [14.2%]; p=0.009). A total of 39/172 (22.7%) families had at least one infected member. The association between the number of dwellers and hookworm positivity in the family was present in a logistic regression multivariate model. Assessment of worm burdens showed 92.2% light, 6.2% moderate, and 1.6% heavy infections. Hookworm eggs (n=34) measured 57.2 - 75.4 um in length and 36.4 - 44.2 um in width (mean +/- SD = 65.86 +/- 4.66 um L and 40.05 +/- 1.99 um W), commensurate with human hookworms. Hotspots suggest that transmission has a focal pattern. STHs persist in impoverished rural areas in Northeastern Brazil where currently available control strategies (mass drug administration) apparently do not allow the elimination of the infection. PMID- 29972466 TI - Hepatitis C in Brazil: lessons learned with boceprevir and telaprevir. AB - In 2012, the first-generation protease inhibitors telaprevir (TVR) and boceprevir (BOC) were introduced in the Brazilian health system for treatment of chronic hepatitis C, after their approval by the National Committee for Health Technology Incorporation (CONITEC). However, these medicines were discontinued in 2015. The short period of use in therapy and their high cost require a discussion about the consequences for patients and for the health system of the early incorporation of new therapies. The article presents a qualitative analysis of the incorporation process of both medications in Brazil and the results of a multicenter study that included patients treated with BOC or TVR between January 2011 and December 2015 in five Brazilian cities. The study included 855 patients (BOC: n=247) and (TVR: n=608). The document analysis showed that CONITEC's decision to incorporate BOC and TVR was based on results of phase III clinical trials that compared sustained virologic response (SVR) rates of patients treated with BOC and TVR with rates of those that received placebo. However, these studies included a low percentage of cirrhotic patients. The SVR rates observed in this multicenter study were worse than clinical trials pointed out (BOC: 45.6%; TVR: 51.8%), but similar to those achieved with previously adopted therapies. The discontinuation rate due to adverse events was (BOC: 15.4%; TVR: 12.7%). Based on these unsatisfactory results, the study brings a discussion that goes beyond the therapy outcomes, exploring the incorporation of these high-cost medicines and the related decision making process, contributing to future decisions in medicine policies and in the treatment of chronic hepatitis C. PMID- 29972468 TI - Acute kidney injury and pancreatitis due to scorpion sting: case report and literature review. AB - Despite the high number of accidents due to scorpion stings in Brazil, severe cases in adults are seldomly reported. In the Northeast region of Brazil, Tityus stigmurus is the most prevalent species. A 69 year-old woman who was stung by a scorpion attended the emergency room 5 hours after envenomation. She got worse due to abdominal pain. Clinical findings were concordant with class III scorpion envenomation (major systemic manifestations), complicated by acute kidney injury and acute pancreatitis. Intensive supportive therapy was adopted. In the follow up, 3 months later, she was completely recovered. This report is being brought to recommend the thorough management of victims of scorpion accidents, enabling early diagnosis of severe complications, which could lead to death if aggressive supportive measures are not early and adequately taken. PMID- 29972467 TI - Prevalence of schistosomiasis mansoni in indigenous Maxakali villages, Minas Gerais, Brazil. AB - Intestinal parasitic infections are a common health problem among Amerindian populations and schistosomiasis represents one of the most prevalent diseases in Maxakali people. The Kato-Katz is the diagnostic method recommended by WHO for epidemiological studies; however, one of the technique's limitations is the failure to detect parasites in individuals with low parasite load. The aim of this study was to establish the prevalence of Schistosoma mansoni in indigenous Maxakali villages, evaluating the TF-Test(r) performance for diagnosis compared to the Kato-Katz technique. Stool samples from 545 individuals were processed by the TF-Test(r) (1 sample) and Kato-Katz (1 slide). The positivity rate for S. mansoni by Kato-Katz was 45.7%. The rate by the TF-Test(r) was 33.2%, and 51.9% by the combined parasitological techniques. The amplitude of parasite load was 24 to 4,056 eggs per gram of feces (epg), with a geometric mean of 139 epg. The co positivity, co-negativity, and accuracy values by TF-Test(r) in relation to Kato Katz were 59.0%, 88.5%, and 75.0%, respectively. The agreement between these techniques was moderate (k=0.486) as determined by the kappa index. Thus, the results of this study demonstrated that the performance of Kato-Katz was superior (p <0.05) to that of TF-Test(r) in the detection of S. mansoni. The combination of TF-Test(r) and Kato-Katz resulted in an increased positivity rate of S. mansoni, demonstrating the high risk of infection to which indigenous populations are exposed and the importance of the implementation of control strategies in Maxakali villages. PMID- 29972469 TI - Cross-cultural adaptation of the Chilean version of the Modern Singing Handicap Index: MSHI. AB - PURPOSE: Perform the cross-cultural equivalence of the Chilean version of the Modern Singing Handicap Index - MSHI, through its cultural and linguistic adaptation. METHODS: A translation of the MSHI for the Chilean Spanish and the back translation for the Italian was made, and discrepancies were found; a committee of four language pathologist had to resolve any discrepancies and, when found, a consensus must be reached resulting in the final version of the Indice de Desventaja Vocal para Canto Popular - IDVCP-Ch, with the same structure than the original of 30 items and four answers options. The IDVCP-Ch was applied to 25 popular singers. Every item had the option "Not applicable" in order to identify questions that were not comprehended or not appropriate for the concerned population. Nine singers' marked eight items as "Not Applicable", therefore, six of them had its translation adapted. The modified IDVCP-Ch was applied to other 11 popular singers who don't participated of the anterior phase. RESULTS: The IDVCP-Ch reflects its original Italian version, both in the number of items and in the limitation of handicap, disability and impairments domains. CONCLUSION: A cross-cultural equivalence od the IDVCP-Ch, was demonstrated for the Chilean Spanish. PMID- 29972470 TI - Aerodynamic, eletroglottographic and acoustic measures of the voiced postalveolar fricative. AB - PURPOSE: Describe and correlate phonological and complementary measures regarding aerodynamics, electroglottography, acoustics, and perceptual judgment of production of the voiced fricative sound /?/ comparing the performance of Brazilian Portuguese-speaking children with and without speech sound disorders. METHODS: Study participants were 30 children aged 5 years to 7 years and 11 months divided into a group of children with typical development - Control Group (CG) and a group of children with speech sound disorders - Research Group (RG). Phonology (PCC, PCC-R, and occurrence of phonological processes) and the aerodynamic (amplitude of the oral airflow and f0), eletroglottographic (open quotient) and acoustic (classification of voicing) measures were evaluated. RESULTS: Numerically, children with speech sound disorders presented higher relative oral airflow amplitude, lower relative f0, and open quotient indicative of less efficient voicing production compared with those of children with typical development. The weak voicing values showed that 66.1% of the children with speech sound disorders presented weaker voicing of the fricative sound /?/ compared with that of the posterior vowel sound, and between-groups comparison demonstrated that these children presented greater difficulty in voicing. The acoustic analysis of speech used to classify the weak/strong voicing showed variations, especially regarding the classification partially devoiced. CONCLUSION: Results suggest that the strategies for voicing production and voicing maintenance of the fricative sound /?/ are still variable in children aged 5 years to 7 years and 11 months; however, children with speech sound disorders seem to have more difficulties in using them effectively. In addition, the study shows the importance of applying complementary tests to obtain a more detailed diagnosis. PMID- 29972471 TI - Can Brazil achieve the new World Health Organization global targets for tuberculosis control? PMID- 29972472 TI - Recreational soccer practice among adults, in Brazilian capitals, 2011-2015. AB - OBJECTIVE: to describe the profile of recreational adult soccer players who lived in the Brazilian capitals in the period from 2011 to 2015. METHODS: descriptive study with a sample of adults interviewed by the Surveillance System for Risk and Protective Factors for Chronic Diseases by Telephone Survey - VIGITEL (2011 to 2015). RESULTS: 11.812 adults (11.375 men and 437 women) pointed to soccer as their main leisure physical exercise, with higher prevalence in the North region (32%) and lower in the South region (10%) of the country; the average reduction of soccer players 3.4% for every 5 years over age (95%CI 2.9;4.1); from 2011 to 2015, there was decrease in the number of soccer players, -1.4% per year (95%CI 0,7;2,2). CONCLUSION: the practice of soccer was predominantly male, presented an inverse relationship with the increase of age, more prevalent in the Northern region and less prevalent in the Southern region. PMID- 29972473 TI - Health communication: a study of the profile and structure of municipal communication advisory services in 2014-2015. AB - OBJETIVO: to investigate the characteristics of health communication services taking the Municipal Health Department Councils network in Brazil as a basis. METHODS: this was a quantitative study with an exploratory design conducted in 2014-2015, using non-probability sampling. Four structured questionnaires were used examining four dimensions: 1) structure of the communication advisory service work; 2) profile of the professionals working in these services; 3) the main duties of these advisory services, and 4) possible variants of municipalities not having this specialized service. RESULTS: 72 of the 122 participating municipalities did not have a communication advisory service and only two network members had communications directorates; work facilities were precarious, professionals had little length of communication advisory service; they did not have job stability and were not members of the health management councils. CONCLUSION: Although they provide direct advice to health secretaries, the working conditions of communication professionals compromise their planning actions. PMID- 29972474 TI - Congenital syndrome associated with Zika virus infection among live births in Brazil: a description of the distribution of reported and confirmed cases in 2015 2016. AB - OBJECTIVE: to describe the temporal and spatial distribution of reported and confirmed cases of congenital Zika virus syndrome (CZS) in live births in Brazil during 2015-2016. METHODS: we conducted a descriptive study with data from the Public Health Events Registry, including cases born in 2015 or 2016, and registered between epidemiological week 45/2015 and 2/2017. RESULTS: we analyzed 9.953 reported cases, of which 2.018 (20.3%) were confirmed and 2.819 (28.3%) were still under investigation at the epidemiological week 2/2017; 404 (4.1%) out of the 9.953 cases had laboratory confirmation for Zika virus; the prevalence of confirmed cases of CZS was 3.8/10 thousand livebirths in 2015 and 3.1/10 thousand live births in 2016. CONCLUSION: one fifth of the cases reported in 2015-16 were confirmed the CZS, reinforcing their relevance as a public health problem; efforts aimed at the diagnostic confirmation of the syndrome should be prioritized. PMID- 29972476 TI - Future prospects for the SUS. AB - The aim of this article is to present political strategies in relation to healthcare and management in order to support a strengthening of the Unified Health System (SUS). Rather than providing 'certainties', the intention is to suggest a basis for a wider discussion regarding the possibilities of universal health rights in Brazil. PMID- 29972475 TI - Unified Health System: 30 years of struggle! PMID- 29972477 TI - Health and class struggle: determining what to do and how to do it. PMID- 29972478 TI - Reaffirming democracy and the universal right to healthcare in times of ultraneoliberalism. PMID- 29972479 TI - A new chapter in the fight to defend Brazil's Unified Health System. PMID- 29972480 TI - Reply: The SUS exists! PMID- 29972481 TI - Thirty years of the Unified Health System (SUS). AB - This article, which aims to explore questions relating to SUS at 30 and to dialogue with other studies, presents an overview of the positive drivers, the obstacles and the threats to Brazil's Unified Health System. It points to a lack of prioritizing the SUS on the part of the government, underfunding and attacks on the system made by capital's policies. The article also suggests that one of the most significant threats to SUS is the financialization of health, linked to the financial dominance. It concludes by arguing that the SUS is not consolidated, justifying alliances between democratic, popular and socialist forces, with new strategies, tactics and forms of organization to face up to the power of capital and its representatives in society and in the State. PMID- 29972482 TI - 30 years of SUS: the beginning, the pathway and the target. AB - In this text, we refer to the solid and historical civilizational roots of the Brazilian Unified Health System, SUS (Sistema Unico de Saude) that give it a perennial status. Data and analyses are systematized, pointing out, in parallel to the construction of SUS, the construction of another public health policy that has subverted the principles and guidelines of the Federal Constitution of 1988: a real, implicit and hegemonic policy. As for SUS, we identify and reinforce explicit advances and resistances with its principles and guidelines, over this 30 year period, but with invaluable accumulation in management, evaluation, knowledge construction, appropriate technologies, resistance strategies and politicization in defense of the constitutional directives. The knowledge that has been acquired over this time is understood to form part of a drive towards a civilizing pathway that was proposed by the 1988 Constitution. Although SUS is considered to be an unfinished work with deviations, and the need, on one hand, to be consolidated in better achievements, and on the other, to be permanently reinvented in order to accomplish its mission. PMID- 29972483 TI - Changes in health and disease in Brazil and its States in the 30 years since the Unified Healthcare System (SUS) was created. AB - The Unified Healthcare System (SUS) was created to ensure the population's right to universal, free and comprehensive healthcare. This study compares the health indicators measured in 1990 to those measured in 2015 in Brazil and its states. The goal is to contribute to understanding the role SUS played in changing the nation's health profile. Analyses use estimates in the Global Burden of Disease (GBD) study for Brazil and its states, and compares 1990 and 2015. The main results are increased life expectancy, as well as an increase in the population's longevity measured in health-adjusted life expectancy. These in turn are due to a sharp decline in mortality due to transmissible diseases, in maternal and infant morbi-mortality, and avoidable causes of death. NTCDs are the leading cause of death, followed by violence. Poor diet is the leading risk factor, followed by metabolic issues. Tobacco use decreased over the period, as did infant malnutrition. In the thirty years since the SUS was created, health indicators in this country have improved, and major progress has been made to reduce inequality across the country's regions. PMID- 29972484 TI - SUS: supply, access to and use of health services over the last 30 years. AB - Significant changes have been witnessed in the Brazilian health system over the last 30 years. This article outlines trends in outpatient and hospital care, staffing, and health service use during this period. There was a significant expansion of the public health network, particularly of primary care services, leading to improved access to consultations and a reduction in hospital admissions. However, there is a persistent shortage of health professionals in Brazil's public health system, particularly dentists. Despite improvements in coverage, the public system continues to face serious challenges, particularly with respect to funding, service provision, and its relationship with the private sector. PMID- 29972485 TI - Universal health system and universal health coverage: assumptions and strategies. AB - In recent years the international debate about universality in health has been marked by a polarization between ideas based on a universal system, and notions proposing universal health coverage. The concept of universal coverage has been disseminated by international organizations and has been incorporated into health system reforms in several developing countries, including some in Latin America. This article explores the assumptions and strategies related to the proposal of universal health coverage. Firstly, a comparison is provided of the models of universal health coverage and universal health systems. This is followed by a contextualization of the international debate, including examples of different health systems. Finally, the implications of the proposal of universal coverage for the right to health in Brazil are discussed. The analysis of different concepts of universality and the experiences of different countries shows that health insurance-based models, either social or private, are not as satisfactory as public, universal health systems. Greater understanding about ongoing international projects is essential in order to identify the possibilities represented by the consolidation of the Unified Health System (SUS) in Brazil, as well as the risks of dismantling the SUS. PMID- 29972486 TI - Federalism and health policy in Brazil: institutional features and regional inequalities. AB - This article analyses the main characteristics of federalism in Brazil and its institutional relations with health policy. It discusses federalism from a classical perspective highlighting the essentially centralized nature of Brazil's system and the prevalence of decentralizing health policies underpinned by the principles enshrined by the 1988 Constitution.We used primary data obtained from an electronic questionnaire responded by secretaries of health sitting on the governing bodies of the country's health region and secondary data Ministry of Health databases covering the current health regions. The findings show that significant progress has been made in the implementation of regional governing bodies, yet without any significant impact on the reduction of deep regional inequalities in primary and hospital care. It concludes by suggesting that the persistence of inequalities is down to weak central coordination capacity and an inappropriate trade-off between a centralized federal system and competition between entities, thus undermining cooperative regionalization of the public health system as envisaged by the 1988 Constitution. PMID- 29972487 TI - Regionalization and Health Networks. AB - The aim of this article was to reflect on the challenges faced in building the Health Regions and Networks in Brazil. These reflections result from studies conducted in several health regions. The central challenges for the constitution of the Health Regions and Networks are as follows: the Care Model, Primary Health Care, Care for Users with Chronic Diseases, and Hospital Care. In order to consolidate the regions and networks the organization needs to incorporate an ethical sense: focusing on social, public and individual needs, derived from comprehensive care, human and social rights, in broad, multi-scale and inter sectorial interactions, with the constitution of a systemic, regionalized innovation. Of prime importance is the capacity to devise which general principles are responsible for maintaining the unity(mode of care), seeking to outline the coherence of the different provision models that the system might develop according to the social needs in regional settings. Without that, users will continue to seek and create ways of accessing health services that challenge the rationale of those very services. Hospital reform is also required to integrate and reorient the hospital networks. These reflections are important for the SUS to uphold its solidarity project, expressed in the trinity of universality-comprehensiveness-equality. PMID- 29972488 TI - Brazil's Unified Health System and the National Health Promotion Policy: prospects, results, progress and challenges in times of crisis. AB - This article examines progress made towards the implementation of the core priorities laid out in the National Health Promotion Policy (PNPS, acronym in Portuguese) and current challenges, highlighting aspects that are essential to ensuring the sustainability of this policy in times of crisis. It consists of a narrative review drawing on published research and official government documents. The PNPS was approved in 2006 and revised in 2014 and emphasizes the importance of social determinants of health and the adoption of an intersectoral approach to health promotion based on shared responsibility networks aimed at improving quality of life. Progress has been made across all core priorities: tackling the use of tobacco and its derivatives; tackling alcohol and other drug abuse; promoting safe and sustainable mobility; adequate and healthy food; physical activity; promoting a culture of peace and human rights; and promoting sustainable development. However, this progress is seriously threatened by the grave political, economic and institutional crisis that plagues the country, notably budget cuts and a spending cap that limits public spending for the next 20 years imposed by Constitutional Amendment No 95, painting a future full of uncertainties. PMID- 29972489 TI - Health surveillance at the SUS: development, effects and perspectives. AB - This article analyses the process of construction of Health Surveillance in Brazil concerning the political, historical and organizational context of this component of the Unified Health System (UHS), by means of its historical view and presentation of the advances, limits, setbacks and perspectives. Throughout trajectory of Health Surveillance, its objects of study and intervention have been expanded, strengthening the integration among the different areas of surveillance, increasing its capacity for prediction and intervention. It evolved from surveillance of people, to surveillance of diseases and now to surveillance of health risks, promoting greater articulation of HS professionals with agents of endemics and Family Health Teams. The first National Health Surveillance Conference, in February 2018, provided opportunities for discussion and formulation of proposals aimed at strengthening HS, expanding its scope of actions with a view to achieving a comprehensive care model. Adequate and audacious alternatives are necessary so that there are no setbacks in the financing modalities in order to maintain and expand the advances achieved in the field of Health Surveillance in Brazil. PMID- 29972490 TI - The achievements of the SUS in tackling the communicable diseases. AB - This article presents the development of the epidemiological situation of some of the major communicable diseases (CD) in Brazil, with emphasis on the interventions by the SUS and other social policies. The data and information were collected from Datasus, epidemiological newsletters from the Brazilian Ministry of Health, and scientific articles on the issue. The universalization, decentralization and expansion of the surveillance, control and prevention of CD has produced an impact on the morbidity and mortality of these diseases, mainly those which are vaccine-preventable. The emergence and re-emergence of three arboviruses, for which there are no effective control instruments, interrupted the downward trend in the morbidity profile of CD in Brazil. Other social and economic programs, which are geared to the needier sectors of the Brazilian population, have also contributed to the improvement of the analyzed health indicators. However, the universalization of access to healthcare services, as well as improvements in the scope of the surveillance of diseases and health risks, has played a key role in improving the health and quality of life of the population, as well as contributing to the process of the democratization of Brazil. PMID- 29972491 TI - A look at the food and nutrition agenda over thirty years of the Unified Health System. AB - Food and nutrition are basic requirements for the promotion and protection of health. Nutrition monitoring and dietary recommendations are included in the mission of the Unified Health System (SUS, in its Portuguese acronym), as established by the Organic Health Law no. 8,080 of 1990. This article presents and discusses the food and nutrition agenda of the SUS and its interface with Food and Nutrition Security, its benchmarks, progress and challenges. This essay was guided by biographical and documentary research and, above all, by the experiences and perceptions of the authors, who, at various times and in various contexts, have been and continue to be actors of Brazil's food and nutrition agenda. We emphasise the idea of the SUS, with its accomplishments and shortcomings, as a living system derived from the technical, ethical and political commitments of its administrators, workers, academics and society as a whole. Thus, we seek to contribute to the debate about the Brazilian path to the construction of a public social welfare system committed to health and adequate nutrition as a human rights. PMID- 29972492 TI - Tobacco Control Policies in Brazil: a 30-year assessment. AB - The article presents a review of Brazilian tobacco control policies from 1986 to 2016, based on contributions from political economics and analyses of public policies. The institutionalization of tobacco control in the country was marked by more general changes in health policies and by specific events related to the theme. Brazil's international leadership role, a robust National Tobacco Control Policy, the role of civil society and the media all contributed to the success of tobacco control in this country. However, challenges remain regarding crop diversification in tobacco farms, illegal trade in cigarettes, pressure from the tobacco industry and the sustainability of the Policy. This study reinforces the importance of bearing in mind the relationship between the domestic and international context, and the articulation between different governmental and non-governmental sectors and players when analyzing complex health policies. Continuity and consolidation of the tobacco control policies depend on the persistence of a broad institutional framework to guide the State's actions in social protection, in accordance with Unified Healthcare System guidelines. PMID- 29972493 TI - Baixada Fluminense, in the shadow of the "Sphinx of Rio": popular movements and health policies in the wake of the SUS. AB - This paper addresses the popular health movement in Nova Iguacu-RJ in the 1970s and 1980s. Amidst political repression, residents organized themselves to find solutions to various problems, including health problems. Health demands are enhanced both by the dengue epidemic and linkages with the Brazilian health reform and a struggle for democracy. Using documental historical sources from newspapers, health dissemination papers and documents from the House of Oswaldo Cruz-Fiocruz collection, this paper concludes that the example of Nova Iguacu reveals both the complexity of the process of political opening at the local level and efforts of conducting a health reform where it was needed the most. Resistance on the part of the medical corporation, private interests in health and the existence of a still incipient popular political organization and culture are some of the elements that account for the hardships in advancing the manifest wishes of policies. The specificities of local arenas also point to possible institutional arrangements, sometimes very peculiar and not reproducible in other settings. PMID- 29972494 TI - National Information and Population Survey Systems: selected contributions from the Ministry of Health and the IBGE for analysis of Brazilian state capitals over the past 30 years. AB - By the late 1980s, increased exchange between WHO regional offices and Health Ministers around the world raised the need for compatible methodologies and data collection tools to measure health status through population surveys, which could then complement the health records of the official statistics agencies in each country, and enabling comparison of National Information Systems. This article analyzes the main contributions of the Ministry of Health and the IBGE for the analysis of the health status of the Brazilian population. As a criterion for inclusion, only data sources in the public domain published periodically for at least the past 20 years, and those generating data at the municipal level were used. From this set, the capitals of Brazil were analyzed. The data shows that after the Unified Healthcare System (SUS) was created, the network of non hospitalization healthcare experienced a rapid transformation. By 2009 85.5% of such units were under the municipal umbrella, compared to 40.7% when SUS was created. In Brazil, the RIPSA initiative has fulfilled the integrative role for the formation of a National Health Information System, recommended by Article 47 of Law 8.080 / 1990 that instituted the SUS, assigning major responsibility to1 the IBGE. PMID- 29972495 TI - Communication interfaces and challenges in the Brazilian Unified Health System. AB - This article aims to reflect on communication and health projects and strategies involved in the struggle for the right to health, construction and defense of the Unified Health System. Drawing on studies, debates and deliberations that have been ongoing since the 8th National Health Conference and based on contemporary communication configurations, it problematizes tensions, challenges and opportunities related to digital culture, journalistic coverage and public communication in health institutions in Brazil. PMID- 29972496 TI - Brazilian international cooperation in health in the era of SUS. AB - This paper addresses the role of health in Brazil's health diplomacy and international cooperation since the emergence of the Brazilian Unified Health System (SUS), focusing in particular on South-South cooperation, in line with the priorities of the country's international technical cooperation since its creation. It highlights the relationship with the Latin American and Caribbean Countries (LAC) and the Community of Portuguese Speaking Countries (CPLP), more specifically, with the Portuguese Speaking African Countries (PALOP) and East Timor. It emphasizes the roles of the Ministry of Health, through the International Advisory Working Group on Health (AISA) and the Oswaldo Cruz Foundation (Fiocruz), the Brazilian Cooperation Agency (ABC), the Ministry of Foreign Affairs, and the Pan American Health Organization (PAHO). The article points out that the TC-41 Co-operation Agreement is one of the main instruments for enabling cooperation. It presents the cases of the structuring networks of health systems, as well as the paradigmatic negotiations of the Framework Convention on Tobacco Control, the TRIPS Agreement and the establishment of UNITAIDS, in which Brazilian diplomacy had a predominant role. PMID- 29972498 TI - The Family Health Strategy: expanding access and reducinghospitalizations due to ambulatory care sensitive conditions (ACSC). AB - Since its creation in 1994, the Family Health Program has become the main strategy for changing care models and increasing access to the first contact service of the Unified Health System (SUS). A little more than ten years later, in 2006 the program was transformed into the Family Health Strategy (FHS) within the National Policy on Primary Care (PNAB). This article evaluates the effects of the implementation of the FHS over the last two decades in Brazil, demonstrating the access provided and the trends in ambulatory care sensitive conditions (ACSC). This is an ecological, time series study with secondary data referring to the number of family health teams that were established and the number of hospital admissions due to ACSC in the SUS from 2001-2016. The results show a 45% reduction of the standardized ACSC rates per 10,000 inhabitants, from 120 to 66 in the period 2001-2016. Although it was not possible to isolate the specific effects of primary care, it is quite plausible that this reduction in ACSC rates is linked to the progress of FHS coverage in Brazil, especially in terms of improved follow-up of chronic conditions, improved diagnosis and easier access to medicines. PMID- 29972497 TI - Development, Innovation and Health: the theoretical and political perspective of the Health Economic-Industrial Complex. AB - The concept and approach of the Health Economic-Industrial Complex (HEIC) were present in the advancement of the Unified Health System (SUS) in the last decades, contributing to the incorporation of an agenda related to the national pattern of development. The paper reconstructs this approach to capture its dynamics and demarcate the vision developed in this paradigm. It reveals the thinking matrices of the field of political economy that provide the analytical substrate for its development, allowing us to confront the reductionist use of the concept. It highlights, therefore, the logical foundations that guided the public policies resulting from this approach, with emphasis on the systemic approach and the use of state purchasing power, through the Productive Development Partnerships (PDP), marking the effort to articulate the social and economic realms of development. At present, this analytical perspective is even more crucial, showing that well-being not only fits into GDP but can also be a lever for a pattern of development committed to the National Health Universal System (SUS), society and economic and technological sovereignty in health. PMID- 29972499 TI - Reproductive, maternal, neonatal and child health in the 30 years since the creation of the Unified Health System (SUS). AB - This study presents an overview of public sector interventions and progress made on the women's and child health front in Brazil between 1990 and 2015. We analyzed indicators of antenatal and labor and delivery care and maternal and infant health status using data from the Live Birth Information System and Mortality Information System, national surveys, published articles, and other sources. We also outline the main women's and child health policies and intersectoral poverty reduction programs. There was a sharp fall in fertility rates; the country achieved universal access to antenatal and labor and delivery care services; access to contraception and breastfeeding improved significantly; there was a reduction in hospital admissions due to abortion and in malnutrition. The rates of congenital syphilis, caesarean sections and preterm births remain excessive. Under-five mortality decreased by more than two-thirds, but less pronounced for the neonatal component. The maternal mortality ratio decreased from 143.2 to 59.7 per 100 000 live births. Despite worsening scores or levelling off across certain health indicators, the large majority improved markedly. PMID- 29972500 TI - Aging in Brazil: the building of a healthcare model. AB - The article discusses the development of a health care model for the elderly, seeking to add to the discussion about the aging of the population in the context of a new epidemiological and demographic scenario. Considering that the aging process in Brazil is relatively recent, more relevant social movements have been described in the construction of health policies directed towards the elderly. After an initial description of the main milestones, we present the model of care considered most appropriate for the best care of the elderly. Based on a critical analysis of health care models for the elderly, the article proposes an approach to care for this age group, focusing on health promotion and prevention, in order to avoid overloading the health system. Integrated care models aim to solve the problem of fragmented and poorly coordinated care in current health systems. The more the healthcare professional knows the history of his patient, the better the results; this is how contemporary and resolutive models of care should work, and it is these that are recommended by the most important national and international health agencies. This article is particularly concerned with a care model that is of higher quality, and is more resolutive and cost-effective. PMID- 29972501 TI - Pharmaceutical Services and comprehensiveness 30 years after the advent of Brazil's Unified Health System. AB - This article examines pharmaceutical services and access to essential medicines in Brazil during the 30 years since the advent of Brazil's Unified Health System from a comprehensiveness perspective. The following topics are addressed: the "realignment" of pharmaceutical services; human resources in pharmaceutical services; the essential medicines concept; the rational use of medicines; technological advances and drug manufacturing; and ethical regulation. With a strong regulatory focus and a structural framework centered on the National Medicines Policy, the past three decades represent a mixture of progress and setbacks, considering the national complexities of the healthcare system and the political, economic and social changes that have influenced policy and access to medicines, which is a key concern even in the world's richest countries, as the forums of discussion on global health have demonstrated. We show that major steps forward have been taken, highlighting that the recent fiscal austerity measures imposed by the government threaten to seriously undermine social progress. PMID- 29972502 TI - Unified health system 30th birthday: health surveillance. AB - This article presents an overview of the nature, functions and history of health surveillance in the structure of the Brazilian Unified Health System (SUS). Bibliographical sources and official documents were used, with references from the careers of the authors, who have worked in health surveillance. Extremely serious adverse events in the mid-1990s gave political visibility to the fragility of Brazilian health surveillance, and were reflected in serious problems for the SUS. The creation of Anvisa and the SNVS surveillance system, and the support for bodies in individual states and municipalities, resulted in improvement in the structure and functioning of health surveillance, and improved recognition of the area as an emerging theme in research and education in public health. Several problems hamper the effective structuring of the SNVS. A change in the conception/design of health promotion is postulated, in which the large corporations, whose activities have strong connections with risk factors related to the current epidemic of chronic diseases, would be given a social responsibility. A set of challenges for better structuring of health surveillance in the SUS is also put forward. PMID- 29972503 TI - A brief history of worker's health in Brazil's Unified Health System: progress and challenges. AB - This article draws on current understandings of workers' health in Brazil that emerged concomitantly with advances in the field of public health. It describes the institutional trajectory of the field of workers' health within the Unified Health System (SUS), emphasizing the challenges faced in developing actions in the sphere of workers' health surveillance. It synthesizes the often tortuous path taken over the last 30 years between multiprofessional training processes, coordination between different levels of the SUS, interinstitutional support, especially from public universities, and interaction with participatory processes. It provides an overview of progress and challenges in the face of continuous changes in working conditions and work organization and the limited effectiveness of government policies designed to address occupational health risks. Finally, it suggest that progress has come out of the intertwining of social and academic movements, with the opening up of institutional spaces that transform the SUS, reviving the underlying principles of participation and health promotion in broad vision of state policy. PMID- 29972504 TI - The Management of Work and Education in Brazil's Unified Health System: thirty years of progress and challenges. AB - This article presents a historical analysis of work management and education in the healthcare field over the three decades since the creation of Brazil's Unified Health System (SUS, acronym in Portuguese). Using the sociology of professions as a frame of reference, it addresses the following topics: the health labor market; trends in healthcare employment; the healthcare workforce; and the regulation and dynamics of undergraduate programs in the health field. It analyzes each of the moments that characterize the area, from the pre-SUS period to the present day. The period has witnessed the following: a boom in health schools, largely in the private sector; an overall increase in the level of education of health professionals , an increase in regional inequity; an alarming increase in distance learning programs; an imbalance between labor supply and demand; the expansion of installed capacity; the municipalization of health employment; an increased focus on multiprofessional teams; and an increase in precarious work and informal contractual relationships and deterioration of pay levels. PMID- 29972505 TI - Environmental health risk reduction in Brazil: conquests, limits and obstacles. AB - The 1988 Constitution represents an important achievement in terms of rights and an important pact sealed around a long-term strategy for the nation's future based on a social development model oriented towards reducing the risk of disease and injuries and an ecologically balanced environment. These achievements manifested themselves in policies, institutionalization and the creation of spaces for public participation. The article outlines the main achievements, limits and obstacles that have affected the environmental and health agendas in the last 30 years since the creation of the Unified Health System . The achievements are framed within the broadening of political space for public participation and the institutionalization of the theme of environmental risks within the SUS, while the limits are framed in the relationship between development and trends of environmental risk at global/regional, local and community scale. Finally, obstacles are outlined showing that the parliamentary coup of 2016 not only accentuated existing limits, but also represents a giant represent a giant step backward in various areas related to environmental health. PMID- 29972506 TI - Gender and sexual rights: their implications on health and healthcare. AB - This article is an objective examination of aspects of gender and sexual rights, and their implications in the field of health field, using the methodology of an essay. The first part discusses femicide, highlighting that there are deaths of women due to the fact of being women, which constitute what could be described as the crimes of lese-humanite or 'femi-genocide'. The second part discusses sexual and gender diversity, with an emphasis on the fragility of the 'right to have rights' expressed in the deterioration in health conditions of the population that is LGBTI (Lesbians, Gays, Bisexuals, Transvestites, Transsexuals and Intersex). Finally, the essay discusses recognition of gender plurality, and the limitations imposed on the rights of non-usual normativebodies bodies; criticism is directed at reiteration of the binary and cisgender normative ethos, which can exacerbate the health vulnerability of people with trans and other non-normative bodies and identities. It is concluded that, in the 30 years' existence of Brazil's Unified Health System (SUS), there have been advances in the political sphere, many of them created by or as a result of social movements, and initiatives that seek to confront femicide and the inadequate assistance available to LGBTI people. In the context of these challenges, it is reiterated that there is a necessary relationship between promotion of health and protection of human rights related to gender and sexuality. PMID- 29972507 TI - Institutionalizing the theme of violence within Brazil's national health system: progress and challenges. AB - This article reflects on the evolution of the theme of violence within the field of public health. It provides an overview of the strategies and actions developed within Brazil's Unified Health System developed in response to the country's main guiding policy on violence, the National Policy for the Reduction of Morbidity and Mortality due to Accidents and Violence, drawing on baseline documents, national and international research, data from the country's main violence information systems, and the firsthand experiences of the authors from their participation in the abovementioned actions. Violence against children and adolescents, women, and older persons have assumed a prominent position on the health agenda, while other forms of violence, such as child labor, human trafficking, homophobic and racial violence, and violence against street dwellers and people with disabilities, who are deprived of their liberty, are gradually finding their way onto the agenda. Despite undeniable progress in institutionalizing the theme, there is a need for greater investment in various areas including out-of-hospital emergency, rehabilitation, and mental health services. It is also necessary to incorporate the theme into the training and development of all of healthcare professionals and intensify continuing training to enhance capacity for detecting and reporting violence and delivering adequate care to victims. PMID- 29972508 TI - Post-graduation in Collective Health and the National Public Health System. AB - This article deals with a public policy in education, Post Graduation in Collective Health, to identify forms of dialogue of this policy, with the public health policy, the SUS, starting in 1990. The main product of PGSC policy is the training of masters and doctors, essential for teaching and research in the field. Bibliographic review and analysis of CAPES documents and databases based the analysis. Education policy was consistent over time and core to social development, alongside health policy, without presenting formal points of intercession, and its impacts occur mainly through the formation of good and committed professionals, teachers and researchers. In PGSC, professional masters programs are more relevant, for a more direct link of postgraduate programs with the SUS, and the initiatives of the Ministry of Health to finance priorities in research for the Health System. Even ininitiatives that explicitly seek to approximate the knowledge produced by PG with praxis in the SUS, the mechanisms involved in translating or impacting scientific knowledge into concrete practice are complex and must be context specific andthematic. PMID- 29972509 TI - The dominance of finance in healthcare: political action of unlimited capital in the 21st century. AB - This article gives, first, a historical account of the action of capital in healthcare in contemporary Brazil and then introduces a debate on the dominance of finance ('financial dominance') in healthcare based on one case to examine: the hypertrophy of the structure for intermediation in private healthcare existing in Brazil, using the theses of Jose Carlos de Souza Braga as its principal reference. The article highlights the nebulous nature of what happens at the interface between the public and private elements of the Brazilian health system, and the limits inherent to the use of reductionary, or dichotomic, models to explain details and factors in this interaction. PMID- 29972510 TI - Financial sustainability of the Brazilian Health System and health-related tax expenditures. AB - Using official data from Brazil's Internal Revenue Service, this article estimates health-related federal tax expenditures between 2003 and 2015. The Ministry of Health will thus be able to assess the relevance of these subsidies within a context of gross underfunding of Brazil's public health system. The analysis was built around concepts and theories developed in the fields of political economy and public finance, focusing on policies directed at public funding of the health sector. The results show that tax expenditures associated with health insurance plans was R$12.5 billion in 2015. It is suggested that these resources could be put to better use in public primary care and medium complexity care services. PMID- 29972511 TI - The first 30 years of the SUS: an uncomfortable balance? AB - This article takes stock of the implementation of Brazil's public health system in the period since the promulgation of the 1988 Constitution, which enshrines the right to health. It analyzes issues affecting the organizational effectiveness of health service provision such as funding and relations between different spheres of government. It focuses on the role of local government, the centralization of legislative powers, which has been shown to weaken the member states, and the financial dependence of local and state governments on federal government and how this has affected policy implementation. It also touches on other issues such as regionalization, poor planning, federal centralism, and Ministry of Health-local government relations, which have hampered state coordination of regional health systems. To close, we put forward some final considerations for improving the implementation of policies oriented towards the development of SUS structures. PMID- 29972512 TI - The future of the Brazilian Health System: a short review of its pathways towards an uncertain and discouraging horizon. AB - This article reflects on the future of the Brazilian Unified Health System (SUS, acronym in Portuguese), based on the foresight exercises conducted by the Brasil Saude Amanha initiative of the Oswaldo Cruz Foundation. The text briefly reviews some paths followed by the SUS as referred to in the Federal Constitution of 1988. It highlights the movement towards the decentralization of care and the constraint of health financial resources that reduced policies of increasing public expenditures. It examines the public and private arrangements for financing and provision of services that have resulted in sectoral privatization, mainly from economic policies articulated with concession of fiscal benefits. It analyzes the changes in the public sector financing through successive constitutional amendments that resulted in the weakening of established social protection policies, particularly of the health sector. For the future, the text considers population aging and analyzes trends in the epidemiological profile, with consequent changes in the health care paradigm. The article concludes by pointing out the consequences of fiscal strangling in the organization of the healthcare system and the need to reverse legal provisions that hamper the fulfillment of the constitutional mandate for equity and universality. PMID- 29972513 TI - Interview with former Health Minister Jose Gomes Temporao. AB - In this interview, the former Minister of Health, Jose Gomes Temporao, professor and retired tenured researcher from Fiocruz in Rio de Janeiro, outlines the trajectory and the challenges facing management in the Ministry of Health in the period from 2007 to 2010 when he held the post. PMID- 29972514 TI - Psychiatric reform in the SUS and the struggle for a society without asylums. AB - T This article presents a historical and epistemological study of the construction of public policies about mental health and psychosocial care in Brazil's Unified Health System, the SUS. To that end, it proposes an approach that identifies actions and strategies related to social participation in the construction of policies, one of the founding principles of SUS, seeking to delineate its importance in the specific trajectory of the psychiatric reform process. Subsequently, it highlights the originality and importance of actions that used culture as a means and as an end, in the sense of not restricting psychiatric reform to a transformation limited to public services or health in the strict sense of the term, emphasizing the principle of construction of a new locus in society for madness. Finally, it provides a historical follow-up of the promulgation of mental health policies in Brazil, identifying the most important initiatives and their impacts on the transformation of the care model, and concludes by questioning the conservative restructuring that is currently taking place. PMID- 29972515 TI - Contributions of nursing care to women. PMID- 29972516 TI - Clinical application of the Standard Operating Procedure of Positioning with Premature Infants. AB - OBJECTIVE: To compare the physiological and behavioral responses of Premature Infant (PREEMIE) positioned by the Unit Routine Decubitus (URD) and the Standard Operating Procedure (SOP). METHOD: A quasi-experimental comparative study performed at a Neonatal Intensive Care Unit in Southern Brazil. We evaluated 30 PREEMIEs with gestational age <=32 weeks, randomly assigned to Unit Routine Decubitus (URD) and Intervention Group (IG), subdivided into Right Lateral Decubitus (RLD), Dorsal Decubitus (DD), Left Lateral Decubitus (LLD) and Ventral Decubitus (VD). It was evaluated before, during and after the procedure: Heart Rate (HR); Respiratory Frequency (RF); Peripheral Oxygen Saturation (SpO2); behavior by the Neonatal Behavioral Assessment Scale (NBAS); by NIPS. RESULTS: During the intervention, RR (p = 0.023), indexes in NBAS (p = 0.01) and NIPS (p <0.0001) reduced significantly in SOP. HR and SpO2 did not present a significant difference. CONCLUSION: Positioning according to the SOP shows benefit in relation to the behavioral and physiological status of PREEMIE. PMID- 29972517 TI - Network to combat violence against rural women: articulation and communication of services. AB - OBJECTIVE: to identify the constituent services of the network to combat violence against rural women in municipalities in the northwestern region of Rio Grande do Sul and to analyze the articulation and communication of services in search of the resolution of situations of violence. METHOD: descriptive-exploratory, qualitative study, carried out through semi-structured interviews with 26 professionals from intersectoral services, as well as managers and/or those responsible for these services. Data were systematized through content analysis. RESULTS: although the professionals collectively discuss and plan coping actions, difficulties were identified in the approximation between services, related to the definition of flow, knowledge of actions/referrals, fear of seeing and reporting violence, understanding that it is not a question of demand of their field of action, and women's access to services. FINAL CONSIDERATIONS: it is evident the need to implement public policies that address the singularities of violence against women in rural settings. PMID- 29972518 TI - Family violence against gay and lesbian adolescents and young people: a qualitative study. AB - OBJECTIVE: To analyze the experiences of gay and lesbian adolescents and young people in the process of revealing sexual orientation to their families. METHOD: A qualitative study carried out in a city in the state of Sao Paulo. Twelve gay and lesbian adolescents and youngsters participated. For the data collection, the semi-structured interview was used and data analysis was performed using the method of interpretation of the senses. RESULTS: The family reactions in the process of "coming out of the closet" of the participants were violent, with persecution and even expulsion from home, in addition to the repression of expressions of homoerotic experiences, which impacted on their health and quality of life. FINAL CONSIDERATIONS: The family is an essential component of the support network, but also a space that can generate and reproduce forms of violence in the name of heteronormativity. Health services should develop care practices and care for the family and adolescent and homosexual youth victim of violence. PMID- 29972519 TI - Every birth is a story: process of choosing the route of delivery. AB - OBJECTIVE: To analyze the discourses on the choice of the route of delivery from the perspective of women and health professionals in a public network. METHOD: The methodological approach is the discourse analysis. The data collection was through interviews and the treatment of the data was based on discourse analysis. RESULTS: The categories were: 1- Between the preference and the decision there is no choice; 2- The complexity of the choice of the route of delivery; 3- It is necessary to legitimize the choice of the woman. FINAL CONSIDERATIONS: From the perspective of women in labor the route of delivery is determined by the physician and women are not proactive. The nurses' performance is timid, although their presence is fundamental for stimulating the physiological delivery and promoting the autonomy of women. It identifies the need for the physician to adopt a welcoming attitude, informing the women about the pros and cons involved in choosing the route of delivery. PMID- 29972520 TI - Violence against children and adolescents: profile and tendencies resulting from Law 13.010. AB - OBJECTIVE: Describing the profile of reported violence against children and adolescents and draw an essay on the initial effects of Law 13.010 on report patterns. METHOD: Analytic study of reported cases on SINAN - Information System on Reportable Harms (from 2013 to 2015) of violence to individuals under 19, in 53 cities of Minas Gerais. RESULTS: 1,481 cases were reported, 49.2% before and 50.8% after Law 13.010 came to force (p = 0.5501). There was a 7% decrease on female reports and a 27.2% in male reports (p = 0.0055). It was noticed a change in report patterns (p = 0.0023), with a 130.7% increase to neglect/abandonment reports and a 33% decrease to sexual abuse report. Higher rates of violence from the parents happens at the 1 to 9-year-old age group (p < 0.0001). CONCLUSION: Main victims were women, individuals from 15 to 19 years, with aggression happening within the household; after Law 13.010, changes to patterns of victim and offender profiles and of kind of violence were noticed. PMID- 29972521 TI - Being born at home is natural: care rituals for home birth. AB - OBJECTIVE: To be aware of the care rituals developed by families when preparing for home birth during the gestational process. METHOD: Qualitative and ethnographic research developed with families during the gestational process. We adopted the observation-participation-reflection model, and the analysis was performed according to ethnonursing. RESULTS: Care rituals are related to the choice of home as a place for childbirth, being characterized as a family's rite of separation to experience this process. Other care rituals involved the preparation of the family and the eldest child as well as the home, the body, and the mind of the pregnant woman, and the choice of destination of the placenta. FINAL CONSIDERATIONS: We must understand the birth process beyond the biological perspective, considering women and their family as a whole, within a cultural context with their beliefs and values. PMID- 29972522 TI - The work of nurses in high-risk prenatal care from the perspective of basic human needs. AB - OBJECTIVE: To analyze the work of nurses in high-risk prenatal care in secondary care, considering nursing problems and the basic human needs of pregnant women. METHOD: Cross-sectional and quantitative study, developed in a high-risk prenatal care clinic. Data were selected in the records of the nursing consultation. The studied variables were related to sociodemographic and obstetric characteristics, in addition to nursing problems. We performed the descriptive analysis of the data and the grouping of nursing problems within the levels of Basic Human Needs (BHN). RESULTS: We evaluated 54 nursing consultations of pregnant women, mostly young, multiparous, and with nine or more years of study. Every pregnant woman reported, on average, 7.4 nursing problems. The psychobiological BHN prevailed in relation to psychosocial ones. CONCLUSION: In high-risk prenatal care, nurses can use the nursing consultation considering their mastery of light technologies to engage with hard and light-hard technologies. PMID- 29972523 TI - The maternity ward of a teaching hospital: reconfiguration of maternal-child nursing care. AB - OBJECTIVE: to analyze the strategies used by nurses and nurse professors for a better position in the maternity ward of the teaching hospital of the Universidade Federal do Espirito Santo. METHOD: this is a social-historical study with a qualitative approach. The primary sources were written documents, such as official letters, memos, ordinances, standards and routines of the hospital; photographic material; and oral testimonies from seven participants. The interviews were performed using a semi-structured questionnaire, with questions regarding the adaptation from a sanatorium to a teaching hospital, the challenges faced, and the strategies adopted by the nursing department. RESULTS: the results allowed us to understand the close link between the maternity ward and the nursing course of the Universidade Federal do Espirito Santo, which created a differentiated nursing care that integrated training and care with a broader and humanized look. FINAL CONSIDERATIONS: the actions of the nurses were recognized and gave them professional visibility, influencing a new form of care in the maternity ward. PMID- 29972524 TI - Computerized nursing process: development of a mobile technology for use with neonates. AB - OBJECTIVE: to build a mobile technology to assist nurses during data collection, diagnostic reasoning, and identification of interventions in neonates. METHOD: methodological study with a qualitative approach. The development was carried out in three phases, namely: bibliographical survey, construction of a database of diagnosis/interventions, and development of the software. We used the development tools Ruby on Rails, IONIC 2, PostgresSQL, and Amazon EC2. RESULTS: The developed technology received the name Natus, able to contribute to the development of the nursing process applied to patients of neonatal units. Its requirements are: to define human needs, select nursing diagnoses, select interventions, define time periods, and issue printed files. FINAL CONSIDERATIONS: the technology built is a computerized tool that allows for the development of the nursing process, facilitating data collection, diagnostic reasoning, and identification and grouping of the clinical signs presented by the newborn in neonatal units. PMID- 29972525 TI - Assistance flowchart for pain management in a Neonatal Intensive Care Unit. AB - OBJECTIVE: To describe and discuss the process of developing a flowchart collectively constructed by the health team of a Neonatal Intensive Care Unit for the management of neonatal pain. METHOD: This is a descriptive and an exploratory study with a qualitative approach that used Problem-Based Learning as a theoretical-methodological framework in the process of developing the assistance flowchart for the management of neonatal pain. RESULTS: Based on this methodology, there was training in service and the discussion of key points of pain management by the health team, which served as input for the construction of the flowchart. FINAL CONSIDERATIONS: The assistance flowchart for pain management, based on scientific evidence, provided means to facilitate the decision-making of the health team regarding the pain of the newborn. It is suggested to use the flowchart frequently to promote the permanent education of the team and identify possible points to be adjusted. PMID- 29972526 TI - Educational technology to mediate care of the "kangaroo family" in the neonatal unit. AB - OBJECTIVE: to validate the content of an educational technology in the form of a booklet developed to mediate care of family members of newborns hospitalized in a neonatal unit. METHOD: Methodological research with content validation. Data collected from October 2011 to February 2012; research developed in three steps: development, evaluation and adaptation. The study population was 15 judges, health professionals and other professionals. The participants answered a Likert type questionnaire with 3 blocks of evaluative items. Data were analyzed statistically. RESULTS: validation reached the results proposed in most responses (80%); 16 items exceeded the parameter, 4 were equal to the score established and 2 were below the parameter. CONCLUSION: the content of educational technologies need to be validated. The booklet, after the evaluation, constitutes an adequate device to mediate care of the family members in the NICU. PMID- 29972527 TI - Family composing the soundtrack of its reintegration: a theoretical model. AB - OBJECTIVE: to understand the meaning of the family's reintegration attributed by the family experiencing it and to construct a representative theoretical model of this experience. METHOD: this is a qualitative study, conducted with four families with a total of 20 interviewees, with Symbolic Interactionism as theoretical framework, Grounded Theory as methodological, participant observation and the experience of musical making, mediating the interview as strategies of data collection. RESULTS: a comparative analysis of the data led to the identification of the main category and to the construction of the theoretical model TRYING TO REBUILD WHAT WAS BROKEN. CONCLUSION: the family experiencing reintegration lives a process of reconstruction that allows to revisit situations of abandonment and review the behavior of caring and re-meaning of family coexistence. For the health professional, this study invites to think about this theme and to review the concept of family, in order to create their own sense of care. PMID- 29972528 TI - Intimate partner violence among postpartum women: associated factors. AB - OBJECTIVE: To identify the profile and assess the self-esteem of postpartum women, to characterize their babies and partners, and to verify the association of these characteristics with the occurrence of intimate partner violence (IPV). METHOD: Cross-sectional study with 207 postpartum women assisted in a public clinic. RESULTS: There was no statistic correlation among the sociodemographic variables, personal and obstetric characteristics with the occurrence of IPV. The postpartum women who showed low self-esteem presented a higher exposure risk to IPV (p<0.01; OR=2.01 and CI 95% [1.40-2.87]). The mothers of the babies that were born with low weight (less than 2,500 g) had almost twice the chances of suffering violence (p<0.05; OR=1.74 and CI 95% [1.00-3.03]). The women whose partners did not consume alcohol presented a lower probability to be exposed to IPV (p<0.05; OR=0.182 and CI 95% [0.03-0.93]). CONCLUSION: Women's low self esteem, babies' inappropriate weight and consumption of alcohol by partners were correlated to the occurrence of IPV. PMID- 29972529 TI - Good practices of labor and birth care from the perspective of health professionals. AB - OBJECTIVE: Determine the understanding of health professionals of an obstetric hospital regarding the good practices of labor and birth care recommended by the World Health Organization. METHOD: Research-initiative, with data collection between April and July 2016 using the focal group technique, with 27 health professionals of an obstetric hospital of Rio Grande do Sul with 21 hospitalization beds. RESULTS: Three thematic categories were achieved: good obstetric practices and their meanings; from the biological character to singular and multidimensional care; from the punctual and fragmented conception to the labor and birth care network. CONCLUSION: Good practices, in addition to enabling rethinking the obstetric model and contributing to organize the maternal and child health care network in order to ensure access, humane care, and problem solving capacity, also foster female protagonism. PMID- 29972530 TI - Existential experience of children with cancer under palliative care. AB - OBJECTIVE: To understand the existential experience of children with cancer under Palliative Care from the Humanistic Nursing Theory's point of view. METHOD: This is a field and qualitative research, in which eleven children participated, supported by the Support Centre for Children with Cancer in Paraiba State. To collect data it was used the Story Drawing Procedure. The data were qualitatively analyzed based on Humanistic Nursing Theory. RESULTS: From the analysis of the empirical study's subject, the following thematic categories have emerged: children experiencing fear, sadness, anguish and insecurity in the face of their diagnosis and children experiencing fear of their family falling apart because of the possibility of dying. CONCLUSION: It is fundamental the participation of nurses in the Palliative Care to the children with cancer in order to strengthen the trust between the children and the professional to have the relationship of dialogue as central axis. PMID- 29972531 TI - Permanent Education in a neonatal unit from Culture Circles. AB - OBJECTIVE: to identify the factors that hinder and facilitate the work of the nursing team in a neonatal unit and to know the demands of Permanent Education described by the nursing team, emerging from the daily care. METHOD: qualitative study that followed the steps recommended by the "Paulo Freire's Method" carried out with 29 professionals of the nursing team of a neonatal unit of a university hospital. Three Culture Circles were carried out to identify the generating themes. RESULTS: The themes generated were organized according to the issues covered in the interviews and during the Culture Circles, with four themes being highlighted: lack of routines; training; improvement of coexistence of the team and improvement of management process. FINAL CONSIDERATIONS: The study made it possible to know the factors that hinder and facilitate the routine practice of nursing professionals by identifying the emergent themes of the Culture Circles that favored the critical reflection of the group, generating subsidies for the collective elaboration of the Permanent Education program in neonatal unit. PMID- 29972532 TI - Instructional therapeutic toy in the culture care of the child with diabetes type 1. AB - OBJECTIVE: To analyze the experience of the child with diabetes type 1 in the care related to the techniques of glycemic monitoring and insulin application by use of instructional therapeutic toy, in accordance with the culture care. METHOD: Qualitative study with premise of the ethnonursing carried out in secondary public service of reference in the treatment of diabetes, in the city Fortaleza, Ceara State, between January and November of 2014, among 26 school-age children. Based on the Observation, Participation, Reflection Enabler, were developed educational activities using instructional therapeutic toy. RESULTS: The children expressed doubts regarding the insulin therapy and the glycaemia checking. They also were interested in the orientations mediated by means of the therapeutic toy in the culture care. They asked about the rotation, location and administration of the insulin. Some children asked for the syringes to play and learn how to inject it in the dolls. CONCLUSION: To bring in this activity promoted approximation and effective communication with the child in the educational approach, increasing its ability in the self care. PMID- 29972533 TI - Pain in the immediate puerperium: nursing care contribution. AB - OBJECTIVE: to analyze the contribution of clinical nursing care to the mother who has recently given birth with immediate postpartum pain based on the Kolcaba's Theory of Comfort. METHOD: qualitative study by the research-care method. Three nurses, who provided care for women in the immediate puerperium as caregiver researchers and 30 postpartum women, were admitted to a public maternity hospital. A semi-structured interview was used for data collection, from which the thematic analysis of the content was carried out. RESULTS: nursing care with influences from the biomedical model was observed, but it expresses concern when being cared for. It offers administration of medications, guidelines and non pharmacological measures for pain relief. FINAL CONSIDERATIONS: nursing care based on the Theory of Comfort contributed to pain relief in the immediate puerperium. PMID- 29972534 TI - Reflections of nurses in search of a theoretical framework for maternity care. AB - OBJECTIVE: To define a theoretical framework to guide the systematization of nursing care in a maternity unit in the South of Brazil. METHOD: This was the preliminary stage of a qualitative methodological study, based on an educational activity and the assumptions of Paulo Freire, involving 15 nurses, between August and November 2015. The aim of data analysis was to identify emerging themes. RESULTS: The following themes emerged: knowledge of nurses about nursing theories; barriers to implementing and systematizing nursing care; the importance of a framework to guide practice and; educational activities as opportunities to systematize nursing care. CONCLUSION: The discussion process involved in establishing the theoretical framework enabled reflections about nursing practices, reinforcing the importance of theoretical frameworks to guide work processes and enhance quality of care. PMID- 29972535 TI - Sleep and salivary cortisol in preterm neonates: a clinical, randomized, controlled, crossover study. AB - OBJECTIVE: Analyze the influence of ear protectors on the baseline levels of salivary cortisol and response and total sleep time of preterm neonates during two periods of environmental management of a neonatal intermediate care unit. METHOD: A clinical, randomized, controlled and crossover study conducted with 12 preterm neonates. The use of ear protectors was randomized in two periods. Sleep evaluation was performed using one Alice 5 Polysomnography System and unstructured observation. RESULTS: No significant difference was observed between the baseline levels of salivary cortisol and response in preterm neonates from the control and experimental groups, and no statistical significance was observed between the total sleep time of both groups. No relationship was observed between the baseline levels of cortisol and response and total sleep time. CONCLUSION: Ear protectors in preterm neonates did not influence the salivary cortisol level and total sleep time in the studied periods. PMID- 29972536 TI - Assessment of the essential attributes of Primary Health Care for children. AB - OBJECTIVE: To identify the presence and extent of essential attributes in primary health care services for children, focusing on the evaluation of structure and process. METHOD: Evaluative, quantitative study carried out in 23 traditional basic health units in a city in Parana State, with 548 caregivers of children under 12 years old, using the Primary Care Assessment Instrument (PCATool Brazil), child version. Essential and general scores of the primary care were calculated according to the methodology proposed, with a cut-off score >=6.6. RESULTS: The scores of the essential attributes in relation to structure are: Accessibility (5.5), Kinship (6.9), Integrality of care - Services Available (6.0) and Coordination - System information (7.4). As for the Process, the following results were obtained: First visit - Use (8.6), Longitudinally (6.1), Integrality - Services Provided (6.1) and Coordination - Integration of Care (6.9). CONCLUSION: The essential score was 6.6 and the general score was 6.3, showing weak focus on primary health care. PMID- 29972537 TI - The adolescent and the institutionalization: understanding the phenomenon and meanings attributed to it. AB - OBJECTIVE: To understand the meaning of being institutionalized and in conflict with the law for the institutionalized adolescent. METHOD: A qualitative, phenomenological-comprehensive study carried out in a Socio-educational Service Foundation in the northern region of Brazil, with 05 institutionalized adolescents. The analysis was carried out under the understanding of the content suggested by Heidgger, thus allowing the construction of analytical categories for a hermeneutical interpretation. RESULTS: Conflicting with the law means something negative and bad for the institutionalized adolescents, in which they understand that although there is deprivation of liberty, the period of hospitalization is an important moment for the reflection on the need to start over. CONCLUSION: The meaning of conflicting with the law goes far beyond a simple word, act or behaviour, it is something that only those who experience the phenomenon are able to unveil, arouse deep feelings and provide reflection to the adolescent about the damages caused by the infraction. PMID- 29972538 TI - The pain of children with sickle cell disease: the nursing approach. AB - OBJECTIVE: To describe how nurses identify the pain in children with sickle cell disease (SCD) and to list the strategies used by them in the evaluation and control of pain. METHOD: This is a qualitative, descriptive and exploratory research, performed through semi-structured interviews with 13 nurses. The interviews were transcribed and after this process the qualitative data were organized according to thematic analysis. RESULTS: This study showed that the nurses can identify pain in children with SCD from the signals they emit, such as: constant crying, restlessness, facial expressions and verbal reports. Pain is difficult to evaluate due to the lack of instruments, such as a pain scale. For pain control they use emotional support, promotion of comfort and the administration of drugs prescribed by the doctor. FINAL CONSIDERATIONS: The nurses recognize the pain of the child and use pharmacological and non pharmacological methods to control it but have difficulties to assess it. PMID- 29972539 TI - Assessment of the preparation and administration of oral medications to institutionalized children. AB - OBJECTIVE: to evaluate the preparation and administration of oral medications to institutionalized children by nursing professionals. METHOD: quantitative study, developed from August to September 2016, in a shelter in Fortaleza, Ceara. 323 observations of preparation and administration of oral drugs were carried out. Interview and non-participant direct observation of the process of drug administration were performed, whose data were analyzed through descriptive statistics. RESULTS: Of the 29 actions of preparation and administration of the drugs, ten were considered satisfactory. Sanitizing of hands before touching the pills occurred in only 5.2% of the observations and cleansing of the bottle for liquid drugs was performed in 23.8%. The actions "check the right child"; "checking medication with the prescription", and "check the right dose" obtained percentages below 15%. CONCLUSION: measures recommended by the literature for the administration of medication were not, in their clear majority, followed, making specific training and protocols necessary. PMID- 29972540 TI - Identification of post-cesarean surgical site infection: nursing consultation. AB - OBJECTIVE: To describe the profile of women in relation to their living conditions, health status and socio-demographic profile, correlating it with the presence of signs and symptoms suggestive of post-cesarean surgical site infection, identifying information to be considered in the puerperium consultation performed by nurses and proposing a roadmap for the systematization of care. METHOD: Quantitative, exploratory, descriptive, cross-sectional and retrospective review of medical records of women who had cesarean deliveries in 2014, in the city of Sao Paulo. RESULTS: 89 medical records were analyzed, 62 of them with incomplete information. In 11, there was at least one of the signs and symptoms suggestive of infection. CONCLUSION: Given the results of the study, the systematization of puerperal consultation is essential. The roadmap is an instrument that can potentially improve the quality of service and the recording of information. PMID- 29972541 TI - Water balance in pediatric nephrology: construction of a Standard Operating Procedure. AB - OBJECTIVE: To construct a Standard Operating Procedure (SOP) about the water balance, to be used by the health team in the care of children hospitalized in a pediatric nephrology unit. METHOD: The study was carried out in two stages: integrative review of the literature for the development of SOP and validation by specialists. The search for literature occurred in the electronic databases PUBMED, SCOPUS, LILACS, BDENF. After the bibliographic survey the construction of the SOP was performed, which was evaluated by specialists. The analysis was performed by calculating the Content Validity Index (CVI). RESULTS: nine studies were selected as results of the integrative review. The sample of specialists was composed of nine professionals. The study was evaluated in six items, five of which presented CVI = 1 and one obtained CVI = 0.77. CONCLUSION: the evaluation of specialists culminated in the validation of SOP, suggesting changes that were accepted and discussed with the literature. PMID- 29972542 TI - Validation of primer for promoting maternal self-efficacy in preventing childhood diarrhea. AB - OBJECTIVE: to validate an educational primer, regarding content and design, for promoting maternal self-efficacy in preventing childhood diarrhea. METHOD: methodological study composed of 31 mothers of children under five years of age, in which the validation of the primer You can prevent diarrhea in your child! was carried out from the Content Validity Index (CVI), being evaluated as to the domains understanding, attractiveness, self-efficacy, cultural acceptance, and persuasion. RESULTS: the primer was considered relevant and clear, with average concordance of 99.4% and 99.8%, respectively. The overall CVI was of 0.99, evidencing satisfactory level of agreement between the mothers. The assessment of domains generated satisfactory results. CONCLUSION: the primer was considered valid by the target audience; thus, it can be implemented for promoting maternal confidence to prevent childhood diarrhea. PMID- 29972543 TI - Children hospitalized due to maltreatment in the ICU of a Public Health Service. AB - OBJECTIVE: to characterize children hospitalized due to violence in a pediatric ICU in 2011; to relate violence and the mechanisms of trauma with death; to know the contextualization of violence, from the records in the medical records. METHOD: retrospective cohort, performed in a first aid hospital, Porto Alegre city, in the records of 22 children hospitalized in the ICU due to violence. Quantitative analysis was performed by absolute and relative frequency rates, chi square and relative risk. RESULTS: 54.5% were boys, 81.8% were white and 50% were up to three years old. Physical violence 50% and neglect 36.4%, family of children (77.3%), highlighting the mother (35.3%). Mechanisms of aggression: fall (22.7%), burns (18.2%). Burns were at high risk for death. Discharge to go home after ICU admission (59.1%). CONCLUSION: It is considered that the characterization of the cases of violence reflects the complexity of the theme, mainly, in face of the life histories that surround each case of children hospitalized by this aggravation. PMID- 29972544 TI - Sexual function of undergraduate women: a comparative study between Brazil and Italy. AB - OBJECTIVE: to evaluate the sexual function of Italian and Brazilian nursing students using the Female Sexual Function Index (FSFI), to estimate the prevalence of sexual dysfunctions and related factors. METHOD: this is a cross sectional study involving 84 Brazilian and 128 Italian undergraduate. For the evaluation of sexual function, the Female Sexual Function Index (FSFI) questionnaire was used. RESULTS: Italian women presented significantly higher sexual dysfunction index (n=78/60.9%) than the Brazilian women (n=32/38.1%) (p=0.00). Only the "desire" and "excitation" domains showed no difference between groups. Younger, single and without a steady relationship women had a higher rate of sexual dysfunction (p<0.05). CONCLUSION: the high rate of sexual dysfunction in a young public suggests the need for more research to increase knowledge about the influence of psychosocial and related factors on female sexual function, directing care towards the promotion of sexual and reproductive health. PMID- 29972545 TI - Nursing diagnoses for elderly women vulnerable to HIV/AIDS. AB - OBJECTIVE: Classify the diagnoses in the conceptual framework of vulnerability of Ayres and in the Orem's self-care theory; Elaborate operational definitions of nursing diagnoses for elderly women vulnerable to HIV/AIDS. METHOD: A descriptive exploratory study, developed from March to December 2016 in the stages: 1. Classification of diagnoses in the conceptual framework of vulnerability of Ayres and in the Orem's self-care theory; 2. Operational definition of nursing diagnoses. RESULTS: 70 nursing diagnoses were classified in the conceptual framework of vulnerability of Ayres and Orem's self-care theory, and their operational definitions were constructed, where 75.7% of these were validated. FINAL CONSIDERATION: Diagnoses represent conditions that make older women vulnerable to HIV/AIDS and are linked to their self-care practices. Operational definitions contribute to a systematic approach to care and greater clarity in its implementation. PMID- 29972546 TI - Accuracy of the defining characteristics of the nursing diagnosis for fatigue in women under radiotherapy. AB - OBJECTIVE: To evaluate the accuracy of the defining characteristics of the nursing diagnosis for "fatigue in women with breast cancer under radiotherapy". METHOD: Study of diagnostic accuracy, with cross-sectional design, performed in 130 women with breast cancer under radiation treatment. A data collection instrument was used to evaluate clinical socio-demographics and to investigate the presence or absence of defining characteristics for fatigue. The latent class analysis model was applied to assess accuracy measurements of the characteristics identified. RESULTS: Fatigue diagnosis was present in 21.9% of the women. The characteristic which showed the highest sensitivity was "Impaired capacity in maintaining the usual level of physical activity", while "Impaired capacity in maintaining usual routines" and "Lack of interest about the surrounding environment" presented greater specificity. CONCLUSION: Accurate diagnostics allow devising an action plan directed to the patients' real needs. PMID- 29972547 TI - Effects of different hormonal contraceptives in women's blood pressure values. AB - OBJECTIVE: To identify evidence in the literature of the relationship between the use of different hormonal contraceptive methods and alterations in women's blood pressure values. METHOD: This is an integrative literature review, consisting of ten scientific articles published in PubMed and BVS, between 2012 and 2016, selected by keywords, available fully and free of charge, in English, Portuguese, or Spanish. RESULTS: The articles showed that exogenous estrogen helps in the activation of the renin-angiotensin-aldosterone system causing hypertensive effects even in small doses; and that combined use with drospirenone reduces these effects. Routes of administration without passage through the liver and use of isolated progestin showed promising results in reducing the effects on blood pressure. CONCLUSION: There is evidence in the literature of pressure alterations associated with different hormonal contraceptives and that personal history of morbidities are to be considered in an attempt to reduce the effects on the cardiovascular system. PMID- 29972548 TI - The effectiveness of post-partum interventions to prevent urinary incontinence: a systematic review. AB - OBJECTIVE: to assess the effectiveness of post-partum interventions to prevent urinary incontinence: a systematic review. METHOD: systematic review of randomized controlled studies conducted in the MEDLINE, Cochrane, Scopus and the Virtual Library on Health (Biblioteca Virtual em Saude, BVS) databases. RESULTS: six articles were included in this review. All studies used the Pelvic Floor Muscle Training as the main procedure to prevent urinary incontinence. The results pointed to a positive and effective intervention in the post-partum period. CONCLUSION: there is evidence that programs of exercise of the pelvic floor musculature performed both in the immediate and late post-partum result in a significant increase in muscle strength and contribute to prevent urinary incontinence. PMID- 29972549 TI - Applicability of Orem: training of caregiver of infant with Robin Sequence. AB - OBJECTIVE: to report the nurses' experience in relation to the training of caregivers of infants with Isolated Robin Sequence (IRS) for maintaining care after hospital discharge from the perspective of Self-Care Theoretical Framework. METHOD: the following categories were considered in this experience report: self care action, self-care capacity, therapeutic self-care demand, self-care deficit, and nursing system. The nursing system was wholly compensatory and supportive educative. RESULTS: caregivers' training by nurses results in the acquisition of technical skills and specific knowledge related to the infant's positioning in elevated ventral decubitus, nasopharyngeal intubation, feeding-facilitating techniques and care with the feeding tube. FINAL CONSIDERATIONS: the continuity of home care is guaranteed from caregivers' training for the therapeutic demand. PMID- 29972550 TI - Application program to prepare child/family for venipuncture: experience report. AB - OBJECTIVE: To report the experience of development of an application program to prepare child and family for venipuncture. METHOD: Experience report on an application program developed in the professional nursing master's degree program in partnership with engineering undergraduate students. RESULTS: The application program allows the child to understand the venipuncture procedure in a ludic and interactive manner. Its development occurred in three stages: identification of client's needs, definition of components, and prototype elaboration. FINAL CONSIDERATIONS: The application program, besides being directed to care and education of children and families, is able to meet the nurses' needs to prepare them for venipuncture. Moreover, it is worth mentioning the importance of multidisciplinary approach for the concretion of similar projects. PMID- 29972551 TI - Caring for the future: decrease in infant mortality in Maranhao State. AB - OBJECTIVE: To report on the experience and care provided by the "Caring for the future" program to decrease infant mortality in 17 municipalities of Maranhao, in a proposal work of the Secretariat of Basic Care, in partnership with the Non Governmental Organization called Centro Popular de Cultura e Desenvolvimento (Popular Center for Culture and Development/PCCD) from 2009 to 2015. METHOD: Experience Report of community care that made it possible to create and strengthen solidary relationships among community members. RESULTS: The program decreased infant mortality rate and created in the supported communities a platform of health support, uniting information and care in Primary Care. The program trained 34 "Guardian Angels" and 170 "Supportive Caregivers", mapped seven thousand "luminous spots" and trained more than 7,000 caregivers in health. It served 17 municipalities, 27,191 pregnant women, 291,266 families. FINAL CONSIDERATIONS: The program was a catalyst for actions: it unveiled hidden resources in the community, awakened collective responsibility, offered training and built solidary relationships. PMID- 29972552 TI - ? AB - [This corrects the article doi: 10.1590/0034-7167-2017-0123]. PMID- 29972553 TI - Has the threat of Zika virus outbreaks come to an end? PMID- 29972554 TI - Zika virus: - a review of the main aspects of this type of arbovirosis. AB - The objective of this study was to integrate findings related to Zika virus from the scientific literature. An integrative review of Medline was conducted, and data search was performed using the Health Sciences Descriptor Zika virus and the following filters: full texts available; studies in humans; full articles; and publications in Portuguese, French, English, and Spanish. After application of the filters, followed by reading of the titles, abstracts, and full texts, 44 studies were included in the review, for which content analysis was performed. A large part of the literature comprised review articles (84%; N=37); the majority was in English (95%, N=42). In 2016, 84% (N=37) of our sample articles was published, while in 2017, 16% (N=7) was published. The main form of viral transmission was thorough the mosquito Aedes aegypti (N=30). In addition, sexual transmission (N=09), transmission through blood transfusion (N=16), vertical transmission (N=21) and transmission from occupational activities (N=03) occurred. It was possible to diagnose the disease by testing blood (N=22), urine (N=14), saliva (N=06), semen/sperm (N=03), cerebrospinal and amniotic fluid, and other tissues (N=02). Symptomatology occurred in 1-5 people (N=10) between 3 and 7 days after a mosquito bite (N=09). Complications observed were Guillain Barre syndrome (N=27); neurological Zika syndrome (N=27); meningitis, meningoencephalitis, and myelitis (N=07); deaths and/or newborns (N=03). The review provides scientific evidence that contributes to the care, planning and implementation of public policies. PMID- 29972555 TI - Prevalence of metallo-beta-lactamase-encoding genes among carbapenem-resistant Pseudomonas aeruginosa strains isolated from burn patients in Iran. AB - Carbapenem-resistant Pseudomonas aeruginosa (CRPA) has been considered a major cause of infection and mortality in burn patients, especially in developing countries such as Iran. One of the most common mechanisms of carbapenem resistance is production of metallo-beta-lactamases [(MBLs), including Verona Integron-encoded Metallo-beta-lactamase (VIM), imipenemase (IMP), Sao Paulo metalo-beta-lactamase (SPM), German imipenemase (GIM), New Delhi metallo-beta lactamase (NDM), Dutch imipenemase (DIM), Adelaide imipenemase (AIM), Seoul imipenemase (SIM), KHM, Serratia metallo-beta-lactamase (SMB), Tripoli metallo beta-lactamase (TMB), and Florence imipenemase (FIM)]. Limited information is available on the prevalence of CRPA and MBLs in Iranian burn units. We performed a systematic search by using different electronic databases, including Medline (via PubMed), Embase, Web of Science, and Iranian Database. Of 586 articles published from January 2000 to December 2016, 14 studies reporting the incidence of CRPA and MBLs as detected by molecular methods in burn patients were included in this review. The meta-analyses showed that the prevalence of CRPA, IMP, and VIM was 76.8% (95% CI 67.5-84.1), 13.1% (95% CI 4.7-31.5), and 21.4% (95% CI 14.6 30.1), respectively, in Iranian burn centers and remaining MBLs types have not yet been detected. There was a high prevalence of MBLs and CRPA in Iranian burn centers. Therefore, these measurements should be applied nationally and rigorous infection control measures and antimicrobial stewardship will be the major pillars to control multidrug resistant microorganisms, such as CRPA. PMID- 29972556 TI - Evaluation of inflammatory biomarkers, carotid intima-media thickness and cardiovascular risk in HIV-1 treatment-naive patients. AB - INTRODUCTION: Mortality among HIV patients is 3-15 times higher than that among the general population. Currently, most deaths are due to non-infectious diseases. Chronic inflammation and adverse events due to antiretroviral therapy play crucial roles in increasing cardiovascular risk (CVR). METHODS: This cross sectional study aimed to evaluate carotid intima-media thickness (CIMT) and inflammatory biomarkers (D-dimer, ADAMTS13, GDF-15, sICAM-1, MPO, myoglobin, NGAL, SAA, sVCAM-1, and p-selectin) among naive patients. RESULTS: Sixty-seven participants were included: median age, 32 years; males, 82.1%; non-white, 61.1%; higher education level, 62.7%; and exposed to HIV through sexual relationship (men who have sex with men), 68.7%. The median viral load and LTCD4+ value were 42,033 copies/mL and 426 cells/mm3. The prevalence of arterial hypertension was 16.4%; those of diabetes mellitus and dyslipidemia were 3% and 70.1%, respectively. The CIMT was 494.08 (+/- 96.84mm). The mean vascular age was 33.2 +/- 18.9 years, one year longer than the chronological age, without statistical significance. CONCLUSIONS: The majority of participants had a low CVR (94%). After reclassification, considering the CIMT percentiles, 13 (19.4%) patients had medium/ high CVR, while 54 (80.6%) patients had low CVR. The difference between the proportions of CVR when considering the CIMT and its corresponding percentile was statistically relevant. Body mass index was the only predictor of higher CVR (p = 0.03). No biomarker was found to predict CVR. People living with HIV have a high prevalence of dyslipidemia before ARV therapy. PMID- 29972557 TI - Variation in temephos resistance in field populations of Aedes aegypti (Diptera: Culicidae) in the State of Sergipe, Northeast Brazil. AB - INTRODUCTION: The organophosphate temephos was first used in Brazil in the 1960s for the control of Aedes aegypti. Because of its extensive and longstanding use worldwide, selection for mosquito populations resistant to the chemical has been observed not only in different regions of Brazil but also in several parts of the world. The objective of this study was to evaluate the susceptibility of Ae. aegypti to the organophosphate temephos, a larvicide used in vector control activities in Sergipe/Northeast Brazil. METHODS: This study included mosquito populations from seven municipalities of Sergipe and was carried out from October 2010 to August 2011. Qualitative bioassays of diagnostic dose and dose responses were performed. The resistance ratio was calculated based on lethal concentrations for mosquitoes of the susceptible Rockefeller strain. RESULTS: All populations were classified as resistant to temephos. The resistance ratio ranged from 22.2 to 297.9, the lowest being seen in Aracaju, a coastal area of the state, and the highest in Pinhao, a semi-arid region, 96.6km from Aracaju. CONCLUSIONS: High levels of temephos resistance were observed in the Ae. aegypti populations of Sergipe. The variation between regions indicates that there have been different regimes of insecticide use and also points to the potential of small cities to generate and spread insecticide resistance. PMID- 29972558 TI - Larvicidal effect of Clinopodium macrostemum essential oil extracted by microwave assisted hydrodistillation against Culex quinquefasciatus (Diptera: Culicidae). AB - INTRODUCTION: In the present study, we determined the chemical composition of Clinopodium macrostemum essential oil obtained by microwave-assisted hydrodistillation and its effect on the growth and development of Culex quinquefasciatus mosquito larvae. METHODS: The essential oil compounds were identified by gas chromatography-mass spectrometry analysis, and bioassays were conducted to evaluate the influence on the developmental stages of early second instar larvae of Cx. quinquefasciatus until the emergence of adults, using essential oil concentrations of 50, 100, 200, 400, and 800mg/L. RESULTS: The gas chromatography-mass spectrometry analyses revealed that the leaf essential oil of C. macrostemum contained 32 compounds and the major chemical compounds identified were linalool (55.4%), nerol (6.4%), caryophyllene (6.25%), menthone (5.8%), geraniol acetate (4.1%), terpineol (3.7%), and pulegone (2.8%). The essential oil yield obtained by microwave-assisted hydrodistillation was 0.8% at 20 min. The treatments showed lethal concentrations (LC50 and LC90) of 22.49 and 833.35mg/L, respectively, after the final measurement of the total number of dead larvae (second, third, and fourth instars), and LC50 and LC90 of 6.62 and 693.35mg/L, respectively, at the end of the experimental period. The essential oil inhibited the growth and development of the mosquito larvae by 32% (relative growth index = 0.68) at 50mg/L, and up to 47% (relative growth index = 0.53) at 800mg/L. CONCLUSION: The present study demonstrated the larvicidal effect of C. macrostemum essential oil on Cx. quinquefasciatus, which can be attributed to the oxygenate compounds obtained by the extraction method. PMID- 29972559 TI - Field evaluation of sticky BR-OVT traps to collect culicids eggs and adult mosquitoes inside houses. AB - INTRODUCTION: Culex quinquefasciatus is a mosquito of importance to public health, as it represents a real and/or potential risk for the transmission of pathogens to humans, such as some arthropod-borne viruses and nematodes that cause filariasis. In Brazil, three municipalities in the Metropolitan Region of Recife (RMR) that are endemic for lymphatic filariasis conducted control actions targeting this vector. With the goal of contributing novel C. quinquefasciatus collection strategies, a sticky trap capable of collecting eggs and imprisoning mosquitoes was investigated. METHODS: To evaluate the performance of the sticky BR-OVT trap, tests were carried out in the neighborhoods of Caixa d'Agua and Passarinho (Olinda-PE-Brasil) between August 2011 and June 2012. Sixty traps were installed in the indoor areas of residences in the two districts. RESULTS: During the 11-month study, 0.52 [standard deviation (SD) = 1.52] Culex egg rafts, 2.16 (SD = 4.78) C. quinquefasciatus/trap/month, and 0.55 (SD = 1.28) Aedes/trap/month were caught. Female specimens predominated the traps (59% of C. quinquefasciatus and 96% of Aedes spp.). CONCLUSIONS: The results demonstrated that the sticky BR OVT trap is a useful tool for the collection of adult culicids of medical importance and offers an innovative way to collect C. quinquefasciatus eggs and adults in a single trap. PMID- 29972560 TI - Occurrence of the vanA gene in Staphylococcus epidermidis from nasopharyngeal secretion of Health-Care Workers, Recife, Brazil. AB - INTRODUCTION: The increasing reports of vancomycin-resistant Staphylococcus strains (VRS) haves caused concern worldwide, from the laboratory detection to patient management. This study aimed to identify the occurrence of VRS strains among healthcare professionals from a university hospital. METHODS: A total of 102 Staphylococcus sp. isolates from healthcare professionals, obtained in a previous study were evaluated according to standard techniques for VRS detection. RESULTS: After screening inoculation of plates containing 6ug/ml of vancomycin, 19 resistant isolates were identified. The susceptibility profile to other antimicrobials revealed 18 multidrug resistant isolates. The minimum inhibitory concentration (MIC) was determined by E-test and broth microdilution. According to E-tests, of 19 isolates grown in BHI-V6, four isolates presented MIC >= 128 ug/ml, seven with MIC ranging from 4 to 8 ug/ml, and eight with MIC <= 2ug/ml. By broth microdilution, 14 isolates presented MIC <= 2 ug/ml and five with MIC >= 16ug/ml. The presence of the gene vanA was determined by PCR in the five resistant isolates, and this gene was detected in one of the strains. Furthermore, among the 19 strains, the gene mecA was found in 13 (39,4%) isolates, including the strain carrying the gene vanA. CONCLUSIONS: Based on these results, we highlight the presence of one strain carrying both vanA and the mecA genes, as well as multidrug-resistant strains colonizing healthcare professionals, and their importance as potential vectors to spread strains carrying resistance genes in the hospital environment. PMID- 29972561 TI - Systematic neonatal screening for congenital Chagas disease in Northeast Brazil: prevalence of Trypanosoma cruzi infection in the Southern region of Sergipe. AB - INTRODUCTION: Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi, being one of the leading causes of morbidity and mortality in the Americas with an estimated six to seven million infected people worldwide. In Brazil, the improvement in vector control and blood donor screening has evidenced the important epidemiological role of congenital transmission of Chagas disease. METHODS: A serological survey for Chagas disease was performed in 3,952 newborns in the southern region of Sergipe using paper filter disks of dried blood samples. The newborns were screened using the Sergipe State Neonatal Screening Program between July 2015 and July 2016, and 3,749 and 750 blood samples were obtained for the IgG enzyme-linked immunosorbent assay and indirect immunofluorescence assay, respectively. In addition, mothers of the children who presented initial reagent serology were examined. RESULTS: Among 3,749 blood samples, samples of two children were positive for the enzyme-linked immunosorbent assay; however, their confirmation test results were negative, suggesting passive transfer of the mother's antibody. One puerpera was identified with Chagas disease, with a prevalence of 0.02%. CONCLUSIONS: Congenital Chagas disease was not observed in newborns in the Southern region of Sergipe. However, Chagas disease was observed in women of reproductive age. Therefore, effective measurements for monitoring and systematic evaluation should be conducted. The Neonatal Screening Program proved to be an effective public health strategy for the prevention and control of Chagas disease. PMID- 29972562 TI - Mucosal leishmaniasis: the experience of a Brazilian referral center. AB - INTRODUCTION: Pentavalent antimonials (Sbv) are the most commonly used drugs for the treatment of mucosal leishmaniasis (ML), despite their high toxicity and only moderate efficacy. The aim of this study was to report therapeutic responses with different available options for ML. METHODS: This study was based on a review of clinical records of 35 patients (24 men and 11 women) treated between 2009 and 2015. RESULTS: The median age of patients was 63 years, and the median duration of the disease was 24 months. Seventeen patients received Sbv, while nine patients were treated with liposomal amphotericin B (AmB), and another nine patients were treated with fluconazole. Patients treated with AmB received a total median accumulated dose of 2550mg. The mean duration of azole use was 120 days, and the daily dose ranged from 450 to 900mg. At the three-month follow-up visit, the cure rate was 35%, 67%, and 22% for Sbv, AmB, and azole groups, respectively. At the six-month follow-up visit, the cure rates for Sbv, AmB, and azole groups were 71%, 78%, and 33%, respectively. CONCLUSIONS: There is a scarcity of effective ML treatment alternatives, and based on our observations, fluconazole is not a valid treatment option. PMID- 29972563 TI - A diagnosis of pulmonary tuberculosis and drug resistance among inmates in Mato Grosso do Sul, Brazil. AB - INTRODUCTION: High endemic levels of pulmonary tuberculosis in prisons result from overcrowding, limited access to healthcare, delayed diagnosis, sustained transmission owing to poor control measures, and multidrug resistance. This study evaluated locally implemented measures for early pulmonary tuberculosis diagnosis and evaluated resistance to anti-tuberculosis drugs. METHODS: This transversal study employed data from the Mato Grosso do Sul State Tuberculosis Control Program obtained from 35 correctional facilities in 16 counties for 2 periods (2007-2010 and 2011-2014). RESULTS: Statewide prevalence (per 100,000) was 480.0 in 2007 and 972.9 in 2014. The following indicators showed improvement: alcohol acid-fast bacillus testing (from 82.7% to 92.9%); cultures performed (55.0% to 81.8%); drug susceptibility testing of positive cultures (71.6% to 62.4%); and overall drug susceptibility testing coverage (36.6% to 47.4%). Primary and acquired resistance rates for 2007-2014 were 21.1% and 30.0%, respectively. Primary and acquired multidrug resistance rates were 0.3% and 1.3%, respectively. CONCLUSIONS: Prevalence rates increased, and laboratory indicators improved as a result of capacity building and coordination of technical teams and other individuals providing healthcare to inmates. Resistance rates were high, thereby negatively affecting disease control. PMID- 29972564 TI - Performance of the IS6110-TaqMan(r) assay in the diagnosis of extrapulmonary tuberculosis from different biological samples. AB - INTRODUCTION: This study evaluated the performance of the IS6110-TaqMan(r) assay in different types of biological samples and tissues for laboratory diagnosis of extrapulmonary tuberculosis. METHODS: 143 biological samples and tissues from patients with suspected extrapulmonary tuberculosis from the health services of Recife/Pernambuco/Brazil were evaluated with the IS6110-TaqMan(r) assay. RESULTS: The sensitivities of the IS6110-TaqMan(r) assay calculated for blood, urine, both blood and urine samples, tissue biopsies, extrapulmonary body fluid samples, and all samples from patients calculated together were 55.9%, 33.3%, 68.8%, 43.8%, 29.6%, and 73.7%, respectively, and the specificities were 80%, 100%, 78.6%, 100%, 100%, and 84.2%, respectively. CONCLUSIONS: The accuracy of qPCR was high in various clinical sample types. The analysis of more than one type of clinical sample collected from the same patient with extrapulmonary tuberculosis enhances the diagnostic power of the IS6110-TaqMan(r) assay when compared with the use of only one clinical sample. PMID- 29972565 TI - Epidemiological study of snakebite cases in Brazilian Western Amazonia. AB - INTRODUCTION: Brazil has the largest number of snakebite cases in South America, of which the large majority is concentrated in the Midwest and North. METHODS: In this descriptive observational study, we assessed the epidemiological and clinical snakebite cases referred to the Centro de Medicina Tropical de Rondonia from September 2008 to September 2010. RESULTS: We followed up 92 cases from admission until discharge, namely 81 (88%) men and 11 (12%) women, with a mean age of 37 years, and mainly from rural areas (91.3%). The snakebites occurred while performing work activities (63%) during the Amazon rainy season (78.3%). The vast majority of individuals presented from the Porto Velho microregion (84.7%). Approximately 95.6% of the snakebites were caused by snakes of the genus Bothrops, followed by two lachetics and two elapidics cases. Surgery was performed in 10 cases (9 fasciotomies in the lower limb and 1 amputation). No deaths were reported in this study, but 4 cases (4.3%) developed sequelae in the lower limb. CONCLUSIONS: This study can contribute to a better understanding of envenomation in the state of Rondonia and thus can be useful for identifying real conditions that can increase the incidence of snakebites in this region. Moreover, the study results can serve as a basis for improving educational campaigns designed to prevent these types of snakebites, as well as for preserving snakes. PMID- 29972566 TI - Neurologic manifestations in emerging arboviral diseases in Rio de Janeiro City, Brazil, 2015-2016. AB - INTRODUCTION: Dengue has affected Rio de Janeiro City since the 1980s. The sequential Zika and chikungunya virus introductions during 2015 aggravated the health scenario, with 97,241 cases of arboviral diseases reported in 2015-2016, some with neurological disorders. METHODS: Arbovirus-related neurologic cases were descriptively analyzed, including neurological syndromes and laboratory results. RESULTS: In total, 112 cases with non-congenital neurologic manifestations (Guillain-Barre syndrome, 64.3%; meningoencephalitis, 24.1%; acute demyelinating encephalomyelitis, 8%) were arbovirus-related; 43.7% were laboratory-confirmed, of which 57.1% were chikungunya-positive. CONCLUSIONS: Emerging arbovirus infections brought opportunities to study atypical, severe manifestations. Surveillance responses optimized case identification and better clinical approaches. PMID- 29972567 TI - Clinical and laboratorial features of oral candidiasis in HIV-positive patients. AB - INTRODUCTION: We describe the clinical and laboratorial features of oral candidiasis in 66 HIV-positive patients. METHODS: Polymerase chain reaction-based techniques were performed for differentiation of Candida spp. isolated from patients at a public teaching hospital in Midwest Brazil. RESULTS: Oral lesions, mainly pseudomembranous, were significantly related to higher levels of immunosuppression. Of 45 Candida isolates, 66.7% were C. albicans. Most of the isolates were susceptible to the antifungal drugs tested. CONCLUSIONS: Oral lesions were associated with higher immunosuppression levels. Lower susceptibility to antifungals by non-albicans isolates supports the importance of surveillance studies using susceptibility tests to aid in the treatment. PMID- 29972568 TI - Depression and anxiety disorders among patients with human T-cell lymphotropic virus type-1: a cross-sectional study with a comparison group. AB - INTRODUCTION: Studies have linked human T-cell lymphotropic virus type-1 (HTLV-1) to psychiatric disease. METHODS: Patients with HTLV-1 were compared to patients seen by family doctors using a semi-structured questionnaire and the Hospital Anxiety and Depression Scale. RESULTS: Participants with (n=58) and without (n=340) HTLV were compared. Anxiety and depression were associated with greater age, being a woman, spastic paraparesis (depression: PR=4.50, 95% CI: 3.10-6.53; anxiety: PR=2.96, 95% CI: 2.08-4.21), and asymptomatic HTLV (depression: PR=4.34, 95% CI: 3.02-6.24; anxiety: PR=2.81, 95% CI: 2.06-3.85). CONCLUSIONS: Symptomatic and asymptomatic patients with HTLV-1 experienced more anxiety and depression than uninfected patients. PMID- 29972569 TI - Coexistence of virulence genes in methicillin-resistant Staphylococcus aureus clinical isolates. AB - INTRODUCTION: The pathogenic versatility of Staphylococcus aureus is attributed to various virulence genes, including enterotoxins and hemolysins. METHODS: Here, the virulence genes in 177 nosocomial MRSA strains in Porto Alegre, Brazil were detected by PCR. RESULTS: The overall prevalence rates were as follows: sea, 4.5%; pvl, 18.6%; tst, 27.7%; hla, 87.6%; and hld, 90.4%. No strain contained all tested genes. However, there was frequent coexistence of tst with pvl and hla with hld (40.7% and 26.6%, respectively). CONCLUSIONS: Horizontal transfer of virulence genes is very common in S. aureus, as suggested by the frequent coexistence of several virulence genes. PMID- 29972570 TI - Serological and molecular detection of Leptospira spp in dogs. AB - INTRODUCTION: This study aimed to detect anti-Leptospira spp antibodies and Leptospira DNA in domestic dogs. METHODS: Blood and urine from 106 dogs were evaluated by microscopic agglutination test (MAT) and polymerase chain reaction (PCR), respectively. RESULTS: Six (5.7%) and one (1%) animals were positive by MAT and PCR, respectively. CONCLUSIONS: These results show a low prevalence of infection by Leptospira spp. The absence of positive results for the Icterohaemorrhagiae serogroup indicates the small relevance of these dogs as sources of human leptospirosis. PMID- 29972571 TI - Detection of antibodies against Leptospira spp in free-living marsupials caught in the Eastern Amazon. AB - INTRODUCTION: Serological surveys are important to assess the health status of wild animals. In this study, antibodies against Leptospira spp, causal agents of leptospirosis, were detected in free-living marsupials in the State of Para, Brazil. METHODS: Nineteen blood samples collected from marsupials in the municipalities of Peixe-Boi, Viseu, and Castanhal were subjected to microscopic agglutination tests. RESULTS: In total, 36.8% (7/19) of samples were positive, and two exhibited co-agglutination. The most frequent serovars were Icterohaemorrhagiae (60%; 3/5), Panama (20%; 1/5), and Nupezo (20%; 1/5). CONCLUSIONS: Anti-Leptospira spp antibodies currently circulate in free-living marsupials in Northeastern Para. PMID- 29972572 TI - Socio-epidemiological characterization of human leptospirosis in the Federal District, Brazil, 2011-2015. AB - INTRODUCTION: Human leptospirosis (HL) in the Federal District (DF), Brazil, is endemic and requires studies to characterize the socio-epidemiological profile of the vulnerable population. METHODS: Seventy-nine autochthonous cases of HL between 2011-2015 were analyzed based on the databases of the Epidemiological and Environmental Health Surveillance Department, DF. RESULTS: The male population aged 31-45 years represented 86% of the leptospirosis cases; most belonged to the social classes D and E. CONCLUSIONS: In the DF, preventive measures should be concentrated on economically active male adults of social classes C, D, and E with the aim of promoting health. PMID- 29972573 TI - Molecular diagnosis of cutaneous leishmaniasis in an endemic area of Acre State in the Amazonian Region of Brazil. AB - INTRODUCTION: This study proposes to identify the Leishmania species found in the skin lesions of cutaneous leishmaniasis (CL) patients from Brasileia municipality (Acre). METHODS: Skin biopsy imprints or biopsy fragments were assayed via kDNA PCR/RFLP and FRET-real-time PCR. RESULTS: Of individuals with suspected CL, 18 were positive for Leishmania kDNA. Leishmania (Viannia) braziliensis (61.1%) and Leishmania (Viannia) guyanensis (5.5%) were identified in the positive samples. CONCLUSIONS: These results are congruent with the previous reports in Acre and Bolivia, revealing L. braziliensis as the most prevalent species. L. guyanensis identification also corroborates with the epidemiology of the disease in the Amazon Basin. PMID- 29972574 TI - Antiplasmodial and antileishmanial activities of compounds from Piper tuberculatum Jacq fruits. AB - INTRODUCTION: This study assessed the activity of compounds from Piper tuberculatum against Plasmodium falciparum and Leishmania guyanensis. METHODS: The effects of compounds from P. tuberculatum fruits on P. falciparum and L. guyanensis promastigote growth in vitro were determined. Hemolytic action and cytotoxicity in HepG2 and J774 cells were measured. RESULTS: Three compounds showed strong antiplasmodial activity and one compound showed strong antileishmanial activity. Two compounds were non-toxic to HepG2 cells and all were toxic to J774 cells. The compounds showed no hemolytic activity. CONCLUSIONS: The tested compounds from P. tuberculatum exhibited antiparasitic and cytotoxic effects. PMID- 29972575 TI - Can Aspergillus fumigatus conidia cause false-positive results in the galactomannan enzyme immunoassay test? AB - INTRODUCTION: Several factors can cause false-positive results in the galactomannan (GM) test; however, others remain unknown. Presently, the impact of airborne contamination by Aspergillus conidia during enzyme-linked immunosorbent assay (ELISA) remains uninvestigated. METHODS: We studied 12 A. fumigatus isolates. Fungal conidia were serially diluted and tested for GM detection using the Platelia(r) Aspergillus enzyme immunoassay (EIA). RESULTS: The conidia concentration required for an EIA-positive result was 4.8 * 103 (median). CONCLUSIONS: This is the first study to evaluate the impact of environmental contamination on the Platelia(r) Aspergillus EIA assay. Only massive contamination can interfere with GM optical readings, suggesting that environmental contamination does not cause false-positive test results. PMID- 29972576 TI - Encephalitis associated with Zika virus infection and reactivation of the varicella-zoster virus in a Brazilian child. AB - We report a case of encephalitis associated with Zika virus infection and reactivation of varicella-zoster virus in the central nervous system of a Brazilian child. This case raises the possibility that reactivation of the latent varicella-zoster virus may be a mechanism of neurological impairment induced by acquired Zika virus infection. PMID- 29972577 TI - Combination therapy with liposomal amphotericin b (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate in a refractory visceral leishmaniasis case. AB - Visceral leishmaniasis is a systemic disease that is potentially severe and endemic in Brazil. It clinically manifests as fever, weight loss, swelling, hepatosplenomegaly, paleness, and edema. In this study, we discuss a case of a 1 year-old child diagnosed with refractory visceral leishmaniasis after being treated with liposomal amphotericin B in two distinct occasions. Considering the persistent clinical features and weak response to conventional treatment, a combination therapy with liposomal amphotericin B (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate was initiated, and response to treatment was good. PMID- 29972578 TI - Atrial fibrillation in acute Chagas disease acquired via oral transmission: a case report. AB - Atrial fibrillation (AF), a type of supraventricular arrhythmia increases the risk of thromboembolism. Chagas disease has been reported in the Brazilian Amazon region over approximately 20 years. Cardiac abnormalities are recorded in at least 50% of patients and among these, 3.3% develop AF. We describe a case of a 41-year-old man from Muana, Para State, who reported a 30-day history of a febrile illness. Acute Chagas disease was confirmed, and an electrocardiogram revealed AF. He was treated with antiparasitic and anti-arrhythmic drugs, beta blockers, and anticoagulants. Reversion to sinus rhythm was observed at his 9 month follow-up. PMID- 29972579 TI - A rare case of gastric mucormycosis in an immunocompetent patient. AB - We report the case of a 23-year-old immunocompetent patient who presented at the emergency department of a Brazilian hospital with epigastric pain and fever. After an investigation that included a computed tomography scan and upper gastrointestinal endoscopy with biopsy, a diagnosis of mucormycosis was established. The patient exhibited favorable progress after surgery and antifungal therapy. Mucormycosis is a rare condition that usually affects immunocompromised patients, with a high mortality rate of up to 85%. Correct diagnosis and fast initiation of therapy are required to ensure improved patient prognosis. PMID- 29972580 TI - Encephalitis and transverse myelitis in dengue and chikungunya coinfection. PMID- 29972581 TI - Neurosyphilis manifesting as trigeminal nerve dysfunction. PMID- 29972583 TI - ZW, XY, and yet ZW: Sex chromosome evolution in snakes even more complicated. AB - Snakes are historically important in the formulation of several central concepts on the evolution of sex chromosomes. For over 50 years, it was believed that all snakes shared the same ZZ/ZW sex chromosomes, which are homomorphic and poorly differentiated in "basal" snakes such as pythons and boas, while heteromorphic and well differentiated in "advanced" (caenophidian) snakes. Recent molecular studies revealed that differentiated sex chromosomes are indeed shared among all families of caenophidian snakes, but that boas and pythons evolved likely independently male heterogamety (XX/XY sex chromosomes). The historical report of heteromorphic ZZ/ZW sex chromosomes in a boid snake was previously regarded as ambiguous. In the current study, we document heteromorphic ZZ/ZW sex chromosomes in a boid snake. A comparative approach suggests that these heteromorphic sex chromosomes evolved very recently and that they are poorly differentiated at the sequence level. Interestingly, two snake lineages with confirmed male heterogamety possess homomorphic sex chromosomes, but heteromorphic sex chromosomes are present in both snake lineages with female heterogamety. We point out that this phenomenon is more common across squamates. The presence of female heterogamety in non-caenophidian snakes indicates that the evolution of sex chromosomes in this lineage is much more complex than previously thought, making snakes an even better model system for the evolution of sex chromosomes. PMID- 29972584 TI - Digest: Pursue or ambush? Phenotypic disparity in the carnivore forelimb. AB - The way an animal moves reveals key aspects of its ecology. Carnivore forelimbs are adapted to their predation style, and the structure of the elbow joint can indicate hunting strategy. In this issue, Figueirido (2018) investigates phenotypic disparity, or morphological variation, in domestic dog breeds, the canid family, and the carnivore order using the elbow joint as an indicator of movement and predatory behavior. PMID- 29972585 TI - The Practice of Picking Produce. PMID- 29972586 TI - What Can One Say? Last Words to an Individual in Hospice. PMID- 29972587 TI - Late Transitions and Bereaved Family Member Perceptions of Quality of End-of-Life Care. AB - OBJECTIVES: To examine associations between healthcare transitions at the end of life (EOL; late transitions) and bereaved family members' and friends' assessment of EOL quality of care (QOC). DESIGN: National Health and Aging Trends Study (NHATS), a prospective cohort of Medicare enrollees aged 65 and older. SETTING: United States, all sites of death. PARTICIPANTS: Family members and close friends of decedents from NHATS Rounds 2 through 6 (N=1,653; weighted 6.0 million Medicare deaths). MEASUREMENTS: Multivariable logistic regression with survey weights was used to examine the association between having a late transition and reports of perceived unmet needs for symptom management, spiritual support, concerns with communication, and overall QOC. RESULTS: Seventeen percent of decedents had a late transition. Bereaved respondents for decedents experiencing late transitions were more likely to report that the decedent was treated without respect (21.3% vs 15.6%; adjusted odds ratio (AOR)=1.59, 95% confidence interval (CI)=1.09-2.33), had more unmet needs for spiritual support (67.4% v 55.2%; AOR=1.48, 95% CI=1.03-2.13), and were more likely to report they were not kept informed about the person's condition (31.0% vs 20.9%; AOR=1.54, 95% CI=1.07 2.23). Bereaved respondents were less likely to rate QOC as excellent when there was a late transition (43.6% vs 48.2%; AOR=0.79, 95% CI=0.58-1.06). Subgroup analyses of those experiencing a transition between a nursing home and hospital (13% of all late transitions) revealed such transitions to be associated with even worse QOC. CONCLUSION: Transitions in the last 3 days of life are associated with more unmet needs, higher rate of concerns, and lower rating of QOC than when such late transitions are absent, especially when that transition is between a nursing home and hospital. PMID- 29972589 TI - Federal and Individual Spending on the 10 Costliest Medications in Medicare Part D from 2011 to 2015. AB - Access to prescription medications is critical as the U.S. population ages. Escalating drug costs have garnered mounting attention from the public with increasing federal scrutiny. The Medicare Part D program will increasingly be relied upon to support the health of our nation's older people. We reviewed the publically available Medicare Part D usage data from 2011 to 2015 to quantify the cost of the 10 costliest medications for Part D, evaluated the number of beneficiaries treated with these medications, and measured beneficiaries' out-of pocket costs. We observed over the analysis period, an increase in spending for these medications, a reduction in number of patients that received them, with increased out-of-pocket costs for the patient. In 2015 U.S. dollars, the amount Medicare Part D spent on the 10 costliest medications increased from $21.5 billion in 2011 to $28.4 billion in 2015-a 32% increase. The number of beneficiaries who received 1 of the 10 costliest medications fell from 12,913,003 in 2011 to 8,818,471-a 32% drop, with an average annual decrease of 7.9%. Out of pocket spending by patients that use these medications increased over the study period. For beneficiaries without the low-income subsidy, the average out-of pocket cost share for 1 of the 10 costliest medications increased from $375 in 2011 to $1,366 in 2015-a 264% increase overall and an average 66% increase per year. Specialty medications are a growing portion of the costliest medications. As medication costs continue to escalate, and specialty medications become more common, the U.S. will be increasingly challenged with devising mechanisms to access sustainable, affordable medications for all older adults. PMID- 29972588 TI - Association Between History of Abuse and Falling in Older Adults. AB - OBJECTIVES: To explore the association between history of several types of abuse and falling. DESIGN: Cross-sectional population-based study. SETTING: Data from the Salud, Bienestar y Envejecimiento (Health, Well-being, and Aging) Bogota Study. PARTICIPANTS: Community-dwelling adults aged 60 and older living in Bogota, Colombia (n=2,000). MEASUREMENTS: Falling was defined as the number of times a person had fallen during the previous 12 months. History of abuse was assessed according to self-report. Logistic regression analyses were used to assess the association between elder abuse and falling, adjusting for potential confounders. RESULTS: Multivariate data analyses showed significant higher odds of any falls (>=1 vs 0) for past emotional (odds ratio (OR)=1.53, 95% confidence interval (CI)=1.23-1.90), physical (OR=1.98, 95% CI=1.57-2.51), or sexual (OR=3.08, 95% CI=1.78-5.32) abuse. Similarly, the odds of recurrent falls (>=2 vs 0-1) were significantly higher with each type of abuse. In addition, the odds of any falls and recurrent falls were significant higher in participants with polyvictimization (>=2 types of abuse) than in those with no history of abuse or 1 type of abuse. CONCLUSION: History of abuse (emotional, physical, or sexual) was strongly associated with falling in older adults living in Bogota. Further research is needed to confirm these findings and further delineate the independent effects of elder abuse on fall risk. PMID- 29972590 TI - Electrocardiogram Monitoring After the Food and Drug Administration Warnings for Citalopram: Unheeded Alerts? AB - OBJECTIVES: To evaluate national trends in electrocardiogram (EKG) monitoring in Veterans Affairs (VA) beneficiaries prescribed high-dose citalopram before and after the 2011-12 Food and Drug Administration (FDA) safety warnings. DESIGN: Interrupted time-series analyses. SETTING: National VA healthcare system data linked to Medicare data for veterans dually eligible for VA and Medicare services. PARTICIPANTS: Adult VA outpatients prescribed citalopram or sertraline from February 2010 to September 2013 (N=1,068,816). MEASUREMENTS: EKG monitoring for VA outpatients prescribed high-dose citalopram (>40 mg/d aged <=60, >20 mg/d aged >60) or sertraline. RESULTS: For individuals prescribed high-dose citalopram, EKG monitoring increased from 9.0% before the start of the first FDA warning to a peak of 12.6% for individuals aged 18 to 60 and from 14.0% to 19.4% for individuals aged 61 to 100. However, following the second FDA warning in 2012, EKG monitoring declined, returning to prewarning levels in both age groups. EKG monitoring did not increase in individuals with a history of previous cardiac risk factors prescribed high-dose citalopram in either age group. CONCLUSIONS: EKG frequency did not significantly change in individuals with cardiac risk factors at greatest potential risk for QT prolongation. Lack of responsiveness to the FDA warnings may be due to many factors, including lack of clarity about which individuals should undergo EKG monitoring, provider substitution of alternative antidepressants for citalopram, conflicting evidence regarding risk for adverse cardiac events with high-dose citalopram use, and lack of provider knowledge regarding the warnings. PMID- 29972591 TI - Incidence of Medication-Related Harm in Older Adults After Hospital Discharge: A Systematic Review. AB - OBJECTIVES: To determine the incidence, severity, and preventability of and risk factors for medication-related harm (MRH) in community-dwelling older adults after hospital discharge. DESIGN: Systematic review. SETTING: A search of Medline, EMBASE, CINAHL, and the Cochrane Library was undertaken without time restrictions. PARTICIPANTS: Older adults (average age >=65) participating in observational studies investigating postdischarge adverse drug reactions (ADRs) or adverse drug events (ADEs) within a defined follow-up period. MEASUREMENTS: One author screened abstracts of all articles to exclude obviously irrelevant articles. Two authors independently screened the remaining articles for inclusion. Two authors independently extracted data, including study characteristics, MRH incidence, and risk factors; a third reviewer critically appraised and verified the data. Disagreements were resolved through discussion. RESULTS: From 584 potentially relevant articles, 8 studies met our inclusion criteria: 5 North American and 3 European. Most of the included studies were of moderate quality. There was a wide range in MRH incidence, from 0.4% to 51.2% of participants, and 35% to 59% of MRH was preventable. MRH incidence within 30 days after discharge ranged from 167 to 500 events per 1,000 individuals discharged (17-51% of individuals). There is substantial methodological heterogeneity across multiple domains of the studies, including ADR and ADE definitions, characteristics of recruited populations, follow-up duration after discharge, and data collection. CONCLUSION: MRH is common after hospital discharge in older adults, but methodological inconsistencies between studies and a paucity of data on risk factors limits clear understanding of the epidemiology. There is a need for international consensus on conducting and reporting MRH studies. Data from large, multicenter studies examining a range of biopsychosocial risk factors could provide insight into this important area of safety. PMID- 29972592 TI - Trajectories of Relative Performance with 2 Measures of Global Cognitive Function. AB - OBJECTIVES: To examine whether trajectories of global cognitive function over time in studies that change assessment protocols may be modeled based on an individual's performance relative to others in the study cohort. DESIGN: Extended follow-up of a cohort originally enrolled in a clinical trial of postmenopausal hormone therapy. SETTING: The Women's Health Initiative Memory Study switched from an in-person interview with the Modified Mini-Mental State Examination to a telephone-based interview with the modified Telephone Interview for Cognitive Status to assess global cognitive function over long-term follow-up. PARTICIPANTS: Women aged 75 to 92 (N=2,561). MEASUREMENTS: Annual cognitive assessments from participants, ranked according to age-, race- and ethnicity adjusted performance levels, were used to identify distinct trajectories. Participants assigned to the resulting trajectories were compared for selected risk factor profiles. RESULTS: Our approach grouped participants into five trajectories according to relative cognitive performance over time. These groups differed significantly according to 3 known risk factors for cognitive decline education level, apolipoprotein E-epsilon4 genotype, and type 2 diabetes mellitus and a biomarker based on brain structure that has been linked to cognitive decline and Alzheimer's disease. Participants with consistently low relative levels of cognitive function over time and those whose relative performance over time declined to these levels tended to have poorer risk factor profiles. CONCLUSION: Longitudinal measures of an individual's relative performance on different assessment protocols for global cognitive function can be used to identify trajectories of change over time that appear to have internal validity with respect to known risk factors. PMID- 29972593 TI - Speed-of-Processing Training in Assisted and Independent Living: A Randomized Controlled Trial. AB - OBJECTIVES: To examine speed-of-processing training (SOPT) in older adults in senior living communities, especially those in assisted living. DESIGN: Two-arm, parallel, randomized controlled trial. SETTING: Assisted and independent residence settings in 31 senior living communities. PARTICIPANTS: Individuals aged 55 to 102 (mean 81.0, 73.8% female, 76.4% living alone, 47.0% residing in assisted living; N=351). INTERVENTION: The intervention was 10 hours of computerized SOPT at baseline with 4-hour boosters at 5 and 11 months; the attention control was 10 hours of solving computerized crossword puzzles at baseline with 4-hour boosters at 5 and 11 months. MEASURES: Outcomes were useful field of view (UFOV) scores and improvements of 0.5 standard deviations (SDs) or more (> 158.4 ms). Data collection occurred at baseline, after training, and 6 and 12 months. Random-effects linear mixed-effect models were used to estimate SOPT effects in intention-to-treat complete-case and multiple imputation analyses. RESULTS: We found statistically significantly small standardized effect sizes (Cohen's ds 0.25-0.40) for SOPT, reflecting processing speed improvements on UFOV scores (of 39-63 ms) and greater percentages (9.8 to 14.9 percentage point advantages) for achieving more than 0.5 SD improvements (> 158.4 ms) over the 3 time periods. CONCLUSION: These findings support public health messaging about the potential benefits of SOPT for older adults in senior living communities and support the feasibility and acceptability of SOPT in assisted and independent living for older adults. PMID- 29972595 TI - The Value of Unstructured Electronic Health Record Data in Geriatric Syndrome Case Identification. AB - OBJECTIVES: To examine the value of unstructured electronic health record (EHR) data (free-text notes) in identifying a set of geriatric syndromes. DESIGN: Retrospective analysis of unstructured EHR notes using a natural language processing (NLP) algorithm. SETTING: Large multispecialty group. PARTICIPANTS: Older adults (N=18,341; average age 75.9, 58.9% female). MEASUREMENTS: We compared the number of geriatric syndrome cases identified using structured claims and structured and unstructured EHR data. We also calculated these rates using a population-level claims database as a reference and identified comparable epidemiological rates in peer-reviewed literature as a benchmark. RESULTS: Using insurance claims data resulted in a geriatric syndrome prevalence ranging from 0.03% for lack of social support to 8.3% for walking difficulty. Using structured EHR data resulted in similar prevalence rates, ranging from 0.03% for malnutrition to 7.85% for walking difficulty. Incorporating unstructured EHR notes, enabled by applying the NLP algorithm, identified considerably higher rates of geriatric syndromes: absence of fecal control (2.1%, 2.3 times as much as structured claims and EHR data combined), decubitus ulcer (1.4%, 1.7 times as much), dementia (6.7%, 1.5 times as much), falls (23.6%, 3.2 times as much), malnutrition (2.5%, 18.0 times as much), lack of social support (29.8%, 455.9 times as much), urinary retention (4.2%, 3.9 times as much), vision impairment (6.2%, 7.4 times as much), weight loss (19.2%, 2.9 as much), and walking difficulty (36.34%, 3.4 as much). The geriatric syndrome rates extracted from structured data were substantially lower than published epidemiological rates, although adding the NLP results considerably closed this gap. CONCLUSION: Claims and structured EHR data give an incomplete picture of burden related to geriatric syndromes. Geriatric syndromes are likely to be missed if unstructured data are not analyzed. Pragmatic NLP algorithms can assist with identifying individuals at high risk of experiencing geriatric syndromes and improving coordination of care for older adults. PMID- 29972596 TI - Medical assistance in dying (MAiD): Canadian nurses' experiences. AB - Medical assistance in dying (MAiD) represents a historic change in Canadian society and the provision of end-of-life care. In this descriptive narrative inquiry, 17 nurses were interviewed during the first 6 months of assisted dying becoming a legal option for patients in Canada. Nurses' experiences of either providing care for a patient who had chosen MAiD, or declining to participate in MAiD, were explored. Findings describe three themes and eight storylines of the impact of MAiD on nurses' view of the profession, clinical practice, and personally. While most nurses perceived MAiD as an extension of the profession and their nursing practice, a small number also expressed moral distress as they grappled with assisted dying. Narratives illustrated an ongoing sensemaking process and spectrum of emotions. These findings offer insight and provide direction for nurses and managers in this new clinical and legal reality. Further research is needed to understand more fully the moral distress of some nurses, as well as the importance of communicating openly and nonjudgmentally with patients, families, and the health-care team. PMID- 29972594 TI - Older Adult and Surrogate Perspectives on Serious, Difficult, and Important Medical Decisions. AB - OBJECTIVES: To elicit decisions that diverse older adults and surrogates perceive as serious, difficult, or important and explore what helped them make those decisions. DESIGN: Focus groups (N=13) in which participants were asked to recall serious, difficult, or important medical decisions and what helped them make those decisions. SETTING: Clinics, support groups and senior centers. PARTICIPANTS: Diverse English- and Spanish-speaking older adults (age: mean 78, range 64-89) and surrogates (age: mean 57, range 33-76) (29% African American, 26% white, 26% Asian or Pacific Islander, 19% Hispanic) (N=69). MEASUREMENTS: We used thematic analysis to analyze transcripts. RESULTS: We identified 168 decisions. Older adults from all racial and ethnic groups frequently recalled cancer treatment decisions and decisions about chronic illness management. Surrogates described decisions about transitions in care and medical crises. Older adults valued self-sufficiency and maximizing survival and relied on personal experiences as often as medical advice. In all racial and ethnic groups, surrogates valued avoiding suffering for loved ones. CONCLUSION: Diverse older adults and surrogates perceive life-threatening illness and day-to-day decisions about chronic disease to be serious, difficult, and important. The surrogates' goal of avoiding suffering of older adults may differ from older adults' priorities of self-sufficiency and maximizing survival. Clinicians should support older adults and surrogates in identifying important and difficult decisions and learn about the values and information sources they bring to decision-making. With this knowledge, clinicians can customize decision support and achieve person centered care. PMID- 29972597 TI - Organocatalytic Arylation of alpha-Ketoesters Based on Umpolung Strategy: Phosphazene-Catalyzed SN Ar Reaction Utilizing [1,2]-Phospha-Brook Rearrangement. AB - An organocatalytic arylation of alpha-ketoesters was developed on the basis of umpolung strategy. Phosphazene P2-tBu efficiently catalyzes the three-component coupling reaction of alpha-ketoesters, a silylated secondary phosphite, and electron-deficient fluoroarenes to provide alpha-hydroxyester derivatives possessing an electron-deficient aryl group at the alpha-position. The reaction involves the catalytic generation of alpha-oxygenated ester enolates from alpha ketoesters through the [1,2]-phospha-Brook rearrangement followed by the SN Ar reaction. PMID- 29972598 TI - Effects of analytical (abstract) versus experiential (concrete) induced rumination of negative self defining memories on schizotypic symptoms. AB - Repetitive thought may have adaptive and functional consequences, depending on, among other things, the interpretation of the content: analytical or abstract (general and decontextualized) and experiential or concrete (specific, contextual and incidental). Studies experimentally manipulating repetitive thought have shown both the constructive consequences of the experiential mode and the dysfunctional consequences of the analytical mode. The aim of the current study is to observe the effect of analytical and experiential rumination of negative self-defining memories on schizotypic symptoms. A sample of 111 university students were randomly assigned to one of the two experimental conditions of induced rumination, "analytical" or "experimental." The participants completed a series of questionnaires (anomalous perception of reality, preoccupation and depression) and a negative self-defining memory was obtained to be used as the content of the induced rumination. Following the rumination induction, participants in the experiential condition significantly decreased their scores on anomalous perception of reality compared with those in the analytical condition. We also observed that post-induction scores on self-reported sadness significantly increased in both experimental conditions while scores on self reported happiness decreased. Our results show that the concrete/experiential rumination, focused here on negative self-defining memories, have positive consequences on schizotypic symptoms, such as decreased anomalous perception of reality. PMID- 29972599 TI - In-vivo compatibility between pacemakers and dental equipment. AB - In-vitro studies suggest that electromagnetic interference can occur under specific conditions involving proximity between electronic dental equipment and pacemakers. At present, in-vivo investigations to verify the effect of using electronic dental equipment in clinical conditions on patients with pacemakers are scarce. This study aimed to evaluate, in vivo, the effect of three commonly used electronic dental instruments - ultrasonic dental scaler, electric pulp tester, and electronic apex locator - on patients with different pacemaker brands and configurations. Sixty-six consecutive non-pacemaker-dependent patients were enrolled during regular electrophysiology follow-up visits. Electronic dental tools were operated while the pacemaker was interrogated, and the intracardiac electrogram and electrocardiogram were recorded. No interferences were detected in the intracardiac electrogram of any patient during the tests with dental equipment. No abnormalities in pacemaker pacing and sensing function were observed, and no differences were found with respect to the variables, pacemaker brands, pacemaker configuration, or mode of application of the dental equipment. Electromagnetic interferences affecting the surface electrocardiogram, but not the intracardiac electrogram, were found in 25 (37.9%) patients, especially while using the ultrasonic dental scaler; the intrinsic function of the pacemakers was not affected. Under real clinical conditions, none of the electronic dental instruments tested interfered with pacemaker function. PMID- 29972600 TI - Diversity of rickettsiae and potential vectors of spotted fever in an area of epidemiological interest in the Cerrado biome, midwestern Brazil. AB - The Brazilian state of Goias, untouched by spotted fever (SF) until 2012, has subsequently reported cases of the disease in several regions. This study aimed to survey the diversity of potential vectors and rickettsia in areas of Goias under environmental surveillance or case investigation for SF. Collected specimens were assayed with molecular biology technology using DNA extraction, amplification and sequencing of fragments of the genes gltA, ompA, ompB and sca4 to detect rickettsia in ticks and fleas. Amplification of cytochrome oxidase subunit II and 16S rRNA was performed to assist tick identification. Rickettsia felis (Rickettsiales: Rickettsiaceae) was found in Ctenocephalides felis (Bouche, 1835) (Siphonaptera: Pulicidae). Rickettsia bellii was found in Amblyomma rotundatum Koch, 1844 (Ixodida: Ixodidae) and in Amblyomma cajennense sensu lato. Rickettsia sp. strain NOD was found in Amblyomma nodosum Neumann, 1899. Of the Amblyomma cajennense complex, Amblyomma sculptum Berlese, 1888 was confirmed in the northern, northeast, midwest and southeast regions of Goias, whereas Amblyomma cajennense sensu stricto (Fabricius, 1787) was found only in the northern region of the state. Amblyomma dubitatum Neumann, 1899 associated with a species of the A. cajennense complex was the most common epidemiological finding, although Rickettsia rickettsii was not detected. This is the first report of Rickettsia sp. strain NOD in Goias. PMID- 29972601 TI - Comparison of outcomes between morphine and concomitant morphine and clonidine treatments for neonatal abstinence syndrome. AB - AIM: To examine whether adding clonidine to the morphine regimen for treatment of neonatal abstinence syndrome (NAS) is associated with a shorter length of treatment compared with morphine alone. METHODS: Using a retrospective cohort design, infants with NAS resulting from opioid exposure delivered between 2006 and 2015 (n = 174) were identified using the Nova Scotia Atlee Perinatal Database (NSAPD). Maternal and infant characteristics were collected from the NSAPD. The database was augmented with chart review for treatment information. RESULTS: The incidence of NAS in the study population increased fivefold from 1.48/1000 live births in 2007 to 7.50/1000 live births in 2015. Of the 174 infants, 22 were treated with morphine and 100 were treated with morphine + clonidine. Longer length of treatment (p = 0.004) and higher peak morphine dose (p = 0.045) were observed in the combination group. CONCLUSION: The increase in the incidence of NAS is consistent with recent published reports. The increase in length of treatment and peak morphine dose in the morphine + clonidine group is in marked contrast to previous work on this treatment combination. Further study on the impact of clinical characteristics such as methadone and antidepressant exposure on the association is warranted. PMID- 29972602 TI - Re: Good practices for observational studies of maternal weight and weight gain during pregnancy. PMID- 29972603 TI - Loneliness, HPA stress reactivity and social threat sensitivity: Analyzing naturalistic social challenges. AB - Loneliness has been linked to poor health through an increased activation of threat surveillance mechanisms, such as the hypothalamic-pituitary-adrenal axis (HPA). The socio-cognitive model (Cacioppo & Hawley) proposes that lonely people have an increased social threat sensitivity which activates the HPA axis. The current study examined the impact of loneliness on HPA stress reactivity and social threat sensitivity in response to naturally occurring social challenges. Participants (N = 45) were prospective undergraduates attending a 3-day university preparation programme over the summer, prior to commencing their university studies. Cortisol levels and perceived stress were measured before and after an ice breaker session on Day 1 and a lecture session on Day 3. Social threat sensitivity was also measured on the first and third day. When meeting unfamiliar peers in the ice breaker session, HPA stress reactivity was evident, but it was not markedly different in those who reported high levels of loneliness than those with low levels. The high loneliness group had higher levels of perceived stress and increased social threat sensitivity than the low loneliness group on both testing days. The findings show partial support for the socio cognitive model of loneliness because increased threat sensitivity was demonstrated in the high loneliness group. The findings indicate that lonely people do not respond in a physiologically different way to specific social challenges, but they typically report higher social threat sensitivity and higher perceived stress than their non-lonely peers. PMID- 29972604 TI - Dotted Core-Shell Nanoparticles for T1 -Weighted MRI of Tumors. AB - Gd-based T 1 -weighted contrast agents have dominated the magnetic resonance imaging (MRI) contrast agent market for decades. Nevertheless, they are reported to be nephrotoxic and the U.S. Food and Drug Administration has issued a general warning concerning their use. In order to reduce the risk of nephrotoxicity, the MRI performance of the Gd-based T 1 -weighted contrast agents needs to be improved to allow a much lower dosage. In this study, novel dotted core-shell nanoparticles (FeGd-HN3-RGD2) with superhigh r 1 value (70.0 mM-1 s-1 ) and very low r 2 /r 1 ratio (1.98) are developed for high-contrast T 1 -weighted MRI of tumors. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and histological analyses show good biocompatibility of FeGd-HN3-RGD2. Laser scanning confocal microscopy images and flow cytometry demonstrate active targeting to integrin alphav beta3 positive tumors. MRI of tumors shows high tumor DeltaSNR for FeGd-HN3-RGD2 (477 +/- 44%), which is about 6-7-fold higher than that of Magnevist (75 +/- 11%). MRI and inductively coupled plasma results further confirm that the accumulation of FeGd-HN3-RGD2 in tumors is higher than liver and spleen due to the RGD2 targeting and small hydrodynamic particle size (8.5 nm), and FeGd-HN3-RGD2 is readily cleared from the body by renal excretion. PMID- 29972606 TI - Neuroendocrine correlates of the critical day length response in the Soay sheep. AB - In mammals, melatonin is the hormone responsible for synchronisation of seasonal physiological cycles of physiology to the solar year. Melatonin is secreted by the pineal gland with a profile reflecting the duration of the night and acts via melatonin-responsive cells in the pituitary pars tuberalis (PT), which in turn modulate hypothalamic thyroid hormone status. Recent models suggest that the actions of melatonin in the PT depend critically on day length-dependent changes in the expression of eyes absent 3 (Eya3), which is a coactivator for thyrotrophin beta-subunit (Tshbeta) gene transcription. According to this model, short photoperiods suppress Eya3 and hence Tshbeta expression, whereas long photoperiods produce the inverse effect. Studies underpinning this model have relied on step changes in photoperiod (from 8 to 16 hours of light/24 hours) and have not compared the sensitive ranges of photoperiods for changes in Eya3 and Tshbeta expression with those for relevant downstream molecular and endocrine responses. We therefore performed a "critical day length" experiment in Soay sheep, in which animals acclimated to 8 hours of light/24 hours (SP) were exposed to a range of increased photoperiods spanning the range 11.75 to 16 hours (LP) and then responses at the level of the PT, hypothalamus and hormonal output were assessed. Although Eya3 and Tshbeta both showed the predicted SP vs LP differences, they responded quite differently to intermediate photoperiods within this range and, at the individual animal level, no clear Eya3-Tshbeta relationship could be seen. This result is inconsistent with a simple coactivator model for EYA3 action in the PT. Further downstream layers of nonlinearity were also seen in terms of the Tshbeta-dio2 and the dio2-testosterone relationships. We conclude that the transduction of progressive changes in photoperiod into transitions in endocrine output is an emergent property of a multistep signalling cascade within the mammalian neuroendocrine system. PMID- 29972605 TI - Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study. AB - BACKGROUND: Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear. METHODS: We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire(c) (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations. RESULTS: Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF AA. Analyses with developmental service use revealed similar null findings. CONCLUSIONS: Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood. PMID- 29972607 TI - Development of a new anti-CD123 monoclonal antibody to target the human CD123 antigen as an acute myeloid leukemia cancer stem cell biomarker. AB - Acute myeloid leukemia (AML) is a clonal hematologic malignancy arising from a small population of leukemic cells initiating the disease. CD123 is differentially expressed in AML blasts compared with normal hematopoietic stem and progenitor cells. The aim of this study was to develop specific monoclonal antibodies (mAbs) directed against AML. Three BALB/c mice were immunized with the human CD123 antigen, and the immune spleen cells were fused with the SP2/0 myeloma cell line. Hybridomas were screened by indirect enzyme-linked immunosorbent assay (ELISA), and the positive hybrids were cloned by limiting dilution. The mAb isotype was determined, ascitic fluids were produced, and antibodies were purified using Fast protein liquid chromatography (Sephacryl S 200). The specificity of the hybridomas was examined by ELISA, cell-based ELISA, and flow cytometry. After three rounds of cell cloning, four anti-CD123 secreting hybridomas were obtained with the IgM isotype. Among them, one stable hybrid, designated sC1, exhibited the higher ability to recognize the CD123 antigen, as compared with the other hybridomas. Our results showed that sC1 has the ability to bind specifically to the CD123 antigen (41.36%) on the cell surface. The anti CD123 mAb produced in this study may be useful for the development of both diagnostic and therapeutic purposes for AML. PMID- 29972608 TI - Pancake Bonding: An Unusual Pi-Stacking Interaction. AB - A category of parallel pi-stacking interaction, termed pancake bonding, is surveyed. The main characteristics are: the interaction occurs among radicals with highly delocalized pi-electrons in their singly occupied molecular orbitals (SOMOs), the contact distances in the pi-stacking direction are shorter than the typical van der Waals distances, and the stabilization obtained by the bonding combination of the SOMO orbitals leads to direct atom-to-atom overlap with strong orientational preferences. These atypical intermolecular interactions contain a component of electron sharing between the radicals that can be viewed as covalent like. Pancake bonded dimers characteristically have low-lying singlet and triplet states and show characteristic interlayer vibrational modes. Pancake bonded aggregates serve as molecular components in many conducting and other functional organic materials. The role of van der Waals (vdW) interactions in pancake bonded dimers, chains, and other aggregates is different from closed shell vdW aggregates: here the Pauli repulsions reduce the attractive dispersion interaction significantly. Fluxionality between pi- and sigma-bonded aggregates often occur in the context of pancake bonding. Both experimental and computational aspects are reviewed. PMID- 29972610 TI - Urbanization as a facilitator of gene flow in a human health pest. AB - Urban fragmentation can reduce gene flow that isolates populations, reduces genetic diversity and increases population differentiation, all of which have negative conservation implications. Alternatively, gene flow may actually be increased among urban areas consistent with an urban facilitation model. In fact, urban adapter pests are able to thrive in the urban environment and may be experiencing human-mediated transport. Here, we used social network theory with a population genetic approach to investigate the impact of urbanization on genetic connectivity in the Western black widow spider, as an urban pest model of human health concern. We collected genomewide single nucleotide polymorphism variation from mitochondrial and nuclear double-digest RAD (ddRAD) sequence data sets from 210 individuals sampled from 11 urban and 10 nonurban locales across its distribution of the Western United States. From urban and nonurban contrasts of population, phylogenetic, and network analyses, urban locales have higher within population genetic diversity, lower between-population genetic differentiation and higher estimates of genetic connectivity. Social network analyses show that urban locales not only have more connections, but can act as hubs that drive connectivity among nonurban locales, which show signatures of historical isolation. These results are consistent with an urban facilitation model of gene flow and demonstrate the importance of sampling multiple cities and markers to identify the role that urbanization has had on larger spatial scales. As the urban landscape continues to grow, this approach will help determine what factors influence the spread and adaptation of pests, like the venomous black widow spider, in building policies for human and biodiversity health. PMID- 29972609 TI - AUDIT-C and ICD codes as phenotypes for harmful alcohol use: association with ADH1B polymorphisms in two US populations. AB - BACKGROUND AND AIMS: Longitudinal electronic health record (EHR) data offer a large-scale, untapped source of phenotypical information on harmful alcohol use. Using established, alcohol-associated variants in the gene that encodes the enzyme alcohol dehydrogenase 1B (ADH1B) as criterion standards, we compared the individual and combined validity of three longitudinal EHR-based phenotypes of harmful alcohol use: Alcohol Use Disorders Identification Test-Consumption (AUDIT C) trajectories; mean age-adjusted AUDIT-C; and diagnoses of alcohol use disorder (AUD). DESIGN: With longitudinal EHR data from the Million Veteran Program (MVP) linked to genetic data, we used two population-specific polymorphisms in ADH1B that are associated strongly with AUD in African Americans (AAs) and European Americans (EAs): rs2066702 (Arg369Cys, AAs) and rs1229984 (Arg48His, EAs) as criterion measures. SETTING: United States Department of Veterans Affairs Healthcare System. PARTICIPANTS: A total of 167 721 veterans (57 677 AAs and 110 044 EAs; 92% male, mean age = 63 years) took part in this study. Data were collected from 1 October 2007 to 1 May 2017. MEASUREMENTS: Using all AUDIT-C scores and AUD diagnostic codes recorded in the EHR, we calculated age-adjusted mean AUDIT-C values, longitudinal statistical trajectories of AUDIT-C scores and ICD-9/10 diagnostic groupings for AUD. FINDINGS: A total of 19 793 AAs (34.3%) had one or two minor alleles at rs2066702 [minor allele frequency (MAF) = 0.190] and 6933 EAs (6.3%) had one or two minor alleles at rs1229984 (MAF = 0.032). In both populations, trajectories and age-adjusted mean AUDIT-C were correlated (r = 0.90) but, when considered separately, highest score (8+ versus 0) of age adjusted mean AUDIT-C demonstrated a stronger association with the ADH1B variants [adjusted odds ratio (aOR) 0.54 in AAs and 0.37 in AAs] than did the highest trajectory (aOR 0.71 in AAs and 0.53 in EAs); combining AUDIT-C metrics did not improve discrimination. When age-adjusted mean AUDIT-C score and AUD diagnoses were considered together, age-adjusted mean AUDIT-C (8+ versus 0) was associated with lower odds of having the ADH1B minor allele than were AUD diagnostic codes: aOR = 0.59 versus 0.86 in AAs and 0.48 versus 0.68 in EAs. These independent associations combine to yield an even lower aOR of 0.51 for AAs and 0.33 for EAs. CONCLUSIONS: The age-adjusted mean AUDIT-C score is associated more strongly with genetic polymorphisms of known risk for alcohol use disorder than are longitudinal trajectories of AUDIT-C or AUD diagnostic codes. AUD diagnostic codes modestly enhance this association. PMID- 29972611 TI - The necessity for a European definition of drug shortages. PMID- 29972612 TI - Waiter, there is a drug in my soup - using Leximancer(r) to explore antecedents to pro-environmental behaviours in the hospital pharmacy workplace. AB - OBJECTIVE/S: The aim of this study was to explore Queensland hospital pharmacists' and pharmacy technicians' knowledge and understanding of the impact of pharmaceuticals on the environment and the handling of pharmaceutical waste. METHODS: This study followed a mixed methods research design. Purposive sampling techniques were used to recruit 64 hospital pharmacists and pharmacy technicians working in five public and private hospitals, in metropolitan and regional Queensland, Australia. Both quantitative and qualitative data were collected. Qualitative data were analysed using both the text analytics using descriptive statistics. KEY FINDINGS: Lack of environmental knowledge regarding the impact of pharmaceuticals on the environment and lack of understanding of systems thinking concepts (that all living things are part of the one environment or system, and therefore any negative impacts on the environment will ultimately have negative impacts on human health) were the key findings of this research. Interviewees expressed concern, but most expressed minimal personal concern, about the impact of pharmaceuticals entering the environment. Most interviewees were unsure as to best practice methods for the disposal of pharmaceutical waste, and by complying with hospital policy assumed appropriate disposal occurred. CONCLUSION: Before the pharmacy profession can take up a leadership role in the more sustainable use of pharmaceuticals, pharmacists and pharmacy technicians require environmental information regarding the negative impacts of pharmaceuticals on the environment, and education on systems thinking to enable them to understand that any negative impacts on the environment will ultimately have negative impacts on human health. PMID- 29972613 TI - On the Mechanism of Gold/NHC Compounds Binding to DNA G-Quadruplexes: Combined Metadynamics and Biophysical Methods. AB - The binding modes and free-energy landscape of two AuI /N-heterocyclic carbene complexes interacting with G-quadruplexes, namely a human telomeric (hTelo) and a promoter sequence (C-KIT1), are studied here for the first time by metadynamics. The theoretical results are validated by FRET DNA melting assays and provide an accurate estimate of the absolute gold complex/DNA binding free energy. This advanced in silico approach is valuable to achieve rational drug design of selective G4 binders. PMID- 29972614 TI - Control of the Stereochemical Course of [4+2] Cycloaddition during trans-Decalin Formation by Fsa2-Family Enzymes. AB - Enzyme-catalyzed [4+2] cycloaddition has been proposed to be a key transformation process in various natural product biosynthetic pathways. Recently Fsa2 was found to be involved in stereospecific trans-decalin formation during the biosynthesis of equisetin, a potent HIV-1 integrase inhibitor. To understand the mechanisms by which fsa2 determines the stereochemistry of reaction products, we sought an fsa2 homologue that is involved in trans-decalin formation in the biosynthetic pathway of an enantiomerically opposite analogue, and we found phm7, which is involved in the biosynthesis of phomasetin. A decalin skeleton with an unnatural configuration was successfully constructed by gene replacement of phm7 with fsa2, thus demonstrating enzymatic control of all stereochemistry in the [4+2] cycloaddition. Our findings highlight enzyme-catalyzed [4+2] cycloaddition as a stereochemically divergent step in natural product biosynthetic pathways and open new avenues for generating derivatives with different stereochemistry. PMID- 29972615 TI - Bis(eta5 :eta1 -pentafulvene)niobium(V) Complexes: Efficient Synthons for Niobium Carbene and Imido Derivatives. AB - Transition-metal carbene complexes and their reactivities are a key topic of chemistry. They are an integral part of researches in catalysis, organic synthesis, coordination chemistry, and numerous other areas. In this context, we report the synthesis of a low-valent bis(eta5 :eta1 -(di-p-tolyl) pentafulvene)niobium chloride. Owing to the pi-eta5 :sigma-eta1 coordination mode of the pentafulvenes and the resulting high nucleophilic character of the exocyclic carbon atom of the ligand, the bis(eta5 :eta1 -pentafulvene)niobium complex is able to achieve the umpolung of a coordinated vinyl unit and the resulting formation of the first eta5 :eta1 cyclic niobium Schrock carbene complex. This new synthetic route is, in comparison to classical alpha-hydrogen elimination reactions or thermolysis of diazo compounds, completely unprecedented. The reactivity of the cyclic carbene function and the remaining fulvene ligand is demonstrated by double N-H bond activation of primary amines to niobium imido complexes. PMID- 29972616 TI - An efficient and accurate method for robust inter-dataset brain extraction and comparisons with 9 other methods. AB - Brain extraction is an important first step in many magnetic resonance neuroimaging studies. Due to variability in brain morphology and in the appearance of the brain due to differences in scanner acquisition parameters, the development of a generally applicable brain extraction algorithm has proven challenging. Learning-based brain extraction algorithms in particular perform well when the target and training images are sufficiently similar, but often perform worse when this condition is not met. In this study, we propose a new patch-based multi-atlas segmentation method for brain extraction which is specifically developed for accurate and robust processing across datasets. Using a diverse collection of labeled images from 5 different datasets, extensive comparisons were made with 9 other commonly used brain extraction methods, both before and after applying error correction (a machine learning method for automatically correcting segmentation errors) to each method. The proposed method performed equal to or better than the other methods in each of two segmentation scenarios: a challenging inter-dataset segmentation scenario in which no dataset specific atlases were used (mean Dice coefficient 98.57%, volumetric correlation 0.994 across datasets following error correction), and an intra-dataset segmentation scenario in which only dataset-specific atlases were used (mean Dice coefficient 99.02%, volumetric correlation 0.998 across datasets following error correction). Furthermore, combined with error correction, the proposed method runs in less than one-tenth of the time required by the other top-performing methods in the challenging inter-dataset comparisons. Validation on an independent multi-centre dataset also confirmed the excellent performance of the proposed method. PMID- 29972617 TI - Ionic Gels and Their Applications in Stretchable Electronics. AB - Ionic gels represent a novel class of stretchable materials where ionic conducting liquid is immobilized in a polymer matrix. This review focuses on the design of ionic gel materials and device fabrication of ionic-gel-based stretchable electronics. In particular, recent progress in ionic-gel-based electronic skin (pressure/strain sensors, electric double-layer transistors, etc.), flexible displays, energy storage devices, and soft actuators are summarized, followed by a discussion of challenges in developing ionic-gel-based electronics and suggestions for future research directions that might overcome those challenges. PMID- 29972618 TI - A multivariate lesion symptom mapping toolbox and examination of lesion-volume biases and correction methods in lesion-symptom mapping. AB - Lesion-symptom mapping has become a cornerstone of neuroscience research seeking to localize cognitive function in the brain by examining the sequelae of brain lesions. Recently, multivariate lesion-symptom mapping methods have emerged, such as support vector regression, which simultaneously consider many voxels at once when determining whether damaged regions contribute to behavioral deficits (Zhang, Kimberg, Coslett, Schwartz, & Wang, ). Such multivariate approaches are capable of identifying complex dependences that traditional mass-univariate approach cannot. Here, we provide a new toolbox for support vector regression lesion-symptom mapping (SVR-LSM) that provides a graphical interface and enhances the flexibility and rigor of analyses that can be conducted using this method. Specifically, the toolbox provides cluster-level family-wise error correction via permutation testing, the capacity to incorporate arbitrary nuisance models for behavioral data and lesion data and makes available a range of lesion volume correction methods including a new approach that regresses lesion volume out of each voxel in the lesion maps. We demonstrate these new tools in a cohort of chronic left-hemisphere stroke survivors and examine the difference between results achieved with various lesion volume control methods. A strong bias was found toward brain wide lesion-deficit associations in both SVR-LSM and traditional mass-univariate voxel-based lesion symptom mapping when lesion volume was not adequately controlled. This bias was corrected using three different regression approaches; among these, regressing lesion volume out of both the behavioral score and the lesion maps provided the greatest sensitivity in analyses. PMID- 29972620 TI - Interaction of matrix metalloproteinase-9 and Zpx in Cronobacter turicensis LMG 23827T mediated infections in the zebrafish model. AB - Bacteria belonging to the genus Cronobacter have been recognized as causative agents of life-threatening systemic infections primarily in premature and low birthweight neonates. Validation of putative bacterial virulence components as well as host factors potentially involved in the response to infection has been hampered in the past by the availability of suitable neonatal animal models. In the current study, the zebrafish embryo model was employed to study the interaction of the zinc metalloproteinase Zpx present in Cronobacter turicensis LMG 23827T , with the eukaryotic MMP-9, a proteinase that functions to cleave extracellular matrix gelatin and collagen. Cleavage and activation of the human recombinant pro-MMP-9 by zpx-expressing C. turicensis cells were demonstrated in vitro, and the presence and increase of the processed, active form of zebrafish pro-MMP-9 were shown in vivo. We provided evidence that Zpx induces the expression of the mmp-9 but also increases the levels of processed MMP-9 during infection. The involvement of the MMP-9 in induction of the expression of the bacterial Zpx was shown in zebrafish mmp-9 morphant experiments. This study identified MMP-9 as a substrate of Zpx and demonstrated yet-undescribed mutual cross-talk between these two proteases in infections mediated by C. turicensis LMG 23827T . PMID- 29972621 TI - Interrogating the Intersections: How Intersectional Perspectives Can Inform Developmental Scholarship on Critical Consciousness. AB - Developmental psychologists widely recognize that the social structures and inequities of American society influence youth development. A burgeoning body of research also considers how youth marginalized by society critically evaluate societal inequities and take action to change them (critical consciousness, Freire [Education for critical consciousness (Vol. 1). Bloomsbury Publishing.]), suggesting that marginalized youth who are more critically conscious experience improved mental health and better educational and occupational outcomes and are more engaged in traditional forms of civic behavior. The current manuscript critically reviews and extends this area of research from an intersectional perspective. Drawing from core writings in intersectionality and more recent psychological applications, we contend that research on marginalized youth's critical consciousness could be further strengthened by (1) focusing on marginalizing systems, rather than marginalized individuals; (2) conceptualizing and examining multiple systems of oppression; and (3) paying greater attention to sociohistorical knowledge. We conclude with some initial concrete recommendations for integrating principles of intersectionality into scholarship on youths' critical consciousness development. PMID- 29972622 TI - Implicit sequence learning in young people with Tourette syndrome with and without co-occurring attention-deficit/hyperactivity disorder. AB - Impaired habit-learning has been proposed to underlie the tic symptoms of Tourette syndrome (TS). However, accounts differ in terms of how habit-learning is altered in TS, with some authors proposing habit formation is impaired due to a deficient 'chunking' mechanism, and others proposing habit-learning is overactive and tics reflect hyperlearned behaviours. Attention deficit/hyperactivity disorder (ADHD) frequently co-occurs with TS and is known to affect cognitive function in young people with co-occurring TS and ADHD (TS + ADHD). It is unclear, however, how co-occurring ADHD symptoms affect habit learning in TS. In this study, we investigated whether young people with TS would show deficient or hyperactive habit-learning, and assessed the effects of co occurring ADHD symptoms on habit-learning in TS. Participants aged 9-17 years with TS (n = 18), TS + ADHD (n = 17), ADHD (n = 13), and typical development (n = 20) completed a motor sequence learning task to assess habit-learning. We used a 2 (TS-yes, TS-no) * 2 (ADHD-yes, ADHD-no) factorial analysis to test the effects of TS, ADHD, and their interaction on accuracy and reaction time indices of sequence learning. TS was associated with intact sequence learning, but a tendency for difficulty transitioning from sequenced to non-sequenced performance was suggestive of hyper-learning. ADHD was associated with significantly poorer accuracy during acquisition of the sequence, indicative of impaired habit learning. There were no interactions between the TS and ADHD factors, indicating young people with TS + ADHD showed both TS- and ADHD-related atypicalities in habit-learning. PMID- 29972619 TI - Episodic memory and executive functions in cognitively healthy individuals display distinct neuroanatomical correlates which are differentially modulated by aging. AB - The neuroanatomical bases of episodic memory (EM) and executive functions (EFs) have been widely addressed in patients with brain damage and in individuals with neurologic disorders. These studies reported that larger brain structures support better outcomes in both cognitive domains, thereby supporting the "bigger is better" account. However, relatively few studies have explored the cerebral morphological properties underlying EM and EFs in cognitively healthy individuals and current findings indicate no unitary theoretical explanation for the structure-function relationship. Moreover, existing studies have typically restricted the analyses to a priori defined regions of interest. Here we conducted unbiased voxel-wise analysis of the associations between regional gray as well as white matter volumes (GMv; WMv) and performance in both cognitive domains in a sample of 463 cognitively intact individuals. We found that efficiency in EM was predicted by lower GMv in brain areas belonging to the default-mode network (DMN). By contrast, EFs performance was predicted by larger GMv in a distributed set of regions, which overlapped with the executive control network (ECN). Volume of white matter bundles supporting both cross-cortical and interhemispheric connections was positively related to processing speed. Furthermore, aging modulated the relationship between regional volumes and cognitive performance in several areas including the hippocampus and frontal cortex. Our data extend the critical role of the DMN and ECN by showing that variability in their morphological properties, and not only their activation patterns, affects EM and EFs, respectively. Moreover, our finding that aging reverts these associations supports previously advanced theories of cognitive neurodevelopment. PMID- 29972623 TI - New Zealand court dismisses Ministry of Health case against 'heat-not-burn' tobacco products, highlighting the need to future-proof tobacco control laws. PMID- 29972624 TI - Intersectional Ecologies: Positioning Intersectionality in Settings-Level Research. AB - Developmental science has recognized the import of ecological theory and research in furthering understanding of development in context. However, despite the fact that ecological and intersectional theory share points of commonality, few researchers to date have attempted to integrate these perspectives. This manuscript addresses this gap and highlights three ways that an intersectional lens can advance settings-level research. With a focus on neighborhoods as settings of development, we (1) describe how intersectionality may manifest itself within neighborhoods, (2) discuss how intersectionality can inform our understanding of how individuals experience neighborhoods, and (3) detail strategies for conceptualizing and measuring intersectionality in neighborhood research. As such, the goal of this manuscript is to push thinking on the ways that intersectionality may inform and advance settings-level research in developmental science. PMID- 29972625 TI - Disseminated erythematous papules and nodules. PMID- 29972626 TI - Vitiligo and autoantibodies: a systematic review and meta-analysis. AB - Many studies have reported the prevalence of autoantibodies in patients with vitiligo; however, results were inconsistent for some autoantibodies. This study aimed to conduct a systematic review and meta-analysis of the prevalence of autoantibodies in vitiligo patients. A systematic review and meta-analysis of the literature published from inception to Dec 31, 2016 was conducted. Case-control studies with vitiligo patients and a control group were included. The prevalence of anti-thyroperoxidase (ATPO) antibodies, anti-thyroglobulin (ATG) antibodies, antinuclear antibodies (ANA), anti-gastric parietal cell antibodies (AGPCA), anti smooth muscle antibodies (ASMA), anti-mitochondrial antibodies (AMA), and anti adrenal antibodies in vitiligo patients were 15.1 %, 9.7 %, 12.5 %, 11.7 %, 12.6 %, 0.2 %, and 2.5 %, respectively. The prevalence of ATPO antibodies (odds ratio [OR]: 3.975; 95 %; confidence interval [CI]: 3.085-5.122), ATG antibodies (OR: 3.759; 95 % CI: 2.554-5.531), ANA (OR: 1.797, 95 % CI: 1.182-2.731), AGPCA (OR: 2.503; 95 % CI: 1.497-2.896), and anti-adrenal antibodies (OR: 9.808, 95 % CI: 1.809-53.159) (Figure 2a-e) were significantly higher in vitiligo patients than in the control group. The routine screening of anti-thyroid antibodies should be performed in vitiligo patients to identify those at high risk of developing autoimmune thyroid disease. PMID- 29972627 TI - Dorsolateral fibromuscular tissue preservation during artificial urinary sphincter cuff placement is associated with low infection and erosion rates. AB - OBJECTIVES: To present a modified technique in artificial urinary sphincter (AUS) placement that is associated with low rates of erosion and infection in a high risk population. PATIENTS AND METHODS: After Institutional Review Board approval, we identified patients who underwent primary AUS placement using the modified technique between January 2007 and November 2015. Our modification consists of preserving the dorsolateral fibromuscular tissue surrounding the bulbar urethra and horizontally transecting the ventral bulbospongiosus muscle during urethral cuff placement. Preoperative variables such as radiotherapy (RT) and bladder neck contractures were recorded. Effectiveness and complications including infections, erosions, and re-operations were recorded at follow-up. RESULTS: The new technique was used on 208 patients: 40% had a history of RT, including 15% who had had a salvage radical prostatectomy; 26% had had previous bladder neck contractures. No patients developed infection. Overall, erosion occurred in six (2.9%) patients and spontaneous erosions occurred in two (0.9%) during the study period. In all, 21 patients underwent re-operation for device failure. The probability of re-operation for 'any' reason was 7% (95% confidence interval [CI] 4-12%) at 1 year. The 1-year social continence rate was 74% (95% CI 67-81%). CONCLUSION: Preservation of dorsolateral fibromuscular tissue during AUS placement is an effective means to achieve a low risk of erosions. Our modified technique is safe with low infection and erosion rates, whilst maintaining good functional outcomes despite a high-risk population. PMID- 29972629 TI - Legal status of sequential digital dermoscopy - significance of dermatologic guidelines. PMID- 29972630 TI - New Experimental Evidences Regarding Conformational Equilibrium in Ammonium Bis(trifluoromethanesulfonyl)imide Ionic Liquids. AB - The X-ray scattering patterns of the two ionic liquids, N-trimethyl-N propylammonium bis(trifluoromethanesulfonyl)imide (TMPA-TFSI) and N-trimethyl-N hexylammonium bis(trifluoromethanesulfonyl)imide (TMHA-TFSI), sharing a common anion and differing in the length of the alkyl chain of the cation, were measured at room temperature. Molecular dynamics calculations supported the interpretation of the data. The two force-field models, GAFF and DLPOLY 4, were adopted to simulate the scattering patterns. Both of them are able to reproduce the main peaks of the experimental data; however, the DLPOLY model seems to better reproduce the finer details. Moreover, from the simulations, the concentration of the two conformers of TFSI are derived. The comparison with previously reported infrared spectroscopy measurements suggests that also under this aspect the DPOLY model has a better agreement with the experiments. PMID- 29972628 TI - Maternal priorities for preventive therapy among HIV-positive pregnant women before and after delivery in South Africa: a best-worst scaling survey. AB - INTRODUCTION: Pregnant women newly diagnosed with HIV during pregnancy are often lost to follow up and their adherence rates drop after delivery. We quantified changes in priorities related to isoniazid preventive therapy (IPT) and antiretroviral therapy (ART) among pregnant women living with HIV. METHODS: We enrolled pregnant women recently diagnosed with HIV from 14 primary health clinics during pregnancy and followed them after delivery in Matlosana, South Africa. Best-worst scaling (BWS) was used to determine the women's priorities out of 11 attributes related to preventive therapy in the ante- versus postpartum periods. Aggregate BWS scores were calculated based on the frequency with which participants selected each attribute as the best or worst among five options (across multiple choice sets). Individual BWS scores were also calculated and rescaled from 0 (always selected as worst) to 10 (always selected as best), and changes in BWS scores in the ante- versus postpartum periods were compared, using a paired t-test. Factors associated with the changes in BWS scores were examined in multiple linear regressions. Spearman's rho was used to compare the ranking of attributes. RESULTS: Out of a total of 204 participants, 154 (75.5%) completed the survey in the postpartum at the median 15 (IQR: 11 to 27) weeks after delivery. Trust in healthcare providers was most highly prioritized both in the ante- (individual BWS Score = 7.34, SE = 0.13) and postpartum periods (BWS = 7.21 +/- 0.11), followed by living a long life (BWS = 6.77 +/- 0.09 in the ante- vs. BWS = 6.86 +/- 0.10 in the postpartum). Prevention for infants' health was more prioritized in the post- (BWS = 6.54 +/- 0.09) versus antepartum periods (BWS = 6.11 +/- 0.10) (p = 0.05). This change was associated with IPT initiation at enrolment (regression coefficient = 0.78 +/- 0.33, p = 0.001). Difficulty in daily pill-uptake was significantly more prioritized in the postpartum (BWS = 5.03 +/- 0.11) than in the antepartum (BWS = 4.43 +/- 0.10) (p < 0.01). Transportation cost and worry about side effects of pills were least prioritized. Overall ranking of attributes was similar in both time periods (spearman's rho = 0.90). CONCLUSIONS: Comprehensive interventions to build trust in healthcare providers and support adherence may increase uptake of preventive therapy. Counselling needs to emphasize medication benefits for both maternal and infant health among HIV-positive pregnant women. PMID- 29972631 TI - Multiple pigmented lesions of the glans penis after circumcision. PMID- 29972632 TI - Models of support for disclosure of HIV status to HIV-infected children and adolescents in resource-limited settings. AB - INTRODUCTION: Disclosure of HIV status to HIV-infected children and adolescents is a major care challenge. We describe current site characteristics related to disclosure of HIV status in resource-limited paediatric HIV care settings within the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS: An online site assessment survey was conducted across the paediatric HIV care sites within six global regions of IeDEA. A standardized questionnaire was administered to the sites through the REDCap platform. RESULTS: From June 2014 to March 2015, all 180 sites of the IeDEA consortium in 31 countries completed the online survey: 57% were urban, 43% were health centres and 86% were integrated clinics (serving both adults and children). Almost all the sites (98%) reported offering disclosure counselling services. Disclosure counselling was most often provided by counsellors (87% of sites), but also by nurses (77%), physicians (74%), social workers (68%), or other clinicians (65%). It was offered to both caregivers and children in 92% of 177 sites with disclosure counselling. Disclosure resources and procedures varied across geographical regions. Most sites in each region reported performing staff members' training on disclosure (72% to 96% of sites per region), routinely collecting HIV disclosure status (50% to 91%) and involving caregivers in the disclosure process (71% to 100%). A disclosure protocol was available in 14% to 71% of sites. Among the 143 sites (79%) routinely collecting disclosure status process, the main collection method was by asking the caregiver or child (85%) about the child's knowledge of his/her HIV status. Frequency of disclosure status assessment was every three months in 63% of the sites, and 71% stored disclosure status data electronically. CONCLUSION: The majority of the sites reported offering disclosure counselling services, but educational and social support resources and capacities for data collection varied across regions. Paediatric HIV care sites worldwide still need specific staff members' training on disclosure, development and implementation of guidelines for HIV disclosure, and standardized data collection on this key issue to ensure the long-term health and wellbeing of HIV-infected youth. PMID- 29972633 TI - Drug-Drug Interaction Study of Apixaban with Cyclosporine and Tacrolimus in Healthy Volunteers. AB - Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P-gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co-administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(0-tlast) ) with associated geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of 143% (112, 183) and 120% (97, 148), respectively. Co-administration with tacrolimus resulted in reduction in apixaban Cmax and AUC(0-tlast) with associated GMRs (90% CI) of 87% (69, 112) and 78% (63, 97), respectively. The observed changes in apixaban exposure margins with cyclosporine or tacrolimus are within the range of the historical clinical development program, therefore, apixaban dose adjustments are not warranted. PMID- 29972634 TI - Interrupter resistance to measure dose-response to salbutamol in wheezy preschool children. AB - AIM: Using a non-invasive lung function technique (interrupter resistance, Rint), we aimed to determine whether a dose-response to salbutamol could be detected in wheezy preschool children and if so, which dose of salbutamol should be administered to routinely evaluate bronchial reversibility. METHOD: Wheezy children (3 to <7 years) were enrolled in a prospective multicenter study. Rint was measured at baseline, and after random assignment to a first dose (100 or 200 MUg) and a second dose (cumulative dose: 400, 600, or 800 MUg) of salbutamol. Data were analyzed using mixed modeling approach with an inhibitory maximal effect (Imax ) model, to account for a sparse sampling design. Simulations were performed to predict the percentage of children with significant Rint reversibility at several doses. RESULTS: Final results were available in 99 children out of 106 children included. The model adequately fitted the data, showing satisfactory goodness-of-fit plots and a low residual error of 8%. Children with uncontrolled symptoms had lower Imax (ie, showed less reversibility) compared to children with totally/partly controlled symptoms (0.23 vs. 0.31, P < 0.001). Dose to reach 50% of Imax (D50 ) was 51 MUg. According to simulations, 88.1% of children with significant reversibility at dose 800 MUg would already show significant reversibility at 400 MUg. CONCLUSION: Interrupter resistance was able to measure a dose-response curve to salbutamol in wheezy preschool children, which was similar to that of older patients. Young children require a high dose of salbutamol to correctly assess airway bronchodilator response, especially these with poor symptom control. PMID- 29972635 TI - Improved growth and developmental activity post tracheostomy in preterm infants with severe BPD. AB - OBJECTIVES: To examine growth, sedation needs, and participation in developmental activities before and after tracheostomy among infants with severe bronchopulmonary dysplasia. METHODS: Retrospective analysis of infants born at <32 weeks' gestation or birth weights <1500 g with severe BPD who underwent tracheostomy placement between January 1, 2010 and December 31, 2016 in a quaternary referral newborn and infant intensive care unit. Changes in growth parameters and frequency/type of participation in physical therapy sessions performed during the 4-weeks before tracheostomy and 4-weeks after the first tracheostomy tube change were compared. RESULTS: A total of 72 patient were included in the study. Average weekly gain in weight, length, and head circumference were significantly higher during the 4-week period after compared to before tracheostomy. The most significant change occurred for linear growth (0.71 +/- 0.40 cm/wk pre vs 0.97 +/- 0.48 cm/wk pre, P < 0.001). Median Z score improved for weight (pre -1.42 [-3,10, -0.33] vs post -0.91 [-2.7, 0.27], P < 0.001), length (pre -3.07 [-4.39, -1.31] vs post -1.95 [-3.83, -0.93], P < 0.001) and weight-to-length ratio (pre 1.66 [0.58, 2.55] vs post 1.32 [0.17, 2.2], P = 0.02). Participation in developmental therapies significantly improved post tracheostomy (pre vs post: 5.2 +/- 2.9 vs 8.7 +/- 4.3 sessions performed over 4 weeks, P < 0.0001). Physical therapy sessions more often promoted developmental skill acquisition after tracheostomy compared to facilitating physiologic stability before tracheostomy. Daily sedation requirements decreased post tracheostomy. CONCLUSIONS: Tracheostomy was associated with improved proportional growth and increased participation in activities promoting developmental skill acquisition and reduced daily sedation requirements in preterm infants with severe BPD. PMID- 29972638 TI - Tailoring the Shape Memory Properties of Segmented Poly(ester urethanes) via Blending. AB - Thermoplastic segmented polyurethanes (PUs) can exhibit shape memory behavior, if they feature multiple kinds of physical cross-links that can be dissociated at different temperatures. This is the case if the hydrogen-bonded hard phase is joined with soft segments that can partially crystallize, so that the melting transition acts as the memory switch. For applications in the biomedical field, it is important that the fixation and recovery temperatures can be minutely controlled. We show here that this tailoring can be easily achieved by formulating a commercial PU featuring poly(1,4-butylene adipate) (PBA) as a crystallizable segment (PBA-PU) with either PBA or poly(epsilon-caprolactone) (PCL) of moderate molecular weight. We show that the nature of the end groups and the processing conditions dictate if there is any reaction between the components or if the product is merely a blend. Interestingly, in either case, the addition of PBA or PCL causes nucleation and thereby a noteworthy increase of the crystallization temperature of the switching element from below to above ambient temperature, so that excellent shape fixity (~98%) can be achieved at 37 degrees C. The melting temperature is maintained above 50 degrees C and significant increases in strength and modulus are achieved. The new materials platform is well suited for applications in which a shape is to be fixed at physiological temperature. PMID- 29972637 TI - NMR Measurements Reveal the Structural Basis of Transthyretin Destabilization by Pathogenic Mutations. AB - Inherited mutations of transthyretin (TTR) destabilize its structure, leading to aggregation and familial amyloid disease. Although numerous crystal structures of wild-type (WT) and mutant TTRs have been determined, they have failed to yield a comprehensive structural explanation for destabilization by pathogenic mutations. To identify structural and dynamic variations that are not readily observed in the crystal structures, we used NMR to study WT TTR and three kinetically and/or thermodynamically destabilized pathogenic variants (V30M, L55P, and V122I). Sequence-corrected chemical shifts reveal important structural differences between WT and mutant TTR. The L55P mutation linked to aggressive early onset cardiomyopathy and polyneuropathy induces substantial structural perturbations in both the DAGH and CBEF beta-sheets, whereas the V30M polyneuropathy-linked substitution perturbs primarily the CBEF sheet. In both variants, the structural perturbations propagate across the entire width of the beta-sheets from the site of mutation. Structural changes caused by the V122I cardiomyopathy-associated mutation are restricted to the immediate vicinity of the mutation site, directly perturbing the subunit interfaces. NMR relaxation dispersion measurements show that WT TTR and the three pathogenic variants undergo millisecond time scale conformational fluctuations to populate a common excited state with an altered structure in the subunit interfaces. The excited state is most highly populated in L55P. The combined application of chemical shift analysis and relaxation dispersion to these pathogenic variants reveals differences in ground state structure and in the population of a transient excited state that potentially facilitates tetramer dissociation, providing new insights into the molecular mechanism by which mutations promote TTR amyloidosis. PMID- 29972639 TI - Palladium-Catalyzed H/D Exchange Reaction with 8-Aminoquinoline as the Directing Group: Access to ortho-Selective Deuterated Aromatic Acids and beta-Selective Deuterated Aliphatic Acids. AB - We develop a palladium-catalyzed H/D exchange reaction with 8-aminoquinoline as the directing group as well as D2O as the source of deuterium atom and solvent. This reaction achieves selectively H/D exchange at the ortho-C-H of aromatic amides and the beta-C-H of aliphatic amide. Ortho-deuterated aromatic acids and beta-deuterated aliphatic acids are obtained by removal of the directing group. And a possible mechanism is also proposed. PMID- 29972640 TI - Midinfrared Multispectral Detection for Real-Time and Noninvasive Analysis of the Structure and Composition of Materials. AB - In situ material identification and object tracking have been demonstrated using a mid-infrared (mid-IR) robotic scanning system. This detection method is capable of inspecting materials noninvasively because the mid-IR spectrum overlaps with numerous characteristic absorption bands corresponding to various chemical function groups. The scanning system consisted of a fiber probe connected to a mid-IR tunable laser with a wavelength tuning range of lambda = 2.45-3.75 MUm. For the high-speed performance of the scanning system to be evaluated, a testing platform was constructed with an object plate rapidly rotating at omega = 231 rpm. The objects on the plate were SU-8 epoxy-based resin and polydimethylsiloxane, which were mid-IR absorptive while visibly transparent. Applying mid-IR multispectral scanning, the system was able to simultaneously track the object position and identify the composition by interpreting the spectral and spatial intensity variation. The mid-IR robotic scanning method thus provides a visualization system critical for process inspection in automatic manufacturing and high-throughput biomedical screening. PMID- 29972641 TI - Effect of Anti-Leishmania Drugs on the Structural and Elastic Properties of Ultradeformable Lipid Membranes. AB - Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetration of drugs deep into the skin, which is aided by encapsulation within ultradeformable liposomes. Penetrability depends on the flexibility of the lipid membrane, which may be affected by the drugs. We have studied the biophysical effects of four anti-Leishmania drugs (miltefosine (Milt), amphotericin B (AmpB), indole (Ind), and imiquimod (Imiq)) on a soy phosphatidylcholine/sodium cholate membrane. Using diffuse X-ray scattering techniques, we determined bending modulus ( KC) and chain order parameter ( SX ray) of the membrane at several drug concentrations. Form factor scattering data allowed construction of electron density profiles, which yielded bilayer thickness and area per lipid. Results show that AmpB had the largest effect on KC and SX-ray, causing the bilayer to lose integrity at high concentrations. Imiq and Ind induced slight membrane stiffening, whereas Milt had little effect. Imiq also notably decreased chain order at high concentrations. These results will aid in the design of new topical treatments, where Milt, Ind, and Imiq could be used at any concentration without affecting liposome integrity or physical properties, whereas AmpB should not be used at high concentrations. PMID- 29972642 TI - Biomimetic Planar Polymer Membranes Decorated with Enzymes as Functional Surfaces. AB - Functional surfaces were generated by a combination of enzymes with polymer membranes composed of an amphiphilic, asymmetric block copolymer poly(ethyleneglycol)- block-poly(gamma-methyl-epsilon-caprolactone)- block poly[(2-dimethylamino)ethylmethacrylate]. First, polymer films formed at the air water interface were transferred in different sequences onto silica solid support using the Langmuir-Blodgett technique, generating homogeneous monolayers and bilayers. A detailed characterization of these films provided insight into their properties (film thickness, wettability, topography, and roughness). On the basis of these findings, the most promising membranes were selected for enzyme attachment. Functional surfaces were then generated by the adsorption of two model enzymes that can convert phenol and its derivatives (laccase and tyrosinase), well known as high-risk pollutants of drinking and natural water. Both enzymes preserved their activity upon immobilization with respect to their substrates. Depending on the properties of the polymer films, different degrees of enzymatic activity were observed: bilayers provided the best conditions in terms of both overall stability and enzymatic activity. The interaction between amphiphilic triblock copolymer films and enzymes is exploited to engineer "active surfaces" with specific functionalities and high efficacy resulting from the intrinsic activity of the biomolecules that is preserved by an appropriate synthetic environment. PMID- 29972643 TI - Structural and Computational Bases for Dramatic Skeletal Rearrangement in Anditomin Biosynthesis. AB - AndA, an Fe(II)/alpha-ketoglutarate (alphaKG)-dependent enzyme, is the key enzyme that constructs the unique and congested bridged-ring system of anditomin (1), by catalyzing consecutive dehydrogenation and isomerization reactions. Although we previously characterized AndA to some extent, the means by which the enzyme facilitates this drastic structural reconstruction have remained elusive. In this study, we have solved three X-ray crystal structures of AndA, in its apo form and in the complexes with Fe(II), alphaKG, and two substrates. The crystal structures and mutational experiments identified several key amino acid residues important for the catalysis and provided insight into how AndA controls the reaction. Furthermore, computational calculations validated the proposed reaction mechanism for the bridged-ring formation and also revealed the requirement of a series of conformational changes during the transformation. PMID- 29972644 TI - Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5-Oxo 6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE). AB - 5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma. PMID- 29972646 TI - Corrigendum. PMID- 29972645 TI - Treatment of sleep apnea with a combination of a carbonic anhydrase inhibitor and an aldosterone antagonist: a patent evaluation of CA2958110 and IN6616DEN2012. AB - INTRODUCTION: Sleep apnoea syndrome (SAS), is a sleep disorder and characterized by very shallow breath or repetitive cessation of breathing during sleep (sleep apnoea). At present, no pharmacological agents have proved to be successful against SAS, and the syndrome is only treated by surgical interventions or devices such as intraoral mandibular advancement and Continuous Positive Air Pressure (CPAP) techniques. Areas covered: two patents published in 2016 describing a new pharmacological application of inhibitors of the metalloenzyme Carbonic Anhydrases (CAs, EC 4.2.1.1) and an aldosterone antagonist agents and their therapeutic application was analysed. Expert opinion: The present patents address an important healthcare problem by proposing a new pharmacological approach and may represent a valid alternative for the treatment of sleep apnea. One of the interesting points raised by these patents is the advantage of using a minor quantity of pharmacological agents in combination than active agent alone and consequently, a significant reduction of the side effects. PMID- 29972647 TI - Predictors of skeletal-related events among cancer patients with bone metastases treated with zoledronic acid: a secondary analysis of a randomized study. AB - BACKGROUND: The purpose of the current study is to assess the predictors of skeletal-related events (SREs) among advanced cancer patients with bone metastases treated with zoledronic acid within a randomized study. RESEARCH DESIGN AND METHODS: This is a secondary analysis of patient-level data of advanced cancer patients with bone metastases who were treated with monthly zoledronic acid in the NCT00330759 clinical trial. RESULTS: A total of 702 patients were included in the current analysis. In univariate logistic regression analysis, higher body mass index (P = 0.034) and lytic nature of bone metastasis (P = 0.008) were found to be predictive of a higher probability of SREs. When the two factors were included in a multivariate logistic regression model, both of them were predictive of the later development of SREs (P value for higher body mass index = 0.015; P value for lytic bone lesions = 0.005). CONCLUSION: Among advanced cancer patients with bone metastases, lytic nature of metastases, as well as higher body mass index, are associated with a higher probability of SREs. TRIAL REGISTRATION NUMBER: this clinical trial was registered at clinicaltrials.gov with the number: nct0033. PMID- 29972649 TI - Antibacterial gold nanoparticle-based photothermal killing of vancomycin resistant bacteria. AB - AIM: The extensive use of vancomycin has given rise to vancomycin-resistant bacterial strains, such as vancomycin-resistant Enterococci (VRE). We aim to explore potent medical treatments that can inhibit the growth of VRE. MATERIALS & METHODS: Vancomycin-immobilized gold nanoparticles (Au@Van NPs) with polygonal shapes from one-pot reactions were generated within approximately 7 min. RESULTS & DISCUSSION: The as-prepared Au NPs exhibit not only antibacterial capability but also photothermal competence. The temperature of the sample solution containing the as-prepared Au@Van NPs can be raised by approximately 15 degrees C under irradiation by a near-infrared laser (lambda = 808 nm) within 5 min. CONCLUSION: The required amount of vancomycin on the as-prepared Au@Van NPs combined with near-infrared irradiation for inhibiting VRE is approximately 16 fold lower than that of free-form vancomycin. PMID- 29972650 TI - Management Strategies for Recurrent Endometrial Cancer. AB - INTRODUCTION: Endometrial cancer is the most common gynecologic malignancy in the developed world, and its incidence is increasing. Mortality from this cancer has not improved in recent decades and is primarily driven by high-grade carcinomas that are more likely to present at an advanced stage and ultimately are more likely to recur. The prognosis for recurrent endometrial cancer is poor, especially for the 50% of these women that present with extrapelvic disease recurrence. As a standard of care, recurrent disease has been treated with platinum-based chemotherapy; however, new therapies are emerging as we identify drivers of proliferation and metastasis at the cellular and molecular levels. Areas Covered: We review currently available data for the management of recurrent endometrial cancer, with a focus on systemic treatment of recurrent disease. We discuss the available evidence for first-line, second-line, and subsequent systemic therapy and discuss emerging therapeutic targets including their biologic plausibility and early clinical data. Expert Commentary: Endometrial cancer, though prevalent, remains underfunded and understudied. Recurrent and metastatic disease remains difficult to treat, and prospective randomized data are limited. Our ability to reduce mortality due to this cancer is dependent on identifying new and effective therapeutic strategies for recurrent disease. PMID- 29972648 TI - 1alpha,25-dihydroxyvitamin D3-eluting nanofibrous dressings induce endogenous antimicrobial peptide expression. AB - AIM: The aim of this study was to develop a nanofiber-based dressing capable of local sustained delivery of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) and augmenting human CAMP induction. MATERIALS & METHODS: Nanofibrous wound dressings containing 1,25(OH)2D3 were successfully prepared by electrospinning, which were examined in vitro, in vivo and ex vivo. RESULTS: 1,25(OH)2D3 was successfully loaded into nanofibers with encapsulation efficiency larger than 90%. 1,25(OH)2D3 showed a sustained release from nanofibers over 4 weeks. Treatment of U937 and HaCaT cells with 1,25(OH)2D3-loaded poly(epsilon-caprolactone) nanofibers significantly induced hCAP18/LL37 expression in monocytes and keratinocytes, skin wounds of humanized transgenic mice and artificial wounds of human skin explants. CONCLUSION: 1,25(OH)2D3 containing nanofibrous dressings could enhance innate immunity by inducing antimicrobial peptide production. PMID- 29972651 TI - Could home-based FeNO measurements breathe new life into asthma management? PMID- 29972652 TI - Depression symptoms and quality of life among individuals with aspirin exacerbated respiratory disease. AB - OBJECTIVE: Patients with aspirin-exacerbated respiratory disease (AERD) have high disease burden due to the severity of asthma and sinonasal symptoms. There is limited research on the psychological well-being and subjective experiences of patients with AERD. This study examined levels of depression symptoms, asthma related quality of life and asthma control among AERD patients. METHODS: Thirty two adults with AERD and 39 patients without AERD (asthma-only) were recruited from outpatient asthma/allergy clinics. The sample was largely comprised of ethnic minority, inner-city patients who ranged in age from 19 to 84 years old. Participants completed the Beck Depression Inventory (BDI), the Mini Asthma Quality of Life Questionnaire (Mini AQLQ), a self-report rating of asthma severity and spirometry testing. Asthma control and severity were determined following national guidelines. RESULTS: AERD patients reported lower levels of depression symptoms (p = 0.049), better overall asthma-related quality of life (p < 0.001), and perceived their asthma to be less severe (p = 0.01) compared to asthma-only patients. However, clinician ratings of asthma severity were more severe for AERD than asthma-only patients (p = 0.006). No significant differences were found between the groups on asthma controller medications or oral corticosteroid bursts for asthma. CONCLUSIONS: AERD patients may be resilient given their low levels of depression symptoms and positive views of asthma related impairment despite higher clinician-rated asthma severity. The adult onset nature of asthma in AERD might be a protective factor on mental health. Future studies should explore mechanisms linking AERD and positive psychological health outcomes and subjective perception of asthma. PMID- 29972653 TI - Preconditioning with partial caloric restriction confers long-term protection against grey and white matter injury after transient focal ischemia. AB - Caloric restriction (CR) has been extensively examined as a preventative strategy against aging and various diseases, but CR effects on cerebral ischemia are largely unknown. We subjected C57BL6/J mice to ad libitum food access (LF) or a diet restricted to 70% of ad libitum food access (RF) for two to four weeks followed by 60 min of transient focal ischemia (tFCI). RF for four weeks protected against subsequent tFCI-induced infarct. RF improved sensorimotor function after stroke in the foot fault and corner tests, as well as performance in the Morris water maze test. In addition, RF preserved ischemic white matter tract integrity assessed by histology and compound action potential. Sirt1 and Sirt3 were both upregulated in RF ischemic brain, but heterozygous deletion of Sirt1 or knockout of Sirt3 did not alter the protection induced by RF against ischemic injury. RF induced significant release of adiponectin, a hormone related to glucose metabolism. Knockout of adiponectin decreased RF-induced protection after tFCI. These data demonstrate the novel finding that white matter, as well as neurons, benefit from CR prior to cerebral ischemic injury, and that adiponectin may contribute to these protective effects. PMID- 29972654 TI - The role of asthma in caries occurrence - meta-analysis and meta-regression. AB - OBJECTIVE: We aimed to conduct a systematic review of the literature regarding the association between asthma and caries, assess the effect of asthma on the occurrence of caries in primary and permanent dentitions, and determine factors that could affect the estimates of this association. DATA SOURCE: We used the following databases: PubMed, Web of Science, SCOPUS, and LILACS/BVS, for the literature review. STUDY SELECTION: We included observational studies that investigated the association between asthma and dental caries, excluding studies with syndromic patients, literature reviews, case reports, and in vitro and in situ studies. A meta-analysis was performed to estimate a pooled effect, and meta regression was conducted to determine study factors that could affect the estimates. RESULTS: From 674 studies initially identified, 40 fulfilled the inclusion criteria, and 36 of these were used in the meta-analysis. Odds ratio (OR) for the pooled effect was 1.45 (95% confidence interval (CI): 1.22-1.72; I2, 71.8%; p < 0.001) and 1.52 (95% CI: 1.34-1.73; I2, 83.1%; p < 0.001) for primary and permanent dentitions, respectively. In addition, a small proportion of the heterogeneity was attributed to included factors in the meta-regression (primary dentition, 10.7%; and permanent dentition, 3.1%). CONCLUSIONS: This study provides reliable and robust evidence that emphasizes the impact of asthma on the occurrence of dental caries in both, primary and permanent, dentitions. The findings provide useful data for recommending that dentists and physicians collaborate to establish the control for both diseases in a multidisciplinary manner. PMID- 29972655 TI - Typhoid conjugate vaccines: making vaccine history in Africa. PMID- 29972656 TI - Clinical implications of the tiotropium/olodaterol inhaler for patients with chronic obstructive pulmonary disease. AB - Oral inhalation is the recommended delivery method of medications for the treatment of patients with chronic obstructive pulmonary disease (COPD). However, patients may struggle when using the various available inhaler platforms, and, as a result, may fail to achieve the benefit of the prescribed medication. Propellant-based, pressurized metered-dose inhaler and powder-based, dry powder inhaler devices are currently the most commonly prescribed delivery systems. Each of these devices has its own advantages and challenges. The Respimat(r) Soft MistTM inhaler (SMI) (Boehringer Ingelheim) is a delivery system that incorporates features intended to improve orally inhaled drug delivery to these patients. These features include simple device actuation, patient inspiratory effort-independent aerosol generation, and a slower spray emission with a longer spray duration, helping to mitigate issues with precise aerosol release and breath coordination. We review the clinical trials assessing lung deposition, efficacy, and safety, and patient satisfaction for the Respimat(r) SMI. These data indicate that the Respimat(r) SMI is a device capable of delivering a consistent, clinically effective dose of medication that patients can use and prefer, which may provide significant clinical benefits for patients with COPD. PMID- 29972657 TI - Validation of fitness tracker for sleep measures in women with asthma. AB - OBJECTIVE: Nighttime wakening with asthma symptoms is a key to assessment and therapy decisions, with no gold standard objective measure. The study aims were to (1) determine the feasibility, (2) explore equivalence, and (3) test concordance of a consumer-based accelerometer with standard actigraphy for measurement of sleep patterns in women with asthma as an adjunct to self-report. METHODS: Panel study design of women with poorly controlled asthma from a university-affiliated primary care clinic system was used. We assessed sensitivity and specificity, equivalence and concordance of sleep time, sleep efficiency, and wake counts between the consumer-based accelerometer Fitbit ChargeTM and Actigraph wGT3X+. We linked data between devices for comparison both automatically by 24-hour period and manually by sleep segment. RESULTS: Analysis included 424 938 minutes, 738 nights, and 833 unique sleep segments from 47 women. The fitness tracker demonstrated 97% sensitivity and 40% specificity to identify sleep. Between device equivalence for total sleep time (15 and 42-minute threshold) was demonstrated by sleep segment. Concordance improved for wake counts and sleep efficiency when adjusting for a linear trend. CONCLUSIONS: There were important differences in total sleep time, efficiency, and wake count measures when comparing individual sleep segments versus 24-hour measures of sleep. Fitbit overestimates sleep efficiency and underestimates wake counts in this population compared to actigraphy. Low levels of systematic bias indicate the potential for raw measurements from the devices to achieve equivalence and concordance with additional processing, algorithm modification, and modeling. Fitness trackers offer an accessible and inexpensive method to quantify sleep patterns in the home environment as an adjunct to subjective reports, and require further informatics development. PMID- 29972658 TI - Respiratory waveform variation can prevent pulsus paradoxus measurement by sphygmomanometry. AB - BACKGROUND: Pulsus paradoxus (PP) represents increased fluctuation of systolic pressure during the respiratory cycle. PP increases in pathologic conditions, including asthma and other obstructive airways diseases. Respiratory waveform variation (RWV) represents arterial-waveform baseline variability resulting from intra-pleural pressure changes during the respiratory cycle in the presence of airway obstruction. It is not known whether RWV influences manual PP measurement using a sphygmomanometer and stethoscope. METHODS: We performed an observational study in six healthy adults. Participants performed tidal-breathing through a breathing apparatus with pre-determined inspiratory (0-45.6 cm H2O) and expiratory (0-24.4 cm H2O) resistance levels for a total of 23 data sets per participant. PP was measured from continuous radial artery pressure recordings as the absolute difference between maximum and minimum systolic pressure levels during a complete respiratory cycle. RESULTS: In this study, PP values measured without applied airway resistance exceeded 10 mmHg, the traditional definition of PP, in five of the six participants. Manual measurement of PP would not be possible at greater RWV because the maximum diastolic pressure exceeded minimum systolic pressure during RWV. CONCLUSIONS: PP in normal adults may exceed 10 mmHg, and RWV may be of sufficient magnitude to preclude manual PP measurement. PMID- 29972660 TI - 70 years of NHS health care. PMID- 29972659 TI - The role of imaging in juvenile idiopathic arthritis. AB - INTRODUCTION: The prognosis of juvenile idiopathic arthritis (JIA) has changed dramatically due to the availability of novel drugs. Prompt diagnosis and treatment are essential to prevent permanent joint damage. As a result, methods to improve JIA diagnosis and prognosis are of high priority to tailor treatment strategies and maximize their efficacy. Musculoskeletal ultrasound and magnetic resonance imaging are more sensitive than clinical examination and radiography in the detection of joint involvement and might play a substantial role to optimize the management of JIA. Areas covered: This review compiles an inventory of potential uses of imaging studies in the modern practice of pediatric rheumatology, together with a critical analysis of the major challenges that are still to be addressed. Imaging appearance of normal growth-related changes of the musculoskeletal system will be discussed. Expert commentary: Knowledge of the evolving patterns of skeletal maturity is paramount to define pathological findings and avoid misinterpretations. Establishing a novel radiological algorithm for a rational use of imaging in JIA is of high priority to allow a speedier integration of imaging into the clinical workflow and decision-making process. PMID- 29972661 TI - Intergenerational living. PMID- 29972662 TI - Being supported to whistle while you work. PMID- 29972663 TI - Managing chronic breathlessness in the community. AB - Breathlessness or dyspnoea is a subjective experience that can be described as an unpleasant or uncomfortable awareness of breathing. It is a subjective experience for patients and often they learn to adapt to the limitations caused by their condition, which makes their breathlessness less apparent to others. Breathlessness can be subdivided in the context of chronic refractory breathlessness, such as acute breathlessness, which is either an episodic breathlessness or breathlessness crisis. Chronic refractory breathlessness is defined as breathlessness at rest or on minimal exertion that will persist chronically despite optimal treatment of the underlying causative factors. The role of the community nurse in managing the breathless patient should involve differentiating between different types of breathlessness and knowing how to effectively manage it in a holistic manner. PMID- 29972664 TI - Correspondence. PMID- 29972666 TI - Evidence-based practice in community nursing. PMID- 29972665 TI - The role of the district nurse in caring for patients with dementia. AB - District nurses require a vast array of skills to enable effective care delivery for patients living with a diagnosis of dementia in the community setting. Complex care needs provide challenges for the provision and delivery of district nursing services, which must be overcome to provide patientcentred care. Demographic and financial constraints hamper service delivery and the availability of services; however, district nurses are required to use their problem solving skills and tacit knowledge to deal with these challenges. The Northern Ireland Single Assessment Tool (NISAT) uses a person-centred framework to provide a holistic approach to care. The case study reflects a holistic and person centred approach to care for a person with dementia by a district nursing student. PMID- 29972667 TI - Preparing for death with a 'buddy'..... PMID- 29972668 TI - Celebrating the past, embracing the future. PMID- 29972669 TI - The role of the district nurse in Northern Ireland. AB - A district nurse is an expert generalist practitioner who uses advanced clinical skills and knowledge to fulfil an ever-evolving role. The district nurse is accountable for the care planning, coordination and management of people with multi-faceted and intricate health care needs. In addition, an interprofessional approach to health and social care is required to enable the district nurse to co ordinate care and enable patients to be cared for and remain within their homes. As the demand on primary and community services increases, care is further enriched by working in partnership with families, carers and voluntary service providers. The nurse patient relationship is the founding component for person centred, holistic care. Through holistic assessment and shared decision making, co-produced care planning permits people to fundamentally take ownership of their health and enhances formal care provision. This case study reflects the role of the district nurse in Northern Ireland, through comprehensive assessment in clinical practice and highlights how a therapeutic relationship, being centred on the patient and shared decision-making impact positively on the care process. PMID- 29972670 TI - District nurses must guard against inappropriately accessing patient records. AB - Two NHS workers were recently disciplined after inappropriately accessing the records of the singer Ed Sheeran who had required treatment for a fractured wrist and elbow after falling from his bicycle ( Embury-Dennis 2018 ). The increasingly common use of electronic records across the NHS now allows nurses, including district nurses, to access a large archive of patient information that was much more difficult to obtain when records were manually held paper records. There have been several instances where curiosity and, occasionally, more malicious reasons have led district nurses and others to access those records and read the notes of high profile patients or persons known to them. In this article Richard Griffith cautions that district nurses who access and read the record of a person who is not in their care is in breach of both their duty of confidence and the requirements of the General Data Protection Regulation (Regulation 2016/679 EU ). PMID- 29972671 TI - Compression therapy and exercise: enhancing outcomes. AB - Compression therapy is the main method used within the treatment and management of lymphoedema and chronic oedema. The increasing prevalence of the condition, which has multiple causes, such as genetic factors, age and external factors, require the effective management of the condition, and to enhance the management methods used to contain the condition. The use of exercise alongside the mainstay method of treatment (compression therapy) has been an underutilised area. The application of a structured exercise programme in conjunction with multi-layer lymphoedema bandaging combined with an adjustable velcro wrap based systems led to a decrease in limb volume in one case study. The results of the programme indicate that the approach is beneficial and requires embedding further within Walsall lymphoedema service, due to improved patient outcomes, and cost effectiveness in terms of resources. PMID- 29972672 TI - Breast surgery for metastatic breast cancer. PMID- 29972673 TI - Preventing loneliness in older patients. PMID- 29972675 TI - Codelivery of benzoyl peroxide & adapalene using modified liposomal gel for improved acne therapy. AB - AIM: Current study investigates therapeutic efficacy and tolerability of benzoyl peroxide (BPO)- and adapalene (AD)-loaded modified liposomal gel (BPO-AD-mLipo gel) for improved acne therapy. MATERIALS & METHOD: BPO-AD-mLipo were optimized and loaded in Carbopol gel. Both BPO-AD-mLipo and BPO-AD-mLipo-gel were extensively characterized for different quality attributes. Ex vivo dermal bioavailability, dermal distribution, in vivo anti-acne efficacy and skin irritation studies were performed and compared with marketed formulation (Epiduo(r), Galderma Laboratories LP, TX, USA). RESULTS: BPO-AD-mLipo illustrated size 256.4 +/- 9.3 nm with polydispersity index ~ 0.2. Significantly enhanced dermal bioavailability (AD-2.1, 5.4; BPO-3.0, 7.83-fold) and reduction in skin irritation and papule density in animal model were observed with BPO-AD-mLipo-gel as compared with free drugs and Epiduo, respectively. CONCLUSION: BPO-AD-mLipo gel provides effective and safer alternative approach for codelivery of anti-acne drugs. PMID- 29972674 TI - Pregnant women with inflammatory bowel disease: the effects of biologicals on pregnancy, outcome of infants, and the developing immune system. AB - INTRODUCTION: Relapse of inflammatory bowel disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review. Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, antitumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti-interleukin (IL)-12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search. The occurrence of unfavorable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFalpha, but the effects on the developing immune system are largely unknown. For anti-integrins and anti IL-12/23, the numbers of exposed pregnancies are too small to draw any conclusions. Expert commentary: Follow-up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design. PMID- 29972676 TI - Gold nanoparticles as tracking devices to shed light on the role of caveolin-1 in early stages of melanoma metastasis. AB - AIM: To track early events during lung metastasis, we labeled cells expressing (B16F10CAV1) or lacking CAV1 (B16F10mock) with gold nanoparticles conjugated to the peptide TAT (AuNPs-PEG-TAT). METHODS: B16F10 expressing or lacking CAV1 were labeled with AuNPs-PEG-TAT. The physicochemical properties and cytotoxicity of these nanoparticles, as well as their effects on migration and invasiveness of B16F10 cells in vitro were evaluated. Ex vivo lung distribution of the labeled cells after tail vein injection into C57BL/6 mice was examined. RESULTS: AuNPs PEG-TAT did not affect B16F10 viability, migration and invasiveness. The metastatic and tumorigenic capability of the labeled B16F10 was also not modified in comparison to unlabeled B16F10 cells. CAV1 expression favored the retention of B16F10 cells in the lungs of mice 2 h post injection, suggesting CAV1 promoted adherence to endothelial cells and transendothelial migration. CONCLUSIONS: We developed a protocol to label B16F10 cells with AuNPs-PEG-TAT that permits subsequent tracking of cells in mice. CAV1 overexpression was found to increase retention and transendothelial migration of B16F10 cells in the lung. PMID- 29972677 TI - Factors relating to the biodistribution & clearance of nanoparticles & their effects on in vivo application. AB - Nanoparticles have promising biomedical applications for drug delivery, tumor imaging and tumor treatment. Pharmacokinetics are important for the in vivo application of nanoparticles. Biodistribution and clearance are largely defined as the key points of pharmacokinetics to maximize therapeutic efficacy and to minimize side effects. Different engineered nanoparticles have different biodistribution and clearance processes. The interactions of organs with nanoparticles, which are determined by the characteristics of the organs and the biochemical/physical properties of the nanoparticles, are a major factor influencing biodistribution and clearance. In this review, the clearance functions of organs and the properties related to pharmacokinetics, including nanoparticle size, shape, biodegradation and surface modifications are discussed. PMID- 29972678 TI - Targeted bioadhesive nanomedicine: an effective approach for synergistic drug delivery to cancers. PMID- 29972679 TI - Empowering aspects for healthy food and physical activity habits: adolescents' experiences of a school-based intervention in a disadvantaged urban community. AB - PURPOSE: This study aimed to describe adolescents' experiences of participating in a health-promoting school-based intervention regarding food and physical activity, with a focus on empowering aspects. Method: The school was located in a urban disadvantaged community in Sweden, characterized by poorer self-reported health and lower life expectancy than the municipality average. Focus group interviews with adolescents (29 girls, 20 boys, 14-15 years) and their teachers (n = 4) were conducted two years after intervention. Data were categorized using qualitative content analysis. RESULTS: A theme was generated, intersecting with all the categories: Gaining control over one's health: deciding, trying, and practicing together, in new ways, using reflective tools. The adolescents appreciated influencing the components of the intervention and collaborating with peers in active learning activities such as practicing sports and preparing meals. They also reported acquiring new health information, that trying new activities was inspiring, and the use of pedometers and photo-food diaries helped them reflect on their health behaviours. The adolescents' experiences were also echoed by their teachers. Conclusions: To facilitate empowerment and stimulate learning, health-promotion interventions targeting adolescents could enable active learning activities in groups, by using visualizing tools to facilitate self-reflection, and allowing adolescents to influence intervention activities. PMID- 29972680 TI - Biomedical Applications and Toxicological Aspects of Functionalized Carbon Nanotubes. AB - Currently, nanomedicines exhibit implausible capability in overcoming the hurdles faced in gene therapy, cancer treatments, as well as other life-threatening diseases. Worldwide, the unique features of carbon nanotubes (CNTs) are still being explored by researchers to tap their potential. Different types of CNTs exhibit capabilities in the transportation of vaccines, bioactives, and nucleic acids deep into the cell to previously unreachable targets. This review sheds light on the different aspects of biomedical applications and toxicities associated with functionalized CNTs. To better understand the biomedical scope of CNTs, more research into the toxicological behavior of CNTs as well as functionalized CNTs is needed. The exploration of appropriate cell lines to investigate specific receptors and intracellular targets as well as long-term toxicity beyond the proof-of-concept is needed. These issues facing the translation of surface-engineered CNT nanoarchitectures are vital to moving CNT applications from the laboratory to the clinic. The future of pharmaceutical as well as biomedical applications of CNTs will certainly depend upon whether we are able to prove their safety beyond doubt. And if we succeed through vigorous research efforts, then CNTs will have tremendous application as a freely available and economic biomaterial. PMID- 29972681 TI - Perspectives of Lipid-Based Drug Carrier Systems for Transdermal Delivery. AB - Transdermal delivery serves as non-invasive and effortless terminable means for systemic as well as topical drug delivery and finds itself as an option to conventional delivery route. Significant impervious nature of skin is the greatest hurdle for successful delivery of drug molecules to the deeper layers of skin for systemic absorption. Many approaches have been carried out for delivery of a medicament across skin barrier to enhance the efficacy. Among them lipid based colloidal carriers have gained a unique position for transdermal delivery of drugs and bioactives owing to the presence of epidermal lipids as the chief component within the penetration barrier in high amount. Skin-carrier interaction involves attachment of these carriers to skin with a view to permit exchange of lipid between the outermost layers of the stratum corneum. Based on extensive literature search, although numerous reviews are available on lipid-based systems, but none of them relates exclusively to their transdermal uptake and toxicity. This review specifically focuses on the hurdles of transdermal drug delivery, role of lipid vehicular systems in transdermal drug delivery, uptake pathways, sequential uptake mechanism and cytotoxicity issues of lipid-based carriers which although considered safe, are not completely free from toxicity. PMID- 29972682 TI - Novel 'Stereoscopic Response' Strategy Can Be Used in Combination Therapy. AB - Future cancer therapy will depend on combination therapy with multiple drugs to achieve maximum effects and minimum toxicity. Due to the complexity and significance of the tumor microenvironment (TME), it is vital to elucidate this complicated environment when designing a co-delivery system. There are numerous potent target sites in the TME to facilitate simultaneous and selective delivery. Currently, nanocarriers are used frequently in co-delivery systems for multiple antitumor treatments. Nanocarriers can efficiently deliver drugs and achieve synergistic effects, but the potent barriers in the TME and their inherent limitations have restricted their use. It is crucial to design an effected co delivery system associated with the TME to achieve better anti-tumor activity, which we define as a "stereoscopic response." Although there are many obstacles in this field, the combination of simultaneous response in the TME with drug activity may present a promising strategy to achieve innovative, safe, and effective treatment. PMID- 29972683 TI - Enhanced photovoltaic performance of inverted polymer solar cells through atomic layer deposited Al2O3 passivation of ZnO-nanoparticle buffer layer. AB - In this work, an atomic layer deposited (ALD) Al2O3 ultrathin layer was introduced to passivate the ZnO-nanoparticle (NP) buffer layer of inverted polymer solar cells (PSCs) based on P3HT:PCBM. The surface morphology of the ZnO NP/Al2O3 interface was systematically analyzed by using a variety of tools, in particular transmission electron microscopy (TEM), evidencing a conformal ALD Al2O3 deposition. The thickness of the Al2O3 layers was optimized at the nanoscale to boost electron transport of the ZnO-NP layer, which can be attributed to the suppression of oxygen vacancy defects in ZnO-NPs confirmed by photoluminescence measurement. The optimal inverted PSCs passivated by ALD-Al2O3 exhibited an ~22% higher power conversion efficiency than the control devices with a pristine ZnO-NP buffer layer. The employment of the ALD-Al2O3 passivation layer with precisely controlled thickness provides a promising approach to develop high efficiency PSCs with novel polymer materials. PMID- 29972684 TI - Dexamethasone Stimulates Hepatitis B Virus (HBV) Replication Through Autophagy. AB - BACKGROUND Reactivation of hepatitis B virus (HBV) is a fatal complication of chemotherapy. Occult HBV infection might be reactivated in patients undergoing chemotherapy or immunosuppression. However, the mechanism of HBV reactivation induced by chemotherapy or immunosuppression remains unclear. MATERIAL AND METHODS HepG2.2.15 cells were treated with an autophagy inducer (rapamycin), an inhibitor (3-methyladenine, 3-MA), and dexamethasone. Autophagosomes were observed by a transmission electron microscope (TEM). LC3-I, LC3-II, and P62 were analyzed by western blot. HBV replicative intermediates were detected by southern blot. HBV DNA expression was quantitated with real-time polymerase chain reaction (PCR). The level of HBV surface antigen (HBsAg) in culture medium was examined by ELISA. RESULTS In this study, we find that dexamethasone stimulates HBV replication and protein expression by inducing autophagy in HepG2.2.15 cells. In contrast, autophagy inhibitor (3-MA) abrogates HBsAg secretion stimulated by dexamethasone. CONCLUSIONS Our results suggest that dexamethasone stimulates HBV replication through autophagy. This might provide a novel insight into the mechanism of glucocorticoid-mediated HBV reactivation through autophagy, which might be a new therapeutic target. PMID- 29972685 TI - The neglected terminators: Rho family GAPs in neutrophils. AB - BACKGROUND: GTPase-activating proteins (GAPs) accelerate the rate of hydrolysis of GTP bound to small GTPases, thereby limiting the prevalence and concentration of the active, GTP-bound form of these proteins. The large number of potential GAPs acting on members of the Rho family of small GTPases raises the question of specificity or redundancy. RESULTS: In this review, we summarize experimental data obtained on the role of Rho family GAPs in neutrophils, highlight cases where more than one GAP is involved in a physiological function and show examples that GAPs can be involved not only in termination but also in initiation of cellular processes. We demonstrate that the expression-level regulation of GAPs may also occur in short-living cells such as neutrophils. Finally, we provide insight into the existence and structure of molecular complexes in which Rho family GAPs are involved. CONCLUSION: GAPs play more complex and varied roles than being simple terminators of cellular processes. PMID- 29972687 TI - Reciprocal modulation of Cav 2.3 voltage-gated calcium channels by copper(II) ions and kainic acid. AB - Kainic acid (KA) is a potent agonist at non-N-methyl-D-aspartate (non-NMDA) ionotropic glutamate receptors and commonly used to induce seizures and excitotoxicity in animal models of human temporal lobe epilepsy. Among other factors, Cav 2.3 voltage-gated calcium channels have been implicated in the pathogenesis of KA-induced seizures. At physiologically relevant concentrations, endogenous trace metal ions (Cu2+ , Zn2+ ) occupy an allosteric binding site on the domain I gating module of these channels and interfere with voltage-dependent gating. Using whole-cell patch-clamp recordings in human embryonic kidney (HEK 293) cells stably transfected with human Cav 2.3d and beta3 -subunits, we identified a novel, glutamate receptor-independent mechanism by which KA can potently sensitize these channels. Our findings demonstrate that KA releases these channels from the tonic inhibition exerted by low nanomolar concentrations of Cu2+ and produces a hyperpolarizing shift in channel voltage-dependence by about 10 mV, thereby reconciling the effects of Cu2+ chelation with tricine. When tricine was used as a surrogate to study the receptor-independent action of KA in electroretinographic recordings from the isolated bovine retina, it selectively suppressed a late b-wave component, which we have previously shown to be enhanced by genetic or pharmacological ablation of Cav 2.3 channels. Although the pathophysiological relevance remains to be firmly established, we speculate that reversal of Cu2+ -induced allosteric suppression, presumably via formation of stable kainate-Cu2+ complexes, could contribute to the receptor-mediated excitatory effects of KA. In addition, we discuss experimental implications for the use of KA in vitro, with particular emphasis on the seemingly high incidence of trace metal contamination in common physiological solutions. PMID- 29972686 TI - Local exchange of metabolites shapes immunity. AB - Immune cell differentiation and function depend on metabolic changes for the provision of energy and metabolites. Consequently, cellular metabolism relies on the availability of micronutrients such as vitamins and energy-rich sources including amino acids and fatty acids. The bone marrow controls the continuous production of blood cells and is thereby reliant on the sophisticated interplay of progenitor and mature immune cells with its stromal microenvironment. The significance of stromal subsets in immunopoiesis is undisputed; however, our current knowledge is limited to their role in the production and secretion of a variety of soluble proteins such as cytokines. In contrast, the role of the haematopoietic niche in controlling and providing nutrients such as fatty acids, amino acids and vitamins, which are required for immune cell differentiation and function, remains largely elusive. In this review, we summarize the current understanding of local nutritional exchange and control between immune and stromal cells in peripheral tissue and, when it is known, in the bone marrow. The parallels found between peripheral tissues and bone marrow stroma raises the question of how local metabolism is capable of influencing haematopoiesis and immunopoiesis. A better understanding of the local exchange of nutrients in the bone marrow can be used to improve immune cell formation during ageing, after haematopoietic stem cell transplantation and during immune challenge. PMID- 29972688 TI - Comparative pharmacokinetics of three alkaloids in normal and acute hepatitis rats after oral administration of Yanhuanglian total alkaloids extract. AB - Acute hepatitis is a severe inflammatory disease with high mortality rates. Dehydrocavidine (DC), berberine (BB) and palmatine (PT), the bioactive components of Yanhuanglian total alkaloids extract (YTAE), may play important roles in its protective effect against acute hepatitis. The present study was designed to compare the pharmacokinetic properties of DC, BB and PT after oral administration of YTAE in normal and acute hepatitis rats. The plasma pharmacokinetic profiles of three major bioactive alkaloids from YTAE were analyzed using an LC-MS/MS method. It was found that the pharmacokinetic parameters of DC, BB and PT represented a statistically significant difference (p ? 0.05) between the normal rats and the acute hepatitis rats after administration of YTAE. The results indicated that the Cmax , T1/2beta and AUC of DC, BB and PT in acute hepatitis rats were significantly increased, whereas the CL and Vd values were remarkably decreased (p ? 0.05) over those of the normal rats. The results suggested that the pharmacokinetic behavior of the active constituents from YTAE could be changed when it was used in acute hepatitis animals, which provide a meaningful basis for developing a clinical dosage regimen in the treatment of acute hepatitis by YTAE. PMID- 29972689 TI - Rotenone inhibits axonogenesis via an Lfc/RhoA/ROCK pathway in cultured hippocampal neurons. AB - Rotenone, a broad-spectrum insecticide, piscicide and pesticide, produces a complete and selective suppression of axonogenesis in cultured hippocampal neurons. This effect is associated with an inhibition of actin dynamics through activation of Ras homology member A (RhoA) activity. However, the upstream signaling mechanisms involved in rotenone-induced RhoA activation were unknown. We hypothesized that rotenone might inhibit axon growth by the activation of RhoA/ROCK pathway because of the changes in microtubule (MT) dynamics and the concomitant release of Lfc, a MT-associated Guanine Nucleotide Exchange Factor (GEF) for RhoA. In this study, we demonstrate that rotenone decreases MT stability in morphologically unpolarized neurons. Taxol (3 nM), a drug that stabilizes MT, attenuates the inhibitory effect of rotenone (0.1 MUM) on axon formation. Radiometric Forster Resonance Energy Transfer, revealed that this effect is associated with inhibition of rotenone-induced RhoA and ROCK activation. Interestingly, silencing of Lfc, but not of the RhoA GEF ArhGEF1, prevents the inhibitory effect of rotenone on axon formation. Our results suggest that rotenone-induced MT de-stabilization releases Lfc from MT thereby promoting RhoA and ROCK activities and the consequent inhibition of axon growth. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/. PMID- 29972690 TI - Evaluation of the immune response against Trypanosoma cruzi cytosolic tryparedoxin peroxidase in human natural infection. AB - Trypanosoma cruzi, the aetiological agent of Chagas disease, has a highly efficient detoxification system to deal with the oxidative burst imposed by its host. One of the antioxidant enzymes involved is the cytosolic tryparedoxin peroxidase (c-TXNPx), which catalyses the reduction to hydrogen peroxide, small chain organic hydroperoxides and peroxynitrite. This enzyme is present in all parasite stages, and its overexpression renders parasites more resistant to the oxidative defences of macrophages, favouring parasite survival. This work addressed the study of the specific humoral and cellular immune response triggered by c-TXNPx in human natural infection. Thus, sera and peripheral blood mononuclear cells (PBMC) were collected from chronically infected asymptomatic and cardiac patients, and non-infected individuals. Results showed that levels of IgG antibodies against c-TXNPx were low in sera from individuals across all groups. B-cell epitope prediction limited immunogenicity to a few, small regions on the c-TXNPx sequence. At a cellular level, PBMC from asymptomatic and cardiac patients proliferated and secreted interferon-gamma after c-TXNPx stimulation, compared with mock control. However, only proliferation was higher in asymptomatic patients compared with cardiac and non-infected individuals. Furthermore, asymptomatic patients showed an enhanced frequency of CD19+ CD69+ cells upon exposure to c-TXNPx. Overall, our results show that c-TXNPx fails to induce a strong immune response in natural infection, being measurable only in those patients without any clinical symptoms. The low impact of c-TXNPx in the human immune response could be strategic for parasite survival, as it keeps this crucial antioxidant enzyme activity safe from the mechanisms of adaptive immune response. PMID- 29972691 TI - Community Pharmacists' Contribution to Medication Reviews for Older Adults: A Systematic Review. AB - OBJECTIVES: To identify medication review interventions for older adults that involve community pharmacists and evidence of outcomes of these interventions. DESIGN: Systematic review. MEASUREMENTS: Cinahl, MEDLINE (Ovid), Scopus, International Pharmaceutical Abstracts, and Cochrane Library were searched for articles published between January 2000 and February 2016. Articles involving community pharmacists in medication reviews for outpatients aged 65 and older were included. Evidence of economic, clinical, and humanistic outcomes of interventions was summarized. RESULTS: Sixteen articles were found that described 12 medication review interventions, of which 6 were compliance and concordance reviews, 4 were clinical medication reviews, and 2 were prescription reviews according to a previously developed typology. Community pharmacists' contributions to reviewing medications varied from sending the dispensing history to other healthcare providers to comprehensive involvement in medication management. The most commonly assessed outcomes of the interventions were medication changes leading to reduction in actual or potential drug-related problems (n=12) and improved adherence (n=5). CONCLUSION: Regardless of community pharmacists' contributions to interventions, medication review interventions seem to reduce drug-related problems and increase medication adherence. More well designed, rigorous studies with more sensitive and specific outcomes measures need to be conducted to assess the effect of community pharmacists' contributions to reviewing medications and improving the health of older adults. PMID- 29972693 TI - Low-rank magnetic resonance fingerprinting. AB - PURPOSE: Magnetic resonance fingerprinting (MRF) is a relatively new approach that provides quantitative MRI measures using randomized acquisition. Extraction of physical quantitative tissue parameters is performed offline, without the need of patient presence, based on acquisition with varying parameters and a dictionary generated according to the Bloch equation simulations. MRF uses hundreds of radio frequency (RF) excitation pulses for acquisition, and therefore, a high undersampling ratio in the sampling domain (k-space) is required for reasonable scanning time. This undersampling causes spatial artifacts that hamper the ability to accurately estimate the tissue's quantitative values. In this work, we introduce a new approach for quantitative MRI using MRF, called magnetic resonance fingerprinting with low rank (FLOR). METHODS: We exploit the low-rank property of the concatenated temporal imaging contrasts, on top of the fact that the MRF signal is sparsely represented in the generated dictionary domain. We present an iterative recovery scheme that consists of a gradient step followed by a low-rank projection using the singular value decomposition. RESULTS: Experimental results consist of retrospective sampling that allows comparison to a well defined reference, and prospective sampling that shows the performance of FLOR for a real-data sampling scenario. Both experiments demonstrate improved parameter accuracy compared to other compressed-sensing and low-rank based methods for MRF at 5% and 9% sampling ratios for the retrospective and prospective experiments, respectively. CONCLUSIONS: We have shown through retrospective and prospective experiments that by exploiting the low-rank nature of the MRF signal, FLOR recovers the MRF temporal undersampled images and provides more accurate parameter maps compared to previous iterative approaches. PMID- 29972692 TI - Interleukin-6 signalling mediates Galectin-8 co-stimulatory activity of antigen specific CD4 T-cell response. AB - Galectin-8 (Gal-8) is a mammalian lectin endowed with the ability to co-stimulate antigen-specific immune responses. We have previously demonstrated that bone marrow-derived dendritic cells produce high levels of interleukin-6 (IL-6) in response to Gal-8 stimulation. As IL-6 is a pleiotropic cytokine that has a broad effect on cells of the immune system, we aimed to elucidate whether IL-6 was involved in Gal-8-dependent co-stimulatory signals during antigen recognition by specific CD4 T cells. With this aim, splenocytes from DO11.10 mice were incubated with a low dose of the cognate ovalbumin peptide in combination with Gal-8. Interleukin-6 was found significantly increased in cultures stimulated with Gal-8 alone or Gal-8 plus cognate peptide. Moreover, IL-6 signalling was triggered during Gal-8-induced co-stimulation, as determined by phosphorylation of signal transducer and activator of transcription 3. Interleukin-6 blockade by neutralizing monoclonal antibody precluded Gal-8 co-stimulatory activity but did not affect the antigen-specific T-cell receptor activation. Different subsets of dendritic cells, as well as macrophages and B cells, were identified as the cellular source of IL-6 during Gal-8-induced co-stimulation. To confirm that IL-6 mediated the Gal-8 co-stimulatory effect, antigen-presenting cells from IL-6 deficient or wild-type mice were co-cultured with purified CD4 T cells from OTII mice in the presence of cognate peptide and Gal-8. Notably, Gal-8-induced co stimulation, but not the antigen-specific response, was significantly impaired in the presence of IL-6-deficient antigen-presenting cells. In addition, exogenous IL-6 fully restored Gal-8-induced co-stimulation. Taken together, our results demonstrate that IL-6 signalling mediates the Gal-8 immune-stimulatory effect. PMID- 29972694 TI - Abnormal irisin level in serum and endometrium is associated with metabolic dysfunction in polycystic ovary syndrome patients. AB - INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-age women. Irisin is considered to play a role in metabolic disorder and PCOS. However, correlation between irisin and metabolic disorder in PCOS is not clear. MATERIAL AND METHODS: This is a prospective study. Forty patients with PCOS and thirty patients without PCOS were recruited for in vitro fertilization and embryo transfer (IVF-ET). All PCOS women fulfilled all three Rotterdam consensus criteria. In each group, patients were also divided into obese and nonobese patients, and patients with or without dyslipidaemia. RESULTS: Serum irisin level in PCOS patients was significantly reduced. Irisin level in obese PCOS patients was significantly lower than in nonobese PCOS patients. Irisin level in PCOS patients with dyslipidaemia was significantly higher than in PCOS patients with normal blood lipid profile. In both PCOS and control patients, serum irisin level was negatively correlated with body weight and waist-hip ratio (WHR). Moreover, serum irisin level was positively correlated with body fat rate, BAI, fasting plasma glucose (FPG) and HOMA-IR in PCOS patients. In addition, serum irisin level was positively correlated with HOMA-IR in control patients. In PCOS patients, body weight and HOMA-IR could predict the level of irisin. In control patients, body mass index (BMI) could predict the level of irisin. Expression of irisin in PCOS patients was lower than that in control patients. However, there was no significant difference of irisin expression between the subdivided groups in PCOS and control patients. CONCLUSIONS: Taken together, the present findings enriched the knowledge about the role of irisin in metabolic dysfunction in PCOS patients. PMID- 29972695 TI - Implications of Off-Target Serotoninergic Drug Activity: An Analysis of Serotonin Syndrome Reports Using a Systematic Bioinformatics Approach. AB - STUDY OBJECTIVE: Serotonergic adverse drug events (ADEs) are caused by enhanced intrasynaptic concentrations of 5-hydroxytryptamine (5-HT). No systematic process currently exists for evaluating cumulative 5-HT and off-target toxicity of serotonergic drugs. The primary study aim was to create a Serotonergic Expanded Bioactivity Matrix (SEBM) by using a molecular bioinformatics, polypharmacologic approach for assessment of the participation of individual 5-HT drugs in serotonin syndrome (SS) reports. DATA SOURCES: Publicly available databases including the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), ChEMBL, DrugBank, PubChem, and Kyoto Encyclopedia of Genes and Genomes (KEGG) were queried for computational and pharmacologic data. DESIGN: An in-house bioinformatics TargetSearch program ( http://dxulab.org/software) was used to characterize 71 serotonergic drugs interacting at 13 serotonin receptor subtypes and serotonin reuptake transporter protein (SERT). In addition, off target interactions at norepinephrine transporter (NET), monoamine oxidase (MAO), and muscarinic receptors were included to define seven polypharmacological drug cohorts. Serotonin syndrome reports for each serotonergic drug were extracted from FAERS by using the Sternbach and Hunter criteria. MEASUREMENTS AND MAIN RESULTS: A proportional reporting adverse drug reaction (ADR) ratio (PRR) was calculated from each drug's total ADEs and SS case reports and aggregated by drug bioactivity cohorts. Triple-receptor interactions had a disproportionately higher number of SS cases using both the Hunter criteria (mean PRR 1.72, 95% CI 1.05 2.39) and Sternbach (mean PRR 1.54, 95% CI 1.29-1.79). 5-Hydroxytryptamine agonists were associated with a significantly lower proportion of SS cases using the Hunter and Sternbach criteria, respectively (mean PRR 0.49, 95% CI 0.17-0.81 and mean PRR 0.49, 95% CI 0.15-0.83). Drugs with disproportionately higher participation in SS vary considerably between the two diagnostic criteria. CONCLUSION: The SEBM model suggests a possible polypharmacological role in SS. Although further research is needed, off-target receptor activity may help explain differences in severity of toxicity and clinical presentation. PMID- 29972696 TI - Saliva and serum biomarkers in periodontitis and coronary artery disease. AB - AIM: Matrix metalloproteinase (MMP)-8, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1 and myeloperoxidase (MPO) participate in extracellular matrix breakdown both in periodontium and atherosclerotic plaques. We investigated the diagnostic value of serum and saliva biomarkers in periodontitis and acute coronary syndrome (ACS). MATERIALS AND METHODS: The population was PAROGENE (n = 481), a random cohort of patients with an indication for coronary angiography. All patients underwent a clinical and radiographic oral examination. Groups consisting of periodontitis versus non-periodontitis, and ACS versus non ACS patients were compared. RESULTS: Saliva MMP-8, MMP-9 and MPO provided significant area-under-curve (AUC) values for periodontitis, 0.69 (<0.001), 0.66 (<0.001) and 0.68 (<0.001), respectively. Serum MMP-8, MMP-9 and MPO levels distinguished ACS from non-ACS patients with AUCs of 0.73 (<0.001), 0.58 (0.03) and 0.68 (<0.001), respectively. Periodontitis confounded the use of serum MMP-9 in diagnostics of ACS. Cardiac status complicated the use of saliva TIMP-1 in periodontal diagnostics. Saliva biomarkers could not be used in ACS diagnosis, and serum biomarkers were not useful in diagnosis of periodontitis. CONCLUSIONS: MMP-8, MMP-9, TIMP-1and MPO are valuable biomarkers for both ACS and periodontitis, but the selection of sample material is crucial; serum is suitable for ACS and saliva for periodontal diagnostic aid. PMID- 29972697 TI - Pharmacokinetics of tiotropium in asthmatic children aged 6-11 years support its safety profile. PMID- 29972698 TI - Renal swelling indicates renal damage in infants with their first urinary tract infection. AB - AIM: We used ultrasound to evaluate renal swelling as a predictor of acute and permanent renal damage in infants with their first urinary tract infection (UTI). METHODS: The cohort at the Queen Silvia Children's Hospital, Gothenburg, Sweden, comprised 101 infants with their first UTI at a mean age of 3.9 +/- 3.0 months. Acute and follow-up ultrasounds were carried out a few days and one month after treatment started, and a 99m technetium dimercaptosuccinic acid (DMSA) scan was carried out after one month and after a year if the first scan was abnormal. RESULTS: The acute ultrasounds showed that renal length and volume, calculated as standard deviation scores (SDS), were 1.39 +/- 1.43 SDS and 1.30 +/- 1.08 SDS. We found that 52% of the one-month DMSA scans and 25% of the one-year DMSA scans were abnormal. Renal length (p = 0.0026) and initial volume (p = 0.0005) on the ultrasound predicted acute renal damage at the one-month DMSA scan and initial renal length (p = 0.030) predicted permanent renal damage at the one-year DMSA scan. CONCLUSION: Renal swelling was associated with renal damage. Although the diagnostic performance compared with the DMSA scan was weak, renal swelling may help clinicians to make decisions about further investigations and follow-ups of infants with UTIs. PMID- 29972699 TI - Potential killers exposed: tracking endogenous influenza-specific CD8+ T cells. AB - Current influenza A virus (IAV) vaccines stimulate antibody responses that are directed against variable regions of the virus, and are therefore ineffective against divergent strains. As CD8+ T cells target the highly conserved, internal IAV proteins, they have the potential to increase heterosubtypic immunity. Early T-cell priming events influence lasting memory, which is required for long-term protection. However, the early responding, IAV-specific cells are difficult to monitor because of their low frequencies. Here, we tracked the dissemination of endogenous IAV-specific CD8+ T cells during the initial phases of the immune response following IAV infection. We exposed a significant population of recently activated, CD25+ CD43+ IAV-specific T cells that were not detected by tetramer staining. By tracking this population, we found that initial T-cell priming occurred in the mediastinal lymph nodes, which gave rise to the most expansive IAV-specific CD8+ T-cell population. Subsequently, IAV-specific CD8+ T cells dispersed to the bronchoalveolar lavage and blood, followed by spleen and liver, and finally to the lung. These data provide important insight into the priming and tissue dispersion of an endogenous CD8+ T-cell response. Importantly, the CD25+ CD43+ phenotype identifies an inclusive population of early responding CD8+ T cells, which may provide insight into TCR repertoire selection and expansion. A better understanding of this response is critical for designing improved vaccines that target CD8+ T cells. PMID- 29972700 TI - Isolation and characterization of a novel nicotinophilic bacterium, Arthrobacter sp. aRF-1 and its metabolic pathway. AB - Nicotine is a potent parasympathomimetic stimulant and an important natural alkaloid mainly found in the Nicotiana genus of plants. It can directly threaten ecological security and human health in tobacco waste, wastewater, and other forms of tobacco production. Therefore, it is the basis of nicotine pollution prevention and of great application value to explore efficient and a wide range of nicotinophilic bacteria for tobacco industry and environmental protection. In this study, one nicotinophilic bacterium was isolated from the soil, which accumulated tobacco waste over 50 years at a Hefei cigarette factory. The strain was named aRF-1, which was identified as Arthrobacter sp. by analysis. The nicotine degradation tests showed that the optimum temperature for cell growth and metabolism of nicotine of Arthrobacter sp. aRF-1 was 30 degrees C, and the optimum initial pH value was about 7.0. Under the optimum experimented conditions, it can tolerance nicotine concentration as high as 8 g.L-1 . The highest removal rate of nicotine was 93.8% in 72 H in nonsterilization contaminated soil by Arthrobacter sp. aRF-1. LC-MS/MS was used to analyze the nicotine metabolic intermediates of strain Arthrobacter sp. aRF-1. A total of nine major metabolites that were detected were able to metabolize nicotine along a variant pathway of pyridine and pyrrolidine, and there may be more than two nicotine metabolic pathways for Arthrobacter sp. aRF-1 through the analysis of the main intermediate products. PMID- 29972701 TI - Physical activity preferences of 10-year-old children and identified activities with positive and negative associations to cardiorespiratory fitness. AB - AIM: This study investigated children's physical activity (PA) preferences, as these can aid the design of school-based interventions. METHODS: Data were collected in 2014 as a part of the Active Smarter Kids study and 1026 students (52% boys) from 57 Norwegian primary schools completed a questionnaire about their favourite physical activities at a mean age of 10.2 +/- 0.3 years. We identified five patterns of PA and studied whether gender, cardiorespiratory fitness and abdominal adiposity were associated with these patterns. RESULTS: Soccer and slalom skiing were the favourite activities, and the most pronounced gender differences were for activities favoured by girls, which included dancing, gymnastics, exercising to music and jumping rope (p < 0.001). When the five component patterns were analysed using linear mixed-effect models, this showed a strong female preference for dancing, gymnastics, exercising to music and climbing. Cardiovascular fitness was negatively associated with frisbee, dodgeball, baseball and floorball, and positively associated with team handball, volleyball and basketball and with slalom skiing and cross-country skiing. It was interesting that the children's preferences were not related to their abdominal adiposity. CONCLUSION: The results showed different gender-based PA preferences and positive and negative associations with cardiovascular fitness, but no relationship with abdominal adiposity. PMID- 29972702 TI - Development of a colloidal gold nanoparticle-based immunochromatographic strip for the one-step detection of miroestrol and puerarin. AB - Pueraria candollei or White Kwao Krua (Leguminosae) is an indigenous plant in Thailand which has long been used in Thai traditional medicine. The tuberous root of this plant is widely used for rejuvenation, particularly in elder women. Among the bioactive compounds in P. candollei, miroestrol and puerarin exhibit estrogenic activity. This study aims to develop an immunochromatographic strip (ICS) with a colloidal gold-based detection system for the simultaneous detection of miroestrol and puerarin in a one-step analysis. The developed method is sensitive and specific for the detection of miroestrol and puerarin in raw materials and marketed products. The detection limits of miroestrol and puerarin were 0.15 and 4.5 MUg, respectively. In addition, the results from the developed ICS were confirmed with an enzyme-linked immunosorbent assay and presented a good correlation between these two methods. This is the first report on the development of an ICS that can detect miroestrol and puerarin in one step. The developed ICS provides a simplified method for the detection of miroestrol and puerarin in P. candollei and Pueraria spp. PMID- 29972704 TI - Human jaw joint hypermobility: Diagnosis and biomechanical modelling. AB - Patients with hypermobility disorders of the jaw joint experience joint sounds and jerky movements of the jaw. In severe cases, a subluxation or luxation can occur. Clinically, hypermobility disorders should be differentiated from disc displacements. With biomechanical modelling, we previously identified the anterior slope angle of the eminence and the orientation of the jaw closers to potentially contribute to hypermobility disorders. Using cone-beam computed tomography (CBCT), we constructed patient-specific models of the masticatory system to incorporate these aspects. It is not known whether the clinical diagnosis of hypermobility disorders is associated with the prediction of hypermobility by a patient-specific biomechanical model. Fifteen patients and eleven controls, matched for gender and age, were enrolled in the study. Clinical diagnosis was performed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and additional testing to differentiate hypermobility from disc displacements. Forward simulations with patient-specific biomechanical models were performed for maximum opening and subsequent closing of the jaw. This predicted a hypermobility disorder (luxation) or a control (normal closing). We found no association between the clinical diagnosis and predictions of hypermobility disorders. The biomechanical models overestimated the number of patients, yielding a low specificity. The role of the collagenous structures remains unclear; therefore, the articular disc and the ligaments should be modelled in greater detail. This also holds for the fanned shape of the temporalis muscle. However, for the osseous structures, we determined post hoc that the anterior slope angle of the articular eminence is steeper in patients than in controls. PMID- 29972703 TI - The effect of lithium on the progression-free and overall survival in patients with metastatic differentiated thyroid cancer undergoing radioactive iodine therapy. AB - OBJECTIVE: Pretreatment with lithium (Li) is associated with an increased residence time of radioactive iodine (RAI) in differentiated thyroid cancer (DTC) metastases. There are no data translating this observation into long-term outcomes. The study goal was to compare the efficacy of three methods of preparation for RAI therapy in metastatic DTC-thyroid hormone withdrawal (THW), THW with pretreatment with Li (THW+Li), and recombinant human TSH (rhTSH). DESIGN/PATIENTS/MEASUREMENTS: We performed a cohort study comparing overall survival (OS) and progression-free survival (PFS) between the three groups: THW (n = 52), THW+Li (n = 41) and rhTSH (n = 42). Kaplan-Meier analyses were performed to compare OS and PFS between the groups. Cox proportional hazards regression model with a stepwise variable selection was performed to study the contribution of age, gender, histology, TNM status, a location of distant metastases and RAI dose. RESULTS: During the follow-up of median 5.1 (IQR = 3.0 8.1) years, 52% of patients had disease progression and 12.6% died. Although THW+Li group was characterized by the longest OS (P = 0.007), only age (HR 1.05, CI 1.01-1.09, P = 0.01) and widespread disease (HR 3.8, CI 1.2-11.8, P = 0.02) were found to affect OS in a multivariate model. There was no difference in PFS between the groups (P = 0.47). Presence of distant metastases limited to the lungs only was associated with longer PFS (PFS HR 0.35, CI 0.20-0.60, P = 0.0002). CONCLUSION: The older age is associated with shorter OS, while disease burden affects OS and PFS in patients with metastatic thyroid cancer. The method of preparation for RAI therapy does not affect the outcome. PMID- 29972705 TI - The Relative Risk of Achilles Tendon Injury in Patients Taking Quinolones. AB - OBJECTIVE: To examine the association between quinolone use and Achilles tendon injury, comparing well-matched cohorts of users of quinolone and nonquinolone antibiotics, and well-matched cohorts of quinolone users and patients not using any nonquinolone antibiotics. PATIENTS AND METHODS: This retrospective cohort study used Clinformatics data from 2008-2014. Using the propensity score, we matched quinolone users with other antibiotic users and quinolone users with nonusers. The primary outcome was Achilles tendon injury within 6 months. Bivariate analyses determined risk factors for Achilles tendon injury, and conditional logistic regression assessed the impact of quinolone use on these injuries. RESULTS: A total of 716,522 fluoroquinolone users were matched with other antibiotic users, and 645,034 fluoroquinolone users were matched with nonusers. Rates of Achilles tendon injury were less than 0.5% in all groups. Quinolone use increased the risk of Achilles tendon injury compared with other antibiotic users (odds ratio [OR] 1.24, 95% confidence interval [CI] 1.17-1.31) and nonusers (OR 1.54, 95% CI 1.44-1.64). Interaction with age did not significantly impact the relationship between quinolone use and Achilles injury; however, older quinolone users had a slightly higher relative risk of injury than nonusers versus younger patients. Furthermore, the youngest group of patients had similarly elevated relative risk for injury with quinolone use as did the elderly. CONCLUSION: Although quinolone use increases the risk of Achilles tendon injury, the absolute risk increase is minimal, especially when compared with similar morbidity patients taking other nonquinolone antibiotics. In relatively healthy populations, such as the one studied here, quinolone use may not make a clinically significant contribution to risk of Achilles tendon injury, at any age range, among those in need of such drugs. PMID- 29972706 TI - Retrospective study showed that palpitations with tachycardia on admission to a paediatric emergency department were related to cardiac arrhythmias. AB - AIM: This retrospective study reviewed the prevalence and long-term prognosis of children aged 0-18 with palpitations who were admitted to the emergency department (ED) of an Italian paediatric hospital. METHODS: We examined all admissions to the ED of the IRCCS Burlo Garofolo between January 2009 and December 2015 by selecting triage diagnoses of palpitations. The hospital discharge cards were reviewed to assess vital parameters, physical examinations, diagnostic tests, cardiology consultations and final diagnoses. RESULTS: Of the 142 803 patients who attended our ED for any reason, 96 (0.07%) complained of palpitations. Despite this low prevalence, it was noteworthy that 13.5% had a real underlying arrhythmic cause and needed medical assistance. Over half (52.1%) were women and the mean age was 12.7 years. At the long-term follow-up, at a mean of 47 +/- 23 months, 53.8% of patients with a cardiac arrhythmia had received medical therapy and 46.1% had undergone trans-catheter ablation for supraventricular tachycardia. A heart rate above 146 beats per minute or palpitations for more than an hour was statistically related to a cardiac arrhythmia. CONCLUSION: Palpitations were an infrequent cause of admission to our ED, but 13.5% who displayed them had an underlying cardiac arrhythmia. PMID- 29972707 TI - Prevalence of psychosocial impairment in temporomandibular disorder patients: A systematic review. AB - BACKGROUND: Several studies have described high levels of psychosocial disorders in patients with temporomandibular disorders (TMD), but an estimate of their prevalence in populations of TMD patients has never been assessed systematically. OBJECTIVE: To conduct a systematic review of the literature on the prevalence of research diagnostic criteria for TMD (RDC/TMD) Axis II findings in TMD patients. METHODS: Search for articles was carried out by two independent researchers to retrieve papers published after 1992. Inclusion was reserved to observational studies with a minimum sample size of 100 individuals, which used RDC/TMD diagnostic protocol. Quality assessment was performed with the adoption of the methodological evaluation of observational research (MORE). RESULTS: A total of 1186 citations were obtained from search strategy, but only 14 filled the inclusion criteria. Included papers reported somatisation, depression and/or pain related disability prevalence or scores from populations of 12 different countries. A broad range in the prevalence of moderate-to-severe somatisation in patients with TMD was observed, ranging from 28.5% to 76.6%. Similar results were found for depression, with moderate-to-severe levels in 21.4%-60.1% of patients. Finally, most patients were rated as grade I or II of the Graded Chronic Pain Scale, whereas high pain-related impairment was present in 2.6% to 24% of the individuals. CONCLUSION: The prevalence of severe-to-moderate somatisation and depression was high in TMD patients, while severe physical impairment was not commonly reported. PMID- 29972708 TI - Anxiety and malocclusion are associated with temporomandibular disorders in adolescents diagnosed by RDC/TMD. A cross-sectional study. AB - BACKGROUND: Temporomandibular Disorders (TMD) is a multifactorial condition, which could be associated to occlusal and psychological factors, such as anxiety. OBJECTIVE: Investigate if anxiety and malocclusion are associated with the prevalence of TMD in adolescents. METHODS: To ensure a population-based representative sample, 934 adolescents aged 10 to 14 years old from Curitiba-PR, Brazil were randomly selected and examined according to Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) and malocclusion by a single calibrated examiner (Kappa > 0.80). Anxiety was assessed according to trait anxiety (STAI-T), categorised as high, moderate and low levels. For occlusal exam, it was considered: Angel's molar relationship, anterior and posterior crossbite, excessive overjet, open and deep bite. The associations were analysed by the crude and adjusted prevalence ration (RPa ) of TMJ, calculated by a Poisson multivariate regression with robust variance (alpha = 0.05). RESULTS: The prevalence of at least one type of malocclusion was found in 52.3%. Anxiety was found in high level (12.2%), moderate (70.4%) and low (17.5%). Presence of high anxiety was significantly associated with the prevalence of TMD symptoms (RPa = 4.06, P < 0.001), as well as the prevalence of myofascial pain (RPa = 24.78; P < 0.001) and prevalence of disc displacement with reduction (RPa = 11.08, P < 0.001). Adolescents Class II had higher prevalence of myofascial pain (Class II RPa = 1.73; P < 0.015) than adolescents Class I. Adolescents Class III presented higher prevalence of myofascial pain (PRa 2.53; P = 0.004) than adolescents Class I. CONCLUSION: Anxiety is strongly associated with TMD in adolescents. Presence of Class II or III is associated with higher prevalence of myofascial pain in adolescentsPLESAE check and approve the edit made in the article title. PMID- 29972709 TI - Periodontal treatment limits platelet activation in patients with periodontitis-a controlled-randomized intervention trial. AB - AIM: Periodontitis results in platelet activation and enhanced risk for cardiovascular disease. As it is currently unknown whether periodontal treatment reverses platelet hyper-reactivity, we aimed to investigate the role of periodontal treatment on platelet activation. MATERIALS AND METHODS: In a prospective controlled therapeutic trial, 52 patients were enrolled and randomly selected for periodontal treatment or monitored without treatment for 3 months. Patient blood was analysed by flow cytometry for platelet activation markers and by light transmission aggregometry for platelet aggregation in response to pro thrombotic stimuli. RESULTS: In this study, platelet activation in the control group aggravated over the observation period of 3 months, whereas patients that underwent periodontal treatment showed unchanged levels of platelet activation, measured by surface expression of CD62P, CD40L, generation of reactive oxygen production, activation of GPIIb/IIIa and fibrinogen binding. Moreover, platelet turnover, measured by platelet RNA content and platelet aggregation in response to collagen, differed significantly between patients that were treated and those who were untreated. CONCLUSIONS: Subgingival debridement reduces the risk of aggravated platelet activation and therefore might potentially diminish subsequent diseases such as cardiovascular disease in periodontal patients. PMID- 29972710 TI - Identifying key components for a psychological intervention for people with vitiligo - a quantitative and qualitative study in the United Kingdom using web based questionnaires of people with vitiligo and healthcare professionals. AB - BACKGROUND: Psychological interventions are recommended as part of routine management of vitiligo. However, the development and effectiveness of such interventions have been rarely addressed. This study aimed to identify key components for a psychological intervention for people with vitiligo. This is the first time perspectives of people with vitiligo, and healthcare professionals (HCPs) have been directly explored to inform intervention content and delivery. OBJECTIVES: To identify 1. which psychological difficulties are highlighted that can be targeted by an intervention; 2. what is important in terms of intervention content and delivery. METHODS: Web-based questionnaires containing both quantitative and qualitative items were completed by people with vitiligo and HCPs. Questionnaires collected data from people with vitiligo on demographics, clinical features, psychological difficulties and priority areas for psychological interventions, including ideas on delivery and content. HCPs questionnaires collected data on psychological difficulties reported, use of psychological interventions and suitability within health services. Quantitative data were analysed using descriptive statistics, and qualitative data utilized thematic framework analysis. RESULTS: A total of 100 people with vitiligo (66% female, 92% Caucasian) and 39 HCPs (54% dermatologists) participated. Key areas of difficulty were the impact of vitiligo, coping, issues with appearance/body image and the sun, and medical interactions. Vitiligo on sensitive sites was associated with more psychological impact. Interventions directed at increasing acceptance, confidence and self-esteem, as well as managing embarrassment, were important. These issues could be managed through interventions such as cognitive behavioural therapy, mindfulness and acceptance and commitment therapy. Both people with vitiligo and HCPs favoured individual interventions. CONCLUSION: Vitiligo has significant impact, requiring ongoing psychosocial support. There is a strong need for a psychoeducational intervention with focus on acceptance and managing social impact. The results of this study are the first steps to informing the development of a patient-centred psychological intervention. PMID- 29972711 TI - SOD2 is upregulated in periodontitis to reduce further inflammation progression. AB - OBJECTIVES: Periodontitis is a highly prevalent chronic inflammatory disease that results in destruction of tooth-supporting structures followed by tooth-loss. Until now, periodontitis has been regarded to be initiated by bacterial infection followed by aberrant host response. Although increasing evidence suggests a strong association between oxidative stress and periodontitis, precise molecular mechanism has been left unanswered. In this study, we investigated roles of SOD2, the main antioxidant enzyme maintaining reactive oxygen species (ROS) homeostasis, under inflammatory conditions. METHODS: We computationally analyzed SOD2 expression in periodontitis. To confirm this data, immunoblot assay was performed with samples from periodontitis patients. The cellular mechanism of change in SOD2 expression was identified through immunoblot assay and immunofluorescence. To evaluate the molecular function of SOD2, we generated SOD2 deficient cells by utilizing the CRISPR/Cas9 system. RESULTS: We first determined that SOD2 expression was significantly increased in periodontitis. We also confirmed that SOD2 expression was upregulated through the NF-kappaB pathway when the inflammatory signal was stronger and extended. Gene manipulation against SOD2 through the CRISPR/Cas9 system showed that the absence of SOD2 increased production of NLRP3 inflammasome components. CONCLUSIONS: Our study demonstrates that intracellular SOD2 has a protective role by suppressing NLRP inflammasome caspase-1-IL-1beta axis under inflammatory conditions. PMID- 29972712 TI - A randomized, double-blind controlled study of the efficacy and safety of topical solution of 0.25% finasteride admixed with 3% minoxidil vs. 3% minoxidil solution in the treatment of male androgenetic alopecia. AB - BACKGROUND: The synergism of combined use between oral finasteride and topical minoxidil has been established in treating androgenetic alopecia among men. However, the concern regarding adverse effects of finasteride use has been rising. OBJECTIVE: To compare the efficacy and safety of topical solution of 0.25% finasteride admixed with 3% minoxidil vs. 3% minoxidil solution in men with androgenetic alopecia. METHODS: Forty men aged 18-60 years with androgenetic alopecia were randomized to 24 weeks of treatment with a finasteride/minoxidil or minoxidil solution twice daily. Primary efficacy endpoint was the change from baseline in hair density and hair diameter at week 24. Secondary endpoints included global photographic assessment by treatment-blinded investigators and subjects. Changes in plasma dihydrotestosterone levels and adverse events were recorded. RESULTS: At week 24, the combined solution of finasteride and minoxidil was significantly superior to minoxidil alone in improvements of hair density, hair diameter and global photographic assessment (all P < 0.05). About 90% of patients treated with the combined solution experienced moderate to marked improvement. The combined solution also had minimal effect on plasma dihydrotestosterone levels, approximately 5% reduction. There were also no systemic adverse events reported by patients in both groups. CONCLUSION: Treatment with topical solution of 0.25% finasteride admixed with 3% minoxidil was significantly superior to 3% minoxidil solution for promoting hair growth in male androgenetic alopecia, and well tolerated. PMID- 29972713 TI - A Far-Red Fluorescent DNA Binder for Interaction Studies of Live Multidrug Resistant Pathogens and Host Cells. AB - Transgene expression of green fluorescent protein (GFP) has facilitated the spatiotemporal investigation of host-pathogen interactions; however, introduction of the GFP gene remains challenging in drug-resistant bacteria. Herein, we report a novel far-red fluorescent nucleic acid stain, 6-TramTO-3, which efficiently labels bacteria through a DNA binding mode without affecting growth and viability. Exemplarily, we stained Klebsiella pneumoniae, a major threat to hospitalized patients, and deciphered divergent interaction strategies of antibiotic-resistant and antibiotic-sensitive Klebsiella strains with immune cells. 6-TramTO-3 constitutes an off-the-shelf reagent for real-time analysis of bacterial infection, including strains for which the use of genetically encoded reporters is not feasible. Eventually, our approach may aid the development of strategies to combat a major worldwide health threat: multidrug-resistant bacteria. PMID- 29972714 TI - Thymosin beta4 suppresses CCl4 -induced murine hepatic fibrosis by down regulating transforming growth factor beta receptor-II. AB - BACKGROUND: The present study aimed to clarify the effects of thymosin beta4 (Tbeta4) on CCl4 -induced hepatic fibrosis in mice and to further explore the underlying mechanisms. METHODS: Expression of Tbeta4 in fibrotic liver tissues was assessed by a quantitative real time-reverse transcriptase polymerase chain reaction and immunohistochemistry. The effects of intraperitoneal adeno associated virus-Tbeta4 (AAV-Tbeta4) on CCl4 -induced hepatic fibrosis were observed by the evaluation of collagen deposition, hepatic stellate cell (HSC) activation and pro-fibrotic cytokine expression. In vitro tests with HSCs and hepatocytes were performed to confirm the effects of Tbeta4. RESULTS: The expression of Tbeta4 was down-regulated in fibrotic mouse livers but was rapidly up-regulated by CCl4 -induced acute injury. AAV-Tbeta4 pre-treatment significantly attenuated liver injury, collagen deposition, HSC activation and pro-fibrotic cytokine over-expression, such as transforming growth factor beta1 (TGF-beta1), platelet-derived growth factor B (PDGF-B), connective tissue growth factor (CTGF) and plasminogen activator inhibitor-1 (PAI-1) in CCl4 -intoxicated mouse livers. In vitro experiments showed that Tbeta4 suppressed HSC proliferation, blunted TGF-beta1-induced HSC activation and reduced TGF-beta1 induced TGF-beta1, PDGF-B, CTGF and PAI-1 expression in both HSCs and hepatocytes. Ectopic Tbeta4 ameliorated the over-expression of TGF-beta receptor II (TGF-betaRII) in the fibrotic mouse livers. Exogenous Tbeta4 down-regulated TGF-betaRII expression, whereas neutralizing endogenous extracellular Tbeta4 with a specific antibody up-regulated TGF-betaRII expression in cultured HSCs and hepatocytes. CONCLUSIONS: Tbeta4 possesses anti-fibrotic activity in the liver, which is attributable, at least partly, to down-regulating TGF-betaRII and thereby blunting TGF-beta1-mediated fibrogenetic signaling in both HSCs and hepatocytes. PMID- 29972715 TI - A loss of a velocity-duration trade-off impairs movement precision in patients with cerebellar degeneration. AB - Current theories discussing the role of the cerebellum have been consistently pointing towards the concept of motor learning. The unavailability of a structure for motor learning able to use information on past errors to change future movements should cause consistent metrical deviations and an inability to correct them; however, it should not boost "motor noise." However, dysmetria, a loss of endpoint precision and an increase in endpoint variability ("motor noise") of goal-directed movements is the central aspect of cerebellar ataxia. Does the prevention of dysmetria or "motor noise" by the healthy cerebellum tell us anything about its normal function? We hypothesize that the healthy cerebellum is able to prevent dysmetria by adjusting movement duration such as to compensate changes in movement velocity. To address this question, we studied fast goal directed index finger movements in patients with global cerebellar degeneration and in healthy subjects. We demonstrate that healthy subjects are able to maintain endpoint precision despite continuous fluctuations in movement velocity because they are able to adjust the overall movement duration in a fully compensatory manner ("velocity-duration trade-off"). We furthermore provide evidence that this velocity-duration trade-off accommodated by the healthy cerebellum is based on a priori information on the future movement velocity. This ability is lost in cerebellar disease. We suggest that the dysmetria observed in cerebellar patients is a direct consequence of the loss of a cerebellum-based velocity-duration trade-off mechanism that continuously fine-tunes movement durations using information on the expected velocity of the upcoming movement. PMID- 29972717 TI - Report of the International Symposiums at the 95th Congress of Japan Gastroenterological Endoscopy Society in Tokyo, 2018. PMID- 29972718 TI - Barriers to adequate first aid for paediatric burns at the scene of the injury. AB - ISSUE ADDRESSED: The recommended first aid for burns, consisting of 20 minutes of cool running water (CRW) delivered within three hours of the injury, offers a simple yet effective means of improving health outcomes. The aim of this study was to determine patient and injury characteristics associated with inadequate CRW therapy among children with thermal burns, with the goal of identifying populations at greatest risk of undertreatment. METHODS: A cross-sectional study was performed on children treated at a large tertiary paediatric burns centre. First aid was evaluated as either "adequate" or "inadequate", and then descriptive analyses were conducted to examine differences between the groups in age, ethnicity, location and socioeconomic status, among others. RESULTS: From 2013 to 2016, the families of 2522 patients were interviewed. Overall, 31.3% of children received adequate CRW at the scene of the injury. Provision of adequate CRW did not significantly differ with sex, ethnicity or nationality. Factors that were associated with inadequate first aid included very young age and early adolescence (P < 0.001), rural or remote location (P = 0.045), low socioeconomic status (P = 0.030), radiant heat and flame burns (P < 0.001), as well as burns occurring at recreational sites, on farm/trade/industrial properties and in the street (P = 0.001). CONCLUSIONS: Although most burns occurred in close proximity to sources of CRW, first aid was poor across all demographics. The highest levels of undertreatment were found in children aged 0-2, adolescents aged 15-16, those living rurally or remotely, and the socioeconomically disadvantaged. SO WHAT?: The study highlights the need for improved public education of first aid for burn injuries. PMID- 29972716 TI - Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations. AB - Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged >=20 years) with NSCLC previously treated with >=1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, alpha = 0.05, beta = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received >=1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations. PMID- 29972719 TI - Antimicrobial activity and phytochemical screening of Alpinia malaccensis (Ran kiriya) against food-borne bacteria. AB - AIMS: Investigation of antimicrobial activity and phytochemicals of Alpinia malaccensis (Ran-kiriya) against foodborne bacteria Staphyloccocus aureus, Listeria monocytogenes, Escherichia coli and Salmonella Typhimurium. METHODS AND RESULTS: Antibacterial activity was tested on the above four foodborne bacteria using agar disc diffusion and broth dilution assay. Alpinia malaccensis rhizome extract chemical composition was determined using gas chromatography-mass spectrometry (GCMS). Active compound was identified using thin-layer chromatography (TLC) and confirmed by nuclear magnetic resonance spectroscopy (NMR). The A. malaccensis rhizome hexane crude extract showed significantly (P < 0.05) higher diameter of inhibition (DIZ) 40 +/- 0.52, 38 +/- 0.96 and 36 +/- 1.45 mm for S. aureusSA113, MSSASS25D and methicillin-resistant S. aureus compared with other tested bacteria. The minimum inhibition concentration and minimum bactericidal concentration were 0.625 and 5 mg ml-1 for S. aureus 113. TLC showed DIZ 39 +/- 0.12 mm only for one fraction. The crude extract showed 82.87% a major compound by GCMS which is the active fraction. This purified active fraction was confirmed as 1'acetoxychavicol acetate (1'ACA) by NMR. No significantly different inhibition was observed for crude extract and purified compound. CONCLUSIONS: Bioactive 1'ACA of A. malaccensis showed strong antibacterial activity against S. aureus strains including MRSA strain. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first to identify 1'ACA from A. malaccensis. The crude or purified compound could potentially be developed as antimicrobials. PMID- 29972721 TI - Anorectal symptoms during pregnancy and postpartum: a prospective cohort study. AB - AIM: The aim was to determine the prevalence and risk factors of anal symptoms prepartum and postpartum. METHOD: A prospective observational cohort study was carried out in Ghent University Hospital, Belgium. Ninety-four pregnant women between their 19th and 25th week of pregnancy were included. An anal symptom questionnaire was filled in at four different times: in the second and third trimester, immediately postpartum and 3 months postpartum. Descriptive data were obtained from patient files. A proctological diagnosis was presumed on the basis of combined symptoms (i.e. rectal bleeding, anal pain and swelling). Constipation was defined by the Rome III criteria. Risk factors were identified using multivariate analysis. RESULTS: Sixty-eight per cent of the patients developed anal symptoms. The most prevalent symptom was anal pain. Constipation was reported by 60.7% during the study period. Seven women (7.9%) suffered from faecal incontinence. The most prevalent diagnoses were haemorrhoidal thrombosis (immediately postpartum), haemorrhoidal prolapse (in the third trimester and immediately postpartum) and anal fissure (not episode related). The two independent risk factors for anal complaints were constipation, with a 6.3 odds ratio (95% CI 2.08-19.37), and a history of anal problems, with a 3.9 odds ratio (95% CI 1.2-13). The Bristol Stool Chart was shown to be a reliable indicator in pregnancy and postpartum as significant correlations were observed in all study periods. CONCLUSION: Two-thirds of pregnant women have anal symptoms during pregnancy and postpartum, especially haemorrhoidal complications and anal fissure. The most important risk factor is constipation. The prevention of constipation in pregnant women is therefore highly recommended. PMID- 29972722 TI - Activities and specificities of CRISPR/Cas9 and Cas12a nucleases for targeted mutagenesis in maize. AB - CRISPR/Cas9 and Cas12a (Cpf1) nucleases are two of the most powerful genome editing tools in plants. In this work, we compared their activities by targeting maize glossy2 gene coding region that has overlapping sequences recognized by both nucleases. We introduced constructs carrying SpCas9-guide RNA (gRNA) and LbCas12a-CRISPR RNA (crRNA) into maize inbred B104 embryos using Agrobacterium mediated transformation. On-target mutation analysis showed that 90%-100% of the Cas9-edited T0 plants carried indel mutations and 63%-77% of them were homozygous or biallelic mutants. In contrast, 0%-60% of Cas12a-edited T0 plants had on target mutations. We then conducted CIRCLE-seq analysis to identify genome-wide potential off-target sites for Cas9. A total of 18 and 67 potential off-targets were identified for the two gRNAs, respectively, with an average of five mismatches compared to the target sites. Sequencing analysis of a selected subset of the off-target sites revealed no detectable level of mutations in the T1 plants, which constitutively express Cas9 nuclease and gRNAs. In conclusion, our results suggest that the CRISPR/Cas9 system used in this study is highly efficient and specific for genome editing in maize, while CRISPR/Cas12a needs further optimization for improved editing efficiency. PMID- 29972723 TI - Unilateral vs bilateral sphenopalatine artery ligation in adult unilateral epistaxis: A comparative retrospective study of 83 cases. PMID- 29972720 TI - FOXA1 levels are decreased in pleural breast cancer metastases after adjuvant endocrine therapy, and this is associated with poor outcome. AB - Estrogen receptor-alpha (ERalpha)-positive breast cancer is often treated with antihormonal regimens. However, resistance to treatment is common, leading to metastatic disease. ERalpha activity requires the functional involvement of pioneer factors FOXA1 and GATA3, which enable ERalpha-chromatin binding and are crucial for ERalpha-driven cell proliferation. FOXA1 was found increased in metastatic breast cancers in relation to the primary tumor, but a comprehensive clinical assessment thereof, in relation to different metastatic sites and endocrine therapy usage, is currently lacking. Prior cell line-based reports, however, have revealed that FOXA1 is required for tamoxifen-resistant tumor cell proliferation. We studied expression levels of ERalpha, GATA3, and FOXA1 by immunohistochemistry in samples from both primary tumors and various metastatic sites. For all factors, expression levels varied between the metastatic sites. For pleural metastases, strong variation was found in FOXA1 and GATA3 levels. Although GATA3 levels remained unaltered between primary breast cancer and pleural metastases, FOXA1 levels were reduced exclusively in metastases of patients who received endocrine therapies in the adjuvant setting, even though ERalpha was still expressed. Importantly, decreased FOXA1 levels in pleural metastases correlated with hormone irresponsiveness in the palliative setting, while no such correlation was found for GATA3. With this, we show divergent clinical correlations of the two ERalpha pioneer factors FOXA1 and GATA3 in metastatic breast cancer, where endocrine therapy resistance was associated with decreased FOXA1 levels in pleural metastases. PMID- 29972724 TI - Seed ecology of the geophyte Conopodium majus (Apiaceae), indicator species of ancient woodland understories and oligotrophic meadows. AB - Conopodium majus is a geophyte with pseudomonocotyly, distributed in Atlantic Europe. It is an indicator of two declining European habitats: ancient woodland understories and oligotrophic hay meadows. Attempts to reintroduce it by seed have been hindered by scarce seedling emergence and limited knowledge of its seed biology. Micro-CT scanning was used to assess pseudomonocotyly. Embryo growth and germination were studied in the laboratory and the field, using dissection and image analysis. The effects of temperature, light, nitrate and GA3 on germination were tested. Seed desiccation tolerance was investigated by storage at different RHs and by drying seeds at different stages of embryo growth. Seeds possess morphological but not physiological dormancy. Embryo growth and germination were promoted by temperatures between 0 and 5 degrees C, arrested above 10 degrees C, and indifferent to alternating temperatures, light, nitrate and GA3 . Pseudomonocotyly appears to result from cotyledon fusion. While seeds tolerated drying to 15% RH and storage for 1 year at 20 degrees C, viability was lost when storage was at 60% RH. Seeds imbibed at 5 degrees C for 84 days had significant internal embryo growth but were still able to tolerate drying to 15% RH. Reproduction by seed in C. majus follows a strategy shared by geophytes adapted to deciduous temperate forests. The evolution of fused cotyledons may enable the radicle and the hypocotyl to reach deeper into the soil where a tuber can develop. The embryo is capable of growth within the seed at low temperatures so that germination is timed for early spring. PMID- 29972726 TI - Plastics of the Future? The Impact of Biodegradable Polymers on the Environment and on Society. AB - In recent years the littering of plastics and the problems related to their persistence in the environment have become a major focus in both research and the news. Biodegradable polymers like poly(lactic acid) are seen as a suitable alternative to commodity plastics. However, poly(lactic acid) is basically non degradable in seawater. Similarly, the degradation rate of other biodegradable polymers also crucially depends on the environments they end up in, such as soil or marine water, or when used in biomedical devices. In this Minireview, we show that biodegradation tests carried out in artificial environments lack transferability to real conditions and, therefore, highlight the necessity of environmentally authentic and relevant field-testing conditions. In addition, we focus on ecotoxicological implications of biodegradable polymers. We also consider the social aspects and ask how biodegradable polymers influence consumer behavior and municipal waste management. Taken together, this study is intended as a contribution towards evaluating the potential of biodegradable polymers as alternative materials to commodity plastics. PMID- 29972725 TI - Explanations for less small fibre neuropathy in South Asian versus European subjects with type 2 diabetes in the UK. AB - BACKGROUND: Low foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans. METHODS: In a cross-sectional, population-based study, age- and sex-matched South Asians (n = 77) and Europeans (n = 78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage. RESULTS: Corneal nerve fibre length (22.0 +/- 7.9 vs. 19.3 +/- 6.3 mm/mm2 ; P = 0.037), corneal nerve branch density (geometric mean (range): 60.0 (4.7 246.2) vs. 46.0 (3.1-129.2) no./mm2 ; P = 0.021) and heart rate variability (geometric mean (range): 7.9 (1.4-27.7) vs. 6.5 (1.5-22.0); P = 0.044), were significantly higher in South Asians vs. Europeans. All other neuropathy measures did not differ, except for better sural nerve amplitude in South Asians (geometric mean (range): 10.0 (1.3-43.0) vs. 7.2 (1.0-30.0); P = 0.006). Variables with the greatest impact on attenuating the P value for age- and HbA1C adjusted ethnic difference in corneal nerve fibre length (P = 0.032) were pack years smoked (P = 0.13), BMI (P = 0.062) and triglyceride levels (P = 0.062). CONCLUSIONS: South Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers. PMID- 29972727 TI - Impact of bitter taste receptor phenotype upon clinical presentation in chronic rhinosinusitis. AB - BACKGROUND: Genetic variation of the bitter taste receptor T2R38 has been associated with recalcitrant chronic rhinosinusitis (CRS). Specific T2R38 polymorphisms, correlating with bitter taste sensitivity to phenylthiocarbamide (PTC), have been identified as an independent risk factor for surgical intervention in CRS patients without polyps; however, the exact role of PTC tasting ability in clinical practice remains unknown. In this investigation we characterize PTC taste sensitivity in a tertiary care rhinology practice with pertinent clinical measures of disease and quality of life (QOL). METHODS: Adult CRS patients were prospectively assessed for their ability to taste PTC and categorized as nontasters, tasters, or supertasters. Objective taste was assessed with strips for bitter, sweet, sour, and salty, whereas olfactory testing was measured with Sniffin' Sticks. Correlation was performed between PTC tasting ability and patient demographics, endoscopy scores, validated QOL surveys, and both subjective and objective measures of taste and olfaction. RESULTS: Sixty seven patients were enrolled. Fifty-two percent were identified as nontasters, 34% as tasters, and 13% as supertasters. Nontasters were more likely to be non Hispanic (p = 0.018), white (p = 0.027), without nasal polyposis (p = 0.004), and nonasthmatics (p = 0.019). There were no other statistical differences in patients' demographics, QOL measures, and subjective or objective olfactory and taste scores when compared with patients' oral PTC-sensing ability. CONCLUSION: Oral PTC-sensing ability may serve as a convenient marker of increased disease severity in white CRS patients without polyps and vary among regional populations. PTC tasting ability appears to provide unique phenotypic information not obtained using other subjective or objective measures of smell and taste. PMID- 29972728 TI - Laryngeal dysplasia and narrow band imaging: Secondary analysis of published data supports the role in patient follow-up. AB - BACKGROUND: Clinicians have recognised the role of narrow band imaging (NBI) in the management of head and neck cancer in several studies. However, a recent systematic review was unable to pool the data on diagnostic efficacy in this setting owing to the heterogeneity in the published data. METHODS: Secondary analysis of data, utilising Bayes' theorem, from meta-analyses and randomised trials. RESULTS: In patients with a histological diagnosis of mild dysplasia who show no abnormalities on NBI, the post-test probability of malignancy is estimated to be 2.3%, compared to 10.3% with conventional white light imaging (WLI). For severe dysplasia, similar post-test probabilities after NBI and WLI are estimated to be 8.0% and 29.7%, respectively. Post-test probabilities in this setting indicate the chance of missing malignancy following a negative NBI or WLI in patients who undergo no further intervention. This study also provides a nomogram designed for use in this setting. CONCLUSIONS: This study identifies the evidence base for use of NBI in the follow-up for laryngeal dysplasia. PMID- 29972729 TI - Revision stapes surgery: A review of 102 cases. PMID- 29972730 TI - Pregnancy and lupus erythematosus - a therapeutic challenge. PMID- 29972731 TI - Gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma - where do we stand? PMID- 29972732 TI - Microsatellite instability in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus: a retrospective study. AB - AIM: To analyze the loss of mismatch repair (MMR) system protein expression in metaplasia-dysplasia-adenocarcinoma sequence of Barrett esophagus (BE). METHODS: This study retrospectively analyzed the data from 70 patients with pathohistological diagnosis of BE or esophageal adenocarcinoma (EAC) treated at the Clinical Department of Pathology and Cytology, University Hospital Center Zagreb, from January 2009 to January 2011. Patients were divided into three groups: BE without dysplasia (22 patients), BE with dysplasia (37 patients), and EAC (11 patients). Immunohistochemical expression of MutL homologue 1 (MLH1), MutS homologue 2 (MSH2), postmeiotic segregation increased 2 (PMS2), and MutS homologue 6 (MSH6) of DNA MMR system was measured and compared with tumor protein p53 expression. RESULTS: A total of 81.8% and 81.8% patients with EAC, 32.4% and 35.1% patients with dysplasia, and 50% and 54.5% patients without dysplasia had loss of MLH1 and PMS2 expression, respectively. Patients with EAC and patients with dysplasia did not have loss of MSH2 and MSH6 expression, and 18.2% patients without dysplasia had loss of MSH2 and MSH6 expression. There was a strong positive correlation between MLH1 and PMS2 expression (Spearman rho 0.97; P<0.001) and between MSH2 and MSH6 expression (Spearman rho 0.90, P<0.001) in the entire sample and in all BE groups. No significant correlations of MLH1 and PMS2 with p53 expression were found, except in dysplasia group (phi 0.402, P=0.030 for MSH1; phi 0.371, P=0.042 for PMS2). CONCLUSION: Although we demonstrated considerable loss of MLH1 and PMS2 expression in BE-associated carcinoma sequence, due to the retrospective study design and low number of patients we cannot conclude that MLH1 and PMS2 can be used as biomarkers for patient surveillance and therapy-making decisions. Oxford Centre for Evidence-based Medicine level of evidence: 3. PMID- 29972733 TI - Plasminogen activator inhibitor-1 activity and long-term outcome in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention: a prospective cohort study. AB - AIM: To determine the relationship between plasminogen activator inhibitor-1 (PAI 1) activity rise during the first 24 hours of ST-elevation myocardial infarction (STEMI) treatment and death after 5 years. METHODS: From May 1, 2009 to March 23, 2010, 87 STEMI patients treated with primary percutaneous coronary intervention (PCI) at the Sestre Milosrdnice University Hospital Center were consecutively enrolled in prospective single-center cohort study. PAI-1 activity was determined on admission and 24 hours later. The primary end-point was death after 5 years. The predictive value of PAI-1 activity variables as biomarkers of death was assessed using receiver operating characteristic (ROC) curve, independent predictors of death were assessed using multivariate Cox regression, and covariates independently related to higher PAI-1 activity rise were assessed using linear regression. RESULTS: Two patients died during the hospital treatment and 11 during the follow-up. PAI-1 activity rise had the largest area under curve (0.748) for predicting death rate (optimal cut-off point 3.7 U/mL, sensitivity 53.8%, specificity 90.5%). Patients with PAI-1 activity rise higher than 3.7 U/mL had significantly higher mortality (P<0.001). Kaplan-Meier survival curve diverged within the first year after STEMI. Independent predictors of death were PAI-1 rise and final Thrombolysis in Myocardial Infarction flow. PAI-1 activity rise was independently related to heart failure, thrombus aspiration, and body weight. CONCLUSION: PAI-1 activity rise higher than 3.7 U/mL is associated with higher 5-year death rate in STEMI patients treated with primary PCI. PMID- 29972734 TI - Mortality patterns in Southern Adriatic islands of Croatia: a registry-based study. AB - AIM: To investigate the mortality patterns on the Southern Adriatic islands of Croatia and compare them with those in two, mainly coastal, mainland counties. METHODS: In this registry-based study we used the official mortality register data to analyze the mortality patterns on seven Croatian islands (Brac, Hvar, Korcula, Lastovo, Mljet, Solta, and Vis) and Peljesac peninsula in the 1998-2013 period and calculated the average lifespan, life expectancy, and standardized mortality ratios (SMR). We compared the leading causes of death with those in the mainland population of two southernmost Croatian counties. RESULTS: The average lifespan of the island population was 3-10 years longer for men and 2-7 years longer for women than that on the mainland. All-cause SMRs were significantly lower for both men and women on Korcula, Brac, Mljet, and Peljesac but significantly higher for women on Solta (1.22; 95% confidence intervals 1.07 1.38). The leading causes of death on the islands were cardiovascular diseases, with higher percentages in men and lower in women in comparison with those on the mainland. There were no substantial differences in the life expectancy at birth. CONCLUSIONS: Despite longer lifespan, lack of differences in life expectancy at birth suggests that the recent generations of islanders no longer show beneficial mortality patterns, possibly due to diminishing adherence to the Mediterranean diet and lifestyle. Restoring the traditional lifestyles is a public health priority, with the ultimate aim of reducing inequalities and improving the health of island inhabitants. PMID- 29972735 TI - Adverse drug reaction reporting and development of pharmacovigilance systems in Bosnia and Herzegovina, Croatia, Serbia, and Montenegro: a retrospective pharmacoepidemiological study. AB - AIM: To compare individual case safety reports (ICSR) rates and characteristics between Croatia, Serbia, Montenegro, and Bosnia and Herzegovina (B&H). METHODS: This retrospective pharmacoepidemiological study used the data from ICSR received by the Agency for Medicines and Medical Devices in B&H in 2011-2016. The number, characteristics, and sources of reports, suspected drugs, and patient characteristics were analyzed. The results were compared with the publicly available data from Croatia, Serbia, and Montenegro. RESULTS: The number of reported adverse drug reactions per one million of inhabitants was lowest in B&H and highest in Croatia. There were significant differences in reporter characteristics, sources of reports, and the percentage of missing data in ICSR, while the Anatomical Therapeutic Chemical product classes, patient's sex, and adverse drug reaction System Organ Classes were similar. CONCLUSION: Despite the historical and geographical vicinity of B&H and its neighboring countries, there were significant differences in indicators of pharmacovigilance development. PMID- 29972736 TI - Knowledge-for-data trade at the interface between precision medicine and person centered care. PMID- 29972737 TI - Experimental Measurement of Surface Charge Effects on the Stability of a Surface Bound Biopolymer. AB - Quantitative experimental studies of the thermodynamics with which biopolymers interact with specific surfaces remain quite limited. In response, here we describe experimental and theoretical studies of the change in folding free energy that occurs when a simple biopolymer, a DNA stem-loop, is site specifically attached to a range of chemically distinct surfaces generated via self-assembled monolayer formation on a gold electrode. Not surprisingly, the extent to which surface attachment alters the biopolymer's folding free energy depends strongly on the charge of the surface, with increasingly negatively charged surfaces leading to increased destabilization. A simple model that considers only the excluded volume and electrostatic repulsion generated by the surface and models the ionic environment above the surface as a continuum quantitatively recovers the observed free energy change associated with attachment to weakly charged negative surfaces. For more strongly charged negative surfaces a model taking into account the discrete size of the involved ions is required. Our studies thus highlight the important role that electrostatics can play in the physics of surface-biomolecule interactions. PMID- 29972738 TI - Effects of adipokine zinc-alpha2-glycoprotein on adipose tissue metabolism after dexamethasone treatment. AB - Zinc-alpha2-glycoprotein (ZAG) has been demonstrated to play a role in stimulating lipid mobilization under normal conditions. However, further studies are required to determine whether ZAG overexpression can alleviate the reduction in plasma lipid levels under stress conditions. In the present study, we investigated the effects of ZAG on lipometabolism in white adipose tissue (WAT) after dexamethasone (DEX) stimulation using C57BL/6 male mice as the experimental models. Transcript and protein levels of genes associated with the beta adrenoreceptor (beta-AR)/cyclic adenosine monophosphate/protein kinase a (PKA) pathway, lipid mobilization, and energy metabolism were determined by quantitative real-time PCR and western blotting. Plasma levels of non-esterified fatty acid (NEFA) were measured using an automatic biochemical analyzer. Results indicated that plasma NEFA levels were decreased in the DEX group, but NEFA levels were rescued by ZAG overexpression. ZAG overexpression resulted in the upregulation of beta3-AR and phosphorylated PKA protein relative to those of the DEX group. Analysis of lipometabolism showed that protein levels of phosphorylated hormone-sensitive lipase was reduced upon DEX treatment but were restored by ZAG overexpression. For energy metabolism, ZAG significantly upregulated the protein expression of carnitine palmitoyltransferase1a (CPT1a) and cytochrome c oxidase subunit 1 (COX1) relative to those of the DEX group. In conclusion, ZAG could alleviate DEX-induced decrease in plasma NEFA levels and this could be associated with the promoting lipid mobilization in WAT. PMID- 29972739 TI - Benralizumab for the add-on maintenance treatment of patients with severe asthma aged 12 years and older with an eosinophilic phenotype. AB - INTRODUCTION: Asthma is an airway disease characterized by airway inflammation. It is associated with significant morbidity, mortality, and costs to the health care system and society. Eosinophils and interleukin-5 (IL-5) play a key role in the inflammatory response in T-helper 2-high asthma. IL-5 is pivotal for eosinophil development, maturation, and survival in tissues. Asthma severity has been related to both airway and peripheral blood eosinophilia. Areas covered: In this review, we present the pharmacokinetics and pharmacodynamics of benralizumab in addition to efficacy and safety data in the treatment of severe eosinophilic asthma. Expert commentary: Benralizumab is a potent biologic targeting the IL-5 receptor on eosinophils and basophils leading to depletion of target cells in peripheral blood and tissues. It is effective in reducing asthma exacerbations and has an oral corticosteroid-sparing effect in the treatment of asthma patients who are not controlled with medium-to-high-dose inhaled corticosteroids and long acting beta agonists. The side effect profile is similar to placebo with the most reported adverse events being nasopharyngitis and worsened asthma in the pivotal trials. Its long-term safety is currently under investigation. PMID- 29972740 TI - Determining treatment intensity in elderly patients with multiple myeloma. AB - INTRODUCTION: In the majority of cases, multiple myeloma is a disease occurring in elderly patients. In the last decades, a major improvement in myeloma patients' outcome has been achieved with the introduction of several new drugs. However, this positive outcome was less likely to occur in elderly patients. Areas covered: An overall increase of myeloma cases in elderly patients is expected in the next years. This patient population is highly heterogeneous in terms of physiological functions and ability to resist stressing conditions such as myeloma and its treatment. While physicians cannot prevent the stress arising from the disease itself, the intensity of therapeutic approaches can be tuned according to patients' predicted tolerance. In this review, we focus on the assessment of patients' fitness and on available significant data on treatment efficacy and tolerability in elderly patients. Expert commentary: Fit, elderly patients should undergo full-dose therapy to maximize the depth of response, while intermediate and frail patients benefit from reduced-dose regimens in order to avoid toxicity and preserve quality of life. Ongoing trials will provide further evidence to individualize treatment on the basis of geriatric assessment and disease characteristics. PMID- 29972741 TI - Disseminated Cutaneous Blastomycosis. PMID- 29972743 TI - Edoxaban for Cancer-Associated Venous Thromboembolism. PMID- 29972742 TI - Oral Tecovirimat for the Treatment of Smallpox. AB - BACKGROUND: Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed. METHODS: We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo controlled pharmacokinetic and safety trial involving 449 adult volunteers. RESULTS: The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng*hours per milliliter in rabbits and 14,352 ng*hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng*hours per milliliter). No pattern of troubling adverse events was observed. CONCLUSIONS: On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .). PMID- 29972744 TI - Methadone in Primary Care - One Small Step for Congress, One Giant Leap for Addiction Treatment. PMID- 29972745 TI - Moving Addiction Care to the Mainstream - Improving the Quality of Buprenorphine Treatment. PMID- 29972746 TI - Primary Sjogren's Syndrome. PMID- 29972747 TI - Ultrasound-Guided Cannulation of the Subclavian Vein. PMID- 29972748 TI - Primary Care and the Opioid-Overdose Crisis - Buprenorphine Myths and Realities. PMID- 29972749 TI - Immune Checkpoint Blockade in Advanced Renal-Cell Carcinoma. PMID- 29972750 TI - Oligonucleotide Drugs for Transthyretin Amyloidosis. PMID- 29972752 TI - Chronic Occlusion of the Superior Vena Cava. PMID- 29972751 TI - Platelet Counts during Pregnancy. AB - BACKGROUND: Platelet counts of less than 150,000 per cubic millimeter during uncomplicated pregnancies are described as gestational thrombocytopenia if no alternative cause is identified. Platelet counts may be even lower in women with pregnancy-related complications. However, the occurrence and severity of thrombocytopenia throughout pregnancy are not defined. METHODS: We evaluated platelet counts throughout pregnancy in women who delivered at Oklahoma University Medical Center between 2011 and 2014. These platelet counts were compared with those of nonpregnant women who were included in the National Health and Nutrition Examination Survey from 1999 through 2012. RESULTS: Among the 15,723 deliveries that occurred during the study period, 7351 women had sufficient data for our analyses. Of these women, 4568 had uncomplicated pregnancies, 2586 had pregnancy-related complications, and 197 had preexisting disorders associated with thrombocytopenia. Among the women who had uncomplicated pregnancies, the mean platelet count in the first trimester (mean gestation, 8.7 weeks) was 251,000 per cubic millimeter, which was lower than the mean platelet count in the 8885 nonpregnant women (273,000 per cubic millimeter) (P<0.001). At the time of delivery, 9.9% of the women with uncomplicated pregnancies had a platelet count below 150,000 per cubic millimeter. During the course of the uncomplicated pregnancies and deliveries, only 45 women (1.0%) had a platelet count below 100,000 per cubic millimeter. Among the 12 women with uncomplicated pregnancies who had a platelet count below 80,000 per cubic millimeter, only 5 (0.1%, among whom the range of platelet counts was 62,000 to 78,000 per cubic millimeter; median, 65,000) were identified by medical record review as having no alternative cause for the thrombocytopenia. Platelet counts of less than 150,000 per cubic millimeter at the time of delivery were more common among women who had pregnancy-related complications than among women who had uncomplicated pregnancies (11.9% vs. 9.9%, P=0.01). Throughout their pregnancies and deliveries, 59 women (2.3%) with pregnancy-related complications had a platelet count below 100,000 per cubic millimeter, and 31 (1.2%) had a platelet count below 80,000 per cubic millimeter. CONCLUSIONS: Mean platelet counts decreased during pregnancy in all the women, beginning in the first trimester. In women who have a platelet count of less than 100,000 per cubic millimeter, a cause other than pregnancy or its complications should be considered. (Funded by the National Heart, Lung, and Blood Institute.). PMID- 29972754 TI - Chimeric Antigen Receptor Therapy. PMID- 29972755 TI - Will You Forgive Me for Saving You? PMID- 29972753 TI - Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. AB - BACKGROUND: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]*albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/-SD) mNIS+7 at baseline was 80.9+/-41.5 in the patisiran group and 74.6+/-37.0 in the placebo group; the least-squares mean (+/ SE) change from baseline was -6.0+/-1.7 versus 28.0+/-2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/-SD) baseline Norfolk QOL-DN score was 59.6+/-28.2 in the patisiran group and 55.5+/-24.3 in the placebo group; the least-squares mean (+/-SE) change from baseline was -6.7+/-1.8 versus 14.4+/-2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08+/-0.02 m per second with patisiran versus -0.24+/ 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7+/-9.6 versus -119.4+/-14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .). PMID- 29972756 TI - F(ab')2 Fragments to Overcome Daratumumab Interference in Transfusion Tests. PMID- 29972758 TI - A Sickening Tale. PMID- 29972757 TI - Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. AB - BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P<0.001) for the mNIS+7 and -11.7 points (95% CI, -18.3 to -5.1; P<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were five deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (in 3 patients [3%]) and thrombocytopenia (in 3 patients [3%]), with one death associated with one of the cases of grade 4 thrombocytopenia. Thereafter, all patients received enhanced monitoring. CONCLUSIONS: Inotersen improved the course of neurologic disease and quality of life in patients with hereditary transthyretin amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. (Funded by Ionis Pharmaceuticals; NEURO-TTR ClinicalTrials.gov number, NCT01737398 .). PMID- 29972760 TI - A Look Forward - The Frontiers in Medicine Series. PMID- 29972759 TI - Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. AB - BACKGROUND: Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, phase 3 trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. METHODS: A total of 707 patients were randomly assigned in a 2:1 ratio to receive cabozantinib (60 mg once daily) or matching placebo. Eligible patients had received previous treatment with sorafenib, had disease progression after at least one systemic treatment for hepatocellular carcinoma, and may have received up to two previous systemic regimens for advanced hepatocellular carcinoma. The primary end point was overall survival. Secondary end points were progression free survival and the objective response rate. RESULTS: At the second planned interim analysis, the trial showed significantly longer overall survival with cabozantinib than with placebo. Median overall survival was 10.2 months with cabozantinib and 8.0 months with placebo (hazard ratio for death, 0.76; 95% confidence interval [CI], 0.63 to 0.92; P=0.005). Median progression-free survival was 5.2 months with cabozantinib and 1.9 months with placebo (hazard ratio for disease progression or death, 0.44; 95% CI, 0.36 to 0.52; P<0.001), and the objective response rates were 4% and less than 1%, respectively (P=0.009). Grade 3 or 4 adverse events occurred in 68% of patients in the cabozantinib group and in 36% in the placebo group. The most common high-grade events were palmar plantar erythrodysesthesia (17% with cabozantinib vs. 0% with placebo), hypertension (16% vs. 2%), increased aspartate aminotransferase level (12% vs. 7%), fatigue (10% vs. 4%), and diarrhea (10% vs. 2%). CONCLUSIONS: Among patients with previously treated advanced hepatocellular carcinoma, treatment with cabozantinib resulted in longer overall survival and progression-free survival than placebo. The rate of high-grade adverse events in the cabozantinib group was approximately twice that observed in the placebo group. (Funded by Exelixis; CELESTIAL ClinicalTrials.gov number, NCT01908426 .). PMID- 29972761 TI - Epigenetic Control of Interleukin-9 in Asthma. PMID- 29972762 TI - Goal-directed fluid therapy versus conventional fluid therapy in colorectal surgery: A meta analysis of randomized controlled trials. AB - OBJECTIVES: This meta-analysis was conducted to compare the effects of goal directed fluid therapy (GDFT) versus conventional fluid therapy (CFT) in colorectal surgery on patients' postoperative outcome and to detect whether the results differ between studies with the Enhanced Recovery After Surgery (ERAS) protocol and those without, between studies using different devices for GDFT, or between different surgical approaches (laparoscopy or laparotomy). METHODS: The Cochrane Library, PubMed, Embase, Wanfang Data and ClinicalTrials.com were searched for studies from January,1990 to February, 2018. Randomized controlled trials (RCTs) comparing both two abovementioned fluid therapy protocols in colorectal surgery were included. The primary outcome was 30-day mortality after surgery. Secondary outcomes were length of hospital stay (LOS), complication rate, ICU admission and gastrointestinal indicators. RESULTS: Eleven studies were included, including a total of 1281 patients: the GDFT group included 624 patients and the control group included 657 patients. No significant differences were found between groups in 30-day mortality (relative risk, RR 0.86,0.28 to 2.63, P = 0.79), LOS (weighted mean difference, WMD 0.22,-0.1 to 0.55, P = 0.18), and ICU admission (RR 0.42, 0.17 to 1.04, P = 0.06). However, the GDFT group had a lower complication rate (RR 0.84,0.71 to 0.99, P = 0.04). In subgroup analyses, time to first flatus and time to tolerate an oral diet were shorter in GDFT group than the control group in studies who did not use the ERAS protocol. No publication bias was identified according to Begg's test. CONCLUSION: Compared with conventional fluid therapy, GDFT may not improve patients' postoperative outcome in colorectal surgery. However, the improvement of gastrointestinal function associated with GDFT over conventional fluid therapy was significant in the surgeries that did not use the ERAS protocol. PMID- 29972763 TI - Evaluating the potential of indigenous methanogenic consortium for enhanced oil and gas recovery from high temperature depleted oil reservoir. AB - In past years, lots of research has been focused on the indigenous bacteria and their mechanisms, which help in enhanced oil recovery. Most of the oil wells in Indian subcontinent have temperature higher than 60 degrees C. Also, the role of methanogenic consortia from high temperature petroleum reservoir for enhanced oil recovery (EOR) has not been explored much. Hence, in the present study methanogens isolated from thermophilic oil wells (70 degrees C) were evaluated for enhanced oil recovery. Methane gas is produced by methanogens, which helps in oil recovery from depleted oil wells through reservoir re-pressurization and also can be recovered from reservoir along with crude oil as alternative energy source. Therefore, in this study indigenous methanogenic consortium (TERIL146) was enriched from high temperature oil reservoir showing (12 mmol/l) gas production along with other metabolites. Sequencing analysis revealed the presence of Methanothermobacter sp., Thermoanaerobacter sp., Gelria sp. and Thermotoga sp. in the consortium. Furthermore, the developed indigenous consortium TERIL146 showed 8.3% incremental oil recovery in sandpack assay. The present study demonstrates successful recovery of both oil and energy (gas) by the developed indigenous methanogenic consortium TERIL146 for potential application in thermophilic depleted oil wells of Indian subcontinent. PMID- 29972764 TI - Diagnosis of invasive aspergillosis in hematological malignancy patients: Performance of cytokines, Asp LFD, and Aspergillus PCR in same day blood and bronchoalveolar lavage samples. AB - BACKGROUND: Aspergillus spp. induce elevated levels of several cytokines. It remains unknown whether these cytokines hold value for clinical routine and enhance diagnostic performances of established and novel biomarkers/tests for invasive aspergillosis (IA). METHODS: This cohort study included 106 prospectively enrolled (2014-2017) adult cases with underlying hematological malignancies and suspected pulmonary infection undergoing bronchoscopy. Serum samples were collected within 24 hours of bronchoalveolar lavage fluid (BALF) sampling. Both, serum and BALF samples were used to evaluate diagnostic performances of the Aspergillus-specific lateral-flow device test (LFD), Aspergillus PCR, beta-D-glucan, and cytokines that have shown significant associations with IA before. RESULTS: Among 106 cases, 11 had probable IA, and 32 possible IA; 80% received mold-active antifungals at the time of sampling. Diagnostic tests and biomarkers showed better performance in BALF versus blood, with the exception of serum interleukin (IL)-8 which was the most reliable blood biomarker. Combinations of serum IL-8 with either BALF LFD (sensitivity 100%, specificity 94%) or BALF PCR (sensitivity 91%, specificity 97%) showed promise for differentiating probable IA from no IA. CONCLUSIONS: High serum IL-8 levels were highly specific, and when combined with either the BALF Aspergillus-specific LFD, or BALF Aspergillus PCR also highly sensitive for diagnosis of IA. PMID- 29972765 TI - Raddeanin A inhibits growth and induces apoptosis in human colorectal cancer through downregulating the Wnt/beta-catenin and NF-kappaB signaling pathway. AB - AIMS: Colorectal cancer (CRC) remains one of the most lethal human malignancies with high incidence and lack of effective therapy. Raddeanin A (RA), an active triterpenoid saponins, has been demonstrated the ability to inhibit the growth of tumor. But the therapeutic effects and mechanisms of RA in CRC remain elusive. Here, we investigated the efficacy and mechanism of RA in CRC both in vitro and in vivo. MAIN METHODS: Cell viability was investigated to evaluate cytotoxic activity by MTT method. Apoptosis induced by RA was studied using Annexin V FITC/PI binding and JC-1 staining by flow cytometry analysis. The xenograft mouse model of CRC was used to investigate anti-tumor effects in vivo. The key proteins involved in mitochondrial apoptotic, Wnt/beta-catenin and NF-kappaB pathway were detected by Western blotting, Immunofluorescence, and Immunohistochemistry. KEY FINDINGS: RA induced apoptosis and inhibited cell proliferation of SW480 and LOVO cells in a concentration-dependent manner. Moreover, RA efficiently inhibited tumor growth in xenograft mouse model. RA could down regulate the Wnt/beta catenin signaling to display anti-tumor effects via suppression of p-LRP6, induction of AKT inactivation, removal of GSK-3beta inhibition and attenuation of beta-catenin. Meanwhile, RA also suppressed the NF-kappaB pathway by decreasing the phosphorylation of IKBalpha to induce subsequently mitochondrial apoptotic pathway. SIGNIFICANCE: In summary, RA suppressed the growth and triggered the apoptosis of CRC through discontinuing Wnt/beta-catenin signaling and inhibiting the NF-kappaB pathway. These findings suggested that RA may hold a promise as a novel therapeutic agent for CRC therapy. PMID- 29972767 TI - Extraction, characterization and antioxidant activities of mannan from yeast cell wall. AB - Extraction and antioxidant activities of mannan from yeast cell wall were investigated. The crude mannan was extracted with the hot water. It indicated that the isoelectric point method was ideal for deproteinization. The mannan was linked by the alpha-glycosidic bond, and it was a homopolysaccharide containing only mannose. In addition, it showed that mannan had good antioxidant activities. PMID- 29972768 TI - Optimization of preparing a high yield and high cationic degree starch graft copolymer as environmentally friendly flocculant: Through response surface methodology. AB - To pursuit effective and environmentally friendly flocculant, a bio-copolymer was prepared by starch grafting with acrylamide (AM) and dimethyl diallyl ammonium chloride (DMDAAC) through an initiator system KMnO4/HIO4. The initiation and grafting reaction were optimized by the Response Surface Methodology. In the initiation reaction, the optimum condition was KMnO4 at 0.28 mmol, HIO4 at 0.25 mmol, and the temperature at 67.64 degrees C, when the highest copolymer yield of 13.43 g was obtained from 4 g raw starch. In the grafting reaction, the optimum condition was the temperature at 68.71 degrees C, (AM + DMDAAC)/starch anhydroglucose units molar ratio at 2 and the AM / (AM + DMDAAC) molar ratio at 0.34, when the copolymer had the maximum cationic degree of 1.54 meq/g. The optimized preparing method had a high grafting efficiency of 97.12 +/- 0.14% and high raw material utilization. The flocculation ability of the optimized graft copolymer was also tested. The result showed the graft starch was effective to remove reactive dyes and disperse dyes from wastewater. The dye removal efficiency of the graft starch was nearly 10% higher than polyacrylamide. Therefore, through the optimization of initiation and grafting reaction, the graft starch was a promising environmentally friendly flocculant. PMID- 29972769 TI - Effect of Mesona chinensis polysaccharide on the pasting, thermal and rheological properties of wheat starch. AB - In this study, the effects of Mesona chinensis polysaccharide (MCP) on the pasting, thermal, rheological, and textural properties of wheat starch were investigated. Rapid viscosity analysis results showed that MCP protects the integrity of starch granules at low concentration in the early stage of pasting. The gelatinization temperature of wheat starch-MCP gels was markedly increased with the increase in polysaccharide concentration, whereas gelatinization enthalpy (DeltaHgel) decreased. Rheological analysis showed that the starch:MCP = 8.5:1.5 system exhibited a strong thixotropic property and the highest G' and G" among the other systems. The same results were observed in the textural experiment, indicating the existence of strong intermolecular interactions between starch granules and MCP. These results indicated that MCP can improve the thermal stability in the early stage of pasting and enhance the rheological properties of wheat starch. PMID- 29972766 TI - Puberty and the human brain: Insights into adolescent development. AB - Alongside the exponential flourish of research on age-related trajectories of human brain development during childhood and adolescence in the past two decades, there has been an increase in the body of work examining the association between pubertal development and brain maturation. This review systematically examines empirical research on puberty-related structural and functional brain development in humans, with the aim of identifying convergent patterns of associations. We emphasize longitudinal studies, and discuss pervasive but oft-overlooked methodological issues that may be contributing to inconsistent findings and hindering progress (e.g., conflating distinct pubertal indices and different measurement instruments). We also briefly evaluate support for prominent models of adolescent neurodevelopment that hypothesize puberty-related changes in brain regions involved in affective and motivational processes. For the field to progress, replication studies are needed to help resolve current inconsistencies and gain a clearer understanding of pubertal associations with brain development in humans, knowledge that is crucial to make sense of the changes in psychosocial functioning, risk behavior, and mental health during adolescence. PMID- 29972770 TI - Domain Gymnastics of an ABC Transporter. AB - Bacterial pathogens can switch signaling by sensing threonine phosphorylation. In this issue of Structure, Heinkel et al. (2018) report novel rearrangements linking threonine phosphorylation to tandem forkhead-associated (FHA) domains from an ATP-binding cassette (ABC) transporter. The resulting associations probably regulate oligomerization and transport in Mycoplasma tuberculosis. PMID- 29972773 TI - CaMKK2 Regulates Mechanosensitive Assembly of Contractile Actin Stress Fibers. AB - Stress fibers are contractile actomyosin bundles that guide cell adhesion, migration, and morphogenesis. Their assembly and alignment are under precise mechanosensitive control. Thus, stress fiber networks undergo rapid modification in response to changes in biophysical properties of the cell's surroundings. Stress fiber maturation requires mechanosensitive activation of 5'AMP-activated protein kinase (AMPK), which phosphorylates vasodilator-stimulated phosphoprotein (VASP) to inhibit actin polymerization at focal adhesions. Here, we identify Ca2+ calmodulin-dependent kinase kinase 2 (CaMKK2) as a critical upstream factor controlling mechanosensitive AMPK activation. CaMKK2 and Ca2+ influxes were enriched around focal adhesions at the ends of contractile stress fibers. Inhibition of either CaMKK2 or mechanosensitive Ca2+ channels led to defects in phosphorylation of AMPK and VASP, resulting in a loss of contractile bundles and a decrease in cell-exerted forces. These data provide evidence that Ca2+, CaMKK2, AMPK, and VASP form a mechanosensitive signaling cascade at focal adhesions that is critical for stress fiber assembly. PMID- 29972772 TI - Intrinsic Projections of Layer Vb Neurons to Layers Va, III, and II in the Lateral and Medial Entorhinal Cortex of the Rat. AB - Layer V of the entorhinal cortex (EC) receives input from the hippocampus and originates main entorhinal outputs. The deep-sublayer Vb, immunopositive for the transcription factor Ctip2, is thought to be the main recipient of hippocampal projections, whereas the superficial-sublayer LVa, immunonegative for Ctip2, originates the main outputs of EC. This disrupts the proposed role of EC as mediating hippocampal-cortical interactions. With the use of specific (trans)synaptic tracing approaches, we report that, in medial entorhinal cortex, layer Vb neurons innervate neurons in layers Va, II, and III. A similar circuitry exists in the lateral entorhinal cortex. We conclude that EC-layer Vb neurons mediate two circuits in the hippocampus-memory system: (1) a hippocampal output circuit to telencephalic areas by projecting to layer Va and (2) a feedback projection, sending information back to the EC-hippocampal loop via neurons in layers II and III. PMID- 29972771 TI - Systemic Loss and Gain of Chromatin Architecture throughout Zebrafish Development. AB - The spatial organization of chromosomes is critical in establishing gene expression programs. We generated in situ Hi-C maps throughout zebrafish development to gain insight into higher-order chromatin organization and dynamics. Zebrafish chromosomes segregate in active and inactive chromatin (A/B compartments), which are further organized into topologically associating domains (TADs). Zebrafish A/B compartments and TADs have genomic features similar to those of their mammalian counterparts, including evolutionary conservation and enrichment of CTCF binding sites at TAD borders. At the earliest time point, when there is no zygotic transcription, the genome is highly structured. After zygotic genome activation (ZGA), the genome loses structural features, which are re established throughout early development. Despite the absence of structural features, we see clustering of super-enhancers in the 3D genome. Our results provide insight into vertebrate genome organization and demonstrate that the developing zebrafish embryo is a powerful model system to study the dynamics of nuclear organization. PMID- 29972774 TI - Immature CD8 Single-Positive Thymocytes Are a Molecularly Distinct Subpopulation, Selectively Dependent on BRD4 for Their Differentiation. AB - T cell differentiation in the thymus proceeds in an ordered sequence of developmental events characterized by variable expression of CD4 and CD8 coreceptors. Here, we report that immature single-positive (ISP) thymocytes are molecularly distinct from all other T cell populations in the thymus in their expression of a gene profile that is dependent on the transcription factor BRD4. Conditional deletion of BRD4 at various stages of thymic differentiation reveals that BRD4 selectively regulates the further differentiation of ISPs by targeting cell cycle and metabolic pathways, but it does not affect the extensive proliferation that results in the generation of ISPs. These studies lead to the conclusion that the ISP subpopulation is not a hybrid transitional state but a molecularly distinct subpopulation that is selectively dependent on BRD4. PMID- 29972775 TI - Embryonic Microglia Derive from Primitive Macrophages and Are Replaced by cmyb Dependent Definitive Microglia in Zebrafish. AB - Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors. PMID- 29972776 TI - Migratory Dendritic Cells, Group 1 Innate Lymphoid Cells, and Inflammatory Monocytes Collaborate to Recruit NK Cells to the Virus-Infected Lymph Node. AB - Circulating natural killer (NK) cells help protect the host from lympho hematogenous acute viral diseases by rapidly entering draining lymph nodes (dLNs) to curb virus dissemination. Here, we identify a highly choreographed mechanism underlying this process. Using footpad infection with ectromelia virus, a pathogenic DNA virus of mice, we show that TLR9/MyD88 sensing induces NKG2D ligands in virus-infected, skin-derived migratory dendritic cells (mDCs) to induce production of IFN-gamma by classical NK cells and other types of group 1 innate lymphoid cells (ILCs) already in dLNs, via NKG2D. Uninfected inflammatory monocytes, also recruited to dLNs by mDCs in a TLR9/MyD88-dependent manner, respond to IFN-gamma by secreting CXCL9 for optimal CXCR3-dependent recruitment of circulating NK cells. This work unveils a TLR9/MyD88-dependent mechanism whereby in dLNs, three cell types-mDCs, group 1 ILCs (mostly NK cells), and inflammatory monocytes-coordinate the recruitment of protective circulating NK cells to dLNs. PMID- 29972777 TI - Constitutive Interferon Maintains GBP Expression Required for Release of Bacterial Components Upstream of Pyroptosis and Anti-DNA Responses. AB - Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria. In addition, endogenous GBP levels were sufficient for the release of DNA from cytosol-exposed bacteria, preceding the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway for Ifnb induction. Mice deficient for chromosome 3 GBPs were unable to mount a rapid IL-1/chemokine (C-X-C motif) ligand 1 (CXCL1) response during Legionella-induced pneumonia, with defective bacterial clearance. Our results show that rapid GBP activity is controlled by host-intrinsic cytokine signaling and that GBP activities precede immune amplification responses, including IFN induction, inflammasome activation, and cell death. PMID- 29972778 TI - Group 2 Innate Lymphoid Cells Attenuate Inflammatory Arthritis and Protect from Bone Destruction in Mice. AB - Group 2 innate lymphoid cells (ILC2s) were detected in the peripheral blood and the joints of rheumatoid arthritis (RA) patients, serum-induced arthritis (SIA), and collagen-induced arthritis (CIA) using flow cytometry. Circulating ILC2s were significantly increased in RA patients compared with healthy controls and inversely correlated with disease activity. Induction of arthritis in mice led to a fast increase in ILC2 number. To elucidate the role of ILC2 in arthritis, loss- and gain-of-function mouse models for ILC2 were subjected to arthritis. Reduction of ILC2 numbers in RORalphacre/GATA3fl/fl and Tie2cre/RORalphafl/fl mice significantly exacerbated arthritis. Increasing ILC2 numbers in mice by IL-25/IL 33 mini-circles or IL-2/IL-2 antibody complex and the adoptive transfer of wild type (WT) ILC2s significantly attenuated arthritis by affecting the initiation phase. In addition, adoptive transfer of IL-4/13-competent WT but not IL-4/13-/- ILC2s and decreased cytokine secretion by macrophages. These data show that ILC2s have immune-regulatory functions in arthritis. PMID- 29972781 TI - The RNA-Binding Protein Scp160p Facilitates Aggregation of Many Endogenous Q/N Rich Proteins. AB - The RNA-binding protein Scp160p is the yeast homolog of the conserved vigilin protein family. These proteins influence a variety of nuclear and cytoplasmic functions. One of Scp160p's reported roles is to increase translation elongation efficiency in a manner related to codon usage. Thus, it can affect translation speed and co-translational folding of nascent peptides. We used polyglutamine (polyQ) reporters to assess Scp160p's effect on protein synthesis and observed that, in the absence of Scp160p, aggregation of polyQ is reduced and toxicity is abolished. We additionally took a proteomic approach and analyzed the impact of Scp160p on the aggregation of endogenous proteins under normal growth conditions. In the absence of Scp160p, aggregation of many Q/N-rich proteins was reduced. Because aggregation mediated by these regions can be important for the proteins' functions, Scp160p may affect many processes via aggregation of Q/N-rich proteins. PMID- 29972779 TI - Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. AB - Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and beta cell dysfunction. We show that CE prevent insulin deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-alpha (ERalpha), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERalpha modulator bazedoxifene mimics CE protection of beta cells in females but not in males. PMID- 29972780 TI - Rbfox-Splicing Factors Maintain Skeletal Muscle Mass by Regulating Calpain3 and Proteostasis. AB - Maintenance of skeletal muscle mass requires a dynamic balance between protein synthesis and tightly controlled protein degradation by the calpain, autophagy lysosome, and ubiquitin-proteasome systems (proteostasis). Several sensing and gene-regulatory mechanisms act together to maintain this balance in response to changing conditions. Here, we show that deletion of the highly conserved Rbfox1 and Rbfox2 alternative splicing regulators in adult mouse skeletal muscle causes rapid, severe loss of muscle mass. Rbfox deletion did not cause a reduction in global protein synthesis, but it led to altered splicing of hundreds of gene transcripts, including capn3, which produced an active form of calpain3 protease. Rbfox knockout also led to a reduction in autophagy flux, likely producing a compensatory increase in general protein degradation by the proteasome. Our results indicate that the Rbfox-splicing factors are essential for the maintenance of skeletal muscle mass and proteostasis. PMID- 29972784 TI - Integrative Bayesian Analysis Identifies Rhabdomyosarcoma Disease Genes. AB - Identifying oncogenic drivers and tumor suppressors remains a challenge in many forms of cancer, including rhabdomyosarcoma. Anticipating gene expression alterations resulting from DNA copy-number variants to be particularly important, we developed a computational and experimental strategy incorporating a Bayesian algorithm and CRISPR/Cas9 "mini-pool" screen that enables both genome-scale assessment of disease genes and functional validation. The algorithm, called iExCN, identified 29 rhabdomyosarcoma drivers and suppressors enriched for cell cycle and nucleic-acid-binding activities. Functional studies showed that many iExCN genes represent rhabdomyosarcoma line-specific or shared vulnerabilities. Complementary experiments addressed modes of action and demonstrated coordinated repression of multiple iExCN genes during skeletal muscle differentiation. Analysis of two separate cohorts revealed that the number of iExCN genes harboring copy-number alterations correlates with survival. Our findings highlight rhabdomyosarcoma as a cancer in which multiple drivers influence disease biology and demonstrate a generalizable capacity for iExCN to unmask disease genes in cancer. PMID- 29972782 TI - Remodeling of the Acetylproteome by SIRT3 Manipulation Fails to Affect Insulin Secretion or beta Cell Metabolism in the Absence of Overnutrition. AB - SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent mitochondrial protein deacetylase purported to influence metabolism through post-translational modification of metabolic enzymes. Fuel-stimulated insulin secretion, which involves mitochondrial metabolism, could be susceptible to SIRT3-mediated effects. We used CRISPR/Cas9 technology to manipulate SIRT3 expression in beta cells, resulting in widespread SIRT3-dependent changes in acetylation of key metabolic enzymes but no appreciable changes in glucose- or pyruvate-stimulated insulin secretion or metabolomic profile during glucose stimulation. Moreover, these broad changes in the SIRT3-targeted acetylproteome did not affect responses to nutritional or ER stress. We also studied mice with global SIRT3 knockout fed either standard chow (STD) or high-fat and high-sucrose (HFHS) diets. Only when chronically fed HFHS diet do SIRT3 KO animals exhibit a modest reduction in insulin secretion. We conclude that broad changes in mitochondrial protein acetylation in response to manipulation of SIRT3 are not sufficient to cause changes in islet function or metabolism. PMID- 29972785 TI - A Live-Cell Imaging Approach for Measuring DNA Replication Rates. AB - We describe a simple and direct approach to measure the progression of single DNA replication forks in living cells by monitoring two fluorescently labeled loci downstream of an origin of replication. We employ this approach to investigate the roles of several leading and lagging strand factors in overall replisome function and show that fork progression is strongly dependent on proper maturation of Okazaki fragments. We also demonstrate how related cellular phenotypes, such as cell-cycle progression and the dynamics of sister chromatid cohesion, may be simultaneously monitored and correlated to DNA replication at the single-cell level. PMID- 29972783 TI - Regulation of Breast Cancer-Induced Osteoclastogenesis by MacroH2A1.2 Involving EZH2-Mediated H3K27me3. AB - Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer-derived osteoclastogenesis. This repressive effect requires macroH2A1.2-dependent attenuation of expression and secretion of lysyl oxidase (LOX) in breast cancer cells. Furthermore, our mechanistic studies reveal that macroH2A1.2 physically and functionally interacts with the histone methyltransferase EZH2 and elevates H3K27me3 levels to keep LOX gene in a repressed state. Collectively, this study unravels a role for macroH2A1.2 in regulating osteoclastogenic potential of breast cancer cells, suggesting possibilities for developing therapeutic tools to treat osteolytic bone destruction. PMID- 29972787 TI - Functional Genome-wide Screen Identifies Pathways Restricting Central Nervous System Axonal Regeneration. PMID- 29972786 TI - Classification of Single Particles from Human Cell Extract Reveals Distinct Structures. AB - Multi-protein complexes are necessary for nearly all cellular processes, and understanding their structure is required for elucidating their function. Current high-resolution strategies in structural biology are effective but lag behind other fields (e.g., genomics and proteomics) due to their reliance on purified samples rather than heterogeneous mixtures. Here, we present a method combining single-particle analysis by electron microscopy with protein identification by mass spectrometry to structurally characterize macromolecular complexes from human cell extract. We identify HSP60 through two-dimensional classification and obtain three-dimensional structures of native proteasomes directly from ab initio classification of a heterogeneous mixture of protein complexes. In addition, we reveal an ~1-MDa-size structure of unknown composition and reference our proteomics data to suggest possible identities. Our study shows the power of using a shotgun approach to electron microscopy (shotgun EM) when coupled with mass spectrometry as a tool to uncover the structures of macromolecular machines. PMID- 29972788 TI - Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase. AB - Multiple sulfatase deficiency (MSD) is a fatal, inherited lysosomal storage disorder characterized by reduced activities of all sulfatases in patients. Sulfatases require a unique post-translational modification of an active-site cysteine to formylglycine that is catalyzed by the formylglycine-generating enzyme (FGE). FGE mutations that affect intracellular protein stability determine residual enzyme activity and disease severity in MSD patients. Here, we show that protein disulfide isomerase (PDI) plays a pivotal role in the recognition and quality control of MSD-causing FGE variants. Overexpression of PDI reduces the residual activity of unstable FGE variants, whereas inhibition of PDI function rescues the residual activity of sulfatases in MSD fibroblasts. Mass spectrometric analysis of a PDI+FGE variant covalent complex allowed determination of the molecular signature for FGE recognition by PDI. Our findings highlight the role of PDI as a disease modifier in MSD, which may also be relevant for other ER-associated protein folding pathologies. PMID- 29972789 TI - Longitudinal Alzheimer's Degeneration Reflects the Spatial Topography of Cholinergic Basal Forebrain Projections. AB - The cholinergic neurons of the basal forebrain (BF) provide virtually all of the brain's cortical and amygdalar cholinergic input. They are particularly vulnerable to neuropathology in early Alzheimer's disease (AD) and may trigger the emergence of neuropathology in their cortico-amygdalar projection system through cholinergic denervation and trans-synaptic spreading of misfolded proteins. We examined whether longitudinal degeneration within the BF can explain longitudinal cortico-amygdalar degeneration in older human adults with abnormal cerebrospinal fluid biomarkers of AD neuropathology. We focused on two BF subregions, which are known to innervate cortico-amygdalar regions via two distinct macroscopic cholinergic projections. To further assess whether structural degeneration of these regions in AD reflects cholinergic denervation, we used the [18F] FEOBV radiotracer, which binds to cortico-amygdalar cholinergic terminals. We found that the two BF subregions explain spatially distinct patterns of cortico-amygdalar degeneration, which closely reflect their cholinergic projections, and overlap with [18F] FEOBV indices of cholinergic denervation. PMID- 29972791 TI - Melanin Pathway Genes Regulate Color and Morphology of Butterfly Wing Scales. AB - The cuticular skeleton of a butterfly wing scale cell is an exquisitely finely sculpted material that can contain pigments, produce structural colors, or both. While cuticle rigidity and pigmentation depend on the products of the melanin pathway, little is known about whether genes in this pathway also play a role in the development of specific scale morphologies. Here, we use CRISPR/Cas9 to show that knockout mutations in five genes that function in the melanin pathway affect both the fine structure and the coloration of the wing scales. Most dramatically, mutations in the yellow gene lead to extra horizontal laminae on the surface of scales, whereas mutations in DDC gene lead to taller and sheet-like vertical laminae throughout each scale. We identify genes affecting the development of color and scale morphology, the regulation and pleiotropic effects of which may be important in creating and limiting the diversity of the structural and pigmentary colors observed in butterflies. PMID- 29972790 TI - Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer. AB - Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu. PMID- 29972793 TI - Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain. AB - The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain. PMID- 29972792 TI - Spatial Fold Change of FGF Signaling Encodes Positional Information for Segmental Determination in Zebrafish. AB - Signal gradients encode instructive information for numerous decision-making processes during embryonic development. A striking example of precise, scalable tissue-level patterning is the segmentation of somites-the precursors of the vertebral column-during which the fibroblast growth factor (FGF), Wnt, and retinoic acid (RA) pathways establish spatial gradients. Despite decades of studies proposing roles for all three pathways, the dynamic feature of these gradients that encodes instructive information determining segment sizes remained elusive. We developed a non-elongating tail explant system, integrated quantitative measurements with computational modeling, and tested alternative models to show that positional information is encoded solely by spatial fold change (SFC) in FGF signal output. Neighboring cells measure SFC to accurately position the determination front and thus determine segment size. The SFC model successfully recapitulates results of spatiotemporal perturbation experiments on both explants and intact embryos, and it shows that Wnt signaling acts permissively upstream of FGF signaling and that RA gradient is dispensable. PMID- 29972794 TI - MTSS1 Regulation of Actin-Nucleating Formin DAAM1 in Dendritic Filopodia Determines Final Dendritic Configuration of Purkinje Cells. AB - Dendritic filopodia of developing neurons function as environmental sensors, regulating the spatial organization of dendrites and proper targeting to presynaptic partners. Dendritic filopodia morphology is determined by the balance of F-actin assembled via two major nucleating pathways, the ARP2/3 complex and formins. The inverse-BAR protein MTSS1 is highly expressed in Purkinje cells (PCs) and has been shown to upregulate ARP2/3 activity. PCs in MTSS1 conditional knockout mice showed dendrite hypoplasia due to excessive contact-induced retraction during development. This phenotype was concomitant with elongated dendritic filopodia and was phenocopied by overactivation of the actin nucleator formin DAAM1 localized in the tips of PC dendritic protrusions. Cell biology assays including single-molecule speckle microscopy demonstrated that MTSS1's C terminus binds to DAAM1 and paused DAAM1-mediated F-actin polymerization. Thus, MTSS1 plays a dual role as a formin inhibitor and ARP2/3 activator in dendritic filopodia, determining final neuronal morphology. PMID- 29972795 TI - Monogenic Obesity; Using Drugs to Bypass the Problem. AB - Safe and effective pharmacological treatments for severe obesity remain scarce. In this issue of Cell Metabolism, Iepsen et al. (2018) show that obese patients with pathogenic melanocortin 4 receptor mutations, the most common form of monogenic obesity, lose weight with glucagon-like peptide 1 (GLP-1) receptor agonist therapy. PMID- 29972796 TI - A Glycolysis Outsider Steps into the Cancer Spotlight. AB - Glycolysis is prudently regulated and coupled to cell growth. Phosphofructokinase 2 controls glycolytic flux by generating fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase 1. In a recent paper in Nature, Dasgupta et al. address the novel role of PFKFB4, an isoform of phosphofructokinase 2, in regulating gene expression to promote tumor growth. PMID- 29972797 TI - Cancer: The Tumor-Driven Disease of the Host. AB - Tumors interact reciprocally with their hosts' physiology and metabolism, making cancer a systemic disease. In this issue of Cell Metabolism, Borniger et al. (2018) demonstrate this phenomenon by linking the endocrine control of food intake with sleep behavior and liver metabolism in a mouse model of non metastatic breast carcinoma. PMID- 29972799 TI - Melanin-Concentrating Hormone-Dependent Control of Feeding: When Volume Matters. AB - In contrast to synaptic transmission, the mechanism of volume transmission-in which neurotransmitters or neuropeptides diffuse to many effector cells-is not extensively investigated, although it represents an important mode of neuronal communication. In this issue of Cell Metabolism, Noble et al. (2018) demonstrate how the orexigenic melanin-concentrating hormone (MCH) controls feeding behavior through cerebrospinal fluid (CSF) volume transmission. PMID- 29972800 TI - Metabolic Effects of Dietary Nitrate in Health and Disease. AB - Nitric oxide (NO), generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored. The inorganic anions nitrate (NO3-) and nitrite (NO2 ), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues. The described cardio-metabolic effects of dietary nitrate from experimental and clinical studies include lowering of blood pressure, improved endothelial function, increased exercise performance, and reversal of metabolic syndrome, as well as antidiabetic effects. The mechanisms underlying the salutary metabolic effects of nitrate are being revealed and include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress. Here we review the recent advances in the nitrate nitrite-NO pathway, focusing on metabolic effects in health and disease. PMID- 29972798 TI - Targeting Breast Cancer Stem Cell State Equilibrium through Modulation of Redox Signaling. AB - Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2O2, or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state. This transition is reversed by N-acetylcysteine and mediated by activation of the AMPK HIF1alpha axis. Moreover, E-BCSCs exhibit robust NRF2-mediated antioxidant responses, rendering them vulnerable to ROS-induced differentiation and cytotoxicity following suppression of NRF2 or downstream thioredoxin (TXN) and glutathione (GSH) antioxidant pathways. Co-inhibition of glycolysis and TXN and GSH pathways suppresses tumor growth, tumor-initiating potential, and metastasis by eliminating both M- and E-BCSCs. Exploiting metabolic vulnerabilities of distinct BCSC states provides a novel therapeutic approach targeting this critical tumor cell population. PMID- 29972801 TI - Modeling the Hidden Pathways of IKs Channel Activation. PMID- 29972802 TI - Enhanced Nucleocytoplasmic Transport due to Competition for Elastic Binding Sites. AB - Nuclear pore complexes (NPCs) control all traffic into and out of the cell nucleus. NPCs are molecular machines that simultaneously achieve high selectivity and high transport rates. The biophysical details of how cargoes rapidly traverse the pore remain unclear but are known to be mediated by interactions between cargo-binding chaperone proteins and natively unstructured nucleoporin proteins containing many phenylalanine-glycine repeats (FG nups) that line the pore's central channel. Here, we propose a specific and detailed physical mechanism for the high speed of nuclear import based on the elasticity of FG nups and on competition between individual chaperone proteins for FG nup binding. We develop a mathematical model to support our proposed mechanism. We suggest that the recycling of nuclear import factors back to the cytoplasm is important for driving high-speed import and predict the existence of an optimal cytoplasmic concentration of cargo for enhancing the rate of import over a purely diffusive rate. PMID- 29972803 TI - Fluid Phase Coexistence in Biological Membrane: Insights from Local Nonaffine Deformation of Lipids. AB - Lateral heterogeneities in biomembranes play a crucial role in various physiological functions of the cell. Such heterogeneities lead to demixing of lipid constituents and formation of distinct liquid domains in the membrane. We study lateral heterogeneities in terms of topological rearrangements of lipids to identify the liquid-liquid phase coexistence in model membranes. Using ideas from the physics of amorphous systems and glasses, we calculate the degree of nonaffine deformation associated with individual lipids to characterize the liquid-ordered (Lo) and liquid-disordered (Ld) regions in model lipid bilayers. We explore the usage of this method on all-atom and coarse-grained lipid bilayer trajectories. This method is helpful in defining the instantaneous Lo-Ld domain boundaries in complex multicomponent bilayer systems. The characterization is also used to highlight the effect of line-active molecules on the phase boundaries and domain mixing. Overall, we propose a framework to explore the molecular origin of spatial and dynamical heterogeneity in biomembrane systems, which can be exploited not only in computer simulations but also in experiments. PMID- 29972804 TI - Membrane Solubilization by Styrene-Maleic Acid Copolymers: Delineating the Role of Polymer Length. AB - Styrene-maleic acid (SMA) copolymers have attracted interest in membrane research because they allow the solubilization and purification of membrane-spanning proteins from biological membranes in the form of native-like nanodisks. However, our understanding of the underlying SMA-lipid interactions is hampered by the fact that SMA preparations are very polydisperse. Here, we obtained fractions of the two most commonly used SMA preparations: SMA 2:1 and SMA 3:1 (both with specified Mw ~10 kD), with different number-average molecular weight (Mn) and styrene content. The fractionation is based on the differential solubility of styrene-maleic anhydride (SMAnh) in hexane and acetone mixtures. SMAnh fractions were hydrolyzed to SMA and added to lipid self-assemblies. It was found that SMA fractions inserted in monolayers and solubilized vesicles to a different extent, with the highest efficiency being observed for low-Mn SMA polymers. Electron microscopy and dynamic light scattering size analyses confirmed the presence of nanodisks independent of the Mn of the SMA polymers forming the belt, and it was shown that the nanodisks all have approximately the same size. However, nanodisks bounded by high-Mn SMA polymers were more stable than those bounded by low-Mn polymers, as indicated by a better retention of the native lipid thermotropic properties and by slower exchange rates of lipids between nanodisks. In conclusion, we here present a simple method to separate SMAnh molecules based on their Mn from commercial SMAnh blends, which allowed us to obtain insights into the importance of SMA length for polymer-lipid interactions. PMID- 29972805 TI - Errors in Energy Landscapes Measured with Particle Tracking. AB - Tracking Brownian particles is often employed to map the energy landscape they explore. Such measurements have been exploited to study many biological processes and interactions in soft materials. Yet video tracking is irremediably contaminated by localization errors originating from two imaging artifacts: the "static" errors come from signal noise, and the "dynamic" errors arise from the motion blur due to finite frame-acquisition time. We show that these errors result in systematic and nontrivial biases in the measured energy landscapes. We derive a relationship between the true and the measured potential that elucidates, among other aberrations, the presence of false double-well minima in the apparent potentials reported in recent studies. We further assess several canonical trapping and pair-interaction potentials by using our analytically derived results and Brownian dynamics simulations. In particular, we show that the apparent spring stiffness of harmonic potentials (such as optical traps) is increased by dynamic errors but decreased by static errors. Our formula allows for the development of efficient corrections schemes, and we also present in this work a provisional method for reconstructing true potentials from the measured ones. PMID- 29972806 TI - Oscillatory Switches of Dorso-Ventral Polarity in Cells Confined between Two Surfaces. AB - To maneuver in a three-dimensional space, migrating cells need to accommodate to multiple surfaces. In particular, phagocytes have to explore their environment in the search for particles to be ingested. To examine how cells decide between competing surfaces, we exposed single cells of Dictyostelium to a defined three dimensional space by confining them between two planar surfaces: those of a cover glass and of a wedged microcantilever. These cells form propagating waves of filamentous actin and PIP3 on their ventral substrate-attached surface. The dynamics of wave formation in the confined cells was explored using two-focus fluorescence imaging. When waves formed on one substrate, wave formation on the other substrate was efficiently suppressed. The propensity for wave formation switched between the opposing cell surfaces with periods of 2-5 min by one of two modes: 1) a rolling mode involving the slipping of a wave along the nonattached plasma membrane and 2) de novo initiation of waves on the previously blank cell surface. These data provide evidence for a cell-autonomous oscillator that switches dorso-ventral polarity in a cell simultaneously exposed to multiple substrate surfaces. PMID- 29972807 TI - Alternative Splicing at N Terminus and Domain I Modulates CaV1.2 Inactivation and Surface Expression. PMID- 29972808 TI - Membrane Bending Moduli of Coexisting Liquid Phases Containing Transmembrane Peptide. PMID- 29972809 TI - Do Cellular Condensates Accelerate Biochemical Reactions? Lessons from Microdroplet Chemistry. AB - Cellular condensates-phase-separated concentrates of proteins and nucleic acids provide organizational structure for biochemistry that is distinct from membrane bound compartments. It has been suggested that one major function of cellular condensates is to accelerate biochemical processes that are normally slow or thermodynamically unfavorable. Yet, the mechanisms leading to increased reaction rates within cellular condensates remain poorly understood. In this article, we highlight recent advances in microdroplet chemistry that accelerate reaction rates by many orders of magnitude as compared to bulk and suggest that similar mechanisms may also affect reaction kinetics in cellular condensates. PMID- 29972810 TI - Dynamic Allostery in PLCgamma1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR. AB - Phosphatidylinositol phospholipase Cgamma (PLCgamma) is an intracellular membrane associated second-messenger signaling protein activated by tyrosine kinases such as fibroblast growth factor receptor 1. PLCgamma contains the regulatory gamma specific array (gammaSA) comprising a tandem Src homology 2 (SH2) pair, an SH3 domain, and a split pleckstrin homology domain. Binding of an activated growth factor receptor to gammaSA leads to Tyr783 phosphorylation and consequent PLCgamma activation. Several disease-relevant mutations in gammaSA have been identified; all lead to elevated phospholipase activity. In this work, we describe an allosteric mechanism that connects the Tyr783 phosphorylation site to the nSH2-cSH2 junction and involves dynamic interactions between the cSH2-SH3 linker and cSH2. Molecular dynamics simulations of the tandem SH2 protein suggest that Tyr783 phosphorylation is communicated to the nSH2-cSH2 junction by modulating cSH2 binding to sections of the cSH2-SH3 linker. NMR chemical shift perturbation analyses for designed tandem SH2 constructs reveal combined fast and slow dynamic processes that can be attributed to allosteric communication involving these regions of the protein, establishing an example in which complex N-site exchange can be directly inferred from 1H,15N-HSQC spectra. Furthermore, in tandem SH2 and gammaSA constructs, molecular dynamics and NMR results show that the Arg687Trp mutant in PLCgamma1 (equivalent to the cancer mutation Arg665Trp in PLCgamma2) perturbs the dynamic allosteric pathway. This combined experimental and computational study reveals a rare example of multistate kinetics involved in a dynamic allosteric process that is modulated in the context of a disease-relevant mutation. The allosteric influences and the weakened binding of the cSH2-SH3 linker to cSH2 should be taken into account in any more holistic investigation of PLCgamma regulation. PMID- 29972811 TI - Unraveling the Mechanical Unfolding Pathways of a Multidomain Protein: Phosphoglycerate Kinase. AB - Phosphoglycerate kinase (PGK) is a highly conserved enzyme that is crucial for glycolysis. PGK is a monomeric protein composed of two similar domains and has been the focus of many studies for investigating interdomain interactions within the native state and during folding. Previous studies used traditional biophysical methods (such as circular dichroism, tryptophan fluorescence, and NMR) to measure signals over a large ensemble of molecules, which made it difficult to observe transient changes in stability or structure during unfolding and refolding of single molecules. Here, we unfold single molecules of PGK using atomic force spectroscopy and steered molecular dynamic computer simulations to examine the conformational dynamics of PGK during its unfolding process. Our results show that after the initial forced separation of its domains, yeast PGK (yPGK) does not follow a single mechanical unfolding pathway; instead, it stochastically follows two distinct pathways: unfolding from the N-terminal domain or unfolding from the C-terminal domain. The truncated yPGK N-terminal domain unfolds via a transient intermediate, whereas the structurally similar isolated C-terminal domain has no detectable intermediates throughout its mechanical unfolding process. The N-terminal domain in the full-length yPGK displays a strong unfolding intermediate 13% of the time, whereas the truncated domain (yPGKNT) transitions through the intermediate 81% of the time. This effect indicates that the mechanical properties of yPGK cannot be simply deduced from the mechanical properties of its constituents. We also find that Escherichia coli PGK is significantly less mechanically stable as compared to yPGK, contrary to bulk unfolding measurements. Our results support the growing body of observations that the folding behavior of multidomain proteins is difficult to predict based solely on the studies of isolated domains. PMID- 29972812 TI - The Structural Properties in Solution of the Intrinsically Mixed Folded Protein Ataxin-3. AB - It has increasingly become clear over the last two decades that proteins can contain both globular domains and intrinsically unfolded regions that can both contribute to function. Although equally interesting, the disordered regions are difficult to study, because they usually do not crystallize unless bound to partners and are not easily amenable to cryo-electron microscopy studies. NMR spectroscopy remains the best technique to capture the structural features of intrinsically mixed folded proteins and describe their dynamics. These studies rely on the successful assignment of the spectrum, a task not easy per se given the limited spread of the resonances of the disordered residues. Here, we describe the structural properties of ataxin-3, the protein responsible for the neurodegenerative Machado-Joseph disease. Ataxin-3 is a 42-kDa protein containing a globular N-terminal Josephin domain and a C-terminal tail that comprises 13 polyglutamine repeats within a low complexity region. We developed a strategy that allowed us to achieve 87% assignment of the NMR spectrum using a mixed protocol based on high-dimensionality, high-resolution experiments and different labeling schemes. Thanks to the almost complete spectral assignment, we proved that the C-terminal tail is flexible, with extended helical regions, and interacts only marginally with the rest of the protein. We could also, for the first time to our knowledge, observe the structural propensity of the polyglutamine repeats within the context of the full-length protein and show that its structure is stabilized by the preceding region. PMID- 29972813 TI - Retinal Configuration of ppR Intermediates Revealed by Photoirradiation Solid State NMR and DFT. AB - Pharanois phoborhodopsin (ppR) from Natronomonas pharaonis is a transmembrane photoreceptor protein involved in negative phototaxis. Structural changes in ppR triggered by photoisomerization of the retinal chromophore are transmitted to its cognate transducer protein (pHtrII) through a cyclic photoreaction pathway involving several photointermediates. This pathway is called the photocycle. It is important to understand the detailed configurational changes of retinal during the photocycle. We previously observed one of the photointermediates (M intermediates) by in situ photoirradiation solid-state NMR experiments. In this study, we further observed the 13C cross-polarization magic-angle-spinning NMR signals of late photointermediates such as O- and N'-intermediates by illumination with green light (520 nm). Under blue-light (365 nm) irradiation of the M-intermediates, 13C cross-polarization magic-angle-spinning NMR signals of 14- and 20-13C-labeled retinal in the O-intermediate appeared at 115.4 and 16.4 ppm and were assigned to the 13-trans, 15-syn configuration. The signals caused by the N'-intermediate appeared at 115.4 and 23.9 ppm and were assigned to the 13 cis configuration, and they were in an equilibrium state with the O-intermediate during thermal decay of the M-intermediates at -60 degrees C. Thus, photoirradiation NMR studies revealed the photoreaction pathways from the M- to O intermediates and the equilibrium state between the N'- and O-intermediate. Further, we evaluated the detailed retinal configurations in the O- and N' intermediates by performing a density functional theory chemical shift calculation. The results showed that the N'-intermediate has a 63 degrees twisted retinal state due to the 13-cis configuration. The retinal configurations of the O- and N'-intermediates were determined to be 13-trans, 15-syn, and 13 cis, respectively, based on the chemical shift values of [20-13C] and [14-13C] retinal obtained by photoirradiation solid-state NMR and density functional theory calculation. PMID- 29972814 TI - HIV-1 Env gp41 Transmembrane Domain Dynamics Are Modulated by Lipid, Water, and Ion Interactions. AB - The gp41 transmembrane domain (TMD) of the envelope glycoprotein of the human immunodeficiency virus modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Targeting the envelope glycoprotein with small-molecule and antibody therapies requires an understanding of gp41 TMD dynamics, which is often challenging given the difficulties in describing native membrane properties. Here, atomistic molecular dynamics simulations of a trimeric, prefusion gp41 TMD in a model, asymmetric viral membrane that mimics the native viral envelope were performed. Water and chloride ions were observed to permeate the membrane and interact with the highly conserved arginine bundle, (R696)3, at the center of the membrane and influenced TMD stability by creating a network of hydrogen bonds and electrostatic interactions. We propose that this (R696)3 - water - anion network plays an important role in viral fusion with the host cell by modulating protein conformational changes within the membrane. Additionally, R683 and R707 at the exofacial and cytofacial membrane-water interfaces, respectively, are anchored in the lipid headgroup region and serve as a junction point for stabilization of the termini. The membrane thins as a result of the tilting of the gp41 trimer with nearby lipids increasing in volume, leading to an entropic driving force for TMD conformational change. These results provide additional detail and perspective on the influence of certain lipid types on TMD dynamics and a rationale for targeting key residues of the TMD for therapeutic design. These insights into the molecular details of TMD membrane anchoring will build toward a greater understanding of the dynamics that lead to viral fusion with the host cell. PMID- 29972815 TI - TraceSpecks: A Software for Automated Idealization of Noisy Patch-Clamp and Imaging Data. AB - Experimental records of single molecules or ion channels from fluorescence microscopy and patch-clamp electrophysiology often include high-frequency noise and baseline fluctuations that are not generated by the system under investigation and have to be removed. Moreover, multiple channels or conductance levels can be present at a time in the data that need to be quantified to accurately understand the behavior of the system. Manual procedures for removing these fluctuations and extracting conducting states or multiple channels are laborious, prone to subjective bias, and likely to hinder the processing of often very large data sets. We introduce a maximal likelihood formalism for separating signal from a noisy and drifting background such as fluorescence traces from imaging of elementary Ca2+ release events called puffs arising from clusters of channels, and patch-clamp recordings of ion channels. Parameters such as the number of open channels or conducting states, noise level, and background signal can all be optimized using the expectation-maximization algorithm. We implement our algorithm following the Baum-Welch approach to expectation-maximization in the portable Java language with a user-friendly graphical interface and test the algorithm on both synthetic and experimental data from the patch-clamp electrophysiology of Ca2+ channels and fluorescence microscopy of a cluster of Ca2+ channels and Ca2+ channels with multiple conductance levels. The resulting software is accurate, fast, and provides detailed information usually not available through manual analysis. Options for visual inspection of the raw and processed data with key parameters are provided, in addition to a range of statistics such as the mean open probabilities, mean open times, mean close times, dwell-time distributions for different number of channels open or conductance levels, amplitude distribution of all opening events, and number of transitions between different number of open channels or conducting levels in asci format with a single click. PMID- 29972817 TI - Removing the Incarcerated Tunneled Cuffed Venous Catheters: An Experience from a Single Center. PMID- 29972816 TI - Coupling Magnetically Induced Electric Fields to Neurons: Longitudinal and Transverse Activation. AB - We present a theory and computational models to couple the electric field induced by magnetic stimulation to neuronal membranes. Based on the characteristics of magnetically induced electric fields and the modified cable equation that we developed previously, quasipotentials are derived as a simple and accurate approximation for coupling of the electric fields to neurons. The conventional and modified cable equations are used to simulate magnetic stimulation of long peripheral nerves by circular and figure-8 coils. Activation thresholds are obtained over a range of lateral and vertical coil positions for two nonlinear membrane models representing unmyelinated and myelinated straight axons and also for undulating myelinated axons. For unmyelinated straight axons, the thresholds obtained with the modified cable equation are significantly lower due to transverse polarization, and the spatial distributions of thresholds as a function of coil position differ significantly from predictions by the activating function. However, the activation thresholds of unmyelinated axons obtained with either cable equation are very high and beyond the output capabilities of conventional magnetic stimulators. For myelinated axons, threshold values are similar for both cable equations and within the range of magnetic stimulators. Whereas the transverse field contributes negligibly to the activation thresholds of myelinated fibers, axonal undulation can significantly increase or decrease thresholds depending on coil position. The analysis provides a rigorous theoretical foundation and implementation methods for the use of the cable equation to model neuronal response to magnetically induced electric fields. Experimentally observed stimulation with the electric fields perpendicular to the nerve trunk cannot be explained by transverse polarization and is likely due to nerve fiber undulation and other geometrical inhomogeneities. PMID- 29972818 TI - Continuous Veno-Venous High Cut-Off Hemodialysis Compared to Continuous Veno Venous Hemodiafiltration in Intensive Care Unit Acute Kidney Injury Patients. AB - AIMS: High cut-off (HCO) continuous veno-venous hemodialysis (CVVHD) was compared to high-flux membrane (HFM) continuous veno-venous hemodiafiltration (CVVHDF) in intensive care unit (ICU) acute kidney injury (AKI) in terms of efficiency, hemodynamic tolerance, medium-sized molecules removal, albumin loss, and inflammatory system activation. METHODS: In a prospective cross-over randomized study, 10 AKI patients underwent successively HCO (Ultraflux EmiC2: beta2 microglobulin [beta2M] sieving coefficient [SC]: 0.9) CVVHD and HFM (Ultraflux AV1000S: beta2M SC: 0.65) -CVVHDF. RESULTS: Over the 20 sessions, hypotensive and febrile episodes, reduction rates of urea, creatinine, and beta2M were similar in both modalities. Though dialysis dose was higher with CVVHDF (36 +/- 4 vs. 21 +/- 6 mL/Kg/h), urea, creatinine, and beta2M instantaneous and plasmatic clearances did not differ except for urea at 12 h. Protein loss, superoxide anion production, cytokines, and growth factors variations were also comparable. CONCLUSION: HCO CVVHD is well tolerated and is as effective as HFM CVVHDF in clearance of solutes and removal of beta2M. It induces neither protein loss nor overproduction of superoxide anion. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=489082. PMID- 29972819 TI - Mitochondrial Activity and Unfolded Protein Response are Required for Neutrophil Differentiation. AB - BACKGROUND/AIMS: Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) are involved in hematopoietic differentiation. However, the mechanistic linkage between ER stress/UPR and hematopoietic differentiation remains unclear. METHODS: We used bipotent HL-60 cells as an in vitro hematopoietic differentiation system to investigate the role of ER stress and UPR activity in neutrophil and macrophage differentiation. RESULTS: The in vitro differentiation analysis revealed that ER stress decreased during both neutrophil and macrophage differentiations, and the activities of PERK and ATF6 were decreased and that of IRE1alpha was increased during neutrophil differentiation in a stage-specific manner. By contrast, the activities of ATF6 and ATF4 decreased during macrophage differentiation. When the cells were treated with oligomycin, the expression of CD11b, a myelocytic differentiation marker, and morphological differentiation were suppressed, and XBP-1 activation was inhibited during neutrophil differentiation, whereas CD11b expression was maintained, and morphological differentiation was not obviously affected during macrophage differentiation. CONCLUSION: In this study, we demonstrated that neutrophil differentiation is regulated by ER stress/UPR that is supported by mitochondrial ATP supply, in which IRE1alpha-XBP1 activation is essential. Our findings provide the evidence that mitochondrial energy metabolism may play a critical role in neutrophil differentiation. PMID- 29972820 TI - Activator Protein-2beta Promotes Tumor Growth and Predicts Poor Prognosis in Breast Cancer. AB - BACKGROUND/AIMS: Activator protein-2 (AP-2) transcription factors have been proved to be essential in maintaining cellular homeostasis and regulating the transformation from normal growth to neoplasia. However, the role of AP-2beta, a key member of AP-2 family, in breast cancer is rarely reported. METHODS: The effect of AP-2 on cell growth, migration and invasion in breast cancer cells were measured by MTT, colony formation, wound-healing and transwell assays, respectively. The expression levels of AP-2beta and other specific markers in breast cancer cell lines and tissue microarrays from the patients were detected using RT-PCR, Western blot and immunohistochemical staining. The regulation of AP 2beta on tumor growth in vivo was analyzed in a mouse xenograft model. RESULTS: We demonstrated the tumor-promoting function of AP-2beta in breast cancer. AP 2beta was found to be highly expressed in breast cancer cell lines and tumor tissues of breast cancer patients. The shRNA-mediated silencing of AP-2beta led to the dramatic inhibition of cell proliferation, colony formation ability, migration and invasiveness in breast cancer cells accompanied by the down regulated expression of some key proteins involved in cancer progression, including p75, MMP-2, MMP-9, C-Jun, p-ERK and STAT3. Overexpression of AP-2beta markedly up-regulated the levels of these proteins. Consistent with the in vitro study, the silencing or overexpression of AP-2beta blocked or promoted tumor growth in the mice with xenografts of breast cancers. Notably, the high AP-2beta expression levels was correlated with poor prognosis and advanced malignancy in patients with breast cancer. CONCLUSIONS: Our study demonstrates that AP-2beta promotes tumor growth and predicts poor prognosis, and may represent a potential therapeutic target for breast cancer. PMID- 29972821 TI - Concern about Falling and Complexity of Free-Living Physical Activity Patterns in Well-Functioning Older Adults. AB - BACKGROUND: Fall-related psychological concerns are common among older adults, potentially contributing to functional decline as well as to restriction of activities and social participation. To effectively prevent such negative consequences, it is important to understand how even very low concern about falling could affect physical activity behavior in everyday life. We hypothesized that concern about falling is associated with a reduction in diversity, dynamics, and performance of daily activities, and that these features can be comprehensively quantified in terms of complexity of physical activity patterns. METHODS: A sample of 40 community-dwelling older adults were assessed for concern about falling using the Falls Efficacy Scale-International (FES-I). Free-living physical activity was assessed using a set of metrics derived from data recorded with a chest-worn tri-axial accelerometer. The devised metrics characterized physical activity behavior in terms of endurance (total locomotion time, longest locomotion period, usual walking cadence), performance (cadence of longest locomotion period, locomotion periods with at least 30 steps and 100 steps/min), and complexity of physical activity patterns. Complexity was quantified according to variations in type, intensity, and duration of activities, and was considered as an adaptive response to environmental exigencies over the course of the day. RESULTS: Based on FES-I score, participants were classified into two groups: not concerned at all/fully confident (n = 25) and concerned/less confident (n = 15). Demographic and health-related variables did not differ significantly between groups. Comparison of physical activity behavior indicated no significant differences for endurance-related metrics. In contrast, performance and complexity metrics were significantly lower in the less confident group compared to the fully confident group. Among all metrics, complexity of physical activity patterns appeared as the most discriminative feature between fully confident and less confident participants (p = 0.001, non-parametric Cliff's delta effect size = 0.63). CONCLUSIONS: These results extend our understanding of the interplay between low concern about falling and physical activity behavior of community dwelling older persons in their everyday life context. This information could serve to better design and evaluate personalized intervention programs in future prospective studies. PMID- 29972824 TI - Haemodialysis with Tinzaparin Versus Dialysate Citrate as Anticoagulation. AB - Anticoagulation with citrate-containing haemodialysate (cHD) is an alternative to tinzaparin haemodialysate (tHD). The study investigated whether cHD would differ when changed from tHD. The same 18 patients were their own controls followed up with cHD for 5 months. LDL-cholesterol decreased at the end of a cHD session (p = 0.01). Neutrophils (p = 0.013) and monocytes (p = 0.007) dropped more during a cHD session. During the follow-up period of cHD, approximately 50% needed additional tinzaparin. Before the cHD session could start, there was a lower total cholesterol at 2 weeks (p = 0.014) and LDL-cholesterol at 1 month (p = 0.011) versus an increase of LDL at 5 months (p = 0.02). Only patients without additional tinzaparin had a reduction of -C-reactive protein (CRP) at 2 months of cHD (p < 0.05) but not later. Solely cHD seems possible only in half of the patients. A greater reduction in granulocytes and monocytes during cHD indicates a more extensive blood membrane interaction, while CRP may be lower. PMID- 29972822 TI - Deep RNA Sequencing Reveals a Repertoire of Human Fibroblast Circular RNAs Associated with Cellular Responses to Herpes Simplex Virus 1 Infection. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs), a new class of regulators of gene expression, are involved in diverse physiological and pathogenic processes. However, their role in cellular responses to virus infection is yet unclear. METHODS: A human lung fibroblast cell line was infected or mock infected by herpes simplex virus 1 (HSV-1). Deep RNA sequencing was used to profile the global changes in circRNAs, genes, and miRNAs following HSV-1 infection. Altered circRNAs, genes, and miRNAs were validated using quantitative reverse transcription polymerase chain reaction (RT-qPCR). An integration analysis of circRNAs, genes, and miRNAs was applied to investigate the putative function of the dysregulated circRNAs. RESULTS: A total of 536 circRNAs, 3,885 genes, and 207 miRNAs were significantly dysregulated after HSV-1 infection. An integration analysis of circRNAs, genes, and miRNAs revealed the alleged involvement of dysregulated circRNAs in cellular responses to HSV-1 infection via the circRNA miRNA-gene regulatory axis. These genes regulated by circRNAs were enriched to NOD-like receptor/JAK-STAT signaling pathway, and pathways of apoptosis, cell cycle progression, and cell death, all of which may be implicated in the viral pathogenesis and cellular immunity. CONCLUSIONS: These data present a comprehensive view for circRNAs induced by HSV-1 and their interplay with miRNAs and genes during HSV-1 infection, thus offering new insights into the mechanisms of interactions between HSV-1 and the host. PMID- 29972823 TI - Fetal Hydrops Secondary to in utero Pancytopenia. AB - Nonimmune hydrops remains a challenge in the prenatal setting with many cases not having a clear etiology determined prior to birth. We present an unusual case of one fetus of a dichorionic twin pair presenting at 24 weeks' gestation with hydrops and fetal pancytopenia with complete absence of white cells of unknown etiology, as revealed by cordocentesis. Serial red blood cell transfusions resulted in resolution of hydrops and continuation of the pregnancy until 35 weeks' gestation. Pancytopenia was noted throughout gestation and persisted in the newborn period. Moreover, the T-cell receptor excision circle (TREC) assay, a newborn screening test for severe T-cell deficiency, was abnormal at birth. Further evaluation revealed detectable TRECs and normal response to lymphocyte mitogens indicating some preserved thymic and lymphocyte function. The affected child had spontaneous resolution of the pancytopenia, including her severe T-cell deficiency, by 10 weeks of life. There has been no recurrence as of 24 months of age. The self-resolving nature of the pancytopenia is an important feature of this case of nonimmune hydrops. The abnormal TREC assay at birth in the affected infant may help explain the discordant prenatal findings. PMID- 29972825 TI - Coupled Plasma Filtration Adsorption: A Multipurpose Extracorporeal Detoxification Therapy. AB - Coupled plasma filtration adsorption (CPFA) is a detoxification system that combines a plasma adsorption circuit with a continuous renal replacement therapy. The circuit consists of a plasma filter, a resin/adsorbent cartridge and a haemofilter. It differs from many other types of extracorporeal therapies in that the upper part of the circuit can be considered a "closed loop". In this manner, the plasma separated by the plasma filter passes through an adsorbent cartridge containing a resin with high affinity to many cytokines, mediators and toxins/poisons. After passing through the cartridge, the purified plasma is returned to the patient. The second part of the circuit, the haemofilter, can then be used to remove small toxins that are not adsorbed by the resin or to modulate the patient hematic volume. Although more complex, the use of a plasma separation step prior to the passage through the resin cartridge offers advantages over adsorption by haemoperfusion. The plasma passes through the resin cartridge with a lower velocity than the blood flow, and this allows better contact time for the toxins with the resin, and more thorough penetration into the resin pores. The adsorption of many toxins is highly dependent on a factor expressed as linear velocity. In addition, the plasma does not contain cells or a very limited number of platelets, allowing less potential activation upon contact with the resin. Although the technique was originally developed for the treatment of sepsis and septic shock, there are many additional applications where there can be an advantage of having access to larger molecular weight toxins (compared to haemofiltration) and avoiding the loss of important physiologic substances such as albumin. Some of these new applications, in patients with or without acute kidney injury, include liver failure, rhabdomyolysis, severe autoimmune exacerbations and poisonings. In this article, we discuss some of the basic principles involved in sorbent technology, and how these may contribute to treatment efficacy, review the actual experiences with CPFA and finally discuss the results of recent human studies and their implications. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=490234. PMID- 29972827 TI - Effects of Initiation Time of Glycemic Control on Skin Collagen Recovery in Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND: Diabetes damages the collagen in the skin. No study has investigated the relationship between the treatment initiation time and the degree of collagen recovery. This study aimed to evaluate the effects of the initiation time of glycemic control on collagen recovery and to determine the basic molecules mediating the process. METHODS: Streptozotocin-induced diabetic rats were divided into five groups: normal controls (C), those with untreated diabetes (DM), and those with diabetes treated with daily insulin injections from 7 weeks (7W), 10 weeks (10W), and 13 weeks (13W) after diabetes induction. The levels of collagen and several molecules were compared among skin tissues collected at 14 weeks. RESULTS: The amounts of total collagen, collagen 1, and collagen 3 were significantly lower in DM than in C. Among the treated groups, recovery reaching normal levels was only observed in 7W and 10W. The earlier the treatment began, the greater was the collagen recovery. Similar to that of collagen, the expression of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), and insulin-like growth factor 1 receptor (IGF-1R) significantly decreased in DM compared with that in C. Higher recovery of TGF beta1 and VEGF was detected in groups with earlier treatment, whereas the IGF-1R level was identically elevated in all treated groups. The results suggest that these molecules affect collagen recovery at different time points during glycemic control. CONCLUSION: The initiation time of glycemic control is expected to have a considerable effect on collagen recovery in the diabetic skin through modulation of TGF-beta1, VEGF, and IGF-1R. PMID- 29972826 TI - Plasma Level of Retinol-Binding Protein 4, N-Terminal proBNP and Renal Function in Older Patients Hospitalized for Heart Failure. AB - BACKGROUND/AIM: Elevated plasma concentration of retinol-binding protein 4 (RBP4) has recently emerged as a potential new risk factor for cardiovascular diseases, including hypertension (HT) and coronary artery disease (CAD). Limited data suggest that RBP4 promotes inflammatory damage to cardiomyocytes and participates in the development of heart failure (HF). This study aimed to analyze the relationship between concentrations of plasma RBP4 and serum N-terminal proBNP (NT-proBNP), a powerful biomarker of left ventricle dysfunction, in the older Polish population. METHODS: The study sample consisted of 2,826 (1,487 men) participants of the PolSenior study, aged 65 years and older, including a subgroup hospitalized for HF (n = 282). In all subjects, plasma concentrations of RBP4, interleukin-6 (IL-6), serum level of NT-proBNP, and hs-CRP were measured. Additionally, BMI, estimated glomerular filtration rate (eGFR), and HOMA-IR were calculated. The prevalence of HT, CAD, atrial fibrillation (AF), and medication were considered as potential confounders. RESULTS: Similar RBP4 levels were found in subjects with NT-proBNP < 125 and >=125 ng/mL, with and without AF, and in the subgroups hospitalized for HF with and without AF. Regression analysis revealed no association between log10(NT-proBNP) and log10(RBP4). Plasma levels of RBP4 were increased by HT occurrence and diuretic therapy, while diminished with regard to female gender, age, eGFR values, AF, and IL-6 levels. CONCLUSION: Our results show that RBP4 is affected by GFR but cannot be considered as an independent biomarker of heart muscle dysfunction. PMID- 29972828 TI - Reducing Fibrinogen and Factor XIII Using Double-Filtration Plasmapheresis for Antibody-Mediated Rejection: Predictive Models. AB - BACKGROUND/AIMS: Antibody-mediated rejection (AMR) is related to circulating donor-specific anti-human leukocyte antigen alloantibodies (DSAs). DSAs can be removed by apheresis, for example, double-filtration plasmapheresis (DFPP). However, DFPP removes some clotting factors (fibrinogen and factor XIII [FXIII]). METHODS: This was a prospective trial including 6 DSA-mediated AMR kidney transplant recipients. Patients received 2 cycles of 3-4 consecutive DFPP sessions followed by 1 injection of rituximab (break of 4-5 days between the 2 cycles). We monitored fibrinogen and FXIII levels before and after each session of DFPP. RESULTS: Overall, fibrinogen and FXIII levels were significantly decreased after each session, and were significantly reduced between the very first and very last sessions. In addition, we established a model that predicted fibrinogen and FXIII values after each session and after 2 cycles. CONCLUSION: We established a model in order to predict fibrinogen and FXIII depletion after DFPP sessions; it may help clinicians supplement fibrinogen and/or FXIII when appropriate. PMID- 29972829 TI - Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells. AB - Coronary heart disease (CHD) remains a major public health burden. Endothelial dependent coronary artery vasoreactivity is a significant indicator of vascular function. Endothelial dysfunction is characterized by decreased nitric oxide (NO) bioavailability and predicts late cardiovascular events. Astragaloside IV (AGIV) is the main active component of the herb Astragalus membranaceus. Although it shows a significant protective effect against vascular endothelial dysfunction, the mechanisms of AGIV promoting the vascular dilation have not been elucidated. This study investigated the vasodilator effect of AGIV on rat aortic rings and the underlying effect of AGIV via the PI3K/Akt/eNOS signaling pathway. We measured the relaxation of isolated RARs after different concentrations of AGIV treatment. Rat aorta endothelial cells were cultured with different doses of AGIV, dimethylsulfoxide, and NG-nitro L-arginine methyl ester. The expression of phosphorylated (p)-Akt and -endothelial nitric oxide synthase (p-eNOS) were tested by Western blot analysis. The messenger (m)RNA expression of eNOS was quantified by real-time polymerase chain reaction. AGIV exerted a vasodilator effect on the aortic rings and increased the NO content in a concentration dependent manner. The vasorelaxation was suppressed by an eNOS inhibitor. AGIV regulated the PI3K/Akt/eNOS signaling pathway via phosphorylation of Akt at Ser473 and dephosphorylation of eNOS at Thr495. The mRNA expression of eNOS was remarkably upregulated by AGIV. AGIV significantly induced the dilation of the aortic rings, leading to the vasodilator response by enhancing the eNOS release via the PI3K/Akt/eNOS signaling pathway. PMID- 29972830 TI - Dyskalemia in Chronic Kidney Disease: How Concerned Should We Be? AB - CONTEXT: The widespread use of diuretics, potassium supplements, and medications that block renin angiotensin system puts the chronic kidney disease (CKD) population at high risk for dyskalemia, both hyperkalemia and hypokalemia. The optimal potassium level in a CKD patient is unknown. Subject of review: Two recent studies found conflicting results on the association of dyskalemia with outcomes. The Renal Research Institute CKD study [Clin J Am Soc Nephrol 2010; 5: 762-769] found increased mortality and incidence of end-stage renal disease (ESRD) with mild to moderate hypokalemia, whereas hyperkalemia was not significantly associated, compared to eukalemia. On the other hand, the Multi Ethnic Study of Atherosclerosis (MESA)/Cardiovascular Health Study [Clin J Am Soc Nephrol 2017; 12: 245-252] showed both cardiovascular and noncardiovascular mortality to be higher with hyperkalemic patients, whereas associations with hypokalemic patients were statistically nonsignificant. Second opinion: If mild hypo- or hyperkalemia is associated with adverse outcomes, is it related to the hyperkalemia per se or to conditions associated with dyskalemia, such as kidney disease or cardiovascular disease? We interpret these articles in the context of criteria to support causality in epidemiologic studies. The cardiovascular effects of dyskalemia is well described and there is biological plausibility for increased cardiovascular mortality but the association of increased non cardiovascular mortality with dyskalemia has little mechanistic basis. The explanation for a causal association of dyskalemia with ESRD is not adequate. Based on current evidence, targeting a potassium level of 4-5 mmol/L can be considered safe. PMID- 29972835 TI - [Inflammatory bowel disease: pathogenesis and therapy]. PMID- 29972834 TI - [Quality of Blood Pressure Control in General Practice Using Ambulatory Blood Pressure Monitoring - a Retrospective Monocentric Cross-Sectional Study]. AB - INTRODUCTION: The diagnosis and therapy of arterial hypertension is a continuous challenge in general practice. The aim of this study is to analyze the nature and effectiveness of blood pressure control in patients with known arterial hypertension in a primary care practice using office- (OBPM) and ambulatory (ABPM) blood pressure measurement. METHODS: 283 patients (90 % of all regularly treated patients having hypertension) were retrospectively examined for the achievement of the target blood pressure values in ABPM and OBPM in the past 1 to 2 years. Target blood pressure levels were in line with current ESH recommendations (office blood pressure < 140/90 mmHg, mean 24-h ABPM < 130/80 mmHg). RESULTS: The OBPM of all patients (age: 68 +/- 12.7, 48 % women) was 132 +/- 11.8/80 +/- 4.2 mmHg, the 24-h ABPM was 128 +/- 10.7/74 +/- 7.9 mmHg. An isolated office hypertension had 11.3 %, a masked hypertension 21.9 %. Only 33.9 % had physiological dipping behavior (49.1 % non-dipper, 13.8 % reverse dipper and 3.2 % extreme dipper). The blood pressure control rate (reaching the target blood pressure) was 67.8 % in the OBPM and 57.2 % in the 24-h ABPM. 23.0 % were treated with monotherapy, 37.5 % with dual combination, 19.8 % with a triple combination and 14.5 % with > 3 antihypertensives. 83.9 % of all had RAS blockers. The OBPM target was achieved in 75.0 % under a triple and 71.7 % under dual combination. The 24-hour ABPM target was mostly achieved in patients requiring only monotherapy (66.2 %) or dual therapy (60.4 %); others < 60 %. CONCLUSION: In the family practice examined, the treatment control of patients with arterial hypertension was mostly guideline-based and better than described in the literature. The parallel and consistent implementation of ABPM in addition to OBPM as well as the high prescription rate of RAS blockers and recommended combination therapies might be the key for this result. PMID- 29972836 TI - [Optical Coherence Tomography in ST-Elevation Myocardial Infarction]. PMID- 29972837 TI - [Inflammatory bowel disease: cardinal signs and their diagnostics]. AB - Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, often occur early in life. Therefore, they affect our patient's individual path of life, their ability to work and the quality of life tremendously, which calls for close and comprehensive medical care. This article features 5 cardinal signs and their diagnostics. PMID- 29972838 TI - [Inflammatory Bowel Diseases - Diagnosis and Therapy in Practice]. AB - Significant increases in Crohn's disease incidence have been noticed in recent decades. Therefore it gets more important to increase practical knowledge, present therapy innovations and draw attention to the need for vaccinations of immunosuppressed IBD patients as well as useful supportive therapy options. PMID- 29972839 TI - [Crohn's Disease - New Therapies]. AB - New promising treatment options for chronic inflammatory bowel diseases, confirm the expanded pathophysiological understanding in terms of the interactions of the gastrointestinal microbiome with the adaptive and innate immune response and barrier protection. Therefore, these interrelations are focus of research and therapeutic strategies. The following review will give insights into the pathomechanisms, current treatment options and future developments. PMID- 29972840 TI - [The use of Idarucizumab in intracerebral bleeding - a case report]. AB - HISTORY AND CLINICAL FINDINGS: 82-year old male patient suspected of having cerebral hemorrhage under anticoagulation therapy with Dabigatran due to atrial fibrillation. INVESTIGATIONS: CT scan showed bilateral chronic subdural hematomas with fresh blood in left-subdural hematoma and midline shift. Laboratory analysis shows only a moderately high Dabigatran level but thrombin time was high out of range. DIAGNOSIS: Fall-related intracerebral haemorrhage and subdural hematoma under anticoagulation therapy. THERAPY AND COURSE: Neurosurgical hematoma evacuation and trepanation after preoperative use of Idarucizumab as an antidote for Dabigatran to stop anticoagulative effects and secure normal bleeding conditions, led to reduced midline shift. We started heparin-based anticoagulation first followed by Dabigatran again in clinical steady state and after rehabilitation with neurologically low-grade residuals. PMID- 29972841 TI - [Urine Examination - Step by Step]. AB - The examination of the urine is the oldest and a very basic technique for every nephrologist. It helps to detect, diagnose and classify diseases of the kidneys and the urinary tract. Proteinuria is an important sign of kidney disease and an own factor in the pathophysiology of renal progression. Acanthocytes in the urine (> 5 %) have a high specifity (98 - 100 %) for diagnosing a glomerular hematuria. PMID- 29972842 TI - [Peripheral neuropathy as a side effect of chemotherapy and targeted therapy]. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and common side effect induced by a variety of anticancer drugs. CIPN presents as a sensory, motor, and sometimes autonomic dysfunction with a large variability, from a mild tingling sensation and hyperesthesia, to severe neuropathic pain. Up to 40 % of patients will develop CIPN which may lead to dose-reduction or discontinuation of their current treatment and largely affects their quality of life (QoL). This review presents specific clinical features and pathomechanisms and discusses current preventive strategies and therapeutic options. PMID- 29972843 TI - ? PMID- 29972844 TI - ? PMID- 29972845 TI - Ultrasound Nomograms of the Fetal Optic Nerve Sheath Diameter. PMID- 29972846 TI - ? PMID- 29972847 TI - ? PMID- 29972848 TI - Reply to the Letter: 'Le Scientisme, c'est la Pretention indue au Monopole de verite, alors que le Propre de la Science c'est de dire: il n'y a pas de Monopole' (Edgar Morin). PMID- 29972849 TI - 'Imitation is the Sincerest of Flattery'...Except When It Negatively Impacts Canine and Client Welfare. PMID- 29972850 TI - [Implementation of Medical Emergency Teams to Improve Perioperative Patient Safety. Who? When? How?] AB - In contrast to prehospital emergency medicine, there are no comparable established structures or statutory requirements for structural and procedural organisation, or qualification of personnel and equipment for in-hospital emergency care in Germany. However, in perioperative patients, unexpected complications are fairly common on regular wards. Often, even hours before a possible critical event, warning signs of deterioration are present, which too often go unnoticed. Subsequently, potentially avoidable serious complications or cardiac arrest may occur. The establishment of so-called medical emergency teams (MET) serves to improve the emergency care organisation of the hospital and helps to avoid in-hospital cardiac arrest. The MET is alerted at an early stage of deterioration and uses a preventive therapy approach for pathophysiological deviations of the vital signs. This preventative approach can help to avoid in hospital cardiac arrest and unplanned admission to an intensive care unit and thus contribute to increase perioperative patient safety. PMID- 29972851 TI - Evaluation of Vascular Remodeling in Carotid Atherosclerosis Among Type 2 Diabetes Mellitus Patients Using High-Frequency Ultrasonography Combined with Serum Resistin. AB - Diabetes remains a long standing public health issue among the Chinese population, with an incidence of up to 11.6%, of which type 2 diabetes mellitus (T2DM) accounts for 85%-95%. During this study, we aimed to elucidate the value of high-frequency ultrasonography (HFUS) combined with serum resistin on vascular remodeling (VR) in carotid atherosclerosis (CA) among patients suffering from T2DM. A total of 432 T2DM were recruited and assigned into the short T2DM duration group (<5 years), middle T2DM duration group (5~10 years) and long T2DM duration group (>10 years), while another 172 healthy cases were recruited as the control group. The intima-media thickness (IMT) as well as plaque score, detection rate and type were detected by the HFUS. The respective blood pressure readings were measured and pulse pressure was calculated accordingly. The serum resistin level, remodeling incidence and type, levels of total cholesterol (TC), fasting blood glucose (FBG), low-density lipoprotein cholesterol (LDL-C), high density liproprotein cholesterol (HDL-C), and triglyceride (TG) were measured. The correlation between IMT, the plaque detection rate and blood pressure were analyzed. A receiver operating characteristic (ROC) curve was constructed in order to evaluate the impact of VR in CA on T2DM patients who were solely using HFUS and serum resistin respectively, as well as a combination of HFUS with serum resistin. As In comparison with the control group, the short, middle and long T2DM duration groups all displayed increased IMT, plaque score and detection rate, serum resistin level and VR incidence, especially for the long T2DM duration group. Levels of TC, TG, FBG and LDL-C were much higher while HDL-C was lower among patients with T2DM than those in the control group. A positive correlation was detected between the disease course and IMT. The detection rate of plaque with thickening IMT exhibited upregulated levels when compared to those with normal IMT. The HFUS, serum resistin and HFUS combined with serum resistin respective areas under the ROC curve were 0.873, 0.867 and 0.923, respectively, suggesting that the combination of HFUS and serum resistin was superior to that of individual HFUS or individual serum resistin in regard to the impact of VR in CA on T2DM patients. The results of this study revealed that the combination of HFUS and serum resistin was superior to individual HFUS or individual serum resistin in relation to its ability to evaluate the impact of VR in CA in patients with T2DM. PMID- 29972852 TI - [Peripheral Arterial Disease: When is a PCSK9 Inhibitor Useful?] AB - The guideline of the European Society of Cardiology recommends an LDL-C target < 70 mg/dL or a 50 % reduction in patients with manifest peripheral arterial disease (PAD) as well as in CHD or cerebrovascular disease when the baseline LDL C is between 70 and 135 mg/dL. Application of a PCSK9 inhibitor allows target attainment for those patients who do not achieve this under maximal conventional therapy with a statin in combination with ezetemib. In the Fourier study, patients with PAOD who had neither a myocardial infarction nor a stroke at admission of the study had a significant risk reduction (RR) of both cardiovascular (RR = 0.67, 0.47 - 0.96, p = 0.0283) as well as extremity endpoints (RR = 0.43 (0.19 - 0.99; p = 0.042). In Germany these patients are primarily seen by angiologists. This group of vascular specialists is specifically mentioned in the decision of the Federal Joint Committee as one of those who may indicate treatment with PCSK9 inhibitors. PMID- 29972853 TI - Correction: Amiodarone-Induced Thyroid Dysfunction: A Clinical Update. PMID- 29972854 TI - [Bilateral Proximal Humerus Fracture - a Rare Combination with a High Complication Rate after Surgery]. AB - INTRODUCTION: Bilateral acute proximal humerus fractures are rare. There are no data available about these bilateral injuries. The aim of the study was to analyse bilateral proximal humerus fractures retrospectively in terms of incidence, complications and revisions. METHODS: All bilateral proximal humerus fractures were evaluated retrospectively using the institution's database, with the focus on cause of the injury, fracture severity and the clinical course compared to published information on monolateral proximal humerus fractures. Bilateral posterior dislocation fractures were excluded, because these fractures are a separate entity. RESULTS: Between 2005 and 2016, n = 17 patients were primarily treated within our hospital for an acute proximal humerus fracture on both sides (n = 12 female, n = 5 male, average age: 68 years; overall 34 proximal humerus fractures). The general trauma mechanism was a fall on both arms (82% [18% polytrauma]). There were 65% displaced 3-/4-part proximal humerus fractures. Angle-stable plate osteosynthesis was performed predominantly (64%), followed by fracture prosthesis (18%; tension wiring: 3%; non-operatively: 15%). Overall, n = 10 patients (59%) or n = 18 (53%) proximal humerus fractures developed a complication, primarily with loss of reduction or implant loosening (44%). In n = 14 (78%) of the complications further operations were necessary. Alcohol abuse was increasingly found in 29% of the cases within the bilateral patient cohort compared to patients with monolateral fractures. CONCLUSION: Bilateral proximal humerus fractures are mainly associated with comminuted displaced fractures and a higher complication rate in comparison to monolateral fractures after surgical treatment. PMID- 29972855 TI - Metastasis from Intracranial Mesenchymal Chondrosarcoma: Report of a Rare Case. AB - Chondrosarcoma is a rare malignant tumor originating from cartilaginous tissue with a tendency to localize in the epiphysis of long and pelvic bones. Only 7% of all chondrosarcomas originate in the craniocervical region. Metastasis from intracranial chondrosarcoma is extremely rare with only two previously reported cases. We report on a young patient with intracranial chondrosarcoma who presented with extracranial metastasis 2 years after surgical excision of the primary lesion. Gross total excision combined with radiotherapy so far has led to a favorable outcome. PMID- 29972856 TI - Immunohistochemical Analysis of Cerebral Intraparenchymal Choroid Plexus Tumor: Case Report. AB - BACKGROUND: It is very rare for a choroid plexus tumor to occur intraparenchymally in the absence of a relation to the choroid plexus. CLINICAL PRESENTATION: A case of cerebral intraparenchymal choroid plexus tumor in a 30 year-old woman presenting with left hemiparesis is described. Brain magnetic resonance imaging depicted a large cystic mass in the right frontal lobe. Tumor resection was performed by right frontal craniotomy. No connection with the choroid plexus was observed during the operation. Histologically, the tumor exhibited a glandular structure with a papillary pattern suggesting a neoplasm of epithelial origin. Immunohistochemical analyses revealed the tumor as an atypical choroid plexus papilloma. CONCLUSION: Immunohistochemical findings, especially regarding Kir7.1, are very important for the differential diagnosis of cerebral intraparenchymal choroid plexus tumors from metastatic tumors. The present case reveals that an atypical choroid plexus papilloma can occur intraparenchymally without an association with the choroid plexus. Intraparenchymal atypical choroid plexus papillomas may have previously been diagnosed incorrectly as metastatic adenocarcinomas of unknown origin. PMID- 29972857 TI - Hemifacial Trigeminal Pain Referred from Occipital Neuralgia Due to Compression of the Greater Occipital Nerve by the Occipital Artery. AB - Although pathologic vascular contact between the occipital artery and the greater occipital nerve (GON) at the crossing point in the nuchal subcutaneous layer can cause occipital neuralgia, referred hemifacial trigeminal pain from chronic occipital neuralgia owing to this cause is extremely rare.A 61-year-old female patient with left-sided occipital neuralgia for 4 years presented with a new onset of left-sided hemifacial pain. Decompression of the left GON from pathologic contacts with the occipital artery resulted in immediate relief for hemifacial pain and chronic occipital neuralgia. The present case implies that sensitization and hyperactivity of the trigeminocervical complex that receives the convergent input from trigeminal and high cervical occipital nociceptive pathways can be a pathogenic mechanism in referred hemifacial pain from occipital neuralgia. In the present case, a branching tributary of the occipital artery at the crossing point forming a constricting loop above the course of the GON was found to be the cause of entrapment. Because the occipital artery is reported to be consistently located superficial to the GON at the crossing point, a spatial relationship between the occipital artery and the GON rather than a mere adhesion or contact might have pathologic significance in the development of occipital neuralgia. PMID- 29972858 TI - Atlantoaxial Instability in Patients Older Than 70 Years: What Is the Outcome When Further Conservative Treatment Is Not an Option? AB - OBJECTIVE: We report on our experiences of navigated posterior C1-C2 spondylodesis in the elderly (>= 70 years of age). PATIENTS: This retrospective cohort study evaluated all patients >= 70 years of age treated with navigated posterior spondylodesis C1-C2 (at the most to C3) from 2008 to 2015 with a minimum follow-up of 1 year. Minor and major complications within 30 days after surgery, patient outcome, and the rate of solid fusion in computed tomography were recorded. The follow-up over 1 year was conducted by outpatient examinations and via telephone interviews. RESULTS: Twenty-two patients with a mean age of 79.9 years (range: 71-91 years) were treated. Minor complications were mild pneumonia (18.2%), postoperative confusion (9.1%), and urinary tract infection (4.5%). Major complications were severe pneumonia (4.5%) and clinically asymptomatic vertebral artery injury (4.5%). The mortality rate was 13.6% (n = 3) within the first 30 days after surgery and 22.7% (n = 5) within 1 year. All deceased patients were > 85 years of age. CONCLUSION: In our patient population, posterior spondylodesis was shown to be beneficial for patients > 70 years up to age ~ 85 years. The mortality rate increased sharply in patients > 85 years. In these patients the indication for surgery should be critically evaluated. PMID- 29972859 TI - Reintroduction of the Rat for Experimental Subarachnoid Hemorrhage with Accelerated Clot Formation: A Low Mortality Model with Persistent Clots as a Precondition for Studies in Vasospasm. AB - BACKGROUND: Cerebral vasospasm as a delayed, possibly treatable sequel of subarachnoid hemorrhage (SAH) is a focus of experimental animal research. For this purpose, the rat is not a good model because of the difficulty creating a stable subarachnoid clot that persists > 1 to 2 days and could induce vasospasm. Only in rat models with a high mortality of ~ 50% or more can SAH and its effects be investigated. Therefore, other animals than rodents are used for investigating the delayed effects of SAH. Only animal studies addressing the acute effects of SAH use rats. OBJECTIVE: We designed a model that allows intensive clot formation combined with low mortality to facilitate studies on the delayed effects of experimental SAH, for example, delayed vasospasm or other alterations of vessels. METHODS: After in vitro acceleration of the clotting process in the rats' blood by tissue factor and preliminary in vivo testing, we induced a SAH by injecting blood together with tissue factor in 22 rats. We analyzed clot expansion, length of clot persistence, chronic alterations, and histologic changes. RESULTS: The injection of blood supplemented by tissue factor led to persistent voluminous blood clots in the subarachnoid space close to the large arteries. Despite the pronounced SAH, all animals survived, allowing investigation of delayed SAH effects. All animals killed within the first 7 days after surgery had extensive clots; in some animals, the clots remained until postoperative day 12. During further clot degradation connective tissue appeared, possibly as a precursor of SAH-related late hydrocephalus. CONCLUSION: The injection of blood together with tissue factor significantly improves SAH induction in the rat model. This rat model allows studying delayed SAH effects as found in humans. PMID- 29972860 TI - No Association between Thrombin Generation and Intra-Plaque Haemorrhage in Symptomatic Carotid Atherosclerotic Plaques: The Plaque at RISK (PARISK) Study. AB - BACKGROUND: Carotid atherosclerosis is an important cause of stroke. Intra plaque haemorrhage (IPH) on magnetic resonance imaging (MRI) increases stroke risk. Development of IPH is only partly understood. Thrombin is an essential enzyme in haemostasis. Experimental animal studies have shown conflicting results on the relation between thrombin and plaque vulnerability. We hypothesize that decreased thrombin generation (TG) is associated with IPH and plaque vulnerability. OBJECTIVE: This article investigates whether TG is associated with IPH and other features of plaque vulnerability in stroke patients. METHODS: Recently symptomatic stroke patients underwent carotid MRI and blood sampling. MRI plaque features include plaque burden, presence of IPH, amount of lipid-rich necrotic core (LRNC), calcified tissue and fibrous tissue (% of total wall volume). TG was assessed in platelet-poor plasma and expressed as: peak height (PH) and endogenous thrombin potential (ETP). MR images could be analysed in 224 patients. Blood samples were available in 161 of 224 patients. Binary multivariate logistic and linear regression were used to investigate the association between TG and MRI plaque features. RESULTS: IPH and LRNC were present in 65 (40%) and 102 (63%) of plaques. There were no significant associations between TG and IPH; PH odds ratio (OR) = 1, 95% confidence interval (CI): 0.76 to 1.45 and ETP OR = 1, 95% CI: 0.73 to 1.37. After correction for age, sex and hypercholesterolaemia, the association was weak but non-significant; PH: OR = 0.76, 95% CI: 0.52 to 1.10 and ETP: OR = 0.73, 95% CI: 0.53 to 1.37. CONCLUSION: Features of carotid plaque on MRI show no significant association with TG in stroke patients. Systemic TG does not seem to be an important factor in IPH development. PMID- 29972861 TI - Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial. AB - : Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration-time curve (AUC0-24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0-24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02683707 (: NCT02683707). PMID- 29972863 TI - Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients. AB - von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF, ABO and STXBP5. Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5. The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of pi = 3.2 * 10-4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population. PMID- 29972862 TI - Major Changes of von Willebrand Factor Multimer Distribution in Cirrhotic Patients with Stable Disease or Acute Decompensation. AB - BACKGROUND: There is an unstable balance between pro- and anti-haemostatic processes in patients with cirrhosis. We hypothesized, that in patients with acute decompensation (AD) the major alterations of von Willebrand factor (VWF) could contribute to the pro-thrombotic situation as compared to patients with stable (ST) cirrhosis. PATIENTS AND METHODS: We analysed different parameters of VWF, including detailed multimer distribution by densitometry and platelet adhesion, together with adisintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) activity and antigen and C-reactive protein (CRP) levels in patients with ST cirrhosis (n = 99), with AD (n = 54) and controls (n = 92). RESULTS: VWF antigen, ristocetin co-factor as well as collagen-binding activities were elevated in both cirrhotic groups in a stepwise manner. There was a decrease in high and an increase in low molecular weight multimer ratios in the majority of ST cirrhosis. However, in 24 out of 54 AD patients, ultra-large VWF multimers (ultra-large molecular weight multimers [ULMWM]) were found. ADAMTS13 activity in ST and AD patients without ULMWM was similar to controls (median [interquartile range; IQR]%: 98 [67-132] and 91 [60 110] vs. 106 [88-117], respectively). The presence of ULMWM in AD patients was associated with low ADAMTS13 activity [33 (24-49)%] and high CRP level [23 (7.1 83.6) mg/L]. Adhesion of normal platelets showed a stepwise increase in the presence of cirrhotic plasmas, reaching the highest level in AD patients with ULMWM. CONCLUSION: Characteristic changes of VWF parameters are seen in ST cirrhosis. In AD patients, highly increased VWF and reduced ADAMTS13 activity could be found, along with the presence of ULMWM, which are possible markers and contributors of the disease progression. PMID- 29972864 TI - Predicting Post-Thrombotic Syndrome with Ultrasonographic Follow-Up after Deep Vein Thrombosis: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a common and potential severe complication of deep venous thrombosis (DVT). Elastic compression stocking therapy may prevent PTS if worn on a daily basis, but stockings are cumbersome to apply and uncomfortable to wear. Hence, identification of predictors of PTS may help physicians to select patients at high risk of PTS. AIMS: This article identifies ultrasonography (US) parameters assessed during or after treatment of DVT of the leg, that predict PTS. METHODS: This is a systematic review and meta analysis study. Databases were searched for prospective studies including consecutive patients with DVT who received standardized treatment, had an US during follow-up assessing findings consistent with vascular damage after DVT and had a follow-up period of at least 6 months for the occurrence of PTS assessed by a standardized protocol. RESULTS: The literature search revealed 1,156 studies of which 1,068 were irrelevant after title and abstract screening by three independent reviewers. After full-text screening, 12 relevant studies were included, with a total of 2,684 analysed patients. Two US parameters proved to be predictive of PTS: residual vein thrombosis, for a pooled odds ratio (OR) of 2.17 (95% confidence interval [CI], 1.79-2.63) and venous reflux at the popliteal level, for a pooled OR of 1.34 (95% CI, 1.03-1.75). CONCLUSION: The US features reflux and residual thrombosis measured at least 6 weeks after DVT predict PTS. Whether these features may be used to identify patients who may benefit from compression therapy remains to be assessed in further studies. PMID- 29972865 TI - Celiac disease gene expression data can be used to classify biopsies along the Marsh score severity scale. AB - BACKGROUND AND AIM: The diagnosis of celiac disease autoimmune pathology relies on the subjective histological assignment of biopsies into Marsh score categories. It is hypothesized that Marsh score categories have unique gene expression signatures. The aims were as follows: first, to develop a celiac disease quantitative reverse transcription-polymerase chain reaction (RT-PCR) array; second, define gene expression signatures associated with Marsh score categories; and third, develop equations that classify biopsies into Marsh score categories and to monitor the efficacy of patient treatment. METHODS: Gene targets for inclusion in the celiac RT-PCR (qRT-PCR) array were identified using systematic analysis of published celiac transcriptomic data. The array was used to assess the gene expression associated with histological changes in duodenal biopsies obtained from adult patients. Finally, Marsh score classification equations were defined using discriminant analysis. RESULTS: The array contained 87 genes. The expression of 26 genes were significantly (p < 0.06) associated with the discrete Marsh score categories. As the Marsh score pathology of biopsies increased, there was a progression of innate immune gene expression through adaptive Th1-specific gene expression with a concurrent decrease in intestinal structural gene expression in high Marsh score samples. These 26 genes were used to define classification equations that accounted for 99% of the observed experimental variation and which could classify biopsies into Marsh score categories and monitor patient treatment progression. CONCLUSIONS: This proof-of-concept study successfully developed a celiac RT-PCR array and has provided evidence that discriminant equations defined using gene expression data can objectively and accurately classify duodenal biopsies into Marsh score categories. PMID- 29972866 TI - Physicochemical characterization of inorganic deposits associated with granulomas in cutaneous sarcoidosis. AB - BACKGROUND: Sarcoidosis, characterized by epithelioid granulomas, is considered to be caused by a complex interplay between genetics and environmental agents. It has been hypothesized that exogenous inorganic particles as crystalline silica could be a causal or adjuvant agent in sarcoidosis onset. OBJECTIVES: To investigate the location, frequency and physicochemical characteristics of foreign materials and mineral tissue deposits in the granulomatous area of cutaneous sarcoidosis. METHODS: Skin biopsies (n = 14) from patients diagnosed with cutaneous sarcoidosis (mean age 43 years; 11 patients with extracutaneous involvement) were investigated using polarized light examination (PLE), MUFourier Transform Infra-Red (MUFT-IR) spectroscopy and Field Emission Scanning Electron Microscopy coupled with Energy Dispersive X-ray Spectroscopy (FE-SEM/EDX). RESULTS: Combined PLE, MUFT-IR, FE-SEM/EDX analysis allowed to characterize mineral deposits in 7/14 biopsies (50%). It identified crystalline silica (SiO2 ) inside granulomas in three biopsies and calcite (CaCO3 ) at their periphery in 4. CONCLUSION: This study emphasizes the need of using combined methods for assessment of mineral deposits in granulomatous diseases. According to the location and characteristics of deposits, we can hypothesize that SiO2 particles contribute to the granuloma formation, whereas CaCO3 deposits are related to the granuloma biology. However, the significance of the association between SiO2 deposits and sarcoidosis is still disputed. PMID- 29972867 TI - Indium-111 labeling of high-density lipoprotein-mimicking phospholipid-styrene maleic acid copolymer complexes and its biodistribution in mice. AB - Discoidal lipid nanoparticles mimicking native high-density lipoproteins (HDL) are promising delivery vehicles of drugs and/or imaging agents. However, little is known about the in vivo biodistribution of such discoidal lipid nanoparticles compared to liposomes, clinically available spherical lipid nanoparticles. Recently, it has been reported that synthetic polymers instead of apolipoproteins can be complexed with phospholipid to form discoidal nanoparticles. In the present study, with the aim of developing phospholipid-synthetic polymer complexes for future clinical applications, the biodistribution of such particles in normal mice was investigated. Lipid nanoparticles comprising 1-palmitoyl-2 oleoyl-glycero-3-phosphocholine (POPC) and styrene maleic acid copolymer (SMA), having sizes similar to native HDL, were prepared using the freeze-sonication method. POPC-SMA complexes remained stable at 37 degrees C for at least 3 days in buffer. By devising ways to avoid detrimental effects accompanied by pH reduction and nonspecific binding of 111 In to SMA, POPC-SMA complexes were successfully labeled with 111 In without affecting particle integrity. The biodistribution of POPC-SMA complexes in normal mice was similar to that of discoidal lipid nanoparticles composed of POPC and apolipoprotein A-I, the major protein constituent of native HDL. Unlike liposomes, the accumulation of POPC-SMA complexes in the spleen was low, suggesting that these complexes are not recognized as foreign substances. To the best of our knowledge, this is the first in vivo study of HDL-mimicking phospholipid-synthetic polymer complexes. PMID- 29972868 TI - Technical Note: Enhancing soft tissue contrast and radiation-induced image changes with dual-energy CT for radiation therapy. AB - PURPOSE: The purpose of this work is to investigate the use of low-energy monoenergetic decompositions obtained from dual-energy CT (DECT) to enhance image contrast and the detection of radiation-induced changes of CT textures in pancreatic cancer. METHODS: The DECT data acquired for 10 consecutive pancreatic cancer patients during routine nongated CT-guided radiation therapy (RT) using an in-room CT (Definition AS Open, Siemens Healthcare, Malvern, PA) were analyzed. With a sequential DE protocol, the scanner rapidly performs two helical acquisitions, the first at a tube voltage of 80 kVp and the second at a tube voltage of 140 kVp. Virtual monoenergetic images across a range of energies from 40 to 140 keV were reconstructed using an image-based material decomposition. Intravenous (IV) bolus-free contrast enhancement in pancreas patient tumors was measured across a spectrum of monoenergies. For treatment response assessment, the changes in CT histogram features (including mean CT number (MCTN), entropy, kurtosis) in pancreas tumors were measured during treatment. The results from the monoenergetic decompositions were compared to those obtained from the standard 120 kVp CT protocol for the same subjects. RESULTS: Data of monoenergetic decompositions of the 10 patients confirmed the expected enhancement of soft tissue contrast as the energy is decreased. The changes in the selected CT histogram features in the pancreas during RT delivery were amplified with the low energy monoenergetic decompositions, as compared to the changes measured from the 120 kVp CTs. For the patients studied, the average reduction in the MCTN in pancreas from the first to the last (the 28th) treatment fraction was 4.09 HU for the standard 120 kVp and 11.15 HU for the 40 keV monoenergetic decomposition. CONCLUSIONS: Low-energy monoenergetic decompositions from DECT substantially increase soft tissue contrast and increase the magnitude of radiation-induced changes in CT histogram textures during RT delivery for pancreatic cancer. Therefore, quantitative DECT may assist the detection of early RT response. PMID- 29972870 TI - Further thoughts on combining Rome III criteria with alarm symptoms for functional gastrointestinal disorders. PMID- 29972869 TI - "But Problems Dwell so the Urge Is Constant..." Qualitative Data Analysis of the OST CHOICES Program. AB - BACKGROUND: Fetal alcohol spectrum disorders are a major public health concern including among American Indian (AI)/Alaska Native (AN) communities. Various studies have demonstrated higher alcohol consumption among AI/AN women during pregnancy compared with other groups. This study intends to understand the milieu within which such consumption patterns flourish. The study utilizes qualitative and quantitative data from the Oglala Sioux Tribe (OST) CHOICES Program, a tribally run public health program that aims to reduce alcohol-exposed pregnancy preconceptually in AI women. METHODS: Alcohol consumption pattern (n = 264) is analyzed using descriptive statistics. Consumption patterns included average drinks consumed daily, their choice of drinks (beer, whiskey, wine, etc.), how much money participants were spending on alcohol and amount of calories consumed from alcohol. Qualitative data analysis included open coding of data from decisional balance exercise of the CHOICES program that looked at good things and not so good things about participants' drinking. RESULTS: Women reported drinking an average of 12 drinks daily, ranging between 1 and 86. Women drinking at home spent a median of $4,320 and $12,960 if drinking at a bar. A median of 1,200 calories per day from alcohol was reported. More women reported drinking beer compared with other types of alcohol within a domestic setting. Qualitative data analysis identified positive and negative aspects of drinking among the participants of OST CHOICES Program. Positive aspects included escaping from problems, socializing, and relaxation. Negative aspects included impact on families and domestic violence. CONCLUSIONS: While understanding their milieu, our study also unraveled different struggles (such as violence, peer pressure, financial burden, and depression) encountered by Native women in their daily lives. According to the participants, positive aspects of drinking outweigh the negative aspects and they viewed their drinking as a solution and not a problem. PMID- 29972871 TI - The Effects of Long-term Administration of rhPTH(1-84) in Hypoparathyroidism by Bone Histomorphometry. AB - Hypoparathyroidism is a rare disorder that is associated with abnormal bone properties. Recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] in short term studies has beneficial skeletal effects. Although rhPTH(1-84) will likely be used indefinitely, long-term effects on skeletal microstructure are unknown. We therefore studied histomorphometric changes with transiliac crest bone biopsies before and after 8.3 +/- 1 years of rhPTH(1-84) in 13 hypoparathyroid subjects compared with 45 controls. Before institution of rhPTH(1-84), skeletal remodeling indices were markedly suppressed. With long-term treatment, indices of bone remodeling increased. Mineralizing surface increased by 26-fold (0.3 +/- 1 to 7.9 +/- 7%, p = 0.003), bone formation rate increased by 15-fold (0.003 +/- 0.01 to 0.047 +/- 0.05 MUm2 /MUm/day, p = 0.007), osteoid width doubled (1.9 +/- 1 to 4.3 +/- 1 lamellae, p = 0.017), and osteoid surface tripled (3.3 +/- 3 to 10.8 +/- 6%, p = 0.011). Bone resorption as measured by eroded surface increased (4.6 +/- 2 to 7.5 +/- 3%, p = 0.021). Structural changes demonstrated intratrabecular tunneling, with increases in cancellous bone volume (19.6 +/- 5 to 29.1 +/- 11%, p = 0.017) and trabecular number (1.8 +/- 1 to 2.5 +/- 1 #/mm, p = 0.025). Cortical porosity tended to increase (6.3 +/- 5 to 9.5 +/- 3%, p = 0.07). Mineralizing surface, osteoid surface, and eroded surface surpassed control levels, as did cancellous bone volume, trabecular number, and cortical porosity. These data, the first to reflect such long exposure of any PTH for any disease, illustrate that PTH establishes and maintains a new skeletal state for at least 8 years in hypoparathyroidism. (c) 2018 American Society for Bone and Mineral Research. PMID- 29972872 TI - A unique presentation of 'petrified ears' with pain due to fracture. PMID- 29972873 TI - Uric Acid: A Less-than-Perfect Probe for Singlet Oxygen. AB - Uric acid and/or its monoanion has long been used as chemical-trapping agents to demonstrate the presence of singlet oxygen, O2 (a1 Deltag ), in aqueous systems. "Oxidative bleaching" of uric acid, generally monitored through changes in the uric acid absorption spectrum, is often used in support of claims for the intermediacy of O2 (a1 Deltag ). The bleaching of uric acid has also been used to quantify photosensitized O2 (a1 Deltag ) yields in selected systems. Unfortunately, experiments performed to these ends often neglect processes and phenomena that can influence the results obtained. For the present study, we experimentally examined the behavior of uric acid under a variety of conditions relevant to the photoinitiated creation and subsequent removal of O2 (a1 Deltag ). Although the oxidative destruction of uric acid can indeed be a useful tool in some cases, we conclude that caution must be exercised such as not to incorrectly interpret the data obtained. PMID- 29972875 TI - Issue Information-Declaration of Helsinki. PMID- 29972874 TI - Whole-body biomechanical differences between limbs exist 9 months after ACL reconstruction across jump/landing tasks. AB - INTRODUCTION: Previous studies examining jump tasks after anterior cruciate ligament reconstruction (ACLR) have focused on performance measures without examining joint kinematic and kinetic variables. The aim of this study was to identify differences in biomechanical and performance measures between limbs across tests 9 months after surgery. METHODS: Four jump tests (double-leg drop jump (DLDJ), single-leg drop jump (SLDJ), single-leg hop for distance (SLHD) and hurdle hop (HH)) were carried out on 156 male subjects in a 3D motion capture laboratory 9 months after surgery. Statistical parametric mapping was used to identify differences in jump performance and biomechanical variables between limbs. RESULTS: Biomechanical measures were lower on the ACLR side across all four tests for internal knee valgus moment (effect size (ES) 0.77-0.92), knee internal rotation angle (ES 0.59-0.8), and ankle external rotation moment (ES 0.59-0.73), with the center of mass less posterior to the knee during the single leg tests (ES 0.61-0.82). The timing of the largest difference between limbs was not at the same % stance between variables within a test or for any variable across tests. Large ES differences were observed in performance in the SLDJ (ES 0.73-0.81; LSI 78%) and small differences in the SLHD (ES 0.36; LSI 94%) between the limbs. CONCLUSION: Findings highlighted biomechanical differences between limbs which are consistent across jump tasks suggesting insufficient rehabilitation at 9 months post surgery. Results indicate that the SLDJ may identify greater performance deficits between limbs than SLHD, which may over estimate rehabilitation status. PMID- 29972876 TI - The cotton stainer's gut microbiota suppresses infection of a cotransmitted trypanosomatid parasite. AB - The evolutionary and ecological success of many insects is attributed to mutualistic partnerships with bacteria that confer hosts with novel traits including food digestion, nutrient supplementation, detoxification of harmful compounds and defence against natural enemies. Dysdercus fasciatus firebugs (Hemiptera: Pyrrhocoridae), commonly known as cotton stainers, possess a simple but distinctive gut bacterial community including B vitamin-supplementing Coriobacteriaceae symbionts. In addition, their guts are often infested with the intestinal trypanosomatid parasite Leptomonas pyrrhocoris (Kinetoplastida: Trypanosomatidae). In this study, using experimental bioassays and fluorescence in situ hybridization (FISH), we report on the protective role of the D. fasciatus gut bacteria against L. pyrrhocoris. We artificially infected 2nd instars of dysbiotic and symbiotic insects with a parasite culture and measured parasite titres, developmental time and survival rates. Our results show that L. pyrrhocoris infection increases developmental time and slightly modifies the quantitative composition of the gut microbiota. More importantly, we found significantly higher parasite titres and a tendency towards lower survival rates in parasite-infected dysbiotic insects compared to symbiotic controls, indicating that the gut bacteria successfully interfere with the establishment or proliferation of L. pyrrhocoris. The colonization of symbiotic bacteria on the peritrophic matrix along the gut wall, as revealed by FISH, likely acts as a barrier blocking parasite attachment or entry into the hemolymph. Our findings show that in addition to being nutritionally important, D. fasciatus' gut bacteria complement the host's immune system in preventing parasite invasions and that a stable gut microbial community is integral for the host's health. PMID- 29972877 TI - Speciation in sympatry with ongoing secondary gene flow and a potential olfactory trigger in a radiation of Cameroon cichlids. AB - The process of sympatric speciation in nature remains a fundamental unsolved problem. Cameroon crater lake cichlid radiations were long regarded as one of the most compelling examples; however, recent work showed that their origins were more complex than a single colonization event followed by isolation. Here, we performed a detailed investigation of the speciation history of a radiation of Coptodon cichlids from Lake Ejagham, Cameroon, using whole-genome sequencing data. The existence of the Lake Ejagham Coptodon radiation is remarkable as this 0.5 km2 lake offers limited scope for divergence across a shallow depth gradient, disruptive selection is currently weak, and the species are sexually monochromatic. We infer that Lake Ejagham was colonized by Coptodon cichlids soon after its formation 9,000 years ago, yet speciation occurred only in the last 1,000-2,000 years. We show that secondary gene flow from a nearby riverine species has been ongoing, into ancestral as well as extant lineages, and we identify and date river-to-lake admixture blocks. One block contains a cluster of olfactory receptor genes that introgressed near the time of the first speciation event and coincides with a higher overall rate of admixture. Olfactory signalling is a key component of mate choice and species recognition in cichlids. A functional role for this introgression event is consistent with previous findings that sexual isolation appears much stronger than ecological isolation in Ejagham Coptodon. We conclude that speciation in this radiation took place in sympatry, yet may have benefited from ongoing riverine gene flow. PMID- 29972878 TI - Pathway position constrains the evolution of an ecologically important pathway in aspens (Populus tremula L.). AB - Many ecological interactions of aspens and their relatives (Populus spp.) are affected by products of the phenylpropanoid pathway synthesizing condensed tannins (CTs), whose production involves trade-offs with other ecologically important compounds and with growth. Genes of this pathway are candidates for investigating the role of selection on ecologically important, polygenic traits. We analysed sequences from 25 genes representing 10 steps of the CT synthesis pathway, which produces CTs used in defence and lignins used for growth, in 12 individuals of European aspen (Populus tremula). We compared these to homologs from P. trichocarpa, to a control set of 77 P. tremula genes, to genome-wide resequencing data and to RNA-seq expression levels, in order to identify signatures of selection distinct from those of demography. In Populus, pathway position exerts a strong influence on the evolution of these genes. Nonsynonymous diversity, divergence and allele frequency shifts (Tajima's D) were much lower than for synonymous measures. Expression levels were higher, and the direction of selection more negative, for upstream genes than for those downstream. Selective constraints act with increasing intensity on upstream genes, despite the presence of multiple paralogs in most gene families. Pleiotropy, expression level, flux control and codon bias appear to interact in determining levels and patterns of variation in genes of this pathway, whose products mediate a wide array of ecological interactions for this widely distributed species. PMID- 29972879 TI - Diagnosis of anti-laminin gamma-1 pemphigoid by immunoblot analysis. AB - BACKGROUND: Anti-laminin-gamma1 (lam-gamma1) pemphigoid, a recently described immunobullous disorder sharing immune serological features of bullous pemphigoid and epidermolysis bullosa acquisita (EBA), is characterized by the detection of serum IgG autoantibodies against the lam-gamma1 chain, a 200 kDa heterotrimeric component of the dermal-epidermal junction (DEJ). OBJECTIVE: The aim of the study was to develop an easy-to-perform and reliable assay for the serological detection of anti-lam-gamma1 IgG autoantibodies. The clinical appearance alone is not sufficient to establish diagnosis of anti-lam-gamma1 pemphigoid and rather requires immune serological evidence of (i) IgG reactivity against the dermal portion of salt-split human skin; (ii) exclusion of IgG against other components of the DEJ; and (iii) IgG reactivity with a 200 kDa protein of dermal extracts by immunoblot analysis (IB). METHODS: The sera of 55 patients with anti-lam-gamma1 pemphigoid were tested by IB with two recombinant heterotrimers, laminin 111 (lam 111) and laminin 421 (lam-421), as well as with a recombinant lam-gamma1 chain monomer. Additionally, a total of 41 control sera from patients with EBA (n = 15), psoriasis vulgaris (PV; n = 14), and healthy controls (HC; n = 12) were tested. RESULTS: Immunoblot analysis revealed a positive reactivity with lam-111 and/or lam-421 in 46/55 (84%) of anti-lam-gamma1 pemphigoid sera. Moreover, 8/9 of the initially non-reactive sera were positive with the lam-gamma1 monomer, leading to an overall sensitivity of 98.2%. Analyses of 41 control sera with the three lam-gamma1 recombinants led to a specificity of 88%. Specifically, 3/15 EBA sera, 1/14 PV serum and 1/12 HC serum reacted with the lam-gamma1 monomer while only the 3 EBA sera reacted with lam-421. CONCLUSIONS: Here we show a novel two step IB assay using the two recombinant laminin trimers and lam-gamma1 chain monomer for the detection of anti-lam-gamma1 serum IgG with high sensitivity and specificity. This assay will facilitate the diagnosis and further characterization of this disease. PMID- 29972880 TI - Genomic parallelism and lack thereof in contrasting systems of three-spined sticklebacks. AB - Parallel evolution and the extent to which it involves gene reuse have attracted much interest. Whereas it has theoretically been predicted under which circumstances gene reuse is expected, empirical studies that directly compare systems showing high and low parallelism are rare. Three-spined stickleback (Gasterosteus aculeatus), where freshwater populations have been independently founded by ancestral marine populations, represent prime examples of phenotypic and genomic parallelism, but cases exist where parallelism is low. Based on RAD (restriction site associated DNA) sequencing, we analysed SNPs and chromosome inversions in populations in Denmark and Greenland showing low and high parallelism, respectively. We identified parallelism across freshwater populations in Greenland at genomic regions previously identified to be associated with marine-freshwater divergence. These same markers also separated Danish marine and freshwater sticklebacks, albeit to a weaker extent. Hence, parallelism was not absent in Denmark but possibly constrained by spatially and temporally varying selection. Divergence time estimates found one Danish freshwater population to be much older than the others. It also deviated strongly with respect to parallelism and may represent earlier postglacial colonization based on a different pool of standing variation and eliciting different adaptive responses to freshwater conditions. These findings provide empirical support to previous suggestions that the time since replicate populations had access to a common pool of standing variation is a major factor determining gene reuse. At last, based on the observed parallelism in the Greenlandic system we discuss the predictability of adaptive responses in newly established populations. PMID- 29972881 TI - Inferring selection in instances of long-range colonization: The Aleppo pine (Pinus halepensis) in the Mediterranean Basin. AB - Teasing apart the effects of natural selection and demography on current allele frequencies is challenging, due to both processes leaving a similar molecular footprint. In particular, when attempting to identify selection in species that have undergone a recent range expansion, the increase in genetic drift at the edges of range expansions ("allele surfing") can be a confounding factor. To address this potential issue, we first assess the long-range colonization history of the Aleppo pine across the Mediterranean Basin, using molecular markers. We then look for single nucleotide polymorphisms (SNPs) involved in local adaptation using: (a) environmental correlation methods (bayenv2), focusing on bioclimatic variables important for the species' adaptation (i.e., temperature, precipitation and water availability); and (b) FST -related methods (pcadapt). To assess the rate of false positives caused by the allele surfing effect, these results are compared with results from simulated SNP data that mimics the species' past range expansions and the effect of genetic drift, but with no selection. We find that the Aleppo pine shows a previously unsuspected complex genetic structure across its range, as well as evidence of selection acting on SNPs involved with the response to bioclimatic variables such as drought. This study uses an original approach to disentangle the confounding effects of drift and selection in range margin populations. It also contributes to the increased evidence that plant populations are able to adapt to new environments despite the expected accumulation of deleterious mutations that takes place during long-range colonizations. PMID- 29972884 TI - Acetylsalicylic acid does not prevent first-trimester unexplained recurrent pregnancy loss: A randomized controlled trial. AB - INTRODUCTION: Recurrent pregnancy loss occurs in about 1% of fertile couples. Without proper evidence for an effect, different treatments have been used when no etiological factor has been detected. The present trial is the first randomized trial to compare 75 mg acetylsalicylic acid with placebo for women with recurrent pregnancy loss. MATERIAL AND METHODS: This randomized, double blind, placebo-controlled trial was conducted at a single center between 2008 and 2015. Recurrent pregnancy loss was defined as at least 3 consecutive first trimester miscarriages within the couple. Women < 40 years old with a body mass index < 35 kg/m2 were eligible if the workup was negative. Randomization was through a third party, who manufactured and delivered the study drugs, and occurred when fetal heartbeat was detected, to either 75 mg acetylsalicylic acid or placebo; 200 women in each group. Group allocation was concealed until all the study participants had a pregnancy outcome registered. All women attended the same control program. Primary outcome was live birth. Statistical analyses were according to intention-to-treat. RESULTS: All 400 women completed the follow up. Live birth rate was 83.0% (n = 166) and 85.5% (n = 171) for the acetylsalicylic acid and placebo groups, respectively (P = 0.58). The difference was -2.5% (95% CI -10.1% to 5.1%). The risk ratio was 0.97 (95% CI 0.89-1.06). CONCLUSIONS: Treatment with acetylsalicylic acid did not prevent recurrent miscarriage in women with at least three consecutive miscarriages in the first trimester, of unknown reasons and in the same relationship. The fertility prognosis is very good, the live birth rate being > 80% with or without acetylsalicylic acid. PMID- 29972885 TI - Dependency relationships within the fission yeast polarity network. AB - The ability to regulate polarised cell growth is crucial to maintain the viability of cells. Growth is modulated to facilitate essential cell functions and respond to the external environment. Failure to do so can lead to numerous developmental and disease states, including cancer. We have undertaken a detailed analysis of the regulatory interplay between molecules involved in the regulation and maintenance of polarised cell growth within fission yeast. Internally controlled live cell imaging was used to examine interactions between 10 key polarity proteins. Analysis reveals interplay between the microtubule and actin cytoskeletons, as well as multiple novel dependency pathways and feedback networks between groups of proteins. This study provides important insights into the conserved regulation of polarised cell growth within eukaryotes. PMID- 29972886 TI - Crystal structure of the ligand-free form of the Vps10 ectodomain of dimerized Sortilin at acidic pH. AB - Sortilin is a multifunctional sorting receptor involved in cytokine production in immune cells. To understand the mechanism of Sortilin-mediated cytokine trafficking, we determined the 2.45-A structure of the dimerized Sortilin ectodomain (sSortilin or the Vps10-domain) crystallized at acidic pH. Substantial conformational changes upon dimerization lead to the intermolecular hydrophobic interaction between the conserved E455 and F137. Analysis of the electrostatic surface and size-exclusion chromatography revealed that sSortilin dimerization occurs due to an increase in hydrophobic interactions at the neutral dimer interface at acidic pH. The N682-attached N-glycan in the vicinity of the dimer interface implies its involvement in the dimerization. The disruption of Sortilin dimerization by mutations impairs efficient interferon-alpha secretion from cells. These results suggest the functional importance of Sortilin dimerization in cytokine trafficking. PMID- 29972882 TI - The translational regulation of maternal mRNAs in time and space. AB - Since their discovery, the study of maternal mRNAs has led to the identification of mechanisms underlying their spatiotemporal regulation within the context of oogenesis and early embryogenesis. Following synthesis in the oocyte, maternal mRNAs are translationally silenced and sequestered into storage in cytoplasmic granules. At the same time, their unique distribution patterns throughout the oocyte and embryo are tightly controlled and connected to their functions in downstream embryonic processes. At certain points in oogenesis and early embryogenesis, maternal mRNAs are translationally activated to perform their functions in a timely manner. The cytoplasmic polyadenylation machinery is responsible for the translational activation of maternal mRNAs, and its role in initiating the maternal to zygotic transition events has recently come to light. Here, we summarize the current knowledge on maternal mRNA regulation, with particular focus on cytoplasmic polyadenylation as a mechanism for translational regulation. PMID- 29972883 TI - Noncoding RNAs in disease. AB - Noncoding RNAs are emerging as potent and multifunctional regulators in all biological processes. In parallel, a rapidly growing number of studies has unravelled associations between aberrant noncoding RNA expression and human diseases. These associations have been extensively reviewed, often with the focus on a particular microRNA (miRNA) (family) or a selected disease/pathology. In this Mini-Review, we highlight a selection of studies in order to demonstrate the wide-scale involvement of miRNAs and long noncoding RNAs in the pathophysiology of three types of diseases: cancer, cardiovascular and neurological disorders. This research is opening new avenues to novel therapeutic approaches. PMID- 29972887 TI - Cryptotanshinone Attenuates Oxidative Stress and Inflammation through the Regulation of Nrf-2 and NF-kappaB in Mice with Unilateral Ureteral Obstruction. AB - Oxidative stress and inflammatory responses are closely implicated in the progression of renal interstitial fibrosis, thereby leading to chronic kidney disease. Cryptotanshinone (CTS) is a natural compound involved in antioxidant and anti-inflammatory activities. We evaluated the effects of CTS on inflammation and oxidative stress in obstructed kidneys. Mice received gastric gavage of CTS from 7 days before unilateral ureteral obstruction operation to 1 week after surgery. Administration of CTS at 50 and 100 mg/kg/day significantly decreased collagen production, as shown by Masson staining. Immunohistochemistry staining and RT-PCR confirmed that CTS reduced extracellular matrix proteins, such as fibronectin and collagen-1, in the obstructed kidneys in a dose-dependent manner. Furthermore, immunohistochemistry staining indicated that CTS inhibited infiltration of the macrophage (CD68-positive) and lymphocyte (CD3-positive) cells, which were associated with the suppression of the nuclear factor-kappaB signalling activation. CTS increased superoxide dismutase, catalase and glutathione while decreased malondialdehyde production. More importantly, CTS activated Nrf-2 and HO-1 in the obstructed kidneys for 7 days. CTS could protect renal interstitial fibrosis by ameliorating inflammation and oxidative stress, which might be through the regulation of NF-kappaB and Nrf-2/HO-1 signalling pathways. PMID- 29972888 TI - On confusing cause and effect in the oxygen limitation of fish. AB - This letter deals with the critique by Lefevre, McKenzie, and Nilsson (2017, 2018) of the use of Gill-Oxygen Limitation Theory (GOLT) to explain observed and predict further decreases of the maximum body size of fish under warming. PMID- 29972889 TI - Direct analysis in real time coupled to high resolution mass spectrometry as a rapid tool to assess salmon (Salmo salar) freshness. AB - Direct analysis in real time-high resolution mass spectrometry (DART-HRMS) was applied to the detection of lipid species in the lipid extracts of farmed salmon samples collected from a local retailer and analyzed right after the purchase and after storage for 4 and 6 days under refrigerated conditions. The recognition of type and composition of lipids detected in DART-HRMS spectra was performed by using the relevant accurate m/z data (accuracy better than 5 ppm) as input for a search on the LipidMaps database. As a result, several fatty acids (FA), either saturated or mono-/poly-unsaturated, and triacylglycerols (TAG) were recognized in the three types of samples from the corresponding negative and positive ion DART-HRMS spectra, respectively. Following, spectral intensities were exploited to monitor the evolution of selected FA and TAG during the refrigeration of salmon meat. In particular, after 4 days of refrigeration, a statistically significant increase was recorded for FA with side chain compositions 18:2, 18:1, 20:5, and 22:6 despite a significant decrease found for TAG with overall side chain compositions 50:4, 52:5, 52:4, and 52:3 after the same time. These evolutions were consistent with a general model already proposed for the effect of low temperature treatments on seafood, implying the action of endogenous lipases, with consequent increase of the free FA amount and decrease in glycerophospholipids and triglycerides contents. The described results indicate DART-HRMS as a promising MS-based rapid tool for the assessment of fish, or other seafood, freshness. PMID- 29972890 TI - Development of a fast gas chromatography-tandem mass spectrometry method for volatile aromatic compound analysis in oenological products. AB - Aroma plays an important role in food quality, and knowledge of volatile composition is essential to support technological choices during industrial transformation processes. In this study, an innovative GC-MS/MS method useful for fast analysis of the broad aroma profile of oenological products was developed. Fifty volatile compounds of oenological interest belonging to the main chemical classes (acetates, acids, alcohols, aldehydes, esters, ketones, phenols, terpenes, and thiols) were identified and quantified in a single chromatographic run taking only 15 minutes. The high sensitivity of the mass spectrometer, combined with accurate fast chromatography performed with a suitable capillary column, allowed us to avoid further concentration steps after solid phase extraction. Validation of the method was performed in relation to the limit of detection, limit of quantification, linearity range, repeatability, reproducibility, and recovery. Once validated, the method was successfully tested on commercial oenological samples, demonstrating its applicability to fast routine multiaroma analysis. PMID- 29972891 TI - "Two Rules of Speciation" revisited. PMID- 29972892 TI - Development and Validation of a Measure to Assess Patients' Threat Perceptions in the Emergency Department. AB - OBJECTIVE: Threat perceptions in the emergency department (ED; e.g., patients' subjective feelings of helplessness or lack of control) during evaluation for an acute coronary syndrome (ACS) are associated with the development of posttraumatic stress disorder (PTSD), and PTSD has been associated with medication nonadherence, cardiac event recurrence, and mortality. This study reports the development and validation of a seven-item measure of ED threat perceptions in English- and Spanish-speaking patients evaluated for ACS. METHODS: Participants were drawn from an observational cohort study of 1,000 patients evaluated for ACS between 2013 and 2016 in a large New York City hospital. Participants reported on threat perceptions in the ED and during inpatient stay (using 12 items previously identified as predictive of PTSD) and reported on cardiac-induced PTSD 1 month postdischarge. Exploratory and confirmatory factor analyses were used to establish the factor structure and test measurement invariance. Validity and reliability were examined, as was the association of ED threat perceptions with cardiac-induced PTSD. RESULTS: Factor analyses identified a seven-item measure of ED threat perceptions (e.g., "I feel helpless," "I am worried that I am going to die") for both English- and Spanish-speaking patients. ED threat perceptions demonstrated convergent validity, correlating with ED stress and ED crowdedness (r = 0.29 and r = 0.14), good internal consistency (alpha = 0.82), and stability (r = 0.61). Threat perceptions were associated with cardiac-induced acute stress at inpatient and PTSD symptoms at 1 month (r = 0.43 and r = 0.39). CONCLUSIONS: This brief tool assessing ED threat perceptions has clinical utility for providers to identify patients at risk for developing cardiac-induced PTSD and is critical to inform research on whether threat may be modified in-ED to reduce PTSD incidence. PMID- 29972893 TI - Impregnation of catheters with anacardic acid from cashew nut shell prevents Staphylococcus aureus biofilm development. AB - AIM: The effect of anacardic acid impregnation on catheter surfaces for the prevention of Staphylococcus aureus attachments and biofilm formations were evaluated. METHODS AND RESULTS: Silicon catheter tubes were impregnated using different concentrations of anacardic acids (0.002-0.25%). Anacardic acids are antibacterial phenolic lipids from cashew nut (Anacardium occidentale) shell oil. Anacardic acid-impregnated silicon catheters revealed no significant haemolytic activity and were cytocompatible against fibroblast cell line (L929). Sustained release of anacardic acids was observed for 4 days. Anacardic acid-impregnated silicon catheters efficiently inhibited S. aureus colonization and the biofilm formation on its surface. The in vivo antibiofilm activity of anacardic acid impregnated catheters was tested in an intraperitoneal catheter-associated medaka fish infection model. Significant reduction in S. aureus colonization on anacardic acid-impregnated catheter tubes was observed. CONCLUSIONS: Our data suggest that anacardic acid-impregnated silicon catheters may help in preventing catheter-related staphylococcal infections. SIGNIFICANCE AND IMPACT OF THE STUDY: This study opens new directions for designing antimicrobial phytochemical-coated surfaces with ideal antibiofilm properties and could be of great interest for biomedical research scientists. PMID- 29972894 TI - The Association between Social Support and Happiness among Elderly in Iran. AB - Background: Elderly people's life is affected by multiple factors including social support, which is of the utmost importance. This study aimed to explore the association between social support and happiness as well as the impact of types of social support on happiness among elders. METHODS: This descriptive and analytical study was carried out on 411 elderly men and women referred to the retirement, cultural, and rehabilitation centers in Hamadan, west of Iran. Participants were selected by a multi-stage random sampling method. The research instrument included a questionnaire consisting of three parts: demographic information, the Oxford Argyle Happiness Inventory, and a Questionnaire derived from Social Support Theory. The questionnaire was completed through a self-report study. The collected data were analyzed using Pearson correlation coefficients, multiple linear regression, independent t-tests, and one-way analysis of variance in IBM SPSS Software ver. 22.0. RESULTS: The mean for happiness was reported as 41.17+/-15.2. The values given for social support were 29.40+/-11.95 and for its dimensions were 7.53+/-3.89 and 13.70+/-4.90 for informational support and emotional support, respectively. Moreover, the mean value for appraisal support was 3.48+/-2.37 and was 4.70+/-2.56 for instrumental support. Multiple linear regression analysis revealed that social support and demographic variables could account for approximately 25% (R2 =0.25) of changes in the variable of happiness. CONCLUSION: High social support could increase happiness among elders. The quality and quantity of social support can be taken into account as proper determinants and predictors of happiness among elders. PMID- 29972895 TI - Best Practice for Prolonged Fever in Primary Care Setting: Close Follow-Up or Empiric Antibiotic Therapy? AB - The management of prolonged fever in low-socioeconomic-status areas by primary care providers such as general practitioners is challenging. Given the endemic nature of many infectious diseases, physicians typically start empirical antibiotic therapy following a limited diagnostic workup including serologic examinations. Herein, we report the case of a young male patient with prolonged fever and arthralgia initially diagnosed with and treated for brucellosis but with a confirmed diagnosis of systemic lupus erythematosus on follow-up. This unique case shows that close follow-up is the best practice for managing prolonged fever in cases with non-specific laboratory findings. PMID- 29972896 TI - Persistent Shoulder Pain in Young Male: Osteosarcoma. AB - A 16-year-old Malay boy presented to Kota Bharu Health Care Centre, Kelantan, with left shoulder pain after sustaining a fall. On further history taking, it was noted that the pain preceded the fall by 1 month. The early changes of osteosarcoma were visible on an X-ray during the initial presentation; however, this was missed by the primary care doctors. Three months later, the patient presented with persistent pain in the left shoulder and was diagnosed with osteosarcoma. PMID- 29972897 TI - Benign Acute Childhood Myositis: Perplexing Complication after Acute Viral Pharyngitis. AB - Benign acute childhood myositis (BACM) is a rare transient condition that occurs in children during the early convalescent phase of a viral upper respiratory infection. BACM is self-limiting and characterized by sudden-onset bilateral calf pain that leads to difficulty in walking. We report a case of a 5-year-old boy with BACM who presented with acute-onset bilateral calf pain after a resolved episode of viral pharyngitis and subsequently refused to walk. With conservative treatment, the patient recovered completely after approximately 1 week. Although perplexing and challenging for clinicians unfamiliar with BACM, awareness of this rare clinical condition is essential to preventing unnecessary investigations and reassuring the patient and parents of its excellent prognosis. PMID- 29972898 TI - Cut-Off Values for Visceral Fat Area Identifying Korean Adults at Risk for Metabolic Syndrome. AB - Background: Cut-off values for visceral fat area (VFA) measured by computed tomography (CT) for identifying individuals at risk of metabolic syndrome (MetS) have not been clearly established in Korean adults, particularly for large populations. We aimed to identify optimal VFA and waist circumference (WC) cut off values and compare the ability of VFA and WC to predict the presence of >=2 metabolic risk factors. METHODS: We included 36,783 subjects aged 19-79 years undergoing abdominal fat CT during regular health checkups between January 2007 and February 2015 in Seoul. The risk factors for MetS except WC were based on the International Diabetes Federation criteria. Receiver operating characteristic curve analyses were used to determine the appropriate VFA and WC cut-off values for MetS. RESULTS: VFA was a more significant predictor of metabolic risk factors than WC and body mass index (BMI). The optimal cut-off values for VFA and WC were 134.6 cm2 and 88 cm for men and 91.1 cm2 and 81 cm for women, respectively. We estimated age-specific cut-off values for VFA, WC, and BMI. VFA cut-off values increased with age, particularly among women. CONCLUSION: This large population study proposed the cut-off values for VFA and WC for identifying subjects at risk of MetS among Korean adults. For more accurate diagnosis, different age-specific cut-off values for VFA and WC may be considered. PMID- 29972899 TI - Higher Serum Calcium Levels Are Associated with Preclinical Peripheral Arterial Disease among the Apparently Healthy Individuals. AB - BACKGROUND: Epidemiological studies suggest that serum calcium levels correlate with cardiovascular events. An ankle-brachial index (ABI) between 0.9 and 1.00 is a surrogate estimation of preclinical peripheral arterial disease (PAD). Prior studies have shown that an ABI of 0.9-1.0 is also associated with endothelial dysfunction. Therefore, we sought to investigate the relationship between serum calcium levels and preclinical PAD in apparently healthy Korean individuals. METHODS: We evaluated the association between serum calcium levels and preclinical PAD in 596 participants (334 males, 262 females) in a health examination program. Preclinical PAD was defined by an ABI of 0.9-1.0. Multiple logistic regression analysis was used to determine whether the serum calcium level was an independent determinant of preclinical PAD. RESULTS: The overall prevalence of preclinical PAD was 14.3%. The mean age was 44.0+/-12.5 years in the non-PAD group and 48.3+/-11.4 years in the preclinical PAD group (P=0.001). After adjusting for age, gender, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, g glutamyltransferase, uric acid, hypertension medication, diabetes medication, and hyperlipidemia medication, the odds ratio (95% confidence intervals) for preclinical PAD was 2.28 (1.02-5.11) with a 1-mg/dL increase in the serum calcium. CONCLUSION: These findings suggest that increased serum calcium is independently and positively associated with preclinical PAD regardless of the presence of classic cardiovascular risk factors. PMID- 29972900 TI - Association between Sleep Duration and Body Composition Measures in Korean Adults: The Korea National Health and Nutrition Examination Survey 2010. AB - Background: The association between sleep duration and body composition measures in Korean adults remains unclear. METHODS: This cross-sectional study included 3,532 subjects aged >=40 years (1,542 men and 1,990 women) who participated in the 2010 Korea National Health and Nutrition Examination Survey V-1. Self reported sleep duration and anthropometric data were collected. Appendicular skeletal muscle mass (ASM) was quantified via dual-energy X-ray absorptiometry. Obesity was defined according to the body mass index and waist circumference. Sarcopenia was defined as the muscle mass percentage (ASM/weight) below the lowest quintile computed for the study population. Multivariate logistic regressions with or without adjustment for sociodemographic and lifestyle factors were used to evaluate the association of sleep duration with obesity and sarcopenia for participants who slept <=5, 6-8, and >=9 h/d. The results were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: In women, the association between sleep duration and sarcopenia was stronger for individuals who slept >=9 h/d than for those who slept 6-8 h/d (unadjusted OR, 1.99; 95% CI, 1.19-3.34; adjusted OR, 1.77; 95% CI, 1.06- 2.96). CONCLUSION: Longer sleep duration is associated with a significantly higher incidence of sarcopenia in Korean women aged >=40 years. PMID- 29972901 TI - [Professional development of oral and maxillofacial trauma since the founding of the People's Republic of China]. AB - Oral and maxillofacial trauma surgery in modern China has experienced four stages of growth in different social and economic backgrounds: initiation, stagnation, exploring and development. It is now an important branch of oral and maxillofacial surgery with unique Chinese characteristics. This paper retrospectively summarizes the representative figures and important events, as well as the research and technology advances in each of the four growth stages. It also includes an analysis of current advantages and problems, and provides some foresights for future development of this subspecialty in China. PMID- 29972902 TI - [The standardization of China dental technology of advanced vocational and technical education (draft)]. AB - Advanced vocational education of dental technology aims to cultivate high-quality professional personnel with technical skills who will take the jobs related to various types of dental prosthesis fabricating technology. The standardized training process is a prerequisite for training qualified dental technical personnel, and strengthening quality supervision is the key to ensure the quality of education. In order to ensure the domestic talents of dental technology professional training quality, and to standardize the dental technology education of relevant domestic universities and colleges, this paper formulates the criteria of China dental technology of advanced vocational education in combination with the China high education standards of stomatology, the international standards of medical education, domestic standards of medical education and the criteria of dental technology made by National Health Vocational Education Committee. This criteria includes education purpose, plan, examination, student management, teachers, educational resource, assessment, administration, reform and development. PMID- 29972903 TI - [Evaluation on efficacy of corticotomy-facilitated treatment in skeletal class II patients]. AB - Objective: To investigate the effect of corticotomy-facilitated orthodontics on the treatment time and final outcome in skeletal class II division 1 patients. Methods: Twenty adult skeletal class II division 1 patients treated with two maxillary first premolar extractions were included and randomly divided into two groups (the corticotomy group and the control group). The treatment time was recorded and the changes of soft and hard tissue were compared by using three dimensional measurement and analysis of cone-beam CT images before and after treatment. Results: There was no significant difference in the alignment time between two groups, while the time of maxillary space closure and the total treatment time in corticotomy group ([5.8+/-1.3] and [24.9+/-5.1] months, respectively) were shorter than that in the control group ([9.9+/-1.1] and [30.8+/-4.6] months, respectively) and the differences were significant (P<0.01). In the corticotomy group, the retraction amount of the upper central in cisal margin, apical tip, supradentale, labrale superius and the increase of nasolabial angle were greater than those in the control group (P<0.05). Conclusions: In patients with mild to moderate skeletal class II division 1 malocclusion, corticotomy-facilitated orthodontics can not only shorten the treatment time, but is more conductive to the retraction of upper anterior teeth and improvement of the profile. PMID- 29972904 TI - [Preliminary study of subgingival microorganism changes after glycine powder air polishing treatment during periodontal maintenance phase]. AB - Objective: To research the variation of subgingival microorganisms after 65 MUm glycine powder air-polishing (GPAP) in patients with periodontitis during periodontal maintenance phase and make comparison with conventional method. Methods: From Department of Periodontology, Peking University School and Hospital of Stomatology, twenty-one patients at the age of 35-72 (8 males and 13 females) who were systematically healthy were recruited in this study. According to splitting-mouth design, one side of a mouth was randomly assigned to the experiment group (21 patients, 248 teeth, 1 488 sites) with 65 MUm GPAP therapy while the opposite side served as the control group (21 patients, 249 teeth, 1 494 sites) with ultrasonic scaling plus polishing paste therapy. The clinical periodontal parameters including probing depth (PD), bleeding index (BI), bleeding on probing (BOP) and plaque index (PLI) were recorded. Using sterile currette, the subgingival plaque samples were collected at the mesio-buccal site of the first or second molars at baseline, 2, 4, 8 and 12 weeks after therapy, respectively. After Congo red staining, the microorganisms were classified into cocci, bacilli and spirochetes and counted respectively. Results: All clinical periodontal parameters have no difference between two groups at baseline and after treatment 12 weeks. In the experiment group and the control group, PD ([2.33+/-0.90] and [2.37+/-1.18] mm), BI (0.96+/-0.70 and 0.98+/-0.78) and PLI (0.00[1.00] and 0.00[1.00]) of two groups after treatment 12 weeks were better than those at baseline (PD: [2.48+/-1.17] and [2.46+/-0.99] mm; BI: 1.07+/-0.72 and 1.08+/-0.75; PLI: 0.00 [1.00] and 0.00 [1.00]) (P<0.05). But BOP(+)% was observably reduced only in the control group after treatment 12 weeks ([17.25+/ 2.21]% vs [25.23+/-2.83]%) (P<0.05). The percentages of cocci, bacilli and spirochetes were stable and there were not significant differences between the two groups (P>0.05). Conclusions: After 65 MUm GPAP therapy, the differences of proportion of subgingival microorganisms are not significant, while the control group has the same trend. The spirochetes remained at a low level, but they rebounded fasterly in the test group than that in the control group. The results indicate that 65 MUm glycine powder air-polishing has the similar clinical effects compared with ultrasonic scaling plus polishing paste. However, the clinical indications should be limited to the patients with shallow pockets and without obvious dental calculus. PMID- 29972905 TI - [Centronuclear myopathy: clinical characteristics and MRI image features of oral and maxillofacial region]. AB - Objective: To provide biomechnical basis for orthodontics of centronuclear myopathy (CNM) patients, we studied the oral and maxillofacial clinical features and MRI image manifestations to explore application of MRI to objective evaluation the affected facial muscles. Methods: The study consisted of 8 patients who were diagnosed as CNM (CNM group) and 20 healthy volunteers (control group). Their medical information were gathered and then we examined the ptosis situation and the facial index calculation of them. To measure the maximal hight of palate and the width of palate, patients and volunteers were made impressions. We also checked their maximum bite force with occlusion pressure tester. And they took lateral cephalometric radiographs to measure mandibular plane-Frankfort horizontal plane angle (MP-FH). At last, they were taken oral and maxillofacial region MRI to observe the affected situation of masseter muscle, medial pterygoid muscle and lateral pterygoid muscle. Results: Six patients were ptosis; 6 patients had inverse V-shaped mouth; 3 patients were difficulty in swallowing; 4 patients were anterior open bites; 4 patients were mouth breathing; 7 patients liked to eat soft foods. Morphological facial index ([91.3+/-0.5]%), MP-FH (34.9 degrees +/-2.0 degrees ) of CNM group were greater than the control group, male maximal hight of palate ([19.0+/-0.2] mm), female maximal hight of palate ([18.0+/-0.6] mm) of CNM group were greater than the control group (P<0.05). Male width of palate ([34.5+/-0.8] mm), female width of palate ([33.4+/-1.0] mm), male maximum bite force ([464.3+/-78.2] N), female maximum bite force ([320.7+/-13.8] N), maximal opening of mouth ([3.4+/-0.3] cm) of CNM group were less than the control group (P<0.05). And these had significant difference compared with the control group (P<0.05). In MRI examination, there were 7 patients' masseter muscles, 4 patients' medial pterygoid muscles and 6 patients' lateral pterygoid muscles to atrophy asymmetrically. These three pieces of muscular fatty infiltration were inordinately, focused on Grade 0 to 4 and the both sides were similar. Conclusions: CNM patients with long and thin face, high palatine arches and low bite force together were the biomechanical basis of the maxillofacial deformities. MRI can clearly show the affected masseter muscle, medial pterygoid muscle, lateral pterygoid muscle, and can serve as an objective examination method for the evaluation of facial muscles. It can be worth of clinical popularization and application. PMID- 29972906 TI - [Effect of plumbagin on epithelial-mesenchymal transition and underlying mechanisms in human tongue squamous cell carcinoma cells]. AB - Objective: To study the effect of plumbagin on epithelial-mesenchymal transition (EMT) and underlying mechanisms in human tongue squamous cell carcinoma (TSCC) cells. Methods: Methyl thiazolyl tetrazolium assay was apllied to examine the proliferation inhibition effect and half maximal inhibitory concentration (IC(50)) of plumbagin (0.1, 1.0, 5.0, 10.0, 20.0 MUmol/L) in 12, 24, 48 h in TSCC cells. Transwell assay was used to count the number of transmembrane cells and scratch test was performed to examine cells mobility. The flow cytometry was applied to measure intracellular reactive oxygen species (ROS) level in control group, plumbagin group (1.0 MUmol/L, 24 h) and glutathione (GSH)+plumbagin group. The expression of E-cadherin, vimentin, Slug, p38 mitogen activated protein kinases (p38MAPK) and phospho-p38MAPK (p-p38MAPK) proteins were determined by Western blotting. The expression of E-cadherin, vimentin and Slug were detected by Western blotting in control group, plumbagin group, activator combined group (p38MAPK activator+plumbagin) and inhibitor combined group (p38MAPK inhibitor+plumbagin). Results: After the treatment of plumbagin for 12, 24, and 48 h, the IC(50) of TSCC cells were 10.3, 3.1, 1.5 MUmol/L. After treated by 1.0 MUmol/L plumbagin for 24 h, the number of transmembrane cells were significantly reduced ([50+/-13], P<0.05) in comparison to control group (204+/-6), as well as the cells mobility ([18.2+/-2.3]%, P<0.05) in comparison to control group ([49.3+/-1.2]%). Compared to control group (2.32+/-0.52), the ROS level was increased in plumbagin group (902.20+/-10.69), while compared to plumbagin group, the ROS level was reduced in GSH combined group (2.18+/-0.15). In comparison to control group, the expression of E-cadherin was up-regulated (P<0.05), and vimentin, Slug, p-p38MAPK/p38MAPK were down-regulated in plumbagin group (P<0.05). In comparison to plumbagin group, the expression of E-cadherin was down regulated (P<0.05), and vimentin, Slug, p-p38MAPK/p38MAPK were up-regulated in GSH combined group (P<0.05). Treatment of cells with p38MAPK activator could decrease the expression of E-cadherin significantly (P<0.05) and increase the expression of vimentin (P<0.05) and Slug (P<0.05) in comparison to plumbagin group. Treatment of cells with p38MAPK inhibitor could increase the expression of E-cadherin significantly (P<0.05) and decrease the expression of vimentin (P<0.05) and Slug (P<0.05) in comparison to plumbagin group. Conclusions: Plumbagin inhibits EMT via ROS/p38MAPK-mediated pathway in human TSCC cells. PMID- 29972907 TI - [Effects of Wnt3a on osteogenic differentiation of dental pulp stem cells]. AB - Objective: To investigate the effect of Wnt3a on osteogenic differentiation of human dental pulp stem cells (DPSC). Methods: DPSCs were subjected to different concentrations of Wnt3a (0, 5, 20, 50 and 100 MUg/L) and at seven days after culture the alkaline phosphatase (ALP) activity was tested. Mineralized nodule formation was examined by alizarin red staining. Osteogenic-related gene expression of bone sialoprotein (BSP), osteocalcin (OCN), collagen type I (COL I), Runt-related transcription factor-2 (RUNX2) was examined by quantitative real time PCR (qPCR). Results: After seven days of induction by DPSC, Wnt3a protein could inhibit the ALP activity (concentration 0: 1.076+/-0.203, 5 MUg/L: 0.828+/ 0.118, 20 MUg/L: 0.505+/-0.044, 50 MUg/L: 0.499+/-0.038, 100 MUg/L: 0.483+/ 0.060). The expression of OCN in 5 MUg/L Wnt3a group (0.092+/-0.005) was lower than that in culture medium (0.858+/-0.190)(P<0.05). Alizarin red staining showed that 5 MUg/L Wnt3a had no mineralization induction effect on DPSC. Conclusions: Wnt3a could inhibit osteogenic differentiation of dental pulp stem cells. PMID- 29972908 TI - [Naked cuticle homolog 2 positively regulates the osteogenic differentiation of rat dental follicle cells]. AB - Objective: To examine the expression of naked cuticle homolog 2 (Nkd2) in the process of root development and osteogenic differentiation of dental follicle cells of rat (rDFC), in order to explore the molecular mechanisms of Nkd2 on the osteoblast differentiation of rDFCs. Methods: Immunohistochemical analysis was used to detect the expression of Nkd2 in the base dental follicle of the mandibular first molar of rat at 1, 3, 5, 7, 9, 11 and 13 days postnatal. Mineralization nodule formation of rDFCs was detected by alizarin red staining and cetylpyridine. The change of Nkd2 during osteogenic differentiation of rDFCs was evaluated by Western blotting and the associations between Nkd2 and osteogenic cytokines of alkaline phosphatase (ALP), Runt-related transcription factor-2 (RUNX2) and osteocalcin (OCN) were examined. The rDFCs were transfected with small interfering RNA (siRNA) to knock down the expression of Nkd2 and Western blotting and quantitative real-time PCR (qPCR) were adopted to explore the effects of Nkd2 on osteogenic differentiation by detecting variations of Nkd2 and osteogenic factors ALP, RUNX2, OCN among silencing group (Si), negative control RNA group (Nc) and mock control group (Mock), respectively. Results: The expression of Nkd2 in the base dental follicle of the mandibular first molar of rat was time dependent. Mineralization nodules of rDFCs and absorbance of cetylpyridine after osteogenic induction increased gradually (the absorbances of cetylpyridine were 0 week: 0.017+/-0.005, 1 week: 0.702+/-0.044, 2 weeks: 1.812+/ 0.531, 3 weeks: 2.767+/-0.253, respectively). Results of Western blotting showed that Nkd2 (1.60+/-0.23) of mineralization group was significantly higher than that of control group (1) (P<0.05) at the early stage of osteogenic differentiation along with the expression of other osteogenic factors. The protein and mRNA of Nkd2 and osteogenic factors were significantly decreased in Si group compared with Nc and Mock groups (P<0.05), and no changes between Nc and Mock groups were observed. The changes of protein in Si, Nc and Mock groups were Nkd2: 0.42+/-0.10, 1.12+/-0.07, 1, ALP: 0.70+/-0.15, 1.11+/-0.14, 1, RUNX2: 0.58+/-0.08, 0.93+/-0.08, 1 and OCN: 0.64+/-0.06, 0.99+/-0.02, 1, respectively. The mRNA variances in Si, Nc and Mock groups were Nkd2: 0.39+/-0.05, 0.96+/-0.10, 1, ALP: 0.15+/-0.13, 1.01+/-0.07, 1, RUNX2: 0.39+/-0.31, 0.97+/-0.13, 1, OCN: 0.17+/-0.08, 1.08+/-0.21, 1, respectively. Conclusions: Nkd2 participates in the root development process in rat and may acts as a positive role in the early stage of osteogenic differentiation of rDFCs in rat. PMID- 29972909 TI - [Effect of sandblasting on bending strength and subcritical crack growth of the dental zirconia ceramics]. AB - Objective: To evaluate the effect of sandblasting on bending strength and subcritical crack growth (SCG) under cyclic loading of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) ceramics. Methods: After being polished, sixty bar-shaped specimens of Y-TZP (Wieland zirconia ceramics) were assigned to two groups (n=30) according to the random number table, the sandblasting group (SG) which was treated with sandblasting and the control group (CG) which remained untouched. In each group, half of the specimens (n=15) were subjected to bending strength test, and the results were examined by Weibull statistics and analyzed with ANOVA. The other 15 specimens in each group were subjected to fatigue tests. The results were examined by Weibull statistics and subcritical crack propagation rates were calculated. Results: The bending strengths of SG and CG were (1 291+/-133) and (1 140+/-124) MPa (F=10.117, P=0.004), and the Weibull modules of the two groups were 11.06 and 10.64 respectively. The crack growth rate of SCG of SG was lower than that of CG under the same cyclic loading. Conclusions: Proper sandblasting on Y-TZP ceramic can increase its bending strength and resistance to SCG. PMID- 29972910 TI - [Summary of Chinese Expert Consensus Workshop on Temporomandibular Joint Disc Displacement]. PMID- 29972911 TI - [Evaluation and influencing factors of surgical margin status of oral squamous cell carcinoma]. AB - Surgical resection with adequate margins is an essential component of the treatment for patients with oral squamous cell carcinoma (OSCC). A distance of 5 mm or more between healthy tissue to the tumor front is generally accepted as a safe margin. It is very important for surgeons to precisely evaluate the resection area of tumor both pre- and intra-operatively and try to achieve a safe margin, which will result in a decreased risk of local recurrence. The relationship of surgical margin status to patients' prognosis, and factors which will affect surgical margin distance demand are discussed in this paper. We recommend that adequate margins evaluation should take consideration of many factors such as anatomical location, depth of tumor invasion, pattern of tumor invasion, mucosal dysplasia grade and so on. With the development of molecular biology, surgical margin study at molecular level can give us a new strategy to evaluate its adequacy. PMID- 29972913 TI - [Positive and negative aspects of clear aligner technique advancement]. PMID- 29972912 TI - [Research progress in titanium dental implant biological modification]. AB - During the past three decades, the technology of implant surface modification has already formed well-developed methods including physical and chemical means. However, titanium is a kind of bioinert material, which will directly result in slowly bone-bond with bone tissue after implantation and ultimately reduce the success rate of dental implant surgery. Therefore, the introduction of bioactive substances which can effectively regulate and promote the proliferation of bone cells to modify the titanium implant surface has received tremendous attention in the research of oral implant field. The research of biological modification starts relatively late and it has not formed well-established system yet. The research progress is given in this paper concerning the bioactivators and methods used in biological modification. Furthermore, the current situation as well as the recent developments involving the biological modification of dental implant are also discussed in this review. PMID- 29972914 TI - [Consensus of Chinese stomatological experts on the efficacy of toothpaste and functional toothpaste]. AB - Toothpaste is an oral health care product that can be used to help cleansing teeth and improve oral hygiene. Currently use of toothpaste has been transferred from the conventional objective of oral hygiene to the new era of prevention and intervention of oral diseases. Therefore, functional toothpaste has been developed in a fast way. It is imperative to investigate toothpaste, because the wise use of specific functional toothpaste could prevent or reduce oral diseases such as dental caries and periodontal diseases, improve people's oral and general health and save social healthcare resources. However, dental professionals have various understandings on the efficacy and differentiations of functional toothpastes. For example, there are different explanations for the efficacy of functional toothpastes, which may exaggerate, depreciate or deny their clinical efficacy. To ensure the highest level of the patient's safety and professional satisfaction for both toothpaste products and related informatics, and also to make the dentists be acquainted with the updated research findings, developments and standards, it is necessary to review systematically the efficacy of functional toothpaste. PMID- 29972915 TI - [Invisible orthodontics: clear aligners and customized lingual appliances]. AB - In recent years, invisible orthodontics has been one of the concerns of both orthodontists and patients. As two types of invisible orthodontics, clear aligners fit for cases that have high demand for living quality, need distalization of molars or intrusion of incisors, suffer from severe periodontitis, or that have non-abundant time for visits. While customized lingual appliances fit for cases that have high demand for aesthetics, have deep overbite or complex malocclusion, need maxillary expansion or retraction of incisors, or that have low compliance and good economic conditions. Based on aspects of clinical application, this article presents the characteristics of these two types of invisible orthodontics, in order to provide reference for individualized options according to different situations. PMID- 29972916 TI - [Extraction cases using clear aligners]. AB - Clear aligner treatment achieves patients' precise tooth movements through utilizing patients' digital dental models and tooth movement planning by orthodontists. Originated from the rudimentary form in 1940's, clear aligner has undergone many innovations and developments. A strict selection of extraction patients for clear aligner treatments is a prerequisite of good treatment outcomes. Orthodontists should first master the unique features of aligner biomechanics and mechanisms. For extraction patients treated with clear aligners, orthodontists should focus on anchorage control, torque control and vertical control, and strictly monitoring treatment progressions, as to achieve satisfactory treatment outcomes. With the development of dental materials and techniques, we believe that clear aligner treatment will be a mainstay of future orthodontic treatments. PMID- 29972917 TI - [Advantages and disadvantages of clear aligner treatment in orthodontics]. AB - As biomaterial and biomechanics have been growing and developing rapidly, the indication of clear aligner treatment has been broadened from simple crowding or spacing to moderate malocclusion including either extraction or non-extraction cases. Considering the advantage of its prospective three-dimensional digital planning as well as the disadvantage of limited capability of three-dimensional tooth movement control, orthodontists have to be fully aware of the characteristics and weakness of this appliance so as to choose proper indications and achieve good treatment results. Meanwhile, orthodontists also have to play an important role in modifying the three-dimensional digital plan with pouring in their clinical experience on treating cases and estimating different tooth movement efficiency in various kinds of malocclusions. PMID- 29972918 TI - [Maxillary expansion efficiency with clear aligner and its possible influencing factors]. AB - Objective: To evaluate the efficiency of maxillary expansion with clear aligners and to analyze the possible influence factors. Methods: Thiry-one clear aligner cases (Invisalign) with maxillary expansion were enrolled in this study. The three-dimensional (3D) digital models of pre-treatment, planned in Clincheck software and post-treatment were collected. Upper dental arch width, buccal inclination of posterior teeth, and the expansion efficiency (expansion acquired/expansion planned) were measured and calculated. The impact of factors such as planned buccal inclination, planned expansion amount, attachment, and the mode of expansion on the expansion efficiency were analyzed. Results: The increases of upper arch width in canine, 1st and 2nd premolar, 1st and 2nd molar were (2.0+/-1.3), (2.8+/-1.5), (3.0+/-1.4), (1.8+/-1.0) and 0.5 (0.1, 1.1) mm, with their efficiency of 68%, 70%, 68%, 55% and 29%, respectively. The posterior teeth showed significantly more buccal inclination than the planned position (P<0.05). However, the most buccally inclined tooth detected in 1st molars was only 3.1 degrees +/-3.9 degrees . When the planned inter-molar width increase was less than 2 mm (n=15), the expansion efficiency of premolars was higher compared with those cases with the planned inter-molar width increase more than 2 mm (n=16, P<0.05). The planned buccal inclination, attachments, and the expansion mode had no significant effect on the expansion efficiency (P>0.05). Conclusions: The expansion of maxillary arch with clear aligners was achieved by the buccal movement of the posterior teeth with limited buccal inclination. The efficiency of expansion declines from 1st premolars to second molars. The planned inter molar width had a significant influence on the efficiency of premolar expansion. PMID- 29972919 TI - [Clinical efficacy of clear aligners in treating bimaxillary protrusion]. AB - Objective: To evaluate the efficiency of clear aligners in treating bimaxillary protrusion patients with first premolar extractions. Methods: Eleven patients with bimaxillary protrusion were selected in this study. All of them were treated by using clear aligners with four first premolar extractions and need maximal anchorage. Cephalometric analysis was carried out before and after treatment. Results: Cephalometric analysis results showed that significant changes in teeth and profile could be detected after clear aligner treatment and no change could be found in skeletal pattern. Upper and lower anterior teeth were retracted. The control of anterior torque and posterior anchorage were effective. The soft tissue analysis showed that position of upper and lower lip was significantly changed which improve the profile of patients. After treatment, the distance of U1 to NA and L1 to NB reduced by (5.19+/-4.12) mm and (4.53+/-1.20) mm, respectively. The differences were statistically significant (P<0.01). Conclusions: Bimaxillary protrusion patients who needed premolar extractions and maximal anchorage could be treated with clear aligners. PMID- 29972920 TI - [Four-premolar extraction treatment with clear aligner: a case report]. PMID- 29972921 TI - [Molar distalization with clear aligner: a case report]. PMID- 29972922 TI - [Clear aligner treatment of class II division 2 patient with deep overbite: a case report]. PMID- 29972923 TI - [Role of specificity protein 1 in transcription regulation of microRNA-92b in head and neck squamous cell carcinoma]. AB - Objective: To investigate the role of transcription factor specificity protein 1 (SP1) in proliferation, migration and invasion in head and neck squamous cell carcinoma (HNSCC), and the role of SP1 in transcription regulation of microRNA (miRNA)-92b. Methods: Predicted the possible target miRNA of transcription factor SP1 by bioinformatic analysis. Furthermore, confirmed the binding sites of transcription factor SP1 and miRNA-92b promoter regions by chromatin immunoprecipitation. After transfecting SP1 siRNA and negative control siRNA, also performed quantitative real-time PCR (qPCR), cell proliferation assay and Transwell assay. Results: The bioinformatic analysis shows SP1 is a possible transcription factor of miRNA-92b. Chromatin immunoprecipitation suggests there are three binding sites in miRNA-92b promoter regions that can be combined with SP1. qPCR suggests in PCI-4A and PCI-37A cells the expression of SP1 in experimental group (respectively was 0.064+/-0.020 and 0.639+/-0.008) were significantly lower than negative control group (both were 1)(P<0.05). In PCI-4A and PCI-37A cells the expression of miRNA-92b in experimental group (respectively was 0.215+/-0.033 and 0.497+/-0.104) were significantly lower than negative control group (both were 1)(P<0.05). In experimental group proliferation of SP1 in PCI-4A and PCI-37A cells value A were significantly lower than negative control group (P<0.05). In experimental group migration of SP1 in PCI-4A and PCI 37A cells (respectively was 37.0+/-4.6 and 40.7+/-2.1) were significantly lower than negative control group (101.0+/-5.3 and 82.7+/-5.7) (P<0.05). In experimental group invasion of SP1 in PCI-4A and PCI-37A cells (respectively was 31.3+/-10.8 and 37.0+/-4.6) were significantly lower than negative control group (92.3+/-3.1 and 70.3+/-3.1)(P<0.05). Conclusions: SP1 promotes proliferation, migration and invasion abilities of HNSCC cells. SP1 is a transcription factor of miRNA-92b and can directly be involved in transcription regulation of miRNA-92b. PMID- 29972924 TI - [Expression of large tumor suppressor homolog 2 gene and its promotor methylation in oral squamous cell carcinoma]. AB - Objective: To investigate the expression of large tumor suppressor homolog 2 (LATS2) gene and its promotor methylation in oral squamous cell carcinoma (OSCC). Methods: Reverse transcription-PCR (RT-PCR) and pyrosequencing were used to detect the mRNA and promotor methylation of LATS2 gene in 72 OSCC specimens and normal oral mucosa tissues. Western blotting was used to detect the LATS2 protein in six OSCC specimens and normal oral mucosa tissues. Results: All cases had expression of LATS2 mRNA in normal oral mucosa tissues, but the expression was down-regulated significantly, only 47% (34/72) in 72 cases of OSCC showed LATS2 mRNA expression. The expression was correlated with the degree of tumor differentiation and lymph node metastasis (P<0.05). The results of pyrosequencing show that 68% of promotor methylation (49/72) in 72 cases of OSCC. Furthermore, there was significant correlation between the mRNA and promotor methylation of LATS2 gene (chi(2)=16.980, P<0.01). All the six specimens had the low LATS2 protein expression. Conclusions: The promotor methylation of LATS2 gene may play an important role in the occurrence of OSCC. PMID- 29972925 TI - [Application of mind mapping in the teaching of oral and maxillofacial development]. AB - Oral and maxillofacial development is the course that the oral students first learn, and their mastery directly influences the study of other courses that follow. The application of mind mapping in the teaching of the development of oral maxillofacial region can make the temporal and spatial features of oral and maxillofacial development in the form of visual presentation, help students build development mode of thinking, stimulate students' interest in learning, improve the quality of teaching of oral histopathology, and promote the new teaching concept in oral pathology teaching. PMID- 29972926 TI - [Hypophosphatasia: a case report and gene mutation analysis]. PMID- 29972927 TI - [Minutes of Symposium on the Application of Three-Dimensional Printing in Stomatology]. PMID- 29972928 TI - [Advances of self-healing dental composite resin]. AB - Degradation of composite resin during ageing always produces micro-cracks, the latter could gradually expand, leading to the fracture of tooth restoration. In order to extend the service life of composite resin by repairing cracks intelligently, self-healing microcapsule models have been introduced in resin based dental materials. This paper will present the concept and classification of self-healing materials, and review the research progresses on self-healing dental resin. PMID- 29972929 TI - [Stem cell-based regeneration: one of the emerging fields in stomatology]. PMID- 29972930 TI - [Tooth and its supporting tissues regeneration using functional tooth modules]. AB - Stem cell based generation of functional tissue modules is becoming a hotspot in the field of tissue regeneration. These functional tissue modules, which can be prepared through a variety of ways, including self-organization of stem cells, cell sheets, electrospinning and bio-printing, can serve as the basic unit and be assembled to form larger tissues and organs. This new technology can be a break through to address current issues in tissue regeneration and further promote the translational use of regenerated tissues/organs. Construction of functional tooth modules is still in its early stage, where the stem cell source, preparing method and strategy of translational use are not clearly defined yet. How to construct the functional tissue module through the existing technology still needs further study. Here, we would like to share our current understanding and thoughts on constructing strategies and potential clinical application of functional tooth modules including dental pulp, periodontal tissue and tooth root, and hope it could shed new lights on the regeneration of tooth. PMID- 29972931 TI - [Topographies of biomaterials regulate cell functions under epigenetic mechanisms]. AB - Topographies of biomaterials can act as potent regulators of cell functions, including proliferation, migration, differentiation, and reprograming. The mechanisms involve not only signaling pathways, but also epigenetic regulations. A clearer picture of how topographies of biomaterials alter epigenetic states facilitates the design of highly-functionalized and individualized biomaterials, and provides novel insights into epigenetic manipulation in controlling cell fates in regenerative medicine and disease treatment. PMID- 29972932 TI - [Biomaterials for bone defect repair and bone regeneration]. AB - The treatment of large jaw bone defects remains an urgent clinical problem to be solved. With the development of biomaterials, stem cells and bone tissue engineering, new ideas and hopes for the regeneration of jaw have been offered. In addition to meeting the basic requirements of bone repair materials, scaffolds for the regeneration of large jaw bones require the ability of stem cells to participate in bone regeneration. Methods like optimization of scaffolds composition, design of porous structure and combination of gel and microsphere technology can enhance stem cell delivery in vivo, and the osteogenic differentiation of stem cells can be stimulated through controlled release of drugs, preparation of surface micron/nano topography and modifications of ionic components. Moreover, application of three-dimensional printing and channel structure in large-scale scaffolds fabrication present promising strategies for customized, accurate bone reconstruction and vascularization. It is only through synergistic optimization in all aspects that it is possible to obtain scaffold materials suitable for regeneration of large jaw bones. This article focuses on biological materials regulation, stem cell delivery, survival and differentiation, and their role in bone regeneration. PMID- 29972933 TI - [The key factors which affect the bio-root regeneration]. AB - The morbidity of tooth missing is the highest one among all the human organ diseases. The present restorations used in clinic, including fixed bridges, removable dentures and implant prosthetics, all exhibit their own defects, and hardly to restore the whole tooth structure and function. With the development of stem cells and tissue engineering, as an alternative, tooth regeneration, aiming at the generation of a structure like nature tooth, will be the therapeutic orientation to restore the lost tooth. The dental root, which supports the crown and occlusal force, is the fundamental part for tooth function. Based on the theory of tissue engineering, bio-roots were successfully generated by using mesenchymal stem cells (MSC) in miniature pigs. But the success rate of bio-root is not too high, is urgent to be improved for future clinic application. MSC mediated bio-root regeneration is depended on the dentinogenic differentiation regulation of MSC. Up to now, many factors affect the directed differentiation of MSC and further for the success rate of bio-root, including seeding cells, scaffold, growth factors and microenvironmental niche, etc. Microenvironmental niche is the key factor for affecting the MSC characteristics and special tissue regeneration. Basically, the bio-root is regenerated in jaw, while the jaw microenvironmental niche is prone to induce MSC for osteogenic differentiation, instead of dentinogenic differentiation. How to improve the dentinogenic differentiation of MSC in jaw microenvironmental niche is the key issue for increasing the success rate of bio-root. PMID- 29972934 TI - [Periodontal tissue engineering and regeneration]. AB - The clinical management of periodontal disease is a global concern, and the regeneration of periodontal tissue defects due to periodontitis faces a huge challenge in the field of regenerative dentistry. Although conventional periodontal therapies focusing on in flammation control could stop or delay the progression of the disease, periodontal regeneration remains an elusive but laudable goal. Since late 1980s, concerted efforts have been made to accelerate and augment periodontal repair by using guided tissue regeneration (GTR), guided bone regeneration (GBR) and a wide range of other regenerative paradigms. Those advances have largely improved the clinical outcomes of periodontal therapies. In the past several years of 21st century, many progresses were made in the developments of stem cell therapy and tissue engineering, including remarkable biological discoveries in the laboratory as well as great curative successes in preclinical scenarios. The use of the principles, techniques and procedures of tissue engineering in periodontology showed great potential to regenerate new functional periodontal tissues such as alveolar bone, periodontal ligament, root cementum and finally and predictably the normal structure and functionality of the periodontium around a previously diseased tooth. PMID- 29972935 TI - [Bioinductive biomaterials for periodontal regeneration]. AB - Periodontal regeneration is a great challenge faced by clinical treatment, and traditional therapies are not effective in regenerating periodontal tissues. Bioinductive biomaterials are materials that are able to induce the regeneration of damaged tissues, and they can induce the migration of stem cells or precursor cells to the defect site to proliferate, differentiate for tissue regeneration. For example, the osteoinductive biomaterials are able to induce regeneration of alveolar bone. In this review, the writer combined the recent advances of both clinical and scientific field, and summarize the application of bioinductive biomaterials includingautogenous bone, human derived growth factors, enamel matrix proteins and platelet-rich fibrin. PMID- 29972936 TI - [Host immune and mesenchymal stem cells-based bone regeneration]. AB - Mesenchymal stem cell (MSC)-based regenerative medicine represents a promising frontier for bone reconstruction. However, the prognosis of transplanted MSCs in vivo, as well as the general inter relationship with the local microenvironment and general immune system of the host is largely unclear and the clinical use of MSCs is limited. The prospects for more widespread stem cell-based bone engineering depends on understanding the interplay between host immune system and implanted MSCs. This article provides a concise summary of current knowledge pertaining to the interplay between donor MSCs and host immune response in the process of MSC-based bone regeneration. PMID- 29972937 TI - [Lateral cephalometric analysis of patients with maxillary alveolar protrusion and advanced periodontitis treated with immediate implants and cross-arch fixed prostheses]. AB - Objective: To investigate the changes of the lateral cephelometric landmarks of soft tissue and hard tissue of patients with maxillary alveolar protrusion and advanced periodontitis treated with immediate implants and cross-arch fixed prostheses. Methods: From January 2013 to October 2016, consecutive patients with advanced periodontitis and maxillary alveolar protrusion in need of immediate implants and cross-arch fixed prostheses were included in this study. All the patients were treated with provisional cross-arch fixed prostheses supported with 4 to 6 immediate implants after extraction of all the residual teeth and reduction of excessive alveolar bone. After 6 months, a final cross-arch fixed prosthesis was delivered. The lateral cephalometric landmarks of soft tissue and hard tissue at the time of pre-operation and final prosthesis delivery were analyzed. The change of patients' facial aesthetics was assessed using visual analogue scale (VAS). Results: Ten patients were included in the study. All the patients underwent full arch rehabilitation of both jaws supported by a total of 89 dental implants. In the maxillae, the average number of inserted implants were 4.5. The mean height of alveolar bone reduction was (6.3+/-1.8) mm. Both the distance of U1-NA (the upper incisor to nasion-A point line) and U1-PP (the upper incisor to palatal plane) were significantly reduced by (5.5+/-2.7) mm and (1.6+/ 1.2) mm, respectively. The angle of U1-SN (between upper incisor to sella-nasion line) was reduced by 9.6 degrees +/-8.1 degrees palatally. The nasolabial angles were significantly increased by 10.5 degrees +/-6.4 degrees . Both the patients and dentists considered that the facial aesthetics was improved greatly after the treatment. Conclusions: With the reduction of excessive alveolar bone and the realignment of artificial teeth, the treatment of immediate implants and cross arch fixed prostheses could improve the facial aesthetics of the patients with advanced periodontitis and maxillary alveolar protrusion. PMID- 29972938 TI - [Investigation of sagittal root position in relation to the anterior maxillary alveolar bone: a cone-beam CT study in 300 cases with normal occlusion]. AB - Objective: To investigate the sagittal root position and apical bone height of the maxillary anterior teeth in order to provide anatomical information for immediate implant placement in the esthetic region. Methods: Cone-beam CT (CBCT) data from 300 randomly selected patients who met the inclusion criteria were included in this study. After three-dimensional reconstruction, the sagittal plane (the sagittal plane through the long axis of the tooth) was determined. The positions and angulations of the tooth roots were classified with reference to the alveolar process. By comparing the buccal and palatal bone thickness at the mid-root level, the toot positions with reference to the mid-alveolar line were defined and classified as follows, type B (closer to the buccal alveolar surface), type M (midway between the buccal and palatal alveolar surface) and type P (closer to the palatal alveolar surface). By comparing the angulations of the alveolar process with the long axis of the roots, the angulations were classified as follows, type 1 (root apex angulated toward the palatal side or parallel to the alveolus), type 2 (root apex angulated toward the buccal side with the long axis passing posterior to point A) and type 3 (root apex angulated toward the buccal side with the long axis passing anterior to point A). The frequency of each category was counted and the apical bone height was measured. The subjects were divided into three age groups, 19-30 years, 31-50 years and 51 75 years. Results: The overall mean apical bone height of the healthy maxillary central incisors was (9.2+/-3.0) mm, the lateral incisors was (10.0+/-2.9) mm and the canine was (8.1+/-3.1) mm. There was no significant difference in the height of apical bone between central incisors and lateral incisors (P>0.05). There was no significant difference in the height of apical bone between male and female (P>0.05). The height of apical bone in group 31-50 years and 51-75 years were greater than that in group 19-30 years (P<0.05), respectively. The proportion of the maxillary anterior teeth type B, M, P was 98.5% (1 774/1 800), 0.3% (5/1 800) and 1.2% (21/1 800) respectively. The proportion of type 1, 2, 3 was 2.6% (46/1 800), 58.6% (1 055/1 800) and 38.8% (699/1 800) respectively. Conclusions: There was enough apical bone height in the area of maxillary anterior teeth, but the majority of roots positioned more buccally. PMID- 29972939 TI - [Positional relationship between branches of the facial nerve and the plane of angulus oris: an anatomical study]. AB - Objective: To investigate the relationship between the inferior buccal branch and mandibular marginal branch of the facial nerve in the plane of angulus oris. Methods: Twenty unilateral adults cadaveric heads were dissected. In the vicinity of the posterior border of mandibular ramus, the positional relationship between mandibular marginal branch and the plane of angulus oris, the inferior buccal branch and the plane of angulus oris was recoded and analyzed. Results: In 18 of the 20 samples, the plane of angulus oris was between the inferior buccal branch and mandibular marginal branch in the vicinity of the posterior border of mandibular ramus. In one sample, the plane of angulus oris was below the inferior buccal branch and mandibular marginal branch in the vicinity of the posterior border of mandibular ramus. Another sample was excluded because the starting points of the inferior buccal branch and mandibular marginal branch were in front of the posterior border of mandibular ramus. The distance from the intersection of the posterior border of mandibular ramus and the plane of angulus oris to the intersection of inferior buccal branch and the plane of angulus oris was (14.96+/ 8.55) mm. Conclusions: In most cases studied, the plane of angulus oris is between the inferior buccal branch and mandibular marginal branch in the vicinity of the posterior border of mandibular ramus. Along the plane of angulus oris, within 1.0 cm anterior to the posterior border of mandibular ramus, it is a relatively safe place for surgical approach. PMID- 29972940 TI - [Exploration of training pattern on periodontal probing during pre-clinical periodontal practice of undergraduate students]. AB - Objective: To explore the training pattern of periodontal probing practice so as to improve the accuracy of probing depth measurements of undergraduate students. Methods: Sixty-two undergraduate dental students in their pre-clinical training course were divided into two groups (31 students in each group): the reform group and the control group. The students in reform group learned and practiced periodontal probing by using transparent gingiva models for 30 minutes, and using conventional periodontal probing models for further 90 minutes in two sessions. The total practicing time was 2 hours. The students in control group learned and practiced periodontal probing using conventional periodontal probing models only for 1 hour of practicing time. After the training, new conventional periodontal probing models were used to evaluate the accuracy of probing depth measurements of the students in the two groups. The probing depths of Ramfjord index teeth were recorded by the students and were compared with the results of an experienced teacher's measurements. Results: The percentage of absolutely consistent sites in the reform group (63.4% [708/1 116]) was significantly higher than that of the control group (60.0% [670/1 116]) (P=0.012). In both reform group and control group, the percentages of absolutely consistent sites of the incisors (reform group: 69.1% [257/372], control group: 65.9% [245/372]) were significantly higher than those of the molars (reform group 58.9% [219/372], control group 54.3% [202/372])(P< 0.01), meanwhile, the percentages of absolutely consistent sites of the buccal-lingual sites (reform group: 88.7% [330/372], control group: 80.4% [299/372]) were significantly higher than those of the interproximal sites (reform group: 50.8% [378/744], control group: 49.9% [371/744])(P<0.01). Conclusions: The comprehensive reform of periodontal probing training could improve the accuracy of probing depth measurement of the undergraduate students. During the pre-clinical practice, probing training in the molar areas and the interproximal sites should be reinforced. PMID- 29972941 TI - [Burning mouth syndrome in the views of modern stomatology and traditional Chinese medicine]. AB - Burning mouth syndrome (BMS) is a common clinical disorder characterized by burning of the mouth or other discomfort, which significantly affects the quality of life of patients. The present article introduces and makes comparison of the mechanisms and clinical treatments of BMS in modern stomatology and traditional Chinese medicine. Modern stomatology studies have shown that BMS is related to the factors of neuropathy, psychology, endocrine or metabolic disorders, drug effects and local adverse stimuli. Traditional Chinese medicine suggests that BMS is mainly caused by diet, fatigue, bad emotion, poor health, oldness, etc. Individualized therapy is advocated in the treatment of BMS. Modern stomatology pays attention to comprehensive treatment for psychological disorder, systematic and oral local diseases. The thoughts of dialectical therapy and health keeping in traditional Chinese medicine also have clinical value. PMID- 29972942 TI - [A study on effects of immediate bone grafting at mandibular first molar fresh extraction socket on maintaining alveolar bone height after space closure]. AB - Objective: To investigate the effect of immediate bone grafting at mandibular first molar extraction socket on maintaining alveolar bone height after space closure. Methods: Thirty adult orthodontic patients who need to extract mandibular first molar, totally 38 target teeth, were included. The samples were divided into two groups randomly: graft group and non-graft group. All extraction space was closed orthodontically. Dental models of all patients were taken before extraction (T0), before space closure(T1) and after space closure (T2). The distance, time of the space closure and the velocity of tooth movement were recorded. Probing depth (PD) and clinical attachment level (CAL) at six sites (mesial buccal, buccal, mesial lingual, lingual, distal buccal and distal lingual) on adjacent teeth were measured before extraction (T0) and after space closure (T2). Cone-beam CT (CBCT) was taken at T0 and T2 to compare the changes of alveolar bone height at six sites on adjacent teeth using Invivo Dental 5.0 software. Results: The extraction space in both graft group and non-graft group was closed successfully. However, the space in graft group was closed more slowly than in non-graft group. In graft group, PD and CAL at the six sites on both the second molar and the second premolar did not change significantly after space closure, and CBCT showed that the alveolar bone height of the second premolar had no significant difference after treatment. In non-graft group, alveolar bone height decreased in both adjacent teeth and periodontal attachment loss was found after space closure. On average, alveolar bone height and periodontal attachment of the second premolar decreased (0.75+/-0.16) mm and (0.64+/-0.15) mm, respectively. Meanwhile, alveolar bone height and periodontal attachment of the second molar decreased (0.79+/-0.23) mm and (0.80+/-0.24) mm, respectively. Conclusions: Bone graft immediately after mandibular first molar extraction could delay alveolar bone resorption and preserve the periodontal attachment of the adjacent teeth during space closure. However, the procedure could slow down tooth movement. PMID- 29972943 TI - [Classification of the anatomical structures of maxillary central incisor root by cone-beam CT]. AB - Objective: To examine the root position of the maxillary central incisors and to provide clinical reference before the immediate implant placement. Methods: Cone beam CT (CBCT) data of the maxillary central incisors of 934 patients (934 incisors) was selected and the root position classsified. The sagittal root position in the alveolar bone was classified as buccal, middle, or palatal. The buccally positoined type was further classified into three subtypes of I,II, and III. Results: Most of the maxillary incisor root (95.4% [891/934]) was positioned buccally. Among the buccal-type incisors, the subtypes I, II and III accounted for 47.5% (423/891), 44.2% (394/891), and 8.3% (74/891). In the 4 mm apical to the cemento-enamel junction and the middle of the root, the thickest buccal bone wall was 0.86 and 0.95 mm, the thickest palatal bone wall was 1.65 and 2.37 mm. In the apical location, the thickest buccal bone wall was 1.89 mm, the thickest palatal bone wall was 7.83 mm. Conclusions: Most of the maxillary central incisors studied are positioned buccally, and half of these patients have adequate buccal bone and are suitable for immediate implant placement. PMID- 29972945 TI - [A 2-year cohort study on the caries risk assessment of 3-year-old caries-free children using Cariostat caries activity test]. AB - Objective: To evaluate the caries status of a cohort of 3-year-old caries-free children from 2 kindergartens in Beijing in a period of 2 years by using Cariostat caries activity test and to assess the sensitivity and specificity of Cariostat score as a caries risk indicator for caries-free children. Methods: Totally 426 3-year-old caries-free children from 2 kindergartens in Beijing were recruited in the present study. Informed consents were obtained from the children's parents. Dental plaque samples of the children were collected and the Cariostat caries activity tests were conducted at baseline and once a year for 2 years. After two years, the caries status of the cohort children were re evaluated and the caries incidences amongst children with high (2.0, 2.5, 3.0), medium (1.5) and low (1.0, 0.5, 0.0) levels of Cariostat scores were compared and analyzed. Results: Totally 864 3-year-old children from 2 kindergartens were screened before the study startedand 426 (49.3%) children were caries free. After 2-year follow-up, 312 out of 426 (73.2%) remained in the study. The overall caries incident rate was 46.5% (145/312). The caries incident rate of children with high level of Cariostat scores was 88.9% (88/99), while the caries incident rates of children with medium and low levels of Cariostat scores was 38.7% (36/93) and 17.5% (21/120), respectively. The sensitivity and specificity of the Cariostat test in assessing the caries risk of 3-year-old caries-free children in a period of 2 years were 60.7% and 93.4%, respectively. Conclusions: Cariostat caries activity test can be used as an indicator to predict the caries risk of 3 year-old caries-free children. Comprehensive caries management could be conducted for children in kindergartens based on the caries risk assessment results of caries experience and the Cariostat score. PMID- 29972944 TI - [Postoperative complications following dental rehabilitation under general anesthesia in children]. AB - Objective: To assess the postoperative complications in systemically healthy children treated for dental caries under general anesthesia (GA) after discharge and analysis of the correlative factors. Methods: This prospective observational study included 124 children aged 2-8 years old who received extensive dental treatment under GA. General conditions and treatment information were obtained from questionnaires filled by the dentist and the anesthesiologist. Postoperative data were collected from a questionnaire filled by the parents in one week. Pain was assessed by using the dental discomfort questionnaire-8 (DDQ-8) pain assessment scale. Results: The mean anesthesia time for GA procedures was 102.6 min and the mean number of treated teeth was 13.5. Approximately 66.9% (83/124) of the children had one or more postoperative complaints on the first day after the treatments. The most common complaints reported were cough, hoarseness, and dental pain followed by throat discomfort, problems in eating, swelling, weakness, sleepiness, vomiting, fever and nausea. By the seventh day after the treatment, the main complications remained were dental pain and cough, while most of other symptoms disappeared. Preoperative DDQ-8 score and the number of extracted teeth were the factors that showed a significant association with postoperative dental pain on the first day. Conclusions: Dental pain and pharynx discomfort were most frequently noted postoperative symptoms. Postoperative dental discomfort on the first day might be predicted by dental pain before GA and tooth extraction under GA. PMID- 29972946 TI - [Analysis of the effect of mesial implant position on surrounding bone stress of mandibular edentulous jaw under dynamic loads]. AB - Objective: To evaluate the effect of different placement of mesial implants in edentulous jaws on the stress of the implant and the surrounding bone tissue by three-dimensional (3D)finite element analysis. Methods: Cone-beam CT data of mandibular edentulous patients was transferred into Mimics 17.0 and UG NX8.5 software, and three groups of 3D solid model were established: two mesial implants were implanted in the anterior region of the mandible (bilateral central incisor, lateral incisor, canine), and two distal oblique implant with 30 degrees were implanted in the mandibular second premolar area(5 mm near the mental foramen). Set mandible 3D model with 4 implant by using UG NX8.5 software, produced 3 groups (mandible I-III). We took dynamic loading on models with help of software Abaqus 6.12, working side posterior teeth loading was set to 150 N and the simulation cycle was 0.875 s. The first stage: 0.000 s to 0.130 s, the lower jaw moves outward (moving toward the side of the work), with no contact between the upper and lower teeth; the second stage: 0.130 s to 0.150 s, mandibular upward, the same tooth tip of the working side were relative, the loading position were the posterior buccal tip, tongue tip; the third stage: 0.150 s to 0.260 s, the buccal slopes of buccal tips of mandibular posterior teeth glide along the lingual slopes of buccal tips of maxillary posterior teeth, the loading force was from the buccal side to the lingual side, the long axis of the tooth was 45 degrees , loaded on the buccal slopes of buccal tips of posterior teeth; the fourth stage: 0.260 s to 0.300 s, the lingual slopes of buccal tips of mandibular posterior teeth glide along the buccal slopes of the tongue tips of maxillary posterior teeth, separate from the tip of the tooth at half the length, the loading force was from the lingual side to the buccal side, the long axis of the tooth was 45 degrees , loaded on the lingual slopes of buccal tips of posterior teeth; the fifth stage: 0.300 s to 0.875 s, at the unloading stage, mandibular posterior teeth were separated from the maxillary teeth and returned to the intercuspal position. The loading position varied according to the mastication cycle. The stress distribution of implant and surrounding bone tissue at different stages of each model were observed. Results: From the early stage to chew occlusal contact to the end of the mastication cycle, three groups of models were displayed: the stress of distal implants was greater than that of mesial implants and the neck stress reached the maximum and gradually decreased to the root tip. The stress of distal implant bone was greater than that of mesial implant bone and the stress of distal bone of distal implant was greater than that of mesial bone of distal implant. All the stress peak showed a gradual increase, and the stress reach the maximum at the fourth stage. In the 3 models, the bone stress around the distal implant of model of the anterior implant located in the lateral incisor region was the lowest. The peak stress of cortical bone of the distal position of implant was 58.7 MPa. The bone stress around the distal implant of model of the anterior implant located in the canine region reached the maximum, and the peak stress of cortical bone of the distal position of implant was 135.6 MPa. Conclusions: When mesial implants of edentulous jaws located in the lateral incisor region, it is good for stress dispersion. PMID- 29972947 TI - [Effect of three types of rapid maxillary expansion: a three-dimensional finite element study]. AB - Objective: To evaluate the transverse displacement, stress distribution and tendency of change in tooth, alveolar bone and mid-palatal suture using three kinds of rapid maxillary expansion methods. Methods: Cone-beam CT image data was obtained by scanning skulls of a volunteer. Three-dimensional models of maxillary complex were re-established using Mimics and Geomagic Studio and models of Hyrax expander, Haas expander and miniscrew-assisted rapid palatal expander (MARPE) were established using ANSYS Workbench. Stress distribution, displacement and tendency of change in tooth, alveolar bone and mid-palatal suture were evaluated. Results: Hyrax expander brought 0.105 mm lateral displacement of crown, 0.022 mm mid-palatal suture width increase, wedge opening and clockwise rotation tendency of maxilla. Haas expander created uniform stress distribution, 0.216 mm lateral displacement of crown, and 0.031 mm mid-palatal suture width increase. In MARPE model, the lateral displacement of crown was 0.267 mm, and mid-palatal suture width increased 0.315 mm. The maximum of mid-palatal suture expansion and stress distribution appeared in the middle region, and maxilla had tendency of counterclockwise rotation. Conclusions: The lateral changes of teeth and bones brought by MARPE were the most significant. Haas expander had some advantages in comparison with Hyrax. PMID- 29972948 TI - [A cone-beam CT investigation on condylar growth in beagle dog treated with Herbst appliance and prostaglandin E2 during late stage of growth]. AB - Objective: To assess the mandibular condylar growth using cone-beam CT (CBCT) in beagle dogs treated with Herbst appliance and exogenous prostaglandin E2 (PGE2) during late stage of growth. Methods: Twenty-four male beagle dogs aged 8 months were divided into four groups according to the random number table (n=6 in each group): natural growth group, mandibular protraction group (Herbst group), injected prostaglandin E2 group (PGE2 group), mandibular protraction plus injected prostaglandin E2 group (Herbst+PGE2 group). The beagle dogs in Herbst+PGE2 group and PGE2 group were injected 0.1 ml of prostaglandin E2 (dose of 0.05 mg) into bilateral temporomandibular joint articular cavity. The dogs in natural growth group and Herbst group were injected 0.1 ml of saline into bilateral temporomandibular joint articular cavity as control. PGE2 and saline were injected once every 3 days for 60 days, respectively. CBCT was taken before the application of Herbst appliance and after removal of the appliance for all beagle dogs in four groups at the same time. The CBCT images were reconstructed using Invivo5 software and the relevant parameters of temporomandibular joint were measured. Results: No significant difference was found in natural growth group before and after the experiment (P>0.05). After the treatment, the condylar height and condylar size in Herbst group ([0.19+0.04] and [0.18+0.30] mm), PGE2 group ([0.38+0.14] and [0.51+0.24] mm) and Herbst+PGE2 group ([0.65+0.08] and [0.70+0.24] mm) slightly increased (P<0.05). The condylar changes in all experimental groups were greater than the natural growth group (P<0.05), and the ranges of change, in descending order, were Herbst+PGE2 group, PGE2 group and Herbst group (P<0.05). However, the condylar longitudinal distances, condyle width, condylar transverse diameter, glenoid fossa width and glenoid fossa depth had no statistically significant difference among the four groups (P>0.05). Conclusions: Injection of exogenous PGE2 into the temporomandibular joint articular cavity, or using Herbst appliance separately, a certain amount of growth was observed on the mandibular condyle in beagle dogs during late stage of growth. The combination of Herbst appliance and exogenous PGE2 injection made the condylar growth more obviously. PMID- 29972949 TI - [Mechanism of cleft palate in C57BL/6N mice induced by retinoic acid]. AB - Objective: To investigate the mechanism of cleft palate in mice induced by excessive all-trans retinoic acid (atRA). Methods: The pregnant mice were randomly divided into atRA-treated group (n=27) and control group (n=27). atRA treated group was given by gavage a single dose of atRA (100 mg/kg) at 8: 00 AM on gestation day 10 (GD10) and the control group was given by gavage the isopyknic corn oil. At GD13-GD15, the fetal mice palate development was observed by HE staining. The mouse embryonic palatal mesenchymal cell proliferation was detected by 5-bromo-2-deoxyuridine (BrdU) immunohistochemistry. The expressions of Smad2, phospho-Smad2 (p-Smad2), Smad4 and Smad7 in mouse embryonic palatal mesenchyme were analyzed by Western blotting. Results: At GD13-GD15, compared with the control, the ratio of BrdU-positive cells in the palatal mesenchyme of atRA-treated fetuses decreased significantly (P<0.05), especially at GD14, atRA inhibition rate was (65.4+/-1.7)%. Moreover, atRA decreased the levels of p-Smad2 and Smad4 in embryonic palate mesenchymal cells, whereas the expression of Smad7 was significantly increased at GD14 and GD15. Conclusions: atRA may lead to cleft palate by inhibiting the activation of Smad signaling pathway and affecting the proliferation of palatal mesenchymal cells. PMID- 29972950 TI - [Clinical application of intraoperative CT in management of maxillofacial fracture]. AB - Nine patients with maxillofacial fracture that received intraoperative CT examination in Lanzhou General Hospital of Lanzhou Military Command from January 2017 to March 2017 were retrospectively studied. The procedure of intraoperative CT was introduced. The value of this technique was preliminarily discussed in order to provide a new method for the accurate implementation of maxillofacial fracture surgery. PMID- 29972951 TI - [Computer aided design of mandibular distraction osteogenesis in the treatment of Robin sequence related mandibular deformities in children: a case report]. PMID- 29972952 TI - [Diagnostic criteria and treatment progress of PHACE syndrome]. AB - PHACE syndrome is a syndrome of multiple organ and multisystem abnormalities associated with infantile segmental hemangioma, characterized by abnormal posterior fossa development, infant hemangioma, aortic abnormalities, aortic coarctation and heart defects, eye anomalies and other symptoms. The incidence of the disease is low, but there exist life-threatening factors. Once clinically diagnosed, it should be highly valued and multidisciplinary consultation must be conducted. This article reviews the diagnostic criteria of PHACE syndrome and its associated facial segmental hemangioma, as well as the treatment and prognosis of brain abnormalities. PMID- 29972953 TI - [Advance and review: implant-abutment microgap]. AB - Implant-abutment microgap (IAM) exists in two-piece implant systems. Researchers have proved that IAM influences success rate of dental implants in the long term. The relationship between IAM and the biological, mechanical complication of dental implants has been proven in some studies. Implant-abutment connection type, abutment material and insertion torque may all have impact on IAM size. On the other hand, ways to reduce or seal this gap are discussed in some literature. The relationship between IAM and bacteria colonization, long-term implantation complication and its influencing factors are discussed in this review. PMID- 29972954 TI - [Research progress of xerostomia assessment tools]. AB - Xerostomia is an important problem affecting oral health and quality of life, and effective assessment is the basis of management of xerostomia. This review summarizes the subjective and objective assessment tools for xerostomia, so as to provide references for the evaluation and management of xerostomia. PMID- 29972955 TI - [Exploit to forge ahead and encourage to move forward]. PMID- 29972956 TI - [Clinical application of submental artery perforator flap in oral and maxillofacial defect restoration after tumor resection]. AB - Objective: To summarize the clinical anatomical features and surgical technique of the submental artery perforator flap (SMAPF), and to evaluate the outcome and value of the flap for oral cavity reconstruction after cancer ablation. Methods: A total of 56 patients with oral cancer were included in this study. The modified SMAPF excluded the anterior belly of the digastric muscle and submental fatty tissue. The primary sites of malignancy were buccal mucosa (n=24), tongue (n=21), mandibular gingiva (n=6), mouth floor (n=3), soft palate (n=2). Results: The flap size varied from 3 cm*5 cm to 5 cm*12 cm. Four flaps presented mild venous congestion, which was salvaged with conservative measures such as acupuncture and blood letting. Overall flap survival rate was 100%. The SMAPF with septocutaneous perforator was used in 49 cases and with musculocutaneous perforator in seven cases. External jugular vein and internal jugular vein provides venous drainage were applied in half cases respectively. All the patients showed a good recovery of tongue mobility and mouth opening with a follow-up of 3-41 months. Local recurrence was detected in one patient 4 months after operation. Conclusions: The SMAPF is a reliable flap for oral cavity reconstruction with outstanding functional and aesthetic outcomes. PMID- 29972957 TI - [Morphometric analysis of the infrazygomatic crest zone in 84 mini-implants using cone-beam CT]. AB - Objective: To investigate the soft and hard tissue morphology in the infrazygomatic crest zone by observing the cone-beam computed tomography (CBCT) scans in patients with mini-implants. Methods: CBCT scans of 43 patients performed from January 2014 to December 2016 in the Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, with 84 existing mini implants in the infrazygomatic crest region were collected. The bone thickness and cortical bone thickness were measured in the palatal and buccal side of the mini-implant. The maxillary sinus membrane thickness, sinus septa, reverse fold, and the sinus opening angle were also determined and analyzed in the maxillary posterior region. Results: The bone thicknesses in the buccal and palatal side of the existing mini-implant were 2.5 (1.5, 3.2) and 5.2 (4.0, 6.4) mm, respectively. However, the corresponding cortical bone thicknesses were only 2.1 (1.3, 2.8) and 1.5 (1.0, 1.9) mm, respectively. The prevalences of the septa and the reverse fold were 33% (28/84) and 45% (38/84), respectively. The sinus opening angle was the largest in the mid-coronal plane of the maxillary first molar (71.6 degrees +/-15.6 degrees ). In the coronal plane located at 10 mm mesially, the angle was the smallest (46.1 degrees +/-18.0 degrees ), and in this area, 20% (16/82) of the angle was less than 30 degrees . Conclusions: The outer cortical plate of the infrazygomatic crest along with the cortical plate of sinus floor could be related to the initial stability of mini-implant anchorage. The anatomic variation such as the reverse fold indicated thorough consideration of insertion depth and angle to avoid unexpected sinus injury. PMID- 29972958 TI - [Expression and significance of interleukin-35 in lesion tissue of oral lichen planus patients]. AB - Objective: To investigate the expression of Epstein-Barr virus-induced gene 3 (EBi3) and interleukin-12p35 (IL-12p35) in two subunits of interleukin-35 (IL-35) in oral lichen planus (OLP) lesions, and to explore the role of IL-35 played in the formation and development of OLP lesions. Methods: Totally 41 samples of OLP lesions and 15 samples of normal tissues were collected from patients of the Department of Periodontology and Oral Medicine, Affiliated Stomatological Hospital of Guizhou Medical University from October 2010 to December 2016. The expression levels of EBi3 mRNA and IL-12p35 mRNA in the samples were detected by quantitative real-time PCR (qPCR) and the distribution and expression of protein EBi3 and IL-12p35 were detected by immunohistochemistry. The potential relationship between IL-35 and clinicopathological features of OLP was analyzed. Results: The expression [M(Q(25), Q(75))] of EBi3 [3.38 (1.63, 11.25)] and IL 12p35 mRNA [6.39 (2.55, 14.30)] in OLP lesion tissues were significantly higher than those in normal control group [1.41 (0.33, 3.16), 2.47 (1.10, 5.14)] (Z= 2.806, P=0.005; Z=-2.276, P=0.023), respectively. The positive expression rates of EBi3 and IL-12p35 were 66% (27/41) and 39% (16/41), respectively, were significantly higher in OLP lesion tissues comparing with that in normal oral mucosa tissues [0%(0/15)] (P<0.05). The relative expressions of EBi3 and IL-12p35 were positively correlated (r=0.404, P=0.009). A significant correlation was found between EBi3 protein over expression and the degeneration of base cells in OLP lesions (chi(2)=9.172, P=0.010). The positive expression rate of IL-12p35 protein in erosive type lesions was higher than that in non-erosive type lesions (chi(2)=7.220, P=0.007). The positive expression rate of IL-35 protein in OLP lesions [34% (14/41)] was higher than that in normal control group (chi(2)=6.829, P=0.009). The expression rate of IL-35 in erosive type lesions (10/20) was significantly higher than that in eruption type lesions (4/21) (chi(2)=4.364, P=0.037). Conclusions: The expression of IL-35 in OLP localized lesions was up regulated, suggesting that IL-35 might play an important role in OLP lesion formation. PMID- 29972959 TI - [Association of fimA genotype to kgp genotype in Porphyromonas gingivalis from infected root canals of primary apical periodontitis]. AB - Objective: To investigate the distribution of fimA and kgp genotypes as well as the common genotype combination of Porphyromonas gingivalis (Pg) in infected root canals of primary apical periodontitis for virulent isolates screening in future. Methods: Thirty-four samples harboring Pg were selected from infected root canals of primary apical periodontitis from patients of the Department of Endodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine from June 2013 to September 2015. FimA type-specific primers were used to amplify the samples, revealing the distribution of various fimA genotypes. The genotypes of kgp were obtained by using Mse I restriction endonuclease. The prevalence of each genotype and common genotype combinations were then calculated. Pearson's chi squared test was performed to analyze the correlation between genotype combinations and clinical symptoms and major signs of apical periodontitis. In addition, the bioflim architectures between Pg isolates with different fimA and kgp genotype combinations were observed compared using confocal laser scanning microscope. Results: Among the 34 Pg-positive samples, fimA II was the most prevalent genotype [47% (16/34)] followed by fimA I [26% (9/34)], while fimA V was detected in only one sample. The prevalence of kgp I [56% (19/34)] was slightly higher than that of kgp II [44% (15/34)]. Both fimA II+kgp I and fimAII+kgp II were the most prevalent genotype combinations [24% (8/34) each]. No significant correlation was found between specific genotype combination and such major clinical manifestations as gingival swelling and sinus tract of dental origin (P>0.05). Three Pg isolates with different genotype combinations were acquired. Isolate A (fimAI+kgpI) formed densest biofilm, while the biofilm of isolate C (fimAV+kgp I) was much looser. The biofilm feature of isolate B (fimAIII+kgp II) fell in between A and C. Conclusions: Pg with fimA II was most frequently detected in infected root canals of primary apical periodontitis. The prevalence of Pg with kgp I was slightly higher than that with kgp II, and fimAII+kgp I as well as fimA II+kgp II were the commonest genotype combinations. According to the comparison of Pg biofilms formed by clinical isolates, it might be possible that different genotype combinations may lead to distinct biofilm architectures. PMID- 29972960 TI - [Implant restoration on folded fibular graft for the repair of mandibular defect]. AB - Objective: To discuss the key points of implant restoration on folded fibular graft for mandibular defect. Methods: Fifteen patients with mandibular ameloblastoma were treated by segmental resection of the mandible.The mandibular defect was reconstructed with vascularized folded fibular graft. Implant restoration on the graft was conduced 6-9 months after operation.The results were evaluated. Results: All patients had no tenderness in the temporomandibular joint region. The mouth opening reached 3.1-3.9 cm and the occlusion relationship was good. There was no obvious abnormality in masticatory and swallowing function. After 12-48 months of follow-up, the implants were all survived. Conclusions: The application of folded fibula for both mandible defect repair and postoperative implant restoration could achieve satisfactory results in restoration of the facial appearance and physiological function of oral cavity. PMID- 29972961 TI - [Photoelastic analysis of the influence of prosthetic material on the stress distribution in bone around implant]. AB - Objective: To provide a reference for a suitable alternative treatment choice for implant-supported prostheses, and to explore the influence of 3 types of prosthetic material on the stress distribution around implant. Methods: The implant-abutment analogs were embedded individually into photoelastic resin blocks, which were medical pure titanium castings reproducing the surface and outline of implant (diameter 4.3 mm, length 11.5 mm) and esthetic abutment (regular profile, 1 mm). The prostheses were divided into 3 groups according to the type of prosthetic material. Each group consisted of 5 samples. The samples of composite resin ceramic and zirconia group were milled by chair-side computer aided design and computer aided manufacture (CAD/CAM) system. The samples of porcelain-fused-to-metal crown group were made manually and a pre-arranged silicone rubber impression of CAD/CAM crown would guide to shape the veneer porcelain. Each set was submitted to a 300 N compressive load axially or obliquely (75 degrees ). The stress value in the peri-implant bone at the level of the neck, neck1/3, middle1/3 and root1/3 of the sections (0.5, 1.5, 2.5, 3.5 mm) from implant was analyzed by digital photoelasticity, and the stress cushioning effect of 3 types of prosthetic material was comprehensively evaluated. Results: The time spent reaching the stress peak of composite resin ceramic group [(1.58+/-0.08) s, axially; (2.75+/-0.21) s, obliquely] was larger than that of the zirconia group [(1.40+/-0.12) s, axially; (2.30+/-0.25) s, obliquely] (P<0.05) under the same download mode. Although there were no significant differences in equivalent stress values of the measurement points among the three groups (P>0.05), a downward trend of equivalent stress values of composite resin ceramic group was observed compared to zirconia group, regardless of load type. When loaded obliquely, the highest degree of stress concentration at the level of the neck of implant were found in the porcelain-fused-to-metal crown group. Conclusions: Within the limitations of this study, composite resin ceramic was more beneficial to the biomechanical behavior of implant in stress buffer compared to zirconia. PMID- 29972962 TI - [Hedgehog pathway antagonist-induced oromandibular limb hypogenesis in mouse]. AB - Objective: To analysis teratogenic effect of GDC-0449 to fetus and set up the animal model of GDC-0449 induced oromandibular limb hypogenesis in mouse for further research of its pathogenesis. Methods: Twenty-seven pregnant Institute of Cancer Research (ICR) mice were randomly divided into: control group, embryonic day 8.5 (E8.5) exposed groups, E9.5 exposed groups, E10.5 exposed groups, E11.5 exposed groups, E12.5 exposed groups, E13.5 exposed groups, E14.5 exposed groups and E15.5 exposed groups. Each group had 3 mice. Exposed groups were treated with the Hedgehog pathway antagonist GDC-0449 at a single dose 150 mg/kg by oral gavage from E8.5 to E15.5. At E16.5, embryonic phenotypes were analyzed in detail by stereo microscope and histology. After establish an optimal dysmorphogenic concentration, 6 pregnant ICR mice were randomly divided into control group and the optimal group, embryonic phenotypes were analyzed by whole-mount skeletal staining and micro-computed tomography at E18.5. Results: The mice were exposed to GDC-0449 on E11.5 and E12.5 had a high incidence of cleft palate. GDC-0449 exposed between E9.5 and E10.5 caused craniofacial and limb dysmorphology, including micrognathia, microglossia, ectrodactylia, partial anodontia and cleft palate. Most interestingly, these are extremely similar to oromandibular limb hypogenesis syndrome. Conclusions: The results of this study indicate that GDC 0449 can be used to induce micrognathia, microglossia, ectrodactylia, partial anodontia and cleft palate. This work established a novel mouse model for oromandibular limb hypogenesis. PMID- 29972963 TI - [Vascular endothelial growth factor-loaded microspheres promote dental pulp regeneration and vascularization]. AB - Objective: To evaluate the effect of vascular endothelial growth factor (VEGF) loaded microspheres on dental pulp tissue regeneration and vascularization in vivo. Methods:In vitro release experiment and human umbilical vein endothelial cell migration experiment were conducted with VEGF loaded microspheres. The dental pulp stem cells (DPSC) were co-cultured with VEGF microspheres to observe the compatibility between the cells and the microspheres. DPSC and VEGF loaded microspheres were injected into the root lumen through the apical foramen, which were then transplanted subcutaneously into nude mice. Histological and immunohistochemical features were observed after nine weeks. Results: DPSCs attached and spread on the surface of the microspheres. HE staining showed that the regenerated pulp-like tissue fulfilled the whole apex and middle third of the root. Differentiated odontoblast-like cells aligned with the existing tubular root dentin. Conclusions: VEGF-loaded microspheres promoted the regeneration of pulp-like tissues and formation of blood vessels. PMID- 29972964 TI - [Effect of treatment of infant parotid hemangioma with no response to oral propranolol]. AB - Hemangioma is the most common vascular tumor in infantile period, and propranolol is the first choice, but there are still a few patients with poor curative effect. Seven cases of infant parotid hemangioma with no response to oral propranolol were treated with transcatheter arterial sclerosing embolization combined with cortisol and satisfactory results achievod. The treatment and efficacy are disccused in this paper. PMID- 29972965 TI - [Accidental foreign body aspiration in dental practice: a case report]. PMID- 29972966 TI - [Research progress of salivary glands mucosa-associated lymphoid tissue lymphoma]. AB - Salivary glands mucosa-associated lymphoid tissue lymphoma (SGML) is a distinct subtype of marginal zone B-cell type non-Hodgkin's lymphoma (NHL), which is commonly seen in middle aged females. SGML is usually associated with autoimmune diseases such as Sjogren's syndrome or with chronic infection such as hepatitis C virus (HCV) infection. Chromosomal abnormalities are frequently seen in SGML, which usually activate nuclear factor-kappaB molecular pathway to modulate cell survival and proliferation, resulting in lymphoma occurrence. SGML tends to arise from parotid gland, presenting frequently as a localized and indolent lesion, a long-term follow-up and biopsy are needed for accurate diagnosis. Surgery, radiotherapy and chemotherapy are usually effective disseminated diseases at multiple sites need combined treatment. SGML has a relatively better prognosis with a higher relapse rate than other types of NHLs, dissemination or higher degree of malignant transformation may occur. Thus, a long-term and close follow up is essential for patients with SGML. PMID- 29972967 TI - [Research and development of digital design and fabrication of complete denture]. AB - Removable complete denture are still the primary prosthetic solution for edentulous patients. Functional pressure impression obtaining, jaw relation recording, personalized balance occlusion and highly precise fabrication of denture are difficult. The digital restoration technique represented by intraoral three-dimensional scanning and three-dimensional (3D) printing compensates for the shortages of the manual techniques, but there are still many limitations in the application of complete dentures. At present, a few computer aided design and computer aided manufacture (CAD/CAM) complete denture systems have been developed both domestically and abroad, and these system are mainly focused on the digital design and manufacture of denture, and are seldom used for the recording of impression and jaw relation. This review is based on the main clinical procedures of the traditional complete denture restoration, elaborating the research and application status of digital technique in each steps, in order to provide reference for clinical application. PMID- 29972968 TI - [Research progress in the function of monocyte/macrophage-lineage origin cells in the peri-implant osseointegration interface]. AB - Although many studies have focused on how material surface modifications can promote stem cell differentiation toward osteogenic osteoblasts, little is known about the reaction between material surface and other cells, including osteoclasts and foreign body giant cells. Dental implant osseointegration results from the functional coupling and equilibrium not only between osteoblasts and osteoclasts but also between bone tissue and immune system. Osteoclasts and foreign body giant cells share the same origin, monocyte/macrophage lineage cells, which have initially got concerns in the field of implant osseointegration with regard to their peri-implant distribution and biological functions. Up-to date data has shown that cells of monocyte/macrophage lineage origin manifest key roles in the establishment of peri-implant osseointegration and the long-term maintenance of marginal bone level and the prevalence of peri-implantitis. However, preliminary progress has been made in the subtypes, phenotypes vs. genotypes, and functions of monocyte/macrophage-lineage-originated cells on the osseointegration interface, quite a lot of facts still remain unclear, especially the potential and the rapeutic targets which could coordinate the cellular peri implant microenvironment and the implant osseointegrated interface in the short and long term. This review will focus on the current progress in the function of monocyte/macrophage-lineage origin cells on the peri-implant osseointegration interface. PMID- 29972969 TI - [A glance at the American training mode of the clinical postgraduate students of periodontology through postdoctoral program in periodontics of University of Washington School of Dentistry]. AB - To provide references and recommendations about periodontal professionals training for our country by introducing American training mode of clinical postgraduate students of periodontology. Based on ground visits and surveys of University of Washington School of Dentistry's postdoctoral program in periodontics, the professional training mode and its characteristics which adapt to the development trend of American periodontology were summarized and concluded. The discussion is in the following three parts: the overall status of postgraduate education of periodontology in the United States, the training mode of the clinical postgraduate students of periodontology at University of Washington School of Dentistry, and the observation of the American Academy of Periodontology's annual conferences. This kind of training mode supervised by the American Dental Association, giving priority to clinical practice and emphasizing cultivating the multidisciplinary comprehensive ability are worth learning. Meanwhile, the development trend of periodontology in the United States which pay increasing attention to carry out implant therapy with periodontal features and the adaptive training mode of clinical postgraduate students of periodontology also deserves our deep reflection and can be used for reference. PMID- 29972970 TI - [A preliminary study on the effect of histatin 5 inhibiting Porphyromonas gingivalis and Fusobacterium nucleatum co-aggregation]. AB - Objective: To detect the inhibitory ability of histatin 5 on the auto-aggregation of Porphyromonas gingivalis (Pg), and the co-aggregation of Pg with Fusobacterium nucleatum (Fn); and to provide a theoretical basis for the role of oral innate immunity played in the inhibition of chronic periodontitis. Methods: Saliva and supragingival, subgingival plaque samples were collected from 49 chronic periodontitis patients in School of Stomatology, China Medical University and 27 periodontal healthy individuals. Enzyme linked immunosorbent assay was used to assess the amount of histatin 5 in saliva, absolute quantitative real-time PCR (qPCR) was applied to detect the DNA copies of Fn, Pg and total bacteria in supragingival and subgingival plaque samples. The effects of histatin 5 on auto- and co-aggregation were assessed by bacterial adhesion test and scanning electron microscopy. Hemagglutinin gene, arginine-gingipains gene in Pg and FomA gene in Fn were tested by relative qPCR. Independent samples t-test was used to calculate the significance between the experimental group and the control group. P value<0.05 was considered statistically significant. Results: For chronic periodontitis patients, there was an inverse correlation between the concentration of histatin 5 and Fn and Pg in supragingival plaque samples (r= 0.379, r=-0.624). Similarly, an inverse correlation was also observed between the concentration of histatin 5 and subgingival Fn and Pg, respectively (r=-0.404, r= 0.314). As for periodontally healthy individuals, there was an inverse correlation between the concentration of histatin 5 and supragingival and subgingival Pg (r=-0.572, r=-0.533). Bacterial adhesion test and scanning electron microscopy certified that 25 mg/L histatin 5 inhibited the auto aggregation of Pg-Pg and the co-aggregation of Pg-Fn. Results of qPCR showed that 25 mg/L histatin 5 up-regulated hemagglutinin gene by (14.52+/-3.25) fold and down-regulated FomA gene to (0.22+/-0.10) fold. Conclusions: Histatin 5 could inhibit the auto-aggregation of Pg-Pg and the co-aggregation of Pg-Fn by regulating hemagglutinin gene and FomA gene expression. PMID- 29972972 TI - [Combined periodontal and implant treatment of chronic periodontitis patient with severe alveolar bone defects: a case report]. PMID- 29972971 TI - [Temporal expression of triggering receptors expressed by myeloid cells-1 during the development of experimental periodontitis in rat]. AB - Objective: To illuminate the temporal expression of the triggering receptor expressed on myeloid cells-1 (TREM-1) in the experimental periodontitis in rat and to investigate the function of TREM-1 in the pathogenesis of experimental periodontitis in rat. Methods: The experimental periodontitis model was established in the maxillary first molar by means of 'wire ligation + vaccination periodontal pathogen Porphyromanus gingivalis (Pg) + high-sugar diet' in Sprague Dawley (SD) rats. The experimental animals were divided into six groups: the control group and each of the time points of establishing the models for one week and two to five weeks. There were six rats for each of the six groups. The bone loss of the palatal site was calculated to estimate whether the periodontitis model was successfully established. The expression of TREM-1, proinflammatory cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL 6, anti-inflammatory cytokines: IL-4, IL-10 and transforming growth factor-beta (TGF-beta) were examined by using quantitative real-time PCR. The expression level of TREM-1 protein was analyzed by the method of immunohistochemistry. Results: The average bone loss area of the palatal site was (0.17+/-0.04) mm(2) in the group of three weeks and was statistically significant (P<0.05) compared to the control group [(0.10+/-0.01) mm(2)]. The experimental periodontitis model was successfully established in the group of three weeks. The expression of TREM 1 increased significantly in the inflamed periodontal tissues and reached to its maximum expression in the three weeks group accounting for 159.50+/-38.26 in protein expression and 4.35+/-0.60 in mRNA expression, respectively. TREM-1 expression difference between the three weeks group and control group was statistically significant (P<0.01). The expression of IL-6 by gingival tissues was correlated with the mRNA level of TREM-1 (r=0.813 P=0.049). Conclusions: TREM 1, as a proinflammatory receptor, could facilitate the periodontal inflammatory response. The possible way of TREM-1 to promote inflammation may be through controling the expression of IL-6. PMID- 29972973 TI - [Treatment of gingival recession at mandibular anterior tooth by transplantation of subepithelial connective tissue graft combined with coronally repositioned: a case report]. PMID- 29972974 TI - [Mucogingival surgery for treatment of multiple recession defects of gingiva: a case report]. PMID- 29972975 TI - [Combined periodontal-orthodontal treatment for generalized aggressive periodontitis: a case report]. PMID- 29972976 TI - [Multi-disciplinary treatment of generalized aggressive periodontitis: a case report]. PMID- 29972977 TI - [Langerhans cell histiocytosis with periodontal lesions as the initial manifestation: a case report]. PMID- 29972978 TI - [Clinicopathological analysis of 98 cases of benign lymphoidenosis of oral mucosa]. AB - Objective: To investigate the clinical manifestations and pathological changes of benign lymphoadenosis of oral mucosa. Methods: The clinical data of 98 cases of benign lymphoadenosis of oral mucosa were analyzed. Results: The clinical manifestations of benign lymphoadenosis of oral mucosa included erosive ulcer (64%) and nodule (9%) and the rate of misdiagnosis was 98%. Neutrophil infiltration occurred in the epithelium of 51% cases and the lymphocyte was diffusely infiltrated in lamina propria of 83% cases. Conclusions: When the mucous membrane of the lamina propria is characterized by complex cell components, diffuse infiltrating lymphocytes and infiltration of neutrophils in mucosal epithelium without erosion and ulceration, it is necessary to highly suspect benign lymphoadenosis of oral mucosa. Finding the focal aggregation of lymphoid follicles or lymphocytes is helpful for the correct diagnosis. PMID- 29972979 TI - [Effects of casein phosphopeptide-amorphic calcium phosphate on enamel erosion: an in situ study]. AB - Objective: To evaluate the effects of casein phosphopeptide-amorphic calcium phosphate (CPP-ACP) on enamel erosion using an improved in situ experimental protocol. Methods: Forty-eight enamel blocks were prepared from fresh-extracted human premolars and further embedded in the acrylic resins. The present study was divided into 2 parts. In part 1 of the study, two volunteers were recruited to test the availability and safety of the in situ erosion protocol. Customized intraoral appliance was made with 4 reservoirs containing the specimens for each volunteer. For each intraoral applicance, 2 reservoirs were made with the openings and the other 2 remained intact. All volunteers were instructed to drink 150 ml cola within 5 min using the gargling method after placing appliances intraorally for 2 h. After erosion, the appliances were remained undisturbed intraorally for 1 h until the next erosive attack. The in situ erosion cycles were performed 4 times daily over 7 d. In part 2 of the study, forty specimens were randomly divided into 2 groups (n=20): CPP-ACP group and control group. The surfaces of specimens in CPP-ACP group were pretreated with CPP-ACP for 3 min before in situ erosion, whereas the specimens in control group were pretreated with deionized water for 3 min. For each intraoral applicance, 4 reservoirs were made with openings. Ten healthy volunteers were recruited and the above-mentioned in situ erosion protocol was applied to test the effects of CPP-ACP on enamel erosion. The surface microhardness and surface microstructure of the samples were examined before and after erosion in both parts of the study. The data were statistically analyzed using ANOVA and LSD tests. Data were considered statistically significant at a level of P<0.05. Results: Significant surface softening was observed in all specimens after erosion (P<0.001). The surface microhardness in the CPP-ACP group and control group were (198.8+/-23.2) and (152.4+/-42.1) HV, respectively (P=0.040). The specimens in the CPP-ACP group showed significantly fewer changes in surface microstructure compared with those in the control group. Conclusions: Based on this in situ experimental protocol, short-time consuming of acid beverages would produce significant effects on the surface microhardness of the human enamel, whereas the application of CPP-ACP can increase the erosion resistance of the enamel. PMID- 29972980 TI - [Treatment of occlusal disorder caused by old mid-facial fracture]. AB - Objective: To investigate the treatment results of occlusal disorder caused by old mid-facial fracture. Methods: A total of 299 patients aged 26-51 years were enrolled in this study. All cases experienced a delay of treatment over 4 weeks after injury. The old mid-facial fracture was scanned by spiral CT and model surgery conducted. Ostectomy and rigid internal fixation were performed. Results: The wound was healed by first intention without infection and other complications. After 1-24 months of follow-up, 299 patients achieved well-shaped mid-face and the occlusion was recovered with mouth opening of over 2 cm. Conclusions: Model surgery combined with ostectomy and rigid internal fixation can achieve satisfied treatment results in patients with old mid-facial fractures. PMID- 29972981 TI - [Analysis on the reasons for orthodontic re-treatment]. AB - Objective: To analyze the type of malocclusion which was more likely to cause undesirable orthodontic results and the reasons for orthodontic re-treatment. Methods: In this study, 202 patients who received orthodontic retreatment in School of Stomatology, China Medical University from 2004 to 2016 were collected. Forty-seven patients were teenagers under 18 years old, and 155 patients were adults over 18 years old. The chief complaint of all patients was analyzed. Seven orthodontic specialists were invited to analyze the reasons caused the orthodontic re-treatment according to the treatment records, plaster models, photographs, panoramic radiographs and lateral cephalograms. They were offered an evaluation form to fill in by their judgement. The reasons for orthodontic re treatment and the problems related to previous orthodontic treatment were analyzed. Results: In 202 patients, the chief complaints were protrusion of the teeth [30.2% (61/202)], protrusion of the mandible [20.8% (42/202)], and irregularity of the teeth [17.8% (36/202)]. The proportion of patients chosen undesirable treatment design was 68.3% (138/202). The proportion of patient having unusual growth tendency was 24.3% (49/202). The proportion of patients with poor compliance during treatment and retention was 24.3% (49/202). Conclusions: In this study, the protrusion of the teeth, the protrusion of the mandible and the dental crowding were the main chief complaints for orthodontic re-treatment. Undesirable treatment design and unfavorable growth tendency were the main reasons for orthodontic re-treatment. Poor compliance of patients during the period of treatment or retention was an important reason for the patient to seek orthodontic re-treatment. PMID- 29972982 TI - [Clinical application of the bilateral radial forearm flap for tongue cancer reconstruction]. AB - The forearm radial flap is a reliable flap for the repair of the defect caused by tongue cancer resection. The clinical data of 11 tongue cancer patients that received this surgery were retrospectively analyzed. The clinical application of this technique is preliminarily discussed. PMID- 29972983 TI - [Research progress of gingival aesthetics evaluation in aesthetic restoration of anterior area]. AB - Gingival aesthetics is one of the factors that affect the clinical effects of prosthesis, and is particularly important in the aesthetic restoration of anterior teeth. However, gingival aesthetics involves a number of parameters for which there is no standardized evaluating criteria available so far. In addition to implant, other methods of restoration still lack recognized aesthetic evaluation systems for clinical use. At present, there are lots of solutions to improve anterior gingival esthetics, and most of the solutions can effectively improve the aesthetic effect in clinical treatment. This article reviews the aesthetics criteria of the anterior gingival area and the aesthetics restoration methods. PMID- 29972984 TI - [Standardized training system for oral and maxillofacial radiology specialist in the United States]. AB - Oral and maxillofacial radiology (OMR) in the United States is one of the nine dental specialties recognized by the American Dental Association (ADA). It has a nearly 100-year history of development and has also established a complete set of specialist training system. Staffing, base facilities, financial status, timing of training courses, contents, plans, and goals to be achieved are all clearly defined. All training centers need to undergo regular assessments every seven years with the ADA's Commission on Dental Accreditation (CODA). After graduation, the specialist graduates can be engaged in the clinical teaching and scientific research of radiological diagnosis in universities or general hospitals. They also have the option to open their own business by setting up imaging diagnostic centers or being specialized in tele-radiology to provide imaging diagnosis or consultation report to clinicians in other disciplines, or even assisting in the development of treatment planning for dental implants and orthodontic procedures. Of course, stomatology and OMR education systems are different in China and the United States due to different national conditions. Although the experience in the United States cannot be completely copied, many concepts, standards and goals of OMR specialty training there have been practiced and improved for a long period of time and are worth learning by the Chinese OMR counterparts or relevant agencies. PMID- 29972985 TI - [(*)AG490 could suppress bone marrow mesenchymal stem cells migration, mineralization and bone defect healing via inhibiting Jak2-STAT3 pathway]. AB - Objective: To study the effect of Jak2-STAT3 pathway on cell proliferation, migration, mineralization and bone defect healing via simulating Jak2-STAT3 pathway inhibitor AG490 to bone marrow mesenchymal stem cells (BMSC) and bone defect mice models. Methods: The effect of AG490 on BMSC proliferation was measured by MTT (methyl thiazolyl tetrazolium) assay. Regulation of AG490 on BMSC migration was tested by scratch assay and transwell assay. The BMSC migration related gene, matrix metalloproteinase (MMP)-7, MMP-9 and CXC subfamily receptor 4 (CXCR4), regulated by AG490 was studied by real-time PCR. Western blotting was adopted to analyze the regulation of Jak2-STAT3 phosphorylation through the simulation of AG490. The alizarin red staining and alkaline phosphatase (ALP) activity assay were performed to measure the effect of AG490 on BMSC mineralization and osteogenic differentiation. Mice femur bone defect models were built to analyzed the effect of AG490 on bone remodeling. Results: AG490 significantly suppressed the migration rate of BMSC at 1 d and 2 d in the experiment group [(12.42+/-7.50) %, (41.8+/-2.6)%] compared with the control group [(55.5+/-9.9)%, (86.9+/-8.7)%] in scratch assay (P=0.000, P=0.000), the number of migrated BMSC in the experiment group (22.8+/- 5.9) was significantly suppressed compared with the control group (58.3+/-6.6) in Transwell assay (P=0.000). The expression of MMP-7, MMP-9 and CXCR4 were significantly downregulated in experiment group [(0.5+/- 0.1), (0.1+/-0.1) and (0.35+/-0.07)] compared with the control group [(1.1+/-0.1), (1.06+/-0.33), (1.08+/-0.13)] (P= 0.0003, P=0.000 and P=0.000). Also, the phosphorylation of Jak2-STAT3 was downregulated by AG490 in western blotting. After BMSCs were osteogenic induced for 14 days, the formation of mineralized nodule and the ALP activity of BMSC is significantly suppressed in experiment group (8.0+/-2.1) compared with the control group (35.7 +/- 1.8) (P=0.0005). AG490 suppressed the bone defects healing,the expression level of phosphorylated Jak2 and phosphorylated STAT3, and the number of alkaline phosphatase positive cell at defect area in vivo is lower in experiment group than the control group. AG490 suppressed the relatively bone density at the defect area significantly (P=0.0004) at 5(th) week after the surgery. Conclusions: AG490 could suppress proliferation, migration and mineralization to of BMSCs regulate bone defect healing via inhibiting Jak2-STAT3 pathway. PMID- 29972986 TI - [Analysis of birth defect rate trend of cleft lip and palate in Shanghai from 2007 to 2016]. AB - Objective: To analysis the rate of birth defects of cleft lip and palate among newborns in Shanghai during 2007 and 2016 and describe its change trend, for the purpose of prevention, treatment and nursing of newborns with cleft lip and palate. Methods: Birth registration information in Shanghai during January 2007 and December 2016 were collected. Rate of birth defects, gender ratio and maternal age of newborns with cleft lip and palate were analyzed. Annual percent change was applied to analyze the trend. Results: The total birth defect rate of children with cleft lip and palate was 937/million in the past 10 years in Shanghai, showing an overall decreasing trend, decreased 28.20% compared to the data of 2007. The total birth defect rate of newborns with cleft lip decreased 40.86%. Overall decline rate of newborns with cleft lip and palate was 54.60%, but birth defect rate of newborns with the isolated cleft palate rised 14.34%. The number of female isolated cleft palate newborns were 1.6 times higher than those of male isolated cleft palate newborns, male newborns with cleft lip were 1.8 times higher than that of the female newborns with cleft lip. Male newborns with cleft lip and palate were 1.5 times as much as the female newborns with cleft lip and palate. Maternal age is mainly 25 to 29 years old, accounting for 42.01% of the total number of mothers, the according birth defect rate was lowest as 853/million. When maternal age is too low or too high, the risk of neonatal cleft lip and palate could increase. Birth defects of cleft lip and palate was up to 130.8/million when maternal age is less than 20, while birth defects of cleft lip and palate was up to 188.2/million when maternal age over 40 years old. Conclusions: In recent 10 years, the overall rate of birth defects of cleft lip and palate in Shanghai shows a decreasing trend, with cleft lip and palate declining obviously, but isolate cleft palate has an increasing tendency. Maternal age less than 20 years old or more than 40 years old will increase the risk of birth defects in newborns with cleft lip and palate. PMID- 29972987 TI - [Compensation of upper first molar in skeletal class III patients treated with orthodontic-surgical treatment]. AB - Objectives: To investigate the compensation of upper first molar in adult skeletal class III patients. Methods: The sample consisted of 48 skeletal class III patients with orthodontic-surgical treatment from February 2011 to January 2015 in Peking University School and Hospital of Stomatology. They were allocated into 2 groups based on extraction, 28 patients in extraction group and 22 patients in non-extraction group. Dental casts were taken before and after treatment, and all the casts were scanned with a computer-assisted three dimensional (3D) scanning system. Acquired 3D data were analyzed by Rapidform 2006. The tip and torque of the upper first molar were measured and analyzed. Results: The tip and torque of the upper first molar in the skeletal class III patients after treatment had no difference between extraction group and non extraction group (P=0.150, P=0.144). The torque of upper first molar in extraction group [-3.32 degrees (-5.10 degrees , 1.16 degrees )] before treatment was bigger than that in non-extraction group [-6.94 degrees (-13.06 degrees , -0.42 degrees )] (P=0.005), and the inclination of upper first molar in extraction group was more obvious. Conclusions: In skeletal class III patients, the upper first molar inclined buccally to compensate the discrepancy and extraction was usually necessary for decompensation. PMID- 29972988 TI - [Clinical significance of interleukin-6 and -8 in patients with chronic periodontal disease and acute exacerbation of chronic obstructive pulmonary disease]. AB - Objective: To investigate the serum levels of interleukin (IL)-6 and -8 in patients with chronic periodontal disease and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the possible relationship between IL-6 and IL-8 with two diseases. Methods: A total of 40 cases of healthy subjects (control group 1) from graduate school of Anhui Medical University, and 120 cases (40 cases in each of the 3 groups) of eligible patients were collected, of which 40 were patients with chronic periodontal disease and AECOPD (experimental group) from Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University and Anhui NO.2 Provincial People's Hospital, 40 were patients with chronic periodontal disease (control group 2) from Department of Stomatology, The First Affiliated Hospital of Anhui Medical University, 40 were patients with AECOPD (control group 3) from Department of Respiratory Medicine, The First Affiliated Hospital of Anhui Medical University. The clinical indicators of all subjects were collected, including tooth mobility degree, probing depth (PD), bleeding index (BI), attachment level (AL), vital capacity max (VC Max), forced expiratory volume in first second (FEV1) and forced expiratory volume in first second to forced vital capacity (FEV1/FVC) ratio. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of IL-6 and IL-8 in the subjects of four groups. Results: The attachment levels had no significant differences between experimental group and control group 2 (P>0.05). The pulmonary function indices of experimental group including VC MAX% pre[(56.1+/-11.1)%], FEV1 %pre [(44.8+/-12.2)%], FEV1/FVC(%) [(56.8+/-11.4)%] were significantly different from those in control group 3 [(66.3+/-10.1)%, (53.0+/-10.4)%, (66.5+/-8.2)%, respectively]. The IL-6 levels of experimental group, control groups 1, 2 and 3 were (14.4+/-3.9), (2.1+/-1.1), (4.8+/-1.9) and (8.6+/-1.4) ng/L, respectively. And the IL-8 levels were (35.3+/-33.3), (4.8+/ 1.7), (9.7+/-3.3) and (15.6+/-9.6) ng/L. In experimental group the IL-6 and IL-8 levels were significantly higher than those in control groups 1, 2, and 3 (P<0.01). In control group 2 and 3 the IL-6 and IL-8 levels were significantly higher than that in control group 1 (P< 0.01). Conclusions: The IL-6 and IL-8 levels of experimental group were significantly increased. IL-6 and IL-8 may be associated with the development of periodontal disease and AECOPD closely. PMID- 29972989 TI - [Facial symmetry after conservative treatment of unilateral condylar fracture in children: a three-dimensional study]. AB - Objective: To investigate the influence of condylar fractures on the growth of condylars after conservative treatments by three-dimensional measurement. Methods: Twenty three children with unilateral condylar fracture followed-up for at least 1 year in Shanghai Ninth People's Hospital were included from June 2016 to March 2017. CT scans were performed for each patient. Three-dimensional virtual skulls were reconstructed and measuring points were defined with Simplant 11.04 software. The depth of glenoid fossa, height of articular eminence, width, height and depth of condylar, deviation of pogonion were measured. Statistical analyses were conducted to assess difference between the bifid group and the normal group. Results: No difference was observed in the vertical position of crest of the articular eminence between two groups (P=0.110). The vertical position of roof of the glenoid fossa in bifid side was significantly superior than the one in normal side (P=0.010). Bifid side had a shorter (P=0.002) and wider(P=0.002) condylar than normal side did. No difference was observed in the depth of condylar between two groups (P=0.071). The average deviation of pogonion was (0.69+/-1.75) mm (P=0.072) from sagittal plan. Conclusions: This short-termed study indicates that children's growth potential of condylar is under average after conservative treatments. Because the bone hyperosteogeny of glenoid fossa compensates the hypotrophy of condylar, no deviation of pogonion is detected. PMID- 29972990 TI - [Effect of psychological nursing based on relaxation training for the psychological state in patients with impacted third molar removal surgery]. AB - Objective: To discuss the effect of psychological nursing based on relaxation training for the psychological state in patients with impatced third molar removal surgery. Methods: A total of one hundred patients with impacted third molar removal surgery were selected from June 2015 to June 2017 in People's Liberation Army No. 105 hospital. According to the nursing method, all patients were divided into psychological intervention group and the control group, 50 cases in each group, the control group was given routine nursing intervention and the psychological intervention group was given psychological nursing intervention based on relaxation training. Results: The after intervention Corah's modified dental anxiety scale (6.3+/-1.2), Stouthard dental fear scale (62.9+/-6.5) scores and heart rate [(76.4+/-5.2) bpm], systolic blood pressure [(102.5+/-6.3) mmHg], diastolic blood pressure [(75.3+/-3.1) mmHg] levels of psychological group were significantly lower than those of the control group. The once removal success rate, intraoperative relaxation sense rate of psychological group were significantly higher than those of the control group, the teeth extraction time of psychological group was significantly lower than that of the control group, the difference was statistically significant (P=0.013, P=0.003). Conclusions: Psychological nursing intervention based on relaxation training can effectively improve the mental state and stress state of patients with impacted third molar removal surgery, which is beneficial to the process of the surgery. PMID- 29972991 TI - [Effect of silane coupling agent on composite-composite bond strength: an in vitro study]. AB - Objective: To investigate the effect of silane coupling agent on composite composite bond strength, and to provide experimental basis for improving composite-composite bond strength clinically. Methods: Self-etching adhesive Clearfil SE Bond (CSE) and silane-containing universal adhesive Single Bond Universal (SBU) were used as adhesives. A silane coupling agent (RelyX ceramic primer) was tested. P60 resin composite blocks were prepared and divided into 4 groups according to whether silane coupling agent was applied or the type of the adhesives: CSE group, in which CSE was applied as an adhesive; Silane + CSE group, in which the surface was treated with silane coupling agent followed by CSE; SBU group, in which SBU was applied as an adhesive; Silane+ SBU group, in which the surface was treated with silane coupling agent followed by SBU, then filling a new composite. All the composite blocks were cut into about twenty 1 mm*1 mm*14 mm samples to detect the micro-tensile bond strength. Fractographic analysis were performed under a three-dimensional laser scanning microscope. The micro-tensile bond strength data were analyzed statistically by one-way ANOVA and the failure pattern data were analyzed statistically by Chi-square test. Results: Silane + SBU group [(69.6 +/- 3.3) MPa] showed a significantly higher micro tensile bond strength than the other groups (P<0.05). Silane+CSE group showed a significantly higher micro-tensile bond strength [(63.9+/-3.7) MPa] than CSE group [(55.7+/-4.2) MPa] and SBU group [(55.4+/-4.0) MPa] (P<0.05); There was no significant difference in micro-tensile bond strength between the SBU group and the CSE group (P>0.05). Failure patterns in the 4 groups were adhesive failure, cohesive failure and mixed failure. There was no significant difference in the proportion of adhesive failure between the Silane+CSE group and the Silane+SBU group, and the proportion of adhesive failure in these two groups were significantly less than that in the CSE and the SBU group (P<0.05). Conclusions: Silane coupling agent pretreatment could improve composite-composite bond strength, however, the bond strength could not be higher when silane was mixed with adhesives in one bottle. PMID- 29972993 TI - [Effects of zirconia micron coating on the proliferation and differentiation of osteoblasts]. AB - Objective: To investigate the effects of zirconia micro coating on the proliferation and differentiation of osteoblasts on the surface of zirconia ceramic, and to provide a strategy for zirconia implant surface treatment. Methods: Forty tablets of zirconia ceramic, with the diameter of 15 mm and the thickness of 1.5 mm, were prepared. Then, twenty tablets polished by water sandpaper were taken as the control group, and 20 pieces of the zirconia coating after sintering micron were taken as the experimental group. The micromorphology of the surface of the two groups were observed by scanning electron microscope. The cell morphology after inoculation with MC3T3-E1 of osteoblasts on the surface of the material was investigated for 1, 3, and 5 days by scanning electron microscope. The cell proliferation was detected at 1 and 3 days by methyl thiazolyl tetrazolium. The cell differentiation ability was detected at 3 and 7 days by real-time quantitative PCR. Statistical analysis was conducted by independent sample t test. Results: After coating with zirconia micron particles, pores with the diameter of 1-20 MUm could be observed on the surface of the test group of tiles through high temperature sintering. The growth of osteoblasts on the surface of the ceramic chip in the test group and control group exhibited the similar cell morphology. As they were cultured for 1 day, the experimental group exhibited a similar quality of cells as those in the test group (P>0.05). After 3 days' incubation, comparing with the cell quality of the test group (1.067 +/- 0.077) (P<0.05), the quality of osteoblasts on the surface of zirconia ceramics coating increased to 1.763+/-0.165, and the expression of mRNA in alkaline phosphatase (ALP), osteopotin (OPN) and osteocalcin (OCN) also increased with the amount of 1.63+/-0.28, 1.99+/-0.41 and 1.60+/-0.30, respectively, compared with the test group (1.00+/- 0.00) (P<0.05). Seven days later, the expression of mRNA in Runt-related transcription factor-2 (RNUX2) (1.33+/-0.19), special AT-rich sequence binding protein-2 (SATB2) (1.64 +/- 0.36), as well as alkaline phosphatase (ALP) (1.78+/-0.40), OPN (2.25+/-0.36), and OCN (1.88+/-0.21), showed a remarkably increase compared with the test group (1.00+/-0.00) (P<0.05). Conclusions: Zirconia micro coating on the surface of zirconia ceramics promoted the proliferation and differentiation of osteoblasts adhered. PMID- 29972992 TI - [Semaphorin 3A-stimulated bone marrow mesenchymal stem cells sheets promotes osteogenesis of type 2 diabetic rat]. AB - Objective: To evaluate the effect of semaphorin 3A (Sema3A) pre-treated bone marrow mesenchymal stem cells (BMSC) sheets on new bone formation in type 2 diabetes mellitus rats. Methods: Type 2 diabetes mellitus (T2DM) were induced by injection of streptozotocin, and the BMSC were isolated, controlled, identified and induced into cell sheets. Fifteen T2DM rats were randomly divided into control, sheets and Sema3A-sheets group and the calvarial critical size defect (CSD) model of rats were established. The defect zone of rats from control group were implanted with bone powder. The defect zone of rats from sheets group were implanted with bone powder and BMSC sheets. The defect zone of rats from Sema3A sheets group were implanted with bone powder and BMSC sheets pretreated with 1.0 mg/L Sema3A. After 8 weeks, the bone samples were harvested and analyzed by micro CT scanning, HE staining for the evaluation of new bone formation, and the immunohistochemical analysis for the expression of osteogenesis-related proteins including type I collagen (COL- I ), bone morphogenetic protein-2 (BMP-2), and osteocalcin (OCN). Results: The BMSC were isolated and cultured, and oil red O and Alizarin red S staining proved the multi-potential differentiation. Eight weeks after the establishment of calvarial CSD model, Sema3A-sheet group showed the most abundant new bone formation (0.516+/-0.070), with increased bone volume fraction, namely bone volume/tissue volume (BV/TV) compared with sheets group (0.319+/-0.050) and control group (0.224+/-0.037) (P<0.05), and the sheets group showed increased BV/TV compared with control group (P<0.05). While trabecular thickness (Tb.Th) control group showed no difference in three groups (P>0.05). HE staining also confirmed that Sema3A-sheets group showed the most new bone formation. Sheet group (0.174+/-0.051) compared showed difference with control group (0.099+/-0.033) (P< 0.05), and Sema3A-sheet group (0.421+/-0.069) showed increased bone formation compared with sheet group and control group (P<0.05). Immunohistochemistry showed that BMSC sheet increased the expression of osteogenesis-related proteins including COL-I, BMP-2 and OCN, while Sema3A pretreatment showed more obvious increase of the expression of COL-I and OCN. Conclusions: The combined implantation of bone powder and Sema3A stimulated BMSC sheets significantly increased bone regeneration in vivo. Therefore, Sema3A pre treated BMSC sheets transplantation provides a new strategy for restoring bone defect in T2DM. PMID- 29972994 TI - [An experimental study of the effect of extraction and retention of canine primary intruded teeth to the permanent successors]. AB - Objective: To compare the influence of extraction and retention of the intruded dogs' teeth on permanent successors. Methods: Nine healthy 45-days-old Chinese rural puppies were selected, and six were submitted to the intrusion of the bilateral canine. Intruded teeth on the left side were extracted 30 minutes later and the teeth on the right side were kept in their sockets. After 8 months, all dogs were sacrificed. General observation, periapical radiograph and cone beam CT were used to observe the preoperative and postoperative deciduous teeth, permanent germs and permanent teeth development. The structure and content of successors' enamel were observed by scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). Results: In the extraction groups, the enamel hypoplasia was found in 19 permanent successors, ectopic eruption in 2 cases and abnormal teeth were in 19 cases in total (79%). In the retention groups, enamel hypoplasia of the permanent successors occurred in 2 cases, root dilaceration in 6 cases, and ectopic eruption in 5 cases, retained deciduous teeth in 3 cases, and there were 22 abnormal teeth in total (92%). In blank control group, there was no abnormal teeth. The major effect of intruded deciduous teeth on the permanent successors exhibited enamel hypoplasia [85% (41/48)], presented as enamel coloration and enamel defect (P=0.416). Conclusions: The intruded deciduous teeth should be removed early in order to reduce the effect on the permanent teeth. PMID- 29972995 TI - [A decision tree for treatment of patients with gingival Stillman's cleft]. AB - Gingival Stillman's cleft is a mucogingival triangular- shaped defect which influence on health and appearance of gingiva. Due to a lack of clinical reports, five cases of gingival Stillman's cleft were recruited in the present study. The treatment methods were selected according to the etiological factors of the defect in each patient. Satisfactory treatment responses were achieved in all cases during a 6 to 20 month follow up after the treatments. In this study, we summarized the treatment strategies in various types of gingival Stillman's cleft, so as to provide the reference for clinicians. PMID- 29972996 TI - [Cyclosporin-related gingival enlargement in patient with severe chronic periodontitis: a case report]. PMID- 29972997 TI - [Dietary patterns and prevention as well as treatment of chronic diseases]. PMID- 29972998 TI - [A goal-oriented reform on public health education]. PMID- 29972999 TI - [Theory of cancer evolution-development and its significance for research of colorectal carcinoma]. PMID- 29973000 TI - [Compliance rate of screening colonoscopy and its associated factors among high risk populations of colorectal cancer in urban China]. AB - Objective: To evaluate the compliance rate of screening colonoscopy and associated factors in high-risk populations of colorectal cancer (CRC) in urban China. Methods: CRC screening data from the Program of Cancer Screening in Urban China conducted in 12 provinces in 2012-2014 was used in the present study. All 97 445 participants were asked to take epidemiological questionnaire survey to evaluate their cancer risk. Participants who were evaluated as "high risk for CRC" were recommended to receive colonoscopy at designated hospitals. Chi-square tests were used to compare the differences of participation rates between groups. Multivariate logistic regression models were applied to explore the potential factors associated withthe compliance rate of screening colonoscopy. Results: Overall, 97 445 participants of CRC high-risk were included in this analysis, and 14 949 of them took screening colonoscopy, yielding a participation rate of 15.3%. The participation rate varied greatly across provinces, ranging from 25.2% (2 785/11 071) in Heilongjiang to 9.7% (1 698/17 515) in Liaoning. Moreover, the participation rate in 2013-2014 was significantly higher than that in 2012-2013 (17.1%(9 766/57 280) vs 12.9% (5 183/40 165), chi(2)=57.67, P<0.001) . The multivariate logistic regression analyses showed that: compared with individuals of 40-49 years old, individuals of 50-59 or 60-69 years old were more willing to accept screening colonoscopy, with OR of 1.17 (95% CI: 1.12-1.22) and 1.13 (95% CI: 1.08-1.19), respectively; compared with uneducated individuals, individuals with good educational background of equivalent to high school or higher (OR=1.29, 95% CI:1.10-1.50) were more willing to accept screening colonoscopy; compared with individuals who never took fecal occult blood tests (FOBT) before, individuals with previous positive FOBT results (OR=1.40, 95% CI:1.31-1.50) were more willing to accept screening colonoscopy; compared with individuals with no inflammatory bowel diseases (IBD), individuals with IBD (OR=1.63, 95%CI:1.56 1.69) were more willing to accept screening colonoscopy; Compared with individuals without polyp history, individuals having history of previous polyp detection (OR=1.43, 95% CI:1.37-1.50) were more willing to accept screening colonoscopy; compared to individuals with no family history of CRC, individuals with history of CRC (OR=1.60, 95% CI:1.53-1.66) were more willing to accept screening colonoscopy. Conclusion: The overall participation rate of screening colonoscopy among high-risk population of CRC in the 12 participating sites was 15.3%. The study findings indicated that age, education level, history of past fecal occult blood test, IBD, history of polyp, family history of CRC were associated with the compliance rate of colonoscopy in this population-based CRC screening program. PMID- 29973001 TI - [Analysis survival of screening and non-screening patients of esophageal cancer in Linzhou city]. AB - Objective: To evaluate effect of screening of esophageal cancer though comparing difference of survival level between screening and non-screening patients in Linzhou city. Methods: The records pathologically diagnosed as serious hyperplasia/carcinoma and esophageal cancer were drawn from database of first round screening in Linzhou city from 2005-2013 and were assigned to the screening group. The records of new esophageal cancer cases which diagnosed within 2 years before, screening from the same village aged from 40 to 69, were drawn from database of cancer registry in Linzhou city and were assigned to the non screening group. Five or 10 year survival rate with 95%CI of patients with different malignant degree diseases in the screening group and the patients with esophageal cancer in the non-screening group was calculated respectively. The survival curves between the screening and non-screening group were compared by Log rank method. Results: All 26 908 persons were examined in first round screening in Linzhou city from 2005 to 2013. There were 374 persons with serious hyperplasia/carcinoma in situ, 157 persons with esophageal cancer (141 intramucosal carcinomas/submucosal cancers, 16 invasive cancers). The 5 year survival rate of serious hyperplasia/carcinoma, intramucosal carcinoma/submucosal cancer and invasive cancer were 95.0% (95%CI: 91.7%-97.0%) , 72.0% (95%CI: 62.7% 79.3%) and 41.7% (95%CI: 17.4%-64.6%) separately. The 5 year survival rate of esophageal cancer in screening and non-screening group were 68.7% (95%CI:59.9% 75.9%) and 40.8% (95%CI: 36.4%-45.2%). The 10 year survival rate of esophageal cancer in screening and non-screening group were 58.0% (95% CI: 44.6%-69.3%) and 34.3% (95% CI:29.1%-39.5%). The 5 or 10 year survival rate of esophageal cancer in the screening group were higher than that in the non-screening group in whatever sex or age. The survival distribution of the screening group was better than non-screening group (chi(2)=38.88, P<0.001). Conclusion: More precancerous lesions and early esophageal cancer can be detected and patients' survival level was improved through organized esophageal cancer screening, which provided support to evaluate value of organized screening. PMID- 29973002 TI - [Association between polymorphism in notch signaling pathway and lung cancer risk]. AB - Objective: To analyze the relationship between single nucleotide polymorphisms (SNP) of Notch signaling pathway and susceptibility to lung cancer. Methods: The present study was a hospital-based case-control study. All 1 121 patients of lung cancer diagnosed by histopathology three hospitals in Fujian and Nanjing were selected as cases from January 2006 to December 2012. At the same time, 1 121 healthy population from other departments of the hospital to visit patients or community, excluding those with tumor, chronic disease, and immediate family members of lung cancer, were enrolled in control group. A uniform questionnaire was used to collect general information. Matrix-assisted laster desorption ionization time of flight mass spectrometry (MALDI-TOF-MS) was used to identify the polymorphisms of 9 SNP (Notch3 rs3815188, Notch4 rs915894, Notch4 rs520692, DLL1 rs1033583, JAG1 rs8708, JAG2 rs9972231, HEY1 rs1046472, HEY2 rs3734637, HES2 rs11364) in 1 121 lung cancer patients and 1 121 healthy controls. The association between SNP and lung cancer was analyzed by chi(2) and logistic regression model. Results: The average age of cases and controls was (58.70+/ 10.73) and (58.98+/-10.85) years old. The OR for genotype AC carriers of HEY1 rs1046472 was 0.80 (95%CI: 0.66-0.97) when comparing with genotype CC. The OR for genotype AC+AA carriers of HEY1 rs1046472 was 0.81 (95% CI: 0.67-0.98) when comparing with genotype CC. The OR for genotype AC carriers of HEY2 rs3734637 was 0.82 (95%CI: 0.67-0.99) when comparing with genotype AA. In the stratified analysis, Notch3 rs3815188, DLL1 rs1033583, JAG1 rs8708, JAG2 rs9972231, HEY1 rs1046472, HEY2 rs3734637, HES2 rs11364 were associatied with the risk of lung cancer, P were 0.041, 0.030, 0.043, 0.003, 0.004, 0.026 and 0.038, respectively.The interactions analysis done by logistic regression model showed JAG1 rs8708 and family history, JAG2 rs9972231 and BMI had interaction in the study, OR were 2.07 (95% CI:1.21-3.52) and 1.73 (95% CI:1.21-2.47), respectively. Conclusion: Notch3 rs3815188, DLL1 rs1033583, JAG1 rs8708, JAG2 rs9972231, HEY1 rs1046472, HEY2 rs3734637 and HES2 rs11364 were significantly associated with susceptibility to lung cancer. PMID- 29973003 TI - [Association of plasma leptin levels and soluble leptin receptor with breast cancer]. AB - Objective: To explore the association between plasma leptin (LEP) levels, soluble leptin receptor(SLR), free leptin index and breast cancer. Methods: 245 new female cases of primary breast cancer confirmed by histopathology examination were sequentially recruited into the study. A total of 245 age-matched healthy women were enrolled as controls during the same period. A standardized questionnaire was used to collect the demographic information of the subjects. Blood samples were collected and the levels of LEP and SLR in plasma were measured by enzyme linked immunosorbent assay. The differences of LEP, SLR and FLI expression between control and cases group, as well as different breast cancer subtypes and TNM stages were compared using t-test and ANOVA after stratification by menopause status. Multivariate logistic regression was used to explore the contributions of the three indexes to the risk of breast cancer. Results: Females in both cases and control group were (50.7 +/- 9.4) years old. The level of SLR and FLI (P(50)(P(25),P(75))) in premenopausal women were 18.4 (11.2, 28.7), 0.5 (0.4, 0.6) MUg/L in case group and 27.7 (19.2, 43.4), 0.3 (0.3, 0.4) MUg/L in control group (P<0.001). While the level of postmenopausal women in case group were 20.3 (12.8, 31.8), 0.5 (0.4, 0.6) MU g/L (P<0.001), and 30.1 (18.8, 40.5), 0.3 (0.3, 0.5) MUg/L in control group (P<0.001), respectively. After adjustment for confounding factors and BMI, the relationship between FLI and breast cancer remained significant for both pre- and postmenopausal women while the association between SLR and breast cancer was significant only in premenopausal women. Compared with the lowest level of SLR, higer levels of SLR is associated with a reduced risk of breast cancer (premenopausal women, OR=0.10, 95% CI: 0.04-0.29, P(trend)<0.001). Compared with the lowest level of FLI, FLI at higher levels is associated with an increased risk of breast cancer (premenopausal women, OR=7.14, 95% CI: 2.86-17.83, P(trend)<0.001; postmenopausal women, OR=8.10, 95% CI: 2.85-22.98, P(trend)<0.001). No significant association between LEP and breast cancer or association between the three indexes and breast cancer subtypes and TNM stages was found (P>0.05). Conclusion: SLR may be a protective factor for breast cancer while FLI may increase the risk of breast cancer. PMID- 29973004 TI - [The impact of five-year Chinese rural area cervical cancer screening program on screening rate]. AB - Objective: To assess the impact of Chinese Cervical Cancer Screening Program for Rural Area (NACCSPRA) on population-based screening rates. Methods: The subjects were selected from 2013-2014 Chinese Chronic Diseases and Risk Factors Surveillance (CDRFS2013), which adopting multi-stage stratified cluster sampling from 31 provinces. A total of 169 632 participants aged 18 years and older in 297 surveillance points were interviewed, of whom 65 476 women aged 35-64 years were included in the analysis. The surveillance points in CDRFS 2013 were divided into the screening areas and the control areas by matching points in CDRFS2014 with counties in NACCSPRA. The difference in socioeconomic status between areas was compared. The screening rates and 95% confidence interval (95%CI) were estimated by Tylar series variance method. The Propensity Score was evaluated for individuals by multivariate logistic regression and the greedy matching method based on propensity score value was used to conduct 1?1 matching sample for the screening areas and the control areas. After matching, multivariate conditional logistic regression model was fitted to assess the impact of national cervical cancer screening intervention on the likelihood of undergoing cervical cancer screening at population level. Results: Among 65 476 subjects, 48.6% (n=31 794) was in the screening areas. Before matching, in the rural area the screening rate in the screening areas (24.0% (4 763/19 838), 95%CI: 21.8%-26.3%) was higher than that in the control areas (15.6% (2 331/14 942), 95%CI: 13.4%-17.8%); whereas in the urban area the screening rate in the screening areas (28.5% (3 413/11 956), 95%CI: 26.1%-31.0%) was similar to that in the control areas (26.3% (4 923/18 740), 95%CI: 24.1%-28.4%). After matching, in rural area the screening rate in the screening areas (23.2% (3 454/14 875), 95% CI: 20.9%-25.5%) was higher than that in the control areas (15.6% (2 315/14 875), 95% CI: 13.3%-17.8%); in urban area the screening rate in the screening areas (28.7% (3 202/11 146), 95% CI: 26.2%-31.2%) was higher than that in the control areas (23.1% (2 571/11 146), 95%CI: 20.9%-25.3%). Multivariate conditional logistic regression model showed that the cervical cancer screening rates in intervention areas significantly increased among women aged 35-64 years both in urban areas (OR=1.44, 95%CI: 1.34 1.54) and rural areas (OR=1.78, 95%CI: 1.67-1.90) as compared with those in control areas. Conclusion: The implementation of Chinese cervical cancer screening program during the five years substantially increased the population based screening rates both in urban and rural areas. PMID- 29973005 TI - [Evaluation on the short term effectiveness of two doses mumps-containing vaccine policy in Shandong, China]. AB - Objective: To evaluate the effectiveness of mumps prevention and control after implementation of two doses mumps-containing combined vaccine (MuCV) policy by analyzing epidemiological characteristics of mumps and mumps antibody levels in general population. Methods: We obtained data on cases of mumps reported during 2004-2015 from National Notifiable Diseases Reporting System (NNDRS). Descriptive analysis methods were used to describe the epidemiological characteristics of mumps during 2004-2015. MuCV immunization information from 2005 to 2015 was obtained from the immunization information management system in Shandong Province. Antibody data of mumps in healthy people were from a cross-sectional survey according to the principle of stratified random sampling from 0 to 60 years old healthy people in 2015. Commercial ELISA kits were used to detect and quantify human IgG antibodies against mumps virus in sera, and the results were analyzed statistically. Results: The average incidence of mumps from 2004 to 2015 was 11.43/100 000 in Shandong. The incidence of mumps in the central region (14.64/100 000) was higher than that in the eastern and western regions (11.14/100 000, 11.33/100 000). The incidence of mumps was still high in 2009 2013 (stage of one-dose MuCV free, 16.07/100 000) with the highest incidence of 25.33/100 000 and 24.45/100 000 occurred in 2012 and 2013 and the cases were mainly 6 to 9 years old group (172.67/100 000). Since the second dose MuCV was introduced into NIP for 6 years old children in May 2013 in Shandong, the incidence of mump decreased significantly in 2014-2015 (7.81/100 000), especially in children of 6-8 years old who were vaccinated with two doses of MuCV (2009 2013 was 114.02/100 000; 2014-2015 was 45.66/100 000) and lower than 3-5 years old vaccinated one doses of MuCV. A total of 1 785 serum samples were collected from the healthy population, the average seroprevalence was 80.62% and Geometric Mean Concentration (GMC) was 38.11 IU/ml (95%CI: 37.03-39.19 IU/ml) . There was no significant difference about seroprevalence in different regions, while the GMC in middle region was significantly higher compared to east and west region. The prevalence and GMC in children aged 19 months-2 years and 3-5 years old who received one dose of MuCV were significantly higher than those of <19 months old children. The GMC (46.88 IU/ml, 95%CI: 39.43-55.74 IU/ml) in children aged 6-9 years old who received the two doses MuCV was significantly higher than that of aged 3-5 years old children (31.71 IU/ml, 95%CI: 27.23-36.93 IU/ml). Conclusion: The incidence of mumps in Shandong was still at a high level in spite of coverage one doses MuCV to children. Compared with the period of the 1 dose MuCV immunization strategy, the incidence the groups coverage two doses MuCV was significantly reduced and lower the groups coverage one dose MuCV, but the prevalence and GMC were higher than that of the groups coverage one dose MuCV. PMID- 29973006 TI - [Characteristics and drug resistance of non-O157 Shiga toxin-producing E. coli in animal feces, from Shandong Province]. AB - Objective: To understand the infection status, characteristics and drug resistance of non-O157 Shiga toxin-producing E. coli (STEC) in animal feces in Shandong Province. Methods: From 2015 to 2016, convient sampling method was used to collect 1 022 fresh feces of animals in Weishan county and Laizhou city, and 24 non-O157 STEC were isolated. The serotypes of non-O157 STEC strains were confirmed through serum agglutination test. The susceptibility was explored through the antimicrobial sensitivity experiments. ESBLs activity was confirmed by double-disc diffusion. PCR method was used to detect the resistance genes. PFGE typing was operated to assess the relatedness and variability of the strains. The multi-locus sequence typing (MLST) was adopted to get the allelic profile and ST sequence of strains. Analysis was made on the evolutionary relationship between different ST groups was made through CLC Sequence Viewer and Counting Express. Results: A total of 24 non-O157 STEC were isolated from animal feces. 23 strains were from pig feces, and 1 strain was from cow feces, and the serotypes were more dispersed. All of the 24 strains carried stx2 genes. The highest resistance rate was sulfamethoxazole(22 strains), the mount of cotrimoxazole and nalidixic acid was 18 strains, chloramphenicol was 13 strains, tetracycline was 19, and there was a phenomenon of multiple drug resistance. The drug resistance spectrum was sulfamethoxazole tetracycline-compound novammin naphthidine-chloramphenicol. All strains were sensitive to cefepime and imipenem. The ESBLs confirmatory test showed that 4 strains of non O157 STEC produced beta lactamase. PCR detected 7 resistance genes, and 4 tetracycline resistance genes (Tet A, Tet B, tetC and tetD) were detected. The beta lactamase resistance genes (blaSHV-1, bla CTX-M, bla TEM) were all negative. 24 strains were divided into 15 PFGE types, and their clustering results were more dispersed and no dominant PFGE type. There were 11 kinds of MLST types, most of them are ST540 and ST5133 types, each of which was 4 strains, and clustered into 1 MLST genomes. Conclusion: The serotypes of non-O157 STEC in animal feces O157 STEC were dispersed, and the resistant rate to common antibiotic was high. MLST typing results presents obvious polymorphism. Surveillance and manage ment of these strains should be strengthened. PMID- 29973007 TI - [Study on the relationship between HIV drug resistance and CD4(+)T cell counts among antiretroviral therapy patients with low viral load]. AB - Objective: To explore drug resistance of different viral loads, and investigate the relationship between drug resistance and CD4(+)T cell counts in patients with HIV antiretroviral therapy (ART) in China from 2003 to 2015. Methods: Data were extracted from the Chinese National HIVDR Surveillance database from 2003 to 2015. For this study, the data collected were as follows: having received ART for >=12 months; 18 years or older; demographic characteristics, information of ART, CD4(+)T cell counts, viral load (VL) and HIV drug resistance of a total of 8 362 patients were collected. Multi-variables non-conditional logistic regression model was used to study the relationship between viral load, HIV drug resistance and CD4(+)T cell counts. Results: Participants with age of (41.8+/-10.5) years were enrolled in this study. Among them, 59.9% (5 009 cases) were men. The percentage of CD4(+)T cell counts <200 cells/MUl in the total population was 17.9% (1 496 cases), the highest was in VL >=1 000 copies/ml with drug resistance, which was 43.0% (397/923) , followed by VL 50-999 copies/ml with drug resistance, which was 31.1% (69/222), and the lowest was in VL 50-999 copies/ml without drug resistance 13.2% (273/2 068). Compared to VL 50-999 copies/ml without drug resistance, VL<50 copies/ml, VL 50-999 with drug resistance, VL>=1 000 copies/ml without drug resistance, and VL >=1 000 copies/ml with drug resistance, the OR (95%CI) of CD4 <200 cells/MUl were 0.9 (0.7-1.0), 3.2 (2.3 4.4), 2.6 (2.1-3.2), and 4.9 (4.0-5.9), respectively. Among 222 patients with VL 50-999 and HIVDR, the most frequent antiretroviral drugs were EFV and NVP, both of which were NNRTI, and whose percentage both were 94.1% (209 cases). The most frequent mutations were M184V/I (NNRTI), and the percentage was 26.1% (58 cases). The second one was K103N (NNRTI), and the percentage was 22.5% (50 cases). The percentage of V32L/E (PI) and V82A (PI) were lower, they were 0.9% (2 cases) and 0.5% (1 case) respectively. Conclusion: Decreased CD4(+)T cell counts were associated with HIV drug resistance at low viraemia. In the case of low viral load, the most vulnerable were the NNRTI antiviral drugs such as EFV and NVP. PMID- 29973008 TI - [Analysis of vaccination situation of orial live attenuated rotavirus vaccine (LLR strain) among children in 6 provinces of China]. AB - Objective: To analyze vaccination situation of oral live attenuated rotavirus vaccine (LLR strain) among children from six provinces in China. Methods: In 2014, we selected 12 counties in Guangdong, Jiangsu, Chongqing, Jiangxi, Heilongjiang and Gansu provinces by using stratified cluster random sampling method and extract information of children born from January 1, 2008 to December 31, 2012 from Children's Immunization Information System. We investigated ten children of each birth cohort in each county by checking the vaccination certification, and a total of 606 children were investigated. A survey was conducted to check the information of the children's vaccination certification with the data of Children's Immunization Information System by questionnaire including the basic information (province, county, name, gender, birth date, etc) and the rotavirus vaccination (vaccination date, dose, etc) to analyze the rotavirus vaccination situation. Results: 340 of 606 children were male. There were 121, 124, 122, 119 and 120 children born in 2008-2012, respectively. The proportions of the first and the second dose of rotavirus vaccination were 32.8% (199) and 9.7% (59). The proportion of the third dose of rotavirus vaccination among children born between 2008 and 2010 was 3.5% (13) since children born in 2011 and 2012 did not reach the age of third dose vaccination. The proportion of the first dose of rotavirus vaccination in high, middle and low per capita disposable income areas was 45.0% (91), 37.7% (77) and 15.5% (31) respectively (chi(2)= 43.15, P<0.001). Among 199 children vaccinated with the first dose of vaccine, the vaccination age mainly concentrated in 2 to 21 months, of which the peak was 5 to 13 months (66.8%, 133). The intervals between 2 doses of vaccination were mainly from 12 to 13 months (42.4%, 25) among the 59 children who received at least 2 doses of vaccine. In the 13 children vaccinated with 3 doses, the intervals between the second and the third dose were 12 months (5). Of the 271 doses of rotavirus vaccine vaccinated during 2008-2014, 34.7% (94 doses) were vaccinated in June-August, 88 were vaccinated simultaneously with 18 other vaccines, accounting for 32.5% of the total. Of the 18 other vaccines, inactivated vaccines such as diphtheria vaccine (30 doses), Hib vaccine (14 doses), group A meningitis vaccine (10 doses) were predominant. Conclusion: The proportion of rotavirus vaccination was low and the vaccination age was relatively late. The vaccination mode was different from the recommendation of WHO. It is recommended that routine immunization of rotavirus vaccines should be carried out in early-months of children. PMID- 29973009 TI - [Blocking effects of serum antibodies against HBGA binding to norovirus GII.4 of population in oyster culture area of Guangdong Province]. AB - Objective: Evaluate GII.4 norovirus infection and blocking effects of serum antibodies against HBGAs binding to GII.4 norovirus of population in oyster culture area, provide references for screening of fully human monoclonal antibody. Methods: Using a random survey method to collect blood and saliva samples in oyster culture area, select serum samples from the inland region of Guangdong as control group. Identification of salivary HBGA receptor phenotype and detection of serum antibody levels between two areas by ELISA. A vitro neutralization model was to determine the efficiency of serum antibodies blocking GII.4 norovirus and HBGA receptors binding. Results: The age were (50.68 +/- 15.17), (52.52 +/- 15.90) and (51.37 +/- 13.32) years old of 2015, 2016 in experimental group, and in control group, respectively. Males accounted for 5.9% (70/195), 36.6%(60/164), 40.8% (69/169) (chi(2)=0.93, P=0.334). The mean value of serum antibodies Absorbance value was 2.521+/-0.05 of 2015 and was 2.583+/-0.045 of 2016 in oyster culture area, the mean value was 2.249+/-0.05 in control group, there was a statistical difference among three group (F=13.28, P<0.001). The antibody prevalence in the three groups was 100%. BT50 geometric mean titer (GMT) of oyster culture area in 2015 was 423.1+/-40.11, culture group was 248.2+/ 25.63, there was a statistical difference (t=3.73, P<0.001). Conclusion: The population in oyster culture area does have more chance of exposure and infection GII.4 norovirus, Serum antibody of blocking ability in oyster culture areas is better than the general population in inland city. Suggesting that the population is more immunity resistant infected GII.4 norovirus. PMID- 29973010 TI - [Analysis on the epidemic features of male HIV-infected and AIDS patients by sexual transmission in Shandong Province from 2007 to 2016]. AB - Objective: To analyze the epidemic features of male HIV-infected and AIDS patients by sexual transmission in Shandong Province. Methods: Data on HIV infected people and AIDS patients (HIV/AIDS) were derived from HIV/AIDS Comprehensive Response Information Management System. To analysis the epidemiological data of male HIV/AIDS by sexual transmission reported in Shandong Province from 1997 to 2016. Results: A total of 8 584 HIV/AIDS were reported by heterosexual transmission or homosexual transmission from 2007 to 2016. 2 421 cases were reported by heterosexual transmission and 6 163 cases were reported by homosexual transmission. Among cases infected by heterosexual transmission. The average age of cases infected by heterosexual transmission was (38.13+/-12.39) and (31.62+/-10.22) among cases who infected by homosexual transmission (t=24.95, P<0.001). 84 cases were reported by homosexual transmission and 138 cases by heterosexual transmission from 2007 to 2008, and 6 079 cases were reported by homosexual transmission and 2 283 cases by heterosexual transmission from 2009 to 2016. A total of 770 cases were dead after reported. Among the dead cases, 337 cases were infected by homosexual transmission and 433 cases by heterosexual transmission (chi(2)=328.21, P<0.001). 61.4% of the dead cases by heterosexual transmission were no longer than 6 months after reported and 54.3% in homosexual transmission (chi(2)=3.96, P=0.047). Conclusion: Homosexual transmission has been the main transmission of HIV/AIDS in Shandong Province. Epidemiological features and social demographic characteristics of each sexual transmission were different. As part of HIV cases developed to death in 6 months. PMID- 29973011 TI - [Association between the internal exposure levels of phthalates and executive function of preschool children]. AB - Objective: To investigate the association between the internal exposure levels of phthalic acid esters (PAEs) and executive function (EF) of preschool children. Methods: Between October 2008 and October 2010, pregnant women who accepted pregnancy health care services in four municipal medical and health institutions in Ma'anshan city, Anhui Province, were recruited as study objects. A total of 5 084 pregnant women and 4 669 singleton live births were enrolled in this cohort. The follow-up study was conducted from April 2014 to April 2015. A total of 3 725 data-completed preschool children aged 3 to 6 years older entered in this study. The method of analysis seven metabolites of phthalates in urine was high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and divided objects into low (P(0)-P(24)), medium (P(25)-P(74)) and high (P(75) P(100)) groups according to their exposure concentrations. To investigate the executive function of preschool children, we used the Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P). Univariate and multivariate statistical method was used to analyze the etiology association between the phthalate metabolites levels and preschool children's executive function. Results: In this study, 53.6% (1 997/3 725) of preschoolers were boys, children's age was (51.5+/-5.6) months. The detection rates of seven phthalate esters were: mono-n-methyl phthalate (MMP) was 99.89% (3 721/3 725); mono-ethyl phthalate (MEP) was 99.97% (3 724/3 725); mono-benzyl phthalate (MBzP) was 69.10% (2 574/3 725); mono-butyl phthalate (MBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono- (2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were 100.00% and mono-ethylhexyl phthalate (MEHP) was 99.95% (3 723/3 725). The median concentrations of the seven phthalate metabolites were: 17.71, 15.36, 0.07, 155.24, 10.73, 14.67, 3.59 ug/L, respectively. The median concentrations corrected by urinary creatinine were 29.65, 26.65, 0.12, 257.73, 17.94, 24.80, 6.27 ug/g Cr, respectively. The P(25) and P(7)5 concentration of the total PAEs metabolites corrected by urinary creatinine were 1.20 umol/g Cr and 3.04 umol/g Cr. After adjusted the relevant demographic information: children sex, children age in month, maternal age, parental education levels, household exposure to secondhand smoke and whether the child is the only child as confounds, multivariate logistic regression model showed that the risk of inhibitory self-control index (ISCI) dysplasia in MEHHP high concentration group and MEOHP high concentration group were 1.71 and 1.54 times (OR=1.71, 95% CI: 1.11-2.62; OR=1.54, 95% CI: 1.01-2.34) than in low concentration group. The risk of ISCI dysplasia in total PAEs metabolites high concentration group was 1.55 times (OR=1.55, 95% CI: 1.00-2.38) than in low concentration group. Conclusion: Phthalates exposure may damage the executive function of preschool children. PMID- 29973012 TI - [Analysis of nutritional status among Chinese students of five ethnic minorities aged 7-18 years in 2014]. AB - Objective: To understand the nutritional status among Chinese students of five ethnic minorities aged 7-18 years. Methods: Chinese National Survey on Students Constitution and Health in 2014 applied multi-stage stratified cluster random sampling, including 214 354 students from 31 province of China mainland. 73 students whose height or weight information were missing, were excluded. 25 968 minority students aged 7-18 years from Inner Mongolia Autonomous Region, Ningxia Hui Autonomous Region, Xinjiang Uygur Autonomous Region, Guangxi Zhuang Autonomous Region and Jilin Provinces were included for data analysis, including Mongolian (n=5 107), Hui (n=5 308), Uygur (n=5 740), Zhuang (n=5 267) and Korean (n=4 546) students. According to the BMI standard of Working Group on Obesity in China (WGOC) and the new students' health standard of Screening Standard for Malnutrition of School-age Children and Adolescents (WS/T 456-2014) , students were defined as wasting, normal weight, overweight and obesity groups and the nutritional status in different minorities and other characteristics was described and analyszed. Results: The prevalences of wasting in Zhuang, Hui, Uygur, Korean and Mongolian students were 6.1% (318/5 267), 5.1% (266/5 308), 3.2% (187/5 740), 2.6% (116/4 546) and 1.3% (65/5 107) in descending order (chi(2)=212.60, P<0.001), respectively. The prevalences of overweight in Korean, Mongolian, Hui, Uygur and Zhuang students were 15.2% (686/4 546), 13.1% (669/5 107), 10.3% (549/5 308), 7.8% (446/5 740) and 7.8% (413/5 267) in descending order (chi(2)=220.80, P<0.001), respectively. The prevalences of obesity in Korean, Mongolian, Hui, Zhuang and Uygur students were 15.3% (695/4 546), 9.5% (488/5 107), 5.7% (304/5 308), 4.6% (242/5 267) and 3.6% (206/5 740) in descending order (chi(2)=647.02, P<0.001), respectively. The prevalences of wasting in Mongolian, Uygur and Korean rural students were 1.7% (44/2 623), 3.9% (113/2 868) and 3.4% (74/2 154), higher than urban students (all P values <0.05) which were 0.8% (21/2 484), 2.6% (74/2 872) and 1.8% (42/2 392) in Mongolian, Uygur and Korean students. The prevalence of obesity in Mongolian, Hui, Uygur, Zhuang and Korean urban students were 10.8% (269/2 484), 7.6% (193/2 554), 4.1% (117/2 872), 5.9% (153/2 601) and 16.6% (396/2 392), higher than rural students (all P values <0.05) which were 8.3% (219/2 623), 4.0% (111/2 754), 3.1% (89/2 868), 3.3% (89/2 666) and 13.9% (299/2 154) in Mongolian, Hui, Uygur, Zhuang and Korean students. The prevalence of obesity in Hui, Zhuang and Korean boys were 7.2% (188/2 570), 6.0% (157/2 628) and 17.2% (394/2 282), respectively, higher than that of girls which were 4.2% (116/2 738), 3.3% (85/2 639) and 13.3% (301/2 264) (all P values <0.05). Conclusion: The prevalence of wasting, overweight and obesity varied by ethnic minorities in mainland China. The prevalence of overweight and obesity appears higher among mongolian and Korean students, while the prevalence of wasting was higher in Zhuang students. PMID- 29973013 TI - [Analysis of relationship between personal wellbeing index and related factors in the elderly aged 55 or above, who visit the day care centers in Macao, Hong Kong and Guangzhou]. AB - Objective: To investigate the personal wellbeing index (PWI) among elderly aged 55 and above from the elderly day care centers in Macao, Hong Kong and Guangzhou, and associated factors. Methods: We used convenient sampling to select participants from 16 elderly day care centers in Macao, Hong Kong and Guangzhou. Inclusion criteria were: females aged 55 or above, males 60 or above, the participants who were conscious and clearly understood the questionnaire. Informed consent form was signed by the participants. A total of 324 elderly participated in the study: 90 from Macao, 100 from Hong Kong, and 134 from Guangzhou. Close-end questionnaire was used to collect demographic information and PWI inventory (Cantonese version) was used to assess the PWI scores. Comparison in the PWI scores difference was conducted. Multiple regression method was used to analyze factors associated with PWI. Results: The PWI was 7.3+/-1.9 (Macao: 7.7+/-1.9, Hong Kong: 7.2+/-1.7, Guangzhou: 7.0+/-1.9) (F=3.32, P=0.037). The multiple regression analysis showed that comparing to those who did exercised 3 times or less, or single/devoiced/separated, or had no education, the elderly who did exercised 4 times or more per week or married/widowed, or received education in primary school or above had higher PWI scores. The beta values (95%CI) were 0.82 (95% CI: 0.31-1.34), 1.03 (95% CI: 0.12-1.94), 0.51 (95% CI: 0.04-0.99) respectively. Conclusion: The elderly participants aged 55 or above who went to elderly day care centers in three cities had higher PWI score generally. Marital status, participate in sufficient physical activity and advanced education level were significant related to PWI. PMID- 29973014 TI - [A study and practice on public health education and teaching reform for the students in clinical medicine science]. PMID- 29973015 TI - [A descriptive study of massive open online courses in school of public health, Peking University]. PMID- 29973016 TI - [Study on the goal oriented curriculum system of preventive medicine]. PMID- 29973017 TI - [Study on teaching capacity building of public health]. PMID- 29973018 TI - [Practice of flipped classroom in nutrition education]. PMID- 29973019 TI - [Advances on research of nutrition literacy and nutrition literacy assessment tools]. AB - Health literacy has become a vibrant area of research, and the nutrition literacy and health literacy were closely related as well as a growing number of inquiries have focused on direct measures of nutrition literacy. In this paper, we summarized some features such as the structure, the content, the reliability, the validity and the application of the general nutrition literacy assessment tools and the health literacy assessment tools related to nutrition literacy, furthermore the evaluation contents were listed as the understanding capacity, numeracy capacity, household food measurement, food group, and basic nutrition knowledge. In addition, the briefly the nutrition information readability assessment tools were also summarized. The research results of nutritional literacy and its assessment tools would provide reference for the development of nutrition literacy assessment tools and evaluation work in China. PMID- 29973020 TI - [Epidemic characteristics and prophylaxis/control measures of infectious diseases caused by hydrological disasters]. AB - Hydrological disasters are associated with infectious disease outbreaks and epidemics. Hydrological disasters will lead to water pollution, increased vulnerability to diseases, and increased density of vectors. These factors will facilitate the outbreaks of water-borne/food-borne diseases, vector-borne diseases, and air-borne/contagious diseases. Pre-event preparedness for disasters and post-event reconstruction of both disease surveillance system and water supply system are key measures to prevent infectious disease outbreaks caused by hydrological disasters. This study reviews the domestic and overseas experiences of controlling infectious diseases after hydrologic disasters, outlines the spectrum of post-disaster infectious disease as well as their epidemiological characteristics, and provides practicable suggestions accordingly. PMID- 29973021 TI - [Regenerative rehabilitation medicine: new requirement, new fusion and new direction]. AB - Regenerative rehabilitation medicine is not just the combination of two disciplines of regenerative medicine and rehabilitation medicine but the new fusion of two disciplines, and it represents the development direction of regenerative medicine and rehabilitation medicine. With the improvement of people's demands for tissue injury or disease recovery, new technology and means should be required, and regenerative rehabilitation medicine will emerge and develop rapidly. It will play a key role in repair, regeneration and rehabilitation of diseases or injuries in patients. PMID- 29973022 TI - [Attaching importance to sepsis-induced acute kidney injury after burn]. AB - Acute kidney injury (AKI) is a common complication after severe burn, which portends a worse prognosis. Sepsis is the leading etiology of late AKI after severe burn. The pathogenesis of sepsis-induced AKI remains incompletely understood. Although there have been numerous preventive and therapeutic measures evaluated for sepsis-induced AKI, the precise and available intervention in sepsis-induced AKI after burn has yet to be defined. PMID- 29973024 TI - [Clinical characteristics of burn patients infected with Stenotrophomonas maltophilia and antibiotic resistance of the strains]. AB - Objective: To investigate the clinical characteristics of burn patients infected with Stenotrophomonas maltophilia (SM) and antibiotic resistance of the strains. Methods: Clinical data of burn patients detected with SM, admitted to our unit from July 2011 to July 2017 were retrospectively analyzed. API 20NE bacteria identification panel or fully automated microbial identification instrument was used to identify pathogen. Minimal inhibitory concentration method was used in drug sensitivity test of levofloxacin, compound sulfamethoxazole, minocycline, and cefoperazone/sulbactam. Annual detection of SM, clinical characteristics and prognosis of patients infected with SM, sample source and detection time of SM, detection of the pathogens and antibiotics application of patients before their detection of SM, and drug resistance of SM to the above four antibiotics were analyzed. The results of drug sensitivity test were analyzed by software WHONET 5.5. Results: (1) There were totally 119 patients detected with SM, with 11, 12, 21, 22, 28, 13, and 12 cases from 2011 to 2017, respectively. (2) Among patients infected with SM, there were 86 (72.3%) males and 33 (27.7%) females. Patients aged more than or equal to 65 years accounted for 11.8% (14/119). Patients aged more than or equal to 18 years and less than 65 years accounted for 76.5% (91/119). Patients aged less than 18 years accounted for 11.8% (14/119). Patients with scald were the most common (totally 72 cases, accounted for 60.5%), and patients with total burn area less than or equal to 10% total body surface area were the most common (totally 35 cases, accounted for 29.4%), too. The proportion of patients with history of basic disease was 16.8% (20/119), with tracheotomy of 46.2% (55/119), with deep vein catheterization of 47.9% (57/119), with history of staying in intensive care unit (ICU) of 61.3% (73/119). Seventy-five (63.0%) patients were cured. Twenty-four (20.2%) patients were improved. Fourteen (11.8%) patients gave up treatment. Six (5.0%) patients died. (3) SM detected from wounds exudate of patients occupied the highest proportion (58.0%, 69/119), which was followed by samples of sputum (17.6%, 21/119), blood (14.3%, 17/119), wound tissue (4.2%, 5/119), catheter (4.2%, 5/119), and urine (1.7%, 2/119). The detection time of SM was 10 hours to 71 days post admission, with the average time of 12.7 days. (4) The proportion of patients detected with pathogens before detection of SM was 66.4% (79/119), and Acinetobacter baumannii and Staphylococcus aureus occupied high proportion among the strains. (5) The proportion of patients using antibiotics before detection of SM was 91.6% (109/119), and 44.0% (48/109) patients used 3 kinds of antibiotics or more. The antibiotics were applied for 271 times. The most frequently used antibiotics were glycopeptides antibiotics (63 times), followed by carbapenems antibiotics (61 times). (6) The total sensitivity rates of SM to levofloxacin and minocycline in 7 years were high (91.6% and 99.4%, respectively). The total sensitivity rate of SM to cefoperazone/sulbactam was low (52.5%). The total sensitivity rate of SM to compound sulfamethoxazole was high (77.6%), and the annual sensitivity rate was higher than 90.0% in recent 3 years. Conclusions: Burn patients infecting SM have high rates of tracheotomy and deep vein catheterization, and most of them stay in ICU and use broad-spectrum antibiotics. SM has high sensitivity to levofloxacin, minocycline, and compound sulfamethoxazole. PMID- 29973023 TI - [Effects of application of citrate anticoagulation in bedside continuous blood purification of severe burn patients with sepsis]. AB - Objective: To investigate the effects of application of citrate anticoagulation in bedside continuous blood purification (CBP) of severe burn patients with sepsis, so as to provide reference for choosing anticoagulants in CBP of these patients. Methods: Thirty severe burn patients with sepsis, conforming to the study criteria, were admitted to our burn intensive care unit from January 2014 to July 2017. Patients were divided into heparin group and citrate group according to computer randomization method, with 15 cases in each group. Patients in two groups all received bedside CBP treatment. Patients in heparin group used local heparin anticoagulation, while patients in citrate group used local citrate anticoagulation. Time of predicted single-time CBP treatment, time of single-time CBP treatment, time of accumulative CBP treatment, and rate of reaching the standard of CBP treatment time were counted. Changes of prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR), fibrinogen, serum procalcitonin, and C-reactive protein (CRP) of patients before and after treatment were monitored. Hemorrhage in wounds, incision on trachea, and arteriovenous intubation point, and other complications during and after CBP treatment were observed. Data were processed with independent sample t test and chi-square test. Results: (1) Time of predicted single-time CBP treatment of patients in the two groups was equal. Time of single-time CBP treatment and time of accumulative CBP treatment of patients in citrate group were longer than those in heparin group. Rate of reaching the standard of CBP treatment time of patients in citrate group was significantly higher than that in heparin group (chi(2)=16.655, P<0.01). (2) There was no statistically significant difference in PT, APTT, INR, fibrinogen, serum procalcitonin, and CRP of patients in the two groups before CBP treatment (t=0.203, -1.006, 0.203, 0.039, -1.591, 0.824, P>0.05). PT and APTT of patients in citrate group after CBP treatment were (14.2+/-1.6) and (45+/-7) s, respectively, significantly shorter than (15.5+/ 1.4) and (53+/-6) s in heparin group (t=2.395, 3.321, P<0.05 or P<0.01). INR of patients in citrate group after CBP treatment was 1.13+/-0.12, significantly lower than 1.24+/-0.12 in heparin group (t=2.395, P<0.05). Fibrinogen of patients in citrate group after CBP treatment was (3.5+/-0.6) g/L, significantly higher than (3.0+/-0.6) g/L in heparin group (t=-2.427, P<0.05). Serum procalcitonin and CRP of patients in citrate group after CBP treatment were significantly lower than those in heparin group (t=2.520, 2.710, P<0.05). Decreased degree of serum procalcitonin and CRP of patients in citrate group after CBP treatment were (1.8+/-0.6) ng/mL and (143+/-69) mg/L, respectively, significantly higher than (0.9+/-0.6) ng/mL and (95+/-50) mg/L in heparin group (t=-4.033, -2.170, P<0.05 or P<0.01). (3) During CBP treatment, patients in heparin group experienced 21 times of exacerbation of wound hemorrhage and 10 times of new hemorrhage, including 2 times of hemorrhage at incision on trachea and 8 times of hemorrhage at arteriovenous intubation point. No exacerbation of hemorrhage or new hemorrhage happened in patients of citrate group. After CBP treatment, no electrolyte disturbance happened in patients of heparin group, but 1 patient in citrate group experienced hypocalcemia. Conclusions: Application of citrate anticoagulation in bedside CBP of severe burn patients with sepsis shows light impact on systematic coagulation status, and can effectively decrease inflammation reaction of burn sepsis with low rate of hemorrhage. PMID- 29973025 TI - [Investigation of acquired drug-resistant genes and strains relationship in Pseudomonas aeruginosa isolated from burn patients]. AB - Objective: To investigate the acquired drug-resistant genes and strains relationship in 40 strains of Pseudomonas aeruginosa isolated from burn patients. Methods: Forty strains of Pseudomonas aeruginosa isolated from burn patients hospitalized in our burn department from January 2014 to December 2015 were selected, with 20 strains from each year. Kirby-Bauer paper disk diffusion method was used to detect sensitivity of the isolated Pseudomonas aeruginosa to 9 kinds of antibiotics of cefotaxime, ceftazidime, cefepime, imipenem, meropenem, gentamicin, amikacin, ciprofloxacin, and levofloxacin. Polymerase chain reaction was applied to detect 9 kinds of acquired beta-lactamase antibiotics-resistant genes, outer membrane porin protein oprD2 genes, 12 kinds of acquired aminoglycosides antibiotics-resistant genes, and 6 kinds of acquired disinfectant resistant genes and genetic marker genes of mobile genetic elements. Among the above genes, positive expression genes were verified by DNA sequencing and comparison. Sequences of twenty-eight acquired drug-resistant genes of the above 40 Pseudomonas aeruginosa strains were analyzed by unweighted pair-group method with arithmetic means cluster analysis. Results: Forty strains of Pseudomonas aeruginosa were resistant to the above 9 kinds of antibiotics. Two kinds of acquired beta-lactamase antibiotics-resistant genes of bla(TEM), bla(CARB), 5 kinds of acquired aminoglycosides antibiotics-resistant genes of aac(6')-Ib, aac(6')-II, ant(2")-I, ant(3")-I, and rmtB, and 3 kinds of acquired disinfectant resistant genes and genetic marker genes of mobile genetic elements of qacE?1 sul1, merA, and intI1were detected in 40 strains of Pseudomonas aeruginosa with oprD2 gene deficiency. Forty strains aggregated obviously, with a total of 7 gene modes and 3 clones. Drug-resistant gene sequences of strains of number 2 to 4, 6 to 9, 11, 14, and 17 to 39 were similar and with close relationship. Drug resistant gene sequences of number 12 and 13 strains were similar and with close relationship. Drug-resistant sequences of number 10 and 16 strains were similar and with close relationship. Conclusions: Genes of bla(TEM), bla(CARB), aac(6') Ib, aac(6')-II, ant(2")-I, rmtB, qacE?1-sul1, merA, and intI1 were prevalent in these strains of Pseudomonas aeruginosa with oprD2 gene deficiency isolated from burn patients, which may play key roles in resistance of Pseudomonas aeruginosa to beta-lactamase, aminoglycoside, and quinolone antibiotics, and the drug resistant phenotypes were in good coincidence with genotypes. Pseudomonas aeruginosa strains isolated from burn patients were with similar acquired drug resistant genes and close relationship. PMID- 29973026 TI - [Interventional effects of BAY11-7082 on lung inflammatory response at the early stage and acute lung injury of rats with severe burns]. AB - Objective: To investigate the interventional effects of BAY11-7082 on lung inflammatory response at the early stage and acute lung injury of rats with severe burns. Methods: (1) Experiment 1. Twelve Sprague-Dawley (SD) rats were divided into control (C) group and burn (B) group according to the random number table, with 3 rats in group C and 9 rats in group B. Rats in group C did not receive any special treatment. Rats in group B were inflicted with 30% total body surface area full-thickness burn on the back. Immediately after injury, rats in group B were intraperitoneally injected with normal saline in the dosage of 50 mL/kg. Abdominal aorta blood and lung tissue samples were collected from three rats in group B at post injury hour (PIH) 12, 24, and 48, respectively. The interleukin-1beta (IL-1beta) and the IL-18 content of serum were determined with enzyme-linked immunosorbent assay. The mRNA expressions of IL-1beta and IL-18 in lung tissue were determined with real-time fluorescent quantitative reverse transcription polymerase chain reaction (RT-PCR). Sample collection and determination in rats of group C were performed as above. (2) Experiment 2. Eighteen SD rats were divided into control (C) group, simple burn (SB) group, and BAY11-7082 intervention (BI) group according to the random number table, with 6 rats in each group. Rats in group C did not receive any special treatment. Rats in groups SB and BI were inflicted with injury as in experiment 1. Immediately after injury, rats in group SB were intraperitoneally injected with normal saline in the dosage of 50 mL/kg, and those in group BI with 8 mg/mL (final mass concentration) BAY11-7082 solution in the dosage of 50 mL/kg. Lung tissue and bronchoalveolar lavage fluid (BALF) of rats with burns were collected at the optimal observation time point concluded from experiment 1. The morphology of lung tissue was observed with hematoxylin-eosin staining, and the pathological damage of lung tissue was graded. The myeloperoxidase (MPO) content of lung tissue and the total protein content of BALF were detected by microplate reader. The protein expressions of nucleotide-binding oligomerization domain-like receptor-3 (NLRP3) and cysteine-aspartic proteases 1 (caspase-1) in lung tissue were determined with Western-blotting. The mRNA expressions of IL-1beta, IL-18, NLRP3, and caspase-1 in lung tissue were determined with real-time fluorescence quantitative RT-PCR. Sample collection and determination in rats of group C were performed as above. Data were processed with one-way analysis of variance and LSD t test. Results: (1) The IL-1beta and IL-18 content of serum in rats of group B at PIH 12, 24, and 48 were significantly higher than those of group C (t=10.55, 22.05, 12.47, 10.60, 15.22, 11.94, P<0.01). The mRNA expressions of IL-1beta and IL-18 in rats of group B at PIH 12, 24, and 48 were significantly higher than those of group C (t=3.62, 7.19, 5.28, 3.20, 12.62, 7.31, P<0.05 or P<0.01). PIH 24 was the optimal observation time point for the following experiment. (2) At PIH 24, compared with those in group SB, the inflammatory cell infiltration and erythrocyte exudates of alveolar in group BI were obviously reduced, and the pulmonary interstitial edema obviously subsided. The pathological damage score of lung tissue in rats of group SB was (9.00+/-1.00) points, significantly higher than (1.10+/-0.26) points of group C (t=13.23, P<0.01). The pathological damage score of lung tissue in rats of group BI was (4.93+/-0.70) points, which was significantly lower than that of group SB (t=5.76, P<0.01) but still significantly higher than that of group C (t=8.84, P<0.01). At PIH 24, the MPO content of lung tissue and the total protein content of BALF in rats of group SB were (1.83+/-0.15) U/mg and (1.39+/-0.20) mg/mL, respectively, significantly higher than (0.51+/-0.10) U/mg and (0.44+/-0.05) mg/mL of group C (t=12.50, 7.86, P<0.01). The MPO content of lung tissue and the total protein content of BALF in rats of group BI were (0.91+/-0.12) U/mg and (0.60+/-0.10) mg/mL, respectively, significantly lower than those of group SB (t=8.36, 6.06, P<0.01). At PIH 24, the protein expressions of NLRP3 and caspase-1 in lung tissue of rats of group SB were 3.10+/-0.09 and 2.99+/-0.30, respectively, significantly higher than 1.00 and 1.00 of group C (t=9.06, 11.28, P<0.01). The protein expressions of NLRP3 and caspase-1 in lung tissue of rats of group BI were 1.13+/-0.08 and 1.81+/-0.11, respectively, significantly lower than those of group SB (t=7.24, 3.91, P<0.05 or P<0.01). At PIH 24, the mRNA expressions of IL-1beta, IL-18, NLRP3, and caspase-1 in lung tissue of rats in group SB were 5.0+/-0.4, 3.32+/-0.21, 3.54+/-0.42, and 6.3+/-1.0, respectively, significantly higher than 1.0, 1.00, 1.00, and 1.0 of group C (t=13.97, 14.14, 11.78, 7.13, P<0.01). The mRNA expressions of IL-1beta, IL-18, NLRP3, and caspase-1 in lung tissue of rats in group BI were 2.6+/-0.5, 2.00+/-0.28, 1.39+/-0.21, and 2.5+/-0.5, respectively, significantly lower than those of group SB (t=7.11, 5.80, 9.99, 4.65, P<0.05 or P<0.01). Conclusions: Applying BAY11-7082 at the early stage of acute lung injury of rats with severe burn can reduce the expression of caspase-1, decrease the levels of IL-1beta and IL-18, and decrease the MPO content of lung tissue and the total protein content of BALF through inhibiting NLRP3, thus alleviating the lung inflammatory response and lung injury. PMID- 29973027 TI - [Effects of denatured collagen type I on differentiation of human fibroblasts into myofibroblasts]. AB - Objective: To investigate the effects of denatured collagen type I on differentiation of human fibroblasts into myofibroblasts. Methods: A small amount of normal skin donated by burn patients undergoing scar surgery was collected. Human fibroblasts were obtained by method of explant culture and then sub cultured. The fourth passage of cells were used in the following experiments. (1) Fibroblasts were divided into normal collagen group and denatured collagen group according to the random number table, with 10 wells in each group. Fibroblasts in normal collagen group were cultured on normal collagen type I coated coverslips. Fibroblasts in denatured collagen group were cultured on denatured type I collagen coated coverslips. Expression of proliferating cell nuclear antigen (PCNA) was detected by immunohistochemical method, and the percentage of PCNA positive cells was calculated. (2) Another batch of fibroblasts were grouped and treated as in (1), with 12 wells in each group. Proliferation activity of cells was determined with methyl-thiazolyl-tetrazolium colorimetry method. (3) Another batch of fibroblasts were grouped and treated as in (1), and the microfilament morphology of cells was observed by rhodamine-phalloidin staining. (4) Another batch of fibroblasts were grouped and treated as in (1). Expression of alpha smooth muscle actin (alpha-SMA) of cells was detected by immunohistochemical method, and expression of OB-cadherin of cells was detected by immunofluorescence method. (5) Another batch of fibroblasts were divided into normal collagen, denatured collagen, and common coverslips groups according to the random number table, with 6 wells in each group. Fibroblasts in normal collagen and denatured collagen groups were treated as in (1), while fibroblasts in common coverslips group were cultured on coverslips without collagen coating. Expressions of alpha SMA and OB-cadherin of cells were determined with Western blotting. (6) Another batch of fibroblasts were grouped and treated as in (5), and then the mRNA expressions of collagen type I, collagen type III, and alpha-SMA of cells were determined with real-time fluorescent quantitative reverse transcription polymerase chain reaction. Data were processed with t test, one way analysis of variance, and least-significant difference test. Results: (1) The percentage of PCNA positive cells in denatured collagen group was (83+/-9)%, significantly higher than (29+/-9)% in normal collagen group (t=13.53, P<0.01). (2) The proliferation activity of fibroblasts in denatured collagen group was 0.32+/ 0.06, significantly higher than 0.25+/-0.05 in normal collagen group (t=3.06, P<0.01). (3) The microfilament of fibroblasts in normal collagen group was arranged vertically and in parallel way, paralleling the long axis of cells. The microfilament of fibroblasts in denatured collagen group was denser and thicker. (4) Most fibroblasts in normal collagen group showed long shuttle-like shape typically. Morphology of fibroblasts in denatured collagen group changed, and cells were obviously spreading. Expressions of alpha-SMA and OB-cadherin of fibroblasts in denatured collagen group were stronger than those in normal collagen group. (5) Expressions of alpha-SMA of fibroblasts in denatured collagen, normal collagen, and common coverslips groups were respectively 1.69+/ 0.41, 0.89+/-0.27, and 1.46+/-0.42. Expression of alpha-SMA of fibroblasts in denatured collagen group was significantly higher than that in normal collagen group (P<0.01). Expressions of OB-cadherin of fibroblasts in denatured collagen, normal collagen, and common coverslips groups were respectively 5.17+/-0.28, 2.21+/-0.10, and 4.01+/-0.56. Expression of OB-cadherin of fibroblasts in denatured group was significantly higher than that in normal collagen group (P<0.01). (6) There was no significant difference in mRNA expression of collagen type I of fibroblasts in denatured collagen, normal collagen, and common coverslips groups (F=2.71, P>0.05). The mRNA expressions of collagen type III and alpha-SMA of fibroblasts in normal collagen group were significantly lower than those in denatured collagen group (P<0.01). Conclusions: Denatured collagen type I may influence the activity of fibroblasts, thus inducing fibroblasts differentiating into myofibroblasts. PMID- 29973028 TI - [Mechanism of cell autophagy for regulating skeletal muscle wasting of rats after severe burns]. AB - Objective: To investigate the mechanism of cell autophagy for regulating skeletal muscle wasting of rats after severe burns. Methods: Seventy-two Sprague-Dawley rats were collected and divided into sham injury group, simple burn group, burn+ phosphate buffer solution (PBS) group, and burn+ 3-methyladenine (3-MA) group according to the random number table, with 18 rats in each group. Rats in simple burn group, burn+ PBS group, and burn+ 3-MA group were inflicted with 30% total body surface area full-thickness scald (hereinafter referred to as burns). Rats in sham injury group were sham injured. Immediately after burns and fluid resuscitation, rats in burn+ PBS group were intraperitoneally injected with 1 mL PBS, and rats in burn+ 3-MA group were intraperitoneally injected with 1 mL 3-MA (125 g/L). On post injury day 3 and 7, the weights of anterior tibial muscle of right hind limbs and body of rats were measured to calculate percentage of anterior tibial muscle of right hind limbs weight. Protein expressions of microtubule related protein 1 light chain 3A (LC3A) and Beclin-1 of anterior tibial muscle were observed by immunofluorescence method and detected by Western blotting, and ratio of microtubule related protein 1 LC3A-II to LC3A-I was calculated. Data were processed with analysis of variance of factorial design, one-way analysis of variance, t-test and Bonferroni correction. Results: On post injury day 3 and 7, percentages of anterior tibial muscle of right hind limbs weight of rats in simple burn group were (0.148+/-0.009)% and (0.134+/-0.018)%, respectively, which were significantly lower than those in sham injury group [(0.203+/-0.009)%, (0.181+/-0.015)%, t=10.585, 4.913, P<0.01]. Percentages of anterior tibial muscle of right hind limbs weight of rats in burn+ 3-MA group were (0.187+/-0.004)% and (0.192+/-0.009)%, respectively, which were obviously higher than those in burn+ PBS group [(0.162+/-0.005)%, (0.167+/-0.005)%, t=9.564, 5.948, P<0.01]. On post injury day 3 and 7, protein expressions of Beclin-1 and microtubule related protein 1 LC3A of anterior tibial muscle of rats in simple burn group were significantly higher than those in sham injury group, while protein expressions of Beclin-1 and microtubule related protein 1 LC3A of anterior tibial muscle of rats in burn+ 3-MA group were significantly lower than those in burn+ PBS group. Ratios of microtubule related protein 1 LC3A-II to LC3A I of anterior tibial muscle of rats in simple burn group were significantly higher than those in sham injury group (t=3.461, 3.353, P<0.05), while ratios of microtubule related protein 1 LC3A-II to LC3A-I of anterior tibial muscle of rats in burn+ 3-MA group were significantly lower than those in burn+ PBS group (t=3.129, 3.977, P<0.05). Conclusions: Cell autophagy induced by severe burns is involved in the process of skeletal muscle wasting of rats, and inhibition of cell autophagy may contribute to the remission of skeletal muscle wasting of rats induced by burns. PMID- 29973029 TI - The Japanese Wagyu beef industry: current situation and future prospects - A review. AB - In Japan, Wagyu cattle include four Japanese breeds; Black, Brown, Shorthorn, and Polled. Today, the renowned brand name Wagyu includes not only cattle produced in Japan, but also cattle produced in countries such as Australia and the United States. In recent years, the intramuscular fat percentage in beef (longissimus muscle) from Japanese Black cattle has increased to be greater than 30%. The Japanese Black breed is genetically predisposed to producing carcass lipids containing higher concentrations of monounsaturated fatty acids than other breeds. However, there are numerous problems with the management of this breed including high production costs, disposal of untreated excrement, the requirement for imported feed, and food security risks resulting from various viral diseases introduced by imported feed. The feeding system needs to shift to one that is more efficient, and improves management for farmers, food security for consumers, and the health environment for residents of Japan. Currently, we are developing a metabolic programming and an information and communications technology (ICT, or Interne of Things) management system for Wagyu beef production as future systems. If successful, we will produce safe, high-quality Wagyu beef using domestic pasture resources while solving the problems of how to utilize increasing areas of abandoned agricultural land and to make use of the plant-based feed resources in Japan's mountainous areas. PMID- 29973030 TI - Current situation and future trends for beef production in the United States of America - A review. AB - USA beef production is characterized by a diversity of climates, environmental conditions, animal phenotypes, management systems, and a multiplicity of nutritional inputs. The USA beef herd consists of more than 80 breeds of cattle and crosses thereof, and the industry is divided into distinct, but ofttimes overlapping sectors, including seedstock production, cow-calf production, stocker/backgrounding, and feedlot. Exception for male dairy calves, production is predominantly pastoral-based, with young stock spending relatively brief portions of their life in feedlots. The beef industry is very technology driven, utilizing reproductive management strategies, genetic improvement technologies, exogenous growth promoting compounds, vaccines, antibiotics, and feed processing strategies, focusing on improvements in efficiency and cost of production. Young steers and heifers are grain-based diets fed for an average of 5 months, mostly in feedlots of 1,000 head capacity or more, and typically are slaughtered at 15 to 28 months of age to produce tender, well-marbled beef. Per capita beef consumption is nearly 26 kg annually, over half of which is consumed in the form of ground products. Beef exports, which are increasingly important, consist primarily of high value cuts and variety meats, depending on destination. In recent years, adverse climatic conditions (i.e., draught), a shrinking agricultural workforce, emergence of food-borne pathogens, concerns over development of antimicrobial resistance, animal welfare/well-being, environmental impact, consumer perceptions of healthfulness of beef, consumer perceptions of food animal production practices, and alternative uses of traditional feed grains have become increasingly important with respect to their impact on both beef production and demand for beef products. Similarly, changing consumer demographics and globalization of beef markets have dictated changes in the types of products demanded by consumers of USA beef, both domestically and abroad. The industry is highly adaptive, however, and responds quickly to evolving economic signals. PMID- 29973031 TI - Usefulness of ultrasonography for the evaluation of catheter misplacement and complications after central venous catheterization. AB - Objective: To assess whether ultrasonographic examination compared to chest radiography (CXR) is effective for evaluating complications after central venous catheterization. Methods: We performed a prospective observational study. Immediately after central venous catheter insertion, we asked the radiologic department to perform a portable CXR scan. A junior and senior medical resident each performed ultrasonographic evaluation of the position of the catheter tip and complications such as pneumothorax and pleural effusion (hemothorax). We estimated the time required for ultrasound (US) and CXR. Results: Compared to CXR, US could equivalently identify the catheter tip in the internal jugular or subclavian veins (P=1.000). Compared with CXR, US examinations conducted by junior residents could equivalently evaluate pneumothorax (P=1.000), while US examinations conducted by senior residents could also equivalently evaluate pneumothorax (P=0.557) and pleural effusion (P=0.337). The required time for US was shorter than that for CXR (P<0.001). Conclusion: Compared to CXR, US could equivalently and more quickly identify complications such as pneumothorax or pleural effusion. PMID- 29973032 TI - Usefulness of delta neutrophil index for early prediction of overt disseminated intravascular coagulopathy in patients with venomous snakebite. AB - Objective: Clinically, consumptive coagulopathy, such as disseminated intravascular coagulopathy (DIC), is the most important among the common venomous snakebite complications owing to the serious hemorrhage risk associated with this condition. We evaluated the predictive value of the delta neutrophil index (DNI) a new indicator for immature granulocytes-for DIC diagnosis. Methods: This retrospective observational study consecutively assessed adult patients with venomous snakebites for over 51 months. Patients were categorized into the no DIC and DIC groups. DNI values were measured within 24 hours after snakebite. Results: Thirty patients (26.3%) developed DIC. The DIC group had significantly higher median initial DNI than the no DIC group (0% vs. 0.2%, P<0.001). When the DIC group was divided into early and late groups (within and over 24 hours after snakebite, respectively), the DNI of the former was significantly higher than that of the latter and no DIC group. The late DIC group had significantly higher DNI than the no DIC group. Furthermore, DNI positively correlated with the DIC score (r=0.548, P<0.001). The initial DNI (odds ratio, 4.449; 95% confidence interval, 1.738 to 11.388; P=0.002) was an early DIC predictor. The area under the curve based on the initial DNI's receiver operating characteristic curve was 0.724. Conclusion: DNI values were significantly higher in the DIC group. Additionally, DNI was an early predictor of DIC development in patients with venomous snakebites in the emergency department. PMID- 29973033 TI - Injury pyramid of unintentional injuries according to sex and age in South Korea. AB - Objective: The injury-related disease burden in South Korea is relatively high compared to that in other nations. This study was conducted to identify the scale and causes of injury by severity, using an injury pyramid and analyzing the sex and age-dependent differences and the basic demographic characteristics. Methods: Unintentional injury was estimated for each group after classifying injury related deaths, hospitalizations, and outpatient department (OPD) visits based on their severity. The injury pyramid was calculated by classifying the injury outcomes into deaths, hospitalizations, and outpatient visits. Results: The incidence of unintentional injury included 31.74 deaths, 1,715.27 hospitalizations, and 7,317.55 OPD visits per 100,000 persons. The incidence of injury was higher among males than that among females. There were more hospitalizations and OPD visits than deaths among females. The mortality and hospitalization rates due to injury per 100,000 persons were the highest among those >=75 years old, and the OPD visit rate was the highest among preschool children aged 0 to 6 years. The injury mechanisms that caused most deaths and hospitalizations in South Korea were injuries related to traffic, falls, poisoning, and burns/fires. Conclusion: The scale of unintentional injury varies based on sex, age, and injury mechanism; additionally there are differences in the incidence of injuries between males and females depending on their age and injury mechanism. The high incidence of injury in elderly people could be a factor that increases the burden of injury in South Korea; hence, it is necessary to develop an injury prevention program that targets the elderly. PMID- 29973034 TI - Radial access for percutaneous coronary procedure: relationship between operator expertise and complications. AB - Objective: The aim of this study was to investigate (1) whether the learning curve of new catheterization laboratory operators increases the incidence of complications of transradial access during percutaneous coronary interventions and (2) whether manual compression with a two-step approach is safe and efficient for radial access hemostasis. Methods: We performed a prospective study with all consecutive patients who underwent a coronary diagnostic or intervention procedure with radial access. The primary end point was a composite of pulseless radial artery of the wrist and hematoma evaluated after 24 hours. The secondary end point of efficacy was defined as the presence of bleeding or hematoma after 30 seconds. Results: From March 2016 to June 2016, 150 consecutive patients, of whom 147 underwent coronary angiography and/or percutaneous coronary intervention through radial access, were included in the present study. The primary end point was present in 33%, but pulseless radial artery of the wrist was present only in 5.3%. We found that the incidence of primary end point was statistically different according to the number of puncture attempts, with a cutoff of two punctures with blood. The secondary end point of safety was present only in 4.7% of the cases. Conclusion: Radial access is feasible and safe even if performed by training physicians. Manual compression with early evaluation after 30 seconds is a safe technique for managing the radial access after sheath removal. PMID- 29973035 TI - Diagnostic performance of brain computed tomography to detect facial bone fractures. AB - Objective: Most patients with head trauma require brain computed tomography (CT) in the emergency department. However, the requirement for facial CT remains controversial. The aim of this study was to evaluate the diagnostic value of brain CT alone for detection of facial fractures and its ability to determine the requirement for additional facial CT. Methods: This retrospective multicenter study was conducted in two tertiary hospitals in Seoul, Republic of Korea, between January 2014 and December 2015. Data were collected from the medical records of adult patients (aged over 18 years) who had undergone both brain and facial CT on the same day as their presentation to the emergency department with blunt trauma to the head and face. The same radiologist analyzed all brain and facial CT images. Results: Eight hundred and sixty patients (668 men, 192 women; mean age 48.60+/-18.2 years) were identified to have had facial fractures. There was a statistically significant predominance of men but not of any particular age group. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of brain CT were 83.72%, 98.87%, 97.17%, 92.92%, and 94.08%, respectively. Conclusion: These findings suggest that brain CT has high diagnostic value for detection of upper facial bone fractures with high accuracy and can aid emergency physicians when determining the requirement for additional facial CT. PMID- 29973036 TI - Validation and proposal for cut-off values of an abbreviated version of the Alcohol Use Disorder Identification Test using the Korean National Health and Nutrition Examination Survey. AB - Objective: Several abbreviated versions of the Alcohol Use Disorder Identification Test (AUDIT) have been developed and are widely used in clinical settings. In this study, we provide evidence supporting the use of abbreviated versions of AUDIT by comparing the utility of various abbreviated versions and determining cut-off values for the population of South Korea. Methods: Data were obtained from the 4th to 6th Korean National Health and Nutrition Examination Surveys. After calculating the whole AUDIT score, we applied the cut-off value of at-risk drinking proposed by the World Health Organization and divided the study sample into normal and at-risk drinking groups. Receiver operating characteristic curves were drawn for AUDIT-3rd question (Q3) alone, AUDIT-quantity and frequency (QF), AUDIT-consumption (C), AUDIT-4, and AUDIT-primary clinic (PC), and optimal cut-off values were obtained for each group. Results: A total of 46,450 subjects were analyzed. The at-risk drinking group comprised 29.2% of all subjects. The area under receiver operating characteristic curve (AUROC) of the abbreviated versions of AUDIT increased from 0.954 to 0.991 as the number of questions increased from one to four. The differences in AUROC between the abbreviated versions of AUDIT were statistically significant. The most appropriate cut-off values for AUDIT-Q3 alone, AUDIT-QF, AUDIT-C, AUDIT-4, and AUDIT-PC for adults over age 19 were 2, 4, 5, 6, and 4 points, respectively. Conclusion: As the number of items analyzed increased from one to four items, the AUROC increased to a statistically significant level. Cut-off values for abbreviated versions of AUDIT are similar in South Korea to other countries. PMID- 29973037 TI - Pediatric food impaction detected through point-of-care ultrasonography. AB - A previously healthy 1-year-old boy suddenly began coughing while eating a dried sweet potato. Because he continued gagging after vomiting a piece of the dried sweet potato, his mother brought him to our emergency room. Upon arrival, despite normal pulmonary findings, he was drooling and gagging. Ultrasonography was performed because food impaction at the upper esophagus was suspected based on his medical history and physical examination, and results showed that a linear hyperechoic lesion was obstructing the posterior esophageal wall. Computed tomography was also considered for a detailed examination of the foreign body. However, the patient vomited the dried sweet potato before the test was performed. After vomiting the foreign body, the patient stopped gagging, and his ultrasonographic findings were normal. Therefore, the patient was discharged without any complications. PMID- 29973038 TI - Use of Hypnotics and Risk of Cancer: A Meta-Analysis of Observational Studies. AB - Background: Previous observational epidemiological studies have shown inconsistent results on the relationship between hypnotics use and risk of cancer. To determine the association between hypnotics use and risk of cancer, we conducted a meta-analysis of available literature. METHODS: We searched databases PubMed, EMBASE, and the bibliographies of relevant articles to locate additional publications in February 2016. Three evaluators independently reviewed and selected eligible studies based on pre-determined selection criteria. RESULTS: A total of six observational epidemiological studies including three case-control studies and three cohort studies, which involved 1,830,434 participants (202,629 hypnotics users and 1,627,805 non-users), were included in the final analyses. In a random-effects meta-analysis, compared with non-use of hypnotics, the odds ratio for overall hypnotics use was 1.29 for various cancers (95% confidence interval, 1.08-1.53). Subgroup meta-analyses by various factors such as study design, type of case-control study, study region, and methodological quality of study revealed consistent findings. CONCLUSION: Our findings from a meta-analysis of low-biased epidemiological studies suggested evidence linking the use of hypnotics to an increased risk of cancers. The results should be cautiously interpreted because of considerable heterogeneity with a high I square value. PMID- 29973039 TI - The Effects of Weight Control Behaviors among Korean Obese Adults. AB - Background: This study aimed to identify and examine the effects of weight control behaviors correlated with weight loss in obese individuals who attempted to lose weight within the past year. METHODS: In this cross-sectional study, data from 9,461 obese individuals were collected from the fifth and sixth Korean National Health and Nutrition Examination Survey (2010-2014). Three of nine verified methods of weight control suggested in the survey were selected: diet therapy (reduced food intake), exercise therapy (exercise), and medication therapy (prescribed weight loss medications). Participants were divided into one of seven groups (diet therapy alone; exercise therapy alone; drug therapy alone; combined diet and exercise therapy; combined exercise and drug therapy; combined diet and drug therapy; or combined diet, exercise, and drug therapy). Logistic regression analysis was used to determine whether the group that tried to lose weight in the past year had indeed lost weight compared to the group that did not. RESULTS: The odds ratios for weight loss (>=3 but <6 kg vs. >=6 but <10 kg) for the combined therapies were 2.05 (95% confidence interval, 1.23-3.41) for combined diet and exercise therapy and 5.43 (1.74-16.92) for combined diet, exercise, and drug therapy. CONCLUSION: All levels of weight loss were significantly associated with combined diet and exercise therapy. Weight loss >=6 kg but <10 kg was significantly associated with combined diet and exercise therapy as well as with combined diet, exercise, and medication therapy among individuals who tried to lose weight in the past year. PMID- 29973041 TI - Hierarchical Carbon Nanotube-Coated Carbon Fiber: Ultra Lightweight, Thin, and Highly Efficient Microwave Absorber. AB - Strong EM wave absorption and lightweight are the foremost important factors that drive the real-world applications of the modern microwave absorbers. This work mainly deals with the design of highly efficient microwave absorbers, where a hierarchical carbon nanotube (CNT) forest is first grown on the carbon fiber (CF) through the catalytic chemical vapor deposition method. The hierarchical carbon nanotube grown on the carbon fiber (CNTCF) is then embedded in the epoxy matrix to synthesize lightweight nanocomposites for their use as efficient microwave absorbers. The morphological study shows that carbon nanotubes (CNTs) self assemble to form a trapping center on the carbon fiber. The electromagnetic characteristics of resultant nanocomposites are investigated exclusively in the X band (8.2-12.4 GHz) using the network analyzer. The synthesized nanocomposites, containing 0.35 and 0.50 wt % CNTCFs, exhibit excellent microwave absorption properties, which could be attributed to the better impedance matching conditions and high dielectric losses. The reflection loss (RL) of -42.0 dB (99.99% absorption) with -10 dB (90% absorption) and -20 dB (99% absorption) bandwidths of 2.7 and 1.16 GHz, respectively, is achieved for 0.35 wt % CNTCF loading at 2.5 mm thickness. The composite with 0.50 wt % CNTCF loading illustrates substantial absorption efficiency with the RL reaching -24.5 dB (99.65% absorption) at 9.8 GHz and -10 dB bandwidth comprising 84.5% of the entire X band. The excellent microwave properties obtained here are primarily due to the electric dipole polarization, interfacial polarization, and unique trapping center. These trapping centers basically induce multiple reflections and scatterings, which attenuate more microwave energy. This investigation opens a new approach for the development of extremely lightweight, small-thickness, and highly efficient microwave absorbers for X-band applications. PMID- 29973040 TI - Immunotherapy in Head and Neck Squamous Cell Cancer. AB - Prognosis in relapsed metastatic head and neck squamous cell cancer (RM-HNSCC) is dismal. Platinum based chemotherapy in combination with Cetuximab is used in first-line setting, while no further validated options are available at progression. Immunotherapy has produced durable clinical benefit in some patients with RM-HNSCC although the premises are several patients are nonresponders. Studies are ongoing to determine predictive factors and the ideal setting/combination of novel immunotherapies. In this paper, we discuss the past and present of immunotherapy in head and neck cancer and provide an up-to-date information regarding the potential ways to improve immunotherapy outcomes in HNSCC. PMID- 29973042 TI - Time-Resolved Measurements of Nitric Oxide, Nitrogen Dioxide, and Nitrous Acid in an Occupied New York Home. AB - Indoor oxidizing capacity in occupied residences is poorly understood. We made simultaneous continuous time-resolved measurements of ozone (O3), nitric oxide (NO), nitrogen dioxide (NO2), and nitrous acid (HONO) for two months in an occupied detached home with gas appliances in Syracuse, NY. Indoor NO and HONO mixing ratios were higher than those outdoors, whereas O3 was much lower (sub ppbv) indoors. Cooking led to peak NO, NO2, and HONO levels 20-100 times greater than background levels; HONO mixing ratios of up to 50 ppbv were measured. Our results suggest that many reported NO2 levels may have a large positive bias due to HONO interference. Nitrous acid, NO2, and NO were removed from indoor air more rapidly than CO2, indicative of reactive removal processes or surface uptake. We measured spectral irradiance from sunlight entering the residence through glass doors; hydroxyl radical (OH) production rates of (0.8-10) * 107 molecules cm-3 s 1 were calculated in sunlit areas due to HONO photolysis, in some cases exceeding rates expected from ozone-alkene reactions. Steady-state nitrate radical (NO3) mixing ratios indoors were predicted to be lower than 1.65 * 104 molecules cm-3. This work will help constrain the temporal nature of oxidant concentrations in occupied residences and will improve indoor chemistry models. PMID- 29973043 TI - Highly Sensitive Fluorescence Imaging of Zn2+ and Cu2+ in Living Cells with Signal Amplification Based on Functional DNA Self-Assembly. AB - Intracellular trace Zn2+ and Cu2+ play important roles in the regulation of cell function. Considering the limitations of existing metal ion detection methods regarding sensitivity and applicability to living cells, an amplification strategy based on functional DNA self-assembly under DNAzyme catalysis to improve the sensitivity of intracellular Zn2+ and Cu2+ imaging is reported. In this process, metal ions as cofactor can activate the catalysis of DNAzyme to shear substrate chains, and each broken substrate chain can initiate consecutive hybridizations of hairpin probes (Hx) labeled with fluorophore, which can reflect the information on a single metal ion with multiple fluorophores. The detection limit can reach nearly 80 pM and high-sensitivity fluorescence imaging of intracellular Zn2+ and Cu2+ can be achieved. The results are important for research on cell function regulation associated with trace Zn2+ and Cu2+. This approach is also a new way to improve the sensitivity of other trace metal ion imaging. PMID- 29973044 TI - A Dual-Response Fluorescent Probe for the Detection of Viscosity and H2S and Its Application in Studying Their Cross-Talk Influence in Mitochondria. AB - Intracellular viscosity is an essential microenvironmental parameter and H2S is a critical gaseous signaling molecule, which are both related to various physiological processes. It is reported that the change of viscosity and an imbalance of H2S production in the mitochondria are both associated with overexpression of amyloid betapeptide (Abeta), which is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, to our best knowledge, no fluorescent probe is found for dual detection of mitochondrial viscosity and H2S. Herein, a dual-response fluorescent probe (Mito-VS) is designed and synthesized to monitor the level of viscosity and H2S, respectively. Mito-VS itself is nonfluorescent due to a free intramolecular rotation between dimethylaniline and pyridine. After the increase of viscosity, the rotation is prohibited and an intense red fluorescence is released. Upon the addition of H2S, the probe can react with H2S to form compound 3 and a strong green fluorescence can be observed. Moreover, the probe possesses a good mitochondrion-targeting ability and is applied for imaging the change of viscosity on the red channel and visualizing the variation of exogenous and endogenous H2S concentration on the green channel in mitochondria. Most importantly, the probe is capable of studying the cross-talk influence of viscosity and H2S in mitochondria, which is very beneficial for knowing the pathogenesis of AD. PMID- 29973045 TI - Chemoenzymatic Synthesis of Trehalosamine, an Aminoglycoside Antibiotic and Precursor to Mycobacterial Imaging Probes. AB - Trehalosamine (2-amino-2-deoxy-alpha,alpha-d-trehalose) is an aminoglycoside with antimicrobial activity against Mycobacterium tuberculosis, and it is also a versatile synthetic intermediate used to access imaging probes for mycobacteria. To overcome inefficient chemical synthesis approaches, we report a two-step chemoenzymatic synthesis of trehalosamine that features trehalose synthase (TreT) catalyzed glycosylation as the key transformation. Soluble and recyclable immobilized forms of TreT were successfully employed. We demonstrate that chemoenzymatically synthesized trehalosamine can be elaborated to two complementary imaging probes, which label mycobacteria via distinct pathways. PMID- 29973046 TI - Highly Bright Self-Assembled Copper Nanoclusters: A Novel Photoluminescent Probe for Sensitive Detection of Histamine. AB - In this work, highly photoluminescent (PL) self-assembled copper nanoclusters (Cu NCs) capable of rapid, sensitive, and selective detection of histamine were developed. Cu NCs were synthesized in facile conditions by using 2,3,5,6 tetrafluorothiophenol (TFTP) as both the reducing agent and the protecting ligand, which exhibited intense saffron yellow (590 nm) PL via self-assembled induced emission (SAIE), and the absolute quantum yield (QY) of assembly was as high as 43.0%. The size, electronic states, and morphologies of the assembled nanoribbons were characterized, and the geometric structure and spectral properties of the Cu NCs were investigated by theoretical study. Furthermore, the mechanism of the excellent sensing performance of Cu NCs toward histamine was demonstrated by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), and energy dispersive X ray analysis (EDX). With this sensing system, the amount of histamine in fish, shrimp, and red wine were analyzed, and experiment results verified the application of the sensor. Importantly, the luminescent test strips based on Cu NCs were fabricated for colorimetric detection of histamine in foods. This proposed technique may provide an alternative to traditional methods for histamine detection. PMID- 29973047 TI - Contributions of Condensable Particulate Matter to Atmospheric Organic Aerosol over Japan. AB - Because emission rates of particulate matter (PM) from stationary combustion sources have been measured without dilution or cooling in Japan, condensable PM has not been included in Japanese emission inventories. In this study, we modified an emission inventory to include condensable PM from stationary combustion sources based on the recent emission surveys using a dilution method. As a result, emission rates of organic aerosol (OA) increased by a factor of 7 over Japan. Stationary combustion sources in the industrial and energy sectors became the largest contributors to OA emissions over Japan in the revised estimates (filterable-plus-condensable PM), while road transport and biomass burning were the dominant OA sources in the previous estimate (filterable PM). These results indicate that condensable PM from large combustion sources makes critical contributions to total PM2.5 emissions. Simulated contributions of condensable PM from combustion sources to atmospheric OA drastically increased around urban and industrial areas, including the Kanto region, where OA concentrations increased by factors of 2.5-6.1. Consideration of condensable PM from stationary combustion sources improved model estimates of OA in winter but caused overestimation of OA concentrations in summer. Contributions of primary and secondary OA should be further evaluated by comparing with organic tracer measurements. PMID- 29973049 TI - Students and Collaborators of Manuel Yanez and Otilia Mo. PMID- 29973050 TI - Tribute to Manuel Yanez and Otilia Mo. PMID- 29973048 TI - A Ratiometric Fluorescent Bioprobe Based on Carbon Dots and Acridone Derivate for Signal Amplification Detection Exosomal microRNA. AB - Recently, sensitive and selective detection of exosomal microRNAs (miRNAs) has been garnering significant attention, because it is related to many complex diseases, including cancer. Herein, we report a ratiometric fluorescent bioprobe based on DNA-labeled carbon dots (DNA-CDs) and 5,7-dinitro-2-sulfo-acridone (DSA) coupling with the target-catalyzing signal amplification for the detection of exosomal miRNA-21. There was high fluorescence resonance energy transfer (FRET) efficiency between carbon dots (CDs) and DSA when the bioprobe was assembled. However, in the presence of the target, with disassembling of the fluorescent bioprobe, the fluorescence intensities of CDs and DSA were changed simultaneously. Because of the ratio of dual fluorescence intensities, this ratiometric fluorescent bioprobe was able to cancel out environmental fluctuations by calculating emission intensity ratio at two different wavelengths, being robust and stable enough for detection of exosomal miRNA-21. In addition, we displayed that a single miRNA-21 can catalyze the disassembly of multiple CDs with DSA theoretically, yielding significant change in the fluorescence ratio for the detection of miRNA-21. With this signal amplification strategy, the limit of detection was as low as 3.0 fM. Furthermore, because of the introduction of lock nucleic acid to mediate the strand displacement reaction, the selectivity of this strategy was improved remarkably, even against single base mismatch sequence. More importantly, our strategy could monitor the dynamic change of exosomal miRNA-21, which maybe becomes a potential tool to distinguish cancer exosomes and nontumorigenic exosomes. In a short, this ratiometric fluorescence bioprobe possessed high stability, sensitivity and selectivity coupling with ease of operation and cost efficiency, leading to great potential for wide application. PMID- 29973051 TI - Autobiographies of Manuel Yanez and Otilia Mo. PMID- 29973053 TI - Spotlights: Volume 9, Issue 13. PMID- 29973052 TI - Publications of Manuel Yanez and Otilia Mo. PMID- 29973055 TI - The utility of the lumbar puncture in idiopathic intracranial hypertension. PMID- 29973056 TI - The Supervisor's Perceived Role in Employee Well-Being: Results From Mayo Clinic. AB - PURPOSE: Novel approaches are needed to enhance employee well-being and perhaps supervisors can be an effective agent for worksite health promotion. The aim of this study was to examine the supervisor's perceived needs, barriers, and role for influencing employee well-being for incorporation into program development. DESIGN: Semistructured, qualitative interviews of supervisors. SETTING: Large, integrated academic health-care organization with over 30 000 employees and 2600 supervisors having access to comprehensive well-being programs and a successful well-being champion network comprised of 600 champions. PARTICIPANTS: Twenty supervisors representing clinical, research, and administrative units. METHODS: Semistructured, one-on-one interviews were conducted and audio recorded. Analysis included content log development and open coding by a trained analyst to reveal key themes. More formalized content coding using specialized software for qualitative analyses was also conducted. RESULTS: Supervisor responses were wide ranging regarding their perceived and desired role in promoting workplace well being. Barriers from the supervisor perspective included high current workload, ambivalence about promoting wellness, lack of support from leadership, lack of flexibility and control at work, and difficulty accessing on-site resources. They perceived their potential role in well-being as remaining a positive role model and encouraging their staff in wellness activities. CONCLUSION: Although findings are generated from a small sample size, these qualitative data provide compelling and early insights into building a workplace well-being strategy leveraging an underutilized key stakeholder, the workplace supervisor. PMID- 29973057 TI - A qualitative study of barriers and enablers associated with colorectal cancer screening among Somali men in Minnesota. AB - : The rate of cancer screening is generally increasing in the US. In Minnesota, the statewide average rate of screening for colorectal cancer (CRC) is 73%. However, screening completion is relatively low among Somali men; overall, only 27% of Somali immigrants have been screened for CRC. Factors contributing to this disparity have not been well researched. The purpose of this pilot study was to employ focus group methodology to describe and advance understanding of the barriers and enablers associated with CRC screening among Somali men ages 50-74 in Minnesota. Three focus groups were conducted among 27 Somali men in Minnesota. A 9-question, semi-structured interview guide was used. The sessions were audio recorded, transcribed verbatim, and checked for accuracy by research staff prior to data analysis. Three research team members utilized the constant comparative method and NVivo to conduct data analysis. Five barriers to CRC screening emerged from the analyses: (1) lack of knowledge, (2) emotional barriers, (3) acculturation, (4) accountability, and (5) fatalistic beliefs. In addition, two factors enabling CRC screening and prevention emerged: the need for tailored interventions and preventive lifestyle behaviors. The insights gained from this research will assist in developing health promotion and education-focused interventions that encourage Somali immigrants in Minnesota and beyond to seek early detection screening for CRC. ABBREVIATIONS: CRC: Colorectal Cancer; FIT: Fecal Immunochemical Test; FOBT: Fecal Occult Blood Test; FQHC: Federally Qualified Health Center; PA: Project Assistant; PI: Principal Investigator. PMID- 29973059 TI - Incorporation of Quality and Safety Principles in Maintenance of Certification: A Qualitative Analysis of American Board of Medical Specialties Member Boards. AB - Maintenance of Certification (MOC) is one way physicians demonstrate to the public that they are competent to deliver safe, high-quality medical care. The authors conducted a qualitative content analysis of information from 24 Member Boards of the American Board of Medical Specialties. A constant comparative approach was used to categorize themes of quality and safety and related concepts. All Boards (24/24) had public websites with formal documents and 23/24 had at least 1 representative respond to a survey. Sixty-three percent (15/24) of Boards had a patient safety requirement, and 96% (23/24) of Boards had a quality improvement requirement. Nearly all Boards incorporate quality improvement and most incorporate patient safety, but their assessment methods and level of inclusion on the topic vary. Sharing methods of incorporating quality and safety among certifying Boards will allow Member Boards to cater to the evolution of the MOC landscape and benefit from other Boards' experiences. PMID- 29973058 TI - CYP2B6 Genetic Polymorphisms, Depression, and Viral Suppression in Adults Living with HIV Initiating Efavirenz-Containing Antiretroviral Therapy Regimens in Uganda: Pooled Analysis of Two Prospective Studies. AB - Single-nucleotide polymorphisms (SNPs) in CYP2B6 have been shown to predict variation in plasma efavirenz concentrations, but associations between these SNPs and efavirenz-mediated depression and viral suppression are less well described. We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419) in Ugandan persons living with HIV. To define exposure, we used previously published pharmacokinetic modeling data to categorize participants as normal, intermediate, and poor efavirenz metabolizers. Our outcomes were probable depression in the first 2 years after antiretroviral therapy (ART) initiation (mean score of >1.75 on the Hopkins Symptom Depression Checklist) and viral suppression 6 months after ART initiation. We fit generalized estimating equation and modified Poisson regression models adjusted for demographic, clinical, and psychosocial characteristics with or without individuals with depression at the time of ART initiation. Among 242 participants, there were no differences in the pre-ART depression or viral load by efavirenz metabolism strata (p > .05). Participants were classified as normal (32%), intermediate (50%), and poor (18%) metabolizers. Seven percent (56/242) of follow-up visits met criteria for depression. Eighty five percent (167/202) of participants who completed a 6-month visit achieved viral suppression. CYP2B6 metabolizer strata did not have a statistically significant association with either depression [adjusted risk ratio (aRR) comparing intermediate or poor vs. normal, 1.46; 95% confidence interval (CI), 0.72-2.95] or 6-month viral suppression (aRR, 1.01; 95% CI, 0.88-1.15). However, in analyses restricted to participants without pre-ART depression, poorer CYP2B6 metabolism was associated with increased odds of depression (adjusted odds ratio, 4.11; 95% CI, 1.04-16.20). Efavirenz-metabolizing allele patterns are strongly associated with risk of incident depression. Future work should elucidate further region-specific gene-environment interactions and whether alternate polymorphisms may be associated with efavirenz metabolism. PMID- 29973060 TI - Measurement Invariance of the Modified Yale Food Addiction Scale 2.0 Across Gender and Racial Groups. AB - OBJECTIVE: Food addiction reflects a substance use disorder framework, suggesting certain foods (e.g., high-fat, high-sugar foods) may trigger an addictive-like eating response in vulnerable individuals. This study explored whether the Modified Yale Food Addiction Scale 2.0 (mYFAS 2.0), a newly validated and shortened measure of food addiction, is appropriate for use in heterogeneous samples. Assessment of mYFAS 2.0 invariance is essential, as this measure was developed for use as a brief screener in large epidemiological samples that are likely demographically diverse. METHOD: Multigroup confirmatory factor analysis examined measurement invariance across racial/ethnic (White, Black, and Hispanic) and gender (male, female) groups. Participants were recruited through Qualtrics qBus, which uses demographic quotas to recruit a sample representative of the U.S. census reference population. Individuals were included in analyses if they identified their race/ethnicity as White, Black, or Hispanic ( N = 923). RESULTS: Results supported full and partial measurement invariance across racial and gender groups, respectively. DISCUSSION: Results increase confidence in the generalizability of findings using the mYFAS 2.0 and indicate that observed differences in prevalence rates, such as the higher rates of food addiction observed for women and Hispanic individuals, are likely due to true differences in the population rather than due to measurement bias. PMID- 29973061 TI - Corrigendum. PMID- 29973062 TI - The participation of people with dementia in the planning of their care and support: An integrative literature review. AB - Background People with dementia continue to voice concerns that health professionals are reluctant to engage with them about the planning of their care and support. Instead, their perspective is that such plans are often made by others and fail to reflect their wishes. Objective This review aimed to examine investigations of the participation of people living with dementia in the planning of their care and support, when they have also provided study data. Methods An integrative literature review was conducted to identify, critique, and synthesise relevant research findings. Eight electronic databases were searched to identify peer reviewed journal articles that met inclusion criteria. In addition, reference lists of included articles were searched, and a subject expert was consulted about any possible omissions. Results From the 346 articles accessed, seven met inclusion criteria for review. The quality appraisal showed that one article reported only pilot data; several more reported small sample sizes; and, in two instances, there was a lack of information about the psychometric properties of data collection tools and about recruitment and attrition rates. Conclusions There has been limited investigation of the participation of people with dementia in the planning of their support when they have also contributed research data. Findings provide some evidence of their participation by attending education programme, setting goals in cognitive rehabilitation therapy and contributing to advance care planning. PMID- 29973063 TI - The use of smartphones for wayfinding by people with mild dementia. AB - The aim of this study was to explore the acceptability, feasibility and usability of older people with mild dementia to use smartphone for wayfinding. Thirty cognitively normal older people and 16 people with mild dementia were recruited to participate in a wayfinding trial in the free-living environment. Five feasibility and three acceptability markers were compared between the groups. Content analysis on the video-recorded trial processes and individual interviews was employed to identify the usability issues. The results found that there were no significant between-group differences on the feasibility markers, except that the people with mild dementia needed significantly more time to complete the wayfinding trial and workshop; or on the acceptability items. Sensory/cognitive impairment and GPS signal reliability affected their usability. Mild dementia does not limit the older people to use smartphones for wayfinding in the free living environment. Future studies should examine the efficacy and safety of smartphone to promote outdoor independence of the people with mild dementia. PMID- 29973064 TI - "Cancer is in style": lifestyle change and the perceived impact of globalization on Andean indigenous communities in Ecuador. AB - INTRODUCTION: There is a paucity of information on cancer among Indigenous populations in Latin America. METHODS: Guided by tenets of community engaged research and syndemic theory, we conducted eight focus groups (n = 59) with Kichwa men and women in the province of Imbabura, Ecuador. Data were analyzed using applied thematic analysis techniques. RESULTS: Cancer emerged as an important health problem and was reported as a growing concern. Kichwa participants in this study attributed the rise in cancer to (1) exposure to chemicals and pesticides, (2) urbanization and development, and (3) the rise of innutritious, westernized diets. CONCLUSION: Our findings suggest that the Kichwa are attuned to the global phenomena in which traditional diet has been replaced by western, processed foods and fast food, which result in higher levels of chronic diseases such as cancer. More research is needed to understand the cancer burden among Indigenous peoples in Latin America. PMID- 29973065 TI - Frequent Indoor Tanners' Beliefs About Indoor Tanning and Cessation. AB - PURPOSE: Indoor tanning is associated with an increased risk of developing skin cancer. In the United States, nearly 1 in 5 white women aged 18 to 25 are indoor tanners. This study elicited beliefs about tanning indoors and quitting/cutting back on indoor tanning. DESIGN: Semi-structured interviews. PARTICIPANTS AND SETTING: Forty 18- to 25-year-old white females who engaged in frequent indoor tanning participated in either in-person or telephone interviews. Most were college students from southeastern Pennsylvania and Delaware. METHOD: A semi structured interview was used to elicit beliefs about indoor tanning and quitting or cutting back. Data analyses using NVivo and multiple coders identified key themes about going and quitting/cutting back on indoor tanning. RESULTS: Key themes stated as reasons for indoor tanning included improving physical appearance, social acceptance, increased confidence, and happiness. The main themes identified as advantages of quitting/cutting back on indoor tanning were to decrease skin cancer risk and save money. Perceived disadvantages of quitting/cutting back included themes of concerns about being pale and a decline in self-confidence. The prospect of saving money and warm weather were seen as facilitating quitting/cutting back. CONCLUSION: Findings suggest the necessity of addressing appearance concerns, psychological benefits associated with feeling more attractive, and short-term gains such as saving money. These findings provide a foundation for developing effective anti-indoor tanning communication. PMID- 29973066 TI - Health-Care Provider Personal Religious Preferences and Their Perspectives on Advance Care Planning With Patients. AB - OBJECTIVE:: To understand how health-care providers' (HCPs) religious preferences influence their willingness to undertake advance care planning (ACP) with patients and their acceptance of other HCP's involvement. METHODS:: Online anonymous survey distributed to HCPs in hospital, ambulatory offices, and hospice settings in Dayton, Ohio. We evaluated the associations of HCP religion with their personal ACP, willingness to facilitate ACP, and acceptance of other HCPs' ACP participation. RESULTS:: 704 respondents: nurses (66.2%), physicians (18.8%), other HCPs (15.0%), white (88.9%), and primarily Catholic (23.3%) or Protestant (32.0%). "No religion" was marked by 13.9%. Respondents were favorable to ACP with patients. Religious respondents were more likely to have a living will ( P = .035) and health-care power of attorney ( P = .007) and more accepting of clergy as ACP decision coaches ( P = .030). HCP's religion was not associated with willingness to facilitate ACP discussions. There were minor differences between Catholics and Protestants. CONCLUSIONS:: Personal religious preference is associated with HCP's own ACP but had little relationship with their willingness to facilitate ACP conversations with patients or acceptance of other professional types of HCPs involvement in ACP conversations. Regardless of religious affiliation, HCPs have interest in undertaking ACP and endorse other HCPs ACP involvement. As results of this study suggest that personal religious affiliation is not a barrier for HCPs engaging in ACP with patients, attempts to overcome barriers to increasing ACP should be directed to other factors. PMID- 29973067 TI - Changes in Urinary Tract Infection Hospitalizations Post 2011 Revised American Academy Pediatrics Guidelines. AB - BACKGROUND: Multiple randomized trials over the past 2 decades have supported oral antimicrobial treatment for urinary tract infection (UTI), and the 2011 revised American Academy Pediatrics guidelines on the management of UTI provide further support for outpatient management. It is unknown whether practice patterns have changed as a result of these developments. OBJECTIVE: To examine temporal trends in UTI hospitalizations between 1997 and 2012 as measured by the Kids' Inpatient Database. DESIGN AND METHODS: The Kid's Inpatient Database was used to analyze trends in UTI hospitalizations between 1997 and 2012. This triennial database is publicly available through the Agency for Healthcare Research and Quality. Hospitalization volume for clinical classification software principal diagnosis category 159 Urinary tract infection was examined for trends across years by age. Changes in length of stay and charges corrected for inflation were also examined. RESULTS: There were significantly fewer weighted UTI hospitalizations in 2012 compared with 1997 to 2009 (48 102 SE +/- 1494 in 2009 vs 41 177 SE +/- 1467 in 2012, P < .0001). The largest decrease was in 15- to 17-year-old (19.2%) and <1-year-old (18.6%) groups. The length of stay trended down consistently, but charges have increased despite correcting for consumer price index. CONCLUSIONS: Year 2012 represents the first significant decrease in national hospitalization rates for UTI since 1997, a trend that may be explained by the accumulating evidence supporting outpatient management in addition to recommendations from the 2011 American Academy of Pediatrics UTI guidelines. PMID- 29973068 TI - Comparative study of visual outcome between open- and closed-globe injuries following surgical treatment of traumatic cataract in children. AB - OBJECTIVE: To compare final visual outcomes of surgically treated traumatic cataract between open-globe and closed-globe injuries in children, as classified by the Birmingham Eye Trauma Terminology system. METHODS: This is an observational cohort study with permission from Hospital Ethical Committee. We enrolled children meeting specific inclusion criteria, examined their eyes to review any co-morbidities due to trauma, performed surgery for traumatic cataracts, and implanted lenses. The patients were re-examined postoperatively. We classified the cases of traumatic cataract as either open-globe (Group 1) or closed-globe (Group 2) according to the Birmingham Eye Trauma Terminology system and compared visual acuity. RESULT: Our study cohort of 1076 eyes with traumatic cataracts included 405 eyes in Group 1 and 671 in Group 2. Postoperatively, the visual acuity was >20/60 in 223 (55.3%) and 377 (56.3%) operated eyes in Groups 1 and 2, respectively ( p < 0.001, analysis of variance). With further follow-up, >20/60 vision was significantly higher in Group 2 as compared to Group 1 (odds ratio = 1.61; 95% confidence interval = 0.85-3.02). Overall, 600 eyes (55.7%) regained final visual acuity >20/60. CONCLUSION: Closed-globe injury has more favourable prognosis for the satisfactory (>20/60) visual recovery after effective management of traumatic cataracts in children. PMID- 29973069 TI - Crystalline lens endocapsular fragmentation using an elastic loop filament. AB - PURPOSE: To describe a novel mechanical endocapsular fragmentation technique of the crystalline lens during cataract surgery using a loop elastic-thin filament. METHODS: An alternative method to mechanically fragment the crystalline lens utilizing a nitinol loop is described. This device achieves lens sectioning in multiple pieces, decreasing ultrasonic energy expenditure during cataract surgery. RESULTS: Endocapsular fragmentation of crystalline lens was achieved using a nitinol loop filament, without the use of ultrasound energy. CONCLUSION: This surgical technique demonstrates that a micro loop filament may be used as an alternative surgical approach for energy-free mechanical endocapsular nucleus disassembly and fragmentation. PMID- 29973070 TI - Health technology assessment: A primer for ophthalmology. AB - Rising healthcare costs and increasing demands for health care require techniques to choose between competing uses and even rationing of health care. Economic evaluations and health technology assessments are increasingly a means to assess the cost effectiveness of healthcare interventions so as to inform such resource allocation decisions. To date, the adoption of health technology assessments, as a way of assessing cost effectiveness, in ophthalmology has been slower, relative to their implementation in other specialities. Nevertheless, demands for eye services are increasing due to an ageing population. The prevalence of conditions such as glaucoma, cataract, diabetic eye disease and age-related macular degeneration increases with age, and it is predicted that global blindness will triple by 2050. So there is a challenge for ophthalmologists to ensure that they can contribute to, interpret, critically evaluate, and use findings from economic evaluations in their clinical practice. To aid this, this article serves as a primer on the use of health technology assessments to assess cost effectiveness using economic evaluation techniques for ophthalmologists. Healthcare systems face many challenges worldwide - changing demographics and evolution of new technologies are only going to intensify. With this in mind, ophthalmology needs to be ready and able to engage with health economists to prepare, interpret, critically evaluate and use findings of economic evaluations and health technology assessments. PMID- 29973071 TI - Stegmann Canal Expander for canaloplasty: A novel technique. AB - INTRODUCTION: The concept of canaloplasty is to increase aqueous egress through all structures that control the aqueous outflow, such as the trabecular meshwork, Schlemm's canal, and collector channels, by viscomodulation and by placing of a suture stent into the canal. Clinical studies show canaloplasty to be safe and efficient in lowering the intraocular pressure; however, proper knotting of the tensioning suture is technically challenging and even impossible if circumferential cannulation cannot be achieved; furthermore, protrusion of the suture stent is a potential lifelong risk. METHODS: The specific design of the Stegmann Canal Expander allows a permanent expansion of the canal and distension of the trabecular meshwork. Two expanders are implanted on either side of the surgically created ostium of Schlemm's canal to treat half of the circumferential outflow system. This article describes the technique step by step, provides the clinician with surgical pearls, and highlights the management of adverse events. RESULTS: Technically, implantation of the Stegmann Canal Expander is simple and does not require a long learning curve, compared to placing and knotting a tensioning suture. Most issues are related to the two-flap dissection technique (deep sclerectomy technique) and not to implantation of the Stegmann Canal Expander. Intraocular pressure reduction without medications to the low teens can be achieved. CONCLUSIONS: The Stegmann Canal Expander is a novel micro-device that has the potential to make canaloplasty a simplified, more controlled, and reproducible surgical procedure. PMID- 29973072 TI - Intraocular pressure variation by pneumatic tonometer before and after phacoemulsification. AB - OBJECTIVE: To evaluate the intraocular pressure variation before and after phacoemulsification through pneumatic tonometry in addition to correlating it with the age, gender, and preoperative intraocular pressure of the patients evaluated. METHODS: This is a cross-sectional observational study. Inclusion criteria were older than 18 years, deep anterior chamber visualized by the slit lamp and estimation of open angle using the Van Herick technique, intraocular pressure less than 21 mmHg, without surgical complications, and without any ocular disease. The intraocular pressure was measured by the pneumatic tonometer. The intraocular pressure assessment was performed at the last consultation before phacoemulsification surgery and 30 days after. RESULTS: A sample of 182 eyes was used. The mean age was 68.41 +/- 10.84 years. Of the patient, 65% were females and 35% were males. The mean intraocular pressure in the preoperative period was 16.0 mmHg (+/-3.3 mmHg) and the mean intraocular pressure in the postoperative period was 13.44 mmHg (+/-3.31 mmHg). There was no correlation between intraocular pressure variations in both eyes (age-matched open angle) and age. There was a statistically significant correlation between the preoperative intraocular pressure value and the intraocular pressure changes in the postoperative period. In the comparison of the intraocular pressure variation between the genders, the female gender presented a statistically significant negative variation. CONCLUSION: We conclude that the cataract surgery is related to the reduction of intraocular pressure in the postoperative period and this reduction is more influenced by its preoperative value. Other studies of high epidemiological impact are needed, which may corroborate that the cataract surgery could directly influence intraocular pressure variation. PMID- 29973073 TI - Is macular pigment optical density really involved in fixation preference? AB - PURPOSE: To evaluate macular pigment optical density in healthy children and to compare the values with those of strabismic children with respect to fixation preference. METHODS: The study recruited 54 healthy and 41 strabismic children. Two groups were matched in terms of gestational age, birth weight, and body mass index. All participants underwent complete ophthalmological evaluation and macular pigment optical density measurement and filled a self-reported food frequency questionnaire. Strabismic children were categorized according to fixation preference. RESULTS: The mean age was 9.87 +/- 2.39 years in healthy children and 9.07 +/- 2.07 years in children with strabismus (p = 0.091). Mean macular pigment optical density was 0.23 +/- 0.25 in healthy eyes and 0.25 +/- 0.27 in non-preferred eyes of strabismic children (p = 0.964). Macular pigment optical density was significantly higher in preferred eyes of strabismic children (0.43 +/- 0.34) compared to non-preferred eyes (p = 0.004) and healthy eyes (p = 0.001). There was a difference of macular pigment optical density between both eyes in patients with grades 1, 2, and 3 fixation preference, whereas patients with grade 4 preference had similar macular pigment optical density in both eyes (p = 0.008). There was a statistically significant positive correlation between macular pigment optical density in preferred eyes and body mass index (r = 0.354, p = 0.023). CONCLUSION: Preferred eyes of children with strabismus seem to have higher macular pigment optical density readings. This difference may emerge from the higher tendency of recognizing the flicker stimulus while preferred eye is under testing. Similar macular pigment optical density in healthy and non preferred eyes and the fact that both lower than preferred eyes remain unexplained. It should be kept in mind that macular pigment optical density results should be carefully interpreted and macular pigment optical density in cases with strabismus should be further investigated. PMID- 29973074 TI - One-port vitreous cavity lavage with hybrid 27G infusion and 23G cannula. AB - PURPOSE: To describe a new surgical technique for performing vitreous cavity lavage. METHODS: After a 23G trocar cannula was inserted into the vitreous cavity at the lowest point of the eyeball 3.5 or 4 mm posterior to the limbus, a 27G infusion line with balanced salt solution was attached to the cannula. The infusion tube was partially withdrawn and the vitreous fluid with blood flowed out through the space between the larger lumen of the cannula and the smaller infusion tube. Meanwhile, vitreous cavity was irrigated with fresh balanced salt solution through the infusion line and the intraocular pressure (IOP) was maintained. The vitreous clarity was checked by indirect ophthalmoscopy. RESULTS: A total of 14 eyes of 14 patients with postvitrectomy hemorrhage were treated with the lavage technique. The vision improved and the fundus could be sufficiently viewed next day in all cases. This fluid/fluid exchange procedure was also performed in fluid/air exchange in two cases of unclosed idiopathic macular hole with switching to air infusion instead of balanced salt solution infusion. CONCLUSION: This minimally invasive technique is a simple, safe, and efficient way of performing postvitrectomy vitreous cavity fluid/fluid or fluid/air exchange. PMID- 29973075 TI - Prediction of surgically induced astigmatism in manual and femtosecond laser assisted clear corneal incisions. AB - PURPOSE: To assess the surgically induced astigmatism with femtosecond laser assisted and manual temporal clear corneal incisions and to evaluate the performance of a model for prediction of the surgically induced astigmatism based on the preoperative corneal astigmatism. METHODS: Clinical data of 104 right eyes and 104 left eyes undergoing cataract surgery, 52 with manual incisions and 52 with femtosecond laser-assisted incisions in each eye group, were extracted and revised retrospectively. In all cases, manual incisions were 2.2 mm width and femtosecond incisions were 2.5 mm width, both at temporal location. A predictive model of the surgically induced astigmatism was obtained by means of simple linear regression analyses. RESULTS: Mean surgically induced astigmatisms for right eyes were 0.14D@65 degrees (manual) and 0.24D@92 degrees (femtosecond) (p > 0.05) and for left eyes, 0.15D@101 degrees (manual) and 0.19D@104 degrees (femtosecond) (p > 0.05). The orthogonal components of the surgically induced astigmatism (XSIA, YSIA) were significantly correlated (p < 0.05) with the preoperative orthogonal components of corneal astigmatism (Xpreop, Ypreop) (r = 0.29 for X and r = -0.1 for Y). The preoperative astigmatism explained 8% of the variability of the XSIA and 3% of the variability of YSIA. The postoperative corneal astigmatism prediction was not improved by the surgically induced astigmatism obtained from the model in comparison with the simple vector subtraction of the mean surgically induced astigmatism. CONCLUSION: Temporal incisions induce similar astigmatism either for manual or for femtosecond procedures. This can be clinically negligible for being considered for toric intraocular lens calculation due to the great standard deviation in comparison with the mean. The usefulness of the prediction model should be confirmed in patients with high preoperative corneal astigmatism. PMID- 29973076 TI - The influence of South Asian ethnicity on the incremental shuttle walk test in UK adults. AB - The objective of this study was to compare incremental shuttle walking test (ISWT) performance between South Asian and Caucasian British adults, identify predictors of ISWT distance and produce ethnicity-specific reference equations. Data from a mixed gender sample aged 40-75 years from Leicestershire, United Kingdom, were selected for analyses. Analysis of covariance determined differences in ISWT performance between South Asian and Caucasian British ethnic groups. Linear regressions identified predictors of ISWT distance, which determined the reference equations. In total, 144 participants took part in the study (79 South Asian (54 +/- 8 years, 71% female) and 65 Caucasian British (58 +/- 9 years, 74% female)). Distance walked for the ISWT was shorter for South Asian individuals compared with Caucasian British (451 +/- 143 vs. 575 +/- 180 m, p < 0.001). The ethnicity-specific reference equations for ISWT distance explained 33-50% of the variance (standard error of the estimate (SEE): 107-119 m) for South Asians and explained 14-58% of the variance (SEE: 121-169 m) for Caucasian British. Ethnicity univariately explained 12.9% of the variance in ISWT distance and was significantly associated with ISWT distance after controlling for age, gender, height, weight, dyspnoea and lung function ( B = -70.37; 1 = Caucasian British, 2 = South Asian), uniquely explaining 3.7% of the variance. Predicted values for ISWT performance were lower in South Asian people than in Caucasian British. Ethnicity-specific reference equations should account for this. PMID- 29973078 TI - Heptapeptide-based modification leading to enhancing the action of MTCA on activated platelets, P-selectin, GPIIb/IIIa. AB - AIM: The modification of platelet inhibitor to enhance its targeting capacity toward platelets is of clinical importance. Thus, (1R, 3S)-1-methyl-1, 2, 3, 4 tetrahydro-beta-carboline-3-carboxylic acid (MTCA), a platelet inhibitor, was modified with Lys(Pro-Ala-Lys)-Arg-Gly-Asp-Val (KKV), platelet targeting peptide, to form MTCA-KKV. MATERIALS & METHODS: MTCA and MTCA-KKV were synthesized to identify the effect of KKV modification on MTCA and platelets. RESULTS: Atomic force microscopy imaged MTCA-KKV effectively accumulated on activated platelets. UV spectra showed that MTCA-KKV concentration dependently changed P-selectin and GPIIb/IIIa conformations. For platelet aggregation, the IC50 of MTCA-KKV was approximately 1/10 folds of MTCA. CONCLUSION: KKV modification led to forming MTCA-KKV that is superior to MTCA in terms of accumulating on activated platelets, targeting P-selectin and GPIIb/IIIa and inhibiting platelet aggregation. MTCA-KKV could be a promising lead for further investigation. PMID- 29973079 TI - Predictive factors for intensive birth resuscitation in a developing-country: a 5 year, single-center study. AB - OBJECTIVE: To identify risk factors outlined in the International Liaison Committee on Resuscitation (ILCOR) 2010 guideline and requirement for high intensity resuscitation. STUDY DESIGN: A retrospective cross-sectional study of infants born to high-risk mothers from 2011 to 2015. RESULTS: Totally 11,446 infants were analyzed; 37% were preterm, 36% were low-birth weight infants or less. 1506 infants required respiratory support; 82 (0.7%) and 61 (0.5%) infants needed chest compression and/or epinephrine. Very-preterm infants received more intensive resuscitation than moderate preterm or term infants. Breech presentation, maternal infection and maternal diabetes were significantly associated with need for respiratory support. Fetal anomalies, breech presentation, oligohydramnios, and multiple gestation were significantly associated with need for hemodynamic support. CONCLUSION: Most infants defined in the ILCOR 2010 guideline required nonintensive ventilation. Very-preterm infants, fetal anomalies, and breech presentation necessitate neonatal attendance at delivery. In developing countries, maternal infection and diabetes remain high risk criteria despite deletion from the ILCOR 2016 guideline. PMID- 29973081 TI - In vivo evaluation of the new PHIL low viscosity in a swine rete mirabile model. AB - INTRODUCTION: Few liquid embolic materials are available for treatment of arteriovenous malformations. We describe the in vivo experience with the new PHIL low viscosity (LV) liquid embolic agent in a swine rete mirabile model. METHODS: Eight swine were treated. Two animals underwent embolization of a rete with PHIL LV and the contralateral rete with Squid 12 (euthanized the same day). Six animals underwent embolization of the right rete: two with balloon flow arrest (euthanized at 14 d) and four with a microcatheter alone (euthanized at 14 and 90 d). Performance characteristics of the embolic agents were evaluated. Microscopic and histological analysis of the harvested retia was performed. Macroscopic examinations and high contrast digital-based radiographs of the central nervous system were obtained. RESULTS: We did not experience any technical complication during embolization of each rete. Overall occlusion ability, on/off injection and ease to retrieve the microcatheter/balloon with PHIL LV were optimal. Fluoroscopic visualization of the PHIL LV cast was adequate to optimal. Average embolization time with flow arrest was 9.5 min versus 19.5 min with microcatheter plugging. Embolizations with PHIL LV required less volume and were shorter when compared to Squid 12. Subacute (14 d) and chronic (90 d) microscopic and histological analysis demonstrated minimal inflammatory changes in the perivascular tissues and permanent occlusion of the embolized vasculature. CONCLUSION: In this swine rete model, the new PHIL LV embolic agent had an excellent embolization performance. Vessels embolized remained occluded up to 90 d from the procedure with minimal inflammatory changes. PMID- 29973082 TI - Rete mirabile of posterior inferior cerebellar artery: A rare cause of subarachnoid hemorrhage. AB - Rete mirabile is a congenital aberrant arterial collateral network resulting from abnormal embryonic activity during native vessel formation. Even though frequently observed in mammals, this entity is rare in humans except when there is hypoplasia, aplasia or narrowing of native vessels. Rete mirabile is reported involving internal carotid and vertebral arteries. Rete mirabile of the posterior inferior cerebellar artery (PICA) is not described in the literature. We report the clinical presentation, imaging findings and management of PICA rete mirabile formation with subarachnoid hemorrhage. PMID- 29973080 TI - Methoxychlor metabolite HPTE alters viability and differentiation of embryonic thymocytes from C57BL/6 mice. AB - Endocrine-disrupting chemicals (EDC) are widespread in the built and natural environments. Heightened public awareness of their potential danger has led to concern about whether EDC and their metabolites have significant negative biological effects. Studies have shown that EDC like DDT and other organochlorine pesticides, such as methoxychlor (MXC), have adverse effects on immune cells, but no studies have addressed the impact of HPTE, the primary metabolite of MXC. To elucidate the presence and significance of HPTE adverse effects, this study explored the impact of HPTE on a critical window and component of immune system development, embryonic T-cell development. Lesions at this phase of development can lead to lifelong immune dysfunction and increased incidence of immune disease, such as autoimmunity. Embry-onic thymocytes (GD 16-18) from C57BL/6 mice were subjected to an in vitro differentiation culture that mimicked early steps in thymocyte development in the presence of 0.005, 0.05, 0.5, 5, or 50 MUM HPTE, or a model endocrine disruptor, DES. The results indicated that compared to the vehicle control, HPTE- and DES-induced death of thymocytes. Annexin-V staining and Caspase 8, markers of programed cell death, revealed that the loss of cells was due at least in part to induction of apoptosis. Moreover, HPTE-induced cell death not only resulted in selective loss of double positive thymocytes, but also loss of developing CD4 intermediate cells (post-double positive partially differentiated thymocyte population). Phenotypic analysis of thymocyte maturation (T-cell receptor, TCR) and TCR ligation (CD5) surface markers revealed that surviving embryonic thymocytes expressed low levels of both. Taken together these data demonstrate that immature embryonic thymocytes are sensitive to HPTE exposure and that HPTE exposure targets thymocyte populations undergoing critical differentiation steps. These findings suggest HPTE may play a pivotal role in MXC exposure-induced immune dysfunction. PMID- 29973077 TI - Imaging of pancreatic neuroendocrine tumors: recent advances, current status, and controversies. AB - INTRODUCTION: Recently, there have been a number of advances in imaging pancreatic neuroendocrine tumors (panNETs), as well as other neuroendocrine tumors (NETs), which have had a profound effect on the management and treatment of these patients, but in some cases are also associated with controversies. Areas covered: These advances are the result of numerous studies attempting to better define the roles of both cross-sectional imaging, endoscopic ultrasound, with or without fine-needle aspiration, and molecular imaging in both sporadic and inherited panNET syndromes; the increased attempt to develop imaging parameters that correlate with tumor classification or have prognostic value; the rapidly increasing use of molecular imaging in these tumors and the attempt to develop imaging parameters that correlate with treatment/outcome results. Each of these areas and the associated controversies are reviewed. Expert commentary: There have been numerous advances in all aspects of the imaging of panNETs, as well as other NETs, in the last few years. The advances are leading to expanded roles of imaging in the management of these patients and the results being seen in panNETs/GI-NETs with these newer techniques are already being used in more common tumors. PMID- 29973083 TI - Imaging artifacts of Onyx and PHIL on conventional CT, cone-beam CT and MRI in an animal model. AB - BACKGROUND AND PURPOSE: A frequently reported drawback of ethylene vinyl alcohol copolymer-based liquid embolic agents is the production of artifacts in diagnostic imaging. New embolic agents, such as Precipitating hydrophobic injectable liquid (PHIL; MicroVention, Tustin, CA, USA), are supposed to induce significantly fewer artifacts. The purpose of this study is to assess the degree of artifacts induced by the liquid embolic agents Onyx (Medtronic Neurovascular, Irvine, CA, USA) and PHIL in conventional computed tomography (CT), cone-beam CT and magnetic resonance imaging (MRI) in an experimental in vivo model. MATERIALS AND METHODS: In 10 pigs the rete mirabile was embolized with Onyx ( n = 5) or PHIL ( n = 5). After embolization, conventional CT, cone-beam CT and MRI were performed. The degree of artifacts was graded qualitatively (five-point scale; for CT and MRI) and quantitatively (HUs of well-defined regions of interest (ROIs); for CT only). RESULTS: Artifacts were significantly more severe for Onyx both in the qualitative (e.g. conventional CT: 2 versus 5 (medians); p = 0.008) and in the quantitative image analysis (e.g. cone-beam CT: standard deviation of a ROI near to the embolic agent cast, 94 HU versus 38 HU (medians); p = 0.008). Neither Onyx nor PHIL produced any apparent artifacts in MRI. CONCLUSION: PHIL produces fewer artifacts than Onyx in conventional CT and cone-beam CT in an experimental in vivo model. PMID- 29973084 TI - The effect of two different speed endurance training protocols on a multiple shuttle run performance in young elite male soccer players. AB - There is not enough evidence on the impact of different speed endurance training regimes on footballers' ability to perform multiple shuttle run performance. This study examined the effect of 4 weeks of speed endurance maintenance (SEM) and speed endurance production (SEP) training on the 5-meter multiple shuttle run test (5-m MST) performance in young elite soccer players. A parallel two-groups, longitudinal design was used. Fifteen players were divided to either SEM (8 repetitions of 20-s all-out sprint interspersed with 40 s of recovery) or SEP (8 repetitions of 20-s all-out bout interspersed with 120 s of recovery) training group. SEM improved the ability to tolerate fatigue and maintained the performance development during the 5-m MST while SEP increased only the 1st sprint showing, simultaneously, an increased fatigue index and performance decrement. The selection of which training regimes to prioritize should be based on the players' characteristics and individual game requirements Abbreviations: SEP: Speed Endurance Production; SEM: Speed Endurance Maintenance; PRE: Baseline; POST: End of experimental protocol; 5-m MST: 5-meters Multiple Shuttle Run Test; TD: Total Distance; FI: Fatigue Index; MSTdec: Percentage Decrement Score; BMI: Body Mass Index. PMID- 29973085 TI - Abdominal computed tomography (CT) scan in the evaluation of refractory puerperal fever: impact on management. AB - INTRODUCTION: Computed tomography (CT) imaging should be employed judiciously, given its cost, use of intravenous contrast, and ionizing radiation. The aim of this study was to determine the clinical benefit of a CT scan in the evaluation of refractory puerperal fever and to identify the appropriate candidates for its use. METHODS: This was a retrospective cohort study conducted in a single tertiary care center between January 2007 to April 2017. Indications for CT scan were refractory postpartum fever of >=3 days and/or ultrasound findings suggesting complex abdominal fluid collection. Primary outcome was defined as a change in the mode of treatment due to the CT findings. In addition, a multivariate analysis of risk factors for puerperal fever was performed to identify patients who would benefit from the CT scan evaluation. RESULTS: There were 520 women that underwent an abdominal and pelvic CT scan during the study period, 238 (45.7%) met inclusion criteria, 94 (39.5%) had a normal CT scan, and 144 (60.5%) had abnormal findings including 32 (13.4%) cases with pelvic thrombophlebitis and 112 (47%) cases with pelvic fluid collections. Results of the CT changed clinical management in 93 (39.0%) patients, including: switching antibiotics in 24 (10%) patients, adding low molecular weight heparin for 28 (11.8%) patients, and surgical intervention (laparotomy or drainage insertion) in 41 (17.2%) patients. In the regression model, we didn't find any significant risk factors associated with treatment change following the CT scan. CONCLUSIONS: Abdominal and pelvic CT scan in women with refractory puerperal fever has a high clinical yield and lead to a change in management in a substantial number of patients. PMID- 29973086 TI - Cognitive performance and self-reported sleepiness are modulated by time-of-day during a mountain ultramarathon. AB - Ninety-two runners completed the study during a 168 km mountain ultramarathon (MUM). Sleepiness, self-reported sleep duration, and cognitive performance were assessed the day before the race and up to eight checkpoints during the race. Sleepiness was assessed using the Karolinska Sleepiness Scale. Cognitive performance was also assessed using the Digital Symbol Substitution Task (DSST). Runner reported 23.40 +/- 22.20 minutes of sleep (mean +/- SD) during the race (race time: 29.38 to 46.20 hours). Sleepiness and cognitive performance decrements increased across this race, and this was modulated by time-of-day with higher sleepiness and greater performance decrements occurring during the early morning hours. Runners who slept on the course prior to testing had poorer cognitive performance, which may suggest that naps on the course were taken due to extreme exertion. This study provides evidence that cognitive performance deficits and sleepiness in MUM are sensitive to time into race and time-of-day. PMID- 29973087 TI - Tissue-specific delta13C in ancient and modern tropical seabirds and flying fish in the Xisha Islands, South China Sea. AB - We analyzed 13C characteristics in samples of bird bones, feathers, eggshell carbonate and membrane from modern specimens of red-footed booby (Sula sula) as well as fish muscle, scales, and bones from its predominant food source, flying fish (Exocoetus volitans), and muscle from its secondary food source squid (Loligo chinensis), as well as in ancient sub-fossil samples of seabird and flying fish at the Xisha Islands, South China Sea. delta13C is tissue-specific in both seabirds and flying fish due to the variance in turn-over among the tissues and differences in the type and content of amino acids across a diverse range of tissues. The delta13C discrimination factors also differed significantly among the various tissues between tropical seabirds and their prey. A Suess effect, caused by fossil fuel combustion and the emission of carbon with fewer 13C isotopes, was observed in the bird and fish tissue from ancient to modern time. Our study provides a multiple variability index for delta13C in organisms along a food chain, and verifies that tissue-specific 13C analysis is essential to identify diet and species and thus is a valuable tool for research on tropical seabird ecology. PMID- 29973088 TI - High prevalence of widespread pain in women with early rheumatoid arthritis. AB - OBJECTIVES: The aim of the study was to determine the prevalence of widespread pain (WP) in women with early rheumatoid arthritis (RA) and to compare physical function, activity limitations, health-related quality of life, mental distress, and disease activity between women with WP and non-widespread pain (NWP). METHOD: This cross-sectional study included 102 women with early RA. Participants were provided with self-reported questionnaires quantifying activity limitations, physical activity, pain intensity, health-related quality of life, and fatigue. Hand-grip force, muscle function test of the lower extremities, erythrocyte sedimentation rate, and number of tender and swollen joints were assessed. RESULTS: One-third (35.9%) of the women fulfilled the American College of Rheumatology criteria for WP 20 months after disease onset. Women with RA + WP had significantly higher 28-joint Disease Activity Score (DAS28) (p = 0.004), number of tender joints (p = 0.001), pain intensity (p < 0.001), fatigue (p < 0.001), Health Assessment Questionnaire score (p < 0.001), and Hospital Anxiety and Depression Scale - Depression (p = 0.001). Furthermore, women with RA + WP showed significantly worse global health (p < 0.001) and physical health (36-item Short Form Health Survey - Physical Component Summary) (p < 0.001). The hand-grip force was found to be significantly reduced (p = 0.001), as was the muscle function of the lower extremities (p < 0.001), for women with RA + WP compared to women with RA + NWP. After adjustment for inflammatory joint disease, the significant differences between the groups remained. CONCLUSION: A significant group of women with early RA experience WP with a high DAS28 and increased pain intensity level. These women display severe muscle function deficiency in clinical examinations, and report general activity limitations and low psychological and physical health, despite an absence of or low objective signs of inflammation. PMID- 29973089 TI - Biomedical applications of prokaryotic carbonic anhydrases. AB - INTRODUCTION: The hydration/dehydration of CO2 catalyzed by carbonic anhydrases (CAs, EC 4.2.1.1) is a crucial physiological reaction for the survival of all living organisms because it is connected with numerous biosynthetic and biochemical pathways requiring CO2 or HCO3-, such as respiration, photosynthesis, carboxylation reactions, pH homeostasis, secretion of electrolytes, transport of CO2, bicarbonate, etc. Areas covered: The bacterial genome encodes CAs belonging to the alpha-, beta-, and gamma-CA classes able to ensure the survival and/or satisfying the metabolic needs of the bacteria, as demonstrated by in vivo and in vitro experiments. The discovery of new anti-infectives that target new bacterial pathways, such as those involving CAs, may lead to effective therapies against diseases subject to the antibiotic resistance. This aspect is important in pharmaceutical and biomedical research but received little attention till recently. Expert opinion: An overview of the potential use of CAs in biomedical applications, as drug targets, bioindicators, and within artificial organs is presented. The discovery of thermostable bacterial CAs allowed the use of CAs in biotechnological applications, but patents related to the use of bacterial CAs in the development of pharmacological agents are scarce. PMID- 29973090 TI - Effect of batch age on potency and dissolution of levothyroxine sodium tablets: impact of BP and USP monograph differences on dissolution results. AB - Controversies surround levothyroxine sodium as a drug and product, and are reflected in compendia (USP vs BP) differences in levothyroxine sodium tablets specifications concerning potency limit and dissolution test conditions, and in lack of consensus on several issues such as whether the drug BCS class I or III. We have recently published a clinical study in patients comparing the efficacy of multisource 100 mcg levothyroxine sodium tablets (three sources, two brands, a total of five batches). Clinical efficacy and dissolution rate data varied among the tablet batches studied and indicated that brand/source interchangeability could not be claimed. The efficacy parameters showed good correlation with dissolution data generated under BP 2014, but not under USP 2014 dissolution test conditions. In the present study, we decided to expand the number of tablet batches studied in vitro to a total of 12, to report potency and content uniformity data missing in the clinical study, and to further examine the discrepancy in dissolution results based on the medium used. The wide range of batch age in the studied samples allowed investigating the effect of batch age on in-vitro tablet performance parameters. Generated potency values indicated the prevalence of super-potent tablet batches. The dissolution data reflected the effect of compendia monograph differences in dissolution medium. The results also indicated an inverse relationship between tablet potency and batch age and, between dissolution and batch age. The possible effect of potency results on the generated dissolution data was discussed. Statistical significance of correlations examined was assessed by linear and non-linear regression analysis. Statistical significance was evident for the relation between batch age and BP 2014 dissolution data, compared to USP 2014 dissolution results. PMID- 29973091 TI - Evoked potentials in diagnosis of visual dysfunction in amateur boxers. AB - OBJECTIVE: Injuries with varying degrees of temporary or permanent visual dysfunction are common in boxing. This study presents clinical diagnostic information regarding the functional integrity of the visual system in elite amateur boxers. The objective of this study was to assess the presence of normal or abnormal pattern visual evoked potentials (VEP). VEP in boxers were analyzed in relation to the nonathletic group and years of boxing activity. METHODS: Clinical examination involved 31 boxers (21 male and 10 female) and 31 controls homogeneous in terms of age and gender. Pattern-reversal VEP elicited by checkerboard stimuli with large (LC) and small checks (SC) under monocular condition were applied. The latency and amplitude of N75, P100 and N135 components of the VEP waveform were analyzed. Absolute values and interocular differences of P100 latency and N75-P100 amplitude were used in determining VEP abnormalities. RESULTS: Individual analysis showed prolonged P100 latency in both eyes in one male boxer. Interocular P100 latency differences beyond 8 ms were observed in three male boxers. The N75-P100 amplitude of four boxers exceeded the normal range in both eyes for the LC stimulation and one boxer for the SC stimulation. Interocular N75-P100 amplitude differences beyond the normal range in two cases for both the LC and the SC stimulation were confirmed. There was a positive correlation between years of boxing activity and N75 latency in SC (R = 0.480, p < 0.05) and N75-P100 amplitude in LC (R = -0.370, p < 0.05). CONCLUSION: Long-term boxing training may cause impairments in neural conductivity in the visual pathway. VEP seem to be a valuable tool in the neurophysiological diagnosis of visual function in contact sports. They can be recommended as a systematical examination for boxers during training processes for the indication and reduction in the incidence of vision-threatening injuries. PMID- 29973092 TI - Highlighting the need for reliable clinical trials in glioblastoma. AB - INTRODUCTION: Several recent phase III studies have attempted to improve the dismal survival seen in glioblastoma patients, with disappointing results despite prior promising phase II data. Areas covered: A literature review of prior phase II and phase III studied in glioblastoma was performed to help identify possible areas of concern. Numerous issues in previous phase II trials for glioblastoma were found that may have contributed to these discouraging outcomes and discordant results. Expert commentary: These concerns include the improper selection of therapeutics warranting investigation in a phase III trial, suboptimal design of phase II studies (often lacking a control arm), absence of molecular data, the use of imaging criteria as a surrogate endpoint, and a lack of pharmacodynamic testing. Hopefully, by recognizing prior phase II trial limitations that contributed to failed phase III trials, we can adapt quickly to improve our ability to accurately discover survival-prolonging treatments for glioblastoma patients. PMID- 29973093 TI - Cultural Change: Implementation of a Recovery Program in a Veterans Health Administration Medical Center Inpatient Unit. AB - INTRODUCTION: The Freedom Commission's recommendations, Substance Abuse and Mental Health Services Administration's framework, and policy directives on recovery-oriented services have fueled the recovery transformation. Mental health recovery services have been implemented in a broad range of outpatient settings. However, psychiatric inpatient units remained embedded in the traditional model of care. AIMS: The purpose of this article is to describe an ongoing quality improvement implementation of recovery services in a Veterans Health Administration acute psychiatric inpatient unit. METHOD: An interprofessional Partnership for Wellness delivered 4 to 6 hours per day of evidence-based recovery and holistic population-specific health programs. Veteran, system, and program indicators were measured. RESULTS: Preliminary indicators over a 2-year period suggest that Veterans rated group content and relevance high, pre-post psychiatric rehospitalization rates decreased by 46%, and fidelity to recommended strategies was high. CONCLUSIONS: The project success reflects strong leadership, a partnership of committed staff, effective training, and an organizational culture exemplifying excellence in Veteran services and innovation. PMID- 29973094 TI - Intraobserver and interobserver reliability of visible light spectroscopy during upper gastrointestinal endoscopy. AB - BACKGROUND: Visible light spectroscopy (VLS) performed during upper gastrointestinal endoscopy allows measuring mucosal oxygen saturation levels to determine gastrointestinal ischemia. We aimed to determine the observer variability of VLS. METHODS: This is a single-center prospective study of 24 patients planned for usual care upper endoscopy. To test intraobserver variability, VLS measurements were performed in duplicate by a single endoscopist in 12 patients. For interobserver variability analysis, in another 12 patients VLS measurements were repeatedly and independently performed by two endoscopists in the same patient during the same endoscopy session. Observer variability was assessed with intraclass correlation coefficient (ICC) and clinical disagreement defined as >5% difference between first and second set of VLS measurements. RESULTS: The intraobserver reliability was excellent (ICC antrum 0.77, duodenal bulb 0.81 and duodenum 0.84) with clinical disagreement only in antrum (3% of all intraobserver measurements). The interobserver reliability was good for the duodenal bulb (ICC 0.70) without clinical disagreement; however, interobserver reliability was fair for duodenum (ICC 0.49) and antrum (ICC 0.56) with clinical disagreement occurring in 11% of all interobserver measurements. CONCLUSIONS: The observer reliability of VLS is fair to good with intraobserver reliability being better than interobserver reliability. This supports the use of VLS for detection of gastrointestinal ischemia. PMID- 29973095 TI - Is there a role for cardiac magnetic resonance imaging during pregnancy? AB - PURPOSE: To assess the role of cardiac magnetic resonance imaging (CMR) for the evaluation and management of women with cardiac disorders in pregnancy and postpartum. METHODS: Retrospective record review of women at a university affiliated, single institution referred for CMR without contrast due to known or suspected cardiac disorders between January 2010 and December 2015. Medical records, echocardiogram and CMR reports were reviewed. Instances where clinical management was changed based on CMR findings were identified. RESULTS: There were 17 peripartum CMR studies performed without contrast in 17 pregnancies from 16 women. Indications for CMR included congenital heart disease (N = 8, 47.1%), Marfan syndrome or strong family history of Marfan syndrome (N = 5, 29.4%), cardiomyopathy (N = 1, 5.9%), cardiac mass (N = 1, 5.9%), persistent dyspnea with a normal echocardiogram (N = 1, 5.9%), and hypertension with suspected aortic root dilation (N = 1, 5.9%). CMR confirmed the echocardiogram diagnosis in eight (47.1%) and improved the diagnosis in five (29.4%). Availability of CMR findings changed the delivery management in 2/17 (11.8%) women. CMR was especially helpful in assessing the size of the aortic root in women at risk for dilation. CONCLUSIONS: Although echocardiogram imaging of the heart is considered the first line method for assessing the maternal cardiac status, CMR can provide information about cardiac anatomy and function in pregnant women with complex cardiac disease or suspected aortic pathology. Management may be changed based on results. PMID- 29973096 TI - Analysis of chosen polymorphisms rs2476601 a/G - PTPN22, rs1990760 C/T - IFIH1, rs179247 a/G - TSHR in pathogenesis of autoimmune thyroid diseases in children. AB - BACKGROUND: Autoimmune thyroid diseases are multifactorial diseases with a genetic susceptibility and environmental factors. A potential role of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, the interferon-induced helicase domain 1 (IFIH1) gene, the thyroid-stimulating hormone receptor (TSHR) gene polymorphisms on autoimmune thyroid diseases (AITDs) in adults has been established unequivocally, but there is still lack of research articles including group of children. Objective and hypotheses: To estimate the association of polymorphisms of PTPN22, IFIH1 and TSH-R genes with the pre-disposition to Graves' disease (GD) and Hashimoto's thyroiditis (HT) in children. METHODS: The study was performed in 142 patients with GD, 57 with HT and 160 healthy volunteers. The three single-nucleotide polymorphisms (SNPs): rs2476601 - PTPN22, rs1990760 - IFIH1 and rs179247 - TSHR were genotyped by TaqMan SNP genotyping assay using the real-time PCR. RESULTS: Rs2476601 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = .009 with odds ratio [OR] = 2.13). Rs2476601 A alleles were more frequent in patients with HT in comparison to healthy subjects (p = .008, OR = 2.48). Rs1990760 T alleles were more frequent in male patients with GD in comparison to healthy males (p = .003, OR = 3.00). In case of HT patients, rs1990760 T alleles were also more frequent in males compared to healthy subjects (p = .086, OR =2.47). Rs179247 A alleles were more frequent in patients with GD in comparison to healthy subjects (p = 0.039, OR = 1.51). CONCLUSIONS: Rs2476601 A/G, Rs1990760 C/T and Rs179247 A/G polymorphisms could contribute to the development of AITDs in children. The main risk factor for rs2476601 and rs179247 is allele A. In case of rs1990760, the main risk factor is allele T. PMID- 29973097 TI - Eupatilin: a natural pharmacologically active flavone compound with its wide range applications. AB - Eupatilin (5,7-dihydroxy-3',4',6-trimethoxyflavone) is a pharmacologically active flavone which has been isolated from a variety of medicinal plants. Eupatilin is known to possess various pharmacological properties such as anti-cancer, anti oxidant, and anti-inflammatory. It is speculated that eupatilin could be subjected to structural optimization for the synthesis of derivative analogs to reinforce its efficacy, to minimize toxicity, and to optimize absorption profiles, which will ultimately lead towards potent drug candidates. Although, reported data acclaim multiple pharmacological activities of eupatilin but further experimentations on its molecular mechanism of action are yet mandatory to elucidate full spectrum of its pharmacological activities. PMID- 29973098 TI - Propolis emulgel: a natural remedy for burn and wound. AB - OBJECTIVES: To develop an alternative medicine, propolis, in emulgel formulation for burn and wound treatment. METHODS: The effect of two independent variables: emulsifying agent concentration and oil concentration on the cumulative amount of propolis release (dependent variable) from liquid paraffin and isopropyl palmitate emulgels was investigated. Eight formulations were prepared and evaluated for physical appearance, pH, propolis content, viscosity, and in vitro propolis release. The release results were fitted into different kinetic equations and analyzed using contour plot, interaction surface plot and one-way ANOVA. The selected emulgel formulation was investigated for its wound and burn healing activity in rats. RESULTS: All the prepared emulgels showed acceptable physical properties concerning color, homogeneity, consistency, and pH value. The concentration of emulsifying agent had more pronounced effect on propolis release than oil concentration. Formulations F1-F6 showed "anomalous" drug release, while Formulations F7 and F8 showed zero-order kinetic. CONCLUSION: The formulation F7 with 5% isopropyl palmitate, 5% emulsifier mixture, 1% hydroxyl propyl methyl cellulose, 1% oleic acid, and 10% propylene glycol is a promising formula for better management of wound and burn. PMID- 29973099 TI - Acute bone marrow suppression and gastrointestinal toxicity following acute oral methotrexate overdose. AB - OBJECTIVE: Acute methotrexate overdose rarely causes systemic toxicity due to saturable absorption and rapid renal elimination. We present a case of methotrexate toxicity following acute overdose. CASE REPORT: A 56-year-old female presented soon after an overdose of 1250 mg of methotrexate, zopiclone and tramadol. The methotrexate was initially under-reported (500 mg) and folinic acid was not provided. Despite normal renal function, the patient developed toxicity. She represented 5 days following the overdose with mucositis, bone marrow suppression and prolonged febrile neutropenia. Treatment included folinic acid, broad-spectrum antibiotics, filgrastim, red cell and platelet transfusion. Her bone marrow began to recover 12 days following the overdose. She was discharged home on Day 17. DISCUSSION: Severe toxicity following an acute ingestion of a large amount of methotrexate is rarely reported. The development of toxicity was unexpected in this case given methotrexate's pharmacokinetics and the patient's normal renal function. The serum methotrexate concentrations were below the treatment threshold of the folinic acid rescue therapy nomogram suggesting that the nomogram should not be relied on in acute ingestions. Large acute oral methotrexate poisoning can result in systemic toxicity and folinic acid therapy should be provided in ingestions >1000 mg. PMID- 29973100 TI - Editorial Commentary on Gregers et al. PMID- 29973101 TI - Where can obesity management policy make the largest impact? Evaluating sub populations through a microsimulation approach. AB - BACKGROUND: There is a critical need to focus limited resources on sub-groups of patients with obesity where we expect the largest return on investment. This paper identifies patient sub-groups where an investment may result in larger positive economic and health outcomes. METHODS: The baseline population with obesity was derived from a public survey database and divided into sub populations defined by demographics and disease status. In 2016, a validated model was used to simulate the incidence of diabetes, absenteeism, and direct medical cost in five care settings. Research findings were derived from the difference in population outcomes with and without weight loss over 15 years. Modeled weight loss scenarios included initial 5% or 12% reduction in body mass index followed by a gradual weight regain. Additional simulations were conducted to show alternative outcomes from different time courses and maintenance scenarios. RESULTS: Univariate analyses showed that age 45-64, pre-diabetes, female, or obesity class III are independently predictive of larger savings. After considering the correlation between these factors, multivariate analyses projected young females with obesity class I as the optimal sub-group to control obesity-related medical expenditures. In contrast, the population aged 20-35 with obesity class III will yield the best health outcomes. Also, the sub-group aged 45-54 with obesity class I will produce the biggest productivity improvement. Each additional year of weight loss maintained showed increased financial benefits. CONCLUSIONS: This paper studied the heterogeneity between many sub populations affected by obesity and recommended different priorities for decision makers in economic, productivity, and health realms. PMID- 29973102 TI - First-trimester measurements of the three-dimensional ultrasound placental volume and uterine artery Doppler in early- and late-onset fetal growth restriction. AB - OBJECTIVES: To clarify whether early-onset fetal growth restriction (EO-FGR) could be distinguished from late-onset (LO)-FGR using ultrasonographic evaluations of the uterine artery (UtA) Doppler indices and the three-dimensional (3D) ultrasound placental volume (PV) in the first trimester. METHODS: Subjects with 1362 singleton pregnancies who underwent an ultrasound scan at 11-13 weeks were enrolled prospectively. The UtA Doppler and PV indices in cases with EO-FGR (<32 weeks at diagnosis) and LO-FGR (>=32 weeks at diagnosis) later in pregnancy were compared with the control group. RESULTS: Twenty-eight EO-FGR, 73 LO-FGR, and 1261 control groups were analyzed. The crown-rump length (CRL) and PV were smaller in both EO and LO-FGR groups than in the control group. The UtA resistance index (RI) Z-score was significantly higher in the EO-FGR group than in the control group (0.723 versus 0.086, p < .001), but did not differ between LO-FGR and the control group. The area under the receiver operating characteristics curve for the prediction of EO-FGR by combining the uterine artery resistance index (UtA-RI) and CRL was 0.760 (95% CI: 0.654-0.865). The detection rate for EO-FGR was 45.8%, with a 10% false-positive rate. CONCLUSIONS: Both EO- and LO-FGR are associated with a small CRL in the first trimester. High UtA-RI is associated with EO-FGR, while a small maternal height and PV are associated with LO-FGR. PMID- 29973103 TI - Keloid formation after syndactyly release in a patient with macrodactyly - methotrexate treatment. PMID- 29973104 TI - Masculinity and Depression: A Longitudinal Investigation of Multidimensional Masculine Norms Among College Men. AB - The transition from high school to college represents a pivotal developmental period that may result in significant maladjustment for first-year college men. Men may feel pressured to "prove" their masculinity by engaging in traditional masculine behaviors that could be negative for their overall well-being. Although adherence to multidimensional masculine norms has been associated with poorer mental health, no studies have examined the role of masculine norms on prospective depressive symptoms among first-year college men. Examining college men's adherence to multidimensional masculine norms longitudinally can offer a promising theoretical framework to explain within-group variability in depression symptomatology. The sample included 322 men from the Mid-Atlantic region of the United States. Masculine norms were assessed during the beginning of their first year of college. Depressive symptomatology was assessed 6 months after the first wave of data collection. Masculine norms were positively and negatively related to prospective depression scores, such that men who endorsed the masculine norms of Self-Reliance, Playboy (i.e., desire to have multiple sexual partners), and Violence, had heightened risk, whereas men who endorsed Winning and Power Over Women were less likely to report depressive symptomatology. Distinct masculine norms appear to confer risk for depression while other norms appear to be protective. This study was the first to examine the role of multidimensional masculine norms on prospective depressive symptomatology among college men. The results suggest that practitioners working with men should consider assessing their clients' adherence to distinct masculine norms and explore how these might be impacting their current mental health. PMID- 29973105 TI - Preparation, characterization, and in vivo evaluation of nano formulations of ferulic acid in diabetic wound healing. AB - Diabetes mellitus is most common disorder characterize by hyperglycemia. Chronic hyperglycemia may lead to over production of free radicals thereby results in oxidative stress which impaired healing of wounds. Ferulic acid (FA) has been shown to have antidiabetic and antioxidant properties. The aim of the present study was to develop Ferulic acid nanoparticles and to study its hypoglycemic and wound healing activities. Ferulic acid-poly(lactic-co-glycolic acid) (FA-PLGA) nanoparticles were prepared by nano precipitation method. The prepared FA-PLGA nanoparticles had an average size of 240 nm. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) analysis showed the prepared FA-PLGA nanoparticles were spherical in shape. Drug encapsulation assay showed that 88.49% FA was encapsulated in PLGA. Carbopol 980 was used to formulate FA-PLGA nanoparticles loaded hydrogel. FA-loaded polymeric nanoparticles dispersion (oral administration) and FA-loaded polymeric nanoparticles based hydrogel (topical administration) treated wounds were found to epithelize faster as compared with diabetic wound control group. The hydroxyproline content increased significantly when compared with diabetic wound control. Therefore, the results indicate that FA significantly promotes wound healing in diabetic rats. PMID- 29973106 TI - The Effect of Sleep Deprivation on Recognition of Ambiguous Emotional Facial Expressions in Individuals With ADHD. AB - OBJECTIVE: The present study sought to investigate whether young adults with ADHD have more difficulty recognizing emotional facial expressions compared with young adults without ADHD, and whether such a difference worsens following sleep deprivation. METHOD: Thirty-one young men ( M = 25.6) with ( n = 15) or without ( n = 16) a diagnosis of ADHD were included in this study. The participants were instructed to sleep 7 hr or more each night for one week, and their sleep quality was monitored via actigraph. Subsequently, the participants were kept awake in a controlled environment for 30 hr. The participants completed a visual emotional morph task twice-at the beginning and at the end of this period. The task included presentation of interpolated face stimuli ranging from neutral facial expressions to fully emotional facial expressions of anger, sadness, or happiness, allowing for assessment of the intensity threshold for recognizing these facial emotional expressions. RESULTS: Actigraphy data demonstrated that while the nightly sleep duration of the participants with ADHD was similar to that of participants without ADHD, their sleep efficiency was poorer. At the onset of the experiment, there were no differences in recognition thresholds between the participants with ADHD and those without ADHD. Following sleep deprivation, however, the ADHD group required clearer facial expressions to recognize the presence of angry, sad, and, to a lesser extent, happy faces. CONCLUSION: Among young adults with ADHD, sleep deprivation may hinder the processing of emotional facial stimuli. PMID- 29973107 TI - Laparoscopic right posterior sectionectomy versus laparoscopic right hemihepatectomy for hepatocellular carcinoma in posterior segments: Propensity Score Matching Analysis. AB - BACKGROUND AND AIMS: This study was designed to analyze the feasibility of laparoscopic right posterior sectionectomy compared to laparoscopic right hemihepatectomy in patients with hepatocellular carcinoma located in the posterior segments. MATERIAL AND METHODS: The study included patients who underwent either laparoscopic right posterior sectionectomy or laparoscopic right hemihepatectomy for hepatocellular carcinoma located in segment 6 or 7 from January 2009 to December 2016 at Samsung Medical Center. After 1:1 propensity score matching, patient baseline characteristics and operative and postoperative outcomes were compared between the two groups. Disease-free survival and overall survival were compared using Kaplan-Meier log-rank test. RESULTS: Among 61 patients with laparoscopic right posterior sectionectomy and 37 patients with laparoscopic right hemihepatectomy, 30 patients from each group were analyzed after propensity score matching. After matching, baseline characteristics of the two groups were similar including tumor size (3.4 +/- 1.2 cm in laparoscopic right posterior sectionectomy vs 3.7 +/- 2.1 cm in laparoscopic right hemihepatectomy, P = 0.483); differences were significant before matching (3.1 +/ 1.3 cm in laparoscopic right posterior sectionectomy vs 4.3 +/- 2.7 cm in laparoscopic right hemihepatectomy, P = 0.035). No significant differences were observed in operative and postoperative data except for free margin size (1.04 +/ 0.71 cm in laparoscopic right posterior sectionectomy vs 2.95 +/- 1.75 cm in laparoscopic right hemihepatectomy, P < 0.001). Disease-free survival (5-year survival: 38.0% in laparoscopic right posterior sectionectomy vs 47.0% in laparoscopic right hemihepatectomy, P = 0.510) and overall survival (5-year survival: 92.7% in laparoscopic right posterior sectionectomy vs 89.6% in laparoscopic right hemihepatectomy, P = 0.593) did not differ between the groups based on Kaplan-Meier log-rank test. CONCLUSION: For hepatocellular carcinoma in the posterior segments, laparoscopic right posterior sectionectomy was feasible compared to laparoscopic right hemihepatectomy when performed by experienced laparoscopic surgeons. PMID- 29973108 TI - Effect of hospital volume on outcomes of percutaneous peripheral atherectomy - An observational analysis from National Inpatient Sample. AB - BACKGROUND: Although the published literature has reported an inverse association between hospital volume and outcomes of coronary interventions, sparse data are available for percutaneous peripheral atherectomy (PPA). The aim of our study was to examine the effect of hospital volume on outcomes of PPA. METHODS: Using the Nationwide Inpatient Sample (NIS) database of the year 2012, PPA with ICD-9 code of 17.56 was identified. The primary outcomes were mortality and amputation rates; secondary outcomes were peri-procedural complications, cost, and length of hospitalization and discharge disposition of the patient. Multivariate models were generated for predictors of the outcomes. RESULTS: We identified a total of 21,015 patients with mean age of 69.53 years, with 56% males. Higher hospital volume centers were associated with a significantly lower mortality (OR 0.42, 95% CI 0.30-0.57, p < 0.0001), amputation rates (5.34% vs. 9.32%, p < 0.0001), combined endpoint of mortality and complications (OR 0.53, 95% CI 0.49-0.58, p < 0.0001), shorter length of hospital stay (LOS) (4.86 vs. 6.79 days, p < 0.0001) and lower hospitalization cost ($23,062 vs. $30,794, p < 0.0001). Subgroup analysis for acute and chronic limb ischemia showed similar results. CONCLUSION: Hospital procedure volume is an independent predictor of mortality, amputation rates, complications, LOS, and costs in patients undergoing PPA with an inverse relationship. PMID- 29973109 TI - Radon Testing Status in Schools by Radon Zone and School Location and Demographic Characteristics: United States, 2014. AB - Radon is a naturally occurring, radioactive, colorless, odorless gas, and the second leading cause of lung cancer. The 1990-1991 National School Radon Survey estimated that more than 70,000 schoolrooms nationwide had "high short-term radon levels." Using data from a nationally representative survey of schools in the United States ( N = 568; response rate = 69%), we examined the location and demographic characteristics of U.S. schools that had ever been tested for radon and whether having been tested varied by radon zone, which predicts average indoor radon levels in U.S. counties. Overall, 46.0% (95% confidence interval [39.8%, 52.4%]) of schools reported that they had ever been tested for radon. Testing significantly varied by region, percentage of minority students, and radon zone. These findings highlight the need for improved awareness of radon testing in schools, as testing is the only way to identify when remediation is needed. PMID- 29973110 TI - A Quality Improvement Initiative to Improve Medication Management in an Acute Care for Elders Program Through Integration of a Clinical Pharmacist. AB - PURPOSE: To describe the implementation and impact of integrating a clinical pharmacist into interdisciplinary Acute Care for Elderly (ACE) rounds at a teaching hospital. METHODS: Pre- and postanalyses were performed 6 months before and 12 months after the intervention. We report the total number, type, and frequency of recommendations made by the clinical pharmacist, the acceptance rate by the physician, and interventions on potentially inappropriate medications (PIM). RESULTS: Among the 588 patients who met the ACE inclusion criteria, mean age was 81.2 years, 54.9% were female, and 79.8% were of white race. A total of 1243 pharmacy recommendations were recorded. The median number of recommendations per patient increased from a median of 1 (range: 1-7) in the preintervention to 2 (1-13) in the postintervention period, resulting in an incidence rate ratio of 1.25 (95% confidence interval [CI]: 1.10-1.40). The main categories of recommendations were dose adjustment, avoidance of inappropriate therapy, and prevention of adverse drug events. In the postintervention period, there was an increase in recommendations among analgesics (from 3.7% to 7.5%), PIMs (from 12% to 14%), and, in particular, antidepressant/antipsychotics (from 1.9% to 6.0%). The acceptance rate of the recommendations remained roughly the same (86.5% vs 84.4%). CONCLUSION: Proactive involvement of a clinical pharmacist in ACE rounds resulted in a substantial increase in recommendation for medication changes, most notably for PIMs. These recommendations generally were accepted by physicians. The integration of a clinical pharmacist requires significant dedicated time but leads to increased recognition of drug-related problems in the acute-care setting, resulting in improved patient outcomes. PMID- 29973111 TI - Multiple episodes of 1080 (sodium monofluoroacetate) intoxication in a California calf-raising operation. AB - Over a 1-y period, a California calf-raising operation experienced 4 separate episodes of sudden death in 4-6-mo-old steers. Each episode occurred in 1-3 contiguous pens on 1 of 3 properties owned by the operation, but eventually all 3 properties were involved. In each episode, animals appeared normal at the evening feeding but at the subsequent morning feeding were found dead or dying. Remaining live calves had a stiff gait and were often dribbling urine, but did not show respiratory signs until they were down and agonal. At postmortem examination, calves consistently had moderate-to-large numbers of ecchymotic and suffusive hemorrhages on the epicardial surface and moderate-to-large amounts of fluid in the pericardial sac. Pulmonary edema and/or moderate amounts of watery fluid in the thoracic and abdominal cavities were present in a smaller percentage. On histologic examination, the myocardium had variable myofiber degeneration characterized by hypereosinophilia and fragmentation with mild interstitial infiltrates. Testing of heart and liver samples for monensin found levels lower than in previous cases of monensin toxicity. Rumen content was negative for oleandrin and grayanotoxins. Sodium monofluoroacetate (trade name: 1080) was consistently detected at ?10 ppb in kidney and liver, and was concluded to be the cause of the intoxication. PMID- 29973112 TI - Five-Year Outcome of Laparoscopic Sleeve Gastrectomy, Resolution of Comorbidities, and Risk for Cumulative Nutritional Deficiencies. AB - BACKGROUND AND AIMS: The aim of this study was to evaluate the long-term (5-year follow-up) results of laparoscopic sleeve gastrectomy in terms of weight loss and obesity-related comorbidities, as well as the risk factors associated with postoperative nutritional deficiencies. MATERIAL AND METHODS: The first 99 consecutive patients who underwent laparoscopic sleeve gastrectomy for the treatment of morbid obesity between October 2008 and August 2011 at Tartu University Hospital were followed prospectively in cohort study. The outpatient hospital follow-up visits were conducted at 3 months, 1 year, and 5 years postoperatively. At 5 years, the follow-up rate was 90.9%; 86 laparoscopic sleeve gastrectomy patients were included in final analysis. RESULTS: The mean excess weight loss (%EWL) was 44.3% +/- 13.0%, 75.8% +/- 23.1%, and 61.0% +/- 24.3% at 3 months, 1 year, and 5 years, respectively. A linear association between preoperative weight and weight at 5 years was found. Remission rates at 5-year follow-up for type 2 diabetes, hypertension, dyslipidemia, and obstructive sleep apnea were 68.8%, 32.7%, 27.4%, and 61.5%, respectively (all p < 0.05). There was a statistical difference (p < 0.05) in the dynamics of triglyceride, low-density lipoprotein, and high-density lipoprotein level at 5-year follow-up but the level of total cholesterol did not show significant improvement. The risk for cumulative iron, vitamin B12 deficiency, and anemia was 20%, 48%, and 28%, respectively. CONCLUSION: In conclusion, laparoscopic sleeve gastrectomy ensured long-term excess weight loss 61.0% at 5 years. Laparoscopic sleeve gastrectomy has a long-term effect on significant improvement in the median values of triglycerides, low-density lipoproteins, and high-density lipoproteins, but not on total cholesterol levels. There is a risk of postoperative vitamin B12 and iron deficiency. PMID- 29973113 TI - Green tea infusion alleviates neurodegeneration induced by mutant Huntingtin in Drosophila. AB - OBJECTIVES: Green tea infusion contains a complex mixture of polyphenolic compounds that were shown to provide health benefits. It was previously demonstrated that (-)-epigallocatechin-3-gallate, one of the major polyphenols present in green tea, has a suppressing effect on various aspects of pathogenesis in models of Huntington's disease (HD), an inherited neurodegenerative disorder. In this study, we aimed to investigate, whether green tea infusion prepared as for human consumption has similar positive effects. METHODS: We used a transgenic Drosophila model of HD to study the effects of green tea on mutant Huntingtin induced phenotypes. We tested the effects of green tea infusion on mutant Huntingtin induced neurodegeneration, impaired motor performance, reduced viability and lifespan by pseudopupil assay, climbing assay, eclosion and survival tests, respectively. We used immunoblots to measure Huntingtin protein levels and tested generic health benefits of green tea by longevity analysis. RESULTS: We found that green tea supplementation reduced mutant Huntingtin induced neurodegeneration in Drosophila and positively impacted the longevity of mutant Huntingtin expressing flies. However, green tea did not rescue reduced viability of Drosophila expressing mutant Huntingtin or increased longevity of wild-type fruit flies. DISCUSSION: Our results indicate that green tea consumption might have a modest positive effect on symptoms of HD. PMID- 29973114 TI - Pus Samples in Complicated Appendicitis: An Important Investigation or a Waste of Resources: A Prospective Cohort Study. AB - BACKGROUND AND AIMS: Appendicitis is a common presentation to hospital with appendectomy being the treatment of choice. Pre-operative administration of broad spectrum antibiotics is common, but obtaining intra-abdominal pus samples is not. After an initial 6-month retrospective audit and departmental teaching on the importance of intra-peritoneal pus sampling, we aimed to determine whether intra operative pus samples changed antibiotic management. MATERIALS AND METHODS: Following the initial audit cycle, a 6-month prospective cohort study was conducted. Clinical data were collected on a predetermined proforma to assess the effectiveness of the intervention and antibiotic prescribing practice. The data collected during the whole 1-year period was analyzed. RESULTS: During the 1-year period, 440 patients were identified as undergoing a laparoscopic procedure. After exclusion, 261 patients were identified as undergoing laparoscopic appendectomies, of which 141 (54%) were classified as complicated laparoscopic appendectomies. A total of 35 out of 141 (25%) pus samples were sent of which 24 (17%) resulted in positive cultures, with only nine of these positive cultures reported prior to the patient being discharged. No patient had their antibiotic regimen changed as a result of the culture results. There were three cases of cultures resistant to local antibiotics, but without significant clinical outcome. One of these patients developed a post-operative complication, but the antibiotic regimen was changed to broad spectrum rather than a specific antibiotic based on culture sensitivity. Of the 141 patients with complicated laparoscopic appendectomies, five (3.5%) developed post-operative complications: one readmission requiring a laparoscopic washout for pelvic collection, three (2%) cases of pelvic collections managed conservatively, and one case of prolonged paralytic ileus managed non-operatively. CONCLUSION: Overall, none of the patients with positive cultures had a change in prescribed antibiotics based on culture results. Hence, the routine practice of intra-peritoneal pus sampling following complicated appendicitis remains of little clinical value. PMID- 29973115 TI - Comparison of Community Pharmacy Practice in Japan and US State of Illinois. AB - In 2006, a new 6-year educational system of pharmaceutical sciences was initiated to turn out strong clinical pharmacists in Japan. However, this new attempt is estimated not to fully satisfy the demand of clinical sites and the needs of the society in Japan. The objective of this study is to assess the performance of pharmaceutical services of community pharmacists in Illinois, United States, and Japan with the aim of comparing these services and barriers to pharmacy service delivery. The study designed as a cross-sectional, web-based study among US and Japan pharmacists. The survey asks several questions about demographic data, technical-related information and pharmaceutical services offered to patients, and pharmacy service performance. Almost 50 (92.6%) community pharmacists in United States reported that they dispensed more than 100 prescriptions in 1 day during the study period. In contrast, in Japan, community pharmacists (55.2%) dispensed 10 to 50 prescriptions during the same period. Half of the pharmacists in Japan either strongly agreed or agreed that they lack sufficient interpersonal and management skills. And many pharmacists agreed that lack of appropriate knowledge and insufficient training before graduation are major barriers to optimized pharmacy services in Japan. These findings can be used to promote discussion between Japanese pharmacists and stakeholders about pharmacy education programs in Japan and the future role of the community pharmacists in patient care in Japan. PMID- 29973116 TI - Selection of Activity Items for Development of the Activity Card Sort-Japan Version. AB - The Activity Card Sort (ACS) can both record the clients' participation and any changes, which is a useful tool for practitioners to establish tailored occupation-focused goals. However, there is a limitation to apply the ACS to Japanese older adults as it consists of culturally relevant activities in the United States. The aim of this study was to select activity items reflecting Japanese older adults' lifestyles and opinions to develop the Activity Card Sort Japan Version (ACS-JPN). In the item selection process, a two-round questionnaire survey was conducted for community-dwelling Japanese older adults (Round 1: n = 177, M age = 69.9 years; Round 2: n = 178, M age = 74.9 years). Seventy-two activity items were finally included in the ACS-JPN and were classified into four domains. The ACS-JPN has some unique features compared with other ACS versions. This study only selected activity items. Further work on psychometric properties is needed. PMID- 29973117 TI - Comparison of Interactive Education Versus Fluorescent Concretization on Hand Hygiene Compliance Among Primary School Students: A Randomized Controlled Trial. AB - Hand hygiene for children is crucial to keep them healthy. The purpose of the study was to evaluate the effects of two educational initiatives on "handwashing effectiveness (HWE)." A randomized controlled trial was carried out during April/June 2016, and 96 primary school students were randomly assigned to Group I receiving education with fluorescent gel; Group II receiving interactive education or control group continuing its normal education. Evaluation was made by scoring the fluorescent areas on the hands with photographs. There were significant differences in handwashing scores between preprogram and postprogram for all areas in only Group II ( p < .05). HWE increased from 17.9% to 18.4% in Group I, from 15.4% to 37.7% in Group II, and from 35.5% to 35.8% in control group. Only concretization with fluorescent gel is not a sufficiently strong motivator for increasing HWE. New techniques should be integrated into the training programs for children. PMID- 29973119 TI - The Golgi stacking protein GORASP2/GRASP55 serves as an energy sensor to promote autophagosome maturation under glucose starvation. AB - The Golgi apparatus is a central intracellular membrane organelle in the secretory pathway. The formation of the unique stacked architecture of the Golgi ensures accurate protein glycosylation and sorting. However, how the Golgi structure and function respond to extracellular stresses is largely unexplored. In a recent study, we reported that under short-term glucose deprivation, a subpopulation of the Golgi stacking protein GORASP2/GRASP55 is targeted from the Golgi to the interface between autophagosomes and lysosomes to promote autophagosome maturation; this process is regulated by O-GlcNAcylation. Under growth condition, GORASP2 is O-GlcNAcylated and functions as a stacking protein in the Golgi. Upon glucose starvation, GORASP2 is de-O-GlcNAcylated and is partially relocated from the Golgi to the autophagosome-lysosome interface, where it interacts with lipidated LC3 on autophagosomes and LAMP2 on lysosomes, and functions as a membrane tether to facilitate autophagosome-lysosome fusion. Therefore, our study uncovered an unconventional role of the Golgi 'glue' protein in autophagy that acts by sensing the glucose level. PMID- 29973118 TI - Interaction between autophagic vesicles and the Coxiella-containing vacuole requires CLTC (clathrin heavy chain). AB - Coxiella burnetii is an intracellular bacterial pathogen which causes Q fever, a human infection with the ability to cause chronic disease with potentially life threatening outcomes. In humans, Coxiella infects alveolar macrophages where it replicates to high numbers in a unique, pathogen-directed lysosome-derived vacuole. This compartment, termed the Coxiella-containing vacuole (CCV), has a low internal pH and contains markers both of lysosomes and autophagosomes. The CCV membrane is also enriched with CLTC (clathrin heavy chain) and this contributes to the success of the CCV. Here, we describe a role for CLTC, a scaffolding protein of clathrin-coated vesicles, in facilitating the fusion of autophagosomes with the CCV. During gene silencing of CLTC, CCVs are unable to fuse with each other, a phenotype also seen when silencing genes involved in macroautophagy/autophagy. MAP1LC3B/LC3B, which is normally observed inside the CCV, is excluded from CCVs in the absence of CLTC. Additionally, this study demonstrates that autophagosome fusion contributes to CCV size as cell starvation and subsequent autophagy induction leads to further CCV expansion. This is CLTC dependent, as the absence of CLTC renders autophagosomes no longer able to contribute to the expansion of the CCV. This investigation provides a functional link between CLTC and autophagy in the context of Coxiella infection and highlights the CCV as an important tool to explore the interactions between these vesicular trafficking pathways. PMID- 29973120 TI - Memory and affective changes during the antepartum: A narrative review and integrative hypothesis. AB - INTRODUCTION AND OBJECTIVES: Many women report diminished memory function during the second or third trimesters of pregnancy, but objective neuropsychological tests often fail to show any decrement in performance. The present paper systematically reviews published studies that have investigated this phenomenon over the past 25 years and considers newer studies showing that affective changes occur during gestation in a subset of pregnant women. METHOD: A systematic search was conducted to identify articles relevant to pregnancy and memory function. Articles published since 1990 that included a nonpregnant comparison group were retained for review. RESULTS: A literature review of studies using objective memory testing suggests that a mild antepartum decline in explicit verbal recall occurs in some women. There is little empirical support for objective changes in semantic or implicit memory during pregnancy. Findings for working memory are mixed, with evidence supporting both decrements and enhancements. Inconsistencies in the literature potentially reflect a moderating influence of pregnancy-linked depressive affect on cognitive performance, not simply domain specificity, as previously suggested. CONCLUSIONS: Diminished memory function may occur in a specific subset of pregnant women who display depressive symptoms associated with pregnancy. PMID- 29973121 TI - The effects of cognitive-focused interventions on cognition and psychological well-being in persons with multiple sclerosis: A meta-analysis. AB - Cognitive impairment affects more than half of persons with multiple sclerosis (PwMS), and it is associated with difficulties in multiple aspects of daily functioning. There is a growing body of literature that has explored the use of cognitive-focused interventions in PwMS, which aim to improve cognition-related function through drill and practice exercises, training in compensatory strategies, or a combination of the two. The current study aimed to expand upon previously published meta-analyses in this area, exploring the effects of cognitive-focused interventions on objective and subjective functioning in PwMS, as well as determining demographic and treatment-related factors that may influence intervention efficacy. Thirty-three studies, with a total of 1890 participants, were included in the meta-analysis. Outcome measures were categorised based on the domain they presumably assessed. For objective cognitive functioning, weighted effect-size analysis revealed small effects of cognitive focused interventions on working memory (g = 0.31) and visual learning (g = 0.32). Small mean effect sizes were also noted on self-reported anxiety (g = 0.30) and depression (g = -0.23). Cognitive-focused interventions did not produce changes in subjective cognitive functioning. Moderating variables and clinical applications are also discussed. PMID- 29973123 TI - Patient Factors That Influence How Physicians Discuss Active Surveillance With Low-Risk Prostate Cancer Patients: A Qualitative Study. AB - For men diagnosed with prostate cancer, making treatment decisions can be overwhelming. Navigating treatment options, along with potential treatment side effects, can be difficult, and patients often rely heavily on the advice of their physicians. This study was aimed at understanding more about the way urologists talk with their patients about one treatment option: active surveillance (AS), a recognized management strategy for men with low-risk prostate cancer that includes close observation and monitoring of the cancer. This study reports, through 22 interviews with urologists, that urologists believe patients are hesitant about AS for a number of reasons, including misperceptions about cancer severity, anxiety, aversion to repeated biopsies that accompany AS, or family member preferences. Because urologists play an influential role in educating patients about treatment options, the discussion around AS can be impacted by barriers that physicians believe matter for their patients. Improving awareness among urologists about what factors impact their patient education about low-risk prostate cancer is important. Identifying tools to improve shared decision making in this area could result in treatment decisions that are increasingly concordant with patients' values, concerns, and goals. PMID- 29973124 TI - EIF5A mediates autophagy via translation of ATG3. AB - The core macroautophagy/autophagy machinery consists of a large group of autophagy-related (ATG) proteins, that mediate highly controlled, step-wise execution of this conserved intracellular degradation process. Whereas ATG proteins have been intensely studied in terms of protein interactions, post translational modifications and transcriptional regulation, the mechanisms ensuring efficient translation of ATG proteins are not well understood. In a recent study, we describe an evolutionarily conserved role for EIF5A (eukaryotic translation initiation factor 5A) in autophagy. We demonstrate that EIF5A mediates Atg8-family protein lipidation and autophagosome formation via translation of the E2-like ATG3 protein. Moreover, we identify a particular motif in ATG3 causing EIF5A-dependency for its efficient translation. PMID- 29973122 TI - Insights into the genetic and host adaptability of emerging porcine circovirus 3. AB - Porcine circovirus 3 (PCV3) was found to be associated with reproductive disease in pigs, and since its first identification in the United States, it subsequently spread worldwide, especially in China, where it might pose a potential threat to the porcine industry. However, no exhaustive analysis was performed to understand its evolution in the prospect of codon usage pattern. Here, we performed a deep codon usage analysis of PCV3. PCV3 sequences were classified into two clades: PCV3a and PCV3b, confirmed by principal component analysis. Additionally, the degree of codon usage bias of PCV3 was slightly low as inferred from the analysis of the effective number of codons. The codon usage pattern was mainly affected by natural selection, but there was a co-effect of mutation pressure and dinucleotide frequency. Moreover, based on similarity index analysis, codon adaptation index analysis and relative codon deoptimization index analysis, we found that PCV3 might pose a potential risk to public health though with unknow pathogenicity. In conclusion, this work reinforces the systematic understanding of the evolution of PCV3, which was reflected by the codon usage patterns and fitness of this novel emergent virus. PMID- 29973125 TI - Bone Toolbox: Biomarkers, Imaging Tools, Biomechanics, and Histomorphometry. AB - Bone is a unique tissue with turnover, metabolic, and cellular activities that vary through development to aging and with a mineralized matrix in which the current state and the history of a bone coexist. Qualitative histopathology often lacks sensitivity to detect changes in bone formation, mineralization and resorption, which often requires chronic dosing to result in structural changes such as variation in bone mass and geometry. A large panel of modalities can be used to fully analyze the health of the skeleton, including biomarker evaluation in serum or urine, imaging techniques ranging from radiology to computed tomography, biomechanical testing, and undecalcified tissue processing with bone histomorphometry. The use of clinically relevant biomarkers provides an important noninvasive, sensitive, rapid, and real-time tool to monitor bone activity at the whole skeleton level when conducting safety assessments in a preclinical setting. Imaging modalities also allow in vivo longitudinal assessments with a powerful, noninvasive and clinically translatable tools to monitor drug effects. Different imaging modalities are used in the preclinical studies to evaluate the bone tissues: standard radiography, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), micro-computed tomography, and high resolution pQCT. Bone histomorphometry is an important tool that provides sensitive evaluation to detect effects of test articles on bone resorption, formation, mineralization, remodeling rates and growth to address a potential target- or class-related theoretical bone liability. Ultimately, the measurement of bone mechanical properties in pharmaceutical testing is critical to understand the potential effects of that pharmaceutical on bone health and fracture risk. Important considerations are required for including these different techniques in toxicology rodents and nonrodent studies, to actually integrate these into safety assessment. PMID- 29973127 TI - Corrigendum. PMID- 29973126 TI - Oncologists' Treatment Responses to Mental Health Distress in Their Cancer Patients. AB - The objectives of this study were to identify how oncologists respond to mental health distress in their patients, what specific strategies they use in treating this distress, and what barriers they report responding to their patients' emotional distress. Twenty-three oncologists at two cancer centers were interviewed. The grounded theory method of data collection and analysis was used. Oncologists varied in their response to patients' emotional distress. Strategies used in responding to patients' distress included creating supportive relationships and prescribing medications, while barriers included patient reluctance, a lack of protocol on how to respond to patients, limited psychosocial resources, and a lack of time. Developing and adopting clear guidelines to addressing mental health distress among cancer patients is critical in assuring quality care for the whole patient and reduce the risk for poor quality of life and potential disease-related morbidity and mortality. PMID- 29973128 TI - Observational study of anorectal Chlamydia trachomatis infections in France through the lymphogranuloma venereum surveillance network, 2010-2015. AB - The objective of this article is to describe the epidemiology of lymphogranuloma venereum (LGV) and non-LGV Chlamydia trachomatis anorectal infections in France and to examine the characteristics of the affected populations via a voluntary sentinel surveillance system for LGV between 2010 and 2015. Anorectal samples positive for C. trachomatis (CT) were sent by the participating laboratories to the National Reference Center for CT for LGV identification. Biological and clinical data were collected by biologists and clinicians. There were 1740 LGV episodes and 2248 non-LGV episodes. Continuous monitoring highlighted a sharp increase in the number of LGV and non-LGV anorectal infections, which were 2.3 fold and 6.5-fold, respectively. Most of the infections occurred in men who have sex with men. LGV patients were older than non-LGV patients and were more frequently human immunodeficiency virus (HIV)-positive compared to non-LGV patients. Anorectal LGV was significantly associated with residence in Paris, HIV co-infection, concurrent syphilis and bloody anal discharge. Undocumented patient characteristics were strongly associated with anorectal LGV. The anorectal LGV epidemic is poorly controlled in France. Early detection and prompt treatment of patients and their sexual partners are required to prevent transmission in the context of pre-exposure prophylaxis (PrEP) for HIV infection. PMID- 29973129 TI - Partner meeting venue typology and sexual risk behaviors among French men who have sex with men. AB - Previous research has given considerable attention to venues where men who have sex with men (MSM) meet their sex partners. However, no previous study examined a vast range of sexual risk behaviors. The objective of this study was to examine the association between the types of venues for meeting sexual partners, condomless anal intercourse, engagement in group sex, and HIV and sexually transmitted infection (STI) risk among a sample of MSM. Users of a popular geosocial-networking app in Paris were provided an advertisement with text encouraging them to complete an anonymous web-based survey ( n = 580), which included questions about sex-seeking venues, condomless anal intercourse, HIV status and STI history, and sociodemographic characteristics. A log-binomial model was used to assess association between venues (i.e. public venues [gay clubs, bars, and discos], cruising venues [such as gay saunas, beaches, and parks], and internet-based venues [internet chat sites and geosocial-networking apps]), condomless anal intercourse, engagement in group sex, and HIV infection as well as infection with other STIs, after adjustment for sociodemographics. In multivariable models, attending cruising venues was associated with condomless receptive anal intercourse (adjusted relative risk [aRR] = 1.47; 95% confidence interval [CI] = 1.20-1.81), any kind of condomless anal intercourse (aRR = 1.34; 95% CI = 1.14-1.58), an STI (aRR = 1.50; 95% CI = 1.09-2.05), engagement in group sex (aRR = 1.42; 95% CI = 1.27-1.59), and multiple partners for both condomless insertive (aRR = 2.00; 95% CI = 1.38-2.88), and receptive (aRR = 1.70; 95% CI = 1.23-2.36) anal intercourse, STI infection (aRR = 1.50, 95% CI = 1.09-2.05) and HIV infection (aRR = 1.76; 95% CI = 1.05-2.96). No associations were found with other venue types and sexual risk behaviors, STIs, and HIV infection, except for group sex, which was associated with all venue types. Use of cruising where the primary aim is to have sex was found to be associated with risky sexual behavior. Risky behavior reduction strategies such as preexposure prophylaxis campaigns should be targeted to MSM who frequent cruising venues. PMID- 29973130 TI - Patient satisfaction with remote orthopaedic consultation by using telemedicine: A randomised controlled trial. AB - Introduction Decentralised services through outreach clinics or modern technology reduce patient travel time and cost to society. Telemedicine consultation through videoconference is one such modality. Here, we compared patient-reported health outcomes and satisfaction between video-assisted remote and standard face-to-face orthopaedic consultations. Methods This randomised controlled trial included two parallel groups: (1) patients receiving video-assisted remote consultation at a regional medical centre (RMC); and (2) patients receiving standard consultation at the orthopaedic outpatient clinic of the University Hospital of North Norway (UNN). This study included patients referred to or scheduled for a consultation at the orthopaedic outpatient clinic. After each consultation, patient satisfaction was determined using patient-completed questionnaires containing questions on patient-reported health (three-level European quality of life five dimension index (EQ-5D-3L)/European quality of life visual analogue scale (EQ VAS)) and questions from a validated OutPatient Experiences Questionnaire (OPEQ). Results This study included 389 patients, of which 199 received remote consultation and 190 received standard consultation (total of 559 consultations). In all, 99% RMC-randomised patients and 99% UNN-randomised patients evaluated the consultation as very satisfactory or satisfactory. Moreover, 86% RMC-randomised patients preferred video-assisted consultation as the next consultation. No difference was observed in patient-reported health after 12 months between the two groups. EQ-5D index scores were 0.77 and 0.75 for RMC- and UNN-randomised patients, respectively ( p = 0.42). Discussion We did not observe any difference in patient-reported satisfaction and health (EQ-5D/EQ-VAS) between video-assisted and standard consultations, suggesting that video-assisted remote consultation can be safely offered to some orthopaedic patients. Moreover, a significantly high proportion of patients selected video-assisted remote consultation as their next consultation, thus strengthening the findings of this study. However, economic aspects should be assessed before widely recommending video-assisted consultation. PMID- 29973131 TI - E-consults in gastroenterology: An opportunity for innovative care. AB - Background and aim Deploy and evaluate a gastroenterology (GI) electronic consultation (e-consult) program. E-consults are a promising approach to enhance provider communication, facilitate timely specialty advice and may replace some outpatient visits. Study As part of our health system's efforts to provide more cost-effective care under risk-based contracts, we implemented an e-consult program where referring providers submit patient-specific clinical questions electronically via an electronic referral system. A GI consultant then reviews the patient's record and provides a written recommendation back to the referring physician. For our program evaluation, we conducted chart reviews of each e consult to understand how the program was being used and surveyed the participating providers and consultants. Results From September 2015 to March 2016, we received 144 e-consults, with most questions concerning GI symptoms or abnormal hepatology labs. Only 36% of e-consults recommended an in-person GI consult or procedure. In our survey of participating providers, referring providers strongly agreed that the GI e-consults promoted good patient care (88%) and were satisfied with the program (84%). The majority of GI consultants felt strongly that e-consults were useful for referring providers and their patients, but that current reimbursement and time allotted were not adequate. Conclusions We report on the implementation of a GI e-consult program within an ACO, showing that many clinical questions could be answered using this mechanism. E-consults in gastroenterology have the potential to reduce unnecessary visits and/or procedures for patients who can be managed by their primary provider, potentially increasing access for other patients. PMID- 29973132 TI - Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial of Bupropion as Treatment for Methadone-Emergent Sexual Dysfunction in Men. AB - Methadone is largely recognized as an effective treatment for opiate-dependent patients; however, it causes reduced brain dopaminergic action resulting in significant sexual dysfunction. Bupropion is a dopamine reuptake inhibitor which can potentially improve erectile function among male patients on methadone (MMT). This is a phase II, randomized, double-blind, parallel-group, placebo-controlled trial, involving 80 MMT male patients (73.4%) with mean age of 42.83 years +/ 9.68. These MMT male patients were randomly assigned into two groups to receive bupropion and placebo, respectively. The primary efficacy outcome measure was the difference between the two groups in end-point mean improvement scores using the measurement of Clinical Global Impression Scale adapted for Sexual Function (CGI SF) at baseline (week 0) and at weeks 2, 4, and 6. Malay version of the sexual desire inventory-2 (SDI-2-BM) and Malay version of International Index of Erectile Function 15 (Mal-IIEF-15) domain scores were evaluated as secondary parameters. Improvement of the end-point mean from baseline were seen across the scores of SDI-2-BM (mean difference = 11.77 +/- 2.90, 95% confidence interval (CI) [3.89, 19.54], p < .001) and Mal-IIEF-15 (mean difference = 8.37 +/- 2.71, 95% CI [15.75, 0.99], p = .02), and the total plasma testosterone level (mean difference = 4.03, 95% CI [0.90, 7.15], p = .01). A categorical improvement of "much/very much improved" (CGI-SF score = 2) was reported by 58.3% ( n = 21/36) of bupropion SR-assigned versus 27.7% ( n = 10/36) placebo-assigned patient. Bupropion was well tolerated with no serious adverse events reported other than insomnia (17.7%). Six weeks of bupropion SR treatment reported significant improvement in key aspects of sexual function among male opiate-dependent patients on methadone maintenance treatment with emergent sexual dysfunction. PMID- 29973133 TI - Correction to: The cytidine deaminase under-representation reporter (CDUR) as a tool to study evolution of sequences under deaminase mutational pressure. AB - Following publication of the original article [1], the authors reported that Figs. 1 and 3 were interchanged. The original article has been corrected. PMID- 29973134 TI - Spectrum of genomic variations in Indian patients with progressive familial intrahepatic cholestasis. AB - BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is caused by variations in ATP8B1, ABCB11 or ABCB4 genes. Data on genetic variations in Indian patients with PFIC are lacking. METHODS: Coding and splice regions of the three genes were sequenced in unrelated Indian children with PFIC phenotype. The variations identified were looked for in parents, 30 healthy persons and several variation databases, and their effect was assessed in-silico. RESULTS: Among 25 children (aged 1-144 months), nine (36%) had unique major genomic variations (ATP8B1: 4, ABCB11: 3 and ABCB4: 2). Seven had homozygous variations, which were assessed as 'pathogenic' or 'likely pathogenic'. These included: (i) four amino acid substitutions (ATP8B1: c.1660G > A/p.Asp554Asn and c.2941G > A/p.Glu981Lys; ABCB11: c.548 T > C/p.Met183Thr; ABCB4: c.431G > A/p.Arg144Gln); (ii) one 3 nucleotide deletion causing an amino acid deletion (ATP8B1: c.1587_1589delCTT/p.Phe529del); (iii) one single-nucleotide deletion leading to frame-shift and premature termination (ABCB11: c.1360delG/p.Val454Ter); and (iv) a complex inversion of 4 nucleotides with a single-nucleotide insertion leading to frame-shift and premature termination (ATP8B1: c.[589_592inv;592_593insA]/p.Gly197LeufsTer10). Two variations were found in heterozygous form: (i) a splice-site variation likely to cause abnormal splicing (ABCB11: c.784 + 1G > C), and (ii) a nucleotide substitution that created a premature stop codon (ABCB4: c.475C > T/p.Arg159Ter); these were considered as variations of uncertain significance. Three of the nine variations were novel. CONCLUSIONS: Nine major genomic variations, including three novel ones, were identified in nearly one-third of Indian children with PFIC. No variation was identified in nearly two-thirds of patients, who may have been related to variations in promoter or intronic regions of the three PFIC genes, or in other bile-salt transport genes. PMID- 29973135 TI - Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients. AB - BACKGROUND: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. METHODS: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 * 10- 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. RESULTS: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (beta = - 4.8%, P = 9.6 * 10- 9 for systolic and beta = - 4.3%, P = 2.2 * 10- 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 * 10- 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (beta = - 0.8%, P = 0.4 for systolic and beta = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (beta = - 7.6 g/m2, P = 0.02). CONCLUSIONS: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology. PMID- 29973136 TI - Caspase-independent cell death does not elicit a proliferative response in melanoma cancer cells. AB - BACKGROUND: Apoptosis, the most well-known type of programmed cell death, can induce in a paracrine manner a proliferative response in neighboring surviving cells called apoptosis-induced proliferation (AiP). While having obvious benefits when triggered in developmental processes, AiP is a serious obstacle in cancer therapy, where apoptosis is frequently induced by chemotherapy. Therefore, in this study, we evaluated the capacity of an alternative type of cell death, called caspase-independent cell death, to promote proliferation. RESULTS: Using a novel in vitro isogenic cellular model to trigger either apoptosis or caspase independent cell death, we found that the later has no obvious compensatory proliferation effects on neighboring cells. CONCLUSIONS: This study enforces the idea that alternative types of cell death such as caspase-independent cell death could be considered to replace apoptosis in the context of cancer treatment. PMID- 29973138 TI - Correction to: Association between NAT2, CYP1A1, and CYP1A2 genotypes, heterocyclic aromatic amines, and prostate cancer risk: a case control study in Japan. AB - Following publication of the original article [1], the authors reported a correction in the units in the methods section under "Subjects". PMID- 29973137 TI - Identification of candidate chemosensory genes in Mythimna separata by transcriptomic analysis. AB - BACKGROUND: The oriental armyworm, Mythimna separata, is an economically important and common Lepidopteran pest of cereal crops. Chemoreception plays a key role in insect life, such as foraging, oviposition site selection, and mating partners. To better understand the chemosensory mechanisms in M. separata, transcriptomic analysis of antennae, labial palps, and proboscises were conducted using next-generation sequencing technology to identify members of the major chemosensory related genes. RESULTS: In this study, 62 putative odorant receptors (OR), 20 ionotropic receptors (IR), 16 gustatory receptors (GR), 38 odorant binding proteins (OBP), 26 chemosensory proteins (CSP), and 2 sensory neuron membrane proteins (SNMP) were identified in M. separata by bioinformatics analysis. Phylogenetic analysis of these candidate proteins was performed. Differentially expressed genes (DEGs) analysis was used to determine the expressions of all candidate chemosensory genes and then the expression profiles of the three families of receptor genes were confirmed by real-time quantitative RT-PCR (qPCR). CONCLUSIONS: The important genes for chemoreception have now been identified in M. separata. This study will provide valuable information for further functional studies of chemoreception mechanisms in this important agricultural pest. PMID- 29973139 TI - Association of genetic polymorphisms in vascular endothelial growth factor with susceptibility to coronary artery disease: a meta-analysis. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) located in the vascular endothelial growth factor (VEGF) gene may be correlated with the susceptibility to coronary artery disease (CAD) - although results have been controversial. The aim of this meta-analysis is to clarify the effects of VEGF -2578A/C (rs699947), 1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039) polymorphisms on CAD risk. METHODS: Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between VEGF gene polymorphisms and CAD risk. Fixed- or random-effects model was used depending on the heterogeneity between studies. RESULTS: In total, 13 eligible articles containing 29 studies were analysed. The pooled analysis indicated that the VEGF gene polymorphisms of rs699947, rs2010963, and rs3025039 were associated with an increased risk of CAD, whereas no significant associations were observed with the rs1570360 polymorphism. A subgroup analysis stratified by ethnicity revealed that the rs699947 and rs3025039 polymorphisms were associated with CAD risk in Asian populations. In addition, stratification by control source indicated an increased risk of CAD susceptibility with the rs699947 polymorphism for population-based studies of reduced heterogeneity. CONCLUSIONS: In summary, we concluded that the VEGF gene polymorphisms rs699947, rs2010963, and rs3025039 are correlated with an elevated CAD risk. PMID- 29973140 TI - Yield of household contact tracing for tuberculosis in rural South Africa. AB - BACKGROUND: Efficient and effective strategies for identifying cases of active tuberculosis (TB) in rural sub-Saharan Africa are lacking. Household contact tracing offers a potential approach to diagnose more TB cases, and to do so earlier in the disease course. METHODS: Adults newly diagnosed with active TB were recruited from public clinics in Vhembe District, South Africa. Study staff visited index case households and collected sputum specimens for TB testing via smear microscopy and culture. We calculated the yield and the number of households needed to screen (NHNS) to find one additional case. Predictors of new TB among household contacts were evaluated using multilevel logistic regression. RESULTS: We recruited 130 index cases and 282 household contacts. We identified 11 previously undiagnosed cases of bacteriologically-confirmed TB, giving a prevalence of 3.9% (95% CI: 2.0-6.9%) among contacts, a yield of 8.5 per 100 (95% CI: 4.2-15.1) index cases traced, and NHNS of 12 (95% CI: 7-24). The majority of new TB cases (10/11, 90.9%) were smear negative, culture positive. The presence of TB symptoms was not associated with an increased odds of active TB (aOR: 0.3, 95% CI: 0.1-1.4). CONCLUSIONS: Household contacts of recently diagnosed TB patients in rural South Africa have high prevalence of TB and can be feasibly detected through contact tracing, but more sensitive tests than sputum smear are required. Symptom screening among household contacts had low sensitivity and specificity for active TB in this study. PMID- 29973141 TI - Genome variants associated with RNA splicing variations in bovine are extensively shared between tissues. AB - BACKGROUND: Mammalian phenotypes are shaped by numerous genome variants, many of which may regulate gene transcription or RNA splicing. To identify variants with regulatory functions in cattle, an important economic and model species, we used sequence variants to map a type of expression quantitative trait loci (expression QTLs) that are associated with variations in the RNA splicing, i.e., sQTLs. To further the understanding of regulatory variants, sQTLs were compare with other two types of expression QTLs, 1) variants associated with variations in gene expression, i.e., geQTLs and 2) variants associated with variations in exon expression, i.e., eeQTLs, in different tissues. RESULTS: Using whole genome and RNA sequence data from four tissues of over 200 cattle, sQTLs identified using exon inclusion ratios were verified by matching their effects on adjacent intron excision ratios. sQTLs contained the highest percentage of variants that are within the intronic region of genes and contained the lowest percentage of variants that are within intergenic regions, compared to eeQTLs and geQTLs. Many geQTLs and sQTLs are also detected as eeQTLs. Many expression QTLs, including sQTLs, were significant in all four tissues and had a similar effect in each tissue. To verify such expression QTL sharing between tissues, variants surrounding (+/-1 Mb) the exon or gene were used to build local genomic relationship matrices (LGRM) and estimated genetic correlations between tissues. For many exons, the splicing and expression level was determined by the same cis additive genetic variance in different tissues. Thus, an effective but simple-to implement meta-analysis combining information from three tissues is introduced to increase power to detect and validate sQTLs. sQTLs and eeQTLs together were more enriched for variants associated with cattle complex traits, compared to geQTLs. Several putative causal mutations were identified, including an sQTL at Chr6:87392580 within the 5th exon of kappa casein (CSN3) associated with milk production traits. CONCLUSIONS: Using novel analytical approaches, we report the first identification of numerous bovine sQTLs which are extensively shared between multiple tissue types. The significant overlaps between bovine sQTLs and complex traits QTL highlight the contribution of regulatory mutations to phenotypic variations. PMID- 29973143 TI - Spontaneous remission of adult-onset minimal change nephrotic syndrome associated with influenza B infection: a case report. AB - BACKGROUND: While the majority of adult-onset minimal change nephrotic syndrome (MCNS) is a primary or an idiopathic form of disease, it can also occur as a secondary form. Reports on the spontaneous remission of MCNS are rare since the condition is typically treated with corticosteroids. We herein describe the spontaneous remission of adult-onset MCNS in a patient who developed nephrotic syndrome after type B influenza infection. CASE PRESENTATION: A 50-year-old woman experienced fever, cough, malaise, and low back pain, which had persisted for 6 days before she presented to our hospital, and edema of the face and limbs, which had persisted for 5 days before her presentation. She was diagnosed with type B influenza infection and later exhibited an exacerbation of facial edema, decreased urine output, and a high level of proteinuria. She was referred to our department after the diagnosis of nephrotic syndrome. On admission, her proteinuria level was 20.88 g/gCr and her selectivity index value was 0.13. The examination of a kidney biopsy specimen obtained on the fourth day of hospitalization under a light microscope revealed minor abnormalities. An immunofluorescence showed only nonspecific granular IgM deposits in the mesangium. Electron microscopy showed extensive foot process effacement without any immune complex deposits. Based on these findings, the patient was diagnosed with MCNS. After admission, the proteinuria decreased to 0.06 g/gCr with rest and sodium restriction (6 g/day) alone; a complete remission from nephrotic syndrome was observed at approximately 2 weeks after the onset of symptoms. There have been no signs of recurrence of nephrotic syndrome in the one years since. CONCLUSION: We experienced a rare case in which spontaneous remission of MCNS occurred within a short period of 2 weeks after influenza B infection. When patients present with nephrotic syndrome after an infection, it is necessary to consider MCNS in the differential diagnosis, which also includes post-infectious glomerulonephritis and the acute exacerbation of IgA nephropathy. PMID- 29973142 TI - What is impact of nonsteroidal anti-inflammatory drugs in the prevention of post endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Recently, although studies have investigated the role of NSAIDs in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP), selection of the ideal drug, the time and route of its administration for the appropriate population remain controversial. METHODS: A systematic search was done in sources including PubMed, Embase, Web of Science, the Cochrane Library Central, and ClinicalTrials.gov from from August 1, 1990 to August 1, 2017. Randomized controlled trials comparing the prophylactic use of NSAIDs versus a placebo were included. Statistical analysis was performed using the RevMan 5.3 software to assess the outcomes. RESULTS: A total of 21 randomized controlled trials were included in the meta-analysis. Our study showed that NSAIDs significantly reduced the incidence of PEP (RR, 0.61, 95%CI,0.52-0.72; p < 0.00001). The analysis showed that indomethacin administration post-ERCP (RR, 0.47; 95% CI, 0.31-0.70; p = 0.0002) appeared to be more effective in preventing PEP than indomethacin administration pre-ERCP (RR, 0.59; 95% CI, 0.45-0.79; P = 0.0003), but there was no significant difference between the high-risk and average-risk population(p = 0.13). In the diclofenac group, it was noted that administration of diclofenac pre-ERCP (RR, 0.32; 95% CI, 0.16-0.63; p = 0.001) was more effective than that in post-ERCP (RR, 0.65; 95% CI, 0.27-1.599; p = 0.35). The relative risk of PEP was 0.63 (95% CI, 0.27-1.50; p = 0.30) in high risk patients and 0.41 (95% CI, 0.17-0.98; p = 0.02) in average-risk patients. With regard to the route of administration, PEP decreased significantly only in patients receiving the drug rectally (RR, 0.53; 95% CI, 0.44-0.63; p < 0.00001), but not for those who received intramuscularly (RR, 0.74; 95% CI, 0.47-1.17; p = 0.20), intravenously (RR, 0.97; 95% CI, 0.51-1.83; p = 0.93), and orally (RR = 0.88; 95% CI, 0.55-0.1.43; p = 0.62). CONCLUSIONS: Rectal administration of NSAIDs (both indomethacin and diclofenac) was effective in preventing PEP in unselected patients. A single dose of indomethacin after ERCP might be effective in preventing PEP in both high-risk and average-risk patients. However, diclofenac administered rectally before ERCP might be protective against PEP in high-risk patients compared to a placebo. However, more high quality head-to-head RCTs are required. PMID- 29973144 TI - Melatonin ameliorates cognitive memory by regulation of cAMP-response element binding protein expression and the anti-inflammatory response in a rat model of post-traumatic stress disorder. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is an important psychological disease that can develop following the physical experience or witnessing of traumatic events. The psychopathological response to traumatic stressors increases inflammation in the hippocampus and induces memory deficits. Melatonin (MTG) plays critical roles in circadian rhythm disorders, Alzheimer's disease, and other neurological disorders. However, the cognitive efficiency of MTG and its mechanisms of action in the treatment of PTSD remain unclear. Thus, the present study investigated the effects of MTG on spatial cognitive impairments stimulated by single prolonged stress (SPS) in rats, an animal model of PTSD. Male rats received intraperitoneal (i.p.) administration of various doses of MTG for 21 consecutive days after the SPS procedure. RESULTS: SPS-stimulated cognitive impairments in the object recognition task and Morris water maze were reversed by MTG treatment (25 mg/kg, i.p). Additionally, MTG significantly increased cognitive memory-related decreases in cAMP-response element-binding (CREB) protein and mRNA levels in the hippocampus. Our results also demonstrate that MTG significantly inhibited SPS-stimulated cognitive memory impairments by inhibiting the expression of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) in the rat brain. CONCLUSION: The present results indicate that MTG can be beneficial for SPS-stimulated memory impairments via changes in CREB expression and proinflammatory mediators. Thus, MTG may be a prophylactic strategy for the prevention or mitigation of the progression of some features of the PTSD pathology. PMID- 29973145 TI - Metabolically healthy and metabolically unhealthy obese children both have increased carotid intima-media thickness: a case control study. AB - BACKGROUND: The cardiovascular disease risk was assessed in metabolically healthy obese (MHO) children, obese children with metabolic disorders (MUO), and to a control group of normal-weight children using carotid intima-media thickness (CIMT). METHODS: Participants were 204 obese children (114 M, 90 F), including 162 MUO (74 M, 88 F) and 42 MHO (24 M, 18 F), and 99 gender- and age-matched controls (45 M, 54 F). Glucose, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, and other serum values were determined in peripheral blood. Anthropometric parameters, blood pressure, and a carotid Doppler ultrasound scan were also acquired. The mean CIMT of obese subjects and controls was compared by analysis of variance. Abnormality of even one of the metabolic parameters assessed involved assignation to the MUO group. Mean CIMT was compared in MHO and MUO children. RESULTS: Mean CIMT in control children was 402.97 +/- 53.18 MUm (left carotid artery) and 377.85 +/- 52.47 MUm (right carotid artery). In MHO and MUO patients CIMT was respectively 453.29 +/- 62.04 and 460.17 +/- 92.22 MUm (left carotid artery) and 446.36 +/- 49.21 and 456.30 +/ 85.7 MUm (right carotid artery). The mean CIMT was not significantly different in MUO and MHO children, whereas it showed a significant difference between both groups of obese children and controls (p < 0.01). CONCLUSION: CIMT was significantly greater in obese patients, also in those without metabolic alterations, than in normal-weight children. Obesity is therefore an important risk factor for cardiovascular disease in itself, also in the absence of metabolic abnormalities. PMID- 29973146 TI - Meta-analysis of binary outcomes via generalized linear mixed models: a simulation study. AB - BACKGROUND: Systematic reviews and meta-analyses of binary outcomes are widespread in all areas of application. The odds ratio, in particular, is by far the most popular effect measure. However, the standard meta-analysis of odds ratios using a random-effects model has a number of potential problems. An attractive alternative approach for the meta-analysis of binary outcomes uses a class of generalized linear mixed models (GLMMs). GLMMs are believed to overcome the problems of the standard random-effects model because they use a correct binomial-normal likelihood. However, this belief is based on theoretical considerations, and no sufficient simulations have assessed the performance of GLMMs in meta-analysis. This gap may be due to the computational complexity of these models and the resulting considerable time requirements. METHODS: The present study is the first to provide extensive simulations on the performance of four GLMM methods (models with fixed and random study effects and two conditional methods) for meta-analysis of odds ratios in comparison to the standard random effects model. RESULTS: In our simulations, the hypergeometric-normal model provided less biased estimation of the heterogeneity variance than the standard random-effects meta-analysis using the restricted maximum likelihood (REML) estimation when the data were sparse, but the REML method performed similarly for the point estimation of the odds ratio, and better for the interval estimation. CONCLUSIONS: It is difficult to recommend the use of GLMMs in the practice of meta-analysis. The problem of finding uniformly good methods of the meta-analysis for binary outcomes is still open. PMID- 29973147 TI - Predictors of high-cost hospitalization in the treatment of acute coronary syndrome in Asia: findings from EPICOR Asia. AB - BACKGROUND: The EPICOR Asia (long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients in Asia) study (NCT01361386) was an observational study of patients hospitalized for acute coronary syndromes (ACS) enrolled in 218 hospitals in eight countries/regions in Asia. This study examined costs, length of stay and the predictors of high costs during an ACS hospitalization. METHODS AND RESULTS: Data for patients hospitalized for an ACS (n = 12,922) were collected on demographics, medical history, event characteristics, socioeconomic and insurance status at discharge. Patients were followed up at 6 weeks' post-hospitalization for an ACS event to assess associated treatment costs from a health sector perspective. Primary outcome was the incurring of costs in the highest quintile by country and index event diagnosis, and identification of associated predictors. Cost data were available for 10,819 patients. Mean length of stay was 10.1 days. The highest-cost countries were China, Singapore, and South Korea. Significant predictors of high cost care were age, male sex, income, country, prior disease history, hospitalization in 3 months before index event, no dependency before index event, having an invasive procedure, hospital type and length of stay. CONCLUSIONS: Substantial variability exists in healthcare costs for hospitalized ACS patients across Asia. Of concern is the observation that the highest costs were reported in China, given the rapidly increasing numbers of procedures in recent years. TRIAL REGISTRATION: NCT01361386 . PMID- 29973148 TI - Development and validation of an updated computational model of Streptomyces coelicolor primary and secondary metabolism. AB - BACKGROUND: Streptomyces species produce a vast diversity of secondary metabolites of clinical and biotechnological importance, in particular antibiotics. Recent developments in metabolic engineering, synthetic and systems biology have opened new opportunities to exploit Streptomyces secondary metabolism, but achieving industry-level production without time-consuming optimization has remained challenging. Genome-scale metabolic modelling has been shown to be a powerful tool to guide metabolic engineering strategies for accelerated strain optimization, and several generations of models of Streptomyces metabolism have been developed for this purpose. RESULTS: Here, we present the most recent update of a genome-scale stoichiometric constraint-based model of the metabolism of Streptomyces coelicolor, the major model organism for the production of antibiotics in the genus. We show that the updated model enables better metabolic flux and biomass predictions and facilitates the integrative analysis of multi-omics data such as transcriptomics, proteomics and metabolomics. CONCLUSIONS: The updated model presented here provides an enhanced basis for the next generation of metabolic engineering attempts in Streptomyces. PMID- 29973149 TI - Secreted protein acidic and rich in cysteine-like 1 suppresses metastasis in gastric stromal tumors. AB - BACKGROUND: Malignant growth and metastasis of gastrointestinal stromal tumors (GIST) occur in some patients even during the course of treatment, but their mechanisms remains poorly understand at the molecular level so far. METHODS: Profiles of protein expression in gastric GIST tissues were explored using protein microarray analysis, down-regulation of SPARCL1 (secreted protein acidic and rich in cysteine-like protein 1) was validated by RT-qPCR, western blot and immunohistochemistry. The effect of specific shRNA-induced SPARCL1 downregulation on the biological traits of GIST 882 cell was investigated. We then employed a mouse xenograft model to investigate whether the low-expression of SPARCL1 impact the metastasis ability of GIST cells in vivo. RESULTS: SPARCL1 was significantly downregulated in the gastric GIST with high-grade malignance as compared with low grade malignance, its expression was closely correlated with tumor size, mitotic index, distant metastasis at the time of initial diagnosis and tumor progression of GIST (P < 0.05). Moreover, results of the Cox analysis showed that expression of SPARCL1 is an independent prognostic predictors for gastric GIST (P = 0.008; HR 0.157, 95% CI 0.040~ 0.612). Downregulation of SPARCL1 promoted cell migration and invasion, but did not affect proliferation, cell cycle and apoptosis of GIST 882 cells. In mouse xenograft model, GIST cells with the decreased expression of SPARCL1 presented an enhanced ability of liver metastasis (P < 0.05). CONCLUSIONS: Taken together, our present study demonstrated that SPARCL1 have a certain degree of malignancy-suppressing potential through inhibiting the metastasis of gastric GIST. PMID- 29973150 TI - ECMO use and mortality in adult patients with cardiogenic shock: a retrospective observational study in U.S. hospitals. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly used in resuscitation of critically ill patients with documented improved survival. Few studies describe ECMO use in cardiogenic shock. This study examines ECMO use and identifies variables associated with mortality in patients treated for cardiogenic shock in US hospitals. METHODS: A retrospective observational study of the US Nationwide Emergency Department Sample (NEDS) database of 2013 was conducted. Weighted visits for cardiogenic shock (discharge diagnosis) with ECMO use were included. Collected data was analyzed and variables associated with mortality were identified. RESULTS: A total of 922 weighted patients with cardiogenic shock and ECMO were included. Mean age was 50.8 years. They were more commonly males (66.3%; n = 658). Slightly over half (51.0%, n = 506) survived to hospital discharge. Mean charges per patient were $589,610.5. Mean length of stay was 21.8 days. Increased mortality was associated with presence of respiratory diseases (OR = 3.83), genitourinary diseases (OR = 4.97), undergoing an echocardiogram (OR = 4.63), and presenting during seasons other than Fall. Lower mortality was noted in patients with injury and poisoning (OR = 0.47), in those who underwent certain vascular procedures (OR = 0.49) and those with increasing length of stay (OR = 0.90). CONCLUSION: Mortality in patients with cardiogenic shock remains high despite ECMO use. Season of admission (other than Fall) and presence of specific comorbidities (Respiratory and genitourinary diseases) are associated with increased mortality in this population. Familiarity with these variables can help identify patients at higher risk of death and can help improve outcomes further in cardiogenic shock. PMID- 29973151 TI - Association between increased serum alkaline phosphatase and the coronary slow flow phenomenon. AB - BACKGROUND: Despite marked advances in our understanding of the pathophysiology of the coronary slow flow phenomenon (CSFP), the exact mechanism remains unclear. Previous studies have suggested that CSFP might be associated with generalized atherosclerosis, endothelial dysfunction, and low-grade chronic inflammation. High serum alkaline phosphatase (ALP) levels are associated with vascular calcification, atherosclerotic disease, and an increased risk of cardiovascular events. However, the relationship between ALP and CSFP is unclear. METHODS: We investigated 64 patients with angiographically proven CSFP and 50 with normal coronary flow. Serum ALP levels were measured in all studied individuals. RESULTS: Serum ALP levels in patients with CSFP were significantly higher than those in the control group (70.5 +/- 17.1 vs. 61.9 +/- 16.1 U/L, P = 0.007). A positive association was observed (r = 0.42, P = 0.032) between serum ALP levels and the mean thrombolysis in myocardial infarction frame count (mTFC). Regression analysis showed a high serum ALP level was the only independent predictor of the mTFC (beta = 0.309, P < 0.001). Moreover, our study showed that a serum ALP level > 67.5 U/L was a predictor of CSFP (sensitivity = 83.3%, specificity = 84.1%). CONCLUSIONS: Patients with CSFP show high serum ALP levels, which may be associated with the pathogenesis of CSFP. A high serum ALP level is a predictor of CSFP. Future studies are needed to clarify the role of ALP in patients with CSFP. PMID- 29973153 TI - Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy. AB - BACKGROUND: We have previously shown that 8 weeks' treatment with phenylbutyrate (PBA) (500mgx2/day) with or without vitamin D3 (vitD3) (5000 IU/day) as host directed therapy (HDT) accelerated clinical recovery, sputum culture conversion and increased expression of cathelicidin LL-37 by immune cells in a randomized, placebo-controlled trial in adults with pulmonary tuberculosis (TB). In this study we further aimed to examine whether HDT with PBA and vitD3 promoted clinically beneficial immunomodulation to improve treatment outcomes in TB patients. METHODS: Cytokine concentration was measured in supernatants of peripheral blood mononuclear cells (PBMC) from patients (n = 31/group). Endoplasmic reticulum stress-related genes (GADD34 and XBP1spl) and human beta defensin-1 (HBD1) gene expression were studied in monocyte-derived-macrophages (MDM) (n = 18/group) from PBMC of patients. Autophagy in MDM (n = 6/group) was evaluated using LC3 expression by confocal microscopy. RESULTS: A significant decline in the concentration of cytokines/chemokines was noted from week 0 to 8 in the PBA-group [TNF-alpha (beta = - 0.34, 95% CI = - 0.68, - 0.003; p = 0.04), CCL11 (beta = - 0.19, 95% CI = - 0.36, - 0.03; p = 0.02) and CCL5 (beta = - 0.08, 95% CI = - 0.16, 0.002; p = 0.05)] and vitD3-group [(CCL11 (beta = - 0.17, 95% CI = - 0.34, - 0.001; p = 0.04), CXCL10 (beta = - 0.38, 95% CI = - 0.77, 0.003; p = 0.05) and PDGF-beta (beta = - 0.16, 95% CI = - 0.31, 0.002; p = 0.05)] compared to placebo. Both PBA- and vitD3-groups showed a decline in XBP1spl mRNA on week 8 (p < 0.03). All treatment groups demonstrated increased LC3 expression in MDM compared to placebo over time (p < 0.037). CONCLUSION: The use of PBA and vitD3 as adjunct therapy to standard TB treatment promoted favorable immunomodulation to improve treatment outcomes. TRIALS REGISTRATION: This trial was retrospectively registered in clinicaltrials.gov, under identifier NCT01580007 . PMID- 29973152 TI - The first next-generation sequencing approach to the mitochondrial phylogeny of African monogenean parasites (Platyhelminthes: Gyrodactylidae and Dactylogyridae). AB - BACKGROUND: Monogenean flatworms are the main ectoparasites of fishes. Representatives of the species-rich families Gyrodactylidae and Dactylogyridae, especially those infecting cichlid fishes and clariid catfishes, are important parasites in African aquaculture, even more so due to the massive anthropogenic translocation of their hosts worldwide. Several questions on their evolution, such as the phylogenetic position of Macrogyrodactylus and the highly speciose Gyrodactylus, remain unresolved with available molecular markers. Also, diagnostics and population-level research would benefit from the development of higher-resolution genetic markers. We aim to offer genetic resources for work on African monogeneans by providing mitogenomic data of four species (two belonging to Gyrodactylidae, two to Dactylogyridae), and analysing their gene sequences and gene order from a phylogenetic perspective. RESULTS: Using Illumina technology, the first four mitochondrial genomes of African monogeneans were assembled and annotated for the cichlid parasites Gyrodactylus nyanzae, Cichlidogyrus halli, Cichlidogyrus mbirizei (near-complete mitogenome) and the catfish parasite Macrogyrodactylus karibae (near-complete mitogenome). Complete nuclear ribosomal operons were also retrieved, as molecular vouchers. The start codon TTG is new for Gyrodactylus and for Dactylogyridae, as is the incomplete stop codon TA for Dactylogyridae. Especially the nad2 gene is promising for primer development. Gene order was identical for protein-coding genes and differed between the African representatives of these families only in a tRNA gene transposition. A mitochondrial phylogeny based on an alignment of nearly 12,500 bp including 12 protein-coding and two ribosomal RNA genes confirms that the Neotropical oviparous Aglaiogyrodactylus forficulatus takes a sister group position with respect to the other gyrodactylids, instead of the supposedly 'primitive' African Macrogyrodactylus. Inclusion of the African Gyrodactylus nyanzae confirms the paraphyly of Gyrodactylus. The position of the African dactylogyrid Cichlidogyrus is unresolved, although gene order suggests it is closely related to marine ancyrocephalines. CONCLUSIONS: The amount of mitogenomic data available for gyrodactylids and dactylogyrids is increased by roughly one-third. Our study underscores the potential of mitochondrial genes and gene order in flatworm phylogenetics, and of next-generation sequencing for marker development for these non-model helminths for which few primers are available. PMID- 29973154 TI - Social networks in relation to self-reported symptomatic infections in individuals aged 40-75 - the Maastricht study. AB - BACKGROUND: Most infections are spread through social networks (detrimental effect). However, social networks may also lower infection acquisition (beneficial effect). This study aimed to examine associations between social network parameters and prevalence of self-reported upper and lower respiratory, gastrointestinal and urinary tract infections in a population aged 40-75. METHODS: In this population-based cross-sectional cohort study (N = 3004, mean age 60.0 +/- 8.2 years, 49% women), infections within the past two months were assessed by self-administered questionnaires. Social network parameters were assessed using a name generator questionnaire. To examine the associated beneficial and detrimental network parameters, univariable and multivariable logistic regression was used. RESULTS: Participants reported an average of 10 people (alters) with whom they had 231 contacts per half year. Prevalences were 31.1% for upper respiratory, 11.5% for lower respiratory, 12.5% for gastrointestinal, and 5.7% for urinary tract infections. Larger network size, and a higher percentage of alters that were friends or acquaintances were associated with higher odds of upper respiratory, lower respiratory and/or gastrointestinal infections (detrimental). A higher total number of contacts, higher percentages of alters of the same age, and higher percentages of family members/acquaintances were associated with lower odds of upper respiratory, lower respiratory and/or gastrointestinal infections (beneficial). CONCLUSION: We identified both detrimental and beneficial associations of social network parameters with the prevalence of infections. Our findings can be used to complement mathematical models on infection spread, as well as to optimize current infectious disease control. PMID- 29973155 TI - Extra-haematological manifestations related to human parvovirus B19 infection: retrospective study in 25 adults. AB - BACKGROUND: To describe extra-haematological manifestations associated with human parvovirus B19 (HPV-B19) infection. METHODS: We conducted a nationwide multicentre study to retrospectively describe the characteristics and outcome of extra-haematological manifestations in French adults. RESULTS: Data from 25 patients followed from 2001 to 2016 were analysed. Median age was 37.9 years (range: 22.7-83.4), with a female predominance (sex ratio: 4/1). Only 3 patients had an underlying predisposing condition (hemoglobinopathy or pregnancy). The most common manifestations were joint (80%) and skin (60%) involvement. Four patients (16%) had renal involvement (endocapillary proliferative or membranoproliferative glomerulonephritis, focal segmental glomerulosclerosis). Three patients (12%) had peripheral nervous system involvement (mononeuritis, mononeuritis multiplex, Guillain-Barre syndrome) and 2 (8%) presented muscle involvement. Other manifestations included hemophagocytic lymphohistiocytosis (n = 1), myopericarditis and pleural effusion (n = 1), and lymphadenopathy and splenomegaly mimicking lymphoma with spleen infarcts (n = 1). Immunological abnormalities were frequent (56.5%). At 6 months, all patients were alive, and 54.2% were in complete remission. In 2 patients, joint involvement evolved into rheumatoid arthritis. Six patients (24%) received intravenous immunoglobulin (IVIg), with a good response in the 3 patients with peripheral nervous system involvement. CONCLUSIONS: HPV-B19 infection should be considered in a wide range of clinical manifestations. Although the prognosis is good, IVIg therapy should be discussed in patients with peripheral nerve involvement. However, its efficacy should be further investigated in prospective studies. PMID- 29973156 TI - Gene expression polymorphism underpins evasion of host immunity in an asexual lineage of the Irish potato famine pathogen. AB - BACKGROUND: Outbreaks caused by asexual lineages of fungal and oomycete pathogens are a continuing threat to crops, wild animals and natural ecosystems (Fisher MC, Henk DA, Briggs CJ, Brownstein JS, Madoff LC, McCraw SL, Gurr SJ, Nature 484:186 194, 2012; Kupferschmidt K, Science 337:636-638, 2012). However, the mechanisms underlying genome evolution and phenotypic plasticity in asexual eukaryotic microbes remain poorly understood (Seidl MF, Thomma BP, BioEssays 36:335-345, 2014). Ever since the 19th century Irish famine, the oomycete Phytophthora infestans has caused recurrent outbreaks on potato and tomato crops that have been primarily caused by the successive rise and migration of pandemic asexual lineages (Goodwin SB, Cohen BA, Fry WE, Proc Natl Acad Sci USA 91:11591-11595, 1994; Yoshida K, Burbano HA, Krause J, Thines M, Weigel D, Kamoun S, PLoS Pathog 10:e1004028, 2014; Yoshida K, Schuenemann VJ, Cano LM, Pais M, Mishra B, Sharma R, Lanz C, Martin FN, Kamoun S, Krause J, et al. eLife 2:e00731, 2013; Cooke DEL, Cano LM, Raffaele S, Bain RA, Cooke LR, Etherington GJ, Deahl KL, Farrer RA, Gilroy EM, Goss EM, et al. PLoS Pathog 8:e1002940, 2012). However, the dynamics of genome evolution within these clonal lineages have not been determined. The objective of this study was to use a comparative genomics and transcriptomics approach to determine the molecular mechanisms that underpin phenotypic variation within a clonal lineage of P. infestans. RESULTS: Here, we reveal patterns of genomic and gene expression variation within a P. infestans asexual lineage by comparing strains belonging to the South American EC-1 clone that has dominated Andean populations since the 1990s (Yoshida K, Burbano HA, Krause J, Thines M, Weigel D, Kamoun S, PLoS Pathog 10e1004028, 2014; Yoshida K, Schuenemann VJ, Cano LM, Pais M, Mishra B, Sharma R, Lanz C, Martin FN, Kamoun S, Krause J, et al. eLife 2:e00731, 2013; Delgado RA, Monteros-Altamirano AR, Li Y, Visser RGF, van der Lee TAJ, Vosman B, Plant Pathol 62:1081-1088, 2013; Forbes GA, Escobar XC, Ayala CC, Revelo J, Ordonez ME, Fry BA, Doucett K, Fry WE, Phytopathology 87:375 380, 1997; Oyarzun PJ, Pozo A, Ordonez ME, Doucett K, Forbes GA, Phytopathology 88:265-271, 1998). We detected numerous examples of structural variation, nucleotide polymorphisms and loss of heterozygosity within the EC-1 clone. Remarkably, 17 genes are not expressed in one of the two EC-1 isolates despite apparent absence of sequence polymorphisms. Among these, silencing of an effector gene was associated with evasion of disease resistance conferred by a potato immune receptor. CONCLUSIONS: Our findings highlight the molecular changes underpinning the exceptional genetic and phenotypic plasticity associated with host adaptation in a pandemic clonal lineage of a eukaryotic plant pathogen. We observed that the asexual P. infestans lineage EC-1 can exhibit phenotypic plasticity in the absence of apparent genetic mutations resulting in virulence on a potato carrying the Rpi-vnt1.1 gene. Such variant alleles may be epialleles that arose through epigenetic changes in the underlying genes. PMID- 29973158 TI - Correlation of clinical illness with viremia in Zika virus disease during an outbreak in Singapore. AB - BACKGROUND: The first autochthonous Zika virus (ZIKV) outbreak in Singapore was detected in August 2016. We report an analysis of the correlation of clinical illness with viremia and laboratory parameters in this Asian cohort. METHODS: We conducted a prospective longitudinal cohort study of patients with a positive blood ZIKV polymerase chain reaction (PCR) result who were admitted to Tan Tock Seng Hospital, Singapore, for isolation and management. RESULTS: We included 40 patients in our study. Rash was present in all patients, while 80% (32/40) had fever, 62.5% (25/40) myalgia, 60% (24/40) conjunctivitis and 38% (15/40) arthralgia. The median duration of viremia was 3.5 days (IQR: 3-5 days). Patients with viremia of >=4 days were more likely to have prolonged fever compared to those with viremia of less than 4 days (95% versus 63%, p = 0.01), but had no significant correlation with other clinical signs and symptoms, or laboratory investigations. However, 21 patients (53%) had hypokalemia despite the absence of gastrointestinal symptoms. CONCLUSION: Although fever correlated with duration of viremia, 30% of patients remained viremic despite defervescence. Laboratory abnormalities such as leukopenia or thrombocytopenia were not prominent in this cohort but about half the patients were noted to have hypokalemia. PMID- 29973157 TI - Transcriptome analysis of alternative splicing in peanut (Arachis hypogaea L.). AB - BACKGROUND: Alternative splicing (AS) represents a mechanism widely used by eukaryotes for the post-transcriptional regulation of genes. The detailed exploration of AS in peanut has not been documented. RESULTS: The strand-specific RNA-Seq technique was exploited to characterize the distribution of AS in the four samples of peanut (FH1-seed1, FH1-seed2, FH1-root and FH1-leaf). AS was detected as affecting around 37.2% of the full set of multi-exon genes. Some of these genes experienced AS throughout the plant, while in the case of others, the effect was organ-specific. Overall, AS was more frequent in the seed than in either the root or leaf. The predominant form of AS was intron retention, and AS in transcription start site and transcription terminal site were commonly identified in all the four samples. It is interesting that in genes affected by AS, the majority experienced only a single type of event. Not all of the in silico predicted transcripts appeared to be translated, implying that these are either degraded or sequestered away from the translation machinery. With respect to genes involved in fatty acid metabolism, about 61.6% were shown to experience AS. CONCLUSION: Our report contributes significantly in AS analysis of peanut genes in general, and these results have not been mentioned before. The specific functions of different AS forms need further investigation. PMID- 29973159 TI - Characterizing interactions of Leptospira interrogans with proximal renal tubule epithelial cells. AB - BACKGROUND: Leptospira interrogans is a pathogenic, spirochetal bacterium that is responsible for leptospirosis, an emerging worldwide zoonosis. Leptospires colonize the renal proximal tubules and chronically infect the kidney. Live bacteria are excreted into urine, contaminating the environment. While it is well known that leptospires can persist in the kidneys without signs of disease for several months, the interactions of leptospires with the proximal renal epithelial tubule cells that allow the chronic renal colonization have not been elucidated yet. In the present study, we compared the interactions between a virulent, low passage (LP) strain and a cultured-attenuated, high passage (HP) strain with renal proximal tubule epithelial cells (RPTECs) to elucidate the strategies used by Leptospira to colonize the kidney. RESULTS: Kinetics analysis of kidney colonization in a mouse model of chronic infection performed by quantitative real-time PCR and immunofluorescence, showed that the LP strain reached the kidney by 3 days post infection (pi) and attached to the basal membrane side of the renal epithelial cells. At 10 days pi, some leptospires were attached to the luminal side of the tubular epithelia and the number of colonizing leptospires gradually increased. On the other hand, the HP strain was cleared during hematogenous dissemination and did not colonize the kidney. Transmission electron microscopy analysis of LP-infected kidneys at 25 days pi showed aggregated leptospires and membrane vesicles attached to the epithelial brush border. Leptospiral kidney colonization altered the organization of the RPTEC brush border. An in vitro model of infection using TCMK-1 cells, showed that leptospiral infection induced a host stress response, which is delayed in LP infected cells. CONCLUSIONS: After hematogenous dissemination, leptospires create protective and replicative niches in the base membrane and luminal sides of the RPTECs. During the long-term colonization, leptospires attached to the RPTEC brush borders and membrane vesicles might be involved in the formation of a biofilm-like structure in vivo. Our results also suggested that the virulent strain is able to manipulate host cell stress responses to promote renal colonization. PMID- 29973161 TI - Identification of deletion-duplication in HEXA gene in five children with Tay Sachs disease from India. AB - BACKGROUND: Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion. METHODS: Multiplex Ligation dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene. RESULTS: The study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527 2A > T as a second allele. CONCLUSION: This is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene. PMID- 29973160 TI - Fine-scale genetic structure of the European bitterling at the intersection of three major European watersheds. AB - BACKGROUND: Anthropogenic factors can have a major impact on the contemporary distribution of intraspecific genetic diversity. Many freshwater fishes have finely structured and locally adapted populations, but their natural genetic structure can be affected by river engineering schemes across river basins, fish transfers in aquaculture industry and conservation management. The European bitterling (Rhodeus amarus) is a small fish that is a brood parasite of freshwater mussels and is widespread across continental Europe. Its range recently expanded, following sharp declines in the 1970s and 1980s. We investigated its genetic variability and spatial structure at the centre of its distribution at the boundary of three watersheds, testing the role of natural and anthropogenic factors in its genetic structure. RESULTS: Sequences of mitochondrial cytochrome B (CYTB) revealed that bitterling colonised central Europe from two Ponto-Caspian refugia, which partly defines its contemporary genetic structure. Twelve polymorphic microsatellite loci revealed pronounced interpopulation differentiation, with significant small-scale differentiation within the same river basins. At a large scale, populations from the Baltic Sea watershed (middle Oder and Vistula basins) were distinct from those from the Black Sea watershed (Danube basin), while populations from rivers of the North Sea watershed (Rhine, Elbe) originated from the admixture of both original sources. Notable exceptions demonstrated the potential role of human translocations across watersheds, with the upper River Oder (Baltic watershed) inhabited by fish from the Danube basin (Black Sea watershed) and a population in the southern part of the River Elbe (North Sea watershed) basin possessing a signal of admixture from the Danube basin. CONCLUSIONS: Hydrography and physical barriers to dispersal are only partly reflected in the genetic structure of the European bitterling at the intersection of three major watersheds in central Europe. Drainage boundaries have been obscured by human-mediated translocations, likely related to common carp, Cyprinus carpio, cultivation and game-fish management. Despite these translocations, populations of bitterling are significantly structured by genetic drift, possibly reinforced by its low dispersal ability. Overall, the impact of anthropogenic factors on the genetic structure of the bitterling populations in central Europe is limited. PMID- 29973162 TI - Preoperative serum uric acid predicts incident acute kidney injury following cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is a frequent complication and several risk factors increasing its incidence have already been characterized. This study evaluates the influence of preoperative increased serum uric acid (SUA) levels in comparison with other known risk factors on the incidence of AKI following cardiac surgery. METHODS: During a period of 5 month, 247 patients underwent elective coronary artery bypass grafting, valve replacement/ repair or combined bypass and valve surgery. Datas were prospectively analyzed. Primary endpoint was the incidence of AKI as defined by the AKI criteria comparing patients with preoperative serum uric acid (SUA) levels below versus above the median. Multivariate logistic regression analysis was used to identify independent predictors of postoperative AKI. RESULTS: Thirty (12.1%) of the 247 patients developed postoperative AKI, 24 of 30 (80%) had preoperative SUA- levels above the median (>=373 MUmol/l) (OR: 4.680, CI 95% 1.840; 11.904, p = 0.001). In the multivariate analysis SUA levels above the median (OR: 5.497, CI 95% 1.772; 17.054, p = 0.003), cardiopulmonary bypass (CPB) time > 90 min (OR: 4.595, CI 95% 1.587; 13.305, p = 0.005), cardiopulmonary bypass (CPB) > 30 kg/m2 (OR: 3.208, CI 95% 1.202; 8.562; p = 0.02), and preoperative elevated serum-creatinine levels (OR: 1.015, CI 95% 1.001; 1.029, p = 0.04) were independently associated with postoperative AKI. CONCLUSIONS: Serum uric acid is an independent risk marker for AKI after cardiac surgery. From all evaluated factors it showed the highest odds ratio. PMID- 29973163 TI - Factors associated with type 2 diabetes in patients with vascular dementia: a population-based cross-sectional study. AB - BACKGROUND: Incidence of dementia is growing rapidly and affects many people worldwide. Type 2 diabetes mellitus (DM) might link cognitive decline and dementia, but the reasons for this association remain unclear. Our study explored the factors associated with type 2 DM in patients with dementia. METHODS: Patients (n = 40,404) with vascular dementia were identified in Taiwan's 1997 to 2008 National Health Insurance Research Database and divided into a DM group and non-DM group. Eleven comorbidities were identified and categorized into four groups: cardiovascular and cerebrovascular diseases, digestive system diseases, renal and metabolic system diseases, and cancer. The associations of these factors with type 2 DM were explored through multivaraible logistic regression. RESULTS: Of the patients with dementia, 22.5% had DM. Associated with a higher likelihood of DM in this population were female sex (adjusted odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.36-1.52), young age (range of adjusted OR: 0.55-1.13), low income (range of adjusted OR: 1.09-1.18), and renal and metabolic system diseases (OR: 2.81, 95% CI: 2.64-2.98). CONCLUSIONS: The findings of this study suggest that clinicians should encourage patients with dementia to receive regular glucose impairment screening if they are female, have low socioeconomic status, or have renal or metabolic diseases. PMID- 29973164 TI - Is there a relationship between fetal sex and placental pathological characteristics in twin gestations? AB - BACKGROUND: Placenta plays a central role in mediating growth and development of fetuses. Sex-specific placentas may complicate this role. METHODS: The study aimed at investigating the association between fetal sex and placental pathological findings in twin gestations using generalized estimating equation modeling. We used a large population-based clinical data born in British Columbia (BC) and linked the fetal-maternal data to hand-searched pathology reports of 1493 twin placentas from twins born in BC Women hospital. We analyzed the data using generalized estimating equations taking the cluster nature of twins into consideration. RESULTS: About 26.5% of twins were monochorionic and 73.5% were dizygotic. Most twins were male (51.3%). About 2/3 of twins were sex concordant (66.6%). Of the sex concordant twins, similar percentages were male-male (34.7%) and female-female (31.2%). Of the sex discordant twins, the male-female (33.3%) group constituted about 1/3 of the whole population. Adjusted for chorionicity, birth weight discordance >=30% and gestational age, the odds of chorionitis (1.38, 95% CI = 1.04-1.84), anastomosis (1.63, 95% CI = 1.22-2.19), unequal sharing of placenta (1.72, 95% CI = 1.11-2.64), placental inflammation (1.30, 95% CI = 1.05-1.62) and lesions (1.83, 95% CI = 1.02-3.31) were higher in male twins compared with females. Twins of either sex from sex-discordant pairs were less likely to have placental anastomosis compared to the reference category. Males from male-male pairs had higher odds of unequal placental sharing (74% higher) and composite inflammation (52% higher) compared with the reference twins. CONCLUSION: Our findings suggest a relationship between sex and placental pathological results. PMID- 29973165 TI - The TALENT II study: a randomized controlled trial assessing the impact of an individual health management (IHM) on stress reduction. AB - BACKGROUND: Unfavorable lifestyle factors influence the risk of stress disorders. For risk reduction, lifestyle modifications, such as regular physical activity, balanced nutrition and competence in stress management, are a means of choice. The clinical study examines the efficacy of an intensive lifestyle intervention, named Individual Health Management (IHM), - with regard to a reduction of perceived stress. The study is supported by the major regional health insurance, which conducts, in cooperation with the Traditional Chinese Medicine (TCM) hospital, Bad Kotzting, a local model project offering insurants the IHM program as prevention measure against stress and related aftermath. METHODS: The study is a controlled, randomized, monocentric trial with a 12-months intervention phase. Feasible persons are checked according to inclusion and exclusion criteria and assigned to the intervention or control group. Randomization ratio is 1:1. (A) Participants of the intervention group receive the lifestyle program IHM, have access to a web-based health portal ( www.viterio.de ), and join 3 full-day and 10 two-hour training sessions during the first 3 months. During the remaining 9 months, 4 training sessions and a weekly monitoring are performed with remote assistance. Besides measurement of perceived stress, examinations include burnout symptoms, heart rate variability, laboratory and physical findings. Further patient reported outcomes are documented (e.g. well-being, life satisfaction, severity of mood state, sense of coherence, psycho-vegetative test, cardio metabolic risk factors, hypertension and diabetes risk. (B) Participants in the control group have access to the intensive lifestyle intervention IHM after a waiting period of at least 6 months. Examinations are conducted at baseline, after 3 and 6 months and in the intervention group additionally after 9 and 12 months. The confirmatory analysis examines the differences between the two groups with regard to changes in perceived stress after 6 months compared to the initial value. DISCUSSION: In order to enhance adherence, avoid attrition and to insure data quality, different measures will be implemented in the study. Based on a blended learning concept including a web-based e-health tool named VITERIO(r), the program promises to achieve sustainable effects in perceived stress. TRIAL REGISTRATION: German Clinical Trial Register Freiburg (DRKS): DRKS00013040 (date registered 2017-10-1). PMID- 29973166 TI - Does work-personal life interference predict turnover among male and female managers, and do depressive symptoms mediate the association? A longitudinal study based on a Swedish cohort. AB - BACKGROUND: In the present study we used a longitudinal design to examine if work personal life interference predicted managerial turnover, if depressive symptoms mediated the association, and if the relationships differed by gender. METHODS: Data were drawn from four waves (2010, 2012, 2014 and 2016) of the Swedish Longitudinal Occupational Survey of Health (SLOSH), a cohort of the Swedish working population. Participants who in any wave reported to have a managerial or other leading position were included (n = 717 men and 741 women). Autoregressive longitudinal mediation models within a multilevel structural equation modelling (MSEM) framework, in which repeated measures (level 1) were nested within individuals (level 2), were fitted to data. First, bivariate autoregressive and cross-lagged paths between the variables were fitted in gender stratified models. Secondly, a full gender stratified mediation model was built to estimate if the association between work-personal life interference and turnover was mediated through depressive symptoms. Gender differences in cross-lagged paths were estimated with multiple-group analysis. All analyses were adjusted for age, education, labour market sector, civil status and children living at home, and conducted in MPLUS 7. RESULTS: In both genders there were significant paths between work-personal life interference and turnover. Depressive symptoms were, however, not found to mediate in the relationship between work-personal life interference and turnover. The models differed significantly between genders. CONCLUSIONS: Establishing organisational prerequisites for good work-personal life balance among managers may be a means to retain both male and female managerial talent. PMID- 29973167 TI - Medication adherence to antiretroviral therapy among newly treated people living with HIV. AB - BACKGROUND: Free antiretroviral therapy has been implemented in China since 2004, but adherence to antiretroviral therapy among people living with HIV is suboptimal. The effectiveness of antiretroviral therapy is subject to medication adherence, which decreases with prolonged treatment times. The aim of this study was to investigate medication adherence and related factors among people living with HIV with newly initiated antiretroviral therapy. METHODS: This observational study was conducted in consecutive samples of people living with HIV who had newly initiated antiretroviral therapy. Participants were recruited between March 1, 2013, and August 31, 2014, from the local Center for Disease Control and Prevention and Infectious Disease hospital in a capital city in central China. A standard set of questionnaires was adopted, including the Community Programs for Clinical Research on AIDS Antiretroviral Medications and Self-Report Questionnaire (CPCRA), the Patient Health Questionnaire-9 (PHQ-9) and the 7-item Generalized Anxiety Disorder Scale (GAD-7). T-test, Chi square test and multivariate logistic regression analysis with backward stepwise were performed to explore factors that might influence medication adherence. RESULTS: Of the 207 participants, 85.5% of the participants (177/207) were categorized with good adherence, and 14.5% (30/207) with poor adherence. The multivariate logistic regression analyses showed that participants with positive depression (OR = 5.95, 95% CI: 2.34-15.11) and without disclosure of their HIV status to others (OR = 2.62, 95% CI: 1.06-6.50) were more susceptible to poor adherence. CONCLUSIONS: One-sixth of the participants reported suboptimal medication adherence within the first 6 months. Factors associated with poor adherence included non-disclosure of their HIV status, had positive depression. Tailored interventions, such as effective psychological coping strategies, should be implemented for people living with HIV with newly initiated antiretroviral therapy to improve their medication adherence. PMID- 29973168 TI - Bilineal inheritance of pathogenic PKD1 and PKD2 variants in a Czech family with autosomal dominant polycystic kidney disease - a case report. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder, leading to end stage renal failure and kidney transplantation in its most serious form. The severity of the disease's manifestation depends on the genetic determination of ADPKD. The huge variability of different phenotypes (even within a single family) is not only modulated by the two main ADPKD genes (PKD1 and PKD2) but also by modifier genes and the whole genetic background. CASE PRESENTATION: This is a report of an ADPKD family with co-inheritance of PKD1 and PKD2 pathogenic variants. The proband, with an extremely serious manifestation of ADPKD (the man was diagnosed in early childhood, and with end stage renal disease aged 23), underwent genetic analysis of PKD1 and PKD2, which revealed the presence of pathogenic mutations in both of these genes. The missense PKD2 mutation p.Arg420Gly came from the proband's father, with a mild ADPKD phenotype. The same mutation of the PKD2 gene and similar mild disease presentation were found in the proband's aunt (father's sister) and her son. The nonsense mutation p.Gln2196* within the PKD1 gene was probably inherited from the proband's mother, who died at the age of 45. It was only discovered post mortem, that the real cause of her death was kidney failure as a consequence of untreated ADPKD. Unfortunately, neither the DNA of the proband's mother nor the DNA of any other family members from this side of the pedigree were available for further examination. The proband underwent successful cadaveric kidney transplantation at the age of 24, and this replacement therapy lasted for the next 15 years. CONCLUSIONS: Here, we present a first case of bilineal ADPKD inheritance in the Czech Republic. This report highlights the significant role of modifier genes in genetic determination of ADPKD, especially in connection with seriously deteriorated disease phenotypes. In our case, the modifying role is probably mediated by the PKD2 gene. PMID- 29973169 TI - Green dialysate and gallbladder perforation in a peritoneal dialysis patients: a case report and literature review. AB - BACKGROUND: Gallbladder perforation is a rare but lethal condition and its diagnosis is usually difficult and delayed. Frequently, gallbladder rupture is associated with cholecystitis, but spontaneous perforation was ever described. However, spontaneous rupture of gallbladder has never been reported in patients underwent peritoneal dialysis. CASE PRESENTATION: We report a 62-year-old man who presented with abdominal pain for 2 days to clinic. Peritoneal dialysis-related peritonitis was diagnosed initially. It was followed by spontaneous gallbladder perforation with greenish dialysate. The patient was managed successfully by antibiotic treatment and primary closure of gallbladder perforation with external drainage. He recovered from this critical condition and stayed on dialysis. CONCLUSIONS: Early diagnosis and timely surgical intervention yields a good prognosis in PD patients with gallbladder perforation. Surgical intervention and antibiotic treatment are the mainstay of treatment. Both of them should take place promptly. PMID- 29973170 TI - A village-matched evaluation of providing a local supplemental food during pregnancy in rural Bangladesh: a preliminary study. AB - BACKGROUND: Prenatal balanced protein energy supplementation consumed by undernourished women improves mid-upper arm circumference in early infancy. This study aimed to identify whether locally produced maternal food-based supplementation improved anthropometric measures at birth and early infancy. METHODS: A village-matched evaluation, applying principles of a cluster randomised controlled trial, of a locally produced supplemental food to 87 undernourished pregnant women. 12 villages (intervention: n = 8; control: n = 4) in Pirganj sub-district, Rangpur District, northern Bangladesh. Daily supplements were provided. RESULTS: Anthropometric data at birth were available for 77 mother infant dyads and longer-term infant growth data for 75 infants. Mid-upper arm circumference (MUAC) was significantly larger in infants of mothers in the intervention group compared with the control group at 6 months (p < 0.05). The mean birth weight in babies of supplemented mothers (mean: 2.91 kg; SD: 0.19) was higher than in babies of mothers in the control group (mean: 2.72 kg; SD: 0.13), and these changes persisted until 6 months. Also, the proportion of low birth weight babies in the intervention group was much lower (event rate = 0.04) than in the control group (event rate = 0.16). However, none of these differences were statistically significant (p > 0.05; most likely due to small sample size). The intervention reduced the risk of wasting at 6 months by 63.38% (RRR = 0.6338), and of low birth weight by 88.58% (RRR = 0.8858), with NNT of 2.22 and 6.32, respectively. Only three pregnant women require this intervention in order to prevent wasting at 6 months in one child, and seven need the intervention to prevent low birth weight of one child. CONCLUSIONS: Locally produced food-based balanced protein energy supplementation in undernourished pregnant women in northern Bangladesh resulted in larger MUAC in infants at 6 months. Further research, with larger sample sizes, is required to confirm the role of locally produced supplementation for undernourished pregnant women on weight and linear growth in newborns and infants. TRIAL REGISTRATION: This research was registered with the ISRCTN registry (ISRCTN97447076). This project had human research ethical approval from the James Cook University (Australia) Ethics committee (H4498) and the Bangladesh Medical Research Council (BMRC/NREC/2010-2013/58). PMID- 29973171 TI - The role of counseling on modern contraceptive utilization among HIV positive women: the case of Northwest Ethiopia. AB - BACKGROUND: Over 90% of the children with Human Immunodeficiency Virus are infected through the mother to child transmission process according to literatures. Preventing unintended pregnancy by using contraceptive methods is crucial for reducing maternal and child mortality and morbidity. Here we set out to assess the prevalence and associated factors of modern contraceptive utilization among sexually active reproductive age women attending Anti Retroviral Therapy clinics in Amhara Region referral hospitals in 2016. METHODS: An institution based cross sectional study was carried out from April to July 2016 surveying women of reproductive age attending the Anti-Retroviral Therapy clinics in the five Amhara Region referral hospitals. A pretested and semi structured questionnaire was used to collect data. EpiInfo7 and SPSS version 20 soft wares were used for data entry and analysis, respectively. Significant associations were identified on the basis of the adjusted odds ratio, with 95% Confidence Interval, and p value <=0.05, was taken as statistically significant. RESULT: The proportion of women utilizing modern contraceptives was 47.7% with (95% CI: 43, 52.5%), the male condom being the most (64.2%) utilized method. The use of the contraceptive methods was most prevalent among women 15-24 years of age (AOR = 6.5, 95% CI: 2-10) and age of 25-34 (AOR = 3, 95% CI: 1.6-5.5), having an urban residence (AOR = 0.095, 95% CI: 0.03-0.28), having discussed contraceptives with partner (AOR = 7, 95% CI: 5.3-11.9), receiving counseling from health care providers (AOR = 4.8, 95% CI: 1.8-7), previous history of contraceptive utilization (AOR = 5.6, 95% CI: 2.6-8.3), and with CD4 count >500mm3/dl (AOR = 2.4, 95% CI: 1.3-4.3). CONCLUSION: The proportion of women utilizing contraceptive has been low in Amhara Region referral hospitals. Encouraging patients to discuss about contraception with partners and repeated counseling by health care providers may strengthen contraceptive utilization. PMID- 29973172 TI - What are the effects of supporting early parenting by enhancing parents' understanding of the infant? Study protocol for a cluster-randomized community based trial of the Newborn Behavioral Observation (NBO) method. AB - BACKGROUND: Support to strengthen the early parent-infant relationship is recommended to ensure the infant's future health and development. Little is known about the universal approaches taken by health visitor to support this early relationship. The aim of this study is to investigate the effects of health visitors' use of the Newborn Behavioral Observation (NBO) method among new parents. METHODS: This is a cluster-randomised community-based study implemented in four Danish municipalities. Health visitors will conduct the trial, and the geographical districts they work in will constitute the clusters as units of randomisation. The participants will be approximately 2800 new families, randomised into an intervention or a comparison group according to their health visitor. The families are recruited at the first postpartum home visit. Parents in both groups receive care as usual: parents in the intervention group also receive the standardised NBO method in home visits performed from 3 weeks to 3 months postpartum. Data consist of self-reported parent questionnaires and video recordings of a selected group of vulnerable first-time mothers recorded 4 months postpartum. The self-reported data are obtained: at baseline 1 week postpartum and then at follow-up 3, 9 and 18 months postpartum. Data will be analysed using the intention-to-treat method and the analyses will include comparison of change in the primary variables across time supplemented by multiple regression analysis. The primary study outcomes are measured by the following factors: parental confidence, infants' socio-emotional development and mother-infant relationship. Other measures include parental mood and stress, breastfeeding duration and utility of the health visitor services. Data collection among the health visitors in both groups will serve to monitor any change in practice regarding the work with early parent-infant interactions. DISCUSSION: This protocol describes an evaluation of the NBO method used universally in health visiting practice. The intervention seeks to support early parenting by increasing parents' understanding of their infants' cues. The NBO is currently implemented in Denmark even though an evaluation of the NBO has yet to be made in a community setting in Denmark and internationally. The study may contribute to building an increasingly evidence-based practice for health visitors. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03070652 . Registered February 22, 2017. PMID- 29973173 TI - The association between age and accelerometry-derived types of habitual daily activity: an observational study over the adult life span in the Netherlands. AB - BACKGROUND: Advances in sensor technology allow for objective and high-resolution monitoring of physical activity and sedentary behaviour. Novel epidemiological data is required to provide feedback on an individual's habitual daily activity in comparison to peers and might eventually lead to refined physical activity guidelines. METHODS: We merged data of 762 people between 18 and 99 years of age, who all wore a DynaPort MoveMonitor accelerometer on their lower back during 1 week in daily-life, to provide insight into habitual types and durations of daily activities, and examine the association between age and physical activity and sedentary behaviour. RESULTS: We found associations between age and almost all activity outcomes. These associations suggested that physical activity declines and sedentary behaviour increases from the age of 50. We further describe an association with gender, with men walking more often in fewer but longer bouts and having fewer, longer bouts of sitting and standing. CONCLUSIONS: These data provide a valuable reference and may call for more age- and gender-specific activity interventions. PMID- 29973174 TI - Association of recent gay-related stressful events with depressive symptoms in Chinese men who have sex with men. AB - BACKGROUND: To assess the association of different gay-related stressful events (GRSEs) with depressive symptoms in Chinese men who have sex with men (MSM). METHOD: A total of 807 MSM were recruited using respondent-driven sampling from four cities in northeastern China. GRSEs were measured using the Gay Related Stressful Life Events Scale, and depressive symptoms were assessed using the Self Rating Depression Scale (SDS). RESULTS: A total of 26.0% of study participants experienced GRSEs in the past three months, and the average SDS score was lower than the previously reported national average for China. The study participants had significantly elevated risks of depression (SDS score >= 53) due to recent troubles with a boss (OR = 4.92, 95% CI = 1.87-12.97) or a workmate (OR = 3.68, 95% CI = 1.52-8.88), loss of a close friend (OR = 2.41, 95% CI = 1.39-4.18), argument with a close friend (OR = 2.07, 95% CI = 1.33-3.22), and being physically assaulted (OR = 2.08, 95% CI = 0.98-4.43). Arguments with family members or classmates had no significant effect on depression. Multiple logistic regression analysis showed that the number of GRSEs, a lower level of education, more advanced age, and HIV infection significantly increased the risk of depression. CONCLUSIONS: There are large differences in the associations of different types of GRSEs with depressive symptoms. Reducing the stigmatization and discrimination toward MSM in all social environments and improving the capability of MSM to cope with different types of GRSEs may improve their emotional wellbeing. PMID- 29973175 TI - Donation after brain death followed by circulatory death, a novel donation pattern, confers comparable renal allograft outcomes with donation after brain death. AB - BACKGROUND: Organ donation after brain death (DBD) is the standard strategy for organ transplantation; however, the concept of brain death is not universally accepted due to cultural beliefs and barriers amongst billions of people worldwide. Hence, a novel donation pattern has been established in China which outlines the concept of donation after brain death followed by circulatory death (DBCD). Differently from any current donation classification, this new concept is formulated based on combination of recognizing brain death and circulatory death. Should approval be gained for this definition and approach, DBCD will pave a novel donation option for billions of people who cannot accept DBD due to their cultural beliefs. METHODS: A multi-center, cohort study was conducted from February 2012 to December 2015. 523 kidney transplant recipients from four kidney transplant institutions were enrolled into the study, of which, 383 received kidneys from DBCD, and 140 from DBD. Graft and recipient survivals following transplantation were retrospectively analyzed. Postoperative complications including delayed graft function,, and acute rejection, were also analyzed for both groups. RESULTS: DBCD could achieve comparable graft and recipient survivals in comparison with DBD (Log-rank P = 0.32 and 0.86,respectively). One-year graft and recipient survivals were equal between DBCD and DBD groups (97.4% versus 97.9%, P = 0.10;98.4% versus 98.6%, P = 1.0, respectively). Furthermore, DBCD did not increase incidences of postoperative complications compared with DBD, including delayed graft function (19.3% versus 22.1%, P = 0.46) and acute rejection (9.1% versus 8.6%, P = 1.0). Additionally, antithymocyte globulin as induction therapy and shorter warm ischemia time decreased incidence of delayed graft function in DBCD group (16.8% on antithymocyte globulin versus 27.2% on basiliximab, P = 0.03; 16.7% on <=18 min versus 26.7% on > 18 min group, P = 0.03). CONCLUSIONS: Kidney donation through DBCD achieves equally successful outcomes as DBD, and could provide a feasible path to graft availability for billions of people who face barriers to organ donation from DBD. PMID- 29973177 TI - Management of Caesarean scar pregnancy with or without methotrexate before curettage: human chorionic gonadotropin trends and patient outcomes. AB - BACKGROUND: To evaluate the effects of systemic methotrexate in cesarean scar pregnancy (CSP) patients treated with ultrasound-guided suction curettage. METHODS: A retrospective review of all women presenting with CSP treated with ultrasound-guided suction curettage at Tongji Hospital, Wuhan, China, between January 1, 2013 and December 31, 2015, was conducted. Patients were grouped into those not treated with methotrexate before curettage (group 1), treated with methotrexate by intramuscular injection (group 2) and treated with methotrexate by intravenous injection (group 3). The clinical characteristics and outcomes were analyzed. RESULTS: Among 107 patients, 47 patients were not treated with methotrexate before curettage, 46 patients had methotrexate administered by intramuscular injection and 14 patients had methotrexate injected intravenously. There were no significant differences among the groups in basic and clinical characteristics, such as age, gravity, parity, positive fetal heart beat and gestational age at diagnosis. Patients presented similar initial human chorionic gonadotropin (hCG) levels in all groups. After treatment with methotrexate or curettage, the percentage changes and varied ranges of the hCG levels were also similar in all groups. There were no significant differences in intraoperative blood loss and retained products of conception among the three groups. However group 1 had significantly shorter hospital stays than the two groups that were treated with methotrexate (p<0.001). CONCLUSION: By grouping CSP patients who shared similar age, gravity, parity, fetal heart beat positive and gestational age at diagnosis, we found that the presence or absence of methotrexate treatment before curettage resulted in comparable outcomes and hCG levels, although patients who were not treated with methotrexate had significantly shorter stays in the hospital. PMID- 29973176 TI - Cancer incidence and mortality rates and trends in Trinidad and Tobago. AB - BACKGROUND: Cancer is the second leading cause of death in the Caribbean, including the islands of Trinidad and Tobago (TT). The population of TT consists of over 1.3 million people with diverse ancestral and sociocultural backgrounds, both of which may influence cancer incidence and mortality. The objective of this study was to examine incidence and mortality patterns and trends in TT. METHODS: Cancer surveillance data on 29,512 incident cancer cases reported to the Dr. Elizabeth Quamina Cancer Registry (population-based cancer registry of TT) between 1995 and 2009 were analyzed. Age-standardized rates, overall and by sex, ancestry, and geography, were reported. RESULTS: The highest incidence and mortality rates were observed for cancers related to reproductive organs in women, namely, breast, cervical, and uterine cancers, and prostate, lung and colorectal cancers among men. Average incidence rates were highest in areas covered by the Tobago Regional Health Authority (TRHA) (188 per 100,000), while average mortality rates were highest in areas covered by the North West Regional Health Authority (108 per 100,000). Nationals of African ancestry exhibited the highest rates of cancer incidence (243 per 100,000) and mortality (156 per 100,000) compared to their counterparts who were of East Indian (incidence, 125 per 100,000; mortality, 66 per 100,000) or mixed ancestry (incidence, 119 per 100,000; mortality, 66 per 100,000). CONCLUSIONS: Our findings highlight the need for national investment to improve the understanding of the epidemiology of cancer in Trinidad and Tobago, and to ultimately guide much needed cancer prevention and control initiatives in the near future. PMID- 29973178 TI - Excessive gestational weight gain in accordance with the IOM criteria and the risk of hypertensive disorders of pregnancy: a meta-analysis. AB - BACKGROUND: Excessive gestational weight gain (GWG) is a potential risk factor for hypertensive disorders of pregnancy (HDP). METHODS: We systematically reviewed three electronic databases for relevant articles published in English: PubMed, EMBASE and Web of Science. The Newcastle-Ottawa Scale was used to assess study quality. Random-effects meta-analyses were performed to supply a pooled estimation of the OR comparing the risk of HDP among healthy pregnant women with and without excessive GWG. RESULTS: The pooled estimation for the association between excessive GWG and the risk of HDPs yielded an odds ratio (OR) of 1.79 (95% CI: 1.61-1.99). A subgroup analysis showed that women who had excessive GWG were more likely to have an HDP (OR 1.82; 95% CI 1.53-2.17), preeclampsia (OR 1.92; 95% CI 1.36-2.72), or gestational hypertension (OR 1.67; 95% CI 1.43-1.95). The pooled estimation for the association between excessive GWG and the risk of HDPs among pregestational normal weight women yielded an OR of 1.57 (95% CI 1.26 1.96). A subgroup analysis showed that women who had excessive GWG were more likely to have HDP (OR 1.45; 95% CI 1.09-1.92) or gestational hypertension (OR 1.51; 95% CI 1.22-1.86). The summary ORs of pre-gestational underweight women and pre-gestational overweight and obese women were 2.17 (95% CI 1.56-3.02) and 1.32 (95% CI 1.08-1.63), respectively. CONCLUSIONS: The findings of this study suggest that excessive GWG in accordance with the IOM recommendations influences the rate of HDP. PMID- 29973179 TI - "Taking away the chaos": a health needs assessment for people who inject drugs in public places in Glasgow, Scotland. AB - BACKGROUND: Public injecting of recreational drugs has been documented in a number of cities worldwide and was a key risk factor in a HIV outbreak in Glasgow, Scotland during 2015. We investigated the characteristics and health needs of people involved in this practice and explored stakeholder attitudes to new harm reduction interventions. METHODS: We used a tripartite health needs assessment framework, comprising epidemiological, comparative, and corporate approaches. We undertook an analysis of local and national secondary data sources on drug use; a series of rapid literature reviews; and an engagement exercise with people currently injecting in public places, people in recovery from injecting drug use, and staff from relevant health and social services. RESULTS: Between 400 and 500 individuals are estimated to regularly inject in public places in Glasgow city centre: most experience a combination of profound social vulnerabilities. Priority health needs comprise addictions care; prevention and treatment of blood-borne viruses; other injecting-related infections and injuries; and overdose and drug-related death. Among people with lived experience and staff from relevant health and social care services, there was widespread - though not unanimous - support for the introduction of safer injecting facilities and heroin-assisted treatment services. CONCLUSIONS: The environment and context in which drug consumption occurs is a key determinant of harm, and is inextricably linked to upstream social factors. Public injecting therefore requires a multifaceted response. Though evidence-based interventions exist, their implementation internationally is variable: understanding the attitudes of key stakeholders provides important insights into local facilitators and barriers. Following this study, Glasgow plans to establish the world's first co located safer injecting facility and heroin-assisted treatment service. PMID- 29973181 TI - Do supportive family behaviors promote diabetes self-management in resource limited urban settings? A cross sectional study. AB - BACKGROUND: Self-management is an essential component of prevention and treatment of type 2 diabetes. Social and family support has been shown to influence self management behaviors as well as glycemic control and complications. This study was conducted to assess whether diabetes family support improves diabetes self management and glycemic control in a typical urban population in India. METHODS: A cross-sectional study using a questionnaire that had items from the Summary of Diabetes Self Care Activities Scale (SDSCA), the Diabetes Family Behavior Checklist (DFBC) and some sociodemographic and diabetes related clinical data was conducted. The participants were consecutively sampled from the diabetes outpatient department in a tertiary care hospital in Chennai, south India. RESULTS: A total of 200 consecutive patients from the diabetes outpatient department were interviewed. Diabetes self-management practices were good with respect to avoiding fatty foods and carbohydrates and undergoing regular blood testing for glucose. But the self-management with respect to exercise and foot related care was rare. It was observed that a vast majority of the patients did not report receiving any support from their families. However, in the small proportion who did receive good family support, there is an association between diabetes self-management and diabetes family support (beta = 0.527; p = 0.015). Further, the path model showed that there is a positive statistically significant association between family support score and the diabetes self-management score (beta = 0.254, p < 0.001). However, the negative association between the diabetes self-management score and the mean plasma glucose did not reach statistical significance (beta = - 46.378, p = 0.082). CONCLUSIONS: In the urban south Indian setting, family support was significantly associated with better self-management activities, but better self-management did not reflect as better glycaemic control. PMID- 29973180 TI - Is there an association between maternal anxiety propensity and pregnancy outcomes? AB - BACKGROUND: Several studies have shown inconsistent associations between anxiety during pregnancy and adverse pregnancy outcome. This inconsistency may be due to lack of controlling for the timing and type of maternal anxiety. We aimed to isolate a specific type of anxiety - maternal anxiety propensity, which is not directly related to pregnancy, and evaluate its association with adverse pregnancy outcome. METHODS: We conducted a prospective observational study of 512 pregnant women, followed to delivery. The trait anxiety scale of the State-Trait Anxiety Inventories was used in order to detect a propensity towards anxiety. The association between anxiety propensity (defined as trait-anxiety subscale score above 38) and adverse pregnancy outcome was evaluated. Primary outcome was a composite outcome including preterm birth prior to 37 gestational weeks, hypertensive disorders in pregnancy, small for gestational age newborn and gestational diabetes mellitus. Secondary outcomes were each one of the above mentioned gestational complications. RESULTS: There were no significant between group differences in adverse pregnancy outcomes, including the rate of preterm birth, hypertensive disorders, small for gestational age, gestational diabetes or a composite outcome of them all. CONCLUSION: Anxiety propensity is not associated with adverse pregnancy outcome. PMID- 29973182 TI - Domestic and intimate partner violence among pregnant women in a low resource setting in South Africa: a facility-based, mixed methods study. AB - BACKGROUND: Rates of violence against women are reported to be highest in Africa compared to other continents. We aimed to determine associations between mental illness, demographic, psychosocial and economic factors with experience of intimate partner violence (IPV) among pregnant women in a low resource setting in Cape Town and to explore the contextual elements pertaining to domestic violence. METHODS: We recruited adult women attending antenatal services at a primary-level maternity facility. Demographic, socioeconomic and psychosocial data were collected by questionnaire. The Expanded Mini- International Neuropsychiatric Interview (MINI) Version 5.0.0 was used to assess mental health status and the Revised Conflict Tactic Scale (CTS2) used to assess IPV in the six months prior to the study. Non-parametric tests, Wilcoxon sum of rank test, Fisher Exact and two sample T test and multicollinearity tests were performed. Descriptive, bivariate and logistic regression analyses were conducted to identify associations between the outcome of interest and key predictors. A probability value of p <= 0.05 was selected. From counselling case notes, a thematic content analysis was conducted to describe contextual factors pertaining to forms of domestic violence (DV). RESULTS: The prevalence of IPV was 15% of a sample of 376 women. Women who were food insecure, unemployed, in stable but unmarried relationships, had experienced any form of past abuse and were not pleased about the current pregnancy were more likely to experience IPV. MINI-defined mental health problems and a history of mental illness were significantly associated with IPV. Qualitative analysis of 95 counselling case notes revealed that DV within the household was not limited to intimate partners and, DV in this context was often perceived as 'normal' behaviour by the participants. CONCLUSIONS: This study contributes towards a greater understanding of the risk profile for IPV amongst pregnant women in low-income settings. Adversity, including food insecurity and mental ill-health are closely associated with IPV during the antenatal period. Advocates against violence against pregnant women are advised to consider that violence in the home may be perpetrated by non-intimate partners and may by enabled by a pervasive belief in the acceptability of the violence. PMID- 29973183 TI - Potential gains in life expectancy by reducing inequality of lifespans in Denmark: an international comparison and cause-of-death analysis. AB - BACKGROUND: Reducing lifespan inequality is increasingly recognized as a health policy objective. Whereas lifespan inequality declined with rising longevity in most developed countries, Danish life expectancy stagnated between 1975 and 1995 for females and progressed slowly for males. It is unknown how Danish lifespan inequality changed, which causes of death drove these developments, and where the opportunities for further improvements lie now. METHODS: We present an analytical strategy based on cause-by-age decompositions to simultaneously analyze changes in Danish life expectancy and lifespan inequality from 1960 to 2014, as well as current Swedish-Danish differences. RESULTS: Stagnation in Danish life expectancy coincided with a shorter period of stagnation in lifespan inequality (1975-1990). The stagnation in life expectancy was mainly driven by increases in cancer and non-infectious respiratory mortality at higher ages (-.63 years) offsetting a reduction in cardiovascular and infant mortality (+ 1.52 years). Lifespan inequality stagnated because most causes of death did not show compression over the time period. Both these observations were consistent with higher smoking related mortality in Danes born in 1919-1939. After 1995, life expectancy and lifespan equality increased in lockstep, but still lag behind Sweden, mainly due to infant mortality and cancer. CONCLUSIONS: Since 1960, Danish improvements in life expectancy and lifespan equality were halted by smoking-related mortality in those born 1919-1939, while also reductions in old-age cardiovascular mortality held back lifespan equality. The comparison with Sweden suggests that Denmark can reduce inequality in lifespans and increase life expectancy through a consistent policy target: reducing cancer and infant mortality. PMID- 29973184 TI - An atypical presentation of high potassium renal secretion rate in a patient with thyrotoxic periodic paralysis: a case report. AB - BACKGROUND: Hypokalemia is one of the most common clinical electrolyte imbalance problems, and thyrotoxic periodic paralysis (TPP) is a leading cause of presentation to the emergency department. Low renal potassium secretion rates, a normal acid-base balance in the blood, and hyperthyroidism are the hallmarks of suspected TPP. CASE PRESENTATION: Here we report the case of a 36-year-old man who presented to the emergency department with a sudden onset of acute muscle weakness at 5 h prior to admission. Biochemistry tests revealed hypokalemia with hyperthyroidism and renal potassium wasting. TPP was initially not favored due to the presence of renal potassium wasting. However, his serum potassium level rebounded rapidly within several hours after potassium supplementation, indicating that the intracellular shifting of potassium ions was the main etiology for his hypokalemia. The early stage of TPP development may have contributed to this paradox. CONCLUSION: Therefore, it is premature to rule out TPP based on the presentation of high renal potassium secretion rates alone. This finding may result in an incorrect impression being made in the early stage of TTP and may consequently lead to an inappropriate potassium supplementation policy. PMID- 29973185 TI - Program assessment of efforts to improve the quality of postpartum counselling in health centers in Morogoro region, Tanzania. AB - BACKGROUND: The postpartum period represents a critical window where many maternal and child deaths occur. We assess the quality of postpartum care (PPC) as well as efforts to improve service delivery through additional training and supervision in Health Centers (HCs) in Morogoro Region, Tanzania. METHODS: Program implementers purposively selected nine program HCs for assessment with another nine HCs in the region remaining as comparison sites in a non-randomized program evaluation. PPC quality was assessed by examining structural inputs; provider and client profiles; processes (PNC counselling) and outcomes (patient knowledge) through direct observations of equipment, supplies and infrastructure (n = 18) and PPC counselling (n = 45); client exit interviews (n = 41); a provider survey (n = 62); and in-depth provider interviews (n = 10). RESULTS: While physical infrastructure, equipment and supplies were comparable across study sites (with water and electricity limitations), program areas had better availability of drugs and commodities. Overall, provider availability was also similar across study sites, with 63% of HCs following staffing norms, 17% of Reproductive and Child Health (RCH) providers absent and 14% of those providing PPC being unqualified to do so. In the program area, a median of 4 of 10 RCH providers received training. Despite training and supervisory inputs to program area HCs, provider and client knowledge of PPC was low and the content of PPC counseling provided limited to 3 of 80 PPC messages in over half the consultations observed. Among women attending PPC, 29 (71%) had delivered in a health facility and sought care a median of 13 days after delivery. Barriers to PPC care seeking included perceptions that PPC was of limited benefit to women and was primarily about child health, geographic distance, gaps in the continuity of care, and harsh facility treatment. CONCLUSIONS: Program training and supervision activities had a modest effect on the quality of PPC. To achieve broader transformation in PPC quality, client perceptions about the value of PPC need to be changed; the content of recommended PPC messages reviewed along with the location for PPC services; gaps in the availability of human resources addressed; and increased provider-client contact encouraged. PMID- 29973186 TI - Manufacturing of an immediate removable partial denture with an intraoral scanner and CAD-CAM technology: a case report. AB - BACKGROUND: Incisor loss constitutes a strong aesthetic and psychologic traumatism for the patient and it remains a challenging situation for the dental practitioner because of the necessity to rapidly replace the lacking tooth. Various therapeutic procedures have been proposed to replace the incisor concerned, for example by using a removable partial denture. However, the manufacturing of such a denture with classical procedures is often subject to processing errors and inaccuracies. The computer-aided design and computer-aided manufacturing (CAD-CAM) technology could represent a good alternative, but it is currently difficult because of the lack of dental softwares able to design easily immediate removable partial dentures. CASE PRESENTATION: A 30-year- patient complained about pain caused by a horizontally and vertically mobile maxillary right central incisor. After all options were presented, extraction of the traumatized incisor was decided due to its very poor prognosis, and the patient selected the realization of a removable denture for economic reasons. The present paper proposes an innovative procedure for immediate removable denture, based on the use of an intraoral scanner, CAD with two different softwares used sequentially, and CAM with a 5-axis machine. CONCLUSIONS: We show in this report that associating an intraoral scanner and CAD-CAM technology can be extended to immediate dentures manufacturing, which could be a valuable procedure for dental practitioners and laboratories, and also for patients. PMID- 29973187 TI - Improving shared decision-making in a clinical obstetric ward by using the three questions intervention, a pilot study. AB - BACKGROUND: Shared decision-making (SDM) is an important aspect of modern health care. Many studies evaluated different interventions to improve SDM, however, none in an inpatient clinical setting. A tool that has been proven effective in an outpatient department is the three questions intervention. These questions are created for patients to get optimal information from their medical team and to make an informed medical decision. In this study, we evaluated the feasibility and effectiveness of this simple intervention on SDM in the obstetric inpatient department of a university hospital in the Netherlands. METHOD: This is a clinical pilot before and after study, using mixed methods with quantitative and qualitative data collection. The three questions were stated on a card; (i.e. 1) What are my options; 2) What are the possible benefits and harms of those options; 3) How likely are each of those benefits and harms to happen to me?). The study period lasted 6 weeks in which all patients admitted to the obstetric ward were asked to participate in the study. In the first 3 weeks patients did not receive the three questions intervention (pre-intervention group). In the final 3 weeks all patients included received the intervention (intervention group). The main quantitative outcome measure was the level of SDM measured using the SDM-Q9 questionnaire at discharge (range 0-100). In addition, interviews with four patients of the intervention group were conducted and qualitatively analyzed. RESULTS: Thirty-three patients were included in the pre-intervention group, 29 patients in the intervention group. The mean score of the SDM-Q9 in the pre-intervention group was 65.5 (SD 22.83) and in the intervention group 63.2 (SD 20.21), a not statistically significant difference. In the interviews, patients reported the three questions to be very useful. They used the questions mainly as a prompt and encouragement to ask more specific questions. DISCUSSION: No difference in SDM was found between the two groups, possibly because of a small sample size. Yet the intervention appeared to be feasible and simple to use in an inpatient department. Further studies are needed to evaluate the impact of implementation of these three questions on a larger scale. PMID- 29973188 TI - The development, implementation and evaluation of interventions to reduce workplace sitting: a qualitative systematic review and evidence-based operational framework. AB - BACKGROUND: Prolonged sitting is associated with increased risks of cardiovascular disease, Type 2 diabetes, some cancers, musculoskeletal disorders and premature mortality. Workplaces contribute to a large proportion of daily sitting time, particularly among office-based workers. Interventions to reduce workplace sitting therefore represent important public health initiatives. Previous systematic reviews suggest such interventions can be effective but have reported wide variations. Further, there is uncertainty as to whether effectiveness in controlled trials can be replicated when implemented outside the research setting. The aims of this review are to identify factors important for the implementation of workplace sitting interventions and to translate these findings into a useful operational framework to support the future implementation of such interventions. METHODS: A qualitative systematic review was conducted. Four health and social science databases were searched for studies set in the workplace, with office-based employees and with the primary aim of reducing workplace sitting. Extracted data were primarily from author descriptions of interventions and their implementation. Inductive thematic analysis and synthesis was undertaken. RESULTS: Forty studies met the inclusion criteria. Nine descriptive themes were identified from which emerged three higher-order analytical themes, which related to the development, implementation and evaluation of workplace sitting interventions. Key findings included: the importance of grounding interventions in theory; utilising participative approaches during intervention development and implementation; and conducting comprehensive process and outcome evaluations. There was a general under reporting of information relating to the context within which workplace sitting interventions were implemented, such as details of local organisation processes and structures, as well as the wider political and economic landscape, which if present would aid the translation of knowledge into "real-world" settings. CONCLUSIONS: These findings provided the basis for an operational framework, which is a representation of all nine descriptive themes and three higher-order analytical themes, to support workplace sitting intervention development, implementation and evaluation. Once tested and refined, this framework has the potential to be incorporated into a practical toolkit, which could be used by a range of organisations to develop, implement and evaluate their own interventions to reduce workplace sitting time amongst staff. PMID- 29973189 TI - Testicular histopathology, semen analysis and FSH, predictive value of sperm retrieval: supportive counseling in case of reoperation after testicular sperm extraction (TESE). AB - BACKGROUND: To provide indicators for the likelihood of sperm retrieval in patients undergoing testicular sperm extraction is a major issue in the management of male infertility by TESE. The aim of our study was to determine the impact of different parameters, including testicular histopathology, on sperm retrieval in case of reoperation in patients undergoing testicular sperm extraction. METHODS: We retrospectively analyzed 486 patients who underwent sperm extraction for intracytoplasmic sperm injection and testicular biopsy. Histology was classified into: normal spermatogenesis; hypospermatogenesis (reduction in the number of normal spermatogenetic cells); maturation arrest (absence of the later stages of spermatogenesis); and Sertoli cell only (absence of germ cells). Semen analysis and serum FSH, LH and testosterone were measured. RESULTS: Four hundred thirty patients had non obstructive azoospermia, 53 severe oligozoospermia and 3 necrozoospermia. There were 307 (63%) successful sperm retrieval. Higher testicular volume, lower levels of FSH, and better histological features were predictive for sperm retrieval. The same parameters and younger age were predictive factors for shorter time for sperm recovery. After multivariable analysis, younger age, better semen parameters, better histological features and lower values of FSH remained predictive for shorter time for sperm retrieval while better semen and histology remained predictive factors for successful sperm retrieval. The predictive capacity of a score obtained by summing the points assigned for selected predictors (1 point for Sertoli cell only, 0.33 points for azoospermia, 0.004 points for each FSH mIU/ml) gave an area under the ROC curve of 0.843. CONCLUSIONS: This model can help the practitioner with counseling infertile men by reliably predicting the chance of obtaining spermatozoa with testicular sperm extraction when a repeat attempt is planned. PMID- 29973190 TI - A randomised controlled trial of a program based on the theory of planned behavior to promote fruit and vegetable intake among schoolchildren: PROFRUVE study protocol. AB - BACKGROUND: The PROFRUVE study is a controlled intervention based on the Theory of Planned Behavior (TPB), which follows those behavioral theories that have proved to be the most effective at changing infant fruit and vegetable (FV) intake pattern. The main purpose of the study is to evaluate the effectiveness of an intervention program in increasing FV consumption in schoolchildren aged 8 to 10 and based on TPB. METHODS: Eligible classrooms within schools from Vitoria Gasteiz (Basque Country, Spain) will be randomly assigned to the intervention (classrooms n = 4; children n = 86) or control (classrooms n = 4; children n = 86) group. The intervention group will receive 14 sessions of 60 min during an academic year (October to June). These sessions, designed by a multidisciplinary team, are based on TPB and are directed at modifying determinants of behavior (attitudes, subjective norms, perceived behavioral control and intention of consumption), and intake of FV itself. Both the process and the evolution of consumption and determinants of behavior will be evaluated (before, during, shortly after and a year after) using validated surveys, 7 day food records, 24 h reminders and questionnaires. DISCUSSION: This study will provide a valid and useful tool to achieve changes in the consumption of FV at school level. A negative result will be helpful in redefining new strategies in the framework of changing habits in the consumption of FV. TRIAL REGISTRATION: This study has been retrospectively registered at ClinicalTrials.gov. Identifier: NCT03400891 . Data registered: 17/01/2018. PMID- 29973191 TI - Comparing different intensities of active referral to smoking cessation services in promoting smoking cessation among community smokers: a study protocol of a cluster randomized controlled trial. AB - BACKGROUND: Actively referring smokers to smoking cessation (SC) services could increase quitting and is scalable for the population. The objective of this study is to compare 2 different intensities of SC active referral for smokers in the community of Hong Kong. METHODS/DESIGN: This is a single-blind, parallel 3-armed cluster randomized controlled trial (cRCT) consisting of high-intensity SC active referral (HAR Group), low-intensity SC referral by text messaging on promoting SC services use (Text Group) and a control group receives general very brief advice. Biochemically validated daily smokers will be proactively recruited in the community from 68 clusters (recruitment sessions). The primary outcome is self reported 7-days point prevalence abstinence (PPA) at the 3- and 6- month follow ups. Secondary outcomes are SC service use, smoking reduction rate (SRR, daily cigarette consumption reduced by >=50%; excluding quitters) and biochemically validated quit rate (exhaled CO < 4 ppm and salivary cotinine < 10 ng/ml). Outcome assessors and data analysts will be blinded to group allocation. Intention-to-treat principle and Generalized Estimating Equation (GEE) regressions will be used for data analysis. DISCUSSION: This will be the first trial on evaluating the efficacy of the 2 different intensities of SC active referral on smoking cessation in community smokers. It is anticipated that the results from this trial can provide evidence to the effectiveness of high intensity active referral to SC services and low intensity SC referral by using text messaging in achieving smoking abstinence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02804880 , June 17, 2016. PMID- 29973192 TI - Short and long-term costs among women experiencing preterm labour or preterm birth: the German experience. AB - BACKGROUND: Preterm labour and birth (PTL/PTB) is characterised by major health and developmental risks for children, life-changing consequences for their families, and substantial healthcare and economic challenges for wider society. While it is known that PTL/PTB impacts infant healthcare costs in the short and long term in Germany, maternal costs have not been described in detail. The aim of this study was to comprehensively describe costs and resource use among PTL/PTB mothers during pregnancy, at hospitalisation for delivery, and up to three years after delivery-overall and according to gestational age (GA) at delivery. METHODS: This study used data from the Statutory Health Insurance (SHI) sample of the AOK Hessen database in Germany. Mothers aged 12-44 years with deliveries between 2009 and 2013 and > 9 months of medical history prior to delivery were included. PTL/PTB mothers were defined by an International Classification of Diseases, 10th Revision (ICD-10) code for PTL during pregnancy, a diagnosis-related group (DRG) code indicating birthweight < 2500 g, or delivery of an infant < 37 weeks GA. Inpatient and outpatient resource use and total direct medical costs were examined during pregnancy, at delivery hospitalisation, and up to three years post-delivery. RESULTS: Of all mothers, 2147 (20%) experienced PTL/PTB. During pregnancy, median costs for PTL/PTB mothers were ?2130. During delivery hospitalisation, the mean length of stay for all PTL/PTB mothers was 6.0 days, and median costs were ?2037. Length of stay and costs declined with increasing GA. Long term, PTL/PTB mothers' total median costs were ?607 in Year 1, ?332 in Year 2, and ?388 in Year 3 post-delivery. In each year after delivery, median costs appeared to be greater for mothers who delivered at lower GAs. CONCLUSION: In this description of costs and resource use among PTL/PTB mothers in Germany throughout the pregnancy and up to three years after delivery, the greatest costs were noted prior to delivery. Costs appeared to decrease with increasing GA, particularly during the delivery hospitalisation and the first year after delivery. PMID- 29973193 TI - Physical activity to improve cognition in older adults: can physical activity programs enriched with cognitive challenges enhance the effects? A systematic review and meta-analysis. AB - BACKGROUND: Aging-related cognitive decline and cognitive impairment greatly impacts older adults' daily life. The worldwide ageing of the population and associated wave of dementia urgently calls for prevention strategies to reduce the risk of cognitive decline. Physical activity (PA) is known to improve cognitive function at older age through processes of neuroplasticity. Yet, emerging studies suggest that larger cognitive gains may be induced when PA interventions are combined with cognitive activity (CA). This meta-analysis evaluates these potential synergistic effects by comparing cognitive effects following combined PA + CA interventions to PA interventions (PA only), CA interventions (CA only) and control groups. METHODS: Pubmed, Embase, PsycInfo, CINAHL and Sportdiscus were searched for English peer-reviewed papers until April 2018. Data were extracted on cognition and factors potentially influencing the cognitive effects: mode of PA + CA combination (sequential or simultaneous), session frequency and duration, intervention length and study quality. Differences between older adults with and without mild cognitive impairments were also explored. RESULTS: Forty-one studies were included. Relative to the control group, combined PA + CA intervention showed significantly larger gains in cognition (g = 0.316; 95% CI 0.188-0.443; p < .001). Studies that compared combined PA + CA with PA only, showed small but significantly greater cognitive improvement in favor of combined interventions (g = 0.160; 95% CI 0.041-0.279; p = .008). No significant difference was found between combined PA + CA and CA only interventions. Furthermore, cognitive effects tended to be more pronounced for studies using simultaneous designs (g = 0.385; 95%CI 0.214-0.555; p < .001) versus sequential designs (g = 0.114; 95%CI -0.102- 0.331, p = .301). Effects were not moderated by session frequency, session duration, intervention length or study quality. Also, no differences in effects were found between older adults with and without mild cognitive impairments. CONCLUSION: Findings of the current meta-analysis suggest that PA programs for older adults could integrate challenging cognitive exercises to improve cognitive health. Combined PA + CA programs should be promoted as a modality for preventing as well as treating cognitive decline in older adults. Sufficient cognitive challenge seems more important to obtain cognitive effects than high doses of intervention sessions. PMID- 29973194 TI - Risk factors for asymptomatic malaria infections from seasonal cross-sectional surveys along the China-Myanmar border. AB - BACKGROUND: Border malaria, a shared phenomenon in the Greater Mekong Sub-region of Southeast Asia, is a major obstacle for regional malaria elimination. Along the China-Myanmar border, an additional problem arose as a result of the settlement of internally displaced people (IDP) in the border region. Since asymptomatic malaria significantly impacts transmission dynamics, assessment of the prevalence, dynamics and risk factors of asymptomatic malaria infections is necessary. METHODS: Cross-sectional surveys were carried out in 3 seasons (March and April, July and November) and 2 sites (villages and IDP camps) in 2015. A total of 1680 finger-prick blood samples were collected and used for parasite detection by microscopy and nested RT-PCR (nRT-PCR). Logistic regression models were used to explore the risk factors associated with asymptomatic malaria at individual and household levels. RESULTS: The prevalence of asymptomatic Plasmodium infections was 23.3% by nRT-PCR, significantly higher than that detected by microscopy (1.5%). The proportions of Plasmodium vivax, Plasmodium falciparum and mixed-species infections were 89.6, 8.1 and 2.3%, respectively. Asymptomatic infections showed obvious seasonality with higher prevalence in the rainy season. Logistic regression analysis identified males and school children (<= 15 years) as the high-risk populations. Vector-based interventions, including bed net and indoor residual spray, were found to have significant impacts on asymptomatic Plasmodium infections, with non-users of these measures carrying much higher risks of infection. In addition, individuals living in poorly constructed households or farther away from clinics were more prone to asymptomatic infections. CONCLUSIONS: Sub-microscopic Plasmodium infections were highly prevalent in the border human populations from IDP camps and surrounding villages. Both individual- and household-level risk factors were identified, which provides useful information for identifying the high-priority populations to implement targeted malaria control. PMID- 29973195 TI - Effects of a hydroalcoholic extract of Juglans regia (walnut) leaves on blood glucose and major cardiovascular risk factors in type 2 diabetic patients: a double-blind, placebo-controlled clinical trial. AB - BACKGROUND: We aimed to evaluate the effects of a hydroalcoholic extract of Juglans regia L. leaves on blood glucose level and cardiovascular risk factors in type 2 diabetic patients. METHODS: In this randomized, double-blind, placebo controlled, parallel-group (2 arms) clinical trial, 50 diabetic patients were divided into two groups: treatment group (receive the capsules containing 100 mg J. regia leaf extract) and control group (receive the capsules containing placebo, microcrystallin cellulose). Baseline participant data were matched between the two arms of the study. We administered the prepared capsules to the patients twice daily for 8 weeks. Blood glucose level, glycosylated hemoglobin (HbA1c) level, body weight, body mass index, blood pressure, lipid profile, serum insulin, and insulin resistance were compared between the two groups before and after the intervention. P < 0.05 was considered significant. RESULTS: After excluding eleven patients, 20 received J. regia leaf extract and 20 patients received placebo. The J. regia leaf extract did not significantly change the blood glucose and insulin resistance condition. However, in this group, body weight, body mass index, and systolic blood pressure significantly decreased compared with the baseline measurements (P = 0.028, P = 0.030, and P = 0.005, respectively). The lipid profile did not change significantly compared with the baseline measurements. In the control group, postprandial glucose and HbA1c levels significantly decreased after the intervention (P = 0.030 and P = 0.028, respectively). The other variables were not significantly different in this group. At the end of the study, the variables were not significantly different between the two groups. CONCLUSION: In this double-blind study, 200 mg/d of J. regia leaf extract had no significant effect on blood glucose level and HOMA-IR score in patients with type 2 diabetes. However, the J. regia leaf extract was effective in reducing body weight and blood pressure. An accidental finding of our study was that microcrystalline cellulose, a widely used placebo in clinical trials, led to a reduction in blood glucose level. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT: 138901203180 N2 , 2010/6/6); retrospectively registered. PMID- 29973196 TI - Geospatial blockchain: promises, challenges, and scenarios in health and healthcare. AB - A PubMed query run in June 2018 using the keyword 'blockchain' retrieved 40 indexed papers, a reflection of the growing interest in blockchain among the medical and healthcare research and practice communities. Blockchain's foundations of decentralisation, cryptographic security and immutability make it a strong contender in reshaping the healthcare landscape worldwide. Blockchain solutions are currently being explored for: (1) securing patient and provider identities; (2) managing pharmaceutical and medical device supply chains; (3) clinical research and data monetisation; (4) medical fraud detection; (5) public health surveillance; (6) enabling truly public and open geo-tagged data; (7) powering many Internet of Things-connected autonomous devices, wearables, drones and vehicles, via the distributed peer-to-peer apps they run, to deliver the full vision of smart healthy cities and regions; and (8) blockchain-enabled augmented reality in crisis mapping and recovery scenarios, including mechanisms for validating, crediting and rewarding crowdsourced geo-tagged data, among other emerging use cases. Geospatially-enabled blockchain solutions exist today that use a crypto-spatial coordinate system to add an immutable spatial context that regular blockchains lack. These geospatial blockchains do not just record an entry's specific time, but also require and validate its associated proof of location, allowing accurate spatiotemporal mapping of physical world events. Blockchain and distributed ledger technology face similar challenges as any other technology threatening to disintermediate legacy processes and commercial interests, namely the challenges of blockchain interoperability, security and privacy, as well as the need to find suitable and sustainable business models of implementation. Nevertheless, we expect blockchain technologies to get increasingly powerful and robust, as they become coupled with artificial intelligence (AI) in various real-word healthcare solutions involving AI-mediated data exchange on blockchains. PMID- 29973197 TI - Nuclear Klf4 accumulation is associated with cetuximab drug-resistance and predicts poor prognosis of nasopharyngeal carcinoma. AB - BACKGROUND: The functions of the protein expressed in the nucleus and cytoplasm were different or opposite. The previous study found that oncogene Klf4 played a role of tumor suppressor in the nasopharyngeal cytoplasm. Cetuximab targeted epidermal growth factor receptor (EGFR) for the treatment of nasopharyngeal carcinoma. METHODS: A cohort of 231 cases of advanced nasopharyngeal carcinoma (7th AJCC III-IVa) samples was assessed by immunohistochemistry (IHC), of which, 63 cases were treated with basic treatment without cetuximab, the basic treatment include chemotherapy and radiotherapy, the regent of the chemotherapy include cisplatin and fluorouracil and 168 cases were treated with cetuximab in addition to the basic treatment. The expression of the KLF4 protein was detected in nucleus and cytoplasm, c-Met protein and nuclear EGFR protein (nEGFR) by IHC, and H-Ras and PI3K mutations by an arms-PCR method in vivo. KLF4 was found to specifically express in the cytoplasm by deleting the NES, while H-Ras and PI3K genes were mutated in the nasopharyngeal carcinoma 5-8F and HONE1cell line. The cetuximab resistance in differentially mutated 5-8F and HONE1 cells was analyzed. RESULTS: The expression of Klf4 in the nucleus was associated with prognosis in 168 patients with cetuximab-treated nasopharyngeal carcinoma, which was found by retrospective analysis. The KLF4 expression in the nucleus was not significantly correlated with the prognosis in 63 nasopharyngeal carcinoma patients treated with basic treatment (P = 0.261). The expression of Klf4 in the nucleus was correlated with mutations of H-Ras and PI3K in 168 cases of nasopharyngeal carcinoma with cetuximab treatment. In vitro experiments showed that Klf4 was specifically expressed in the nucleus of 5-8F and HONE1 cells as assessed by deleting nuclear export signal, which led to cetuximab resistance. H-Ras and PI3K mutations in 5-8F and HONE1 cells also led to the expression of Klf4 in the nucleus and resistance to cetuximab. In HONE1 cells, Klf4 was specifically localized in the cytoplasm by deleting the NES, and the H-Ras and PI3K mutations did not result in an increased expression of Klf4 in the nucleus and cetuximab resistance. CONCLUSION: The prognosis of nasopharyngeal carcinoma was not significantly improved by cetuximab treatment when the Klf4 was highly expressed in the nucleus of nasopharyngeal carcinoma tissues. The expression of Klf4 in the nucleus can be used as a biomarker for predicting the effects of cetuximab treatment in nasopharyngeal carcinoma, which might be attributed to the H-RAS and PI3K mutations, leading to cetuximab resistance. PMID- 29973198 TI - Unique sperm haplotypes are associated with phenotypically different sperm subpopulations in Astyanax fish. AB - BACKGROUND: The phenotypes of sperm are generally believed to be under the control of the diploid genotype of the male producing them rather than their own haploid genotypes, because developing spermatids share cytoplasm through intercellular bridges. This sharing is believed to homogenize their content of gene products. However, not all developing spermatids have identical gene products and estimates are that alleles at numerous gene loci are unequally expressed in sperm. This provides scope for the hypothesis that sperm phenotypes might be influenced by their unique haplotypes. Here we test a key prediction of this hypothesis. RESULTS: The haploid hypothesis predicts that phenotypically different sperm subpopulations should be genetically distinct. We tested this by genotyping different sperm subpopulations that were generated by exposing sperm to a chemical dye challenge (Hoechst 33342). Dye treatment caused the cells to swell and tend to clump together. The three subpopulations of sperm we distinguished in flow cytometry corresponded to single cells, and clumps of two or three. Cell clumping in the presence of the dye may reflect variation in cell adhesivity. We found that allelic contents differed among the three populations. Importantly, the subpopulations with clumped sperm cells were significantly enriched in allelic combinations that had previously been observed to have significantly lower transmission success. CONCLUSIONS: We show that at least one sperm phenotype is correlated with its haploid genotype. This supports a broader hypothesis that the haploid genotypes of sperm cells may influence their fitness, with potentially significant implications for the transmission of deleterious alleles or combinations of alleles to their offspring. PMID- 29973199 TI - Exploring the combination and modular characteristics of herbs for alopecia treatment in traditional Chinese medicine: an association rule mining and network analysis study. AB - BACKGROUND: Although alopecia affects the quality of life, its pathogenesis is unknown, because cellular interactions in the hair follicle are complex. Several authors have suggested using herbal medicine to treat alopecia, and bioinformatics and network pharmacology may constitute a new research strategy in this regard because herbal medicines contain various chemical components. This study used association rule mining (ARM) and network analysis to analyze the combinations of medicinal herbs used to treat alopecia. METHODS: We searched Chinese, Korean, and English databases for literature about alopecia treatment, extracting the names of each herbal prescription and herb. The meridian tropism and classification category of each herb were also investigated. Using ARM, we identified frequently combined two-herb and three-herb sets. Using network analysis, we divided the herbs into several modules according to prescription pattern. RESULTS: Fifty-six articles and 489 herbal medicines were included-312 internal and 177 external medicines. Among the 312 medicinal herbs used in internal medicine group, the most frequently combined two-herb set was Polygonum multiflorum Thunb. () and Angelica sinensis (Oliv.) Dlels (). The most frequently used three-herb combination was Polygonum multiflorum Thunb., Angelica sinensis (Oliv.) Dlels, and Ligusticum chuanxiong Hort. (). In network analysis, three modules were identified. The herbs of Module 1 were related to the liver and kidney meridians, and those of Module 3 were related to the Stomach meridian. CONCLUSIONS: We identified the frequency, characteristics, and functional modules of herb combinations frequently used in alopecia treatment. We confirmed the value of classical medicinal herb theory. This finding will prompt further bioinformatics and network pharmacology research on alopecia. PMID- 29973200 TI - Clinical and economic impact of pharmacist interventions on sampled outpatient prescriptions in a Chinese teaching hospital. AB - BACKGROUND: Limited studies have evaluated the effectiveness of pharmacist interventions on outpatient prescription. The goal of this study was to evaluate the clinical and economic impacts of pharmacist interventions on randomly sampled outpatient prescriptions. METHOD: Outpatient prescriptions of our hospital were sampled automatically and reviewed by pharmacists since 2011. Pharmacists intervened in inappropriate prescriptions (IPs) real-timely, and summarized and analyzed the information monthly. Cost-benefit analysis was performed to estimate the economic benefit of the pharmacist intervention. RESULTS: From 2011 to 2016, pharmacists reviewed 101,271 prescriptions and intervened in 5155 prescriptions. With the interventions of pharmacists, the number of IPs decreased from 1845 to 238, while the inappropriate percentage decreased from 12.60 to 1.22%. The inappropriate rates of different departments and the types decreased annually. IPs were mainly from the Department of Medicine and Department of Surgery and category 1 (Non-indicated medications) in all years. The benefit-to-cost ratios of pharmacist interventions were always more than 1. In the same years, the benefit-to-cost ratios in public payments were higher than those with insurance and self-payment. CONCLUSION: This form of pharmacist intervention constitutes a method that showed positive clinical and economic benefits and is worth expanding in large hospitals. Pharmacists should pay more attention on prescriptions in department of surgery or prescriptions with public payments. PMID- 29973201 TI - Aroma formation during cheese ripening is best resembled by Lactococcus lactis retentostat cultures. AB - BACKGROUND: Cheese ripening is a complex, time consuming and expensive process, which involves the generation of precursors from carbohydrates, proteins and fats and their subsequent conversion into a wide range of compounds responsible for the flavour and texture of the cheese. This study aims to investigate production of cheese aroma compounds outside the cheese matrix that could be applied for instance as food supplements in dairy or non-dairy products. RESULTS: In this study, aroma formation by a dairy Lactococcus lactis was analysed as a function of the growth medium [milk, hydrolysed micellar casein isolate (MCI) and chemically defined medium (CDM)] and the cultivation conditions (batch culture, retentostat culture and a milli-cheese model system). In the retentostat cultures, the nutrient supply was severely restricted resulting in low growth rates (~ 0.001 h-1), thereby mimicking cheese ripening conditions in which nutrients are scarce and bacteria hardly grow. In total 82 volatile organic compounds were produced by the bacteria. Despite the use of a chemically defined medium, retentostat cultures had the biggest qualitative overlap in aroma production with the milli-cheese model system (36 out of 54 compounds). In the retentostat cultures, 52 known cheese compounds were produced and several important cheese aroma compounds and/or compounds with a buttery or cheese-like aroma increased in retentostat cultures compared to batch cultures and milli cheeses, such as esters, methyl ketones, diketones and unsaturated ketones. In cultures on CDM and MCI, free fatty acids and their corresponding degradation products were underrepresented compared to what was found in the milli-cheeses. Addition of a mixture of free fatty acids to CDM and MCI could help to enhance flavour formation in these media, thereby even better resembling flavour formation in cheese. CONCLUSIONS: This study demonstrates that retentostat cultivation is the preferred method to produce cheese flavours outside the cheese matrix by mimicking the slow growth of bacteria during cheese ripening. PMID- 29973202 TI - Interaction between endothelial nitric oxide synthase rs1799983, cholesteryl ester-transfer protein rs708272 and angiopoietin-like protein 8 rs2278426 gene variants highly elevates the risk of type 2 diabetes mellitus and cardiovascular disease. AB - BACKGROUND: The aim of the present study was to examine the association of angiopoietin-like proteins-8 (ANGPTL8) rs2278426, cholesteryl ester-transfer protein (CETP) rs708272 and endothelial nitric oxide synthase (NOS3) rs1799983 variants with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), and to investigate the effect of the potential interaction between these variants on disease risk. METHODS: Our study included 272 subjects classified into 68 patients with T2DM, 68 patients with T2DM complicated with CVD and 136 control subjects. ANGPTL8 c194C>T, CETP Taq1B and NOS3 G894T polymorphisms were genotyped using TaqMan(r) SNP Genotyping Assay. RESULTS: The presence of NOS3, ANGPTL8, and homozygous CETP B1 variants were associated with increased risk of T2DM by 3.07-, 2.33- and 1.75-fold, respectively. NOS3 variant was associated with 3.08-fold increased risk of CVD (95% CI 1.70-5.60), while ANGPTL8 C allele was associated with 2.8-fold increased risk of CVD in T2DM patients (95% CI 1.13-6.97). Concomitant presence of both, CETP B1 and NOS3 T allele, associated with increased risk of T2DM, CVD and CVD in T2DM by 8.36-, 6.33- and 7.87-fold, respectively, while concomitant presence of ANGPTL8 variant with either CETP B1 or NOS3 T allele was not associated with increased risk of T2DM or CVD. However, concomitant presence of the three variants together elevated the risk of T2DM by 13.22-fold (p = 0.004), CVD risk by 8.86-fold (p = 0.03) and highly elevated the risk of CVD in T2DM patients by 13.8-fold (p = 0.008). CONCLUSIONS: Concomitant presence of CETP B1, NOS3 T and ANGPTL8 T alleles augments the risk of CVD and T2DM. Further studies to clarify the mechanism of gene-gene interaction in the pathogenesis of CVD and T2DM are needed. PMID- 29973203 TI - UK medical students' attitudes towards their future careers and general practice: a cross-sectional survey and qualitative analysis of an Oxford cohort. AB - BACKGROUND: Against the background of the recruitment crisis in general practice, we aimed to determine what United Kingdom (UK) medical students value in their future careers, how they perceive careers in general practice (GP) and what influences them. METHODS: Cross-sectional survey of 280 final and penultimate year medical students at the University of Oxford, with questions relating to career choices, factors of importance when choosing a career and attitudes towards general practice as a career. Quantitative methods included cluster analysis, chi squared tests of independence and logistic regression analysis. Qualitative data were analysed thematically using the Framework method. RESULTS: Response rate was 89% (280/315). 40% of participants said that general practice was an attractive or very attractive career option. Respondents valued job satisfaction, work-life balance and close relationships with patients. However, fewer than 20% of respondents agreed that community-based working was important to them and many (often citing particular GPs they had observed) felt that general practice as currently structured may not be satisfying or fulfilling because of high workload, financial pressures and externally imposed directives. 63% perceived GPs to have lower status than hospital specialties and 49% thought the overall culture of their medical school had negatively influenced their views towards general practice. Some respondents considered that general practice would not be intellectually challenging or compatible with a research career; some appeared to have had limited exposure to academic primary care. CONCLUSIONS: With the caveat that this was a sample from a single medical school, medical students may be put off careers in general practice by three main things: low perceived value of community-based working and low status of general practice (linked to a prevailing medical school culture); observing the pressures under which GPs currently work; and lack of exposure to academic role models and primary care based research opportunities. To improve recruitment of the next generation of GPs, medical schools must provide high quality placements in general practice, expose students to academic role models and highlight to policymakers the links between the current pressures in UK general practice and the recruitment crisis. PMID- 29973204 TI - Long term impact of CTLA4 blockade immunotherapy on regulatory and effector immune responses in patients with melanoma. AB - BACKGROUND: We previously reported early on-treatment significant modulation in circulating regulatory T cell (Treg), myeloid derived suppressor cells (MDSC) and antigen-specific type I CD4+ and CD8+ T cells that correlated with clinical outcome in regionally advanced melanoma patients treated with neoadjuvant ipilimumab. Here, we investigated the long term immunologic impact of CTLA4 blockade. METHODS: Patients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery. Blood specimens were collected at baseline and during treatment for up to 9 months. We tested immune responses at 3, 6, and 9 months utilizing multicolor flow cytometry. We compared frequencies of circulating Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1). RESULTS: Levels of Treg significantly increased when measured at 6 weeks following ipilimumab but returned to baseline by 3 months, with no significant difference in Treg levels between relapsed and relapse-free groups at 3, 6 or 9 months. However, lower baseline levels of circulating Treg (CD4+CD25hi+CD39+) were significantly associated with better relapse free survival (RFS) (p = 0.04). Levels of circulating monocytic HLA-DR+/loCD14+ MDSC were lower at baseline in the relapse-free group and further decreased at 6 weeks, though the differences did not reach statistical significance including measurements at 3, 6 or 9 months. We detected evidence of type I (interferon gamma producing), activated (CD69+) CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly boosted at 6 weeks and persisted at 3, 6 and 9 months following the initiation of ipilimumab. CONCLUSIONS: Lower Treg levels at baseline are significantly associated with RFS and increased Treg frequency after CTLA4 blockade was only transient. Lower MDSC was also associated with RFS and MDSC levels were further decreased after ipilimumab. Tumor specific effector immune responses are boosted with CTLA4 blockade and tend to be durable. Trial registration ClinicalTrials.gov Identifier: NCT00972933. PMID- 29973206 TI - Oleanolic acid attenuates TGF-beta1-induced epithelial-mesenchymal transition in NRK-52E cells. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays an important role in the progression of renal interstitial fibrosis, which finally leads to renal failure. Oleanolic acid (OA), an activator of NF-E2-related factor 2 (Nrf2), is reported to attenuate renal fibrosis in mice with unilateral ureteral obstruction. However, the role of OA in the regulation of EMT and the underlying mechanisms remain to be investigated. This study aimed to evaluate the effects of OA on EMT of renal proximal tubular epithelial cell line (NRK-52E) induced by TGF beta1, and to elucidate its underlying mechanism. METHODS: Cells were incubated with TGF-beta1 in the presence or absence of OA. The epithelial marker E cadherin, the mesenchymal markers, alpha-smooth muscle actin (alpha-SMA), fibronectin, Nrf2, klotho, the signal transducer (p-Smad2/3), EMT initiator (Snail), and ILK were assayed by western blotting. RESULTS: Our results showed that the NRK-52E cells incubated with TGF-beta1 induced EMT with transition to the spindle-like morphology, down-regulated the expression of E-cadherin but up regulated the expression of alpha-SMA and fibronectin. However, the treatment with OA reversed all EMT markers in a dose-dependent manner. OA also restored the expression of Nrf2 and klotho, decreased the phosphorylation of Smad2/3, ILK, and Snail in cells which was initiated by TGF-beta1. CONCLUSION: OA can attenuate TGF beta1 mediate EMT in renal tubular epithelial cells and may be a promising therapeutic agent in the treatment of renal fibrosis. PMID- 29973205 TI - Inhibition of CRM1 activity sensitizes endometrial and ovarian cell lines to TRAIL-induced cell death. AB - BACKGROUND: CRM1 enrichment has been shown to be indicative of invasive as well as chemoresistant tumors. On the other hand, TRAIL, a powerful and specific anti tumoral agent, has yet to be used effectively to treat gynecological tumors in patients. In the present study, we examined if CRM1, a nuclear exporter capable of mediating protein transport, could be a relevant target to restore chemosensitivity in chemoresistant cells. We thus explored the hypothesis that CRM1-driven nuclear exclusion of tumor suppressors could lead to chemoresistance and that CRM1 inhibitors could present a novel therapeutic approach, allowing sensitization to chemotherapeutic agents. METHODS: Ovarian cancer cell lines, as well as endometrial cancer cell lines, were treated with leptomycin B (LMB), cisplatin and TRAIL, either singly or in combination, in order to induce apoptosis. Western blot and flow cytometry analysis were used to quantify caspases activation and apoptosis induction. Immunofluorescence was used to determine nuclear localization of p53. Colony formation assays were performed to determine therapeutic effectiveness; p53 siRNA were used to establish p53 role in sensitization. Additional information from GEO database and Prognoscan allowed us to contextualise the obtained results. Finally, qRT-PCR was performed to measure apoptotic regulators expression. RESULTS: TRAIL and LMB combination therapy lead to cleavage of caspase-3 as well as the appearance of cleaved-PARP, and thus, apoptosis. Further experiments suggested that sensitization was achieved through the synergistic downregulation of multiple inhibitor of apoptosis, as well as the activation of apoptotic pathways. p53 was enriched in the nucleus following LMB treatments, but did not seem to be required for sensitization; additional experiments suggested that p53 opposed the apoptotic effects of LMB and TRAIL. Results obtained from public data repositories suggested that CRM1 was a driver of chemoresistance and poor prognostic; DR5, on the other hand, acted as as a marker of positive prognostic. CONCLUSIONS: Taken together, our results suggest that the use of CRM1 inhibitors, in combination to chemotherapeutic compounds, could be highly effective in the treatment of gynecological malignancies. PMID- 29973208 TI - A novel gene-expression-signature-based model for prediction of response to Tripterysium glycosides tablet for rheumatoid arthritis patients. AB - BACKGROUND: Approximately 30% of rheumatoid arthritis (RA) patients treated with Tripterysium glycosides (TG) tablets fail to achieve clinical improvement, implying the essentiality of predictive biomarkers and tools. Herein, we aimed to identify possible biomarkers predictive of therapeutic effects of TG tablets in RA. METHODS: Gene expression profile in peripheral blood mononuclear cells obtained from a discovery cohort treated with TG tablets was detected by Affymetrix EG1.0 arrays. Then, a list of candidate gene biomarkers of response to TG tablets were identified by integrating differential expression data analysis and gene signal transduction network analysis. After that, a partial-least squares (PLS) model based on the expression levels of the candidate gene biomarkers in RA patients was constructed and evaluated using a validation cohort. RESULTS: Six candidate gene biomarkers (MX1, OASL, SPINK1, CRK, GRAPL and RNF2) were identified to be predictors of TG therapy. Following the construction of a PLS-based model using their expression levels in peripheral blood, both the 5-fold cross-validation and independent dataset validations showed the high predictive efficiency of this model, and demonstrated a distinguished improvement of the PLS-model based on six candidate gene biomarkers' expression in combination over the commonly used clinical and inflammatory parameters, as well as the gene biomarkers alone, in predicting RA patients' response to TG tablets. CONCLUSIONS: This hypothesis-generating study identified MX1, OASL, SPINK1, CRK, GRAPL and RNF2 as novel targets for RA therapeutic intervention, and the PLS model based on the expression levels of these candidate biomarkers may have a potential prognostic value in RA patients treated with TG tablets. PMID- 29973207 TI - Comparison of audio vs. audio + video for the rating of shared decision making in oncology using the observer OPTION5 instrument: an exploratory analysis. AB - BACKGROUND: How non-verbal data may influence observer-administered ratings of shared decision making is unknown. Our objective for this exploratory analysis was to determine the effect of mode of data collection (audio+video vs. audio only) on the scoring of the OPTION5 instrument, an observer rated measure of shared decision making. METHODS: We analyzed recordings of 15 encounters between cancer patients and clinicians in which a clinical decision was made. Audio+video or audio only recordings of the encounters were randomly assigned to four trained raters, who reviewed them independently. We compared the adjusted mean scores of audio+video and audio only. RESULTS: Forty-one unique decisions were identified within the 15 encounters. The mean OPTION5 score for audio+video was 17.5 (95% CI 13.5, 21.6) and for audio only was 21.8 (95% CI 17.2, 26.4) with a mean difference of 4.28 (95% CI = 0.36, 8.21; p = 0.032). CONCLUSION: A rigorous and well established measure of shared decision making performs differently when the data source is audio only. Data source may influence rating of observer administered measures of shared decision making. This potential bias needs to be confirmed as video recording to examine communication behaviors becomes more common. PMID- 29973210 TI - Endometriosis in the rectum accompanied by hemorrhoids leading to diagnostic pitfalls: a rare case report. AB - BACKGROUND: Hemorrhoid is a common anorectal disease. Hemorrhoids accompanied by endometriosis are unusual. As endometriosis in the rectum may mimic many other diseases, including cancer and inflammation, its diagnosis may be difficult, especially when it is combined with other diseases. CASE PRESENTATION: Here, we present a rare case of a patient with hemorrhoids accompanied by endometriosis in the rectum. The endometriosis mass was detected by digital rectal examination and CT scan and confirmed by pathological examination. The mass was approximately 0.8 cm * 0.6 cm and located in the muscularis and submucosa of the rectum 8 cm from the anus. CONCLUSIONS: In this case, hemorrhoid is a common disease of rectum and anal canal. However, when it is complicated by another rare disease, the rare one can be easily neglected because of the existence of the common one, especially when the two diseases have similar lesions or symptoms. We suggest that strict physical examination, such as the digital rectal examination in the current case, is critical for correct disease diagnosis. PMID- 29973209 TI - A study on the value of narrow-band imaging (NBI) for the general investigation of a high-risk population of nasopharyngeal carcinoma (NPC). AB - BACKGROUND: This study aims to explore the feasibility of narrow-band imaging (NBI) applied for the diagnostic screening of a high-risk population of nasopharyngeal carcinoma (NPC) and increase the accuracy rate of nasopharyngeal biopsy and the diagnosis rate of early-stage patients. METHODS: The positive high risk population of NPC to EB virus antibody was followed up. At the same time, serological screening and pharyngorhinoscopy were carried out. The specific methods were as follows: (1) all subjects received nasopharyngeal examinations through both the HD endoscopic white light mode (WL) and NBI mode, (2) nasopharyngeal biopsy was conducted on positive subjects with microscopic examination, and, finally, (3) a comparative analysis was conducted between the biopsy pathology results and microscopy results. In addition, the following comparative indicators were recorded under different modes: sensitivity, specificity, accuracy, positive likelihood ratio, and negative likelihood ratio. Then, the area under the ROC curve and the kappa coefficient were calculated. RESULTS: A total of 115 subjects were detected to be positive by microscopic examination under the WL mode. Among these subjects, 19 subjects were diagnosed with NPC. In addition, 24 subjects were detected to be positive by microscopic examination under the NBI mode. Among these subjects, 23 subjects were diagnosed with NPC. Under the WL mode, the specific values of the comparative indicators were as follows: sensitivity, 82.61%; specificity, 0%; and area under the ROC curve, 0.413. Furthermore, the WL mode in the diagnosis on the high-risk population of NPC exhibited poor consistency with the biopsy pathology results (kappa coefficient = - 0.069). Under the NBI mode, the specific values of the comparative indicators were as follows: sensitivity, 100%; specificity, 98.96%; and area under the ROC curve, 0.995. Furthermore, the NBI mode in the diagnosis on the high-risk population of NPC exhibited relatively satisfactory consistency with the biopsy pathology results (kappa coefficient = 0.973). Therefore, the NBI mode is significantly superior to the WL mode. CONCLUSION: NBI endoscopic examinations should be conducted on a routine basis for high-risk populations of NPC. This can decrease the frequency of biopsies and enhance diagnostic effects. PMID- 29973211 TI - Greater improvements in diet quality among overweight participants following a group-based commercial weight loss programme than those receiving support to lose weight in primary care. AB - BACKGROUND: Relatively little is known about dietary changes and their relationships with weight change during behavioural weight loss interventions. In a secondary analysis of data from a multicentre RCT, we investigated whether greater improvements in diet would be achieved by overweight adults following a 12 month group-based commercial weight loss programme (CP) than those receiving standard care (SC) in primary practice, and if these dietary changes were associated with greater weight loss. METHODS: Adults with a BMI 27-35 kg/m2 and >1 risk factor for obesity-related disorders were recruited in study centres in Australia and the UK during 2007-2008. Dietary intake and body weight were measured at baseline, 6 and 12 months. Linear mixed effects models compared mean changes in dietary macronutrient intake, fibre density and energy density over time between groups, and their relationships with weight loss. RESULTS: The CP group demonstrated greater mean weight loss than the SC group at 6 months (3.3 kg, 95% CI: 2.2, 4.4) and 12 months (3.3 kg, 95% CI: 2.1, 4.5). Diet quality improved in both intervention groups at 6 and 12 months. However, the CP group (n = 228) achieved significantly greater mean reductions in energy intake (mean difference; 95% CI: - 503 kJ/d; - 913, - 93), dietary energy density (- 0.48 MJ/g; - 0.81, - 0.16), total fat (- 6.9 g/d; - 11.9, - 1.8), saturated fat (- 3.3 g/d; - 5.4, - 1.1), and significantly greater mean increases in fibre density (0.30 g/MJ; 0.15, 0.44) at 6 months than the SC group (n = 239). Similar differences persisted at 12 months and the CP group showed greater mean increases in protein density (0.65 g/MJ). In both groups, weight loss was associated with increased fibre density (0.68 kg per g/MJ, 95% CI: 0.08, 1.27) and protein density (0.26 kg per g/MJ, 95% CI: 0.10, 0.41). CONCLUSIONS: Following a group based commercial program led to greater improvements in diet quality than standard care. Increases in dietary protein and fibre density were independently associated with weight loss in both behavioural weight loss interventions. Greater increases in protein and fibre density in the commercial program likely contributed to their greater weight loss. TRIAL REGISTRATION: ISRCTN: ISRCTN85485463 Registered 03/08/2007 Retrospectively Registered. PMID- 29973212 TI - Efficacy of two artemisinin-based combinations for the treatment of malaria in pregnancy in India: a randomized controlled trial. AB - BACKGROUND: In India, the recommended first-line treatment for malaria in the second and third trimester of pregnancy is artesunate + sulfadoxine-pyrimethamine (AS+SP). However, data on safety and efficacy of artemisinin-based combination therapy (ACT) in pregnancy is limited. This study assessed the safety and efficacy of AS+SP and artesunate + mefloquine (AS+MQ) for treatment of Plasmodium falciparum in pregnancy in India. METHODS: This open-label, randomized clinical trial was conducted from October 2010 to December 2013 at three sites in India (Ranchi and Jamshedpur in Jharkhand state, and Rourkela in Odisha state). Pregnant women in the second or third trimester who had P. falciparum mono infection of any parasite density with or without fever were randomized to receive AS+SP or AS+MQ. Blood slides and filter paper samples for Polymerase Chain Reaction (PCR) were collected on days 0, 1, 2, 3, 14, 21, 28, 42 and 63 post treatment. Women were followed up at delivery and at day 42 postpartum. FINDINGS: Two hundred and forty-eight women of 7064 pregnant women (3.5%) who were screened at monthly antenatal clinics had a P. falciparum mono-infection and were randomized to receive AS+SP (125) or AS+MQ (123) and all of these women were included in the intention to treat (ITT) analysis. The primary endpoint of an adequate clinical and parasite response (ACPR) on day 63 was not available for 9 women who were counted as treatment failure in the ITT analysis. In the ITT population, the ACPR was 121/125 (96.8%; 95% Confidence interval (CI) 92.0-99.1%) in the AS+SP group and 117/123 (95.1%; 95% CI 89.7-98.2) in the AS+MQ group. Among the 239 women (121 from the AS+SP arm and 118 from the AS+MQ arm) who completed the day 63 follow up (per protocol analysis) the ACPR was 100% in the AS+SP group and 99.2% (117/118) in the AS+MQ group. There were five serious adverse events (SAE) among pregnant women (4 in the AS+SP group and 1 in the AS+MQ group) and 13 fetal/neonatal SAEs (7 in the AS+SP group and 6 in the AS+MQ) but none of them were related to the study drugs. A higher proportion of women in the AS+MQ arm reported vomiting within 7 days post-treatment than did women in the AS+SP arm (6.9 vs. 1.6%; p = 0.001). CONCLUSION: Both AS+SP and AS+MQ are safe and effective for treatment of uncomplicated falciparum malaria in pregnancy in India. Trial registration CTRI This study is registered with Clinical Trial Registry India (CTRI), number CTRI/2009/091/001055. Date of Registration 11 January 2010, http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=1185&EncHid=&userName=anv kar. PMID- 29973213 TI - Effects of low-molecular-weight chitosan on the growth performance, intestinal morphology, barrier function, cytokine expression and antioxidant system of weaned piglets. AB - BACKGROUND: Chitosan was used as an alternative to promote the growth of weaned piglets. And low-molecular-weight chitosan (LC) is one of chitosan derivatives and maintain beneficial biological properties of chitoson. The present experiment was carried out to examine the effects of LC on the growth performance, intestinal morphology, barrier function, cytokine expression, and antioxidant system of weaned piglets. RESULTS: A total of 40 piglets weaned at 21 d of age, with average body weight 6.37 +/- 0.08 kg, were randomly assigned (5 pens/diet; 4 pigs/pen) to 2 treatments (a basal diet and the basal diet supplemented with 50 mg/kg LC) and were fed for 28 d. Compared with the control group, average daily feed intake (ADFI), and the expression of intestinal barrier protein ZO-1 was increased (P < 0.05) when the piglets fed the diet supplemented with LC. No significant differences were found in average daily gain (ADG, P > 0.05), gain-to feed ratio (G:F, P > 0.05), the incidence of diarrhea (P > 0.05), or the antioxidant capacity (P > 0.05) between two groups. The expression of IL-1beta and TNF-alpha in jejunal mucosa were significantly decreased (P < 0.05) in piglets fed the LC-supplemented diet in comparison to the control. CONCLUSION: The results of this study indicate that dietary supplementation with LC at 50 mg/kg was effective for enhancing the growth performance in weaned piglets, improving intestinal barrier function and alleviating intestinal inflammation. PMID- 29973214 TI - Clinical utility of the S3-score for molecular prediction of outcome in non metastatic and metastatic clear cell renal cell carcinoma. AB - BACKGROUND: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR. METHODS: A 97 gene-based S3-score (S397) was evaluated in a set of 52 primary non metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S315). This S315-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints. RESULTS: The S397-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, PLog-rank = 3.3 * 10-2) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, PLog-rank = 2.2 * 10-2). The qRT-PCR based S315-score performed similarly to the S397 score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, PLog-rank = 5.1 * 10-5) including metastatic (9.3, 1.8 50.0, PLog-rank = 2.3 * 10-3) and non-metastatic patients (4.4, 1.2-16.3, PLog rank = 1.6 * 10-2), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, PWald = 3.3 * 10-4). Matched primary tumors and metastases revealed similar S315-scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S315 score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 * 10-3). CONCLUSION: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting. PMID- 29973215 TI - Weak HIF-1alpha expression indicates poor prognosis in resectable pancreatic ductal adenocarcinoma. AB - BACKGROUND: HIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities. METHODS: We investigated the expression and prognostic role of HIF 1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry. RESULTS: In our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216 3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival. CONCLUSIONS: Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia related prognostic factor should be addressed with caution. PMID- 29973216 TI - Efficient undergraduate learning of liver transplant: building a framework for teaching subspecialties to medical students. AB - BACKGROUND: Liver recipients may develop various diseases after transplant. However, because of inadequate study of liver transplant during undergraduate education, the quality of post-transplant care provided to these patients remains suboptimal. Herein, we introduce an innovative and integrated multimodal pedagogical approach to effectively disseminate key information regarding liver transplant to undergraduate students. The goal is to examine this approach through students' assessment in multiple dimensions. METHODS: This prospective observational study evaluated student reactions to our pedagogical approach. Fifth-year medical students during the academic year 2015-2016 attended a 2-h session on what nontransplant doctors should know about liver transplants. The pedagogical strategy consisted of an online preclass self-learning exercise, an in-class interactive discussion (facilitated by the class teacher who is a liver transplant specialist to avoid distractions within the short-time frame), and a postclass essay assignment (to integrate and apply concepts). After the class, questionnaires were distributed to individual students to collect data, if returned, concerning the students' learning experience and feedback to improve teaching quality. Descriptive statistics, Mann-Whitney U tests, chi-squared tests, and McNemar's tests were used to analyze quantitative data. Qualitative data were content-coded through a descriptive approach using thematic analysis. RESULTS: Of the 266 attendees, 263 (98.9%) completed the questionnaires and 182 (69.2%) provided comments. Student feedback indicated they "felt better" and "more satisfied" compared with problem-based learning (PBL) (51.0 and 63.1%, respectively) or large-lecture class (92.0 and 88.6%, respectively) approaches. Regarding confidently managing liver transplant patients in future, 80 (30.4%) and 246 (93.5%) students expressed preclass and postclass confidence, respectively (p < 0.001). The bell curve of the postclass self-assessment score of learning shifted toward right and became steeper compared with that of the preclass score (p < 0.001), suggesting students acquired considerable knowledge. The course was typically perceived to be cost-effective, practical, tension-free, and student-friendly. CONCLUSION: This pedagogical approach effectively propagated knowledge concerning liver transplant to medical students, who expressed considerable satisfaction with the approach. PMID- 29973217 TI - Ethics of task shifting in the health workforce: exploring the role of community health workers in HIV service delivery in low- and middle-income countries. AB - BACKGROUND: Task shifting is increasingly used to address human resource shortages impacting HIV service delivery in low- and middle-income countries. By shifting basic tasks from higher- to lower-trained cadres, such as Community Health Workers (CHWs), task shifting can reduce overhead costs, improve community outreach, and provide efficient scale-up of essential treatments like antiretroviral therapies. Although there is rich evidence outlining positive outcomes that CHWs bring into HIV programs, important questions remain over their place in service delivery. These challenges often reflect concerns over whether CHWs can mitigate HIV through a means that does not overlook the ethical and practical constraints that undergird their work. Ethical and practical guidance thus needs to become the cornerstone of CHW deployment. This paper analyzes such challenges through the lens of Ethical Principlism. METHODS: We examined papers identifying substantive and ethical challenges impacting CHWs as they provide HIV services in low- and middle-income contexts. To do this, we analyzed papers written in English and published from year 2000 or later. These articles were identified using MEDLINE, Cochrane Database of Systematic Reviews, and Google Scholar databases. In total, 465 articles were identified, 78 of which met our inclusion criteria. Article reference lists and grey literature were also examined. RESULTS: CHWs experience specific challenges while carrying out their duties, such as conducting emotionally- and physically-demanding tasks with often inadequate training, supervision and compensation. CHWs have also been poorly integrated into health systems, which not only impacts quality of care, but can hinder their prospects for promotion and lead to CHW disempowerment. As we argue, these challenges can be addressed if a set of ethical principles is prioritized, which specifically entail the principles of respect for persons, justice, beneficence, proportionality and cultural humility. CONCLUSIONS: CHWs play a crucial role in HIV service delivery, yet the ethical challenges that can accompany their work cannot be overlooked. By prioritizing ethical principles, policymakers and program implementers can better ensure that CHWs are combatting HIV through a means that does not exploit or take their critical role within service delivery for granted. PMID- 29973219 TI - Burden of NCDs in SNNP region, Ethiopia: a retrospective study. AB - BACKGROUND: Non-communicable diseases (NCDs) are medical conditions or diseases that are non-transmissible. As NCDs are becoming one of major public health problem, providing local description of diseases and injuries is key to health decision- making and planning processes. So, this study aimed to describe caseload of NCDs in Southern Nations Nationalities and People's Region, Ethiopia. METHODS: A facility based retrospective study was conducted in February 2015 in SNNPR, Ethiopia. A total of 22,320 records of three years retrieved from 23 health facilities using systematic sampling. Data were entered in to Epi-Info 3.5.3 and descriptive analysis was carried out using SPSS version 20. RESULTS: From 22,320 records reviewed, 6633 (29.7%) clients visited health facilities due to Non-Communicable Diseases (NCDs). Majority (37.2%) of NCD cases were in productive age groups (20-35 year). Near to half (43%) of NCD cases were from rural and 45.8% were females. Digestive disorder (26.7%), cardiovascular diseases (18.8%) and Diabetes Mellitus (13.1%) were the most prevalent types of NCDs. CONCLUSION: Health facilities are burdened with significant proportion of clients with NCDs. Young population accounts large share and NCDs are becoming public health problem of urban and rural area within a health care system that focus on communicable diseases. There is a need to strengthen the health system to work towards NCDs, and investigate risk factors associated with NCDs at individual level. PMID- 29973218 TI - Glucocorticoids promote transition of ductal carcinoma in situ to invasive ductal carcinoma by inducing myoepithelial cell apoptosis. AB - BACKGROUND: The microenvironment and stress factors like glucocorticoids have a strong influence on breast cancer progression but their role in the first stages of breast cancer and, particularly, in myoepithelial cell regulation remains unclear. Consequently, we investigated the role of glucocorticoids in ductal carcinoma in situ (DCIS) in breast cancer, focusing specially on myoepithelial cells. METHODS: To clarify the role of glucocorticoids at breast cancer onset, we evaluated the effects of cortisol and corticosterone on epithelial and myoepithelial cells using 2D and 3D in vitro and in vivo approaches and human samples. RESULTS: Glucocorticoids induce a reduction in laminin levels and favour the disruption of the basement membrane by promotion of myoepithelial cell apoptosis in vitro. In an in vivo stress murine model, increased corticosterone levels fostered the transition from DCIS to invasive ductal carcinoma (IDC) via myoepithelial cell apoptosis and disappearance of the basement membrane. RU486 is able to partially block the effects of cortisol in vitro and in vivo. We found that myoepithelial cell apoptosis is more frequent in patients with DCIS+IDC than in patients with DCIS. CONCLUSIONS: Our findings show that physiological stress, through increased glucocorticoid blood levels, promotes the transition from DCIS to IDC, particularly by inducing myoepithelial cell apoptosis. Since this would be a prerequisite for invasive features in patients with DCIS breast cancer, its clinical management could help to prevent breast cancer progression to IDC. PMID- 29973220 TI - Their view: difficulties and challenges of patients and physicians in cross cultural encounters and a medical ethics perspective. AB - BACKGROUND: In todays' super-diverse societies, communication and interaction in clinical encounters are increasingly shaped by linguistic, cultural, social and ethnic complexities. It is crucial to better understand the difficulties patients with migration background and healthcare professionals experience in their shared clinical encounters and to explore ethical aspects involved. METHODS: We accompanied 32 migrant patients (16 of Albanian and Turkish origin each) during their medical encounters at two outpatient clinics using an ethnographic approach (participant observation and semi-structured interviews with patients and healthcare professionals). Overall, data of 34 interviews with patients and physicians on how they perceived their encounter and which difficulties they experienced are presented. We contrasted the perspectives on the difficult aspects and explore ethical questions surrounding the involved issues. RESULTS: Patients and physicians describe similar problem areas, but they have diverging perspectives on them. Two main themes were identified by both patients and physicians: >patients' behaviour in relation to doctors' advice< and > relationship issues<. CONCLUSIONS: A deeper understanding of the difficulties and challenges that can arise in cross-cultural settings could be provided by bringing together healthcare professionals' and patients' perspectives on how a cross- cultural clinical encounter is perceived. Ethical aspects surrounding some of the difficulties could be highlighted and should get more attention in clinical practice and research. PMID- 29973221 TI - Frequency of CD19+CD24hiCD38hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study. AB - BACKGROUND: To understand the relationship between regulatory B cells (Bregs) and juvenile idiopathic arthritis (JIA), we analyzed the percentages of Bregs and their function in peripheral blood (PB) and synovial fluid (SF) of JIA patients. METHODS: Twenty-one JIA patients and 11 children with growing pain but without known rheumatic diseases as controls were included. The B cell phenotype and intracellular production of IL-10 of Bregs were assessed by flow cytometry. Mononuclear cells from PB and SF were stimulated to produce IL-10 in vitro for the identification of IL-10- producing regulatory B cells. RESULTS: The percentage of CD24hiCD38hi Bregs in the PB of JIA patients was significantly decreased compared to that in controls, and it was even lower in the SF of JIA patients compared to that in the PB. CD24hiCD38hi Bregs frequency was significantly lower in the PB of RF-positive patients than in RF-negative patients. Frequency of IL-10-producing regulatory B cells (B10 cells) was significantly lower in active JIA patients than that in inactive patients. CONCLUSIONS: The inability of the host to produce enough regulatory B cells in PB and especially in SF of JIA patients may contribute to the disease, especially the local inflammation. PMID- 29973222 TI - Interleukin-1 beta promotes neuronal differentiation through the Wnt5a/RhoA/JNK pathway in cortical neural precursor cells. AB - Pro-inflammatory cytokine interleukin-1 beta (IL-1beta) is a key mediator of inflammation and stress in the central nervous system (CNS), and is highly expressed in the developing brain. In this study, we investigated the possible role of IL-1beta in neuronal differentiation of cortical neural precursor cells (NPCs). We showed that stimulation with IL-1beta increased expression levels of neurotrophin-3 (NT3) and neurogenin 1 (Ngn1) and promoted neurite outgrowth. We also found that IL-1beta increased mRNA and protein levels of Wnt5a. Knockdown of Wnt5a by transfection with Wnt5a siRNA inhibited IL-1beta-induced neuronal differentiation. Moreover, IL-1beta-induced Wnt5a expression was regulated by nuclear factor kappa B (NF-kappaB) activation, which is involved in IL-1beta mediated neuronal differentiation. To examine the role of Wnt5a in neuronal differentiation of NPCs, we exogenously added Wnt5a. We found that exogenous Wnt5a promotes neuronal differentiation, and activates the RhoA/Rho-associated kinase (ROCK)/c-jun N-terminal kinase (JNK) pathway. In addition, Wnt5a-induced neuronal differentiation was blocked by RhoA siRNA, as well as by a specific Rho kinase inhibitor (Y27632) or a SAPK/JNK inhibitor (SP600125). Furthermore, treatment with RhoA siRNA, Y27632, or SP600125 suppressed the IL-1beta-induced neuronal differentiation. Therefore, these results suggest that the sequential Wnt5a/RhoA/ROCK/JNK pathway is involved in IL-1beta-induced neuronal differentiation of NPCs. PMID- 29973223 TI - Wounding promotes ovarian cancer progression and decreases efficacy of cisplatin in a syngeneic mouse model. AB - BACKGROUND: Primary cytoreductive surgery followed by adjuvant chemotherapy is the standard treatment for advanced epithelial ovarian cancer. The average interval between surgery and chemotherapy initiation is approximately 4-weeks at most centers; however, since surgery may accelerate residual tumor growth, a shorter interval may be more beneficial. METHODS: The murine ID8 cell model of ovarian cancer was used to examine the efficacy of cisplatin treatment administered perioperatively or 7 days after surgical wounding. Luciferase expressing cells ID8 cells were injected intraperitoneally (i.p.) into female C57/Bl6 mice. Fourteen days post-injection, animals received an abdominal incision or anesthesia alone and received i.p. cisplatin either on the surgical day or 7 days later, or received no chemotherapy. Additional animals received cisplatin 28 days after wounding for comparison. RESULTS: Abdominal tumor mass increased 2.5-fold in wounded vs. unwounded animals as determined by bioluminescent in vivo tumor imaging. Cisplatin administered on the day of wounding decreased tumor burden by 50%, as compared to 90% in unwounded animals. Cisplatin on day 7 or day 28 decreased tumor burden by 80 and 37% respectively. CONCLUSIONS: Surgical wounding increases ovarian tumor mass and decreases perioperative cisplatin efficacy in this animal model. Administration of cisplatin 1 week after surgery was more effective than cisplatin administered perioperatively or 4 weeks after surgery. PMID- 29973224 TI - The effect of perioperative intravenously administered iron isomaltoside 1000 (Monofer(r)) on transfusion requirements for patients undergoing complex valvular heart surgery: study protocol for a randomized controlled trial. AB - BACKGROUND: Anemia is a frequent complication after cardiac surgery especially following reoperation due to previous prosthetic valve failure or multiple valve surgery (including combined coronary artery bypass grafting). This trial explores whether intravenously administered iron isomaltoside 1000 (Monofer(r)) results in better clinical outcomes in patients undergoing complex heart valve surgery who are expected to receive transfusion. METHODS/DESIGN: In this prospective, single center, double-blinded, randomized controlled trial, 214 patients undergoing reoperation or multiple valve surgery are randomly allocated to either the iron isomaltoside 1000 (IVFe) or the control group from August 2016 to August 2018. The IVFe group receives iron isomaltoside 1000 mg (maximum dose 20 mg/kg) intravenously 3 days before and after the surgery. The control group receives an equivalent volume of normal saline. The primary endpoint is transfusion requirement (more than 1 unit of packed erythrocytes) for postoperative care until discharge and secondary endpoint are major complications, such as delayed ventilator therapy, acute kidney injury, and mortality. Reticulocyte count, plasma hepcidin, iron profiles (serum iron, serum ferritin, total iron-binding capacity, transferrin, transferrin saturation), coagulation profiles, urinary analysis, and chemical profiles are measured for three preoperative baseline-data days and just before surgery, except for hepcidin. After surgery, daily routine basic laboratory tests are measured just before discharge and reticulocyte count, iron profiles, and hepcidin are repeatedly checked for three postoperative days. DISCUSSIONS: From our study, we can clarify the following points: the first is the perioperative IVFe effect on the demand for transfusion, and clinical outcomes in reoperation or complex valve surgery and the second is the role of hepcidin in the effect of IVFe on the hemoglobin level increase. TRIAL REGISTRATION: ClinicalTrials.gov , Identifier: NCT02862665 . Registered on August 2016. PMID- 29973225 TI - Implementation and use of computerised clinical decision support (CCDS) in emergency pre-hospital care: a qualitative study of paramedic views and experience using Strong Structuration Theory. AB - BACKGROUND: Computerised clinical decision support (CCDS) has been shown to improve processes of care in some healthcare settings, but there is little evidence related to its use or effects in pre-hospital emergency care. CCDS in this setting aligns with policies to increase IT use in ambulance care, enhance paramedic decision-making skills, reduce avoidable emergency department attendances and improve quality of care and patient experience. This qualitative study was conducted alongside a cluster randomised trial in two ambulance services of the costs and effects of web-based CCDS system designed to support paramedic decision-making in the care of older people following a fall. Paramedics were trained to enter observations and history for relevant patients on a tablet, and the CCDS then generated a recommended course of action which could be logged. Our aim was to describe paramedics' experience of the CCDS intervention and to identify factors affecting its implementation and use. METHODS: We invited all paramedics who had been randomly allocated to the intervention arm of the trial to participate in interviews or focus groups. The study was underpinned by Strong Structuration Theory, a theoretical model for studying innovation based on the relationship between what people do and their context. We used the Framework approach to data analysis. RESULTS: Twenty out of 22 paramedics agreed to participate. We developed a model of paramedic experience of CCDS with three domains: context, adoption and use, and outcomes. Aspects of context which had an impact included organisational culture and perceived support for non-conveyance decisions. Experience of adoption and use of the CCDS varied between individual paramedics, with some using it with all eligible patients, some only with patients they thought were 'suitable' and some never using it. A range of outcomes were reported, some of which were different from the intended role of the technology in decision support. CONCLUSION: Implementation of new technology such as CCDS is not a one-off event, but an ongoing process, which requires support at the organisational level to be effective. TRIAL REGISTRATION: ISRCTN Registry 10538608 . Registered 1 May 2007. Retrospectively registered. PMID- 29973226 TI - Comprehensive genetic characteristics of dystrophinopathies in China. AB - BACKGROUND: Dystrophinopathies are a set of severe and incurable X-linked neuromuscular disorders caused by mutations in the dystrophin gene (DMD). These mutations form a complex spectrum. A national registration network is essential not only to provide more information about the prevalence and natural history of the disease, but also to collect genetic data for analyzing the mutational spectrum. This information is extremely beneficial for basic scientific research, genetic diagnosis, trial planning, clinical care, and gene therapy. METHODS: We collected data from 1400 patients (1042 patients with confirmed unrelated Duchenne muscular dystrophy [DMD] or Becker muscular dystrophy [BMD]) registered in the Chinese Genetic Disease Registry from March 2012 to August 2017 and analyzed the genetic mutational characteristics of these patients. RESULTS: Large deletions were the most frequent type of mutation (72.2%), followed by nonsense mutations (11.9%), exon duplications (8.8%), small deletions (3.0%), splice-site mutations (2.1%), small insertions (1.3%), missense mutations (0.6%), and a combination mutation of a deletion and a duplication (0.1%). Exon 45-50 deletion was the most frequent deletion type, while exon 2 duplication was the most common duplication type. Two deletion hotspots were calculated-one located toward the central part (exon 45-52) of the gene and the other toward the 5'end (exon 8-26). We found no significant difference between hereditary and de novo mutations on deletion hotspots. Nonsense mutations accounted for 62.9% of all small mutations (197 patients). CONCLUSION: We built a comprehensive national dystrophinopathy mutation database in China, which is essential for basic and clinical research in this field. The mutational spectrum and characteristics of this DMD/BMD group were largely consistent with those in previous international DMD/BMD studies, with some differences. Based on our results, about 12% of DMD/BMD patients with nonsense mutations may benefit from stop codon read-through therapy. Additionally, the top three targets for exon-skipping therapy are exon 51 (141, 13.5%), exon 53 (115, 11.0%), and exon 45 (84, 8.0%). PMID- 29973227 TI - Long-term safety and efficacy of pegvaliase for the treatment of phenylketonuria in adults: combined phase 2 outcomes through PAL-003 extension study. AB - BACKGROUND: Deficiency of phenylalanine hydroxylase causes phenylketonuria (PKU) with elevated phenylalanine (Phe) levels and associated neuropsychiatric and neurocognitive symptoms. Pegvaliase (PEGylated phenylalanine ammonia lyase) is an investigational agent to lower plasma Phe in adults with PKU. This study aimed to characterize the long-term efficacy, safety, and immunogenicity of pegvaliase in adults with PKU. METHODS: PAL-003 is an ongoing, open-label, long-term extension study of the pegvaliase dose-finding parent phase 2 studies. Participants continued the dose of pegvaliase from one of three parent studies, with dose adjustments to achieve a plasma Phe concentration between 60 and 600 MUmol/L. RESULTS: Mean (standard deviation [SD]) plasma Phe at treatment-naive baseline for 80 participants in the parent studies was 1302.4 (351.5) MUmol/L. In the 68 participants who entered the extension study, plasma Phe decreased 58.9 (39)% from baseline, to 541.6 (515.5) MUmol/L at Week 48 of treatment. Plasma Phe concentrations <=120 MUmol/L, <=360 MUmol/L, and <= 600 MUmol/L were achieved by 78.7, 80.0, and 82.5% of participants, respectively. Mean (SD) protein intake at baseline was 69.4 (40.4) g/day (similar to the recommended intake for the unaffected population) and remained stable throughout the study. All participants experienced adverse events (AEs), which were limited to mild or moderate severity in most (88.8%); the most common AEs were injection-site reaction (72.5%), injection-site erythema (67.5%), headache (67.5%), and arthralgia (65.0%). The AE rate decreased from 58.3 events per person-year in the parent studies to 18.6 events per person-year in the extension study. CONCLUSIONS: Pegvaliase treatment in adults with PKU produced meaningful and persistent reductions in mean plasma Phe concentration with a manageable safety profile for most subjects that continued with long-term treatment. TRIAL REGISTRATION: ClinicalTrials.gov , NCT00924703. Registered June 18, 2009, https://clinicaltrials.gov/ct2/show/NCT00924703. PMID- 29973228 TI - Artefacts in 1.5 Tesla and 3 Tesla cardiovascular magnetic resonance imaging in patients with leadless cardiac pacemakers. AB - BACKGROUND: There are limited data on patients with leadless cardiac pacemakers (LCP) undergoing magnetic resonance imaging. The aim of this prospective, single center, observational study was to evaluate artefacts on cardiovascular magnetic resonance (CMR) images in patients with LCP. METHODS: Fifteen patients with MicraTM LCP, implanted at least 6 weeks prior to CMR scan, were enrolled and underwent either 1.5 Tesla or 3 Tesla CMR imaging. Artefacts were categorized into grade 1 (excellent image quality), grade 2 (good), grade 3 (poor) and grade 4 (non-diagnostic) for each myocardial segment. One patient was excluded because of an incomplete CMR investigation due to claustrophobia. RESULTS: LCP caused an arc-shaped artefact (0.99 +/- 0.16 cm2) at the right ventricular (RV) apex. Of 224 analyzed myocardial segments of the left ventricle (LV) 158 (70.5%) were affected by grade 1, 27 (12.1%) by grade 2, 17 (7.6%) by grade 3 and 22 (9.8%) by grade 4 artefacts. The artefact burden of grade 3 and 4 artefacts was significantly higher in the 3 Tesla group (3 Tesla vs 1.5 Tesla: 3.7 +/- 1.6 vs 1.9 +/- 1.4 myocardial segments per patient, p = 0.03). A high artefact burden was particularly observed in the mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV and in the mid and apical segments of the RV. Quantification of LV function and assessment of valves were feasible in all patients. We did not observe any clinical or device-related adverse events. CONCLUSION: CMR imaging in patients with LCP is feasible with excellent to good image quality in the majority of LV segments. The artefact burden is comparable small allowing an accurate evaluation of LV function, cardiac structures and valves. However, artefacts in the mid anteroseptal, inferoseptal and apical septal myocardial segments of the LV due to the LCP may impair or even exclude diagnostic evaluation of these segments. Artefacts on CMR images may be reduced by the use of 1.5 Tesla CMR scanners. PMID- 29973230 TI - Strategies to integrate community-based traditional and complementary healthcare systems into mainstream HIV prevention programs in resource-limited settings. AB - BACKGROUND: Global spending for HIV prevention has been decreasing over the years. As a result, several low-income countries, including Nepal, are increasingly facing the challenge to minimize the funding gap to continue providing HIV prevention services to the people. In this paper, we have attempted to clarify why it is important to integrate community-based traditional and complementary healthcare systems and mobilize them into the mainstream HIV programs to ensure access to HIV prevention messages, HIV testing, and treatment in resource-limited settings. MAIN BODY: First, we argue that the traditional and complementary healthcare practitioners can be mobilized to routinely provide HIV prevention messages to their clients, and, next, some of them can be trained to build their capacity to work as counselors or educators for HIV prevention in the community. CONCLUSION: These approaches, if implemented, can help continue HIV prevention initiatives and contain the HIV epidemic at the local level in the rural communities with limited cost and resources. PMID- 29973229 TI - mHealth intervention to improve the continuum of maternal and perinatal care in rural Guatemala: a pragmatic, randomized controlled feasibility trial. AB - BACKGROUND/OBJECTIVE: Guatemala's indigenous Maya population has one of the highest perinatal and maternal mortality rates in Latin America. In this population most births are delivered at home by traditional birth attendants (TBAs), who have limited support and linkages to public hospitals. The goal of this study was to characterize the detection of maternal and perinatal complications and rates of facility-level referral by TBAs, and to evaluate the impact of a mHealth decision support system on these rates. METHODS: A pragmatic one-year feasibility trial of an mHealth decisions support system was conducted in rural Maya communities in collaboration with TBAs. TBAs were individually randomized in an unblinded fashion to either early-access or later-access to the mHealth system. TBAs in the early-access arm used the mHealth system throughout the study. TBAs in the later-access arm provided usual care until crossing over uni-directionally to the mHealth system at the study midpoint. The primary study outcome was the monthly rate of referral to facility-level care, adjusted for birth volume. RESULTS: Forty-four TBAs were randomized, 23 to the early-access arm and 21 to the later-access arm. Outcomes were analyzed for 799 pregnancies (early-access 425, later-access 374). Monthly referral rates to facility-level care were significantly higher among the early-access arm (median 33 referrals per 100 births, IQR 22-58) compared to the later-access arm (median 20 per 100, IQR 0-30) (p = 0.03). At the study midpoint, the later-access arm began using the mHealth platform and its referral rates increased (median 34 referrals per 100 births, IQR 5-50) with no significant difference from the early-access arm (p = 0.58). Rates of complications were similar in both arms, except for hypertensive disorders of pregnancy, which were significantly higher among TBAs in the early access arm (RR 3.3, 95% CI 1.10-9.86). CONCLUSIONS: Referral rates were higher when TBAs had access to the mHealth platform. The introduction of mHealth supportive technologies for TBAs is feasible and can improve detection of complications and timely referral to facility-care within challenging healthcare delivery contexts. TRIAL REGISTRATION: Clinicaltrials.gov NCT02348840 . PMID- 29973231 TI - The inhibitory effect of LPS on the expression of GPR81 lactate receptor in blood brain barrier model in vitro. AB - BACKGROUND: Lipopolysaccharide (LPS) is one of the main constituents of the cell wall of gram-negative bacteria. As an endotoxin, LPS induces neuroinflammation, which is associated with the blood-brain barrier impairment. Lactate is a metabolite with some significant physiological functions within the neurovascular unit/blood-brain barrier (BBB). Accumulation of extracellular and cerebrospinal fluid lactate is a specific feature of bacterial meningitis. However, the role of lactate production, transport, and sensing by lactate receptors GPR81 in the pathogenesis of bacterial neuroinflammation is still unknown. METHODS: In this study, we analyzed effects of LPS on the expression of GPR81 and MCT-1 and proliferation of cerebral endothelial cells in the BBB model in vitro. We used molecular profiling methods to measure the expression of GPR81, MCT-1, IL-1beta, and Ki67 in the cerebral endothelium after treatment with different concentrations of LPS followed by measuring the level of extracellular lactate, transendothelial electric resistance, and permeability of the endothelial cell layer. RESULTS: Our findings showed that exposure to LPS results in neuroinflammatory changes associated with decreased expression of GPR81 and MCT-1 in endothelial cells, as well as overproduction of IL-1beta and elevation of lactate concentrations in the extracellular space in a dose-dependent manner. LPS treatment reduced JAM tight junction protein expression in cerebral endothelial cells and altered BBB structural integrity in vitro. CONCLUSION: The impairment of lactate reception and transport might contribute to the alterations of BBB structural and functional integrity caused by LPS-mediated neuroinflammation. PMID- 29973232 TI - Medical device landscape for communicable and noncommunicable diseases in low income countries. AB - BACKGROUND: This study characterized the landscape of commercially available medical devices specifically designed for use in low-income countries (LICs). METHODS: A state-of-the-art review of peer-reviewed publications, patents, global health databases, and online resources was performed. The criteria established for a health technology's inclusion in the study were: it met the definition of a medical device; it was designed and developed to address one of the top ten causes of death in LICs, Millennium Development Goal (MDG) 4, or MDG 5; and there was evidence of its commercialization. RESULTS: Analysis identified 134 commercialized devices exclusively designed for use in LICs. More than 85% of devices were designed to address infectious diseases or child or maternal health (MDG 4 or 5, respectively). None of the identified devices addressed prevention of noncommunicable diseases (NCDs). Only 8% of devices were designed for use in primary health facilities by non-physician health providers. CONCLUSION: There is a significant mismatch between the projected global burden of disease due to NCDs and the relevant number of commercialized medical devices designed specifically for use in LICs. A limited number of commercialized devices were designed for use by non-physician health providers. These findings suggest the need for medical devices targeting NCDs in LICs and design processes that consider the broader context of design and engage stakeholders throughout all phases of design. PMID- 29973233 TI - Postoperative cellular stress in the kidney is associated with an early systemic gammadelta T-cell immune cell response. AB - BACKGROUND: Basic science data suggest that acute kidney injury (AKI) induced by ischemia-reperfusion injury (IRI) is an inflammatory process involving the adaptive immune response. Little is known about the T-cell contribution in the very early phase, so we investigated if tubular cellular stress expressed by elevated cell cycle biomarkers is associated with early changes in circulating T cell subsets, applying a bedside-to-bench approach. METHODS: Our observational pilot study included 20 consecutive patients undergoing endovascular aortic repair for aortic aneurysms affecting the renal arteries, thereby requiring brief kidney hypoperfusion and reperfusion. Clinical-grade flow cytometry-based immune monitoring of peripheral immune cell populations was conducted perioperatively and linked to tubular cell stress biomarkers ([TIMP-2]*[IGFBP7]) immediately after surgery. To confirm clinical results and prove T-cell infiltration in the kidney, we simulated tubular cellular injury in an established mouse model of mild renal IRI. RESULTS: A significant correlation between tubular cell injury and a peripheral decline of gammadelta T cells, but no other T-cell subpopulation, was discovered within the first 24 hours (r = 0.53; p = 0.022). Turning to a mouse model of kidney warm IRI, a similar decrease in circulating gammadelta T cells was found and concomitantly was associated with a 6.65-fold increase in gammadelta T cells (p = 0.002) in the kidney tissue without alterations in other T-cell subsets, consistent with our human data. In search of a mechanistic driver of IRI, we found that the damage-associated molecule high mobility group box 1 protein HMGB1 was significantly elevated in the peripheral blood of clinical study subjects after tubular cell injury (p = 0.019). Correspondingly, HMGB1 RNA content was significantly elevated in the murine kidney. CONCLUSIONS: Our investigation supports a hypothesis that gammadelta T cells are important in the very early phase of human AKI and should be considered when designing clinical trials aimed at preventing kidney damage. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01915446 . Registered on 5 Aug 2013. PMID- 29973234 TI - Genetic characterisation of molecular targets in carcinoma of unknown primary. AB - BACKGROUND: Carcinoma of unknown primary (CUP) is a metastatic epithelial malignancy in the absence of an identifiable primary tumour. Prognosis for patients with CUP is poor because treatment options are generally limited to broad spectrum chemotherapy. A shift towards personalised cancer management based on mutation profiling offers the possibility of new treatment paradigms. This study has explored whether actionable, oncogenic driver mutations are present in CUP that have potential to better inform treatment decisions. METHODS: Carcinoma of unknown primary cases (n = 21) were selected and DNA was isolated from formalin-fixed paraffin embedded sections prior to amplification and sequencing. Two distinct yet complementary targeted gene panels were used to assess variants in up to 76 known cancer-related genes for the identification of biologically relevant and actionable mutations. RESULTS: Variants were detected in 17/21 cases (81%) of which 11 (52%) were potentially actionable with drugs currently approved for use in known primary cancer types or undergoing clinical trials. The most common variants detected were in TP53 (47%), KRAS (12%), MET (12%) and MYC (12%). Differences at the molecular level were seen between common CUP histological subtypes. CUP adenocarcinomas and poorly differentiated carcinomas harboured the highest frequency of variants in genes involved in signal transduction pathways (e.g. MET, EGFR, HRAS, KRAS, and BRAF). In contrast, squamous cell carcinoma exhibited a higher frequency of variants in cell cycle control and DNA repair genes (e.g. TP53, CDKN2A and MLH1). CONCLUSION: Taken together, mutations in biologically relevant genes were detected in the vast majority of CUP tumours, of which half provided a potentially novel treatment option not generally considered in CUP. PMID- 29973235 TI - The comorbidity of low back pelvic pain and risk of depression and anxiety in pregnancy in primiparous women. AB - BACKGROUND: Approximately 50% of Australian women experience low back pain in pregnancy, with somewhere between 8 and 36% of women suffering from pregnancy related depression/anxiety. Both low back and pelvic pain and depression and anxiety are associated with poor maternal health outcomes, including increased sick leave, higher rates of functional disability, and increased access to healthcare. It also impacts upon time and mode of delivery with an increase in inductions and elective caesarean sections. For babies of women with depression and anxiety preterm birth, low birth weight and intrauterine growth restriction are all common complications. Given these poor health outcomes, it is important to determine the co-morbidity of low back and pelvic pain and depression/anxiety in pregnancy. METHODS: A cross sectional study of a hospital based sample of 96 nulliparous women were assessed at 28 weeks as part of their routine antenatal appointment. Data was collected via interview and clinical records and included the Edinburgh Depression Scale (EDS), the Numerical Rating Scale (NRS) and the Modified Oswestry Low Back Pain Disability Questionnaire (MODQ). Spearman's correlation co-efficients, prevalence ratios and ANOVA were used to determine comorbidity. RESULTS: 96 women consented to participation in the study. All study outcomes were moderately correlated. There were three main findings: One, there was a positive correlation between low back and pelvic girdle pain (LBPP) and depression/anxiety was rho = 0.39, p < 0.001, between LBPP and functional disability was rho = 0.51, p < 0.001 and between risk of depression/anxiety and functional disability was rho = 0.54, p < 0.001. Two, a woman with LBPP was 13 times more likely to have increased risk of depression/anxiety, whilst a woman with increased risk of depression/anxiety was 2.2 times more likely to have LBPP and finally three, amongst women who reported LBPP, the level of disability experienced was significantly higher in women who had concurrent increased risk of depression/anxiety (p = 0.003). This occurred even though the severity of pain did not differ between groups (NRS score mean p = 0.38). CONCLUSIONS: This study found a high level of co-occurrence of LBPP, functional disability and depression/anxiety in women in their third trimester of pregnancy. Importantly women who reported higher depression/anxiety symptoms appeared to experience higher levels of functional disability in relation to their LBPP, than women with lower depression/anxiety symptoms and LBPP. PMID- 29973236 TI - Sperm quality in frozen beef and dairy bull semen. AB - BACKGROUND: There is speculation that beef bull semen quality is inferior to that of dairy bulls although few scientific studies are available in the literature. The aim of this study was to evaluate sperm quality in beef bull semen and to determine which parameters could be indicative of fertility after insemination. Sperm quality, assessed by computer assisted sperm motility analysis and flow cytometric evaluation of membrane integrity, levels of reactive oxygen species, mitochondrial membrane potential, acrosome status and DNA fragmentation index, was evaluated in beef and dairy bull semen. RESULTS: For beef bulls, normal morphology (r = 0.62, P < 0.05) and WOBBLE (r = 0.57, P < 0.05) were significantly correlated with 56-day non-return rate, whereas sperm quality was not significantly correlated with the fertility index score for dairy bulls. Membrane integrity (46 +/- 8.0% versus 40 +/- 11%, P < 0.05), normal morphology (87 +/- 6% versus 76 +/- 8%; P < 0.05), and high respiratory activity (52 +/- 13 versus 12 +/- 4%; P < 0.001) were higher for dairy bulls than for beef bulls. The DNA fragmentation index was lower for dairy bull spermatozoa than beef (3.8 +/- 1.1% versus 6.1 +/- 2.9%; P < 0.01), whereas some sperm kinematics were higher. Multivariate analysis indicated that type of bull (beef versus dairy) had an impact on sperm quality. CONCLUSIONS: Different assays of sperm quality may be needed for appropriate analysis of beef and dairy bull semen. These finding could be important for cattle breeding stations when evaluating semen quality. PMID- 29973237 TI - Up-regulation of FGF15/19 signaling promotes hepatocellular carcinoma in the background of fatty liver. AB - BACKGROUND: Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC. METHODS: A steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high fat diet (HFD). A mouse HCC cell line (Hepa1-6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor beta-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis. RESULTS: HCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/beta-klotho, aberrant epithelial-mesenchymal transition (EMT) and Wnt/beta-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/beta-catenin signaling. CONCLUSIONS: Up-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/beta-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients. PMID- 29973239 TI - Accuracy of MRI diagnosis of early osteonecrosis of the femoral head: a meta analysis and systematic review. AB - OBJECTIVE: To evaluate the overall diagnostic value related to magnetic resonance imaging (MRI) in patients with early osteonecrosis of the femoral head. METHODS: By searching multiple databases and sources, including PubMed, Cochrane, and Embase database, by the index words updated in December 2017, qualified studies were identified and relevant literature sources were also searched. The qualified studies included prospective cohort studies and cross-sectional studies. Heterogeneity of the included studies were reviewed to select proper effect model for pooled weighted sensitivity, specificity, and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) analyses were performed for meniscal tears. RESULTS: Forty-three studies related to diagnostic accuracy of MRI to detect early osteonecrosis of the femoral head were involved in the meta analysis. The global sensitivity and specificity of MRI in early osteonecrosis of the femoral head were 93.0% (95% CI 92.0-94.0%) and 91.0% (95% CI 89.0%-93.0%), respectively. The global positive likelihood ratio and global negative likelihood ratio of MRI in early osteonecrosis of the femoral head were 2.74 (95% CI 1.98 3.79) and 0.18 (95% CI 0.14-0.23), respectively. The global DOR was 27.27 (95% CI 17.02-43.67), and the area under the SROC was 93.38% (95% CI 90.87%-95.89%). CONCLUSIONS: This review provides a systematic review and meta-analysis to evaluate the diagnostic accuracy of MRI in early osteonecrosis of the femoral head. Moderate to strong evidence indicated that MRI appears to be significantly associated with higher diagnostic accuracy for early osteonecrosis of the femoral head. PMID- 29973238 TI - T cell senescence and CAR-T cell exhaustion in hematological malignancies. AB - T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies. PMID- 29973240 TI - Factors associated with low birthweight in North Shewa zone, Central Ethiopia: case-control study. AB - BACKGROUND: Low birthweight (LBW) is an important predictor of neonatal and post neonatal child morality. Though its risk factors have been extensively studied in the developed world; limited epidemiological evidence is available in developing countries including Ethiopia. The purpose of the study is to determine the risk factors of LBW in North Shewa zone, Central Ethiopia. METHODS: Unmatched case control study involving 94 cases and 376 controls was conducted from Jan to Mar 2017 in three public hospitals in the zone. A case was defined as a singleton live birth with birthweight less than 2.5 kg; whereas, a control was a newborn that weighs 2.5-4.0 kg. Cases and controls were recruited on an ongoing basis until the required sample sizes were fulfilled. Data were collected by interviewing mothers, reviewing medical records and measuring the anthropometry of the mothers and the newborns. Bivariable and multivariable logistic regression analyses were used to identify risk factors of LBW. The outputs of the analyses are presented using adjusted odds ratio (AOR) with the respective 95% confidence interval (CI). RESULTS: Mothers with no formal education had two times increased odds of delivering LBW babies than women with formal education [AOR = 2.20 (95% CI: 1.11, 4.38)]. Mothers with no history of nutrition counseling during pregnancy had three times increased odds of giving LBW babies than those who were counseled [AOR = 3.35 (95% CI: 1.19, 9.43)]. Non-married women had higher odds of giving LBW newborns as compared to married ones [AOR = 3.54 (95% CI: 1.83, 6.83)]. Mothers from food insecure households had about four times higher odds of LBW as compared to food secure mothers [AOR = 4.42 (95% CI: 1.02,22.25)]. In contrast to mothers who had the recommended four or more antenatal care (ANC) visits, those who were not booked had three times increased odds of giving to LBW baby [AOR = 3.03 (95% CI: 1.19,7.69)]. CONCLUSION: Improving the socio-economic status of mothers, enhancing the utilization of ANC and strengthening the integration of nutrition counseling into ANC help to reduce LBW. PMID- 29973241 TI - Safe Birth and Cultural Safety in southern Mexico: study protocol for a randomised controlled trial. AB - BACKGROUND: Indigenous women in the southern Mexican state of Guerrero face poor maternal health outcomes. Living as they do at the very periphery of the Western health system, they often receive low-quality care from health services that lack human and financial resources. Traditional health systems remain active in indigenous communities where traditional midwives accompany women through motherhood. Several interventions have explored training birth attendants in Western birthing skills, but little research has focussed on supporting traditional midwives by recognising their knowledge. This trial supports traditional midwifery in four indigenous groups and measures its impact on maternal health outcomes. METHODS: The study includes four indigenous populations in the State of Guerrero (Nahua, Na savi/Mixteco, Me'phaa/Tlapaneco and Nancue nomndaa/Amuzgo), covering approximately 8000 households. A parallel-group cluster randomised controlled trial will compare communities receiving usual care with communities where traditional midwives received support in addition to the usual care. The intervention was defined in collaboration with participants in a 2012 pilot study. Supported midwives will receive a small stipend, a scholarship to train one apprentice, and support from an intercultural broker to deal with Western health personnel; additionally, the health staff in the intervention municipalities will participate in workshops to improve understanding and attitudes towards authentic traditional midwives. A baseline and a final survey will measure changes in birth and pregnancy complications (primary outcomes), and changes in gender violence, access to healthcare, and engagement with traditional cultural activities (secondary outcomes). The project has ethical approval from the participating communities and the Universidad Autonoma de Guerrero. DISCUSSION: Indigenous women at the periphery of Western health services do not benefit fully from the attenuated services which erode their own healthcare traditions. Western health service providers in indigenous communities often ignore traditional knowledge and resources, inadvertently or in ignorance, disrespecting indigenous cultures. Improved understanding between midwives and the official healthcare system can contribute to more appropriate referral of high-risk cases, improving the use of scarce resources while lowering costs of healthcare for indigenous families. TRIAL REGISTRATION: ISRCTN12397283 . Retrospectively registered on 6 December 2016. PMID- 29973242 TI - Identification and validation of single-sample breast cancer radiosensitivity gene expression predictors. AB - BACKGROUND: Adjuvant radiotherapy is the standard of care after breast-conserving surgery for primary breast cancer, despite a majority of patients being over- or under-treated. In contrast to adjuvant endocrine therapy and chemotherapy, no diagnostic tests are in clinical use that can stratify patients for adjuvant radiotherapy. This study presents the development and validation of a targeted gene expression assay to predict the risk of ipsilateral breast tumor recurrence and response to adjuvant radiotherapy after breast-conserving surgery in primary breast cancer. METHODS: Fresh-frozen primary tumors from 336 patients radically (clear margins) operated on with breast-conserving surgery with or without radiotherapy were collected. Patients were split into a discovery cohort (N = 172) and a validation cohort (N = 164). Genes predicting ipsilateral breast tumor recurrence in an Illumina HT12 v4 whole transcriptome analysis were combined with genes identified in the literature (248 genes in total) to develop a targeted radiosensitivity assay on the Nanostring nCounter platform. Single-sample predictors for ipsilateral breast tumor recurrence based on a k-top scoring pairs algorithm were trained, stratified for estrogen receptor (ER) status and radiotherapy. Two previously published profiles, the radiosensitivity signature of Speers et al., and the 10-gene signature of Eschrich et al., were also included in the targeted panel. RESULTS: Derived single-sample predictors were prognostic for ipsilateral breast tumor recurrence in radiotherapy-treated ER+ patients (AUC 0.67, p = 0.01), ER+ patients without radiotherapy (AUC = 0.89, p = 0.02), and radiotherapy-treated ER- patients (AUC = 0.78, p < 0.001). Among ER+ patients, radiotherapy had an excellent effect on tumors classified as radiosensitive (p < 0.001), while radiotherapy had no effect on tumors classified as radioresistant (p = 0.36) and there was a high risk of ipsilateral breast tumor recurrence (55% at 10 years). Our single-sample predictors developed in ER+ tumors and the radiosensitivity signature correlated with proliferation, while single-sample predictors developed in ER- tumors correlated with immune response. The 10-gene signature negatively correlated with both proliferation and immune response. CONCLUSIONS: Our targeted single-sample predictors were prognostic for ipsilateral breast tumor recurrence and have the potential to stratify patients for adjuvant radiotherapy. The correlation of models with biology may explain the different performance in subgroups of breast cancer. PMID- 29973243 TI - Evaluation of a new predictor of heart and left anterior descending artery dose in patients treated with adjuvant radiotherapy to the left breast. AB - BACKGROUND: Heart-sparing techniques are time and resource intensive, although not all patients require the use of these strategies. This study evaluates the performance of different distance metrics in predicting the need for breath-hold radiotherapy in left-sided breast cancer patients receiving adjuvant radiotherapy. METHODS: Fifty left-sided breast cancer patients treated with breast conserving surgery and adjuvant radiotherapy to the breast from a single institution were retrospectively studied. The left breast and organs at risk were contoured in accordance to guidelines and a plan with tangents was obtained using the free-breathing CT in supine position. Heart (mean heart dose (MHD), heart V25 Gy) and left anterior descending artery dosimetry were computed and compared against distance metrics under investigation (Contact Heart, 4th Arch and 5th Arch). Recursive partitioning analysis (RPA) was used to determine optimal cut points for distance metrics for dosimetric end points. Receiver operating characteristic curves and Pearson correlation coefficients were used to evaluate the association between distance metrics and dosimetric endpoints. Univariable and multivariable logistic regression analysis was performed to identify significant predictors of dosimetric end points. RESULTS: The mean MHD and heart V25 Gy were 2.3 Gy and 10.4 cm3, respectively. With tangents, constraints for MHD (< 1.7 Gy and V25 Gy < 10 cm3) were unattainable in 80% and 46% of patients, respectively. Optimal RPA thresholds included: Contact Heart (73 mm), 4th Arch (7 mm) and 5th Arch (41 mm). Of these, the 4th Arch had the highest overall accuracy, sensitivity, concordance index and correlation coefficient. All metrics were statistically significant predictors for MHD >= 1.7 Gy based on univariable logistic regression. Fifth Arch did not reach significance for heart V25 Gy >= 10 cm3. Fourth Arch was the only predictor to remain statistically significant after multivariable analysis. CONCLUSIONS: We propose a novel "4th Arch" metric as an accurate and practical tool to determine the need for breath-hold radiotherapy for left-sided breast cancer patients undergoing adjuvant radiotherapy with standard tangents. Further validation in an external cohort is necessary. PMID- 29973244 TI - Inequities in maternal health services utilization in Ethiopia 2000-2016: magnitude, trends, and determinants. AB - BACKGROUND: Inequities in maternal health services utilization constitute a major challenge in maternal mortality reduction in Ethiopia. We sought to assess magnitude, trends, and determinants of inequities in maternal health services utilization in Ethiopia from 2000 to 2016. METHODS: The study utilized data from the 2000 and 2016 Ethiopia Demographic and Health Surveys, which were done based on a cross sectional survey design. The wealth-related inequities were assessed by concentration curve and horizontal inequity indices. Trends in inequities were assessed by comparing the concentration indices of maternal health services utilization variables between the 2000 and 2016 surveys using Wagstaff two groups concentration indices comparison method. Finally, the inequities were decomposed into its contributing factors using Wagstaff method of analysis. RESULTS: Wealth related inequities were significantly high in 2016: with horizontal inequities indices and residual regression error of antenatal care, skilled birth attendance, and postnatal care service utilization (- 0.09 and - 0.01), (- 0.06 and 0.01), and (- 0.11 and 0.0001), respectively. These indices increased significantly in 2016 when it is compared with the 2000 indices' with the respective concentration indices difference of - 0.05, 0.05, and - 0.07. The related all p-values were < 0.0001. The main determinants of inequities were low economic status, illiteracy, rural residence, no occupation, and fewer accesses to mass media. CONCLUSIONS: In Ethiopia, maternal health services utilization inequities were significantly high and increased in 2016 compared to 2000. Women who are poor, rural resident, uneducated, unemployed, and fewer mass media exposed are the most disadvantaged. Targeting maternal health interventions for the underserved women is essential to reduce maternal mortality in the country. PMID- 29973245 TI - Anemia prevalence and incidence and red blood cell transfusion practices in aneurysmal subarachnoid hemorrhage: results of a multicenter cohort study. AB - BACKGROUND: Whether a restrictive strategy for red blood cell (RBC) transfusion is applied to patients with aneurysmal subarachnoid hemorrhage (aSAH) is unclear. To inform the design and conduct of a future clinical trial, we sought to describe transfusion practices, hemoglobin (Hb) triggers, and predictors of RBC transfusion in patients with aSAH. METHODS: This is a retrospective cohort study of all consecutively admitted adult patients with aSAH at four tertiary care centers from January 1, 2012, to December 31, 2013. Patients were identified from hospital administrative discharge records and existing local aSAH databases. Data collection by trained abstractors included demographic data, aSAH characteristics, Hb and transfusion data, other major aSAH cointerventions, and outcomes using a pretested case report form with standardized procedures. Descriptive statistics were used to summarize data, and regression models were used to identify associations between anemia, transfusion, and other relevant predictors and outcome. RESULTS: A total of 527 patients met inclusion eligibility. Mean (+/-SD) age was 57 +/- 13 years, and 357 patients (67.7%) were female. The median modified Fisher grade was 4 (IQR 3-4). Mean nadir Hb was 98 +/ 20 g/L and occurred on median admission day 4 (IQR 2-11). RBC transfusion occurred in 100 patients (19.0%). Transfusion rates varied across centers (12.1 27.4%, p = 0.02). Patients received a median of 1 RBC unit (IQR 1-2) per transfusion episode and a median total of 2 units (IQR 1-4). Median pretransfusion Hb for first transfusion was 79 g/L (IQR 74-93) and did not vary substantially across centers (78-82 g/L, p = 0.37). Of patients with nadir Hb < 80 g/L, 66.3% received a transfusion compared with 2.0% with Hb nadir >= 100 g/L (p < 0.0001). Predictors of transfusion were history of oral anticoagulant use, anterior circulation aneurysm, neurosurgical clipping, and lower Hb. Controlling for numerous potential confounders, transfusion was not independently associated with poor outcome. CONCLUSIONS: We observed that moderate anemia remains very common early in admission following SAH. Only one-fifth of patients with SAH received RBC transfusions, mostly in cases of significant anemia (Hb < 80 g/L), and this did not appear to be associated with outcome. PMID- 29973246 TI - Bioluminescence imaging visualizes osteopontin-induced neurogenesis and neuroblast migration in the mouse brain after stroke. AB - BACKGROUND: Osteopontin (OPN), an acidic phosphoglycoprotein, is upregulated in the brain after cerebral ischemia. We previously reported that OPN supports migration, survival, and proliferation of neural stem cells (NSC) in primary cell culture, as well as their differentiation into neurons. We here analyzed the effects of OPN on neuroblasts in vivo in the context of cerebral ischemia. METHODS: Transgenic mice expressing luciferase under the control of the neuroblast-specific doublecortin (DCX)-promoter, allowing visualization of neuroblasts in vivo using bioluminescence imaging (BLI), were injected with OPN intracerebroventricularly while control mice were injected with vehicle buffer. To assess the effects of OPN after ischemia, additional mice were subjected to photothrombosis and injected with either OPN or vehicle. RESULTS: OPN enhanced the migration of neuroblasts both in the healthy brain and after ischemia, as quantified by BLI in vivo. Moreover, the number of neural progenitors was increased following OPN treatment, with the maximum effect on the second day after OPN injection into the healthy brain, and 14 days after OPN injection following ischemia. After ischemia, OPN quantitatively promoted the endogenous, ischemia-induced neuroblast expansion, and additionally recruited progenitors from the contralateral hemisphere. CONCLUSIONS: Our results strongly suggest that OPN constitutes a promising substance for the targeted activation of neurogenesis in ischemic stroke. PMID- 29973247 TI - Administration of cytokine-induced myeloid-derived suppressor cells ameliorates renal fibrosis in diabetic mice. AB - BACKGROUND: Diabetes is a proinflammatory state. Fibrosis of the renal glomerulus is the most common cause of end-stage renal disease. Glomerulosclerosis is caused by the accumulation of extracellular matrix (ECM) proteins in the mesangial interstitial space. Mesangial cells are unique stromal cells in the renal glomerulus that form the vascular pole of the renal corpuscle along with the mesangial matrix. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that rapidly expand to regulate host immunity during inflammation, infection, and cancer. High concentrations of granulocyte macrophage colony-stimulating factor (GM-CSF) alone or in combination with other molecules represent the most common ex-vivo protocol for differentiating MDSCs from bone marrow or from peripheral blood mononuclear cells. In this study, we analyzed and characterized the functions of MDSCs under the influence of mouse mesangial cells (MMCs) in a hyperglycemic environment and investigated whether cytokine-induced MDSCs ameliorated renal glomerulosclerosis in diabetic mice. METHODS: Cytokine-induced MDSCs were propagated from bone marrow cells cultured with mouse recombinant GM-CSF, IL-6, and IL-1beta. Diabetic mice were induced with streptozotocin (STZ) and maintained at a blood glucose concentration exceeding 350 mg/dl. The ECM of the renal cortex and fibronectin expression of MMCs were analyzed through immunohistochemistry and western blotting. Arginase 1 and inducible NO synthase expressions of MDSCs were evaluated using quantitative reverse-transcriptase PCR. Cytokines released from MMCs were examined using a cytokine array assay. RESULTS: MDSCs in the diabetic mice were redistributed from the bone marrow into peripheral organs. An increase in fibronectin production was also observed in the renal glomerulus. MMCs in vitro produced more fibronectin and proinflammatory cytokines, such as macrophage inflammatory protein-2, RANTES, and stromal-cell-derived factor-1, under hyperglycemic conditions. The adoptive transfer of cytokine-induced MDSCs into STZ-induced mice normalized the glomerular filtration rate to reduce the kidney to body weight ratio and decrease fibronectin production in the renal glomerulus, ameliorating renal fibrosis. These results demonstrate the anti-inflammatory properties of cytokine-induced MDSCs and offer an alternative immunotherapy protocol for the management of diabetic nephropathy. CONCLUSIONS: The application of cytokine-induced MDSCs provides a promising treatment for renal fibrosis and the prevention of diabetic nephropathy. PMID- 29973248 TI - Exploration of Plasmodium vivax transmission dynamics and recurrent infections in the Peruvian Amazon using whole genome sequencing. AB - BACKGROUND: Plasmodium vivax poses a significant challenge to malaria elimination due to its ability to cause relapsed infections from reactivation of dormant liver parasites called hypnozoites. We analyzed 69 P. vivax whole genome sequences obtained from subjects residing in three different villages along the Peruvian Amazon. This included 23 paired P. vivax samples from subjects who experienced recurrent P. vivax parasitemia following observed treatment with chloroquine and primaquine. METHODS: Genomic DNA was extracted from whole blood samples collected from subjects. P. vivax DNA was enriched using selective whole genome amplification and whole genome sequencing. We used single nucleotide polymorphisms (SNPs) from the core P. vivax genome to determine characteristics of the parasite population using discriminant analysis of principal components, maximum likelihood estimation of individual ancestries, and phylogenetic analysis. We estimated the relatedness of the paired samples by calculating the number of segregating sites and using a hidden Markov model approach to estimate identity by descent. RESULTS: We present a comprehensive dataset of population genetics of Plasmodium vivax in the Peruvian Amazonian. We define the parasite population structure in this region and demonstrate a novel method for distinguishing homologous relapses from reinfections or heterologous relapses with improved accuracy. The parasite population in this area was quite diverse with an estimated five subpopulations and evidence of a highly heterogeneous ancestry of some of the isolates, similar to previous analyses of P. vivax in this region. Pairwise comparison of recurrent infections determined that there were 12 homologous relapses and 3 likely heterologous relapses with highly related parasites. To the best of our knowledge, this is the first large-scale study to evaluate recurrent P. vivax infections using whole genome sequencing. CONCLUSIONS: Whole genome sequencing is a high-resolution tool that can identify P. vivax homologous relapses with increased sensitivity, while also providing data about drug resistance and parasite population genetics. This information is important for evaluating the efficacy of known and novel antirelapse medications in endemic areas and thus advancing the campaign to eliminate malaria. PMID- 29973249 TI - Rational prescribing of antibiotics in children under 5 years with upper respiratory tract infections in Kintampo Municipal Hospital in Brong Ahafo Region of Ghana. AB - OBJECTIVE: The aim of the study was to assess the rational use of antibiotics in children with URTIs in the Kintampo Municipal Hospital in Ghana. RESULTS: A total of 839 medicines were prescribed, 237 were antibiotics. The mean number of medicines prescribed per patient encounter was 3.1. The percentage of patient encounters with antibiotics was 28.2 and 0.4% for injections. The percentage of medicines prescribed by generic was 93.8% and from the essential medicines list was 94.9%. Ninety-two of patients received amoxicillin. Polypharmacy was common as prescriptions with five to six medicines per patient encounter was found. Some prescribers are not following the WHO/INRUD requirement of prescribing medicines in their generic and from the essential medicine list of the country. PMID- 29973250 TI - The effects of error-augmentation versus error-reduction paradigms in robotic therapy to enhance upper extremity performance and recovery post-stroke: a systematic review. AB - Despite upper extremity function playing a crucial role in maintaining one's independence in activities of daily living, upper extremity impairments remain one of the most prevalent post-stroke deficits. To enhance the upper extremity motor recovery and performance among stroke survivors, two training paradigms in the fields of robotics therapy involving modifying haptic feedback were proposed: the error-augmentation (EA) and error-reduction (ER) paradigms. There is a lack of consensus, however, as to which of the two paradigms yields superior training effects. This systematic review aimed to determine (i) whether EA is more effective than conventional repetitive practice; (ii) whether ER is more effective than conventional repetitive practice and; (iii) whether EA is more effective than ER in improving post-stroke upper extremity motor recovery and performance. The study search and selection process as well as the ratings of methodological quality of the articles were conducted by two authors separately, and the results were then compared and discussed among the two reviewers. Findings were analyzed and synthesized using the level of evidence. By August 1st 2017, 269 articles were found after searching 6 databases, and 13 were selected based on criteria such as sample size, type of participants recruited, type of interventions used, etc. Results suggest, with a moderate level of evidence, that EA is overall more effective than conventional repetitive practice (motor recovery and performance) and ER (motor performance only), while ER appears to be no more effective than conventional repetitive practice. However, intervention effects as measured using clinical outcomes were under most instance not 'clinically meaningful' and effect sizes were modest. While stronger evidence is required to further support the efficacy of error modification therapies, the influence of factors related to the delivery of the intervention (such as intensity, duration) and personal factors (such as stroke severity and time of stroke onset) deserves further investigations as well. PMID- 29973251 TI - The effects of facemasks on airway inflammation and endothelial dysfunction in healthy young adults: a double-blind, randomized, controlled crossover study. AB - BACKGROUND: Facemasks are increasingly worn during air pollution episodes in China, but their protective effects are poorly understood. We aimed to evaluate the filtration efficiencies of N95 facemasks and the cardiopulmonary benefits associated with wearing facemasks during episodes of pollution. RESULTS: We measured the filtration efficiencies of particles in ambient air of six types of N95 facemasks with a manikin headform. The most effective one was used in a double-blind, randomized, controlled crossover study, involving 15 healthy young adults, conducted during 2 days of severe pollution in Beijing, China. Subjects were asked to walk along a busy-traffic road for 2 h wearing authentic or sham N95 facemasks. Clinical tests were performed four times to determine changes in the levels of biomarkers of airway inflammation, endothelial dysfunction, and oxidative stress within 24 h after exposure. The facemasks removed 48-75% of number concentrations of ambient air particles between 5.6 and 560 nm in diameter. After adjustments for multiple comparison, the exhaled nitric oxide level and the levels of interleukin-1alpha, interleukin-1beta, and interleukin-6 in exhaled breath condensate increased significantly in all subjects; however, the increases in those wearing authentic facemasks were statistically significantly lower than in the sham group. No significant between-group difference was evident in the urinary creatinine-corrected malondialdehyde level. In arterial stiffness indicators, the ejection duration of subjects wearing authentic facemasks was higher after exposure compared to the sham group; no significant between-group difference was found in augmentation pressure or the augmentation index. CONCLUSIONS: In young healthy adults, N95 facemasks partially reduced acute particle-associated airway inflammation, but neither systemic oxidative stress nor endothelial dysfunction improved significantly. The clinical significance of these findings long-term remains to be determined. TRIAL REGISTRATION: The trial registration number (TRN) for this study is ChiCTR1800016099 , which was retrospectively registered on May 11, 2018. PMID- 29973252 TI - Healthy Campus Trial: a multiphase optimization strategy (MOST) fully factorial trial to optimize the smartphone cognitive behavioral therapy (CBT) app for mental health promotion among university students: study protocol for a randomized controlled trial. AB - BACKGROUND: Youth in general and college life in particular are characterized by new educational, vocational, and interpersonal challenges, opportunities, and substantial stress. It is estimated that 30-50% of university students meet criteria for some mental disorder, especially depression, in any given year. The university has traditionally provided many channels to promote students' mental health, but until now only a minority have sought such help, possibly owing to lack of time and/or to stigma related to mental illness. Smartphone-delivered cognitive behavioral therapy (CBT) shows promise for its accessibility and effectiveness. However, its most effective components and for whom it is more (or less) effective are not known. METHODS/DESIGN: Based on the multiphase optimization strategy framework, this study is a parallel-group, multicenter, open, fully factorial trial examining five smartphone-delivered CBT components (self-monitoring, cognitive restructuring, behavioral activation, assertion training, and problem solving) among university students with elevated distress, defined as scoring 5 or more on the Patient Health Questionnaire-9 (PHQ-9). The primary outcome is change in PHQ-9 scores from baseline to week 8. We will estimate specific efficacy of the five components and their interactions through the mixed-effects repeated-measures analysis and propose the most effective and efficacious combinations of components. Effect modification by selected baseline characteristics will be examined in exploratory analyses. DISCUSSION: The highly efficient experimental design will allow identification of the most effective components and the most efficient combinations thereof among the five components of smartphone CBT for university students. Pragmatically, the findings will help make the most efficacious CBT package accessible to a large number of distressed university students at reduced cost; theoretically, they will shed light on the underlying mechanisms of CBT and help further advance CBT for depression. TRIAL REGISTRATION: UMIN, CTR-000031307 . Registered on February 14, 2018. PMID- 29973253 TI - Detection of Clostridium botulinum group III in environmental samples from farms by real-time PCR using four commercial DNA extraction kits. AB - OBJECTIVES: Few studies have tested DNA extraction methods to optimize the detection of Clostridium botulinum in environmental samples that can be collected during animal botulism outbreaks. In this study, we evaluated four commercial DNA extraction kits for the detection of C. botulinum group III in 82 various environmental samples (9 manure, 53 swabs, 3 insects, 8 water, 1 silage and 8 soil samples) collected in a context of animal botulism outbreaks. RESULTS: The PowerSoil(r) kit was the most efficient for almost all matrices (83.6% of the 73 tested samples), except manure for which the NucleoSpin(r) Soil kit was the most efficient. The NucleoSpin(r) Soil kit enabled detection in 75.3%, the QIAamp(r) DNA Mini Kit in 68.5%, and the QIAamp(r) Fast DNA Stool Mini Kit in 45.2%. However, the NucleoSpin(r) Soil kit detected C. botulinum in 9 of the 9 manure samples tested, while the PowerSoil(r) kit found C. botulinum in only two samples, and the other two kits in none of the samples. This study showed that PowerSoil(r) can be recommended for DNA extraction from environmental samples except for manure, for which the NucleoSpin(r) Soil kit appeared to be far more appropriate. PMID- 29973254 TI - Prevascularization promotes endogenous cell-mediated angiogenesis by upregulating the expression of fibrinogen and connective tissue growth factor in tissue engineered bone grafts. AB - BACKGROUND: Vascularization is one of the most important processes in tissue engineered bone graft (TEBG)-mediated regeneration of large segmental bone defects. We previously showed that prevascularization of TEBGs promoted capillary vessel formation within the defected site and accelerated new bone formation. However, the precise mechanisms and contribution of endogenous cells were not explored. METHODS: We established a large defect (5 mm) model in the femur of EGFP+ transgenic rats and implanted a beta-tricalcium phosphate (beta-TCP) scaffold seeded with exogenous EGFP- cells; the femoral vascular bundle was inserted into the scaffold before implantation in the prevascularized TEBG group. Histopathology and scanning electron microscopy were performed and connective tissue growth factor (CTGF) and fibrin expression, exogenous cell survival, endogenous cell migration and behavior, and collagen type I and III deposition were assessed at 1 and 4 weeks post implantation. RESULTS: We found that the fibrinogen content can be increased at the early stage of vascular bundle transplantation, forming a fibrin reticulate structure and tubular connections between pores of beta-TCP material, which provides a support for cell attachment and migration. Meanwhile, CTGF expression is increased, and more endogenous cells can be recruited and promote collagen synthesis and angiogenesis. By 4 weeks post implantation, the tubular connections transformed into von Willebrand factor positive capillary-like structures with deposition of type III collagen, and accelerated angiogenesis of endogenous cells. CONCLUSIONS: These findings demonstrate that prevascularization promotes the recruitment of endogenous cells and collagen deposition by upregulating fibrinogen and CTGF, directly resulting in new blood vessel formation. In addition, this molecular mechanism can be used to establish fast-acting angiogenesis materials in future clinical applications. PMID- 29973255 TI - Prevalence of intestinal helminths and associated factors among school children of Medebay Zana wereda; North Western Tigray, Ethiopia 2017. AB - OBJECTIVE: To assess the prevalence of intestinal helminth infections and associated factors among primary school children of Medebay Zana wereda, a northwestern zone of Tigray, northern Ethiopia from March to April 2017. RESULT: The prevalence of intestinal helminths was 12.7%. The highest prevalence of intestinal helminth infections was observed in the age group of 11-14 years old and the most prevalent helminths species were Schistosoma mansoni. Mothers' level of education [AOR = 0.27 [0.13-0.58]], place of defecation [AOR = 2.63, 95% CI 1.14-6.02]], hand wash before meals [AOR = 9.0, 95% CI 3.72-21.74]], hand wash after defecation [AOR = 5.77 [1.78-18.63]] and eating unwashed vegetables [AOR = 5.67 [2.19-14.73]] were associated with higher risk of having intestinal helminths detected in stool. In the study area the risk of detecting intestinal helminths in their stool were more associated the improper personal hygiene of the children. PMID- 29973256 TI - The caries-arresting effect of incorporating functionalized tricalcium phosphate into fluoride varnish applied following application of silver nitrate solution in preschool children: study protocol for a randomized, double-blind clinical trial. AB - BACKGROUND: Dental caries in primary teeth is prevalent, affecting millions of children around the world. Functionalized tricalcium phosphate (fTCP) has been incorporated into sodium fluoride (NaF) varnish to enhance the remineralization process. NaF varnish with the adjunctive application of silver nitrate (AgNO3) solution is effective in arresting dentine caries. So far, there is no published randomized clinical trial investigating the effectiveness of the adoption of AgNO3 solution and NaF varnish containing fTCP in arresting dentine caries in preschool children. The objective of this study is to compare the effectiveness of a 25% AgNO3 solution plus a 5% NaF varnish containing fTCP and a 25% AgNO3 solution plus a 5% NaF varnish in arresting coronal dentine caries among preschool children when applied semi-annually over a 30-month period. METHODS/DESIGN: This is a randomized, double-blind controlled trial. The null hypothesis tested is that no difference exists between the effectiveness of a 25% AgNO3 solution plus a 5% NaF varnish with fTCP and a 25% AgNO3 solution plus a 5% NaF varnish in arresting dentine caries in preschool children when applied semi annually. According to the sample size calculation, approximately 2000 3- to 4 year-old kindergarten children will be screened, and at least 408 children with coronal dentine caries will be recruited. The children will be randomly allocated to two treatment groups via stratified randomization: group A - biannual application of a 25% AgNO3 solution followed by a 5% NaF varnish, and group B - biannual application of a 25% AgNO3 solution followed by a 5% NaF varnish with fTCP. Clinical examinations will be conducted every 6 months to assess whether the carious lesions have become arrested (primary outcome). Confounding factors, such as demographic background and oral hygiene behaviors, will be collected through a parental questionnaire. DISCUSSION: The effectiveness of the topical application of a 25% AgNO3 solution followed by a 5% NaF varnish with fTCP in arresting coronal dentine caries among preschool children remains unknown. Because the proposed caries-arresting methods are simple, noninvasive and low cost, these can be widely recommended for caries control in young children. TRIAL REGISTRATION: ClinicalTrials.gov (U.S.): NCT03423797 on 6 February 2018. PMID- 29973257 TI - A rare case of seven siblings with Waardenburg syndrome: a case report. AB - BACKGROUND: Waardenburg syndrome is a group of rare genetic conditions. It is determined by the absence of melanocytes from the eyes, hair, and skin. There are four types of Waardenburg syndrome with specific criteria to diagnosis the different types. The main clinical manifestations are facial abnormalities, pigmentary defects, and hearing loss with no specific predilection with regard to sex or race. CASE PRESENTATION: An Arabic Syrian family, consisting of 14 siblings from third-degree relative parents with a low income, living in the Syrian countryside, presented to our institute with their 8-year-old son who had congenital hearing loss that had led to his inability to speak. He has six siblings who had congenital sensory hearing loss proven by auditory brainstem response tests at an early age. An otoacoustic emissions test and a pure-tone audiogram were performed for our patient and showed sensory hearing loss. An interesting feature in the last seven siblings was that some of them have heterochromia iris, and the others have segmental heterochromia in their iris. An ophthalmology consultation was performed to detect any other features or disorders. A dermatology consultation, laboratory tests, and chest X-ray were also performed for all the siblings and revealed no abnormalities. There was no history for musculoskeletal system or intestinal disorders. Based on the Waardenburg criteria, our patient and his six siblings all have Waarenburg syndrome. CONCLUSIONS: Although the inheritance of Waardenburg syndrome is autosomal dominant, de novo cases of this rare syndrome are mentioned in the medical literature. We report a unique case of seven siblings with Waardenburg syndrome. This case report shows the crucial role of consanguineous parents on this syndrome, and indicates that the number of children with this rare syndrome is increasing. PMID- 29973259 TI - Towards a health-enabling working environment - developing and testing interventions to decrease HIV and TB stigma among healthcare workers in the Free State, South Africa: study protocol for a randomised controlled trial. AB - BACKGROUND: Occupational exposure to tuberculosis (TB) constitutes a major health risk for healthcare workers (HCWs). The HIV epidemic equally affects the workforce because of the mutually reinforcing epidemiology of HIV and TB. Stigmas associated with HIV and TB have become so intricately entangled that they stop some HCWs from seeking care in a context where serious shortages in human resources for health besiege public health facilities. It is thus imperative to research, as well as attempt to tackle, HIV and TB stigma among HCWs. But little has been done internationally-and nationally, only our own exploratory studies. Our project aims to address this by (1) scientifically assessing the extent and sources of HIV and TB-related stigma among HCWs and (2) developing and testing evidence-based, stigma-reduction interventions in public hospitals in the Free State Province of South Africa. METHODS/DESIGN: The research follows a stratified cluster randomised controlled trial (RCT) design. Pre intervention, a self administered questionnaire with the pilot study's validated stigma scales is used to measure stigma and other key variables among randomly selected HCWs in eight hospitals-stratified by size and district and then randomly allocated to four intervention and four control sites. Interventions comprise HIV- and TB-stigma reduction activities-mainly Social and Behavioural Change Communication (SBCC) interventions-at three social-ecology levels (individual, community, and socio structural). An outside assessor will appraise the trial mid-way through implementation. Post intervention, all baseline respondents will be followed up to complete the baseline questionnaire with additional items on interventions. Qualitative data will be collected to better understand HIV and TB stigma and explore if, and how, interventions impact stigma levels in the workplace. DISCUSSION: The study regards as HCWs all staff, working in all different types of jobs, at all levels in the hospitals. Thus, the research addresses HIV and TB stigma across the whole workforce and the entire workplace. In doing so it will (1) generate essential information on stigma among HCWs and (2) implement stigma reduction interventions that are innovative yet replicable, and potentially beneficial in addressing a pernicious human-rights-based issue. TRIAL REGISTRATION: South African National Clinical Trials Register, registration ID: DOH-27-1115-5204 . Prospectively registered on 26 August 2015. PMID- 29973258 TI - The occurrence, types, consequences and preventability of in-hospital adverse events - a scoping review. AB - BACKGROUND: Adverse events (AEs) seriously affect patient safety and quality of care, and remain a pressing global issue. This study had three objectives: (1) to describe the proportions of patients affected by in-hospital AEs; (2) to explore the types and consequences of observed AEs; and (3) to estimate the preventability of in-hospital AEs. METHODS: We applied a scoping review method and concluded a comprehensive literature search in PubMed and CINAHL in May 2017 and in February 2018. Our target was retrospective medical record review studies applying the Harvard method-or similar methods using screening criteria-conducted in acute care hospital settings on adult patients (>=18 years). RESULTS: We included a total of 25 studies conducted in 27 countries across six continents. Overall, a median of 10% patients were affected by at least one AE (range: 2.9 21.9%), with a median of 7.3% (range: 0.6-30%) of AEs being fatal. Between 34.3 and 83% of AEs were considered preventable (median: 51.2%). The three most common types of AEs reported in the included studies were operative/surgical related, medication or drug/fluid related, and healthcare-associated infections. CONCLUSIONS: Evidence regarding the occurrence of AEs confirms earlier estimates that a tenth of inpatient stays include adverse events, half of which are preventable. However, the incidence of in-hospital AEs varied considerably across studies, indicating methodological and contextual variations regarding this type of retrospective chart review across health care systems. For the future, automated methods for identifying AE using electronic health records have the potential to overcome various methodological issues and biases related to retrospective medical record review studies and to provide accurate data on their occurrence. PMID- 29973260 TI - Insecticide susceptibility status of Anopheles gambiae (s.l.) in South-West Cameroon four years after long-lasting insecticidal net mass distribution. AB - BACKGROUND: Members of the Anopheles gambiae (s.l.) complex are one of the major vectors of malaria in Africa. LLINs and IRS are the most effective tools used in vector control of malaria. However, their effectiveness may be hampered by the development and spread of insecticide resistance in the target vectors species. The objective of this study was to assess the susceptibility of Anopheles gambiae (s.l.) mosquitoes from South-West Cameroon to deltamethrin, permethrin and to malathion, four years after the mass deployment of LLINs. METHODS: Anopheles larvae were collected from Limbe, Tiko and Buea, three cities of the Fako division and reared until adult emergence. Adult mosquitoes from field larvae were identified as belonging to the Anopheles gambiae (s.l.) complex using standard identification keys. Susceptibility of mosquito samples to deltamethrin, permethrin and malathion was assessed using WHO susceptibility tests protocol for adult mosquitoes. Molecular identification of tested samples was performed using the PCR SINE200 protocol and by PCR-RFLP. The kdr alleles were genotyped using the hot ligation oligonucleotide assay (HOLA). RESULTS: Two species of the An. gambiae (s.l.) complex, An. coluzzii and An. gambiae (s.s.) were identified in all three study locations with high proportions of An. coluzzii in Limbe (84.06%) and Tiko (92.2%), while in Buea, An. coluzzii (55.6%) and An. gambiae (s.s.) (44.4%) occurred almost in the same proportions. Tested samples were found resistant to pyrethroids (deltamethrin and permethrin) in all locations (< 90% mortality), with > 3-fold increase of KDT50 values compared with the Kisumu susceptible reference strain of An. gambiae (s.s.). However, the mosquito populations from Limbe and Buea were fully susceptible to malathion. The L1014F kdr was found in both An. coluzzii and An. gambiae (s.s.) with the highest frequencies found in An. gambiae (s.l.) populations from Tiko (94%) and Buea (90%) compared with the Limbe population (66%) (P = 0.00063, df = 2). No kdr L1014S was observed in analyzed samples. CONCLUSIONS: These findings reemphasize the ongoing development of An. gambiae (s.l.) resistance to pyrethroids used in impregnating LLINs and suggest the use of malathion as an alternative insecticide for IRS in complementarity with LLINs. PMID- 29973261 TI - Prevalence and subtype distribution of Blastocystis sp. isolates from poultry in Lebanon and evidence of zoonotic potential. AB - BACKGROUND: Blastocystis sp. is a common protozoan parasite frequently identified in the digestive tract of humans and a large variety of animal hosts worldwide, including birds. It exhibits a large genetic diversity with the identification of 17 subtypes (STs), most of them with low host specificity. ST6 and ST7 were identified in birds and suggested to represent avian STs only in the context of scarce small-scale epidemiological surveys. Moreover, these two STs also account for a significant proportion of human infections whose zoonotic origin has never been clearly confirmed. Therefore, molecular screening of Blastocystis sp. was conducted by quantitative real-time PCR for fecal samples from poultry farms and their in-contact humans from slaughterhouses in Lebanon. In parallel, a control group consisting of patients hospitalized in the same geographical area and reporting no contact with poultry was also screened for the presence of the parasite. RESULTS: The overall prevalence of Blastocystis sp. was shown to reach around 32% in chicken samples and 65% in the farms screened. All the avian isolates were subtyped and belonged to either ST6 or ST7, with a large predominance of ST6. Fifty-four percent of slaughterhouse staff members were positive for Blastocystis sp. compared with a similar prevalence of 56% in hospitalized patients. ST3 was predominant in both human cohorts followed by either ST1 then ST2 among slaughterhouse staff or by ST2 then ST1 among hospitalized patients. ST6 was also identified in two slaughterhouse workers and not in the group of hospitalized patients. Gene sequence identity was observed between chicken and human ST6 isolates from the same slaughterhouse. CONCLUSIONS: Our data revealed a high prevalence of Blastocystis sp. in chicken samples and confirmed that ST6 and ST7 represented avian-adapted STs. Among both human cohorts, Blastocystis sp. infection was shown to exceed 50% with a predominance of ST3. The identification of ST6 in slaughterhouse staff members confirmed the zoonotic transmission of this ST through repeated and direct contact between chickens and their handlers. PMID- 29973262 TI - Assessment of prevalence of dental caries and the associated factors among patients attending dental clinic in Debre Tabor general hospital: a hospital based cross-sectional study. AB - BACKGROUND: Dental caries is the most common dental health problem caused by the interaction of bacteria on tooth enamel. Risk factors for dental caries include salivary composition and inadequate fluoride. However, other factors, such as standard of living, behavior, hygiene, eating habits, social status and socio demographic factors, also contribute to the evolution of caries. Therefore, this study aimed to determine the prevalence of dental caries and associated factors among patients attending the dental clinic in Debre Tabor General Hospital in North West Ethiopia. METHOD: An institution based cross-sectional study was conducted among 280 systematically selected patients attending Debre Tabor General Hospital dental clinic from May 8-20, 2017. The data were collected using pre-tested questionnaire and oral examination by a qualified dental professional. Basic hygienic procedures were observed during an oral examination. The teeth were examined for dental caries by the presence of decay, missing and filled teeth. The data were entered into Epi-Info version 3.5 and cleaned and analyzed using SPSS version 20. Descriptive summary of the data and logistic regression were used to identify possible predictors using odds ratio with 95% confidence interval and P-value of 0.05. RESULTS: A total of 280 subjects participated in the study; among whom 129 (46.1%) were female and nearly two-thirds of the respondents 208 (74.3%) attended formal education. The study revealed k8that the overall prevalence of dental caries was 78.2%. Dental caries was lower among respondents who had good oral hygiene status (AOR = 0.05, 95% CI, 0.02, 0.81). Dental caries was higher among participants who earned less than 5000 Eth Birr per month (AOR = 8.43, 95% CI, 2.6, 27.2). Dental caries was lower among respondents who had good knowledge (AOR = 0.51, 95% CI, 0.03, 0.64). CONCLUSIONS: Prevalence of dental caries was high and found public health problem. Socioeconomic status, educational level, and poor oral hygiene practices were associated factors for dental caries. Health promotion about oral hygiene and integration of services are supremely important for the prevention of the problem of dental caries. PMID- 29973263 TI - Screening, purification and characterization of cellulase from cellulase producing bacteria in molasses. AB - OBJECTIVES: This study was conducted to isolate, screening and purification of cellulase from bacteria present in sugar industry waste (molasses) and characterization by morphological and biochemical analysis. RESULTS: Based on experiments, three bacterial strains produced clear transparent zone into carboxymethyl cellulose (CMC) agar plate were identified as cellulase producing bacteria. Different culture parameters such as pH, temperature, incubation period, substrate concentration and carbon sources were optimized for enzyme production. According to the morphological and biochemical tests, the isolated strains were identified as Paenibacillus sp., Bacillus sp. and Aeromonas sp. The first strain Paenibacillus sp. showed high potentiality for maximum cellulase production (0.9 umol ml-1 min-1) at pH 7.0 after 24 h of incubation at 40 degrees C in a medium containing 1.0% CMC. Then Paenibacillus sp. was selected for enzyme purification by ammonium sulfate precipitation, DEAE-cellulose and CM cellulose column chromatography, respectively. In last step of purification, specific activity, recovery and purification fold were 2655 U/mg, 35.7% and 9.7, respectively. The molecular weight of the purified cellulase was found to be 67 kDa by SDS-PAGE, had an optimal pH and temperature at 7.0 and 40 degrees C. According to substrate specificity, the purified cellulase had high specificity on CMC substrate which indicated it to be an endo-beta-1,4-glucanase. PMID- 29973264 TI - Reflection and observation: cell-based screening failing to detect HBV in HUMSCs derived from HBV-infected mothers underscores the importance of more stringent donor eligibility to reduce risk of transmission of infectious diseases for stem cell-based medical products. AB - BACKGROUND: In cell-based therapy, the transmission of communicable diseases imposes a substantial threat to recipients. In this study, we investigated whether cell-based screening could detect hepatitis B virus (HBV) in human umbilical cord-derived mesenchymal stem cells (HUMSCs) isolated from HBV-infected donors to understand the susceptibility of HUMSCs to HBV infection. METHODS: HBV assay was performed in HUMSCs derived from healthy and HBV-infected donors with enzyme-linked immunosorbent assay (ELISA), fluorescence quantitative PCR (FQ-PCR) assay, and droplet digital PCR (ddPCR) assay. Further, HBV DNA was assayed in HUMSCs derived from healthy donors after incubation with human sera containing a high titer of HBV using FQ-PCR. RESULTS: HBV antigen/antibody and DNA failed to be detected using ELISA, FQ-PCR, and ddPCR. After incubation with HBV infection sera, HBV DNA could be detected, but below the valid titer of the assay kit. The HBV DNA levels in HBV-incubated HUMSCs gradually decreased with medium change every 2 days and then significantly decreased, not even detected after passage. CONCLUSIONS: The current cell-based screening methods could not detect HBV in HUMSCs derived from HBV-infected donors, indicating the importance of more stringent donor eligibility to reduce the risk of transmission of communicable diseases in cell-based therapy. To solve the problem of an occult HBV window period in donor eligibility determination, we recommend that the donors undergo another HBV serological test 3 months after the first serological communicable disease screening. PMID- 29973265 TI - Acupuncture as an early treatment for idiopathic sudden sensorineural hearing loss (ISSNHL) patients with flat or high-frequency drop audiograms: study protocol for a randomized controlled trial. AB - BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is a common form of deafness. Acupuncture has been used as a salvage therapy for ISSNHL in China since 200 BCE. However, the efficacy of acupuncture has not been confirmed in strictly controlled trials. We designed a randomized controlled clinical trial to evaluate the efficacy and long-term effects of acupuncture in patients with early ISSNHL. METHODS/DESIGN: In this randomized controlled clinical trial, we will enroll 124 participants with ISSNHL diagnosed 2 to 4 weeks prior to enrollment, who have shown little hearing improvement after routine Western medical treatment (i.e., corticosteroids). 62 of these participants will have flat audiogram and the other 62 will have a high-frequency drop audiogram; they will all take Methycobal while half of the flat type and half of the high frequency drop type will also receive acupuncture treatments for 4 weeks in a four-group design. The primary outcome measure will be the effective rate of hearing improvement (defined as the proportion of patients with at least 15-dB improvement in the hearing loss frequency band). The secondary outcome will measure the improvements in Pure Tone Average, Word Recognition Score, and Tinnitus Handicap Inventory. The assessments of the participants will be made at baseline, after treatment (week 4), and at follow-up (week 28). DISCUSSION: This study aims to explore the efficacy and long-term effects of acupuncture in patients with ISSNHL. This study will be a randomized controlled trial with strict methodology and few design deficits. If our study yields positive results, acupuncture could be recommended as a salvage therapy for patients with ISSNHL. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-ICR-15006787 . Registered on 12 July 2015. PMID- 29973266 TI - Irf6 directs glandular lineage differentiation of epidermal progenitors and promotes limited sweat gland regeneration in a mouse burn model. AB - BACKGROUND: Damaged or malfunctioning sweat glands (SGs) after a burn injury would cause significant hyperthermia and even death, and there is an unmet need for effective treatment. Genetically reprogrammed stem cells show their potential advantages for inducing SG repair and regeneration. METHODS: The expression of interferon regulatory factor 6 (IRF6) in skin was tested by immunofluorescence, and Irf6 was overexpressed in epidermal progenitors (EPs) to stimulate SG differentiation. For in-vivo studies, second- and third-degree mouse burn wounds were treated with subcutaneous injection of EPs and Irf6-transfected cells, and cell retention and therapeutic effects were assessed. RESULTS: IRF6 demonstrated differential expression between the footpad and dorsal skin and was upregulated along with embryonic and postnatal SG development. The Irf6-transfected cells converted their cell phenotypes as seen by gene and protein expression analyses and their morphology closely resembled epidermal-derived glandular cells. Inductive SG cell (SGC) transplantation and in-vivo tracing examination demonstrated that they could survive at damaged sites for 14 days. In comparison, the positive effects of inductive SGCs only result in restoring SG function in second-degree burn wounds but not in third-degree burn wounds as assessed by both perspiration tests and morphological analyses. CONCLUSIONS: These results suggest that IRF6 plays an important role in directing glandular lineage differentiation of Eps, but that the therapeutic efficacy of inductive SGCs may be restricted to the burn environment. PMID- 29973267 TI - Human mesenchymal stromal cells inhibit platelet activation and aggregation involving CD73-converted adenosine. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) are promising cell therapy candidates. Clinical application is considered safe. However, minor side effects have included thromboembolism and instant blood-mediated inflammatory reactions suggesting an effect of MSC infusion on hemostasis. Previous studies focusing on plasmatic coagulation as a secondary hemostasis step detected both procoagulatory and anticoagulatory activities of MSCs. We now focus on primary hemostasis and analyzed whether MSCs can promote or inhibit platelet activation. METHODS: Effects of MSCs and MSC supernatant on platelet activation and function were studied using flow cytometry and further platelet function analyses. MSCs from bone marrow (BM), lipoaspirate (LA) and cord blood (CB) were compared to human umbilical vein endothelial cells or HeLa tumor cells as inhibitory or activating cells, respectively. RESULTS: BM-MSCs and LA-MSCs inhibited activation and aggregation of stimulated platelets independent of the agonist used. This inhibitory effect was confirmed in diagnostic point-of-care platelet function analyses in platelet-rich plasma and whole blood. Using inhibitors of the CD39 CD73-adenosine axis, we showed that adenosine produced by CD73 ectonucleotidase activity was largely responsible for the LA-MSC and BM-MSC platelet inhibitory action. With CB-MSCs, batch-dependent responses were obvious, with some batches exerting inhibition and others lacking this effect. CONCLUSIONS: Studies focusing on plasmatic coagulation suggested both procoagulatory and anticoagulatory activities of MSCs. We now show that MSCs can, dependent on their tissue origin, inhibit platelet activation involving adenosine converted from adenosine monophosphate by CD73 ectonucleotidase activity. These data may have strong implications for safety and risk/benefit assessment regarding MSCs from different tissue sources and may help to explain the tissue protective mode of action of MSCs. The adenosinergic pathway emerges as a key mechanism by which MSCs exert hemostatic and immunomodulatory functions. PMID- 29973269 TI - Level and factors associated with birth preparedness and complication readiness among semi-pastoral pregnant women in southern Ethiopia, 2016. AB - OBJECTIVE: The objective of this study was to determine the level of birth preparedness and complication readiness (BPCR) and associated factors among semi pastoral pregnant women in southern, Ethiopia. RESULT: This dataset contains the full data collected from 746 pregnant women. Birth preparedness and complication readiness among women in southern Ethiopia was 27.1%. The main predictors for BRCP were attending formal education (AOR = 4.65, 95% CI 2.45-8.63), husband occupation [merchant (AOR = 3.83, 95% CI 1.52-9.64)], spouse attending formal education (AOR = 3.35, 95% CI (1.83-6.14), ANC visits > 4 times (AOR = 17.78, 95% CI 7.11-44.47). In addition, knowledge of women at least two danger signs during pregnancy, delivery and after delivery (AOR = 3.32, 95% CI 1.64-6.69), (AOR = 3.13, 95% CI 1.58-6.20) and (AOR = 3.75, 95% CI 1.93-7.28) respectively were significantly associated with BPCR. In conclusion, the proportion of BPCR among women in southern Ethiopia was found to be low. PMID- 29973268 TI - Chemerin 156F, generated by chymase cleavage of prochemerin, is elevated in joint fluids of arthritis patients. AB - BACKGROUND: Chemerin is a chemoattractant involved in immunity that also functions as an adipokine. Chemerin is secreted as an inactive precursor (chem163S), and its activation requires proteolytic cleavages at its C-terminus, involving proteases in coagulation, fibrinolysis, and inflammation. Previously, we found chem158K was the dominant chemerin form in synovial fluids from patients with arthritis. In this study, we aimed to characterize a distinct cleaved chemerin form, chem156F, in osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: Purified chem156F was produced in transfected CHO cells. To quantify chem156F in OA and RA samples, we developed a specific ELISA for chem156F using antibody raised against a peptide representing the C-terminus of chem156F. RESULTS: Ca2+ mobilization assays showed that the EC50 values for chem163S, chem156F, and chem157S were 252 +/- 141 nM, 133 +/- 41.5 nM, and 5.83 +/- 2.48 nM, respectively. chem156F was more active than its precursor, chem163S, but very much less potent than chem157S, the most active chemerin form. Chymase was shown to be capable of cleaving chem163S at a relevant rate. Using the chem156F ELISA we found a substantial amount of chem156F present in synovial fluids from patients with OA and RA, 24.06 +/- 5.51 ng/ml and 20.35 +/- 5.19 ng/ml (mean +/- SEM, n = 25) respectively, representing 20% of total chemerin in OA and 76.7% of chemerin in RA synovial fluids. CONCLUSIONS: Our data show that chymase cleavage of chem163S to partially active chem156F can be found in synovial fluids where it can play a role in modulation of the inflammation in joints. PMID- 29973270 TI - An improvised one-step sucrose cushion ultracentrifugation method for exosome isolation from culture supernatants of mesenchymal stem cells. AB - BACKGROUND: Exosomes are nanovesicles (30-120 nm) of endosomal origin. These exosomes contain various functional proteins and RNAs that could be used for therapeutic purposes. Currently, having a standard method for exosome isolation retaining its biological properties with increased yield and purity is a major challenge. The most commonly used method is differential ultracentrifugation but it has its own disadvantages, which include high time consumption, low yield due to disruption of exosome integrity, and high protein contaminants. In this study, we have identified an improved method addressing these problems for exosome isolation using ultracentrifugation since it is cost-effective and used worldwide. METHOD: We have compared differential ultracentrifugation with the modified method called one-step sucrose cushion ultracentrifugation for exosome isolation. The conditioned serum-free media from human mesenchymal stem cells cultured for 48 h was collected for exosome isolation. The cellular debris was removed by centrifugation at 300g for 10 min, followed by centrifugation at 10,000g for 30 min to remove microvesicles. Equal volumes of pre-processed conditioned media were used for exosome isolation by direct ultracentrifugation and one-step sucrose cushion ultracentrifugation. The exosomes isolated using these methods were characterized for their size, morphology, concentration, and surface marker protein expression. RESULT: It was observed that the recovery of exosomes with cup-shaped morphology from one-step sucrose cushion ultracentrifugation was comparatively high as estimated by nanoparticle tracking analysis and electron microscopy. These results were confirmed by Western blotting and flow cytometry. CONCLUSION: We conclude that this one-step sucrose cushion ultracentrifugation method provides an effective and reproducible potential standard method which could be used for various starting materials for isolating exosomes. We believe that this method will have a wide application in the field of extracellular vesicle research where exosome isolation with high yield and purity is an imperative step. Schematic representation of comparison of UC and SUC exosome isolation methods for tissue-specific human mesenchymal stem cells. The SUC isolation method yields a greater number of cup-shaped exosomes with a relatively homogenous population for mass-scale production of exosomes for downstream analysis. ABBREVIATIONS: SUC One-step sucrose cushion ultracentrifugation, UC Direct ultracentrifugation. PMID- 29973271 TI - Antibody and cytokine response to Cystoisospora suis infections in immune competent young pigs. AB - BACKGROUND: To date, investigations on the immune response to Cystoisospora suis infections focused on suckling piglets, the age group clinically most affected. Actively immunizing piglets is unfeasible due to their immature immune system and the typically early infection in the first days after birth. Therefore, understanding and possibly enhancing the immune response of immune-competent animals is the prerequisite to develop a passive immunization strategy for piglets which currently rely on very limited treatment options. METHODS: To investigate antibody and cytokine responses of immune-competent animals and the impact of the oral immunization protocol on their immune response, growers with unknown previous exposure to C. suis (10-11 weeks-old) were infected one or three times with different doses (600 and 6000 or 200 and 2000, respectively) of C. suis oocysts, and compared to uninfected controls. Oocyst excretion was evaluated, and blood and intestinal mucus antibody titers were determined by IFAT. Systemic production of Th1, Th2, inflammatory and regulatory cytokines was determined in different immune compartments at mRNA and (after stimulation with a recombinant merozoite-protein) at protein level by PCR and multiplex fluorescent immunoassay, respectively. RESULTS: Infection generated significantly increased serum IgA and IgG levels against C. suis sporozoites and merozoites, irrespective of infection mode, with IgG against merozoites showing the strongest increase. No clinical signs and only occasional excretion were observed. The systemic cytokine response to C. suis was only weak. Nonetheless, in white blood cells, IL-4, IL-6 and IL-10 mRNA-levels significantly increased after infection, whereas IFN-gamma, IL-2 and TGF-beta expression tended to decrease. In mesenteric lymph nodes (MLN), IL-10 and TNF-alpha levels were elevated while splenic cytokine expression was unaltered upon infection. Stimulated MLN-derived lymphocytes from infected pigs produced slightly more IL-12 and less IFN-alpha than controls. CONCLUSIONS: An infection and a subsequent systemic immune response can be induced in immune competent animals by all evaluated infection models and growers can be used as models to mimic sow immunizations. The immune response to C. suis, although mild and with considerable variation in cytokine expression, was characterized by a Th2-associated and regulatory cytokine profile and antibody production. However, none of the parameters clearly stood out as a potential marker associated with protection. Antibody titers were significantly positively related with oocyst excretion and might thus serve as correlates for parasite replication or severity of infection. PMID- 29973272 TI - Discovery of new Toxoplasma gondii antigenic proteins using a high throughput protein microarray approach screening sera of murine model infected orally with oocysts and tissue cysts. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite that causes congenital toxoplasmosis, as well as other serious clinical presentations in immune compromised humans. The parasite has also been recently linked to behavioral diseases in humans and other mammalian hosts. New antigens are being evaluated to develop a diagnostic kit for the diagnosis of acute infection or a protective vaccine. METHODS: In this study, we have focused on the discovery of new antigenic proteins from T. gondii genomic data using a high throughput protein microarray screening. To date, microarrays containing > 2870 candidate exon products of T. gondii have been probed with sera collected from patients with toxoplasmosis. Here, the protein microarrays are probed with well characterized serum samples from animal models administered orally with oocysts or tissue cysts. The aim was to discover the antigens that overlap in the mouse profile with human antibody profiles published previously. For this, a reactive antigen list of 240 antigens recognized by murine IgG and IgM was identified using pooled sera from orally infected mice. RESULTS: Analyses of screening data have identified plenty of antigens and showed strong immunogenicity in both mouse and human antibody profiles. Among them, ROP1, GRA2, GRA3, GRA4, GRA5, GRA6, GRA7, GRA8, GRA14, MIC1, MIC2 and MAG1 have shown strong immunogenicity and used as antigen in development of vaccines or serological diagnostic assays in previous studies. CONCLUSION: In addition to the above findings, ROP6, MIC12, SRS29A and SRS13 have shown strong immunogenicity but have not been tested in development of a diagnostic assay or a vaccine model yet. PMID- 29973273 TI - Klotho expression is a prerequisite for proper muscle stem cell function and regeneration of skeletal muscle. AB - BACKGROUND: Klotho is a well-known anti-aging hormone, which serves as a suppressor of aging through a variety of mechanisms. Aging of skeletal muscle is concomitant with a decrease in muscle stem cell function resulting in impaired regeneration. METHODS: Here we investigate the functional role of the anti-aging hormone Klotho for muscle stem cell function after cardiotoxin-induced injury of skeletal muscle using a klotho hypomorphic mouse line, which is characterized by a premature aging phenotype. Furthermore, we perform floating single myofiber cultures with their adjacent muscle stem cells to investigate the interplay between canonical Wnt signaling and Klotho function. RESULTS: We demonstrate that muscle stem cell numbers are significantly decreased in klotho hypomorphic mice. Furthermore, we show that muscle stem cell function is also severely impaired upon loss of klotho expression, in culture and during regeneration in vivo. Moreover, we demonstrate that addition of recombinant Klotho protein inhibits aberrant excessive Wnt signaling in aged muscle stem cells thereby restoring their functionality. CONCLUSIONS: The anti-aging hormone Klotho counteracts aberrant canonical Wnt signaling in muscle stem cells and might be one of the naturally occurring inhibitors of canonical Wnt signaling in skeletal muscle. PMID- 29973274 TI - Maternal diet during pregnancy is related with the infant stool microbiome in a delivery mode-dependent manner. AB - BACKGROUND: The gut microbiome has an important role in infant health and immune development and may be affected by early-life exposures. Maternal diet may influence the infant gut microbiome through vertical transfer of maternal microbes to infants during vaginal delivery and breastfeeding. We aimed to examine the association of maternal diet during pregnancy with the infant gut microbiome 6 weeks post-delivery in mother-infant dyads enrolled in the New Hampshire Birth Cohort Study. Infant stool samples were collected from 145 infants, and maternal prenatal diet was assessed using a food frequency questionnaire. We used targeted sequencing of the 16S rRNA V4-V5 hypervariable region to characterize infant gut microbiota. To account for differences in baseline and trajectories of infant gut microbial profiles, we stratified analyses by delivery mode. RESULTS: We identified three infant gut microbiome clusters, characterized by increased abundance of Bifidobacterium, Streptococcus and Clostridium, and Bacteroides, respectively, overall and in the vaginally delivered infant stratum. In the analyses stratified to infants born vaginally and adjusted for other potential confounders, maternal fruit intake was associated with infant gut microbial community structure (PERMANOVA, p < 0.05). In multinomial logistic regression analyses, increased fruit intake was associated with an increased odds of belonging to the high Streptococcus/Clostridium group among infants born vaginally (OR (95% CI) = 2.73 (1.36, 5.46)). In infants delivered by Cesarean section, we identified three clusters that differed slightly from vaginally delivered infants, which were characterized by a high abundance of Bifidobacterium, high Clostridium and low Streptococcus and Ruminococcus genera, and high abundance of the family Enterobacteriaceae. Maternal dairy intake was associated with an increased odds of infants belonging to the high Clostridium cluster in infants born by Cesarean section (OR (95% CI) = 2.36 (1.05, 5.30)). Linear models suggested additional associations between maternal diet and infant intestinal microbes in both delivery mode strata. CONCLUSIONS: Our data indicate that maternal diet influences the infant gut microbiome and that these effects differ by delivery mode. PMID- 29973275 TI - Structurally simple synthetic 1, 4-disubstituted piperidines with high selectivity for resistant Plasmodium falciparum. AB - BACKGROUND: Emergence of resistance to artemisinins and some of their combinations in chemotherapy of clinical malaria has intensified the search for novel safe efficacious antimalarial molecules. Fourteen synthetic 1, 4 disubstituted piperidines with simple molecular structures were evaluated in this study. METHODS: Antiplasmodial activity were determined against cultured chloroquine-sensitive 3D7 and resistant Dd2 strains of P. falciparum by in vitro parasite growth inhibition. A primary screen was done to identify active compounds by fluorescence microscopy followed by a secondary screen to determine IC50 and IC90 values of active compounds by the parasite lactate dehydrogenase assay. Cytotoxicity of active compounds was assessed using the MTT/formazan assay and selectivity indices (SIs) determined. Optical densities were analysed to obtain experimental results. RESULTS: The compounds produced 56 to 93% inhibition of parasite growth at 40 MUg/mL. Eight compounds (2 ketone, 5 alcohol and one amine analogues) showed high activity (IC50s between 1 and 5 MUg/mL). Nine compounds were highly selective for the parasite (SIs = 15 to 182). Three promising (alcohol) analogues were identified: [1-(4-fluorobenzyl) piperidin-4 yl] [4-fluorophenyl] methanol, (7), [1-(3, 4-dichlorobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (8) and [1-(4-bromobenzyl) piperidin-4-yl] [4- fluorophenyl] methanol (11) which were more active on the resistant strain (IC50 values between 1.03 to 2.52 MUg/mL), than the sensitive strain (IC50 values between 2.51 to 4.43 MUg/mL). CONCLUSIONS: The alcohol analogues were the most active and most selective for the parasite with three promising hit molecules identified among them, suggesting the hydroxyl group at C-7' in these alcohol analogues is contributing greatly to their antiplasmodial activity. Further exploration of the core structure using chemistry approaches and biological screening including in vivo studies in an animal model of malaria may yield important antimalarial leads. PMID- 29973276 TI - Anthelmintic resistance in gastrointestinal nematodes of alpacas (Vicugna pacos) in Australia. AB - BACKGROUND: Gastrointestinal nematodes (GINs) can cause significant economic losses in alpacas due to lowered production of fibre and meat. Although no anthelmintics are registered for use in alpacas, various classes of anthelmintics are frequently used to control parasitic gastroenteritis in alpacas in Australia and other countries. Very little is known about the current worm control practices as well as the efficacy of anthelmintics used against common GINs of alpacas. This study aimed to assess the existing worm control practices used by Australian alpaca farmers and to quantify the efficacy of commonly used anthelmintics against GINs of alpacas. METHODS: An online questionnaire survey was conducted to assess current worm control practices on 97 Australian alpaca farms, with an emphasis on the use of anthelmintics. Of this group of 97 alpaca farms, 20 were selected to assess the efficacy of eight anthelmintics and/or their combinations (closantel, fenbendazole ivermectin, monepantel, moxidectin and a combination of levamisole, closantel, albendazole, abamectin) using the faecal egg count reduction test (FECRT). A multiplexed-tandem PCR (MT-PCR) was used to identify the prevalent nematode genera/species. RESULTS: The response rate for the questionnaire was 94% (91/97). Almost half of the respondents kept alpacas with sheep and cattle, and 26% of respondents allowed alpacas to co-graze with these ruminants. Although only 63% respondents perceived worms to be an important health concern for alpacas, the majority of respondents (89%) used anthelmintics to control GINs of alpacas. The commonly used anthelmintics were macrocyclic lactones, monepantel, benzimidazoles, levamisole, closantel and their combinations, and they were typically administered at the dose rate recommended for sheep. The FECRT results showed that a combination of levamisole, closantel, albendazole and abamectin was the most effective dewormer followed by single drugs, including monepantel, moxidectin, closantel, fenbendazole and ivermectin. Haemonchus spp. were the most commonly resistant nematodes followed by Trichostrongylus spp., Camelostrongylus mentulatus, Ostertagia ostertagi and Cooperia spp. CONCLUSIONS: This is the first study aimed at assessing worm control practices and efficacy of commonly used anthelmintics in alpacas in Australia. Our findings document the extent of anthelmintics resistance on Australian alpaca farms and identify those anthelmintics that are still effective against GINs of alpacas. PMID- 29973277 TI - A novel LRAT mutation affecting splicing in a family with early onset retinitis pigmentosa. AB - BACKGROUND AND PURPOSE: Retinitis pigmentosa is an important cause of severe visual dysfunction. This study reports a novel splicing mutation in the lecithin retinol acyltransferase (LRAT) gene associated with early onset retinitis pigmentosa and characterizes the effects of this mutation on mRNA splicing and structure. METHODS: Genome-wide linkage analysis followed by dideoxy sequencing of the linked candidate gene LRAT was performed in a consanguineous Pakistani family with autosomal recessive retinitis pigmentosa. In silico prediction and minigene assays were used to investigate the effects of the presumptive splicing mutation. RESULTS: ARRP in this family was linked to chromosome 4q31.21-q32.1 with a maximum LOD score of 5.40. A novel homozygous intronic mutation (NM_004744.4: c.541-15T>G) was detected in LRAT. In silico tools predicted that the AG-creating mutation would activate an intronic cryptic acceptor site, but cloning fragments of wild-type and mutant sequences of LRAT into Exontrap Cloning Vector pET01 and Expression Cloning Vector pCMV-(DYKD4K)-C showed that the primary effect of the sequence change was to weaken the nearby authentic acceptor site and cause exon skipping, with only a small fraction of transcripts utilizing the acceptor site producing the reference transcript. CONCLUSIONS: The c.541 15T>G mutation in LRAT results in aberrant splicing and is therefore predicted to be causal for the early onset retinitis pigmentosa in this family. In addition, this work suggests that minigenes adapted to the specific gene and exon may need to be designed for variants in the first and last exon and intron to mimic the authentic splicing mechanism in vivo. PMID- 29973278 TI - Association of the peripheral blood levels of circulating microRNAs with both recurrent miscarriage and the outcomes of embryo transfer in an in vitro fertilization process. AB - BACKGROUND: Implantation failure is not only a major cause of early pregnancy loss, but it is also an obstacle to assisted reproductive technologies. The identification of potential circulating biomarkers for recurrent miscarriage (RM) and/or recurrent implantation failure would contribute to the development of novel diagnosis and prediction techniques. METHODS: MiR (miR-23a-3p, 27a-3p, 29a 3p, 100-5p, 127-3p and 486-5p) expression in the villi, decidual tissues and peripheral blood plasma and serum were validated by qPCR, and the localization of miRs in the villi and decidual tissues of RM and normal pregnancy (NP) women were detected by in situ hybridization. The invasiveness of HTR8/SVneo cells was determined using a Transwell assay. The predictive values of miRs for RM and the outcome of IVF-ET were respectively calculated by the receiver operating characteristic analysis. RESULTS: The signals of six miRs were observed in the villi and decidual tissues of RM and NP women. The villus miR-27a-3p, miR-29a-3p and miR-100-5p were significantly up-regulated, whereas miR-127-3p and miR-486-5p appeared to be down-regulated in RM women compared to NP women. The invasiveness of HTR8/SVneo cells transfected with miR-23a-3p mimics was evidently weakened, whereas that of cells transfected with miR-127-3p mimics was obviously enhanced. The peripheral blood plasma levels of miR-27a-3p, miR-29a-3p, miR-100-5p and miR 127-3p were significantly increased, whereas that of miR-486-5p was remarkably decreased in RM compared to NP women. By contrast, serum miR-23a-3p and miR-127 3p were significantly decreased, whereas that of miR-486-5p was remarkably increased. The combination of six plasma miRs levels discriminated RM with a sensitivity of 100% and a specificity of 83.3%, whereas that of six serum miRs levels showed a sensitivity of 78.3% and a specificity of 93.1%. In the IVF-ET cohort, the significantly decreased peripheral blood plasma levels of miR-23a-3p, miR-27a-3p, miR-100-5p and miR-127-3p, and the serum levels of miR-100-5p and miR 486-5p, in addition to the significantly increased serum level of miR-27a-3p, were found to be associated with the failure of ET. Moreover, the combination of plasma miR-23a-3p, miR-27a-3p, miR-29a-3p, miR-100-5p, miR-127-3p and miR-486-5p levels discriminated the outcome of IVF-ET with a sensitivity of 68.1% and a specificity of 54.1%, whereas the combination of plasma miR-127-3p and miR-486-5p levels showed a sensitivity of 50.0% and a specificity of 75.3%. CONCLUSIONS: Circulating miR-23a-3p, miR-27a-3p, miR-29a-3p, miR-100-5p, miR-127-3p and miR 486-5 might be involved in RM pathogenesis and present potential diagnostic biomarkers for RM. Meanwhile, these miRs, in particular miR-127-3p and miR-486 5p, provide promising prediction indexes for the outcomes of IVF-ET. PMID- 29973279 TI - The age of onset and evolution of Braak tangle stage and Thal amyloid pathology of Alzheimer's disease in individuals with Down syndrome. AB - While post mortem studies have identified the major cell types and functional systems affected in Alzheimer's disease (AD) the initial sites and molecular characteristics of pathology are still unclear. Because individuals with Down syndrome (DS) (trisomy 21) develop the full pathological changes of AD in a predictable way by the time they reach middle to late age, a study of the brains of such persons at different ages makes an ideal 'model system' in which the sites of earliest onset of pathology can be detected and the subsequent progression of changes be monitored. In the present study we have examined the brains of 56 individuals with DS ranging from new-born to 76 years for the presence of amyloid and tau pathology in key cortical and subcortical regions. Amyloid pathology was found to commence in the late teens to twenties as a deposition of diffuse plaques initially within the temporal neocortex, quickly involving other neocortical regions but only reaching subcortical regions and cerebellum by the late forties. Cerebral amyloid angiopathy did not regularly commence until after 45-50 years of age. Tau pathology usually commenced after 35 years of age, initially involving not only entorhinal areas and hippocampus but also subcortical regions such as locus caeruleus (LC) and dorsal raphe nucleus (DRN). Later, tau pathology spread throughout the neocortex reaching occipital lobes in most instances by mid-50 years of age. Such a pattern of spread is consistent with that seen in typical AD. We found no evidence that tau pathology might commence within the brain in DS before amyloid deposition had occurred, but there was limited data that suggests tau pathology in LC or DRN might predate that in entorhinal areas and hippocampus or at least be coincident. PMID- 29973280 TI - Pay-for-performance as a cost-effective implementation strategy: results from a cluster randomized trial. AB - BACKGROUND: Pay-for-performance (P4P) has been recommended as a promising strategy to improve implementation of high-quality care. This study examined the incremental cost-effectiveness of a P4P strategy found to be highly effective in improving the implementation and effectiveness of the Adolescent Community Reinforcement Approach (A-CRA), an evidence-based treatment (EBT) for adolescent substance use disorders (SUDs). METHODS: Building on a $30 million national initiative to implement A-CRA in SUD treatment settings, urn randomization was used to assign 29 organizations and their 105 therapists and 1173 patients to one of two conditions (implementation-as-usual (IAU) control condition or IAU+P4P experimental condition). It was not possible to blind organizations, therapists, or all research staff to condition assignment. All treatment organizations and their therapists received a multifaceted implementation strategy. In addition to those IAU strategies, therapists in the IAU+P4P condition received US $50 for each month that they demonstrated competence in treatment delivery (A-CRA competence) and US $200 for each patient who received a specified number of treatment procedures and sessions found to be associated with significantly improved patient outcomes (target A-CRA). Incremental cost-effectiveness ratios (ICERs), which represent the difference between the two conditions in average cost per treatment organization divided by the corresponding average difference in effectiveness per organization, and quality-adjusted life years (QALYs) were the primary outcomes. RESULTS: At trial completion, 15 organizations were randomized to the IAU condition and 14 organizations were randomized to the IAU+P4P condition. Data from all 29 organizations were analyzed. Cluster-level analyses suggested the P4P strategy led to significantly higher average total costs compared to the IAU control condition, yet this average increase of 5% resulted in a 116% increase in the average number of months therapists demonstrated competence in treatment delivery (ICER = $333), a 325% increase in the average number of patients who received the targeted dosage of treatment (ICER = $453), and a 325% increase in the number of days of abstinence per patient in treatment (ICER = $8.134). Further supporting P4P as a cost-effective implementation strategy, the cost per QALY was only $8681 (95% confidence interval $1191-$16,171). CONCLUSION: This study provides experimental evidence supporting P4P as a cost-effective implementation strategy. TRIAL REGISTRATION: NCT01016704 . PMID- 29973281 TI - Hospital quality reporting and improvement in quality of care for patients with acute myocardial infarction. AB - BACKGROUND: Although public reporting of hospital performance is becoming common, it remains uncertain whether public reporting leads to improvement in clinical outcomes. This study was conducted to evaluate whether enrollment in a quality reporting project is associated with improvement in quality of care for patients with acute myocardial infarction. METHODS: We conducted a quasi-experimental study using hospital census survey and national inpatient database in Japan. Hospitals enrolled in a ministry-led quality reporting project were matched with non-reporting control hospitals by one-to-one propensity score matching using hospital characteristics. Using the inpatient data of acute myocardial infarction patients hospitalized in the matched hospitals during 2011-2013, difference-in differences analyses were conducted to evaluate the changes in unadjusted and risk-adjusted in-hospital mortality rates over time that are attributable to intervention. RESULTS: Matching between hospitals created a cohort of 30,220 patients with characteristics similar between the 135 reporting and 135 non reporting hospitals. Overall in-hospital mortality rates were 13.2% in both the reporting and non-reporting hospitals. There was no significant association between hospital enrollment in the quality reporting project and change over time in unadjusted mortality (OR, 0.98; 95% CI, 0.80-1.22). In 28,168 patients eligible for evaluation of risk-adjusted mortality, enrollment was also not associated with change in risk-adjusted mortality (OR, 0.98; 95% CI, 0.81-1.17). CONCLUSIONS: Enrollment in the quality reporting project was not associated with short-term improvement in quality of care for patients with acute myocardial infarction. Additional efforts may be necessary to improve quality of care. PMID- 29973282 TI - Possible mechanism of Vitis vinifera L. flavones on neurotransmitters, synaptic transmission and related learning and memory in Alzheimer model rats. AB - BACKGROUND: This study explored the possible mechanism of flavones from Vitis vinifera L. (VTF) on neurotransmitters, synaptic transmission and related learning and memory in rats with Alzheimer disease (AD). METHODS: The researchers injected amyloid-beta(25-35) into the hippocampus to establish AD model rats. The Sprague-Dawley (SD) rats were divided into a control group, a donepezil group, an AD model group, a VTF low-dose group, a VTF medium-dose group and a VTF high-dose group. The researchers detected the activity of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) according to kit instructions. The protein expression of brain-derived neurotrophic factor (BDNF), synaptotagmin-1 (SYT1) and cyclic adenosine monophosphate response element binding protein (CREB) in the rats' hippocampi was detected by immunohistochemistry and Western blot, and the gene expression of cAMP-regulated enhancer (CRE) was detected by real-time quantitative polymerase chain reaction (PCR). RESULTS: VTF may enhance the protein expression of p-CREB, BDNF and SYT1 in rat hippocampi, depending on dose. The messenger RNA (mRNA) level of CREB was significantly higher in the VTF high dose group than in the model group, which was consistent with the results of Western blotting. VTF may reduce the activity of AChE and increase that of ChAT in rat hippocampi. Finally, VTF effectively improved the learning and memory abilities of AD rats. CONCLUSIONS: VTF can promote synaptic plasticity and indirectly affect the expression of cholinergic neurotransmitters, which may be one mechanism of VTF protection in AD rats. PMID- 29973283 TI - DEPTOR regulates osteogenic differentiation via inhibiting MEG3-mediated activation of BMP4 signaling and is involved in osteoporosis. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) pathway plays a significant role in osteogenic differentiation and bone maintenance. As the only known endogenous inhibitor of mTOR function, DEP domain containing mTOR interacting protein (DEPTOR) is potentially involved in stem cell differentiation, although the pathophysiological significance and its molecular mechanisms remain unclear. The present study aimed to elucidate the effects of DEPTOR on the progress of osteoporosis and investigate the underlying molecular mechanisms of osteogenic regulation. METHODS: An ovariectomy mouse model with decreased bone formation and osteogenic induction with bone marrow mesenchymal stem cells (BMSCs) were used to investigate the relationship between DEPTOR and osteogenic events. A loss-of function investigation was then performed to explore the role of DEPTOR in the osteogenic differentiation of BMSCs both in vitro and in vivo. Finally, long noncoding RNA (lncRNA) and mRNA sequences were investigated to reveal the underlying mechanisms of DEPTOR in osteogenic regulation. RNA interference, western blotting, and chromatin immunoprecipitation assays were performed for further mechanistic determination. RESULTS: The results indicated that DEPTOR contributes to the progress of osteoporosis, and higher expression of Deptor was observed in osteoporotic bones. The expression of DEPTOR was reduced during the osteogenic differentiation of BMSCs, and knockdown of DEPTOR promoted BMSC osteogenesis in vitro and in vivo. lncRNA and mRNA sequences indicated that knockdown of DEPTOR upregulated the expression of maternally expressed 3 (nonprotein coding) (MEG3), which subsequently activated bone morphogenetic protein 4 (BMP4) signaling. Furthermore, DEPTOR could bind to a specific region ( 1000 bp ~ 0) of the MEG3 promoter to regulate its transcription, and inhibition of MEG3 reduced BMP4 activation triggered by DEPTOR knockdown. CONCLUSIONS: Taken together, our study revealed a novel function of DEPTOR in osteogenic differentiation by inhibiting MEG3-mediated activation of BMP4 signaling, which suggested that DEPTOR could be a therapeutic target for bone loss diseases and skeletal tissue regeneration. PMID- 29973284 TI - Efficacy of Jia Wei Yang He formula as an adjunctive therapy for asthma: study protocol for a randomized, double blinded, controlled trial. AB - BACKGROUND: Over the past two or three decades, the prevalence of asthma has significantly increased worldwide; therefore, effective treatment without side effects is of utmost importance. Traditional Chinese medicine (TCM) plays a vital role in reducing symptoms and improving the quality of life in persistent-asthma patients. The aim of this study is to evaluate the efficacy of the Jia Wei Yang He (JWYH) formula in the treatment of asthma and to explore the relationship between the airway microbiome and TCM treatment in asthma patients. METHODS/DESIGN: This multicenter, parallel-arm, randomized, double-blinded, placebo-controlled trial will assess the efficacy of JWYH in asthma patients with usual care. Persistent-asthma patients without life-threatening disease will be enrolled on a random basis and are equally assigned to a high- or a low-dose JWYH plus usual care group, or a placebo plus usual care group. Patients are followed up for 4 months. Accordingly, 240 patients will yield sufficient statistical power to determine a difference between groups. Based on modified intent-to-treat (mITT) analyses, the three groups will be compared at 4 weeks after the beginning of treatment. The primary efficacy measurement is the mean change in the Asthma Control Test (ACT) score from baseline to 4 weeks post treatment. Secondary outcomes include forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF), and asthma exacerbations. This trial also includes analyses of the associations between airway microbiome and asthma treatment. DISCUSSION: In this study, a randomized clinical trial design is described. The results are based on several outcomes that estimate the efficacy of the JWYH formula and prospective links between the airway microbiome and asthma treatment. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03299322 . Registered on 3 October 2017. PMID- 29973286 TI - A retrospective comparative study of endoscopic and microscopic Tympanoplasty. AB - BACKGROUND: This study compares endoscopic and microscopic tympanoplasty for the treatment of chronic otitis media (COM) without cholesteatoma. METHODS: This retrospective study included 153 ears (139 patients) treated surgically (endoscopic or microscopic tympanoplasty) for COM in the absence of cholesteatoma at our hospital between January 2008 and October 2015. The adoption of transcanal endoscopic ear surgery (TEES) or microscopic ear surgery (MES) was divided temporally (before and since 2014). Comparisons between these groups focused on the following: (I) surgical outcomes, including successful tympanic membrane healing and post-operative complications; (II) restoration of hearing; and (III) consumption of medical resources, including the duration of surgery and anesthesia. All patients had a follow-up period of at least 3 months after surgery. RESULTS: No statistically significant differences were observed between the two groups regarding surgical outcome or hearing restoration. TEES resulted in the successful healing of 96.2% of ear drums, whereas MES led to successful healing in 92% (p = 0.2826) of cases. The average hearing gains following surgery were 10.27 +/- 6.4 and 12.43 +/- 7.46 dB in TEES and MES, respectively. The consumption of medical resources in the TEES group was lower than that of the MES group (TEES versus MES) regarding the average operating time (87.8 +/- 19.01 min (mins) versus 110.2 +/- 17.0 (mins) (p < 0.0001)) and the mean duration of anesthesia ((for general anesthesia patients) (122.1 +/- 21.25 mins versus 145.8 +/- 16.88 mins) (p <= 0.0001)). CONCLUSIONS: The results indicate that TEES can achieve surgical outcomes and hearing restoration comparable to those of MES. In addition, TEES appears to be associated with shorter surgical and anesthesia time, which makes it an ideal alternative for the management of COM without cholesteatoma. TRIAL REGISTRATION: This study was approved by the Institutional Review Board of the Cathay General Hospital. (CGHIRB No: CGH-P105012 ). PMID- 29973285 TI - A large-scale whole-genome sequencing analysis reveals highly specific genome editing by both Cas9 and Cpf1 (Cas12a) nucleases in rice. AB - BACKGROUND: Targeting specificity has been a barrier to applying genome editing systems in functional genomics, precise medicine and plant breeding. In plants, only limited studies have used whole-genome sequencing (WGS) to test off-target effects of Cas9. The cause of numerous discovered mutations is still controversial. Furthermore, WGS-based off-target analysis of Cpf1 (Cas12a) has not been reported in any higher organism to date. RESULTS: We conduct a WGS analysis of 34 plants edited by Cas9 and 15 plants edited by Cpf1 in T0 and T1 generations along with 20 diverse control plants in rice. The sequencing depths range from 45* to 105* with read mapping rates above 96%. Our results clearly show that most mutations in edited plants are created by the tissue culture process, which causes approximately 102 to 148 single nucleotide variations (SNVs) and approximately 32 to 83 insertions/deletions (indels) per plant. Among 12 Cas9 single guide RNAs (sgRNAs) and three Cpf1 CRISPR RNAs (crRNAs) assessed by WGS, only one Cas9 sgRNA resulted in off-target mutations in T0 lines at sites predicted by computer programs. Moreover, we cannot find evidence for bona fide off-target mutations due to continued expression of Cas9 or Cpf1 with guide RNAs in T1 generation. CONCLUSIONS: Our comprehensive and rigorous analysis of WGS data across multiple sample types suggests both Cas9 and Cpf1 nucleases are very specific in generating targeted DNA modifications and off-targeting can be avoided by designing guide RNAs with high specificity. PMID- 29973288 TI - Bilateral septic arthritis of the sternoclavicular joint complicating infective endocarditis: a case report. AB - BACKGROUND: Septic arthritis is an infectious disease that commonly affects weight-bearing or proximal joints such as the knee and the hip. The sternoclavicular joint is an unusual site of this entity. It usually occurs in patients with diabetes mellitus, intravenous drug abusers, or those with rheumatoid arthritis. Analysis of the previous literature showed few articles and these described essentially cases of unilateral presentation. CASE PRESENTATION: We report a rare case of a bilateral septic arthritis of the sternoclavicular joint sustained by a 71-year-old Tunisian woman whose medical history was significant for methicillin-resistant Staphylococcus aureus infective endocarditis 6 months ago. Imaging investigations revealed destruction of the medial extremities of her two clavicles and bilateral collections in the soft tissues around her sternoclavicular joints. She was treated successfully by needle aspiration drainage combined with a 12-week antibiotherapy. CONCLUSIONS: Bilateral septic arthritis of the sternoclavicular joint is an extremely rare entity, with a paucity of literature. Only early diagnosis, which is obtained from the culture of the joint fluid using needle aspiration, allows satisfactory functional outcome and a good prognosis. Osteoarticular infections should be considered in patients with recent infective endocarditis in cases of fever recurrence. PMID- 29973287 TI - Dipeptide repeat proteins activate a heat shock response found in C9ORF72 ALS/FTLD patients. AB - A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD. PMID- 29973289 TI - Renewing Medicine's basic concepts: on ambiguity. AB - BACKGROUND: Edmund Pellegrino lamented that the cultural climate of the industrialized West had called the fundamental means and ends of medicine into question, leading him to propose a renewed reflection on medicine's basic concepts, including health, disease, and illness. My aim in this paper is take up Pellegrino's call. I argue that in order to usher in this renewal, the concept of ambiguity should take on a guiding role in medical practice, both scientific and clinical. After laying out Pellegrino's vision, I focus on the concept of normality, arguing that it undergirds modern medicine's other basic concepts. I draw on critiques by scholars in disability studies that show the concept of normality to be instructively ambiguous. Discussing the cases of Deafness and body integrity identity disorder (BIID), I argue that if medicine is to uphold its epistemic authority and fulfill its melioristic goals, ambiguity should become a central medical concept. METHODS: In this theoretical paper, I consider how central concepts in the philosophy of medicine are challenged by research on experiences of disability. In particular, the idea that medical knowledge produces universal truths is challenged and the importance of historical, cultural, and otherwise situated knowledge is highlighed. RESULTS: I demonstrate how experiences of disability complicate dominant theories in the philosophy of medicine and why medical practice and the philosophy of medicine should make ambiguity a central concept. CONCLUSIONS: If medical practitioners and philosophers of medicine wish to improve their understanding of the meaning and practice of medicine, they should take seriously the importance and centrality of ambiguity. PMID- 29973290 TI - Identification of the technical and medical requirements for HEMS avalanche rescue missions through a 15-year retrospective analysis in a HEMS in Switzerland: a necessary step for quality improvement. AB - BACKGROUND: Avalanche rescues mostly rely on helicopter emergency medical services (HEMS) and include technical rescue and complex medical situations under difficult conditions. The adequacy of avalanche victim management has been shown to be unexpectedly low, suggesting the need for quality improvement. We analyse the technical rescue and medical competency requirements of HEMS crewmembers for avalanche rescue missions, as well as their clinical exposure. The study aims to identify areas that should be the focus of future quality improvement efforts. METHODS: This 15-year retrospective study of avalanche rescue by the Swiss HEMS Rega includes all missions where at least one patient had been caught by an avalanche, found within 24 h of the alarm being raised, and transported. RESULTS: Our analyses included 422 missions (596 patients). Crews were frequently confronted with technical rescue aspects, including winching (29%) and patient location and extrication (48%), as well as multiple casualty accidents (32%). Forty-seven percent of the patients suffered potential or overt vital threat; 29% were in cardiac arrest. The on-site medical management of the victims required a large array of basic and advanced medical skills. Clinical exposure was low, as 56% of the physicians were involved in only one avalanche rescue mission over the study period. CONCLUSIONS: Our data provide a solid baseline measure and valuable starting point for improving our understanding of the challenges encountered during avalanche rescue missions. We further suggest QI interventions, that might be immediately useful for HEMS operating under similar settings. A coordinated approach using a consensus process to determine quality indicators and a minimal dataset for the specific setting of avalanche rescue would be the logical next step. PMID- 29973291 TI - Sites of gastrointestinal lesion induced by mycophenolate mofetil: a comparison with enteric-coated mycophenolate sodium in rats. AB - BACKGROUND: Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear. METHODS: In this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg.d), mofetil (30 mg/kg.d), EC MPS (72 mg/Kg.d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research. RESULTS: The results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption. CONCLUSIONS: Our data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property. PMID- 29973292 TI - Characterization of differential patient profiles and therapeutic responses of pharmacy customers for four ambroxol formulations. AB - BACKGROUND: Ambroxol relieves cough symptoms based on its secretagogue, anti inflammatory, anti-oxidant, anti-bacterial, anti-viral, immunomodulatory and local anesthetic effects. The present study was designed to explore differential patient profiles and efficacy against acute respiratory symptoms of four formulations registered as over-the-counter medicines. METHODS: Nine hundred sixty-five pharmacy customers purchasing one of four branded ambroxol formulations (extended release capsules, adult syrup, pediatric syrup and soft pastilles) filled a questionnaire including a patient-adapted version of the Bronchitis Severity Scale, several questions on degree of impairment by acute cough, time to onset of symptom relief and duration of treatment. Data on pediatric syrup users were entered by their parents. Based on the exploratory character of the study, no hypothesis-testing statistical analysis was applied. RESULTS: Users of the pediatric syrup and the pastilles reported somewhat less severe baseline symptoms. The patient-adapted Bronchitis Severity Scale proved feasible as a self-administered tool. Among BSS items, ambroxol formulations improved chest pain while coughing to the largest and sputum to smallest degree ( 75% vs. -40%). Reported efficacy was comparable among formulations with minor differences in favor of the pediatric syrup. Time to onset of symptom relief was less than 60 min in more than 90% of patients and occurred prior to known systemic tmax. Time to onset was the parameter with the greatest differences between formulations, being reported fastest with pastilles and pediatric syrup and, as expected, slowest with extended release capsules. All ambroxol formulations were well tolerated. CONCLUSIONS: We conclude that over-the-counter formulations of ambroxol exhibit comparable user profiles and efficacy. Differences in speed of onset of symptom relief may involve not only those in systemic pharmacokinetics but also local anesthetic effects of immediate release formulations. Differences between pediatric and adult syrup may in part reflect reporting bias. PMID- 29973293 TI - Polymyxin B-induced skin hyperpigmentation: a rare case report and literature review. AB - BACKGROUND: Polymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial activities, inflicts several adverse effects on patients. However, skin hyperpigmentaion (SH) induced by PMB is very rare. Here, we report a case of polymyxin B-induced skin hyperpigmentation (PMB-iSH) in a 21-year-old female. To the best of our knowledge, this is the first case of PMB-iSH in China. CASE PRESENTATION: A 21-year-old female patient with sepsis received the administration of PMB by intravenous injection for the treatment of multi-drug resistant Klebsiella pneumoniae (MDR-KP) infection. She later suffered from a rare adverse drug reaction (ADR), namely PMB-iSH, after 5-day PMB administration during her treatment. There were multiple red rashes spread on the whole body skin at first. With the rashes fading away, SH with dark round spots appeared, associated with no pain or pruritus. The skin of the head and neck was darkened evidently, and dark brown spots were spread on the skin of trunk and limbs. About a month after her admission, urged by the relatives, the patient was transferred back to the local hospital for further treatment in the end, and her skin color didn't recover to the previous state at that time. CONCLUSION: Both our case and the literature review highlight that PMB can give rise to SH indeed. Clinicians and pharmacists should attach great importance to this rare pigmentary disorder and further investigation is warranted. PMID- 29973294 TI - HAM-TBS: high-accuracy methylation measurements via targeted bisulfite sequencing. AB - BACKGROUND: The ability to accurately and efficiently measure DNA methylation is critical to advance the understanding of this epigenetic mechanism and its contribution to common diseases. Here, we present a highly accurate method to measure methylation using bisulfite sequencing (termed HAM-TBS). This novel method is able to assess DNA methylation in multiple samples with high accuracy in a cost-effective manner. We developed this assay for the FKBP5 locus, an important gene in the regulation of the stress system and previously linked to stress-related disorders, but the method is applicable to any locus of interest. RESULTS: HAM-TBS enables multiplexed analyses of up to 96 samples and regions spanning 10 kb using the Illumina MiSeq. It incorporates a triplicate bisulfite conversion step, pooled target enrichment via PCR, PCR-free library preparation and a minimum coverage of 1000*. TBS was able to resolve DNA methylation levels with a mean accuracy of 0.72%. Using this method, we designed and validated a targeted panel to specifically assess regulatory regions within the FKBP5 locus that are not covered in commercially available DNA methylation arrays. CONCLUSIONS: HAM-TBS represents a highly accurate, medium-throughput sequencing approach for robust detection of DNA methylation changes in specific target regions. PMID- 29973295 TI - Iberian pig mesenchymal stem/stromal cells from dermal skin, abdominal and subcutaneous adipose tissues, and peripheral blood: in vitro characterization and migratory properties in inflammation. AB - BACKGROUND: Recently, the capacity of mesenchymal stem/stromal cells (MSCs) to migrate into damaged tissues has been reported. For MSCs to be a promising tool for tissue engineering and cell and gene therapy, it is essential to know their migration ability according to their tissue of origin. However, little is known about the molecular mechanisms regulating porcine MSC chemotaxis. The aim of this study was to examine the migratory properties in an inflammatory environment of porcine MSC lines from different tissue origins: subcutaneous adipose tissue (SCA MSCs), abdominal adipose tissue (AA-MSCs), dermal skin tissue (DS-MSCs) and peripheral blood (PB-MSCs). METHODS: SCA-MSCs, AA-MSCs, DS-MSCs and PB-MSCs were isolated and analyzed in terms of morphological features, alkaline phosphatase activity, expression of cell surface and intracellular markers of pluripotency, proliferation, in vitro chondrogenic, osteogenic and adipogenic differentiation capacities, as well as their ability to migrate in response to inflammatory cytokines. RESULTS: SCA-MSCs, AA-MSCs, DS-MSCs and PB-MSCs were isolated and showed plastic adhesion with a fibroblast-like morphology. All MSC lines were positive for CD44, CD105, CD90 and vimentin, characteristic markers of MSCs. The cytokeratin marker was also detected in DS-MSCs. No expression of MHCII or CD34 was detected in any of the four types of MSC. In terms of pluripotency features, all MSC lines expressed POU5F1 and showed alkaline phosphatase activity. SCA-MSCs had a higher growth rate compared to the rest of the cell lines, while the AA-MSC cell line had a longer population doubling time. All MSC lines cultured under adipogenic, chondrogenic and osteogenic conditions showed differentiation capacity to the previously mentioned mesodermal lineages. All MSC lines showed migration ability in an agarose drop assay. DS-MSCs migrated greater distances than the rest of the cell lines both in nonstimulated conditions and in the presence of the inflammatory cytokines TNF-alpha and IL-1beta. SCA-MSCs and DS MSCs increased their migration capacity in the presence of IL-1beta as compared to PBS control. CONCLUSIONS: This study describes the isolation and characterization of porcine cell lines from different tissue origin, with clear MSC properties. We show for the first time a comparative study of the migration capacity induced by inflammatory mediators of porcine MSCs of different tissue origin. PMID- 29973296 TI - Long-term expansion of primary equine keratinocytes that maintain the ability to differentiate into stratified epidermis. AB - BACKGROUND: Skin injuries in horses frequently lead to chronic wounds that lack a keratinocyte cover essential for healing. The limited proliferation of equine keratinocytes using current protocols has limited their use for regenerative medicine. Previously, equine induced pluripotent stem cells (eiPSCs) have been produced, and eiPSCs could be differentiated into equine keratinocytes suitable for stem cell-based skin constructs. However, the procedure is technically challenging and time-consuming. The present study was designed to evaluate whether conditional reprogramming (CR) could expand primary equine keratinocytes rapidly in an undifferentiated state but retain their ability to differentiate normally and form stratified epithelium. METHODS: Conditional reprogramming was used to isolate and propagate two equine keratinocyte cultures. PCR and FISH were employed to evaluate the equine origin of the cells and karyotyping to perform a chromosomal count. FACS analysis and immunofluorescence were used to determine the purity of equine keratinocytes and their proliferative state. Three dimensional air-liquid interphase method was used to test the ability of cells to differentiate and form stratified squamous epithelium. RESULTS: Conditional reprogramming was an efficient method to isolate and propagate two equine keratinocyte cultures. Cells were propagated at the rate of 2.39 days/doubling for more than 40 population doublings. A feeder-free culture method was also developed for long-term expansion. Rock-inhibitor is critical for both feeder and feeder-free conditions and for maintaining the proliferating cells in a stem-like state. PCR and FISH validated equine-specific markers in the cultures. Karyotyping showed normal equine 64, XY chromosomes. FACS using pan-cytokeratin antibodies showed a pure population of keratinocytes. When ROCK inhibitor was withdrawn and the cells were transferred to a three-dimensional air-liquid culture, they formed a well-differentiated stratified squamous epithelium, which was positive for terminal differentiation markers. CONCLUSIONS: Our results prove that conditional reprogramming is the first method that allows for the rapid and continued in vitro propagation of primary equine keratinocytes. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection. This offers the opportunity for treating recalcitrant horse wounds using autologous transplantation. PMID- 29973297 TI - Circulation of Dirofilaria immitis and Dirofilaria repens in the Danube Delta Biosphere Reserve, Romania. AB - BACKGROUND: Dirofilariosis is an emerging vector-borne parasitic disease in Europe. Monitoring of wild and domestic carnivores demonstrated circulation of Dirofilaria spp. in Romania in the past. For the implementation of control measures, knowledge on the native mosquito community responsible for Dirofilaria spp. transmission is required. METHODS: Mosquito samples originated from a longitudinal study previously performed in the Danube Delta Biosphere Reserve. Mosquito pools were screened for Dirofilaria immitis and Dirofilaria repens. The samples comprised 240,572 female mosquito specimens collected every ten days between April and September in 2014 at four different trapping sites. In addition, blood samples of 36 randomly selected dogs were collected in 2016 in each of the four mosquito sampling sites. A duplex real-time assay was used to detect the presence of one or both Dirofilaria species for each sample. This assay targets the cytochrome c oxidase subunit 1 and the 16S rRNA gene fragments to differentiate both parasites. RESULTS: Dirofilaria immitis and D. repens were detected in mosquito pools at all four trapping sites. In the 2118 mosquito pools tested, D. immitis was identified for eight and D. repens for six of the 14 screened mosquito taxa, with a higher prevalence of D. immitis (4.53% of analysed pools) compared to D. repens (1.09%). Dirofilaria spp. were also identified in dogs from the same sampling sites with a prevalence of 30.56%. For both Dirofilaria species, the highest estimated infection rates (EIRs) were found in Anopheles maculipennis (s.l.) (D. immitis: EIR = 0.206 per 100 specimens, D. repens: EIR = 0.066 per 100 specimens). In contrast, Coquillettidia richiardii and Anopheles hyrcanus as the most frequent taxa had infection rates which were significantly lower: Cq. richiardii (D. immitis: EIR = 0.021; D. repens: EIR = 0.004); An. hyrcanus (D. immitis: EIR = 0.028; D. repens: EIR = 0.006). The number of positive pools per calendar week was positively correlated with the number of screened pools per calendar week, suggesting constant Dirofilaria spp. transmission during the observation period. CONCLUSIONS: This study further confirms significant circulation of Dirofilaria spp. in eastern Europe, with high parasite prevalence in domestic canids and mosquitoes. Therefore, systematic monitoring studies are required to better understand the environmental risk factors for Dirofilaria transmission, allowing the implementation of effective surveillance and control measures. PMID- 29973298 TI - Barriers to exclusive breast-feeding in Indonesian hospitals: a qualitative study of early infant feeding practices. AB - OBJECTIVE: Although initiating breast-feeding is common in Indonesia, rates of exclusive breast-feeding are low. Our objective was to identify early barriers to exclusive breast-feeding in Indonesian hospitals. DESIGN: Qualitative. Semi structured interviews were conducted in April-June 2015. The data were analysed using thematic analysis. SETTING: Indonesian provinces of Jakarta, Banten and West Java. SUBJECTS: Fifty-four participants including public health officials, hospital administrators, health-care professionals and parents. RESULTS: Five themes were identified as contributing to low rates of early exclusive breast feeding in Indonesian hospitals: (i) quality and quantity of breast-feeding education; (ii) marketing and influence of infant formula manufacturers; (iii) hospital infrastructure; (iv) policy, legislation and protocols; and (v) perceived need for infant formula supplementation. Participants noted that providers and mothers receive inadequate or incorrect education regarding breast feeding; manufacturers promote infant formula use both inside and outside hospitals; constraints in physical space and hospital design interfere with early breast-feeding; legislation and protocols designed to promote breast-feeding are inconsistently enforced and implemented; and providers and mothers often believe infant formula is necessary to promote infant health. All participants identified numerous barriers to early exclusive breast-feeding that related to more than one identified theme. CONCLUSIONS: Our study identified important barriers to early exclusive breast-feeding in Indonesian hospitals, finding that participants consistently reported multifaceted barriers to early exclusive breast-feeding. Future research should examine whether system-level interventions such the Baby Friendly Hospital Initiative might improve rates of exclusive breast-feeding by improving breast-feeding education, reducing manufacturer influence, modifying existing infrastructure and providing tools needed for protocols and counselling. PMID- 29973299 TI - Pulsatile hyperglycemia increases insulin secretion but not pancreatic beta-cell mass in intrauterine growth-restricted fetal sheep. AB - Impaired beta-cell development and insulin secretion are characteristic of intrauterine growth-restricted (IUGR) fetuses. In normally grown late gestation fetal sheep pancreatic beta-cell numbers and insulin secretion are increased by 7 10 days of pulsatile hyperglycemia (PHG). Our objective was to determine if IUGR fetal sheep beta-cell numbers and insulin secretion could also be increased by PHG or if IUGR fetal beta-cells do not have the capacity to respond to PHG. Following chronic placental insufficiency producing IUGR in twin gestation pregnancies (n=7), fetuses were administered a PHG infusion, consisting of 60 min, high rate, pulsed infusions of dextrose three times a day with an additional continuous, low-rate infusion of dextrose to prevent a decrease in glucose concentrations between the pulses or a control saline infusion. PHG fetuses were compared with their twin IUGR fetus, which received a saline infusion for 7 days. The pulsed glucose infusion increased fetal arterial glucose concentrations an average of 83% during the infusion. Following the 7-day infusion, a square-wave fetal hyperglycemic clamp was performed in both groups to measure insulin secretion. The rate of increase in fetal insulin concentrations during the first 20 min of a square-wave hyperglycemic clamp was 44% faster in the PHG fetuses compared with saline fetuses (P0.23). Chronic PHG increases early phase insulin secretion in response to acute hyperglycemia, indicating that IUGR fetal beta cells are functionally responsive to chronic PHG. PMID- 29973300 TI - A Framework to Assess the Quality of Non-traditional Articles in the Field of Disaster Response and Management. AB - OBJECTIVE: While carrying out a scoping review of earthquake response, we found that there is no universal standardized approach for assessing the quality of disaster evidence, much of which is variable or not peer reviewed. With the lack of a framework to ascertain the value and validity of this literature, there is a danger that valuable insights may be lost. We propose a theoretical framework that may, with further validation, address this gap. METHODS: Existing frameworks - quality of reporting of meta-analyses (QUORUM), meta-analysis of observational studies in epidemiology (MOOSE), the Cochrane assessment of bias, Critical Appraisal Skills Programme (CASP) checklists, strengthening the reporting of observation studies in epidemiology (STROBE), and consensus guidelines on reports of field interventions in disasters and emergencies (CONFIDE)-were analyzed to identify key domains of quality. Supporting statements, based on these existing frameworks were developed for each domain to form an overall theoretical framework of quality. This was piloted on a data set of publications from a separate scoping review. RESULTS: Four domains of quality were identified: robustness, generalizability, added value, and ethics with 11 scored, supporting statements. Although 73 out of 111 papers (66%) scored below 70%, a sizeable portion (34%) scored higher. CONCLUSION: Our theoretical framework presents, for debate and further validation, a method of assessing the quality of non traditional studies and thus supporting the best available evidence approach to disaster response. (Disaster Med Public Health Preparedness. 2018; page 1 of 5). PMID- 29973301 TI - Hospital Disaster Preparedness in Switzerland Over a Decade: A National Survey. AB - OBJECTIVE: The present study aimed to provide a comprehensive assessment of Swiss hospital disaster preparedness in 2016 compared with the 2006 data. METHODS: A questionnaire was addressed in 2016 to all heads responsible for Swiss emergency departments (EDs). RESULTS: Of the 107 hospitals included, 83 (78%) returned the survey. Overall, 76 (92%) hospitals had a plan in case of a mass casualty incident, and 76 (93%) in case of an accident within the hospital itself. There was a lack in preparedness for specific situations: less than a third of hospitals had a specific plan for nuclear/radiological, biological, chemical, and burns (NRBC+B) patients: nuclear/radiological (14; 18%), biological (25; 31%), chemical (27; 34%), and burns (15; 49%), and 48 (61%) of EDs had a decontamination area. Less than a quarter of hospitals had specific plans for the most vulnerable populations during disasters, such as seniors (12; 15%) and children (19; 24%). CONCLUSIONS: The rate of hospitals with a disaster plan has increased since 2006, reaching a level of 92%. The Swiss health care system remains vulnerable to specific threats like NRBC. The lack of national legislation and funds aimed at fostering hospitals' preparedness to disasters may be the root cause to explain the vulnerability of Swiss hospitals regarding disaster medicine. (Disaster Med Public Health Preparedness. 2018;0:1-7). PMID- 29973302 TI - The consumption pattern of 28 species of carabid beetles (Carabidae) to a weed seed, Viola arvensis. AB - Seedbank control has been the cornerstone of agricultural management practices. Regulating weeds by using their predators, as a weed control strategy, may be a prerequisite of decreasing herbicide use, and has thus attracted much research investigating the possible contribution of both vertebrates and invertebrates as weed seed predators. Carabid beetles are considered as one of the most important invertebrate seed predators in agroecosystems. We aimed at investigating carabid beetle preferences to a single prey type, seeds of Viola arvensis. We measured the consumption of seeds in 28 species of carabid beetles, under controlled experimental conditions. Two main tribes are identified in tested species, Harpalini with 12 species and Pterostichini with ten species. We found no relationships between species body mass and Viola's seed consumption, nor with the ratio between mandible length and labrum width (ML/LW). However, trends became significant with the ratio ML/LW when restricting these analyses to species that ate at least five seeds. In addition, we detected a positive and significant relationship between consumption rate and occurrence in trapping sessions over the last 3 years. These results are in favor of weed seeds control by carabids. Clear limits of this study are the use of a single seed species and under control conditions. This experimentation calls for additional studies to check for consistencies in consumption against seed species. PMID- 29973303 TI - The relationship between Interleukin-27 gene polymorphisms and Kawasaki disease in a population of Chinese children. AB - BACKGROUND: Kawasaki disease is the leading cause of acquired heart disease in children from developed countries. The Interleukin-6/ Interleukin-12 cytokine family has many members, including the paradoxical anti- and pro-inflammatory Interleukin-27. Recent studies have demonstrated that Interleukin-27 plays a role in immune diseases. Given this, we sought to evaluate the association between Interleukin-27 genetic polymorphisms and Kawasaki disease in Chinese children.Methods and resultsInterleukin-27 was genotyped in 100 Kawasaki disease children and 98 healthy children (controls), resulting in the direct sequencing of eight Single-nucleotide Polymorphisms: rs17855750, rs40837, rs26528, rs428253, rs4740, rs4905, rs153109, and rs181206). There were no significant differences in Interleukin-27 genotypes between Kawasaki disease and control groups. Of the eight Single-nucleotide Polymorphisms, there was a significant increase in the risk of Kawasaki disease with coronary arterial lesions in children with the rs17855750 (T>G), rs40837 (A>G), rs4740 (G>A), rs4905 (A>G), rs153109 (T>C), and rs26528 (A>G) Single-nucleotide Polymorphisms. This was particularly true for rs17855750 (T>G), which had a greater frequency in Kawasaki disease children with coronary arterial aneurysm. CONCLUSION: These findings may be used as risk factors when assessing a child's likelihood of developing Kawasaki disease, as well as for the development of future therapeutic treatments for Kawasaki disease. PMID- 29973304 TI - Natural factors regulating mustard aphid dynamics in cabbage. AB - Lipaphis erysimi (L.) Kaltenbach (Hemiptera: Aphididae) is one of the most important pests of brassica crops, mainly causing losses due to sap sucking, toxin injection and viral transmission. Knowledge about the main natural factors that regulate populations of this pest, as well as its critical mortality stage, is crucial for the development of integrated pest management of L. erysimi. Here, we determined the critical stage and key mortality factors for L. erysimi in cabbage using an ecological life table. Causes of mortality at each stage of L. erysimi development were monitored daily in the field for seven seasons. From the experimental data, we determined the key factor and critical stage of mortality through correlation and regression analyses. The nymphal stage, especially first instar nymphs, was critical for L. erysimi mortality. The key mortality factors were, in descending order of importance, physiological disturbances and predation by Syrphidae, Coccinellidae and Solenopsis ants. Therefore, control measures should target early stages of L. erysimi and the use of cabbage cultivars that have negative effects against L. erysimi may be a promising strategy for its management. Our results may be useful for plant geneticists who could develop new cabbage cultivars based on these findings. In addition, conservation measures of the main predators of L. erysimi may contribute to the natural control of this pest. PMID- 29973305 TI - Heat stress and thermal ablation induce local expression of nerve growth factor inducible (VGF) in hepatocytes and hepatocellular carcinoma: pre-clinical and clinical studies. AB - Purpose: To test the hypothesis that heat stress and hepatic thermal ablation induce nerve growth factor inducible (VGF) and to determine intrahepatic versus systemic VGF expression induced by thermal ablation in vivo and in patients.Materials and Methods: Hepatocytes and HCC cells were subjected to moderate(45 degrees C) or physiologic(37 degrees C) heat stress for 10 minutes and assessed for VGF expression at 0-72 hours post-heat stress(N>=3 experiments). Orthotopic N1S1 HCC bearing rats were randomized to sham or laser-thermal ablation (3 wattsx90s) and liver/serum were harvested at 0-7 days postablation for analysis of VGF expression(N>=6 per group). Serum was collected from patients undergoing thermal ablation for HCC(N=16) at baseline, 3-6 and 18-24 hours post ablation and analyzed for VGF expression. Data were analyzed using ordinary or repeated measures one-way analysis of variance, and post-hoc pairwise comparison with Dunnett's test.Results: Moderate heat stress induced time-dependent VGF mRNA (3-15-fold; p<0.04) and protein expression and secretion(3.1-3.3-fold; p<0.05). Thermal ablation induced VGF expression at the hepatic ablation margin at 1 and 3 days post ablation but not remote from the ablation zone or distant intrahepatic lobe There was no detectable serum VGF following hepatic thermal ablation in rats and no increase in serum VGF following HCC thermal ablation in patients at 3-6 and 18-24 hours post-ablation compared to baseline(0.71-fold and 0.63-fold, p=0.27 and p=0.16, respectively).Conclusion: Moderate heat stress induces expression and secretion of VGF in HCC cells and hepatocytes in vitro and thermal ablation induces local intrahepatic but not distant intrahepatic or systemic VGF expression in vivo. PMID- 29973306 TI - Evaluating Web-based Educational Modules on Genetic Testing for Autism among Parents of Children with Autism. AB - Objectives New genomic tests for Autism Spectrum Disorders (ASD) are being offered to children and families with ASD; however, these tests are underutilized by parents of children affected with ASD. Methods We designed, implemented and pilot-tested an educational intervention to enhance parental genetic knowledge and assist them to make informed decisions about genomic testing. We utilized a pre-/post-test design to evaluate genetic knowledge and test perceptions in a sample of parents of children with ASD. Results Fifty-three parents participated in our online training (5 modules) and completed pre- and post-assessments. Our surveys queried knowledge, attitudes, and intention to test. The knowledge section contained questions regarding autism, genes, and genetic testing for autism. The other 2 sections included attitudinal questions about testing as well as parents' behavioral intention to seek genetic testing for autism. Conclusions Our results indicate that knowledge significantly improved following the intervention (p < .001). Although attitude and intention scores changed from pre to post-assessment, these changes were not statistically significant. Our results demonstrate that this first-of-its-kind educational program designed for parents of children with ASD was effective at increasing parents' knowledge related to genomic testing for autism. PMID- 29973307 TI - Do Incentives Promote Action Planning in a Web-based Walking Intervention? AB - Objective In this study, we examine the effect of providing an incentive for engagement in self-regulatory behaviors (ie, action planning), in inactive, office-based university employees participating in an 11-week, Web-based walking intervention. Methods Participants were randomly assigned to either control (intervention only) or incentive (intervention plus incentive; CAD $5.00 e-gift card delivered weekly for completing action plans over 4 weeks) conditions. Cohen's d was used to estimate the effect of the incentive on action planning and a RM-ANOVA examined differences in average steps/day, between the 2 conditions, before, during, and after the 4-week incentive period. Results Sixty-nine participants were included in the analysis (incentive: N = 34; control: N = 35; 88% female; Mage = 40.46+/-10.6 years). A large effect size (d = 1.01) in action plan completion was observed, favoring the incentive condition, with the effect of condition remaining high after incentives were withdrawn (d = 1.0). Greater steps/day favored the incentive condition during the post-incentive period (small effect size; d = 0.28). Conclusions Incentives were effective in encouraging engagement in a self-regulatory strategy (action planning). Future research should examine the optimal incentive structure and timing for engagement. PMID- 29973308 TI - Surprising Advantages of Low Self-Efficacy Revealed in a Sports Nutrition Education. AB - Objectives To determine the influence of educational sports nutrition programs on adolescent athlete's nutritional habits and on the general and academic self efficacy of nutrition students who facilitated the program. MethodsAn intervention framework and a convergent mixed-methods approach were used for this study. A questionnaire to examine knowledge of sports nutrition and an eating diary were used for tracking results at 3 points in time; beginning, end of the program and 3 months follow up. Nutrition students completed questionnaires examining their general and academic self-efficacy at 4 points during the study. Participants included 49 athletes aged 13-15 (26 boys and 23 girls) and 30 nutrition students. ResultsSignificant improvements were found in knowledge and nutrition behavior of athletes and in the general and academic self-efficacy of the nutrition students. ConclusionParticipation in the intervention program led to improvements of the adolescent athletes' nutritional knowledge and behavior. Implementation of the program in the framework of an academic nutrition studies course improved the general and academic self-efficacy of the nutrition students. Use of the RRA approach transformed the students from passive learners to active teachers. PMID- 29973309 TI - Exploring the Relationship between Types of Leisure Activities and Life Satisfaction, Health Perception, and Social Support among Korean Individuals with Physical Disabilities. AB - Objectives The purpose of this study was to examine which types of leisure activities are associated with social support, health perception, and life satisfaction among Korean individuals who have physical disabilities. Methods Using a purposive sampling strategy, a total of 238 individuals who have physical disabilities participated in this study. Results This study showed that participation in cultural activities and volunteer activities predicted life satisfaction. Engagement in cultural and social activities was positively associated with social support from family and friends. In addition, participants who engaged in physical activities and cultural activities are likely to perceive higher health perception. Conclusions Particular types of leisure activities may be related to social support, health perception, and life satisfaction among individuals who have physical disabilities. This study provides insights into how to increase life satisfaction and social support by offering various recreational programs for individuals who have physical disabilities. PMID- 29973310 TI - After Sexual Identity Disclosure: An Ecological Perceptive of LGB Young Adults. AB - Objectives A plethora of research exists concerning determinants prior or during the sexual identity disclosure process; yet, information is limited concerning internal and external experiences after one discloses his or her sexual identity to their social support system. Through the lenses of the Social Ecological Model, the purpose of this study was to further understand the current lived experiences of persons in post-sexual identity disclosure. Methods Semi structured interviews were conducted among 15 lesbian, gay, and bisexual young adults. Sample size was determined by thematic saturation. A semiotic phenomenological procedure was used for analyzing the data. Results Based on the reported experiences after sexual identity disclosure among participants, 7 themes were identified. Themes entailed stereotypical perceptions of sexual identity, improvement in mental health, relationship estrangement, development of new relationships, social support, non-acceptance of sexual orientation, and minority stress. Conclusions Through various theories and models, this study provide recommendations for stakeholders invested in the health of lesbian, gay, and bisexual individuals. PMID- 29973311 TI - Self-reported Health Predicts Hispanic Women's Weight Perceptions and Concerns. AB - Objectives In this study, we examined how self-reported health is related to low income, Hispanic women's underestimation and concerns of weight status. Methods Seventy Hispanic women from Houston-area community centers reported their perceptions and concerns about their weight and health. Height and weight were measured to calculate body mass index. Cross-tabulations and Cohen's kappa determined agreement between women's perception of their weight status and measured weight status. Covariate-adjusted OLS regression models analyzed the association between women's self-reported health as a predictor of weight underestimation and concerns about becoming overweight. Results Forty-three percent of women misperceived their weight status [37% (N = 26) underestimated; 6% (N = 4) overestimated]. Overweight and obese women who reported their health as poor had 84% lower odds of underestimating their weight. Women who reported their health as poor health had 52% lower odds of being concerned about becoming overweight. Conclusions Self-reported poor health predicts perceptions of weight and concerns about future weight gain among low-income Hispanic women. Assessing patients' self-reported health status will allow practitioners to identify who may be at risk for underestimating their weight and being unconcerned about becoming overweight. This knowledge may help practitioners identify patients who would benefit from health education. PMID- 29973312 TI - Developing Text Messages to Reduce Community College Student Alcohol Use. AB - Objectives The aim of this study is to evaluate how community college students with hazardous drinking perceived the usefulness of alcohol protective behavioral strategy text messages (TM-PBS). Methods Community college students with past hazardous single occasion or weekly drinking (N = 48; 60% female) were randomized to receive 2 TM-PBS on 3 typical drinking days per week for 2 weeks selected by: (1) research investigators (ie, based on clinical and theoretical application); (2) participants (ie, messages highly rated at baseline by the participants); or (3) a random process. Prior to 2 typical drinking days per week, immediately after receiving TMs, we asked: "How useful do you think this strategy will be for you when you drink? Text a number from 1 (not useful) to 5 (very useful)." Results Response rates for the 12 messages ranged from 72.9% to 87.5%, with no differences in response rates across selection categories (ie, investigator, participant, random). Investigator-selected messages were rated as less useful than messages that were self-selected by participants or messages that were selected at random. Conclusions TM-PBS chosen a priori by students were perceived as more useful than TM-PBS chosen by investigators, supporting this form of tailoring in alcohol interventions to optimize usefulness. PMID- 29973313 TI - Psychometric Evaluation of the Relapse Situation Efficacy Questionnaire in a Weight Loss Treatment Study. AB - Objectives We assessed the psychometric properties of the Relapse Situation Efficacy Questionnaire - Weight (RSEQ-W) including internal consistency reliability, criterion-related validity (concurrent and predictive validity) and construct validity (convergent validity and factor analysis). Methods We administered the RSEQ-W at baseline, and at 6 and 12 months in a 12-month prospective behavioral weight loss study. Spearman correlations were used to examine the convergent and concurrent validity; multivariate linear regression was used to assess the predictive validity; exploratory factor analysis was conducted using principal component analysis. Results The sample (N = 148) was 90.5% women and 81.1% white with a mean body mass index of 34.1 +/- 4.6 kg/m2. The RSEQ-W showed good internal consistency (Cronbach's alpha = .95) and convergent validity (r = .69). PCA results revealed that the 31 items can be factored into 6 components negative affect, positive affect, social occasions, low focus, activity andlack of energy. Conclusion These results provide preliminary support for the reliability and validity of the RSEQ-W. Future work needs to apply RSEQ-W in studies with larger and more diverse samples and also consider adding more items to the factor lack of energy. PMID- 29973314 TI - Lifetime Depression, Other Mental Illness, and Smoking Cessation. AB - Objectives In this study, we attempt to elucidate the relationship between lifetime mental illness (LMI), particularly a depression diagnosis, and smoking cessation. Methods Data were drawn from a previous study and include LMI, demographics, mood, and smoking cessation outcomes. We evaluated the relationship between multiple LMIs and smoking cessation at 7 months post-intervention, and depression in combination with another LMI. Results At 7 months, the adjusted odds of cessation for those with one LMI, including depression, were 0.74 (p = .102), and for those with 2+ LMIs, 0.69 (p = .037), both in comparison with participants who reported no history of LMI. Among those with 2+ LMIs, the adjusted odds of cessation for those with a depression diagnosis were 0.34 (p = .007) compared to those whose multiple LMIs did not include depression. Conclusions Among smokers seeking cessation treatment, those who had 2+ LMIs were at greater risk of relapse, an effect particularly marked in smokers with depression. This study adds to the literature examining the potential impact of LMI on smokers' ability to quit by considering the potential impact of 2+ LMIs and highlights the potential impact of depression as a risk factor for continued smoking. PMID- 29973315 TI - Smokeless Tobacco Use and Related Factors: A Study in the US Military Population. AB - ObjectivesThe prevalence of smokeless tobacco use in the US military is alarmingly high. We aimed to identify factors related to smokeless tobacco use among active duty service members. Methods Participants (N = 2465) from Fort Bragg Army Base, North Carolina and Lackland Air Force Base, Texas completed a self-administered questionnaire. We performed stepwise logistic regression analysis to identify factors statistically associated with smokeless tobacco use. Results The prevalence of use was higher at the Army base than the Air Force base (32.6% vs 11.6%). White race, cigarette smoking, low perception of harm, and family history of use were significant factors identified at both sites. Compared with users from the Air Force base, users from the army base tended to be current heavy users with longer duration of use, and who started at an older age after joining military and made less effort to quit. Current Department of Defense (DoD) cessation resources were not being utilized by active duty service members. Conclusions We identified statistically significant factors related to smokeless tobacco among active duty service members. The non-utilization of the DoD cessation resources calls for a cessation strategy that meets the special needs of military personnel. PMID- 29973316 TI - Perceptions of Alternative Tobacco Products, Anti-tobacco Media, and Tobacco Regulation among Young Adults: A Qualitative Study. AB - Objectives With increased alternative tobacco product (ATP) use and lagging public health action, we explored perceptions of ATPs, anti-tobacco messaging, and tobacco regulation among young adults. Methods Semi-structured interviews were conducted with 60 Georgia college students aged 18-25 using: (1) cigarettes, little cigars/cigarillos (LCCs), smokeless tobacco, or e-cigarettes >=15 days of the past 30; or (2) hookah >=10 of the past 30 days (due to lower frequency of use). Of 99 participants recruited, 80 consented, and 60 participated. Results Participants were on average 21.01 years old (SD = 2.07), 56.7% women, and 65.0% black; 56.7% reported current use of cigarettes, 43.3% LCCs, 26.7% smokeless tobacco, 45.0% e-cigarettes, and 41.7% hookah. Cigarettes were perceived as most harmful to health and most addictive. E-cigarettes and hookah were generally regarded as lowest risk. Many indicated that ATP risk information was limited or inaccessible and that most anti-tobacco campaigns were irrelevant to ATPs. Participants requested more research and dissemination of evidence regarding ATP risks and need for ATP regulation. Conclusions In light of low risk perceptions regarding ATPs among young adults, research, anti-tobacco campaigns, and regulation must address their known and potential risks. PMID- 29973317 TI - [IL-12 contributes to reconstruction of cellular immune function of tumor patients and mice after chemotherapeutics]. AB - Objective To investigate the recovery effects of IL-12 on the immune suppression induced by chemotherapeutic medicine in patients and mouse with malignant tumors. Methods Peripheral blood mononuclear cells (PBMCs) from tumor patients with or without chemotherapy and healthy donors were stimulated with or without anti-CD3 antibody plus anti-CD28 antibody in the presence or absent of IL-12. The levels of IFN-gamma and TNF-alpha in culture supernatants were detected by enzyme-linked immunosorbent assay (ELISA). The expression of IFN-gamma in different subsets of T cells was analyzed by fluorescence activated cell sorter (FACS). Finally, we established the cisplatin toxicity mouse model and measured the levels of IFN gamma and TNF-alpha by ELISA and FACS. Results PBMCs from the patients with malignant tumors produced significantly lower levels of IFN-gamma and TNF-alpha than PBMCs from healthy donors. The production of IFN-gamma and TNF-alpha was higher in pre-chemotherapeutic patients compared with post-chemotherapeutic patients, whereas IL-12 could remarkably recover the production of IFN-gamma and TNF-alpha in the patients with malignant tumors. FACS showed that IL-12 recovered the expression of IFN-gamma by CD4+ and CD8+ T cells in post-chemotherapeutic patients. Finally, the results from the animal studies in vitro and in vivo proved that IL-12 recovered the inhibitory effect of chemotherapeutic drugs on immune function. Conclusion Chemotherapeutics inhibits the immune responses in patients and animals, and IL-12 can recover the suppressive effects of chemotherapeutics on the production of cytokines. Our results indicated that IL 12 might play an important role in the reconstruction of immune function in cancer patients with chemotherapeutics. PMID- 29973318 TI - [Increased expression of HMGB1 and TLR4 in intestinal tissues and intestinal immune dysfunction in severely burned rats]. AB - Objective To investigate the expressions of high mobility group box 1 (HMGB1) and Toll-like receptor 4 (TLR4) in the intestinal tract of severely burned rats and their relationship with intestinal immune function. Methods Forty male SD rats were randomly divided into control group (n=10) and severe burn group (n=30). 60% of the rats' body (the back and ventral side) was burned in the severe burn group, and only anesthesia was performed in normal control group. Rats were sacrificed at 6, 12 and 18 hours after injury in the burn group, while sacrificed immediately after anesthesia in control group. The protein levels of HMGB1 and TLR4 in the intestinal tissue were detected by Western blotting. The purity of total T cells (CD3+ T), as well as the ratio of Th1 to Th2 cell subsets, was measured by flow cytometry. ELISA was performed to detect the concentrations of IFN-gamma, IL-4 and IL-10. Results Compared with the control group, the protein expressions of HMGB1 and TLR4 in the severe burn group were significantly higher than that in the control group at 6, 12 and 18 hours after injury, in a time dependent manner. A positive correlation between HMGB1 and TLR4 protein expressions in the severe burn group was observed. The ratio of Th1 to total T cells was significantly raised at 6, 12 and 18 hours after burn injury, and the ratio of Th2 to total T cells decreased, and the ratio of Th1/Th2 significantly increased. Th1 cell percentage was positively correlated with HMGB1 and TLR4, while Th2 cell percentage was negatively correlated with HMGB1 and TLR4. Compared with the control group, the levels of IFN-gamma and IL-4 in the intestinal tract were significantly elevated at 6, 12 and 18 hours after severe burn injury, while the level of IL-10 was significantly reduced. With the increase of postburn time, the levels of IFN-gamma and IL-4 gradually increased, while the level of IL-10 gradually decreased. Conclusion HMGB1 was recruited in the intestinal tissues to activate TLR4 signaling pathway after severe burn, further activates the downstream signal transcripts and releases a series of inflammatory cytokines to induce inflammatory response, which is involved in Th1 and Th2 cell mediated immune function obstacle of rats. PMID- 29973319 TI - [Preparation of mouse monoclonal antibody against human B7-1 (CD80) and its inhibitory effect on tumor cells in vitro]. AB - Objective To prepare a mouse anti-human B7-1 monoclonal antibody (mAb) and study its effect on growth and migration of tumor cells naturally expressing human B7-1 (CD80) molecular in vitro. Methods BALB/c mice were immunized with L929-B7-1 cells transfected with human B7-1 gene and mAbs were prepared by B lymphocyte hybridoma technology. Then, the recognition ability of mAb to tumor cells expressing membrane B7-1 was detected by flow cytometry. Different concentrations of mAbs (5, 10, 20, 40 MUg/mL) were added into Daudi, Raji, and 8266 cells to investigate the anti-proliferation effect by MTT assay. TranswellTM assay was used to analyze the effect of mAb on tumor cell migration in vitro, and flow cytometry was used to analyze the induction effect of mAb on apoptosis of tumor cells. Results A hybridoma cell stably secreting mouse anti-human B7-1 mAb was successfully obtained and named 5G10. The binding rates to tumor cells Daudi, Raji, 8266, U266, Bel-7402 and MCF-7 were (96.3+/-2.12)%, (95.7+/-1.79)%, (96.8+/ 2.48)%, (23.2+/-2.35)%, (1.68+/-0.35)%, (0.55+/-0.04)%, respectively. Compared with control group, 20 MUg/mL 5G10 mAb significantly inhibited the proliferation of Daudi, Raji and 8266 cells, reduced their migration, and increased cell apoptosis rates remarkably. Conclusion The 5G10 mAb can specifically recognize and bind to membrane B7-1, inhibit the proliferation, migration and promotes apoptosis of tumor cells in vitro. PMID- 29973320 TI - [Abnormal structure and dysfunction of platelets in CD226 knockout mice]. AB - Objective To study the regulatory effect of co-stimulatory molecule CD226 on platelet function in mice. Methods The 40-week-old CD226 knockout (CD226KO) mice were used as an experimental group and the wild wild-type (WT)C57BL/6 mice at the same age were designated as a control group. Caudal venous blood was taken for platelet counting. Tail tips of the mice were snipped for the bleeding time measurement. Ultrastructure of platelets was examined by transmission electron microscope. Carotid artery thrombosis model was established by the induction of ferric chloride in mice, to test the difference of platelet function in CD226KO and WT mice. Human platelet protein was harvested for immunoprecipitation (IP) and mass spectrometry analyses to screen the CD226-interactive proteins. Results Aged mice in CD226KO group had significantly lower platelet counts and longer bleeding time compared with the mice in WT group at the same age. Moreover, the scanning electron microscopic image of platelet also indicated that CD226 knockout induced the shrinkage and distortion of platelet endoplasmic reticulum. The FeCl3-induced thrombosis model showed that the thrombosis time was significantly longer in CD226KO mice, and thrombus stability was significantly reduced. Mass spectrometry indicated that platelet CD226 interacted with BDNF, FABP5, ApoA1 and other proteins. Conclusion Knockout of CD226 gene significantly affects platelet function in mice, and CD226 molecules are involved in the exertion of biological activity of platelets. PMID- 29973321 TI - [Establishment of a chemiluminescent immunoassay(CLIA) and its application]. AB - Objective To establish a chemiluminescent immunoassay(CLIA) for the detection of soluble CD100 (sCD100) and evaluate its preliminary clinical application for the detection of sCD100 in clinical cerebrospinal fluid samples. Methods Ascites were prepared using two hybridomas secreting monoclonal antibody (mAb) to CD100, and the antibodies were purified. Based on sandwich ELISA, the experiment conditions were optimized and the CLIA for detecting sCD100 was established. The sensitivity and stability of CLIA were evaluated. The level of sCD100 in cerebrospinal fluid samples of patients (n=18) was detected. Results CLIA exhibited high performance within a dynamic range 0.098-12.5 ng/mL, and the limit of detection (LOD) was 0.12 ng/mL. The intra-assay coefficient variations (CV) were between 3.8%-6.6% and inter-assay CV were 6.2%-14.1%. Using CLIA, we examined the level of sCD100 in cerebrospinal fluid of viral encephalitis patients. The results showed the level of sCD100 in the patients were higher than that in normal controls. Two cases of them were 9.4 and 13.8 times higher than the normal mean value of control group. Conclusion A rapid, sensitive and stable CLIA for detecting sCD100 has been successfully established, which can be used for the quantitative detection of trace sCD100 in cerebrospinal fluid samples. PMID- 29973322 TI - [Metabolic analysis of serotonin system in serum and gastric tissues of ovalbumin induced allergic mice]. AB - Objective To investigate the changes of 5-HT (serotonin) signaling system in allergic diarrhea mice sensitized with ovalbumin (OVA). Methods The seven-to eight-week-old BALB/c female mice were randomly divided into model group, sodium chromate group and negative control group. The model group and sodium chromate group were intraperitoneally injected with OVAI (50 MUg per mouse) at day 0 and day 14 respectively. And starting from the 28th day, OVAII was orally administered (50 mg per mousee) every other day (8 times in total), and the sodium chromate group was given the sodium chromate (78.0 mg/kg) before the oral administration of OVA every other day (8 times in total). The allergic symptoms, including the systemic score, faeces score and body temperature were recorded following the OVA administration for sensitization. The mice were executed 43 days later. Eyeball blood sample was collected, and then serum was seperated by centrifugation, the gastric tissues was taken out. The serum OVA-specific IgE (OVA-SIgE) was detected by ELISA. The serum content of 5-HT and its related metabolites including kynurenine (KYN), tryptophan (TRP), 5-hydroxytryptophan (5 HTP), and 5-hydroxyindoleacetic acid (5-HIAA) were examined by liquid chromatography-mass spectrometry (LC-MS). The mRNA levels of tryptophan hydroxylase-1 (TPH1), indolamine-2, 3-dioxygenase 1 (IDO1), monoamine oxidase A (MAO-A), 5-hydroxytryptamine 1A receptor (HTR1A), 5-hydroxytryptamine 3 receptor (HTR3), 5-hydroxytryptamine 4 receptor (HTR4) and serotonin reuptake transporter (SERT) were determined by real-time quantitative PCR. Results OVA sensitization caused severe allergic diarrhea in mice. Serum OVA-SIgE increased significantly in mice sensitized by OVA. serum KYN increased remarkably, while 5-HT, 5-HIAA and 5-HTP decreased significantly. The mRNA levels of IDO1, HTR1A and HTR3A increased in gastric tissues, while the levels of TPH1 and MAO-A mRNA decreased. Compared with the model group, the sodium chromate group had lowed systemic score, faeces score, body temperature and OVA-SIgE as well as diarrhea rate. The mRNA levels of 5-HIAA and MAO-A increased in the gastric tissues, and IDO1, 5-HT1A and 5-HT3A mRNAs decreased in the sodium chromate group. Conclusion The serotonin signaling system in ovalbumin-sensitized allergic diarrhea mice has been activated. The administration of sodium chromate can alleviate the allergic symptoms, and change the levels of serum metabolites and the gene expressions of the 5-HT metabolic pathway and its receptors in the stomach. PMID- 29973323 TI - [Decline of secretory function of TM4 Sertoli cells stimulated by D-galactose in mice and its mechanism]. AB - Objective To establish a model of decline in secretion of senescent TM4 cells in vitro induced by D-galactose (D-gal). Methods Different concentrations of D-Gal (25, 50, 100, 150, 200 and 250 mmol/L) were used to induce TM4 cell senescence. The viability of TM4 cells was detected by MTT assay. The cell cycle was analyzed by flow cytometry. The cell morphology was observed by light microscopy and the percentage of senescent cells was observed by senescence-associated beta galactosidase (SA-beta-Gal) staining. The mRNA expression levels of P21, P16, glial-derived neurotrophic factor (GDNF) and stem cell factor (SCF) were detected by reverse transcription PCR. The protein expression levels of GDNF, SCF, nuclear factor erythroid 2 like 2 (NRF2), NAD(P)H dehydrogenase [quinone] 1 (NQO-1) and heme oxygenase-1 (HO-1) were detected by Western blot analysis. Results Compared with normal control group, D-Gal stimulation significantly decreased the cell viability in a concentration-dependent manner. The arrest of D-Gal-treated cells in G1 phase of cell cycle significantly increased, while it significantly decreased in S phase, and D-Gal induced cell cycle arrest at G0/G1 phase in TM4 cells. The percentages of SA-beta-Gal positive cells increased significantly. The expression levels of P21 and P16 mRNAs were significantly up-regulated. The mRNA and protein levels of GDNF and SCF-1 were significantly down-regulated. Furthermore, the expression levels of oxidative stress-related protein NRF2, HO-1 and NQO-1 were significantly reduced. Conclusion The model of declined secretion function of senescent TM4 cells induced by D-Gal we established is stable and reliable. Its mechanism may be related to the down-regulation of NRF2 signaling pathway. PMID- 29973324 TI - [Knockdown of Polo-like kinase 1 (PLK1) inhibits the growth of cervical cancer HeLa cells]. AB - Objective To investigate the effect of knockdown of Polo-like kinase 1 (PLK1) on the growth of HeLa cells. Methods Flow cytometry was used to evaluate the delivery efficiency of siGFP by LAH4-L1 vector. Reverse transcription PCR was used to detect the mRNA level of PLK1. Western blot analysis was performed to detect the level of PLK1 protein. And CCK-8 assay was used to detect the viability and growth of HeLa cells. Results About 70% gene and protein silence was achieved in HeLa cells after LAH4-L1-siPLK1 nanocomplexes transfection, and the proliferation of HeLa cells was significantly inhibited. Besides, the high delivery efficiency of LAH4-L1 could maintain at a stable level. Conclusion Knockdown of PLK1 in HeLa cells can inhibit the growth of HeLa cells. LAH4-L1 is a good gene delivery vector. PMID- 29973325 TI - [Up-regulation of GPR37 promotes the proliferation of human glioma U251 cells]. AB - Objective To investigate the impact of up-regulated G protein-coupled receptor 37 (GPR37) on the proliferation of human glioma U251 cells. Methods The recombinant plasmid of GPR37 gene was constructed and transfected into U251 cells by liposome to up-regulate the expression of GPR37. Real-time quantitative PCR was used to detect the mRNA level of GPR37; Western blotting was used to detect the protein levels of GPR37 and phosphorylated AKT[p-AKT(Ser473)]; CCK-8 assay was used to detect the proliferation of U251 cells; and flow cytometry was performed to detect the cell cycle of U251 cells. Results Compared with the negative control group, the mRNA and protein levels of GPR37 in GPR37 overexpressing cells significantly increased. After up-regulating GPR37 in U251 cells, we found that the proliferation of U251 cells significantly increased, that the proportion of G1/G0 phase cells decreased, that the proportion of cells in S phase and G2 phase increased, and that the level of p-AKT (Ser473) was enhanced. Conclusion Up regulation of GPR37 in U251 cells can accelerate U251 cell cycle progression, activate AKT pathway and promote cell proliferation. PMID- 29973326 TI - [Blockage of mTOR signaling pathway by homoharringtonine inhibits proliferation and induces apoptosis of HT29 human colorectal tumor cells]. AB - Objective To investigate the molecular mechanisms underlying the effect of homoharringtonine (HHT) on the proliferation and apoptosis in HT29 human colorectal tumor cells. Methods HT29 cells were treated by 0, 0.007812, 0.015625, 0.03125, 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8 MUg/mL HHT for 24, 48 and 72 hours. CCK-8 assay was used to assess the cell viability. Colony formation assay was performed to detect the cell proliferation ability. Flow cytometry was used to analyze cell apoptosis. Hoechst33258 fluorescent staining was used to observe the morphology of the cell nuclei. The real-time quantitative PCR was used to detect the mRNA expressions of BAX, Bcl2, caspase-3, caspase-9, mammalian target of rapamycin (mTOR), PI3K, pyruvate dehydrogenase kinase-1 (PDK1), protein kinase B (AKT), raptor, rictor. The protein levels of Bax, Bcl2, pro-caspase-3, cleaved caspase 3 (c-caspase-3), pro-caspase-9, cleaved caspase-9 (c-caspase- 9), poly(ADP-ribose)polymerase (PARP), cleaved PARP (c-PARP), mTOR, raptor, rictor, PI3K, PDK1, AKT, p-AKT were detected by Western blotting. Results Compared with the control group, the proliferation of HT29 cells was inhibited when treated with HHT. Meanwhile, the nuclear fragmentation, chromatin condensation, and apoptotic body of the cells could be observed. Treatment of HHT could increase the mRNA expressions of BAX/Bcl2, caspase-3, caspase-9 and raptor, and decrease PI3K, AKT and rictor in the HT29 cells. The protein levels of pro-caspase-3, pro caspase-9, PARP, PI3K, PDK1, AKT, mTOR, and rictor were down-regulated, and the c caspase-3, c-caspase-9, c-PARP, BAX and raptor were up-regulated. Conclusion HHT has the function of inhibiting the HT29 cell proliferation and inducing its apoptosis by blockage of mTOR signaling pathway. PMID- 29973327 TI - [Lycorine inhibits the proliferation and promotes apoptosis of SGC-7901 gastric cancer cells by downregulating expression of cyclin D1]. AB - Objective To investigate the effect of lycorine on the proliferation and apoptosis of gastric cancer SGC-7901 cells. Methods Effect of lycorine on the proliferation of SGC-7901 cells and 50% inhibitory concentration (IC50) of lycorine were determined by CCK-8 assay. SGC-7901 cells were treated with IC50 lycorine, and 48 hours later, cell cycle and apoptosis were detected by flow cytometry, and the level of cyclin D1 mRNA and protein was detected by real-time fluorescence quantitative PCR and Western blot analysis. Results Lycorine obviously inhibited the proliferation of SGC-7901 gastric cancer cells in a concentration- or time-dependent manner. The IC50 of 24 hours and 48 hours to gastric cancer cells treated with lycorine was (20.85+/-2.36) MUmol/L and (13.29+/-1.28) MUmol/L, respectively. The cell cycle was arrested in G0/G1 phase, the apoptosis rate of cells increased, and the level of cyclin D1 mRNA and protein decreased significantly 48 hours after the treatment with 13 MUmol/L lycorine. Conclusion Lycorine can inhibit the proliferation of SGC-7901 gastric cancer cells, induce cell cycle arrest in G0/G1 phase and promote cell apoptosis. The mechanism may be related to the down-regulation of cyclin D1 expression. PMID- 29973328 TI - [Resveratrol promotes ATP production and the proliferation of human granulosa cells in vitro]. AB - Objective To explore the effects of resveratrol (Res) on the proliferation and ATP production of human ovarian granulosa cells in vitro. Methods Human follicular granulosa cells obtained from the follicle fluid of infertile patients were purified and identified by immunocytochemistry for follicle stimulating hormone receptor (FSHR), and then cultured with medium in vitro. The cells were divided into a blank control group, a solvent control group (DMSO 30 MUmol/L), and Res-treated group (10, 20 and 30 MUmol/L). Cell viability was detected by CCK 8 assay. Cellular ATP levels were measured using the ATP assay kit after 24 hours in Res-treated group (10 MUmol/L) and control group. Results FSHR was immunoreactive-positive in cytoplasm of 90% isolated cells. The proliferation of granulosa cells reached the peak during 24 to 72 hours. Compared with the control group, the proliferation activity of the human follicular granulosa cells treated with Res (10, 20 and 30 MUmol/L) for 24 hours significantly increased. The level of ATP in the Res-treated group (10 MUmol/L) increased compared with the control group after treatment with Res for 24 hours. Conclusion Resveratrol promotes the proliferation activity and increases the ATP production of human granulosa cells in vitro. PMID- 29973329 TI - [A set of methods of amplification of human monoclonal antibody heavy and light chain genes from one single B cell]. AB - Objective To develop a set of methods of amplifying the natural paring heavy and light chain genes from one single B cell. Methods Yanhuang (YH) cells were the first whole genome sequenced human cells of Asian origin. With the immortalized cell lines as the raw material, single CD19+ B cells were sorted into individual PCR tubes by fluorescence-activated cell sorting (FACS). Then its total RNA was released by the lysis buffer, and reverse transcribed. With the cDNA as the templates, the pairing heavy and light chains from the same B cells were amplified by two-step nested PCRs to acquire their variable region sequences. Results Amplifying methodology has been successfully developed for acquiring single cell BCR genes, and the success rate was greater than 80%. The sorted single B cells could be saved in -80DegreesCelsius for up to two weeks, and then successfully amplified. The PCR products in the same tube were TA-cloned and identified by Sanger sequencing, including the heavy and light chain pairing information. A set of effective primers were reported and released in this study. Conclusion A set of methods were successfully developed for amplifying the natural paring heavy and light genes with the beginning of one single B cell. PMID- 29973330 TI - Only recent sexual partners contribute to oropharyngeal gonorrhoea positivity: the number of sexual partners over different time periods as an indicator of gonorrhoea and chlamydia infection duration among men who have sex with men. AB - Background: Mathematical models have demonstrated that the majority of gonococcal transmission is from oropharynx to oropharynx (i.e. kissing) among men who have sex with men (MSM). The aim of this study is to investigate the association between the number of partners within specific time periods and gonorrhoea and chlamydia positivity. Methods: This was a retrospective data analysis of MSM attending the Melbourne Sexual Health Centre between 2007 and 2016. Univariable and multivariable logistic regression analyses, with generalised estimating equations (GEE), were performed to determine if the number of partners within specified time periods was associated with site-specific gonorrhoea and chlamydia positivity. Results: There were 45933 consultations which included 15197 MSM. Oropharyngeal gonorrhoea positivity was associated with the number of partners in the past 3 months, but not the number of partners 4-12 months ago; men who had >=6 partners in the past 3 months had significantly higher odds of acquiring oropharyngeal gonorrhoea (aOR 1.93; 95% CI 1.61-2.31), but this was not the case for men who had >=6 partners 4-12 months ago. Anorectal gonorrhoea and chlamydia and urethral chlamydia were associated with the number of partners in both time periods after adjusting for age and condom use. Conclusions: The association of oropharyngeal gonorrhoea with the number of recent partners, but not partners from an earlier period, unlike anorectal gonorrhoea and anorectal and urethral chlamydia, could be explained by a shorter duration of oropharyngeal gonococcal infection. Annual screening for gonorrhoea may be insufficient to materially reduce oropharyngeal prevalence. PMID- 29973331 TI - Access to sexual health services after the rapid roll out of the launch of pre exposure prophylaxis for HIV in Melbourne, Australia: a retrospective cross sectional analysis. AB - : Background On 26 July 2016, Victoria began a large study of HIV pre-exposure prophylaxis, called PrEPX, that involved the creation of around 2600 appointments over 3 months across multiple sites in Melbourne, Australia. At this time, the Melbourne Sexual Health Centre (MSHC) appeared to have a larger demand on its services. The aim of the present study was to determine whether this apparent increase in demand was substantially different from other demand fluctuations. METHODS: Patients presenting to the MSHC from 2014 to 2016 were reviewed. Demographic characteristics, sexual risks and sexually transmitted infection diagnoses were extracted from the clinical database. RESULTS: There were 115522 walk-in presentations for care and a rise in presentations in the week following the launch of the PrEPX study, but at least six similar peaks occurred that year. The peak coinciding with the launch of PrEPX was only apparent for men who have sex with men. There was a substantial increase in the proportion of patients who could not be seen (i.e. triaged out), from 10% in the week before PrEPX to 22.2% in the second week after, but this was primarily due to staff absences. At the time of the PrEPX study, data were collected on the duration of symptoms for common conditions and found no significant (P>0.29) change in the average duration of symptoms compared with that seen before the PrEPX launch. CONCLUSIONS: The increase in the number of medical consultations required for the PrEPX study did not result in excessive demand for public sexual health services. PMID- 29973332 TI - Privacy, Trust, and Data Sharing in Web-Based and Mobile Research: Participant Perspectives in a Large Nationwide Sample of Men Who Have Sex With Men in the United States. AB - BACKGROUND: Modern research is heavily reliant on online and mobile technologies, which is particularly true among historically hard-to-reach populations such as gay, bisexual, and other men who have sex with men (GBMSM). Despite this, very little empirical research has been published on participant perspectives about issues such as privacy, trust, and data sharing. OBJECTIVE: The objective of our study was to analyze data from an online sample of 11,032 GBMSM in the United States to examine their trust in and perspectives on privacy and data sharing within online and mobile research. METHODS: Participants were recruited via a social networking site or sexual networking app to complete an anonymous online survey. We conducted a series of repeated measures analyses adjusted for between person factors to examine within-person differences in the following: (1) trust for guarding personal information across different venues (eg, online research conducted by a university vs. an online search engine); (2) privacy concerns about 12 different types of data for three distinct data activities (ie, collection by app owners, anonymous selling to third parties, and anonymous sharing with researchers); and (3) willingness to share those 12 different types of data with researchers. Due to the large sample size, we primarily reported measures of effect size as evidence of clinical significance. RESULTS: Online research was rated as most trusted and was more trusted than online and mobile technology companies, such as app owners and search engines, by magnitudes of effect that were moderate-to-large (etapartial2=0.06-0.11). Responding about 12 different types of data, participants expressed more concerns about data being anonymously sold to third-party partners (mean 7.6, median 10.0) and fewer concerns about data being collected by the app owners (mean 5.8, median 5.0) or shared anonymously with researchers (mean 4.6, median 3.0); differences were small-to-moderate in size (etapartial2=0.01-0.03). Furthermore, participants were most willing to share their public profile information (eg, age) with researchers but least willing to share device usage information (eg, other apps installed); the comparisons were small-to-moderate in size (etapartial2=0.03). CONCLUSIONS: Participants reported high levels of trust in online and mobile research, which is noteworthy given recent high-profile cases of corporate and government data security breaches and privacy violations. Researchers and ethical boards should keep up with technological shifts to maintain the ability to guard privacy and confidentiality and maintain trust. There was substantial variability in privacy concerns about and willingness to share different types of data, suggesting the need to gain consent for data sharing on a specific rather than broad basis. Finally, we saw evidence of a privacy paradox, whereby participants expressed privacy concerns about the very types of data-related activities they have likely already permitted through the terms of the apps and sites they use regularly. PMID- 29973333 TI - Web-Based Immersive Patient Simulator as a Curricular Tool for Objective Structured Clinical Examination Preparation in Surgery: Development and Evaluation. AB - BACKGROUND: Objective Structured Clinical Examination is a standard method of testing declarative and process knowledge in clinical core competencies. It is desirable that students undergo Objective Structured Clinical Examination training before participating in the exam. However, establishing Objective Structured Clinical Examination training is resource intensive and therefore there is often limited practice time. Web-based immersive patient simulators such as ALICE (Artificial Learning Interface of Clinical Education) can possibly fill this gap as they allow for the training of complex medical procedures at the user's individual pace and with an adaptable number of repetitions at home. ALICE has previously been shown to positively influence knowledge gain and motivation. OBJECTIVE: Therefore, the aim of this study was to develop a Web-based curriculum that teaches declarative and process knowledge and prepares students for a real Objective Structured Clinical Examination station. Furthermore, we wanted to test the influence of ALICE on knowledge gain and student motivation. METHODS: A specific curriculum was developed in order to implement the relevant medical content of 2 surgical Objective Structured Clinical Examination stations into the ALICE simulator framework. A total of 160 medical students were included in the study, where 100 students had access to ALICE and their performance was compared to 60 students in a control group. The simulator performance was validated on different levels and students' knowledge gain and motivation were tested at different points during the study. RESULTS: The curriculum was developed according to the Kern cycle. Four virtual clinical cases were implemented with different teaching methods (structured feedback, keynote speech, group discussion, and debriefing by a real instructor) in order to consolidate declarative and process knowledge. Working with ALICE had significant impact on declarative knowledge gain and Objective Structured Clinical Examination performance. Simulator validation was positive for face, content, construct, and predictive validity. Students showed high levels of motivation and enjoyed working with ALICE. CONCLUSIONS: ALICE offers Web-based training for Objective Structured Clinical Examination preparation and can be used as a selective didactic intervention as it has positive effect on knowledge gain and student motivation. PMID- 29973334 TI - Online Decision Support Tool for Personalized Cancer Symptom Checking in the Community (REACT): Acceptability, Feasibility, and Usability Study. AB - BACKGROUND: Improving cancer survival in the UK, despite recent significant gains, remains a huge challenge. This can be attributed to, at least in part, patient and diagnostic delays, when patients are unaware they are suffering from a cancerous symptom and therefore do not visit a general practitioner promptly and/or when general practitioners fail to investigate the symptom or refer promptly. To raise awareness of symptoms that may potentially be indicative of underlying cancer among members of the public a symptom-based risk assessment model (developed for medical practitioner use and currently only used by some UK general practitioners) was utilized to develop a risk assessment tool to be offered to the public in community settings. Such a tool could help individuals recognize a symptom, which may potentially indicate cancer, faster and reduce the time taken to visit to their general practitioner. In this paper we report results about the design and development of the REACT (Risk Estimation for Additional Cancer Testing) website, a tool to be used in a community setting allowing users to complete an online questionnaire and obtain personalized cancer symptom-based risk estimation. OBJECTIVE: The objectives of this study are to evaluate (1) the acceptability of REACT among the public and health care practitioners, (2) the usability of the REACT website, (3) the presentation of personalized cancer risk on the website, and (4) potential approaches to adopt REACT into community health care services in the UK. METHODS: Our research consisted of multiple stages involving members of the public (n=39) and health care practitioners (n=20) in the UK. Data were collected between June 2017 and January 2018. User views were collected by (1) the "think-aloud" approach when participants using the website were asked to talk about their perceptions and feelings in relation to the website, and (2) self-reporting of website experiences through open-ended questionnaires. Data collection and data analysis continued simultaneously, allowing for website iterations between different points of data collection. RESULTS: The results demonstrate the need for such a tool. Participants suggest the best way to offer REACT is through a guided approach, with a health care practitioner (eg, pharmacist or National Health Service Health Check nurse) present during the process of risk evaluation. User feedback, which was generally consistent across members of public and health care practitioners, has been used to inform the development of the website. The most important aspects were: simplicity, ability to evaluate multiple cancers, content emphasizing an inviting community "feel," use (when possible) of layperson language in the symptom screening questionnaire, and a robust and positive approach to cancer communication relying on visual risk representation both with affected individuals and the entire population at risk. CONCLUSIONS: This study illustrates the benefits of involving public and stakeholders in developing and implementing a simple cancer symptom check tool within community. It also offers insights and design suggestions for user-friendly interfaces of similar health care Web-based services, especially those involving personalized risk estimation. PMID- 29973335 TI - Characteristics of Cognitive Behavioral Therapy for Older Adults Living in Residential Care: Protocol for a Systematic Review. AB - BACKGROUND: The prevalence rates of depressive and anxiety disorders are high in residential aged care settings. Older adults in such settings might be prone to these disorders because of losses associated with transitioning to residential care, uncertainty about the future, as well as a decline in personal autonomy, health, and cognition. Cognitive behavioral therapy (CBT) is efficacious in treating late-life depression and anxiety. However, there remains a dearth of studies examining CBT in residential settings compared with community settings. Typically, older adults living in residential settings have higher care needs than those living in the community. To date, no systematic reviews have been conducted on the content and the delivery characteristics of CBT for older adults living in residential aged care settings. OBJECTIVE: The objective of this paper is to describe the systematic review protocol on the characteristics of CBT for depression and/or anxiety for older adults living in residential aged care settings. METHODS: This protocol was developed in compliance with the recommendations of the Preferred Reporting Items for Systematic Review and Meta Analysis Protocols (PRISMA-P). Studies that fulfill the inclusion criteria will be identified by systematically searching relevant electronic databases, reference lists, and citation indexes. In addition, the PRISMA flowchart will be used to record the selection process. A pilot-tested data collection form will be used to extract and record data from the included studies. Two reviewers will be involved in screening the titles and abstracts of retrieved records, screening the full text of potentially relevant reports, and extracting data. Then, the delivery and content characteristics of different CBT programs of the included studies, where available, will be summarized in a table. Furthermore, the Downs and Black checklist will be used to assess the methodological quality of the included studies. RESULTS: Systematic searches will commence in May 2018, and data extraction is expected to commence in July 2018. Data analyses and writing will happen in October 2018. CONCLUSIONS: In this section, the limitations of the systematic review will be outlined. Clinical implications for treating late-life depression and/or anxiety, and implications for residential care facilities will be discussed. TRIAL REGISTRATION: PROSPERO 42017080113; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=80113 (Archived by WebCite at http://www.webcitation.org/70dV4Qf54). REGISTERED REPORT IDENTIFIER: RR1-10.2196/9902. PMID- 29973336 TI - Health Care Robotics: Qualitative Exploration of Key Challenges and Future Directions. AB - BACKGROUND: The emergence of robotics is transforming industries around the world. Robot technologies are evolving exponentially, particularly as they converge with other functionalities such as artificial intelligence to learn from their environment, from each other, and from humans. OBJECTIVE: The goal of the research was to understand the emerging role of robotics in health care and identify existing and likely future challenges to maximize the benefits associated with robotics and related convergent technologies. METHODS: We conducted qualitative semistructured one-to-one interviews exploring the role of robotic applications in health care contexts. Using purposive sampling, we identified a diverse range of stakeholders involved in conceiving, procuring, developing, and using robotics in a range of national and international health care settings. Interviews were digitally recorded, transcribed verbatim, and analyzed thematically, supported by NVivo 10 (QSR International) software. Theoretically, this work was informed by the sociotechnical perspective, where social and technical systems are understood as being interdependent. RESULTS: We conducted 21 interviews and these accounts suggested that there are significant opportunities for improving the safety, quality, and efficiency of health care through robotics, but our analysis identified 4 major barriers that need to be effectively negotiated to realize these: (1) no clear pull from professionals and patients, (2) appearance of robots and associated expectations and concerns, (3) disruption of the way work is organized and distributed, and (4) new ethical and legal challenges requiring flexible liability and ethical frameworks. CONCLUSIONS: Sociotechnical challenges associated with the effective integration of robotic applications in health care settings are likely to be significant, particularly for patient-facing functions. These need to be identified and addressed for effective innovation and adoption. PMID- 29973337 TI - Predicting Social Anxiety From Global Positioning System Traces of College Students: Feasibility Study. AB - BACKGROUND: Social anxiety is highly prevalent among college students. Current methodologies for detecting symptoms are based on client self-report in traditional clinical settings. Self-report is subject to recall bias, while visiting a clinic requires a high level of motivation. Assessment methods that use passively collected data hold promise for detecting social anxiety symptoms and supplementing self-report measures. Continuously collected location data may provide a fine-grained and ecologically valid way to assess social anxiety in situ. OBJECTIVE: The objective of our study was to examine the feasibility of leveraging noninvasive mobile sensing technology to passively assess college students' social anxiety levels. Specifically, we explored the different relationships between mobility and social anxiety to build a predictive model that assessed social anxiety from passively generated Global Positioning System (GPS) data. METHODS: We recruited 228 undergraduate participants from a Southeast American university. Social anxiety symptoms were assessed using self-report instruments at a baseline laboratory session. An app installed on participants' personal mobile phones passively sensed data from the GPS sensor for 2 weeks. The proposed framework supports longitudinal, dynamic tracking of college students to evaluate the relationship between their social anxiety and movement patterns in the college campus environment. We first extracted the following mobility features: (1) cumulative staying time at each different location, (2) the distribution of visits over time, (3) the entropy of locations, and (4) the frequency of transitions between locations. Next, we studied the correlation between these features and participants' social anxiety scores to enhance the understanding of how students' social anxiety levels are associated with their mobility. Finally, we used a neural network-based prediction method to predict social anxiety symptoms from the extracted daily mobility features. RESULTS: Several mobility features correlated with social anxiety levels. Location entropy was negatively associated with social anxiety (during weekdays, r=-0.67; and during weekends, r=-0.51). More (vs less) socially anxious students were found to avoid public areas and engage in less leisure activities during evenings and weekends, choosing instead to spend more time at home after school (4 pm-12 am). Our prediction method based on extracted mobility features from GPS trajectories successfully classified participants as high or low socially anxious with an accuracy of 85% and predicted their social anxiety score (on a scale of 0-80) with a root-mean-square error of 7.06. CONCLUSIONS: Results indicate that extracting and analyzing mobility features may help to reveal how social anxiety symptoms manifest in the daily lives of college students. Given the ubiquity of mobile phones in our society, understanding how to leverage passively sensed data has strong potential to address the growing needs for mental health monitoring and treatment. PMID- 29973338 TI - Large-Scale Dissemination of Internet-Based Cognitive Behavioral Therapy for Youth Anxiety: Feasibility and Acceptability Study. AB - BACKGROUND: Internet-based cognitive behavioral therapy (iCBT) for child and adolescent anxiety has demonstrated efficacy in randomized controlled trials, but it has not yet been examined when disseminated as a public health intervention. If effective, iCBT programs could be a promising first-step, low-intensity intervention that can be easily accessed by young people. OBJECTIVE: The objective of our study was to examine the feasibility and acceptability of a publicly available online, self-help iCBT program (BRAVE Self-Help) through exploration of program adherence, satisfaction, and changes in anxiety. METHODS: This study was an open trial involving the analysis of data collected from 4425 children and adolescents aged 7-17 years who presented with elevated anxiety at registration (baseline) for the iCBT program that was delivered through an open access portal with no professional support. We assessed the program satisfaction via a satisfaction scale and measured adherence via the number of completed sessions. In addition, anxiety severity was assessed via scores on the Children's Anxiety Scale, 8-item (CAS-8) at four time points: baseline, Session 4, Session 7, and Session 10. RESULTS: Participants reported moderate satisfaction with the program and 30% completed three or more sessions. Statistically significant reductions in anxiety were evident across all time points for both children and adolescents. For users who completed six or more sessions, there was an average 4 point improvement in CAS-8 scores (Cohen d=0.87, children; Cohen d=0.81, adolescents), indicating a moderate to large effect size. Among participants who completed nine sessions, 57.7% (94/163) achieved recovery into nonelevated levels of anxiety and 54.6% (89/163) achieved statistically reliable reductions in anxiety. CONCLUSIONS: Participant feedback was positive, and the program was acceptable to most young people. Furthermore, significant and meaningful reductions in anxiety symptoms were achieved by many children and adolescents participating in this completely open-access and self-directed iCBT program. Our results suggest that online self-help CBT may offer a feasible and acceptable first step for service delivery to children and adolescents with anxiety. PMID- 29973339 TI - Tumour growth and immune evasion as targets for a new strategy in advanced cancer. AB - It has become clearer that advanced cancer, especially advanced breast cancer, is an entirely displayed pathological system that is much more complex than previously considered. However, the direct relationship between tumour growth and immune evasion can represent a general rule governing the pathological cancer system from the initial cancer cells to when the system is entirely displayed. Accordingly, a refined pathobiological model and a novel therapeutic strategy are proposed. The novel therapeutic strategy is based on therapeutically induced conditions (undetectable tumour burden and/or a prolonged tumour 'resting state'), which enable an efficacious immune response in advanced breast and other types of solid cancers. PMID- 29973340 TI - Performance of the BMJ learning training modules for ECG interpretation in athletes. AB - To assess the accuracy of interpreting the athlete's ECG both pre and post a series of online training modules among a range of healthcare professionals. 10 512 healthcare professionals from 138 different nations commenced the online course. These were primarily doctors (43%), nurses (18.4%) and other healthcare professionals (3.9%). The users came from 102 different specialities, with General Practice/Family Medicine (24.5%), Cardiology (10.6%), Emergency Medicine (8.7%) and Sports Medicine (6.6%) predominating. Among the 2023 users who completed both the pre-course and post-course test, there was an overall improvement of 15.3% (95% CI 13.9% to 16.6%; p<0.001). 930 completed all four other modules, and these users fared significantly better (18.7% increase; 95% CI 17.3 to 20.0) than those completing no additional modules (11.7% increase; 95% CI 3.3 to 17.7, p=0.036). Demographic analysis showed that while the starting pre test scores varied significantly between profession/specialty groups (57.8% 82.6%), post-test scores were largely consistent (80.8%-84.6%). Although users showed the most improvement when interpreting primary electrical diseases (12.4% increase), it was also an area of notable weakness compared with the modules of normal training-related findings and cardiomyopathies. With the evolving criteria for ECG interpretation eliciting ever improving levels of specificity and sensitivity in the detection of conditions associated with sudden cardiac death among athletes, training is required to ensure the infrastructure and personnel is in place to uphold these standards. The BMJ Learning course presented is a valuable first step and demonstrates that such an online tool can be effective in aiding ECG interpretation among healthcare professionals globally. PMID- 29973341 TI - Heart failure resulting from cancer treatment: still serious but an opportunity for prevention. PMID- 29973342 TI - Education and myopia: assessing the direction of causality by mendelian randomisation. PMID- 29973343 TI - Safety and efficacy of physiologist-led dobutamine stress echocardiography: experience from a tertiary cardiac centre. AB - BACKGROUND: Dobutamine stress echocardiography (DSE) services have traditionally been medically led. In some UK institutions DSE lists are led by physiologists with medical support. In our tertiary cardiac centre at New Cross Hospital (NCH), the DSE service was established by a consultant echocardiographer. Following intensive training and assessment, the Trust approved drug administration by named senior cardiac physiologists. We believe this is the first report of a cardiac physiologist-managed DSE service, including physiologist drug administration. We have assessed the feasibility, safety and validity of this physiologist-led DSE service. METHODS: Retrospective analysis of 333 patients undergoing stress echocardiogram for inducible reversible ischaemia, myocardial viability and valvular heart disease over six months. Patients' case notes review after 18-24 months. RESULTS: 92% of all cases (306) were performed by physiologists. In 300 studies dobutamine was administered. The majority of the referrals were for coronary artery disease (CAD) assessment (281). In 235 cases the study was uncomplicated. 67 patients developed dobutamine related side effects. In 16 cases, complications led to early termination of the study. In two cases, urgent medical review was needed. Of the 281 studies for CAD assessment, 239 were negative for ischaemia, 28 were positive and 14 inconclusive. In 5 out of 28 cases with echocardiogram evidence of inducible ischemia, coronary angiography revealed unobstructed coronary arteries. CONCLUSION: This study demonstrates the safety and effectiveness of this practice and provides potential for the expansion of the physiologists' role and physiologist-led DSE services in other hospitals. PMID- 29973344 TI - Left ventricular diastolic dysfunction: identifying presence by left atrial function. AB - OBJECTIVE: The left atrium (LA) is exposed to left ventricular pressure during diastole. Applying the 2016 American Society of Echocardiography left ventricular diastolic function (LVDF) guidelines; this study aims to investigate whether: left atrial ejection fraction (LAEF) and left atrial active emptying fraction (LAAEF) are markers of diastolic dysfunction (LVDD). METHODS: Retrospective cohort of consecutive patients (n=124) who underwent trans-thoracic echocardiography were studied. Doppler peak velocities of passive (MV E) and active filling (MV A) were measured and ratio E/A calculated. Tissue Doppler imaging parameters of peak early (e') of the septal and lateral mitral annulus were measured, and average E/e' ratio (E/e') calculated. Tricuspid regurgitation velocity, left atrial maximum volume, left atrial minimum volume, and LA volume pre-contraction were measured, allowing calculation of LAEF and LAAEF. Subjects were assigned LVDF categories. RESULTS: Binomial logistic regression model (X2(2) =48.924, p<0.01) determined that LAEF and LAAEF predicted diastolic dysfunction with sensitivity 85.5% and specificity 78%. ROC curves determined good diagnostic accuracy for LAEF and LAAEF to predict LVDD, AUC 0.826 and 0.861 respectively. Logistic regression model (X2= (2)39.525, p<0.01) predicted those patients with E/e'>=14 using LAEF and LAAEF with sensitivity 51.6% and specificity 92.4%. Moderate correlations were found between E/e' and log derivatives of LAEF and LAAEF. CONCLUSIONS: A decline in LAAEF and LAEF is associated with worsening LVDD. PMID- 29973345 TI - Painful swelling of the clavicle. PMID- 29973346 TI - We must support international doctors new to the NHS. PMID- 29973347 TI - Hugh Thomas: fifth time lucky. PMID- 29973348 TI - Point-of-care lung ultrasonography for pneumonia in children: does size really matter? PMID- 29973349 TI - Stem cell-based therapies in neonatology: a new hope. AB - Despite progress made in neonatal intensive care, complications of extreme preterm birth still contribute as the main cause of death to children below 5 years of age. Stem cell-based therapies-mesenchymal stromal cells in particular offer a new hope in preventing and/or restoring organ damage in extreme preterm infants. Early phase clinical trials, fueled by promising preclinical studies on lung and brain injury, have begun. While the enthusiasm in the neonatal community is palpable, much more needs to be learnt about cell-based therapies. Maintaining the balance between temptation and a cautious, evidence-based approach will be critical for cell therapies to fulfil their promise in substantially improving the outcome of extreme preterm infants. PMID- 29973350 TI - Overdiagnosis and overtreatment in rheumatology: a little caution is in order. AB - Overdiagnosis is a term coined by experts in cancer screening to point to indolent cancers detected by screening that would have never led to manifest health problems. Overdiagnosis leads to unnecessary medical care (overtreatment), anxiety and cost. In rheumatology overdiagnosis and overtreatment are hardly discussed but likely present. This viewpoint examines how our prevailing views on the management of inflammatory rheumatic diseases may relate to overdiagnosis and overtreatment. Six paradigms of modern rheumatology will be discussed: early diagnosis, intensive treatment, remission, prognosis and risk stratification, evidence-based rheumatology, and precision medicine. It is concluded that, in spite of the enormous progress that they have brought, all paradigms bear the intrinsic dangers of overdiagnosis and overtreatment. So a little caution is in order. PMID- 29973351 TI - Vertebroplasty versus sham procedure for painful acute osteoporotic vertebral compression fractures (VERTOS IV): randomised sham controlled clinical trial. PMID- 29973353 TI - Adiponectin regulates glycogen metabolism at the human fetal-maternal interface. AB - Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules which are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal-maternal interface have not yet been characterized. Among the various factors acting at the fetal maternal interface, we focused on adiponectin - an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation, and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human VTs. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta. PMID- 29973352 TI - Association between maternal adherence to healthy lifestyle practices and risk of obesity in offspring: results from two prospective cohort studies of mother-child pairs in the United States. AB - OBJECTIVE: To examine the association between an overall maternal healthy lifestyle (characterized by a healthy body mass index, high quality diet, regular exercise, no smoking, and light to moderate alcohol intake) and the risk of developing obesity in offspring. DESIGN: Prospective cohort studies of mother child pairs. SETTING: Nurses' Health Study II (NHSII) and Growing Up Today Study (GUTS) in the United States. PARTICIPANTS: 24 289 GUTS participants aged 9-14 years at baseline who were free of obesity and born to 16 945 NHSII women. MAIN OUTCOME MEASURE: Obesity in childhood and adolescence, defined by age and sex specific cutoff points from the International Obesity Task Force. Risk of offspring obesity was evaluated by multivariable log-binomial regression models with generalized estimating equations and an exchangeable correlation structure. RESULTS: 1282 (5.3%) offspring became obese during a median of five years of follow-up. Risk of incident obesity was lower among offspring whose mothers maintained a healthy body mass index of 18.5-24.9 (relative risk 0.44, 95% confidence interval 0.39 to 0.50), engaged in at least 150 min/week of moderate/vigorous physical activities (0.79, 0.69 to 0.91), did not smoke (0.69, 0.56 to 0.86), and consumed alcohol in moderation (1.0-14.9 g/day; 0.88, 0.79 to 0.99), compared with the rest. Maternal high quality diet (top 40% of the Alternate Healthy Eating Index 2010 diet score) was not significantly associated with the risk of obesity in offspring (0.97, 0.83 to 1.12). When all healthy lifestyle factors were considered simultaneously, offspring of women who adhered to all five low risk lifestyle factors had a 75% lower risk of obesity than offspring of mothers who did not adhere to any low risk factor (0.25, 0.14 to 0.47). This association was similar across sex and age groups and persisted in subgroups of children with various risk profiles defined by factors such as pregnancy complications, birth weight, gestational age, and gestational weight gain. Children's lifestyle did not significantly account for the association between maternal lifestyle and offspring obesity risk, but when both mothers and offspring adhered to a healthy lifestyle, the risk of developing obesity fell further (0.18, 0.09 to 0.37). CONCLUSION: Our study indicates that adherence to a healthy lifestyle in mothers during their offspring's childhood and adolescence is associated with a substantially reduced risk of obesity in the children. These findings highlight the potential benefits of implementing family or parental based multifactorial interventions to curb the risk of childhood obesity. PMID- 29973354 TI - A pulmonologist's guide to understanding network meta-analysis. PMID- 29973355 TI - Right heart catheterisation is still a fundamental part of the follow-up assessment of pulmonary arterial hypertension. PMID- 29973356 TI - Structural brain correlates of obstructive sleep apnoea in older adults at risk for dementia. AB - This study aimed to investigate associations between obstructive sleep apnoea (OSA) and cortical thickness in older adults with subjective and objective cognitive difficulties, who are considered "at-risk" for dementia.83 middle-aged to older adults (51-88 years) underwent neuropsychological testing, polysomnography assessment of OSA and a structural magnetic resonance imaging brain scan. A principal components analysis was performed on OSA measures. Cortical thickness and subcortical volumes were compared to extracted components of "oxygen desaturation" and "sleep disturbance".Oxygen desaturation was significantly related to reduced cortical thickness in the bilateral temporal lobes (left: r=-0.44, p<0.001; right: r=-0.39, p=0.003). Conversely, sleep disturbance was associated with increased thickness in the right postcentral gyrus (r=0.48, p<0.001), pericalcarine (r=0.50, p=0.005) and pars opercularis (r=0.46, p=0.009) and increased volume of the hippocampus and amygdala. Decreased thickness in the bilateral temporal regions was associated with reduced verbal encoding (r=0.28, p=0.010).Given the clinical significance of this sample in terms of dementia prevention, these changes in grey matter reveal how OSA might contribute to neurodegenerative processes in older adults. PMID- 29973357 TI - Impact of sleep alterations on weaning duration of mechanically ventilated patients: how much is bad? PMID- 29973358 TI - Impact of sleep alterations on weaning duration of mechanically ventilated patients: how much is bad? PMID- 29973359 TI - Is right heart catheterisation still a fundamental part of the follow-up assessment of pulmonary arterial hypertension? The argument against. PMID- 29973360 TI - Maternal antibiotic use and child asthma: is the association causal? PMID- 29973361 TI - Substrate relay in an Hsp70-cochaperone cascade safeguards tail-anchored membrane protein targeting. AB - Membrane proteins are aggregation-prone in aqueous environments, and their biogenesis poses acute challenges to cellular protein homeostasis. How the chaperone network effectively protects integral membrane proteins during their post-translational targeting is not well understood. Here, biochemical reconstitutions showed that the yeast cytosolic Hsp70 is responsible for capturing newly synthesized tail-anchored membrane proteins (TAs) in the soluble form. Moreover, direct interaction of Hsp70 with the cochaperone Sgt2 initiates a sequential series of TA relays to the dedicated TA targeting factor Get3. In contrast to direct loading of TAs to downstream chaperones, stepwise substrate loading via Hsp70 maintains the solubility and targeting competence of TAs, ensuring their efficient delivery to the endoplasmic reticulum (ER). Inactivation of cytosolic Hsp70 severely impairs TA translocation in vivo Our results demonstrate a new role of cytosolic Hsp70 in directly assisting the targeting of an essential class of integral membrane proteins and provide a paradigm for how "substrate funneling" through a chaperone cascade preserves the conformational quality of nascent membrane proteins during their biogenesis. PMID- 29973363 TI - Repeatability of vessel density measurements using optical coherence tomography angiography in retinal diseases. AB - AIM: To analyse the repeatability of vessel density (VD) measurements using optical coherence tomography angiography (OCTA) in patients with retinal diseases. METHODS: Two consecutive VD measurements using OCTA were analysed prospectively in patients with retinal diseases (diabetic macular oedema (DME), retinal vein occlusion (RVO) with macular oedema, epiretinal membrane (ERM), wet age-related macular degeneration (AMD)). The intraclass correlation coefficient (ICC), coefficient of variation (CV) and test-retest SD of VD measurements were assessed, and linear regression analyses were conducted to identify factors related to repeatability. RESULTS: A total of 134 eyes were analysed involving 20 eyes with DME, 44 eyes with RVO with macular oedema, 50 eyes with ERM and 20 eyes with wet AMD. The mean age was 64.9 years, and the mean best-corrected visual acuity (BCVA) was 0.24. The mean central macular thickness (CMT) was 391.6 um, and the mean ganglion cell-inner plexiform layer (GC-IPL) thickness was 61.4 um. In all four diseases, the ICC and CV of the full VD were 0.812 and 6.72%, respectively. Univariate analyses showed that the BCVA (B, 8.553; p=0.031), signal strength (B, -1.688; p=0.050), CMT (B, 0.019; p=0.015) and mean GC-IPL thickness (B, -0.103; p=0.001) were significant factors that affected the repeatability. Multivariate analyses of these factors showed a significant result for the GC-IPL thickness. CONCLUSIONS: Measurements of the VD using OCTA showed relatively good repeatability for various retinal diseases. The BCVA, signal strength, CMT and GC-IPL thickness affected the repeatability, so these factors should be considered when analysing the VD. PMID- 29973362 TI - Cezanne/OTUD7B is a cell cycle-regulated deubiquitinase that antagonizes the degradation of APC/C substrates. AB - The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and key regulator of cell cycle progression. Since APC/C promotes the degradation of mitotic cyclins, it controls cell cycle-dependent oscillations in cyclin dependent kinase (CDK) activity. Both CDKs and APC/C control a large number of substrates and are regulated by analogous mechanisms, including cofactor dependent activation. However, whereas substrate dephosphorylation is known to counteract CDK, it remains largely unknown whether deubiquitinating enzymes (DUBs) antagonize APC/C substrate ubiquitination during mitosis. Here, we demonstrate that Cezanne/OTUD7B is a cell cycle-regulated DUB that opposes the ubiquitination of APC/C targets. Cezanne is remarkably specific for K11-linked ubiquitin chains, which are formed by APC/C in mitosis. Accordingly, Cezanne binds established APC/C substrates and reverses their APC/C-mediated ubiquitination. Cezanne depletion accelerates APC/C substrate degradation and causes errors in mitotic progression and formation of micronuclei. These data highlight the importance of tempered APC/C substrate destruction in maintaining chromosome stability. Furthermore, Cezanne is recurrently amplified and overexpressed in numerous malignancies, suggesting a potential role in genome maintenance and cancer cell proliferation. PMID- 29973364 TI - Optic nerve oedema at high altitude occurs independent of acute mountain sickness. AB - BACKGROUND/AIMS: The study aims to investigate changes in the optic nerve sheath diameter (ONSD) at high altitude and to assess correlation to optic disc oedema (ODE) and acute mountain sickness (AMS). This investigation is part of the Tubingen High Altitude Ophthalmology study. METHODS: Fourteen volunteers ascended to 4559 m for 4 days before returning to low altitude. Ultrasonography of ONSD, quantification of optic disc parameters using a scanning laser ophthalmoscope and fluorescein angiography were performed at 341 m and at high altitude. Pearson's coefficient was used to correlate changes in ONSD with the optic disc and AMS. Assessment of AMS was performed using the Lake Louise (LL) and AMS-cerebral (AMS C) scores of the Environmental Symptom Questionnaire-III. All volunteers were clinically monitored for heart rate (HR) and oxygen saturation (SpO2). RESULTS: The mean ONSD at high altitude (4.6+/-0.3 mm, p<0.05) was significantly increased compared with baseline (3.8+/-0.4 mm) and remained enlarged throughout high altitude exposure. This change in ONSD did not correlate with AMS (AMS-C, r=0.26, p=0.37; LL, r=0.21, p=0.48) and high-altitude headache (r=0.54, p=0.046), or clinical parameters of SpO2 (r=0.11, p=0.72) and HR (r=0.22, p=0.44). Increased ONSD did not correlate with altered key stereometric parameters of the optic disc describing ODE at high altitude (r<0.1, p>0.5). CONCLUSION: High-altitude exposure leads to marked oedema formation of the optic nerve independent of AMS. Increased ONSD and ODE reflect hypoxia-driven oedema formation of the optic nerve at high altitude, providing important pathophysiological insight into high altitude illness development and for future research. PMID- 29973365 TI - Preservatives in glaucoma medication. AB - Preservatives continue to be in widespread use in ophthalmic medications due to the convenience they provide, regulatory requirements and the higher cost of alternatives. Benzalkonium chloride (BAK) remains the most commonly used preservative but there is a trend towards the use of preservative-free (PF) drops for glaucoma, although at a higher price. An extensive body of literature explores BAK toxicity on ocular structures in animal and laboratory studies (in vitro and in vivo). Non-randomised controlled studies have provided some supporting evidence of its toxicity in patients, especially in those with pre existing ocular surface disease (OSD) or on multiple medications. However, there have been very few randomised controlled trials that compare the same medication with and without BAK preservative. Several of these trials have never been published in any peer reviewed journals. Notwithstanding, those that have been published, have not demonstrated any clear benefits of the BAK-free formulations. Short duration and exclusion of those with OSD are limitations of these studies. There is a lack of evidence of clinically significant harm from a small number of BAK preserved drops in patients without OSD. This means that generally more expensive PF glaucoma medications should only be recommended for those on poly pharmacy or those with OSD but are not necessarily required for all patients. PMID- 29973366 TI - Accuracy of trained rural ophthalmologists versus non-medical image graders in the diagnosis of diabetic retinopathy in rural China. AB - BACKGROUND/AIMS: To determine the diagnostic accuracy of trained rural ophthalmologists and non-medical image graders in the assessment of diabetic retinopathy (DR) in rural China. METHODS: Consecutive patients with diabetes mellitus were examined from January 2014 to December 2015 at 10 county-level facilities in rural Southern China. Trained rural ophthalmologists performed a complete eye examination, recording diagnoses using the UK National Diabetic Eye Screening Programme (NDESP) classification system. Two field, mydriatic, 45 degrees digital photographs were made by nurses using NDESP protocols and graded by trained graders with no medical background using the NDESP system. A fellowship-trained retina specialist graded all images in masked fashion and served as reference standard. RESULTS: Altogether, 375 participants (mean age 60+/-10 years, 48% men) were examined and 1277 images were graded. Grader sensitivity (0.82-0.94 (median 0.88)) and specificity (0.91-0.99 (median 0.98)), reached or exceeded NDESP standards (sensitivity 80%, specificity 95%) in all domains except specificity detecting any DR. Rural ophthalmologists' sensitivity was 0.65-0.95 (median 0.66) and specificity 0.59-0.95 (median 0.91). There was strong agreement between graders and the reference standard (kappa=0.84-0.87, p<0.001) and weak to moderate agreement between rural doctors and the reference (kappa=0.48-0.64, p<0.001). CONCLUSION: This is the first study of diagnostic accuracy in DR grading among non-medical graders or ophthalmologists in low income and middle-income countries. Non-medical graders can achieve high levels of accuracy, whereas accuracy of trained rural ophthalmologists is not optimal. PMID- 29973368 TI - Helen Bevan: Embracing new horizons. PMID- 29973367 TI - Rapid assessment of avoidable blindness and diabetic retinopathy in people aged 50 years and older in the National Capital District of Papua New Guinea. AB - BACKGROUND/AIMS: To conduct an assessment of avoidable blindness, diabetes mellitus and diabetic retinopathy (DR) in adults aged 50 years and older in the National Capital District (NCD) region of Papua New Guinea (PNG). METHODS: A cross-sectional population-based survey was performed for which 25 clusters of 50 people aged >=50 years were randomly selected from the NCD region. The standardised rapid assessment of avoidable blindness (RAAB) with diabetic retinopathy (+DR) methodology was used. Blindness was defined as presenting visual acuity <3/60 in the better eye. Participants were classified as having diabetes if they were known to have diabetes or if their random blood glucose level was >=200 mg/dL. Dilated fundus examination and Scottish DR grading were performed. RESULTS: In total, 1192 out of 1250 eligible participants (95.4%) were examined. Of these, 7.8% had known or newly diagnosed diabetes. Seventy-one per cent of participants with known diabetes had a blood glucose level >=200 mg/dL, and 82.9% had never had an ophthalmological examination for DR. Prevalence of DR and/or maculopathy was 46.4%. The age-adjusted and sex-adjusted prevalence of diabetes was estimated at 8.1% (95% CI 5.7% to 10.4%) in the population aged 50 years or older in the NCD region of PNG. CONCLUSIONS: Prevalence of diabetes in adults aged 50 years and older was lower than reported elsewhere in the region, and lower than other RAAB+DR surveys. Despite this, the prevalence of DR is high compared with other RAAB+DR surveys and demonstrates the need for increased awareness and accessibility to eye services for people with diabetes. PMID- 29973369 TI - Gosport deaths: lethal failures in care will happen again. PMID- 29973371 TI - Postscript to the Liverpool Care Pathway. PMID- 29973372 TI - Recruiting doctors from countries that have a much more desperate need. PMID- 29973370 TI - Two distinct ontogenies confer heterogeneity to mouse brain microglia. AB - Hoxb8 mutant mice show compulsive behavior similar to trichotillomania, a human obsessive-compulsive-spectrum disorder. The only Hoxb8 lineage-labeled cells in the brains of mice are microglia, suggesting that defective Hoxb8 microglia caused the disorder. What is the source of the Hoxb8 microglia? It has been posited that all microglia progenitors arise at embryonic day (E) 7.5 during yolk sac hematopoiesis, and colonize the brain at E9.5. In contrast, we show the presence of two microglia subpopulations: canonical, non-Hoxb8 microglia and Hoxb8 microglia. Unlike non-Hoxb8 microglia, Hoxb8 microglia progenitors appear to be generated during the second wave of yolk sac hematopoiesis, then detected in the aorto-gonad-mesonephros (AGM) and fetal liver, where they are greatly expanded, prior to infiltrating the E12.5 brain. Further, we demonstrate that Hoxb8 hematopoietic progenitor cells taken from fetal liver are competent to give rise to microglia in vivo Although the two microglial subpopulations are very similar molecularly, and in their response to brain injury and participation in synaptic pruning, they show distinct brain distributions which might contribute to pathological specificity. Non-Hoxb8 microglia significantly outnumber Hoxb8 microglia, but they cannot compensate for the loss of Hoxb8 function in Hoxb8 microglia, suggesting further crucial differences between the two subpopulations. PMID- 29973374 TI - MECHANISMS IN ENDOCRINOLOGY: Bone Marrow Adiposity and bone, a bad romance? AB - Bone marrow adipocytes (BMA) constitute an original and heterogeneous fat depot whose development appears interlinked with bone status throughout life. The gradual replacement of the hematopoietic tissue by BMA arises in a well-ordered way during childhood and adolescence concomitantly to bone growth and continues at a slower rate throughout the adult life. Importantly, BM adiposity quantity is found well associated with BMD (Bone Mineral Density) loss at different skeletal sites in primary osteoporosis such as in ageing or menopause but also in secondary osteoporosis consecutive to anorexia nervosa. Since BMA and osteoblasts originate from a common mesenchymal stem cell, adipogenesis is considered as a competitive process that disrupts osteoblastogenesis. Besides, most factors secreted by bone and bone marrow cells (ligands and antagonists of the Wnt/beta catenin pathway, BMP and others) reciprocally regulate the two processes. Hormones such as oestrogens, glucocorticoids, parathyroid and growth hormones that control bone remodelling also modulate the differentiation and the activity of BMA. Actually, BMA could also contribute to bone loss through the release of paracrine factors altering osteoblast and /or osteoclast formation and function. Based on clinical and fundamental studies, this review aims at presenting and discussing these current arguments that support but also challenge the involvement of BMA in the bone mass integrity. PMID- 29973373 TI - Follicular thyroid lesions: is there a discriminatory potential in the computerized nuclear analysis? AB - BACKGROUND: Computerized image analysis seems to represent a promising diagnostic possibility for thyroid tumors. Our aim was to evaluate the discriminatory diagnostic efficiency of computerized image analysis of cell nuclei from histological materials of follicular tumors. METHODS: We studied paraffin embedded materials from 42 follicular adenomas (FA), 47 follicular variants of papillary carcinomas (FVPC) and 20 follicular carcinomas (FC) by the software ImageJ. Based on the nuclear morphometry and chromatin texture, the samples were classified as FA, FC or FVPC using the Classification and Regression Trees method. RESULTS: We observed high diagnostic sensitivity and specificity rates (FVPC: 89.4% and 100%; FC: 95.0% and 92.1%; FA: 90.5 and 95.5%, respectively). When the tumors were compared by pairs (FC vs FA, FVPC vs FA), 100% of the cases were classified correctly. CONCLUSION: The computerized image analysis of nuclear features showed to be a useful diagnostic support tool for the histological differentiation between follicular adenomas, follicular variants of papillary carcinomas and follicular carcinomas. PMID- 29973375 TI - Long-acting FC-fusion rhGH (GX-H9) shows potential for up to twice-monthly administration in GH-deficient adults. AB - OBJECTIVE: Hybrid Fc-fused rhGH (GX-H9) is a long-acting recombinant human growth hormone (GH) under clinical development for both adults and children with GH deficiency (GHD). We compared the safety, pharmacokinetics and pharmacodynamics of weekly and every other week (EOW) dosages of GX-H9 with those of daily GH administration in adult GHD (AGHD) patients. DESIGN: This was a randomized, open label, active-controlled and dose-escalation study conducted in 16 endocrinology centers in Europe and Korea. METHODS: Forty-five AGHD patients with or without prior GH treatment were enrolled. Patients with prior GH treatments were required to have received the last GH administration at least 1 month prior to randomization. Subjects were sequentially assigned to treatment groups. Fifteen subjects were enrolled to each treatment group and randomly assigned to receive either GX-H9 or Genotropin (4:1 ratio). GX-H9 dosage regimens for Groups 1, 2 and 3 were 0.1 mg/kg weekly, 0.3 mg/kg EOW and 0.2 mg/kg EOW, respectively. All Genotropin-assigned subjects received 6 ug/kg Genotropin, regardless of treatment group. Main outcome analyses included measurements of serum insulin-like growth factor 1 (IGF-I), safety, pharmacokinetics, pharmacodynamics and immunogenicity. RESULTS: Mean GX-H9 peak and total exposure increased with an increase in dose after a single-dose administration. The mean IGF-I response was sustained above baseline over the intended dose interval of 168 h for the weekly and 336 h for the EOW GX-H9 groups. Safety profiles and immunogenicity were not different across the treatment groups and with Genotropin. CONCLUSIONS: GX-H9 has the potential for up to twice-monthly administration. PMID- 29973376 TI - Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up? AB - OBJECTIVE: Few studies of patients with a 45,X/46,XY mosaicism have considered those with normal male phenotype. The purpose of this study was to evaluate the clinical outcome of 45,X/46,XY boys born with normal or minor abnormalities of external genitalia, notably in terms of growth and pubertal development. METHODS: Retrospective longitudinal study of 40 patients followed between 1982 and 2017 in France. RESULTS: Twenty patients had a prenatal diagnosis, whereas 20 patients had a postnatal diagnosis, mainly for short stature. Most patients had stunted growth, with abnormal growth spurt during puberty and a mean adult height of 158 +/- 7.6 cm, i.e. -2.3 DS with correction for target height. Seventy percent of patients presented Turner-like syndrome features including cardiac (6/23 patients investigated) and renal malformations (3/19 patients investigated). Twenty-two patients had minor abnormalities of external genitalia. One patient developed a testicular embryonic carcinoma, suggesting evidence of partial gonadal dysgenesis. Moreover, puberty occurred spontaneously in 93% of patients but 71% (n = 5) of those evaluated at the end of puberty presented signs of declined Sertoli cell function (low inhibin B levels and increased FSH levels). CONCLUSION: This study emphasizes the need to identify and follow-up 45,X/46,XY patients born with normal male phenotype until adulthood, as they present similar prognosis than those born with severe genital anomalies. Currently, most patients are diagnosed in adulthood with azoospermia, consistent with our observations of decreased testicular function at the end of puberty. Early management of these patients may lead to fertility preservation strategies. PMID- 29973377 TI - MRI texture analysis as a predictor of tumor recurrence or progression in patients with clinically non-functioning pituitary adenomas. AB - BACKGROUND: There are limited predictors of prognosis in patients with clinically non-functioning pituitary adenomas (NFPAs). We hypothesized that MRI texture analysis may predict tumor recurrence or progression in patients with NFPAs undergoing transsphenoidal pituitary surgery (TSS). OBJECTIVE: To characterize texture parameters on preoperative MRI examinations in patients with NFPAs in relation to prognosis. METHODS: Retrospective study of patients with NFPAs who underwent TSS at our institution between 2009 and 2010. Clinical, radiological and histopathological data were extracted from electronic medical records. MRI texture analysis was performed on coronal T1-weighted non-enhanced MR images using ImageJ (NIH). MRI texture parameters were used to predict tumor recurrence or progression. Both logistic regression and Cox proportional hazard analyses were conducted to adjust for potential confounders. RESULTS: Data on 78 patients were analyzed. On both crude and multivariable-adjusted analyses, mean, median, mode, minimum and maximum pixel intensity were associated with the risk of pituitary tumor recurrence or progression after TSS. Patients whose tumor mean pixel intensity was above the median for the population had a hazard ratio of 0.44 (95% CI: 0.21-0.94, P = 0.034) for recurrence or progression in comparison with tumors below the median. CONCLUSIONS: Our data suggest that MRI texture analysis can predict the risk of tumor recurrence or progression in patients with NFPAs. PMID- 29973378 TI - MECHANISMS IN ENDOCRINOLOGY: ENDOCRINOLOGY OF OPIOIDS. AB - The use of opioids has grown substantially over the past two decades reaching the dimensions of a global epidemic. These drugs have effects on multiple levels of the endocrine system through mechanisms which are still not fully elucidated, and awareness of their endocrine sequelae is vital for all specialists prescribing or managing patients on them. Hypogonadism is the most well recognised consequence of opioid use (prevalence 21-86%) which, however, may remain undiagnosed with potential adverse outcomes for the patients. Although less frequent, cortisol deficiency can be also found. Furthermore, there is negative impact on bone health (with reduced bone mineral density and increased fracture risk) and occasionally hyperprolactinaemia, whereas the clinical significance of alterations in other hormones remains to be clarified. Discontinuation or reduction of the opioid and, in cases of chronic pain, consideration of alternative therapies for pain relief are potential management options. Hormonal replacement, especially when the above measures are not practically feasible, needs to be considered. Further studies are needed to clearly establish the prevalence of hormonal abnormalities with various regimes, doses and routes of opioids and to address reliably the long-term benefits and risks of hormonal treatment in patients on opioids. Until evidence-based, safe and cost-effective clinical guidelines become available, periodical assessment of the gonadal and adrenal function (particularly when relevant clinical manifestations are present) and evaluation of the bone health status are advised. PMID- 29973379 TI - GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 "DSDnet". AB - The differential diagnosis of differences or disorders of sex development (DSD) belongs to the most complex fields in medicine. It requires a multidisciplinary team conducting a synoptic and complementary approach consisting of thorough clinical, hormonal and genetic workups. This position paper of EU COST (European Cooperation in Science and Technology) Action BM1303 "DSDnet" was written by leading experts in the field and focuses on current best practice in genetic diagnosis in DSD patients. Ascertainment of the karyotpye defines one of the three major diagnostic DSD subclasses and is therefore the mandatory initial step. Subsequently, further analyses comprise molecular studies of monogenic DSD causes or analysis of copy number variations (CNV), or both. Panels of candidate genes provide rapid and reliable results. Whole exome and genome sequencing (WES and WGS) represent valuable methodological developments that are currently in the transition from basic science to clinical routine service in the field of DSD. However, in addition to covering known DSD candidate genes, WES and WGS help to identify novel genetic causes for DSD. Diagnostic interpretation must be performed with utmost caution and needs careful scientific validation in each DSD case. PMID- 29973380 TI - Ensuring our future doctors are resilient. PMID- 29973381 TI - P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. AB - Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen- or tissue damage induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro-inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin-induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti-inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage. PMID- 29973383 TI - Dispatches from the editor: highlights of this edition. PMID- 29973382 TI - Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors. AB - Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context-specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone-dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta-adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg. PMID- 29973384 TI - Owner and veterinary surgeon perspectives on the roles of veterinary nurses and receptionists in relation to small animal preventive healthcare consultations in the United Kingdom. AB - Veterinary receptionists and veterinary nurses rarely feature in published practice-based research, yet are integral to small animal veterinary practice in the UK. The aim of this study was to investigate the perspectives of UK-based owners and veterinary surgeons about veterinary nurses and receptionists in relation to their role in preventive healthcare. Semistructured telephone interviews were conducted with 15 dog and cat owners and 14 veterinary surgeons. Interview transcripts were thematically analysed. Reception staff were identified as having a range of important roles, from rapport building to providing healthcare information and advice. The perceived importance of those roles appeared to differ between owners and veterinary surgeons. Veterinary nurses were described as performing a diversity of roles in relation to preventive healthcare, both in the reception area and in the consulting room. Many owners, and some veterinary surgeons, expressed uncertainty about the remit and status of veterinary nurses in relation to providing veterinary advice. This study identifies for the first time the degree of responsibility for preventive healthcare given to veterinary receptionists and veterinary nurses in UK small animal practices. Further work is needed involving reception and nursing staff to fully appreciate and define their roles in small animal practice. PMID- 29973386 TI - Thrombolysis in patients with WAKE-UP or unknown time of stroke onset: ready for prime time? PMID- 29973387 TI - MACRA 2.5: the legislation moves forward. AB - The Medicare and CHIP Reauthorization Act of 2015 remains the payment policy law of the land. 2017 was the first year in which performance reporting will tangibly impact future physician payments. The Centers for Medicare & Medicaid Services (CMS) considers 2017 and 2018 transitional years before full implementation in 2019. As such, 2018 increases the reporting requirements over 2017 in the form of a gradual phase-in while introducing several key changes and new elements. Indeed, it is the nature of the transition itself that led to the somewhat unique title of this manuscript, i.e., MACRA 2.5. Stakeholder feedback to the CMS regarding the program has ranged widely from the elimination of core components to expanding reporting to non-government payers. This article explores the potential impact on neurointerventional physicians. PMID- 29973388 TI - Person-centred care and HIV: challenges and solutions. AB - Person-centred consultations (PCCs) are fundamental to effective healthcare communication, and its use is embedded within key clinical guidance. There are three aspects to PCC: use of the best available research evidence, clinical expertise of the clinician and the patient's circumstances, goals, values and wishes. Balancing theses three aspects in the context of HIV prevention and management can be challenging, and we use three case examples to highlight these. PMID- 29973389 TI - Developing an ethics framework for living donor transplantation. AB - Both living donor transplantation and human subjects research expose one set of individuals to clinical risks for the clinical benefits of others. In the Belmont Report, the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research (National Commission) articulated three principles to serve as the basis for a research ethics framework: respect for persons, beneficence and justice. In contrast, living donor transplantation lacks a framework. In this manuscript, we adapt the three principles articulated in the Belmont Report to serve as the foundation for an ethics framework for living donor transplantation which we supplement with the principles of vulnerability and responsibility. The National Commission supported additional protections for vulnerable groups of potential research participants. In 2001, Kenneth Kipnis effectively argued that the concept of vulnerable groups failed to explore in what ways particular groups of people were vulnerable, thereby risking unnecessary protections for some and inadequate protections for others. He proposed a taxonomy that explored different types of vulnerabilities that all research participants may experience to provide a more robust framework for human subjects protections, which we adapt to living donors. Robert Goodin claims that health professionals, who stand in special relationship with patients, are responsible for promoting and protecting their well-being. In living donor transplantation, the donor transplant team is responsible for empowering prospective donors to address their vulnerabilities and/or for protecting those who cannot by disqualifying them from donation. PMID- 29973390 TI - Device representatives in hospitals: are commercial imperatives driving clinical decision-making? AB - Despite concerns about the relationships between health professionals and the medical device industry, the issue has received relatively little attention. Prevalence data are lacking; however, qualitative and survey research suggest device industry representatives, who are commonly present in clinical settings, play a key role in these relationships. Representatives, who are technical product specialists and not necessarily medically trained, may attend surgeries on a daily basis and be available to health professionals 24 hours a day, 7 days a week, to provide advice. However, device representatives have a dual role: functioning as commissioned sales representatives at the same time as providing advice on approaches to treatment. This duality raises the concern that clinical decision-making may be unduly influenced by commercial imperatives. In this paper, we identify three key ethical concerns raised by the relationship between device representatives and health professionals: (1) impacts on healthcare costs, (2) the outsourcing of expertise and (3) issues of accountability and informed consent. These ethical concerns can be addressed in part through clarifying the boundary between the support and sales aspects of the roles of device representatives and developing clear guidelines for device representatives providing support in clinical spaces. We suggest several policy options including hospital provision of expert support, formalising clinician conduct to eschew receipt of meals and payments from industry and establishing device registries. PMID- 29973391 TI - Alternative reproductive strategies in white-throated sparrows are associated with differences in parasite load following experimental infection. AB - Immune defences often trade off with other life-history components. Within species, optimal allocation to immunity may differ between the sexes or between alternative life-history strategies. White-throated sparrows (Zonotrichia albicollis) are unusual in having two discrete plumage morphs, white-striped and tan-striped. Within each sex, white-striped individuals are more aggressive and provide less parental care than tan-striped individuals. We extended immunocompetence handicap models, which predict sex differences in immunity and parasitism, to hypothesize that infection susceptibility should be greater in white-striped than tan-striped birds. We inoculated birds of both morphs with malarial parasites. Contrary to our prediction, among birds that became infected, parasite loads were higher in tan-striped than white-striped individuals and did not differ between the sexes. Circulating androgen levels did not differ between morphs but were higher in males than females. Our findings are not consistent with androgen-mediated immunosuppression. Instead, morph differences in immunity could reflect social interactions or life-history-related differences in risk of injury, and/or genetic factors. Although plumage and behavioural morphs of white throated sparrow may differ in disease resistance, these differences do not parallel sex differences that have been reported in animals, and do not appear to be mediated by differences in androgen levels. PMID- 29973392 TI - Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. AB - OBJECTIVE: To investigate the associations between direct oral anticoagulants (DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin. DESIGN: Prospective open cohort study. SETTING: UK general practices contributing to QResearch or Clinical Practice Research Datalink. PARTICIPANTS: 132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016. MAIN OUTCOME MEASURES: Major bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied. RESULTS: In patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding (0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding (0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban (1.19, 1.09 to 1.29) or on lower doses of apixaban (1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (0.60, 0.46 to 0.79), any gastrointestinal bleeding (0.55, 0.37 to 0.83), and upper gastrointestinal bleeding (0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding (0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban (1.51, 1.38 to 1.66) and those on lower doses of apixaban (1.34, 1.13 to 1.58). CONCLUSIONS: Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin. PMID- 29973394 TI - Quality and Outcomes Framework faces radical reshape in England but will be retained. PMID- 29973393 TI - Definition and Management of Segmental Pulmonary Hypertension. PMID- 29973395 TI - Ethnic variation in unexplained deaths in infancy, including sudden infant death syndrome (SIDS), England and Wales 2006-2012: national birth cohort study using routine data. AB - BACKGROUND: Unexplained deaths in infancy comprise 'sudden infant death syndrome' (SIDS) and deaths without ascertained cause. They are typically sleep-related, perhaps triggered by unsafe sleep environments. Preterm birth may increase risk, and varies with ethnicity. We aimed to compare ethnic-specific rates of unexplained infant death, explore sociodemographic explanations for ethnic variation, and examine the role of preterm birth. METHODS: We analysed routine data for 4.6 million live singleton births in England and Wales 2006-2012, including seven non-White ethnic groups ranging in size from 29 313 (Mixed Black African-White) to 180 265 (Pakistani). We calculated rates, birth-year-adjusted ORs, and effects of further adjustments on the chi2 for ethnic variation. RESULTS: There were 1559 unexplained infant deaths. Crude rates per 1000 live singleton births were as follows: 0.1-0.2 for Indian, Bangladeshi, Pakistani, White Non-British, Black African; 0.4 for White British; 0.6-0.7 for Mixed Black African-White, Mixed Black-Caribbean-White, Black Caribbean. Birth-year-adjusted ORs relative to White British ranged from 0.38 (95% CI 0.24 to 0.60) for Indian babies to 1.73 (1.21 to 2.47) for Black Caribbean (chi2(10 df)=113.6, p<0.0005). Combined adjustment for parents' marital/registration status and mother's country of birth (UK/non-UK) attenuated the ethnic variation. Adjustments for gestational age at birth, maternal age and area deprivation made little difference. CONCLUSION: Substantial ethnic disparity in risk of unexplained infant death exists in England and Wales. Apparently not attributable to preterm birth or area deprivation, this may reflect cultural differences in infant care. Further research into infant-care practices in low-risk ethnic groups might enable more effective prevention of such deaths in the general population. PMID- 29973396 TI - Cultured cells and wing disc size of silkworm can be controlled by the Hippo pathway. AB - Hippo signalling represents a cell proliferation and organ-size control pathway. Yorki (Yki), a component of the Hippo pathway, induces the transcription of a number of targets that promote cell proliferation and survival. The functions of Yki have been characterized in Drosophila and mammals, while there are few reports on silkworm, Bombyx mori In the present study, we found that BmYki3 facilitates cell migration and cell division, and enlarges the cultured cell and wing disc size. Co-immunoprecipitation results indicated that BmYki3 may interact with thymosin, E3 ubiquitin-protein ligase, protein kinase ASK1, dedicator of cytokinesis protein 1, calcium-independent phospholipase A2 and beta-spectrin. RNA-seq results indicated that 4444 genes were upregulated and 10 291 genes were downregulated after BmYki3 was overexpressed in the cultured cells. GO annotation indicated that the up/downregulated genes were enriched in 268/382 GO terms (p < 0.01); KEGG analysis showed that the up/downregulated genes were enriched in 49/101 pathways. These findings provided novel information to understand the functions of BmYki3 in a cell proliferation and organ-size control pathway. PMID- 29973398 TI - Correction: Secretion of ERP57 is important for extracellular matrix accumulation and progression of renal fibrosis, and is an early sign of disease onset (doi:10.1242/jcs.125088). PMID- 29973399 TI - Correction: Screening and purification of natural products from actinomycetes that affect the cell shape of fission yeast (doi:10.1242/jcs.194571). PMID- 29973400 TI - Biomechanical limits to soil penetration by earthworms: direct measurements of hydroskeletal pressures and peristaltic motions. AB - Burrows resulting from earthworm activity are important for supporting various physical and ecological soil processes. Earthworm burrowing activity is quantified using models for earthworm penetration and cavity expansion that consider soil moisture and mechanical properties. Key parameters in these models are the maximal pressures exerted by the earthworm's hydroskeleton (estimated at 200 kPa). We designed a special pressure chamber that directly measures the pressures exerted by moving earthworms under different confining pressures to delineate the limits of earthworm activity in soils at different mechanical and hydration states. The chamber consists of a Plexiglas prism fitted with inner flexible tubing that hosts the earthworm. The gap around the tubing is pressurized using water, and the earthworm's peristaltic motion and concurrent pressure fluctuations were recorded by a camera and pressure transducer. A model that links the earthworm's kinematics with measured pressure fluctuations was developed. Resulting maximal values of radial pressures for anecic and endogeic earthworms were 130 kPa and 195 kPa, respectively. Mean earthworm peristaltic frequencies were used to quantify burrowing rates that were in agreement with previous results. The study delineates mechanical constraints to soil bioturbation by earthworms by mapping the elastic behaviour in the measurement chamber onto the expected elasto-viscoplastic environment of natural soils. PMID- 29973397 TI - On the networked architecture of genotype spaces and its critical effects on molecular evolution. AB - Evolutionary dynamics is often viewed as a subtle process of change accumulation that causes a divergence among organisms and their genomes. However, this interpretation is an inheritance of a gradualistic view that has been challenged at the macroevolutionary, ecological and molecular level. Actually, when the complex architecture of genotype spaces is taken into account, the evolutionary dynamics of molecular populations becomes intrinsically non-uniform, sharing deep qualitative and quantitative similarities with slowly driven physical systems: nonlinear responses analogous to critical transitions, sudden state changes or hysteresis, among others. Furthermore, the phenotypic plasticity inherent to genotypes transforms classical fitness landscapes into multiscapes where adaptation in response to an environmental change may be very fast. The quantitative nature of adaptive molecular processes is deeply dependent on a network-of-networks multilayered structure of the map from genotype to function that we begin to unveil. PMID- 29973401 TI - Groups and scores: the decline of cooperation. AB - Cooperation among unrelated individuals in social-dilemma-type situations is a key topic in social and biological sciences. It has been shown that, without suitable mechanisms, high levels of cooperation/contributions in repeated public goods games are not stable in the long run. Reputation, as a driver of indirect reciprocity, is often proposed as a mechanism that leads to cooperation. A simple and prominent reputation dynamic function through scoring: contributing behaviour increases one's score, non-contributing reduces it. Indeed, many experiments have established that scoring can sustain cooperation in two-player prisoner's dilemmas and donation games. However, these prior studies focused on pairwise interactions, with no experiment studying reputation mechanisms in more general group interactions. In this paper, we focus on groups and scores, proposing and testing several scoring rules that could apply to multi-player prisoners' dilemmas played in groups, which we test in a laboratory experiment. Results are unambiguously negative: we observe a steady decline of cooperation for every tested scoring mechanism. All scoring systems suffer from it in much the same way. We conclude that the positive results obtained by scoring in pairwise interactions do not apply to multi-player prisoner's dilemmas, and that alternative mechanisms are needed. PMID- 29973402 TI - The asymptotic coarse-graining formulation of slender-rods, bio-filaments and flagella. AB - The inertialess fluid-structure interactions of active and passive inextensible filaments and slender-rods are ubiquitous in nature, from the dynamics of semi flexible polymers and cytoskeletal filaments to cellular mechanics and flagella. The coupling between the geometry of deformation and the physical interaction governing the dynamics of bio-filaments is complex. Governing equations negotiate elastohydrodynamical interactions with non-holonomic constraints arising from the filament inextensibility. Such elastohydrodynamic systems are structurally convoluted, prone to numerical errors, thus requiring penalization methods and high-order spatio-temporal propagators. The asymptotic coarse-graining formulation presented here exploits the momentum balance in the asymptotic limit of small rod-like elements which are integrated semi-analytically. This greatly simplifies the elastohydrodynamic interactions and overcomes previous numerical instability. The resulting matricial system is straightforward and intuitive to implement, and allows for a fast and efficient computation, more than a hundred times faster than previous schemes. Only basic knowledge of systems of linear equations is required, and implementation achieved with any solver of choice. Generalizations for complex interaction of multiple rods, Brownian polymer dynamics, active filaments and non-local hydrodynamics are also straightforward. We demonstrate these in four examples commonly found in biological systems, including the dynamics of filaments and flagella. Three of these systems are novel in the literature. We additionally provide a Matlab code that can be used as a basis for further generalizations. PMID- 29973403 TI - Linking trophic cascades to changes in desert dune geomorphology using high resolution drone data. AB - Vegetation cover is fundamental in the formation and maintenance of geomorphological features in dune systems. In arid Australia, increased woody shrub cover has been linked to removal of the apex predator (Dingoes, Canis dingo) via subsequent trophic cascades. We ask whether this increase in shrubs can be linked to altered physical characteristics of the dunes. We used drone based remote sensing to measure shrub density and construct three-dimensional models of dune morphology. Dunes had significantly different physical characteristics either side of the 'dingo-proof fence', inside which dingoes are systematically eradicated and shrub density is higher over vast spatial extents. Generalized additive models revealed that dunes with increased shrub density were higher, differently shaped and more variable in height profile. We propose that low shrub density induces aeolian and sedimentary processes that result in greater surface erosion and sediment transport, whereas high shrub density promotes dune stability. We speculate that increased vegetation cover acts to push dunes towards an alternate stable state, where climatic variation no longer has a significant effect on their morphodynamic state within the bi-stable state model. Our study provides evidence that anthropogenically induced trophic cascades can indirectly lead to large-scale changes in landscape geomorphology. PMID- 29973405 TI - BCL3 expression promotes resistance to alkylating chemotherapy in gliomas. AB - The response of patients with gliomas to alkylating chemotherapy is heterogeneous. However, there are currently no universally accepted predictors of patient response to these agents. We identify the nuclear factor kappaB (NF kappaB) co-regulator B cell CLL/lymphoma 3 (BCL-3) as an independent predictor of response to temozolomide (TMZ) treatment. In glioma patients with tumors that have a methylated O6-methylguanine DNA methyltransferase (MGMT) promoter, high BCL-3 expression was associated with a poor response to TMZ. Mechanistically, BCL 3 promoted a more malignant phenotype by inducing an epithelial-to-mesenchymal transition in glioblastomas through promoter-specific NF-kappaB dimer exchange. Carbonic anhydrase II (CAII) was identified as a downstream factor promoting BCL 3-mediated resistance to chemotherapy. Experiments in glioma xenograft mouse models demonstrated that the CAII inhibitor acetazolamide enhanced survival of TMZ-treated animals. Our data suggest that BCL-3 might be a useful indicator of glioma response to alkylating chemotherapy and that acetazolamide might be repurposed as a chemosensitizer for treating TMZ-resistant gliomas. PMID- 29973406 TI - MEK inhibition induces MYOG and remodels super-enhancers in RAS-driven rhabdomyosarcoma. AB - The RAS isoforms are frequently mutated in many types of human cancers, including PAX3/PAX7 fusion-negative rhabdomyosarcoma. Pediatric RMS arises from skeletal muscle progenitor cells that have failed to differentiate normally. The role of mutant RAS in this differentiation blockade is incompletely understood. We demonstrate that oncogenic RAS, acting through the RAF-MEK [mitogen-activated protein kinase (MAPK) kinase]-ERK (extracellular signal-regulated kinase) MAPK effector pathway, inhibits myogenic differentiation in rhabdomyosarcoma by repressing the expression of the prodifferentiation myogenic transcription factor, MYOG. This repression is mediated by ERK2-dependent promoter-proximal stalling of RNA polymerase II at the MYOG locus. Small-molecule screening with a library of mechanistically defined inhibitors showed that RAS-driven RMS is vulnerable to MEK inhibition. MEK inhibition with trametinib leads to the loss of ERK2 at the MYOG promoter and releases the transcriptional stalling of MYOG expression. MYOG subsequently opens chromatin and establishes super-enhancers at genes required for late myogenic differentiation. Furthermore, trametinib, in combination with an inhibitor of IGF1R, potently decreases rhabdomyosarcoma cell viability and slows tumor growth in xenograft models. Therefore, this combination represents a potential therapeutic for RAS-mutated rhabdomyosarcoma. PMID- 29973407 TI - Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats. AB - Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90alpha, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD. PMID- 29973404 TI - The human naive B cell repertoire contains distinct subclasses for a germline targeting HIV-1 vaccine immunogen. AB - Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-phase 1 ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the envelope CD4-binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement. PMID- 29973408 TI - Apert syndrome: Be aware of the 'dodgy' hip! AB - Apert syndrome is a rare congenital disorder characterised by craniosynostosis, midface hypoplasia and syndactyly of hands and feet. Here we present a case of a 44-year-old woman, with a genetic diagnosis of Apert syndrome from birth, who presented with symptomatic left-sided hip osteoarthritis secondary to femoral abnormalities. She proceeded to have a total hip replacement. This case report describes the rare occurrence to identify a possible association between Apert syndrome and hip abnormalities. PMID- 29973409 TI - Rare glomangiosarcoma of the tongue. AB - The glomus tumour is a rare neoplasm derived from the glomus apparatus. Subungual sites are most common with only three published cases involving the dorsal tongue. To our knowledge, this is the first case of an intraoral malignant glomus tumour (glomangiosarcoma) to be published in English literature. We report a case of a single glomus tumour located on the posterior dorsal tongue of a middle-aged man, which was surgically excised. Immunohistological features were indicative of a glomus tumour; however, in this case, malignant features were also discovered, warranting re-excision. PMID- 29973410 TI - Clinical spectrum of Dyke-Davidoff-Masson syndrome in the adult: an atypical presentation and review of literature. AB - Dyke-Davidoff-Masson Syndrome (DDMS) is a rare condition usually diagnosed in paediatric patients with clinical features of hemiparesis, seizures, mental retardation and contralateral cerebral hemiatrophy on neuroimaging. This report follows the case of a 22-year-old man presenting with seizures and hemiatrophy and hemiparesis. On review of cases the most common neuroimaging findings were cerebral hemiatrophy (100%) followed by hemicalvarial thickening (71.4%) and hyperpneumatisation of sinuses (71.4%). Apart from our patient, all nine cases with data on epilepsy control had drug-resistant epilepsy. The onset of seizures in adulthood, block vertebra, short stature, absence of mental retardation and well-controlled epilepsy on monotherapy makes our case exceptional-even bringing to mind the possibility of a DDMS variant. This report exhaustively reviews the wide range of clinical and radiological manifestations of DDMS in the adult, thereby adding to the literature on an unusual syndrome that causes significant neurological morbidity. PMID- 29973411 TI - Macrophagic myofasciitis: a challenging diagnosis. AB - A 25-year-old man admitted for generalised muscle pain with an insidious onset 3 years ago. He had exercise intolerance and decrease in muscle strength, requiring gait support. He was previously healthy, with no chronic medication or recent history of drugs or toxics. National vaccination plan actualised with hepatitis B and tetanus vaccines administered 10 and 2 years, respectively, before symptom onset. No analytical, imaging or electromyography changes were found. Muscle biopsy revealed an inflammatory infiltrate predominantly macrophagic with aluminium deposits suggestive of macrophagic myofasciitis (MMF). It is probably associated with vaccines previously administered. MMF lesion can be regarded as pathological only if detected at least 18 months after last aluminic immunisation, as our case illustrates. PMID- 29973413 TI - A garlic burn. PMID- 29973412 TI - Oropharyngeal paraganglioma presenting with stridor: an unusual presentation. AB - Head and neck paraganglioma is a rare disease to encounter in clinical practice and involvement of the base of the tongue in the oropharynx is yet to be described in the current literature. Although various surgical approaches have been described in the literature, transcervical mandibular swing is an effective technique for adequate exposure and complete excision of the oropharyngeal paraganglioma with adequate control on bleeding especially when it is assisted by coblation. PMID- 29973414 TI - Hypoxia-inducible transcription factors in fish: expression, function and interconnection with the circadian clock. AB - The hypoxia-inducible transcription factors are key regulators for the physiological response to low oxygen availability. In vertebrates, typically three Hif-alpha isoforms, Hif-1alpha, Hif-2alpha and Hif-3alpha, are expressed, each of which, together with Hif-1beta, may form a functional heterodimer under hypoxic conditions, controlling expression of hundreds of genes. A teleost specific whole-genome duplication complicates the analysis of isoform-specific functions in fish, but recent studies suggest that the existence of paralogues of a specific isoform opens up the possibility for a subfunctionalization. In contrast to during development inside the uterus, fish eggs are freely accessible and studies analyzing Hif expression in fish embryos during development have revealed that Hif proteins are not only controlling the hypoxic response, but are also crucial for proper development and organ differentiation. Significant advances have been made in our knowledge about tissue-specific functions of Hif proteins, especially with respect to gill or gonadal tissue. The hypoxia signalling pathway is known to be tightly and mutually intertwined with the circadian clock in zebrafish and mammals. Recently, a mechanistic explanation for the hypoxia-induced dampening of the transcriptional clock was detected in zebrafish, including also metabolically induced alterations of cellular redox signalling. In turn, MAP kinase-mediated H2O2 signalling modulates the temporal expression of Hif-1alpha protein, similar to the redox regulation of the circadian clock itself. Once again, the zebrafish has emerged as an excellent model organism with which to explore these specific functional aspects of basic eukaryotic cell biology. PMID- 29973415 TI - Correction: Effects of food availability on metabolism, behaviour, growth and their relationships in a triploid carp (doi: 10.1242/jeb.167783). PMID- 29973416 TI - Insights into the Contribution of Voltage-Gated Sodium Channel 1.7 to Paclitaxel Induced Neuropathy. PMID- 29973417 TI - Cinnamamide pharmacophore for anticonvulsant activity: evidence from crystallographic studies. AB - A number of cinnamamide derivatives possess anticonvulsant activity due to the presence of a number of important pharmacophore elements in their structures. In order to study the correlations between anticonvulsant activity and molecular structure, the crystal structures of three new cinnamamide derivatives with proven anticonvulsant activity were determined by X-ray diffraction, namely (R,S) (2E)-N-(2-hydroxybutyl)-3-phenylprop-2-enamide-water (3/1), C13H17NO2.0.33H2O, (1), (2E)-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylprop-2-enamide, C13H17NO2, (2), and (R,S)-(2E)-N-(1-hydroxy-3-methyl-butan-2-yl)-3-phenylprop-2-enamide, C14H19NO2, (3). Compound (1) crystallizes in the space group P-1 with three molecules in the asymmetric unit, whereas compounds (2) and (3) crystallize in the space group P21/c with one and two molecules, respectively, in their asymmetric units. The carbonyl group of (2) is engaged in an intramolecular hydrogen bond with the hydroxy group. This type of interaction is observed for the first time in these kinds of derivatives. A disorder of the substituent at the N atom occurs in the crystal structures of (2) and (3). The crystal packing of all three structures is dominated by a network of O-H...O and N-H...O hydrogen bonds, and leads to the formation of chains and/or rings. Furthermore, the crystal structures are stabilized by numerous C-H...O contacts. We analyzed the molecular structures and intermolecular interactions in order to propose a pharmacophore model for cinnamamide derivatives. PMID- 29973418 TI - Supramolecular architectures in metal(II) (Cd/Zn) halide/nitrate complexes of cytosine/5-fluorocytosine. AB - Three new metal(II)-cytosine (Cy)/5-fluorocytosine (5FC) complexes, namely bis(4 amino-1,2-dihydropyrimidin-2-one-kappaN3)diiodidocadmium(II) or bis(cytosine)diiodidocadmium(II), [CdI2(C4H5N3O)2], (I), bis(4-amino-1,2 dihydropyrimidin-2-one-kappaN3)bis(nitrato-kappa2O,O')cadmium(II) or bis(cytosine)bis(nitrato)cadmium(II), [Cd(NO3)2(C4H5N3O)2], (II), and (6-amino-5 fluoro-1,2-dihydropyrimidin-2-one-kappaN3)aquadibromidozinc(II)-6-amino-5-fluoro 1,2-dihydropyrimidin-2-one (1/1) or (6-amino-5 fluorocytosine)aquadibromidozinc(II)-4-amino-5-fluorocytosine (1/1), [ZnBr2(C4H5FN3O)(H2O)].C4H5FN3O, (III), have been synthesized and characterized by single-crystal X-ray diffraction. In complex (I), the CdII ion is coordinated to two iodide ions and the endocyclic N atoms of the two cytosine molecules, leading to a distorted tetrahedral geometry. The structure is isotypic with [CdBr2(C4H5N3O)2] [Muthiah et al. (2001). Acta Cryst. E57, m558-m560]. In compound (II), each of the two cytosine molecules coordinates to the CdII ion in a bidentate chelating mode via the endocyclic N atom and the O atom. Each of the two nitrate ions also coordinates in a bidentate chelating mode, forming a bicapped distorted octahedral geometry around cadmium. The typical interligand N H...O hydrogen bond involving two cytosine molecules is also present. In compound (III), one zinc-coordinated 5FC ligand is cocrystallized with another uncoordinated 5FC molecule. The ZnII atom coordinates to the N(1) atom (systematic numbering) of 5FC, displacing the proton to the N(3) position. This N(3)-H tautomer of 5FC mimics N(3)-protonated cytosine in forming a base pair (via three hydrogen bonds) with 5FC in the lattice, generating two fused R22(8) motifs. The distorted tetrahedral geometry around zinc is completed by two bromide ions and a water molecule. The coordinated and nonccordinated 5FCs are stacked over one another along the a-axis direction, forming the rungs of a ladder motif, whereas Zn-Br bonds and N-H...Br hydrogen bonds form the rails of the ladder. The coordinated water molecules bridge the two types of 5FC molecules via O-H...O hydrogen bonds. The cytosine molecules are coordinated directly to the metal ion in each of the complexes and are hydrogen bonded to the bromide, iodide or nitrate ions. In compound (III), the uncoordinated 5FC molecule pairs with the coordinated 5FC ligand through three hydrogen bonds. The crystal structures are further stabilized by N-H...O, N-H...N, O-H...O, N-H...I and N H...Br hydrogen bonds, and stacking interactions. PMID- 29973419 TI - Pharmaceutical salts of emoxypine with dicarboxylic acids. AB - New salt forms of the antioxidant drug emoxypine (EMX, 2-ethyl-6-methylpyridin-3 ol) with pharmaceutically acceptable maleic (Mlt), malonic (Mln) and adipic (Adp) acids were obtained {emoxypinium maleate, C8H12NO+.C4H3O4-, [EMX+Mlt], emoxypinium malonate, C8H12NO+.C3H3O4-, [EMX+Mln], and emoxypinium adipate, C8H12NO+.C6H9O4-, [EMX+Adp]} and their crystal structures determined. The molecular packing in the three EMX salts was studied by means of solid-state density functional theory (DFT), followed by QTAIMC (quantum theory of atoms in molecules and crystals) analysis. It was found that the major contribution to the packing energy comes from pyridine-carboxylate and hydroxy-carboxylate heterosynthons forming infinite one-dimensional ribbons, with [EMX+Adp] additionally stabilized by hydrogen-bonded C(9) chains of Adp- ions. The melting processes of the [EMX+Mlt] (1:1), [EMX+Mln] (1:1) and [EMX+Adp] (1:1) salts were studied and the fusion enthalpy was found to increase with the increase of the calculated lattice energy. The dissolution process of the EMX salts in buffer (pH 7.4) was also studied. It was found that the formation of binary crystals of EMX with dicarboxylic acids increases the EMX solubility by more than 30 times compared to its pure form. PMID- 29973420 TI - Structural and optical profile of a multifunctionalized 2-pyridone derivative in a crystal engineering perspective. AB - The supramolecular structural features of organic molecules are very important with regard to their widespread properties in both solids and solutions. Herein, we describe the synthesis of a novel multifunctional 2-pyridone derivative, namely 6-(4-chlorophenyl)-5-formyl-4-methylsulfanyl-2-oxo-1,2-dihydropyridine-3 carbonitrile, C14H9ClN2O2S, denoted P1, and its structural features were established through X-ray crystallography. A Hirshfeld surface analysis followed by a two-dimensional fingerprint plot analysis was carried out. A frontier molecular orbital investigation and natural bond orbital (NBO) calculations explored the charge-transfer interactions associated with the molecular system. The optical properties of the 2-pyridone derivative were elucidated through UV Vis absorption and emission spectroscopy, indicating a strong blue emissive nature with a colour purity of 82.5%, a short-lived lifetime and a large Stokes shift. Time-dependent density functional theory (TD-DFT) was used to gain some insight into the absorption behaviour and emissive characteristics of P1. PMID- 29973421 TI - A comparative experimental and theoretical investigation of hydrogen-bond, halogen-bond and pi-pi interactions in the solid-state supramolecular assembly of 2- and 4-formylphenyl arylsulfonates. AB - To explore the operational role of noncovalent interactions in supramolecular architectures with designed topologies, a series of solid-state structures of 2- and 4-formylphenyl 4-substituted benzenesulfonates was investigated. The compounds are 2-formylphenyl 4-methylbenzenesulfonate, C14H12O4S, 3a, 2 formylphenyl 4-chlorobenzenesulfonate, C13H9ClO4S, 3b, 2-formylphenyl 4 bromobenzenesulfonate, C13H9BrO4S, 3c, 4-formylphenyl 4-methylbenzenesulfonate, C14H12O4S, 4a, 4-formylphenyl 4-chlorobenzenesulfonate, 4b, C13H9ClO4S, and 4 formylphenyl 4-bromobenzenesulfonate, C13H9BrO4S, 4c. The title compounds were synthesized under basic conditions from salicylaldehyde/4-hydroxybenzaldehydes and various aryl sulfonyl chlorides. Remarkably, halogen-bonding interactions are found to be important to rationalize the solid-state crystal structures. In particular, the formation of O...X (X = Cl and Br) and type I X...X halogen bonding interactions have been analyzed by means of density functional theory (DFT) calculations and characterized using Bader's theory of 'atoms in molecules' and molecular electrostatic potential (MEP) surfaces, confirming the relevance and stabilizing nature of these interactions. They have been compared to antiparallel pi-stacking interactions that are formed between the arylsulfonates. PMID- 29973422 TI - Qualitative and quantitative analysis of intermolecular interactions in xanthenedione derivatives. AB - The existence of intermolecular interactions and the conformational geometry adopted by molecules are related to biological activity. Xanthenedione molecules are promising and emerging antioxidants and acetylcholinesterase inhibitors. To examine the role of different functional groups involved in the intermolecular interactions and conformational geometries adopted in xanthenediones, a series of three substituted xanthenediones have been crystallized [9-(3-hydroxyphenyl) 3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione, C23H26O4, 9 (5-bromo-2-methoxyphenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydro-2H-xanthene 1,8(5H,9H)-dione, C24H27BrO4, and 3,3,6,6-tetramethyl-9-(pyridin-2-yl)-3,4,6,7 tetrahydro-2H-xanthene-1,8(5H,9H)-dione, C22H25NO3] and their intermolecular interactions analyzed via Hirshfeld analysis. The results show that all the derivatives adopt the same structural conformation, where the central ring has a shallow boat conformation and the outer rings have a twisted boat conformation. The intermolecular interactions in the molecules are predominantly O-H...O, C H...O and pi-pi interactions. The optimized structures of the derivatives from theoretical B3LYP/6-311G** calculations show a good correlation with the experimental structures. The lattice energy involved in the intermolecular interactions has been explored using PIXELC. PMID- 29973423 TI - Synthesis, structure and in vitro cytotoxicity testing of some 1,3,4-oxadiazoline derivatives from 2-hydroxy-5-iodobenzoic acid. AB - The syntheses of nine new 5-iodosalicylic acid-based 1,3,4-oxadiazoline derivatives starting from methyl salicylate are described. These compounds are 2 [4-acetyl-5-methyl-5-(3-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4 iodophenyl acetate (6a), 2-[4-acetyl-5-methyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4 oxadiazol-2-yl]-4-iodophenyl acetate (6b), 2-(4-acetyl-5-methyl-5-phenyl-4,5 dihydro-1,3,4-oxadiazol-2-yl)-4-iodophenyl acetate, C19H17IN2O4 (6c), 2-[4-acetyl 5-(4-fluorophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16FIN2O4 (6d), 2-[4-acetyl-5-(4-chlorophenyl)-5-methyl-4,5-dihydro 1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate, C19H16ClIN2O4 (6e), 2-[4-acetyl-5-(3 bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6f), 2-[4-acetyl-5-(4-bromophenyl)-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4 iodophenyl acetate (6g), 2-[4-acetyl-5-methyl-5-(4-methylphenyl)-4,5-dihydro 1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6h) and 2-[5-(4-acetamidophenyl)-4 acetyl-5-methyl-4,5-dihydro-1,3,4-oxadiazol-2-yl]-4-iodophenyl acetate (6i). The compounds were characterized by mass, 1H NMR and 13C NMR spectroscopies. Single crystal X-ray diffraction studies were also carried out for 6c, 6d and 6e. Compounds 6c and 6d are isomorphous, with the 1,3,4-oxadiazoline ring having an envelope conformation, where the disubstituted C atom is the flap. The packing is determined by C-H...O, C-H...pi and I...pi interactions. For 6e, the 1,3,4 oxadiazoline ring is almost planar. In the packing, Cl...pi interactions are observed, while the I atom is not involved in short interactions. Compounds 6d, 6e, 6f and 6h show good inhibiting abilities on the human cancer cell lines KB and Hep-G2, with IC50 values of 0.9-4.5 uM. PMID- 29973424 TI - Evaluation of N-H...S and N-H...pi interactions in O,O'-diethyl N-(2,4,6 trimethylphenyl)thiophosphate: a combination of X-ray crystallographic and theoretical studies. AB - In the crystal structure of O,O'-diethyl N-(2,4,6-trimethylphenyl)thiophosphate, C13H22NO2PS, two symmetrically independent thiophosphoramide molecules are linked through N-H...S and N-H...pi hydrogen bonds to form a noncentrosymmetric dimer, with Z' = 2. The strengths of the hydrogen bonds were evaluated using density functional theory (DFT) at the M06-2X level within the 6-311++G(d,p) basis set, and by considering the quantum theory of atoms in molecules (QTAIM). It was found that the N-H...S hydrogen bond is slightly stronger than the N-H...pi hydrogen bond. This is reflected in differences between the calculated N-H stretching frequencies of the isolated molecules and the frequencies of the same N-H units involved in the different hydrogen bonds of the hydrogen-bonded dimer. For these hydrogen bonds, the corresponding charge transfers, i.e. lp (or pi)->sigma*, were studied, according to the second-order perturbation theory in natural bond orbital (NBO) methodology. Hirshfeld surface analysis was applied for a detailed investigation of all the contacts participating in the crystal packing. PMID- 29973425 TI - Supramolecular architectures of succinates of 1-hydroxypropan-2-aminium derivatives. AB - Aminoalkanol and aroxyalkyl derivatives are known as potential anticonvulsants. Two new salts, namely bis{(R,S)-N-[2-(2,6-dimethylphenoxy)ethyl]-1-hydroxypropan 2-aminium} succinate (1s), C13H22NO2+.0.5C4H4O42-, and bis{(S)-(+)-N-[2-(2,6 dimethylphenoxy)ethyl]-1-hydroxypropan-2-aminium} succinate (2s), C13H22NO2+.0.5C4H4O42-, have been prepared and characterized by single-crystal X ray diffraction. The N atoms are protonated by proton transfer from succinic acid. Salt 1s crystallizes in the space group P21/n with one cation and half an anion in the asymmetric unit across an inversion centre, while (2s) crystallizes in the space group P21 with four cations and two anions in the asymmetric unit. The hydroxy group of the cation of 1s is observed in two R/S disorder positions. The crystals of these two salts display similar supramolecular architectures (i.e. two-dimensional networks), built mainly by intermolecular N+-H...Odelta- and O-H...Odelta- hydrogen bonds, where 'delta-' represents a partial charge. The succinate anions are engaged in hydrogen bonds, not only with protonated N atoms, but also with hydroxy groups. PMID- 29973426 TI - Single-crystal structure determination of two new ternary bismuthides: Rh6Mn5Bi18 and RhMnBi3. AB - A study of the ternary Rh-Mn-Bi phase diagram revealed the existence of two new ternary bismuthides, viz. hexarhodium pentamanganese octadecabismuthide (Rh6Mn5Bi18) and rhodium manganese tribismuthide (RhMnBi3). Their crystal structures represent new structure types. Rh6Mn5Bi18, with a Wyckoff sequence a f2 g2 i5, crystallizes in the tetragonal system (space group P42/mnm; Pearson symbol tP58), and RhMnBi3, with a Wyckoff sequence a c g i q, crystallizes in the orthorhombic system (Cmmm; oS20). In the Rh6Mn5Bi18 structure, the transition metal atoms are linked into ribbon-like structural units aligned along the [001] direction, whereas planar sheets are formed in RhMnBi3. In both crystal structures, the units formed by the transition metal atoms are enveloped by Bi atoms, which themselves form a loosely bound network. The linkage results in a layer structure for RhMnBi3, while in the case of Rh6Mn5Bi18, a three-dimensional network is formed; the latter, however, contains several areas where Bi...Bi distances suggest van der Waals interactions. Both phases under discussion have analogous structural motifs. PMID- 29973427 TI - Infliximab-Induced Tubulointerstitial Nephritis with Image Findings of Striated Nephrogram in Crohn's Disease. AB - Tubulointerstitial nephritis is primary injury to renal tubules and interstititum which could be resulting in decreased renal function. The acute and chronic forms are most often due to allergic drug reactions or to infections. Tubulointerstitial nephritis in Crohn's disease has rarely been reported. Imaging findings of a striated nephrogram on enhanced computed tomography (CT) could represent the clinical state of tubulointerstitial nephritis. This is the first report of tubulointerstitial nephritis caused by infliximab, monoclonal antibody against human tumor necrosis factor-alpha, showing striated nephrograms in Crohn's disease. The case of a 28-year-old man treated with infliximab for Crohn's disease is described. Infliximab was added to his maintenance therapy, and bowel symptoms were stable. The patient presented with a 2-month history of fever and an elevated C-reactive protein after infliximab administration for 4.5 years. Contrast-enhanced CT showed striated nephrograms in both kidneys. Urinalysis showed no abnormal findings. The pathological diagnosis on CT-guided percutaneous renal needle biopsy was drug-induced tubulointerstitial nephritis because of eosinophilic infiltration with neutrophils mainly in the tubulointerstitial areas. The imaging findings of striated nephrogram are important for the diagnosis of tubulointerstitial nephritis. Tubulointerstitial nephritis could be caused by drug-induced inflammation or direct extension of Crohn's disease as an extra-interstitial manifestation. The treatment strategies for these two diseases are contradictory to each other and inappropriate treatment could worsen the renal function. Needle biopsy is therefore indispensable for differential diagnosis. PMID- 29973428 TI - Regulation of compensatory beta-cell proliferation by inter-organ networks from the liver to pancreatic beta-cells. AB - In insulin-resistant states such as obesity, pancreatic beta-cells proliferate to prevent blood glucose elevations. However, the mechanism(s) by which obesity induces compensatory beta-cell responses is not fully understood. Recently, several studies have shown that signals from the liver, such as neuronal signals or humoral factors, regulate beta-cell proliferation during obesity development. We previously reported a liver-brain-pancreas neuronal relay, consisting of afferent splanchnic nerves, the central nervous system and efferent vagal nerves, to promote this compensatory beta-cell proliferation. Furthermore, we recently clarified the molecular mechanisms by which efferent vagal signals induce beta cell proliferation in this inter-organ neuronal network system. Herein, these liver-beta-cell inter-organ networks are reviewed, focusing mainly on the neuronal network. The significance of the neuronal network system in the maintenance of glucose homeostasis is also discussed with reference to the relevant literature. PMID- 29973430 TI - Long-Term Results of Tricuspid Annuloplasty Using MC3 Ring for Functional Tricuspid Regurgitation. AB - BACKGROUND: This study aimed to evaluate the long-term results of tricuspid annuloplasty using the MC3 ring for functional tricuspid regurgitation (TR). Methods and Results: Between 2004 and 2014, 249 patients underwent tricuspid ring annuloplasty using the MC3 ring for functional TR (FTR). Main etiologies of FTR were left-sided valvular disease (n=211) and left-to-right shunt (n=34). Based on the interval between the operation and last echocardiographic scan, patients were divided into short-term and long-term follow-up groups. Mean follow-up duration was 84.4+/-37.1 months. Operative death occurred in 8 patients (3.2%). Predischarge echocardiography showed that both TR grade and systolic pulmonary artery pressure were significantly decreased compared with preoperative values, and these values were sustained during follow-up in both the short-term and long term follow-up groups. There were no ring-related complications in either the postoperative or follow-up period, except for permanent pacemaker implantation in 2 patients. The freedom from TR >=moderate and tricuspid valve (TV)-related events at 10 years were 92.1% and 92.8%, respectively. TV annular size was a risk factor for the recurrence of TR >=moderate (P=0.001), and 42 mm was the cutoff value for predicting the recurrence of TR >=moderate. CONCLUSIONS: Tricuspid annuloplasty using the MC3 ring for FTR provides satisfactory early results that are sustained during long-term follow-up. Preoperative TV annular size was associated with the recurrence of TR >=moderate. PMID- 29973429 TI - Non-Inferiority of Resolute Integrity Drug-Eluting Stent to Benchmark Xience Drug Eluting Stent. AB - BACKGROUND: The Resolute Integrity coronary drug-eluting stent (DES), the next evolution of the Resolute DES, is designed with thinner stent struts and continuous sinusoidal technology to further enhance performance. This study evaluated the performance of the Resolute Integrity DES compared with the historical performance of Xience V. Methods and Results: We assessed the safety, efficacy, and deliverability of Resolute Integrity compared with the Xience DES, the prespecified historical control, in PROPEL, a large, real-world prospective, single-arm, open-label study. A total of 1,204 subjects were enrolled in PROPEL and treated with the Resolute Integrity DES at 76 sites in Japan. Lesion and procedural success rates were 100% and 99%, respectively. Patients were equally complex in the Resolute Integrity and Xience cohorts. At 1 year in the clinical only cohort, the primary endpoint target lesion failure was 4.3% (34/800) in the Resolute Integrity cohort compared with 8.5% (97/1,142) in the Xience historical controls (P<0.001 for non-inferiority). Target vessel failure, major adverse cardiac events, target vessel myocardial infarction, and the composite cardiac death and target vessel myocardial infarction were all lower with Resolute Integrity compared with Xience, including in "high risk" patients. CONCLUSIONS: In the large, prospective, multicenter PROPEL trial, the performance of the Resolute Integrity DES was non-inferior to that of the benchmark Xience DES used as a historical comparator. PMID- 29973431 TI - Association of Subclinical Intrastent Thrombus Detected 9 Months After Implantation of 2nd-Generation Drug-Eluting Stent With Future Major Adverse Cardiac Events - A Coronary Angioscopic Study. AB - BACKGROUND: Detection of yellow plaques (YP) by coronary angioscopy (CAS) 1 year after 1st-generation drug-eluting stent (DES) implantation has been related to future coronary events. However, the association between CAS findings and clinical outcomes following 2nd-generation DES implantation has not been investigated. Methods and Results: This study included a total of 248 2nd generation DES in 179 patients, who were examined by CAS 9+/-2 months after implantation. Angioscopic evaluation included dominant neointimal coverage (NIC) grade, heterogeneity of NIC, presences of YP and intrastent thrombus. The outcome measure was major adverse cardiac events (MACE) defined as a composite of cardiac death, acute myocardial infarction and any coronary revascularization. The association between the CAS findings and MACE was evaluated using the Kaplan Meier method. A Cox proportional hazards model was used to assess the predictors of MACE. The mean follow-up duration was 1,367+/-843 days. Dominant NIC grade (P=0.98), heterogeneity of NIC (P=0.20) and YP (P=0.53) were not associated with the incidence of MACE. However, intrastent thrombus was significantly associated with MACE (P=0.033). Intrastent thrombus (adjusted hazard ratio: 2.22; 95% confidence interval [CI]: 1.12-4.39), acute coronary syndrome (2.83; 95% CI: 1.42 5.67) and B2/C lesion (2.13; CI: 1.12-4.05) were independent predictors of MACE. CONCLUSIONS: Subclinical intrastent thrombus observed by CAS at 9 months after 2nd-generation DES implantation was independently associated with poor clinical outcome. PMID- 29973432 TI - Possible antagonistic effects of the TRPC4 channel blocker ML204 on M2 and M3 muscarinic receptors in mouse ileal and detrusor smooth muscles and atrial myocardium. AB - ML204, a potent transient receptor potential canonical 4 (TRPC4) channel blocker, is often used to elucidate the involvement of TRPC4 channels in receptor-operated signaling processes in visceral smooth muscles. In the present study, we investigated the possible antagonistic actions of ML204 on M2 and M3 muscarinic receptors, which mediate contractions in mouse ileal and detrusor smooth muscles. In ileal and detrusor smooth muscle preparations, ML204 (3 or 10 uM) significantly inhibited electrical field stimulation (EFS)-evoked cholinergic contractions. However, it did not significantly inhibit high K+-induced and EFS evoked non-cholinergic contractions in the ileal preparations. When the muscarinic agonist, carbachol was cumulatively applied, ML204 (1, 3 and 10 uM) caused a rightward parallel shift of the concentration-response curves of carbachol. Additionally, ML204 (1, 3 and 10 uM) inhibited carbachol-induced negative chronotropic response in atrial preparations, which is mediated by M2 muscarinic receptors. Furthermore, ML204 significantly inhibited the contractions evoked by carbachol-induced intracellular Ca2+ release, which is mediated by M3 muscarinic receptors. These results suggested that ML204 might exhibit antagonistic actions on M2 and M3 muscarinic receptors; in addition, the inhibitory effects of ML204 against EFS-induced cholinergic contractions might be attributed to this receptor antagonism rather than inhibition of TRPC4 channel activity. Therefore, these effects should be considered when ML204 is used as a TRPC4 channel blocker. PMID- 29973433 TI - Systematic estimation of insertion dates of endogenous bornavirus-like elements in vesper bats. AB - Endogenous bornavirus-like elements (EBLs) are sequences derived from bornaviruses (the family Bornaviridae) that are integrated into animal genomes. They are formed through germline insertions of segments of bornaviral transcripts into animal genomes. Because EBLs are molecular fossils of bornaviruses, they serve as precious sources of information to understand the evolutionary history of bornaviruses. Previous studies revealed the presence of many EBLs in bat genomes, especially in vesper bats, and suggested the long-term association between bats and bornaviruses. However, insertion dates of EBLs are largely unknown because of the limitations of available bat genome sequences in the public database. In this study, through a combination of database searches, PCR, and sequencing approaches, we systematically determined the gene orthologies of 13 lineages of EBLs in bats of the genus Myotis and Eptesicus and family Vespertilionidae. Using the above data, we estimated their insertion dates: the EBLs in vesper bats were inserted approximately 14.2 to 53 million years ago. These results suggest that vesper bats have been repeatedly infected by bornaviruses at different points in time during evolution. This study provides novel insights into the evolutionary history of bornaviruses and demonstrates the robustness of combining database searches, PCR, and sequencing approaches to estimate insertion dates of bornaviruses. PMID- 29973434 TI - Ostium secundum type of atrial septal defect in a rabbit. AB - A 14-month-old, female mini rex was referred for a detailed examination because of exercise intolerance with associated dyspnea. The thoracic radiograph demonstrated severe cardiac enlargement and elevation of the trachea. The echocardiography revealed dilatations of the right-side heart and pulmonary artery, and the color flow Doppler echocardiography demonstrated an atrial septum defect with left to right shunt, resulting in a disturbed flow. The rabbit died 19 days after the initial presentation, and a necropsy was performed. At the necropsy, a defect, 5 mm in diameter, was detected in the atrial septum. Based on the location of the defect, an ostium secundum type atrial septal defect was diagnosed. This is the first clinical report of atrial septal defect in rabbits. PMID- 29973436 TI - Mechanism of Suppression of Blood Glucose Level by Calcium Alginate in Rats. AB - Calcium alginate (Ca-Alg) is known to suppress the postprandial increase of blood glucose, and therefore may be helpful for preventing lifestyle-related diseases such as diabetes. In this work, we examined the mechanism of this effect. As alpha-amylase activity and alpha-glucosidase activity are involved in the digestion of starch, we examined the in vitro inhibitory effect of Ca-Alg on these enzymes. Ca-Alg showed little inhibition of alpha-amylase, but markedly inhibited alpha-glucosidase activity. The direct binding affinity of glucose for Ca-Alg was low. Also, Ca-Alg had essentially no effect on the membrane permeability of glucose. Therefore, we considered that the suppression of blood glucose by Ca-Alg is predominantly due to a decrease in the efficiency of starch digestion as a result of inhibition of alpha-glucosidase, possibly due to increased viscosity of the gastrointestinal contents. Next, we investigated the optimum amount in the diet and the optimum particle size of Ca-Alg for suppressing postprandial blood glucose level in rats orally administered a diet containing starch with various amounts and particle sizes of Ca-Alg. We found that 5% by weight of 270-mesh-pass Ca-Alg was most effective. PMID- 29973435 TI - Mito-mice? and mitochondrial DNA mutator mice as models of human osteoporosis caused not by aging but by hyperparathyroidism. AB - Mitochondrial DNA (mtDNA) mutator mice showing accelerated accumulation of mtDNA with somatic mutations are potentially useful models of human aging, whereas mito miceDelta showing accelerated accumulation of mtDNA with a deletion mutation (DeltamtDNA) are potentially useful models of mitochondrial diseases but not human aging, even though both models express an age-associated decrease in mitochondrial respiration. Because osteoporosis is the only premature aging phenotype observed in mtDNA mutator mice with the C57BL/6J nuclear genetic background, our previous study precisely examined its expression spectra and reported that both mtDNA mutator mice and mito-miceDelta, but not aged mice, developed decreased cortical bone thickness. Moreover, decreased cortical bone thickness is usually not seen in aged humans but is commonly seen in the patients with hyperparathyroidism caused by oversecretion of parathyroid hormone (PTH). In the present study, we showed higher concentrations of blood PTH in mtDNA mutator mice and mito-miceDelta than in aged mice. We also found that both models developed decreased mitochondrial respiration in the duodenum or renal tubules, which would lead to hypocalcemia, oversecretion of PTH, and ultimately osteoporosis. Thus, mtDNA mutator mice and mito-miceDelta may be useful models of human osteoporosis caused not by aging but by hyperparathyroidism. PMID- 29973437 TI - Randomized, Double-Blind, Crossover Clinical Trial of the Effect of Calcium Alginate in Noodles on Postprandial Blood Glucose Level. AB - We conducted a prospective, randomized, double-blind, 3-group, 3-phase crossover study to evaluate the effect of calcium alginate (Ca-Alg) on the postprandial increase of blood glucose in 15 healthy adult subjects who were given udon noodles containing or not containing Ca-Alg (5 or 8%). The value of DeltaCmax (difference between the maximum (Cmax) and pre-feeding (C0) blood glucose levels) was significantly reduced in both Ca-Alg groups, and the area under the blood glucose level-time curve over 120 min (DeltaAUC, with C0 as the baseline) was also significantly reduced. Thus, supplementation of noodles with Ca-Alg significantly suppressed both the peak postprandial blood glucose level and the total amount of glucose absorption. Blood calcium (Ca) concentration was significantly increased at 120 min after ingestion, but there was no marked change of other parameter values. A questionnaire indicated that addition of Ca Alg did not affect the acceptability of the noodles. These results indicate that Ca-Alg might a useful food additive for helping to prevent lifestyle-related diseases without adversely affecting individual eating habits. PMID- 29973438 TI - DNA fragmentation in epididymal freeze-dried ram spermatozoa impairs embryo development. AB - Sperm freeze-drying is a revolutionary technique, which has been gaining prominence in recent years. The first related significant result was Wakayama and Yanagimachi's demonstration in 1998 of the birth of healthy mouse offspring by Intracytoplasmic Sperm Injection (ICSI), using epididymal freeze-dried spermatozoa. Mouse, rat, and hamster models were the first small mammals born from lyophilized epididymal spermatozoa, whereas most other studies in this field used ejaculated spermatozoa. In this work, we applied this technique to ram epididymal spermatozoa, checking the correlation between DNA integrity and embryo development following ICSI. To do this, epididymal sperm from four rams was lyophilized in a trehalose, glucose, KCl, HEPES, and Trolox media. To evaluate DNA damage and fragmentation after rehydration, samples were processed for Sperm Chromatin Dispersion test (SCD), Two-Tailed Comet Assay, and were used for ICSI. Ram #2 had a higher rate of spermatozoa with intact DNA compared with rams #1, #3, and #4 (28% vs. 3.8%, 2.8%, and 5%, respectively) and the lowest rate of Single-Strand Breaks (SSBs) (70% vs. 95.9%, 92.6%, and 93% respectively). Ram #3 had a higher level of Double-Strand Breaks (DSBs) compared to Ram #1 (4.6% vs. 0.33%, respectively). Embryo development to the blastocyst stage following ICSI was only reached from rams whose sperm had higher level of intact DNA - Rams #2 and #4 (6%, 5/147 and 6.3%, 4/64, respectively). Definitively, the impact of sperm DNA damage on embryonic development depends on the balance between sperm DNA fragmentation extent, fragmentation type (SSBs or DSBs), and the oocyte's repair capacity. PMID- 29973440 TI - ? PMID- 29973439 TI - Evaluation of growth hormone-releasing peptide-2 for diagnosis of thyrotropin producing pituitary adenomas. AB - Thyrotropin (TSH)-producing adenomas are a rare cause of hyperthyroidism and are a type of functional pituitary adenoma. The diagnosis of TSH-producing adenoma is a challenging problem in clinical endocrinology. Since growth hormone-releasing peptide-2 (GHRP-2) fails to induce TSH secretion in normal subjects, the effect of GHRP-2 on TSH levels was therefore examined in patients with TSH-producing adenomas. A total of 5 patients (4 women and 1 man) referred to our departments for further evaluation of pituitary hormones were followed-up using the GHRP-2, TSH-releasing hormone (TRH), octreotide, and bromocriptine tests to examine and evaluate TSH secretory dynamics in TSH-producing adenomas. Of 5 patients, 2 (40%) showed such a significant response, defined as a >50% increase in serum TSH level above baseline in the GHRP-2 test. Additionally, 1 patient showed a 48% increase in serum TSH level. In 1 patient whose adenoma was completely removed, basal serum concentrations of TSH were sufficiently suppressed after the operation, and serum TSH levels failed to increase in response to GHRP-2 administration. In 4 patients (80%), a poor response of serum TSH levels was observed in the TRH test. In 2 out of 5 patients (40%), serum TSH levels were significantly decreased following octreotide administration. No patient demonstrated a significant response to the bromocriptine test. In addition to TRH test, the GHRP-2 test as a potential diagnostic tool for TSH-producing pituitary adenomas. PMID- 29973441 TI - [A novel quantitative JAK2V617F detection kit: prospective clinical performance study comparing MPN patients and healthy subjects]. AB - The JAK2V617F mutation is the commonest major genetic mutation of myeloproliferative neoplasms (MPNs) and has been defined in the WHO diagnostic criteria for MPNs. However, there is still no approved in vitro diagnostic test kit available in Japan. We evaluated a JAK2V617F allele quantification kit (test method) in a prospective, multicenter clinical performance study involving patients with MPNs who were diagnosed with polycythemia vera, essential thrombocythemia, and primary myelofibrosis; healthy volunteers were also included in the analysis. Good correlation was observed between the allele burden determined using the test method vs. that determined using next-generation sequencing (NGS) in the patient group (r=0.998, y=1.071x-0.069; n=156). Furthermore, all allele burdens in the healthy group (n=54) were below the lower limit of the measurement range of the test method (0.042%). Our results confirmed that the test method could quantitatively measure the JAK2V617F allele burden in patients with MPN. Thus, the novel JAK2V617F allele quantification kit can be considered useful for the diagnosis of MPNs. PMID- 29973442 TI - [Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12]. AB - An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 ug mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present. PMID- 29973444 TI - [Systemic lupus erythematosus with marked eosinophilia and clinical features mimicking TAFRO syndrome]. AB - A 76-year-old woman was referred to our hospital because of fever, hemorrhagic skin lesion with pruritus, and severe thrombocytopenia. Anemia; marked eosinophilia; and elevated ALP, CRP, and soluble IL-2 receptor levels were observed on admission. Both anti-nuclear antibody and Coombs tests were positive. Computed tomography revealed bilateral pleural effusion, ascites, abdominal lymphadenopathy, and mild hepatosplenomegaly. A thorough examination for the initial differential diagnoses excluded the possibility of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement, infectious diseases, and eosinophilic granulomatosis with polyangiitis. Remaining possibilities included angioimmunoblastic T-cell lymphoma (AITL) and systemic inflammatory disorders. Although AITL was plausible, there was no histological evidence to support the diagnosis. The patient was then administered prednisolone alone, which led to a lasting resolution of her symptoms. The atypical AITL course raised the suspicion of a misdiagnosis; thus the possibility of an inflammatory disease was reconsidered. TAFRO syndrome was suspected owing to its characteristic clinical features (thrombocytopenia, anasarca, fever and organomegaly). Since a definitive diagnosis required the exclusion of systemic lupus erythematosus (SLE), anti double-stranded DNA antibody was tested in the initial frozen serum sample. An unexpected positive result led to the final diagnosis of SLE. Here, we report a rare case of SLE lacking typical symptoms and exhibiting various hematological abnormalities, such as eosinophilia. PMID- 29973443 TI - [Human parvovirus B19-induced hemophagocytic lymphohistiocytosis and myocarditis in an adult patient with hereditary spherocytosis]. AB - Human parvovirus B19 (HPV-B19) causes hemophagocytic lymphohistiocytosis (HLH). Here we describe a 35-year-old female with hereditary spherocytosis (HS) who developed HLH due to HPV-B19 infection. Upon admission, she had high fever and diarrhea. Laboratory findings included severe pancytopenia and elevated serum triglyceride and ferritin levels. Moreover, high HPV-B19 levels in the peripheral blood and increased reactive lymphocytosis in the bone marrow led to a diagnosis of HLH due to HPV-B19 infection. With supportive therapy and a blood transfusion, HLH symptoms, including fever and myelosuppression, improved in 1 week. However, symptoms of heart failure (HF) suddenly developed, and an echocardiography revealed diffuse systolic dysfunction, suggesting viral myocarditis due to HPV B19 infection. Conservative management with diuretics gradually improved HF symptoms over a period of 2 weeks. HPV-B19 infection in adult patients with HS rarely results in severe HLH, but conservative therapy may improve the symptoms. Nonetheless, a careful follow-up is required after HLH improves because viral myocarditis can develop, as was seen in our patient. PMID- 29973445 TI - [Successful diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein using MYD88 L265P mutation analysis]. AB - A 76-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. M protein of the immunoglobulin G (IgG) type was detected using immunoelectrophoresis. A bone marrow biopsy revealed infiltration of small mature lymphocytes, lymphoplasmacytoid cells with Dutcher bodies, grape cells, and Russell bodies. The MYD88 L265P mutation was detected in the abnormal peripheral lymphocytes, and a diagnosis of lymphoplasmacytoid lymphoma was established. MYD88 L265P mutation analysis is useful for making a diagnosis of non-IgM lymphoplasmacytoid lymphoma because it enables the differentiation from other low grade B-cell malignancies. PMID- 29973446 TI - [Carfilzomib, lenalidomide, and dexamethasone therapy for refractory and relapsed multiple myeloma: a single-center study of 29 patients]. AB - Twenty-nine patients with multiple myeloma were treated with carfilzomib, lenalidomide, and dexamethasone (KLd) therapy. A response better than partial response (PR) was observed in 72.4% patients with relapsed and/or refractory myeloma. Although 13.8% patients developed hypertension, none of them discontinued therapy as they could be managed by appropriate medication. A patient who had an elevated level of BNP prior to initiating KLd therapy developed heart failure. Results from this study demonstrate that KLd therapy is efficacious for treating patients with multiple myeloma; however, they should be carefully monitored for cardiotoxicity. PMID- 29973447 TI - [Overview]. PMID- 29973448 TI - [Management of paroxysmal nocturnal hemoglobinuria: an update]. AB - The accepted therapeutic strategy for treating paroxysmal nocturnal hemoglobinuria (PNH) has drastically changed since eculizumab was introduced in 2010 in Japan. Its clinical impact has paved way for the new area of anti complement therapy, and it has sparked further research and development of anti complement drugs. The long-term safety and efficacy of eculizumab was established in clinical settings by analyzing post-marketing surveillance that is mandatory in Japan and in clinical trial settings. However, new clinical complications such as resistance to eculizumab, breakthrough hemolysis, extravascular hemolysis, and invasive meningococcal disease (IMD) have emerged after the introduction of eculizumab. Therefore, it is important to strategize effective ways to tackle these issues occurring during eculizumab treatment. In Japan, it is an urgent priority to reach a consensus for managing IMD in patients treated with eculizumab and for establishing protocols for prophylaxis to prevent meningococcal infection. PMID- 29973449 TI - [Acquired aplastic anemia: recent advances in pathophysiology and treatment]. AB - Acquired aplastic anemia (AA) is an autoimmune disease caused by T cells specific to hematopoietic stem cells (HSCs). The presence of HLA allele-lacking leukocytes due to uniparental disomy of the short arm of chromosome 6 (6pUPD) or allelic mutations strongly indicates the involvement of such cytotoxic T cells in the pathogenesis of AA. Attempts to improve treatment outcomes by intensification of immunosuppressive therapy (IST) have been unsuccessful. Eltrombopag (EPAG), a thrombopoietin receptor agonist, has recently emerged as a novel therapeutic agent for AA. EPAG directly acts on HSCs and stimulates proliferation, thereby achieving remission in approximately 40% AA patients refractory to IST. However, some cases develop chromosomal aberrations during treatment. Because somatic mutations are common in patients with AA, verifying whether EPAG induces clonal proliferation or evolution of mutant HSCs is critical. PMID- 29973451 TI - [Overview]. PMID- 29973450 TI - [Inherited bone marrow failure syndrome: management and diagnostic advances utilizing next-generation sequencing]. AB - Inherited bone marrow failure syndromes (IBMFS) are part of a heterogeneous disease category in which at least one hematopoietic cell lineage is reduced in the bone marrow owing to a pathogenic genetic mutation. IBMFS comprise >25 defined disease entities, including Fanconi anemia (FA), Diamond-Blackfan anemia, and dyskeratosis congenita. The diagnosis is based on hematological and physical findings with the aid of several disease-specific diagnostic tests, such as the chromosomal breakage test for FA. With recent advances in clinical molecular studies that have revealed a considerable amount of pathognomonic molecular lesions in IBMFS, the role of genetic tests has become more important in the diagnosis of these diseases. Comprehensive genetic diagnostic systems using next generation sequencing has been developed in Japan and other countries, making it technically possible to simultaneously analyze and evaluate >100 causative genes of IBMFS, and it is expected to be widely used in clinical settings. PMID- 29973452 TI - [Acute promyelocytic leukemia: state-of-the-art management]. AB - Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML) retinoic acid receptor (RAR) alpha fusion protein generated by the chromosomal translocation t (15;17) which affects both nuclear receptor signaling and PML nuclear body (NB) assembly. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as molecular targeted therapies directed against PML RARalpha has been a major breakthrough in APL treatment. ATRA and ATO target RARalpha and PML, respectively, and elicit PML-RARalpha degradation, leading to the reformation of normal NBs and cell differentiation. In several multicenter trials, more than 90% of newly diagnosed APL patients treated with ATRA and chemotherapy achieved complete remission, of whom 20%-30% subsequently relapsed; the overall survival was approximately 80% in these studies. However, several major clinical problems continue to account for treatment failure including early death due to hemorrhage, infection during consolidation, disease relapse, and secondary malignancies. These issues are associated mainly with anticancer agents used in combination with ATRA. Combination therapy using ATRA and ATO is the current standard therapy for untreated patients with APL in Western countries. The current problems in patients with APL treated with ATRA and ATO are APL differentiation syndrome and high risk of relapse in patients with an initial leukocyte count of more than 10*109/l. PMID- 29973453 TI - [Acute myeloid leukemia of the elderly: recent progresses in therapy]. AB - Therapeutic modalities for acute myeloid leukemia (AML) in elderly include intensive chemotherapy, less-intensive chemotherapy, and best supportive care. The choice of treatment is based on patients' general physical condition, leukemic prognostic factors, preference of the patient/family, and the available social support. Findings of comprehensive geriatric assessment and comorbidities are considered while selecting therapeutic modalities. AML score may suggest the appropriateness of the use of intensive chemotherapy. When intensive chemotherapy is tolerable, enocitabine or cytarabine + daunorubicin is used as remission induction chemotherapy. Consolidation chemotherapy comprising three courses of cytarabine-based regimens is administered after complete remission. When intensive chemotherapy is not tolerable, low-dose cytarabine is used. CPX351, a novel antileukemic agent, is a liposomal formulation of asynergistic 5 : 1 molar ratio of cytarabine and daunorubicin. In a randomized phase 2 trial in older patients with AML, CPX351 showed better response rate and survival than cyarabine + daunorubicin regimen. PMID- 29973454 TI - [Myeloproliferative neoplasms: recent progresses in therapy]. AB - The expected survival duration of polycythemia vera (PV) and essential thrombocythemia (ET) patients is not substantially lower than that of the general population. The current goal of therapy is to prevent thrombohemorrhagic events associated with PV and ET. The current first line therapy for PV is phlebotomy, hydroxyurea (HU), and aspirin, while that for ET was HU or anagrelide. The follow up phase 3 randomized trial wherein the hematological response was evaluated in PV patients treated with ropeginterferon alfa-2b, a next-generation monopegylated IFN-alpha-2b, or HU, demonstrated a superior hematological effect and a lower incidence of adverse events in patients who were treated with ropeginterferon. The prognosis of primary myelofibrosis (PMF) is poorer than that of PV or ET. The only curative therapeutic option for PMF patients is allogeneic hematopoietic stem cell transplantation (HSCT). Other than HSCT options, ruxolitinib ameliorates splenomegaly and MF-associated symptoms and provides an overall survival benefit in PMF patients with intermediate-2 or high risk. Several different JAK inhibitors have been developed; however, many of them were discontinued because of toxicity concerns. Recently, promising results have been demonstrated for the effect of different JAK inhibitors as well as the drugs that directly target anemia and bone marrow fibrosis. PMID- 29973455 TI - [Chronic myeloid leukemia: state-of-the-art management]. AB - Treatment-free remission leading to a sustained deep molecular response (DMR) following the discontinuation of tyrosine kinase inhibitor (TKI) is a therapeutic goal in patients with chronic myeloid leukemia chronic phase (CML-CP). In 2017, discontinuing TKI treatment at the outside of clinical trials was recommended for the first time by National Comprehensive Cancer Network guidelines. The criteria for TKI discontinuation include at least 3 years of TKI therapy, a stable DMR for >=2 years, and monthly molecular monitoring during the first 6 months following discontinuation of treatment. Moreover, discontinuing TKI treatment at the outset of clinical trials may soon be recommended by the Japanese CML guidelines. Thus, achieving a sustained DMR is the current focus of research in CML-CP patients without a history of TKI resistance. PMID- 29973456 TI - [Overview]. PMID- 29973457 TI - [Acquired hemophilia A]. AB - The Japanese Society on Thrombosis and Hemostasis published the guidelines for the treatment of acquired hemophilia A in November 2011 to promote its early diagnosis and appropriate therapy. Successively, the disease was more readily recognized, and a revised version of the guidelines was published in December 2017. Bleeding in patients with acquired hemophilia A is typically more severe than that in patients with congenital hemophilia A. An analysis using the global coagulation assay revealed that the hemostatic function of the plasma of patient with acquired hemophilia A is extremely low, even if factor VIII activities are retained; we present the presumed mechanism for the same. Regarding immunosuppressive therapy to eliminate inhibitors, a large-scale data analysis of patients enrolled in Europe reported that prednisolone (PSL) monotherapy or combination therapy with PSL and cyclophosphamide is the first-line therapy for this disorder, supporting the recommended therapy mentioned in Japan's guidelines. This study aims to highlight the revised guidelines and the latest findings on pathophysiology, diagnosis, and therapy of acquired hemophilia A. PMID- 29973458 TI - [Congenital thrombocytopenia]. AB - Congenital thrombocytopenias are a genetically and clinically heterogeneous group of platelet disorders that are characterized by thrombocytopenia since birth. Although very rare, these disorders are encountered in routine clinical practice. Since 2011, the application of next generation sequencing has identified more than 15 new genes, which, when mutated, can cause congenital thrombocytopenia. Currently, at least 35 different forms have been identified. Although thrombocytopenia is congenital, some forms present an elevated risk of developing additional complications. In MYH9 disorders, patients often develop nephritis, deafness, and cataract. In a subgroup of congenital thrombocytopenias, with defects in the TPO/MPL signaling pathways or transcription factors, enhanced or reduced hematopoietic cell proliferation properties often culminates in the development of hematological malignancy or bone marrow failure. Proper and early genetic diagnosis is essential for the treatment of congenital thrombocytopenia. PMID- 29973459 TI - [Anticoagulants: current topics]. AB - Despite the introduction of direct oral anticoagulants (DOAC), the need for more effective and safer antithrombotic strategies exists. Recently, the findings stating that the contact system is important for thrombus formation has identified factor XI as a potential target for new anticoagulants. Approximately 20-30% of patients who develop venous thromboembolism (VTE) also have cancer. To date, the drugs primarily used in the treatment of VTE are heparin in the acute phase and warfarin in the chronic phase. Recently, a large-scale international clinical trial, which examined the composite outcomes of VTE recurrence and major bleeding in cancer patients, found that edoxaban, a direct factor Xa inhibitor, is not inferior to low-molecular-weight heparin. The study also showed that DOACs have a promising potential to prove therapeutically effective in future studies. Anticoagulants are associated with a severe side effect, bleeding, which makes emergency neutralization an important concern. Four-factor prothrombin complex concentrate can be used to reverse the effect of warfarin and could also be effective as a neutralizing agent in patients having received DOACs. Moreover, more specific reversing agents include the approved human monoclonal antibody fragment idarucizumab for reversing the effects of dabigatran. PMID- 29973460 TI - [Role of transcription factor C/EBPbeta in the pathophysiology of chronic myeloid leukemia and as a potential target in eradicating leukemic stem cells with interferon-alpha]. AB - Tyrosine kinase inhibitors (TKIs) have markedly improved the prognosis of patients with chronic-phase chronic myeloid leukemia (CML). However, the development of a novel therapeutic strategy that can target and eradicate CML stem cells remains an important requirement to achieve a complete cure for CML because these stem cells cause relapse and drug resistance even in patients receiving TKI treatment. Interferon-alpha (IFNalpha) has long been used for the treatment of chronic-phase CML, and its efficacy is now being re-evaluated as a therapeutic option. Some clinical studies have demonstrated the additive efficacy of IFNalpha in CML patients treated with TKI. However, the mechanism of action is not fully understood. In this review, we introduce our recent findings on the effects of IFNalpha on CML stem cells via the transcription factor CCAAT/enhancer binding protein beta, which regulates stress-induced hematopoiesis. PMID- 29973461 TI - [Ineffective erythropoiesis in myelodysplastic syndrome]. AB - Ineffective hematopoiesis is one of the hallmarks of myelodysplastic syndrome (MDS). Recently, several signaling pathways responsible for inefficient erythropoiesis in MDS have been uncovered. The p53-S100a8/S100a9-TLR4 pathway is involved in ineffective erythropoiesis in 5q minus (5q-) syndrome. Somatic mutations target multiple components of the messenger RNA (mRNA) splicing machinery including Splicing Factor 3 Subunit b1 (SF3b1) and Serine Arginine Rich Splicing Factor 2 (SRSF2) in patients with MDS. SF3b1 is the most frequently mutated spliceosome component in MDS and is mutated approximately 85% of the time in MDS with ring sideroblasts (MDS-RS). SF3b1 mutations are not simple loss-of function or inactivating mutations but result in a change of function and cause aberrant splicing of genes that may be involved in the pathogenesis of MDS-RS. Recurrent mutations are also found in epigenetic regulator genes in MDS, including polycomb repressive complex 2 (PRC2) genes. The loss of enhancer of zeste homolog 2 (EZH2), an enzymatic component of PRC2 in mice, markedly accelerates the development of MDS in combination with representative driver mutations. The loss of EZH2 causes impaired erythropoiesis and increases ineffective hematopoiesis. Of interest, EZH2 is one of the targets of SRSF2 mutants in MDS, and mis-spliced EZH2 mRNA undergoes nonsense-mediated decay (NMD) -dependent degradation. All these data suggest that EZH2 insufficiency causes ineffective erythropoiesis. PMID- 29973462 TI - [Differentiation and proliferation of hematopoietic stem cells are regulated by C/EBPbeta, a transcription factor required for emergency granulopoiesis]. AB - Under stress conditions such as infection, inflammation, and hematopoietic recovery following chemotherapy or transplantation, the hematopoietic system is required to meet the increasing demands, especially from myeloid cells. Therefore, an understanding of the molecular mechanism underlying stress hematopoiesis is clinically imperative. We previously showed that C/EBPbeta, which is a transcription factor required for emergency granulopoiesis, plays a pivotal role at the level of hematopoietic stem/progenitor cells under stress conditions. Upon exposure to stress, the C/EBPbeta protein is upregulated in the hematopoietic stem cells. A close examination of C/EBPbeta knockout mice revealed that C/EBPbeta regulates the proliferation and differentiation of hematopoietic stem cells at the cost of the self-renewing activity. Further elucidation of the functions and regulation of C/EBPbeta in hematopoietic stem cells will facilitate an understanding of stress hematopoiesis. PMID- 29973463 TI - [Functional diversity of disorder-specific macrophages]. AB - Recent research has revealed that macrophages and monocytes comprise various subtypes. Previously, we demonstrated that JMJD3 is vital for macrophage differentiation in response to allergic stimuli. Moreover, we substantiated that Trib1 controls the differentiation of tissue-resident macrophages in peripheral organs, such as adipose tissue. This study aims to elucidate that Ceacam1+Msr1+Ly6C-F4/80-Mac1+ monocytes are essential for the development of fibrosis. Remarkably, these cell types harbor bilobed-like nucleus and some granules in the cytoplasm. Thus, we named these as cell segregated-nucleus containing atypical monocytes (SatM). The results revealed that NFIL6 is critical for the differentiation of SatM, and the lack of this protein causes a complete deficiency of SatM. Furthermore, the development of fibrosis was prevented in NFIL6-/- chimeric mice and the adoptive transfer of SatM into NFIL6-/- chimeric mice resulted in fibrosis. Thus, macrophage and monocytes comprised multiple subtypes with functional diversity. PMID- 29973464 TI - [Identification of a human progenitor strictly committed to monocytic differentiation: a counterpart of mouse cMoPs]. AB - Monocytes give rise to macrophages and dendritic cells (DCs) under steady-state and inflammatory conditions, thereby contributing to host defense and tissue pathology. Inflammation triggers the differentiation of tissue-infiltrating monocytes into monocyte-derived macrophages and DCs, which are associated with homeostatic host defense reactions and inflammatory diseases. In mice, monocytes are divided into classical Ly6chi- and non-classical Ly6clo-expressing subsets. Ly6clo monocytes are present only in the blood; however, Ly6chi monocytes are found in blood and other tissues (wherein they differentiate into macrophages and DCs). In this context, most Ly6clo monocytes are derived from Ly6chi monocytes. In humans, monocytes comprise major CD14+CD16- and other CD14+CD16+ and CD14loCD16+ monocytes. A monocyte lineage-restricted common monocyte progenitor (cMoP) was previously identified in mice; herein, we introduce human cMoP, which was identified as a CLEC12AhiCD64hi subpopulation of conventional granulocyte monocyte progenitors (cGMPs) in umbilical cord blood and bone marrow. The human cMoP produced monocyte subsets without showing any potential of differentiating into myeloid or lymphoid cells ex vivo. Within the cGMP population, we also identified revised GMPs that completely lacked DC and lymphoid potential, which sequentially produced cMoPs, pre-monocytes, and monocytes. Collectively, our findings enhance the current understanding of human myeloid cell differentiation pathways. PMID- 29973465 TI - ? PMID- 29973466 TI - Skin temperature responses to hand-arm vibration in cold and thermoneutral ambient temperatures. AB - Hand-arm vibration (HAV) from hand-held vibrating machines increases the risk of injury in the form of vasoconstriction in the fingers, commonly named as vibration induced white fingers (VWF). Cold temperature may increase that risk. This experimental study examined and compared the effects of the skin temperature of the hands during and after exposure to HAV in thermoneutral and cold conditions. Fourteen subjects were exposed to three conditions: 25 degrees C with HAV, 5 degrees C with HAV or 5 degrees C without HAV. Their skin temperatures were continuously recorded for the thumbs, index fingers, palms, and back of hands. After 20 min of acclimatization, the subjects held, for five min, two handles where the right handle could vibrate at 5 m/s2 and the left was stationary. Finally, they released their grip and stood still for 10 more min. HAV had no additional cooling effect in cold during gripping of the handles. After the subjects released the handles there was only a HAV-induced cooling effect in the left palm with on average 0.5 degrees C colder skin temperature. A single exposure to HAV will not cause an injury such as VWF, but as the present study show: short-term exposure to HAV causes some changes in skin temperature. PMID- 29973467 TI - Identifying shift worker chronotype: implications for health. AB - Shift workers are at risk for developing serious health issues due to short sleep. One cause of short sleep is circadian misalignment: sleep time is not synchronized with the body's natural circadian rhythms. Although circadian rhythms are strongly driven by the light/dark cycle, humans have individualized sleep time preferences (chronotypes) based on genetics, development, and external influences. Evening chronotype individuals fall asleep later than average and have a higher risk for developing various noncommunicable diseases. What is unclear is the association between chronotype, shift work, and risks for acquiring chronic conditions. This review is focused on shift worker chronotype and associations with obesity. Because of the paucity of research, other health issues connected with circadian misalignment were included, allowing for a total of 21 research studies. Evidence from this review supports chronotype and certain health issues are associated with shift work, even after adjusting for short sleep duration. In addition, there is evidence to support future research on how shift worker chronotype matched with shift timing impacts worker health. Through better understanding of this interface, occupational health providers can provide more comprehensive worker education on the risks associated with shift work and sleep disturbances. PMID- 29973468 TI - Workplace fatalities in Brunei Darussalam. AB - In 2012, there were about 2.3 million deaths worldwide attributed to work. The highest workplace fatality rate (WFR) was reported on construction sites due to high risk activities. Globally, fall from height is the leading cause of fatal injuries for construction workers. The objectives are to determine Brunei Darussalam's demographic distribution of occupational fatality; identify causal agents and industry where occupational fatalities commonly occur; and determine WFR by year. This cross-sectional study retrospectively reviewed records of occupational fatality which were notified to the Occupational Health Division, Ministry of Health, from January 2012 until December 2016. Notified occupational fatalities in Brunei over a five-year period was 50. Most of the cases were in 31 40 age group. 38% of fatality cases occurred in Indonesian workers. 60% were from the Construction industry. 38% were due to fall from height. WFR averaged 5.28 and the highest industry-specific fatality rate was seen in the Construction industry, ranging from 27.94 to 56.45 per 100,000 workers. WFR for Brunei Darussalam from 2012 to 2016 was similar to that of Malaysia, but higher than Singapore and the UK. Industry-specific fatality rate for the Construction and Manufacturing industries were higher than those of Singapore and the UK. PMID- 29973469 TI - Acute toxic encephalopathy induced by occupational exposure to 1,2 dichloropropane. AB - 1,2-Dichloropropane (1,2-DCP) is used widely in Korea as a substitute for trichloroethylene or methylene chloride. Some companies mistakenly consider that 1,2-DCP is an eco-friendly detergent because its use is not regulated, but 1,2 DCP is known to inhibit the central nervous system in animals; a few cases of accidental exposure have been reported in humans. We present a case of acute encephalopathy caused by exposure to 1,2-DCP. A 41 yr-old male presented with dizziness, headache, and diplopia after exposure to the detergent without protective equipment. Brain magnetic resonance imaging suggested metabolic encephalopathy, but the patient had no thiamine deficiency and no other metabolic disorder. As the symptoms had commenced after exposure to a large amount of solvent while skimming rust from the surface, and as the symptoms were more severe during the work week, improved on weekends, and disappeared after solvent exposure ceased, the toxic encephalopathy was likely induced by inhalation of the detergent. PMID- 29973470 TI - Effect of Catha edulis (khat) on pancreatic functions in streptozotocin-induced diabetes in male Sprague-Dawley rats. AB - People consume Catha edulis (khat) for its euphoric effect, and type 1 diabetics have claimed that khat could reduce elevated levels of blood sugar. However, khat has been suggested to provoke diabetes mellitus through destruction of pancreatic beta-cells. This study investigated the effect of an ethanolic khat extract on pancreatic functions in type 1 diabetes (T1DM)-induced male Sprague-Dawley rats and to assess its in vitro cytotoxicity in rat pancreatic beta-cells (RIN-14B). T1DM was induced in a total of 20 rats with a single intraperitoneal injection of 75 mg/kg of streptozotocin. The rats were distributed into four groups (n=5): the diabetic control, 8 IU insulin-treated, 200 mg/kg khat-treated, and 400 mg/kg khat-treated groups. Another 5 rats were included as a nondiabetic control. Body weight, fasting blood sugar, and caloric intake were recorded weekly. Four weeks after treatment, the rats were sacrificed, and blood was collected for insulin, lipid profile, total protein, amylase, and lipase analysis, while pancreases were harvested for histopathology. In vitro, khat exerted moderate cytotoxicity against RIN-14B cells after 24 and 48 h but demonstrated greater inhibition against RIN-14B cells after 72 h. Neither 200 mg/kg nor 400 mg/kg of khat produced any significant reduction in blood sugar; however, 200 mg/kg khat extract provoked more destruction of pancreatic beta-cells as compared with the diabetic control. Ultimately, neither 200 mg/kg nor 400 mg/kg of khat extract could produce a hypoglycemic effect in T1DM-induced rats. However, 200 mg/kg of khat caused greater destruction of pancreatic beta-cells, implying that khat may cause a direct cytotoxic effect on pancreatic beta-cells in vitro. PMID- 29973471 TI - Habitat Alterations by Viruses: Strategies by Tupanviruses and Others. PMID- 29973472 TI - Inter-Technique Consistency and Prognostic Value of Intra-Procedural Angiographic and Echocardiographic Assessment of Aortic Regurgitation After Transcatheter Aortic Valve Implantation. AB - BACKGROUND: We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment. Methods and Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time density integral in the LV outflow tract to that in the ascending aorta (LVOT AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05-0.11); mild, 0.12 (IQR, 0.09-0.15); and moderate, 0.17 (IQR, 0.15-0.22; P<0.05 for none-trace vs. mild, and mild vs. moderate). LVOT-AR strongly correlated with %CE (r=0.72, P<0.0001). At 1 year, the rate of the composite end-point of all-cause death or HF re-hospitalization was significantly higher in >mild AR patients compared with no-mild AR on intra procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR <=0.17 (59.5% vs. 16.6%, P=0.03). CONCLUSIONS: VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality. PMID- 29973473 TI - Expansion of the applicability domain for highly volatile substances on the Short Time Exposure test method and the predictive performance in assessing eye irritation potential. AB - The Short Time Exposure (STE) test method is an in vitro method for assessing the eye irritation potential of chemicals and is used to classify the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Category 1 and No Category (NC). The method has been adopted by the Organisation for Economic Co-operation and Development (OECD) as test guideline (TG) 491 since 2015. While this method can be used to classify GHS NC, it is not suitable for testing highly volatile substances and solids other than surfactants. Here we evaluated highly volatile substances to expand the applicability domain. According to TG 491, acetone, ethanol, iso-propanol, and methyl acetate as highly volatile substances resulted in false negatives. Saline was selected as a solvent of these false negatives. In this study, mineral oil was used as the solvent, because these false negatives were amphiphilic. Based on this change, four highly volatile substances were correctly evaluated. The predictive performance for classifying GHS NC was then verified using a substance dataset constructed in reference to the Draize eye test Reference Database and STE Summary Review Document. The accuracy and false-negative rate were 86.6% (194/224) and 3.8% (3/80), respectively. Collectively, the applicability domain was expanded by changing the solvent to mineral oil for highly volatile substances, and the predictive performance for the new applicability domain including highly volatile substances was excellent. The STE test method is suitable to classify GHS NC, indicating its applicability as a test method in a bottom-up approach. PMID- 29973474 TI - A 13-week subchronic toxicity study of acetaminophen using an obese rat model. AB - Although obesity is increasing worldwide, experimental studies examining the possible association between obesity and susceptibility to chemical toxicity are limited. In the present study, we performed a 13-week toxicity study for acetaminophen (APAP), a well-known drug that exhibits hepatotoxicity as an adverse effect, using an obese rat model to investigate the differences in susceptibility between obese and normal individuals. Male F344 and obese Zucker (lean and fatty) rats were administered 0, 80, 253, 800, 2,530, or 8,000 ppm APAP in the diet for 13 weeks. No significant toxicity related to APAP treatment was observed in terms of clinical signs and hematology in all three strains. Body weight gain in F344 and lean rats was significantly decreased by 8,000 ppm APAP treatment. Significant increases in serum total cholesterol level and relative liver weights were detected in F344 rats in the highest dose group. On histopathological assessment, centrilobular hepatocellular hypertrophy was observed in the 8,000 ppm groups of F344 and lean rats, whereas no histopathological changes were induced by APAP in fatty rats. The no-observed adverse-effect levels (NOAELs) of APAP were evaluated to be 2,530 ppm in F344 and lean rats (142.1 and 152.8 mg/kg bw/day, respectively) and more than 8,000 ppm in fatty rats (> 539.9 mg/kg bw/day). These results suggested that obese Zucker rats may be less susceptible to APAP-dependent toxicity in the liver than their lean counterparts. PMID- 29973475 TI - Effect of dosing frequency of teriparatide (PTH 1-34) on bone formation in rats: comparison of bone metabolism marker levels. AB - Teriparatide, a drug used in the treatment of osteoporosis, was administered to rats subcutaneously for the duration of 3 months, at a frequency of either once weekly or once daily to demonstrate the varying levels of anabolic action the drug can have on bone depending on the dosing frequency. The levels of biomarkers in the blood were compared and found to vary in osteocalcin (OC), a biomarker of bone formation, and cross-linked N-telopeptide of type 1 collagen (NTx), a biomarker of bone resorption, according to the dosing frequency. In the once weekly regimen, teriparatide did not affect NTx levels at any of the doses studied, while OC levels increased with dose, peaking at 72 hr, then returning to normal before the next injection (after 1 week). Bone mineral density (BMD) levels increased moderately with no difference between doses. This was thought to result from the steady state achieved following increases in bone formation and bone absorption. In the once-daily dosing regimen, meanwhile, NTx levels increased with dose, and OC levels were markedly higher when compared to those with the once-weekly dosing. BMD levels were higher than those with the once weekly dosing, but with no difference between doses. This was considered a result of unlimited, excessive increases in bone formation due to daily administration of the drug. These results suggest that teriparatide promotes normal bone metabolism ("stationary mini-modeling") when administered once weekly, and has an anabolic action with high metabolic turnover ("high-turnover remodeling") when administered once daily. PMID- 29973476 TI - Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR. AB - The nuclear receptor pregnane X receptor (PXR) plays a major role in the xenobiotic-induced expression of drug-metabolizing enzymes. PXR activation is also associated with several adverse events in the liver. Especially, the receptor enhances hepatocyte proliferation mediated by chemical liver tumor promoters, suggesting that exposure to PXR activators increases the risk of liver cancer. In this study, we have investigated the influences of food additives on PXR to understand their potential adverse effects when they are taken in combination with other chemical compounds. We first screened 25 food additives and related compounds for their PXR-activating ability using reporter assays in HepG2 cells expressing mouse PXR, and found that imazalil dose-dependently activated mouse PXR. Next, to investigate whether imazalil could activate mouse PXR in vivo, mice were treated with imazalil and we found that imazalil treatment increased hepatic mRNA levels of Cyp3a11, a PXR target gene. Finally, to investigate the influence of imazalil exposure on the hepatocyte proliferation induced by nuclear receptor constitutive active/androstane receptor (CAR), mice were treated with imazalil with or without mouse CAR activator TCPOBOP. Although imazalil alone did not induce hepatocyte proliferation, co-treatment with imazalil facilitated the TCPOBOP-dependent proliferation, indicated by the increases in cell proliferation marker levels, Ki-67-positive nuclei and Mcm2 mRNA levels. These results suggest that in mice imazalil activates PXR to enhance hepatocyte proliferation mediated by CAR-activating liver tumor promoters. PMID- 29973477 TI - Generalization tests using different dosing routes from those of drug discrimination training in rats. AB - The purpose of this study was to investigate the discriminative stimulus properties of morphine and codeine using different administration routes to that used at drug discrimination training. Rats were trained to discriminate morphine at 3 mg/kg from saline by the intraperitoneal route in a standard two-lever drug discrimination paradigm. Generalization of morphine by the subcutaneous and the oral routes, and codeine by the intraperitoneal and the oral routes to the discriminative stimulus properties of the morphine training dose were investigated. Morphine at 3 mg/kg by the subcutaneous route generalized to the morphine training dose and 10 of 12 rats showed 80% or more morphine-lever responses. In the administration of morphine by the oral route, morphine at 30 mg/kg generalized to the morphine training dose and all rats showed 80% or more morphine-lever responses within the range of 3 to 30 mg/kg. In the administration of codeine by the intraperitoneal route, codeine at 20 mg/kg generalized to the morphine training dose and 14 of the 15 animals showed 80% or more morphine-lever responses within the range of 3 to 20 mg/kg. In the administration of codeine by the oral route, codeine at 60 mg/kg generalized to the morphine training dose and 14 of the 15 animals showed 80% or more morphine-lever responses within the range of 10 to 60 mg/kg. Thus, the discriminative stimulus properties of morphine and codeine were comparable when using different administration routes to those at discrimination training. PMID- 29973478 TI - Comparison of mercury and methylmercury bioaccumulation in earthworms (Bimastus parvus) native to landfill-leachate-contaminated forest soil. AB - Total mercury (THg) and methylmercury (MeHg) bioaccumulation was explored in the Bimastus parvus species of earthworm (B. parvus) native to the leachate contaminated forest soils around a Hg-polluted traditional landfill in Japan. General soil properties and concentrations of THg and MeHg in forest soils and in B. parvus were determined. The results indicated that the average THg concentrations in B. parvus and in forest soils in the leachate-contaminated sites were 10.21 and 14.90 times higher than those in the reference sites, respectively, whereas similar average MeHg concentrations were observed in forest soils (< 0.01 mg kg-1) and in B. parvus (0.100-0.114 mg kg-1) across all sampled sites. The average bioaccumulation factors of THg in B. parvus (BAFTHg) in forest soil were similar between the leachate-contaminated sites and the reference sites. Cluster and regression analyses demonstrated that the B. parvus Hg (THg and MeHg) and soil THg were positively correlated with each other and with soil organic matter (SOM) and clays, but were negatively correlated with sand and hardly correlated with silts and pH in leachate-contaminated forest soils. From these results, it was proposed that Hg exposure to food chains is possible through B. parvus, because B. parvus showed a high ability to accumulate THg and MeHg in both leachate-contaminated and reference forest soils. Together, these findings indicated that the role of B. parvus in MeHg production is not clear, and it is possible that the MeHg in B. parvus was firstly formed within forest soils and then accumulated in their tissues. PMID- 29973479 TI - Genetic, acute and subchronic toxicity studies of matured hop extract produced by extraction from heat-treated hops. AB - It has been demonstrated that successive ingestion of matured hop extract (MHE), produced by extraction from heat-treated hops, results in body fat reduction in animals and humans; however, preclinical safety studies have not been reported. In this study, we conducted in vitro and in vivo safety studies for MHE. Genotoxicity was evaluated using the Ames test, in vitro chromosomal aberration test, and in vivo micronucleus test. To assess acute safety, a single, oral administration of MHE to rats was monitored. Subchronic safety was assessed by repeated feeding with MHE for 90 days. The in vitro chromosomal aberration test was positive at 3,330 MUg/mL and 5,000 MUg/mL without metabolic activation. However, MHE did not induce any reverse mutation with or without metabolic activation in the Ames test, and no abnormalities were observed at a dose of 2,000 mg/kg body weight in the rat micronucleus test. In the acute and subchronic safety studies, no deaths or toxicological signs were recorded during the observation period. In addition, no changes in body weights, feed/water consumption, clinical signs, ophthalmoscopy, urinalysis, hematology, blood biochemistry, organ weights, or histopathology were observed after repeated administration of MHE. Therefore, the no-observed-adverse-effect-level (NOAEL) of MHE was considered to be over 3,484 and 4,022 mg/kg body weight/day in males and females, respectively. These results indicate that there is no safety concern for MHE in the present preclinical safety study. PMID- 29973480 TI - Molecular characterization and immune responsive expression of feline MDA5 gene. AB - The retinoic acid-inducible gene-I-like receptor (RLR) family is a group of cytosolic RNA helicase proteins that play an important role in sensing viral RNAs. Melanoma differentiation-associated gene 5 (MDA5), an RLR protein, recognizes viral double-stranded RNA and 5'-triphosphate single-stranded RNA in the cytoplasm for the expression of type I interferon (IFN). The expression of MDA5 is also induced by type I IFN. In the present study, we determined the complete coding sequence of the feline MDA5 gene, and analyzed its structure. In addition, we examined tissue expression patterns, inducibilities of the feline MDA5 by polyinosinic-polycytidylic acid and type I IFN, and a functional role of feline MDA5 on type I IFN expression. PMID- 29973481 TI - Effects of temperature, pH and curing on the viability of Sarcocystis, a Japanese sika deer (Cervus Nippon centralis) parasite, and the inactivation of their diarrheal toxin. AB - Recently, the Sarcocystis parasite in horse and deer meat has been reported to be a causative agent of acute food poisoning, inducing nausea, vomiting and diarrhea. Compared with other causative agents, such as bacteria, viruses and other parasites, in deer meat, the Sarcocystis species parasite, including its stability under various conditions, is poorly understood. In this study, we assessed the viability of Sarcocystis spp. and the activity of their diarrhea toxin (a 15-kDa protein) in deer meat under conditions of freezing, cold storage, pH change and curing. In addition, the heat tolerance was assayed using purified bradyzoites. The results showed that the species lost viability by freezing at 20, -30 and -80 degrees C for <1 hr, heating at 70 degrees C for 1 min, alkaline treatment (pH 10.0) for 4 days and addition of salt at 2.0% for <1 day. Immunoblot assays showed that the diarrhea toxin disappeared together with the loss of viability. However, the parasite survived cooling at 0 and 4 degrees C and acidification (pH 3.0 and 5.0) for more than 7 days with the diarrhea toxin intact. These results provide useful information for developing practical applications for the prevention of food poisoning induced by diarrheal toxin of Sarcocystis spp. in deer meat during cooking and preservation. PMID- 29973482 TI - Low Levels of Chito-Oligosaccharides Are Not Effective in Reducing Deoxynivalenol Toxicity in Swine Jejunal Explants. AB - Deoxynivalenol (DON) is a mycotoxin that affects the intestinal morphology of animals, impairing nutrient intake and growth. On the other hand, dietary supplementation with functional oligosaccharides as chito-oligosaccharides (COS) has shown positive effects on the intestinal health of piglets. Therefore, the objective of the present study was to evaluate the effect of low doses of COS in preventing DON-induced intestinal histological changes, using a swine jejunal explant technique. The intestinal explants were incubated at 37 °C in culture medium for 4 h and exposed to the following treatments: (a) control (only culture medium), (b) DON (10 µM), (c) 25COS (0.025 mg·mL−1 of COS); (d) 50COS (0.05 mg·mL−1 of COS); (e) 25COS plus DON (25COS + DON); (f) 50COS plus DON (50COS + DON). Explants exposed to COS presented intestinal morphology similar to control samples. DON induced a significant decrease in the histological score as a consequence of moderate to severe histological changes (apical necrosis, villi atrophy, and fusion) and a significant decrease in morphometric parameters (villi height, crypt depth, villi height:crypt depth ratio, and goblet cells density). The intestinal morphology of samples exposed to COS + DON remained similar to DON treatment. In conclusion, low levels of COS did not counteract DON-induced intestinal lesions. PMID- 29973483 TI - Cynomolgus Monkeys (Macaca fascicularis) as an Experimental Infection Model for Human Group A Rotavirus. AB - Group A rotaviruses (RVA) are one of the most common causes of severe acute gastroenteritis in infants worldwide. Rotaviruses spread from person to person, mainly by faecal-oral transmission. Almost all unvaccinated children may become infected with RVA in the first two years of life. The establishment of an experimental monkey model with RVA is important to evaluate new therapeutic approaches. In this study, we demonstrated viral shedding and viraemia in juvenile-adult Macaca fascicularis orally inoculated with Wa RVA prototype. Nine monkeys were inoculated orally: seven animals with human RVA and two control animals with saline solution. During the study, the monkeys were clinically monitored, and faeces and blood samples were tested for RVA infection. In general, the inoculated animals developed an oligosymptomatic infection pattern. The main clinical symptoms observed were diarrhoea in two monkeys for three days, associated with a reduction in plasmatic potassium content. Viral RNA was detected in seven faecal and five sera samples from inoculated animals, suggesting virus replication. Cynomolgus monkeys are susceptible hosts for human Wa RVA infection. When inoculated orally, they presented self-limited diarrhoea associated with presence of RVA infectious particles in faeces. Thus, cynomolgus monkeys may be useful as animal models to evaluate the efficacy of new antiviral approaches. PMID- 29973484 TI - Sorbicillinoid-Based Metabolites from a Sponge-Derived Fungus Trichoderma saturnisporum. AB - Antibacterial activity assessment and high performance liquid chromatography associated with nuclear magnetic resonance (HPLC/NMR) data revealed that the EtOAc extract of the fermented endophytic fungus Trichoderma saturnisporum DI-IA, obtained from the marine sponge Dictyonella incisa, contained conjugated olefinic metabolites with antibacterial activity. Chemical examination of the fungal strain resulted in the isolation of eight new sorbicillinoid-based compounds, namely saturnispols A-H (1-8). Their structures were determined on the basis of extensive spectroscopic analysis, including the experimental and calculated electronic circular dichroism (ECD) data for the configurational assignments. Saturnispol F exerted significant inhibition against a panel of bacteria strains including vancomycin-resistant enterococci (VRE) with a minimum inhibitory concentrations (MIC) ranging from 1.63 to 12.9 μg/mL, while saturnispol H showed selective effects against VRE and B. subtilis. PMID- 29973485 TI - Transcriptome Analysis of Adipose Tissue Indicates That the cAMP Signaling Pathway Affects the Feed Efficiency of Pigs. AB - Feed efficiency (FE) is one of the main factors that determine the production costs in the pig industry. In this study, RNA Sequencing (RNA-seq) was applied to identify genes and long intergenic non-coding RNAs (lincRNAs) that are differentially expressed (DE) in the adipose tissues of Yorkshire pigs with extremely high and low FE. In total, 147 annotated genes and 18 lincRNAs were identified as DE between high- and low-FE pigs. Seventeen DE lincRNAs were significantly correlated with 112 DE annotated genes at the transcriptional level. Gene ontology (GO) analysis revealed that DE genes were significantly associated with cyclic adenosine monophosphate (cAMP) metabolic process and Ca2+ binding. cAMP, a second messenger has an important role in lipolysis, and its expression is influenced by Ca2+ levels. In high-FE pigs, nine DE genes with Ca2+ binding function, were down-regulated, whereas S100G, which encodes calbindin D9K that serve as a Ca2+ bumper, was up-regulated. Furthermore, ATP2B2, ATP1A4, and VIPR2, which participate in the cAMP signaling pathway, were down-regulated in the upstream of lipolysis pathways. In high-FE pigs, the key genes involved in the lipid biosynthetic process (ELOVL7 and B4GALT6), fatty acid oxidation (ABCD2 and NR4A3), and lipid homeostasis (C1QTNF3 and ABCB4) were down-regulated. These results suggested that cAMP was involved in the regulation on FE of pigs by affecting lipid metabolism in adipose tissues. PMID- 29973486 TI - Exploring Microtubule-Dependent Cellulose-Synthase-Complex Movement with High Precision Particle Tracking. AB - Cellulose synthesis at the plasma membrane is a critical process in plant growth and development. The displacement of cellulose synthase complexes (CSCs) by the rigid cellulose polymers they produce is a measure of enzyme activity. Connections between cortical microtubules and CSCs have been identified but it remains unclear how these affect CSC displacement speed. In this study, we applied a high throughput automated particle tracking method using near-total internal reflection fluorescence microscopy to measure the speed of CSCs. We found CSC speeds did not vary according to their proximity to microtubules, and that inhibiting microtubule polymerization could have opposite effects on CSC speed, depending on the nature of inhibition. While CSC speed increased in the temperature-sensitive mor1-1 mutant, it decreased after treatment with the drug oryzalin. Moreover, introducing the mor1-1 mutation into the CesA1 mutant any1 increased CSC speed, suggesting that microtubule dynamics affect CSC speed by a mechanism other than Cellulose Synthase A (CesA) catalytic activity. CSC speed varied widely in a range of mutants with reduced growth anisotropy, indicating that the relationship between CSC speed and anisotropy is complex. We conclude that microtubules affect CSC speed by finely tuned mechanisms that are independent of their physical association with CSCs. PMID- 29973487 TI - Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer. AB - Macrophages, cells belonging to the innate immune system, present a high plasticity grade, being able to change their phenotype in response to environmental stimuli. They play central roles during development, homeostatic tissue processes, tissue repair, and immunity. Furthermore, it is recognized that macrophages are involved in chronic inflammation and that they play central roles in inflammatory diseases and cancer. Due to their large involvement in the pathogenesis of several types of human diseases, macrophages are considered to be relevant therapeutic targets. Nanotechnology-based systems have attracted a lot of attention in this field, gaining a pivotal role as useful moieties to target macrophages in diseased tissues. Among the different approaches that can target macrophages, the most radical is represented by their depletion, commonly obtained by means of clodronate-containing liposomal formulations and/or depleting antibodies. These strategies have produced encouraging results in experimental mouse models. In this review, we focus on macrophage targeting, based on the results so far obtained in preclinical models of inflammatory diseases and cancer. Pros and cons of these therapeutic interventions will be highlighted. PMID- 29973489 TI - Action Observation in People with Parkinson's Disease. A Motor-Cognitive Combined Approach for Motor Rehabilitation. A Preliminary Report. AB - The aim of this study was to assess the role of Action Observation (AO) to improve balance, gait, reduce falls, and to investigate the changes in P300 pattern. Five cognitively intact People with Parkinson’s disease (PwP) were enrolled in this prospective, quasi-experimental study to undergo a rehabilitation program of AO for gait and balance recovery of 60 min, three times a week for four weeks. The statistical analysis showed significant improvements for Unified Parkinson’s Disease Rating Scale (UPDRS) motor section III p = 0.0082, Short form 12-items Healthy Survey (SF-12) Mental Composite Score (MCS) p = 0.0007, Freezing of gait Questionnaire (FOG-Q) p = 0.0030, The 39-items Parkinson’s Disease Questionnaire (PDQ-39) p = 0.100, and for P300ld p = 0.0077. In conclusion, AO reveals to be a safe and feasible paradigm of rehabilitative exercise in cognitively preserved PwP. PMID- 29973488 TI - Advances in Pharmaceutical Strategies Enhancing the Efficiencies of Oral Colon Targeted Delivery Systems in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD) is a common disease characterized by chronic inflammation in gastrointestinal tracts, which is primarily treated by administering anti-inflammatory and immunosuppressive drugs that inhibit the burden of intestinal inflammation and improve disease-related symptoms. However, the established therapeutic strategy has limited therapeutic efficacy and adverse drug reactions. Therefore, new disease-targeting drug-delivery strategies to develop more effective treatments are urgent. This review provides an overview of the drug-targeting strategies that can be used to treat IBD, and our recent attempts on the colon-specific delivery system (Pae-SME-CSC) with a paeonol loaded self-microemulsion (Pae-SMEDDS) are introduced. PMID- 29973490 TI - Metformin in Pregnancy: Mechanisms and Clinical Applications. AB - Metformin use in pregnancy is increasing worldwide as randomised controlled trial (RCT) evidence is emerging demonstrating its safety and efficacy. The Metformin in Gestational Diabetes (MiG) RCT changed practice in many countries demonstrating that metformin had similar pregnancy outcomes to insulin therapy with less maternal weight gain and a high degree of patient acceptability. A multicentre RCT is currently assessing the addition of metformin to insulin in pregnant women with type 2 diabetes. RCT evidence is also available for the use of metformin in pregnancy for women with Polycystic Ovarian Syndrome and for nondiabetic women with obesity. No evidence of an increase in congenital malformations or miscarriages has been observed even when metformin is started before pregnancy and continued to term. Body composition and metabolic outcomes at two, seven, and nine years have now been reported for the offspring of mothers treated in the MiG study. In this review, we will briefly discuss the action of metformin and then consider the evidence from the key clinical trials. PMID- 29973491 TI - Antioxidant Properties of Buffalo-Milk Dairy Products: A beta-Lg Peptide Released after Gastrointestinal Digestion of Buffalo Ricotta Cheese Reduces Oxidative Stress in Intestinal Epithelial Cells. AB - Redox signaling regulates different gastrointestinal (G.I.) epithelium functions. At the intestinal level, the loss of redox homeostasis in intestinal epithelial cells (IECs) is responsible for the pathogenesis and development of a wide diversity of G.I. disorders. Thus, the manipulation of oxidative stress in IECs could represent an important pharmacological target for different diseases. In this study, peptides released from in vitro gastro intestinal digestion of different buffalo-milk commercial dairy products were identified and evaluated for their bioactive properties. In particular, six G.I. digests of dairy products were tested in a model of oxidative stress for IECs. Among them, buffalo ricotta cheese was the most active and the presence of an abundant β-lactoglobulin peptide (YVEELKPTPEGDL, f:60-72) was also revealed. The antioxidant potential of the identified peptide was also evaluated in a model of hydrogen peroxide (H2O2) induced oxidative stress in the IEC-6 cell line. The peptide was able to reduce ROS release, while, on the other hand, it increased nuclear factor (erythroid derived 2)-like 2 (Nrf2) activation and the expression of antioxidant cytoprotective factors, such as heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD). These results indicate that buffalo ricotta cheese-isolated peptide could have potential in the treatment of some gastrointestinal disorders. PMID- 29973492 TI - Protective Effect of Glycyrrhizic Acid on Alcoholic Liver Injury in Rats by Modulating Lipid Metabolism. AB - Glycyrrhhizic acid (GA), including 18α-glycyrrhizic acid (18α-GA) and 18β-glycyrrhizic acid (18β-GA), is the main active ingredient of licorice. GA is generally considered an effective pharmacological strategy protecting against hepatic disease; however, the optimal compatibility proportion of 18α-GA and 18β-GA against alcoholic liver disease (ALD) and the underlying mechanism are not well established. Hence, this study was designed to explore the optimal compatibility proportion of 18α-GA and 18β-GA against ALD, followed by investigating the underlying mechanisms. SD rats were administered 40% ethanol once a day, accompanied by treatment with different proportions of 18α-GA and 18β-GA for four weeks. Then all rats were anesthetized with chloral hydrate and blood samples were taken from the abdominal aorta for biochemical assay. Livers were also collected and the liver function, lipid profile, ROS production, and mRNA and protein levels of related genes involved in lipid metabolism were assessed. The results showed that 18α-GA and 18β-GA, particularly at a proportion of 4:6, significantly reduced liver damage, lipid accumulation, and oxidative stress in ethanol-induced rats, as indicated by the decreased levels of alanine aminotransferase (ALT) and aminotransferase (AST) in serum, improvement of liver histopathological changes, regulation of total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), and modulation of superoxide dismutase (SOD), glutathione (GSH), and malonaldehyde (MDA). Moreover, the combination treatment with 18α-GA and 18β-GA substantially reduced the mRNA and protein levels of sterol regulatory element-binding protein-1c (SREBP-1c) and acetyl-coal carboxylase (ACC); meanwhile, increased levels of peroxisome proliferators activated receptor α (PPAR-α) and carnitine palmitoy transferase-1 (CTP-1) in the liver tissues of ethanol-induced rats. In conclusion, our results indicated that the optimal compatibility proportion of 18α-GA and 18β-GA protecting against ALD was 4:6, and the mechanism was associated with the regulation of oxidative stress and lipid metabolism. PMID- 29973494 TI - Effects of Dietary Astaxanthin Supplementation on Energy Budget and Bioaccumulation in Procambarus clarkii (Girard, 1852) Crayfish under Microcystin LR Stress. AB - This research aimed to study the effects of astaxanthin on energy budget and bioaccumulation of microcystin-leucine-arginine (microcystin-LR) in the crayfish Procambarus clarkii (Girard, 1852). The crayfish (21.13 +/- 4.6 g) were cultured under microcystin-LR stress (0.025 mg/L) and were fed with fodders containing astaxanthin (0, 3, 6, 9, and 12 mg/g) for 8 weeks in glass tanks (350 mm × 450 mm × 150 mm). Accumulations of microcystin-LR were measured in different organs of P. clarkii. The results suggested that astaxanthin can significantly improve the survival rate and specific growth rate (SGR) of P. clarkii (p < 0.05). The dietary astaxanthin supplement seems to block the bioaccumulation of microcystin-LR in the hepatopancreas and ovaries of P. clarkii to some extent (p < 0.05). Astaxanthin content of 9-12 mg/g in fodder can be a practical and economic choice. PMID- 29973495 TI - Correction: Sao-Jose, C. Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials. Antibiotics 2018, 7, 29. AB - The author wishes to make the following corrections to this paper [...]. PMID- 29973496 TI - Erratum: Demesa, A.G.; et al. Valorization of Lignin by Partial Wet Oxidation Using Sustainable Heteropoly Acid Catalysts. Molecules 2017, 22, 1625. AB - The authors would like to make the following correction to their published paper [1]. [...]. PMID- 29973493 TI - Harnessing Marine Biocatalytic Reservoirs for Green Chemistry Applications through Metagenomic Technologies. AB - In a demanding commercial world, large-scale chemical processes have been widely utilised to satisfy consumer related needs. Chemical industries are key to promoting economic growth and meeting the requirements of a sustainable industrialised society. The market need for diverse commodities produced by the chemical industry is rapidly expanding globally. Accompanying this demand is an increased threat to the environment and to human health, due to waste produced by increased industrial production. This increased demand has underscored the necessity to increase reaction efficiencies, in order to reduce costs and increase profits. The discovery of novel biocatalysts is a key method aimed at combating these difficulties. Metagenomic technology, as a tool for uncovering novel biocatalysts, has great potential and applicability and has already delivered many successful achievements. In this review we discuss, recent developments and achievements in the field of biocatalysis. We highlight how green chemistry principles through the application of biocatalysis, can be successfully promoted and implemented in various industrial sectors. In addition, we demonstrate how two novel lipases/esterases were mined from the marine environment by metagenomic analysis. Collectively these improvements can result in increased efficiency, decreased energy consumption, reduced waste and cost savings for the chemical industry. PMID- 29973497 TI - Isolation, Structural Elucidation of Three New Triterpenoids from the Stems and Leaves of Schisandra chinensis (Turcz) Baill. AB - Schisandra chinensis (Turcz) Baill. is sufficiently well known as a medicinal plant worldwide, which modern research shows has many pharmacological activities such as hepatoprotective, anti-inflammatory effect, potent anti-HIV-1 activity, anti-tumor effect, and activity on the central nervous system. With considerable chemical investigation, three new triterpenoids (1-3), together with four known triterpenoids were isolated from the S. chinensis (Turcz) Baill. Their structures were elucidated by 1D- and 2D-NMR spectroscopic analyses, single-crystal X-ray diffraction and high-resolution mass spectroscopy, which were identified as Schisanlactone I (1), Schinalactone D, (2), Schisanlactone J, (3) Kadsuphilactone B (4), Schisanlactone C (5), Schisphendilactone B (6), and Schinchinenlactone A (7). The cytotoxicity of those compounds (1-7) was tested against Hep-G2 cell lines, but no apparent antitumor activity was observed at 50 µg/mL using MTT method. PMID- 29973499 TI - Modeling Ionic Strength Effects on Hollow-Fiber Nanofiltration Membrane Mass Transfer. AB - In this research, we investigated the influence of feedwater ionic strength on diffusion of divalent ions through a hollow-fiber nanofiltration membrane. The results indicated that solute flux of magnesium was increased as a result of elevating the ionic strength in the feedwater. Specifically, the feedwater ionic strength was observed to have a nonlinear impact on the diffusion of magnesium during the nanofiltration process, which was under-predicted by the homogeneous solution diffusion (HSD) model. This result suggested that elevating the feedwater ionic strength had reduced the strength of the electrostatic double layer at the membrane surface. We then developed a modification of the HSD model (referred to as the HSD-IS model) which incorporated an empirical term related to the effect of feedwater ionic strength (IS) on diffusion of magnesium. The root mean squared error of the HSD-IS model was improved by 77% as compared to the HSD model, which did not incorporate a term related to feedwater ionic strength. This improvement suggested that feedwater ionic strength should be considered when modeling hardness removal during nanofiltration. PMID- 29973498 TI - Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major. AB - Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 +/- 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells. PMID- 29973500 TI - A Study on Dissimilar Friction Stir Welded between the Al-Li-Cu and the Al-Zn-Mg Cu Alloys. AB - In this paper, the microstructure of friction stir welded between the Al-Li-Cu alloy and the Al-Zn-Mg-Cu alloy was studied using optical microscope(OM), electronic backscattered diffraction (EBSD), SEM, and TEM. The hardness profile revealed that the range of heat affect zone for the Al-Zn-Mg-Cu alloy was slightly wider than the Al-Li-Cu alloy when they suffered from the thermal transient. Additionally, the characterization of precipitates inside the different zones was obviously different, which corresponded to the microhardness distribution profile. At the periphery of the kissing line, the Al-Li-Cu and the Al-Zn-Mg-Cu alloys mutually diffused during the weld process. The magnesium element in the Al-Zn-Mg-Cu alloy diffused into the Al-Li-Cu alloy. But the copper and zinc had no change because of the low diffusion coefficient in aluminum. The heat affected zone of the Al-Zn-Mg-Cu alloy showed a higher corrosion susceptibility immersed into the corrosion environment, and the Al-Li-Cu alloy did not show severe corrosion. PMID- 29973501 TI - Bioremediation of Landfill Leachate with Fungi: Autochthonous vs. Allochthonous Strains. AB - Autochthonous fungi from contaminated wastewater are potential successful agents bioremediation thanks to their adaptation to pollutant toxicity and to competition with other microorganisms present in wastewater treatment plant. Biological treatment by means of selected fungal strains could be a potential tool to integrate the leachate depuration process, thanks to their fungal extracellular enzymes with non-selective catalytical activity. In the present work, the treatability of two real samples (a crude landfill leachate and the effluent coming from a traditional wastewater treatment plant) was investigated in decolorization experiments with fungal biomasses. Five autochthonous fungi, Penicillium brevicompactum MUT 793, Pseudallescheria boydii MUT 721, P. boydii MUT 1269, Phanerochaete sanguinea MUT 1284, and Flammulina velutipes MUT 1275, were selected in a previous miniaturized decolorization screening. Their effectiveness in terms of decolorization, enzymatic activity (laccases and peroxidases), biomass growth and ecotoxicity removal was compared with that of five allochthonous fungal strains, Pleurotus ostreatus MUT 2976, Porostereum spadiceum MUT 1585, Trametespubescens MUT 2400, Bjerkanderaadusta MUT 3060 and B. adusta MUT 2295, selected for their well known capability to degrade recalcitrant pollutants. Moreover, the effect of biomass immobilization on polyurethane foam (PUF) cube was assessed. The best decolorization (60%) was achieved by P. spadiceum MUT 1585, P. boydii MUT 721 and MUT 1269. In the first case, the DP was achieved gradually, suggesting a biodegradation process with the involvement of peroxidases. On the contrary, the two autochthonous fungi seem to bioremediate the effluent mainly by biosorption, with the abatement of the toxicity (up to 100%). The biomass immobilization enhanced enzymatic activity, but not the DP. Moreover, it limited the biomass growth for the fast growing fungi, MUT 721 and MUT 1269. In conclusion, robust and versatile strains coming from well characterized collections of microorganisms can obtain excellent results comparing and even exceeding the bioremediation yields of strains already adapted to pollutants. PMID- 29973502 TI - Optimization of TiC Content during Fabrication and Mechanical Properties of Ni-Ti Al/TiC Composites Using Mixture Designs. AB - Ni-Ti-Al alloys are highly promising materials for use in high-temperature structural materials. However, minimal research has been conducted to improve the associated mechanical properties through secondary phase addition. In this study, Ni-Ti-Al/TiC composites were fabricated at a pressure of 40 MPa and a sintering temperature of 1050 °C using spark plasma sintering. The microstructure and interfacial structure were analyzed by scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction analysis. Microscopic analysis revealed that TiC particles interacted with Ti and Al, resulting in the formation of Ti2AlC, which promoted chemical metallurgical bonding between the Ni Ti-Al alloy and TiC. Wear characteristics were measured using the wear test with a ball on disk. It was confirmed that the 40 wt % specimen had the highest hardness due to pores generated inside, but the wear amount was relatively high. The mixture design of a minitap was proceeded using hardness, bending strength, and wear loss. An optimum composition ratio of 32.16 wt % was determined using the composite desirability of the three properties. PMID- 29973503 TI - Palatal Protective Stents Prevent Oro-Nasal Fistulas after Surgery for Velopharyngeal Insufficiency: A Preliminary Report. AB - BACKGROUND: One of the potential complications of surgery for velopharyngeal insufficiency (VPI) is postoperative oral-nasal fistula (ONF). Reported rates vary from 0 to 60%. Several factors are on account of these disproportionate rates. OBJECTIVE: The purpose of this study was to describe the use of a palatal protective stent (PPS) to preserve the VPI repair surgical site and to study its effectiveness for decreasing the incidence of postoperative ONF. MATERIALS AND METHODS: A retrospective study was carried out. All patients undergoing surgery for VPI with complete preoperative and postoperative evaluations including at least one year follow up after surgery from 2012 to 2016 were studied. Some of the patients were operated on using a pre-molded palatal protective stent (PPS). Twenty-seven patients were included in the study group. Most of the patients underwent a customized pharyngeal flap according to findings of imaging procedures. The remaining cases underwent a Furlow palatoplasty. Twelve patients were operated on using PPS. RESULTS: There were no surgical complications during the procedures. ONF was detected in four of the patients operated on without PPS. None of the patients undergoing surgery using PPS demonstrated ONF. All fistulas were located at the soft/hard palate junction. VPI was corrected in 92% of the cases. CONCLUSION: Although only a reduced number of cases were studied, these preliminary results suggest that using PPS during surgical procedures for correcting VPI is a safe and reliable tool for preventing ONF. PMID- 29973504 TI - Overview of Antibody Drug Delivery. AB - Monoclonal antibodies (mAbs) are one of the most important classes of therapeutic proteins, which are used to treat a wide number of diseases (e.g., oncology, inflammation and autoimmune diseases). Monoclonal antibody technologies are continuing to evolve to develop medicines with increasingly improved safety profiles, with the identification of new drug targets being one key barrier for new antibody development. There are many opportunities for developing antibody formulations for better patient compliance, cost savings and lifecycle management, e.g., subcutaneous formulations. However, mAb-based medicines also have limitations that impact their clinical use; the most prominent challenges are their short pharmacokinetic properties and stability issues during manufacturing, transport and storage that can lead to aggregation and protein denaturation. The development of long acting protein formulations must maintain protein stability and be able to deliver a large enough dose over a prolonged period. Many strategies are being pursued to improve the formulation and dosage forms of antibodies to improve efficacy and to increase the range of applications for the clinical use of mAbs. PMID- 29973506 TI - The Role of Cu Length on the Magnetic Behaviour of Fe/Cu Multi-Segmented Nanowires. AB - A set of multi-segmented Fe/Cu nanowires were synthesized by a two-step anodization process of aluminum substrates and a pulsed electrodeposition technique using a single bath. While both Fe segment length and diameter were kept constant to (30 +/- 7) and (45 +/- 5) nm, respectively, Cu length was varied between (15 +/- 5) and (120 +/- 10) nm. The influence of the non-magnetic layer thickness variation on the nanowire magnetic properties was investigated through first-order reversal curve (FORC) measurements and micromagnetic simulations. Our analysis confirmed that, in the multi-segmented Fe/Cu nanowires with shorter Cu segments, the dipolar coupling between Fe segments controls the nanowire magnetic behavior, and its performance is like that of a homogenous Fe nanowire array of similar dimensions. On the other hand, multi-segmented Fe/Cu nanowires with larger Cu segments act like a collection of non-interacting magnetic entities (along the nanowire axis), and their global behavior is mainly controlled by the neighbor-to-neighbor nanodisc dipolar interactions. PMID- 29973505 TI - Engineering Botulinum Toxins to Improve and Expand Targeting and SNARE Cleavage Activity. AB - Botulinum neurotoxins (BoNTs) are highly successful protein therapeutics. Over 40 naturally occurring BoNTs have been described thus far and, of those, only 2 are commercially available for clinical use. Different members of the BoNT family present different biological properties but share a similar multi-domain structure at the molecular level. In nature, BoNTs are encoded by DNA in producing clostridial bacteria and, as such, are amenable to recombinant production through insertion of the coding DNA into other bacterial species. This, in turn, creates possibilities for protein engineering. Here, we review the production of BoNTs by the natural host and also recombinant production approaches utilised in the field. Applications of recombinant BoNT-production include the generation of BoNT-derived domain fragments, the creation of novel BoNTs with improved performance and enhanced therapeutic potential, as well as the advancement of BoNT vaccines. In this article, we discuss site directed mutagenesis, used to affect the biological properties of BoNTs, including approaches to alter their binding to neurons and to alter the specificity and kinetics of substrate cleavage. We also discuss the target secretion inhibitor (TSI) platform, in which the neuronal binding domain of BoNTs is substituted with an alternative cellular ligand to re-target the toxins to non-neuronal systems. Understanding and harnessing the potential of the biological diversity of natural BoNTs, together with the ability to engineer novel mutations and further changes to the protein structure, will provide the basis for increasing the scope of future BoNT-based therapeutics. PMID- 29973507 TI - Discrimination of Aroma Characteristics for Cubeb Berries by Sensomics Approach with Chemometrics. AB - The dried cubeb berries are widely used as medicinal herb and spicy condiment with special flavor. However, there is a significant definition discrepancy for cubeb berries. In this study, an efficient analytical method to characterize and discriminate two popular cubeb fruits (Litsea cubeba and Piper cubeba) was established. The aroma profiles of cubeb berries were evaluated by different extraction methods including hydro-distillation, simultaneous distillation/extraction, and solid-phase micro-extraction followed by gas chromatography-mass spectrometry-olfactometry (GC-MS-O). In total, 90 volatile compounds were identified by HD, SDE, and SPME combined with GC-MS. Principal component analysis was further applied and discriminated ambiguous cubeb berries by their unique aromas: Litsea cubeba was characterized by higher level of d limonene (“fruit, citrus”), citral (“fruit, lemon”) and dodecanoic acid; α-cubebene (“herb”) was identified as a marker compound for Piper cubeba with higher camphor (“camphoraceous”), and linalool (“flower”). Flavor fingerprint combined with PCA could be applied as a promising method for identification of cubeb fruits and quality control for food and medicinal industries. PMID- 29973509 TI - The Spatial-Temporal Characteristics and Influential Factors of NOx Emissions in China: A Spatial Econometric Analysis. AB - While the progress of China’s industrialization and urbanization has made great strides, atmospheric pollution has become the norm, with a wide range of influence and difficult governance. While many previous works on NOx pollution have been developed from the perspectives of natural science and technology, few studies have been conducted from social-economic points of view, and regional differences have not been given adequate attention in driving force models. This paper adopts China’s provincial panel data from 2006 to 2015, an extended STIRPAT (Stochastic Impacts by Regression on Population, Affluence and Technology) model, and spatial econometric models to investigate the socio economic influential factors and spatial-temporal patterns of NOx emissions. According to the spatial correlation analysis results, the provincial NOx emission changes not only affected the provinces themselves, but also neighboring regions. Spatial econometric analysis shows that the spatial effect largely contributes to NOx emissions. The other explanatory variables all have positive impacts on NOx emissions, except for the vehicular indicator (which did not pass the significance test). As shown through the estimated consequences of direct and indirect effects, the indicators have significant positive effects on their own areas, and exacerbate NOx pollution. In terms of indirect effects, only three factors passed the significant test. An increase in gross domestic product (GDP) and energy consumption will exacerbate adjacent NOx pollution. Finally, a series of socio-economic measures and regional cooperation policies should be applied to improve the current air environment in China. PMID- 29973508 TI - Foxn1 in Skin Development, Homeostasis and Wound Healing. AB - Intensive research effort has focused on cellular and molecular mechanisms that regulate skin biology, including the phenomenon of scar-free skin healing during foetal life. Transcription factors are the key molecules that tune gene expression and either promote or suppress gene transcription. The epidermis is the source of transcription factors that regulate many functions of epidermal cells such as proliferation, differentiation, apoptosis, and migration. Furthermore, the activation of epidermal transcription factors also causes changes in the dermal compartment of the skin. This review focuses on the transcription factor Foxn1 and its role in skin biology. The regulatory function of Foxn1 in the skin relates to physiological (development and homeostasis) and pathological (skin wound healing) conditions. In particular, the pivotal role of Foxn1 in skin development and the acquisition of the adult skin phenotype, which coincides with losing the ability of scar-free healing, is discussed. Thus, genetic manipulations with Foxn1 expression, specifically those introducing conditional Foxn1 silencing in a Foxn1+/+ organism or its knock-in in a Foxn1−/− model, may provide future perspectives for regenerative medicine. PMID- 29973510 TI - Hamster Melatonin Receptors: Cloning and Binding Characterization of MT1 and Attempt to Clone MT2. AB - For many years, it was of interest to identify the sequences encoding the two melatonin receptors (MT1 and MT2) from various species. After publishing the basic molecular characterization of the human, rat, mouse, sheep, and platypus MT1, MT2, or Mel1c receptors, we began cloning the genes from other animals, such as birds, bats, and vipers. The goal was to advance the receptor crystallization, which could greatly contribute the understanding of the sequence/stability relationship. European hamster MT1 receptor was cloned for the first time from this gender, was expressed in stable form in cells, and its binding characterized with a sample of 19 melatonin ligands. Siberian hamster (Phodopus sungorus) expresses a non-functional MT2. We observed that unlike this hamster, the European hamster (Cricetus cricetus) does not have a stop codon in the MT2 sequence. Thus, we undertook the tedious task of cloning the MT2 receptor. We partially succeeded, sequencing the complete exon 2 and a fragment of exon 1 (from putative amino acids 12 to 38 and 77 to 323), after several years of efforts. In order to show that the protein parts we cloned were capable to sustain some binding capacities, we designed a chimeric MT2 receptor using a consensus sequence to replace the unknown amino acids, based on other small rodent MT2 sequences. This chimeric construct could bind melatonin in the nanomolar range. This work is meant to be the basis for attempts from other laboratories of the community to determine the complete natural sequence of the European hamster MT2 receptor. The present work is the first to show that, among the hamsters, if the Siberian is a natural knockout for MT2, the European one is not. PMID- 29973511 TI - Data on Determinants Are Needed to Curb the Sedentary Epidemic in Europe. Lessons Learnt from the DEDIPAC European Knowledge Hub. AB - Societal and technological changes have resulted in sitting being the dominant posture during most activities of daily living, such as learning, working, travelling and leisure time. Too much time spent in seated activities, referred to as sedentary behaviour, is a novel concern for public health as it is one of the key lifestyle causes of poor health. The European DEDIPAC (Determinants of Diet and Physical Activity) Knowledge Hub coordinated the work of 35 institutions across 12 European member states to investigate the determinants of sedentary behaviour. DEDIPAC reviewed current evidence, set a theoretical framework and harmonised the available epidemiological data. The main results are summarised. The conclusion is that there is a dire lack of data that is exploitable across Europe to inform policy and intervention. There is an urgent need to develop international data collection compliant with FAIR (Findable, Accessible, Interoperable, Re-usable) and standardised surveillance systems for sedentary behaviour. PMID- 29973512 TI - Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines. AB - A number of new trisubstituted triazine phosphatidylinositol 3-kinase (PI3K) inhibitors were prepared via a three-step procedure utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. All were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor, ZSTK474. The most active inhibitors prepared here were 2-4 times more potent than ZSTK474. A leucine linker was attached to the most active inhibitor since it would remain on any peptide-containing prodrug after cleavage by a prostate specific antigen, and it did not prevent inhibition of protein kinase B (Akt) phosphorylation, and hence, the inhibition of PI3K by the modified inhibitor. PMID- 29973513 TI - C. elegans-An Emerging Model to Study Metal-Induced RAGE-Related Pathologies. AB - The receptor for advanced glycation end products (RAGE), a multi-ligand receptor, is mostly associated with promoting inflammation and oxidative stress. In addition to advanced glycation end products (AGEs), its ligands include High mobility group box 1 protein (HMGB-1), S-100 proteins and beta-sheet fibrils. The effects of several metals and metalloids on RAGE expression and activation have been recently studied: in vivo and in vitro exposure to methylmercury, selenium, zinc, manganese, and arsenic was associated with a variety of RAGE-related alterations and behavioral impairments, which are mostly dependent upon the administration procedure (local vs. systemic) and age during exposure. Recently, C. elegans has been proposed as a potential novel model for studying RAGE-related pathologies; preliminary data regarding such model and its potential contribution to the study of metal-induced RAGE-related pathologies are discussed. PMID- 29973514 TI - Anti-Proliferative Properties and Proapoptotic Function of New CB2 Selective Cannabinoid Receptor Agonist in Jurkat Leukemia Cells. AB - Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3 carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist. PMID- 29973515 TI - Effects of Different Oxidation Degrees of Graphene Oxide on P-Type and N-Type Si Heterojunction Photodetectors. AB - Oxygen-containing functional groups in graphene oxide (GO), a derivative of graphene, can widen the bandgap of graphene. In this study, we varied the amount of hydrogen peroxide used to prepare GO samples with different degrees of oxidation. Transmittance measurement, Raman spectroscopy, and X-ray photoelectron spectroscopy were used to completely characterize the change in oxidation degree. The effects of oxidation degree on p-type and n-type Si heterojunction photodetectors were compared. Notably, GO with a lower oxidation degree led to a larger photoresponse of p-type Si, whereas that with a higher oxidation degree achieved a larger photoresponse of n-type Si. PMID- 29973517 TI - Millimeter Wave High Resolution Radar Accuracy in Fog Conditions-Theory and Experimental Verification. AB - Attenuation and group delay effects on millimeter wave (MMW) propagation in clouds and fog are studied theoretically and verified experimentally using high resolution radar in an indoor space filled with artificial fog. In the theoretical analysis, the frequency-dependent attenuation and group delay were derived via the permittivity of the medium. The results are applied to modify the millimeter-wave propagation model (MPM) and employed to study the effect of fog and cloud on the accuracy of the Frequency-Modulated Continuous-Wave (FMCW) radar operating in millimeter wavelengths. Artificial fog was generated in the experimental study to demonstrate ultra-low visibility in a confined space. The resulted attenuation and group delay were measured using FMCW radar operating at 320-330 GHz. It was found that apart from the attenuation, the incremental group delay caused by the fog also played a role in the accuracy of the radar. The results were compared to the analytical model. It was shown that although the artificial fog has slight different characteristics compare to the natural fog and clouds, in particle composition, size, and density, the model predictions were good, pointing out that the dispersive effects should be considered in the design of remote sensing radars operating in millimeter and sub-millimeter wavelengths. PMID- 29973516 TI - Review of Chirped Fiber Bragg Grating (CFBG) Fiber-Optic Sensors and Their Applications. AB - Fiber Bragg Gratings (FBGs) are one of the most popular technology within fiber optic sensors, and they allow the measurement of mechanical, thermal, and physical parameters. In recent years, a strong emphasis has been placed on the fabrication and application of chirped FBGs (CFBGs), which are characterized by a non-uniform modulation of the refractive index within the core of an optical fiber. A CFBG behaves as a cascade of FBGs, each one reflecting a narrow spectrum that depends on temperature and/or strain. The key characteristic of CFBGs is that their reflection spectrum depends on the strain/temperature observed in each section of the grating; thus, they enable a short-length distributed sensing, whereas it is possible to detect spatially resolved variations of temperature or strain with resolution on the order of a millimeter over the grating length. Based on this premise, CFBGs have found important applications in healthcare, mechanical engineering, and shock waves analysis, among others. This work reviews the present and emerging trends in CFBG sensors, focusing on all aspects of the sensing element and outlining the application case scenarios for which CFBG sensors have been demonstrated. PMID- 29973518 TI - Associations between Work Activity and Work Setting Categories and Dimensions of Pharmacists' Quality of Work Life. AB - The goal for this study was to use data from the most recently conducted National Pharmacist Workforce Survey to compare eight components of quality of work life for actively practicing pharmacists in the United States categorized by (1) work activity and (2) work setting. The eight components of quality of work life were: (1) time stress; (2) responsibility stress; (3) level of control; (4) work in harmony with home life; (5) home life in harmony with work; (6) job satisfaction; (7) professional commitment; and (8) organizational commitment. Data for this study were obtained from the 2014 National Pharmacist Workforce Survey. For inclusion in analysis, respondents needed to report that they were practicing as a pharmacist. In addition, they needed to provide usable responses for both their percent time devoted to medication providing and to patient care services. This resulted in a total of 1191 responses for the analysis. Data were analyzed using cluster analysis, factor analysis, Cronbach coefficient alpha, chi-square analysis, ANOVA, and linear regression. The findings provide a description of pharmacists’ quality of work life in 2014 and show how type of work, variety of work, and work setting categories are associated with quality of work life for pharmacists. PMID- 29973519 TI - Acoustic Parametric Signal Generation for Underwater Communication. AB - This paper presents a study of different types of parametric signals with application to underwater acoustic communications. In all the signals, the carrier frequency is 200 kHz, which corresponds to the resonance frequency of the transducer under study and different modulations are presented and compared. In this sense, we study modulations with parametric sine sweeps (4 to 40 kHz) that represent binary codes (zeros and ones), getting closer to the application in acoustic communications. The different properties of the transmitting signals in terms of bit rate reconstruction, directivity, efficiency, and power needed are discussed as well. PMID- 29973520 TI - Preface to Special Issue on 'Cytochrome P450 Variation in Pharmacogenomics'. PMID- 29973522 TI - Processing Optimization and Characterization of Angiotensin-Iota-Converting Enzyme Inhibitory Peptides from Lizardfish (Synodus macrops) Scale Gelatin. AB - Hypertension can cause coronary heart disease. Synthetic angiotensin-converting enzyme (ACE) inhibitors are effective antihypertensive drugs but often cause side effects. The aim of this study was to prepare potential ACE inhibitors from scales. Gelatin was extracted from lizardfish scales. Then, scale gelatin was enzymolyzed to prepare ACE inhibitory peptides using response surface methodology. Proteolytic conditions after optimization were as follows: pH 7.0, enzyme substrate ratio 3.2%, temperature 47 °C, and proteolysis lasting 2 h and 50 min. The experimental ACE inhibitory activity under optimal conditions was 86.0 +/- 0.4%. Among the 118 peptides identified from gelatin hydrolysates, 87.3% were hydrophilic and 93.22% had a molecular weight <2000 Da. Gelatin peptides had high stability upon exposure to high temperature and pH as well as gastrointestinal tract enzymes. Gelatin peptides showed an antihypertensive effect in spontaneously hypertensive rats at a dosage of 2 g/kg in the long-term experiments. A new ACE inhibitory peptide was isolated from gelatin hydrolysates, and was identified as AGPPGSDGQPGAK with an IC50 value of 420 +/- 20 μM. In this way, ACE inhibitory peptides derived from scale gelatin have the potential to be used as healthy ACE-inhibiting drug raw materials. PMID- 29973521 TI - Self-Assembled Antimicrobial Nanomaterials. AB - Nanotechnology came to stay improving the quality of human life by reducing environmental contamination of earth and water with pathogens. This review discusses how self-assembled antimicrobial nanomaterials can contribute to maintain humans, their water and their environment inside safe boundaries to human life even though some of these nanomaterials display an overt toxicity. At the core of their strategic use, the self-assembled antimicrobial nanomaterials exhibit optimal and biomimetic organization leading to activity at low doses of their toxic components. Antimicrobial bilayer fragments, bilayer-covered or multilayered nanoparticles, functionalized inorganic or organic polymeric materials, coatings and hydrogels disclose their potential for environmental and public health applications in this review. PMID- 29973523 TI - Stability of Antibacterial Silver Carboxylate Complexes against Staphylococcus epidermidis and Their Cytotoxic Effects. AB - The antibacterial effects against Staphylococcus epidermidis of five silver carboxylate complexes with anti-inflammatory ligands were studied in order to analyze and compare them in terms of stability (in solution and after exposure to UV light), and their antibacterial and morphological differences. Four effects of the Ag-complexes were evidenced by transmission electronic microscopy (TEM) and scanning electronic microscopy (SEM): DNA condensation, membrane disruption, shedding of cytoplasmic material and silver compound microcrystal penetration of bacteria. 5-Chlorosalicylic acid (5Cl) and sodium 4-aminosalicylate (4A) were the most effective ligands for synthesizing silver complexes with high levels of antibacterial activity. However, Ag-5Cl was the most stable against exposure UV light (365 nm). Cytotoxic effects were tested against two kinds of eukaryotic cells: murine fibroblast cells (T10 1/2) and human epithelial ovarian cancer cells (A2780). The main objective was to identify changes in their antibacterial properties associated with potential decomposition and the implications for clinical applications. PMID- 29973524 TI - Texas Sour Orange Juice Used in Scaffolds for Tissue Engineering. AB - Fine fibers of polyhydroxybutyrate (PHB), a biopolymer, were developed via a centrifugal spinning technique. The developed fibers have an average diameter of 1.8 µm. Texas sour orange juice (SOJ) was applied as a natural antibacterial agent and infiltrated within the fibrous membranes. The antibacterial activity against common Gram-positive and Gram-negative bacteria (Staphylococcus aureus and Escherichia coli, respectively) was evaluated as well as cell adhesion and viability. The PHB/SOJ scaffolds showed antibacterial activity of up to 152% and 71% against S. aureus and E. coli, respectively. The cell studies revealed a suitable environment for cell growth and cell attachment. The outcome of this study opens up new opportunities for fabrication of fibrous materials for biomedical applications having multifunctional properties while using natural agents. PMID- 29973525 TI - Kefir Supplementation Modifies Gut Microbiota Composition, Reduces Physical Fatigue, and Improves Exercise Performance in Mice. AB - The present study evaluated the potential beneficial effect of kefir (KF) against fatigue. Furthermore, the composition of the gut microbiota is related to health benefits in the host; therefore, the study also investigated the effect of KF on the gut microbiota composition. Male ICR mice from four groups (n = 8 per group) were orally administered KF once daily for four weeks at 0, 2.15, 4.31, and 10.76 g/kg/day and were designated as the vehicle, KF-1X, KF-2X, and KF-5X groups, respectively. The gut microbiota was analyzed using 16S rRNA gene sequencing. The results showed a significant clustering of cecum after treatment in the vehicle, KF-1X, KF-2X, and KF-5X groups. The KF-2X and KF-5X groups showed a decreased Firmicutes/Bacteroidetes ratio compared with the vehicle group. In addition, anti fatigue activity and exercise performance were evaluated on the basis of exhaustive swimming time, forelimb grip strength, and levels of serum lactate, ammonia, glucose, blood urea nitrogen (BUN), and creatine kinase (CK) after a swimming exercise. The exhaustive swimming time for the KF-1X, KF-2X, and KF-5X groups was significantly longer than that for the vehicle group, and the forelimb grip strength of the KF-1X, KF-2X, and KF-5X groups was also significantly higher than that of the vehicle group. KF supplementation also decreased serum lactate, ammonia, BUN, and CK levels after the swimming test. However, tissue glycogen content, an important energy source for exercise, increased significantly with KF supplementation. Thus, KF supplementation can alter the gut microbiota composition, improve performance, and combat physical fatigue. PMID- 29973526 TI - The Importance of Multifrequency Impedance Sensing of Endothelial Barrier Formation Using ECIS Technology for the Generation of a Strong and Durable Paracellular Barrier. AB - In this paper, we demonstrate the application of electrical cell-substrate impedance sensing (ECIS) technology for measuring differences in the formation of a strong and durable endothelial barrier model. In addition, we highlight the capacity of ECIS technology to model the parameters of the physical barrier associated with (I) the paracellular space (referred to as Rb) and (II) the basal adhesion of the endothelial cells (α, alpha). Physiologically, both parameters are very important for the correct formation of endothelial barriers. ECIS technology is the only commercially available technology that can measure and model these parameters independently of each other, which is important in the context of ascertaining whether a change in overall barrier resistance (R) occurs because of molecular changes in the paracellular junctional molecules or changes in the basal adhesion molecules. Finally, we show that the temporal changes observed in the paracellular Rb can be associated with changes in specific junctional proteins (CD144, ZO-1, and catenins), which have major roles in governing the overall strength of the junctional communication between neighbouring endothelial cells. PMID- 29973527 TI - Pain-Associated Transcriptome Changes in Synovium of Knee Osteoarthritis Patients. AB - Joint pain causes significant morbidity in osteoarthritis (OA). The aetiology of joint pain in OA is not well understood. The synovial membrane as an innervated joint structure represents a potential source of peripheral pain in OA. Here we analyse, using a hypothesis-free next generation RNA sequencing, the differences in protein-coding and non-coding transcriptomes in knee synovial tissues from OA patients with high knee pain (n = 5) compared with OA patients with low knee pain (n = 5), as evaluated by visual analogue scale (VAS). We conduct Gene Ontology and pathway analyses on differentially expressed mRNA genes. We identify new protein-coding, long non-coding RNA and microRNA candidates that can be associated with OA joint pain. Top enriched genes in painful OA knees encode neuronal proteins that are known to promote neuronal survival under cellular stress or participate in calcium-dependent synaptic exocytosis and modulation of GABA(γ-aminobutyric acid)ergic activity. Our study uncovers transcriptome changes associated with pain in synovial microenvironment of OA knees. This sets a firm ground for future mechanistic studies and drug discovery to alleviate joint pain in OA. PMID- 29973528 TI - Somatostatin Analogue Treatment Primarily Induce miRNA Expression Changes and Up Regulates Growth Inhibitory miR-7 and miR-148a in Neuroendocrine Cells. AB - Somatostatin (SST) analogues are used to control the proliferation and symptoms of neuroendocrine tumors (NETs). MicroRNAs (miRNA) are small non-coding RNAs that modulate posttranscriptional gene expression. We wanted to characterize the miRNAs operating under the control of SST to elucidate to what extent they mediate STT actions. NCI-H727 carcinoid cell line was treated with either a chimeric SST/dopamine analogue; a SST or dopamine analogue for proliferation assays and for identifying differentially expressed miRNAs using miRNA microarray. The miRNAs induced by SST analogue treatment are investigated in carcinoid cell lines NCI-H727 and CNDT2 using in situ hybridization, qPCR and proliferation assays. SST analogues inhibited the growth of carcinoid cells more potently compared to the dopamine analogue. Principal Component Analysis (PCA) of the samples based on miRNA expression clearly separated the samples based on treatment. Two miRNAs which were highly induced by SST analogues, miR-7 and miR 148a, were shown to inhibit the proliferation of NCI-H727 and CNDT2 cells. SST analogues also produced a general up-regulation of the let-7 family members. SST analogues control and induce distinct miRNA expression patterns among which miR-7 and miR-148a both have growth inhibitory properties. PMID- 29973529 TI - Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors-An Improvement for Breast Cancer Imaging? AB - Heterobivalent peptidic ligands (HBPLs), designed to address two different receptors independently, are highly promising tumor imaging agents. For example, breast cancer has been shown to concomitantly and complementarily overexpress the neuropeptide Y receptor subtype 1 (NPY(Y1)R) as well as the gastrin-releasing peptide receptor (GRPR). Thus, radiolabeled HBPLs being able to bind these two receptors should exhibit an improved tumor targeting efficiency compared to monospecific ligands. We developed here such bispecific HBPLs and radiolabeled them with 68Ga, achieving high radiochemical yields, purities, and molar activities. We evaluated the HBPLs and their monospecific reference peptides in vitro regarding stability and uptake into different breast cancer cell lines and found that the 68Ga-HBPLs were efficiently taken up via the GRPR. We also performed in vivo PET/CT imaging and ex vivo biodistribution studies in T-47D tumor-bearing mice for the most promising 68Ga-HBPL and compared the results to those obtained for its scrambled analogs. The tumors could easily be visualized by the newly developed 68Ga-HBPL and considerably higher tumor uptakes and tumor to-background ratios were obtained compared to the scrambled analogs in and ex vivo. These results demonstrate the general feasibility of the approach to use bispecific radioligands for in vivo imaging of breast cancer. PMID- 29973530 TI - Molecular Diversity of Alkenal Double Bond Reductases in the Liverwort Marchantia paleacea. AB - Alkenal double bond reductases (DBRs), capable of catalyzing the NADPH-dependent reduction of the α,β-unsaturated double bond, play key roles in the detoxication of alkenal carbonyls. Here, the isolation and characterization of two DBRs encoded by the liverwort species Marchantia paleacea are described. The two DBRs share a relatively low similarity, and phylogenetic analysis indicated that MpMDBRL is more closely related to microbial DBRs than to other plant DBRs, while MpDBR shares common ancestry with typical plant DBRs. Both DBR proteins exhibited hydrogenation ability towards hydroxycinnamyl aldehydes; however, their temperature optimums were strikingly different. MpMDBRL demonstrated slightly weaker catalytic efficiency compared to MpDBR, and the structural models of their active binding sites to the substrate may provide a parsimonious explanation. Furthermore, both DBRs significantly responded to phytohormone treatment. In conclusion, M. paleacea produces two distinct types of functional DBRs, both of which participate in the protection against environmental stress in liverwort. The presence of a microbial type of DBR in a plant is herein reported for the first time. PMID- 29973531 TI - Simultaneous Detection of Adenosine Triphosphate and Glucose Based on the Cu Fenton Reaction. AB - Both adenosine triphosphate (ATP) and glucose are important to human health, and their abnormal levels are closely related to angiocardiopathy and hypoglycaemia. Therefore, the simultaneous determination of ATP and glucose with a single test mode is highly desirable for disease diagnostics and early recognition. Herein, a new fluorescence on/off switch sensing platform is developed by carbon nanodots (CNDs) to detect ATP and glucose simultaneously. The fluorescence of CNDs can be quenched by Cu2+ and hydrogen peroxide (H2O2), due to the formation of hydroxyl radicals (·OH) produced in the Cu-Fenton reaction. Based on the high affinity of Cu2+ with ATP, the fluorescence of CNDs will recover effectively after adding ATP. Additionally, glucose can be efficiently catalyzed by glucose oxidase (GOx) to generate H2O2, so the platform can also be utilized to analyze glucose. Under optimum conditions, this sensing platform displays excellent sensitivity and the linear ranges are from 0.1 to 7 μM for ATP with a limit of detection (LOD) of 30.2 nM, and from 0.1 to 7 mM for glucose with a LOD 39.8 μM, respectively. Benefiting from the high sensitivity and selectivity, this sensing platform is successfully applied for simultaneous detection of ATP and glucose in human serum samples with satisfactory recoveries. PMID- 29973532 TI - Lecture 3-Measuring Pharmacy's Work in the 21st Century. AB - The importance of developing a thoroughly shared understanding of mission, vision, and values is highlighted in reference to the creation of meaningful and sustainable key performance indicators (KPIs). A review of clinical practice KPIs (cpKPIs) and operational KPIs (opKPIs) is provided using work load measurement activities from Canada, its province of Alberta, and the United Kingdom. In order for Singaporean pharmacy clinicians and leaders to embrace a unified KPI system, the natural tendency to measure what is easy and available, instead of what matters to patients, is difficult but must be overcome. PMID- 29973533 TI - Kahweol Ameliorates the Liver Inflammation through the Inhibition of NF-kappaB and STAT3 Activation in Primary Kupffer Cells and Primary Hepatocytes. AB - Gut derived bacterial endotoxins, such as lipopolysaccharide (LPS), are involved in one of the important mechanisms that lead to inflammation associated with various liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Kahweol is a coffee-specific diterpene present in coffee bean and exhibits anti-angiogenic and anti-inflammatory activities. However, to date, the effect of kahweol on liver inflammation remains unknown. In this study, we examined whether kahweol exhibits a protective effect by inhibiting liver inflammation in primary Kupffer cells and primary hepatocytes cultures as well as their co-cultures. Kahweol decreased the LPS-induced production of interleukin 1 alpha, interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha. The inhibitory effect of kahweol on the liver inflammation was associated with the down regulation of LPS-stimulated phospho-nuclear factor kappa B and -signal transducer and activator of transcription 3 expression. These results suggest that kahweol might be a novel potent agent to treat liver inflammation induced by LPS. PMID- 29973535 TI - Composition Relation between Nonlinear Bloch Waves and Gap Solitons in Periodic Fractional Systems. AB - Evolution of beams in nonlinear optical media with a fractional-order diffraction is currently attracting a growing interest. We address the existence of linear and nonlinear Bloch waves in fractional systems with a periodic potential. Under a defocusing nonlinearity, nonlinear Bloch waves at the centers or edges of the first Brillouin zone bifurcate from the corresponding linear Bloch modes at different band edges. They can be constructed by directly copying a fundamental gap soliton (in one lattice site) or alternatively copying it and its mirror image to infinite lattice channels. The localized truncated-Bloch-wave solitons bridging nonlinear Bloch waves and gap solitons are also revealed. We thus prove that fundamental gap solitons can be used as unit cells to build nonlinear Bloch waves or truncated-Bloch-wave solitons, even in fractional configurations. Our results provide helpful hints for understanding the dynamics of localized and delocalized nonlinear modes and the relation between them in periodic fractional systems with an optical nonlinearity. PMID- 29973536 TI - A Study on Microstructure and Properties of PHS Fiber Laser Welded Joints Obtained in Air Atmospheres. AB - Press-hardened steels (PHS) with a 1.5-mm-thick coated Al-Si layer is welded using an IPG YLS6000 continuous fiber laser in the air atmosphere. An SU5000 scanning electron microscope (SEM) and an Oxford EDS X-Max20 energy spectrometer are used to characterize the microstructure, which consists of delta (δ) ferrite and lath martensite. It is similar to that of the welding performed in the Ar atmosphere, but the content of δ-ferrite is less. The reason is the formation of Al2O3 inclusions in the molten pool, which reacts with oxygen from the air ambient and the Al from the molten Al-Si coating of PHS. The oxygen content is measured with an ONH-3000 analyzer. An HV-1000 microhardness tester and DNS-100 universal material test equipment are performed to test the hardness and tensile strength. Similar hardness and strength of welded joints are achieved welding in the air atmosphere compared to that of the Ar atmosphere. Fracture was initialed in the fusion line of overlapping zone and propagated along the interface of two plates and fusion line due to the Al segregation. PMID- 29973537 TI - Microstructure and Mechanical Properties of Butt Joints between Stainless Steel SUS304L and Aluminum Alloy A6061-T6 by TIG Welding. AB - The tungsten inert gas (TIG) welding method most commonly used to weld ferrous metals, nonferrous metals, and other metals since it is simple, easily implemented, and achieves consistent high-quality welds. In this study, butt joints produced between aluminum alloy A6061-T6 and stainless steel SUS304L have been achieved by using TIG welding with ER4047 filler metal. The macrostructure and microstructure of the resulting specimens were analyzed by means of an optical microscope (OM), a scanning electron microscope (SEM), and an energy dispersive X-ray spectrometer (EDS). A uniform intermetallic layer was found at the interface between the stainless steel and the weld seam having a thickness of 2 µm, and the intermetallic compound (IMC) includes Fe4Al13, Fe2Al5, and FeAl3 phases. The micro-hardness and tensile strength of the weld joints were also investigated. Due to Si content in the compensating metal, there was a prevention of iron diffusion into the aluminum, thus hindering the development of the IMC layer and reducing its thickness in such a way that the weld joint strength increases. The analyzed results show that the average micro-hardness of the stainless steel, weld seam, aluminum alloys, and IMC layer were 218 HV, 88.3 HV, 63.3 HV, and 411 HV, respectively. The fracture occurred at the brazed interface, and the ultimate tensile strength value reached 225 MPa. PMID- 29973534 TI - Identification of Antifungal Targets Based on Computer Modeling. AB - Aspergillus fumigatus is a saprophytic, cosmopolitan fungus that attacks patients with a weak immune system. A rational solution against fungal infection aims to manipulate fungal metabolism or to block enzymes essential for Aspergillus survival. Here we discuss and compare different bioinformatics approaches to analyze possible targeting strategies on fungal-unique pathways. For instance, phylogenetic analysis reveals fungal targets, while domain analysis allows us to spot minor differences in protein composition between the host and fungi. Moreover, protein networks between host and fungi can be systematically compared by looking at orthologs and exploiting information from host-pathogen interaction databases. Further data—such as knowledge of a three-dimensional structure, gene expression data, or information from calculated metabolic fluxes—refine the search and rapidly put a focus on the best targets for antimycotics. We analyzed several of the best targets for application to structure-based drug design. Finally, we discuss general advantages and limitations in identification of unique fungal pathways and protein targets when applying bioinformatics tools. PMID- 29973538 TI - Second Iteration of Photogrammetric Processing to Refine Image Orientation with Improved Tie-Points ?. AB - Photogrammetric processing is available in various software solutions and can easily deliver 3D pointclouds as accurate as 1 pixel. Certain applications, e.g., very accurate shape reconstruction in industrial metrology or change detection for deformation studies in geosciences, require results of enhanced accuracy. The tie-point extraction step is the opening in the photogrammetric processing chain and therefore plays a key role in the quality of the subsequent image orientation, camera calibration and 3D reconstruction. Improving its precision will have an impact on the obtained 3D. In this research work we describe a method which aims at enhancing the accuracy of image orientation by adding a second iteration photogrammetric processing. The result from the classical processing is used as a priori information to guide the extraction of refined tie points of better photogrammetric quality. Evaluated on indoor and UAV acquisitions, the proposed methodology shows a significant improvement on the obtained 3D point accuracy. PMID- 29973539 TI - Effects of Blue-Light-Induced Free Radical Formation from Catechin Hydrate on the Inactivation of Acinetobacter baumannii, Including a Carbapenem-Resistant Strain. AB - Catechin is a flavan-3-ol, a derivative of flavans, with four phenolic hydroxyl groups, which exhibits a wide range of physiological properties. Chromatographic analyses were employed to examine the effects of blue light irradiation on the changes of catechin hydrate in an alkaline condition. In particular, the detection of a superoxide anion radical (O2•−), a reactive oxygen species (ROS), and the inactivation of Acinetobacter baumannii (A. baumannii)—including a carbapenem-resistant A. baumannii (CRAB)—was investigated during the photoreaction of catechin hydrate. Following basification with blue light irradiation, the transparent solution of catechin hydrate turned yellowish, and a chromogenic catechin dimer was separated and identified as a proanthocyanidin. Adding ascorbic acid during the photolytic treatment of catechin hydrate decreased the dimer formation, suggesting that ascorbic acid can suppress the photosensitive oxidation of catechin. When catechin hydrate was irradiated by blue light in an alkaline solution, O2•− was produced via photosensitized oxidation, enhancing the inactivation of A. baumannii and CRAB. The present findings on the photon-induced oxidation of catechin hydrate provides a safe practice for the inactivation of environmental microorganisms. PMID- 29973540 TI - Time Dependent Pathway Activation of Signalling Cascades in Rat Organs after Short-Term Hyperoxia. AB - Administration of oxygen is one of the most common interventions in medicine. Previous research showed that differential regulated proteins could be linked to hyperoxia-associated signaling cascades in different tissues. However, it still remains unclear which signaling pathways are activated by hyperoxia. The present study analyses hyperoxia-induced protein alterations in lung, brain, and kidney tissue using a proteomic and bioinformatic approach. Pooled data of 36 Wistar rats exposed to hyperoxia were used. To identify possible hyperoxia biomarkers, and to evaluate the relationship between protein alterations in hyperoxia affected organs and blood, proteomics data from brain, lung, and kidney were analyzed. Functional network analyses (IPA®, PathwaysStudio®, and GENEmania®) in combination with hierarchical cluster analysis (Perseus®) was used to identify relevant pathways and key proteins. Data of 54 2D-gels with more than 2500 significantly regulated spots per gel were collected. Thirty-eight differentially expressed proteins were identified and consecutively analyzed by bioinformatic methods. Most differences between hyperoxia and normoxia (21 proteins up-regulated, 17 proteins down-regulated) were found immediately after hyperoxia (15 protein spots), followed by day 3 (13 spots), and day 7 (10 spots). A highly significant association with inflammation and the inflammatory response was found. Cell proliferation, oxidative stress, apoptosis and cell death as well as cellular functions were revealed to be affected. Three hours of hyperoxia resulted in significant alterations of protein expression in different organs (brain, lung, kidney) up to seven days after exposure. Further studies are required to interpret the relevance of protein alterations in signaling cascades during/after hyperoxia. PMID- 29973541 TI - Transmembrane TNF and Partially TNFR1 Regulate TNFR2 Expression and Control Inflammation in Mycobacterial-Induced Pleurisy. AB - Pleural tuberculosis is one of the most frequent forms of extra-pulmonary tuberculosis observed in patients infected with Mycobacterium tuberculosis. Tumor Necrosis Factor (TNF) is a crucial cytokine needed to control tuberculosis infection that remains a leading cause of morbidity and mortality worldwide. TNF blockade compromises host immunity and may increase the risk of reactivation of latent infection resulting in overt pulmonary, pleural and extra-pulmonary tuberculosis. While TNF signaling is mainly considered pro-inflammatory, its requirement for the anti-inflammation process involved in the resolution of infection and tissue repair is less explored. Our study analyzes the role of TNF and TNF receptors in the control of the inflammatory process associated with Bacillus Calmette-Guérin (BCG)-induced pleurisy. This study shows that the absence of TNF causes exacerbated inflammation in the pleural cavity of BCG infected mice which is controlled by the transmembrane TNF (tmTNF) expression. The lack of TNF is associated with an impaired cellular expression and shedding of TNFR2 in the pleural cavity. The presence of tmTNF restores the normal expression of TNFR2 on myeloid cells during BCG-induced pleurisy. We also show that absence of TNFR1 affects the expression of TNFR2 on pleural cells and inflammation in the pleural cavity of BCG-infected mice. In conclusion, tmTNF but not soluble TNF prevents pleural cavity inflammation leading to attenuation and the resolution of the inflammatory process caused by mycobacterial pleurisy in association with the expression of TNFR2 on myeloid cells. PMID- 29973543 TI - InSAR Baseline Estimation for Gaofen-3 Real-Time DEM Generation. AB - For Interferometry Synthetic Aperture Radar (InSAR), the normal baseline is one of the main factors that affects the accuracy of the ground elevation. For Gaofen 3 (GF-3) InSAR processing, the poor accuracy of the real-time orbit determination results in a large baseline error, leads to a modulation error in azimuth and a slope error in the range for timely Digital Elevation Model (DEM) generation. In order to address this problem, a novel baseline estimation approach based on Shuttle Radar Topography Mission (SRTM) DEM is proposed in this paper. Firstly, the orbit fitting is executed to remove the non-linear error factor, which is different from traditional methods. Secondly, the height errors are obtained in a slant-range plane between SRTM DEM and the GF-3 generated DEM, which can be used to estimate the baseline error with a linear variation. Then, the real-time orbit can be calibrated by the baseline error. Finally, the DEM generation is performed by using the modified baseline and orbit. This approach has the merit of spatial and precise orbital free ability. Based on the results of GF-3 interferometric SAR data for Hebei, the effectiveness of the proposed algorithm is verified and the accuracy of GF-3 real-time DEM products can be improved extensively. PMID- 29973542 TI - Transistors for Chemical Monitoring of Living Cells. AB - We review here the chemical sensors for pH, glucose, lactate, and neurotransmitters, such as acetylcholine or glutamate, made of organic thin-film transistors (OTFTs), including organic electrochemical transistors (OECTs) and electrolyte-gated OFETs (EGOFETs), for the monitoring of cell activity. First, the various chemicals that are produced by living cells and are susceptible to be sensed in-situ in a cell culture medium are reviewed. Then, we discuss the various materials used to make the substrate onto which cells can be grown, as well as the materials used for making the transistors. The main part of this review discusses the up-to-date transistor architectures that have been described for cell monitoring to date. PMID- 29973544 TI - Gender Difference in the Association between Environmental Tobacco Smoke and Birth Weight in Africa. AB - The adverse health effects of exposure to environmental tobacco smoke (ETS) on children are well-documented, and yet, gender difference in low birthweight among newborns whose mothers were exposed to ETS during pregnancy still remains contentious. We therefore explored the association between ETS exposure and risk of low birthweight, and further determined the gender difference in the association between exposure to ETS during pregnancy and birth weight in Africa. The Demographic Health Surveys of 23 African countries with information on 208,027 newborns were used. The associations between exposure to ETS and birth weight was estimated using multiple logistic regression models. Exposure to ETS increased the risk of low birthweight in Africa (adjusted odds ratio (OR) = 1.06; 95% Confidence Interval (CI): 1.02-1.10). A stratified analysis, by gender, revealed that male newborns whose mothers were exposed to ETS were 1.08 (95% CI: 1.02-1.14) times more likely to be low in birthweight than those whose mothers were not exposed, with those exposed weekly (adjusted OR = 1.17; 95% CI: 1.01 1.35) and daily (adjusted OR = 1.06; 95% CI: 1.01-1.12) being more likely to have low birthweight. Exposure to ETS is significantly associated with low birthweight in Africa, mainly among male newborns. Gender could possibly be a modifier, and hence, research on biological plausibility is necessary. Moreover, a public health promotion on behavioral changes is likely to have a positive impact on newborns’ health. PMID- 29973545 TI - Multiple Fusion Based on the CCD and MEMS Accelerometer for the Low-Cost Multi Loop Optoelectronic System Control. AB - In the charge-coupled device (CCD) and micro-electro-mechanical system (MEMS) accelerometer based low-cost multi-loop optoelectronic control system (OCS), due to accelerometers’ drift and noise in low frequency, the disturbance suppression (DS) is insufficient. Previously, based on the acceleration and position dual-loop control (ADLC), researchers combined a disturbance observer (DOB) with a virtual velocity loop to make some medium-frequency DS exchange for low-frequency performance. However, it is not optimal because the classic DOB based on accelerometers’ inaccurate signals cannot observe accurate disturbance in low frequency and the velocity based on a CCD and accelerometer time-domain fusion carried the CCD’s delay, resulting in the drop of medium frequency DS. In this paper, considering the CCD’s advantage in low frequency and the accelerometer’s strength in high frequency, we propose to fuse their signals twice with a modified complementary filter method to respectively acquire an acceleration and velocity. The new acceleration with no drift and less noise but lower bandwidth creates a new acceleration model and is only used in fusion DOB (FDOB), while the velocity with little delay is to build an additional velocity loop. Compared with the traditional DOB enhanced by the time-domain fusion velocity loop, experiments verify that the proposed multiple fusion would apparently enhance the system’s DS, especially in low and medium frequency. PMID- 29973546 TI - Misophonia in Singaporean Psychiatric Patients: A Cross-Sectional Study. AB - Misophonia, also known as selective sound sensitivity syndrome, is a condition characterized by strong dislike of specific sounds with accompanying distressing reactions. To date, misophonia is still poorly understood. This study aimed to identify factors associated with severity of misophonic symptoms in Singaporean psychiatric patients. Ninety-two psychiatric patients were recruited from a large teaching hospital in Singapore in a cross-sectional study. Socio-demographics, severity of depression, anxiety and stress, and severity of misophonic symptoms were analyzed. Correlation analysis showed that anxiety, depression, and stress scores—as measured by the Depression, Anxiety and Stress Scales-21 (DASS 21)—were significantly positively correlated with the Amsterdam Misophonia Scale (A-MISO-S) scores. After adjustment for confounding factors, multivariate regression analysis showed that anxiety (β = 0.385, p = 0.029) remained significantly associated with A-MISO-S. Age, gender, depression, and stress were not significantly associated with the severity of misophonia. The findings showed that the severity of anxiety was associated with severity of misophonia in Singaporean psychiatric patients. Further research is needed to explore the nature of misophonia and its relationship with other psychiatric disorders. PMID- 29973547 TI - The Effect of Particle Shape on Sintering Behavior and Compressive Strength of Porous Alumina. AB - Alumina particles with different shapes, such as sphere, rod, and disk, were examined for the sintering behavior and compressive strength of partially sintered porous alumina. While both the spherical and disk-like particles were packed well to the relative density of 61.2-62.3%, the packing density of rod like particles was only 33.5%. The sintering rate of alumina particles increased in the order of disk < rod < sphere. The compressive strength of sintered porous alumina was higher for the spherical particles than for the rod-like and disk like particles. The uniform distribution of the applied load over many developed grain boundaries contributed to the increase in the compressive strength for the spherical particles. The applied load concentrated on a few grain boundaries of rod-like or disk-like particles, caused fracture at a low compressive stress. PMID- 29973548 TI - Verapamil Inhibits TRESK (K2P18.1) Current in Trigeminal Ganglion Neurons Independently of the Blockade of Ca2+ Influx. AB - Tandem pore domain weak inward rectifier potassium channel (TWIK)-related spinal cord K+ (TRESK; K2P18.1) channel is the only member of the two-pore domain K+ (K2P) channel family that is activated by an increase in intracellular Ca2+ concentration ([Ca2+]i) and linked to migraines. This study was performed to identify the effect of verapamil, which is an L-type Ca2+ channel blocker and a prophylaxis for migraines, on the TRESK channel in trigeminal ganglion (TG) neurons, as well as in a heterologous system. Single-channel and whole-cell currents were recorded in TG neurons and HEK-293 cells transfected with mTRESK using patch-clamping techniques. In TG neurons, changes in [Ca2+]i were measured using the fluo-3-AM Ca2+ indicator. Verapamil, nifedipine, and NiCl2 inhibited the whole-cell currents in HEK-293 cells overexpressing mTRESK with IC50 values of 5.2, 54.3, and >100 μM, respectively. The inhibitory effect of verapamil on TRESK channel was also observed in excised patches. In TG neurons, verapamil (10 μM) inhibited TRESK channel activity by approximately 76%. The TRESK channel activity was not dependent on the presence of extracellular Ca2+. In addition, the inhibitory effect of verapamil on the TRESK channel remained despite the absence of extracellular Ca2+. These findings show that verapamil inhibits the TRESK current independently of the blockade of Ca2+ influx in TG neurons. Verapamil will be able to exert its pharmacological effects by modulating TRESK, as well as Ca2+ influx, in TG neurons in vitro. We suggest that verapamil could be used as an inhibitor for identifying TRESK channel in TG neurons. PMID- 29973549 TI - Designing Interactive Experiences for Children with Cochlear Implant. AB - Information and Communication Technologies (ICTs) have grown exponentially in the education context and the use of digital products by children is increasing. As a result, teachers are taking advantage of ICTs to include mobile devices such as Tablets or Smartphones inside the classroom as playful support material to motivate children during their learning. Designing an interactive experience for a child with a special need such as a hearing impairment is a great challenge. In this article, two interactive systems are depicted, using a non-traditional interaction, by the following stages: analysis, design and implementation, with the participation of children with cochlear implant in the Institute of Blind and Deaf Children of Valle del Cauca, Colombia and the ASPAS Institute, Mallorca, Spain, who evaluated both interactive systems, PHONOMAGIC and CASETO. Positive results were obtained, showing that the use of real objects can greatly influence the environment in which children interact with the game, allowing them to explore and manipulate the objects supporting their teaching-learning processes. PMID- 29973551 TI - Measuring Surgery Outcomes of Lung Cancer Patients with Concomitant Pulmonary Fibrosis: A Review of the Literature. AB - Idiopathic pulmonary fibrosis (IPF), the most common form of idiopathic interstitial pneumonias, often progresses to restrictive respiratory disturbance and mortality, typically within 10 years. IPF frequently coexists with lung cancer, and the combination of these two disease entities is far more difficult to treat than either lung cancer or IPF alone. In particular, surgery for lung cancer with IPF in the background increases postoperative morbidity and mortality by exacerbating pre-existing IPF, i.e., acute exacerbation of IPF (AEIPF). Furthermore, the long-term outcome after lung cancer surgery is considerably worsened by the presence of IPF. We present here a comprehensive review of AEIPF and the long-term outcomes after surgery. PMID- 29973553 TI - High-Performance Limiting Current Oxygen Sensor Comprised of Highly Active La0.75Sr0.25Cr0.5Mn0.5O3 Electrode. AB - Zirconia-based limiting current oxygen sensor gains considerable attention, due to its high-performance in improving the combustion efficiency of fossil fuels and reducing the emission of exhaust gases. Nevertheless, the Pt electrode is frequently used in the oxygen sensor, therefore, it restrains the broader application due to the high cost. Quite recently, La0.75Sr0.25Cr0.5Mn0.5O3 (LSCM) has been reported to be highly active to catalyze oxygen reduction. Herein, with the intention of replacing the frequently used Pt, we studied the practicability of adapting the LSCM to zirconia-based limiting current oxygen sensor. Through comparing the electrocatalytic activity of LSCM and Pt, it is confirmed that LSCM gave analogous oxygen reactivity with that of the Pt. Then, limiting the current oxygen sensors comprised of LSCM or Pt are fabricated and their sensing behavior to oxygen in the range of 2-25% is evaluated. Conclusively, quick response/recovery rate (within 7s), linear relationship, and high selectivity (against 5% CO2 and H2O) in sensing oxygen are observed for the sensors, regardless of the sensing materials (LSCM or Pt) that are used in the sensor. Particularly, identical sensing characteristics are observed for the sensors consisting of LSCM or Pt, indicating the practicability of replacing the Pt electrode by adapting the LSCM electrode to future zirconia-based oxygen sensors. PMID- 29973552 TI - Secoiridoids from the Seed of Gonocaryum calleryanum and Their Inhibitory Potential on LPS-Induced Tumor Necrosis Factor and Nitric Oxide Production. AB - Three new secoiridoid constituents, goncarin A−C (1-3), and a new derivative, goncarin A monoacetate (4), along with two known lignins, pinoresinol (5) and paulownin (6), were isolated from the seed of Gonocaryum calleryanum (Baill.) Becc. The structures of the new metabolites were determined on the basis of extensive spectroscopic analysis, particularly mass spectroscopy and 2D NMR (1H-1H COSY, HMQC, HMBC, and NOESY) spectroscopy. The aim of this study was to identify the anti-inflammatory effects of compounds 1-6 on lipopolysaccharide (LPS)-stimulated murine macrophage cell lines (RAW 264.7). Following stimulation with LPS, elevated levels of nitric oxide (NO) production were detected in RAW 264.7 cells; however, pretreatment with compounds 1-6 significantly inhibited the production of NO (around 40-80%, p < 0.01-0.05), by suppressing the expression of inducible NO synthase (iNOS). In addition, LPS-stimulated tumor necrosis factor α (TNF-α) production was significantly reduced by compounds 1-3 (25 40%, p < 0.01-0.05). These results suggested that compounds 1-3 may exert anti inflammatory activity, and that compounds 1-3 may be considered a potential therapeutic for the treatment of inflammatory diseases associated with macrophage activation. PMID- 29973550 TI - Genome Analysis of Vallitalea guaymasensis Strain L81 Isolated from a Deep-Sea Hydrothermal Vent System. AB - Abyssivirga alkaniphila strain L81T, recently isolated from a black smoker biofilm at the Loki’s Castle hydrothermal vent field, was previously described as a mesophilic, obligately anaerobic heterotroph able to ferment carbohydrates, peptides, and aliphatic hydrocarbons. The strain was classified as a new genus within the family Lachnospiraceae. Herein, its genome is analyzed and A. alkaniphila is reassigned to the genus Vallitalea as a new strain of V. guaymasensis, designated V. guaymasensis strain L81. The 6.4 Mbp genome contained 5651 protein encoding genes, whereof 4043 were given a functional prediction. Pathways for fermentation of mono-saccharides, di-saccharides, peptides, and amino acids were identified whereas a complete pathway for the fermentation of n alkanes was not found. Growth on carbohydrates and proteinous compounds supported methane production in co-cultures with Methanoplanus limicola. Multiple confurcating hydrogen-producing hydrogenases, a putative bifurcating electron transferring flavoprotein—butyryl-CoA dehydrogenase complex, and a Rnf complex form a basis for the observed hydrogen-production and a putative reverse electron-transport in V. guaymasensis strain L81. Combined with the observation that n-alkanes did not support growth in co-cultures with M. limicola, it seemed more plausible that the previously observed degradation patterns of crude-oil in strain L81 are explained by unspecific activation and may represent a detoxification mechanism, representing an interesting ecological function. Genes encoding a capacity for polyketide synthesis, prophages, and resistance to antibiotics shows interactions with the co-occurring microorganisms. This study enlightens the function of the fermentative microorganisms from hydrothermal vents systems and adds valuable information on the bioprospecting potential emerging in deep-sea hydrothermal systems. PMID- 29973554 TI - Omega-3 Fatty Acid Supplementation and Cardiovascular Disease Risk: Glass Half Full or Time to Nail the Coffin Shut? AB - There has been a great deal of controversy in recent years about the potential role of dietary supplementation with long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) in the prevention of cardiovascular disease (CVD). Four recent meta-analyses have been published that evaluated randomized, controlled trial (RCT) data from studies that assessed the effects of supplemental n-3 PUFA intake on CVD endpoints. The authors of those reports reached disparate conclusions. This review explores the reasons informed experts have drawn different conclusions from the evidence, and addresses implications for future investigation. Although RCT data accumulated to date have failed to provide unequivocal evidence of CVD risk reduction with n-3 PUFA supplementation, many studies were limited by design issues, including low dosage, no assessment of n-3 status, and absence of a clear biological target or pathophysiologic hypothesis for the intervention. The most promising evidence supports n-3 PUFA supplementation for prevention of cardiac death. Two ongoing trials have enrolled high cardiovascular risk subjects with hypertriglyceridemia and are administering larger dosages of n-3 PUFA than employed in previous RCTs. These are expected to clarify the potential role of long-chain n-3 PUFA supplementation in CVD risk management. PMID- 29973555 TI - A Pilot Study of Iyengar Yoga for Pediatric Obesity: Effects on Gait and Emotional Functioning. AB - Obesity negatively impacts the kinematics and kinetics of the lower extremities in children and adolescents. Although yoga has the potential to provide several distinct benefits for children with obesity, this is the first study to examine the benefits of yoga for gait (primary outcome) in youths with obesity. Secondary outcomes included health-related quality of life (HRQoL), physical activity, and pain. Feasibility and acceptability were also assessed. Nine youths (11-17 years) participated in an eight-week Iyengar yoga intervention (bi-weekly 1-h classes). Gait, HRQOL (self and parent-proxy reports), and physical activity were assessed at baseline and post-yoga. Pain was self-reported at the beginning of each class. Significant improvements were found in multiple gait parameters, including hip, knee, and ankle motion and moments. Self-reported and parent-proxy reports of emotional functioning significantly improved. Time spent in physical activity and weight did not change. This study demonstrates that a relatively brief, non invasive Iyengar yoga intervention can result in improved malalignment of the lower extremities during ambulation, as well as in clinically meaningful improvements in emotional functioning. This study extends current evidence that supports a role for yoga in pediatric obesity. PMID- 29973556 TI - Liquid Chromatography Coupled with Linear Ion Trap Hybrid OrbitrapMass Spectrometry for Determination of Alkaloids in Sinomeniumacutum. AB - The characterization of alkaloids is challenging because of the diversity of structures and the complicated fragmentation of collision induced structural dissociation in mass spectrometry. In this study, we analyzed the alkaloids in Sinomenium acutum (Thunb.) Rehderet Wil by high resolution mass spectrometry. Chromatographic separation was achieved on a Phenomenex Kinetex C18 (2.1 mm × 100 mm, 2.6 μm) column with a mobile phase consisting of acetonitrile and water (0.1% formic acid) under gradient elution. A total of 52 alkaloids were well separated and 45 of them were structurally characterized, including morphinans, aporphines, benzylisoquinolines, and protoberberines. Specially, mass spectrometric study of the morphinan alkaloids were explicitly investigated. Electrostatic potential plot from simulation was calculated for determination of protonation sites. Further fragmentation analysis suggested that the C3H7N, CH4O, and H2O elimination was displayed in MS2 spectrum. These fragmentation pathways are universal for morphinan alkaloids having methoxy substituted cyclohexenone or cyclohexadienone moieties. Additionally, for nitrogen oxides, an ion-neutral complex intermediate is involved in the fragmentation process, generating additional oxygenated ions. All these results provided the universal rules of fragmentation used for detection of alkaloids, and will be expected to be highly useful for comprehensive study of multi-components in the herbal medicine analysis. PMID- 29973558 TI - The Use of Trisodium Citrate to Improve the Textural Properties of Acid-Induced, Transglutaminase-Treated Micellar Casein Gels. AB - In this study, the effect of trisodium citrate on the textural properties and microstructure of acid-induced, transglutaminase-treated micellar casein gels was investigated. Various concentrations of trisodium citrate (0 mmol/L, 10 mmol/L, 20 mmol/L, and 30 mmol/L) were added to micellar casein dispersions. After being treated with microbial transglutaminase (mTGase), all dispersions were acidified with 1.3% (w/v) gluconodelta-lactone (GDL) to pH 4.4-4.6. As the concentration of trisodium citrate increased from 0 mmol/L to 30 mmol/L, the firmness and water holding capacity increased significantly. The final storage modulus (G′) of casein gels was positively related to the concentration of trisodium citrate prior to mTGase treatment of micellar casein dispersions. Cryo-scanning electron microscopy images indicated that more interconnected networks and smaller pores were present in the gels with higher concentrations of trisodium citrate. Overall, when micellar casein dispersions are treated with trisodium citrate prior to mTGase crosslinking, the resulted acid-induced gels are firmer and the syneresis is reduced. PMID- 29973559 TI - Does the Pollen Diet Influence the Production and Expression of Antimicrobial Peptides in Individual Honey Bees? AB - We investigated the importance of protein nutrition for honey bee immunity. Different protein diets (monofloral pollen of Helianthus spp., Sinapis spp., Asparagus spp., Castanea spp., a mixture of the four different pollen and the pollen substitute FeedbeeTM) were fed to honey bees in cages ad libitum. After 18 days of feeding, apidaecin 1 isoforms concentration in the thorax were measured using nanoflow liquid chromatography coupled with mass spectrometry. Expression levels of genes, coding for apidaecins and abaecin in the abdomen were determined using quantitative PCR. The results indicate that protein-containing nutrition in adult worker honey bees can trigger certain metabolic responses. Bees without dietary protein showed lower apidaecin 1 isoforms concentrations. The significantly lowest concentration of apidaecin 1 isoforms was found in the group that was fed no pollen diet when compared to Asparagus, Castanea, Helianthus, and Sinapis pollen or the pollen supplement FeedBeeTM. Expression levels of the respective genes were also affected by the protein diets and different expression levels of these two antimicrobial peptides were found. Positive correlation between concentration and gene expression of apidaecins was found. The significance of feeding bees with different protein diets, as well as the importance of pollen nutrition for honey bee immunity is demonstrated. PMID- 29973560 TI - Assessment of Welfare in Zoo Animals: Towards Optimum Quality of Life. AB - Zoos are required to maintain a high standard of animal welfare, and this can be assessed using a combination of resource-based and animal-based indices usually divided into behavioural indicators, physiological indicators and clinical/pathological signs. Modern animal welfare assessments should aim to encompass positive affective states and the indicators that are useful in assessing these are discussed. When developing factors to be scored for each species, there is huge variability in the available information about the natural biology for some zoo species and even less information concerning those animals in captivity. Wild baselines are not always the most accurate indicator of what is right for an animal in captivity, which makes the identification of factors to include within species-specific welfare assessment even more challenging. When planning a welfare strategy for any species, it is important that the full range of their biological requirements and needs are considered, but this can be challenging for some zoo species and it is not possible to define a “one size fits all” welfare strategy. The different approaches for welfare assessment are reviewed, including the development of the Animal Welfare Assessment Grid which offers an evidence-based tool for continual welfare assessment, using technology where appropriate, to facilitate decision making and lead to improvements in the animals’ quality of life. PMID- 29973562 TI - Investigation of Hydro-Lipophilic Properties of N Alkoxyphenylhydroxynaphthalenecarboxamides ?. AB - The evaluation of the lipophilic characteristics of biologically active agents is indispensable for the rational design of ADMET-tailored structure-activity models. N-Alkoxy-3-hydroxynaphthalene-2-carboxanilides, N-alkoxy-1 hydroxynaphthalene-2-carboxanilides, and N-alkoxy-2-hydroxynaphthalene-1 carboxanilides were recently reported as a series of compounds with antimycobacterial, antibacterial, and herbicidal activity. As it was found that the lipophilicity of these biologically active agents determines their activity, the hydro-lipophilic properties of all three series were investigated in this study. All 57 anilides were analyzed using the reversed-phase high-performance liquid chromatography method for the measurement of lipophilicity. The procedure was performed under isocratic conditions with methanol as an organic modifier in the mobile phase using an end-capped non-polar C18 stationary reversed-phase column. In the present study, a range of software lipophilicity predictors for the estimation of clogP values of a set of N alkoxyphenylhydroxynaphthalenecarboxamides was employed and subsequently cross compared with experimental parameters. Thus, the empirical values of lipophilicity (logk) and the distributive parameters (π) were compared with the corresponding in silico characteristics that were calculated using alternative methods for deducing the lipophilic features. To scrutinize (dis)similarities between the derivatives, a PCA procedure was applied to visualize the major differences in the performance of molecules with respect to their lipophilic profile, molecular weight, and violations of Lipinski’s Rule of Five. PMID- 29973557 TI - Disease Resistance Mechanisms in Plants. AB - Plants have developed a complex defense system against diverse pests and pathogens. Once pathogens overcome mechanical barriers to infection, plant receptors initiate signaling pathways driving the expression of defense response genes. Plant immune systems rely on their ability to recognize enemy molecules, carry out signal transduction, and respond defensively through pathways involving many genes and their products. Pathogens actively attempt to evade and interfere with response pathways, selecting for a decentralized, multicomponent immune system. Recent advances in molecular techniques have greatly expanded our understanding of plant immunity, largely driven by potential application to agricultural systems. Here, we review the major plant immune system components, state of the art knowledge, and future direction of research on plant-pathogen interactions. In our review, we will discuss how the decentralization of plant immune systems have provided both increased evolutionary opportunity for pathogen resistance, as well as additional mechanisms for pathogen inhibition of such defense responses. We conclude that the rapid advances in bioinformatics and molecular biology are driving an explosion of information that will advance agricultural production and illustrate how complex molecular interactions evolve. PMID- 29973563 TI - Integrating Cyber-Physical Systems in a Component-Based Approach for Smart Homes. AB - Integration of different cyber-physical systems involves a development process that takes into account some solutions for intercommunicating and interoperating heterogeneous devices. Each device can be managed as a thing within the Internet of-Things concept by using web technologies. In addition, a “thing” can be managed as an encapsulated component by applying component-based software engineering principles. Based on this context, we propose a solution for integrating heterogeneous systems using a specific component-based technology. Specifically, we focus on enabling the connection of different types of subsystems present in smart home solutions. This technology enables interoperability by applying a homogeneous component representation that provides communication features through web sockets, and by implementing gateways in proprietary network connections. Furthermore, our solution eases the extension of these systems by means of abstract representations of the architectures and devices that form part of them. The approach is validated through an example scenario with different subsystems of a smart home solution. PMID- 29973561 TI - Current Molecular-Targeted Therapies in NSCLC and Their Mechanism of Resistance. AB - Lung cancer is treated with many conventional therapies, such as surgery, radiation, and chemotherapy. However, these therapies have multiple undesirable side effects. To bypass the side effects elicited by these conventional treatments, molecularly-targeted therapies are currently in use or under development. Current molecularly-targeted therapies effectively target specific biomarkers, which are commonly overexpressed in lung cancers and can cause increased tumorigenicity. Unfortunately, several molecularly-targeted therapies are associated with initial dramatic responses followed by acquired resistance due to spontaneous mutations or activation of signaling pathways. Acquired resistance to molecularly targeted therapies presents a major clinical challenge in the treatment of lung cancer. Therefore, to address this clinical challenge and to improve lung cancer patient prognosis, we need to understand the mechanism of acquired resistance to current therapies and develop additional novel therapies. This review concentrates on various lung cancer biomarkers, including EGFR, ALK, and BRAF, as well as their potential mechanisms of drug resistance. PMID- 29973564 TI - Development of a Column-Switching HPLC-MS/MS Method and Clinical Application for Determination of Ethyl Glucuronide in Hair in Conjunction with AUDIT for Detecting High-Risk Alcohol Consumption. AB - It is critical to assess the severity of alcohol consumption in certain diseases such as alcohol liver disease and alcohol addiction. Ethyl glucuronide (EtG) is a highly stable metabolite of ethanol in hair; thus, it was proposed as a long-term monitoring marker for alcohol consumption. Therefore, an HPLC-MS/MS method for EtG in hair was developed and applied to a clinical setting to assess the relevance of the EtG concentration and/or the Alcohol Use Disorders Identification Test (AUDIT) score to high-risk alcohol consumption. EtG was extracted from 10 mg of hair using water and analyzed using on-line sample purification coupled to HPLC-MS/MS. The diagnostic performances of the EtG concentration and/or the AUDIT score for detecting high-risk alcohol consumption were statistically evaluated between alcohol addicts (n = 44) and average alcohol users (n = 19). The on-line sample purification resulted in labor-saving with smaller sample amount. Both the EtG concentrations (4.0-587.4 pg/mg vs. 12.9-74.9 pg/mg) and the AUDIT scores (4-40 vs. 5-28) obtained from the alcohol addicts were significantly higher than those from the average alcohol users. The performance evaluation demonstrated that the integration score of the EtG concentration and the AUDIT score increased diagnostic performance for high-risk alcohol consumption. PMID- 29973565 TI - Weight-Dependent Disparities in Adolescent Girls: The Impact of a Brief Pilot Intervention on Exercise and Healthy Eater Identity. AB - Adolescent girls report low participation in healthy behaviors (e.g., nutritious eating and exercise), and are disproportionately affected by obesity. Short-term interventions, such as behavioral summer camps, may positively influence psychological underpinnings of healthy behavior, particularly exercise identity (EI) and healthy eater identity (HEI). The present study investigates disparities and changes in identity and subsequent health behavior in two cohorts of adolescent girls following a brief, multicomponent intervention. A sample of normal-weight adolescent girls from a health promotion camp and an elevated body mass index (BMI) sample from an obesity treatment camp participated in the study. Both camps ran one-week in duration and delivered comparable intervention components. All families were given access to the same eight-week eHealth program post-camp. Significant EI and HEI role-identity disparities between the health promotion and obesity treatment cohorts were apparent at baseline. Following the one-week camp intervention, EI and HEI scores increased in both groups. At follow up, the treatment group had increased EI and HEI role-identities in such that the groups no longer significantly differed. Positive changes in health behaviors were experienced in each group. This pilot study demonstrates that EI and HEI differ between normal-weight and obese adolescent girls and weight-dependent identity disparities may be mitigated following brief, multicomponent interventions. PMID- 29973566 TI - Analysis of Frequency Stability and Thermoelastic Effects for Slotted Tuning Fork MEMS Resonators. AB - MicroElectroMechanical Systems (MEMS) resonators are attracting increasing interest because of their smaller size and better integrability as opposed to their quartz counterparts. However, thermal drift of the natural frequency of silicon structures is one of the main issues that has hindered the development of MEMS resonators. Extensive investigations have addressed both the fabrication process (e.g., introducing heavy doping of the silicon) and the mechanical design (e.g., exploiting proper orientation of the device, slots, nonlinearities). In this work, starting from experimental data published in the literature, we show that a careful design can help reduce the thermal drift even when slots are inserted in the devices in order to decrease thermoelastic losses. A custom numerical code able to predict the dynamic behavior of MEMS resonators for different materials, orientations and doping levels is coupled with an evolutionary optimization algorithm and the possibility to find an optimal mechanical design is demonstrated on a tuning-fork resonator. PMID- 29973567 TI - Serum Uric Acid in Roma and Non-Roma-Its Correlation with Metabolic Syndrome and Other Variables. AB - Background: The Roma population is one of the major marginalized groups in Europe, having higher incidence of all spectrums of disease and a shorter life expectancy. Yet, the reasons for higher morbidity and its exact prevalence were not properly studied. Objectives: The objective of our study was to compare the frequency of metabolic syndrome (MetS) in Roma people to the non-Roma population in Slovakia, and to compare levels of uric acid and its correlation with components of metabolic syndrome. Methods: A group of 452 Roma people aged 18-55 years, was compared to a control group of 403 non-Roma people. The data were obtained by questionnaire, anthropometric measures, and analyzed blood and urine samples Results: The prevalence of MetS was significantly higher among Roma participants (131; 29.6%) compared with non-Roma participants (80; 20.1%), p = 0.001. Roma people significantly more often fulfilled obesity and low high density lipoprotein (HDL) criteria of MetS (257, 58.9% vs. 180, 45.8%, p < 0.0001, and 312, 70.0% vs. 140, 34.9%, p < 0.0001). There was no difference in the triacylglycerols (TG), glycemia or blood pressure (BP) criteria of MetS. The Roma also presented with greater levels of high sensitivity C-reactive protein (hs-CRP). Baseline levels of uric acid (UA) among the Roma population were significantly lower compared with the majority population (226.54 +/- 79.8 vs. 259.11 +/- 84.53) (p < 0.001). The levels of UA significantly correlated with fulfilled criteria of MetS. Univariate regression showed that UA is a significant predictor of MetS in the whole cohort (unadjusted odds ratio (OR) 1.005; 95% CI 1.004-1.007; p < 0.0001) also after the adjustment for age, sex, and ethnicity (adjusted OR 1.008; 95% CI 1.005-1.010; p < 0.0001). Conclusions: We were able to show that prevalence of MetS among the Roma is higher than in the majority population. Moreover, the uric acid levels are significantly lower in the Roma group as well as when it comes to a cohort with MetS. Levels of UA, besides others, depend on ethnicity, age, and sex. PMID- 29973569 TI - Hidden Policy Attribute-Based Data Sharing with Direct Revocation and Keyword Search in Cloud Computing. AB - Attribute-based encryption can be used to realize fine-grained data sharing in open networks. However, in practical applications, we have to address further challenging issues, such as attribute revocation and data search. How do data users search for the data they need in massive amounts of data? When users leave the system, they lose the right to decrypt the shared data. In this case, how do we ensure that revoked users cannot decrypt shared data? In this paper, we successfully address these issues by proposing a hidden policy attribute-based data sharing scheme with direct revocation and keyword search. In the proposed scheme, the direct revocation of attributes does not need to update the private key of non-revoked users during revocation. In addition, a keyword search is realized in our scheme, and the search time is constant with the increase in attributes. In particular, the policy is hidden in our scheme, and hence, users’ privacy is protected. Our security and performance analyses show that the proposed scheme can tackle the security and efficiency concerns in cloud computing. PMID- 29973570 TI - Are Total and Individual Dietary Lignans Related to Cardiovascular Disease and Its Risk Factors in Postmenopausal Women? A Nationwide Study. AB - The study objectives were to examine total and individual lignan intakes and their dietary sources in postmenopausal Polish women and to investigate the relationship between lignan intake and the prevalence of cardiovascular disease (CVD), hypertension, hypercholesterolemia and central obesity. A total of 2599 postmenopausal women, participants of the Multi-centre National Population Health Examination Surveys (WOBASZ and WOBASZ II) were selected. Of them, 916 had a history of CVD. Nutritional data were collected using a single 24-h dietary recall. Data on lignan content in food, i.e., lariciresinol (LARI), matairesinol (MAT), pinoresinol (PINO) and secoisolariciresinol (SECO), were collected from the available lignan databases. In postmenopausal women, total and individual lignan intakes (SECO, PINO, MAT) were not associated with the prevalence of CVD and its risk factors. The intake of LARI was linked by 30% to the reduced odds for hypercholestrolemia. This study reinforces the existing concept that dietary total lignans are not associated with the prevalence of CVD, and provides further evidence that they are not linked to CVD risk factors such as hypertension, hypercholesterolemia and central obesity. However, the intake of LARI should be taken into consideration in further studies with regard to its potentially beneficial effect in hypercholesterolemia. PMID- 29973568 TI - Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6. AB - Allergy and autoimmune diseases are characterised by a multifactorial pathogenic background. Several genes involved in the control of innate and adaptive immunity have been associated with diseases and variably combine with each other as well as with environmental factors and epigenetic processes to shape the characteristics of individual manifestations. Systemic or local perturbations in salt/water balance and in ion exchanges between the intra- and extracellular spaces or among tissues play a role. In this field, usually referred to as elementary immunology, novel evidence has been recently acquired on the role of members of the transient potential receptor (TRP) channel family in several cellular mechanisms of potential significance for the pathophysiology of the immune response. TRP canonical channel 6 (TRPC6) is emerging as a functional element for the control of calcium currents in immune-committed cells and target tissues. In fact, TRPC6 influences leukocytes’ tasks such as transendothelial migration, chemotaxis, phagocytosis and cytokine release. TRPC6 also modulates the sensitivity of immune cells to apoptosis and influences tissue susceptibility to ischemia-reperfusion injury and excitotoxicity. Here, we provide a view of the interactions between ion exchanges and inflammation with a focus on the pathogenesis of immune-mediated diseases and potential future therapeutic implications. PMID- 29973571 TI - An Analytical Temperature-Dependent Design Model for Contour-Mode MEMS Resonators and Oscillators Verified by Measurements. AB - The importance of micro-electromechanical systems (MEMS) for radio-frequency (RF) applications is rapidly growing. In RF mobile-communication systems, MEMS-based circuits enable a compact implementation, low power consumption and high RF performance, e.g., bulk-acoustic wave filters with low insertion loss and low noise or fast and reliable MEMS switches. However, the cross-hierarchical modelling of micro-electronic and micro-electromechanical constituents together in one multi-physical design process is still not as established as the design of integrated micro-electronic circuits, such as operational amplifiers. To close the gap between micro-electronics and micro-electromechanics, this paper presents an analytical approach towards the linear top-down design of MEMS resonators, based on their electrical specification, by the solution of the mechanical wave equation. In view of the central importance of thermal effects for the performance and stability of MEMS-based RF circuits, the temperature dependence was included in the model; the aim was to study the variations of the RF parameters of the resonators and to enable a temperature dependent MEMS oscillator simulation. The variations of the resonator parameters with respect to the ambient temperature were then verified by RF measurements in a vacuum chamber at temperatures between −35 ?C and 85 ?C. The systematic body of data revealed temperature coefficients of the resonant frequency between −26 ppm/K and −20 ppm/K, which are in good agreement with other data from the literature. Based on the MEMS resonator model derived, a MEMS oscillator was designed, simulated, and measured in a vacuum chamber yielding a measured temperature coefficient of the oscillation frequency of −26.3 ppm/K. The difference of the temperature coefficients of frequency of oscillator and resonator turned out to be mainly influenced by the limited Q-factor of the MEMS device. In both studies, the analytical model and the measurement showed very good agreement in terms of temperature dependence and the prediction of fabrication results of the resonators designed. This analytical modelling approach serves therefore as an important step towards the design and simulation of micro-electronics and micro-electromechanics in one uniform design process. Furthermore, temperature dependences of MEMS oscillators can now be studied by simulations instead of time-consuming and complex measurements. PMID- 29973573 TI - A Tightly Coupled RTK/INS Algorithm with Ambiguity Resolution in the Position Domain for Ground Vehicles in Harsh Urban Environments. AB - Vehicles driving in urban canyons are always confronted with a degraded Global Navigation Satellite System (GNSS) signal environment. The surrounding obstacles may cause signal reflections or blockages, which lead to large multipath noises and intermittent GNSS reception. Under these circumstances, it is not feasible to use conventional real-time kinematic (RTK) algorithms to maintain high-precision performance for positioning. In order to meet the special requirements of safety critical applications under non-ideal observation conditions, a novel tightly coupled RTK/Inertial Navigation System (INS) algorithm is proposed in this paper, which can provide accurate and reliable positioning results continuously. Our integrated RTK/INS algorithm has three features. Firstly, INS measurements are used to help search for integer ambiguities in the position domain. INS solutions can provide a more accurate initial location and a more efficient search region. Secondly, the criterion for determining whether a candidate position is the correct solution is only related to the fractional value of the carrier-phase measurement. Thus, the new algorithm is immune to cycle slips as well as large pseudorange noises. Thirdly, our algorithm can provide more accurate ranging information than the pseudorange, even though it may not necessarily be fixed successfully, because it selects the weighted ambiguity solution as the result rather than the candidate point with maximum probability. The proposed algorithm is demonstrated on both simulated and real datasets. Compared with single epoch RTK and conventional tightly coupled RTK/INS integrations that search integer ambiguities in the ambiguity domain, our method attains better accuracy and stability in a simulated environment. Moreover, the real experimental results are presented to validate the performance of the new integrated navigation algorithm. PMID- 29973574 TI - Functionality in Middle-Aged and Older Overweight and Obese Individuals with Knee Osteoarthritis. AB - Patients with knee osteoarthritis (OA) suffer from immobility and pain. The objective of this cross-sectional study was to investigate the relationship between pain and functionality in middle-aged and older overweight and obese individuals with mild-to-moderate knee OA. Overall pattern, physical activity, and total energy expenditure (TEE) were assessed in 83 participants. The Western Ontario McMaster Universities Arthritis Index (WOMAC) was used to assess lower extremity pain and function. The six-minute walk test (6-MWT) and range of motion (ROM) were also assessed. Results indicated that age was inversely associated with body mass index (BMI) (r = 0.349) and total WOMAC scores (r = 0.247). BMI was positively associated with TEE (r = 0.430) and WOMAC scores (r = 0.268), while ROM was positively associated with the 6-MWT (r = 0.561) and negatively associated with WOMAC (r = 0.338) and pain scores (r = 0.222). Furthermore, women had significantly greater WOMAC scores (p = 0.046) than men. Older participants (≥65 years old) had significantly lower BMI (p = 0.002), and distance traveled during the 6-MWT (p = 0.013). Our findings indicate that older individuals in this population with knee OA had lower BMI, greater ROM, and less pain and stiffness and walked slower than middle-aged individuals. Women reported greater pain, stiffness, and reduced functionality, indicating that the manifestation of OA may vary due to gender. PMID- 29973572 TI - Role of Fatty Acids in Milk Fat and the Influence of Selected Factors on Their Variability-A Review. AB - Fatty acids (FAs) of milk fat are considered to be important nutritional components of the diets of a significant portion of the human population and substantially affect human health. With regard to dairy farming, the FA profile is also seen as an important factor in the technological quality of raw milk. In this sense, making targeted modifications to the FA profile has the potential to significantly contribute to the production of dairy products with higher added value. Thus, FAs also have economic importance. Current developments in analytical methods and their increasing efficiency enable the study of FA profiles not only for scientific purposes but also in terms of practical technological applications. It is important to study the sources of variability of FAs in milk, which include population genetics, type of farming, and targeted animal nutrition. It is equally important to study the health and technological impacts of FAs. This review summarizes current knowledge in the field regarding sources of FA variability, including the impact of factors such as: animal nutrition, seasonal feed changes, type of animal farming (conventional and organic), genetic parameters (influence of breed), animal individuality, lactation, and milk yield. Potential practical applications (to improve food technology and consumer health) of FA profile information are also reviewed. PMID- 29973575 TI - Dietary Intake, Body Composition, and Oral Health Parameters among Female Patients with Primary Sjogren's Syndrome. AB - There is limited knowledge about dietary intake and body composition among patients with primary Sjogren's syndrome. We assessed dietary intakes with 24-h recalls and body composition with anthropometry and bioelectrical impedance in 20 female patients. Various scoring tools were used to assess oral health. The patients had a lower energy percentage (E%) from carbohydrates (p = 0.02) and a higher E% from fat (p = 0.01) compared to a reference group. The lower intake of carbohydrates was due to a lower bread intake (p = 0.04), while the higher intake of fat was due to a higher intake of butter, margarine, and oil (p = 0.01). The patients ate more than twice (p = 0.02) as much fish as the reference group. The compliance to recommended intakes of macro- and micronutrients was good. Forty percent of the patients were overweight/obese. Increased intake of beverages was observed in patients with severe xerostomia and/or low oral health-related quality of life, whereas reduced fat intake was found in hyposmic patients. In conclusion, the dietary intake among the patients was not much different from the reference group and complied with recommendations. Most oral health parameters were not associated with nutrient intakes. Specific dietary guidelines are probably not needed to ensure adequate nutrition among such patients. PMID- 29973576 TI - Genistein Improves Skin Flap Viability in Rats: A Preliminary In Vivo and In Vitro Investigation. AB - Selective estrogen receptor modulators (SERMs) have been developed to achieve beneficial effects of estrogens while minimizing their side effects. In this context, we decided to evaluate the protective effect of genistein, a natural SERM, on skin flap viability in rats and in a series of in vitro experiments on endothelial cells (migration, proliferation, antioxidant properties, and gene expression profiling following genistein treatment). Our results showed that administration of genistein increased skin flap viability, but importantly, the difference is only significant when treatment is started 3 days prior the flap surgery. Based on our in vitro experiments, it may be hypothesized that the underlying mechanism may rather by mediated by increasing SOD activity and Bcl-2 expression. The gene expression profiling further revealed 9 up-regulated genes (angiogenesis/inflammation promoting: CTGF, CXCL5, IL-6, ITGB3, MMP-14, and VEGF A; angiogenesis inhibiting: COL18A1, TIMP-2, and TIMP-3). In conclusion, we observed a protective effect of genistein on skin flap viability which could be potentially applied in plastic surgery to women undergoing a reconstructive and/or plastic intervention. Nevertheless, further research is needed to explain the exact underlying mechanism and to find the optimal treatment protocol. PMID- 29973577 TI - Aflatoxins and A. flavus Reduction in Loaf Bread through the Use of Natural Ingredients. AB - In this study, the antifungal activity of yellow mustard (YMF) and oriental mustard (OMF) meal extracts against 14 strains of fungi was tested on a solid medium. The results obtained with the YMF were next confirmed in liquid medium determining the minimum inhibitory concentration (MIC) and the minimum fungicide concentration (MFC). Finally, the use of YMF as a natural preservative to extend the useful life of bread was evaluated. Breads with different concentrations of YMF (2, 4, 6 and 8 g/kg) were prepared and contaminated with Aspergillus flavus ISPA 8111 and Penicilliumnordicum CECT 2320. For 10 days the formation of mycelium was observed, and after that the fungal growth and the mycotoxins production was determined. The results obtained with the YMF were compared with breads treated with the commercial additive sodium propionate (E-281). The results showed a significant reduction of the fungal population using 6 g/kg and 8 g/kg of YMF in bread contaminated with A. flavus and with P.nordicum and an extensions of the breads shelf life of 7 and 5 days, respectively, in comparison with the control experiment. A reduction of 78% of AFB1 was observed using 6 g/kg of YMF while no AFB1 production was detected employing 8 g/kg of YMF in bread preparation. PMID- 29973579 TI - Esophageal Carcinoma Cuniculatum Associated with Non-Necrotizing Granulomatous Inflammation and Lymphadenopathy: Clinicopathologic Features and Diagnostic Challenges. AB - BACKGROUND Esophageal carcinoma cuniculatum (CC) is an exceptionally rare, well differentiated squamous cell carcinoma (SCC) with initial microscopic evaluation often yielding inconclusive diagnoses due to its characteristically bland histomorphologic appearance on superficial endoscopic biopsy. This can lead to delayed diagnosis and pose challenges in further management of these cases. CASE REPORT We present the case of a 52-year-old man with symptoms of dysphagia and odynophagia. The initial chest CT scan showed gastroesophageal (GE) junction wall thickening and regional lymphadenopathy. Esophagogastroduodenoscopy (EGD) revealed an esophageal mass, but the mucosal biopsies were inconclusive. Repeat endoscopic biopsies also failed to yield a definitive diagnosis. Under strong clinical suspicion for malignancy, an esophagogastrectomy was performed, which yielded the diagnosis of CC, and the associated enlarged lymph nodes revealed non necrotizing granulomatous lymphadenitis. CONCLUSIONS Only 15 cases of esophageal CC have been described in the literature. This particular case is unique due to the associated abundant lymphoplasmacytic and granulomatous inflammation and involvement of regional lymph nodes by non-necrotizing granulomas not previously described. PMID- 29973580 TI - Identification of Critical Genes and Five Prognostic Biomarkers Associated with Colorectal Cancer. AB - BACKGROUND Colorectal cancer (CRC) is a common malignant tumor with high incidence and mortality worldwide. The aim of this study was to evaluate the association between differentially expressed genes (DEGs), which may function as biomarkers for CRC prognosis and therapies, and the clinical outcome in patients with CRC. MATERIAL AND METHODS A total of 116 normal mucous tissue and 930 CRC tissue datasets were downloaded from the Gene Expression Omnibus database (GEO) and The Cancer Genome Atlas (TCGA). After screening DEGs based on limma package in R. Gene Ontology (GO) and KEGG enrichment analysis as well as the protein protein interaction (PPI) networks were performed to predict the function of these DEGs. Meanwhile, Cox proportional hazards regression was used to build a prognostic model of these DEGs. Then, Kaplan-Meier risk analysis was used to test the model in TCGA datasets and validation datasets. RESULTS In the present study, 300 DEGs with 100 upregulated genes and 200 downregulated genes were identified. The PPI networks including 162 DEGs and 256 nodes were constructed and 2 modules with high degree were selected. Moreover, 5 genes (MMP1, ACSL6, SMPD1, PPARGC1A, and HEPACAM2) were identified using the Cox proportional hazards stepwise regression. Kaplan-Meier risk curve in the TCGA and validation cohorts showed that high-risk group had significantly poor overall survival than the low-risk group. CONCLUSIONS Our study provided insights into the mechanisms of CRC formation and found 5 prognostic genes, which could potentially inform further studies and clinical therapies. PMID- 29973578 TI - Apoptosis: Activation and Inhibition in Health and Disease. AB - There are many types of cell death, each involving multiple and complex molecular events. Cell death can occur accidentally when exposed to extreme physical, chemical, or mechanical conditions, or it can also be regulated, which involves a genetically coded complex machinery to carry out the process. Apoptosis is an example of the latter. Apoptotic cell death can be triggered through different intracellular signalling pathways that lead to morphological changes and eventually cell death. This is a normal and biological process carried out during maturation, remodelling, growth, and development in tissues. To maintain tissue homeostasis, regulatory, and inhibitory mechanisms must control apoptosis. Paradoxically, these same pathways are utilized during infection by distinct intracellular microorganisms to evade recognition by the immune system and therefore survive, reproduce and develop. In cancer, neoplastic cells inhibit apoptosis, thus allowing their survival and increasing their capability to invade different tissues and organs. The purpose of this work is to review the generalities of the molecular mechanisms and signalling pathways involved in apoptosis induction and inhibition. Additionally, we compile the current evidence of apoptosis modulation during cancer and Leishmania infection as a model of apoptosis regulation by an intracellular microorganism. PMID- 29973581 TI - Embryos and embryonic stem cells from the white rhinoceros. AB - The northern white rhinoceros (NWR, Ceratotherium simum cottoni) is the most endangered mammal in the world with only two females surviving. Here we adapt existing assisted reproduction techniques (ART) to fertilize Southern White Rhinoceros (SWR) oocytes with NWR spermatozoa. We show that rhinoceros oocytes can be repeatedly recovered from live SWR females by transrectal ovum pick-up, matured, fertilized by intracytoplasmic sperm injection and developed to the blastocyst stage in vitro. Next, we generate hybrid rhinoceros embryos in vitro using gametes of NWR and SWR. We also establish embryonic stem cell lines from the SWR blastocysts. Blastocysts are cryopreserved for later embryo transfer. Our results indicate that ART could be a viable strategy to rescue genes from the iconic, almost extinct, northern white rhinoceros and may also have broader impact if applied with similar success to other endangered large mammalian species. PMID- 29973582 TI - Near infrared fluorescent peptide nanoparticles for enhancing esophageal cancer therapeutic efficacy. AB - Various types of nanoparticles have been proposed for targeted drug delivering, imaging, and tracking of therapeutic agents. However, highly biocompatible nanoparticles with structure-induced fluorescence and capability to conjugate with biomarkers and drugs remain lacking. This research proposes and synthesizes fluorescent nanoparticles (f-PNPs) assembled by cyclic peptides to combine imaging and drug delivering for esophageal cancer (EC). To achieve tumor targeting, f-PNPs are first conjugated with RGD moieties to selectively target EC cells via alphavbeta3 integrin; the nanoparticles are then embedded with epirubicin (EPI). Cell viability assays and analysis of tissue histology reveal that EPI-loaded RGD-f-PNPs (RGD-f-PNPs/EPI) led to significantly reduced cardiotoxicity and improved anti-tumor activity compared to EPI alone. Moreover, the drug delivery to tumor sites and therapeutic responses could be monitored with near-infrared fluorescence using RGD-f-PNPs/EPI. This unique nanoparticle system may lead to potential approaches for bioorganic fluorescence-based delivering, imaging, and drug release tracking. PMID- 29973583 TI - Retraction Note: Liver X receptors constrain tumor development and metastasis dissemination in PTEN-deficient prostate cancer. AB - This paper has been retracted at the request of the authors. PMID- 29973584 TI - Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. AB - The genetic causes of cancer include both somatic mutations and inherited germline variants. Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs). Here we present a statistical method, ALFRED, that tests Knudson's two-hit hypothesis to systematically identify CPGs from cancer genome data. Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs - including the chromatin modifier NSD1 - that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH). Rare germline variants in these genes contribute substantially to cancer risk, including to ~14% of ovarian carcinomas, ~7% of breast tumors, ~4% of uterine corpus endometrial carcinomas, and to a median of 2% of tumors across 17 cancer types. PMID- 29973586 TI - Evaluation of the VITEK MS knowledge base version 3.0 for the identification of clinically relevant Mycobacterium species. AB - Different Mycobacterium spp. infections may indicate varied treatment regimens in the clinic. Thus, the species-level identification of Mycobacterium spp. is one of the most important tasks for a clinical microbiology laboratory. Although matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and accurate method for the identification of mycobacteria, this method lacks a comprehensive evaluation of the identification accuracy for clinically collected mycobacteria using VITEK MS Knowledge Base Version 3.0 (Ver 3.0). The objectives of the present study were to evaluate the identification performance of Mycobacterium spp. using Ver 3.0 and a sample processing kit for strain inactivation and protein extraction. Among the 507 Mycobacterium isolates, 46 isolates were M. tuberculosis, and 461 isolates were nontuberculous mycobacteria (NTM) (including 27 species: 17 species were slowly growing mycobacteria (SGM), and 10 species were rapidly growing mycobacteria (RGM)). The VITEK MS V3.0 library was used to correctly identify 476/507 (93.9%) isolates (425 isolates were correctly identified initially, and 51 more isolates were correctly identified on repeat), 23/507 (4.5%) isolates were unidentified, and 8/507 (1.6%) isolates were misidentified. In summary, we showed that Mycobacterium spp. can be adequately identified by Ver 3.0 in combination with the use of a standard sample processing kit. PMID- 29973588 TI - FerriTag is a new genetically-encoded inducible tag for correlative light electron microscopy. AB - A current challenge is to develop tags to precisely visualize proteins in cells by light and electron microscopy. Here, we introduce FerriTag, a genetically encoded chemically-inducible tag for correlative light-electron microscopy. FerriTag is a fluorescent recombinant electron-dense ferritin particle that can be attached to a protein-of-interest using rapamycin-induced heterodimerization. We demonstrate the utility of FerriTag for correlative light-electron microscopy by labeling proteins associated with various intracellular structures including mitochondria, plasma membrane, and clathrin-coated pits and vesicles. FerriTagging has a good signal-to-noise ratio and a labeling resolution of approximately 10 nm. We demonstrate how FerriTagging allows nanoscale mapping of protein location relative to a subcellular structure, and use it to detail the distribution and conformation of huntingtin-interacting protein 1 related (HIP1R) in and around clathrin-coated pits. PMID- 29973589 TI - From petri dishes to politics - a multi-pronged approach is essential for saving endangered species. PMID- 29973587 TI - Assessment of genetic factor and depression interactions for asthma symptom severity in cohorts of childhood and elderly asthmatics. AB - It is well known that depression is associated with asthma symptoms. We assessed the combined effects of genetic factors and depression on asthma symptom severity using Bayesian network (BN) analysis. The common 100 top-ranked single-nucleotide polymorphisms (SNPs) were obtained from two genome-wide association studies of symptom severity in two childhood asthmatics trials (CAMP (Childhood Asthma Management Program) and CARE (Childhood Asthma Research and Education)). Using SNPs plus five discretized variables (depression, anxiety, age, sex, and race), we performed BN analysis in 529 CAMP subjects. We identified two nodes (depression and rs4672619 mapping to ERBB4 (Erb-B2 receptor tyrosine kinase 4)) that were within the Markov neighborhood of the symptom node in the network and then evaluated the interactive effects of depressive status and rs4672619 genotypes on asthma symptom severity. In childhood asthmatics with homozygous reference alleles, severe depression was related to less severe symptoms. However, in childhood asthmatics with heterozygous alleles and homozygous variant alleles, depression and symptom severity showed a positive correlation (interaction permutation P value = 0.019). We then tried to evaluate whether the interactive effects that we found were sustained in another independent cohort of elderly asthmatics. Contrary to the findings from childhood asthmatics, elderly asthmatics with homozygous reference alleles showed a positive correlation between depression and symptom severity, and elderly asthmatics with heterozygous alleles and homozygous variant alleles showed a negative correlation (interaction permutation P value = 0.003). In conclusion, we have identified a novel SNP, rs4672619, that shows interactive effects with depression on asthma symptom severity in childhood and elderly asthmatics in opposite directions. PMID- 29973590 TI - Highly stable QLEDs with improved hole injection via quantum dot structure tailoring. AB - For the state-of-the-art quantum dot light-emitting diodes, while the ZnO nanoparticle layers can provide effective electron injections into quantum dots layers, the hole transporting materials usually cannot guarantee sufficient hole injection owing to the deep valence band of quantum dots. Developing proper hole transporting materials to match energy levels with quantum dots remains a great challenge to further improve the device efficiency and operation lifetime. Here we demonstrate high-performance quantum dot light-emitting diodes with much extended operation lifetime using quantum dots with tailored energy band structures that are favorable for hole injections. These devices show a T95 operation lifetime of more than 2300 h with an initial brightness of 1000 cd m-2, and an equivalent T50 lifetime at 100 cd m-2 of more than 2,200,000 h, which meets the industrial requirement for display applications. PMID- 29973591 TI - Corrosion engineering towards efficient oxygen evolution electrodes with stable catalytic activity for over 6000 hours. AB - Although a number of nonprecious materials can exhibit catalytic activity approaching (sometimes even outperforming) that of iridium oxide catalysts for the oxygen evolution reaction, their catalytic lifetimes rarely exceed more than several hundred hours under operating conditions. Here we develop an energy efficient, cost-effective, scaled-up corrosion engineering method for transforming inexpensive iron substrates (e.g., iron plate and iron foam) into highly active and ultrastable electrodes for oxygen evolution reaction. This synthetic method is achieved via a desired corrosion reaction of iron substrates with oxygen in aqueous solutions containing divalent cations (e.g., nickel) at ambient temperature. This process results in the growth on iron substrates of thin film nanosheet arrays that consist of iron-containing layered double hydroxides, instead of rust. This inexpensive and simple manufacturing technique affords iron-substrate-derived electrodes possessing excellent catalytic activities and activity retention for over 6000 hours at 1000 mA cm-2 current densities. PMID- 29973592 TI - Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers. AB - To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers. PMID- 29973594 TI - Peptide density targets and impedes triple negative breast cancer metastasis. AB - The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis. Existing therapeutics that block CXCR4 signaling are dependent on single molecule-receptor interactions or silencing CXCR4 expression. CXCR4 localizes in lipid rafts and forms dimers therefore CXCR4 targeting and signaling may depend on ligand density. Herein, we report liposomes presenting a CXCR4 binding peptide (DV1) as a three-dimensional molecular array, ranging from 9k to 74k molecules MUm-2, target triple negative breast cancer (TNBC). TNBC cells exhibit a maxima in binding and uptake of DV1-functionalized liposomes (L-DV1) in vitro at a specific density, which yields a significant reduction in cell migration. This density inhibits metastasis from a primary tumor for 27 days, resulting from peptide density dependent gene regulation. We show that complementing cell membrane receptor expression may be a strategy for targeting cells and regulating signaling. PMID- 29973585 TI - Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries. AB - Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans. PMID- 29973593 TI - miR-130a and miR-145 reprogram Gr-1+CD11b+ myeloid cells and inhibit tumor metastasis through improved host immunity. AB - Tumor-derived soluble factors promote the production of Gr-1+CD11b+ immature myeloid cells, and TGFbeta signaling is critical in their immune suppressive function. Here, we report that miR-130a and miR-145 directly target TGFbeta receptor II (TbetaRII) and are down-regulated in these myeloid cells, leading to increased TbetaRII. Ectopic expression of miR-130a and miR-145 in the myeloid cells decreased tumor metastasis. This is mediated through a downregulation of type 2 cytokines in myeloid cells and an increase in IFNgamma-producing cytotoxic CD8 T lymphocytes. miR-130a- and miR-145-targeted molecular networks including TGFbeta and IGF1R pathways were correlated with higher tumor stages in cancer patients. Lastly, miR-130a and miR-145 mimics, as well as IGF1R inhibitor NT157 improved anti-tumor immunity and inhibited metastasis in preclinical mouse models. These results demonstrated that miR-130a and miR-145 can reprogram tumor associated myeloid cells by altering the cytokine milieu and metastatic microenvironment, thus enhancing host antitumor immunity. PMID- 29973596 TI - Identifying a common backbone of interactions underlying food webs from different ecosystems. AB - Although the structure of empirical food webs can differ between ecosystems, there is growing evidence of multiple ways in which they also exhibit common topological properties. To reconcile these contrasting observations, we postulate the existence of a backbone of interactions underlying all ecological networks-a common substructure within every network comprised of species playing similar ecological roles-and a periphery of species whose idiosyncrasies help explain the differences between networks. To test this conjecture, we introduce a new approach to investigate the structural similarity of 411 food webs from multiple environments and biomes. We first find significant differences in the way species in different ecosystems interact with each other. Despite these differences, we then show that there is compelling evidence of a common backbone of interactions underpinning all food webs. We expect that identifying a backbone of interactions will shed light on the rules driving assembly of different ecological communities. PMID- 29973595 TI - XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1. AB - The DNA damage sensor XPC is involved in nucleotide excision repair. Here we show that in the absence of damage, XPC co-localizes with RNA polymerase II (Pol II) and active post-translational histone modifications marks on a subset of class II promoters in human fibroblasts. XPC depletion triggers specific gene down expression due to a drop in the deposition of histone H3K9 acetylation mark and pre-initiation complex formation. XPC interacts with the histone acetyltransferase KAT2A and specifically triggers the recruitment of the KAT2A containing ATAC complex to the promoters of down-expressed genes. We show that a strong E2F1 signature characterizes the XPC/KAT2A-bound promoters and that XPC interacts with E2F1 and promotes its binding to its DNA element. Our data reveal that the DNA repair factor XPC is also an RNA polymerase II cofactor recruiting the ATAC coactivator complex to promoters by interacting with the DNA binding transcription factor E2F1. PMID- 29973597 TI - microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site. AB - The liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5' end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential for efficient viral replication. The mechanism relies on a dual function of the 5' terminal sequence in the complementary positive (translation) and negative strand (replication), requiring different secondary structures. Predictions and experimental evidence argue for several alternative folds involving the miR binding region (MBR) adjacent to the IRES and interfering with its function. Mutations in the MBR, designed to suppress these dysfunctional structures indeed stimulate translation independently of miR-122. Conversely, MBR mutants favoring alternative folds show impaired IRES activity. Our results therefore suggest that miR-122 binding assists the folding of a functional IRES in an RNA chaperone-like manner by suppressing energetically favorable alternative secondary structures. PMID- 29973598 TI - Discovery of a strain-stabilised smectic electronic order in LiFeAs. AB - In many high temperature superconductors, small orthorhombic distortions of the lattice structure result in surprisingly large symmetry breaking of the electronic states and macroscopic properties, an effect often referred to as nematicity. To directly study the impact of symmetry-breaking lattice distortions on the electronic states, using low-temperature scanning tunnelling microscopy we image at the atomic scale the influence of strain-tuned lattice distortions on the correlated electronic states in the iron-based superconductor LiFeAs, a material which in its ground state is tetragonal with four-fold (C4) symmetry. Our experiments uncover a new strain-stabilised modulated phase which exhibits a smectic order in LiFeAs, an electronic state which not only breaks rotational symmetry but also reduces translational symmetry. We follow the evolution of the superconducting gap from the unstrained material with C4 symmetry through the new smectic phase with two-fold (C2) symmetry and charge-density wave order to a state where superconductivity is completely suppressed. PMID- 29973599 TI - Glucose starvation induces LKB1-AMPK-mediated MMP-9 expression in cancer cells. AB - Cancer cells utilise the glycolytic pathway to support their rapid growth and proliferation. Since cells in most solid tumours are subjected to severe microenvironmental stresses including low nutrient and oxygen availability, such cancer cells must develop mechanisms to overcome these unfavourable growth conditions by metabolic adaptation. Although the liver kinase B1 (LKB1)-adenosine monophosphate-activated kinase (AMPK) signalling pathway plays a pivotal role in maintaining energy homeostasis under conditions of metabolic stress, the role of LKB1-AMPK signalling in aiding cancer cell survival and in malignant tumours has not yet been fully elucidated. We show that glucose starvation promotes cancer cell invasiveness and migration through LKB1-AMPK-regulated MMP-9 expression. Most intriguingly, triggering the LKB1-AMPK signalling pathway by glucose starvation-induced oxidative stress facilitates selective autophagy, which in turn enhances Keap1 degradation and the subsequent activation of Nrf2. Following this, Nrf2 regulates the transactivation of MMP-9 via Nrf2 binding sites in the promoter region of the MMP-9 gene. These mechanisms also contribute to the suppression of excessive oxidative stress under glucose starvation, and protect against cell death. Our data clearly shows that LKB1-AMPK signalling not only maintains energy and oxidative stress homeostasis, but could also promote cancer progression during metabolic stress conditions by MMP-9 induction. PMID- 29973601 TI - Measuring shared knowledge with group false memory. AB - We conducted two experiments to investigate the effects of word list consistency and group collaboration on false memory. Using the DRM (Deese-Roediger-McDermott) paradigm, the first experiment (n = 121) examined false memory in a group; participants collaborated to select keywords using a between-subject condition of a consistent or randomized word list. The proportion of false responses was larger than that of error responses, especially for the consistent word list condition (p < 0.001), and group collaboration increased false recognition for both word lists (p < 0.001). Using an applied within-subject word list condition, the second experiment (n = 119) confirmed the results of Experiment 1. Furthermore, individual differences Euclidean distance model analysis revealed a difference in the shared cognitive dimension related to group false memory. PMID- 29973600 TI - Altered cortical functional network during behavioral inhibition in individuals with childhood trauma. AB - Individuals who have prior history of childhood traumatic experiences are at a high risk for a variety of psychological and behavioral problems throughout their lifetime. This study aimed to investigate whether such individuals exhibit altered cortical functional networks during a behavioral inhibition task. One hundred fifty-three non-clinical individuals were recruited and instructed to perform a Go/NoGo task during an electroencephalograph. Source-level weighted functional networks based on the graph theory were analyzed for NoGo-P3 processing. Based on their total scores on the childhood trauma questionnaire (CTQ) participants were divided into three groups: low CTQ, middle CTQ, and high CTQ. Results at the global level indicated decreased strength, clustering coefficient, and efficiency for the low and gamma bands in the high CTQ group. In addition, the path length of the low beta band was observed to be longer in the high CTQ group than the low CTQ group. At the nodal level, the nodal clustering coefficient of high CTQ group was decreased in left primary somatosensory cortex and middle occipital gyrus for the low beta band, and in left superior temporal gyrus for the gamma band. The nodal clustering coefficient of the left primary somatosensory cortex showed a significant negative correlation with the total CTQ score for the low beta band. In addition, the nodal clustering coefficient of the left middle occipital gyrus for the low beta band and superior temporal gyrus for the gamma band showed significant negative correlations with the emotional neglect score. Our results demonstrate an altered cortical functional network in individuals who experienced childhood trauma. In particular, the left primary somatosensory cortex, middle occipital gyrus, and superior temporal gyrus were found to be vulnerable in individuals who experienced childhood trauma, especially emotional neglect. PMID- 29973602 TI - Combing signal processing methods with algorithm priori information to produce synergetic improvements on continuous imaging of brain electrical impedance tomography. AB - Dynamic electrical impedance tomography (EIT) promises to be a valuable technique for monitoring the development of brain injury. But in practical long-term monitoring, noise and interferences may cause insufficient image quality. To help unveil intracranial conductivity changes, signal processing methods were introduced to improve EIT data quality and algorithms were optimized to be more robust. However, gains for EIT image reconstruction can be significantly increased if we combine the two techniques properly. The basic idea is to apply the priori information in algorithm to help de-noise EIT data and use signal processing to optimize algorithm. First, we process EIT data with principal component analysis (PCA) and reconstruct an initial CT-EIT image. Then, as the priori that changes in scalp and skull domains are unwanted, we eliminate their corresponding boundary voltages from data sets. After the two-step denoising process, we finally re-select a local optimal regularization parameter and accomplish the reconstruction. To evaluate performances of the signal processing priori information based reconstruction (SPR) method, we conducted simulation and in-vivo experiments. The results showed SPR could improve brain EIT image quality and recover the intracranial perturbations from certain bad measurements, while for some measurement data the generic reconstruction method failed. PMID- 29973603 TI - Dissecting Distinct Roles of NEDDylation E1 Ligase Heterodimer APPBP1 and UBA3 Reveals Potential Evolution Process for Activation of Ubiquitin-related Pathways. AB - Despite the similar enzyme cascade in the Ubiquitin and Ubiquitin-like peptide(Ubl) conjugation, the involvement of single or heterodimer E1 activating enzyme has been a mystery. Here, by using a quantitative Forster Resonance Energy Transfer (FRET) technology, aided with Analysis of Electrostatic Similarities Of Proteins (AESOP) computational framework, we elucidate in detail the functional properties of each subunit of the E1 heterodimer activating-enzyme for NEDD8, UBA3 and APPBP1. In contrast to SUMO activation, which requires both subunits of its E1 heterodimer AOS1-Uba2 for its activation, NEDD8 activation requires only one of two E1 subunits, UBA3. The other subunit, APPBP1, only contributes by accelerating the activation reaction rate. This discovery implies that APPBP1 functions mainly as a scaffold protein to enhance molecular interactions and facilitate catalytic reaction. These findings for the first time reveal critical new mechanisms and a potential evolutionary pathway for Ubl activations. Furthermore, this quantitative FRET approach can be used for other general biochemical pathway analysis in a dynamic mode. PMID- 29973604 TI - Evaluation of surface charge shift of collagen fibrils exposed to glutaraldehyde. AB - Collagen fibrils are a major component of the extracellular matrix. They form nanometer-scale "cables" acting as a scaffold for cells in animal tissues and are widely used in tissue-engineering. Besides controlling their structure and mechanical properties, it is crucial to have information of their surface charge, as this affects how cells attach to the scaffold. Here, we employed Kelvin-probe Force Microscopy to determine the electrostatic surface potential at the single fibril level and investigated how glutaraldehyde, a well-established protein cross-linking agent, shifts the surface charge to more negative values without disrupting the fibrils themselves. This shift can be interpreted as the result of the reaction between the carbonyl groups of glutaraldehyde and the amine groups of collagen. It reduces the overall density of positively charged amine groups on the collagen fibril surface and, ultimately, results in the observed negative shift of the surface potential measured. Reactions between carbonyl-containing compounds and proteins are considered the first step in glycation, the non enzymatic reaction between sugars and proteins. It is conceivable that similar charge shifts happen in vivo caused by sugars, which could have serious implications on age-related diseases such as diabetes and which has been hypothesised for many years. PMID- 29973605 TI - Processing and Structure of the Lantibiotic Peptide Nso From the Human Gut Bacterium Blautia obeum A2-162 analysed by Mass Spectrometry. AB - A previously reported gene cluster encoding four nisin-like peptides, three with the same sequence (NsoA1-3) and the unique NsoA4, produced antimicrobial activity in the presence of trypsin after heterologous expression in Lactococcus lactis. Protein extracts were separated by SDS gel electrophoresis or immunoprecipitation using an antibody to the NsoA2 leader. Tryptic peptides observed by LC-MS/MS covered the complete sequence of preNsoA1-3 and part of the leader sequence of preNsoA4 and confirmed the expression and the predicted sequences of the preNsoA peptides. Further, the data revealed that the preNsoA1-3 peptides were partly modified with dehydrations and formation of lanthionine rings. A certain amount of fully modified preNsoA1-3 was observed. Details of modifications of the core peptide and the C-terminal tryptic peptide TATCGCHITGK covering rings D and E indicated that 22% of these preNsoA1-3 peptides were completely modified. A lower amount of ring formation is estimated for rings A-C. Intact masses of immunoprecipitation-derived peptides determined by LC-MS accurately matched the expected preNsoA precursor peptides. The most abundant peptides detected were preNsoA2-3-8H2O followed by preNsoA1-8H2O and other states of dehydration. The results confirm incomplete processing of preNsoA peptides in the heterologous system, with the formation of a certain amount of fully modified peptides. PMID- 29973606 TI - Neural signatures of reinforcement learning correlate with strategy adoption during spatial navigation. AB - Human navigation is generally believed to rely on two types of strategy adoption, route-based and map-based strategies. Both types of navigation require making spatial decisions along the traversed way although formal computational and neural links between navigational strategies and mechanisms of value-based decision making have so far been underexplored in humans. Here we employed functional magnetic resonance imaging (fMRI) while subjects located different objects in a virtual environment. We then modelled their paths using reinforcement learning (RL) algorithms, which successfully explained decision behavior and its neural correlates. Our results show that subjects used a mixture of route and map-based navigation and their paths could be well explained by the model-free and model-based RL algorithms. Furthermore, the value signals of model free choices during route-based navigation modulated the BOLD signals in the ventro-medial prefrontal cortex (vmPFC), whereas the BOLD signals in parahippocampal and hippocampal regions pertained to model-based value signals during map-based navigation. Our findings suggest that the brain might share computational mechanisms and neural substrates for navigation and value-based decisions such that model-free choice guides route-based navigation and model based choice directs map-based navigation. These findings open new avenues for computational modelling of wayfinding by directing attention to value-based decision, differing from common direction and distances approaches. PMID- 29973607 TI - Enzootic frog pathogen Batrachochytrium dendrobatidis in Asian tropics reveals high ITS haplotype diversity and low prevalence. AB - Emerging Infectious Diseases (EIDs) are a major threat to wildlife and a key player in the declining amphibian populations worldwide. One such EID is chytridiomycosis caused by Batrachochytrium dendrobatidis (Bd), a fungal pathogen. Aetiology of Bd infection is poorly known from tropical frogs in Asian biodiversity hotspots. Surveys were carried out in four biodiversity hotspots to ascertain the status of Bd fungus. We collected a total of 1870 swab samples from frogs representing 32 genera and 111 species. Nested PCRs revealed low prevalence (8.4%) and high Bd haplotype richness was revealed after sequencing. We document 57 Bd Internal Transcribed Spacer region (ITS) haplotypes, of which 46 were unique to the global database. Bd ITS region showed indels at the Taqman binding site and qPCR reverse primer binding site, suggesting qPCR is unsuitable for diagnosis in Asian Bd coldspots. Our median-joining network and Bayesian tree analyses reveal that the Asian haplotypes, with the exception of Korea, formed a separate clade along with pandemic BdGPL (Bd Global Panzootic Lineage) haplotype. We hypothesise that the frog populations in Asian tropics might harbour several endemic strains of Bd, and the high levels of diversity and uniqueness of Bd haplotypes in the region, probably resulted from historical host-pathogen co evolution. PMID- 29973609 TI - Stepwise Reduction of Graphene Oxide (GO) and Its Effects on Chemical and Colloidal Properties. AB - Graphene Oxides (GO) typically contains different oxygen containing groups such as hydroxyl, carboxyl and epoxy, and reduced GO (r-GO) represents a family of material with diverse chemical properties. In an effort to understand how properties of r-GO change as GO is reduced, a stepwise reduction of the same GO to r-GO containing different levels of oxygen was carried out, and their corresponding chemical and colloidal properties are reported. Starting with GO containing 49 percent oxygen, r-GOs containing 31, 19 and 9 percent oxygen were synthesized. The aqueous behavior in terms of solubility gradually decreased from 7.4 ug/ml for GO to nearly zero for r-GO with 9% oxygen, while dispersibility under sonication decreased from 8 to 2.5 ug/ml for the same samples. Hydrophobicity index as measured as the octanol water partition coefficient decreased from -3.89 to 5.2% as oxygen content dropped from 49 to 9%. Colloidal behavior was also dramatically affected by reduction, and critical coagulation concentration (CCC) dropped from 28 to 15 in presence of 0.5 mmole/l NaCl and from 6 to 2 in presence of 0.5 mmole/l MgCl2 as the oxygen in the original GO was reduced to 9%. PMID- 29973608 TI - MicroRNA expression analysis identifies a subset of downregulated miRNAs in ALS motor neuron progenitors. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder that is characterized by a progressive degeneration of motor neurons (MNs). The pathomechanism underlying the disease is largely unknown, even though increasing evidence suggests that RNA metabolism, including microRNAs (miRNAs) may play an important role. In this study, human ALS induced pluripotent stem cells were differentiated into MN progenitors and their miRNA expression profiles were compared to those of healthy control cells. We identified 15 downregulated miRNAs in patients' cells. Gene ontology and molecular pathway enrichment analysis indicated that the predicted target genes of the differentially expressed miRNAs were involved in neurodegeneration-related pathways. Among the 15 examined miRNAs, miR-34a and miR504 appeared particularly relevant due to their involvement in the p53 pathway, synaptic vesicle regulation and general involvement in neurodegenerative diseases. Taken together our results demonstrate that the neurodegenerative phenotype in ALS can be associated with a dysregulation of miRNAs involved in the control of disease-relevant genetic pathways, suggesting that targeting entire gene networks can be a potential strategy to treat complex diseases such as ALS. PMID- 29973610 TI - Fossilized Melts in Mantle Wedge Peridotites. AB - The shallow oxidized asthenosphere may contain a small fraction of potassic silicate melts that are enriched in incompatible trace elements and volatiles. Here, to determine the chemical composition of such melt, we analysed fossilized melt inclusions, preserved as multiphase solid inclusions, from an orogenic garnet peridotite in the Bohemian Massif. Garnet-poor (2 vol.%) peridotite preserves inclusions of carbonated potassic silicate melt within Zn-poor chromite (<400 ppm) in the clinopyroxene-free harzburgite assemblage that equilibrated within the hot mantle wedge (Stage 1, > 1180 degrees C at 3 GPa). The carbonated potassic silicate melt, which has a major element oxide chemical composition of K2O = 5.2 wt.%, CaO = 17 wt.%, MgO = 18 wt.%, CO2 = 22 wt.%, and SiO2 = 20 wt.%, contains extremely high concentrations of large ion lithophile elements, similar to kimberlite melts. Peridotites cooled down to ?800 degrees C during Stage 2, resulted in the growth of garnet relatively poor in pyrope content, molar Mg/(Mg + Fe + Ca + Mn), (ca. 67 mol.%). This garnet displays a sinusoidal REE pattern that formed in equilibrium with carbonatitic fluid. Subsequently, subduction of the peridotite resulted in the formation of garnet with a slightly higher pyrope content (70 mol.%) during the Variscan subduction Stage 3 (950 degrees C, 2.9 GPa). These data suggest the following scenario for the generation of melt in the mantle wedge. Primarily, infiltration of sediment-derived potassic carbonatite melt into the deep mantle wedge resulted in the growth of phlogopite and carbonate/diamond. Formation of volatile-bearing minerals lowered the density and strength of the peridotite. Finally, phlogopite-bearing carbonated peridotite rose as diapirs in the mantle wedge to form carbonated potassic silicate melts at the base of the overriding lithosphere. PMID- 29973611 TI - Large second harmonic generation in alloyed TMDs and boron nitride nanostructures. AB - First principles methods are used to explicitly calculate the nonlinear susceptibility (chi(2)(2omega, omega, omega)) representing the second harmonic generation (SHG) of two dimensional semiconducting materials, namely transition metal dichalcogenides (TMDs) and Boron Nitride (BN). It is found that alloying TMDs improves their second harmonic response, with MoTeS alloys exhibiting the highest of all hexagonal alloys at low photon energies. Moreover, careful examination of the relationship between the concentration of Se in MoxSeySz alloys shows that the SHG intensity can be tuned by modifying the stoichiometry. In addition, materials with curvature can have large second harmonic susceptibility. Of all the calculated monolayer structures, the hypothetical TMD Haeckelites NbSSe and Nb0.5Ta0.5S2 exhibit the highest chi(2), while one of the porous 3D structures constructed from 2D hBN exhibits a larger chi(2) than known large band gap 3-D materials. PMID- 29973612 TI - The extensive networks of frequent population mobility in the Samoan Islands and their implications for infectious disease transmission. AB - Population mobility has been demonstrated to contribute to the persistent transmission and global diffusion of epidemics. In the Pacific Islands, population mobility is particularly important for emerging infectious diseases, disease elimination programs, and diseases spread by close contact. The extent of population mobility between American Samoa villages, Samoa districts and other countries was investigated based on travel data collected during community surveys in American Samoa in 2010 and 2014. Within American Samoa, workers commuted daily across the whole of the main island of Tutuila, with work hubs drawing from villages across the island. Of the 670 adult workers surveyed, 37% had traveled overseas in the past year, with 68% of trips to Samoa. Of children aged 8-13 years (n = 337), 57% had traveled overseas, with 55% of trips to Samoa. An extensive network of connections between American Samoa villages and Samoa districts was demonstrated, with most trips lasting one week to one month. Our study showed that populations in the Samoan islands are highly mobile, and quantified the extent and destinations of their travels. Our findings offer insight into the impact of population mobility on the transmission of infectious diseases and data to refine existing models of disease transmission in the Pacific islands. PMID- 29973613 TI - Role of neuritin in retinal ganglion cell death in adult mice following optic nerve injury. AB - Neuritin is a small extracellular protein that plays important roles in the process of neural development, synaptic plasticity, and neural cell survival. Here we investigated the function of neuritin in a mouse model of optic nerve injury (ONI). ONI induced upregulation of neuritin mRNA in the retina of WT mice. The retinal structure and the number of retinal ganglion cells (RGCs) were normal in adult neuritin knockout (KO) mice. In vivo retinal imaging and histopathological analyses demonstrated that RGC death and inner retinal degeneration following ONI were more severe in neuritin KO mice. Immunoblot analyses revealed that ONI-induced phosphorylation of Akt and ERK were suppressed in neuritin KO mice. Our findings suggest that neuritin has neuroprotective effects following ONI and may be useful for treatment of posttraumatic complication. PMID- 29973614 TI - An exciton-polariton bolometer for terahertz radiation detection. AB - We experimentally investigate the feasibility of a bolometric device based on exciton-polaritons. Initial measurements presented in this work show that heating - via thermal expansion and bandgap renormalization - modifies the exciton polariton propagation wavevector making exciton-polaritons propagation remarkably sensitive to thermal variations. By theoretical simulations we predict that using a single layer graphene absorbing layer, a THz bolometric sensor can be realized by a simple exciton-polariton ring interferometer device. The predicted sensitivity is comparable to presently existing THz bolometric devices with the convenience of being a device that inherently produces an optical signal output. PMID- 29973615 TI - Acoustic analog computing system based on labyrinthine metasurfaces. AB - Acoustic computing devices, including switches, logic gates, differentiator and integrator, have attracted extensive attentions in both academic research and engineering. However, no scheme of acoustic computing device with more complex functionality has been proposed, such as ordinary differential equation (ODE) solver. Here, we propose an acoustic analog computing (AAC) system based on three cascaded metasurfaces to solve the nth-order ODEs. The metasurfaces are constructed with layered labyrinthine units featuring broad amplitude and phase modulation ranges. The simulated transmitted pressure of the AAC system agrees well with the theoretical solution of ODE, demonstrating the excellent functionality. Unlike the optical ODE solver based on differentiator or integrator, whose geometry becomes more complicated for solving higher order ODE, the proposed AAC system with fixed geometry can be designed for arbitrary nth order ODE in principle. The proposal may find applications in various scenarios such as acoustic communication, analog computing and signal processing. PMID- 29973616 TI - Mycobacterium tuberculosis CarD, an essential global transcriptional regulator forms amyloid-like fibrils. AB - CarD is an essential global transcription regulator from Mycobacterium tuberculosis (Mtb) that binds RNA polymerase and activates transcription by stabilizing the transcription initiation complex. Available crystal structures have captured two distinct, monomeric and domain-swapped homodimeric, oligomeric states of CarD. However, the actual oligomeric state of CarD in solution and its biological relevance has remained unclear. Here, we confirm the presence of the homodimeric state of CarD in solution by using synchrotron-based small-angle X ray scattering. Furthermore, by using biochemical and biophysical experiments, in addition to mass-spectrometry, transmission electron microscopy, and confocal imaging, we show that CarD is the first soluble cytosolic protein in Mtb which displays the tendency to form amyloid-like fibrils both in vitro as well as in vivo. We demonstrate that the deletion of the fourteen N-terminal residues involved in domain-swapping hampers amyloid formation, thus, suggesting that domain-swapping is crucial in amyloidogenesis. The discovery of the amyloidogenic property of an essential cytosolic global transcription regulator, CarD, in a pathogenic bacteria will further open up new frontiers in research. PMID- 29973617 TI - Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism. AB - Deiodinase 2 (DIO2) plays an important role in thyroid hormone metabolism and its regulation. However, molecular mechanism that regulates DIO2 activity remains unclear; only mutaions in selenocysteine insertion sequence binding protein 2 and selenocysteine tranfer RNA (tRNA[Ser]Sec) are reported to result in decreased DIO2 activity. Two patients with clinical evidence of abnormal thyroid hormone metabolism were identified and found to have TSHR mutations as well as DIO2 T92A single nucleotide polymorphism (SNP). Primary-cultured fibroblasts from one patient present a high level of basal DIO2 enzymatic activity, possibly due to compensation by augmented DIO2 expression. However, this high enzymatic active state yet fails to respond to accelerating TSH. Consequently, TSHR mutations along with DIO2 T92A SNP ("double hit") may lead to a significant reduction in DIO2 activity stimulated by TSH, and thereby may have clinical relevance in a select population of hypothyroidism patients who might benefit from a T3/T4 combination therapy. PMID- 29973618 TI - Flow of CO2 from soil may not correspond with CO2 concentration in soil. AB - The relationship between CO2 flow from soil and soil CO2 concentration was investigated at 72 permanent sampling points at two forested post-mining sites in the northwest of the Czechia. Based on the entire data set (72 points sampled monthly during the growing season), CO2 flow from the soil was positively correlated with soil CO2 concentration. CO2 concentration in deeper soil layers was positively correlated with root biomass and negatively correlated with soil microbial respiration. In individual sampling points relationship between CO2 flow and soil CO2 concentration varied from being significantly positive (30% of points) to significantly negative (7%) but mostly being non-significant (63%). The positive correlation occurred at points with high root biomass in deeper soil layers, while the negative correlation occurred at points with high soil microbial respiration per cm3 of soil. Laboratory experiments showed that the CO2 produced by microbial respiration can reduce microbial respiration but that CO2 produced by root respiration did not reduce root respiration. The results indicate that when soil ventilation is poor, microbial respiration can sufficiently increase soil CO2 concentration so as to reduce microbial respiration, which greatly increases the variability in the relationship between CO2 flow from soil and soil CO2 concentration. PMID- 29973619 TI - Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver. AB - DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses. PMID- 29973620 TI - Assessment of the key regulatory genes and their Interologs for Turner Syndrome employing network approach. AB - Turner Syndrome (TS) is a condition where several genes are affected but the molecular mechanism remains unknown. Identifying the genes that regulate the TS network is one of the main challenges in understanding its aetiology. Here, we studied the regulatory network from manually curated genes reported in the literature and identified essential proteins involved in TS. The power-law distribution analysis showed that TS network carries scale-free hierarchical fractal attributes. This organization of the network maintained the self-ruled constitution of nodes at various levels without having centrality-lethality control systems. Out of twenty-seven genes culminating into leading hubs in the network, we identified two key regulators (KRs) i.e. KDM6A and BDNF. These KRs serve as the backbone for all the network activities. Removal of KRs does not cause its breakdown, rather a change in the topological properties was observed. Since essential proteins are evolutionarily conserved, the orthologs of selected interacting proteins in C. elegans, cat and macaque monkey (lower to higher level organisms) were identified. We deciphered three important interologs i.e. KDM6A WDR5, KDM6A-ASH2L and WDR5-ASH2L that form a triangular motif. In conclusion, these KRs and identified interologs are expected to regulate the TS network signifying their biological importance. PMID- 29973621 TI - Environmental properties of cells improve machine learning-based phenotype recognition accuracy. AB - To answer major questions of cell biology, it is often essential to understand the complex phenotypic composition of cellular systems precisely. Modern automated microscopes produce vast amounts of images routinely, making manual analysis nearly impossible. Due to their efficiency, machine learning-based analysis software have become essential tools to perform single-cell-level phenotypic analysis of large imaging datasets. However, an important limitation of such methods is that they do not use the information gained from the cellular micro- and macroenvironment: the algorithmic decision is based solely on the local properties of the cell of interest. Here, we present how various features from the surrounding environment contribute to identifying a cell and how such additional information can improve single-cell-level phenotypic image analysis. The proposed methodology was tested for different sizes of Euclidean and nearest neighbour-based cellular environments both on tissue sections and cell cultures. Our experimental data verify that the surrounding area of a cell largely determines its entity. This effect was found to be especially strong for established tissues, while it was somewhat weaker in the case of cell cultures. Our analysis shows that combining local cellular features with the properties of the cell's neighbourhood significantly improves the accuracy of machine learning based phenotyping. PMID- 29973622 TI - Direct evidence of a low barrier hydrogen bond in the catalytic triad of a Serine protease. AB - Serine proteases are one of the largest groups of enzymes, found in both eukaryotes and prokaryotes, and are responsible for many different functions. The detailed information about the hydrogen-bonds in the catalytic triad (Asp...His...Ser) of these enzymes is of importance in order to fully understand the mechanism of action. The aspartate of the triad is hydrogen bonded to the histidine but the exact nature of this bond has been under discussion for some time. It is either a common short ionic hydrogen bond (SIHB) or a delocalized low barrier hydrogen bond (LBHB) were the hydrogen bond is shorter. So far, the evidence for LBHB in proteins have not been conclusive. Here we show clear NMR evidence that LBHB does exist in NS3, a serine protease from Dengue. The one bond coupling constant between the hydrogen and nitrogen was shown to be only 52 Hz instead of the usual 90 Hz. This together with a 1H chemical shift of 19.93 ppm is evidence that the hydrogen bond distance between His and Asp is shorter than for SIHB. Our result clearly shows the existence of LBHB and will help in understanding the mechanism of the catalytic triad in the important group of serine proteases. PMID- 29973624 TI - One possible mechanism for eddy distribution in zonal current with meridional shear. AB - Oceanic mesoscale eddies are common, especially in areas where zonal currents with meridional shear exists. The nonlinear effects complicate the analysis of mesoscale eddy dynamics. This study proposes a solitary (eddy) solution based on an asymptotic expansion of the nonlinear potential vorticity equation with a constant meridional shear of zonal current. This solution reveals several important consequences. For example, cyclonic (anticyclonic) eddies can be generated by the negative (positive) shear of the zonal current. Furthermore, the meridional structure of an eddy is asymmetrical, and the center of a cyclonic (anticyclonic) eddy tilts poleward (equatorward). Eddy width is inversely proportional to shear intensity. Eddy phase speed is proportional to shear intensity and the wave amplitude, and their spatial distribution show band-like pattern as they propagate westward. This nonlinear solitary solution is an extension of classical linear Rossby theory. Moreover, these findings could be applied to other areas with similar zonal current shear. PMID- 29973623 TI - MicroRNA interactome analysis predicts post-transcriptional regulation of ADRB2 and PPP3R1 in the hypercholesterolemic myocardium. AB - Little is known about the molecular mechanism including microRNAs (miRNA) in hypercholesterolemia-induced cardiac dysfunction. We aimed to explore novel hypercholesterolemia-induced pathway alterations in the heart by an unbiased approach based on miRNA omics, target prediction and validation. With miRNA microarray we identified forty-seven upregulated and ten downregulated miRNAs in hypercholesterolemic rat hearts compared to the normocholesterolemic group. Eleven mRNAs with at least 4 interacting upregulated miRNAs were selected by a network theoretical approach, out of which 3 mRNAs (beta-2 adrenergic receptor [Adrb2], calcineurin B type 1 [Ppp3r1] and calcium/calmodulin-dependent serine protein kinase [Cask]) were validated with qRT-PCR and Western blot. In hypercholesterolemic hearts, the expression of Adrb2 mRNA was significantly decreased. ADRB2 and PPP3R1 protein were significantly downregulated in hypercholesterolemic hearts. The direct interaction of Adrb2 with upregulated miRNAs was demonstrated by luciferase reporter assay. Gene ontology analysis revealed that the majority of the predicted mRNA changes may contribute to the hypercholesterolemia-induced cardiac dysfunction. In summary, the present unbiased target prediction approach based on global cardiac miRNA expression profiling revealed for the first time in the literature that both the mRNA and protein product of Adrb2 and PPP3R1 protein are decreased in the hypercholesterolemic heart. PMID- 29973625 TI - Application of conicity index adjusted total body fat in young adults-a novel method to assess metabolic diseases risk. AB - The aim of the study was to evaluate the usefulness of conicity index (CI) adjusted total body fat (TBF), which was defined as TBF/CI, in various metabolic diseases in young adults. A cross-sectional study was carried out in Chinese PLA General Hospital and a total of 1365 young adults (age 20-40 years) who underwent a health check-up examination were finally included in the analysis from February 2016 to 2017. Linear Regression and logistic regression were used to further examine relationship between the index and metabolic diseases. The average age was 34.5 years. Odds Ratios (ORs) for the risk of metabolic diseases increased from the lowest to highest TBF/CI quartile (all P trends < 0.001). Young adults with increased TBF/CI had higher risk of hyperhomocysteinemia (Hhcy) (OR = 1.528, 95% confidence interval = 1.057-2.209). There was a 1.407 increase in the odds of obesity, a 1.112 increase in the odds of hyperlipidemia (HLP) and a 1.094 increase in the odds of diabetes mellitus (DM) per standard deviation (SD) increase in TBF/CI (all P < 0.001). TBF/CI showed higher predictive values for obesity, HLP, DM and Hhcy than weight adjusted total body fat (all P < 0.001). Young adults with increased TBF/CI had higher ratios of metabolic diseases, which suggested that TBF/CI can be a good indicator and had a close relationship with metabolic diseases. PMID- 29973626 TI - Floquet Weyl Magnons in Three-Dimensional Quantum Magnets. AB - In three-dimensional (3D) quantum magnets, magnonic Weyl points (WPs) featuring linear band crossing of two non-degenerate magnon branches can emerge in certain lattice geometry when time-reversal symmetry is broken macroscopically. Unfortunately, there are very limited 3D quantum magnets that host magnonic WPs, and they are yet to be observed experimentally because the intrinsic perturbative interactions that break time-reversal symmetry macroscopically can be very negligible. Here, we present an alternative means via photo-irradiation, in which magnonic WPs can emerge in 3D quantum magnets without relying on intrinsic perturbative interactions to break time-reversal symmetry. By utilizing the magnonic Floquet-Bloch theory, we put forward the general theory of magnonic Floquet WPs in 3D quantum magnets. We show that periodically driven 3D magnonic Dirac nodal-line (DNL) and 3D magnonic gapped trivial insulators can generate 3D magnonic Floquet WPs, which can be tuned by the incident circularly-polarized light. We demonstrate the existence of magnonic Floquet WPs by combining the study of the magnon dispersions, Berry curvatures, and the anomalous thermal Hall effect. The general theoretical formalism can be applied to different magnetic insulators, and thus extending the concept of magnonic WPs to a broader class of 3D magnetically ordered systems. PMID- 29973627 TI - Discordance between self-report and clinical diagnosis of Internet gaming disorder in adolescents. AB - This study aimed to estimate overreporting (the false positive) and underreporting (false negative) rates in self-reported IGD assessment compared with clinical diagnosed IGD. The study population consisted of 45 with IGD and 228 without IGD based on clinical diagnosis from the Internet User Cohort for Unbiased Recognition of Gaming Disorder in Early Adolescence (iCURE) study. All participants completed self-reported IGD assessments. Clinical interviews were conducted blindly by trained mental health professionals based on DSM-5 IGD criteria. Self-assessed average daily amount of gaming time and game genre were measured. Psychological characteristics, including anxiety, suicidality, aggression, self-control, self-esteem, and family support, were obtained from the baseline survey. The false-negative rate for self-reported IGD assessment was 44%. The false-negative group reported less time playing online games than the IGD group, though their psychological characteristics were similar to those of the IGD group. The false-positive rate was 9.6%. They reported more time playing online games than non-IGD group, though their psychological characteristics were similar to those of non-IGD group except self-control. The discrepancy of IGD diagnoses between self-reports and clinical diagnosis revealed limitations of self-measurements. Various strategies are required to overcome the methodological shortfalls of self-reports for the assessment of IGD. PMID- 29973628 TI - Towards Laser-Textured Antibacterial Surfaces. AB - Escherichia coli and Staphylococcus aureus bacterial retention on mirror-polished and ultrashort pulse laser-textured surfaces is quantified with a new approach based on ISO standards for measurement of antibacterial performance. It is shown that both wettability and surface morphology influence antibacterial behavior, with neither superhydrophobicity nor low surface roughness alone sufficient for reducing initial retention of either tested cell type. Surface structures comprising spikes, laser-induced periodic surface structures (LIPSS) and nano pillars are produced with 1030 nm wavelength 350 fs laser pulses of energy 19.1 MUJ, 1.01 MUJ and 1.46 MUJ, respectively. SEM analysis, optical profilometry, shear force microscopy and wettability analysis reveal surface structures with peak separations of 20-40 MUm, 0.5-0.9 MUm and 0.8-1.3 MUm, average areal surface roughness of 8.6 MUm, 90 nm and 60 nm and static water contact angles of 160 degrees , 119 degrees and 140 degrees , respectively. E. coli retention is highest for mirror-polished specimens and spikes whose characteristic dimensions are much larger than the cell size. S. aureus retention is instead found to be inhibited under the same conditions due to low surface roughness for mirror polished samples (Sa: 30 nm) and low wettability for spikes. LIPSS and nano pillars are found to reduce E. coli retention by 99.8% and 99.2%, respectively, and S. aureus retention by 84.7% and 79.9% in terms of viable colony forming units after two hours of immersion in bacterial broth due to both low wettability and fine surface features that limit the number of available attachment points. The ability to tailor both wettability and surface morphology via ultrashort pulsed laser processing confirms this approach as an important tool for producing the next generation of antibacterial surfaces. PMID- 29973629 TI - Monomolecular tetrahelix of polyguanine with a strictly defined folding pattern. AB - The G3TG3TG3TG3 (G3T) sequence folds into a monomolecular quadruplex with all parallel G3 segments connected to each other by chain-reversal loops. The homopolymer consisting of n number of G3T domains directly conjugated to each other folds into an uninterrupted and unusually stable polymer, tetrahelical monomolecular DNA (tmDNA). It was demonstrated that the tmDNA architecture has strong potential in nanotechnologies as highly programmable building material, high affinity coupler and the driving force for endergonic reactions. Here, we explore capability of analogous DNA sequences (i.e., monomolecular quadruplexes with G2 or G4 segments) to construct tmDNA architecture. The study demonstrates that tmDNA can have only one building pattern based on a quadruplex domain with three G-tetrads and single-nucleotide loops, G3N (N = G, A, C and T); all other domains demonstrate antiparallel topologies unsuitable for tmDNA. The present study also suggests that polyguanine is capable of tmDNA formation with strictly defined building pattern; G3 segments connected to each other by chain-reversal G loops. These findings can have significant impact on (i) DNA nanotechnologies; (ii) structure prediction of G-rich sequences of genome; and (iii) modeling of abiogenesis. PMID- 29973630 TI - Development of outbred CD1 mouse colonies with distinct standardized gut microbiota profiles for use in complex microbiota targeted studies. AB - Studies indicate that the gut microbiota (GM) can significantly influence both local and systemic host physiologic processes. With rising concern for optimization of experimental reproducibility and translatability, it is essential to consider the GM in study design. However, GM profiles can vary between rodent producers making consistency between models challenging. To circumvent this, we developed outbred CD1 mouse colonies with stable, complex GM profiles that can be used as donors for a variety of GM transfer techniques including rederivation, co housing, cross-foster, and fecal microbiota transfer (FMT). CD1 embryos were surgically transferred into CD1 or C57BL/6 surrogate dams that varied by GM composition and complexity to establish four separate mouse colonies harboring GM profiles representative of contemporary mouse producers. Using targeted 16S rRNA amplicon sequencing, subsequent female offspring were found to have similar GM profiles to surrogate dams. Furthermore, breeding colonies of CD1 mice with distinct GM profiles were maintained for nine generations, demonstrating GM stability within these colonies. To confirm GM stability, we shipped cohorts of these four colonies to collaborating institutions and found no significant variation in GM composition. These mice are an invaluable experimental resource that can be used to investigate GM effects on mouse model phenotype. PMID- 29973631 TI - Association of Lipoprotein-Associated Phospholipase A2 with the Prevalence of Nonalcoholic Fatty Liver Disease: A Result from the APAC Study. AB - Nonalcoholic fatty liver disease (NAFLD) is a worldwide chronic liver disease. Few studies have investigated the association between NAFLD and Lipoprotein associated phospholipase A2 (Lp-PLA2), a unique enzyme correlated with oxidative stress. The aim of this study was to assess the relationship between Lp-PLA2 and NAFLD in a Chinese community-based cohort. A total of 1587 adults aged >=40 years were enrolled in the current study. Participants underwent a standardized evaluation. The serum Lp-PLA2 concentration was measured by ELISA and NAFLD was diagnosed by ultrasonography. Multivariable logistic regression was used to assess the association between Lp-PLA2 and NAFLD. Increased Lp-PLA2 levels were significantly associated with decreased NAFLD prevalence after adjusting for other potential confounders. The adjusted ORs of NAFLD in Q2, Q3 and Q4 compared with Q1 were 0.88 (0.64-1.21), 0.71 (0.51-0.98) and 0.67 (0.48-0.95), respectively (P < 0.05). Furthermore, the adjusted ORs of moderate and heavy NAFLD in Q2, Q3 and Q4 compared to Q1 were 0.64 (0.41-1.01), 0.48 (0.29-0.80) and 0.47 (0.28-0.79), respectively (P < 0.01). In conclusions, increased Lp-PLA2 levels were independently associated with decreased NAFLD prevalence. PMID- 29973632 TI - Physical Insight on Mechanism of Photoinduced Charge Transfer in Multipolar Photoactive Molecules. AB - Two series of novel dyes were designed based on the multipolar structures of the red dye D35 and blue dye DB, by introducing the furan (F), benzene ring (B) and benzo[c]thiophene (BT) groups into the conjugated bridge of D35 in proper order and adjusting the position of diketopyrrolopyrrole(DPP) unit and the incorporation of fluorine in the conjugated bridge of DB, respectively. We performed the quantum chemistry calculation to investigate the ground state and excited properties in a direct correlation with the spectra properties and abilities of losing or accepting electron for the original and designed molecules. Furthermore, the absorption spectra characteristics in consideration of the aggregation of dyes on the TiO2 layer and intermolecular charge transfer rate of the dimers were calculated. The obtained results indicate that the larger intermolecular charge transfer rate leads to the poor photoelectrical properties of the dyes, and the designed dyes D35-3 and DB-2 would exhibit the best photoelectrical properties among the investigated dyes due to their lower energy gaps, widened absorption spectra and prominent charge transfer properties. PMID- 29973633 TI - Genotype-Corrector: improved genotype calls for genetic mapping in F2 and RIL populations. AB - F2 and recombinant inbred lines (RILs) populations are very commonly used in plant genetic mapping studies. Although genome-wide genetic markers like single nucleotide polymorphisms (SNPs) can be readily identified by a wide array of methods, accurate genotype calling remains challenging, especially for heterozygous loci and missing data due to low sequencing coverage per individual. Therefore, we developed Genotype-Corrector, a program that corrects genotype calls and imputes missing data to improve the accuracy of genetic mapping. Genotype-Corrector can be applied in a wide variety of genetic mapping studies that are based on low coverage whole genome sequencing (WGS) or Genotyping-by Sequencing (GBS) related techniques. Our results show that Genotype-Corrector achieves high accuracy when applied to both synthetic and real genotype data. Compared with using raw or only imputed genotype calls, the linkage groups built by corrected genotype data show much less noise and significant distortions can be corrected. Additionally, Genotype-Corrector compares favorably to the popular imputation software LinkImpute and Beagle in both F2 and RIL populations. Genotype-Corrector is publicly available on GitHub at https://github.com/freemao/Genotype-Corrector . PMID- 29973634 TI - Inorganic carbon and nitrogen assimilation in cellular compartments of a benthic kleptoplastic foraminifer. AB - Haynesina germanica, an ubiquitous benthic foraminifer in intertidal mudflats, has the remarkable ability to isolate, sequester, and use chloroplasts from microalgae. The photosynthetic functionality of these kleptoplasts has been demonstrated by measuring photosystem II quantum efficiency and O2 production rates, but the precise role of the kleptoplasts in foraminiferal metabolism is poorly understood. Thus, the mechanism and dynamics of C and N assimilation and translocation from the kleptoplasts to the foraminiferal host requires study. The objective of this study was to investigate, using correlated TEM and NanoSIMS imaging, the assimilation of inorganic C and N (here ammonium, NH4+) in individuals of a kleptoplastic benthic foraminiferal species. H. germanica specimens were incubated for 20 h in artificial seawater enriched with H13CO3- and 15NH4+ during a light/dark cycle. All specimens (n = 12) incorporated 13C into their endoplasm stored primarily in the form of lipid droplets. A control incubation in darkness resulted in no 13C-uptake, strongly suggesting that photosynthesis is the process dominating inorganic C assimilation. Ammonium assimilation was observed both with and without light, with diffuse 15N enrichment throughout the cytoplasm and distinct 15N-hotspots in fibrillar vesicles, electron-opaque bodies, tubulin paracrystals, bacterial associates, and, rarely and at moderate levels, in kleptoplasts. The latter observation might indicate that the kleptoplasts are involved in N assimilation. However, the higher N assimilation observed in the foraminiferal endoplasm incubated without light suggests that another cytoplasmic pathway is dominant, at least in darkness. This study clearly shows the advantage provided by the kleptoplasts as an additional source of carbon and provides observations of ammonium uptake by the foraminiferal cell. PMID- 29973635 TI - Author Correction: Environmental and anthropogenic factors affecting the increasing occurrence of shark-human interactions around a fast-developing Indian Ocean island. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29973636 TI - The prognostic significance of metabolic syndrome and weight loss in esophageal squamous cell carcinoma. AB - Our study aimed to investigate the association between metabolic syndrome and postoperative survival in patients with esophageal squamous cell carcinoma, and evaluate whether metabolic syndrome can predict the prognosis in esophageal cancer patients. The retrospective study reviewed 519 patients with esophageal squamous cell carcinoma who had received esophagetomy and lymphnode dissections in the Department of Thoracic Surgery, Qilu Hospital of Shandong University between January 2007 and December 2011. All patients were followed up until December 2016. The median follow-up time was 39.59 months (range 0.25-72 months). The 3-year and 5-year survival rate was 51.4% and 37.0%, respectively. Kaplan Meier survival analysis revealed a significant correlation between OS and obesity (P = 0.000), weight loss (P = 0.000), diabetes (P = 0.001) and dyslipidemia (P = 0.030). Multivariate analysis indicated that advanced TNM staging (P = 0.007, HR: 1.760, 95% CI: 1.167-2.654) and more weight loss (P = 0.000, HR: 1.961, 95% CI: 1.697-2.267) were independent factors for adverse prognosis of esophageal squamous carcinoma patients. In contrast, diabetes was a protective factor in the prognosis of patients with esophageal cancer (P = 0.018, HR: 0.668, 95% CI: 0.478 0.933). Our findings suggest that TNM staging, weight changes and diabetes were independent predictors for the prognosis of esophageal cancer patients. PMID- 29973638 TI - Single Walled BiI3 Nanotubes Encapsulated within Carbon Nanotubes. AB - Inorganic nanotubes are morphological counterparts of carbon nanotubes (CNTs). Yet, only graphene-like BN layer has been readily organized into single walled nanotubes so far. In this study, we present a simple route to obtain inorganic single walled nanotubes - a novel ultrathin morphology for bismuth iodide (BiI3), embedded within CNTs. The synthesis involves the capillary filling of BiI3 into CNT, which acts as a nanotemplate, by annealing the BiI3-CNT mixture above the melting point of BiI3. Aberration corrected scanning/transmission electron microscopy is used in characterizing the novel morphology of BiI3. A critical diameter which enables the formation of BiI3 nanotubes, against BiI3 nanorods is identified. The relative stability of these phases is investigated with the density functional theory calculations. Remarkably, the calculations reveal that the single walled BiI3 nanotubes are semiconductors with a direct band gap, which remain stable even without the host CNTs. PMID- 29973637 TI - Mito-TEMPO improves development competence by reducing superoxide in preimplantation porcine embryos. AB - Mito-TEMPO is a well-known mitochondria-specific superoxide scavenger. However, the effect of Mito-TEMPO on porcine embryo development, to our knowledge, has not been studied yet. In the present study, porcine embryos were classified into two groups (G1 and G2) based on the cytoplasm lipid contents at the zygote stage. The development of blastocysts derived from G2 zygotes was reduced (G2:16.2 +/- 7.9% vs G1: 26.5 +/- 5.9%; 1.6-fold, p < 0.05) compared to those from G1 zygotes. In G2 embryos, the proportion of TUNEL-positive cells was also higher than that of G1 embryos. Superoxide in G2 embryos was significantly increased compared to that in G1 embryos. Mitochondrial membrane potential and ATP production were lower in G2 embryos than in G1 embryos. Phosphorylation of Drp1 at Ser 616 increased in G1 embryos during the cleavage stages compared to that in the zygote but was not significantly different in G2 embryos. Then, the effects of Mito-TEMPO were investigated in G2 embryos. Blastocyst formation rate (G2: 19.1 +/- 5.1% vs G2 + Mito-TEMPO: 28.8 +/- 4.0%; 1.5-fold, p < 0.05) and mitochondrial aggregation were recovered after superoxide reduction by Mito-TEMPO treatment. Thus, we showed that Mito-TEMPO improves blastocyst development by superoxide reduction in porcine embryos in vitro. PMID- 29973639 TI - Dual role of SND1 facilitates efficient communication between abiotic stress signalling and normal growth in Arabidopsis. AB - Certain plant cells synthesize secondary cell walls besides primary cell walls. This biosynthesis is strictly controlled by an array of transcription factors. Here, we show that SND1, a regulator of cell-wall biosynthesis, regulates abscisic acid (ABA) biosynthesis to ensure optimal plant growth. In Arabidopsis, the lack of SND1 and its homolog NST1 leads to the deficiency of secondary cell walls, preventing snd1nst1 double mutant seedlings from growing upright. Compared to wild type seedlings, the snd1 knockout mutant seedlings accumulated less anthocyanin and exhibited low tolerance to salt stress. Compared to wild type seedlings, the snd1 knockout seedlings were more sensitive to salt stress. Although SND1 can bind to the promoter of Myb46, we observed that SND1 binds directly to the promoter of the ABI4 gene, thereby reducing ABA levels under normal growth conditions. Thus, plants adjust secondary cell wall thickening and growth via SND1. SND1 has a dual function: it activates the Myb46 pathway, fostering lignin biosynthesis to produce sufficient cell wall components for growth, while maintaining a low ABA concentration, as it inhibits growth. This dual function of SND1 may help plants modulate their growth efficiently. PMID- 29973640 TI - Reversible mislocalization of a disease-associated MRE11 splice variant product. AB - Ataxia-telangiectasia (AT) and related disorders feature cancer predisposition, neurodegeneration, and immunodeficiency resulting from failure to respond to DNA damage. Hypomorphic mutations in MRE11 cause an AT-like disorder (ATLD) with variable clinical presentation. We have sought to understand how diverse MRE11 mutations may provide unique therapeutic opportunities, and potentially correlate with clinical variability. Here we have undertaken studies of an MRE11 splice site mutation that was found in two ATLD siblings that died of pulmonary adenocarcinoma at the young ages of 9 and 16. The mutation, termed MRE11 alternative splice mutation (MRE11ASM), causes skipping of a highly conserved exon while preserving the protein's open reading frame. A new mouse model expressing Mre11ASM from the endogenous locus demonstrates that the protein is present at very low levels, a feature in common with the MRE11ATLD1 mutant found in other patients. However, the mechanisms causing low protein levels are distinct. MRE11ASM is mislocalized to the cytoplasm, in contrast to MRE11ATLD1, which remains nuclear. Strikingly, MRE11ASM mislocalization is corrected by inhibition of the proteasome, implying that the protein undergoes strict protein quality control in the nucleus. These findings raise the prospect that inhibition of poorly understood nuclear protein quality control mechanisms might have therapeutic benefit in genetic disorders causing cytoplasmic mislocalization. PMID- 29973641 TI - Author Correction: Infection of microglia with Porphyromonas gingivalis promotes cell migration and an inflammatory response through the gingipain-mediated activation of protease-activated receptor-2 in mice. AB - A correction to this article has been published and is linked from the HTML and PDF version of this paper. The error has been fixed in the paper. PMID- 29973642 TI - Unraveling the Mesoscale Evolution of Microstructure during Supersonic Impact of Aluminum Powder Particles. AB - A critical challenge in the predictive capability of materials deformation behavior under extreme environments is the availability of computational methods to model the microstructural evolution at the mesoscale. The capability of the recently-developed quasi-coarse-grained dynamics (QCGD) method to model mesoscale behavior is demonstrated for the phenomenon of supersonic impact of 20 um sized Al particles on to an Al substrate at various impact velocities and over time and length scales relevant to cold spray deposition. The QCGD simulations are able to model the kinetics related to heat generation and dissipation, and the pressure evolution and propagation, during single particle impact over the time and length scales that are important experimentally. These simulations are able to unravel the roles of particle and substrate deformation behavior that lead to an outward/upward flow of both the particle and the substrate, which is a likely precursor for the experimentally observed jetting and bonding of the particles during cold spray impact. PMID- 29973643 TI - Down-regulation of circPVRL3 promotes the proliferation and migration of gastric cancer cells. AB - Circular RNA (circRNA) is a key regulator in the development and progression of various types of carcinomas. However, its role in gastric cancer (GC) tumorigenesis is not well understood. The present study aimed to investigate the expression profile and potential modulation of circRNAs on GC carcinogenesis. Human circRNA microarray was performed to screen for abnormally expressed circRNA in GC tissue. Results showed that a decrease in the circPVRL3 expression level was associated with the presence of GC, and also with higher TNM stage and lower overall survival rates compared with that in adjacent noncancerous tissues. In vitro assays of the GC cell lines MKN-45 and MGC-803 demonstrated that knockdown of circPVRL3 promoted cell proliferation significantly. Prediction and annotation revealed circPVRL3 was able to sponge to 9 miRNAs and may be also able to have a binding with AGO2, FUS, LIN28A, PTB, and EIF4A3. In addition, based on the structure of internal ribosomal entry sites, open reading frame, and m6A modification, circPVRL3 may have the potential ability to encode proteins. Taken together, our study indicated that down-regulation of circPVRL3 could promote the proliferation in gastric carcinoma and have potential to encode protein. PMID- 29973644 TI - A misaligned magneto-optical trap to enable miniaturized atom chip systems. AB - We describe the application of displaced, or misaligned, beams in a mirror-based magneto-optical trap (MOT) to enable portable and miniaturized atom chip experiments where optical access is limited to a single window. Two different geometries of beam displacement are investigated: a variation on the well-known 'vortex-MOT', and the other a novel 'hybrid-MOT' combining Zeeman-shifted and purely optical scattering force components. The beam geometry is obtained similar to the mirror-MOT, using a planar mirror surface but with a different magnetic field geometry more suited to planar systems. Using these techniques, we have trapped around 6 * 106 and 26 * 106 atoms of 85Rb in the vortex-MOT and hybrid MOT respectively. For the vortex-MOT the atoms are directly cooled well below the Doppler temperature without any additional sub-Doppler cooling stage, whereas the temperature of the hybrid-MOT has been measured slightly above the Doppler temperature limit. In both cases the attained lower temperature ensures the quantum behaviour of the trapped atoms required for the applications of portable quantum sensors and many others. PMID- 29973645 TI - Across-subject offline decoding of motor imagery from MEG and EEG. AB - Long calibration time hinders the feasibility of brain-computer interfaces (BCI). If other subjects' data were used for training the classifier, BCI-based neurofeedback practice could start without the initial calibration. Here, we compare methods for inter-subject decoding of left- vs. right-hand motor imagery (MI) from MEG and EEG. Six methods were tested on data involving MEG and EEG measurements of healthy participants. Inter-subject decoders were trained on subjects showing good within-subject accuracy, and tested on all subjects, including poor performers. Three methods were based on Common Spatial Patterns (CSP), and three others on logistic regression with l1 - or l2,1 -norm regularization. The decoding accuracy was evaluated using (1) MI and (2) passive movements (PM) for training, separately for MEG and EEG. With MI training, the best accuracies across subjects (mean 70.6% for MEG, 67.7% for EEG) were obtained using multi-task learning (MTL) with logistic regression and l2,1-norm regularization. MEG yielded slightly better average accuracies than EEG. With PM training, none of the inter-subject methods yielded above chance level (58.7%) accuracy. In conclusion, MTL and training with other subject's MI is efficient for inter-subject decoding of MI. Passive movements of other subjects are likely suboptimal for training the MI classifiers. PMID- 29973646 TI - Motivational goal-priming with or without awareness produces faster and stronger force exertion. AB - Previous research has demonstrated that barely visible (subliminal) goal-priming with motivational reward can alter the state of the motor system and enhance motor output. Research shows that these affective-motivational effects result from associations between goal representations and positive affect without conscious awareness. Here, we tested whether motivational priming can increase motor output even if the priming is fully visible (supraliminal), and whether the priming effect occurs through increased cortical excitability. Groups of participants were primed with either barely visible or fully visible words related to effort and control sequences of random letters that were each followed by fully visible positively reinforcing words. The priming effect was measured behaviourally by handgrip force and reaction time to the grip cue after the priming was complete. Physiologically, the effects were measured by pupil dilation and motor-evoked potentials (MEPs) in response to transcranial magnetic stimulation during the priming task. Analysis showed that for both the supraliminal and subliminal conditions, reaction time decreased and total force, MEP magnitude, and pupil dilation increased. None of the priming-induced changes in behaviour or physiology differed significantly between the supraliminal and the subliminal groups, indicating that implicit motivation towards motor goals might not require conscious perception of the goals. PMID- 29973647 TI - Stimulating fermentation by the prolonged acceleration of gut transit protects against decompression sickness. AB - Massive bubble formation after diving can lead to decompression sickness (DCS). Gut fermentation at the time of a dive exacerbates DCS due to endogenous hydrogen production. We sought to investigate whether medium-term stimulation of fermentation as a result of polyethylene glycol (PEG)-induced acceleration of bowel transit before diving exacerbates DCS in rats. Seven days before an experimental dry dive, 60 rats were randomly divided in two groups: an experimental group treated with PEG (n = 30) and an untreated control group (n = 30). Exhaled hydrogen was measured before the dive. Following hyperbaric exposure, we assessed for signs of DCS. After anaesthetisation, arterial blood was drawn to assay inflammatory cytokines and markers of oxidative stress. PEG led to a significant increase in exhaled H2 (35 ppm [10-73] compared with control 7 ppm [2-15]; p = 0.001). The probability of death was reduced in PEG-treated rats (PEG: 17% [95% CI 4-41] vs control: 50% [95% CI 26-74]; p = 0.034). In addition, inflammatory markers were reduced, and the antioxidant activity of glutathione peroxidase was significantly increased (529.2 U.l-1 [485.4-569.0] versus 366.4 U.l-1 [317.6-414.8]; p = 0.004). Thus, gut fermentation might have a positive effect on DCS. The antioxidant and neuroprotective properties of the fermentation by-products H2 and butyrate may explain these results. PMID- 29973648 TI - The chemokine receptor CCR7 is a promising target for rheumatoid arthritis therapy. AB - The chemokine receptor CCR7 and its ligands CCL19 and CCL21 guide the homing and positioning of dendritic and T cells in lymphoid organs, thereby contributing to several aspects of adaptive immunity and immune tolerance. In the present study, we investigated the role of CCR7 in the pathogenesis of collagen-induced arthritis (CIA). By using a novel anti-human CCR7 antibody and humanized CCR7 mice, we evaluated CCR7 as a target in this autoimmune model of rheumatoid arthritis (RA). Ccr7-deficient mice were completely resistant to CIA and presented severely impaired antibody responses to collagen II (CII). Selective CCR7 expression on dendritic cells restored arthritis severity and anti-CII antibody titers. Prophylactic and therapeutic treatment of humanized CCR7 mice with anti-human CCR7 mAb 8H3-16A12 led to complete resistance to CIA and halted CIA progression, respectively. Our data demonstrate that CCR7 signaling is essential for the induction of CIA and identify CCR7 as a potential therapeutic target in RA. PMID- 29973649 TI - The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1 IRF3 signaling. AB - Protein arginine methyltransferases (PRMTs) play diverse biological roles and are specifically involved in immune cell development and inflammation. However, their role in antiviral innate immunity has not been elucidated. Viral infection triggers the TBK1-IRF3 signaling pathway to stimulate the production of type-I interferon, which mediates antiviral immunity. We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-beta expression and found that PRMT6 inhibits the antiviral innate immune response. Viral infection also upregulated PRMT6 protein levels. We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity. PRMT6 deficiency promoted the TBK1-IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production. Mechanistically, viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1; this mechanism was independent of PRMT6 methyltransferase activity. Thus, PRMT6 inhibits antiviral innate immunity by sequestering IRF3, thereby blocking TBK1-IRF3 signaling. Our work demonstrates a methyltransferase-independent role for PRMTs. It also identifies a negative regulator of the antiviral immune response, which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection. PMID- 29973651 TI - Author Correction: Changes in Distribution of Dry Eye Disease by the New 2016 Diagnostic Criteria from the Asia Dry Eye Society. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29973652 TI - Subependymal giant cell astrocytoma-like astrocytoma: a neoplasm with a distinct phenotype and frequent neurofibromatosis type-1-association. AB - Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer related genes. The average age at diagnosis was 28 years (range: 4-60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation. PMID- 29973653 TI - Expression of PD-L1/PD-1 in lymphoepithelioma-like carcinoma of the thymus. AB - Poorly differentiated non-keratinizing squamous cell carcinoma of the thymus, also known as lymphoepithelioma-like carcinoma, is a rare primary malignant neoplasm of thymic origin. The mainstay of treatment for these tumors is surgical and they tend to respond poorly to chemotherapy. The checkpoint programmed cell death ligand-1 protein (PD-L1) bound to its receptor (PD-1) has been demonstrated to be an important therapeutic target for many different tumors. Expression of PD L1/PD-1 in lymphoepithelioma-like carcinoma of the thymus may indicate that these tumors are potential targets for inhibitor therapy. Twenty-one cases of lymphoepithelioma-like carcinoma of the thymus were collected and reviewed. Tissue microarrays were created using triplicate 2 mm cores for each case. PD L1/PD-1 staining pattern (neoplastic cells versus tumor infiltrating lymphocytes) was documented for each case. Out of 21 cases, 15 (71.4%) showed various degrees of membranous PD-L1 staining. Of the positive cases, 48% showed high expression of PD-L1 (>50% of tumor cells) and 24% showed low expression (<50%). PD-1 staining showed focal positivity in 12/20 (60%) cases among tumor infiltrating lymphocytes. PD-L1/PD-1 inhibitor therapy has been applied successfully in other solid malignant tumors with high expression of PD-L1/PD-1. The high level of PD L1 expression in our cases indicates that PD-L1 may play a role in the pathogenesis of these tumors and that PD-L1/PD-1 blockade may be a viable therapeutic option for patients with lymphoepithelioma-like carcinoma of the thymus who have failed other first-line therapies. PMID- 29973655 TI - Fear extinction disruption in a developmental rodent model of schizophrenia correlates with an impairment in basolateral amygdala-medial prefrontal cortex plasticity. AB - Schizophrenia patients typically exhibit prominent negative symptoms associated with deficits in extinction recall and decreased ventromedial prefrontal cortex activity (vmPFC, analogous to medial PFC infralimbic segment in rodents). mPFC activity modulates the activity of basolateral amygdala (BLA) and this connectivity is related to extinction. mPFC and BLA activity has been shown to be altered in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. However, it is unknown if there are alterations in extinction processes in this model. Therefore, we investigated extinction and the role of mPFC-BLA balance in MAM rats. Male offspring of pregnant rats treated with Saline or MAM (20 mg/kg; i.p.) on gestational day 17 were used in fear conditioning (contextual/tone) and electrophysiological experiments (mPFC-BLA plasticity). No difference was observed in conditioning, extinction, and test sessions in contextual fear conditioning. However, MAM-treated rats demonstrated impairment in extinction learning and recall in tone fear conditioning. Furthermore, high frequency stimulation (HFS) of the BLA decreased spike probability in the mPFC of saline-treated rats but not in MAM rats. NMDA antagonist microinjected into the BLA disrupted extinction learning and recall in control rats, resulting in a similar deficit as that observed in MAM-treated rats. These data demonstrate extinction impairment in the MAM model that is analogous to that observed in schizophrenia patients, that was probably due to disruption in the regulation of mPFC activity by glutamatergic neurotransmission in the BLA. PMID- 29973656 TI - Downreguation of FoxM1 by miR-214 inhibits proliferation and migration in hepatocellular carcinoma. AB - The FoxM1 transcription factor plays an important role in the progression of HCC. Therefore, it is necessary to study cell regulation of FoxM1. In this study, we determined the expression of miR-214 and it was inversely associated with FoxM1 protein level in HCC; and suppression of FoxM1 translation by miR-214 mimics. We found that miR-214 targeted the 3'untranslated region of FoxM1 mRNA. In addition, the study found that DLX1 was the direct target of FoxM1 in HCC. Downregulation of FoxM1 inhibits the proliferation, migration, and invasion of HCC cells by miR 214. These results indicate that miR-214 may be used as a completely new molecular target by influencing FoxM1 expression in HCC. PMID- 29973657 TI - Tweaking the Electronic and Optical Properties of alpha-MoO3 by Sulphur and Selenium Doping - a Density Functional Theory Study. AB - First-principles calculations were carried out to understand how anionic isovalent-atom doping affects the electronic structures and optical properties of alpha-MoO3. The effects of the sulphur and selenium doping at the three unique oxygen sites (Ot, Oa, and Ot) of alpha-MoO3 were examined. We found that the valence p orbitals of Sulphur/Selenium dopant atoms give rise to impurity bands above the valence band maximum in the band structure of alpha-MoO3. The number of impurity bands in the doped material depends on the specific doping sites and the local chemical environment of the dopants in MoO3. The impurity bands give rise to the enhanced optical absorptions of the S- and Se-doped MoO3 in the visible and infrared regions. At low local doping concentration, the effects of the dopant sites on the electronic structure of the material are additive, so increasing the doping concentration will enhance the optical absorption properties of the material in the visible and infrared regions. Further increasing the doping concentration will result in a larger gap between the maximum edge of impurity bands and the conduction band minimum, and will undermine the optical absorption in the visible and infrared region. Such effects are caused by the local geometry change at the high local doping concentration with the dopants displaced from the original O sites, so the resulting impurity bands are no long the superpositions of the impurity bands of each individual on site dopant atom. Switching from S-doping to Se-doping decreases the gap between the maximum edge of the impurity bands and conduction band minimum, and leads to the optical absorption edge red-shifting further into the visible and infrared regions. PMID- 29973658 TI - Interaction between hydrogen and gallium vacancies in beta-Ga2O3. AB - In this paper, the revised Heyd-Scuseria-Ernzerhof screened hybrid functional (HSE06) is used to investigate the interaction between hydrogen with different concentrations and gallium vacancies in beta-Ga2O3. The hydrogen can compensate a gallium vacancy by forming hydrogen-vacancy complex. A gallium vacancy can bind up to four hydrogen atoms, and formation energies decrease as the number of hydrogen atoms increases. Hydrogen prefers to bind with three coordinated oxygen. The bonding energy and annealing temperatures of complexes containing more than two hydrogen atoms are computed, and show relatively high stability. In addition, vacancy concentrations increase with the increasing vapor pressures. This paper can effectively explain the hydrogen impact in beta-Ga2O3. PMID- 29973659 TI - Sex matters. PMID- 29973654 TI - Neuronal and glial factors contributing to sex differences in opioid modulation of pain. AB - Morphine remains one of the most widely prescribed opioids for alleviation of persistent and/or severe pain; however, multiple preclinical and clinical studies report that morphine is less efficacious in females compared to males. Morphine primarily binds to the mu opioid receptor, a prototypical G-protein coupled receptor densely localized in the midbrain periaqueductal gray. Anatomical and physiological studies conducted in the 1960s identified the periaqueductal gray, and its descending projections to the rostral ventromedial medulla and spinal cord, as an essential descending inhibitory circuit mediating opioid-based analgesia. Remarkably, the majority of studies published over the following 30 years were conducted in males with the implicit assumption that the anatomical and physiological characteristics of this descending inhibitory circuit were comparable in females; not surprisingly, this is not the case. Several factors have since been identified as contributing to the dimorphic effects of opioids, including sex differences in the neuroanatomical and neurophysiological characteristics of the descending inhibitory circuit and its modulation by gonadal steroids. Recent data also implicate sex differences in opioid metabolism and neuroimmune signaling as additional contributing factors. Here we cohesively present these lines of evidence demonstrating a neural basis for sex differences in opioid modulation of pain, with a focus on the PAG as a sexually dimorphic core of descending opioid-induced inhibition and argue for the development of sex specific pain therapeutics. PMID- 29973660 TI - Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms? AB - Nail Patella syndrome (NPS) is a rare autosomal dominant disease characterized by varying degrees of patella, nail, and elbows dysplasia and also ocular and renal congenital abnormalities. The renal involvement, ranging from hematuria and proteinuria to end-stage renal disease, is present in 22-60% of NPS cases. Heterozygous variants in LMX1B are known to be responsible of NPS and it has been hypothesized that the variable expressivity is due to the interaction of LMX1B with other developmental genes. We reported a case of co-presence of LMX1B and PAX2 variants in a child with extrarenal manifestation of NPS and end-stage renal disease but congenital bilateral renal hypodysplasia and vesicoureteral reflux. The LMX1B variant was de novo, whereas the PAX2 variant was inherited from the mother that had bilateral renal hypoplasia although in presence of only a mild chronic kidney disease. The molecular interaction between LMX1B and PAX2 has been already reported in vitro and this finding suggest that the worst renal NPS phenotype of our patient could be due to the defective expression of these two genes during nephrogenesis. In conclusion, our finding suggests that PAX2 may act as modifier gene in Nail Patella phenotype. PMID- 29973661 TI - microRNA-21 and hypertension. AB - Hypertension, a multifactorial disease, is a major risk factor for the development of stroke, coronary artery disease, heart failure, and chronic renal failure. However, its underlying cellular and molecular mechanisms remain largely elusive. Numerous studies have shown that microRNAs (miRNAs) are involved in a variety of cellular processes, including cellular proliferation, apoptosis, differentiation, and the development of diseases. microRNA-21 (miR-21), a conserved single-stranded non-coding RNA that is composed of approximately 22 nucleotides, is one of the most intensively studied miRNAs in recent years, and it can regulate gene expression at the post-transcriptional level. miR-21 is expressed in many kinds of tumors and in the cardiovascular system, and it plays an important role in the occurrence and development of cardiovascular diseases. In recent years, more and more evidence indicates that miR-21 plays an important role in hypertension. This article reviews the source, function, and altered levels of miR-21 in hypertension and the role of miR-21 in the pathogenesis of hypertension and target organ damage (TOD). The potential role of miR-21 as a new target for predicting and treating hypertension is also explored. PMID- 29973663 TI - Objective evaluation of size and shape of superficial foveal avascular zone in normal subjects by optical coherence tomography angiography. AB - This study was conducted to investigate the size and shape of the foveal avascular zone (FAZ) determined by optical coherence tomography angiography (OCTA) and the relationship of the size and shape to the clinical findings in normal subjects. This was a cross-sectional study with seventy eyes of 70 volunteers. The size of the superficial FAZs were assessed by its area, length of perimeter, and Feret's diameter, and the shape by the circularity, axial ratio, roundness, and solidity. The correlations between each parameter and the clinical findings were statistically determined. The coefficients of variation (CV) of the parameters of FAZ size were higher than that of the parameters of FAZ shape. The refractive error and axial length were significantly correlated with area-related factors. The central macular thickness (CMT) was significantly correlated with all parameters. Although the CMT was a critical factor that was significantly correlated with the size and shape characteristics of the FAZ, the shape might be a better factor for characterizing the FAZ than the size because of the low CV of shape-related factors and the characteristics are less affected by the other ocular factors. PMID- 29973664 TI - Umbilical cord milking for neonates who are depressed at birth: a randomized trial of feasibility. AB - OBJECTIVE: To evaluate the feasibility and safety of umbilical cord milking (UCM) in neonates who are depressed at birth. STUDY DESIGN: This is a quasi-randomized, non-blinded, controlled trial on infants (>=35 weeks) who were depressed at birth. UCM (cord milked three times) was performed during the even months and the neonates born during the odd months were in the control group. Primary outcome was feasibility and safety. RESULTS: A total of 101 infants were enrolled (50 UCM group and 51 control group) between January 2015 and October 2016. UCM was performed in 95% of infants (59/62) who qualified to receive UCM. There were no significant differences in resuscitation delay, resuscitation efforts, and short term outcomes between the two groups. CONCLUSIONS: UCM is feasible for term and late preterm infants who are depressed at birth. A larger clinical trial is needed to evaluate long-term benefits of UCM in neonates with HIE. PMID- 29973662 TI - Gene expression profile in peripheral blood mononuclear cells of postpartum depression patients. AB - Postpartum depression (PPD) is a common mental health problem that causes maternal suffering and various negative consequences for offspring. The pathogenesis of PPD and the causes of consequences for offspring remain largely unknown. Here, we applied RNA sequencing to sequence the whole transcriptomes of peripheral blood mononuclear cells (PBMCs) from PPD patients (Edinburgh Postnatal Depression Scale [EPDS] score >=13) and control subjects (EPDS = 0). We found that PPD was positively correlated with multiple genes involved in energy metabolism, neurodegenerative diseases and immune response, while negatively correlated with multiple genes in mismatch repair and cancer-related pathways. Remarkably, genes associated with appetite regulation and nutrient response were differentially expressed between PPD and control subjects. Then, we employed a postnatal growth retardation model by repeated immobilization stress (IS) stimulation to maternal mice. The expression of appetite regulation and nutrient response-related genes in the PBMCs of IS mice and in the hypothalamus of their offspring were also affected. In conclusion, this study provides a comprehensive characterization of the PBMCs transcriptome in PPD and suggests that maternal stress may affect appetite regulation and nutrient response in the hypothalamus of offspring mice. PMID- 29973665 TI - CTLA-4 +49 G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function. AB - To investigate whether CTLA-4 +49 G/A (rs231775), a tagSNP in Asian, is a functional T1D SNP, we genotyped this SNP with 1035 T1D patients and 2575 controls in Chinese Han population. And 1280 controls measured insulin release and sensitivity based on an oral glucose tolerance test; 283 newly diagnosed T1D patients assayed C-peptide level based on a mixed-meal tolerance test. 31 controls were analyzed for different T cell subsets by multi-color flow cytometry. Under additive model, we found that CTLA-4 +49 G/A was significantly associated with T1D (P = 2.82E-04, OR = 1.25, 95% CI: 1.12-1.41), which was further confirmed by meta-analysis (P = 1.19E-08, OR = 1.65, 95% CI: 1.38-1.96) in Chinese Han population. Although we did not find any association between this SNP and beta-cell function in either healthy individuals or newly diagnosed T1D patients, healthy individuals carrying GG/GA genotypes had lower CTLA-4 expression in naive or activated CD4 Treg subsets (P = 0.0046 and 0.0317 respectively). A higher positive rate of IA-2A was observed among T1D patients with GG genotype compared with AA (OR = 0.51, 95% CI: 0.30-0.84, p = 0.008). Collectively, CTLA-4 +49 G/A reached a GWAS significant association with T1D risk in Chinese Han population, affects CTLA-4 expression in Treg subsets and subsequently humoral immunity in T1D patients. PMID- 29973666 TI - Graphene oxide polarizes iNKT cells for production of TGFbeta and attenuates inflammation in an iNKT cell-mediated sepsis model. AB - Graphene oxide (GO) modulates the functions of antigen-presenting cells including dendritic cells (DCs). Although carbon nanotubes affect expression of the MHC class I-like CD1d molecule, whether GO can influence immune responses of CD1d dependent invariant natural killer T (iNKT) cells remains unclear. Here, we investigated the impact of GO on inflammatory responses mediated by alpha galactosylceramide (alpha-GalCer), an iNKT cell agonist. We found that in vivo GO treatment substantially inhibited the capacity of alpha-GalCer to induce the iNKT cell-mediated trans-activation of and cytokine production by innate and innate like cells, including DCs, macrophages, NK cells, and gammadelta T cells. Such effects of GO on alpha-GalCer-induced inflammatory responses closely correlated with iNKT cell polarization towards TGFbeta production, which also explains the capacity of GO to expand regulatory T cells. Interestingly, the absence of TLR4, a receptor for GO, failed to downregulate, and instead partially enhanced the anti-inflammatory activity of GO against alpha-GalCer-elicited responses, implying negative effects of TLR4 signaling on the anti-inflammatory properties of GO. By employing an alpha-GalCer-induced sepsis model, we further demonstrated that GO treatment significantly protected mice from alpha-GalCer-induced lethality. Taken together, we provide strong evidence that GO holds promise as an adjuvant to modulate iNKT cell responses for immunotherapy. PMID- 29973667 TI - Optimization of sample preparation and green color imaging using the mNeonGreen fluorescent protein in bacterial cells for photoactivated localization microscopy. AB - mNeonGreen fluorescent protein is capable of photo-switching, hence in principle applicable for super-resolution imaging. However, difficult-to-control blinking kinetics that lead to simultaneous emission of multiple nearby mNeonGreen molecules impedes its use for PALM. Here, we determined the on- and off- switching rate and the influence of illumination power on the simultaneous emission. Increasing illumination power reduces the probability of simultaneous emission, but not enough to generate high quality PALM images. Therefore, we introduce a simple data post-processing step that uses temporal and spatial information of molecule localizations to further reduce artifacts arising from simultaneous emission of nearby emitters. We also systematically evaluated various sample preparation steps to establish an optimized protocol to preserve cellular morphology and fluorescence signal. In summary, we propose a workflow for super-resolution imaging with mNeonGreen based on optimization of sample preparation, data acquisition and simple post-acquisition data processing. Application of our protocol enabled us to resolve the expected double band of bacterial cell division protein DivIVA, and to visualize that the chromosome organization protein ParB organized into sub-clusters instead of the typically observed diffraction-limited foci. We expect that our workflow allows a broad use of mNeonGreen for super-resolution microscopy, which is so far difficult to achieve. PMID- 29973668 TI - MiR-99b-5p and miR-203a-3p Function as Tumor Suppressors by Targeting IGF-1R in Gastric Cancer. AB - MicroRNAs (miRNAs) have been explored in many critical cellular processes, including proliferation and apoptosis. The purpose of this study was to detect the biological function and regulation of miR-99b-5p and miR-203a-3p in gastric cancer (GC). Here, we demonstrated that miR-99b-5p/203a-3p were downregulated in both GC tissues and cell lines. MiR-99b-5p/203a-3p overexpression reduced GC cell proliferation and cell cycle progression in vitro. Notably, we combined bioinformatics tools with biological validation assays to demonstrate that insulin-like growth factor 1 receptor (IGF-1R) is a direct co-target and functional mediator of miR-99b-5p/203a-3p in GC cells. Mechanistically, the AKT pathway, which is downstream of IGF-1R, is essential for the functional roles of miR-99b-5p/203a-3p in GC cells. Taken together, our data revealed that IGF-1R is a direct co-target of miR-99b-5p/203a-3p, and miR-99b-5p/203a-3p may function as tumor suppressive miRNAs by negatively regulating IGF-1R expression in GC cells. PMID- 29973669 TI - Cold weather increases respiratory symptoms and functional disability especially among patients with asthma and allergic rhinitis. AB - Cold weather affects the respiratory epithelium and induces bronchial hyperresponsiveness. We hypothesized that individuals with allergic rhinitis or/and asthma experience cold weather-related functional disability (FD) and exacerbation of health problems (EH) more commonly than individuals without these. This was a population-based study of 7330 adults aged 25-74 years. The determinants of interest, including doctor-diagnosed asthma and allergic rhinitis, and the outcomes, including cold weather-related FD and EH, were measured using a self-administered questionnaire. The prevalences of cold-related FD and EH were 20.3% and 10.3%, respectively. In Poisson regression, the risk of FD increased in relation to both allergic rhinitis (adjusted prevalence ratio (PR) 1.19, 95% CI 1.04-1.37 among men; 1.26, 95% CI 1.08-1.46 among women), asthma (1.29, 0.93-1.80; 1.36, 0.92-2.02, respectively) and their combination (1.16, 0.90-1.50; 1.40, 1.12-1.76, respectively). Also the risk of cold weather related EH was related to both allergic rhinitis (1.53, 1.15,-2.04 among men; 1.78, 1.43-2.21 among women), asthma (4.28, 2.88-6.36; 3.77, 2.67-5.34, respectively) and their combination (4.02, 2.89-5.59; 4.60, 3.69-5.73, respectively). We provide new evidence that subjects with allergic rhinitis or/and asthma are more susceptible to cold weather-related FD and EH than those without pre-existing respiratory diseases. PMID- 29973670 TI - Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy. AB - BACKGROUND: Prescribing anti-programmed death-1 (PD-1) immunotherapy for advanced melanoma is currently not restricted by any biomarker assessment. Determination of programmed death-ligand-1 (PD-L1)-expression status is technically challenging and is not mandatory, because negative tumours also achieve therapeutic responses. However, reproducible biomarkers predictive of a response to anti-PD-1 therapy could contribute to improving therapeutic decision-making. METHODS: This retrospective study on 70 metastatic melanoma patients was undertaken to evaluate the relationships between clinical, histological, immunohistochemical and/or molecular criteria, and the 6-month objective response rate. RESULTS: Better objective response rates were associated with metachronous metastases (P = 0.04), PD-L1 tumour- and/or immune-cell status (P = 0.01), CD163+ histiocytes at advancing edges (P = 0.009) of primary melanomas and NRAS mutation (P = 0.019). Moreover, CD163+ histiocytes at advancing edges (P = 0.04) were associated with longer progression-free survival (PFS), and metachronous metastases with longer overall survival (P = 0.02) and PFS (P = 0.049). CONCLUSIONS: Combining these reproducible biomarkers could help improve therapeutic decision-making for patients with progressive disease. PMID- 29973673 TI - Publisher Correction: DIY goes in vivo. AB - In the version of this Technology Feature originally published, Andre Maia Chagas' lab affiliation was omitted and the name of his institution, The Centre for Integrative Neuroscience, was incorrectly written. This has now been corrected. PMID- 29973672 TI - Two-step breakdown of a SiN membrane for nanopore fabrication: Formation of thin portion and penetration. AB - For the nanopore sensing of various large molecules, such as probe-labelled DNA and antigen-antibody complexes, the nanopore size has to be customized for each target molecule. The recently developed nanopore fabrication method utilizing dielectric breakdown of a membrane is simple and quite inexpensive, but it is somewhat unsuitable for the stable fabrication of a single large nanopore due to the risk of generating multiple nanopores. To overcome this bottleneck, we propose a new technique called "two-step breakdown" (TSB). In the first step of TSB, a local conductive thin portion (not a nanopore) is formed in the membrane by dielectric breakdown. In the second step, the created thin portion is penetrated by voltage pulses whose polarity is opposite to the polarity of the voltage used in the first step. By applying TSB to a 20-nm-thick SiN membrane, a single nanopore with a diameter of 21-26 nm could be fabricated with a high yield of 83%. PMID- 29973674 TI - Author Correction: Hidden hassium. AB - The original version of this In Your Element contained some inaccuracies regarding the stability of fermium, cold and hot fusion techniques, the naming process and chemical investigations; see the correction notice for details. PMID- 29973675 TI - T cells in coeliac disease: a rational target for diagnosis and therapy. PMID- 29973671 TI - Asymptomatic versus Symptomatic Patients with Severe Aortic Stenosis. AB - It is unknown how much different are the clinical outcomes between asymptomatic and symptomatic patients with severe aortic stenosis (AS). In the CURRENT AS registry enrolling 3,815 consecutive patients with severe AS, we compared the long-term outcomes between 1808 asymptomatic and 1215 symptomatic patients (exertional dyspnea: N = 813, syncope: N = 136, and angina: N = 266) without heart failure (HF) hospitalization. Symptomatic patients had greater AS severity, and more depressed left ventricular function than asymptomatic patients without much difference in other baseline characteristics. During a median follow-up of 3.2 years, aortic valve replacement (AVR) was performed in 62% of symptomatic patients, and 38% of asymptomatic patients. The cumulative 5-year incidences for the primary outcome measure (a composite of aortic valve-related death or HF hospitalization) was higher in symptomatic patients than in asymptomatic patients (32.3% versus 27.6%, P < 0.001). After adjusting for AVR and other variables, the greater risk of symptomatic relative to asymptomatic patients for the primary outcome measure was significant (hazard ratio 1.64, 95% confidence interval 1.41 1.96, P < 0.001). In conclusions, the excess risk of symptomatic relative to asymptomatic patients with severe AS for the aortic valve-related event was significant. However, the prevalence of AVR in symptomatic patients was not optimal. PMID- 29973676 TI - The elusive case of human intraepithelial T cells in gut homeostasis and inflammation. AB - The epithelial barrier of the gastrointestinal tract is home to numerous intraepithelial T cells (IETs). IETs are functionally adapted to the mucosal environment and are among the first adaptive immune cells to encounter microbial and dietary antigens. They possess hallmark features of tissue-resident T cells: they are long-lived nonmigratory cells capable of rapidly responding to antigen challenges independent of T cell recruitment from the periphery. Gut-resident T cells have been implicated in the relapsing and remitting course and persisting low-grade inflammation of chronic gastrointestinal diseases, including IBD and coeliac disease. So far, most data IETs have been derived from experimental animal models; however, IETs and the environmental makeup differ between mice and humans. With advances in techniques, the number of human studies has grown exponentially in the past 5 years. Here, we review the literature on the involvement of human IETs in gut homeostasis and inflammation, and how these cells are influenced by the microbiota and dietary antigens. Finally, targeting of IETs in therapeutic interventions is discussed. Broad insight into the function and role of human IETs in gut homeostasis and inflammation is essential to identify future diagnostic, prognostic and therapeutic strategies. PMID- 29973677 TI - Improving breakfast patterns of portuguese children-an evaluation of ready-to-eat cereals according to the European nutrient profile model. AB - BACKGROUND/OBJECTIVES: Ready-to-eat cereal (RTEC) breakfasts have been increasing in Portugal, among children. Eat Mediterranean (EM), a Portuguese comprehensive community-based intervention, proposed to improve breakfast patterns of children and adolescents and to evaluate the healthiness of RTEC according to WHO/Europe nutrient profile model (Euro-NP). SUBJECTS/METHODS: EM Program was developed during two scholar years (15/16 and 16/17) toward 2333 students (pre to secondary education). Data on breakfast was provided using a family record form. The intervention consisted of 257 educational sessions addressing the principles of Mediterranean Diet, and promoting a "healthy breakfast at home". To check for compliance with Euro-NP, RTEC package food labels' nutritional composition was used. RESULTS: After intervention 92.9% of children/adolescents had breakfast daily with no report of breakfast skippers. RTECs were one of the most frequent (66.5%) breakfasts. Statistically significant improvements were showed for: daily qualitative and complete breakfast frequency (5.6%) and fruit (11.2%). Consumption of RTEC decreased 28%. According to Euro-NP, 84.6% of the RTECs were non-compliant, regarding sugar content. Children's RTECs presented 5% more of energy and 26% more sugar than the "non-children's" RTECs. CONCLUSION: EM strategy showed to be a successful program to improve patterns and quality of breakfast of the children and adolescents, reinforcing the importance of school based nutritional programs in changing lifestyles. Nutrient profiling can be a useful tool to provide a selection of foods to be part of a healthy diet and can be used by policy-makers to design policies to identify the foods to which marketing restrictions to children, will apply. PMID- 29973678 TI - Prevalence and risk factors of latent tuberculosis among Korean healthcare workers using whole-blood interferon-gamma release assay. AB - Because healthcare workers (HCWs) are at high risk for tuberculosis (TB) infection, it is essential to research the prevalence of latent TB infection (LTBI) and to implement health interventions including early treatment of LTBI and TB infection control measures. The purpose of the study was to determine the prevalence and risk factors for LTBI using interferon-gamma release assay (IGRA) among HCWs in South Korea. The cross-sectional study was carried in the National Health Insurance Service Ilsan Hospital, which is a 740-bed general hospital, South Korea. HCWs who participated in this survey were required to complete a questionnaire and IGRA was performed. Of the 1,655 HCWs, 271 results were positive and the prevalence of LTBI was 16% (95% CI; 15-18%). In the multivariate analysis, age (OR; 2.201, 95% CI; 1.911-2.536, P < 0.001), male sex (OR; 1.523, 95% CI; 1.133-2.046, P = 0.005), contact active TB patients (OR; 1.461, 95% CI; 1.061-2.010, P = 0.02) and diabetes (OR; 2.837, 95% CI; 1.001-8.044, P = 0.05) were significant risk factors for LTBI. LTBI among HCWs in Korea, although prevalent, might not exceed the background level of the general population. Because contact with active TB patients has been identified as a risk factor for LTBI, more effective TB infection control measures are essential in healthcare facilities and congregate settings. PMID- 29973680 TI - Population genomics of bacterial host adaptation. AB - Some bacteria can transfer to new host species, and this poses a risk to human health. Indeed, an estimated 60% of all human pathogens have originated from other animal species. Similarly, human-to-animal transitions are recognized as a major threat to sustainable livestock production, and emerging pathogens impose an increasing burden on crop yield and global food security. Recent advances in high-throughput sequencing technologies have enabled comparative genomic analyses of bacterial populations from multiple hosts. Such studies are providing new insights into the evolutionary processes that underpin the establishment of bacteria in new host niches. A better understanding of the genetic and mechanistic basis for bacterial host adaptation may reveal novel targets for controlling infection or inform the design of approaches to limit the emergence of new pathogens. PMID- 29973679 TI - Identifying Recrudescent Plasmodium falciparum in Treated Malaria Patients by Real-time PCR and High Resolution Melt Analysis of Genetic Diversity. AB - Recurrent parasitaemia during follow up of clinical trials of antimalarial drug efficacy results from either recrudescence of parasites surviving treatment or from parasites newly emerging from the hepatic stage of infection. Nested PCR is used to distinguish these two possibilities and the technique is difficult to standardise. There is risk of both false positive and false negative results, leading to misclassification errors. The high-resolution melt (HRM) assay was developed with pairs of conserved primers targeting blocks of merozoite surface protein 1 and 2 (msp1 and msp2) genes, and polymorphisms were compared using sequence-confirmed Plasmodium falciparum DNA samples from laboratory isolates. In this study, the HRM dissociation profiles of msp1 and msp2 amplicons were determined and validated against parasite isolates from malaria patients. The msp1 and msp2 profiles of both laboratory and clinical isolates were reproducibly differentiated by HRM. These rapid assays are performed in a closed-tube system, and so avoid cross-contamination while increasing throughput, which are two major advantages. The HRM assays offer significant gains in simplicity, speed and interpretation of results, and reduced analysis cost, for studies that require discrimination of parasite clones. Assay performance in large-scale studies utilizing DNA samples derived from filter-paper bloodspots should now be evaluated. PMID- 29973681 TI - Engineered production of kitasetalic acid, a new tetrahydro-beta-carboline with the ability to suppress glucose-regulated protein synthesis. AB - beta-Carboline alkaloids and related compounds show a broad spectrum of biological activities. We previously identified new members of the beta-carboline alkaloid family by using an engineered Kitasatospora setae strain and a heterologous Streptomyces host expressing the plausible biosynthetic genes, including the hypothetical gene kse_70640 (kslB). Here, we elucidated the chemical structure of a new tetrahydro-beta-carboline compound (named kitasetalic acid) that appeared in a heterologous Streptomyces host expressing the kslB gene alone. Kitasetalic acid suppressed the expression of glucose-regulated protein 78 (GRP78) without inducing cell death. This is the first report to show that a tetrahydro-beta-carboline compound regulates the expression of the GRP78 protein in cancer cell lines. PMID- 29973682 TI - Asperitaconic acids A-C, antibacterial itaconic acid derivatives produced by a marine-derived fungus of the genus Aspergillus. AB - Three new itaconic acid derivatives, asperitaconic acids A-C (1-3), were isolated from the ethyl acetate extracts of the rice fermentation of a marine-derived fungus Aspergillus niger, and asperitaconic acids A-C were characterized by an itaconic acid unit and an alkyl chain moiety. Their structures were established by interpretation of their spectroscopic data including NMR and HRESIMS. Asperitaconic acids A-C exhibited antibacterial effect against Staphylococcus aureus with MIC values of 16-32 MUg/mL, whereas these compounds showed no cytotoxicity against HepG2 and HeLa cancer cell lines. PMID- 29973683 TI - Fungi in perennial ice from Scarisoara Ice Cave (Romania). AB - Screening of 1,000-years old ice layers from the perennial ice block of Scarisoara Ice Cave (NW Romania) revealed the presence of fungal communities. Using culture-dependent methods and molecular techniques based on DGGE fingerprinting of 18S rRNA gene fragments and sequencing, we identified 50 cultured and 14 uncultured fungi in presently-forming, 400 and 900 years old ice layers, corresponding to 28 distinct operational taxonomic units (OTUs). The dominant ice-contained fungal OTUs were related to Ascomycota, Basidiomycota and Cryptomycota phyla. Representatives of Mucoromycota and Chytridiomycota were also isolated from recent and 400 years old ice samples. The cryophilic Mrakia stokesii was the most abundant fungal species found in the cave ice samples of all prospected ages, alongside other cryophilic fungi also identified in various glacial environments. Ice deposits formed during the Little Ice Age (dated between AD 1,250 and 1,850) appeared to have a higher fungal diversity than the ice layer formed during the Medieval Warm Period (prior to AD 1,250). A more complex fungal community adapted to low temperatures was obtained from all analyzed ice layers when cultivated at 4 degrees C as compared to 15 degrees C, suggesting the dominance of cold-adapted fungi in this glacial habitat. The fungal distribution in the analyzed cave ice layers revealed the presence of unique OTUs in different aged-formed ice deposits, as a first hint for putative further identification of fungal biomarkers for climate variations in this icy habitat. This is the first report on fungi from a rock-hosted cave ice block. PMID- 29973684 TI - The functional and inflammatory response of brain endothelial cells to Toll-Like Receptor agonists. AB - Toll-Like receptors (TLRs) represent an important early warning mechanism for the immune system to detect infection or tissue damage. The focus of this research was to determine the neuroinflammatory responses to commercial TLR ligands and their effects on brain endothelial barrier strength. Using biosensor technology we screened TLR ligands to all human TLRs and found that the brain endothelial hCMVECs cell line only responded to Poly(I:C) (TLR3-ligand), LPS (TLR4-ligand) and Imiquimod (TLR7 ligand). Both Poly(I:C) and LPS induced pronounced pro inflammatory cytokine secretion as expected, whereas Imiquimod did not induce secretion of any pro-inflammatory cytokines. Using ECIS technology to measure endothelial barrier function, LPS and Poly(I:C) both acutely reduced barrier strength, whereas Imiquimod caused immediate and sustained strengthening of the barrier. Further cytokine and ECIS studies showed that Imiquimod could abrogate some of the pro-inflammatory responses to Poly(I:C) and LPS. Most surprisingly, PCR revealed that the hCMVECs lacked TLR7 but expressed both TLR3 and TLR4 and did not respond to other structurally different TLR7 ligands. These data demonstrate that brain endothelial cells can be regulated by TLR 3 and TLR4 ligands in a pro-inflammatory manner and have receptors to Imiquimod, distinct to the classical TLR7, that function in an anti-inflammatory manner. PMID- 29973685 TI - Evidence for facultative protocarnivory in Capsella bursa-pastoris seeds. AB - Many plants derive nutrients by attracting, ensnaring and killing invertebrates, a process that is described as "protocarnivory". This has been observed in seeds of the weed Capsella bursa-pastoris, but it is unclear as to whether it confers any material benefit in terms of germination, establishment and development. In the present study, seeds were germinated in zero, low, medium and high nutrient soils in both the presence and absence of nematodes (Steinernema feltiae). Nematodes were attracted to the seeds, with many dying within three days. Germination rates and seedling fresh masses were higher at all nutrient levels, and seedling fresh lengths were higher in all but the zero nutrient treatment, in the presence of nematodes. After transplantation, young plant fresh root lengths and dried leaf and root masses were generally higher in plants that had been germinated in the presence of nematodes across all nutrient levels, with the majority of significant differences being observed in the low-nutrient treatment. Our findings suggest that protocarnivory may play a role in the germination, establishment and early development of C. bursa-pastoris, and that this process may be facultative, since differences between nematode and non-nematode treatments were generally more pronounced in soils with low nutrient levels. PMID- 29973686 TI - Correction: eEF-2 kinase is a critical regulator of Warbrug effect through controlling PP2A-A synthesis. AB - In this article, the authors recently noticed that the tubulin blots in Figs. 2a and 6a were inadvertently misplaced during the preparation of these figures due to their similarity. The amended versions of the figures are now shown below. The conclusions of this paper are not affected. The authors sincerely apologize for these errors. PMID- 29973687 TI - TR4 nuclear receptor promotes clear cell renal cell carcinoma (ccRCC) vasculogenic mimicry (VM) formation and metastasis via altering the miR490 3p/vimentin signals. AB - While TR4 nuclear receptor plays key roles to promote prostate cancer progression, its roles to alter the progression of clear cell renal cell carcinoma (ccRCC), remains unclear. Here, we demonstrate that TR4 can promote the ccRCC cell vasculogenic mimicry (VM) formation and its associated metastasis via modulating the miR490-3p/vimentin (VIM) signals. Mechanism dissection revealed that TR4 might increase the oncogene VIM expression via decreasing the miR-490-3p expression through direct binding to the TR4-response-elements (TR4REs) on the promoter region of miR-490-3p, which might then directly target the 3' UTR of VIM mRNA to increase its protein expression. Preclinical studies using the in vivo mouse model with xenografted RCC Caki-1 cells into the sub-renal capsule of nude mice also found that TR4 could promote the ccRCC VM and its associated metastasis via modulating the miR490-3p/VIM signals. Together, results from preclinical studies using multiple RCC cell lines and the in vivo mouse model all conclude that TR4 may play a key role to promote ccRCC VM formation and metastasis and targeting the newly identified TR4/miR-490-3p/VIM signals with small molecules may help us to develop a new therapeutic approach to better suppress the ccRCC metastasis. PMID- 29973688 TI - Alternative NF-kappaB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3. AB - Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-kappaB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-kappaB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-kappaB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27Kip1 protein level, which inhibits CRC cell proliferation and retards CRC xenograft growth. Conversely, overexpression of RelB increases proliferation of CRC cells. In addition, we revealed a significant correlation between Bcl-3 and RelB in CRC tissues. The expression of RelB was consistent with the expression of Bcl-3 and the phosphorylation of Bcl-3 downstream proteins p-Akt (S473) and p-GSK3beta (S9). Bcl-3 overexpression can restore the phenotype changes caused by RelB knockdown. Importantly, we demonstrated that alternative NF-kappaB transcriptional factor (p52:RelB) can directly bind to the promoter region of Bcl 3 gene and upregulate its transcription. Moreover, the expression of RelB, NF kappaB2 p52, and Bcl-3 was associated with poor survival of CRC patients. Taken together, these results represent that alternative NF-kappaB signaling may function as an oncogenic driver in CRC, and also provide new ideas and research directions for the pathogenesis, prevention, and treatment of other inflammatory related diseases. PMID- 29973689 TI - GREB1 is an estrogen receptor-regulated tumour promoter that is frequently expressed in ovarian cancer. AB - Estrogenic hormone replacement therapy increases the risk of developing ovarian cancer, and estrogen promotes tumour initiation and growth in mouse models of this disease. GREB1 (Growth regulation by estrogen in breast cancer 1) is an ESR1 (estrogen receptor 1)-upregulated protein which may mediate estrogen action. GREB1 knockdown prevents hormone-driven proliferation of several breast and prostate cancer cell lines and prolongs survival of mice engrafted with ovarian cancer cells, but its mechanism of action remains unclear. In this study, we explored GREB1 function in ovarian cancer. GREB1 overexpression in ovarian cancer cell lines increased cell proliferation and migration and promoted a mesenchymal morphology associated with increased Col1a2, which encodes a collagen I subunit. GREB1 knockdown inhibited proliferation and promoted an epithelial morphology associated with decreased Col1a2. In human tissues, GREB1 was expressed in all ESR1-expressing tissues throughout the normal female reproductive tract, in addition to several tissues that did not show ESR1 expression. In a TMA of ovarian cancer cases, GREB1 was expressed in 75-85% of serous, endometrioid, mucinous, and clear cell carcinomas. Serous, endometrioid, and mucinous ovarian cancers were almost always positive for either ESR1 or GREB1, suggesting a possible reliance on signalling through ESR1 and/or GREB1. Targeting GREB1 may inhibit tumour-promoting pathways both downstream and independent of ESR1 and is therefore a possible treatment strategy worthy of further investigation. PMID- 29973690 TI - FBXL14 abolishes breast cancer progression by targeting CDCP1 for proteasomal degradation. AB - Understanding the molecular mechanisms that underlie the aggressive behavior and relapse of breast cancer may help in the development of novel therapeutic interventions. CUB-domain-containing protein 1 (CDCP1), a transmembrane adaptor protein, is highly maintained and required in the context of cellular metastatic potential in triple-negative breast cancer (TNBC). For this reason, gene expression levels of CDCP1 have been considered as a prognostic marker in TNBC. However, not rarely, transcript levels of genes do not reflect always the levels of proteins, due to the post-transcriptional regulation. Here we show that miR 17/20a control the FBXL14 E3 ligase, establishing FBXL14 as an upstream regulator of the CDCP1 pathway. FBXL14 acts as an novel interaction partner of CDCP1, and facilitates its ubiquitination and proteasomal degradation with an enhanced capacity to suppress CDCP1 protein stability that eventually prevents CDCP1 target genes involved in breast cancer metastasis. Our findings first time uncovers the regulatory mechanism of CDCP-1 protein stabilization, more predictable criteria than gene expression levels for prognosis of breast cancer patients. PMID- 29973691 TI - A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. AB - Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research. PMID- 29973692 TI - Ophthalmic findings in linear scleroderma manifesting as facial en coup de sabre. AB - BACKGROUND: To evaluate ophthalmic involvement in a long-term series of patients with en coup de sabre (ECS) close to the eye based on the hypothesis that this is not commonly affected, or simply under-reported. METHODS: An observational study of ophthalmological findings in patients from Copenhagen University Dermatology Clinics. A standard eye examination further included exophthalmometry, axial length and keratometry (IOLMaster), and horizontal eye muscle thickness (B-scan ultrasonography). RESULTS: Thirty-one consecutive patients were included from 2014 to 2015 (25 females, 6 males; median age, 33 years; range, 11-71 years). Twenty-seven patients had undergone ophthalmic evaluation more than once (observation time, 1-31 years; median, 7 years). Most eyes were normal or had currently adapted to eventual adnexal lesions and to insidious changes in eye position and/or motility. However, significant ipsilateral complications had developed related to 8 eyes, where two patients had more than one disorder. The ophthalmic pathologies were: blind eye (n = 2) due to adult age keratopathy/perforation and to Coats-like retinal detachment in childhood; restricted eye motility and diplopia (n = 2); acquired corneal astigmatism (n = 2); and dense cataract with light sense only (n = 1). Two patients had optic neuritis-like presentations, and lacrimal sac pathology occurred in one. CONCLUSIONS: The main ophthalmic focus possibly explained the high proportion of significant lesions in this patient series (in 8 of 31). In addition to the established feature of enophthalmos, the oculometric evidence suggested smaller eye and rectus muscle involvement, interpreted as a secondary (late) negative trophic effect of the overlying skin disorder on eye structures. PMID- 29973693 TI - Factors associated with the presence of parafoveal scotoma in glaucomatous eyes with optic disc hemorrhages. AB - PURPOSE: Glaucomatous eyes with disc hemorrhage (DH) have a greater risk of paracentral visual field (VF) loss. However, not every DH eye presents with parafoveal scotoma (PFS), and contributing factors are still to be determined. In the present study, we investigated clinical and ocular factors associated with the presence of PFS in glaucomatous eyes with DH. METHODS: A case-control study was carried out. One hundred thirty glaucomatous patients with DH were enrolled. They were divided into two groups based on two reliable 24-2 VF tests: those with PFS (defined as >=3 adjacent points with p < 5% within the central 10 degrees of fixation, >=1 point with p < 1% lying at the innermost paracentral points, in the same hemifield) and those without PFS. Clinical and ocular data from the time of DH detection were compared between groups. Factors associated with the presence of PFS were investigated through logistic regression. RESULTS: The PFS group had a higher prevalence of Caucasian patients (82 vs. 47%; p < 0.01). Eyes with PFS had a more negative spherical equivalent and worse VF mean deviation (MD) index (p <= 0.01). There was a marginally significant intraocular pressure (IOP) difference between eyes with (15 mmHg) and without PFS (18 mmHg) at the time of DH detection (p = 0.10). Univariable analysis revealed PFS to be significantly associated with Caucasian race (OR, 3.02; p = 0.004), myopia (<-3 diopters; OR, 3.44; p = 0.039), and lower IOP (<=16 mmHg; OR, 2.10; p <= 0.047). Multivariable analysis, controlling for VF MD, revealed that only Caucasian race and myopia (as a continuous or categorical variable) remained significant in this model (p <= 0.038). CONCLUSIONS: Caucasian race and the presence and magnitude of myopia were found to be significantly associated with the presence of PFS in glaucomatous eyes with DH. Our results may help clinicians in the identification and surveillance of these eyes at higher risk of central VF loss. PMID- 29973694 TI - Does presentation at a national meeting lead to publication? Evaluating the quality of the Scottish Ophthalmological Club. PMID- 29973695 TI - Imaging Dose, Cancer Risk and Cost Analysis in Image-guided Radiotherapy of Cancers. AB - The purpose of this retrospective study is to evaluate the cumulative imaging doses, the associated cancer risk and the cost related to the various radiological imaging procedures in image-guided radiotherapy of cancers. Correlations between patients' size and Monte Carlo simulated organ doses were established and validated for various imaging procedures, and then used for patient-specific organ dose estimation of 4,832 cancer patients. The associated cancer risk was estimated with published models and the cost was calculated based on the standard billing codes. The average (range) cumulative imaging doses to the brain, lungs and red bone marrow were 38.0 (0.5-177.3), 18.8 (0.4-246.5), and 49.1 (0.4-274.4) cGy, respectively. The associated average (range) lifetime attributable risk of cancer incidence per 100,000 persons was 78 (0-2798), 271 (1 8948), and 510 (0-4487) for brain cancer, lung cancer and leukemia, respectively. The median (range) imaging cost was $5256 (4268-15896) for the head scans, $5180 (4268-16274) for the thorax scans, and $7080 (4268-15288) for the pelvic scans, respectively. The image-guidance procedures and the accumulated imaging doses should be incorporated into clinical decision-making to personalize radiotherapy for individual patients. PMID- 29973696 TI - Publisher Correction: Non-invasive imaging through strongly scattering media based on speckle pattern estimation and deconvolution. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29973697 TI - The effect of low vitamin D status on sexual functioning and depressive symptoms in apparently healthy men: a pilot study. AB - Hypovitaminosis D is associated with sexual dysfunction in apparently healthy women and with erectile dysfunction in men with the presence of concomitant disorders. This study was aimed at investigating sexual functioning and depressive symptoms in young men with low vitamin D status. The study included 15 apparently healthy men (18-40 years old) with vitamin D deficiency (group A), 16 subjects with vitamin D insufficiency (group B), and 16 men with normal vitamin D status (group C). All participants of the study completed questionnaires investigating their sexual function (the International Index of Sexual Function 15-IIEF-15 for heterosexual men), as well as the presence and severity of depressive symptoms (Beck Depression Inventory-Second Edition-BDI-II). Compared with healthy men, subjects with vitamin D deficiency obtained lower scores for erectile function, orgasmic function, and sexual desire, while individuals with vitamin D insufficiency lower scores only for erectile function. Erectile dysfunction was more prominent in group A than group B. The total BDI-II score was higher in group A than in the other study groups. The results of the study suggest that low vitamin D status impairs male sexual functioning and severity of sexual dysfunction correlates with the degree of hypovitaminosis D. PMID- 29973698 TI - Resveratrol treatment may preserve the erectile function after radiotherapy by restoring antioxidant defence mechanisms, SIRT1 and NOS protein expressions. AB - Radiotherapy (RT) for prostate cancer (PC) can cause erectile dysfunction (ED) by damaging neurovascular structures with oxidative stress. In this study, we evaluated the effects of resveratrol, an antioxidant, on post-RT ED. Fifty rats in five groups were evaluated; control (C), prostate-confined radiotherapy with short- and long-term vehicle or resveratrol treatment. Cavernosal tissues were obtained to analyze glutathione (GSH), nitric oxide (NO), cyclic guanosine monophosphate (cGMP), 8-hydroxy-2'-deoxy-guanosine (8-OHdG) levels and superoxide dismutase (SOD), caspase-3 activities, sirtuin-1, Foxo-3, nNOS, and eNOS protein expressions. Intracavernosal pressures (ICP) were measured for the long-term treatment group. In the RT + long-term vehicle treatment group, tissue GSH, NO, cGMP, and SOD activity were decreased while 8-OHdg levels and caspase-3 activities were increased. Radiotherapy caused a decrease in sirtuin-1, nNOS, and eNOS protein expressions. These parameters were reversed by resveratrol treatment. Foxo-3 protein expressions were unaltered in the RT + short-term vehicle treatment group and started to increase as a defense mechanism in the RT + long-term vehicle group; however, resveratrol treatment caused a significant increase in Foxo-3 expressions. Resveratrol preserved the metabolic pathways involved in erectile function and provided functional protection. Resveratrol can be used as a supplementary agent in patients undergoing radiotherapy to preserve erectile function. PMID- 29973699 TI - Introducing the ventral sealing technique using collagen fleece for surgical therapy of patients with ventral Peyronie's curvature: initial experience. AB - Ventral penile curvature in Peyronie's disease (PD) is not very common but may lead to inability for sexual intercourse, especially in severe cases > 60 degrees . Ventral curvatures are most often addressed surgically with plication owing to fear of urethral complications, as it requires the mobilisation of the urethra. In this study, the ventral sealing technique is introduced for correction of ventral curvatures in patients with PD. The surgical approach includes the mobilisation of the neurovascular bundle and the urethra. At the point of maximum curvature on the ventral aspect of the penis, a partial plaque excision is performed and the resulting tunical defect is sealed (closed) with a self adhesive collagen fleece (TachoSil(r), Baxter, IL, USA) that does not require suture fixation. Twelve patients with severe ventral curvature were included in this study. Mean penile curvature was 98.3 degrees (sd +/- 27.6, range: 60-150). Mean operative time was 99.2 minutes (sd +/- 12.4, range: 80-130). Mean follow-up was 17.9 months (sd +/- 8.0, range: 9-29). Ten out of 12 patients (83.3%) showed a totally straight penis. Two patients (16.7%) had a residual curvature of < 30 degrees , which did not interfere with sexual intercourse. All patients were able to perform satisfying sexual intercourse. Initial results of the ventral sealing technique are encouraging. However, long-term data are necessary. PMID- 29973700 TI - Exploiting sorghum genetic diversity for enhanced aluminum tolerance: Allele mining based on the AltSB locus. AB - Root damage due to aluminum (Al) toxicity restricts crop production on acidic soils, which are extensive in the tropics. The sorghum root Al-activated citrate transporter, SbMATE, underlies the Al tolerance locus, AltSB, and increases grain yield under Al toxicity. Here, AltSB loci associated with Al tolerance were converted into Amplification Refractory Mutation System (ARMS) markers, which are cost effective and easy to use. A DNA pooling strategy allowed us to identify accessions harboring rare favorable AltSB alleles in three germplasm sets while greatly reducing genotyping needs. Population structure analysis revealed that favorable AltSB alleles are predominantly found in subpopulations enriched with guinea sorghums, supporting a possible Western African origin of AltSB. The efficiency of allele mining in recovering Al tolerance accessions was the highest in the largest and highly diverse germplasm set, with a 10-fold reduction in the number of accessions that would need to be phenotyped in the absence of marker information. Finally, Al tolerant accessions were found to rely on SbMATE to exclude Al3+ from sensitive sites in the root apex. This study emphasizes gene specific markers as important tools for efficiently mining useful rare alleles in diverse germplasm, bridging genetic resource conservation efforts and pre breeding for Al tolerance. PMID- 29973701 TI - Isoquercetin and inulin synergistically modulate the gut microbiome to prevent development of the metabolic syndrome in mice fed a high fat diet. AB - Dietary fibre positively influences gut microbiome composition, enhancing the metabolism of dietary flavonoids to produce bioactive metabolites. These synergistic activities facilitate the beneficial effects of dietary flavonoids on cardiometabolic health parameters. The aims of this study were to investigate whether isoquercetin (a major dietary flavonoid) and inulin (soluble fibre), either alone or in combination could improve features of the metabolic syndrome. Following a 1 week acclimatization, male C57BL6 mice (6-8 weeks) were randomly assigned to; (i) normal chow diet (n = 10), (ii) high fat (HF) diet (n = 10), (iii) HF diet + 0.05% isoquercetin (n = 10), (iv) HF diet + 5% inulin, or (v) HF diet + 0.05% isoquercetin + 5% inulin (n = 10). Body weight and food intake were measured weekly. At 12 weeks, glucose and insulin tolerance tests were performed, and blood, faecal samples, liver, skeletal muscle and adipose tissue were collected. At 12 weeks, mice on the HF diet had significantly elevated body weights as well as impaired glucose tolerance and insulin sensitivity compared to the normal chow mice. Supplementation with either isoquercetin or inulin had no effect, however mice receiving the combination had attenuated weight gain, improved glucose tolerance and insulin sensitivity, reduced hepatic lipid accumulation, adipocyte hypertrophy, circulating leptin and adipose FGF21 levels, compared to mice receiving the HF diet. Additionally, mice on the combination diet had improvements in the composition and functionality of their gut microbiome as well as production of short chain fatty acids. In conclusion, long term supplementation with the dietary flavonoid isoquercetin and the soluble fibre inulin can attenuate development of the metabolic syndrome in mice fed a high fat diet. This protective effect appears to be mediated, in part, through beneficial changes to the microbiome. PMID- 29973702 TI - Electrophysiological evidence of RML12 mosquito cell line towards neuronal differentiation by 20-hydroxyecdysdone. AB - Continuous cell lines from insect larval tissues are widely used in different research domains, such as virology, insect immunity, gene expression, and bio pharmacology. Previous study showed that introduction of 20-hydroxyecdysone to Spodoptera cell line induced a neuron-like morphology with neurite extensions. Despite some results suggesting potential presence of neuro-receptors, no study so far has shown that these neuron-induced cells were functional. Here, using microelectrode arrays, we showed that the mosquito cell line, RML12, differentiated with 20-hydroxyecdysone, displays spontaneous electrophysiological activity. Results showed that these cells can be stimulated by GABAergic antagonist as well as nicotinic agonist. These results provide new evidence of neuron-like functionality of 20-hydroxyecdysone induced differentiated mosquito cell line. Finally, we used this new model to test the effects of two insecticides, temephos and permethrin. Our analysis revealed significant changes in the spiking activity after the introduction of these insecticides with prolonged effect on the neuronal activity. We believe that this differentiated mosquito neuronal cell model can be used for high-throughput screening of new pesticides on insect nervous system instead of primary neurons or in vivo studies. PMID- 29973704 TI - Prospective Assessment of Normal Pancreatic Secretory Function Measured by MRI in a Cohort of Healthy Children. AB - OBJECTIVES: Magnetic resonance imaging (MRI) with secretin stimulation promises to allow non-invasive testing for exocrine pancreatic insufficiency but normal data do not exist for children. The purpose of this study was to define, in healthy children, normal pancreatic secreted fluid volume and secretion rate, measured by MRI, in response to secretin. METHODS: In this Institutional Review Board-approved, prospective, cross-sectional study, 50 healthy children ages 6 to <16 years underwent MRI with secretin stimulation. Images were obtained before and at 1, 5, 10 and 15 min after secretin administration to calculate total secreted fluid volume and secretion rate based on image segmentation. Regression was used to define the relationship between secretory function and participant size measures, and linear quantile regression was used to define normal secretory values based on size measures. RESULTS: Median total secreted fluid volume post secretin was 79 mL (range: 32-162 mL; 5th and 95th percentiles: 43 and 123 mL) and median secretion rate was 5.1 mL/min (range: 2-9.4 mL/min; 5th and 95th percentiles: 2.3 and 7.7 mL/min). Secreted volume and secretion rate had the strongest correlation with body surface area (BSA) (r = 0.54 and 0.59, respectively) and multiple regression defined BSA as the only significant predictor of secretory function. Each 1 m2 increase in BSA was associated with a 38 mL increase in secreted fluid volume. CONCLUSIONS: In children, pancreatic secretory response to secretin, measured by MRI, depends on participant size, particularly BSA. Secreted volume <43 mL or a secretion rate <2.3 mL/min (5th percentile values) can be considered abnormal for children. PMID- 29973703 TI - Author Correction: Strong constraint on modelled global carbon uptake using solar induced chlorophyll fluorescence data. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29973705 TI - Non-Invasive Markers (ALBI and APRI) Predict Pregnancy Outcomes in Women With Chronic Liver Disease. AB - OBJECTIVES: Rates of pregnancy in women with cirrhosis are increasing. Risk of hepatic decompensation during pregnancy, therefore, merits tailored obstetric and hepatology care. Prognostic markers that determine pregnancy outcomes are lacking. METHODS: Medical records of women who attended hepatology clinic at King's College Hospital with chronic liver disease (CLD) who became pregnant from 1983 to 2017 were reviewed. Information on demographics, clinical history, serology, and outcome of pregnancy was collected. RESULTS: In all, 165 pregnancies occurred in 100 women with CLD including 80 pregnancies in 48 women with cirrhosis. Median age of conception in cirrhotic and non-cirrhotic women were 26 years (16-44) and 28 years (16-51) respectively (p = 0.015). Whilst women with cirrhosis had similar live birth rate to non-cirrhotic women (75 vs. 85% p = 0.119), they were significantly less likely to proceed beyond 37 weeks gestation (45 vs. 58% p = 0.033). Women who received preconception counseling were more likely to have stable liver disease at conception (100 vs 86% p = 0.02). Compared with preconception MELD (model for end stage liver disease), preconception Albumin-Bilirubin score (ALBI) more accurately predicted live birth with an area under the receiver-operator curve (AUROC) of 0.741 (p < 0.001), and preconception AST to platelet ratio index (APRI) more accurately predicted ability to proceed beyond 37 weeks gestation with an AUROC of 0.700 (p < 0.001). CONCLUSIONS: Most women with cirrhosis who conceived achieved a successful pregnancy outcome. ALBI and APRI scores can prognosticate pregnancy outcomes in women with CLD. Preconception counseling by a hepatologist or specialist obstetrician improved patient care in this group. PMID- 29973706 TI - Refractory Ascites in Liver Cirrhosis. AB - Ascites, a common complication of liver cirrhosis, eventually becomes refractory to diuretic therapy and sodium restriction in ~10% of patients. Multiple pathogenetic factors are involved in the development of refractory ascites, which ultimately lead to renal hypoperfusion and avid sodium retention. Therefore, renal dysfunction commonly accompanies refractory ascites. Management includes continuation of sodium restriction, which needs frequent reviews for adherence; and regular large volume paracentesis of 5 L or more with albumin infusions to prevent the development of paracentesis-induced circulatory dysfunction. In the appropriate patients with reasonable liver reserve, the insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS) can be considered, especially if the patient is relatively young and has no previous hepatic encephalopathy or anatomical contraindications, and no past history of renal or cardiopulmonary disease. Response to TIPS with ascites clearance can lead to nutritional improvement. Devices such as an automated low-flow ascites pump may be available in the future for ascites treatment. Patients with refractory ascites and poor liver function and/or renal dysfunction, should be referred for liver transplant, as this will eliminate the portal hypertension and liver dysfunction. Renal dysfunction prior to liver transplant largely improves after transplant without affecting post-transplant survival. PMID- 29973707 TI - Comparative proteomic analysis revealed complex responses to classical/novel duck reovirus infections in Cairna moschata. AB - Duck reovirus (DRV) is an typical aquatic bird pathogen belonging to the Orthoreovirus genus of the Reoviridae family. Reovirus causes huge economic losses to the duck industry. Although DRV has been identified and isolated long ago, the responses of Cairna moschata to classical/novel duck reovirus (CDRV/NDRV) infections are largely unknown. To investigate the relationship of pathogenesis and immune response, proteomes of C. moschata liver cells under the C/NDRV infections were analyzed, respectively. In total, 5571 proteins were identified, among which 5015 proteins were quantified. The differential expressed proteins (DEPs) between the control and infected liver cells displayed diverse biological functions and subcellular localizations. Among the DEPs, most of the metabolism-related proteins were down-regulated, suggesting a decrease in the basal metabolisms under C/NDRV infections. Several important factors in the complement, coagulation and fibrinolytic systems were significantly up-regulated by the C/NDRV infections, indicating that the serine protease-mediated innate immune system might play roles in the responses to the C/NDRV infections. Moreover, a number of molecular chaperones were identified, and no significantly changes in their abundances were observed in the liver cells. Our data may give a comprehensive resource for investigating the regulation mechanism involved in the responses of C. moschata to the C/NDRV infections. PMID- 29973708 TI - Identification of genes underlying the enhancement of immunity by a formula of lentinan, pachymaran and tremelia polysaccharides in immunosuppressive mice. AB - The efficacy of polysaccharides is widespread, especially in immune regulation. However, the genetic basis of the changes in polysaccharides regulating immunity is unclear. To obtain genome-wide insights into transcriptome changes and regulatory networks, we designed a polysaccharide formula, comprising lentinan, pachymaran and tremelia, to increase the availability of their optimized active sites. In this case, we focused on a model of immunosuppression to investigate genes by digital gene expression (DGE) tag profiling in T and B cells. These genes were further validated by qRT-PCR and Western blot experiments. Consequently, polysaccharide formula treatment helped to recover the expression of immune-related genes, including CADM1, CCR2, IGLL1, LIGP1, and FCGR3, FCGR2 in B cells, as well as S100A8, S100A9, ChIL3, MMP8 and IFITM3 in T cells. These results suggest that treatment with polysaccharides improves the immunity of immunosuppressive mice by regulating genes associated with T and B cell functions. PMID- 29973709 TI - Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. AB - In patients with manifestations of cardiovascular disease, acetylsalicylic acid (popularly known as aspirin) has been the mainstay of treatment for decades owing to its capacity to reduce the risk of ischaemic events. Accordingly, novel antithrombotic therapies have been traditionally tested on a background of acetylsalicylic acid therapy. Although the adjunctive use of such antithrombotic therapies can potentially further reduce the risk of ischaemic events, these agents are also inevitably associated with an increased risk of bleeding. However, acetylsalicylic acid also increases the risk of bleeding, challenging the paradigm that this agent should remain the cornerstone of antiplatelet treatment when alternative antithrombotic agents are also used. Many antithrombotic compounds are characterized by increased potency and consistent efficacy, which might lessen the need for concomitant acetylsalicylic acid. Accordingly, numerous investigations are testing the hypothesis that acetylsalicylic acid-sparing regimens based on newer antithrombotic agents might have an increased net benefit for individual patients owing to the reduction in bleeding risk, without a trade-off in efficacy. This Review summarizes the state of the art relating to antithrombotic approaches with and without acetylsalicylic acid for the prevention of cardiovascular disease and cardioembolic stroke. Discussion of the scientific rationale, from bench to bedside, for ongoing studies of acetylsalicylic acid-free pharmacological strategies is included. PMID- 29973710 TI - The complex molecular genetics of familial hypercholesterolaemia. AB - Familial hypercholesterolaemia is the most commonly encountered genetic condition that predisposes individuals to premature cardiovascular disease. Nevertheless, most patients are undiagnosed, and treatment is often suboptimal even when the diagnosis seems certain. Advances in molecular technologies are reshaping our understanding of this condition, including revision upwards of the population prevalence. Furthermore, the underlying pathophysiological complexity has been exposed by the range of causative genetic loci, breadth of types and classes of rare disease-causing variants, and polygenic basis of the phenotype in many patients. Genetic testing is not always helpful or definitive. Familial hypercholesterolaemia can be envisioned as a group of related disorders, of which the classic 'textbook' phenotype is a subset. Features such as clinical stigmata, family history of dyslipidaemia or cardiovascular disease, and presence of a rare pathogenic variant all increase diagnostic certainty. However, even in the absence of these elements, the essential feature remains an elevated level of plasma LDL cholesterol, which alone should prompt a dialogue between the care provider and the patient on lifestyle modification and lipid-lowering therapy as the foundation of a long-term strategy to prevent or delay the onset of cardiovascular disease. PMID- 29973711 TI - Author Correction: Reduced mutation rate in exons due to differential mismatch repair. AB - In the version of this article initially published, the x axis on the fourth plot in Fig. 2e was incorrectly labeled "H3K36me3 exon-to-intron ratio (lower to higher)." The x axis on this plot should read "Genic H3K36me3 coverage bins (higher to lower)". PMID- 29973713 TI - Author Correction: Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. AB - In Fig. 2g of this Article, a panel was inadvertently duplicated. The 'D30 IMQ' image was a duplicate of the 'D6 Ctrl' image. Fig. 2g has been corrected online to show the correct 'D30 IMQ' image (showing skin inflammation induced by the NALP3 agonist imiquimod, IMQ). The Supplementary Information to this Amendment contains the old, incorrect Fig. 2 for transparency. PMID- 29973712 TI - Analysis of the Gut Microbiome of Rural and Urban Healthy Indians Living in Sea Level and High Altitude Areas. AB - The diversity and basic functional attributes of the gut microbiome of healthy Indians is not well understood. This study investigated the gut microbiome of three Indian communities: individuals residing in rural and urban (n = 49) sea level Ballabhgarh areas and in rural high altitude areas of Leh, Ladakh in North India (n = 35). Our study revealed that the gut microbiome of Indian communities is dominated by Firmicutes followed by Bacteroidetes, Actinobateria and Proteobacteria. Although, 54 core bacterial genera were detected across the three distinct communities, the gut bacterial composition displayed specific signatures and was observed to be influenced by the topographical location and dietary intake of the individuals. The gut microbiome of individuals living in Leh was observed to be significantly similar with a high representation of Bacteroidetes and low abundance of Proteobacteria. In contrast, the gut microbiome of individuals living in Ballabhgarh areas harbored higher number of Firmicutes and Proteobacteria and is enriched with microbial xenobiotic degradation pathways. The rural community residing in sea level Ballabhgarh areas has unique microbiome characterized not only by a higher diversity, but also a higher degree of interindividual homogeneity. PMID- 29973714 TI - Author Correction: Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. AB - In this Article, the sentence: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent coding mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).", should have read: "After 7 months of HFD, MUP-uPA mice developed HCC15, which contained numerous (usually 50-100 per tumour) non-recurrent mutations in pathways that are mutated in human HCC (Fig. 2d and Extended Data Fig. 6a).". This has been corrected online. In Extended Data Fig. 6a and b, which show the number of point mutations identified per sample and the mutational signatures, all sequence variants (including non-coding mutations) are shown. Fig. 2d also presents all variants compared to human mutations. In the Supplementary Information to this Amendment, we now provide the comparisons of all variants and coding variants to human mutations. PMID- 29973715 TI - Retraction Note: DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. AB - Change History: This Article has been retracted; see accompanying Retraction. Corrected online 20 January: In this Article, author Frank Rigo was incorrectly listed with a middle initial; this has been corrected in the online versions of the paper. PMID- 29973716 TI - Publisher Correction: An extracellular network of Arabidopsis leucine-rich repeat receptor kinases. AB - In this Letter, an incorrect version of the Supplementary Information file was inadvertently used, which contained several errors. The details of references 59 65 were missing from the end of the Supplementary Discussion section on page 4. In addition, the section 'Text 3. Y2H on ICD interactions' incorrectly referred to 'Extended Data Fig. 4d' instead of 'Extended Data Fig. 3d' on page 3. Finally, the section 'Text 4. Interaction network analysis' incorrectly referred to 'Fig. 1b and Extended Data Fig. 6' instead of 'Fig. 2b and Extended Data Fig. 7' on page 3. These errors have all been corrected in the Supplementary Information. PMID- 29973718 TI - Evolution of cooperation in stochastic games. AB - Social dilemmas occur when incentives for individuals are misaligned with group interests1-7. According to the 'tragedy of the commons', these misalignments can lead to overexploitation and collapse of public resources. The resulting behaviours can be analysed with the tools of game theory8. The theory of direct reciprocity9-15 suggests that repeated interactions can alleviate such dilemmas, but previous work has assumed that the public resource remains constant over time. Here we introduce the idea that the public resource is instead changeable and depends on the strategic choices of individuals. An intuitive scenario is that cooperation increases the public resource, whereas defection decreases it. Thus, cooperation allows the possibility of playing a more valuable game with higher payoffs, whereas defection leads to a less valuable game. We analyse this idea using the theory of stochastic games16-19 and evolutionary game theory. We find that the dependence of the public resource on previous interactions can greatly enhance the propensity for cooperation. For these results, the interaction between reciprocity and payoff feedback is crucial: neither repeated interactions in a constant environment nor single interactions in a changing environment yield similar cooperation rates. Our framework shows which feedbacks between exploitation and environment-either naturally occurring or designed-help to overcome social dilemmas. PMID- 29973717 TI - CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. AB - The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination1. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein-DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins1-4. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor1. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair5. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically. PMID- 29973719 TI - Species-specific activity of antibacterial drug combinations. AB - The spread of antimicrobial resistance has become a serious public health concern, making once-treatable diseases deadly again and undermining the achievements of modern medicine1,2. Drug combinations can help to fight multi drug-resistant bacterial infections, yet they are largely unexplored and rarely used in clinics. Here we profile almost 3,000 dose-resolved combinations of antibiotics, human-targeted drugs and food additives in six strains from three Gram-negative pathogens-Escherichia coli, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa-to identify general principles for antibacterial drug combinations and understand their potential. Despite the phylogenetic relatedness of the three species, more than 70% of the drug-drug interactions that we detected are species-specific and 20% display strain specificity, revealing a large potential for narrow-spectrum therapies. Overall, antagonisms are more common than synergies and occur almost exclusively between drugs that target different cellular processes, whereas synergies are more conserved and are enriched in drugs that target the same process. We provide mechanistic insights into this dichotomy and further dissect the interactions of the food additive vanillin. Finally, we demonstrate that several synergies are effective against multi-drug-resistant clinical isolates in vitro and during infections of the larvae of the greater wax moth Galleria mellonella, with one reverting resistance to the last-resort antibiotic colistin. PMID- 29973720 TI - Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13. AB - The maintenance of genome stability during mitosis is coordinated by the spindle assembly checkpoint (SAC) through its effector the mitotic checkpoint complex (MCC), an inhibitor of the anaphase-promoting complex (APC/C, also known as the cyclosome)1,2. Unattached kinetochores control MCC assembly by catalysing a change in the topology of the beta-sheet of MAD2 (an MCC subunit), thereby generating the active closed MAD2 (C-MAD2) conformer3-5. Disassembly of free MCC, which is required for SAC inactivation and chromosome segregation, is an ATP dependent process driven by the AAA+ ATPase TRIP13. In combination with p31comet, an SAC antagonist6, TRIP13 remodels C-MAD2 into inactive open MAD2 (O-MAD2)7-10. Here, we present a mechanism that explains how TRIP13-p31comet disassembles the MCC. Cryo-electron microscopy structures of the TRIP13-p31comet-C-MAD2-CDC20 complex reveal that p31comet recruits C-MAD2 to a defined site on the TRIP13 hexameric ring, positioning the N terminus of C-MAD2 (MAD2NT) to insert into the axial pore of TRIP13 and distorting the TRIP13 ring to initiate remodelling. Molecular modelling suggests that by gripping MAD2NT within its axial pore, TRIP13 couples sequential ATP-driven translocation of its hexameric ring along MAD2NT to push upwards on, and simultaneously rotate, the globular domains of the p31comet-C-MAD2 complex. This unwinds a region of the alphaA helix of C-MAD2 that is required to stabilize the C-MAD2 beta-sheet, thus destabilizing C-MAD2 in favour of O-MAD2 and dissociating MAD2 from p31comet. Our study provides insights into how specific substrates are recruited to AAA+ ATPases through adaptor proteins and suggests a model of how translocation through the axial pore of AAA+ ATPases is coupled to protein remodelling. PMID- 29973722 TI - Structure of the origin recognition complex bound to DNA replication origin. AB - The six-subunit origin recognition complex (ORC) binds to DNA to mark the site for the initiation of replication in eukaryotes. Here we report a 3 A cryo electron microscopy structure of the Saccharomyces cerevisiae ORC bound to a 72 base-pair origin DNA sequence that contains the ARS consensus sequence (ACS) and the B1 element. The ORC encircles DNA through extensive interactions with both phosphate backbone and bases, and bends DNA at the ACS and B1 sites. Specific recognition of thymine residues in the ACS is carried out by a conserved basic amino acid motif of Orc1 in the minor groove, and by a species-specific helical insertion motif of Orc4 in the major groove. Moreover, similar insertions into major and minor grooves are also embedded in the B1 site by basic patch motifs from Orc2 and Orc5, respectively, to contact bases and to bend DNA. This work pinpoints a conserved role of ORC in modulating DNA structure to facilitate origin selection and helicase loading in eukaryotes. PMID- 29973723 TI - Targeting STING with covalent small-molecule inhibitors. AB - Aberrant activation of innate immune pathways is associated with a variety of diseases. Progress in understanding the molecular mechanisms of innate immune pathways has led to the promise of targeted therapeutic approaches, but the development of drugs that act specifically on molecules of interest remains challenging. Here we report the discovery and characterization of highly potent and selective small-molecule antagonists of the stimulator of interferon genes (STING) protein, which is a central signalling component of the intracellular DNA sensing pathway1,2. Mechanistically, the identified compounds covalently target the predicted transmembrane cysteine residue 91 and thereby block the activation induced palmitoylation of STING. Using these inhibitors, we show that the palmitoylation of STING is essential for its assembly into multimeric complexes at the Golgi apparatus and, in turn, for the recruitment of downstream signalling factors. The identified compounds and their derivatives reduce STING-mediated inflammatory cytokine production in both human and mouse cells. Furthermore, we show that these small-molecule antagonists attenuate pathological features of autoinflammatory disease in mice. In summary, our work uncovers a mechanism by which STING can be inhibited pharmacologically and demonstrates the potential of therapies that target STING for the treatment of autoinflammatory disease. PMID- 29973721 TI - The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. AB - Extracellular ATP (eATP) is an ancient 'danger signal' used by eukaryotes to detect cellular damage1. In mice and humans, the release of eATP during inflammation or injury stimulates both innate immune activation and chronic pain through the purinergic receptor P2RX72-4. It is unclear, however, whether this pathway influences the generation of immunological memory, a hallmark of the adaptive immune system that constitutes the basis of vaccines and protective immunity against re-infection5,6. Here we show that P2RX7 is required for the establishment, maintenance and functionality of long-lived central and tissue resident memory CD8+ T cell populations in mice. By contrast, P2RX7 is not required for the generation of short-lived effector CD8+ T cells. Mechanistically, P2RX7 promotes mitochondrial homeostasis and metabolic function in differentiating memory CD8+ T cells, at least in part by inducing AMP activated protein kinase. Pharmacological inhibitors of P2RX7 provoked dysregulated metabolism and differentiation of activated mouse and human CD8+ T cells in vitro, and transient P2RX7 blockade in vivo ameliorated neuropathic pain but also compromised production of CD8+ memory T cells. These findings show that activation of P2RX7 by eATP provides a common currency that both alerts the nervous and immune system to tissue damage, and promotes the metabolic fitness and survival of the most durable and functionally relevant memory CD8+ T cell populations. PMID- 29973724 TI - Kinase-controlled phase transition of membraneless organelles in mitosis. AB - Liquid-liquid phase separation has been shown to underlie the formation and disassembly of membraneless organelles in cells, but the cellular mechanisms that control this phenomenon are poorly understood. A prominent example of regulated and reversible segregation of liquid phases may occur during mitosis, when membraneless organelles disappear upon nuclear-envelope breakdown and reappear as mitosis is completed. Here we show that the dual-specificity kinase DYRK3 acts as a central dissolvase of several types of membraneless organelle during mitosis. DYRK3 kinase activity is essential to prevent the unmixing of the mitotic cytoplasm into aberrant liquid-like hybrid organelles and the over-nucleation of spindle bodies. Our work supports a mechanism in which the dilution of phase separating proteins during nuclear-envelope breakdown and the DYRK3-dependent degree of their solubility combine to allow cells to dissolve and condense several membraneless organelles during mitosis. PMID- 29973726 TI - An inverse latitudinal gradient in speciation rate for marine fishes. AB - Far more species of organisms are found in the tropics than in temperate and polar regions, but the evolutionary and ecological causes of this pattern remain controversial1,2. Tropical marine fish communities are much more diverse than cold-water fish communities found at higher latitudes3,4, and several explanations for this latitudinal diversity gradient propose that warm reef environments serve as evolutionary 'hotspots' for species formation5-8. Here we test the relationship between latitude, species richness and speciation rate across marine fishes. We assembled a time-calibrated phylogeny of all ray-finned fishes (31,526 tips, of which 11,638 had genetic data) and used this framework to describe the spatial dynamics of speciation in the marine realm. We show that the fastest rates of speciation occur in species-poor regions outside the tropics, and that high-latitude fish lineages form new species at much faster rates than their tropical counterparts. High rates of speciation occur in geographical regions that are characterized by low surface temperatures and high endemism. Our results reject a broad class of mechanisms under which the tropics serve as an evolutionary cradle for marine fish diversity and raise new questions about why the coldest oceans on Earth are present-day hotspots of species formation. PMID- 29973725 TI - Single-cell analysis of early progenitor cells that build coronary arteries. AB - Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre existing veins through a poorly understood process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors. PMID- 29973727 TI - Scaling up molecular pattern recognition with DNA-based winner-take-all neural networks. AB - From bacteria following simple chemical gradients1 to the brain distinguishing complex odour information2, the ability to recognize molecular patterns is essential for biological organisms. This type of information-processing function has been implemented using DNA-based neural networks3, but has been limited to the recognition of a set of no more than four patterns, each composed of four distinct DNA molecules. Winner-take-all computation4 has been suggested5,6 as a potential strategy for enhancing the capability of DNA-based neural networks. Compared to the linear-threshold circuits7 and Hopfield networks8 used previously3, winner-take-all circuits are computationally more powerful4, allow simpler molecular implementation and are not constrained by the number of patterns and their complexity, so both a large number of simple patterns and a small number of complex patterns can be recognized. Here we report a systematic implementation of winner-take-all neural networks based on DNA-strand displacement9,10 reactions. We use a previously developed seesaw DNA gate motif3,11,12, extended to include a simple and robust component that facilitates the cooperative hybridization13 that is involved in the process of selecting a 'winner'. We show that with this extended seesaw motif DNA-based neural networks can classify patterns into up to nine categories. Each of these patterns consists of 20 distinct DNA molecules chosen from the set of 100 that represents the 100 bits in 10 * 10 patterns, with the 20 DNA molecules selected tracing one of the handwritten digits '1' to '9'. The network successfully classified test patterns with up to 30 of the 100 bits flipped relative to the digit patterns 'remembered' during training, suggesting that molecular circuits can robustly accomplish the sophisticated task of classifying highly complex and noisy information on the basis of similarity to a memory. PMID- 29973728 TI - Author Correction: Hyperexpandable, self-healing macromolecular crystals with integrated polymer networks. AB - Change history: In this Letter, Alexander Groisman should have been listed as an author. This error has been corrected online. PMID- 29973730 TI - The role of nephrectomy in metastatic renal cell carcinoma. PMID- 29973729 TI - Author Correction: Environment and host as large-scale controls of ectomycorrhizal fungi. AB - Change history: In the HTML version of this Article, author 'Filipa Cox' had no affiliation in the author list, although she was correctly associated with affiliation 3 in the PDF. In addition, the blue circles for 'oak' were missing from Extended Data Fig. 1. These errors have been corrected online. PMID- 29973731 TI - Structural insights into G-protein-coupled receptor allostery. AB - G-protein-coupled receptors (GPCRs) are key cell-surface proteins that transduce external environmental cues into biochemical signals across the membrane. GPCRs are intrinsically allosteric proteins; they interact via spatially distinct yet conformationally linked domains with both endogenous and exogenous proteins, nutrients, metabolites, hormones, small molecules and biological agents. Here we explore recent high-resolution structural studies, which are beginning to unravel the atomic details of allosteric transitions that govern GPCR biology, as well as highlighting how the wide diversity of druggable allosteric sites across these receptors present opportunities for developing new classes of therapeutics. PMID- 29973732 TI - Spatial correlation bias in late-Cenozoic erosion histories derived from thermochronology. AB - The potential link between erosion rates at the Earth's surface and changes in global climate has intrigued geoscientists for decades1,2 because such a coupling has implications for the influence of silicate weathering3,4 and organic-carbon burial5 on climate and for the role of Quaternary glaciations in landscape evolution1,6. A global increase in late-Cenozoic erosion rates in response to a cooling, more variable climate has been proposed on the basis of worldwide sedimentation rates7. Other studies have indicated, however, that global erosion rates may have remained steady, suggesting that the reported increases in sediment-accumulation rates are due to preservation biases, depositional hiatuses and varying measurement intervals8-10. More recently, a global compilation of thermochronology data has been used to infer a nearly twofold increase in the erosion rate in mountainous landscapes over late-Cenozoic times6. It has been contended that this result is free of the biases that affect sedimentary records11, although others have argued that it contains biases related to how thermochronological data are averaged12 and to erosion hiatuses in glaciated landscapes13. Here we investigate the 30 locations with reported accelerated erosion during the late Cenozoic6. Our analysis shows that in 23 of these locations, the reported increases are a result of a spatial correlation bias-that is, combining data with disparate exhumation histories, thereby converting spatial erosion-rate variations into temporal increases. In four locations, the increases can be explained by changes in tectonic boundary conditions. In three cases, climatically induced accelerations are recorded, driven by localized glacial valley incision. Our findings suggest that thermochronology data currently have insufficient resolution to assess whether late-Cenozoic climate change affected erosion rates on a global scale. We suggest that a synthesis of local findings that include location-specific information may help to further investigate drivers of global erosion rates. PMID- 29973733 TI - Universality of free fall from the orbital motion of a pulsar in a stellar triple system. AB - Einstein's theory of gravity-the general theory of relativity1-is based on the universality of free fall, which specifies that all objects accelerate identically in an external gravitational field. In contrast to almost all alternative theories of gravity2, the strong equivalence principle of general relativity requires universality of free fall to apply even to bodies with strong self-gravity. Direct tests of this principle using Solar System bodies3,4 are limited by the weak self-gravity of the bodies, and tests using pulsar-white dwarf binaries5,6 have been limited by the weak gravitational pull of the Milky Way. PSR J0337+1715 is a hierarchical system of three stars (a stellar triple system) in which a binary consisting of a millisecond radio pulsar and a white dwarf in a 1.6-day orbit is itself in a 327-day orbit with another white dwarf. This system permits a test that compares how the gravitational pull of the outer white dwarf affects the pulsar, which has strong self-gravity, and the inner white dwarf. Here we report that the accelerations of the pulsar and its nearby white-dwarf companion differ fractionally by no more than 2.6 * 10-6. For a rough comparison, our limit on the strong-field Nordtvedt parameter, which measures violation of the universality of free fall, is a factor of ten smaller than that obtained from (weak-field) Solar System tests3,4 and a factor of almost a thousand smaller than that obtained from other strong-field tests5,6. PMID- 29973734 TI - A better measure of research from the global south. PMID- 29973735 TI - Advance the ecosystem approach in cities. PMID- 29973736 TI - Microscope damage, reef recovery and disappearing trees. PMID- 29973737 TI - The labs growing human embryos for longer than ever before. PMID- 29973738 TI - Lights, Chemicals, Action: Studying Red Worms' Responses to Environmental Contaminants. AB - We have developed an experimental module that introduces high school students to guided scientific inquiry. It is designed to incorporate environmental health and ecological concepts into the basic biology or environmental-science content of the high school curriculum. Using the red worm, a familiar live species that is amenable to classroom experimentation, students learn how environmental agents affect the animal's locomotion by altering sensory neuron-muscle interactions and, as a result, influence its distribution in nature. In turn, the results of these experiments have direct application to human-caused environmental disruptions that cause changes in species distribution and indirectly increase the recognition that environmental chemicals affect human health. Students undertake a series of explorations to identify how red worms sense their environment and then apply that knowledge to understand the effects of chemical exposure on locomotor behavior. The activities are designed to generate critical thinking about neuromuscular processes and environmental pollutants that affect them. PMID- 29973739 TI - Discovery of the elusive radical NCO and confirmation of H2NCO+ in space. AB - The isocyanate radical (NCO) is the simplest molecule containing the backbone of the peptide bond, C(=O)-N. This bond has a prebiotic interest since is the one linking two amino acids to form large chains of proteins. It is also present in some organic molecules observed in space such as HNCO, NH2CHO and CH3NCO. In this letter we report the first detection in space of NCO towards the dense core L483. We also report the identification of the ion H2NCO+, definitively confirming its presence in space, and observations of HNCO, HOCN, and HCNO in the same source. For NCO, we derive a column density of 2.2*1012 cm-2, which means that it is only ~5 times less abundant than HNCO. We find that H2NCO+, HOCN and HCNO have abundances relative to HNCO of 1/400, 1/80, and 1/160, respectively. Both NCO and H2NCO+ are involved in the production of HNCO and several of its isomers. We have updated our previous chemical models involving NCO and the production of the CHNO isomers. Taking into account the uncertainties in the model, the observed abundances are reproduced relatively well. Indeed, the detection of NCO and H2NCO+ in L483 supports the chemical pathways to the formation of the detected CHNO isomers. Sensitive observations of NCO in sources where other molecules containing the C(=O)-N subunit have been detected could help in elucidating its role in prebiotic chemistry in space. PMID- 29973740 TI - Data assimilation for the heat equation using stabilized finite element methods. AB - We consider data assimilation for the heat equation using a finite element space semi-discretization. The approach is optimization based, but the design of regularization operators and parameters rely on techniques from the theory of stabilized finite elements. The space semi-discretized system is shown to admit a unique solution. Combining sharp estimates of the numerical stability of the discrete scheme and conditional stability estimates of the ill-posed continuous pde-model we then derive error estimates that reflect the approximation order of the finite element space and the stability of the continuous model. Two different data assimilation situations with different stability properties are considered to illustrate the framework. Full detail on how to adapt known stability estimates for the continuous model to work with the numerical analysis framework is given in "Appendix". PMID- 29973741 TI - Stable polefinding and rational least-squares fitting via eigenvalues. AB - A common way of finding the poles of a meromorphic function f in a domain, where an explicit expression of f is unknown but f can be evaluated at any given z, is to interpolate f by a rational function pq such that r(gammai)=f(gammai) at prescribed sample points {gammai}i=1L , and then find the roots of q. This is a two-step process and the type of the rational interpolant needs to be specified by the user. Many other algorithms for polefinding and rational interpolation (or least-squares fitting) have been proposed, but their numerical stability has remained largely unexplored. In this work we describe an algorithm with the following three features: (1) it automatically finds an appropriate type for a rational approximant, thereby allowing the user to input just the function f, (2) it finds the poles via a generalized eigenvalue problem of matrices constructed directly from the sampled values f(gammai) in a one-step fashion, and (3) it computes rational approximants p^,q^ in a numerically stable manner, in that (p^+Deltap)/(q^+Deltaq)=f with small Deltap,Deltaq at the sample points, making it the first rational interpolation (or approximation) algorithm with guaranteed numerical stability. Our algorithm executes an implicit change of polynomial basis by the QR factorization, and allows for oversampling combined with least squares fitting. Through experiments we illustrate the resulting accuracy and stability, which can significantly outperform existing algorithms. PMID- 29973742 TI - Stability and error analysis for a diffuse interface approach to an advection diffusion equation on a moving surface. AB - In this paper we analyze a fully discrete numerical scheme for solving a parabolic PDE on a moving surface. The method is based on a diffuse interface approach that involves a level set description of the moving surface. Under suitable conditions on the spatial grid size, the time step and the interface width we obtain stability and error bounds with respect to natural norms. Furthermore, we present test calculations that confirm our analysis. PMID- 29973743 TI - Stereocontrolled Synthesis of Quaternary beta,gamma-Unsaturated Amino Acids: Chain Extension of D- & L- alpha-(2-Tributylstannyl)Vinyl Amino Acids. AB - A pair of diastereomeric (4S,5S)- and (4S,5R)-4-methoxycarbonyl-5 phenylselenomethyl-2-phenyl oxazolines, derived from L-vinylglycine, serve as precursors to protected, quaternary, L- and D-alpha-(2-tributylstannyl)vinyl amino acids, respectively, in three steps {(i) alkylative side chain installation, (ii) eliminative ring-opening and (iii) vinyl selenide to vinyl stannane interconversion}. The title compounds may be protodestannylated to the corresponding free, quaternary L- and D-vinyl amino acids. Alternatively, the 2 stannylvinyl alpha-branch (or the derivative 2-iodovinyl branch) may be exploited to access novel quaternary, L- and D-beta,gamma-unsaturated amino acids via a range of transition metal-mediated cross coupling reactions. PMID- 29973744 TI - Practical, efficient, and broadly applicable synthesis of readily differentiable vicinal diboronate compounds by catalytic three-component reactions. AB - A practical, efficient and broadly applicable catalytic method for synthesis of easily differentiable vicinal diboronate compounds is presented. Reactions are promoted by a combination of PCy3 or PPh3, CuCl and LiOt-Bu and may be performed with readily accessible alkenyl boronate substrates. Through the use of an alkenyl-B(pin) (pin = pinacolato) or alkenyl- B(dan) (dan = naphthalene-1,8 diaminato) starting material and commercially available (pin)B- B(dan) or B2(pin)2 as the reagent, a range of vicinal diboronates, including those that contain a B-substituted quaternary carbon center, may be prepared in up to 91% yield and with >98% site selectivity. High enantioselectivities can be obtained (up to 96:4 er) through the use of commercially available chiral bis-phosphine ligands for reactions that afford mixed diboronate products. PMID- 29973745 TI - AVOCADO: Visualization of Workflow-Derived Data Provenance for Reproducible Biomedical Research. AB - A major challenge in data-driven biomedical research lies in the collection and representation of data provenance information to ensure that findings are reproducibile. In order to communicate and reproduce multi-step analysis workflows executed on datasets that contain data for dozens or hundreds of samples, it is crucial to be able to visualize the provenance graph at different levels of aggregation. Most existing approaches are based on node-link diagrams, which do not scale to the complexity of typical data provenance graphs. In our proposed approach, we reduce the complexity of the graph using hierarchical and motif-based aggregation. Based on user action and graph attributes, a modular degree-of-interest (DoI) function is applied to expand parts of the graph that are relevant to the user. This interest-driven adaptive approach to provenance visualization allows users to review and communicate complex multi-step analyses, which can be based on hundreds of files that are processed by numerous workflows. We have integrated our approach into an analysis platform that captures extensive data provenance information, and demonstrate its effectiveness by means of a biomedical usage scenario. PMID- 29973746 TI - A holographic waveguide based eye tracker. AB - We demonstrated the feasibility of using holographic waveguide for eye tracking. A custom-built holographic waveguide, a 20 mm x 60 mm x 3 mm flat glass substrate with integrated in- and out-couplers, was used for the prototype development. The in- and out-couplers, photopolymer films with holographic fringes, induced total internal reflection in the glass substrate. Diffractive optical elements were integrated into the in-coupler to serve as an optical collimator. The waveguide captured images of the anterior segment of the eye right in front of it and guided the images to a processing unit distant from the eye. The vector connecting the pupil center (PC) and the corneal reflex (CR) of the eye was used to compute eye position in the socket. An eye model, made of a high quality prosthetic eye, was used prototype validation. The benchtop prototype demonstrated a linear relationship between the angular eye position and the PC/CR vector over a range of 60 horizontal degrees and 30 vertical degrees at a resolution of 0.64-0.69 degrees/pixel by simple pixel count. The uncertainties of the measurements at different angular positions were within 1.2 pixels, which indicated that the prototype exhibited a high level of repeatability. These results confirmed that the holographic waveguide technology could be a feasible platform for developing a wearable eye tracker. Further development can lead to a compact, see-through eye tracker, which allows continuous monitoring of eye movement during real life tasks, and thus benefits diagnosis of oculomotor disorders. PMID- 29973747 TI - Range-constrained co-occurrence simulation reveals little niche partitioning among rock-dwelling Montenegrina land snails (Gastropoda: Clausiliidae). AB - Aim: Taxon co-occurrence analysis is commonly used in ecology, but it has not been applied to range-wide distribution data of partly allopatric taxa because existing methods cannot differentiate between distribution-related effects and taxon interactions. Our first aim was to develop a taxon co-occurrence analysis method that is also capable of taking into account the effect of species ranges and can handle faunistic records from museum databases or biodiversity inventories. Our second aim was to test the independence of taxon co-occurrences of rock-dwelling gastropods at different taxonomic levels, with a special focus on the Clausiliidae subfamily Alopiinae, and in particular the genus Montenegrina. Location: Balkan Peninsula in south-eastern Europe (46N-36N, 13.5E 28E). Methods: We introduced a taxon-specific metric that characterizes the occurrence probability at a given location. This probability was calculated as a distance-weighted mean of the taxon's presence and absence records at all sites. We applied corrections to account for the biases introduced by varying sampling intensity in our dataset. Then we used probabilistic null-models to simulate taxon distributions under the null hypothesis of no taxon interactions and calculated pairwise and cumulated co-occurrences. Independence of taxon occurrences was tested by comparing observed co-occurrences to simulated values. Results: We observed significantly fewer co-occurrences among species and intra generic lineages of Montenegrina than expected under the assumption of no taxon interaction. Main conclusions: Fewer than expected co-occurrences among species and intrageneric clades indicate that species divergence preceded niche partitioning. This suggests a primary role of non-adaptive processes in the speciation of rock-dwelling gastropods. The method can account for the effects of distributional constraints in range-wide datasets, making it suitable for testing ecological, biogeographical, or evolutionary hypotheses where interactions of partly allopatric taxa are in question. PMID- 29973748 TI - Appendicitis in the HIV Era: a South African perspective. AB - The relationship between HIV infection and the clinical spectrum of appendicitis has not been fully elucidated in the South African context. The aim of this study is to compare the surgical management, histopathology, and outcomes between HIV positive and HIV-negative patients undergoing surgery for appendicitis. A retrospective chart analysis was performed of 50 patients who underwent surgery for appendicitis at King Edward VIII Hospital, Durban, South Africa between January 2012 and December 2012. Patients were stratified by HIV serostatus into HIV-positive and HIV-negative groups. Fifty patients underwent surgery for appendicitis during the study period. Of the 50 patients, 14 were HIV-positive (28 %) and 36 were HIV-negative (72 %). Perforated appendicitis was more frequent in the HIV-positive group (50 vs. 25 %, p > 0.05). There was a significantly higher laparotomy rate in HIV-positive patients (71 vs. 33 %, p < 0.05). Granulomatous inflammation of the appendix was only noted in HIV-positive patients (n = 3). There was no significant difference in the complication rate between the two groups (p > 0.05) and no difference in the mean length of hospital stay (7.8 +/- 4.89 vs. 5.8 +/- 3.94 days, p > 0.05). In this retrospective study, perforated appendicitis was seen to be more common in HIV positive patients resulting in a higher laparotomy rate in this group. Granulomatous inflammation was only found in HIV-positive patients. There was no difference seen in the complication rate, length of hospital stay, and mortality between HIV-positive and HIV-negative patients. PMID- 29973749 TI - Evaluation of Vocal Cord Function Before Thyroidectomy: Experience from a Developing Country. AB - Vocal cord palsy (VCP) is a major complication of thyroidectomy. Some patients have preexisting VCP prompting the need for routine or selective preoperative evaluation of the vocal cords. The study aims at ascertaining the prevalence of preoperative VCP and making appropriate recommendations. This is a retrospective study of all adult patients who had thyroidectomy at the University of Nigeria Teaching Hospital. Case notes of patients who had thyroidectomy at the hospital from July 2010 to June 2015 were retrieved. Variables studied included biodata, duration of goiter, preoperative hoarseness, outcome of indirect laryngoscopy (IDL), histology of specimen, duration of follow-up, and incidence of postoperative hoarseness. Descriptive statistical analysis was done using SPSS version 20. Of the 91 patients aged 21-70 years (mean 42.08 years, SD 15.40), females outnumbered males with a M:F ratio of 1:10.4. Five patients had preoperative hoarseness, but only three had VCP. IDL was done for 25 (27.4%) patients out of which 22 (88.0%) had normal studies while the remaining three (all from the five with hoarseness) had VCP. Histology of the specimens showed malignancy in 10 (11%), benign in 55 (60.4%), and no report in 26 (28.6%). Five of the malignant histology patients showed normal findings on IDL, three had VCP and two had no preoperative IDL. There was no case of asymptomatic VCP. Vocal cord evaluation is recommended for patients with voice symptoms and those with malignant goiter. PMID- 29973750 TI - Importance of Spontaneous Choledochoduodenal Fistulas Detected During ERCP Procedure. AB - Choledochoduodenal fistula (CDF) is an abnormal passage between the choledochus and duodenum. The most common causes of CDF are cholelithiasis, duodenal ulcer, and tumors. There are mainly two types of fistulas depending on the location. Type 1 is usually present on the longitudinal fold just close to the papilla. Type 2 is present at the duodenal mucosa adjacent to the longitudinal fold and probably caused by larger stones, duodenal ulcer penetration, impacted cystic duct stones, and as a complication of laparoscopic cholecystectomy. In this study, we investigate the characteristics of our patients those were diagnosed with CDF. This is a descriptive study. We retrospectively obtained the data of 21 patients with spontaneous CDF out of 2430 endoscopic retrograde cholangiopancreaticography (ERCP) patients between 2000 and 2014. We analyzed the laboratory results, demographic and etiological features, major clinical presentations, diagnostic methods, and treatment modalities of the patients. The mean age of the 21 patients was 66.6 +/- 2.2 years and a female to male ratio was 12:9. In ten patients, interventional procedures were performed via fistulotomy, not through the papilla. The eventual diagnosis was tumor in five patients and stone or sludge in bile ducts in 14 patients. In the remaining two patients, no reason was found as a cause of CDF. Whipple operation was performed in one patient and stents were placed in three patients for malignacy. Among the 14 patients with sludge or stone in bile ducts, ERCP has been therapeutic in ten. One of the remaining patients has been operated for proximal fistula and underwent choledochus exploration and repair of fistula over a T-tube. In the second patient, stone extraction and T-tube drainage were performed. In patients who had bile duct obstruction and got over of jaundice afterwards, one of the most important reasons of this recovery is the development of spontaneous choledochoduodenal fistula. Even if it is very rare, malignancy can be observed in this area. Therefore, it is extremely important to evaluate the papillary area with ERCP and to conduct biopsy; this will make early diagnosis possible in many patients. In these patients, ERCP can both be diagnostic and therapeutic. PMID- 29973751 TI - A Review of 2255 Emergency Abdominal Operations Performed over 17 years (1996 2013) in a Gastrointestinal Surgery Unit in India. AB - There is little information regarding the clinical spectrum and outcome of emergency abdominal operations from specialized units in India. We examined these in our gastrointestinal surgery and liver transplantation unit from a prospective database maintained between July 1996 and April 2013. Out of 9966 operations performed, 2255 (26%) were emergency procedures (reoperations during the same admission, e.g., for necrotizing pancreatitis were excluded). The primary outcome was 30-day postoperative mortality. The mean age of the patients was 47 years (range 1-107) and included the following age groups: 0-18 years (n = 105, 4.7%); 19-64 years (n = 1766, 78.3%), and >65 years (n = 384, 17.0%). The majority were males (1609, 71%), and there were 646 females (29%). The most common indications were small bowel emergencies (598, 26.5%), followed by pancreatic (417, 18.5%) and colonic (281, 12.5%) emergencies. Pancreatic operations were the second commonest in the adult and middle aged group. Colorectal operations were the second commonest in the geriatric age group (>65 years). Emergency operations for other conditions were: postoperative complications following elective operations 171 (7.5%), gastroduodenal bleeding or perforation in 144 (6.3%), and liver surgery in 93 patients (4.1%) patients. In the small bowel emergencies, 223 patients (37.2%) had primary diagnosis of adhesive obstruction, gangrene in 135 patients (22.5%), perforation in 121 patients (20%), and fistula in 56 patients (9.3%). Mesenteric venous thrombosis was found to be the primary cause of small bowel emergencies, either as a primary cause in gangrene or as a secondary cause in perforations and adhesions. The postoperative mortality after emergencies was 12.6% compared to 2% in elective procedures. Mortality was significantly higher in males (14%) than females (9.6%), p < 0.005. Category wise mortality was as follows: pancreatic surgery (n = 86, 20.6%), surgery for postoperative complications (n = 33, 19.3%), duodenal surgery (n = 18, 12.5%), small intestinal surgery (n = 68, 11.4%), and colonic surgery (n = 35, 12.45%). Emergency operations comprise a significant proportion of a GI surgical unit's workload. The mortality is greatest after pancreatic operations followed by those done for postoperative complications. Despite advances in surgical and postoperative care, emergency operations for abdominal emergencies are associated with mortality which is six times higher compared to elective procedures. PMID- 29973752 TI - Micro-Incision of the Cystic Duct Confluence in Laparoscopic Common Bile Duct Exploration for Elderly Patients with Choledocholithiasis. AB - Common bile duct (CBD) stones are common in elderly patients. The laparoscopic transcystic approach with micro-incision of the cystic duct confluence in common bile duct exploration (LTM-CBDE) is a modified laparoscopic transcystic approach. Its safety and efficacy have not been studied in elderly patients with secondary choledocholithiasis. This study evaluates the safety and efficacy of LTM-CBDE in elderly (>=65 years) patients with secondary choledocholithiasis and compares the results with those in younger patients. In this retrospective analysis, 128 patients underwent LTM-CBDE from March 2007 to December 2013. The patients were divided into two groups according to age: the elderly group consisted of 50 patients aged >=65 years and the younger group consisted of 78 patients aged <65 years. The preoperative morbidity rate, American Society of Anesthesiologists (ASA) score, previous abdominal operations, operation time, postoperative hospital stay, open conversion rate, postoperative complication rate, residual stone rate, recurrence rate and mortality were compared in both groups. The preoperative morbidity (41 vs. 28) and ASA score (2.5 +/- 0.7 vs. 1.8 +/- 0.6) were higher in the elderly group (P = 0.000, in both groups). No significant differences in previous abdominal operations, operation time, postoperative hospital stay, open conversion rate, postoperative complication rate, residual stone rate, recurrence rate and mortality (P > 0.05) were found between the two groups from March 2007 to December 2013. LTM-CBDE is a safe and effective treatment procedure for elderly patients with secondary choledocholithiasis. For suitable patients, we recommend LTM-CBDE as the treatment of choice. PMID- 29973753 TI - Effect of Varicocelectomy on Serum FSH and LH Levels for Patients with Varicocele: a Systematic Review and Meta-analysis. AB - Varicocelectomy can improve the function of testicular Leydig cell for patients with varicocele. We carried out a systematic review and meta-analysis to assess effect of varicocelectomy on serum FSH and LH levels for patients with varicocele. A literature review was performed to identify all published randomized preoperation-postoperation clinical trials of assessing serum FSH and LH levels before and after varicocelectomy. The search included the following databases: PUBMED and EMBASE. The reference lists of retrieved studies were also investigated. A systematic review and meta-analysis were conducted. Five studies were selected from 149 studies, including 312 patients. The meta-analysis showed that serum FSH level (95% confidence interval 0.19-0.77, P = 0.001) and serum LH level (95% confidence interval 0.25-0.91, P = 0.0005) were higher preoperation than postoperation. Serum FSH level decreased by 0.48 ng/dL after varicocelectomy. The mean decrease of the serum FSH was from 0.1 to 4.8 ng/dL. And serum LH decreased by 0.58 ng/dL. The mean decrease of the serum LH was from 0.2 to 2.1 ng/dL. This meta-analysis proves that varicocelectomy perhaps can decrease serum FSH and LH levels in patients with varicocele. And it might be related to the improvement of the function of Leydig cell. But it remains to need a large-scale multicenter randomized controlled study to be further confirmed. PMID- 29973754 TI - Morgagni's Hernia: Analysis of 21 Patients with Our Clinical Experience in Diagnosis and Treatment. AB - A Morgagni's hernia is a congenital defect found in the anterior aspect of the diaphragm between the costal and the sternal portions of this muscle. This defect is also referred to as the space of Larrey. It has been reported that 70% of patients with Morgagni's hernia are female, 90% of the hernias are right-sided, and 92% of the hernias have hernia sacs. This type of hernia is a rare clinical entity and accounts for 3% of all surgically treated diaphragmatic hernias. There are no large retrospective or prospective studies on this topic. This type of hernia is a rare type among adults without a well-described prevalence and without well-established definitive management strategies. There are also few clinical reports about this clinical entity and its surgical treatment. We treated 21 patients with Morgagni's hernia in a 12-year period, and we report our experience while discussing the surgical treatment of this disease. We performed a retrospective review of the 21 patients who were operated between 2003 and 2015. These patients had undergone surgical repair of Morgagni's hernia. For each subject, demographic data, symptoms of presentation, physical examination findings, preoperative imaging studies and diagnosis, and surgical procedures were documented. Location of the hernia sac and its contents, postoperative complications, and duration of hospital stay were recorded and evaluated. Twelve patients were females and nine were males. The mean age of patients was 63.85 years. Dyspnea was the most prominent symptom in our patients. Morgagni's hernias were located on the right side in 19 patients and on the left side in 2 patients. Chest X-ray in 10 patients and abdominal computerized tomography in 17 patients were the major diagnostic tools. Four patients were operated as emergency while others underwent elective surgery (17 patients). Twelve patients were operated with laparoscopy and the remaining nine were operated with the conventional open abdominal technique. Hernia sacs were observed in all of the patients and removed except in four of them. The omentum and the transverse colon were the most commonly seen organs in hernia sacs. Hernia defects were repaired with primary sutures in four patients (all open cases) and primary closure supported with mesh in six patients (four laparoscopic, two open cases). In the remaining 11 patients, hernia defects were closed with synthetic meshes (eight laparoscopic, three open cases). Mean postoperative hospital stay was 9.8 days. No recurrence was observed in any patients. Only one of our patients died during follow-up. In Morgagni's hernias, surgical intervention is necessary as the hernia may cause complications such as strangulation of the colon or intestines. A laparoscopic approach has increased its popularity in recent years because of the well-known advantages of laparoscopy. PMID- 29973755 TI - The RAQET Study: the Effect of Eating a Popsicle Directly After Bariatric Surgery on the Quality of Patient Recovery; a Randomised Controlled Trial. AB - : Quality of recovery could be influenced positively if there is less postoperative sore throat (POST). Eating a popsicle might attenuate this sore throat. Especially for bariatric surgery, early recovery is important. Adding popsicles to the postoperative protocol could be beneficial. Our hypothesis is that offering a popsicle in the recovery room to patients after bariatric surgery will decrease POST and will increase quality of postoperative recovery. Patients undergoing elective bariatric surgery, between the 23 February 2015 and 3 April, were randomised to either the popsicle group or control group. Primary endpoint was the incidence of POST and secondly if a reduction in POST influences quality of recovery at the first day postoperative measured with the Bariatric Quality Of Recovery (BQoR) questionnaire. One hundred and thirty-three patients were assessed for eligibility. For the final analysis, 44 patients in the intervention and 65 in the control group were available. Eating a popsicle after bariatric surgery had no significant effect on the incidence of POST. Significant effects (in favour of the popsicle group) were seen in muscle pain score (p = 0.047) and sore mouth score (p = 0.012). Popsicle intragroup analysis revealed that eating the whole popsicle (compared to partially eating the popsicle) has positive effects on nausea (p = 0.059), feeling cold (p = 0.008), and mean total comfort score (p = 0.011). Of the patients who became nauseous and/or had to vomit because of the popsicle, n = 4 had more severe pain (p = 0.04) and the mean pain score was higher (p = 0.09). The present study demonstrates that offering a popsicle early during recovery after bariatric surgery is feasible without adverse effects, although eating popsicle did not reduce postoperative sore throat. There are possible beneficial effects, such as reduced muscle pains and less sore mouth, that may enhance the quality of recovery. More research is necessary to further substantiate the effect of eating popsicles on the quality of recovery in this patient population. TRIAL REGISTRATION: Registration number: NTR4943 (http://www.trialregister.nl). PMID- 29973756 TI - Evaluation of the Clinical Use of Robot-Assisted Retroperitoneal Laparoscopy and Preoperative RENAL Scoring for Nephron Sparing Surgery in Renal Tumor Patients. AB - The present study aims to compare the operative outcomes following the use of robot-assisted retroperitoneal partial nephrectomy (RARPN) with radius, exophytic/endophytic, nearness to sinus, anterior/posterior, and location (RENAL) scoring or laparoscopic retroperitoneal partial nephrectomy (LRPN) for the treatment of renal tumors. Eighty-three nephron-sparing surgery (NSS) procedures performed between January 2013 and December 2015 were reviewed. The study set consisted of 26 robot-assisted retroperitoneal laparoscopes, of which 3 were high risk (RENAL score >=10), 11 were medium risk (RENAL score >=7 < 9), and 12 were low risk (RENAL score <7) and 57 laparoscopic retroperitoneal partial nephrectomy procedures (7 high, 22 medium, and 28 low risk). All surgeries were successful in the absence of conversion or transfusion. Operative times were 96.0 +/- 16.9 and 110.0 +/- 19.4 min for RARPN and LRPN, respectively (P < 0.05). Warm ischemia times (WITs) were 17.6 +/- 3.1 and 22.8 +/- 3.5 min, respectively (P < 0.05). Estimated blood losses (EBLs) were 45 +/- 15 and 97 +/- 25 mL, respectively (P < 0.05). No statistical significance was found in duration of drainage, intestinal recovery time, hospital stay, serum creatinine, and perioperative complications (P > 0.05). RARPN affords significant advantages in outcomes of WIT, EBL, and recovery time over conventional LRPN owing to an increased accuracy in excision and suturing. Patients bearing high-risk renal tumors (RENAL score >=10) are suitable candidates for RARPN. PMID- 29973757 TI - An Assessment Scale for Patients with Postoperative Superficial Incisional Surgical Site Infection: a Cross-Sectional Study. AB - Superficial incisional surgical site infection (SSI) is a common postoperative complication in surgical patients. The aim of this study was to assess the predictive power of an assessment scale for identifying patients at risk of superficial incisional SSI. A cross-sectional survey was conducted at the Department of Surgery at the Medical Research Institute Hospital, Alexandria University. A sample of 150 adult patients aged from 18 to 65 years, who undergoing general surgeries that had clean sutured surgical wounds, was randomly selected. Forty-six patients (30.7%) had SSI. The total score can significantly discriminate between positive and negative superficial incisional SSI patients with diagnostic accuracy of AUC (SE) = 0.66 (0.048). Each score more than the cutoff point (11.5) will increase the risk of surgical site infection development by 2.5 times (OR (95% CI) = 2.5 (1.26-3.1)). The developed assessment scale can discriminate between patients who are at risk of superficial incisional SSI and those who are not. It can be used as a preliminary screening tool for subsequent investigation for the presence of infection. PMID- 29973758 TI - First Ever Robotic Stage One ALPPS Procedure in India: for Colorectal Liver Metastases. AB - Twenty five percent of total liver volume (TLV) is considered as the ideal functional liver remnant (FLR) in major liver resections. In patients with macro vesicular steatosis, early cirrhosis, and post-neoadjuvant chemotherapy (NACT), hepatocellular injury is common. In such instances, up to 40% of FLR may be required. So in cases of marginal FLR, pre-operative portal vein (PV) embolization or two-stage hepatectomy with PV occlusion is used. Both of which take up to 14 weeks between stages and 30% of patients fail to reach the second resection either due to inadequate FLR growth or disease progression. Associated liver partition and portal vein ligation (ALPPS) procedure has become the gold standard for those cases. A 57-year-old male presented with rectosigmoid growth + multiple right liver and segment 4B metastases. Post-NACT MRI showed interval progression of lesions. Preoperative CT (computed tomography) volumetric scan showed a FLR/TLV (future liver remnant/total liver volume) of 22%. Since patient received 10 cycles of NACT, ALPPS procedure was planned ahead of direct liver resection. Robotic ALPPS stage 1 sparing left lateral segment and 4A + anterior resection was done. We transected the parenchyma between the FLR and the diseased part of the liver with concomitant right portal vein ligation done robotically. CT abdomen done on POD7 showed hypertrophied left lateral segment. Second stage was performed on the eighth post-operative day with FLR/TLV increasing to 37%. Robotic ALPPS procedure for stage one is a safe and feasible technique in experienced centers with advanced robotic skills. PMID- 29973759 TI - Surgery for Blue Rubber Bleb Nevus Syndrome-a Case Report. AB - Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterised by multiple venous malformations and haemangioma in the skin and visceral organs. The lesion often involves the cutaneous and gastrointestinal tract. Most common visceral organ affected is the GIT. Most predominant region involved in the GIT is small bowel. However, vascular lesions can occur anywhere from oral mucosa to anal canal. GIT bleed is relatively slow, resulting in minor, chronic and occult blood loss. The syndrome in the GIT may also present with severe complications such as rupture, volvulus, intussusceptions and even death. Cutaneous malformations are usually asymptomatic and do not require treatment. The treatment of GIT lesions is determined by the extent of intestinal involvement and severity of the disease. Most patients respond to supportive therapy such as iron supplementation and blood transfusion. Surgical resection, endoscopic sclerosis and laser photocoagulation have been proposed for more significant haemorrhage and severe complications. Here, we present a case of BRBNS in a 13 year-old girl involving the GIT especially the large bowel, presenting with the complaints of bleeding per rectum and iron deficiency anaemia. Initially, endoscopic sclerotherapy was performed, but to no response. Hence, proceeded with surgical resection. PMID- 29973760 TI - Sporadic Desmoid-Type Fibromatosis Occurring at Laparoscopic Trocar Site: An Unusual Entity. AB - Desmoid-type fibromatosis (DF) or desmoid tumours are rare benign soft tissue tumours of musculo-aponeurotic origin, which have no malignant potential but are locally aggressive and can result in significant morbidity. They may be hereditary (in association with FAP, i.e. familial adenomatous polyposis syndrome resulting from APC gene mutation) or sporadic, with hereditary cases having a much higher risk of developing DF compared to sporadic ones. Desmoids are known to occur in previous surgical scars. However, previous laparoscopic port site/trocar site is an extremely uncommon site for sporadic desmoids, with only two cases of sporadic laparoscopic trocar site desmoids (occurring in absence of FAP) reported in world literature. We thus describe a case of sporadic DF, occurring at the site of umbilical port 8 months following laparoscopic cholecystectomy for cholelithiasis, treated successfully by margin-negative resection. To the best of our knowledge, this appears to be the first such case in Indian literature and the first being reported after laparoscopic cholecystectomy. In the era of laparoscopic surgery, one must be aware of the existence of such an entity after laparoscopy as it may be confused with conditions such as metastatic deposit, port site tumour recurrence, port site hernia, scar site endometriosis, soft tissue sarcoma etc. and may result in diagnostic dilemma. PMID- 29973761 TI - Gallbladder Metastasis from Renal Cell Carcinoma. AB - We experienced a rare case of gallbladder metastasis from renal cell carcinoma. A 68-year-old man was admitted for further evaluation of a gallbladder tumor, which had been identified on follow-up computed tomography after partial nephrectomy for renal cell carcinoma. Enhanced computed tomography and magnetic resonance imaging showed an enhancing polypoid mass in the gallbladder lumen. Endoscopic ultrasonography demonstrated a homogenous hypo-echoic polypoid lesion, and the outer hyper-echoic layer of the adjacent wall was intact. Blood flow signals in the wall side of the mass were observed on color Doppler endoscopic ultrasonography images. Laparoscopic cholecystectomy was performed and he was uneventfully discharged. Macroscopic examination of the specimen revealed a 12 * 7 * 5 mm pedunculated tumor attached by a thin pedicle to the fundus of the gallbladder. Histology confirmed a metastasis of the renal cell carcinoma that had infiltrated the shallow subserosa but had mainly grown into cavity of the gallbladder. These imaging findings are considered characteristic and may assist preoperative diagnosis in patients with a history of renal cell carcinoma. PMID- 29973762 TI - Primary Low-Grade Fibromyxoid Sarcoma of Kidney-an Extremely Rare Entity. AB - Renal LGFMS is an extremely rare tumor. So far, only four cases have been reported in literature. LGFMS are indolent tumor with distinctive histopathological features with potential for late recurrences and metastasis. The diagnosis is made on histopathological examination and supported by immunohistochemical analysis. A 35-year-old young male was presented with flank pain and lump and diagnosed as low-grade fibromyxoid sarcoma after surgery on immunohistochemical analysis. This is the fifth case of renal LGFMS and we presented the review of literature. Radical surgery remains the primary treatment modality. Long follow-up is mandatory. PMID- 29973763 TI - Surgical Management of Cystic Duct Stump Stone or Gall Bladder Remnant Stone. AB - Retained calculi in the cystic duct or gall bladder remnant can present as a post cholecystectomy problem. Increased suspicion is necessary to diagnose this condition in a symptomatic post-cholecystectomy patient. Ultrasonography usually detects this condition, but magnetic resonance cholangiopancreatography is the test of choice for diagnosis as well as for surgical planning. Laparoscopic re excision of the stump in most cases is feasible and safe. It is increasingly becoming the treatment of choice. PMID- 29973764 TI - Anterior Mediastinal Mass in a Child-Known but Rare Entity. AB - Thymomas are exceedingly rare tumours of the anterior mediastinum in children. An early awareness helps timely surgical intervention. Thymomas can occasionally be extremely aggressive. The loss of contour on chest X-Ray, to be confirmed as a large anterior mediastinal mass at computerised tomography, serves identification of a typical bilobed thymic tumour. PMID- 29973765 TI - Plain Radiograph of Abdomen Mimicking Contrast Study. AB - A case of road traffic accident with incidental finding of multiple opacities in the pelvis radiography was evaluated and diagnosed as chalk eating was the cause and managed conservatively. We report here the details of the case. PMID- 29973766 TI - A Primary Jejunal Enterolith Presenting as Small Bowel Obstruction. AB - An elderly male presented to our emergency room with acute abdomen. Clinical and imaging evaluations suggested small bowel obstruction due to primary jejunal enterolith with associated stricture. We performed surgical exploration when initial nonoperative therapeutic management failed to resolve the symptoms. Primary jejunal enterolith obstruction is a rare disease presentation reported in literature. PMID- 29973767 TI - Large Intraperitoneal Loose Body. AB - We report a large, asymptomatic, intraperitoneal loose body in a 72-year-old male, presented with bilateral inguinal hernia. PMID- 29973768 TI - Traveling with an Author. PMID- 29973769 TI - Poetry in Medicine. AB - We are all stressed out to read and understand our medical practice which is so vast and seems monotonous. Amidst so much tension, we can still enjoy our profession if we can narrate the sequence in a different style. Poetry is one way of such expression. Poetry is a combination of knowledge and feeling. Just as we have all read Zachary Cope's Surgery in Verse which correlates the disease with its signs in a different way that is poetry, I have tried to use poetry in my medical practice, too. We can understand as well as express better. The whole topic seems so easy once it comes in the form of poetry. Writing in a poetic form requires a thorough knowledge of the subject. Added to this are empathy and sympathy. It needs a deep sense of understanding to feel what the sufferer would feel. Imagination can take us to any part of the world and beyond however minute the structure imagined may be. This is an attempt to present poetry in medical, both while learning and during practice. PMID- 29973770 TI - 'C S' Perspectives About Thoracic Empyema-the 'Comprehensive Suggestions'. PMID- 29973771 TI - Ethics of Smartphone Usage for Medical Image Sharing. AB - Technology advances in medicine have led to increased usage of smartphones and applications in facilitating provision of care. As the increased power of technology paves the way for advances, it is fundamental that ethical considerations are comprehensively explored. This paper explores the importance of consent, confidentiality, and data security in use of smartphone applications for transferring medical information. PMID- 29973772 TI - Generalization of the space l(p) derived by absolute Euler summability and matrix operators. AB - The sequence space l(p) having an important role in summability theory was defined and studied by Maddox (Q. J. Math. 18:345-355, 1967). In the present paper, we generalize the space l(p) to the space |Ephir|(p) derived by the absolute summability of Euler mean. Also, we show that it is a paranormed space and linearly isomorphic to l(p) . Further, we determine alpha-, beta-, and gamma duals of this space and construct its Schauder basis. Also, we characterize certain matrix operators on the space. PMID- 29973775 TI - Microbial Genome Sequencing: Prospects for Development of Novel Vaccines and Anti Microbial Compounds. PMID- 29973773 TI - Prevalence and Clinical Significance of Streptococcus dysgalactiae subspecies equisimilis (Groups C or G Streptococci) Colonization in Pregnant Women: A Retrospective Cohort Study. AB - Objectives: Little is known about the significance of Streptococcus G or C colonization in pregnant women. The objective of this study was to assess whether vaginal Streptococcus group G or C colonization detected in late pregnancy increases the infectious morbidity of the mother or newborn. Methods: A total of 15,114 rectovaginal cultures taken at 35-37 weeks of pregnancy were analyzed at Tampere University Hospital, Finland, between 2012 and 2014. From this laboratory data, all Streptococcus G or C-positive cultures were included to study maternal and neonatal infectious morbidity after delivery. This study population was compared to women with a positive Streptococcus B culture and to women with a negative culture. Results: The prevalence of Streptococcus G or C colonization was 2.9%. Significantly more postpartum endometritis was found in this study group. No association was found between colonization and neonatal bacteremia. Conclusions: Streptococcus G or C colonization is associated with postpartum endometritis. More research is needed to clarify if antibiotic prophylaxis is reasonable for this group during delivery. PMID- 29973774 TI - Role of High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation for Children and Young Adults with Relapsed Ewing's Sarcoma: A Systematic Review. AB - Background: Relapsed Ewing's sarcoma (RES) is an aggressive malignancy with poor survival. Although high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given after conventional chemotherapy (CC) has shown survival benefits, it is not generally used in the United States for RES. We performed a systemic review to evaluate the benefits of HDCT for RES. Methods: Literature search involved Medline, Embase, and Cochrane database. We included studies with RES patients treated with HDCT/ASCT. Results: Twenty-four studies with total of 345 reported RES patients that got HDCT were included in final analysis. Seventeen studies had patients with multiple malignancies including RES, while seven had only RES patients. At 2 and 3-5 years, event-free survival (EFS) in studies with only RES patients ranged 42-47% and 20-61% and overall survival (OS) ranged 50-66% and 33-77%, respectively. In studies with combined patients that reported outcomes of RES separately, the EFS at 1-3 and 4 years was 36-66% and 17-50%, respectively. The OS at 1-2 and 3-4 years was 40-60% and 50 70%. Conclusions: Most studies using HDCT/ASCT as consolidation regimen showed improved survival benefits compared to CC. Randomized controlled studies are needed to determine true clinical benefits of HDCT followed by ASCT in patients with RES. PMID- 29973776 TI - The Mechanism of RNA Interference and the Transposon Silencing in Caenorhabditis elegans. PMID- 29973777 TI - Structural Genomics: Foundation for the Future of Biology? PMID- 29973778 TI - 96 Well, High Throughput Translation. PMID- 29973779 TI - Genome Analysis of Pass2 a Semi-Automated Database of Protein Alignments Organised as Structural Superfamilies. PMID- 29973780 TI - Mouse Genome Informatics: Mapping/Homology Data. PMID- 29973781 TI - Genetic Models of Aerobic Endurance Running Capacity in Rats. PMID- 29973782 TI - Analysis of the Human 3'-Phosphoadenosine 5'-Phosphosulfate Synthase Genes. PMID- 29973783 TI - Elucidation of Protein Structural and Pharmacophore Features Based on Sequence Clustering by Common Neighbor Comparisons. PMID- 29973784 TI - Candidate Gene in Predicting In Vivo Ovarian Cancer Response to Combination Therapy with Paraplatin and Paclitaxel. PMID- 29973785 TI - Comparing the Speed and Accuracy of the Smith and Waterman Algorithm as Implemented by Mpsrch with the Blast and Fasta Heuristics for Sequence Similarity Searching. PMID- 29973786 TI - Proteomic Analysis of Rough and Smooth Endoplasmic Reticulum. PMID- 29973787 TI - Inteins in Microbial Genomes: Distribution, Mechanism, and Function. AB - Inteins are self-splicing protein elements (134 to 608 amino acids). Over 125 inteins have been cataloged in InBase, the on-line intein database (http://www.neb.com/neb/inteins.html), which includes the Intein Registry[1]. Inteins naturally present in pathogenic microbes represent novel, yet unexploited drug targets. Understanding the chemistry of the splicing reaction has allowed the manipulation of inteins, which are now used in many protein engineering applications[2]. PMID- 29973788 TI - Pattern of Organization of Human Mitochondrial Pseudogenes in the Nuclear Chromosomes. PMID- 29973789 TI - Progress in AB Initio Protein Structure Prediction. PMID- 29973790 TI - Structural Proteomics of Eukaryotic Gene Families. PMID- 29973791 TI - Automated Protein Purification for Structural Studies. PMID- 29973792 TI - Functional Genomics with YBL036c. PMID- 29973793 TI - Extraction and Purification of Proteins from E. Coli without Harvesting Cells. PMID- 29973794 TI - Purification of Gst Fusion Proteins, On-Column Cleavage, and Sample Clean Up. PMID- 29973795 TI - Probing Single Icam-1/Lfa-1 Interaction under External Force. PMID- 29973796 TI - Combining Bioinformatics and Biophysics to Understand Protein-Protein and Protein Ligand Interactions. PMID- 29973797 TI - Studying Protein-Excited States by Nmr. PMID- 29973798 TI - Introducing New Amino Acids into Proteins. PMID- 29973799 TI - The Protein Trinity: Structure/Function Relationships That Include Intrinsic Disorder. PMID- 29973800 TI - Engineering Monomeric Glycogenin. PMID- 29973801 TI - Crystallographic Studies of Bacterial Exoribonucleases. PMID- 29973802 TI - Biochemical and Structural Analysis of the Role of the Wlb Gene Locus in Bordetella Pertussis Lipopolysaccharide Biosynthesis. PMID- 29973803 TI - Subdomains in the F and G Helices of Bacteriorhodopsin Regulate Structural Changes. PMID- 29973804 TI - Mechanism of Unfolding of A Model Helical Peptide. PMID- 29973805 TI - Secondary Structure Changes in a Calcium Binding Protein: Centrin. PMID- 29973806 TI - Structure and Mechanism of E. coli Rnase. PMID- 29973807 TI - Strategies for Structural Genomics Target Selection. AB - We have developed a protein sequence analysis pipeline that ranks proteins as targets for high throughput structure determination. The ranking is designed to maximize both the biological and informational impact of new 3D protein structures solved through the structural genomics initiative. The analysis system accepts proteins from multiple genomes as input, builds sequence families based on remote homology, identifies families with one or more solved structures, and ranks the remaining families according to criteria designed to maximize structure determination efficacy, increase the likelihood of a novel fold, and maximize the number of new protein structure models that can be built from a solved structure. PMID- 29973808 TI - Beyond the Genome: A Drug for Every Gene? PMID- 29973809 TI - Application of In Vitro Protein Expression to Human Prote. PMID- 29973810 TI - HRAD30A, a Gene Encoding a Class Y Low-Fidelity Dna Polymerase Has a Low Complexity Region in Intron I Associated with Tissue-Specific Alternative Splicing. PMID- 29973811 TI - Characterize Protein Functional Relationships Based on Mrna Expression Profile. PMID- 29973812 TI - Prediction of C Regulatory Elements Using Statistical Analysis. PMID- 29973813 TI - The Pedant Human Genome Database ? Functional Annotation of the Human Genome. PMID- 29973814 TI - Identification of Protein Folding Cores Using Charge Center Model of Protein Structure. PMID- 29973815 TI - The Mammalian Cell as a Macromolecular Assembly. PMID- 29973816 TI - Electron Tomography: Towards Visualizing Supramolecular Architecture Inside Cells. PMID- 29973817 TI - Multi-Protein Complexes Studied by Mass Spectrometry. PMID- 29973818 TI - Approaches to Analyze Protein Interactions. PMID- 29973819 TI - Protein Interactions Within the Cytoplasmic Dynein Complex as Probed by Mass Spectrometry and Nmr. PMID- 29973820 TI - Thermodynamic Molecular Switch in Sequence-Specific Hydrophobic Interactions. PMID- 29973821 TI - IA3, A Yeast Proteinase A Inhibitor, Is Intrinsically Unstructured in Solution. PMID- 29973822 TI - A Missing Step in Glycogen Synthesis. PMID- 29973823 TI - Detection of Membrane Protein Interactions Using Split Ubiquitin-Based Membrane Yeast Two-Hybrid Technology. PMID- 29973824 TI - Linking Science with Management of Freshwater Resources - A Forthcoming Collection of Papers in the Freshwater Systems Domain. PMID- 29973825 TI - Crystal Structure of Rhodopsin: Implication for Vision and Beyond. Mechanisms of Acti. PMID- 29973826 TI - Chemical Genetic Analysis of Protein Kinase Cascades. PMID- 29973827 TI - Encoding Selectivity of a Transmembrane Channel. PMID- 29973828 TI - Insight into Residues Critical for Antithrombin Function from an Expanded Database of Sequences That Includes Frog, Turtle and Ostrich Antithrombins. PMID- 29973829 TI - Precursor Structure of Cephalosporin Acylase: Insights into Auto-Proteolytic Activation in a New N-Terminal Hydrolase Family. PMID- 29973830 TI - Synthetic Peptide Corresponding to The Amino-Terminal Region of the Human Tryptophanyl-Trna Synthetase, a Component Of Alzheimer'S Disease Special Congophlic Plaques Aggregates In Vitro to Form Amyloid-Like Fibrils. PMID- 29973831 TI - Crystal Structure of Murine Tcl1 Oncoprotein and Conserved Surface Features of the Molecules of the Tcl1 Family. PMID- 29973832 TI - Eukaryotic Targets of a Bacterial Protein Kinase Virulence Factor. PMID- 29973833 TI - Hypoxia-Inducible Factor-1 (Hif-1) in Experimental Brain Ischemia. PMID- 29973834 TI - Procollagen-Like Protein as a Molecular Target in the Treatment of Primary Brain Tumor. PMID- 29973835 TI - Engineering Polyketide Synthases. PMID- 29973836 TI - Molecular Breeding of Genes, Pathways and Genomes by Dna Shuffling. PMID- 29973837 TI - Announcing Topics in Bone Biology - A Three-Volume Reference Work to be Published by TheScientificWorld. PMID- 29973838 TI - Protein Misfolding and Human Disease. PMID- 29973839 TI - The Use of Antisense-Mediated Inhibition to Delineate The Role of Inflammatory Agents in The Pathophysiology of Spinal Cord Injury. AB - Injuries to the central nervous system (CNS) usually lead to a potent and acute inflammatory response[1]. During this period, glia and immune cells respond to chemical cues associated with the debris of lysed neurons, disrupted axons, and a broken blood-brain-barrier by releasing a battery of cytokines including tumor necrosis factor-alpha (TNF-alpha) and, interleukin-beta (IL-1beta) as well as reactive oxygen species such as nitric oxide (NO-)[2]. The secretion of these factors may be primarily responsible for secondary damage to surrounding uninjured tissue that potentiates the initial injury[3]. Antisense oligonucleotides (ASOs) are designed to hybridize to specific regions of specific mRNAs. Hybridization of the oligonucleotide to the mRNA then interferes with the normal processing of that mRNA at the ribosome or targets the RNA duplex for cleavage by the RNA digestive enzyme, ribonuclease H, resulting in greatly reduced expression of the coded protein. This effectively reduces the amount of corresponding translated protein product and experiments can be designed to examine the requirement of particular inflammatory agents in eliciting specific deleterious responses after injury, e.g., cell death. PMID- 29973840 TI - Selected Peer-Reviewed Papers from the Arsenic Session of the 6th International Conference on the Biogeochemistry of Trace Elements, July 29-August 2, 2001, Guelph, Ontario, Canada. PMID- 29973841 TI - The Four-State Equilibrium Unfolding of a scFv Antibody Fragment. PMID- 29973843 TI - A New Monoclonal Antibody Demonstrates That Muc4, the Intramembrane Ligand for Erbb2/Her2/Neu, Is Overexpressed in Multiple Carcinomas. PMID- 29973842 TI - Expression of Heme Oxygenase-1 Mediated by A Protein Transduction Domain Protects Insulin Producing Cells from Cytokine- Induced Cytotoxicity. PMID- 29973844 TI - Structural Insight into the Mechanisms of Targeting and Signaling of Focal Adhesion Kinas. PMID- 29973845 TI - Some Aspects of Dna-Etbr Interaction Peculiarities. PMID- 29973846 TI - High-Throughput Protein Expression and Purification for Proteomics Research. PMID- 29973847 TI - Defining and Assessing Adverse Environmental Impact: A Collection of Peer Reviewed Papers. PMID- 29973848 TI - Founding Editorial: Higher Level Brain Function. PMID- 29973849 TI - Founding Editorial: Cognition. PMID- 29973850 TI - Founding Editorial - The Pharmaceutical Sciences. PMID- 29973851 TI - Climatic Impact of Volcanic Eruptions. AB - Volcanic eruptions have the potential to force global climate, provided they are explosive enough to emit at least 1-5 megaton of sulfur gases into the stratosphere. The sulfuric acid produced during oxidation of these gases will both absorb and reflect incoming solar radiation, thus warming the stratosphere and cooling the Earth's surface. Maximum global cooling on the order of 0.2-0.3 degrees C, using instrumental temperature records, occurs in the first 2 years after the eruption, with lesser cooling possibly up to the 4th year. Equatorial eruptions are able to affect global climate, whereas mid- to high-latitude events will impact the hemisphere of origin. However, regional responses may differ, including the possibility of winter warming following certain eruptions. Also, El Nino warming may override the cooling induced by volcanic activity. Evaluation of different style eruptions as well as of multiple eruptions closely spaced in time beyond the instrumental record is attained through the analysis of ice-core, tree ring, and geologic records. Using these data in conjunction with climate proxy data indicates that multiple eruptions may force climate on decadal time scales, as appears to have occurred during the Little Ice Age (i.e., roughly AD 1400s 1800s). The Toba mega-eruption of ~75,000 years ago may have injected extremely large amounts of material into the stratosphere that remained aloft for up to about 7 years. This scenario could lead to the initiation of feedback mechanisms within the climate system, such as cooling of sea-surface temperatures. These interacting mechanisms following a mega-eruption may cool climate on centennial time scales. PMID- 29973852 TI - Selected Peer-Reviewed Short Papers from ESF/CSIC Workshop: Analysis, Toxicity and Biodegradation of Organic Pollutants in Groundwater from Contaminated Land, Landfills and Sediments; 8-10 November 2001, Barcelona, Spain. PMID- 29973853 TI - Isotopes as Tracers in Marine Environmental Studies - A Forthcoming Collection of Papers in the Isotopes in the Environment Domain. PMID- 29973854 TI - The ICPEP-2 Meeting in India: Biodiversity to the Rescue! PMID- 29973855 TI - Selected Short Communications from the International Conference on Environmental Concerns and Emerging Abatement Technologies, Beijing, China, 9-12 October, 2001. PMID- 29973856 TI - Molecular Binding Interactions: Their Estimation and Rationalization in QSARs in Terms of Theoretically Derived Parameters. AB - An extensive survey of molecular binding interactions and parameters used in QSARs is reported, which includes consideration of lipophilicity and the derivation of Linear Free Energy Relationships associated with drug-receptor binding, together with an overview of the various contributions to binding energy. The lipophilic parameter, log P, and its relevance to desolvation energy is outlined and explanation of the parameters derived from electronic structure calculation is provided, leading into a summary of molecular dynamics simulations. PMID- 29973857 TI - Founding Editorial - Learning and Memory. PMID- 29973858 TI - The Marine Systems Domain of TheScientificWorldJOURNAL. PMID- 29973859 TI - Serious Mental Illness in Heavy Drinkers Is Associated with Poor Treatment Outcomes in Outpatients with Co-occurring Disorders. AB - The objective of this study was to determine whether the interaction between type of serious mental illness (SMI) and pre-treatment drinking severity, assessed by ethyl glucuronide (EtG), predicts EtG-positive urine samples submitted during treatment in outpatients with co-occurring alcohol dependence and SMI. Seventy nine participants were randomized to treatment-as-usual or treatment-as-usual and contingency management (CM) targeting alcohol abstinence. Generalized estimating equations were used to assess the interaction of pre-treatment drinking (heavy drinking or light drinking) and SMI diagnosis (major depression, bipolar, or schizophrenia-spectrum disorders) across a 12-week treatment period. In the overall sample, the interaction of drinking severity and SMI diagnosis (p = 0.006) was associated with alcohol abstinence. Exploratory analyses of the interaction term among participants randomized to CM (n = 40; p = 0.008) were associated with alcohol abstinence during CM. Type of SMI diagnosis was associated with treatment outcomes in individuals who engaged in heavy drinking, but not light drinking, prior to treatment. PMID- 29973860 TI - Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus. AB - Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2 replaced rats. PMID- 29973861 TI - A Student's Guide to Randomization Statistics for Multichannel Event-Related Potentials Using Ragu. AB - In this paper, we present a multivariate approach to analyze multi-channel event related potential (ERP) data using randomization statistics. The MATLAB-based open source toolbox Randomization Graphical User interface (Ragu) provides, among other methods, a test for topographic consistency, a topographic analysis of variance, t-mapping and microstate analyses. Up to two within-subject factors and one between-subject factor, each with an open number of levels, can be defined and analyzed in Ragu. Ragu analyses include all sensor signals and no a-priori models have to be applied during the analyses. Additionally, periods of significant effects can be controlled for multiple testing using global overall statistics over time. Here, we introduce the different alternatives to apply Ragu, based on a step by step analysis of an example study. This example study examined the neural activity in response to semantic unexpected sentence endings in exchange students at the beginning of their stay and after staying in a foreign-language country for 5 months. PMID- 29973862 TI - Cerebrovascular Resistance: The Basis of Cerebrovascular Reactivity. AB - The cerebral vascular network regulates blood flow distribution by adjusting vessel diameters, and consequently resistance to flow, in response to metabolic demands (neurovascular coupling) and changes in perfusion pressure (autoregulation). Deliberate changes in carbon dioxide (CO2) partial pressure may be used to challenge this regulation and assess its performance since CO2 also acts to change vessel diameter. Cerebrovascular reactivity (CVR), the ratio of cerebral blood flow (CBF) response to CO2 stimulus is currently used as a performance metric. However, the ability of CVR to reflect the responsiveness of a particular vascular region is confounded by that region's inclusion in the cerebral vascular network, where all regions respond to the global CO2 stimulus. Consequently, local CBF responses reflect not only changes in the local vascular resistance but also the effect of changes in local perfusion pressure resulting from redistribution of flow within the network. As a result, the CBF responses to CO2 take on various non-linear patterns that are not well-described by straight lines. We propose a method using a simple model to convert these CBF response patterns to the pattern of resistance responses that underlie them. The model, which has been used previously to explain the steal phenomenon, consists of two vascular branches in parallel fed by a major artery with a fixed resistance unchanging with CO2. One branch has a reference resistance with a sigmoidal response to CO2, representative of a voxel with a robust response. The other branch has a CBF equal to the measured CBF response to CO2 of any voxel under examination. Using the model to calculate resistance response patterns of the examined branch showed sigmoidal patterns of resistance response, regardless of the measured CBF response patterns. The sigmoid parameters of the resistance response pattern of examined voxels may be mapped to their anatomical location. We show an example for a healthy subject and for a patient with steno-occlusive disease to illustrate. We suggest that these maps provide physiological insight into the regulation of CBF distribution. PMID- 29973863 TI - Imbalanced Expression of Tau and Tubulin Induces Neuronal Dysfunction in C. elegans Models of Tauopathy. AB - Tauopathy is a type of dementia defined by the accumulation of filamentous tau inclusions in neural cells. Most types of dementia in the elderly, including Alzheimer's disease, are tauopathies. Although it is believed that tau protein abnormalities and/or the loss of its functions results in neurodegeneration and dementia, the mechanism of tauopathy remains obscure. Loss of microtubules and/or tubulin is a known consequence of tau accumulating in neurons in Alzheimer's disease. In other words, there is an excess level of tau relative to tubulin in tauopathy neurons. To test whether this imbalance of tau and tubulin expression results in the neurotoxicity of tau, we developed several transgenic C. elegans lines that express human tau at various levels in pan-neurons. These worms showed behavioral abnormalities in a tau expression-dependent manner. The knockdown of a tubulin-specific chaperon, or a subset of tubulin, led to enhanced tau toxicity even in low-expressing tau-transgenic worms that showed no abnormal behaviors. In addition, the suppression of tau expression in tubulin knockdown worms rescued neuronal dysfunction. Thus, not only the overexpression of tau but also a reduction in tubulin can trigger the neurotoxicity of tau. Tau expressed in worms was also highly phosphorylated and largely bound to tubulin dimers rather than microtubules. Relative amount of tubulin-unbound tau was increased in high expressing tau-transgenic worms showing tau toxicity. We further demonstrated that tau aggregation was inhibited by co-incubation of purified tubulin in vitro, meaning sufficient amounts of tubulin can protect against the formation of tau inclusions. These results suggest that the expression ratio of tau to tubulin may be a determinant of the tauopathy cascade. PMID- 29973865 TI - Corrigendum: Multi-modal Brain MRI in Subjects with PD and iRBD. AB - [This corrects the article on p. 709 in vol. 11, PMID: 29311789.]. PMID- 29973864 TI - Suppressor of Cytokine Signaling 3: Emerging Role Linking Central Insulin Resistance and Alzheimer's Disease. AB - Currently, the etiology of Alzheimer's disease (AD) is still elusive. Central insulin resistance has been determined to play an important role in the progress of AD. However, the mechanism underlying the development of disrupted insulin signaling pathways in AD is unclear. Suppressor of cytokine signaling 3 (SOCS3) is a member of the SOCS protein family that acts as a negative modulator of insulin signaling in sensitive tissues, such as hepatocytes and adipocytes. However, little is known about its role in neurological diseases. Recent evidence indicates that the level of SOCS3 is increased in the brains of individuals with AD, especially in areas with amyloid beta deposition, suggesting that SOCS3 may regulate the central insulin signaling pathways in AD. Here, we discuss the potential role of SOCS3 in AD and speculate that SOCS3 may be a promising therapeutic target for the treatment of AD. PMID- 29973866 TI - Enhanced Mutant Compensates for Defects in Rhodopsin Phosphorylation in the Presence of Endogenous Arrestin-1. AB - We determined the effects of different expression levels of arrestin-1-3A mutant with enhanced binding to light-activated rhodopsin that is independent of phosphorylation. To this end, transgenic mice that express mutant rhodopsin with zero, one, or two phosphorylation sites, instead of six in the WT mouse rhodopsin, and normal complement of WT arrestin-1, were bred with mice expressing enhanced phosphorylation-independent arrestin-1-3A mutant. The resulting lines were characterized by retinal histology (thickness of the outer nuclear layer, reflecting the number of rod photoreceptors, and the length of the outer segments, which reflects rod health), as well as single- and double-flash ERG to determine the functionality of rods and the rate of photoresponse recovery. The effect of co-expression of enhanced arrestin-1-3A mutant with WT arrestin-1 in these lines depended on its level: higher (240% of WT) expression reduced the thickness of ONL and the length of OS, whereas lower (50% of WT) expression was harmless in the retinas expressing rhodopsin with zero or one phosphorylation site, and improved photoreceptor morphology in animals expressing rhodopsin with two phosphorylation sites. Neither expression level increased the amplitude of the a- and b-wave of the photoresponse in any of the lines. However, high expression of enhanced arrestin-1-3A mutant facilitated photoresponse recovery 2 3-fold, whereas lower level was ineffective. Thus, in the presence of normal complement of WT arrestin-1 only supra-physiological expression of enhanced mutant is sufficient to compensate for the defects of rhodopsin phosphorylation. PMID- 29973867 TI - Deletion of Specific Sphingolipids in Distinct Neurons Improves Spatial Memory in a Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is characterized by progressive neurodegeneration and a concomitant loss of synapses and cognitive abilities. Recently, we have proposed that an alteration of neuronal membrane lipid microdomains increases neuronal resistance toward amyloid-beta stress in cultured neurons and protects from neurodegeneration in a mouse model of AD. Lipid microdomains are highly enriched in a specific subclass of glycosphingolipids, termed gangliosides. The enzyme glucosylceramide synthase (GCS) catalyzes the rate-limiting step in the biosynthesis of these gangliosides. The present work now demonstrates that genetic GCS deletion in subsets of adult forebrain neurons significantly improves the spatial memory and counteracts the loss of dendritic spines in the hippocampal dentate gyrus of 5x familial AD mice (5xFAD//Ugcgf/f//Thy1 CreERT2//EYFP mice), when compared to 5xFAD//Ugcgf/f littermates (5xFAD mice). Aberrantly activated glial cells and their expression of pro-inflammatory cytokines have emerged as the major culprits for synaptic loss in AD. Typically, astrocytic activation is accompanied by a thickening of astrocytic processes, which impairs astrocytic support for neuronal synapses. In contrast to 5xFAD mice, 5xFAD//Ugcgf/f//Thy1-CreERT2//EYFP display a less pronounced thickening of astrocytic processes and a lower expression of tumor necrosis factor-alpha and interleukin 1-alpha in the hippocampus. Thus, this work further emphasizes that GCS inhibition may constitute a potential therapeutic target against AD. PMID- 29973868 TI - Phosphorylation Modulates the Subcellular Localization of SOX11. AB - SOX11 is a key Transcription Factor (TF) in the regulation of embryonic and adult neurogenesis, whose mutation has recently been linked to an intellectual disability syndrome in humans. SOX11's transient activity during neurogenesis is critical to ensure the precise execution of the neurogenic program. Here, we report that SOX11 displays differential subcellular localizations during the course of neurogenesis. Western-Blot analysis of embryonic mouse brain lysates indicated that SOX11 is post-translationally modified by phosphorylation. Using Mass Spectrometry, we found 10 serine residues in the SOX11 protein that are putatively phosphorylated. Systematic analysis of phospho-mutant SOX11 resulted in the identification of the S30 residue, whose phosphorylation promotes nuclear over cytoplasmic localization of SOX11. Collectively, these findings uncover phosphorylation as a novel layer of regulation of the intellectual disability gene Sox11. PMID- 29973869 TI - Endocannabinoid Signaling at Hypothalamic Steroidogenic Factor 1/Proopiomelanocortin Synapses Is Sex- and Diet-Sensitive. AB - We tested the hypotheses that steroidogenic factor (SF)-1 neurons in the hypothalamic ventromedial nucleus (VMN) provide sexually disparate, endocannabinoid (EC)- and diet-sensitive glutamatergic input onto proopiomelanocortin (POMC) neurons. Electrophysiological recordings were performed in hypothalamic slices from intact and castrated guinea pigs, along with in vitro optogenetic experiments in intact male as well as cycling and ovariectomized female NR5A1-Cre mice. In slices from castrated male and female guinea pigs, depolarized-induced suppression of excitation (DSE) time-dependently reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) in POMC neurons generated by electrically stimulating the dorsomedial VMN. Androgen stimulation rapidly enhanced this DSE, which was also found in insulin-resistant, high-fat diet (HFD)-fed males. By contrast, retrograde signaling at VMN/ARC POMC synapses was markedly attenuated in periovulatory females. HFD potentiated central cannabinoid-induced hyperphagia in both males and females, but exerted differential influences on cannabinoid-induced increases in energy expenditure. In NR5A1-Cre mice, the reduction in light-evoked EPSC amplitude caused by postsynaptic depolarization in cycling females was modest in comparison to that seen in intact males. Estradiol attenuated the DSE in light-evoked EPSC amplitude in slices from ovariectomized females. Moreover, the retrograde inhibition of transmission was further accentuated in HFD-fed males. Chemogenetic activation of SF-1 neurons suppressed appetite and increased energy expenditure in males, effects which were attenuated by HFD. Conversely, energy expenditure was increased in estradiol- but not vehicle-treated ovariectomized females. Together with our previous studies indicating that DSE in POMC neurons is EC-mediated, these findings indicate that VMN SF-1/ARC POMC synapses represent a sexually differentiated, EC- and diet-sensitive anorexigenic component within the hypothalamic energy balance circuitry. PMID- 29973871 TI - Electrical Synapses Enhance and Accelerate Interneuron Recruitment in Response to Coincident and Sequential Excitation. AB - Electrical synapses are ubiquitous in interneuron networks. They form intercellular pathways, allowing electrical currents to leak between coupled interneurons. I explored the impact of electrical coupling on the integration of excitatory signals and on the coincidence detection abilities of electrically coupled cerebellar basket cells (BCs). In order to do so, I quantified the influence of electrical coupling on the rate, the probability and the latency at which BCs generate action potentials when stimulated. The long-lasting simultaneous suprathreshold depolarization of a coupled cell evoked an increase in firing rate and a shortening of action potential latency in a reference basket cell, compared to its depolarization alone. Likewise, the action potential probability of coupled cells was strongly increased when they were simultaneously stimulated with trains of short-duration near-threshold current pulses (mimicking the activation of presynaptic granule cells) at 10 Hz, and to a lesser extent at 50 Hz, an effect that was absent in non-coupled cells. Moreover, action potential probability was increased and action potential latency was shortened in response to synaptic stimulations in mice lacking the protein that forms gap junctions between BCs, connexin36, relative to wild-type (WT) controls. These results suggest that electrical synapses between BCs decrease the probability and increase the latency of stimulus-triggered action potentials, both effects being reverted upon simultaneous excitation of coupled cells. Interestingly, varying the delay at which coupled cells are stimulated revealed that the probability and the speed of action potential generation are facilitated maximally when a basket cell is stimulated shortly after a coupled cell. These findings suggest that electrically-coupled interneurons behave as coincidence and sequence detectors that dynamically regulate the latency and the strength of inhibition onto postsynaptic targets depending on the degree of input synchrony in the coupled interneuron network. PMID- 29973872 TI - Commentary: A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia. PMID- 29973870 TI - Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats. AB - Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II-III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD. PMID- 29973873 TI - Memory Recall for High Reward Value Items Correlates With Individual Differences in White Matter Pathways Associated With Reward Processing and Fronto-Temporal Communication. AB - When given a long list of items to remember, people typically prioritize the memorization of the most valuable items. Prior neuroimaging studies have found that cues denoting the presence of high value items can lead to increased activation of the mesolimbic dopaminergic reward circuit, including the nucleus accumbens (NAcc) and ventral tegmental area (VTA), which in turn results in up regulation of medial temporal lobe encoding processes and better memory for the high value items. Value cues may also trigger the use of elaborative semantic encoding strategies which depend on interactions between frontal and temporal lobe structures. We used diffusion tensor imaging (DTI) to examine whether individual differences in anatomical connectivity within these circuits are associated with value-induced modulation of memory. DTI data were collected from 19 adults who also participated in an functional magnetic resonanceimaging (fMRI) study involving a value-directed memory task. In this task, subjects encoded words with arbitrarily assigned point values and completed free recall tests after each list, showing improved recall performance for high value items. Motivated by our prior fMRI finding of increased recruitment of left-lateralized semantic network regions during the encoding of high value words (Cohen et al., 2014), we predicted that the robustness of the white matter pathways connecting the ventrolateral prefrontal cortex (VLPFC) with the temporal lobe might be a determinant of recall performance for high value items. We found that the mean fractional anisotropy (FA) of each subject's left uncinate fasciculus (UF), a fronto-temporal fiber bundle thought to play a critical role in semantic processing, correlated with the mean number of high value, but not low value, words that subjects recalled. Given prior findings on reward-induced modulation of memory, we also used probabilistic tractography to examine the white matter pathway that links the NAcc to the VTA. We found that the number of fibers projecting from left NAcc to VTA was reliably correlated with subjects' selectivity index, a behavioral measure reflecting the degree to which recall performance was impacted by item value. Together, these findings help to elucidate the neuroanatomical pathways that support verbal memory encoding and its modulation by value. PMID- 29973874 TI - Commentary: Transcranial Magnetic Stimulation over Left Inferior Frontal and Posterior Temporal Cortex Disrupts Gesture-Speech Integration. PMID- 29973875 TI - Differential Path-Length Factor's Effect on the Characterization of Brain's Hemodynamic Response Function: A Functional Near-Infrared Study. AB - Functional near-infrared spectroscopy (fNIRS) has evolved as a neuro-imaging modality over the course of the past two decades. The removal of superfluous information accompanying the optical signal, however, remains a challenge. A comprehensive analysis of each step is necessary to ensure the extraction of actual information from measured fNIRS waveforms. A slight change in shape could alter the features required for fNIRS-BCI applications. In the present study, the effect of the differential path-length factor (DPF) values on the characteristics of the hemodynamic response function (HRF) was investigated. Results were compiled for both simulated data sets and healthy human subjects over a range of DPF values from three to eight. Different sets of activation durations and stimuli were used to generate the simulated signals for further analysis. These signals were split into optical densities under a constrained environment utilizing known values of DPF. Later, different values of DPF were used to analyze the variations of actual HRF. The results, as summarized into four categories, suggest that the DPF can change the main and post-stimuli responses in addition to other interferences. Six healthy subjects participated in this study. Their observed optical brain time-series were fed into an iterative optimization problem in order to estimate the best possible fit of HRF and physiological noises present in the measured signals with free parameters. A series of solutions was derived for different values of DPF in order to analyze the variations of HRF. It was observed that DPF change is responsible for HRF creep from actual values as well as changes in HRF characteristics. PMID- 29973876 TI - Therapeutic Effect of Amomum villosum on Inflammatory Bowel Disease in Rats. AB - Introduction:Amomum villosum Lour., a herbaceous plant in the ginger family, has been proven to be effective in treating gastrointestinal diseases. It has been listed in the Chinese Pharmacopeia as a legal source of Amomi Fructus. In our previous study, we demonstrated that treatment with extracts of A. villosum prevented the development and progression of intestinal mucositis. In the current study, we aimed to verify and explain the potential beneficial effects of A. villosum on inflammatory bowel disease (IBD). Methods: The effect of water extracts (WEAV) and volatile oil of A. villosum (VOAV) were evaluated on the immunological role of T lymphocytes and intestinal microecology in IBD rats induced with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Body weight, food intake, colon length/weight, and disease activity index (DAI) as well as tissue damage scores were evaluated. The inflammatory response to IBD was assessed by measuring the expression of myeloperoxidase, interleukin (IL)-17 (IL-17), interferon-gamma (IFN-gamma), IL-10, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta (TGF-beta). The percentage of regulatory CD4+ T cells in rat spleen was measured by flow cytometry and effects on the microbial community were evaluated by 16S rDNA gene sequencing. Results: All TNBS-induced rats showed typical clinical manifestations of IBD. IBD rats in the WEAV and VOAV treatment groups were effective in relieving body weight and appetite loss. Middle and high dosage of VOAV and WEAV significantly reduced the DAI, and tissue damage scores, whereas colon weight/length ratio was increase. All rats in the WEAV and VOAV groups showed significantly decreased IFN-gamma levels and increased levels of IL 10 and TGF-beta. Moreover, we observed that the percentage of regulatory CD4+ T cells was significantly enhanced during treatment with WEAV. In addition, administration of WEAV and VOAV effectively inhibited the release of enterogenic endotoxin, increased short-chain fatty acid-producing bacteria belonging to Firmicutes and Bacteroidetes, and decreased the abundance of Proteobacteria. Conclusion: Treatment with WEAV and VOAV significantly attenuated intestinal inflammation in IBD rats, which was possibly associated with its regulation on inflammatory cytokine and CD4+CD25+FOXP3+ T cells. Moreover, WEAV and VOAV may help maintaining the balance of intestinal microecology. PMID- 29973877 TI - Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers. AB - Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers. Methods: This study was conducted in two parts. Study I was a dose-escalating (5-15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay. Results: Vicagrel (5-15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day). Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260). PMID- 29973878 TI - 18beta-Glycyrrhetinic Acid Inhibits Osteoclastogenesis In Vivo and In Vitro by Blocking RANKL-Mediated RANK-TRAF6 Interactions and NF-kappaB and MAPK Signaling Pathways. AB - Bone metabolism is determined by a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts. The imbalance due to over activated osteoclasts plays an important role in various diseases. Activation of NF-kappaB and MAPK signaling pathways by receptor activator of nuclear factor kappaB ligand (RANKL) is vital for osteoclastogenesis. Here, we for the first time explored the effects of 18beta-glycyrrhetinic acid (18beta-GA), a pentacyclic triterpenoid found in the Glycyrrhiza glabra L roots, on RANKL induced osteoclastogenesis, osteoclast functions and signaling pathways in vitro and in vivo. In bone marrow monocytes (BMMs) and RAW264.7 cells, 18beta-GA inhibited osteoclastogenesis, decreased expression of TRAP, cathepsin K, CTR and MMP-9, blocked actin ring formation and compromised osteoclasts functions in a dose-dependent manner at an early stage with minimal effects on osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). For underlying molecular mechanisms, 18beta-GA inhibited RANKL-induced phosphorylation of p65, p50, and IkappaB, blocked p65 nuclear translocation and decreased the DNA-binding activity of NF-kappaB. Besides, 18beta-GA inhibited the activation of the MAPK pathways. Co-immunoprecipitation showed that 18beta-GA treatment blocked RANK-TRAF6 association at an upstream site. In vivo, 18beta-GA treatment inhibited ovariectomy-induced osteoclastogenesis and reduced bone loss in mice. Overall, our results demonstrated that 18beta-GA inhibited RANKL-induced osteoclastogenesis by inhibiting RANK expression in preosteoclasts and blocking the binding of RANK and TRAF6 which lead to the inhibition of NF-kappaB and MAPK signaling pathways. 18beta-GA is a promising novel candidate in the treatment of osteoclast-related diseases such as postmenopausal osteoporosis. PMID- 29973880 TI - Major Bioactive Compounds in Essential Oils Extracted From the Rhizomes of Zingiber zerumbet (L) Smith: A Mini-Review on the Anti-allergic and Immunomodulatory Properties. AB - Zingiber zerumbet (L) Smith is part of the Zingiberaceae family, one of the largest families of the plant kingdom. Z. zerumbet is a perennial, aromatic and tuberose plant that grows in humid locations where its center of distribution is located in the South-East Asia region. This plant has been traditionally used in foods and beverages and for ornamental purposes. Although many studies have reported on the biomedical applications of Z. zerumbet, the anti-allergic effects of Z. zerumbet and its major bioactive compounds have not yet been summarized in detail. Many major metabolites that have been reported to contain anti-allergic properties are terpene compounds which can be found in the essential oil extracted from the rhizomes of Z. zerumbet, such as zerumbone, limonene, and humulene. The rhizome is among the part of Z. zerumbet that has been widely used for many studies due to its exceptional biomedical applications. Most of these studies have shown that the essential oil, which can be obtained through hydro distillation of the rhizomes from Z. zerumbet, is enriched with various active metabolites. Therefore, this mini-review provides an overview of the main aspects related to the anti-allergic and immunomodulatory properties of the major bioactive compounds found in the essential oils extracted from the rhizomes of Z. zerumbet, with the aim of demonstrating the importance of essential oil extracted from the rhizomes of Z. zerumbet and its bioactive compounds in the treatment of allergy and allergy-related diseases, in addition to other widely reported and extensively studied biomedical applications. PMID- 29973879 TI - Chemoprevention of LA7-Induced Mammary Tumor Growth by SM6Met, a Well Characterized Cyclopia Extract. AB - Breast cancer (BC) is the leading cause of cancer-related deaths in women. Chemoprevention of BC by using plant extracts is gaining attention. SM6Met, a well-characterized extract of Cyclopia subternata with reported selective estrogen receptor subtype activity, has shown tumor suppressive effects in a chemically induced BC model in rats, which is known to be estrogen responsive. However, there is no information on the estrogen sensitivity of the relatively new orthotopic model of LA7 cell-induced mammary tumors. In the present study, the potential chemopreventative and side-effect profile of SM6Met on LA7 cell induced tumor growth was evaluated, as was the effects of 17beta-estradiol and standard-of-care (SOC) endocrine therapies, such as tamoxifen (TAM), letrozole (LET), and fulvestrant (FUL). Tumor growth was observed in the tumor-vehicle control group until day 10 post tumor induction, which declined afterward on days 12-14. SM6Met suppressed tumor growth to the same extent as TAM, while LET, but not FUL, also showed substantial anti-tumor effects. Short-term 17beta-estradiol treatment reduced tumor volume on days prior to day 10, whereas tumor promoting effects were observed during long-term treatment, which was especially evident at later time points. Marked elevation in serum markers of liver injury, which was further supported by histological evaluation, was observed in the vehicle-treated tumor control, TAM, LET, and long-term 17beta-estradiol treatment groups. Alterations in the lipid profiles were also observed in the 17beta-estradiol treatment groups. In contrast, SM6Met did not augment the increase in serum levels of liver injury biomarkers caused by tumor induction and no effect was observed on lipid profiles. In summary, the results from the current study demonstrate the chemopreventative effect of SM6Met on mammary tumor growth, which was comparable to that of TAM, without eliciting the negative side-effects observed with this SOC endocrine therapy. Furthermore, the results of this study also showed some responsiveness of LA7-induced tumors to estrogen and SOC endocrine therapies. Thus, this model may be useful in evaluating potential endocrine therapies for hormone responsive BC. PMID- 29973881 TI - 4-Hydroxyphenylacetic Acid Prevents Acute APAP-Induced Liver Injury by Increasing Phase II and Antioxidant Enzymes in Mice. AB - Acetaminophen (APAP) overdose is the principal cause of drug-induced acute liver failure. 4-hydroxyphenylacetic acid (4-HPA), a major microbiota-derived metabolite of polyphenols, is involved in the antioxidative action. This study seeks to investigate the ability of 4-HPA to protect against APAP-induced hepatotoxicity, as well as the putative mechanisms involved. Mice were treated with 4-HPA (6, 12, or 25 mg/kg) for 3 days, 1 h after the last administration of 4-HPA, a single dose of APAP was intraperitoneally infused for mice. APAP caused a remarkable increase of oxidative stress markers, peroxynitrite formation, and fewer activated phase II enzymes. 4-HPA increased Nrf2 translocation to the nucleus and enhanced the activity of phase II and antioxidant enzymes, and could thereby ameliorate APAP-induced liver injury. Studies reveal that 4-HPA, as an active area of bioactive dietary constituents, could protect the liver against APAP-induced injury, implying that 4-HPA could be a new promising strategy and natural hepatoprotective drug. PMID- 29973882 TI - Pharmacotoxicology of Non-fentanyl Derived New Synthetic Opioids. AB - A class of opioid agonists not structurally related to fentanyl, derived from research publications of pharmaceutical companies or patents within the United States and abroad are contributing to the current opioid epidemic. Novel synthetic opioids (NSOs) created to circumvent drug control laws such as U-47700, U-49900, AH-7921, or MT-45 have no recognized therapeutic use, are clandestinely manufactured and sold on conventional or dark web. We herein provide a review of the pharmacological properties available on most of these substances trying to provide a better knowledge on these compounds, particularly with respect to toxicity and dangerous adverse effects in users. Indeed, these NSOs share not only a great potency of action and receptor affinity with respect to natural or synthetic opiates (e.g., morphine, heroin, and methadone) but also a non negligible toxicity leading to intoxications and fatalities, posing a serious harm to public health and society. PMID- 29973883 TI - Modulation of the ATP-Binding Cassette B1 Transporter by Neuro-Inflammatory Cytokines: Role in the Pathogenesis of Alzheimer's Disease. PMID- 29973884 TI - Exploring the Leaves of Annona muricata L. as a Source of Potential Anti inflammatory and Anticancer Agents. AB - The use of anti-inflammatory natural products to treat inflammatory disorders for cancer prevention and therapy is an appealing area of interest in the last decades. Annona muricata L. is one of the many plant extracts that have been explored owing to their anti-inflammatory and anticancer effects. Different parts of A. muricata especially the leaves have been used for various ethnomedicinal purposes by traditional healers to treat several diseases including cancer, inflammation, diabetes, liver diseases, and abscesses. Some of these experience based claims on the use of the plant have been transformed into evidence-based information by scientific investigations. The leaves of the plant have been extensively investigated for its diverse pharmacological aspects and found eminent for anti-inflammatory and anticancer properties. However, most studies were not on the bioactive isolates which were responsible for the activities but were based on crude extracts of the plant. In this comprehensive review, all significant findings from previous investigations till date on the leaves of A. muricata, specifically on their anti-inflammatory and anticancer activities have been compiled. The toxicology of the plant which has been shown to be due to the presence of neurotoxic annaceous acetogenins and benzyltetrahydro-isoquinoline alkaloids has also been updated to provide recent information on its safety aspects. The present knowledge of the plant has been critically assessed, aimed at providing direction toward improving its prospect as a source of potential anti-inflammatory and anticancer agents. The analysis will provide a new path for ensuring research on this plant to discover new agents to treat inflammatory diseases and cancer. Further in vitro and in vivo studies should be carried out to explore the molecular mechanisms underlying their anti-inflammatory responses in relation to anticancer activity and more detail toxicity study to ensure they are safe for human consumption. Sufficient preclinical data and safety data generated will allow clinical trials to be pursued on this plant and its bioactive compounds. PMID- 29973885 TI - Salvianolic Acid B and Ginsenoside Re Synergistically Protect Against Ox-LDL Induced Endothelial Apoptosis Through the Antioxidative and Antiinflammatory Mechanisms. AB - Salvianolic acid B (SalB) and ginsenoside Re (Re) protect endotheliocytes against apoptosis through different mechanisms. However, whether both compounds could synergistically protect endothelial cells against oxidized low-density lipoprotein (Ox-LDL)-induced apoptosis is unclear. This study aimed to assess the protective effect of combined SalB and Re (SR) treatment on Ox-LDL-induced endothelial apoptosis and to explore the mechanism underlying this effect. Results showed that SalB, Re, or SR could protect against Ox-LDL-induced endothelial apoptosis. Furthermore, the composition of SR was optimized through central composite design with response surface methodology. SR with a composition of 60 MUg/mL of SalB and 120 MUg/mL of Re exerted the optimal protective effect. Network pharmacology research revealed that SalB and Re in SR synergistically protect against Ox-LDL-induced endothelial apoptosis by regulating oxidative stress and phlogistic pathways. In vitro experiments confirmed these results. Compared with the same dose of SalB or Re alone, SR significantly decreased the contents of inflammatory mediators and increased the activities of antioxidant enzymes. SR could synergistically restore the balanced redox state of the cells and inhibit the activation of nuclear transcription factor kappa B and the caspase cascade by activating the phosphatidylinositol 3 kinase/protein kinase B pathway and inhibiting the phosphorylation of p38 mitogen-activated protein kinase. These pathways are regulated by down-regulating the expression of lectin like Ox-LDL receptor-1 and NADPH oxidase and up-regulating the expression of estrogen receptor alpha. Therefore, SR effectively prevents Ox-LDL-induced endothelial apoptosis through antioxidative and antiinflammatory mechanisms. PMID- 29973886 TI - Antennal Protein Profile in Honeybees: Caste and Task Matter More Than Age. AB - Reproductive and task partitioning in large colonies of social insects suggest that colony members belonging to different castes or performing different tasks during their life (polyethism) may produce specific semiochemicals and be differently sensitive to the variety of pheromones involved in intraspecific chemical communication. The main peripheral olfactory organs are the antennal chemosensilla, where the early olfactory processes take place. At this stage, members of two different families of soluble chemosensory proteins [odorant binding proteins (OBPs) and chemosensory proteins (CSPs)] show a remarkable affinity for different odorants and act as carriers while a further family, the Niemann-Pick type C2 proteins (NPC2) may have a similar function, although this has not been fully demonstrated. Sensillar lymph also contains Odorant degrading enzymes (ODEs) which are involved in inactivation through degradation of the chemical signals, once the message is conveyed. Despite their importance in chemical communication, little is known about how proteins involved in peripheral olfaction and, more generally antennal proteins, differ in honeybees of different caste, task and age. Here, we investigate for the first time, using a shotgun proteomic approach, the antennal profile of honeybees of different castes (queens and workers) and workers performing different tasks (nurses, guards, and foragers) by controlling for the potential confounding effect of age. Regarding olfactory proteins, major differences were observed between queens and workers, some of which were found to be more abundant in queens (OBP3, OBP18, and NPC2-1) and others to be more abundant in workers (OBP15, OBP21, CSP1, and CSP3); while between workers performing different tasks, OBP14 was more abundant in nurses with respect to guards and foragers. Apart from proteins involved in olfaction, we have found that the antennal proteomes are mainly characterized by castes and tasks, while age has no effect on antennal protein profile. Among the main differences, the strong decrease in vitellogenins found in guards and foragers is not associated with age. PMID- 29973887 TI - The Role of T Lymphocytes in Skeletal Muscle Repair From Traumatic and Contraction-Induced Injury. AB - Skeletal muscle is prone to damage from a range of stimuli, and initiates a robust repair process that requires the participation of immune cells. Among the more well characterized immune cells involved in muscle repair are those of the myeloid lineage, including neutrophils, macrophages, monocytes, and eosinophils. More recently, studies have begun to elucidate the role of the lymphoid-derived immune cells, most notably T lymphocytes (T-cells), in the complex processes of muscle repair. Though T-cells have been traditionally been associated with pathological degeneration of skeletal muscle in disease, recent studies show that T-cells are instrumental in the repair/regeneration process following severe muscle damage in mice. Furthermore, a few studies using basic immunohistochemical assays have shown that T-cells accumulate in human skeletal muscle in the days following contraction-induced muscle damage. The functional significance of T cells in the repair and adaptation process following contraction-induce muscle damage remains uncertain, and is an active area of intense investigation. This mini-review summarizes recent findings on the involvement of T-cells in skeletal muscle repair. PMID- 29973888 TI - Physiological and Physical Profile of Snowboarding: A Preliminary Review. AB - The sport of snowboarding has grown in popularity as both a recreational winter activity as well as a prominent Olympic sport. Both forms are comprised of one of three different disciplines within the sport: freestyle, alpine, and snowboard cross. In recent years, the increased professionalism and substantial growth of snowboarding as a global sport has increasingly attracted the interest of exercise physiologists and sport scientists. Given the small (but growing) number of studies that have been published, the research analyzing the physiological and performance characteristics and requirements of snowboarding remains limited. The absence of such studies signifies a lack of examination into this important but under-explored area of research, which could contribute valuable information to the scientific community and international snowboarding teams. The studies conducted thus far have indicated different requirements of physiological and physical traits dependent upon the specific discipline of snowboarding in question. For example, in order to meet the divers demands of each discipline, athletes must develop various qualities, such as muscular strength and power. This can increase their ability to withstand the high forces and loads on the muscular system during competition, and further decrease their risk of lower limbs injuries. At the same time, the studies acknowledge the potential advantages of aerobic fitness in terms of recovery, to more efficiently sustain the athlete through both competitive and on- and off-snow training sessions. Given the value and breadth of application of these limited studies, further analysis and research could contribute greater knowledge and benefits to the field of snowboarding. Therefore, it is the purpose of this preliminary review to explore the current literature, providing further insight into the physiological and physical demands of snowboarding performance. This preliminary review is intended to stimulate interest among the communities of exercise physiologists, sport scientists and particularly coaches in order to improve our current understanding of snowboarding and its demands as a sport. This preliminary review further seeks to develop protocols and strategies to assess physiological and performance characteristics of snowboarding, monitor athletic performance, provide practical recommendations for training, identify new areas of scientific research, and develop accurate talent identification programs. PMID- 29973889 TI - Cross-Cultural Notions of Risk and Liberty: A Comparison of Involuntary Psychiatric Hospitalization and Outpatient Treatment in New York, United States and Zurich, Switzerland. AB - Involuntary hospitalization is a frequently discussed intervention physicians must sometimes execute. Because this intervention has serious implications for the citizens' civil liberties it is regulated by law. Every country's health system approaches this issue differently with regard to the relevant laws and the logistical processes by which involuntary hospitalization generally is enacted. This paper aims at analyzing the regulation and process of involuntary hospitalization in New York (United States) and Zurich (Switzerland). Comparing the respective historical, political, and economic backgrounds shows how notions of risk and liberty are culture-bound and consequently shape legislation and local practices. It is highly relevant to reconsider which criteria are required for involuntary hospitalization as this might shape the view of society on psychiatric patients and psychiatry itself. Furthermore, this article discusses the impact that training and experience of the person authorized to conduct and maintain an involuntary hospitalization has on the outcome. PMID- 29973890 TI - The Relevance of Explanatory First-Person Approaches (EFPA) for Understanding Psychopathological Phenomena. The Role of Phenomenology. AB - The main aim of this paper is to demonstrate the contributions of phenomenology inspired approaches to the explanation of psychopathological phenomena. First, I introduce the notion of Explanatory First-Person Approaches (EFPA) which share the assumption that the explanation of consciousness and conscious phenomena necessitates, at least partially, phenomenal facts functioning as explanans. Phenomenal facts refer to facts about structures and processes of consciousness. To differentiate phenomenology from other EFPA and to extract its distinctive feature, I compare phenomenology to the method falling under the category of EFPA it overlaps with the most: new introspective methods as recently described. I then present genetic phenomenology as the distinctive feature of phenomenology and show how particularly genetic phenomenology complements biological explanations of psychopathological phenomena in the context of psychiatric disorders such as schizophrenia. Moreover, I present Cognitive Theory (CT) as the most acknowledged EFPA in the broader scientific community, demonstrate CT's limitations in explaining conscious phenomena in the context of psychological disturbances such as depression, and show how genetic phenomenology can also significantly complement the cognitive approach. An example in the context of burnout-depression will be given. The overall argument for the significance of phenomenology is as follows: Genetic phenomenology renders phenomenology a distinctive kind of EFPA; genetic phenomenology can complement one of the most dominant non-EFPA accounts in the science of psychiatric disorders: biological reductionism; and genetic phenomenology can complement the most dominant existing EFPA in the science of psychological disturbances: Cognitive Theory. PMID- 29973891 TI - Outcome Evaluation in Social Context Measured by Event-Related Potentials Is Partially Dependent on the Partner's Sex. AB - Outcome evaluation is a cognitive process that people rely on feedback information to evaluate behavior results. It can help people to modify the previous mistakes in order to facilitate the performance of the behavior. In the present study, we examined sex differences in outcome evaluation when men and women performed a "Chuck-A-Luck" dice game with a same-versus opposite-sex partner. We recruited 40 college students (Half of women) to perform the gambling game task, and event-related potentials (ERPs) were recorded for outcome feed back when male or female participants performed the game alone, or with same versus opposite-sex partners. Two main findings are reported in our study. (1) FRN amplitude of same-sex condition was significantly greater than alone condition for male when the feedback was loss. However, FRN amplitude of opposite sex condition was significantly greater than alone condition for female when feedback was loss. (2) The loss feedback induced greater P300 than gain only in alone condition. It suggests that sex differences in outcome evaluation is a complex process that is partially influenced by the partner's sex. PMID- 29973892 TI - Humor Assessment and Interventions in Palliative Care: A Systematic Review. AB - Background: The central goal of palliative care is to optimize the quality of life of patients suffering from life-limiting illnesses, which includes psychosocial and spiritual wellbeing. Research has demonstrated positive correlations between humor and laughter with life satisfaction and other aspects of wellbeing, and physiological symptoms can be improved by humorous stimuli. Objectives: The aim of this review is to evaluate humor interventions and assessments that have been applied in palliative care and to derive implications for future research. Methods: A systematic review of four databases identified 13 included studies. Criteria for inclusion were peer-reviewed English-language studies on humor interventions or assessments in a palliative care context. Results: Two studies on humor interventions and 11 studies on humor assessment were included in the systematic review. Most of these studies were about the patients' perspective on humor in palliative care. Findings showed that humor had a positive effect on patients, their relatives, and professional caregivers. Humor was widely perceived as appropriate and seen as beneficial to care in all studies. Conclusions: Even though humor interventions seem to be potentially useful in palliative care, descriptions evaluating their use are scarce. Overall, research on humor assessment and interventions in palliative care has remained limited in terms of quantity and quality. More research activities are needed to build a solid empirical foundation for implementing humor and laughter as part of regular palliative care activities. PMID- 29973893 TI - Preliminary Validation of Japanese Version of the Parental Burnout Inventory and Its Relationship With Perfectionism. AB - Parenting is a precious experience and also a very hard task, which could result in parental burnout for some parents. The present study sought to validate a Japanese version of the Parental Burnout Inventory (PBI-J) by replicating and extending the pioneering work of Roskam et al. (2017). We conducted a web survey (N = 1200) to first validate the PBI-J and second to investigate the association between the PBI-J and perfectionism as a new interrelation. Similar to the prior study of Roskam et al. (2017), confirmatory factor analysis supported a model of three-factor structure of the PBI-J: emotional exhaustion, lack of personal accomplishment, and emotional distancing. In addition, we found low to moderate correlations of parental burnout with job burnout, parental stress, and depression. These findings provided initial evidence for validity of the PBI-J and suggested that parental burnout appeared to be different from job burnout. Our further evaluation of perfectionism confirmed such a difference between parental and job burnout by showing that parental perfectionism [i.e., combination of parental personal standards (PS) and parental concern over mistakes (CM)] has a unique contribution to parental burnout than does job perfectionism (i.e., combination of job PS and job CM). In addition, CM was positively correlated with burnout in both domains whereas the associations between PS and burnout were more complex. Finally, the proportion of parents experiencing burnout was estimated to lie somewhere between 4.2 and 17.3% in Japan. Overall, the present study confirmed preliminary validity of the PBI-J and found that parental perfectionism is one of the vulnerability factors in parental burnout. PMID- 29973894 TI - Skiing and Thinking About It: Moment-to-Moment and Retrospective Analysis of Emotions in an Extreme Sport. AB - Happiness is typically reported as an important reason for participating in challenging activities like extreme sport. While in the middle of the activity, however, participants do not seem particularly happy. So where does the happiness come from? The article proposes some answers from a study of facially expressed emotions measured moment-by-moment during a backcountry skiing event. Self reported emotions were also assessed immediately after the skiing. Participants expressed lower levels of happiness while skiing, compared to when stopping for a break. Moment-to-moment and self-reported measures of emotions were largely unrelated. These findings are explained with reference to the Functional Wellbeing Approach (Vitterso, 2013), which argues that some moment-to-moment feelings are non-evaluative in the sense of being generated directly by the difficulty of an activity. By contrast, retrospective emotional feelings are more complex as they include an evaluation of the overall goals and values associated with the activity as a whole. PMID- 29973895 TI - The Cardiac Rehabilitation Psychodynamic Group Intervention (CR-PGI): An Explorative Study. AB - Objective: An explorative study focusing on the process of a Cardiac Rehabilitation Psychodynamic Group Intervention (CR-PGI) addressed to myocardial infarction (MI) patients is discussed. The study aimed at analyzing whether the treatment based on CR-PGI serves as a communicational context within which MI patients are enabled to explore new interpretations of their post-infarction condition. Methods: The intervention, divided into 12 weekly one-hour group sessions, was addressed to MI patients recruited within a Public Hospital of southern Italy. Each session was audio-recorded and lexical correspondence analysis (LCA) was applied to the verbatim transcripts, in order to provide a map of the evolution of the communication exchange occurring over the 12 sessions. Results: The findings showed that the discourses associated to the first eight sessions differed from the discourses of the last four sessions. Two main transitions occurred. The first concerns the response to the infarction, first interpreted as a process of affective elaboration and afterwards as practical management of the functional aspects associated with the condition of MI patients. The second concerns the nature of the change and contrasts a lifestyle oriented model with a social role approach, which refers to social, legal, and medical practices related to the acknowledgment of being an MI patient. Conclusion: The findings offer preliminary support to the capacity of CR-PGI to work as a context where new meanings for the biographical rupture of the MI can be explored. Consistently with the rationale of the model, the intervention seems to have promoted the emergence of new ways of feeling and understanding one's condition. PMID- 29973896 TI - Absence of Alpha-tACS Aftereffects in Darkness Reveals Importance of Taking Derivations of Stimulation Frequency and Individual Alpha Variability Into Account. AB - Transcranial alternating current stimulation (tACS) has found widespread use as a basic tool in the exploration of the role of brain oscillations. Many studies have shown that frequency-specific tACS is able to not only alter cognitive processes during stimulation, but also cause specific physiological aftereffects visible in the electroencephalogram (EEG). The relationship between the emergence of these aftereffects and the necessary duration of stimulation is inconclusive. Our goal in this study was to narrow down the crucial length of tACS-blocks, by which aftereffects can be elicited. We stimulated participants with alpha-tACS in four blocks of 1-, 3-, 5-, and 10-min length, once in increasing and once in decreasing order. After each block, we measured the resting EEG for 10 min during a visual vigilance task. We could not find lasting enhancement of alpha-power following any stimulation block, when comparing the stimulated groups to the sham group. These findings offer no information regarding the crucial stimulation duration. In addition, this conflicts with previous findings, showing a power increase following 10 min of tACS in the alpha range. We performed additional explorative analyses, based on known confounds of (1) mismatches between stimulation frequency and individual alpha frequency and (2) abnormalities in baseline alpha-activity. The results of an ANCOVA suggested that both factor explain variance, but could not resolve how exactly both factors interfere with the stimulation effect. Employing a linear mixed model, we found a significant effect of stimulation following 10 min of alpha-tACS in the increasing sequence and a significant effect of the mismatch between stimulated frequency and individual alpha frequency. The implications of these findings for future research are discussed. PMID- 29973897 TI - The Effect of Mindfulness Training on Proactive and Reactive Cognitive Control. AB - Previous studies have demonstrated that mindfulness practice can improve general cognitive control. However, little research has examined whether mindfulness practices affect different cognitive control strategies. According to the dual mechanisms of control (DMC) model, different cognitive control strategies may play distinct roles in individuals' lives. Proactive control allows people to maintain and prepare for goals, whereas reactive control allows them to respond flexibly to a changing environment. Thus, this study investigates the influences of mindfulness training on proactive and reactive control measured by the AX version of the Continuous Performance Test (AX-CPT). Thirty participants completed AX-CPT and the Five Facet Mindfulness Questionnaire (FFMQ) before and after random assignment to either an 8-week mindfulness training group or a control group. The results showed no interaction between group and test time for AY or BX trial type, but the training group had fewer post-test errors on the BX trial and a higher Behavior Shift Index (BSI) of reaction time (RT) compared with the control group. This finding indicates enhanced trend of proactive control with mindfulness training. A positive correlation between the BSI of RT and observing scores on the FFMQ confirmed the connection between attentional components in mindfulness and proactive control. Errors on the AY trial in the post-test decreased in both groups, reflecting reactive control that did not differ between groups. The 8-week mindfulness training demonstrates a potential improvement effect on proactive control and could be helpful in overcoming interference. PMID- 29973898 TI - The Effect of Blindness on Long-Term Episodic Memory for Odors and Sounds. AB - We recently showed that compared with sighted, early blind individuals have better episodic memory for environmental sounds, but not odors, after a short retention interval (~ 8 - 9 min). Few studies have investigated potential effects of blindness on memory across long time frames, such as months or years. Consequently, it was unclear whether compensatory effects may vary as a function of retention interval. In this study, we followed-up participants (N = 57 out of 60) approximately 1 year after the initial testing and retested episodic recognition for environmental sounds and odors, and identification ability. In contrast to our previous findings, the early blind participants (n = 14) performed at a similar level as the late blind (n = 13) and sighted (n = 30) participants for sound recognition. Moreover, the groups had similar recognition performance of odors and identification ability of odors and sounds. These findings suggest that episodic odor memory is unaffected by blindness after both short and long retention intervals. However, the effect of blindness on episodic memory for sounds may vary as a function of retention interval, such that early blind individuals have an advantage over sighted across short but not long time frames. We speculate that the finding of a differential effect of blindness on auditory episodic memory across retention intervals may be related to different memory strategies at initial and follow-up assessments. In conclusion, this study suggests that blindness does not influence auditory or olfactory episodic memory as assessed after a long retention interval. PMID- 29973899 TI - Observing the World Through Your Own Lenses - The Role of Perceived Adaptability for Epistemological Beliefs About the Development of Scientific Knowledge. AB - Students are exposed to vast amounts of information and knowledge that is rapidly changing. This exposure requires them to be adaptive, that is, to constantly adjust their thinking, behavior, and even their affect to successfully solve information-rich and knowledge-lean problems. Considering these developments, the purpose of the present study is twofold: First, it is aimed at exploring the link between students' beliefs about their adaptability in an ever-changing world and their beliefs about the changing nature of scientific knowledge, thus linking two educationally relevant belief systems. Second, this study further explores validity issues related to the well-established and commonly used "Epistemological Beliefs about the Development of Scientific Knowledge (EBDE)" scale. Performing structural equation modeling on a large-scale data set of 1,662 Norwegian tenth-grade students, we estimated the correlations among different aspects of adaptability (i.e., cognitive-behavioral and affective-emotional adaptability) and EBDE. Moving beyond these correlations, we tested whether students' perceived adaptability had an impact on the functioning of EBDE items by means of moderated factor analysis. Our analyses revealed that adaptability was associated with sophisticated EBDE in science, and the EB scale functioned differently with respect to different adaptability scores. The results of this study indicate that students perceive the development of scientific knowledge through the lenses of their own adaptability. Furthermore, the differential functioning of the EBDE scale challenges its validity. PMID- 29973901 TI - Commentary: Effects of Sleep on Word Pair Memory in Children-Separating Item and Source Memory Aspects. PMID- 29973902 TI - Corrigendum: Better Cognitive Performance Is Associated With the Combination of High Trait Mindfulness and Low Trait Anxiety. AB - [This corrects the article on p. 627 in vol. 9, PMID: 29780338.]. PMID- 29973900 TI - Maggot Instructor: Semi-Automated Analysis of Learning and Memory in Drosophila Larvae. AB - For several decades, Drosophila has been widely used as a suitable model organism to study the fundamental processes of associative olfactory learning and memory. More recently, this condition also became true for the Drosophila larva, which has become a focus for learning and memory studies based on a number of technical advances in the field of anatomical, molecular, and neuronal analyses. The ongoing efforts should be mentioned to reconstruct the complete connectome of the larval brain featuring a total of about 10,000 neurons and the development of neurogenic tools that allow individual manipulation of each neuron. By contrast, standardized behavioral assays that are commonly used to analyze learning and memory in Drosophila larvae exhibit no such technical development. Most commonly, a simple assay with Petri dishes and odor containers is used; in this method, the animals must be manually transferred in several steps. The behavioral approach is therefore labor-intensive and limits the capacity to conduct large-scale genetic screenings in small laboratories. To circumvent these limitations, we introduce a training device called the Maggot Instructor. This device allows automatic training up to 10 groups of larvae in parallel. To achieve such goal, we used fully automated, computer-controlled optogenetic activation of single olfactory neurons in combination with the application of electric shocks. We showed that Drosophila larvae trained with the Maggot Instructor establish an odor-specific memory, which is independent of handling and non-associative effects. The Maggot Instructor will allow to investigate the large collections of genetically modified larvae in a short period and with minimal human resources. Therefore, the Maggot Instructor should be able to help extensive behavioral experiments in Drosophila larvae to keep up with the current technical advancements. In the longer term, this condition will lead to a better understanding of how learning and memory are organized at the cellular, synaptic, and molecular levels in Drosophila larvae. PMID- 29973903 TI - Corrigendum: Modified Logistic Regression Approaches to Eliminating the Impact of Response Styles on Differential Item Functioning Detection in Likert-Type Scale. AB - [This corrects the article on p. 1143 in vol. 8, PMID: 28736542.]. PMID- 29973905 TI - Ovarian Reserve in Women With Neuromyelitis Optica Spectrum Disorder. AB - Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disease. The majority of NMOSD patients is seropositive for aquaporin-4 (AQP4) antibodies. AQP4 is the main water channel protein in the central nervous system, but has also been identified in the female reproductive system. Fertility issues and ovarian reserve has not yet been studied in females with NMOSD. The purpose of this study was to measure serum Anti-Mullerian hormone (AMH) in females with NMOSD compared to healthy controls (HC), in combination with other lifestyle and reproduction parameters. AMH is independent from the menstrual cycle and a reliable indicator of both ovarian reserve and ovarian function. We included a total of 32 reproductive-age females, 18 HC and 14 with NMOSD. We used an enzymatically amplified two-site immunoassay to determine serum AMH level. In comparison to HC, mean AMH value was reduced in NMOSD. Apart from that significantly more women with NMOSD showed low AMH levels (< 0.8 ng/ml). Low AMH was associated with disease activity. In contrast, none of the immunotherapies for NMOSD, neither any reproductive life style parameter was associated with a decreased AMH. Our results contribute to understanding of hindered fertility in females with NMOSD and enables neurologists to better counsel female patients. PMID- 29973904 TI - Mild Intrauterine Hypoperfusion Leads to Lumbar and Cortical Hyperexcitability, Spasticity, and Muscle Dysfunctions in Rats: Implications for Prematurity. AB - Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders. PMID- 29973906 TI - Automated Long-Term EEG Review: Fast and Precise Analysis in Critical Care Patients. AB - Background: Ongoing or recurrent seizure activity without prominent motor features is a common burden in neurological critical care patients and people with epilepsy during ICU stays. Continuous EEG (CEEG) is the gold standard for detecting ongoing ictal EEG patterns and monitoring functional brain activity. However CEEG review is very demanding and time consuming. The purpose of the present multirater, EEG expert reviewer study, is to test and assess the clinical feasibility of an automatic EEG pattern detection method (Neurotrend). Methods: Four board certified EEG reviewers used Neurotrend to annotate 76 CEEG datasets a 6 h (in total 456 h of EEG) for rhythmic and periodic EEG patterns (RPP), unequivocal ictal EEG patterns and burst suppression. All reviewers had a predefined time limit of 5 min (+/- 2 min) per CEEG dataset and were compared to a predefined gold standard (conventional EEG review with unlimited time). Subanalysis of specific features of RPP was conducted as well. We used Gwet's AC1 and AC2 coefficients to calculate interrater agreement (IRA) and multirater agreement (MRA). Also, we determined individual performance measures for unequivocal ictal EEG patterns and burst suppression. Bonferroni-Holmes correction for multiple testing was applied to all statistical tests. Results: Mean review time was 3.3 min (+/- 1.9 min) per CEEG dataset. We found substantial IRA for unequivocal ictal EEG patterns (0.61-0.79; mean sensitivity 86.8%; mean specificity 82.2%, p < 0.001) and burst suppression (0.68-0.71; mean sensitivity 96.7%; mean specificity 76.9% p < 0.001). Two reviewers showed substantial IRA for RPP (0.68-0.72), whereas the other two showed moderate agreement (0.45-0.54), compared to the gold standard (p < 0.001). MRA showed almost perfect agreement for burst suppression (0.86) and moderate agreement for RPP (0.54) and unequivocal ictal EEG patterns (0.57). Conclusions: We demonstrated the clinical feasibility of an automatic critical care EEG pattern detection method on two levels: (1) reasonable high agreement compared to the gold standard, (2) reasonable short review times compared to previously reported EEG review times with conventional EEG analysis. PMID- 29973907 TI - Pre-alpha-pro-GDNF and Pre-beta-pro-GDNF Isoforms Are Neuroprotective in the 6 hydroxydopamine Rat Model of Parkinson's Disease. AB - Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-alpha-pro GDNF (alpha-GDNF) and pre-beta-pro-GDNF (beta-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the alpha GDNF isoform, and nothing is known about the in vivo effects of the shorter beta GDNF variant. Here we compare for the first time the effects of overexpressed alpha-GDNF and beta-GDNF in non-lesioned rat striatum and the partial 6 hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno associated virus (AAV) vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non lesioned striatum, both isoforms increased the density of dopamine transporter positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only alpha-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both alpha-GDNF and beta-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, beta-GDNF, and the full-length alpha-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry. PMID- 29973908 TI - Distribution and Structure of DM2 Repeat Tract Alleles in the German Population. AB - Autosomal dominant inherited Myotonic dystrophy type 1 and 2 (DM1 and DM2) are the most frequent muscle dystrophies in the European population and are caused by repeat expansion mutations. For Germany cumulative empiric evidence suggests an estimated prevalence of DM2 of roughly 9 in 100,000, therefore being as prevalent as DM1. In DM2, a (CCTG)n repeat tract located in the first intron of the CNBP gene is expanded. The CCTG repeat tract is part of a complex repeat structure comprising not only CCTG tetraplets but also repeated TG dinucleotides and TCTG tetraplet elements as well as NCTG interruptions. Here, we provide the distribution of normal sized alleles in the German population, which was found to be highly similar to the Slovak population. Sequencing of 34 unexpanded healthy range alleles in DM2 positive patients (heterozygous for a full expansion) revealed that the CCTG repeat tract is usually interrupted by at least three tetraplets which according to current opinion is supposed to render it stable against expansion. Interestingly, only the largest analyzed normal allele had 23 uninterrupted CCTGs and consequently could represent an instable early premutation allele. In our diagnostic history of DM2 cases, a total of 18 premutations were detected in 16 independent cases. Here, we describe two premutation families, one with an expansion from a premutation allele and the other with a contraction of a full expansion down to a premutation allele. Our diagnostic results support the general assumption that the premutation range of unstable CCTG stretches lies obviously between 25 and 75 CCTGs. However, the clinical significance of premutation alleles is still unclear. In the light of the two described families we suggest incomplete penetrance. Thus, as it was proposed for other repeat expansion diseases (e.g., Huntington's disease), a fluid transition of penetrance is more likely rather than a clear cut CCTG number threshold. PMID- 29973909 TI - Longitudinal Changes of Caudate-Based Resting State Functional Connectivity in Mild Traumatic Brain Injury. AB - Mild traumatic brain injury (mild TBI) is associated with dysfunctional brain network and accumulating evidence is pointing to the caudate as a vulnerable hub region. However, little is known about the longitudinal changes in the caudate based resting-state functional connectivity following mild TBI. In the current study, 50 patients with mild TBI received resting-state functional magnetic resonance imaging as well as neuropsychological assessments within 7 days post injury (acute phase) and 1 month later (subacute phase). Thirty-six age- and gender- matched healthy controls underwent the same protocol. The caudate was segmented into the dorsal and ventral sub-regions based on their related functionally distinct neural circuits and separate functional connectivity was investigated. Results indicated that patients with mild TBI at acute phase exhibited reduced left dorsal caudate-based functional connectivity with ventral lateral prefrontal cortex, dorsal anterior cingulate cortex, and inferior parietal lobule, which mainly distributed in the cognitive control network, and reduced right ventral caudate-based functional connectivity with the dorsal lateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and bilateral ventral anterior cingulate cortex (vACC), which mainly distributed in the executive network and emotional processing network. Furthermore, patients with mild TBI presented the reduced functional connectivity between the left dorsal caudate and the ventral lateral prefrontal cortex (vlPFC) compared with healthy controls at acute phase while this difference became no significance and return to the normal level following 1 month post-injury subacute phase. Similarly, the functional connectivity between the right ventral caudate and anterior cingulate cortex (both dorsal and ventral part) showed the reduced strength in patients compared with healthy controls only at the acute phase but presented no significant difference at subacute phase following mild TBI. Along the same line, patients with mild TBI presented the impaired performance on the information processing speed and more complaints on the pain impact index at acute phase compared with healthy controls but showed no significant difference at the follow up 1 month post-injury subacute phase. The longitudinal changes of caudate-based dysfunction connectivity could serve as a neuroimaging biomarker following patients with mild TBI, with the evidence that the abnormal caudate-based functional connectivity at acute phase have returned to the normal level accompanying with the recovery of the neuropsychological syndromes following patients with mild TBI at subacute phase. PMID- 29973910 TI - Diffusion Tensor Imaging (DTI) Correlates of Self-Reported Sleep Quality and Depression Following Mild Traumatic Brain Injury. AB - Background: Mild traumatic brain injuries (mTBIs) are a significant social, sport, and military health issue. In spite of advances in the clinical management of these injuries, the underlying pathophysiology is not well-understood. There is a critical need to advance objective biomarkers, allowing the identification and tracking of the long-term evolution of changes resulting from mTBI. Diffusion weighted imaging (DWI) allows for the assessment of white-matter properties in the brain and shows promise as a suitable biomarker of mTBI pathophysiology. Methods: 34 individuals within a year of an mTBI (age: 24.4 +/- 7.4) and 18 individuals with no history of mTBI (age: 23.2 +/- 3.4) participated in this study. Participants completed self-report measures related to functional outcomes, psychological health, post-injury symptoms, and sleep, and underwent a neuroimaging session that included DWI. Whole-brain white matter was skeletonized using tract-based spatial statistics (TBSS) and compared between groups as well as correlated within-group with the self-report measures. Results: There were no statistically significant anatomical differences between the two groups. After controlling for time since injury, fractional anisotropy (FA) demonstrated a negative correlation with sleep quality scores (higher FA was associated with better sleep quality) and increasing depressive symptoms in the mTBI participants. Conversely, mean (MD) and radial diffusivity (RD) demonstrated positive correlations with sleep quality scores (higher RD was associated with worse sleep quality) and increasing depressive symptoms. These correlations were observed bilaterally in the internal capsule (anterior and posterior limbs), corona radiata (anterior and superior), fornix, and superior fronto-occipital fasciculi. Conclusion: The results of this study indicate that the clinical presentation of mTBI, particularly with respect to depression and sleep, is associated with reduced white-matter integrity in multiple areas of the brain, even after controlling for time since injury. These areas are generally associated not only with sleep and emotion regulation but also cognition. Consequently, the onset of depression and sleep dysfunction as well as cognitive impairments following mTBI may be closely related to each other and to white matter integrity throughout the brain. PMID- 29973911 TI - Traumatic Brain Injury and Firearm Use and Risk of Progressive Supranuclear Palsy Among Veterans. AB - Background: Progressive supranuclear palsy (PSP) is a tauopathy that has a multifactorial etiology. Numerous studies that have investigated lead exposure and traumatic brain injury (TBI) as risk factors for other tauopathies, such as Alzheimer's disease, but not for PSP. Objective: We sought to investigate the role of firearm usage, as a possible indicator of lead exposure, and TBI as risk factors for PSP in a population of military veterans. Methods: We included participants from a larger case-control study who reported previous military service. Our sample included 67 PSP cases and 68 controls. Participants were administered a questionnaire to characterize firearm use in the military and occurrence of TBI. Results: Cases were significantly less educated than controls. In unadjusted analyses, the proportion of PSP cases (80.6%) and controls (64.7%) who reported use of firearms as part of their military job was positively associated with PSP, odds ratio (OR) 2.2 (95% CI: 1-5.0). There were no significant case-control differences in mean service duration. There was only a weak association with history of TBI, OR 1.6 (95% CI: 0.8-3.4). In multivariate models, firearm usage (OR 3.7, 95% CI: 1.5, 9.8) remained significantly associated with PSP. Conclusions: Our findings show a positive association between firearm usage and PSP and an inverse association between education and PSP. The former suggests a possible etiologic role of lead. Further studies are needed to confirm the potential etiologic effects of metals on PSP. The study was registered in clinicaltrials.gov. ClinicalTrials.gov Identifier: NCT00431301. PMID- 29973912 TI - A Comparative Study of Two Blast-Induced Traumatic Brain Injury Models: Changes in Monoamine and Galanin Systems Following Single and Repeated Exposure. AB - Repeated mild blast-induced traumatic brain injury (rmbTBI), caused by recurrent exposure to low levels of explosive blast, is a significant concern for military health systems. However, the pathobiology of rmbTBI is currently poorly understood. Animal models are important tools to identify the molecular changes of rmbTBI, but comparisons across different models can present their own challenges. In this study, we compared two well-established rodent models of mbTBI, the "KI model" and the "USU/WRAIR model." These two models create different pulse forms, in terms of peak pressure and duration. Following single and double exposures to mild levels of blast, we used in situ hybridization (ISH) to assess changes in mRNA levels of tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH2), and galanin in the locus coeruleus (LC) and dorsal raphe nucleus (DRN). These systems and their transmitters are known to mediate responses to stress and anxiety. We found increased mRNA levels of TH, TPH2 and galanin in the LC and DRN of single-exposed rats relative to sham rats in the KI but not the USU/WRAIR model. Sham mRNA values measured in the USU/WRAIR model were substantially higher than their KI counterparts. Double exposure caused similarly significant increases in mRNA values in the KI model but not the USU/WRAIR model, except TPH2 and galanin levels in the DRN. We detected no cumulative effect of injury in either model at the used inter-injury interval (30 min), and there were no detectable neuropathological changes in any experimental group at 1 day post-injury. The apparent lack of early response to injury as compared to sham in the USU/WRAIR model is likely caused by stressors (e.g., transportation and noise), associated with the experimental execution, that were absent in the KI model. This study is the first to directly compare two established rodent models of rmbTBI, and to highlight the challenges of comparing findings from different animal models. Additional studies are needed to understand the role of stress, dissect the effects of psychological and physical injuries and to identify the window of increased cerebral vulnerability, i.e., the inter-injury interval that results in a cumulative effect following repeated blast exposure. PMID- 29973913 TI - Cognitive Profiles and Hub Vulnerability in Parkinson's Disease. AB - The clinicopathological correlations between aspects of cognition, disease severity and imaging in Parkinson's Disease (PD) have been unclear. We studied cognitive profiles, demographics, and functional connectivity patterns derived from resting-state fMRI data (rsFC) in 31 PD subjects from the Parkinson's Progression Markers Initiative (PPMI) database. We also examined rsFC from 19 healthy subjects (HS) from the Pacific Parkinson's Research Centre. Graph theoretical measures were used to summarize the rsFC patterns. Canonical correlation analysis (CCA) was used to relate separate cognitive profiles in PD that were associated with disease severity and demographic measures as well as rsFC network measures. The CCA model relating cognition to demographics suggested female gender and education supported cognitive function in PD, age and depression scores were anti-correlated with overall cognition, and UPDRS had little influence on cognition. Alone, rsFC global network measures did not significantly differ between PD and controls, yet some nodal network measures, such as network segregation, were distinguishable between PD and HS in cortical "hub" regions. The CCA model relating cognition to rsFC global network values, which was not related to the other CCA model relating cognition to demographic information, suggested modularity, rich club coefficient, and transitivity was also broadly related to cognition in PD. Our results suggest that education, aging, comorbidity, and gender impact cognition more than overall disease severity in PD. Cortical "hub" regions are vulnerable in PD, and impairments of processing speed, attention, scanning abilities, and executive skills are related to enhanced functional segregation seen in PD. PMID- 29973915 TI - Nonalcoholic Fatty Liver Disease in University Rugby Football Players. AB - Physical activity improves various metabolic disturbances. The effect of physical activity on non-alcoholic fatty liver disease (NAFLD) has not been defined, particularly in athletes who are able to consume a diet to increase body mass. The aim of this study was to evaluate the prevalence of NAFLD and associated factors of NAFLD among male university rugby football players [n = 69, 37 forwards (FW) and 32 backs (BK)], relative to age-matched controls (CON; n = 29). For FW players exercise consists of physical contact play, such as ruck, mall, scrum, and tackle. For BK players exercise consists of sprints and endurance running. Liver function tests and bioimpedance analysis to assess body composition were performed. Subjects consuming <= 20 g/day of ethanol and exhibiting an aspartate transaminase (AST) level >= 33 U/L, and/or alanine transaminase (ALT) level >= 43 U/L, were considered to have NAFLD. The PNPLA3 and MTP genotypes were determined using real-time polymerase chain reaction (PCR). The body mass index, body fat mass, and lean body mass were significantly higher in the FW group than in the BK and CON groups (P < 0.05). The total cholesterol, low-density lipoprotein cholesterol, triglyceride, AST, ALT, and alkaline phosphatase levels were significantly higher in the FW group than in the CON group (P < 0.05). The prevalence of NAFLD was significantly higher in the FW group than in the BK group and CON group (18.9, 8.6, and 0.0%, respectively), whereas there were non-significant between-group differences in the frequency of the PNPLA3 and MTP genotypes. These findings indicate that rugby football players, especially those in the FW position, are at higher risk of developing NAFLD, which emphasizes the role of diet and exercise in the development of NAFLD. PMID- 29973914 TI - Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging? AB - Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 +/- 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (>=1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods. PMID- 29973916 TI - An Engineered Distant Homolog of Pseudomonas syringae TTSS Effector From Physcomitrella patens Can Act as a Bacterial Virulence Factor. AB - Pseudomonas syringae pv. phaseolicola is the causative agent of halo blight in common bean (Phaseolus vulgaris). Similar to other pathogenic gram-negative bacteria, it secrets a set of type III effectors into host cells to subvert defense mechanisms. HopQ1 (for Hrp outer protein Q) is one of these type III effectors contributing to virulence of bacteria. Upon delivery into a plant cell, HopQ1 undergoes phosphorylation, binds host 14-3-3 proteins and suppresses defense-related signaling. Some plants however, evolved systems to recognize HopQ1 and respond to its presence and thus to prevent infection. HopQ1 shows homology to Nucleoside Hydrolases (NHs), but it contains a modified calcium binding motif not found in the canonical enzymes. CLuster ANalysis of Sequences (CLANS) revealed that HopQ1 and alike proteins make a distinct group of putative NHs located distantly from the classical enzymes. The HopQ1 - like protein (HLP) group comprises sequences from plant pathogenic bacteria, fungi, and lower plants. Our data suggest that the evolution of HopQ1 homologs in bacteria, fungi, and algae was independent. The location of moss HopQ1 homologs inside the fungal clade indicates a possibility of horizontal gene transfer (HGT) between those taxa. We identified a HLP in the moss Physcomitrella patens. Our experiments show that this protein (referred to as PpHLP) extended by a TTSS signal of HopQ1 promoted P. syringae growth in bean and was recognized by Nicotiana benthamiana immune system. Thus, despite the low sequence similarity to HopQ1 the engineered PpHLP acted as a bacterial virulence factor and displayed similar to HopQ1 virulence properties. PMID- 29973917 TI - Parallel Tests Using Culture, Xpert MTB/RIF, and SAT-TB in Sputum Plus Bronchial Alveolar Lavage Fluid Significantly Increase Diagnostic Performance of Smear Negative Pulmonary Tuberculosis. AB - At present, tuberculosis remains a serious threat to human health. The diagnosis of pulmonary tuberculosis (PTB) is still difficult, and the prominent challenge for diagnosis is the lack of a highly sensitive and specific method. In order to explore the diagnostic value of parallel tests, this study prospectively enrolled 258 patients with smear-negative PTB from May 2, 2015 to December 31, 2016. The sputum specimens and bronchial alveolar lavage fluid (BALF) samples from all patients were assessed for MTB detection by culture, Xpert MTB/RIF, and simultaneous amplification and testing method for TB (SAT-TB). Overall, the sensitivity of any single test using culture, Xpert MTB/RIF, or SAT-TB was lower than that for parallel tests (p < 0.05), and the sensitivity rates for MTB detection in BALF were significantly higher than those in sputum samples. There were lower agreements in the detection results between sputum samples and BALF for all tests (p < 0.05). The parallel tests models of using culture plus Xpert MTB/RIF plus SAT-TB, culture plus Xpert, or culture plus SAT-TB achieved higher sensitivities compared with all three single test models (p < 0.05). Additionally, joint detection using sputum and BALF samples achieved a high sensitivity (0.8566, 95% CI: 0.8086-0.8941). In conclusion, the parallel tests model using culture, Xpert MTB/RIF, and SAT-TB in sputum plus BALF significantly increases the diagnostic performance of smear-negative PTB; thus, this method should be applied clinically when PTB is suspected but smear results are negative. PMID- 29973918 TI - Taxonomic and Functional Compositions Impacted by the Quality of Metatranscriptomic Assemblies. AB - Metatranscriptomics has recently been applied to investigate the active biogeochemical processes and elemental cycles, and in situ responses of microbiomes to environmental stimuli and stress factors. De novo assembly of RNA Sequencing (RNA-Seq) data can reveal a more detailed description of the metabolic interactions amongst the active microbial communities. However, the quality of the assemblies and the depiction of the metabolic network provided by various de novo assemblers have not yet been thoroughly assessed. In this study, we compared 15 de novo metatranscriptomic assemblies for a fracture fluid sample collected from a borehole located at 1.34 km below land surface in a South African gold mine. These assemblies were constructed from total, non-coding, and coding reads using five de novo transcriptomic assemblers (Trans-ABySS, Trinity, Oases, IDBA tran, and Rockhopper). They were evaluated based on the number of transcripts, transcript length, range of transcript coverage, continuity, percentage of transcripts with confident annotation assignments, as well as taxonomic and functional diversity patterns. The results showed that these parameters varied considerably among the assemblies, with Trans-ABySS and Trinity generating the best assemblies for non-coding and coding RNA reads, respectively, because the high number of transcripts assembled covered a wide expression range, and captured extensively the taxonomic and metabolic gene diversity, respectively. We concluded that the choice of de novo transcriptomic assemblers impacts substantially the taxonomic and functional compositions. Care should be taken to obtain high-quality assemblies for informing the in situ metabolic landscape. PMID- 29973919 TI - Evaluation of a Solid Dispersion of Curcumin With Polyvinylpyrrolidone and Boric Acid Against Salmonella Enteritidis Infection and Intestinal Permeability in Broiler Chickens: A Pilot Study. AB - In the present study, in vitro assays were conducted to evaluate the solubility of curcumin (CUR) alone or with polyvinylpyrrolidone (PVP) at different pH, as well as its permeability in Caco-2 cells. Results confirmed that the solid dispersion of CUR with PVP (CUR/PVP) at a 1:9 ratio, significantly increased (P < 0.05) solubility and permeability compared to CUR alone. Then, the antimicrobial activity of CUR/PVP, boric acid (BA), and a combination of 0.5% CUR/PVP and 0.5% BA (CUR/PVP-BA) against Salmonella Enteritidis (SE) was determined using an in vitro digestion model that simulates crop, proventriculus, and intestine. The results revealed that in the proventriculus and intestinal compartments significant reductions of SE were observed in all the experimental treatments, but 1% BA eliminated SE in the intestinal compartment and CUR/PVP-BA showed a synergistic effect on antimicrobial activity against SE. To complement these findings, two independent in vivo trials were conducted to determine the effect of 0.1% CUR/PVP; 0.1% BA; or the combination of 0.05% CUR/PVP (1:9 ratio) and 0.05% BA (CUR/PVP-BA) on the antimicrobial activity against SE, intestinal permeability and inflammatory responses in broiler chickens. BA at 0.1% had no significant in vivo effects against SE. However, the combination of 0.05% BA and 0.05% CUR/PVP and 0.05% BA was sufficient to reduce crop and intestinal SE colonization in broiler chickens in two independent trials, confirming the synergic effect between them. A similar antimicrobial impact against SE intestinal colonization was observed in chickens treated with 0.1% CUR/PVP at a 1:9 ratio, which could be due to the increase in solubility of CUR by PVP. Furthermore, 0.1% CUR/PVP reduced the intestinal permeability of FITC-d and total intestinal IgA, as well as increase the activity of SOD when compared to control, while, CUR/PVP-BA only decreased SOD activity. Further studies to confirm and expand the in vivo results obtained in this pilot study, adding intestinal microbial commensal groups and more inflammatory biomarkers to get a complete description of the effects of BA and CUR deserves further investigation. PMID- 29973920 TI - Streptococcus suis 2 Transcriptional Regulator TstS Stimulates Cytokine Production and Bacteremia to Promote Streptococcal Toxic Shock-Like Syndrome. AB - Two large-scale outbreaks of streptococcal toxic shock-like syndrome (STSLS) have revealed Streptococcus suis 2 to be a severe and evolving human pathogen. We investigated the mechanism by which S. suis 2 causes STSLS. The transcript abundance of the transcriptional regulator gene tstS was found to be upregulated during experimental infection. Compared with the wild-type 05ZY strain, a tstS deletion mutant (DeltatstS) elicited reduced cytokine secretion in macrophages. In a murine infection model, tstS deletion resulted in decreased virulence and bacterial load, and affected cytokine production. Moreover, TstS expression in the P1/7 strain of S. suis led to the induction of STSLS in the infected mice. This is noteworthy because, although it is virulent, the P1/7 strain does not normally induce STSLS. Through a microarray-based comparative transcriptomics analysis, we found that TstS regulates multiple metabolism-related genes and several virulence-related genes associated with immune evasion. PMID- 29973921 TI - Genome Mining of the Marine Actinomycete Streptomyces sp. DUT11 and Discovery of Tunicamycins as Anti-complement Agents. AB - Marine actinobacteria are potential producers of various secondary metabolites with diverse bioactivities. Among various bioactive compounds, anti-complement agents have received great interest for drug discovery to treat numerous diseases caused by inappropriate activation of the human complement system. However, marine streptomycetes producing anti-complement agents are still poorly explored. In this study, a marine-derived strain Streptomyces sp. DUT11 showing superior anti-complement activity was focused, and its genome sequence was analyzed. Gene clusters showing high similarities to that of tunicamycin and nonactin were identified, and their corresponding metabolites were also detected. Subsequently, tunicamycin I, V, and VII were isolated from Streptomyces sp. DUT11. Anti complement assay showed that tunicamycin I, V, VII inhibited complement activation through the classic pathway, whereas no anti-complement activity of nonactin was detected. This is the first time that tunicamycins are reported to have such activity. In addition, genome analysis indicates that Streptomyces sp. DUT11 has the potential to produce novel lassopeptides and lantibiotics. These results suggest that marine Streptomyces are rich sources of anti-complement agents for drug discovery. PMID- 29973922 TI - Electron Bifurcation and Confurcation in Methanogenesis and Reverse Methanogenesis. AB - Reduction of the disulfide of coenzyme M and coenzyme B (CoMS-SCoB) by heterodisulfide reductases (HdrED and HdrABC) is the final step in all methanogenic pathways. Flavin-based electron bifurcation (FBEB) by soluble HdrABC homologs play additional roles in driving essential endergonic reactions at the expense of the exergonic reduction of CoMS-SCoM. In the first step of the CO2 reduction pathway, HdrABC complexed with hydrogenase or formate dehydrogenase generates reduced ferredoxin (Fdx2-) for the endergonic reduction of CO2 coupled to the exergonic reduction of CoMS-SCoB dependent on FBEB of electrons from H2 or formate. Roles for HdrABC:hydrogenase complexes are also proposed for pathways wherein the methyl group of methanol is reduced to methane with electrons from H2. The HdrABC complexes catalyze FBEB-dependent oxidation of H2 for the endergonic reduction of Fdx driven by the exergonic reduction of CoMS-SCoB. The Fdx2- supplies electrons for reduction of the methyl group to methane. In H2- independent pathways, three-fourths of the methyl groups are oxidized producing Fdx2- and reduced coenzyme F420 (F420H2). The F420H2 donates electrons for reduction of the remaining methyl groups to methane requiring transfer of electrons from Fdx2- to F420. HdrA1B1C1 is proposed to catalyze FBEB-dependent oxidation of Fdx2- for the endergonic reduction of F420 driven by the exergonic reduction of CoMS-SCoB. In H2- independent acetotrophic pathways, the methyl group of acetate is reduced to methane with electrons derived from oxidation of the carbonyl group mediated by Fdx. Electron transport involves a membrane-bound complex (Rnf) that oxidizes Fdx2- and generates a Na+ gradient driving ATP synthesis. It is postulated that F420 is reduced by Rnf requiring HdrA2B2C2 catalyzing FBEB-dependent oxidation of F420H2 for the endergonic reduction of Fdx driven by the exergonic reduction of CoMS-SCoB. The Fdx2- is recycled by Rnf and HdrA2B2C2 thereby conserving energy. The HdrA2B2C2 is also proposed to play a role in Fe(III)-dependent reverse methanogenesis. A flavin-based electron confurcating (FBEC) HdrABC complex is proposed for nitrate-dependent reverse methanogenesis in which the oxidation of CoM-SH/CoB-SH and Fdx2- is coupled to reduction of F420. The F420H2 donates electrons to a membrane complex that generates a proton gradient driving ATP synthesis. PMID- 29973923 TI - Non-pathogenic Escherichia coli Enhance Stx2a Production of E. coli O157:H7 Through Both bamA-Dependent and Independent Mechanisms. AB - Intestinal colonization by the foodborne pathogen Escherichia coli O157:H7 leads to serious disease symptoms, including hemolytic uremic syndrome (HUS) and hemorrhagic colitis (HC). Synthesis of one or more Shiga toxins (Stx) is essential for HUS and HC development. The genes encoding Stx, including Stx2a, are found within a lambdoid prophage integrated in the E. coli O157:H7 chromosome. Enhanced Stx2a expression was reported when specific non-pathogenic E. coli strains were co-cultured with E. coli O157:H7, and it was hypothesized that this phenotype required the non-pathogenic E. coli to be sensitive to stx converting phage infection. We tested this hypothesis by generating phage resistant non-pathogenic E. coli strains where bamA (an essential gene and Stx phage receptor) was replaced with an ortholog from other species. Such heterologous gene replacement abolished the ability of the laboratory strain E. coli C600 to enhance toxin production when co-cultured with E. coli O157:H7 strain PA2, which belongs to the hypervirulent clade 8. The extracellular loops of BamA (loop 4, 6, 7) were further shown to be important for infection by stx2a converting phages. However, similar gene replacement in another commensal E. coli, designated 1.1954, revealed a bamA-independent mechanism for toxin amplification. Toxin enhancement by 1.1954 was not the result of phage infection through an alternative receptor (LamB or FadL), lysogen formation by stx2a converting phages, or the production of a secreted molecule. Collectively, these data suggest that non-pathogenic E. coli can enhance toxin production through at least two mechanisms. PMID- 29973924 TI - Correlation Between Anti-gp41 Antibodies and Virus Infectivity Decay During Primary HIV-1 Infection. AB - Recent experiments have suggested that the infectivity of simian immunodeficiency virus (SIV) and human immunodeficiency virus type-1 (HIV-1) in plasma decreases over time during primary infection. Because anti-gp41 antibodies are produced early during HIV-1 infection and form antibody-virion complexes, we studied if such early HIV-1 specific antibodies are correlated with the decay in HIV-1 infectivity. Using a viral dynamic model that allows viral infectivity to decay and frequent early viral load data obtained from 6 plasma donors we estimate that HIV-1 infectivity begins to decay after about 2 weeks of infection. The length of this delay is consistent with the time before antibody-virion complexes were detected in the plasma of these donors and is correlated (p = 0.023, r = 0.87) with the time for antibodies to be first detected in plasma. Importantly, we identify that the rate of infectivity decay is significantly correlated with the rate of increase in plasma anti-gp41 IgG concentration (p = 0.046, r = 0.82) and the increase in IgM+IgG anti-gp41 concentration (p = 8.37 * 10-4, r = 0.98). Furthermore, we found that the viral load decay after the peak did not have any significant correlation with the rate of anti-gp41 IgM or IgG increase. These results indicate that early anti-gp41 antibodies may cause viral infectivity decay, but may not contribute significantly to controlling post-peak viral load, likely due to insufficient quantity or affinity. Our findings may be helpful to devise strategies, including antibody-based vaccines, to control acute HIV-1 infection. PMID- 29973925 TI - Functional Genetic Diversity and Culturability of Petroleum-Degrading Bacteria Isolated From Oil-Contaminated Soils. AB - In this study, we compared the culturability of aerobic bacteria isolated from long-term oil-contaminated soils via enrichment and direct-plating methods; bacteria were cultured at 30 degrees C or ambient temperatures. Two soil samples were collected from two sites in the Shengli oilfield located in Dongying, China. One sample (S0) was close to the outlet of an oil-production water treatment plant, and the other sample (S1) was located 500 m downstream of the outlet. In total, 595 bacterial isolates belonging to 56 genera were isolated, distributed in Actinobacteria, Firmicutes, Bacterioidetes, and Proteobacteria. It was interesting that Actinobacteria and Firmicutes were not detected from the 16S rRNA gene clone library. The results suggested the activation of rare species during culture. Using the enrichment method, 239 isolates (31 genera) and 96 (22 genera) isolates were obtained at ambient temperatures and 30 degrees C, respectively, from S0 soil. Using the direct-plating method, 97 isolates (15 genera) and 163 isolates (20 genera) were obtained at ambient temperatures and 30 degrees C, respectively, from two soils. Of the 595 isolates, 244 isolates (41.7% of total isolates) could degrade n-hexadecane. A greater number of alkane degraders was isolated at ambient temperatures using the enrichment method, suggesting that this method could significantly improve bacterial culturability. Interestingly, the proportion of alkane degrading isolates was lower in the isolates obtained using enrichment method than that obtained using direct-plating methods. Considering the greater species diversity of isolates obtained via the enrichment method, this technique could be used to increase the diversity of the microbial consortia. Furthermore, phenol hydroxylase genes (pheN), medium-chain alkane monooxygenases genes (alkB and CYP153A), and long-chain alkane monooxygenase gene (almA) were detected in 60 isolates (11 genotypes), 91 isolates (27 genotypes) and 93 isolates (24 genotypes), and 34 isolates (14 genotypes), respectively. This study could provide new insights into microbial resources from oil fields or other environments, and this information will be beneficial for bioremediation of petroleum contamination and for other industrial applications. PMID- 29973926 TI - Faba Bean (Vicia faba L.) Nodulating Rhizobia in Panxi, China, Are Diverse at Species, Plant Growth Promoting Ability, and Symbiosis Related Gene Levels. AB - We isolated 65 rhizobial strains from faba bean (Vicia faba L.) from Panxi, China, studied their plant growth promoting ability with nitrogen free hydroponics, genetic diversity with clustered analysis of combined ARDRA and IGS RFLP, and phylogeny by sequence analyses of 16S rRNA gene, three housekeeping genes and symbiosis related genes. Eleven strains improved the plant shoot dry mass significantly comparing to that of not inoculated plants. According to the clustered analysis of combined ARDRA and IGS-RFLP the isolates were genetically diverse. Forty-one of 65 isolates represented Rhizobium anhuiense, and the others belonged to R. fabae, Rhizobium vallis, Rhizobium sophorae, Agrobacterium radiobacter, and four species related to Rhizobium and Agrobacterium. The isolates carried four and five genotypes of nifH and nodC, respectively, in six different nifH-nodC combinations. When looking at the species-nifH-nodC combinations it is noteworthy that all but two of the six R. anhuiense isolates were different. Our results suggested that faba bean rhizobia in Panxi are diverse at species, plant growth promoting ability and symbiosis related gene levels. PMID- 29973927 TI - Mining Novel Constitutive Promoter Elements in Soil Metagenomic Libraries in Escherichia coli. AB - Although functional metagenomics has been widely employed for the discovery of genes relevant to biotechnology and biomedicine, its potential for assessing the diversity of transcriptional regulatory elements of microbial communities has remained poorly explored. Here, we experimentally mined novel constitutive promoter sequences in metagenomic libraries by combining a bi-directional reporter vector, high-throughput fluorescence assays and predictive computational methods. Through the expression profiling of fluorescent clones from two independent soil sample libraries, we have analyzed the regulatory dynamics of 260 clones with candidate promoters as a set of active metagenomic promoters in the host Escherichia coli. Through an in-depth analysis of selected clones, we were able to further explore the architecture of metagenomic fragments and to report the presence of multiple promoters per fragment with a dominant promoter driving the expression profile. These approaches resulted in the identification of 33 novel active promoters from metagenomic DNA originated from very diverse phylogenetic groups. The in silico and in vivo analysis of these individual promoters allowed the generation of a constitutive promoter consensus for exogenous sequences recognizable by E. coli in metagenomic studies. The results presented here demonstrates the potential of functional metagenomics for exploring environmental bacterial communities as a source of novel regulatory genetic parts to expand the toolbox for microbial engineering. PMID- 29973928 TI - Progesterone Modulation of Pregnancy-Related Immune Responses. AB - Progesterone (P4) is an important steroid hormone for the establishment and maintenance of pregnancy and its functional withdrawal in reproductive tissue is linked with the onset of parturition. However, the effects of P4 on adaptive immune responses are poorly understood. In this study, we took a novel approach by comparing the effects of P4 supplementation longitudinally, with treatment using a P4 antagonist mifepristone (RU486) in mid-trimester pregnancies. Thus, we were able to demonstrate the immune-modulatory functions of P4. We show that, in pregnancy, the immune system is increasingly activated (CD38, CCR6) with greater antigen-specific cytotoxic T cell responses (granzyme B). Simultaneously, pregnancy promotes a tolerant immune environment (IL-10 and regulatory-T cells) that gradually reverses prior to the onset of labor. P4 suppresses and RU486 enhances antigen-specific CD4 and CD8 T cell inflammatory cytokine (IFN-gamma) and cytotoxic molecule release (granzyme B). P4 and RU486 effectively modulate immune cell-mediated interactions, by regulating differentiated memory T cell subset sensitivity to antigen stimulation. Our results indicate that P4 and RU486, as immune modulators, share a reciprocal relationship. These data unveil key contributions of P4 to the modulation of the maternal immune system and suggests targets for future modulation of maternal immune function during pregnancy. PMID- 29973929 TI - New Insights Into the Regulation of Natural-Killer Group 2 Member D (NKG2D) and NKG2D-Ligands: Endoplasmic Reticulum Stress and CEA-Related Cell Adhesion Molecule 1. AB - Natural-killer group 2 member D (NKG2D) is a well-characterized activating receptor expressed by natural killer (NK) cells, NKT cells, activated CD8+ T cells, subsets of gammadelta+ T cells, and innate-like T cells. NKG2D recognizes multiple ligands (NKG2D-ligands) to mount an innate immune response against stressed, transformed, or infected cells. NKG2D-ligand surface expression is tightly restricted on healthy cells through transcriptional and post transcriptional mechanisms, while transformed or infected cells express the ligands as a danger signal. Recent studies have revealed that unfolded protein response pathways during endoplasmic reticulum (ER) stress result in upregulation of ULBP-related protein via the protein kinase RNA-like ER kinase-activating factor 4-C/EBP homologous protein (PERK-ATF4-CHOP) pathway, which can be linked to the pathogenesis of autoimmune diseases. Transformed cells, however, possess mechanisms to escape NKG2D-mediated immune surveillance, such as upregulation of carcinoembryonic antigen (CEA)-related cell adhesion molecule 1 (CEACAM1), a negative regulator of NKG2D-ligands. In this review, we discuss mechanisms of NKG2D-ligand regulation, with a focus on newly discovered mechanisms that promote NKG2D-ligand expression on epithelial cells, including ER stress, and mechanisms that suppress NKG2D-ligand-mediated killing of cancer cells, namely by co expression of CEACAM1. PMID- 29973930 TI - RIG-I-Like Receptors as Novel Targets for Pan-Antivirals and Vaccine Adjuvants Against Emerging and Re-Emerging Viral Infections. AB - Emerging and re-emerging viruses pose a significant public health challenge around the world, among which RNA viruses are the cause of many major outbreaks of infectious diseases. As one of the early lines of defense in the human immune system, RIG-I-like receptors (RLRs) play an important role as sentinels to thwart the progression of virus infection. The activation of RLRs leads to an antiviral state in the host cells, which triggers the adaptive arm of immunity and ultimately the clearance of viral infections. Hence, RLRs are promising targets for the development of pan-antivirals and vaccine adjuvants. Here, we discuss the opportunities and challenges of developing RLR agonists into antiviral therapeutic agents and vaccine adjuvants against a broad range of viruses. PMID- 29973931 TI - Induction of Hypergammaglobulinemia and Autoantibodies by Salmonella Infection in MyD88-Deficient Mice. AB - Growing evidence indicates a link between persistent infections and the development of autoimmune diseases. For instance, the inability to control Salmonella infection due to defective toll-like receptor (TLR)/myeloid differentiation primary response 88 (MyD88) signaling has linked the development of persistent infections to a breakdown in B cell tolerance. However, the extent of immune dysregulation in the absence of TLR-MyD88 signaling remains poorly characterized. Here, we show that MyD88-/- mice are unable to eliminate attenuated Salmonella enterica serovar Typhimurium, even when challenged with a low-dose inoculum (200 CFUs/mouse), developing a persistent and progressive infection when compared to wild-type (MyD88+/+) animals. The splenic niche of MyD88-/- mice revealed increased counts of activated, Sca-1-positive, myeloid subpopulations highly expressing BAFF during persistent Salmonella infection. Likewise, the T cell compartment of Salmonella-infected MyD88-/- mice showed increased levels of CD4+ and CD8+ T cells expressing Sca-1 and CD25 and producing elevated amounts of IL-4, IL-10, and IL-21 in response to CD3/CD28 stimulation. This was associated with increased Tfh cell differentiation and the presence of CD4+ T cells co-expressing IFN-gamma/IL-4 and IFN-gamma/IL-10. Noteworthy, infected MyD88-/- mice had enhanced serum titers of both anti-Salmonella antibodies as well as autoantibodies directed against double-stranded DNA, thyroglobulin, and IgG rheumatoid factor, positive nuclear staining with HEp-2 cells, and immune complex deposition in the kidneys of MyD88-/- mice infected with live but not heat-killed Salmonella. Infection with other microorganisms (Acinetobacter baumanii, Streptococcus agalactiae, or Escherichia coli) was unable to trigger the autoimmune phenomenon. Our findings suggest that dysregulation of the immune response in the absence of MyD88 is pathogen dependent and highlight potentially important genotype-environmental factor correlations. PMID- 29973932 TI - Equal Expansion of Endogenous Transplant-Specific Regulatory T Cell and Recruitment Into the Allograft During Rejection and Tolerance. AB - Despite numerous advances in the definition of a role for regulatory T cells (Tregs) in facilitating experimental transplantation tolerance, and ongoing clinical trials for Treg-based therapies, critical issues related to the optimum dosage, antigen-specificity, and Treg-friendly adjunct immunosuppressants remain incompletely resolved. In this study, we used a tractable approach of MHC tetramers and flow cytometry to define the fate of conventional (Tconvs) and Tregs CD4+ T cells that recognize donor 2W antigens presented by I-Ab on donor and recipient antigen-presenting cells (APCs) in a mouse cardiac allograft transplant model. Our study shows that these endogenous, donor-reactive Tregs comparably accumulate in the spleens of recipients undergoing acute rejection or exhibiting costimulation blockade-induced tolerance. Importantly, this expansion was not detected when analyzing bulk splenic Tregs. Systemically, the distinguishing feature between tolerance and rejection was the inhibition of donor-reactive conventional T cell (Tconv) expansion in tolerance, translating into increased percentages of splenic FoxP3+ Tregs within the 2W:I-Ab CD4+ T cell subset compared to rejection (~35 vs. <5% in tolerance vs. rejection). We further observed that continuous administration of rapamycin, cyclosporine A, or CTLA4-Ig did not facilitate donor-specific Treg expansion, while all three drugs inhibited Tconv expansion. Finally, donor-specific Tregs accumulated comparably in rejecting tolerant allografts, whereas tolerant grafts harbored <10% of the donor specific Tconv numbers observed in rejecting allografts. Thus, ~80% of 2W:I-Ab CD4+ T cells in tolerant allografts expressed FoxP3+ compared to <=10% in rejecting allografts. A similar, albeit lesser, enrichment was observed with bulk graft-infiltrating CD4+ cells, where ~30% were FoxP3+ in tolerant allografts, compared to <=10% in rejecting allografts. Finally, we assessed that the phenotype of 2W:I-Ab Tregs and observed that the percentages of cells expressing neuropilin-1 and CD73 were significantly higher in tolerance compared to rejection, suggesting that these Tregs may be functionally distinct. Collectively, the analysis of donor-reactive, but not of bulk, Tconvs and Tregs reveal a systemic signature of tolerance that is stable and congruent with the signature within tolerant allografts. Our data also underscore the importance of limiting Tconv expansion for high donor-specific Tregs:Tconv ratios to be successfully attained in transplantation tolerance. PMID- 29973933 TI - Effects of Newcastle Disease Virus Infection on Chicken Intestinal Intraepithelial Natural Killer Cells. AB - The intestinal intraepithelial natural killer cells (IEL-NK) are among the earliest effectors of antiviral immunity in chicken. Unfortunately, their role during Newcastle disease virus (NDV) infection remains obscure. Previous study has reported the development of a monoclonal antibody (mAb) known as 28-4, which is specifically directed against the CD3- IEL-NK cells. In the present study, we used this mAb to investigate the effects of velogenic and lentogenic NDV infection on avian IEL-NK cells. Our findings revealed that chickens infected with velogenic NDV strains have a reduced population of purified CD3-/28-4+ IEL NK cells as determined by flow cytometry. Furthermore, the CD3-/28-4+ IEL-NK cells from chicken infected with velogenic NDV strains were shown to have a downregulated expression of activating receptors (CD69 and B-Lec), effector peptide (NK-LYSIN), and IFN gamma. On the contrary, the expression of the inhibitory receptor (B-NK) and bifunctional receptor (CHIR-AB1) were upregulated on these purified CD3-/28-4+ IEL-NK cells following velogenic NDV infection. Meanwhile, the lentogenic NDV demonstrated insignificant effects on both the total population of CD3-/28-4+ IEL-NK cells and the expression of their surface receptors. In addition, using real-time PCR and transmission electron microscopy, we showed that CD3-/28-4+ IEL-NK cells were susceptible to velogenic but not lentogenic NDV infection. These findings put together demonstrate the ability of different strains of NDV to manipulate the activating and inhibitory receptors of CD3-/28-4+ IEL-NK cells following infection. Further studies are, however, required to ascertain the functional importance of these findings during virulent or avirulent NDV infection. PMID- 29973934 TI - Interaction of Non-Specific Lipid-Transfer Proteins With Plant-Derived Lipids and Its Impact on Allergic Sensitization. AB - Non-specific lipid-transfer proteins (nsLTPs) represent a family of ubiquitous plant proteins belonging to the prolamin superfamily. nsLTPs are characterized by a globular alpha-helical structure stabilized by four disulfide bonds and a hydrophobic cavity which acts as ligand-binding site for a broad spectrum of lipids and hydrophobic molecules. nsLTPs are involved in membrane biogenesis and in the adaption of plants to abiotic and biotic stress. They display antimicrobial activity by the ability to permeabilize the cell membrane of phytopathogens. Moreover, in the presence of lipids, nsLTPs are suggested to activate the plant immune system by a receptor-dependent mechanism. Additionally, nsLTPs from pollen and plant-derived food, in particular type 1 nsLTPs (9 kDa), are described as potent allergens. Within the nsLTP family Pru p 3 from peach is the clinically most relevant allergen which can cause genuine food allergy and frequently elicits severe clinical reactions. So far, the allergenic properties of nsLTPs are attributed to both their low molecular mass and their high thermal and proteolytic stability which allow them to reach the immune system in a biological intact form. Recently, the interaction of nsLTPs with lipids has been suggested to increase their allergenic properties and to promote the allergic sensitization to these proteins. This review will summarize the current knowledge on diversity of lipid ligands of plant LTPs, and illustrate recent studies performed with allergenic nsLTPs to investigate the effect of lipid binding on the structural modification and IgE-binding properties of proteins, and finally the potential effect on the innate immune responses. PMID- 29973935 TI - Molecular Regulation of Histamine Synthesis. AB - Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC), which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of HDC gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis. PMID- 29973937 TI - Molecular Mechanisms for the Adaptive Switching Between the OAS/RNase L and OASL/RIG-I Pathways in Birds and Mammals. AB - Host cells develop the OAS/RNase L [2'-5'-oligoadenylate synthetase (OAS)/ribonuclease L] system to degrade cellular and viral RNA, and/or the OASL/RIG-I (2'-5'-OAS like/retinoic acid inducible protein I) system to enhance RIG-I-mediated IFN induction, thus providing the first line of defense against viral infection. The 2'-5'-OAS-like (OASL) protein may activate the OAS/RNase L system using its typical OAS-like domain (OLD) or mimic the K63-linked pUb to enhance antiviral activity of the OASL/RIG-I system using its two tandem ubiquitin-like domains (UBLs). We first describe that divergent avian (duck and ostrich) OASL inhibit the replication of a broad range of RNA viruses by activating and magnifying the OAS/RNase L pathway in a UBL-dependent manner. This is in sharp contrast to mammalian enzymatic OASL, which activates and magnifies the OAS/RNase L pathway in a UBL-independent manner, similar to 2'-5' oligoadenylate synthetase 1 (OAS1). We further show that both avian and mammalian OASL can reversibly exchange to activate and magnify the OAS/RNase L and OASL/RIG I system by introducing only three key residues, suggesting that ancient OASL possess 2-5A [px5'A(2'p5'A)n; x = 1-3; n >= 2] activity and has functionally switched to the OASL/RIG-I pathway recently. Our findings indicate the molecular mechanisms involved in the switching of avian and mammalian OASL molecules to activate and enhance the OAS/RNase L and OASL/RIG-I pathways in response to infection by RNA viruses. PMID- 29973938 TI - Synthetic Standards Combined With Error and Bias Correction Improve the Accuracy and Quantitative Resolution of Antibody Repertoire Sequencing in Human Naive and Memory B Cells. AB - High-throughput sequencing of immunoglobulin (Ig) repertoires (Ig-seq) is a powerful method for quantitatively interrogating B cell receptor sequence diversity. When applied to human repertoires, Ig-seq provides insight into fundamental immunological questions, and can be implemented in diagnostic and drug discovery projects. However, a major challenge in Ig-seq is ensuring accuracy, as library preparation protocols and sequencing platforms can introduce substantial errors and bias that compromise immunological interpretation. Here, we have established an approach for performing highly accurate human Ig-seq by combining synthetic standards with a comprehensive error and bias correction pipeline. First, we designed a set of 85 synthetic antibody heavy-chain standards (in vitro transcribed RNA) to assess correction workflow fidelity. Next, we adapted a library preparation protocol that incorporates unique molecular identifiers (UIDs) for error and bias correction which, when applied to the synthetic standards, resulted in highly accurate data. Finally, we performed Ig seq on purified human circulating B cell subsets (naive and memory), combined with a cellular replicate sampling strategy. This strategy enabled robust and reliable estimation of key repertoire features such as clonotype diversity, germline segment, and isotype subclass usage, and somatic hypermutation. We anticipate that our standards and error and bias correction pipeline will become a valuable tool for researchers to validate and improve accuracy in human Ig-seq studies, thus leading to potentially new insights and applications in human antibody repertoire profiling. PMID- 29973936 TI - Invariant Natural Killer T Cell Subsets-More Than Just Developmental Intermediates. AB - Invariant natural killer T (iNKT) cells are a CD1d-restricted T cell population that can respond to lipid antigenic stimulation within minutes by secreting a wide variety of cytokines. This broad functional scope has placed iNKT cells at the frontlines of many kinds of immune responses. Although the diverse functional capacities of iNKT cells have long been acknowledged, only recently have distinct iNKT cell subsets, each with a marked functional predisposition, been appreciated. Furthermore, the subsets can frequently occupy distinct niches in different tissues and sometimes establish long-term tissue residency where they can impact homeostasis and respond quickly when they sense perturbations. In this review, we discuss the developmental origins of the iNKT cell subsets, their localization patterns, and detail what is known about how different subsets specifically influence their surroundings in conditions of steady and diseased states. PMID- 29973939 TI - Transforming Growth Factor-beta1/Smad7 in Intestinal Immunity, Inflammation, and Cancer. AB - In physiological conditions, the activity of the intestinal immune system is tightly regulated to prevent tissue-damaging reactions directed against components of the luminal flora. Various factors contribute to maintain immune homeostasis and diminished production and/or function of such molecules trigger and/or propagate detrimental signals, which can eventually lead to chronic colitis and colon cancer. One such a molecule is transforming growth factor-beta1 (TGF-beta1), a cytokine produced by many inflammatory and non-inflammatory cells and targeting virtually all the intestinal mucosal cell types, with the down stream effect of activating intracellular Smad2/3 proteins and suppressing immune reactions. In patients with inflammatory bowel diseases (IBD), there is defective TGF-beta1/Smad signaling due to high Smad7, an inhibitor of TGF-beta1 activity. Indeed, knockdown of Smad7 with a specific antisense oligonucleotide restores endogenous TGF-beta1 activity, thereby inhibiting inflammatory pathways in patients with IBD and colitic mice. Consistently, mice over-expressing Smad7 in T cells develop severe intestinal inflammation in various experimental models. Smad7 expression is also upregulated in colon cancer cells, in which such a protein controls positively intracellular pathways that sustain neoplastic cell growth and survival. We here review the role of TGF-beta1 and Smad7 in intestinal immunity, inflammation, and cancer. PMID- 29973941 TI - Combined Drought and Heat Activates Protective Responses in Eucalyptus globulus That Are Not Activated When Subjected to Drought or Heat Stress Alone. AB - Aiming to mimic a more realistic field condition and to determine convergent and divergent responses of individual stresses in relation to their combination, we explored physiological, biochemical, and metabolomic alterations after drought and heat stress imposition (alone and combined) and recovery, using a drought tolerant Eucalyptus globulus clone. When plants were exposed to drought alone, the main responses included reduced pre-dawn water potential (Psipd) and gas exchange. This was accompanied by increases in malondialdehyde (MDA) and total glutathione, indicative of oxidative stress. Abscisic acid (ABA) levels increased while the content of jasmonic acid (JA) fell. Metabolic alterations included reductions in the levels of sugar phosphates accompanied by increases in starch and non-structural carbohydrates. Levels of alpha-glycerophosphate and shikimate were also reduced while free amino acids increased. On the other hand, heat alone triggered an increase in relative water content (RWC) and Psipd. Photosynthetic rate and pigments were reduced accompanied by a reduction in water use efficiency. Heat-induced a reduction of salicylic acid (SA) and JA content. Sugar alcohols and several amino acids were enhanced by the heat treatment while starch, fructose-6-phosphate, glucose-6-phosphate, and alpha-glycerophosphate were reduced. Contrary to what was observed under drought, heat stress activated the shikimic acid pathway. Drought-stressed plants subject to a heat shock exhibited a sharp decrease in gas exchange, Psipd and JA, no alterations in electrolyte leakage, MDA, starch, and pigments and increased glutathione pool in relation to control. Comparing this with drought stress alone, subjecting drought stressed plants to an additional heat stress alleviated Psipd and MDA, maintained an increased glutathione pool and reduced starch content and non-structural carbohydrates. A novel response triggered by the combined stress was the accumulation of cinnamate. Regarding recovery, most of the parameters affected by each stress condition reversed after re-establishment of control growing conditions. These results highlight that the combination of drought and heat provides significant protection from more detrimental effects of drought-stressed eucalypts, confirming that combined stress alter plant metabolism in a novel manner that cannot be extrapolated by the sum of the different stresses applied individually. PMID- 29973940 TI - Activation of the Immune-Metabolic Receptor GPR84 Enhances Inflammation and Phagocytosis in Macrophages. AB - GPR84 is a member of the metabolic G protein-coupled receptor family, and its expression has been described predominantly in immune cells. GPR84 activation is involved in the inflammatory response, but the mechanisms by which it modulates inflammation have been incompletely described. In this study, we investigated GPR84 expression, activation, and function in macrophages to establish the role of the receptor during the inflammatory response. We observed that GPR84 expression in murine tissues is increased by endotoxemia, hyperglycemia, and hypercholesterolemia. Ex vivo studies revealed that GPR84 mRNA expression is increased by LPS and other pro-inflammatory molecules in different murine and human macrophage populations. Likewise, high glucose concentrations and the presence of oxidized LDL increased GPR84 expression in macrophages. Activation of the GPR84 receptor with a selective agonist, 6-(octylamino) pyrimidine-2,4(1H,3H) dione (6-n-octylaminouracil, 6-OAU), enhanced the expression of phosphorylated Akt, p-ERK, and p65 nuclear translocation under inflammatory conditions and elevated the expression levels of the inflammatory mediators TNFalpha, IL-6, IL 12B, CCL2, CCL5, and CXCL1. In addition, GPR84 activation triggered increased bacterial adhesion and phagocytosis in macrophages. The enhanced inflammatory response mediated by 6-OAU was not observed in GPR84-/- cells nor in macrophages treated with a selective GPR84 antagonist. Collectively, our results reveal that GPR84 functions as an enhancer of inflammatory signaling in macrophages once inflammation is established. Therefore, molecules that antagonize the GPR84 receptor may be potential therapeutic tools in inflammatory and metabolic diseases. PMID- 29973942 TI - Which Plants Used in Ethnomedicine Are Characterized? Phylogenetic Patterns in Traditional Use Related to Research Effort. AB - Plants are important resources in healthcare and for producing pharmaceutical drugs. Pharmacological and phytochemical characterization contributes to both the safe use of herbal medicines and the identification of leads for drug development. However, there is no recent assessment of the proportion of plants used in ethnomedicine that are characterized in this way. Further, although it is increasingly apparent that plants used in ethnomedicine belong to preferred phylogenetic lineages, it is not known how this relates to the focusing of research effort. Here we identify species and lineages rich in ethnomedicinal use and develop methods to describe how well they are known pharmacologically and/or phytochemically. We find 50% of plant species of the family Leguminosae used in ethnomedicine in Brazil, a geographical area where plants are an important part of healthcare, have been the focus of either phytochemical screening or testing for biological activity. Plant species which have more use reports are studied significantly more often (p < 0.05). Considering the taxonomic distribution of use, 70% of genera that include species with ethnomedicinal use have been studied, compared to 19% of genera with no reported use. Using a novel phylogenetic framework, we show that lineages with significantly greater numbers of ethnomedicinal species are phylogenetically over-dispersed within the family, highlighting the diversity of species used. "Hotnode clades" contain 16% of species but 46% of ethnomedicinally-used species. The ethnomedicinal species in hotnode clades have more use reports per species (p < 0.05), suggesting they are more frequently used. They are also more likely to be characterized pharmacologically and/or phytochemically. Research focus has followed traditional use by these measures, at least for these Brazilian plants, yet ethnomedicinal species yielding candidate drugs, raising public health concerns and more intensively studied lie outside of the hotnode clades. PMID- 29973943 TI - CRABS CLAW Acts as a Bifunctional Transcription Factor in Flower Development. AB - One of the crucial steps in the life cycle of angiosperms is the development of carpels. They are the most complex plant organs, harbor the seeds, and, after fertilization, develop into fruits and are thus an important ecological and economic trait. CRABS CLAW (CRC), a YABBY protein and putative transcription factor, is one of the major carpel developmental regulators in A. thaliana that includes a C2C2 zinc finger and a domain with similarities to an HMG box. CRC is involved in the regulation of processes such as carpel fusion and growth, floral meristem termination, and nectary formation. While its genetic interactions with other carpel development regulators are well described, its biochemical properties and molecular way of action remain unclear. We combined Bimolecular Fluorescence Complementation, Yeast Two-Hybrid, and Yeast One-Hybrid analyzes to shed light on the molecular biology of CRC. Our results showed that CRC dimerizes, also with other YABBY proteins, via the YABBY domain, and that its DNA binding is mainly cooperative and is mediated by the YABBY domain. Further, we identified that CRC is involved in floral meristem termination via transcriptional repression while it acts as a transcriptional activator in nectary development and carpel fusion and growth control. This work increases our understanding on how YABBY transcription factors interact with other proteins and how they regulate their targets. PMID- 29973945 TI - Nectar-Secreting and Nectarless Epidendrum: Structure of the Inner Floral Spur. AB - Epidendrum, the largest genus of Neotropical orchids, contains both nectar secreting and nectarless species. Here, we compare the fine structure of the inner floral spur, termed the cuniculus, in nectariferous (E. difforme, E. nocturnum,E. porpax, E. rigidum, E. vesicatum) and seemingly nectarless (E. capricornu, E. ciliare, E. criniferum, E. pseudepidendrum, E. radicans, E. xanthoianthinum) species. This is the first time for such a detailed investigation of cuniculus structure to be undertaken for Epidendrum. Our aim was to characterize features indicative of secretory activity and to ascertain whether flowers presumed to be nectarless produce alternative pollinator food rewards. The cuniculus is formed by fusion of the basal part of the labellum and column and extends alongside the ovary and transmitting tract. Our study indicates that all investigated species produce nectar or nectar-like secretion to varying degrees, and no alternative pollinator food-rewards were observed. Even though macroscopic investigation of presumed rewardless species failed to reveal the presence of secretion within the cuniculus, close observations of the cells lining the cuniculus by LM, SEM, and TEM revealed the presence of cuticular blisters and surface material. Moreover, the similarity of both the thick tangential cell walls (with the exception of E. vesicatum) and organelle complement of cuniculus epidermal cells in both copiously nectariferous species and those producing only small quantities of surface secretion confirmed the presence of secretory activity in species generally regarded to be rewardless. The secretory character was particularly obvious in the cells of the cuniculus of E. nocturnum, but also in E. ciliare, E. radicans and E. xanthoianthinum, since electron-dense cytoplasm and mitochondria, ER and secretory vesicles were abundant. Furthermore, cell wall protuberances occurred in E. nocturnum, which was indicative of intense transmembrane transport. This investigation highlights the need to examine more closely whether Epidendrum spp. considered to lack food rewards based solely on macroscopic examination really are rewardless and deceptive. PMID- 29973944 TI - Regulation of Seed Germination and Abiotic Stresses by Gibberellins and Abscisic Acid. AB - Overall growth and development of a plant is regulated by complex interactions among various hormones, which is critical at different developmental stages. Some of the key aspects of plant growth include seed development, germination and plant survival under unfavorable conditions. Two of the key phytohormones regulating the associated physiological processes are gibberellins (GA) and abscisic acid (ABA). GAs participate in numerous developmental processes, including, seed development and seed germination, seedling growth, root proliferation, determination of leaf size and shape, flower induction and development, pollination and fruit expansion. Despite the association with abiotic stresses, ABA is essential for normal plant growth and development. It plays a critical role in different abiotic stresses by regulating various downstream ABA-dependent stress responses. Plants maintain a balance between GA and ABA levels constantly throughout the developmental processes at different tissues and organs, including under unfavorable environmental or physiological conditions. Here, we will review the literature on how GA and ABA control different stages of plant development, with focus on seed germination and selected abiotic stresses. The possible crosstalk of ABA and GA in specific events of the above processes will also be discussed, with emphasis on downstream stress signaling components, kinases and transcription factors (TFs). The importance of several key ABA and GA signaling intermediates will be illustrated. The knowledge gained from such studies will also help to establish a solid foundation to develop future crop improvement strategies. PMID- 29973947 TI - An Integrative Volatile Terpenoid Profiling and Transcriptomics Analysis for Gene Mining and Functional Characterization of AvBPPS and AvPS Involved in the Monoterpenoid Biosynthesis in Amomum villosum. AB - Amomum villosum, also known as Fructus Amomi, has been used to treat digestive diseases such as abdominal pain, vomiting, and dysentery. Volatile terpenoids are the active metabolites in the essential oil of Fructus Amomi. Nevertheless, downstream genes responsible for activating metabolites biosynthesis in A. villosum still remain unclear. Here, we report the use of an integrative volatile terpenoid profiling and transcriptomics analysis for mining the corresponding genes involved in volatile terpenoid biosynthesis. Ten terpene synthase (TPS) genes were discovered, and two of them were cloned and functionally characterized. AvTPS1 (AvPS: pinene synthase) catalyzed GPP to form alpha-pinene and beta-pinene; AvTPS3 (AvBPPS: bornyl diphosphate synthase) produced bornyl diphosphate as major product and the other three monoterpenoids as minor products. Metabolite accumulation and gene expression pattern combined with AvPS biochemical characterization suggested that AvPS might play a role in biotic defense. On the other hand, the most active ingredient, bornyl acetate, was highly accumulated in seeds and was consistent with the high expression of AvBPPS, which further indicated that AvBPPS is responsible for the biosynthesis of bornyl acetate, the final metabolite of bornyl diphosphate in A. villosum. This study can be used to improve the quality of A. villosum through metabolic engineering, and for the sustainable production of bornyl acetate in heterologous hosts. PMID- 29973946 TI - Editing of Chloroplast rps14 by PPR Editing Factor EMB2261 Is Essential for Arabidopsis Development. AB - RNA editing in plastids is known to be required for embryogenesis, but no single editing event had been shown to be essential. We show that the emb2261-2 mutation is lethal through a failure to express an editing factor that specifically recognizes the rps14-2 site. EMB2261 was predicted to bind the cis-element upstream of the rps14-2 site and genetic complementation with promoters of different strength followed by RNA-seq analysis was conducted to test the correlation between rps14-2 editing and EMB2261 expression. Rps14-2 is the only editing event in Arabidopsis chloroplasts that correlates with EMB2261 expression. Sequence divergence between the cis-element and the EMB2261 protein sequence in plants where rps14-2 editing is not required adds support to the association between them. We conclude that EMB2261 is the specificity factor for rps14-2 editing. This editing event converts P51 in Rps14 to L51, which is conserved among species lacking RNA editing, implying the importance of the editing event to Rps14 function. Rps14 is an essential ribosomal subunit for plastid translation, which, in turn, is essential for Arabidopsis embryogenesis. PMID- 29973950 TI - Corrigendum: Cloning and functional validation of early inducible Magnaporthe oryzae responsive CYP76M7 promoter from rice. AB - [This corrects the article on p. 371 in vol. 6, PMID: 26052337.]. PMID- 29973948 TI - FtsH Protease in the Thylakoid Membrane: Physiological Functions and the Regulation of Protease Activity. AB - Protein homeostasis in the thylakoid membranes is dependent on protein quality control mechanisms, which are necessary to remove photodamaged and misfolded proteins. An ATP-dependent zinc metalloprotease, FtsH, is the major thylakoid membrane protease. FtsH proteases in the thylakoid membranes of Arabidopsis thaliana form a hetero-hexameric complex consisting of four FtsH subunits, which are divided into two types: type A (FtsH1 and FtsH5) and type B (FtsH2 and FtsH8). An increasing number of studies have identified the critical roles of FtsH in the biogenesis of thylakoid membranes and quality control in the photosystem II repair cycle. Furthermore, the involvement of FtsH proteolysis in a singlet oxygen- and EXECUTER1-dependent retrograde signaling mechanism has been suggested recently. FtsH is also involved in the degradation and assembly of several protein complexes in the photosynthetic electron-transport pathways. In this minireview, we provide an update on the functions of FtsH in thylakoid biogenesis and describe our current understanding of the D1 degradation processes in the photosystem II repair cycle. We also discuss the regulation mechanisms of FtsH protease activity, which suggest the flexible oligomerization capability of FtsH in the chloroplasts of seed plants. PMID- 29973949 TI - Effects of an Animal-Derived Biostimulant on the Growth and Physiological Parameters of Potted Snapdragon (Antirrhinum majus L.). AB - To assess the effect a new animal-derived biostimulant on the growth, root morphology, nitrogen content, leaf gas exchange of greenhouse potted snapdragon, three treatments were compared: (a) three doses of biostimulant (D): 0 (D0 or control), 0.1 (D0.1), and 0.2 g L-1 (D0.2); (b) two biostimulant application methods (M): foliar spray and root drenching; (c) two F1Antirrhinum majus L. hybrids (CV): "Yellow floral showers" and "Red sonnet." The treatments were arranged in a randomized complete-block design with four replicates, with a total of 48 experimental units. Plant height (+11%), number of shoots (+20%), total shoot length (+10%), number of leaves (+33%), total leaf area (+29%), and number of flowers (+59%) and total aboveground dry weight (+13%) were significantly increased by the biostimulant application compared to the control, regardless of the dose. The lowest dose resulted in the best effect on the ground plant dry weight (+38%) and, in order to the root system, on total length (+55%), average diameter (+36%), volume (+66%), tips (+49%), crossings (+88%), forks (+68%), projected (+62%), and total surface area (+28%). Compared to the control, plants treated with the biostimulant significantly enhanced leaf (+16%) and root (+8%) nitrogen content, photosynthetic rate (+52%), transpiration rate (+55%), and stomatal conductance (+81%), although there were no changes in dark-adapted chlorophyll fluorescence. Differences in the application method were not evident in the aboveground morphological traits, except in the plant shoot number (root drenching: +10%). The foliar spray compared to root drenching had a significant effect only on flower dry weight (3.8 vs. 3.0 g plant-1). On the other hand, root drenching had a positive effect on ground dry weight (2.7 vs. 2.3 g plant-1), root morphology, leaf-N and root-N content (+3%), transpiration rate (+21%), stomatal conductance (+40%), concentration of CO2 in intracellular spaces (+11%), as well as on the efficiency of Photosystem II (+11%). A higher pot quality was obtained in "Red sonnet" compared to "Yellow floral shower." Based on our findings, applying the biostimulant to potted snapdragon at the lowest dose, as part of a fertilizing regime, improves the crop quality in an agro-environmental sustainable way. PMID- 29973951 TI - Skin Cancer Knowledge, Attitudes, and Practices among Chinese Population: A Narrative Review. AB - Skin cancers are becoming a substantial public health problem in China. Fair skin and increased exposure to ultraviolet B (UVB) rays from the sun are among the most substantial risk factors for skin cancer development, thus making the Chinese people vulnerable to this group of diseases. The purpose of this article is to present a narrative review of the knowledge, attitudes, and practices (KAP) related to skin cancers within the Chinese population. A systematic electronic search of MEDLINE (PubMed), CINAHL, ScienceDirect, and Google Scholar databases yielded nine articles that met the inclusion criteria. The review found that although sunscreen application was a commonly used method of skin protection among the general Chinese population, educational interventions enhancing current knowledge and attitudes about the effects of UVB rays on skin from undue sun exposure were limited in many smaller communities of the country. Hence, there is an essential need to design effective, evidence-based educational programs promoting sun protection behaviors in both congregated and sparsely populated areas of China. PMID- 29973952 TI - Erratum to "From Localized Scleroderma to Systemic Sclerosis: Coexistence or Possible Evolution". AB - [This corrects the article DOI: 10.1155/2018/1284687.]. PMID- 29973953 TI - Comment on "Pregabalin Effect on Acute and Chronic Pain after Cardiac Surgery". PMID- 29973954 TI - Ultrasound-Guided Combined Interscalene-Cervical Plexus Block for Surgical Anesthesia in Clavicular Fractures: A Retrospective Observational Study. AB - Objective: We aim to report our experiences regarding the implementation of the ultrasound-guided combined interscalene-cervical plexus block (CISCB) technique as a sole anesthesia method in clavicular fracture repair surgery. Materials and Methods: Charts of patients, who underwent clavicular fracture surgery through this technique, were reviewed retrospectively. We used an in-plane ultrasound guided single-insertion, double-injection combined interscalene-cervical plexus block technique. During the performance of each block, the block areas were visualized by using a linear transducer, and the needles were advanced by using the in-plane technique. Block success and complication rates were evaluated. Results and Discussion: 12 patients underwent clavicular fracture surgery. Surgical regional anesthesia was achieved in 100% of blocks. None of the patients necessitated conversion to general anesthesia during surgery. There were no occurrences of acute complications. Conclusions: The ultrasound-guided combined interscalene-cervical plexus block was a successful and effective regional anesthesia method in clavicular fracture repair. Prospective comparative studies would report the superiority of the regional technique over general anesthesia. PMID- 29973955 TI - Effects of Different Treatment Strategies and Tumor Stage on Survival of Patients with Advanced Laryngeal Carcinoma: A 15-Year Cohort Study. AB - Background: Laryngeal cancer is the second most common cancer in the head and neck. Since laryngeal cancer management is a complex process, there is still no standard strategy to treat this disease in order to increase the survival rate of the patients especially among those with advanced form of the disease. Methods: A cohort study was undertaken to analyze factors predicting survival of the patients in advanced stage laryngeal cancer in the Southern Iran among all patients newly diagnosed with laryngeal cancer between 2000 and 2015. Results: Data of a total number of 415 patients who have had been diagnosed with advanced laryngeal cancer during this period was used for analysis. The patients' 1-, 3-, 5-, and 10-year survival rates were 81%, 62%, 53%, and 38%, respectively. Multivariable Cox regression analyses indicated a significant relationship between patients' survival and age at diagnosis (P < 0.001), disease stage (P = 0.002), tumor grade (P = 0.008), positive L. node (P = 0.008), and type of treatment (P < 0.001). As expected, treatment strategy was identified as the most effective factor in survival of the patients. According to the results, patients who undergone surgical treatment experienced a longer survival than those who received other treatments. Conclusion: This study showed that the survival of patients depends on several factors, among which, treatment strategy is the most important. Combination of total laryngectomy plus chemoradiation provides superior local control and better survival compared to either radiotherapy or chemoradiation in patients with advanced laryngeal cancer. PMID- 29973956 TI - Cytokine Secretion of Peripheral Blood Mononuclear Cells by Hydnocarpus anthelminthicus Seeds. AB - Background: Hydnocarpus anthelminthicus is primarily used as a traditional medicine for the treatment of leprosy. Previous studies demonstrated that the clinical course of leprosy and the susceptibility to mycobacteria are recognized by the immune response of the host. The current study aims to investigate the effect of H. anthelminthicus seed oil and extracts on the secretion of cytokines from PBMCs involved in immune regulation. Methods: PBMCs from healthy volunteers were cultured and treated with LPS and H. anthelminthicus seed oil or extracts. Cell viability was detected with WST-1 cell proliferation assay reagent. Proinflammatory cytokines were quantified using ELISA with a specific antibody. Results: LPS-treated PBMCs significantly increased IL6 and TNF-alpha secretion. H. anthelminthicus seed oil had a synergistic effect with LPS on TNF-alpha secretion. The aqueous extract of H. anthelminthicus seed kernels and hulls significantly induced IL6 and TNF-alpha secretion. However, the ethanol extract of H. anthelminthicus seed kernels and hulls significantly decreased IL6, IL8, and TNF-alpha secretion in LPS-treated PBMCs. Conclusions: Extracts of H. anthelminthicus seeds demonstrated various effects on the proinflammatory cytokine secretion of PBMCs. The application of these extracts should depend on the immune response of the host, which determines the manifestation of the disease. PMID- 29973957 TI - Presence of Rickettsia Species in a Marginalized Area of Yucatan, Mexico. AB - In the state of Yucatan, Mexico, rickettsiosis has become a common vector-borne disease in the general population. Ectoparasite species such as Rhipicephalus sanguineus and Amblyomma mixtum have been identified as Rickettsia vectors in Yucatan by studies focused on the wild animal population in rural areas. There have been studies that have tried to determine the presence of Rickettsia species in ectoparasites collected in Yucatan, but these studies did not include marginalized areas, where living in close contact with domestic and peridomestic animals that carry ectoparasites is a high-risk factor for acquiring rickettsial infection or many other vector-borne diseases. We evaluated the vector diversity and the presence of Rickettsia species presence in the ectoparasite population that parasitizes domestic animals in a marginalized rural town of Yucatan, Mexico; we also evaluated the seroprevalence of rickettsial antibodies in the human population of this town in order to determine the prevalence of rickettsial infection. A total of 437 ectoparasites were collected from the study area. The tick specimens collected belonged to the species Rhipicephalus sanguineus (n=380, 49 positive), Amblyomma mixtum (n=3, 0 positive), Ixodes affinis (n=4, 0 positive), Ctenocephalides felis (n=33, 0 positive), and Trichodectes canis (n=17, 0 positive). Conventional polymerase chain reaction and sequencing were used to identify the DNA of Rickettsia. Six out of 354 (1.8%) serum samples were positive for antibody to R. typhi. The combination of low antibody titers and the presence of Rickettsia species infecting ectoparasite species found in the study area requires eco-epidemiological studies and the identification of potentially protective practices or habits. PMID- 29973958 TI - Right Here Right Now (RHRN) pilot study: testing a method of near-real-time data collection on the social determinants of health. AB - Background: Informing policy and practice with up-to-date evidence on the social determinants of health is an ongoing challenge. One limitation of traditional approaches is the time-lag between identification of a policy or practice need and availability of results. The Right Here Right Now (RHRN) study piloted a near real-time data-collection process to investigate whether this gap could be bridged. Methods: A website was developed to facilitate the issue of questions, data capture and presentation of findings. Respondents were recruited using two distinct methods - a clustered random probability sample, and a quota sample from street stalls. Weekly four-part questions were issued by email, Short Messaging Service (SMS or text) or post. Quantitative data were descriptively summarised, qualitative data thematically analysed, and a summary report circulated two weeks after each question was issued. The pilot spanned 26 weeks. Results: It proved possible to recruit and retain a panel of respondents providing quantitative and qualitative data on a range of issues. The samples were subject to similar recruitment and response biases as more traditional data-collection approaches. Participants valued the potential to influence change, and stakeholders were enthusiastic about the findings generated, despite reservations about the lack of sample representativeness. Stakeholders acknowledged that decision-making processes are not flexible enough to respond to weekly evidence. Conclusion: RHRN produced a process for collecting near-real-time data for policy-relevant topics, although obtaining and maintaining representative samples was problematic. Adaptations were identified to inform a more sustainable model of near-real-time data collection and dissemination in the future. PMID- 29973959 TI - Mitochondrial genomes of the South American frogs Eupsophus vertebralis and E. emiliopugini (Neobatrachia: Alsodidae) and their phylogenetic relationships. AB - We report the sequencing and compare the mitochondrial genomes of the South American ground frogs Eupsophus vertebralis and E. emiliopugini and reconstruct phylogenetic relationships among Eupsophus species. These genomes consist of 16,156 and 16,711 bp in length, respectively and contain 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes (tRNA), and partial non-coding D loop region. Both genomes share 94.5% identity with 879 variable sites. A phylogenetic analysis with other available mitogenomes recovered both species as the sister clade of Alsodes gargola. Sequences from D-loop, CO1, and Cyt b, amplified and sequenced with primers developed from the mitochondrial genomes, allowed us to reconstruct phylogenetic relationships among Eupsophus species. Since our report represents the first mitogenomes for the genus Eupsophus, we expect these data will be valuable for further studies on conservation genetics and on the evolution of Patagonian amphibians. PMID- 29973961 TI - Erratum to "ADRB2 Arg16Gly Polymorphism and Pulmonary Function Response of Inhaled Corticosteroids plus Long-Acting Beta Agonists for Asthma Treatment: A Systematic Review and Meta-Analysis". AB - [This corrects the article DOI: 10.1155/2018/5712805.]. PMID- 29973960 TI - Expression and network analysis of YBX1 interactors for identification of new drug targets in lung adenocarcinoma. AB - Y-Box Binding protein 1 (YBX-1) is known to be involved in various types of cancers. It's interactors also play major role in various cellular functions. Present work aimed to study the expression profile of the YBX-1 interactors during lung adenocarcinoma (LUAD). The differential expression analysis involved 57 genes from 95 lung adenocarcinoma samples, construction of gene network and topology analysis. A Total of 43 genes were found to be differentially expressed from which 17 genes were found to be down regulated and 26 genes were up regulated. We observed that Polyadenylate-binding protein 1 (PABPC1), a protein involved in YBX1 translation, is highly correlated with YBX1. The interaction network analysis for a differentially expressed non-coding RNA Growth Arrest Specific 5 (GAS5) suggests that two proteins namely, Growth Arrest Specific 2 (GAS2) and Peripheral myelin protein 22 (PMP22) are potentially involved in LUAD progression. The network analysis and differential expression suggests that Collagen type 1 alpha 2 (COL1A2) can be potential biomarker and target for LUAD. PMID- 29973962 TI - The Relation between Pregnancy-Associated Plasma Protein A and Obstructive Sleep Apnea Syndrome. AB - Aim: We aimed to investigate the relationship between serum pregnancy-associated plasma protein A (PAPP-A) levels and obstructive sleep apnea syndrome (OSAS). Materials and Method: 44 patients with OSAS and 44 healthy adults were included in this study. The participants having rheumatic or systemic inflammatory disease, advanced liver or kidney failure, diabetes, heart failure, hypertension, pregnancy, prerenal azotemia, known history of coronary artery disease, any pulmonary disease, rhinitis, or atopy, history of major trauma or surgery within the last six 6 months, and inhaled nasal or systemic corticosteroid use or other anti-inflammatory medications and those with <18 years of age were excluded. Serum PAPP-A levels were determined by the Elisa method with the immune sandwich measuring method. Statistical analysis of the study was performed with SPSS 17.0 statistical analysis package program, and p < 0.05 was considered as significant. Results: Serum PAPP-A levels of patients with OSAS (2.350 ng/ml (0.641-4.796)) were significantly higher (p < 0.001) when compared with healthy controls (0.971 ng/ml (0.109-2.679)). There was a statistically significant difference in serum PAPP-A levels between groups of OSAS patients according to the classification of OSAS severity. Between the groups of patients with OSAS, serum levels of PAPP-A in moderate group was significantly higher when compared with severe OSAS group (p < 0.001). There was positive correlations between PAPP-A levels and night minimum (p=0.042, r=0.309), and average oxygen levels (p=0.006, r=0.407). There was a negative correlation between PAPP-A levels and AHI (p=0.002, r=-0.460). Conclusion: Higher PAPP-A levels in OSAS patients that were found in this study show inflammatory component in OSAS. PMID- 29973963 TI - Inhalation Techniques Used in Patients with Respiratory Failure Treated with Noninvasive Mechanical Ventilation. AB - The administration of aerosolized medication is a basic therapy for patients with numerous respiratory tract diseases, including obstructive airway diseases (OADs), cystic fibrosis (CF), and infectious airway diseases. The management and care for patients requiring mechanical ventilation remains one of the greatest challenges for medical practitioners, both in intensive care units (ICUs) and pulmonology wards. Aerosol therapy is often necessary for patients receiving noninvasive ventilation (NIV), which may be stopped for the time of drug delivery and administered through a metered-dose inhaler or nebulizer in the traditional way. However, in most severe cases, this may result in rapid deterioration of the patient's clinical condition. Unfortunately, only limited number of original well planned studies addressed this problem. Due to inconsistent information coming from small studies, there is a need for more precise data coming from large prospective real life studies on inhalation techniques in patients receiving NIV. PMID- 29973964 TI - Determinants of Mortality in Patients with Nosocomial Acinetobacter baumannii Bacteremia in Southwest China: A Five-Year Case-Control Study. AB - Purpose: This study was aimed to identify the determinants of in-hospital mortality in Acinetobacter baumannii (A. baumannii) bacteremia and to assess impact of carbapenem resistance on mortality. Methods: A five-year case-control study was conducted from January 2011 to December 2015 in a tertiary teaching hospital with 3200 beds, Southwest China. Clinical outcomes and potential determinants of mortality in patients with nosocomial A. baumannii bacteremia and carbapenem-resistant A. baumannii (CRAB) bacteremia were evaluated using Cox and logistic regression analyses. Results: A total of 118 patients with nosocomial A. baumannii bacteremia were included. Seventy-one percent (84/118) of them had carbapenem-resistant A. baumannii (CRAB) bacteremia. The in-hospital mortality of nosocomial A. baumannii bacteremia was 21.2%, and the attributable in-hospital mortality rate due to CRAB was 21.5%. Significant difference of 30-day in hospital mortality in the Kaplan-Meier curves was found between CRAB and CSAB groups (log-rank test, P=0.025). The Cox regression analysis showed that patients with CRAB bacteremia had 2.72 times higher risk for 30-day in-hospital mortality than did those with carbapenem-susceptible A. baumannii (CSAB) bacteremia (95% confidence intervals (CIs) 1.14-6.61, P=0.016). The logistic regression analysis reported that mechanical ventilation and respiratory tract as origin of bacteremia were independent predictors of mortality among patients with nosocomial A. baumannii bacteremia and CRAB bacteremia, while high APACHE II score on the day of bacteremia and multiple organ dysfunction syndromes (MODS) during hospitalization were independent predictors of mortality among patients with nosocomial A. baumannii bacteremia but not CRAB bacteremia. Conclusion: It was the severity of illness (high APACHE II score and MODS) not carbapenem resistance that highlighted the mortality of patients with nosocomial A. baumannii bacteremia. The impact of mechanical ventilation on mortality suggested that respiratory dysfunction might prime the poor outcome. Protection of respiratory function during the progression of nosocomial A. baumannii bacteremia should be given more importance. Early identification and intervention of patients with nosocomial A. baumannii bacteremia in critical ill conditions were advocated. PMID- 29973965 TI - Pleasant Pain Relief and Inhibitory Conditioned Pain Modulation: A Psychophysical Study. AB - Background: Inhibitory conditioned pain modulation (ICPM) is one of the principal endogenous pain inhibition mechanisms and is triggered by strong nociceptive stimuli. Recently, it has been shown that feelings of pleasantness are experienced after the interruption of noxious stimuli. Given that pleasant stimuli have analgesic effects, it is therefore possible that the ICPM effect is explained by the confounding effect of pleasant pain relief. The current study sought to verify this assumption. Methods: Twenty-seven healthy volunteers were recruited. Thermal pain thresholds were measured using a Peltier thermode. ICPM was then measured by administering a tonic thermal stimulus before and after a cold-pressor test (CPT). Following the readministration of the CPT, pleasant pain relief was measured for 4 minutes. According to the opponent process theory, pleasant relief should be elicited following the interruption of a noxious stimulus. Results: The interruption of the CPT induced a mean and peak pleasant pain relief of almost 40% and 70%, respectively. Pleasant pain relief did not correlate with ICPM amplitude but was positively correlated with pain level during the CPT. Finally, a negative correlation was observed between pleasant pain relief and anxiety. Discussion: Results show that the cessation of a strong nociceptive stimulus elicits potent pleasant pain relief. The lack of correlation between ICPM and pleasant pain relief suggests that the ICPM effect, as measured by sequential paradigms, is unlikely to be fully explained by a pleasant pain relief phenomenon. PMID- 29973966 TI - Pregabalin Prescription for Neuropathic Pain and Fibromyalgia: A Descriptive Study Using Administrative Database in Japan. AB - Objective: To assess dose, characteristics, and coprescribed analgesics in patients newly prescribed pregabalin for neuropathic pain and fibromyalgia in Japan. Methods: Based on the medical and prescription information present in the Medical Data Vision database, we analyzed the initial and maximum daily doses, prescription period, coprescribed analgesics, and neuropathic pain-related disorders of patients newly prescribed pregabalin between 01 July 2010 and 31 December 2013. Results: A total of 45,331 patients (mean age 66.8 years, 48.7% men) were newly prescribed pregabalin during this period. The mean initial and maximum daily doses were 97.3 mg and 127.8 mg, respectively, and decreased yearly. The duration of the prescription period was 111.9 (mean) and 53 (median) days, and the frequently coprescribed analgesics included NSAIDs, opioids, and Neurotropin(r). About one half of the patients had spinal disorders. Conclusion: In Japan during the period examined, the number of newly prescribed pregabalin users increased, but the initial and maximum daily doses decreased yearly after pregabalin went on the market. The maximum daily dose in Japan was lower than those reported in the USA and Europe. These differences might be associated with patient age and physical status and with anxiety about possible adverse events. PMID- 29973967 TI - Development of a Multimodal Analgesia Protocol for Perioperative Acute Pain Management for Lower Limb Amputation. AB - Multimodal analgesia may include pharmacological components such as regional anesthesia, opioid and nonopioid systemic analgesics, nonsteroidal anti inflammatories, and a variety of adjuvant agents. Multimodal analgesia has been reported for a variety of surgical procedures but not yet for lower limb amputation in vasculopathic patients. Perioperative pain management in these patients presents a particular challenge considering the multiple sources and pathways for acute and chronic pain that are involved, such as chronic ischemic limb pain, postoperative residual limb pain, coexisting musculoskeletal pain, phantom limb sensations, and chronic phantom limb pain. These pain mechanisms are explored and a proposed protocol for multimodal analgesia is outlined taking into account the common patient comorbidities found in this patient population. PMID- 29973968 TI - Migraine Pain Location and Measures of Healthcare Use and Distress: An Observational Study. AB - Introduction: Lateralized pain is a core diagnostic feature of migraine. In previous research, left-sided spinal pain was more frequent and associated with greater emotional distress and healthcare use than right-sided pain. We hypothesized therefore that patients with left-sided head pain might experience higher levels of distress or healthcare use than those with right-sided or bilateral pain. Methods: Medical record information was extracted for 477 randomly selected patients with migraine seen in 2011 in a tertiary headache clinic. This included demographic data, pain location, handedness, comorbid psychiatric diagnoses, medical and emergency department visits, and use of selected headache medications. Results and Discussion: Two hundred twenty-eight of four hundred seventy-seven (47.8%) patients reported lateralized pain, of which 107 (47.9%) patients were right sided compared with 65 (28.5%) left-sided patients (p=0.001), while 56 (24.5%) reported unilateral pain with no side predominance. Contrary to expectations, with the exception of self-reported posttraumatic stress disorder, there were no statistically significant differences between left and right in measures of psychiatric distress, emergency department visits, or healthcare use. Conclusion: Although unilateral pain location can be helpful in making a migraine diagnosis, it does not appear to have additional clinical implications. Additionally, its absence does not rule out a diagnosis of migraine since more than half of migraineurs have bilateral head pain. PMID- 29973969 TI - Evoked and Ongoing Pain-Like Behaviours in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy. AB - Paclitaxel-induced neuropathic pain is a major dose-limiting side effect of paclitaxel therapy. This study characterises a variety of rat behavioural responses induced by intermittent administration of clinically formulated paclitaxel. 2 mg/kg paclitaxel or equivalent vehicle was administered intraperitoneally on days 0, 2, 4, and 6 to adult male Sprague-Dawley rats. Evoked pain-like behaviours were assessed with von Frey filaments, acetone, or radiant heat application to plantar hind paws to ascertain mechanical, cold, or heat sensitivity, respectively. Motor coordination was evaluated using an accelerating RotaRod apparatus. Ongoing pain-like behaviour was assessed via spontaneous burrowing and nocturnal wheel running. Mechanical and cold hypersensitivity developed after a delayed onset, peaked approximately on day 28, and persisted for several months. Heat sensitivity and motor coordination were unaltered in paclitaxel-treated rats. Spontaneous burrowing behaviour and nocturnal wheel running were significantly impaired on day 28, but not on day 7, indicating ongoing pain-like behaviour, rather than acute drug toxicity. This study comprehensively characterises a rat model of paclitaxel-induced peripheral neuropathy, providing the first evidence for ongoing pain-like behaviour, which occurs in parallel with maximal mechanical/cold hypersensitivity. We hope that this new data improve the face validity of rat models to better reflect patient reported pain symptoms, aiding translation of new treatments to the clinic. PMID- 29973970 TI - Comparison between Collagen and Lidocaine Intramuscular Injections in Terms of Their Efficiency in Decreasing Myofascial Pain within Masseter Muscles: A Randomized, Single-Blind Controlled Trial. AB - Background and Objective: A novel option for myofascial pain (MFP) management and muscle regeneration is intramuscular collagen injections. The aim of the study was to evaluate the efficiency of intramuscular injections of collagen and lidocaine in decreasing MFP within masseter muscles. Methods: Myofascial pain within masseter muscles was diagnosed on the basis of the Diagnostic Criteria for Temporomandibular Disorders (II.1.A. 2 and 3). A total of 43 patients with diagnosed MFP within masseter muscles were enrolled to the study (17 male and 26 female, 40 +/- 3.8 years old) and randomly divided into three groups. The first group received injections using 2 ml of collagen MD Muscle (Guna), the second group received 2 ml of 2% lidocaine without a vasoconstrictor, and the third group 2 ml of saline as a control (0.9% NaCl). All patients received repeated injections at one-week intervals (days 0 and 7). The visual analogue scale was used to determine pain intensity changes during each follow-up visit (days 0, 7, and 14) in each group. The masseter muscle activity was measured on each visit (days 0, 7, and 14) with surface electromyography (sEMG) (Neurobit Optima 4, Neurobit Systems). Results: We found that sEMG masseter muscle activity was significantly decreased in Group I (59.2%), less in Group II (39.3%), and least in Group III (14%). Pain intensity reduction was 53.75% in Group I, 25% in Group II, and 20.1% in Group III. Conclusions: The study confirmed that intramuscular injection of collagen is a more efficient method for reducing myofascial pain within masseter muscles than intramuscular injection of lidocaine. PMID- 29973971 TI - Off-the-Grid Recovery of Piecewise Constant Images from Few Fourier Samples. AB - We introduce a method to recover a continuous domain representation of a piecewise constant two-dimensional image from few low-pass Fourier samples. Assuming the edge set of the image is localized to the zero set of a trigonometric polynomial, we show the Fourier coefficients of the partial derivatives of the image satisfy a linear annihilation relation. We present necessary and sufficient conditions for unique recovery of the image from finite low-pass Fourier samples using the annihilation relation. We also propose a practical two-stage recovery algorithm which is robust to model-mismatch and noise. In the first stage we estimate a continuous domain representation of the edge set of the image. In the second stage we perform an extrapolation in Fourier domain by a least squares two-dimensional linear prediction, which recovers the exact Fourier coefficients of the underlying image. We demonstrate our algorithm on the super-resolution recovery of MRI phantoms and real MRI data from low-pass Fourier samples, which shows benefits over standard approaches for single-image super-resolution MRI. PMID- 29973972 TI - Development, Validity, and Reliability of the Women's Capabilities Index. AB - We report the results of a series of validity and reliability tests performed during the development of the Women's Capabilities Index (WCI) in Malawi. The WCI is a multidimensional measure based on Sen's capability framework for assessing women's quality of life. Construct validity was assessed by investigating the expected relationships of the dimensions with key socioeconomic characteristics. The majority of hypothesized associations were found to be statistically significant in the expected direction. This provides evidence that the index is measuring quality of life as intended in the conceptual model. Further evidence in support of the index's validity was given by the high degree of correlation between the WCI and another scale measuring comparable (but not identical) domains of quality of life. The results from the internal consistency and the test-retest repeatability also offered encouraging evidence on the reliability of the instrument. This is the first study to rigorously and comprehensively test for validity and reliability a capabilities index for a low-income setting. The results of the validity and reliability tests provide supportive evidence that a locally developed measure of capabilities can be used as a robust tool for the assessment of women's quality of life. PMID- 29973973 TI - The Best of Times, the Worst of Times: Understanding Pro-cyclical Mortality. AB - It is well known that mortality rates are pro-cyclical. In this paper, we attempt to understand why. We find little evidence that cyclical changes in individuals' own employment-related behavior drives the relationship; own-group employment rates are not systematically related to own-group mortality. Further, most additional deaths that occur when the economy is strong are among the elderly, particularly elderly women and those residing in nursing homes. We also demonstrate that staffing in nursing homes moves counter-cyclically. These findings suggest that cyclical fluctuations in the quality of health care may be a critical contributor to cyclical movements in mortality. PMID- 29973974 TI - ESTIMATING SHAPE CORRESPONDENCE FOR POPULATIONS OF OBJECTS WITH COMPLEX TOPOLOGY. AB - Statistical shape analysis captures the geometric properties of a given set of shapes, obtained from medical images, by means of statistical methods. Orthognathic surgery is a type of craniofacial surgery that is aimed at correcting severe skeletal deformities in the mandible and maxilla. Methods assuming spherical topology cannot represent the class of anatomical structures exhibiting complex geometries and topologies, including the mandible. In this paper we propose methodology based on non-rigid deformations of 3D geometries to be applied to objects with thin, complex structures. We are able to accurately and quantitatively characterize bone healing at the osteotomy site as well as condylar remodeling for three orthognathic surgery cases, demonstrating the effectiveness of the proposed methodology. PMID- 29973975 TI - 4D CONTINUOUS MEDIAL REPRESENTATION BY GEODESIC SHAPE REGRESSION. AB - Longitudinal shape analysis has shown great potential to model anatomical processes from baseline to follow-up observations. Shape regression estimates a continuous trajectory of time-discrete anatomical shapes to quantify temporal changes. The need for shape alignment and point-to-point correspondences represent limitations of current shape analysis methodologies, and present significant challenges in shape evaluation. We propose a method that estimates a continuous trajectory of continuous medial representations (CM-Rep) from a set of time-discrete observed shapes. To avoid the traditional step of aligning individual objects, shape changes are modeled via diffeomorphic ambient space deformations. Using a medial shape representation, we separately capture object pose changes and intrinsic geometry changes. Tests and validation with synthetic and real anatomical shapes demonstrate that the new method captures extrinsic shape changes as well as intrinsic shape changes encoded with CM-Reps, a highly relevant property for studying growth and disease processes. PMID- 29973976 TI - Improved Surface-Based Registration of CT and Intraoperative 3D Ultrasound of Bones. AB - The intraoperative registration of preoperative CT volumes is a key process of most computer-assisted orthopedic surgery (CAOS) systems. In this work, is reported a new method for automatic registration of long bones, based on the segmentation of the bone cortical in intraoperative 3D ultrasound images. A bone classifier was developed based on features, obtained from the principal component analysis of the Hessian matrix, of every voxel in an intraoperative ultrasound volume. 3D freehand ultrasound was used for the acquisition of the intraoperative ultrasound volumes. Corresponding bone surface segmentations in ultrasound and preoperative CT imaging were used for the intraoperative registration. Validation on a phantom of the tibia produced encouraging results, with a maximum mean segmentation error of 0.34?mm (SD=0.26?mm) and a registration accuracy error of 0.64?mm (SD=0.49?mm). PMID- 29973977 TI - Approaches to Medical Decision-Making Based on Big Clinical Data. AB - The paper discusses different approaches to building a medical decision support system based on big data. The authors sought to abstain from any data reduction and apply universal teaching and big data processing methods independent of disease classification standards. The paper assesses and compares the accuracy of recommendations among three options: case-based reasoning, simple single-layer neural network, and probabilistic neural network. Further, the paper substantiates the assumption regarding the most efficient approach to solving the specified problem. PMID- 29973978 TI - Assessing Effectiveness and Costs in Robot-Mediated Lower Limbs Rehabilitation: A Meta-Analysis and State of the Art. AB - Robots were introduced in rehabilitation in the 90s to meet different needs, that is, reducing the physical effort of therapists. This work consists of a meta analysis of robot-mediated lower limbs rehabilitation for stroke-affected patients; it aims at evaluating the effectiveness of the robotic approach through the use of wearable robots or operational machines with respect to the conventional approach (i.e., manual rehabilitation therapy). The primary assessed outcome is the patient's ability to recover walking independence, whereas the secondary outcome is the average walking speed. The therapy acceptability and the treatment costs are also assessed. The assessment shows that the robot-mediated therapy is more effective than the conventional one in reaching the primary outcome. As for the secondary outcome, there is no significant difference between the robotic (wearable robots or operational machines) and the conventional approach. Rehabilitation using wearable robots has a greater acceptability than the conventional one. This does not apply to operational machines. The cost of robotic treatment with wearable robots ranges from double to triple the cost of the conventional approach. On the contrary, rehabilitation using operational machines costs the same as the conventional treatment. Robotic rehabilitation based on operational machines is the most cost-effective approach. PMID- 29973979 TI - Prognostic Factors in Anti-Neutrophil Cytoplasmic Antibody-Associated Glomerulonephritis with Severe Glomerular Sclerosis: A National Registry-Based Cohort Study. AB - Background: Classification of patients with anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN) into histological classes is useful for predicting a patient's risk of progression to end-stage renal disease (ESRD). However, even in the worst prognostic group, the 5-year end-stage renal disease free survival rate is as high as 50%. Objectives: To investigate those prognostic factors indicative of progression to ESRD in patients with ANCA-GN and sclerosing histology. Methods: Patients from the Norwegian Kidney Biopsy Registry between 1991 and 2012 who had biopsy verified pauci-immune glomerulonephritis, positive ANCA serology, and sclerosing histology were included. Cases with ESRD during follow-up were identified via linkage with the Norwegian Renal Registry. Potential prognostic factors with relevant cut-offs were compared in patients with and without progression to ESRD during follow-up. Results: Of 23 included patients, 10 progressed to ESRD. ESRD patients had a lower initial estimated glomerular filtration rate (eGFR; 21 versus 52 ml/min/1.73 m2) and a lower percentage of normal glomeruli (4% versus 15%). Five-year risks of ESRD with eGFR >15 versus <=15 ml/min/1.73 m2 were 77% and 15%, with percentage normal glomeruli >10% versus <=10%, 83% and 39%. Conclusions: eGFR and percentage of normal glomeruli are strong risk factors for ESRD in ANCA-GN with sclerosing histology. PMID- 29973980 TI - Best Practices for The Interdisciplinary Rehabilitation Team: A Review of Mental Health Issues in Mild Stroke Survivors. AB - Individuals with mild strokes are generally considered fully functional and do not traditionally receive rehabilitation services. Because patients with mild stroke are assumed to have a good recovery, they may have deficits in other areas, including mental health, that are not addressed. As a result, patients with mild stroke are unable to meet quality of life standards. In addition, healthcare professionals are likely unaware of the potential mental health issues that may arise in mild stroke. To address this gap in knowledge, we review the evidence supporting mental health evaluation and intervention in mild stroke. Specifically, we review comorbid diagnoses including depression, anxiety, fatigue, and sleep disturbances and their potential effects on health and function. Finally, we conclude with general recommendations describing best practice derived from current evidence. PMID- 29973981 TI - Epidemiology of Hip Fractures in Two Regions of Ukraine. AB - Worldwide, the number of hip fractures, the most important osteoporotic complication in the elderly, continues to increase in line with the ageing of the population. In some countries, however, including the Ukraine, data on the incidence of hip fracture are limited. This article describes the first analysis to characterize the incidence of hip fracture in the Ukrainian population from the age of 40 years. It is based on data from two regional studies, namely, the Vinnitsa city study and the STOP study, which were performed during 1997-2002 and 2011-2012 years, respectively. Hip fracture incidence rates were demonstrated to increase with increasing age. The rates were higher among younger men than women, however, with a female preponderance from the age of 65 years upwards. The incidence of hip fractures in Ukraine is 255.5 per 100,000 for women aged 50 years and older and 197.8 per 100,000 for men of the corresponding age. Overall, the incidence of hip fracture was comparable with data from neighboring countries, such as Poland and Romania. Hip fractures constitute a serious healthcare problem in Ukraine, and changes in healthcare are required to improve the management and long-term care of osteoporosis and its complications. PMID- 29973983 TI - Diurnal hormonal responses in exercise and sports medicine research: range effect adjustments. AB - The paper discusses the means in which exercise hormonal data are transformed and expressed as a way to deal with the inherent variability in endocrine measurements. Specifically, the aim of the paper is to present an alterative transformation adjustment method for expressing the exercise responses of hormones, especially those which exhibit a diurnal behaviour in their circulating concentrations. The suggested alterative adjustment method attempts to account for the influence of the "range effect" on diurnal hormonal data and the subsequent effects it may have on statistical, and perhaps physiological, outcomes and data interpretation. PMID- 29973982 TI - Perceived stress across the midlife: longitudinal changes among a diverse sample of women, the Study of Women's health Across the Nation (SWAN). AB - Background: In women, midlife is a period of social and physiological change. Ostensibly stressful, cross-sectional studies suggest women experience decreasing stress perceptions and increasing positive outlook during this life stage. The aim of this paper was to describe the longitudinal changes in perceived stress as women transitioned through the midlife. Methods: Premenopausal women (n = 3044) ages 42-52 years at baseline, were recruited from seven sites in the Study of Women's Health Across the Nation, and followed approximately annually over 13 visits with assessment of perceived stress and change in menopausal status. Longitudinal regression models were used to assess the effects of age, menopausal status and baseline sociodemographic variables on the trajectory of perceived stress over time. Results: At baseline, mean age was 46.4 +/- 2.7 years; participants were white (47%), black (29%), Hispanic (7%), Japanese (9%), or Chinese (8%). Hispanic women, women with lesser educational attainment, and women reporting financial hardship were each more likely to report high perceived stress levels at baseline (all p < 0.0001). After adjustment for baseline sociodemographic factors, perceived stress decreased over time for most women (p < 0.0001), but increased for both Hispanic and white participants at the New Jersey site (p < 0.0001). Changing menopausal status was not a significant predictor of perceived stress. Conclusions: Self-reported stress decreased for most women as they transitioned across the midlife; changing menopausal status did not play a significant role after adjustment for age and sociodemographic factors. Future studies should explore the stress experience for women by racial/ethnic identity and demographics. PMID- 29973984 TI - Ramadan Fasting in Kidney Transplant Recipients: A Single-Centre Retrospective Study. AB - Background: Fasting during the lunar month of Ramadan is mandatory to all healthy adult Muslims. Renal transplant recipients are often worried about the impact of fluid and electrolyte deprivation during fasting on the function of their allograft. We aimed to examine the effect of fasting Ramadan on the graft function in renal transplant recipients. Methods: This retrospective cohort study included patients who underwent kidney transplantation in our tertiary referral center. Baseline pre-Ramadan estimated glomerular filtration rate (eGFR), mean arterial pressure (MAP), and urinary protein excretion were compared to those during and after Ramadan within and between the fasting and non-fasting groups. Results: The study population included 280 kidney transplant recipients who chose to fast during the Ramadan month (June-July 2014) and 285 recipients who did not fast. In the fasting group, baseline eGFR did not change from that during or post Ramadan (72.6 +/- 23.7 versus 72.3 +/- 24.5 mL/min/1.73 m2, P = 0.53; and 72.6 +/ 23.7 versus 72 +/- 23.2 mL/min/1.73 m2, P = 0.14, respectively). Compared to baseline, there were no significant differences between the fasting and the non fasting groups in terms of mean percent changes in eGFR, MAP, and urinary protein excretion. Conclusion: Fasting during the month of Ramadan did not have significant adverse effects on renal allograft function. PMID- 29973987 TI - Combination of APACHE Scoring Systems with Adductor Pollicis Muscle Thickness for the Prediction of Mortality in Patients Who Spend More Than One Day in the Intensive Care Unit. AB - Background: The objective of the present study was to compare the ability of Acute Physiology and Chronic Health Evaluation (APACHE) scoring systems with the combination of an anthropometric variable score "adductor pollicis muscle (APM) thickness" to the APACHE systems in predicting mortality in the intensive care unit. Methods: A prospective observational study was conducted with the APM thickness in the dominant hand, and APACHE II and III scores were measured for each patient upon admission. Given scores for the APM thickness were added to APACHE score systems to make two composite scores of APACHE II-APM and APACHE III APM. The accuracy of the two composite models and APACHE II and III systems in predicting mortality of patients was compared using the area under the ROC curve. Results: Three hundred and four patients with the mean age of 54.75 +/- 18.28 years were studied, of which 96 (31.57%) patients died. Median (interquartile range) of APACHE II and III scores was 15 (12-20) and 47 (33-66), respectively. Median (interquartile range) of APM thickness was 15 (12-17) mm, respectively. The area under the ROC curves for the prediction of mortality was 0.771 (95% CI: 0.715-0.827), 0.802 (95% CI: 0.751-0.854), 0.851 (95% CI: 0.807-0.896), and 0.865 (95% CI: 0.822-0.908) for APACHE II, APACHE III, APACHE II-APM, and APACHE III APM, respectively. Conclusion: Although improvements in the area under ROC curves were not statistically significant when the APM thickness added to the APACHE systems, but the numerical value added to AUCs are considerable. PMID- 29973985 TI - Management of Pregnant Women after Bariatric Surgery. AB - The prevalence of obesity is growing worldwide, and strategies to overcome this epidemic need to be developed urgently. Bariatric surgery is a very effective treatment option to reduce excess weight and often performed in women of reproductive age. Weight loss influences fertility positively and can resolve hormonal imbalance. So far, guidelines suggest conceiving after losing maximum weight and thus recommend conception at least 12-24 months after surgery. As limited data of these suggestions exist, further evidence is urgently needed as well for weight gain in pregnancy. Oral glucose tolerance tests for the diagnosis of gestational diabetes mellitus (GDM) should not be performed after bariatric procedures due to potential hypoglycaemic adverse events and high variability of glucose levels after glucose load. This challenges the utility of the usual diagnostic criteria for GDM in accurate prediction of complications. Furthermore, recommendations on essential nutrient supplementation in pregnancy and lactation in women after bariatric surgery are scarce. In addition, nutritional deficiencies or daily intake recommendations in pregnant women after bariatric surgery are not well investigated. This review summarizes current evidence, proposes clinical recommendations in pregnant women after bariatric surgery, and highlights areas of lack of evidence and the resulting urgent need for more clinical investigations. PMID- 29973986 TI - Multilevel Analysis of Determinants of Anemia Prevalence among Children Aged 6-59 Months in Ethiopia: Classical and Bayesian Approaches. AB - Background: Anemia is a widely spread public health problem and affects individuals at all levels. However, there is a considerable regional variation in its distribution. Objective: Thus, this study aimed to assess and model the determinants of prevalence of anemia among children aged 6-59 months in Ethiopia. Data: Cross-sectional data from Ethiopian Demographic and Health Survey was used for the analysis. It was implemented by the Central Statistical Agency from 27 December 2010 through June 2011 and the sampling technique employed was multistage. Method: The statistical models that suit the hierarchical data such as variance components model, random intercept model, and random coefficients model were used to analyze the data. Likelihood and Bayesian approaches were used to estimate both fixed effects and random effects in multilevel analysis. Result: This study revealed that the prevalence of anemia among children aged between 6 and 59 months in the country was around 42.8%. The multilevel binary logistic regression analysis was performed to investigate the variation of predictor variables of the prevalence of anemia among children aged between 6 and 59 months. Accordingly, it has been identified that the number of children under five in the household, wealth index, age of children, mothers' current working status, education level, given iron pills, size of child at birth, and source of drinking water have a significant effect on prevalence of anemia. It is found that variances related to the random term were statistically significant implying that there is variation in prevalence of anemia across regions. From the methodological aspect, it was found that random intercept model is better compared to the other two models in fitting the data well. Bayesian analysis gave consistent estimates with the respective multilevel models and additional solutions as posterior distribution of the parameters. Conclusion: The current study confirmed that prevalence of anemia among children aged 6-59 months in Ethiopia was severe public health problem, where 42.8% of them are anemic. Thus, stakeholders should pay attention to all significant factors mentioned in the analysis of this study but wealth index/improving household income and availability of pure drinking water are the most influential factors that should be improved anyway. PMID- 29973988 TI - Adherence to Hemodialysis and Associated Factors among End Stage Renal Disease Patients at Selected Nephrology Units in Rwanda: A Descriptive Cross-Sectional Study. AB - Introduction: Worldwide, End Stage Renal Disease (ESRD) has become a public health concern increasing the number of patients maintained on hemodialysis prior to renal transplantation. Nonadherence to hemodialysis continues to impact on the care of ESRD patients, causing high increase in morbidity and mortality. Purpose of the Study: The purpose of this study was to determine the level of adherence to hemodialysis and the associated factors among End Stage Renal Disease (ESRD) patients in selected nephrology units in Rwanda. Methods: This was a descriptive cross-sectional design involving 41 participants. Participants were recruited using a purposive sampling technique. Demographic and adherence to hemodialysis data were collected with the use of structured interview schedules. Descriptive statistics were used to describe the demographic variables and the level of adherence to hemodialysis. Inferential statistics of chi-square was used to establish factors associated with adherence to hemodialysis. Results: Twenty-one (51%) of ESRD participants adhered highly (scores < 80%) to HD. Seventeen (42%) adhered moderately (70-79%) to HD while three (7%) had low level of adherence to HD (below 70%). The factors associated with adherence to hemodialysis were age (mean = 27; 95% CI 26.76-29, 17; p = 038) and religion (95% CI 26.29-60.12, p = 003). Frequencies of education of health care workers about the importance of not missing dialysis (95% CI 26.71-42.56, p = .000), perceived relative importance of hemodialysis (95% CI 20.44-27.76, p = .020), and experiencing difficulties during the procedure (95% CI 20.80-28.36, p = .004) were significantly associated with adherence to hemodialysis. Conclusion. Adherence to hemodialysis is still a public health concern in Rwanda. Health care providers and particularly nurses should continue to advocate for adherence to HD for better health outcomes. Further research is needed to identify the barriers to HD in Rwanda. PMID- 29973989 TI - Corrigendum to "Hepatic Iron Quantification on 3 Tesla (3 T) Magnetic Resonance (MR): Technical Challenges and Solutions". AB - [This corrects the article DOI: 10.1155/2013/628150.]. PMID- 29973990 TI - Feasibility and Safety of Perilla Seed Oil as an Additional Antioxidative Therapy in Patients with Mild to Moderate Dementia. AB - Dementia is a broad-spectrum terminology for a degenerate in cognitive function severe enough to intervene in activities of daily living. Oxidative stress plays a major role in the neurodegenerative cascade, leading to the irreversible mechanism in dementia. Perilla seed oil is extracted from its seeds and contains a high source of antioxidative substances such as omega-3 fatty acid. With its prominent antioxidative property, perilla seed oil demonstrates neuroprotective effects against dementia in preclinical studies. We aim to prove the feasibility and safety of perilla seed oil as an additional antioxidative therapy in patients with dementia. This single-centered, double-blinded, placebo-controlled trial randomized 239 patients with clinical diagnosis of mild to moderate dementia according to the Thai Mini-Mental State Examination (TMSE) score of 10 to 23 or the Thai Montreal Cognitive Assessment score of 12 to 25. Either two capsules containing 500 milligrams of perilla seed oil or similarly appearing two capsules containing 500 milligrams of olive oil (placebo) four times daily was added to conventional standard treatment of dementia for six months. Clinical side effects and routine laboratory results at baseline and after treatment were compared between both groups. Nausea and vomiting were the most common clinical side effects (3%) found equally in both groups. Three patients in the placebo group prematurely discontinued the medication, while only one patient in the treatment group quit the medication early. However, about 5% of patients in both groups could not comply with the regimen of the treatment. The routine laboratory results, including complete blood counts, kidney function tests, and liver function panels, at baseline and after treatment, were not significantly different in both groups. In conclusion, perilla seed oil was feasible and safe to add on with standard treatment in patients with mild to moderate dementia. Further study is needed to confirm its benefit to use as additional antioxidative therapy in patients with dementia. PMID- 29973991 TI - Comment on "Effect of Exercise Intervention on Flow-Mediated Dilation in Overweight and Obese Adults: Meta-Analysis". PMID- 29973992 TI - Basosquamous Carcinoma: A Single Centre Clinicopathological Evaluation and Proposal of an Evidence-Based Protocol. AB - Basosquamous carcinoma (BSC) is an uncommon skin malignancy with significant invasive and metastatic potential. There are currently no clear management guidelines. This study evaluates the management and outcomes of patients diagnosed with BSC over a 7-year period. We present an evidence-based unit protocol for the management of BSC. All patients treated for BSC between 2009 and 2015 were reviewed. Data collected included patient demographics, tumour-specific information, management strategy, presence of recurrence or metastasis, and details of follow-up. 74 patients were identified, making this one of the largest cohorts of BSC patients reported. Mean age at diagnosis was 75.4 years, with a male:female ratio of 1.6:1. The most common tumour site was the head and neck (n=43, 58.1%). All tumours were graded at pT1 (n=51) or pT2 (n=23). Inadequate excision occurred in 17 patients (23%). Mean excision margins were >4mm peripherally and deep. Inadequately excised BSCs were further treated with wide local excision (n=6) or radiotherapy (n=5), or both (n=1). There were no cases of local recurrence or metastatic disease. This study demonstrates a cohort of patients with BSCs that appear less aggressive than previously reported. Current management with surgical excision appears to produce adequate results. However, an evidence-based guideline is still lacking. PMID- 29973993 TI - Development and Characterization of Solid Lipid Nanoparticles Containing Herbal Extract: In Vivo Antidepressant Activity. AB - In alternate systems of medicine like Ayurveda and traditional Chinese medicine, Hibiscus rosa sinensis and its extracts have been traditionally prescribed for their antidepressant activity. Crude extracts and rudimentary formulations approaches are good for proof-of-concept studies; however, these formulations are fraught with problems like poor oral bioavailability and high variability between subjects. Systematic drug delivery approaches could prove effective in addressing some of these problems. In this study, we report the development of Hibiscus rosa sinensis extract loaded solid lipid nanoparticles (HSLNs) using glycerol monostearate or beeswax as lipids. The HSLNs were evaluated for their size, surface charge, and morphology. The optimized HSLNs were tested for antidepressant activity in male Swiss albino mice. It was found that, with the optimized procedure, HSLNs of ~175 nm, carrying negative charge and nearly spherical shape, could be obtained. The in vivo test results suggested that there were marked differences in the immobility times of the test animals. Moreover, with HSLNs, it was found that at doses several times lower than the native crude extract dose, similar pharmacological effect could be obtained. These initial findings suggest that encapsulating phytopharmaceuticals into advanced delivery systems like solid lipid nanoparticles can be an effective strategy in improving their in vivo performance. PMID- 29973994 TI - Effect of Helicobacter pylori Infection on Serum Lipid Profile. AB - Background: Some studies suggest a significant relationship between Helicobacter pylori infection and atherogenesis; but the mechanism of the relationship is almost unknown. The current study aimed at evaluating the relationship between H. pylori infection and serum lipid profile. Patients and Methods: The current study was conducted on 2573 patients, from 2008 to 2015. The serum anti-Helicobacter pylori antibody titer and serum lipid profile were assessed in the study population; data were statistically analyzed by SPSS version 16. P values < 0.05 were considered significant. Results: In the current study, 66.5% of the cases were serologically positive for H. pylori. Among male cases, the level of low density lipoprotein (LDL) was higher in patients with H. pylori infection, compared with that of the ones without the infection (P = 0.03); although level of triglyceride (TG) was higher and the level of high density lipoprotein (HDL) was lower in the cases with H. pylori infection; there was no statistically significant difference between the cases with and without H. pylori infection regarding the level of HDL and TG. Among female cases, the level of TG was significantly lower in patients with H. pylori infection, compared with that of the ones without the infection (P = 0.001); but there was no significant difference between the cases with and without H. pylori infection regarding the level of LDL and HDL. The mean fasting blood sugar (FBS) in the cases with H. pylori infection was significantly higher than that of the ones without the infection (P = 0.04). Conclusion: According to the results of the current study, the levels of LDL and FBS were high among the male cases with H. pylori infection. However, in females with H. pylori infection the level of TG was low; hence, it seems that the atherogenicity of H. pylori affected the level of blood sugar more. PMID- 29973996 TI - A Population-Based Cross-Sectional Study of the Association between Liver Enzymes and Lipid Levels. AB - Background: To examine the association between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels and liver enzyme functions. Methods: The National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2012 was used to examine the association between liver enzymes and lipid levels amongst adults in the United States. Results: Sixteen percent adults had ALT > 40 U/L, 11% had AST > 40 U/L, and 96% had ALP > 120 U/L. Age, gender, and race/ethnicity showed significant association with LDL, HDL, and triglycerides levels. LDL greater than borderline high was associated with little over two times higher odds of elevated ALT (OR: 2.33, 95% CI: 2.17, 2.53, p <= 0.001) and AST (OR: 2.79, 95% CI: 2.55, 3.06, p <= 0.001). High HDL was associated with 50% higher odds for elevated ALT (OR: 1.51, 95% CI: 1.39, 1.64, p <= 0.001) and over two-and-half fold elevated AST (OR: 2.77, 95% CI: 2.47, 3.11, p <= 0.001). LDL-C, HDL-C, and triglycerides were found to be good predictor of elevated ALT, AST, and ALP levels. Similarly, old age and female gender were significant predictor of elevated ALT and AST (p <= 0.001). Conclusions: Underlying hepatic pathophysiology from dyslipidemia deserves further exploration due to its potential effects on hepatic drug metabolism/detoxification. PMID- 29973995 TI - Antibody-Mediated Therapy against HIV/AIDS: Where Are We Standing Now? AB - Acquired immunodeficiency syndrome (AIDS) cases are on the rise globally. To date, there is still no effective measure to eradicate the causative agent, human immunodeficiency virus (HIV). Highly active antiretroviral therapy (HAART) is being used in HIV/AIDS management, but it results in long-term medication and has major drawbacks such as multiple side effects, high cost, and increasing the generation rate of escape mutants. In addition, HAART does not control HIV related complications, and hence more medications and further management are required. With this, other alternatives are urgently needed. In the past, small molecule inhibitors have shown potent antiviral effects, and some of them are now being evaluated in clinical trials. The challenges in developing these small molecules for clinical use include the off-target effect, poor stability, and low bioavailability. On the other hand, antibody-mediated therapy has emerged as an important therapeutic modality for anti-HIV therapeutics development. Many antiviral antibodies, namely, broad neutralizing antibodies (bnAbs) against multiple strains of HIV, have shown promising effects in vitro and in animal studies; further studies are ongoing in clinical trials to evaluate their uses in clinical applications. This short review aims to discuss the current development of therapeutic antibodies against HIV and the challenges in adopting them for clinical use. PMID- 29973997 TI - Newer Oral Anticoagulants in the Treatment of Acute Portal Vein Thrombosis in Patients with and without Cirrhosis. AB - Background: Newer oral anticoagulants (NOACs) are being utilized increasingly for the treatment of venous thromboembolism (VTE). NOAC use is the standard of care for stroke prophylaxis in nonvalvular atrial fibrillation and treatment of acute VTE involving extremities and pulmonary embolism. In contrast, most guidelines in the literature support the treatment of acute portal vein thrombosis (PVT) with low molecular weight heparin (LMWH) and vitamin K antagonists (VKA). Literature evaluating NOAC use in the treatment of acute portal vein thrombosis is sparse. This review focuses on the safety and efficacy of the use of NOACs in the treatment of acute PVT in patients, with or without concomitant cirrhosis, based on the most recent data available in the current literature. Methods: A systematic review was conducted through a series of advanced searches in the following medical databases: PubMed, BioMed Central, Cochrane, and Google Scholar. Keywords utilized were as follows: NOAC, DOAC (direct oral anticoagulants), portal vein thrombosis, rivaroxaban, apixaban, dabigatran, and edoxaban. Articles related to newer anticoagulant use in patients with portal vein thrombosis were included. Results: The adverse events, including bleeding events (major and minor) and the failure of anticoagulation (propagation of thrombus or recurrence of PVT), are similar between the NOACs and traditional anticoagulants for the treatment of acute PVT, irrespective of the presence of cirrhosis. Conclusions: Newer oral anticoagulants are safe and efficacious alternatives to traditional anticoagulation with low molecular weight heparin and vitamin K antagonists in the treatment of acute portal vein thrombosis with or without cirrhosis. PMID- 29973998 TI - A Comparison of Two Nights of Ambulatory Sleep Testing in Arrhythmia Patients. AB - Introduction: Obstructive sleep apnea (OSA) is common and usually underdetected in patients with cardiac arrhythmia. Ambulatory sleep testing may provide an alternative method for detection of OSA under realistic conditions compared to in laboratory polysomnography. We aimed to (1) determine the sleep architecture in arrhythmia patients; (2) detect differences in sleep parameters between patients with and without OSA; and (3) compare the results of two consecutive nights of unattended ambulatory sleep testing. Methods: Consecutive patients with unknown OSA status were recruited from arrhythmia clinics. Patients underwent two consecutive nights of self-applied in-home sleep testing replete with electroencephalogram (EEG) recording. Results: One hundred patients were recruited. The mean age was 64 +/- 13 years (70% males). OSA (AHI >= 5/h) was detected in 85% of patients. In the total sample, the sleep efficiency was reduced, and sleep onset latency was longer compared to a reference population of the same age. In patients with OSA, the sleep efficiency and the percentage of slow wave sleep were reduced; however, the arousal and periodic limb movement indices were increased compared to patients without OSA. The two nights of the ambulatory sleep testing showed consistent results with an excellent test-retest reliability for the AHI (ICC = 0.813). REM latency was shorter during the second night of sleep recording (p = 0.02). There were no other significant differences in the sleep architecture, respiratory indices, and other sleep parameters between the first and the second night of the ambulatory sleep recording. Conclusions: There is no significant difference in the respiratory parameters obtained during two consecutive nights of ambulatory sleep testing. Ambulatory studies incorporating EEG may provide a reliable, convenient, and economically efficient method for sleep assessment and there appears to be no significant night-to-night variability. PMID- 29973999 TI - Central Pontine Myelinolysis in Pediatric Diabetic Ketoacidosis. AB - Central pontine myelinolysis (CPM) is rarely reported in pediatric patients with diabetic ketoacidosis (DKA). We report this case of a 16-year-old female with new onset diabetes presenting with DKA, who received aggressive fluid resuscitation and sodium bicarbonate in the emergency department. Later she developed altered mental status concerning for cerebral edema and received hyperosmolar therapy with only transient improvement. Soon she became apneic requiring emergent endotracheal intubation. MRI brain showed cerebral edema, CPM, and subdural hemorrhage. She was extubated on day seven and exhibited mild dysmetria, ataxia, unilateral weakness, and neglect. Upon discharge she was able to ambulate with a walker and speak and eat without difficulty. Although less common than cerebral edema, CPM should be considered in DKA patients with acute neurologic deterioration. Fluid and bicarbonate therapy should be individualized, but larger studies would help guide the management. Although poor outcomes are reported in CPM, favorable outcomes are possible. PMID- 29974000 TI - Intra-Abdominal Hemorrhage following Cardiopulmonary Resuscitation: A Report of Two Cases. AB - Cardiopulmonary resuscitation (CPR) represents an emergency procedure, consisting of chest compressions and artificial ventilation. Two rare cases of intra abdominal bleeding following cardiac compressions are reported. The first case was a 29-year-old female with massive pulmonary embolism (PE). Following CPR due to cardiac arrest, she showed signs of intra-abdominal bleeding. A liver laceration was found and sutured. The patient passed away, due to massive PE. The second patient was a 62-year-old female, suffering from cardiac arrest due to drowning at sea. CPR was performed in situ. At presentation to the emergency department she showed signs of intra-abdominal bleeding. The origin of the hemorrhage was found to be vessels of the lesser curvature of the stomach, which were ligated. Regarding the first patient PE has already been described as a cause for liver lacerations in CPR due to stasis and liver enlargement. The second case is the first report of gastric vessel injury without gastric rupture/laceration and pneumoperitoneum. Complications of CPR should not represent a drawback to performing cardiac compressions. Parenchymatic injuries have been related to inappropriate technique of chest compressions during basic life support. Therefore, it is of utmost importance for the providers to refresh their knowledge of performing CPR. PMID- 29974001 TI - Accidental Drowning: The Importance of Early Measures of Resuscitation for a Successful Outcome. AB - Case Report: The case of a drowning teenager is described involving application of cardiopulmonary resuscitation (CPR) by an untrained rescuer in the field and fast transport to a hospital enabling a positive resuscitation outcome despite an underorganized emergency medical service in a rural area. In our case hypoxia led to extended functional disorders of the cardiovascular system, which fully recovered after adequate therapy. Conclusion: Knowledge about BLS measures by ordinary citizens, together with continuous education of health professionals concerning modern techniques of CPR, is crucial for increasing the number of patients surviving after cardiac arrest. PMID- 29974002 TI - Iatrogenic Splenic Laceration Presenting as Syncope. AB - Millions of colonoscopies are performed annually for routine health maintenance in the United States. Patients commonly have adverse events from colonoscopy preparation, anesthesia, and procedural complications. We report a case of syncope secondary to iatrogenic splenic laceration from colonoscopy. PMID- 29974003 TI - Rupture of Hepatocellular Carcinoma after Transarterial Chemoembolization followed by Massive Gastric Bleeding. AB - Introduction: Transarterial chemoembolization (TACE) is the first-line therapy for patient with unresectable hepatocellular carcinoma (HCC). Although TACE is a generally safe procedure, major complications can be occurred. We describe a patient with rupture of HCC after TACE followed by gastric bleeding. Case Presentation: An 81-year-old man presented with worsening epigastric pain. He had been diagnosed with multiple HCC with nonalcoholic steatohepatitis and underwent TACE 19 days previously. A contrast enhanced computed tomography (CT) scan of the abdomen showed rupture of an HCC. He was treated nonoperatively and discharged on hospital day 18. Five weeks after TACE, he was emergently admitted with massive hematochezia and shock. A contrast enhanced CT scan demonstrated extrinsic gastric compression by an HCC lesion with extravasation of contrast into the stomach. Emergent upper gastrointestinal endoscopy showed a bleeding gastric ulcer with extraluminal compression which was successfully controlled by hypertonic saline-epinephrine injection. Due to tumor progression, he was discharged for palliative care and died six weeks after TACE. Conclusion: Rupture of HCC is a life-threatening complication after TACE with mortality rates up to 50%. After treatment of a ruptured HCC, extragastric compression and bleeding can occur due to direct compression by a primary lesion or intraperitoneal dissemination. PMID- 29974004 TI - Delayed Diagnosis of Acute Rheumatic Fever in a Patient with Multiple Emergency Department Visits. AB - While the incidence of acute rheumatic fever (ARF) in the United States has declined over the past years, the disease remains one of the causes of severe cardiovascular morbidity in children. The index of suspicion for ARF in health care providers may be low due to decreasing incidence of the disease and clinical presentation that can mimic other conditions. We present the case of a 5-year-old boy with a history of intermittent fevers, fatigue, migratory joint pain, and weight loss following group A Streptococcus pharyngitis. The patient presented to the emergency department twice with the complaints described above. On his 3rd presentation, the workup for his symptoms revealed the diagnosis of acute rheumatic fever with severe mitral and aortic valve regurgitation. The patient was treated with penicillin G benzathine and was started on glucocorticoids for severe carditis. The patient was discharged with recommendations to continue secondary prophylaxis with penicillin G benzathine every 4 weeks for the next 10 years. This case illustrates importance of primary prevention of acute rheumatic fever with adequate antibiotic treatment of group A Streptococcus pharyngitis. Parents should also receive information and education that a child with a previous attack of ARF has higher risk for a recurrent attack of rheumatic fever. This can lead to development of severe rheumatic heart disease. Prevention of recurrent ARF requires continuous antimicrobial prophylaxis. Follow-up with a cardiologist every 1-2 years is essential to assess the heart for valve damage. PMID- 29974005 TI - Effect of Skin Model on In Vitro Performance of an Adhesive Dermally Applied Microarray Coated with Zolmitriptan. AB - Franz cell studies, utilizing different human skin and an artificial membrane, evaluating the influence of skin model on permeation of zolmitriptan coated on an array of titanium microprojections, were evaluated. Full thickness and dermatomed ex vivo human skin, as well as a synthetic hydrophobic membrane (Strat-M(r)), were assessed. It was found that the choice of model demonstrated different absorption kinetics for the permeation of zolmitriptan. For the synthetic membrane only 11% of the zolmitriptan coated dose permeated into the receptor media, whilst for the dermatomed skin 85% permeated into the receptor. The permeation of zolmitriptan through full thickness skin had a significantly different absorption profile and time to maximum flux in comparison to the dermatomed skin and synthetic model. On the basis of these results dermatomed skin may be a better estimate of in vivo performance of drug-coated metallic microprojections. PMID- 29974006 TI - An Ethnobotanical Study of the Medicinal Plants Used as Anti-Inflammatory Remedies in Gampaha District, Western Province, Sri Lanka. AB - The application of traditional medicinal plants as anti-inflammatory remedies has been practiced in Sri Lanka for thousands of years. Although there is a rich reserve of indigenous knowledge of medicinal plants, the preservation and the scientific validation of these claims are still in its infancy. Thus, the study was carried out in one of the administrative areas of Sri Lanka known as Gampaha District to assess the significance and contribution of medicinal plants in inflammatory conditions. The data were collected through semistructured and open ended interviews from 458 volunteers. Ethnobotanical data were analyzed using the relative frequency of citation (RFC), family importance value (FIV), and use value (UV). Out of the total participants, 50.7% claimed the use of medicinal plants for the treatment of inflammatory conditions such as fever, cough, asthma, swellings, and pain in the joints. A total of 43 medicinal plants belonging to 28 plant families were mentioned, out of which Coriandrum sativum (RFC = 0.23) was the most cited species. The most cited plant family was Fabaceae, and the family importance value was highest in Apiaceae. The majority of the nonusers of the herbal remedies mentioned that they would shift to herbal products if scientific information is available on the efficacy of these products. PMID- 29974007 TI - Chronic Subdural Hematoma Associated with Congenital Arachnoid Cysts: Management Dilemmas. AB - Chronic subdural hematoma (CSDH) is one of the commonest diseases encountered by a neurosurgeon in daily practice. It is however rarely seen in young patients. Congenital arachnoid cysts have been implicated in both traumatic and spontaneous CSDH in young individuals. Optimum treatment strategies to address the CSDH and arachnoid cyst are not very well described. We report a young gentleman who was treated for a CSDH with arachnoid cysts, two months after a mild head injury. The patient was operated with a simple burr hole drainage of hematoma with a drain. He was discharged with no further need to address the arachnoid cyst. CSDH associated with arachnoid cysts can be treated with simple burr hole drainage. Craniotomy, fenestration and cerebrospinal fluid (CSF) diversion should be reserved only as secondary procedures. PMID- 29974008 TI - A Silent Left Atrial Myxoma: A Rare Benign Cardiac Tumor. AB - Primary cardiac tumors are extremely rare. In one study, incidence was reported being less than 0.1%. The purpose of this case report is to review different presentations of cardiac myxoma. A 34-year-old female with past medical history of drug abuse was brought into the emergency department (ED) after a motor vehicle collision. She was found to have multiple fractures with a hypodense mass in the left atrium. Further evaluation showed a left atrial myxoma. The patient underwent myxoma resection. The clinical appearance of myxoma varies from non specific to life-threatening complications, such as stroke, acute heart failure, or even sudden death. A surgical resection is the treatment of choice for cardiac myxomas. PMID- 29974009 TI - Olanzapine-induced Cataract in a Teenage Girl. AB - Cataract, defined as cloudiness of the lens, is a common adverse effect of first generation antipsychotic medications. Newer generation antipsychotics, also known as atypical antipsychotics, are less commonly associated with cataract. A 19-year old girl with underlying schizophrenia on olanzapine for the past two years complained of gradual blurring of vision in both eyes for four months prior to presentation. On examination, the best corrected visual acuity was counting finger in both eyes. The anterior segment examination showed bilateral diffuse cortical cataract precluding fundus examination. Systemic examination was unremarkable. Blood investigations revealed a high random blood sugar, which normalised after she was initiated on oral hypoglycemic medication. After bilateral lens aspiration, her visual acuity was 6/6 bilaterally. Olanzapine may be cataractogenic via its action as a serotonin antagonist, which results in reduced glucose responsiveness of the pancreatic beta-cells. Patients on anti psychotic medication are at risk of developing diabetes mellitus and cataract compared to the general population. Screening for diabetes mellitus should be part of the follow-up of these patients. Ophthalmological evaluation is warranted in the presence of visual complaints. PMID- 29974010 TI - Capillary Leak Syndrome Aggravated by Influenza Type A Infection. AB - A 41-year-old female presented to the emergency department with nausea, vomiting, and diarrhea. Five days prior to this, she tested positive for influenza type A in an urgent care clinic and received Tamiflu. She also complained of generalized weakness in her extremities. Her initial labs were concerning for a grossly elevated hemoglobin and hematocrit despite adequate fluid resuscitation. Her condition continued to worsen as she developed distal cyanosis in all of her extremities and pulselessness. She was treated with IV hydration, bicarbonate, heparin, vasopressors, albumin replacement, Tamiflu, and phlebotomy. Her blood pressure continued to deteriorate rapidly. The arterial blood gas (ABG) depicted a case of severe metabolic acidosis that ultimately resulted in respiratory failure, and she required mechanical ventilation within 24 hours. Systemic capillary leak syndrome is a rare disease that is characterized by hypotension, hemoconcentration, and hypoalbuminemia. In this instance, influenza type A played a large role in its development. PMID- 29974011 TI - A Pacemaker that was Avoided. AB - Thyroxine is an essential hormone in the human body and exerts many effects on the cardiovascular system. The low metabolic state in hypothyroidism causes bradycardia and reduced cardiac contractility leading to reduced cardiac output. Severe bradycardia and atrioventricular (AV) blocks secondary to hypothyroidism have also been reported. We present a case of severe hypothyroidism causing a high-grade AV block which was successfully treated with thyroxine hormone replacement without requiring cardiac pacemaker placement. PMID- 29974012 TI - An Unnecessary Pain: Using Pharmacogenetics for Statin-related Skeletal Muscle Toxicity. AB - Statins are an important class of medications in reducing the risk of cardiovascular events as well as overall mortality. However, a well-known adverse effect of statins is skeletal muscle toxicity, which may lead to abrupt discontinuation of the statin. In turn, patients may miss out on the benefits of statin therapy. An important factor to consider is a patient's solute carrier organic anion transporter 1B1 (SLCO1B1) gene T521C polymorphism status. Herein, an overview of the pharmacogenetics of SLCO1B1 is provided as well as recommendations for use in practice. PMID- 29974013 TI - Implementation of LURIES: A New Handoff Tool for Pediatric Residents. AB - Introduction At our institution, inpatient pediatric residents spend about 50 hours each month on 52 total handoff encounters. We created a modifiable electronic handoff tool (LURIES) and measured its impact on resident perception of self-efficacy. We also elicited feedback and identified topics omitted in the handoffs following its adoption on general medicine, intensive care, and sub specialty wards. Our objective was to standardize the handoff tool used by residents and to measure the impact of the new tool on resident perception of self-efficacy. Methods Residents were trained to use LURIES and completed a voluntary online survey during the first and second year of implementation. Senior residents reflected on experiences prior to and after implementation of LURIES. Night team residents reported key items omitted from the handoff. Results 65/96 (68%) residents responded in year one and 45/97 (46%) in year two of implementation. The majority of residents perceived that LURIES improved handoff efficiency, promoted active listening, and reduced the number of missed tasks overnight. There was a statistically significant increase in self-efficacy for all queried overnight tasks. Omitted information was most commonly identified on complex subspecialty services and pertained to communication with parents, late admissions, and discharges. Conclusion LURIES increased resident self-efficacy with patient management. There was no difference in findings when controlled for previous medical school handoff training or type of handoff tool used in medical school clerkships. More data are needed to establish the significance of this trend in relation to handoffs beyond residency, patient safety, and patient satisfaction scores. PMID- 29974014 TI - Closed Stereotactic Needle Biopsy of Brainstem Small Cell Glioblastoma: A Case Report and Literature Review. AB - Glioblastoma is the deadliest and most common of the malignant primary brain tumors that can occur in adults. In contrast, brainstem gliomas are extremely uncommon in adults; however, their precise incidence is not known, due to the difficult nature of obtaining tissue from the brainstem provoking low biopsy and resection rates. In this case report, we have examined a 34-year-old female who was diagnosed with pontomedullary small cell glioblastoma following a successful biopsy of the brainstem lesion. A closed stereotactic needle biopsy with a contralateral approach was utilized using stealth computed tomography (CT) neuronavigation for tissue diagnosis without causing additional neurological deficits. Our goal is to share this novel approach of obtaining tissue from the brainstem in order to aid others in definitively diagnosing brainstem gliomas and subsequently providing appropriate treatment early in the disease process. PMID- 29974015 TI - An Unusual Method for Controlling Bile Leak from an Immature T-tube Fistula. AB - T-tubes have been used by surgeons for the decompression of the choledocus for over a hundred years. Errors in the operative technique and patient-related risk factors, such as immune comprehensive therapy, diabetes mellitus, steroid drug usage, T-tube morphology, T-tube material, and the T-tube extraction technique, are some of the factors that affect the risk of bile leak. In most cases, a surgical approach is required. Herein, we present a case of bile leak after T tube removal and an unusual solution to this difficult complication. PMID- 29974016 TI - Persistent Lactic Acidosis: Thinking Outside the Box. AB - A 54-year-old male presented with possible sepsis and elevated serum lactic acid (LA) of 18.7 mmol/L. Despite the sepsis treatment protocol and the management of other causes of type A lactic acidosis, his LA remained elevated. Herein, we present a case of type B lactic acidosis in the setting of a diffuse large B cell lymphoma. The proposed mechanisms of persistent lactic acidosis in malignancy are highlighted in this case report. PMID- 29974017 TI - Spontaneous Pneumomediastinum as a Consequence of Severe Vomiting in Diabetic Ketoacidosis. AB - Spontaneous pneumomediastinum (SPM) is a rare entity with a reported incidence of approximately 1:7,000 to 1:100,000 of hospital admissions. It has been described as a complication of various conditions related to increased intrathoracic pressure, like recurrent vomiting, post-partum state, vigorous coughing or sneezing, and others. We present a 25-year-old man who came in with intractable vomiting, secondary to diabetic ketoacidosis (DKA), and was found to have pneumomediastinum on chest imaging. The patient was treated conservatively, eventually recovering and being discharged after several days. SPM is rarely seen as a complication of DKA. Diagnosis and management may present a challenge. Usually, the condition is benign and treated conservatively. We report this case to increase awareness among physicians of possible pneumomediastinum in a young male presenting with DKA and dyspnea and to emphasize the benign course of this condition. PMID- 29974018 TI - What Makes for Good Anesthesia Teaching by Faculty in the Operating Room? The Perspective of Anesthesiology Residents. AB - Background Teaching during patient care is an important competency for faculty. Little is known about anesthesiology resident preferences for teaching by anesthesiology faculty in the operating room (OR). If the behaviors and characteristics of anesthesia teaching in the OR that are most valued by residents were identified, faculty could incorporate that best practice to teach residents during OR cases. The objective of this phenomenological study was to interview anesthesiology residents to determine what they perceive the best faculty teachers are doing in the OR to educate residents. Methods Thirty randomly selected anesthesiology residents (10 in each post-graduate year class) were interviewed using a semi-structured approach with a predetermined question: "Based on your experiences as a resident, when you think about the best-attending teachers in the OR, what are the best-attending teachers doing in the OR to teach that other faculty maybe are not doing?" Interviews were recorded, transcribed, converted into codes, and grouped into themes derived from the cognitive apprenticeship framework, which includes content, teaching methods, sequencing, and social characteristics. Results Resident responses were separated into a total of 134 answers, with similar answers grouped into one of 27 different codes. The most commonly mentioned codes were: autonomy - step back and let resident work through (mentioned by 13 residents), reasoning - explain why attending does things (12), context - teach something relevant to the case (8), commitment - take time to teach (8), literature - bring relevant papers (8), prior knowledge - assess the baseline level (7), flexibility - be open to trying different approaches (7), focus on just a few learning points (6), reflection - ask resident questions (6), provide real-time feedback (6), teach back - ask residents to explain what they were taught in their own words (5), belonging - facilitate communication with the OR team (5), psychological safety - be open and approachable (5), equanimity - stay calm and collected (5), select proper timing for instruction when the resident is not occupied with patient care (5), visualization - use graphs or diagrams (5), and specify learning goals ahead of time (5). Conclusion The best practice for OR teaching, as perceived by anesthesia residents, includes social characteristics, such as context, commitment, psychological safety, equanimity, and proper timing, as well as teaching methods, such as autonomy, reasoning, literature, prior knowledge, flexibility, reflection, real-time feedback, and teach back. Further studies can determine if training anesthesiology faculty to incorporate these elements increases the caliber of daily teaching in the OR. PMID- 29974019 TI - Criteria for Ending the Distal Fusion at the L3 Vertebra vs. L4 in Surgical Treatment of Adolescent Idiopathic Scoliosis Patients with Lenke Type 3C, 5C, and 6C Curves: Results After Ten Years of Follow-up. AB - Introduction The selection of the most distal caudal vertebra in spinal fusion surgeries in adolescent idiopathic scoliosis patients with structural lumbar curvatures is still a matter of debate. The aim of this study was to determine the preoperative radiological criteria on the traction X-rays under general anesthesia (TrUGA) for selection between the L3 and L4 vertebrae and to assess the efficacy of these criteria via the long-term results of patients with Lenke Type 3C, 5C, and 6C curves. Methods Radiological data of 93 patients (84 females, 9 males) who met the inclusion criteria were retrospectively evaluated. The relationship between the L3 vertebra and the central sacral vertebral line, the portion of the L3 vertebra in the stable zone of Harrington, the parallelism of the L3 with the sacrum, and the tilt and rotation of the L3 on TrUGA radiographs were evaluated for the selection of the lowest instrumented vertebrae (LIV). Clinical results were analyzed using the Scoliosis Research Society-22 (SRS-22) questionnaire. Results The mean follow-up period of the study group was 149.3 months. According to the Lenke classification, 29 patients had Type 3C, 33 had Type 5C, and 31 had Type 6C curves. The preoperative analysis was based on standing anteroposterior (AP), supine traction, and bending X-rays, and the L3 vertebra was selected as the LIV in 37 patients (40%). These X-rays suggested L4 as the LIV in 56 patients (60%); however, based on our study criteria, the L3 vertebra was selected. No significant loss of correction was observed nor additional surgery due to decompensation was required in the follow-up period. Conclusion The use of TrUGA radiographs with the identified criteria is an efficient alternative method in the selection of the LIV in patients with Lenke Type 3C, 5C, and 6C curves. PMID- 29974020 TI - Exfoliative Cheilitis as a Manifestation of Factitial Cheilitis. AB - Factitial cheilitis is a rare diagnosis of exclusion that occurs most frequently in young women with a history of anxiety disorders and recent psychosocial stressors. It presents as continuous keratinaceous build-up, crusting, and desquamation of the lips, consistent with exfoliative cheilitis. Affected areas can progress to superinfection with Staphylococcus aureus or Candida albicans. We report a case of a 23-year-old woman who presented with diffuse hyperkeratosis of the upper and lower lips that was initially suspected to be allergic or irritant contact dermatitis based on clinical examination. Clinical and histologic correlation of two separate biopsies plus a negative infectious workup led to the consideration of a factitial etiology. Through open and direct communication between the patient and the provider, the appropriate diagnosis was discerned. Referral for the psychiatric symptoms as well as management of the same resulted in complete resolution of her lip findings. This case highlights the importance of considering factitial cheilitis as the etiology of exfoliative cheilitis, especially in the presence of concomitant psychiatric disorders. PMID- 29974022 TI - Left-sided Catamenial Pneumothorax: A Rare Clinical Entity. AB - Catamenial pneumothorax (CP) is an extremely rare pulmonary pathology seen in women of reproductive age, typically occurring within 72 hours from the onset of menstrual bleeding. Multiple theories have been proposed to explain the etiopathogenesis of CP; however, the exact underlying mechanism remains elusive. More than 90% of reported cases in the literature describe a right-sided presentation of pneumothorax. In this case report, we describe a rare left-sided presentation of CP and discuss the current literature on underlying etiopathogenesis, diagnostics, and available therapeutic modalities for managing this rare clinical entity. PMID- 29974021 TI - Hyperglycemic Crisis in an Anuric Peritoneal Dialysis Patient with Profound and Symptomatic Hypertonicity. AB - An anuric peritoneal dialysis patient with diabetes mellitus, congestive heart failure, and anasarca developed severe hyperglycemia with hypertonicity causing profound neurological manifestations after prolonged and continuous use of hypertonic (4.25%) dextrose dialysate. She expired with hypotensive shock from a new myocardial infarction soon after completion of treatment with insulin infusion. The degree of the presenting hypertonicity far exceeded the value expected from the degree of hyperglycemia. We identified prolonged peritoneal dialysis with hypertonic solutions and profound extracellular volume expansion as the causes of the excessive hypertonicity. Hyperglycemia developing in diabetic patients treated for anasarca by peritoneal dialysis after continuous use of hypertonic dextrose dialysate is associated with the risk of excessive hypertonicity with severe clinical manifestations. PMID- 29974023 TI - Underutilization of Research Journals by Undergraduate Students of Medical Colleges in Islamabad: A Cross-sectional Study. AB - OBJECTIVE: To analyze the factors behind the underutilization of research articles as an adjuvant source of knowledge by medical students. MATERIALS & METHODS: We conducted a cross-sectional study of students from medical colleges in Islamabad from June 2017 to August 2017. The students were verbally informed about the study, and those who gave their consent were included. The data was collected through a self-constructed questionnaire. Cronbach's alpha was used to assess the internal consistency of the questionnaire, and it was found to be 0.68. The data obtained was analyzed on IBM's statistical package for the social sciences (SPSS) version 21 (IBM, Armonk, NY, US). RESULTS: A total of 382 students participated in the study. The use of research articles for the preparation of problem-based learning (PBL), small group discussions, or assessments was very low. Students did, however, consult journals if emphasized by the faculty. A majority of the students did appreciate the importance of medical journals to explore detailed information about disease states and health issues encountered by self or family members. The use of research articles by students for preparing for exams was very low. CONCLUSION: The students' underutilization of journals may be attributable to an over-familiarity with books, a lack of faculty prompting, and a lack of knowledge on how to access such journals. These factors should be addressed while designing the medical curriculum to enhance journal perusal among medical students. PMID- 29974024 TI - Cerebral Malaria in a Patient with HIV, Hepatitis B, and Hepatitis C. AB - Cerebral malaria is one of the most common causes of non-traumatic encephalopathy. A 25-year-old man who is a known intravenous and oral drug abuser presented to our clinic with fever and sore throat for two days prior and an altered level of consciousness for one day. On examination, the patient was icteric, and his Glasgow coma scale score on arrival was 10/15; he had dilated pupils reactive to light and a positive corneal reflex. All cranial nerves were intact; however, signs of meningeal irritation were positive. Motor examination showed an increased tone and rigidity in all limbs, patellar reflex was 3+, plantars were down-going, and clonus was negative. A fundoscopic examination was unremarkable. Additional investigations revealed he was positive for Plasmodium falciparum, HIV, hepatitis B, and hepatitis C. In addition, a test of his cerebrospinal fluid revealed evidence of cerebral malaria. We initiated artemether 120 mg, intravenous ceftriaxone 2 g, and 5% dextrose saline for the intermittent hypoglycemia. The patient's condition eventually improved drastically. This case outlines the possible exacerbating effect of HIV on malaria, and it calls for HIV screening and staging alongside suspected malaria. This case also underlines the need for further evaluation of a potential protective role of hepatitis B and C to find an alternative therapeutic cure for malaria. PMID- 29974025 TI - Association of Hemodialysis Inadequacy and Duration with Restless Legs Syndrome: A Cross-sectional Study. AB - Restless legs syndrome (RLS) is a common neurological disorder in hemodialysis (HD) patients. It is associated with poor sleep and decreased quality of life. The precipitants for the disorder are still poorly understood. The condition has not been studied extensively in Pakistan, which has a vast majority of end-stage renal disease patients on maintenance HD. We aimed to determine the prevalence of this condition in patients attending HD units of the largest renal dialysis center in Northern Pakistan. We also strived to determine any associations with dialysis inadequacy and the total duration of HD. This was an observational study comprising 279 patients. RLS was diagnosed using the International Restless Leg Syndrome Study Group criteria. Dialysis adequacy was determined using the Urea Reduction Ratio and the Kt/V technique. The prevalence of RLS in this large HD population was 24%. Our results show that a longer duration and greater number of HD sessions were significantly associated with the development of RLS (p<0.05). Dialysis inadequacy was not associated with the development of the disorder. These results may indicate that the pro-inflammatory nature of hemodialysis may have a role in the pathophysiology of RLS in HD patients and prolonged exposure to it may make them more prone to developing the disorder. PMID- 29974026 TI - Obliterating Bronchiolitis: Result of Iron Pill Aspiration. AB - Foreign body aspiration occurs in all age groups, especially in children and the elderly. The aspiration of an organic foreign body such as iron sulfate can cause significant bronchial destruction via oxidizing necrosis. When iron comes into contact with bronchial mucosa, it gets oxidized from ferrous ions into a ferric form which is highly toxic to the mucosa causing severe inflammation, mucosal damage, and fibrosis. Physicians should be very prudent with prescribing iron sulfate or any other pills in individuals who are at high risk of aspiration. Diagnosis is based on the history of iron aspiration, intense airway inflammation or necrosis on bronchoscopic examination, and iron particles observed on pathology. Prompt diagnosis and management should take place to prevent further morbidities. We report a case of 61-year-old female who was admitted to the hospital with a four-week history of aspirating iron pill. Computed tomography (CT) of the thorax showed ground glass infiltrates in the right lower lobe. She underwent flexible bronchoscopy which showed distal right bronchus intermedius (RBI) necrosis and stenosis with near-complete obstruction of distal RBI. She underwent multiple advanced bronchoscopic interventions with minimal improvement of the obliterated bronchus. PMID- 29974027 TI - Enalapril-Induced Angioedema: Two Case Reports in a Rural Health Facility in Kenya. AB - Tolerability, a good safety profile, affordability, and a preponderance to afford cardio-renal protection in patients with diabetes make enalapril one of the most commonly prescribed angiotensin-converting enzyme (ACE) inhibitors. However, there is low awareness of enalapril/ACE inhibitor-induced angioedema among medical personnel. This is because the diagnosis presents an ongoing challenge, particularly when the presentation is delayed following long-term therapy with ACE inhibitors. Here, we present two cases: a 58-year-old female and a 55-year old male who presented to the outpatient department of Nyakach County Hospital, Pap Onditi village, Kenya, with progressive swelling of the face and upper and lower lips and stridor of 11 and 10 hours, respectively, after their usual dose of enalapril. Case 1 resolved following the administration of stat doses of intravenous (IV) hydrocortisone 200 mg and IV chlorpheniramine 20 mg as well as thrice daily peroral doses of chlorpheniramine 8 mg, and tapered peroral doses of prednisolone: 40 mg thrice daily for five days, 20 mg thrice daily for five days, 10 mg thrice daily for five days, and 5 mg thrice daily for five days. Case 2 resolved following the administration of a stat dose of IV dexamethasone, a twice daily peroral dose of cetrizine 10 mg, and tapered peroral doses of prednisolone: 20 mg thrice daily for five days, 10 mg thrice daily for five days, and 5 mg thrice daily for five days. PMID- 29974028 TI - The Ideal Size of Mesh for Open Inguinal Hernia Repair: A Morphometric Study in Patients with Inguinal Hernia. AB - Introduction This study was done to analyze the morphometric features of the inguinal canal with different types of inguinal hernias to determine the appropriate size of mesh required to cover potential sites of recurrence. A morphometric assessment in the particular population is essential to recommend the appropriate mesh size in inguinal hernias to cover all the potential sites of recurrence. Materials and methods This was a prospective observational study, including all consecutive patients undergoing open inguinal hernia repair under local/regional/general anesthesia over a period of three years. Surgeries that were done in emergencies for complicated hernias, laparoscopic repair, and recurrent inguinal hernias were excluded. Intra-operative parameters were studied to predict the appropriate mesh size, which included the position of the superficial and deep inguinal ring (SIR and DIR) with the diameter, the distance of SIR and DIR from the anterior superior iliac spine (ASIS), and the distance from the summit of the muscular arch to the inguinal ligament. The differences in morphometric details between the types of hernias and categorical variables were assessed using the chi-square test. Results The study included a total of 170 patients with a mean age of 50.67 + 17.59 years. An indirect hernia was the most common type in patients less than 60 years. The mean distance from ASIS to SIR was 10.2+ 1.9 cm, and in indirect hernia patients, it was found to be significantly increased (p=0.042). The mean distance from ASIS to DIR was 4.14+1.57 cm, where the indirect hernia patients had a significantly less distance (p=0.029). The mean length of the inguinal canal in a direct hernia was 5.66 + 0.5 cm, whereas, in an indirect inguinal hernia, it was 6.46 + 0.8 cm, which was significant (p=0.029). The mean distance from the midpoint of the inguinal ligament to the summit of the muscular arch was 4.03 cm, and there was no significant difference between the indirect and direct hernia patients. Conclusion After considering the morphometric assessments of the length of the inguinal canal, the mean distance from the midpoint of the inguinal ligament to the summit of the muscular arch, the mean distance from ASIS to DIR, the ideal mesh size for the population would be 9 X 15 cm to cover all the potential sites of recurrence. PMID- 29974029 TI - Sex-specific mortality forecasting for UK countries: a coherent approach. AB - This paper introduces a gender specific model for the joint mortality projection of three countries (England and Wales combined, Scotland, and Northern Ireland) of the United Kingdom. The model, called 2-tier Augmented Common Factor model, extends the classical Lee and Carter [26] and Li and Lee [32] models, with a common time factor for the whole UK population, a sex specific period factor for males and females, and a specific time factor for each country within each gender. As death counts in each subpopulation are modelled directly, a Poisson framework is used. Our results show that the 2-tier ACF model improves the in sample fitting compared to the use of independent LC models for each subpopulation or of independent Li and Lee models for each couple of genders within each country. Mortality projections also show that the 2-tier ACF model produces coherent forecasts for the two genders within each country and different countries within each gender, thus avoiding the divergence issues arising when independent projections are used. The 2-tier ACF is further extended to include a cohort term to take into account the faster improvements of the UK 'golden generation'. PMID- 29974030 TI - Parisian ruin for the dual risk process in discrete-time. AB - In this paper we consider the Parisian ruin probabilities for the dual risk model in a discrete-time setting. By exploiting the strong Markov property of the risk process we derive a recursive expression for the finite-time Parisian ruin probability, in terms of classic discrete-time dual ruin probabilities. Moreover, we obtain an explicit expression for the corresponding infinite-time Parisian ruin probability as a limiting case. In order to obtain more analytic results, we employ a conditioning argument and derive a new expression for the classic infinite-time ruin probability in the dual risk model and hence, an alternative form of the infinite-time Parisian ruin probability. Finally, we explore some interesting special cases, including the binomial/geometric model, and obtain a simple expression for the Parisian ruin probability of the gambler's ruin problem. PMID- 29974031 TI - NSAID hypersensitivity - recommendations for diagnostic work up and patient management. AB - Background: Adverse drug reactions (ADR) to analgesics (i.e., non-steroidal anti inflammatory drug hypersensitivity, NSAID-HS) are one of the most common ADR, affecting approximately 1.6% of all patients. Despite the fact that they are common, they still pose a diagnostic challenge. Methods: This article is an overview of selected scientific articles and is based on research in PubMed, specialist databases, and guidelines. Results: Approximately 80% of side effects are pharmacologically predictable and are classified as type A reactions, such as abdominal pain and bleeding events. More advanced diagnostic investigations are not useful in such cases. Type B reactions, which account for the remaining 20%, are subdivided into the far more frequent cross-reactive, non-immunological NSAID HS (acronyms NERD [NSAID exacerbated respiratory disease], NECD [NSAID exacerbated cutaneous disease], NIUA [NSAID-induced urticaria/angioedema]) and the much rarer true drug allergies of type I and IV (acronyms SNIUAA [single NSAID-induced urticara/angioedema or anaphylaxis] and SNIDR [single NSAID-induced delayed reaction]). The two latter are not cross-reactive and all other NSAIDs are generally well tolerated. Conclusion: The diagnostic work-up begins with a detailed patient's history. Skin tests are only useful in SNIDR and SNIUAA, while in vitro tests are helpful merely in exceptional cases. In general, the diagnosis can only be confirmed by provocation testing, when required. Although cross reactivity is usually present, provocation testing is often able to find an alternative, tolerable analgesic. Individual patient management usually enables a solution to be found for most patients. PMID- 29974032 TI - Perioperative drug reactions - practical recommendations for allergy testing and patient management. AB - Background: Allergy testing for perioperative drug reactions poses a particular diagnostic challenge. Neuromuscular blocking agents (NMBA) and antibiotics are among the most common triggers. In principle, however, any drug administered perioperatively is capable of causing a hypersensitivity reaction. Methods: This article is an overview of selected scientific articles and is based on research in PubMed, specialist databases, and guidelines. Results: Besides patient's history and laboratory tests (the latter being feasible to only a limited extent), skin tests play a particularly important role. To obtain clinical relevant results, profound knowledge on the best point in time for testing, the drug concentrations to be used, how to perform tests correctly, and the assessment criteria is of special importance. Conclusion: Final outcomes of the diagnostic procedures should be providing thorough information of the patient about the findings, drugs that should be avoided in the future as well as alternative preparations, and, if necessary, preventive measures to be taken in the event of further surgical interventions. PMID- 29974033 TI - The Artificial Moral Advisor. The "Ideal Observer" Meets Artificial Intelligence. AB - We describe a form of moral artificial intelligence that could be used to improve human moral decision-making. We call it the "artificial moral advisor" (AMA). The AMA would implement a quasi-relativistic version of the "ideal observer" famously described by Roderick Firth. We describe similarities and differences between the AMA and Firth's ideal observer. Like Firth's ideal observer, the AMA is disinterested, dispassionate, and consistent in its judgments. Unlike Firth's observer, the AMA is non-absolutist, because it would take into account the human agent's own principles and values. We argue that the AMA would respect and indeed enhance individuals' moral autonomy, help individuals achieve wide and a narrow reflective equilibrium, make up for the limitations of human moral psychology in a way that takes conservatives' objections to human bioenhancement seriously, and implement the positive functions of intuitions and emotions in human morality without their downsides, such as biases and prejudices. PMID- 29974034 TI - Using population registers for migration and integration research: examples from Denmark and Sweden. AB - The paper starts from the observation that research on immigrants' integration trajectories needs detailed information, both objective and attitudinal, and ideally longitudinal. This study uses the cases of Denmark and Sweden - whose registers produce detailed records about all natives' and immigrants' lives in their host countries - in order to, first, review existing research on immigrants and their integration and, second, discuss the way in which register data are used, their caveats and their potential. The study finds that, in Denmark and Sweden, registers provide systematic objective data which are fully available to researchers and have the potential to help in the collection of high-quality subjective data. However, the population registers have some traits which may impact on the representativeness of the samples. The authors argue that, if researchers are aware of the caveats, registers can be used to obtain representative samples of immigrants, and register data can be complemented with survey-based attitudinal data, thus opening up new research opportunities for testing propositions on integration theories. PMID- 29974035 TI - Cancer Immunotherapy and the Immune Response in Follicular Lymphoma. AB - Follicular lymphoma (FL) is the most frequent indolent lymphoma in the Western world and is characterized in almost all cases by the t(14;18) translocation that results in overexpression of BCL2, an anti-apoptotic protein. The entity includes a spectrum of subentities that differ from an indolent to a very aggressive growth pattern. As a consequence, treatment can include watch & wait up to intensive chemotherapy including allogeneic stem cell transplantation. The immune cell microenvironment has been recognized as a major driver of outcome of FL patients and gene expression profiling has identified a clinically relevant gene expression signature that classifies an immune response to the lymphoma cells. It is known for some time that the immune cell composition of the lymphoma microenvironment is important because high numbers of tissue-infiltrating macrophages correlate with poor outcome in patients receiving chemotherapy but not in patients receiving the combination of chemotherapy and CD20-specific monoclonal antibody rituximab. In addition, TCR signaling of tumor-infiltrating lymphocytes is dysfunctional leading to an impaired capacity to form an intact immunologic synapse. Approaches restoring local T cell function, e.g., by usage of checkpoint inhibitors has demonstrated clinical activity (ORR 40%) and can achieve long-term remissions. Ongoing trials with re-programmed autologous CART cells achieve response rates in approximately 50% of FL patients with relapsed and even refractory disease. Responses lasting for more than 6 months might be durable, indicative for a successful restoration of a functional immune system. In summary, FL is a malignant disease where the control by the immune system ultimately decides about progression and transformation rate. The advent of monoclonal antibodies has changed the way we treat FL and new approaches restoring the individual immune control will hopefully improve results further. PMID- 29974036 TI - The Warburg Effect as a Type B Lactic Acidosis in a Patient With Acute Myeloid Leukemia: A Diagnostic Challenge for Clinicians. AB - Introduction: The Warburg effect (WE) is an uncommon cause of type B lactic acidosis (LA) due to a deregulation of carbohydrate metabolism in neoplastic cells where lactic fermentation predominates over oxidative phosphorylation regardless of the oxygen level. Case presentation: We report the case of a 57 year-old man presenting with concomitant acute myeloid leukemia and type B LA with asymptomatic hypoglycemia. We did not find arguments for a septic state, liver dysfunction, or acute mesenteric ischemia. The WE was suspected, and chemotherapy was immediately undertaken. We observed a rapid and sustained decrease in lactate level and normalization of blood glucose. Unfortunately, we noted a relapse of acute leukemia associated with WE soon after treatment initiation and the patient died in the Intensive Care unit. Discussion: Some patients may present complications directly related to an underlying hematological malignancy. The WE is one of these complications and should be suspected in patients with both hypoglycemia and LA. We propose a checklist in order to help clinicians manage this life-threatening complication. Before considering WE, clinicians should eliminate diagnoses such as septic shock or mesenteric ischemia, which require urgent and specific management. Conclusion: The diagnosis of WE can be challenging for clinicians in the Hematology department and the Intensive Care unit. Prompt diagnosis and rapid, adapted chemotherapy initiation may benefit patient survival. PMID- 29974038 TI - Commentary: Reducing Viability Bias in Analysis of Gut Microbiota in Preterm Infants at Risk of NEC and Sepsis. PMID- 29974037 TI - Leptospirosis Pathophysiology: Into the Storm of Cytokines. AB - Leptospirosis is a neglected tropical zoonosis caused by pathogenic spirochetes of the genus Leptospira. Infected reservoir animals, typically mice and rats, are asymptomatic, carry the pathogen in their renal tubules, and shed pathogenic spirochetes in their urine, contaminating the environment. Humans are accidental hosts of pathogenic Leptospira. Most human infections are mild or asymptomatic. However, 10% of human leptospirosis cases develop into severe forms, including high leptospiremia, multi-organ injuries, and a dramatically increased mortality rate, which can relate to a sepsis-like phenotype. During infection, the triggering of the inflammatory response, especially through the production of cytokines, is essential for the early elimination of pathogens. However, uncontrolled cytokine production can result in a cytokine storm process, followed by a state of immunoparalysis, which can lead to sepsis and associated organ failures. In this review, the involvement of cytokine storm and subsequent immunoparalysis in the development of severe leptospirosis in susceptible hosts will be discussed. The potential contribution of major pro-inflammatory cytokines in the development of tissue lesions and systemic inflammatory response, as well as the role of anti-inflammatory cytokines in contributing to the onset of a deleterious immunosuppressive cascade will also be examined. Data from studies comparing susceptible and resistant mouse models will be included. Lastly, a concise discussion on the use of cytokines for therapeutic purposes or as biomarkers of leptospirosis severity will be provided. PMID- 29974039 TI - Independent Heath Facility Meets Cancer Care Ontario and Canadian Association of Gastroenterology Guidelines for Endoscopic Procedure Wait Times While Meeting Quality Indicators: A Retrospective Review. AB - Background: Canadian independent health facilities (IHFs) have been implemented to reduce hospital endoscopy volume and expedite endoscopic evaluations for patients suspected to have underlying colorectal cancer. Methods: We conducted a retrospective review of a prospective database at a large-volume urban IHF. The primary outcomes were wait times, and the secondary outcomes were colonoscopy quality indicators and complication rates. Results: Median wait times from referral to colonoscopy met the recommendations set out by the Canadian Association of Gastroenterology and Cancer Care Ontario for all indications: chronic abdominal pain: 43 days; new onset change in bowel habits: 36 days; bright red rectal bleeding: 42 days; documented iron-deficiency anemia: 43 days; fecal occult blood test positive: 38 days; cancer likely based on imaging or physical exam: 23 days; chronic diarrhea and chronic constipation: 42 days; and screening colonoscopies: 55 days. Secondary outcomes of quality indicators and complication rates all met or exceeded the CCO and CAG recommendations. Conclusions: This IHF met the recommended wait times for all indications for colonoscopy while maintaining high procedural quality and safety. IHFs are one solution to help meet the increasing demand for colonoscopy in Ontario. PMID- 29974041 TI - Indications for Endoscopic Ultrasound-Guided Pancreatic Drainage: For Benign or Malignant Cases? AB - Background and Aims: Recurrent pancreatitis associated with pancreatic strictures requires treatment with endoscopic retrograde pancreatography (ERP), but it is sometimes technically unsuccessful. Endoscopic ultrasound-guided pancreatic drainage (EUS-PD) was developed as an alternative to a surgical approach after failed ERP; however, the indications for EUS-PD are unclear. In this study, we evaluated the outcomes of EUS-PD and established the indications for EUS-PD. Methods: A total of 15 patients had indications for EUS-PD for recurrent pancreatitis due to pancreatic strictures. There were eight patients with benign pancreatic strictures and seven with malignant pancreatic strictures. The success rate, adverse events, and long-term outcomes were evaluated. Results: The technical success rates of benign and malignant strictures were 75% (6/8) and 100% (7/7), respectively, and clinical success was achieved in 100% (6/6) and 87.5% of cases (6/7), respectively. Rendezvous procedures were performed in two patients with benign strictures. The adverse event (AE) rate was 26.7% (4/15) and included cases of peritonitis, bleeding, and stent migration. Reinterventions were performed in three patients with benign strictures and two with malignant strictures. Conclusions: EUS-PD was an appropriate treatment for not only benign strictures but also malignant strictures with recurrent pancreatitis after failed ERP. However, the AE rate was high, and reinterventions were required in some cases during long-term follow-up. The indications for EUS-PD should be considered carefully, and careful follow-up is needed. PMID- 29974040 TI - Percutaneous Ablation for Hepatocellular Carcinoma: Comparison of Various Ablation Techniques and Surgery. AB - Image-guided percutaneous ablation is considered best in the treatment of early stage hepatocellular carcinoma (HCC). Ablation is potentially curative, minimally invasive, and easily repeatable for recurrence. Ethanol injection used to be the standard in ablation. However, radiofrequency ablation has recently been the most prevailing ablation method for HCC. Many investigators have reported that radiofrequency ablation is superior to ethanol injection, from the viewpoints of treatment response, local tumor curativity, and overall survival. New-generation microwave ablation can create a larger ablation volume in a shorter time period. Further comparison studies are, however, mandatory between radiofrequency ablation and microwave ablation, especially in terms of complications and long term survival. Irreversible electroporation, which is a non-thermal ablation method that delivers short electric pulses to induce cell death due to apoptosis, requires further studies, especially in terms of long-term outcomes. It is considerably difficult to compare outcomes in ablation with those in surgical resection. However, radiofrequency ablation seems to be a satisfactory alternative to resection for HCC 3 cm or smaller in Child-Pugh class A or B cirrhosis. Furthermore, radiofrequency ablation may be a first-line treatment in HCC 2 cm or smaller in Child-Pugh class A or B cirrhosis. Various innovations would further improve outcomes in ablation. Training programs may be effective in providing an excellent opportunity to understand basic concepts and learn cardinal skills for successful ablation. Sophisticated ablation would be more than an adequate alternative of surgery for small- and possibly middle-sized HCC. PMID- 29974042 TI - Pediatric Videosomnography: Can Signal/Video Processing Distinguish Sleep and Wake States? AB - The term videosomnography captures a range of video-based methods used to record and subsequently score sleep behaviors (most commonly sleep vs. wake states). Until recently, the time consuming nature of behavioral videosomnography coding has limited its clinical and research applications. However, with recent technological advancements, the use of auto-videosomnography techniques may be a practical and valuable extension of behavioral videosomnography coding. To test an auto-videosomnography system within a pediatric sample, we processed 30 videos of infant/toddler sleep using a series of signal/video-processing techniques. The resulting auto-videosomnography system provided minute-by-minute sleep vs. wake estimates, which were then compared to behaviorally coded videosomnography and actigraphy. Minute-by-minute estimates demonstrated moderate agreement across compared methods (auto-videosomnography with behavioral videosomnography, Cohen's kappa = 0.46; with actigraphy = 0.41). Additionally, auto-videosomnography agreements exhibited high sensitivity for sleep but only about half of the wake minutes were correctly identified. For sleep timing (sleep onset and morning rise time), behavioral videosomnography and auto-videosomnography demonstrated strong agreement. However, nighttime waking agreements were poor across both behavioral videosomnography and actigraphy comparisons. Overall, this study provides preliminary support for the use of an auto-videosomnography system to index sleep onset and morning rise time only, which may have potential telemedicine implications. With replication, auto-videosomnography may be useful for researchers and clinicians as a minimally invasive sleep timing assessment method. PMID- 29974044 TI - A Review of Tertiary Referrals for Management of Pediatric Esophageal Eosinophilia. AB - Background: Eosinophilic esophagitis is a chronic, immune-mediated disease characterized by symptoms of esophageal dysfunction and >=15 eosinophils/high powered field (eos/hpf). Proton pump inhibitor responsive esophageal eosinophilia (1) is an entity of esophageal eosinophilia that responds to PPI therapy and is thought to be clinically and histologically similar to EoE. Current guidelines suggest therapy with PPI prior to endoscopy and use of PPI as first line for esophageal eosinophilia. In order to gain a better understanding of community practice patterns and to try differentiate between these two entities, we sought to evaluate the clinical presentations, treatment and final diagnoses of patients presenting to our institution for second opinions of esophageal eosinophilia. Methods: A search of our electronic medical record yielded a list of patients presenting for a second opinion of esophageal eosinophilia. Charts were reviewed for clinical information. Results: A total of 187 charts were included. Patients ranged from 1-19 years old with 75% being male and 74% being Caucasian. Of the patients who had documentation of their medications at the time of initial endoscopy, 70% were not on any PPI prior to their endoscopy, and 94% were on <2 mg/kg/day. Of the 19 patients who had full response to PPI therapy and were diagnosed with PPI-REE, close to half had previously been treated with diet, steroids, or both. Patients with final diagnosis of EoE had significantly higher eos/hpf on initial endoscopy compared to those with diagnosis of PPI-REE (51.9 +/ 30.6 v. 35.8 +/- 16.4. p = 0.027), as well as higher likelihood of having IgE mediated food allergy (79 v. 47%, p = 0.003). Conclusions: Diagnostic and therapeutic algorithms are needed for esophageal eosinophilia to prevent misdiagnosis and unnecessary procedures and therapies. PMID- 29974043 TI - Malnutrition in Chronic Kidney Disease. AB - Patients with chronic kidney disease are at substantial risk for malnutrition, characterized by protein energy wasting and micronutrient deficiency. Studies show a high prevalence rate of malnutrition in both children and adults with chronic kidney disease. Apart from abnormalities in growth hormone-insulin like growth factor axis, malnutrition also plays a role in the development of stunted growth, commonly observed in children with chronic kidney disease. The pathogenic mechanisms of malnutrition in chronic kidney disease are complex and involve an interplay of multiple pathophysiologic alterations including decreased appetite and nutrient intake, hormonal derangements, metabolic imbalances, inflammation, increased catabolism, and dialysis related abnormalities. Malnutrition increases the risk of morbidity, mortality and overall disease burden in these patients. The simple provision of adequate calorie and protein intake does not effectively treat malnutrition in patients with chronic kidney disease owing to the intricate and multifaceted derangements affecting nutritional status in these patients. A clear understanding of the pathophysiologic mechanisms involved in the development of malnutrition in chronic kidney disease is necessary for developing strategies and interventions that are effective, and capable of restoring normal development and mitigating negative clinical outcomes. In this article, a review of the pathophysiologic mechanisms of malnutrition in chronic kidney disease is presented. PMID- 29974045 TI - A Rare Case of Double-System With Ectopic Ureteral Openings Into Vagina. AB - The presence of an ectopic ureter may be indicated by continuous wetting, despite a normal voiding pattern, especially in girls. In most cases, an ectopic ureter is associated with a duplex collecting system and complete ureteral duplication. A 5-year-old girl presented with urinary incontinence regardless of the successful toilet training and a suspicion of left duplex kidney on a previous ultrasound. Contrast-enhanced computed tomography revealed a double left kidney with double ureters, both inserting together into the vagina. The surgical treatment consisted in the "en block" reimplantation of the ectopic ureters into the bladder, with complete resolution of the symptoms. The reported case does not represent just a typical presentation of a single ectopic ureter, as the duplex kidney system had ectopic both ipsilateral ureters (with insertion into the vagina). This case reminds us that congenital abnormalities of the genito-urinary tract should be considered in case of urinary incontinence and recurrent urinary tract infections. PMID- 29974046 TI - Prenatal and Neonatal Factors Predicting Sleep Problems in Children Born Extremely Preterm or With Extremely Low Birthweight. AB - Objective: Prematurely born children have been reported to have more sleep problems throughout childhood than children born at term. The aim of this study was to explore if prenatal or neonatal factors can predict sleep problems at age 11 years in children born extremely preterm (EPT). Method: A prospective observational study of all infants who were born EPT in Norway in 1999 and 2000. Prenatal and neonatal data were collected by all Norwegian obstetric and pediatric departments. Parental questionnaire mapped sleep problems and sleep habits at the age of 11 years. Results: Of the 372 eligible children, 221 participated. Of those, 28.1% snored, 27.5% had difficulty falling asleep or frequent awakenings and 17.2% suffered from daytime sleepiness. The mean sleep duration was 9.4 h (range 4.3-11.0 h). Smoking in pregnancy predicted snoring (odds ratio 4.3). Neonatal cerebral hemorrhage and being born small for gestational age predicted difficulty falling asleep or frequent awakenings (odds ratio 2.2 and 2.3). Other morbidities during pregnancy or the newborn period, gestational age or the burden of treatment in the neonatal intensive care unit did not predict sleep problems. None of the studied prenatal or neonatal factors predicted daytime sleepiness or sleep duration <9 h. Conclusion: Of numerous prenatal and neonatal factors, only smoking during pregnancy, being born small for gestational age and cerebral hemorrhage predicted sleep problems at 11 years of age among these children born EPT. PMID- 29974047 TI - Changes to the Employers' Use of Genetic Information and Non-discrimination for Health Insurance in the USA: Implications for Australians. AB - In the USA, a bill has been introduced to the senate that may jeopardize an individual's rights to privacy and non-discrimination. This piece examines the proposed Preserving Employee Wellness Programs Act (PEWPA), and implications this will have on the use of genetic information. The Act allows for employers to apply financial penalties for health insurance based on genetic information, which raises concerns as the capacity to interpret genetic results is limited by knowledge of the significance of both benign and pathogenic variants. In Australia, genetic information can only be used to determine life insurance, not to stratify health insurance, and any precedent set internationally should raise concerns of the potential for change on the horizon. PMID- 29974048 TI - A Novel Metal-Based Imaging Probe for Targeted Dual-Modality SPECT/MR Imaging of Angiogenesis. AB - Superparamagnetic iron oxide nanoparticles with well-integrated multimodality imaging properties have generated increasing research interest in the past decade, especially when it comes to the targeted imaging of tumors. Bevacizumab (BCZM) on the other hand is a well-known and widely applied monoclonal antibody recognizing VEGF-A, which is overexpressed in angiogenesis. The aim of this proof of-concept study was to develop a dual-modality nanoplatform for in vivo targeted single photon computed emission tomography (SPECT) and magnetic resonance imaging (MRI) of tumor vascularization. Iron oxide nanoparticles (IONPs) have been coated with dimercaptosuccinic acid (DMSA), for consequent functionalization with the monoclonal antibody BCZM radiolabeled with 99mTc, via well-developed surface engineering. The IONPs were characterized based on their size distribution, hydrodynamic diameter and magnetic properties. In vitro cytotoxicity studies showed that our nanoconstruct does not cause toxic effects in normal and cancer cells. Fe3O4-DMSA-SMCC-BCZM-99mTc were successfully prepared at high radiochemical purity (>92%) and their stability in human serum and in PBS were demonstrated. In vitro cell binding studies showed the ability of the Fe3O4-DMSA SMCC-BCZM-99mTc to bind to the VEGF-165 isoform overexpressed on M-165 tumor cells. The ex vivo biodistribution studies in M165 tumor-bearing SCID mice showed high uptake in liver, spleen, kidney and lungs. The Fe3O4-DMSA-SMCC-BCZM-99mTc demonstrated quick tumor accumulation starting at 8.9 +/- 1.88%ID/g at 2 h p.i., slightly increasing at 4 h p.i. (16.21 +/- 2.56%ID/g) and then decreasing at 24 h p.i. (6.01 +/- 1.69%ID/g). The tumor-to-blood ratio reached a maximum at 24 h p.i. (~7), which is also the case for the tumor-to-muscle ratio (~18). Initial pilot imaging studies on an experimental gamma-camera and a clinical MR camera prove our hypothesis and demonstrate the potential of Fe3O4-DMSA-SMCC-BCZM-99mTc for targeted dual-modality imaging. Our findings indicate that Fe3O4-DMSA-SMCC BCZM-99mTc IONPs could serve as an important diagnostic tool for biomedical imaging as well as a promising candidate for future theranostic applications in cancer. PMID- 29974049 TI - MicroNIR/Chemometrics Assessement of Occupational Exposure to Hydroxyurea. AB - Portable Near Infrared spectroscopy (NIRs) coupled to chemometrics was investigated for the first time as a novel entirely on-site approach for occupational exposure monitoring in pharmaceutical field. Due to a significant increase in the number of patients receiving chemotherapy, the development of reliable, fast, and on-site analytical methods to assess the occupational exposure of workers in the manufacture of pharmaceutical products, has become more and more required. In this work, a fast, accurate, and sensitive detection of hydroxyurea, a cytotoxic antineoplastic agent commonly used in chemotherapy, was developed. Occupational exposure to antineoplastic agents was evaluated by collecting hydroxyurea on a membrane filter during routine drug manufacturing process. Spectra were acquired in the NIR region in reflectance mode by the means of a miniaturized NIR spectrometer coupled with chemometrics. This MicroNIR instrument is a very ultra-compact portable device with a particular geometry and optical resolution designed in such a manner that the reduction in size does not compromise the performances of the spectrometer. The developed method could detect up to 50 ng of hydroxyurea directly measured on the sampling filter membrane, irrespective of complexity and variability of the matrix; thus extending the applicability of miniaturized NIR instruments in pharmaceutical and biomedical analysis. PMID- 29974050 TI - Genomes and Transcriptomes of Duckweeds. AB - Duckweeds (Lemnaceae family) are the smallest flowering plants that adapt to the aquatic environment. They are regarded as the promising sustainable feedstock with the characteristics of high starch storage, fast propagation, and global distribution. The duckweed genome size varies 13-fold ranging from 150 Mb in Spirodela polyrhiza to 1,881 Mb in Wolffia arrhiza. With the development of sequencing technology and bioinformatics, five duckweed genomes from Spirodela and Lemna genera are sequenced and assembled. The genome annotations discover that they share similar protein orthologs, whereas the repeat contents could mainly explain the genome size difference. The gene families responsible for cell growth and expansion, lignin biosynthesis, and flowering are greatly contracted. However, the gene family of glutamate synthase has experienced expansion, indicating their significance in ammonia assimilation and nitrogen transport. The transcriptome is comprehensively sequenced for the genera of Spirodela, Landoltia, and Lemna, including various treatments such as abscisic acid, radiation, heavy metal, and starvation. The analysis of the underlying molecular mechanism and the regulatory network would accelerate their applications in the fields of bioenergy and phytoremediation. The comparative genomics has shown that duckweed genomes contain relatively low gene numbers and more contracted gene families, which may be in parallel with their highly reduced morphology with a simple leaf and primary roots. Still, we are waiting for the advancement of the long read sequencing technology to resolve the complex genomes and transcriptomes for unsequenced Wolffiella and Wolffia due to the large genome sizes and the similarity in their polyploidy. PMID- 29974051 TI - Patents as Early Indicators of Technology and Investment Trends: Analyzing the Microbiome Space as a Case Study. AB - The human microbiome is the collective of microbes living in symbiosis on and within humans. Modulating its composition and function has become an attractive means for the prevention and treatment of a variety of diseases including cancer. Since the initiation of the human microbiome project in 2007, the number of academic publications and active patent families around the microbiome has grown exponentially. Screening patent databases can be useful for the early detection and the tracking of new technology trends. However, it is not sufficient to assess portfolio sizes because emerging players with small but high-quality patent portfolios will be missed within the noise of large but low-quality portfolio owners. Here we used the consolidated database and software tool PatentSight to benchmark patent portfolios, and to analyze key patent owners and innovators in the microbiome space. Our study shows how in-depth patent analyses combining qualitative and quantitative parameters can identify actionable early indicators of technology and investment trends from large patent datasets. PMID- 29974053 TI - Feline Troglostrongylosis: Current Epizootiology, Clinical Features, and Therapeutic Options. AB - Parasitic bronchopneumonia plays an important role in feline respiratory medicine, thus it is receiving growing attention by researchers and practitioners. In recent years, Troglostrongylus brevior, a lungworm usually infecting wild felids, has been recognized as an agent of the lower respiratory tract in domestic cats. In particular, as a likely consequence of a spill-over from wild reservoirs (e.g., the European wildcat), T. brevior infection is increasingly reported in cats from Mediterranean and Balkan countries. This parasitic nematode has an indirect life cycle, and its biology overlaps that of the better known "cat lungworm" Aelurostrongylus abstrusus. In fact, cases of co infections caused by both lungworms are not infrequent in domestic cats. Knowledge on clinical features of troglostrongylosis is still incomplete. Available data indicates that clinical signs and radiographic evidence are severe especially in kittens and young cats, are non-specific and often overlap with those of other feline respiratory diseases, such as feline bronchial disease/asthma, or infectious pneumonia. These characteristics make a definitive diagnosis of troglostrongylosis challenging, this disease requires a timely ancillary therapy and an appropriate anthelminthic treatment. As feline troglostrongylosis is an emerging parasitic disease of domestic cats, it should be included in differential diagnosis for lower respiratory tract disease in cats from regions where this parasite is present but also where it is unexpected. This article reviews current knowledge on the pathogenic role of T. brevior in domestic cats and resulting respiratory illness, with a special focus on clinical aspects, diagnosis, and management of the disease. PMID- 29974055 TI - Editorial: Mechanisms of Persistence, Survival, and Transmission of Bacterial Foodborne Pathogens in Production Animals. PMID- 29974054 TI - Detection of Astrovirus, Rotavirus C, and Hepatitis E Viral RNA in Adult and Juvenile Farmed Mink (Neovison vison). AB - Mink astrovirus (MiAstV) is known to play a major role in mink pre-weaning diarrhea, and rotavirus and hepatitis E virus (HEV) are both considered potentially zoonotic agents. These viruses are not monitored in commercial mink, and the role of these viral infections in mink health is not well understood. This study assessed the prevalence of mink astrovirus, rotavirus C, mink HEV and swine HEV in 527 pooled healthy adult female mink and mink kit fecal samples from 50 Canadian mink farms in two seasons over 4 years. Viral RNA was extracted and amplified in RT-PCR to detect mink astrovirus and HEV RdRp genes, swine HEV ORF2, and rotavirus C VP6 gene. At least 26% of all positive samples for each virus was sequenced for phylogenetic analysis. Fourteen percent of samples were astrovirus positive, while 3 and 9% of samples were rotavirus C and mink HEV positive, respectively. One adult female sample was found to be positive by PCR for swine HEV. A significantly higher number of kit samples were astrovirus- and HEV positive compared to adult female samples (p = 0.01 and p < 0.0001, respectively). Astrovirus was detected in significantly more summer samples from adult females compared to winter samples from adult females (p = 0.001). The detected sequences were closely related to previously reported MiAstV, swine rotavirus C, and mink and swine HEV strains. Two astrovirus sequences were distantly related to all other detected sequences as well as previously reported MiAstVs. These results demonstrate low to moderate prevalence of the three viruses in feces from clinically healthy Canadian commercial mink, and suggest that further monitoring of these viruses may provide a better understanding of how these potentially zoonotic agents may play a role in mink enteritis and overall productivity. PMID- 29974056 TI - Basal Insulin Dose in Adults with Type 1 Diabetes Mellitus on Insulin Pumps in Real-Life Clinical Practice: A Single-Center Experience. AB - Introduction: Basal insulin (BI) infusion in pump therapy of type 1 diabetes (T1DM) mimics physiological secretion during the night and between meals. The recommended percentage of the total BI to daily insulin dose (termed the %BI) ranges between 30 and 50%. We analyzed whether this recommendation was followed in adults with T1DM from a university center, and whether BI doses were linked with glycemic control. Materials and Methods: We included 260 consecutive patients with T1DM (159 women and 101 men) treated with continuous subcutaneous insulin infusion at the Department of Metabolic Diseases, Krakow, Poland. Data were downloaded from patients' pumps and collected from medical records. We analyzed the settings of BI and the association of %BI with HbA1c level. Linear regression was performed. Results: The mean age of T1DM individuals was 26.6 +/- 8.2 years, BMI was 23.1 +/- 3.0 kg/m2, T1DM duration was 13.3 +/- 6.4 years, and HbA1c level was 7.4%. There were 69.6% (n=181) of T1DM patients with %BI in the recommended range. The T1DM duration and HbA1c level of patients with a %BI <30% (n=23) was 9.5 years and 6.4%, respectively; for a %BI of 30-50%, it was 13.2 years and 7.4%; and for a %BI >50% (n=56), it was 15.8 years and 7.8% (p < 0.001 for both three-group comparisons). Multiple regression identified %BI among independent predictors of the HbA1c level. Conclusion: In this real-life analysis, the recommendations concerning %BI dosing were not followed by almost one-third of adult T1DM patients. Low %BI was associated with better glycemic control; however, this requires further confirmation. PMID- 29974052 TI - Cycling to Meet Fate: Connecting Pluripotency to the Cell Cycle. AB - Pluripotent stem cells are characterized by their high proliferative rates, their ability to self-renew and their potential to differentiate to all the three germ layers. This rapid proliferation is brought about by a highly modified cell cycle that allows the cells to quickly shuttle from DNA synthesis to cell division, by reducing the time spent in the intervening gap phases. Many key regulators that define the somatic cell cycle are either absent or exhibit altered behavior, allowing the pluripotent cell to bypass cell cycle checkpoints typical of somatic cells. Experimental analysis of this modified stem cell cycle has been challenging due to the strong link between rapid proliferation and pluripotency, since perturbations to the cell cycle or pluripotency factors result in differentiation. Despite these hurdles, our understanding of this unique cell cycle has greatly improved over the past decade, in part because of the availability of new technologies that permit the analysis of single cells in heterogeneous populations. This review aims to highlight some of the recent discoveries in this area with a special emphasis on different states of pluripotency. We also discuss the highly interlinked network that connects pluripotency factors and key cell cycle genes and review evidence for how this interdependency may promote the rapid cell cycle. This issue gains translational importance since disruptions in stem cell proliferation and differentiation can impact disorders at opposite ends of a spectrum, from cancer to degenerative disease. PMID- 29974057 TI - Patients' Perception of Quality of Diabetes Care Received in Ibadan, Nigeria. AB - Diabetes Mellitus (DM) is one of the diseases of public health concerns of the 21st century with rising burden in developing countries. The evaluation of care for diabetes from patients' perspective an important indicator of measuring quality of health services and improving treatment approaches but data of the nature are scarce in Nigeria. The study therefore investigated Patients' Evaluation of the Quality of Diabetes care (PEQD) in Ibadan. This descriptive cross-sectional study recruited 384 diabetic patients from three hospitals where specialised services are offered in Ibadan. A semi-structured pre-tested questionnaire was used to collect data. A 42-point PEQD questionnaire scale was used to collect data and a score of >21 was rated as good Perceived Quality of Care (PQC). Data were analysed using descriptive statistics, chi-square test and logistic regression set at 5% level of statistical significance. Mean age of respondents was 62.5 + 10.8 years and mean diabetes duration was 8.4 + 7.6. Majority (58.3%) of the respondents didn't know the type of diabetes they had. Patients aged less than 60 years were less likely to PQC received as good (OR: 0.21; CI: 0.05 - 0.91) compared to those who were above 60 years. More than half (55.0%) of the respondents perceive quality of care as good. Patients' assessment of the quality of diabetes care received was perceived good. There is need to sustain current satisfactory services in diabetic care and institutionalize periodic survey patients' satisfaction to provide feedback for future quality improvement. PMID- 29974058 TI - Additively manufactured medical products - the FDA perspective. AB - Additive manufacturing/3D printing of medical devices is becoming more commonplace, a 3D printed drug is now commercially available, and bioprinting is poised to transition from laboratory to market. Despite the variety of technologies enabling these products, the US Food and Drug Administration (FDA) is charged with protecting and promoting the public health by ensuring these products are safe and effective. To that end, we are presenting the FDA's current perspective on additive manufacturing/3D printing of medical products ranging from those regulated by the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research (CBER). Each Center presents an overview of the additively manufactured products in their area and the specific concerns and thoughts on using this technology in those product spaces. PMID- 29974059 TI - A Conversation with Amy Prieto. PMID- 29974060 TI - One-Handed Helical Orbitals in Conjugated Molecules. PMID- 29974061 TI - Programming Framework Materials for Ammonia Capture. PMID- 29974062 TI - All-Inorganic Metal Halide Perovskite Nanocrystals: Opportunities and Challenges. AB - The past decade has witnessed the growing interest in metal halide perovskites as driven by their promising applications in diverse fields. The low intrinsic stability of the early developed organic versions has however hampered their widespread applications. Very recently, all-inorganic perovskite nanocrystals have emerged as a new class of materials that hold great promise for the practical applications in solar cells, photodetectors, light-emitting diodes, and lasers, among others. In this Outlook, we first discuss the recent developments in the preparation, properties, and applications of all-inorganic metal halide perovskite nanocrystals, with a particular focus on CsPbX3, and then provide our view of current challenges and future directions in this emerging area. Our goal is to introduce the current status of this type of new materials to researchers from different areas and motivate them to explore all the potentials. PMID- 29974063 TI - SpliceRCA: in Situ Single-Cell Analysis of mRNA Splicing Variants. AB - Immune cell heterogeneity due to the differential expression of RNA splicing variants still remains unexplored. This is mainly because single-cell imaging technologies of splicing variants with precise sequence or base resolution are now not readily available. Herein, we design a splice-junction anchored padlock probe-mediated rolling circle amplification assay (SpliceRCA) for single-cell imaging of splice isoforms of essential regulatory immune gene (CD45) upon T-cell activation. Two recognition regions in the padlock probe can target the splice junction sequence, resulting in a close proximity for triggering in situ one target-one-amplicon amplification. With the read length of ~30 nucleotides, this method allows discrimination of isoforms with single-base precision and quantification of isoforms with single-molecule resolution. We applied SpliceRCA to single-cell image splice variants of essential regulatory immune gene (CD45) upon T-cell activation. It is found that CD45RO isoform presents a distal nuclear spatial distribution and is coregulated with CD45RB upon activation. Our strategy provides a single-cell analysis platform to investigate the mechanism of complex immune responses and may further guide immunotherapy. PMID- 29974064 TI - Coarctate and Mobius: The Helical Orbitals of Allene and Other Cumulenes. AB - As brought to the attention of the community by Hendon et al. and noted by previous workers, the pi orbitals of the equilibrium geometry odd-carbon (even number of double bonds = n) [n]cumulenes may be written in either rectilinear or helical form. We trace the origins and detailed composition of the helical orbitals of cumulenes, which emerge in the simplest Huckel model and are not much modified in advanced computations. For the alpha,omega-disubstituted even [n]cumulenes, the helical representation is obligatory as the symmetry is reduced from D2d to C2. A relationship is apparent between these helical orbitals of the even [n]cumulenes, seen as a Herges coarctate system, and the corresponding Mobius cyclic polyene orbitals. The twist of the orbitals varies in interesting ways along the helix, and so does the contribution of the component atomic orbitals. Though the electronic structures of even [n]cumulenes and Mobius cyclopolyenes are closely related, they differ for higher n in intriguing ways; these are linked to the constrained rotation of the basis orbitals along the helical twist itinerary. Relations are constructed between the level patterns of the pi-systems of even [n]cumulenes and ideas of Huckel and Mobius aromaticity. PMID- 29974065 TI - From Tree to Tape: Direct Synthesis of Pressure Sensitive Adhesives from Depolymerized Raw Lignocellulosic Biomass. AB - We report a new and robust strategy toward the development of high-performance pressure sensitive adhesives (PSAs) from chemicals directly obtained from raw biomass deconstruction. A particularly unique and translatable aspect of this work was the use of a monomer obtained from real biomass, as opposed to a model compound or lignin-mimic, to generate well-defined and nanostructure-forming polymers. Herein, poplar wood depolymerization followed by minimal purification steps (filtration and extraction) produced two aromatic compounds, 4 propylsyringol and 4-propylguaiacol, with high purity and yield. Efficient functionalization of those aromatic compounds with either acrylate or methacrylate groups generated monomers that could be easily polymerized by a scalable reversible addition-fragmentation chain-transfer (RAFT) process to yield polymeric materials with high glass transition temperatures and robust thermal stabilities, especially relative to other potentially biobased alternatives. These lignin-derived compounds were used as a major component in low-dispersity triblock polymers composed of 4-propylsyringyl acrylate and n-butyl acrylate (also can be biobased). The resulting PSAs exhibited excellent adhesion to stainless steel without the addition of any tackifier or plasticizer. The 180 degrees peel forces were up to 4 N cm-1, and tack forces were up to 2.5 N cm-1, competitive with commercial Fisherbrand labeling tape and Scotch Magic tape, demonstrating the practical significance of our biomass-derived materials. PMID- 29974067 TI - Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility. AB - Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymerization-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated l-asparaginase (clinically used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodology as an attractive alternative to the covalent PEGylation of enzymes. PMID- 29974069 TI - Outer-Sphere Water Clusters Tune the Lanthanide Selectivity of Diglycolamides. AB - Fundamental understanding of the selective recognition and separation of f-block metal ions by chelating agents is of crucial importance for advancing sustainable energy systems. Current investigations in this area are mostly focused on the study of inner-sphere interactions between metal ions and donor groups of ligands, while the effects on the selectivity resulting from molecular interactions in the outer-sphere region have been largely overlooked. Herein, we explore the fundamental origins of the selectivity of the solvating extractant N,N,N',N'-tetraoctyl diglycolamide (TODGA) for adjacent lanthanides in a liquid liquid extraction system, which is of relevance to nuclear fuel reprocessing and rare-earth refining technologies. Complementary investigations integrating distribution studies, quantum mechanical calculations, and classical molecular dynamics simulations establish a relationship between coextracted water and lanthanide extraction by TODGA across the series, pointing to the importance of the hydrogen-bonding interactions between outer-sphere nitrate ions and water clusters in a nonpolar environment. Our findings have significant implications for the design of novel efficient separation systems and processes, emphasizing the importance of tuning both inner- and outer-sphere interactions to obtain total control over selectivity in the biphasic extraction of lanthanides. PMID- 29974066 TI - Lipid-Protein Interactions Are Unique Fingerprints for Membrane Proteins. AB - Cell membranes contain hundreds of different proteins and lipids in an asymmetric arrangement. Our current understanding of the detailed organization of cell membranes remains rather elusive, because of the challenge to study fluctuating nanoscale assemblies of lipids and proteins with the required spatiotemporal resolution. Here, we use molecular dynamics simulations to characterize the lipid environment of 10 different membrane proteins. To provide a realistic lipid environment, the proteins are embedded in a model plasma membrane, where more than 60 lipid species are represented, asymmetrically distributed between the leaflets. The simulations detail how each protein modulates its local lipid environment in a unique way, through enrichment or depletion of specific lipid components, resulting in thickness and curvature gradients. Our results provide a molecular glimpse of the complexity of lipid-protein interactions, with potentially far-reaching implications for our understanding of the overall organization of real cell membranes. PMID- 29974068 TI - Tuning the Bandgap of Photo-Sensitive Polydopamine/Ag3PO4/Graphene Oxide Coating for Rapid, Noninvasive Disinfection of Implants. AB - Bacterial infection and associated complications are threats to human health especially when biofilms form on biomedical devices and artificial implants. Herein, a hybrid polydopamine (PDA)/Ag3PO4/graphene oxide (GO) coating is designed and constructed to achieve rapid bacteria killing and eliminate biofilms in situ. By varying the amount of GO in the hybrid coating, the bandgap can be tuned from 2.52 to 2.0 eV so that irradiation with 660 nm visible light produces bacteria-killing effects synergistically in concert with reactive oxygen species (ROS). GO regulates the release rate of Ag+ to minimize the cytotoxicity while maintaining high antimicrobial activity, and a smaller particle size enhances the yield of ROS. After irradiation with 660 nm visible light for 15 min, the antimicrobial rates of the PDA/Ag3PO4/GO hybrid coating against Escherichia coli and Staphylococcus aureus are 99.53% and 99.66%, respectively. In addition, this hybrid coating can maintain a repeatable and sustained antibacterial efficacy. The released Ag+ and photocatalytic Ag3PO4 produce synergistic antimicrobial effects in which the ROS increases the permeability of the bacterial membranes to increase the probability of Ag+ to enter the cells to kill them together with ROS synergistically. PMID- 29974070 TI - Surface Pore Engineering of Covalent Organic Frameworks for Ammonia Capture through Synergistic Multivariate and Open Metal Site Approaches. AB - Ammonia (NH3) is a commonly used industrial gas, but its corrosiveness and toxicity are hazardous to human health. Although many adsorbents have been investigated for NH3 sorption, limited ammonia uptake remains an urgent issue yet to be solved. In this article, a series of multivariate covalent organic frameworks (COFs) are explored which are densely functionalized with various active groups, such as -N-H, -C=O, and carboxyl group. Then, a metal ion (Ca2+, Mn2+, and Sr2+) is integrated into the carboxylated structure achieving the first case of an open metal site in COF architecture. X-ray photoelectron spectroscopy reveals conclusive evidence for the multiple binding interactions with ammonia in the modified COF materials. Infrared spectroscopy indicates a general trend of binding capability from weak to strong along with -N-H, -C=O, carboxyl group, and metal ion. Through the synergistic multivariate and open metal site, the COF materials show excellent adsorption capacities (14.3 and 19.8 mmol g-1 at 298 and 283 K, respectively) and isosteric heat (Qst) of 91.2 kJ mol-1 for ammonia molecules. This novel approach enables the development of tailor-made porous materials with tunable pore-engineered surface for ammonia uptake. PMID- 29974071 TI - Taming the Strength of Interfacial Interactions via Nanoconfinement. AB - The interaction between two immiscible materials is related to the number of contacts per unit area formed by the two materials. For practical reasons, this information is often parametrized by the interfacial free energy, which is commonly derived via rather cumbersome approaches, where properties of the interface are described by combining surface parameters of the single materials. These combining rules, however, neglect any effect that geometry might have on the strength of the interfacial interaction. In this Article, we demonstrate that the number of contacts at the interface between a thin polymer coating and its supporting substrate is altered upon confinement at the nanoscale level. We show that explicitly considering the effect of nanoconfinement on the interfacial potential allows a quantitative prediction of how sample geometry affects the number of contacts formed at the interface between two materials. PMID- 29974072 TI - The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin. AB - Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K+-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear. Here, we develop a functionally competent fluorescent conjugate of salinomycin to investigate the molecular mechanism of this compound. By subcellular imaging, we demonstrate a rapid cellular uptake of the conjugate and accumulation in the endoplasmic reticulum (ER). This localization is connected to induction of Ca2+ release from the ER into the cytosol. Depletion of Ca2+ from the ER induces the unfolded protein response as shown by global mRNA analysis and Western blot analysis of proteins in the pathway. In particular, salinomycin-induced ER Ca2+ depletion up regulates C/EBP homologous protein (CHOP), which inhibits Wnt signaling by down regulating beta-catenin. The increased cytosolic Ca2+ also activates protein kinase C, which has been shown to inhibit Wnt signaling. These results reveal that salinomycin acts in the ER membrane of breast cancer cells to cause enhanced Ca2+ release into the cytosol, presumably by mediating a counter-flux of K+ ions. The clarified mechanistic picture highlights the importance of ion fluxes in the ER as an entry to inducing phenotypic effects and should facilitate rational development of cancer treatments. PMID- 29974073 TI - Delineating Physical Organic Parameters in Site-Selective C-H Functionalization of Indoles. AB - Site-selective C-H functionalization is a great challenge in homogeneous transition-metal catalysis. Herein, we present a physical organic approach to delineate the origin of regioselective amidation of N-acylindoles through Ir(III) catalysis. Bulkiness of N-directing groups of indole substrates and electronics of carboxylate additives were identified as two major factors in controlling C2 and C7 selectivity, and their microscopic mechanisms were studied with DFT-based transition state analysis. Computational insights led us to interrogate a linear free energy relationship, and parametrization of molecular determinants enabled the establishment of an intuitive yet robust statistical model that correlates an extensive number of validation data points in high accuracy. This mechanistic investigation eventually allowed the development of a new C2 amidation and alkenylation protocol of indoles, which affords the exclusive functionalization at the C2 position with up to >70:1 selectivity. PMID- 29974074 TI - Rationalization of Asymmetric Amplification via Autocatalysis Triggered by Isotopically Chiral Molecules. AB - Asymmetric amplification induced in the Soai autocatalytic reaction by chiral initiators that are enantiomeric only by virtue of an isotope, e.g., -CH3 vs CD3 , is examined by spectroscopic, kinetic, and DFT modeling studies to help understand requirements for the emergence of biological homochirality. We find that the initiator inhibits the autocatalytic pathway at the outset of the reaction but ultimately provides the imbalance required for asymmetric amplification. This work provides clues in the ongoing search for prebiotically plausible versions of asymmetric autocatalysis. PMID- 29974075 TI - Toxic chemical weapons of assassination and warfare: nerve agents VX and sarin. AB - The use of VX and sarin as weapons of assassination and warfare raises important considerations for healthcare professionals who may encounter victims, bystanders, and responders who require prompt assessment and treatment. Chemical warfare agents such as VX and sarin constitute a considerable threat to the health of the civilian population, military personnel, and peacekeeping forces. Healthcare providers should recognize symptoms of nerve agent exposure, understand regional and international notification procedures for potential attacks, as well as the indications for and available supply of antidotal therapy. PMID- 29974076 TI - The Case for Computational Health Science. AB - In this introductory paper, we begin by making the case for Computational Health Science, which we define as the interdisciplinary efforts of health scientists, computer scientists, engineers, psychologists, and other social scientists, to conduct innovative research that will inform future practice directed at changing health behavior through improved communication, networking, and social capital. We recognize and discuss some of the main challenges involved with such an enterprise, but also highlight the associated benefits, which, we argue, significantly outweigh them. We then provide a brief summary of the contributions to this first Special Issue on Computational Health Science. PMID- 29974078 TI - Comparison of the effects of selenomethionine and selenium-enriched yeast in the triple-transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disease that exhibits multiple pathogeneses and heterogeneity. Selenium (Se) is an essential trace element for human and animal nutrition. It has been shown that supplementation with two organic forms of Se, Se-enriched yeast (Se-yeast) and selenomethionine (Se-Met), could improve cognitive impairment, reverse synaptic deficits and mitigate tau pathology in triple-transgenic (3* Tg) AD mice. Se yeast is well known for its high Se-Met content, which may mediate its anti-AD effects. In addition, a large amount of the physiological and biochemical mechanisms of these two Se drugs in the amelioration AD pathology remains unknown. In this study, the content of Se-yeast aside from Se was analyzed, and the effects of Se-Met and Se-yeast on 3* Tg-AD mice were investigated and compared. The results showed that both Se-Met and Se-yeast not only significantly increased the Se levels, enhanced the antioxidant capacity and improved the cognitive decline in the model, but also decreased the Abeta and tau pathologies in the brain tissue of the AD mice. Moreover, the ability of Se-Met to increase the Se levels in different tissues of the AD mice was more significant than that of Se-yeast. However, the positive effect of Se-yeast on improving the cognitive ability of the AD mice was better than that of Se-Met, likely due to the various elements, vitamins and other nutrients in Se-yeast. Collectively, these results suggest that Se-yeast has potential as a clinical health product or drug for AD but that Se-Met, as a pure organic Se compound, is more suitable for studying the therapeutic mechanism of Se because of its comprehensive effects on AD. PMID- 29974079 TI - Extending the scope of the carbonyl facilitated triplet excited state towards visible light excitation. AB - A series of extended pi-conjugated benzophenone analogs was synthesized through a facile Lewis-acid catalyzed Friedel-Crafts reaction in order to exploit the integral triplet state properties of benzophenone. Extending the pi-conjugated plane of the phenyl ring of benzophenone allowed tuning of the excitation wavelength from the far-UV end (~260 nm) to the visible spectrum (~446 nm). Compared to benzophenone, significant red-shifts in the absorption (up to 450 nm in solution) with high photostability were observed for the synthesized benzophenone analogs. As is evident from the density functional theory calculations, expansion of the ring size of the aromatic part of the benzophenone analogs induces a decrease in the HOMO-LUMO gap. The considerable extension of the electron density to the carbonyl group in the LUMO substantiates the triplet nature associated with the benzophenone analogs. By virtue of the properties of the carbonyl functionality, an apparent increase in the triplet quantum yield (PhiT = 5.4% to 87.7%) was observed for the benzophenone analogs when compared to the corresponding bare polyaromatic hydrocarbon. The spin orbit coupling was computationally estimated for the benzophenone analogs to propose pathways for the observed intersystem crossing process. The plausibility to photoexcite the aromatic-ring-fused benzophenone frameworks for triplet activation in the visible range opens the door for a new class of materials for photonic application. PMID- 29974080 TI - Ab initio design of light absorption through silver atomic cluster decoration of TiO2. AB - A first-principles study of the stability and optical response of subnanometer silver clusters Agn (n <= 5) on a TiO2(110) surface is presented. First, the adequacy of the vdW-corrected DFT-D3 approach is assessed using the domain-based pair natural orbital correlation DLPNO-CCSD(T) calculations along with the Symmetry-Adapted Perturbation Theory [SAPT(DFT)] applied to a cluster model. Next, using the DFT-D3 treatment with a periodic slab model, we analyze the interaction energies of the atomic silver clusters with the TiO2(110) surface. Finally, the hybrid HSE06 functional and a reduced density matrix treatment are applied to obtain the projected electronic density of states and photo-absorption spectra of the TiO2(110) surface, with and without adsorbed silver clusters. Our results show the stability of the supported clusters, the enhanced light absorbance intensity of the material upon their deposition, and the appearance of intense secondary broad peaks in the near-infrared and the visible regions of the spectrum, with positions depending on the size and shape of the supported clusters. The secondary peaks arise from the photo-induced transfer of electrons from intra-band valence 5s orbitals of the noble-metal cluster to 3d Ti band states of the supporting material. PMID- 29974081 TI - Correction: Hybrid micro-/nano-structures derived from metal-organic frameworks: preparation and applications in energy storage and conversion. AB - Correction for 'Hybrid micro-/nano-structures derived from metal-organic frameworks: preparation and applications in energy storage and conversion' by Xiehong Cao et al., Chem. Soc. Rev., 2017, 46, 2660-2677. PMID- 29974077 TI - Aberrant expression of ETS1 and ETS2 proteins in cancer. AB - The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. They are both involved in oncogenesis and tumor suppression depending on the biological situations used. The essential roles of ETS proteins in human telomere maintenance have been suggested, which have been linked to creation of new Ets binding sites. Recently, preferential binding of ETS2 to gain-of-function mutant p53 and ETS1 to wild type p53 (WTp53) has been suggested, raising the tumor promoting role for the former and tumor suppressive role for the latter. The oncogenic and tumor suppressive functions of ETS1 and 2 proteins have been discussed. PMID- 29974082 TI - Unveiling the multifunctional roles of hitherto known capping ligand oleic acid as blue emitter and sensitizer in tuning the emission colour to white in red emitting phosphors. AB - Capping ligands are vital in stabilizing various nanostructures and semiconductor quantum dots in which unusual optical properties, especially white light emission, have been realized. Oleic acid (OA) is a widely used capping ligand. Here, we report blue emission from OA in its free molecular form and further demonstrate this by anchoring OA over the surfaces of Al2O3, ZnAl2O4(ZA), ZnAl2O4:Eu3+ (ZA:Eu3+), and Y2O3:Eu3+. White light emission was observed from OA modified ZA:Eu3+ nanophosphor due to mixing of broad blue emission of OA and red emission of Eu3+ through energy transfer from OA to Eu3+. A detailed study revealed the characteristic binding modes of OA and their dependence on Eu3+ concentration, structural inversion in ZA, and the optical properties and surface states in the pristine and OA-modified ZA:Eu3+. First principles density functional theory calculations were employed to provide an insight into the HOMO LUMO levels of OA molecule and, electronic structure of pristine and OA-modified ZA surface. The binding of OA with the ZA:xEu3+ surface changes from bridging bidentate to chelating bidentate with increasing Eu3+ concentration in the lattice. The surface binding nature of the carboxylate group with the optimized surface of ZA and the creation of mid-gap states were deduced theoretically by using butanoic acid instead of OA. The blue emission from OA and its mixing with Eu3+ emission was further confirmed experimentally by anchoring it over Y2O3:Eu3+ red phosphor. These results show the multifunctional roles of OA as capping ligand, blue emitter and sensitizer in tuning the emission colour of red phosphors into white. PMID- 29974083 TI - Single-system based discriminative optical sensors: different strategies and versatile applications. AB - Discriminative optical sensors with pattern recognition properties and high throughput ability have been widely developed as they can distinguish multiple chemically similar analytes. Compared to traditional sensor arrays composed of a series of sensor elements, single-system based discriminative sensors using an array of optical changes at different wavelengths to provide input signals have drawn intensive attention recently. On the one hand, they can provide discrimination ability that is lack in using selective sensors; on the other hand, they can simplify the complex data acquisition process accompanied by multiple-element-based sensor arrays and reduce consumption of sensor samples. This tutorial review gives an overview of the development of single-system based discriminative optical sensors. Different strategies for the construction of single-system based discriminative sensors including dynamic combinatorial libraries, cross-reactive conjugated polymers, DNA G-quadruplex ensembles, combinatorial fluorescent molecular sensors, and fluorophore/surfactant aggregate ensembles are particularly introduced. PMID- 29974084 TI - Highly sensitive detection of nucleic acids using a cascade amplification strategy based on exonuclease III-assisted target recycling and conjugated polyelectrolytes. AB - In this paper, a novel ratiometric and cascade amplification strategy was developed by combining the unique signal amplification and effective fluorescence resonance energy transfer (FRET) property of conjugated polymers with the Exo III assisted target recycling method. The target DNA (ssDNAc) could be hybridized with the duplex-stranded probe to trigger the cyclic digestion of the probe strands and lead to the continuous release of fluorescein from the probe. The proposed strategy thus shows enhanced sensitivity toward target DNA with a detection limit of 0.38 nM, which is more sensitive than the previously reported comparable biosensors based on conjugated polyelectrolytes. Furthermore, this method exhibited an improved performance to discriminate single mismatched targets through an efficient FRET-based ratiometric detection method using a conjugated polymer as a donor and an optical transducer. More importantly, this cascade amplification approach offers the advantages of simplicity, which avoids multiple utilization of probes and complex assay steps required in traditional amplification methods. PMID- 29974085 TI - Rapid access to RNA resonances by proton-detected solid-state NMR at >100 kHz MAS. AB - Fast (>100 kHz) magic angle spinning solid-state NMR allows combining high sensitive proton detection with the absence of an intrinsic molecular weight limit. Using this technique we observe for the first time narrow 1H RNA resonances and assign nucleotide spin systems with only 200 MUg of uniformly 13C,15N-labelled RNA. PMID- 29974086 TI - Iron(ii) coordination polymer catalysed hydroboration of ketones. AB - Catalytic hydroboration of ketones with pinacolborane was achieved with a 2D iron(ii) coordination polymer (CP) of a divergent 4,2';6',4''-terpyridine (tpy) derivative under mild conditions with high efficiency. This solid iron catalyst system is more active towards the hydroboration of ketones than that of aldehydes, displaying a different trend of reactivity from known homogeneous iron hydroboration catalysts. PMID- 29974087 TI - Structural characterization and immunomodulatory activity of a novel polysaccharide from Ficus carica. AB - A novel polysaccharide (FCPW80-2) with a molecular weight of 1.21 * 105 Da was first isolated from Ficus carica through hot water extraction and several chromatographic methods. The structure of FCPW80-2 was determined by chemical and instrumental analysis. The results showed that the backbone of FCPW80-2 consists of (1->5)-linked alpha-l-Ara, (1->3,6)-linked beta-d-Man and (1->4,6)-linked beta d-Gal. The branches of FCPW80-2 consist of (1->4)-linked alpha-d-Glc and (1->3) linked beta-l-Rha terminated with (1->)-linked beta-d-Glc. In vitro immunomodulatory activity assays revealed that FCPW80-2 could markedly promote the secretion of cytotoxic molecules (NO) and cytokines (TNF-alpha and IL-6) as well as the phagocytosis of RAW264.7 macrophages. Moreover, TLR2 was found to be a pattern recognition receptor (PRR) of FCPW80-2, and its related mitogen activated protein kinases (MAPKs), including p-ERK, p-JNK and p-p38, were rapidly upregulated by FCPW80-2 in RAW264.7 macrophages. Furthermore, FCPW80-2 could not only upregulate the expression of p-p65 and p-IkappaB-alpha, but also cause the translocation of nuclear factor-kappa B (NF-kappaB) p65 from cytosol to nuclei in RAW264.7 macrophages. The results demonstrated that MAPK and NF-kappaB signalling pathways participated in FCPW80-2-induced macrophage activation and FCPW80-2 could be developed as a potential immunomodulating functional food. PMID- 29974088 TI - A study of dynamic nanoscale corrosion initiation events using HS-AFM. AB - Atomic force microscopes (AFMs) are capable of high-resolution mapping of structures and the measurement of mechanical properties on nanometre scales within gaseous, liquid and vacuum environments. The contact mode high-speed AFM (HS-AFM) developed at Bristol Nano Dynamics Ltd. operates at speeds that are orders of magnitude faster than conventional AFMs, and is capable of capturing multiple frames per second. This allows for direct observation of dynamic events in real-time, with nanometre lateral resolution and subatomic height resolution. HS-AFM is a valuable tool for the imaging of nanoscale corrosion initiation events, such as metastable pitting, grain boundary (GB) dissolution and short crack formation during stress corrosion cracking (SCC). Within this study HS-AFM was combined with SEM and FIB milling to produce a multifaceted picture of localised corrosion events occurring on thermally sensitised AISI 304 stainless steel in an aqueous solution of 1% sodium chloride (NaCl). HS-AFM measurements were performed in situ by imaging within a custom built liquid cell with parallel electrochemical control. The high resolution of the HS-AFM allowed for measurements to be performed at individual reaction sites, i.e. at specific GB carbide surfaces. Topographic maps of the sample surface allowed for accurate measurements of the dimensions of pits formed. Using these measurements it was possible to calculate, and subsequently model, the volumes of metal reacting with respect to time, and so the current densities and ionic fluxes at work. In this manner, the local electrochemistry at nanoscale reaction sites may be reconstructed. PMID- 29974089 TI - Investigation of modified nanopore arrays using FIB/SEM tomography. AB - The investigation of electrochemical processes at the interface of two immiscible electrolyte solutions (ITIES) is of great interest for sensing applications, and serves as a surrogate to the study of biological transport phenomena, e.g. ion channels. Alongside e-beam lithography, focused ion beam (FIB) milling is an attractive method to prototype and fabricate nanopore arrays that support nanoITIES. Within this contribution, we explore the capability of FIB/scanning electron microscopy (SEM) tomography to visualize the actual pore structure and interfaces at silica-modified nanoporous membranes. The nanopores were also characterized by atomic force microscopy (AFM) using ultra-sharp AFM probes to determine the pore diameter, and using scanning transmission electron microscopy (STEM) and energy dispersive X-ray (EDX) spectroscopy, providing additional information on the elemental composition of deposits within the pores. Si-rich particles could be identified within the pores as well as at the orifice that had faced the organic electrolyte solution during electrochemical deposition. The prospects of the used techniques for investigating the interface at or within FIB milled nanopores will be discussed. PMID- 29974090 TI - A magnetic resonance and electrochemical study of the role of polymer mobility in supporting hydrogen transport in perfluorosulfonic acid membranes. AB - Perfluorosulfonic acid (PFSA) materials have been used in polymer electrolyte membrane fuel cells (PEMFCs) as electrolyte materials due to their mechanical durability and high proton conductivity. To understand the fundamental chemistry at a molecular level in material performance properties, we have developed and validated method for evaluating local dynamics using 19F double-quantum solid state nuclear magnetic resonance (ssNMR) spectroscopy. The local dynamics information can be separated and analyzed in terms of fluorine interactions with respect to the different temperatures and hydration levels. The polymer side chain is proven to be more locally mobile which is reflected by the lower apparent dipolar coupling constant (Dapp) compared to the backbone. This observation agrees with the micro-phase separation morphology evolution. In the current study, different types of PFSA materials were explored and compared. The dynamics investigation of the PFSA materials has been conducted at various conditions. In operando membrane performance analyses were performed in parallel at Ballard Power Systems. PFSA membranes were prepared into membrane electrode assemblies (MEAs), with catalyst layers and gas diffusion layers. From the cyclic voltammetry measurements, the H2 crossover values were extracted. These data reveal a strong correlation between the proton conductivity and the site-specific PFSA side chain local dynamics. Moreover, a correlation was drawn between increasing side chain mobility (lower Dapp), and increased H2 permeability. The link between the fundamental dynamics study and this key PFSA performance analysis provides insight into proton transport mechanisms. PMID- 29974091 TI - Manufacture and characterization of anti-inflammatory liposomes from jumbo flying squid (Dosidicus gigas) skin phospholipid extraction. AB - The anti-inflammation properties of marine phospholipids enriched with n-3 fatty acids contribute to anti-inflammatory and inflammation-resolving mediators. Functional squid-skin (SQ) liposomes were manufactured from squid-skin phospholipids, and their anti-inflammatory effects were investigated. SQ liposomes included phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylcholine (PC), and lysophosphatidylcholine (Lyso-PC), and had an approximate diameter of 100 mm. When RAW264.7 cells were treated with the SQ liposome, no (p > 0.05) cytotoxicity was observed below a concentration of 7.5 mg mL-1. An SQ-liposome pretreatment of lipopolysaccharide (LPS)-induced RAW 264.7 cells showed decreased (p < 0.05) prostaglandin E2 (PGE2), nitric oxide (NO), interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha). The engulfment of SQ liposomes by the RAW264.7 cells resulted in lower (p < 0.05) LPS-induced intracellular levels of reactive oxygen species. Furthermore, an SQ-liposome administration ameliorated (p < 0.05) carrageenan-induced paw edema in mice. SQ liposomes may act via apoptotic mimicry to elicit the resolution of inflammation and prevent chronic inflammation-related diseases. PMID- 29974092 TI - Transition metal cations on the move: simultaneous operando X-ray absorption spectroscopy and X-ray diffraction investigations during Li uptake and release of a NiFe2O4/CNT composite. AB - We report on results of a comprehensive investigation on reaction mechanisms occurring during Li uptake and release of the composite NiFe2O4/CNT. Operando X ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) data collected simultaneously using one in situ cell allowed thorough elucidation of structural and electronic alterations happening during Li uptake. From the beginning of Li uptake, the Bragg intensity of the spinel reflections decreases which can be explained by reduction of Fe3+ ions and simultaneous movement of the Fe2+ cations from tetrahedral 8a to empty octahedral 16c sites. The reduction of Fe3+ is clearly evidenced by XAS. The occupation of tetrahedral sites by Li+ can be excluded based on results of density functional theory calculations. Increasing the Li content leads to formation of a new crystalline phase resembling a monoxide with a NaCl-like structure. The appearance of the new phase is accompanied by a steady decrease of the sizes of coherently scattering domains of the spinel and a growth of the domains of the monoxide phase. After uptake of about 2.5 Li per NiFe2O4, all Fe3+ cations are reduced to Fe2+ and the tetrahedral 8a sites are empty (XAS spectra). Careful Rietveld refinements of X ray powder patterns demonstrate that the tetrahedral 8a site is successively depleted with increasing Li content. Interestingly, the occupancy of the octahedral 16d site is also slightly reduced. Increasing the Li content beyond 2.5 Li/NiFe2O4 leads to successive reduction of the cations to very small metal particles embedded in a Li2O matrix (as evidenced by 7Li MAS NMR investigations). During Li release metallic Ni and Fe are reoxidized to Ni2+ resp. Fe3+. The cycling stability of NiFe2O4/CNT is significantly improved compared to pure NiFe2O4 or a mechanical mixture of NiFe2O4 and CNTs. PMID- 29974093 TI - Rapid "turn-on" photoluminescence detection of bisulfite in wines and living cells with a formyl bearing bis-cyclometalated Ir(iii) complex. AB - A new photoluminescence (PL) probe based on a formyl bearing bis-cyclometalated Ir(iii) complex, [Ir(ppy)2phen-CHO]+PF6- (1), is synthesized and applied to the selective detection of a bisulfite anion (HSO3-). Probe 1 is prepared using 2 phenylpyridine (ppy) as the C^N main ligand and 1,10-phenanthroline-5 carboxaldehyde (phen-CHO) as the N^N ancillary ligand. Probe 1 displayed excellent selective PL enhancement in response to HSO3- in acetic acid-sodium acetate buffer solution (pH = 5.0). The increase of PL signal is directly proportional to the concentration of HSO3- in the range of 2 MUM to 45 MUM with a detection limit of 0.9 MUM using 50 MUM probe 1 and in the range of 0.5 MUM to 6 MUM with a detection limit of 0.3 MUM using 10 MUM probe 1. More importantly, probe 1 can respond to HSO3- rapidly within 40 s. Furthermore, probe 1 was successfully applied to detect HSO3- in real white wines and the bioimaging of HSO3- in living cells. The superior properties of probe 1 make it of great potential use for studying the effects of HSO3- in other biosystems. PMID- 29974094 TI - Probing the propeller-like loops of DNA G-quadruplexes with looped-out 2 aminopurine for label-free switchable molecular sensing. AB - We report a new signal readout mechanism for DNA molecular sensing devices using ligand-free fluorogenic G-quadruplexes in which the propeller-like loops are distinguished from the diagonal and lateral loops with incorporated 2-aminopurine (2-AP, a fluorescent analogue of adenine). We study the fluorescence behavior of looped-out 2-AP in duplexes and G-quadruplexes and demonstrate that it shows better fluorescence properties in shorter loops. In particular, 2-AP in the propeller-like loops of parallel or hybrid G-quadruplexes displays a perfect fluorescence emission whereas that in the diagonal and lateral loops does not. This loop-environment-sensitive feature allows 2-AP to probe the propeller-like loops of G-quadruplexes, illustrated by an ion-tuned allosteric G-quadruplex FG9A and a (3 + 1) hybrid human telomeric DNA. In the presence of K+, FG9A folds into a parallel structure where 2-AP is in the propeller-like loops and shows a high fluorescence signal, which can probe K+ concentrations down to 25 MUM. Upon addition of Pb2+, the folded FG9A converts into an antiparallel structure which is revealed by a sharp decrease in 2-AP fluorescence, which can easily be reset with EDTA. This process is utilized to reversibly sense Pb2+ with a detection limit of 100 nM. Furthermore, its ability to probe the propeller-like loops may allow 2-AP to identify the folding topologies of unknown G-quadruplexes in human gene regions. PMID- 29974095 TI - Tetranuclear and dinuclear phenoxido bridged copper complexes based on unsymmetrical thiosemicarbazone ligands. AB - We report on the synthesis of new dinucleating phenol-based "end-off" compartmental ligands HLMeH and HLMe2 bearing two different binding sites, one bis(2-methylpyridyl)aminomethyl (BPA) and one thiosemicarbazone (TSC) site, and their corresponding copper(ii) complexes 1t and 2d. With the ligand HLMeH, a tetranuclear entity (1t) has been isolated in the solid state, whereas with HLMe2, which differs from HLMeH by a methyl substituent on the N-terminal amino group of the TSC arm, a dinuclear form (2d) is obtained. X-ray crystallography analysis shows that the nuclearity di vs. tetra is modulated by interactions between copper atoms and hydroxido bridges along with the sulphur atoms of TSC arms. From a magnetic point of view, 1t can be considered as an association of two dinuclear forms leading for both complexes to overall antiferromagnetic coupling. Analysis in acetonitrile solution of structure-property relationships has been carried out by comparing their UV/Vis, electrochemistry, ESI-MS, and NMR (variable temperature and DOSY = diffusion ordered spectroscopy) properties with trends from computational calculations (DFT). HRMAS-DOSY (High Resolution Magic Angle Spinning) NMR spectroscopy has been performed to evaluate the presence of different species in solution at room temperature. PMID- 29974098 TI - From channel proteins to industrial biomimetic membrane technology. AB - Biomimetic membrane technology, based on the use of nano-scale functional additives in the form of channel proteins or artificially made channel structures, represents an attractive way of optimizing membrane separation technology. However, the nano-scale nature of the additives inherently points to the challenge in up-scaling the membranes to square meter areas. Thus, the ability to up-scale the processes involved in manufacturing will be crucial for translating the protein/nano-science into technology. Here we discuss how highly selective aquaporin proteins can be used to enhance the performance of the classical thin film composite membrane, and how this can be used in relevant membrane elements and module form factors. A particular up-scaling challenge lies in securing large scale membrane protein production. We demonstrate our framework for making batch amounts which are compatible with the large scale production of biomimetic membranes for water purification based on the use of the E. coli expression system. PMID- 29974096 TI - Real-time determination of aggregated alpha-synuclein induced membrane disruption at neuroblastoma cells using scanning ion conductance microscopy. AB - Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder and has affected approximately one million people in the United States alone. A large body of evidence has suggested that deposition of aggregated alpha-synuclein (alpha-Syn), a brain protein abundant near presynaptic termini, in intracellular protein inclusions (Lewy bodies) results in neuronal cell damage and ultimately contributes to the progression of PD. However, the exact mechanism is still unclear. One hypothesis is that alpha-Syn aggregates disrupt the cell membrane's integrity, eventually leading to cell death. We used scanning ion conductance microscopy (SICM) to monitor the morphological changes of SH-SY5Y neuroblastoma cells and observed dramatic disruption of the cell membrane after adding alpha-Syn aggregates to the culturing media. This work demonstrates that SICM can be applied as a new approach to studying the cytotoxicity of alpha-Syn aggregates. PMID- 29974097 TI - Synthesis, in vitro cytotoxicity, and structure-activity relationships (SAR) of multidentate oxidovanadium(iv) complexes as anticancer agents. AB - Multidentate oxidovanadium(iv) complexes with different geometric configurations [VO(ox)(bpy)(H2O)] 1, [VO(ox)(phen)(H2O)] 2, [VO(ida)(bpy)].2H2O 3, (phen)[VO(ida)(phen)].4H2O 4, and (Hphen)[VO(H2O)(nta)].2H2O 5 [ox = oxalic acid, bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline, ida = iminodiacetic acid, nta = nitrilotriacetic acid] have been obtained from the reactions of oxidovanadium sulfate or vanadium pentoxide with oxalates, amino-polycarboxylates and N heterocyclic ligands in neutral solution by the hydrothermal method, and have been fully characterized by elemental, thermogravimetric analyses and single crystal X-ray diffraction, as well as a wide range of spectroscopic techniques such as FT-IR, UV/Vis, NMR, ESI-MS. The anti-tumor properties of oxidovanadium compounds 1-5 were further evaluated in human HepG2 and SMMC-7721 hepatocellular carcinoma cell lines in vitro. The profiles of cytotoxicity, cell cycle distribution, as well as cell apoptosis upon test compound exposure, were determined by MTT and flow cytometry assays. Compound 2 exhibited a much higher anti-tumor activity than others. The IC50 values of 2 were 5.34 +/- 0.034 MUM and 29.07 +/- 0.017 MUM in SMMC-7721 and HepG2 cells after 48 h treatment, respectively. Furthermore, compound 2 could significantly arrest the cell cycle in the S and G2/M phases and further induce cell apoptosis in a dose-dependent manner. The structure-activity relationship (SAR) studies revealed that structural elements, for example, metal components, variations of coordination mode, labile water molecules, chelated ligands etc., probably exert an essential cooperative effect on the antitumor activity. In short, these findings not only provide an accessible model system to exploit V-based complexes as potential simple, safe and effective multifunctional antitumor agents, but also open up a rational approach to shed new light on the selection and optimization of ideal drug candidates. PMID- 29974099 TI - 2D graphene oxide channel for water transport. AB - Layer-stacked graphene oxide (GO) membranes, in which unique two-dimensional (2D) water channels are formed between two neighboring GO nanosheets, have demonstrated great potential for aqueous phase separation. Subjects of crucial importance are to fundamentally understand the interlayer spacing (i.e. channel height) of GO membranes in an aqueous environment, elucidate the mechanisms for water transport within such 2D channels, and precisely control the interlayer spacing to tune the membrane separation capability for targeted applications. In this investigation, we used an integrated quartz crystal mass balance (QCM-D) and ellipsometry to experimentally monitor the interlayer spacing of GO, reduced GO and crosslinked GO in aqueous solution and found that crosslinking can effectively prevent GO from swelling and precisely control the interlayer spacing. We then used molecular dynamics simulations to study the mass transport inside the 2D channels and proved that the chemical functional groups on the GO plane dramatically slow down water transport in the channels. Our findings on GO structure and water transport provide a necessary basis for further tailoring and optimizing the design and fabrication of GO membranes in various separation applications. PMID- 29974100 TI - Carboxyl-functionalized nanochannels based on block copolymer hierarchical structures. AB - When building artificial nanochannels, having a scalable robust platform with controlled morphology is important, as well as having the option for final functionalization of the channels for the selective transport of water and proteins. We have previously developed asymmetric membranes that have a surface layer of very sharp pore size distribution, surface charge and pore functionalization. Here, a more complex bioinspired platform is reported. Hierarchical isotropic porous structures with spherical micrometer-sized cavities, interconnected by hexagonally ordered nanochannels, were prepared based on the phase separation of polystyrene-b-poly(t-butyl acrylate) block copolymers, following a nucleation and growth mechanism. The structure was imaged by scanning electron microscopy, which demonstrated a high density of ordered nanochannels. The hexagonal order formed by the self-assembly in solution was confirmed by small-angle X-ray scattering. The structure evolution was investigated by time resolved grazing-incidence small-angle X-ray scattering. The assembled hydrophobic hierarchical structure was then converted to a hydrophilic structure by acid hydrolysis, leading to nanochannels covered by carboxylic groups and therefore convenient for water transport. PMID- 29974101 TI - Impacts of Mn ion in ZnSe passivation on electronic band structure for high efficiency CdS/CdSe quantum dot solar cells. AB - Surface passivation in quantum dot-sensitized solar cells (QDSSCs) plays a very important role in preventing surface charge recombination and thus enhancing the power conversion efficiency (PCE). ZnSe passivation with dopant in CdS/CdSe co sensitized QDSSCs has been demonstrated as an effective way to improve the PCE. In the present study, a series of characterizations revealed that a Mn-doped ZnSe passivation layer can not only reduce surface charge recombination, but also enhance light harvesting. By means of density functional theory calculation along with a systematic study of electronic band structure, it has been found that the valence band of ZnSe moves upward on Mn-ion doping which leads to acceleration of charge separation and broader light absorption range. The impact of the Mn ion on charge recombination and light harvesting has been interpreted reasonably and the PCE of CdS/CdSe co-sensitized QDSSCs with Mn-doped ZnSe passivation layer is as high as 6.46%, which is 1.5 times that of the solar cell without the passivation layer. PMID- 29974102 TI - The effect of unadsorbed proteins on the physiochemical properties of the heteroaggregates of oppositely charged lactoferrin coated lutein droplets and whey protein isolate coated DHA droplets. AB - It was reported that the controlled heteroaggregation of oppositely charged lactoferrin (LF)-lutein droplets and whey protein isolate (WPI)-DHA droplets enhanced the physicochemical properties of emulsions. The effect of the unadsorbed proteins on the physicochemical properties of the heteroaggregates of emulsions has not been clear. Therefore, the effects of unadsorbed proteins on the physicochemical stability of heteroaggregates of LF-lutein droplets and WPI DHA droplets were investigated. The particle size, zeta-potential, transmission physical stability, microstructure were observed by confocal laser scanning microscopy (CLSM) and cryo-scanning electron microscopy (cryo-SEM) and the chemical stability (lutein degradation and DHA oxidation) of the unwashed and washed heteroaggregates were measured. The results showed that compared with unwashed emulsions, the particle sizes and instability indexes of WPI-DHA emulsions, heteroaggregated LF-lutein/WPI-DHA emulsions and LF-lutein emulsions changed after washing. The instability index of washed-1 heteroaggregated LF lutein/WPI-DHA emulsion was 10.5 times greater compared with the unwashed samples. The microstructure images showed that the washed single and heteroaggregated emulsions resulted in creaming. The unadsorbed proteins had a great protective effect on the physical stability of the emulsions, especially for the heteroaggregated LF-lutein/WPI-DHA emulsion. The degradation rate of lutein, lipid hydroperoxides and thiobarbituric acid reactive substance (TBARS) values of DHA in washed single and heteroaggregated emulsions were higher than those of the unwashed samples. This proved that the unadsorbed proteins dominated the physicochemical stabilities of heteroaggregates. This laid the foundation for the study of a delivery system of functional component heteroaggregates. PMID- 29974103 TI - Water permeation across artificial I-quartet membrane channels: from structure to disorder. AB - Artificial water channels (AWCs) have been designed for water transport across membranes with the aim to mimic the high water permeability observed for biological systems such as aquaporins (~108-109 water molecules per s per channel), as well as their selectivity to reject ion permeation at the same time. Recent works on designed self-assembling alkylureido-ethylimidazole compounds forming imidazole-quartet channels (I-quartets), have shown both high water permeability and total ionic-rejection. I-quartets are thus promising candidates for further development of AWCs. However, the molecular mechanism of water permeation as well as I-quartet organization and stability in a membrane environment need to be fully understood to guide their optimal design. Here, we use a wide range of all-atom molecular dynamics (MD) simulations and their analysis to understand the structure/activity relationships of the I-quartet channels. Four different types with varying alkyl chain length or chirality have been studied in a complex fully hydrated lipid bilayer environment at both microsecond and nanosecond scale. Microsecond simulations show two distinct behaviors; (i) two out of four systems maintain chiral dipolar oriented water wires, but also undergo a strong reorganization of the crystal shape, (ii) the two other I-quartet channels completely lose the initial organization, nonetheless keeping a water transport activity. Short MD simulations with higher time resolution were conducted to characterize the dynamic properties of water molecules in these model channels and provided a detailed hypothesis on the molecular mechanism of water permeation. The ordered confined water was characterized with quantitative measures of hydrogen-bond life-time and single particle dynamics, showing variability among I-quartet channels. We will further discuss the underlying assumptions, currently based on self-aggregation simulations and crystal patches embedded in lipid bilayer simulations and attempt to describe possible alternative approaches to computationally capture the water permeation mechanism and the self-assembly process of these AWCs. PMID- 29974104 TI - Biomimetic ion channels formation by emulsion based on chemically modified cyclodextrin nanotubes. AB - Biomimetic ion channels can be made to display the high sensitivity of natural protein nanopores and to develop new properties as a function of the material used. How to design the best future biomimetic channels? The main challenges are to control their sensitivity, as well as their syntheses, chemical modifications, insertion and lifetime in a lipid membrane. To address these challenges, we have recently designed short cyclodextrin nanotubes characterized by mass spectrometry and high-resolution transmission electron microscopy. They form non-permanent ion channels in lipid bilayers. Here we show how to improve the nanotube insertion in order to limit multiple insertions, how to stabilize biomimetic channels into the membrane, and how to understand the ion dynamics in confined medium scale. PMID- 29974105 TI - Two bifunctional desferrioxamine chelators for bioorthogonal labeling of biovectors with zirconium-89. AB - We report two bifunctional chelators, DFO-Cys and DFO-CBT, to label biovectors with zirconium-89 according to the 2-cyanobenzothiazole/1,2-aminothiol cycloaddition. Their features are high labeling yields, rapid and efficient bioconjugation, metabolically stable luciferin-based end products, and applicability to orthogonal two-step labeling of sensitive biomolecules. PMID- 29974106 TI - Nanodispersions of beta-carotene: effects on antioxidant enzymes and cytotoxic properties. AB - Beta-carotene is a carotenoid precursor of vitamin A, known for its biological activities. Due to its high hydrophobicity, nanonization processes, i.e. the transformation into nanoparticles, can improve its water affinity, and therefore the activity in aqueous systems. The objective of this study was to produce beta carotene nanoparticles by the solid dispersion method and to evaluate their effects on the activity of glutathione-S-transferase and acetylcholinesterase enzymes using Drosophila melanogaster (DM) homogenate, the superoxide dismutase- and catalase-like activities under in vitro conditions, and their cytotoxic properties against tumor and non-tumor cells. The formed nanometric beta-carotene particles resulted in stable colloids, readily dispersed in water, able to modulate acetylcholinesterase (AChE) activity, and presenting high potential to control the cholinergic system. Beta-carotene nanoparticles, at concentrations much lower than the pure pristine beta-carotene, presented in vitro mimetic activity to superoxide dismutase and altered glutathione-S-transferase activity in DM tissue. The content of hydrogen peroxide was neither affected by the nanoparticles (in aqueous solution) nor by pristine beta-carotene (in DMSO). In the cytotoxic assays, beta-carotene nanoparticles dispersed in water showed activity against four different tumor cell lines. Overall, beta-carotene nanoparticles presented significant bioactivity in aqueous medium surpassing their high hydrophobicity constraint. PMID- 29974107 TI - An evolutionary transcriptomics approach links CD36 to membrane remodeling in replicative senescence. AB - Cellular senescence, the irreversible ceasing of cell division, has been associated with organismal aging, prevention of cancerogenesis, and developmental processes. As such, the evolutionary basis and biological features of cellular senescence remain a fascinating area of research. In this study, we conducted comparative RNAseq experiments to detect genes associated with replicative senescence in two different human fibroblast cell lines and at different time points. We identified 841 and 900 genes (core senescence-associated genes) that are significantly up- and downregulated in senescent cells, respectively, in both cell lines. Our functional enrichment analysis showed that downregulated core genes are primarily involved in cell cycle processes while upregulated core gene enrichment indicated various lipid-related processes. We further demonstrated that downregulated genes are significantly more conserved than upregulated genes. Using both transcriptomics and genetic variation data, we identified one of the upregulated, lipid metabolism genes, CD36, as an outlier. We found that overexpression of CD36 induces a senescence-like phenotype and, further, the media of CD36-overexpressing cells alone can induce a senescence-like phenotype in proliferating young cells. Moreover, we used a targeted lipidomics approach and showed that phosphatidylcholines accumulate during replicative senescence in these cells, suggesting that upregulation of CD36 could contribute to membrane remodeling during senescence. Overall, these results contribute to the understanding of evolution and biology of cellular senescence and identify several targets and questions for future studies. PMID- 29974108 TI - Multiple particle tracking microrheology measured using bi-disperse probe diameters. AB - Multiple particle tracking microrheology (MPT) is a powerful tool for quantitatively characterizing rheological properties of soft matter. Traditionally, MPT uses a single particle size to characterize rheological properties. But in complex systems, MPT measurements with a single size particle can characterize distinct properties that are linked to the materials' length scale dependent structure. By varying the size of probes, MPT can measure the properties associated with different length scales within a material. We develop a technique to simultaneously track a bi-disperse population of probe particles. 0.5 and 2 MUm particles are embedded in the same sample and these particle populations are tracked separately using a brightness-based squared radius of gyration, Rg2. Bi-disperse MPT is validated by measuring the viscosity of glycerol samples at varying concentrations. Bi-disperse MPT measurements agree well with literature values. This technique then characterizes a homogeneous poly(ethylene glycol)-acrylate:poly(ethylene glycol)-dithiol gelation. The critical relaxation exponent and critical gelation time are consistent and agree with previous measurements using a single particle. Finally, degradation of a heterogeneous hydrogenated castor oil colloidal gel is characterized. The two particle sizes measure a different value of the critical relaxation exponent, indicating that they are probing different structures. Analysis of material heterogeneity shows measured heterogeneity is dependent on probe size indicating that each particle is measuring rheological evolution of a length scale dependent structure. Overall, bi-disperse MPT increases the amount of information gained in a single measurement, enabling more complete characterization of complex systems that range from consumer care products to biological materials. PMID- 29974109 TI - Exploiting the signatures of nanoplasmon-exciton coupling on proton sensitive insulator-semiconductor devices for drug discovery applications. AB - Multimodal sensing methods have a great promise in biosensing applications as they can measure independently several properties that characterise the biomolecular interaction to be detected as well as providing inherent on-chip validation of the sensing signals. This work describes the mechanisms of a concept of insulator-semiconductor field-effect devices coupled with nanoplasmonic sensing as a promising technology, which can be used for a wide range of analytical sensing applications. The developed method involves coupling of the localized surface plasmons (LSPs) within gold nanoparticles (AuNPs) and excitons within pH sensitive silicon nitride (Si3N4) nanofilms for screening inhibitors of kinase, which constitute an important class of chemotherapy drugs. In parallel to this optical sensing, the pH sensitivity of silicon nitride is used to detect the release of protons associated with kinase activity. By changing the insulator and AuNPs characteristics, this work demonstrates the nanoplasmonic-exciton effects taking place, enabling the developed platform to be used for screening kinase inhibitors and as a dual mode electro-optical biosensor for routine bio/chemical sensing applications. PMID- 29974110 TI - Impacts of glycation and transglutaminase-catalyzed glycosylation with glucosamine on the conformational structure and allergenicity of bovine beta lactoglobulin. AB - beta-Lactoglobulin (beta-LG) is recognized as the major milk allergen. In this study, the effects of transglutaminase (TGase) and glucosamine (GlcN)-catalyzed glycosylation and glycation on the conformational structure and allergenicity of beta-LG were investigated. The formations of cross-linked peptides were demonstrated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE), and GlcN-conjugated modification was identified using matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Structural analysis revealed that glycosylation and glycation of beta-LG induced unfolding of the primary protein structure followed by a loss of the secondary structure. As revealed by circular dichroism (CD) spectroscopy, glycosylated beta LG exhibited the highest increase in the beta-sheets from 32.6% to 40.4% (25 degrees C) and 44.2% (37 degrees C), and the percentage of alpha-helices decreased from 17.7% to 14.4% (25 degrees C) and 12.3% (37 degrees C), respectively. The tertiary and quaternary structures of beta-LG also changed significantly during glycosylation and glycation, along with reduced free amino groups and variation in surface hydrophobicity. Immunoblotting and indirect enzyme-linked immuno sorbent assay (ELISA) analyses demonstrated that the lowest IgG- and IgE-binding capacities of beta-LG were obtained following glycosylation at 37 degrees C, which were 52.7% and 56.3% lower than that of the native protein, respectively. The reduction in the antigenicity and potential allergenicity of glycosylated beta-LG was more pronounced compared to TGase treated- and glycated beta-LG, which correlated well with the structural changes. These results suggest that TGase-catalyzed glycosylation has more potential compared to glycation for mitigating the allergenic potential of milk products. PMID- 29974111 TI - Influence of surfactants of different nature and chain length on the morphology, thermal stability and sheet resistance of graphene. AB - The effects of surfactants of different nature (anionic, cationic and non-ionic) and chain length on the morphology, microstructure, thermal stability and electrical resistivity of liquid exfoliated graphene (G) were investigated. Microscopic (SEM and AFM) observations revealed that the thickness of G in the dispersions depended on the surfactant nature: non-ionic surfactants rendered the highest level of exfoliation, whilst dispersions in the cationic ones exhibited fully-covered thicker sheets; the flake thickness increased with increasing surfactant chain length. X-ray diffraction studies indicated an increased interlamellar G spacing with increasing surfactant content. Raman spectra showed an increase in the ID/IG ratio with decreasing G loading. Larger upshifts of the G, 2D and D + G bands were found with increasing surfactant concentration, particularly for dispersions in the cationic surfactants. For the same G/surfactant weight ratio, the electrical resistivity of the dispersions followed the order: cationic > non-ionic > anionic, consistent with the amount of surfactant adsorbed onto G calculated via TGA. It is demonstrated herein that the thermal and electrical properties of liquid exfoliated G can be tuned by varying the surfactant concentration, nature and chain length, which is of great importance for numerous applications like solar power harvesting, high temperature devices and flexible nanoelectronics. PMID- 29974112 TI - Design and synthesis of interconnected hierarchically porous anatase titanium dioxide nanofibers as high-rate and long-cycle-life anodes for lithium-ion batteries. AB - We suggest an efficient and simple synthetic strategy to prepare interconnected hierarchically porous anatase TiO2 (IHP-A-TiO2) nanofibers by two synergetic effects: phase separation between polymers and relative humidity control during electrospinning. The macro channels formed by polystyrene decomposition were interconnected by numerous mesopores that were formed by evaporation of infiltrated water vapor in the structure. The resulting IHP-A-TiO2 nanofibers showed better Li+ ion storage performances than the TiO2 materials reported in the literature. The discharge capacity of IHP-A-TiO2 nanofibers for the 3000th cycle at 1.0 A g-1 and corresponding coulombic efficiency from the 20th cycle onward were 142 mA h g-1 and >99.0%, respectively. Well-interconnected, ultrafine TiO2 nanocrystals within the nanofiber showed structural stability during cycling and facilitated facile charge transfer at the electrode-electrolyte interface. PMID- 29974113 TI - Lithium-ion storage performances of sunflower-like and nano-sized hollow SnO2 spheres by spray pyrolysis and the nanoscale Kirkendall effect. AB - Nanostructured metal selenides with a variety of morphologies are crucial for fabricating porous, hollow metal-oxide nanomaterials by nanoscale Kirkendall diffusion. Herein, SnSe-SnO2 composite powders and SnSe nanospheres were synthesized via one-pot spray pyrolysis by optimizing the concentration of the Se precursor in the spray solution; these were then used to fabricate sunflower-like SnO2 and hollow SnO2 nanospheres, respectively, via nanoscale Kirkendall diffusion. Post-treatment of the SnSe-decorated SnO2 under air produced sunflower like SnO2, in which ray and disk florets consisting of hollow nanoplates and dense nanospheres, respectively, were present. The mean diameter of the homogeneous hollow SnO2 nanospheres was 150 nm. The hollow morphology shortens the diffusion length, increasing the contact area between the electrolyte and voids and buffering large volume changes during repeated cycling. As anode materials for lithium-ion batteries, the hollow SnO2 nanospheres showed excellent cycling and rate performances. The discharge capacity of the hollow SnO2 nanospheres, after 500 cycles from 0.001 V to 3.0 V, was 1043 mA h g-1, at a current density of 3.0 A g-1. The hollow SnO2 nanospheres showed a high reversible capacity of 638 mA h g-1, even at current density as high as 10 A g-1. PMID- 29974114 TI - Different bending models predict different dynamics of sedimenting elastic trumbbells. AB - The main goal of this paper is to examine theoretically and numerically the impact of a chosen bending model on the dynamics of elastic filaments settling in a viscous fluid under gravity at low-Reynolds-number. We use the bead-spring approximation of a filament and the Rotne-Prager mobility matrix to describe hydrodynamic interactions between the beads. We analyze the dynamics of trumbbells, for which bending angles are typically larger than for thin and long filaments. Each trumbbell is made of three beads connected by springs and it exhibits a bending resistance, described by the harmonic or - alternatively - by the 'cosine' (also called the Kratky-Porod) bending models, both often used in the literature. Using the harmonic bending potential, and coupling it to the spring potential by the Young's modulus, we find simple benchmark solutions: stable stationary configurations of a single elastic trumbbell and attraction of two elastic trumbbells towards a periodic long-lasting orbit. As the most significant result of this paper, we show that for very elastic trumbbells at the same initial conditions, the Kratky-Porod bending potential can lead to qualitatively and quantitatively different spurious dynamics, with artificially large bending angles and unrealistic shapes. We point out that for the bead models of an elastic filament, the range of applicability of the Kratky-Porod model might not go beyond bending angles smaller than pi/2 for touching beads and beyond an even much lower value for beads well-separated from each other. The existence of stable stationary configurations of elastic trumbbells and a family of periodic oscillations of two elastic trumbbells are very important findings on their own. PMID- 29974115 TI - Thermomechanical properties of monodomain nematic main-chain liquid crystal elastomers. AB - Two-stage thiol-acrylate Michael addition reactions have proven useful in programming main-chain liquid crystal elastomers (LCEs). However, the influence of excess acrylate concentration, which is critical to monodomain programming, has not previously been examined with respect to thermomechanical properties in these two-stage LCEs. Previous studies of thiol-acrylate LCEs have focused on polydomain LCEs and/or variation of thiol crosslinking monomers or linear thiol monomers. This study guides the design of monodomain LCE actuators using the two stage methodology by varying the concentration of mesogenic acrylate monomers from 2 mol% to 45 mol% in stoichiometric excess of thiol. The findings demonstrate a technique to tailor the isotropic transition temperature by 44 degrees C using identical starting monomers. In contrast to expectations, low amounts of excess acrylate showed excellent fixity (90.4 +/- 2.9%), while high amounts of excess acrylate did not hinder actuation strain (87.3 +/- 2.3%). Tensile stress-strain properties were influenced by excess acrylate. Linear elastic behavior was observed parallel to the director with modulus increasing from 1.4 to 6.1 MPa. The soft elastic plateau was observed perpendicular to the director with initial modulus and threshold stresses increasing from 0.6 MPa to 2.6 MPa and 14 kPa to 208 kPa, respectively. Overall, this study examines the influence of excess acrylate on mechanical properties of LCE actuators. PMID- 29974116 TI - Mannan-oligosaccharide modulates the obesity and gut microbiota in high-fat diet fed mice. AB - The gut microbiota is considered to be associated with high-fat diet (HFD) induced obesity and metabolic syndrome (MS). Mannan-oligosaccharide (MOS) is widely used as a natural additive, and its effect on promoting fat metabolism has been reported. Here, we performed a 11-week study on C57BL/6J mice fed a high-fat diet (HFD) with/without MOS supplementation, and the results showed that MOS could attenuate high-fat diet induced metabolic syndrome, including slower body weight gain, lowered serum lipids and reduced insulin resistance. Next generation sequencing (NGS) of the gut microbiota indicated that MOS modulated the overall structure of the gut microbiome, which was highly correlated with MS parameters. Specifically, the intake of MOS decreased the Firmicutes/Bacteroidetes ratio and could reverse the changes in the relative abundance of several species caused by HFD, including Akkermansia muciniphila, Bacteroides acidifaciens, Lactobacillus gasseri and Bifidobacterium pseudolongum. Thus, MOS has the potential to be used as a new prebiotic for regulating the gut microbiota and helping in attenuating metabolic disorders. PMID- 29974117 TI - Structural characterization of a novel acidic polysaccharide from Rosa roxburghii Tratt fruit and its alpha-glucosidase inhibitory activity. AB - A novel acidic polysaccharide (RTFP-3) was isolated and purified from Rosa roxburghii Tratt fruits. Structural analyses revealed that RTFP-3 is a homogeneous polysaccharide with a molecular weight of 67.2 kDa and mainly consists of arabinose (37.20%), galactose (34.40%), glucose (10.02%) and fucose (18.30%). The structural chain of RTFP-3 was proven to be composed of ->6)-alpha d-Galp-(1->, ->4)-alpha-d-GalpA-(1->, ->5)-alpha-l-Araf-(1->, ->4)-beta-d-Glcp-(1 >, beta-d-Glcp-(1-> and ->3,4)-beta-l-Fucp-(1-> residues by periodate oxidation Smith degradation, methylation, and 1D- and 2D-NMR analyses. Bioassay results showed that RTFP-3 exerted favorable mixed type inhibitory activities against alpha-glucosidase, and its half inhibitory concentration (IC50) value was determined as 4.15 mg mL-1. RTFP-3 showed static type quenching of the intrinsic fluorescence of alpha-glucosidase, during which the binding process induced the conformational change of alpha-glucosidase. These results suggest that RTFP-3 has the potential to be a novel alpha-glucosidase inhibitory agent for use in functional foods. PMID- 29974118 TI - Playing with Pearson's concept: orthogonally functionalized 1,4-diaza-1,3 butadienes leading to heterobinuclear complexes. AB - By reacting 1,2-diketones and ortho- diphenylphosphinoyl aniline in the presence of zinc(ii) as a templating agent, cationic zinc(ii) complexes of novel phosphine oxide functionalized 1,4-diaza-1,3-butadiene ligands are acessible. Herein the zinc(ii) site is bound to all four donor atoms of the ligand. Depending on the flexibility of the 1,4-diaza-1,3-butadiene backbone, the bonds to zinc(ii) from the 1,4-diaza-1,3-butadiene donors can be broken. Reaction with oxalate cleaves the zinc(ii) coordination completely and makes accessible the free ligands possessing orthogonal (N,N: soft; O,O: hard) sets of donor sites. This allows for the specific coordination of soft and hard Lewis acids and thus for the generation of heterobimetallic complexes, here exemplarily shown for the combination of palladium(ii) (soft) and zinc(ii) (hard) centres. PMID- 29974119 TI - Immature Auditory Evoked Potentials in Children With Moderate-Severe Developmental Language Disorder. AB - Purpose: Immature auditory processing has been proposed to underlie language impairments in children with developmental language disorder (DLD; also known as specific language impairment). Using newly available normative auditory evoked potential (AEP) waveforms, we estimated AEP maturity in individual children with DLD and explored whether this maturational index was related to their language abilities. Method: AEPs were elicited by 225 trials of a 490-Hz pure tone. Using intraclass correlation and our previously established normative AEP waveforms of 7- to 10-year-old children with typical development, we estimated the age equivalent of the AEPs (AEP-age) from 21 children with DLD. The relation between AEP maturity and language was explored through regression analysis. Results: AEP age predicted 31% of the variance in the language abilities of children with DLD. The AEP-age of children with mild DLD was similar to their chronological age, whereas children with moderate-severe DLD showed, on average, a 1.3-year delay in their neural responses. AEP-age predicted receptive, but not expressive, language performance. Conclusion: Maturation in auditory neural responses is a significant predictor of language ability, particularly in children with moderate-severe DLD. PMID- 29974120 TI - Prevention of diabetic foot complications. AB - This paper discussed the importance of prevention of diabetic foot ulcers and our institution's protocol for prevention, reviewing the existing evidence in the literature regarding the effectiveness of the preventive approach. Diabetes mellitus is the second most significant cause of disease in Singapore after ischaemic heart disease. National University Hospital, Singapore, adopts a two pronged strategy for the management of diabetic foot ulcers. The most important strategy is prevention, and education is key. Education should mainly be directed at patients and caregivers, but also professionals (general practitioners, allied health professionals and nurses) so that they can effectively educate patients and caregivers. Patient education includes care of diabetes mellitus, care of the foot and use of appropriate footwear. Patients also tend to have poor foot hygiene. Annual foot screening for diagnosed diabetics plays an important role. However, prolonged and sustained government intervention is necessary to provide education and screening on a national scale. PMID- 29974121 TI - Dementia management: a brief overview for primary care clinicians. AB - With the increasing life expectancy and ageing population in Singapore, we are likely to see more patients with dementia seeking help from their primary care clinicians. Acetylcholinesterase inhibitors and N-Methyl-D-aspartate receptor antagonists for dementia management can be costly given their modest efficacy, and it is important to discuss the risks and benefits with patients before a shared decision is made. Non-pharmacological management such as regular structured routine, good sleep hygiene, reminiscence and other activities are also useful in improving the well-being of dementia patients. Caregivers and family members can be advised on what to watch out for to keep patients safe at home and outdoors, as dementia patients have poor safety awareness. The primary care clinician can manage depression, if present, and refer the patient to memory clinics or appropriate specialist clinics for further assessment when indicated. PMID- 29974122 TI - Erratum: Singapore Urological Association Clinical Guidelines for Male Lower Urinary Tract Symptoms/Benign Prostatic Hyperplasia. PMID- 29974123 TI - Acquired double pylorus. PMID- 29974124 TI - Tamsulosin-induced photosensitivity rash. PMID- 29974125 TI - Corrigendum: Approach to frailty in the elderly in primary care and the community. PMID- 29974126 TI - Clinics in diagnostic imaging (187). Popliteal artery entrapment syndrome (PAES) Type II. AB - A 26-year-old male patient was referred for exercise-induced claudication that had interfered with his military duties for the past two years. He was an occasional smoker with no other significant cardiovascular risk factors. Initial Doppler ultrasonography showed narrowing of the popliteal artery. Further evaluation with magnetic resonance angiography demonstrated a short segment occlusion of the popliteal artery secondary to an anomalous origin of the medial head of the gastrocnemius muscle from the lateral femoral condyle. Based on the clinical presentation and imaging findings, he was diagnosed with popliteal artery entrapment syndrome. In this article, we discussed the typical presenting signs and symptoms of popliteal artery entrapment syndrome, the different imaging modalities available to aid diagnosis, classification of the condition and the available treatment options. PMID- 29974128 TI - [Congenital myasthenic syndromes in adulthood : Challenging, rare but treatable]. AB - The congenital myasthenic syndromes (CMS) represent a heterogeneous group of diseases with a broad spectrum of phenotypes. The common characteristic is an inherited genetic defect of the neuromuscular junction. Although in some patients the specific gene defect remains to be detected, the increasing identification of causative genes in recent years has already provided unique insights into the functionality of structural proteins at the neuromuscular junction. Neonatal and early childhood onset is observed in most CMS subtypes; however, late onset in adolescence or adulthood also occurs and establishing the diagnosis at these stages imposes particular challenges. To enable appropriate therapeutic interventions for an at least in principle treatable condition, determining the genetic cause is warranted. In this overview, the critical clinical and diagnostic features of the different CMS subtypes are presented and illustrated using typical cases. Furthermore, specific diagnostic clues are outlined. Finally, the overlap between CMS and muscular dystrophies is discussed. Illustrating characteristic patient examples, the essential clinical and additional diagnostic findings of various CMS subtypes and special diagnostic indications are presented. PMID- 29974129 TI - [Funicular myelosis due to abuse of nitrous oxide]. PMID- 29974130 TI - Associations of intimate partner violence with screening for mental health disorders among women in urban Bangladesh. AB - OBJECTIVES: We examined the association between intimate partner violence (IPV) and screening for depression in Bangladesh, a country with high prevalence of IPV and lack of data, awareness and provider infrastructure for mental illness. METHODS: We used data from a representative sample of 11,202 women from the 2006 Bangladesh Urban Health Survey. Elements of social learning theory were used to examine the association. Additionally, we examined the interaction effect of experiencing IPV and justification of IPV on screening for mental health disorders. RESULTS: Results indicate that women who experienced IPV were significantly more likely to be screened for mental health disorders (AOR = 2.09; 95% CI = 1.86-2.34). However, the direction of this association is reversed for women who justify various forms of IPV to varying degrees. CONCLUSIONS: These findings reflect the importance of how women's perception of violence may influence their mental health. Our results indicate a counter-intuitive association, given that we found that women's justification of IPV is adaptive for them in terms of preventing symptoms of mental health problems and have potential to inform future public health policy and research. PMID- 29974127 TI - Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview. AB - Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, alpha-ketoglutarate, and ATP serve as cofactors for chromatin modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome-metabolome to speculate as to how this may influence autoimmune diseases. PMID- 29974131 TI - Barriers and facilitators to implementation of cancer treatment and palliative care strategies in low- and middle-income countries: systematic review. AB - OBJECTIVES: To appraise improvement strategies adopted by low- and middle-income countries to increase access to cancer treatments and palliative care; and identify the facilitators and barriers to implementation. METHODS: A systematic review was conducted and reported in accordance with PRISMA statement. MEDLINE, CINAHL, and the Cochrane Library databases were searched. Bias was assessed using the Standards for Quality Improvement Reporting Excellence, and evidence graded using the Australian National Health and Medical Research Council system. RESULTS: Of 3069 articles identified, 18 studied were included. These studies involved less than a tenth (n = 12, 8.6%) of all low- and middle-income countries. Most were case reports (58%), and the majority focused on palliative care (n = 11, 61%). Facilitators included: stakeholder engagement, financial support, supportive learning environment, and community networks. Barriers included: lack of human resources, financial constraints, and limited infrastructure. CONCLUSIONS: There is limited evidence on sustainable strategies for increasing access to cancer treatments and palliative care in low- and middle income countries. Future strategies should be externally evaluated and be tailored to address service delivery; workforce; information; medical products, vaccines, and technologies; financing; and leadership and governance. PMID- 29974133 TI - [Identification of rare diseases in the oral cavity]. AB - In 2013, a national action plan for people with rare diseases (Nationaler Aktionsplan fur Menschen mit Seltenen Erkrankungen, NAMSE) was adopted in the Federal Republic of Germany which is currently in the implementation phase. People with rare diseases are often confronted with huge difficulties in the diagnosis and therapy, and being repeatedly misdiagnosed also leads to psychological stress for those affected and their families. Of the up to 8000 rare diseases, about 15% can manifest in the orofacial region and thus give an indication of the underlying disease. A look in the oral cavity or consultative support to determine the cause of symptoms in the oral and maxillofacial region can possibly help the specialists in internal medicine to find the appropriate diagnosis. PMID- 29974132 TI - Neoadjuvant chemotherapy for breast cancer-background for the indication of locoregional treatment. AB - Neoadjuvant chemotherapy (NACT) has been widely adopted into the multidisciplinary management of breast cancer. The prognostic impact of treatment response has been clearly demonstrated. However, the impact of treatment response on the indication for adjuvant radiotherapy is unclear. This review summarizes important implications of NACT and treatment response on the risk of recurrence and locoregional multidisciplinary management from the standpoint of radiation oncology. PMID- 29974134 TI - [Ready for the hybrid operating room?] PMID- 29974135 TI - [Urology-quo vadis?] PMID- 29974137 TI - [Systematic literature search in PubMed : A short introduction]. AB - In order to identify current (and relevant) evidence for a specific clinical question within the unmanageable amount of information available, solid skills in performing a systematic literature search are essential. An efficient approach is to search a biomedical database containing relevant literature citations of study reports. In this article, we explain step by step how to perform a systematic literature search via PubMed (MEDLINE) by means of an example research question in the field of ophthalmology. First, we demonstrate how to translate the clinical problem into a well-framed and searchable research question, how to identify relevant search terms and how to conduct a text word search and a search with keywords in MeSH terms. We then show how to limit the number of search results if the search yields too many irrelevant hits and how to increase the number in the case of too few citations. Finally, we summarize all essential principles that guide a literature search via PubMed. PMID- 29974136 TI - Effects of osteoporosis drug treatments on cortical and trabecular bone in the femur using DXA-based 3D modeling. AB - : Effects of osteoporosis drugs on proximal femur cortical and trabecular bone were studied using dual-energy x-ray absorptiometry (DXA)-based 3D modeling method. Changes observed in this head-to-head study were consistent with those obtained using computed tomography in the literature. INTRODUCTION: The aim of the present study was to assess the effects of osteoporosis drugs on cortical and trabecular bone at the proximal femur using DXA-based 3D modeling. METHODS: We retrospectively analyzed 155 patients stratified by treatments: naive of treatment (NAIVE), alendronate (AL), denosumab (DMAB), and teriparatide (TPTD). DXA scans were performed at baseline and after treatment, and areal bone mineral density at spine and femur were measured. A software algorithm (3D-SHAPER) was used to derive 3D models from hip DXA scans and compute: trabecular and cortical volumetric BMD (vBMD), cortical thickness (Cth), and cortical surface BMD (cortical sBMD). Changes from baseline were normalized at 24 months and evaluated in terms or percentage. RESULTS: After 24 months, a non-significant decrease was observed for trabecular vBMD, Cortical sBMD, Cth, and cortical vBMD (- 2.3, - 0.8, - 0.3, and - 0.5%) in the NAIVE group. Under AL and DMAB, significant increases were observed in trabecular vBMD (3.8 and 7.3%), cortical vBMD (1.4 and 2.0%), and cortical sBMD (1.5 and 3.6%). An increase in Cth was observed in patients under DMAB (1.8%). Under TPTD, a significant increase in Trabecular vBMD was observed (5.9%) associated with a non-significant increase of Cth (+ 1%) concomitant with a decrease in cortical vBMD (- 1.1%). CONCLUSION: Results obtained in this head-to-head study are consistent with those obtained using computed tomography in the literature. DXA-based modeling techniques could complement standard DXA examination to monitor treatment effects on trabecular and cortical compartments. PMID- 29974138 TI - Technique development and measurement of cross-sectional area of the pubovisceral muscle on MRI scans of living women. AB - INTRODUCTION AND HYPOTHESIS: Measurements of the anatomic cross-sectional area (CSA) of the pubovisceral muscle (PVM) in women are confounded by the difficulty of separating the muscle from the adjacent puborectal (PRM) and iliococcygeal (ICM) muscles when visualized in a plane orthogonal to the fiber direction. We tested the hypothesis that it might be possible to measure the PVM CSA within a defined region of interest based on magnetic resonance images (MRI). METHODS: MRI scans of 11 women with unilateral PVM tears and seven primiparous women with intact muscles following elective C-section were used to identify the PVM injury zone defined by the mean location of its boundaries with the adjacent intact PRM and ICM from existing anatomic reference points using 3D Slicer and ImageJ software. Then, from the 15 or more 2-mm transverse slices available, the slice with the maximum anatomic CSA of the left and right PVM was found in 24 primiparous women with bilaterally intact muscles who had delivered via C section. RESULTS: Mean [+/- standard deviation (SD)] of the maximum left or right PVM cross-section areas for the 24 women, measured by two different raters, was 1.25 +/- 0.29 cm2 (range 0.75-1.86). The 5th, 50th, and 95th percentile values were 0.77, 1.23, and 1.80 cm2, respectively. Inter- and intrarater measurement repeatability intraclass correlation coefficients exceeded 0.89 and 0.90, respectively. CONCLUSIONS: It is possible to use MRI to identify the volume of interest with the maximum anatomic cross section of the PVM belly while minimizing the inadvertent inclusion of adjacent PRM or ICM in that measurement. PMID- 29974139 TI - [Will laparoscopic sleeve gastrectomy continue to exist as a stand-alone procedure? : A procedure critical perspective]. AB - BACKGROUND: Sleeve gastrectomy is currently the most frequently performed bariatric procedure worldwide; however, with respect to a certain need for revisional surgery (due to reflux disease or weight regain) there is an ongoing discussion about the value of sleeve gastrectomy in terms of a stand-alone procedure. OBJECTIVE: The aim of this article is to critically discuss whether sleeve gastrectomy can still be considered a stand-alone procedure. MATERIAL AND METHODS: The current literature was searched for results after sleeve gastrectomy and the recommendations regarding this procedure are discussed. RESULTS: Currently approximately 50% of primary bariatric procedures are sleeve gastrectomies, which has become a well-established stand-alone procedure. Sleeve gastrectomy leads to good mid-term results; however, the results of the Roux-en-Y gastric bypass are comparatively superior in terms of type 2 diabetes remission, control of preexisting or de novo reflux disease and weight loss. The mortality is comparable; however, the morbidity is lower after sleeve gastrectomy but there is a relevant rate of fistulas of the stapler suture. CONCLUSION: Patients considered for sleeve gastrectomy must be informed of the procedure-specific risks, including the unforeseeable need for revision or redo surgery firstly due to weight regain or failing to reach the individual therapy target and secondly for worsening of a preexisting or de novo reflux disease. PMID- 29974140 TI - [Surgical treatment of peritoneal metastases from gynecological primary tumors]. AB - BACKGROUND: The principle of surgical treatment of peritoneal metastases of ovarian cancer in the primary as well as in the recurrent disease setting includes macroscopic complete cytoreductive surgery. The addition of intraperitoneal chemotherapy after cytoreduction is currently not part of the standard treatment. OBJECTIVE: Data on intraperitoneal chemotherapy for treatment of peritoneal metastases of ovarian cancer are presented focusing on overall and progression-free survival and on morbidity and mortality rates. METHOD: PubMed search including the following terms: ovarian cancer, peritoneal metastases, cytoreduction and HIPEC. RESULTS: Randomized-controlled and non-randomized controlled trials showed that intraperitoneal chemotherapy after maximum cytoreductive surgery results in a survival benefit regarding overall and progression-free survival for primary as well as recurrent disease. Addition of HIPEC does not impact on the initiation of postoperative systemic chemotherapy. CONCLUSION: Macroscopic complete cytoreduction is the most important prognostic factor. The addition of intraperitoneal chemotherapy for the treatment of peritoneal metastases of ovarian cancer showed promising results but so far it is not accepted as a part of a multimodal treatment concept. PMID- 29974141 TI - The proportion of women with central sensitivity syndrome in gynecology outpatient clinics (GOPDs). AB - INTRODUCTION AND HYPOTHESIS: Patients in gynecology outpatient clinics (GOPDs) may present with symptoms that do not correlate well with the observed pathology and are usually labelled as having a functional disorder or medically unexplained symptoms (MUS). Underlying central sensitivity syndrome (CSS) with central sensitization (CS) as a potential mechanism may be responsible for some of their symptoms. The aim of this study is to identify the proportion of women with central sensitivity syndrome attending GOPDs. METHODS: This was a prospective study. All women attending a GOPD included in the study were asked to complete a validated Central Sensitization Inventory (CSI). The responses were graded on a Likert scale from 0 (never) to 4 (always). The total score ranges from 0 to 100. For screening purposes, a single CSI cutoff score of 40 was used to identify the group of women who may have central sensitization syndrome. RESULTS: Three hundred twenty-six women participated in the study. Overall, 123 (37%) women achieved a score above 40. This could be interpreted as these patients having increased risk of underlying central sensitization. Of these, 43 had a previously confirmed diagnosis of migraine, 55 (44%) depression, 39 (31.7%) anxiety, 11 fibromyalgia (FM), 34 irritable bowel syndrome (IBS) and 16 chronic fatigue syndrome (CFS/ME). CONCLUSIONS: Managing patients and their expectations in gynecological outpatient departments when symptoms are inconsistent with observable pathological findings is challenging. This is further complicated when patients have a concomitant central sensitivity syndrome, which can also influence the surgical outcome. Identifying these patients is a key factor for appropriate management. PMID- 29974142 TI - Normal development of sacrococcygeal centrum ossification centers in the fetal spine: a postmortem magnetic resonance imaging study. AB - PURPOSE: To describe the temporal pattern of the appearance of the S1-Co1 centrum ossification centers (COCs) and provide reference data for the S1-S5 COCs and sacral length at various gestational ages (GAs). METHODS: Postmortem magnetic resonance imaging (MRI) was performed on 71 fetuses (GA, 17-42 weeks) using the 3D dual-echo steady-state with water excitation T2 sequence in the sagittal plane. To confirm the reliability of this sequence, the MRI data were compared with the CT and histologic data obtained from two fetuses (GAs, 21 and 30 weeks). The presence or absence of each sacrococcygeal COC was recorded. Sacral length and S1-S5 COC height, sagittal diameter, transverse diameter, cross-sectional area, and volume were measured. RESULTS: All fetuses showed S1-S3 COCs by 17 weeks, S4 COCs by 19 weeks, and S5 COCs by 28 weeks. The S4, S5, and Co-1 COCs were visualized in 70 (98.59%), 51 (71.83%), and 21 (29.58%) fetuses, respectively. Sacral length, height, sagittal, and transverse diameters increased linearly, while cross-sectional area and volume increased exponentially with advancing GA. Mean growth rates of the sagittal and transverse diameters, cross sectional area, and volume, but not of height, significantly differed among the S1-S5 vertebrae. CONCLUSION: We have presented the timing of appearance of individual sacrococcygeal COCs and the age-specific, normative MRI reference values for sacral length and the morphometric parameters of the sacral COCs, which are of clinical importance in the diagnosis of congenital sacral abnormalities and skeletal dysplasia. PMID- 29974144 TI - High-throughput metabolism-induced toxicity assays demonstrated on a 384-pillar plate. AB - The US Environmental Protection Agency (EPA) launched the Transform Tox Testing Challenge in 2016 with the goal of developing practical methods that can be integrated into conventional high-throughput screening (HTS) assays to better predict the toxicity of parent compounds and their metabolites in vivo. In response to this need and to retrofit existing HTS assays for assessing metabolism-induced toxicity of compounds, we have developed a 384-pillar plate that is complementary to traditional 384-well plates and ideally suited for culturing human cells in three dimensions at a microscale. Briefly, human embryonic kidney (HEK) 293 cells in a mixture of alginate and Matrigel were printed on the 384-pillar plates using a microarray spotter, which were coupled with 384-well plates containing nine model compounds provided by the EPA, five representative Phase I and II drug metabolizing enzymes (DMEs), and one no enzyme control. Viability and membrane integrity of HEK 293 cells were measured with the calcein AM and CellTiter-Glo(r) kit to determine the IC50 values of the nine parent compounds and DME-generated metabolites. The Z' factors and the coefficient of variation measured were above 0.6 and below 14%, respectively, indicating that the assays established on the 384-pillar plate are robust and reproducible. Out of nine compounds tested, six compounds showed augmented toxicity with DMEs and one compound showed detoxification with a Phase II DME. This result indicates that the 384-pillar plate platform can be used to measure metabolism-induced toxicity of compounds in high-throughput with individual DMEs. As xenobiotics metabolism is a complex process with a variety of DMEs involved, the predictivity of our approach could be further improved with mixtures of DMEs. PMID- 29974143 TI - Pharmacodynamic interaction between intravenous nitroglycerin and oral sacubitril/valsartan (LCZ696) in healthy subjects. AB - PURPOSE: Sacubitril/valsartan (LCZ696) and nitroglycerin share the second messenger cGMP and lower blood pressure. Given the potential for co administration of both drugs in patients with heart failure, this study was designed to investigate the potential for a pharmacodynamic drug interaction affecting blood pressure. METHODS: In this double-blind, placebo-controlled, randomised, crossover study, 40 healthy subjects received sacubitril/valsartan 200 mg bid (97/103 mg bid) or placebo for 5 days. Two hours after the morning dose of sacubitril/valsartan or placebo on day 5, subjects received intravenous nitroglycerin infusion at increasing doses up to 40 MUg/min or placebo. Serial measurements of blood pressure (BP), heart rate, biomarkers and sacubitril/valsartan pharmacokinetics were conducted. RESULTS: Administration of nitroglycerin alone led to a dose- and time-dependent decrease in supine systolic BP (SBP) and diastolic BP (DBP) which was similar when nitroglycerin was co administered with sacubitril/valsartan. At the highest dose of nitroglycerin, the mean (95% CI) decrease from baseline of SBP/DBP was 19.54 (- 21.99, - 17.09)/12.38 (- 13.85, - 10.92) mmHg for nitroglycerin alone compared to 22.63 (- 25.06, - 20.21)/12.94 (- 14.38, - 11.49) mmHg when co-administered with sacubitril/valsartan. Co-administration of sacubitril/valsartan and nitroglycerin did not result in further plasma cGMP increase compared to sacubitril/valsartan alone. The co-administration of nitroglycerin and sacubitril/valsartan was safe and well tolerated and did not impact the pharmacokinetics of sacubitril/valsartan. CONCLUSIONS: The results from this study demonstrate no pharmacodynamic drug interaction between nitroglycerin and sacubitril/valsartan in healthy subjects, suggesting that no change of dose selection and escalation recommendations or clinical monitoring during nitroglycerin administration is required. PMID- 29974145 TI - Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation. AB - Tamoxifen (TAM) is commonly used for cell type specific Cre recombinase-induced gene inactivation and in cell fate tracing studies. Inducing a gene knockout by TAM and using non-TAM exposed mice as controls lead to a situation where differences are interpreted as consequences of the gene knockout but in reality result from TAM-induced changes in hepatic metabolism. The degree to which TAM may compromise the interpretation of animal experiments with inducible gene expression still has to be elucidated. Here, we report that TAM strongly attenuates CCl4-induced hepatotoxicity in male C57Bl/6N mice, even after a 10 days TAM exposure-free period. TAM decreased (p < 0.0001) the necrosis index and the level of aspartate- and alanine transaminases in CCl4-treated compared to vehicle-exposed mice. TAM pretreatment also led to the downregulation of CYP2E1 (p = 0.0045) in mouse liver tissue, and lowered its activity in CYP2E1 expressing HepG2 cell line. Furthermore, TAM increased the level of the antioxidant ascorbate, catalase, SOD2, and methionine, as well as phase II metabolizing enzymes GSTM1 and UGT1A1 in CCl4-treated livers. Finally, we found that TAM increased the presence of resident macrophages and recruitment of immune cells in necrotic areas of the livers as indicated by F4/80 and CD45 staining. In conclusion, we reveal that TAM increases liver resistance to CCl4-induced toxicity. This finding is of high relevance for studies using the tamoxifen inducible expression system particularly if this system is used in combination with hepatotoxic compounds such as CCl4. PMID- 29974146 TI - The influence of obstacles on grasp planning. AB - When reaching to grasp for an object in the absence of obstacles, the choice of contact points is highly consistent within and between healthy humans, suggesting a preplanning of grasping movements (Gilster et al. in Exp Brain Res 217:137-151, 2012). In real life, objects may obstruct the favored contact points at a target object, requiring adjustments to avoid collision. In the present study, we investigated how an obstacle that directly obstructs the favored contact points for two-digit grasping changes the planning and execution of reach-to-grasp movements. Furthermore, we elucidated to what extent an obstacle placed at various angular positions around the target object (thereby not directly obstructing the favored contact points) still influences trajectories, contact points, and time-related parameters. When obstacles directly obstructed favored contact points participants either chose a completely new contact point or grasped the object only slightly away from the favored contact point. Obstacles located near the favored contact points but not directly obstructing them still resulted in a repulsive effect, meaning that contact points were shifted away from the obstacle to ensure sufficient distance to the obstacle. We found that the position of an obstacle even influences the direction in which the fingers set off. This leads to a deviation of the trajectory very early in the time course, yielding longer movement times if the main contact points are obstructed. Taken together, the early significant influence of obstacles on the grasping movement supports the assumption that grasping movements are preplanned. PMID- 29974147 TI - Coherence in general and personal semantic knowledge: functional differences of the posterior and centro-parietal N400 ERP component. AB - A growing body of scientific literature investigated the difference between general and personal semantic knowledge. In contrast to general world knowledge, personal semantics comprises highly individual knowledge about oneself. The present study aimed to differentiate processes of integration into personal as opposed to general semantic knowledge. For that purpose, participants were presented with pictures of themselves (Self-condition) or unknown persons (Other condition) superimposed on a congruent or incongruent background. We hypothesized that self-referential processing is based on automatic retrieval of personal information as opposed to the processing of unknown persons, which requires voluntary, i.e., strategic, attention demanding processing. The topography of the N400 effect varied as a function of the type of semantic knowledge. We found a centro-parietal N400 effect within the Self-condition and a posterior effect within the Other-condition. The voluntary integration of facial expressions of unknown persons within the Other-condition was, furthermore, indexed by an N170 effect. The unresolved tension in personal semantics was reflected by the N500. Our study thus provides new impulses for interpretation of the N400's functional properties and extends our knowledge about the N500. Implications for the functional properties of the self as an organizational structure are discussed. PMID- 29974148 TI - Supportive effect of interferential current stimulation on susceptibility of swallowing in guinea pigs. AB - Sensory-motor control of the pharyngeal swallow requires sensory afferent inputs from the pharynx and larynx evoked by introducing bolus into the pharynx. Patients with reduced sensitivity of the pharynx and larynx are likely to have a swallowing impairment, such as pre-swallow aspiration due to delayed swallow triggering. Interferential current stimulation applied to the neck is thought to improve the swallowing function of dysphagic patients, although the mechanism underlying the facilitatory effect of such stimulation remains unknown. In the present study, we examined the changes in the elicitability of swallowing due to the stimulation and the responses of the swallowing-related neurons in the nucleus tractus solitarius and in the area adjacent to the stimulation in decerebrate and paralyzed guinea pigs. The swallowing delay time was shortened by the stimulation, whereas the facilitatory effect of eliciting swallowing was attenuated by kainic acid injection into the nucleus tractus solitarius. Approximately half of the swallowing-related neurons responded to the stimulation. These data suggest that the interferential current stimulation applied to the neck could enhance the sensory afferent pathway of the pharynx and larynx, subserving excitatory inputs to the neurons of the swallowing pattern generator, thereby facilitating the swallowing reflex. PMID- 29974149 TI - Feasibility study of a candidate reference material for ions in PM2.5: does commutability matter also for inorganic matrices? AB - The existing Air Quality Directive 2008/50/EC establishes within the European Union (EU) member states limit values for fine air particulate matter (PM2.5) including the possibility to discount natural sources of pollution when assessing compliance with the legislation. In proving this, EU member states shall determine, amongst others, the rural background concentration of some anions (Cl , NO3- and SO42-) and cations (Na+, NH4+, K+, Ca2+ and Mg2+). To deliver reliable data and to comply with the data quality objectives of the legislation, environmental control laboratories should use certified reference materials (CRMs) to validate or verify the performance of their analytical methods. Since no CRMs for anions and cations in PM2.5 are presently available, we present the commutability issues encountered during the first attempt to develop such a material. We demonstrate that a dust, collected in a road tunnel and previously used for the production of two CRMs of a PM10-like material, does not behave as an authentic fine particulate matter collected according to EN12341:2014 when measured by an established method proposed by the European Committee for Standardization (CEN/TR 16269:2011). The water-soluble fractions of SO42-, NH4+, K+, Ca2+ and Mg2+ in a PM2.5-like candidate CRM produced from that road tunnel dust are only fully extracted after 3 h of sonication and not after 30 min, as stated in the method. Moreover, we found that the particle size of the test material influenced the extraction yield of K+, Ca2+ and Mg2+, suggesting that these ionic species were incorporated in the core of the particles and inaccessible to the extraction procedure. These particular features make the material unsuitable for the measurements of ions with the CEN method. The difference in the extraction time can be seen as a commutability issue and the candidate CRM should be considered as not commutable with routine samples. This demonstrates that commutability studies should not only be considered for clinical CRMs, but also for inorganic CRMs when they are intended to be used to quantify operationally defined analytes. PMID- 29974150 TI - Sheathless coupling of microchip electrophoresis to ESI-MS utilising an integrated photo polymerised membrane for electric contacting. AB - In this article, we present a novel approach for the sheathless coupling of microchip electrophoresis (MCE) with electrospray mass spectrometry (ESI-MS). The key element is an ion-conductive hydrogel membrane, placed between the separation channel and an adjacent microfluidic supporting channel, contacted via platinum electrodes. This solves the persistent challenge in hyphenation of mass spectrometry to chip electrophoresis, to ensure a reliable electrical connection at the end of the electrophoresis channel without sacrificing separation performance and sensitivity. Stable electric contacting is achieved via a Y shaped supporting channel structure, separated from the main channel by a photo polymerised, ion permeable hydrogel membrane. Thus, the potential gradient required for performing electrophoretic separations can be generated while simultaneously preventing gas formation due to electrolysis. In contrast to conventional make-up or sheathflow approaches, sample dilution is also avoided. Rapid prototyping allowed the study of different chip-based approaches, i.e. sheathless, open sheathflow and electrode support channel designs, for coupling MCE to ESI-MS. The performance was evaluated with fluorescence microscopy and mass spectrometric detection. The obtained results revealed that the detection sensitivity obtained in such Y-channel chips with integrated hydrogel membranes was superior because sample dilution or loss was prevented. Furthermore, band broadening is reduced compared to similar open structures without a membrane. PMID- 29974151 TI - Employing proteomics to understand the effects of nutritional intervention in cancer treatment. AB - Lifestyle optimizations are implementable changes that can have an impact on health and disease. Nutrition is a lifestyle optimization that has been shown to be of great importance in cancer initiation, progression, and metastasis. Dozens of clinical trials are currently in progress that focus on the nutritional modifications that cancer patients can make prior to and during medical care that increase the efficacy of treatment. In this review, we discuss various nutritional inventions for cancer patients and the analytical approaches to characterize the downstream molecular effects. We first begin by briefly explaining the many different forms of nutritional intervention currently being used in cancer treatment as well as their motivating biology. The forms of nutrient modulation described in this review include calorie restriction, the different practices of fasting, and carbohydrate restriction. The review then shifts to explain how proteomics is used to determine biomarkers of cancer and how it can be utilized in the future to determine the metabolic phenotype of a tumor, and inform physicians if nutritional intervention should be recommended for a cancer patient. Nutrigenomics aims to understand the relationship of nutrients and gene expression and can be used to understand the downstream molecular effects of nutrition restriction, partially through proteomic analysis. Proteomics is just beginning to be used as cancer diagnostic and predictive tools. However, these approaches have not been used to their full potential to understand nutritional intervention in cancer. Graphical abstract ?. PMID- 29974152 TI - Determination of the beta-glycosylate fraction of contaminants of emerging concern in lettuce (Lactuca sativa L.) grown under controlled conditions. AB - The uptake of a large variety of contaminants of emerging concern (CECs) by crops has already been reported, and the occurrence of phase II metabolites or conjugates has only been detected in plant cell cultures. However, the extent of their formation under cropping conditions is largely unknown. In this study, an analytical strategy to assess the conjugation of 11 CECs in lettuce (Lactuca sativa L.) irrigated with different concentrations (0, 0.05, 0.5, 5, and 50 MUg L 1) of CECs was developed. The methodology involved enzymatic digestion with beta glucosidase to obtain the total fraction (free form + conjugates) of CECs. The conjugation fraction was then obtained based on the difference. The highest extent of conjugation (i.e., 27 to 83%) was found with the most hydrophobic compounds, such as bisphenol A, carbamazepine, methyl paraben, and triclosan. So, the CEC conjugate fraction cannot be neglected in the estimate of human daily intake. PMID- 29974154 TI - Correction to: Monitoring dynamic release of intracellular hydrogen peroxide through a microelectrode based enzymatic biosensor. AB - The authors would like to call the reader's attention to the fact that unfortunately Alberto Pasquarelli's and Kay-Eberhard Gottschalk's affiliations were wrong in the original publication. PMID- 29974153 TI - Headspace analysis for screening of volatile organic compound profiles of electronic juice bulk material. AB - The use of electronic nicotine delivery systems continues to gain popularity, and there is concern for potential health risks from inhalation of aerosol and vapor produced by these devices. An analytical method was developed that provided quantitative and qualitative chemical information for characterizing the volatile constituents of bulk electronic cigarette liquids (e-liquids) using a static headspace technique. Volatile organic compounds (VOCs) were screened from a convenience sample of 146 e-liquids by equilibrating 1 g of each e-liquid in amber vials for 24 h at room temperature. Headspace was transferred to an evacuated canister and quantitatively analyzed for 20 VOCs as well as tentatively identified compounds using a preconcentrator/gas chromatography/mass spectrometer system. The e-liquids were classified into flavor categories including brown, fruit, hybrid dairy, menthol, mint, none, tobacco, and other. 2,3-Butanedione was found at the highest concentration in brown flavor types, but was also found in fruit, hybrid dairy, and menthol flavor types. Benzene was observed at concentrations that are concerning given the carcinogenicity of this compound (max 1.6 ppm in a fruit flavor type). The proposed headspace analysis technique coupled with partition coefficients allows for a rapid and sensitive prediction of the volatile content in the liquid. The technique does not require onerous sample preparation, dilution with organic solvents, or sampling at elevated temperatures. Static headspace screening of e-liquids allows for the identification of volatile chemical constituents which is critical for identifying and controlling emission of potentially hazardous constituents in the workplace. PMID- 29974155 TI - Ionic liquids on optical sensors for gaseous carbon dioxide. AB - This work presents a study on the influence of eight different ionic liquids (ILs) in the composition of dry membranes used for gaseous CO2 optical sensing. The presence of CO2 causes a displacement of a colorimetric pH indicator toward its acid form that increases the emission intensity of the luminophore by an inner filter process. The influence of ILs in the membrane on the stability and dynamic behavior-usually the main drawbacks of these sensors-of the membranes is studied. The characterization of the different membranes prepared was carried out and the discussion of the results is presented. In all cases, the response and recovery times improved considerably, with the best case being response times of only 10 s and recovery times of 48 s, compared to response and recovery times of 41 and 100 s, respectively, for membranes without IL. The useful life of the detection membranes is also considerably longer than that of membranes that do not include IL, at least 292 days in the best case. The sensing membrane without luminophore and only containing the pH indicator is proposed for the color-based measurement of CO2 using a digital camera for possible use in food-packaging technology. Graphical abstract ?. PMID- 29974156 TI - Phylogenetic diversity and metabolic potential of microbiome of natural healing clay from Chamliyal (J&K). AB - Clay therapy for skin disease treatment is an ancient practice popular worldwide as a cheap alternative to pharmaceutical products. Effectiveness of clay against skin problems has been linked to its mineral composition and to microbial activity. The clay-water paste of a holy shrine Chamliyal in the Jammu region of J&K, India is used as an ointment to treat different skin disorders particularly psoriasis. Using the 16 SrDNA amplicon pyrosequencing and whole-metagenome direct shotgun Illumina sequencing, microbial phylogeny and potential metabolic functions were catalogued for Chamliyal's clay. Microbial diversity profile of the Chamliyal's clay is similar to other medicinal clays, particularly Dead Sea; there is some uniqueness as well. Although Proteobacteria, Actinomycetes and Firmicutes are common inhabitants of all the clay types, sulphur- and iron reducing bacteria like Deferribacterales are particular to clays used for skin healing. In the present study it is proposed that healing properties of clay may be due to the microbes and microbial genes associated with metabolism of minerals like iron and sulphur, that lead to mineral acquisition in the Chamliyal's clay. PMID- 29974157 TI - Investigation of Yersinia pestis and Yersinia pseudotuberculosis strains from Georgia and neighboring countries in the Caucasus by high-density SNP microarray. AB - Yersinia pestis, the causative agent of plague, is a recently evolved clone of the enteropathogenic bacterium Yersinia pseudotuberculosis. Y. pestis has been extensively studied for decades; however, there are insufficient data about the intra-species diversity of this microorganism in certain parts of the world, including the Caucasus region. Using a high-density single-nucleotide polymorphism (SNP) microarray, we genotyped a total of 46 Y. pestis isolates from two plague foci in Georgia and neighboring Caucasus countries together with 12 Y. pseudotuberculosis isolates from Georgia. The genotyping microarray captured a total of 13,525 SNP positions across the Y. pestis and Y. pseudotuberculosis genomes and plasmids with high-throughput capability and superior reproducibility. From this analysis, we confirmed the presence of two independent and relatively distant phylogenetic groups of Y. pestis in the Caucasus region. The signature SNP patterns identified from this study will allow assay development for plague surveillance and pseudotuberculosis diagnostics. PMID- 29974158 TI - Aliibacillus thermotolerans gen. nov., sp. nov.: a thermophilic and heterotrophic ammonia-oxidizing bacterium from compost. AB - A novel moderately thermophilic and heterotrophic ammonia-oxidizing bacterium, designated strain BM62T, was isolated from compost in the thermophilic stage in Harbin, China. Phylogenetic analysis based on the 16S rRNA gene indicated that strain BM62T belongs to the family Bacillaceae within the class Bacilli and was most closely related to Alteribacillus iranensis X5BT (only 94.6% sequence similarity). Cells of strain BM62T were Gram-positive, rod-shaped, motile by periflagella, catalase-positive and oxidase-negative. Growth of strain BM62T was observed at salinities of 0-4% (optimum 2-3%), temperatures of 35-65 degrees C (optimum 50 degrees C) and pH values of 5-9 (optimum pH 7). The major cellular fatty acid was iso-C16:0, and the predominant ubiquinone was MK-7. The peptidoglycan type is A1gamma, and meso-diaminopimelic acid was the diagnostic diamino acid. The major polar lipids were diphosphatidylglycerol, phospholipid and phosphatidylglycerol. The G + C content of its genomic DNA was 36.5 mol%. Data from this polyphasic taxonomy study suggested that strain BM62T should be classified as the type strain of the type species of a new genus within the family Bacillaceae for which the name Aliibacillus thermotolerans gen. nov., sp. nov. is proposed. The type strain of the species Aliibacillus thermotolerans sp. nov. is BM62T (= DSM 101851T = CGMCC 1.15790T). The respective DPD Taxon Number is GA00057. PMID- 29974159 TI - Buttiauxella chrysanthemi sp. nov., isolated from a chrysanthemum plantation in Brazil. AB - A novel Gram-negative, rod-shaped, non-motile bacterium, designated C1BT was isolated from a soil sample of a chrysanthemum plantation in Campinas, Brazil. Strain C1BT formed white colonies on BHI medium, it produces acid from D-lactose, D-mannose, D-arabinose, but does not produce from D-adonitol, m-inositol, D melibiose, D-raffinose and D-sorbitol and it is negative for lysine and ornithine decarboxylase, phenylalanine deaminase, and citrate. Phylogenetic analysis based on 16S rRNA and rpoB genes sequences showed that strain C1BT has a similarity of 98.2 and 96.8% with different species of Buttiauxella genus. Major fatty acids were C16:0, summed features 4 (C16:1 omega7c and iso-C15:0 2OH), summed features 7 (C18:1 omega7c, C18:1 omega9t, and/or C18:1 omega12t), C17:0 cyclo, summed features 3 (iso-C16:1 I and C14:0 3OH) and C14:0. The mole percent of G+C was 49.6 mol%. Based on these results, a new species Buttiauxella chrysanthemi is proposed. The type strain is C1BT (= CPQBA 1120/15T = CMRVSP5791T). PMID- 29974160 TI - [Malformations and anomalies of the central nervous system]. PMID- 29974162 TI - [The minimally invasive AMIS technique for total hip replacement : Video article]. AB - OBJECTIVE OF THE SURGERY: Minimally-invasive implantation of a total hip arthroplasty without damage to or incision of muscles. INDICATIONS: Osteoarthritis, femoral neck fracture, general indications for total hip arthroplasty. CONTRAINDICATIONS: Contraindications for hip arthroplasty. SURGICAL TECHNIQUE: The surgical technique is demonstrated in detail with the help of a video of the surgical procedure, which is available online: positioning on a fracture table with a special leg holder, anterior approach between tensor fasciae latae and rectus femoris muscle, incision of hip capsule and capsular protection, osteotomy of femoral neck in situ, removal of femoral head and acetabular reaming, minimally invasive implantation of acetabular cup, release of pubofemoral ligament and-if necessary-ischiofemoral ligament, external rotation and hyperextension in leg holder with elevation of the proximal femur by a hypomochlion, femoral preparation and implantation of femoral implant, reposition, capsular suture, wound closure. FOLLOW-UP: Weight-bearing as tolerated, free movement without limitation of range of motion. EVIDENCE: Randomized trials and systematic reviews report faster rehabilitation with early mobilization, within the first 3 months after surgery; less postoperative pain, less muscle damage and shorter hospital stay; older patients benefit from reduced morbidity and mortality. PMID- 29974163 TI - [Atypical distal tibial shaft fractures in a patient with bilateral TKA and antiresorptive treatment]. AB - There are many cases in the literature that describe atypical femur fractures under antiresorptive therapy. Other localizations of fractures of this genesis, especially if occurring bilaterally, are rare. This case reports about the diagnosis, treatment and process of a 76-year old patient, who within a 4-month period suffered from bilateral distal tibial shaft fractures, after years of treatment with bisphosphonates, strontium ranelate and denosumab. PMID- 29974164 TI - Toxicity of Diclofenac: Cadmium Binary Mixtures to Algae Desmodesmus subspicatus Using Normalization Method. AB - Algal test using chlorococcal algae Desmodesmus subspicatus was used to determine single acute toxicity of either diclofenac or cadmium and to assess acute toxicity of their binary mixtures. The test confirmed significant acute toxicity of both diclofenac and cadmium; diclofenac with acute toxicity ErC50 60.44 +/- 0.20 mg/L and cadmium with acute toxicity ErC50 2.14 +/- 0.02 mg/L. This study of acute toxicity of binary cadmium-diclofenac mixtures confirmed their negative effects on aquatic producers and it also proved influence of the above substances on acute toxicity of their mixtures. Normalization method was applied to predict acute toxicity of binary mixtures composed of chemicals with significantly different acute toxicities. Normalization method used molar ratio (R) of chemicals in binary mixtures as their composition descriptor. PMID- 29974165 TI - Response of Taste and Odor Compounds to Elevated Cyanobacteria Biomass and Temperature. AB - Taste and odor (T&O) compounds are frequently reported during black blooms, however, their production mechanisms and influencing factors are far from clear. In this study, laboratory simulation experiment was carried out to investigate the formation processes of T&O compounds under the influences of temperature, cyanobacteria biomass and their combined effects. The decay of cyanobacteria blooms caused increased T&O compounds loading to water. Results showed the maximum dimethyl sulfide (DMS) release concentration was observed at 35 degrees C compared with that at 25 and 30 degrees C. DMS release concentration under cyanobacteria biomass of 25000 g/m3 demonstrated the highest production, whereas the minimum DMS production were obtained under 7500 g/m3. Similar patterns were observed for dimethyl disulfide, dimethyl trisulfide, beta-cyclocitral and beta ionone production. Therefore, higher temperature and higher cyanobacteria biomass can enhance the concentration of T&O compounds. Furthermore, there were synergistic effects of cyanobacteria biomass and temperature on the production of T&O compounds. PMID- 29974166 TI - Suitability Assessment of Surface Water Quality with Reference to Drinking, Irrigation and Fish Culture: A Human Health Risk Perspective. AB - A multi-purpose Water Quality Index (WQI) was developed to assess the suitability of surface water for drinking, fish-culture, as well as irrigation in Durgapur industrial city, India. WQI was calculated for 48 sampling locations, where 2.08%, 4.17% and 22.91% of the sampling locations have excellent water quality (WQI: 0-25) and 20.83%, 33.33% and 34.35% have good quality (WQI: 25-50), which represents its suitability for drinking, irrigation, and fish-culture respectively. Further, health risk was evaluated by Hazard Index (HI), which reflected that the population were prone to risk on oral ingestion [HI (female): 1.52; HI (male): 1.29], while safe for dermal contact (HI < 1). Potent toxic pollutants like Co, F, Mn, NO3 were identified to cause health hazards. The pollutants were attributed to rock-weathering, industries, agriculture and municipal sources, was investigated by factor analysis. This novel assessment technique with integration of geographical information system affirmed its effectiveness and easiness to evaluate water quality for multiple uses in any area. PMID- 29974167 TI - Tibiofemoral conformity variation offers changed kinematics and wear performance of customized posterior-stabilized total knee arthroplasty. AB - PURPOSE: Posterior-stabilized (PS)-total knee arthroplasty (TKA) can be applied in any of several variations in terms of the tibiofemoral conformity and post-cam mechanism. However, previous studies have not evaluated the effect of the condylar surface radii (tibiofemoral conformity) on wear in a customized PS-TKA. The present study involved evaluating the wear performance with respect to three different conformities of the tibiofemoral articular surface in a customized PS TKA by means of a computational simulation. METHODS: An adaptive computational simulation method was developed that conduct wear simulation for tibial insert to predict kinematics, weight loss due to wear, and wear contours to results. Wear predictions using computational simulation were performed for 5 million gait cycles with force-controlled inputs. Customized PS-TKA designs were developed and categorized as conventional conformity (CPS-TKA), medial pivot conformity (MPS TKA), and anatomical conformity (APS-TKA). The post-cam design in the customized PS-TKA is identical. We compared the kinematics, contact mechanics, and wear performance. RESULTS: The findings revealed that APS-TKA exhibited the highest internal tibial rotation relative to other TKA designs. Additionally, the higher contact area led to there being less contact stress although it did not directly affect the wear performance. Specifically, MPS-TKA exhibited the lowest volumetric wear. CONCLUSIONS: The results of the present study showed that tibiofemoral articular surface conformity should be considered carefully in customized PS-TKA design. Different wear performances were observed with respect to different tibiofemoral conformities. Even though APS-TKA exhibited an inferior wear performance compared to MPS-TKA, it proved to be better in terms of kinematics so its functionality may be improved through the optimization of the tibiofemoral articular surface conformity. Additionally, it should be carefully designed since any changes may affect the post-cam mechanism. PMID- 29974168 TI - Cutaneous infection with Mycobacterium abscessus. PMID- 29974169 TI - Conflicts of interest in critical care partnerships: are we living up to our values? PMID- 29974170 TI - An unusual drain in the pleural cavity: iatrogenic pneumothorax due to pulmonary misplacement of a nasogastric tube. PMID- 29974171 TI - Acute sensory and motor response to 45-s heavy isometric holds for the plantar flexors in patients with Achilles tendinopathy. AB - PURPOSE: The purpose of this study was to explore the immediate effects of heavy isometric plantar flexor exercise on sensory output (pain during a functional task and mechanical pain sensitivity) and motor output (plantar flexor torque) in individuals with Achilles tendinopathy. METHODS: Sixteen subjects with Achilles tendinopathy participated in the study, mean (SD) age 48.6 (8.9) years and Victorian institute assessment-Achilles (VISA-A) score 61.3 (23.0). Sensory testing assessing pain during a functional task, mechanical pain sensitivity and motor output, and plantar flexor peak torque was completed prior to the intervention. All subjects completed a 45-s heavy isometric plantar flexor contraction and were then re-tested using the same sensory and motor tests. Motor output was assessed using isokinetic dynamometry at speeds previously identified as of interest in subjects with Achilles tendinopathy. RESULTS: Only 9 of the 16 subjects experienced pain during a functional task, self-reported pain was 4.2 (1.9) numerical rating scale (NRS) pre-intervention and 4.9 (3.2) NRS postintervention (n.s.). Mechanical pressure sensitivity was 446.5 (+/- 248.5) g/mm2 pre-intervention and 411.8 (+/- 211.8) g/mm2 post-intervention (n.s.). Mean concentric plantar flexor torque at 90 and 225 degrees /s was 47.1 (14.5) and 33.6 (11.6) Nm, respectively, pre-intervention and 53.0 (18.5) and 33.4 (6.6) Nm post-intervention (p = 0.039 and n.s.). Eccentric torque at 90 degrees /s was 98.5 (34.2) Nm preintervention versus 106.0 (41.4) Nm post-intervention (n.s.). CONCLUSION: In this exploratory study, patients with Achilles tendinopathy had a varied sensory and motor output response to heavy isometric contractions. Using the recommended approach of heavy 45-s isometric contractions did not offer a meaningful acute benefit for sensory or motor output for subjects with Achilles tendinopathy. Based on this study, heavy 45-s isometric contractions cannot be recommended for immediate pain relief or improved motor output for patients with Achilles tendinopathy. LEVEL OF EVIDENCE: IV, prospective cohort study. PMID- 29974172 TI - PROMIS: a valid and efficient outcomes instrument for patients with ACL tears. AB - PURPOSE: The current study compares the Patient Reported Outcomes Information System Physical Function Computer Adaptive Test (PROMIS PF CAT) to traditional knee PRO instruments in a healthy population undergoing surgery for ACL injuries with the following objectives: (1) identify and determine the strength of any correlations between the scores of PROMIS PF CAT and current knee PROs or their subscales that measure physical function; (2) evaluate PROMIS PF CAT's test burden; and (3) determine if PROMIS PF CAT has any floor or ceiling effects in this population. METHODS: Patients indicated for ACL surgery completed the Short Form-36 Physical Function (SF-36 PF), Knee Injury and Osteoarthritis Outcome Score (KOOS), Marx Knee Activity Rating Scale (Marx), the EuroQol 5-dimensions Questionnaire (EQ-5D), and PROMIS PF CAT. Correlations between PROs were defined as follows: High (>= 0.7); high-moderate (0.61-0.69); moderate (0.4-0.6); moderate-weak (0.31-0.39); and weak (<= 0.3). Floor or ceiling effects were considered significant if 15% or more patients reported the lowest or highest possible total score, respectively. RESULTS: 100 patients participated with a mean age of 26 years (range 11-57). The PROMIS PF CAT demonstrated high correlations with SF-36 PF (r = 0.82, p < 0.01), EQ-5D (r = - 0.70, p < 0.01) KOOS ADL (r = 0.74, p < 0.01), and KOOS Sport (r = 0.70, p < 0.01). There were no ceiling or floor effects for PROMIS PF CAT (0%). The mean number of items completed for the PROMIS PF CAT was 4.2 (median 4; range 4-11). CONCLUSIONS: The PROMIS PF CAT shows a high correlation with commonly employed PROs that also measure physical function with low test burden and without ceiling effects in this relatively young and healthy population. PMID- 29974173 TI - No difference between full thickness and partial thickness quadriceps tendon autografts in anterior cruciate ligament reconstruction: a systematic review. AB - PURPOSE: The purpose of this review was to compare outcomes and complication profiles of anterior cruciate ligament reconstruction (ACL-R) between full thickness (FT-Q) and partial thickness (PT-Q) quadriceps tendon (QT) autografts. METHODS: As per PRISMA guidelines, PubMed, EMBASE, and MEDLINE were searched in September 2017 for English language, human studies of all levels of evidence on patients undergoing primary ACL-R with FT-Q or PT-Q. This search was repeated in March 2018 to capture additional articles. Data regarding postoperative outcomes and complications were abstracted. Due to heterogeneous reporting, data were not combined in meta-analysis and were summarized descriptively. RESULTS: Upon screening 3670 titles, 18 studies satisfied inclusion/exclusion criteria. The second search identified an additional two studies for a total of 20 studies (50% case-control, 50% case series). These studies examined 1212 patients (1219 knees) of mean age 29.8 years (range 15-59) followed a mean of 42.2 months (range 12 120). FT-Q and PT-Q autografts were used in eight studies (50.5% of knees), and thirteen studies (49.5% of knees), respectively. Only one study directly compared FT-Q to PT-Q. Instrumented laxity was less than 3 mm in 74.8 and 72.4% of the FT Q and PT-Q groups, respectively. Postoperative IKDC Subjective Knee Form scores were similar between the FT-Q (82.5) and PT-Q (82.1) groups. Postoperative quadriceps strength, measured as a percentage of the contralateral side, were similar in the FT-Q (89.5%) and PT-Q (85.1%) groups. Graft failure rates for the FT-Q and PT-Q groups were 3.7 and 3.0%, respectively. CONCLUSION: Across the 20 studies included in this review, there appeared to be no difference in outcomes or complications between either FT-Q or PT-Q in primary ACL-R. Moreover, primary ACL-R using QT autografts appears to have successful outcomes with a low rate of graft failure, irrespective of tendon thickness. While further comparative studies are needed to better delineate the optimal thickness of quadriceps tendon for primary ACL-R, these data suggest that, in primary ACL-R, either FT-Q or PT-Q is efficacious and, in the clinical setting, surgeons may be justified in using either graft thickness. LEVEL OF EVIDENCE: IV, Systematic Review of Level III and IV studies. PMID- 29974174 TI - High heterogeneity in in vivo instrumented-assisted patellofemoral joint stress testing: a systematic review. AB - PURPOSE: Summarize the in vivo instrumented-assisted patellofemoral evaluation methods for quantifying the patellar mobility in response to a known external force. METHODS: A systematic review using PubMed, EMBASE, Cochrane Library, and SPORTDiscus electronic databases was conducted to search for studies reporting in vivo instrumented-assisted patellofemoral evaluation of patellar mobility. Searches were conducted in duplicate up to October 2017. Methodologic quality of included articles was assessed using a modified version of the Critical Appraisal Skills Program (CASP) critical appraisal tool. RESULTS: From the original 2614 records, 9 studies comprising 568 individuals (24 +/- 4.8 years old, 51.4% females)-355 (62.5%) asymptomatic individuals, 87 (15.3%) patellofemoral pain, and 126 (22.2%) patellofemoral instability patients-were included. The average maximum force applied by the instruments to the patella was 38.9 +/- 27.7 N (range 11.25 to 80 N). Patellar displacement ranged from 3.9 to 10.4 mm, medially, and 3.5 to 14.8 mm, laterally, for asymptomatic individuals. For patellofemoral instability patients, these values were higher, ranging from 3.8 to 22.1 mm, medially, and 7.0 to 21.9 mm, laterally, being these mean values similar across the instability subgroups (medial, lateral, or multidirectional). Patellofemoral pain had a mean of 10 mm and 10.9 mm for medial and lateral displacements, respectively. Mean methodological quality score was 9.8 +/- 2.6 (range 6-13) out of 18 possible points. CONCLUSIONS: There is high heterogeneity within the available instrumented assessment methods and respective measurement outcomes, highlighting the need for better methodological standardization and further developments in this field. This would allow a more accurate and reliable quantification of patellar movement and, subsequently, improve diagnosis, and refine treatment. LEVEL OF EVIDENCE: Systematic review of level II-IV studies, Level IV. PMID- 29974175 TI - Contralateral knee hyperextension is associated with increased anterior tibial translation and fewer meniscal injuries in the anterior cruciate ligament-injured knee. AB - PURPOSE: To investigate the influence of hyperextension of the contralateral healthy knee on anterior tibial translation (ATT) and the presence of associated injuries in the anterior cruciate ligament (ACL)-injured knee. METHODS: A local patient data register containing the surgical and clinical data of patients undergoing ACL reconstruction was analyzed. Patients were divided into groups according to the degree of hyperextension of the contralateral knee: normal (Group A <= 0 degrees ), mild (Group B 1 degrees -5 degrees ), moderate (Group C 6 degrees -10 degrees ), and severe (Group D > 10 degrees ). The ATT was measured in both knees preoperatively and 6 months postoperatively using the KT-1000 arthrometer. The presence of associated meniscal and cartilage injuries was noted. Using multivariate analysis, Groups B, C, and D were compared with Group A, using this group as a reference. RESULTS: A total of 10,957 patients were available in the register and 8502 (Group A n = 4335, Group B n = 3331, Group C n = 771, Group D n = 65) were included in the final analysis. Groups B (10.3 mm; 95% CI 0.06-0.042, p < 0.0001) and C (10.6 mm; 95% CI 0.23-0.89, p = 0.006) showed significantly greater preoperative ATT in the injured knee compared with the control group (10.1 mm). Moreover, at the 6-month follow-up, greater ATT was observed for Groups B (8.5 mm; 95% CI 0.13-0.45, p < 0.0001), C (8.5 mm; 95% CI 0.02-0.60, p = 0.035), and D (9.1 mm; 95% CI - 0.08-1.77, p = 0.082) compared with Group A (8.2 mm). Meniscal injuries were less frequent in patients with contralateral hyperextension [Group B 903 (27.1%) p < 0.0001, Group C 208 (27.0%) p = 0.0003, and Group D 12 (18.5%), 0.012] compared with the control group [Group A 1479 (34.1%)]. CONCLUSION: Contralateral knee hyperextension is associated with greater pre- and postoperative ATT in the ACL-injured knee. In patients with contralateral knee hyperextension, concomitant injuries to the menisci are less frequent. Surgeons should consider grafts with superior properties regarding postoperative anteroposterior laxity to patients with contralateral knee hyperextension. LEVEL OF EVIDENCE: Retrospective cohort study, Level IV. PMID- 29974176 TI - Evolution of the Biosynthetic Pathway for Cyanogenic Glucosides in Lepidoptera. AB - Cyanogenic glucosides are widespread defence compounds in plants, and they are also found in some arthropods, especially within Lepidoptera. The aliphatic linamarin and lotaustralin are the most common cyanogenic glucosides in Lepidoptera, and they are biosynthesised de novo, and/or sequestered from food plants. Their biosynthetic pathway was elucidated in the burnet moth, Zygaena filipendulae, and consists of three enzymes: two cytochrome P450 enzymes, CYP405A2 and CYP332A3, and a glucosyl transferase, UGT33A1. Heliconius butterflies also produce linamarin and lotaustralin and have close homologs to CYP405A2 and CYP332A3. To unravel the evolution of the pathway in Lepidoptera, we performed phylogenetic analyses on all available CYP405 and CYP332 sequences. CYP332 sequences were present in almost all Lepidoptera, while the distribution of CYP405s among butterflies and moths was much more limited. Negative purifying selection was found in both CYP enzyme families, indicating that the biosynthesis of CNglcs is an old trait, and not a newly evolved pathway. We compared CYP405A2 to its close paralog, CYP405A3, which is not involved in the biosynthetic pathway. The only significant difference between these two enzymes is a smaller substrate binding pocket in CYP405A2, which would make the enzyme more substrate specific. We consider it likely that the biosynthetic pathway of CNglcs in butterflies and moths have evolved from a common pathway, perhaps based on a predisposition for detoxifying aldoximes by way of a CYP332. Later the aldoxime metabolising CYP405s evolved, and a UGT was recruited into the pathway to establish de novo biosynthesis of CNglcs. PMID- 29974177 TI - Imaging and staging of neuroendocrine cervical cancer. AB - Neuroendocrine cervical cancer (NECC) is a rare and aggressive subtype of cervical cancer, accounting for less than 2% of cervical tumors. They are divided into low-grade and high-grade tumors. High-grade NECC is associated with human papillomavirus (HPV) 18 and to a smaller extent type 16. The most common molecular alterations in NECC include PIK3CA, KRAS, and TP53 mutations. Immunohistochemical staining for CD56, synaptophysin, and chromogranin is a helpful tool in the diagnosis. NECCs pose a significant clinical and therapeutic challenge because of their aggressive nature which is explained by their tendency towards early nodal and hematogenous spread. They have a median survival of 21-22 months, compared to 10 years in cervical squamous cell carcinomas. NECCs have a homogeneous high T2 signal intensity, homogeneous contrast enhancement and lower ADC values in MRI, compared to non-neuroendocrine tumors of the cervix. It is recommended to treat NECC with a multimodality therapeutic approach combining radical hysterectomy, systemic chemotherapy, and radiotherapy. The objective of this manuscript is to address the pathogenesis of NECC, elaborate the role of radiological imaging in the diagnosis and staging of NECCs, evaluate their prognosis, and summarize the suggested management plans for this lethal disease. PMID- 29974179 TI - Can visual analogue scale be used in radiologic subjective image quality assessment? AB - BACKGROUND: Assessment of qualitative or subjective image quality in radiology is traditionally performed using a fixed-point scale even though reproducibility has proved challenging. OBJECTIVE: Image quality of 3-T coronary magnetic resonance (MR) angiography was evaluated using three scoring methods, hypothesizing that a continuous scoring scale like visual analogue scale would improve the assessment. MATERIALS AND METHODS: Adolescents corrected for transposition of the great arteries with arterial switch operation, ages 9-15 years (n=12), and healthy, age matched controls (n=12), were examined with 3-D steady-state free precession magnetic resonance imaging. Image quality of the coronary artery origin was evaluated by using a fixed-point scale (1-4), visual analogue scale of 10 cm and a visual analogue scale with reference points (figurative visual analogue scale). Satisfactory image quality was set to a fixed-point scale 3=visual analogue scale/figurative visual analogue scale 6.6 cm. Statistical analysis was performed using Cohen kappa coefficient and agreement index. RESULTS: The mean interobserver scores for the fixed-point scale, visual analogue scale and figurative visual analogue scale were, respectively, in the left main stem 2.8, 5.7, 7.0; left anterior descending artery 2.8, 4.7, 6.6; circumflex artery 2.5, 4.5, 6.2, and right coronary artery 3.2, 6.3, 7.7. Scoring with a fixed-point scale gave an intraobserver kappa of 0.52-0.77 while interobserver kappa was lacking. For visual analogue scale and figurative visual analogue scale, intraobserver agreement indices were, respectively, 0.08-0.58 and 0.43-0.71 and interobserver agreement indices were up to 0.5 and 0.65, respectively. CONCLUSION: Qualitative image quality evaluation with coronary 3-D steady-state free precession MR angiography, using a visual analogue scale with reference points, had better reproducibility compared to a fixed-point scale and visual analogue scale. Image quality, being a continuum, may be better determined by this method. PMID- 29974180 TI - Clinical Symptoms, Neurological Signs, and Electrophysiological Findings in Surviving Residents with Probable Arsenic Exposure in Toroku, Japan. AB - Chronic arsenic intoxication is known to cause multisystem impairment and is still a major threat to public health in many countries. In Toroku, a small village in Japan, arsenic mines operated from 1920 to 1962, and residents suffered serious sequelae of arsenic intoxication. We have performed annual medical examinations of these residents since 1974, allowing us to characterize participants' long-term health following their last exposure to arsenic. The participants could not be described as having "chronic arsenic intoxication," because their blood arsenic levels were not measured. In this study, we defined them as having "probable arsenic intoxication." Symptoms frequently involved the sensory nervous system, skin, and upper respiratory system (89.1-97.8%). In an analysis of neurological findings, sensory neuropathy was common, and more than half of the participants complained of hearing impairment. Longitudinal assessment with neurological examinations and nerve conduction studies revealed that sensory dysfunction gradually worsened, even after exposure cessation. However, we could not conclude that arsenic caused the long-term decline of sensory function due to a lack of comparisons with age-matched healthy controls. This is the first study to characterize the longitudinal sequelae after probable arsenic exposure. Our study will be helpful to assess the prognosis of patients worldwide who still suffer from chronic arsenic intoxication. PMID- 29974181 TI - The prevalence and characteristics of the subclavius posticus muscle in the adult population on MRI. AB - PURPOSE: The subclavius posticus muscle (SPM) is an aberrant muscle, and the presence of the SPM has a clinical significance, since the SPM might lead to thoracic outlet syndrome (TOS). To date, no radiological study has been evaluated the prevalence of the SPM in the adult population. In this study, we aimed to assess the prevalence of the SPM using magnetic resonance imaging (MRI). METHODS: We retrospectively reviewed brachial plexus, neck, and thoracic MRI of the patients who underwent MRI for various pathologies. Only the patients whose MRI examinations did not have sufficient image quality and the patients who had any pathology that directly involved the thoracic outlet region were excluded from the study. The observers assessed images in the coronal plane to detect the presence of the SPM. The thickness of the muscle and the distance between the SPM and brachial plexus were also noted. RESULTS: MRI examinations of 350 patients, 174 males and 176 females, were evaluated. SPM was detected in 29 patients (8.3%). In 6 patients (1.7%), we identified bilateral SPM. The mean thickness of the muscle was 6.10 +/- 1.60 mm (range 2.5-10 mm). In 21 sides (60%), the brachial plexus and SPM were touching each other. In the remaining 14 sides (40%), the mean distances between the SPM and brachial plexus were 2.32 +/- 0.62 mm (range from 1.7 to 3.6 mm). CONCLUSIONS: We conducted the first radiological study that evaluated the prevalence of the SPM, and we also assessed the thickness of the SPM and the distance between the SPM and brachial plexus. We highlight that our study might be accounted as a first step for future studies to assess the role of the SPM in TOS. PMID- 29974183 TI - Antibiotic discovery: combining isolation chip (iChip) technology and co-culture technique. AB - Antibiotics had been a useful tool for treating bacterial infections since their discovery, but with the passage of time, the evolution of resistance among microbes against antibiotics has rendered them useless. Many approaches are being used to tackle this problem which include discovery of new antibiotics, modification of the existing ones, and elucidating mechanisms of resistance in microbes for a better understanding. In this review, we have discussed that discovery of new antibiotics is a basic need to fight emerging infectious bacteria, and for this purpose, we should target those microbes from the environment which are not easily culturable. For this purpose, culturing technique should be modified to the in situ culturing as nutritional requirements of unculturable bacteria are unknown. Two different cultivation strategies, diffusion chambers and iChip technology, have been reviewed for their excellent improvement in culturing compared to conventional techniques. Since co-culture is also an important factor which can result in exploring new microbial diversity, we hypothesize that if iChip and co-culture can be combined in a single device, it can allow production of novel antibiotics from those bacteria which are difficult to be cultured in the future. PMID- 29974182 TI - A current view on long noncoding RNAs in yeast and filamentous fungi. AB - Long noncoding RNAs (lncRNAs) are crucial players in epigenetic regulation. They were initially discovered in human, yet they emerged as common factors involved in a number of central cellular processes in several eukaryotes. For example, in the past decade, research on lncRNAs in yeast has steadily increased. Several examples of lncRNAs were described in Saccharomyces cerevisiae and Schizosaccharomyces pombe. Also, screenings for lncRNAs in ascomycetes were performed and, just recently, the first full characterization of a lncRNA was performed in the filamentous fungus Trichoderma reesei. In this review, we provide a broad overview about currently known fugal lncRNAs. We make an attempt to categorize them according to their functional context, regulatory strategies or special properties. Moreover, the potential of lncRNAs as a biotechnological tool is discussed. PMID- 29974184 TI - Light and Dehydration but Not Temperature Drive Photosynthetic Adaptations of Basal Streptophytes (Hormidiella, Streptosarcina and Streptofilum) Living in Terrestrial Habitats. AB - Streptophyte algae are the ancestors of land plants, and several classes contain taxa that are adapted to an aero-terrestrial lifestyle. In this study, four basal terrestrial streptophytes from the class Klebsormidiophyceae, including Hormidiella parvula; two species of the newly described genus Streptosarcina (S. costaricana and S. arenaria); and the newly described Streptofilum capillatum were investigated for their responses to radiation, desiccation and temperature stress conditions. All the strains showed low-light adaptation (Ik < 70 MUmol photons m-2 s-1) but differed in photoprotective capacities (such as non photochemical quenching). Acclimation to enhanced photon fluence rates (160 MUmol photons m-2 s-1) increased photosynthetic performance in H. parvula and S. costaricana but not in S. arenaria, showing that low-light adaptation is a constitutive trait for S. arenaria. This lower-light adaptation of S. arenaria was coupled with a higher desiccation tolerance, providing further evidence that dehydration is a selective force shaping species occurrence in low light. For protection against ultraviolet radiation, all species synthesised and accumulated different amounts of mycosporine-like amino acids (MAAs). Biochemically, MAAs synthesised by Hormidiella and Streptosarcina were similar to MAAs from closely related Klebsormidium spp. but differed in retention time and spectral characteristics in S. capillatum. Unlike the different radiation and dehydration tolerances, Hormidiella, Streptosarcina and Streptofilum displayed preferences for similar thermal conditions. These species showed a temperature dependence of photosynthesis similar to respiration, contrasting with Klebsormidium spp. and highlighting an interspecific diversity in thermal requirements, which could regulate species distributions under temperature changes. PMID- 29974185 TI - The evaluation of mean platelet volume in microscopic polyangiitis: methodological drawbacks. PMID- 29974186 TI - Non-obese visceral adiposity is associated with the risk of atherosclerosis in Japanese patients with rheumatoid arthritis: a cross-sectional study. AB - Rheumatoid arthritis (RA) patients often have altered body composition including reduced muscle mass and increased fat mass. Some RA patients are likely to increase visceral fat without obesity [Body Mass Index (BMI) >= 25]. The objective of the study was to determine the association between obesity and/or visceral adiposity and the risk for atherosclerosis in Japanese RA patients. Obesity was evaluated using the BMI, with visceral adiposity evaluated using the visceral fat area (VFA) and the visceral/subcutaneous fat ratio (V/S ratio), quantified using the dual bioelectrical impedance method. Atherosclerosis was evaluated based on the intima-media thickness (IMT) and Plaque score (PS) of the carotid artery, measured using ultrasonography. Multivariate analysis was performed to determine the factors associated with IMT and PS. IMT and PS were compared among groups of patients sub-classified according to BMI and VFA levels. The V/S ratio was higher in RA patients than healthy controls, after adjustment for age, BMI, and waist circumference. On multivariate analysis, the V/S ratio, but not the BMI, was independently associated with the IMT and PS. Among the sub classifications for BMI and VFA, non-obese patients with a high visceral adiposity (18.5 <= BMI < 25 kg/m2 and VFA >= 100 cm2) had the highest IMT (mean IMT, 0.93 +/- 0.29 mm; maximum IMT, 1.44 +/- 0.71 mm) and PS (1.43 +/- 0.61), compared to all other BMI and VFA subgroups. RA patients have increased visceral adiposity, which is associated with a high prevalence of atherosclerotic of plaques. Non-obese RA patients who have visceral adiposity have a specifically higher risk for atherosclerosis. PMID- 29974187 TI - Hydration facilitates oxygenation of hemocyanin: perspectives from molecular dynamics simulations. AB - Molecular dynamics simulations were applied to deoxy- and oxy-hemocyanins using newly developed force field parameters for the dicopper site to evaluate their structural and dynamical properties. Data obtained from the simulations provided information of the oxygenation effect on the active site and overall topology of the protein that was analyzed by root-mean-square deviations, b-factors, and dicopper coordination geometries. Domain I of the protein was found to demonstrate higher flexibility with respect to domain II because of the interfacial rotation between domain I and II that was further endorsed by computing correlative domain movements for both forms of the protein. The oxygenation effect on the overall structure of the protein or polypeptide subunit was further explored via gyration radii evaluated for the metal-binding domain and for the whole subunit. The evaluation of hydration dynamics was carried out to understand the water mediated role of amino acid residues of the solvent tunnel facilitating the entry of oxygen molecule to the dicopper site of hemocyanin. PMID- 29974188 TI - Factors influencing urinary retention after transperineal template biopsy of the prostate: outcomes from a regional cancer centre. AB - INTRODUCTION: Multi-parametric MRI (MP-MRI) prior to prostate biopsy is the investigation of choice for an elevated age-related PSA and abnormal digital rectal examination. MP-MRI in combination with transperineal template mapping biopsy has facilitated the development of the concept of targeted biopsies, either cognitively or with software fusion. Urinary retention is a recognised complication of transperineal prostate biopsy, with reported incidence being 1.6 11.4%. We present patient and procedure-related factors, which influence occurrence of urinary retention after transperineal template biopsy. PATIENTS AND METHODS: Retrospective data collection of 243 consecutive cases of transperineal template biopsies performed at a single institution were recorded and analysed. Biopsies were taken using a standard 5-mm template in 4-6 sectors, depending on the prostate volume. RESULTS: 31/243 (12.8%) patients developed urinary retention, defined as patient discomfort and inability to micturate and bladder scan of >= 600 ml. Patients in the retention group were significantly older (mean 68.7 vs. 65.8 years, P = 0.034). Prostate volume was significantly greater in comparison with the non-retention group (mean 75.4 vs. 57.2 cc, P = 0.0016). The number of biopsies taken was positively correlated with urinary retention (median 35 vs. 32 biopsies, P = 0.045), and this was independent of prostate size (R2 = 0.2). Presenting PSA, pre-operative flow and histopathological outcome were independent of urinary retention. CONCLUSIONS: Factors resulting in an increased risk of urinary retention are advancing age (> 68.7 years); a larger prostate volume (> 75 cc); greater number of biopsies (> 35); greater severity of lower urinary tract symptoms prior to biopsy and diabetes. Targeted biopsies alone, instead of a full template, may avoid urinary retention in the high-risk groups identified. PMID- 29974190 TI - Does discoid lateral meniscus have inborn peripheral rim instability? Comparison between intact discoid lateral meniscus and normal lateral meniscus. AB - INTRODUCTION: Little is known about peripheral rim instability (PRI) of adult discoid lateral meniscus (DLM). We compared PRI of the intact DLM (iDLM) to those of intact normal lateral meniscus (LM) in adult patients and also investigated whether there was any association between PRI and DLM tears. MATERIALS AND METHODS: We investigated PRI in 17 DLMs and 60 normal LMs without tears during arthroscopic surgery for medial compartmental pathologies between June 2012 and October 2015. We also investigate PRI of torn DLM (tDLM) excluding peripheral tear to compare the PRI between intact and torn DLM. Stability parameters were measured using a probing hook and arthroscopic ruler at the anterior, middle, and posterior parts of the peripheral rim of the menisci: translating the anterior horn (AH) and mid-body (MB) and lifting the posterior horn (PH). RESULTS: AH and PH instabilities were greater in the iDLM group than in the iLM group (2.2 +/- 1.4 vs. 0.9 +/- 1.4 mm, p = 0.006 and 3.4 +/- 1.7 vs. 1.7 +/- 1.2 mm, p = 0.004, respectively). However, there was no significant difference in MB instability between two groups. In addition, no significant difference was observed in all the parameters between the iDLM and tDLM groups. CONCLUSION: Both iDLM and tDLM had greater PRI of the AH and PH than the iLM in adult patients. Thus, the DLM is prone to tear and careful inspection is needed not to overlook PRI of a DLM even if the peripheral attachment is intact. LEVEL OF EVIDENCE: Level 3, comparative study of anatomical instability of living subjects. PMID- 29974189 TI - Levels of peripheral blood polymorphonuclear myeloid-derived suppressor cells and selected cytokines are potentially prognostic of disease progression for patients with non-small cell lung cancer. AB - Polymorphonuclear-MDSC (PMN-MDSC) have emerged as an independent prognostic factor for survival in NSCLC. Similarly, cytokine profiles have been used to identify subgroups of NSCLC patients with different clinical outcomes. This prospective study investigated whether the percentage of circulating PMN-MDSC, in conjunction with the levels of plasma cytokines, was more informative of disease progression than the analysis of either factor alone. We analyzed the phenotypic and functional profile of peripheral blood T-cell subsets (CD3+, CD3+CD4+ and CD3+CD8+), neutrophils (CD66b+) and polymorphonuclear-MDSC (PMN-MDSC; CD66b+CD11b+CD15+CD14-) as well as the concentration of 14 plasma cytokines (IL 1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-17A, IL-27, IL-29, IL-31, and IL-33, TNF-alpha, IFN-gamma) in 90 treatment-naive NSCLC patients and 25 healthy donors (HD). In contrast to HD, NSCLC patients had a higher percentage of PMN MDSC and neutrophils (P < 0.0001) but a lower percentage of CD3+, CD3+CD4+ and CD3+CD8+ cells. PMN-MDSC% negatively correlated with the levels of IL1-beta, IL 2, IL-27 and IL-29. Two groups of patients were identified according to the percentage of circulating PMN-MDSC. Patients with low PMN-MDSC (<= 8%) had a better OS (22.1 months [95% CI 4.3-739.7]) than patients with high PMN-MDSC (9.3 months [95% CI 0-18.8]). OS was significantly different among groups of patients stratified by both PMN-MDSC% and cytokine levels. In sum, our findings provide evidence suggesting that PMN-MDSC% in conjunction with the levels IL-1beta, IL 27, and IL-29 could be a useful strategy to identify groups of patients with potentially unfavorable prognoses. PMID- 29974191 TI - Orlistat induces apoptosis and protective autophagy in ovarian cancer cells: involvement of Akt-mTOR-mediated signaling pathway. AB - INTRODUCTION: Orlistat possesses anti-tumor capacity by inducing apoptosis in ovarian cancer cells. However, the mechanism is not clearly understood. Emerging evidence indicates the overlaps between autophagy and apoptosis. In this study, we have investigated the role of autophagy in orlistat-induced apoptosis in ovarian cancer (OC) cells. METHODS: The effect of orlistat on apoptosis was evaluated in SKOV3 and A2780 cell lines by MTT and TUNEL assay. The formations of autophagosomes were observed by acridine orange and GFP-LC3 fluorescence. In addition, conversions of LC3-I to LC3-II were analyzed by western blot, as well as other autophagy-related proteins. 3-Methyladenine (3-MA) was used as an autophagy inhibitor in combined treatment with orlistat. Western blot was further conducted to investigate the molecular mechanisms of orlistat-affected apoptosis and autophagy on protein level. RESULTS: The proliferation activities of OC cells were inhibited by orlistat in a dose-dependent manner. The expressions of cleaved caspase 3 and 9 in orlistat-treated cells were increasing, which suggested that orlistat-induced apoptosis was caspase-dependent. At the same time, the average number of GFP-LC3 dots per cell was increased after 48 h of orlistat treatment. The expression levels of LC3-II were significantly up-regulated, as well as other autophagy-related proteins such as Vsp34, Atg7 and UVRAG. These results suggested orlistat-induced autophagy flux, which was further found involved in inhibiting the Akt/mTOR/p70S6K signaling pathway. However, combined treatment of orlistat and 3-MA significantly suppressed the cell viability, which indicated a pro survival role of autophagy in OC cells. CONCLUSION: We suggested that orlistat had anti-cancer effect in OC cells. In addition, autophagy played a pro-survival role, suppressing which the orlistat-induced anti-cancer effect would be more significant. PMID- 29974193 TI - Impact of surgeon's experience on outcome parameters following ureterorenoscopic stone removal. AB - Within the BUSTER trial, we analyzed the surgeon's amount of experience and other parameters associated with URS procedures regarding the stone-free rate, complication rate, and operative time. Patient characteristics and surgical details on 307 URS procedures were prospectively documented according to a standardized study protocol at 14 German centers 01-04/2015. Surgeon's experience was correlated to clinical characteristics, and its impact on the stone-free rate, complication rate, and operative time subjected to multivariate analysis. 76 (25%), 66 (21%) and 165 (54%) of 307 URS procedures were carried out by residents, young specialists, and experienced specialists (> 5 years after board certification), respectively. Median stone size was 6 mm, median operative time 35 min. A ureteral stent was placed at the end of 82% of procedures. Stone-free rate and stone-free rate including minimal residual stone fragments (adequate for spontaneous clearance) following URS were 69 and 91%, respectively. No complications were documented during the hospital stays of 89% of patients (Clavien-Dindo grade 0). According to multivariate analysis, experienced specialists achieved a 2.2-fold higher stone-free rate compared to residents (p = 0.038), but used post-URS stenting 2.6-fold more frequently (p = 0.023). Surgeon's experience had no significant impact on the complication rate. We observed no differences in this study's main endpoints, namely the stone-free and complication rates, between residents and young specialists, but experienced specialists' stone-free rate was significantly higher. During this cross sectional study, 75% of URS procedures were performed by specialists. The experienced specialists' more than two-fold higher stone-free rate compared to residents' justifies ongoing efforts to establish structured URS training programs. PMID- 29974192 TI - Lateral undulation of the flexible spine of sprawling posture vertebrates. AB - Sprawling posture vertebrates have a flexible spine that bends the trunk primarily in the horizontal plane during locomotion. By coordinating cyclical lateral trunk flexion and limb movements, these animals are very mobile and show extraordinary maneuverability. The dynamic and static stability displayed in complex and changing environments are highly correlated with such lateral bending patterns. The axial dynamics of their compliant body can also be critical for achieving energy-efficient locomotion at high velocities. In this paper, lateral undulation is used to characterize the bending pattern. The production of ground reaction forces (GRFs) and the related center of mass (COM) dynamics during locomotion are the fundamental mechanisms to be considered. Mainly based on research on geckos, which show unrestricted movement in three-dimensional space, we review current knowledge on the trunk flexibility and waveforms of lateral trunk movement. We investigate locomotion dynamics and mechanisms underlying the lateral undulation pattern. This paper also provides insights into the roles of this pattern in obtaining flexible and efficient walking, running, and climbing. Finally, we discuss the potential application of lateral undulation patterns to bio-inspired robotics. PMID- 29974194 TI - Phenotype variability in tumor disorders of the skin appendages associated with mutations in the CYLD gene. AB - Mutations in the tumor suppressor gene CYLD underlie phenotypically heterogeneous hereditary tumor disorders of the skin appendages. These diseases are inherited autosomal dominantly and include Brooke-Spiegler syndrome (BSS; OMIM 605041), familial cylindromatosis (FC; OMIM 132700) and multiple familial trichoepithelioma (MFT; OMIM 601606). Clinically, cylindromas, trichoepitheliomas and spiradenomas can be found in affected individuals. We sought to elucidate the molecular genetic basis in individuals with newly diagnosed cylindromas, trichoepitheliomas and/or spiradenomas. Mutation analysis using polymerase chain reaction (PCR)-based techniques was performed in seven German patients and one Turkish patient. We detected two missense, two nonsense, two deletions and two duplication mutations in the CYLD gene, of which seven have not yet been reported. No genotype-phenotype correlation was detected amongst the patients. Our data provide additional information on the clinical and molecular genetic heterogeneity of disorders associated with CYLD mutations. PMID- 29974196 TI - Targeting tumor-associated acidity in cancer immunotherapy. AB - Checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA 4) and programmed cell death-1 (PD-1) monoclonal antibodies have changed profoundly the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, Hodgkin lymphoma, and bladder cancer. Currently, they are tested in various tumor entities as monotherapy or in combination with chemotherapies or targeted therapies. However, only a subgroup of patients benefit from checkpoint blockade (combinations). This raises the question, which all mechanisms inhibit T cell function in the tumor environment, restricting the efficacy of these immunotherapeutic approaches. Serum activity of lactate dehydrogenase, likely reflecting the glycolytic activity of the tumor cells and thus acidity within the tumor microenvironment, turned out to be one of the strongest markers predicting response to checkpoint inhibition. In this review, we discuss the impact of tumor associated acidity on the efficacy of T cell-mediated cancer immunotherapy and possible approaches to break this barrier. PMID- 29974195 TI - Coronary computed tomography angiography: a method coming of age. AB - In patients with stable symptoms suggestive of coronary artery disease (CAD), coronary CT angiography (CTA) allows for assessing several aspects of coronary atherosclerosis. Coronary artery stenoses are reliably detected, plaque formation can be quantified and characterized as calcified or non-calcified, and markers of potential instability such as expansive vascular remodeling, spotty calcification, and atheroma size can be described. As opposed to invasive coronary angiography, CTA visualizes the vessel lumen and wall. Being a purely anatomic test, even small plaques are detected with excellent sensitivity. At the other end of the spectrum, the hemodynamic significance of large plaque burden is sometimes overestimated. This may in part be corrected using mathematical modeling. Computational fluid dynamics of vascular anatomy and subtended myocardial mass provide for measures of CT-based fractional flow reserve (FFRCT). Large prospective trials have demonstrated the diagnostic utility of CTA in particular for ruling out obstructive CAD. The ability to detect non-obstructive plaque allows for improved risk prediction in comparison with functional testing, because even patients with sub-clinical atherosclerosis can be identified and selected for preventive medical treatment. This has led to incorporating CTA as one of several possible diagnostic tests for the evaluation of stable CAD in the actual European guidelines. Recently, it has even been forwarded as the first line diagnostic test in the United Kingdom. The clinical implications of novel quantitative CTA-derived parameters such as FFRCT and non-calcified plaque volume are being examined in ongoing studies. PMID- 29974197 TI - Clinical results of a dorsally positioned hydraulic ID-sling in male patients with post-prostatectomy-incontinence. AB - PURPOSE: To prospectively evaluate the effectiveness and safety of and the long term experience with a re-adjustable hydraulic sling (ID-sling) device positioned dorsally to the urethra for the treatment of male post-prostatectomy incontinence (PPI). MATERIALS AND METHODS: Between September 2007 and November 2009 13 patients with persisting SUI were treated consecutively with an ID-slingTM in two European tertiary centers by a single surgeon. Physical examinations and standardized questionnaires (ICIQ-SF + VAS), pad tests, and 24-h pad number counts were performed at baseline and during follow-up. RESULTS: The implantation of the hydraulic cuff was uncomplicated in all cases. The ICIQ-SF score diminished from a preoperative mean value of 18 to a mean of five postoperatively. One patient remained completely dry with normal micturition. All patients demonstrated a mild improvement at primary filling but did not show any significant improvement after the second or any subsequent filling. In total, 1/13 (7.7%) patients were completely dry and 5/13 (38.4%) showed improved continence. In 6/13 (46.2%) patients, satisfactory continence results according to subjective criteria, were not achieved. Subsequently, artificial urinary sphincter (AUS) implantation was offered to one patient (7.7%) after 12 months and to ten patients (76,9%) after 24 months. CONCLUSIONS: The implantation of a dorsally placed hydraulic sling is a not yet standardized and complex procedure, even for the experienced surgeon. To date, this implantation method is not an alternative to other devices. An improved sling design is necessary to simplify the surgical procedure and to improve long-term stability. PMID- 29974198 TI - Stroke volume ratio derived from magnetic resonance imaging as an indicator of interventricular dyssynchrony predicts future cardiac event in patients with biventricular Fontan circulation. AB - The prognostic factors in patients with biventricular heart who underwent Fontan surgery remain unclear. This study wanted to assess the hypothesis that interventricular dyssynchrony evaluated by cardiac magnetic resonance imaging (MRI) can predict future cardiac events in patients with biventricular heart who have undergone Fontan surgery. We prospectively enrolled consecutive patients with biventricular Fontan circulation from 2003 to 2016, and performed protocolized cardiac MRI. We determined the stroke volume ratio (SVr) using the following formula to assess interventricular dyssynchrony: (stroke volume (SV) of the two whole ventricles)/(SV of the right ventricle + SV of the left ventricle), by tracing cine MRI data. If interventricular dyssynchrony existed, blood flowed and returned to each ventricle through the ventricular septal defect; therefore, the SVr in this instance should be less than 1.0. We enrolled 40 patients. SVr ranged from 0.81 to 1.0 (median 0.95). Low SVr (< 0.95) was associated with worse New York Heart Association functional class, longer QRS duration, right bundle branch block, low biventricular indexed stroke volume, and low biventricular ejection fraction. During the follow-up period (median 53.5 months), 10 cardiac events occurred (six cases of acute exacerbation of heart failure, three cases of supraventricular tachycardia, and one case of exacerbation of protein-losing enteropathy). Univariate analysis showed four clinical predictors: SVr < 0.95 [hazard ratio (HR) 9.3, 95% confidential interval (CI) 1.7-171.5]; biventricular ejection fraction < 0.45 (HR 9.4, 95% CI 2.2-65.3); left ventricular indexed end diastolic volume > 73 mL/m2 (HR 4.5, 95% CI 1.1-15.7); and the presence of the aorta directly arising from the right ventricular conus (HR 5.8, 95% CI 1.1-106). SVr derived from MRI can predict future cardiac events in Fontan patients with biventricular hearts. PMID- 29974199 TI - Association between plasma levels of PCSK9 and the presence of coronary artery disease in Japanese. AB - The ability of pro-protein convertase subtilisin/kexin type 9 (PCSK9) levels to predict the presence or severity of coronary artery disease (CAD) remains controversial. The purpose of this study was to investigate these associations. We enrolled 393 patients who were clinically suspected to have CAD or who had at least one cardiac risk factor and underwent multidetector-row computed tomography coronary angiography. The presence of CAD (>=50% coronary stenosis), the number of significantly stenosed coronary vessels, and plasma levels of PCSK9 by ELISA were analyzed. Plasma PCSK9 levels (log-transformed data) were significantly associated with the presence of CAD. Next, we divided the patients into two groups (non-statin and statin groups) according to statin treatment. PCSK9 levels in the non-statin group were significantly lower than those in the statin group. There were no significant differences in PCSK9 levels between the absence and presence of CAD in the statin group. However, in the non-statin group, PCSK9 levels in patients with CAD were significantly higher than those in patients without CAD. PCSK9 levels, in addition to age, gender, BMI, DM and HDL-C, were independently associated with the presence of CAD by a multivariable analysis. In conclusion, our results demonstrated that plasma PCSK9 levels may be a marker for evaluating the presence of CAD. PMID- 29974200 TI - Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin. AB - PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 uCi. METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC). RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces. CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data. PMID- 29974201 TI - Host contact structure is important for the recurrence of Influenza A. AB - An important characteristic of influenza A is its ability to escape host immunity through antigenic drift. A novel influenza A strain that causes a pandemic confers full immunity to infected individuals. Yet when the pandemic strain drifts, these individuals will have decreased immunity to drifted strains in the following seasonal epidemics. We compute the required decrease in immunity so that a recurrence is possible. Models for influenza A must make assumptions on the contact structure on which the disease spreads. By considering local stability of the disease free equilibrium via computation of the reproduction number, we show that the classical random mixing assumption predicts an unrealistically large decrease of immunity before a recurrence is possible. We improve over the classical random mixing assumption by incorporating a contact network structure. A complication of contact networks is correlations induced by the initial pandemic. We provide a novel analytic derivation of such correlations and show that contact networks may require a dramatically smaller loss of immunity before recurrence. Hence, the key new insight in our paper is that on contact networks the establishment of a new strain is possible for much higher immunity levels of previously infected individuals than predicted by the commonly used random mixing assumption. This suggests that stable contacts like classmates, coworkers and family members are a crucial path for the spread of influenza in human populations. PMID- 29974202 TI - Trinucleotide repeat instability during double-strand break repair: from mechanisms to gene therapy. AB - Trinucleotide repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to repeat length changes, creating expansions and contractions of the repeat tract. The present review focuses on recent developments on double strand break repair involving trinucleotide repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large repeat tract expansions, while frequent contractions occur either by single-strand annealing between repeat ends or by gene conversion, triggering near-complete contraction of the repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to trinucleotide repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders. PMID- 29974203 TI - An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer. AB - PURPOSE: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. METHODS: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12 lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (DeltaQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. RESULTS: Forty-five men were enrolled; 82% received treatment for >= 3 months. At steady state, the maximum DeltaQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs. CONCLUSION: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide. PMID- 29974204 TI - How does Hsp90 function in RNAi-dependent heterochromatin assembly? AB - Heat-shock protein 90 (Hsp90) was recently identified as a silencing factor required for RNA interference (RNAi)-dependent heterochromatin assembly in the fission yeast Schizosaccharomyces pombe. As Hsp90 is known to contribute to the formation of small RNA-containing effector complexes, it would be expected that Hsp90 is also involved in the RNAi pathway in fission yeast. However, upon investigation, we found it very difficult to determine how Hsp90 modulates RNAi dependent heterochromatin assembly in the cell. A lack of detectable small interfering RNAs in hsp90 mutant cells prevented us from examining the role of Hsp90 in the siRNA loading in the cell. In addition, deletion of genes encoding co-chaperones for Hsp90 appears not to affect RNAi-dependent pericentromeric silencing. One possible approach for elucidating the role of Hsp90 in RNAi dependent heterochromatin assembly is the use of forward genetic screens to identify novel factors linking Hsp90 with other known RNAi factors. Here, we discuss the benefits of conducting further screenings and present some technical hints to help identify new factors. PMID- 29974205 TI - Correction to: Central 10-degree visual field change following non-penetrating deep sclerectomy in severe and end-stage glaucoma: preliminary results. AB - The published online version contain mistake in the author list. The correct presentation is also given above. PMID- 29974206 TI - Coexisting narcolepsy (with and without cataplexy) and multiple sclerosis : Six new cases and a literature review. AB - BACKGROUND: There are increasing data suggesting the involvement of the immune system in narcolepsy. The co-occurrence of narcolepsy with other autoimmune disorders (including multiple sclerosis, MS) is rare. PATIENTS AND METHODS: International multicenter sleep center survey and literature review on narcolepsy with (NC) and without (NwC) cataplexy. RESULTS: A total of 26 patients (pts), 6 in the survey and 20 in the literature were found. Two different types of association were identified: (1) Symptomatic type (5 pts): MS preceding the onset of narcolepsy, which was always without cataplexy (NwC); sleep onset REM episodes (SOREM) and hypocretin deficiency were observed in some, and lesions in the hypothalamus in all patients. (2) Coexisting type (18 pts): MS preceding or following the appearance of NC with SOREM, hypocretin deficiency but no lesions in the hypothalamus. A positive effect of steroids, immunoglobulins or natalizumab on narcolepsy symptoms was observed in four patients. DISCUSSION: Narcolepsy and MS are rarely associated. In addition to NwC secondary to hypothalamic demyelination, some patients present a coexistence of MS with NC without detectable hypothalamic lesions. The rarity of reports on this association probably reflects underrecognition. The elucidation of underlying genetic and immune mechanisms needs further studies. PMID- 29974207 TI - Corpus callosal involvement is correlated with cognitive impairment in multiple system atrophy. AB - OBJECTIVE: We examined the anatomical involvement related to cognitive impairment in patients with multiple system atrophy (MSA). METHODS: We examined 30 patients with probable MSA and 15 healthy controls. All MSA patients were assessed by the Unified MSA-Rating scale and Addenbrooke's Cognitive Examination-Revised (ACE-R). We classified 15 MSA patients with ACE-R scores > 88 as having normal cognition (MSA-NC) and 15 with scores <= 88 as having cognitive impairment (MSA-CI). All subjects underwent 3 T MRI scanning and were investigated using voxel-based morphometry and diffusion tensor imaging. RESULTS: Both the MSA-NC and MSA-CI patients exhibited cerebellar but not cerebral atrophy in voxel-based morphometry compared to controls. In contrast, tract-based spatial statistics revealed widespread and significantly decreased fractional anisotropy (FA) values, as well as increased mean diffusivity, radial diffusivity, and axial diffusivity in both the cerebrum and cerebellum in MSA-CI patients compared to controls. MSA-NC patients also exhibited similar involvement of the cerebellum but less extensive involvement of the cerebrum compared with the MSA-CI patients. In particular, FA values in MSA-CI patients were significantly decreased in the anterior part of the left corpus callosum compared with those in MSA-NC patients. The mean FA values in the left anterior part of the corpus callosum were significantly correlated with total ACE-R scores and subscores (memory, fluency, and language) in MSA patients. CONCLUSIONS: Decreased FA values in the anterior corpus callosum showed a significant correlation with cognitive impairment in MSA. PMID- 29974208 TI - Neonatal hypertension: an educational review. AB - Hypertension is encountered in up to 3% of neonates and occurs more frequently in neonates requiring hospitalization in the neonatal intensive care unit (NICU) than in neonates in newborn nurseries or outpatient clinics. Former NICU neonates are at higher risk of hypertension secondary to invasive procedures and disease related comorbidities. Accurate measurement of blood pressure (BP) remains challenging, but new standardized methods result in less measurement error. Multiple factors contribute to the rapidly changing BP of a neonate: gestational age, postmenstrual age (PMA), birth weight, and maternal factors are the most significant contributors. Given the natural evolution of BP as neonates mature, a percentile cutoff of 95% for PMA has been the most common definition used; however, this is not based on outcome data. Common causes of neonatal hypertension are congenital and acquired renal disease, history of umbilical arterial catheter placement, and bronchopulmonary dysplasia. The treatment of neonatal hypertension has mostly been off-label, but as evidence accumulates, the safety of medical management has increased. The prognosis of neonatal hypertension remains largely unknown and thankfully most often resolves unless secondary to renovascular disease, but further research is needed. This review discusses important factors related to neonatal hypertension including BP measurement, determinants of BP, and management of neonatal hypertension. PMID- 29974209 TI - Cyanobacterial production of plant essential oils. AB - MAIN CONCLUSION: Synechocystis (a cyanobacterium) was employed as an alternative host for the production of plant essential oil constituents. beta-Phellandrene synthase (PHLS) genes from different plants, when expressed in Synechocystis, enabled synthesis of variable monoterpene hydrocarbon blends, converting Synechocystis into a cell factory that photosynthesized and released useful products. Monoterpene synthases are secondary metabolism enzymes that catalyze the generation of essential oil constituents in terrestrial plants. Essential oils, including monoterpene hydrocarbons, are of interest for their commercial application and value. Therefore, heterologous expression of monoterpene synthases for high-capacity essential oil production in photosynthetic microorganism transformants is of current interest. In the present work, the cyanobacterium Synechocystsis PCC 6803 was employed as an alternative host for the production of plant essential oil constituents. As a case study, beta phellandrene synthase (PHLS) genes from different plants were heterologously expressed in Synechocystis. Genomic integration of individual PHLS-encoding sequences endowed Synechocystis with constitutive monoterpene hydrocarbons generation, occurring concomitant with photosynthesis and cell growth. Specifically, the beta-phellandrene synthase from Lavandula angustifolia (lavender), Solanum lycopersicum (tomato), Pinus banksiana (pine), Picea sitchensis (Sitka spruce) and Abies grandis (grand fir) were active in Synechocystis transformants but, instead of a single product, they generated a blend of terpene hydrocarbons comprising beta-phellandrene, alpha-phellandrene, beta-myrcene, beta-pinene, and delta-carene with variable percentage ratios ranging from < 10 to > 90% in different product combinations and proportions. Our results suggested that PHLS enzyme conformation and function depends on the cytosolic environment in which they reside, with the biochemical properties of the latter causing catalytic deviations from the products naturally observed in the corresponding gene-encoding plants, giving rise to the terpene hydrocarbon blends described in this work. These findings may have commercial application in the generation of designer essential oil blends and will further assist the development of heterologous cyanobacterial platforms for the generation of desired monoterpene hydrocarbon products. PMID- 29974210 TI - Dose-reduced first cycle of chemotherapy for prevention of life-threatening acute complications in nonseminomatous germ cell tumor patients with ultra high tumor markers and/or poor performance status. AB - PURPOSE: Patients with metastatic nonseminomatous germ cell tumors (mNSGCT) and a high tumor burden or a poor performance status at initial diagnosis are at risk from potentially life-threatening early complications during or after the first chemotherapy cycle. The outcomes with dose-reduced first cycle of chemotherapy in this population of patients are not well established. METHODS: We performed a retrospective analysis of patients with mNSGCT and International Germ Cell Cancer Collaborative Group (IGCCCG) poor risk features. All patients received cisplatin and etoposide-based combinations as first-line treatment. Ultra high tumor marker levels were defined as alpha-fetoprotein >= 100,000 ng/ml or human chorionic gonadotropin >= 200,000 mIU/ml. Before 2005, the first treatment cycle was administered at a full dose in our center. After 2005, we used an abbreviated course of cisplatin and etoposide (EP) for the first cycle, followed by subsequent full-dose administration. RESULTS: From 1987 to 2012, 265 patients with poor risk features according to IGCCCG received first-line chemotherapy. Among them, 63 out of 265 (24%) patients had ultra high tumor marker levels and/or ECOG performance status of 3-4. Dose reduction of the first chemotherapy cycle was associated with a significant decrease of life-threatening complications from 76 to 44% (p = 0.01), but not with the overall survival (HR 0.99, 95% CI 0.44-2.26). CONCLUSIONS: Dose reduction of the first EP cycle by 40 60% in the subgroup of poor risk patients with ultra high tumor marker levels and/or ECOG performance status 3-4 is associated with significantly lowered acute complication rates but not with overall survival. PMID- 29974211 TI - Towards an individual screening strategy for first-degree relatives of celiac patients. AB - Celiac disease (CD) is known to be more prevalent in first-degree relatives of patients. In this retrospective cohort study of 609 relatives between 1994 and 2016, we investigated the effect of sex, HLA type, and age at time of index celiac diagnosis. Pearson's chi-square test and Kaplan-Meier survival analysis were used as statistical analyses. CD screening was carried out for 427 relatives (70%), resulting in a prevalence of 15%. HLA typing in 335 relatives showed HLA DQ2/DQ8 positivity in 87.5%. In 63% of children and all parents, celiac disease was diagnosed at first screening. It was diagnosed significantly more often in females, HLA-DQ2 homozygosity, and children (all p < 0.05). In children aged 0-1 year at time of index diagnosis, celiac disease was diagnosed after consecutive screening in 58%, after 3.9 +/- 2.5 (max 10) years (p < 0.001).Conclusion: Future screening policies for relatives of celiac patients should include retesting, especially in HLA-positive relatives younger than 10 years of age. In addition, one-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients. What is Known: * Celiac disease is more prevalent in first-degree relatives of celiac patients (risk 3-12%). * HLA-DQ2 homozygous sisters/daughters are at highest risk (25%). What is New: * If younger than 10 years of age, repeated testing is necessary in HLA-DQ2/DQ8-positive first-degree relatives when celiac disease is diagnosed in a family. * One-time celiac-specific antibody testing alone could be sufficient to rule out the disease in adolescent siblings and parents of newly diagnosed celiac patients. PMID- 29974213 TI - [Progressive muscle relaxation according to Jacobson for migraine prophylaxis : Clinical effectiveness and mode of action]. AB - Progressive muscle relaxation (PMR) after Jacobson has been used for migraine prophylaxis since the early 1970s. Migraine patients are assumed to have an enhanced autonomic arousal which can be counterbalanced by systematic relaxation. Relaxation techniques are thought to reduce the activation level, to alter cortical pain processing and to enhance activation in pain-reducing cortical structures in the periaqueductal grey matter. Meta-analyses could show PMR to be just as efficacious as pharmacological treatment options. A beneficial effect can only arise if regular daily exercises of 5-25 min are performed and the exercises are transferred into the daily routine. This review critically summarizes the empirical findings concerning the effects of PMR on migraine. A lack of recent research on this topic was determined. In a study by this group 50 migraine patients and 46 healthy controls were examined. It could be shown that in addition to the clinical efficacy on migraine frequency, changes in cortical information processing, measured by means of the evoked potential contingent negative variation (CNV) could also be determined. The initially increased CNV amplitude became normalized after regular PMR training in migraine patients. With the review of PMR studies on migraine prophylaxis and the results of our own study it could be shown that PMR is an efficacious non-pharmacological treatment option for migraine prophylaxis. In addition to its clinical effects, alterations in cortical stimulation processing in terms of a normalization of the CNV could be documented. PMID- 29974214 TI - Depressive symptoms at 13 years as predictors of depression in older adolescents: a prospective 4-year follow-up study in a nonclinical population. AB - Depression is the most important source of disability in adolescents, partially due to its recurrence. There is a lack of studies on population-based samples investigating the continuity of depressive symptoms during adolescence. This study evaluates depressive symptoms at early adolescence as predictors of depressive symptoms later in adolescence. Urban adolescents born in 1990 and enrolled in schools of Porto, Portugal, in 2003-2004 (EPITeen study) were evaluated at 13 and 17 years (n = 1106, 55.9% females), and completed a questionnaire comprising health behaviors and Beck Depression Inventory II (BDI II) to assess depressive symptoms. A questionnaire on socio-demographic and clinical characteristics was self-reported. Regression coefficients (beta) and 95% confidence intervals (CI) were estimated using simple linear regression. The prevalence of adolescents with depressive symptoms above the cut-off (BDI-II > 13) was 11.9% at 13 years (girls: 17.1%; boys: 5.3%) and 10.8% at 17 years (girls: 14.7%; boys: 5.7%). Almost 6% of girls and 2% of boys had BDI-II > 13 at both assessments, and 35% of girls and boys with BDI-II > 13 at baseline also had BDI-II > 13 at follow-up. For both genders, depressive symptoms at age 13 were independently associated with depressive symptoms at age 17 (girls: beta = 0.35, 95% CI 0.28-0.42; boys: beta = 0.37, 95% CI 0.30-0.44). Depressive symptoms at age 13 were an independent predictive factor for adolescents' depressive symptoms at age 17. The prevalence of adolescents with BDI-II > 13 was higher in females, but the strength of this association was similar in both genders, highlighting the heavy burden of depressive symptoms already at an early age, among girls and boys. PMID- 29974212 TI - Comparison between different criteria for metabolic syndrome in schoolchildren from southern Brazil. AB - : The metabolic syndrome (MetS), although more frequent in adults, is already evident in the infant-juvenile population. On the other hand, there are different criteria for the diagnosis, without a consensus of which is the best to be used in this population. The aim of this study was to evaluate the agreement between different criteria for diagnosis of MetS in adolescents from southern Brazil. A cross-sectional study consisting of a sample of 1200 subjects, 679 females, aged between 12 and 17 years. MetS was assessed by three different criteria: Cook (2003), Ferranti (2004), and International Diabetes Federation - IDF (2007). The agreement between the criteria was evaluated by the Kappa index. Low prevalence of MetS was found among schoolchildren (1.9% for Cook, 5.0% for Ferranti, and 2.1% for IDF). Regular (Ferranti - IDF: Kappa 0.382; p < 0.001) and moderate (Cook - Ferranti: Kappa 0.542; p < 0.001; Cook - IDF: Kappa 0.532; p < 0.001) agreement was demonstrated between the criteria. Elevated blood pressure was the most frequent condition in all the criteria, and the least frequent condition was in the glycemia (Cook and Ferranti) and high-density lipoprotein cholesterol levels. CONCLUSION: The low prevalence of MetS and the low agreement among the existing criteria suggest the elaboration of new criteria for the diagnosis of MetS in the child and adolescent population. What is Known: * There are different criteria for the diagnosis of the metabolic syndrome (MetS), without a consensus of which is the best to be used in the infant-juvenile population. What is New: * Low prevalence of MetS identified among schoolchildren and the low agreement among the existing criteria suggest the elaboration of new criteria for the diagnosis of MetS in the child and adolescent population. PMID- 29974215 TI - Prognostic factors for the outcome of arthroscopic capsular repair of peripheral triangular fibrocartilage complex tears. AB - BACKGROUND: Little information is available about prognostic factors of arthroscopic capsular repair for peripheral triangular fibrocartilage complex (TFCC) lesions. The purpose of this study was to analyze factors that affect the treatment outcomes of arthroscopic capsular repair for peripheral TFCC tears. METHODS: This study retrospectively enrolled 60 patients who were treated with arthroscopic outside-in capsular repair for peripheral TFCC tears. Functional survey, including pain numeric rating scale (NRS) on an ulnar provocation test, distal radio-ulnar joint (DRUJ) stress test, Disability of the Arm, Shoulder, and Hand (DASH) score, and satisfaction with treatment, was conducted at 12-month follow-up. Patients who were enthusiastic or satisfied comprised the satisfied group, and those who were noncommittal or disappointed the dissatisfied group. Demographic, clinical, and arthroscopic findings were compared between the satisfied and dissatisfied groups. RESULTS: The mean pain NRS and DASH scores exhibited significant clinical improvement at the 12-month follow-up. Out of the total participants, 46 were satisfied and 14 were dissatisfied about the treatment, with significantly more female subjects in the dissatisfied group than in the satisfied one. The patients in the satisfied group had a shorter duration of symptoms, were more likely to have trauma history, and exhibited positive DRUJ stress test results compared to the dissatisfied group. There were no significant group differences in age, hand dominance, work level, and the extent of ulnar plus variance. Multivariable analysis revealed that female gender, a longer duration of symptoms, or negative DRUJ stress test results were associated with an increased disability after arthroscopic TFCC repair. CONCLUSION: Female gender, a longer duration of symptom, and a negative DRUJ stress test are associated with a higher likelihood of treatment failure after arthroscopic outside-in capsular repair of peripheral TFCC tears. PMID- 29974216 TI - Arthroscopic meniscal surgery versus conservative management in patients aged 40 years and older: a meta-analysis. AB - INTRODUCTION: The efficacy of arthroscopic meniscus surgery in old aged patients remains controversial. The purpose of the present study was to review published studies comparing arthroscopic meniscal surgery with conservative management to treat meniscal injuries in patients 40 years of age and older. MATERIALS AND METHODS: Several electronic databases were queried for articles published until July 2017 that evaluated outcomes of arthroscopic meniscal surgery in patients aged 40 years and older. Data searches, extraction, analysis, and quality assessment were performed according to the Cochrane Collaboration guidelines, and the clinical outcomes were evaluated using various outcome values. The results are presented as the standard mean difference (SMD) for continuous outcomes with 95% confidence intervals (CIs). RESULTS: Nine randomized controlled trials (RCTs) were included. There were no significant differences in clinical outcomes such as relief in knee pain (SMD = 0.01, 95% CIs = - 0.15 to 0.18, I2 = 38%) and improved knee function (SMD = 0.01, 95% CIs = - 0.19 to 0.21, I2 = 57%) between arthroscopic meniscal surgery and conservative management for degenerative meniscal tears. CONCLUSIONS: The efficacy of arthroscopic surgery was not superior to conservative management in this type of patients. Therefore, arthroscopic meniscal surgery should not be recommended as a first choice of treatment for degenerative meniscal tears. In patients over 40 years of age, arthroscopic surgery should be cautiously considered for degenerative meniscal tears and only when there has not been a satisfactory response to conservative management. PMID- 29974217 TI - The subchondral bone layer and glenoid implant design are relevant for primary stability in glenoid arthroplasty. AB - BACKGROUND: Clinical studies suggest that reaming of the subchondral bone layer to achieve good implant seating is a risk factor for glenoid loosening. This study aims to evaluate (1) the importance of the subchondral bone layer and (2) the influence of the design of the glenoid component. METHODS: Different techniques for preparation of an A1 glenoid were compared: (1) preserving the subchondral bone layer; (2) removal of the subchondral bone layer; (3) implantation of a glenoid component that does not adapt to the native anatomy. Artificial glenoid bones (n = 5 each) were used with a highly standardized preparation and implantation protocol. Biomechanical testing was performed during simulated physiological shoulder motion. Using a high-resolution optical system, the micromotions between implant and bone were measured up to 10,000 motion cycles. RESULTS: At the 10,000 cycle measuring point, significantly more micromotions were found in the subchondral layer removed group than in the subchondral layer preserved group (p = 0.0427). The number of micromotions in the nonadapted group was significantly higher than in the subchondral layer preserved group (p = 0.0003) or the subchondral layer removed group (p = 0.0207). CONCLUSION: Conservative reaming proved important to diminish the micromotions of the glenoid component. Implantation of a glenoid component that matches with the bony underlying glenoid can help to preserve the subchondral bone layer without sacrificing proper implant seating. PMID- 29974218 TI - Correction to: CT diagnosis of gallbladder adenomyomatosis: importance of enhancing mucosal epithelium, the "cotton ball sign". AB - The original version of this article, published on 09 April 2018, unfortunately contained a mistake. The following correction has therefore been made in the original: The presentation of Fig. 2 was incorrect, "Cotton ball sign" was mistakenly named "Polka-dot sign". PMID- 29974219 TI - Magnetic resonance hysterosalpingography in diagnostic work-up of female infertility - comparison with conventional hysterosalpingography: a randomised study. AB - OBJECTIVE: To compare diagnostic accuracy of MR-hysterosalpingography (MR-HSG) and conventional hysterosalpingography (X-HSG) in the evaluation of female infertility. METHODS: Forty women received prospectively both X-HSG, the gold standard technique, and MR-HSG on the same day but the order in which they were conducted was randomised. A 1.5 Tesla MRI was performed with classical sequences for pelvic analysis and an additional 3D T1-weighted sequence with intra-uterine injection of gadolinium. Two radiologists independently interpreted X-HSG and MR HSG according to randomisation, blinded to the other results. They both then performed a second interpretation of MR-HSG blinded to the first reading with a minimum time delay of 1 week. Diagnostic performance of MR-HSG for analysis of tubal and intracavity abnormalities was evaluated by calculating sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Twenty-six patients were included. Diagnostic performance of MR-HSG was: Se: 91.7% (95% CI 61.5-99.8); Sp: 92.9% (95% CI 66.1-99.8) ; PPV: 91.7% (95% CI 61.5-99.8); NPV: 92.9% (95% CI 66.1-99.8). Pain analysis showed a significant statistical difference between the two procedures: average VAS for X HSG was 4.43 (95% CI 3.50-5.36) versus 3.46 (95% CI 2.62-4.31) for MR-HSG, p=0,01. Intra- and inter-rater agreements for detection of tubal or intracavity abnormalities were 0.92 (95% CI 0.78-1.00) and 0.76 (95% CI 0.52-1.00). CONCLUSION: MR-HSG is a well-tolerated technique demonstrating high accuracy in investigating tubal patency and intra-uterine abnormalities for diagnostic work up of female infertility. KEY POINTS: * MR-hysterosalpingography is an innovative technique. * Hysterosalpingography can be used to investigate tubal patency and intracavity abnormalities. * Hysterosalpingography is a potential 'one-stop-shop' imaging technique for a single comprehensive examination of female infertility. PMID- 29974220 TI - Comparison of single and tandem ureteral stenting for malignant ureteral obstruction: a prospective study of 104 patients. AB - OBJECTIVES: The aim of this study was to compare single and tandem ureteral stenting in the management of malignant ureteral obstruction (MUO). METHODS: Our hospital's institutional review board approved this prospective study. Between November 2014 and June 2017, single ureteral stenting was performed in 56 patients (94 renal units) and tandem ureteral stenting in 48 patients (63 renal units) for MUO. A comparative analysis of the technical success rate, patient survival, stent patency, and complications was performed. RESULTS: Similar demographic data were observed in patients receiving either single or tandem ureteral stenting. The technical success rate was 93.6% (88/94) for single ureteral stenting and 95.2% (60/63) for tandem ureteral stenting. There was no difference in overall survival between patients receiving single or tandem ureteral stenting (p = 0.41), but the duration of stent patency in tandem ureteral stenting was significantly longer (p = 0.022). The mean patency time was 176.7 +/- 21.3 days for single ureteral stenting, and 214.7 +/- 21.0 days for tandem ureteral stenting. The complications of ureteral stenting were urinary tract infection (n = 18), lower urinary tract symptoms (n = 5), haematuria (n = 3), and stent migration (n = 1). CONCLUSIONS: Tandem ureteral stenting is a safe and feasible treatment for MUO, and had better efficacy compared to single ureteral stenting. KEY POINTS: * Ureteral stenting is an established treatment for the management of malignant ureteral obstruction (MUO) * Prospective single centre study showed that tandem ureteral stenting is a safe and feasible treatment for MUO * Tandem ureteral stenting provides longer stent patency compared to single ureteral stenting in patient with MUO. PMID- 29974221 TI - Optimal criteria for hepatocellular carcinoma diagnosis using CT in patients undergoing liver transplantation. AB - OBJECTIVE: To compare the diagnostic performance of various guidelines for hepatocellular carcinoma (HCC) diagnosis using computed tomography (CT) in patients undergoing liver transplantation (LT). METHODS: In total, 216 patients who underwent preoperative CT and subsequent LT were included. Two radiologists retrospectively evaluated focal hepatic lesions independently according to various guidelines and allocated patients according to the Milan criteria. The diagnostic performance of the guidelines was compared using alternative free response receiver-operating characteristics (AFROC) analysis with bootstrapping. Comparisons of sensitivity, specificity, and accuracy of patient allocation based on the Milan criteria between guidelines were performed using logistic regression with generalized estimating equations (GEE). RESULTS: Fifty-two of 216 patients had 87 HCCs. The reader-averaged figure of merit obtained using AFROC analysis was 0.738 for the AASLD/EASL or KLCSG-NCC guidelines and 0.728 for the LI-RADS v2014 or OPTN/UNOS (bootstrapping, p = 0.005). The per-lesion sensitivity for HCCs (all and 1-2-cm lesions) was significantly higher with the AASLD/EASL (37.9 41.4% and 30.8-41.0%) than with LI-RADS (28.7% and 15.4-18.0%) (logistic regression with GEE, p = 0.008 and 0.030 for reader 1 and p = 0.005 for reader 2). The per-patient specificity (98.8-99.4%) was the same for all guidelines. The accuracy of the Milan criteria was 81.5-83.3% without significant differences among the four guidelines (logistic regression with GEE, p > 0.05). CONCLUSION: AASLD/EASL showed higher diagnostic performance and sensitivity, particularly for 1-2-cm HCCs, and the same specificity with LI-RADS. All guidelines are comparable for patient allocation based on the Milan criteria for LT. KEY POINTS: * The overall diagnostic performance of CT for HCC diagnosis was highest with AASLD/EASL. * AASLD/EASL showed higher sensitivity for diagnosis of 1-2-cm HCCs than LI-RADS. * The accuracy of the Milan criteria using CT was comparable among the four guidelines. PMID- 29974222 TI - Abnormalities of white and grey matter in early multiple system atrophy: comparison of parkinsonian and cerebellar variants. AB - OBJECTIVE: Multiple system atrophy (MSA) is a neurodegenerative disorder with progressive motor and autonomic dysfunction. There is a paucity of information on the early neurostructural changes in MSA, especially its subtypes, MSA-P (patients with predominant parkinsonism) and MSA-C (patients with predominant cerebellar signs). This study investigates the abnormalities of grey matter (GM) and white matter (WM) in early MSA and its subtypes using multi-modal voxel-based analysis. MATERIALS AND METHODS: Twenty-six patients with MSA with duration of symptoms <= 2.5 years (mean duration: 1.6 +/-0.9 years) were assessed clinically and with 3T MRI. Voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) were performed to identify the structural changes in MSA and its subtypes. The GM changes and diffusion parameters of WM tracts were correlated with the clinical scores. The results were compared with MRI of 25 age- and gender-matched healthy controls. RESULTS: The early structural changes in MSA included GM loss of the cerebellum and subcallosal gyrus with widespread involvement of supratentorial and infratentorial WM fibres. In MSA-C, GM loss was limited to the cerebellum with WM changes predominantly affecting the infratentorial WM and association tracts. In contrast, MSA-P did not demonstrate any GM loss and the WM involvement was mainly supratentorial. There was no significant correlation between structural changes and clinical severity score. CONCLUSION: In early MSA, WM microstructure was more affected than GM. These changes were greater in MSA-C than in MSA-P, suggesting variable deterioration in the subtypes of MSA. KEY POINTS: * Structural changes in early multiple system atrophy were evaluated using multi-modal neuroimaging. * White matter was more affected than grey matter in early MSA. * Clinical variables did not correlate with early structural changes. PMID- 29974223 TI - Causal association between smoking behavior and the decreased risk of osteoarthritis: a Mendelian randomization. AB - OBJECTIVE: This study aimed to examine whether smoking behavior is causally associated with osteoarthritis. METHODS: A two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR Egger regression methods was performed. We used the publicly available summary statistics datasets of smoking behavior genome-wide association studies (GWASs; n = 85,997) as an exposure, and a GWAS in 7410 patients with osteoarthritis in the arcOGEN study and 11,009 controls of European ancestry as an outcome. RESULTS: We selected four single nucleotide polymorphisms (SNPs) from GWASs of smoking behavior as instrumental variables (IVs) to improve inference. These SNPs were located at CHRNA3 (rs1051730), SLC25A5P5A9 (rs215614), CHRNB3 (rs6474412), and CYP2B6 (rs7260329). The IVW method showed evidence to support an inverse causal association between smoking behavior and osteoarthritis in the knee and hip (beta = -0.056, standard error [SE] = 0.027, p = 0.035). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = 0.005; p = 0.848), but showed no causal association between smoking behavior and osteoarthritis (beta = -0.048, SE = 0.048, p = 0.427). However, the weighted median approach yielded evidence of a negative causal association between smoking behavior and osteoarthritis (beta = -0.056, SE = 0.028, p = 0.046). Cochran's Q test and the funnel plot indicated no evidence of heterogeneity between IV estimates based on the individual variants. CONCLUSION: The results of MR analysis support that smoking behavior was causally associated with a reduced risk of osteoarthritis. PMID- 29974224 TI - [Rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic and progressive systemic disease of the connective tissue, which is particularly manifested with destructive alterations to the joints. Inflammatory reactions in the synovium lead to the influx of peripheral inflammatory cells as well as the activation of local cells. Released growth factors, chemokines and especially cytokines play a key role in chronic inflammatory responses. In addition to the central lymphocytes, the T and B cells and their subpopulations, locally resident cells, such as neutrophils, macrophages and fibroblasts as well as cells of bone metabolism are activated by the inflammatory milieu and contribute to and drive inflammation and tissue damage. The destruction of cartilage and bone substance by local tissue cells, synovial fibroblasts and osteoclasts is characteristic for this disease. Untreated, the local inflammatory and destructive processes as well as systemic inflammatory factors lead to progressive and irreversible joint destruction. Cellular and immunological processes in RA are closely interwoven; therefore, besides the general inhibition of immunological processes, specific inhibition of central key molecules can reduce or completely stop the inflammatory destructive processes; however, a high heterogeneity can be observed among RA patients and disease progression. Therefore, an expansion of the therapeutic options is desirable as not all patients are able to equally benefit from the therapeutic treatment. It is important to characterize new molecular mechanisms, which could lead to the development of new therapeutic options. Some of the more recent insights are summarized in this overview. PMID- 29974225 TI - Causal association between rheumatoid arthritis and a decreased risk of Alzheimer's disease : A Mendelian randomization study. AB - OBJECTIVE: This study aimed to examine whether rheumatoid arthritis (RA) is causally associated with Alzheimer's disease (AD). METHODS: We performed a two sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We used the publicly available summary statistics datasets from three-stage trans-ethnic genome-wide association studies (GWAS) meta-analyses of 29,880 RA cases and 73,758 controls as exposures and a meta-analysis of 4 GWAS datasets consisting of 17,008 AD cases and 37,154 controls of European descent as outcomes. RESULTS: We selected 80 single nucleotide polymorphisms (SNPs) from GWAS data on RA as instrumental variables (IVs), 60 of which were associated with RA on a genome-wide significance level. The IVW method showed evidence to support an inverse causal association between RA and AD (beta = -0.039, standard error [SE] = 0.017, P = 0.021). MR-Egger regression revealed that directional pleiotropy was unlikely to be a source of bias in the results (intercept = 0.002; P = 0.649). The MR-Egger analysis showed no causal association between RA and AD (beta = -0.050, SE = 0.030, P = 0.096). However, the weighted median approach showed that RA and AD were causally linked (beta = -0.078, SE = 0.024, P = 0.001). The funnel plot did not show heterogeneity between IV estimates based on the individual variants. CONCLUSIONS: The MR analysis supports that RA was causally associated with a reduced risk of AD. PMID- 29974226 TI - Metabolite profiles evaluated, according to sex, do not predict resting energy expenditure and lean body mass in healthy non-obese subjects. AB - PURPOSE: Differences in resting energy expenditure (REE) between men and women mainly result from sex-related differences in lean body mass (LBM). So far, a little is known about whether REE and LBM are reflected by a distinct human metabolite profile. Therefore, we aimed to identify plasma and urine metabolite patterns that are associated with REE and LBM of healthy subjects. METHODS: We investigated 301 healthy male and female subjects (18-80 years) under standardized conditions in the cross-sectional KarMeN (Karlsruhe Metabolomics and Nutrition) study. REE was determined by indirect calorimetry and LBM by dual X ray absorptiometry. Fasting blood and 24 h urine samples were analyzed by targeted and non-targeted metabolomics methods using GC * GC-MS, GC-MS, LC-MS, and NMR. Data were evaluated by predictive modeling of combined data using different machine learning algorithms, namely SVM, glmnet, and PLS. RESULTS: When evaluating data of men and women combined, we were able to predict REE and LBM with high accuracy (> 90%). This, however, was a clear effect of sex, which is supported by the high degree of overlap in identified important metabolites for LBM, REE, and sex, respectively. The applied machine learning algorithms did not reveal a metabolite pattern predictive of REE or LBM, when analyzing data for men and women, separately. CONCLUSIONS: We could not identify a sex independent predictive metabolite pattern for REE or LBM. REE and LBM have no impact on plasma and urine metabolite profiles in the KarMeN Study participants. Studies applying metabolomics in healthy humans need to consider sex specific data evaluation. PMID- 29974227 TI - Iodine status in Norwegian preschool children and associations with dietary iodine sources: the FINS-KIDS study. AB - PURPOSE: Iodine is an essential trace element necessary for thyroid hormone synthesis. Iodine deficiency is a continuing public health problem despite international efforts to eliminate it. Studies on iodine status in preschoolers are scarce. Thus, the aims of the current study were to determine the iodine status and to investigate possible associations between urinary iodine concentration (UIC) and estimated 24 h iodine extraction (UIE) and iodine-rich foods. METHODS: Data are cross-sectional baseline data, obtained from the two armed randomized controlled dietary trial "Fish Intervention Studies-KIDS" (FINS KIDS) conducted in Bergen, Norway. UIC was determined by inductively coupled plasma-mass spectrometry in spot urine samples. Inadequate UIC was defined as median < 100 ug/L, and low estimated 24 h UIE as < 65 ug/day. Habitual dietary intake was assessed by a short food frequency questionnaire. Logistic regression models were used to investigate possible associations between UIC and estimated 24 h UIE and iodine-rich dietary sources including seafood, dairy products and eggs. Iodine/creatinine ratio (I/Cr) was also estimated. RESULTS: Urinary spot samples were obtained from 220 children. The median (interquartile range) UIC and estimated 24 h UIE was 132 (96) ug/L, and 65 (55) ug/day, respectively. The majority of children had an estimated I/Cr ratio within 100-199 ug/g. Intake of sweet milk < 2 times/day versus >= 2 times/day was associated with UIC < 100 ug/L (OR 2.17, 95% CI 1.07-4.38, p = 0.031). Intake of dairy products (OR 3.59, 95% CI 1.13-11.43, p = 0.031) and sweet milk (OR 2.77, 95% CI 1.37-5.61, p = 0.005) < 2 times/day versus >= 2 times day was associated with estimated 24 h UIE < 65 ug/day. CONCLUSIONS: The preschoolers had adequate iodine status. Low intake of sweet milk and dairy products were associated with low iodine status. PMID- 29974228 TI - Increased bioavailability of curcumin using a novel dispersion technology system (LipiSperse(r)). AB - PURPOSE: Curcumin has been shown to deliver protective effects against numerous degenerative conditions associated with high levels of inflammation and oxidative stress. Owing to its poor bioavailability when delivered orally, it is difficult to deliver a high concentration therapeutic dose. LipiSperse(r) is a novel delivery system that uses dispersion technology to enhance bioavailability of hydrophobic agents. In this study, we investigated the pharmacokinetics of a commercially available curcumin extract, with or without the curcumin LipiSperse(r) delivery complex. METHODS: Eighteen healthy male and female volunteers participated in this single equivalent dose, randomised, double blinded study. Seven of those volunteers further participated in the crossover phase of the trial. Plasma concentrations were determined at baseline and at regular intervals over a 24-h period following 750 mg of curcuminoid ingestion. RESULTS: In both the parallel and crossover trial, Curcumin with LipiSperse(r) delivered significantly higher plasma curcuminoid concentrations compared to the raw curcumin product (807 vs 318 ng/mL in the crossover trial). CONCLUSIONS: The novel delivery system LipiSperse(r) is safe in humans, and demonstrates superior bioavailability for the supply of curcumin when compared to a standard curcumin extract. PMID- 29974230 TI - Bloodstream infections with gram-negative organisms and the impact of multidrug resistance in patients with hematological malignancies. AB - Infections and especially blood stream infections (BSI) with gram-negative bacteria (GNB) represent a major threat for patients with hematological diseases undergoing chemotherapy and mainly contribute to morbidity and mortality. In this retrospective single-center study, we analyzed the impact of BSI with different gram-negative multidrug-resistant bacteria (MDRGN) compared to BSI with antibiotic susceptible gram-negative bacteria. Data of 109 patients with hematological malignancies and GNB BSI were analyzed with overall survival (OS) 30 days after BSI being the primary endpoint. BSI with non-fermentative gram negative bacteria were found in 26.6% of all patients and 73.4% suffered from a BSI with an Enterobacteriaceae. Thirty-two of 109 patients suffered from BSI with MDRGN. Characteristics of MDRGN and non-MDRGN BSI patients did not differ besides the fact that significantly more patients received an immunosuppressive therapy in the MDRGN BSI group. OS (30 days after BSI) of patients with MDRGN BSI was significantly lower (85.6 vs. 55.9%; p < 0.001) compared to patients with non MDRGN BSI. Patients with MDRGN BSI with non-fermentative pathogens had a worse OS after 30 days compared to MDRGN BSI with Enterobacteriaceae and the same holds true for non-MDRGN BSI. In multivariate analysis of MDRGN BSI, non-fermenters and ICU admission were independently associated with increased 30-day mortality. Our data demonstrate the negative impact of non-fermentative gram-negative pathogens causing BSI compared to Enterobacteriaceae in hematological patients and thereby underlining the heterogeneity of gram-negative BSI. PMID- 29974231 TI - Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma. AB - Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after >= 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population. PMID- 29974229 TI - Diet as a moderator in the association of sedentary behaviors with inflammatory biomarkers among adolescents in the HELENA study. AB - AIM: To assess if a healthy diet might attenuate the positive sedentary inflammation relation, whereas an unhealthy diet may increase the effect of sedentary behaviors on inflammatory biomarkers. METHODS: In 618 adolescents (13 17 years) of the European HELENA study, data were available on body composition, a set of inflammation markers, and food intake assessed by a self-administered computerized 24 h dietary recall for 2 days. A 9-point Mediterranean diet score and an antioxidant-rich diet z-score were used as dietary indices and tested as moderators. A set of low-grade inflammatory characteristics was used as outcome: several cytokines in an inflammatory ratio (IL-6, IL-10, TNF-alpha, TGFbeta-1), C reactive protein, three cell-adhesion molecules (sVCAM-1, sICAM-1, sE-selectin), three cardiovascular risk markers (GGT, ALT, homocysteine) and three immune cell types (white blood cells, lymphocytes, CD3). Sedentary behaviors were self reported and analyzed as total screen time. Multiple linear regression analyses tested moderation by diet in the sedentary behaviors-inflammation association adjusted for age, sex, country, adiposity (sum of six skinfolds), parental education, and socio-economic status. RESULTS: Both diet scores, Mediterranean and antioxidant-rich diet, were significant protective moderators in the effect of sedentary behaviors on alanine-transaminase enzyme (P = 0.014; P = 0.027), and on the pro/anti-inflammatory cytokine ratio (P = 0.001; P = 0.004), but not on other inflammatory parameters. CONCLUSION: A higher adherence to the Mediterranean diet or an antioxidant-rich diet may attenuate the onset of oxidative stress signs associated by sedentary behaviors, whereas a poor diet seems to increase inflammation. PMID- 29974233 TI - Lopinavir serum concentrations of critically ill infants: a pharmacokinetic investigation in South Africa. AB - The role of therapeutic drug monitoring in pediatric antiretroviral therapy is unclear. A little pharmacokinetic datum from clinical practice exists beyond controlled approval studies including clinically stable children. The aim of this study is to quantify LPV exposure of critically ill infants in an ICU and-by identifying risk factors for inadequate exposure-to define sensible indications for TDM in pediatric HIV care; in addition, assume total drug adherence in ICU to compare LPV exposure with a setting of unknown adherence. In this prospective investigation, 15 blood samples from critically ill infants in the pediatric ICU at Tygerberg Hospital were analyzed for LPV-serum concentrations. They were then compared to those of 22 blood samples from out-patient children. Serum-level measurements were performed with an established high-performance liquid chromatography method. All LPV-serum levels of ICU patients were higher than a recommended Ctrough (= 1.000 ng/ml), 60% of levels were higher than Cmax (8.200 ng/ml). Partly, serum levels reached were extremely high (Maximum: 28.778 ng/ml). Low bodyweight and age correlated significantly with high LPV concentrations and were risk factors for serum levels higher than Cmax. Significantly fewer serum levels from infants in ICU care (mean: 11.552 ng/ml +/- SD 7760 ng/ml) than from out-patient children (mean: 6.756 ng/ml +/- SD 6.003 ng/ml) were subtherapeutic (0 vs. 28%, p = 0.008). Under total adherence in the ICU group, there were no subtherapeutic serum levels, while, in out-patient, children with unknown adherence 28% of serum levels were found subtherapeutic. Low bodyweight and age are risk factors for reaching potentially toxic LPV levels in this extremely fragile population. TDM can be a reasonable tool to secure sufficient and safe drug exposure in pediatric cART. PMID- 29974232 TI - PA-X: a key regulator of influenza A virus pathogenicity and host immune responses. AB - PA-X, a fusion protein belonging to influenza A viruses (IAVs), integrating the N terminal 191 amino acids of PA gene and the ribosomal frame-shifting product that lengthens out to 41 or 61 amino acids. Since its discovery in 2012, multiple functions have been attributed to this small protein, including a process, where wide-spread protein synthesis in infected host cells is shut down (called host shutoff), and viral replication, polymerase activity, viral-induced cell apoptosis, PA nuclear localization, and virulence are modulated. However, many of its proposed functions may be specific to strain, subtype, host, or cell line. In this review, we start by describing the well-defined global host-shutoff ability of PA-X and the potential mechanisms underlying it. We move on to the role played by PA-X in modulating innate and acquired immune responses in the host. We then systematically discuss the role played by PA-X in modulating the virulence of influenza viruses of different subtypes and host origins, and finish with a general overview of the research advances made in identifying the host cell partners that interact with PA-X. To uncover possible clues about the differential effects of PA-X in modulating viral virulence, we focus on systemically evaluating polymorphisms in PA-X from various viral subtypes and hosts, including avian and human H5N1, H5N6, H9N2, and H7N9 viruses. Finally, we conclude with a proposition regarding the possible future research directions for this important protein. PMID- 29974234 TI - Upregulation of insulin-like growth factor II mRNA-binding protein 3 (IMP3) has negative prognostic impact on early invasive (pT1) adenocarcinoma of the esophagus. AB - PURPOSE: Therapeutic decisions in esophageal adenocarcinomas (EAC) restricted to mucosa (pT1a) or submucosa (pT1b) depend mainly on classic histomorphology-based criteria like tumor grading or lymphovascular invasion with limited success. There is a strong need for reliable pre-therapeutical biomarker-based evaluation also applicable on endoscopically obtained biopsies. METHODS: Patients who underwent esophagectomy due to EAC in a high volume center between 1999 and 2016 were included. Tissue microarrays (TMA) were retrospectively established from the formalin-fixed and paraffin-embedded material of the resected specimens and immunohistochemically stained using a monoclonal primary antibody specific for IMP3. IMP3 staining intensity was scored manually according to a 3-tier-scoring system (negative, weak and strong). RESULTS: 371 EACs were interpretable for analysis. 109 patients (29%) had early invasive (pT1a/pT1b) and 262 patients (71%) locally advanced EAC (> pT2). 259 EACs (70%) revealed positive immunostaining for IMP3 including 167 strongly and 92 weakly positive. Early EAC had significantly lower IMP3 expression compared to advanced tumor stages (p < 0.0001). IMP3 positive pT1 EAC revealed higher levels of lymph node metastases (LNM) (p = 0.0001) and pT1b tumors showed higher rates of IMP3 positivity compared to pT1a (p = 0.007). Subdividing the submucosa in thirds, there was a significant trend for higher IMP3 expression with deeper tumor infiltration from pT1a to pT1b (sm3) (p = 0.0001). There was an association between IMP3 expression and shortened survival in pT1 EAC (p = 0.038). CONCLUSIONS: IMP3 expression correlates with depth of tumor infiltration, rate of LNM and is associated with worse outcome. Thus, IMP3 might be useful for therapeutic decisions in early invasive EAC. PMID- 29974236 TI - The evolution of cranial meningioma surgery-a single-center 25-year experience. AB - BACKGROUND: There have been major developments in diagnostic and surgical and non surgical techniques used in the management of meningiomas over last three decades. We set out to describe these changes in a systematic manner. METHOD: Clinical and radiological data, surgical procedures, complications, and outcome of 817 patients who underwent surgery for primarily diagnosed meningioma between 1991 and 2015 were investigated. RESULTS: Median age at diagnosis increased significantly from 56 to 59 years (p = .042), while tumor location and preoperative Karnofsky performance status did not change during the observation period. Availability of preoperative MRI increased, and rates of angiography and tumor embolization decreased (p < .001, each). Median duration of total, pre-, and postoperative stay was 13, 2, and 9 days, respectively, and decreased between 1991 and 2015 (p < .001, each). Median incision-suture time varied annually (p < .001) but without becoming clearly longer or shorter during the entire observation period. The use of intraoperative neuronavigation and neuromonitoring increased, while the rates of Simpson grade I and III surgeries decreased (p < .001). Rates of postoperative hemorrhage (p = .997), hydrocephalus (p = .632), and wound infection (p = .126) did not change, while the frequency of early postoperative neurological deficits decreased from 21% between 1991 and 1995 to 13% between 2011 and 2015 (p = .003). During the same time, the rate of surgeries for postoperative cerebrospinal fluid leakage slightly increased from 2 to 3% (p = .049). Within a median follow-up of 62 months, progression was observed in 114 individuals (14%). Progression-free interval did not significantly change during observation period (p > .05). Multivariate analyses confirmed the lack of correlation between year of surgery and tumor relapse (HR: 1.1, p > .05). CONCLUSIONS: Preoperative diagnosis and surgery of meningiomas have been substantially evolved. Although early neurological outcome has improved, long term prognosis remains unchanged. PMID- 29974235 TI - Challenges in investigation of diabetes-related aviation fatalities-an analysis of 1491 subsequent aviation fatalities in USA during 2011-2016. AB - Diabetes mellitus (DM) could cause pilot incapacitation and result in aviation fatalities. The mechanisms could be directly as a consequence of acute hypoglycemia/subacute diabetic ketoacidosis (DKA) or indirectly as an acute cardiovascular event by contributing to the development of atherosclerosis in coronary or carotid and cerebral arteries. In this study, DM-related fatal flight accidents in the US National Transport Bureau's database between years 2011-2016 were analyzed with special emphasis on postmortem (PM) glucose levels and correlation of toxicological reports with anamnestic information on DM. Additionally, autopsy results on coronary arteries were reviewed. In 43 out of 1491 (~ 3%) fatal accidents pilots had DM. Postmortem glucose or glycated hemoglobin percentage (Hb1Ac) was measured in 12 of the 43 cases; while antidiabetic medication was found in 14 of the cases (only two of the cases had both glucose measurements and medication). With the increasing prevalence of DM, a possibility of pilot incapacitation due to DM or complications of DM should be actively studied, even if no anamnestic information of DM was available. While PM hypoglycemia is difficult to assess, we propose a systematic investigation based on measurement of glucose, Hb1Ac%, and ketone bodies, and documentation of atherosclerotic lesions in major arteries to identify or rule out DM as a cause of pilot incapacitation. PMID- 29974237 TI - Huge myxoid chondrosarcoma expanded into the thoracic cavity with spinal involvement. AB - PURPOSE: En bloc resection is the treatment of choice of myxoid chondrosarcoma. These tumors can produce huge masses. Anatomical constraints limit the possibility to perform en bloc resection in the spine. METHODS: A very huge myxoid chondrosarcoma (14.2 * 10.8 * 11.4 cm) arising from T2 to T5 and invading the whole higher left pleural cavity was observed. Surgical planning according to WBB staging system was performed. RESULTS: The tumor was successfully submitted to en bloc resection achieving a tumor-free margin as demonstrated by the pathologist's report. CONCLUSIONS: A careful planning and a multidisciplinary collaboration make possible to perform en bloc resection even in apparently impossible cases. PMID- 29974238 TI - Evidence that shrublands and hummock grasslands are fire-mediated alternative stable states in the Australian Gibson Desert. AB - Alternative stable state theory predicts that different disturbance regimes may support contrasting ecosystem states under otherwise analogous environmental conditions. In fire-prone systems, this theory is often invoked to explain abrupt ecotones, especially when adjacent vegetation types have contrasting flammabilities and differing tolerances to pyric perturbation. Despite being well documented in forest-savanna transitions, unambiguous examples of fire-driven alternate stable states (FDASS) in arid systems are rare. The current study examined whether flammable spinifex (Triodia spp.) grasslands and fire-sensitive waputi (Aluta maisonneuvei subsp. maisonneuvei) shrublands in Australia's Gibson Desert represent FDASS. Specifically, analyses of soil and topographic variables assessed whether environmental differences explain habitat zonation. To determine whether different flammabilities of Aluta and Triodia systems may perpetuate alternative states via vegetation-fire feedback processes, community-level fuelloads were quantified to provide an indirect measure of flammability. To determine the propensity for fire to trigger 'state-shifting', community responses to a single high-severity fire were evaluated. Habitat segregation did not relate to between-site environmental differences, and the fuel-load study indicated that the more pyrophytic community (Triodia grassland) is more flammable, and hence more likely to experience higher frequency fire-cycles. Fire was identified as a potential vector of 'state-change', because although both systems regenerated well after fire, Triodia reproduced more prolifically at a younger age than Aluta, and hence should tolerate shorter fire-return intervals. In the absence of between-community topographic and edaphic differences, or herbivores that consume either plant, it is likely that Aluta shrublands and Triodia grasslands represent fire-mediated alternative equilibrium states. PMID- 29974239 TI - Low-grade infection due to annular closure device. PMID- 29974240 TI - Posterior interosseous nerve entrapments: review of the literature. Is the entrapment distal to the arcade of Frohse a really rare condition? AB - INTRODUCTION: Spontaneous posterior interosseous nerve palsy is a rare condition. Entrapment is mostly at level of the arcade of Frohse, and a few cases of distal entrapment have been described. METHODS: A case of entrapment distal to the arcade of Frohse is described here. Cases of distal entrapment have been reviewed from the published literature in order to evaluate the frequency of atraumatic mechanical palsy. RESULTS: Seven cases of distal entrapment have been identified. Lesion is the cause of palsy in 58.7% of the cases and entrapment in 20.65%. The pathology is at the elbow in 33.7% of the cases, at the arcade of Frohse in 28.26%, and at the supinator canal in 10.33%. Entrapment is at the arcade of Frohse in 64.45%, proximal in 20%, and distal in 15.55%. CONCLUSION: Posterior interosseous nerve distal entrapment is a rare condition; therefore, further investigation is needed when radiological images at the arcade of Frohse do not show any entrapment. PMID- 29974241 TI - Extensive perineural spread of an intrapelvic sciatic malignant peripheral nerve sheath tumor: a case report. AB - Perineural spread has been described in multiple neoplasms of neural and non neural origin. The peripheral nervous system may represent a highway by which tumors can spread throughout the body. Malignant peripheral nerve sheath tumor (MPNST) is a neoplasm arising from peripheral nerves with high rates of local recurrence and distant metastases, leading to a poor 5-year overall survival. In many cases, the optimal treatment involves wide en bloc excision with negative margins as well as chemotherapy and radiation. Even in cases of negative surgical margins, recurrence rates are high, suggesting possible skip lesions or very distant infiltration along the involved nerve. We report a case of high-grade MPNST of the sciatic nerve with post-mortem dissection and histopathologic characterization of perineural spread of microscopic disease to sites significantly proximal and distal to areas with evidence of gross disease, which may help to explain the high rates of local and distal recurrence in MPNST. PMID- 29974242 TI - A computational study on the endohedral alkali metal and ion B40 nanocluster. AB - Recent exploration of the boron fullerenes has raised exciting new prospects for boron applications. Here, the endohedral X/X+@B40 complexes (X = Li, Na, and K) were explored by means of density functional theory calculations. By increasing the atomic number, the interaction of alkali metals with the B40 nanocage is unusually weakened. It was concluded that by increasing the alkali metals' size, their electrons repel those of the cage, and the interaction weakens. The interaction of X with B40 is more favorable than that of X+. For example, the calculated DeltaG of interaction at 298 K and 1 atm is about -108.3 and + 18.4 kJ mol-1 for X and X+, respectively. Compared to the X+ cations, the X atoms considerably enhance the boron cluster electrical conductivity, by reducing the gap. We found that the B40 nanocluster is not large enough to freely embed large atoms, such as Na and K. Also, the electron emission from the surface of B40 cluster is increased and reduced by X and X+ encapsulations, respectively. PMID- 29974243 TI - A low cost PS based microfluidic platform to investigate cell cycle towards developing a therapeutic strategy for cancer. AB - Inhibition of DNA damage response pathway in combination with DNA alkylating agents may enhance the selective killing of cancer cells leading to better therapeutic effects. MDM2 binding protein (MTBP) in human has a role in G1 phase (interphase of cell cycle) and its overexpression leads to breast and ovarian cancers. Sld7 is an uncharacterized protein in budding yeast and a potential functional homologue of MTBP. To investigate the role of Sld7 as a therapeutic target, the behavior of the wild-type cells and sld7? mutants were monitored in 0.5 nL microbioreactors. The brightfield microscopy images were used to analyze the change in the cell size and to determine the durations of G1 and S/G2/M phases of wild type cells and mutants. With the administration of the alkylating agent, the cell size decreased and the duration of cell cycle increased. The replacement of the medium with the fresh one enabled the cells to repair their DNA. The application of calorie restriction together with DNA alkylating agent to mutant cells resulted in smaller cell size and longer G1 phase compared to those in control environment. For therapeutic purposes, the potential of MTBP in humans or Sld7 in yeast as a drug target deserves further exploration. The fabrication simplicity, robustness and low-cost of this microfluidic bioreactor made of polystyrene allowed us to perform yeast culturing experiments and show a potential for further cell culturing studies. The device can successfully be used for therapeutic applications including the discovery of new anti-microbial, anti inflammatory, anti-cancer drugs. PMID- 29974244 TI - Colorimetric and visual detection of mercury(II) based on the suppression of the interaction of dithiothreitol with agar-stabilized silver-coated gold nanoparticles. AB - A colorimetric and visual method is described for the determination of mercury(II) ion. A gel consisting of agar-stabilized silver-coated gold nanoparticles (Au@Ag NPs) was prepared. The reaction with dithiothreitol (DTT) via thiol-Ag chemistry results in an orange to purple color change of the gel. However, in the presence of Hg(II), the reaction of DTT with the silver shells is suppressed due to the strong thiophilicity of Hg(II). The color of the gel changes from purple to red to orange in the presence of increasing concentrations of Hg(II). The Au@Ag NPs therefore are a viable optical probe for Hg(II) which can be detected in concentration as low as 78 nM via dual-wavelength ratiometric absorbance (A390/A520), and at 1 MUM levels with bare eyes. The use of agar as a support is mandatory to prevent the aggregation of the NPs and also improves selectivity. The method was applied to the analysis of spiked samples, and recoveries ranged between 96.3 and 104%. The assay is easy, inexpensive, and in our perception represents an attractive tool for on-site visual detection of Hg(II). Graphical abstract Schematic of the assay. With increasing concentrations of Hg(II), the oxidative etching of silver shells caused by dithiothreitol (DTT) is gradually inhibited, and the color of agar-stabilized Au@Ag NP gel varies from purple to red, and finally to orange. This can be used for visual detection of Hg(II). PMID- 29974245 TI - Do autism spectrum disorder and anorexia nervosa have some eating disturbances in common? AB - A possible overlap between autism spectrum disorder (ASD) and anorexia nervosa (AN), in terms of both behavioural and cognitive features, has led to new areas of research. The aim of the present study was to examine the occurrence of eating behaviours frequently seen in ASD among adolescents and young adults with AN. The participants were females within the age range 15-25 years: 36 with current AN (32 were followed up after 1 year), 19 with ASD, and 30 healthy females. The participants completed the SWedish Eating Assessment for Autism spectrum disorders (SWEAA) and the Autism Spectrum Quotient tool (AQ). AN groups had significantly higher SWEAA scores than the healthy comparison group, also when patients had gained weight. Typical autistic eating behaviours, such as selective eating, were more common in the AN groups than in the ASD group. This is the first time that SWEAA has been implemented in an AN population. Eating behaviours frequently seen in ASD seem to be frequent in AN and some remain also after weight gain. PMID- 29974246 TI - The effects of changes in water and nitrogen availability on alien plant invasion into a stand of a native grassland species. AB - Plant invasions are a major component of global change, but they may be affected by other global change components. Here we used a mesocosm-pot experiment to test whether high water availability, nitrogen (N) enrichment and their interaction promote performance of three invasive alien plants (Lepidium virginicum, Lolium perenne and Medicago sativa) when competing with a native Chinese grassland species (Agropyron cristatum). Single plants of the three invasive and the one native species were grown in the center of pots with a matrix of the native A. cristatum under low, intermediate or high water availability and low or high N availability. The invasive species L. virginicum and M. sativa grew larger, and produced a higher biomass relative to competitors than the native species A. cristatum did. Increasing water availability promoted biomass production of all species, but water availability did not change the biomass of the central plants relative to that of the competitors. Nitrogen addition also increased biomass production of all species, and it increased the biomass of the central plants more so than that of the competitors. The positive effect of N addition on the biomass of the central plants relative to that of the competitors increased with increasing water availability. However, compared to central plants of the native species, the positive effect of N addition on the relative biomass of L. virginicum decreased when water availability increased. These interactions indicate that future changes in water availability and N enrichment may affect the invasion success of different alien species differently. PMID- 29974247 TI - Quantum-chemical simulations of the hydration of Pb(II) ion: structure, hydration energies, and pKa1 value. AB - Thermodynamic and structural aspects of the hydration of Pb(II) ions were explored based on DFT calculations combined with the supermolecular/continuum solvent model. Hydration of Pb(II) was considered as the formation of Pb(H2O)n2+ aqua complexes (n=6-9) from the gas phase Pb(II) ion. Hexa- and hepta-aqua Pb(II) complexes were shown to exhibit the hemidirected symmetry, while those containing eight and nine water molecules are characterized by the holodirected symmetry. The calculations showed that because Pb(H2O)n2+ complexes with six to nine water molecules have comparable thermodynamic stabilities, such complexes are likely to coexist in aqueous solutions. The deprotonation of Pb(H2O)n2+ complexes was shown to result in the formation of the mono-hydroxo complex [Pb(H2O)4OH]+. The pKa1 value determined for this reaction (7.58 for Pb(H2O)62+) was close to the experimental value of 7.61 used in recent models of aquatic equilibria. The density functional method omega-B97X(PCM-UAO) in combination with the atomic basis set 6-311++G(d,p) for O and H and the small-core electron effective pseudopotential (ECP) with the aug-cc-pvdz-PP basis set for Pb can be recommended for such calculations. Graphical abstract Structures of Pb(II) ions with varying numbers of water molecules in the inner hydration shell. PMID- 29974248 TI - A cathodic photoelectrochemical sensor for chromium(VI) based on the use of PbS quantum dot semiconductors on an ITO electrode. AB - Under visible-light irradiation, a cathodic photoelectrochemical (PEC) sensor is presented for highly sensitive determination of Cr(VI) at a potential of -0.25 V (vs SCE). PbS quantum dots (QDs) were capped with mercaptoacetic acid and assembled on the surface of an indium tin oxide (ITO) electrode via the linker poly(diallyl dimethyl ammonium chloride) providing a photoactive sensor. Cr(VI) accepts the photoelectrons generated by the PbS QDs. This promotes the separation of electron holes and enhances the cathodic photocurrent generated by a 470-nm LED. The sensor has 10 pM detection limit and a linear working range from 0.02 nM to 2 MUM of chromate. The method was successfully applied to the determination of Cr(VI) and total chromium in spiked environmental water samples. Graphical abstract Schematic illustration of the photocurrent enhancement response of ITO/PbS toward chromium(VI). In the presence of Cr(VI) (red line), Cr(VI) accepts the photoelectrons generated by the PbS QDs under 470-nm LED irradiation, resulting in improved photocurrent of ITO/PbS. PMID- 29974249 TI - Toxicity of some aquatic pollutants to fish. AB - Pesticide residues threaten fish that live in rivers. This study investigated the effects of Nemacur, malathion, and diuron on freshwater fish behavior, mortality, acetylcholinesterase (ACHE) activity, liver biomarkers, and residue accumulation. Fish were exposed to individual concentration of Nemacur, malathion, and diuron at 1 mg/L and to binary mixtures in glass aquarium 16 L capacity. Mortality of fish was also investigated at a range of 0.0-1 mg/L of Nemacur and malathion. The biochemical effects of the tested compounds were recorded. The results showed abnormal fish behavior at low concentration (0.1 mg/L) of malathion, high fish mortality at 0.1 mg/L of Nemacur and mixtures with Nemacur, and no mortality with diuron. Mortality increased and became more intense after 48 h rather than after 24 h. Diuron increased the effect of Nemacur and malathion at low concentration. ACHE was inhibited at different percentages in the blood serum and brain homogenate due to exposure to Nemacur, malathion, diuron, and/or a combination of these pesticides. Liver biomarker levels were higher in the blood serum of the treated fish than the control group. The interesting outcome of the study is that Nemacur is several folds more toxic than malathion and diuron. Mixtures showed synergistic effects. The pesticide residues in the fish muscles were less than those in the water. It can be concluded that low concentrations of Nemacur, malathion, and diuron are negatively affecting fish in rivers. PMID- 29974250 TI - Copper-catalyzed cyclopropanation reaction of but-2-ene. AB - The mechanism of the copper(I)-catalyzed cyclopropanation reaction for methyl diazoacetate with both (Z)- and (E)-but-2-ene stereoisomers has been studied using the 6-311++G(d,p) basis set by means of M06-2X and O3LYP functionals. According to both methods, the rate-limiting step is the formation of a copper carbene intermediate, formed by association between methyl diazoacetate and bis(acetonitrile)-copper(I) ion with the concomitant extrusion of dinitrogen. Cis/trans diastereoselectivity for the cyclopropanation reaction of a 1,2 disubstituted alkene ((Z)-but-2-ene) has been theoretically studied for the first time through the proper location of transition states on the potential-energy surface with the O3LYP method, since no transition structures could be found with the M06-2X functional due to the extreme flatness of the potential-energy surface. The calculated stereoselectivities involving two acetonitrile ligands or one dichloromethane molecule show qualitative agreement with experimental data. This study allows attributing the origin of the selectivity to steric interactions between the ligands of the catalyst system and the olefin substituents. The comparison between the corresponding activation barriers for the direct insertion step shows a higher reactivity for the Z stereoisomer of but 2-ene, consistently with the larger reactant destabilization through steric interactions. PMID- 29974251 TI - Developing japonica rice introgression lines with multiple resistance genes for brown planthopper, bacterial blight, rice blast, and rice stripe virus using molecular breeding. AB - Yield losses as a result of biotic stresses by fungi, bacteria, viruses, and insects are a key challenge in most rice cultivation areas. The development of resistant cultivars is considered an efficient and sustainable approach to mitigate rice yield reduction. In the present study, we describe the development of japonica rice introgression lines with multiple resistance genes (MR lines), resistant to four different types of biotic stresses, and compare the agronomic performance, yield, and grain quality parameters of these lines with those of the recurrent parent. A total of nine MR lines were developed by marker-assisted backcrossing, which combined five single-R genes in a japonica background with a minimum of linkage drag. All the MR lines harbored the R genes Bph18 and qSTV11SG and two Pi genes (Pib + Pik) in common, offering resistance to brown planthopper (BPH), rice stripe virus (RSV), and rice blast disease, respectively. In the case of bacterial blight (BB), Xa40 was detected in only five out of the nine and Xa3 was validated in the others. In particular, the five MR lines pyramiding the R genes (Bph18 + qSTV11SG + Pib + Pik) in combination with Xa40 showed stable resistance to all bioassays for BPH, BB, blast, and RSV. The MR lines did not show any negative effects on the main agronomic traits, including yield production and rice grain quality. The lines have significant potential to stabilize rice yield and minimize production costs in disease and pest-prone areas in Korea, through the pyramiding of five R genes using a marker-assisted backcrossing strategy. PMID- 29974252 TI - A RNAscope whole mount approach that can be combined with immunofluorescence to quantify differential distribution of mRNA. AB - RNAscope(r) technology provided by Advanced Cell Diagnostics (ACD) allows the detection and evaluation of coinciding mRNA expression profiles in the same or adjacent cells in unprecedented quantitative detail using multicolor fluorescent in situ hybridization (FISH). While already extensively used in thinly sectioned material of various pathological tissues and, to a lesser extent, in some whole mounts, we provide here a detailed approach to use the fluorescent RNAscope method in the mouse inner ear and thick brain sections by modifying and adapting existing techniques of whole mount fluorescent in situ hybridization (WH-FISH). We show that RNAscope WH-FISH can be used to quantify local variation in overlaying mRNA expression intensity, such as neurotrophin receptors along the length of the mouse cochlea. We also show how RNAscope WH-FISH can be combined with immunofluorescence (IF) of some epitopes that remain after proteinase digestion and, to some extent, with fluorescent protein markers such as tdTomato. Our WH-FISH technique provides an approach to detect cell-specific quantitative differences in developing and mature adjacent cells, an emerging issue revealed by improved cellular expression profiling. Further, the presented technique may be useful in validating single-cell RNAseq data on expression profiles in a range of tissue known or suspected to have locally variable mRNA expression levels. PMID- 29974253 TI - Electronic properties of FeCl3 and CrO3 interacting with GaN nanotubes from density functional calculations. AB - The structural and electronic properties of FeCl3 and CrO3 interacting with (10,0) GaNNT were obtained using first principles calculations based on the density functional theory. The results show that for the CrO3 interacting with the GaNNT, the structure was locally deformed. However, in case of FeCl3 adsorbed with the GaNNT, the structure remained practically the same with the negligible deformation observed on tube surface. The projected density of states for the pristine GaNNT was modified with adsorption of FeCl3 molecule by the appearance of three strongly localized states in gap region. In case of GaNNT plus CrO3 molecule, one strongly localized level appeared in energy gap region with high contributions of molecule atoms. The analysis of the binding energy shows that the CrO3 interacting with the GaNNT is more favorable and the process occurs through chemisorption regime in both systems. Graphical Abstract Projected density of states of pristine GaNNT and FeCl3 interacting with GaNNT. PMID- 29974254 TI - On chip quadruplex priming amplification for quantitative isothermal diagnostics. AB - Nucleic acid testing is a common technique for medical diagnostics. For example, it is used to detect HIV treatment failure by monitoring viral load levels. Quadruplex Priming Amplification (QPA) is an isothermal nucleic acid amplification technique that requires little power and few chemical reagents per assay, all features that make QPA well suited for point-of-care (POC) diagnostics. The QPA assay can be further optimized by integrating it with microfluidic devices that can automate and combine multiple reaction steps and reduce the quantity and cost of reagents per test. In this study, a real-time, exponential QPA reaction is demonstrated for the first time in a microfluidic chip, where the reaction was not inhibited and supported performance levels comparable to a commercially-available, non-microfluidics setup. PMID- 29974256 TI - A real-time hourly water index for flood risk monitoring: Pilot studies in Brisbane, Australia, and Dobong Observatory, South Korea. AB - A water resources index based on weight-accumulated precipitation over the passage of time in heavy rainfall events is used in this study for monitoring flood risk and peak danger, as well as to develop flood warnings. In this research, an hourly water resources index (WRIhr) based on rainfall accumulations over the passage of time is proposed. WRIhr is able to monitor flood risk by taking into account the hourly effective precipitation that accumulates the precipitation (Phr) of both current and antecedent hours, while the contributions from the preceding hours is subjected to a time-dependent reduction function that addresses the depletion of water volume by various hydrological processes (e.g., discharge, runoff, evapotranspiration). By converting rainfall into a water resources index (WRI), the hourly precipitation over a 24-h period is redistributed to formulate a long-term water resources index (WRIhr-L) that monitors flood status based on long-term (more than 1 year) fluctuations in Phr and a short-term water resources index (WRID-hr-S) that considers shorter (D = 24 148 hourly) accumulations of the Phr data. WRI was assessed for its potential in flood monitoring at two hydrologically diverse sites: Dobong (South Korea; August 1998) and Brisbane (Australia; December 2010-January 2011), and its applicability was verified using river water level (H) measurements at hydrological stations. The power spectrum density and spectral coherence of hourly rainfall, river water level, and the corresponding WRI showed good agreements, as did the low and high frequency wavelet components using the discrete wavelet transform algorithm. Importantly, WRI24-hr-S computed over 24 hourly accumulation periods was able to mimic the risk of short-term (flash-style) floods caused by concentrated rainfall, whereas WRIhr-L was more useful for flood risk assessment caused by an event over a long-term period. Dynamical changes in H were closely in-phase with the patterns of change noted in the WRIhr over the respective temporal scale. We conclude that the proposed WRI was able to replicate the flood evolution over the passage of time and, therefore, could possibly aid in the early warning of water related disasters, demonstrating its practicality for continuous monitoring of the flood risk when a sustained period of rainfall event is observed. PMID- 29974255 TI - The PA-interacting host protein nucleolin acts as an antiviral factor during highly pathogenic H5N1 avian influenza virus infection. AB - Polymerase acidic (PA) protein is a multifunctional regulator of influenza A virus (IAV) replication and pathogenesis. In a previous study, we reported that nucleolin (NCL) is a novel PA-interacting host protein. In this study, we further explored the role of NCL during highly pathogenic H5N1 avian influenza virus infection. We found that depletion of endogenous NCL in mammalian cells by siRNA targeting during H5N1 infection resulted in significantly increased viral polymerase activity, elevated viral mRNA, cRNA and vRNA synthesis, accelerated viral replication, and enhanced apoptosis and necrosis. Moreover, siRNA silencing of NCL significantly exacerbated the inflammatory response, resulting in increased secretion of IL-6, TNF-alpha, TNF-beta, CCL-4, CCL-8, IFN-alpha, IFN beta and IFN-gamma. Conversely, overexpression of NCL significantly decreased IAV replication. Collectively, these data show that NCL acts as a novel potential antiviral factor during H5N1 infection. Further studies exploring the antiviral mechanisms of NCL may accelerate the development of new anti-influenza drugs. PMID- 29974257 TI - Investigation on side-product formation during the synthesis of a lactoferrin derived lactam-bridged cyclic peptide. AB - Bovine lactoferrin C-lobe is able to prevent both influenza virus hemagglutination and cell infection. In particular, it was demonstrated that the fragment 418SKHSSLDCVLRP429 is a potent antiviral peptide. Therefore, we tried to increase the stability of this fragment through side-chain lactam cyclization of the peptide, S[KHSSLD]CVLRP (1). However, classic strategy involving solid supported cyclization of the linear precursor, containing orthogonal allyl/alloc based protection for the key amino and carboxyl residues, did not provide the desired cyclic peptide. Here, we report the identification of problematic stretches during the sequence assembly process and the optimization of the different parameters involved in the construction of 1. Results indicated a significant influence of beta-protecting group of both aspartic acid and adjacent cysteine residues on the formation of side products. Therefore, the identification of suitable beta-protecting groups of these residues allowed us to optimize the synthesis of designed lactam-bridged cyclic peptide. PMID- 29974258 TI - Clinical and genetic analyses of a Dutch cohort of 40 patients with a nephronophthisis-related ciliopathy. AB - BACKGROUND: Nephronophthisis is an autosomal recessive ciliopathy and important cause of end-stage renal disease (ESRD) in children and young adults. Diagnostic delay is frequent. This study investigates clinical characteristics, initial symptoms, and genetic defects in a cohort with nephronophthisis-related ciliopathy, to improve early detection and genetic counseling. METHODS: Forty patients from 36 families with nephronophthisis-related ciliopathy were recruited at university medical centers and online. Comprehensive clinical and genotypic data were recorded. Patients without molecular diagnosis were offered genetic analysis. RESULTS: Of 40 patients, 45% had isolated nephronophthisis, 48% syndromic diagnosis, and 7% nephronophthisis with extrarenal features not constituting a recognizable syndrome. Patients developed ESRD at median 13 years (range 5-47). Median age of symptom onset was 9 years in both isolated and syndromic forms (range 5-26 vs. 5-33). Common presenting symptoms were fatigue (42%), polydipsia/polyuria (33%), and hypertension (21%). Renal ultrasound showed small-to-normal-sized kidneys, increased echogenicity (65%), cysts (43%), and abnormal corticomedullary differentiation (32%). Renal biopsies in eight patients showed nonspecific signs of chronic kidney disease (CKD). Twenty-three patients (58%) had genetic diagnosis upon inclusion. Thirteen of those without a genetic diagnosis gave consent for genetic testing, and a cause was identified in five (38%). CONCLUSIONS: Nephronophthisis is genetically and phenotypically heterogeneous and should be considered in children and young adults presenting with persistent fatigue and polyuria, and in all patients with unexplained CKD. As symptom onset can occur into adulthood, presymptomatic monitoring of kidney function in syndromic ciliopathy patients should continue until at least age 30. PMID- 29974259 TI - Stroke Risk and Vascular Dementia in South Asians. AB - PURPOSE OF REVIEW: South Asians (SA) are at a higher risk for stroke and vascular dementia due to the disproportionate burden of diabetes, hypertension, and dyslipidemia. This review summarizes the rationale for screening, early detection, and aggressive control of metabolic factors, and critically examines the published literature on primary and secondary stroke prevention. RECENT FINDINGS: South Asians have a higher prevalence of diabetes than non-SA. SA with diabetes are at a higher risk of recurrent ischemic stroke and have a higher incidence of stroke-related dementia compared to non-South Asians. South Asians are one of the fastest-growing ethnic groups worldwide with an unusually increased risk of heart disease and stroke. An accurate assessment of those at risk of stroke and cognitive impairment is urgently needed to plan preventive strategies. PMID- 29974260 TI - Advances in Coronary No-Reflow Phenomenon-a Contemporary Review. AB - PURPOSE OF REVIEW: Coronary artery no-reflow phenomenon is an incidental outcome of percutaneous coronary intervention in patients presenting with acute myocardial infarction. Despite advances in pharmacologic and non-pharmacologic therapies, coronary no-reflow phenomenon occurs more commonly than desired. It often results in poor clinical outcomes and remains as a relevant consideration in the cardiac catheterization laboratory. In this systematic review, we have sought to discuss the topic in detail, and to relay the most recent discoveries and data on management of this condition. RECENT FINDINGS: We discuss several pharmacologic and non-pharmacologic treatments used in the prevention and management of coronary no-reflow and microvascular obstruction. Covered topics include the understanding of pharmacologic mechanisms of current and future agents, and recent discoveries that may result in the development of future treatment options. We conclude that the pathophysiology of coronary no-reflow phenomenon and microvascular obstruction still remains incompletely understood, although several plausible theories have led to the current standard of care for its management. We also conclude that coronary no-reflow phenomenon and microvascular obstruction must be recognized as a multifactorial condition that has certain predispositions and characteristics, therefore its prevention and treatment must begin pre-procedurally and be multi-faceted including certain medications and operator techniques in the cardiac catheterization laboratory. PMID- 29974261 TI - The Diagnostic and Therapeutic Challenge of Anal Intraepithelial Neoplasia. AB - PURPOSE OF REVIEW: No single modality of care serves as the defined best practice for the treatment of anal intraepithelial neoplasia (AIN). This review aims to present the common treatment modalities germane to AIN while considering evolving evidence. RECENT FINDINGS: AIN affords an opportunity to evaluate and treat patients before the development of invasive diseases. Efforts to screen for AIN have yielded mixed results. The major available pharmacotheraputic and surgical options offer efficacious options to reduce the bioburden of disease but can be met with high levels of recurrent disease. None affords a predictably durable response in severe disease. Vaccination as primary prevention will likely reduce the overall upward trend in AIN. Evidence suggests vaccination also affords improvement in recurrent disease. Early evidence reveals potential benefit in multimodal approaches to control AIN. Valuable data is anticipated from the phase III, randomized ANCHOR study evaluating the management of high-grade AIN in HIV +patients. PMID- 29974262 TI - Arterial Stiffness in Hypertension: an Update. AB - PURPOSE OF REVIEW: To update and review novel insights into the mechanisms, measurements, and therapeutic approaches to arterial stiffness. RECENT FINDINGS: Arterial (e.g., vascular) stiffness has been shown over time to prognosticate for cardiovascular and kidney outcomes. In this context, there has been increased interest behind the mechanisms that drive arterial stiffness beyond aging and interest in how to apply newer technologies in measurement of arterial stiffness. Pulse wave velocity has been the gold standard for measurement but industry has been innovating to improve measurement with use of single-point PWV as well as pharmacologic approaches with anti-hypertensives and oral hypoglycemic agents. Emerging data on the role of the mineralocorticoid receptor, the endothelial sodium channel (EnNaC), and uric acid in arterial stiffness are promising a number of potential therapies. Newer techniques of measuring PWV for arterial stiffness and novel therapies may soon lead to better outcomes from hypertension complications. PMID- 29974263 TI - Diabetes Among Non-Overweight Individuals: an Emerging Public Health Challenge. AB - PURPOSE OF REVIEW: Overweight and obesity are well-established risk factors for type 2 diabetes. However, a substantial number of individuals develop the disease at underweight or normal weight. In this review, we discuss the epidemiology of type 2 diabetes in non-overweight adults; pose questions about etiology, pathophysiology, diagnosis, and prognosis; and examine implications for prevention and treatment. RECENT FINDINGS: In population-based studies, the prevalence of type 2 diabetes ranged from 1.4-10.9%. However, the prevalence of type 2 diabetes in individuals with BMI < 25 kg/m2 ranged from 1.4-8.8%. In countries from Asia and Africa, the proportion of individuals with diabetes who were underweight or normal weight ranged from 24 to 66%, which is considerably higher than the US proportion of 10%. Impairments in insulin secretion, in utero undernutrition, and epigenetic alterations to the genome may play a role in diabetes development in this subgroup. A substantial number of individuals with type 2 diabetes, particularly those with recent ancestry from Asia or Africa, are underweight or normal weight. Future research should consist of comprehensive studies of the prevalence of type 2 diabetes in non-overweight individuals; studies aimed at understanding gaps in the mechanisms, etiology, and pathophysiology of diabetes development in underweight or normal weight individuals; and trials assessing the effectiveness of interventions in this population. PMID- 29974264 TI - A Review of Alternative Access for Transcatheter Aortic Valve Replacement. AB - With the advent of transcatheter aortic valve replacement (TAVR), appropriately selected intermediate-, high-, and extreme-risk patients with severe aortic stenosis (AS) are now offered a less invasive option compared to conventional surgery. In contemporary practice, TAVR is performed predominantly via a transfemoral arterial approach, whereby a transcatheter heart valve (THV) is delivered in a retrograde fashion through the iliofemoral arterial system and thoraco-abdominal aorta, into the native aortic valve annulus. While the majority of patients possess suitable anatomy for transfemoral arterial access, there is a subset of patients with extensive peripheral vascular disease that precludes this traditional approach to TAVR. Fortunately, innovation in the field of structural heart disease has led to the refinement of alternative access options for THV delivery. Selection of the most appropriate route of therapy mandates a careful consideration of multiple factors, including patient anatomy, technical feasibility, and equipment specifications. Furthermore, understanding the risks conferred by each access site for valve delivery-notably stroke, vascular injury, and major bleeding-is of paramount importance when selecting the approach that will best optimize the outcome for an individual. In this review, we provide a comprehensive summary of alternative approaches to transfemoral arterial TAVR as well as the available outcome data supporting each of these various techniques. PMID- 29974266 TI - What Have We Learned from Recent Clinical Studies in Low-Grade Gliomas? AB - PURPOSE OF REVIEW: The management of low-grade gliomas (grade II WHO) is still controversial, due to the rarity of these tumors and continuous advances in molecular diagnosis and new technologies for treatment. This article reviews the current understanding of management of grade II gliomas in light of the recent clinical and translational studies. RECENT FINDINGS: The role of an extensive surgery at onset is now fully recognized. Recent clinical trials in the USA and Europe have demonstrated the importance of chemotherapy either in association with radiotherapy or as initial treatment to delay the risk of cognitive defects following radiation. Molecular factors, such as IDH1 or 2 mutations and 1p/19q codeletion, are favorable prognostic factors, and seem to predict a better response to chemotherapy as well. The role of conventional therapeutic options (surgery, radiotherapy, chemotherapy), in various combinations or sequences, has been better defined by clinical trials, but still there are areas of controversy. A future challenge is to reevaluate the role of these options within the different molecular subgroups of prognostic significance according to the last WHO classification of CNS tumors of 2016. PMID- 29974265 TI - Metal oxide nanoparticles in electrochemical sensing and biosensing: a review. AB - This review (with (318) refs) describes progress made in the design and synthesis of morphologically different metal oxide nanoparticles made from iron, manganese, titanium, copper, zinc, zirconium, cobalt, nickel, tungsten, silver, and vanadium. It also covers respective composites and their function and application in the field of electrochemical and photoelectrochemical sensing of chemical and biochemical species. The proper incorporation of chemical functionalities into these nanomaterials warrants effective detection of target molecules including DNA hybridization and sensing of DNA or the formation of antigen/antibody complexes. Significant data are summarized in tables. The review concludes with a discussion or current challenge and future perspectives. Graphical abstract ?. PMID- 29974267 TI - A population-based analysis of urban-rural disparities in advanced pancreatic cancer management and outcomes. AB - Given the significant morbidity burden associated with advanced pancreatic cancer (APC), its management is complex and frequently requires multidisciplinary care. Because of potential geographical barriers to healthcare access, we aimed to determine the effect of rurality on management and outcomes of APC patients. Patients diagnosed with APC from 2008 to 2015 and received Gemcitabine (Gem), Gemcitabine plus nab-Paclitaxel (Gem/Nab), or FOLFIRINOX at any 1 of 6 British Columbia cancer centers across the province were reviewed. Using postal codes, the Google Maps Distance Matrix determined the distance from each patient's residence to the closest cancer center. Rural and urban status were defined as patients living >= 100 and < 100 km from the closest treatment site, respectively. Univariate and Cox regression analyses were applied to examine whether rurality resulted in variations in management and outcomes. In total, we identified 659 patients: median age 68 years, 54.3% men, and 76.6% metastatic disease. For treatment, 67.7, 9.2, and 23.0% received Gem, Gem/Nab, and FOLFIRINOX, respectively. However, there were no differences in baseline clinical characteristics between rural and urban patients (all p > 0.05). Also, there were no significant variations in treatment patterns. For example, time from diagnosis to oncology appointment and time from appointment to treatment were 31.5 and 29.5 days for rural patients and 28.6 and 40.1 days for urban patients, respectively (all p > 0.05). Use of Gem/Nab (10.1% vs 9.1%) and FOLFIRINOX (21.0% vs 23.5%) were similar regardless of rurality. In multivariate Cox regression, risk of death was similar between rural and urban groups (HR 0.864, 95% CI 0.619-1.206, p = 0.09). Our findings suggest that there is no correlation between rurality and outcomes in APC. The strategic and geographic allocation of cancer care delivery across the province of British Columbia may serve as a model for other jurisdictions that experience disparities in the outcomes of cancers that often require complex multidisciplinary care. PMID- 29974268 TI - Sub-picosecond proton tunnelling in deformed DNA hydrogen bonds under an asymmetric double-oscillator model. AB - We present a model of proton tunnelling across DNA hydrogen bonds, compute the characteristic tunnelling time (CTT) from donor to acceptor and discuss its biological implications. The model is a double oscillator characterised by three geometry parameters describing planar deformations of the H bond, and a symmetry parameter representing the energy ratio between ground states in the individual oscillators. We discover that some values of the symmetry parameter lead to CTTs which are up to 40 orders of magnitude smaller than a previous model predicted. Indeed, if the symmetry parameter is sufficiently far from its extremal values of 1 or 0, then the proton's CTT under any physically realistic planar deformation is guaranteed to be below one picosecond, which is a biologically relevant time scale. This supports theories of links between proton tunnelling and biological processes such as spontaneous mutation. PMID- 29974269 TI - Soil quality of an Iranian forest ecosystem after conversion to various types of land use. AB - The impact of land-use change on parameters of the soil was evaluated in soil samples from arable land, orchard land, and grassland in West Azerbaijan, Iran, compared with their adjacent natural forestland, using some biological indices. Microbial biomass carbon (MBC); microbial basal respiration (BR); metabolic quotient (qCO2); substrate induced respiration (SIR); carbon availability index (CAI); the microbial quotient, i.e., the ratio of microbial carbon to soil organic carbon (Cmic/Corg); and soil organic carbon (SOC) were calculated in collected soil samples. Deforestation and long-term land use showed adverse effects on soil biological properties. The spatial distribution of MBC, BR, SIR, and SOC, followed the order: forestland > grassland > orchard land > arable land. SOC showed the highest decline by 67.7% in arable land, 43.6% in orchard land, and 36.3% in grassland, with an average reduction of 49.2% compared with forestland. Similarly, BR and MBC decreased by an average reduction of 41.3 and 34.8%, respectively, compared with forestland. By contrast, the qCO2 index, the CAI index, and the Cmic/Corg ratio were not affected significantly by land use, except from a significant raise of the Cmic/Corg ratio in the arable land. Land use change exerted a remarkable negative influence on soil quality with several soil attributes affected due to cropping compared with adjacent grassland and forestland. At the field level, proper management practices that increase SOC in the soil, e.g., effective recycling of crop residues and manures, should be considered, when land is continuously cultivated. PMID- 29974270 TI - Secure Cloud-Based EHR System Using Attribute-Based Cryptosystem and Blockchain. AB - To achieve confidentiality, authentication, integrity of medical data, and support fine-grained access control, we propose a secure electronic health record (EHR) system based on attribute-based cryptosystem and blockchain technology. In our system, we use attribute-based encryption (ABE) and identity-based encryption (IBE) to encrypt medical data, and use identity-based signature (IBS) to implement digital signatures. To achieve different functions of ABE, IBE and IBS in one cryptosystem, we introduce a new cryptographic primitive, called combined attribute-based/identity-based encryption and signature (C-AB/IB-ES). This greatly facilitates the management of the system, and does not need to introduce different cryptographic systems for different security requirements. In addition, we use blockchain techniques to ensure the integrity and traceability of medical data. Finally, we give a demonstrating application for medical insurance scene. PMID- 29974271 TI - Perspective on Lignin Oxidation: Advances, Challenges, and Future Directions. AB - Lignin valorization has gained increasing attention over the past decade. Being the world's largest source of renewable aromatics, its valorization could pave the way towards more profitable and more sustainable lignocellulose biorefineries. Many lignin valorization strategies focus on the disassembly of lignin into aromatic monomers, which can serve as platform molecules for the chemical industry. Within this framework, the oxidative conversion of lignin is of great interest because it enables the formation of highly functionalized, valuable compounds. This work provides a brief overview and critical discussion of lignin oxidation research. In the first part, oxidative conversion of lignin models and isolated lignin streams is reviewed. The second part highlights a number of challenges with respect to the substrate, catalyst, and operating conditions, and proposes some future directions regarding the oxidative conversion of lignin. PMID- 29974272 TI - Synthesis and Investigation of CuGeO3 Nanowires as Anode Materials for Advanced Sodium-Ion Batteries. AB - Germanium is considered as a potential anode material for sodium-ion batteries due to its fascinating theoretical specific capacity. However, its poor cyclability resulted from the sluggish kinetics and large volume change during repeated charge/discharge poses major threats for its further development. One solution is using its ternary compound as an alternative to improve the cycling stability. Here, high-purity CuGeO3 nanowires were prepared via a facile hydrothermal method, and their sodium storage performances were firstly explored. The as-obtained CuGeO3 delivered an initial charge capacity of 306.7 mAh g-1 along with favorable cycling performance, displaying great promise as a potential anode material for sodium ion batteries. PMID- 29974273 TI - Headaches in Patients with Pituitary Tumors: a Clinical Conundrum. AB - PURPOSE OF REVIEW: Pituitary tumors account for approximately 17% of all intracranial neoplasms, with the majority being pituitary adenomas. Often, these are found incidentally during a workup for headache; however, the relationship between symptom and pathology remains unclear. The purpose of this article is to review the most recent literature on the epidemiology, pathophysiology, and management of headaches in patients with pituitary tumors. RECENT FINDINGS: The current literature is limited, with few prospective trials focusing on this question. With the exception of pituitary apoplexy, the relationship between headaches and pituitary masses remains unclear. Intervention does not always improve headache and can lead to development of new headache syndromes. Further research is needed to better elucidate the relationship between pituitary tumors and headaches. Headache alone is rarely an indication for surgical management of a pituitary adenoma. PMID- 29974274 TI - Consistent individual differences in associative learning speed are not linked to boldness in female Atlantic mollies. AB - Recent studies on consistent individual differences in behavioural tendencies (animal personality) raised the question of whether individual differences in cognitive abilities can be linked to certain personality types. We tested female Atlantic mollies (Poecilia mexicana) in two different classical conditioning experiments. For the first time, we provide evidence for highly consistent individual differences in associative learning speed in fish. We characterized the same individuals for boldness in two experimental situations (latency to emerge from shelter and freezing time after a simulated predator attack) and found high behavioural repeatability. When we tested for a potential correlation between associative learning speed and boldness, however, there was no evidence for a link between them. Our study design included several steps to avoid typical pitfalls of disadvantaging shy individuals during learning tests. We caution that other experimental studies may have suffered from erroneous interpretations due to a more cautious coping style of shy individuals in the respective setup used to assess learning. PMID- 29974275 TI - Controlling breath figure patterns on PDMS by concentration variation of ethanol methanol binary vapors. AB - In this paper, the self-assembly of condensed droplets on smooth and constrained surfaces under saturated vapor atmosphere of ethanol and methanol binary system is reported. Hexagonally ordered array of pores are obtained on smooth surfaces with saturated vapors of binary liquids without the assistance of any additives. The results show that the addition of a small amount of ethanol to methanol plays a role very similar to that of surface active agents in inducing the formation of a regular droplet array. The effect of constraints on a self-assembled droplet pattern such as the movement of the contact line and the depinning of the contact line is also investigated. It is observed that the pore size, pore shape, pore depth and ring diameter are influenced by the atmosphere of binary vapors in addition to the commonly held attribution to the surface tension of the solvent. Contact angle studies of the patterned substrates show hydrophobicity with high adhesiveness and transitions between the Wenzel and Cassie impregnating state over the entire concentration region. PMID- 29974276 TI - Sensing adsorption kinetics through slip velocity measurements of polymer melts. AB - The evolution over time of the nonlinear slip behavior of a polydimethylsiloxane (PDMS) polymer melt on a weakly adsorbing surface made of short non-entangled PDMS chains densely end-grafted to the surface of a fused silica prism has been measured. The critical shear rate at which the melt enters the nonlinear slip regime has been shown to increase with time. The adsorption kinetics of the melt on the same surface has been determined independently using ellipsometry. We show that the evolution of slip can be explained by the slow adsorption of melt chains using the Brochard-de Gennes's model. PMID- 29974277 TI - Prognostic factors after aflibercept therapy for typical age-related macular degeneration and polypoidal choroidal vasculopathy. AB - PURPOSE: To determine factors predictive of visual outcomes in eyes treated with intravitreal aflibercept injections (IAIs) for typical neovascular age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: Retrospective, multicenter, institutional, consecutive, interventional case series. METHODS: One hundred nine eyes (107 patients) with treatment-naive neovascular AMD at 3 university hospitals were studied. After a loading phase of 3 monthly 2.0-mg IAIs, injections were administered every 2 months. The baseline clinical characteristics were investigated in relation to the 12-month visual outcomes. Changes in the mean best-corrected visual acuity (BCVA) were measured at 12 months after initiation of aflibercept therapy. RESULTS: Forty-five eyes (41.3%) had typical neovascular AMD, and 64 eyes (58.7%) had PCV. The changes in the mean BCVA at 12 months compared with baseline did not differ significantly (P = .737) between the 2 groups. Stepwise analysis showed that larger gains in the BCVA at 12 months were associated with poor BCVA (P < .001), no pigment epithelial detachment (P = .004), and subretinal fluid (P = .039) at baseline in eyes with typical neovascular AMD; larger gains in the BCVA were associated with poorer BCVA (P < .001), presence of choroidal vascular hyperpermeability (CVH) (P = .013), and subretinal fluid (P = .044) at baseline in eyes with PCV. CONCLUSIONS: Although poorer BCVA and the presence of subretinal fluid predicted larger gains in BCVA in both subtypes treated with aflibercept, eyes with typical neovascular AMD had greater improvement if no pigment epithelial detachment was present, while eyes with PCV had greater improvement if CVH was present. PMID- 29974279 TI - Improved diagnosis of active Schistosoma infection in travellers and migrants using the ultra-sensitive in-house lateral flow test for detection of circulating anodic antigen (CAA) in serum. AB - Schistosomiasis is a parasitic disease affecting over 250 million people in the tropics. In non-endemic regions, imported Schistosoma infections are commonly diagnosed by serology, but based on antibody detection an active infection cannot be distinguished from a cured infection and it may take more than 8 weeks after exposure before seroconversion occurs. In endemic populations, excellent results have been described in diagnosing low-grade active Schistosoma infections by the detection of the adult worm-derived circulating anodic antigen (CAA) utilising robust lateral flow (LF) assays combined with up-converting phosphor (UCP) reporter technology. The purpose of this study is to explore the diagnostic value of the UCP-LF CAA assay in a non-endemic setting. CAA concentrations were determined in 111 serum samples originating from 81 serology-positive individuals. In nine individuals, serum could be collected before travel and an additional five provided samples before and after seroconversion occurred. Based on detectable CAA levels, an active infection was seen in 56/81 (69%) of the exposed individuals, while the 10 controls and the 9 sera collected before travel were tested negative for CAA. Positive CAA levels were observed starting 4 weeks after exposure and in four cases CAA was detected even before Schistosoma specific antibodies became positive. Higher serum CAA levels were seen in migrants than in travellers and CAA concentrations dropped sharply when testing follow-up samples after treatment. This explorative study indicates the UCP-LF CAA serum assay to be a highly accurate test for detecting active low-grade Schistosoma infections in a non-endemic routine diagnostic setting. PMID- 29974278 TI - Additive effects of orthokeratology and atropine 0.01% ophthalmic solution in slowing axial elongation in children with myopia: first year results. AB - PURPOSE: To investigate the additive effects of orthokeratology (OK) and atropine 0.01% ophthalmic solution, both of which are effective procedures to slow axial elongation in children with myopia. STUDY DESIGN: Prospective randomized clinical trial. METHODS: Japanese children aged 8-12 years with a spherical equivalent refractive error of - 1.00 to - 6.00 diopters were included. A total of 41 participants who had been wearing the OK lenses successfully for 3 months were randomly allocated into two groups to receive either the combination of OK and atropine 0.01% ophthalmic solution (combination group) or monotherapy with OK (monotherapy group). Subjects in the combination group started to use atropine 0.01% ophthalmic solution once nightly from 3 months after the start of OK. Axial length was measured every 3 months using non-contact laser interferometry (IOLMaster), and the axial length measurement at month 3 of OK therapy was used as the baseline value in both groups. The increase in axial length over 1 year was compared between the two groups. RESULTS: A total of 40 consecutive subjects (20 subjects in the combination group and 20 in the monotherapy group) were followed for 1 year. The increase in axial length over 1 year was 0.09 +/- 0.12 mm in the combination group and 0.19 +/- 0.15 mm in the monotherapy group (P = 0.0356, unpaired t test). CONCLUSION: During the 1-year follow-up, the combination of OK and atropine 0.01% ophthalmic solution was more effective in slowing axial elongation than OK monotherapy in children with myopia. PMID- 29974280 TI - Evaluation of scars in children after treatment with low-level laser. AB - Burn scars are known for their tendency to worsen with hypertrophy and contracture, causing esthetic and functional problems. The objective is to analyze the effectiveness of low-level laser therapy on post-burn hypertrophic scar tissue in children. A randomized controlled study included 15 children, ranging from 2 to 10 years of age, presented with post-burn hypertrophic scars. They received He-Ne laser and topical treatment. Each scar was divided into two halves. One half was treated with laser therapy and topical treatment (study area), and the other half was treated with topical treatment only (control area). The children were evaluated before, and after 3 months of the study by Vancouver Scar Scale (VSS), ultrasonography, and laser Doppler perfusion imaging. Significant improvement was reported in the studied area, compared to the control area for patients with P values (P = 0.003) and (P = 0.005), for VSS and U/S scores, respectively. No differences were detected for blood perfusion of the scar between both areas (P = 0.73). In addition, no adverse effects were reported. Photobiomodulation (PBM) is an efficient and safe therapeutic modality for post-burn hypertrophic scars in children, with no side effects, and should be considered a part of combination therapy for better results. PMID- 29974282 TI - Comparison of radiological and clinical characteristics between blood blister like aneurysms (BBAs) and non-blister aneurysms at the supraclinoid segment of internal carotid artery. AB - Blood blister-like aneurysms (BBAs) were considered a therapeutic challenge for both microsurgeons and endovascular therapists. While a great deal of efforts had been put to refining the treatment of BBAs, the diagnostic criteria had not been established yet. In this study, we reviewed data of 43 suspicious, small (< 1 cm), broad-necked aneurysms at supraclinoid segment of internal carotid artery (ICA) in 41 patients who had been treated with microsurgery in our hospital during the past 5 years. Diagnosis of BBAs and non-blister aneurysms was based on intraoperative findings. Epidemiological, clinical, and radiological features of BBAs and non-blister aneurysms were compared. Subtypes of BBAs were also compared. Discriminant analysis was used to generate a differentiating model for BBAs. Seventeen aneurysms were diagnosed as BBAs and 26 were diagnosed as non blister aneurysms. No significant difference regarding age, gender, association of multiple aneurysms, or location on ICA was found between the groups. Dome/neck ratio and distal angle (intersection angle of aneurysm with ICA, distal to ophthalmic artery branching site) of BBAs were smaller than those of non-blister aneurysms (P = 0.009 and P = 0.002). A discriminant function including aforementioned factors with an overall accuracy of 76.2% was yielded (P = 0.005). BBAs and non-blister aneurysms were difficult to differentiate by clinical and radiological features as they share many characteristics in common. Dome/neck ratio < 1 did not guarantee accurate diagnosis of BBAs. A discriminant function incorporating dome/neck ratio and degree of distal angle as factors might increase the accuracy of pre-surgical diagnosis of BBAs. PMID- 29974281 TI - An epidemiological study of the prevalence rate of inflammatory back pain and axial spondyloarthritis in a university in the south of China. AB - Inflammatory back pain (IBP) is an important clinical feature for axial spondyloarthritis (SpA). Yet, little is known about their prevalences in China. We conducted an epidemiological study in a university to detect the prevalences of IBP and axial SpA according to the Assessment of SpondyloArthritis International Society (ASAS) criteria. We investigated 3770 participants from South China Agricultural University by face-to-face questionnaires and evaluated the prevalences of chronic low back pain (CLBP) and IBP. In addition, 333 students including all IBP patients volunteered to do HLA-B27 test, and we performed X-ray examination on students with suspect axial SpA. Axial SpA was confirmed by rheumatologists according to ASAS criteria. The mean (+/- SD) age of screened population was 19.48 (+/- 2.80) years, while female to male ratio was 1.45:1 (2229/1541). Seven hundred thirty-one (19.39%) of all participants had CLBP and 111 (2.94%) had IBP. Among the 333 students receiving HLA-B27 test, 13 (0.34%, 13/3770) fulfilled ASAS criteria for axial SpA. Nine students had sacroiliitis on imaging plus at least one SpA feature (IBP and positive HLA-B27 results). Four students had positive HLA-B27 plus at least two other SpA features (arthritis/enthesitis and good response to NSAIDs). For CLBP, female/male was 485/246. For axial SpA, female/male was 4/9(P = 0.014). In southern China, the prevalences of CLBP and IBP were respectively 19.39 and 2.94% in university, and the prevalence of axial SpA was 0.34%. Although more female students had CLBP, males were more likely to suffer from axial SpA. PMID- 29974283 TI - Early operative outcomes of endoscopic (eTEP access) robotic-assisted retromuscular abdominal wall hernia repair. AB - BACKGROUND: The enhanced-view totally extraperitoneal (eTEP) hernia repair technique was first described for laparoscopic inguinal hernia repair and later applied to laparoscopic ventral and incisional hernia repair. We present our center's early operative outcomes utilizing principles of this technique during robotic ventral and incisional hernia repair for implementation of the robotic eTEP Rives-Stoppa (eRS) and eTEP transversus abdominis release (eTAR) techniques. METHODS: A review of a prospectively maintained database of hernia patients was conducted identifying 37 patients who underwent robotic eTEP for ventral, incisional, flank or parastomal hernia repair between March and October 2017. All patients underwent retrorectus dissection with selective utilization of transversus abdominis release (TAR) as indicated. RESULTS: 37 patients including 13 male and 24 female with mean age, body mass index, and ASA score of 54, 35.5, and 2.4, respectively, underwent a mean operation room time of 198 min. Mean length of stay was 0.7 days. There were no intraoperative complications. Two patients developed subcutaneous seromas requiring interventional radiology drainage. One patient was readmitted at 30 days for PO intolerance that was managed expectantly. Mean postoperative follow-up visit occurred at 36 days with no sign of early hernia recurrences. CONCLUSION: The enhanced-view totally extraperitoneal approach is both safe and feasible in robotic-assisted repair of ventral and incisional hernias. Although long-term outcomes and patient selection criteria require further study, we believe this technique will become an important tool in the armamentarium of minimally invasive hernia surgeons. PMID- 29974284 TI - Clinical impact of upper gastrointestinal endoscopy in critically ill patients with suspected bleeding. AB - BACKGROUND AND AIMS: Upper gastrointestinal endoscopies' (UGE) profitability is undisputable in patients admitted for an overt upper digestive tract bleeding. In critically ill subjects admitted for other causes, its performances have scarcely been investigated despite its broad use. We sought to question the performance of bedside UGE in intensive care unit (ICU) patients, admitted for another reason than overt bleeding. METHODS: This was a six-year (January 2007-December 2012) retrospective observational study of all UGE performed in a medico-surgical ICU. Exclusion of those performed: in patients admitted for a patent upper digestive bleeding; for a second-look gastroscopy of a known lesion; as a planned interventional procedure. Main demographic and clinical data were recorded; UGE indication and profitability were rated according to its findings and therapeutic impact. Operative values of the indications of UGE were calculated. This study received approval from the Ethics Committee of the French Society of Intensive Care (n degrees 12-363). RESULTS: Eighty-four patients (74% male, mean age 61 +/ 14 years) underwent a diagnostic UGE, all for a suspected upper digestive tract bleeding. The main symptoms justifying the procedure were anemia (52%), digestive bleeding (27%), vomiting (15%), hemodynamic instability (3%) and hyperuremia (3%). The profitability of UGE was rated as major (n = 5; 5.8%); minor (n = 34; 40.5%); or null (n = 45; 53.6%). CONCLUSIONS: When ICU admission is not warranted by a digestive bleeding, UGE has limited diagnostic and therapeutic interest, despite being often performed. PMID- 29974285 TI - Design and effects of outcome-based payment models in healthcare: a systematic review. AB - INTRODUCTION: Outcome-based payment models (OBPMs) might solve the shortcomings of fee-for-service or diagnostic-related group (DRG) models using financial incentives based on outcome indicators of the provided care. This review provides an analysis of the characteristics and effectiveness of OBPMs, to determine which models lead to favourable effects. METHODS: We first developed a definition for OBPMs. Next, we searched four data sources to identify the models: (1) scientific literature databases; (2) websites of relevant governmental and scientific agencies; (3) the reference lists of included articles; (4) experts in the field. We only selected studies that examined the impact of the payment model on quality and/or costs. A narrative evidence synthesis was used to link specific design features to effects on quality of care or healthcare costs. RESULTS: We included 88 articles, describing 12 OBPMs. We identified two groups of models based on differences in design features: narrow OBPMs (financial incentives based on quality indicators) and broad OBPMs (combination of global budgets, risk sharing, and financial incentives based on quality indicators). Most (5 out of 9) of the narrow OBPMs showed positive effects on quality; the others had mixed (2) or negative (2) effects. The effects of narrow OBPMs on healthcare utilization or costs, however, were unfavourable (3) or unknown (6). All broad OBPMs (3) showed positive effects on quality of care, while reducing healthcare cost growth. DISCUSSION: Although strong empirical evidence on the effects of OBPMs on healthcare quality, utilization, and costs is limited, our findings suggest that broad OBPMs may be preferred over narrow OBPMs. PMID- 29974286 TI - A Multilevel Meta-analysis on Academic Achievement Among Maltreated Youth. AB - Maltreatment can influence normative development and negatively impact emotional, behavioral, and social functioning in youth. As a result, it is not surprising that maltreated youth, as compared to non-maltreated youth, tend to underperform academically. Research on the academic performance of maltreated youth has increased over the last decade and several review papers have been published in this area. While the conclusions of these review articles have been that maltreated youth are at greater risk for academic deficits as compared to their non-maltreated peers, there are several conflicting findings within the literature that make it difficult to determine if or to what extent maltreated youth may demonstrate academic difficulty. Using a multilevel, structural equation model meta-analysis technique, the current study sought to provide a quantitative synthesis of the literature by examining the mean difference between maltreated and non-maltreated youth on measures of academic performance. Moreover, the current study also examined group differences between academic subject and maltreatment type. A total of 72 effect sizes were extracted from 32 studies that met inclusion criteria. Results demonstrated an overall negative, medium effect size, such that maltreated youth tended to perform slightly greater than half a standard deviation below non-maltreated youth on measures of academic performance. Moderation analyses suggest deficits may be greater on measures of general academic performance, as compared to language arts measures. No differences were observed for maltreatment type. These findings highlight the need for increased focus on academic difficulties among maltreated youth. PMID- 29974287 TI - Zinc preconditioning protects against renal ischaemia reperfusion injury in a preclinical sheep large animal model. AB - Ischaemia-reperfusion injury (IRI) during various surgical procedures, including partial nephrectomy for kidney cancer or renal transplantation, is a major cause of acute kidney injury and chronic kidney disease. Currently there are no drugs or methods for protecting human organs, including the kidneys, against the peril of IRI. The aim of this study was therefore to investigate the reno-protective effect of Zn2+ preconditioning in a clinically relevant large animal sheep model of IRI. Further the reno-protective effectiveness of Zn2+ preconditioning was tested on normal human kidney cell lines HK-2 and HEK293. Anaesthetised sheep were subjected to uninephrectomy and 60 min of renal ischaemia followed by reperfusion. Sheep were preconditioned with intravenous injection of zinc chloride prior to occlusion. Serum creatinine and urea were measured before ischaemia and for 7 days after reperfusion. HK-2 and HEK293 cells were subjected to in vitro IRI using the oxygen- and glucose-deprivation model. Zn2+ preconditioning reduced ischaemic burden determined by creatinine and urea rise over time by ~ 70% in sheep. Zn2+ preconditioning also increased the survival of normal human kidney cells subjected to cellular stress such as hypoxia, hydrogen peroxide injury, and serum starvation. Overall, our protocol incorporating specific Zn2+ dosage, number of dosages (two), time of injection (24 and 4 h prior), mode of Zn2+ delivery (IV) and testing of efficacy in a rat model, a large preclinical sheep model of IRI and cells of human origin has laid the foundation for assessment of the benefit of Zn2+ preconditioning for human applications. PMID- 29974288 TI - Longitudinal Assessment of Hippocampal Atrophy in Midlife and Early Old Age: Contrasting Manual Tracing and Semi-automated Segmentation (FreeSurfer). AB - It is important to have accurate estimates of normal age-related brain structure changes and to understand how the choice of measurement technique may bias those estimates. We compared longitudinal change in hippocampal volume, laterality and atrophy measured by manual tracing and FreeSurfer (version 5.3) in middle age (n = 244, 47.2[1.4] years) and older age (n = 199, 67.0[1.4] years) individuals over 8 years. The proportion of overlap (Dice coefficient) between the segmented hippocampi was calculated and we hypothesised that the proportion of overlap would be higher for older individuals as a consequence of higher atrophy. Hippocampal volumes produced by FreeSurfer were larger than manually traced volumes. Both methods produced a left less than right volume laterality difference. Over time this laterality difference increased for manual tracing and decreased for FreeSurfer leading to laterality differences in left and right estimated atrophy rates. The overlap proportion between methods was not significantly different for older individuals, but was greater for the right hippocampus. Estimated middle age annualised atrophy rates were - 0.39(1.0) left, 0.07(1.01) right, - 0.17(0.88) total for manual tracing and - 0.15(0.69) left, - 0.20(0.63) right, - 0.18(0.57) total for FreeSurfer. Older age atrophy rates were - 0.43(1.32) left, - 0.15(1.41) right, - 0.30 (1.23) total for manual tracing and - 0.34(0.79) left, - 0.68(0.78) right, - 0.51(0.65) total for FreeSurfer. FreeSurfer reliably segments the hippocampus producing atrophy rates that are comparable to manual tracing with some biases that need to be considered in study design. FreeSurfer is suited for use in large longitudinal studies where it is not cost effective to use manual tracing. PMID- 29974289 TI - Breast cancer and its impact in male transsexuals. AB - INTRODUCTION: Lesbian, gay, and bisexuals have unique healthcare needs. Breast cancer is leading cancer in women, worldwide, accounting for 25% of all cases. Annual incidence rates increased significantly in all countries and age groups. The occurrence of breast cancer is rare in transgender population. As they have very limited access to medical care, it is much less likely to pursue breast cancer screening than in other individuals not identified as transgender. REVIEW OF THE CASES FROM LITERATURE: Up to date, only 13 cases of the breast cancer transsexuals (female to male) have been reported in six published papers worldwide. Histological examination of the breast tumor in female-to-male transgender showed progesterone/estrogen-positive invasive ductal carcinoma. DISCUSSION: Gender identity describes a person's inherent sense of being a woman, man, or of neither gender, whereas sexual orientation refers to how people identify their physical and emotional attraction to others. Gender reassignment surgery, as series of complex surgical genital and non-genital procedures, is recognized as the most effective treatment for patients with gender dysphoria. The two main principles of hormone therapy for transgender patients are to reduce endogenous hormone levels and their associated sex characteristics and replace them with hormones of the preferred sex. Breast cancer infrequently occurs in transgender patients. Even breast core biopsies can be difficult for interpreting after changes in breast tissue in female-to-male transsexuals following gender reassignment. CONCLUSION: Reviewing the literature, so many different data concerning probability of breast cancer in sexual minority can be found. Breast cancer screening program should be offered to all transgender individuals according to national guidelines. Very important is to take into consideration a transgender person's natal and surgical anatomy, unique clinical concerns for depression and anxiety, risk of suicide together with risk factors including experiences of harassment or physical or sexual violence, low education level, and unemployment. Understanding the need for mammography in these often marginalized groups is very important in addressing breast cancer disparities despite differences in insurance coverage in some countries and greater concern for the cancer of the breast in residual breast tissue. The best screening rule, ever, for breast cancer in male transsexuals and other similar population should be, besides surgical history and hormonal status, "Screen Now, Screen Regularly and Screen What You Have." PMID- 29974291 TI - Pure high-grade fetal adenocarcinoma of the lung: a case report. AB - BACKGROUND: Pure high-grade fetal adenocarcinoma of the lung (H-FLAC) is a very rare tumor. CASE PRESENTATION: An annual check-up revealed an abnormal shadow in the left middle lung field of a 63-year-old Japanese man. Chest computed tomography (CT) showed a 3.6 * 2.8 cm pulmonary lesion with clear boundary in the left upper lobe. A transbronchial lung biopsy revealed non-small cell carcinoma. A left upper lobectomy and mediastinal lymph node dissection were performed. Histologically, the tumor consisted of solid proliferation of atypical cell with clear cytoplasm. Another histological component and morulae were not contained. Immunohistochemically, the tumor was focally positive for alpha-fetoprotein (AFP) and beta-catenin in the cell membrane. Accordingly, we made the diagnosis of pure H-FLAC, pT2aN2M0, stage IIIA. Two courses of adjuvant chemotherapy (cisplatin and vinorelbine) were administered but then the treatment was discontinued due to the patient's adverse reaction. At 25 months after the surgery, the patient had relapsed. CONCLUSIONS: We report a very rare case of pure H-FLAC. This histology has been considered to predict an extremely poor prognosis; therefore, the elucidation of genetic abnormalities and effective treatment is awaited. PMID- 29974290 TI - Neurogenic hypertension: pathophysiology, diagnosis and management. AB - Discussions about the cause and treatment of essential hypertension usually focus on mechanisms such as sodium/volume and the renin-angiotensin system. Less often discussed is hypertension driven by the sympathetic nervous system, i.e., neurogenic hypertension. In this review I discuss the pathophysiology of neurogenic hypertension, the controversy of renal versus central origin, the clinical clues that suggest neurogenic hypertension, and the interventions best suited in its treatment. Neurogenic hypertension is most likely to occur in patients with labile or paroxysmal hypertension, but evidence of increased sympathetic tone also suggests a neurogenic component in hypertension in patients with severe or resistant hypertension, chronic renal disease, comorbidities associated with increased sympathetic tone, and ingestion of drugs that stimulate sympathetic tone. The importance of combined alpha- and beta-blockade in pharmacologic treatment and the status of renal denervation are discussed. Although there is much that is unclear in its pathophysiology, recognition of neurogenic hypertension is of considerable clinical importance in individualizing drug therapy and achieving blood pressure control. PMID- 29974292 TI - Effective Light Absorption Using the Double-sided Pyramid Gratings for Thin-Film Silicon Solar Cell. AB - The design of double-sided pyramid grating structure can be used to enhance broadband light absorption. The front grating can greatly reduce the light reflection, especially in the short-wavelength region, and the rear grating can also achieve that same effect in the longer wavelength region. In the paper, for the double-sided pyramid grating structure, the photon absorption distribution of each part is studied and compared with the bare crystalline silicon. Theoretical results show that, by reasonably adjusting the structure parameters of the double sided grating, the light reflection of the whole band can be reduced greatly which is beneficial for black silicon formation and the total light absorption is also increased. However, further studies have shown that using the rear grating does not improve the effective light absorption of the crystalline silicon. PMID- 29974294 TI - Cardiac output response to exercise in patients before allogenic hematopoietic stem cell transplantation. AB - INTRODUCTION: High-dose chemotherapy for remission induction can induce cardiac toxicity prior to hematopoietic stem cell transplantation (HSCT). However, the details of cardiac function in patients undergoing HSCT are unclear, particularly during exercise. The aim of present study was to evaluate cardiac output responses to exercise in patients after high-dose chemotherapy before HSCT compared with in age-matched healthy controls. METHODS: Twenty-nine patients before HSCT (age 44.6 +/- 15.2 years) and 13 controls (45.8 +/- 16.0 years) performed the 6-min walk test (6MWT). Cardiac output (CO), stroke volume (SV), heart rate (HR), and cardiac index (CI) were continuously measured during the 6MWT using the noninvasive thoracic impedance method. RESULTS: No significant difference was observed in the six-minute walk distance (6MD) between the two groups. SV, CO, and CI both at rest and the end of the 6MWT in the patients were significantly lower, compared with the controls, but there was no significant difference in HR. In all subjects, the 6MD was positively correlated with SV, CO, CI, and HR after the 6MWT. CONCLUSION: These findings suggest that cardiac output response to exercise indicates exercise intolerance, which may not be detected by 6MD in patients before HSCT. PMID- 29974293 TI - Cardiac myxoma: a contemporary multimodality imaging review. AB - Cardiac myxoma (CM) is by far the most common primary benign cardiac tumor, typically arising in the left atrium with an attachment point in the fossa ovalis region. Although the etiology of CM remains unclear, we know that this endocardial-based mass originates from undifferentiated mesenchymal cells. Continuous technical improvements in the field of echocardiography since the 1960s has profoundly changed the diagnostic approach by allowing a good tumor detection as well as the preoperative planning by providing crucial information concerning the attachment point location. However, echocardiography has its limitations among which lack of tissue characterization and restricted field of view can arise diagnosis difficulties in atypical presentations. With the widespread and routine use of echocardiography and chest computed tomography (CT), incidental detection of CM is not infrequent. As a consequence, it has become mandatory for cardiologists and radiologists evolving in a multimodality imaging world to be familiar with the wide range of presentations of this tumor. The authors present here a review of the common and less common aspects of CM using the main imaging modalities available: echocardiography, cardiovascular magnetic resonance imaging, CT, positron emission tomography and coronary angiography. PMID- 29974296 TI - Correction to: Dying to communicate: apoptotic functions of Eph/Ephrin proteins. AB - The original version of this article contained a mistake in reference. The references in Table 1 are incorrect. The corrected Table with proper citation is given below. The field codes ADDIN REFMGR.CITE inadvertently appeared along the article. This was overlooked during the process. PMID- 29974295 TI - Comparison of the University of Pittsburgh staging system and the eighth edition of the American Joint Committee on Cancer TNM classification for the prognostic evaluation of external auditory canal cancer. AB - BACKGROUND: The purpose was to compare survival differences between patients with external auditory canal (EAC) cancer treated according to the University of Pittsburgh modified TNM staging system and those treated in accordance with the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual on the TNM staging system for cutaneous cancers of the head and neck. METHODS: We performed a retrospective, single-institution review of 60 patients with EAC cancer treated with curative intent between September 2002 and March 2018. Survival outcomes were measured on the basis of the two staging systems. RESULTS: The C-index values for the overall survival (OS) rate revealed that the University of Pittsburgh staging system had higher prognostic accuracy than the 8th edition of the AJCC staging system. Univariable and multivariable analysis showed that T classification according to the University of Pittsburgh staging system was an independent predictor of the OS rate (hazard ratio 5.25; 95% confidence interval 1.38-24.9; P = 0.015). Meanwhile, the AJCC staging system could not differentiate T2 from T3-4 cancers. CONCLUSION: The University of Pittsburgh staging system for patients with EAC cancer is a valuable tool for use in clinical decision-making and predicting survival outcome. PMID- 29974297 TI - Expanding the phenotype of the X-linked BCOR microphthalmia syndromes. AB - Two distinct syndromes arise from pathogenic variants in the X-linked gene BCOR (BCL-6 corepressor): oculofaciocardiodental (OFCD) syndrome, which affects females, and a severe microphthalmia ('Lenz'-type) syndrome affecting males. OFCD is an X-linked dominant syndrome caused by a variety of BCOR null mutations. As it manifests only in females, it is presumed to be lethal in males. The severe male X-linked recessive microphthalmia syndrome ('Lenz') usually includes developmental delay in addition to the eye findings and is caused by hypomorphic BCOR variants, mainly by a specific missense variant c.254C > T, p.(Pro85Leu). Here, we detail 16 new cases (11 females with 4 additional, genetically confirmed, affected female relatives; 5 male cases each with unaffected carrier mothers). We describe new variants and broaden the phenotypic description for OFCD to include neuropathy, muscle hypotonia, pituitary underdevelopment, brain atrophy, lipoma and the first description of childhood lymphoma in an OFCD case. Our male X-linked recessive cases show significant new phenotypes: developmental delay (without eye anomalies) in two affected half-brothers with a novel BCOR variant, and one male with high myopia, megalophthalmos, posterior embryotoxon, developmental delay, and heart and bony anomalies with a previously undescribed BCOR splice site variant. Our female OFCD cases and their affected female relatives showed variable features, but consistently had early onset cataracts. We show that a mosaic carrier mother manifested early cataract and dental anomalies. All female carriers of the male X-linked recessive cases for whom genetic confirmation was available showed skewed X-inactivation and were unaffected. In view of the extended phenotype, we suggest a new term of X-linked BCOR-related syndrome. PMID- 29974298 TI - The association between quality of supernumerary embryos in a cohort and implantation potential of the transferred blastocyst. AB - PURPOSE: Despite studies focused on the association between embryo morphology and implantation potential, it is unknown how the collective quality of the supernumerary embryos in a cohort is associated with the implantation rate (IR) of the transferred embryo. This study tested the hypothesis that a relationship exists between the quality of the supernumerary cohort and IR. METHODS: A retrospective cohort study of first fresh autologous IVF cycles from 05/2012 to 09/2016, with >= 3 blastocysts, resulting in a single blastocyst transfer (n = 819) was performed. Cohorts were grouped in two ways: by mean priority score (PS; 1 being best) of supernumerary embryos and by percent supernumerary embryos with low implantation potential. The relationship between cohort quality and IR was assessed using logistic regression. RESULTS: As mean cohort PS increased, IR of the transferred embryo decreased (test for linear trend, p = 0.05). When >= 75% of the supernumerary cohort was predicted to have low implantation potential, IR of the transferred embryo was significantly lower compared to when < 75% of the cohort was predicted to have low implantation potential (OR 0.71; 95% CI (0.53 0.94)). All associations were attenuated when adjusting for PS of the transferred embryo. CONCLUSIONS: Our findings suggest that quality of supernumerary embryos is associated with IR of the transferred embryo, among patients with >= 3 blastocysts available on day 5. As cohort quality declines and the proportion of low implantation potential embryos increases, the IR of the transferred embryo declines. These associations are attenuated when controlling for quality of the transferred embryo, suggesting that the relationship between embryo cohort quality and implantation is not independent of the transferred embryo quality. PMID- 29974299 TI - Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial. AB - BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function. PMID- 29974300 TI - California Autism Prevalence Trends from 1931 to 2014 and Comparison to National ASD Data from IDEA and ADDM. AB - Time trends in U.S. autism prevalence from three ongoing datasets [Individuals with Disabilities Education Act, Autism and Developmental Disabilities Monitoring Network, and California Department of Developmental Services (CDDS)] are calculated using two different methods: (1) constant-age tracking of 8 year-olds and (2) age-resolved snapshots. The data are consistent across methods in showing a strong upward trend over time. The prevalence of autism in the CDDS dataset, the longest of the three data records, increased from 0.001% in the cohort born in 1931 to 1.2% among 5 year-olds born in 2012. This increase began around ~ 1940 at a rate that has gradually accelerated over time, including notable change points around birth years 1980, 1990 and, most recently, 2007. PMID- 29974301 TI - Utilitarian Attention by Children with Autism Spectrum Disorder on a Filtering Task. AB - The findings are evidence that persons with ASD benefit more than typically developing (TD) persons from spatial framing cues in focusing their attention on a visual target. Participants were administered a forced-choice task to assess visual filtering. A target stimulus was presented on a screen and flanker stimuli were presented simultaneously with or after the target, with varying stimuli onset asynchronies (SOAs). Regardless of SOA, TD children showed the expected distracting effects with slower reaction times (RTs) when flankers were at closer distances from the target. However, children with ASD displayed shorter RTs in the conditions in which the stimuli were presented simultaneously or with a short SOA. These findings are interpreted as reflecting utilitarian attention among children with ASD. PMID- 29974303 TI - Can the interchangeability of somatic oximeters in cardiac surgery inform cerebral applications? PMID- 29974302 TI - Novel mandibular advancement bite block with supplemental oxygen to both nasal and oral cavity improves oxygenation during esophagogastroduodenoscopy: a bench comparison. AB - Drug-induced respiratory depression is a major cause of serious adverse events. Adequate oxygenation is very important during sedated esophagogastroduodenoscopy (EGD). Nasal breathing often shifts to oral breathing during open mouth EGD. A mandibular advancement bite block was developed for EGD using computer-assisted design and three-dimensional printing techniques. The mandible is advanced when using this bite block to facilitate airway opening. The device is composed of an oxygen inlet with one opening directed towards the nostril and another opening directed towards the oral cavity. The aim of this bench study was to compare the inspired oxygen concentration (FiO2) provided by the different nasal cannulas, masks, and bite blocks commonly used in sedated EGD. A manikin head was connected to one side of a two-compartment lung model by a 7.0 mm endotracheal tube with its opening in the nasopharyngeal position. The other compartment was driven by a ventilator to mimic "patient" inspiratory effort. Using this spontaneously breathing lung model, we evaluated five nasal cannulas, two face masks, and four new oral bite blocks at different oxygen flow rates and different mouth opening sizes. The respiratory rate was set at 12/min with a tidal volume of 500 mL and 8/min with a tidal volume of 300 mL. Several Pneuflo resistors of different sizes were used in the mouth of the manikin head to generate different degrees of mouth opening. FiO2 was evaluated continuously via the endotracheal tube. All parameters were evaluated using a Datex anesthesia monitoring system. The mandibular advancement bite block provided the highest FiO2 under the same supplemental oxygen flow. The FiO2 was higher for devices with oxygen flow provided via an oral bite block than that provided via the nasal route. Under the same supplemental oxygen flow, the tidal volume and respiratory rate also played an important role in the FiO2. A low respiratory rate with a smaller tidal volume has a relative high FiO2. The ratio of nasal to oral breathing played an important role in the FiO2 under hypoventilation but less role under normal ventilation. Bite blocks deliver a higher FiO2 during EGD. The ratio of nasal to oral breathing, supplemental oxygen flow, tidal volume, and respiratory rate influenced the FiO2 in most of the supplemental oxygen devices tested, which are often used for conscious sedation in patients undergoing EGD and colonoscopy. PMID- 29974304 TI - A new self-learning computational method for footprints of early human migration processes. AB - We present a new self-learning computational method searching for footprints of early migration processes determining the genetic compositions of recent human populations. The data being analysed are 26- and 18-dimensional mitochondrial and Y-chromosomal haplogroup distributions representing 50 recent and 34 ancient populations in Eurasia and America. The algorithms search for associations of haplogroups jointly propagating in a significant subset of these populations. Joint propagations of Hgs are detected directly by similar ranking lists of populations derived from Hg frequencies of the 50 Hg distributions. The method provides us the most characteristic associations of mitochondrial and Y chromosomal haplogroups, and the set of populations where these associations propagate jointly. In addition, the typical ranking lists characterizing these Hg associations show the geographical distribution, the probable place of origin and the paths of their protection. Comparison to ancient data verifies that these recent geographical distributions refer to the most important prehistoric migrations supported by archaeological evidences. PMID- 29974305 TI - Cytological and transcriptome analyses reveal abrupt gene expression for meiosis and saccharide metabolisms that associated with pollen abortion in autotetraploid rice. AB - Autotetraploid rice is a useful germplasm that has four chromosome sets and strong biological advantages; however, low fertility limits its commercial utilization. Little information is available about the DNA variation and differential gene expressions associated with low fertility in autotetraploid rice. In the present study, 81 SNPs and 182 InDels were identified in T449 (an autotetraploid rice line with low fertility) compared to E249 (diploid counterpart) by whole-genome re-sequencing. We detected only three non-synonymous SNPs and six large-effect InDels, which were associated with three and six genes, respectively. A total of 75 meiosis-related differentially expressed genes were detected during the meiosis stage by transcriptome analysis, including OsMTOPVIB, which is essential for meiotic DSB formation, and OsMOF, which takes part in homologous chromosome pairing and synapsis. Approximately 20.69% lagging chromosome at metaphase I and 4.65% abnormal tetrad were observed in T449. Moreover, transcriptome analysis revealed down-regulation of a sucrose transporter (OsSUT5) and two monosaccharide transporters (OsMST1 and OsMST8) in T449 at the single microspore stage, and their expression levels were verified by qRT-PCR. Cytological observation of saccharide distribution showed abnormal accumulation of saccharides in T449 and the contents of fructose and glucose were markedly higher in T449 than E249 at the single microspore stage. Our results suggested that polyploidy not only induces abrupt expression changes in the meiosis-related genes that lead to abnormal chromosome behavior, but also causes changes in the saccharide distribution and expression patterns of saccharide related genes, which jointly causes sterility in the autotetraploid rice. PMID- 29974306 TI - Combined QTL mapping, physiological and transcriptomic analyses to identify candidate genes involved in Brassica napus seed aging. AB - Seed aging is an inevitable problem in the germplasm conservation of oil crops. Thus, clarifying the genetic mechanism of seed aging is important for rapeseed breeding. In this study, Brassica napus seeds were exposed to an artificial aging environment (40 degrees C and 90% relative humidity). Using a population of 172 recombinant inbred lines, 13 QTLs were detected on 8 chromosomes, which explained ~ 9.05% of the total phenotypic variation. The QTLs q2015AGIA-C08 and q2016AGI C08-2 identified in the two environments were considered the same QTL. After artificial aging, lower germination index, increased relative electrical conductivity, malondialdehyde and proline content, and reduced soluble sugar, protein content and antioxidant enzyme activities were detected. Furthermore, seeds of extreme lines that were either left untreated (R0 and S0) or subjected to 15 days of artificial aging (R15 and S15) were used for transcriptome sequencing. In total, 2843, 1084, 429 and 1055 differentially expressed genes were identified in R15 vs. R0, S15 vs. S0, R0 vs. S0 and R15 vs. S15, respectively. Through integrated QTL mapping and RNA-sequencing analyses, seven genes, such as BnaA03g37460D, encoding heat shock transcription factor C1, and BnaA03g40360D, encoding phosphofructokinase 4, were screened as candidate genes involved in seed aging. Further researches on these candidate genes could broaden our understanding of the regulatory mechanisms of seed aging. PMID- 29974307 TI - Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity. AB - No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale = 1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-beta (n = 6), IFN-beta, or azathioprine followed by fingolimod (n = 4), fingolimod (n = 4), and IFN-beta followed by natalizumab (n = 1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as >= 0.4% per year. Importantly, these nine patients included all patients receiving IFN-beta therapy (n = 6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-beta did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN beta therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts. PMID- 29974308 TI - Effectiveness of At-Risk Gamblers' Temporary Self-Exclusion from Internet Gambling Sites. AB - To prevent risks associated with online gambling, many jurisdictions propose self exclusion strategies as a part of a responsible gambling policy. To protect online gamblers, French law provides for a 7-day temporary non-reducible and voluntary self-exclusion measure that applies only to select websites. The objective of our study was to evaluate the effectiveness of this self-exclusion measure for at-risk online gamblers. It was an experimental randomized controlled trial targeted at risk prevention. The main outcomes were the money wagered and time spent gambling assessed 15 days (short-term) and 2 months (medium-term) after the implementation of the self-exclusion measure. The effectiveness of self exclusion was also compared according to the gambling type (pure chance games, such as lottery or scratch tickets, skill and chance bank games such as sports betting or horserace betting, and skill and chance games such as poker). Sixty participants were randomly assigned to the experimental condition (n = 30; with the implementation of a self-exclusion measure) or control condition (n = 30). The randomization was stratified according to their favorite game [pure chance games (n = 20), skill and chance bank games (n = 20), and skill and chance social games (n = 20)]. The results revealed that self-exclusion had no short-term impact-but did have a medium-term impact-on gambling habits. After 2 months, the gambling-related cognitions ("illusion of control" and "the perceived inability to stop gambling") and the subscale "desire" of the Gambling Craving Scale (GACS) have decreased. Participants' opinions about the impact and effectiveness of self exclusion were discussed. To conclude, it appeared that temporary self-exclusion is an interesting tool to protect online gamblers from excessive practices, but several modifications have to be made to improve its effectiveness and use. PMID- 29974309 TI - In vitro and in vivo evaluation of xenogeneic bone putty with the carrier of hydrogel derived from demineralized bone matrix. AB - The demineralized bone matrix (DBM) putty is a traditional bone graft utilized to facilitate the repair and reconstruction of bone. Recent studies indicated the DBM putties with the various carriers were different in bone repairing ability. In order to prepare a kind of DBM putty with a good biocompatibility and bioactivity, the DBM gel was processed from the DBM and the feasibility as a carrier for the DBM putty was evaluated. After the bovine DBM gel was prepared, the BMPs content as well as the ability to promote osteogenic differentiation of MC3T3-E1 cells in vitro were investigated. Then the DBM putty was prepared and filled into the rat calvarial defect model to evaluate the bone repairing ability by micro-CT and histology. The result showed there was 2.953 +/- 0.054 ng BMP contained in per gram of the DBM gel. And the ALP production of MC3T3-E1 cells in the DBM gels group increased with prolonged culturing, the mineralized nodules formed in MC3T3-E1 cells on 14th day after co-culture. The putty prepared by DBM gel was easy to handle without loss of DBM particles at room temperature. In the rat calvarial bone defect experiment, histological observation showed more mature bone formed in the DBM putty group than that in the type I collagen group at 12 weeks, which indicated the bone putty prepared by DBM gel exhibited a better bone repair capability. PMID- 29974310 TI - Triptolide prevents osteoarthritis via inhibiting hsa-miR-20b. AB - Triptolide has been widely reported to exhibit potential therapeutic value in multiple inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Although its safety and efficacy as an anti inflammatory agent have been verified by many studies, the effect of triptolide on osteoarthritis (OA) was not clearly understood. In this study, we found that triptolide prevented OA development in a surgical destabilization of the medial meniscus (DMM) mouse model. In addition, triptolide inhibited both DMM-induced and LPS-induced expression of pro-inflammatory cytokines in the human monocytic cell line THP-1. Further mechanistic studies showed that the reduction of pro inflammatory cytokines by triptolide was mediated by the upregulation of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) and downregulation of caspase-1. Finally, we identified that hsa-miR-20b, a microRNA targeting the NLRP3 gene, was downregulated by triptolide. This study provides a novel insight into the effect on triptolide in preventing OA pathogenesis. PMID- 29974311 TI - Effective synthesis of some novel pyrazolidine-3,5-dione derivatives via Mg(II) catalyzed in water medium and their anticancer and antimicrobial activities. AB - Novel pyrazolidine-3,5-dione derivatives (2a-g, 4a-g, and 6a-g) were synthesized by an easy-to-perform Mg(II) acetylacetonate-catalyzed reaction with high yields using water as the reaction medium. Synthesized compounds were screened for anticancer and antimicrobial activities. The compound 6c (LD50 19.1 ug/mL) showed anticancer activity higher than that of all other compounds against MCF-7 breast cancer cell line. Results of antimicrobial activities revealed that the compound 4d (MIC 0.5 MUg/mL) had higher activity than ciprofloxacin against Staphylococcus aureus, whereas the compound 2b (MIC 0.5 MUg/mL) had higher activity than clotrimazole against Candida albicans. Overall results of this study envisaged that the compounds 2b, 4d, and 6c have the potential to be developed as anticancer and antimicrobial agents. Novel pyrazolidine-3,5-dione derivatives (2a g, 4a-g, and 6a-g) were synthesized via an easy-to perform Mg(II) catalysis in water medium. The synthesized compounds were screened for anticancer and antimicrobial activities. PMID- 29974313 TI - Brief Report: Texas School District Autism Prevalence in Children from Non English-Speaking Homes. AB - Previous studies have implicated migration and ethnicity as possible risk factors for autism spectrum disorder (ASD) in developed countries. Using Texas education data, we calculated district-reported ASD prevalence stratified by geographic region, with reported home language as a proxy for immigration. Prevalence ratios were also stratified by race. Prevalence estimates were significantly lower for White children from homes speaking Spanish and other non-English languages compared to those from English-speaking homes. This is the first study, to our knowledge, that investigates ASD prevalence of children from non-English-speaking households in a large sample. Barriers in identification of children of immigrants with ASD indicate that the increased district-reported prevalence seen in our study may only be a small indicator of a potentially larger prevalence. PMID- 29974312 TI - Association between abnormal thalamic metabolites and sleep disturbance in patients with end-stage renal disease. AB - Sleep disturbances are common in end-stage renal disease (ESRD) patients. However, the underlying neuropathological mechanisms are largely unclear. Previous studies have revealed the important role of the thalamus in the potential mechanisms of sleep disorders. We hypothesized that the sleep disturbances in ESRD patients may correspond to metabolic changes of thalamus and the uremic factors may have a vital contribution on these changes. We performed multi-voxel 1H-MRS of bilateral thalami in 27 ESRD patients who currently receiving hemodialysis treatment and 21 age-matched healthy volunteers. ESRD patients underwent Pittsburgh Sleep Quality Index (PSQI) scale and restless legs syndrome (RLS) rating scale assessment. Laboratory blood tests including serum creatinine, serum urea, cystatin-C, serum parathyroid hormone (PTH), calcium and phosphorus levels, hemoglobin and hematocrit were performed in all ESRD patients close to the time of the MR examination. We found correlations among elevated PTH, higher PSQI score and RLS rating score in ESRD patients. ESRD patients displayed decreased N-acetylaspartate and creatine ratio (NAA/Cr) of thalami compared with controls. There were significantly negative correlation between NAA/Cr and serum PTH level or PSQI score. The metabolic changes of thalami played an important role in the neuropathological mechanisms of lower sleep quality in ESRD patients. Secondary hyperparathyroidism as one of the main uremia-related factors was closely related to abnormal metabolites of the thalamus in patients with ESRD, revealing the crosstalk procedure between renal impairment and brain function. PMID- 29974315 TI - A Micelle-Enhanced Spectrofluorimetric Determination of Pirfenidone: Application to Content Uniformity Testing and Human Urine. AB - The present manuscript gives a detailed account of highly selective, validated and sensitive method for quantification of pirfenidone in its pharmaceutical dosage forms and spiked human urine. The developed method is relied on the systematic study of the fluorescence action of Pirfenidone in Tween - 80 micellar medium. The Pirfenidone exhibits strong fluorescence at lambdaem 396 nm upon excitation at lambdaex 318 nm in Tween -80 medium. The fluorescence - concentration plot was linear over concentration range of 0.5 - 5 MUg/mL. There was greater extent (1.02 fold) of enhancement in fluorescence intensity in presence of tween - 80 with very low limit of detection and quantitation of 0.04 MUg/mL and 0.11 MUg/mL respectively. The application of developed methodology is successfully applied to content uniformity testing and spiked human urine. The proposed study was successfully applied for analysis of pirfenidone in commercially available pharmaceutical formulations. PMID- 29974314 TI - Presentation and Correlates of Hoarding Behaviors in Children with Autism Spectrum Disorders and Comorbid Anxiety or Obsessive-Compulsive Symptoms. AB - We investigated the presentation and correlates of hoarding behaviors in 204 children aged 7-13 with autism spectrum disorder (ASD) and comorbid anxiety or obsessive-compulsive disorder (OCD) symptoms. Approximately 34% of the sample presented at least moderate levels, and with 7% presenting severe to extreme levels of hoarding. Child gender predicted hoarding severity. In addition, child ASD-related social difficulties together with attention-deficit and hyperactivity disorder symptom severity positively predicted hoarding controlling for child gender and restricted and repetitive behaviors. Finally, child anxiety/OCD symptoms positively predicted hoarding, controlling for all other factors. These results suggest hoarding behaviors may constitute a common feature of pediatric ASD with comorbid anxiety/OCD, particularly in girls and children with greater social difficulties and comorbid psychiatric symptom severity. PMID- 29974316 TI - Pheromones Regulating Reproduction in Subsocial Beetles: Insights with References to Eusocial Insects. AB - Beetles have evolved diverse strategies to cope with environmental challenges. Although parents of the vast majority of beetle species do not take care of their offspring, there are some species, in which parents provide elaborate post hatching care and remain temporarily associated with their offspring to defend them from competitors or to provision them with food. Usually, socially induced reproductive "control" is a core feature of eusocial societies, but here we highlight that already in small family groups, socially induced reproductive regulation can play a fundamental role. By discussing the family life of burying beetles, we illustrate the mechanisms behind such a reproductive "control" and show that - similar to eusocial insects - pheromones can be an important regulating factor. However, apart from burying beetles, our knowledge of pheromones or other signals mediating reproductive regulation is surprisingly rudimentary for social beetles. More data are required to broaden our currently patchy picture. PMID- 29974317 TI - Microsatellite loci obtained by next generation sequencing on the sablefish (Anoplopoma fimbria). AB - Eleven microsatellite loci were developed and characterized for the sablefish, Anoplopoma fimbria. The markers were identified from sequences obtained by next generation sequencing. Thirty samples from Aleutians Islands were genotyped. The amplifications were performed with three different annealing temperature and amplification products were visualized in ABI 3500 Genetic Analyzer. No evidence for scoring errors was detected by stuttering or due large allele dropout and neither of the loci presented a high null allele frequency (> 0.2). The number means of alleles per locus was of 12.21 and mean of observed and expected heterozygosity were of 0.60 and 0.75 respectively. The sablefish represents a resource of high commercial value on the coasts of Japan, Russia, Canada and west coast of the United States and these new primers could be useful to future diversity and structure population studies. PMID- 29974318 TI - Protective role of curcumin in ameliorating AFB1-induced apoptosis via mitochondrial pathway in liver cells. AB - It is well documented that liver is the primary target organ of aflatoxin B1 (AFB1) and curcumin proved to be effective against AFB1-induced liver injury. In the present study, we investigated the preventive effects of curcumin against AFB1-induced apoptosis through the molecular regulation of p53, caspase-3, Bax, caspase-9, Bcl-2 and cytochrome-C associated with mitochondrial pathway. Liver antioxidant levels were measured. The hallmarks of apoptosis were analysed by methyl green-pyronin-Y staining, transmission electron microscopy, RT-PCR and western blot. Results revealed that dietary curcumin ameliorated AFB1-induced oxidative stress in a dose-dependent manner. Methyl green-pyronin-Y staining and transmission electron microscopy showed that AFB1 induced apoptosis and caused abnormal changes in liver cells morphology such as condensation of chromatin material, reduces cell volume and damaged mitochondria. Moreover, mRNA and protein expression results manifested that apoptosis associated genes showed up regulation in AFB1 fed group. However, the supplementation of dietary curcumin (dose-dependently) alleviated the increased expression of the apoptosis associated genes at mRNA and protein level, and restored the hepatocytes normal morphology. The study provides an insight and a better understanding of the preventive mechanism of curcumin against AFB1-induced apoptosis in hepatocytes and provide scientific basis for the therapeutic uses of curcumin. PMID- 29974319 TI - Who Benefits from Community Mental Health Care? Using Latent Profile Analysis to Identify Differential Treatment Outcomes for Youth. AB - Treatment effectiveness has been shown to vary across subgroups of youth based on characteristics such as comorbidity, problem severity, gender, and age. The current study aims to explore if subgroups of youth, identified by applying latent profile analysis to parent-reported symptoms, age, and gender, are better served by specific usual care services. Archival data from a community mental health center were utilized, including parent-reports of symptoms for 953 youth (44.4% female; ages 4-18) across multiple time-points, and services received. Latent profile analysis identified five subgroups including Low Risk, High Risk, Internalizing, Externalizing, and Delinquent/Depressed. The relationship between the intensity level of services and symptoms varied across subgroups. Specifically, high intensity services were related to a greater reduction in symptoms for the Internalizing, Externalizing, and High Risk subgroups. Implications for future developmental research and clinical applications are discussed. PMID- 29974321 TI - How to perform and manage low-dose and slow/ultra-slow tissue type plasminogen activator infusion regimens in patients with prosthetic valve thrombosis. PMID- 29974320 TI - Iron-oxidizing bacteria in marine environments: recent progresses and future directions. AB - Iron-oxidizing bacteria (FeOB) refers to a group of bacteria with the ability to exchange and accumulate divalent iron dissolved in water as trivalent iron inside and outside the bacterial cell. Most FeOB belong the largest bacterial phylum, Proteobacteria. Within this phylum, FeOB with varying physiology with regards to their response to oxygen (obligate aerobes, facultative and obligate anaerobes) and pH optimum for proliferation (neutrophiles, moderate and extreme acidophiles) can be found. Although FeOB have been reported from a wide variety of environments, most of them have not been isolated and their biochemical characteristics remain largely unknown. This is especially true for those living in the marine realm, where the properties of FeOB was not known until the isolation of the Zetaproteobacteria Mariprofundus ferrooxydans, first reported in 2007. Since the proposal of Zetaproteobacteria by Emerson et al., the detection and isolation of those microorganisms from the marine environment has greatly escalated. Furthermore, FeOB have also recently been reported from works on ocean drilling and metal corrosion. This review aims to summarize the current state of phylogenetic and physiological diversity in marine FeOB, the significance of their roles in their environments (on both global and local scales), as well as their growing importance and applications in the industry. PMID- 29974323 TI - Case Report: A Case of Chromoblastomycosis Caused by Fonsecaea pedrosoi in Vietnam. AB - BACKGROUND: Chromoblastomycosis is a chronic fungal infection of the skin and subcutaneous tissues caused by different melanized fungi. The disease occurs worldwide, particularly in tropical and subtropical regions but not reported in Vietnam. A 47-year-old women was admitted to hospital 103, Hanoi, Vietnam, with a 10-year lasting lesion on backside of her right shank. Diagnosis of chromoblastomycosis was made after discovery of a muriform cell in histopathological examination. A black, slow-growth fungus was isolated and identified as Fonsecaea pedrosoi after molecular analysis. After 1-month treatment with itraconazole, the lesion has significant improvement. CONCLUSION: This is the first case of chromoblastomycosis caused by Fonsecaea pedrosoi reported in Vietnam. PMID- 29974322 TI - Experiences of Women Who Have Had Carrier Testing for Duchenne Muscular Dystrophy and Becker Muscular Dystrophy During Adolescence. AB - Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X linked recessive degenerative muscular conditions. Carrier testing is available to at-risk females. Though carrier testing is often offered to adolescent females, it raises ethical issues related to autonomy. This study aimed to address the impact of DMD/BMD carrier testing during adolescence, to elucidate what motivates adolescents to seek testing, and to assess the carrier testing experience. Retrospective semi-structured telephone interviews were conducted with 12 women out of 28 initially contacted. Data were coded using thematic analysis. For most (8/12) participants, discovering their carrier status during adolescence appeared to have helped alleviate uncertainty. The majority (9/12) of participants felt that they had made an autonomous decision and most (10/12) seemed to have adjusted well to their test result. Reproductive factors were framed as having been a key motivator prior to testing. However, following testing, participants' views on prenatal diagnosis seemed more closely linked to their lived experience than to their test result. Just over half (7/12) the participants reported having not had the opportunity for genetic counseling prior to testing and after receiving their result, an issue that warrants further consideration. PMID- 29974324 TI - The effect of indirect admission via hospital transfer on hip fracture patients in Ireland. AB - BACKGROUND AND AIMS: Current best practice states that hip fracture patients should undergo surgery within 48 hours to minimise perioperative complications. There are 10 emergency departments (EDs) in Ireland that receive hip fracture patients without a trauma and orthopaedic surgery unit on site. Idle periods and duplicated preoperative investigations can lead to a prolonged time to surgery. The aim of this study was to identify the effect of admission route on the time to surgery, length of stay and pressure ulcer development in patients who sustain a hip fracture in Ireland. METHODS: A retrospective cohort study was performed, using 2013 and 2014 data from the Irish Hip Fracture Database. Age, gender and ASA grade were identified as confounders and adjusted for accordingly. RESULTS: Of the 3893 hip fractures identified, indirect admissions via hospital transfer occurred in 8.6% of cases. Surgery was performed within 48 h in 72.0% of indirect admission and 73.7% of direct admission cases (p = 0.502). The length of stay was significantly prolonged for patients admitted via hospital transfer (25.6 compared to 19.6 days, p < 0.001). CONCLUSION: Delayed discharges post hip fracture have been shown to expose patients to increased perioperative morbidity and mortality rates, as well as reduced rehabilitation potential and less chance of returning home on discharge. This has significant cost implications for the health service and justifies the introduction of hospital bypass protocols for patients with hip fractures. PMID- 29974325 TI - HLA and lung transplantation. AB - Lung transplantation is increasingly practiced for patients with end-stage lung disease. The successful outcome of solid organ transplantation today is severely impeded by the production of alloantibodies, mainly directed against the protein products of the HLA complex of the organ donor. While the association between antibody mediated rejection and allograft damage has been well established in renal and heart transplantation, it has not yet been well characterized in lung transplantation. This review addresses the question of HLA matching in lung transplantation and current knowledge of the allogenicity of different HLA class I and II antigens. The role of the antibody mediated immune response is discussed as well as the importance of pre-transplant or de novo posttransplant circulating antibodies. Finally, potential mechanisms, which may act individually or in combination, of antibody mediated damage to solid organ transplants are considered. PMID- 29974327 TI - Will iPS Cells Regenerate or Just Provide Trophic Support to the Diseased Tissues? PMID- 29974326 TI - Environmental assessment concerning trace metals and ecological risks at Guanabara Bay, RJ, Brazil. AB - Three-stage sequential extraction BCR was applied to surface sediments from the west part of Guanabara Bay to assess the mobility of Zn, Cu, Pb, Ni, Cr, and Mn. Results were satisfactory for the analysis of certificate standard material (BCR 701), with recoveries between 71 (Cu) and 123% (Cr). Evaluation of organic matter composition classified the area as eutrophic (CHO:PRT > 1), with aged organic detritus at some stations. Zn exhibited by far the greatest bioavailability, with 43.49% of its concentrations associated with the exchangeable fraction. Cu and Cr showed stronger affinity for organic matter, with 51.18 and 48.73% of their concentrations, respectively, bounded to the oxidizable fraction. Pb presented higher concentrations in the reducible fraction (45.41%). The strongest lithogenic contribution was shown by Ni (31.91%) and Mn (35.44%). PCA clearly showed the determinant role of organic matter and fine sediments in the distribution of metals in the study area and also a common source for these elements, with the exception of Cu. Risk Assessment Code (RAC) established Zn as the most concerning element in the study area. The decreasing mobility order, based on the sum of the three extractable fractions of BCR, was Pb > Cu > Cr > Zn > Ni > Mn. The comparison of the results with sediments quality guidelines (SQG) proved fractionation to be mandatory in the evaluation of effective ecological risk concerning trace elements in sediments. PMID- 29974328 TI - A Graft Mimic Strategy for Verticillium Resistance in Tomato. AB - Grafting vegetables for disease resistance has increased greatly in popularity over the past 10 years. Verticillium wilt of tomato is commonly controlled through grafting of commercial varieties on resistant rootstocks expressing the Ve1 R-gene. To mimic the grafted plant, proteomic analyses in tomato were used to identify a suitable root-specific promoter (TMVi), which was used to express the Ve1-allele in susceptible Craigella (Cs) tomato plants. The results indicate that when infected with Verticillim dahliae, race 1, the transformed plants are comparable to resistant cultivars (Cr) or grafted plants. PMID- 29974329 TI - Identity of Haemaphysalis (Rhipistoma) muhsamae Santos Dias, 1954 (Acari: Ixodidae) and H. (R.) subterra Hoogstraal, El Kammah & Camicas, 1992, parasites of carnivores and rodents in eastern and southern Africa. AB - Haemaphysalis (Rhipistoma) muhsamae Santos Dias, 1954 (Acari: Ixodidae) and H. (R.) subterra Hoogstraal, El Kammah & Camicas, 1992, are redescribed based on males and females. Adults of H. muhsamae were mostly collected from various mongooses (Carnivora: Herpestidae) but also from the striped polecat, Ictonyx striatus (Perry) (Carnivora: Mustelidae), serval, Leptailurus serval (Schreber) (Carnivora: Felidae), red veld rat, Aethomys chrysophilus (de Winton) and Selinda veld rat, Aethomys silindensis Roberts (Rodentia: Muridae) in Botswana, Kenya, Mozambique, South Africa, Tanzania and Zimbabwe. Adults of H. subterra were mostly found on various species of African mole rats, Tachyoryctes spp. (Rodentia: Spalacidae) but also on striped polecat, I. striatus and slender mongoose, Galerella sanguinea (Ruppell) (Carnivora: Herpestidae) in Ethiopia and Kenya. Males and females of both species can be differentiated from each other and other H. spinulosa-like ticks by their size, pattern of punctations on conscutum/scutum, shape of genital structures, shape and size of posterodorsal and posteroventral spurs on palpal segment II, hypostome dentition, and shape and size of spurs on coxae. Taxonomic issues of both species and those related to the identity of H. (R.) spinulosa Neumann, 1906 are discussed and a neotype of H. muhsamae has been designated. PMID- 29974331 TI - Science as a Vocation in the Era of Big Data: the Philosophy of Science behind Big Data and humanity's Continued Part in Science. AB - We now live in the era of big data, and according to its proponents, big data is poised to change science as we know it. Claims of having no theory and no ideology are made, and there is an assumption that the results of big data are trustworthy because it is considered free from human judgement, which is often considered inextricably linked with human error. These two claims lead to the idea that big data is the source of better scientific knowledge, through more objectivity, more data, and better analysis. In this paper I analyse the philosophy of science behind big data and make the claim that the death of many traditional sciences, and the human scientist, is much exaggerated. The philosophy of science of big data means that there are certain things big data does very well, and some things that it cannot do. I argue that humans will still be needed for mediating and creating theory, and for providing the legitimacy and values science needs as a normative social enterprise. PMID- 29974330 TI - Twelve cases of pituitary metastasis: a case series and review of the literature. AB - PURPOSE: The pituitary gland is an unusual site for metastatic spread, but as patients with metastatic malignancy are living longer, it may become more prevalent. Compression of important anatomy adjacent to the sella may produce disabling symptoms and endocrine derangement, leading to significant morbidity. METHODS: An ambispective review of patient records between 2013 and 2017 from three neurosurgical centres was performed. After identifying cases, further investigation was performed to evaluate patient demographic, symptoms at presentation, radiological and histological findings, management, and outcome. RESULTS: Our investigation identified 12 patients with pituitary metastasis. The average age of the cases was 63.4 years, with breast (n = 4) and lung (n = 4) being the most common primary cancers. In half the cases there was a history of metastatic disease, while in one-quarter of cases, pituitary symptoms were the first sign of malignancy. Adenohypophyseal dysfunction (83%), diabetes insipidus (DI) (75%), headache (67%) and visual field defects (67%) were the most common findings at presentation. Glucocorticoid replacement increased the sensitivity for diagnosis of DI. All cases were contrast enhancing on MRI and the endoscopic trans-sphenoidal approach was preferred for biopsy and debulking. CONCLUSIONS: The pituitary should not be overlooked as a site of metastasis and sellar symptoms may be the first presentation of neoplastic disease. Any biochemical or clinical sign of pituitary pathology in a patient with known cancer should raise suspicion for sellar metastasis. Moreover, the development of DI or ophthalmoplegia from any pituitary lesion is suggestive of metastatic disease even in patients with no known primary. PMID- 29974332 TI - Do clinical and radiologic features help predict malignancy of B3 breast lesions without epithelial atypia (B3a)? AB - OBJECTIVES: To evaluate excision histology outcome of B3a lesions diagnosed at imaging-guided core biopsy and assess whether clinical and radiologic features may predict upgrade to malignancy. METHODS: A total of 153 B3a lesions (74 papillomas, 51 radial scars and 28 fibro-epithelial lesions) that underwent surgical excision were assessed. PPV for malignancy in all B3a lesions and specific for each sub-category was evaluated. Multivariate analysis was conducted to identify association between clinical (age, family or personal history of breast cancer, symptoms), diagnostic findings (imaging modality, lesion size, final BI-RADS category) and final excision outcome. RESULTS: Eleven (7%) of 153 B3a lesions were upgraded to malignancy. All carcinomas diagnosed on excision were non-high grade DCIS. Following features were significantly associated with malignancy: lesions identified only on mammography (3/21; 14%), both mammography and ultrasound (7/44; 16%), lesion size > 10 mm (10/74; 13.5%) and BI-RADS category 4-5 (8/29; 27.6%). The absence of residual microcalcification after biopsy was associated with decreased risk for malignancy (15/16[93.7%]; p = 0.0297). Lesion size > 10 mm (OR = 9.3832; 95%; p = 0.0398) and BI-RADS category 4-5 (OR = 12.6004; 95%; p = 0.0006) were found to be independent predictors of upgrade to malignancy. CONCLUSIONS: B3a lesions are associated with low risk of malignancy at excision. Lesion size > 10 mm and BI-RADS 4-5 category may represent useful predictors of upgrade to malignancy. PMID- 29974333 TI - Prefrontal TDCS attenuates medial prefrontal connectivity upon being criticized in individuals scoring high on perceived criticism. AB - The mechanisms by which transcranial direct current stimulation (tDCS) influences emotional processing - and whether this is related to individual vulnerability for psychopathology - are still poorly understood. The present study aimed to investigate if one prefrontal tDCS session modulates mood and neural functional connectivity after being exposed to negative information differently in individuals low or high in perceived criticism (PC), which has been related to vulnerability for psychiatric illness. In a randomized cross-over design, one session of MRI-compatible prefrontal tDCS (neuronavigated placement of the anodal electrode at the left dorsolateral prefrontal cortex and the cathodal electrode at the right supraorbital region; vs. sham) was administered to healthy females, prior to listening to self-referential criticism. PC-dependent (low vs. high PC) changes in mood and resting-state functional connectivity patterns following tDCS and after hearing criticism were explored. After being criticized all females (low and high PC) felt angrier and more depressed, both in the active tDCS or sham tDCS condition. However, in contrast to low PC females, in high PC females prefrontal tDCS reduced connectivity between the left dorsal anterior cingulate cortex and the right dorsomedial prefrontal cortex following criticism. Despite having no differential effects on self-reported mood, prefrontal tDCS reduces medial prefrontal neural connectivity after being criticized in high PC females compared to low PC females. Depending on individual vulnerability for psychopathology, a single tDCS session differentially affects neural processing of negative emotional information, especially in brain regions involved in monitoring, experiencing and appraising/evaluating emotional material. PMID- 29974336 TI - Study on Contribution of Biological Interpretable and Computer-Aided Features Towards the Classification of Childhood Medulloblastoma Cells. AB - Diagnosis and Prognosis of brain tumour in children is always a critical case. Medulloblastoma is that subtype of brain tumour which occurs most frequently amongst children. Post-operation, the classification of its subtype is most vital for further clinical management. In this paper a novel approach of pathological subtype classification using biological interpretable and computer-aided textural features is forwarded. The classifier for accurate features prediction is built purely on the feature set obtained by segmentation of the ground truth cells from the original histological tissue images, marked by an experienced pathologist. The work is divided into five stages: marking of ground truth, segmentation of ground truth images, feature extraction, feature reduction and finally classification. Kmeans colour segmentation is used to segment out the ground truth cells from histological images. For feature extraction we used morphological, colour and textural features of the cells followed by feature reduction using Principal Component Analysis. Finally both binary and multiclass classification is done using Support Vector Method (SVM). The classification was compared using six different classifiers and performance was evaluated employing five-fold cross-validation technique. The accuracy achieved for binary and multiclass classification before applying PCA were 95.4 and 62.1% and after applying PCA were 100 and 84.9% respectively. The run-time analysis are also shown. Results reveal that this technique of cell level classification can be successfully adopted as architectural view can be confusing. Moreover it conforms substantially to the pathologist's point of view regarding morphological and colour features, with the addition of computer assisted texture feature. PMID- 29974337 TI - Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in children and adolescents. PMID- 29974335 TI - Discriminating radiation injury from recurrent tumor with [18F]PARPi and amino acid PET in mouse models. AB - BACKGROUND: Radiation injury can be indistinguishable from recurrent tumor on standard imaging. Current protocols for this differential diagnosis require one or more follow-up imaging studies, long dynamic acquisitions, or complex image post-processing; despite much research, the inability to confidently distinguish between these two entities continues to pose a significant dilemma for the treating clinician. Using mouse models of both glioblastoma and radiation necrosis, we tested the potential of poly(ADP-ribose) polymerase (PARP)-targeted PET imaging with [18F]PARPi to better discriminate radiation injury from tumor. RESULTS: In mice with experimental radiation necrosis, lesion uptake on [18F]PARPi-PET was similar to contralateral uptake (1.02 +/- 0.26 lesion/contralateral %IA/ccmax ratio), while [18F]FET-PET clearly delineated the contrast-enhancing region on MR (2.12 +/- 0.16 lesion/contralateral %IA/ccmax ratio). In mice with focal intracranial U251 xenografts, tumor visualization on PARPi-PET was superior to FET-PET, and lesion-to-contralateral activity ratios (max/max, p = 0.034) were higher on PARPi-PET than on FET-PET. CONCLUSIONS: A murine model of radiation necrosis does not demonstrate [18F]PARPi avidity, and [18F]PARPi-PET is better than [18F]FET-PET in distinguishing radiation injury from brain tumor. [18F]PARPi-PET can be used for discrimination between recurrent tumor and radiation injury within a single, static imaging session, which may be of value to resolve a common dilemma in neuro-oncology. PMID- 29974334 TI - Current Concepts in Talar Neck Fracture Management. AB - PURPOSE OF THE REVIEW: Talar neck fractures are a rare but potentially devastating injury, which require a comprehensive understanding of the unique osteology, vasculature, and surrounding anatomy to recognize pathology and treat correctly. The purpose of this article is to describe both classic and current literature to better understand the evolution of talar neck fracture management. RECENT FINDINGS: Urgent reduction of displaced fractures and dislocations remains the standard of care to protect the soft tissue envelope and neurovascular structures. Delayed definitive fixation has proven to be safe. CT is the imaging modality of choice to fully identify the fracture pattern and associated injuries. Anatomic reduction and restoration of the peritalar articular surfaces are the pillars of talar neck fracture treatment. Dual incision approach with plate and screw fixation has become the modern surgical strategy of choice to accomplish these goals. Although complications such as osteonecrosis (ON) and posttraumatic arthritis (PTA) can still occur at high rates, treatment should be dictated by patient symptoms. Talar neck fractures pose treatment challenges with both initial injury and potential sequelae. Future research will determine whether modern treatment algorithms will decrease complication rate and improve patient outcome. PMID- 29974339 TI - Vitamin D Supplementation in Childhood - A Review of Guidelines: Correspondence. PMID- 29974338 TI - Small-Molecule Targets in Tumor Immunotherapy. AB - Cancer immunotherapy has been widely recognized as a powerful approach to fight cancers. To date, over 50 phase III trials in cancer immunotherapy are in progress. Among the many immunotherapy approaches, immune checkpoint therapy has attracted considerable attention. The reported clinical success of targeting the T cell immune checkpoint receptors PD-1 or CTLA4 by antibodies blockade in advanced stages of cancers has demonstrated the importance of immune modulation. But antibodies-based immunotherapy confronted with some disadvantages, such as immunogenicity, stability, membrane permeability, and production cost. Therefore, alternative approaches including small-molecule-regulated immune response are being introduced. In this review, we focused on some of the key intracellular pathways where small-molecule therapeutic is potential and attractive, which highlights the great potential of natural products in this field. PMID- 29974340 TI - Intracardiac Sewing Needle in a Child. PMID- 29974341 TI - Microarray Analysis of Gene Expression Changes in Neuroplastin 65-Knockout Mice: Implications for Abnormal Cognition and Emotional Disorders. AB - Neuroplastin 65 (Np65) is an immunoglobulin superfamily cell adhesion molecule involved in synaptic formation and plasticity. Our recent study showed that Np65 knockout (KO) mice exhibit abnormal cognition and emotional disorders. However, the underlying mechanisms remain unclear. In this study, we found 588 differentially-expressed genes in Np65-KO mice by microarray analysis. RT-PCR analysis also revealed the altered expression of genes associated with development and synaptic structure, such as Cdh1, Htr3a, and Kcnj9. In addition, the expression of Wnt-3, a Wnt protein involved in development, was decreased in Np65-KO mice as evidenced by western blotting. Surprisingly, MRI and DAPI staining showed a significant reduction in the lateral ventricular volume of Np65 KO mice. Together, these findings suggest that ablation of Np65 influences gene expression, which may contribute to abnormal brain development. These results provide clues to the mechanisms underlying the altered brain functions of Np65 deficient mice. PMID- 29974342 TI - In vivo genome editing targeted towards the female reproductive system. AB - The discovery of sequence specific nucleases such as ZFNs, TALENs, and CRISPR/Cas9 has revolutionized genome editing. The CRISPR/Cas9 system has particularly emerged as a highly simple and efficient approach towards generating genome-edited animal models of most of the experimental species. The limitation of these novel genome editing tools is that, till date, they depend on traditional pronuclear injection (PI)-based transgenic technologies developed over the last three decades. PI requires expensive micromanipulator systems and the equipment operators must possess a high level of skill. Therefore, since the establishment of PI-based transgenesis, various research groups worldwide have attempted to develop alternative and simple gene delivery methods. However, owing to the failure of chromosomal integration of the transgene, none of these methods gained the level of confidence as that by the PI method in order to be adapted as a routine approach. The recently developed genome editing systems do not require complicated techniques. Therefore, presently, attention is being focused on non PI-based gene delivery into germ cells for simple and rapid production of genetically engineered animals. For example, a few reports during the previous 1 2 years demonstrated the use of electroporation (EP) in isolated zygotes that helped to overcome the absolute dependency on PI techniques. Recently, another breakthrough technology called genome editing via oviductal nucleic acids delivery (GONAD) that directly delivers nucleic acids into zygotes within the oviducts in situ was developed. This technology completely relieves the bottlenecks of animal transgenesis as it does not require PI and ex vivo handling of embryos. This review discusses in detail the in vivo gene delivery methods targeted towards female reproductive tissues as these methods that have been developed over the past 2-3 decades can now be re-evaluated for their suitability to deliver the CRISPR/Cas9 components to produce transgenic animals. This review also provides an overview of the latest advances in CRISPR-enabled delivery technologies that have caused paradigm shifts in animal transgenesis methodologies. PMID- 29974343 TI - Use of Enteral Nutrition for Gastrointestinal Bleeding Prophylaxis in the Critically Ill: Review of Current Literature. AB - PURPOSE OF REVIEW: This review provides a comprehensive overview of the etiology of stress-related mucosal disease, current acid suppression therapy recommendations, and the role enteral nutrition may play in disease prevention. RECENT FINDINGS: Recent literature indicates enteral nutrition may prevent complications of stress-related mucosal disease by increasing splanchnic blood flow, enhancing gastrointestinal motility, and promoting cellular immunity and integrity through local nutrient delivery. Stress-related mucosal disease is a common complication of hospitalization in the critically ill which may lead to overt gastrointestinal bleeding and enhanced mortality. High-risk patients have historically been prescribed acid suppression therapy, though enteral nutrition may also have a role in disease mitigation. PMID- 29974344 TI - The Role of Nutrition in Cognitive Function and Brain Ageing in the Elderly. AB - PURPOSE OF REVIEW: The purposes of this review were to examine literature published over the last 5 years and to evaluate the role of nutrition in cognitive function and brain ageing, focussing on the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets. RECENT FINDINGS: Results suggest that higher adherence to a healthy dietary pattern is associated with preservation of brain structure and function as well as slower cognitive decline, with the MIND diet substantially slowing cognitive decline, over and above the MeDi and DASH diets. Whilst results to-date suggest adherence to a healthy diet, such as the MeDi, DASH, or MIND, is an important modifiable risk factor in the quest to develop strategies aimed at increasing likelihood of healthy brain ageing, further work is required to develop dietary guidelines with the greatest potential benefit for public health; a research topic of increasing importance as the world's population ages. PMID- 29974345 TI - Kohlmeier-Degos disease with constrictive pericarditis and atrial fibrillation. PMID- 29974346 TI - Adenocarcinoma Ex-Goblet Cell: a Retrospective Experience. AB - PURPOSE: Adenocarcinoma ex-goblet cell carcinoids (AGCCs) are rare appendiceal tumors with mixed neuroendocrine and glandular features. They tend to behave more aggressively than typical carcinoid tumors, affect younger patients, and have a greater predilection for spreading to the peritoneum. Outcomes of AGCC patients treated with chemotherapy, extrapolated from colon cancer regimens, in the adjuvant or metastatic setting have not been explicitly reported. We sought to explore outcomes of AGCC patients with either local disease treated with adjuvant FOLFOX or metastatic disease treated with FOLFOX/FOLFIRI post-cytoreductive debulking (or CRS plus HIPEC in the peritoneal-limited setting). METHODS: We performed a single-institution retrospective analysis of 23 pathologically identified AGCC patients from Vanderbilt University Medical Center treated with chemotherapy in either the adjuvant or metastatic settings. Each patient's tumor was categorized as group B or group C based on the criteria from Tang et al. Median progression-free survival (PFS) or disease-free survival (DFS) (in the curative setting) and overall survival (OS) were determined for each patient and specified patient subgroup. RESULTS AND CONCLUSION: AGCC patients who were treated with FOLFOX chemotherapy in the adjuvant setting or FOLFOX/FOLFIRI in the metastatic setting experienced prolonged PFS, DFS, and OS. Five patients with peritoneal-limited disease treated with CRS plus HIPEC have not yet reached median PFS or OS. While small sample size, patient selection, and retrospective nature limit the generalizability of findings from our analysis, the efficacy signals we observed suggest prospective evaluation with chemotherapy and CRS plus HIPEC is warranted in AGCC patients. PMID- 29974347 TI - Frequency of Defective Mismatch Repair System in a Series of Consecutive Cases of Colorectal Cancer in a National Cancer Center. AB - BACKGROUND: The frequency of colorectal cancer (CRC) with defective mismatch repair (dMMR) is estimated between 5 and 15%. In our population, the frequency of dMMR is unknown. Our objective was to show the frequency of dMMR. METHODS: Determination of dMMR with immunohistochemistry was performed prospectively for 202 patients who presented consecutively with CRC for the first time at our institution. RESULTS: The median age was 59 years (IQR 47 to 68), 119 (58.9%) were women, and 43 (21.3%) cases showed dMMR. The only clinicopathological characteristics associated with dMMR were the location in the right colon and the presence of a family history of cancer. In the multivariate analysis, only the presence of the tumor in the right colon was associated with dMMR (OR = 5.823, 95%-C.I. = 2.653-12.784, p < .001). CONCLUSION: The 21.3% of the cases demonstrated a dMMR and the only clinical-pathological characteristic associated with dMMR was location in the right colon. PMID- 29974349 TI - Cerebrospinal fluid monoamines, pterins, and folate in patients with mitochondrial diseases: systematic review and hospital experience. AB - Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes. PMID- 29974348 TI - Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-a successful strategy for clinical research of rare diseases. AB - BACKGROUND: To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS: Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS: Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS: The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (<= 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS: Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilising differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies. PMID- 29974350 TI - Untiring Researches for Alternative Resources of Rhizoma Paridis. AB - Rhizoma Paridis (RP, ), a traditional Chinese medicine, is the rhizoma of Paris polyphylla var. yunnanensis (PPY) or P. polyphylla var. chinensis which are widely used as important raw materials for several Chinese patent drugs. However, the wild resources of these herbs have become less and less due to their slow growing characteristics and previously excessive excavation. This review covers untiring investigations on alternative resources of RP by our research group over the past decades, including non-medicinal parts of PPY as well as other plants of Liliaceae and Liliflorae families. The arial parts of PPY and the whole plants of Trillium kamtschaticum might be alternative resources for RP based on the fact that they shared the same or similar saponins and bioactivities. PMID- 29974351 TI - Observational Study Evaluating the Economic Impact of Breakthrough Pain in Cancer Patients in Clinical Practice in Spain: The IMDI Study. AB - INTRODUCTION: Breakthrough pain (BTP) has great repercussions on the quality of life, and on the use of health resources. The scope of BTP costs in cancer patients is unknown. The purpose of this study was to evaluate the economic cost of BTP in patients with cancer and the relationship with their quality of life. METHODS: A 1-month observational prospective cost-of-illness study was designed. The patients recorded the consumption of health resources and drugs related to BTP in a diary. The current symptoms in Edmonton Symptoms Assessment Scale (ESAS) and their quality of life (EORTC QLQ-C30, version 3) were assessed. The direct medical and non-medical costs fixed and variable and the indirect costs of the patient and the caregivers were evaluated. Factors related to cost and quality of life were identified using linear generalized models (LGM) type gamma and logistic link. Participants were oncologic patients with BTP, older than 18 years, with controlled basal pain. RESULTS: Eight Spanish pain units, eight palliative care units, and one oncology department included 152 patients. One hundred patients (65.8%) were male and the mean age was 66.8 years (95% CI 64.8 68.8). The total cost per patient was 2941.60 euros per month: 88% direct medical costs, 5% non-medical direct costs, and 7% indirect costs due to lost productivity. A better score in EORTC QLQ-30 quality of life was associated with a reduction in overall costs. CONCLUSIONS: The study showed the results of the first real-life prospective study evaluating the cost of illness of BTP in cancer patients demonstrating that the presence of breakthrough pain in a cancer patient causes a very significant increase in healthcare costs. FUNDING: Kyowa Kirin Farmaceutica, S.L.U. PMID- 29974352 TI - Up-regulated lncRNA AFAP1-AS1 indicates a poor prognosis and promotes carcinogenesis of breast cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have been reported to play crucial roles in breast cancer. This study aimed to determine the clinical significance and biological functions of lncRNA AFAP1-AS1 in breast cancer. METHODS: The expression of AFAP1-AS1 in breast cancer tissue and adjacent normal tissue from 160 patients and breast cancer cell lines were determined by qRT-PCR. The clinical characteristics of patients were collected to analyse the correlation between AFAP1-AS1 expression and malignancy status. Kaplan-Meier and Cox proportional hazards model were used to analyze whether AFAP1-AS1 expression impacted prognosis. To assess the effect of AFAP1-AS1 on MCF-7 cells proliferation, cell viability, EdU incorporation and colony formation assays were conducted after AFAP1-AS1 knockdown by siRNA. The apoptosis was detected by Caspase-3 activity, cell cycle analysis, Bcl-2 and Bax protein expression. Wound scratch assay and EMT-related protein expression (E-cadherin, N-cadherin and Vimentin) were conducted to evaluate the metastasis ability. To further determine the effect of AFAP1-AS1 on AFAP1, the mRNA and protein expression of AFAP1 and subsequent actin filament integrity were measured after AFAP1-AS1 knockdown. RESULTS: The expression of AFAP1-AS1 was up-regulated in human breast cancer tissue and associated with malignancy status, high expression of AFAP1-AS1 had a poor prognosis in breast cancer patients. AFAP1-AS1 expression was up-regulated in 4 breast cancer cell lines (MCF-7, SK-RB-3, MDA-MB-231and MDA-MB-468) compared with normal breast cell line HBL-100. MCF-7, the most up-regulation cancer cell, was used for following studies. AFAP1-AS1 knockdown can inhibit the proliferation, metastasis and promote apoptosis of MCF-7. However, the AFAP1 expression and actin filament integrity was not affected after AFAP1-AS1 knockdown. CONCLUSION: Up-regulated lncRNA AFAP1-AS1 indicates a poor prognosis in breast cancer patients and regulated the breast cancer cells proliferation, apoptosis and metastasis. PMID- 29974353 TI - Bowel preparation in elective colorectal surgery: back to the future? PMID- 29974354 TI - Mannheimia haemolytica OmpP2-like is an amyloid-like protein, forms filaments, takes part in cell adhesion and is part of biofilms. AB - Mannheimia haemolytica causes respiratory disease in cattle. Amyloid proteins are a major component of biofilms; they aid in adhesion and confer resistance against several environmental insults. The amyloid protein curli is highly resistant to protease digestion and physical and chemical denaturation and binds Congo red (CR) dye. The purpose of this study was to characterize an approximately 50-kDa CR-binding amyloid-like protein (ALP) expressed by M. haemolytica. This protein resisted boiling and formic acid digestion and was recognized by a polyclonal anti-Escherichia coli curli serum, suggesting its relationship with amyloid proteins. Immunolabeling and transmission electron microscopy showed that antibodies bound long, thin fibers attached to the bacterial surface. Mass spectrometry analysis indicated that these fibers are M. haemolytica OmpP2-like proteins. The purified protein formed filaments in vitro, and antiserum against it reacted positively with biofilms. An in silico analysis of its amino acid sequence indicated it has auto-aggregation properties and eight amyloid peptides. Rabbit polyclonal antibodies generated against this ALP diminished the adhesion of ATCC 31612 and BA1 M. haemolytica strains to A549 human epithelial cells, indicating its participation in cell adhesion. ALP expressed by M. haemolytica may be important in its pathogenicity and ability to form biofilms. PMID- 29974355 TI - 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: comments from the Dutch ACS working group. AB - On behalf of the Dutch ACS working group, we discuss the most important changes in recommendations in the 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation relevant for both the general and interventional cardiologist. PMID- 29974356 TI - Efficacy and safety of fulvestrant in postmenopausal patients with hormone receptor-positive advanced breast cancer: a systematic literature review and meta analysis. AB - PURPOSE: This meta-analysis was conducted to compare the efficacy and safety of fulvestrant with aromatase inhibitors in postmenopausal women with hormone receptor-positive (estrogen and/or progesterone receptor positive) advanced breast cancer. METHODS: Electronic databases were searched for randomized controlled trials comparing the efficacy and safety of fulvestrant with three aromatase inhibitors (anastrozole/letrozole/exemestane) published through August 31, 2017. Time to progression/progression-free survival was the primary outcome, while overall survival and safety were the secondary outcomes. Time to progression/progression-free survival was evaluated in subgroups determined on age, hormone receptor status, visceral metastasis, and measurable disease. Hazard ratios with 95% confidence intervals were analyzed by STATA 12.0. RESULTS: Total of seven randomized controlled trials, with 3168 patients were included for analysis. In the overall population, fulvestrant and aromatase inhibitors had similar time to progression/progression-free survival (Hazard ratio 0.93; 95% confidence interval 0.86-1.01, P = 0.102); however, time to progression/progression-free survival for fulvestrant 500 mg was significantly longer compared with aromatase inhibitors (hazard ratio 0.75; 95% confidence interval 0.62-0.91, P = 0.003). Subgroup analysis revealed significant prolongation of time to progression/progression-free survival with fulvestrant compared with aromatase inhibitors in the patients of estrogen and progesterone receptor-positive (hazard ratio 0.86; 95% confidence interval, 0.75-0.98, P = 0.022) and patients aged >= 65 years (hazard ratio 0.81; 95% confidence interval 0.68-0.96, P = 0.014). Overall survival was similar in both groups (hazard ratio 0.89; 95% confidence interval 0.70, 1.13, P = 0.334). CONCLUSION: In postmenopausal women with estrogen and/or progesterone receptor-positive advanced breast cancer, fulvestrant 500 mg showed better efficacy than aromatase inhibitor, which was not seen with fulvestrant 250 mg. Compared to aromatase inhibitors, fulvestrant prolonged time to progression/progression-free survival in the subgroups including estrogen and progesterone receptor-positive patients and those aged >= 65 years. PMID- 29974357 TI - Screening mammography: benefit of double reading by breast density. AB - PURPOSE: The currently recommended double reading of all screening mammography examinations is an economic burden for screening programs. The sensitivity of screening is higher for women with low breast density than for women with high density. One may therefore ask whether single reading could replace double reading at least for women with low density. We addressed this question using data from a screening program where the radiologists coded their readings independently. METHODS: Data include all screening mammography examinations in the Capital Region of Denmark from 1 November 2012 to 31 December 2013. Outcome of screening was assessed by linkage to the Danish Pathology Register. We calculated sensitivity, specificity, number of interval cancers, and false positive-tests per 1000 screened women by both single reader and consensus BI RADS density code. RESULTS: In total 54,808 women were included. The overall sensitivity of double reading was 72%, specificity was 97.6%, 3 women per 1000 screened experienced an interval cancer, and 24 a false-positive test. Across all BI-RADS density codes, single reading consistently decreased sensitivity as compared with consensus reading. The same was true for specificity, apart from results across BI-RADS density codes set by reader 2. CONCLUSIONS: Single reading decreased sensitivity as compared with double reading across all BI-RADS density codes. This included results based on consensus BI-RADS density codes. This means that replacement of double with single reading would have negative consequences for the screened women, even if density could be assessed automatically calibrated to the usual consensus level. PMID- 29974358 TI - Optimal vascular access strategies for patients receiving chemotherapy for early stage breast cancer: a systematic review. AB - IMPORTANCE: Systemic chemotherapy can be administered either through a peripheral vein (IV), or centrally through peripherally inserted central catheter (PICC), totally implanted vascular access devices (PORTs) or tunnelled cuffed catheters. Despite the widespread use of systemic chemotherapy in patients with breast cancer, the optimal choice of vascular access is unknown. OBJECTIVE: This systematic review evaluated complication rates and patient satisfaction with different access strategies for administering neo/adjuvant chemotherapy for breast cancer. EVIDENCE REVIEWED: Ovid Medline, EMBASE and the Cochrane Central Register of Controlled Trials were searched from 1946 to September 2017. Two reviewers independently assessed each citation. The Newcastle-Ottawa scale was used to assess the quality of cohort and case-control studies. FINDINGS: Of 1584 citations identified, 15 unique studies met the pre-specified eligibility criteria. There were no randomised studies comparing types of vascular access. Reports included six single-institution retrospective cohort studies, one retrospective multi-institution cohort, one retrospective cohort database study, five prospective single-institution studies, one prospective multi-institution study and one nested case-control study. Median complication rates were infection: 6.0% PICC (2 studies) versus 2.1% PORT (8 studies); thrombosis: 8.9% PICC (2 studies) versus 2.6% PORT (9 studies); extravasation: 0 PICC (1 study) versus 0.4% PORT (4 studies) and mechanical issues: PICC 3.8% (1 study) versus 1.8% PORT (9 studies). Satisfaction/quality of life appeared high with each device. CONCLUSION: In the absence of high-quality data comparing vascular access strategies, randomised, adequately powered, prospective studies would be required to help inform clinical practice and reduce variation. PMID- 29974359 TI - Patient-reported factors influencing the treatment decision-making process of older women with non-metastatic breast cancer: a systematic review of qualitative evidence. AB - PURPOSE: Older women (>= 70 years old) with breast cancer undergo different treatments than young women. Studies have examined factors that influence this disparity, but synthesized patient-reported data are lacking in the literature. This study aims to identify, appraise, and synthesize the existing qualitative evidence on patient-reported factors influencing older women's decision to accept or decline breast cancer treatment. METHODS: A systematic review was performed in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA) principles. Medline, Embase, CINAHL, and PsycINFO were searched for qualitative studies describing patient-reported factors influencing the decision-making process of older women (>= 70 years old) with non-metastatic invasive breast cancer. Quality was assessed using the Standards for Reporting Qualitative Research (SRQR) criteria. Common ideas were coded, thematically organized, and synthesized within a theoretical framework. RESULTS: Of 5998 studies identified, 10 met eligibility criteria. The median SRQR total score was 13.04 (IQR 12.84-13.81). The studies represented a range of cancer treatments; most of the studies focused on surgery and primary endocrine therapy. Our data show that the most common patient-reported factors in the decision-making process included treatment characteristics, personal goals/beliefs, patient characteristics, physician's recommendation, and personal/family experience. These factors led the patient to either accept or decline treatment, and were not consistent across all studies included. Studies used different interview guides, which may have affected these results. CONCLUSIONS: This systematic review highlights the complexity of factors that influence an older woman's treatment decision-making process. Acknowledging and addressing these factors may improve discussions about treatment choices between older women and their health care providers, and encourage maximization of a patient-centered approach. PMID- 29974360 TI - Validation Strategy for Ultrasensitive Mutation Detection. AB - BACKGROUND: Ultrasensitive detection of low-abundance DNA point mutations is a challenging molecular biology problem, because nearly identical mutant and wild type molecules exhibit crosstalk. Reliable ultrasensitive point mutation detection will facilitate early detection of cancer and therapeutic monitoring of cancer patients. OBJECTIVE: The objective of this study was to develop a method to correct errors in low-level cell line mixes. MATERIALS AND METHODS: We tested sample mixes with digital-droplet PCR (ddPCR) and next-generation sequencing. RESULTS: We introduced two corrections: baseline variant allele frequency (VAF) in the parental cell line was used to correct for copy number variation; and haplotype counting was used to correct errors in cell counting and pipetting. We found ddPCR to have better correlation for detecting low-level mutations without applying any correction (R2 = 0.80) and be more linear after introducing both corrections (R2 = 0.99). CONCLUSIONS: The VAF correction was found to be more significant than haplotype correction. It is imperative that various technologies be evaluated against each other and laboratories be provided with defined quality control samples for proficiency testing. PMID- 29974362 TI - The Routine Use of Intracameral Antibiotics to Prevent Endophthalmitis After Cataract Surgery: How Good is the Evidence? AB - Post-operative endophthalmitis (POE) following cataract surgery is an uncommon, vision-threatening complication that has been reported to occur at rates of between approximately 0.03% and 0.2%. Prompt diagnosis and treatment of endophthalmitis is critical for minimizing vision loss, but most recent efforts have focused on the prophylactic administration of antibiotics to prevent the development of endophthalmitis. Surgeons from around the world have different topical and intracameral antibiotic usage patterns to prevent endophthalmitis, and to date no general consensus regarding best practice has emerged. Several studies have reported on the routine use of intracameral cefuroxime, moxifloxacin, and vancomycin, including a single randomized clinical trial by the European Society of Cataract and Refractive Surgery (ESCRS) in 2007. These studies have notable shortcomings, but many authors suggest that intracameral cefuroxime together with topical antibiotics probably decreases the risk of endophthalmitis. However, the deleterious effects of routine prophylactic antibiotics, which include toxicity, cost, and increasing antimicrobial resistance, among others, are noteworthy. In contrast, aseptic technique with pre operative instillation of povidone-iodine remains the only technique supported by level I evidence to reduce the incidence of endophthalmitis. Although the routine use of intracameral antibiotics continues to increase throughout the world, data from multicenter, randomized, prospective trials is needed to provide better guidance regarding the prophylactic use of antibiotics. PMID- 29974361 TI - Alpha satellite DNA biology: finding function in the recesses of the genome. AB - Repetitive DNA, formerly referred to by the misnomer "junk DNA," comprises a majority of the human genome. One class of this DNA, alpha satellite, comprises up to 10% of the genome. Alpha satellite is enriched at all human centromere regions and is competent for de novo centromere assembly. Because of the highly repetitive nature of alpha satellite, it has been difficult to achieve genome assemblies at centromeres using traditional next-generation sequencing approaches, and thus, centromeres represent gaps in the current human genome assembly. Moreover, alpha satellite DNA is transcribed into repetitive noncoding RNA and contributes to a large portion of the transcriptome. Recent efforts to characterize these transcripts and their function have uncovered pivotal roles for satellite RNA in genome stability, including silencing "selfish" DNA elements and recruiting centromere and kinetochore proteins. This review will describe the genomic and epigenetic features of alpha satellite DNA, discuss recent findings of noncoding transcripts produced from distinct alpha satellite arrays, and address current progress in the functional understanding of this oft-neglected repetitive sequence. We will discuss unique challenges of studying human satellite DNAs and RNAs and point toward new technologies that will continue to advance our understanding of this largely untapped portion of the genome. PMID- 29974363 TI - Esmolol indirectly stimulates vagal nerve activity in endotoxemic pigs. AB - BACKGROUND: There is an increasing interest in beta-blockade as a therapeutic approach to sepsis following consistent experimental findings of attenuation of inflammation and improved survival with beta1 selective antagonist. However, the mechanism of these beneficial effects remains very uncertain. Thus, this study is aimed at investigating the effects of a beta-1 selective blockade on sympathetic/parasympathetic activity in endotoxin-challenged pigs using heart rate variability. The hypothesis is that an adrenergic blockade could promote parasympathetic activity. Indeed, the increase of parasympathetic activity is a mechanism recently described as beneficial in septic states. METHODS: Fifty-one endotoxin-challenged pigs were studied. After 30 min of endotoxin infusion and 30 min of evolution without intervention, the pigs were randomly assigned the placebo or esmolol treatment and were observed for 200 min. Overall heart rate variability was assessed continuously, in the temporal domain by standard deviation of RR intervals (SDNN, ms),and in the frequency domain by spectral powers of low frequency (LF, ms2 * 103/Hz) and high frequency (HF, ms2 * 103/Hz) bands. RESULTS: Variations of power in these frequency bands were interpreted as putative markers of sympathetic (LF) and parasympathetic (HF) activity. In LPS treated animals, Esmolol did not increase SDNN, but instead decreased LF and increased HF power. CONCLUSION: These spectral modifications associated to a beta blocker treatment after an endotoxemic challenge are interpreted as a significant decrease of sympathetic activity and an indirect increase of vagal autonomic tone. PMID- 29974364 TI - Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists. AB - Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 +/- 1.1 MUM) showed better activity compared to SIPI-7623 (IC50 = 40.8 +/- 1.7 MUM) and guggulsterone (IC50 = 45.9 +/- 1.1 MUM). Docking of A-11 in FXR's ligand-binding domain was also studied. PMID- 29974365 TI - Transient Marked Increase of gammadelta T Cells in WHIM Syndrome After Successful HSCT. PMID- 29974366 TI - Actinoplanes deserti sp. nov., isolated from a desert soil sample. AB - A novel actinomycete, designated strain YIM CF22T, was isolated from a desert soil sample collected from Turpan in Xinjiang Uyghur Autonomous Region, north western China. The taxonomic position of the strain YIM CF22T is described based on a polyphasic approach. Strain YIM CF22T was found to form irregular sporangia on agar media. It contains meso-diaminopimelic acid in the cell wall peptidoglycan. The major menaquinone was identified as MK-9(H4); the polar lipids were identified as diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, two unidentified phospholipids and two unidentified glycolipids. The whole cell sugars were found to be ribose, mannose, galactose, glucose and xylose. The major cellular fatty acids were found to be (> 5%) iso C16:0 (43.5%), anteiso-C17:0 (10.2%), iso-C15:0 (7.1%), C17:1 omega8c (6.3%) and iso H-C16:1 (5.9%). The G+C content was determined to be 70.8%. 16S rRNA gene sequence analysis of strain YIM CF22T showed high similarity (97.0%) to Actinoplanes rishiriensis NBRC 108556T. The strain also showed high 16S rRNA gene sequence similarities to Verrucosispora sediminis CGMCC 4.3550T (96.9%) and Micromonospora tulbaghiae DSM 45142T (96.8%). Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain YIM CF22T clusters with A. rishiriensis NBRC 108556T, Actinoplanes globisporus JCM 3186T and Actinoplanes rhizophilus NEAU-A-2T. Based on the differential phenotypic characteristics and the results of DNA-DNA relatedness and phylogenetic analysis, it is proposed that strain YIM CF22T represents a novel species of the genus Actinoplanes, for which the name Actinoplanes deserti sp. nov. is proposed. The type strain is YIM CF22T (= KCTC 39543T = CCTCC AB2018113T). PMID- 29974367 TI - Evidence for expression and functionality of FSH and LH/hCG receptors in human endometrium. AB - PURPOSE: Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) mediate intracellular functions by binding their specific protein G-coupled gonadotrophin receptor, respectively FSH receptor (FSHR) and LH/choriogonadotrophin receptor (LHCGR). Whereas the expression of FSHR and LHCGR in mammals was considered gonad specific and cell-specific, studies identified gonadotrophin receptors in human female extragonadal reproductive tissues. This study aims to demonstrate that gonadotrophin receptors are expressed in endometrium and mediates intracellular functions. METHODS: Collected endometria (n = 12) from healthy patients (mean age of 36 +/- 6) were primary cultured for 24 h. The presence of gonadotrophin receptors was evaluated by RT-PCR followed by the sequencing of the resulted amplicons and by immunohistochemistry in original samples. Endometrial primary cultures were treated with increasing concentration (range 0-100 ng/ml) of either recombinant human LH (rhLH) or recombinant human FSH (rhFSH). Endometria controls had gonadotrophin replaced by the same volume of the culture medium. In gonadotrophin-treated samples, it was evaluated the intracellular cyclic adenosine monophosphate (cAMP) content by enzymatic immunoassay and the expression of steroidogenic genes by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). RESULTS: The sequencing of the RT-PCR amplicons confirmed the presence of both gonadotrophin receptors and immunohistochemistry localized them on the membrane of endometrial glands cells throughout the glandular epithelium. The gonadotrophin-receptor complex was able to increase the intracellular cAMP in a dose-response and time-course manner and to induce steroidogenic genes expression. CONCLUSION: This study demonstrates that both gonadotrophin receptors are expressed along the glandular epithelium of endometria and they mediate the effects of gonadotrophins on intracellular functions. PMID- 29974368 TI - Local privileges not universal rights: geographic variations in the science and clinical practice of reproductive medicine. AB - Based on personal experience in the science and clinical practice of reproductive medicine in different settings, enormous variations are highlighted, demonstrating that freedom of research and clinical practice in reproductive medicine is a local privilege, not a universal right. PMID- 29974369 TI - Enhancement of the efficiency of oocyte vitrification through regulation of histone deacetylase 6 expression. AB - OBJECTIVE: Successful oocyte vitrification (OV) is critical for cryopreservation of the oocytes from female patients with infertility, polycystic ovaries, and gynecologic cancers. Recent evidence suggests that relatively low levels of histone acetylation are critical for maintenance of the maturation capacity of cryopreserved oocytes. However, previous studies have only demonstrated a key role of histone deacetylases (HDAC) 1 and 2 in the cryopreservation of oocytes. METHODS: In this study, we investigated the role of HDAC6 in these settings. We found that mouse oocytes with low HDAC6 levels decreased survival rate, cleavage rate, and blastocyst rate after OV. Bioinformatics analyses were used to predict HDAC6-targeting microRNAs (miRNAs), while the functional binding of miRNAs to HDAC6 mRNA was evaluated by a dual luciferase reporter assay. RESULTS: Among all HDAC6-targeting miRNAs, we detected expression of miR-558, miR-527, and miR-762 in mouse oocytes. Specifically, we found that only miR-762 significantly inhibited protein translation of HDAC6 via binding to the 3'-UTR of the HDAC6 mRNA. Transfection of oocytes with HDAC6 or antisense of miR-762 significantly increased the survival rate, the cleavage rate, and blastocyst rate after OV. CONCLUSION: As a result, our data suggest that induction of HDAC6 levels by miR 762 suppression may improve the current protocol for OV. PMID- 29974370 TI - Fertility preservation in women with cancer: a national study about French oncologists awareness, experience, and feelings. AB - PURPOSE: This study was designed to evaluate patient management and quality of information given by French oncologists to cancer women concerning fertility issues and possibilities of fertility preservation. METHODS: An online survey was sent to 1161 physicians in all major cancer centers throughout France between May 2012 and January 2013. RESULTS: A total of 102 responses were received and analyzed. Only 46% of all physicians surveyed reported discussing infertility risks with patients of reproductive age and 22% referred them to a fertility center before beginning treatments. Only 14% of practitioners considered themselves knowledgeable in FP techniques and ovarian transposition was the most frequently mentioned technique in consultation. CONCLUSION: This study is at the best of our knowledge the first nationwide survey to assess the state of the art in oncofertility management. It highlights inadequate management of fertility preservation for female patients in France. Physicians reported lacking knowledge and tools that would allow them to provide patients with appropriate information. A better collaboration between cancer and fertility centers needs to be organized in France as already organized in other countries. PMID- 29974371 TI - Synergy at work: two heads are better than one. PMID- 29974372 TI - Is 18F-FDG PET/CT useful for the differential diagnosis of solitary pulmonary nodules in patients with idiopathic pulmonary fibrosis? AB - OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is associated with an increased incidence of lung cancer, but patients with IPF often have poor pulmonary function and are vulnerable to pneumothorax and so using an invasive procedure to diagnose a single nodule detected on chest CT risks a critical adverse outcome. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is recognized to be useful for differentiating between benign and malignant solitary pulmonary nodules (SPN) in patients without IPF, but its diagnostic accuracy has not been investigated in patients with IPF. In this study, therefore, we investigated whether 18F-FDG PET/CT is useful for the differential diagnosis of SPNs in patients with IPF. METHODS: From the IPF patient cohort of our institution, we retrospectively reviewed 55 patients (54 men, 1 woman; age 67.8 +/- 7.6 years) with an SPN sized 8-30 mm (mean 18.5 +/- 5.7 mm) who underwent chest CT followed by 18F-FDG PET/CT between April 2004 and March 2016. The 18F-FDG uptake of the SPN was analyzed visually and semiquantitatively, and these determinations were compared with the final diagnosis obtained by pathology (n = 52) or imaging follow-up (n = 3). RESULTS: The final diagnoses showed that 41 (75%) of the SPNs were malignant (21 squamous cell carcinomas, 9 adenocarcinomas, 5 small-cell carcinomas, 4 mixed-type carcinomas, 1 large-cell neuroendocrine carcinoma, and 1 sarcoid carcinoma) and 14 (25%) were benign. The determination of malignant SPNs by visual analysis of the PET/CT images had a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 98, 86, 95, and 92%, respectively. The semiquantitative analysis using a maximum standardized uptake value of 2.0 as the cut-off had a sensitivity, specificity, PPV, and NPV of 95, 93, 98, and 87%, respectively. CONCLUSIONS: 18F-FDG PET/CT is useful for differentiating benign and malignant SPNs in patients with IPF, as it is for patients without IPF. PMID- 29974373 TI - Aqueous solution interactions with sex hormone-binding globulin and estradiol: a theoretical investigation. AB - Sex hormone-binding globulin (SHBG) is a binding protein that regulates the availability of steroid hormones in the plasma. Although best known as a steroid carrier, recent studies have associated SHBG in modulating behavioral aspects related to sexual receptivity. Among steroids, estradiol (17beta-estradiol, oestradiol or E2), documented as the most active endogenous female hormone, exerts important physiological roles in both reproductive and non-reproductive functions. In this framework, we employed molecular dynamics (MD) and docking techniques for quantifying the interaction energy between a complex aqueous solution, composed by different salts, SHBG and E2. As glucose concentration resembles measured levels in diabetes, special emphasis was devoted to analyzing the interaction energy between this carbohydrate, SHBG and E2 molecules. The calculations revealed remarkable interaction energy between glucose and SHBG surface. Surprisingly, a movement of solute components toward SHBG was observed, yielding clusters surrounding the protein. The high energy and short distance between glucose and SHBG suggests a possible scenario in favor of a detainment state between the sugar and the protein. In this context, we found that glucose clustering does not insert modification on binding site area nor over binding energy SHBG-E2 complex, in spite of protein superficial area increment. The calculations also point to a more pronounced interaction between E2 and glucose, considering the hormone immersed in the solution. In summary, our findings contribute to a better comprehension of both SHBG and E2 interplay with aqueous solution components. PMID- 29974375 TI - Increased Plasma Nitrite and von Willebrand Factor Indicates Early Diagnosis of Vascular Diseases in Chemotherapy Treated Cancer Patients. AB - Chemotherapy induced cardiotoxicity leads to development of hypertension, conduction abnormalities, and congestive heart failure. However, there is no simple test to detect and assess cardiovascular risk in a chemotherapy treated cancer patient. The aim of the present study on cancer patients treated with (n = 66) and without (n = 66) chemotherapy is to identify indicators from plasma for vascular injury. The levels of plasma nitrite, asymmetric dimethyl arginine (ADMA), von Willebrand factor (vWF), cardiac troponins, lipid peroxidation (MDA), and lactate dehydrogenase (LDH) were estimated. An R package, namely, Optimal Cutpoints, and a machine learning method-support vector machine (SVM) were applied for identifying the indicators for cardiovascular damage. We observed a significant increase in nitrite (p < 0.001) and vWF (p < 0.001) level in chemotherapy treated patients compared to untreated cancer patients and healthy controls. An increased MDA and LDH activity from plasma in chemotherapy treated cancer patients was found. The R package analysis and SVM model developed using three indicators, namely, nitrite, vWF, and MDA, can distinguish cancer patients before and after chemotherapy with an accuracy of 87.8% and AUC value of 0.915. Serum collected from chemotherapy treated patients attenuates angiogenesis in chick embryo angiogenesis (CEA) assay and inhibits migration of human endothelial cells. Our work suggests that measurement of nitrite along with traditional endothelial marker vWF could be used as a diagnostic strategy for identifying susceptible patients to develop cardiovascular dysfunctions. The results of the present study offer clues for early diagnosis of subclinical vascular toxicity with minimally invasive procedure. Schematic representation of chemotherapy induced elevated plasma nitrite level in cancer patients. PMID- 29974374 TI - p38 Inhibition Ameliorates Inspiratory Resistive Breathing-Induced Pulmonary Inflammation. AB - Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with strenuous contractions of the inspiratory muscles and increased negative intrathoracic pressures that act as an injurious stimulus to the lung. We have shown that IRB induces pulmonary inflammation in healthy animals. p38 kinase is activated in the lung under stress. We hypothesized that p38 is activated during IRB and contributes to IRB-induced pulmonary inflammation. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve. Resistance was connected to the inspiratory port to provoke a peak tidal inspiratory pressure 50% of maximum. Following 3 and 6 h of IRB, respiratory system mechanics were measured and bronchoalveolar lavage (BAL) was performed. Phosphorylated p38, TNF-alpha, and MIP-2alpha were detected in lung tissue. Lung injury was estimated histologically. SB203580 (p38 inhibitor) was administered prior to IRB (1 mg kg-1). Six hours of IRB increased phosphorylated p38 in the lung, compared with quietly breathing controls (p = 0.001). Six hours of IRB increased the numbers of macrophages and neutrophils (p = 0.01 and p = 0.005) in BAL fluid. BAL protein levels and lung elasticity increased after both 3 and 6 h IRB. TNF-alpha and MIP-2alpha increased after 6 h of IRB (p = 0.01 and p < 0.001, respectively). Increased lung injury score was detected at 6 h IRB. SB203580 administration blocked the increase of neutrophils and macrophages at 6 h IRB (p = 0.01 and p = 0.005 to 6 h IRB) but not the increase in BAL protein and elasticity. TNF-alpha, MIP-2alpha, and injury score at 6 h IRB returned to control. p38 activation contributes to IRB-induced pulmonary inflammation. PMID- 29974376 TI - Screening Colonoscopy Withdrawal Time Threshold for Adequate Proximal Serrated Polyp Detection Rate. AB - INTRODUCTION: For adequate adenoma detection rate (ADR), guidelines recommend a mean withdrawal time (MWT) of >= 6 min. ADR has been shown to correlate strongly with proximal serrated polyp detection rate (PSP-DR), which is another suggested quality measure for screening colonoscopy. However, the impact of directly measured withdrawal time on PSP-DR has not been rigorously studied. We examined the relationship between MWT to ADR and PSP-DR, with the aim of identifying a functional threshold withdrawal time associated with both increased ADR and PSP DR. METHODS: This was a retrospective study of endoscopy and pathology data from average-risk screening colonoscopy examinations performed at a large system with six endoscopy laboratories. A natural language processing tool was used to determine polyp location and histology. ADR and PSP-DR were calculated for each endoscopist. MWT was calculated from colonoscopy examinations in which no polyps were resected. RESULTS: In total, 31,558 colonoscopy examinations were performed, of which 10,196 were average-risk screening colonoscopy examinations with cecal intubation and adequate prep by 24 gastroenterologists. When assessing the statistical significance of increasing MWT by minute, the first significant time mark for PSP-DR was at 11 min at a rate of 14.2% (p = 0.01). There was a significant difference comparing aggregated MWT < 11 min compared to >= 11 min looking at the rates of adenomas [OR 1.65 (1.09-2.51)] and proximal serrated polyps [OR 1.81 (1.06-3.08)]. While ADR linearly correlated well with MWT (R = 0.76, p < 0.001), the linear relationship with PSP-DR was less robust (R = 0.42, p = 0.043). CONCLUSION: In this large cohort of average-risk screening colonoscopy, a MWT of 11 min resulted in a statistically significant increase in both ADR and PSP-DR. Our data suggest that a longer withdrawal time may be required to meet both quality metrics. PMID- 29974378 TI - Resolvin D1 Resolve Inflammation in Experimental Acute Pancreatitis by Restoring Autophagic Flux. AB - BACKGROUND: Acute pancreatitis (AP) is a common acute gastrointestinal disorders. Increasing evidence indicated that autophagy is involved in the development of AP. Resolvin D1 is an endogenous pro-resolving lipid mediator, which can protect mice from cerulein-induced acute pancreatitis and facilitate autophagy in macrophage, but its mechanism remians unclear. AIMS: To investigate the effect of resolvin D1 on autophagy in mouse models of cerulein-induced AP. METHODS: C57BL/6 mice were randomly divided into control group, AP group and resolvin D1 group. The models of cerulein-induced AP were constructed by intraperitoneally cerulein. Resolvin D1 group was established by intraperitoneally resolvin D1 based on AP models, simultaneously, control group received normal saline. The severity of AP, the level of inflammatory cytokines, the number of autophagic vacuoles, and the expression of autophagy-related markers were evaluated among three groups. RESULTS: The AP models were established successfully. Compared to control group, the number of autophagic vacuoles and expressions of autophagy-related markers including Beclin-1, p62 and LC3-II were increased in AP models, In contrast, the degree of inflammation and levels of inflammatory cytokines in AP models were reduced after resolvin D1 treatment. Moreover, resolvin D1 attenuated the number of autophagic vacuoles and expressions of autophagy-related markers. CONCLUSIONS: Autophagic flux is impaired in cerulein-induced AP. Resolvin D1 ameliorate the severity of mice with cerulein-induced acute pancreatitis, possible attributing to its reducing impaired autophagy and restoring autophagic flux. PMID- 29974377 TI - Effect of Homocysteine on the Differentiation of CD4+ T Cells into Th17 Cells. AB - BACKGROUND: The hyperhomocysteinaemia (Hhcy) is a common phenomenon observed in patients with inflammatory bowel disease (IBD). Our previous study showed that Hhcy aggravated intestinal inflammation in an animal model of colitis. Increased levels of IL-17 and RORgammat were also observed in this animal model of colitis with Hhcy. However, the direct effect of homocysteine on the differentiation of Th17 cells has never been studied. The aim of this study was to investigate the direct effect of Hhcy on the differentiation of CD4+ T cells into Th17 cells. METHOD: Lamina propria lymphocytes (LPLs) in colonic mucosa of Wistar rats were isolated and cultured under Th17-inducing (iTH17) environments. Different concentrations of the Hcy (0-100 MUmol/ml) were added alone or combined with IL 23 (100 ng/ml) or folate (5 MUmol/ml). The LPLs were divided into eight groups as follows: (1) Control group; (2) 10 MUmol/ml Hcy group; (3) 25 MUmol/ml Hcy group; (4) 50 MUmol/ml Hcy group; (5) 100 MUmol/ml Hcy group; (6) 100 ng/ml IL-23 group; (7) 50 MUmol/ml Hcy + 100 ng/ml IL-23 group and (8) 50 MUmol/ml Hcy + 100 ng/ml IL-23 + 5 MUmol/ml folate group. The protein expression levels of IL-17, retinoid related orphan nuclear receptor-gammat (RORgammat), p38 MAPK, phosphorylated p38 MAPK, cytosolic phospholipase A2 (cPLA2), phosphorylated-cPLA2 and cyclooxygenase 2 (COX2) were detected by immunoblot analysis. The protein level of prostaglandin E2 (PGE2) and IL-17 was detected by ELISA, and IL-17 and RORgammat-positive CD4+ T cells were stained and analyzed by flow cytometry. RESULTS: Hcy increased the protein levels of IL-17, RORgammat, the ratio of phosphorylated p38 MAPK to p38 MAPK (p-p38/p38), the ratio of phosphorylated cPLA2 to cPLA2 (p-cPLA2/cPLA2) and COX2. The effect was concentration dependent to a certain degree; Hcy of 50 MUmol/ml was the optimal concentration to increase the protein levels of those molecules. The level of IL-17 and PGE2 in the cell culture supernatants and the expression of IL-17 and RORgammat in positive CD4+ T cells were also increased in the group of Hhcy. IL-23 showed a cooperative effect with Hcy on the differentiation of CD4+ Th cells into Th17 cells, whereas folate supplementation showed an inhibition action. CONCLUSIONS: Homocysteine promoted the differentiation of CD4+ T cells into Th17 cells in a dose-dependant manner. This effect could be inhibited by folate. PMID- 29974379 TI - Factors Affecting Production of Itaconic Acid from Mixed Sugars by Aspergillus terreus. AB - Itaconic acid (IA; a building block platform chemical) is currently produced industrially from glucose by fermentation with Aspergillus terreus. In order to expand the use of IA, its production cost must be lowered. Lignocellulosic biomass has the potential to serve as low-cost source of sugars for IA production. It was found that the fungus cannot produce IA from dilute acid pretreated and enzymatically saccharified wheat straw hydrolysate even at 100 fold dilution. The effects of typical compounds (acetic acid, furfural, HMF and Mn2+, enzymes, CaSO4), culture conditions (initial pH, temperature, aeration), and medium components (KH2PO4, NH4NO3, CaCl2.2H2O, FeCl3.6H2O) on growth and IA production by A. terreus NRRL 1972 using mixed sugar substrate containing glucose, xylose, and arabinose (4:3:1, 80 g L-1) mimicking the wheat straw hydrolysate were investigated. Acetic acid, furfural, Mn2+, and enzymes were strong inhibitors to both growth and IA production from mixed sugars. Optimum culture conditions (pH 3.1, 33 degrees C, 200 rpm) and medium components (0.8 g KH2PO4, 3 g NH4NO3, 2.0 g CaCl2.2H2O, 0.83-3.33 mg FeCl3.6H2O per L) as well as tolerable levels of inhibitors (0.4 g acetic acid, < 0.1 g furfural, 100 mg HMF, < 5.0 ppb Mn2+, 24 mg CaSO4 per L) for mixed sugar utilization were established. The results will be highly useful for developing a bioprocess technology for IA production from lignocellulosic feedstocks. PMID- 29974380 TI - Association Between the Serum Uric Acid Levels and Lacunar Infarcts in the Elderly. AB - Increasing evidence suggests that uric acid (UA) is a relevant risk factor for arteriolosclerosis and recent studies have demonstrated the positive relationship between UA concentrations and the severity of leukoaraiosis. However, the association between lacunar infarcts (LI) and UA levels has seldom been reported in the literature. The aim of our study was to assess whether serum UA levels may be related to the presence of LI. We recruited 242 patients (113 males and 129 females, aged 82.83 +/- 6.49 years) from our Geriatric Department for whom CAT scans (CT) were available. Clinical and laboratory data was collected. Patients CT images were examined to identify the presence, the size, the number, and the location of LI. LI without neurological symptoms were considered silent LI. Serum UA levels were found to be positively associated with the presence (p = 0.0001), the number (p = 0.001), the size (p = 0.001), and the location of LI in the basal ganglia (p = 0.0038), the deep white matter (DWM) (p < 0.0001), and the pons (p = 0.0156). A significant association was also found between UA and silent LI (p = 0.0002). The prevalence of LI increased starting from UA levels of 5.7 mg/dl. Stepwise multiple regression analysis confirmed that UA was independently related with the presence, the number, the size, LI in the basal ganglia, the DWM, the pons, and with silent LI. Our study suggests a positive association between UA levels and LI, which is independent of traditional cardiovascular risk factors. This data suggests that UA plays an influential role on the physiopathology of LI and could represent a potential target to prevent cerebral microinfarcts. PMID- 29974381 TI - Levo-tetrahydropalmatine Attenuates Neuron Apoptosis Induced by Cerebral Ischemia Reperfusion Injury: Involvement of c-Abl Activation. AB - Ischemic stroke is one of the most dangerous acute diseases which causes death or deformity. Apoptosis has been shown to play an important role in the development and pathogenesis of cerebral ischemia-reperfusion injury (I/R injury), but the related mechanism is unclear. Levo-tetrahydropalmatine (L-THP), a bioactive ingredient extracted from the Chinese herb Corydalis, can penetrate the blood brain barrier and exert various pharmacological effects on neural tissues. The present study examined the neuroprotective effect of L-THP on neuronal apoptosis induced by cerebral I/R injury. Results showed that pretreatment with L-THP (12.5, 25, and 50 mg/kg) improved neurological outcomes and reduced infarct volume and cerebral edema in comparison with the brains of the middle cerebral artery occlusion (MCAO) group. These findings provided evidence for the neuroprotective effects of L-THP against cerebral I/R injury. Furthermore, administration of L-THP enhanced the expression of Bcl-2 and attenuated the content of Bax, cleaved caspase-3, and PARP. L-THP could improve the reduction of NeuN-positive cells induced by I/R injury. These results suggested that L-THP could inhibit neuroapoptosis in cerebral ischemic rats. c-Abl was discovered as the critical protein responsible for neurocyte apoptosis; however, few data have been published on the relation between ischemic stroke and the expression of c Abl. We found that both c-Abl expression and neuronal apoptosis were significantly increased in the MCAO group, while pretreatment with L-THP could ameliorate this effect. Therefore, we deduced that reduced c-Abl overexpression may play a role in the anti-apoptosis effect of L-THP after cerebral I/R injury. Thus, L-THP may provide a potential therapeutic approach for the treatment of ischemic stroke. Graphical Abstract ?. PMID- 29974382 TI - Mapping between HAQ-DI and EQ-5D-5L in a Chinese patient population. AB - OBJECTIVES: In order to address the current deficiency of health utility evidence relevant for economic evaluations involving treatments for rheumatoid arthritis (RA) in the Chinese setting, this study aims to develop a mapping algorithm linking the Health Assessment Questionnaire (HAQ) and EQ-5D-5L in a Chinese population of patients with RA. METHODS: An estimation sample was obtained from a cross-sectional study that collected HAQ, the pain Visual Analogue Scale, and EQ 5D-5L in RA patients in two tertiary referral hospitals in China. Mapping algorithms were derived in this study using two alternative regression methods: the beta regression and a multivariate ordered probit regression. The internal validity of the mapping algorithms was assessed in each case by calculating predictive performance using a bootstrapping procedure. RESULTS: Of the several algorithms developed using these data, predictive performance was shown to be better when VAS pain was included as a predictor and when the multivariate ordered probit regression method was used, rather than the beta regression method. The algorithms developed were shown to be comparable, in terms of predictive performance, to existing mapping studies despite the small sample size of the estimation data. CONCLUSION: It is hoped that the availability of these algorithms will facilitate the development of cost-effectiveness studies evaluating RA treatments in the Chinese health care setting. PMID- 29974383 TI - Correction to: Introducing Students of Color to Health Sciences Research: An Evaluation of the Health Disparities Summer Internship Program. AB - The original version of this article unfortunately contained a mistake. PMID- 29974384 TI - Copper-Mediated Mitochondrial Fission/Fusion Is Associated with Intrinsic Apoptosis and Autophagy in the Testis Tissues of Chicken. AB - The aim of this study is to investigate whether copper (Cu) could induce testicular poisoning and influence the mitochondrial dynamics, apoptosis, and autophagy in chickens. For this purpose, thirty-six 1-day-old male Hy-line chickens were divided into control group (C group) and test group (Cu group). The chickens were exposed to 0 (C group) or 300 mg/kg (Cu group) of copper sulfate (CuSO4) for 30, 60, and 90 days. CuSO4 was added into the basal diet to make supplements. Testis tissues were subjected to observation of ultrastructure and detection of testis-related indexes. The results indicated that in the test group, the levels of the pro-apoptotic genes were up-regulated and the levels of the anti-apoptotic genes were down-regulated; the levels of mitochondrial fission related genes markedly increased, and the levels of mitochondrial fusion-related genes were highly decreased; autophagy-related gene (autophagy-associated gene 4B (ATG4B), dynein, microtubule-associated protein 1 light chain 3 beta (LC3-II), ATG5, and beclin-1) levels were increased, while mammalian target of rapamycin (mTOR) and LC3-I levels were declined. The results of transmission electron microscopy (TEM) demonstrated that Cu induced mitochondrial fragmentation, which induced autophagy and apoptosis in chicken testes. In conclusion, CuSO4 exposure can influence the mitochondrial dynamics balance and lead to mitochondria initiated intrinsic pathway of apoptosis and autophagy, which triggers the testicular poisoning in chickens. What is more, there is a correlation among mitochondrial dynamics, apoptosis, and autophagy. PMID- 29974385 TI - Health Effects of Trace Metals in Electronic Cigarette Aerosols-a Systematic Review. AB - Electronic cigarettes (ECs) are essentially nicotine delivery devices that mimic the appearance of a conventional cigarette (CC). Lately, they have been marketed as tools for quitting smoking. Even though they are promoted as safe alternatives to CC, they are not devoid of hazardous components. Literature reveals that the EC aerosols and e-liquids are a potential source of elements that induce and promote development of chronic conditions. These include trace metals which are leached from their core assembly. Some of these metals like nickel, chromium, cadmium, tin, aluminum, and lead are potential carcinogens. They have been associated with fatal conditions like lung and sinonasal cancer. Besides, they may have adverse effects on oral tissues like periodontal ligament and mucosa where they may trigger chronic periodontitis and oral cancer. However, there is only trivial evidence related to health hazards of metals released from ECs. With this background, the present review first focuses on the structure of the ECs followed by an appraisal of the data from experimental studies about the metals released in EC aerosols and their associated health hazards. PMID- 29974386 TI - Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study. AB - INTRODUCTION: Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa). OBJECTIVE: To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa. PATIENTS AND METHODS: Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway. RESULTS: The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0-7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8-5.4]. Among tGA+ patients who did not receive tNGS based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6-6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy). CONCLUSION: In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population. PMID- 29974387 TI - Malarial fevers in the fourteenth century Divine Comedy. PMID- 29974389 TI - Evaluation of respiratory functions and quality of life in multiple sclerosis patients. AB - The aim of this study was to evaluate respiratory muscle strength, respiratory functions and quality of life in multiple sclerosis (MS) patients and compare the results with the healthy volunteers. The study included a group of 24 patients diagnosed with MS (16 women, 8 men) with an EDSS score of <= 5, who were without clinical respiratory impairment. MS patients were compared with the healthy volunteer group (16 women, 8 men). Respiratory muscle strength and respiratory functions were evaluated with specific devices. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) parameters were measured for the muscle strength. Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC, peak expiratory flow, and forced expiratory flow (FEF25-75) parameters were measured for the respiratory functions. Questionnaire SF-36 was applied to evaluate health-related quality of life. A total of 24 MS patients' respiratory function test results were compared with healthy volunteers and significant changes were found at MIP, MEP, and FEV1 parameters. Quality of life was compared between the groups and there was a significant difference in parameters related with physical performance and physical-health-related role limitations. There is an early involvement of the respiratory muscles in patients with MS, yet clinical symptoms appear in later stages. Respiratory functions should be evaluated at the earlier stage of the disease so that rehabilitation can be planned in order to reduce respiratory complications and improve the quality of life in patients. PMID- 29974390 TI - Reduced gait and postural stability under challenging conditions in fallers with upper limb fracture. AB - BACKGROUND: While most fractures are caused by falls, not all falls result in fractures. Risk factors for falls are well established, but only weak associations have been demonstrated for risk factors for fractures. Conflicting results on the implication of bone mineral density (BMD) suggest that other risk factors should be studied, such as gait and balance disorders. AIMS: Gait and postural stability in challenging conditions were, therefore, compared between fallers with and without fracture. METHODS: We enrolled 80 adults aged 55 and older who fell in the previous year. We compared gait and posture after obstacle crossing between fallers with an upper-limb fracture (n = 38), and fallers without fracture (n = 42). Data on BMD, body mass index, handgrip strength, fear of falling, number of comorbidities, number of falls, global cognition, executive functioning and education level were collected. RESULTS: Compared to fallers without fracture, fallers with fracture had significant lower gait velocity (Likelihood-Ratio = 4.93; P = 0.03) and lower postural stability during stabilization after obstacle crossing (Likelihood-Ratio = 10.99; P < 0.001). In addition, fallers with fracture had lower handgrip strength (Likelihood-Ratio = 9.92; P = 0.002), lower education level (Likelihood-Ratio = 8.32; P = 0.004), poorer executive functions (Likelihood-Ratio = 5.81; P = 0.02, higher fear of falling (Likelihood-Ratio = 5.55; P = 0.02) and were more likely women (Likelihood-Ratio = 17.55; P < 0.001), compared to fallers without fracture. DISCUSSION: This study demonstrated that the main difference between fallers with upper-limb fracture and fallers without fracture is mobility in dynamic condition. Poor executive function and low muscular strength could also be involved. CONCLUSIONS: These factors should be taken into account when assessing risk factors for fracture and implementing preventive programs. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov. NCT02292316. PMID- 29974388 TI - Diabetes was the only comorbid condition associated with mortality of invasive pneumococcal infection in ICU patients: a multicenter observational study from the Outcomerea research group. AB - PURPOSES: Streptococcus pneumoniae is a leading pathogen of severe community, hospital or nursing facility infections. We sought to describe characteristics of invasive pneumococcal infection (IPI) and pneumonia (due to the high mortality of intensive care-associated pneumonia) and to report outcomes according to various types of comorbidity. METHODS: Multicenter observational cohort study on the prospective Outcomerea database, including adult patients, with a hospital stay < 48 h before ICU admission and a documented IPI within the first 72 h of ICU admission. Comorbid conditions were defined according to the Knaus and Charlson classification. RESULTS: Of the 20,235 patients, 5310 (26.4%) had an invasive infection, including 560/5,310 (10.6%) who had an IPI. The ICU 28-day mortality was 109/560 (19.8%). Four factors were independently associated with mortality: SOFA day 1-2: [hazard ratio (HR) 1.21; 95% confidence interval (95% CI) 1.15 1.27, p < 0.001]; maximum lactate level day 1-2: (HR 1.07, 95% CI 1.02-1.12, p = 0.006); diabetes mellitus: (HR 1.91, 95% CI 1.23-3.03, p = 0.006) and appropriate antibiotics (HR 0.28, 95% CI 0.15-0.50, p < 0.001). Comparable results were obtained when other comorbid conditions were forced into the model. Diabetes impact was more pronounced in case of micro- or macro-angiopathy (HR 4.17, 95%CI 1.68-10.54, p = 0.003), in patients >= 65 years old (HR 2.59, 95% CI 1.56-4.28, < 0.001) and in those with body mass index (BMI) < 25 kg/m2 (HR 2.11, 95% CI 1.10 4.06, p = 0.025). CONCLUSIONS: Diabetes mellitus was the only comorbid condition which independently influenced mortality in patients with IPI. Its impact was more pronounced in patients with complications, aged >= 65 years and with BMI < 25 kg/m2. PMID- 29974391 TI - Feasibility of simplifying renal dosimetry in 177Lu peptide receptor radionuclide therapy. AB - BACKGROUND: Recently, 177Lu-dotatate therapy for neuroendocrine tumours has received regulatory approval. Dosimetry can be used to optimize treatment on an individual basis, but there is no international consensus as to how it should be done. The aim of this study is to determine a feasible and accurate dosimetry method to guide individualized peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumours. As part of a clinical trial on 177Lu dotatate therapy, renal dosimetry was performed for all patients in each treatment cycle, using a hybrid planar-SPECT/CT method. In the present study, we use the image data acquired from 22 patients and 119 cycles and define a set of alternative treatment planning strategies, each representing a simplification in terms of image acquisition and dosimetric calculations. The results from the simplified strategies are compared to the results from the protocol-prescribed hybrid planar-SPECT/CT-based method by analysing differences both in per-cycle and total cumulative absorbed dose (AD) analyses. RESULTS: In general, the SPECT based methods gave results that were largely consistent with the protocol specified hybrid method, both in the per-cycle and cumulative AD analyses. Notably, performing one SPECT/CT per cycle at 96 h yielded ADs that were very similar to the protocol method. The methods using planar dosimetry resulted in larger variations, as expected, while giving 4 cycles to all patients resulted in the largest inter-individual differences in cumulative AD. CONCLUSIONS: Performing one SPECT/CT at 96 h in every treatment cycle gives sufficiently reliable dosimetric results to base individualized treatment planning on, with a reasonable demand on resources. PMID- 29974393 TI - Tibial pilon fractures treated with hybrid external fixator: analysis of 75 cases. AB - INTRODUCTION: The treatment of tibial pilon fractures is a surgical challenge due to the particular anatomical and vascular characteristics of this area, and the severity of the injury that can compromise soft tissues. Nowadays there is no gold-standard treatment for these fractures. MATERIALS AND METHODS: We reviewed 75 patients with tibial pilon fracture type C (AO classification) treated with hybrid external fixation (Stryker TenXor(r)). The surgical technique was reported. We evaluated clinical (Tornetta's score, VAS score, range of motion) and radiographic outcomes. RESULTS: In 71 cases, the first surgical treatment was definitive. Instead, in four cases, it was necessary a second surgical procedure to achieve fracture healing. We obtained 44% excellent, 40% good, 7% discrete, and 9% bad results. We found a 30% of superficial infections of the pin site, resolved with oral antibiotic treatment (amoxicillin and clavulanic acid). We never had deep infections, no neurovascular injury, and no cases of secondary amputation. Although not statistically significant, we noticed a correlation between longer recovery times and trauma severity, with slower recovery in open or grade III fractures or when associated with other fractures. CONCLUSIONS: According to the recent literature, we think that the best treatment for non articular fracture is the internal osteosynthesis within 6 h or after 6 days from trauma. In articular fractures, the elective treatment is the two-step management. In complicated articular fractures (Tscherne > 2, open, comminuted type III) is highly indicated the external fixation combined with minimal internal synthesis. PMID- 29974392 TI - Expression of P2X1 receptors in somatostatin-containing cells in mouse gastrointestinal tract and pancreatic islets of both mouse and human. AB - With immunohistochemical and Western blot techniques, P2X1 receptors were detected in the whole mouse gastrointestinal tract and pancreatic islets of mouse and human. (1) delta Cells containing somatostatin (SOM) in the stomach corpus, small intestines, distal colon, pancreatic islets of both mouse and human express P2X1 receptors; (2) strong immunofluorescence of P2X1 receptors was detected in smooth muscle fibers and capillary networks of the villus core of mouse intestine; and (3) P2X1 receptor-immunoreactive neurons were also detected widely in both mouse myenteric and submucosal plexuses, all of which express SOM. The present data implies that ATP via P2X1 receptors is involved in SOM release from pancreatic delta cells, enteric neurons, and capillary networks in villi. PMID- 29974394 TI - Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models. AB - End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFalpha, TGFbeta1, VCAM 1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM. PMID- 29974395 TI - Erratum to: Epidemiology of Dementia: The Burden on Society, the Challenges for Research. AB - The name of the Chapter 1 author had been inadvertently mentioned as M. Arfan Ikram. PMID- 29974396 TI - Escherichia coli AlkB interacts with single-stranded DNA binding protein SSB by an intrinsically disordered region of SSB. AB - Intrinsically disordered regions (IDRs) of proteins often regulate function through interactions with folded domains. Escherichia coli single-stranded DNA binding protein SSB binds and stabilizes single-stranded DNA (ssDNA). The N terminal of SSB contains characteristic OB (oligonucleotide/oligosaccharide binding) fold which binds ssDNA tightly but non-specifically. SSB also forms complexes with a large number proteins via the C-terminal interaction domain consisting mostly of acidic amino acid residues. The amino acid residues located between the OB-fold and C-terminal acidic domain are known to constitute an IDR and no functional significance has been attributed to this region. Although SSB is known to bind many DNA repair protein, it is not known whether it binds to DNA dealkylation repair protein AlkB. Here, we characterize AlkB SSB interaction and demonstrate that SSB binds to AlkB via the IDR. We have established that AlkB-SSB interaction by in vitro pull-down and yeast two-hybrid analysis. We mapped the site of contact to be the residues 152-169 of SSB. Unlike most of the SSB-binding proteins which utilize C-terminal acidic domain for interaction, IDR of SSB is necessary and sufficient for AlkB interaction. PMID- 29974397 TI - The association between cardiovascular disease gene mutations and recurrent pregnancy loss in the Lebanese population. AB - Recurrent pregnancy loss (RPL) is a problem affecting up to 5% of women of childbearing age due to many factors. Studies have shown that RPL and cardiovascular disease (CVD) may have shared risk factors. We compared the prevalence of 12 cardiovascular disease related gene mutations in patients with a history of RPL to normal controls in a major tertiary care center in Lebanon. The CVD StripAssay (ViennaLab, Austria) was used to analyze the CVD genes on 70 women with RPL history as part of the initial routine workup for recurrent miscarriage at the American University of Beirut Medical Center. The obtained results were compared with data of controls from the Lebanese population using Fisher's exact test and Chi square analysis. Two genes of the CVD panel demonstrated a strong relationship with RPL, including, MTHFR (C677T homozygosity, A1298C homozygosity, and compound heterozygosity for C677T and A1298C) and Factor II (heterozygosity for G20210A). Moreover, a protective role of positive APO-E3 isoform was observed. This study is the first in the Lebanese population in associating RPL with a large panel of CVD related genes. PMID- 29974399 TI - Pelagic larval dispersal habits influence the population genetic structure of clam Gomphina aequilatera in China. AB - Pelagic larval dispersal habits influence the population genetic structure of marine mollusk organisms via gene flow. The genetic information of the clam Gomphina aequilatera (short larval stage, 10 days) which is ecologically and economically important in the China coast is unknown. To determine the influence of planktonic larval duration on the genetic structure of G. aequilatera. Mitochondrial markers, cytochrome oxidase subunit i (COI) and 12S ribosomal RNA (12S rRNA), were used to investigate the population structure of wild G. aequilatera specimens from four China Sea coastal locations (Zhoushan, Nanji Island, Zhangpu and Beihai). Partial COI (685 bp) and 12S rRNA (350 bp) sequences were determined. High level and significant FST values were obtained among the different localities, based on either COI (FST = 0.100-0.444, P < 0.05) or 12S rRNA (FST = 0.193-0.742, P < 0.05), indicating a high degree of genetic differentiation among the populations. The pairwise Nm between Beihai and Zhoushan for COI was 0.626 and the other four pairwise Nm values were > 1, indicating extensive gene flow among them. The 12S rRNA showed the same pattern. AMOVA test results for COI and 12S rRNA indicated major genetic variation within the populations: 77.96% within and 22.04% among the populations for COI, 55.73% within and 44.27% among the populations for 12S rRNA. A median-joining network suggested obvious genetic differentiation between the Zhoushan and Beihai populations. This study revealed the extant population genetic structure of G. aequilatera and showed a strong population structure in a species with a short planktonic larval stage. PMID- 29974398 TI - Ciprofloxacin: from infection therapy to molecular imaging. AB - Diagnosis of deep-seated bacterial infection remains a serious medical challenge. The situation is becoming more severe with the increasing prevalence of bacteria that are resistant to multiple antibiotic classes. Early efforts to develop imaging agents for infection, such as technetium-99m (99mTc) labeled leukocytes, were encouraging, but they failed to differentiate between bacterial infection and sterile inflammation. Other diagnostic techniques, such as ultrasonography, magnetic resonance imaging, and computed tomography, also fail to distinguish between bacterial infection and sterile inflammation. In an attempt to bypass these problems, the potent, broad-spectrum antibiotic ciprofloxacin was labeled with 99mTc to image bacterial infection. Initial results were encouraging, but excitement declined when controversial results were reported. Subsequent radiolabeling of ciprofloxacin with 99mTc using tricarbonyl and nitrido core, fluorine and rhenium couldn't produce robust infection imaging agent and remained in discussion. The issue of developing a robust probe can be approached by reviewing the broad-spectrum activity of ciprofloxacin, labeling strategies, potential for imaging infection, and structure-activity (specificity) relationships. In this review we discuss ways to accelerate efforts to improve the specificity of ciprofloxacin-based imaging. PMID- 29974400 TI - Are We Going Nuts on Coconut Oil? AB - PURPOSE OF REVIEW: Sales and consumption of coconut oil have been on the raise due to effective marketing strategies. Coconut oil is stated to offer various benefits including weight loss, improvement in immunity, heart health support, and memory enhancement. Also, it is often portrayed as an excellent source of medium chain triglycerides (MCTs). Here, we review the evidence behind the clinical utility of coconut oil consumption. RECENT FINDINGS: Several studies consistently showed consumption of coconut oil increases low-density lipoprotein cholesterol (LDL-C) and thereby could increase adverse cardiovascular health. Even though coconut oil has relatively high MCT concentration, the clinical benefits of commercial MCT oils cannot be generalized to coconut oil. Until the long-term effects of coconut oil on cardiovascular health are clearly established, coconut oil should be considered as a saturated fat and its consumption should not exceed the USDA's daily recommendation (less than 10% of total calorie intake). PMID- 29974402 TI - Usefulness of fragile X checklist and CGG distribution in specialized institutions in Kinshasa, DR Congo. AB - Screening for fragile X syndrome (FXS) is essential in children with developmental delay or intellectual disability (ID). In addition, using clinical screening checklists remains of high interest in resource-limited settings. We aimed to gain insight into the prevalence of FXS and the distribution of CGG alleles and to evaluate the usefulness of three checklists in specialized institutions in Kinshasa, DR Congo. We recruited 80 males and 25 females from six specialized institutions in Kinshasa and administered a questionnaire comprising items from the following FXS checklists: Hagerman, Maes, and Guruju. FMR1 CGG repeats were assessed for every patient. About 37% of patients were referable for FX testing based on Hagerman's checklist, 35% for Maes', and 43.80% for Guruju's, but none of them was molecularly confirmed to have FXS. Thus, specificities were 62.86, 64.76, and 56.5%, respectively, for Hagerman, Maes, and Guruju, respectively. The mean CGG allele size was 28.55 +/- 2.83 (ranges, 17-48). The 29 CGG was the most frequent allele (24.61%). Thus, existing checklists should not be automatically applied to Congolese patients without adjustments. The distribution of CGG repeats and the number of CGG alleles are similar to other African studies. PMID- 29974401 TI - Selenium exposure and the risk of type 2 diabetes: a systematic review and meta analysis. AB - In 2007, supplementation with the trace element selenium in a trial was unexpectedly found to be associated with an excess risk of type 2 diabetes. Given the concerns raised by these findings and the large number of recent studies on this topic, we reviewed the available literature with respect to this possible association. In this paper, we assessed the results of both experimental and nonexperimental epidemiologic studies linking selenium with type 2 diabetes incidence. Through a systematic literature search, we retrieved 50 potentially eligible nonexperimental studies and 5 randomized controlled trials published through June 11, 2018. To elucidate the possible dose-response relation, we selected for further analysis those studies that included multiple exposure levels and serum or plasma levels. We computed a pooled summary risk ratio (RR) of diabetes according to selenium exposure in these studies. We also computed a RR for diabetes incidence following supplementation with 200 ug/day of selenium compared with placebo in trials. In the nonexperimental studies, we found a direct relation between selenium exposure and risk of diabetes, with a clear and roughly linear trend in subjects with higher plasma or serum selenium levels, with RR at 140 ug/L of selenium exposure compared with a referent category of < 45 ug/L equal to 3.6 [95% confidence interval (CI) 1.4-9.4]. A dose-response meta analysis focusing on studies with direct assessment of dietary selenium intake showed a similar trend. In experimental studies, selenium supplementation increased the risk of diabetes by 11% (RR 1.11, 95% CI 1.01-1.22) compared with the placebo-allocated participants, with a higher RR in women than in men. Overall, results from both nonexperimental and experimental studies indicate that selenium may increase the risk of type 2 diabetes across a wide range of exposure levels. The relative increase in risk is small but of possible public health importance because of the high incidence of diabetes and the ubiquity of selenium exposure. PMID- 29974403 TI - Special Considerations in the Management of Diabetic Ankle Fractures. AB - PURPOSE OF REVIEW: Ankle fractures and diabetes mellitus are both increasing in prevalence. Patients with both diabetes and an ankle fracture have been shown to have an increased rate of complications which can be catastrophic. The purposes of this review are to identify factors placing patients at an increased risk and offer guidance on the management of these injuries, in order to reduce potential complications. RECENT FINDINGS: Non-operative management of unstable ankle fractures in patients with diabetes results in an unacceptably high rate of complications. Operatively managed patients with uncomplicated diabetes seem to fair as well as patients without diabetes. Thus, it is important to recognize patients as either complicated or uncomplicated at the onset of their treatment based on comorbidities. There is limited evidence to guide the management of ankle fractures in patients with diabetes, in particular those deemed complicated. Non-operative management of unstable fractures in diabetic patients should be avoided. PMID- 29974404 TI - Variations of the renal function parameters in rectal cancer patients with a defunctioning loop ileostomy. AB - PURPOSE: The objective of this study is to investigate the impact of the temporary loop ileostomy on renal function and also to assess the factors associated with the change in renal function observed between the index surgery (the moment of the radical surgical procedure) and the closure of the ileostomy (the moment of the secondary surgical act of suppression of the ileostomy). METHODS: A total of 69 rectal cancer patients from a single referral surgical unit who had a loop ileostomy during low anterior resection of the rectum were included in this study. Serum creatinine levels were evaluated, and estimated glomerular filtration rate (eGFR) was calculated prior to index surgery and closure of the ileostomy. RESULTS: During this time interval, there was a significant decrease in eGFR levels (mean difference - 4.5 mL/min/1.73 m2, 95% CI - 7.8 to - 1.3 mL/min/1.73 m2), and also a significant increase in the serum creatinine values (mean difference 0.07, 95% CI 0.02-0.12 mg/dL). The eGFR decrease was more pronounced in diabetic patients, in those with a baseline Charlson Comorbidity Index score >= 1 or in those that received chemotherapy. In a multivariable regression analysis, the use of neoadjuvant chemotherapy was the only variable significantly associated with the change in eGFR levels between the two surgical interventions. CONCLUSION: Renal function impairment is an important event that the surgeon has to take into consideration when deciding upon opting for a loop ileostomy to temporarily defunction a colorectal anastomosis. PMID- 29974405 TI - Initiation of the inflammatory response after renal ischemia/reperfusion injury during renal transplantation. AB - Ischemia/reperfusion injury (IRI) occurs commonly during renal transplantation. It has been well demonstrated that the inflammatory response has an important role in the pathogenesis and pathological processes of IRI. However, the signaling events that trigger the activation of the inflammatory response are less clear. Accumulated evidence has identified the role of various injury factors released from or exposed in ischemic, damaged, or dying cells, which serve as initiators of the inflammatory response and exacerbate kidney injury after renal IRI. Signaling pathways triggered by these endogenous molecules that activate different pathogen recognition receptors have also been widely investigated. Here, we review the molecular signaling molecules that initiate the inflammatory response during renal IRI and that provide potential therapeutic options for the disease. PMID- 29974406 TI - Impact of hemoglobin variability on cardiovascular mortality in maintenance hemodialysis patients. AB - PURPOSE: Although the association between anemia and cardiovascular mortality in hemodialysis patients is well established, whether hemoglobin variability (Hgb Var) affects the prognosis remains unclear. We aimed to evaluate the association between Hgb-Var and cardiovascular mortality in Chinese hemodialysis patients. METHODS: This retrospective study included 252 patients starting hemodialysis in Xin Hua Hospital between January 2009 and December 2015. Patients were divided into three tertiles based on Hgb-Var, as reflected by SD Hgbmean, SD Hgbrange, and Hgbdeflection during a 12-month evaluation period after hemodialysis initiation. Left ventricular ejection fraction (EF) and left ventricular mass index (LVMI) were evaluated by echocardiography. Information on cardiovascular deaths occurred by December 2017 was collected. Multivariate Cox regression models were constructed to evaluate the association between Hgb-Var and cardiovascular mortality. RESULTS: A total of 75 deaths and 52 cardiovascular deaths occurred during the 47-month follow-up (range 29.5-70). Under multivariate regression, the subgroup with the highest Hgb-Var had a higher risk of cardiovascular mortality after adjusting for relevant factors (HR vs. lowest SD Hgbmean: 9.15, 95% CI 2.82, 29.693, P < 0.0001; HR vs. lowest SD Hgbrange: 3.81, 95% CI 1.40, 10.38, P = 0.005). Per 1 SD of Hgbmean and Hgbrange elevations were both related to a 10% increase in the cardiovascular mortality risk. Baseline EF% and LVMI did not differ across the Hgb-Var subgroups. EF% upon the last patient visit to the clinic was lower in the subgroup with the highest SD Hgbmean (P = 0.02). CONCLUSIONS: High Hgb-Var is an independent risk factor for cardiovascular mortality in hemodialysis patients and might influence the cardiac function. PMID- 29974408 TI - The Impact of Bacillus subtilis KATMIRA1933 Supplementation on Telomere Length and Mitochondrial DNA Damage of Laying Hens. AB - In the current study, we performed in vivo investigation of probiotic intake influence on nuclear and mitochondrial DNA damage of hens, using quantitative PCR techniques. The probiotic supplementation to the diet of Hisex Brown hens had no significant effect on the rate of telomere shortening. After prolonged probiotic intake (225 and 445 days), the 18-21% decrease in the mtDNA lesions was detected. Since avian mitochondrial DNA damage investigations are rare, the current study of the probiotic-enriched diet's impact on the damage of the hen mitochondrial DNA is novel and highly important. The decrease of mtDNA damage is a beneficial property, which could positively affect the reproductive aging of hens. The positive impact of probiotic supplementation on hens' performance traits such as hen-day egg production, egg weight and mass, and feed conversion ratio was observed. PMID- 29974407 TI - Molecular Profiling Based on KRAS/BRAF Mutation, Methylation, and Microsatellite Statuses in Serrated Lesions. AB - AIM: The aim of your study is to characterize serrated lesions according to their molecular patterns, specifically BRAF/KRAS mutation, methylation, and microsatellite statuses. We evaluated the molecular patterns of 163 serrated lesions, including 37 microvesicular hyperplastic polyps, 73 sessile serrated adenomas/polyps (SSA/Ps), 31 traditional serrated adenomas, and 22 SSA/Ps with cytological dysplasia/adenocarcinoma. METHODS: Mutations in BRAF (V600E)/KRAS (exon 2) and microsatellite status [microsatellite stability (MSS) vs. MSI] were examined using a pyrosequencer and the PCR-based microsatellite method, respectively. DNA methylation status was classified as low (LME), intermediate (IME), or high methylation epigenotype (HME) according to a PCR-based two-step method. In addition, mucin and annexin A10 expression was examined. Finally, we performed a hierarchical clustering analysis of the BRAF/KRAS mutation, DNA methylation, and microsatellite statuses. RESULTS: The molecular patterns observed in the serrated lesions could be divided into five subgroups: lesions characterized by (1) BRAF mutation, HME, and MSI; (2) BRAF mutation, HME, and MSS; (3) BRAF mutation, LME/IME, and MSS; (4) no BRAF/KRAS mutations, LME/IME, and MSS; and (5) KRAS mutation, LME/IME, and MSS. In addition, we demonstrated that these observed molecular patterns help identify the associations of the molecular patterns and markers (i.e., mucin and annexin A10) with the clinicopathological findings, including histological features and histological diagnosis. CONCLUSIONS: We suggest that the identified molecular patterns play an important role in the pathway of serrated lesion development. PMID- 29974409 TI - Bifidobacterium bifidum TMC3115 Can Characteristically Influence Glucose and Lipid Profile and Intestinal Microbiota in the Middle-Aged and Elderly. AB - : Bifidobacterium bifidum TMC3115 strain (TMC3115) was orally administrated to 47 subjects with mild hyperglycaemia and dyslipidaemia aged 45 to 75 years for 3 weeks. Blood samples were collected before and after intervention for profiling plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol and triglyceride concentrations, as well as fasting blood glucose. Before and 3 and 4 weeks after intervention, the faecal samples were collected to analyse faecal microbiota using the sequencing of 16S rRNA genes with a next-generation sequencer. TMC3115 significantly decreased plasma TC and LDL-C levels of the tested subjects after intervention (P < 0.05). The frequencies of defaecation and faecal odour after the intervention and 1 week later were significantly better than at pre-intervention, respectively. TMC3115 administration increased Firmicutes, Bacteroides and Actinobacteria and decreases in Proteobacteria and Fusobacteria. There were significant increases in the proportions of Dorea and Lachnospira after the intervention (P < 0.05). TMC3115 also increased the level of Firmicutes and decreased that of Bacteroidetes 1 week after the intervention (P < 0.05). Serum triglycerides correlated negatively with the proportions of Bacteroidetes (R = - 0.21, P = 0.047) and Bacteroides (R = - 0.23, P = 0.029), while the relative abundance of Dialister of Firmicutes correlated negatively and significantly with the serum LDL-C (R = - 0.24, P = 0.022) and TC levels (R = - 0.22, P = 0.030). These results indicate that TMC3115 might exhibit beneficial effects on the serum cholesterol metabolism of subjects with dyslipidaemia through modulation of their intestinal microbiota. TRIAL REGISTRATION: ChiCTR-OOC-16010271. PMID- 29974411 TI - Malignant Transformation of a Desmoplastic Ameloblastoma to Squamous Cell Carcinoma: A Case Report. AB - Ameloblastomas are the most common odontogenic tumors, excluding odontomas. Several morphologic variants have been described including follicular, plexiform, acanthomatous, granular cell, basaloid and desmoplastic. Desmoplastic ameloblastoma differs from other conventional ameloblastomas microscopically, clinically, and radiographically. Ameloblastic carcinoma, the malignant counterpart of ameloblastoma is characterized by cytologic features of malignancy combined within the overall histologic features of conventional ameloblastoma. Malignant transformation of ameloblastoma to squamous cell carcinoma is a controversial subject. Here we report a case of a desmoplastic ameloblastoma with malignant transformation to squamous cell carcinoma in a 49 year old African American man. The patient underwent tumor resection and radiation therapy with no evidence of disease recurrence or progression 16 months post operatively. To our knowledge malignant transformation of a desmoplastic ameloblastoma to squamous cell carcinoma has not so far been reported. This observation may lend some support to the argument that desmoplastic ameloblastoma is phenotypically and biologically distinct entity. PMID- 29974412 TI - Awareness and Beliefs About Cervical Cancer, the HPV Vaccine, and Cervical Cancer Screening Among Ghanaian Women with Diverse Education Levels. AB - Cervical cancer is the leading cause of cancer death among women in Ghana. Cost effective tools for the primary and secondary prevention of cervical cancer, such as the Pap test, the HPV DNA test, and the HPV vaccine, are available in hospitals and clinics throughout Ghana. However, participation in cervical cancer prevention behaviors is low among Ghanaian women. Our objective was to determine if there were significant differences in cervical cancer awareness and stigmatizing beliefs about women with cervical cancer between Ghanaian women of different education levels. We surveyed 288 Ghanaian women who were at least 18 years old. Data on the participants' demographic characteristics, awareness of cervical cancer, cervical cancer screening, and the HPV vaccine, beliefs about cervical cancer screening, and stigmatizing beliefs about women with cervical cancer was collected. Chi-square tests for independence and Fisher's exact test of independence were preformed to determine if education level was associated with those factors. Participation in cervical cancer screening and uptake of the HPV vaccine was significantly lower among women with less than a senior high school education. Awareness about cervical cancer, cervical cancer screening, and the HPV vaccine was lower among women with less education. Women with lower levels of education were more likely to agree with the negative statements about cervical cancer screening and stigmatizing beliefs about women with cervical cancer. Cervical cancer education interventions that are tailored for Ghanaian women with different educational levels are needed to increase awareness of and participation in cervical cancer prevention strategies. PMID- 29974410 TI - Non-alcoholic hepatic steatosis attenuates hepatitis B virus replication in an HBV-immunocompetent mouse model. AB - OBJECTIVE: The relationship between chronic hepatitis B virus (HBV) infection and fatty liver in patients remains unclear. Although high-fat diets-induced hepatic steatosis was proved to reduce HBV replication in transgenic mice, the interplay between HBV and fatty liver in immunocompetent mouse model is yet to be elucidated. Here, we aimed to develop an effective animal model for intracellular HBV persistence combined with hepatic steatosis and to explore their interactions. METHODS: FVB/N mice with HBV genotype B replicon DNA were established by hydrodynamic injection. Mice injected with HBV or control plasmid vectors were then randomized into NAFLD + HBV, HBV, NAFLD, and control groups and treated with a high-fat or standard diet for up to 14 weeks. The characteristics of NAFLD were evaluated by physical indices, liver function tests, glycolipid metabolism, and liver histopathological changes. Viral dynamics were also analyzed by HBV DNA and HBV-related antigens. RESULTS: HBV clone persistently replicated in the livers of FVB/N mice, and hepatic steatosis was induced by a high-fat diet. The NAFLD and NAFLD + HBV groups shared similar physical features, glycolipid metabolism, liver function, and hepatic steatosis. Serum hepatitis B e antigen (HBeAg), hepatic hepatitis B s antigen (HBsAg),hepatitis B c antigen (HBcAg), and HBV DNA were decreased in the NAFLD + HBV group compared with those in the HBV group at the end of 14 weeks. CONCLUSION: In an HBV-immunocompetent mouse model, non-alcoholic hepatic steatosis inhibited HBV replication, as indicated by the reduction of HBV DNA and HBV-related antigens. HBV replication did not alter lipid metabolism in mice. PMID- 29974413 TI - Color Tests for the Preliminary Identification of New Psychoactive Substances. AB - Color tests are a key tool for the rapid and simple identification of seized illicit drugs. This chapter outlines a series of color tests that can be used for the preliminary identification of new psychoactive substances such as cathinones, piperazines, tryptamines, and amphetamine-type stimulants. PMID- 29974414 TI - Illicit and Counterfeit Drug Analysis by Morphologically Directed Raman Spectroscopy. AB - Morphologically directed Raman spectroscopy (MDRS) is a novel tool for the forensic analysis of illicit and counterfeit drug samples. MDRS combines Raman microspectroscopy with automated particle imaging so that physical and chemical information about the components of a mixture sample can be obtained. Results of automated particle imaging are used to determine samples for Raman analysis. The use of MDRS for these types of samples can be employed for both forensic investigations and adjudications of cases. The method provides insight about the physical and chemical composition of the sample, as well as about manufacturing and sample history. Here, MDRS was used in four different illicit and counterfeit drug analyses: (1) examination of a multicomponent drug mixture where the results could be used for comparative source attribution, (2) the detection of low (or trace) concentration particles in a drug sample, (3) the analysis of synthetic cathinone samples (i.e., bath salts), and (4) a study of counterfeit pharmaceutical products. PMID- 29974415 TI - Analysis of Drugs of Abuse by Gas Chromatography-Mass Spectrometry (GC-MS). AB - Analysis of drugs of abuse constitutes a major portion of work for many crime laboratories. The most important and most utilized technique for the screening and identification of solid-dosage drugs is gas chromatography-mass spectrometry (GC-MS). A detailed practical procedure is described for the rapid screening and identification by GC-MS of most drugs of abuse that are commonly encountered in forensic drug laboratories. PMID- 29974416 TI - Toward Confirmatory On-Site Real-Time Detection of Emerging Drugs Using Portable Ultrafast Capillary Electrophoresis Mass Spectrometry. AB - Currently, law enforcement agencies rely upon presumptive tests such as color tests (or spot tests) for on-site, real-time identification of forensic evidence, such as controlled substances. These tests are simple and easy to use and require no instrumentation. However, they are unreliable and have a large false positive rate. On the other hand, confirmatory tests are done in analytical laboratories using sophisticated instrumentation by expert analysts, and have lower false positive rates. However, they are bulky and impractical for on-site real-time analysis. To provide more accurate identification of forensic evidence on-site, in real-time, it is important to develop portable confirmatory instrumentation using information-rich technologies. Moreover, because the analysis of controlled substances could be complicated by the existence of various isomers (including optical isomers) it is desirable that the portable instruments have the capability to separate structural and optical isomers of the controlled substances, because scheduling is some times dependent upon which isomer is present. To this end, we have developed a portable ultrafast capillary electrophoresis (UFCE) system for the separation of controlled substances and their structural and optical isomers. The UFCE instrument has an integrated porous tip for facile interfacing with electrospray ionization mass spectrometry. The technique has been successfully applied to the analysis of mixtures of several controlled substances such as amphetamines, cathinones, nor-mephedrone, and pregabalin and their optical isomers in about a minute. PMID- 29974417 TI - Use of DART-TOF-MS for Screening Drugs of Abuse. AB - Screening is an integral component of an analytical scheme to identify the presence of controlled substances in submissions to the crime laboratory. Many techniques are utilized, including color tests, thin-layer chromatography, and ultraviolet spectroscopy. While these are useful techniques to guide the examiner, all will, at best, categorize the material into a broad group of compounds. Direct Analysis in Real Time (DART), coupled with a time-of-flight (TOF) mass spectrometer, is an emerging technique that yields highly definitive screening data leading to the identity of controlled substances present in a case sample. Sample preparation is quick and simple and run times are typically only a few minutes. Collected data will allow the examiner to determine appropriate standards for confirmation, making the overall analysis much more efficient. Presented here is a guide to using this technique for the screening of case submissions for controlled substances. PMID- 29974418 TI - Confirmation of Pharmaceutical Identifiers via DART-TOF-MS. AB - A direct analysis in real time ion source coupled with a time-of-flight mass spectrometer (DART-TOF-MS) is a suitable confirmatory technique for the analysis of pharmaceutical preparations, with accompanying reference sources for preparation markings. The DART-TOF-MS instrument allows for simple sample preparation and decreased analysis time, both crucial in a forensic laboratory setting. Differentiation can be made between active drug ingredients with the same molecular weight, such as hydrocodone and codeine, as well as pharmaceutical preparation mixtures, such as oxycodone and acetaminophen, using exact masses of the protonated molecules and fragment peaks compared to a standard. PMID- 29974419 TI - UPLC-Orbitrap(r) Screening for over 35 Drugs of Abuse and Metabolites in Biological Fluids in Under 10 min. AB - We present a UPLC(r)-High Resolution Mass Spectrometric method to simultaneously screen for 19 benzodiazepines, 12 opiates, cocaine and three metabolites, and 3 "Z-drug" hypnotic sedatives in both blood and urine specimens. Sample processing consists of a high-speed, high-temperature enzymatic hydrolysis for urine samples followed by a rapid supported liquid extraction (SLE). The combination of ultrahigh-resolution chromatography with high resolution mass spectrometry allows all analytes to be uniquely detected with a 10 min analytical run. Limits of detection for all target analytes are 3 ng/mL or better, with only 300 MUL of specimen used for analysis. The combination of low sample volume with fast processing and analysis makes this method a suitable replacement for immunoassay screening of the targeted drug classes, while providing far superior specificity and better limits of detection than can routinely be obtained by immunoassay. PMID- 29974420 TI - Sensitivity Enhancement in Capillary Electrophoresis Using Magnetic Particles as Solid-Phase Extraction Sorbents for the Determination of Drugs of Abuse in Urine. AB - Over the last few years, different types of magnetic particles have been investigated and successfully used in sample preparation, of which iron oxides are the most popular, due to their low price and low toxicity. For analytical purposes, these particles have always been modified and functionalized with different materials to improve their stability and introduce new surface properties. Here we describe the preparation of silica-coated iron oxide particles functionalized with C18 and their application as solid-phase extraction sorbents coupled in-line with capillary electrophoresis for determining drugs of abuse in human urine. PMID- 29974421 TI - High-Throughput Extraction and Detection of Drugs in Urine: Parallel Sampling with Solid-Phase Microextraction (SPME) Fibers Coupled with Direct Analysis in Real Time-Mass Spectrometry (DART-MS) Detection. AB - Determination of drugs of abuse in urine is routinely accomplished by utilizing solid-phase extraction to isolate the drugs and gas chromatography/mass spectrometry (GC/MS) for their detection. Although robotic systems are employed, throughput is limited by the extraction process and GC chromatographic separation.A method that utilizes an array of 12 solid-phase microextraction (SPME) fibers for simultaneous isolation of drugs of abuse from urine is provided as a means to increase productivity. A SPME probe holder that permits movement of up to 12 fibers through the various steps of the extraction process in parallel is utilized. Use of an automated stage for fiber presentation into the ionization region of a Direct Analysis in Real Time equipped LC/MS facilitates rapid interrogation of each SPME. PMID- 29974422 TI - Analysis of Drugs of Abuse in Hair Samples by Ultrahigh-Performance Liquid Chromatography-Tandem Mass Spectrometry (UHPLC-MS/MS). AB - The determination at low concentrations of common psychotropic drugs is increasingly requested in hair samples for the retrospective investigation of habitual drug abuse and dependence as well as in other toxicological investigations. The dramatic improvements of the instrumentation based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) make the detection of tiny amounts of almost whatever drug is in hair possible, even after single-dose intake. Therefore, LC-MS/MS is gradually replacing gas chromatographic techniques in both screening and confirmation procedures, and is increasingly acknowledged as the technique of choice for hair analysis. We describe a simple procedure for the quantitative determination in hair samples of 15 common drugs of abuse, or metabolites, based on methanol extraction and direct analysis by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). PMID- 29974423 TI - Comprehensive Drug Screening by Thermal Desorption and Pyrolysis Combined with Direct Analysis in Real Time-Mass Spectrometry (TDP/DART-MS). AB - Rapid and accurate analysis of drugs using direct analysis in real time-mass spectrometry (DART-MS) combined with thermal desorption pyrolysis (TDP/DART-MS) is described in this chapter. Rapid drug screening is very important in cases of suspected drug abuse. However, acquiring accurate analytical data requires highly optimized sample handling and technical expertise. Although rapid drug analysis using mass spectrometry provides reliable data, it is not commonly used because of its complexity. Thus, a comprehensive analysis system for drugs that requires minimal optimization of sample preparation and analytical conditions is strongly desired. DART-MS involves ambient ionization mass spectrometric analysis with little to no sample preparation. We have coupled this approach with thermal TDP/DART-MS and demonstrate how it can be used to detect drugs in complex matrices such as urine or blood. PMID- 29974424 TI - Detection of Diagnostic Plant-Derived Psychoactive Biomarkers in Fingerprints by MALDI-SpiralTOF-Mass Spectrometry Imaging. AB - One of the current challenges in forensics is establishment of a connection between an individual and substances to which they have been exposed, and which might have relevance in crime scene investigation. An example of a situation in which this arises is when an individual has handled, and is under the influence of any one of a large number of currently unscheduled plant-based mind-altering substances. In such instances as a medical emergency or a crime scene investigation , one way to establish a connection between an individual and their exposure to such substances is to take advantage of the high information content of their fingerprint. The fingerprint pattern not only establishes the identity of the individual, but also contains rarely exploited chemical information about molecules to which they have been exposed that might have a bearing on a crime. If the fingerprint image is based on the spatial distribution of diagnostic molecular markers indicative of a substance, then an individual's identity can be definitively tied to exposure to the substance. The fingerprint image derived from the spatial distribution of diagnostic molecules can be obtained by mass spectrometry imaging (MSI). Here, we demonstrate how the handling by an individual of a plant-derived psychoactive brew called ayahuasca can be established through determination, by matrix-assisted laser desorption ionization (MALDI) MSI, of ion images featuring biomarkers from the plants from which the brew is made. PMID- 29974425 TI - Matrix-Assisted Laser Desorption Ionization Imaging Mass Spectrometry of Drug Distribution in Mouse Brain Tissue by High-Resolution Time-of-Flight Mass Spectrometry. AB - Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry provides the opportunity to visualize the distributions of drugs and metabolites in tissue specimens without requiring radioisotopes, as are used for whole-body autoradiography. However, the analysis of low-molecular-weight compounds is often difficult using the common reflectron-type MALDI time-of-flight mass spectrometers. Insufficient mass resolving power causes overlapping of the target drug peak with matrix compound or surface contaminant peaks. To solve this issue, we describe the procedure for imaging mass spectrometry using a high-mass resolution mass spectrometer that can separate isobaric peaks. PMID- 29974426 TI - Estimation of Community Usage of Drugs Utilizing Sewage Epidemiology. AB - Drug abuse is considered to be a national epidemic in many countries including the USA, and is associated with impaired social indicators including economic loss and adverse public health. The conventional methods of estimation of drug usage in communities are based on self-reported surveys, overdose or toxicological reports, drug-related crime statistics, and hospital admissions. Conventional methods suffer from several shortcomings including cost and time intensiveness, nonresponse bias, bias in the selection of sample population, and consumer's unawareness on the actual composition of used drugs. Sewage epidemiology utilizes the mass load of drugs in wastewater influent to estimate the drug usage in a community. Despite several challenges to the determination of the human excretion profile of drugs, the stability of drugs in wastewater, the dynamics of the population, sewage epidemiology provides several opportunities, including a cost-effective, comprehensive, noninvasive, and nearly real-time measure of trends of drug use over time. PMID- 29974427 TI - LC-MS-MS Method Development and Analysis of Stimulants, Opiates, Synthetic Opiates, PCP, and Benzodiazepines in Wastewater. Preponderance of these Drugs During Football Games. AB - A method was developed for the analysis of stimulant drugs, opiates, synthetic opiates, PCP, and benzodiazepines in wastewater samples using liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). A total of 33 compounds (stimulant-type drugs and metabolites of opiates, synthetic opiates, PCP, and benzodiazepines) were analyzed. These drugs included amphetamine (Amp) (1), methamphetamine (Meth) (2), methylenedioxyamphetamine (MDA) (3), methylenedioxymethamphetamine (MDMA) (4), methylenedioxyethylamphetamine (MDEA) (5), benzoylecgonine (BE, the major metabolite of Coc) (6), cocaine (Coc) (7), 6 monoacetylmorphine (6-MAM, the primary urinary metabolite of heroin) (8), codeine (9), hydrocodone (10), hydromorphone (11), morphine (12), norhydrocodone (the primary urinary metabolite of hydrocodone) (13), oxycodone (14), oxymorphone (15), 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrolidine (EDDP, the primary urinary metabolite of methadone) (16), fentanyl (17), meperidine (18), methadone (19), norfentanyl (the primary urinary metabolite of fentanyl) (20), normeperidine (the primary urinary metabolite of meperidine) (21), phencyclidine (PCP) (22), tramadol (23), alprazolam (24), temazepam (25), nordiazepam (26), chlordiazepoxide (27), flurazepam (28), oxazepam (29), alpha-OH-alprazolam (the primary urinary metabolite of alprazolam) (30), alpha-OH-triazolam (the primary urinary metabolite of triazolam) (31), 2-OH-ethylflurazepam (the primary urinary metabolite of flurazepam) (32), and 7-NH2-flunitrazepam (the primary urinary metabolite of flunitrazepam) (33). These drugs were chosen because of their widespread abuse. Wastewater samples were collected at both the Oxford Wastewater Treatment Plant in Oxford, Mississippi (MS), and the University Wastewater Treatment Plant in University, MS. Samples were collected on weekends on which the Ole Miss Rebel football team held home games (Vaught-Hemingway Stadium, University, MS 38677). The collected samples were analyzed using a validated method and found to contain Amp, Meth, MDMA, MDA, Coc, BE, codeine, hydrocodone, hydromorphone, morphine, norhydrocodone, oxycodone, oxymorphone, tramadol, EDDP, meperidine, normeperidine, methadone, alprazolam, alpha-OH-alprazolam, nordiazepam, oxazepam, and temazepam. None of the samples contained MDEA, 6-MAM, fentanyl, norfentanyl, PCP, chlordiazepoxide, flurazepam, 2-OH-ethylflurazepam, 7 NH2-flunitrazepam, and alpha-OH-triazolam. PMID- 29974428 TI - Analysis of Illicit Drugs in Wastewater Using High-Performance Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry (HPLC-ESI-MS/MS). AB - Consumption of illicit drugs is considered to be a global socioeconomic burden of adverse ecological and public health. Proper identification and quantification of trace level residues of illicit drugs in wastewater allow for an estimation of drug usage in a community, the amount of drug discharge into the environment, and the overall fate of drugs in the environment. This chapter provides a procedural detail of the determination of select illicit drugs and their metabolites in wastewater, suspended particulate matter, and sewage sludge using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. PMID- 29974429 TI - Analysis of Trace Drugs of Abuse by Direct Analysis in Real Time (DART) Mass Spectrometry. AB - Analysis of trace amounts of drugs of abuse is important in a variety of situations, including forensic casework. Here, a method for the facile, rapid collection of traces of drugs from a variety of porous and nonporous surfaces, including fabrics, is detailed. A small amount of extraction solvent, including an internal standard, is applied to the fabric surface, followed by application of a patterned absorbent disk which resorbs much of the extraction solvent along with dissolved traces of any drug present. Over half of the extraction solvent is recovered in 15 s from many natural and synthetic fabrics, with weights ranging from 64 to 374 mg/in.2, by pressing a half-inch diameter patterned glass fiber membrane disk to the wetted area. The patterned disk is then placed in a standard OpenSpotTM holder of a direct analysis in real time (DART) mass spectrometer with a data collection time of 1 or 2 min. Semi-quantitation of low microgram levels of drugs is achieved by comparison of spectra to those from a standard control disk. PMID- 29974430 TI - A Rapid, High-Throughput Validated Method for the Quantification of Atropine in Datura stramonium Seeds Using Direct Analysis in Real Time-High Resolution Mass Spectrometry (DART-HRMS). AB - The utility of direct analysis in real time-high resolution mass spectrometry (DART-HRMS) for quantification of a variety of compounds has been explored, but the number of reports of validated methods using this technique is limited. Furthermore, despite the increasing use in crime labs of DART-HRMS for the detection and identification of drugs of abuse, very few published reports have appeared describing how the method can be exploited for the analysis of small molecules of interest within complex matrices such as plant tissues. Herein we describe the steps to be taken to establish a validated quantification method for psychoactive compounds within complex plant matrices through its application to the detection and quantification of atropine in Datura stramonium seeds. Six calibration standard series are analyzed eight times over a period of several days to create a calibration curve. The resulting calibration curve is tested using six quality control samples and finally utilized to determine the concentration of atropine in a D. stramonium seed extract. The linear range for quantification of atropine in this study was found to be comparable to that reported previously using GC, LC, HPLC, and UHPLC-MS methods. Furthermore, the method can be applied to the quantification of other biomarkers in plant materials, despite the complexity of the plant matrix. The speed of the analysis (<10 min for duplicate analysis of 20 samples) and the ability to integrate peaks using accurate masses for specificity are advantages of the DART-HRMS quantification approach. PMID- 29974431 TI - Utilizing Direct Analysis in Real Time-High Resolution Mass Spectrometry-Derived Dark Matter Spectra to Classify and Identify Unknown Synthetic Cathinones. AB - Herein we describe a new method of statistical analysis processing of direct analysis in real time-high resolution mass spectrometry-derived neutral loss spectra of synthetic cathinones. The dark matter observed under collision-induced dissociation conditions is rendered as "neutral loss spectra," and these are subsequently subjected to statistical analysis processing, specifically hierarchical clustering analysis. The resulting hierarchical clustering dendrogram provides a means by which to classify an unknown as a member of a subgroup of cathinones, based on structural similarity of its backbone to that of the scaffolds of the drugs represented in the training set. The described method can be utilized for the classification and identification of a number of classes of psychoactive compounds. PMID- 29974432 TI - [Terms for the feeling of itching in the Bavarian dialect]. AB - BACKGROUND: Pruritus can have many different causes and is a very subjective sensation. As dialects show a greater diversity of linguistic expressions than standard languages, the description of the sensation of pruritus in a dialect might carry additional information about the quality of pruritus. METHOD: This cross-sectional study was carried out in Q1/2016 in the rural Bavarian Forest region in Bavaria, Germany. Participants were recruited in the waiting rooms of local doctors. They were asked to complete four sentences composed in the Bavarian dialect in which one word per sentence that signified the sensation of pruritus had been replaced by a blank space. RESULTS: In total, the 1,007 participants (mean age 49.97 years, SD = 15.76; 58.2% female) named 2,870 expressions, 144 excluding duplicates. 98.7% of the expressions could be matched to 13 underlying terms. The most frequent ones were "jucken" ('to itch'', 59.5%), "brennen" ('to burn', 26.5%), "kribbeln" (no English equivalent, 1.1%), "kratzen" ('to scratch', 0.7%) and "beibetaen" ('to bite', 0.6%). The use of the different expressions was strongly situational: In 75% of the cases "brennen" ('to burn') was used in the context of contact to a stinging nettle (in German 'Brennnessel'). Two of the 13 expressions ("kribbeln" and "bitzeln", no English equivalents) were even used only in this scenario. DISCUSSION: In the Bavarian dialect several different expressions for the sensation of pruritus exist. Although "jucken" ('to itch') is the most common expression for the sensation of pruritus, the German medical terms "Pruritus" ('pruritus') and "Juckreiz" ('itch') don't do justice to the situational use of expressions in the dialect. PMID- 29974433 TI - [Fentanyl buccal tablets in the treatment of breakthrough cancer pain. German cohort of a pan-European multicentre study]. AB - BACKGROUND: Patients with breakthrough cancer pain (BtCP) experience significant limitations in their physical, mental and social functions. Fentanyl buccal tablets (FBT), a rapid onset opioid, are specifically indicated for the treatment of BtCP. METHOD: The results of the German cohort of a pan-European study are presented. This included cancer pain patients from 32 German centers. Patients were on continuous opioid medication and had at least 4 BtCP episodes per day. After randomization to 2 groups, 66 patients started the titration of FBT with 100 MUg (group A) and 200 MUg (group B), respectively. All patients were titrated to their individual EAD, which could be a maximum of 800 MUg FBT per episode, regardless of the initial dose. Subsequently, up to 8 BtCP episodes were treated with this EAD. At baseline and after treatment, patients assessed the effects of BtCP on their functional status using the modified BPI-7S and answered questions about the efficacy, simplicity, and ease-of-use of the treatment. RESULTS AND CONCLUSIONS: Successful titration was achieved by 49 patients (74.2%). There was no statistically significant difference between group A and group B. The global score of the modified BPI-7S increased by 8.5 (+/- 12.8) points (from 34.7 +/- 13.6 at the beginning to 26.2 +/- 15.8 at the end of treatment), from which a statistically significant improvement in the quality of life of patients can be derived. Global patient contentment improved, most notably the rapid onset of 2.4 points to 3.4 points at the end of the study. 76.9% of patients found taking FBT simple or very simple. PMID- 29974434 TI - [Pulmonary infiltrates in haematological patients]. AB - BACKGROUND: Pulmonary complications are frequent in haematologic patients. METHOD: This review article summarizes the outcome of a discussion that took place during an expert meeting on the subject of pulmonary infiltrates. RESULTS AND CONCLUSIONS: The most common causes of pulmonary infiltrates in haematologic patients are bacterial infections. Viral infections are subject to relevant seasonal variations, but they may also cause an important proportion of pulmonary infiltrates. Microbiological examination of respiratory tract material (if possible, bronchoalveolar lavage, BAL) is the most important diagnostic procedure. Particularly in the case of prolonged (> 7 days) neutropenia, the likelihood of infiltrates being caused by fungal infections increases. For a differential diagnosis, however, also non-infectious causes, e.g. drug-induced infiltrates, have to be taken into consideration. The diagnostic workup, however, should not delay a timely start of an adequate antimicrobial therapy. PMID- 29974435 TI - [Iron deficiency in heart failure. A new diagnostic therapy algorithm - evidence tested and workable]. AB - BACKGROUND: Iron deficiency is a diagnostic and therapy-requiring comorbidity in heart failure with a negative impact on the prognosis. Even without signs of anemia, iron deficiency can lead to reduced performance with physical weakness and dyspnoea in patients with chronic heart failure. METHOD: Well-known cardiologists discussed this at an expert meeting on the topic of iron deficiency in heart failure. RESULTS AND CONCLUSIONS: Despite the high relevance for patients' outcome, this complication is still under-addressed, although specific diagnosis and effective therapy are possible and are also recommended in current ESC guidelines. A new evidence-tested algorithm should now help to facilitate diagnosis and therapy in everyday practice. The prerequisite is that it can be well integrated into clinical routine. PMID- 29974436 TI - [Significance of hawthorn extract in general practice - a current positioning]. AB - BACKGROUND: Traditionally, hawthorn extract has been used for preventive and curative support in mild forms of age-related cardiovascular problems. There are now solid data demonstrating pre-clinical effects and mechanisms of action on a molecular-biological and cellular level that appear to be of particular interest in influencing vascular ageing and in arterial vascular disorders. METHOD: The review presents the results of a meeting of experts that took place to work out a current assessment of the therapeutic suitability of hawthorn extract in the treatment of cardiovascular disease. RESULTS AND CONCLUSIONS: Although currently no general recommendation can be given on the use of hawthorn extract in cardiac insufficiency, its use is indicated for typical challenges arising in general practice, where particularly patients with functional cardiorespiratory complaints present, possibly those with cardiac insufficiency with preserved heart function for whom there has thus far been no effective therapy apart from exercise. This recommendation is supported by the findings of studies on the safety and very good tolerability of hawthorn extract, particularly for therapy adjuvant to standard practice. PMID- 29974437 TI - Maize shoot cell walls under cadmium stress. AB - The composition of shoot cell walls of two maize hybrids (Zea mays L.), the sensitive Novania and the tolerant Almansa, both after cadmium treatment was studied. Previous results showed a smaller effect of cadmium on shoot physiological parameters (e.g., elongation, dry mass, photosynthetic pigments content) in both hybrids compared to their roots. Changes in the composition of shoot cell walls were observed. It was ascertained that the amount of hemicelluloses in shoot cell walls decreased and the amount of lignocellulose complex increased in the sensitive hybrid; the opposite was observed in the tolerant Almansa. Dissimilarities in the cell wall structure of shoots, compared to the roots, in both hybrids were observed mainly in higher quantities of total lignin, in hemicelluloses fractions. The lignocellulose complex remained unchanged in the shoots in comparison to the roots. Nevertheless, in both hybrids, the highest Cd2+ amount was found in hemicelluloses. Such modification of the cell walls might affect the amount of binding sites resulting in lower cell wall permeability and subsequently in a lower pollutant influx into the protoplast. PMID- 29974438 TI - Influence of nano-additive on performance and emission characteristics of a diesel engine running on neat neem oil biodiesel. AB - This work investigates the experimental study to examine the operation characteristics of a neat neem oil methyl ester (BD100) along with silver oxide nano-particles as a metal-based additive in various mass fractions. Silver oxide nano-particle is mixed into 100% of BD100 at 5 and 10 ppm. The experimental investigation on diesel engine reveals that the addition of silver oxide nano particles to BD100 resulted in enhancement of brake thermal efficiency (BTE) with a reduction in brake specific fuel consumption (BSFC). The tested emission parameters such as CO, HC, NOx, and smoke were decreased by 12.22, 10.89, 4.24, and 6.61% for BD100+ Ag2O (5 ppm) and 16.47, 14.21, 6.66, and 8.34% for BD100 respectively when compared to BD100. Overall, improvement in ignition characteristics of the engine was finer by adding 5 and 10 ppm of silver oxide nano-particle to BD100 on account of the enhanced surface area to volume ratio. PMID- 29974439 TI - Removal of hexavalent chromium from water by modified sponge iron particles and insights into mechanism. AB - Sponge iron particles modified with expanded graphite and Cu were used to purify solutions contaminated with aqueous Cr(VI). A removal mechanism that involved physical adsorption and a redox reaction is proposed. The reaction, which consisted of rapid adsorption, a desorption stage, and an adsorption-desorption equilibrium stage, corresponded to a first-order kinetic model. The properties of the adsorption materials before and after use were investigated by X-ray diffraction, scanning electron microscopy-energy-dispersive spectroscopy, Fourier transform infrared spectroscopy, energy-dispersive X-ray fluorescence spectroscopy, and surface area measurements. Changes in the surface properties, e.g., attachment of material to the surface and filling of pores with Cr, were clearly observed. The Langmuir model best described Cr(VI) adsorption on the sponge iron and its modified particles. Removal efficiencies of 98.7, 98.8, and 100% were achieved in 7 h at a Cr(VI) dosage of 10 mg/L. Sponge iron particles are therefore potential adsorbents and after modification give good removal of Cr(VI) ions from contaminated water. PMID- 29974440 TI - Removal of vanadium from wastewater using surface-modified lignocellulosic material. AB - Palm fruit husk, a lignocellulosic material, is an agricultural solid waste. Since raw palm fruit husk does not adsorb V (V), it was subjected to surface modification with a cationic surfactant cetyl trimethyl ammonium bromide (CTAB). The surface-modified palm fruit husk showed adsorption capability for V (V). The maximum adsorption of V (V) takes place at pH 4. Adsorption equilibrium data were fitted to Langmuir, Freundlich, and Dubinin Radushkevich (D-R) isotherm models. Kinetic studies showed that the adsorption data fit second-order kinetic model better than first order. Desorption of V (V) proved that it is feasible to recover V (V) from the spent adsorbent. Effect of coexisting anions like Molybdate, sulfate, nitrate, phosphate, and thiocyanate on the adsorption of V (V) was also studied and the foreign ions compete for the adsorption sites with V (V) anionic species. Quantitative removal of V (V) was achieved from synthetic wastewater. PMID- 29974442 TI - Comparative health risk of inhaled exposure to organic solvents, toxic metals, and hexavalent chromium from the use of spray paints in Taiwan. AB - The study investigated the exposure of spray painters to organic solvents, toxic metals, and hexavalent chromium over 21 working days in 2017. The results found these concentrations of 12 VOCs to be below the short-term exposure limit (STEL) established by the US Occupational Safety and Health Administration (OSHA). The mass concentration of total particulate matter (PM) exposure to workers was 20.01 +/- 10.78 mg/m3, which exceeds OSHA's permissible exposure level of 15 mg/m3. The mean concentration of the total metals for all particle sizes was 109.1 +/- 12.0 MUg/m3, and those for lead (496,017.0 ng/m3) and iron (252,123.8 ng/m3) were the highest of metal elements. Significantly, the mean concentrations of Pb and As exceeded OSHA's permissible exposure limits (PELs) of 0.05 and 0.01 mg/m3, respectively. The total hexavalent chromium concentration was 1163.01 ng/m3, and the individual particle sizes (PM1-2.5, PM1, and PM0.25) were strongly and positively correlated with the Cr(VI) concentrations for PM2.5. The study determined that approximately 56.14% of the hexavalent chromium inhaled during the spray-painting process was deposited in the upper respiratory system of the head airway region, followed by the alveolar and tracheobronchial regions, with fractions of 11.93 and 0.05%, respectively. Although the mean ratio of hexavalent chromium to total chromium was only 3.6% for all particle sizes, the cancer risk of the total particles in Cr(VI) (1.6 * 10-3) exceeded the acceptable risk value (10-6). The cancer risks of As and Cr(VI) associated with quasi-ultrafine particles, PM0.5-1, PM1-2.5, and PM> 2.5, also exceeded 10-6. Comparison of the carcinogenicity risk of VOCs and metals suggests that the adverse health effect of inhaled particles on spray-painting workers is more serious than that from VOC exposure. PMID- 29974441 TI - The LIFE PERSUADED project approach on phthalates and bisphenol A biomonitoring in Italian mother-child pairs linking exposure and juvenile diseases. AB - Phthalates and bisphenol A (BPA), plasticizers used in several products of daily life, are considered as endocrine disrupters, therefore children exposure is particularly relevant. The LIFE PERSUADED project aims to define the following: (a) the evaluation of internal levels of DEHP's metabolites and BPA in Italian children and their mothers, (b) the association of the exposure with puberty development and obesity diseases, and (c) the effects of exposure in juvenile in vivo model. The cross-sectional study has involved 2160 mother-child pairs, including males and females, children and adolescents, from urban and rural areas of North, Center, and South Italy. A structured questionnaire and a food diary are designed to evaluate the association between lifestyle variables potentially related to DEHP/BPA exposure and internal levels, through univariate and multivariate analyses. Two pilot case-control studies are carried out on idiopathic premature thelarche and precocious puberty (30 girls each group, aged 2-7 years) and idiopathic obesity (30 boys and 30 girls, aged 6-10 years), matched to healthy controls. BPA and DEHP's metabolites are analyzed in urine samples from all recruited subjects. Clinical and toxicological biomarkers are evaluated in serum of case-control subjects. Moreover, the toxicity study is carried out in a juvenile rodent model exposed to mixtures of BPA and DEHP at dose levels recorded in children population. The scientific results of LIFE PERSUADED will contribute to risk assessment of BPA and DEHP. PMID- 29974443 TI - Industry mimetic isomorphism and sustainable development based on the X-STATIS and HJ-biplot methods. AB - Based on both neo-institutional theory and comparative institutional analysis, this paper studies the role that mimetic forces play in the patterns and evolution of behavior concerning company sustainability. The panel data is composed of 6600 observations of 600 international large listed companies belonging to 39 different activity sectors for the period 2004-2014. Through employing the multivariate statistical methods HJ-biplot and X-STATIS, which provide a useful visualization of a complex data structure in a low-dimensional space, it can be observed that mimetic forces indicate that firms operating in high-impact sectors-sectors that operate under greater pressure from interest groups-face greater social and environmental risks and have higher corporate social responsibility (CSR) scores than companies from other sectors. The adoption or development of CSR practices depends largely on the type of industry in which the company operates, as stakeholder engagement in different industry sectors has different areas of concern. Therefore, companies operating in more polluting sectors, such as mining, paper, chemicals, or oil, give higher priority to environmental protection and defense of human rights, while other, less polluting companies involved in the communication sector are concerned to a greater extent by social issues, such as business ethics or the rights of their employees. Finally, this paper evidences that firms operating in similar contexts, in industries that face analogous risks and challenges, probably develop common policies and regulations with the aim of mitigating the pressures applied by their major stakeholder groups. PMID- 29974444 TI - A new decentralized biological treatment process based on activated carbon targeting organic micropollutant removal from hospital wastewaters. AB - Although hospital wastewaters (HWWs) are usually discharged in urban sewage systems, their separate treatment has several benefits, such as the specific treatment of potential toxics as well as avoidance of further dilutions. In this work, an integrated industrial pilot plant (2200 L) corresponding to the technology SeMPAC(r) is proposed and validated for such purpose. The process consists of a sequential batch reactor (SBR) connected to an external submerged microfiltration membrane, in which powdered activated carbon (PAC) is directly added into the biological reactor to enhance the removal of the organic micropollutants (OMPs). The combination of different redox conditions in the SBR, as well as the operation at long sludge retention times (SRTs) and high biomass concentrations favored OMP biotransformation in the SBR, being their final removal efficiencies enhanced clearly after PAC addition, especially for the recalcitrant compounds. A periodical renewal of the adsorbent is necessary to overcome its gradual saturation. The main operational conditions were influenced by (i) the recalcitrant OMP carbamazepine, which defines the PAC dosage; (ii) the easily degradable OMP ibuprofen, which can be used to optimize the duration of the aerobic cycle; and (iii) the denitrification efficiency, which defines the correct time length of the anoxic period. PMID- 29974446 TI - Temporary immobile leaflet following transcatheter aortic valve replacement of a SAPIEN-XT valve. PMID- 29974445 TI - Occurrence and distribution of antibiotic resistance genes in the sediments of drinking water sources, urban rivers, and coastal areas in Zhuhai, China. AB - Antibiotic resistance genes (ARGs) are regarded as emerging contaminants related with human activities. Aquatic environments of an urban city are apt for the persistence and prevalence of ARGs. In this study, we investigated the occurrence and distribution of ARGs and integrase genes in the sediment samples collected from drinking water sources, urban rivers, and coastal areas of Zhuhai, China, in the dry and wet seasons of 2016. The results show that sulfonamide resistance gene of sulII was present at the highest detection frequency (85.71%); and its average concentrations were also the highest in both dry and wet seasons (3.78 * 107 and 9.04 * 107 copies/g sediment, respectively), followed by tetC, tetO, tetA, ermB, dfrA1, and blaPSE-1. Temporally, the concentrations of total ARGs in the wet season were likely higher than those in the dry season; and spatially, the concentrations of total ARGs in the drinking water sources were substantially lower than those in the urban rivers and nearby coastal areas, indicating the different degrees of anthropogenic impact and consequent health risks. Positive correlations were found between intI1 and each quantitative ARG in all wet season samples rather than dry season samples, which suggested higher temperature and more rain in summer might have positive influences on ARG dissemination, especially that mediated by intI1 gene and class I integrons. PMID- 29974447 TI - Heartfelt sepsis: microvascular injury due to genomic storm. AB - Sepsis is one of the ten leading causes of death in developed and developing countries. In the United States, sepsis mortality approaches that of acute myocardial infarction and exceeds deaths from stroke. Neonates and the elderly are the most vulner-able patients, with these groups suffering from the highest sepsis mortality. In both groups, many survivors respectively display serious developmental disabilities and cognitive decline. The National Institute of Health/National Heart, Lung, and Blood Institute Panel redefined sepsis as a "severe endothelial dysfunction syndrome in response to intravascular and extravascular infections causing reversible or irreversible injury to the microcirculation responsible for multiple organ failure." Microvas-cular endothelial injury in sepsis due to microbial inflammation encompasses small blood vessels (< 100 MUm in diameter). While the lungs remain the principal organ of interest due to sepsis-associated acute respiratory distress syndrome, "septic heart" or "septic cardiomyopathy" accelerates sepsis' transition to potentially lethal septic shock. This review analyses both new advances in understanding the septic mechanism and possible resolutions of sepsis. The concept of a "genomic storm," caused by microbes triggering florid production of inflammatory mediators, is based on septic reprogramming of the human genome. This genomic storm leads to microvascular endothelial injury, persistent hypotension, and organ failure. While very early control of sepsis-causing bacterial, fungal and viral infections remains crucial for the treatment of sepsis, supportive measures are likewise necessary to maintain blood pressure, respiration, and kidney function. New evidence indicates that preadmission b-blockers may reduce sepsis associated mortality. The fundamental role of nuclear signalling in the progres sion and resolution of sepsis was established with a new class of cell penetrating nuclear transport modifiers (NTMs). NTMs target the translocation of proinflammatory and metabolic transcription factors to the cell's nucleus while also enhancing bacterial clearance in experimental polymicrobial sepsis models. The result is a 700-fold reduction in the bacterial burden of the lungs and improvement of sepsis-associated thrombocytopaenia and blood markers of endothelial injury. When added to anti-microbial therapy, NTM has increased survival from 30% to 55%, when compared to antimicrobial therapy alone. Yet, the prevention of sepsis remains the most rational and beneficial path. Anti pneumococcal vaccination has reduced the incidence of pneumonia and sepsis caused by increasingly antibiotic-resistant Streptococcus pneumoniae in all age groups. Similarly, the incidence of meningococcal sepsis known as "purpura fulminans" has been reduced by a recently approved vaccine thereby preventing hearing loss, neurologic damage, and limb amputations in young survivors of septic outbreaks. We urgently need further preventive, diagnostic, and therapeutic measures as the tide of sepsis rises in the United States and around the world. PMID- 29974448 TI - Differences in regional diastolic function between restrictive and normal right ventricular physiology in adult patients late after tetralogy of Fallot repair. AB - BACKGROUND: Restrictive right ventricular physiology (RRVP) is a common finding in adult patients after tetralogy of Fallot (TOF) repair. Despite many attempts to relate this phenomenon to various factors, its clinical importance and the underlying myocardial pathologies are still enigmatic. AIM: We sought to evaluate the regional diastolic right ventricular (RV) function in patients after TOF repair with and without RRVP. METHODS: A group of 112 consecutive patients with repaired TOF underwent transthoracic echocardiography with tissue Doppler imaging, cardiopulmonary exercise test, cardiac magnetic resonance, and laboratory test. Of them, 83 patients met the inclusion criteria. Regional deformations of the RV and interventricular septum (IVS) in patients with and without RRVP were compared. RESULTS: Tetralogy of Fallot patients demonstrated an inhomogeneous pattern of strain rate (SR) values in the atrial contraction phase (A wave) of the RV free wall compared to healthy volunteers. Patients with RRVP had significantly lower values of A wave curves of IVS segments (velocities and SR) and higher values of RV free wall SR during early filling (E wave) and atrial contraction phases compared to patients without RRVP. In multiple factor analysis RRVP was correlated with lower values of end-diastolic IVS velocities (A wave) and higher values of RV SR A waves. CONCLUSIONS: Tissue Doppler imaging may show diastolic abnormalities in patients with RRVP. This group of patients demonstrated a deterioration in IVS diastolic function as measured by SR A waves. The diastolic function of RV free wall segments was better in patients with RRVP compared to patients without restriction of the RV measured by SR. PMID- 29974449 TI - The use of rotational atherectomy in high-risk patients: results from a high volume centre. AB - BACKGROUND: Rotational atherectomy (RA) is indicated for fibrocalcified lesions when traditional percutaneous coronary intervention (PCI) could not be successfully performed. In some of the high-risk patients the RA procedure is the last resort for successful revascularisation. Such patients are, among others, those in whom coronary artery bypass grafting (CABG) is not feasible. AIM: The aim of the study was to assess in-hospital and one-year outcomes of PCI with RA in high-risk patients without other revascularisation options (RA-only group), in comparison to lower-risk patients undergoing RA. METHODS: We evaluated data of 207 consecutive patients who underwent PCI with RA. Primary endpoints were one year all-cause mortality and one-year major adverse cardiac events (MACEs). Secondary endpoints were in-hospital outcomes. RESULTS: During the study 35% of patients fulfilled the inclusion criteria to the high-risk group. Those patients had significantly lower left ventricular ejection fraction, more often prior CABG, higher admission glucose level, and higher EuroSCORE II and Syntax Score. Procedural success was similar in both groups (85% in RA-only group vs. 91% in remaining patients, p = 0.18). In-hospital outcomes were similar, except more frequent no/slow-flow phenomenon in the RA-only group. The MACE and mortality rates in one-year follow-up were not statistically different in both groups (19% vs. 18%, p = 0.82 and 11% vs. 9%, p = 0.64, respectively). CONCLUSIONS: Despite the high-risk characteristics of the study subgroup, no significant differences between in-hospital and one-year outcomes were found in comparison to lower-risk RA patients. Complex PCI with RA in patients without other revascularisation options should be taken into consideration. PMID- 29974450 TI - Remote ischaemic conditioning for preventing and treating ischaemic stroke. AB - BACKGROUND: Remote ischaemic conditioning (RIC) has been developed as a neuroprotective strategy to prevent and treat ischaemic stroke. It usually involves restricting blood flow to limbs and then releasing the ischaemic blood to promote a neuroprotective effect. Preclinical studies have suggested that RIC may have beneficial effects in ischaemic stroke patients and those at risk of ischaemic stroke. However, existing evidence is insufficient to demonstrate the efficacy and safety of RIC in preventing and treating ischaemic stroke. OBJECTIVES: To assess the benefits and harms of RIC for preventing ischaemic stroke and for treating people with ischaemic stroke and those at risk for ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (16 January 2018), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 12) in the Cochrane Library (January 2018), MEDLINE Ovid (1946 to January 2018), Embase Ovid (1974 to January 2018), Web of Science Core Collection (1950 to January 2018) and three Chinese databases (January 2018). We also searched four ongoing trials registers, reference lists, and conference proceedings. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing RIC with sham RIC or medical management in people with ischaemic stroke or at risk of ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed trial quality and risk of bias, and extracted data. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included seven trials, involving 735 participants, in this review. We analysed the effects of RIC on preventing and treating ischaemic stroke respectively.We evaluated risk of bias and judged it to be low for generation of allocation sequence in six studies and unclear in one study; unclear for allocation concealment in four studies and low in three studies; high for incomplete outcome data (attrition bias) in five studies and low in two studies; high for blinding in three studies and low in four studies; low for selective reporting; and high for other sources of bias in six studies and low in one study.We included three trials (involving 371 participants) in the analysis of the effects of RIC on ischaemic stroke prevention. In people with symptomatic intracerebral artery stenosis, recurrent stroke was significantly reduced by RIC (risk ratio (RR) 0.32, 95% confidence interval (CI) 0.12 to 0.83; 2 trials, 182 participants, low-quality evidence). In people with carotid stenosis undergoing carotid stenting, there was no significant difference in the incidence of ischaemic stroke between participants treated with RIC and non-RIC (RR 0.22, 95% CI 0.01 to 4.03; 1 trial, 189 participants, low-quality evidence); however the stroke severity (assessed by infarct volume) was significantly lower in participants treated with RIC (mean difference (MD) -0.17 mL, 95% CI -0.23 to 0.11; 1 trial, 189 participants, low-quality evidence). Adverse events associated with RIC were significantly higher in participants treated with RIC (RR 10.91; 95% CI 2.01 to 59.28; 3 trials, 371 participants, low-quality evidence), but no severe adverse event was attributable to RIC treatment. No participants experienced death or cardiovascular events during the period of the studies; and no trial reported haemorrhagic stroke or improvement in neurological, phycological or cognitive impairment.We included four trials (involving 364 participants) in the analysis of the effects of RIC on ischaemic stroke treatment. In acute ischaemic stroke, for people receiving intravenous thrombolysis, the rate of death or dependency was significantly increased by RIC treatment compared with non-RIC treatment (RR 2.34; 95% 1.19 to 4.61; 1 trial, 285 participants, low-quality evidence). In people with acute ischaemic stroke, there was no significant difference between RIC and non-RIC for reducing stroke severity as assessed by the National Institutes of Health Stroke Scale score and the final infarct volume (standardised mean difference (SMD) -0.24 mL, 95% CI 1.02 to 0.54; 2 trials, 175 participants, very low quality evidence). There was no significant difference between RIC and non-RIC for improving the psychological impairment (SMD -0.37 points, 95% CI -1.15 to 0.41; 1 trial, 26 participants, very low quality evidence) and the cognitive impairment (SMD -0.26 points; 95% CI -0.72 to 0.21; 3 trials, 79 participants, low-quality evidence) in people with acute ischaemic stroke and cerebral small vessel disease. No trial reported ischaemic stroke, recurrent ischaemic stroke, improvement in neurological impairment, hemorrhagic stroke, cardiovascular events, and RIC associated adverse events. AUTHORS' CONCLUSIONS: We found low-quality evidence that RIC may reduce the risk of recurrent stroke in participants with intracerebral artery stenosis and reduce stroke severity in participants undergoing carotid stenting, but it may increase death or dependence in participants with acute ischaemic stroke who are undergoing intravenous thrombolysis. However, there is considerable uncertainty about these conclusions because of the small number of studies and low quality of the evidence. PMID- 29974452 TI - The effectiveness of combination therapy with 308-nm excimer laser in vitiligo in Han Chinese People. PMID- 29974451 TI - Management of depression in patients with schizophrenia spectrum disorders: a critical review of international guidelines. AB - OBJECTIVES: Depression is a frequent but potentially treatable clinical dimension in patients with schizophrenia spectrum disorders (PWS). However, there is a lack of consensual recommendations regarding the optimal strategy to manage depression in PWS. In this study, we aimed to compare the various proposed strategies to define a core set of valid care recommendations for depression management in PWS. METHODS: After a systematic search of the literature, the methodological quality of 10 international guidelines from four continents was compared using a validated guideline appraisal instrument (AGREE II). Key recommendations for the management of depression in PWS were subsequently reviewed and discussed. RESULTS: The methodological quality of the guidelines was heterogeneous. Although all guidelines proposed pharmacotherapy, psychosocial interventions were a minor concern. Waiting for antipsychotic effects mostly was recommended during the acute phase of schizophrenia. During the postpsychotic phase of the illness, a switch to a second-generation antipsychotic and/or the adjunction of an antidepressant were the primary recommendations. Cognitive behavioural therapy and other medications were considered with strong variations. CONCLUSIONS: Further studies are needed to strengthen the level of evidence for antidepressive approaches in PWS. The inclusion of PWS as stakeholders is also considered to be a major issue for future guideline development. PMID- 29974453 TI - Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. AB - BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) gamma, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARgamma agonist with > 20-fold selectivity over RARalpha and RARbeta. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0.01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0.005% cream. CONCLUSIONS: Based on its RARgamma selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders. PMID- 29974454 TI - Pigmented purpura masquerading as acral melanoma. PMID- 29974455 TI - Meta-analysis of the cumulative risk of endometrial malignancy and systematic review of endometrial surveillance in extended tamoxifen therapy. AB - BACKGROUND: Optimal management of the endometrium in patients with oestrogen receptor-positive breast cancer taking extended tamoxifen therapy (for 10 years) remains uncertain. A meta-analysis was performed to determine the cumulative risk ratio (RR) for endometrial malignancy following extended compared with standard tamoxifen treatment. A systematic review was undertaken to identify whether routine endometrial surveillance in patients receiving tamoxifen is associated with earlier detection and reduced incidence of endometrial malignancy. METHODS: Two independent searches were undertaken in the Cochrane Library, PubMed and MEDLINE. A meta-analysis was performed of RCTs reporting on endometrial malignancy risk in extended tamoxifen therapy. A systematic review included prospective studies investigating the benefit of endometrial surveillance during tamoxifen therapy. RESULTS: Four RCTs reported on endometrial risk in extended tamoxifen therapy. The cumulative risk of endometrial malignancy increased twofold from 1.5 to 3.2 per cent with extended therapy compared with the standard 5 years of tamoxifen (RR 2.29, 95 per cent c.i. 1.60 to 3.28; P < 0.001). Four studies analysed the value of endometrial screening in 5-year cohorts. Endometrial cancer rates of up to 2 per cent were reported, which is higher than rates in the large extended tamoxifen trials. CONCLUSION: Extended adjuvant tamoxifen is associated with an increase in endometrial cancer. No clear benefit has been shown for routine endometrial surveillance in asymptomatic patients on tamoxifen therapy. PMID- 29974456 TI - Sleep spindles in bipolar disorder - a comparison to healthy control subjects. AB - OBJECTIVE: Bipolar disorder is a severe mental disorder for which currently no reliable biomarkers exist. It has been shown that patients with schizophrenia but not with unipolar depression have a reduced density of fast sleep spindles during N2 sleep. The aim of this study was to assess fast sleep spindle density in euthymic patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 24) and healthy control subjects (n = 25) were assessed using all-night polysomnography. Sleep spindles within stage N2 sleep were identified by visual inspection and subdivided into fast (>13 Hz) and slow (<=13 Hz) spindles. All spindles were subsequently characterised by density, frequency, amplitude, duration and coherence. RESULTS: Euthymic patients with bipolar disorder were found to have a reduced density and a lower mean frequency of fast spindles. Slow spindle density and frequency did not differ between groups. There were no differences regarding amplitude, duration or coherence. CONCLUSIONS: A reduction in fast spindle density during N2 sleep points towards thalamic dysfunction as a potential neurobiological mechanism of relevance in bipolar disorder. In addition, a reduced sleep spindle density could be interpreted as a common endophenotype shared with schizophrenia but not unipolar depression and may - if replicated - be of utility in early recognition and risk stratification. PMID- 29974457 TI - Evidence of linkage to chromosome 5p13.2-q11.1 in a large inbred family with genetic generalized epilepsy. AB - The clinical genetics of genetic generalized epilepsy suggests complex inheritance; large pedigrees, with multiple affected individuals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks; in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic-clonic seizures were seen in 11. One individual had generalized tonic-clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected individual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2-q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein-coding variants within the highly significant linkage region that includes HCN1 as a promising candidate. PMID- 29974458 TI - Increased risk of hospital admission for ICD-9-CM psychotic episodes following admission for epilepsy. AB - OBJECTIVE: To determine whether epilepsy admissions are associated with a higher readmission risk for psychotic episodes compared to admissions for other medical causes. METHODS: The Nationwide Readmissions Database is a nationally representative dataset from 2013. We used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to identify medical conditions. There were 58 278 index admissions for epilepsy, and this group was compared against admissions for stroke (n = 215 821) and common medical causes (pneumonia, urinary tract infection [UTI], congestive heart failure [CHF], and chronic obstructive pulmonary disease [COPD], n = 973 078). Readmission rates for psychotic episodes within 90 days from discharge for index hospitalizations were calculated. Cox regression was used to test for associations between admission type and readmission for psychotic episodes up to 1 year after index admission, in univariate models and adjusted for multiple medical, social, and psychiatric variables. RESULTS: Up to 90 days from index admission, there were 683/100 000 readmissions for psychotic episodes in the epilepsy group, 92/100 000 in the stroke group, and 58-206/100 000 in the medical group. The relative rate of readmission in the epilepsy group was highest in the first 30 days following index admission (311/100 000). Unadjusted hazard ratio (HR) for readmission for psychotic episodes within 1 year in the epilepsy group compared to the stroke group was 6.58 (95% confidence interval [CI] 5.69-7.61, P < 2 * 10-16 ), and 4.41 compared to the medical group (95% CI 4.00-4.85, P < 2 * 10-16 ). The fully adjusted HR for readmission in the epilepsy group remained elevated at 3.63 compared to the stroke group (95% CI 3.08-4.28, P < 2 * 10-16 ), and 1.95 compared to the medical group (95% CI 1.76-2.15, P < 2 * 10-16 ). Confounding factors most strongly associated with psychosis readmission were documented psychosis history at the time of index admission, younger age, and lower income quartile. SIGNIFICANCE: An epilepsy admission was independently associated with subsequent hospital readmission for psychotic episodes, even after adjustment for confounding variables. PMID- 29974459 TI - Implementation of a new strategy to improve the peri-operative management of neuromuscular blockade and its effects on postoperative pulmonary complications. AB - Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93 0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications. PMID- 29974460 TI - New onset epilepsy among patients with periodic discharges on continuous electroencephalographic monitoring. AB - OBJECTIVE: To evaluate the incidence of new onset epilepsy and associated risk factors in patients with periodic patterns on continuous electroencephalography (cEEG) during critical illness. METHODS: The local cEEG database and then medical records were reviewed from January 1, 2013 to June 30, 2013 to find adult patients with no history of epilepsy who had periodic discharges-either lateralized (LPDs) or generalized (GPDs)-or nonperiodic/nonepileptogenic (NP/NE) findings on cEEG and >=3 months of clinical follow-up. Clinical seizure after discharge was the primary outcome. Chi-square test, Kruskal-Wallis test, and Cox proportional hazards models were used for statistical analysis. RESULTS: A total of 195 patients (median age = 67.8 years) were included. There were 53 (27%), 73 (37%), and 69 (35%) patients with LPDs, GPDs, and NP/NE findings on cEEG, respectively. These three groups did not differ by demographic or clinical variables. A total of 29 (15%) patients (LPDs = 20 [38%], GPDs = 4 [6%], and NP/NE = 5 [7%]) developed epilepsy during a median follow-up of 32.1 (95% confidence interval [CI] = 13.2-42.8) months. The hazard ratio for epilepsy development among LPD patients was 7.7 (95% CI = 2.9-20.7) times compared to the NP/NE group, and the risk further increased to 11.4 (95% CI = 4-31.4) times if they also had electrographic seizures. This association remained significant despite adjusting for each covariate at a time. SIGNIFICANCE: Patients with LPDs on cEEG during critical illness are at least seven times more likely to develop epilepsy compared to patients with NP/NE findings. This risk is further increased if patients with LPDs have electrographic seizures. In comparison, the presence of GPDs does not seem to impact the risk for developing epilepsy. cEEG findings at the time of acute insult have potential to serve as prognostic biomarkers for epilepsy development. PMID- 29974461 TI - Mouse models for the study of fate and function of innate lymphoid cells. AB - Natural killer (NK) cells and lymphoid tissue inducer (LTi) cells were discovered more than 40 and 20 years ago, respectively. These two cell types were initially studied for their unique functions in the elimination of infected or transformed cells, and in the development of lymphoid tissues. It took an additional 10 years to realize that NK cells and LTi cells were members of a larger family of innate lymphoid cells (ILCs), whose phenotypes and functions mirror those of T cells. Many mouse models have since been developed to identify and isolate ILCs, map their developmental pathways and characterize their functions. Because of the similarity between ILCs and T cells, this exploration remains a challenge. In spite of this, a broad range of mouse models available to researchers has lead to significant progress in untangling the unique roles of ILCs early in defense, regulation of adaptive immunity and homeostasis. Here, we review these mouse models, and discuss their strengths and limitations. PMID- 29974462 TI - Fountain of youth for squamous cell carcinomas? On the epigenetic age of non small cell lung cancer and corresponding tumor-free lung tissues. AB - Aging affects the core processes of almost every organism, and the functional decline at the cellular and tissue levels influences disease development. Recently, it was shown that the methylation of certain CpG dinucleotides correlates with chronological age and that this epigenetic clock can be applied to study aging-related effects. We investigated these molecular age loci in non small cell lung cancer (NSCLC) tissues from patients with adenocarcinomas (AC) and squamous cell carcinomas (SQC) as well as in matched tumor-free lung tissue. In both NSCLC subtypes, the calculated epigenetic age did not correlate with the chronological age. In particular, SQC exhibited rejuvenation compared to the corresponding normal lung tissue as well as with the chronological age of the donor. Moreover, the younger epigenetic pattern was associated with a trend toward stem cell-like gene expression patterns. These findings show deep phenotypic differences between the tumor entities AC and SQC, which might be useful for novel therapeutic and diagnostic approaches. PMID- 29974463 TI - Analysis of metabolic profiles of generalized aggressive periodontitis. AB - BACKGROUND AND OBJECTIVE: The specific pathogenesis of generalized aggressive periodontitis (GAgP) has not yet been clarified, and few studies have focused on the association between GAgP and metabolomics. To elucidate the roles of metabolic profiles in the status of GAgP, this study aimed to identify the differential metabolic profiles between patients with GAgP and healthy controls using an untargeted metabolomic profiling method. MATERIAL AND METHODS: Serum and gingival crevicular fluid samples were collected from healthy controls (n = 20) and patients with GAgP (n = 20) in this cross-sectional study. The relative levels of biomarkers in the samples were measured by gas chromatography-mass spectrometry. Principal components analysis and orthogonal partial least-squares discriminant analysis were used for statistical analysis. Metabolites were analysed qualitatively using the FiehnLib and NIST databases. Full-mouth probing depth and clinical attachment loss were recorded as indexes of periodontal disease. RESULTS: A total of 349 metabolites were qualitatively detected in the gingival crevicular fluid samples, and 200 metabolites were detected in the serum samples. Compared with healthy controls, patients with GAgP showed significant increases in serum urea and allo-inositol levels. In contrast, glutathione, 2,5 dihydroxybenzaldehyde, adipic acid and 2-deoxyguanosine levels were decreased in patients with GAgP. In the gingival crevicular fluid samples, noradrenaline, uridine, alpha-tocopherol, dehydroascorbic acid, xanthine, galactose, glucose-1 phosphate and ribulose-5-phosphate levels were increased in patients with GAgP, while thymidine, glutathione and ribose-5-phosphate levels were decreased. CONCLUSION: The metabolomics analysis by gas chromatography-mass spectrometry is an effective and minimally non-invasive way to differentiate the metabolites characteristic of patients with GAgP. Both serum and gingival crevicular fluid metabolomics are significantly different between patients with GAgP and healthy controls. These metabolic profiles have great potential in detecting GAgP and helping to understand its underlying mechanisms. PMID- 29974464 TI - Circulating enterolactone concentrations and prognosis of postmenopausal breast cancer: assessment of mediation by inflammatory markers. AB - Higher lignan exposure has been associated with lower all-cause mortality (ACM) and breast cancer-specific mortality (BCSM) for postmenopausal breast cancer patients. However, the biological mechanisms underpinning these associations are still unclear. We investigated for the first time whether and to what extent the association between enterolactone (ENL), the major lignan metabolite, and postmenopausal breast cancer prognosis is mediated by inflammatory biomarkers. Circulating concentrations of ENL and inflammatory markers were measured in a population-based prospective cohort of 1,743 breast cancer patients recruited between 2002 and 2005 and followed-up until 2009. Hazard ratios (HR) and 95% CIs were estimated using multivariable Cox regression. Mediation analysis was performed to estimate the percentage association between ENL (log2) and ACM, BCSM and distant disease-free survival (DDFS), which is mediated by C-reactive protein (CRP) (log2), as the strongest potential mediator, and also interleukin (IL)-10. Median serum/plasma ENL and CRP concentrations for all patients, including 180 deceased patients, were 23.2 and 17.5 nmol/L, and 3.2 and 6.5 mg/l, respectively. ENL concentrations were significantly inversely associated with ACM, BCSM and DDFS (per doubling of ENL concentrations: HRs 0.93 [0.87, 0.99], 0.91 [0.84, 0.99] and 0.92 [0.87, 0.99]), after adjusting for prognostic factors and BMI. Estimated 18, 14 and 12% of the effects of ENL on ACM, BCSM and DDFS, respectively, were mediated through CRP. No mediational effect of IL-10 was found. We provide first evidence that the proinflammatory marker CRP may partially mediate the association of ENL with postmenopausal breast cancer survival, which supports hormone-independent mechanisms. PMID- 29974465 TI - The future of radiotherapy in small animals - should the fractions be coarse or fine? AB - Radiation therapy has been used to treat animal cancers for more than 100 years. Clinical experiences and experimental results have been widely published and provide a basis for the recognition of radiation therapy as an integral component of multimodal cancer management in veterinary oncology. As the expectations of pet owners and the demand for treatment of companion animals with cancer have increased, veterinary oncology itself has undergone dramatic advances in the past several decades both in terms of improved diagnostics and treatments, including increased accessibility of radiation therapy. Synchronous with development of the specialism of veterinary radiation oncology, confusion and controversy have arisen with regard to distinguishing between different types of radiotherapy and methods of treatment delivery. Importantly, the confusion extends beyond semantics, and includes opinionated debate about defining which forms of therapy (if any at all) are optimal for a given patient. This exemplifies how, despite marks of maturity including age and a robust publication history, the field of veterinary radiation oncology is in some ways still in its infancy. The purpose of this article is to review the evidence base for daily (fine) fractionation versus weekly (coarse) hypofractionation in veterinary oncology, using selected tumour types as examples. PMID- 29974466 TI - Gastroprotectants in small animal veterinary practice - a review of the evidence. Part 1: cyto-protective drugs. AB - Diverse drugs with presumed cytoprotective effect have been used therapeutically in small animal veterinary practice for various gastro-intestinal conditions such as oesophagitis, gastric ulceration, gastritis or chronic gastro-enteropathies. Their efficacy has been doubted in human medicine, raising similar questions in the veterinary field. The aim of this review was to assess the current evidence on the efficacy and safety of these drugs in dogs and cats. Through a systematic review of the literature, we identified 37 articles on the use of misoprostol, sucralfate and other gastroprotectants in dogs and cats. There was evidence to support use of misoprostol in the prevention of aspirin-induced gastroduodenal mucosal injury in dogs, and for use of sucralfate in the prevention of acid induced oesophagitis in cats. However, the overall quality of evidence supporting the use of these drugs in small animal patients was poor. In contrast, there was evidence of important adverse effects, especially drug interaction and gastro intestinal signs. We therefore recommend prescribing these drugs with caution until further well-conducted studies reveal a useful gastroprotectant effect. PMID- 29974467 TI - Drought-induced senescence of Medicago truncatula nodules involves serpin and ferritin to control proteolytic activity and iron levels. AB - Drought is a major constraint for legume growth and yield. Senescence of nitrogen fixing nodules is one of the early drought responses and may cause nutrient stress in addition to water stress in legumes. For nodule senescence to function as part of a drought-survival strategy, we propose that the intrinsically destructive senescence process must be tightly regulated. Medicago truncatula protease inhibitor and iron scavenger-encoding genes, possibly involved in controlling nodule senescence, were identified. RNA interference (RNAi) lines were constructed in which expression of a serpin or ferritins was knocked down. Both wild-type and RNAi lines were subjected to drought stress and nodule activity and plant physiological responses were measured. Drought caused M. truncatula to initiate nodule senescence before plant growth was affected and before an increase in papain-like proteolytic activity and free iron levels was apparent. Knock-down expression of serpin6 and ferritins caused increased protease activity, free iron levels, early nodule senescence and reduced plant growth. The results suggest that M. truncatula nodule-expressed serpin6 and ferritins mediate ordered drought-induced senescence by regulating papain-like cysteine protease activity and free iron levels. This strategy may allow the drought-stressed plants to benefit maximally from residual nitrogen fixation and nutrient recovery resulting from break down of macromolecules. PMID- 29974468 TI - Identification of Stipules reduced, a leaf morphology gene in pea (Pisum sativum). AB - Pea (Pisum sativum) is one of relatively few genetically amenable plant species with compound leaves. Pea leaves have a variety of specialized organs: leaflets, tendrils, pulvini and stipules, which enable the identification of mutations that transform or affect distinct parts of the leaf. Characterization of these mutations offers insights into the development and evolution of novel leaf traits. The previously characterized morphological gene Cochleata, conferring stipule identity, was known to interact with Stipules reduced (St), which conditions stipule size in pea, but the St gene remained unknown. Here we analysed Fast Neutron irradiated pea mutants by restriction site associated DNA sequencing. We identified St as a gene encoding a C2H2 zinc finger transcription factor that is regulated by Cochleata. St regulates both cell division and cell expansion in the stipule. Our approach shows how systematic genome-wide screens can be used successfully for the analysis of traits in species for which whole genome sequences are not available. PMID- 29974469 TI - Isoprene emission structures tropical tree biogeography and community assembly responses to climate. AB - The prediction of vegetation responses to climate requires a knowledge of how climate-sensitive plant traits mediate not only the responses of individual plants, but also shifts in the species and functional compositions of whole communities. The emission of isoprene gas - a trait shared by one-third of tree species - is known to protect leaf biochemistry under climatic stress. Here, we test the hypothesis that isoprene emission shapes tree species compositions in tropical forests by enhancing the tolerance of emitting trees to heat and drought. Using forest inventory data, we estimated the proportional abundance of isoprene-emitting trees (pIE) at 103 lowland tropical sites. We also quantified the temporal composition shifts in three tropical forests - two natural and one artificial - subjected to either anomalous warming or drought. Across the landscape, pIE increased with site mean annual temperature, but decreased with dry season length. Through time, pIE strongly increased under high temperatures, and moderately increased following drought. Our analysis shows that isoprene emission is a key plant trait determining species responses to climate. For species adapted to seasonal dry periods, isoprene emission may tradeoff with alternative strategies, such as leaf deciduousness. Community selection for isoprene-emitting species is a potential mechanism for enhanced forest resilience to climatic change. PMID- 29974470 TI - Privacy Issues in Smartphone Applications: An Analysis of Headache/Migraine Applications. AB - BACKGROUND: Headache diaries are a mainstay of migraine management. While many commercial smartphone applications (apps) have been developed for people with migraine, little is known about how well these apps protect patient information and whether they are secure to use. OBJECTIVE: We sought to assess whether there are privacy issues surrounding apps so that physicians and patients could better understand what medical information patients are providing to the app companies, and the potential privacy implications of how the app companies (and other third parties) might use that information. METHODS: We conducted a systematic search of the most popular "headache" and "migraine" apps and developed a database of the types of data the apps requested for input by the user and whether the apps had clear privacy policies. We also examined the content of the privacy policies. RESULTS: Twenty-nine apps were examined (14 diary apps, 15 relaxation apps). Of the diary applications, 79% (11/14) had visible privacy policies. Of the diary apps with privacy policies, all (11/11) stated whether or not the app collects and stores information remotely. A total of 55% (6/11) stated that some user data were used to serve targeted advertisements. A total of 11/15 (73%) of the relaxation apps had privacy policies. CONCLUSIONS: Headache apps shared information with third parties, posing privacy risks partly because there are few legal protections against the sale or disclosure of data from medical apps to third parties. PMID- 29974471 TI - The best thing since sliced bread? Optical mapping of transverse cardiac slices in the mouse heart. PMID- 29974472 TI - The Neolithic Plant Invasion Hypothesis: the role of preadaptation and disturbance in grassland invasion. AB - A long-standing hypothesis is that many European plants invade temperate grasslands globally because they are introduced simultaneously with pastoralism and cultivation, to which they are 'preadapted' after millennia of exposure dating to the Neolithic era ('Neolithic Plant Invasion Hypothesis' (NPIH)). These 'preadaptations' are predicted to maximize their performance relative to native species lacking this adaptive history. Here, we discuss the explanatory relevance of the NPIH, clarifying the importance of evolutionary context vs other mechanisms driving invasion. The NPIH makes intuitive sense given established connections between invasion and agricultural-based perturbation. However, tests are often incomplete given the need for performance contrasts between home and away ranges, while controlling for other mechanisms. We emphasize six NPIH-based predictions, centring on trait similarity of invaders between home vs away populations, and differing perturbation responses by invading and native plants. Although no research has integrated all six predictions, we highlight studies suggesting preadaptation influences on invasion. Given that many European grasslands are creations of human activity from the past, current invasions by these flora may represent the continuation of processes dating to the Neolithic. Ironically, European Neolithic-derived grasslands are becoming rarer, reflecting changes in management and illustrating the importance of human influences on these species. PMID- 29974473 TI - Ultrasonography as a promising methodology to indicate captured-induced abortion in viviparous elasmobranchs. AB - This study aimed to characterize morphological aspects related to abortion through a non-lethal approach in the shortnose guitarfish Zapteryx brevirostris, an endemic and threatened species commonly caught by artisanal fisheries. Two females with signs of abortion and one female exhibiting external signs of pregnancy were purchased alive at a fish market during the period when this species has developing embryos in southern Brazil. Scans were conducted using a portable ultrasound. Females with signs of abortion revealed an absence of embryos despite having a similar morphology of the uterus when compared to the pregnant female. Examination of the pregnant female revealed the presence of two embryos, measuring c. 100 mm, each detected through their midline. This study presents new data on uterine macromorphology following successive abortive events in a viviparous elasmobranch species and validates ultrasonography as a diagnostic tool for the species. Ultrasonography is an effective, non-lethal and less-invasive methodology that is recommended for use in future studies of abortion and other reproductive events in elasmobranchs. PMID- 29974474 TI - An optimized 4-day diet meal plan for 'Lunar Palace 1'. AB - BACKGROUND: Bioregenerative life support systems (BLSS) provide self-sufficient food ingredients to support long-term manned missions. It is crucial to transform raw food ingredients that are regenerated in situ in BLSS into nutritional and delectable meals for spacecraft crews. It is in our interest to develop a dietary menu with Chinese characteristics that comprises biomass produced in situ with BLSS regenerated ingredients. RESULTS: Here we report an optimized Chinese 4-day diet meal plan for 'Lunar Palace 1' that is nutritionally balanced and highly acceptable. The 2900 cal diet menu not only meets the requirements of a balanced diet for crews but also exceeds the recommended levels for most nutrients. Specifically, daily fresh food consumption in our meal plan is 1267 g day-1 , of which 78% is provided by crops and insects regenerated in situ in the BLSS. The meal plan is highly favored by Chinese crews, with acceptability as high as 7.8 8.2 on a 9-point hedonic scale. We further confirmed that our meal plan satisfies crews' basic nutritional needs through a 105-day closed habitation experiment. CONCLUSION: In brief, the findings provide new insights for dietary meal plan design in future long-term manned missions. (c) 2018 Society of Chemical Industry. PMID- 29974475 TI - False positive viral marker results in blood donors and their unintended consequences. AB - False positive (FP) viral marker results in blood donors continue to pose many challenges. Informing donors of FP results and subsequent deferral can result in stress and anxiety for donors and additional complexity and workload for blood services. Donor management strategies need to balance the requirement to minimise donor anxiety and inconvenience while maintaining sufficiency of supply. Decisions about how and when to inform donors of FP results and determine deferral periods can be difficult as FP results, while often transitory, can take up to several years to resolve. Additional complexities include the interpretation of indeterminate serological confirmatory testing without detectable viral RNA or non-discriminated NAT results with concomitant anti-HBc reactivity - both may be due to FP results, but the former may also represent past infection and the later may represent occult hepatitis B infection. In this review we discuss strategies to minimise indeterminate serological confirmatory results, possible donor deferral policies and the impact on donors when notified of FP results. We also provide some new data from Australia that address the challenge of interpreting non-discriminated NAT results with concomitant anti-HBc reactivity. Ultimately, the challenge is for each blood service to develop appropriate strategies for donor management, taking into account local information and requirements. PMID- 29974477 TI - Hepatitis B virus infection and the risk of cancer in the elderly US population. AB - Hepatitis B virus (HBV) infection causes hepatocellular carcinoma (HCC). Associations with other cancers are not established. We systematically assessed associations between HBV infection and cancers in the US elderly population. We conducted a case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database in US adults aged >=66 years. Cases (N = 1,825,316) were people with first cancers diagnosed in SEER registries (1993 2013). Controls (N = 200,000) were randomly selected, cancer-free individuals who were frequency-matched to cases on age, sex, race and calendar year. Associations with HBV infection (ascertained by Medicare claims) were assessed by logistic regression. HBV prevalence was higher in cases than controls (0.6% vs. 0.5%). HBV was positively associated with cancers of the stomach (adjusted odds ratio [aOR] = 1.19; 95% confidence intervals [CI] = 1.03-1.37), anus (1.66; 1.17-2.33), liver (10.6; 9.66-11.6), intrahepatic bile ducts (1.67; 1.18-2.37), nasopharynx (2.08; 1.33-3.25), as well as myelodysplastic syndrome (1.26; 1.07-1.49) and diffuse large B-cell lymphoma (DLBCL) (1.24; 1.06-1.46). Inverse associations were observed with female breast (aOR = 0.86; 95%CI = 0.76-0.98) and prostate (0.81; 0.73-0.91) cancers and chronic lymphocytic leukemia (0.77; 0.62-0.96). Associations were maintained in sensitivity analyses conducted in people without claims for cirrhosis or hepatitis C or human immunodeficiency virus infections. HBV infection is associated with increased risk of cancers other than HCC, such as bile duct cancers and DLBCL. The biological mechanisms by which HBV may lead to these cancers need to be explored. PMID- 29974476 TI - Matrix metalloproteinase-7 in periodontitis with type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: Elevated levels of matrix metalloproteinase-7 (MMP7) have been observed in serum samples of subjects with type 2 diabetes mellitus (T2DM) and in gingival tissues of subjects with periodontitis. The aim of the present study was to collect in vivo and in silico evidence on the role of MMP7 in the interplay between T2DM and generalized periodontitis (GP). MATERIAL AND METHODS: The extent of MMP7 expression and localization were immunohistochemically analyzed in gingival tissues of patients with GP with T2DM (T2DM/GP, n = 11), systemically healthy patients with GP (n = 7), and systemically and periodontally healthy controls (n = 11). An in silico network model was built to determine the interactions between MMP7 and T2DM pathways. Regulation of neutrophil transmigration by MMP7 was analyzed in a knock-out mice model. RESULTS: In human gingival tissues, the proportion of cells with robust MMP7 expression was elevated in patients with T2DM/GP in comparison to controls (P = .014). According to the in silico analysis, "hydroxyl radical" and "hydrogen peroxide" compounds were among the most central nodes of the network, and were within the shortest paths connecting "glucose" to "MMP7." In MMP7 knock-out mice, an intense accumulation of neutrophils was observed in the gingival epithelium as compared to wild-type mice (P = .0001). CONCLUSION: Elevated MMP7 expression in gingival tissues of patients with T2DM/GP is related to the activation of reactive oxygen species by hyperglycemia. Suppression of MMP7 expression results in impaired neutrophil transmigration in gingiva. PMID- 29974478 TI - ClC-3: biophysical properties clarify cellular functions. PMID- 29974479 TI - Decomposition of the dose conversion factor based on fluence spectra of secondary charged particles: Application to lateral dose profiles in photon fields. AB - PURPOSE: The dose conversion factor plays an important role in the dosimetry by enabling the absorbed dose in the sensitive volume of a detector to be converted into the absorbed dose in the surrounding medium (in most cases water). The purpose of this paper is to demonstrate that a specific fluence-based approach for the decomposition of the dose conversion factor is in particular useful for the interpretation of the influences of detector properties on measurements under nonreference conditions. METHODS: Data for the dose conversion factor and secondary fluence spectra were obtained by the Monte Carlo method. The calculation of the secondary charged particle fluence (electrons and positrons) in the sensitive detector volume was imbedded into the code for the calculation of absorbed dose in the detector. The decomposition method into subfactors is based on the use of these fluence data applied to a stepwise transition from the dose at the point of measurement next to a pure water detector and finally to the fully simulated detector geometry. Each subfactor is obtained as a ratio, at which the stopping power only is different in the numerator and the denominator or at which the fluence only is different in the numerator and the denominator. This method was applied at photon dose profiles obtained in water at different radiation qualities and with various detectors of cylindrical type. RESULTS: The resulting subfactors can be well identified as a stopping power ratio and as perturbation factors each reflecting particular detector properties. Two of them (f1 and f4 ) are equivalent with perturbation factors which have already been introduced by other authors previously. These are the volume perturbation factor and the extracameral perturbation factor. Subfactor f2 denoted as medium perturbation factor was found to resemble the density perturbation factor. Results obtained for the volume perturbation factor applied to dose profiles measured with cylindrical detectors confirm that the volume effect can be well described by a convolution of the true profile in water with a Gaussian kernel. It was found that the sigma parameter depends on the cylinder radius only and amounts almost exactly to half of its value. The medium perturbation factor strongly depends on the density of the detector medium. For an air-filled detector, the influence of the air again can be described by a Gauss convolution, however, with a less good agreement. For detectors with a density of the cavity medium larger than that of water, for instance, for a diamond detector, it was found that there is a tendency of compensation between the volume averaging effect and the medium effect. CONCLUSION: The fluence-based decomposition of the dose conversion factor leads to a fluence-based formulation of perturbation factors, referred to as volume, medium, and extracameral perturbation factor. These factors offer useful explanations for the behavior of detectors in nonreference conditions. An example was given for cylindrical detectors at dose profile measurements. PMID- 29974480 TI - Pesticide contact dermatitis in agricultural workers of Himachal Pradesh (India). AB - BACKGROUND: Common pesticides used in the region by agricultural workers may cause contact allergy. METHODS: Thirty agricultural workers with a history of pesticide exposure and dermatitis involving the face, neck, trunk or extremities, and 20 controls comprising 2 groups of 10 subjects each, group 1 with dermatitis and no exposure to pesticides, and group 2 with neither exposure to pesticides nor dermatitis, were patch tested with 10 pesticides commonly used in the region by use of the Finn Chamber method. RESULTS: The 30 patients, 20 of whom were male, aged 30-77 years, had dermatitis for 1 month to 18 years, with relapses and remissions. Seasonal exacerbation was present in 18 patients. Six patients attributed aggravation of their dermatitis to pesticide exposure, and 2 of these reacted positively to propiconazole. Positive patch test reactions to pesticides occurred in 10 patients, but not in controls. Thiuram was the commonest sensitizer (4 patients). Three patients were sensitized to propiconazole, and 2 patients reacted positively to metaldehyde. Formaldehyde, mercaptobenzothiazole, cypermethrin and isoproturon gave positive reactions in 1 patient each. CONCLUSION: The sensitizing potential of pesticides remains a concern. Apparently, pesticide contact dermatitis is more common than expected, but remains under-reported, as the implicated pesticides vary across regions and according to the crop patterns. PMID- 29974481 TI - Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide. AB - WHAT IS KNOWN AND OBJECTIVES: Optimal strategies for treating patients with very advanced relapsed and refractory multiple myeloma (RRMM) have not been clarified. CASE SUMMARY: A 80-year-old patient with RRMM experienced extramedullary relapse following treatment with bortezomib, lenalidomide and pomalidomide. However, he achieved very good partial remission after retreatment with lenalidomide. WHAT IS NEW AND CONCLUSION: This report illustrates that patients with very advanced RRMM can still respond to prior therapy even after being exposed and refractory to several agents. Considering the depth or duration of response to prior treatment, "retreatment" may improve the outcome of frail RRMM. PMID- 29974482 TI - Frankenstein or a Submarine Alkaline Vent: Who is Responsible for Abiogenesis?: Part 2: As life is now, so it must have been in the beginning. AB - We argued in Part 1 of this series that because all living systems are extremely far-from-equilibrium dynamic confections of matter, they must necessarily be driven to that state by the conversion of chemically specific external disequilibria into specific internal disequilibria. Such conversions require task specific macromolecular engines. We here argue that the same is not only true of life at its emergence; it is the enabling cause of that emergence; although here the external driving disequilibria, and the conversion engines needed must have been abiotic. We argue further that the initial step in life's emergence can only create an extremely simple non-equilibrium "seed" from which all the complexity of life must then develop. We assert that this complexity develops incrementally and progressively, each step tested for value added "in flight." And we make the case that only the submarine alkaline hydrothermal vent (AHV) model has the potential to satisfy these requirements. PMID- 29974483 TI - Clinical performance of non-surgical periodontal therapy in a large Chinese population with generalized aggressive periodontitis. AB - AIM: This study aimed to evaluate clinical performance of non-surgical periodontal treatment (NSPT) and its influential factors in a large Chinese population with generalized aggressive periodontitis (GAgP). MATERIAL AND METHODS: Longitudinal periodontal examination data of 1,004 GAgP patients (numbers of patients with observation periods 6 weeks~, 3 months~, 6 months~, 1 year~, 3 years~ and >5 years were 203, 310, 193, 205, 70 and 23, respectively) were extracted from a hospital-based electronic periodontal charting record system and analysed by multilevel analysis. RESULTS: Mean probing depth (PD) and attachment loss (AL) reductions at patient level were 1.17 mm and 1.07 mm, respectively. Multilevel analysis demonstrated PD reductions after maintenance were mainly influenced by frequency of supportive periodontal treatment (FSPT), gender, adjunctive systemic use of antibiotics, baseline mobility, tooth type and baseline PD and bleeding index reductions were mainly influenced by FSPT, adjunctive systemic use of antibiotics, baseline AL, baseline mobility, tooth type and baseline PD. CONCLUSION: The clinical performance of NSPT on patients with GAgP was proved in the large Chinese population. Outcomes of NSPT were mainly influenced by FSPT, adjunctive systemic use of antibiotics, baseline mobility, tooth type and baseline PD. PMID- 29974484 TI - Periodontal disease and susceptibility to breast cancer: A meta-analysis of observational studies. AB - OBJECTIVE: While some individual studies have suggested an association between periodontal disease and breast cancer, there has not been a formal meta-analysis that collates the existing evidence supporting the hypothesis that periodontal disease leads to a higher risk of developing breast cancer. Accordingly, this meta-analysis was conducted. METHODS: Relevant studies published until April 2018 were retrieved and were screened according to established inclusion criteria. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated to assess the association between periodontal disease and the risk of breast cancer and fixed effect models were used according to the results of the heterogeneity test. RESULTS: Eight studies, involving 168,111 individuals, were identified as having explored the association between periodontal disease and breast cancer. Summary estimates in view of adjusted data showed that periodontal disease did increase susceptibility to breast cancer (RR = 1.18, 95%CI: 1.11-1.26, I2 = 17.6%), with robust results confirmed by sensitivity analysis. CONCLUSION: Our results provided evidence of a modest positive association between periodontal disease and breast cancer. Implementation of practical measures to prevent and treat periodontal disease is of great public health significance. Moreover, additional studies are recommended to explore this topic in more detail. PMID- 29974485 TI - Clinical, histological and high-frequency ultrasonographic evaluation (50 MHz) of morphoea treated with ultraviolet A1 phototherapy. AB - BACKGROUND: There are few studies in the literature correlating the ultrasonographic findings, clinical scoring systems or histological findings in morphoea after ultraviolet (UV)A1 phototherapy. AIMS: To evaluate the quantitative and morphological aspects of high-frequency ultrasonography in the treatment of plaque morphoea in response to UVA1 phototherapy, and to correlate these with clinical and histological scores. METHODS: In total, 17 patients with morphoea were studied. Initially and at study end, high-frequency ultrasonography (50 MHz) was performed on the edge of a morphoea lesion treated with UVA1 phototherapy. A quantitative and qualitative analysis of dermal features was performed and compared with the features of healthy skin. Skin biopsy specimens were obtained from lesions analysed at the beginning and end of the study, assessing dermal sclerosis and dermal inflammatory infiltrate and their distribution. RESULTS: All affected skin showed a statistically significant increase in dermal thickness and hypoechogenicity, corresponding to a reduction in dermal density by ultrasonography compared with healthy skin. Morphological evaluation identified undulations of the dermis in 11 of 17 lesions (64.7%) and in 5 healthy skin areas (29.4%) (P = 0.08), while 'yoyo' figures were identified in 8 lesions (47%) but only 1 healthy skin area (5.9%) (P = 0.02). Ultrasonographic morphological analysis highlighted an improvement in dermal hyperechogenic bands and disappearance of yoyo figures after UVA1 treatment. Histology revealed a reduction in dermal sclerosis and inflammation, although this was not statistically significant. CONCLUSIONS: Ultrasonographic pattern analysis of morphoea is a suitable technique for monitoring UVA1 phototherapy response. PMID- 29974486 TI - Transcription factor c-Maf is essential for IL-10 gene expression in B cells. AB - Interleukin (IL)-10 is an essential anti-inflammatory cytokine that plays important roles as a negative regulator of immune responses to microbial antigens. c-Maf has been suggested as an essential transcriptional factor for IL 10 production in CD4+ T cells and macrophages. However, it remains unclear whether c-Maf participates in IL-10 expression in B cells. In this study, we investigated the role of c-Maf in the transcriptional regulation of IL-10 in regulatory B cells, as well as the underlying molecular mechanism. We found that c-Maf was constitutively expressed in resting B cells. c-Maf expression was upregulated in the presence of LPS and dose-dependently enhanced IL-10 production following binding to the IL-10 promoter. Moreover, a lower expression of c-Maf and decreased production of regulatory B (Breg) cells were detected in mice with collagen-induced arthritis (CIA), which may contribute to the pathological changes. Taken together, these data demonstrate that c-Maf is an indispensable yet constitutive transcription factor for IL-10 gene expression in LPS-activated B cells. PMID- 29974487 TI - Identification and interaction analysis of key genes and microRNAs in atopic dermatitis by bioinformatics analysis. AB - BACKGROUND: Atopic dermatitis (AD) is a skin disease that carries a major health burden, but the exact mechanism of the disease is not yet known. AIM: To identify the key genes and micro (mi)RNAs in AD, and to explore their potential molecular mechanisms. METHODS: From the Gene Expression Omnibus (GEO) database, we downloaded microarray data for GSE32924 (mRNA profile) and GSE31408 (miRNA profile), which were analysed using GEO2R. Functional and pathway enrichment analyses were performed using the DAVID database, and the protein-protein interaction network was constructed with Cytoscape software. In addition, targets of differentially expressed miRNAs (DEMs) were predicted by the online resource miRDB. RESULTS: In total, 328 differentially expressed genes (DEGs) were identified, including 121 upregulated and 207 downregulated genes. Gene Ontology analyses showed that upregulated genes were significantly enriched in immune responses, while downregulated genes were mainly involved in epidermis development. In addition, we identified three DEMs, all of which were downregulated. Hsa-let-7a-5p may target CCR7, and hsa-miR-26a-5p probably targets HAS3. CONCLUSIONS: We identified lists of DEGs and DEMs in AD. Bioinformatics and interaction analysis may provide new clues for further studies of AD. PMID- 29974488 TI - Mycophenolic acid concentrations in peripheral blood mononuclear cells are associated with the incidence of rejection in renal transplant recipients. AB - AIMS: Although therapeutic drug monitoring of plasma mycophenolic acid (MPA) concentrations has been recommended to individualize dosage in transplant recipients, little is known regarding lymphocyte concentrations of MPA, where MPA inhibits inosine monophosphate dehydrogenase (IMPDH). This study investigated the utility of measuring predose MPA concentrations in peripheral blood mononuclear cells (C0C ) and predose IMPDH activity, as predictors of graft rejection in renal transplant recipients. METHODS: Forty-eight patients commencing mycophenolate mofetil (1 g twice daily) in combination with tacrolimus and prednisolone were recruited. Blood was collected for determination of trough total (C0P ) and unbound (C0u ) plasma MPA concentrations. Peripheral blood mononuclear cells were isolated for determination of C0C and IMPDH activity. The incidence of rejection within 2 days of sample collection was determined histologically and classified according to the Banff 2007 criteria. RESULTS: There was no association between MPA C0C and C0P (rs = 0.28, P = 0.06), however, MPA C0C were weakly correlated with MPA C0u (rs = 0.42, P = 0.013). Multivariate analysis indicated that MPA C0C was the only covariate independently associated with rejection (FDR-adjusted P = 0.033). The receiver operating characteristic area under the curve (AUC) for the prediction of severe rejection using MPA C0C was 0.75 (P = 0.013), with 73% sensitivity and specificity at a C0C threshold of 0.5 ng 10-7 cells. However, predose IMPDH activity was not a predictor of rejection (P > 0.15). CONCLUSIONS: MPA C0C measurement within the early post transplant period may be useful to facilitate early titration of MPA dosing to significantly reduce rejection. PMID- 29974490 TI - Cross-cultural differences in types and beliefs about treatment in women with temporomandibular disorder pain. AB - OBJECTIVES: Women with temporomandibular disorder (TMD) pain from three cultures were assessed for type of treatment received and core illness beliefs. METHODS: In a clinical setting, 122 women patients with chronic TMD pain (39 Saudis, 41 Swedes and 42 Italians) were evaluated for patient characteristics, type of practitioner, type of treatment received and beliefs about TMD prior to consultation in TMD specialist centres. Measures included a survey of treatments received and a belief scale regarding contributing, aggravating and treatment relevant factors related to the pain. All questionnaires were translated from English and culturally adapted. Comparisons among cultural groups were performed using a linear regression model for continuous variables and logistic regression model for dichotomous variables. A P-value < 0.05 was considered statistically significant. RESULTS: The study found no significant associations between cultures and the type of practitioners consulted previously. Treatments differed among cultures: Swedes most commonly received behavioural therapy, acupuncture and an occlusal appliance; Saudis most commonly received Islamic medicine; and Italians most commonly received an antidepressant. Swedes were significantly more likely than Saudis and Italians to believe that TMD pain treatment should address behavioural factors. CONCLUSIONS: Among Saudi, Italian and Swedish women with chronic TMD pain, culture does not influence the type of practitioner consulted before visiting a TMD specialist or their beliefs about contributing and aggravating factors for their pain. However, treatment types and beliefs concerning mechanisms underlying the pain differed cross-culturally, with local availability or larger cultural beliefs also probably influencing the types of treatments that TMD patients pursue. PMID- 29974489 TI - Drugs for treating severe hypertension in pregnancy: a network meta-analysis and trial sequential analysis of randomized clinical trials. AB - AIMS: Several antihypertensive drugs are used in the treatment of severe hypertension in pregnancy. The present study is a network meta-analysis comparing the efficacy and safety of these drugs. METHODS: Electronic databases were searched for randomized clinical trials comparing drugs used in the treatment of severe hypertension in pregnancy. The number of women achieving the target blood pressure (BP) was the primary outcome. Doses required and time taken for achieving the target BP, failure rate, and incidences of maternal tachycardia, palpitation, hypotension, headache, and neonatal death and stillbirth were the secondary outcomes. Mixed treatment comparison pooled estimates were generated using a random-effects model. Odds ratios for the categorical and mean difference for the numerical outcomes were the effect estimates. RESULTS: Fifty-one studies were included in the systematic review and 46 in the meta-analysis. No significant differences in the number of patients achieving target BP was observed between any of the drugs. Diazoxide [-15 (-20.6, -9.4)], nicardipine [ 11.8 (-22.3, -1.2)], nifedipine/celastrol [-19.3 (-27.4, -11.1)], nifedipine/vitamin D [-17.1 (-25.7, -9.7)], nifedipine/resveratrol [-13.9 (-22.6, -5.2)] and glyceryl trinitrate [-33.8 (-36.7, -31)] were observed to achieve the target BP (in minutes) more rapidly than hydralazine. Nifedipine required fewer doses than hydralazine for achieving the target BP. Glyceryl trinitrate and labetalol were associated with fewer incidences of tachycardia and palpitation respectively than hydralazine. Trial sequential analysis concluded adequate evidence for hydralazine and nifedipine compared with labetalol. Moderate quality of evidence was observed for direct comparison estimate between labetalol and hydralazine but was either low or very low for other comparisons. CONCLUSION: The present evidence suggests similar efficacy between nifedipine, hydralazine and labetalol in the treatment of severe hypertension in pregnancy. Subtle differences may exist in their safety profile. The evidence is inadequate for other drugs. PMID- 29974491 TI - Reducing uncertainty in estimating associations of oral exposures with Helicobacter pylori serology in the general population. AB - AIM: Evidence for reducing Helicobacter (H.) pylori by periodontal therapy comes from small studies in China, limiting generalizability. To estimate the association between periodontal disease and anti-H. pylori IgG titer levels in a European country, we used population-based data from the Study of Health in Pomerania. MATERIALS AND METHODS: For pocket depth as the primary exposure, we restricted the age range to participants younger than 60 years (n = 2,481) to avoid selection bias due to edentulism in this cross-sectional study. For the full age range up to 81 years, we chose the number of missing teeth (n = 3,705). RESULTS: The association between pocket depth and the outcome was weak. Given the ceiling effect for the number of missing teeth (ordinal logistic regression; odds ratio of the interquartile range effect = 1.6; 95% CI: 1.3-1.9; p-value for linearity = 0.005), we checked whether wearing removable dental prosthesis was associated with higher anti-H. pylori IgG titer levels (odds ratio = 1.3; 95% CI: 1.1-1.5). CONCLUSIONS: Tooth loss and wearing removable dental prosthesis were weakly to moderately associated with higher anti-H. pylori IgG titer levels in the general population of a European country. PMID- 29974492 TI - The global-local tension in medical education: turning 'think global, act local' on its head? AB - CONTEXT: Medical education has not been immune from forces for globalisation in the contemporary world. At the same time the social accountability of medical schools in addressing local health priorities has been emphasised. This paper explores the global-local tension in medical education through a careful selection of key overview papers. GLOBALISATION: Globalisation in medical education has taken two main forms: economic and altruistic. The former includes licensing curricula, recruiting internationally and establishing 'offshore' schools or campuses. Altruistic collaborations focus on the spread of learning and educational innovations. Both forms bring benefits but have been subject to critique for their differential impact and focus on educational inputs rather than outputs. SOCIAL ACCOUNTABILITY: Social accountability requires medical schools to direct their activities to local priorities and to serving local health systems. Adoption of the principles of social accountability compels all medical schools to ask questions of their educational programmes and graduate outcomes. However, these are globally interdependent questions and are the intent of some well-known social accountability collaborations. It is naive to think that adoption of a social accountability agenda by all medical schools would necessarily reduce global health inequity. A recent Australian example shows that workforce maldistribution, for example, is resistant to even high-level intervention. CONCLUSIONS: It is yet too early to fully accept that 'think global, act local can be turned on its head'. There is much research to be carried out, particularly on the outcomes and impacts of medical education. Establishing cause and effect is a challenge, as is determining whether globalisation or localisation can contribute to greater global health equity. If we are ever to resolve the global-local tension in medical education, we need more evidence on the outcomes of what we do, whether globally or locally inspired. PMID- 29974493 TI - The incremental predictive value of frailty measures in elderly patients undergoing cardiac surgery: A systematic review. AB - Emerging evidence demonstrates that frailty measures can predict adverse outcomes after cardiac procedures. Our objectives were to examine whether the inclusion of frailty measures adds incremental predictive value to existing surgical risk prediction models in patients undergoing cardiac surgery and to evaluate the reporting and methods of studies that investigated the prediction of frailty measures in cardiology. The inclusion of frailty measures adds incremental predictive value on existing perioperative risk-scoring systems. We systematically searched the EMBASE, MEDLINE, and Web of Science databases for relevant studies. Studies were included according to predefined inclusion criteria. The quality of included studies was appraised using the QUADAS-2 tool. Data were extracted and synthesized according to predefined methods. Twelve studies were included in the analysis. Included studies demonstrated the incremental predictive value of frailty measures on existing surgical risk models for mortality, but the predictive value of frailty measures alone was not consistent across literature. Few studies that investigated the predictive ability of frailty measures reported all important model performance measures. When comparing the predictive value of frailty measures with existing models, few studies reported if the frailty measurement was separately performed from the existing perioperative risk assessment. The addition of frailty measures to the existing perioperative risk models improved the prediction performance for mortality, but the incorporation of frailty assessment into perioperative risk assessment requires further evidence before making health policy recommendations. PMID- 29974494 TI - Study design with staggered sampling times for evaluating sustained unresponsiveness to peanut sublingual immunotherapy. AB - In this work, we delineate an altered study design of a pre-existing clinical trial that is currently being implemented in the Department of Pediatrics at the University of North Carolina at Chapel Hill. The purpose of the ongoing investigation of the desensitized pediatric cohort is to address the effectiveness of sublingual immunotherapy in achieving sustained unresponsiveness (SU) as assessed by repeated double-blind placebo-controlled food challenges (DBPCFC). With scarce published literature characterizing SU, the length of time off-therapy that would represent clinically meaningful benefit remains undefined. We use the new design features to assess time to loss of SU, an important efficacy endpoint, that to our knowledge, no prior study has investigated. Our work has two-fold objectives: first is to propose and discuss aspects of the altered design that would allow us to study SU and second is to explore methodology to evaluate the time to loss of SU and its association with risk factors in the context of the data originating from the trial. The salient feature of the new design is the allocation scheme of study subjects to staggered sampling timepoints when a subsequent DBPCFC is administered. Due to this feature, the time to loss of SU is either left or right censored. Additionally, some participants at study entry fail the DBPCFC, leading to what can be construed as an instantaneous failure. Through in-depth numerical studies, we examine the performance and power of a recently proposed mixture proportional hazards model specifically designed for the analysis of interval-censored data subject to instantaneous failures. PMID- 29974495 TI - Bayesian inference under cluster sampling with probability proportional to size. AB - Cluster sampling is common in survey practice, and the corresponding inference has been predominantly design based. We develop a Bayesian framework for cluster sampling and account for the design effect in the outcome modeling. We consider a two-stage cluster sampling design where the clusters are first selected with probability proportional to cluster size, and then units are randomly sampled inside selected clusters. Challenges arise when the sizes of the nonsampled cluster are unknown. We propose nonparametric and parametric Bayesian approaches for predicting the unknown cluster sizes, with this inference performed simultaneously with the model for survey outcome, with computation performed in the open-source Bayesian inference engine Stan. Simulation studies show that the integrated Bayesian approach outperforms classical methods with efficiency gains, especially under informative cluster sampling design with small number of selected clusters. We apply the method to the Fragile Families and Child Wellbeing study as an illustration of inference for complex health surveys. PMID- 29974496 TI - Management of respiratory complications in a western lowland gorilla (Gorilla gorilla gorilla) born by cesarean section. AB - A female western lowland gorilla (Gorilla gorilla gorilla) infant was delivered by cesarean section (C-section) to an 18-year-old primiparous dam after prolonged labor. The infant required resuscitation at birth and was hospitalized for management of pneumonia and associated respiratory distress secondary to the aspiration of meconium-stained amniotic fluid. The infant received nine days of intensive care with respiratory support, antibiotics, intravenous fluid therapy, anti-inflammatory drugs, bronchodilators, and chest physiotherapy. Respiratory support included nasal continuous positive airway pressure (CPAP), and supplemental oxygen. Complications included right lung atelectasis secondary to bronchial obstruction and pneumonia. Following the resolution of pneumonia, visual reintroductions with the troop were initiated. The dam was given a medical lactation supplement (metoclopramide) and her mammary glands were stimulated to increase milk production. After several days of visual and olfactory introductions, the infant was successfully physically reintroduced to her dam at 12 days of age; the dam showed appropriate maternal response and nursing of the infant. The infant had appropriate growth and development, and 4 years later, has no evidence of negative side effects of neonatal respiratory disease. This is the first reported case of management of neonatal gorilla respiratory disease associated with a C-section, with successful reintroduction to the family group after hospitalization. PMID- 29974497 TI - Germline BRCA1-associated protein 1 mutation presenting as BAP1 inactivated melanocytic nevi in a child of a father with fatal paraganglioma. AB - BRCA1-associated protein 1(BAP1) inactivated melanocytic nevi are pink to tan and dome-shaped in clinical appearance, resembling dermal nevi, but with distinct histologic features of two melanocytic subpopulations: larger atypical melanocytes and nests of smaller, blander nevoid melanocytes. Pedigrees with BAP1 mutations are at greater risk of various malignancies. We report the case of a 16 year-old boy with multiple benign-appearing nevi, all demonstrating loss of BAP1 on immunohistochemistry. History revealed that his father had died of paraganglioma, which is also associated with BAP1 mutations. PMID- 29974498 TI - Automation, machine learning, and artificial intelligence in echocardiography: A brave new world. AB - Automation, machine learning, and artificial intelligence (AI) are changing the landscape of echocardiography providing complimentary tools to physicians to enhance patient care. Multiple vendor software programs have incorporated automation to improve accuracy and efficiency of manual tracings. Automation with longitudinal strain and 3D echocardiography has shown great accuracy and reproducibility allowing the incorporation of these techniques into daily workflow. This will give further experience to nonexpert readers and allow the integration of these essential tools into more echocardiography laboratories. The potential for machine learning in cardiovascular imaging is still being discovered as algorithms are being created, with training on large data sets beyond what traditional statistical reasoning can handle. Deep learning when applied to large image repositories will recognize complex relationships and patterns integrating all properties of the image, which will unlock further connections about the natural history and prognosis of cardiac disease states. The purpose of this review article was to describe the role and current use of automation, machine learning, and AI in echocardiography and discuss potential limitations and challenges of in the future. PMID- 29974499 TI - Correction of complete thoracic duct obstruction with lymphovenous bypass: A case report. AB - Thoracic duct injury can be a devastating injury with disruption of lymphatic flow leading to potentially chylothorax and/or severe lymphedema. Standard treatment modalities include thoracic duct ligation or embolization for chylothorax, but treatment options to date are few for resultant lymphedema. In this case report, we describe lymphaticovenous bypass of the thoracic duct to the jugular venous system in a 21-year-old male with secondary lymphedema after iatrogenic thoracic duct injury. The patient experienced improvement of lymphedema symptoms including decreased weight and limb girth as well as normalization of serum markers indicating improved lymphatic delivery to the venous system. Lymphangiogram at 3 months post op demonstrated patency of the lymphaticovenous anastomoses. At 6-month follow-up, the patient had returned to his preoperative level of activity and showed continued improvement of his lymphedema symptoms. Lymphovenous bypass of the thoracic duct may be an effective technique to treat secondary lymphedema from thoracic duct obstruction, though further studies are required to determine long-term efficacy. PMID- 29974500 TI - Combined use of external therapeutic ultrasound and tirofiban has synergistic therapeutic effects on no-reflow after myocardial reperfusion. AB - OBJECTIVE: This study aimed to evaluate the effects of the combined use of external therapeutic ultrasound (ETUS) and the specific glycoprotein IIb/IIIa inhibitor tirofiban on myocardial no-reflow in a canine model of acute myocardial infarction after reperfusion. METHODS: The canine myocardial no-reflow model was established by a 3-hour occlusion of the left anterior desecending coronary artery followed by a 2-hour reperfusion. Twenty-four canines were divided into four groups (6/group): (1) control, (2) tirofiban alone, (3) ETUS combined with tirofiban (ETUS + tirofiban), and (4) ETUS alone. RESULTS: The area of no-reflow in each of the three treatment groups was significantly decreased, compared with the control group, with the ETUS + tirofiban group having the smallest area. Also, the ETUS + tirofiban group had the highest recanalized rate of microvessels in the no-reflow area and fewer impaired cellular organelles. The recovery rates of the endocardial and middle circumferential strain as well as longitudinal strain in the ETUS + tirofiban group were significantly greater than those of the tirofiban group. Moreover, the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) was significantly increased in the ETUS + tirofiban group, compared with the other groups. CONCLUSIONS: The combined use of ETUS and tirofiban offers synergistic benefits for the treatment of myocardial no-reflow. PMID- 29974501 TI - Management of afebrile neonates with pustules and vesicles in a pediatric emergency department. AB - OBJECTIVES: To assess the management and outcomes of vesicles and pustules in afebrile neonates presenting to the pediatric emergency department. METHODS: Using International Classification of Diseases, Ninth Revision, codes, we identified patients 0-60 days old presenting to our pediatric emergency department from 2008 to 2015 with a possible diagnosis of pustules or vesicles. We then used natural language processing followed by manual chart review to identify afebrile neonates with pustules or vesicles. We collected clinical data from the electronic medical record. We also assessed current practice patterns for neonatal pustules or vesicles using a survey administered to attending physicians. RESULTS: Of the 971 possible cases identified using International Classification of Diseases, Ninth Revision, codes for fluid-filled lesions, only 64 patients had vesicles (n = 9) and pustules (n = 55). One-third (22/64) of afebrile neonates with pustules and vesicles were admitted to the hospital and received empiric parenteral therapy. Admission, parenteral antibiotics, and antiviral therapy were more common in neonates presenting with vesicles than in those with pustules alone. Apart from 2 presumed blood culture contaminants, there were no positive blood or cerebrospinal fluid cultures. Two patients had positive urine cultures. Institutional survey data showed practice patterns consistent with these retrospective results. CONCLUSION: Although one-third of neonates with pustules and vesicles were admitted to the hospital and received parenteral therapy, there were no cerebrospinal fluid or blood infections or any confirmed evidence of herpes simplex virus disease. These findings suggest that afebrile, well-appearing neonates presenting with pustules alone may not need a full serious bacterial infection examination. Larger studies are needed to confirm these findings and assess outcomes, especially in afebrile neonates with vesicles. PMID- 29974502 TI - Reply to comment on: Ileocecal vascularized lymph node transfer for the treatment of extremity lymphedema: A case report. PMID- 29974503 TI - The calculation and comparison of the Detrusor Contractility Parameter and Watts Factor. AB - AIMS: To test the significance of association between a validated index of detrusor contractility, vCE , the Watts Factor, and the Detrusor Contractility Parameter, t20-80 ; and to test whether t20-80 depends on outflow tract resistance as indicated by Bladder Outlet Obstruction Index (BOOI). METHODS: Thirty-seven pressure-flow traces from 20 male and 17 female patients were analyzed and forms of the Watts Factor, t20-80 and BOOI were compared with vCE . RESULTS: The Detrusor Contractility Parameter, t20-80 , is significantly associated with vCE for both women and men without a high degree of bladder outlet obstruction. The Watts Factor only had a significant association with vCE at the point of maximum flow in women. CONCLUSIONS: The Detrusor Contractility Parameter (DCP) (t20-80 ), can be measured easily from the pressure flow curves of a urodynamic test. The Watts Factor at maximum urine flow, WFQmax , can be readily calculated, but is only applicable to women. In both women and men without a high degree of bladder outlet obstruction, DCP is better associated with true detrusor contractility than any Watts Factor analysis. PMID- 29974504 TI - Afebrile neonates with pustules should not be managed as febrile infants. PMID- 29974506 TI - Coronary risk assessment using traditional risk factors with CT coronary artery calcium scoring in clinical practice. AB - As coronary artery calcium (CAC) is atherosclerosis and not just a marker of cardiovascular (CV) disease, measurement of a patient's coronary artery calcium score (CACS) is a strong predictor of risk. Clinically performed in asymptomatic patients, the CACS, along with several CV risk factors, namely age, sex, ethnicity, diabetes, tobacco use, family history, cholesterol level, blood pressure, and use of cholesterol or hypertensive medications, provide a predictive model of 10 year risk for CV events. A smartphone "App" makes this quick to obtain and use. This helps the clinician in making recommendations for both lifestyle changes and statin therapy. Those patients in which the most benefit occur from measurement of a CACS are those at an intermediate CV risk. Measurement of the CACS has become an integral part of the clinician's assessment of a patient's CV risk and for guiding preventative therapies. PMID- 29974505 TI - Clinical algorithm to manage anemia in epidermolysis bullosa. AB - Epidermolysis bullosa is a group of rare genetic disorders with multiple organ system involvement. In one severe form, recessive dystrophic epidermolysis bullosa, chronic anemia is common. This report outlines the multifactorial nature of anemia in recessive dystrophic epidermolysis bullosa and presents a practical clinical algorithm based on expert consensus for the diagnosis and treatment of anemia in recessive dystrophic epidermolysis bullosa. PMID- 29974507 TI - Children's Understanding of the Natural Numbers' Structure. AB - When young children attempt to locate numbers along a number line, they show logarithmic (or other compressive) placement. For example, the distance between "5" and "10" is larger than the distance between "75" and "80." This has often been explained by assuming that children have a logarithmically scaled mental representation of number (e.g., Berteletti, Lucangeli, Piazza, Dehaene, & Zorzi, ; Siegler & Opfer, ). However, several investigators have questioned this argument (e.g., Barth & Paladino, ; Cantlon, Cordes, Libertus, & Brannon, ; Cohen & Blanc-Goldhammer, ). We show here that children prefer linear number lines over logarithmic lines when they do not have to deal with the meanings of individual numerals (i.e., number symbols, such as "5" or "80"). In Experiments 1 and 2, when 5- and 6-year-olds choose between number lines in a forced-choice task, they prefer linear to logarithmic and exponential displays. However, this preference does not persist when Experiment 3 presents the same lines without reference to numbers, and children simply choose which line they like best. In Experiments 4 and 5, children position beads on a number line to indicate how the integers 1 100 are arranged. The bead placement of 4- and 5-year-olds is better fit by a linear than by a logarithmic model. We argue that previous results from the number-line task may depend on strategies specific to the task. PMID- 29974508 TI - Meta-analysis of the impact of successful chronic total occlusion percutaneous coronary intervention on left ventricular systolic function and reverse remodeling. AB - BACKGROUND: We sought to examine the impact of coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on left ventricular (LV) function. METHODS: We performed a systematic review and meta-analysis of studies published between January 1980 and November 2017 on the impact of successful CTO PCI on LV function. RESULTS: A total of 34 observational studies including 2735 patients were included in the meta-analysis. Over a weighted mean follow-up of 7.9 months, successful CTO PCI was associated with an increase in LV ejection fraction by 3.8% (95%CI 3.0-4.7, P < 0.0001, I2 = 45%). In secondary analysis of 15 studies (1248 patients) that defined CTOs as occlusions of at least 3-month duration and reported follow-up of at least 3-months after the procedure, successful CTO PCI was associated with improvement in LV ejection fraction by 4.3% (95%CI [3.1, 5.6], P < 0.0001). In the 10 studies (502 patients) that reported LV end-systolic volume, successful CTO PCI was associated with a decrease in LV end-systolic volume by 4 mL, (95%CI -6.0 to -2.1, P < 0.0001, I2 = 0%). LV end-diastolic volume was reported in 9 studies with 403 patients and did not significantly change after successful CTO PCI (-2.3 mL, 95%CI -5.7 to 1.2 mL, P = 0.19, I2 = 0%). CONCLUSIONS: Successful CTO PCI is associated with a statistically significant improvement in LV ejection fraction and decrease in LV end-systolic volume, that may reflect a beneficial effect of CTO recanalization on LV remodeling. The clinical implications of these findings warrant further investigation. PMID- 29974510 TI - What if there were no tapes? AB - It is possible that the controversy involving prostheses implanted into women with pelvic floor problems might result in the majority of, or even all such products being restricted, banned or withdrawn in certain jurisdictions. A clear distinction between "tapes" for urinary incontinence and "mesh" for prolapse has been made in the enquiries and subsequent rulings in Australia and New Zealand. Transvaginal "mesh" will be unavailable with the range of "tapes" much more restricted in those countries from January 2018. The Chair of the all-party parliamentary group on surgical mesh implants in the United Kingdom was reported as describing the New Zealand announcement as "hugely significant" and "it's precisely what we've been calling for the UK." The title of this article has changed from a hypothetical piece to a potential reality review. Where does that leave the clinicians treating stress urinary incontinence (SUI) and the large number of female sufferers? "Tapes" (synthetic midurethral slings-MUS) have become very popular over the last 20 years since their original development and introduction in Scandanavia. Evidence-based medicine has shown their advantages over previous surgeries, in terms of ease of use, safety and efficacy. This article outlines the options which countries potentially rejecting the use of tapes, must now resort to for women with SUI. Those countries considering such action need the note of caution that none of the options are as good as tapes. PMID- 29974509 TI - Mesenchymal stem cells enhance autophagy of human intrahepatic biliary epithelial cells in vitro. AB - : Dysfunctional autophagy in intrahepatic biliary epithelial cells (IBECs) is the main mechanism underlying the pathogenesis of bile duct lesions in primary biliary cholangitis. Autophagy may be a key pathogenesis for aetiology of primary biliary cholangitis. Immunoblotting and immunofluorescence analyses were used for the evaluation of autophagy in human intrahepatic biliary epithelial cells (HiBECs) at various time points. Glycochenodeoxycholate (GCDC) induced autophagy in HiBECs; the ratio of microtubule-associated protein light chain 3 II/microtubule-associated protein light chain 3-I (LC3-II/LC3-I) expression markedly increased at 48 hours, and then declined. However, compared with cells treated with GCDC alone, the expression of LC3-II increased and the clearance of autophagosome enhanced in GCDC-treated cells cocultured with mesenchymal stem cells (MSCs). Furthermore, the level of phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) decreased in HiBECs cocultured with MSCs relative to those cultured without MSCs. Following STAT3 silencing, decreased expression of phosphorylated eukaryotic initiation factor 2alpha was consistently observed. The present data suggest that mesenchymal stem cells may enhance autophagic flux of HiBECs through the inhibition of STAT3 activity. SIGNIFICANCE PARAGRAPH: The present findings constitute the first report that human umbilical cord-derived MSCs enhance autophagic flux in HiBECs through a STAT3-dependent way: MSCs enhance the autophagic flux by increasing the formation of autophagosome and autolysosome in GCDC-treated HiBECs. MSCs decrease the STAT3 activity and the expression of eIF2alpha in GCDC-treated HiBECs; in addition, MSCs increase the expression of PKR. With STAT3 silencing, MSCs enhance neither the levels of LC3II nor the expression of PKR in GCDC-treated HiBECs. PMID- 29974511 TI - Pelvic floor dysfunction in women with fibromyalgia and control subjects: Prevalence and impact on overall symptomatology and psychosocial function. AB - AIMS: To evaluate the prevalence, distress, and impact of pelvic floor dysfunction (PFD) symptomatology in women with fibromyalgia and control women. We also aimed to evaluate the impact of PFD symptomatology on several psychosocial measures such as mood, sleep, pain, and quality of life. METHODS: We conducted a cross-sectional study in women with fibromyalgia and control women from the general population. Using a structured survey, we collected sociodemographic and clinical data, assessed the prevalence of PFD and evaluated the distress (PFDI 20) and the impact (PFIQ-7) caused by its symptomatology. Using Spanish-validated questionnaires, we also evaluated mood and sleep disturbances, bodily pain, and quality of life in subjects with and without PFD. In participants with fibromyalgia, we assessed the severity and impact of the disease using the Fibromyalgia Impact Questionnaire (FIQR). RESULTS: Two hundred and twenty-six patients with fibromyalgia and 222 control women completed the surveys. Two hundred and twenty patients (93%) and 140 controls (63%) reported PFD-related symptoms. Both the scores of distress (143.1 +/- 5.7 vs 96.1 +/- 4.8, P < 0.0001) and impact (122.4 +/- 5.6 vs 100.6 +/- 6.4, P < 0.0001) caused by PFD symptoms were significantly higher in women with fibromyalgia than in controls. There was a significant positive relationship between fibromyalgia severity and both PFDI 20 (r2 = 0.32, P < 0.0001) and PFIQ-7 scores (r2 = 0.375, P < 0.0001). Depression severity, sleep disturbances, bodily pain, and low quality of life were highest in women with fibromyalgia and PFD and lowest in control women without PFD. CONCLUSIONS: PFD-related symptoms were significantly more frequent in women with fibromyalgia than in controls. PFD symptomatology, when present, negatively influenced mood, sleep quality, and quality of life of both patients with fibromyalgia and controls. PMID- 29974512 TI - Posterior vaginal compartment repairs: Does vaginal vault (level I) fixation significantly improve the vaginal introital (level III) repair? AB - INTRODUCTION: Limited data exist associating vaginal vault and introital defects before and after posterior repairs (PR). We hypothesize: (i) a positive association between the size of vaginal vault and introital defects preoperatively; and (ii) a positive association between the reduction of these defects postoperatively if vault fixation (sacrospinous colpopexy-SSC) is used with the PR. METHODS: In a cross-sectional study of 300 consecutive PRs, the following were measured pre- and immediately postoperatively: (i) from POP-Q: genital hiatus (GH-Level III); (ii) from PR-Q: perineal gap (PG-Level III), posterior vaginal vault descent (PVVD-Level I). The data for introital defects (GH, PG) were separated according to the need for vault fixation using a SSC due to a larger vaginal defect (PVVD over 5 cm). RESULTS: Mean (SD) preoperative GH and PG were both significantly larger in the SSC versus no SSC group: GH (3.73 [0.94] vs 3.36 [0.83] cm, P = 0.01); PG (2.91 [1.0] vs 2.61 [0.91] cm, P = 0.05). SSC performed with the PR (84%); not performed (16%) cases. The mean (SD) postoperative reduction in GH (antero-posterior) was significantly (29%-P = 0.002) greater-1.1 (0.69) cm (29.5%) in the SSC group and 0.77 (0.49) cm (22.9%) in the no SSC group. The decrease in the PG (transverse) was greater by 11% (0.05). CONCLUSIONS: Levels I and III defects are associated with PRs; preoperatively larger vaginal vault (PVVD over 5 cm) and larger introital defects (GH, PG). Postoperatively, vault fixation resulted in significantly greater reduction in the introital defects. SUMMARY: Vaginal vault fixation (SSC) significantly improves the vaginal introital repair. PMID- 29974513 TI - Inflammatory linear verrucous epidermal nevus associated with erosive monoarthritis. AB - Inflammatory linear verrucous epidermal nevus and linear psoriasis are different entities with clinical and histopathologic similarities. Isolated reports of inflammatory linear verrucous epidermal nevus with concomitant psoriasis or a positive family history of psoriasis have been described, and the possibility that inflammatory linear verrucous epidermal nevus may be a mosaic form of cutaneous psoriasis has been postulated. We report a 17-year-old boy with a congenital, linear, erythematous, keratotic plaque on the dorsum of the fifth finger of the left hand with ipsilateral nail dystrophy. Histopathologic examination showed epidermal hyperplasia with alternating orthokeratosis and parakeratosis. During follow-up, he developed erosive monoarthritis of the distal interphalangeal joint. This case seems to confirm the association between inflammatory linear verrucous epidermal nevus and arthritis and supports a possible relationship between inflammatory linear verrucous epidermal nevus and psoriasis. PMID- 29974514 TI - Bullying in Australian children and adolescents with food allergies. AB - BACKGROUND: Food allergy is an increasing concern worldwide. The significant impact of food allergies on quality of life and bullying has been well described in international studies. No studies have yet investigated the occurrence of bullying in children and adolescents with food allergies in the Australian population. This study aimed to characterize and examine the frequency of bullying and describe those most responsible and the effects of the bullying on the victims. METHODS: Questionnaires were developed based on those used in previous studies and were distributed throughout paediatric allergy clinics. Children and adolescents aged 10-19 with food allergies were recruited to complete the questionnaire independently, whilst parents completed the questionnaire on behalf of their children aged 5-9 with food allergies. The data were tabulated and analysed using descriptive statistics. RESULTS: Ninety-three questionnaires were completed. Overall, 39 (42%) children experienced some form of bullying. This was higher in the older children and adolescent group, where 53% (18/34) were bullied. In addition, 23% (21/93) of the cohort were bullied or teased specifically because of their allergy. Food allergens had been used in the bullying in 24 cases, but no child reported being forced to eat foods to which they were allergic. Two adolescents experienced allergic reactions. CONCLUSIONS: This study highlights that those with food allergy are subject to a high degree of bullying. This risk of bullying for children with food allergy indicates a significant social problem that requires addressing to positively assist these children. PMID- 29974515 TI - Lysophosphatidylcholine-induced cytotoxicity and protection by heparin in mouse brain bEND.3 endothelial cells. AB - A pathological feature in atherosclerosis is the dysfunction and death of vascular endothelial cells (EC). Oxidized low-density lipoprotein (LDL), known to accumulate in the atherosclerotic arterial walls, impairs endothelium-dependent relaxation and causes EC apoptosis. A major bioactive ingredient of the oxidized LDL is lysophosphatidylcholine (LPC), which at higher concentrations causes apoptosis and necrosis in various EC. There is hitherto no report on LPC-induced cytotoxicity in brain EC. In this work, we found that LPC caused cytosolic Ca2+ overload, mitochondrial membrane potential decrease, p38 activation, caspase 3 activation and eventually apoptotic death in mouse cerebral bEND.3 EC. In contrast to reported reactive oxygen species (ROS) generation by LPC in other EC, LPC did not trigger ROS formation in bEND.3 cells. Pharmacological inhibition of p38 alleviated LPC-inflicted cell death. We examined whether heparin could be cytoprotective: although it could not suppress LPC-triggered Ca2+ signal, p38 activation and mitochondrial membrane potential drop, it did suppress LPC-induced caspase 3 activation and alleviate LPC-inflicted cytotoxicity. Our data suggest LPC apoptotic death mechanisms in bEND.3 might involve mitochondrial membrane potential decrease and p38 activation. Heparin is protective against LPC cytotoxicity and might intervene steps between mitochondrial membrane potential drop/p38 activation and caspase 3 activation. PMID- 29974516 TI - Assessing sensitivities of marine areas to stressors based on biological traits. AB - Analysis of the biological traits (e.g., feeding mode and size) that control how organisms interact with their environment has been used to identify environmental drivers of, or impacts on, species and to explain the importance of biodiversity loss. Biological trait analysis (BTA) could also be used within risk-assessment frameworks or in conservation planning if one understands the groups of traits that predict the sensitivity of habitats or communities to specific human activities. Deriving sensitivities from BTA should extend sensitivity predictions to a variety of habitats, especially those in which it would be difficult to conduct experiments (e.g., due to depth or risk to human life) and to scales beyond the norm of most experiments. We used data on epibenthos, collected via video along transects at 27 sites in a relatively pristine region of the seafloor, to determine scales of natural spatial variability of derived sensitivities and the degree to which predictions of sensitivity differed among 3 stressors (extraction of species, sedimentation, and suspended sediments) or were affected by underlying community compositions. We used 3 metrics (weighted abundance, abundance of highly sensitive species, and number of highly sensitive species) to derive sensitivity to these stressors and simulated the ability of these metrics to detect a range of stressor intensities. Regardless of spatial patterns of sensitivities across the sampled area, BTA distinguished differences in sensitivity to different stressors. The BTA also successfully separated differences in community composition from differences in sensitivity to stressors. Conversely, the 3 metrics differed widely in their ability to detect simulated impacts and likely reflect underlying ecological processes, suggesting that use of multiple metrics would be informative for spatial planning and allocating conservation priorities. Our results suggest BTA could be used as a first step in strategic prioritization of protected areas and as an underlying layer for spatial planning. PMID- 29974517 TI - Comparison of whole-blood tacrolimus concentrations measured by different immunoassay systems. AB - INTRODUCTION: Different measured values for tacrolimus were obtained with different automated immunoassays. We aimed to examine the differences in the blood tacrolimus concentrations measured by the major immunoassay systems commercially available in Japan. METHODS: Whole-blood samples from 118 patients were assayed by 3 commercial assays: chemiluminescent enzyme immunoassay (CLIA), affinity column-mediated immunoassay (ACMIA), and enzyme-multiplied immunoassay technique (EMIT). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for reference. KEY FINDINGS: The correlation coefficient of immunoassay vs LC-MS/MS was excellent for ACMIA (.83) and CLIA (.81) and good for EMIT (.71). The mean error was negative for ACMIA and positive for CLIA and EMIT. The mean absolute error and root-mean-square error were almost the same for ACMIA and CLIA and lower than those for EMIT. CONCLUSIONS: The ACMIA and CLIA yield considerably better results than the EMIT for monitoring blood tacrolimus concentrations. PMID- 29974518 TI - Silver Atomic Quantum Clusters of Three Atoms for Cancer Therapy: Targeting Chromatin Compaction to Increase the Therapeutic Index of Chemotherapy. AB - Nanomaterials with very low atomicity deserve consideration as potential pharmacological agents owing to their very small size and to their properties that can be precisely tuned with minor modifications to their size. Here, it is shown that silver clusters of three atoms (Ag3 -AQCs)-developed by an ad hoc method-augment chromatin accessibility. This effect only occurs during DNA replication. Coadministration of Ag3 -AQCs increases the cytotoxic effect of DNA acting drugs on human lung carcinoma cells. In mice with orthotopic lung tumors, the coadministration of Ag3 -AQCs increases the amount of cisplatin (CDDP) bound to the tumor DNA by fivefold without modifying CDDP levels in normal tissues. As a result, CDDP coadministered with Ag3 -AQCs more strongly reduces the tumor burden. Evidence of the significance of targeting chromatin compaction to increase the therapeutic index of chemotherapy is now provided. PMID- 29974519 TI - Extracellular vesicles isolated from Toxoplasma gondii induce host immune response. AB - This study established a protocol to purify Toxoplasma gondii tachyzoite microvesicles and exosomes, called as extracellular vesicles (EVs). In addition, the investigations were conducted to determine the kinetic of EV release by tachyzoites and whether EV proteins are able to modulate the host immune response. The particle size and concentration released by tachyzoites in culture medium at different incubation-period were characterized by nanoparticle tracking analysis. Tachyzoites (1 * 106 ) released around 4.37 +/- 0.81 * 108 EVs/mL/h, with size varying between 138.2 and 171.9 nm. EVs released into the medium were purified by gel-exclusion chromatography and screened by ELISA, using a pool of human positive sera for toxoplasmosis. EV-fractions contained high concentration of proteins, and EVs were analyzed by scanning and transmission electron microscopies. Tachyzoites released EVs into the culture medium throughout all membrane surface, and these vesicles contain small RNAs/miRNA. Pooled sera from chronically infected human or mice (infected with 2 different T. gondii strains) recognized distinct EV electrophoretic patterns in immunoblotting. T. gondii EVs significantly induced IL-10, TNF-alpha and iNOS in murine macrophages. In conclusion, this study shows that T. gondii secrete/excrete EVs (microvesicles and exosomes) contain miRNA and they were immunologically recognized by host immune response. PMID- 29974520 TI - Exploiting Singlet Fission in Organic Light-Emitting Diodes. AB - Harvesting of both triplets and singlets yields electroluminescence quantum efficiencies of nearly 100% in organic light-emitting diodes (OLEDs), but the production efficiency of excitons that can undergo radiative decay is theoretically limited to 100% of the electron-hole pairs. Here, breaking of this limit by exploiting singlet fission in an OLED is reported. Based on the dependence of electroluminescence intensity on an applied magnetic field, it is confirmed that triplets produced by singlet fission in a rubrene host matrix are emitted as near-infrared (NIR) electroluminescence by erbium(III) tris(8 hydroxyquinoline) (ErQ3 ) after excitonic energy transfer from the "dark" triplet state of rubrene to an "emissive" state of ErQ3 , leading to NIR electroluminescence with an overall exciton production efficiency of 100.8%. This demonstration clearly indicates that the harvesting of triplets produced by singlet fission as electroluminescence is possible even under electrical excitation, leading to an enhancement of the quantum efficiency of the OLEDs. Electroluminescence employing singlet fission provides a route toward developing high-intensity NIR light sources, which are of particular interest for sensing, optical communications, and medical applications. PMID- 29974521 TI - alpha-lipoic acid reduces postreperfusion syndrome in human liver transplantation - a pilot study. AB - A double-blind randomized controlled trial was performed to compare the safety and efficacy of alpha-lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA-perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. Quantitative polymerase chain reaction (qPCR) analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed postreperfusion syndrome (PRS), but seven of them belonged to the control group. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia-inducible factor-1 (HIF-1alpha) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA-treated patients than control patients, which suggests that ALA-treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS. PMID- 29974522 TI - Intra-arterial spread of Mucormycetes mediates early ischemic necrosis of brain and suggests new venues for prophylactic therapy. AB - Intracranial invasion by Mucormycosis carries high mortality mostly related to arterial occlusion and ischemic necrosis. We report clinical, imaging and autopsy findings in an adult immunodeficiency syndrome (AIDS) patient with fungal infection extending from a tooth. We report a striking discordance between a restriction of fungal growth to the initial branches of the circle of Willis and extensive ischemic infarcts of deep brain structures. This lends to a suggestion of apparently lost opportunities for brain salvage and prompts a re-assessment of clinical approaches to treat mucormycosis. PMID- 29974523 TI - Gal d 1-specific IgE predicts allergy to heated egg in Finnish children. AB - BACKGROUND: Allergen-specific IgE levels can be useful in predicting outcomes of oral food challenges, but optimal cutoff levels vary in different populations. The aim was to determine cutoff values for egg white- and Gal d 1-, Gal d 2-, Gal d 3-, and Gal d 4-specific IgE (sIgE) predicting positive oral heated egg challenges in 185 Finnish children and adolescents. METHODS: A total of 185 egg sensitized patients (age: 1-19 years, median: 6.3, mean: 7.0 years) with suspected egg allergy underwent double-blind, placebo-controlled (n = 78), or open (n = 107) oral food challenges with heated egg white. Specific IgE levels to egg white, Gal d 1 (ovomucoid), Gal d 2 (ovalbumin), Gal d 3 (conalbumin), and Gal d 4 (lysozyme) were measured by ImmunoCAP and compared with challenge outcomes. RESULTS: Of the 185 challenges, 124 (67%) were positive. Gal d 1 sIgE levels were significantly higher in the challenge-positive (median 13.5 kU/L, mean 33.2 kU/L) than in the challenge-negative group (median 0.2 kU/L, mean 1.2 kU/L), P < 0.0001. The diagnostic capacity of sIgE to egg white and Gal d 2, 3, and 4 was clearly weaker. In ROC analysis, the AUC for egg white was 0.86, Gal d 2 0.84, Gal d 3 0.79, and Gal d 4 0.77. Sensitization to Gal d 1 with a cutoff of value of >3.7 kU/L predicted a positive challenge with a specificity of 95% and sensitivity of 78%. The likelihood ratio was 15.9. In ROC analysis, the area under the curve was 0.94 (95% CI, 0.91-0.97). With a cutoff value of >14 kU/L, all challenges were positive, and with a cutoff of <0.9 kU/L, 95% of the challenges were negative. In the children aged 1-5 years (n = 88), the cutoff for Gal d 1 was >3.8 kU/L, and in the children above 6 years of age (n = 97), it was >3.5 kU/L. CONCLUSION: Gal d 1-specific IgE is useful in distinguishing egg sensitized patients with clinically reactive egg allergy from those tolerant of heated egg. The optimal cutoff point in a Finnish population of 185 children and adolescents was 3.7 kU/L with no significant difference between the younger and older age groups. PMID- 29974524 TI - Clinical relevance of copeptin plasma levels as a biomarker of disease severity and mortality in critically ill patients. AB - BACKGROUND: Copeptin, also termed C-terminal pre-pro-vasopressin or CTproAVP, mirrors endogenous vasopressin (anti-diuretic hormone, ADH) activity and might thereby serve as a biomarker reflecting the biological stress level. We therefore hypothesized that copeptin plasma concentrations are associated with disease severity in critically ill patients and could predict mortality. METHODS: We analyzed plasma copeptin levels in a prospective, single-center, observational study comprising 218 critically ill patients at admission to the medical intensive care unit (ICU). Mortality was assessed during a 2-year observational follow-up period. RESULTS: Copeptin plasma levels were significantly elevated in critically ill patients (n = 218) at ICU admission, as compared with 66 healthy controls. Neither sepsis as the cause of critical illness nor pre-existing metabolic disorders (type 2 diabetes, obesity) were found to influence copeptin levels. On the contrary, plasma copeptin was closely associated with disease severity (eg APACHE-II score) and correlated with biomarkers of inflammation, renal failure, metabolism, vascular tone, and tissue perfusion. Elevated copeptin levels at ICU admission predicted short-term and long-term mortality. CONCLUSIONS: Copeptin plasma concentrations are significantly elevated in critically ill patients, correlate with disease severity and predict ICU and long term outcome. Thus, copeptin could be a promising tool for prognostication and management of critically ill patients. PMID- 29974525 TI - In Situ Nanoparticle Embedding for Authentication of Epoxy Composites. AB - In situ reduction of chloroauric acid inside an amine-cured epoxy matrix leads to formation of gold nanoparticles which are embedded inside the part. This phenomenon is leveraged to design an authentication system for composites wherein the particles are embedded spatially and are invisible to the naked eye. Under UV light, the particles diffract light and create an easily visible path. The particles penetrate inside the part and create a permanent, cost-effective, tamper-proof code. The advantage of this technique is that this authentication system can be built in composite parts after fabrication of the composite structure. As very small amount (nanograms) of particles are present in the part, negligible change in the thermal characteristics of the parent matrix is observed. The particles can be embedded easily in carbon fiber as well as glass fiber reinforced epoxy structures. PMID- 29974526 TI - Artificial Synapses Emulated by an Electrolyte-Gated Tungsten-Oxide Transistor. AB - Considering that the human brain uses ~1015 synapses to operate, the development of effective artificial synapses is essential to build brain-inspired computing systems. In biological synapses, the voltage-gated ion channels are very important for regulating the action-potential firing. Here, an electrolyte-gated transistor using WO3 with a unique tunnel structure, which can emulate the ionic modulation process of biological synapses, is proposed. The transistor successfully realizes synaptic functions of both short-term and long-term plasticity. Short-term plasticity is mimicked with the help of electrolyte ion dynamics under low electrical bias, whereas the long-term plasticity is realized using proton insertion in WO3 under high electrical bias. This is a new working approach to control the transition from short-term memory to long-term memory using different gate voltage amplitude for artificial synapses. Other essential synaptic behaviors, such as paired pulse facilitation, the depression and potentiation of synaptic weight, as well as spike-timing-dependent plasticity are also implemented in this artificial synapse. These results provide a new recipe for designing synaptic electrolyte-gated transistors through the electrostatic and electrochemical effects. PMID- 29974527 TI - Sex-based differences in apnoea of prematurity: A retrospective cohort study. AB - NEW FINDINGS: What is the central question of the study? Is there a sex-based difference in the incidence of apnoea of prematurity and the success or failure of caffeine therapy in preterm infants? What is the main finding and its importance? Our data show that females received fewer days of caffeine treatment than males. This was most noticeable in infants born between 260/7 and 276/7 weeks of gestational age. These results highlight the importance of considering sex in clinical and basic research investigating the pathophysiology of apnoea of prematurity. ABSTRACT: This retrospective cohort study assessed whether sex influences the occurrence of apnoea of prematurity (AOP) in preterm infants. The analysis included a cohort of 24,387 preterm infants born between the gestational ages (GA) of 240/7 and 336/7 weeks that were admitted to tertiary neonatal care units participating in the Canadian Neonatal Network from January 2011 to December 2015. Of those, 13,983 (57%) were diagnosed with AOP. More females were diagnosed with AOP than males, but the difference in the male/female ratio was marginal (P = 0.058). The majority (89%) of infants diagnosed with AOP received caffeine (89% of males; 89% of females). By using the discontinuation of caffeine therapy as a proxy for the resolution of significant AOP, data analysis showed that females born before 336/7 weeks of GA stopped caffeine treatment earlier than males whether the caffeine was discontinued before 34 or 37 weeks of GA. Consequently, females had fewer days of caffeine therapy than males, especially infants born between 260/7 and 276/7 weeks (P < 0.004), 280/7 and 296/7 weeks (P < 0.03), and 320/7 and 336/7 weeks of GA (P < 0.04). Similar trends were observed when the corrected GA at discontinuation of caffeine was used. Given that AOP is indicative of an immature respiratory system, our data suggest that the maturation of the respiratory system might occur more rapidly in females than males. We conclude that sex needs to be considered in future studies on AOP. PMID- 29974528 TI - Tuning the Photoinduced Electron Transfer in a Zr-MOF: Toward Solid-State Fluorescent Molecular Switch and Turn-On Sensor. AB - The immobilization of fluorescent photoinduced electron transfer (PET) switches/sensors into solid state, which usually cannot maintain their identical properties in solution, has remained a big challenge. Herein, a water-stable anthracene and maleimide appended zirconium-based-metal-organic framework (Zr MOF; UiO-68-An/Ma) is reported. Unlike the regular intramolecular "fluorophore spacer-receptor" format, the separated immobilization of fluorescent (anthracene) and acceptor (maleimide) groups into the framework of a multivariate MOF can also favor a pseudo-intramolecular fluorescent PET process, resulting in UiO-68-An/Ma with very weak fluorescence. Interestingly, after Diels-Alder reaction or thiol ene reaction of maleimide groups, the pseudo-intramolecular fluorescent PET process in UiO-68-An/Ma fails and the solid-state fluorescence of the crystals is recovered. In addition, UiO-68-An/Ma shows an interesting application as solid state fluorescent turn-on sensor for biothiols, with the naked eye response at a low concentration of 50 umol L-1 within 5 min. This study represents a general strategy to enable the efficient tuning of fluorescent PET switches/sensors in solid state, and considering the fluorescence of the PET-based MOFs can be restored after addition of analyte/target species, this research will definitely inspire to construct stimuli-responsive fluorescent MOFs for interesting applications (e.g., logic gate) in future. PMID- 29974529 TI - Room-Temperature Solution-Synthesized p-Type Copper(I) Iodide Semiconductors for Transparent Thin-Film Transistors and Complementary Electronics. AB - Here, room-temperature solution-processed inorganic p-type copper iodide (CuI) thin-film transistors (TFTs) are reported for the first time. The spin-coated 5 nm thick CuI film has average hole mobility (uFE ) of 0.44 cm2 V-1 s-1 and on/off current ratio of 5 * 102 . Furthermore, uFE increases to 1.93 cm2 V-1 s-1 and operating voltage significantly reduces from 60 to 5 V by using a high permittivity ZrO2 dielectric layer replacing traditional SiO2 . Transparent complementary inverters composed of p-type CuI and n-type indium gallium zinc oxide TFTs are demonstrated with clear inverting characteristics and voltage gain over 4. These outcomes provide effective approaches for solution-processed inorganic p-type semiconductor inks and related electronics. PMID- 29974530 TI - Detection of blood Gb3 deposits as a new tool for diagnosis and therapy monitoring in patients with classic Fabry disease. AB - BACKGROUND: The X-linked Fabry disease (FD) is a multiorgan disorder due to alpha galactosidase A (alpha-GAL) deficiency with consequent lysosomal accumulation of globotriaosylceramide (Gb3). We established the immunocytochemical detection of Gb3 in blood cells of FD patients as a new method for FD diagnostics, follow-up and treatment control. METHODS: We enrolled 67 FD patients (37 men, 30 women) and 52 healthy controls (26 men, 26 women). PBMC were isolated from whole venous blood and 3x105 cells were immunoreacted with antibodies against CD77 as a marker for Gb3. Using fluorescence microscopy, the mean percentage of Gb3 positive PBMC was determined by an investigator blinded to subject allocation. As a second method, we qualitatively assessed Gb3 positive cells in blood smears. RESULTS: Gb3 deposits were unequivocally visible in PBMC and in blood smears. Men (P < 0.001) and women (P < 0.01) with classical FD had more Gb3-positive PBMC than healthy controls, whose samples only occasionally showed positive cells. The number of Gb3 positive PBMC was negatively correlated with alpha-GAL activity and positively correlated with plasma lyso-Gb3 levels. Only the PBMC Gb3 load but not plasma lyso-Gb3 reflected short- and long-term effects of enzyme replacement therapy (P < 0.01). CONCLUSIONS: Gb3 can be visualized in PBMC and blood smears and can be used as a novel marker for diagnostics, follow-up and treatment control in FD. PMID- 29974531 TI - Guidelines for pediatric anogenital examination: Insights from our vulvar dermatology clinic. AB - To our knowledge, there are no guidelines in the dermatology literature for performing anogenital examinations in prepubescent children. Based on experience in our joint pediatric dermatology-gynecology vulvar clinic, we aim to provide a framework for conducting genital examinations in children, focusing on the vulvar examination. Our goal is to enhance confidence in the pediatric dermatologist's ability to perform thorough examinations by providing general principles as well as concrete "do's" and "don'ts" that will create a maximally comfortable and productive experience. These steps will help create a positive experience for the patient and family, encouraging further follow-up and enhancing the overall well being of the child. PMID- 29974532 TI - Genetic variants associated with skin photosensitivity in a southern European population from Spain. AB - BACKGROUND/PURPOSE: Recent GWAS studies, mostly performed in populations of North European origin, have identified the genetic loci associated with pigmentation, sun sensitivity, freckling and skin cancer susceptibility. Here, we aimed at addressing the genetic determinants of sunlight sensitivity in Spain, a southern European population. METHODS: Nine SNPs located in 8 pigmentation-related genes (IRF4, TYR, ASP, HERC2, OCA2, BNC2, SLC24A4 and SLC45A2) were genotyped in 456 Spaniards. Additionally, the complete sequence of the MC1R gene was obtained, testing each nonsynonymous mutation supported by the classification as R or r alleles. A standardised questionnaire was used to collect demographic characteristics, pigmentation and sun sensitivity traits, as well as sun exposure habits. RESULTS: MC1R R alleles and IRF4 rs12203592 were significantly associated with sunlight sensitivity at the Bonferroni-corrected level (P-value < 4.54 * 10 3 ). Genetic variants in SLC45A2 (rs16891982) and HERC2 (rs12913832) were also found to be significantly associated with skin photosensitivity in our Spanish sample. Interaction analysis using the MDR method revealed epistatic effects when these four variants were considered together. CONCLUSION: MC1R, IRF4, HERC2 and SLC45A2 play a significant role in skin sensitivity to sunlight in the Spanish population. Moreover, interaction among these four loci seems to modulate the ability of the skin to respond to UV radiation. PMID- 29974533 TI - Skin commensal bacteria Staphylococcus epidermidis promote survival of melanocytes bearing UVB-induced DNA damage, while bacteria Propionibacterium acnes inhibit survival of melanocytes by increasing apoptosis. AB - BACKGROUND/PURPOSE: Skin commensal bacteria have been described to help orchestrate skin homeostasis, signaling through innate immunity pathways. This study for the first time aimed at studying the relationship between skin commensals and melanocytes after UVB exposure. METHODS: An in vitro UVB radiation model with normal human epidermal melanocytes (NHMs) and skin commensal bacteria supernatant from Staphylococcus epidermidis and Propionibacterium acnes was established. Melanocytes DNA damage, cyclobutane pyrimidine dimers (CPD), and cellular proliferation marker Ki-67 were measured by ELISA and immunofluorescence staining. Cell apoptosis was assessed by flow cytometry and PCR array and RT qPCR. RESULTS: Normal human epidermal melanocytes are able to survive and proliferate while bearing DNA damage after UVB radiation. Skin commensal bacteria S. epidermidis and its by-product LTA promote melanocytes survival by inducing upregulation of TRAF1, CASP14, CASP5, and TP73. On the other hand, P. acnes can inhibit UVB-irradiated melanocytes survival by increasing apoptosis. CONCLUSION: Our studies show different aspects of commensal activity on melanocytes during irradiation. The possible balance achieved by the different skin commensal can influence NHM potential to become cancer cells. PMID- 29974534 TI - Genetic testing for familial hypercholesterolemia among survivors of acute coronary syndrome. AB - BACKGROUND: Familial hypercholesterolemia could be prevalent among patients with acute coronary syndrome. OBJECTIVE: To investigate both the frequency of causative mutations for familial hypercholesterolemia (FH) and the optimal selection of patients for genetic testing among patients with an acute coronary syndrome (ACS). METHODS: One hundred and sixteen patients with an ACS during 2009 2015 were identified through the SWEDEHEART registry. Patients who had either a high total cholesterol level >=7 mmol L-1 combined with a triglyceride level <=2.6 mmol L-1 , or were treated with lipid-lowering medication and had a total cholesterol level >4.9 mmol L-1 and a triglyceride level <=2.6 mmol L-1 were included. Genetic testing was performed first with a regionally designed FH mutation panel (118 mutations), followed by testing with a commercially available FH genetic analysis (Progenika Biopharma). RESULTS: A total of 6.9% (8/116) patients had a FH-causative mutation, all in the LDL-receptor. Five patients were detected on the panel, and further testing of the remaining 111 patients detected an additional 3 FH-causative mutations. Baseline characteristics were similar in FH-positive and FH-negative patients with respect to age, gender, prior ACS and diabetes. Patients with a FH-causative mutation had higher Dutch Lipid Clinical Network (DLCN) score (5.5 (5.0-6.5) vs 3.0 (2.0-5.0), P < 0.001) and a higher low density lipoprotein level (5.7 (4.7-6.5) vs 4.9 (3.5-5.4), P = 0.030). The Dutch Lipid Clinical Network (DLCN) score had a good discrimination with an area under the curve of 0.856 (95% CI 0.763-0.949). CONCLUSION: Genetic testing for FH should be considered in patients with ACS and high DLCN score. PMID- 29974535 TI - Functional Control of Peptide Amphiphile Assemblies via Modulation of Internal Cohesion and Surface Chemistry Switch. AB - Understanding the impacts of the internal cohesion and surface chemistry of supramolecular systems on the collective behaviors in the contacts between the systems and biomolecules can greatly expand the functional diversity and adaptivity of supramolecular nanostructures. Here we show how the tuned molecular interactions modulate the morphologies and internal cohesion of peptide amphiphile (PA) self-assemblies and their resultant functions. Circular dichroism spectroscopy, fluorescence probing, atomic force and electron microscopy, along with molecular dynamics simulations, revealed that the PA self-assembly formed compact long fibers when surface charge repulsion was screened, but formed loose short fibers or micelle-like assemblies when hydrogen bonding was disrupted or hydrophobic core was enhanced. More importantly, depending on the strength of the phospholipid affinity for the cationic segment of the PA, the same internal cohesion of PA nanostructures can lead to either cell death or cell survival, providing unique insights into the design of supramolecular materials. PMID- 29974536 TI - Evolution of Morphology of POEGMA-b-PBzMA Nano-Objects Formed by PISA. AB - The evolution of particle morphology occurring during polymerization-induced self assembly (PISA) of a block copolymer poly(oligo(ethylene glycol) methacrylate)-b poly(benzyl methacrylate) (POEGMA-b-PBzMA) is studied. A well-controlled reversible addition-fragmentation chain transfer (RAFT) polymerization yields nano-objects with various morphologies: spheres, aggregates, worm-like structures, and vesicles. A comparison of the morphology of the nano-objects formed from two different chain-length stabilizers established that the unreacted monomer played an important role during the morphology transitions, which is contrary to previous observations. In addition, morphology evolution to higher order structures could be attained simply by extending the reaction time, after reaching full monomer conversion. PMID- 29974537 TI - New Insights into RAFT Dispersion Polymerization-Induced Self-Assembly: From Monomer Library, Morphological Control, and Stability to Driving Forces. AB - Polymerization-induced self-assembly (PISA) has been established as an efficient, robust, and versatile approach to synthesize various block copolymer nano-objects with controlled morphologies, tunable dimensions, and diverse functions. The relatively high concentration and potential scalability makes it a promising technique for industrial production and practical applications of functional polymeric nanoparticles. This feature article outlines recent advances in PISA via reversible addition-fragmentation chain transfer dispersion polymerization. Considerable efforts to understand morphological control, broaden the monomer library, enhance morphological stability, and incorporate multiple driving forces in PISA syntheses are summarized herein. Finally, perspectives on the future of PISA research are discussed. PMID- 29974538 TI - Living Supramolecular Polymerization of DNA. AB - Recently there have been notable synthetic successes in supramolecular polymerization. By contrast, it has long been known that DNA can undergo supramolecular polymerization (concatemerization). Concatemerization is a step like polymerization and consequently suffers from broad molecular weight distributions and generally undesirable cyclization reactions. Here we demonstrate that another supramolecular polymerization of DNA, hybridization chain reaction (HCR), is in fact a living polymerization. After consumption of initial monomer, the polymerization can be continued with further addition of monomer, and the molecular weight can be varied by the ratio of monomer to initiator. In contrast to concatemerization, HCR produces polymers with narrow dispersity while avoiding cyclization. Identification of the living character of this supramolecular polymerization presents new opportunities in structural DNA nanotechnology and molecular biology. PMID- 29974539 TI - Synthesis of Trifluoromethylated Quinoxaline-Based Polymers for Photovoltaic Applications. AB - A series of quinoxaline-based conjugated polymers, in which the electron-donating benzodithiophene (BDT) unit is linked to the electron-accepting 6,7-difluorinated quinoxaline (DFQ) derivatives by a thiophene bridge, is synthesized. To investigate their effects on the intrinsic properties of polymers, strong electron-withdrawing trifluoromethyl (CF3 ) groups were incorporated into the meta-position of the phenyl ring at the 2,3-positions of the DFQ unit of the reference polymer, labelled PEhB-FQx, to yield the target polymer PEhB-FQxCF3. In addition, the 2-ethylhexyloxy substituents on the BDT donor in PEhB-FQxCF3 are changed to the more planar 2-ethylhexyl thiophene units to produce another target polymer PThB-FQxCF3. Owing to the significant contributions of the CF3 moiety, PEhB-FQxCF3 exhibits quite discernible optical and electrochemical properties along with significant enhancement in photovoltaic performances compared to the reference polymer PEhB-FQx. Furthermore, the incorporation of the alkylthienyl side chains on the BDT moiety confers on the resultant PThB-FQxCF3 to possess the maximum power conversion efficiency of 7.26% with an open circuit voltage of 0.88 V, short-circuit current density of 12.20 mA cm-2 , and fill factor of 67.80%. PMID- 29974540 TI - Women's role in the rise in drinking in Australia 1950-80: an age-period-cohort analysis of data from the Melbourne Collaborative Cohort Study. AB - BACKGROUND AND AIMS: In Australia, as in many countries, alcohol consumption increased dramatically during the second half of the 20th century, with increased availability of alcohol, relaxation of attitudes towards drinking and shifting roles and opportunities for women as facilitating factors. We sought to investigate drinking trends by gender and birth cohort in Australia during this period. DESIGN: Retrospective cohort study. SETTING, PARTICIPANTS AND MEASUREMENTS: Using the usual frequency and quantity of beverage-specific alcohol intake for 10-year periods from age 20, reported retrospectively from 40 789 participants aged 40-69 years (born 1920-49) at recruitment to the Melbourne Collaborative Cohort Study in 1990-94, we compared trends in alcohol consumption by sex in Australia between 1950 and 1990. Participants' average daily consumption for age decades were transformed to estimated intakes for 1950, 1960, 1970, 1980 and 1990. FINDINGS: Alcohol consumption was higher for men than women during each decade. Alcohol consumption increased for both sexes in the 1950s, 1960s and 1970s, and fell after 1980. The rise before 1980 was roughly equal in absolute terms for both sexes, but much greater relative to 1950 for women. Women born during 1930-39 and 1940-49 drank more alcohol during early-middle adulthood (ages 20-40) than women born during 1920-29. In the 1980s, the fall was greater in absolute terms for men, but roughly equal relative to 1950 for both sexes. In both sexes, the decline in drinking in the 1980s for birth-decade cohorts was roughly in parallel. CONCLUSIONS: Specific birth cohorts were influential in the rise in alcohol consumption by Australian women born in 1920-49 after World War II. Much of the convergence with men's drinking after 1980 reflects large reductions in drinking among men. PMID- 29974541 TI - Crystal Structure and Magnetic Properties of epsilon-Rux Fe2-x O3 Nanosize Hard Ferrite. AB - A new series of metal-substituted epsilon-iron oxides, epsilon-Rux Fe2-x O3 (x=0 (1), 0.005 (2), and 0.014 (3)) nanoparticles (average size=20 nm) is synthesized by sintering iron oxide hydroxide with ruthenium hydroxide in a silica matrix. The samples are characterized by inductively coupled plasma mass spectrometry, and energy dispersive X-ray spectroscopy (EDS) of transmission electron microscope. The X-ray diffraction pattern shows that epsilon-Rux Fe2-x O3 has an orthorhombic crystal structure with a space group of Pna21 and the Rietveld analyses show that Ru is doped selectively at the regular octahedral C site among the four non-equivalent Fe sites (A, B, C, and D site). Magnetization vs. temperature plots show that the Curie temperature (TC ) depends on x, and TC =498 K for 1, 497 K for 2, and 496 K for 3. Magnetization vs. external magnetic field plots indicate that the coercive field (Hc ) increases from 17.7 kOe (1) to 20.3 kOe (3). This increment of 15 % on Hc is attributed to the single ion anisotropy of the magnetic spin on RuIII (4d5 , S=1/2). PMID- 29974542 TI - Reactive Polymorphic Nanoparticles: Preparation via Polymerization-Induced Self Assembly and Postsynthesis Thiol-para-Fluoro Core Modification. AB - The use of 2,3,4,5,6-pentafluorobenzyl methacrylate (PFBMA) as a core-forming monomer in ethanolic reversible addition-fragmentation chain transfer dispersion polymerization formulations is presented. Poly[poly(ethylene glycol) methyl ether methacrylate] (pPEGMA) macromolecular chain transfer agents were chain-extended with PFBMA leading to nanoparticle formation via polymerization-induced self assembly (PISA). pPEGMA-pPFBMA particles exhibited the full range of morphologies (spheres, worms, and vesicles), including pure and mixed phases. Worm phases formed gels that underwent a thermo-reversible degelation and morphological transition to spheres (or spheres and vesicles) upon heating. Postsynthesis, the pPFBMA cores were modified through thiol-para-fluoro substitution reactions in ethanol using 1,8-diazabicyclo[5.4.0]undec-7-ene as the base. For monothiols, conversions were 64% (1-octanethiol) and 94% (benzyl mercaptan). Spherical and worm-shaped nano-objects were core cross-linked using 1,8-octanedithiol, which prevented their dissociation in nonselective solvents. For a temperature responsive worm sample, cross-linking additionally resulted in the loss of the temperature-triggered morphological transition. The use of the reactive monomer PFBMA in PISA formulations presents a simple method to prepare well-defined nano objects similar to those produced with nonreactive monomers (e.g., benzyl methacrylate) and to retain morphologies independent of solvent and temperature. PMID- 29974543 TI - Rapid analysis of ricin using hot acid digestion and MALDI-TOF mass spectrometry. AB - Ricin is a protein toxin of considerable interest in forensics. A novel strategy is reported here for rapid detection of ricin based on microwave-assisted hot acid digestion and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. Ricin samples are subjected to aspartate-selective hydrolysis, and biomarker peptide products are characterized by mass spectrometry. Spectra are obtained using post source decay and searched against a protein database. Several advantages are offered by chemical hydrolysis, relative to enzymatic hydrolysis, notably speed, robustness, and the production of heavier biomarkers. Agglutinin contamination is reliably recognized, as is the disulfide bond strongly characteristic of ricin. PMID- 29974544 TI - Prevalence of night sleep duration, sleep quality and sleep hygiene practices among children attending childcare services in New South Wales, Australia. AB - AIM: To describe parent-reported child: (i) sleep duration; (ii) sleep quality; (iii) sleep hygiene practices; and (iv) the proportion of children meeting sleep duration recommendations. METHODS: A convenience sample of parents of Australian pre-school-aged children (3-5 years) were surveyed from the Hunter New England region of New South Wales. The cross-sectional survey was conducted via computer assisted telephone interview. The survey assessed parent and child demographic characteristics and parent-reported child sleep duration, quality and sleep hygiene practices. RESULTS: A total of 488 eligible parents or guardians took part in the study. Parents reported that children slept an average of 11.03 h per night. Approximately 96% of children met daily sleep duration recommendations from sleep guidelines for their age group. The majority of parents reported that their child had 'good' sleep quality (86.89%). Almost 40% reported that their child woke at least once a night. Sleep hygiene practices were relatively well established; however, a small proportion of parents indicated that they had no rules surrounding bedtime (13.52%) or television use before bed (14.52%). CONCLUSIONS: The current study describes the sleep duration, quality and sleep hygiene practices of a sample of pre-school-aged children in New South Wales, Australia. Future research using objective measures of sleep duration and hygiene, as well as assessing a broader spectrum of sleep hygiene practices, is needed. PMID- 29974545 TI - Efficacy of Cyberbullying Prevention on Somatic Symptoms-Randomized Controlled Trial Applying a Reasoned Action Approach. AB - The theory of reasoned action (ToRA) has been proposed as a framework for cyberbullying prevention design, targeting attitudes and norms. In this study effects of a long (10 weekly sessions) and a short (one day, four sessions) cyberbullying prevention program based on the ToRA were compared with a control group over 9 months. Longitudinal data from 722 students (mean age = 13.36) on cyberbullying, somatic symptoms, attitudes, and norms were analyzed within a structural equation model. Participation in the long intervention group significantly reduced cyberbullying (d = -0.584) and somatic symptoms (d = 0.316). No between-group differences emerged for attitudes and norms. Developmental trajectories and associations were found to be as suggested by ToRA in both cross-sectional and change-score analyses. PMID- 29974546 TI - Evaluation of the staining potential of silver diamine fluoride: in vitro. AB - BACKGROUND: Silver diamine fluoride (SDF) is a cariostatic agent used to adjunctively manage dental caries in high-risk groups. However, black staining is a frequently reported side effect following SDF application and influences the acceptability of this treatment. AIM: To evaluate the staining potential of SDF and the influence of the potassium Iodide (KI) application on the degree of black staining over time. DESIGN: Extracted carious primary molars were collected and sorted into pairs matched by tooth type, size and location of the carious lesion (n = 35). Teeth were stratified to receive either 38% SDF, KI immediately after SDF application, or 12% SDF. Standardised timelapse photography and image processing software was used to evaluate staining over a period of 7 days. RESULTS: Following SDF application, the onset of black staining occurred within 2 min and increased in value for up to 6 h post-application. The use of KI immediately after SDF application resulted in no noticeable staining of the carious dentine or surrounding enamel. No significant differences were evident in the staining potential between the different SDF concentrations (38% and 12%). Furthermore, root surface and cementum was found to stain darker and more readily when compared with the coronal enamel surface. CONCLUSION: SDF has the ability to visibly stain dental hard tissues and its staining potential may be modified by application of KI. PMID- 29974547 TI - Enhanced Adhesion of Polydimethylsiloxane Using an Interlocked Finger Structure. AB - Silicone-based polymers have been widely used for many applications, but their extremely low surface energies and the resulting poor adhesion have been the cause for continuous problems. Herein, a novel adhesion improvement technique using an interlocked finger structure is demonstrated, which enables up to 24.8 and 7.3-fold increases in adhesion compared to the untreated and conventional plasma-treated cases, respectively. The interlocked finger structure is fabricated by surface-confined dissolution and subsequent directional melt crystallization of a solvent. After removing the solvent crystals, porous surfaces are prepared from polyurethane, polyvinyl alcohol, and polystyrene, and these are used to fabricate interfaces of interlocked finger structures with polydimethylsiloxane. The improvement in adhesion strength linearly depends on the pore depth of the prepared surfaces. This novel technique of surface adhesion could improve the performance of polymers with intrinsically poor adhesion in future applications. PMID- 29974548 TI - Salivary pH and colonization by oral Candida in children and adolescents submitted to haemodialysis. AB - BACKGROUND: Fungal infections are a serious problem among haemodialysis patients. AIM: The aims of this study were to estimate the frequency of oral Candida species among children and adolescents undergoing haemodialysis (HD), to identify the isolated species, and to study the relationship between haemodialysis duration, amounts of colony-forming units, and salivary pH. DESIGN: A matched sample of 52 patients undergoing HD and 52 healthy individuals were selected. The samples were obtained from the dorsum of the tongue, and the colonies were identified through a substrate assimilation test. Stimulated whole saliva was collected from each patient for evaluation of salivary pH. RESULTS: The frequency of oral Candida species was 34.6% (18/52) and 46.20% (24/52) in the HD and control groups (P = 0.23), respectively. Candida parapsilosis complex was the most frequently isolated fungi species in the HD group (P = 0.03). A HD therapy duration of more than 1 year was statistically correlated with a higher number of colony-forming units (P = 0.03) but was not statistically related to salivary pH. CONCLUSIONS: Candida parapsilosis complex was the most frequently isolated fungal species in the young HD patients, and the duration therapy was associated with higher oral colonization. PMID- 29974550 TI - Presence of gastric Helicobacter species in children suffering from gastric disorders in Southern Turkey. AB - BACKGROUND: Infections with gastric Helicobacter spp. are associated with gastritis, peptic ulceration, and malignancies. Helicobacter pylori is the most prevalent Helicobacter species colonizing the human stomach. Other gastric non-H. pylori helicobacters (NHPHs) have been described in 0.2%-6% of human patients with gastric disorders. Nevertheless, due to difficulties in the diagnosis of NHPH infections and lack of routine screening, this is most likely an underestimation of their true prevalence. To the best of our knowledge, no studies have been performed in the presence of Helicobacter spp. in children suffering from gastric disorders in Southern Turkey. MATERIALS AND METHODS: In total, 110 children with gastric complaints were examined at the Cukurova University Balcali hospital, Turkey. Gastroscopy was performed to evaluate the presence of gastric mucosal lesions. Biopsies of the pyloric gland zone were taken for histopathological analysis, rapid urease testing, and presence of Helicobacter spp. DNA by PCR. RESULTS: Based on the PCR results, the prevalence of Helicobacter spp. was 32.7% (36/110). H. pylori was found in 30.9% (34/110), H. suis in 1.8% (2/110), and H. heilmannii/H. ailurogastricus in 0.9% (1/110) of the human patients. A mixed infection with H. pylori and H. suis was present in one patient. The presence of mucosal abnormalities, such as nodular inflammation, ulceration, and hyperemia, as well as gastritis, was significantly higher in Helicobacter spp. positive patients. CONCLUSION: Helicobacter pylori, H. suis, and H. heilmannii/H. ailurogastricus were present in children with gastric complaints. Infection with these pathogens may be involved in the development of gastritis and ulceration. PMID- 29974551 TI - Power morcellation-induced dissemination of sarcomatous component arising in leiomyoma. AB - In 2014, the US Food and Drug Administration issued a safety communication warning against the use of power morcellators during laparoscopic hysterectomy or myomectomy. We report a case of peritoneal leiomyosarcomatosis attributable to power morcellation. A 49-year-old nulligravid woman presented with a huge uterine tumor measuring 15 * 8 cm that was diagnosed as benign leiomyoma on magnetic resonance imaging. The uterine tumor had shrunk to 13 * 7 cm after five treatment courses with a gonadotropin-releasing hormone agonist. She underwent laparoscopic hysterectomy using power morcellation; postoperative pathological diagnosis was benign leiomyoma. After 6 months, urinary ascites developed because of right ureteral rupture. She underwent laparotomy and was diagnosed with peritoneal leiomyosarcomatosis. Meticulous and thorough reevaluation of the morcellated specimens revealed a small component of leiomyosarcoma. Use of power morcellation should be minimized until the advent of novel methods that can perfectly differentiate benign from malignant uterine tumors preoperatively. PMID- 29974552 TI - Benzene-d6 and toluene-d8 as guest molecules in micropores of a layered zirconium phosphonate: 2 H, 13 C{1 H}, and 31 P{1 H} solid-state NMR, deuterium NMR relaxation, and molecular motions. AB - For the first time, pore spaces in the Zr (IV) phosphonate (1) as a representative of layered metal (IV) phosphonate materials have been investigated by studying mobility of guest molecules, benzene-d6 , and toluene-d8 . Guest molecules located in micropores of 1 have been characterized by solid-state 13 C{1 H} and 2 H NMR spectra in static samples with varying temperatures. At moderately low temperatures, the benzene and toluene molecules experience fast isotropic reorientations and show the motionally averaged liquid-like carbon and deuterium line shapes in the NMR spectra. At lower temperatures, two anisotropic motional modes have been found for benzene molecules by analyzing the 2 H NMR line shapes: the well-known in-plane C6 rotation and composite motions. Interpretation of the variable-temperature 2 H T1 relaxation times identifies the composite motions as 120 degrees flips around the C6 axis perpendicular to the molecular plane and the rotations around the molecular para-C-C axis. The data obtained resulted in the idealized (cylinder-shaped) model of micropores in compound 1 with the diameter of 20-30 A. Furthermore, the activation energy of 20.1 kJ/mol determined for the benzene motions classifies the molecule-surface interactions as weak but enough for absorption. PMID- 29974553 TI - The neural underpinnings of cross-cultural differences in creativity. AB - Whereas Western individualistic cultures emphasize uniqueness, collectivistic East-Asian cultures discourage it. Here we examined whether cross-cultural differences in creativity as measured by a task of divergent thinking (DT) are explained by enhanced activity in brain regions that mediate inhibitory control (e.g., the left inferior frontal gyrus [L-IFG]). We therefore predicted that the L-IFG would be "hyperactive" among individuals from East-Asian cultures compared to Western ones. In Study 1, Israeli and South Korean participants were compared on a classic DT task (AUT; "Alternate uses: Manual of instructions and interpretation"). Israelis generated more original ideas compared to South Koreans. In Study 2, Israeli participants and South Korean participants currently living in Israel were scanned while performing the AUT. In line with previous studies, the results indicate that generation of original ideas across cultures is associated with activation of the posterior cingulate cortex (PCC), which is part of the default mode network (DMN). As hypothesized, South Koreans showed enhanced activation of the L-IFG compared to Israelis. This enhanced activation was associated with lower originality scores. The cultural dimension of traditionalism, being higher in the South Korean sample than in the Israeli Sample, was related to enhance L-IFG activity, further supporting our hypothesis regarding cultural influences on inhibitory control. Furthermore, functional connectivity analysis indicated that activation of the L-IFG was positively coupled with PCC activity among Israelis and with preSMA activity among South Koreans. The results suggest that cross-cultural differences in creativity might be explained by variations in inhibitory control. PMID- 29974554 TI - Zeylenone inhibits proliferation and promotes apoptosis in ovarian carcinoma cells via Janus kinase 2 / signal transducers and activators of transcription 3 pathways. AB - AIM: Ovarian cancer is the fifth common cancer in females. The aim of our study was to determine function of Zeylenone on cell viability and apoptosis of ovarian carcinoma SKOV3 cells. METHODS: Cell viability was measured by Cell counting kit 8 (CCK8) assay; Mitochondrial membrane potential (MMP) and apoptosis were detected by flow cytometry. The mRNA and protein levels of related factors were determined by Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. RESULTS: Cell viability was decreased by Zeylenone in a dose-dependent manner. Zeylenone with concentrations of 2.5, 5 and 10 MUmol/L was used to treat ovarian carcinoma SKOV3 cells for 24 h in the following study. The loss of MMP and apoptosis were both significantly increased by Zeylenone. The mRNA and protein levels of cytochrome c (cyto c) and apoptosis inducing factor (AIF) in cytosol were increased by Zeylenone. The mRNA and protein levels of Caspase-3, Fas, Fasl and Bax were increased; while the expression of Bcl-2 was decreased by Zeylenone. The expression of (Janus family of tyrosine kinase) p-JAK and signal transducer and activator of transcription (p-STAT) was decreased significantly by Zeylenone. CONCLUSION: Zeylenone inhibited cell proliferation and promoted apoptosis in ovarian carcinoma cells. The JAK-STAT pathway was involved in this progress. PMID- 29974555 TI - Recurrence after fertility-preserving surgery for low-grade endometrial stromal sarcoma. AB - Considering the characteristics of low-grade endometrial stromal sarcoma (ESS), such as relative indolent course, younger age at diagnosis and favorable prognosis, the fertility-preserving management of low-grade ESS has been described by several authors. We report a 34-year-old female with stage IB low grade ESS who developed recurrence 7 years after neoadjuvant high-dose progestin therapy followed by fertility-preserving surgery and postoperative progestin therapy. The patient stopped progestin therapy and was disease free for 4 years after diagnosis but experienced recurrence with peritoneal dissemination at 7 years. Considering the tendency of late recurrence, long-term surveillance is necessary to ensure timely action. Long-term progestin treatment might be considered after complete remission even beyond 5 years. We performed a literature review and found that many of the cases did not meet solid pathological criteria of low-grade ESS. The diagnostic criteria of low-grade ESS (vs endometrial stromal nodule) should be deliberately documented for future studies of this rare disease. PMID- 29974556 TI - Serum and cerebrospinal neurofilament light chain levels in patients with acquired peripheral neuropathies. AB - Neurofilament light chain (NFL) levels reflect axonal damage in different inflammatory and neurodegenerative central nervous system conditions, in correlation with disease severity. Our aim was to determine the possible diagnostic and prognostic value of serum and cerebrospinal fluid (CSF) NFL levels in subjects with different forms of acquired peripheral neuropathies (PN). Paired serum and CSF samples of 25 patients with acquired PN were analysed for NFL using an ultrasensitive technique (Quanterix, Simoa, Lexington, MA, USA) and compared with a group of 25 age-matched healthy subjects. Demographic, clinical, CSF and neurophysiological data were reviewed. Cases with Guillain-Barre syndrome (N = 5), multifocal motor neuropathy (N = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) and variants (N = 12), anti-myelin-associated glycoprotein (MAG) neuropathy (N = 3), both CIDP and anti-MAG neuropathy (N = 1), and non systemic vasculitic neuropathy (N = 1) were studied. NFL levels were significantly (P < 0.001) increased in patients with PN and were higher in the CSF (median: 1407 pg/mL, range: 140.2-12 661) than in serum (median: 31.52 pg/mL, range: 4.33-1178). A statistically significant correlation was observed between serum and CSF levels in cases with blood-nerve-barrier damage (r = 0.71, P < 0.01), and between serum NFL levels and disease activity at sampling (r = 0.52, P < 0.01) and at last follow-up (r = 0.53, P < 0.01) in all subjects. The increase of NFL values in both serum and CSF of patients with acquired PN and the significant correlation between serum NFL levels, disease severity and final outcome support the possible role of NFL as disease activity and prognostic biomarker also in peripheral nervous system disorders. PMID- 29974557 TI - Fibrosis and wall thickness affect ventricular repolarization dynamics in hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. METHODS: HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n = 46) and control subjects without mutation and hypertrophy (n = 35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. RESULTS: Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p = 0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6 mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p < 0.001 and p = 0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p = 0.044 and p = 0.001, respectively). LGE was an independent predictor of QTe/RR slope (p = 0.023, B = 0.043). CONCLUSION: Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM. PMID- 29974558 TI - Maternal and perinatal complications in pregnant women with urinary tract infection caused by Escherichia coli. AB - AIM: The incidence of urinary tract infection (UTI) in pregnant women may vary from 5-10% and depends on parity, race, socioeconomic status and anatomical and functional changes in pregnancy. In Mexico, preterm birth accounts for 75% of perinatal deaths and 50% of the neurological sequelae attributable directly to prematurity. The objective of the present study is to describe maternal and perinatal complications in pregnant women with UTI caused by Escherichia coli and to find out the antimicrobial susceptibility pattern. METHODS: A descriptive and longitudinal study of pregnant women admitted to the Women's Hospital in Culiacan, Sinaloa, Mexico, was carried out from January 2013 to December 2014. Patients with E. coli infection were included, and infections caused by other microorganisms were excluded. The sociodemographic variables, causes of hospitalization and the type of maternal and perinatal complications were determined. RESULTS: The causes of admission to the hospital were threatened preterm labor, and fever and threatened abortion. Of 38 patients with threatened preterm labor, 33 went on to delivery, four were preterm births and two were neonatal deaths. E. coli was sensitive to over 90% of piperacillin-tazobactam, amikacin, nitrofurantoin and carbapenems. CONCLUSION: According to this study in a Mexican population, the number one admission diagnosis in women with UTI due to E. coli was threatened preterm labor, and fever and threatened abortion. E. coli was sensitive to more than 90% of piperacillin-tazobactam, amikacin, nitrofurantoin and carbapenems. PMID- 29974559 TI - Is the consumption of fast foods associated with asthma or other allergic diseases? AB - The associations between the consumption of fast foods and asthma or allergic diseases have not been clarified. The aim of this study was to determine whether fast foods consumption is associated with asthma or allergic diseases. Databases were searched up to February 2018. Studies investigating the associations between fast foods consumption and asthma or allergic diseases were considered eligible. Included studies were assessed for quality using standardized critical appraisal checklists. The quality scores were 5.33 +/- 1.16 in case-control studies and 5.69 +/- 1.55 in cross-sectional studies. Adjusted odds ratios (aOR) with 95% confidence interval (CI) were pooled. Sixteen studies (13 cross-sectional and 3 case-control studies) were included. The consumption of fast foods was significantly related to current asthma (aOR: 1.58; 95% CI: 1.17-2.13 for case control study and aOR: 1.58; 95% CI: 1.10-2.26 for cross-sectional studies), severe asthma (aOR: 1.34; 95% CI: 1.23-1.46), asthma ever (aOR: 1.36; 95% CI: 1.06-1.75), current wheeze (aOR: 1.21; 95% CI: 1.16-1.27), wheeze ever (aOR: 1.65; 95% CI: 1.07-2.52), physician-diagnosed allergic rhinitis (odds ratio: 1.43; 95% CI: 1.05-1.95), severe eczema (aOR: 1.51; 95% CI: 1.16-1.96) and severe rhino-conjunctivitis (aOR: 1.54; 95% CI: 1.18-2.00). The consumption of hamburgers was associated with current asthma (aOR: 1.59; 95% CI: 1.13-2.25), severe asthma (aOR: 1.34; 95% CI: 1.23-1.46), asthma ever (aOR: 1.47; 95% CI: 1.13-1.92), severe eczema (aOR: 1.51; 95% CI: 1.16-1.96), severe rhino conjunctivitis (aOR: 1.54; 95% CI: 1.18-2.00) and rhino-conjunctivitis (aOR: 1.21; 95% CI: 1.15-1.27). The consumption of fast foods, especially hamburgers, >=3 times/week, was more likely to be associated with severe asthma and current wheeze compared with the consumption of 1-2 times/week (both P < 0.001). In conclusion, the consumption of fast foods, particularly hamburgers, correlates to asthma in a dose-response pattern, which needs to be further validated in longitudinal and interventional studies. PMID- 29974560 TI - Evidence for a general performance-monitoring system in the human brain. AB - Adaptive behavior relies on the ability of the brain to form predictions and monitor action outcomes. In the human brain, the same system is thought to monitor action outcomes regardless of whether the information originates from internal (e.g., proprioceptive) and external (e.g., visual) sensory channels. Neural signatures of processing motor errors and action outcomes communicated by external feedback have been studied extensively; however, the existence of such a general action-monitoring system has not been tested directly. Here, we use concurrent EEG-MEG measurements and a probabilistic learning task to demonstrate that event-related responses measured by electroencephalography and magnetoencephalography display spatiotemporal patterns that allow an effective transfer of a multivariate statistical model discriminating the outcomes across the following conditions: (a) erroneous versus correct motor output, (b) negative versus positive feedback, (c) high- versus low-surprise negative feedback, and (d) erroneous versus correct brain-computer-interface output. We further show that these patterns originate from highly-overlapping neural sources in the medial frontal and the medial parietal cortices. We conclude that information about action outcomes arriving from internal or external sensory channels converges to the same neural system in the human brain, that matches this information to the internal predictions. PMID- 29974562 TI - Hypercoiled cord can cause a reversible abnormal Doppler in ductus venosus in cases of fetal growth restriction. AB - AIM: Although an absent or reversed a-wave in ductus venosus (DV-RAV) is reported to be the terminal finding of fetal growth restriction (FGR), we have seen DV-RAV that disappears within a short span of time in some FGR cases with a hypercoiled cord. The purpose of this study was to investigate the relationship between hypercoiled cord and reversible DV-RAV in FGR. METHODS: This was a retrospective study of 499 FGR cases, including 14 with DV-RAV. Transabdominal amnioinfusion (AI) was performed when oligohydramnios was severe (maximum vertical pocket <2 cm) and/or variable deceleration was detected. DV-RAV that disappeared quickly was defined as 'temporary DV-RAV'. DV-RAV that continued until delivery or fetal death (FD) was defined as 'persistent DV-RAV'. A hypercoiled cord was defined as one with an umbilical coiling index >0.6 antenatally or >0.3 postnatally. Clinical characteristics and clinical courses of the two types of DV-RAV were compared. RESULTS: DV-RAV disappeared after AI in all five cases in which temporary DV-RAV was identified. The incidence of a hypercoiled cord was significantly higher among temporary DV-RAV cases (100%) than among persistent DV RAV cases (14.3%; P = 0.015). The time from detection of DV-RAV to delivery or FD was significantly longer among temporary DV-RAV cases (4.5 weeks) than among persistent DV-RAV cases (0.7 weeks; P = 0.027). CONCLUSION: Temporary DV-RAV is suspected to be related to the combination of a hypercoiled cord and oligohydramnios. DV-RAV may not be always be a terminal finding in FGR with a hypercoiled cord. PMID- 29974561 TI - Chemoenzymatic Route to Oxyfunctionalized Cembranoids Facilitated by Substrate and Protein Engineering. AB - Cembranoids constitute a large family of 14-membered oxygenated macrocyclic diterpenoids with potential as therapeutic agents. Selective late-stage oxidations of cembranoid scaffolds remain a challenge for chemical catalysts but can be accomplished by enzymes. Here, a new chemoenzymatic route to oxyfunctionalized 14-membered macrocycles including cembranoids is described. This route combines a metal-catalyzed ring-closing metathesis with a subsequent P450 BM3-catalyzed hydroxylation and delivers cembranoid-like analogues. Systematic substrate probing with a set of synthetic 14-membered macrocycles revealed that the regioselectivity of a P450 BM3-based biocatalyst increased with increasing ring rigidity as well as size and polarity of the exocyclic substituents. Enzyme regioselectivity could further be improved by first-sphere active site mutagenesis. The V78A/F87A variant catalyzed hydroxylation of cembranoid-ol (9S/R)-3 d with 90 % regioselectivity for C5 position. Extensive NMR analysis of Mosher esters and single crystal X-ray structure determination revealed a remarkable diastereoselectivity of this P450 BM3 mutant depending on substrate stereochemistry, which led exclusively to the syn-cembranoid-diols (5S,9S)-4 and (5R,9R)-4. PMID- 29974563 TI - A randomized clinical trial of the effectiveness of a Web-based health behaviour change support system and group lifestyle counselling on body weight loss in overweight and obese subjects: 2-year outcomes. AB - BACKGROUND: Weight loss can prevent and treat obesity-related diseases. However, lost weight is usually regained, returning to the initial or even higher levels in the long term. New counselling methods for maintaining lifestyle changes are urgently needed. OBJECTIVES: An information and communication technology-based health behaviour change support system (HBCSS) that utilizes persuasive design and methods of cognitive behavioural therapy (CBT) was developed with the aim of helping individuals to maintain body weight. The purpose of this study was to assess whether CBT-based group counselling combined with HBCSS or HBCSS alone helps to maintain improved lifestyle changes needed for weight loss compared to self-help guidance or usual care. METHODS: A randomized lifestyle intervention for overweight or obese persons (BMI 27-35 kg m-2 and age 20-60 years), recruited from the population registry in the city of Oulu, Finland, was conducted. This study comprised six randomly assigned study arms: CBT-based group counselling (eight sessions led by a nutritionist), self-help guidance-based group counselling (SHG; two sessions led by a nurse) and control, each with or without HCBSS, for 52 weeks. Subjects visited the study centre for anthropometric measurements, blood sample collection and to complete questionnaires at baseline, 12 and 24 months. The main outcome was weight change from baseline to 12 months and from baseline to 24 months. RESULTS: Of the 1065 volunteers screened for the study, 532 subjects (51% men) met the inclusion criteria and were enrolled. The retention rate was 80% at 12 months and 70% at 24 months. CBT-based counselling with HBCSS produced the largest weight reduction without any significant weight gain during follow-up. The mean weight change in this arm was 4.1% [95% confidence interval (CI), -5.4 to -2.8, P < 0.001) at 12 months and 3.4% (95% CI, -4.8 to -2.0, P < 0.001) at 24 months. HBCSS even without any group counselling reduced the mean weight by 1.6% (95% CI, -2.9 to -0.3, P = 0.015) at 24 months. CONCLUSION: The combination of CBT-based group counselling and HBCSS-based weight management is feasible for overweight or obese individuals. Moreover, HBCSS alone could be disseminated to the population at large as an effective means of treating obesity. PMID- 29974564 TI - Daily walking is effective for the management of pregnant women with gestational diabetes mellitus. AB - AIM: This study evaluated the usefulness of daily walking for gestational diabetes mellitus (GDM) management by analyzing the relationship between daily walking and glucose tolerance in pregnant women with GDM who were in the second trimester. METHODS: This longitudinal study was conducted at TOYOTA Memorial Hospital in Toyota, Japan, from January 2015 to June 2016. Pregnant women with GDM wore accelerometers on the waist for 7-12 weeks. RESULTS: Seventy-three women with GDM were included in the present study; data collected from 24 women were analyzed. The estimated number of steps walked daily showed a significant positive correlation (r = 0.798, P = 0.000) with energy expenditure related to physical activity. There was a significant negative correlation (r = -0.603, P = 0.014) between the post- to pre-research casual glucose level (CGL) ratio and the number of steps walked daily. No significant correlation (r = -0.004, P = 0.986) was detected between the ratio of hemoglobin A1c and the number of steps taken. When the study was completed, the 11 participants who walked >=6000 steps/day showed significantly lower CGL (95 + 10 mg/dL [mean + SD]) than the 13 participants in the <6000 steps/day group (111 + 18 mg/dL) (P = 0.013). CONCLUSION: Simple walking for light intensity physical activity is effective for controlling the CGL in pregnant women with GDM. We recommend that pregnant women with GDM should walk a minimum of 6000 steps/day. PMID- 29974565 TI - Factors associated with mental health among high school students in Iran: Does mobile phone overuse associate with poor mental health? AB - PROBLEM: Mobile phone (MP) overuse is extensively rising among high school students in developing countries. Our aim in this study is to investigate the association between MP overuse and mental health, in the presence of other determinant factors, among high school students in Iran. METHODS: We recruited a clustered random sample of 1,034 high school students in Saqqez County, Iran, to complete a self-administered questionnaire with three sections: a sociodemographic questionnaire, Mobile Phone Addiction Index, and General Health Questionnaire. FINDINGS: A majority of the students (n = 654, 63.2%) were found to be with poor mental health. Applying multiple logistic regression, gender (odds ratio [OR] = 1.5; 95% confidence interval [CI] = 1.15-1.97), education degree (OR = 1.47; 95% CI = 1.30-1.67), frequency of daily messages (OR = 1.18; 95% CI = 1.07-1.31), being awakened at night for MP use (OR = 1.83; 95% CI = 1.54 2.18), and MP overuse (OR = 3.21; 95% CI = 1.20-8.58) were found in significant associations with poor mental health. CONCLUSIONS: Planning gender-based health education programs on proper use of MP for students and their parents is suggested to school healthcare providers. The parents should be educated on the proper ways of dealing with their adolescents while using MP at home. PMID- 29974566 TI - Prevalence of primary dysmenorrhea and its relationship with body mass index. AB - AIM: To identify the association between primary dysmenorrhea (PD) and body mass index (BMI). METHODS: This cross sectional study was conducted on 370 female students (aged 18-25 years) of Immam Abdulrahman Bin Faisal University Dammam, from March 2016 till March 2017. Pretested dysmenorrhea questionnaire was filled by the students. Weight and heights of the subjects were measured, and BMI was calculated. Based on BMI, subjects were divided into four groups (underweight [UW], normal weight, overweight and obese [OB]). Subjects were also categorized into mild, moderate and severe dysmenorrhic groups based on numeric pain relating scale. SPSS version 20.0 was used to analyze the data. RESULTS: This study showed that 85.7% of the students were suffering from PD, out of which 12.7% had mild, 65.6% had moderate and 8.4% had severe dysmenorrhea. In total, 54.5% of the students mentioned that dysmenorrhea interferes with their daily activities. Whereas 55.8% of the students mentioned that they got pain relief by using non steroidal anti-inflammatory drugs. Pair wise comparison of dysmenorrhea between different BMI groups showed a statistically significant difference in the frequency of moderate and severe dysmenorrhea between UW and OB subjects (P values 0.003 and 0.06) respectively, indicating that UW females are at a higher risk of having PD. CONCLUSION: This study indicates a higher prevalence of moderate and severe dysmenorrhea in UW as compared to the OB subjects. We recommend further studies to explore the underlying pathophysiological mechanisms responsible for this association. PMID- 29974567 TI - Uterine rupture due to placenta percreta in the first trimester of a pregnancy subsequent to a transverse uterine fundal cesarean section: A case report. AB - Transverse uterine fundal cesarean section in cases of total placenta previa reduces blood loss, but its influence on subsequent pregnancies, including the uterine rupture risk, remains unclear. We report a case of uterine rupture due to placenta percreta in the first trimester in a 43-year-old woman who underwent transverse uterine fundal incision in a previous pregnancy (at 40 years old). The patient did not undergo assessment of the uterine scare after the previous operation. Oocyte donation and in vitro fertilization at another institution resulted in the current pregnancy. At 11 weeks 3 days, she was admitted to the emergency department because of sudden severe abdominal pain. Ultrasound showed massive accumulation of free fluid in the peritoneal cavity and the fetus was outside the uterine cavity; uterine rupture was diagnosed. During emergency laparotomy, the uterine rupture was detected at exactly the previous incision site; a total hysterectomy was performed. Pregnancy after a transverse uterine fundal cesarean section is at high risk. As uterine scar dehiscence might have caused the uterine rupture, wounds should be evaluated before allowing subsequent pregnancies. PMID- 29974568 TI - Intermittent aortic balloon occlusion combined with cesarean section for the treatment of patients with placenta previa complicated by placenta accreta: A retrospective study. AB - AIM: To compare the efficacy of cesarean section (CS) combined with intermittent aortic balloon occlusion with that of CS alone for treating patients with placenta previa complicated by placenta accreta. METHODS: Forty-five patients with placenta previa complicated by placenta accreta who underwent CS were retrospectively studied. Twenty-two patients had undergone CS combined with intermittent aortic balloon occlusion (combination group) and 23 patients received conventional hemostatic support only (control group). The postpartum hemorrhage, transfusion requirements, operation time and recovery time, and the ability to preserve the uterus and fertility were analyzed. RESULTS: Intermittent aortic balloon occlusion significantly decreased the volume of blood loss in the combination group relative to the control group (597 +/- 359 mL vs 2687 +/- 575 mL; P < 0.001), and transfusion requirements were also reduced (498 +/-195 mL vs 2390 +/-789 mL; P <0.001). We observed shorter operation time in the combination group relative to the control group (63.8 +/- 12.3 min vs 118.8 +/- 22.4 min; P < 0.001), and fewer patients required uterine cavity stuffing followed by uterine artery embolization (n = 2 vs n = 10; P <0.05), uterine artery ligation (n = 1 vs n = 9; P < 0.05), and hysterectomy (n = 0 vs n =7; P < 0.05). CONCLUSION: Intermittent aortic balloon occlusion may control postpartum hemorrhage in pregnancies complicated by placenta accreta, and improve the postoperative conditions. PMID- 29974569 TI - Addiction Lives: Betsy Thom. PMID- 29974571 TI - Early medical abortion with self-administered low-dose mifepristone in combination with misoprostol. AB - AIM: The aim of the present study was to investigate the safety and efficacy of low-dose mifepristone combined with self-administered misoprostol for termination of early pregnancy. METHODS: A total of 533 women seeking medical abortion in early pregnancy (<=49 days since the last menstrual period) were divided randomly into hospital- (H-Mis, 250) and self- (S-Mis, 283) administered misoprostol groups. Women in two groups took 100 mg of oral mifepristone in hospital followed by 200 MUg of sublingual misoprostol 24 h later in hospital or home. The primary outcome parameter was complete abortion without surgical intervention. Secondary outcomes were uterine bleeding, return of regular menses, side effects and patient acceptability. RESULTS: High rates of complete abortion were observed for both the H-Mis group (243/250; 94.8%) and the S-Mis group (266/283; 94.0%). No significant differences in outcomes (complete abortion/failure rates) or side effects were observed between the two groups. General satisfaction rates were similar for the two groups (H-Mis, 231/250, 92.4%; S-Mis, 263/283, 92.9%; P > 0.05). Higher convenience of administration (H-Mis, 211/250, 84.4%; S-Mis, 270/283, 95.4%; P < 0.05) and privacy protection (H-Mis, 214/250, 85.6%; S-Mis, 267/283, 94.3%; P < 0.05) satisfaction rates were obtained for the S-Mis group than for the H-Mis group. CONCLUSION: Self-administered sublingual misoprostol is as safe and effective as hospital-administered misoprostol following low-dose mifepristone to terminate early pregnancy (<=49 days of amenorrhoea) with fewer side effects. PMID- 29974570 TI - Disrupted neural variability during propofol-induced sedation and unconsciousness. AB - Variability quenching is a widespread neural phenomenon in which trial-to-trial variability (TTV) of neural activity is reduced by repeated presentations of a sensory stimulus. However, its neural mechanism and functional significance remain poorly understood. Recurrent network dynamics are suggested as a candidate mechanism of TTV, and they play a key role in consciousness. We thus asked whether the variability-quenching phenomenon is related to the level of consciousness. We hypothesized that TTV reduction would be compromised during reduced level of consciousness by propofol anesthetics. We recorded functional magnetic resonance imaging signals of resting-state and stimulus-induced activities in three conditions: wakefulness, sedation, and unconsciousness (i.e., deep anesthesia). We measured the average (trial-to-trial mean, TTM) and variability (TTV) of auditory stimulus-induced activity under the three conditions. We also examined another form of neural variability (temporal variability, TV), which quantifies the overall dynamic range of ongoing neural activity across time, during both the resting-state and the task. We found that (a) TTM deceased gradually from wakefulness through sedation to anesthesia, (b) stimulus-induced TTV reduction normally seen during wakefulness was abolished during both sedation and anesthesia, and (c) TV increased in the task state as compared to resting-state during both wakefulness and sedation, but not anesthesia. Together, our results reveal distinct effects of propofol on the two forms of neural variability (TTV and TV). They imply that the anesthetic disrupts recurrent network dynamics, thus prevents the stabilization of cortical activity states. These findings shed new light on the temporal dynamics of neuronal variability and its alteration during anesthetic-induced unconsciousness. PMID- 29974572 TI - Volatile, phenolic, and sensory profiles of in-amphorae Chardonnay wine by mass spectrometry and chemometric analysis. AB - The sensory properties, the phenolic composition, and the volatile profile of Chardonnay wine made in amphorae were compared with the wine obtained in large wooden barrels (2000 L) and small toasted barrels (225 L). Hierarchical cluster analysis and principal component analysis built on the phenolics and volatiles variables allowed to group effectively the samples according to the winemaking material used. In-amphorae wines showed more abundant catechin and caffeic acid and less abundant caftaric acid and trans-coutaric acid. Condensation reactions proceeded in the wood containers leading to esterification of organic acids with ethanol and alcohols, whereas in-amphorae wines were characterized by a higher content of free phenolic acids and higher volatile alcohols. Among the volatile compounds, ramified ethyl esters contributed mostly in samples made in small toasted barrels, whereas nonbranched ethyl esters contributed more for the samples made in large wooden tanks; higher alcohols contributed more for the in amphorae wine. The sensory analysis showed negligible differences induced by the in-amphorae vinification with respect to the wooden one. Four variables could distinguish wines made in-amphorae compared with the other containers: solvent and acetone (SA), astringent/pungency (AP), fruity (FR), and color intensity (CI). The overall approach proposed here is promising for future developments of innovative types of Chardonnay wine blends. PMID- 29974573 TI - Pregnancy in liver transplant recipients: A single center outcomes. AB - AIM: Liver transplantation (LT) is the only effective treatment for the end-stage liver disease. Although pregnancy after LT is considered to be safe, these patients are difficult to manage for obstetricians. In this study, we aimed to determine maternal and fetal outcomes in pregnancies after LT. METHODS: We conducted a retrospective review of liver transplant recipients who had received prenatal care and delivered pregnancy at Istanbul University Istanbul Medical Faculty, Department of Obstetrics and Gynecology January 2010 and January 2017. RESULTS: A total of eight pregnancies were identified during the study period. The mean age of the patients at the time of LT was 25.6 +/- 5.3 years (range 19 36 years), and the mean age at conception was 30.1 +/- 5.2 years (range 25-41 years). The mean interval between transplantation and conception was 54.2 +/- 18.6 months (range 24-82 months). There was no a miscarriage or a stillbirth was observed in any of patients. Mean birth week was 37.2 +/- 2.1 weeks and mean birthweight was 2852 +/- 562 g (range 2150-3470 g). Three of eight deliveries (37.5%) occurred before 37 gestational weeks. Preeclampsia was detected in one patient, one pregnancy was complicated by intrauterine growth retardation and one case with gestational diabetes mellitus. Mean postnatal follow-up period was 3.2 +/- 2.4 years (range 1-7 years) and all of the babies were healthy. Graft rejection occurred in one patient after delivery. CONCLUSION: More favorable pregnancy outcomes can be achieved with a multidisciplinary team and satisfactory counseling is mandatory either preconception and through the pregnancy to reduce maternal-fetal risks. PMID- 29974574 TI - Complications with vacuum delivery from a forceps-delivery perspective: Progress toward safe vacuum delivery. AB - AIM: To examine the rates of medical malpractice and cerebral palsy after vacuum delivery in comparison with forceps delivery and establish approaches for enabling safe vacuum delivery from the perspective of forceps delivery. METHODS: This study reviewed the Japan Obstetric Compensation System report data, which contains data from studies involving 188 cases through May 2013, including cases of emergency delivery. These cases included 118 cases of cesarean section (62.8%) and 70 cases of vaginal delivery (37.2%). Of the 188 patients, 145 required emergency delivery (77.1%), of which cesarean sections were performed in 117 patients (80.7%), vacuum delivery in 24 patients (16.6%) and forceps delivery in 4 patients (2.8%). RESULTS: In evaluating the contents of the report with a focus on vacuum delivery, it was found that vacuum delivery was attempted in 35 patients, and delivery was successful in 24 of these patients (68.6%); however, in 11 patients (31.4%), delivery was unsuccessful and cesarean section was required. Thus, vacuum delivery was unsuccessful in approximately one third of the cases. CONCLUSION: For delivery to be completed as successfully and quickly as possible, it is essential for obstetricians to have a good understanding of the process of vacuum delivery, and to have expertise in the relevant techniques. However, it is also necessary to modify the indications under which vacuum delivery is considered safe to perform, from fetal station +/-0, that is, engagement of the fetal head, to station +2, or descent of the fetal head. PMID- 29974576 TI - Neighbourhood social inclusion from the perspective of people with intellectual disabilities: Relevant themes identified with the use of photovoice. AB - BACKGROUND: Earlier studies show that to gain more understanding of the concept of social inclusion, the views and experiences of people with intellectual disabilities are needed. The aim of this study was to investigate their perspective on neighbourhood social inclusion from an ecological point of view. METHOD: We carried out a photovoice study with 18 people with intellectual disabilities in three neighbourhoods in the Netherlands. Participants took photographs in their neighbourhood they considered relevant, and these photographs were discussed during an interview. RESULTS: Six themes emerged from qualitative analysis: attractiveness of the neighbourhood, social contacts in the neighbourhood, activities in the neighbourhood, social roles in the neighbourhood, independence and public familiarity. CONCLUSIONS: As regards neighbourhood social inclusion, participants were often focused on small and informal activities and situations. Public familiarity proved very important. Framing the concept of neighbourhood social inclusion within an ecological approach may help to better understand processes of social inclusion. PMID- 29974575 TI - UHPLC-ESI-QqTOF-MS/MS characterization of minor chlorogenic acids in roasted Coffea arabica from different geographical origin. AB - Chlorogenic acids are relevant coffee quality markers, taste, and aroma precursors as well as important bioactive compounds. A number of mono-acyl, di acyl, and tri-acyl quinic acid isomers were found in green coffee beans, being mono-caffeoyl, mono-feruloyl, mono-p-coumaroyl, and di-caffeoylquinic acid isomers considered as quantitatively major compounds. Roasting process increases the chemical complexity of coffee by inducing the formation of a number of lactones (quinides), shikimates, and other chlorogenic acids derivatives. So far, little attention has been paid in characterizing minor chlorogenic acids and derivatives in roasted Coffea arabica, also known as Arabica. In the present work, roasted C. arabica samples from different geographical origins (Brazil, Colombia, Costa Rica, Ethiopia, Guatemala, and India) were characterized by UHPLC ESI-QqTOF-MS/MS. Several minor chlorogenic acid isomers were identified. In particular, HR-MS/MS provided putative identification of four dimethoxycinnamoyl quinic acid derivatives, such as 4-dimethoxycinnamoylquinic acid, 4 dimethoxycinnamoyl-3-caffeoylquinic acid, 3-dimethoxycinnamoyl-4-feruloylquinic acid, 4-dimethoxycinnamoyl-5-feruloylquinic acid, and two caffeoyl, feruloyl quinic acid derivatives (3-caffeoyl-4-feruloylquinic acid and 3-feruloyl-4 caffeoylquinic acid). To our knowledge, these compounds were found in roasted Arabica coffee for the first time, and their presence is independent on the different geographical origins examined. PMID- 29974577 TI - Lewis Acid Guests in a {P8 W48 } Archetypal Polyoxotungstate Host: Enhanced Proton Conductivity via Metal-Oxo Cluster within Cluster Assemblies. AB - Complexes made by hosts that completely surround their guests provide a means to stabilize reactive chemical intermediates, transfer biologically active cargo to a diseased cell, and construct molecular-scale devices. By the virtue of inorganic host-guest self-assembly, nucleation processes in the cavity of a {P8 W48 }-archetype phosphotungstate has afforded a nanoscale 16-AlIII -32-oxo cluster and its GaIII analogue that contain the largest number of AlIII /GaIII ions yet found in polyoxometalate (POM) chemistry. Interestingly, the rich Lewis acid AlIII centers within the Lewis base POM support shows an exceptional proton conductivity of 4.5*10-2 S cm-1 (85 degrees C, 70 % RH; RH: relative humidity), which is by far the highest conductivity reported among POM-based single-crystal proton conductors. PMID- 29974578 TI - Carboxylic acid Functionalized Cage-Type Mesoporous Silica FDU-12 as Support for Controlled Synthesis of Platinum Nanoparticles and Their Catalytic Applications. AB - Carboxylic acid functionalized 3D cage-type mesoporous silica FDU-12 with high surface area and pore volume was synthesized by a one-pot co-condensation method and used as support to synthesize Pt nanoparticles (NPs). The uniformly distributed COOH groups in the cage can control the growth of Pt NPs with high dispersion (Pt@CF-12). Pt@CF-12 was used as catalyst for the hydrolysis of ammonia borane to generate H2 and for the reduction of 4-nitrophenol to 4 aminophenol. The catalyst exhibits higher catalytic activity (H2 generation rate of 17.8 L H2 min-1 gcat-1 ) and lower activation energy of 30.67 kJ mol-1 compared with other Pt-based silica catalysts due to the small size of the Pt NPs (3.5 nm) and cage-type porous structure of the support, which allowed easy diffusion of reactants. Pt@CF-12 has excellent durability, since the support prevented NP aggregation and leaching of NPs during catalysis. Pt@CF-12 can convert 93 % of 4-nitrophenol to 4-aminophenol within 10 min. PMID- 29974579 TI - Urogenital symptoms in women with Tarlov cysts. AB - AIM: To describe the clinical findings and urogenital symptoms associated with sacral perineural cysts (Tarlov cysts). METHODS: A retrospective chart review including 65 female patients with Tarlov cysts was completed. Clinical findings were collected from a database of subjects seen in our institution's urogynecology and neurosurgery clinics between 2004 and 2015. A statistical analysis was performed to test for any correlation between cyst size or location, and patient symptoms or examination findings. RESULTS: Tarlov cysts were most commonly located from S2 to S3 (73%), and ranged in size from 1 to 2 cm (55%). Frequently reported symptoms included lower back pain (83%, 95% confidence interval [CI] 0.71-0.91), lower extremity radiculopathy (75%, CI 0.63-0.85), positional pain (62%, CI 0.50-0.73), urinary urgency (54%, CI 0.41-0.66) and urinary frequency (48%, CI 0.35-0.61). Common urodynamic findings included an early sensation of filling (70%), involuntary detrusor contractions (33%), urethral instability (33%) and stress urinary incontinence (33%). A statistical analysis comparing cyst size and location to clinical findings was significant for a correlation between an S2 location and central nervous system symptoms (P = 0.02), larger cyst size and urinary dysfunction (P = 0.05) and smaller cyst size and an early sensation of filling (P = 0.05). CONCLUSION: Patients with symptomatic sacral Tarlov cysts frequently report pain and neuropathy related to the lower back, pelvis and urogenital system. As compared to the general population, urinary urgency and urodynamic findings associated with urgency were more frequent in our patient sample. These findings suggest that Tarlov cysts may have a clinically significant impact on urogenital function. PMID- 29974580 TI - Geometrical Structure of the Gold-Iron(III) Oxide Interfacial Perimeter for CO Oxidation. AB - The geometrical structure of the Au-Fe2 O3 interfacial perimeter, which is generally considered as the active sites for low-temperature oxidation of CO, was examined. It was found that the activity of the Au/Fe2 O3 catalysts not only depends on the number of the gold atoms at the interfacial perimeter but also strongly depends on the geometrical structure of these gold atoms, which is determined by the size of the gold particle. Aberration-corrected scanning transmission electron microscopy images unambiguously suggested that the gold particles, transformed from a two-dimensional flat shape to a well-faceted truncated octahedron when the size slightly enlarged from 2.2 to 3.5 nm. Such a size-induced shape evolution altered the chemical bonding environments of the gold atoms at the interfacial perimeters and consequently their catalytic activity. For Au particles with a mean size of 2.2 nm, the interfacial perimeter gold atoms possessed a higher degree of unsaturated coordination environment while for Au particles with a mean size of 3.5 nm the perimeter gold atoms mainly followed the atomic arrangements of Au {111} and {100} facets. Kinetic study, with respect to the reaction rate and the turnover frequency on the interfacial perimeter gold atom, found that the low-coordinated perimeter gold atoms were intrinsically more active for CO oxidation. 18 O isotopic titration and Infrared spectroscopy experiments verified that CO oxidation at room temperature occurred at the Au-Fe2 O3 interfacial perimeter, involving the participation of the lattice oxygen of Fe2 O3 for activating O2 and the gold atoms for CO adsorption and activation. PMID- 29974581 TI - Evolution of protein trafficking in kinetoplastid parasites: Complexity and pathogenesis. AB - The kinetoplastida and their close relatives are unicellular organisms prevalent within the biosphere and important for significant impacts on global health, economy and ecosystems. They are, under most models, an early branching lineage. Individual species adapted to highly diverse environments by adopting complex life styles; parasitic species can infect a wide range of eukaryotic hosts, while many relatives are free-living and some autotrophic from acquiring a plastid for photosynthesis. Adaptation is especially evident in the evolution of kinetoplastid cell surface architecture and is supported by endomembrane trafficking and serves as a platform for interaction with its environment. Here we summarize and discuss recent genomic and experimental studies of the protein trafficking system in kinetoplastids, with focus on the composition and function of the surface as well as mechanisms for constructing, maintaining and regulating the cell surface proteome. We hope this provides a broad view of how protein trafficking contributes to the intricate and dynamic host-parasite interfaces that are critical for successful environmental adaptation of this highly important lineage. PMID- 29974582 TI - The hepatitis C cascade of care in people who inject drugs in Dar es Salaam, Tanzania. AB - The World Health Organisation has recently called for hepatitis C virus (HCV) elimination and has identified people who inject drugs (PWID) as a key population to scale-up screening and linkage to care. This study reports the cascade of care for HCV in PWID attending the largest opioid substitution treatment (OST) clinic in Dar-es-Salaam, Tanzania. Between February 2011 and March 2016, HCV serology for all PWID registered at the Muhimbili National Hospital OST clinic, Dar-es Salaam were obtained from records. In 2015, consecutive HCV-seropositive PWID were invited to undergo a clinical evaluation including epidemiological questionnaire, liver stiffness measurement (Fibroscan) and virological analysis (HCV RNA viral load and genotyping). During the study period, 1350 persons registered at the OST clinic: all had a HCV serology including 409 (30%) positive results. Among the HCV-seropositive individuals, 207 (51%) were active attenders and 153 (37%) were enrolled for clinical assessment: 141 (92%) were male, median age: 38 years (IQR 34-41), and 65 (44%) were co-infected with HIV; 116 patients (76%) had detectable HCV RNA, with genotypes 1a (68%) and 4a (32%); 21 (17%) had clinically significant fibrosis (>=F2) and 6 (5%) had cirrhosis (F4). None were offered HCV treatment. Chronic hepatitis C among PWID enrolled in the OST centre in Dar-es-Salaam is frequent, but its continuum of care is insufficient; integration of HCV diagnosis and treatment should form a part of OST intervention in PWID in Tanzania. PMID- 29974583 TI - Stack the Bowls: Tailoring the Electronic Structure of Corannulene-Integrated Crystalline Materials. AB - We report the first examples of purely organic donor-acceptor materials with integrated pi-bowls (piBs) that combine not only crystallinity and high surface areas but also exhibit tunable electronic properties, resulting in a four-orders of-magnitude conductivity enhancement in comparison with the parent framework. In addition to the first report of alkyne-azide cycloaddition utilized for corannulene immobilization in the solid state, we also probed the charge transfer rate within the Marcus theory as a function of mutual piB orientation for the first time, as well as shed light on the density of states near the Fermi edge. These studies could foreshadow new avenues for piB utilization for the development of optoelectronic devices or a route for highly efficient porous electrodes. PMID- 29974584 TI - The fronto-insular cortex causally mediates the default-mode and central executive networks to contribute to individual cognitive performance in healthy elderly. AB - The triple network model that consists of the default-mode network (DMN), central executive network (CEN), and salience network (SN) has been suggested as a powerful paradigm for investigation of network mechanisms underlying various cognitive functions and brain disorders. A crucial hypothesis in this model is that the fronto-insular cortex (FIC) in the SN plays centrally in mediating interactions between the networks. Using a machine learning approach based on independent component analysis and Bayesian network (BN), this study characterizes the directed connectivity architecture of the triple network and examines the role of FIC in connectivity of the model. Data-driven exploration shows that the FIC initiates influential connections to all other regions to globally control the functional dynamics of the triple network. Moreover, stronger BN connectivity between the FIC and regions of the DMN and the CEN, as well as the increased outflow connections from the FIC are found to predict individual performance in memory and executive tasks. In addition, the posterior cingulate cortex in the DMN was also confirmed as an inflow hub that integrates information converging from other areas. Collectively, the results highlight the central role of FIC in mediating the activity of large-scale networks, which is crucial for individual cognitive function. PMID- 29974586 TI - Family and community in the lives of UK Bangladeshi parents with intellectual disabilities. AB - BACKGROUND: Little is known about the lives of parents with intellectual disabilities from minority ethnic communities. Previous research suggests that what it means to live with intellectual disabilities varies across cultural contexts. The current research aimed to explore how cultural values and practices impact upon the experiences of parents with intellectual disabilities within the Bangladeshi community in London, England. METHOD: Six members of the Bangladeshi community, four Bangladeshi parents with intellectual disabilities and four of their family members were interviewed. Thematic analysis was used to identify key themes. RESULTS: Both parenting and intellectual disability are thought about in this community in ways that make parenting more accessible for people with learning disabilities, but also create tensions to be negotiated. CONCLUSIONS: Bangladeshi family carers face dilemmas balancing the benefits and risks of promoting parenting for sons and daughters with intellectual disabilities, particularly in the context of service principles of autonomy and informed consent. PMID- 29974587 TI - Cesarean scar pregnancy with deep serosal invasion at 16 weeks: Uterus-sparing surgery with posterior hysterotomy after transcatheter arterial embolization. AB - We report a case of cesarean scar pregnancy at 16 weeks. Magnetic resonance imaging confirmed the isthmic ectopic location with an empty fundus and a high suspicion of placental invasion to the anterior myometrium. Because of pelvic pain, bleeding and the major risks of hysterectomy, a decision was made to terminate the pregnancy. After a preventive pelvic artery embolization, we performed an unusual posterior isthmic hysterotomy for the extraction of the fetus, followed by conservative management of the placenta. Bleeding loss was 300 mL, and no complication was reported. Successive magnetic resonance imaging was planned and 6 months later, there were no placental remnants. At 7 months, an office hysteroscopy revealed a normal uterine cavity. In case of cesarean scar pregnancy in the second trimester with an emergency need to interrupt pregnancy, posterior hysterotomy with conservative treatment of placenta may be an option to avoid massive bleeding and hysterectomy. PMID- 29974585 TI - Effects of the interaction between glycated haemoglobin genetic risk score and postpartum weight reduction on glycaemic changes: A gene-weight interaction analysis. AB - AIM: To investigate the effects of the interaction between glycated haemoglobin (HbA1c) genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on long-term glycaemic changes in the largest cohort of women with a history of gestational diabetes mellitus (GDM). METHODS: This was a retrospective cohort using the baseline data from the Tianjin Gestational Diabetes Mellitus Prevention Programme. A genetic risk score was established by combining 10 HbA1c-related single-nucleotide polymorphisms, which were identified by genome-wide association studies. General linear regression models were applied to evaluate the effect of interaction between HbA1c genetic risk score and weight changes during and after pregnancy (postpartum weight reduction and gestational weight gain) on glycaemic changes. RESULTS: 'A total of 1156 women with a history of GDM were included in this respective cohort study. Statistical differences in pre-pregnancy weight, pre delivery weight and postpartum weight were evidenced across different groups of postpartum weight reduction. After adjusting for covariates, statistical significance for changes in HbA1c level was only observed in the postpartum weight reduction <5 kg/y group (P = 0.002), and a significant effect of interaction between HbA1c genetic risk score and postpartum weight reduction on long-term changes in HbA1c was evidenced (P interaction = 0.01). In women with postpartum weight reduction >=8 kg/y, those with a lower HbA1c genetic risk score had a greater decrease in HbA1c level. CONCLUSIONS: HbA1c genetic risk score interacts with postpartum weight reduction to affect long-term changes in HbA1c levels among women with a history of GDM. PMID- 29974588 TI - Peripheral Amplification of Multi-Resonance Induced Thermally Activated Delayed Fluorescence for Highly Efficient OLEDs. AB - Multi-resonance induced by boron and nitrogen atoms in opposite resonance positions endows a thermally activated delayed fluorescence (MR-TADF) emitter with a strikingly small full width at half maximum of only 26 nm and excellent photoluminescence quantum yield of up to 97.48 %. The introduction of a carbazole unit in the para position of the B-substituted phenyl-ring can significantly boost up the resonance effect without compromising the color fidelity, subsequently enhancing the performances of the corresponding pure blue TADF-OLED, with an outstanding external quantum efficiency (EQE) up to 32.1 % and low efficiency roll-off, making it one of the best TADF-OLEDs in the blue region to date. Furthermore, utilizing this material as host for a yellow phosphorescent emitter, the device also shows a significantly reduced turn-on voltage of 3.2 V and an EQEmax of 22.2 %. PMID- 29974589 TI - Ovarian reserve after internal iliac artery ligation. AB - AIM: Ligation of major vessels supplying ovaries may alter hormones and ovarian reserve due to disturbances of vascular circulation. Our purpose is to measure serum anti-Mullerian hormone (AMH) levels and ovarian volume in patients who had internal iliac artery ligation (IIAL) and/or IIAL plus hysterectomy due to uterine atony. METHODS: Patients who underwent IIAL and IIAL+ hysterectomy were evaluated 6 months after their operations and were compared with the control group. The hormones, ovarian volume and antral follicle count (AFC) were measured in each group. RESULTS: Serum AMH levels in the post-partum 6th month interval were lower in the IIAL group than in the control group and were the lowest in the IIAL+ hysterectomy group. Similar to AMH results, AFC and ovarian volumes were also lowest in the IIAL+ hysterectomy group. CONCLUSION: IIAL and hysterectomy are lifesaving interventions during peripartum hemorrhage; however, they might alter ovarian reserve in the short term. PMID- 29974590 TI - Erratum. PMID- 29974591 TI - Reply. PMID- 29974592 TI - Ultrasound fetal weight estimation at term may do more harm than good. PMID- 29974593 TI - Re: De-novo abnormal uteroplacental circulation in third trimester: pregnancy outcome and pathological implications. J. Binder, C. Monaghan, B. Thilaganathan, S. Carta and A. Khalil. Ultrasound Obstet Gynecol 2018; 52: 60-65. PMID- 29974595 TI - Re: Small-for-gestational-age babies after 37 weeks: impact study of risk stratification protocol. M. Veglia, A. Cavallaro, A. Papageorghiou, R. Black and L. Impey. Ultrasound Obstet Gynecol 2018; 52: 66-71. PMID- 29974594 TI - Re: Three-dimensional ultrasound imaging of intra-abdominal cervical-isthmus cerclage. PMID- 29974596 TI - ISUOG Practice Guidelines: intrapartum ultrasound. AB - PURPOSE AND SCOPE: The purpose of these Guidelines is to review the published techniques of ultrasound in labor and their practical applications, to summarize the level of evidence regarding the use of ultrasound in labor and to provide guidance to practitioners on when ultrasound in labor is clinically indicated and how the sonographic findings may affect labor management. We do not imply or suggest that ultrasound in labor is a necessary standard of care. PMID- 29974597 TI - Erratum. PMID- 29974598 TI - Mass spectrometric detection of the Gibbs reaction for phenol analysis. AB - This paper describes a new method for detecting phenols, by reaction with Gibbs reagent to form indophenols, followed by mass spectrometric detection. Unlike the standard Gibbs reaction, which uses a colorometric approach, the use of mass spectrometry allows for simultaneous detection of differently substituted phenols. The procedure is demonstrated to work for a large variety of phenols without para-substitution. With para-substituted phenols, Gibbs products are still often observed, but the specific product depends on the substituent. For para groups with high electronegativity, such as methoxy or halogens, the reaction proceeds by displacement of the substituent. For groups with lower electronegativity, such as amino or alkyl groups, Gibbs products are observed that retain the substituent, indicating that the reaction occurs at the ortho or meta position. In mixtures of phenols, the relative intensities of the Gibbs products are proportional to the relative concentrations, and concentrations as low as 1 MUmol/L can be detected. The method is applied to the qualitative analysis of commercial liquid smoke, and it is found that hickory and mesquite flavors have significantly different phenolic composition. PMID- 29974599 TI - Basic research on uterus transplantation in nonhuman primates in Japan. AB - Uterus transplantation (UTx) is now a potential option for women with uterine factor infertility to have a child. However, UTx is still in an experimental stage and basic animal studies including in nonhuman primates are needed for accumulation of data that will provide important information for establishment of UTx in humans. Herein, we summarized our experiences using cynomolgus macaques, with the goal of promoting further development of UTx studies in nonhuman primates. Our basic studies using cynomolgus macaques were summarized, including the results of other teams in nonhuman primates. Our team in Japan launched UTx research in 2009 using cynomolgus macaques and has accumulated a large archive of results in the UTx research field, including examination of uterine blood flow, surgical procedures of autologous and allogeneic UTx, organ perfusion methods in deceased donor models, immunological response and rejection and ischemia/reperfusion injury. We achieved the first delivery after autologous UTx in primates and the first periodic recovery of menstruation after allogeneic UTx in nonhuman primate models. Results from animal studies, including those in nonhuman primates, provide the basis for clinical application of UTx. Therefore, our accumulated data since 2009 and our basic experience in cynomolgus macaque are meaningful for future UTx trials in Japan. In addition, more validation in nonhuman primate models is needed for resolution of medical issues and further development of UTx in humans, despite clinical application of UTx in several countries. PMID- 29974600 TI - 47-Fold rise of diabetes in childbearing age Chilean women: Markov model and cost effectiveness of prevention of birth defects. AB - AIM: Prevalence of type 2 diabetes mellitus (T2DM) during childbearing age in Chile had a 47-fold rise in 7 years, reaching 120 844 women, half of which are unaware of their condition. We aimed to project pregnancies and births among Chilean women of childbearing age (WCBA) with T2DM and report the incidence of birth defects and the associated years of life lost and lifetime costs. METHODS: Markov model of cohort of WCBA with T2DM (WCBA-DM) with a 20-year time horizon (2018-2037), using data from previous studies. Two scenarios were assessed: scenario A: no universal detection of T2DM and scenario B: universal screening of T2DM using glycosylated hemoglobin levels. Both lifetime costs and disability adjusted life years (DALY) were calculated with a 5% discount rate (US$ of 2017). RESULTS: In scenario A, 12 163 infants with birth defects could be born among the analyzed cohort, resulting in 243 260 years of life lost, 296 652 DALY and in lifetime costs of US$ 1 957 657 966. In scenario B, the first three figures could be reduced by 70.4% to 3599 infants with birth defects, 71 980 years of life lost and 87 794 DALY. Due to the addition of diabetes screening and new patient costs to scenario B, there would be a lesser reduction (67.3%) in total lifetime costs, to US$ 640 669 296. CONCLUSION: Screening of diabetes in WCBA would yield a 20 year reduction of 70.4% in the number of infants with birth defects, years of life lost and DALY. Total lifetime costs could be reduced by 67.3%. PMID- 29974601 TI - Small bowel perforation from foreign body ingestion. PMID- 29974602 TI - The role of adaptive strategies in plant naturalization. AB - Determining the factors associated with the naturalization of alien species is a central theme in ecology. Here, we tested the usefulness of a metric for quantifying Grime's seminal concept of adaptive strategies - competitors, stress tolerators and ruderals (CSR) - to explain plant naturalizations worldwide. Using a global dataset of 3004 vascular plant species, and accounting for phylogenetic relatedness and species' native biomes, we assessed the associations between calculated C-, S- and R-scores and naturalization success for species exhibiting different life forms. Across different plant life forms, C-scores were positively and S-scores negatively associated with both the probability of naturalization and the number of regions where the species has naturalized. R-scores had positive effects on the probability of naturalization. These effects of the scores were, however, weak to absent for tree species. Our findings demonstrate the utility of CSR-score calculation to broadly represent, and potentially explain, the naturalization success of plant species. PMID- 29974603 TI - Hydrocarbon biomarkers preserved in carbonate veins of potentially Paleoproterozoic age, and implications for the early biosphere. AB - Research on the early rise of oxygenic photosynthesis and eukaryotes has recently encountered a major pitfall, as some hopane and sterane biomarkers reported in Archaean rocks are the results of contamination. Following an extensive petrological framework in the Pilbara Craton, Western Australia, oil-bearing fluid inclusions and solid bitumens were identified in replacement and hydrothermal carbonate veins cross-cutting Archaean metasedimentary rocks. The 2.55-2.63 billion years old metasedimentary rocks were found to be depleted of indigenous biomarkers. Here we show novel biomarker results from the solvent extraction of the carbonate veins. Volcanic rock blanks, outside rinses, and instrumental blanks showed no biomarkers, and the surrounding rocks were metamorphosed to a sufficiently high extent to not yield any biomarkers, but the biomarkers found in the veins are most likely indigenous. Biomarkers detected include C21-22 alphaalphaalpha- and alphabetabeta-steranes (pregnanes), C27-29 alphabetabeta-steranes, C19-26 tricyclic terpanes, C29-30,34 alphabeta-hopanes, C30 17alpha-diahopane, and trisnorhopanes, which are in the range 2-180 pg/g. The extracted organic matter is highly mature, based on the biomarker configurations and calculated vitrinite reflectance that ranges from 2.4-3.0 (methylphenanthrene index), 1.4-1.9 (methyladamantane index), and 1.4-2.3 (methyldiamantane index). As the biomarkers are highly mature and the biomarker assemblages have a distinctive pattern to each vein type the likelihood of sample contamination by recent, less mature, biomarkers from a different assemblage is unlikely. The detection of steranes suggests that molecular oxygen was available when the veins were formed, possibly between 2.2 and 1.8 billion years ago, but no evidence for oxygenic photosynthesis in the form of cyanobacterial biomarkers has been found. Carbonate minerals that seem to better preserve biomarkers, such as concretions or veins, show the growing importance of new and exciting opportunities to seek biomarkers in the early Earth rock record, and potentially on other planets. Our results demonstrate for that first time that biomarkers can be found in veins cutting through highly metamorphosed Archaean rocks, and gives an insight into ancient environments. PMID- 29974604 TI - Value of repeat radical transurethral resection for selected patients with muscle invasive bladder cancer. AB - BACKGROUND: This study was conducted to evaluate the efficacy and necessity of repeat transurethral resection (re-TUR) treatment for selected patients with muscle-invasive bladder cancer and to investigate the possibility of bladder sparing. METHODS: The study included 61 selected patients with invasive bladder cancer who were treated by re-TUR and in whom biopsies of the muscle layer of the tumour bed were negative. Re-TUR was performed within 4-6 weeks of the initial resection. Pirarubicin instillation was scheduled for the bladder-preserving group. The prognosis was compared with that of patients in our previous research, which included 93 selected patients with invasive bladder cancer who were treated by radical TUR. In that research, we found that the overall survival and disease specific survival rates were 59.1 and 65.2%, respectively. The clinical stage of tumour influenced the survival rates. RESULTS: Of the 61 patients who underwent re-TUR, 31 never had disease relapse, 19 had disease recurrence and 11 had disease progression. The clinical stage of the tumour influenced the overall survival and disease-specific survival. The 5-year overall survival rate was 70% and disease-specific survival rate was 74%, respectively. Compared with the TUR group, both the overall survival and disease-specific survival rates of the re TUR group both increased significantly (P < 0.05). CONCLUSIONS: Re-TUR combined with pirarubicin instillation is a suitable bladder-preserving treatment for selected patients with muscle-invasive bladder cancer, based on good overall survival and disease-specific survival rates demonstrated in this research. The clinical stage of tumour has a major influence on the survival rates. PMID- 29974605 TI - GMI, a fungal immunomodulatory protein from Ganoderma microsporum, induce apoptosis via beta-catenin suppression in lung cancer cells. AB - beta-catenin is important in development of lung cancer. In our previous study, GMI, a fungal immunomodulatory protein, inhibits lung cancer cell survival. The aim of this study is to evaluate the effect of GMI on beta-catenin inhibition and apoptosis induction. GMI induced apoptosis in lung cancer cells bearing wild-type and mutated EGFR. GMI did not reduce the beta-catenin mRNA expression but suppressed the protein expressions of beta-catenin that resulted in the transcriptional downregulation of its target genes: survivin and cyclin-D1. The transcriptional activation activity of beta-catenin was demonstrated by TOPFLASH/FOPFLASH luciferase reporter assay. Inhibition of GSK-3beta and proteasome blocked the inhibiting effect of GMI on beta-catenin and its target genes. beta-catenin silencing increased activation of apoptosis in GMI-treated H1355 cells. This is the first study to reveal the novel function of GMI in inducing apoptosis via beta-catenin inhibition. These results provide a new potential of GMI in against lung cancer. PMID- 29974606 TI - #Checkmate: could checkpoint inhibitors be the game changer in the fight against metastatic urothelial carcinoma? PMID- 29974607 TI - Practical use of C1 esterase inhibitor concentrate for clinical amniotic fluid embolism. AB - Amniotic fluid embolism (AFE) causes consumption coagulopathy, which requires a massive transfusion to save the mother's life. The preparation of such a massive transfusion is too time-consuming in extremely emergent clinical settings and occasionally leads to devastating side effects such as transfusion-associated acute lung injury. C1 esterase inhibitor (C1INH) is a protein with the ability to inhibit complement, coagulation and kinin pathways. The C1INH concentration in AFE patients is low, and it has been speculated that the administration of C1INH concentrate could have a striking and beneficial effect on AFE patients in critical condition by ameliorating their perturbed coagulation system. We report the case of a 32-year-old Japanese AFE patient in whom deteriorated vital signs and coagulopathy recovered within minutes after an injection of C1INH concentrate. C1INH concentrate can quickly revive the deteriorated vital signs and the atonic uterus that stem from AFE and may reduce the total amount of transfusion. PMID- 29974608 TI - How to reverse the decline in the number of Japanese obstetricians and gynecologists. PMID- 29974609 TI - Obstructing colon mass in the setting of intestinal non-rotation. PMID- 29974610 TI - Alcohol consumption and the risk of incident pulmonary embolism in US women and men. AB - : Essentials The association of moderate alcohol consumption with pulmonary embolism (PE) risk remains unclear. In three large US cohorts, we evaluated the association of alcohol consumption with PE risk. We found no evidence of an association of alcohol consumption amount or frequency with PE risk. Secondary analyses of type and heavy episodic drinking also yielded null findings. SUMMARY: Background Moderate alcohol consumption has been variably associated with hemostatic and fibrinolytic factor levels, but the association between alcohol consumption and the risk of incident pulmonary embolism (PE) remains uncertain. Objective To evaluate alcohol consumption amount and frequency in relation to PE risk. Methods Nurses' Health Study (NHS), NHS II and Health Professionals Follow Up Study participants free of venous thromboembolism (VTE) at baseline (n = 217 442) reported alcohol consumption by type, quantity and frequency, every 2-4 years. Incident PE cases were identified by self-report and confirmed for participants without cancer. In this cohort study, we used Cox proportional hazards models to estimate multivariable-adjusted hazard ratios (HRs) for PE associated with alcohol consumption amount and, separately, frequency. Secondary analyses evaluated alcohol type and heavy episodic drinking in relation to PE risk, and amount and frequency in relation to medical record-confirmed idiopathic PE and any self-reported VTE risk. Cohort-specific analyses were pooled using random-effects meta-analysis. Results During >= 20 years of follow-up, we identified 1939 PE events. We found no strong evidence of an association between PE risk and alcohol consumption amount (pooled HRadj for 5.0-14.9 g day-1 vs. abstention = 0.97 [95% CI, 0.79, 1.20]) or frequency (pooled HRadj for 5-7 drinking days per week vs. abstention = 1.04 [95% CI, 0.88, 1.23]). Secondary analyses of type, heavy episodic drinking, idiopathic PE and VTE also yielded null findings. Conclusions Among three large prospective cohorts of US men and women, we found no evidence of an association between the amount or frequency of alcohol consumption and PE risk. PMID- 29974611 TI - Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism. AB - : Essentials Factor Xa inhibitors cause more abnormal menstrual bleeding (AUB) than vitamin-K antagonists (VKA). We analyzed data of AUB in women, evaluating dabigatran versus VKA. We observed a 41% lower risk of AUB in women on dabigatran compared to those on VKA. Our findings of lower AUB risk on dabigatran should be corroborated in future studies. SUMMARY: Introduction Although direct oral anticoagulants (DOACs) are associated with a better safety profile than warfarin in patients with acute venous thromboembolism (VTE), direct factor Xa inhibitors involve a higher risk of abnormal uterine bleeding (AUB). We aimed to determine the risk of AUB during anticoagulation with dabigatran compared with warfarin. Methods Post-hoc analysis of the pooled RE-COVER studies and the RE-MEDY trial. Incidences of AUB, based on a defined preferred terms search for adverse events, in female patients aged 18-50 years treated with dabigatran, were compared with those in women treated with warfarin. Results Of the 2964 women included in the above-mentioned trials, 1280 women were in the relevant age category (18-50 years) and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 8.1%, 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an odds ratio for dabigatran-treated patients of 0.59 (95% confidence interval [CI], 0.39-0.90; P = 0.015). In the dabigatran treated patients, three (0.5%) suffered major bleeding (MB) vs. five (0.8%) in the warfarin-treated patients (HR, 0.65; 95% CI, 0.15-2.72). MB or non-major relevant bleeding occurred in 30 (4.7%) patients randomized to receive dabigatran and 57 (8.9%) randomized to receive warfarin (HR, 0.53; 95% CI, 0.34-0.83). None of the bleeding events was fatal. Conclusion Dabigatran treatment was associated with a significantly (41%) lower risk of AUB than warfarin. Future studies in daily practice are needed to corroborate these findings. PMID- 29974612 TI - Ecologically realistic model of infection for exploring the host damage caused by Vibrio aestuarianus. AB - Although vibrios are frequently associated with marine organisms mortality outbreaks, knowledge on their ecology and pathogenicity is sparse, thus limiting disease management and prophylactic strategies. Here, we investigated V. aestuarianus infection onset and progression in the wild, taking advantage of a 'claire' pond: a semi-closed system with limited seawater renewal, theoretically more adapted to disease transmission. We showed a positive association of the bacteria with oysters, which can constitute a reservoir for the bacteria in the winter. Moreover, passage through oysters was found to be necessary for experimental disease reproduction as vibrios shedding from diseased oysters have higher infectivity than from in vitro grown. We next developed an experimental 'ecologically realistic' infection model in a mesocosm, allowing infection by natural route. By means of this non-invasive protocol, we analysed the pathogenesis of the bacteria and demonstrated the importance of haemolymph for initial colonization and the septicaemic nature of this disease. PMID- 29974613 TI - Eriobotrya japonica ameliorates cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats. AB - Eriobotrya japonica (EJ) is a traditional Chinese plant with high medicinal value. EJ extracts are reported to exhibit antioxidant and anti-inflammatory biological attributes. The current study aims to evaluate the prospective efficacy of E. japonica leave extract (EJLE) against Angiotensin-II induced cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats (SHRs). For the in vitro studies, Angiotensin-II pretreated H9c2 cells were treated with EJLE and analyzed through Western blotting and rhodamine phalloidin staining for their cardio-protective attributes. In the in vivo studies, 12-week old SHRs were randomly divided into groups: SHRs supplemented with EJLE, control SHR group supplemented with PBS; in addition, a control group of Wistar-Kyoto rats (WKY) was also employed. All rats were supplemented twice a week for 8 week time interval. Finally, echocardiography, morphological, histology, and Western blot analysis were performed to assess their role against cardiac hypertrophy. Interestingly, we could observe that supplementation of EJLE could rescue Ang-II induced cardiac hypertrophy as evident through Western blot, rhodamine phalloidin staining, and Hematoxylin-Eosin staining. Notably, morphological and echocardiography data provided further supports for their ability to ameliorate cardiac characteristics. Cumulatively, the results clearly suggests that supplementation of EJLE promotes cardio-protective effects through amelioration of cardiac hypertrophy in vitro and in vivo. PMID- 29974614 TI - Letter to 'Effectiveness of antenatal perineal massage in reducing perineal trauma and post-partum morbidities: A randomized controlled trial'. PMID- 29974615 TI - Management of primary spontaneous pneumothorax: a review. AB - Primary spontaneous pneumothorax is a common problem faced by doctors in medical practice. It is a significant global health problem affecting adolescent and young adults. This article will review the etiopathology, diagnosis and current management guidelines. It aims to improve clinical practice and compliance to the complexities of procedures involved in management. PMID- 29974616 TI - Thiazolidinediones and reduced risk of incident bacterial abscess in adults with type 2 diabetes: A population-based cohort study. AB - AIM: Previous research has suggested that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) may play an important role in immunomodulation. We aimed to examine the association between thiazolidinediones, PPAR-gamma agonists and incidence of bacterial abscess among patients with type 2 diabetes. MATERIALS AND METHODS: This retrospective cohort study between 2000 and 2010 included 46 986 propensity (PS)-matched patients diagnosed with type 2 diabetes. We compared the incidence of bacterial abscess, including liver and non-liver abscesses, between patients treated with metformin plus a thiazolidinedione (M + T, N = 7831) or metformin plus a sulfonylurea (M + S, N = 39 155). Data were retrieved from a population-based Taiwanese database. We applied Cox proportional hazard regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), comparing M + T and M + S after PS matching. RESULTS: During a median follow-up of 4.5 years, the incidence rate of bacterial abscess was lower with M + T than with M + S treatment (1.89 vs 3.15 per 1000 person-years) in the PS matched cohort. M + T was associated with a reduced risk of bacterial abscess (HRs after PS matching, 0.58; 95% CI, 0.42-0.80 for total bacterial abscess; 0.54; 95% CI, 0.28-1.07 for liver abscess; 0.59; 95% CI, 0.41-0.85 for non-liver abscess). Results did not change materially after accounting for unmeasured confounding factors using high-dimenional PS matching and differential censoring between regimen groups. Rosiglitazone and pioglitazone, in combination with metformin, produced similar reductions in risk of all abscess outcomes. CONCLUSION: We found that M + T may provide a protective benefit in reducing the incidence of bacterial abscesses. These findings merit further investigation. PMID- 29974617 TI - Female adnexal tumor of probable Wolffian origin arising from mesosalpinx: A case report and review. AB - Female adnexal tumors of probable Wolffian origin (FATWO) are a rare neoplasm from the mesonephric duct remnants with less than 90 cases having been reported worldwide. A 34-year-old nulliparous woman was referred to our clinic for a recent discovery of a pelvic mass, the diagnosis of FATWO has been confirmed based on the pathological and immunohistochemical results. PMID- 29974619 TI - Response to Arredondo: Birth weight and social determinants in diabetes and hypertension. PMID- 29974618 TI - Propensity-score-matched comparative analyses of simultaneously administered fixed-ratio insulin glargine 100 U and lixisenatide (iGlarLixi) vs sequential administration of insulin glargine and lixisenatide in uncontrolled type 2 diabetes. AB - AIM: To conduct two exploratory analyses to compare indirectly the efficacy and safety of simultaneous administration of insulin glargine 100 U (iGlar) and the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide (Lixi) as a single-pen, titratable, fixed-ratio combination (iGlarLixi [LixiLan trials]) vs sequential administration of iGlar + Lixi (GetGoal Duo trials) in people with type 2 diabetes (T2D). MATERIALS AND METHODS: Propensity-score matching based on baseline covariates was used to compare simultaneous iGlarLixi vs sequential combination of iGlar + Lixi with the addition of Lixi in patients who did not reach the glycated haemoglobin (HbA1c) goal of <53 mmol/mol (<7%) after short term use of iGlar alone (LixiLan-O vs GetGoal Duo-1 comparison) and vs sequential addition of Lixi in uncontrolled patients after long-term use of iGlar alone (LixiLan-L vs GetGoal Duo-2 comparison). RESULTS: In both analyses, compared with sequential iGlar + Lixi, iGlarLixi led to significantly greater HbA1c reductions with associated weight loss and significantly more patients reaching target HbA1c <53 mmol/mol despite lower insulin doses. Symptomatic hypoglycaemia rates were similar, despite greater HbA1c reductions with iGlarLixi. Lower rates of gastrointestinal adverse events were observed with iGlarLixi, probably as a result of the more gradual titration of Lixi with iGlarLixi. CONCLUSIONS: Indirect propensity-score-matched exploratory comparisons suggest that early treatment with a simultaneous, titratable, fixed-ratio combination of basal insulin and a GLP-1RA (iGlarLixi) may be more effective and possess better gastrointestinal tolerability than a sequential approach of adding a GLP-1RA in patients with uncontrolled T2D initiating or intensifying basal insulin therapy. PMID- 29974620 TI - Reactive Self-Assembly and Specific Cellular Delivery of NCO-sP(EO-stat-PO) Derived Nanogels. AB - This study presents the reactive self-assembly of isocyanate functional and amphiphilic six-arm, star-shaped polyether prepolymers in water into nanogels. Intrinsic molecular amphiphilicity, mainly driven by the isophorone moiety at the distal endings of the star-shaped molecules, allows for the preparation of spherical particles with an adjustable size of 100-200 nm by self-assembly and subsequent covalent cross-linking without the need for organic solvents or surfactants. Covalent attachment of a fluorescence dye and either the cell penetrating TAT peptide or a random control peptide sequence shows that only TAT labeled nanogels are internalized by HeLa cells. The nanogels thus specifically enter the cells and accumulate in the perinuclear area in a time- and concentration-dependent manner. PMID- 29974621 TI - Intraoperative Raman-Guided Chemo-Photothermal Synergistic Therapy of Advanced Disseminated Ovarian Cancers. AB - Abdominal miliary spread and metastasis is one of the most aggressive features in advanced ovarian cancer patients. The current standard treatment of advanced ovarian cancer is cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). However, most patients cannot receive optimal CRS outcomes due to the extreme difficulty of completely excising all microtumors during operation. Though HIPEC can improve prognosis, treatment is untargeted and may damage healthy organs and cause complications. New strategies for precise detection and complete elimination of disseminated microtumors without side effects are therefore highly desirable. Here, cisplatin-loaded gap enhanced Raman tags (C-GERTs) are designed specifically for the intraoperative detection and elimination of unresectable disseminated advanced ovarian tumors. With unique and strong Raman signals, good biocompatibility, decent plasmonic photothermal conversion, and good drug loading capacity, C-GERTs enable detection and specific elimination of microtumors with a minimum diameter of 1 mm via chemo photothermal synergistic therapy, causing minimal side effects and significantly prolonging survival in mice. The results demonstrate that C-GERTs-based chemo photothermal synergistic therapy can effectively control the spread of disseminated tumors in mice and has potential as a safe and powerful method for treatment of advanced ovarian cancers, to improve survival and life quality of patients. PMID- 29974622 TI - Retrieval of an embedded suprarenal inferior vena cava filter using the Hangman technique. AB - Inferior vena cava filters should be ideally placed in the infrarenal caval segment to maintain renal vein outflow and thereby patency; however, in certain circumstances a suprarenal position may be required. Suprarenal filters are subject to the same risks as for infrarenal filters including tilt. While many advanced techniques have been used for infrarenal filter retrievals, there is a paucity of evidence supporting the use of these retrieval techniques in the suprarenal segment. We show a case of successful retrieval of a suprarenal filter using the Hangman technique. PMID- 29974623 TI - From Conversations to Digital Communication: The Mnemonic Consequences of Consuming and Producing Information via Social Media. AB - Social media has become one of the most powerful and ubiquitous means by which individuals curate, share, and communicate information with their friends, family, and the world at large. Indeed, 90% of the American adolescents are active social media users, as well as 65% of American adults (Perrin, 2015; see also Duggan & Brenner, 2013). Despite this, psychologists are only beginning to understand the mnemonic consequences associated with social media use. In this article, we will distill this nascent literature by focusing on two primary factors: the type of information (personal vs. public) and the role (producer vs. consumer) individuals play when engaging with social media. In particular, we will highlight research examining induced forgetting for personal information as well as false memories and truthiness for public information. We will end by providing some tentative conclusions and a discussion of areas in need of additional research that will provide a more holistic understanding of the mnemonic consequences associated with social media use. PMID- 29974625 TI - Influence of hydatid disease on the pregnancy outcomes: An experimental study. AB - AIM: Hydatid disease during pregnancy may lead to various complications in both mother and child. Accordingly, enough knowledge is required to manage these complications. This study was done to evaluate the interaction between hydatid disease and pregnancy in laboratory mice. METHODS: Twenty female BALB/c mice (Mus musculus) were divided into test and control groups, 10 animal in each. The mice of the test group were infected intraperitoneally by injection of 1000 protoescolices. Six months after infection, the mice of test and control groups were mated with male mice for a week. After parturition, the size and weight of babies were measured and compared between two groups. RESULTS: While all the mice of control group delivered healthy babies, 3 out of 10 mice of test group showed no pregnancy. The infected mice delivered lower number of babies than the mice of control group. The mean size of fetuses or babies obtained from the infected mice were statistically lower than those obtained from the mice of control group (P = 0.000). The weight of babies delivered by the infected mice not only at the time of birth (P = 0.005) but also 10 days after birth (P = 0.021), were significantly lower than those delivered by the mice of control group. The level of progesterone and estradiol in the mice of test group were significantly lower (P = 0.009) and higher (P = 0.043), respectively, in comparison to the mice of control group. CONCLUSION: Hydatid disease during pregnancy may considerably affect the pregnancy outcomes. PMID- 29974624 TI - Accuracy of non-invasive scoring systems for diagnosing non-alcoholic steatohepatitis-related fibrosis: Multicenter validation study. AB - AIM: Hepatic fibrosis is the most important factor for estimating the prognosis of patients with non-alcoholic fatty liver disease (NAFLD). A novel non-invasive scoring system, the FM-fibro index, showed high accuracy in a pilot study. The purpose of this study was to validate the efficacy of the FM-fibro index in a multicenter cohort. METHODS: Among 18 institutions, we analyzed 400 Japanese patients with biopsy-proven NAFLD. We evaluated the accuracies of the FM-fibro index, CA-fibro index, and European Liver Fibrosis (ELF) panel by area under the receiver operator characteristics curves (AUROC). The FM-fibro index includes three formulas for type IV collagen 7S, hyaluronic acid, and vascular cell adhesion molecule-1. RESULTS: Among 400 patients, 205 were women, and the median age was 56 years. The histological distribution of Matteoni types 1, 2, 3, and 4 was 11, 40, 15, and 334, and the distribution of hepatic fibrosis stages 0 to 4 was 67, 183, 55, 63, and 32, respectively. The AUROCs of the FM-fibro index, CA fibro index, and ELF panel for non-alcoholic steatohepatitis (NASH)-related fibrosis were 0.7178/0.7095/0.7065, 0.7093, and 0.7245, respectively. The sensitivity and specificity of the FM-fibro index for predicting NASH-related fibrosis was 0.5359/0.5210/0.4641 and 0.8333/0.8182/0.8788, respectively. The accuracy of the FM-fibro index was not significantly different from that of the CA-fibro index or the ELF panel. CONCLUSIONS: The FM-fibro index can predict NASH related fibrosis with sufficient accuracy compared with previous scoring systems. Further analyses that verify the accuracy of the FM-fibro index to distinguish significant or advanced fibrosis in patients with NAFLD are awaited. (UMIN-CTR: UMIN000018158). PMID- 29974626 TI - My Village Is Dying? Integrating Methods from the Inside Out. AB - The purpose of this paper is to confront the notion of "decline" at the village level by illustrating a more immersive approach to sociological and demographic research within rural and remote communities. The research uses case studies of three villages in Australia, Canada, and Sweden, all of which have been labeled as "declining villages," typified by population loss, an aging population, high rates of youth outmigration, and loss of businesses and services. This paper argues that focusing solely on quantitative indicators of demographic change provides a narrow view of rural village trajectories and ignores subtle processes of local adaptation that are hidden from quantitative data sets. Our research integrates quantitative data from the "outside" with qualitative data from the "inside," including visual ethnography, to develop a more balanced perspective on how villages have been changing and what change could mean locally. These objectives are accomplished by revisiting a Dirt Research methodology applicable to a broad range of research into rural and remote villages. PMID- 29974628 TI - James "Jim" Heavner, PhD, DVM, FIPP (Hon). PMID- 29974629 TI - The Corporate Elite and the Architecture of Climate Change Denial: A Network Analysis of Carbon Capital's Reach into Civil Society. AB - This study employs social network analysis to map the Canadian network of carbon capital corporations whose boards interlock with key knowledge-producing civil society organizations, including think tanks, industry associations, business advocacy organizations, universities, and research institutes. We find a pervasive pattern of carbon-sector reach into these domains of civil society, forming a single, connected network that is centered in Alberta yet linked to the central-Canadian corporate elite through hegemonic capitalist organizations, including major financial companies. This structure provides the architecture for a "soft" denial regime that acknowledges climate change while protecting the continued flow of profit to fossil fuel and related companies. PMID- 29974630 TI - Prevalence of Chronic Kidney Disease in Iranian General Population: A Meta Analysis and Systematic Review. AB - The aim of this study was to determine the prevalence of CKD in the Iranian general population. In this systematic review and meta-analysis study, international (PubMed, Web of Science, Scopus, and Google scholar) and national databases (SID, Magiran) were searched until December 30, 2017. The quality of the studies was evaluated using the Hoy instrument. Out of 1170 initial studies, 9 studies with a total of 70 605 participants were included in the final stage of this study. Based on the results of the random effect method (95% CI), the overall prevalence of chronic kidney disease in 70 605 people was 15.14% (I2 = 99.77%). The prevalence of CKD in female patients (18.80%) was 1.7 times higher than in male patients (10.83). The results of the present study indicate a higher than the global average prevalence of CKD in Iran and the need for additional attention of policy makers on better planning for control and implementation of screening programs in high-risk populations, such as patients with hypertension and diabetes. PMID- 29974631 TI - Correlations between the sizes of lateral pelvic lymph nodes and metastases in rectal cancer patients treated with preoperative chemoradiotherapy. AB - BACKGROUND: Lateral pelvic lymph node (LLN) dissection is suggested to improve the prognosis of rectal cancer patients; however, accurate diagnosis of LLN metastasis is challenging, especially after preoperative chemoradiotherapy (CRT). The aim of this study was to clarify the diagnostic value of LLN size in rectal cancer patients treated with CRT in terms of metastasis. METHODS: A total of 204 LLNs dissected from 29 rectal cancer patients treated with CRT were examined. The correlation between the resected LLN size (long and short axes) and patients' metastasis status was examined. RESULTS: The long axes of metastatic LLNs were significantly longer than those of non-metastatic LLNs (11.0 +/- 5.3 versus 4.4 +/- 2.8 mm, respectively; P < 0.0001) as were the short axes (8.1 +/- 4.5 versus 2.3 +/- 1.2 mm, respectively; P < 0.0001). Receiver operating characteristic analyses of the long and short axes indicated optimal cut-off values of 7 and 4 mm for the prediction of pathological LLN metastasis; the area under the curve values were 0.89 and 0.96, respectively. The accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the long axis for the prediction of pathological metastasis were 82.4, 88.2, 82.2, 48.4 and 97.2%, respectively; those of the short axis were 91.7, 94.1, 87.1, 59.3 and 98.7%, respectively. CONCLUSIONS: The sizes of LLNs significantly correlated with patients' pathological statuses, and their accuracies for the prediction of pathological metastases were high. However, in contrast to the very high NPVs, the PPVs were low (approximately 50%). PMID- 29974632 TI - A national serosurvey to determine the prevalence of paratuberculosis in cattle in Bhutan following detection of clinical cases. AB - Johne's disease is an economically important ruminant disease predominantly affecting cattle, sheep and goats. The economic losses are due to early culling, reduced growth rate, progressive weight loss and reduced production. It is caused by Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease was reported in cattle in Bhutan, based on clinical signs and histopathology; in the late 1990s samples from one mithun that was suspected to have died due to this disease was confirmed by molecular testing at the Faculty of Veterinary Science, University of Sydney, Australia. However, no detailed study on prevalence of JD has been attempted in Bhutan. Objective of this study was to conduct serosurveillance to determine the national prevalence of Johne's disease in cattle for the period 2013-2014 to provide the basis for planning a future control strategy. A national serosurvey was conducted wherein a two-stage sampling procedure was used with 95% confidence and an error level of +/-0.05. The sample size required for the survey was calculated using the software-Survey Toolbox for Livestock Diseases, available as Epitools at http://www.ausvet.com.au. A total of 1123 serum samples were collected from an administrative structure of 52 villages, 40 sub-districts and 15 districts. Serum samples were tested using commercially available antibody enzyme linked immunosorbent assay. Statistical analysis was performed using GraphPad Prism 5.0. Illustration such as maps was produced using QGIS version 2.18 'Las Palmas. The mean national apparent prevalence of Johne's disease was found to be 2.31 (26/1123) (95% CI: 0.80-4.50) with an estimated true prevalence was found to be 8.00 (95% CI: 2.00-17.00). Trongsa district had the highest prevalence (12.96) followed by Zhemgang (4.34), Lhuntse (4.25), Sarpang (3.89), Bumthang (3.60), Trashigang (2.67) and Haa (2.63). Prevalence for all other districts was 2.00 or below. Seropositive samples were reported from all over the country with varying levels of sero-positivity. In the recent past many more cattle were imported from India to boost dairy production. Nevertheless, the wide distribution of seroreactive JD cattle all over the country is a concern for future control. Therefore, in future, a detailed study on the impact of cattle import with regard to disease incursion such as Johne's disease and other diseases should be undertaken. PMID- 29974633 TI - Comparison of the efficacy of diegnogest and levonorgestrel-releasing intrauterine system after laparoscopic surgery for endometriosis. AB - AIM: To compare the efficacy between dienogest and levonorgestrel-releasing intrauterine system (LNG-IUS) after laparoscopic surgery for endometriosis. METHODS: A total of 285 women were diagnosed as endometriosis by laparoscopy between 2011 and 2015. Patients were grouped into no treatment (n = 83), treatment with dienogest (n =130) and treatment with LNG-IUS (n =72) after laparoscopic surgery. The changes of the pain scores were checked at 6, 12 and 24 months after the surgery, and the rates of disease recurrence and treatment discontinuation rate were determined. RESULTS: The participants' mean age was 38.9 years (range 21-54 years). The mean age of LNG-IUS group (43.7 years) was significantly higher than the no treatment and dienogest groups (39.3 vs 33.9 years, respectively). At 6 and 12 months, the median pain scores in treatment (dienogest and LNG-IUS) groups were significantly lower than control group. Both treatment groups had significantly lower recurrence rate than control group (3.8% and 9.7%, respectively, vs 32.5%, P =0.001). No significant difference was found in the recurrence rate between the two treatment groups (P =0.461). Patients in the LNG-IUS group showed lower rate of discontinuation due to complication (27.8%) than those in dienogest group (35.6%, P =0.010). CONCLUSION: LNG-IUS treatment in the patients with endometriosis is effective for postoperative pain control and preventing recurrence, however, the LNG-IUS group is older, it is difficult to compare the efficacy between dienogest and LNG-IUS in present study. PMID- 29974634 TI - Barriers and facilitators to participant recruitment to randomised controlled trials: A qualitative perspective. AB - Low recruitment rates for randomised controlled trials (RCTs) are a common issue. Information on barriers and facilitators to recruitment for RCTs may inform researchers on how to improve the recruitment rate. The aim of this qualitative project was to identify barriers and facilitators to participant recruitment for a randomised double-blinded placebo-controlled trial on the clinical effectiveness of aspirin as an adjunct to compression therapy in healing chronic venous leg ulcers. We have conducted interviews with health professionals and project workers to understand their perspective on low recruitment rate, barriers to, and facilitators of recruitment. NVivo 11 software was used for data management and coding. Thematic analysis was applied as a method of data analysis. Although strict recruitment criteria were the main barrier, there were other recruitment barriers that should be considered when planning RCTs. We have further developed a framework of factors influencing the recruitment rate. The main recruitment barriers, including study-related, participant-related, practitioner-related, collaboration-related, ethics-related, practice-related, and health system-related barriers, should be considered for inclusion in the "Other Information" section of Consolidated Standards of Reporting Trials Statement to improve the quality of reporting and ensure the strategic planning of future RCTs. PMID- 29974635 TI - Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor. AB - A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pKi =4.73+/-0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pKi value of 5.16+/-0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers. PMID- 29974636 TI - Small Is Beautiful? Emerging Organizational Strategies among Italian Professionals. AB - The traditional debate about professional groups has mainly focused on conflicts between professions and organizations, reinforcing dualisms and dichotomies. Few scholars have investigated the extent to which professionalism and organizations are intertwined while focusing on the case of professionals integrated into large organizations, and even less attention has been paid to emerging forms of organization among self-employed professionals. Taking as an example organizational trends among architects (liberal professionals) and management consultants (emerging professionals) in Italy, this article investigates how small, flexible, and (often) interprofessional organizations promoted by self employed professionals are increasingly instrumental in overcoming market pressures and responding to emerging social needs in times of crisis and austerity. PMID- 29974638 TI - Biosynthetic Gene Cluster of a d-Tryptophan-Containing Lasso Peptide, MS-271. AB - MS-271, produced by Streptomyces sp. M-271, is a lasso peptide natural product comprising 21 amino acid residues with a d-tryptophan at its C terminus. Because lasso peptides are ribosomal peptides, the biosynthesis of MS-271, especially the mechanism of d-Trp introduction, is of great interest. The MS-271 biosynthetic gene cluster was identified by draft genome sequencing of the MS-271 producer, and it was revealed that the precursor peptide contains all 21 amino acid residues including the C-terminal tryptophan. This suggested that the d-Trp residue is introduced by epimerization. Genes for modification enzymes such as a macrolactam synthetase (mslC), precursor peptide recognition element (mslB1), cysteine protease (mslB2), disulfide oxidoreductases (mslE, mslF), and a protein of unknown function (mslH) were found in the flanking region of the precursor peptide gene. Although obvious epimerase genes were absent in the cluster, heterologous expression of the putative MS-271 cluster in Streptomyces lividans showed that it contains all the necessary genes for MS-271 production including a gene for a new peptide epimerase. Furthermore, a gene-deletion experiment indicated that MslB1, -B2, -C and -H were indispensable for MS-271 production and that some interactions of the biosynthetic enzymes were essential for the biosynthesis of MS-271. PMID- 29974637 TI - The effects of kisspeptin on beta-cell function, serum metabolites and appetite in humans. AB - AIMS: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. MATERIALS AND METHODS: In 15 healthy men (age: 25.2 +/- 1.1 years; BMI: 22.3 +/- 0.5 kg m-2 ), we compared the effects of 1 nmol kg-1 h-1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human beta-cell line (EndoC-betaH1 cells). RESULTS: Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. CONCLUSIONS: Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions. PMID- 29974639 TI - Biosafe, Eco-Friendly Levan Polysaccharide toward Transient Electronics. AB - New options in the material context of transient electronics are essential to create or expand potential applications and to progress in the face of technological challenges. A soft, transparent, and cost-effective polymer of levan polysaccharide that is capable of complete, programmable dissolution is described when immersed in water and implanted in an animal model. The results include chemical analysis, the kinetics of hydrolysis, and adjustable dissolution rates of levan, and a simple theoretical model of reactive diffusion governed by temperature. In vivo experiments of the levan represent nontoxicity and biocompatibility without any adverse reactions. On-demand, selective control of dissolution behaviors with an animal model demonstrates an effective triggering strategy to program the system's lifetime, providing the possibility of potential applications in envisioned areas such as bioresorbable electronic implants and drug release systems. PMID- 29974640 TI - Mcr colistin resistance gene: a systematic review of current diagnostics and detection methods. AB - Resistance to colistin, mediated by chromosomal mutations and more recently, by plasmid-borne mcr genes, is increasingly being reported in bacterial isolates taken from humans, animals, farms, foods, and the environment. To easily identify and contain this quickly spreading menace, efficient diagnostics that are cheaper, faster, simpler, sensitive, and specific have become indispensable and urgently necessary. A thorough and systematic review of the literature available at Pubmed, ScienceDirect and Web of Science was thus undertaken to identify articles describing novel and efficient colistin resistance- and mcr gene detecting methods. From the final 23 studies included in this review, both phenotypic and molecular tests were found. The phenotypic tests consisted of novel culture media viz., SuperPolymyxinTM, CHROMagar COL-APSE and LBJMR media, commercial automated MIC-determining instruments such as MICRONAUT-S, Vitek 2, BD Phoenix, Sensititre and MicroScan, and novel assays such as Colistin MAC test, Colispot, rapid polymxin NP test (RPNP), alteration of Zeta potential, modified RPNP test, MICRONAUT-MIC Strip, MIC Test Strip, UMIC System, and SensitestTM Colistin. Molecular diagnostics consisted of the CT103XL microarray, eazyplex(r) SuperBug kit, and Taqman(r) /SYBR Green(r) real-time PCR assays, with 100% sensitivity and specificity plus a shorter turnaround time (<3 hr). Based on the sensitivity, specificity, cost, required skill and turnaround time, the RPNP test and/or novel culture media is recommended for under-resourced laboratories while the Multiplex PCR or Taqman(r) /SYBR Green(r) real-time PCR assay alongside the RPNP or novel culture media is suggested for well-resourced ones. PMID- 29974641 TI - Effect of Increased Blood Flow Rate on Hemodialysis Tolerability and Achieved Urea Reduction Ratio. AB - Long-term hemodialysis (HD) imposes a significant burden on the quality of life of end-stage kidney disease patients. Optimizing dialysis dose is an important consideration in this population; however, evidence exists that suggests that attainment of population dialysis targets is associated with increased intradialytic complications. In this prospective, before-after study, the blood flow rate (BFR) of 63 maintenance HD patients was increased by 100 mL/min to a maximum BFR of 400 mL/min to determine the impact on patient tolerability and urea reduction ratio (URR) of an increased BFR. Tolerability was assessed by time to recovery (TTR) after dialysis, a validated measure of patient tolerability, and intradialytic complications. Median pre-increase BFR was 252 mL/min compared to 349 mL/min post-increase. Mean TTR decreased from 4.67 h to 4.03 h (P = 0.688). No association was observed between percentage change in BFR (R2 = 0.0) or post-increase BFR (R2 = 0.0) and absolute change in TTR. A significant, positive association was observed between both the absolute and relative changes to BFR and the achieved URR. We found no evidence that increasing BFR by 100 mL/min diminishes patient tolerability. PMID- 29974642 TI - Elevated Circulating Osteoprotegerin Levels in the Plasma of Hemodialyzed Patients With Severe Artery Calcification. AB - We studied the correlations between circulating osteoprotegerin (OPG) level and radial artery calcification (RAC) assessed histologically and carotid artery intima-media thickness (CCA-IMT). Moreover, we studied the relationship between OPG levels and all-cause and cardiovascular (CV) mortality during a 5-year observation period. The study comprised 59 CKD patients (36 hemodialyzed (HD), 23 predialysis). The biochemical parameters included: creatinine, calcium, phosphate, intact parathormone, C-reactive protein, interleukin-6, tumor necrosis factor receptor II (TNFRII), transforming growth factor-beta, hepatocyte growth factor, fibroblast growth factor 23, osteonectin (ON), osteopontin, osteoprotegerin, and osteocalcin. CCA-IMT and the presence of atherosclerotic plaques was assessed by ultrasound. Fragments of radial artery obtained during creation of HD access were prepared for microscopy and stained for calcifications with alizarin red. RAC was detected in 34 patients (58%). In multiple regression adjusted for dialysis status, TNFRII, ON and Framingham risk score (FRS) were identified as the independent predictors of OPG. Serum OPG above the median value of 7.55 pmol/L significantly predicted the presence of RAC in simple logistic regression (OR 5.33; 95%CI 1.39-20.4; P = 0.012) and in multiple logistic regression adjusted for FRS, dialysis status and CCA-IMT values (OR 6.56; 95%CI 1.06-40.6; P = 0.036). OPG levels above the median were associated with higher CCA-IMT values (1.02 +/- 0.10 vs. 0.86 +/- 0.13; P < 0.001) and predicted the presence of atherosclerotic plaques in carotid artery (OR 14.4; 95%CI 2.84-72.9; P < 0.001), independently of FRS, dialysis status and RAC. In this study, elevated serum OPG levels correlated with higher CCA-IMT, the presence of atherosclerotic plaques and the severity of the RAC independently of each other. During follow-up, 25 patients (42%) died, including 21 due to CV causes. In multiple Cox regression, OPG above the median predicted overall survival independently of dialysis status, Framingham risk score, CCA-IMT above the median value, and the presence of atherosclerotic plaques in CCA, but not independently of RAC. We postulate that circulating OPG may play a dual role as a marker for both medial arterial calcification and atherosclerosis, hence it seems to be a valuable tool for assessing CV risk in patients with CKD. OPG might be an early indicator of all-cause mortality in CKD patients with advanced medial arterial calcification. PMID- 29974643 TI - Fractional 532-nm KTP diode laser and 595-nm pulsed dye laser in treatment of facial telangiectatic erythema. AB - BACKGROUND: A 595-nm pulsed dye laser (PDL) and the fractional 532-nm potassium titanyl phosphate (KTP) laser have also been demonstrated to be effective for facial telangiectasias. OBJECTIVE: To compare the clinical therapeutic effects of a fractional 532-nm KTP laser with those of a 595-nm pulsed dye laser (PDL) for treating facial erythematous skin lesions. METHODS: Twenty healthy adults with facial erythematous skin lesions were treated using a fractional 532-nm KTP laser on one side of the face and a 595-nm PDL on the other cheek. Three treatments were administered at 4-week intervals. The degree of improvement in facial telangiectasias was evaluated by colorimeter analysis, a physician's assessment using clinical photographs, and the subject's self-assessment. RESULTS: In the physician's assessment with clinical photography, a significant improvement was observed from baseline to posttreatment in both groups. As measured by a colorimeter, the a* value decreased from 16.23 (+/-2.81) to 12.22 (+/-2.75) in the 595-nm PDL group and from 16.02 (+/-2.93) to 12.77 (+/-2.77) in the fractional 532-nm KTP laser group. The a* value showed a significant reduction in both groups (P < .0001). There was no significant difference in efficacy between the two groups. In the subjective self-assessment, scores improved by 1.68 (+/ 0.95) in the fractional 532-nm KTP laser group and by 1.78 (+/-0.92) in the 595 nm PDL group. CONCLUSION: A fractional 532-nm KTP laser is a valid option for the treatment of facial erythematous skin lesions with telangiectasia. PMID- 29974644 TI - The Stratification of Attendance at Cultural Activities in Canada. AB - Scholars have debated the relative applicability of homology and omnivorousness, two theories of cultural stratification, for explaining links between socioeconomic position and cultural repertoires. However, the discussion has mostly focused on musical tastes rather than attendance at cultural activities. Using data from the 2010 Canadian General Social Survey on Time Use, I examine how measures of socioeconomic position predict attendance at 12 different kinds of cultural activities. I apply three analytical techniques to this data set: (1) binary logistic regressions to investigate the socioeconomic bases of attendance at each cultural activity; (2) ordered logistic regression to assess the nature of the relationship between socioeconomic position and omnivorous attendance; and (3) latent class analysis to identify clusters of attendance and the socioeconomic bases thereof. Controlling for demographic factors, I find that education and income are positively associated with attendance at each activity and with omnivorous cultural engagement. The latent class model reveals four distinct groups: highbrow omnivores, selective omnivores, univores, and inactive people. Education and income predict membership in the omnivorous groups, with stronger effects for highbrow omnivores. I confirm that omnivorousness is associated with cultural and economic elites, but also reveal different gradations of omnivorousness, thus suggesting that the two theoretical frameworks are to a degree entangled with one another. PMID- 29974646 TI - The relationships between environmental sensitivity, ecological worldview, personal norms and pro-environmental behaviors in Chinese children: Testing the value-belief-norm model with environmental sensitivity as an emotional basis. AB - This study addresses the relationships that ecological worldview, environmental sensitivity, and personal norms have with pro-environmental behaviors in a particular child population in urban China. The survey questionnaires were distributed to 410 Grade 6 students from eight Green Schools in Shenzhen, China. The sample included 223 (54.3%) boys and 187 (45.6%) girls with ages ranging from 10 to 13 years. The results from structural equation modelling reveal that environmental sensitivity and personal norms were two critical factors in determining students' pro-environmental behaviors. The influence of ecological worldview was fully mediated by personal norms, whereas the effect of environmental sensitivity was partially mediated by both personal norms and ecological worldview. PMID- 29974645 TI - Multispectral optoacoustic tomography of systemic sclerosis. AB - The study aimed to evaluate the clinical feasibility of hybrid ultrasound/multispectral optoacoustic tomography (MSOT) for assessing microvascular dysfunction in systemic sclerosis (SSc). A handheld US/MSOT imaging system was applied for imaging patients diagnosed with SSc (n = 7) and healthy volunteers (n = 8). Semiquantitative MSOT values for deoxygenated (HbR), oxygenated (HbO2 ) and total haemoglobin (HbT) were analysed for subcutaneous finger tissue of both hands (8 fingers per subject, 120 fingers in total) and used to assess disease activity (progressive vs stable). Grouped data were compared by one-way nested analysis of variance, Tukey post-hoc test as well as student's t test were used for statistical analysis.Subcutaneous finger tissue of patients with SSc provided significantly lower MSOT values for HbO2 (26.16 +/- 0.71 vs 38.2 +/- 1.54, P = .023) and HbT (55.92 +/- 1.62 vs 72.46 +/- 1.90, P = .018) compared to healthy volunteers. Patients with progressive SSc had significantly lower MSOT values compared to patients with stable disease and healthy volunteers.This pilot study shows the feasibility of MSOT imaging to resolve microvascular dysfunction in SSc as a marker of disease activity. By providing biological tissue properties not revealed by other imaging modalities, MSOT might help to grade SSc non-invasively and monitor early therapy response. PMID- 29974647 TI - DNA-Binding Properties of New Fluorescent AzaHx Amides: Methoxypyridylazabenzimidazolepyrroleimidazole/pyrrole. AB - DNA minor groove binding polyamides have been extensively developed to control abnormal gene expression. The establishment of novel, inherently fluorescent 2-(p anisyl)benzimidazole (Hx) amides has provided an alternative path for studying DNA binding in cells by direct observation of cell localization. Because of the 2:1 antiparallel stacking homodimer binding mode of these molecules to DNA, modification of Hx amides to 2-(p-anisyl)-4-azabenzimidazole (AzaHx) amides has successfully extended the DNA-recognition repertoire from central CG [recognized by Hx-I (I=N-methylimidazole)] to central GC [recognized by AzaHx-P (P=N methylpyrrole)] recognition. For potential targeting of two consecutive GG bases, modification of the AzaHx moiety to 2- and 3-pyridyl-aza-benzimidazole (Pyr AzaHx) moieties was explored. The newly designed molecules are also small-sized, fluorescent amides with the Pyr-AzaHx moiety connected to two conventional five membered heterocycles. Complementary biophysical methods were performed to investigate the DNA-binding properties of these molecules. The results showed that neither 3-Pyr-AzaHx nor 2-Pyr-AzaHx was able to mimic I-I=N-methylimidazole N-methylimidazole to target GG dinucleotides specifically. Rather, 3-Pyr-AzaHx was found to function like AzaHx, f-I (f=formamide), or P-I as an antiparallel stacked dimer. 3-Pyr-AzaHx-PI (2) binds 5'-ACGCGT'-3' with improved binding affinity and high sequence specificity in comparison to its parent molecule AzaHx PI (1). However, 2-Pyr-AzaHx is detrimental to DNA binding because of an unfavorable steric clash upon stacking in the minor groove. PMID- 29974649 TI - ANZUP Annual Scientific Meeting, Putting People First, 8-10 July 2018, Hyatt Regency, Sydney, NSW, Australia. PMID- 29974650 TI - ANZUP Convenor Welcome. PMID- 29974648 TI - Targeted profiling and relative quantification of benzoyl diterpene alkaloids in Aconitum roots by using LC-MS/MS with precursor ion scan. AB - Benzoyl aconite alkaloids have myocardial protective effects at a low dose and produce toxic effects at high dose. Due to lack of enough reference compounds, most of the benzoyl alkaloids had few concerns, except the typical ones, i.e. aconitine, mesaconitine, and hypaconitine. To rapidly screen out and quantify benzoyl alkaloids, a high performance liquid chromatography combined with tandem mass spectrometry was proposed based on precursor ion scanning mode. First, a diagnostic ion at m/z 105 corresponding to benzoyl group was observed by using tandem mass spectrometry, which could be used for the rapid identification of benzoyl alkaloids. The targeted screening of these alkaloids was then conducted by using precursor ion scan of characteristic ion at m/z 105. Shengfuzi (the lateral root of A. carmichaelii) was taken as example, and 24 benzoyl-containing alkaloids were identified. The six major alkaloids including aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine, and benzoylhypaconine were determined in the precursor ion scan mode by the standard curve method. Reliable linearity, sensitivity, precision, accuracy, and repeatability were obtained and validated. Then the relative response factors between these six analytes were calculated, which were not more than two times using any alkaloid as reference. Thus, the other 18 alkaloids lacking reference compounds were relatively quantified. This approach provides a useful tool for rapid identification and quantitative analysis of toxic benzoyl alkaloids, and also an efficient method for the safety assessment of Aconitum roots. PMID- 29974652 TI - International Speakers. PMID- 29974651 TI - ANZUP MDT Masterclass Convenor Welcome. PMID- 29974653 TI - ANZUP Chair Welcome. PMID- 29974654 TI - ANZUP Scientific Program and Pre-Conference Meetings 2018: Putting People First - Celebrating ANZUP's 10th anniversary. PMID- 29974656 TI - National Speakers. PMID- 29974655 TI - ANZUP Fellowships and Awards. PMID- 29974657 TI - ANZUP Advisory Committee and Subcommittee Chairs. PMID- 29974659 TI - NINTH ANNUAL GENERAL MEETING ANZUP CANCER TRIALS GROUP LTD (ANZUP) (ACN 133 634 956). PMID- 29974658 TI - Sponsor Acknowledgements. PMID- 29974660 TI - Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores. AB - Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome-wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross-disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women. PMID- 29974661 TI - Microparticles Locally Deliver Active Interleukin-1 Receptor Antagonist In Vivo. AB - Despite significant research in therapeutic protein delivery, localized and sustained delivery of active therapeutic proteins remains a challenge. Delivery is a particular challenge for therapeutic proteins with a short half-life. Herein, localized delivery of interleukin-1 receptor antagonist (IL-1Ra) by mineral coated microparticles (MPs) is assessed in a healing rat medial collateral ligament (MCL). The local tissue concentration and systemic serum concentration of IL-1Ra, the anti-inflammatory activity of IL-1Ra delivered with MPs, and whether IL-1Ra loaded MPs (IL-1Ra MPs) are immunogenic in a healing ligament are also examined. IL-1Ra MPs significantly increase the local concentration of IL-1Ra compared to soluble IL-1Ra at 7 and 14 days after treatment but do not elevate the systemic concentration of IL-1Ra at these time points, indicating localized delivery of IL-1Ra. IL-1Ra MPs significantly reduce inflammation caused by the MPs themselves, indicating the IL-1Ra is active. Finally, IL-1Ra MPs do not induce a foreign body response and decrease the immunogenicity of human IL-1Ra in a healing rat MCL. Overall, mineral coated microparticles have the ability to locally deliver active therapeutic proteins for an extended period of time. PMID- 29974662 TI - Progress in Applications of Prussian Blue Nanoparticles in Biomedicine. AB - Prussian blue nanoparticles (PBNPs) with favorable biocompatibility and unique properties have captured the attention of extensive biomedical researchers. A great progress is made in the application of PBNPs as therapy and diagnostics agents in biomedicine. This review begins with the recent synthetic strategies of PBNPs and the regulatory approaches for their size, shape, and uniformity. Then, according to the different properties of PBNPs, their application in biomedicine is summarized in detail. With modifiable features, PBNPs can be used as drug carriers to improve the therapeutic efficacy. Moreover, the exchangeable protons and adsorbability enable PBNPs to decontaminate the radioactive ions from the body. For biomedical imaging, photoacoustic and magnetic resonance imaging based on PBNPs are summarized, as well as the strategies to improve the diagnostic effectiveness. The applications related to the photothermal effects and nanoenzyme activities of PBNPs are described. The challenges and critical factors for the clinical translation of PBNPs as multifunctional theranostic agents are also discussed. Finally, the future prospects for the application of PBNPs are considered. The aim of this review is to provide a better understanding and key consideration for rational design of this increasingly important new paradigm of PBNPs as theranostics. PMID- 29974663 TI - Prolonged balloon tamponade in the initial management of inferior vena cava injury following complicated filter retrieval, without the need for surgery. AB - Advanced techniques have been described to remove embedded inferior vena cava (IVC) filters including the loop snare and modified loop snare (Hangman) techniques. Retrieval of embedded filters have been associated with higher rates of complications including IVC injury and stenosis. We report two challenging embedded retrievals complicated by IVC injury and haemorrhage. Haemostasis was successfully achieved with prolonged balloon tamponade, suggesting that injury to the IVC during filter retrieval may not need urgent surgery. However, both patients received short-term complications related to caval thrombosis and patients in this cohort should be closely observed after retrieval. These cases support rigorous attention to filter indication and follow-up. PMID- 29974664 TI - Negative pressure wound treatment with computer-controlled irrigation/instillation decreases bacterial load in contaminated wounds and facilitates wound closure. AB - Microbial wound contamination is known to be a hindrance to wound healing. Negative pressure wound therapy (NPWT) with or without irrigation is known to optimise conditions in problem wounds. The aim of this study was to investigate the influence of computer-controlled wound irrigation with NPWT on the bacterial load in contaminated wounds. A total of 267 patients were treated with NPWT with automated instillation because of problematic wounds using an antiseptic instillation solution. In 111 patients, a minimum of 4 operative procedures were necessary, and swabs were taken at least at the first and at the fourth operation in a standardised procedure. The number of different bacteria and the amount of bacteria were analysed during the course. In a subgroup of 51 patients, swabs were taken at all 4 operative procedures and analysed separately. In an overall analysis, the number of different bacteria and the amount of bacteria significantly decreased independent of wound localisation and diagnosis. NPWT with automated instillation demonstrates a positive influence in the reduction of bacterial load in problem wounds. Thus, it may help to optimise wound conditions before definite wound closure. PMID- 29974665 TI - Sofosbuvir and ledipasvir are associated with high sustained virologic response and improvement of health-related quality of life in East Asian patients with hepatitis C virus infection. AB - Although HCV infection is highly prevalent in East Asia, these patients have been underrepresented in HRQL studies. Here, we assess HRQL in East Asian HCV patients treated with different anti-HCV regimens. Patients completed Short Form-36 (SF 36) before, during and after treatment. A total of 989 HCV patients were enrolled in two phase 3 clinical trials [China: 60.2%, South Korea: 22.4%, Taiwan: 17.4%; genotype 1: 55.3%, treatment-naive: 57.5%; cirrhosis: 14.0%]. Patients received pegylated interferon, sofosbuvir and ribavirin (Peg-IFN + SOF + RBV; n = 130, genotypes 1, 6) or SOF + RBV (n = 475, all genotypes) or SOF and ledipasvir (LDV/SOF; n = 384, genotype 1). The SVR-12 rates were 94.6%, 96.2% and 99.2%, respectively (P = 0.005). During treatment, Peg-IFN + SOF + RBV-treated group experienced significant declines in most HRQL scores (by the end of treatment, mean decline up to -12.0 points, all P < 0.05). Patients on SOF + RBV had milder HRQL impairment (up to -5.8 points, P < 0.05 for 5 of 8 HRQL domains). In contrast, patients receiving IFN- and RBV-free regimen with LDV/SOF had their HRQL scores improve (mean up to +4.3 points, P < 0.0001 for 3 of 8 scales). In multivariate analysis, receiving Peg-IFN + SOF + RBV was consistently independently associated with HRQL impairment during treatment (beta: -10.3 to 16.4) and after achieving SVR-12 (beta: -4.4 to -9.1) (all P < 0.01). The results were reproduced in a subgroup of patients enrolled in China. We conclude that in East Asian patients with HCV, HRQL improved from baseline after treatment with LDV/SOF but not with Peg-IFN + RBV-containing or Peg-IFN-free RBV-containing regimens. The HRQL impairment associated with the use of Peg-IFN persists even after achieving sustained virologic clearance. PMID- 29974666 TI - Signalling through Src family kinase isoforms is not redundant in models of thrombo-inflammatory vascular disease. AB - The Src family kinases (SFK) are a group of signalling molecules with important regulatory functions in inflammation and haemostasis. Leucocytes and platelets express multiple isoforms of the SFKs. Previous studies used broad-spectrum pharmacological inhibitors, or murine models deficient in multiple SFK isoforms, to demonstrate the functional consequences of deficiencies in SFK signalling. Here, we hypothesized that individual SFK operate in a non-redundant fashion in the thrombo-inflammatory recruitment of monocyte during atherosclerosis. Using in vitro adhesion assays and single SFK knockout mice crossed with the ApoE-/- model of atherosclerosis, we find that SFK signalling regulates platelet-dependent recruitment of monocytes. However, loss of a single SFK, Fgr or Lyn, reduced platelet-mediated monocyte recruitment in vitro. This translated into a significant reduction in the burden of atherosclerotic disease in Fgr-/- /ApoE-/- or Lyn-/- /ApoE-/- animals. SFK signalling is not redundant in thrombo inflammatory vascular disease and individual SFK may represent targets for therapeutic intervention. PMID- 29974667 TI - Correlation between cortical lesions and cognitive impairment in multiple sclerosis. AB - OBJECTIVES: Gray matter (GM) damage is well known as a fundamental aspect of multiple sclerosis (MS). Above all, cortical lesions (CLs) burden, detectable at MRI with double inversion recovery (DIR) sequences, has been demonstrated to correlate with cognitive impairment (CI). The aim of this study was to investigate the role of CLs number in predicting CI in a cohort of patients with MS in a clinical practice setting. MATERIALS AND METHODS: Thirty consecutive patients with MS presenting CLs (CL+) at high-field (3.0 T) MRI 3D-DIR sequences and an even group of MS patients without CLs (CL-) as a control, were investigated with the Rao Brief Repeatable Battery of Neuropsychological Tests (BRB), Version A. Total and lobar CLs number were computed in CL+ patients. RESULTS: Among the sixty patients with MS enrolled, forty-seven (78.3%) had a relapsing-remitting course, while thirteen (21.7%) a progressive one, eleven secondary progressive, and two primary progressive. Compared to CL-, CL+ patients had a greater proportion of progressive forms (p = .03). The most affected region was the frontal lobe (73.3% of patients), followed by temporal and parietal ones (both 60.0%). Multivariate (logistic regression) analysis revealed a significant correlation between total CLs number and the presence of mild cognitive impairment defined as pathologic score in at least one BRB test (p = .04); it was also correlated with deficit at PASAT 3 (p = .05) and Stroop Test (p = .02). CONCLUSIONS: We confirmed CLs number, evaluated with a technique quite commonly available in clinical practice, as a predictive factor of CI in patients with MS, in order to improve the diagnosis and management of CI and monitor potential neuroprotective effects of therapies. PMID- 29974668 TI - Prognostic value of association of OCT4 with LEF1 expression in esophageal squamous cell carcinoma and their impact on epithelial-mesenchymal transition, invasion, and migration. AB - Esophageal squamous cell carcinoma (ESCC) is a malignant disease with poor prognosis. Because of early metastasis prior to diagnosis and therapeutic resistance, ESCC has become one of the leading causes of cancer-related death. Here, we investigated the clinicopathological significance of the association of octamer-binding transcription factor 4 (OCT4) with lymphoid enhancer-binding factor 1 (LEF1) expression and the potential molecular mechanism in the epithelial-mesenchymal transition (EMT), invasion, and migration of ESCC. The expression of OCT4 and LEF1 was detected via immunohistochemistry analysis. High levels of LEF1 expression were observed in 95 ESCC specimens and were obviously associated with aberrant clinicopathological features and poor patient prognosis. Our previous study showed that OCT4 expression level is elevated in ESCC, and statistical analysis showed that the elevated expression of OCT4 and LEF1 in ESCC was significantly associated with histologic grade, lymph node metastasis, TNM stage, and poor patient prognosis. The specific inhibition of OCT4 expression via a lentivirus encoding OCT4-shRNA (LV-shOCT4) in Eca109 cells led to decreased levels of OCT4 and LEF1 in vitro. Additionally, we applied a rescue strategy by infecting LV-shOCT4 Eca109 cells with a LEF1 overexpression plasmid (p-LEF1) and detected changes in EMT, migration, and invasion. Unsurprisingly, the p-LEF1 group exhibited greater EMT, invasion, and migration than did the LV-shOCT4 and negative control groups. This study demonstrates for the first time the relationship between OCT4 and LEF1 expression. The combination of high expression of OCT4 and LEF1 was associated with clinicopathological features of atypical patients, and this combination might be an ideal prognostic factor in ESCC. OCT4 positively regulated LEF1 expression, and LEF1 mediated the effects of OCT4 in cancer cell EMT, invasion, and migration. The data presented here suggest that the inhibition of OCT4-LEF1 signaling may be a new therapeutic target for the treatment of ESCC. PMID- 29974669 TI - Development on a magnetic anchoring robot system based on visual servo control for laparoendoscopic single-site surgery. AB - BACKGROUND: Surgical robot systems have been used in laparoendoscopic single-site surgery (LESS) to improve patient outcomes. A magnetic anchoring surgical robot system for LESS can effectively extend the operation space. METHODS: A robot system based on visual servo control for LESS is proposed. It includes a magnetic anchoring robot and a control subsystem, in which an uncalibrated visual servo control method obtains an accurate positioning capability of the robot for LESS. RESULTS: The results of the simulation and the tissue experiment show that the robot system can successfully accomplish the expected control functionalities for LESS. The average positioning error of the proposed system is 1.622 mm. CONCLUSION: The magnetic anchoring robot system is able to implement the autonomous positioning of its end-effector through the proposed control approach according to experimental results. PMID- 29974670 TI - Reply to the comment of Wilbrink et al. on Retrospective analysis of liraglutide and basal insulin combination therapy in Japanese type 2 diabetes: The association between remaining beta-cell function and the achievement of the HbA1c target 1 year after initiation. AB - We have reported that the HbA1c-lowering effects of liraglutide/basal insulin combination rely on remaining beta-cell function and that the cut-off value of the C-peptide immunoreactivity index (CPI), a beta-cell function-related index frequently used in Japanese clinical settings, is 1.103 for the achievement of HbA1c <7.0% at 54 weeks after initiating the liraglutide/basal insulin combination. Wilbrink et al claimed that glucose-lowering effects of glucagon like peptide-1 receptor agonist liraglutide depend of duration of type 2 diabetes; while our resent study published in the Journal of Diabetes Investigation failed to detect such dependency. This discrepancy might be due to several reasons including co-administration of basal insulin with liraglutide in our study; ethnic difference in T2D pathophysiology between the two study; and difference in sample size (The Usui study on liraglutide/basal insulin, n = 38; the Usui study on liraglutide monotherapy or SU combination, n=88; and the Wilbrink study, n = 69). PMID- 29974671 TI - Disease duration as an indicator of the efficacy of liraglutide in patients with type 2 diabetes mellitus. AB - Comment on the article of Usui et al. Retrospective cohort study of obese patients with type 2 diabetes mellitus (n = 69) demonstrates that the glucose lowering effect of liraglutide as add on therapy to insulin relies on the remaining beta-cell function in type 2 diabetes. Shorter disease duration implies a more favourable prognosis for response on instantaneous substitution of insulin with liraglutide (HR 2.39 (95% CI: 1.20-4.76). PMID- 29974673 TI - Persistence of oral antidiabetic treatment for type 2 diabetes characterized by drug class, patient characteristics and severity of renal impairment: A Japanese database analysis. AB - AIM: To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. MATERIALS AND METHODS: This retrospective, observational study extracted data from a large scale hospital database (April 2008 to September 2016). Patients with T2DM aged >=40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or alpha-glucosidase inhibitors [alpha GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan-Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: >=90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). RESULTS: We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, alpha-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for alpha-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1-G4+), followed by BGs at stages G1/G2. CONCLUSIONS: The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+. PMID- 29974674 TI - Anterior approach in right hepatectomy. PMID- 29974672 TI - High background in ELISpot assays is associated with elevated levels of immune activation in HIV-1-seronegative individuals in Nairobi. AB - INTRODUCTION: Spontaneous interferon-gamma (IFNgamma) released detected by enzyme linked immunospot (ELISpot) assays may be a biological phenomenon. Markers of immune activation levels were assessed as correlates of high background among individuals in Kenya. METHODS: Couples concordantly seronegative for HIV-1 were enrolled. IFN-gamma ELISpot assays were conducted and negative control wells were categorized as having either high or low background (>=50 and <50 SFU/106 peripheral blood mononuclear cells [PBMC], respectively). PBMC were stained for CD4, CD8, and immune activation markers (CD38 and HLA-DR) and analyzed using flow cytometry. Proportions of activated T-cells were compared between those with low and high background by Mann-Whitney U test. Correlates of background SFU and immune activation were assessed using regression models. RESULTS: Among 58 individuals, 14 (24%) had high background. Frequencies of CD4+ CD38+ HLA-DR+ and CD8+ CD38+ HLA-DR+ cells were higher in individuals with high background compared to those with low background (P = 0.02). Higher background SFU was associated with history of sexually transmitted infections (P = 0.03), and illness in the past 3 months (P = 0.005), in addition to increased levels of activated CD4+ and CD8+ cells (P range = 0.008-0.03). Female gender and male circumcision decreased levels of CD4+ and CD8+ immune activation (P range = 0.002-0.03). Additionally, higher background SFU and activated CD4+ and CD8+ cells were individually associated with positive ELISpot responses to HIV-1 peptide pools (P range = 0.01 0.03). CONCLUSIONS: These findings suggest that increased basal immune responses may be a biological mechanism contributing to higher background ELISpot SFU. Systematic exclusion of data from individuals with increased background in IFN gamma release assays may bias results in population-based studies. PMID- 29974675 TI - Rectal cancer staging: An up-to-date pictorial review. AB - Colorectal cancer is the third most common malignancy worldwide, and rectal cancer (RC) accounts for 29% of all cases. Local staging of RC is crucial for the purposes of addressing patients appropriately to surgery alone or to preoperative chemoradiotherapy (pCRT) followed by total mesorectal excision (TME). Combined pCRT and TME may negatively affect rectal function, so rectum-sparing approaches such as transanal local excision have been proposed as an alternative to TME for patients showing a major or complete clinical response on restaging after pCRT. Magnetic resonance imaging (MRI) has a fundamental role in the local staging and restaging of RC, with or without positron emission tomography (PET). PET/MRI enables a multiplanar high-resolution morphological study of the pelvis, providing important information on cell density and metabolic activity with diffusion-weighted imaging (DWI) and 18 F fluorodeoxyglucose uptake respectively. This article offers a pictorial review of the MRI anatomy of the ano-rectal region and an update on local RC staging with a hybrid 18 F-FDG PET/MRI scan. PMID- 29974676 TI - Prevalence and Severity of Postdialysis Fatigue Are Higher in Patients on Chronic Hemodialysis With Functional Disability. AB - The aim of the present study was to determine the intensity, duration, frequency and prevalence of postdialysis fatigue (PDF) in patients on chronic hemodialysis (PCD) with and without functional disability. Patients underwent assessment of functional ability by the Katz ADL (activity daily living) questionnaire and the Lawton and Brody scale for the instrumental activity daily living (IADL) fatigue using the SF-36 Vitality Subscale, comorbidity through the Charlson comorbidity score index (CDI), and time of recovery after hemodialysis (TIRD). We studied 271 PCD. ADL and IADL disabilities were present in 75 (27.6%) and 168 (62%) patients, respectively. Patients with ADL disability were significantly older and showed higher CDI scores, and lower levels of serum albumin and Kt/V. Prevalence of PDF was significantly higher in patients with ADL disability as well as its severity, intensity, duration and frequency. Patients with IADL disability were significantly older, had a higher CCI score, had lower levels of serum albumin and Kt/V, and had a higher severity, intensity, duration and frequency of PDF. At multivariate regression analysis, ADL disability was positively associated with age, prevalence and severity of PDF, and dialysate temperature and inversely associated with serum albumin levels. IADL disability was instead positively associated with age and dialysate temperature and inversely associated with serum albumin levels. In conclusion, prevalence and severity of PDF are significantly higher in PCD with ADL disability than in those without it. This knowledge may have important implications for the development of interventions to reduce PDF in PCD. PMID- 29974677 TI - Detection of Japanese Encephalitis Virus in bone marrow of healthy young wild birds collected in 1997-2000 in Central Italy. AB - Japanese Encephalitis Virus (JEV) is a flavivirus responsible for an important zoonotic, vector-borne disease included in the OIE list. JEV is endemic in a large area of Asia. In Italy, JEV has been found in dead birds collected in 1997 2000 and in a pool of Culex pipiens mosquitoes collected in 2010. Viral ecology in the inter-epidemic periods is not known. The aim of this study was to investigate JEV in FFPE archival samples of healthy birds collected in 1997-2000 in Tuscany (Italy) in the same area and a few months after collection of birds resulted infected by JEV. Different samples from 37 young birds and 83 adults were available. Immunohistochemistry detected JEV antigen only in bone marrow samples from 12 young healthy birds. Positive cells were morphologically referable to monocyte-macrophages lineage and were positive for anti-CD11b in serial sections. Real-time PCR detected JEV RNA in four of these samples. These results suggest that healthy birds can harbour JEV in bone marrow cells, while no other organs resulted infected. The role of healthy birds in JEV ecology should be better investigated. Surveillance programmes should include sampling of the most appropriate target organs. PMID- 29974679 TI - [Spatial pattern of plant community in original karst tiankeng: A case study of Zhanyi tiankeng in Yunnan, China]. AB - Damaosi is one of original karst tiankengs with underground virgin forest in Yunnan Pro-vince. The spatial point pattern analysis and the woody individual spatial structure parameters, including the uniform angle index, mingling degree and storey index, were used to estimate spatial pattern of the tiankeng's underground forest community. We also analyzed the intraspecific spatial distribution characteristics and interspecific spatial association on the basis of the individual relative position information of plant community. The results showed that the spatial distribution of plant community in Damaosi tiankeng was random. Plant species in the forest were moderately mixed. The vertical stratification of this forest was relatively simple, with stable structure and mature development characteristics of climax forest community. The populations in this community were mainly clustered in spatial distribution, negatively correlated between species and stronger negative correlation on the same vertical level. The larger the difference in the vertical level, the smaller the space competition was. The negative correlation in space became weaker with the increases of spatial scale. Tiankeng ecosystem was one type of precious natural habitats and plant refuges with high ecological stability. The stable structure of tiankeng plant community had important implications for the ecological resto ration in karst areas. PMID- 29974680 TI - [Interspecific association and functional group classification of the dominant populations in shrub layer in secondary forest of Pinus tabuliformis in Qinling Mountain, China.] AB - We analyzed the interspecific association among 20 dominant populations in shrub layer in secondary natural forest of Pinus tabuliformis in Qinling Mountain, China, with X2-test, the association coefficients and the percentage of common occurrence. The results showed that the species pairs with significant positive associations accounted for only 7.4% of the total 190 species pairs. The species pairs such as Lespedeza bicolor and Elaeagnus pungens, Toxicodendron vernicifluum and Pinus tabuliformis, Euonymus alatus and Cerasus tomentosa had extremely significant positive correlations, whereas most of the species pairs showed weak interspecific association. The ratio of positive and negative correlations was less than 1. The results suggested that the interspecific association was relatively weak. Species were with certain independence among dominant populations. Community structure was at an unstable mid-stage with dynamic succession. According to the interspecific association and cluster analysis, combined with biological and ecological characters, the 20 dominant populations in shrub layer were classified into four functional groups. The ecological requirement and resource use pattern of species within the same functional groups were similar, exhibiting a close connection between the shrub species. The connection between different functional groups was relatively loose. PMID- 29974678 TI - A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing. AB - BACKGROUND: Glycosylphosphatidylinositol (GPI) anchoring is a special type of protein posttranslational modification, by which proteins with diverse function are attached to cell membrane through a covalent linkage between the protein and the glycolipid. Phosphatidylinositol glycan anchor biosynthesis class A (PIGA) is a key enzyme in GPI anchor biosynthesis, somatic mutations or genetic variants of which have been associated with paroxysmal nocturnal hemoglobinuria (PNH), or PIGA deficiency, respectively. More than 10 PIGA pathogenic or likely pathogenic variants have been reported in a wide spectrum of clinical syndromes of PIGA deficiency, including multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2). METHODS: Whole-exome sequencing (WES) was performed on two trios, that is., the proband's family and his affected maternal cousin's family, from a nonconsanguineous Chinese family pedigree with hypotonia-encephalopathy-seizures disease history and putative X-linked recessive inheritance. Sanger sequencing for PIGA variant was performed on affected members as well as unaffected members in the family pedigree to verify its familial segregation. RESULTS: A novel likely pathogenic variant in PIGA was identified through comparative WES analysis of the two affected families. The single-nucleotide substitution (NC_000023.9:g.15343279T>C) is located in intron 3 of the PIGA gene and within the splice acceptor consensus sequence (NM_002641.3:c.849-5A>G). Even though we have not performed RNA studies, in silico tools predict that this intronic variant may alter normal splicing, causing a four base pair insertion which creates a frameshift and a premature stop codon at position 297 (NP_002632.1:p.(Arg283Serfs*15)). Sanger sequencing analysis of the extended family members confirmed the presence of the variant and its X-linked inheritance. CONCLUSION: WES data analysis along with familial segregation of a rare intronic variant are suggestive of a diagnosis of X-liked PIGA deficiency with clinical features of MCAHS2. PMID- 29974681 TI - [Construction of empirical models for leaf area and leaf dry mass of two broadleaf species in Xiaoxing'an Mountains, China.] AB - Rapid and accurate measurement of leaf area (LA) and leaf dry mass (LM) is one of the basic requirement for leaf geometry and plant functional studies. It is important not only for studying leaf morphology and biomass estimation, but also for understanding the response mechanism of vegetation to climate change. In this study, we took two temperate deciduous broad-leaved tree species, Ulmus laciniata and Acer tegmentosum, as the study objects, constructed empirical models between LA or LM and leaf structure parameters (e.g., leaf length, L; leaf width, W) to reveal the interspecific variability in the selection of empirical model formats (linear or non-linear) and independent variables. We evaluated the forecast accuracy of these empirical models in predicting LA and LM for each species. The results showed that the optimal empirical models for predicting LA were LA=0.614L1.468W0.464 and LA=0.865(LW)0.933, and for predicting LM were LM=0.003L1.537W0.365 and LM=0.001L2.318 for U. laciniata and A. tegmentosum, respectively. The forecast accuracies of empirical models in predicting LA were 88% and 96%, and for LM were 73% and 83% for U. laciniata and A. tegmentosum, respectively. In addition, based on the empirical models for predicting LA and LM, the specific leaf area also could be indirectly measured under non destructive conditions, with the forecast accuracies being 83% and 90% for U. laciniata and A. tegmentosum, respectively. These results provide a technical support for the efficient measurement of leaf traits and their dynamics. PMID- 29974682 TI - [Effects of N-fixing tree species (Alnus sibirica)on amino sugars in soil aggregates of Larix kaempferi plantation in eastern Liaoning Province, China.] AB - Soil microbial residues are important components of soil stable carbon (C) pools. How N-fixing tree species influence microbial residues in soil aggregates in larch plantations is still unclear. To determine the effects of N-fixing tree species on the distribution of microbial residues in different aggregates, we compared the distribution of amino sugars, biomarker of microbial residues, among aggregates in a pure larch (Larix kaempferi) plantation and a mixed plantation of larch (Larix kaempferi) and alder (Alnus sibirica) in eastern Liaoning Province. The results showed that alder did not affect the distribution of amino sugars, but significantly increased amino sugars content in soil aggregates. The total amino sugars in different soil aggregates were enriched by 130%-170% in the mixed larch plantation compared with those in pure larch plantation. The contributions of glucosamine, galactosamine and muramic acid to the increases of total amino sugars caused by alder introduction were 66.5%-66.9%, 30.0%-30.6% and 2.5%-3.2%, respectively. Alder introduction significantly accelerated the glucosamine/muramic acid ratios in >2000 MUm and <250 MUm aggregates, but not in 250-2000 MUm aggregates. Moreover, alder introduction increased the microbial contribution to soil organic C in all aggregates, but did not influence this contribution among aggregates, indicating that the effects of alder introduction on microbial contribution to aggregates were homogeneous. PMID- 29974683 TI - [Effects of drought and rewatering on growth and photosynthetic physioecological characteristics of Xanthoceras sorbifolia.] AB - An experiment was conducted to examine the effects of drought and rewatering on growth and photosynthetic physioecological characteristics of Xanthoceras sorbifolia, with 2-year-old seedlings as test materials. There are three treatments, i.e., light drought stress (soil water content 14.3%-16.2%), moderate drought stress(10.6%-12.5%) and severe drought stress (6.8%-8.7%), with the control (21.8%-23.7%). The results showed that with the increases of drought stress, the dry mass per plant, height, basal diameter, leaf number, and leaf area significantly decreased, and length of the main root and the secondary root increased. The gas exchange parameters gradually decreased with the increases of drought stress. The level of Pn was caused by stomatal factors from 10:00 to 14:00 and by non-stomatal factors after 14:00. Apparent CO2 use efficiency (CUE) of X. sorbifolia was obviously increased under the moderate and severe drought stress. With the increases of drought stress, Fv/Fo, Fv/Fm, qP, ETR and FPS2 gradually decreased, and NPQ gradually increased. The changes of all those characters after rewatering were contrary to those after drought. After rewatering for eight days, Fv/Fo, Fv/Fm, qP, ETR, FPS2 were significantly higher than that of drought stress treated for 30 days. With the increases of drought stress, SOD and POD activities and MDA content gradually increased, but CAT activity decreased, showing the contrary changes after rewatering. After rewatering, the root activity under drought stress increased. X. sorbifolia was strongly resistant to heavy drought stress, and thus could be widely used as energy or garden plants in garden landscaping in North China. PMID- 29974684 TI - [Application of near-surface remote sensing in monitoring the dynamics of forest canopy phenology.] AB - Near-surface remote sensing is an important technique for in-situ monitoring of forest phenology and a robust tool for scaling of the phenology with a high temporal resolution and mode-rate spatial coverage. Here, we first reviewed the methods of near-surface remote sensing with three major optical sensors (i.e., radiometer, spectrometer, and digital camera) for monitoring forest phenology. Second, we analyzed sources of uncertainties from distinguishing the phenophases by using the data obtained at the Maoershan flux site in the temperate forest. We found that the error was mainly attributed to the extracting method. Third, we analyzed the linkage of near-surface remote sensing with other methods and its intrinsic problems. Finally, we proposed four priorities in the research of this field: 1) linking optical (or canopy structural) phenology with functional phenology (physiological and ecological processes); 2) integrating the regional networks of canopy phenology for global networking observation and data sharing of canopy phenology; 3) integrating multi-source and multi-scale phenological data with the help of near-surface remote sensing; 4) developing phenology models based on near-surface remote sensing in order to improve the phenology simulation in the dynamic global vegetation models. PMID- 29974685 TI - [Responses of soil and aggregate-associated organic carbon mineralization to throughfall reduction in a Pinus massoniana plantation.] AB - To examine the effects of altered precipitation pattern on the mechanism of forest soil carbon (C) emission under climate change scenarios, we established plots with 50% reduction in throughfall in a subtropical Pinus massoniana plantation. The effects of throughfall reduction on the mineralization of both soil and aggregate-associated organic C were quantified by laboratory incubation at constant temperature. The results showed that the cumulative mineralization of organic C in the 1-2 mm aggregates was higher than that in other sizes of aggregates. In the dry and wet seasons, the surface soil water content in the throughfall reduction plots was 82.1% and 82.7% of that in the control, but the mass fractions of 0.106-0.25 mm soil aggregates in the throughfall reduction plots increased by 1.8% and 4.2% than the control, respectively. The throughfall reduction treatment significantly reduced the mineralization rate of labile C pools (k1) of soil and micro-aggregates in the dry season, increased the mineralization rate of recalcitrant C pool (k2) of soil and <1 mm aggregates, and had no significant effects on the cumulative mineralization of soil organic C. Results from the correlation analyses revealed significant and positive correlations between k1 of soil and that of the micro-aggregates and between k2 of soil and that of the 0.25-1 mm aggregates. Under the influence of aggregate structure, water condition and soil organic carbon content, the throughfall reduction suppressed the mineralization of labile organic C while stimulated that of recalcitrant organic C. PMID- 29974686 TI - [Turbulence micro-meteorological characteristics over the plantation canopy.] AB - Based on the eddy-covariance system monitoring during leaf germination (15th March to 15th April 2015) and leaf forming (15th July to 15th August), the turbulence characteristics, turbulence intensity, normalized standard variance of turbulent wind speed and bulk transfer coefficient over forest plantation canopy in the Xiaolangdi Ecosystem Location Research Station were analyzed, aiming to deepen the understanding of the micro-meteorological characteristics of the forest ecosystem and provide scientific basis for the further studies of energy balance and material exchange. Results showed that turbulence spectrum of the plantation had a peak frequency in the low frequency zone and the inertial subarea had an obvious dissipation tendency, which was basically in accor-dance with the law of -5/3. Turbulence intensity was significantly affected by canopy structure. When the turbulence was strong, the wind speed was less than 3 m.s-1 in spring and less than 2 m.s-1 in summer. Normalized standard variance of turbulent wind speed in horizontal direction was better than that in vertical direction, which conformed to the similarity law of 1/3 power. The ratio of normalized standard deviation and the friction velocity in u, v, w components of canopy wind speed was 2.55, 2.06 and 1.30 in spring, 2.61, 2.45 and 1.21 in summer, respectively. The bulk transfer coefficient decreased with the increases of stability, with a difference of 1-2 orders of magnitude or more between unstable and stable conditions. Canopy structure had direct influence on the turbulence of the wind speed in each direction, and thereby changed the diffusion direction of the canopy material and energy. PMID- 29974687 TI - [Diversity of bryophytes in urban area of Nanjing, China]. AB - Bryophytes are morphologically special higher plants, with unique ornamental values and a wide application prospect. Its species richness was just secondary to angiosperms. To more effectively utilize bryophytes for greening and landscape construction, 77 plots in 10 green spaces were investigated in urban area of Nanjing. 55 species belonging to 36 genera and 21 families were recorded, among which Pottiaceae and Thuidiaceae were widely distributed. The species richness in green space gradually reduced from the center to the surrounding areas of the city. The 10 green spaces could be clustered into three groups based on bryophyte diversity, habitats, human distur-bance frequency, green space areas. Results from Canonical correspondence analysis (CCA) showed that canopy density, humidity, and substrate types were the major environmental factors the distribution of bryophytes. In Nanjing, most bryophytes preferred to grow in moderate humidity and open areas. PMID- 29974688 TI - [Landscape pattern change and simulation in the SanJiang Plain based on the CLUE S model.] AB - The SanJiang Plain is one of the most concentrated and contiGuous area of marshes, which plays an irreplaceable role in maintaining regional ecological security. Based on the 3S technology, we examined the changes in land use and landscape pattern of the SanJiang Plain from 1980 to 2010. The results showed that marshland area lost 7135 km2, with a loss rate of 59.1%. The paddy area increased 18010 km2, with a growth rate of 610.1%. The results of landscape indices analysis showed that the number of patches increased, the landscape fragmentation became stronger, the landscape heterogeneity increased, and the different landscape types became homogenized. The CLUE-S model was validated based on the five different periods of land use maps during 1980-2010. The Kappa index between the simulation and actual measurement at the time scale of 30 years was 0.71, indicating that the model was suitable for 30 years simulation in the study area. The future wetland changes in the SanJiang Plain from 2010 to 2030 was simulated with validated CLUE-S models, including historical development scenario, planning scenario, and ecological restoration scenario. The simulation results showed that the marsh land would decrease 2515.44 km2 and the paddy area would increase 19656.24 km2 in the historical development scenario. The marsh land would decrease 303.28 km2, but the paddy area would increase 1392.08 km2 in the planning scenario. The marsh land would increase 3585.61 km2 and the paddy area would increase 289.72 km2 in the ecological restoration scenario. The landscape patterns of the three scenarios were estimated using landscape indices. The results showed that the landscape pattern fragmentation would become more and more serious in the historical development scenario. The landscape pattern would have no signifi-cant changes in the planning scenario. The wetland area and connectivity would increase, the different landscape types would become balanced, and the landscape pattern would be gradually optimized in the ecological restoration scenario. PMID- 29974689 TI - [Multi-scale effects of urban landscape pattern on plant diversity in Xuzhou City, Jiangsu Province, China.] AB - The changes of urban surface landscape will lead to damage, fragmentation, and losses of biodiversity, resulting in urban biodiversity decline. In order to explore the responses of urban plant diversity to the changes of landscape pattern, we chose the urban area surrounded by round-city highway as research object, set 36 plots in different directions with the Gupeng Square as the center, investigated the plant group in each of the plots through coverage rank method of Braun-Blanquet, and examined the features of plant species diversity in Xuzhou's greenlands. Meanwhile, we divided the landscape of the research area into seven categories: buildings, grasslands, forest lands, waste lands, water areas, roads and farmlands with the help of Erdas, GIS software and Landsat TM remote sensing images from 2005 to 2015 as basic data source. The features of landscape pattern in the research area were analyzed by Fragstats software. We set nine different buffer districts within each of the sample plot by applying the space analyzing function of GIS, calculated 39 landscape pattern metrics using Fragstats, and explored the features of how plant diversity responsed to landscape pattern. After that, the landscape pattern metrics with significant influence on the plant diversity of urban greenlands under different extents were selected by redundant analysis (RDA). The results showed that the plant diversity had obvious temporal and spatial scale effects in responses to landscape pattern and landscape elements. In 2005, the patch area and shape metrics of unused land and farmland could better explain plant diversity in 800 m buffer zone. The patch fragmentation and connectivity metrics of construction land had significant impacts on plant diversity within the extent of 800-2000 m. In 2015, grassland and forest landscapes better explained plant diversity in the 800 m buffer zone while construction sites and unused land had a remarkable impact on plant diversity in the extent of 1000-2000 m. The current plant diversity was more strongly influenced by the 2005 landscape type metrics, indicating that the plant diversity lagged in its response to the changes of landscape pattern. The pattern metrics of landscape level were more consistent with the landscape-class level metrics, indicating that the interaction between species and spatial scale was more dependent on the landscape type. This study would provide effective decision making information for Xuzhou City planning and construction as well as effective protection of urban green space biodiversity. PMID- 29974690 TI - [Effects of precipitation changes on the precipitation use efficiency and aboveground productivity of alpine steppe-meadow on northern Tibetan Plateau, China.] AB - Total amount, distribution pattern and occurrence time of precipitation determine the water condition of alpine vegetation growth on the Tibetan Plateau, China. Precipitation use efficiency (the ratio of aboveground productivity to precipitation, PUE) is an effective indicator for the relationship between precipitation and vegetation productivity. In this study, we calculated aboveground net primary productivity (ANPP) of an alpine steppe-meadow in northern Tibetan Plateau from 2000 to 2016 based on the correlation model between long-term monitoring biomass data and enhanced vegetation index (EVI) in Damxung. Meteorological data during the same period was also analyzed. Growing season precipitation (GSP) represented the amount of precipitation, improved precipitation concentrated index (PCI) indicated their distribution pattern in the growing season, and precipitation centroid (PC) represented the time of precipitation occurrence. Structural equation model was used to explore the effects of climatic factors on PUE and ANPP, with the consideration of growing season temperature (GST). Results showed that ANPP of this alpine steppe-meadow was mainly controlled by precipitation during the growing season. GSP and ANPP showed significantly positive correlation, whereas the correlation of GST with PUE and ANPP was not significant. PCI and PUE showed significantly positive correlation, which indicated that concentrated distribution of precipitation was beneficial to the increase of PUE. Indirect coefficient between PCI and ANPP was greater than direct coefficient, indicating that PCI influenced ANPP through PUE. Changes of precipitation concentrated time did not show significant effect on PUE and ANPP. Our results suggested that under the rapid climate warming on the Tibetan Plateau, future changes of precipitation and their concentration would have important impacts on aboveground productivity of the alpine grassland. PMID- 29974691 TI - [Responses of net ecosystem carbon exchange to diffuse radiation in an alpine meadow on the Qinghai-Tibetan Plateau, China.] AB - Qinghai-Tibetan Plateau, one of the regions on the earth that receives the most solar radiation, is the world's highest alpine meadow ecosystem, with significance to regional and global carbon cycles. To examine the effects of solar radiation on ecosystem carbon dynamics in an alpine meadow, the net ecosystem CO2 exchange (NEE), solar radiation, diffuse radiation, and related environmental variables were measured using eddy-covariance technique and micro meteorological system. Sky conditions were divided into three categories of clear days (CI>=0.7), cloudy days (0.3=0.7, indicating that photo-inhibition might occur under high solar radiation conditions and increasing diffuse radiation would improve carbon sequestration of alpine meadow. Ecosystem respiration (Re) increased exponentially with the increases of air temperature (Ta). The maximum NEE was found at the air temperature of about 15 C from the relationship of NEE and air temperature, but NEE tended to decrease with increasing air temperature when Ta>15 C. Under clear sky day conditions, Re increased with increasing CI due to the increases of air temperature, with negative effects on NEE. NEE increased with the increases of VPD up to 0.6 kPa, then slowly decreased when VPD>0.6 kPa, illustrating that NEE was reduced due to the relatively high VPD. Our results suggested that strong solar radiation on clear days would not increase carbon uptake capacity of alpine meadow, while cloudy days with clearness index of 0.6-0.7 would help increase carbon sequestration on the Qinghai-Tibetan Plateau. PMID- 29974692 TI - [Effects of grassland management on soil nutrients and their spatial distribution on the Qinghai-Tibetan Plateau, China]. AB - After grasslands were contracted to individual households on the Qinghai-Tibetan Pla-teau, two grassland management patterns were formed, i.e., the single household management pattern (SMP) and the multi-household management pattern (MMP). The soil nutrients and their spatial distributions under those two patterns were compared in the Nagchu Prefecture of Tibet. The results showed that the soil organic carbon, total nitrogen, and total phosphorus under the MMP (84.31, 6.87 and 0.59 g.kg-1) were all significantly higher than those under the SMP (73.57, 6.07 and 0.54 g.kg-1). On the vertical dimension, the variation coefficient of soil total phosphorous between 0-15 cm layer and 15-30 cm layer under SMP had no significant difference, while that of soil pH, soil organic carbon and total nitrogen in 15-30 cm layer were all higher than 0-15 cm layer under both patterns. On the horizontal dimension, the variation coefficients of soil organic carbon and total nitrogen under SMP were significantly higher than those under MMP, with the estimated values for the former being 25.7% and 23.5%, and for the latter being 19.3% and 18.6%, respectively. Compared with the MMP, the uneven distribution of nutrients could easily lead to soil nutrient loss under the SMP. PMID- 29974693 TI - [Population spatial patterns of grassland plant communities in different slope aspects in the ?loess hilly area, China.] AB - We investigated the species composition and diversity of four grassland communities with different slope aspects in the loess hilly area of China. The power law was used to analyze spatial heterogeneity of the community and spatial pattern of the population. The results showed that Artemisia sacrorum was the dominant species and occurred in each site. Other species had different status and contributed differently to the spatial pattern of communities. Moreover, the spatial patterns of communities responded differently to various slope aspects, with the degree of aggregation ranked as sunny > half-sunny > half-shady > shady. The spatial heterogeneity index of community was positively correlated with the Simpson diversity index, but was negatively correlated with Margalef richness, Shannon diversity and Pielou evenness. The relative spatial heterogeneity index of the dominant species (A. sacrorum), sub-dominant species (Lespedeza dahurica and Stipa bungeana), and a few associated species (Artemisia scoparia, Melica scabrosa) were larger than that of the community, which resulted in cluster distribution. However, the relative spatial heterogeneity index of most associated species (Phragmites communis, Sonchus arvensis, and Bothriochloa flaccidum) showed the similar trends with the distribution of the community. In contrast, the relative spatial heterogeneity index of Cephalanoplos segetum, Gueldenstaedtia multiflora and Artemisia giraldii was lower than that of the community. These differences reduced the aggregation degree of the community. In summary, the aggregation degree of community was determined by dominant species, sub-dominant species and occasional species. Specifically, the dominant species, sub-dominant species and some associated species could promote the aggregation of the community, but occasional species would reduce the cluster distribution. PMID- 29974694 TI - [Effect of row spacing on physiological characteristics and yield of intercropped peanut with wheat.] AB - Using two peanut varieties Shanhua108 (early-maturing variety) and 780-15 (late maturing variety), a field experiment was conducted to investigate the influences of row-spacing of wheat (25 cm, 30 cm, 40 cm+20 cm) and two peanut cropping patterns (intercropped peanut with wheat, summer-sowing peanut) on yield components, photosynthetic characteristics, antioxidant system, and dry matter accumulation and transportation. The results showed that wide spacing form of wheat and wide-narrow row planting pattern increased the pod yield, kernel yield, leaf area index, total dry matter accumulation and photosynthetic capacity, as well as SOD, POD and CAT activities, but decreased the MDA content. There are no obvious differences of wheat yield between the two row-spacing. Intercropping system increased peanut yield compared with summer-sowing peanut, which were much higher for wide-narrow row planting pattern than row spacing of 25 cm or 30 cm. The wide-narrow row planting pattern increased the pod yield and kernel yield by 6.3%, 13.3% and 7.7%, 16.5% for Shanhua108 and 780-15 than those of row spacing of 30 cm, respectively. Wide-narrow row planting could enlarge photosynthetic area, improve the net photosynthetic rate, and increase total dry matter accumulation. Meanwhile, it could alleviate the contradictionbetween the plant individual and group, delay the senescence, and increase peanut yield. PMID- 29974695 TI - [Effects of ultrasound on the germination and seedling growth of three aged forage seeds.] AB - To examine the effects and physiological mechanisms of ultrasound treatment on the germination and seedling growth of naturally aged seeds, an [L9(34)] orthogonal matrix experiment was carried out, which included ultrasound time, ultrasound temperature, output power and seed soaking time with tall fescue Festuca arundinacea stored for one year and five years at room temperature, perennial ryegrass (Lolium perenne, stored for five years), and Russian wildrye (Psathyrostachys juncea, stored for six years) as test materials. The results showed that ultrasound temperature was the most important factor for the germination of aged seeds. The appropriate ultrasound treatment promoted germination percentage and significantly enhanced root and shoot length in aged seeds of tall fescue (stored for five years) and Russian wildrye. The positive effect of ultrasound was not significant on the germination of aged seeds of tall fescue (stored for one year) and perennial ryegrass, but was significant on the root length. Ultrasound treatment reinvigorated aged seeds by increasing superoxide dismutase (SOD) and peroxidase (POD) activities and reducing malondialdehyde (MDA) content. A regression model analysis was performed to determine the final optimal ultrasound condition for aged grass seeds that resulted in ultrasound time of 22 min, at 26 C, output power of 254.29 W and a seed soaking time of 2.89 h. PMID- 29974696 TI - [Carbon sequestration characteristics and regional differences of typical warm and tropical grasslands in Henan Province, China.] AB - In this study, we examined the vegetation and soil carbon density characteristics and carbon distribution differences of four typical grasslands in two climatic zones, including warm-tempe-rate tussock (WT), warm-temperate shrub tussock (WS), tropical tussock (TT), and tropical shrub tussock (TS) in Henan Province. The results showed that the average aboveground biomass of grasslands was significantly higher in Northwest Henan (327.4 g.m-2) than that in South Henan (221.4 g.m-2), whereas the average root biomass in Northwest Henan (1.58X103 g.m 2) was significantly lower than that in South Henan (1.94X103 g.m-2). The average aboveground carbon density of grasslands in Northwest and South Henan was 113.75 and 77.35 g C.m-2, respectively. The aboveground carbon density of WT in Northwest Henan was higher than that of WS, though not statistically significant. The living biomass carbon density of TT was significantly lower than that of other grasslands in Southwest Henan. The average underground carbon density of grasslands in Northwest and South Henan were 6.35X103 and 5.14X103 g C.m-2, respectively. In Northwest Henan, there was no difference between WT and WS for both the root and soil carbon density. In South Henan, the root carbon density of TS was significantly lower than other grasslands, while the soil carbon density of TT was significantly higher than other grasslands. The average carbon density of grassland ecosystem in Northwest and South Henan was 6.46X103 and 5.22X103 g C.m-2, respectively. Soil was the main contributor of ecosystem carbon storage and accounted for about 78%-90% of total grassland ecosystem carbon density. In addition, there were no significant differences in the ecosystem carbon density between WT and WS in Northwest Henan, while TT possessed significantly higher ecosystem carbon density (9.70X103 g C.m-2) compared with other grasslands in Southern Henan. Our results provide basic data for accurately calculating ecosystem carbon storage and assessing carbon sequestration potential of different grasslands in Henan Province. PMID- 29974697 TI - [Spatial-temporal distribution of vegetation net primary productivity and its driving factors from 2000 to 2015 in Shaanxi, China.] AB - Using MOD17A3 NPP time series data, surface cover type data, weather data, MOD16 evapotranspiration products and terrain data, the temporal and spatial variability of vegetation net primary productivity (NPP) in Shaanxi Province from 2000 to 2015 was analyzed, and its response to each influencing factor were discussed. The results showed that the NPP of Shaanxi had a significant upward trend in the past 16 years with a slope of 5.02 g C.m-2.a-1. The annual average of NPP was 344 g C.m-2.a-1 with a range from 247 to 390 g C.m-2.a-1. The NPP at 61.2% area of Shaanxi Province showed a significant increasing trend, which were mainly distributed at northern part of Shaanxi, Weibei area and western part of Qinba Mountain. There was a decrease trend of NPP for the area around Xi'an and Baoji City, accounting for only 2.5% of the whole province. During the study period, the variation of annual mean temperature and annual precipitation in Shaanxi showed no significance. The temperature showed a increase trend and the precipitation showed a decrease trend, implying a drier and warmer climate trend in Shaanxi Province. The areas with significant correlation between NPP and precipitation and temperature accounted for 9.4% and 1.5% of the total area of the province. The frequent intervention of human activities reduced the impact of climate on the changes of NPP, so human activity had gradually become the dominant factor. NPP in northern Shaanxi and Guanzhong areas was significantly correlated with evapotranspiration. The increases of NPP in these areas would have great influence on the water and heat balance. The average NPP at different land cover was farmland > forestland > grassland > garden, increasing rate of NPP at different land cover was garden > grassland > forestland > farmland, and proportional changes of NPP was grassland > garden > forestland > farmland. The increasing percentage of NPP at three gradient ranges were 14.6% (0 degrees -5 degrees ), 25.7% (5 degrees -25 degrees ) and 35.9% (>25 degrees ), respectively. PMID- 29974698 TI - [Impacts of adaptive measures to climate changes on climatic potential productivity of maize in northeast China.] AB - To understand how would the maize production in northeast China adapt to climate change, we adopted two strategies, inclduing using stress resistant varieties and delayed sowing date, combined with the daily meteorological data of RCP4.5 scenario and RCP8.5 scenario from 2010 to 2099 simulated by regional climatic model, to analyze the changes of climatic potential productivity of maize under different climate change scenarios. The results showed that in 2010-2099, the spatial characteristics of climatic potential productivity of maize in northeast China decreased from southeast to northwest. The climatic potential productivity of maize under RCP4.5 scenario was higher than that under RCP8.5 scenario, while years with the lowest values under RCP8.5 scenario was more than that under RCP4.5 scenario. The climatic potential productivity for stress resistant varieties of maize was higher than the original varieties. Under RCP4.5 scenario, the heat resistant variety had higher productivity. Under RCP8.5 scenario, the drought resistant variety performed better. The variety with both heat and drought resistance characters achieved the highest productivity under both scenarios. Under RCP4.5 scenario, yield increased with postponed sowing, with 30 40 days delay achieving the highest yield. Under RCP8.5 scenario, yield reduction occurred in some areas. Such a result indicated that the appropriate delay in sowing is conducive to improve the maize productivity, with differences among regions. PMID- 29974699 TI - [Spatial variability of nutrients and heavy metals in paddy field soils based on GIS and Geostatistics.] AB - Based on a grid (25 m X 25 m) equidistant sampling, the spatial variability of pH, organic matter, total nitrogen, available phosphorus, CEC and three typical heavy metal elements Cd, As and Pb in soil tillage layer (0-20 cm) were analyzed by using GIS and Geostatistics in the paddy field of 3.56 hm2 in Beishan Town, Changsha County, Hunan Province. The results showed that soil pH value and Pb content showed weak variation, and other indexes showed moderate variation. The order of variation was following available phosphorus > Cd > total nitrogen > organic matter > CEC > As > Pb > pH. Results of the semi-variance test showed that the best fitting model of the semi-variance function of organic matter, available phosphorus and As was exponential, and the best semi-variance function of pH, total nitrogen, CEC, Cd, Pb was spherical. All the indicators had a strong spatial correlation except for CEC, which showed moderate spatial correlation. Kriging interpolation analysis showed that pH, total nitrogen, CEC, Pb were plaque distribution, while organic matter, available phosphorus, Cd and As were block and banded distribution. Vegetation, topography and human activities were the main factors driving the variation of soil nutrients and heavy metals in the study area. The correlation between soil nutrients and heavy metals content was significant, among which pH and organic matter, Cd and Pb reached a very significant correlation level. PMID- 29974700 TI - [Effects of Myospalax baileyi disturbance on plant community at alpine meadow in Three Rivers Headwater Region, China.] AB - Plateau zokor (Myospalax baileyi) is one of the major rodent species at the alpine meadow in Three Rivers Headwater Region. They eat plant roots, excavate many tunnels and deposit soil on the surface, which result in many exposed mounds to cover the aboveground part of plants. Here, taking plateau zokor mound density in a plot as their disturbance degree, we selected seven plots with different plateau zokor mound densities and one control plot which was not disturbed by plateau zokor to explore the effects of M. baileyi disturbance on community composition, species diversity and productivity. The results showed that, with the increases of available mound density, the dominant species were changed from Cyperaceae and Gramineae species to forb species, including Poly-gonum viviparum, Potentilla anserine, and Polygonum sibiricum. The community coverage and height were significantly decreased. Light or intermediate disturbance by plateau zokor improved species diversity, whereas the evenness index showed no significant change. The changes of community productivity did not support the 'intermediate disturbance hypothesis'. With the increases of plateau zokor disturbance, the aboveground biomass, belowground biomass, total biomass of community significantly decreased. Our findings revealed the effects of plateau zokor's activity on plant community at alpine meadow and presented important information for the management and restoration of degraded grassland and the sustainable utilization of grassland in Three Rivers Headwater Region. PMID- 29974701 TI - [Soil physical properties and its effects on wheat yield in typical dark loessial soil on Weibei Plateau, China.] AB - Based on the investigations of fertilizer application rates, wheat yield and soil properties (soil compaction) of dark loessial soil on Weibei Plateau in 2015, soil samples from 0-50 cm depth were collected in 61 winter wheat fields. The variability of soil compaction, bulk density, water-stable aggregates and their partial correlations with wheat yield and partial factor productivity were analyzed. The results showed that soil compaction and water-stable aggregates in 0-50 cm depth had weak variability, with the variation coefficients of 9.9% and 4.9%, respectively. Soil bulk density had moderate variability, with the variation coefficient of 27.5%. Wheat yield and fertilizer partial factor productivity were negatively correlated with soil compaction, which were more closely correlated in soil depths of 0-10 cm, 10-20 cm and 20-35 cm. Results from multiple regression showed that wheat yield was determined by soil compaction and organic matter. The improvement of soil organic matter and reduction of soil compaction in top soil (0-20 cm) and plough pan layer (20-35 cm) would be the key strategies to enhance wheat yield in dark loessial soil on Weibei Plateau. PMID- 29974702 TI - [The interactive effects of water and nitrogen addition on ammonia volatilization loss and yield of winter wheat.] AB - An experiment with winter wheat of Shimai 15 and treatments of two types of fertilizers (organic manure, M; urea, U), two amounts of nitrogen application (180 kg.hm-2, M1U1; 90 kg.hm-2, M2U2), two irrigation levels (500 mm, W1; 250 mm, W2) was carried out in the lysimeters in 2015-2017. The results showed that ammonia volatilization was substantial after fertilization and irrigation. The dynami of ammonia volatilization during two years was similar. The process of ammonia volatilization after fertilization lasted for seven days. In 2015-2016, the total amount of ammonia volatilization ranged from 13.36 to 46.04 kg.hm-2, and the loss rate of ammonia nitrogen ranged from 8.9% to 41.1%. The total amount of ammonia volatilization in 2016-2017 ranged from 14.78 to 52.99 kg.hm-2, and the ammonia nitrogen loss rate ranged from 9.2% to 45.8%. During the two years, the highest loss of ammonia volatiles occurred in W2U1, the highest loss rate of ammonia volatilization occurred in W2U2. Ammonia volatilization loss rate significantly decreased under appropriate water and nitrogen management. Ammonia loss under the application of urea was about 2-3 times of organic manure. The highest yield occurred in W1M1 during the two growing seasons. The type of fertilizer, the amount of irrigation and nitrogen applied interactively affected the yield of winter wheat. As for the increases of production, organic manure was better than urea. Under the experimental condition, the best treatment was irrigation amount of 500 mm and application of organic manure with about 180 kg.hm-2 of N fertilizers, which could be applied in practice for wheat production in Huang-Huai-Hai region. PMID- 29974703 TI - [Effects of returning straw with nitrogen application on soil water and nutrient status, and yield of maize]. AB - The study focused on the problems of lean soil and low fertility in arid area of central Ningxia. To explore the optimum rate of nitrogen (N) fertilizer application under straw returning, taking the treatment with straw return and no nitrogen fertilization as control, we investigated the effects of three N application levels (150, 300, 450 kg.hm-2) with return of total maize straw (9000 kg.hm-2) on soil water and nutrient status and maize yield. The results showed that the soil water storage (0-100 cm) at 300 and 450 kg N.hm-2 in middle and late growing period of maize was significantly increased by 10.1% and 9.0%. The enhancement of soil fertility was highest at 300 kg N.hm-2, with significant increases of the contents of soil organic matter, total N, alkali-hydrolyzable-N, available P, and available K by 12.8%, 31.6%, 11.6%, 20.6% and 74.2%, respectively. The enhancement of maize grain yield was highest at 300 and 450 kg N.hm-2, with the value being 32.1% and 23.7%, respectively. The net income at 300 and 450 kg.hm-2 N was significantly increased by 31.8% and 16.8%, respectively. Our results showed that straw returning plus proper quantity of N fertilizer could improve soil water and fertilizer status and enhance maize yield and net income in arid area of central Ningxia. The treatment of straw returning with 300 kg.hm-2 N was the best one. PMID- 29974704 TI - [Effects of plastic film mulching patterns on maize grain yield, water use efficiency, and soil water balance in the farming system with one film used two years.] AB - The aim of this study was to develop cost-saving and efficiency-improving technologies in whole plastic mulching and double ridge-furrow maize in semi-arid region of Loess Plateau. The objective was to investigate soil water balance in farming system with one film used two years. A field experiment was conducted to investigate the effects of different mulching and tillage patterns under one film used two years conditions on the yield, economic benefits, and water use efficiency of maize. There are four treatments: Ridge-furrow planting with complete plastic film mulching, F1M; flat-planting with complete plastic film mulching, F2M; flat-planting with half plastic film mulching, F3M; and flat planting without mulching, F4M, the control. The results showed that the F1M and F2M treatments had significant effects on the improvement of the production and efficiency compared with the control. The F1M and F2M treatments improved biomass by 32.8% and 32.9%, enhanced grain yield by 60.0% and 51.7%. Water use efficiency and rainfall use efficiency in F1M and F2M treatments were increased by 59.8%, 35.9% and 87.6%, 64.4%, respectively. Furthermore, gross output value and input output ratio of F1M and F2M treatments under every new plastic film mulched pattern were enhanced by 51.0%, 41.2% and 15.1%, 16.2%, respectively. The production pattern on cost-saving and efficiency-increasing of the system on double ridge-furrow and flat planting with one film used two years, this pattern increased gross output value by 40.8%, 42.2%, and increased input-output ratio by 40.3%, 42.2%, respectively. Under the condition of low precipitation (606.5 mm), total water consumption of ridge-furrow and flat planting under the system of one film used within two years was 731.3 mm and 746.8 mm, the soil moisture deficit was 124.8 mm and 140.3 mm, with enhancement of 22.7% and 38.0%, respectively. The total water consumption of ridge-furrow and flat planting treatments was reduced by 28.6% and 30.0%, and the fallow efficiency was improved by 178.9% and 148.3%. In conclusion, whole plastic mulching with double ridge-furrow and flat planting farming system had positive effects on yield and water use efficiency in semi arid region of Loess Plateau. Combined with the technology of one film used within two years, this cropping system could be cost saving and efficiency increasing. However, the water deficit under low water condition should be seriously considered in practice. PMID- 29974705 TI - [Effects of drought stress at different growth stages on photosynthetic efficiency and water consumption characteristics in sweet potato.] AB - To investigate the effects of drought stress on the growth of sweet potato, photosynthesis, yield, and water consumption characteristics were investigated in field-grown sweet potato plants (Jishu 21, a drought-tolerant cultivar) at different growth stages in 2014-2015. There were five drought treatments, including the whole growth period (DS), the early stage of growth (rooting and branching period, DS1), the middle stage of growth (storage root initiation period, DS2), and the late stage of growth (storage root bulking period, DS3), and a normal irrigation treatment (WW) as control. The results showed that sweet potato plants in DS significantly decreased in dry mass, biomass, and harvest index during two years. The biomass of sweet potato under DS, DS1, DS2 and DS3 was decreased by 31.3%, 21.2%, 19.6% and 7.7%; the harvest index was decreased by 19.9%, 14.5%, 14.1% and 6.5%, and the dry mass was decreased by 45.3%, 33.1%, 31.3% and 14.2%, respectively. The leaf area index in DS, DS1, DS2 and DS3 was decreased by 77.1%, 60.1%, 39.2% and 17.1% at 100 days after transplanting (DAT), and the net photosynthesis was decreased by 56.7%, 26.6%, 18.7% and 9.5% at 90 DAT, respectively. Plants under drought stress reduced diurnal evaporation, transpiration rate, water consumption, daily water consumption, and soil water use efficiency, but increased irrigation water use efficiency. Drought stress decreased leaf area index, Pn, biomass and the allocation of biomass to storage root, resulting in a significant reduction of yield. The early drought and the long stress duration had significant impacts on leaf area index, Pn, biomass and harvest index, leading to a greater reduction in yield and water use efficiency. Therefore, drought stress at the early growth stages of sweet potato should be avoided during cultivation. PMID- 29974706 TI - [Effects of consecutive application of composted sewage sludge on active organic nitrogen fractions in the sandy fluvo-aquic soil.] AB - A field experiment was conducted with sandy fluvo-aquic soil under wheat-maize rotation system during 2012 to 2016 in Henan Province, with four treatments: Chemical fertilizer (CK), composted sewage sludge (CS) 15 t.hm-2(CS1), 30 t.hm 2(CS2), 45 t.hm-2(CS3). We investigated the effects of CS on soil active organic nitrogen and its allocation ratio. Results showed that CS significantly enhanced soil water content, decreased soil pH, increased contents of soil organic carbon and total nitrogen (TN) and available nutrients. Soil TN was increased by 93.1% 284.3%. The CS3 treatment significantly improved the content of light fraction organic nitrogen (LFON), particulate organic nitrogen (PON) and microbial biomass nitrogen (MBN). CS treatments promoted the allocation of PON/TN and MBN/TN. with an enhancement of 12.3% and 539.9% in the CS2 treatment, respectively. The distributions of LFON/TN and DON/TN were decreased by 17.3%-40.1% and 38.5% 71.3%, respectively. The contribution of soil active organic nitrogen fractions to TN was: PON>LFON>DON>MBN. Results from the principal component analysis showed that organic nitrogen and their distribution had high load value in CS2 and CS3 treatments. Results from redundancy analysis showed that positive correlations existed between the soil physicochemistry, enzymatic activity and soil active organic nitrogen as well as their distribution. In summary, CS had positive impacts on soil organic matter, soil properties, and the formation of active organic nitrogen. The rates of 30 and 45 t.hm-2 CS application had significant effects on soil fertility, which could be an effective way to improve sandy fluvo aquic soil quality. PMID- 29974707 TI - [Food utilization and excretion mechanism of Cd in gypsy moth larvae fed on Cd enriched Populus albaXP. berolinensis leaves]. AB - To investigate the eco-physiological responses of phytophagous insects to host plants exposed to heavy metal stress, the gypsy moth (Lymantria dispar) larvae were reared with leaves of Populus albaXP. berolinensis grown in Cd-contaminated soil to analyze their food utilization and mechanisms underlying Cd excretion. Our results showed that after feeding on Cd-stressed poplar leaves, Cd concentrations and contents in the 3rd-6th instar larvae were significantly higher than those in control. The Cd concentrations significantly decreased with the larval age, whereas it was reverse for Cd contents. Cd concentrations in the larval faces and exuvia were significantly higher than those in control. Food digestion/consumption rate and conversion rate of the 3rd-5th instar larvae in the Cd-treatment group were significantly higher and lower than those in the control, respectively. Food utilization rate of the Cd-stressed 3rd-4th instar larvae were not significantly different from that of the control larvae with the same age. In contrast, the Cd-stressed 5th instar larvae showed a significantly lower food utilization rate than the control. These results indicated that gypsy moth larvae could remove some Cd from their bodies through effective excretion (e.g. feces and exuvia), with the mature larvae being more effective than the juveniles. The increases of larval body mass seemed to have a "dilution effect" on its Cd concentration. Under Cd stress, the gypsy moth larvae might maintain a certain level of food utilization rate for growth and development via a modulation of food consumption/conversion rates, but Cd-stress would still reduce the larval food utilization rate when it was beyond a certain threshold. PMID- 29974708 TI - [Spatiotemporal dynamics and driving forces of soil bacterial communities on the dam of Shibahe copper mine tailings in Shanxi, China.] AB - The maintaining mechanism of community diversity is the core of community ecology. The mine tailing is a good field for studying on the underlying mechanism of community diversity, as a kind of original bare land with heavy metal pollution, where the physicochemical characteristics of soil change with the restoration periods. We examined the driving forces for bacterial community diversity based on the investigation of edaphic factors, plant community, and bacterial communities in Shibahe copper mine tailing, Shanxi. The results showed that nutrient contents in soil increased with restoration periods. The seasonal dynamics of soil nutrient in different restoration time were different. Shannon diversity and richness of bacterial community showed an increasing trend, indicating community stability was improved with restoration. Influenced by plant community, the seasonal changes of those indices differed with restoration. Results from the RDA analysis showed that the diversity and structure of bacterial communities were determined by environmental factors (edaphic, plant and heavy metals). Results from the structure equation models further confirmed that soil nutrients (TC, TN, NO3--N, NO2-N), plant community, and soil enzyme activities jointly drove bacterial community assembly on the copper mine tailings. PMID- 29974709 TI - [Analysis of chlorophyll and photosynthesis of a tomato chlorophyll-deficient mutant induced by EMS.] AB - We analyzed the growth, leaf chlorophyll content, and photosynthetic parameters of a tomato leaf yellowing mutant (Y55) induced by ethyl methane sulfonate (EMS) from the cultivar "Heinz 1706" (WT). Results showed that the plant height, stem diameter, and fresh mass of Y55 significantly . The contents of chlorophyll a, chlorophyll b, carotenoid, total chlorophyll and the chlorophyll a/b ratio of the mutant were significantly lower than those of WT. The contents of all precursor materials of chlorophyll synthesis, especially porphyrinogen III and those involved in the chlorophyll biosynthesis pathway, were significantly lower in Y55 than those in WT. Moreover, the net photosynthesis (Pn), transpiration rate (Tr), intercellular CO2 concentration (Ci), and conductance to H2O (gs) significantly in Y55. The maximum photosynthetic rate, CO2 saturation and compensation point, and light saturation and compensation point. The Fv/Fm significantly, whereas the Fo significantly in Y55. The photosynthetic electron production and electron transport rates of PSII and PSI also significantly decreased. The total photosynthetic pigment molecules (No) and the minimum average lifetime of photosynthetic pigment molecules in the excited state (taumin) significantly in Y55. All these results suggest that blocking the synthesis of porphyrinogen III ould decrease the chlorophyll content in the mutant Y55. Furthermore, the reduced amount of leaf pigment could affect photosynthesis in leaves and slow down the growth of mutant plants. PMID- 29974710 TI - [Construction of ecological security pattern in the agro-pastoral ecotone based on surface humid index: A case study of Hangjin Banner, Inner Mongolia Autonomous Region, China.] AB - The construction of regional ecological security pattern can effectively protect regional ecological security and achieve regional sustainable development, which has become one of the key topics in landscape ecology. The construction of regional ecological security pattern is particularly important for the Inner Mongolia Plateau, which is characterized by relatively fragile ecological environment and single land cover type. Considering regional natural environment characteristics, five typical ecosystem services, such as food supply, carbon fixation and oxygen release, soil conservation, water yield and habitat conservation, were selected to assess the importance of natural habitats with Hangjin Banner of Inner Mongolia Autonomous Region as a case study area. Based on comprehensive consideration of single ecosystem service quality and landscape multi-functionality, ecological sources were identified. The basic ecological resistance surface based on the land cover was revised by the surface humid index. The minimum cumulative resistance model was used to identify the ecological corridors, to construct the ecological security pattern of Hangjin Banner. The results showed that the ecological source of Hangjin Banner was 6781.70 km2, accounting for 35.9% of the whole area, which mainly located in the northern Hetao Plain and southern Ordos steppe zone. The total ecological corridor length of Hangjin Banner was 498.51 km, which was divided into two groups from north to south by Kubuqi Desert. Based on the arid and ecologically fragile characteristics in the agro-pastoral ecotone in northern China, this study constructed regional ecological security pattern to provide decision-making guidelines for local economic development and ecological conservation. PMID- 29974711 TI - [Effects of storage temperature and time on the contents of different nitrogen forms in fresh soil samples.] AB - Soil nitrogen forms and contents are of great importance in ecological studies. The storage methods of soil samples have great effects on the accuracy of determination of nitrogen contents. We aimed to select a reasonable storage method for soil samples with forest soil of Castanopsis faberi fore-st at Wanmulin Nature Reserve in Jian'ou City as an example. The contents of soil ammonium, nitrate, total nitrogen, soluble organic nitrogen, amino acid nitrogen and microbial biomass nitrogen were measured in soil samples under the storage conditions of different temperature (at 25, 4 and -20 C) and different times (0, 7 and 30 days). The nitrogen contents during the process of cultivating under the room temperature after being frozen were also measured. The results showed that the contents of all nitrogen forms except for amino acid nitrogen were increased in the soil samples that stored at the room temperature for seven days. There were no significant differences between the contents of all the tested nitrogen forms in the refrigerated or frozen samples and the fresh soil samples. The changes of nitrogen content in soil samples at refrigerated and frozen storage were more stable than those at room temperature storage. The low temperature storage could stimulate soil mineralization. Hence, after stored for 30 days, contents of all the tested nitrogen forms in the refri-gerated and frozen storage soil samples were significantly higher than those in the fresh samples except for the soluble organic nitrogen, whereas there was no significant difference between the refrigerated and frozen storage methods. Therefore, fresh samples should be promptly processed when taken back to the laboratory. If the samples needed to storage, it should not be stored more than half a month. If the samples need a longer storage time, it must be placed in lower temperature (at -40 or -80 C). Pre-incubation treatment was required when the low temperature storage soil sample was subjected to an experiment. In the process of pre-incubation, the contents of all the tested nitrogen form in soil samples gradually approached the level of fresh soil sample with the increases of incubation time except for that of nitrate which decreased firstly and then increased rapidly. After incubation for about one week, the nitrogen content of soil sample returned to the level that was close to that of the fresh soil. In combination with studies previously reported, soil samples collected from field and air dried samples needed a pre incubation for 5-14 days, and the pre-incubation time for the cold storage sample should not be less than one week. PMID- 29974712 TI - [Difference analysis in estimating biomass conversion and expansion factors of masson pine in Fujian Province, China based on national forest inventory data: A comparison of three decision tree models of ensemble learning.] AB - Biomass conversion and expansion factors (BCEFs) are important parameters for estimating carbon storage in forest biomass. Clarifying the source of differences in estimating BCEFs could reduce uncertainties in forest biomass carbon estimation. The decision tree models of ensemble learning can be used to properly figure out the source of differences in estimating BCEFs. However, the comparison of different decision tree models for analyzing differences in estimating BCEFs has never been reported. In this study, three models [the boosted regression trees (BRT), random forest(RF), and Cubist] and data of 331 masson pine plots from the 8th Chinese National Forest Inventory for Fujian Province were used to analyze the differences in estimating BCEFs (including above- and below-ground). The results showed that BCEFs were following right-skewed distribution, with the mean, minimum and maximum value being 0.69 t.m-3, 0.67 t.m-3 and 0.71 t.m-3, respectively. All three models performed well in BCEFs prediction and fitting, and could explain more than 92.8% variations of BCEFs. All three models showed that average DBH and volume were the top two highest relative importance predictors. BCEFs decreased with the increases of average DBH and volume. Stand characteristics factors, such as average DBH, volume, average age and average height, had great influence on BCEFs. Both soil factors and topographic factors had little influence on BCEFs. Using a few variables (such as average DBH, volume, average age and avera-ge height) which contained more BCEFs prediction information could have preferable forecasting precision when building BCEFs models. Moreover, widely representative samples with different average tree ages, average DBH and volume should be chosen to calculate BCEFs when applying constant BCEFs. PMID- 29974713 TI - [Parameter estimation and verification of DSSAT-CROPGRO-Tomato model under different irrigation levels in greenhouse.] AB - Based on the greenhouse experiment in Shenyang, the growth, development, and yield formation of tomato under different irrigation levels were simulated by growth model DSSAT-CROPGRO-Tomato. The optimal scheme of parameter estimation and model validation was determined. There were four treatments in this experiment. Irrigation upper limit of whole growth season was set as field capacity, while the lower limit was 50% (W1), 60% (W2), 70% (W3), and 80% of field capacity (CK), respectively. The relevant genetic coefficients were estimated by DSSAT-GLUE, a program package for parameter estimation in DSSAT. The differences between simulated and observed values of phenological phase, canopy height, shoot dry matter, tomato fresh mass, leaf area index (LAI), and soil moisture were analyzed to determine the accuracy of simulation. The results showed that the estimated value of genetic parameter of tomato (thermal time for final pod load appeared greater variability under optimal genetic coefficient of tomato, PODUR) had large variability, with the coefficient of variation being 11.5%. When the CROPGRO Tomato model was applied to the greenhouse in different regions, the PODUR should be estimated adequately. Otherwise, the accuracy of simulation would be affected. In the process of model application, the observation data of sufficient irrigation treatment should be selected for estimating genetic parameters, which could improve the simulation precision. The absolute relative error and standard root mean square error were 8.7% and 10.5%, respectively. The simulation results of LAI and soil moisture showed that the higher the irrigation level was, the higher accuracy of simulation was. By leave-one-out cross validation, the overall error validation ranged from 10.5% to 12.5%. Our results indicated that the growth, development, and yield formation of tomato could be accurately simulated by DSSAT CROPGRO-Tomato model under different irrigation conditions in Shenyang greenhouse. PMID- 29974714 TI - [The effects of climate change on isoprene emission rate from leaves of Pleioblastus amarus in different regions.] AB - Based on the RCP2.6, RCP4.5, RCP6.0 and RCP8.5 climate change scenarios produced by the global climate model NorESM1-M and plant isoprene emissions model, the effects of climate change on the isoprene emission rate from leaves of Pleioblastus amarus in Yixing City of Jiangsu Province, Longmen County of Guangdong Province, Yulong Naxi Autonomous County of Yunnan Province and Wanyuan City of Sichuan Province were simulated. The differences of isoprene emission rate from leaves of P. amarus distributed in four regions were compared under future climate change scenarios. The results showed that mean annual air temperature would increase, annual precipitation and radiation intensity would greatly fluctuate, with the coexistence of increasing and decreasing trends in the four regions. In the baseline scenario, daily mean emission rate of isoprene from leaves of P. amarus was 71-470 MUg.g-1.d-1, and annual mean value was 25954 171231 MUg.g-1.a-1. The daily and annual emission rates in the four regions decreased with the order of Longmen, Yixing, Wanyuan and Yulong. Compared with the baseline scenario, daily mean emission rate of isoprene from leaves of P. amarus was about 4-45 MUg.g-1.d-1 higher in future climate change scenario, and which was about 23, 29, 4, and 14 MUg.g-1.d-1 higher than that in baseline in Yixing, Longmen, Yulong and Wanyuan, respectively. In addition, the emission rate of isoprene from leaves of P. amarus was more than 5% higher in the future climate change scenario than that in the baseline scenario, which was higher in Wanyuan and Yixing (>13%) than and lower in Longmen and Yulong (>5%). All the four regions reached the highest rate under RCP8.5 scenario (increased by about 11%-18%). Compared with the baseline scenario, annual emission rate of isoprene in the future climate change scenario was about 1500-17000 MUg.g-1.a-1, and which was about 8560-13208 MUg.g-1.a-1 higher in Yixing, 10862-16131 MUg.g-1.a-1 higher in Longmen, 1574-3028 MUg.g-1.a-1 higher in Yulong, 5288-8532 MUg.g-1.a-1 higher in Wanyuan. In addition, the increasing rate of annual isoprene emission rates was 6%-14%. The rates in Yixing (8%-12%) and Wanyuan (8%-14%) were higher than that in the other two regions, the rate in Yulong (6%-12% increase) was the lowest, with all four regions increasing substantially (9%-14%) under RCP8.5 scenario. The results suggested that climate change would have different effects on the rate of isoprene emissions from leaves of P. amarus distributed in diffe rent regions. PMID- 29974715 TI - [Distribution characteristics of dissolved inorganic carbon in soil of typical estuarine wetlands in Jiaozhou Bay, China.] AB - We examined the dissolved inorganic carbon (DIC) content, ion content, and soil physi-cal and chemical properties in Dagu River and Yanghe River estuary wetland of Jiaozhou Bay. Soil samples were collected by stratified sampling in the mudflat paralleled to the coastal zone and the river flat perpendicular to the coastal zone. Duncan method and Pearson correlation analysis were used to investigate the characteristics of soil DIC distribution and its driving factors. The results showed that the scouring action of water bodies led to the lowest content of soil DIC in the river estuary of mudflat, which showed an increasing trend with the increases of distance from the estuary. In river flat, the soil DIC content first decreased and then increased with the distance from the sea, which was influenced by human activities. Invasion of Spartina alterniflora significantly decreased soil DIC content, with its root transformation being the main reason for such decreases. The farming activities changed the environmental factors of aquaculture pond, and then changed the distribution of soil DIC. The surface soil of the pond had higher DIC content than that of the mudflat, while the other soil layers had lower DIC content than that of the mudflat. Soil DIC content was significantly positively correlated with soil salt content and total inorganic carbon content, and negatively correlated with soil pH. PMID- 29974716 TI - [Suitability of various benthic biotic indices in assessing the coastal ecological quality in Fujian Province, China]. AB - Three benthic biotic indices, AZTI marine biotic index (AMBI), benthic opportunistic polychaetes amphipods (BOPA), and benthic polychaetes amphipods (BPA), combined with Shannon diversity index (H) were applied in ecological quality status (EQS) assessment, to investigate their suitability at four bays and an estuary in Fujian Province. The results showed that there were substantial differences in the performance of these indices. There were only four sites with the same assessment grades using different indices, accounting for 8.7% of the applied sites. AMBI classified 76.1% of the sites as "Good", while 89.1% of the sites were classified as "High" using BOPA. The assessment results of BPA and H showed obvious gradient changes. For the bay areas, all the BOPA, BPA and AMBI values had no significant correlation with dissolved inorganic phosphate (DIP) and dissolved inorganic nitrogen (DIN) concentrations, suggesting that these indices did not respond to eutrophication pressure. The H value was significantly and negatively correlated with DIN concentration. For the estuarine area, the three indices, i.e . BOPA, BPA and AMBI, had significantly positive correlations with DIN and DIP, and there was no clear spatial variation in the assessment grades of these indices with the distance toward sea. The results suggested that BOPA, BPA and AMBI would overestimate the EQS and would show no response to the eutrophication pressure in estuarine area. Similar to the result from the bay areas,H value in the estuary area was significantly and negatively correlated to DIN. Meanwhile, the assessment grades of the seven sections in the estuary tended to increase with the distance toward the sea. In summary, our results suggested that BOPA, BPA and AMBI would not be suitable for the EQS assessment for Fujian coastal area, while H would be more suitable as it could respond to the main anthropogenic pressures. PMID- 29974717 TI - [Effects of light intensity and photoperiod on the embryonic development of Sepia pharaonis.] AB - We investigated the effects of lumination on hatching of fertilized eggs of Sepia pharaonis, to reveal the best light conditions for its embryonic development. A single-factor experiment was carried out to examine the effects of different light intensities (10, 30, 50, 70, 90 MUmol.m-2.s-1) and different photoperiod L:D (24 h:0 h, 18 h:6 h, 12 h:12 h, 6 h:18 h, 0 h:24 h) on the embryonic development. The results showed that the effects of light intensity on the hatching rate, fractured yolk sac rate, incubation period, mass of newly hatched larvae and mantle length was significant. There was no significant effect on hatching period and survival rate after hatching 7 days. With the increases of light intensity, the hatching rate, incubation period, mass of newly hatched larvae and mantle length first increased and then decreased, while the fractured yolk sac rate gradually increased. The optimum light intensity was 30 MUmol.m-2.s 1. Exposed to this light intensity, the hatching rate, fractured yolk sac rate, incubation period, hatching period, mass of newly hatched larvae, mantle length and survival rate after hatching 7 days were (90.0+/-4.1)%, (7.3+/-1.5)%, (25.50+/-0.35) d, (8.10+/-0.89) d, (0.213+/-0.011) g, (1.013+/-0.022) cm, (97.1+/ 4.0)%, respectively. The effects of photoperiod on the hatching rate, incubation period, hatching period were significant, but there was no significant effect on fractured yolk sac rate, mass of newly hatched larvae, mantle length and survival rate after hatching 7 days. With the increases of illumination time, the hatching rate and hatching period first increased and then decreased. The optimum photoperiod was L:D (12 h:12 h). When exposed to this photoperiod environment, the hatching rate, fractured yolk sac rate, incubation period, hatching period, mass of newly hatched larvae, mantle length and survival rate after hatching 7 days were (88.7+/-1.8)%, (8.7+/-1.8)%, (25.00+/-0.50) d, (7.00+/-3.20) d, (0.209+/-0.005) g, (0.998+/-0.026) cm, (96.8+/-7.1)%, respectively. In conclusion, embryo hatchability of S. pharaonis preferred to low light intensity (30 MUmol.m-2.s-1) and normal photoperiod L:D (12 h:12 h). In production practice, sunproof measures should be taken to keep the eggs in weak light condition. PMID- 29974718 TI - [Plant anti-herbivore defense priming: Concept, mechanisms and application.] AB - Plant anti-herbivore defense priming refers to the increased readiness of anti herbivore defense after the initial exposure to a series of biotic or abiotic factors. The primed plants can respond to herbivory more quickly and strongly and thereby show enhanced resistance to insect herbivory. It is a newly recognized strategy of plant defense against insect herbivores. Insect feeding, secretion, oviposition, herbivore-inducible plant volatiles (HIPVs), beneficial microorgani sms, certain plant nutrient elements, heavy metals and some chemical compounds have been found to be able to prime plant defense. The defense priming is highly efficient, durable, environmental friendly, and even trans-generational. This review summarized current research progress on the plant anti-herbivore defense priming in recent years, and analyzed general characteristics, priming agents and potential mechanisms involved, and proposed the future development and the perspective of practical application in the field. Moreover, the unresolved questions and the research directions in this field were also discussed. Appropriate management of plant defense priming would minimize use of insecticide and serve as an important approach of integrated pest management. PMID- 29974719 TI - The Cochrane Rehabilitation eBook: a knowledge translation tool to transfer evidence to different rehabilitation audiences. PMID- 29974720 TI - Resistance of uropathogens to antibacterial agents: Emerging threats, trends and treatments. AB - Urinary tract infections are among the most common infectious diseases in humans. Today, resistance to nearly all antimicrobial classes is dramatically growing, and extremely drug-resistant or even pan-drug resistant pathogens are increasingly isolated around the world. It is foreseen that in the next decades the world will be facing a major medical emergency generated by the rapid spread of pathogens carrying resistance determinants of unprecedented power. Carbapenemase-producing Enterobacteriaceae, multidrug- resistant Enterococci and fluoroquinolone resistance determinants in both Gram-negative and Gram-positive uropathogens are among the greatest emergencies. In this article, the major emerging threats of particular interest to urologists are reviewed, worldwide resistance trends are illustrated, and novel and older - but still active - recommended drugs are summarized. PMID- 29974721 TI - The sufficiency of 6 core sextant prostate biopsy in patients with prostate specific antigen (PSA) values over 20 ng/mL. AB - OBJECTIVE: In this study, we aimed to investigate sufficiency of 6 core prostate biopsy in patients with PSA levels elevated above 20 ng/mL. MATERIALS AND METHODS: The medical record of the patients who received prostate biopsy at our institution between August 2011 to August 2016 who had serum total PSA values above 20 ng/mL, were reviewed retrospectively. In this study, we included 40 patients who received 6 core prostate biopsy and 40 patients who received 12 core prostate biopsy. A total number of 80 patients were enrolled in this study. Patients were divided into two groups, a 6 core biopsy group and a 12 core biopsy group. These groups are compared according to age, total PSA, prostate volume and final pathological diagnosis. RESULTS: Based on final pathological diagnosis, 2 patients (5%) had benign pathology and 38 patients (95%) had PCa in both group 1 and 2. The cancer detection rate in both groups was 95%. Although there were higher values of mean age, mean total PSA, and mean prostate volume in group 1, there was no statistically significantly difference at this variables in both groups. CONCLUSION: Although taking 6 core biopsies is not recently recommended, we proved that 6 core biopsy is adequate for patients with PSA values above 20 ng/mL. PMID- 29974722 TI - Utility of uroflowmetry during the follow-up of children affected by balanitis xerotica obliterans (BXO). AB - INTRODUCTION: To evaluate the outcome of circumcised patients with balanitis xerotica obliterans (BXO) using uroflowmetry (UF). METHODS: Between 2011 and 2013, 180 children underwent a circumcision for phimosis. The foreskin was examined on microscopy. Patients with an histological diagnosis of BXO were included in the study. Patients with BXO underwent UF two weeks after surgery and treatment with clobetasol propionate ointment. Patients were re-evaluated at 6, 12, 18 and 24 months postoperatively clinically and using UF. RESULTS: 75 of 180 circumcised patients (41.6%) were included. At two weeks, Thirtytwo of 75 patients (42.7%) displayed a pathological UF. At six months, 15 patients (20%) had pathological UF and a new cycle of clobetasol was prescribed. At one year, 10 patients (13.3%) displayed patholgocial UF and underwent progressive urethral dilatation or meatoplasty. At 18 months, 71 patients (94.7%) displayed regular UF, 3 underwent a meatoplasty and one a staged urethroplasty for a severe urethral stenosis. At two years, UF was normal in 74 out of 75 (98.7%). CONCLUSIONS: We recommend to send for hystological examination all foreskins excised after circumcision. We believe that a clinical and uroflowmetric follow up of pediatric patients with BXO is mandatory for a prompt identification of post-voiding dysfunction. PMID- 29974723 TI - Clinical comparison between conventional and microdissection testicular sperm extraction for non-obstructive azoospermia: Understanding which treatment works for which patient. AB - OBJECTIVES: The superiority of microdissection testicular sperm extraction (mTESE) over conventional TESE (cTESE) for men with non-obstructive azoospermia (NOA) is debated. We aimed to compare the sperm retrieval rate (SRR) of mTESE to cTESE and to identify candidates who would most benefit from mTESE in a cohort of Caucasian-European men with primary couple's infertility. MATERIAL AND METHODS: Data from 49 mTESE and 96 cTESE patients were analysed. We collected demographic and clinical data, serum levels of LH, FSH and total testosterone. Patients with abnormal karyotyping were excluded from analysis. Age was categorized according to the median value of 35 years. FSH values were dichotomized according to multiples of the normal range (N) (N and 1.5 N: 1-18 mIU/mL, and > 18 mIU/mL). Testicular histology was recorded for each patient. Descriptive statistics and logistic regression analyses tested the impact of potential predictors on positive SRR in both groups. RESULTS: No differences were found between groups in terms of clinical and hormonal parameters with the exception of FSH values that were higher in mTESE patients (p = 0.004). SRR were comparable between mTESE and cTESE (49.0% vs. 41.7%, p = 0.40). SRRs were significantly higher after mTESE in patients with Sertoli cell-only syndrome (SCOS) (p = 0.038), in those older than 35 years (p = 0.03) and with FSH >1.5N (p < 0.001), as compared to men submitted to cTESE. Multivariable logistic regression analysis showed that mTESE was independent predictor of positive SR in patients older than 35 years (p = 0.002) and with FSH > 1.5N (p = 0.018). Moreover, increased FSH levels (p = 0.03) and both SCOS (p = 0.01) and MA histology (p = 0.04) were independent predictors of SRR failure. CONCLUSIONS: Microdissection and cTESE showed comparable success rates in our cohort of patients with NOA. mTESE seems beneficial for patients older than 35 years, with high FSH values, or when SCOS can be predicted. Given the high costs associated with the mTESE approach, the identification of candidates most likely to benefit from this procedure is a major clinical need. PMID- 29974724 TI - Predictive factors of successful salvage microdissection testicular sperm extraction (mTESE) after failed mTESE in patients with non-obstructive azoospermia: Long-term experience at a single institute. AB - OBJECTIVE: To observe the clinical practice of salvage microdissection testicular sperm extraction (mTESE) in patients with non-obstructive azoospermia (NOA) and to determine the factors that may predict the presence of spermatozoa in preoperative salvage mTESE. METHODS: We retrospectively reviewed the medical records of 445 patients with the diagnosis of NOA, who had undergone the mTESE operation consecutively in our institution between the dates of March 2008 and June 2017. The study included a total of 49 patients with failure to detect spermatozoa in the first mTESE and who had then undergone salvage mTESE. In order to investigate the factors that predict the result of salvage mTESE, the patients were classified into two groups according to the outcome of salvage mTESE, as those with and without spermatozoa retrieval. Patients in these two groups were compared with regard to age, body mass index, history of varicocele, history of cryptorchidism, duration of infertility, outcomes of genetic analysis, results of hormone profiles and the testicular histopathology results of the first mTESE. RESULTS: The sperm retrieval rate following salvage mTESE was observed to be 42.8%. Statistically a significant difference was determined between the mean follicle stimulating hormone (FSH) values of the groups (p = 0.013). No significant difference was observed between the groups with regard to the remaining parameters. CONCLUSION: It was observed that among the factors that predict the success of sperm retrieval in salvage mTESE in patients with NOA and previous unsuccessful sperm retrieval in mTESE operation, only the pre-operative FSH level was observed to significantly correlate with the success in salvage mTESE. PMID- 29974725 TI - L-Methionine associated with Hibiscus sabdariffa and Boswellia serrata extracts are not inferior to antibiotic treatment for symptoms relief in patients affected by recurrent uncomplicated urinary tract infections: Focus on antibiotic-sparing approach. AB - OBJECTIVE: To evaluate the efficacy of a phytotherapic combination of L Methionine associated with Hibiscus sabdariffa and Boswellia serrata for treatment of acute episodes of uncomplicated urinary tract infections (UTI) in women affected by recurrent UTIs. MATERIALS AND METHODS: In this randomized phase III clinical trial, adult females with uncomplicated UTI were enrolled into one of the following treatment groups: Group A: phytotherapic combination 1 tablet in the morning and 1 tablet in the evening for 7 days; Group B: Short term antibiotic treatment according to international guidelines recommendations. At baseline, all patients were evaluated by a urologist and quality of life (QoL) questionnaires and mid-stream urine culture. Same clinical and laboratory investigations were repeated at each follow-up visit. RESULTS: Forty-six patients were enrolled in Group A and 47 in Group B. At the first follow-up (30 days), both groups showed a statistically significant improvement in quality of life scores as compared with baseline assessment [Group A: (QoL 94.3 VS 98.5 p < 0.001); Group B: (QoL 94.5 VS 98.7 p < 0.001)]. An improvement from baseline was also seen at the second followup evaluation after 3 months [Group A: (QoL 94.3 VS 99.1 p < 0.001); Group B: (QoL 94.5 VS 98.1 p < 0.001)]. At the second follow-up visit, a statistically significant difference in QoL was reported between the two groups (99.1 VS 98.1; p < 0.003) and a transition from UTI to asymptomatic bacteriuria (ABU) was observed 12 of 46 (26%) patients in Group A, while no patients in Group B demonstrated ABU (p = 0.007). CONCLUSIONS: Here, we demonstrated that this phytotherapic combination is able, in comparison to antibiotic treatment, to improve patients quality of life, reducing symptoms in acute setting and preventing the recurrences. Interestingly, a significantly higher proportion of patients in the phytotherapy group had ABU after three months. Our findings are of great interest in an antibiotic stewardship perspective. PMID- 29974726 TI - The effect of the American Society of Anesthesiology classification scores on complications associated with percutaneous nephrolithotomy. AB - OBJECTIVES: We aimed to evaluate the effect of American Society of Anesthesiology (ASA) classification scoring and age on complications and surgical outcomes during and after percutaneous nephrolithotomy (PCNL) operation. MATERIAL AND METHODS: The records of 263 patients, above the age of 18 years, that underwent PCNL surgery between October 2014 and May 2017 were evaluated retrospectively. The patients were divided into three groups based on their ASA risk scores (ASA 1, 2, 3) and into two groups based on their age (younger and older than 65 years). Postoperative complications were assessed according to the ASA groups and age and according to the Clavien classification system. RESULTS: The number of patients in the ASA 1, 2, and 3 groups were 97 (36.8%), 131 (49.8%) and 35 (13.3%), respectively. Four patients in ASA4 were not included in the study. There was no significant difference in ASA 1, 2, 3 groups in terms of changes in Hgb values, mean duration of operation, and mean hospital stay. When ASA1 was compared to ASA3 and ASA2 was compared to ASA3, there was no significant difference in the incidence of all complication rates. There were 159 (60.4%) patients in the young group and 104 (39.5%) patients in the elderly group. Postoperative PCNL complications of these 2 groups were compared according to Clavien classification system and no significant difference was found in incidence of complications. CONCLUSIONS: We believe that PCNL operation can be performed effectively and safely in both ASA3 patients and patients above the age of 65 years. PMID- 29974727 TI - Tadalafil versus alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive therapy for < 10 mm distal and proximal ureteral stones. AB - OBJECTIVES: To evaluate the effect of tadalafil compared with four alpha blockers (alfuzosin, doxazosin, tamsulosin and silodosin) as medical expulsive treatment for ureteral stones in male adults. MATERIALS AND METHODS: Male adults who were admitted to urology clinic with flank pain and diagnosed with non complicated < 10 mm ureteral stone on non-contrast computed tomography (NCCT) between June 2014 September 2015 were retrospectively evaluated. A total of 273 patients with ureteral stone were divided into five groups. Alfuzosin 10 mg/daily, doxazosin 8 mg/daily, tamsulosin 0.4 mg/daily, silodosin 8 mg/daily and tadalafil 5 mg/daily for 6 weeks were prescribed respectively. Stone localization, diameter, volume and Hounsfield units were noted as NCCT findings. The patients were divided into the two groups based on their stone localization as distal and mid-proximal stones. These two groups were evaluated separately. Expulsion rate were noted at the end of 6 weeks. NCCT and treatment findings were compared between five drug groups in distal and mid-proximal stones separately. RESULTS: Age was higher in tadalafil group in distal stones (p = 0.032). Expulsion rate was found 78.1% for alfuzosin, 75.7% for doxazosin, 76.5% for tamsulosin, 88.6% for silodosin and 90% for tadalafil in distal (p = 0.44) and 21.7%, 30%, 30%, 30% and 54.5% in mid proximal stones (p = 0.034) respectively. CONCLUSIONS: Expulsion rate was higher in silodosin and tadalafil for distal ureteral stones but the difference didn't meet statistical significance. However the expulsion rate was significantly higher in tadalafil than in the other groups for mid-proximal ureteral stones. The result of this study showed that tadalafil may increases ureteric stone expulsion. PMID- 29974728 TI - Recurrent bacterial symptomatic cystitis: A pilot study on a new natural option for treatment. AB - OBJECTIVES: The aim of our study was to explore the effectiveness of the combination of D-mannose, Salicin, and Lactobacillus acidophilus (La-14) in patients complaining recurrent symptomatic cystitis due to E. coli. MATERIALS AND METHODS: From July 2013 to September 2014, 85 consecutive subjects (68 women and 17 men) affected by recurrent symptomatic cystitis were enrolled. Of those, 46 (33 women and 13 men) suffered from neurogenic bladder. Overall 78 patients received an initial 5-days regimen consisting on a tid oral combination of 1000 mg of D-mannose plus 200 mg of dry willow extract (salicin) (attack phase), followed by bid 7-days with 700 mg of D-mannose plus 50 mg (1x109 CFU) of Lactobacillus acidophilus (La-14) (maintenance treatment). The maintenance treatment was repeated every 15 days for the next two months. Patients' symptoms were evaluated through a 3-days bladder diary and a Visual Analogic Scale (VAS). RESULTS: After treatment VAS scores decreased from 8.07 +/- 1.70 to 4.74 +/- 2.07 (p = 0.001) in non-neurological patients (group A) and from 7.21 +/- 1.90 to 3.74 +/- 3.12 (p = 0.001) in the neurological patients (group B). A significant reduction of daily frequency was noted in both groups: from 14 +/- 3 to 7 +/- 3 (p = 0.001) in group A and from 15 +/- 3 to 8 +/- 3 (p = 0.001) in group B. A reduction of incontinence episodes in Group A patients was observed, as well as in 12/39 Group B. Improvements were maintained during follow-up. CONCLUSION: This therapeutic approach combining D-Mannose with Salicin (acute treatment) and Lactobacillus acidophilus La-14 (maintaining treatment) seems to be effective in symptomatic bacterial UTIs. Further larger and randomized control trials (RCTs) are needed to confirm our results. PMID- 29974729 TI - Effect on prostatic specific antigen by a short time treatment with a Curcuma extract: A real life experience and implications for prostate biopsy. AB - INTRODUCTION AND OBJECTIVES: PSA elevation is associated with prostate cancer and it is used in screening programs for its diagnosis. It is one of the most common indications for referral to an urologist. There's no consensus about what to do in PSA elevation management. Antibiotics, nutraceuticals or anti-inflammatories are commonly prescribed in daily practice. Our objective was to verify the effect on the PSA value of a short 30-day trial of a curcuma extract, than to discuss the implications in terms of reducing the number of prostate biopsies performed. PATIENTS AND METHODS: We enrolled 50 consecutive patients admitted at our attention for a first PSA over the level of 4 ng/ml or for a suspected PSA rising defined as PSA velocity (PSAv) > 0.75 ng/ml/years. They received treatment with curcuma extract, 2 tablets per day for 30 day. All patients received a second PSA measurement and TRUS within 6 days from the end of the therapy. In case of PSA reduction below 4 ng/ml, patients were reassured and invited to repeat a PSA control over the time. When PSA level were persistently high over 4 ng/ml or in case of any rising, patients underwent a transrectal ultrasound guided 12-core prostatic biopsy (TRUSbx). RESULTS: Mean age of the patients was 64.56 +/- 8.88 (range, 42- 81 years). Prostate volume was 48.34 +/- 15,77 ml (range, 18-80 ml). At visit 1, PSA value was in mean 6,84 +/- 3.79 ng/ml (range 2.93-21ng/ml). Consequently, mean PSA density value was 0.16 +/- 0.16 (range 0.05-1.11). PSA free and PSA total ratio at baseline was 16.85 +/- 3.9% (range 8-26%). At visit 2, the prostate volume did not change. Total PSA was 4.65 +/- 2,67 ng/ml (range 1 16.82 ng/ml). PSA free and PSA total ratio (PSAF/T) after treatment was 19.68 +/- 5.35 % (range 7.8-29%). The differences of total PSA and PSAF/T between visit 1 and visit 2 were < 0.0001 and p < 0.0036, respectively. We performed 26 TRUSbx. Prostate cancer was diagnosed in 6 cases, PIN HG in 2 cases and non neoplastic findings in the remnants 18 patients. CONCLUSIONS: Use of the Curcuma extract is able to lower the PSA value after a 30-day intake period. We are not able to state that the reduction of PSA after intake of this Curcuma extract may exclude a prostate cancer. We need further studies to evaluate that. PMID- 29974730 TI - Desmopressin 120 mcg, 180 mcg, 240 mcg: The right treatment for the right patient. AB - BACKGROUND: The first-line drug therapy for patients with nocturnal enuresis (NE) associated with nocturnal polyuria and normal bladder function is desmopressin (dDAVP). OBJECTIVE: To evaluate if increasing dose of oral desmopressin lyophilisate (MELT) can improve response rates to dDAVP and is useful in enuretic children. MATERIALS AND METHODS: We enrolled a total of 260 children all diagnosed with NE. Enuretic children were treated with increasing MELT at a dose of 120, 180 and 240 mcg a day. RESULTS: We included in our study a total of 237 children, 164 males (69.2%) and 73 females (30.8%) aged between 5 and 18 years (mean age 10.32 +/- 2.52 years). Of the 237 patients enrolled in the study and treated with MELT 120 mcg, a full response was achieved in 135 (56.9%). A partial response was achieved in 21 (8.9%) patients, therefore the dose was increased up to 180 mcg, with further improving symptoms (14.3%) or full response (9.5%), and up to 240 mcg, without usefulness. CONCLUSIONS: MELT at the dose of 120 mcg resulted efficacy and safety; the increased dose up to 180 mcg resulted poorly efficacy; finally, the further increase up to 240 mcg did not improve the symptoms with the increased risk of side effects. PMID- 29974731 TI - Skin flap squamous cell carcinoma developed after urethroplasty. AB - OBJECTIVES: To describe our experience in diagnosis and treatment of urethral carcinoma following urethroplasty with a Orandi penile skin flap. MATERIAL AND METHODS: Our patient underwent to Orandi penile skin flap urethroplasty then developed a urethral epidermoid carcinoma on the flap approximately 15 years later. We treated this case with a partial penectomy surgery and perineostomy. Surgery was followed by chemotherapy with cisplatin and 5-fluorouracil. The progression of the disease led to a salvage surgery of total penectomy and asportation of testicles and scrotum. RESULTS: Despite the success of the surgery, the disease progressed and three months after the last surgical operation the patient died. CONCLUSIONS: Urethral carcinoma on skin flap is a rare complication of the urethroplasty surgery but with severe consequences, so we recommend to undertake a long-term urological follow up in patients undergone such kind of surgery. PMID- 29974732 TI - Surgical approach to adrenal ganglioneuroma: Case report and literature review. AB - OBJECTIVE: Ganglioneuroma (GN) is a benign tumor with a slow growth that can originate from any paravertebral sympathetic plexus. It is usually asymptomatic or with nonspecific symptoms. TC and RM scan are helpful to study GN. It is usually represented by an ovalshaped retroperitoneal mass or, in case of adrenal impairment, by low radiologic contrast media attenuation. Surgical treatment is mandatory. Literature shows how the laparoscopic approach is the most used, especially in lesions that are 6 cm or smaller. Our purpose is to describe our experience on an incidental adrenal GN of about 5 cm treated by the laparoscopic transperitoneal approach. MATERIALS AND METHODS: A 33-year-old male had ultrasound occasional finding of an about 4 cm adrenal mass. TC and RM scan identified a retroperitoneal mass (max diameter 48 mm). The lesion was removed with a transperitoneal laparoscopic approach. RESULTS: No intraoperative or postoperative complications occurred. The patient was discharged 3 days after surgery. CONCLUSIONS: Up to the present laparoscopic surgery is the best approach for GN treatment. PMID- 29974733 TI - Rupture of the cavernous body diagnosed by contrast-enhanced ultrasound: Presentation of a clinical case. AB - Penile trauma represents a urological emergency characterized by the breaking of the albuginea tunic. A fast diagnosis and early surgical repair are the best treatments to avoid post-operative sequelae such as curvatures or deformities of the penis. An ultrasound evaluation may not be able to identify the injury in the tunica albuginea due to the edematous swelling of the penis and clots within the tear deteriorate the image contrast and can hide the injury. We here report a case study of successful management via surgical treatment for rupture of the cavernous body diagnosed by contrast-enhanced ultrasound in a young patient with penile trauma. PMID- 29974735 TI - Significance of Early and Late Stages of Coupled Aggregation and Sedimentation in the Fate of Nanoparticles: Measurement and Modeling. AB - Despite aggregation's crucial role in controlling the environmental fate of nanoparticles (NP), the extent to which current models can describe the progressive stages of NP aggregation/sedimentation is still unclear. In this paper, 24 model combinations of two population-balance models and various collision frequency and settling velocity models are used to analyze spatiotemporal variations in the size and concentration of hydroxyapatite (HAp) NP. The impact of initial conditions and variability in attachment efficiency, alpha, with aggregate size are investigated. Although permeability models perform well in calculating collision frequencies, they are not appropriate for describing settling velocity because of their negative correlation or insensitivity in respect to fractal dimension. Considering both early and late stages of aggregation, both experimental and model data indicate overall mass removal peaks at an intermediate ionic strength (5 mM CaCl2) even though the mean aggregate size continued to increase through higher ionic strengths (to 10 mM CaCl2). This trend was consistent when different approaches to the initial particle size distribution were used and when a variable or constant alpha was used. These results point to the importance of accurately considering different stages of aggregation in modeling NP fate within various environmental conditions. PMID- 29974734 TI - In Ovo Feeding of Creatine Pyruvate Increases the Glycolysis Pathway, Glucose Transporter Gene Expression, and AMPK Phosphorylation in Breast Muscle of Neonatal Broilers. AB - This study aims to investigate in ovo feeding (IOF) of creatine pyruvate (CrPyr) on glucose metabolism, hormone concentration, and the 5'-AMP-activated protein kinase (AMPK) pathway in breast muscle of embryos and neonatal broilers. The three treatments were noninjected control, 0.75% NaCl treatment, and 12 mg CrPyr/egg treatment. The solution was injected on the 17.5 day of incubation. At hatch, 120 male broilers from each treatment were chosen for a 7 day feeding trial. Compared with other treatments, CrPyr treated broilers enhanced insulin and thyroxine levels in plasma, adenosine triphosphate (ATP) concentration, hexokinase and pyruvate kinase activities, glucose transporter protein mRNA expressions, as well as protein abundances of phosphor-liver kinase B1 and phosphor-AMPK in breast muscle at hatch. In conclusion, IOF of CrPyr improved the energy status, increased the gene expression of glucose transporter proteins, and facilitated glycolysis in breast muscle, which may be associated with the activated AMPK pathway. PMID- 29974736 TI - Frequency Shift Raman-Based Sensing of Serum MicroRNAs for Early Diagnosis and Discrimination of Primary Liver Cancers. AB - Frequency shift surface-enhanced Raman scattering (SERS) achieves multiplex microRNA sensing for early serological diagnosis of, and discrimination between, primary liver cancers in a patient cohort for whom only biopsy is effective clinically. Raman reporters microprinted on plasmonic substrates shift their vibrational frequencies upon biomarker binding with a dynamic range allowing direct, multiplex assay of serum microRNAs and the current best protein biomarker, alpha-fetoprotein. Benchmarking against current gold-standard polymerase chain reaction and chemiluminescence methods validates the assay. The work further establishes the frequency shift approach, sensing shifts in an intense SERS band, as a viable alternative to conventional SERS sensing which involves the more difficult task of resolving a peak above noise at ultralow analyte concentrations. PMID- 29974737 TI - Hollow N-Doped Carbon Polyhedron Containing CoNi Alloy Nanoparticles Embedded within Few-Layer N-Doped Graphene as High-Performance Electromagnetic Wave Absorbing Material. AB - Magnetic metal nanostructures have exhibited good electromagnetic wave (EMW) absorption properties. However, the surface of the nanostructures is easily oxidized upon exposure to air, leading to the bad stability of the EMW absorption properties. We use metal-organic framework structure as a template to fabricate hollow N-doped carbon polyhedron containing CoNi alloy nanoparticles embedded within N-doped graphene (CoNi@NG-NCPs). The atomic ratio of Co/Ni can be tuned from 1:0.54 to 1:0.91 in the hollow CoNi@NG-NCPs. Experimental results demonstrate that the EMW absorption properties of the CoNi@NG-NCPs can be improved through the Ni introduction and increased with an increase of the Ni content. Typically, the minimal reflection loss of the optimal CoNi@NG-NCP can reach -24.03 dB and the effective absorption bandwidth (reflection loss below -10 dB) is as large as 4.32 GHz at the thickness of 2.5 mm. Furthermore, our CoNi@NG NCPs exhibit favorably comparable or superior EMW absorption properties to other magnetic absorbers. In addition, because the CoNi alloy nanoparticles are coated with N-doped graphene layers, their surface oxidation behavior can be efficiently limited. The mechanism of the enhanced EMW absorption property is relevant to the enhanced dielectric loss and better impedance matching characteristic caused by the Ni incorporation. PMID- 29974738 TI - Relationship between Hydrogen-Atom Transfer Driving Force and Reaction Rates for an Oxomanganese(IV) Adduct. AB - Hydrogen atom transfer (HAT) reactions by high-valent metal-oxo intermediates are important in both biological and synthetic systems. While the HAT reactivity of FeIV-oxo adducts has been extensively investigated, studies of analogous MnIV-oxo systems are less common. There are several recent reports of MnIV-oxo complexes, supported by neutral pentadentate ligands, capable of cleaving strong C-H bonds at rates approaching those of analogous FeIV-oxo species. In this study, we provide a thorough analysis of the HAT reactivity of one of these MnIV-oxo complexes, [MnIV(O)(2pyN2Q)]2+, which is supported by an N5 ligand with equatorial pyridine and quinoline donors. This complex is able to oxidize the strong C-H bonds of cyclohexane with rates exceeding those of FeIV-oxo complexes with similar ligands. In the presence of excess oxidant (iodosobenzene), cyclohexane oxidation by [MnIV(O)(2pyN2Q)]2+ is catalytic, albeit with modest turnover numbers. Because the rate of cyclohexane oxidation by [MnIV(O)(2pyN2Q)]2+ was faster than that predicted by a previously published Bells-Evans-Polanyi correlation, we expanded the scope of this relationship by determining HAT reaction rates for substrates with bond dissociation energies spanning 20 kcal/mol. This extensive analysis showed the expected correlation between reaction rate and the strength of the substrate C-H bond, albeit with a shallow slope. The implications of this result with regard to MnIV-oxo and FeIV oxo reactivity are discussed. PMID- 29974739 TI - Electrochemical Biosensing of Algal Toxins in Water: The Current State-of-the Art. AB - Due to increasing stringency of water legislation and extreme consequences that failure to detect some contaminants in water can involve, there has been a strong interest in developing electrochemical biosensors for algal toxin detection during the past decade, evidenced by literature increasing from 2 journal papers pre-2009 to 24 between 2009 and 2018. In this context, this review has summarized recent progress of successful algal toxin detection in water using electrochemical biosensing techniques. Satisfactory detection recoveries using real environmental water samples and good sensor repeatability and reproducibility have been achieved, along with some excellent limit-of-detection (LOD) reported. Recent electrochemical biosensor literature in algal toxin detection is compared and discussed to cover three major design components: (1) biorecognition elements, (2) electrochemical read-out techniques, and (3) sensor electrodes and signal amplification strategy. The recent development of electrochemical biosensors has provided one more step further toward quick in situ detection of algal toxins in the contamination point of the water source. In the end, we have also critically reviewed the current challenges and research opportunities regarding electrochemical biosensors for algal toxin detection that need to be addressed before they attain commercial viability. PMID- 29974740 TI - Potent Anti-adhesion Barrier Combined Biodegradable Hydrogel with Multifunctional Turkish Galls Extract. AB - Clinically, postoperative adhesions are common and serious complications, which almost always happen after abdominal or pelvic surgery. The adhesion development process is accompanied by increased inflammatory cell infiltration and oxygen free radical production. In this study, the naturally occurring antioxidative and anti-inflammatory compounds extracted from Turkish galls by ethyl acetate (GEA) were encapsulated into an injectable and biodegradable thermosensitive hydrogel. Antiadhesion efficacy of the barrier system (GEA-NP/H) was tested on a rat peritoneum injury-cecum abrasion model. Upon injection, the mildly viscous liquid formed a potent physical barrier over the injured cecum and peritoneum without any additional cross-linkers or light sources. Once formed, GEA-NP/H acted as a durable wound dressing for more than 5 days, as well as a sustained drug depot of GEA. The polymer hydrogel can be degraded and absorbed gradually. After 14 days, severe adhesion occurred among rats treated with normal saline and GEA-loaded nanoparticles (GEA-NP). Whereas, frequency of score 1 adhesion among the blank hydrogel group is 30%, and 90% of the rats from GEA-NP/H group exhibited no adhesion. In addition, pathological sections and scanning electron microscopy assay demonstrated that operative defects treated with GEA-NP/H suffered from mild oxidative stress and inflammatory damages at early days after injury, as well as accelerated wound healing and more mature mesothelial cell deposition at the 14th day in contrast to the blank hydrogel treatment. Therefore, the study provided an available biodegradable hydrogel barrier to effectively prevent postsurgical adhesion. PMID- 29974741 TI - Correction to Fish Oil Supplementation Alleviates the Altered Lipid Homeostasis in Blood, Liver, and Adipose Tissues in High-Fat Diet-Fed Rats. PMID- 29974742 TI - [1,2,4]Triazolo[1,5- a]pyridine-Based Host Materials for Green Phosphorescent and Delayed-Fluorescence OLEDs with Low Efficiency Roll-Off. AB - Herein, a series of universal bipolar host materials, 9,9'-([1,2,4]triazolo[1,5- a]pyridine-2,6-diylbis(4,1-phenylene))bis(9 H-carbazole) (TP26Cz1), 3-(2-(4-(9 H carbazol-9-yl)phenyl)-[1,2,4]triazolo[1,5- a] pyridine-6-yl)-9-phenyl-9 H carbazole (TP26Cz2), 9,9'-([1,2,4]triazolo[1,5- a]pyridine-2,7-diylbis(4,1 phenylene))bis(9 H-carbazole) (TP27Cz1), and 3-(2-(4-(9 H-carbazol-9-yl)phenyl) [1,2,4]triazolo[1,5- a]pyridin-7-yl)-9-phenyl-9 H-carbazole (TP27Cz2), using [1,2,4]triazolo[1,5- a]pyridine (TP) as electron-transporting moiety and carbazole as hole-transporting moiety, were designed and synthesized. All four compounds possess remarkable carrier-transporting properties and excellent thermal stability with high glass-transition temperature ( Tg) in the range of 136-144 degrees C. The hole- and electron-transporting abilities could be regulated by adjusting the linkage mode between the carbazole and TP units, and balanced charge-transporting properties were realized in TP26Cz2 and TP27Cz2. The phosphorescent and thermally activated delayed-fluorescence (TADF) organic light emitting diodes (OLEDs) based on these host materials exhibit superior performance with high efficiency and low roll-off. For example, TP26Cz2-hosted phosphorescent OLED (PhOLED) exhibits the maximum external quantum efficiency (etaext) of 25.6%, and at the high luminance of 5000 cd m-2, the etaext still remained at 25.2%. TP27Cz1-hosted TADF device exhibits the maximum etaext of 15.5% and only dropped to 15.4% at the luminance of 1000 cd m-2. Moreover, the influence of linking mode of carbazole unit and TP units in these hosts on their photophysical and carrier-transporting properties as well as the electroluminescence (EL) performance of devices was discussed. PMID- 29974743 TI - Super-Resolution Imaging of Clickable Graphene Nanoribbons Decorated with Fluorescent Dyes. AB - The functional integration of atomically defined graphene nanoribbons (GNRs) into single-ribbon electronic device architectures has been limited by access to nondestructive high-resolution imaging techniques that are both compatible with common supports such as Si or Si/SiO2 wafers and capable of resolving individual ribbons in dilute samples. Conventional techniques such as scanning probe (AFM, STM) or electron microscopy (SEM, TEM) have been restricted by requisite sample preparation techniques that are incompatible with lithographic device fabrication. Here we report the design and synthesis of ultralong (~10 MUm) cove type GNRs (cGNRs) featuring azide groups along the edges that can serve as a universal handle for late-stage functionalization with terminal alkynes. Copper catalyzed click-chemistry with Cy5 fluorescent dyes gives rise to cGNRs decorated along the edges with fluorescent tags detectable by optical microscopy. The structures of individual dye-functionalized cGNRs spin-coated from a dilute solution onto transparent and opaque insulating substrates were resolved using diffraction-limited fluorescence microscopy and super-resolution microscopy (SRM) imaging techniques. Analysis of SRM images reveals an apparent width of cGNRs in the range 40-50 nm and lengths in excess of 10 MUm, the longest GNRs imaged to date. Isolated cGNRs can even be distinguished from bundles and larger aggregates as long as the center-to-center distance is greater than the apparent width. PMID- 29974744 TI - Folic Acid Derived Hydrogel Enhances the Survival and Promotes Therapeutic Efficacy of iPS Cells for Acute Myocardial Infarction. AB - Stem cell therapy has obtained extensive consensus to be an effective method for post myocardial infarction (MI) intervention. Induced pluripotent stem (iPS) cells, which are able to differentiate into multiple cell types, have the potential to generate cardiovascular lineage cells for myocardial repair after ischemic damage, but their poor retention rate significantly hinders the therapeutic efficacy. In the present study, we developed a supramolecular hydrogel which is formed by the self-assembly of folic acid (FA)-modified peptide via a biocompatible method (glutathione reduction) and suitable for cell encapsulation and transplantation. The iPS cells labeled with CM-Dil were transplanted into the MI hearts of mice with or without FA hydrogel encapsulation. The results corroborated that the FA hydrogel significantly improved the retention and survival of iPS cells in MI hearts post injection, leading to augmentation of the therapeutic efficacy of iPS cells including better cardiac function and much less adverse heart remodeling, by subsequent differentiation toward cardiac cells and stimulation of neovascularization. This study reported a novel supramolecular hydrogel based on FA-peptides capable of improving the therapeutic capacity of iPS cells, which held big potential in the treatment of MI. PMID- 29974745 TI - Enantioselective Hetero-Diels-Alder Reaction and the Synthesis of Spiropyrrolidone Derivatives. AB - An efficient enantioselective hetero-Diels-Alder reaction was developed under catalysis of a chiral copper complex. A variety of spiropyrrolidones, which bear a tetra-substituted carbon stereocenter, can be obtained in good yields with excellent enantioselectivities by virtue of this method. Furthermore, a substrate dependent reaction pathway was proposed on the basis of the isolated intermediates. PMID- 29974746 TI - Terpyridine-Micelles for Inhibiting Bacterial Biofilm Development. AB - Iron plays a critical role in bacterial infections and is especially critical for supporting biofilm formation. Until recently, Fe(III) was assumed to be the most relevant form of iron to chelate in therapeutic antimicrobial strategies due to its natural abundance under normal oxygen and physiologic conditions. Recent clinical data obtained from cystic fibrosis (CF) patients found that there is actually quite an abundance of Fe(II) present in sputum and that there exists a significant relationship between sputum Fe(II) concentration and severity of the disease. A biocompatible mixed micelle formed from the self-assembly of poly(lactic- co-glycolic acid)- block-methoxy poly(ethylene glycol) (PLGA- b mPEG) and poly(lactic- co-glycolic acid)- block-poly(terpyridine)5 [PLGA- b p(Tpy)5] polymers was prepared to chelate Fe(II) (Tpy-micelle). Tpy-micelles showed high selectivity for Fe(II) over Fe(III), decreased biofilm mass more effectively under anaerobic conditions at >4 MUM Tpy-micelles, reduced bacteria growth in biofilms by >99.9% at 128 MUM Tpy-micelles, effectively penetrated throughout a 1-day old biofilm, and inhibited biofilm development in a concentration-dependent manner. This study reveals that Fe(II) chelating Tpy micelles are a promising addition to Fe(III) chelating strategies to inhibit biofilm formation in CF lung infections. PMID- 29974748 TI - Efficient Electrochemical Self-Catalytic Platform Based on l-Cys-hemin/G quadruplex and Its Application for Bioassay. AB - Commonly, in the artificial enzyme-involved signal amplification approach, the catalytic efficiency was limited by the relatively low binding affinity between artificial enzyme and substrate. In this work, substrate l-cysteine (l-Cys) and hemin were combined into one molecule to form l-Cys-hemin/G-quadruplex as an artificial self-catalytic complex for the improvement of the binding affinity between l-Cys-hemin/G-quadruplex and l-Cys. The apparent Michaelis-Menten constant ( Km = 2.615 MUM) on l-Cys-hemin/G-quadruplex for l-Cys was further investigated to assess the affinity, which was much lower than that of hemin/G quadruplex ( Km = 8.640 MUM), confirming l-Cys-hemin/G-quadruplex possessed better affinity to l-Cys compared with that of hemin/G-quadruplex. Meanwhile, l Cys bilayer could be further assembled onto the surface of l-Cys-hemin/G quadruplex based on hydrogen-bond and electrostatic interaction to concentrate l Cys around the active center, which was beneficial to the catalytic enhancement. Through this efficient electrochemical self-catalytic platform, a sensitive thrombin aptasensor was constructed. The results exhibited good sensitivity from 0.1 pM to 80 nM and the detection limit was calculated to be 0.032 pM. This self catalytic strategy with improved binding affinity between l-Cys-hemin/G quadruplex and l-Cys could provide an efficient approach to improve artificial enzymatic catalytic efficiency. PMID- 29974749 TI - Identification of the Missing Protein Hyaluronan Synthase 1 in Human Mesenchymal Stem Cells Derived from Adipose Tissue or Umbilical Cord. AB - Currently, 14% of the human proteome is made up of proteins whose existence is not confirmed by mass spectrometry. We performed a proteomic profiling of human mesenchymal stem cells derived from adipose tissue or umbilical cord (PRIDE accession number: PXD009893) and identified peptides derived from 13 of such missing proteins. Remarkably, we found compelling evidence of the expression of hyaluronan synthase 1 (NX_Q92839-1) and confirmed its identification by the fragmentation of four heavy-labeled peptides that coeluted with their endogenous light counterparts. Our data also suggest that mesenchymal stem cells constitute a promising source for the detection of missing proteins. PMID- 29974747 TI - Protective Effects of Sesquiterpenoids from the Root of Panax ginseng on Fulminant Liver Injury Induced by Lipopolysaccharide/d-Galactosamine. AB - It is reported that sesquiterpenoids from Panax ginseng (SPG) possess various pharmacological activities, for example, antidepressant, antioxidative, and anti inflammatory activities. The purpose of this study was to examine the hepatoprotective effects of SPG (2.5 and 10 mg/kg, i.g.) on fulminant liver injury induced by d-galactosamine (d-GalN) and lipopolysaccharide (LPS) and discuss its mechanisms of action. After 24 h of d-GalN (400 mg/kg, i.p.) and LPS (25 MUg/kg, i.p.) exposure, the serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), hepatic malondialdehyde (MDA) level, hepatic activities of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), and hepatic tissue histology were measured. Expression levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were detected by enzyme linked immunosorbent assay and real-time polymerase chain reaction. Moreover, the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB), nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuin type 1 (Sirt 1), and heme oxygenase 1 (HO-1) were determined by western blotting. The results indicated that SPG evidently restrained the increase of serum ALT and AST levels induced by d-GalN/LPS. SPG obviously downregulated TNF-alpha and IL-1beta levels and their mRNA expression in liver. In addition, d-GalN/LPS injection induced severe oxidative stress in liver by boosting the MDA level as well as decreasing CAT, GSH, and SOD capacities, and SPG reversed these changes. Meanwhile, SPG inhibited NF-kappaB activation induced by d-GalN/LPS and upregulated Sirt 1, Nrf2, and HO-1 expression levels. Therefore, SPG might protect against the fulminant liver injury induced by d-GalN/LPS via inhibiting inflammation and oxidative stress. The protective effect of SPG on fulminant liver injury induced by d-GalN/LPS might be mediated by the Sirt 1/Nrf2/NF-kappaB signaling pathway. All of these results implied that SPG might be a promising food additive and therapeutic agent for fulminant liver injury. PMID- 29974750 TI - Behavior of Marine Bacteria in Clean Environment and Oil Spill Conditions. AB - Alcanivorax borkumensis is a bacterial community that dominates hydrocarbon degrading communities around many oil spills. The physicochemical conditions that prompt bacterial binding to oil/water interfaces are not well understood. To provide key insights into this process, A. borkumensis cells were cultured either in a clean environment condition (dissolved organic carbon) or in an oil spill condition (hexadecane as the sole energy source). The ability of these bacteria to bind to the oil/water interface was monitored through interfacial tension measurements, bacterial cell hydrophobicity, and fluorescence microscopy. Our experiments show that A. borkumensis cells cultured in clean environment conditions remain hydrophilic and do not show significant transport or binding to the oil/water interface. In sharp contrast, bacteria cultured in oil spill conditions become partially hydrophobic and their amphiphilicity drives them to oil/water interfaces, where they reduce interfacial tension and form the early stages of a biofilm. We show that it is A. borkumensis cells that attach to the oil/water interface and not a synthesized biosurfactant that is released into solution that reduces interfacial tension. This study provides key insights into the physicochemical properties that allow A. borkumensis to adhere to oil/water interfaces. PMID- 29974751 TI - Correction to Cerium Tetrakis(tropolonate) and Cerium Tetrakis(acethylacetonate) Are Not Diamagnetic but Temperature-Independent Paramagnets. PMID- 29974752 TI - Toward Negatively Curved Carbons. AB - Negatively curved carbons are theoretical carbon allotropes as proposed by embedding heptagons or octagons in a graphitic lattice. Unlike five-membered rings in fullerenes, which induce positive curvature, the seven- or eight membered rings induce negative curvature, giving rise to a variety of esthetic carbon nanostructures known as Mackay crystals or carbon schwarzites. In addition, hypothetical toroidal carbon nanotubes consisting of five-, six-, and seven-membered rings present positive curvature on the outside and negative curvature on the inside of the torus. These carbon allotropes with negative curvature are predicted to have interesting properties and potential applications on the basis of computational studies but are yet to be synthesized. A promising bottom-up approach to these intriguing but still imaginary carbon structures is organic synthesis of negatively curved polycyclic arenes, which are also known as negatively curved nanographenes. They not only are segments of negatively curved carbon allotropes containing important structural information but also can in principle be used as templates or monomer units for the synthesis of carbon schwarzites and toroidal carbon nanotubes. This Account describes research on the design, synthesis, structure, stereochemical dynamics, and properties of negatively curved nanographenes, with emphasis on our efforts in this field. In our designs of negatively curved nanographenes, a few heptagon- or octagon embedded pi systems were employed as basic structural units, including [7]circulene, heptagon-embedded hexa- peri-benzocoronene, tetrabenzodipleiadiene, and [8]circulene. They present a saddle-shaped geometry and consist of a relatively small number of sp2 carbon atoms. By expanding or connecting these structural units, we designed and synthesized larger negatively curved nanographenes consisting of up to 96 sp2 carbon atoms. A method of key importance in the synthesis of negatively curved nanographenes is the Scholl reaction, which enables the formation of multiple carbon-carbon bonds in a single step by intramolecular oxidative cyclodehydrogenation. The unique structures of negatively curved nanographenes were studied by experimental and computational methods. In particular, X-ray crystallography of single crystals revealed remarkably curved pi faces accompanied by severe out-of-plane deformation of benzenoid rings, which sheds light on the limit of pi bonds and the aromaticity of polycycles. As found mainly from calculations, the flexible polycyclic frameworks of negatively curved nanographenes are associated with stereochemical dynamics that is not available for planar polycyclic aromatics. In addition, some negatively curved nanographenes have been found to function as organic semiconductors in the solid state. We envision that the study of negatively curved nanographenes will serve as an important initial step toward the eventual synthesis of new carbon allotropes with negative curvature and new frontiers of nanocarbon materials. PMID- 29974753 TI - [Bread and salt: an indissoluble binomial?] PMID- 29974754 TI - Early nutrition support therapy in patients with head-neck cancer. AB - BACKGROUND: weight loss is commonly observed in head-neck cancer patients, affecting 75-80% of them during their treatment period; weight loss is severe in 30-50% of cases. According to ESPEN publications, nutritional assessment in cancer patients should be frequently performed and nutrition support therapy must be started when any deficiency is observed. OBJECTIVE: to evaluate the effect of early nutrition support (ENS) in nutritional markers and treatment response in patients with head-neck cancer receiving radiotherapy (RT). PATIENTS AND METHODS: one hundred and two patients with head-neck cancer and more than two points in the malnutrition screening tool (MUST) before receiving RT were included. ENS was provided to all patients consisting in nutrition counselling, oral supplements and/or enteral nutrition. RESULTS: one hundred and two patients were included; 76% had a stage IV of disease. At the end of RT, after ENS, a slightly decreased body mass index (BMI) with an increased fat-free body mass was observed (p < 0.001); biochemical nutrition parameters remained stable despite decreased oral intake. Less than 40% of patients had severe epithelitis or mucositis; 92% of patients received the total amount and doses of originally planned RT sessions, while 22.8% required RT-sessions interruption. Patients with caloric malnutrition had a lower fulfillment of RT than those without caloric malnutrition (p < 0.001). Mortality was related to lower Karnosfsky, higher weight loss before RT and higher grade of mucositis/epitelitis (p < 0.05). CONCLUSIONS: patients who receive ENS keep their nutritional condition instead of associated effects due to RT. ENS represents an efficient treatment and could prevent malnutrition associated comorbidities in oncologic patients. PMID- 29974755 TI - Epidemiology of home enteral nutrition: an approximation to reality. AB - INTRODUCTION: home enteral nutrition (HEN) has undergone an important development; however, there is a notable lack of information with regard to its incidence and characteristics. OBJECTIVES: our aim was to assess the state of HEN in our area. METHODS: an observational, prospective study, involving all patients who had initiated HEN in the Nutrition Unit during a year. Epidemiological, functional, and nutritional evolution of the patients was described and incidence of HEN was calculated. RESULTS: HEN incidences totalled 229/100,000 inhabitants/year. The HEN population in our area was characterized by the aged and a high frequency of comorbidity and functional limitations. Neurological and oncological diseases accounted for 50% of indications. The remaining cases were malnourished patients who had received short periods of HEN after hospitalization or a hip fracture. Oral supplements (60%) with standard and hypercaloric formulas were used the most. At baseline, 75% of the patients suffered from malnutrition. During the follow-up, patients showed weight gain (1.6%), an increase in the percentage of normal weight and overweight (from 74% to 82.7%, p = 0.001) and a reduction in pressure ulcers (15.7% vs10.3%, p < 0.001). The median duration of HEN was 8.5 months. Only a quarter of the patients experienced complications (mostly mild gastrointestinal complications); 43.1% had died at the end of the follow-up. CONCLUSIONS: in our area, the HEN incidence was much higher than those described in the literature. HEN appears to be a safe therapy with few complications that improves the nutritional status of the patients, even with short periods of administration. PMID- 29974756 TI - Assessment of micronucleus and oxidative stress in peripheral blood from malnourished children. AB - INTRODUCTION: malnutrition is one of the most common health problems among children in underdeveloped countries, including Mexico. Previous studies have indicated increased genetic damage in malnourished humans and animal models, but the essential mechanisms remain unclear. In the present study, we assessed the effects of malnutrition on the frequency of micronucleus (MN) in reticulocytes (RET) from the peripheral blood of well-nourished uninfected (WN), well-nourished infected (WNI), moderately malnourished infected (UNM) and severely malnourished infected (UNS) children. Moreover, lipid peroxidation and the antioxidant status were evaluated to investigate the role of oxidative processes in malnutrition associated genotoxicity. METHODS: the antioxidant status of the study population was determined by measuring superoxide dismutase (SOD) in the red blood cells and glutathione peroxidase (GPX) in whole blood. RESULTS: the UNS and UNM groups have increased percentages of MN-RET compared to the WNI group. Moreover, the data showed a significant increase in lipid peroxidation and a decrease in erythrocyte SOD activity and GPX activity in the malnourished group compared to the well nourished infected children. CONCLUSION: the data suggest that the antioxidant system was impaired in the cells of malnourished children and that oxidative stress causes a significant increase in DNA damage, as evaluated by the MN-RET frequency. PMID- 29974757 TI - Physical activity values in two- to seven-year-old children measured by accelerometer over five consecutive 24-hour days. AB - INTRODUCTION: interpretation of accelerometer-derived physical activity in preschool children is confounded by differences in cut-off points. AIM: the purpose of this study was to analyze physical activity in 2-to-7-year-old children to establish reference values for daily activity. METHODS: observational study in children aged 2-7 years, without chronic diseases and whose parents provided informed consent. The main variable was physical activity, measured continuously over 120 hours (three workdays and two weekend days) by accelerometer. Secondary variables were weight status (body mass index [BMI] Z score) and gender. The relationship between the main variable and secondary variables was determined through the t-test, ANOVA and the Pearson correlation coefficient. A multivariate model was used to obtain the standard deviation (SD) of all possible combinations of values, constructing percentiles of normality (x +/- SD and x +/- 2.SD). RESULTS: one hundred and thirty-six children (35% of municipality children) were included in the study (54.4% of them were girls). Their weight status distribution was: 25 underweight (18.4%), 54 normal weight (39.7%), 12 risk of overweight (8.8%), 22 overweight (16.2%) and 23 obese (16.8%). The median age was 5.7 years and the mean physical activity was 592 counts/minute. The boys undertook more physical activity (p = 0.031) and the underweight and normal-weight children undertook more physical activity than the overweight and obese children (p = 0.012). There were no significant differences according to age. The multivariate analysis showed significant differences (p < 0.001) according to gender and weight status. In boys, physical activity decreased as weight status increased. In contrast, the girls in the extreme BMI groups obtained higher levels of physical activity. CONCLUSION: overweight and obese preschool children had lower levels of physical activity than normal weight children. Physical activity levels were higher in boys. PMID- 29974758 TI - [Childhood obesity and its association with the feeling of unhappiness and low levels of self-esteem in children of public schools]. AB - INTRODUCTION: overweight children are at increased risk for psychosocial disorders. OBJECTIVE: the purpose of this research was to relate the condition of overweight and obesity to the levels of self-esteem and happiness in schoolchildren of public schools. METHODS: a total of 364 schoolchildren (180 boys and 184 girls) were enrolled between eleven and 13 years old (12.44 +/- 1.14 years old). Anthropometric measurements were performed and the levels of self esteem and happiness were evaluated through the School Self-Esteem Test (APT). RESULS: school self-esteem was significantly higher in boys (p < 0.001); 55.49% (n = 204) of the students evaluated were overweight. Overweight and obese subjects had lower levels of self-esteem compared to normal weight children (p = 0.032). In addition, 43 students had very low self-esteem, and a relationship between very low and low self-esteem levels (n = 119) and the overweight and obesity was observed (p = 0.033). In relation to the question "Am I a happy person?", a greater proportion of students answered positively (n = 296). The negative response to the question was associated with weight excess (p = 0.042). CONCLUSION: overweight and obesity were related to low levels of self-esteem and happiness in schoolchildren. These results are alarming since self-esteem is one's appreciation of oneself and happiness is an index of subjective personal well-being and is a topic that concerns families and the entire education system. PMID- 29974759 TI - [Measurement of rest energy expanditure in pediatric oncological patients: concordance between indirect calorimetry and predictive equations]. AB - INTRODUCTION: in childhood cancer, the disease impacts resting energy expenditure (GER) in a way that is not estimable by predictive equations. OBJECTIVE: the aim of this study is to determine the concordance between the measurement of resting energy expenditure (REE) by indirect calorimetry in pediatric oncology patients versus the World Health Organization (WHO) and Schofield predictive equations. METHOD: cross-sectional study in children aged 5-15 years receiving chemotherapy, in outpatient Clinica Las Condes and Hospital Dr. Sotero del Rio, from July 2013 to July 2015. REE measurement was performed by indirect calorimetry and WHO and Schofield equations. Concordance analysis, with clinically relevant cut-off point and concordance coefficient of 90%. RESULTS: twenty-seven children were included and 27 calorimetries were performed; 66% of these children were diagnosed with leukemia, 15% with central nervous system tumor and 81% were in the maintenance stage of their treatment. There is no significant difference between indirect calorimetry measurement versus WHO (p 0.18) or Schofield (p 0.07), neither when stratifying by nutritional status or type of cancer diagnosis. Concordance was calculated between calorimetry and Schofield, with a concordance coefficient of Lin = 79.4% (95% CI = 65.2-93.6) and versus WHO = 78% (95% CI = 62.9-93.2). CONCLUSION: this level of agreement, less than 80% in both cases, is insufficient. With both equations for estimating REE, there is overestimation or underestimation of energy requirements in more than 20% of cases. There is no agreement between the measurement of REE measured with indirect calorimetry versus its estimation with Schofield's and the WHO equations. Consequently, indirect calorimetry is required as part of the nutritional assessment in a nutritionally at-risk population such as pediatric patients with oncological pathology. PMID- 29974760 TI - [Analysis of bone mineral density in children with celiac disease. Densitometry indications and effect of gluten-free diet]. AB - INTRODUCTION: one of the main extradigestive manifestations of celiac disease is the decrease in bone mineral density (BMD). Bone densitometry performed with DXA is the method of choice for BMD assessment. Indications for its use in celiac children are controversial. OBJECTIVE: analyzing BMD and various clinical analytical variables in celiac children when diagnosed and after a gluten-free diet. Define a profile of patients who are more likely to present BMD involvement based on several individual characteristics, to perform DXA indications. METHODS: study performed in 24 celiac children (12 boys) (age: 8.7 +/- 3.3 years). Their BMD was determined at diagnosis and after a gluten-free diet using DXA. The BMD was compared in each patient in the two moments of the study and at the moment of diagnosis between groups of patients stratified according to severity criteria dependent on clinical, analytical and histological variables. RESULTS: BMD was normal in all patients studied at the time of diagnosis and after treatment, with no difference between the two moments of the analysis. Children who presented symptomatology when diagnosed with celiac disease had lower spine and femur BMD than asymptomatic ones. The calcemia had an inverse correlation with the time of evolution of the disease before its diagnosis. CONCLUSIONS: in general, in our setting, the study of bone mineralization in celiac children is not indicated, unless there has been a prolonged clinical course before diagnosis. PMID- 29974761 TI - Adolescents' eating behaviors and its relationship with family meals, body mass index and body weight perception. AB - INTRODUCTION: healthy diet is important because it affects wellbeing and health, and can reduce the risk of developing diseases or illnesses. OBJECTIVES: this study aimed to analyze the relationship of eating behaviors with family meals, body mass index and body weight perception on adolescents. METHODS: data from 3,693 (1,723 boys) adolescents aged 14-17 years were collected. Adolescents were classified as realistic positive, realistic negative, overestimators, and underestimators, according to their eating habits and eating practices. Logistic regression models were used to analyze the data. RESULTS: having breakfast with family several times a week (OR = 1.42, p < 0.001) or everyday (OR = 1.64, p < 0.001), and having normal weight (OR = 1.74, p < 0.001) were associated with being realistic positive. On the contrary, realistic negatives were less likely to have breakfast with family several times a week (OR = 0.57, p < 0.001) or everyday (OR = 0.48, p < 0.001), and have normal weight (OR = 0.40, p < 0.001). CONCLUSION: adolescents' eating behaviors are related to family meals, and body weight perception. Eating breakfast with family and having normal weight are positive factors in adolescents' awareness of good eating behaviors. PMID- 29974762 TI - [Body mass index, motives for extracurricular sport practice and family type in grade 6 Primary Education children]. AB - INTRODUCTION: obesity has many edges. Therefore, three complementary studies were conducted. OBJECTIVES: study 1: determining body mass index (BMI) of the whole population of grade 6 students of a middle-size city and assessing their extracurricular sport habits. Study 2: assessing the motives for sport practice. Study 3: examining the role that family plays in extracurricular sport practice. METHODS: mixed focus, ex-post-facto transversal design. Study 1: 377 grade 6 students. INSTRUMENTS: measuring rod, scale and questionnaire. Study 2: 275 grade 6 students. INSTRUMENTS: questionnaire (BREQ-3; MPAM-R). Study 3: 228 parents. INSTRUMENT: Families' Perception Questionnaire. RESULTS: study 1: BMI: 20.73 +/- 4.12 kg/m2, 38.7% overweight, 10.1% obesity, 73% practice sport. BMI: no significant differences between those who practice sports and those who do not; significant differences based on socioeconomic status. Study 2: high intrinsic motivation; motive to participate: enjoyment. Study 3: parents value the importance of doing physical activity; significant differences favor those whose children play sports and have medium-high socioeconomic status. Parents whose children play sport: good for their health/development, he/she likes/choses it, socialization and values; parents whose children do not play sport: children's lack of time, he/she does not like it (can't find a sport he/she likes), parent's lack of time. CONCLUSIONS: BMI close to overweight; extracurricular sports do not make a difference in BMI, socioeconomic status does (study 1). Sport participants intrinsically motivated, playing sports for enjoyment (study 2). Family: a model for sport practice (study 3). PMID- 29974763 TI - Nutritional evaluation of geriatric patients with Alzheimer's disease in Southern Brazil: case-control study. AB - INTRODUCTION: elderly's malnutrition is linked, among other factors, to chronic degenerative diseases, requiring an improvement in the clinical evaluation of nutritional status of this population. Studies have tried to find out new tools to assess aged-people nutritional status. One of most used scales to investigate nutritional status on geriatric patients is the Mini Nutritional Assessment (MNA). OBJECTIVE: the present study aims to evaluate nutritional status of Alzheimer's disease (AD) patients, by comparison with a control group, via Mini Nutritional Assessment. METHODS: a cross-sectional study, which includes 35 alzheimer's old-people and 43 control old-people, was performed evaluating nutritional status with MNA. RESULTS: total score of MNA in the alzheimer group shows that 71.42% were in malnutrition risk, 14.28% were malnourished and 14.25% presented normal nutritional status. In addition, in the control group 79.06% of patients (n = 34) were classified as having normal nutritional status and 20.93% (n = 9), as being at risk of malnutrition. CONCLUSION: results reinforce the purpose that MNA can be used as a proper instrument to evaluate nutritional status in elderly, mainly in AD, because measuring risk and nutritional status of this population is indispensable. PMID- 29974764 TI - Green tea supplementation promotes leukocyte telomere length elongation in obese women. AB - INTRODUCTION: inflammation and oxidative stress are factors that may play a substantial role in telomere attrition. In line of this, obesity is associated with telomere shortening. Green tea had anti-inflammatory and antioxidant effects and may alter telomere length (TL). OBJECTIVES: we evaluated the effect of decaffeinated green tea supplementation in obese women on TL. METHODS: we conducted a cross-sectional interventional study with ten obese (body mass index [BMI] > 40 kg/m2) and eight normal weight (BMI > 18.5 and < 24.9 kg/m2) women (age between 27 and 48 years). The supplementation was carried out with capsules (each contained 450.7 mg of epigallocatechin-3-gallate) during eight weeks. Anthropometric and dietary intake assessment, and blood collection (for biochemical and TL analysis by quantitative PCR) were performed before and after supplementation. Normal weight patients were evaluated at a single moment. RESULTS: we observed a significant increase on TL after supplementation (1.57 +/- 1.1 to 3.2 +/- 2.1 T/Sratio; p < 0.05). Moreover, we found shorter TL in obese patients (day 0) when compared to normal weight individuals (3.2 +/- 1.9 T/Sratio; p < 0.05) and an inverse association between TL and BMI, even after age adjustment (beta = -0.527; r2 = 0.286; IC = -0.129, -0.009). CONCLUSION: obesity is related to shorter telomeres. Green tea supplementation during eight weeks promotes telomere elongation in obese women. PMID- 29974765 TI - Visceral adiposity increases the risk of breast cancer: a case-control study. AB - INTRODUCTION: in recent decades, lifestyle changes in women involving physical inactivity, insulin resistance and body fat distribution have been associated with an increase in breast cancer. OBJECTIVE: to assess whether insulin resistance, lipid profile, and visceral adiposity are associated with increased risk of breast cancer. METHODS: a hospital-based case control study was conducted with 116 women newly diagnosed with breast cancer and 226 controls. Body mass index, waist circumference, total cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL), very-low-density lipoproteins (VLDL), triglycerides, glycated hemoglobin, HOMA-IR, HOMA-beta, lipid accumulation product (LAP), and visceral adiposity index (VAI) were assessed. Logistic regression was adjusted for body mass index and age to quantify the association between breast cancer risk and insulinresistance, dyslipidemias, and visceral adiposity. RESULTS: the case group had higher insulin resistance (p < 0.001), LAP (p = 0.012), and VAI (p = 0.004), and lower concentrations of HDL (p = 0.024) and HOMA-beta(p = 0.010) compared to the control. Insulin resistance (OR = 3.00, 95% CI: 1.75-5.17, p < 0.001) and higher VAI (OR = 1.91, 95% CI: 1.17-3.13, p = 0.01) were associated with breast cancer, whereas the highest concentration of HDL reduces the chances of cancer by 53% (95% CI: 0.32-0.86, p = 0.026). In the multivariate analysis, only LAP and VAI were associated to breast cancer. CONCLUSIONS: visceral fat accumulation increases the risk of breast cancer. PMID- 29974766 TI - [Increasing consumption of dietary fiber complementary to the treatment of metabolic syndrome]. AB - INTRODUCTION: the amount of fiber ingested in Latin American countries is lower (10-20 g/d) than recommended (35 g/d). An increase isrecommended for patients with metabolic syndrome (MS) to reduce cardiovascular risk, as well as to prevent obesity and other complications. OBJECTIVE: to evaluate whether increased dietary fiber consumption complements MS treatment and improves clinical and laboratory parameters in subjects at the San Martin Mexicapam "La Joya" Health Center, Oaxaca (Mexico). METHODS: an analytical-longitudinal study was carried out from January to April 2017, to evaluate nutritional status before and after intervention with dietary fiber and to measure cholesterol levels, triglycerides and fasting blood glucose. An increase of 15 g of fiber (fruits-vegetables and/or oat bran and/or wheat bran) was indicated in the usual diet over eight weeks. RESULTS: the sample consisted of 30 participants from the Mutual Aid Group diagnosed with MS, with an average age of 37.26 years, starting from a body mass index (BMI) of 30.75 kg/cm2 and levels of fasting glycemia at 153.87 mg/dl, triglycerides at 209.67 mg/dl, and cholesterol at 213.81 mg/dl. Following the intervention, a statistically significant difference (p < 0.05) was obtained with a BMI of 29.7 kg/cm2, fasting glycemia at 127.77 mg/dl, triglycerides at 179.71 mg/dl and cholesterol at 207.13 mg/dl. CONCLUSION: a reduction in the results for the parameters tested in patients of MS is improved by a greater consumption of dietary fiber, such as oat bran. However, additional studies are required to generate clearer recommendations. PMID- 29974767 TI - Effects of modified banana (Musa cavendish)starch on glycemic control and blood pressure in rats with high sucrose diet. AB - INTRODUCTION: insulin resistance (IR) is the preliminary stage of diseases such as diabetes and hypertension. These diseases can be controlled through medication, yet the consumption of functional foods (FF) may be one complementary treatment option. Ingredients for these FF could be the pyrodextrin and enzymatically resistant maltodextrin (ERM) obtained from the native starch (NS) of M. cavendishin this study. OBJECTIVE: to evaluate the effects of modified banana starch on glycemic control and blood pressure in rats with high sucrose diet (HSD). METHODS: we utilized 25 male Wistar rats 20 of which received a HSD and five were fed a normal diet and purified water (PW) for 12 weeks. At the end of week 8, the rats fed a HSD were divided into four groups: positive control (PC), native starch (NS), pyrodextrin (PI), and enzymatically resistant maltodextrin (ERM). The negative control (NC) comprised the five rats fed PW. We evaluated the glucose tolerance test, blood pressure (BP), insulin levels, total cholesterol (TC), high-density lipoproteins (HDL), and triglycerides. RESULTS: differential scanning calorimetry and scanning electron microscopy of the modified starches demonstrated that the pyroconversion treatment did not visibly affect the NS granules, while ERM was modified by the action of alpha-amylase. Starch treatments reduced glucose, insulin, HOMA-IR, and BP in comparison with PC (p < 0.05). Glucose AUC (0-120 min) was also decreased after starch treatments with respect to PC (p < 0.05). CONCLUSION: NS and its modified products exerted beneficial effects on glycemic control, lipid metabolism, and BP in obese rats fed a HSD. Although the modified starches presented lower resistance to digestion than NS, their expected properties were maintained. PMID- 29974768 TI - Dietary intake of pregnant adolescents cared for in primary health care units of a Brazilian urban municipality. AB - OBJECTIVE: to evaluate the adequacy of dietary intake and the anthropometric nutritional status of pregnant adolescents in the city of Niteroi, Rio de Janeiro, Brazil. METERIALS AND METHODS: forty-two adolescents (13-19 years of age), with single-fetus gestation, assisted in the public prenatal health care units between 2008-2014, participated in the study. Body mass index (BMI) was used to assess the nutritional status. Dietary intake was assessed by 24h dietary recalls on two days during a week and one during weekend. Basal metabolic rate was measured by indirect calorimetry and used to determine the energy requirements. Mixed effects models were used to assess dietary intake over the gestational weeks (random effect) and BMI. RESULTS: mean age (SD) of the pregnant women was 16.5 (1.5) years and the majority received allowance from a cash transfer federal program. Overall, 30.3% were overweight/obese pre-pregnancy and 16.7%, during pregnancy. Energy and protein intake adequacies decreased with increasing BMI and gestational week. There was adequate dietary intake of energy, protein, vitamin A and zinc and insufficient intakes of iron and calcium. There was excessive intake of sodium. CONCLUSION: pregnant adolescents living in underprivileged socio-economic environments assisted for prenatal care in primary health care units have adequate intakes of energy, protein, vitamin A and zinc. Pre-pregnancy overweight and high sodium intake are causes of concern due to the future implications for their health. The official Brazilian recommended criterion for anthropometric assessment in pregnancy of adolescents proved to be inadequate. PMID- 29974769 TI - [Improvement of the nutritional status and quality of life of cancer patients through a protocol of evaluation and nutritional intervention]. AB - OBJECTIVE: to apply a protocol that facilitates the detection of malnutrition in cancer patients during their treatment of radiotherapy or chemotherapy, selecting those that could benefit from a specific nutritional intervention. METHODOLOGY: malnutrition was assessed with the Malnutrition Screening Tool (MST). Patients at malnutrition risk were evaluated with patient generated subjective-global assessment (PG-SGA) and a subgroup of the sample studied was also assessed with a quality of life (CV) using the EORTC QLQ-C30 questionnaire. RESULTS: from 222 patients, risk of malnutrition was observed in 126 (56.7%). The PG-SGA shows an initial prevalence of malnutrition of 69.2% (61.7% moderately malnourished and 7.5% severe malnutrition) and a mean weight loss of -10.27 kg. In the last evaluation (+12 months), the percentage of malnutrition or risk was significantly reduced to 23.5% and the mean weight loss decreased to -7.1 kg. During follow-up, the scores of the EORTC QLQ-C30 questionnaire improved, especially at three months on the diarrhea scale (p = 0.037), at six months on the pain scale (p = 0.009), and at 12 months on the pain (p = 0.026), nausea and vomiting (p = 0.002), dyspnea (p = 0.016), loss of appetite (p = 0.002) and constipation (p = 0.05) scales. CONCLUSION: the protocol has been effective in improving the nutritional status and quality of life of cancer patients with partial recovery of lost weight. PMID- 29974770 TI - Hydration habits before, during and after training and competition days among amateur basketball players. AB - BACKGROUND: fluid intake before, during and after exercise is the most important way to replace water lost during exercise and avoid dehydration. AIM: to assess fluid intake habits before, during and after exercise in amateur basketball players on both training and competition days. METHODS: one hundred and eighty three amateur basketball players (87 women and 96 men, 19-29 years old) were interviewed. Data was obtained from a drinking habits questionnaire. RESULTS: overall, 20.8%, 5.5% and 2.7% of subjects did not drink before, during and after exercise on training days, respectively; 17.5% of subjects did not drink before exercise on competition days. Water was the preferred beverage before, during and after exercise on both training and competition days, with fruit juice being the second most consumed beverage before exercise. All subjects also drank fizzy drinks and other beverages during exercise on competition days. According to the recommendations, good hydration habits were found in 54.6%, 74.2% and 76.5% of subjects before, during and after training days, respectively. CONCLUSIONS: most amateur basketball players drink before, during and after exercise on both training and competition days, but not all of them complied with the hydration recommendations. PMID- 29974771 TI - Depression and food consumption in Mexican college students. AB - INTRODUCTION: depression is frequently accompanied by overeating and a preference for certain foods that may consequently lead to weight gain. OBJECTIVES: a) to determine the prevalence of depression and the consumption of unhealthy food in first-year college students; and b) to analyze the association between depression score and food consumption frequency. METHODS: a cross-sectional study was carried out in 1,104 freshman students, 40.3% men and 59.7% women, at a public university in Mexico City. The 20-item depression scale (CES-D) and Food Frequency Questionnaire were applied to measure depressive symptoms and food consumption. Logistic regression analysis was carried out for food consumption frequency and CES-D depression score grouped in quartiles. RESULTS: the prevalence of depression symptoms was 18.2% in men and 27.5% in women (p < 0.001). A considerable proportion of the students reported poor eating habits: consumption of fried food (30.3%), sweetened drinks (49.0%) and sugary food (51.8%) 2-7 times/week; and less than half the students practiced vigorous physical activity (39.7%). In women, a higher depression score was associated with a higher frequency of consumption of fast food (OR = 2.08, p = 0.018), fried food (OR = 1.92, p = 0.01) and sugary food (OR = 2.16, p = 0.001), and a lower frequency of physical exercise (< 75 min/week; OR = 1.80, p = 0.017). In men, no association was observed between depression score and food consumption variables. An association was observed between depression and low exercise frequency (OR = 2.22, p = 0.006). CONCLUSIONS: women vulnerable to depression may use food to cope with negative mood states. Therefore, institutional health promotion and nutritional education programs should include adequate emotion and stress management. PMID- 29974773 TI - Score of "eat-ability" as a predictor of malnutrition in patients with gastrointestinal tract cancer: a pilot study. AB - INTRODUCTION: decreased food intake, loss of appetite, and dysphagia are relevant symptoms in patients with gastrointestinal tract (GIT) cancer. However, these symptoms have been isolated or indirectly assessed when comprising quality of life questionnaires or risk assessment tools. OBJECTIVE: to determine whether a combined assessment of dysphagia, appetite and food intake may be used as a parameter of eat-ability (food capacity) in patients with GIT cancer. METHODS: a cross-sectional pilot study on 41 patients with GIT cancer were evaluated using a score for "eat-ability"(SEA) as compared to the Patient Generated Subjective Global Assessment(PG-SGA), anthropometry and laboratory profile. RESULTS: eleven (27%) patients had full eat-ability(SEA 0), three (7%) had moderate (SEA 1) and 27 (66%) had poor (SEA >= 2) eat-ability, which were significantly different, between upper and lower GIT tumors (p <= 0.05). By ROC curves, SEA 1 and >= 2 showed an 80% for both sensibility (95% CI: 0.48-0.95) and specificity (95% CI: 0.63-0.91) to PG-SGA (A and B), with an area under curve (AUC) of 0.79 (95% CI: 0.64-0.95) (p = 0.006). Patients with SEA >= 2 had a significant weight loss within three (p = 0.001) and six months (p < 0.001) when compared to patients with SEA 0 and 1. Mortality was also significantly higher (p = 0.01) among patients with critical food capacity by SEA (77%) in severely malnourished patients by PG-SGA (84%). CONCLUSION: by combining food intake, dysphagia and appetite assessment altogether, a reliable score clearly demonstrated compromised eating capacity affecting nutritional status of patients with GIT tumors at a higher risk for death. PMID- 29974772 TI - Serum zinc and copper concentrations and ratios in cirrhotic patients: correlation with severity index. AB - INTRODUCTION: zinc (Zn) and copper (Cu) are essential elements that play an important role in the whole-body metabolism and seems to have a role in the pathogenesis of the liver cirrhosis (LC). OBJECTIVE: the aim of this study is to evaluate the influence on serum Zn and Cu concentrations and Cu/Zn ratios of different factors like cirrhosis, severity index, age, sex, death, and disease complications. METHODS: ninety-three patients with LC were included. The severity index was measured by the Child-Pugh index (CPI). RESULTS: mean serum Cu concentration and Cu/Zn ratio were significantly higher in patients than in healthy controls (p <= 0.001). Serum Zn concentrations were reduced with higher cirrhosis severity (specifically low vsmedium severity CPI, p < 0.05). Mean serum Cu concentration was significantly higher in the oldest (> 50 years) versusyoungest (< 30 years) age group. Serum Zn concentrations were lower and Cu/Zn ratios were higher (p < 0.05) in patients that died. Among complications, significantly higher serum Zn concentrations were found in cirrhotic patients with ascites than in those with bacteremia-sepsis. CONCLUSIONS: levels of Zn, Cu and Cu/Zn ratio are affected by the presence of hepatic cirrhosis. Serum Zn concentrations are lower with higher severity of cirrhosis, while those for Cu are increased in cirrhotic patients. We can observe that the presence of elevated Cu/Zn ratios in these patients might be useful in the evaluation of suspected liver cirrhosis. PMID- 29974774 TI - Food neophobia, Mediterranean diet adherence and acceptance of healthy foods prepared in gastronomic workshops by Spanish students. AB - INTRODUCTION: food neophobia can affect dietary variety and hedonic acceptance due to rejection of healthy foods. OBJECTIVE: to evaluate the impact of dietary neophobia on adherence to the Mediterranean diet and on the hedonic acceptance of healthy foods made in gastronomic workshops by schoolchildren. METHODOLOGY: descriptive cross-sectional study of Primary (8-11) and Secondary (12-18) schoolchildren from Murcia, Spain, participating in gastronomic workshops, where two recipes were prepared and tasted (vegetables + blue fish and fruits). Food neophobia (FN) and adherence to the Mediterranean diet (KIDMED) were identified and each participant assessed the acceptance of each recipe using a hedonic scale (seven points). RESULTS: a total of 1,491 students (49.5% girls) participated in the study; 13.5% were neophobic and 61.1% presented optimal diet quality. A linear inverse relationship between the degree of neophobia and the quality of the diet (rho[rho] = -0.31, p = 0.001) was found. High adherence to the Mediterranean diet was associated with lower neophobia and better hedonic scores, compared to intermediate or low adhesions (p < 0.0001). Neophobic schoolchildren presented significantly worse results in vegetable consumption, especially at the Secondary level, and in the acceptance of healthy preparations (p < 0.05). A good acceptance of the prepared preparations was associated with the usual adequate consumption of fruits, vegetables, fish and legumes. CONCLUSION: food neophobia affects the adherence to the Mediterranean diet and the acceptance of healthy foods elaborated in gastronomic workshops by Spanish schoolchildren. PMID- 29974775 TI - Salt content in bread in Spain, 2014. AB - INTRODUCTION: excess salt intake is associated to the risk of cardiovascular diseases. Bread is one of the foods that contributes the most salt to the diet in Spain. It is important to monitor the salt content of bread. OBJECTIVE: to quantify the amount of salt in bread in Spain in 2014, and to compare it to the amount of salt in 2008. METHODS: this cross-sectional study was conducted in Spain in 2014, and 1,137 loaves of bread (three types: barra, a Spanish style, similar in shape to a baguette; baguettes and wholemeal) were purchased at bakeries with and without on-site workrooms and at supermarkets in all of Spain's autonomous communities. Salt content (g/100 g bread) was estimated by determining total sodium. In one subsample, mean salt content was estimated by determining chlorides; it was compared to previous data of 2008 salt content (chloride determination). RESULTS: the mean salt content was 2.08 g/100 g (SD: 0.32) with a minimum value of 0.30 and a maximum of 3.33. The mean salt content was similar in barraand baguette-type breads (2.09 g/100 g) and somewhat lower in wholemeal. The mean salt was 2.07 g/100 g in breads made with fresh dough and 2.12 g/100 g in breads made with frozen dough. The mean salt content (chlorides) was 1.64 g/100 g (SD: 0.42) in 2014 and 1.63 g/100 g (SD: 0.37) in 2008. This was not a significant difference (p = 0.428). CONCLUSIONS: the amount of salt in common bread in Spain remains stable from 2008. PMID- 29974776 TI - [Progression of renal function in patients with chronic kidney disease on a low protein diet supplemented with aminoacids and ketoanalogues]. AB - INTRODUCTION: chronic kidney disease (CKD) is a public health problem. Low protein diets supplemented with ketoacids and essential aminoacids have proved effective at different CKD stages. AIM: to assess the progression of renal failure in adult patients with CKD stages 3b and 4 receiving a protein-controlled diet supplemented with aminoacids and ketoanalogues. METHODS: retrospective, descriptive intervention study. The nutritional intervention consisted of a protein/calorie intake of 0.4-0.6 g/kg/day and 30-35 kcal/kg/day plus a tablet of ketoanalogues (Ketosteril(r))/5 kg weight. We assessed nutritional condition, glomerular filtration (GF) and creatinine, urea and albumin levels at 0, 3, 6, 9 and 12 months. SPSS version 18 was used for data statistical analysis. RESULTS: thirty-three patients were studied (67% male; mean age 59.7 years, r: 24-87). Protein/calorie intake was 0.55 +/- 0.20 g/kg/day and 34 +/- 4.51 kcal/kg/day. Ketosteril(r) intake was 11.87 tablets/day (r: 9-14). Initial GF was 24.97 +/- 6.64 ml/min/1.73 m2, showing a significant increase between three and 12 months (25.51 +/- 8.57 and 29.26 +/- 10.33 ml/min/1.73 m2; p = 0.006). Urea nitrogen decreased significantly at six months compared with the initial level (p < 0.005). Body mass index did not change significantly (initial, 26. 63 +/- 4.08 kg/m2; after a year, 26.78 +/- 3.98 kg/m2). Initial and final albumin levels were 3.53 +/- 0.64 g/l and 4.00 +/- 0.53 g/l, respectively (p = 0.79). CONCLUSION: a low-protein diet supplemented with ketoanalogues administered to patients with CKD stages 3b and 4 preserved nutritional condition and mineral balance, improved GF significantly and decreased urea levels. PMID- 29974777 TI - [Perception and distortion of body image in Spanish women dancers based on academic year and age]. AB - INTRODUCTION: young dancers are at a higher risk of developing body image distortion. OBJECTIVE: to analyze body image perception and distortion in dancer students based on academic year and age. METHODS: two hundred and ninety-eight women dancers between 11 and 24 years, who were studying between the 1st and 6th year of Professional Program, were evaluated. Dancers completed the "silhouette scale for adolescents" in order to determine their perception of the female and male figures, their perceived and ideal images, and the distortion, dissatisfaction and real-ideal indexes. RESULTS: participants were more severe with male figures than with female ones. Dancers of the lower courses, especially from the 1st year, and youngest showed the highest values in distortion and real ideal indexes. They thought that they look like thicker than they are, but their ideal figure was thicker than they really were (p < 0.001). In relation to the dissatisfaction index, all dancers desired to be thinner, without differences based on academic year or age (p > 0.05). Ten dancers showed a high risk to develop an eating disorder. CONCLUSIONS: dancers of the initial courses and youngest have a tendency to see themselves fatter than they are. They want to look thinner, but they are thinner than they would like to be. This could act as a trigger for developing body dissatisfaction. PMID- 29974778 TI - Cachexia in hospitalized patients with heart failure. AB - AIMS: to evaluate cachexia prevalence in hospitalized heart failure (HF) patients by comparing two methods for diagnosing cachexia and alterations in each component involved in its diagnosis. METHOD: a cross-sectional study, involving patients diagnosed with HF and admitted between April and August 2015 to a public hospital in the Brazilian Northeast. Cardiac cachexia was defined using the Cachexia Consensus criteria (Washington, DC), which defines cachexia as >= 5% unintentional weight loss in the previous 12 months or a body mass index (BMI) <= 20.0 kg/m2, in combination with at least two of the following criteria: fatigue, anorexia, low hand grip strength, low muscle strength, and biological alterations (hemoglobin < 12 g/dl, albumin < 3.2 g/dl, and PCR >= 5 mg/dl), and for comparative purposes a diagnostic criterion which considers weight loss >= 6% in at least six months as a cachexia diagnosis. RESULTS: one hundred and fifty-six individuals were evaluated, with an average age of 59.1 (+/- 15.3). Cachexia prevalence was 37.2% and associated with a low BMI (p < 0.001), low muscle mass (p < 0.001), reduced ejection fraction (p = 0.005), hypoalbuminemia (p = 0.040), and anemia (p = 0.002). Among the diagnostic components, the greatest alterations were observed in relation to fatigue (88.2%), anorexia (72.1%) and weight loss (61.7%). CONCLUSIONS: the high prevalence of diagnosed cachexia indicates that this condition is common and is associated with poor nutritional state and clinical condition. PMID- 29974779 TI - Malnutrition is a key prognostic factor related to high mortality-rate in patients with severe alcoholic hepatitis. AB - BACKGROUND AND AIM: comparatively with European or North-American populations, severe alcoholic hepatitis has a high mortality rate in Mexican population, becoming as high as 50 to 81% in those classified as ABIC B or C; this is true even when they receive specific therapy with steroids or pentoxifylline. The aim of this study was to know which clinical factors are related to early mortality (first 30 days) in Mexican patients with severe alcoholic hepatitis. SUBJECTS AND METHODS: this was a retrospective cohort study that included patients with severe alcoholic hepatitis, defined by a Maddrey's discriminant function >= 32, treated at a tertiary care center in a period of five years (2010 to 2015). RESULTS: seventy-six patients were included, 72 (94.7%) were males, mean age was 43 +/- 9.1 year-old, and 58 (76.3%) had also cirrhosis. According to the subjective global assessment (SGA), 38 (50%) had severe malnutrition, 22 (28.9%) were at risk of malnutrition, and 16 (21.1%) were well-nourished. At 30 days, 46 patients (60.5%) died. In the multivariate analysis, only the presence of severe malnutrition was associated with 30-day mortality: OR = 6.4; 95% CI: 1.9-22.1; p = 0.003. CONCLUSIONS: the nutritional status seems to be a cardinal prognostic factor associated with early mortality (first 30 days). Malnutrition can explain the high mortality rate observed in Mexican patients with severe alcoholic hepatitis. PMID- 29974780 TI - Maximal expiratory pressure predicts mortality in patients hospitalized in medical and surgical wards. AB - BACKGROUND: the prognostic value of maximal inspiratory and expiratory pressures on functional capacity and mortality of hospitalized patients are not well established. AIM: to evaluate the prognostic value of respiratory pressures in hospitalized patients. METHODS: patients admitted to a general hospital in Santiago-Chile were prospectively studied. Within 48 hours of admission, handgrip strength and inspiratory and expiratory pressures were measured. Subjective global assessment of nutritional status (SGA) was determined and Apache II score was calculated. Functional status was assessed using the Karnofski index. Patients were followed for a period of 30 days. Mortality and decline in functional capacity, defined as a reduction in at least two stages of the Karnofski index were determined. Normal values for handgrip strength and respiratory pressures were obtained in 366 healthy subjects aged 20 to 89 years, thus the results obtained in patients were expressed as age and sex matched z scores. RESULTS: one hundred and eight patients were recruited and 18 had to be excluded. Thus, 90 patients aged 58 +/- 16 years (46 females) were studied. During the observation period, six patients died and nine experienced a decline in functional status. Patients who died had significantly lower maximal inspiratory and expiratory pressures, hand grip strength and worse SGA. Logistic regression analysis only accepted maximal expiratory pressure expressed as z score as a predictor of mortality. In addition, it was the only significant predictor of death or functional decline. CONCLUSIONS: maximal expiratory pressure on admission was a predictor of death or functional decline at 30 days. PMID- 29974781 TI - [Comparative study of the variables of physical fitness and health among young athletes and sedentary males]. AB - INTRODUCTION: today, the practice of physical activity during adolescence brings important physical-health benefits that help develop a future well-being in later life. OBJECTIVES: the objective of this comparative study was to evaluate the physical condition, body composition and cardiorespiratory capacity among young athletes and sedentary people of the Autonomous Community of Extremadura (Spain). METHODS: two hundred and twenty-five male subjects, aged between 12 and 18 years, were divided into two groups: 175 athletes, divided into aerobic group (AEG), anaerobic group (ANAEG) and mixed sports group (MG); and 50 sedentary (SG) or control group. Their respiratory capacity (forced expiratory volume [FEV], peak expiratory flow [PEF], vital capacity [VC], maximum voluntary ventilation [MVV]) and body composition were assessed. They also performed the "Forest Service" step test by finding the VO2max. Also, the heart rate (HR) was recorded before the step, the maximum heart rate during the test and the HR in the subsequent recovery, as well as pre and post-test blood pressure. RESULTS: there were significant differences in body composition, blood pressure, heart rate and respiratory capacity in relation to athletes compared to the control group (p < 0.05). CONCLUSIONS: physical activity provides benefits in aspects such as body composition, and cardio-respiratory function. PMID- 29974782 TI - Hyperlipidemia during gestational diabetes and its relation with maternal and offspring complications. AB - INTRODUCTION: lipid profile suffers adaptive changes during pregnancy due to estrogen stimulation and insulin resistance. Several relations have been suggested between maternal lipid profile, glucose tolerance, endothelial cell dysfunction and long-term cardiovascular risk; the effects of maternal lipid profile metabolism in fetal growth are also inconclusive. Since a regular evaluation and follow-up of lipid profile during pregnancy has not been established yet, we aimed to evaluate the incidence of dyslipidemia in patients with gestational diabetes (GDM) and analyze some putative relations with pregnancy, offspring complications and maternal metabolic syndrome parameters determined three and twelve months after delivery. PATIENTS AND METHODS: two hundred and fifty patients with GDM were included. Full medical history, offspring characteristics, lipid profile and maternal variables of metabolic syndrome were evaluated during pregnancy and three- and twelve-months after delivery. The incidence of dyslipidemia during pregnancy was determined using two different classifications. RESULTS: lower plasma HDL and hypertriglyceridemia were the most current disorders; prematurity or birth weight were not correlated with dyslipidemia. During pregnancy, the lipid-related parameter that better predicted the risk of offspring macrosomia was triglycerides (TG). High TG three months after delivery were correlated to macrosomia and metabolic syndrome variables before and after pregnancy (three and twelve months). CONCLUSIONS: TG during pregnancy is the parameter that best predicts the risk of macrosomia and is related to increased metabolic risk after delivery. The evaluation of lipid profile and other metabolic variables during pregnancy and after delivery is required to early diagnose cardiovascular risk factors, especially in high risk population. PMID- 29974783 TI - [Validity of neck circumference as a marker of adiposity in children and adolescents, and in adults: a systematic review]. AB - The objective of this systematic review was doing a search of the validity of neck perimeter as a marker of adiposity in children and adolescents as well as in adults. A systematic search for articles published before June 30, 2017 was conducted using the PubMed and Web of Science databases. Original studies, in Spanish or English, were searched to analyze the association between neck circumference and any other marker of adiposity. MeSH (Medical Subject Heading) categories were used in PubMed. The search criteria used were: (("neck circumference" or "neck diameter") AND ("Body Composition" [Mesh] OR "Anthropometry" [Mesh])). This search was repeated in Web of Science. We identified 494 studies, of which 47 were finally selected for this review. From the total, 66% of studies (16 in children and adolescents and 15 in adults) only specify that there is a relationship between neck circumference and body mass index or waist circumference, waist/hip circumference ratio in children and adults. We also observed that neck circumference was directly associated with adiposity markers indirectly measured by reference methods such as computed tomography (CT) or dual-energy x-ray absorptiometry (DXA) in adults. Conversely, no studies were found in children and adolescents. In conclusion, neck circumference is associated with doubly-indirect markers of total and central fat mass in children and adolescents, while in adults it is associated with adiposity parameters measured with indirect and doubly-indirect methods. Further studies including methods that address the association between neck circumference and body composition analyzed using reference methods are required, especially in children and adolescents. PMID- 29974784 TI - Modulation of intestinal microbiota, control of nitrogen products and inflammation by pre/probiotics in chronic kidney disease: a systematic review. AB - Dysbiosis may favor the occurrence of inflammation and oxidative stress in chronic kidney disease (CKD). It has been suggested that the intake of pre/probiotics may control the progression of chronic kidney disease. Thus, the objective of this study was to systematically review the literature on the effects of pre/probiotic intake on the intestinal microbiota, control of nitrogen products, oxidative stress, and inflammation in CKD patients.The literature search was conducted on MEDLINE, LILACS, Cochrane Library of Clinical Trials, and Science Direct. After careful evaluation by the reviewers, ten potentially relevant articles were selected for this study. Based on previous studies, intake of prebiotics appears to have the following effects: increased bifidobacteria and lactobacillus counts; reduced formation of uremic toxin, p-cresol, and its serum concentrations; improved lipid profiles; reduced systemic inflammatory state and concentrations of oxidative stress markers. Similarly, consumption of probiotics can reduce blood urea and serum phosphate concentrations. Furthermore, an increase in fecal volume and intestinal Bifidobacteriumand a reduction in p cresol serum and blood urea concentrations were observed in response to symbiotic intake. These results suggest that consumption of pre/probiotics may modulate the intestinal microbiota, and promote the growth and metabolism of anaerobic bacteria by decreasing the production of uremic solutes, further causing oxidative stress and systemic inflammation in CKD patients. PMID- 29974785 TI - Intestinal adaptation in short bowel syndrome. What is new? AB - Short bowel syndrome (SBS) is a well-known cause of intestinal failure (IF) (1). SBS occurs after extensive resection of the small bowel (RSB) resulting in a bowel length of less than 150/200 cm. The colon may have been partially or completely removed. SBS patients experience severe water and nutrient malabsorption, so that they are often managed with parenteral nutrition (PN) to supplement their oral intake (2-4). A complete understanding of the pathophysiology of SBS and postoperative adaptations may allow identifying the spontaneous processes that compensate for the reduction in absorptive surface. A better knowledge of these adaptive mechanisms may help to improve the management of patient nutrition, to reduce the need for PN and to prevent D-encephalopathy episodes. This review focuses on the overall adaptations described in adult SBS patients but does not review pediatric cases. PMID- 29974786 TI - [Dissemination of clinical nutrition through societies and scientific journals. A meeting at the Spanish Royal Academy of Pharmacy>]. AB - This special article defines very briefly some central aspects of artificial nutrition as nutritional support in special situations in patients that are not able to maintain a sufficient and adequate digestive function to restore or maintain optimal nutritional status or in those who are malnourished or in the way to be. It also reviews the central aspects of a round table attended by executives of journals and scientific entities in the field of health and, in particular, of nutrition. The roundtable was organized under the auspices of a tribute to Dr. Jesus M. Culebras, in January 2018 at the headquarters of the Spanish Royal Academy of Pharmacy. Prof. Culebras was founder of the journal Nutricion Hospitalaria journal and architect of many achievements and initiatives of the Spanish Society of Enteral and Parenteral Nutrition of great importance for nutrition and artificial nutrition in Spain. During the workshop, the convenience of increasing collaboration between the scientific journals Nutricion Hospitalaria, Farmacia Hospitalaria, Anales de la Real Academia Nacional de Farmacia and Journal of Negative and No Positive Results and the entities they represent was highlighted, especially concerning the framework of clinical nutrition and, particularly, artificial feeding, insisting on the need to initiate a series of meetings in the very near future with the purpose of delimiting competencies and rights, and taking joint positions in publications, and consensus agreements that would guarantee the dissemination and visibility of this issue of enormous importance for health. PMID- 29974787 TI - [Obesity treatment with liraglutide in a patient with Prader-Willi syndrome: a case report]. AB - BACKGROUND: Prader-Willi syndrome (PWS) is a major cause of syndromic obesity, caused by deletions on chromosome 15q11-q13. It is characterized by neonatal hypotonia, difficulty in feeding with low birth-weight and subsequent development of hyperphagia, behavioral disorders and obesity. Treatment options for weight control in those patients is limited and there are controversies for a surgical approach. CASE REPORT: we present the case of a patient with PWS who achieved weight loss and control through the use of liraglutide, nutritional therapy and physical activity. DISCUSSION: the treatment of obesity in patients with PWS is challenging and requires an adequate nutritional approach combined with psychological therapy. In those patients that persist with uncontrolled appetite, medications such as metformin or GLP-1 analogs can be used. PMID- 29974789 TI - [Erratum]. PMID- 29974788 TI - [Nutritional management of functional chronic diarrhea associated to malnutrition with peptide diet: a case report]. AB - BACKGROUND: functional bowel disorders are characterized by an absence of structural or biochemical damage, but can lead to chronic diarrhea and intestinal malabsorption. If not properly treated, they predispose to a state of malnutrition that, depending on the underlying pathologies, could affect the evolution of other concomitant diseases. CASE REPORT: the relevance of this case stems from the fact that our 43-year-old patient, with multiple comorbidities, with progressive weight and muscle mass loss, after five years of inefficiency in the treatment of chronic diarrhea, achieves, on a peptide enteral formula basis, a good nutritional status and quality of life, which finally leads to the control of the chronic diarrhea and malnutrition. DISCUSSION: in the unintentional weight loss caused by long-term functional diarrhea, the choice of a peptide diet may have a fundamental role for a satisfactory patient's progress. PMID- 29974790 TI - Study of dynamic of chicken infectious anaemia virus infection: which sample is more reliable for viral detection? AB - Chicken infectious anaemia virus (CIAV) is a widely distributed immunosuppressive agent. SPF flocks and eggs used for vaccine production and diagnostics must be CIAV-free. Detection of CIAV infection in SPF flocks involves primarily serology or other invasive methods. In order to evaluate different types of samples for rapid detection of CIAV infection, a trial was conducted in serologically negative broiler breeder pullets vaccinated with a commercial live-attenuated CIAV vaccine. Controls and vaccinated groups were sampled before and after vaccination. Invasive and non-invasive samples were used for CIAV DNA detection by real-time PCR. Seroconversion occurred at 14 days post-inoculation (DPI) in the vaccinated group, whereas CIAV genome was detected by qPCR at 7 DPI in both invasive and non-invasive samples. Only invasive samples remained qPCR positive for CIAV DNA by 21 DPI despite seroconversion of the chickens. PMID- 29974791 TI - Blood urea nitrogen and risk of insulin use among people with diabetes. AB - Laboratory evidence suggests that urea suppresses insulin secretion and sensitivity. Emerging epidemiologic evidence suggests that higher levels of urea are associated with increased risk of incident diabetes mellitus. However, whether elevated levels of blood urea nitrogen are associated with increased risk of insulin use among people with diabetes is unknown. We used the Department of Veterans Affairs databases to assemble a cohort of 197,994 incident users of non insulin hypoglycaemic agents with an estimated glomerular filtration rate > 60 mL/min per 1.73 m2 and followed them for a median of 4.93 years. Spline analyses suggested that the relationship between blood urea nitrogen and the risk of insulin use was neutral below blood urea nitrogen level of 25 mg/dL and increased exponentially with blood urea nitrogen levels above 25 mg/dL. In survival models, compared to those with blood urea nitrogen ? 25 mg/dL, those with blood urea nitrogen > 25 mg/dL had an increased risk of insulin use (hazard ratio = 1.40; confidence interval = 1.30-1.50). The risk of insulin use was increased in models which accounted for haemoglobin A1c at time zero (hazard ratio = 1.39; confidence interval = 1.28-1.50) and as a time-varying variable (hazard ratio = 1.38; confidence interval = 1.28-1.50). Two-step residual estimation analyses showed that, independent of the impact of estimated glomerular filtration rate, every 10 mg/dL increase in blood urea nitrogen concentration was associated with increased risk of insulin use (hazard ratio = 1.16; confidence interval = 1.12-1.20). Our results suggest that, among people with diabetes, higher levels of blood urea nitrogen are associated with an increased risk of insulin use. PMID- 29974792 TI - Transendocardial CD34+ Cell Transplantation in Noncompaction Cardiomyopathy: First-in-Man Case Study. AB - Noncompaction cardiomyopathy is a rare congenital heart disorder characterized by an arrest of the myocardial compaction process. This results in the altered formation of coronary microvessels with a resulting decrease in myocardial perfusion. Transendocardial CD34+ cell transplantation has been shown to increase myocardial perfusion and function in patients with non-ischemic heart failure. In our first-in-man case study, we investigated the feasibility, safety and clinical effect of transendocardial CD34+ cell therapy in a patient with noncompaction cardiomyopathy. PMID- 29974793 TI - Human peripheral blood mononuclear cells enriched in endothelial progenitor cells via quality and quantity controlled culture accelerate vascularization and wound healing in a porcine wound model. AB - The transplantation of endothelial progenitor cells (EPCs) is used to promote wound angiogenesis. In patients with chronic wounds and accompanying morbidities, EPCs are often compromised in number and function. To overcome these limitations, we previously developed a quality and quantity controlled (QQ) culture system to enrich peripheral blood mononuclear cells (PBMNCs) in EPCs. To evaluate the wound healing efficacy of mononuclear cells (MNCs) harvested after QQ culture (QQMNCs), preclinical studies were performed on large animals. MNCs harvested from the blood of healthy human subjects were cultured in the presence of angiogenic cytokines and growth factors in a serum-free medium for 7 days. A total of 5 * 106 QQMNCs per full-thickness skin defect or control saline was injected into wounds induced in cyclosporine-immunosuppressed pigs. EPC colony-forming assays revealed a significantly higher number of definitive (partially differentiated) EPC colony-forming units in QQMNCs. Flow cytometry evaluation of QQMNC surface markers showed enrichment of CD34+ and CD133+ stem cell populations, significant reduction in CCR2+ cell percentages, and a greater than 10-fold increase in the percentage of anti-inflammatory M2-type macrophages (CD206+ cells) compared with PBMNCs. Wounds treated with QQMNCs had a significantly higher closure rate. Wounds were harvested, frozen, and sectioned at day 21 postoperatively. Hematoxylin and eosin staining revealed that the epithelization of QQMNC-treated wounds was more advanced than in controls. Treated wounds developed granulation tissue with more mature collagen and larger capillary networks. CD31 and human mitochondrial co-staining confirmed the presence of differentiated human cells within newly formed vessels. Real-time polymerase chain reaction (PCR) showed upregulation of interleukin 6 (IL-6), IL-10, and IL-4 in the wound bed, suggesting paracrine activity of the transplanted QQMNCs. Our data demonstrate for the first time that QQ culture of MNCs obtained from a small amount of peripheral blood yields vasculogenic and therapeutic cells effective in wound healing. PMID- 29974796 TI - Subchondral drilling for chondral flaps reduces the risk of total hip arthroplasty in femoroacetabular impingement surgery at minimum five years follow up. AB - INTRODUCTION: The best treatment of acetabular chondral flaps during surgery for femoroacetabular impingement (FAI) is unknown. We asked if subchondral drilling improves clinical and radiographic outcome and if there are factors predicting failure. METHODS: We treated 79 patients with symptomatic FAI and acetabular chondral flaps with surgical hip dislocation between January 2000 and December 2007. Exclusion of all patients with previous hip pathology or trauma resulted in 62 patients (80 hips). The chondral flap was slightly debrided in 43 patients/51 hips (control group). In 28 patients/29 hips (study group), additional osseous drilling was performed. 4 patients (5 hips, 6%) were lost to follow-up. Mean follow-up was 9 years (5-13 years). The groups did not differ in demographic data, radiographic parameters or follow-up. Clinical outcome was assessed with the Merle d'Aubigne score, modified Harris Hip Score and University of California Los Angeles activity score and progression of osteoarthritis with the Tonnis grade. RESULTS: No patient underwent conversion to total hip arthroplasty (THA) in the drilling group compared to 7 patients (8 hips, 16%) in the control group (p = 0.005); in the remaining hips, clinical scores and progression of Tonnis grade did not differ. Increased acetabular coverage, age and body mass index were univariate predictive factors for conversion to THA. No drilling was as an independent predictive factor for conversion to THA (hazard ratio 58.07, p = 0.009). CONCLUSION: Subchondral drilling under acetabular chondral flaps during surgical treatment of FAI is an effective procedure to reduce the rate of conversion to THA. PMID- 29974797 TI - Shell-Shock and Medical Culture in First World War Britain. PMID- 29974798 TI - Malaysian Team Awarded the WHO Dr. Lee Jong-Wook Memorial Prize for Public Health. PMID- 29974799 TI - Stereoselective synthesis of 4beta-acyloxypodophyllotoxin derivatives as insecticidal agents. AB - As our ongoing work on research of natural-product-based insecticidal agents, some 4alpha/beta-acyloxypodophyllotoxin derivatives were synthesized, and were evaluated against the pre-third-instar larvae of B. mori, A. dissimilis and M. separate in vivo at the concentration of 1 mg ml-1, respectively. Among all derivatives, compounds 2 g, h and 4c, d showed more promising insecticidal activities than their precursors - podophyllotoxin and epipodophyllotoxin. Furthermore, derivatives 2 g, h and 4c, d exhibited more relative amicable activities than their precursors - podophyllotoxin and epipodophyllotoxin. This results indicated that 4beta-acyloxy moiety in the podophyllotoxin derivatives was significant for obtaining the more potent compounds. PMID- 29974800 TI - Functional Significance of the Excitatory Effects of GABA in the Suprachiasmatic Nucleus. AB - Over 90% of neurons within the suprachiasmatic nucleus (SCN) express gamma aminobutyric acid (GABA). Although GABA is primarily an inhibitory neurotransmitter, in vitro studies suggest that the activation of GABAA receptors (GABAAR) elicits excitation in the adult SCN. The ratio of excitatory to inhibitory responses to GABA depends on the balance of chloride influx by Na+-K+ Cl- cotransporter 1 (NKCC1) and chloride efflux by K+-Cl- cotransporters (KCCs). Excitatory responses to GABA can be blocked by inhibition of the inward chloride cotransporter, NKCC1, with the loop diuretic bumetanide. Here we investigated the role of NKCC1 activity in phase shifting the circadian pacemaker in response to photic and nonphotic signals in male Syrian hamsters housed in constant darkness. In the early subjective night (CT 13.5), injection of bumetanide into the SCN reduced light-induced phase delays. However, during the late subjective night (CT 19), bumetanide administration did not alter light-induced phase advances. Injection of bumetanide during the subjective day (CT 6) did not alter the phase of free-running circadian rhythms but attenuated phase advances induced by injection of the GABAAR agonist muscimol into the SCN. These data support the hypothesis that the excitatory effects of endogenously released GABA contribute to the ability of light to induce phase delays, thereby contributing to the most important function of the circadian system, its entrainment with the day-night cycle. Further, the finding that bumetanide inhibits the phase-advancing effects of muscimol during the subjective day supports the hypothesis that the excitatory responses to GABA also contribute to the ability of nonphotic stimuli to phase shift the circadian pacemaker. PMID- 29974801 TI - Spontaneous remission in large-vessel vasculitis: Takayasu arteritis and paraneoplastic disorder associated with thymic carcinoma. PMID- 29974802 TI - Radiostereometric analysis using clinical radiographic views: Validation with model-based radiostereometric analysis for the knee. AB - Radiostereometric analysis is a sophisticated radiographic technique with high measurement accuracy. In order to improve the accessibility of radiostereometric analysis for clinical use, a modified radiostereometric analysis procedure has been previously proposed that enables clinical radiographic views to be used for radiostereometric analysis. It has been successfully validated for its application to the hip wear study with the conventional bead-based radiostereometric analysis environment using computed radiography. In this study, we describe the implementation and validation of this technique for the knee study with the model-based radiostereometric analysis environment using digital radiography. A knee-joint phantom with 6 degrees of freedom was examined, and the bias and repeatability/reproducibility of the modified radiostereometric analysis approach were investigated following the newly updated ASTM recommendations. The bias parameters (mean +/- 95% confidence interval) ranged from 0.008 +/- 0.003 mm to 0.027 +/- 0.006 mm for translation and from 0.014 degrees +/- 0.007 degrees to 0.040 degrees +/- 0.020 degrees for rotation. The repeatability standard deviation ranged from 0.004 to 0.020 mm for translation and from 0.005 degrees to 0.015 degrees for rotation. The 95% repeatability limit ranged from 0.011 to 0.055 mm for translation and from 0.014 degrees to 0.041 degrees for rotation. The reproducibility standard deviation ranged from 0.004 to 0.023 mm for translation and from 0.006 degrees to 0.040 degrees for rotation. The 95% reproducibility limit ranged from 0.012 to 0.063 mm for translation and from 0.016 degrees to 0.112 degrees for rotation. The modified procedure allows routine clinical radiographs to be used for radiostereometric analysis, which provides the possibility of adding quantitative measurements to current patient registries. PMID- 29974803 TI - Gamification of nutrition: A preliminary study on the impact of gamification on nutrition knowledge, attitude, and behaviour of adolescents in Nigeria. AB - BACKGROUND:: In Nigeria and many parts of sub-Saharan Africa, the availability of foods that are high in salt, sugar, and saturated fat is steadily increasing. This has led to an increase in the consumption of such foods among Nigerians, particularly among adolescents. AIM:: This pilot study was undertaken to understand whether, and how, gamification of nutrition can have an impact on addressing the problem of unhealthy eating among Nigerian adolescents. METHODS:: Gamification of nutrition through board games, clubs and vouchers was introduced in three secondary schools in Abuja, Nigeria over a span of three to four months. Semi-structured focus groups were conducted with grade 11 and 12 students in the three secondary schools. Participants were asked about their perceptions of the intervention and how it influenced their eating behaviour, attitudes and knowledge about nutrition. RESULTS:: A total of 31 students participated in four focus groups. Participants reported that the intervention shifted their perceptions and preferences, leading them to alter their behaviour by incorporating more nutritious foods (such as fruits and vegetables) into their diet and engaging in more physical activity. Five themes emerged from the analyses: improved eating behaviour; increased physical activity; improved overall well-being; increased nutrition knowledge; and influencing others. CONCLUSIONS:: The results from the focus groups suggest that gamification of nutrition can lead to improvements in dietary behaviour among adolescents over the short-term. More studies are needed to evaluate the long-term effects of nutrition interventions that use gamification techniques. PMID- 29974804 TI - Expertise, advocacy and activism: A qualitative study on the activities of prostate cancer peer support workers. AB - Peer support workers are now working with patients in a variety of settings, coming into close contact and even work alongside health professionals. Despite the potentially influential position peer support workers hold in relation to those engaged in support activities, their role, duties and their relationship to peers and health professionals lack clarity and is often defined by other actors. This study explores how peer support workers interpret and define the activities, responsibilities and knowledge associated with their work. Using methods of membership categorisation analysis, we analysed interview materials generated by conducting individual semi-structured interviews during the autumn of 2016 with prostate cancer peer support workers ( n = 11) who currently volunteer as support workers in Finland. Although the peer support workers acknowledged the psychosocial aspects of the work, we argue that their interpretations extend far beyond this and encompass expertise, advocacy and activism as central features of their work. These can be used to strengthen their position as credible commentators and educators on issues relating to cancer and men's health; raise awareness and represent the 'patient's voice' and attempt to influence both policy and clinical practice. These findings suggest that by categorising their work activities in different ways, voluntary sector actors such as peer support workers can attempt to portray themselves as legitimate authorities on a range of issues and influence decision-making ranging from individual level treatment decisions all the way to health policy. PMID- 29974805 TI - A two-step procedure for coupling development and usage of a pair of human neck models. AB - Both finite element models and multi-body models of human head-neck complex had been widely used in neck injuries analysis, as the former could be used to generate detailed stress strain information and the later could generate dynamic responses with high efficiency. Sometimes, detailed stress and strain information were hoped to be obtained more efficiently, but current methods were not effective enough when they were used to analyze responses of human head neck complex to long duration undulate accelerations. In this paper, a two-step procedure for 'parallel' development and 'sequential' usage of a pair of human head neck models was discussed. The pair of models contained a finite element model and a multi-body model, which were developed based on the coupling 'parallel' procedure using the same bio-realistic geometry. After being validated using available data, the pair of human neck models were applied to analyze biomechanical responses of pilot's neck during arrested landing operation according to the 'sequential' procedure, because typical sustained undulate accelerations usually appeared during such processes. The results, including both kinematic and detailed biomechanical responses of human head-neck complex, were obtained with preferable efficiency. This research provided an effective way for biomechanical analysis of human head neck responses to sustained undulate accelerations. PMID- 29974806 TI - Nanotribological response of a-C:H coated metallic biomaterials: the cases of stainless steel, titanium, and niobium. AB - Background Wear and corrosion have been identified as two of the major forms of medical implant failures. This study aims to improve the surface, protective and tribological characteristics of bare metals used for medical implants, so as to improve scratch resistance and increase lifetime. Methods Hydrogenated amorphous carbon (a-C:H) films were deposited, using plasma enhanced chemical vapor deposition (PECVD), on stainless steel (SS), titanium (Ti) and niobium (Nb) metal plates. Nanomechanical and nanotribological responses were investigated before and after a-C:H deposition. Film thickness and density were quantified through X ray reflectivity, and surface morphology before and after deposition were measured using atomic force microscopy, whereas the tribomechanical characteristics were probed using instrumented indentation. Results and conclusions Films of approximately 40 nm in thickness and density of 1.7 g/cm3 were deposited. The a-C:H films reduce the roughness and coefficient of friction while improving the tribomechanical response compared with bare metals for Ti, SS and Nb plates. The very good tribomechanical properties of a-C:H make it a promising candidate material for protective coating on metallic implants. PMID- 29974807 TI - Relationship between alkaline phosphatase and impaired coronary flow in patients with ST-segment elevated myocardial infarction. AB - Objective Recent studies have shown that alkaline phosphatase (ALP) might play a negative role in clinical outcomes of patients with peripheral and coronary artery disease. This study aimed to investigate the relationship between serum ALP levels and coronary thrombolysis in myocardial infarction (TIMI) frame counts in patients with ST-segment elevated myocardial infarction undergoing primary percutaneous coronary intervention (PCI). Methods A total of 198 patients were enrolled in the current study. Serum ALP levels were measured in lithium-heparin plasma samples via a standardized, colorimetric enzyme assay. Coronary TIMI flow was evaluated by counting the number of cine frames that were required for contrast to reach a standardized distal coronary landmark in the culprit vessel. Results The Spearman correlation coefficient test showed strong positive relationships between coronary TIMI frame counts after primary PCI and serum ALP levels on admittance for the left anterior descending, circumflex, and right coronary arteries (r = 0.774, r = 0.831, and r = 0.730, respectively). Conclusion Elevated serum ALP levels appear to be a predictor of impaired coronary TIMI frame count in patients suffering from ST-segment elevated myocardial infarction. PMID- 29974808 TI - Mindfulness-based cognitive therapy for obsessive-compulsive disorder: Study protocol for a randomized controlled trial with functional magnetic resonance imaging and a 6-month follow-up. AB - This article presents a study protocol for a single-blind randomized controlled trial to test the efficacy and feasibility of mindfulness-based cognitive therapy. A total of 120 un-medicated Chinese obsessive-compulsive disorder patients will be randomized to the mindfulness-based cognitive therapy group, the selective serotonin reuptake inhibitor group or the psycho-education group for 11 sessions in 10 weeks. A range of scales for clinical symptoms and functional magnetic resonance imaging will be completed at baseline (week 0), mid intervention (week 4), post-intervention (week 10) and the 6-month follow-up (weeks 14, 22 and 34). The study will have relevance to decisions about treatment options for un-medicated obsessive-compulsive disorder patients. PMID- 29974809 TI - Influence of injectable microparticle size on cardiac progenitor cell response. AB - INTRODUCTION: Injectable scaffolds are emerging as a promising strategy in the field of myocardial tissue engineering. Among injectable scaffolds, microparticles have been poorly investigated. The goal of this study was the development of novel gelatin/gellan microparticles that could be used as an injectable scaffold to repair the infarcted myocardium. In particular, the effect of particle size on cardiac progenitor cell response was investigated. METHODS: Particles were produced by a water-in-oil emulsion method. Phosphatidylcholine was used as a surfactant. Particles with different diameter ranges (125-300 um and 350-450 um) were fabricated using two different surfactant concentrations. Morphological, physicochemical, and functional characterizations were carried out. Cardiac progenitor cell adhesion and growth on microparticles were tested both in static and dynamic suspension culture conditions. RESULTS: Morphological analysis of the produced particles showed a spherical shape and porous surface. The hydrophilicity of particle matrix and the presence of intermolecular interactions between gellan and gelatin were pointed out by the physicochemical characterization. A weight loss of 75 +/- 5 % after 90 days of hydrolytic degradation was observed. Injectability through a narrow needle (26 G) and persistence of the microparticles at the injection site were preliminarily verified by ex vivo test. In vitro cell culture tests showed a preservation of rat cardiac progenitor biologic properties and indicated a preferential cell adherence to microparticles with a smaller size. CONCLUSION: Overall, the obtained results indicate that the produced gelatin/gellan microparticles could be potentially employed as injectable scaffolds for myocardial regeneration. PMID- 29974810 TI - A meta-methodology to enhance pluralist qualitative research: One man's use of socio-sexual media and midlife adjustment to HIV. AB - AIM: Our aim is to offer and illustrate a novel meta-methodology to enhance the rigour of method selection and understanding of results in pluralist qualitative research (PQR). METHOD: To do so, we make innovative use of articulation of four discrete dimensions characterising different forms of thematic analysis. We provide secondary analyses of an interview from the Social Media, Men who have Sex with Men and Sexual Health project using critical discursive psychology, dialogical analysis, interpretative phenomenological analysis and psychosocial narrative analysis. RESULTS: All four methods identified aspects of three central foci: Compartmentalisation, Detachment and Jouissance. CONCLUSION: We discuss how our proposed meta-methodology provides a rationale for the selection of methods in a PQR, offer evidence that it can anticipate the relative similarity in focus of the methods employed, and argue that our meta-methodology reveals the possibility of identifying an 'axial' or 'hub' method of a PQR which might be particularly fruitful in exploring commonalities and differences in results. Finally, we examine the synergies and challenges of combining pairs of the methods we used. PMID- 29974811 TI - Effects of nutritional status on acetaminophen measurement and exposure. AB - INTRODUCTION: Fasting, as well as a high-fat diet, might increase the risk on acetaminophen-induced toxicity after an acute overdose. Therefore, it has been suggested to lower the threshold for acetylcysteine treatment to prevent liver injury in case of fasting. This study aims to investigate the effects of 36 hours of fasting and three days of a hypercaloric high-fat diet on acetaminophen measurement and exposure. METHODS: Nine healthy male subjects were enrolled in a randomized crossover intervention study. Subjects received 1000mg oral acetaminophen after an overnight fast following: (1) regular diet,(2) 36h of fasting and (3) three days of a hypercaloric high-fat diet consisting of 500ml of cream (1715 kcal) supplemented to their regular diet. Pharmacokinetic parameters were determined by non-compartmental analysis. Samples were analyzed by an enzymatic colorimetric method used in routine practice and by LC-MS/MS being the gold standard. Agreement between these methods was assessed by the Bland-Altman method. RESULTS: Short-term fasting increased acetaminophen exposure by 20% (DeltaAUC0-8 hours, p = .04) in comparison with the control diet. Three days of hypercaloric high-fat diet did not affect acetaminophen exposure (DeltaAUC0-8 hours= 9%, p = .67). The intraclass correlation coefficient between the enzymatic assay and LC-MS/MS methods of the fasting samples was 0.46 (0.28-0.61), compared to 0.87 (0.81-0.92) and 0.87 (0.79-0.91) in the control and high-fat samples respectively. CONCLUSIONS: Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect is observed after a high-fat diet. Furthermore, short-term fasting decreases the accuracy of the enzymatic colorimetric method when measuring relatively low acetaminophen concentrations. This suggests considering nutritional status when assessing the risk of acetaminophen-induced toxicity, although further research at toxic doses is needed. PMID- 29974812 TI - Meta-analysis investigating post-exertional malaise between patients and controls. AB - Post-exertional malaise is either required or included in many previously proposed case definitions of myalgic encephalomyelitis/chronic fatigue syndrome. A meta-analysis of odds ratios (ORs; association between patient status and post exertional malaise status) and a number of potential moderators (i.e. study-level characteristics) of effect size were conducted. Post-exertional malaise was found to be 10.4 times more likely to be associated with a myalgic encephalomyelitis/chronic fatigue syndrome diagnosis than with control status. Significant moderators of effect size included patient recruitment strategy and control selection. These findings suggest that post-exertional malaise should be considered a cardinal symptom of myalgic encephalomyelitis/chronic fatigue syndrome. PMID- 29974813 TI - Coping with trauma and adversity among Palestinians in the Gaza Strip: A qualitative, culture-informed analysis. AB - In this article, we propose that coping is not only an individual property but also a structural feature. Coping shapes what is referred to in social network theory as multiplex networks, which are based on relations with multiple functions, values and meanings. Focus groups with adult Palestinians were held and content analysed. Five main coping strategies were identified: (a) creating cultural and religious meaning; (b) individualism to collectivism; (c) normalization and habituation; (d) belonging, acceptance, expectation and readiness; and (e) social support. Participants also reported culture-specific expressions for indicating psychological distress. Implications for cultural informed clinical work are then discussed. PMID- 29974814 TI - Tonal Neutralization of Taiwanese Checked and Smooth Syllables: An Acoustic Study. AB - Taiwanese tonal alternation is realized in a circular chain shift fashion for both smooth and checked syllables. Debate regarding the processes of less productive Taiwanese tonal alternation has centered on whether a surface tone is derived from an underlying tone, or whether a surface tone is selected without undergoing any derivation. The current study investigates this controversial issue by examining Taiwanese checked tone and smooth tone sandhi neutralization in production. In particular, we analyzed whether checked citation and sandhi tone 53 (C21->C53), checked citation and sandhi tone 21 (C53->C21), smooth citation and sandhi tone 55 (S51->S55), and smooth citation and sandhi tone 21 (S33->S21) are acoustically completely neutralized in fundamental frequency (F0) height, contour, and duration. A non-sandhi exception was also included to evaluate the effect of position-in-word on F0 height and duration given that citation tones always appear in phrase-final position. Any trace of influence from the underlying representation would indicate a computational mechanism, whereas the absence of any trace would suggest a lexical mechanism for the production of Taiwanese tonal alternation. Results did not show any influence of F0 height, F0 contour, or tone duration from the underlying representation for both checked and smooth tones, supporting a lexical mechanism in speech production for less productive tonal alternations. PMID- 29974815 TI - Exploring the YouTube science communication gender gap: A sentiment analysis. AB - YouTube has become the second most popular web search engine (see Alexa.com ) and the primary website for individuals and organisations to freely distribute video content. Popularity statistics indicate that Science, Technology, Engineering and Mathematics-related content is of significant interest to YouTube audiences, yet analysis of the 391 most popular science, engineering and mathematics-themed channels reveals a conspicuous absence of female communicators, with the hosts of just 32 of these channels presenting as female. To help understand potential causes of this gap, analysis was conducted on popularity indicators and audience sentiments of 450 videos from 90 Science, Technology, Engineering and Mathematics related channels. Female hosted channels were found to accumulate more comments per view, and significantly higher proportions of appearance, hostile, critical/negative and sexist/sexual commentary. PMID- 29974816 TI - Lobbying against sugar taxation in the European Union: Analysing the lobbying arguments and tactics of stakeholders in the food and drink industries. AB - AIMS: This study investigates the lobbying actors of the food and drink industry (FDI), their web lobbying arguments used in the sugar taxation debate and the tactics deployed when facing legislative restrictions on their products to curb the burden of non-communicable diseases in Europe. METHODS: A stakeholder analysis was performed to identify the FDI's actors lobbying against sugar taxation within the EU Platform for Action on Diet, Physical Activity and Health during December 2015. Qualitative content analysis was applied to assess the FDI's web lobbying claims related to three main concepts (sugar as a product, sugar's association with non-communicable diseases and sugar taxation), guided by a framework for corporate political activity. RESULTS: The web site content of a front organization and six FDI lobbyists was analysed. Some new strategies emerged alongside known corporate strategies ('questioning the effectiveness of regulation and promoting benefits of a withdrawal', 'promoting sugar's good traits and shift the blame away from it' and 'establishing relationships with trade unions'). The lobby tactics were similar to those previously applied by the tobacco industry in Europe, although the argument that sugar is a natural ingredient in many foods was unique to the FDI. CONCLUSIONS: The observed tactics and arguments presented by the FDI in opposition to sugar taxation have striking similarities with those previously used by the tobacco industry. An improved understanding of the stakeholders' mandate and resources and their most important tactics will strengthen the position of public health experts when debating sugar taxation with the FDI, which may contribute to improving population health. PMID- 29974817 TI - Gender segregation of occupations and sustainable employment: A prospective population-based cohort study. AB - BACKGROUND: Although the labour market is characterized by a strong numerical gender segregation of occupations, there is little knowledge about the associations of this with the future labour market situation for an individual person. OBJECTIVES: This study aimed to elucidate whether working in a gender segregated or gender-integrated occupation is associated with future labour market attachment and sickness absence or disability pensions among women and men. METHODS: We used a population-based prospective cohort study with univariate and multiple logistic regression analyses stratified by gender, including all people living in Sweden aged 20-56 years and in paid work in 2003 ( n=3,239,989). They were followed up eight years later with regard to employment status, sickness absence and disability pension. RESULTS: Women and men employed in extremely female-dominated occupations in 2003 had the highest employment levels and the lowest unemployment levels at follow up in 2011. When adjusting for age, level of education and sector of employment, the highest odds ratios (ORs) for not being employed in 2011 were found for women working in extremely male dominated occupations in 2003 (OR 1.27; 95% CI 1.21-1.33) and for men in female dominated occupations (OR 1.42; 95% CI 1.39-1.45) relative to those in gender integrated occupations. Women in extremely male-dominated occupations had the highest ORs for sickness absence or the receipt of a disability pension at follow up (OR 1.26; 95% CI 1.17-1.36) and men in female-dominated occupations had the highest OR 1.15 (95% CI 1.11-1.20). CONCLUSIONS: For both women and men, the gender composition of the occupation they work in seems to be of importance for their future labour market attachment and sickness absence or receipt of a disability pension. PMID- 29974818 TI - Food Sources of Sodium in Korean Americans With Type 2 Diabetes: Implications for Cardiovascular Disease. AB - INTRODUCTION: Excess sodium intake can increase the risk of high blood pressure and cardiovascular disease, common comorbidities for those with type 2 diabetes mellitus (T2DM). The purpose of this study is to describe sodium intake and high sodium food sources among Korean Americans (KAs) with T2DM. METHOD: This study, a descriptive, secondary analysis of baseline data from a clinical trial for diabetes, recruited KAs with T2DM ( n = 232) from the community. RESULTS: Average dietary sodium intake was 3,433 mg. Major sources of dietary sodium were from bicultural diets: noodles and dumplings, Korean-style soups, kimchi, breads and snacks, and boiled or seasoned vegetables. Participants who consumed excessive sodium were more likely to consume more calories and be male, married, and more recently diagnosed with T2DM. DISCUSSION: High consumption of sodium among KAs with T2DM supports the need to develop effective, tailored interventions addressing dietary sodium that incorporates the individual's culture. PMID- 29974819 TI - Effects of organic matter on mechanical properties of dredged sediments for beneficial use in road construction. AB - In France, the road construction sector is the greatest consumer of granular materials, with a yearly consumption of about 200 million tons. With the shortage of standard materials, the valorisation of dredged sediments for road construction could constitute an interesting solution. Dredged sediments generally consist of a mineral phase, an organic phase (in various forms) and a liquid phase (water). The presence of organic matter (OM) in sediments, even in small amounts, affects their engineering properties. The main objective of this study is to investigate the effects of organic matter content on the engineering properties of dredged sediments. For this purpose, a specific methodology to reconstitute samples with different amounts of organic matter contents is proposed. The evaluation of the effects of organic matter content in term of compressibility, shear strength, compaction and bearing capacity show that even for high amount of organic matter the performances of the studied samples are compatible with the use in road construction sector. PMID- 29974820 TI - Determinants of work disability following lumbar spine decompression surgery. AB - AIMS: Scientific knowledge about risk factors for work disability in terms of long-term sickness absence and disability pension following lumbar spine decompression surgery remains insufficient. This study aimed to investigate the associations between socio-demographic, work-related, and medical characteristics with subsequent long-term sickness absence (>90 days) and disability pension for individuals who underwent lumbar spine decompression surgery. METHODS: A prospective cohort study of all individuals aged 19-60 years with diagnosed dorsopathies, who underwent lumbar spine decompression surgery 2008-10 in Sweden ( n=7373) was performed. Univariate and multivariate hazard ratios with 95% confidence intervals regarding long-term sickness absence and disability pension with a 3-year follow-up period were estimated by Cox proportional regression. RESULTS: Low educational level, being a non-European immigrant and preoperative sickness absence were risk factors for both long-term sickness absence and disability pension (hazard ratios: 1.2-3.8). Female sex was a risk factor for long-term sickness absence (hazard ratios: 1.3) whereas age >44 years and being a Nordic immigrant were risk factors for disability pension (hazard ratios: 1.9 2.6). Medical factors as common mental disorders, other mental disorders, prescribed psychiatric medication and somatic comorbidity were risk factors for both long-term sickness absence and disability pension (hazard ratios: 1.2-3.4). A simultaneous lumbar fusion surgery and high preoperative pain severity were risk factors for long-term sickness absence (hazard ratios 1.2-1.8). CONCLUSIONS: To prevent long-term work disability after lumbar spine decompression surgery, specific focus is required on older and female patients, those with mental or somatic comorbidities, high levels of preoperative pain or sickness absence, with a simultaneous lumbar fusion surgery, a low educational level or a non-European immigrant background. PMID- 29974821 TI - Examining the viability of carbon fiber reinforced three-dimensionally printed prosthetic feet created by composite filament fabrication. AB - BACKGROUND:: A low-cost, yet high-functioning, fabrication method for prosthetic components is needed to provide underserved amputee communities with quality mobility devices. Three-dimensional printing is a potential alternative, yet limitations in material characteristics have previously prevented the technology from emerging as a solution. OBJECTIVE:: To validate the application of a novel three-dimensional printing technique as a fabrication method for creating fiber composite patient end-use prosthetic feet. STUDY DESIGN:: Experimental designs were iterated upon throughout mechanical testing. METHODS:: A testing apparatus capable of loading prosthetic feet in dorsiflexion and plantarflexion was constructed. Load displacement data were gathered, and energy analyses were conducted. The three-dimensionally printed feet were compared to a Freedom Innovations Renegade(r) MX carbon fiber foot and a solid-ankle cushion heel foot. RESULTS:: The three-dimensionally printed feet achieved energy profiles that were similar, and in some cases preferable, to the energy profiles of the Renegade MX and solid-ankle cushion heel foot. The stiffness profiles of the three dimensionally printed feet varied widely and depended greatly on the design of the feet, as well as the amount and location of the fiber reinforcement. CONCLUSION:: Composite filament fabrication three-dimensional printing has the potential to serve as a fabrication method for the production of energy returning prosthetic feet. CLINICAL RELEVANCE:: The results of this study indicate that carbon fiber reinforced three-dimensionally printed prosthetic feet have the potential to serve as a low-cost alternative to carbon fiber prosthetic feet and that three-dimensional printing has the capacity to function as a viable fabrication method for patient end-use prosthetic components. PMID- 29974822 TI - Demonstration of the ability of the bacterial polysaccharide FucoPol to flocculate kaolin suspensions. AB - In this study, the flocculation properties of FucoPol, a bacterial extracellular polysaccharide, were investigated. FucoPol is a high molecular weight polymer and negatively charged due to the presence of glucuronic acid and the acyl groups succinyl and pyruvyl. High flocculation rate values (>70%) were achieved with a low bioflocculant dosage of 1 mg/L, for pH values in the range 3-5 and temperature within 15-20 degrees C. The bioflocculant was also shown to be stable after freezing/thawing and heating up to 100 degrees C. Given the polymer's anionic character, the size of flocs formed and their surface profile, bridging seems to be the main flocculation mechanism of FucoPol. This study demonstrated that FucoPol is a promising natural, biodegradable and biocompatible alternative to the currently used synthetic or inorganic hazardous products, with potential to be used as a novel flocculation agent in several applications, such as water treatment, food or mining. Further studies will involve evaluating the reduction of cation dosage on flocculation efficiency, as well as testing the applicability of FucoPol to flocculate different types of suspended solids, such as, for example, activated carbons, soil solids or yeast cells. PMID- 29974823 TI - Health Equity Assessment Toolkit Plus (HEAT Plus): software for exploring and comparing health inequalities using uploaded datasets. AB - As a key step in advancing the sustainable development goals, the World Health Organisation (WHO) has placed emphasis on building capacity for measuring and monitoring health inequalities. A number of resources have been developed, including the Health Equity Assessment Toolkit (HEAT), a software application that facilitates the assessment of within-country health inequalities. Following user demand, an Upload Database Edition of HEAT, HEAT Plus, was developed. Launched in July 2017, HEAT Plus allows users to upload their own databases and assess inequalities at the global, national or subnational level for a range of (health) indicators and dimensions of inequality. The software is open-source, operates on Windows and Macintosh platforms and is readily available for download from the WHO website. The flexibility of HEAT Plus makes it a suitable tool for both global and national inequality assessments. Further developments will include interactive graphs, maps and translation into different languages. PMID- 29974824 TI - Promoting additional activity in youth soccer: a half-longitudinal study on the influence of autonomy-supportive coaching and basic psychological need satisfaction. AB - This study investigated the relationships between perceptions of coach autonomy support, basic psychological need satisfaction and the frequency at which youth soccer players engage in additional soccer activity outside of team sessions. We employed structural equation modelling to test a two-wave (T1 and T2) half longitudinal study to see if basic psychological need satisfaction mediated the relationship between coach autonomy support and additional soccer activity across a competitive season. The sample consisted of 527 youth soccer players, aged 10 15 years. Results revealed moderate to strong temporal stability for autonomy, competence, relatedness and frequency of additional soccer activity. Furthermore, no support is offered for mediation as T1 coach autonomy support was not related to any of the three basic needs at T2 when accounting for their T1 levels. However, a positive relationship between T1 autonomy and T2 additional soccer activity emerged. This suggests that those who experience high levels of autonomy in the team setting at the start of the season report an increased frequency of additional activity at the end of the season. Results are discussed in light of the Self-Determination Theory and the Trans-Contextual Model. PMID- 29974825 TI - Multidisciplinary teams for the proper management of patients with genitourinary tumors: When topics set scientific societies' agenda. AB - INTRODUCTION: The multidisciplinary management of oncologic patients is identified as the bottom line element of quality in tumor care. METHODS: In 2015, 7 Italian scientific societies representing the specialists involved in the diagnosis and treatment of genitourinary tumors joined efforts in the Italian uro oncologic multidisciplinary teams (MDTs) project. The aims were to promote the reorganization of genitourinary cancer care, switching to a multidisciplinary approach, reach a consensus on the core elements for the setup of MDTs in genitourinary oncology, and support health policy makers and managers in remodeling of the assistance and care of uro-oncologic patients on a national level. RESULTS: The first activity was the setup of 5 working groups, given the task of exploring selected topics: general principles, organization of MDTs, minimal requirements, economic evaluation, and relations with authorities. The groups participated in the writing of a document that was approved by the scientific societies and published on their web sites. Moreover, a few items summarizing the extensive document were approved in the first MDT Consensus Conference held in Milan in December 2015. CONCLUSIONS: The experience of this initial phase led to the opening of the team to other professionals and societies, in line with a correct management of patients with genitourinary tumors, which need a multidisciplinary as well as a multiprofessional approach with emerging techniques and procedures, and with a new project work package on genitourinary paths of care and indicators. PMID- 29974827 TI - HMGA2 Modulates the TGFbeta/Smad, TGFbeta/ERK and Notch Signaling Pathways in Human Lens Epithelial-Mesenchymal Transition. AB - BACKGROUND AND OBJECTIVE: Multiple signaling pathways coordinately promote epithelial-mesenchymal transition (EMT) in lens epithelial cells (LECs), where transforming growth factor beta (TGFbeta)-mediated signaling plays a central role. But the mechanism of crosstalk among these pathways remains obscure. The objective of this study is to investigate the regulatory effect of the high mobility group protein A2 (HMGA2) on the signaling pathways in lens fibrosis. METHODS: The human anterior capsulorhexis specimens were collected. The human SRA01/04 LEC line was cultured and treated with recombinant human TGFbeta2 (5ng/ml). For inhibition of signaling pathways, a selective inhibitor SB431542, U0126 or DAPT was added to LECs respectively. The specific small interfering RNA (siRNA) were transfected to LECs for gene silence. The mRNAs expressions were measured by realtime PCR and the proteins expressions were determined by western blot and immunofluorescent staining. RESULTS: HMGA2 and EMT markers alpha-smooth muscle actin (SMA), fibronectin (FN) and collagen type I (Col I) were overexpressed in human ASC specimens and TGFbeta2 stimulated EMT in LECs. While blockage of EMT by a selective inhibitor of TGFbeta/Smad, TGFbeta/extracellular signal-regulated kinase (ERK) or Notch signaling pathway could significantly inhibited HMGA2 protein expression. And silence of HMGA2 by siRNA could significantly inhibit TGFbeta2 induced expression of EMT markers including FN, Col I, collagen type IV (Col IV), key transcription factors Snail and Slug, and remarkably upregulate the epithelial markers E-cadherin and tight junction protein (ZO-1). In addition, silence of HMGA2 gene could abrogate TGFbeta2 induced phosphorylation of Smad2, Smad3 as well as ERK1/2. Blockage of HMGA2 could also inhibit the upregulation of Jagged1, Notch2, and Notch3 induced by TGFbeta2. CONCLUSION: This study indicated that HMGA2 functions as a shared effector in TGFbeta2- induced lens fibrosis, modulating the signaling network necessary for EMT in a positive feedback loop. PMID- 29974826 TI - Decreased Expression of TIM-3 on Th17 Cells Associated with Ophthalmopathy in Patients with Graves' Disease. AB - PURPOSE: Thyroid-associated Ophthalmopathy (TAO) is one of the most common orbital immunological diseases in adults. CD4+ helper T (Th) cells play important roles in the pathogenesis of TAO. But the mechanisms regulating CD4+ T cell activity is unclear. This study examines T cell immunoglobulin domain and mucin domain 3 (TIM-3) expression in helper T cell type 1 (Th1), Th17, and regulatory T cells in sufferers of TAO. METHODS: Participants were divided into 3 groups: patients with TAO, patients with Graves' disease but without orbitopathy (GD), and healthy control patients (HC). Peripheral blood samples were collected for each patient in the designated group. Flow cytometry methods assessed the frequency of Th1 (CD4+IFN-gamma+), Th17 (CD4+IL-17+), regulatory T cells (CD4+CD25hiCD127lo), and TIM-3 protein expression. Mean fluorescence intensity (MFI) measured the magnitude of TIM-3 expression and the percentage of TIM-3+ cells for each patient. RESULTS: Compared to the GD group, TAO patients possessed higher frequencies of Th1 and Th17 cells in peripheral blood samples. The percentage of TIM-3+ Th1 and Th17 cells was significantly lower in the TAO patients than the GD group. Across all patients sampled, TIM-3+ cell percentage negatively correlated with Th1 cell frequency. Th1 and Th17 cells exhibited significantly decreased expression of TIM-3 in TAO patients compared to healthy controls. Regulatory T cells showed little TIM-3 expression and we observed no significant differences in frequency between groups. CONCLUSION: These results suggest a role for TIM-3 in the regulation of Th1 and Th17 cells and the pathogenesis of Graves' ophthalmopathy. PMID- 29974828 TI - The LEPR K109R and Q223R Might Contribute to the Risk of NAFLD: A Meta-Analysis. AB - BACKGROUND: Leptin and insulin resistance have been pointed out to play a role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Increasing genes were shown to be associated with the risk of NAFLD. OBJECTIVE: The study aimed to investigate the genetic association between two leptin receptor (LEPR) polymorphisms (Q223R and K109R) and the NAFLD risk. METHODS: Studies were retrieved and included by using PubMed, Web of Science, the Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI) and EMBASE database. Genetic associations were assessed with pooled odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Five case-control studies with 1711 NAFLD patients and 1732 healthy controls were included in this meta-analysis. The K109R was significantly associated with NAFLD in allelic model in Southeast Asian subgroup (p=0.01, OR=0.59, 95% CI [0.39- 0.90]), but not in Chinese subgroup (p=0.24, OR=1.10, 95% CI [0.94-1.29]). The Q223R was significantly associated with NAFLD in both allelic and recessive models (allelic model: p<0.001, OR=0.57, 95% CI [0.50-0.65]; recessive model: p=0.001, OR=0.67, 95% CI [0.52-0.85]). However, subgroup analysis showed that the significant association between Q223R and NAFLD in allelic model cannot be found in Southeast Asians subgroup (p=0.07, OR=0.67, 95% CI [0.52-0.85]). CONCLUSION: LEPR K109R might be a susceptible factor for NAFLD in Southeast Asian population. And LEPR Q223R might be a susceptible factor for NAFLD in Chinese population. PMID- 29974830 TI - Adipokine Visfatin's Role in Pathogenesis of Diabesity and Related Metabolic Derangements. AB - Visfatin is one of the prominent adipokines secreted by adipose tissue. The level of visfatin increases significantly in persons with obesity owing to increased body mass index (BMI). During obesity, the adipocytes, which populate adipose tissue, undergo hypertrophy and hyperplasia and secrete a number of adipocytokines including visfatin. Visfatin, which also acts as an enzyme nicotinamide phosphoribosyl transferase, is one of the prominent adipokines that influence metabolic homeostasis in the body. Visfatin exists in two forms, extracellular and intracellular, and enacts a multitude of actions. The direct and indirect evidence gathered from in-vitro, in-vivo and clinical studies indicate that visfatin modulates obesity and metabolic syndrome-related pathophysiological activities including enhanced inflammation, angiogenesis, synthesis of NAD mononucleotide, and upregulation of antiapoptotic proteins in a number of cell types. It has been implicated in a number of obesity-related alterations and metabolic derangement such as diabetes, cardiovascular complications and some forms of cancers. In this review, the novel hypothesis about the role of visfatin in diabesity has been proposed which implies recent advances in studies about the pathophysiological roles of visfatin during obesity and chronic high glucose in the circulation. Visfatin at high concentration attracts immune cells and produces chronic inflammation in adipocytes. Additionally, it induces insulin resistance in many tissues and causes pancreatic beta cells dysfunction at later stages. Further, its potential as an important target to develop molecular medicine in diabesity and related metabolic syndrome has been highlighted. PMID- 29974829 TI - ZNF424 Induces Apoptosis and Inhibits Proliferation in Lung Carcinoma Cells. AB - BACKGROUND: Previously, we showed that the Zinc finger-containing transcription factor ZNF424 inhibits p21 transcription, which has been widely associated with various cancers. However, because the roles of ZNF424 in tumorigenesis have not been characterized, we correlated ZNF424 expression with tumorigenesis in lung cancer. RESULTS: The present immunohistochemical analyses show significantly lower ZNF424 expression levels in 43 of 60 lung cancer tissues compared with adjacent tissues. Moreover, flow cytometry assays indicated that overexpression of ZNF424 induces apoptosis in A549 human lung carcinoma cells, and overexpression of ZNF424 significantly increases numbers of G1 phase cells and decreases numbers of S phase cells, suggesting that ZNF424 inhibits proliferation. Western Blot analyses show that overexpression of ZNF424 decreases protein expression levels of the mitogen-activated protein kinase (MAPK) signaling proteins P-P38 and P-ERK in A549 cells. CONCLUSION: These are the first data to associate ZNF424 with tumorigenesis and demonstrate an inhibitory role in lung cancer, indicating the potential of ZNF424 expression as a diagnostic marker of lung tumorigenesis. PMID- 29974831 TI - Decreased Expression of MYPT1 Contributes to Tumor Angiogenesis and Poor Patient Prognosis in Human Prostate Cancer. AB - BACKGROUND: Our previous study demonstrated that Myosin Phosphatase Targeting subunit 1 (MYPT1) may function as a direct target of microRNA-30d, which promotes tumor angiogenesis and tumor growth of prostate cancer (PCa). Here, we aimed to investigate the clinical significance of MYPT1 expression and its functions in PCa. METHODS: Roles of MYPT1 deregulation in tumor angiogenesis of PCa was determined in vitro and in vivo experiments. Expression patterns of MYPT1 and CD31 proteins were examined by immunohistochemistry and immunofluorescence, respectively. Associations of MYPT1/CD31 combination with various clinicopathological features and patients' prognosis of PCa were also statistically evaluated. RESULTS: Through gain- and loss-of-function experiments, MYPT1 inhibited capillary tube formation of endothelial cells and in vivo tumor angiogenesis in a mouse model with the downregulation of VEGF and CD31 expression. In addition, MYPT1 expression was significantly decreased, while CD31 expression was dramatically increased in PCa tissues compared to benign prostate tissues. Notably, MYPT1 expression levels in PCa tissues were negatively correlated with that of CD31. Statistically, MYPT1-low/CD31- high expression was distinctly associated with high Gleason score, positive biochemical recurrence, and reduced overall survival of PCa patients. Moreover, PCa patients with MYPT1 low/CD31-high expression more frequently had shorter overall, biochemical recurrence-free and metastasis-free survivals. MYPT1/CD31 combination was identified as an independent factor to predict biochemical recurrence-free and metastasis-free survivals of PCa patients. CONCLUSIONS: Our findings indicate that MYPT1 may inhibit angiogenesis and contribute favorable prognosis in PCa patients, implying that MYPT1 might be a potential drug candidate in anticancer therapy. PMID- 29974832 TI - Adaptive Filtering of the Arterial Wall: Frequency Response and Dynamical Parameters: Clinical Evaluation. AB - Adaptive identification systems focus on dynamical approaches based on the observed data from an experiment and/or clinical data. These systems establish a relationship between an input (arterial or vein instantaneous pressure) and an output (instantaneous arterial or vein diameter). Several dynamics relationships and applications can be established because of this adaptive identification as an arterial dynamic range (frequency response), biomechanical behavior of cryopreserved arteries, regional differences in veins as artery substitution, role of vascular smooth muscle in human hypertension and time invariance in the biomechanics of wall arteries. The aim of this review is to summarize some of those relevant results obtained from adaptive filter identification in cardiovascular dynamics research and clinical evaluation. PMID- 29974833 TI - SES effects on the use of variation sets in child-directed speech. AB - Socio-economic status (SES) impacts the amount and type of input children hear in ways that have developmental consequences. Here, we examine the effect of SES on the use of variation sets (successive utterances with partial self-repetitions) in child-directed speech (CDS). Variation sets have been found to facilitate language learning, but have been studied only in higher-SES groups. Here, we examine their use in naturalistic speech in two languages (Hebrew and English) for both low- and high-SES caregivers. We find that variation sets are more frequent in the input of high-SES caregivers in both languages, indicating that SES also impacts structural properties of CDS. PMID- 29974834 TI - Comparison of three cryptosporidiosis outbreaks in Western Australia: 2003, 2007 and 2011. AB - Cryptosporidium is a protozoan parasite that causes the diarrhoeal disease, cryptosporidiosis. Although many species have been identified, the majority of human disease worldwide is caused by two species; Cryptosporidium parvum and Cryptosporidium hominis. In Australia, data from the National Notifiable Diseases Surveillance System (NNDSS) show that cryptosporidiosis outbreaks occur every few years. To better understand the transmission, trends and nature of cryptosporidiosis outbreaks in Western Australia, epidemiological and genomic data from three cryptosporidiosis outbreaks in 2003, 2007 and 2011 were reviewed. The 2007 outbreak was the largest (n = 607) compared with the outbreaks in 2003 (n = 404) and 2011 (n = 355). All three outbreaks appeared to have occurred predominantly in the urban metropolitan area (Perth), which reported the highest number of case notifications; increases in case notifications were also observed in rural and remote areas. Children aged 0-4 years and non-Aboriginal people comprised the majority of notifications in all outbreaks. However, in the 2003 and 2007 outbreaks, a higher proportion of cases from Aboriginal people was observed in the remote areas. Molecular data were only available for the 2007 (n = 126) and 2011 (n = 42) outbreaks, with C. hominis the main species identified in both outbreaks. Subtyping at the glycoprotein 60 (gp60) locus identified subtype IbA10G2 in 46.3% and 89.5% of C. hominis isolates typed, respectively, in the 2007 and 2011 outbreaks, with the IdA15G1 subtype was identified in 33.3% of C. hominis isolates typed in the 2007 outbreak. The clustering of cases with the IdA15G1 subtype in the remote areas suggests the occurrence of a concurrent outbreak in remote areas during the 2007 outbreak, which primarily affected Aboriginal people. Both the C. hominis IbA10G2 and IdA15G1 subtypes have been implicated in cryptosporidiosis outbreaks worldwide; its occurrence indicates that the mode of transmission in both the 2007 and 2011 outbreaks was anthroponotic. To better understand the epidemiology, sources and transmission of cryptosporidiosis in Australia, genotyping data should routinely be incorporated into national surveillance programmes. PMID- 29974835 TI - Is there any effect of neurotrophin-3 on the pathogenesis of non-allergic nasal polyps? AB - BACKGROUND: Although the role of neurotrophins such as nerve growth factor and brain-derived neurotrophic factor in nasal polyps development has been studied, the contribution of neurotrophin-3 has not been evaluated yet. This study aimed to investigate the possible role of neurotrophin-3 in nasal polyps pathogenesis. METHODS: The study group comprised 70 non-allergic nasal polyps patients and the control group consisted of 53 patients with middle turbinate concha bullosa. Specimens were taken, during surgery, from the ethmoid sinus nasal polyps in the nasal polyps group and from the lateral part of the middle turbinate concha bullosa in the control group. Tissue and serum levels of neurotrophin-3 were assessed by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. RESULTS: Nasal polyps patients had higher tissue neurotrophin-3 scores (p < 0.001). There was no statistically significant difference between groups regarding serum neurotrophin-3 levels (p = 0.417). Tissue neurotrophin-3 staining scores in the nasal polyps group had no statistically significant correlation with Lund-Mackay scores (p = 0.792). CONCLUSION: Neurotrophin-3 may have a local effect in nasal polyps pathogenesis, without joining systemic circulation. PMID- 29974836 TI - Prevalence of hepatitis E in liver transplant recipients in Greece. AB - Hepatitis E virus (HEV) is a well-known cause of acute hepatitis. Immunocompromised subjects, including liver transplant recipients, are considered to be at risk for HEV infection, which occasionally follows a chronic course. The diagnosis of HEV infection in these patients must be based on HEV RNA testing, as serology has variable performance. The aim of this study was to assess the prevalence of HEV infection in liver transplant recipients in Greece by means of HEV RNA testing. Liver transplant recipients followed in the sole transplant centre in Greece were prospectively included. HEV RNA was detected by real-time RT-PCR. Positive samples were further analysed using a nested reverse transcription RT-PCR kit, which amplifies a 137-nucleotide sequence within the ORF2/ORF3 overlapping region to detect the HEV genotype and perform phylogenetic analysis. The mean age of the included patients (n = 76) was 54 years. The most common indication for liver transplantation was viral hepatitis (57%). The majority of the patients (75%) received a calcineurin inhibitor as part of their immunosuppressive regimen and had normal liver enzymes. HEV RNA was found positive in only 1/76 (1.3%) patient. Phylogenetic analysis showed that the sequence clustered into the HEV genotype 3 clade. This patient experienced an acute hepatitis flare, which nonetheless did not become chronic. The prevalence of HEV infection in liver transplant recipients in Greece is similar (1.3%) to that reported previously in other countries. Transplant physicians should be aware of this condition and its associated consequences. PMID- 29974837 TI - The role of benzathine penicillin G in predicting and preventing all-cause acute respiratory disease in military recruits: 1991-2017. AB - The adenovirus vaccine and benzathine penicillin G (BPG) have been used by the US military to prevent acute respiratory diseases (ARD) in trainees, though these interventions have had documented manufacturing problems. We fit Poisson regression and random forest models (RF) to 26 years of weekly ARD incidence data to explore the impact of the adenovirus vaccine and BPG prophylaxis on respiratory disease burden. Adenovirus vaccine availability was among the most important predictors of ARD in the RF, while BPG was the ninth most important. BPG was a significant protective factor against ARD (incidence rate ratio (IRR) = 0.68; 95% confidence interval (CI) 0.67-0.70), but less so than either the old or new adenovirus vaccine (IRR = 0.39, 95% CI 0.38-0.39 and IRR = 0.11, 95% CI 0.11 0.11), respectively. These results suggest that BPG is moderately predictive of, and significantly protective against ARD, though to a lesser extent than either the old or new adenovirus vaccine. PMID- 29974839 TI - Cytotoxic effect of 2, 5-dimethyl-celecoxib as a structural analog of celecoxib on human colorectal cancer (HT-29) cell line. AB - Dimethyl-celecoxib (DMC), a close derivative of celecoxib (CXB) with a low COX-2 inhibitory function, exhibits significant anti-neoplastic properties. In this study, we have investigated the effect of CXB and DMC on the human HT-29 cell line. The cellular viability, caspase-3 activity, and VEGF, NF-kappaB, and COX-2 genes expressions were assessed respectively with MTT, colorimetric, and real time RT-PCR methods. DMC, a close analogue of CXB, was more potent in inhibiting the growth of cells (IC50: 23.45 uM at 24 hr) than CXB (IC50: 30.41 uM at 24 hr). Both CXB and DMC caused a significant difference in caspase-3 activity compared to the control group. DMC significantly decreased the NF-kappaB expression. Down regulation of the COX-2 mRNA expression in the celecoxib-treated group was significant compared with that in the DMC-treated group. Alterations in the mRNA expression of VEGF were not significant between the groups. Owing to the more potent growth inhibitory effects of DMC compared to that of celecoxib, it may be important to conduct research on the anticancer application of this compound, which can reduce the side effects relating to COX2 inhibition. PMID- 29974838 TI - Epirubicin-calf thymus DNA interaction: a comprehensive investigation using molecular docking, spectroscopy and fluorescent quantum dots. AB - Reviewing the mode of interaction between this kind of active pharmaceutical ingredients and DNA has received much more attention in current years. Anthracycline drugs such as Epirubicin are frequently used in cancer treatment for breast cancer treatment. In the present study, the Epirubicin -calf thymus DNA interaction was investigated by using spectroscopic, fluorimetric and molecular docking methods. Water-soluble quantum dots (QDs) with nanometric particle size fabricated and characterized by transmission electron microscope and photon correlation spectroscopy. The binding constant value and the free energy change for this interaction were obtained to be 3.00*106 M-1 and -42.26 kJ mol-1, using the spectroscopic method and docking investigations, respectively. Additionally, fluorescent thioglycolic acid-capped CdTe QDs were used for investigation of EPI and DNA interaction. Epirubicin as a quencher quenched the fluorescence of CdTe QDs after electrostatic adsorption on the surface of QDs. With the addition of DNA, EPI will be desorbed from the surface of CdTe QDs, inserted into the DNA. Subsequently, fluorescence changes of QDs were used for calculation of binding constant value, which was in good agreement with that obtained by the spectroscopic method. By the comparison of the achieved results, the intercalation mode of interaction between Epirubicin and DNA proved. PMID- 29974840 TI - Antioxidant capacity and phylogenetic analysis of twenty native grape cultivars in Siirt province, Turkey. AB - The quality of grape cultivars not only depends on the grape cultivar but also is influenced by the molecular concepts and agro-climatic factors. For this purpose, four different grape cultivars were collected from five different locations in Siirt province (Turkey). Totally twenty different grape cultivars were investigated. In the present study, the antioxidant activity (total phenolic, flavonoid, proanthocyanidin content, DPPH and FRAP activity) in seeds were indicated and phylogenetic analysis (cpDNA;trnL-F region) of twenty native grape cultivars were investigated to construct their phylogenetic tree. According to reported data on antioxidant activity and content of phytochemicals, all cultivars exhibited different values from each other, but Rutik and Gaduv cultivars were found as significantly higher in comparison to others. According to bioinformatics analysis, twenty grape cultivars were distributed into six different major groups. Rutik and Sevkeye cultivars exhibit significant distinction from other grape cultivars. The phylogenetic analysis was also associated and supported with the results of obtained data from bioactivity. The bioactivity and phylogenetic analysis were firstly identified and quantified in these grape cultivars, however, with regard to obtained data from the current study, the grape cultivars grown in Siirt province were indicated significant and valuable results and as a result, these cultivars have to be evaluated before extinction. PMID- 29974841 TI - Purification and properties of Manganese Superoxide Dismutase (MnSOD) from Tamarix aphylla L. AB - Superoxide dismutase (SOD) of the Tamarix aphylla leaves were detected at optimum conditions that collected in April, May and June. Results indicated the specific activity in the crude extract reaching to 36.76 unit/ mg protein. Crude SOD was purified by several techniques, precipitation with ammonium sulfate (50-75) %, Ion exchange chromatography using DEAE-cellulose and two steps of size exclusion chromatography on sephacryl S-200 column. The obtained specific activity (310 unit/mg protein) and purification fold 7.91. The purified enzyme revealed one band by SDS-polyacrylamide gel electrophoresis with molecular mass 85.703 kDa. while 89.125 kDa by Sephacryl S-200. The optimal pH and temperature for enzyme activity were 7.5, and 50oC respectively. EDTA, SDS and NaN3 reduced activity, contrariwise of H2O2 and KCN, pointed to the studied SOD is MnSOD. Michalis constant Km and maximum velocity Vmax values were 0.016 mM and 55.86 mM/min, respectively by using Pyrogallol as substrate. According to the results, we conclude Tamarix aphylla produce MnSOD which can have purified by serial purification techniques for better activity and characterized for further studies. PMID- 29974842 TI - ROS related enzyme levels and its association to molecular signaling pathway in the development of head and neck cancer. AB - Given the prevalence and annual incidence of cancer, head and neck cancer is affecting more than 600,000 people each year. In this research, it was decided to investigate that which genes are involved and how MPO, NQO1, SOD2 enzyme levels effective to develop of head and neck cancer and for the first time at the tissue level. 35 tumor tissues in all head and neck anatomy and their surrounding tissue (70 in total) were enclosed the research that received surgery. Determination of the apoptosis genes expression levels (Mtch1, Akt1, Caspase3, Caspase9, Bcl2, Mdm2, mTOR) were determined by RT-PCR techniques and the same patients' sample used for ROS associated oxidant-antioxidant system by using MPO, NQO1, SOD2 enzyme levels using ELISA method. According to statistical results, caspase 9 gene was found statistically high expressed in early stage in contrast to late stage (p=0,013). Level of SOD2, NQO1 and MPO was determined and only MPO level was found significantly important on tumor tissues p=0,008). Specially, our findings for high expression of Cas9 on early stage were thought to be the target for treatment with its well-known initiator role of the apoptosis. Our results suggest that the higher level of MPO in tumor tissues and indicates that it has some role on pathology of head and neck cancers. We believe that, our research will lead the proposal in-vivo studies and will open new areas on therapeutic targets. PMID- 29974843 TI - Effects of Cichorium intybus on serum oxidative stress, liver and kidney volume, and cyclin B1 and Bcl-2 levels in the brains of rats with ethanol induced damage. AB - We investigated the effects of an aqueous root extract of Cichorium intybus on Bcl-2 and cyclin B1 levels in the brain, kidney and liver volumes and changes of serum total antioxidant status (TAS) and total oxidant status (TOS) levels in ethanol induced damage in rats. The rats were divided into five groups: non treated controls (C), maltodextrin in tap water treated (MD), 6.4% ethanol in tap water treated (ET), Cichorium intybus + maltodextrin in tap water treated (CI+MD), and Cichorium intybus + 6.4% ethanol in tap water treated (CI+ET). Rats in the CI+MD and CI+ET groups were treated with 200 mg/kg water extract of Cichorium intybus. Chronic ethanol aMDinistration significantly increased cyclin B1 and decreased Bcl-2 levels in the brain and significantly decreased TAS values, increased TOS values of serum and significantly decreased kidney volume in the ET group. There was no significant difference in the liver volume or liver cell count. Our data revealed that ethanol aMDinistration induces an overexpression of cyclin B1 and decreases levels of Bcl-2 in rat brains and induced oxidative stress in the blood. C. intybus treatment possessed a partial amelioration effect on cyclin B1 levels and TAS values. PMID- 29974844 TI - GSK2193874 treatment at heatstroke onset reduced cell apoptosis in heatstroke mice. AB - Heatstroke is still a potentially fatal threat during summer heat waves, despite improved prevention and treatment. It is reported that the transient receptor potential vanilloid 4 (TRPV4) inhibitor may protect septicemia mice. Many aspects of heatstroke have been defined, from the sepsis-mimic inflammatory response to hyperthermia. Hence, TRPV4 may be a therapeutic target for heatstroke. The results in murine models of heatstroke verified that GSK2193874, as a selected TRPV4 inhibitor, was injected at heatstroke onset, and then reduced the reduction of core temperature, the death rate, wet/dry ratio of the lung, levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6, coagulation indicators, the degree of organ injury, and caspase-3/7 activity (P<0.05). But GSK2193874 treatment before heat stress did not improve the symptoms of heatstroke mice. Therefore, TRPV4 should be involved in heatstroke-induced injury. Timely GSK2193874 administration may be useful to reduce heatstroke-induced injury. TRPV4 may be a potential new therapeutic target in fatal heatstroke. PMID- 29974845 TI - Cyclic stretch induces VEGFA alternative splicing via Serine/Arginine-Rich Splicing Factor 1. AB - Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by high cyclic stretch is crucial in the vascular remodeling during hypertension. Vascular endothelial growth factor A (VEGFA) alternative splicing plays important roles in the pathological process of vascular diseases and remodeling. However, the roles of VEGFA isoforms in modulating VSMC functions in response to cyclic stretch remain unclear. We hypothesize that high cyclic stretch may induce VEGFA alternative splicing via Serine/arginine-rich splicing factor 1 (SRSF1) which subsequently induce VSMC proliferation. In the present research, hypertensive rat model was established using the abdominal aortic constriction method. In comparison with sham-operated group, immunohistology staining showed translocation of SRSF1 into nuclei in hypertensive rat thoracic aorta, and RT-PCR detected a shift of VEGFA expression pattern, including the increased expression of VEGFA120 and VEGFA164, but not VEGFA188.Then VSMCs were subjected to cyclic stretch in vitro using a Flexercell strain unit. VEGFA ELISA assay showed 15% cyclic stretch increased the secretion of VEGFA which significantly increased proliferation of VSMCs. Western blot and immunofluorescence detected accumulation of SRSF1 in nuclei after 15% cyclic stretch application. Furthermore, SRSF1 specific siRNA transfection reversed the VEGFA secretion induced by pathological high cyclic stretch. Our present results suggested that pathologically high cyclic stretch induces the shuttling of SRSF1 which results in the secretive pattern splicing of VEGFA and finally contributes to the proliferation of VSMCs. PMID- 29974846 TI - Involvement of transforming growth factor beta 1 in the transcriptional regulation of nicotinamide N-methyltransferase in clear cell renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common tumor of the kidney and its major histologic subtype is clear cell RCC (ccRCC). About 30% of diagnosed ccRCCs already have metastasis. Traditionally, localized ccRCC is treated with nephrectomy but the relapse rate is 30%. Thus, the discovery of effective biomarkers for early detection, as well as the identification of new targets for molecular-based therapy of ccRCC are urgently required. In this study, we focused on molecules that could modulate the trascription of the enzyme nicotinamide N methyltransferase (NNMT) that is known to be up-regulated in ccRCC. Signal transducer and activator of transcription 3 (STAT3), interleukin 6 (IL-6), hepatocyte nuclear factor 1 beta (HNF-1beta) and transforming growth factor beta 1 (TGF-beta1) expression levels were determined in tumor and non tumor samples obtained from 30 patients with ccRCC, using Real-Time PCR. Results obtained showed that TGF-beta1 is significantly (p<0.05) overexpressed in tumor compared with normal tissue samples of ccRCC patients. Conversely, we did not find any statistically significant difference concerning STAT3, IL-6, HNF-1beta gene expression levels. TGF-beta1 up-regulation could be responsible for the high levels of NNMT observed in ccRCC. Targeting TGF-beta1 could improve the outcome of ccRCC patients due to its role in epithelial-mesenchymal transition (EMT), that is known to be associated with a worse overall survival (OS) in this neoplasm. PMID- 29974847 TI - Kisspeptin increases intracellular calcium concentration by protein kinase C mediated signaling in the primary cultured neurons from rat hippocampus. AB - In addition to the fact that kisspeptin and its receptor GPR54 are well known to be abundantly expressed in the hypothalamus with suggestive roles in the initiation of puberty and similar reproductive system properties, there is also proof showing that kisspeptin might have influences on hippocampal functions. In our previous study, it was shown that kisspeptin increased free intracellular Ca2+ values ([Ca2+]i) through protein kinase C (PKC) activation in GT1-7 cells. For this reason, we examined the influences of kisspeptin on [Ca2+]i in hippocampal neurons to determine if kisspeptin shows its effects on hippocampus through the same mechanism. Hippocampal neurons were excised from the brains of fetuses on 17th embryonic day from maternal rats. The influences of kisspeptin on [Ca2+]i in hippocampal neurons were examined through in vitro calcium imaging system. The responses of [Ca2+]i to kisspeptin were quantified by the changes in 340nm/380nm ratio. Kisspeptin-10 caused [Ca2+]i transients in hippocampal neurons. The change in [Ca2+]i by 100 nM kisspeptin was prevented by pre-treating the cells in PKC inhibitor chelerythrine chloride. According to the results, kisspeptin activates intracellular calcium signaling in hippocampal neurons via the pathway that depends on PKC. The results of this study suggest that kisspeptin may have a role in hippocampal neuron functions. PMID- 29974848 TI - Bioinformatic analysis reveals CYP2C9 as a potential prognostic marker for HCC and liver cancer cell lines suitable for its mechanism study. AB - Hepatocellular carcinoma (HCC) is a common cancer and the sixth most lethal malignancy in the world. We chose gene expression profile of GSE14520 from GEO database aiming to find key genes that affect HCC progression. 22 paired tumor and non-tumor samples were included in this analysis. Differentially expressed genes (DEGs) between tumor and non-tumor were selected using GEO2R. Gene ontology (GO) enrichment and protein-protein interaction (PPI) of the DEGs were done using Metascape. There were 357 DEGs, including 70 up-regulated genes and 287 down regulated genes. These DEGs were enriched in drug metabolic process, organic acid catabolic process, monocarboxylic metabolic process and etc. Three important modules were detected from PPI network using Molecular Complex Detection (MCODE) algorithm. Moreover, the Kaplan-Meier analysis for overall survival and disease free survival were applied to those genes in top PPI group. In conclusion, this bioinformatic analysis demonstrated that DEGs, such as CYP2C9, might promote the development of HCC, especially in drug metabolism. It could also be used as a new biomarker for diagnosis. PMID- 29974849 TI - Molecular epidemiology of ESBL-producing Klebsiella pneumoniae isolates in intensive care units of a tertiary care hospital, North of Iran. AB - The emergence of extended-spectrum beta-lactamases (ESBL) producing strains become a great concern, because few antimicrobial agents remain active against them. Due to the lack of data on the genotyping characteristics and antibiotics resistance of clinical isolates of Klebsiella pneumoniae in the north of Iran, this study aimed to determine the occurrence of ESBL-producing isolates and their molecular characteristics in order to analyses their epidemiological relationships. This cross-sectional study performed on 60 K. pneumoniae isolates which were recovered from different clinical specimens within May and November 2016. Isolates were identified by standard microbiologic tests and confirmed by API 20E strip. Antimicrobial susceptibility testing was carried out by disk diffusion method. The genetic relatedness among the isolates was assessed by RAPD PCR. Totally, the lowest level of susceptibility was toward amoxicillin/clavulanat, and nalidixic acid. On the other hand, the highest level of susceptibility was toward imipenem (86.7%). The rate of ESBL-producing isolates was 45% (27/60). There was a significant association between production of ESBLs and higher antibiotic resistance in tested isolates. The RAPD-PCR dendrogram revealed 5 major clusters with a similarity of 80% which indicates the high relatedness of the studied isolates. Twenty-one isolates out of the 27 ESBL producing isolates were clustered in cluster A. In summary, results showed the high prevalence of multiple-drug resistant and ESBL-producing K. pneumoniae isolates in our ICUs. Also, results revealed a significant similarity between ESBL-producing isolates that necessitate restricted infection control policies and rational prescription and use of antibiotics. PMID- 29974850 TI - Sustenance of endothelial cell stability in septic mice through appropriate activation of transient receptor potential vanilloid-4. AB - Therapeutic target transient receptor potential vanilloid-4 (TRPV-4) is frequently applied in endotoxemia research. It has been reported that HC067047, an inhibitor of TRPV-4, mitigated LPS-induced injury. However, the inhibition of TRPV-4 with HC06047 did not attenuate LPS-induced symptoms and exaggerated pathology. This study was carried with a view to unravelling the reason(s) behind these conflicting results. Different doses of the inhibitor were used in the same degree of sepsis, and their effects were determined through assays for sepsis related physiological indicators such as endothelial injury markers, coagulation index, organ damage indicators, inflammatory factor levels, and cell apoptosis. The results showed that high or low inhibitor levels had no significant effect on sepsis-related physiological indicators. These findings suggest that proper activation of TRPV-4 in sepsis is important for maintaining normal physiological function. Thus, the degree of TRPV-4 activation should match the severity of sepsis. PMID- 29974851 TI - Pomegranate peel extract inhibits expression of beta-catenin, epithelial mesenchymal transition, and metastasis in triple negative breast cancer cells. AB - The standard treatment for triple-negative breast cancer (TNBC) is chemotherapy, which is highly toxic to patients; thereby, there is a need to identify safer and more effective therapeutic approaches. Medicinal plants constitute a common alternative for cancer treatment. Pomegranate is a well-known fruit in this context, but its antimetastatic property has not been extensively studied. As breast cancer-related deaths from TNBC are mainly due to metastasis, the present study was designed to investigate the antimigratory effect of pomegranate peel extract (PPE) on TNBC cells. For this purpose, the MDA-MB-231 cells were treated with different concentrations of PPE for 24, 48 and 72 hr. The effects of PPE on cell migration and invasion were determined by wound healing and transwell assays. To address the possible molecular mechanisms underlying the antimetastatic effect of PPE, real-time quantitative PCR analysis of selected epithelial mesenchymal transition (EMT) markers were performed. Moreover, the expression of beta-catenin as a critical factor in promoting cancer metastasis was examined. PPE markedly inhibited the migration and invasion of cells at concentrations of 25, 50, 100, 250, 500, and 1000ug/ml. At relatively high concentrations (500, 1000ug/ml), PPE induced apoptosis. Moreover, PPE decreased the gene expression of vimentin, ZEB1, and beta-catenin and also increased the expression of E-cadherin in TNBC cells. The protein level of beta-catenin, as measured using western analysis, revealed a time-dependent decrease at the concentration of 1000ug/ml PPE. Downregulation of EMT markers and beta-catenin showed accordance with the inhibition of migration and invasion. The present data show that PPE could be a promising drug candidate to reduce metastasis in TNBC cells. PMID- 29974852 TI - Cell dedifferentiation and multiplication of Burdock (Arctium Lappa) as a medicinal plant. AB - Arctium lappa L. (Burdock) is an important plant with various pharmacological effects. According to the importance of this plant, optimization of its tissue culture will lead to more investigation and application of it. The aim of this study was to develop protocols for callus induction and shoot regeneration of A. lappa. In order to optimize of tissue culture in A. lappa, callus induction, indirect regeneration and direct regeneration were carried out in factorial experiment based on Completely Randomized Designs (CRDs). Hypocotyl and cotyledon were cultured on the Murashige and Skoog (MS) medium supplemented with different concentrations and combinations of 2,4-Dichlorophenoxyacetic acid (2,4-D) and 6 Benzylaminopurine (BAP) for callus induction. In indirect regeneration experiment various levels of BAP and alpha-Naphthaleneacetic acid (NAA) and two types of explants (calli derived from cotyledon and hypocotyl) were investigated. In direct regeneration section, various levels of BAP plus 2 mg/l NAA and different explants (cotyledon, hypocotyl and bud) were compared. In both cotyledon and hypocotyl, the maximum callus induction was observed on a media containing 2 mg/l 2,4-D plus 1 mg/l BAP (100% and 76.19% respectively). The highest percentage of indirect regeneration (65%) was observed at 1 mg/l BAP plus 0.5 mg/l NAA on calli from hypocotyl. The highest percentage of direct regeneration (90.33) was observed in hypocotyl with a lateral bud explant on MS medium supplemented with 0.5 mg/l BAP plus 2 mg/l NAA. In this study, optimization of tissue culture protocol for A. lappa was carried out as a research technique, as well as technique for further exploitation of this plant. PMID- 29974853 TI - Effect of HOTAIR rs12826786 and rs1899663 polymorphisms on lung cancer susceptibility and clinicopathological characteristics in a turkish population: a hospital-based case-control study. AB - Overexpression of Hox transcript antisense intergenic RNA (HOTAIR), a long non coding RNA (lncRNA), is associated with tumorigenesis and multiple cancer types including lung cancer. In this study, the association between two HOTAIR single nucleotide polymorphisms (SNPs) (rs12826786 and rs1899663) on the risk and clinical characteristics of lung cancer in a Turkish population was investigated. We genotyped HOTAIR rs12826786 and rs1899663 polymorphisms in 180 Turkish people including 87 lung cancer patients (71 males and 16 females) and 93 age-matched healthy controls (67 males and 26 females) by a TaqMan real-time polymerase chain reaction method. The mean age value of the lung cancer patients and control subjects were 59.27 +/- 10.55 and 61.77 +/- 12.00, respectively. We found that none of the two HOTAIR polymorphisms (rs12826786 T>C, rs1899663A>C) has any significant association with the increased risk of lung cancer in any type of inheritance genetic models. However, our research indicated that carriers of Trs12826786/Crs1899663 (ht3) (P = 0.03) had an increased risk of lung cancer susceptibility. PMID- 29974854 TI - Vitamin D status and oxidative stress in diabetes mellitus. AB - Diabetes mellitus is an epidemic that is gaining global concern. Chronic hyperglycemia in diabetes induces the excess production of free radicals. The deleterious effects of excess free radicals are encountered by endogenous antioxidant defense system. Imbalance between free radicals production and antioxidants defense mechanisms leads to a condition known as "oxidative stress". Diabetes mellitus is associated with augmented oxidative stress that induced micro- and macrovascular complications, which presents a significant risk for cardiovascular events. Low vitamin D levels in the body have also been reported to be associated with the pathogenesis of diabetes and enhanced oxidative stress. The article is to review available literature and summarize the relationship between oxidative stress and vitamin D levels in diabetes. We also review the effects of vitamin D analogs supplementation in improving oxidative stress in diabetics. PMID- 29974855 TI - Cardiac MRI assessment in children and young adults with end-stage renal disease?. AB - Assessment of cardiovascular structure and dysfunction is imperative as cardiovascular disease (CVD) is a major cause of morbidity and mortality in pediatric patients with end-stage renal disease (ESRD). Cardiac magnetic resonance allows for accurate measurement of myocardial volumes, global function, and regional deformation (strain). We studied 38 patients aged from 11 to 26 years: 10 on hemodialysis (HD), 10 on peritoneal dialysis (PD), and 18 post renal transplantation (RT). First, we found no difference in the amount of left ventricular hypertrophy among the three cohorts, but we did find uncontrolled hypertension and black race to be independently associated with increased normalized left ventricular mass. We found left ventricular ejection fraction (LVEF) to be significantly higher in patients after RT compared to those on HD. There was no significant difference in peak systolic circumferential strain (Ecc) among the 3 groups, however, 7 of 9 participants with normal LVEF had low Ecc. We also found a strong association between uncontrolled hypertension and reduced Ecc. These findings indicate the presence of subclinical cardiac dysfunction and the importance of proper management of hypertension in pediatric patients with ESRD.?. PMID- 29974856 TI - Monocyte count modifies the association between chronic kidney disease and risk of death?. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased all-cause mortality. How non-traditional risk factors modify the mortality risk associated with CKD has not been studied. We approached this question using elevated monocyte count, which is associated with increased risk of death in the general population; however, there is very limited data in CKD. MATERIALS AND METHODS: A national cohort of 1,706,589 U.S. veterans without end-stage renal disease (ESRD) was followed over a median of 9.16 years. Estimated glomerular filtration rate (eGFR; mL/min/1.73m2) was divided into 6 categories: 15 - 30, 30 - 45, 45 - 60, 60 - 90, 90 - 105 (reference), and > 105. Monocyte count (k/cmm) was grouped into quartiles: 0.00 - 0.40 (reference), 0.40 - 0.56, 0.56 - 0.70, and > 0.70. Multinomial logistic regression, Cox proportional hazard regression, and formal interaction analyses on both the multiplicative and additive scales were undertaken. RESULTS: Monocyte count > 0.56 k/cmm was associated with increased risk of death overall (hazard ratio (HR) 1.40, confidence interval (CI) 1.38, 1.41 in monocyte quartile 4) and across each eGFR category. Very high (> 105 mL/min/1.73m2) and low (15 - 30 mL/min/1.73m2) eGFR categories were associated with increased mortality risk (HR 1.40, CI 1.38, 1.42 and HR 2.07, CI 2.03, 2.11, respectively). The mortality risk associated with high monocyte count and low eGFR exhibited a strong negative interaction (p < 0.001). No interaction was noted at very high eGFR. CONCLUSION: While low and very high eGFR were both associated with increased mortality risk, a monocyte count > 0.56 k/cmm only modified the risk associated with low eGFR. This suggests a shared underlying mechanism of death between CKD and high monocyte count.?. PMID- 29974857 TI - Baclofen-induced neurotoxicity in patients with compromised renal function: Review. AB - Baclofen is a centrally-acting gamma-amino butyric acid agonist used mainly in the symptomatic management of spasticity originating from the spinal cord. It is absorbed completely from the gastrointestinal tract, metabolized by the liver to a minor degree, and excreted unchanged by the kidneys. Baclofen is moderately lipophilic and can cross the blood-brain barrier easily. At the usual dosage, it acts mainly at the spinal level without central nervous system (CNS) side effects. During renal failure, however, the elimination of the drug will decrease with a prolonged half-life, resulting in a larger area-under-the-curve exposure and disproportionate CNS toxicity. Clinically, these patients with renal failure may present with a variety of toxic symptoms manifesting at therapeutic/sub therapeutic doses of baclofen. In cases of unexplained mental status changes in a patient receiving baclofen therapy, a careful assessment of renal function and a high suspicion of baclofen-induced encephalopathy will be key to the diagnosis.?. PMID- 29974858 TI - Correction: Membranes, Energetics, and Evolution Across the Prokaryote-Eukaryote Divide. PMID- 29974859 TI - "Rho"ing a Cellular Boat with Rearward Membrane Flow. AB - The physicist Edward Purcell wrote in 1977 about mechanisms that cells could use to propel themselves in a low Reynolds number environment. Reporting in Developmental Cell, O'Neill et al. (2018) provide direct evidence for one of these mechanisms by optogenetically driving the migration of cells suspended in liquid through RhoA activation. PMID- 29974860 TI - A Rapid Method for Directed Gene Knockout for Screening in G0 Zebrafish. AB - Zebrafish is a powerful model for forward genetics. Reverse genetic approaches are limited by the time required to generate stable mutant lines. We describe a system for gene knockout that consistently produces null phenotypes in G0 zebrafish. Yolk injection of sets of four CRISPR/Cas9 ribonucleoprotein complexes redundantly targeting a single gene recapitulated germline-transmitted knockout phenotypes in >90% of G0 embryos for each of 8 test genes. Early embryonic (6 hpf) and stable adult phenotypes were produced. Simultaneous multi-gene knockout was feasible but associated with toxicity in some cases. To facilitate use, we generated a lookup table of four-guide sets for 21,386 zebrafish genes and validated several. Using this resource, we targeted 50 cardiomyocyte transcriptional regulators and uncovered a role of zbtb16a in cardiac development. This system provides a platform for rapid screening of genes of interest in development, physiology, and disease models in zebrafish. PMID- 29974862 TI - A Touch from Myofibroblasts Puts the Squeeze on Myonuclei. AB - The even positioning of nuclei at the periphery of differentiated myofibers is among the most striking examples of cellular organization. In this issue of Developmental Cell, Roman et al. (2018) show that fibronectin deposited by the associated myofibroblasts initiates both lateral and peripheral nuclear movements by distinct downstream mechanisms. PMID- 29974863 TI - A Cytoskeletal Symphony: Owed to TOG. AB - Like permutating motifs in music, similar protein folds are employed across biology for distinct functions. In this issue of Developmental Cell, Aher et al. (2018) provide insight into how variable TOG domains within an array in the microtubule regulator CLASP are used to prevent microtubule catastrophe and potentiate rescue. PMID- 29974864 TI - Interdependent Nutrient Availability and Steroid Hormone Signals Facilitate Root Growth Plasticity. AB - Plants acquire essential elements from inherently heterogeneous soils, in which phosphate and iron availabilities vary. Consequently, plants have developed adaptive strategies to cope with low iron or phosphate levels, including alternation between root growth enhancement and attenuation. How this adaptive response is achieved remains unclear. Here, we found that low iron accelerates root growth in Arabidopsis thaliana by activating brassinosteroid signaling, whereas low-phosphate-induced high iron accumulation inhibits it. Altered hormone signaling intensity also modulated iron accumulation in the root elongation and differentiation zones, constituting a feedback response between brassinosteroid and iron. Surprisingly, the early effect of low iron levels on root growth depended on the brassinosteroid receptor but was apparently hormone ligand independent. The brassinosteroid receptor inhibitor BKI1, the transcription factors BES1/BZR1, and the ferroxidase LPR1 operate at the base of this feedback loop. Hence, shared brassinosteroid and iron regulatory components link nutrient status to root morphology, thereby driving the adaptive response. PMID- 29974861 TI - Apical and Basal Matrix Remodeling Control Epithelial Morphogenesis. AB - Epithelial tissues can elongate in two dimensions by polarized cell intercalation, oriented cell division, or cell shape change, owing to local or global actomyosin contractile forces acting in the plane of the tissue. In addition, epithelia can undergo morphogenetic change in three dimensions. We show that elongation of the wings and legs of Drosophila involves a columnar-to cuboidal cell shape change that reduces cell height and expands cell width. Remodeling of the apical extracellular matrix by the Stubble protease and basal matrix by MMP1/2 proteases induces wing and leg elongation. Matrix remodeling does not occur in the haltere, a limb that fails to elongate. Limb elongation is made anisotropic by planar polarized Myosin-II, which drives convergent extension along the proximal-distal axis. Subsequently, Myosin-II relocalizes to lateral membranes to accelerate columnar-to-cuboidal transition and isotropic tissue expansion. Thus, matrix remodeling induces dynamic changes in actomyosin contractility to drive epithelial morphogenesis in three dimensions. PMID- 29974867 TI - Complex structures generated by competing interactions in harmonically confined colloidal suspensions. AB - We investigate the structural properties of colloidal particle systems interacting via an isotropic pair potential and confined by a three-dimensional harmonic potential. The interaction potential has a repulsive-attractive repulsive profile that varies with the interparticle distance (also known as a 'mermaid' potential). We performed Langevin dynamics simulations to find the equilibrium configurations of the system. We show that particles can self assemble in complex structural patterns, such as compact disks, fringed disks, rods, spherical clusters with superficial entrances among others. Also, for particular values of the parameters of the interaction potential, we could identify that some configurations were formed by quasi two-dimensional (2D) structures which are stable for 2D systems. PMID- 29974865 TI - MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts. AB - The ability to convert human somatic cells efficiently to neurons facilitates the utility of patient-derived neurons for studying neurological disorders. As such, ectopic expression of neuronal microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9* 124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. However, how miR-9/9*-124 break the cell fate barrier to activate the neuronal program remains to be defined. Here, we identified an anti-neurogenic function of EZH2 in fibroblasts that acts outside its role as a subunit of Polycomb Repressive Complex 2 to directly methylate and stabilize REST, a transcriptional repressor of neuronal genes. During neuronal conversion, miR-9/9*-124 induced the repression of the EZH2-REST axis by downregulating USP14, accounting for the opening of chromatin regions harboring REST binding sites. Our findings underscore the interplay between miRNAs and protein stability cascade underlying the activation of neuronal program. PMID- 29974866 TI - 3D Culture Method for Alzheimer's Disease Modeling Reveals Interleukin-4 Rescues Abeta42-Induced Loss of Human Neural Stem Cell Plasticity. AB - Neural stem cells (NSCs) constitute an endogenous reservoir for neurons that could potentially be harnessed for regenerative therapies in disease contexts such as neurodegeneration. However, in Alzheimer's disease (AD), NSCs lose plasticity and thus possible regenerative capacity. We investigate how NSCs lose their plasticity in AD by using starPEG-heparin-based hydrogels to establish a reductionist 3D cell-instructive neuro-microenvironment that promotes the proliferative and neurogenic ability of primary and induced human NSCs. We find that administration of AD-associated Amyloid-beta42 causes classical neuropathology and hampers NSC plasticity by inducing kynurenic acid (KYNA) production. Interleukin-4 restores NSC proliferative and neurogenic ability by suppressing the KYNA-producing enzyme Kynurenine aminotransferase (KAT2), which is upregulated in APP/PS1dE9 mouse model of AD and in postmortem human AD brains. Thus, our culture system enables a reductionist investigation of regulation of human NSC plasticity for the identification of potential therapeutic targets for intervention in AD. PMID- 29974868 TI - Impedimetric phosphorene field-effect transistors for rapid detection of lead ions. AB - Stimuli-responsive field-effect transistors (FETs) based on 2D nanomaterials have been considered as attractive candidates for sensing applications due to their rapid response, high sensitivity, and real-time monitoring capabilities. Here we report on an impedance spectroscopy technique for FET sensor applications with ultra-high sensitivity and good reproducibility. An alumina-gated FET, using an ultra-thin black phosphorus flake as the channel material, shows significantly improved stability and ultra-high sensitivity to lead ions in water. In addition, the phase angle in the low frequency region was found to change significantly in the presence of lead ion solutions, whereas it was almost unchanged in the high frequency region. The dominant sensing performance was found at low frequency phase spectrum around 50 Hz and a systematic change in the phase angle in different lead ion concentrations was found. Applying the impedance spectroscopy technique to insulator-gated FET sensors could open a new avenue for real-world sensor applications. PMID- 29974869 TI - Impact of new ICRU Report 90 recommendations on calculated correction factors for reference dosimetry. AB - In 2016 the ICRU published a new report dealing with key data for ionizing radiation dosimetry (ICRU Report 90). New recommendations have been made for the mean excitation energies I for air, graphite and liquid water as well as for the graphite density to use when evaluating the density effect. In addition, the ICRU Report 90 discusses renormalized photoelectric cross sections, but refuses to give a recommendation on the use of renormalization factors. However, the Consultative Committee for Ionizing Radiation recommends to use renormalized photoeffect cross sections. Goal of the present work is to evaluate the impact of these new recommendations on clinical reference dosimetry for high energy photon and electron beams. The beam quality correction factor k Q was calculated by Monte Carlo simulations for compact and parallel plate ionization chambers. In case of photons seven phase space files from clinical accelerators and twelve spectra taken from literature from 4 MV to 24 MV and additionally a 60Co source were applied. As electron source thirteen electron spectra available in literature were used in the range of 4 MeV-21 MeV. The new ICRU recommendations have a small impact on Monte Carlo calculated k Q values for the chosen ionization chambers in the range of 0.1%-0.35% only-the difference increases for higher photon energies. The impact of the ICRU Report 90 recommendations on Monte Carlo calculated stopping power ratios s w,a , perturbation factors p and beam quality correction factors k Q was investigated and confirmed a decrese of s w,a by a fraction of a percent for photon and electron beams. This study indicates that the impact of the new ICRU recommendation is within 0.35%. The determined deviations should be taken into account, when widely published Monte Carlo calculated values are examined. PMID- 29974870 TI - PHBV wet-spun scaffold coated with ELR-REDV improves vascularization for bone tissue engineering. AB - A bone tissue replacement with relevant anatomical size requires the production of 3D scaffolds, which in turn limits the mass transport of nutrients and oxygen to sustain cell survival. A viable vascular network is required to overcome this problem. However, this cannot be established immediately after the implantation of a scaffold. The aim of this study was to develop a 3D wet-spun bone tissue engineering scaffold, coated with an elastin-like recombinamer (ELR) peptide with an endothelial cell-attracting REDV sequence to promote early vascularization. Scaffolds were produced using biodegradable poly(3-hydroxybutyrate-co-3 hydroxyvalerate) (PHBV), and an ELR was immobilized onto it after oxygen plasma treatment (PHBV-O2-ELR-REDV). O2 plasma treatment and ELR modification of the PHBV changed the wettability, topography, and composition of the surface. A moderately hydrophilic surface was obtained after oxygen plasma treatment and ELR REDV coating with a contact angle of 66.63 +/- 0.77 degrees . The surface roughness decreased after plasma treatment from 343.4 to 160.0 nm and increased to 280.3 nm after ELR-REDV coating. FTIR-ATR showed amide I and amide II bonds after ELR-REDV coating showing that the coating was successful. Scaffolds were tested in vitro with rabbit bone marrow mesenchymal cells. ELR modification did not cause a significant difference in adhesion or proliferation compared to unmodified controls. On the other hand, ELR-modified scaffolds attracted a higher number of human umbilical vein endothelial cells (HUVECs) due to the REDV sequence. The Alamar Blue test and confocal laser scanning microscopy micrographs showed that HUVEC migration and attachment on PHBV-O2-ELR-REDV scaffolds was around 2.5-fold higher than untreated PHBV scaffolds after 14 d. Plasma-treated scaffolds (PHBV-O2) showed an increase in the number of adhered HUVECs due to increased surface wettability. It can, therefore, be suggested that PHBV-O2-ELR REDV scaffolds have significant potential to induce early vascularization due to increased attractiveness for endothelial cells. This could alleviate the vascularization problem of 3D implants for bone tissue engineering. PMID- 29974871 TI - Techniques and pitfalls of laparoscopic paraesophageal hernia repair in severe kyphoscoliosis patients. AB - Background: Increasing evidence suggests that kyphoscoliosis may play a role in the pathophysiology of paraesophageal hernia development. The presence of severe kyphoscoliosis not only increases the incidence of paraesophageal hernia but also increases the risk of hiatal hernia (HH) repair. Moreover, the technical skills and the pitfalls of laparoscopic repair of HH in this special condition have yet been described. Methods: The technical skills, experience and pitfalls of laparoscopic paraesophageal hernia repair in severe kyphoscoliosis patients were described. These include perioperative care of patients' pulmonary function, patients' operating position and trocar placement, and the key steps and risks of laparoscopic HH repair in this special condition. Results: Paraesophageal HHs were successfully laparoscopically repaired, and prolonged hospital stay was due to post-operative pulmonary complications. Conclusion: These techniques are essential to minimise the perioperative complications in laparoscopic paraesophageal hernia repair in severe kyphoscoliosis patients, and great pulmonary care is required in these patients. PMID- 29974872 TI - A standardised and simplified technique for laparoscopic resection of the splenic flexure. AB - The splenic flexure is an uncommon location of colorectal cancer, being involved in 2%-3% of cases. The low chance of being engaged in resecting cancer of the splenic flexure can make it difficult for surgeons to build their learning curve and to achieve a reliable experience. As the majority of colectomies are still performed by low-volume surgeons, there is growing agreement that providing local services with adequate surgical education and training could be an effective strategy to improve outcomes and global health. Arming surgeons with simplified and easy-to-learn surgical techniques could be an important step of this strategy. A novel simplified technique for laparoscopic resection of the splenic flexure is presented, which combines laparoscopic mobilisation of the right colon with extracorporeal vascular ligation and bowel anastomosis. PMID- 29974873 TI - Laparoscopic and robotic specimen retrieval system (Modified Nadiad Bag): Validation and cost-effectiveness study model. AB - Aim: To construct and validate a cost-effective indigenously made retrieval system (Modified Nadiad bag) in minimal access urology. Method: The components of the modified Nadiad bag are a polyethylene roll, fishnet thread, and a 5 Fr ureteral catheter. The bag is indigenously made in our institute and used for organ retrieval after proper sterilization. The video recordings of entrapments and retrievals done over the past few months were reviewed. The procedures under review in which the bag was used were: Robot Assisted Radical Prostatectomy (50 cases), laparoscopic radical nephrectomy (50 cases), laparoscopic simple nephrectomy (50 cases) and laparoscopic adrenalectomy (18 cases). We also compared the retrieval time with experts and novices. Results: The retrieval times, the organ size (largest dimension) and specimen weight were records for each case. Multivariate analysis of the data was done and we extrapolated the retrieval time with organ size, specimen weight and expertise of the surgeon. There was no significant difference among expert surgeons and novice surgeons with regards to retrieval times (p value = 0.29), with regards to organ size (p value = 0.83) and with regards to specimen weight (p value = 0.99). Conclusion: Our design of retrieval system offers a cost-effective option which is easy to make, without the risk of tumor seeding and without the need for separate access sheath. It's a retrieval system which has proved its efficacy in laparoscopic as well as robotic procedures with no bearing on the expertise of the surgeon involved. PMID- 29974874 TI - Double indocyanine green technique of robotic right colectomy: Introduction of a new technique. AB - In robotic right hemicolectomy for colorectal cancer (CRC), appropriate lymphadenectomy and anastomotic leak prevention are critical. Visualisation of lymph nodes and blood flow with near-infrared (NIR) fluorescence DaVinci(r) imaging system is a recent development. Herein, we present an improved robotic modified complete mesocolic excision (mCME) technique using indocyanine green (ICG) fluorescence. Before surgery, ICG is injected into the submucosa around the tumour with endoscopy for intraoperative detection of lymph nodes. Robotic mCME with central vascular ligation is performed, supplemented in most of the cases with selective extended lymphadenectomy. Intestinal blood flow before anastomosis is evaluated by administering ICG intravenously and NIR visualisation. Visualisation of the lymph nodes with ICG facilitates standard mCME lymphadenectomy and enables extended lymphadenectomy. Blood flow of the intestinal walls of the anastomotic site can be assessed and determines the extent of intestinal resection. Robotic double ICG technique for robotic right hemicolectomy enables improved lymphadenectomy and warrants the extent of intestinal resection; thus, becoming a strong candidate for gold standard in robotic resections of the right colon for CRC. PMID- 29974875 TI - Human fibrin sealant reduces post-operative bile leakage of primary closure after laparoscopic common bile duct exploration in patients with choledocholithiasis. AB - Context: Primary closure of the common bile duct (CBD) without drainage is considered a suitable approach after laparoscopic CBD exploration (LCBDE); however, the risk of post-operative bile leakage is high. Up to now, it has not been clear whether human fibrin sealant can reduce post-operative bile leakage of the primary suture. Aims: In this study, we evaluated the role of human fibrin sealant in primary closure of the CBD after LCBDE. Subjects and Methods: Patients with choledocholithiasis who had undergone primary duct closure of the CBD after LCBDE were divided into two groups according to whether fibrin sealant was used. Statistical Analysis Used: Fisher's exact test or the Chi-square test was used for categorical variables to calculate frequencies and percentages between the groups. The Student's t-test was used to compare the means of the continuous variables between the groups. Results: The human fibrin sealant group had a lower rate of post-operative bile leakage compared to the other group (P < 0.05). There were no significant differences in additional parameters such as operative time, post-operative stay duration, time to drain removal, bile duct stenosis, acute allergic reaction and overall mortality. Conclusions: Human fibrin sealant can reduce post-operative bile leakage in primary closure of CBD after LCBDE in patients with choledocholithiasis. PMID- 29974876 TI - Total laparoscopic Billroth-I gastrectomy for corrosive-induced antropyloric stricture. AB - Antro-pyloric stricture with gastric outlet obstruction is a common manifestation of corrosive-induced gastric injury. Surgical management is the only curative option as endoscopic dilatation usually fails in the long term. Billroth I gastrectomy with gastroduodenostomy is the preferred surgery as it restores normal alimentary pathway, reduces dumping and does not complicate colon mobilisation for the future oesophageal bypass. Conventionally, it is performed by the open approach. The present report is the first technical description of total laparoscopic Billroth-I gastrectomy using the laparoscopic linear cutter for corrosive-induced antropyloric stricture. The two patients who underwent this procedure had patent gastroduodenal anastomosis on the post-operative contrast study and tolerating normal diet at 9 and 6 months follow-up, respectively. PMID- 29974877 TI - Laparoscopic left lateral sectionectomy: A three-port method. AB - Background: Laparoscopic liver resection has become popular recent years. Laparoscopic left lateral sectionectomy (LLS) is now a standard operation with sufficient safety and feasibility. To improve the benefits of minimally invasive surgery, we invented and have been performing a reduced port LLS procedure using 3 ports since 2009. Materials and Methods: All patients who underwent LLS at Toranomon Hospital (Tokyo, Japan) were included, except for patients with a previous history of upper abdominal surgery or those who had undergone the simultaneous resection of another organ. An essential point of this procedure was the extracorporeal traction of the divided round ligament using a ligature. As a result, the operator was able to perform the parenchymal transection within a good operative field. Results: Twelve patients were enrolled in the study. All the patients had a Child-Pugh classification of Class A. The median indocyanine green retention rate at 15 min was 9.5%. Compared with previously reported results for conventional LLS, the median operation time (82.5 min), blood loss (0 mL) and rate of blood transfusion (0%) were lower for the 3-port LLS procedure. The rates of complications (9%) and a positive surgical margin (0%) were similar to those reported for the conventional approach. Conclusion: Three-port LLS appears to be a safe and feasible procedure. PMID- 29974878 TI - Minimally invasive neck dissection: A 3-year retrospective experience of 45 cases. AB - Objective: Robot-assisted neck dissection requires a larger wound, is expensive and requires specialised equipment which is not easily available. We have developed an inexpensive minimally invasive neck dissection (MIND) procedure using simple endoscopic instruments in the past. This study was conducted to evaluate the safety, efficacy and reproducibility of the technique. Materials and Methods: From January 2013 to December 2016, we performed MIND on 45 patients with oral cancer using the standard endoscopic equipment. CO2gas insufflation was used to create the working space. Intra-operative data, post-operative data and pathological characteristics were evaluated and overall survival (OS) and disease free survival (DFS) Kaplan-Meier curves were compared using the Log-Rank test. Results: Median operative time was 130 (80-190) min with a mean blood loss of 63 (20-150) ml. Major intra-operative complications were not observed. The median number of nodes retrieved was 14 (range: 7-38). Three patients with a positive lymph node were advised to undergo adjuvant radiotherapy. After consultation, 12 out of 13 tongue cancer patients with a tumour depth >3 mm underwent adjuvant radiotherapy. Mean follow-up period was 31.5 (95% confidence interval [CI] 27.9 35.1) months and 27.8 (95% CI 23.6-32.1) months for OS and DFS, respectively. Four (8.9%) deaths and 8 (17.8%) recurrences were observed. The 3-year OS and DFS was 91.1% and 82.2%, respectively. Conclusion: MIND is aesthetically better than conventional procedures for oral cancer patients due to its safety, efficacy and reproducibility at any centre using the standard laparoscopic equipment. PMID- 29974879 TI - A prospective study of gastro-oesophageal reflux disease symptoms and quality of life 1-year post-laparoscopic sleeve gastrectomy. AB - Introduction: There are concerns that laparoscopic sleeve gastrectomy (LSG) can cause severe gastro-oesophageal reflux disease (GORD). The aim of this study was to assess GORD symptoms and quality of life following LSG. Methods: A prospective study of patients undergoing LSG (2014-2016) was performed with follow-up by DeMeester Reflux/Regurgitation Score, Bariatric Quality of Life Index (BQLI) and Bariatric Analysis and Reporting Outcome System (BAROS) Score pre-operatively, 6 months and 1-year post-operatively. Results: Twenty-two patients were studied. Mean modified DeMeester Reflux/Regurgitation Score improved from 2.25 (+/-0.67) pre-operatively to 0.81 (+/-0.25) at 12 months (P = 0.04). At 12 months, two patients had symptomatic reflux, but overall satisfaction score was unaffected. Mean BQLI Score underwent a non-significant improvement at 12 months. BAROS Score showed all patients to have excellent (n = 19) or very good (n = 3) results (12 months). Conclusion: GORD symptoms improve for most patients' 1-year post operatively. A small proportion of patients will develop troublesome GORD, but overall satisfaction remains high. PMID- 29974880 TI - A study of primary single and layered suture technique by using two-port laparoscopic choledocholithotomy. AB - Background: The aim of this study is to explore the application value of layered suture technique in two-port laparoscopic choledocholithotomy with primary suture. Materials and Methods: A prospective study of 267 patients received laparoscopic common bile duct choledocholithotomy with primary suture in our hospital from January 2014 to July 2017. Of these cases, layered suture technique was utilised in 110 patients, and single-suture technique was used in 157 patients. The operation time, post-operative hospital stay and post-operative complications were compared between the two groups. Results: Two groups of patients were operated smoothly, with no conversations to laparotomy. Post operative recovery was symptom free. The operative time was not significantly different between the two groups of patients (t = -0.587, P = 0.086). The post operative hospital stay and incidence of post-operative bile leakage were significantly lower in layered suture group than those in single-layer suture group ([7.6 +/- 1.8] days vs. [5.8 +/- 1.7] days, t = 2.776, P = 0.000; 4.5% [5/110] vs. 20.4% [32/157], chi2 = 9.885, P = 0.002). In the single-layer suture group, the incidence of post-operative bile leakage was significantly higher in patients complicated with acute cholangitis (44.4% [12/27] vs. 15.4% [20/130], chi2 = 11.634, P = 0.001), whereas in the layered suture group, the incidence of post-operative bile leakage was insignificantly different among patients with and without acute cholangitis (11.8% [2/17] vs. 3.2% [3/93], chi2 = 0.848, P = 0.357). Conclusion: Application of layered suture technique in laparoscopic choledocholithotomy with primary suture is feasible and safe, with advantages of less bile leakage and shorter hospital stay. PMID- 29974881 TI - Laparoscopic two-stage procedure for gallstone ileus. AB - Gallstone is a rare cause of bowel obstruction and is associated with high rates of morbidity and mortality. Here, we report a case of gallstone ileus treated by laparoscopic two-stage procedure. A 65-year-old man, without a history of any surgery, presented to our hospital with abdominal pain and vomiting. His abdominal computed tomography revealed gallstone ileus with cholecystoduodenal fistula. Then, enterolithotomy was performed as an emergency laparoscopic surgery. After 1 year of the surgery, a second laparoscopic procedure was performed for cholecystectomy and fistula closure. The patient was discharged on the 7th postoperative day. Laparoscopic two-stage procedure is a safe and an efficient approach for the management of gallstone ileus. This definitive treatment is minimally invasive, thereby suitable for treating elderly patients. PMID- 29974882 TI - How to write an article: An introduction to basic scientific medical writing. AB - An original scientific article published in a peer-reviewed professional journal of repute provides great personal satisfaction, adds stature and endows professional respectability to contributing authors. Various types of surgical publications that exist nowadays are case report, cohort study, case-control study, randomised controlled trial narrative review, systematic review, Cochrane review, meta-analysis, editorials and leading articles. A study/research protocol is a standardised document, common to all research projects that typically comprise study objectives, study design, selection of participants, study intervention, study evaluations, safety assessments, statistics and participant rights committees. Once the study protocol is completed and reviewed, it is submitted to the local Institutional Review Board/Institutional Ethics Committee for approval. An outline of the levels of evidence and grades of recommendation is available from the Centre for evidence-based medicine at the University of Oxford. A standardised, structured template exists for scientific presentations in the field of medicine which is also followed in medical writing and publications Introduction Methods Results And Discussion (IMRAD). Instructions to authors would normally include reference to International Committee of Medical Journal Editors and Committee on Publication Ethics guidelines for good and ethical publication practice. It is strongly advised to follow the recommended guidelines appropriate for the published study. PMID- 29974883 TI - Battle of the sexes: contrasting roles of testis-specific protein Y-encoded (TSPY) and TSPX in human oncogenesis. AB - The Y-located testis-specific protein Y-encoded (TSPY) and its X-homologue TSPX originated from the same ancestral gene, but act as a proto-oncogene and a tumor suppressor gene, respectively. TSPY has specialized in male-specific functions, while TSPX has assumed the functions of the ancestral gene. Both TSPY and TSPX harbor a conserved SET/NAP domain, but are divergent at flanking structures. Specifically, TSPX contains a C-terminal acidic domain, absent in TSPY. They possess contrasting properties, in which TSPY and TSPX, respectively, accelerate and arrest cell proliferation, stimulate and inhibit cyclin B-CDK1 phosphorylation activities, have no effect and promote proteosomal degradation of the viral HBx oncoprotein, and exacerbate and repress androgen receptor (AR) and constitutively active AR variant, such as AR-V7, gene transactivation. The inhibitory domain has been mapped to the carboxyl acidic domain in TSPX, truncation of which results in an abbreviated TSPX exerting positive actions as TSPY. Transposition of the acidic domain to the C-terminus of TSPY results in an inhibitory protein as intact TSPX. Hence, genomic mutations/aberrant splicing events could generate TSPX proteins with truncated acidic domain and oncogenic properties as those for TSPY. Further, TSPY is upregulated by AR and AR-V7 in ligand-dependent and ligand-independent manners, respectively, suggesting the existence of a positive feedback loop between a Y-located proto-oncogene and male sex hormone/receptors, thereby amplifying the respective male oncogenic actions in human cancers and diseases. TSPX counteracts such positive feedback loop. Hence, TSPY and TSPX are homologues on the sex chromosomes that function at the two extremes of the human oncogenic spectrum. PMID- 29974884 TI - A novel experience of deferential vessel-sparing microsurgical vasoepididymostomy. AB - Microsurgical longitudinal intussusception vasoepididymostomy (LIVE) has been widely used to treat epididymal obstructive azoospermia since 2004. Although the deferential vasculature plays an important role in supplying blood to the testis and epididymis, little attention has been paid to the potential benefits of sparing the deferential vessels during the anastomosis in LIVE. This study aimed to evaluate the efficacy and safety of deferential vessel-sparing LIVE in humans. From December 2013 to December 2015, 69 azoospermic men with epididymal obstruction due to a genital infection, trauma, or idiopathic factors underwent deferential vessel-sparing LIVE in the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. The outcomes of these patients were analyzed retrospectively. The mean age was 31.1 years for men and 28.3 years for their partners. Fifty-nine (85.5%, 59/69) men were followed up after surgery for approximately 16 months. Patency was noted and confirmed by semen analysis (>10 000 sperm/ml) in 83.1% (49/59) of men. The natural pregnancy rate was 40.7% (24/59) by the end of the study, with 87.5% (21/24) of these natural pregnancies achieved within 12 months after surgery. No severe adverse events or complications were observed. In this study, we present a novel technique for sparing the deferential vessels during LIVE. The preliminary outcomes show this technique to be safe with favorable patency and pregnancy rates. PMID- 29974885 TI - Pelvic muscle floor rehabilitation as a therapeutic option in lifelong premature ejaculation: long-term outcomes. AB - The aim of the study was to evaluate the long-term outcomes of pelvic floor muscle (PFM) rehabilitation in males with lifelong premature ejaculation (PE), using intravaginal ejaculatory latency time (IELT) and the self-report Premature Ejaculation Diagnostic Tool (PEDT) as primary outcomes. A total of 154 participants were retrospectively reviewed in this study, with 122 completing the training protocol. At baseline, all participants had an IELT <=60 s and PEDT score >11. Participants completed a 12-week program of PFM rehabilitation, including physio-kinesiotherapy treatment, electrostimulation, and biofeedback, with three sessions per week, with 20 min for each component completed at each session. The effectiveness of intervention was evaluated by comparing the change in the geometric mean of IELT and PEDT values, from baseline, at 3, 6, and 12 months during the intervention, and at 24 and 36 months postintervention, using a paired sample 2-tailed t-test, including the associated 95% confidence intervals. Of the 122 participants who completed PFM rehabilitation, 111 gained control of their ejaculation reflex, with a mean IELT of 161.6 s and PEDT score of 2.3 at the 12-week endpoint of the intervention, representing an increase from baseline of 40.4 s and 17.0 scores, respectively, for IELT and PEDT (P < 0.0001). Of the 95 participants who completed the 36-month follow-up, 64% and 56% maintained satisfactory ejaculation control at 24 and 36 months postintervention, respectively. PMID- 29974887 TI - Annular scaly plaques in a girl. PMID- 29974888 TI - Vacuum sealing drainage: A novel treatment method for primary cutaneous Mycobacterium intracellulare infection. AB - The incidence of primary cutaneous Mycobacterium intracellulare infection is very low. We report a case of primary cutaneous M. intracellulare infection which presented as painful erythematous swelling of the right upper limb without systemic involvement. A novel technique of vacuum sealing drainage was successfully implemented after antimycobacterial treatment proved ineffective at the end of 3 months. Our technique also revealed some additional practical advantages. PMID- 29974886 TI - Secondary male hypogonadism: A prevalent but overlooked comorbidity of obesity. AB - Male hypogonadism associated with obesity is a very prevalent condition and is increasing in parallel with the epidemic prevalence of obesity. Low testosterone levels promote higher fat mass with reduced lean mass. Male hypogonadism is related to an increase in associated cardiometabolic complications, such as hypertension, type 2 diabetes mellitus, the metabolic syndrome, and cardiovascular disease. Its influence as a comorbidity of obesity is becoming more evident and should be evaluated and treated in at-risk patients. Mechanisms involved in this relationship include body composition changes, the presence of adipokines, insulin resistance, and other factors, some of which are still unknown. Weight loss and treatment to replace testosterone levels improve the metabolic profile and quality of life in patients with obesity and hypogonadism; these beneficial effects depend on treatment modality and duration of therapy. The use of testosterone replacement therapy may be indicated, as it has not been shown to increase cardiovascular risk, and retrospective studies suggest a reduction in events in men with metabolic syndrome and type 2 diabetes. PMID- 29974889 TI - Fragmented QRS (fQRS) Complex Predicts Adverse Cardiac Events of ST-Segment Elevation Myocardial Infarction Patients Undergoing Percutaneous Coronary Intervention and Thrombolysis. AB - BACKGROUND ST-segment elevation myocardial infarction (STEMI) is an acute and life-threatening disease. Adverse cardiac events (ACEs) are defined as cardiovascular death or worsening congestive heart failure in STEMI patients. The present study investigated the predictive role of fragmented QRS complex (fQRS) in risks of ACEs in STEMI. MATERIAL AND METHODS This study was a retrospective analysis involving patients who underwent percutaneous coronary intervention (PCI) or thrombolysis. STEMI patients were divided into the fQRS group (259 cases) and the non-fQRS group (161 cases). Basic information and clinical parameters were evaluated. ACEs, including hemodynamic instability, electrical instability (ventricular tachycardia event, ventricular fibrillation or atrioventricular heart-block) and death, were observed. The 12-lead ECG was used to obtain fQRS recordings. Thrombolytic recanalization was evaluated to confirm clinical outcomes of PCI and thrombolysis therapy. RESULTS Hemodynamic instability rates, electrical instability rates, and death in the fQRS group were significantly higher compared to the non-fQRS group (P=0.002, 0.000, and 0.010, respectively). PCI triggered significantly fewer ACEs compared to thrombolytic therapy in the fQRS group (P=0.000, 0.000, and 0.019, respectively). The fQRS group had higher thrombolysis failure rates and three-vessel lesion of coronary artery rates compared to the non-fQRS group (P=0.009 and 0.029, respectively). There were no differences between fQRS and non-fQRS groups in death rates of STEMI patients undergoing PCI and thrombolytic therapy. GRACE scores more than 140, EF less than 35%, and fQRS illustrated predictive potential for ACEs of STEMI patients. CONCLUSIONS fQRS is an independent predictor for the adverse cardiac events of STEMI patients undergoing PCI or thrombolysis. PMID- 29974890 TI - The analysis of drivers' reaction time using cell phone in the case of vehicle stabilization task. AB - OBJECTIVES: The article analyzes the driver's psychophysiological qualities such as complex reaction and individual ability to control the vehicle that has suddenly lost its stability. The comparative analysis of the duration of reaction time was performed to assess the negative influence of speaking on a phone and driving with one hand. MATERIAL AND METHODS: The experimental research was carried out on special training grounds with the road surface having low adhesion coefficient, where sudden lateral vehicle destabilization was caused by the moving plate mounted on the road surface. The vehicle onboard equipment was used for identifying the difference between the destabilization moment and the responsive driver's steering wheel movement which in this research was assumed as the reaction time. RESULTS: Statistical methods of research applied for the analysis of results showed high probability that the driver's actions would be significantly late in controlling a vehicle. When stabilizing a vehicle movement, the complex reaction time of a vehicle driver speaking on a mobile phone is increased by 18.1% as compared with the conventional driving by a driver not speaking on a phone. CONCLUSIONS: The risk of using the phone depends on the driver characteristics, traits and attitudes that affect the level of their experienced dangers, and the intensity of using mobile phones and driving. Speaking on a phone while driving increases the driver's reaction time and mental workload, and changes his or her visual overview ability as well as understanding of the situation. Int J Occup Med Environ Health 2018;31(5):633-648. PMID- 29974891 TI - Viral and Bacterial Co-Infection and Its Implications. PMID- 29974892 TI - Erratum: Mental health in UK Biobank: development, implementation and results from an online questionnaire completed by 157 366 participants - CORRIGENDUM. AB - [This corrects the article DOI: 10.1192/bjo.2018.12.]. PMID- 29974893 TI - Endothelial Cells May Have Tissue-Specific Origins. AB - Endothelial heterogeneity reflects many functions performed by endothelial cells (ECs) in various tissues. However, the origin of this heterogeneity is unclear. Here, we report that tissue-specific ECs in lungs, brain and liver co-expressed the lineage markers of their coordinating tissue-specific cells at very early stages. Specifically, we found that the pulmonary EC population was significantly suppressed after pulmonary epithelial-specific (Nkx2.1-Cre mediated) deletion of fetal liver kinase-1 (Flk1). Together, the results suggest that tissues-specific ECs may originate from the same progenitor cells as tissue-specific cells. PMID- 29974894 TI - An arene-tethered silylene ligand enabling reversible dinitrogen binding to iron and catalytic silylation. AB - An arene-tethered silylene ligand, L (L = PhC(tBuN)2SiCH2C(tBu)NAr, Ar = 2,6 iPr2C6H3), allowed the synthesis of three-coordinate Fe(ii) silylamido and piano stool Fe(0) dinitrogen complexes LFe[N(SiMe3)2]2 (3) and LFe-N2 (4), which not only exhibit interesting bonding but also enabled the catalytic silylation of N2 to yield N(SiMe3)3 under 1 atm of N2 at room temperature with high TONs. PMID- 29974902 TI - Parameterization and atomistic simulations of biomimetic membranes. AB - Biomimetic membranes, designed by combining proteins or protein-mimics with self assembled block copolymers, are emerging as novel hybrid materials with applications in the next generation of sensing and separation devices. However, designing such membranes requires a fundamental understanding of the atomic-scale interactions between biological channel proteins and their non-native polymeric membrane environment as it affects their stability and function. In principle, all-atom molecular dynamics (MD) simulations are well-suited to probe the atomistic details of channel/membrane interactions, but the absence of interatomic potentials is a major limiting factor in conducting such simulations. To alleviate this, we have developed CHARMM force-field compatible parameters and conducted all-atom explicit-solvent MD simulations of biomimetic membranes composed of block copolymers of poly(butadiene), poly(isoprene), and poly(ethylene oxide). Consistent with scaling laws and literature data, we report measurements on several structural properties that inform on molecular-scale features of chain conformations. Finally, we report simulations of a synthetic transport channel in selected membranes and characterize its functional behavior by measuring the single-channel water permeability. We suggest that the interatomic potentials and membrane models reported here could be useful in studies of other proteins as well as for deriving potentials for coarse-grained models to permit future simulations of large-scale protein/polymer membranes. PMID- 29974895 TI - High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo. AB - A novel Al18F labelled peptide tracer for PET imaging of oxytocin receptor has been accessed through a high radiochemical yield approach. This tracer showed comparable affinity and higher selectivity and stability compared to oxytocin, and was used to demonstrate direct nose-to-brain uptake following intranasal administration, a common yet controversial delivery route for oxytocin-based therapeutics. PMID- 29974903 TI - Glutathione-responsive homodithiacalix[4]arene-based nanoparticles for selective intracellular drug delivery. AB - Glutathione-responsive, paclitaxel-loaded nanoparticles based on homodithiacalix[4]arene were successfully developed, exhibiting selective drug release in cancer cells. PMID- 29974904 TI - Molecular dynamics simulations of carbon nanotube porins in lipid bilayers. AB - Artificial channels made of carbon nanotube (CNT) porins are promising candidates for applications in filtration and molecular delivery devices. Their symmetric shape and high mechanical, chemical, and thermal stability ensure well-defined transport properties, and at the same time make them ideal model systems for more complicated membrane protein pores. As the technology to produce and tune CNTs advances, simulations can aid in the design of customized membrane porins. Here we concentrate on CNTs embedded in lipid membranes. To derive design guidelines, we systematically studied the interaction of CNT porins with their surrounding lipids. For our simulations, we developed an AMBER- and Lipid14-compatible parameterization scheme for CNTs with different chirality and with functional groups attached to their rim, and a flexible coarse-grained description for open ended CNTs fitting to the MARTINI lipid model. We found that the interaction with lipid acyl chains is independent of the CNT chirality and the chemical details of functional groups at the CNT rims. The latter, however, are important for the interactions with lipid head groups, and for water permeability. The orientation and permeability of the pore are mainly determined by how well its hydrophobicity pattern matches the membrane. By identifying the factors that determine the structure both of isolated CNTs in lipid membranes and of CNT clusters, we set the foundation for a targeted design of CNT-membrane systems. PMID- 29974906 TI - Emerging investigator series: sunlight photolysis of 2,4-D herbicides in systems simulating leaf surfaces. AB - Pesticides are commonly applied on foliage, forming dry deposits on the leaf cuticular wax. However, their photochemical transformation in this lipophilic environment is much less understood compared with that in surface water. In this work, sunlight photolysis of six chlorinated phenoxyacetic acid herbicides (i.e., 2,4-D and structural analogues) was evaluated in four organic solvents, on quartz, and on paraffin wax. In solvents of low polarity (i.e., n-heptane and 2 propanol), direct photolysis of 2,4-D herbicides was enhanced due to the relatively high quantum yields in these solvents. Photolysis on paraffin wax was slower than photolysis on quartz by a factor of 3-9, but was comparable with that in solvents of low polarity. With environmentally relevant irradiation and surface loading, the half-lives of 2,4-D herbicides on paraffin wax were 27-159 h, which are within the same range reported for biodegradation, the dominant dissipation pathway in the current 2,4-D fate model. Product analyses showed that photoreductive dechlorination is the dominant pathway in organic solvents, accounting for 68-100% of parent compound decay. On quartz and paraffin wax surfaces, however, photoreductive dechlorination products accounted for <60% of parent compound decay. Combining kinetic modeling and product analyses, it was shown that neither could the two additional putative pathways (photosubstitution of chlorine by hydroxyl group and cleavage of the ether bond) fully account for the total phototransformation on surfaces. These results suggest that rapid photolysis on surfaces can be attributed to unique pathways that are absent in the organic solvent phase. PMID- 29974907 TI - A wet-chemistry-based hydrogel sensing platform for 2D imaging of pressure, chemicals and temperature. AB - Human skin can perceive pressure, chemical compounds and temperature with a high spatial resolution via specific receptors. Inspired by human skin, we present a wet-chemistry based hydrogel sensing platform for 2D imaging sensitive to specific external stimuli, e.g., pressure, chemicals and temperature. This platform is composed of a hydrogel pyramidal array on a single electrode. Each pyramid serves as a spatially separated reservoir for chemical reactions, enabling independent pixels for sensing without individual electrodes. Depending on the electrochemiluminescence (ECL) electrolyte for specific stimuli, our platform possesses 2D imaging capabilities with high sensitivity for pH and temperature in addition to pressure via the deformation of the viscoelastic hydrogel. This work represents an important step toward the application of sensitive chemical reactions for various external stimuli to biocompatible electronic skins based on hydrogels without addressing circuit for each pixel. PMID- 29974910 TI - A redox cycling-amplified electrochemical immunosensor for alpha-fetoprotein sensitive detection via polydopamine nanolabels. AB - A sandwich-type electrochemical immunosensor for sensitive detection of a tumor marker, alpha-fetoprotein (AFP), was fabricated by employing polydopamine detection antibody nanoparticles (PDANPs-Ab2) as selective redox cycling-based signal amplifiers on an electrodeposited nano-gold electrode. In this research, PDANPs prepared through oxidative polymerization of dopamine were found to amplify the oxidation charge transfer of the electrochemical mediator (1,1' ferrocene dimethanol, FDM), which was supported by cyclic voltammetry (CV) and X ray photoelectron spectroscopy (XPS) investigation. Therefore, PDANPs were utilized as label materials of electrochemical immunosensors to enhance sensitivity for the first time. Meanwhile, the nano-gold electrode was used as a platform to accelerate electron transfer and immobilize capture antibody (Ab1). The electrochemical performance of the AFP immunosensor was investigated in PBS containing FDM with CV. Under optimal conditions, the constructed AFP immunosensor exhibited a wide linear range from 1 pg mL-1 to 50 ng mL-1 and a low detection limit of 0.3 pg mL-1, as well as excellent stability, reproducibility and selectivity. Measurements of AFP in human serum gave excellent correlation with the clinical standard Chemiluminescence Microparticle Immuno Assay (CMIA). These results indicated that the developed immunosensor may have promising application in the clinical diagnosis of AFP and other tumor markers. PMID- 29974911 TI - Continuous wave pumped single-mode nanolasers in inorganic perovskites with robust stability and high quantum yield. AB - Perovskite lasers have aroused great interest in recent years due to their ultra low lasing threshold, high quantum yields, easily tuned emission colors and great potential for electrically pumped nanolasing, which opens up new possibilities in obtaining highly coherent light sources at the nanoscale. Compared with the widely studied organic-inorganic hybrid perovskites, the inorganic (CsPbX3) have gradually become an emerging research focus because of their relatively better stability. However, some problems still hinder their actual applications, such as the seldom explored lasing quantum yield and the difficulties of further improving stability. Herein, a simple method is proposed to synthesize CsPbX3 nanowires in ambient conditions, and these CsPbX3 nanowires exhibit perfect crystallization and outstanding stability (over 1 year). Perovskite lasing with single mode and a low threshold of 12.33 MUJ cm-2 as well as a high lasing quantum yield up to ~58% are obtained. More interestingly, a high quality single mode laser with ultra-narrow linewidth of 0.09 nm can be obtained when the CsPbX3 NWs are excited by continuous wave in low-temperature condition. Our results not only enrich the study of inorganic perovskite materials with a new synthetic method, but also uncover new lasing properties of CsPbX3 NWs, suggesting a broad application of the inorganic perovskite materials. PMID- 29974912 TI - Ligament size-dependent electrocatalytic activity of nanoporous Ag network for CO2 reduction. AB - Electrochemical CO2 reduction (ECR) depends significantly on the nanostructures of electrocatalysts. Here we show a nanoporous Ag network catalyst (np-Ag) for efficient electrochemical reduction of CO2. The np-Ag samples with an average ligament size of 21 nm (denoted by np-Ag (21 nm)) and 87 nm (denoted by np-Ag (87 nm)) were fabricated by dealloying the rapidly solidified Mg80Ag20 (wt%) alloy ribbons in 1 wt% citric acid and 5 wt% phosphoric acid, respectively. The ligament size effect on the electrocatalytic activity and selectivity of CO2 conversion into CO is investigated. When catalysing CO2 reduction in 0.1 M KHCO3, the np-Ag (21 nm) catalyst exhibits a significantly enhanced selectivity with a faradaic efficiency for CO formation of 85.0% at -0.8 V versus RHE, about two times that (41.2%) over the np-Ag (87 nm). Additionally, a superior catalytic activity is also achieved over the np-Ag (21 nm), with a >2.5-fold increase in the CO partial current density relative to the np-Ag (87 nm). The improved selectivity and activity of np-Ag (21 nm) are attributed to the enhanced electrochemical surface area, higher local pH derived from ligament size effect, as well as more defect sites (i.e., grain boundaries) in ligaments. PMID- 29974915 TI - Synthesis of hydrophilic HYNIC-[1,2,4,5]tetrazine conjugates and their use in antibody pretargeting with 99mTc. AB - Pretargeted imaging, based on the highly reactive process between [1,2,4,5]tetrazines with trans-cyclooctene (TCO), appears as an attractive strategy to overcome disadvantages associated with traditional radioimmunoconjugates. To be successful, the radiolabeled component should react in vivo with the conjugated antibody and the non reactive excess clear fast from the organism. Herein, we explore the in vivo effects of hydrophilic linker incorporation into [1,2,4,5]tetrazine systems bearing a 6-hydrazinonicotinyl (HYNIC) moiety for technetium-99m coordination. Incorporation of a polypeptide chain containing hydrophilic aminoacids, resulted in a derivative with renal clearance. Pretargeted bevacizumab imaging was used as proof of concept. PMID- 29974916 TI - Dynamic interfacial mechanical-thermal characteristics of atomically thin two dimensional crystals. AB - Owing to the flexible nanoelectronic applications of two-dimensional (2D) materials, further exploration of their nanoscale local mechanical properties and their coupled physical characteristics becomes extremely significant. The puckering effect is a typical micro/nanoscale local frictional characteristic generally in the tip-film-substrate system, which is simultaneously expected to be coupled with a dynamic thermal interfacial response. Here, applying scanning thermal microscopy (SThM), we observed a novel mechanical-thermal coupling effect in monolayer/bilayer MoS2 and WS2 films: puckering deformation can induce the enhancement of interfacial thermal resistance (TR). By the SThM method, the puckering effect was further proved to depend on the film thickness and the scan velocity. More importantly, the crystallographic orientation-dependent anisotropy of the puckering effect in atomically thin two-dimensional crystals was demonstrated by SThM. It is inferred that the puckering deformation of the film redistributes the in-plane stress, resulting in the isotropy breaking of the in plane stiffness. Such new findings are of great significance to help optimize the nanoscale tribological/thermal design and dynamic mechanical-thermal management of 2D-materials in nanoelectronics. PMID- 29974917 TI - Palladium catalyzed stereocontrolled synthesis of C-aryl glycosides using glycals and arenediazonium salts at room temperature. AB - A stereocontrolled synthesis of aryl-C-glycosides was achieved using glycals and aryldiazonium salts in the presence of palladium acetate. A wide range of glycals including d-glucal, d-galactal, l-rhamnal, d-xylal and d-ribal underwent C arylation at the anomeric carbon in the presence of different aryldiazonium tetrafluoroborates and gave synthetically useful 2,3-deoxy-3-keto-alpha-aryl-C glycosides in good to excellent yields. Broad substrate scope, simple operation and room temperature reactions make this protocol very attractive in organic synthesis. PMID- 29974918 TI - Synthesis of cationic molybdenum-cobalt heterometallic clusters protected against hydrolysis by macrocyclic triazacyclononane complexes. AB - Four kinds of cobalt-polyoxomolybdenum clusters were synthesized by a combination of polyoxomolybdates and a Co-tacn (tacn = 1,4,7-triazacyclononane) complex. The heterometallic polynuclear clusters were obtained by the reaction of Na2MoO4 and [Co(tacn)(H2O)3](CF3SO3)3.H2O in water. The peripherals of polyoxomolybdates are capped by thermodynamically stable [Co(tacn)]3+ protecting groups to prevent further hydrolysis and condensation reactions. Intra-molecular hydrogen bonds between N-H groups on tacn and oxygen atoms on the molybdate core contribute to the stability of the complexes in water. Under the optimized synthetic conditions, the molar ratios of Na2MoO4 and [Co(tacn)(H2O)3](CF3SO3)3.H2O were adjusted to 1 : 0.3, 1 : 0.9, or 1 : 1.5, producing [{Co(tacn)}2Mo3O12].2NaCF3SO3.7H2O (1), [{Co(tacn)}4H2Mo7O27](CF3SO3)2.13H2O (2), and [{Co(tacn)}4H3Mo4O17](CF3SO3)5.6H2O (3), respectively. As one of the most important factors, the adjustments of the pH values by changing the molar ratio enabled us to isolate these clusters. The presence of pyridine produces a neutral complex, [Co2(tacn)2(pyridine)Mo5O18].4.5H2O (4) containing a lacunary Lindqvist type polyoxomolybdate. The synthesis of complexes 2-4 is also possible starting from cluster 1, implying that 1 is a precursor for the formation of 2-4 in aqueous solution. Complexes 2-4 have a common structural building block, [{Co(tacn)}2Mo3O13], in each of the cluster units. The 1H NMR spectra of 2 and 3 in aqueous solution show multiple splitting patterns of methylene signals on tacn ligands according to the chemical environments indicated by the crystallographic structure. The 59Co NMR spectrum of cluster 3 in CH3NO2 has two signals from two different Co units with a 3 : 1 integration ratio ensuring the structural integrity in solution. The broadening of one of the signals for the 59Co NMR spectrum of cluster 3 in water as a protic solvent reveals the presence of the deprotonation equilibrium of the acidic protons on the cluster framework in water. PMID- 29974919 TI - Atomic structure of defects and dopants in 2D layered transition metal dichalcogenides. AB - Layered transition metal dichalcogenides (TMDs) offer monolayer 2D systems with diverse properties that extend beyond what graphene alone can achieve. The properties of TMDs are heavily influenced by the atomic structure and in particular imperfects in the crystallinity in the form of vacancy defects, grain boundaries, cracks, impurity dopants, ripples and edge terminations. This review will cover the current knowledge of the detailed structural forms of some of the most intensively studied 2D TMDs, such as MoS2, WSe2, MoTe2, WTe2, NbSe2, PtSe2, and also covers MXenes. The review will utilize results achieved using state-of the-art aberration corrected transmission electron microscopy, including annular dark-field scanning transmission electron microscopy (ADF-STEM) and electron energy loss spectroscopy (EELS), showing how elemental discrimination can be achieved to understand structure at a deep level. The review will also cover the impact of single atom substitutional dopants, such as Cr, V and Mn, and electron energy loss spectroscopy used to understand the local bonding configuration. It is expected that this review will provide an atomic level understanding of 2D TMDs with a connection to imperfections that can arise from chemical vapour deposition synthesis, intentional doping, rips and tears, dislocations, strain, polycrystallinity and confinement to nanoribbons. PMID- 29974921 TI - Proton transfer in nonpolar solvents: an approach to generate electrolytes in aprotic media. AB - Stabilizing charged species in nonpolar solvents is challenging due to their low dielectric constant. As a contrast to formally ionic electrolytes, two series of acidic "potential" electrolytes have been developed in this study. These can be ionized by combining them stoichiometrically with a small molecule base in a typical nonpolar solvent, n-dodecane. The electrolytic conductivity of solutions of bis(2-ethylhexyl)phosphoric acid as mixtures with linear and branched dioctylamines and trioctylamines was measured, and the solutions were found to become increasingly conductive as the concentration increased, demonstrating that proton transfer occurred between the two species. Linear octylamines were found to be most effective at deprotonation. An acid-tipped poly(lauryl methacrylate) polymer (PLMA48-COOH) was also studied to give a polymer soluble in n-dodecane with a single ionizable group located precisely at the end of the polymer chain. Trioctylamine could successfully deprotonate this acid group. Even in an aprotic solvent, the transfer of protons between acidic and basic moieties is a useful method for controlling the properties of dissolved molecules. PMID- 29974922 TI - Assembling Ni-Co phosphides/carbon hollow nanocages and nanosheets with carbon nanotubes into a hierarchical necklace-like nanohybrid for electrocatalytic oxygen evolution reaction. AB - Currently, designing and developing high-performance, cost-effective yet stable electrocatalysts for oxygen evolution reaction (OER) is a challenging task owing to the existing high overpotential and sluggish OER kinetics. Herein, we successfully fabricated a hierarchical necklace-like nanohybrid via assembling Ni Co mixed metal phosphides/carbon (NiCoP/C) hollow nanocages and nanosheets with carbon nanotubes (CNTs). It was revealed that Ni-Co-layered double hydroxide/carbon hollow nanocages and nanosheets derived from Co-based MOF polyhedrons (ZIF-67) could pass through CNTs and perpendicularly anchor onto the surface of CNTs, respectively, thus finally constructing a hierarchical CNTs@NiCoP/C nanohybrid via further low-temperature phosphorization. The as assembled CNTs@NiCoP/C electrocatalyst exhibited promising electrocatalytic performance towards OER with a low overpotential of about 0.297 V for reaching a current density of 10.0 mA cm-2 and a low Tafel slope of 57.35 mV dec-1 in 1.0 M KOH owing to the advantages of its unique superstructure and multiple composition. Furthermore, the present CNTs@NiCoP/C also possessed good long-term operation stability. This synthesis strategy involving the combination of transition metal phosphides and CNTs to form hierarchical nanostructures holds promising potential for designing highly OER-active electrocatalysts. PMID- 29974926 TI - [New Aims and Methods of Internal Psychosomatic Care - Guided by the Bio-Psycho Social Model]. PMID- 29974927 TI - [Web Surveys on Mobile Devices: Opportunities and Challenges]. PMID- 29974929 TI - Acute myeloid/T-lymphoblastic leukaemia (ATML) - a disease entity to look out for. PMID- 29974930 TI - Pleural effusion at diagnosis predicts extremely poor outcomes in patients with diffuse large B-cell lymphoma harbouring MYC rearrangement. PMID- 29974931 TI - Advances in understanding the pathogenesis of acquired aplastic anaemia. AB - This review examines the evidence that bone marrow failure (BMF) in aplastic anaemia (AA) is due to loss of haematopoietic stem cells (HSCs), which, in turn, is caused by deranged immunity and inflammation. We also consider how the course of the disease and the response to immuno-suppressive therapy are influenced by the nature and specificity of the pathogenic process. A somatic mutation of the PIGA gene underlies the clonal disease paroxysmal nocturnal haemoglobinuria (PNH): there is direct evidence that the expansion of the PIGA mutant clone results from Darwinian selection exerted by a glycosyl-phosphatidyl-inositol specific auto-immune attack. Thus, PNH patients are a unique subset of patients with AA, in whom haematopoiesis recovers through this escape mechanism. A similar process, although less effective, may operate when the auto-immune attack is against a human leucocyte antigen (HLA) molecule and an HLA mutation has produced a clone missing that molecule. We then discuss the significance of other mutant clones that are frequently found in AA, presumably due to a combination of genetic drift and selection. These clones are not causative of AA, but they emerge in AA and they may be pre-leukaemic: unlike a PIGA mutant clone, in general they are unable to effectively reconstitute haematopoiesis. PMID- 29974932 TI - Daily intra-abdominal pressure, Sequential Organ Failure Score and fluid balance predict duration of mechanical ventilation. AB - BACKGROUND: Elevated intra-abdominal pressure (IAP) is a common occurrence in mechanically ventilated patients in the intensive care unit (ICU). This study was undertaken to determine the relationship between IAP, pulmonary compliance and the duration of mechanical ventilation. METHODS: A prospective study of 220 consecutively enrolled mechanically ventilated patients admitted to a mixed surgical-medical ICU in a tertiary referral hospital. The IAP was measured at least twice daily, benchmarked against consensus guidelines. Dynamic pulmonary compliance was calculated together with admission Acute Physiology and Chronic Health Evaluation (APACHE III) score and daily Sequential Organ Failure Assessment (SOFA) score. RESULTS: No relationship between highest IAP for the day and pulmonary compliance (P = 0.61) was found. For each 5 mm Hg increase in IAP, the risk of remaining intubated increased 19% (HR = 1.19, 95% CI: 0.98-1.44); for each standard deviation increase in SOFA score (3.7 points), the risk of remaining intubated increased by 14% (HR = 1.14, 95% CI: 0.98-1.33); and for each 1 L increase in fluid balance, the risk of remaining intubated increased by 11% (HR = 1.11, 95% CI: 1.04-1.19). A nomogram was developed to predict the probability of extubation based on daily highest IAP for the day, SOFA score and fluid balance. CONCLUSION: IAPs did not correlate with pulmonary compliance in critically ill patients. Increased IAP was associated with a longer duration of mechanical ventilation. A nomogram integrating daily IAP, SOFA score and fluid balance may be used to predict the duration of mechanical ventilation. PMID- 29974933 TI - Cognitive impairment in hodgkin lymphoma survivors. AB - Cancer-related cognitive impairment (CRCI) is commonly reported post-chemotherapy in adults with solid tumours. Hodgkin lymphoma (HL) mostly affects young adults. Data regarding CRCI in HL survivors (HLS) are scarce. The current study aimed to objectively assess CRCI incidence and characteristics in HLS. HLS, who completed first-line (chemotherapy +/- radiation) therapy and remained in complete remission for 6 months to 5 years from therapy end, were evaluated. Age- and education-matched healthy individuals served as controls (n = 14). Test results were compared to population norms and healthy controls. Study participants completed self-reported questionnaires evaluating fatigue, depression, anxiety, quality of life and cognitive function. Subjects underwent neurocognitive evaluation, assessing processing speed, memory, attention, executive functions and intelligence domains. The present study included 51 HLS with a median age of 28 years, mean education of 14.5 +/- 2.5 years. Complaints related to cognitive deterioration and fatigue were significantly more severe and frequent in HLS compared to healthy controls. Objective neurocognitive evaluation demonstrated that 30% of HLS were impaired in >=2 cognitive domains. In conclusion, the present study demonstrates that fatigue and cognitive impairment, predominantly in executive functions and memory, constitute frequent and alarming findings in HLS. These adverse effects can persist and exert an impact on all aspects of life. PMID- 29974934 TI - Pressure measurement in the upper esophagus during cricoid pressure: A high resolution solid-state manometry study. AB - BACKGROUND: The use of cricoid pressure is controversial, and its ability to occlude the esophagus has been questioned. In this study, high-resolution solid state manometry was used to analyze pressure changes in the upper esophagus from cricoid pressure during modified rapid sequence induction. This is a secondary analysis of data from a previous study. METHODS: Seventeen healthy volunteers participated in a double-blind, randomized, placebo-controlled, cross-over study with primary aim to compare differences in the barrier pressure on the lower esophageal sphincter during rapid sequence induction with or without alfentanil. Standardized cricoid pressure of 30 N was applied 2 minutes after propolipid injection and held for 15 seconds and pressures in the esophagus were measured. RESULTS: Cricoid pressure resulted in a pressure increase of 127 +/- 98 mmHg (95% CI: 73-182) (placebo) and 123 +/- 74 mmHg (95% CI: 84-162) (alfentanil) at the level of the upper esophageal sphincter (UES), compared to baseline. The pressure difference around the UES compared to the proximal esophagus during cricoid pressure application was 165 +/- 100 mmHg (placebo) and 159 +/- 87 mmHg (alfentanil) (mean +/- 1 SD). CONCLUSION: This study using high-resolution solid state manometry under clinically relevant conditions shows that 30 N cricoid pressure generates high pressure in the area of the UES, far exceeding the levels previously considered necessary to prevent regurgitation. Additional studies are needed to clarify the effectiveness of cricoid pressure in preventing passive regurgitation before it is rejected as a part of rapid sequence induction. PMID- 29974935 TI - A population-based analysis of second primary malignancies in T-cell neoplasms. PMID- 29974936 TI - Second primary malignancy after multiple myeloma-population trends and cause specific mortality. AB - The management of multiple myeloma (MM) has evolved with the increased use of autologous haematopoietic cell transplantation (AHCT) and the introduction of new agents. AHCT and lenalidomide maintenance have been associated with increased risk of second primary malignancy (SPM). We iseutilised the Surveillance, Epidemiology and End Results 13 registries to analyse 9 833 patients diagnosed at age <65 years for three eras: 1995-99 (pre-thalidomide, limited use of AHCT), 2000-04 (post-thalidomide, pre-lenalidomide and bortezomib, increased isautilisation of AHCT) and 2005-09 (post-lenalidomide and bortezomib, higher isautilisation of AHCT). Changes in risk of SPM were assessed by utilising standardised incidence ratio (SIR) and cause-specific risk of death. Cumulative incidence of SPM at 90 months was 4.7%, 6.0% and 6.3% respectively, P = 0.0008. SIR for haematological malignancies in years 1-5 increased, from 1.28 (95% confidence interval [CI] 0.47-2.78) in 1995-99 to 2.17 (95% CI: 1.27-3.48) in 2005-09, due to increased risk of acute leukaemias and lymphomas. A similar trend was observed in years 6-10. Overall mortality in patients with MM declined sharply over time due to declines in MM-associated and cardiovascular mortality with no increase in risk of death from SPM. The evolution of MM therapy is linked to population-level increase in risk with no discernible effect in death from SPM. PMID- 29974937 TI - The Aging Tsunami and Senior Healthcare Development in China. AB - China faces an aging tsunami. By the end of 2016, the number of older adults aged 60 and older reached 230 million. This number is projected to reach 418 million by 2035 and peak at 487 million by 2053. The number of individuals aged 80 and older, the oldest adults, reached 26 million and continues to grow by 1 million a year. The socioeconomic context, characterized by an inverted pyramid family structure and the number of "empty nesters," has greatly compromised traditional Chinese family support for older adults. This article aims to provide an overview of geriatrics development in China. It begins with a brief account of the dramatic demographic shift, major socioeconomic factors, China's healthcare system, and reform related to senior health with a historical perspective. It then describes recent advances in government policy and support and development of a geriatrics physician workforce, care models, primary care networks, and privately owned senior care facilities and support services. Although it is impossible to cover all aspects of the topic, it is hoped that this article provides readers an overall picture of Chinese geriatrics and senior healthcare development in a complex and evolving healthcare system. Geriatrics communities in the United States and around the world will undoubtedly learn and benefit from the unparalleled and continued efforts to address this unprecedented opportunity and challenge in China. PMID- 29974938 TI - Applying the human factors analysis and classification system to critical incident reports in anaesthesiology. AB - BACKGROUND: The Human Factors Analysis and Classification System (HFACS) was developed as a practical taxonomy to investigate and analyse the human contribution to accidents and incidents. Based on Reason's "Swiss Cheese Model", it considers individual, environmental, leadership and organizational contributing factors in four hierarchical levels. The aim of this study was to assess the applicability of a modified HFACS taxonomy to incident reports from a large, anonymous critical incident database with the goal of gaining valuable insight into underlying, more systemic conditions and recurring schemes that might add important information for future incident avoidance. METHODS: We analysed 50 reports from an anonymous, anaesthesiologic, single-centre Critical Incident Reporting System using a modified HFACS-CIRS taxonomy. The 19 HFACS categories were further subdivided into a total of 117 nanocodes representing specific behaviours or preconditions for incident development. RESULTS: On an individual level, the most frequent contributions were decision errors, attributed to inadequate risk assessment or critical-thinking failure. Communication and Coordination, mostly due to inadequate or ineffective communication, was contributory in two-thirds of reports. Half of the reports showed contributory complex interactions in a sociotechnical environment. Ratability scores were noticeably lower for categories evaluating leadership and organizational influences, necessitating careful interpretation. CONCLUSIONS: We applied the HFACS taxonomy to the analysis of CIRS reports in anaesthesiology. This constitutes a structured approach that, especially when applied to a large data set, might help guide future mitigation and intervention strategies to reduce critical incidents and improve patient safety. Improved, more structured reporting templates could further optimize systematic analysis. PMID- 29974939 TI - The prevalence of specific learning disorder in mathematics and comorbidity with other developmental disorders in primary school-age children. AB - Mathematics difficulties are common in both children and adults, and they can have a great impact on people's lives. A specific learning disorder in mathematics (SLDM or developmental dyscalculia) is a special case of persistent mathematics difficulties, where the problems with maths cannot be attributed to environmental factors, intellectual disability, or mental, neurological or physical disorders. The aim of the current study was to estimate the prevalence rate of SLDM, any gender differences in SLDM, and the most common comorbid conditions. The DSM-5 provides details regarding these only for specific learning disorders in general, but not specifically for SLDM. We also compared the prevalence rates obtained on the basis of the DSM-IV and DSM-5 criteria. We investigated the performance of 2,421 primary school children on standardized tests of mathematics, English, and IQ, and several demographic factors over the primary school years. We applied the DSM-5 diagnostic criteria to identify children with a potential diagnosis of SLDM. Six per cent of our sample had persistent, severe difficulties with mathematics, and, after applying the exclusion criteria, 5.7% were identified as having an SLDM profile. Both persistent maths difficulties and consistently exceptionally high performance in maths were equally common in males and females. About half of the children with an SLDM profile had some form of language or communication difficulty. Some of these children also had a diagnosis of autism, social, emotional, and behavioural difficulties or attention deficit and hyperactivity disorder. Our findings have important implications for research and intervention purposes, which we discuss in the study. PMID- 29974940 TI - Skin bacterial colonizations and superinfections in immunocompetent patients with scabies. AB - BACKGROUND: Skin bacterial colonizations and superinfections are well-known complications of scabies, in particular, in tropical and subtropical countries. However, only very rare studies on skin bacterial colonizations and superinfections have been carried out in immunocompetent patients with scabies living in Western countries. METHODS: Eighty-nine Caucasian adult immunocompetent patients with scabies living in Milan, Italy, were subjected to bacteriologic examinations of the skin. Clinical diagnosis of scabies was confirmed in all patients by means of microscopic examinations: they were considered positive when adults or eggs or feces of Sarcoptes scabiei var. hominis were visible. In all patients, six skin swabs (three for aerobic and three for anaerobic bacteria) were taken in three different areas before the beginning of the treatment. RESULTS: No clinical manifestations of pyoderma were observed. Bacteriologic examinations were positive in 5/89 patients (5.6%). Bacteriologic cultures were positive for Staphylococcus aureus in all five patients; in one patient, they were also positive for Escherichia coli. No growth of anaerobic bacteria was recorded. CONCLUSIONS: According to the results of this study, skin bacterial colonizations and superinfections in immunocompetent adult patients with scabies living in Milan are uncommon. Bacteriologic examinations may therefore be considered as an unnecessary routine procedure. PMID- 29974941 TI - Recurrent deep venous thrombosis in a leprosy patient on Sofosbuvir regimen for HCV: a lepra reaction? PMID- 29974942 TI - Tracing the origins of active amide group-positive drug-induced pemphigus vulgaris along the Silk Road: a case report of candesartan-induced pemphigus vulgaris and review of nonthiol drug-induced pemphigus. PMID- 29974944 TI - Direct-acting antiviral drugs are triggers for psoriasis: report of three cases. PMID- 29974943 TI - Gene mutations and clonal architecture in myelodysplastic syndromes and changes upon progression to acute myeloid leukaemia and under treatment. AB - Knowledge of the molecular and clonal characteristics in the myelodysplastic syndromes (MDS) and during progression to acute myeloid leukaemia (AML) is essential to understand the disease dynamics and optimize treatment. Sequencing serial bone marrow samples of eight patients, we observed that MDS featured a median of 3 mutations. Mutations in genes involved in RNA-splicing or epigenetic regulation were most frequent, and exclusively present in the major clone. Minor subclones were distinguishable in three patients. As the MDS progressed, a median of one mutation was gained, leading to clonal outgrowth. No AML developed genetically independent of a pre-existing clone. The gained mutation mostly affected genes encoding signalling proteins. Additional acquisition of genomic aberrations frequently occurred. Upon treatment, emergence of new clones could be observed. As confirmed by single-cell sequencing, multiple mutations in identical genes in different clones were present within individual patients. DNA methylation profiling in patients without identification of novel mutations in AML revealed methylation changes in individual genes. In conclusion, our data complement previous observations on the mutational and clonal characteristics in MDS and at progression. Moreover, DNA-methylation changes may be associated with progression in single patients. Redundancy of mutated genes in different clones suggests fertile grounds promoting clonal selection or acquisition. PMID- 29974945 TI - Acne prevalence in 9 to 14-year-old old patients attending pediatric ambulatory clinics in Italy. AB - BACKGROUND: Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous follicles that affects patients of all ages with a younger onset being more common than in the past. OBJECTIVES: To investigate on the prevalence, clinical features and treatments of acne in 9 to 14-year-old patients. METHODS: A prospective observational study was conducted between April 2016 and May 2016. The study population consisted of patients attending 32 different pediatric ambulatory clinics located in Italy (North: 56.25%, Center: 18.75%, South: 25%). For each patient, a specific questionnaire was registered: i) demographic data; ii) past personal history of acne; iii) auxologic parameters. Further data were gathered for patients suffering from acne at study enrollment: i) body areas involved by the disease; ii) acne severity evaluated through a 0-5 scale (Global Evaluation Acne scale); iii) acne treatments. RESULTS: A total of 683 children (49.2% male; mean age 11.05 +/- 1.4 years) were enrolled. Acne was present in 234/683 (34.3%) of the patients, and its prevalence increased with age being higher after 13 years of age (85/234; 36.3%) and lowest at 9 years of age (14/234; 6%). The majority of the patients suffering from acne showed a mild or almost clear disease state severity (GEA scale 1 or 2) (207/234, 88.5%), whereas severe or very severe forms (GEA scale 4 or 5) represented only 4/234, 1.7% of the cases. CONCLUSIONS: Acne is not a rare disease in pre-adolescent age. Adequate and prompt treatment is also needed in this class of patient to minimize disease burden and potential future disease worsening. PMID- 29974947 TI - Early psoriatic arthritis in psoriatic patients: risk factors and screening for rheumatological evaluation. PMID- 29974948 TI - An unbalanced monocyte macrophage polarization in the bone marrow microenvironment of patients with poor graft function after allogeneic haematopoietic stem cell transplantation. AB - Poor graft function (PGF) is a severe complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). Murine studies have demonstrated that effective haematopoiesis depends on the specific bone marrow (BM) microenvironment. Increasing evidence shows that BM macrophages (MFs), which constitute an important component of BM immune microenvironment, are indispensable for the regulation of haematopoietic stem cells (HSCs) in the BM. However, little is known about the number and function of BM MFs or whether they directly interact with HSCs in PGF patients. In the current prospective case control study, PGF patients showed a significant increase in classically activated inflammatory MFs (M1; 2.18 +/- 0.11% vs. 0.82 +/- 0.06%, P < 0.0001), a striking reduction in alternatively activated anti-inflammatory MFs (M2; 3.02 +/- 0.31% vs. 21.89 +/- 0.90%, P < 0.0001), resulting in a markedly increased M1/M2 ratio (0.82 +/- 0.06 vs. 0.06 +/- 0.002; P < 0.0001) in the BM compared with good graft function patients. Meanwhile, standard monocyte subsets were altered in PGF patients. Dysfunctional BM MFs, which were characterized by reduced proliferation, migration and phagocytosis, were evident in PGF patients. Furthermore, BM MFs from PGF patients with high tumour necrosis factor-alpha and interleukin 12 levels and low transforming growth factor-beta levels, led to impaired BM CD34+ cell function. In summary, our data indicate that an unbalanced BM M1/M2 ratio and dysfunctional MFs may contribute to the occurrence of PGF following allo-HSCT. PMID- 29974949 TI - Prevalence and outcomes of uncommon BCR-ABL1 fusion transcripts in patients with chronic myeloid leukaemia: data from a single centre. AB - To explore the type, prevalence and outcomes in chronic myeloid leukaemia (CML) patients with uncommon BCR-ABL1 transcripts in the era of tyrosine kinase inhibitors (TKIs), uncommon BCR-ABL1 transcripts were screened in 4750 patients by multiplex polymerase chain reaction (PCR), and type-specific real-time quantitative PCR was regularly performed for molecular monitoring. A total of 19 uncommon transcripts, including e1a2, e1a3, e6a2, e8a2, e12a2, unusual e13a2, e13a3, unusual e14a2, e14a3 and e19a2 were identified in 83 (1.7%) patients. The three most frequent types were e19a2, e13a3/e14a3 and e1a2. Compared with the 571 newly diagnosed CML patients in chronic phase with common e13a2/e14a2 transcripts receiving frontline imatinib therapy, patients with the e19a2 (n = 16) and e1a2 (n = 11) transcripts had significantly reduced probabilities of 1-year complete cytogenetic response (CCyR, P = 0.0004 and 0.016) and major molecular response (MMR, P = 0.0018 and 0.0035), and patients with the e13a3/e14a3 transcript (n = 10) had significantly increased probabilities of 1-year CCyR (P = 0.0072) and MMR (P = 0.0073). Patients with the e19a2 transcript had low probabilities of 2-year event-free survival (EFS, P = 0.0004) and progression-free survival (P = 0.0067), and patients with the e1a2 transcript had low probability of 2-year EFS (P < 0.0001). Therefore, uncommon BCR-ABL1 fusion transcripts are rare and diverse in patients with CML and may be relevant for TKI therapy outcomes. PMID- 29974946 TI - Effectiveness of a multidisciplinary patient care bundle for reducing surgical site infections. AB - BACKGROUND: Surgical-site infection (SSI) is associated with significant healthcare costs. To reduce the high rate of SSI among patients undergoing colorectal surgery at a cancer centre, a comprehensive care bundle was implemented and its efficacy tested. METHODS: A pragmatic study involving three phases (baseline, implementation and sustainability) was conducted on patients treated consecutively between 2013 and 2016. The intervention included 13 components related to: bowel preparation; oral and intravenous antibiotic selection and administration; skin preparation, disinfection and hygiene; maintenance of normothermia during surgery; and use of clean instruments for closure. SSI risk was evaluated by means of a preoperative calculator, and effectiveness was assessed using interrupted time-series regression. RESULTS: In a population with a mean BMI of 30 kg/m2 , diabetes mellitus in 17.5 per cent, and smoking history in 49.3 per cent, SSI rates declined from 11.0 to 4.1 per cent following implementation of the intervention bundle (P = 0.001). The greatest reductions in SSI rates occurred in patients at intermediate or high risk of SSI: from 10.3 to 4.7 per cent (P = 0.006) and from 19 to 2 per cent (P < 0.001) respectively. Wound care modifications were very different in the implementation phase (43.2 versus 24.9 per cent baseline), including use of an overlying surface vacuum dressing (17.2 from 1.4 per cent baseline) or leaving wounds partially open (13.2 from 6.7 per cent baseline). As a result, the biggest difference was in wound-related rather than organ-space SSI. The median length of hospital stay decreased from 7 (i.q.r. 5-10) to 6 (5-9) days (P = 0.002). The greatest reduction in hospital stay was seen in patients at high risk of SSI: from 8 to 6 days (P < 0.001). SSI rates remained low (4.5 per cent) in the sustainability phase. CONCLUSION: Meaningful reductions in SSI can be achieved by implementing a multidisciplinary care bundle at a hospital-wide level. PMID- 29974951 TI - Impressum. PMID- 29974950 TI - DTR-mediated conditional cell ablation-Progress and challenges. AB - Cell ablation is a valuable complement to mutagenesis for experimentally defining specific cell functions in physiology and pathophysiology in small animal models. One of the most popular ablation strategies involves transgenic expression of a primate diphtheria toxin receptor (DTR) on murine cells that are otherwise resistant to the bacterial exotoxin. The efforts of many laboratories using the DTR approach over the years have yielded numerous valuable insights into specific cell functions. Here, we will discuss the technical aspects of the DTR approach, including the strengths, pitfalls, and future strategies to overcome the shortcomings, highlighting a recent paper published in the European Journal of Immunology [El Hachem et al. Eur. J. Immunol. 2018 https://doi.org/10.1002/eji.201747351]. A particular focus will be given to the application of DTR approach to decipher in vivo functions of the murine myeloid cell compartment. PMID- 29974952 TI - Rothenfels Castle - the place to be for immunology of infection. PMID- 29974953 TI - Effects of total fat intake on bodyweight in children. AB - BACKGROUND: As part of efforts to prevent childhood overweight and obesity, we need to understand the relationship between total fat intake and body fatness in generally healthy children. OBJECTIVES: To assess the effects and associations of total fat intake on measures of weight and body fatness in children and young people not aiming to lose weight. SEARCH METHODS: For this update we revised the previous search strategy and ran it over all years in the Cochrane Library, MEDLINE (Ovid), MEDLINE (PubMed), and Embase (Ovid) (current to 23 May 2017). No language and publication status limits were applied. We searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov for ongoing and unpublished studies (5 June 2017). SELECTION CRITERIA: We included randomised controlled trials (RCTs) in children aged 24 months to 18 years, with or without risk factors for cardiovascular disease, randomised to a lower fat (30% or less of total energy (TE)) versus usual or moderate-fat diet (greater than 30%TE), without the intention to reduce weight, and assessed a measure of weight or body fatness after at least six months. We included prospective cohort studies if they related baseline total fat intake to weight or body fatness at least 12 months later. DATA COLLECTION AND ANALYSIS: We extracted data on participants, interventions or exposures, controls and outcomes, and trial or cohort quality characteristics, as well as data on potential effect modifiers, and assessed risk of bias for all included studies. We extracted body weight and blood lipid levels outcomes at six months, six to 12 months, one to two years, two to five years and more than five years for RCTs; and for cohort studies, at baseline to one year, one to two years, two to five years, five to 10 years and more than 10 years. We planned to perform random effects meta-analyses with relevant subgrouping, and sensitivity and funnel plot analyses where data allowed. MAIN RESULTS: We included 24 studies comprising three parallel-group RCTs (n = 1054 randomised) and 21 prospective analytical cohort studies (about 25,059 children completed). Twenty-three studies were conducted in high-income countries. No meta-analyses were possible, since only one RCT reported the same outcome at each time point range for all outcomes, and cohort studies were too heterogeneous to combine.Effects of dietary counselling to reduce total fat intake from RCTsTwo studies recruited children aged between 4 and 11 years and a third recruited children aged 12 to 13 years. Interventions were combinations of individual and group counselling, and education sessions in clinics, schools and homes, delivered by dieticians, nutritionists, behaviourists or trained, supervised teachers. Concerns about imprecision and poor reporting limited our confidence in our findings. In addition, the inclusion of hypercholesteraemic children in two trials raised concerns about applicability.One study of dietary counselling to lower total fat intake found that the intervention may make little or no difference to weight compared with usual diet at 12 months (mean difference (MD) -0.50 kg, 95% confidence interval (CI) -1.78 to 0.78; n = 620; low-quality evidence) and at three years (MD -0.60 kg, 95% CI -2.39 to 1.19; n = 612; low-quality evidence). Education delivered as a classroom curriculum probably decreased BMI in children at 17 months (MD -1.5 kg/m2, 95% CI -2.45 to -0.55; 1 RCT; n = 191; moderate-quality evidence). The effects were smaller at longer term follow-up (five years: MD 0 kg/m2, 95% CI 0.63 to 0.63; n = 541; seven years; MD -0.10 kg/m2, 95% CI -0.75 to 0.55; n = 576; low-quality evidence).Dietary counselling probably slightly reduced total cholesterol at 12 months compared to controls (MD -0.15 mmol/L, 95% CI -0.24 to 0.06; 1 RCT; n = 618; moderate-quality evidence), but may make little or no difference over longer time periods. Dietary counselling probably slightly decreased low-density lipoprotein (LDL) cholesterol at 12 months (MD -0.12 mmol/L, 95% CI -0.20 to -0.04; 1 RCT; n = 618, moderate-quality evidence) and at five years (MD -0.09, 95% CI -0.17 to -0.01; 1 RCT; n = 623; moderate-quality evidence), compared to controls. Dietary counselling probably made little or no difference to HDL-C at 12 months (MD -0.03 mmol/L, 95% CI -0.08 to 0.02; 1 RCT; n = 618; moderate-quality evidence), and at five years (MD -0.01 mmol/L, 95% CI 0.06 to 0.04; 1 RCT; n = 522; moderate-quality evidence). Likewise, counselling probably made little or no difference to triglycerides in children at 12 months (MD -0.01 mmol/L, 95% CI -0.08 to 0.06; 1 RCT; n = 618; moderate-quality evidence). Lower versus usual or modified fat intake may make little or no difference to height at seven years (MD -0.60 cm, 95% CI -2.06 to 0.86; 1 RCT; n = 577; low-quality evidence).Associations between total fat intake, weight and body fatness from cohort studiesOver half the cohort analyses that reported on primary outcomes suggested that as total fat intake increases, body fatness measures may move in the same direction. However, heterogeneous methods and reporting across cohort studies, and predominantly very low-quality evidence, made it difficult to draw firm conclusions and true relationships may be substantially different. AUTHORS' CONCLUSIONS: We were unable to reach firm conclusions. Limited evidence from three trials that randomised children to dietary counselling or education to lower total fat intake (30% or less TE) versus usual or modified fat intake, but with no intention to reduce weight, showed small reductions in body mass index, total- and LDL-cholesterol at some time points with lower fat intake compared to controls. There were no consistent effects on weight, high-density lipoprotein (HDL) cholesterol or height. Associations in cohort studies that related total fat intake to later measures of body fatness in children were inconsistent and the quality of this evidence was mostly very low. Most studies were conducted in high-income countries, and may not be applicable in low- and middle-income settings. High-quality, longer-term studies are needed, that include low- and middle-income settings to look at both possible benefits and harms. PMID- 29974954 TI - Low urinary levels of angiotensin-converting enzyme 2 may contribute to albuminuria in children with sickle cell anaemia. PMID- 29974955 TI - BCR kinase inhibitors, idelalisib and ibrutinib, are active and effective in Richter syndrome. PMID- 29974956 TI - Infectious and immunological sequelae of daratumumab in multiple myeloma. PMID- 29974957 TI - Potential involvement of ubiquitin-proteasome system dysfunction associated with oxidative stress in the pathogenesis of sickle cell disease. AB - The ubiquitin-proteasome system (UPS) is an important intracellular proteolytic pathway responsible for the degradation of proteins and oxidative damage; hence it plays a central role in maintaining homeostasis of red blood cells (RBCs). The present study investigated the levels of polyubiquitination, the function of proteasomes and effect of hydroxycarbamide (HC) therapy in RBCs from sickle cell disease (SCD) patients. Polyubiquitinated proteins were found to be elevated in untreated SCD (UT-SCD) patients compared to those in HC-treated SCD patients (HC SCD) and controls. Activities of beta1 and beta2 subunits were a little higher in UT-SCD patients, and much higher proteolytic activities were observed in all three subunits (beta1, beta2 and beta5) of RBCs in HC-SCD patients compared to those of UT-SCD patients and controls, although the protein levels of these subunits remained approximately the same. It is notable that, despite HC therapy, some patients showed persistent complications and accumulation of polyubiquitinated proteins. The enhanced proteasomal activity among HC-treated patients might remove the polyubiquitinated protein and could be one of the important mechanisms of therapeutic action. These findings could be useful to understand the pathophysiology of SCD and its clinical heterogeneity and identify a suitable therapeutic target for the better management of these patients. PMID- 29974958 TI - Accounting for landscape heterogeneity improves spatial predictions of tree vulnerability to drought. AB - As climate change continues, forest vulnerability to droughts and heatwaves is increasing, but vulnerability varies regionally and locally through landscape position. Also, most models used in forecasting forest responses to heat and drought do not incorporate relevant spatial processes. In order to improve spatial predictions of tree vulnerability, we employed a nonlinear stochastic model of soil moisture dynamics accounting for landscape differences in aspect, topography and soils. Across a watershed in central Texas we modeled dynamic water stress for a dominant tree species, Juniperus ashei, and projected future dynamic water stress through the 21st century. Modeled dynamic water stress tracked spatial patterns of remotely sensed drought-induced canopy loss. Accuracy in predicting drought-impacted stands increased from 60%, accounting for spatially variable soil conditions, to 72% when also including lateral redistribution of water and radiation/temperature effects attributable to aspect. Our analysis also suggests that dynamic water stress will increase through the 21st century, with trees persisting at only selected microsites. Favorable microsites/refugia may exist across a landscape where trees can persist; however, if future droughts are too severe, the buffering capacity of an heterogeneous landscape could be overwhelmed. Incorporating spatial data will improve projections of future tree water stress and identification of potential resilient refugia. PMID- 29974959 TI - The neurobiology of interoception in health and disease. AB - Interoception is the sensing of internal bodily sensations. Interoception is an umbrella term that encompasses (1) the afferent (body-to-brain) signaling through distinct neural and humoral (including immune and endocrine) channels; (2) the neural encoding, representation, and integration of this information concerning internal bodily state; (3) the influence of such information on other perceptions, cognitions, and behaviors; (4) and the psychological expression of these representations as consciously accessible physical sensations and feelings. Interoceptive mechanisms ensure physiological health through the cerebral coordination of homeostatic reflexes and allostatic responses that include motivational behaviors and associated affective and emotional feelings. Furthermore, the conscious, unitary sense of self in time and space may be grounded in the primacy and lifelong continuity of interoception. Body-to-brain interactions influence physical and mental well-being. Consequently, we show that systematic investigation of how individual differences, and within-individual changes, in interoceptive processing can contribute to the mechanistic understanding of physical and psychological disorders. We present a neurobiological overview of interoception and describe how interoceptive impairments at different levels relate to specific physical and mental health conditions, including sickness behaviors and fatigue, depression, eating disorders, autism, and anxiety. We frame these findings in an interoceptive predictive processing framework and highlight potential new avenues for treatments. PMID- 29974960 TI - From manual periodontal probing to digital 3-D imaging to endoscopic capillaroscopy: Recent advances in periodontal disease diagnosis. AB - Deepened periodontal pockets exert a significant pathological burden on the host and its immune system, particularly in a patient with generalized moderate to severe periodontitis. This burden is extensive and longitudinal, occurring over decades of disease development. Considerable diagnostic and prognostic successes in this regard have come from efforts to measure the depths of the pockets and their contents, including level of inflammatory mediators, cellular exudates and microbes; however, the current standard of care for measuring these pockets, periodontal probing, is an analog technology in a digital age. Measurements obtained by probing are variable, operator dependent and influenced by site specific factors. Despite these limitations, manual probing is still the standard of care for periodontal diagnostics globally. However, it is becoming increasingly clear that this technology needs to be updated to be compatible with the digital technologies currently being used to image other orofacial structures, such as maxillary sinuses, alveolar bone, nerve foramina and endodontic canals in 3 dimensions. This review aims to summarize the existing technology, as well as new imaging strategies that could be utilized for accurate evaluation of periodontal pocket dimensions. PMID- 29974961 TI - Preclinical models for the study of Barrett's carcinogenesis. AB - Barrett's esophagus (BE) is clinically significant, as it is the only known precursor lesion for esophageal adenocarcinoma. To develop improved therapies for the treatment of BE, a greater understanding of the disease process at the molecular genetic level is needed. However, achieving a greater understanding will require improved preclinical models so that the disease process can be more closely studied and novel therapies can be tested. Our concise review highlights progress in the development of preclinical models for the study of BE and identifies the most suitable model in which to test novel therapies. PMID- 29974962 TI - Preparing plants for improved cold tolerance by priming. AB - Cold is a major stressor, which limits plant growth and development in many parts of the world, especially in the temperate climate zones. A large number of experimental studies has demonstrated that not only acclimation and entrainment but also the experience of single short stress events of various abiotic or biotic kinds (priming stress) can improve the tolerance of plants to chilling temperatures. This process, called priming, depends on a stress "memory". It does not change cold sensitivity per se but beneficially modifies the response to cold and can last for days, months, or even longer. Elicitor factors and antagonists accumulate due to increased biosynthesis or decreased degradation either during or after the priming stimulus. Comparison of priming studies investigating improved tolerance to chilling temperatures highlighted key regulatory functions of ROS/RNS and antioxidant enzymes, plant hormones, especially jasmonates, salicylates, and abscisic acid, and signalling metabolites, such as beta- and gamma-aminobutyric acid (BABA and GABA) and melatonin. We conclude that these elicitors and antagonists modify local and systemic cold tolerance by integration into cold-induced signalling cascades. PMID- 29974963 TI - Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: A randomized, double-blind, placebo controlled study. AB - BACKGROUND: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double blind, placebo-controlled study. METHODS: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages. RESULTS: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes >=16). CONCLUSION: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU. PMID- 29974964 TI - Bayesian population pharmacokinetic modeling of florfenicol in pigs after intravenous and intramuscular administration. AB - Bayesian population pharmacokinetic models of florfenicol in healthy pigs were developed based on retrospective data in pigs either via intravenous (i.v.) or intramuscular (i.m.) administration. Following i.v. administration, the disposition of florfenicol was best described by a two-compartment open model with the typical values of half-life at alpha phase (t1/2alpha ), half-life at beta phase (t1/2beta ), total body clearance (Cl), and volume of distribution (Vd ) were 0.132 +/- 0.0289, 2.78 +/- 0.166 hr, 0.215 +/- 0.0102, and 0.841 +/- 0.0289 L kg-1 , respectively. The disposition of florfenicol after i.m. administration was best described by a one-compartment open model. The typical values of maximum concentration of drug in serum (Cmax ), elimination half-life (t1/2Kel ), Cl, and Volume (V) were 5.52 +/- 0.605 MUg/ml, 9.96 +/- 1.12 hr, 0.228 +/- 0.0154 L hr-1 kg-1 , and 3.28 +/- 0.402 L/kg, respectively. The between-subject variabilities of all the parameters after i.m. administration were between 25.1%-92.1%. Florfenicol was well absorbed (94.1%) after i.m. administration. According to Monte Carlo simulation, 8.5 and 6 mg/kg were adequate to exert 90% bactericidal effect against Actinobacillus pleuropneumoniae after i.v. and i.m. administration. PMID- 29974965 TI - Reductions in tree performance during hotter droughts are mitigated by shifts in nitrogen cycling. AB - Climate warming should result in hotter droughts of unprecedented severity in this century. Such droughts have been linked with massive tree mortality, and data suggest that warming interacts with drought to aggravate plant performance. Yet how forests will respond to hotter droughts remains unclear, as does the suite of mechanisms trees use to deal with hot droughts. We used an ecosystem scale manipulation of precipitation and temperature on pinon pine (Pinus edulis) and juniper (Juniperus monosperma) trees to investigate nitrogen (N) cycling induced mitigation processes related to hotter droughts. We found that while negative impacts on plant carbon and water balance are manifest after prolonged drought, performance reductions were not amplified by warmer temperatures. Rather, increased temperatures for 5 years stimulated soil N cycling under pinon trees and modified tree N allocation for both species, resulting in mitigation of hotter drought impacts on tree water and carbon functions. These findings suggest that adjustments in N cycling are likely after multi-year warming conditions and that such changes may buffer reductions in tree performance during hotter droughts. The results highlight our incomplete understanding of trees' ability to acclimate to climate change, raising fundamental questions about the resistance potential of forests to long-term, compound climatic stresses. PMID- 29974966 TI - Accuracy of genotype imputation in Labrador Retrievers. AB - The dog is a valuable model species for the genetic analysis of complex traits, and the use of genotype imputation in dogs will be an important tool for future studies. It is of particular interest to analyse the effect of factors like single nucleotide polymorphism (SNP) density of genotyping arrays and relatedness between dogs on imputation accuracy due to the acknowledged genetic and pedigree structure of dog breeds. In this study, we simulated different genotyping strategies based on data from 1179 Labrador Retriever dogs. The study involved 5826 SNPs on chromosome 1 representing the high density (HighD) array; the low density (LowD) array was simulated by masking different proportions of SNPs on the HighD array. The correlations between true and imputed genotypes for a realistic masking level of 87.5% ranged from 0.92 to 0.97, depending on the scenario used. A correlation of 0.92 was found for a likely scenario (10% of dogs genotyped using HighD, 87.5% of HighD SNPs masked in the LowD array), which indicates that genotype imputation in Labrador Retrievers can be a valuable tool to reduce experimental costs while increasing sample size. Furthermore, we show that genotype imputation can be performed successfully even without pedigree information and with low relatedness between dogs in the reference and validation sets. Based on these results, the impact of genotype imputation was evaluated in a genome-wide association analysis and genomic prediction in Labrador Retrievers. PMID- 29974967 TI - MC1R polymorphism associated with plumage color variations in Coturnix chinensis. AB - The melanocortin 1 receptor (MC1R) gene was investigated as a candidate for plumage variations in Chinese painted quail, Coturnix chinensis. Four silent and two missense nucleotide polymorphisms were identified. The correspondent amino acid changes, p.Glu92Lys and p.Pro292Leu, were found in Blue Face and Red Breasted animals respectively. Blue Face is a melanic phenotype similar to the co dominant Extended Brown of Japanese quail, and both share the p.Glu92Lys mutation. The association of p.Pro292Leu with the recessive Red Breasted was confirmed in 23 animals from an experimental F2 cross. PMID- 29974968 TI - Ex vivo penetration of fosfomycin into healthy and Lawsonia intracellularis colonized swine intestinal mucosa. AB - Fosfomycin (FOS) is an antibiotic used, mostly in Latin America, for the treatment of lung and enteric infections of pigs. Intracellular fluids of enterocytes can act as biophase for Lawsonia intracellularis, the causative agent of porcine proliferative enteropathy (PPE). The aim of this study was to determine whether the presence of L. intracellularis in the enterocytes modifies FOS penetration. Eight healthy pigs in growth-finishing stage were used to produce healthy (group A) and L. intracellularis-colonized (group B) intestinal explants. For both groups, treatment consisted of a 580 MUg/ml concentration of calcium FOS, which was added to each explant (0.5-6 hr). For group B, the Enterisol Ileitis(r) vaccine was used as source of the micro-organism. Previously to the assay, the time necessary for L. intracellularis to colonize the enterocytes was defined. Also, a PCR protocol was optimized to determine the presence of the pathogen in the explants. There were nonstatistical differences for the penetration of the antibiotic into healthy and L. intracellularis colonized enterocytes. MIC90 of FOS for L. intracellularis is unknown; nevertheless, MIC90 of various antibiotics ranges between 0.125 and 128 MUg/ml. FOS reaches inside the enterocyte concentrations which surpass the MICs90 of other antibiotics that also act by the inhibition of cell wall synthesis; however, further studies should be carried out to determine fosfomycin MIC90 for L. intracellularis to discern the usefulness of this antibiotic in the treatment of PPE. PMID- 29974970 TI - Usefulness of dual-energy computed tomography for the evaluation of psoriatic arthritis accompanied by knee osteoarthritis. PMID- 29974969 TI - Identification of a large SNP dataset in Larimichthys crocea using specific-locus amplified fragment sequencing. AB - The large yellow croaker, Larimichthys crocea, is a commercially important drum fish (Family: Sciaenidae) native to the East and South China Sea. Habitat deterioration and overfishing have led to significant population decline and the collapse of its fishery over the past decades. Today, the market supply of L. crocea depends solely on stocks produced in hatcheries and farms. Common issues that occur in the culture of L. crocea include germplasm degradation, precocious puberty, elevated disease susceptibility and growth retardation. In this study, we employed SLAF-seq (specific-locus amplified fragment sequencing) technology to identify single nucleotide polymorphism (SNP) loci across the L. crocea genome. Sixty samples were selected for SLAF analysis out of 1000 progeny in the same cohort of a cultured stock. Our analysis obtained a total of 151 253 SLAFs, of which 65.88% (99 652) were identified to be polymorphic, scoring a total of 710 567 putative SNPs. Further filtration resulted in a final panel of 1782 SNP loci. The data derived from this work could be beneficial for understanding the genetics of complex phenotypic traits as well as for developing marker-selection assisted breeding programs in L. crocea. PMID- 29974971 TI - Classification of breast lesions in ultrasonography using sparse logistic regression and morphology-based texture features. AB - PURPOSE: This work proposes a new reliable computer-aided diagnostic (CAD) system for the diagnosis of breast cancer from breast ultrasound (BUS) images. The system can be useful to reduce the number of biopsies and pathological tests, which are invasive, costly, and often unnecessary. METHODS: The proposed CAD system classifies breast tumors into benign and malignant classes using morphological and textural features extracted from breast ultrasound (BUS) images. The images are first preprocessed to enhance the edges and filter the speckles. The tumor is then segmented semiautomatically using the watershed method. Having the tumor contour, a set of 855 features including 21 shape-based, 810 contour-based, and 24 textural features are extracted from each tumor. Then, a Bayesian Automatic Relevance Detection (ARD) mechanism is used for computing the discrimination power of different features and dimensionality reduction. Finally, a logistic regression classifier computed the posterior probabilities of malignant vs benign tumors using the reduced set of features. RESULTS: A dataset of 104 BUS images of breast tumors, including 72 benign and 32 malignant tumors, was used for evaluation using an eightfold cross-validation. The algorithm outperformed six state-of-the-art methods for BUS image classification with large margins by achieving 97.12% accuracy, 93.75% sensitivity, and 98.61% specificity rates. CONCLUSIONS: Using ARD, the proposed CAD system selects five new features for breast tumor classification and outperforms state-of-the-art, making a reliable and complementary tool to help clinicians diagnose breast cancer. PMID- 29974972 TI - The effects of alcohol intoxication and sexual interest on men's sexual persistence and hostility in a dating simulation. AB - Perpetrators of sexual assault are often intoxicated; however, few experimental studies evaluate alcohol's "in the moment" effects on sexual aggression. This study extends past theory and research by examining the acute effects of alcohol on men's decisions about how to respond to sexual refusals in a dating simulation. Men (N = 62) ages 21-29 were randomly assigned to consume alcohol (target breath alcohol level 0.080%) or no alcohol. Participants were encouraged to talk to a simulated woman and act as they would on an actual date. They made choices from a list which included nonsexual and sexual options. The female agent was programmed to engage in some sexual activities but refuse others. Refusals became more intense if participants persisted. Negative binomial regression analysis was used to test a path analytic model. As predicted, participants' self reported desire to have sex was positively associated with choosing more consensual sexual activities during the simulation (i.e., activities in which the woman willingly engaged). Consensual sexual activities were positively associated with the number of times participants persisted after the woman refused. Alcohol moderated this relationship such that it was stronger for intoxicated men than sober men. The more sexual refusals participants received, the more hostile verbal comments they made to the woman. Contrary to our predictions, this relationship was not moderated by alcohol condition. Because participants had multiple opportunities to escalate their aggression or desist, this paradigm provides new insights into the mechanisms through which intoxication enhances the likelihood of sexual aggression in dating situations. PMID- 29974973 TI - Identification of a novel splice site mutation in the LIPH gene in a Japanese family with autosomal recessive woolly hair. PMID- 29974974 TI - Dialogic reading in the rehabilitation of Children with Hearing Loss and the "Born to Read" Project: A pilot study. AB - The "born to read" initiative entails a dialogic reading to children in poor socio-economical conditions aimed at fostering cognitive and relational skills. Reading is professionally delivered by experts to promote psycho-social development of children and their parents. In this study the project was extended to include children positive at early screening for hearing impairment. A total of 26 children were included and 14 parents were taught to read aloud and emphatically. Reading session were delivered for at least 10 minutes at least 3 times/week, usually at bedtime, for one year. The Griffiths scale were applied to explore the expressive and receptive language skills (Scale C) and eye and hand coordination (Scale D), as measures of linguistic and neurocognitive skills. Program sustainability and reactions by the parents were also investigated. All 14 families successfully received the training, becoming capable of reading aloud and emphatically and provided reading sessions for the entire duration of the study. Children receiving the intervention performed slightly better than controls and those who were exposed to increased number of sessions, performed even better although the differences with controls were not significant. Parents enjoyed reading to their children. They expressed satisfaction and gratitude for being able to play an active and productive role in children rehabilitation. The results of this pilot study suggest that the born to read initiative may be considered in adjunct to medical and psychological interventions to enhance the benefits of early screening of hearing function. PMID- 29974975 TI - Recent advances in Barrett's esophagus. AB - Barrett's esophagus (BE) is the only known precursor of esophageal adenocarcinoma, one of the few cancers with increasing incidence in developed countries. The pathogenesis of BE is unclear with regard to either the cellular origin of this metaplastic epithelium or the manner in which malignant transformation occurs, although recent data indicate a possible junctional origin of stem cells for BE. Treatment of BE may be achieved using endoscopic eradication therapy; however, there is a lack of discriminatory tools to identify individuals at sufficient risk for cancer development in whom intervention is warranted. Reduction in gastroesophageal reflux of gastric contents including acid is mandatory to achieve remission from BE after endoscopic ablation, and can be achieved using medical or nonmedical interventions. Research topics of greatest interest include the mechanism of BE development and transformation to cancer, risk stratification methods to identify individuals who may benefit from ablation of BE, optimization of eradication therapy, and surveillance methods to ensure that remission is maintained after eradication is achieved. PMID- 29974976 TI - Chromatin remodeling factor CHR18 interacts with replication protein RPA1A to regulate the DNA replication stress response in Arabidopsis. AB - DNA replication is a fundamental process for the faithful transmission of genetic information in all living organisms. Many endogenous and environmental signals impede fork progression during DNA synthesis, which induces replication errors and DNA replication stress. Chromatin remodeling factors regulate nucleosome occupancy and the histone composition of the nucleosome in chromatin; however, whether chromatin remodeling factors are involved in the DNA replication stress response in plants is unknown. We reveal that chromatin remodeling factor CHR18 plays important roles in DNA replication stress in Arabidopsis thaliana by interacting with the DNA replication protein RPA1A. According to the genetic analysis, the loss of function of either CHR18 or RPA1A confers a high sensitivity to DNA replication stress in Arabidopsis. CHR18 interacts with RPA1A in both yeast cells and tobacco epidermal cells. The coexpression of RPA1A and CHR18 enhances the accumulation of CHR18 in nuclear foci in plants. CHR18 is a typical nuclear-localized chromatin remodeling factor with ATPase activity. Our results demonstrate that during DNA synthesis in plants, RPA1A interacts with CHR18 and recruits CHR18 to nuclear foci to resolve DNA replication stress, which is important for cell propagation and root growth in Arabidopsis plants. PMID- 29974977 TI - Effect of mercury chloride on oxidative stress and nuclear factor erythroid 2 related factor 2 signalling molecule in liver and kidney of laying hens. AB - This study investigated the effects of mercury chloride (HgCl2 ) on the deposition of mercury (Hg), histopathology and oxidative stress in liver and kidney of laying hens. The gene expressions of antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2)-Kelch-like ECH-associated protein 1 (Keap1) were further studied to uncover the molecular mechanism. A total of 960 40-week-old Hyline brown laying hens were randomly allocated to five treatments with eight pens per treatment and 24 hens per pen. The hens were fed with five experimental diets containing graded levels of Hg at 0.270, 1.250, 3.315, 9.405 and 27.230 mg/kg respectively. Results revealed that both deposition of Hg and score of injury in liver and kidney were significantly increased as dietary Hg dosage up to 27.230 mg/kg diet. Deposition of Hg was positively related to score of injury in liver and kidney of laying hens. Besides, the activities of superoxidative dismutase (SOD), catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GSH-Px), and glutathione (GSH) content all significantly decreased (p < 0.05), while malondialdehyde (MDA) content significantly increased (p < 0.05) after Hg exposure in liver and kidney of laying hens. In addition, positive relationships occurred between antioxidant enzyme activities and antioxidant enzyme gene expressions except between SOD activity and manganese superoxide dismutase (MnSOD) gene expression in liver. Meanwhile, Nrf2 gene expression was positively related to antioxidant gene expressions and negatively connected with Keap1 gene expression. Negative relationships occurred between Nrf2 and Keap1 protein levels in liver and kidney. In conclusion, Hg could dose dependently damage liver and kidney and induced hepatic and renal oxidative stress by means of suppressing Nrf2-Keap1 signalling molecule in laying hens. PMID- 29974978 TI - Endoscopic ultrasonography-guided ethanol-lipiodol ablation of small neuroendocrine tumors: What volume should we inject? PMID- 29974979 TI - Survival, graft function, and incidence of allograft vasculopathy in heart transplant patients receiving adverse risk profile donor hearts. AB - AIM: To clarify if use of adverse cardiovascular risk profile (ARP) grafts is associated with impaired long-term outcomes after heart transplantation (HTx). METHODS: Survival was obtained from Scandia Transplant and a local database. ARP DONOR INCLUSION CRITERIA: >=55 years, diabetes mellitus, arterial hypertension, hypoxemia-induced death, impaired left ventricular (LV) ejection fraction. ARP donors were compared to donors not meeting the eligibility criteria. Sub-analyses were made for donor age. RESULTS: In total, 302 HTxs were performed in 296 patients from 31 December 1992 to 11 August 2016. Median survival was 16.5 years (95% CI, 14.3-22.9), there was no difference between profiles (HR 0.63 (95% CI, 0.33-1.19), P = 0.15). LV systolic function was significantly better in ARP donors (P < 0.05). Freedom from cardiac allograft vasculopathy (CAV) was comparable between profiles, HR 0.9 (95% CI 0.5-1.5). Donor age predisposes to CAV (high to low age: HR 2.8 (95% CI 1.7-4.5), P < 0.0001). Median survival was comparable in patients receiving allograft >=55 and <55 years (HR 0.77 (95% CI 0.4-1.4), P = 0.38). CONCLUSION: Long-term survival and graft function were excellent in patients receiving ARP grafts. Older grafts were associated with CAV but did not influence survival. Thus, the strategy of expanding availability using ARP grafts seems safe. PMID- 29974980 TI - Comments on Balp et al. PMID- 29974981 TI - Impact of contrast agent injection duration on dynamic contrast-enhanced MRI quantification in prostate cancer. AB - The volume transfer constant Ktrans , which describes the leakage of contrast agent (CA) from vasculature into tissue, is the most commonly reported quantitative parameter for dynamic contrast-enhanced (DCE-) MRI. However, the variation in reported Ktrans values between studies from different institutes is large. One of the primary sources of uncertainty is quantification of the arterial input function (AIF). The aim of this study is to determine the influence of the CA injection duration on the AIF and tracer kinetic analysis (TKA) parameters (i.e. Ktrans , kep and ve ). Thirty-one patients with prostate cancer received two DCE-MRI examinations with an injection duration of 5 s in the first examination and a prolonged injection duration in the second examination, varying between 7.5 s and 30 s. The DCE examination was carried out on a 3.0 T MRI scanner using a transversal T1 -weighted 3D spoiled gradient echo sequence (300 s duration, dynamic scan time of 2.5 s). Data of 29 of the 31 were further analysed. AIFs were determined from the phase signal in the left and right femoral arteries. Ktrans , kep and ve were estimated with the standard Tofts model for regions of healthy peripheral zone and tumour tissue. We observed a significantly smaller peak height and increased width in the AIF for injection durations of 15 s and longer. However, we did not find significant differences in Ktrans , kep or ve for the studied injection durations. The study demonstrates that the TKA parameters Ktrans , kep and ve , measured in the prostate, do not show a significant change as a function of injection duration. PMID- 29974982 TI - Antegrade radiofrequency ablation and stenting for biliary stricture through endoscopic ultrasound-guided hepaticogastrostomy. PMID- 29974983 TI - Star-Like Glycosaminoglycans with Superior Bioactivity Assemble with Proteins into Microfibers. AB - Here it is shown that glycosaminoglycans (GAGs) with high molecular weight can be grafted via their reducing end on hyperbranched synthetic cores by oxime condensation without the need of any previous functionalisation of the polysaccharide. The versatility of this reaction is demonstrated by the use of hyaluronan, chondroitin sulfate and heparin with up to 60 sugar units. The isothermal calorimetry analysis demonstrated that the generated star-like glycopolymers have superior bioactivity. Moreover, when mixed with positively charged proteins (e.g., fibroblast growth factor-2, FGF-2) they form microfiber structures instead of the spherical nanocomplexes described for linear GAGs. The results suggest that the described star-like GAG are closer mimics of the proteoglycans at the structural and functional level and therefore have huge potential in the development of tissue engineering platforms and therapeutics by modulating the activity and presentation of various proteins such as growth factors. PMID- 29974984 TI - Local Structural Effects of Eu3+ Incorporation into Xenotime-type Solid Solutions with Different Host Cations. AB - In this study, the effect of host cations on the local structure around the dopant site of materials from the xenotime family is systematically studied on the molecular level. A series of six Eu3+ -doped xenotime-type single crystals (Tb, Y, Ho, Er, Yb, and LuPO4 ) have been grown and spectroscopically analyzed by using polarization-dependent laser-induced luminescence spectroscopy (p-TRLFS). Our results demonstrate that the structural disorder changes in a non-linear manner with a structural break between Yb3+ and Lu3+ . Despite adopting identical crystal structures, the solid solutions of these materials vary significantly, and differ from monazite solid solutions. Similar Eu3+ incorporation behavior with a strongly distorted dopant site is found for the early members of the xenotime family, whereas LuPO4 with the largest host versus dopant radii mismatch is anomalous in that it contains the most symmetrical lattice site. This goes along with a significantly stronger crystal field, indicating a shorter Eu-O bond length, as well as a strong vibronic coupling to external translational lattice vibrations. The p-TRLFS analysis confirms the breakdown of the crystallographic site symmetry from D2d to C1 in YPO4 , whereas a small distortion of the crystallographic site in LuPO4 results in an S4 point symmetry for the Eu3+ cation. The lattice with the smallest cation host site is no longer sufficiently flexible to make room for Eu3+ and instead "forces" the guest ion to occupy a less distorted Lu3+ site. PMID- 29974985 TI - The influence of spaying and its timing relative to the onset of puberty on urinary and general behaviour in Labrador Retrievers. AB - Benefits and risks of spaying on the behaviour of female dogs are controversially discussed. Increased aggressiveness and male urinary behaviour were postulated to be the consequence of masculinization after spaying in some female dogs. To investigate if spaying or its timing relative to the onset of puberty may have a masculinization effect, urinary behaviour, that is, frequency of urination, urinary posture and ground scratching after urination were recorded in 58 female Labrador Retrievers during 15 min of a daily walk with their owners. General behaviour of the dogs during the walks was assessed using an owner questionnaire. Data were analysed for age, reproductive status, lifetime of ovary exposure and/or time interval since spaying. Urinary behaviour of intact females (n = 12) and dogs spayed before (n = 17) or after (n = 29) puberty was similar and not influenced by age, lifetime of ovary exposure and/or time interval since spaying. Owners of spayed dogs described more frequent or more intense fear reaction in their animals in response to loud noises, unfamiliar objects approaching on or near the sidewalk, or if they were approached by unknown dogs barking, growling or jumping. In conclusion, we found no evidence of a masculinization effect after spaying on urinary behaviour in female Labrador Retrievers. In contrast to popular belief, gonadectomy did not inevitably result in a behaviourally more stable dog. Extrapolation of our findings from female Labrador Retrievers to other breeds should be performed with caution, as the effect of spaying on behaviour may differ among dog breeds. PMID- 29974986 TI - Multiple Multicomponent Reactions: Unexplored Substrates, Selective Processes, and Versatile Chemotypes in Biomedicine. AB - Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienayme reaction on a range of alpha-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner. PMID- 29974987 TI - Fluoropolymer-Coated PDMS Microfluidic Devices for Application in Organic Synthesis. AB - In recent years there has been huge interest in the development of microfluidic reactors for the synthesis of small molecules and nanomaterials. Such reaction platforms represent a powerful and versatile alternative to traditional formats since they allow for the precise, controlled, and flexible management of reactive processes. To date, the majority of microfluidic reactors used in small-molecule synthesis have been manufactured using conventional lithographic techniques from materials such as glasses, ceramics, stainless steel, and silicon. Surprisingly, the fabrication of microfluidic devices from such rigid materials remains ill defined, complex, and expensive. Accordingly, the microfluidic toolkit for chemical synthesis would significantly benefit from the development of solvent resistant microfluidic devices that can be manufactured using soft-lithographic prototyping methods. Whilst significant advances in the development of solvent resistant polymers have been made, only modest steps have been taken towards simplifying their use as microfluidic reactors. Herein, we emphasize the benefits of using a commercially available, amorphous perfluorinated polymer, CYTOP, as a coating with which to transform PDMS into a chemically inert material for use in organic synthesis applications. Its efficacy is demonstrated through the subsequent performance of photooxidation reactions and reactions under extremely acidic or basic conditions. PMID- 29974988 TI - Identification of peptides with tolerogenic potential in a hydrolysed whey-based infant formula. AB - BACKGROUND: Failure to induce oral tolerance may result in food allergy. Hydrolysed cow's milk-based infant formulas are recommended in subjects with a high risk of developing allergic disease. Presentation of T cell epitopes is a prerequisite to generate regulatory T cells that could contribute to oral tolerance. OBJECTIVE: To investigate whether a specific hydrolysed whey-based infant formula contains peptides that function as T cell epitopes to support the development of oral tolerance to whey. METHODS: First, a novel liquid chromatography-mass spectrometry (LC-MS) method was developed to characterize beta-lactoglobulin-derived peptides present in a specific infant formula with a focus on region AA#13-48 of beta-lactoglobulin, which has previously been described to contain T cell epitopes with tolerogenic potential. Second, the formula was subjected to the ProImmune ProPresent(r) antigen presentation assay and MHC class II binding algorithm to identify relevant HLA-DRB1-restricted peptides. Third, identified peptides were tested on human cow's milk protein specific T cell lines to determine T cell recognition. RESULTS: Thirteen peptides of minimal 9AAs long that overlap with AA#13-48 of beta-lactoglobulin were identified. Six of them were found across all batches analysed. It was further confirmed that these peptides were processed and presented by human dendritic cells. The identified HLA-DRB1-restricted peptides were correlated to AA#11-30 and AA#23-39 of beta-lactoglobulin. Importantly, the proliferation assay showed that the synthetic peptides were recognized by cow's milk protein-specific T cell lines and induced T cell proliferation. CONCLUSION AND CLINICAL RELEVANCE: This study demonstrates that the tested hydrolysed infant formula contains functional HLA-DRB1-restricted T cell epitopes, which can potentially support the development of oral tolerance to whey. PMID- 29974989 TI - Decoupling of a double-row 16-element tight-fit transceiver phased array for human whole-brain imaging at 9.4 T. AB - One of the major challenges in constructing multi-channel and multi-row transmit (Tx) or transceiver (TxRx) arrays is the decoupling of the array's loop elements. Overlapping of the surface loops allows the decoupling of adjacent elements and also helps to improve the radiofrequency field profile by increasing the penetration depth and eliminating voids between the loops. This also simplifies the design by reducing the number of decoupling circuits. At the same time, overlapping may compromise decoupling by generating high resistive (electric) coupling near the overlap, which cannot be compensated for by common decoupling techniques. Previously, based on analytical modeling, we demonstrated that electric coupling has strong frequency and loading dependence, and, at 9.4 T, both the magnetic and electric coupling between two heavily loaded loops can be compensated at the same time simply by overlapping the loops. As a result, excellent decoupling was obtained between adjacent loops of an eight-loop single row (1 * 8) human head tight-fit TxRx array. In this work, we designed and constructed a 9.4-T (400-MHz) 16-loop double-row (2 * 8) overlapped TxRx head array based on the results of the analytical and numerical electromagnetic modeling. We demonstrated that, simply by the optimal overlap of array loops, a very good decoupling can be obtained without additional decoupling strategies. The constructed TxRx array provides whole-brain coverage and approximately 1.5 times greater Tx efficiency relative to a transmit-only/receive-only (ToRo) array, which consists of a larger Tx-only array and a nested tight-fit 31-loop receive (Rx)-only array. At the same time, the ToRo array provides greater peripheral signal-to-noise ratio (SNR) and better Rx parallel performance in the head-feet direction. Overall, our work provides a recipe for a simple, robust and very Tx-efficient design suitable for parallel transmission and whole-brain imaging at ultra-high fields. PMID- 29974991 TI - Relative response to digital tablet devices and painting as sensory enrichment in captive chimpanzees. AB - Digital devices, including tablet computers and other touchscreens, can potentially serve as flexible and convenient means for providing behavioral enrichment activities to captive primates. Despite increased interest in incorporating technology into enrichment programs, no direct quantitative comparison has previously been made between the effectiveness of typical tactile enrichment activities and enrichment activities on digital devices. One way in which these activities differ is in the degree of controllability afforded the animals in interacting with the enrichment objects, since digital devices will be limiting to varying degrees based on the particulars of software and the interface format. This study compared the effects of painting with brush on paper to those of a painting application on a digital tablet device (iPadTM) in eight group-living chimpanzees at the Honolulu Zoo. Observations were analyzed across baseline, enrichment, and post-enrichment periods to measure significant differences in the reduction of displacement and stereotypic behaviors. We found that the digital tablet device running an application that permits production of semi-automated visualizations, was as effective as painting with brush on paper in reducing some stereotypic and displacement behaviors, including yawning and self-picking. However, the digital tablet was not as effective in reducing other displacement behaviors, nor was it as effective in retaining the chimpanzee's attention. These results confirm a useful role for digital devices in enrichment programs but suggest a need to assess individual device applications in their capacity to promote greater controllability and sensory breadth of the enrichment experience. PMID- 29974990 TI - Early development of porcine parthenogenetic embryos and reduced expression of primed pluripotent marker genes under the effect of lysophosphatidic acid. AB - To further promote the early development of porcine embryos and capture "naive" pluripotent state within blastocyst, the experiment explored the effects of lysophosphatidic acid (LPA) on the early development of porcine parthenogenetic embryos and the expression of pluripotency relevant genes. The results showed that the addition of 50 MUM LPA significantly improved parthenogenetic embryo cleavage rate (82.7% vs. 74.7%, p < 0.05), blastocyst rate (24.5% vs. 11.3%, p < 0.05) and blastocyst cell count (56 +/- 7.9 vs. 42 +/- 1.0, p < 0.05) than that of the control group. In addition, immunostaining experiment determined that the fluorescence intensity of OCT4 was also significantly higher than that of the control group. The quantitative real-time polymerase chain reaction (qRT-PCR) test revealed that addition of 50 MUM LPA could significantly enhance the expression level of pluripotent gene OCT4 and trophoblast marker genes CDX2, however, decrease the expression of primitive hypoblast marker gene GATA4. The results also indicated that LPA might decrease the expression of GATA4 through the ROCK signalling pathway. For further investigating the effect of the addition of LPA on the expression of "primed" and "naive" genes, we also detected the expression of those pluripotency-related genes by qRT-PCR. The results showed addition of LPA had no significant effect on the expression of "naive" pluripotent genes, but it was able to significantly decrease the expression of "primed" pluripotent genes, NODAL and Activin-A; furthermore, it also could significantly improve the expression of OCT4 and c-Myc which act as two important ES cell renewal factors. Above all, the addition of LPA can facilitate the early development of porcine parthenogenetic embryos, which may be able to benefit for capturing "naive" pluripotency in vitro through inhibiting "primed" pluripotency. PMID- 29974992 TI - The effect of 25-hydroxyvitamin D3 and phytase inclusion on pig performance, bone parameters and pork quality in finisher pigs. AB - The objective of this study was to investigate the effects of supplementing both phytase and 25-hydroxyvitamin D3 (25-OH-D3) on pig performance, nutrient digestibility, carcass characteristics, bone parameters and pork quality in finisher pigs. The experimental design was a 2 * 2 factorial comprising of four dietary treatments. One hundred and twenty pigs (60 male, 60 female) were blocked according to live weight and sex and allocated to the following dietary treatments: low P (4.81 g/kg) diet (basal) (T1); low P diet + phytase (T2); low P diet + 25-OH-D3 (T3) and low P diet + phytase + 25-OH-D3 (T4). Pigs supplemented with phytase had a lower average daily feed intake (ADFI) (2.45 kg vs. 2.59 kg; p < 0.05) and lower feed conversion ratio (FCR) (2.74 kg/kg vs. 2.85 kg/kg; p < 0.05) compared to pigs offered the nonphytase diets. Pigs offered phytase diets had a higher (p < 0.05) coefficient of apparent total tract digestibility (CATTD) of ash, phosphorous (P) and calcium (Ca) compared with pigs offered the nonphytase supplemented diets. Pigs offered the 25-OH-D3 diets had a higher CATTD of N and ash. Pigs offered the phytase diets had increased (p < 0.05) bone DM, ash, Ca, P and density compared to the nonphytase diets. There was a significant interaction (p < 0.05) between phytase and 25-OH-D3 on cook loss. Pigs offered 25 OH-D3 had increased cook loss over the basal diet; however, there was no effect on cook loss when phytase and 25-OH-D3 were offered in combination compared to the phytase only diet. Pigs offered 25-OH-D3 exhibited higher (p < 0.05) Warner Bratzler shear force values and lower (p < 0.05) pork lightness (L*) surface colorimeter values. In conclusion, there was no benefit to offering a combination of phytase and 25-OH-D3 on pig performance, bone parameters or pork quality. PMID- 29974993 TI - Expression of ameloblastin in the human tooth germ and ameloblastoma. AB - OBJECTIVE: To analyse the immunohistochemical expression of ameloblastin in the bell stage of tooth germ and compare with ameloblastoma to determine the level of differentiation of tumour cells. STUDY DESIGN: This study included eleven human tooth germs with four in the early and seven in the late bell stage, and six selected archival tissue samples of ameloblastomas were studied using haematoxylin and eosin, Masson's trichrome and ameloblastin. RESULTS: All eleven tooth germs reacted positively to ameloblastin with a characteristic inverted and sequential pattern of expression in the acellular zone of the dental papilla and enamel organ. Of the six cases of ameloblastoma, five cases showed a variable level of expression of ameloblastin in the tumour cells, whereas in one case, ameloblastin was negative in the tumour cells but positive in the stromal fibrous tissue collar. CONCLUSION: Expression of ameloblastin in human tooth germ is related to differentiation and mineralization, and it correlates with the state of differentiation of the tumour cells in ameloblastoma. PMID- 29974994 TI - Hummingbirds and bumble bees exposed to neonicotinoid and organophosphate insecticides in the Fraser Valley, British Columbia, Canada. AB - To measure exposure to neonicotinoid and other pesticides in avian pollinators, we made novel use of cloacal fluid and fecal pellets from rufous (Selasphorus rufus) and Anna's (Calypte anna) hummingbirds living near blueberry fields in the Fraser River Valley and Vancouver Island, British Columbia, Canada. To examine on farm exposure to pesticides in invertebrate pollinators, we also collected bumble bees native to Canada (Bombus mixtus, Bombus flavifrons, and Bombus melanopygus), their pollen, and blueberry leaves and flowers from within conventionally sprayed and organic blueberry farms. By sites and sample type, the results reported in the present study represent pooled samples (n = 1). In 2015 to 2016, the combined concentration of the neonicotinoid insecticides imidacloprid, thiamethoxam, and clothianidin detected in hummingbird cloacal fluid from sites near conventionally sprayed blueberry fields was 3.63 ng/mL (ppb). Among the 18 compounds measured in fecal pellets, including one neonicotinoid (imidacloprid), only piperonyl butoxide was detected (1.47-5.96 ng/g). Piperonyl butoxide is a cytochrome P450 inhibitor applied with some insecticides to increase their toxic efficacy. Only diazinon was detected in bumble bees (0.197 ng/g), whereas diazinon (1.54-1.7 ng/g) and imidacloprid (up to 18.4 ng/g) were detected in pollen collected from bumble bees including the bees from organic sites located near conventionally sprayed blueberry farms. Imidacloprid was also detected at 5.16 ng/g in blueberry flowers collected 1 yr post spray from 1 of 6 conventionally sprayed blueberry farms. Environ Toxicol Chem 2018;37:2143-2152. (c) 2018 SETAC. PMID- 29974995 TI - Contrast-enhanced 18F-FDG-PET/CT for Differentiating Tumour and Radionecrosis in Head and Neck Cancer: Our experience in 37 Patients. PMID- 29974996 TI - Storm impacts on alpine lakes: Antecedent weather conditions matter more than the event intensity. AB - Extreme weather events may be just as important as gradual trends for the long term trajectories of ecosystems. For alpine lakes, which are exposed to both exacerbated atmospheric warming and intense episodic weather events, future conditions might not be appropriately forecast by only climate change trends, i.e. warming, if extreme events have the potential to deflect their thermal and metabolic states from their seasonal ranges. We used high-frequency monitoring data over three open-water seasons with a one-dimensional hydrodynamic model of the high-altitude Lake Muzelle (France) to show that rainstorms or windstorms, notwithstanding their intensity, did not trigger long-lasting consequences to the lake characteristics when light penetration into the lake was not modified. In contrast, storms associated with high turbidity input from the watershed ("turbid storms") strongly modified the lacustrine hydrodynamics and metabolism for the rest of the open-water season through reduced light penetration. The long-lasting effects of turbid storms were related to the inputs and in-lake persistence of very light glacial suspensoids from the watershed. The occurrence of the observed turbid storms was not related to the wind or rain intensities during the events. Instead, the turbid storms occurred after dry and atypically warm spells, i.e. meteorological conditions expected to be more frequent in this alpine region in the upcoming decades. Consequently, storm events, notwithstanding their intensity, are expected to strongly imprint the future ecological status of alpine lakes under climate warming. PMID- 29974998 TI - HO-1 regulates the function of Treg: Association with the immune intolerance in vitiligo. AB - In vitiligo, cutaneous depigmentation is accompanied by increased T cell cytolytic activity targeting melanocytes, indicating that autoimmune tolerance is disrupted. The inhibited amount and function of Tregs have been indicated to be involved in the autoimmune intolerance in vitiligo, however, with the conclusion still controversial and the involved mechanism unknown. In this study, we explored the molecular and cellular alterations accounting for the impaired Treg response in vitiligo. Our results showed that the amount of Tregs was drastically reduced in peripheral blood of active vitiligo patients. Furthermore, the immunoregulatory function of Tregs was attenuated, with lower expression of CTLA4, IL-10 and TGF-beta. Moreover, the expression of HO-1, a functional modulator of Tregs, was decreased in vitiligo Tregs, and the concentrations of HO 1 metabolites, including bilirubin, CoHb and iron, were correspondingly decreased in serum of vitiligo patients. In addition, we treated the Tregs from vitiligo patients with Hemin, an agonist of HO-1, and found that enhanced HO-1 expression restored the function of Tregs by up-regulating IL-10 expression. Our study demonstrates the essential role of HO-1 in the impaired Treg response in vitiligo and indicates the potential of HO-1 as a therapeutic target in vitiligo management. PMID- 29974997 TI - RNF168 facilitates oestrogen receptor alpha transcription and drives breast cancer proliferation. AB - Oestrogen receptor alpha (ERalpha) is overexpressed in two-thirds of all breast cancers and involves in development and breast cancer progression. Although ERalpha-positive breast cancer could be effective treated by endocrine therapy, the endocrine resistance is still an urgent clinical problem. Thus, further understanding of the underlying mechanisms ERalpha signalling is critical in dealing with endocrine resistance in breast cancer patients. MCF-7 and T47D breast cancer cell lines are used to carry out the molecular biological experiments. Western blot is used to assess the relative protein level of ERalpha, RNF168 and actin. Real-time PCR is used the measure the relative ERalpha related gene mRNA level. Luciferase assay is used to measure the relative ERalpha signalling activity. Chromatin immunoprecipitation is used to measure the RNF168 binding affinity to ERalpha promoter regions. WST assay and flow cytometry are used to measure the cell proliferation capacity. We use Student's t test and one way ANOVA test for statistical data analysis. Here, we report an important role in ERalpha-positive breast cancer cells for RNF168 protein in supporting cell proliferation by driving the transcription of ERalpha. RNF168 is highly expressed in breast cancer samples, compared with normal breast tissue. In patients with breast cancer, RNF168 expression level is correlated with poor endocrine treatment outcome. Depletion of RNF168 causes decreased cell proliferation in MCF 7 and T47D cells. Besides, depletion RNF168 reduced mRNA level of ERalpha and its target genes, such as PS2 and GREB1. Chromatin immunoprecipitation revealed that ERalpha transcription is associated with RNF168 recruitment to ERalpha promoter region, suggesting that transcriptional regulation is one mechanism by which RNF168 regulates ERalpha mRNA level and ERalpha signalling in breast cancer cells. RNF168 is required for ERalpha-positive breast cancer cell proliferation and facilitate ERalpha signalling activity possibly through promoting transcription of ERalpha. PMID- 29974999 TI - The MocR-like transcription factors: pyridoxal 5'-phosphate-dependent regulators of bacterial metabolism. AB - Many biological functions played by current proteins were not created by evolution from scratch, rather they were obtained combining already available protein scaffolds. This is the case of MocR-like bacterial transcription factors (MocR-TFs), a subclass of GntR transcription regulators, whose structure is the outcome of the fusion between DNA-binding proteins and pyridoxal 5'-phosphate (PLP)-dependent enzymes. The resultant chimeras can count on the properties of both protein classes, i.e. the capability to recognize specific DNA sequences and to bind PLP and amino-compounds; it is the modulation of such binding properties to confer to MocR-TFs chimeras the ability to interact with effector molecules and DNA so as to regulate transcription. MocR-TFs control different metabolic processes involving vitamin B6 and amino acids, which are canonical ligands of PLP-dependent enzymes. However, MocR-TFs are also implicated in the metabolism of compounds that are not substrates of PLP-dependent enzymes, such as rhizopine and ectoine. Genomic analyses show that MocR-TFs are widespread among eubacteria, implying an essential role in their metabolism and highlighting the scarcity of our knowledge on these important players in microbial metabolism. Although MocR TFs have been discovered 15 years ago, the research activity on these transcriptional regulators has only recently intensified, producing a wealth of information that needs to be brought back to general principles. This is the main task of this review, which reports and analyses the available information concerning MocR-TFs functional role, structural features, interaction with effector molecules and the characteristics of DNA transcriptional factor-binding sites of MocR-based regulatory systems. PMID- 29975000 TI - Effect of particulate matter 2.5 on gene expression profile and cell signaling in JEG-3 human placenta cells. AB - Particulate matter the environmental toxicant, with a diameter less than or equal to 2.5 MUm (PM2.5 ) is a common cause of several respiratory diseases. In recent years, several studies have suggested that PM2.5 can influence diverse diseases, such as respiratory diseases, cardiovascular diseases, metabolic diseases, dementia, and female reproductive disorders, and unhealthy birth outcomes. In addition, several epidemiological studies have reported that adverse health effects of PM2.5 can differ depending on regional variations. In the present study, to evaluate specific adverse health effects of PM2.5 , we collected two different PM2.5 samples from an underground parking lot and ambient air, and we evaluated cytotoxicity with eight different cell lines originating from human organs. Then, we selected JEG-3 human placenta cells, which show high cytotoxicity to both PM samples. Through RNA sequencing, gene expression profiling, and a gene ontology (GO) analysis of JEG-3 after exposure to two different PM2.5 samples, we identified 1021 commonly expressed genes involved in immune responses, the regulation of apoptosis, and so forth, which are known to induce several adverse health effects. In addition, we identified genes related to the calcium-signaling pathway, steroid hormone biosynthesis, and the cytokine cytokine receptor interaction through a Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Then, we confirmed these gene expressions using qRT-PCR, and the protein levels of mitogen-activated protein kinases and COX-2 with progesterone decreased using western blotting and enzyme-linked immunosorbent assay. In conclusion, this study suggests the possible toxic mechanism of human placenta that might be associated with PM2.5 -induced female reproductive disorders. PMID- 29975002 TI - A proposed plan for conducting sample stability studies incorporating testing for equivalence as well as differences. PMID- 29975001 TI - Increased Dkk-1 plasma levels may discriminate disease subtypes in myeloproliferative neoplasms. AB - Alterations in the bone marrow niche induced by abnormal production of cytokines and other soluble factors have been associated with disease progression in classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Variations in circulating proteins might reflect local disease processes and plasma proteome profiling could serve to identify possible diagnostic and prognostic biomarkers. We employed a human cytokine array to screen for 105 distinct analytes in pooled plasma samples obtained from untreated young MPN patients (<35 years) with different clinical phenotypes and driver mutations, as well as from healthy individuals. Among molecules that exhibited significantly increased levels in MPN patients versus controls, the top of the list was represented by Dickkopf-related protein 1 (Dkk-1), which also showed the highest potential for discrimination between MPN subtypes. In the next step, a quantitative ELISA was used to measure plasma Dkk-1 levels in 30 young-onset MPN-10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 pre-fibrotic primary myelofibrosis (pre-PMF)-and 10 controls. The results suggested that plasma Dkk-1 levels could differentiate ET from pre-PMF, in JAK2 V617F-positive as well as in CALR-positive patients, and also ET from PV in JAK2 V617F-positive patients. PMID- 29975003 TI - Acquired platelet antagonism: off-target antiplatelet effects of malignancy treatment with tyrosine kinase inhibitors. AB - Platelets can contribute to tumor progression and metastasis. Cancer patients are at increased risk of thrombosis, and advanced stages of cancer are associated with thrombocytosis or increased platelet reactivity. Tyrosine kinase inhibitors (TKIs) are widely used as a targeted strategy for cancer treatment, with the aim of prolonging progression-free survival of the patients. Because of their broad kinase target spectrum, most TKIs inevitably have off-target effects. Platelets rely on tyrosine kinase activity for their activation. Frequently observed side effects are lowering of platelet count and inhibition of platelet functions, whether or not accompanied by an increased bleeding risk. In this review, we aim to give insights into: (i) 38 TKIs that are currently used for the treatment of different types of cancer, either on the market or in clinical trials; (ii) how distinct TKIs can inhibit activation mechanisms in platelets; and (iii) the clinical consequences of the antiplatelet effects of TKI treatment. For several TKIs, the knowledge on affinity for their targets does not align with the published effects on platelets and reported bleeding events. This review should raise awareness of the potential antiplatelet effects of several TKIs, which will be enhanced in the presence of antithrombotic drugs. PMID- 29975004 TI - Structural Complexity of the Cerebellum and Cerebral Cortex is Reduced in Spinocerebellar Ataxia Type 2. AB - BACKGROUND AND PURPOSE: Fractal dimension (FD) is an index of structural complexity of cortical gray matter (GM) and white matter (WM). Application of FD to pontocerebellar degeneration has revealed cerebellar changes. However, so far, possible concurrent cerebral changes and progression of changes in brain complexity have not been investigated. METHODS: We computed FD of cerebellar and cerebral cortex and WM derived from longitudinal brain MRI of patients with spinocerebellar ataxia type 2 (SCA2), which is an inherited cause of pontocerebellar degeneration. Nine SCA2 patients and 16 age-matched healthy controls were examined twice (3.6 +/- .7 and 3.3 +/- 1.0 years apart, respectively) on the same 1.5T MR scanner with T1-weighted imaging. Cortical GM and WM of the cerebrum and cerebellum were segmented using FreeSurfer and FD of these segmentations were computed. RESULTS: At baseline, FD values of cerebellar GM and WM were significantly (P < .001) lower in SCA2 patients (2.48 +/- .04 for GM and 1.74 +/- .09 for WM) than in controls (2.56 +/- .02 for GM and 2.22 +/- .19 for WM). Also, FD values of cerebral GM were significantly (P < .05) lower in SCA2 patients (2.39 +/- .03) than in controls (2.43 +/- .02). No significant differences were observed for FD of the cerebral WM. The rate of change of FD values was not significantly different between SCA2 patients and controls. CONCLUSIONS: The structural complexity of the cerebellum and cerebral cortex is reduced in SCA2 patients. Fractal analysis seems not to be able to demonstrate progression of changes associated with degeneration in SCA2. PMID- 29975006 TI - Silanylidene and Germanylidene Anions: Valence-Isoelectronic Species to the Well Studied Phosphinidene. AB - The reduction of TipMCl3 (Tip=2,4,6-triisopropylphenyl) (M=Si, Ge) with KC8 in the presence of cyclic alkyl(amino) carbene (cAAC) afforded the acyclic silanylidene and germanylidene anions in the form of potassium salt [K(cAAC)MTip]2 (M=Si (1); Ge (2)). The silanylidene and germanylidene anions are valence-isoelectronic to the well-studied phosphinidene and are a new class of acyclic anions of Group 14. Compounds 1 and 2 were isolated and well characterized by NMR and single-crystal X-ray structure analysis. Furthermore, the structure and bonding of compounds 1 and 2 was investigated by computational methods. PMID- 29975007 TI - Health professionals' experiences and barriers encountered when implementing hip surveillance for children with cerebral palsy. AB - AIM: This study aimed to explore health professionals' experiences of implementing hip surveillance for young people with cerebral palsy (CP) and to identify any barriers they encounter. METHODS: A cross-sectional web-based survey of health professionals supporting children with CP was conducted. Responses were analysed through mixed methods. Responses to items presented as ordinal scales were analysed using descriptive statistics, and open-ended responses through a qualitative approach to identify themes. RESULTS: A total of 32 paediatricians, 2 rehabilitation specialists and 50 physiotherapists completed the survey, with respondents working within both hospital- and community-based settings. Barriers most frequently reported were inconsistency in radiology practice and reporting (35%), parent engagement (32%), limited communication between clinicians (31%), lack of clarity in lines of responsibility (27%) and forgetting to undertake surveillance (26%). Four major themes were identified through qualitative analysis: (i) recognition of the importance of clinical guidelines to hip surveillance; (ii) the value of each role in the team around a child; (iii) the challenge of sharing responsibility; and (iv) the importance of communication in facilitating collaboration. CONCLUSIONS: Barriers can be encountered at each phase of the hip surveillance process, but there are also factors that act as facilitators. Locally, the results will inform the development of an enhanced state-wide approach to hip surveillance for all children with CP. The identified barriers do not appear unique to the local context, and the findings may be transferable to other settings. Awareness of the potential barriers and facilitators would be valuable to those implementing hip surveillance in other areas. PMID- 29975005 TI - Striatal subdivisions that coherently interact with multiple cerebrocortical networks. AB - The striatum constitutes the cortical-basal ganglia loop and receives input from the cerebral cortex. Previous MRI studies have parcellated the human striatum using clustering analyses of structural/functional connectivity with the cerebral cortex. However, it is currently unclear how the striatal regions functionally interact with the cerebral cortex to organize cortical functions in the temporal domain. In the present human functional MRI study, the striatum was parcellated using boundary mapping analyses to reveal the fine architecture of the striatum by focusing on local gradient of functional connectivity. Boundary mapping analyses revealed approximately 100 subdivisions of the striatum. Many of the striatal subdivisions were functionally connected with specific combinations of cerebrocortical functional networks, such as somato-motor (SM) and ventral attention (VA) networks. Time-resolved functional connectivity analyses further revealed coherent interactions of multiple connectivities between each striatal subdivision and the cerebrocortical networks (i.e., a striatal subdivision-SM connectivity and the same striatal subdivision-VA connectivity). These results suggest that the striatum contains a large number of subdivisions that mediate functional coupling between specific combinations of cerebrocortical networks. PMID- 29975008 TI - Down the Rabbit Hole: Specialty Influence on SCS Outcomes. PMID- 29975009 TI - Microbiota-Dependent Involvement of Th17 Cells in Murine Models of Inflammatory Arthritis. AB - OBJECTIVE: Intestinal microbiota are associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine whether the presence of Th17 cells, beyond involvement of the cytokine interleukin-17 (IL 17), is required for arthritis development, and whether the involvement of Th17 cells in arthritis depends on the composition of the host microbiota. METHODS: Mucosal T cell production of IL-17, interferon-gamma, tumor necrosis factor alpha (TNFalpha), IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF) was analyzed by flow cytometry and Luminex assay before arthritis onset in mice immunized to develop collagen-induced arthritis (CIA). Pathogenic features of arthritis in mice with CIA and mice with antigen-induced arthritis were compared between Th17 cell-deficient (CD4-Cre+ Rorcflox/flox ) and Th17 cell-sufficient (CD4-Cre- Rorcflox/flox ) mice. In addition, the impact of intestinal microbiota on the Th17 cell dependence of CIA was assessed. RESULTS: Lamina propria CD4 T cells were activated before the onset of arthritis in mice with CIA, with marked up-regulation of several cytokines, including IL-17A, TNFalpha, and GM-CSF. CD4 Cre+ Rorcflox/flox mice showed a specific reduction in intestinal mucosal levels of Th17 cells and partially reduced levels of IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by gammadelta T cells and neutrophils, were unaffected. The severity of arthritis was significantly reduced in Th17 cell-deficient mice, suggesting that Th17 cells have additional, IL-17A independent roles in inflammatory arthritis. Accordingly, antigen-stimulated T cells from Th17 cell-deficient mice produced less IL-17A, IL-17F, and GM-CSF. Importantly, the dependence of CIA on the involvement of Th17 cells was mitigated in the presence of an alternative microbiome. CONCLUSION: These data from murine models suggest that activation of mucosal immunity precedes the development of arthritis, and also that Th17 cells have a microbiota-dependent role in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies. PMID- 29975010 TI - Protein Aggregation. PMID- 29975011 TI - One-Pot Synthesis of Biomass-Derived Surfactants by Reacting Hydroxymethylfurfural, Glycerol, and Fatty Alcohols on Solid Acid Catalysts. AB - A new type of biomass-derived non-ionic surfactants has been obtained by reacting hydroxymethylfurfural (HMF), glycerol, and fatty alcohols. For instance, 5 (octyloxymethyl)furfural glyceryl acetal can be obtained in a one-pot process by etherification of HMF with fatty alcohols followed by acetalization with glycerol. For a successful solid catalyst, acidity and polarity have to be optimized to improve conversion, selectivity, and catalyst deactivation owing to the different adsorption characteristics of the reactant molecules. Accordingly, Beta zeolite with a high Si/Al ratio and practically free of connectivity defects showed good results when dealing with these biomass derivatives, which include a highly polar reactant such as glycerol. The scope of the reaction is good and a variety of new stable surfactant molecules can be obtained that present hydrophilic-lipophilic balance (HLB ) values in the range 4.9 to 6.6, which are of interest for water in oil emulsions. PMID- 29975013 TI - Osteoarthritis-related walking disability and arterial stiffness-results from a cross-sectional study. AB - OBJECTIVES: To compare 6 minute walking distance (6MWD) in a population-based osteoarthritis (OA) cohort with matched peers from the general population, and to explore the associations between walking ability and CVD risk (arterial stiffness) in the OA cohort. DESIGN: This cross-sectional study included participants (40-80 years) who self-reported OA (n=500) in a population-based study and age- and gender-matched peers from the general population (n=235). Clinical examinations of the OA participants included classification according to the American College of Rheumatology criteria, blood samples and measuring arterial stiffness (pulse wave velocity, PWV). Group differences in 6MWD were calculated with t-tests. The association between walking ability and CVD risk in the OA cohort was explored in multivariate regression models. RESULTS: In age stratified analyses, the largest mean difference in 6MWD was observed in the youngest age groups (40-49 years); the OA group walked 84.6 meters (female; 579.4 m vs 663.9 m, p<0.001) and 88.3 meters (male; 619.9 m vs 708.3 m, p=0.001) shorter than the reference groups, respectively. In the OA group, the 6MWD was significantly associated to PWV in adjusted analysis (p=0.001); 100 m longer walking distance corresponded to 0.3 m/s reduction in arterial stiffness. CONCLUSION: Already from the age of forty, people with OA have significantly shorter mean walking distance compared to matched peers, underlining the importance of early clinical approach to OA. Further, in the OA-group, the 6MWD was significantly associated with arterial stiffness, suggesting that walking ability is important for the CVD risk profile in OA. This article is protected by copyright. All rights reserved. PMID- 29975012 TI - Pain mechanisms and ultrasonic inflammatory activity as prognostic factors in patients with psoriatic arthritis: A prospective cohort study. AB - OBJECTIVE: To study the prognostic value of widespread pain and of musculoskeletal ultrasound (US) examination for subsequent treatment outcomes in patients with psoriatic arthritis (PsA). METHODS: An exploratory prospective cohort study enrolled PsA patients initiating biologic/conventional synthetic disease modifying anti-rheumatic drugs in routine care. Clinical-, US- and patient-reported measures were retrieved at baseline and after 4 months. Widespread non-arthritic pain (WP) was defined as Widespread Pain Index >=4 with pain in >=4/5 regions. PsA activity by US was defined as colour Doppler (CD) (yes/no) in selected entheses, joints or tendons. Main response criteria included American College of Rheumatology 20% (ACR20), Disease Activity in Psoriatic Arthritis 50% (DAPSA50), and Minimal Disease Activity (MDA). The primary analyses were age-and gender adjusted logistic regression. RESULTS: WP was present in 24 (35%) of 69 included patients, and associated with worse patient-reported and composite baseline measures while US and other objective findings were similar to patients without WP. The odds of 4-months MDA were significantly greater for patients enrolled without WP (OR=18.43 [95% CI: 1.51-224.41], p=0.022), while WP did not impair other response measures. Patients with baseline CD activity (n=42 [61%]) had worse objective PsA burden but their chance of treatment response was comparable to those without CD. CONCLUSIONS: More than one-third of PsA patients presented with widespread non-arthritic pain, which was associated with worse patient-reported scores and failure to achieve MDA following cs/bDMARD therapy. PsA activity by colour Doppler ultrasound had no influence on subsequent treatment response in this PsA cohort. This article is protected by copyright. All rights reserved. PMID- 29975014 TI - Natural Product Dietary Supplement Use by Individuals with Rheumatoid Arthritis: A Scoping Review. AB - OBJECTIVE: Natural-product dietary supplements (NDS), defined as non-mineral, non vitamin, ingested natural product-derived substances, are the most frequently used CAM modality in the United States, with musculoskeletal disease being the most frequent reason for their use. Because NDS usage is frequently unreported and individuals with RA may be at higher risk for NDS-related side effects due the underlying nature of the disease and frequent use of complex pharmaceutical regimens, a scoping review of the literature was undertaken to examine population based patterns of NDS use for RA self-management. METHODS: Using guidelines for scoping reviews, AMED, CINAHL, the Cochrane Library, Embase, Ovid/MEDLINE, and Web of Science databases were searched to identify references presenting primary data related to the prevalence or patterns of use of NDS in RA populations. RESULTS: Twenty-three studies, published between 1980-2015 and conducted in 11 countries, met inclusion criteria. The overall prevalence of NDS use in RA was 47% worldwide and did not differ by geographic region. On average, 47% of subjects found NDS to be effective and 13% reported adverse side effects, with only 30% informing their physicians about use of NDS, which were used concomitantly with RA pharmaceuticals in a majority of cases. Marine oils, glucosamine, vinegar and chondroitin were among the most commonly reported NDS worldwide. CONCLUSION: Given the apparent communication gap between patients and providers regarding NDS use and higher potential risks associated with this usage in RA, ongoing surveillance of population-based practices may help facilitate RA management and direct future NDS research. This article is protected by copyright. All rights reserved. PMID- 29975015 TI - Body fat percentage, waist circumference and obesity as risk factors for rheumatoid arthritis - A Danish cohort study. AB - OBJECTIVES: To investigate the relationship between bioimpedance-derived total body fat percentage, waist circumference (WC) and Body Mass Index (BMI) and the subsequent development of rheumatoid arthritis (RA). METHODS: A population-based prospective cohort study among 55,037 persons enrolled into the Danish Diet, Cancer and Health cohort. Baseline data included anthropometric measures and lifestyle factors. Persons who developed RA were identified through linkage with the Danish National Patient Registry. The relationships between bioimpedance derived body fat percentage, WC, BMI and incident RA were assessed using Cox proportional hazards regression models, stratifying by gender. All analyses were performed for overall RA and the serological subtypes: 'seropositive RA' and 'other RA'. RESULTS: A total of 210 men (37.6% seropositive RA) and 456 women (41.0% seropositive RA) developed RA during a median follow-up of 20.1 years. In women, overall RA risk was 10% higher for each 5% increment of total body fat (Hazard Ratio (HR) 1.10; 95% CI 1.02-1.18), 5% higher for each 5cm increment of WC (HR 1.05; 95% CI 1.01-1.10) and nearly 50% higher in those with an obese compared to normal BMI (HR 1.46; 95% CI 1.12-1.90). These positive associations were also found for 'other RA'. In men, there were no clear associations between body fat percentage, WC, or BMI and RA. No significant associations were found for 'seropositive RA' in women or men, possibly related to low sample size. CONCLUSIONS: In women, higher body fat percentage, higher waist circumference and obesity were associated with higher risk of RA. This article is protected by copyright. All rights reserved. PMID- 29975016 TI - Corrigendum: Validating Eaton's Hypothesis: Cubane as a Benzene Bioisostere. PMID- 29975017 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 28/2018. PMID- 29975018 TI - Patients' self-evaluation of symptoms, signs and compliance to therapy for heart failure surveillance: A pilot study on identification of worsening heart failure. AB - In patients with chronic heart failure (HF), it is unclear whether self evaluation of HF-related symptoms and signs may contribute to the surveillance of clinical stability over time or the early identification of worsening HF. Therefore, HF-related symptoms and signs, and compliance to therapy were investigated by a self-administrated questionnaire in patients hospitalized due to worsening HF (cases) as well in those with stable HF (controls). The temporal interval of interest for the questionnaire focused on 2 to 7 days before the hospitalization of the control visit. A method called "classic" extrapolated a surveillance score by 4 questions revealing HF-related symptoms or signs (higher score indicative of more symptoms or sings reported). Alternatively, 3 additional questions enriched the "classic" questionnaire, including one on whether the health status was perceived as stable, improved or worsening. The score from "perceived health status" inquiry was used as "conditional factor" to computed the surveillance score as: conditional factor + [conditional factor X (the sum of the points yielded by the responses to each question on symptoms, sings and compliance to therapy)]. Among 51 patients hospitalized due to worsening HF and 104 with chronic HF (retrospective study), the area under the curve (receiver operating characteristic) discriminating worsening HF was 0.90 by the classic, and 0.96 by the conditional method (both p<0.001), yielding error rates of 2 in 10 by the classic and 1 in 10 by the conditional method. In a pilot longitudinal study in 37 ambulatory HF patients from a different population source, predicting worsening HF by alternative questionnaires within 12 weeks from the visit yielded consistent results. In conclusion, patients' self monitoring symptoms, signs and compliance by a standardized questionnaire and a conditional method for generating relative a score, may be a promising method for HF stability surveillance. PMID- 29975019 TI - The Centers for Medicare & Medicaid Services Reimbursement Policy and Nursing Sensitive Adverse Patient Outcomes. AB - The Centers for Medicare & Medicaid Services (CMS) reimbursement policy identified 11preventable adverse outcomes. Of these 11 patient outcomes, four (severe pressure ulcers, falls and trauma, catheter-associatedurinary tract infections, and vascular catheter-associated infections) are considered nursing sensitive quality outcomes thatcan be decreased with greater and better nursing care. A cross-sectional study examined the CMS reimbursement policyfocusing on nursing-sensitive adverse patient outcomes. The percentage of Medicare patients served as a proxy for ameasure of the CMS changes in reimbursement. The CMS reimbursement policy measured by the proxy variablewas not related to a reduction of the four adverse outcomes. PMID- 29975020 TI - Behcet syndrome: effects of Pycnogenol(r) supplementation during regression phases. AB - BACKGROUND: The aim of this comparative registry study was to evaluate the supplementation with Pycnogenol(r) in subjects with Behcet syndrome (BS) with symptoms impairing their quality of life despite being in a remitting phase of the disease. METHODS: Thirty-four patients with a confirmed diagnosis of BS were divided into the control group (without supplement) or the active group, in this specific case using Pycnogenol(r) (Horphag Research LTD) supplement at the daily dose of 150 mg (50 mg tid) for 4 weeks. RESULTS: All subjects receiving Pycnogenol(r) reported a significant decrease in symptoms, such as burning/pain due to dryness and ulcerations (P<0.05). In addition, Pycnogenol(r) showed important anti-inflammatory activity by decreasing ESR, leucocytosis and Pathergy Test response. CONCLUSIONS: Pycnogenol(r) may be a useful supplementation for the management of BS. PMID- 29975021 TI - An overview on STEMI. PMID- 29975022 TI - Assessment of a Novel Tool for Identifying Hospitalized Patients with Heart Failure at Risk for 30-Day Readmission, High Cost, and Longer Length of Stay. AB - Hospitals are penalized financially for high 30-day readmission rates for specific diagnoses, including heart failure. The economic imperative exists to better manage the heart-failure population and acute care providers are in need of appropriate tools to aid in their efforts. This study was conducted to determine if the Rothman Index score may be useful to prospectively identify patients with heart failure at risk for extended hospitalization, high inpatient cost of care, and 30-day readmission. Results from this study suggest the Rothman Index score can be a useful adjunct to current clinical assessment methods in helping multidisciplinary teams better manage patient care and limited resources. PMID- 29975023 TI - Guiding Global Nursing: An Interview with Annette Mwansa Nkowane. PMID- 29975024 TI - Video Monitoring to Reduce Falls And Patient Companion Costs For Adult Inpatients. AB - With increasing acuity and simultaneous pressures for optimal productivity, reducing unnecessary patient companions has been a focus for many health care organizations. At the same time, nursing leaders are seeking to accelerate improvement in patient safety, specifically the prevention of falls. This study suggests the use of remote video monitoring is a safe tool for fall prevention. While there was a decrease in 1:1 sitter usage, there was no corollary increase in falls. In fact, falls decreased 35%. Not only was video monitoring a safe intervention, it was more effective than patient companions alone in decreasing falls by expanding the number of patients who are directly observed 24/7. PMID- 29975025 TI - A Global Health Agenda: It Is Who We Are. PMID- 29975026 TI - Accountability of Nursing Interventions vs. Severity of Illness Scores for the Hospital Care Cost Of Total Hip Replacement. AB - The main purpose of this study was to investigate the extent to which nursing care compared to severity of illness (SOI) accounted for direct hospital costs. The type, frequency, and duration of nursing interventions required for patients undergoing total hip replacement surgery by the SOI stages with independent t tests were identified. Although patients in Stage 3 generally needed a greater amount of each intervention than patients in Stage 2, the differences in needs for nursing interventions were not consistent using SOI. With hierarchical multiple regression analyses, results indicated nursing interventions explained significantly more variability in hospital care costs than SOI scores. Relying only on SOI scores for reimbursement may not accurately reflect the resource consumption of health care. PMID- 29975027 TI - Immune Checkpoint Blockade in Advanced Renal-Cell Carcinoma. PMID- 29975028 TI - Ambulatory Care Nurse-Sensitive Indicators Series: Starting with Low-Hanging Fruit: Proposing the Adaptation Of Health Care Measures to the Role of the Nurse in Ambulatory Care. AB - The American Academy of Ambulatory Care Nursing's Nurse-Sensitive Indicator Task Force was charged with identifying and developing meaningful measures for the ambulatory care environment. Several strategies were used to identify measures that would reflect the value of the role of the nurse in this setting. One such strategy was to conduct a comprehensive review of the health care environment as a whole and the measures within it, to identify measures that already existed that could easily be adapted to the role of the nurse in ambulatory care settings. Because of the complexity of the ambulatory care patient care environment, the group sought to reach momentum in indicator development by starting with the proposal of measures that would be less complex to develop, pilot, and adapt in organizations across the country. PMID- 29975029 TI - Edoxaban for Cancer-Associated Venous Thromboembolism. PMID- 29975030 TI - The World Health Organization Launches the 2016-2020 Global Strategic Directions for Strengthening Nursing and Midwifery. AB - The World Health Organization (WHO) Global Strategic Directions for Strengthening Nursing and Midwifery 2016-2020 provide a framework to ensure nursing and midwifery interventions are developed, implemented, and evaluated at global, regional, and country levels and in partnership with key stakeholders. The Global Strategic Directions for Strengthening Nursing and Midwifery 2016-2020 supports the WHO's Global Strategy on Human Resources for Health: Workforce 2030. The WHO Global Strategic Directions for Strengthening Nursing and Midwifery 2016-2020 presents a vision, guiding principles, and four themes to maximize nursing and midwifery workforce contributions to improve global health. Implementation of the strategy is articulated in the context of country and regional needs, areas for expedited action, partnerships and alliances, and accountability for ongoing monitoring and evaluation. As a framework, the 2016-2020 Global Strategic Directions for Nursing and Midwifery can help countries achieve the United Nations' Sustainable Development Goals and universal health coverage. PMID- 29975031 TI - Edoxaban for Cancer-Associated Venous Thromboembolism. PMID- 29975032 TI - Edoxaban for Cancer-Associated Venous Thromboembolism. PMID- 29975033 TI - Edoxaban for Cancer-Associated Venous Thromboembolism. PMID- 29975034 TI - Policy, Politics, and the Presidential Campaign: What's at Stake for Nursing? PMID- 29975035 TI - Primary Sjogren's Syndrome. PMID- 29975036 TI - Exploring Explanations for the Female-Male Earnings Difference Among Registered Nurses in the United States. AB - Research has shown male registered nurses (RNs) outearn their female colleagues by approximately $5,000 annually. The aim of this study was to explore differences in characteristics of female and male fulltime employed RNs, and to examine whether these differences help account for the female-male earnings gap in nursing. Specifically, the researchers tested whether the gender earnings gap could be explained by differences in career aspiration, workplace experience, time taken out of the labor force for child-rearing, and physical strength. While some evidence suggested motivational differences in career aspirations between female and male RNs exist, evidence supporting other hypotheses was not found. Given the expansion of nurses' roles in health care delivery, serious deliberations of how to respond to the earnings gap in nursing is warranted. PMID- 29975037 TI - Primary Sjogren's Syndrome. PMID- 29975038 TI - Is There a Business Case for Nursing Home Quality Improvement? AB - Evidence supporting a relationship between costs and quality in nursing homes has been inconsistent. The Minnesota Performance-based Incentive Payment Program (PIPP) is an innovative public policy that promotes quality improvement (QI) in the state's nursing facilities. The objective of this study was to investigate the economic or business perspective surrounding QI participation by exploring nursing home leader perceptions regarding market-based motivations for improvements, or a business case for engaging in a quality improvement project. There appeared to be a perception that without the increased rates provided by PIPP, needed changes to improve quality would not have occurred. PMID- 29975039 TI - High-Performance All-Solid-State Polymer Electrolyte with Controllable Conductivity Pathway Formed by Self-Assembly of Reactive Discogen and Immobilized via a Facile Photopolymerization for a Lithium-Ion Battery. AB - All-solid-state polymer electrolytes (SPEs) have aroused great interests as one of the most promising alternatives for liquid electrolyte in the next-generation high-safety, and flexible lithium-ion batteries. However, some disadvantages of SPEs such as inefficient ion transmission capacity and poor interface stability result in unsatisfactory cyclic performance of the assembled batteries. Especially, the solid cell is hard to be run at room temperature. Herein, a novel and flexible discotic liquid-crystal (DLC)-based cross-linked solid polymer electrolyte (DLCCSPE) with controlled ion-conducting channels is fabricated via a one-pot photopolymerization of oriented reactive discogen, poly(ethylene glycol)diacrylate, and lithium salt. The experimental results indicate that the macroscopic alignment of self-assembled columns in the DLCCSPEs is successfully obtained under annealing and effectively immobilized via the UV photopolymerization. Because of the existence of unique oriented structure in the electrolytes, the prepared DLCCSPE films exhibit higher ionic conductivities and better comprehensive electrochemical properties than the DLCCSPEs without controlled ion-conductive pathways. Especially, the assembled LiFePO4/Li cells with oriented electrolyte show an initial discharge capacity of 164 mA h g-1 at 0.1 C and average specific discharge capacities of 143, 135, and 149 mA h g-1 at the C-rates of 0.5, 1, and 0.2 C, respectively. In addition, the solid cell also shows the first discharge capacity of 124 mA h g-1 (0.2 C) at room temperature. The outstanding cell performance of the oriented DLCCSPE should be originated from the macroscopically oriented and self-assembled DLC, which can form ion conducting channels. Thus, combining the excellent performance of DLCCSPE and the simple one-pot fabricating process of the DLC-based all-solid-state electrolyte, it is believed that the DLC-based electrolyte can be one of the most promising electrolyte materials for the next-generation high-safety solid lithium-ion batteries. PMID- 29975040 TI - Preparation and Post-Assembly Modification of Metallosupramolecular Assemblies from Poly( N-Heterocyclic Carbene) Ligands. AB - Although the coordination chemistry of N-heterocyclic carbenes (NHCs) with transition metals has been explored for half a century, only in the past ten years has the chemistry of metallosupramolecular assemblies based on poly-NHC ligands been studied more extensively. Remarkable discrete assemblies featuring poly-NHC ligands including two-dimensional metallacycles and three-dimensional metallaprisms/cages have since emerged. These assemblies are mostly obtained starting from various imidazolium or benzimidazolium salts. Driven by the increasing interest in new supramolecular architectures from carbon donor ligands, design, and construction of poly-NHC metal assemblies has become a rapidly growing area of research. The metal-carbene bond length is fixed to approximately 2.0 A in linear NHC-M-NHC complexes. This allows the use of such complexes bearing olefin-substituted NHC ligands as templates for subsequent photochemical [2 + 2] cycloaddition reactions. The postassembly modification of such assemblies has been actively explored in recent years. In this review, we focus on the synthetic methods, characterization, structural features, and postassembly modifications of metallosupramolecular assemblies obtained from poly NHC ligands. PMID- 29975041 TI - A Fluorescent Probe for Early Detection of Melanoma and Its Metastasis by Specifically Imaging Tyrosinase Activity in a Mouse Model. AB - Melanoma is a type of highly malignant and metastatic skin cancer, and early detection of melanoma by analyzing the level of its biomarker may decrease the likelihood of mortality. In this study, a fluorescent probe called NBR-AP for detecting tyrosinase (a biomarker of melanoma) has been created by incorporating a hydroxyphenylurea group (as a substrate for the enzyme) onto a fluorescent dye phenoxazine derivative (as an activatable signal reporter). This probe can be activated to generate fluorescence through a tyrosinase-mediated oxidation followed by hydrolysis of the urea linkage. The probe is able to detect the endogenous tyrosinase level in live cells and in zebrafish sensitively and selectively. Moreover, by imaging the tyrosinase activity, NBR-AP has been successfully applied to diagnose the melanoma and its metastasis in xenogeneic mouse models established via subcutaneous injection of B16F10 cells. PMID- 29975042 TI - Directional Emission of Fluorescent Dye-Doped Dielectric Nanogratings for Lighting Applications. AB - By structuring a luminescent dielectric interface as a relief diffraction grating with nanoscale features, it is possible to control the intensity and direction of the emitted light. The composite structure of the grating is based on a fluorescent dye (Lumogen F RED 305) dispersed in a polymeric matrix (poly(methyl methacrylate)). Measurements demonstrate a significant enhancement of the emitted light for specific directions and wavelengths when the grating interface is compared to nonstructured thin films made of the same material. In particular, the maximum enhancement of photoluminescence for a given pump wavelength is obtained at an angle of incidence that is close to the Rayleigh anomaly condition for the first-order diffracted waves. In this condition, the maximum extinction of incident light is observed. Upon excitation with coherent and monochromatic sources, photoluminescence plots show that the Rayleigh anomalies confine the angular interval of the emitted light. Being the anomalies directly related to the pitch of the diffraction grating, the system can be thus implemented as an optical device whose directional emission can be designed for specific applications. The exploitation of nanoimprinting techniques for the fabrication of the luminescent grating enables production of the device on large areas, paving the way for low-cost lighting and solar applications. PMID- 29975043 TI - Extending Single Molecule Imaging to Proteome Analysis by Quantitation of Fluorescent Labeling Homogeneity in Complex Protein Samples. AB - Fluorescence-based electrophoresis has been widely used for proteome analysis in which every protein species in cells is labeled with a fluorescent dye, separated by electric migration, and quantified using fluorescence detection. The ultimate limit of sensitivity for this approach could be reached by single-molecule fluorescence imaging and counting individual proteins, requiring exhaustive fluorescent labeling of proteins across molecular populations and species. However, it remains unclear how homogeneous the fluorescence labeling of individual protein molecules of each species is across the proteome. To address this question, we developed a method to measure the labeling homogeneity based on a single-molecule fluorescence counting assay. Our results reveal that the proportion of proteins labeled with at least one dye, called labeling occupancy (LO), was 35% for fluorescently labeled BSA using existing protocols. We then found that the LO could be improved to 82% under high pH and surfactant-rich conditions. Furthermore, when a proteome sample from a human cell lysate was analyzed, the total LO was 71%, whereby the values varied between 50 and 90% for low and high molecular weight proteome fractions, respectively. The results support the possibility of sensitive detection of proteins using single-molecule counting with fluorescent labeling at the proteome scale. PMID- 29975044 TI - On the Mechanism of Trimethylphosphine-Mediated Reductive Dimerization of Ketones. AB - High-level single-reference calculations reveal that trimethylphosphine-mediated reductive dimerization of properly substituted (e.g., CF3) ketones proceeds via initial formation of an oxaphosphirane intermediate, with the oxygen atom occupying an equatorial position at phosphorus. In the "oxirane route", this oxaphosphirane intermediate loses a trimethylphosphine oxide unit, thus behaving as a carbene transfer agent toward a second carbonyl molecule and giving rise to a carbonyl ylide that cyclizates to the corresponding oxirane. This in turn transfers the carbene unit to a second phosphine molecule, with loss of acetone, affording a phosphorane. The latter undergoes typical Wittig reaction to the final homocoupling product through the oxaphosphetane intermediate. The alternative direct conversion of oxaphosphirane into phosphorane constitutes the lowest energy path as it skips the highest barrier oxirane -> phosphorane conversion. The oxirane route is favored by the use of polar solvents and electron deficient carbonyl components. The lowest barrier most exergonic process from oxaphosphirane is the pericyclic cycloaddition of the acetone C?O bond along the endocyclic P-C bond, furnishing the stable 1,3,2-dioxaphospholane product. PMID- 29975045 TI - Morphology Tuning of Aggregation-Induced Emission Probes by Flash Nanoprecipitation: Shape and Size Effects on in Vivo Imaging. AB - Aggregation-induced emission (AIE) imaging probes have recently received considerable attention because of their unique property of high performance in the aggregated state and their imaging capability. However, the tendency of AIE molecules to aggregate into micron long irregular shapes, which significantly limits their application in vivo, is becoming a serious issue that needs to be addressed. Here, we introduce a novel engineering strategy to tune the morphology and size of AIE nanoaggregates, based on flash nanoprecipitation (FNP). Quinolinemalononitrile (ED) is encapsulated inside properly selected amphiphilic block copolymers of varying concentration. This leads to a variety of ED particle morphologies with different sizes. The shape and size are found to have strong influences on tumor targeting both in vitro and in vivo. The current results therefore indicate that the FNP method together with optimal choice of an amphiphilic copolymer is a universal method to systematically control the aggregation state of AIE materials and hence tune the morphology and size of AIE nanoaggregates, which is potentially useful for precise imaging at specific tumor sites. PMID- 29975046 TI - Kinetics and Degradation Mechanism of Adrenaline Derivative CpQ in Diluted Aqueous Solutions. AB - The degradation kinetics of an adrenaline (epinephrine) derivative, CpQ, was studied in solution in the pH range of 1-12 at 40-80 degrees C by high performance liquid chromatography and ultraviolet-visible spectroscopy. The pH rate profile exhibits a bell-shaped curve with two sigmoidal regions in the specific acid-catalyzed and specific base-catalyzed regions. The pH range of maximum stability was 2.5-4.5 with the main degradation pathway being the oxidative N-dealkylation of the aliphatic amino moiety followed by fast interconversion of the resulting fragments to stable degradation products. The autoxidation reaction was slower than the reaction of the oxygen reactive species. The chiral center underwent R to S racemization by a polar reaction mechanism under acidic conditions with a rate minimum at pH 4. The rates of degradation of the R and S enantiomers were similar across all pHs. CpQ degradation in the presence of hydrogen peroxide at 40 degrees C was significantly faster, and the extent of increases with pH. Metal ions bind to CpQ and catalyze its hydrolysis in the order Fe3+ > Fe2+ > Mg2+ > Mn2+ > Ti3+ > Sr2+ > Zn2+, with a rate enhancement of <=1 order of magnitude at the studied pH values of 1 and 5. There was no buffer catalysis observed in the hydrolysis of the studied compound for maleate and phosphate but significant buffer catalysis in the case of citrate and malate. PMID- 29975047 TI - The Polyene Natural Product Thailandamide A Inhibits Fatty Acid Biosynthesis in Gram-Positive and Gram-Negative Bacteria. AB - Burkholderia thailandensis produces an impressive array of secondary metabolites, most with yet unknown targets. One of these metabolites is thailandamide, a linear polyene natural product that is constitutively synthesized by the corresponding tha gene cluster. Using broad bioactivity screens, we observed strong yet selective antibacterial activity by thailandamide against Gram positive and cell wall-weakened Gram-negative bacteria. Bacterial cytological profiling and comparison with 10 antibiotics with known modes of action revealed a unique profile for thailandamide, suggesting a distinct mechanism of inhibition. To address the target of the drug, we obtained resistant mutants of Bacillus subtilis and mapped the resistant phenotype to accA, the product of which catalyzes the first committed step in fatty acid biosynthesis. Interestingly, the tha gene cluster encodes an accA homologue with a similar amino acid substitution. Heterologous expression showed that it confers resistance to otherwise susceptible Escherichia coli cultures, indicating that it provides immunity to thailandamide-producing B. thailandensis cells. Aside from moiramide B and andrimid, thailandamide represents only the second class of natural products that inhibits bacterial growth by targeting AccA/AccD. PMID- 29975048 TI - Identification of a PDE4-Specific Pocket for the Design of Selective Inhibitors. AB - Inhibitors of phosphodiesterases (PDEs) have been widely studied as therapeutics for the treatment of human diseases, but improvement of inhibitor selectivity is still desirable for the enhancement of inhibitor potency. Here, we report identification of a water-containing subpocket as a PDE4-specific pocket for inhibitor binding. We designed against the pocket and synthesized two enantiomers of PDE4 inhibitor Zl-n-91. The ( S)-Zl-n-91 enantiomer showed IC50 values of 12 and 20 nM for the catalytic domains of PDE4D2 and PDE4B2B, respectively, selectivity several thousand-fold greater than those of other PDE families, and potent neuroprotection activities. Crystal structures of the PDE4D2 catalytic domain in complex with each Zl-n-91 enantiomer revealed that ( S)-Zl-n-91 but not ( R)-Zl-n-91 formed a hydrogen bond with the bound water in the pocket, thus explaining its higher affinity. The structural superposition between the PDE families revealed that this water-containing subpocket is unique to PDE4 and thus valuable for the design of PDE4 selective inhibitors. PMID- 29975049 TI - Mechanistic Studies of [AlCp*]4 Combustion. AB - The combustion mechanism of [AlCp*]4 (Cp* = pentamethylcyclopentadienyl), a ligated aluminum(I) cluster, was studied by a combination of experimental and theoretical methods. Two complementary experimental methods, temperature programmed reaction and T-jump time-of-flight mass spectrometry, were used to investigate the decomposition behaviors of [AlCp*]4 in both anaerobic and oxidative environments, revealing AlCp* and Al2OCp* to be the major decomposition products. The observed product distribution and reaction pathways are consistent with the prediction from molecular dynamics simulations and static density functional theory calculations. These studies demonstrated that experiment and theory can indeed serve as complementary and predictive means to study the combustion behaviors of ligated aluminum clusters and may help in engineering stable compounds as candidates for rocket propellants. PMID- 29975050 TI - Correction to "Calcium-Mediated Control of S100 Proteins: Allosteric Communication via an Agitator/Signal Blocking Mechanism". PMID- 29975052 TI - Necklace-like Molecularly Imprinted Nanohybrids Based on Polymeric Nanoparticles Decorated Multiwalled Carbon Nanotubes for Highly Sensitive and Selective Melamine Detection. AB - In this study, molecularly imprinted nanohybrids with "necklace-like" nanostructures were developed based on self-assembled polymeric nanoparticles decorated multiwalled carbon nanotubes (MWCNTs) by employing melamine as template molecules. An amphiphilic copolymer poly(acrylic acid- co-(7-(4-vinylbenzyloxy)-4 methyl coumarin)- co-ethylhexyl acrylate) (poly(AA- co-VMc- co-EHA), PAVE) containing photosensitive coumarin units was synthesized first. Then, the PAVE copolymers were co-assembled with MWCNTs in the presence of template molecules, generating photosensitive molecularly imprinted nanohybrids (MIP-MWCNTs) with necklace-like structures. Subsequently, the MIP-MWCNTs nanohybrids were used to modify electrode surface followed by photo-polymerization of the coumarin units in the nanohybrids, leading to a network architectured complex film. After extracting melamine molecules by electrolysis, a melamine MIP sensor was successfully developed. The as-prepared sensor exhibited a significantly wide linear range (1.0 * 10-12-1.0 * 10-6 mol L-1) and a low detection limit (5.6 * 10 13 mol L-1) for melamine detection. High selectivity of the sensor toward melamine was well demonstrated with respect to other melamine analogues and interferents. Furthermore, the MIP sensor showed high stability and reproducibility. The excellent performance of the MIP sensor can be attributed to the unique nanostructure of the complex film provided by these necklace-like nanohybrids. On the one hand, the nanosized polymeric MIP nanoparticles along the MWCNTs increase the effective electrode surface area and thus offer a high melamine-binding capacity. On the other hand, the MWCNTs in MIP-MWCNTs nanohybrids serve as "electronic bridges" to accelerate the electron transfer among the complex MIP film. More importantly, the MIP sensor was practically used to monitor melamine in milk samples, demonstrating a promising feature for applications in the analysis of food like milk and other food products including milk powder, infant formula, and animal feed. Considering the ease of polymeric nanoparticles functionalization, the necklace-like nanohybrids would be extended to wider applications in many other sensors and devices. PMID- 29975051 TI - Photoprogramming Allostery in Human Serum Albumin. AB - Developing strategies to interfere with allosteric interactions in proteins not only promises to deepen our understanding of vital cellular processes but also allows their regulation using external triggers. Light is particularly attractive as a trigger being spatiotemporally selective and compatible with the physiological environment. Here, we engineered a hybrid protein in which irradiation with light opens a new allosteric communication route that is not inherent to the natural system. We select human serum albumin, a promiscuous protein responsible for transporting a variety of ligands in plasma, and show that by covalently incorporating a synthetic photoswitch to subdomain IA we achieve optical control of the ligand binding in subdomain IB. Molecular dynamics simulations confirm the allosteric nature of the interactions between IA and IB in the engineered protein. Specifically, upon illumination, photoconversion of the switch is found to correlate with a less-coordinated motion of the two subdomains and an increased flexibility of the binding pocket in subdomain IB, whose fluctuations are cooperatively enhanced by the presence of ligands, ultimately facilitating their release. Our combined experimental and computational work demonstrates how harnessing artificial molecular switches enables photoprogramming the allosteric regulation of binding activities in such a prominent protein. PMID- 29975053 TI - Effects of Selenium Supplementation on Glucosinolate Biosynthesis in Broccoli. AB - Selenium (Se)-enriched broccoli has health-beneficial selenium-containing compounds, but it may contain reduced amounts of chemopreventive glucosinolates. To investigate the basis by which Se treatment influences glucosinolate levels, we treated two broccoli cultivars with 25 MUM Na2SeO4. We found that Se supplementation suppressed the accumulation of total glucosinolates, particularly glucoraphanin, the direct precursor of a potent anticancer compound, in broccoli florets and leaves. We showed that the suppression was not associated with plant sulfur nutrition. The levels of the glucosinolate precursors methionine and phenylalanine as well as the expression of genes involved in glucosinolate biosynthesis were greatly decreased following Se supplementation. Comparative proteomic analysis identified proteins in multiple metabolic and cellular processes that were greatly affected and detected an enzyme affecting methionine biosynthesis that was reduced in the Se-biofortified broccoli. These results indicate that Se-conferred glucosinolate reduction is associated with negative effects on precursor amino acid biosynthesis and glucosinolate-biosynthetic-gene expression and provide information for a better understanding of glucosinolate accumulation in response to Se supplementation in broccoli. PMID- 29975054 TI - Catalytic Enantioselective Total Synthesis of the Picrotoxane Alkaloids (-) Dendrobine, (-)-Mubironine B, and (-)-Dendroxine. AB - A concise enantioselective total synthesis of three sesquiterpenoid alkaloids-(-) dendrobine, (-)-mubironine B, and (-)-dendroxine-is presented, which highlights the state-of-art catalytic methods, including enantioselective Diels-Alder cycloaddition, iron-catalyzed aerobic lactonization, copper-catalyzed cycloisomerization, and free-radical-initiated hydroazidation. PMID- 29975055 TI - Marine Natural Products for Drug Discovery: First Discovery of Kealiinines A-C and Their Derivatives as Novel Antiviral and Antiphytopathogenic Fungus Agents. AB - Leucetta alkaloid kealiinines A-C and kealiinine B derivatives were designed, synthesized, and characterized on the basis of NMR and HR-MS. The anti-TMV and antiphytopathogenic fungus activities of these alkaloids were evaluated for the first time. Kealiinine B exhibited a higher anti-TMV activity than kealiinines A and C. Kealiinine B derivatives 2m (inhibitory rates: 68, 66, and 71% at 500 MUg/mL for inactivation, curative, and protection activity in vivo, respectively) and 2y (inhibitory rates: 69, 64, and 63% at 500 MUg/mL for inactivation, curative, and protection activity in vivo, respectively) showed significantly higher antiviral activity than ningnanmycin (inhibitory rates: 56, 56, and 58% at 500 MUg/mL for inactivation, curative, and protection activity in vivo, respectively), thus emerging as new lead compounds for novel antiviral agent development. Structure-activity relationship research provided the basis for structural simplification of these alkaloids. Further fungicidal activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds 2i and 2p displayed good fungicidal activities in vitro against Sclerotinia sclerotiorum and Rhizoctonia cerealis with inhibition rates of 71%/50 mg/kg and 70%/50 mg/kg, respectively. PMID- 29975056 TI - Surface-Layer Protein from Lactobacillus acidophilus NCFM Inhibits Lipopolysaccharide-Induced Inflammation through MAPK and NF-kappaB Signaling Pathways in RAW264.7 Cells. AB - The objective of our research was to evaluate the molecular mechanism of the anti inflammatory effects of surface-layer protein (Slp) derived from Lactobacillus acidophilus NCFM in lipopolysaccharide-induced RAW264.7 cells. Our results presented that Slp, with an apparent size of 46 kDa, attenuated the production of TNF-alpha, IL-1beta, and reactive oxygen species (ROS), by inhibiting the MAPK and NF-kappaB signaling pathways. In addition, 10 MUg mL-1 of Slp significantly inhibited NO and PGE2 production ( P < 0.001) through downregulating the expression levels of iNOS and COX-2 protein. Furthermore, Slp was found to inhibit NF-kappaB p65 translocation into the nucleus to activate inflammatory gene transcription. These findings suggest that Slp is a potential immune modulating bioactive protein derived from probiotics and holds promise for use as an additive in functional foods. PMID- 29975057 TI - Temperature-Dependent Photoluminescence of CH3NH3PbBr3 Perovskite Quantum Dots and Bulk Counterparts. AB - Organic-inorganic lead halide perovskite is emerging as a potential emissive material for light emitting devices, such as, light emitting diodes (LEDs) and lasers, which has emphasized the necessity of understanding its fundamental opto physical properties. In this work, the temperature-dependent photoluminescence of CH3NH3PbBr3 perovskite quantum dots (QDs), polycrystalline thin film (TF), and single crystal (SC) has been studied. The optophysical properties, such as exciton-phonon scattering, exciton binding energy, and exciton decay dynamics, were investigated. The exciton-phonon scattering of perovskite is investigated, which is responsible for both PL line width broadening and nonradiative decay of excitons. The exciton binding energy of QDs, TF, and SC were estimated to be 388.2, 124.3, and 40.6 meV, respectively. The observed main exciton decay pathway for QDs is the phonon assisted thermal escape, while that for TF and SC was the thermal dissociation due to low exciton binding energy. PMID- 29975058 TI - Correction to "The Suzuki-Miyaura Coupling of Nitroarenes". PMID- 29975059 TI - Melatonin: A Multifunctional Molecule That Triggers Defense Responses against High Light and Nitrogen Starvation Stress in Haematococcus pluvialis. AB - Melatonin (MLT), a ubiquitously distributed small molecule, functions in plant responses to various biotic and abiotic stresses. However, the interactions between melatonin and other important molecules in Haematococcus pluvialis response stresses are largely unknown. In the present study, exogenous melatonin improved H. pluvialis resistance to nitrogen starvation and high light. We concluded that exogenous melatonin treatment prevented the reactive oxygen species (ROS) burst and limited cell damage induced by abiotic stress through activation of antioxidant enzymes and antioxidants. Astaxanthin, a major antioxidant in H. pluvialis cells, exhibited a 2.25-fold increase in content after treatment with melatonin. The maximal astaxanthin content was 32.4 mg g-1. The functional roles of the nitric oxide (NO)-mediated mitogen activated protein kinase (MAPK) signaling pathway and cyclic adenosine monophosphate (cAMP) signaling pathway induced by melatonin were also evaluated. The results clearly indicate that cAMP signaling pathways are positively associated with microalgal astaxanthin biosynthesis. Additionally, the NO-dependent MAPK signaling cascade is activated in response to astaxanthin accumulation induced by melatonin, confirming that MAPK is a target of NO action in physiological processes. This work is the first to use H. pluvialis as in vivo model and documents the influence of melatonin on the physiological response to abiotic stress in this microalgae. PMID- 29975060 TI - Pd-Catalyzed Dearomative Allylation of Benzyl Phosphates. AB - Dearomative C-C bond formation of benzyl phosphates has been developed. In the presence of a palladium/PAr3 catalyst, benzyl phosphates reacted with allyl borates to generate the allylated product in a dearomative fashion. The resulting dearomatized molecules were successfully derivatized by Simmons-Smith cyclopropanation and oxidation. PMID- 29975061 TI - Comparative Metabolomics Elucidates Postprandial Metabolic Modifications in Plasma of Obese Individuals with Metabolic Syndrome. AB - Although higher intakes of dairy milk are associated with a lower risk of metabolic syndrome (MetS), the underlying protective mechanism remains unclear. This study investigated the dynamic metabolic profile shift following the ingestion of low-fat milk or an isocaloric volume of rice milk in obese individuals with metabolic syndrome (MetS). In a randomized, double-blind, crossover study, postprandial plasma samples ( n = 266) were collected from 19 MetS participants. Plasma samples were analyzed by a targeted metabolomics platform which specifically detects 117 metabolites from 25 metabolic pathways. The comprehensive time-course metabolic profiling in MetS participants indicated that the postprandial metabolic profiles distinguish low-fat milk and rice milk consumption in a time-dependent manner. Metabolic biomarkers, such as orotate, leucine/isoleucine and adenine, showed significantly different trends in the two test beverages. Bayesian statistics identified 12 metabolites associated with clinical characteristics of postprandial vascular endothelial function, such as flow-mediated dilation (FMD), postprandial plasma markers of oxidative stress and NO status. Furthermore, metabolic pathway analysis based on these metabolite data indicated the potential utility of metabolomics to provide mechanistic insights of dietary interventions to regulate postprandial metabolic excursions. PMID- 29975062 TI - Pestynol, an Antifungal Compound Discovered Using a Saccharomyces cerevisiae 12geneDelta0HSR-iERG6-Based Assay. AB - The multidrug-sensitive budding yeast, Saccharomyces cerevisiae 12geneDelta0HSR iERG6, is very useful in antifungal screens. A novel compound, named pestynol (1), was discovered from a culture of the fungus Pestalotiopsis humus FKI-7473 using the multidrug-sensitive yeast. The structure of 1 was elucidated by NMR studies and modified Mosher's method as (1 R,2 R,3 R,4 R)-( E)-5-(7,11-dimethyl-3 methylenedodeca-6,10-dien-1-yn-1-yl)cyclohex-5-ene-1,2,3,4-tetraol. Compound 1 showed antimicrobial activity against the Gram-positive bacteria, Klebsiella pneumoniae, and S. cerevisiae 12geneDelta0HSR-iERG6 and Mucor racemosus, but displayed only weak cytotoxicity against various human cancer cell lines. Compound 1 displayed antifungal activities against S. cerevisiae 12geneDelta0HSR iERG6 and Mucor racemosus at 10 MUg/disc. PMID- 29975063 TI - Biogenic Polyphosphate Nanoparticles from Synechococcus sp. PCC 7002 Exhibit Intestinal Protective Potential in Human Intestinal Epithelial Cells In Vitro and Murine Small Intestine Ex Vivo. AB - Polyphosphates are one of the active compounds from probiotics to maintain gut health. The current research extracted and purified intact biogenic polyphosphate nanoparticles (BPNPs) from Synechococcus sp. PCC 7002 cells. BPNPs were near spherical anionic particles (56.9 +/- 15.1 nm) mainly composed of calcium and magnesium salt of polyphosphate and were colloidally stable at near-neutral and alkaline pH. BPNPs survived gastrointestinal digestion in mice and could be absorbed and transported by polarized Caco-2 cell monolayers. They dose dependently increased the tightness of intercellular tight junction and the expression of claudin-4, occludin, zonula occludens-1, and heat shock protein 27 in Caco-2 cell monolayers. BPNPs also effectively attenuated H2O2-induced cell death, plasma membrane impairment, and intracellular superoxide production in NCM460 cells. In addition, they conferred resistance to H2O2-induced barrier disruption in freshly excised mouse small intestine. Our results suggest that BPNPs are a promising postbiotic nanomaterial with potential applications in gut health maintenance. PMID- 29975064 TI - Sulfur Diffusion within Nitrogen-Doped Ordered Mesoporous Carbons Determined by in Situ X-ray Scattering. AB - The low intrinsic conductivity of sulfur necessitates conductive additives, such as mesoporous carbons, to the cathode to enable high-performance metal-sulfur batteries. Simultaneous efforts to address polysulfide shuttling have introduced nitrogen-doped carbons to provide both conductivity and suppressed shuttling because of their strong interaction with sulfur. The strength of this interaction will impact the ability to fill the mesopores with sulfur via melt infusion. Here, we systematically investigate how nitrogen doping influences the rate that molten sulfur can infiltrate the mesopores and the overall extent of pore filling of highly ordered mesoporous doped carbons using in situ small angle X-ray scattering (SAXS). The similarity in electron density between molten sulfur and the soft carbon framework of the mesoporous material leads to a precipitous decrease in the scattered intensity associated with the ordered structure as voids are filled with sulfur. As the nitrogen doping increases from 1 to 20 at. %, the effective diffusivity of sulfur in the mesopores decreases by an order of magnitude (2.7 * 10-8 to 2.3 * 10-9 cm/s). The scattering becomes nearly invariant within 20 min of melt infiltration at 155 degrees C for all but the most doped carbon, which indicates that submicron-sized mesoporous carbon particles can be filled rapidly. Additionally, the nitrogen doping decreases the sulfur content that can be accommodated within the mesopores from 95% of the mesopores filled without doping to only 64% filled with 20 at. % N as determined by the residual scattering intensity. Sulfur does not crystallize within the mesopores of the nitrogen-doped carbons, which is further indicative of the strong interactions between the nitrogen species and sulfur that can inhibit polysulfide shuttling. In situ SAXS provides insights into the diffusion of sulfur in mesopores and how the surface chemistry of nitrogen-doped carbon appears to significantly hinder the infiltration by sulfur. PMID- 29975065 TI - Palladium-Catalyzed Synthesis of Dihydrobenzoindolones via C-H Bond Activation and Alkyne Insertion. AB - A palladium-catalyzed intramolecular carbopalladation, intramolecular C-H bond activation, and alkyne insertion sequence for the generation of dihydrobenzoindolones is described. Products are obtained in moderate to excellent yields as single regioisomers. Various functional groups on both reaction partners were tolerated, and the scalability of this method was determined. PMID- 29975066 TI - Lewis Acid Catalyzed Tandem 1,4-Conjugate Addition/Cyclization of in Situ Generated Alkynyl o-Quinone Methides and Electron-Rich Phenols: Synthesis of Dioxabicyclo[3.3.1]nonane Skeletons. AB - A versatile Lewis acid catalyzed tandem cyclization of in situ generated alkynyl o-quinone methides ( o-AQMs) with electron-rich phenols has been developed on the basis of the mode involving an intermolecular 1,4-conjugate addition/6-endo cyclization/1,3-aryl shift/intramolecular 1,4-conjugate addition cascade. This reaction provides a new method for expeditious assembly of synthetically and biologically interesting tetracyclic bridged dioxabicyclo[3.3.1]nonane skeletons featuring a congested bridgehead oxa-quaternary stereocenter. PMID- 29975067 TI - Cyclopropanation by Gold- or Zinc-Catalyzed Retro-Buchner Reaction at Room Temperature. AB - Through the design of a second generation of more reactive 7-substituted 1,3,5 cycloheptatrienes, a room-temperature gold(I)-catalyzed retro-Buchner cyclopropanation sequence and the first zinc(II)-catalyzed version of this process, which uses inexpensive ZnBr2 as catalyst, have been developed. This led to a broad-scope cyclopropanation of both activated and unactivated alkenes, including late-stage derivatization of biologically relevant compounds, and to the total synthesis of (+/-)-lactobacillic acid. PMID- 29975068 TI - Synthesis of Secondary Amides from Thiocarbamates. AB - The synthesis of secondary amides from readily accessible and bench-stable substituted S-phenyl thiocarbamates and Grignard reactants is reported. Oxidative workup allows recycling of the thiolate leaving group as diphenyl disulfide. Diphenyl disulfide can be transformed into S-phenyl benzenethiosulfonate, a reactant required for thiocarbamate synthesis. This amide synthesis is suitable for the preparation of challenging amides that are not or hardly accessible via classical approaches. PMID- 29975069 TI - Asymmetric Robinson Annulation of 3-Indolinone-2-carboxylates with Cyclohexenone: Access to Chiral Bridged Tricyclic Hydrocarbazoles. AB - A chiral bifuntional thiourea catalyzed diastereo- and enantioselective Michael addition followed by an intramolecular Aldol reaction of 3-indolinone-2 carboxylates with cyclohexenone has been accomplished using a chiral thiourea catalyst. It is a novel strategy for the construction of chiral bridged tricyclic hydrocarbazole derivatives bearing four contiguous stereocenters with excellent diastereo- and enantioselectivity. PMID- 29975070 TI - Nickel and Nucleophilic Cobalt-Catalyzed Trideuteriomethylation of Aryl Halides Using Trideuteriomethyl p-Toluenesulfonate. AB - Herein, a novel approach for the trideuteriomethylation of aryl halides using nickel and nucleophilic cobalt catalysts and the readily available trideuteriomethyl p-toluenesulfonate (CD3OTs) is described. This method provides access to a wide range of CD3-containing arenes. Moreover, a transmethylation step is revealed as crucial in the nickel/cobalt catalytic mechanism. PMID- 29975071 TI - Identifying adolescents with alcohol use disorder: Optimal screening using the National Institute on Alcohol Abuse and Alcoholism screening guide. AB - The National Institute on Alcohol Abuse and Alcoholism (NIAAA) screening guide (SG) uses a 2-question screening process to identify adolescents at risk for alcohol use. The aim of this study was to identify the optimal screening rule in terms of identifying adolescents with alcohol use disorder (AUD) using the NIAAA questions by examining whether the cutpoint should vary by gender, race/ethnicity, grade, and/or age. Youth aged 12 through 18 years (N = 1,573; 27% Black, 51% Hispanic) were screened using the NIAAA SG, and then completed a survey. We used receiver operating characteristic curve analyses to identify the optimal cutpoint for the NIAAA screener question on self-use with AUD as the outcome. We compared the resulting screening rule with the NIAAA SG rule. We found that the optimal cutpoint depended on age and grade of adolescents. The resulting screening rule was the same as the NIAAA SG, and thus independently validated the NIAAA SG, with the exception of screening for adolescents 18 years of age, for which a lower cutpoint was indicated. The performance of both screening rules was highly similar when applied to the study sample, with a sensitivity of 0.89 for the optimal screening rule and a sensitivity of 0.87 for the NIAAA SG. In settings in which the cost of a false positive is relatively low (depending on available resources and cost of the intervention), lower cutpoints for older adolescents should be considered, as this may increase sensitivity of identifying these individuals at risk for AUD. (PsycINFO Database Record PMID- 29975072 TI - Memory dysfunction in school-aged children exposed prenatally to antiepileptic drugs. AB - OBJECTIVE: Prenatal exposure to antiepileptic drugs (AEDs) and in particular valproate (VPA) has been shown to impair intellectual and language development in children, but the impact on memory functioning has not been thoroughly investigated. This study aimed to evaluate memory skills in school-age children who were exposed to AEDs prenatally. METHOD: The sample comprised of 105 children aged 6 to 8 years. Information on AED exposure, maternal epilepsy, pregnancy, and medical history was prospectively obtained. Children completed a neuropsychological assessment including measures of verbal and nonverbal memory. RESULTS: Children exposed to VPA performed lower than expected on list learning, story recall, and figure recall tasks. Those exposed to VPA in a polytherapy regime achieved poorer verbal memory scores compared with other drug exposure groups. VPA dose was negatively correlated with both verbal and nonverbal memory measures. Language ability predicted performance on all verbal memory measures and VPA dose was an additional predictor of retroactive interference on the list learning task. Performance on figure recall was predicted by exposure to VPA in polytherapy. Children exposed to carbamazepine (CBZ) also showed a higher rate of impairment on nonverbal memory measures. CONCLUSION: Both verbal and nonverbal memory skills are at risk in children exposed prenatally to VPA, particularly in those exposed to higher VPA doses. There may also be a selective vulnerability of the medial temporal lobe to VPA exposure. Our data highlight the possibility that nonverbal memory may also be affected in children exposed to CBZ. These findings have significant implications for the provision of cognitive and educational strategies to children exposed to AEDs in utero. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975074 TI - The closer they are, the more they interfere: Semantic similarity of word distractors increases competition in language production. AB - Heterogeneous effects of semantic distance in language production have sparked a debate on the central assumption of many language production models, namely that lexical selection is a competitive process. In the present ERP study, we manipulated semantic distance in the picture word interference (PWI) paradigm systematically within taxonomic hierarchies. Target-distractor pairs were either closely related members of the same basic level category, hence sharing many semantic features (e.g., orangutan and gorilla), or distantly related members of the same superordinate category, sharing fewer features (e.g., orangutan and horse). Across related conditions, broad category membership (e.g., animals) was kept constant. Naming times reflected a systematic increase of semantic interference as semantic distance decreased. Early and later ERP modulations related to the semantic distance manipulation were observed at posterior regions starting at 234 ms and with an additional fronto-central cluster starting at 346 ms. Early effects are interpreted as indexing lexical selection while the late effects may reflect an N400-like component. Taking the behavioral and ERP modulations together, these results are in line with models of lexical selection that include an early competitive lexical selection process. (PsycINFO Database Record PMID- 29975073 TI - Conventional and functional assessment of spatial neglect: Clinical practice suggestions. AB - OBJECTIVE: Spatial neglect (SN) constitutes a substantial barrier to functional recovery after acquired brain injury. However, because of its multimodal nature, no single test can capture all the signs of SN. To provide a clinically feasible solution, we used conventional neuropsychological tests as well as the Catherine Bergego Scale (CBS) via the Kessler Foundation Neglect Assessment Process (KF NAP). The goal was to add evidence that a global approach should detect better even subtle signs of SN. METHOD: Fourteen individuals with lesions located in the right cerebral hemisphere participated in the study. Participants were assessed with a comprehensive battery of neuropsychological tests, comprising a set of visuospatial tests to evaluate several spatial domains. In addition, patients underwent functional assessment with the Barthel Index, the Functional Independence Measure (FIM), and the CBS via KF-NAP. RESULTS: The CBS via KF-NAP was associated with the visuospatial paper-based tests (p = .004) as well as the Motor FIM (p = .003), and was more sensitive than the Behavioral Inattention Test Conventional in detecting SN (p = .014). CONCLUSIONS: We showed that the CBS via KF-NAP was able: (a) to detect functional impairment, especially motor, related to SN; (b) to selectively measures spatial rather than nonspatial dysfunctions; and (c) to be highly sensitive in detecting SN signs especially in those patients with mild severity, covering several aspects of SN manifestations. The patient's SN diagnosis based on the CBS via KF-NAP is clinically important and directly relevant to care planning and goal setting. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975075 TI - Towards a deeper understanding of impression formation-New insights gained from a cognitive-ecological perspective. AB - Impression formation is a basic module of fundamental research in social cognition, with broad implications for applied research on interpersonal relations, social attitudes, employee selection, and person judgments in legal and political context. Drawing on a pool of 28 predominantly positive traits used in Solomon Asch's (1946) seminal impression studies, two research teams have investigated the impact of the number of person traits sampled randomly from the pool on the evaluative impression of the target person. Whereas Norton, Frost, and Ariely (2007) found a "less-is-more" effect, reflecting less positive impressions with increasing sample size n, Ullrich, Krueger, Brod, and Groschupf (2013) concluded that an n-independent averaging rule can account for the data patterns obtained in both labs. We address this issue by disentangling different influences of n on resulting impressions, namely varying baserates of positive and negative traits, different sampling procedures, and trait diagnosticity. Depending on specific task conditions, which can be derived on theoretical grounds, the strength of resulting impressions (in the direction of the more prevalent valence) (a) increases with increasing n for diagnostic traits, (b) is independent of n for nondiagnostic traits, or (c) decreases with n when self truncated sampling produces a distinct primacy effect. This refined pattern, which holds for the great majority of individual participants, illustrates the importance of strong theorizing in cumulative science (Fiedler, 2017) built on established empirical laws and logically sound theorizing. (PsycINFO Database Record PMID- 29975076 TI - Should job applicants be excited or calm? The role of culture and ideal affect in employment settings. AB - Do cultural differences in emotion play a role in employment settings? We predicted that cultural differences in ideal affect-the states that people value and ideally want to feel-are reflected in: (a) how individuals present themselves when applying for a job, and (b) what individuals look for when hiring someone for a job. In Studies 1-2 (NS1 = 236, NS2 = 174), European Americans wanted to convey high arousal positive states (HAP; excitement) more and low arousal positive states (LAP; calm) less than did Hong Kong Chinese when applying for a job. European Americans also used more HAP words in their applications and showed more "high intensity" smiles in their video introductions than did Hong Kong Chinese. In Study 3 (N = 185), European American working adults rated their ideal job applicant as being more HAP and less LAP than did Hong Kong Chinese, and in Study 4a (N = 125), European American Masters of Business Administration (MBAs) were more likely to hire an excited (vs. calm) applicant for a hypothetical internship than were Hong Kong Chinese MBAs. Finally, in Study 4b (N = 300), employees in a U.S. company were more likely to hire an excited (vs. calm) applicant for a hypothetical internship. In Studies 1-4a, observed differences were partly related to European Americans valuing HAP more than Hong Kong Chinese. These findings support our predictions that culture and ideal affect shape behavior in employment settings, and have important implications for promoting cultural diversity in the workplace. (PsycINFO Database Record PMID- 29975078 TI - Landmark learning, cue conflict, and outbound view sequence in navigating desert ants. AB - Mobile animals need to reliably find goal locations and animal navigators acquire and use multiple cue sets within their environment designating direction and distance estimates of these locations. Foraging ants use multiple navigational tools including path integration and the learning of the landmark panorama. During landmark-based navigation, foragers first acquire the landmark cues around the nest through preforaging learning walks, and then learn non-nest site cues along their foraging routes. Here, we explore both foragers' ability to extrapolate views from around the nest to local displacement sites and landmark learning during the first foraging trips away from the nest area. During Experiment 1, foragers were given variable amounts of exposure to the nest area before being displaced 8 m away where their return trips were recorded. In Experiment 2, foragers' return trips from a site 8 m from the nest were recorded with the surrounding landmarks during either the outbound or inbound trip obstructed from view and with/without the aid of a homeward vector. Foragers were unable to correctly orient or return home efficiently regardless of the exposure level to the nest panorama, suggesting an inability to extrapolate views from learning walks and supporting recognition-based navigation. Foragers were able to use experience of either the outbound- or inbound-view sequence to initially orient home, yet were unable to quickly return to the nest when only exposed to the inbound route. Our results suggest that exposure to the outbound foraging path is critical for efficient homeward route formation. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975077 TI - African American emerging adults' experiences with racial discrimination and drinking habits: The moderating roles of perceived stress. AB - OBJECTIVES: Despite the abundance of research aimed at quantifying the impact of racism on the mental and physical health of African Americans, results remain inconclusive largely because of challenges with operationalization, as well as conflation with the concept of racial discrimination, which may be more readily assessed. The purpose of the current study was to: (a) determine whether racial discrimination had an impact on the degree of alcohol use and binge drinking among African American emerging adults, and if so, (b) determine whether perceived stress linked to racially discriminatory experiences moderated these associations. METHOD: We used a series of hierarchical regressions to examine associations among racial discrimination, perceived stress, and degree of alcohol consumption in a sample of African American emerging adults in the southeast (n = 235). RESULTS: We found that the association between racial discrimination and degree of alcohol consumption (alcohol use and binge drinking) was strongest among individuals who reported greater levels of perceived stress linked to racial discrimination experiences. This association, however, was not significant for individuals who reported lower levels of perceived stress in response to racial discrimination. CONCLUSIONS: African Americans who experience a high degree of perceived stress in response to experiences with racial discrimination may be at greater risk for problem drinking than their peers with less perceived stress. These findings highlight the need for novel intervention efforts aimed at mitigating the effects of stress and racial discrimination on health outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975079 TI - Intention insertion: Activating an action's perceptual consequences is sufficient to induce non-willed motor behavior. AB - It feels intuitive that our actions are intentional, but there is considerable debate about whether (and how) humans control their motor behavior. Recent ideomotor theories of action argue that action intentions are fundamentally perceptual, that actions are not only controlled by anticipating-imagining-their intended perceptual consequences, but are also initiated when this action effect activation is strong. Here, the authors report a study (plus a replication) that provides direct evidence for this proposal, showing that even nonintended actions are executed when their effects are activated strongly enough. Participants mentally rehearsed a movement sequence and were unexpectedly presented with salient visual cues that were either compatible or incompatible with their currently imagined action. As predicted by ideomotor theories, the combined activation through imagery and perception was sufficient to trigger involuntary actions, even when participants were forewarned and asked to withhold them. Ideomotor cues, therefore, do not only influence preplanned responses but can effectively insert intentions to act, creating behavior de novo, as predicted from ideomotor theories of action control. (PsycINFO Database Record PMID- 29975081 TI - The relationship among design parameters for statistical power between continuous and binomial outcomes in cluster randomized trials. AB - While research on statistical power for designs with continuous outcomes is extensive, the literature on power for designs with binary outcomes is notably more limited. Because statistical power for continuous outcomes is well known, a natural question is whether power may be estimated in a similar way for the case of binary outcomes. This question involves establishing the appropriate analogy between design parameters in the continuous and binary outcome cases, which consists of an analogy in effect sizes and an analogy in the intraclass correlation coefficient (ICC). This article proposes two possible analogies for the ICC and discusses the challenges in establishing a valid and useful analogy for statistical power in designs with binary outcomes. Using the results from two simulation studies, we compare the power estimates and Type I error rates under two analytic models for binary outcomes and the corresponding values under the ICC analogies. We use the simulation results to assess the implications for power and statistical inference when no useful analogy in ICCs exists for a given study. We provide a discussion on how researchers might think of the analogies using an empirical example on a preschool intervention in Ghana. We conclude with final thoughts on the limitations in establishing an analogy in design parameters and ideas for future research. (PsycINFO Database Record PMID- 29975080 TI - Chronic nicotine exposure in preadolescence enhances later spontaneous recovery of fear memory. AB - Preadolescent mice have been shown to be differentially susceptible to the effects of both acute and chronic nicotine exposure on contextual fear learning relative to adults. For this study, we tested the effects of chronic nicotine exposure in preadolescence on adulthood extinction and spontaneous recovery of fear memory in a model in which contextual fear acquisition occurred prior to nicotine exposure. Preadolescent (postnatal day 23) and adult (postnatal day 53) male C57BL/6J mice underwent contextual fear conditioning and were then exposed to chronic nicotine at 12.6 mg/kg/day for 12 days via osmotic minipump. Eighteen days following the removal of nicotine, both groups of mice underwent fear extinction, followed by a spontaneous recovery session a week later. History of chronic nicotine did not affect later extinction of fear memory in adult-trained mice, whereas adolescent-trained mice exhibited a global impairment in retention of fear memory that precluded detection of effects of early nicotine on later fear extinction. However, it was found that adult spontaneous recovery of fear memory was impaired in mice exposed to nicotine as adults and enhanced in mice exposed to nicotine as preadolescents. These results may indicate greater vulnerability to recurrence of traumatic memory as well as compromised inhibitory control in young smokers. (PsycINFO Database Record PMID- 29975082 TI - Aging effects on symbolic number comparison: No deceleration of numerical information retrieval but more conservative decision-making. AB - Whereas many cognitive tasks show pronounced aging effects, even in healthy older adults, other tasks seem more resilient to aging. A small number of recent studies suggests that number comparison is possibly one of the abilities that remain unaltered across the life span. We investigated the ability to compare single-digit numbers in young (19-39 years; n = 39) and healthy older (65-79 years; n = 39) adults in considerable detail, analyzing accuracy as well as mean and variance of their response time, together with several other well-established hallmarks of numerical comparison. Using a recent comprehensive process model that parsimoniously accounts quantitatively for many aspects of number comparison (Reike & Schwarz, 2016), we address two fundamental problems in the comparison of older to young adults in numerical comparison tasks: (a) to adequately correct speed measures for different levels of accuracy (older participants were significantly more accurate than young participants), and (b) to distinguish between general sensory and motor slowing on the one hand, as opposed to a specific age-related decline in the efficiency to retrieve and compare numerical magnitude representations. Our results represent strong evidence that healthy older adults compare magnitudes as efficiently as young adults, when the measure of efficiency is uncontaminated by strategic speed-accuracy trade-offs and by sensory and motor stages that are not related to numerical comparison per se. At the same time, older adults aim at a significantly higher accuracy level (risk aversion), which necessarily prolongs processing time, and they also show the well-documented general decline in sensory and/or motor functions. (PsycINFO Database Record PMID- 29975083 TI - Reading and recovery expectations: Implementing a recovery-oriented bibliotherapy program in an acute inpatient psychiatric setting. AB - OBJECTIVE: This study examined the feasibility and acceptability of developing a recovery-oriented book club in an acute inpatient psychiatric setting, and the impact of participation on measures of hope and recovery orientation. METHOD: Participants were recruited from an inpatient psychiatric hospital and assigned to control (N = 13) or experimental (N = 13) conditions. Participants completed the Herth Hope Index (HHI) and the Mental Health Confidence Scale (MHCS) at baseline and follow-up. Book club participants completed a satisfaction survey. ANOVA was performed to examine changes on HHI and MHCS. RESULTS: No significant differences were found between conditions on HHI or MHCS. On the satisfaction survey, most book club participants agreed "somewhat" or "strongly" that the intervention increased self-understanding (92.3%) and hope (61.6%). CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Book club groups may help individuals in inpatient psychiatric settings feel more hopeful. Future research may examine the adaptability of this intervention for outpatient settings. (PsycINFO Database Record PMID- 29975084 TI - Student veterans with posttraumatic stress symptoms: Perceived preferences for on campus psychoeducation. AB - OBJECTIVE: This investigation aimed to better understand perceived barriers to academic success and preferences for a veteran-specific psychosocial course among veterans with symptoms of posttraumatic stress (PTS). METHOD: Ninety-three veterans participated in this investigation as part of a larger study examining psychosocial functioning among veterans with PTS symptoms. Participants completed a self-report survey focused on perceived barriers to academic success and psychoeducational preferences related to health and well-being. RESULTS: Perceived barriers to academic success reported as most problematic were sleep difficulties, stress, depression, and financial concerns. Results indicated that veterans would be interested in attending an on-campus course focusing on these areas. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These findings contribute to the understanding of student veterans with PTS symptoms' perceived needs and inform the development of campus programs for this population. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975085 TI - What is social inclusion? A thematic analysis of professional opinion. AB - OBJECTIVE: Social inclusion is increasingly recognized as an important contributor to positive mental health outcomes, particularly for people with mental illness. There is a lack of consensus regarding what it means to be socially included and what the key contributors to social inclusion may be. The aim of this investigation was to determine such key contributors, as identified by those with professional experience. METHOD: A thematic analysis of literature regarding social inclusion was conducted to obtain the opinions of professionals regarding key contributors of social inclusion. Seventy-one pieces of literature were reviewed: peer-reviewed literature (academic literature regarding social inclusion in general [n = 25] and social inclusion and mental illness [n = 26]), and gray literature (organizational reports [n = 20]). Within- and between-groups analyses were performed to determine group differences and increase understanding of which contributors were deemed important consistently across groups. RESULTS: A comprehensive list of 90 contributors to social inclusion and exclusion was compiled, categorized into 13 domains based on commonalities. Contributors related to employment and education, housing and neighborhood, and social activities and support were highly cited. Differences were observed between groups regarding specificity of contributors, with organizational reports reporting more detailed contributors. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: A comprehensive and specific understanding of social inclusion was obtained. This improved understanding will allow for better measurement of social inclusion which will assist in evaluating programs and interventions, identifying areas of greatest need, and in planning services, policy and strategies to target specific contributors proven to improve social inclusion and subsequent mental health outcomes. (PsycINFO Database Record PMID- 29975086 TI - "Validation of the Narcissistic Grandiosity Scale and creation of reduced item variants": Correction to Crowe et al. (2016). AB - Reports an error in "Validation of the Narcissistic Grandiosity Scale and creation of reduced item variants" by Michael Crowe, Nathan T. Carter, W. Keith Campbell and Joshua D. Miller (Psychological Assessment, 2016[Dec], Vol 28[12], 1550-1560). In the article, the reliabilities (alphas) for the NPI were reported in the "NPI: Samples 1, 2, and 3" section as follows: NPI LA: alpha = .73; NPI GE: alpha = .71; NPI EE: alpha = .73. These values are incorrect. The correct values are as follows: NPI LA: alpha = .79; NPI GE: alpha = .79; NPI EE: alpha= .54. (The following abstract of the original article appeared in record 2016 03883-001.) The Narcissistic Grandiosity Scale (NGS) is a short adjective-based measure of narcissistic grandiosity (Rosenthal, Hooley, & Steshenko, 2007). The NGS has already shown promise as a measure of grandiose narcissism, but it has never been the subject of a formal validation study. In the current study (N = 870 across 3 samples), the factor structure of NGS was examined and item response theory analyses were used to generate abbreviated versions of the scale. The NGS scales' relations to measures of grandiose and vulnerable narcissism, the five factor model (FFM), the interpersonal circumplex, self-esteem, and the Personality Inventory of the Diagnostic and Statistical Manual for Mental Disorders-Fifth Edition (DSM-5, PID-5) were assessed. The correlation profile of the NGS was also correlated with expert ratings of prototypical cases of narcissistic personality disorder using both the FFM and PID-5 trait profiles. Overall, the NGS was found to be a unidimensional measure of narcissistic grandiosity with good convergent, discriminant, and criterion validity. The abbreviated versions of the NGS manifested strong reliability and associations entirely consistent with the full version. (PsycINFO Database Record PMID- 29975087 TI - "Development of a self-distancing task and initial validation of responses": Correction to Shepherd et al. (2016). AB - Reports an error in "Development of a self-distancing task and initial validation of responses" by Kathrine A. Shepherd, Karin G. Coifman, Lindsey M. Matt and David M. Fresco (Psychological Assessment, 2016[Jul], Vol 28[7], 841-855). In the article, several textual errors were introduced because the accuracy variable was interpreted as an error rate rather than as a percent correct. These errors appeared (1) under the Results section for Study 2, in the first sentence; (2) in the "Tests of correctness hypotheses" section of the Results for Study 2; and (3) in the fourth sentence of the second paragraph of the Discussion section. (The following abstract of the original article appeared in record 2016-17963-001.) Mindfulness-based interventions are believed to counteract cognitive biases that exacerbate cognitive and physiological reactivity to emotional experiences and that contribute to the development and persistence of psychopathology. One process by which mindful practices may produce such salutary effects is by enhancing the capacity to "decenter"-or to adopt a self-distanced, nonjudgmental perspective on conscious experiences (e.g., thoughts, memories, and feelings). Findings consistently indicate that decentering, assessed via self-report, represents an important aspect of mental health and well-being; however, numerous researchers have called for more objective measures of skills associated with mindfulness and decentering to further evaluate the mechanisms and benefits of mindfulness-based practices. Thus, in the current investigation, we developed a behavioral task that requires mental manipulation of negative emotional (and neutral) material away from the self (self-distancing), as a means to assess the skills associated with mindfulness and decentering that likely underlie healthy emotional processing. In 2 nonmeditating, university samples, we found that higher levels of self-reported mindfulness and higher levels of 1 facet of decentering (the capacity to adopt a distanced perspective on experiences) predicted behavioral indicators of self-distancing. Results suggest that the self distancing task shows considerable promise for capturing skills associated with mindfulness and at least 1 element of decentering. (PsycINFO Database Record PMID- 29975088 TI - The Triarchic Psychopathy Measure: An examination in a Lithuanian inmate sample. AB - The goal of the current investigation was to evaluate the Lithuanian translation of the Triarchic Psychopathy Measure (TriPM; Patrick, 2010) as well as more broadly extend the construct validity of this psychopathy measurement model to forensic and correctional criteria. Two samples derived from male Lithuanian correctional facilities were merged for this study. The TriPM Meanness and Disinhibition scales evinced acceptable internal reliability coefficients, whereas that for the TriPM Boldness scale was in the questionable range. All three TriPM scales were generally associated with external criteria reflecting psychopathy, aggression, and transdiagnostic clinical and personality constructs in ways consistent with the extant literature, though TriPM Boldness evinced surprisingly small negative correlations with measures of negative emotionality and fear. Furthermore, TriPM Disinhibition was associated with the largest correlations with two risk assessment measures. Implications of these findings in the context of the broader literature are discussed. (PsycINFO Database Record PMID- 29975089 TI - Do smart people have better intuitions? AB - There is much evidence that high-capacity reasoners perform better on a variety of reasoning tasks (Stanovich, 1999), a phenomenon that is normally attributed to differences in either the efficacy or the probability of deliberate (Type II) engagement (Evans, 2007). In contrast, we hypothesized that intuitive (Type I) processes may differentiate high- and low-capacity reasoners. To test this hypothesis, reasoners were given a reasoning task modeled on the logic of the Stroop Task, in which they had to ignore one dimension of a problem when instructed to give an answer based on the other dimension (Handley, Newstead, & Trippas, 2011). Specifically, in Experiment 1, 112 reasoners were asked to give judgments consistent with beliefs or validity for 2 different types of deductive reasoning problems. In Experiment 2, 224 reasoners gave judgments consistent with beliefs (i.e., stereotypes) or statistics (i.e., base-rates) on a base rate task; half responded under a strict deadline. For all 3 problem types and regardless of the deadline, high-capacity reasoners performed better for logic/statistics than did belief judgments when the 2 conflicted, whereas the reverse was true for low capacity reasoners. In other words, for high-capacity reasoners, statistical information interfered with their ability to make belief-based judgments, suggesting that, for them, probabilities may be more intuitive than stereotypes. Thus, at least part of the accuracy-capacity relationship observed in reasoning may be because of intuitive (Type I) processes. (PsycINFO Database Record PMID- 29975090 TI - Learning through clamor: The allocation and perception of study time in noise. AB - Memory tasks involve a degree of judgment and strategic decision-making, based upon the perceived benefits of particular learning, maintenance and recall strategies. The consequences of these metacognitive judgments for memory have been amply documented under experimental conditions that require participants to focus upon a task in the absence of distractors. Eight experiments consider the impact of less benign environmental conditions-specifically, the presence of distracting speech-upon the metacognitive aspects of memory. Distraction reliably disrupted free recall and, as indicated by judgments of learning, participants were aware of this effect. However, because participants did not adjust study time in compensation, the distraction effect was exaggerated relative to experimenter-imposed presentation rates. This finding appears to be the consequence of distraction-induced disruption of time perception at encoding, rather than any deliberate strategy. The results highlight the need to consider the impact of more challenging environments on metacognition generally. (PsycINFO Database Record PMID- 29975091 TI - Thinking of oneself as an object of observation reduces reliance on metacognitive information. AB - This research explores the consequences of two states of mind on judgment: a subjective state, looking at the world from one's own eyes, and an objective state, in which one thinks of oneself from the imagined perspective of an external observer. In six experiments, we show that judgments people make while they are in a subjective state of mind are more influenced by metacognitive experience compared with judgments people make when they are in an objective state of mind. This is demonstrated in Experiments 1-3, using two different manipulations for the two states of mind and two different fluency tasks. Experiment 4 explores the underlying mechanism and demonstrates that an objective state does not lessen the metacognitive experience itself; rather, it affects the reliance on this experience as a relevant source of information. Finally, in Experiments 5 and 6 we investigate implications of our hypothesis for doing experimental research in psychology. We find that taking part in a laboratory experiment resembles the experimental condition of an objective state of mind, as participants rely less on their metacognition compared with conditions aimed to restore the subjective state of mind within the lab setting. We discuss the theoretical and practical implications of our findings regarding social influences on judgments and decisions in psychology labs and in the real world. (PsycINFO Database Record PMID- 29975092 TI - Shifting the balance between goals and habits: Five failures in experimental habit induction. AB - Habits are repetitive behaviors that become ingrained with practice, routine, and repetition. The more we repeat an action, the stronger our habits become. Behavioral and clinical neuroscientists have become increasingly interested in this topic because habits may contribute to aspects of maladaptive human behavior, such as compulsive behavior in psychiatry. Numerous studies have demonstrated that habits can be induced in otherwise healthy rats by simply overtraining stimulus-response behaviors. However, despite growing interest in this topic and its application to psychiatry, a similar body of work in humans is absent. Only a single study has been published in humans that shows the effect of extensive training on habit expression. Here, we report five failed attempts to demonstrate that overtraining instrumental behavior leads to the development of inflexible habits in humans, using variants of four previously published outcome devaluation paradigms. Extensive training did not lead to greater habits in two versions of an avoidance learning task, in an appetitive slips-of-action task, or in two independent attempts to replicate the original demonstration. The finding that these outcome devaluation procedures may be insensitive to duration of stimulus-response training in humans has implications for prior work in psychiatric populations. Specifically, it converges with the suggestion that the failures in outcome devaluation in compulsive individuals reflect dysfunction in goal-directed control, rather than overactive habit learning. We discuss why habits are difficult to experimentally induce in healthy humans, and the implications of this for future research in healthy and disordered populations. (PsycINFO Database Record PMID- 29975094 TI - Incremental learning in word production: Tracing the fate of non-selected alternative picture names. AB - Picture naming studies have shown that alternative picture names become phonologically coactivated even when they are eventually not produced (e.g., dog when poodle is produced and vice versa). The authors investigated whether this pattern is shaped by recent experience. Specifically, they tested whether the phonological coactivation of an alternative name is attenuated, when speakers consistently only use one particular name in a large number of naming episodes. In 3 picture-word interference experiments, the authors measured the phonological coactivation of basic-level alternative names during subordinate-level naming (Experiments 1 and 3) and of subordinate-level alternative names during basic level naming (Experiment 2). They measured the coactivation of the alternative name at different points in time with distractor words that were phonologically related or unrelated to that name. If the pattern of lexical activation is shaped by previous naming episodes and the phonological coactivation of the nonproduced alternative name decreases, interference from related distractors should be reduced in the course of the experiment. Contrary to this prediction, the interference effect from distractors phonologically related to the alternative name remained stable. This was also true when participants were not familiarized with the pictures, more naming episodes were implemented, and a consolidation phase was introduced (Experiment 3). Overall, these results indicate some limitation of incremental learning in word production. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975093 TI - Brain activation covaries with reported criminal behaviors when making risky choices: A fuzzy-trace theory approach. AB - Criminal behavior has been associated with abnormal neural activity when people experience risks and rewards or exercise inhibition. However, neural substrates of mental representations that underlie criminal and noncriminal risk-taking in adulthood have received scant attention. We take a new approach, applying fuzzy trace theory, to examine neural substrates of risk preferences and criminality. We extend ideas about gist (simple meaning) and verbatim (precise risk-reward tradeoffs) representations used to explain adolescent risk-taking to uncover neural correlates of developmentally inappropriate adult risk-taking. We tested predictions using a risky-choice framing task completed in the MRI scanner, and examined neural covariation with self-reported criminal and noncriminal risk taking. As predicted, risk-taking was correlated with a behavioral pattern of risk preferences called "reverse framing" (preferring sure losses over a risky option and a risky option over sure gains, the opposite of typical framing biases) that has been linked to risky behavior in adolescents and is rarely observed in nondisordered adults. Experimental manipulations confirmed processing interpretations of typical framing (gist-based) and reverse-framing (verbatim based) risk preferences. In the brain, covariation with criminal and noncriminal risk-taking was observed predominantly when subjects made reverse-framing choices. Noncriminal risk-taking behavior was associated with emotional reactivity (amygdala) and reward motivation (striatal) areas, whereas criminal behavior was associated with greater activation in temporal and parietal cortices, their junction, and insula. When subjects made more developmentally typical framing choices, reflecting nonpreferred gist processing, activation in dorsolateral prefrontal cortex covaried with criminal risk-taking, which may reflect cognitive effort to process gist while inhibiting preferred verbatim processing. (PsycINFO Database Record PMID- 29975095 TI - Pitch perception in music: Do scoops matter? AB - Studies of musical pitch perception typically treat pitches as if they are stable within a tone. Although pitches are represented this way in notation, performed tones are rarely stable, particularly in singing, which is arguably the most common form of melody production. This paper examines how brief dynamic changes at the beginnings and endings of sung pitches, a.k.a. "scoops," influence intonation perception. Across three experiments, 110 participants evaluated the intonation of four-tone melodies in which the third tone's tuning could vary within the central steady-state (the asymptote), or by virtue of scoops at the beginning and/or end of the tone. As expected, listeners were sensitive to mistuning. Importantly, our results also point to unique contributions of scoops. As in the language domain, dynamic changes in a small time window are perceptually significant in music. More specifically, this study revealed the coexistence of two distinct mechanisms: sensitivity to the average pitch across the duration of the tone (assimilating the scoop), and processing the relationship of the scoop to the surrounding context. In addition to clarifying intonation perception in music, the identification of these mechanisms paves the way to cross-domain comparisons and, more generally, to the better understanding of auditory sequences processing. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975096 TI - When specific action biases meet nonspecific preparation: Event repetition modulates the variable-foreperiod effect. AB - Preparing for the moment of action speeds up reaction time (RT) performance even if the particular response is unknown beforehand. When the preparatory interval, or foreperiod (FP), varies unpredictably between trials, responses usually become faster with increasing FP length. This variable-FP effect has been demonstrated to partly originate from trial-to-trial sequential effects of FP length, which are asymmetric as they occur mainly in short-FP but not in long-FP trials. In two experiments, we examined whether and how event-specific biases arising from previous target processing and responding affect both variable-FP and sequential FP effects. We found that trial-to-trial repetitions (vs. alternations) of imperative events produced response time benefits in short-FP but not in long-FP trials, almost eliminating the variable-FP effect, while the sequential FP effect remained intact. This asymmetric contribution to speeded performance in variable FP settings suggests that sequential event-specific biases may be highly transient and not necessarily an integral part of the mental representations that guide time-based expectancy, or may be overridden by high levels of nonspecific preparation in long-FP trials. In conclusion, temporal preparation appears to be a nonspecific mechanism (i.e., generally not bound to particular event features) for prioritizing certain positions on the mental time line, on which event specific short-term biases are superimposed if time-based preparation is weak. (PsycINFO Database Record PMID- 29975097 TI - Attentional modulation of hierarchical ensemble coding for the identities of moving faces. AB - Observers can accurately compute summary statistics from a set of similar objects, which is referred to as ensemble coding. Few studies have investigated whether ensemble coding can be modulated by attention (i.e., whether attention can be selectively deployed to exclude irrelevant items from the ensemble coding of relevant items), and no studies have tested whether this coding represents the average of a relevant subset, the average of an irrelevant subset, or the average of the entire set. The present study employed an adapted paradigm of the multiple object tracking (MOT) task in which participants viewed multiple moving target faces and were asked to indicate whether a subsequent test face was one of the preceding targets. Experiment 1 showed that ensemble coding occurred for moving faces, and Experiments 2, 3, and 4 showed that participants were more likely to judge the individual and the average of tracked target faces than the average of all (target and nontarget) faces in the display and average nontarget faces. These findings suggest that ensemble coding for facial identities is hierarchical and can, at least partially, be modulated by attention. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975098 TI - A preference for visual speed during smooth pursuit eye movement. AB - Does the preference for visual speed extend to motion perception when the eye moves? Current evidence from psychophysics and neuroscience is limited to small patches of image motion and stationary fixation. Active observers, however, are more likely to use large patches of retinal flow and extraretinal signals accompanying eye movement to judge motion. We therefore investigated whether speed remains a primary dimension during smooth pursuit using a "discrimination contour" technique. Our results showed that observers struggled most when trying to discriminate pursued stimuli that traveled at the same speed but moved over different distances and durations. This remained the case when retinal flow was added, and when we isolated trials in which extraretinal signals were the only salient cue to motion. Our results suggest that preferential sensitivity for visual speed is quite general, supported by the many different types of motion mechanism used by active observers. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975099 TI - Characterizing individual variation in the strategic use of attentional control. AB - Goal-directed attentional control can substanially aid visual search, but only if it is recruited in an effective manner. Previously we found that strategies chosen to control attention vary considerably across individuals, and we proposed that effort avoidance may lead some individuals to choose suboptimal strategies. Here we present a more thorough analysis of individual differences in attentional control strategies. We used the adaptive choice visual search, which provides a method to quantify an individual's attentional control strategy in a dynamically changing, unconstrained environment. We found that individual's strategy choices are highly reliable across sessions, suggesting that attentional control strategies are stable and trait-like. In Experiment 2, we explored the extent to which strategy use was related to subjective evaluations of effort and performance. Results showed that the extent to which individuals found the optimal strategy to be effortful and effective predicted their likelihood of making optimal choices on a subsequent choice block. These results provide the first evidence for a relationship between effort and strategic attentional control, and they highlight the important and often neglected role of strategy in understanding attentional control. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29975100 TI - Measuring teacher practices and student academic engagement: A convergent validity study. AB - We examined the convergent validity of observer ratings of teachers' use of evidence-based instructional and behavior management practices using the Classroom Strategies Assessment System (CSAS; Reddy & Dudek, 2014) with student academic engagement as measured by the Cooperative Learning Observational Code for Kids (CLOCK; Volpe & DiPerna, 2010). This study was conducted with a sample of 107 teachers and 2,000 students in 11 urban elementary schools serving students in a community with high concentrations of poverty. Correlational and multiple linear regression analyses examined whether CSAS instructional and behavior management scores predicted classwide academic engagement. Results provide initial evidence of the relationship between observer ratings of teacher practices and student engagement. Specifically, CSAS scores indicating higher quality instruction and behavior management were associated with higher student engagement. Multiple linear regression revealed that instructional practice scores (as measured by the CSAS) uniquely predicted student academic engagement (i.e., attention and participation during instruction) while behavior management practice scores did not. Implications for future research and practice are discussed. (PsycINFO Database Record PMID- 29975101 TI - Toward a standard assembly of linear graphs. AB - Single-case data are frequently used in school psychology. In research, single case designs allow experimenters to provide rigorous demonstrations of treatment effects on a smaller scale and with more precise measurement than traditional group experimental design. In practice, single-case data are used to evaluate the effects of school-based services to make decisions at the individual level within a multitiered system of support (MTSS). School psychology and related fields (e.g., special education) have worked to increase the rigor of single-case data by developing standards for single-case experimental design and developing robust single-case effect size statistics; however, in practice, single-case data are often collected with less experimental rigor and evaluated using visual analysis of a linear graph as opposed to quantitative effect sizes. This is concerning, as an emerging body of literature suggests that simple elements of the graphical display (e.g., ordinate axis scaling, ratio of X to Y axis length) can have a profound impact on effect size judgments made by visual analysts. Currently, there are no standards guiding the construction of linear graphs used to display single-case data. The purpose of this paper is to advance the perspective that our field must develop and adopt standards of linear graph construction or risk inaccurate decisions within a MTSS framework. (PsycINFO Database Record PMID- 29975102 TI - Lung eosinophilia induced by house dust mites or ovalbumin is modulated by nicotinic receptor alpha7 and inhibited by cigarette smoke. AB - Eosinophilia (EOS) is an important component of airway inflammation and hyperresponsiveness in allergic reactions including those leading to asthma. Although cigarette smoking (CS) is a significant contributor to long-term adverse outcomes in these lung disorders, there are also the curious reports of its ability to produce acute suppression of inflammatory responses including EOS through poorly understood mechanisms. One possibility is that proinflammatory processes are suppressed by nicotine in CS acting through nicotinic receptor alpha7 (alpha7). Here we addressed the role of alpha7 in modulating EOS with two mouse models of an allergic response: house dust mites (HDM; Dermatophagoides sp.) and ovalbumin (OVA). The influence of alpha7 on EOS was experimentally resolved in wild-type mice or in mice in which a point mutation of the alpha7 receptor (alpha7E260A:G) selectively restricts normal signaling of cellular responses. RNA analysis of alveolar macrophages and the distal lung epithelium indicates that normal alpha7 function robustly impacts gene expression in the epithelium to HDM and OVA but to different degrees. Notable was allergen-specific alpha7 modulation of Ccl11 and Ccl24 (eotaxins) expression, which was enhanced in HDM but suppressed in OVA EOS. CS suppressed EOS induced by both OVA and HDM, as well as the inflammatory genes involved, regardless of alpha7 genotype. These results suggest that EOS in response to HDM or OVA is through signaling pathways that are modulated in a cell-specific manner by alpha7 and are distinct from CS suppression. PMID- 29975103 TI - Dissociation, cellular isolation, and initial molecular characterization of neonatal and pediatric human lung tissues. AB - Human lung morphogenesis begins by embryonic life and continues after birth into early childhood to form a complex organ with numerous morphologically and functionally distinct cell types. Pulmonary organogenesis involves dynamic changes in cell proliferation, differentiation, and migration of specialized cells derived from diverse embryonic lineages. Studying the molecular and cellular processes underlying formation of the fully functional lung requires isolating distinct pulmonary cell populations during development. We now report novel methods to isolate four major pulmonary cell populations from pediatric human lung simultaneously. Cells were dissociated by protease digestion of neonatal and pediatric lung and isolated on the basis of unique cell membrane protein expression patterns. Epithelial, endothelial, nonendothelial mesenchymal, and immune cells were enriched by fluorescence-activated cell sorting. Dead cells and erythrocytes were excluded by 7-aminoactinomycin D uptake and glycophorin-A (CD235a) expression, respectively. Leukocytes were identified by membrane CD45 (protein tyrosine phosphatase, receptor type C), endothelial cells by platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial cadherin (CD144), and both were isolated. Thereafter, epithelial cell adhesion molecule (CD326)-expressing cells were isolated from the endothelial- and immune cell depleted population to enrich epithelial cells. Cells lacking these membrane markers were collected as "nonendothelial mesenchymal" cells. Quantitative RT-PCR and RNA sequencing analyses of population specific transcriptomes demonstrate the purity of the subpopulations of isolated cells. The method efficiently isolates major human lung cell populations that we announce are now available through the National Heart, Lung, and Blood Institute Lung Molecular Atlas Program (LungMAP) for their further study. PMID- 29975104 TI - TWISTed HIF: revisiting smooth muscle HIF-1alpha signaling in pulmonary hypertension. PMID- 29975105 TI - Dyslexia and dyscalculia are characterized by common visual perception deficits. AB - A number of studies have investigated the cognitive deficits underlying dyslexia and dyscalculia. Yet, it remains unclear as to whether dyslexia and dyscalculia are associated with the common visual perception deficits. The current investigation analyzed cognitive performance in children with dyslexia, dyscalculia, comorbidity, and typically developing subjects. The results showed that children with dyslexia, dyscalculia and comorbidity exhibited common deficits in numerosity processing and visual perception. Furthermore, visual perception deficits accounted for deficits in numerosity processing in all three groups. The results suggest that visual perception deficits are a common cognitive deficit underlying both developmental dyslexia and dyscalculia. PMID- 29975106 TI - Extracellular vesicles transfer nuclear Abl-dependent and radiation-induced miR 34c into unirradiated cells to cause bystander effects. AB - Ionizing radiation (IR) not only activates DNA damage response (DDR) in irradiated cells but also induces bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways activated in irradiated cells stimulate BE is not well understood. We show here that extracellular vesicles secreted by irradiated cells (EV-IR), but not those from unirradiated controls (EV-C), inhibit colony formation in unirradiated cells by inducing reactive oxygen species (ROS). We found that uEV-IR from Abl nuclear localization signal-mutated ( Abl-uNLS) cells could not induce ROS, but expression of wild-type Abl restored that activity. Because nuclear Abl stimulates miR-34c biogenesis, we measured miR 34c in EV and found that its levels correlated with the ROS-inducing activity of EV. We then showed that EV from miR-34c minigene-transfected, but unirradiated cells induced ROS; and transfection with miR-34c-mimic, without radiation or EV addition, also induced ROS. Furthermore, EV-IR from miR34-family triple-knockout cells could not induce ROS, whereas EV-IR from wild-type cells could cause miR 34c increase and ROS induction in the miR-34 triple-knockout cells. These results establish a novel role for extracellular vesicles in transferring nuclear Abl dependent and radiation-induced miR-34c into unirradiated cells to cause bystander oxidative stress. PMID- 29975107 TI - D-dimer during pregnancy: establishing trimester-specific reference intervals. AB - Pregnancy is associated with an increased risk of venous thromboembolism (VTE). D dimer is a biomarker used as an exclusion criterion of VTE disease, but its usefulness during pregnancy shows limitations because D-dimer levels physiologically increase through pregnancy. The aim of our study was to follow the changes of D-dimer levels and to establish trimester-specific reference intervals during normal pregnancy. This is a longitudinal prospective study in which the reference population finally included 102 healthy pregnant women. Plasma D-dimer levels were measured during the three trimesters of pregnancy, using a latex-based immunoturbidimetric assay. Reference intervals were calculated according to the Clinical and Laboratory Standards Institute recommendations. D-dimer levels increased progressively and significantly through pregnancy and peaked in the third trimester, in which D-dimer levels were above the conventional cut-off point (500 ug/L) in 99% of pregnant women. The following reference intervals were defined: first trimester: 169-1202 ug/L, second trimester: 393-3258 ug/L and third trimester: 551-3333 ug/L. The study provides reference intervals of D-dimer during the pregnancy using latex-based immunoturbidimetry on the ACL 300 TOP automated coagulation analyser. Further prospective studies of pregnant women with clinical suspicion of VTE are needed to validate these results. PMID- 29975108 TI - Wait wait, don't tell me: Handedness questionnaires do not predict hand preference for grasping. AB - Handedness questionnaires are a common screening tool in psychology and neuroscience, used whenever a participant's performance on a given task may conceivably be affected by their laterality. Two widely-used examples of such questionnaires are the Edinburgh Handedness Inventory and the Waterloo Handedness Questionnaire. Both instruments ask respondents to report their hand preference for performing a variety of common tasks (e.g., throwing a ball, or opening a drawer). Here we combined questions from the two instruments (E-WHQ; 22 questions total) and asked participants to report their preferred hand for each via a five point scale. The purpose of this study was to determine whether responses on the E-WHQ are accurate, reliable, and/or predictive of hand-preference for a simple grasp-to-construct task. Regarding accuracy, handedness scores were 5% lower when participants used a scrambled response key versus a consistent one. Test-retest reliability of the questionnaire was weak, with any given inventory item eliciting a different response from 34% of respondents upon retesting. Neither was the E-WHQ predictively useful-although both left- and right-handers preferred their dominant hands, E-WHQ score did not correlate with overall percentage of dominant-hand grasps in either group. We conclude that the E-WHQ is unsuited for predicting hand preference for grasping. PMID- 29975109 TI - Is growth hormone administration essential for in vitro fertilization treatment of female patients with growth hormone deficiency? AB - : Available evidence suggests that the fertility of growth hormone deficient female patients could be decreased, although the responsible mechanisms are unknown. Taking into account the multiple effects of growth hormone on reproduction suggested by experimental and clinical studies in women without growth hormone deficiency, the growth hormone deficit by itself could contribute to infertility in these patients. However, the necessity of growth hormone administration and the profile of the infertile patients with growth hormone deficiency who would benefit from treatment are largely unknown. Growth hormone effects on oocyte quality is one of the possible mechanisms through which growth hormone could be involved in fertility of these patients. However, this hypothesis was not tested in patients with adequately diagnosed growth hormone deficiency. We present the case of a 29-year-old female patient with growth hormone deficiency and tubal infertility who was referred for in vitro fertilization treatment. The couple underwent two conventional in vitro fertilization procedures: the first one, without growth hormone treatment and, because no pregnancy was achieved, the second one after growth hormone (somatropinum) administration for 3 months. Although the number of the retrieved oocytes was the same, the quality of the oocytes was improved and their ability to evolve into good quality embryos after fertilization was increased after growth hormone administration. Consequently, the pregnancy was obtained after the second in vitro fertilization treatment and patient gave birth to a healthy boy. In conclusion, our case report suggests that adequate levels of growth hormone are essential for an adequate competence of the oocytes in infertile patients with growth hormone deficiency. Therefore, growth hormone administration should be taken into consideration for patients with this deficiency in order to optimize the results of infertility treatment. ABBREVIATIONS: GH: growth hormone; GHD: growth hormone deficiency; HCG: human chorionic gonadotropin; IVF: in vitro fertilization; IGF: insulin like growth factor. PMID- 29975110 TI - Investigational hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) for the treatment of anemia associated with chronic kidney disease. AB - INTRODUCTION: In the last decade, concerns have been raised around the use of erythropoiesis-stimulating agents (ESAs) and intravenous iron in chronic kidney disease (CKD) patients, especially when given at high doses. Moreover, treatment with ESA is expensive. Areas covered: We searched PubMed for original articles, reviews, and editorials having as a topic anemia, CKD, hypoxia inducible factor, hepcidin, iron, and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF PHI). HIF-PHI are a new class of small molecules activating HIF-alfa isoforms (the main mediators of the effects of hypoxia on the body). This causes the secretion of endogenous erythropoietin and increased iron availability. Differing from ESA, HIF-PHI are administered orally. Preliminary data from phase-II clinical studies have shown their efficacy and safety in the short term. Expert Opinion: HIF-PHI are a new promising class of drugs. The results of large, phase III clinical studies are awaited to prove their efficacy and safety on cardiovascular events and cancer development in the long term. Their capability of penetrating the ESA market in the future will be influenced also by their selling price. The oral administration of HIF-PHI will be weighed to the 'intra lines' infusion of ESA in hemodialysis or to the infrequent subcutaneous injections of long-acting ESA. PMID- 29975111 TI - Ketamine ameliorates ischemia-reperfusion injury after liver autotransplantation by suppressing activation of Kupffer cells in rats. AB - This study aimed to investigate the protective effects of ketamine against hepatic ischemia-reperfusion (I/R) injury by suppressing activation of Kupffer cells (KCs) in rat liver autotransplantation. Male Sprague-Dawley rats were randomized into 3 groups (n = 10 each). Group I, the sham group, received saline. Group II received saline and underwent orthotopic liver autotransplantation (OLAT). Group III received 10 mg/kg ketamine and underwent OLAT. Blood samples were obtained at 3, 6, 12, and 24 h after I/R, and following ALT, AST, LDH, IL-6, TNF-alpha, IL-1beta, and IL-10 in serum were detected. Model rats were sacrificed at the indicated time points and the graft liver tissues were evaluated histologically. KCs were isolated from rat liver tissues, and inflammatory products and proteins of NF-kappaB signaling pathway were detected using quantitative RT-PCR and Western blotting. Our results showed that ketamine significantly decreased ALT, AST, LDH, IL-6, TNF-alpha, and IL-1beta levels and increased IL-10 level. Furthermore, ketamine alleviated the histopathology changes, by less KC infiltration and lower hepatocyte apoptosis. Moreover, activity of NF-kappaB signaling pathway in KCs was suppressed. In addition, production of pro- and anti-inflammatory factors is consistent with the results in tissues. Ketamine ameliorated I/R injury after liver transplantation by suppressing activation of KCs in rats. PMID- 29975112 TI - Noninvasive options for 'wearing-off' in Parkinson's disease: a clinical consensus from a panel of UK Parkinson's disease specialists. AB - In the past 4 years, two adjunctive treatment options to levodopa have been licensed for use in the UK in patients with Parkinson's disease (PD) and motor fluctuations: opicapone, a third-generation catechol-O-methyl transferase inhibitor, and safinamide, a monoamine oxidase B inhibitor. This clinical consensus outlines the practical considerations relating to motor fluctuations and managing wearing-off in patients with PD, and provides a clinical insight to adjunctive treatment options, including opicapone and safinamide. Practice-based opinion was provided from a multidisciplinary steering Group of eight UK-based movement disorder and PD specialists, including neurologists, geriatricians and a nurse specialist, from England, Scotland and Wales. PMID- 29975113 TI - Relief of the Dma1-mediated checkpoint requires Dma1 autoubiquitination and dynamic localization. AB - Chromosome segregation and cell division are coupled to prevent aneuploidy and cell death. In the fission yeast Schizosaccharomyces pombe, the septation initiation network (SIN) promotes cytokinesis, but upon mitotic checkpoint activation, the SIN is actively inhibited to prevent cytokinesis from occurring before chromosomes have safely segregated. SIN inhibition during the mitotic checkpoint is mediated by the E3 ubiquitin ligase Dma1. Dma1 binds to the CK1 phosphorylated SIN scaffold protein Sid4 at the spindle pole body (SPB), and ubiquitinates it. Sid4 ubiquitination antagonizes the SPB localization of the Pololike kinase Plo1, the major SIN activator, so that SIN signaling is delayed. How this checkpoint is silenced once spindle defects are resolved has not been clear. Here we establish that Dma1 transiently leaves SPBs during anaphase B due to extensive autoubiquitination. The SIN is required for Dma1 to return to SPBs later in anaphase. Blocking Dma1 removal from SPBs by permanently tethering it to Sid4 prevents SIN activation and cytokinesis. Therefore, controlling Dma1's SPB dynamics in anaphase is an essential step in S. pombe cell division and the silencing of the Dma1-dependent mitotic checkpoint. PMID- 29975114 TI - An Informatics Approach to Facilitate Clinical Management of Patients With Retrievable Inferior Vena Cava Filters. AB - OBJECTIVE: Long indwelling times for inferior vena cava (IVC) filters that are used to prevent venous thromboembolism can result in complications. To improve care for patients receiving retrievable IVC filters, we developed and evaluated an informatics-based initiative to facilitate patient tracking, clinical decision making, and care coordination. MATERIALS AND METHODS: A semiautomated filter tracking application was custom-built to query our radiology information system to extract and transfer key data elements related to IVC filter insertion procedures into a database. A web-based interface displayed key information and facilitated communication between the interventional radiology clinical team and referring physicians. A set of filter management options was provided depending on each patient's clinical condition. The system was launched in April 2016. Using retrospective observational cohort methods, we compared filter retrieval rates during a test period from July through December 2016 with a control period of the same 6 months in 2015. RESULTS: System development required approximately 100 hours of development time. Two hundred ninety-three IVC filter placements and 83 filter retrievals were tracked during the study periods. The overall filter retrieval rate was 23% in the control period and 34% in the test period. Mean times from filter placement to retrieval in the control and test periods were not significantly different (88.9 and 102.7 days, respectively; p = 0.32). CONCLUSION: A semiautomated approach to tracking patients with IVC filters can facilitate care coordination and clinical decision-making for a device with known potential complications. Similar applications designed to improve provider communication and documentation of filter management plans, including appropriateness for retrieval, can be replicated. PMID- 29975115 TI - Downgrading and Upgrading Gray-Scale Ultrasound BI-RADS Categories of Benign and Malignant Masses With Optoacoustics: A Pilot Study. AB - OBJECTIVE: False-positive findings remain challenging in breast imaging. This study investigates the incremental value of optoacoustic imaging in improving BI RADS categorization of breast masses at ultrasound. SUBJECTS AND METHODS: The study device is an optoacoustic breast imaging device with a handheld duplex laser and internal gray-scale ultrasound probe, fusing functional and morphologic information (optoacoustic ultrasound). In this prospective multisite study, breast masses assessed as BI-RADS category 3, 4A, 4B, 4C, or 5 by site radiologists underwent both gray-scale ultrasound and optoacoustic imaging with the study device. Independent reader radiologists assessed internal gray-scale ultrasound and optoacoustic ultrasound features for each mass and assigned a BI RADS category. The percentage of mass reads for which optoacoustic ultrasound resulted in a downgrade or upgrade of BI-RADS category relative to internal gray scale ultrasound was determined. RESULTS: Of 94 total masses, 39 were biopsy proven malignant, 44 were biopsy-proven benign, and 11 BI-RADS category 3 masses were stable at 12-month follow-up. The sensitivity of both optoacoustic ultrasound and internal gray-scale ultrasound was 97.1%. The specificity was 44.3% for optoacoustic ultrasound and 36.4% for internal gray-scale ultrasound. Using optoacoustic ultrasound, 41.7% of benign masses or BI-RADS category 3 masses that were stable at 12-month follow-up were downgraded to BI-RADS category 2 by independent readers; 36.6% of masses assigned BI-RADS category 4A were downgraded to BI-RADS category 3 or 2, and 10.1% assigned BI-RADS category 4B were downgraded to BI-RADS category 3 or 2. Using optoacoustic ultrasound, independent readers upgraded 75.0% of the malignant masses classified as category 4A, 4B, 4C, or 5, and 49.4% of the malignant masses were classified as category 4B, 4C, or 5. CONCLUSION: Optoacoustic ultrasound resulted in BI-RADS category downgrading of benign masses and upgrading of malignant masses compared with gray scale ultrasound. PMID- 29975116 TI - Neuroendocrine Tumor Diagnosis and Management: 68Ga-DOTATATE PET/CT. AB - OBJECTIVE: The purpose of this article is to provide a review of the use of 68Ga tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate (DOTATATE) PET/CT, a functional imaging modality for assessment of well-differentiated neuroendocrine tumors (NETs). It has become the preferred imaging modality for initial diagnosis, selection of patients for peptide receptor radionuclide therapy, and localization of unknown primary tumors. The National Comprehensive Cancer Network guideline has added 68Ga-DOTATATE PET/CT as an appropriate test in the management of NETs. CONCLUSION: In combination with FDG PET/CT, 68Ga-DOTATATE PET/CT can noninvasively assess tumor heterogeneity, especially in G2 and G3 NETs, for personalized management of patients. PMID- 29975117 TI - The Optimal Energy Level of Virtual Monochromatic Images From Spectral CT for Reducing Beam-Hardening Artifacts Due to Contrast Media in the Thorax. AB - OBJECTIVE: The purpose of this study is to determine the optimal energy level of virtual monochromatic images from spectral CT compared with conventional polychromatic images for reducing beam-hardening artifacts caused by contrast media in the thorax. MATERIALS AND METHODS: A total of 101 consecutive patients who underwent chest CT with contrast enhancement were retrospectively included in this study. The same contrast media and injection protocols were applied to the whole study population. Virtual monochromatic image datasets ranging from 70 to 200 keV and conventional polychromatic images were obtained. Readers' subjective image quality scores were recorded for conventional polychromatic and virtual monochromatic images obtained at 70, 100, 130, and 200 keV. Image noise, CT attenuation difference, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) were also obtained in each algorithm. Comparisons of parameters between algorithms were performed. RESULTS: The best subjective image quality score and significantly lower image noise were observed for 130-keV virtual monochromatic images compared with conventional polychromatic images (all p < 0.001). Also, CT attenuation differences were significantly lower for both 100- and 130-keV virtual monochromatic images than for conventional polychromatic images (all p < 0.001). Meanwhile, the lowest differences in CT attenuation were observed for 100 keV virtual monochromatic images compared with conventional polychromatic images. However, there were no significant differences in CT attenuation between 100- and 130-keV virtual monochromatic images. SNR was similar between 130-keV virtual monochromatic images and conventional polychromatic images, although both SNR and CNR decreased as the energy level increased. CONCLUSION: Virtual monochromatic imaging reduced beam-hardening artifacts and improved image quality, and optimal evaluation of chest CT was best achieved at 100 and 130 keV. PMID- 29975118 TI - Interventional Radiology in Canada: Current Challenges and Future Directions. AB - OBJECTIVE: We aim to define the practice of interventional radiology (IR) in Canada, barriers that have been faced by interventional radiologists, and ways in which the Canadian Interventional Radiology Association (CIRA) have attempted to address these issues. CONCLUSION: IR has faced significant challenges in the Canadian setting. Recognizing the need to address these challenges, leaders in the field of IR in Canada founded the CIRA to serve as our national voice and lobby group. PMID- 29975119 TI - The Impact of Risk Standardization on Variation in CT Use and Emergency Physician Profiling. AB - OBJECTIVE: The purpose of this study is to use detailed electronic health record data to profile the use of condition-specific, risk-standardized imaging by emergency physicians. MATERIALS AND METHODS: CT utilization in four emergency departments in a single health care system was retrospectively analyzed. The primary outcome for analysis was indication-specific, risk-standardized CT utilization. We constructed seven clinical cohorts on the basis of the presence or absence of a traumatic indication for the most frequently performed CT studies. Risk standardization was performed using machine learning algorithms and hierarchic logistic regression models. Variation in CT utilization for each cohort was analyzed using coefficients of variation and box plots, the effect of risk standardization on physician profiling was determined using slope diagrams and kappa values, and within-physician correlation was assessed using correlation coefficients and matrices. RESULTS: For the seven cohorts, the number of physicians ordering more than 25 CT studies for a particular indication ranged from 70 to 88, and the number of ED visits ranged from 17,458 to 117,489. The unadjusted variation was large for each indication (coefficient of variation, 30.2-57.9). Risk standardization resulted in reduced but persistent variation for all indications (coefficient of variation, 12.3-22.3). Among indication-specific models, risk standardization resulted in reclassification by two or more deciles for 14.0-39.1% of physicians. The R value for within-physician correlation varied from 0.02 to 0.80 and was highest between chest and abdominal imaging for trauma. CONCLUSION: In this multisite study of CT utilization, risk standardization had a substantial impact on variation in CT utilization and emergency physician profiling. Administrators and payers should include risk standardization in future measures of physician imaging to ensure valid assessment of performance and achieve improvements in emergency care value. PMID- 29975121 TI - Should we really STOP treating patients with IgA nephropathy with steroids? AB - IgA nephropathy (IgAN) is the most common primary glomerulonephritis all over the world. Once considered as a benign disease, today the scientific community is aware that a significant percentage of patients eventually progress to end-stage kidney disease (ESKD). The rate of progression is often very slow. Since 1980s, several therapeutic attempts have been made with steroids. Despite different molecules, doses, and lengths of treatment, the majority of uncontrolled and controlled studies found benefits in terms of proteinuria reduction and reduction of the risk of ESKD. This was obtained with reasonable safety and tolerability, especially when steroids are given at relatively low dose and for a period not exceeding 6 months. Recently, two randomized controlled trials have questioned the efficacy and safety of steroid therapy in IgAN. However, these trials have many drawbacks that are to be considered when interpreting the findings. PMID- 29975120 TI - Effects of low dose of aliskiren on isoproterenol-induced acute myocardial infarction in rats. AB - This study examined the effects of aliskiren (Ali) (direct renin inhibitor) on serum cardiac enzymes (LDH and CK-MB), electrocardiography (ECG) changes, myocardial oxidative stress markers (MDA, CAT, and GSH) and the expression of Bcl2, HO-1, and Nrf2 genes in isoproterenol (ISO)-induced myocardial infarction (MI). A total of 40 male albino rats were allocated into four groups, (1) normal control (NC) group, (2) Ali group (rats received Ali at 10 mg/kg/day p.o. for 5 days), (3) ISO group (rats received ISO 150 mg/kg i.p. for two consecutive days at 24 h intervals), and (4) Ali + ISO group (rats received ISO + Ali at 10 mg/kg/day p.o. for 5 days from the 2nd dose of ISO). ISO group showed significant rise in serum cardiac enzymes (CK-MB and LDH), myocardial damage scores, myocardial MDA, HO-1, myocardial Nrf2 expression with significant reduction in myocardial antioxidants (CAT and GSH), and Bcl2 expression compared to the normal group (p < 0.05). ECG showed ST segment elevation, prolonged QT interval and QRS complex, and increased heart rate in ISO group. Co-administration of Ali and ISO caused significant increase in cardiac enzymes and morphology with increase in MDA, serum K, and creatinine with significant decrease in Bcl2, HO-1, and Nrf2 without significant changes in ECG parameters compared to ISO group. We concluded that low dose of Ali seems to exacerbate the myocardial injury in ISO-MI, which might be due to the enhanced oxidative stress and apoptosis. PMID- 29975122 TI - The affective and behavioral responses to repeated "strength snacks". AB - Background A training program consisting of only one-repetition maximum (1RM) training results in similar strength adaptations as traditional resistance exercise. However, little is known regarding the affective or behavioral responses to this type of training. Aim To examine the affective and behavioral response to either a traditional resistance exercise program or a biweekly 1RM training program. Methods Participants were trained for 8 weeks (2* per week). The HYPER group completed four sets of 8-12 repetitions; the 1RM group (TEST) worked up to a single maximal repetition. Results The TEST group felt more revitalized and had an increase in positive engagement during their first visit, whereas the HYPER group showed an increase in feelings of physical exhaustion during their first and last visits. There were no pre to post differences for the change in behavior or self-efficacy between groups. Conclusion 1RM training appears to elicit a more favorable affective response, compared with HYPER training, which may ultimately improve adherence to resistance-type exercise. PMID- 29975123 TI - Impact of loganin on pro-inflammatory cytokines and depression- and anxiety-like behaviors in male diabetic rats. AB - Behavioral disturbances are observed in most patients suffering from diabetes. According to some evidence, pro-inflammatory cytokines have a key role both in diabetes and behavioral disorders, such as anxiety and depression. In this study, the effect of chronic administration of loganin, as a bioflavonoid, was investigated on pro-inflammatory cytokines and depression- and anxiety-like behaviors in streptozotocin-induced diabetes in male Wistar rats. Blood levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were assessed by enzyme-linked immunosorbent assay method. Depression- and anxiety-like behaviors were evaluated by forced swimming test (FST), elevated plus maze (EPM), and open field test (OFT), respectively. Body weight was also measured before the interventions and after the experiments in all groups. Our findings show that loganin-treated animals had significantly lower serum concentrations of IL-6 and TNF-alpha compared with the diabetic group. In the EPM test, loganin treatment significantly increased the percentage of the open arm time and open arm entries. Moreover, loganin treatment significantly decreased the grooming time and restored distance traveled and center crossing in the OFT. However, it decreased immobility time in the FST. Loganin treatment also significantly restored body weight gain and attenuated blood glucose changes in the diabetic rats. These results indicate that loganin possibly alleviates depression- and anxiety-like behaviors associated with diabetes through lowering the blood glucose and pro inflammatory cytokine levels. More research is required to show the exact mechanism of antidepressant and anxiolytic effects of loganin in diabetes. PMID- 29975124 TI - The immune system cell populations were increased in salt-induced hypertensive rats without an increase in the serum testosterone level (Short communication). AB - The consumption of dietary salt has significantly increased globally, especially in the developed countries. High dietary salt intake has been linked to onset and complications in hypertension with a dimorphism tendency. There is scanty information about the influence of high salt diet on the immune cell population and androgen level in circulation. Male Sprague-Dawley rats of 8 weeks old were used for this study. They were divided into control (fed 0.1% salted feed) and salt-loaded groups (fed 8% salted feed) for 8 weeks. All experimental rats were allowed access to clean drinking water; daily feed consumption was measured in addition to weekly weight. On confirmation of hypertension using PowerLab(r) data acquisitions system, the rats were sacrificed and blood samples were collected into EDTA and sterile sample bottles. EDTA-blood samples were used for white blood cell and CD4 counts while the serum was used for hormonal assays. All salt loaded rats became hypertensive, with a significant increase in total white blood cell, lymphocyte, neutrophil, monocyte, and CD4 cell counts. However, the eosinophil count was significantly decreased in salt-loaded rats. This study showed no change in the serum testosterone in salt-loaded male rats compared with control. In summary, dietary salt loading while precipitating hypertension also activated increased production of white blood cells and CD4 cells without any change in the serum testosterone level. PMID- 29975126 TI - Effects of submaximal cycling at different exercise intensities on maximal isometric force output of the non-exercised elbow flexor muscles. AB - The purpose of this study was to examine the effects of submaximal cycling at different exercise intensities on maximal isometric force output of the non exercised elbow flexor muscles after the cycling. A total of 8 healthy young men performed multiple maximal voluntary contractions by the right elbow flexion before, immediately after, 5 min after, and 10 min after a 6-min submaximal cycling at ventilatory threshold (LI), 70% [Formula: see text] (MI), and 80% [Formula: see text] (HI) with both arms relaxed in the air. Force and surface electromyogram (EMG) of the right biceps brachii muscle during the multiple MVCs, blood lactate concentration ([La]), cardiorespiratory responses, and sensations of fatigue for legs (SEF-L) were measured before, immediately after, 5 min after, and 10 min after the submaximal cycling with the three different exercise intensities. Immediately after the submaximal cycling, [La], cardiorespiratory responses, and SEF-L were enhanced in proportion to an increase in exercise intensity of the cycling. Changes in force and EMG activity during the multiple MVCs were not significantly different across the three conditions. The findings imply that group III/IV muscle afferent feedback after the submaximal cycling does not determine the magnitude of MVC force loss of the non-exercised upper limb muscles. PMID- 29975125 TI - Effect of one bout of local vibration exercise with blood flow restriction on neuromuscular and hormonal responses. AB - This study aimed to investigate the effects of single local vibration (LV) with and without blood flow restriction (BFR) on muscle activity and hormonal responses. A total of 12 physically inactive males were exposed to 10 sets of intermittent LV (35-40 Hz) on unilateral mid-quadriceps in the supine lying position and LV + BFR (inflated to 140 mmHg) sessions in a repeated-measures randomized crossover design, with a 1-week interval separating the sessions. The results indicated that the electromyography values from the rectus femoris during LV + BFR were greater than those during LV (p < 0.05). LV + BFR caused a minor increase in the lactate (LA) response (p < 0.05); LV with or without BFR failed to elicit change in growth hormone (GH) and testosterone (T) levels (p > 0.05). Cortisol (C) levels were decreased postexercise in both the sessions (p < 0.05). In conclusion, BFR elicited higher increase in muscle activity and metabolic response, but it did not induce hormonal responses. The exposure of LV and LV + BFR may only have a relief effect as detected by the reduction in C levels, probably because the LV did not elicit sufficient stimulus to the muscles. PMID- 29975128 TI - Arterial stiffness may predict renal and cardiovascular prognosis in autosomal dominant polycystic kidney disease. AB - Background and aims Autosomal-dominant polycystic kidney disease (ADPKD) is one of the most common causes of end-stage renal disease (ESRD). The most important cause of death among ADPKD patients is cardiovascular (CV). The aim of this study was to examine the prognostic significance of arterial stiffness on CV and renal outcomes in ADPKD. Methods A total of 55 patients with ADPKD were examined. Pulse wave velocity was determined and stiffness index (SIDVP) was calculated. Combined primary endpoints (CV and renal) were major CV events (myocardial infarction, stroke, and CV intervention) as CV endpoints, and attaining of ESRD or start of renal replacement therapy as renal endpoints. Secondary endpoints were CV or renal endpoints separately. Results The mean age of those 55 ADPKD patients was 45 +/- 12 years, 21 patients were male. The average value of the SIDVP was 11.11 +/- 2.22 m/s. The patients were divided into two groups by the cutoff value of 11 m/s of SIDVP and then outcomes were analyzed. In the higher arterial stiffness group (SIDVP > 11 m/s), occurrence of combined primary endpoint (CV and renal) was significantly higher than in the group with more elastic arteries (p = 0.033). A statistically significant difference was found in the renal endpoints (p = 0.018), but not in the CV endpoints (p = 0.952) between the two groups. Conclusions Increased arterial stiffness predicts the onset of ESRD in ADPDK. Assessment of SIDVP appears to be a useful method for estimating the renal and CV prognosis in ADPKD. PMID- 29975130 TI - From Reconstruction to Construction: The Power of Corrective Emotional Experiences in Memory Reconsolidation and Enduring Change. PMID- 29975127 TI - Sitting to standing postural changes: Energy expenditure and a possible mechanism to alleviate sedentary behavior. AB - Background and aims Sedentary lifestyles have recently been identified as potential mechanism for obesity and associated metabolic diseases linked to ill health. The aim of this study was to investigate the effects of standing and sitting-standing positional changes on energy cost and consequently interrupting sedentary sitting time while working. Methods A total of 26 healthy male volunteers performed normal typing and editing work for 100 min under three conditions. The conditions included sustained sitting, sustained standing, and sitting-standing alternation every 20 min using a sit-stand desk. Respiratory parameters measured included minute ventilation (VE), oxygen consumption (VO2), and energy expenditure (EE). Measurements were recorded using a calibrated Cosmed K4b2 portable gas analysis system. Results The mean value for VE was the highest in the standing position (VE = 13.33 +/- 0.71), followed by sitting-standing alternation (VE = 12.04 +/- 0.62). Both were significantly different from sitting (VE = 10.59 +/- 0.69). The maximum VE and EE for standing (VE = 14.81 +/- 0.43 and EE = 1.84 +/- 0.10) and sitting-standing alternation (VE = 14.80 +/- 0.40 and EE = 1.93 +/- 0.08) were significantly higher than that of sitting (VE = 12.15 +/ 0.42 and EE = 1.67 +/- 0.07). No significant differences were observed in the mean VO2 among the three conditions. However, the maximum VO2 for both standing (VO2 = 5.40 +/- 0.20) and sitting-standing alternation (VO2 = 5.14 +/- 0.17) had shown to be significantly higher than sitting (VO2 = 4.50 +/- 0.18). There were no significant differences observed in the mean EE levels between sitting (EE = 1.43 +/- 0.07) and sitting-standing alternation (EE = 1.55 +/- 0.08). However, the mean EE while standing (EE = 1.62 +/- 0.09) significantly increased compared to sitting. Conclusions The findings of this study indicate that sitting-standing alternations may be implemented as an effective intervention to interrupt prolonged sitting while working. PMID- 29975131 TI - How Does History Become Accessible? Reconstruction as an Emergent Product of the Interpersonal Field. PMID- 29975133 TI - The Past in the Present, the Present in the Past: Introduction to Panel on Reconstruction from Today's Two-person Perspective. PMID- 29975134 TI - Discussion: Reconstruction in Relation to Therapeutic Action. PMID- 29975139 TI - Invited Readers 2017. PMID- 29975141 TI - The Correspondence Between Sigmund Freud and Eugen Bleuler, 1904-1937: Introduction to Maetzener and Tessier. PMID- 29975143 TI - Twos and Threes: Musical Chairs in Female Psychic and Social Life. AB - Jockeying for position in the context of a threesome is a major preoccupation in female social behavior, and in female inner experience, throughout the life cycle. This oscillating phenomenon can be thought of as "twos and threes." While such configurations are often understood in terms of sibling rivalry or social influences, the focus here is on underlying female triangular dynamics. "Twos and threes" are differentiated from the more familiar rivalries among siblings and from the concept of sibling oedipal triangles. Clinical examples and a contemporary novel by Tana French are presented to demonstrate that concealed and overlooked female oedipal or persephonal conflicts may underlie these experiences and appear in the transference and countertransference. PMID- 29975147 TI - Reconstruction in the Present Two-person Psychoanalysis: The Wolf Man Case Reconstructed. PMID- 29975148 TI - So What is Gender Anyway? And Who's Having Sex with Whom? PMID- 29975145 TI - The Erotics of Knowing: A Neglected Contribution to Analytic Erotism. AB - An erotics of knowing is posited that comprises embodied aspects of psychological and emotional closeness, and derives not from transference dynamics but from psychological and emotional intimacy-both component and consequence of the analytic process. The experience of knowing and being known is invested with erotism via its interpenetrative and interreceptive aspects; regardless of gender, to know the other is to enter a hidden interior "space" that represents that person's embodied inner world. Yet the interrogation of the intrinsic relationship between knowing and loving is stunningly absent from the psychoanalytic literature. This historical neglect is traced to a split in the discourse presaged by Freud's essay on transference love, which distinguishes between the qualified reality of the erotic transference and the de-erotized but "real" construct of the "analytic love" relationship. A more recent split relocates erotism to the maternal transference, divesting it of aggression and oedipal sexuality. These splits constitute a vigorous collective defense against engaging with the erotics of knowing: from Oedipus to Genesis, our forbidden fruit. PMID- 29975149 TI - Dasatinib induces gene expression of CYP1A1, CYP1B1, and cardiac hypertrophy markers (BNP, beta-MHC) in rat cardiomyocyte H9c2 cells. AB - Dasatinib is a new selective tyrosine kinase inhibitor that targets certain kinases involved in cellular growth and development. This drug belongs to a novel anticancer therapy aiming to increase the survival in patients with imatinib resistant mutations. However, the dasatinib toxicity was reported as a side effect leading to arrhythmias and/or heart failure. Here, we investigated the possibility of dasatinib-induced toxicity in rat cardiomyocyte H9c2 cells. Our objectives were to investigate the ability of dasatinib to induce expression of cytochrome P450 (CYP1A1, CYP1B1) and cardiac hypertrophy markers (BNP, beta-MHC) genes in H9c2 cells. To test this hypothesis, H9c2 cells were incubated with dasatinib at two concentrations (20 and 40 MUM). Thereafter, CYP1A1, CYP1B1, BNP, and beta-MHC were determined at gene expression level. Our findings showed that dasatinib induces the CYP1A1, CYP1B1, BNP, and beta-MHC mRNA. The involvement of AhR/CYP1A1 pathway in dasatinib toxicity was tested by resveratrol (RES), an AhR antagonist. Interestingly, the increase in mRNA of different genes by dasatinib was not affected by RES, which confirms that these effects are not mediated through AhR. In addition, this was accompanied by a significant inhibition of constitutive expression of these genes by RES. The current work provides the first evidence for the ability of dasatinib to induce hypertrophic markers in H9c2 cells through AhR-independent pathway. PMID- 29975150 TI - Differentiating vacuum-assisted breast biopsy from core needle biopsy: Is it necessary? AB - Needle biopsy has replaced excisional biopsy as a definitive diagnostic technique for breast tumours, although excisional biopsy is still used for complete tumour removal for therapeutic and/or diagnostic purposes. Many vacuum-assisted breast biopsy (VAB) systems have been made available by several manufacturers since the release of the Mammotome (MMT) by Johnson & Johnson in 1995. Several recent discussions have been conducted to identify whether core needle biopsy (CNB) or VAB, is more appropriate. However, currently available VAB systems differ from the conventional system (i.e. articulate arm type 11-gauge(G) MMT), and the characteristics of both CNB and VAB have been improved. In CNB, a 14-G needle is frequently used to obtain a larger sample. By contrast, VAB is considered easier to perform because it uses a thinner needle and a lighter, non-tethered system. When differentiating CNB from VAB, the type of VAB should also be defined. In this review, we discuss the characteristics of ultrasonography-guided VAB and CNB with a focus on practical issues such as the number of samples and volume of tissue obtained during ultrasonography-guided needle biopsy. PMID- 29975151 TI - Automatic multiatlas based organ at risk segmentation in mice. AB - OBJECTIVE: During the treatment planning of a preclinical small animal irradiation, which has time limitations for reasons of animal wellbeing and workflow efficiency, the time consuming organ at risk (OAR) delineation is performed manually. This work aimed to develop, demonstrate, and quantitatively evaluate an automated contouring method for six OARs in a preclinical irritation treatment workflow. METHODS: Microcone beam CT images of nine healthy mice were contoured with an in-house developed multiatlas-based image segmentation (MABIS) algorithm for six OARs: kidneys, eyes, heart, and brain. The automatic contouring was compared with the manual delineation using three quantitative metrics: the Dice Similarity Coefficient (DSC), 95th percentile Hausdorff Distance, and the centre of mass displacement. RESULTS: A good agreement between manual and automatic contouring was found for OARs with sharp organ boundaries. For the brain and the heart, the median DSC was larger than 0.94, the median 95th Hausdorff Distance smaller than 0.44 mm, and the median centre of mass displacement smaller than 0.20 mm. Lower DSC values were obtained for the other OARs, but the median DSC was still larger than 0.74 for the left eye, 0.69 for the right eye, 0.89 for the left kidney and 0.80 for the right kidney. CONCLUSION: The MABIS algorithm was able to delineate six OARs with a relatively high accuracy. Segmenting OARs with sharp organ boundaries performed better than low contrast OARs. Advances in knowledge: A MABIS algorithm is developed, evaluated, and demonstrated in a preclinical small animal irradiation research workflow. PMID- 29975152 TI - Feasibility of a novel liquid fiducial marker for use in image guided radiotherapy of oesophageal cancer. AB - OBJECTIVE:: To evaluate the feasibility of a new liquid fiducial marker for use in image-guided radiotherapy for oesophageal cancer. METHODS:: Liquid fiducial markers were implanted in patients with metastatic or inoperable locally advanced oesophageal or gastro-oesophageal junction cancer receiving radiotherapy. Markers were implanted using a conventional gastroscope equipped with a 22 G Wang needle. Marker visibility was evaluated on fluoroscopy, CT, MRI and cone beam CT scans. RESULTS:: Liquid markers (n = 16) were injected in four patients. No Grade 2 or worse adverse events were observed in relation to the implantation procedure, during treatment or in the follow-up period. 12/16 (75%) markers were available at the planning CT-scan and throughout the treatment- and follow-up period. The implanted markers were adequately visible in CT and cone beam CT but were difficult to distinguish in fluoroscopy and MRI without information from the corresponding CT image. CONCLUSION:: Liquid fiducial marker placement in the oesophagus proved safe and clinically feasible. ADVANCES IN KNOWLEDGE:: This paper presents the first clinical use of a new liquid fiducial marker in patients with oesophageal cancer and demonstrates that marker implantation using standard gastroscopic equipment and subsequent use in three-dimensional image-guided radiation therapy is safe and clinically feasible. PMID- 29975153 TI - Proton relative biological effectiveness (RBE): a multiscale problem. AB - Proton radiotherapy is undergoing rapid expansion both within the UK and internationally, but significant challenges still need to be overcome if maximum benefit is to be realised from this technique. One major limitation is the persistent uncertainty in proton relative biological effectiveness (RBE). While RBE values are needed to link proton radiotherapy to our existing experience with photon radiotherapy, RBE remains poorly understood and is typically incorporated as a constant dose scaling factor of 1.1 in clinical plans. This is in contrast to extensive experimental evidence indicating that RBE is a function of dose, tissue type, and proton linear energy transfer, among other parameters. In this article, we discuss the challenges associated with obtaining clinically relevant values for proton RBE through commonly-used assays, and highlight the wide range of other experimental end points which can inform our understanding of RBE. We propose that accurate and robust optimization of proton radiotherapy ultimately requires a multiscale understanding of RBE, integrating subcellular, cellular, and patient-level processes. PMID- 29975154 TI - Clinical application and technical considerations of T1 & T2(*) mapping in cardiac, liver, and renal imaging. AB - Pathological tissue alterations due to disease processes such as fibrosis, edema and infiltrative disease can be non-invasively visualized and quantified by MRI using T1 and T2 relaxation properties. Pixel-wise mapping of T1 and T2 image sequences enable direct quantification of T1, T2(*), and extracellular volume values of the target organ of interest. Tissue characterization based on T1 and T2(*) mapping is currently making the transition from a research tool to a clinical modality, as clinical usefulness has been established for several diseases such as myocarditis, amyloidosis, Anderson-Fabry and iron deposition. Other potential clinical applications besides the heart include, quantification of steatosis, cirrhosis, hepatic siderosis and renal fibrosis. Here, we provide an overview of potential clinical applications of T1 andT2(*) mapping for imaging of cardiac, liver and renal disease. Furthermore, we give an overview of important technical considerations necessary for clinical implementation of quantitative parametric imaging, involving data acquisition, data analysis, quality assessment, and interpretation. In order to achieve clinical implementation of these techniques, standardization of T1 and T2(*) mapping methodology and validation of impact on clinical decision making is needed. PMID- 29975155 TI - Mesenchymal chondrosarcoma of the orbit: imaging features of CT and MRI. AB - OBJECTIVE:: Mesenchymal chondrosarcoma (MCS) of the orbit is a rare and aggressive form of chondrosarcoma. The purpose of this study was to retrospectively identify the imaging features of mesenchymal chondrosarcoma of the orbit. METHODS:: This study included five patients with histologically confirmed MCS of the orbit who had undergone either CT, MRI, or both. Images were evaluated for the following: location, size, margin, CT density and presence or absence of calcification and/or ossification, MRI findings including dynamic contrast-enhancement and time-intensity curves. RESULTS:: CT was performed in four of the five patients, and all four (100%) demonstrated calcification and ossification of the mass. MRI was performed in all five patients. In two patients (40%), the mass demonstrated areas of hyperintensity on T1 weighted images. CONCLUSION:: The presence of a well-defined, orbital mass with calcification and ossification on CT and, marked heterogenous enhancement and a rapid-washout pattern on dynamic MRI indicate a high probability of MCS of the orbit. In addition, MCS of the orbit can demonstrate areas of hyperintensity on T1 weighted images, representing bone marrow fat tissue of ossification. ADVANCES IN KNOWLEDGE:: MCS of the orbit is a highly malignant tumor, and early diagnosis by imaging is important. Radiologists should be aware of the imaging features of MCS of the orbit. PMID- 29975156 TI - Down the rabbit hole: assessing the influence of schizotypy on the experience of the Barbie Doll Illusion. AB - INTRODUCTION: "Body swapping" illusions have been used to explore factors contributing to the experience of "owning" an artificial body. Preliminary research indicated that those people diagnosed with schizophrenia experience more vivid illusions of this kind than do "normal" individuals. OBJECTIVES: Here, we explored whether participants who rated themselves "high" on the cognitive perceptual factor of the Schizotypal Personality Questionnaire (SPQ) experienced a more compelling sense of immersion in a variation of the body swapping illusion: The Barbie Doll Illusion. We also hypothesised that these individuals would experience a change in size perception when immersed in the illusion. METHOD: Forty-four participants wore a pair of Head-Mounted Display goggles connected to a video-camera, and thus a doll's body replaced their own body in their visual field. In two conditions, touch was either applied synchronously or asynchronously to the doll's and each participant's leg. After each condition, participants filled out a questionnaire relating to their experience in the illusion. When both conditions were completed, they filled out the SPQ. RESULTS: Our first hypothesis was confirmed, which suggested that people with higher cognitive-perceptual SPQ scores do indeed experience a more compelling Barbie Doll Illusion; however, our second hypothesis was not supported. CONCLUSION: Our study demonstrated, for the first time, that proneness to the positive and interpersonal factors of schizotypy in a normal population is sufficient to produce a compelling sense of swapping bodies. PMID- 29975157 TI - Analysis of the contribution of phosphoinositides to medial septation in fission yeast highlights the importance of PI(4,5)P2 for medial contractile ring anchoring. AB - In Schizosaccharomyces pombe, loss of the plasma membrane PI4-kinase scaffold Efr3 leads to sliding of the cytokinetic ring (CR) away from the cell center during anaphase, implicating phosphoinositides (PIPs) in CR anchoring. However, whether other PIP regulators contribute to CR anchoring has not been investigated. Here we report that mutants of other PIP kinases and their regulators divide with off-center septa, similar to efr3?. Using new biosensors for S. pombe PIPs, we confirm that these mutants have disrupted PIP composition. We extend a previous finding that a mutant known to decrease PI(3,5)P2 levels indirectly affects CR positioning by increasing vacuole size which disrupts nuclear position at the onset of mitosis. Indeed, we found that other mutants with increased vacuole size also disrupt medial division via this mechanism. Although elevated plasma membrane PI(4,5)P2 levels do not affect medial cytokinesis, mutants with decreased levels display CR sliding events indicating a specific role for PI(4,5)P2 in CR anchoring. PMID- 29975158 TI - Rhizosphere Fungal Community Dynamics Associated with Rehmannia glutinosa Replant Disease in a Consecutive Monoculture Regime. AB - Consecutive monoculture of Rehmannia glutinosa in the same field leads to a severe decline in both quality and yield of tuberous roots, the most useful part in traditional Chinese medicine. Fungi are an important and diverse group of microorganisms in the soil ecosystem and play crucial roles in soil health. In this study, high-throughput pyrosequencing of internal transcribed spacer 2 ribosomal DNA amplicons was applied to gain insight into how consecutive monoculture practice influence and stimulate R. glutinosa rhizosphere and bulk soil fungal communities. The results from nonmetric multidimensional scaling ordination and clustering analysis revealed distinctive differences between rhizosphere and bulk soil fungal communities. However, longer-term monocultured bulk soils were more similar to the rhizosphere soils in comparison with the shorter-term monocultured bulk soils. Moreover, consecutive monoculture caused a gradual shift in the composition and structure of the soil fungal community. The cultivation of this plant led to the appearance of some exclusive operational taxonomic units in rhizosphere or bulk soils that were assigned to the genera Fusarium, Rhizoctonia, and so on. Furthermore, the sum of the relative abundance of species of Fusarium, Cylindrocarpon, and Gibberella (belonging to the family Nectriaceae); Rhizoctonia, Thanatephorus, and Ceratobasidium (belonging to the family Ceratobasidiaceae); and Lectera and Plectosporium (belonging to the family Plectosphaerellaceae) was significantly higher in consecutively monocultured (CM) than in newly planted (NP) soil in both rhizosphere and bulk soils. In particular, Fusarium abundance was significantly higher in CM than in NP in the rhizosphere, and higher in rhizosphere soils than in bulk soils for each treatment. A pathogenicity test showed that both Fusarium strains isolated were pathogenic to R. glutinosa seedlings. In addition, the culture filtrate and mycotoxins produced by Fusarium oxysporum significantly repressed the growth of the antagonistic bacterium, Pseudomonas aeruginosa. In conclusion, consecutive monoculture of R. glutinosa restructured the fungal communities in both rhizosphere and bulk soils but bulk effects developed more slowly over time in comparison with rhizosphere effects. Furthermore, microbial interactions might lead to a reduction in the abundance of beneficial microbes. PMID- 29975159 TI - PFLP-Intensified Disease Resistance Against Bacterial Soft Rot Through the MAPK Pathway in PAMP-Triggered Immunity. AB - Bacterial soft rot is a devastating disease affecting a variety of vegetable crops worldwide. One strategy for controlling this disease could be the ectopic expression of the plant ferredoxin-like protein (pflp) gene. PFLP was previously shown to intensify pathogen-associated molecular pattern-triggered immunity (PTI), an immune response triggered, for example, by the flagellin epitope flg22. To gain further insight into how PFLP intensifies PTI, flg22 was used as an elicitor in Arabidopsis thaliana. First, PFLP was confirmed to intensify the rapid generation of H2O2, callose deposition, and the hypersensitive response when coinfiltrated with flg22. This response correlated with increased expression of the FLG22-induced receptor kinase 1 gene, which is part of the mitogen activated protein kinase (MAPK) pathway. Although the increased response to flg22 alone did not depend on the MAPK pathway genes MEKK1, MKK5, and MPK6, the protective effect of PFLP decreased when plants mutated in these genes were inoculated with Pectobacterium carotovorum subsp. carotovorum. Furthermore, expression of PR1 and PDF1.2 also increased upon treatment with flg22 in the presence of PFLP. Taken together, these results suggest that activation of the MAPK pathway contributes to the increased resistance to bacterial soft rot observed in plants treated with PFLP. PMID- 29975160 TI - A 2'-O-Methyltransferase Responsible for Transfer RNA Anticodon Modification Is Pivotal for Resistance to Pseudomonas syringae DC3000 in Arabidopsis. AB - Transfer RNA (tRNA) is the most highly modified class of RNA species in all living organisms. Recent discoveries have revealed unprecedented complexity in the tRNA chemical structures, modification patterns, regulation, and function, suggesting that each modified nucleoside in tRNA may have its own specific function. However, in plants, our knowledge of the role of individual tRNA modifications and how they are regulated is very limited. In a genetic screen designed to identify factors regulating disease resistance in Arabidopsis, we identified SUPPRESSOR OF CSB3 9 (SCS9). Our results reveal SCS9 encodes a tRNA methyltransferase that mediates the 2'-O-ribose methylation of selected tRNA species in the anticodon loop. These SCS9-mediated tRNA modifications enhance susceptibility during infection with the virulent bacterial pathogen Pseudomonas syringae DC3000. Lack of such tRNA modification, as observed in scs9 mutants, specifically dampens plant resistance against DC3000 without compromising the activation of the salicylic acid signaling pathway or the resistance to other biotrophic pathogens. Our results support a model that gives importance to the control of certain tRNA modifications for mounting an effective disease resistance in Arabidopsis toward DC3000 and, therefore, expands the repertoire of molecular components essential for an efficient disease resistance response. PMID- 29975161 TI - Disruption of the Pathogenicity and Sex Ratio of the Beet Cyst Nematode Heterodera schachtii by Host-Delivered RNA Interference. AB - The beet cyst nematode (BCN) Heterodera schachtii causes serious damage and yield losses in numerous important crops worldwide. This study examines the efficacy of three types of transgenic Arabidopsis RNA interference (RNAi) lines to decrease the biological activity of this devastating nematode. The first RNAi construct (E1E2-RNAi) targets two nematode endoglucanase genes, which are involved in BCN pathogenicity, the second construct (MSP-RNAi) contains a fragment corresponding to the major sperm protein transcript necessary for BCN development and reproduction, and the third construct (E1E2MSP-RNAi) comprises all three target fragments. Transcript expression profiles of the target genes in all biological stages of the nematode were determined for the initial inoculated population and the resulting progeny. Bioassay data under indoor aseptic cultivation indicated that feeding on these RNAi lines did not affect pathogenic activity and reproductive capacity of the initial population, whereas inoculating the progeny into new transgenic plants corresponding with the lines from which they were recovered reduced the nematode penetration and the number of eggs per cyst. In addition, the male/female ratio increased more than the double, and the effects of RNAi continued in the second generation of the nematodes, because the progeny derived from E1E2-RNAi and E1E2MSP-RNAi lines showed an impaired ability to infect wild-type plants. PMID- 29975162 TI - Cortical excitability varies across different muscles. AB - The aim of the present study was to determine whether significant differences in cortical excitability were evident across different body regions in healthy humans. Threshold tracking transcranial magnetic stimulation (TMS) was undertaken in 28 healthy controls. Short-interval intracortical inhibition [SICI between interstimulus intervals (ISI) 1-7 ms], intracortical facilitation (ICF, between ISI 10-30 ms), resting motor threshold (RMT), cortical silent period (CSP) duration (generated at stimulus intensity 150% RMT), and motor evoked potential amplitude were recorded from the abductor pollicis brevis (APB), tibialis anterior (TA), and trapezius muscles. These muscles were selected as they are frequently affected in neurodegenerative diseases, such as amyotrophic lateral sclerosis. SICI and ICF are measured as a percentage difference between conditioned and an unconditioned test response. SICI was significantly greater when recorded over the APB (9.9 +/- 1.5%) and TA (8.6 +/- 1.4%) muscles compared with the trapezius (4.5 +/- 1.9%, P < 0.05). The CSP duration was significantly shorter (CSPtrapezius, 131.0 +/- 6.3 ms; CSPTA, 175.7 +/- 9.9 ms; CSPAPB, 188.3 +/- 4.0 ms; P < 0.001) and ICF greater ( P < 0.01) in the trapezius muscle. There were no significant correlations between inhibitory and facilitatory processes recorded across the three muscles. The present study established significant differences in cortical excitability across three body regions, with evidence of more prominent inhibition and less facilitation in the limb muscles. NEW & NOTEWORTHY Cortical excitability of muscles with differing motor functions was assessed using threshold tracking transcranial magnetic stimulation. Significantly greater intracortical inhibition and less facilitation were evident over the limb muscles. These findings could relate to differences in the functional organization of the corticomotoneuronal system innervating different muscle regions. PMID- 29975163 TI - Firing responses mediated via distinct nicotinic acetylcholine receptor subtypes in rat prepositus hypoglossi nuclei neurons. AB - We previously reported that cholinergic current responses mediated via nicotinic acetylcholine (ACh) receptors (nAChRs) in the prepositus hypoglossi nucleus (PHN), which participates in gaze control, can be classified into distinct types based on different kinetics and are mainly composed of alpha7- and/or non-alpha7 subtypes: fast (F)-, slow (S)-, and fast and slow (FS)-type currents. In this study, to clarify how each current type is related to neuronal activities, we investigated the relationship between the current types and the membrane properties and the firing responses that were induced by each current type. The proportion of the current types differed in neurons that exhibited different afterhyperpolarization (AHP) profiles and firing patterns, suggesting that PHN neurons show a preference for specific current types dependent on the membrane properties. In response to ACh, F-type neurons showed either one action potential (AP) or multiple APs with a short firing duration, and S-type neurons showed multiple APs with a long firing duration. The firing frequency of F-type neurons was significantly higher than that of S-type and FS-type neurons. An alpha7 subtype-specific antagonist abolished the firing responses of F-type neurons and reduced the responses of FS-type neurons but had little effect on the responses of S-type neurons, which were reduced by a non-alpha7-subtype-specific antagonist. These results suggest that the different properties of the current types and the distinct expression of the nAChR subtypes in PHN neurons with different membrane properties produce unique firing responses via the activation of nAChRs. NEW & NOTEWORTHY Prepositus hypoglossi nucleus (PHN) neurons show distinct nicotinic acetylcholine receptor (nAChR)-mediated current responses. The proportion of the current types differed in the neurons that exhibited different afterhyperpolarization profiles and firing patterns. The nAChR-mediated currents with different kinetics induced firing responses of the neurons that were distinct in the firing frequency and duration. These results suggest that the different properties of the current types in PHN neurons with different membrane properties produce unique firing responses via the activation of nAChRs. PMID- 29975164 TI - Detection of activity-dependent vasopressin release from neuronal dendrites and axon terminals using sniffer cells. AB - Our understanding of neuropeptide function within neural networks would be improved by methods allowing dynamic detection of peptide release in living tissue. We examined the usefulness of sniffer cells as biosensors to detect endogenous vasopressin (VP) release in rat hypothalamic slices and from isolated neurohypophyses. Human embryonic kidney cells were transfected to express the human V1a VP receptor (V1aR) and the genetically encoded calcium indicator GCaMP6m. The V1aR couples to Gq11, thus VP binding to this receptor causes an increase in intracellular [Ca2+] that can be detected by a rise in GCaMP6 fluorescence. Dose-response analysis showed that VP sniffer cells report ambient VP levels >10 pM (EC50 = 2.6 nM), and this effect could be inhibited by the V1aR antagonist SR 49059. When placed over a coverslip coated with sniffer cells, electrical stimulation of the neurohypophysis provoked a reversible, reproducible, and dose-dependent increase in VP release using as few as 60 pulses delivered at 3 Hz. Suspended sniffer cells gently plated over a slice adhered to the preparation and allowed visualization of VP release in discrete regions. Electrical stimulation of VP neurons in the suprachiasmatic nucleus caused significant local release as well as VP secretion in distant target sites. Finally, action potentials evoked in a single magnocellular neurosecretory cell in the supraoptic nucleus provoked significant VP release from the somatodendritic compartment of the neuron. These results indicate that sniffer cells can be used for the study of VP secretion from various compartments of neurons in living tissue. NEW & NOTEWORTHY The specific functional roles of neuropeptides in neuronal networks are poorly understood due to the absence of methods allowing their real-time detection in living tissue. Here, we show that cultured "sniffer cells" can be engineered to detect endogenous release of vasopressin as an increase in fluorescence. PMID- 29975165 TI - Simulation of electromyographic recordings following transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) is a technique that enables noninvasive manipulation of neural activity and holds promise in both clinical and basic research settings. The effect of TMS on the motor cortex is often measured by electromyography (EMG) recordings from a small hand muscle. However, the details of how TMS generates responses measured with EMG are not completely understood. We aim to develop a biophysically detailed computational model to study the potential mechanisms underlying the generation of EMG signals following TMS. Our model comprises a feed-forward network of cortical layer 2/3 cells, which drive morphologically detailed layer 5 corticomotoneuronal cells, which in turn project to a pool of motoneurons. EMG signals are modeled as the sum of motor unit action potentials. EMG recordings from the first dorsal interosseous (FDI) muscle were performed in four subjects and compared to simulated EMG signals. Our model successfully reproduces several characteristics of the experimental data. The simulated EMG signals match experimental EMG recordings in shape and size, and change with stimulus intensity and contraction level as in experimental recordings. They exhibit cortical silent periods that are close to the biological values, and reveal an interesting dependence on inhibitory synaptic transmission properties. Our model predicts several characteristics of the firing patterns of neurons along the entire pathway from cortical layer 2/3 cells down to spinal motoneurons and should be considered as a viable tool for explaining and analyzing EMG signals following TMS. PMID- 29975166 TI - Motor adaptations to trunk perturbation: effects of experimental back pain and spinal tissue creep. AB - In complex anatomical systems, such as the trunk, motor control theories suggest that many motor solutions can be implemented to achieve a similar goal. Although reflex mechanisms act as a stabilizer of the spine, how the central nervous system uses trunk redundancy to adapt neuromuscular responses under the influence of external perturbations, such as experimental pain or spinal tissue creep, is still unclear. The aim of this study was to identify and characterize trunk neuromuscular adaptations in response to unexpected trunk perturbations under the influence of spinal tissue creep and experimental back pain. Healthy participants experienced a repetition of sudden external trunk perturbations in two protocols: 1) 15 perturbations before and after a spinal tissue creep protocol and 2) 15 perturbations with and without experimental back pain. Trunk neuromuscular adaptations were measured by using high-density electromyography to record erector spinae muscle activity recruitment patterns and a motion analysis system. Muscle activity reflex attenuation was found across unexpected trunk perturbation trials under the influence of creep and pain. A similar area of muscle activity distribution was observed with or without back pain as well as before and after creep. No change of trunk kinematics was observed. We conclude that although under normal circumstances muscle activity adaptation occurs throughout the same perturbations, a reset of the adaptation process is present when experiencing a new perturbation such as experimental pain or creep. However, participants are still able to attenuate reflex responses under these conditions by using variable recruitment patterns of back muscles. NEW & NOTEWORTHY The present study characterizes, for the first time, trunk motor adaptations with high-density surface electromyography when the spinal system is challenged by a series of unexpected perturbations. We propose that the central nervous system is able to adapt neuromuscular responses by using a variable recruitment pattern of back muscles to maximize the motor performance, even under the influence of pain or when the passive structures of the spine are altered. PMID- 29975168 TI - Editorial Focus on "Invariant and heritable local cortical organization as revealed by fMRI". PMID- 29975167 TI - Decrease in force steadiness with aging is associated with increased power of the common but not independent input to motor neurons. AB - Declines in motor function with advancing age have been attributed to changes occurring at all levels of the neuromuscular system. However, the impact of aging on the control of muscle force by spinal motor neurons is not yet understood. In this study on 20 individuals aged between 24 and 75 yr (13 men, 7 women), we investigated the common synaptic input to motor neurons of the tibialis anterior muscle and its impact on force control. Motor unit discharge times were identified from high-density surface EMG recordings during isometric contractions at forces of 20% of maximal voluntary effort. Coherence analysis between motor unit spike trains was used to characterize the input to motor neurons. The decrease in force steadiness with age ( R2 = 0.6, P < 0.01) was associated with an increase in the amplitude of low-frequency oscillations of functional common synaptic input to motor neurons ( R2 = 0.59; P < 0.01). The relative proportion of common input to independent noise at low frequencies increased with variability (power) in common synaptic input. Moreover, variability in interspike interval did not change and strength of the common input in the gamma band decreased with age ( R2 = 0.22; P < 0.01). The findings indicate that age-related reduction in the accuracy of force control is associated with increased common fluctuations to motor neurons at low frequencies and not with an increase in independent synaptic input. NEW & NOTEWORTHY The influence of aging on the role of spinal motor neurons in accurate force control is not yet understood. We demonstrate that aging is associated with increased oscillations in common input to motor neurons at low frequencies and with a decrease in the relative strength of gamma oscillations. These results demonstrate that the synaptic inputs to motor neurons change across the life span and contribute to a decline in force control. PMID- 29975169 TI - Dynamic communication of attention signals between the LGN and V1. AB - Correlations and inferred causal interactions among local field potentials (LFPs) simultaneously recorded in distinct visual brain areas can provide insight into how visual and cognitive signals are communicated between neuronal populations. Based on the known anatomical connectivity of hierarchically organized visual cortical areas and electrophysiological measurements of LFP interactions, a framework for interareal frequency-specific communication has emerged. Our goals were to test the predictions of this framework in the context of the early visual pathways and to understand how attention modulates communication between the visual thalamus and primary visual cortex. We recorded LFPs simultaneously in retinotopically aligned regions of the visual thalamus and primary visual cortex in alert and behaving macaque monkeys trained on a contrast-change detection task requiring covert shifts in visual spatial attention. Coherence and Granger-causal interactions among early visual circuits varied dynamically over different trial periods. Attention significantly enhanced alpha-, beta-, and gamma-frequency interactions, often in a manner consistent with the known anatomy of early visual circuits. However, attentional modulation of communication among early visual circuits was not consistent with a simple static framework in which distinct frequency bands convey directed inputs. Instead, neuronal network interactions in early visual circuits were flexible and dynamic, perhaps reflecting task-related shifts in attention. NEW & NOTEWORTHY Attention alters the way we perceive the visual world. For example, attention can modulate how visual information is communicated between the thalamus and cortex. We recorded local field potentials simultaneously in the visual thalamus and cortex to quantify the impact of attention on visual information communication. We found that attentional modulation of visual information communication was not static, but dynamic over the time course of trials. PMID- 29975172 TI - Giant dissecting aortic aneurysm in a chronic amphetamine user. PMID- 29975171 TI - Selective adsorption and separation of illegal cationic dyes from foodstuffs with anionic polyelectrolyte functionalised metal-organic frameworks. AB - A novel adsorbent, poly(sodium 4-styrenesulfonate) modified MIL-101(Cr)-NH2, was successfully prepared. Owing to its high surface area and degree of negative surface charge, it enables effective adsorption and separation of illegal cationic dyes, such as rhodamine B, pararosaniline, and auramine O, from foodstuffs prior to high performance liquid chromatography analysis. Under optimised conditions, good linearity was obtained over 1.0-80.0 or 1.0-120 ng mL 1 with a correlation coefficient (R2) > 0.999. Limits of detection and limits of quantification of the three dyes were 0.28-0.65 and 0.94-2.13 MUg kg-1, respectively. The recoveries of the three dyes in shrimp powder, chili powder, tofu sheets, and tomato sauce were in the range of 86.8-119.3%, suggesting that the developed method is a promising tool for accurate quantification of the three dyes at trace levels in foodstuffs. PMID- 29975170 TI - Electrophysiological properties of medium spiny neurons in the nucleus accumbens core of prepubertal male and female Drd1a-tdTomato line 6 BAC transgenic mice. AB - The nucleus accumbens core (AcbC) is a striatal brain region essential for integrating motivated behavior and reward processing with premotor function. In humans and rodents, research has identified sex differences and sex steroid hormone sensitivity in AcbC-mediated behaviors, in disorders, and in rats in the electrophysiological properties of the AcbC output neuron type, the medium spiny neuron (MSN). It is unknown whether the sex differences detected in MSN electrophysiological properties extend to mice. Furthermore, MSNs come in distinct subtypes with subtle differences in electrophysiological properties, and it is unknown whether MSN subtype-specific electrophysiology varies by sex. To address these questions, we used male and female Drd1a-tdTomato line 6 bacterial artificial chromosome transgenic mice. We made acute brain slices of the AcbC, and performed whole cell patch-clamp recordings across MSN subtypes to comprehensively assess AcbC MSN subtype electrophysiological properties. We found that ( 1 mice MSNs did not exhibit the sex differences detected in rat MSNs, and 2) electrophysiological properties differed between MSN subtypes in both sexes, including rheobase, resting membrane potential, action potential properties, intrinsic excitability, input resistance in both the linear and rectified ranges, and miniature excitatory postsynaptic current properties. These findings significantly extend previous studies of MSN subtypes performed in males or animals of undetermined sex and indicate that the influence of sex upon AcbC MSN properties varies between rodent species. NEW & NOTEWORTHY This research provides the most comprehensive assessment of medium spiny neuron subtype electrophysiological properties to date in a critical brain region, the nucleus accumbens core. It additionally represents the first evaluation of whether mouse medium spiny neuron subtype electrophysiological properties differ by sex. PMID- 29975173 TI - New-onset atrial fibrillation is associated with increased mortality in critically ill patients: a systematic review and meta-analysis. AB - INTRODUCTION: Atrial fibrillation (AF) is one of the most comorbid conditions in critically ill patients requiring intensive care unit (ICU). Multiple studies have suggested that there may be an association between new-onset AF and adverse outcome in critically ill patients. However, there are no meta-analyses to assess this association. METHODS: Studies were systematically searched from electronic databases. Studies that examined the relationship between new-onset AF and adverse outcomes including mortality and length of stay in ICU patients were included. Studies that included patients with prior AF were excluded. The pooled effect size was calculated with a random-effect model, weighted for the inverse of variance, to determine an association between new-onset AF and in-hospital mortality. Heterogeneity was assessed with I2. RESULTS: Twelve studies were included. Pooled analysis showed statistically significant difference rate of the hospital mortality between patients with and without new-onset AF (OR 2.70; 95% CI 2.43-3.00). Subgroup analysis of only patients with sepsis or septic shock showed a significant association between new-onset AF and in-hospital mortality (OR 2.32; 95% CI 1.88-2.87). No significant heterogeneity was observed (I2 = 0%) in both analyses. Pooled analysis of four studies also showed a significant association between new-onset AF and short-term mortality (OR 2.22; 95% CI 1.28 3.83) with moderate heterogeneity (I2 = 67%). CONCLUSIONS: New-onset AF is associated with worse outcome in critically ill patients. Further studies should be done to evaluate for causality and adjust for confounders. PMID- 29975174 TI - Reduced impact of imagery processing on false autobiographical recollection: the effects of dynamic visual noise. AB - Research has demonstrated that merely imagining an autobiographical event can bring about false memories for that event. One explanation for this is that imagination leads to the creation and incorporation of visual-imagistic information into the event representation. This idea was tested in two experiments in which visual-imagery processing was disrupted by the use of Dynamic Visual Noise (DVN). In Experiment 1, autobiographical memories that were rated as "known" and lacking in event detail were subsequently rated as more "remembered" following imagination. In Experiment 2, imagination led to improbable autobiographical events being rated as more believable and vivid. In both experiments, interfering with imagery processing by DVN reduced these effects. It was concluded that visual-imagistic processing plays an important role in altering the mnemonic status of autobiographical representations. PMID- 29975175 TI - Beyond handedness: assessing younger adults and older people lateral preference in six laterality dimensions. AB - Lateral preference is influenced by many different factors. Although studies that assessed handedness contributed greatly to our understanding of the phenomenon, looking to other dimensions of motor laterality, such as lower limbs, trunk, visual and hearing preference, may be an interesting strategy to further advance in the field. Comparing different age groups with a complete inventory also contributes to understanding the ageing impact on these variables. Our aim, therefore, was to assess six motor laterality dimensions in younger adults and older people. Two hundred subjects participated in this study (102 adults, 30.6 +/- 11.2 years old, and 98 elders, 70.4 +/- 7.22 years old) and lateral preference was assessed by the Global Lateral Preference Inventory. We verified significant differences between groups in all dimensions, except the visual one, with proportionally stronger right preference in the older group. Compared to other dimensions, higher frequency of ambidexterity was observed in trunk, hearing and visual preference for both groups. These results might indicate that lateral preference is, indeed, multifactorial, being affected by ageing, task complexity and other possible related aspects. PMID- 29975177 TI - Transition from service to civvy street: the needs of armed forces veterans and their families in the UK. AB - AIMS: Although many veterans make the transition from military to civilian life without difficulty, a small proportion struggle due to an impact on mental and physical wellbeing. Stigma and a reluctance to seek help further exacerbate this problem. The Armed Forces Covenant outlines the importance of ensuring that public services are aware of the specific needs of veterans; however, evidence suggests that knowledge among professional staff may be limited. METHODS: This exploratory study included three phases. Phase 1 (questionnaires) explored the needs of veterans and their families in Warwickshire (UK) regarding information about their health and wellbeing and the barriers and facilitators to accessing local public health services. Also in Phase 1, health and public services staff knowledge of veterans' needs and the Covenant is explored. In Phase 2, both samples attended a related focus group for a more in-depth exploration of the issues identified in Phase 1; in order to inform a Phase 3 workshop to co-develop an intervention. RESULTS: Veterans, their families and friends, wanted more information about what services do, how and when to access them and what to expect. Confusion over when to seek help for mental health 'symptoms' was highlighted. More support for families was identified, alongside a need for health and social care staff to have a better understanding of the unique experiences and needs of veterans. Only 35% of staff reported a good understanding of the Armed Forces Covenant and their responsibilities to uphold it. CONCLUSIONS: Public health teams within UK local authorities are well placed to ensure veterans have more knowledge about and access to public services. Interventions to address stigma and veterans' reluctance to seek help were needed. To this end, interventions for local veterans, their loved ones and staff in public services, designed in co-creation with these groups, is discussed. PMID- 29975176 TI - New mothers' struggles to love their child. An interpretative synthesis of qualitative studies. AB - PURPOSE: New mothers may question the nature of their motherly love after the birth. Most mothers find that feelings of affection come within a week from birth. However, some mothers are still struggling with this after many months. Many studies place strong emphasis on the importance of maternal affection for the development of the child. Few studies look into mothers' experiences when maternal affection or love remains a struggle. Method:We present an interpretative synthesis based on a systematic analysis of five qualitative studies that report findings related to mothers' stated inability to exhibit maternal affection. Result:In answer to our question "what characterizes the experiences of women who struggle with, or are unable to exhibit, maternal affection after birth", we identified the uncertainty involved in imagining the unborn child, birth and maternal future, birth as a disillusionment, and the ensuing process of decreasing agency and increasing alienation. Especially a traumatic birth may lead to disillusionment. Conclusion: Health care workers and research can support a mother's positive resolution of her struggle by promoting realistic and more open expectations for maternal affection as well as her sense of agency and ownership during birth and the early mother-child relationship. PMID- 29975178 TI - Characterization of a novel hydroxynitrile lyase from Nandina domestica Thunb. AB - The leaves of Nandina domestica Thunb. exhibited high hydroxynitrile lyase (HNL) activity in (R)-mandelonitrile synthesis. The specific activity of young leaves was significantly higher than that of mature leaves. We isolated two HNLs with molecular mass of 24.9 kDa (NdHNL-S) and 28.0 kDa (NdHNL-L) from the young leaves. Both NdHNLs were composed of two identical subunits, without FAD and carbohydrates. We purified NdHNL-L and revealed its enzymatic properties. The whole deduced amino acid sequence of NdHNL-L was not homologous to any other HNLs, and the specific activity for mandelonitrile synthesis by NdHNL-L was higher than that by other plant HNLs. The enzyme catalyzed enantioselective synthesis of (R)-cyanohydrins, exhibited high activity at pH 4.0, and high stability in the pH range of 3.5-8.0 and below 55 degrees C. Thus, NdHNL-L is a novel HNL with novel amino acid sequence and has a potential for the efficient production of (R)-cyanohydrins. PMID- 29975179 TI - '"For a better life ..." A study on migration and health in Nicaragua'. AB - BACKGROUND: Nicaraguans have migrated internally and internationally for centuries due to economic, political and sociocultural factors. Deficiencies in the country's health care system have produced inequities in people's access to health care and medicines. Remittances have become an important source of income, partly invested in health. OBJECTIVES: The overall aim of the study was to analyse migration-health relations in contemporary Nicaragua within a broader context of socio-economic transformations. METHODS: The study uses a mixed methods approach, combining qualitative interview data and quantitative survey data. RESULTS: The findings show that migration is commonly practised as a strategy for making a living and is related to the struggle for a better life. Health concerns are indirectly embedded in people's mobile livelihoods, but also directly influence migration motives. Furthermore, migration involves both advantages and disadvantages for health. Physical and sexual violence can come to an end for migrating women, health care and medicine can become more accessible for internal migrants, and vulnerabilities caused by environmental disasters can be avoided by moving. Moreover, remittances can improve people's everyday life and health. Yet migration can also be a stressful and health-damaging event. International migrants, particularly the undocumented, can have problems accessing health care, and also experience much danger at border crossings. Transnational families can suffer emotionally as well as physically due to separation. Findings from the survey show that family members of migrants do not rate their physical health as good as often as non-migrating families. CONCLUSIONS: The Nicaraguan population is not guaranteed its social rights of citizenship. This results in mobile livelihoods and the need for translocal social support (e.g. remittances). Migration can have both positive and negative effects on health for migrants and their family members; geographical distance and social differences are key to the outcome. PMID- 29975180 TI - Experimental Effects of Acute Exercise on Episodic Memory Function: Considerations for the Timing of Exercise. AB - Our previous work employing a between-subject randomized controlled trial design suggests that exercising prior to memory encoding is more advantageous in enhancing retrospective episodic memory function when compared to exercise occurring during or after memory encoding. The present experiment evaluates this potential temporal effect of acute exercise on memory function while employing a within-subject, counterbalanced design. In a counterbalanced order (via Latin squares), 24 participants completed four visits including (1) exercising (moderate-intensity walking) prior to memory encoding, (2) exercising during memory encoding, (3) exercising after memory encoding, and (4) a control visit (no exercise). Retrospective memory function (short term and long term; 24-hour follow-up) was assessed from a multitrial word list. Prospective memory was assessed from a time-based task. Compared to all other visits, short-term memory was greater in the visit that involved exercising prior to memory encoding (F = 3.76; P = .01; eta2 = .79). Similar results occurred for long-term memory, with no significant effects for prospective memory performance. We provide robust evidence demonstrating that acute moderate-intensity exercise prior to memory encoding is optimal in enhancing short-term and long-term memory function when compared to no exercise as well as exercising during and after memory encoding. PMID- 29975181 TI - An interesting case of narrow QRS tachycardia with rightward axis. PMID- 29975183 TI - Understanding the systems that characterise the circular economy and the bioeconomy. PMID- 29975182 TI - "To be, or not to be": experiencing deterioration among people with young-onset dementia living alone. AB - Having dementia before the age of 65 (YOD) represents a radical break from an age normative and expected life course. The disease afflicts the person's identity, threatens the self-image and self-confidence, and erodes the person's plans. The aim of the study was toexamine how people living alone with YOD perceive the course of dementia, their needs, and coping strategies, with a focus on narrating everyday life experiences. A longitudinal study using a qualitative approach was used. Five interviews, each with 10 informants, took place every 6 months from 2014 to 2017. The main theme is the person's experiences of changes of identity over time. The most significant aspects of their experiences of the dementia affecting them and their reactions are these: the initial signs, coping efforts, concealing the diagnosis, social retraction, existential anxiety, revival of the self, worse and worse, and health personnel as background. The study concluded thatpeople with dementia are able to describe their experiences and needs for a long time during the progression of dementia. Their voices should be listened to for planning of services. Personalized care should be used to support them in order to preserve their identity in a normalized everyday life as far as possible. PMID- 29975184 TI - Elevated antibodies against Epstein-Barr virus among individuals predicted to carry nasopharyngeal carcinoma susceptibility variants. AB - Epstein-Barr virus (EBV) is an obligatory factor in the development of nasopharyngeal carcinoma (NPC), and anti-EBV IgA antibodies are elevated many years prior to the development of NPC. Nearly all adults are infected with EBV, but only a few develop cancer, suggesting that additional co-factors, including genetic susceptibility, must be required for the disease to manifest. Individuals were selected from the Taiwan Family Study, a cohort of 3389 individuals from NPC multiplex families. Primary analyses were conducted among 671 individuals from 69 pedigrees with the strongest family history of disease (>3 NPC-affected family members). The likelihood that a given family member carried a NPC susceptibility variant was estimated using Mendelian segregation rules, assuming a dominant mode of inheritance. We compared anti-EBV IgA antibody seropositivity between family members predicted to be carriers of NPC-linked genetic variants and those with a lower likelihood of carrying such variants. Obligate carriers of NPC susceptibility variants (100 % predicted probability of harbouring the genetic mutation) were nine-fold more likely to be anti-EBV IgA positive compared to family members predicted not to carry disease-causing variants (OR=9.2; P trend<0.001). This elevated risk was confirmed in analyses restricted to both unaffected individuals and pedigrees with EBV-related pathway variants identified through exome sequencing. Our data indicate that family members who are more likely to carry NPC susceptibility variants are also more likely to be anti-EBNA1 IgA seropositive. Genetic susceptibility associated with control over this common herpes virus is likely a co-factor in determining which EBV-infected adults develop NPC. PMID- 29975185 TI - Confirmation of Zika virus infection through hospital-based sentinel surveillance of acute febrile illness in Uganda, 2014-2017. AB - Zika virus (ZIKV), transmitted by Aedes species mosquitoes, was first isolated in Uganda in 1947. From February 2014 to October 2017, the Uganda Virus Research Institute, in collaboration with the US Centers for Diseases Control and Prevention, conducted arbovirus surveillance in acute febrile illness (AFI) patients at St Francis hospital in Nkonkonjeru. Three hundred and eighty-four serum samples were collected and tested for IgM antibodies to yellow fever virus (YFV), West Nile virus (WNV), dengue virus (DENV), chikungunya virus (CHIKV) and ZIKV. Of the 384 samples, 5 were positive for ZIKV IgM. Of these five, three were confirmed by plaque reduction neutralization test (PRNT) to be ZIKV infections. Of the remaining two, one was determined to be a non-specific flavivirus infection and one was confirmed to be alphavirus-positive by reverse transcriptase polymerase chain reaction (RT-PCR). This study provides the first evidence of laboratory-confirmed ZIKV infection in Uganda in five decades, and emphasizes the need to enhance sentinel surveillance. PMID- 29975187 TI - Graphically Hearing: Enhancing Understanding of Geospatial Data through an Integrated Auditory and Visual Experience. AB - Effective presentation of data is critical to a users understanding of it. In this manuscript, we explore research challenges associated with presenting large geospatial datasets through a multimodal experience. We also suggest an interaction schema that enhances users cognition of geographic information through a user-driven display that visualizes and sonifies geospatial data. PMID- 29975188 TI - LightPainter: Creating Long-Exposure Imagery from Videos. AB - This article presents LightPainter, an interactive tool that promotes creative long-exposure photography through an intuitive drawing metaphor and flexible spatiotemporal mapping from videos to composite images. We discuss the power of software-defined exposure and the tools capability to facilitate creating sophisticated long-exposure effects in challenging scenarios. PMID- 29975186 TI - Sphingobium aquiterrae sp. nov., a toluene, meta- and para-xylene-degrading bacterium isolated from petroleum hydrocarbon-contaminated groundwater. AB - A Gram-negative, aerobic, slightly yellow-pigmented bacterium, designated as SKLS A10T, was isolated from groundwater sample of the 'Siklos' petroleum hydrocarbon contaminated site (Hungary). Phylogenetic analysis based on 16S rRNA gene sequence revealed that strain SKLS-A10T formed a distinct phyletic lineage within the genus Sphingobium. It shared the highest 16S rRNA gene homology with Sphingobium abikonense DSM 23268T (97.29 %), followed by Sphingobium lactosutens DSM 23389T (97.23 %), Sphingobium phenoxybenzoativorans KCTC 42448T (97.16 %) and Sphingobium subterraneum NBRC 109814T (96.74 %). The predominant fatty acids (>5 % of the total) are C18 : 1omega7c, C14 : 0 2-OH, C16 : 1omega7c/iso C15 : 0 2 OH, C17 : 1omega6c and C16 : 0. The major ubiquinone is Q-10. The predominant polyamine is spermidine. The major polar lipids are sphingoglycolipid and diphosphatidylglycerol. The DNA G+C content of strain SKLS-A10T is 65.9 mol%. On the basis of evidence from this taxonomic study using a polyphasic approach, strain SKLS-A10T represents a novel species of the genus Sphingobium for which the name Sphingobiumaquiterrae sp. nov. is proposed. The type strain is SKLS-A10T (=DSM 106441T=NCAIM B. 02634T). PMID- 29975189 TI - Interactive Partitioning of 3D Models into Printable Parts. AB - This article presents an easy, flexible and interactive tool for partitioning a 3D model, which is larger than a 3D printers working volume, into printable parts in an intuitive way. Our tool is based on the elegant partitioning optimization framework Chopper. Our tool aims at improving Chopper by providing users three easy-to-use interactive operations: no-go region painting, cutting plane specification and components reunion. With these operations, we show that (1) exhaustive search in the BSP tree-the most time-consuming step in Chopper-can be avoided, (2) more flexible geometric configurations can be provided, (3) users design intention is considered naturally and efficiently, and customized 3D partitioning results can be obtained. We test our tool on a wide range of 3D models and observe promising results. A preliminary user study also demonstrates its effectiveness and efficiency. PMID- 29975190 TI - SpiroSurface: A Repulsive and Attractive Force Display for Interactive Tabletops Using a Pneumatic System. AB - We present SpiroSurface, a novel force display for interactive tabletops. SpiroSurface uses a pneumatic system to generate both repulsive and attractive forces. We develop a prototype with 5x5 grid holes on the surface connected to an air compressor and vacuum tanks through electromagnetic valves. The display can output a maximum of +1.0 and -0.08 megapascal (MPa) pressure from a hole that generates 74 and -6 N force. We investigated the latency of the output pressure through pneumatics and an experiment, which indicated a minimum of 50-ms latency. The display allows the creation of three kinds of novel interactions: (1) enhancement of GUI, (2) deformation of soft objects, and (3) three-degree-of freedom rotation of objects. In the first application, users can feel the force from the display without holding or attaching additional devices. In the second and third applications, the shape and motion of an object on the surface can be manipulated without embedding additional active components in the objects. These aspects allow users to easily experience interaction and expand the freedom of interaction design. We introduce several examples combining video projection and motion tracking. These examples demonstrate the potential of the display. PMID- 29975191 TI - LevelMerge: Collaborative Game Level Editing by Merging Labeled Graphs. AB - Game development is commonly seen as a collaborative effort, with teams cooperating on the same project. Nowadays, a variety of cloud-based services have shown the benefits of performing tasks in real-time collaboration with others. In this article, we present a system for collaborative game level editing. We model this problem as a special instance of merging labeled directed acyclic graphs. We propose an algorithm that guarantees that the shared game level is always coherent between edits, both hierarchically and semantically. We establish real time collaboration by initiating merges automatically and by augmenting the game editor interface to allow users to monitor all others edits in real time. We validate our algorithm by merging complex edits and large game levels. We further validate the collaborative workflow by running a user study with expert game developers, showing that our system works well and collaborative workflows are beneficial to game development. PMID- 29975192 TI - Visual Analytics for Explainable Deep Learning. AB - Recently, deep learning has been advancing the state of the art in artificial intelligence to a new level, and humans rely on artificial intelligence techniques more than ever. However, even with such unprecedented advancements, the lack of explanation regarding the decisions made by deep learning models and absence of control over their internal processes act as major drawbacks in critical decision-making processes, such as precision medicine and law enforcement. In response, efforts are being made to make deep learning interpretable and controllable by humans. This article reviews visual analytics, information visualization, and machine learning perspectives relevant to this aim, and discusses potential challenges and future research directions. PMID- 29975193 TI - Wetting characteristics of vertically aligned graphene nanosheets. AB - Vertically aligned graphene nanosheets (VAGNs) are a class of graphitic carbon in which few layers of graphene nanosheets are aligned perpendicular to the plane of the substrate. The change in water contact angle (from 103 degrees to 135 degrees ) with VAGNs, as a function of change in the surface geometry, is analysed. Theoretical calculations and comparison with the experimental data shows that the apparent contact angle values of VAGNs are closer to that of the fully non-wetting mode or ideal Cassie mode of wetting. The ideal Cassie mode of wetting also explains the variation of the water contact angle of VAGNs with the surface morphology of the material and predicts how surface parameters can be modified to get the required wettability for a certain application of this material. PMID- 29975194 TI - Dynamic magnetization on the low temperature magnetoelectric effect in multiferroic composites. AB - The dependence of frequency and applied magnetic field in the magnetoelectric effect (ME) of the composites 0.68Pb(Mg1/3Nb2/3)-0.32PbTiO3/CoFe2O4 (PMN-PT/CFO) and 0.68Pb(Mg1/3Nb2/3)-0.32PbTiO3/NiFe2O4 (PMN-PT/NFO) are investigated. The results for PMN-PT/CFO composite, show a hysteretic behavior for the ME coefficient, at low temperatures (5 K), for frequencies higher than 1000 Hz. Contrasting with these results, the ME coefficient for the PMN-PT/NFO shows a well-known peak-peak related with the magnetostriction coefficient. Based on energy levels of stabilization for each ferromagnetic phase, it was possible to explain the ME hysteretic distinct behavior of PMN-PT/CFO, because of the degeneracy in the energy levels, due to the spin-orbit coupling causing changes in the dynamic properties of the magnetoelastic interactions. PMID- 29975195 TI - Nanotube and poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) composite film for the electrode applications in organic thin-film transistor and dye-sensitized solar cells. AB - In this study, composite films made of coiled carbon nanotubes (CCNTs) and poly(3,4-ethylenedioxythiophene) polymerized with poly(4-styrenesulfonate) (PEDOT:PSS) were fabricated with different composition ratios. The variations in film properties (including surface morphology, work function, and electrical conductivity) in accordance with the amount of CCNT dosing were investigated. Subsequently, through HCl-methanol treatment, we achieved a significant enhancement in electrical conductivity with little damage to the CCNT features. The characteristics of CCNT/PEDOT:PSS composite film are generally comparable to those of PEDOT:PSS film, and some of them, such as catalytic activity and work function, are significantly higher. On the basis of these versatile features, the CCNT/PEDOT:PSS composite films exhibit excellent performance as source/drain electrode in organic thin-film transistors and as catalytic counter electrode in dye-sensitized solar cells. PMID- 29975196 TI - Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer. AB - BACKGROUND: Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS: A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P<0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04). CONCLUSIONS: Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness. PMID- 29975197 TI - Is an Extensive ERAS Program Able to Bring a Better Outcome in Contrast With Standard ERAS Program for Laparoscopic Colorectal Cancer Surgery? PMID- 29975198 TI - Response to: "MySurgeryRisk: Development and Validation of a Machine-learning Risk Algorithm for Major Complications and Death After Surgery". PMID- 29975199 TI - Monitoring and Molecular Characterization of Staphylococcus aureus Isolated from Chronic Wounds. AB - OBJECTIVE: Researchers analyzed chronic wounds treated with 2% hydrogel to determine whether the presence of methicillin-resistant Staphylococcus aureus (MRSA) is related to the presence of clinical signs of infection. METHODS: Thirty five patients were recruited for this descriptive study using a quantitative approach. Staphylococcus aureus was identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Antibiotic susceptibility was determined using a disk diffusion test according to Clinical and Laboratory Standards Institute standards. Polymerase chain reaction, pulsed-field gel electrophoresis, and multilocus sequence typing were performed. Statistical analyses were performed using Spearman correlation coefficients for the variables MRSA and clinical signs of infection. MAIN OUTCOME MEASURES: The identification of MRSA or methicillin-sensitive S aureus (MSSA), presence or absence of an infection in the wound, and molecular characterization of bacteria were measured. MAIN RESULTS: Of the 35 patients analyzed, 8 (22.9%) were classified as having an infection in their wounds. Spearman rho indicated a strong positive correlation between the increase in the number of clinical signs of infection and MSSA (P =.84), but only a moderate positive correlation with MRSA (P =.60). The S aureus clonal pattern was unique for each of the major bacteria isolated. Global MRSA sequence-type clones (ST-1 and ST-72) were detected in 2 patients. CONCLUSIONS: Compared with those colonized by MSSA, chronic wounds colonized by MRSA did not display a strong correlation with the presence of a greater number of clinical signs of infection. PMID- 29975200 TI - Lacosamide: Associated Hyponatremia. PMID- 29975202 TI - Does Surgically Managed Grade I Degenerative Lumbar Spondylolisthesis Require Fusion? PMID- 29975201 TI - Impact of underlying plaque type on strut coverage in the early phase after drug eluting stent implantation. AB - BACKGROUND: The aim of this study was to investigate whether the underlying plaque type affects the neointimal coverage after drug-eluting stent implantation. METHODS: A total of 1793 struts in 22 zotarolimus-eluting stents were assessed using optical coherence tomography imaging within 3 months of implantation. Neointimal coverage was evaluated within 5 mm from each stent edge on cross-sectional optical coherence tomography images at every 1-mm interval. The percentage of struts covered by neointima was compared among the normal segment group, the fibrous plaque group, and the lipid plaque group on the basis of the underlying plaque type. RESULTS: The percentage of covered strut was significantly lower in the normal segment group than in the fibrous plaque group (35.9+/-30.2 vs. 57.1+/-31.0%, P<0.05) and the lipid plaque group (vs. 64.7+/ 23.5%, P<0.01). The neointima was significantly thinner in the normal segment group than in the lipid plaque group (19.0+/-22.3 vs. 32.0+/-18.8 MUm, P<0.01). The percentage of struts on the normal segment was significantly higher in cross sections with a ratio of uncovered to total struts per section more than 0.3 than in cross-sections with a ratio up to 0.3 (32.4+/-31.7 vs. 19.5+/-33.8%, P<0.01). CONCLUSION: Struts on the normal segment were less covered and had thinner neointima than struts on the lipid plaque at the stent edge within 3 months after zotarolimus-eluting stent implantation. Caution should be exercised when implanting longer drug-eluting stents to achieve uniform strut coverage in the early phase. PMID- 29975203 TI - Preoperative Fascia Iliaca Block Does Not Improve Analgesia after Arthroscopic Hip Surgery, but Causes Quadriceps Muscles Weakness: A Randomized, Double-blind Trial. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Ambulatory hip arthroscopy is associated with postoperative pain routinely requiring opioid analgesia. The potential role of peripheral nerve blocks for pain control after hip arthroscopy is controversial. This trial investigated whether a preoperative fascia iliaca block improves postoperative analgesia. METHODS: In a prospective, double-blinded trial, 80 patients scheduled for hip arthroscopy were randomized to receive a preoperative fascia iliaca block with 40 ml ropivacaine 0.2% or saline. Patients also received an intraarticular injection of 10-ml ropivacaine 0.2% at procedure end. Primary study endpoint was highest pain score reported in the recovery room; other study endpoints were pain scores and opioid use 24 h after surgery. Additionally, quadriceps strength was measured to identify leg weakness. RESULTS: The analysis included 78 patients. Highest pain scores in the recovery room were similar in the block group (6 +/- 2) versus placebo group (7 +/- 2), difference: -0.2 (95% CI, -1.1 to 0.7), as was opioid use (intravenous morphine equivalent dose: 15 +/- 7mg [block] vs. 16 +/- 9 mg [placebo]). Once discharged home, patients experienced similar pain and opioid use (13 +/- 7 mg [block] vs. 12 +/- 8 mg [placebo]) in the 24 h after surgery. The fascia iliaca block resulted in noticeable quadriceps weakness. There were four postoperative falls in the block group versus one fall in the placebo group. CONCLUSIONS: Preoperative fascia iliaca blockade in addition to intraarticular local anesthetic injection did not improve pain control after hip arthroscopy but did result in quadriceps weakness, which may contribute to an increased fall risk. Routine use of this block cannot be recommended in this patient population. PMID- 29975204 TI - Weaning from Mechanical Ventilation: Have We, so Far, Missed a Crucial Point? PMID- 29975205 TI - New Worlds to Conquer. PMID- 29975206 TI - Emotional Influences on Cognitive Processing in Fibromyalgia Patients With Different Depression Levels: An Event-related Potential Study. AB - OBJECTIVES: Comorbid symptoms in fibromyalgia (FM) syndrome, such as mood disorders and cognitive dysfunction, may lead to greater functional impairment than pain itself. This study aimed to unravel the modulating role of depression in response execution and inhibition in FM using an emotional go/no-go task. MATERIALS AND METHODS: In total, 17 FM patients with low depression, 18 FM patients with high depression, and 18 pain-free controls were included. Pain, happy, and neutral faces were pseudorandomly presented, and participants were asked to respond to male faces (go trials) by pressing a button, and to inhibit their responses if female faces were presented (no-go trials). RESULTS: FM patients with high depression showed lower positive affect scores, higher negative affect and pain vigilance scores, and slower reaction times, than FM patients with low depression and pain-free controls. Both subgroups of FM patients also rated pain faces as more arousing than pain-free controls. The lack of group differences in our electrophysiological data, neither in N200 nor in P300 amplitudes, seems to indicate that there was no significant impairment in response execution in response inhibition due to pain. DISCUSSION: Taken together, these results add evidence to the notion that depression is associated with higher affective dysregulation and deficit of information-processing speed in FM. Furthermore, our data suggest that pain induces a bias to pain-related information, but the absence of significant group differences in event-related potential amplitudes, calculated with analyses of covariance (ANCOVA) (with pain intensity), seem to show that pain intensity is not a predictor for cognitive dysfunctions. PMID- 29975207 TI - Folate Supplementation for Methotrexate Therapy in Patients With Rheumatoid Arthritis: A Systematic Review. AB - OBJECTIVE: To review the evidence for benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), to assess whether or not folate supplementation would reduce MTX toxicity or reduce MTX benefits, and to decide whether a higher MTX dosage is essential. METHODS: We performed a sensitive search strategy and searched systematically the Medline, Embase, Web of Science and Cochrane Library databases from inception to 2 June 2016. Abstracts from major rheumatology meetings and major trial registers were also searched to retrieve all randomized controlled trials that interested us. RESULTS: Seven studies with 709 patients were included. No significant heterogeneity was found between these trials. For RA patients treated with MTX, those supplied with folate were less likely to have elevated transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [P < 0.00001]) and gastrointestinal side-effects such as nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [P = 0.04]). Folate appeared to promote compliance to MTX as it reduced patient withdrawal compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [P < 0.00001]). There was no statistical difference for mouth sores between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [P = 0.35]). As the markers of disease activity in those trials were not consistent, it was impossible to decide whether folate supplementation reduced MTX efficacy. Besides, we compared high-dose folate (>=25 mg per week) and low-dose folate (<=10 mg per week) on MTX efficacy, finding no statistical difference (OR 2.07; 95% CI 0.81, 5.30 [P = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [P = 0.19]). CONCLUSION: Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA. It can also reduce patient withdrawal from MTX treatment. Although it tended to reduce mouth sores, it had no statistical significance. No significant difference was found between high-dose folate and low-dose folate on MTX efficacy or toxicity. PMID- 29975208 TI - Early Results of Penetrating Keratoplasty in Patients With Unilateral Chemical Injury After Simple Limbal Epithelial Transplantation. AB - PURPOSE: To evaluate clinical outcomes of sequential PKP in eyes with unilateral chemical injury, which have previously undergone autologous simple limbal epithelial transplantation (SLET) at a tertiary eye center in North India. METHODS: This is a single-center, retrospective, noncomparative interventional case series reviewing patients with unilateral limbal stem cell deficiency treated by SLET and sequential PKP between 2012 and 2017. The primary outcome was defined as allograft survival, defined as a completely epithelialized, clear, avascular graft. The secondary outcome was improvement in best-corrected visual acuity by 2 lines or any complications. RESULTS: Seven eyes of 7 patients, all aged below 40 years, who underwent SLET followed by PKP for unilateral ocular surface injury were included. Most of the patients were male (71.4%), and alkali injury (42.8%) was the most common cause of limbal stem cell deficiency. The mean duration between SLET and PK was 9.5 +/- 11.9 months (2-36 mo), and the mean follow-up duration after PKP was 15.1 +/- 5.4 months (6-21 mo). A successful outcome after SLET was achieved in all 7 patients and clear grafts in 6 patients, with a graft survival rate of 85% at 6 months. Visual success was noted in 4 patients. Poor vision in 3 patients was due to glaucoma, amblyopia, and graft failure. CONCLUSIONS: PKP was found to have a good outcome when the surface has been stabilized by SLET as an initial procedure in unilateral ocular chemical injury. The visual outcome was restricted mainly by other causes such as glaucoma and amblyopia. PMID- 29975209 TI - Mindfulness and Cognitive Training in a CBT-resistant Patient With Gambling Disorder: A Combined Therapy to Enhance Self-control. AB - : Despite the major health consequences of problem gambling, such as suicide, over-indebtedness, delinquency, or family problems, there is currently no approved drug available for the treatment of problem gambling. The efficacy of cognitive behavioral therapies (CBTs) has been demonstrated repeatedly. However, some people seem resistant to conventional CBT alone. We present the case of a 59 year-old woman with a gambling disorder, who relapsed, despite a CBT-based intervention, and who then received a combined therapy aiming to enhance self control: a mindfulness-based therapy and cognitive training targeting inhibition. PMID- 29975210 TI - ISMICS Membership Application. PMID- 29975211 TI - Choosing Between Daily and Event-Driven Pre-exposure Prophylaxis: Results of a Belgian PrEP Demonstration Project. AB - BACKGROUND: Daily pre-exposure prophylaxis and event-driven pre-exposure prophylaxis (PrEP) are efficacious in reducing HIV transmission among men who have sex with men (MSM). We analyzed baseline data from a PrEP demonstration project "Be-PrEP-ared" in Antwerp, Belgium, to understand preferences for daily PrEP or event-driven PrEP among MSM at high risk of HIV and factors influencing their initial choice. METHODS: Cross-sectional data from an open-label prospective cohort study, using mixed methods. Participants who preregistered online were screened for eligibility and tested for sexually transmitted infections (STIs). Eligible participants chose between daily PrEP and event driven PrEP and reported on behavioral data through an electronic questionnaire. In-depth interviews were conducted with a selected subsample. Bivariate associations were examined between preferred PrEP regimens and sociodemographic factors, sexual behavior, and STIs at screening. RESULTS: In total, 200 participants were enrolled between October 2015 and December 2016. Self-reported levels of sexual risk-taking before enrollment were high. STI screening revealed that 39.5% had at least 1 bacterial STI. At baseline, 76.5% of participants preferred daily PrEP and 23.5% event-driven PrEP. Feeling able to anticipate HIV risk was the most frequent reason for preferring event-driven PrEP. Regimen choice was associated with sexual risk-taking behavior in the past 3 months. Almost all participants (95.7%) considered it likely that they would change their dosing regimen the following year. CONCLUSION: Event-driven PrEP was preferred by 23.5% of the participants, which better suits their preventive needs. Event driven PrEP should be included in PrEP provision as a valuable alternative to daily PrEP for MSM at high risk of HIV. PMID- 29975213 TI - Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics. AB - Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival. PMID- 29975212 TI - Skeletal muscle and solitary bone metastases from malignant melanoma: multimodality imaging and oncological outcome. AB - Malignant melanoma solitary metastases to bone or skeletal muscle occur in 0.8% of patients. The aim of this study was to evaluate features of skeleton and muscle metastases with multimodality imaging and review the oncological outcome. Thirteen patients with melanoma metastases from January 2006 to February 2016 were included. Histologic confirmation was obtained. Imaging studies included computed tomography (CT), MRI, and/or positron emission tomography/CT. Treatment received and BRAF status were recorded. Differences in BRAF status and overall survival (OS) were analyzed using the chi-test. Associations between OS and metastases were analyzed using Cox proportional models. Nine (69%) patients showed osseous involvement. Lower extremity bones were affected in three (23%) patients: first toe, right calcaneal spurs, and knee. The spine was involved in three (23%) patients. In two (15%) patients, the pelvic bones were involved. In one (8%) patient, the temporal bone was affected. Nine (70%) patients had a history of malignant melanoma, with a median time to progression of 28 months. The median OS was 18 months: 24 months in patients with a history of melanoma and 3 months in patients with metastases at first diagnosis. The median follow-up duration was 28 months. BRAF mutant versus wild-type tumors showed significant differences in OS (P=0.03). The hazard ratio for death in the metastatic group at diagnosis was 6.83, 95% confidence interval: 1.060-144.072 (P=0.04). Solitary metastases from melanoma to the skeleton and muscle are rare. CT, MRI, and positron emission tomography/CT are useful for the evaluation of musculoskeletal findings. Image findings are not definitive for diagnosing a malignant solitary lesion; thus, a pathologic confirmation with a biopsy is recommended. PMID- 29975214 TI - Fractionated elution of 99Mo/99mTc generators using calibrated vials. AB - Fractionated elution consists in collecting the fractions of an eluate with the highest radioactive concentration. It may be useful to meet the requirements of a subset of clinical radiopharmacy procedures. This study aims to describe and evaluate straightforward procedures allowing to readily perform fractionated elution on dry and wet columns Mo/Tc generators by using calibrated vials. The main objectives of this study consisted in determining the relationship between eluate volume and elution yield using different vials calibration and assessing repeatability of the procedure. Elution vials were calibrated to obtain different eluate volumes by addition of air for wet column generator (WCG) and subtraction of saline for dry column generator (DCG) (n>=5 for each calibration). The relationship between the eluate volume and the elution yield was determined by a regression model for both DCG and WCG. Then repeatability evaluation was performed using 3-ml vial calibration. Relationships between the eluate volume (V) and the elution yield (Y) for DCG and WCG were Y=57.551 ln(V)+10.526 and Y=50.256 ln(V)+17.597, respectively. For repeatability assessment (n=30 for DCG and n=31 for WCG), the median volume and the interquartile range for DCG and WCG were 2.98 ml (2.92-3.01) and 3.28 ml (2.71-3.40), respectively, and median (interquartile range) eluate yields were 84.73% (81.30-86.33) and 81.78% (78.91 85.20), respectively. The volume was significantly higher for WCG than DCG (P=0.036) and also significantly more variable (P<0.001). The elution yield was significantly lower for WCG than DCG (P=0.025), but no difference in variability between the two generators was found (P=0.874). Easy-to-handle fractionated elution methods are compatible with both DCG and WCG. Fractionation using calibrated vials exhibits a better reproducibility with DCG than WCG generators and represents the only proposed method so far to master fractionated elution with DCG. PMID- 29975215 TI - Medication Administration Errors: Perceptions of Jordanian Nurses. AB - BACKGROUND: Medication administration errors (MAEs) have short- and long-term implications on patients' health as well as on hospitals' accreditation and financial status. PURPOSE: The purpose was to explore Jordanian nurses' perceptions about MAEs. METHODS: A cross-sectional design was used with a convenience sample of 470 nurses. RESULTS: The most common types of MAEs were wrong time (32.6%) and wrong patient (30.5%). In addition, night shifts accounted for 42.9% of MAEs; the factor that contributed the most to MAEs was workload. CONCLUSION: Developing effective quality assurance programs in relation to medications and medication administration in all Jordanian health care settings is vital to ensure patient safety. Nursing educators in clinical and academic settings need to reinforce the importance of medication rights as well as medication calculation. A distraction-free zone should be created and reinforced in all medication rooms. PMID- 29975216 TI - Quality of Pediatric Emergency Care as Assessed by Children and Their Parents. AB - BACKGROUND: Pediatric patients comprise a large user group for emergency services. However, few studies have concerned the views of children and parents on emergency care. PURPOSE: To describe and compare assessments of the quality of pediatric emergency care by children and their parents. METHODS: Ninety-eight children and their parents from 4 emergency departments participated in the survey. Data were analyzed using descriptive methods and logistic regression analysis. RESULTS: Participants considered emergency care of high quality. Although children and parents gave similar assessments, children gave lower scores than parents on children's ability to participate in care and private discussions with emergency staff. The predicting factors for children's and their parents' satisfaction with emergency department care were the parents' vocational degree and fewer visits of the child to the emergency department within the current year. CONCLUSIONS: Pediatric emergency care should focus on innovative ways of improving children's involvement in their care. PMID- 29975217 TI - Implementation Strategies to Improve Evidence-Based Bathing Practices in a Neuro ICU. AB - BACKGROUND: Evidence supports daily bathing using chlorhexidine gluconate (CHG) cloths to decrease preventable hospital-acquired central line-associated bloodstream infections (CLABSIs). However, implementation of this practice is inconsistent. Using multifaceted strategies to promote implementation is supported in the literature, yet there is a gap in knowing which strategies are most successful. PURPOSE: Using the Grol and Wensing Model of Implementation as a guide, the purpose of this study was to determine whether using tailored, multifaceted strategies would improve implementation of daily CHG bathing and decrease CLABSIs in a large neuro ICU. METHODS: An observational pre-/postdesign was used. RESULTS: Following implementation, infection rates decreased (P = .031). Statistically significant improvements were also seen across all process measures: bathing documentation, nursing knowledge, and perceived importance of CHG bathing. CONCLUSIONS: This study assists in closing the research-practice gap by using tailored, multifaceted implementation strategies to increase use of evidence-based nursing care for infection prevention practices. PMID- 29975219 TI - The All of Us Research Program: One size does not fit all. PMID- 29975218 TI - Nurses' Perception of the Impact of Electronic Documentation on the Nurse-Patient Relationship. AB - BACKGROUND: While there are many benefits of electronic medical record documentation, the presence of a computer may adversely affect provider-patient interaction. PURPOSE: The purpose of this project was to examine staff nurses' perception of the impact of electronic documentation in the presence of the patient on the nurse-patient relationship. METHODS: A survey was administered to 276 staff nurses, and open-ended interviews were conducted with 11 novice and 20 expert nurses. RESULTS: Nurses identified benefits and challenges to electronic medical record documentation as well as strategies used to maintain therapeutic relationships and communication. Numerous nurses commented that documenting with their back to the patient had a negative impact on the nurse-patient relationship and communication. CONCLUSIONS: Both novice and expert nurses identified strategies that they used to ensure they were "maintaining the connection" to patients during electronic medical record documentation. PMID- 29975220 TI - Anaesthesiology and ethics: Autonomy in childbirth. PMID- 29975221 TI - Cannot oxygenate, cannot intubate in small children: Urgent need for better data! PMID- 29975222 TI - The performance of ultrasound-based quantification of the hyomental distance ratio in predicting difficult airway in anaesthesia: A STARD-compliant prospective diagnostic study. PMID- 29975223 TI - Limited maximal mouth opening in patients with spinal muscular atrophy complicates endotracheal intubation: An observational study. PMID- 29975224 TI - Comparison of the ease of tracheal intubation using a McGrath Mac videolaryngoscope and a standard Macintosh laryngoscope in normal airways: A randomised trial. PMID- 29975225 TI - The European Society of Anaesthesiology research support programme at 15 years. PMID- 29975226 TI - Dexamethasone and postoperative cognitive decline. PMID- 29975227 TI - Reply to: dexamethasone and postoperative cognitive decline. PMID- 29975228 TI - Quality of evidence in Cochrane systematic reviews in anaesthesia, critical care and emergency medicine. PMID- 29975229 TI - Reply to: quality of evidence in Cochrane systematic reviews in anaesthesia, critical care and emergency medicine. PMID- 29975230 TI - A Novel Technique for Correcting Radial Length and Translation in Distal Radius Fractures. AB - We describe a novel technique in correcting distal radius fractures deformed with significant shortening or coronal plane translation in both the acute or chronic setting. The technique involves using a modified push-pull device to assist the surgeon in correcting length and/or translation of the articular block without the use additional hardware outside of the volar plate. PMID- 29975231 TI - Interrelatedness of Distress Among Chinese-Speaking Patients and Family Caregivers. AB - BACKGROUND: Cancer is a family disease, affecting the individual patient and the family. For Chinese patients and their families in Canada, adjusting to cancer may be particularly distressing when culture and language are not congruent with the mainstream model of care delivery. OBJECTIVE: In view of the limited research on the cancer experience of Chinese families, this study aims to examine the interrelatedness of patients and family caregivers' distress among a Chinese speaking cancer population in Canada. METHODS: Semi-structured interviews were conducted with a purposive sample of 10 Chinese-speaking cancer patients and 6 family caregivers. Qualitative analysis of the interview data was conducted to construct cross-cutting themes regarding the experiences of distress after a cancer diagnosis. RESULTS: Four overarching themes emerged from the analysis: (1) misconception about cancer, (2) tensions in disclosure, (3) patient and family caregiver distress, and (4) concealing emotion in patient and family caregiver. Notably, the interrelatedness of patients and family caregivers' distress was highlighted, as patients and family caregivers both sought to regulate their own emotions to protect one another's mental well-being. CONCLUSION: The study provides insights into the distress of living with cancer and the impact on family relationships. Understanding the patients and family members' cultural and social contexts also provides the foundation for patient- and family-centered care. IMPLICATIONS FOR PRACTICE: Healthcare professionals can provide culturally appropriate care by recognizing the needs, values, and beliefs of cancer patients and their families. Furthermore, the patient-family caregiver dyad needs to be considered as the unit of care. PMID- 29975232 TI - Resident Attrition in Plastic Surgery: A National Survey of Plastic Surgery Program Directors. AB - BACKGROUND: Attrition in plastic surgery is poorly characterized in the literature with previous data indicating that independent residents may have a higher rate of voluntary attrition with integrated residents having a higher rate of involuntary attrition. The aim of this study is to identify risk factors, note differences between pathways, and provide insight into resident attrition from plastic surgery residencies. METHODS: An institutional review board-approved anonymous, multiple-choice and short answer, online survey regarding resident attrition was sent to all plastic surgery program directors (PDs) in the United States focusing from 2003 to 2013. Outcomes measured included demographics of the program and attritional resident, timing and reasons for attrition, and possibility of preventing attrition. RESULTS: Thirty-three (35%) of 95 PDs responded. Average attrition rates were calculated at 2.15% for independent and 0.85% for integrated programs. Risk factors for attrition included being single, divorced, male, and having no dependents. One hundred percent of independent residents left by year 2, and 86% of integrated residents left by year 4. Lifestyle and loss of interest were most sited reasons for attrition. Most independent residents returned to their original field of training, whereas integrated residents were more likely to transfer to another integrated program. Only 17% of PDs believed attrition could have been prevented. CONCLUSIONS: Approximately 3.0% of all plastic surgery residents underwent attrition. Being single, male, divorced, or having no dependents increases the risk of attrition in plastic surgery residencies. This is the first study to demonstrate potential risks factors for plastic surgery residents undergoing attrition. PMID- 29975233 TI - Long-term Outcomes After Pediatric Free Flap Reconstruction. AB - INTRODUCTION: Whereas free tissue transfer has evolved to minimize morbidity in adults, less is known about outcomes after free flaps in children. This study sought to assess short- and long-term outcomes after microvascular reconstruction in the pediatric population. METHODS: Short- and long-term outcomes of free tissue transfer were assessed using chart-review and quality-of-life surveys. The Pediatric Outcomes Data Collection Instrument was used to evaluate overall health, pain, and ability to participate in normal daily and more vigorous activities. Patient or parent responses were compared against normative data. RESULTS: Forty-two patients underwent 48 flap reconstructions at a mean age of 8 years. Median follow-up was 14.9 years. Indications included congenital nevi (n = 19, 42%), lymphatic/vascular malformations (n = 8, 19%), and trauma/burns (n = 6, 14%). There were 21 fasciocutaneous (44%), 19 muscle/myocutaneous (40%), 6 fascial/peritoneal (13%), and 2 osteocutaneous flaps (4%). Major flap complications were observed in 4 patients (9%), whereas major donor-site complications occurred in 2% (1 patient). Valid contact information was available for 25 patients; 16 of these completed surveys (64%). Pediatric Outcomes Data Collection Instrument scores for mobility (median, 52), sports/physical functioning (median, 56), happiness (median, 50), and pain/comfort (median, 56) were not significantly different from normative population score of 50. Similarly, median global functioning score was 99 (maximum, 100) and did not differ between flap types. DISCUSSION: Free tissue transfer in the pediatric population is reliable and well-tolerated over time. Surgeons should not hesitate to use free flaps when clinically indicated for pediatric patients. PMID- 29975234 TI - Reply to "Ablation of Apocrine Glands With the Use of a Suction-Assisted Cartilage Shaver for Treatment of Axillary Osmidrosis: An Analysis of 156 Cases" Annals of Plastic Surgery March 2009;62(3):278-283. PMID- 29975235 TI - Surgical Resection of Occult Subungual Glomus Tumors: Cold Sensitivity and Sonographic Findings. AB - PURPOSE: We surgically treated subungual masses that were suspected glomus tumors, although definitive clinical and radiological findings were lacking. We report the outcomes of a retrospective case series. METHODS: Of 42 patients treated by surgical resection between March 1996 and December 2015, 7 who met our inclusion/exclusion criteria were evaluated. At least 1 symptom of the typical triad (temperature sensitivity, severe pain, and localized tenderness) was absent, and computed tomography (CT) and magnetic resonance imaging (MRI) findings were normal. After ultrasonographic evaluation, we resected the masses using a transungual approach or a nail-preserving method. After pathological confirmation of the diagnosis, we followed all patients for at least 2 years to evaluate tumor recurrence and nail deformity. RESULTS: In 5 patients, cold sensitivity was the only symptom; no physical finding was suggestive of a glomus tumor. Tenderness was evidenced by the 2 patients who lacked cold sensitivity. None of the 7 patients exhibited CT or MRI abnormalities, but small acoustic shadows were evident in 4 patients, and blood-rich nodules were noted in 2 patients. The mean diameter of the 7 tumors was 2.1 mm, and pathological examination revealed typical glomus bodies. No major surgery-associated complication developed during follow-up. The final mean visual analog scale score (assessing pain) improved to 0.3 from the mean preoperative value of 3.6. CONCLUSIONS: Small glomus tumors exhibit few traditional symptoms and signs and no definitive radiological CT/MRI finding. However, cold sensitivity alone is a powerful surgical indication, and occasionally, ultrasonographic findings are useful even in the absence of CT/MRI findings. PMID- 29975236 TI - Should Constricted Ear Be Treated as Auricular Malformation or Deformity? PMID- 29975237 TI - Commentary on Intraoperative Analgesic Consumption and Hospital Discharge Criteria in Select Reduction Mammaplasty Patients: A Closer Look. PMID- 29975238 TI - Intraoperative Analgesic Consumption and Hospital Discharge Criteria in Select Reduction Mammaplasty Patients: A Closer Look. PMID- 29975239 TI - Acupuncture, Its Place in Holistic Care: Granting Access to This Critical and Timely Exposition on the Art of This Modality. AB - Traditional Chinese medicine remains a valuable portal into an alternative way of perceiving health and illness. In view of holistic health care, this article supports nursing professionals embracing the concept and the skill of acupuncture as a great gift to empower them to expand on their already remarkable capacity in the nursing profession. PMID- 29975240 TI - How We Approach Combination Antifungal Therapy for Invasive Aspergillosis and Mucormycosis in Transplant Recipients. AB - Invasive aspergillosis and mucormycosis are life-threatening infections in solid organ and hematopoietic cell transplant recipients. Despite medical advancements in the care of these patients and the availability of new mold-active drugs, the outcomes remain suboptimal. Therefore, there has been increased interest in the use of combination antifungal therapy, in hopes that leveraging the possible in vitro synergy of these agents will improve the prognosis of invasive mold disease. However, there has been a large disconnect between the results of experimental and clinical investigations, as clinical studies have not unequivocally demonstrated the superiority of combination therapy over monotherapy. This is particularly true for mucormycosis, where the rarity of the condition has made it nearly impossible to prospectively study novel therapeutic strategies. We review the current standard of antifungal therapy and the preclinical and clinical data addressing the merit of combination therapy, and we provide guidance to optimize the management of these mycoses. PMID- 29975241 TI - Functional Maturation and In Vitro Differentiation of Neonatal Porcine Islet Grafts. AB - BACKGROUND: There is a strong rationale to pursue the use of neonatal porcine islets (NPIs) as an unlimited source of islets for clinical xenotransplantation. Because NPIs are composed of immature insulin producing beta (beta) cells and ductal precursor cells, they provide an ideal model to examine culture conditions to enhance beta cell proliferation and/or beta cell neoformation from ductal cells. In an attempt to optimize the potential of NPIs as a source of beta cell grafts, we used an in vitro differentiation protocol and measured its effect on the functional maturation and differentiation of NPIs. METHODS: Pancreata from 1- to 3-day-old neonatal pigs were digested and cultured in standard Ham's F10 media for 5 days. Each independent preparation was then further cultured in Dulbecco's modified Eagle medium nutrient mixture-F12 differentiation media containing growth factors added in a stepwise fashion, or cultured in control Ham's F10 media. After 20 days in culture, islets were assessed for insulin secretory capacity, cellular composition, gene expression, and metabolic activity after transplantation in immunodeficient mice with diabetes. RESULTS: Compared with control islets, differentiated islets exhibited a significantly higher proportion of endocrine cells, proliferating cell nuclear antigen double positive beta cells, and an enhanced glucose-stimulated insulin secretory activity. Mice transplanted with differentiated islets had significantly lower blood glucose values at weeks 18 and 20 compared with nondifferentiated controls and were shown to be more glucose tolerant. CONCLUSIONS: Culturing NPIs in a 20-day stepwise differentiation media increases the proportion of endocrine cells and augments both in vitro and in vivo function of the islets. PMID- 29975242 TI - Optimized thiopurine therapy before withdrawal of anti-tumour necrosis factor alpha in patients with Crohn's disease. AB - OBJECTIVE: Two meta-analyses have found that the risk of relapse in Crohn's disease (CD) was ~40 and 50% 1 and 2 years, respectively, after withdrawal of anti-tumour necrosis factor-alpha (anti-TNFalpha). The aim of this study was to evaluate relapse rates in CD when thiopurine therapy was optimized before anti TNFalpha withdrawal. PATIENTS AND METHODS: An observational study was conducted including patients with CD in remission with optimized thiopurine therapy before anti-TNFalpha withdrawal. We defined optimized thiopurine therapy as 6 thioguanine levels of at least 150 nmol/mmol haemoglobin (~300 pmol*10 red blood cells) and clinical/biochemical remission as Harvey-Bradshaw Index of 5 or less and faecal calprotectin of 200 ug/g or less. RESULTS: We included 33 patients (median age: 31 years, 55% males, and median disease duration: 7 years) followed for a median of 36 months. A total of three (9%) patients relapsed during the first year and six patients (in total 27%) relapsed after 2 years. After 2 years, none of the additional patients relapsed. The disease duration and duration of anti-TNFalpha treatment and faecal calprotectin levels before inclusion did not predict relapse. Calprotectin levels of at least 180 after 1 year predicted relapse at year 2. CONCLUSION: This study found that 73% of patients with CD maintained remission (>2 years) when thiopurine therapy was optimized before withdrawal of anti-TNFalpha. Additional prospective evidence is needed to confirm the findings. PMID- 29975243 TI - Treatment of hepatitis C with direct-acting antivirals significantly reduces liver-related hospitalizations in patients with cirrhosis. AB - BACKGROUND: The availability of direct-acting antivirals (DAA) for the treatment of hepatitis C (HCV) has resulted in the ability to safely and effectively treat patients with cirrhosis and end-stage liver disease. However, information is limited with regard to the impact of DAA treatment on inpatient health-related resource utilization in patients with advanced HCV-related cirrhosis. We aimed to ascertain the impact of DAA treatment on the frequency of liver-related hospitalizations and associated costs in patients with cirrhosis. PATIENTS AND METHODS: Retrospective cohort analysis carried out at a single US reference center that compared patients with HCV cirrhosis according to treatment status: the untreated group (January 2011 to December 2013) and the DAA-treated group (January 2014 to March 2017). The primary outcome was the difference in the incidence rate of liver-related hospitalizations. Secondary outcomes included differences in the incidence of hepatocellular carcinoma, liver transplant, and all-cause mortality. We calculated the projected savings per-patient treated per year on the basis of calculated hospitalization rate stratified by Child Turquotte-Pugh (CTP) score. RESULTS: Baseline characteristics were similar between the untreated (n=182) and DAA-treated (n=196) cohorts. Mean follow-up time in the untreated and treated cohort was 20.4 and 17.7 months, respectively. The incidence rates of liver-related hospitalizations were 29.1/100 and 10.4/100 person-years of follow-up (P<=0.0001) in the untreated and treated cohorts, respectively. This was accounted for by a decreased incidence of hospitalizations in patients with CTP-A (75.8%) and CTP-B (64.5%), but not CTP-C. CONCLUSION: Successful DAA treatment reduces hospitalization rate and resource utilization costs in patients with CTP-A and CTP-B, but not in those with CTP-C. PMID- 29975244 TI - Assessment of a glyoxalase I frameshift variant, p.P122fs, in Japanese patients with schizophrenia. AB - Enhanced carbonyl stress has been observed in a subgroup of patients with schizophrenia. Glyoxalase I, which is encoded by GLO1, is an enzyme that protects against carbonyl stress. In this study, we focused on the association between rare genetic variants of GLO1 and schizophrenia. First, we identified one heterozygous frameshift variant, p.P122fs, in 370 Japanese schizophrenia cases with allele frequencies of up to 1% by exon-targeted mutation screening of GLO1. We then performed an association analysis on 1282 cases and 1764 controls with this variant. The variant was found in three cases and eight controls. There was no statistically significant association between p.P122fs in GLO1 and schizophrenia (P=0.25). This frameshift variant in GLO1 might occur at near polymorphic frequencies in the Japanese population, although further investigations using larger samples and biological analyses are needed to exclude the possibility of a low-penetrance genetic risk associated with this variant. PMID- 29975245 TI - Poorly Differentiated Nonkeratinizing Squamous Cell Carcinoma of the Thymus: Clinicopathologic and Molecular Genetic Study of 25 Cases. AB - Thymic carcinoma represents a rare and poorly understood type of thymic epithelial neoplasm that has been the subject of much controversy. Poorly differentiated nonkeratinizing squamous cell carcinoma, also known as lymphoepithelioma-like thymic carcinoma, is a rare variant of thymic carcinoma that has not been adequately characterized in the literature. The clinicopathologic, immunohistochemical, ultrastructural, and molecular features of 25 cases are reported. The patients were 19 men and 6 women, ranging in age from 20 to 85 years (mean: 60 y). The tumors presented clinically as anterior mediastinal masses with chest pain and shortness of breath or were found incidentally on imaging studies. Tumor size ranged from 2.0 to 13.5 cm in greatest diameter. Most of the tumors were small, well-circumscribed and confined to the mediastinum. Five cases presented with large, bulky, and infiltrative masses. Histologically, the hallmark of these tumors was a neoplastic proliferation of large, round to oval cells with vesicular nuclei, prominent eosinophilic nucleoli, and scant cytoplasm. Two histologic growth patterns were identified: tumors with a heavy lymphoplasmacytic stroma (lymphoepithelioma-like pattern), and tumors showing abundant desmoplastic stroma (desmoplastic pattern). Immunohistochemical stains showed strong positivity of the tumor cells for cytokeratin AE1/AE3, CK5/6, CK18, MOC31, p16, p40, and p63. MIB-1 showed on average 35% nuclear positivity. CD117 was positive in 21/25 cases and CD5 in 20/25 cases. Epstein-Barr encoded RNA in situ hybridization was positive in only 1 case. Electron microscopy in 4 cases showed primitive round to oval cells with prominent nucleoli, scant cytoplasm and immature cell junctions. Molecular features were studied by next-generation sequencing using high quality sequence data obtained from 18 patients. Variants with allele frequency between 5% and 45% and quality scores >50 were classified as somatic. A total of 16/18 cases had one or more somatic variants of unknown significance. One case showed an IDH1 p. R132C mutation, also of unknown significance. No "actionable" genes amenable to currently available targeted therapies were identified in this cohort. Clinical follow-up was obtained in 20 patients; 14 patients were alive and well with no evidence of disease between 1.5 and 16 years after diagnosis (median survival: 4 y; mean: 5.5 y). Most survivors had relatively small tumors (<5 cm. diameter), were in stage I and II at diagnosis and showed clear surgical margins. Five patients died of their tumors with metastases to bone, brain, chest wall, lungs and lymph nodes; all were in advanced stages and showed positive margins. Prognosis for these tumors appears to be correlated with the staging and status of the margins at the time of initial surgery. PMID- 29975247 TI - Pyloric Gland Adenoma (PGA) of the Gallbladder: A Unique and Distinct Tumor from PGAs of the Stomach, Duodenum, and Pancreas. AB - Twenty-four surgically resected, gallbladder pyloric gland adenomas (GB-PGAs) were examined and their features were compared with the reported features of stomach, duodenum, and pancreatic PGAs to better understand GB-PGAs. Clinical information on background gallbladder lesions and histologic data, including tumor grade, existence of squamoid morules, intratumoral cholesterosis, and intracytoplasmic mucins were collected. Immunohistochemical staining for MUC2, MUC5AC, MUC6, CDX2, pepsinogen I, p53, and MIB-1/nuclear beta-catenin were evaluated. Targeted mutational analyses of KRAS exon2, GNAS exon 7, and CTNNB1 exon 3 were conducted. We found that 29.2% of the GB-PGAs were histologically high-grade dysplasias/carcinomas; 70.8% were low grade; and 20.8% and 33.3% contained squamoid morules and intratumoral cholesterosis, respectively. In addition, 45.8% and 54.2% of GB-PGAs were mucin-rich and mucin-poor types, respectively. Immunohistochemically, MUC6 was diffusely positive in all GB-PGAs; MUC2, MUC5AC, and CDX2 were only focally positive, and no pepsinogen-I positive cells were observed. Nuclear beta-catenin accumulation was observed in all cases; however, the ratio varied among cases. Mucin-poor types were significantly associated with high histologic grade dysplasias/carcinomas and high nuclear beta catenin labeling indices. Mutational analyses identified CTNNB1 mutations in 100% of GB-PGAs (21/21), KRAS in 4.2% (1/23), and GNAS in 0% (0/22). The present study clarified the unique histologic features, phenotypic differentiation, and molecular statuses frequently associated with GB-PGAs. Altogether, our data suggest that tumorigenesis of GB-PGA is distinct from that of stomach, duodenum, and pancreatic PGAs. PMID- 29975248 TI - Frequent GNAQ and GNA14 Mutations in Hepatic Small Vessel Neoplasm. AB - Hepatic small vessel neoplasm (HSVN) is a recently described infiltrative vascular neoplasm of the liver, composed of small vessels. Although the infiltrative nature can mimic angiosarcoma, HSVN are thought to be benign or low grade neoplasms because they lack cytologic atypia and increased proliferation. To characterize the molecular pathogenesis of HSVN, we performed both targeted panel sequencing and exome sequencing on 18 benign or low-grade vascular neoplasms in the liver including 8 HSVN, 6 classic cavernous hemangioma (CH), and 4 variant lesions (VL) with overlapping features between HSVN and CH. All 18 lesions had simple genomes without copy number alterations. In total, 75% (6/8) of HSVN demonstrated known activating hotspot mutations in GNAQ (2/8, p.Q209H) or GNA14 (4/8, p.Q205L), and the remaining 2 had the same missense mutation in GNAQ, p.G48L, which has not been previously described. 25% (1/4) of VL had a hotspot GNAQ p.Q209H mutation and another VL had a GNAQ p.G48L mutation. Known pathogenic mutations were not identified in any of the 6 CH. These data suggest that HSVN share a similar molecular biology to several other vascular lesions (congenital hemangioma, tufted angioma, anastomosing hemangioma, lobular capillary hemangioma, and kaposiform hemangioendothelioma) recently reported to have GNAQ, GNA11, or GNA14 mutations. PMID- 29975246 TI - The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profiling and Implications for Treatment. AB - The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2013 guidelines for HER2 assessment have increased the number of HER2 equivocal breast carcinomas following in situ hybridization reflex testing, that is, HER2 "double equivocal" (equivocal protein expression and equivocal gene copy number). Forty-five double-equivocal carcinomas were subjected to Prosigna analysis. Twenty-seven cases were investigated for the expression of genes found to be differentially expressed between estrogen receptor (ER)-positive/HER2 positive (N=22) and ER-positive/HER2-negative (N=22) control cases. Twenty-nine of the 45 cases were also analyzed by targeted sequencing using a panel of 14 genes. We then explored the pathologic complete response rates in an independent series of double-equivocal carcinoma patients treated with trastuzumab-containing chemotherapy. All cases were ER-positive, with a mean Ki67 of 28%. Double equivocal carcinomas were predominantly luminal B (76%); 9 cases (20%) were luminal A, and 2 cases (4%) HER2-enriched. The majority (73%) showed a high risk of recurrence by Prosigna, even when the carcinomas were small (<2 cm), node negative/micrometastatic, and/or grade 2. Double-equivocal carcinomas showed TP53 (6/29, 20%), PIK3CA (3/29, 10%), HER2 (1/29, 3%), and MAP2K4 (1/29, 3%) mutations. Compared with grade-matched ER-positive/HER2-negative breast carcinomas from METABRIC, double-equivocal carcinomas harbored more frequently TP53 mutations and less frequently PIK3CA mutations (P<0.05). No significant differences were observed with grade-matched ER-positive/HER2-positive carcinomas. Lower pathologic complete response rates were observed in double equivocal compared with HER2-positive patients (10% vs. 60%, P=0.009). Double equivocal carcinomas are preferentially luminal B and show a high risk of recurrence. A subset of these tumors can be labeled as HER2-enriched by transcriptomic analysis. HER2 mutations can be identified in HER2 double equivocal cases. PMID- 29975249 TI - Eosinophilic Solid and Cystic (ESC) Renal Cell Carcinomas Harbor TSC Mutations: Molecular Analysis Supports an Expanding Clinicopathologic Spectrum. AB - Eosinophilic solid and cystic (ESC) renal cell carcinoma (RCC) has recently been described as a potentially new subtype of RCC based upon morphologic and immunohistochemical features. These neoplasms typically demonstrate solid and cystic architecture, and the neoplastic cells contain voluminous eosinophilic cytoplasm with granular cytoplasmic stippling. There is frequently focal immunoreactivity for cytokeratin 20. Although the initial cases all occurred in adult females and had benign outcome, we recently expanded the proposed spectrum of this neoplasm to include pediatric cases, multifocal neoplasms, and a case with hematogenous metastasis. ESC has been postulated to be analogous to a subtype of RCC consistently identified in tuberous sclerosis complex patients, and while previous work has demonstrated loss of heterozygosity at the TSC1 locus and copy number gains at TSC2 in ESC RCC, these genes have not been sequenced in ESC RCC. Using capture-based and amplicon-based next-generation sequencing, we now demonstrate the consistent presence of either TSC1 or TSC2 gene mutations in pediatric ESC RCC (8/9 cases) and adult ESC RCC (6/6 cases). These included a metastatic ESC RCC which had a complete response to mTOR targeted therapy. We also found these mutations in some neoplasms with variant morphology and thus potentially expand the spectrum of ESC RCC. These include one of our adult cases which demonstrated dominant "type 2" papillary RCC morphology and 2 of 3 previously unclassified pediatric RCC with features of ESC RCC minus granular cytoplasmic stippling. We also demonstrate TSC mutations in a case of so-called "oncocytoid RCC after neuroblastoma" with identical morphology and immunoprofile, providing a molecular link between the latter and ESC RCC. In summary, ESC RCC consistently harbors actionable TSC1 or TSC2 mutations, which are infrequently seen in established subtypes of RCC. These findings support TSC1/2 mutation as a molecular marker of ESC RCC, and suggest expansion of the clinicopathologic spectrum to include neoplasms with papillary architecture, occasional cases lacking well-developed granular cytoplasmic stippling, and a subset of RCC with oncocytic features in patients who have survived neuroblastoma. PMID- 29975250 TI - Molecular Profiling of Hyalinizing Clear Cell Carcinomas Revealed a Subset of Tumors Harboring a Novel EWSR1-CREM Fusion: Report of 3 Cases. AB - We describe a novel gene fusion, EWSR1-CREM, identified in 3 cases of clear cell carcinoma (CCC) using anchored multiplex polymerase chain reaction, a next generation sequencing-based technique. CCC is a low-grade salivary tumor recently characterized to have EWSR1-ATF1 fusions in the majority of cases. Three cases of malignant tumor presenting in the base of tongue, lung, and nasopharynx were studied. All cases shared a clear cell morphology with hyalinized stroma, presence of mucin and p63 positivity and were initially diagnosed as mucoepidermoid carcinoma but were negative for evidence of any of the expected gene fusions. Anchored multiplex polymerase chain reaction demonstrated a EWSR1 CREM fusion in all 3 cases to confirm a diagnosis of CCC. This finding is biologically justified as CREM and ATF1 both belong to the CREB family of transcription factors. EWSR1-CREM fusions have not been previously reported in CCC and have only rarely been reported in other tumors. We show that the ability to discover novel gene variants with next-generation sequencing-based assays has clinical utility in the pathologic classification of fusion gene-associated tumors. PMID- 29975251 TI - Human Herpes Virus 6 (HHV-6)-associated Lymphadenitis: Pitfalls in Diagnosis in Benign and Malignant Settings. AB - Human herpes virus 6 (HHV-6) is a member of the beta-herpesvirinae subfamily. Most people acquire HHV-6 primary infection early in life and reactivation may occur, most often in immunocompromised individuals, leading to various clinical manifestations. HHV-6 infected cells may be identified in lymph nodes in both reactive and neoplastic conditions. Cases were retrieved from the hematopathology consultation service archives at National Institutes of Health from 2003 to 2017 in which infection by HHV-6 had been documented by immunohistochemical stains to HHV-6 gp60/110 envelope glycoprotein. Five cases of reactive lymphadenitis and 3 cases of lymphoma; 2 angioimmunoblastic T-cell lymphoma and 1 classic Hodgkin lymphoma, positive for HHV-6 were identified. The reactive lymph nodes showed marked paracortical hyperplasia and admixed large atypical lymphoid cells exhibiting pleomorphic nuclei, vesicular chromatin, and prominent eosinophilic intranuclear inclusions. Vascular proliferation and necrosis were also present, raising suspicion of peripheral T-cell lymphoma. The 3 cases of lymphoma showed similar viral inclusions, in addition to the characteristic features diagnostic of the lymphoma. Staining for HHV-6 was positive with a membranous and Golgi pattern and was restricted to cells with evident inclusions on hematoxylin and eosin. HHV-6 infected cells were positive for CD3 and CD4. HHV-6 lymphadenitis can present with morphologic atypia creating a diagnostic pitfall for lymphoma. In such cases, careful attention to the characteristic viral inclusions can lead to immunohistochemical analysis highlighting the replicating virus. In cases of lymphoma, identification of the inclusions is key in detecting the associated infection as well as in avoiding misinterpretation of the lymphoma subtype. PMID- 29975252 TI - Managing mild TBI in adults. PMID- 29975254 TI - Obesity and Overweight Problems Among Individuals 1 to 25 Years Following Acute Rehabilitation for Traumatic Brain Injury: A NIDILRR Traumatic Brain Injury Model Systems Study. AB - OBJECTIVE: Examine the prevalence of weight classifications and factors related to obesity/overweight among persons 1 to 25 years following traumatic brain injury (TBI) using the Traumatic Brain Injury Model Systems national database. DESIGN: Multicenter, cross-sectional, observational design. SETTING: Traumatic Brain Injury Model Systems inpatient rehabilitation facilities. PARTICIPANTS: Persons (N = 7287) 1, 2, 5, 10, 15, 20, or 25 years after TBI who required inpatient acute rehabilitation. MAIN OUTCOME MEASURES: Body mass index, demographic characteristics, functional, health, satisfaction with life, and global outcomes. RESULTS: Overall postinjury weight prevalence rates were 23% obese, 36% overweight, 39% normal, and 3% underweight. Higher rates for obesity and overweight problems were associated with increasing time since injury. Younger (18-19 years) and older (80+ years) age, those in a vegetative state, and those reporting excellent health were less likely to be obese. Individuals with a history of hypertension, heart failure, or diabetes were more likely to be obese. CONCLUSIONS: Being obese or overweight presents a health risk in the years following rehabilitation for TBI. The findings support the need for longitudinal studies and highlight the advisability of monitoring weight and promoting healthy lifestyle behaviors over time in survivors of TBI. PMID- 29975255 TI - Towards a Clinical Neuroethics for Brain Injury Practice: An Introduction to a New Special Feature for Ethics in JHTR. PMID- 29975256 TI - Alterations of resting-state functional network centrality in patients with asthma: evidence from a voxel-wise degree centrality analysis. AB - Several previous studies have reported that asthma patients have abnormal brain activities, whereas alterations in the resting-state network still remain unknown. The aim of this study was to investigate the changes in functional network centrality in asthma patients using voxel-wise degree centrality (DC) method. Asthma patients and healthy controls (HCs) were matched closely in age, sex, and education of participants. The DC method was used to evaluate the functional network centrality. The receiver operating characteristic curve was used to distinguish the asthma group from the HCs group. The Pearson correlation coefficient was used to explore the relationship between the observed mean values of DC in different brain areas and the behavioral performance. Compared with HCs, DC values were significantly decreased in the right middle temporal gyrus and the right putamen of asthma patients. In contrast, in asthma patients, DC values were markedly increased in the right posterior lobe of the cerebellum, right inferior temporal gyrus, left superior frontal gyrus, left postcentral gyrus and inferior parietal lobule, left middle frontal gyrus, and left postcentral gyrus. However, there was no relationship between the observed mean DC values in different brain areas and the behavioral performance. The results showed that the DC values were altered in various brain regions of asthma patients, which were related to default mode network, the cortex-basal ganglia network, the frontoparietal network, and the sensorimotor network, leading to some useful information for clinical studies in asthma patients. PMID- 29975257 TI - Acute Pain Is Associated With Chronic Opioid Use After Total Knee Arthroplasty. AB - BACKGROUND AND OBJECTIVES: Pain scores are routinely reported in clinical practice, and we wanted to examine whether this routinely measured, patient reported variable provides prognostic information, especially with regard to chronic opioid use, after taking preoperative and perioperative variables into account in a preoperative opioid user population. METHODS: In 32,874 preoperative opioid users undergoing primary total knee arthroplasty at Veterans Affairs hospitals between 2010 and 2015, we compared preoperative and perioperative characteristics in patients reporting lower versus higher acute pain (scores <=4/10 vs >4/10 averaged over days 1-3). We calculated the propensity for lower acute pain based on all available data. After 1:1 propensity score matching, to identify similar patients differing only in acute pain, we contrasted rates of chronic significant opioid use (mean >30 mg/d in morphine equivalents) beyond postoperative month 3, discharge prescriptions, and changes in postoperative versus preoperative dose categories. Sensitivity analysis examined associations with dose escalation. RESULTS: Rates of chronic significant opioid use (21% overall) differed in patients with lower versus higher acute pain (36% vs 64% of the overall cohort). After propensity matching (total n = 20,926 patients) and adjusting for all significant factors, lower acute pain was associated with less chronic significant opioid use (rates 12% vs 16%), smaller discharge prescriptions (ie, supply <30 days and daily oral morphine equivalent <30 mg/d), and more reduction in dose, all P < 0.001. In sensitivity analysis, dose escalation was 15% less likely with lower acute pain (odds ratio, 0.85; 95% confidence interval, 0.80-0.91). CONCLUSIONS: Acute pain predicts chronic opioid use. Prospective studies of efforts to reduce acute pain, in terms of long-term effects, are needed. PMID- 29975258 TI - ASYMMETRIC HYDROXYCHLOROQUINE MACULAR TOXICITY WITH APHAKIC FELLOW EYE. AB - BACKGROUND/PURPOSE: Retinal toxicity associated with antimalarial drug use in inflammatory conditions is well described and may be more common than previously recognized. Antimalarial drugs bind to melanin in ocular tissues, particularly the retinal pigment epithelium, but the mechanism of toxicity and its relation to light is unclear. METHODS: Case report. RESULTS: A 62-year-old white woman with erosive rheumatoid arthritis developed hydroxychloroquine toxicity in her phakic eye, with her aphakic fellow eye only mildly affected. CONCLUSION: We report the clinical evaluation of this rare case of asymmetrical hydroxychloroquine retinopathy and present a hypothesis regarding the mechanism of drug toxicity. PMID- 29975259 TI - MACULAR HOLE ASSOCIATED WITH TOXOPLASMOSIS: A SURGICAL CASE SERIES. AB - PURPOSE: There are currently limited data addressing the surgical outcomes of pars plana vitrectomy (PPV) in toxoplasmosis-related macular hole (tMH). We aim to report and discuss safety and efficacy of PPV for tMH. METHODS: Surgical case series (n = 11), with minimum postoperative follow-up time of 6 months. Consecutive patients who underwent PPV for tMH from 2013 to 2016 were included. Indications for surgery were: visual acuity >= 0.6 logarithm of the minimum angle of resolution (Snellen 20/80 or less), no intraocular inflammation for more than 6 months, extrafoveal toxoplasmosis scar, elevated tMH borders on optical coherence tomography, and patient agreement with surgery. Surgery was performed PPV with epiretinal (if present) and internal limiting membrane peeling. Safety and efficacy of PPV for tMH were addressed by evaluating: 1) surgery-related complications and 2) visual acuity improvement. RESULTS: A total of 11 patients (6 male), with a mean age of 33.2 +/- 11.0 years were studied. Mean preoperative best-corrected visual acuity significantly improved from 1.10 +/- 0.24 (Snellen 20/252) to 0.43 +/- 0.18 logarithm of the minimum angle of resolution (Snellen 20/54) at last follow-up visit (P < 0.01). The rate of visual acuity improvement (i.e., a gain of at least three lines) and tMH closure was 100% for both. The only reported surgery-related complication was cataract in one case. CONCLUSION: Our results suggest that PPV is a safe and effective option in tMH cases. A controlled, longitudinal study would contribute to confirm these findings. PMID- 29975260 TI - Orbital Air Embolism After Intravenous Injection. AB - An asymptomatic air embolism in the right superior ophthalmic vein was discovered incidentally during a cerebral computed tomography, most likely due to a preceding intravenous fluid bolus. This case illustrates the potential risk of air emboli being propagated to the cerebral venous circulation during routine injections and fluid resuscitation. PMID- 29975261 TI - Congenital Oculonasal Synkinesis. AB - A 4-year-old girl with maxillary hypoplasia, intermittent exotropia, and high myopia displayed congenital oculonasal synkinesis. We examine the implications for pathogenesis of these disparate craniofacial findings. PMID- 29975262 TI - B. Todd Troost, MD (1937-2017): Erratum. PMID- 29975263 TI - Scapular Notching After Reverse Total Shoulder Arthroplasty: Prediction Using Patient-Specific Osseous Anatomy, Implant Location, and Shoulder Motion. AB - BACKGROUND: Scapular notching is frequently observed following reverse total shoulder arthroplasty (rTSA), although the etiology is not well understood. METHODS: Twenty-nine patients with preoperative computed tomography (CT) scans who underwent rTSA with a Grammont design were evaluated after a minimum of 2 years of follow-up with video motion analysis (VMA), postoperative three dimensional (3D) CT, and standard radiographs. The glenohumeral range of motion demonstrated by the VMA and the postoperative implant location on the CT were used in custom simulation software to determine areas of osseous impingement between the humeral implant and the scapula and their relationship to scapular notching on postoperative CT. Patients with and without notching were compared with one another by univariable and multivariable analyses to determine factors associated with notching. RESULTS: Seventeen patients (59%) had scapular notching, which was along the posteroinferior aspect of the scapular neck in all of them and along the anteroinferior aspect of the neck in 3 of them. Osseous impingement occurred in external rotation with the arm at the side in 16 of the 17 patients, in internal rotation with the arm at the side in 3, and in adduction in 12. The remaining 12 patients did not have notching or osseous impingement. Placing the glenosphere in a position that was more inferior (by a mean of 3.4 +/ 2.3 mm) or lateral (by a mean of 6.2 +/- 1.4 mm) would have avoided most impingement in the patients' given range of motion. Notching was associated with glenosphere placement that was insufficiently inferior (mean inferior translation, -0.3 +/- 3.4 mm in the notching group versus 3.0 +/- 2.9 mm in the no-notching group; p = 0.01) or posterior (mean, -0.3 +/- 3.5 mm versus 4.2 +/- 2.2 mm; p < 0.001). Two-variable models showed inferior and posterior (area under the curve [AUC], 0.887; p < 0.001), inferior and lateral (AUC, 0.892; p < 0.001), and posterior and lateral (AUC, 0.892; p < 0.001) glenosphere positions to be significant predictors of the ability to avoid scapular notching. CONCLUSIONS: Osseous impingement identified using patients' actual postoperative range of motion and implant position matched the location of scapular notching seen radiographically. Inferior, lateral, and posterior glenosphere positions are all important factors in the ability to avoid notching. Only small changes in implant position were needed to avoid impingement, suggesting that preoperative determination of the ideal implant position may be a helpful surgical planning tool to avoid notching when using this implant design. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975264 TI - One Dose of Intravenous Tranexamic Acid Is Equivalent to Two Doses in Total Hip and Knee Arthroplasty. AB - BACKGROUND: Tranexamic acid (TXA) helps to prevent excessive blood loss during total hip arthroplasty (THA) and total knee arthroplasty (TKA), but the most efficacious dosing protocol has not been ascertained. The purpose of this study was to identify whether 1 dose of intravenous TXA is equivalent to 2 doses for reducing blood loss and transfusion rates following THA and TKA without an increase in complications. METHODS: We identified 1,736 patients who underwent THA (592 who did not receive TXA, 454 who received 1 dose of TXA, and 690 who received 2 doses) and 2,042 patients who underwent TKA (744 who did not receive TXA, 499 who received 1 dose, and 799 who received 2 doses) from 2012 to 2016. The differences among groups with regard to the change in hemoglobin levels, rate of allogeneic blood transfusions, and rate of complications were assessed. RESULTS: Patients who underwent THA and received 1 dose or 2 doses of TXA had similar drops in the mean hemoglobin levels postoperatively (2.9 g/dL and 3.1 g/dL, respectively; p = 0.197) and both had a smaller drop than the control group (3.6 g/dL; p < 0.001 compared with the 1 and 2-dose groups). These findings were confirmed by a multivariate analysis that controlled for age, sex, and preoperative hemoglobin level. Transfusion was required for 12.5% of the patients who underwent THA without receiving TXA, no patient who received 1 dose, and 0.7% of the patients who received 2 doses. The patients who underwent TKA and received 1 dose or 2 doses of TXA had similar mean drops in the hemoglobin level postoperatively (2.4 g/dL and 2.4 g/dL, respectively; p = 0.891), and both had less of a drop than the control group (2.9 g/dL; p < 0.001 compared with the 1 and 2-dose groups). These findings were also confirmed by a multivariate analysis that controlled for age, sex, and preoperative hemoglobin level. Transfusion was required for 4.3% of the patients who underwent TKA without receiving TXA, 0.4% of those who received 1 dose, and 0.3% of those who received 2 doses. Similar rates of perioperative complications occurred among all groups. CONCLUSIONS: One dose of TXA was as effective as 2 doses for decreasing blood loss and transfusion rates after THA and TKA without an increase in complications. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975265 TI - Trabecular Metal Versus Non-Trabecular Metal Acetabular Components and the Risk of Re-Revision Following Revision Total Hip Arthroplasty: A Propensity Score Matched Study from the National Joint Registry for England and Wales. AB - BACKGROUND: Studies have suggested that Trabecular Metal (TM)-coated acetabular components may reduce implant failure following revision total hip arthroplasty. However, these studies have predominantly been limited to small, single-center cohorts, with many lacking a comparator group. Using National Joint Registry data from England and Wales, we compared re-revision rates following revision total hip arthroplasty between TM and non-TM-coated acetabular components from 1 manufacturer. METHODS: This retrospective observational study included all revision total hip arthroplasties performed with use of 1 of 4 cementless acetabular components produced by the same manufacturer (Zimmer Biomet). The acetabular components either had a TM surface coating (TM Modular and Continuum designs) or a non-TM surface coating (Trilogy and Trilogy IT designs). Revision total hip arthroplasties with TM and non-TM implants were matched for multiple potential patient and surgical confounding factors using propensity scores. Outcomes following revision total hip arthroplasty (re-revision for all acetabular indications, aseptic acetabular loosening, or infection) were compared between matched groups using competing risk regression analysis. Analyses were repeated in a subgroup initially revised for infection. RESULTS: Of 3,862 matched revision total hip arthroplasties (1,931 in the TM group and 1,931 in the non-TM group), the overall prevalence of acetabular re-revision (2.7%; 95% confidence interval [CI] = 2.1% to 3.2%), re-revision for aseptic acetabular loosening (0.96%; 95% CI = 0.68% to 1.3%), and re-revision for infection (1.4%; 95% CI = 1.0% to 1.8%) were low. Six-year rates of re-revision for all causes (subhazard ratio [SHR] = 0.91; 95% CI = 0.61 to 1.35; p = 0.636), aseptic acetabular loosening (SHR = 1.32; 95% CI = 0.68 to 2.53; p = 0.410), and infection (SHR = 0.68; 95% CI = 0.39 to 1.20; p = 0.165) were similar between revision total hip arthroplasties with TM and non-TM coatings. Of 247 total hip arthroplasties initially revised for infection (116 TM and 131 non-TM), the rates of re-revision for all causes (SHR = 0.48; 95% CI = 0.15 to 1.56; p = 0.225), aseptic acetabular loosening (SHR = 0.54; 95% CI = 0.05 to 5.74; p = 0.608), and infection (SHR = 0.82; 95% CI = 0.28 to 2.36; p = 0.706) were similar between the TM and non-TM groups. CONCLUSIONS: Following revision total hip arthroplasty, TM-coated acetabular components had a low risk of both aseptic and septic re-revision, with rates that were comparable with those of non-TM components. Extended follow-up of large revision total hip arthroplasty cohorts will establish whether TM components have any clinical benefit over non-TM designs when used in patients with similar acetabular bone stock. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975266 TI - Increased Postoperative Glucose Variability Is Associated with Adverse Outcomes Following Total Joint Arthroplasty. AB - BACKGROUND: Increased glucose variability during hospitalization has been associated with a longer length of stay in the hospital and a higher mortality rate following non-orthopaedic surgical procedures. Our aim was to investigate the association between glucose variability and postoperative complications following total joint arthroplasty. METHODS: We analyzed data on 21,487 patients who had undergone total hip arthroplasty (THA) or total knee arthroplasty (TKA) at a single center from 2001 to 2017. Patients with a minimum of 2 postoperative glucose values per day or >3 values overall were included in the study. Glucose variability was assessed using a coefficient of variation. Adverse outcomes included an increased length of stay in the hospital, 90-day mortality, reoperations, periprosthetic joint infection, and surgical site infection. Periprosthetic joint infection was defined using the Musculoskeletal Infection Society criteria. RESULTS: The final cohort included 2,360 patients who had undergone THA and 2,698 who had undergone TKA; 1,007 (19.9%) had diabetes. Higher glycemic variability was associated with an increased length of stay, 90-day mortality, periprosthetic joint infection, and surgical site infection. Adjusted analysis indicated that for every 10-percentage-point increase in the coefficient of variation, the length of stay increased by 6.1% (95% confidence interval [CI], 5.1% to 7.2%; p < 0.001), the risk of mortality increased by 26% (odds ratio [OR] = 1.26, 95% CI = 0.98 to 1.61; p = 0.07), and the risks of periprosthetic joint infection and surgical site infection increased by 20% (OR = 1.20, 95% CI = 1.02 to 1.41; p = 0.03) and 14% (OR = 1.14, 95% CI = 1.00 to 1.31; p = 0.06), respectively. These associations were independent of the year of surgery, age, body mass index, Elixhauser comorbidity index, diagnosis of diabetes, in-hospital use of insulin or steroids, and mean glucose values during hospitalization. CONCLUSIONS: Higher glucose variability in the postoperative period is associated with increased rates of surgical site and periprosthetic joint infections and may be a useful predictor of the risk of mortality following THA and TKA. Efforts should be made to control the glucose variability in the early postoperative period, and future studies should examine the role of continuous glucose monitoring in a subset of patients with high glucose fluctuations. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975267 TI - Innovation in Resident Education: What Orthopaedic Surgeons Can Learn from Other Disciplines. PMID- 29975268 TI - A Comparison of the Effect of One, Three, or Six Weeks of Immobilization on Function and Pain After Open Reduction and Internal Fixation of Distal Radial Fractures in Adults: A Randomized Controlled Trial. AB - BACKGROUND: The optimum period of immobilization following open reduction and internal fixation (ORIF) of distal radial fractures has not been established. METHODS: One hundred and thirty-three adults with a distal radial fracture treated with ORIF (using a volar locked plate) were randomly allocated, with stratification according to age, to 1, 3, or 6 weeks of postoperative immobilization in a parallel-design, assessor-blinded, randomized controlled trial (RCT). After cast removal, a standardized education and exercise program was followed for 6 weeks. Primary outcomes were function (according to the Patient-Rated Wrist Evaluation [PRWE]), worst (visual analog scale [VAS]-W) and usual (VAS-U) pain in the past week, and active wrist extension and forearm supination range of motion. All measures were recorded at 6, 12, and 26 weeks following surgery. Secondary outcomes were wrist flexion, radial deviation, ulnar deviation, and forearm pronation active range of motion; function (Disabilities of the Arm, Shoulder and Hand [DASH]); grip strength; postoperative adverse events; return to work and/or usual daily activities; and compliance with the home exercise program. RESULTS: More than 90% of the participants received treatment as allocated, and 87% completed the 6-month follow-up. At 6 weeks, both the 1-week and 3-week groups had significantly better PRWE scores, wrist extension, and flexion active range of motion than the 6-week group. However, no treatment group was superior to another with respect to primary or secondary outcomes at 12 weeks or 6 months following surgery. Analyses considering only the main effect of the intervention group indicated a preference for the 3-week group, which performed significantly better than the 6-week group with respect to the PRWE, pain (VAS-W and VAS-U), wrist flexion, ulnar deviation, forearm pronation active range of motion, and DASH score. CONCLUSIONS: For patient function, range of motion, and pain, this investigation demonstrated that immobilization periods of 1 and 3 weeks produced superior short-term outcomes compared with those after 6 weeks of immobilization. These differences were not evident at 3 and 6 months following surgery, with the immobilization period having no significant effect on long-term function, range of motion, or pain. There were no significant differences in adverse events associated with shorter immobilization periods. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975269 TI - A Classification for Kyphosis Based on Column Deficiency, Curve Magnitude, and Osteotomy Requirement. AB - BACKGROUND: There is a lack of a classification system providing uniformity in description and guiding management decisions for kyphotic spinal deformities. We developed such a classification based on column deficiency, flexibility of disc spaces, curve magnitude, and correlation with the corrective osteotomy required. METHODS: A classification was developed based on analysis of 180 patients with thoracolumbar kyphosis requiring osteotomy. The deformity was classified as Type I if the anterior and posterior columns were intact (IA indicated mobile disc spaces and IB, ankylosed segments). Type II indicated deficiency of only 1 column (IIA = anterior column and IIB = posterior column). Type III indicated deficiency of both columns (IIIA = kyphosis of <=60 degrees , IIIB = kyphosis of >60 degrees , and IIIC = buckling collapse). A prospective analysis of 76 patients was performed to determine interobserver variability and the ability of the classification to guide selection of osteotomies of increasing complexity, including the Ponte osteotomy, pedicle subtraction osteotomy, disc bone osteotomy, single vertebrectomy, multiple vertebrectomies, and anterior in situ strut fusion procedure. RESULTS: The mean age of the 76 patients was 21.2 years, the mean kyphosis was 69.9 degrees (range, 26 degrees to 120 degrees ), and the mean follow-up duration was 30 months. Six deformities were classified as IA, 5 as IB, 5 as IIA, 2 as IIB, 13 as IIIA, 35 as IIIB, and 10 as IIIC. Four surgeons classifying the deformities had a high agreement rate (kappa = 0.83), with the highest agreement for Types IA, IB, and IIIB. A correlation between the type of deformity and the osteotomy performed demonstrated that the classification could indicate the type of osteotomy required. All 18 patients with Type-I or II kyphosis were treated with Ponte, pedicle subtraction, or disc bone osteotomy. Forty-three (90%) of the 48 patients with Type IIIA or IIIB underwent vertebrectomy (single in 27 [56%] and multiple in 16 [33%]), and only 5 (10%) underwent disc bone osteotomy. Seven of the 10 patients with Type-IIIC kyphosis were treated with multiple vertebrectomies, with 5 of them needing preoperative halo gravity traction; the other 3 patients underwent an anterior in situ strut fusion procedure. CONCLUSIONS: The proposed classification based on the morphology of column deficiency, flexibility, and curve magnitude demonstrated a high interobserver agreement and ability to guide selection of the appropriate osteotomy. CLINICAL RELEVANCE: A novel classification system for kyphosis based on spinal column deficiency, flexibility of disc spaces, and curve magnitude would bring uniformity in management and help guide surgeons in the choice of the appropriate corrective osteotomy. PMID- 29975270 TI - Percutaneous Needle Fasciotomy Versus Collagenase Treatment for Dupuytren Contracture: A Randomized Controlled Trial with a Two-Year Follow-up. AB - BACKGROUND: Local disruption of the cord that causes contracture of the finger in Dupuytren disease can be achieved either through mechanical division by percutaneous needle fasciotomy (PNF) or through enzymatic digestion by injectable collagenase Clostridium histolyticum (CCH). This study was designed to compare clinical and patient-reported outcomes between patients who had been treated with each method. METHODS: A prospective, randomized, single-blinded, controlled trial was designed and included 156 patients with a contracture of the metacarpophalangeal (MCP) joint of >=20 degrees . The patients were allocated to treatment with either PNF or CCH. The primary outcome was a reduction of the MCP contracture to <5 degrees . Secondary outcomes included the reduction of any concomitant contracture of the proximal interphalangeal (PIP) joint, the presence of Dupuytren cords, and changes in patient-reported outcomes as measured with the URAM (Unite Rhumatologique des Affections de Main) and QuickDASH (an abbreviated version of the Disabilities of the Arm, Shoulder and Hand [DASH]) questionnaires and visual analog scales for patient satisfaction. All treatments were performed by a single surgeon and all blinded follow-up measurements were made by a single physiotherapist. The participants were assessed at 1 week, 6 months, and 1 and 2 years after the interventions. RESULTS: A total of 152 patients (97%) were examined at 2 years, at which time 58 patients (76%) treated with CCH and 60 (79%) treated with PNF retained a straight MCP joint. No cords were detectable in >50% of the patients at 2 years. There were no significant differences in the reduction of PIP contracture, range of motion, or patient-reported outcomes between the 2 treatments. CONCLUSIONS: This trial demonstrated no advantage of CCH treatment compared with PNF in terms of clinical outcome at any time during the 2-year follow-up. The significant decrease in the number of pathological cords (p < 0.0001, Wilcoxon signed-rank test) after disruption regardless of the method used may indicate that resorption of pathological collagen occurs when the tension in the Dupuytren cord is diminished. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975271 TI - The Future of Orthopaedic Care: Promoting Psychosocial Resiliency in Orthopaedic Surgical Practices. PMID- 29975273 TI - Association Between Race and Ethnicity and Hip Fracture Outcomes in a Universally Insured Population. AB - BACKGROUND: Prior studies have documented racial and ethnic disparities in hip fracture treatment and outcome, and unequal access is commonly cited as a potential mediator. We sought to assess whether disparities in hip fracture outcome persist within a universally insured population of patients enrolled in a managed health-care system. METHODS: A U.S. integrated health systems registry was used to identify patients who underwent treatment for a hip fracture when they were >=60 years of age from 2009 to 2014. Patient demographics, procedure details, and outcomes were obtained from the registry. Differences in outcome according to race/ethnicity were analyzed using multivariable regression analysis with adjustment for socioeconomic status and other potential confounders. RESULTS: Of 17,790 patients, 79.4% were white, 3.9% were black, 9.4% were Hispanic, and 7.4% were Asian. Compared with white patients, black patients had a similar 1-year mortality rate (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.79 to 1.09, p = 0.37), Hispanic patients had a lower rate (OR = 0.85, 95% = CI = 0.75 to 0.96, p = 0.01), and Asian patients also had a lower rate (OR = 0.65, 95% CI = 0.56 to 0.76, p < 0.001). There were no differences in terms of surgical delay, 90-day emergency department visits, or reoperations during the patient's lifetime (p > 0.05) between the groups. Compared with white patients, black and Hispanic patients had fewer 90-day postoperative complications (p = 0.04 and p = 0.01, respectively); 90-day unplanned readmissions were less common among Asian patients (p = 0.03) but more common among black patients (p = 0.01). CONCLUSIONS: In this study of hip fractures treated in an integrated managed care system, minority patients were found to have postoperative mortality rates that were similar to, or lower than, those of white patients. These findings may be related to the equal access and/or standardized protocols associated with treatment in this managed care system. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975272 TI - Adductor Canal Block Compared with Periarticular Bupivacaine Injection for Total Knee Arthroplasty: A Prospective Randomized Trial. AB - BACKGROUND: In the last decade, the widespread use of regional anesthesia in total knee arthroplasty has led to improvements in pain control, more rapid functional recovery, and reductions in the length of the hospital stay. The aim of this study was to compare the efficacy of adductor canal blocks (ACB) and periarticular anesthetic injections (PAI), both with bupivacaine, for pain management in total knee arthroplasty. METHODS: One hundred and fifty-five patients undergoing primary total knee arthroplasty under spinal anesthesia were randomized to 1 of 3 groups: ACB alone (15 mL of 0.5% bupivacaine), PAI alone (50 mL of 0.25% bupivacaine with epinephrine), and ACB+PAI. The primary outcome in this study was the visual analog scale (VAS) pain score in the immediate postoperative period. Secondary outcomes included postoperative opioid use, activity level during physical therapy, length of hospital stay, and knee range of motion. RESULTS: The mean VAS pain score was significantly higher after use of ACB alone, compared with the score after use of ACB+PAI, on postoperative day 1 (POD1) (3.9 versus 3.0, p = 0.04) and POD3 (4.2 versus 2.0, p = 0.02). Total opioid consumption through POD3 was significantly higher when ACB alone had been used (131 morphine equivalents [ME]) compared with PAI alone (100 ME, p = 0.02) and ACB+PAI (98 ME, p = 0.02). Opioid consumption in the ACB-alone group was significantly higher than that in the ACB+PAI group on POD2 and POD3 and significantly higher than that in the PAI-alone group on POD2. There was no significant difference in opioid consumption between the patients treated with PAI alone and those who received ACB+PAI. The activity level during physical therapy on POD0 was significantly lower after use of ACB alone (26 steps) than after use of PAI alone (68 steps, p < 0.001) or ACB+PAI (65 steps, p < 0.001). CONCLUSIONS: This randomized controlled clinical trial demonstrated significantly higher pain scores and opioid consumption after total knee arthroplasty done with an ACB and without PAI, suggesting that ACB alone is inferior for perioperative pain control. There were no significant differences between PAI alone and ACB+PAI with regard to pain or opioid consumption. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975275 TI - Outcomes of Physeal-Sparing ACL Reconstruction with Iliotibial Band Autograft in Skeletally Immature Prepubescent Children. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are occurring in youth athletes with increasing frequency. Many ACL reconstruction procedures designed to allow for continued growth in patients with open physes have been described, but large series with mid- to long-term outcomes data are lacking. The purpose of the current study was to assess the clinical outcomes of a large cohort of prepubescent children who underwent a physeal-sparing, combined intra- and extra articular ACL reconstruction with iliotibial (IT) band autograft over a 23-year period. METHODS: Included in our analysis were 237 patients (240 knees) who underwent ACL reconstruction using IT band autograft at Tanner stage 1 or 2 (mean age of 11.2 +/- 1.7 years). Physical examination data were analyzed for 225 of the 240 knees (mean follow-up, 25.8 months), and 137 (57%) of the knees had corresponding patient-reported clinical outcomes (patient-reported graft rupture and Pediatric International Knee Documentation Committee [Pedi-IKDC], Tegner activity scale, and Lysholm scores; mean follow-up, 6.2 years). Rates of growth arrest, IT band graft-harvest morbidity, and return to sports were analyzed. RESULTS: Physical examination revealed that 96.8% of the knees were grade A on the Lachman test and 98.8% were grade A on the pivot-shift test. Graft rupture occurred in 9 (6.6%) of 137 knees, at an average of 33.5 months (range, 8.2 months to 8.0 years) postoperatively. For patients who did not sustain a graft rupture, the mean Pedi-IKDC score was 93.3 +/- 11.0, the mean Lysholm score was 93.4 +/- 9.9, and the mean score on the Tegner activity scale was 7.8 (mode, 7). While lateral thigh asymmetry at the IT band harvest site was noted by 48% of the subjects, only 1.6% reported associated pain. No cases of limb-length discrepancy or angular deformity were observed. CONCLUSIONS: This procedure was associated with excellent functional outcomes, minimal risk of growth disturbance, and a low graft-rupture rate in skeletally immature prepubescent children. These results appear durable at mid- to long-term follow-up, at an average of >6 years postoperatively. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29975274 TI - Validation Study of the Thumb Ossification Composite Index (TOCI) in Idiopathic Scoliosis: A Stage-to-Stage Correlation with Classic Tanner-Whitehouse and Sanders Simplified Skeletal Maturity Systems. AB - BACKGROUND: The new simplified thumb ossification composite index (TOCI) based on ossification of the thumb epiphyses and adductor sesamoid has demonstrated simplicity, excellent reliability, and high accuracy for predicting skeletal maturity, comparable with the Sanders simplified skeletal maturity system (SSMS). It was our belief that, because the terminology of the SSMS system has been commonly used for skeletal maturity prediction in idiopathic scoliosis in publications over the past decade, the clinical applicability of the TOCI system would increase if the stages in the 2 systems were found to be interchangeable and highly correlated. METHODS: Hand radiographs of 125 premenarchal girls with newly diagnosed adolescent idiopathic scoliosis who had been followed longitudinally until skeletal maturity were all scored with use of the Tanner Whitehouse III (TW3) system (stages E through I), the TOCI, and the SSMS. The scores for the epiphyses of the ulnar 4 digits were compared with those for the thumb and correlated with the timing of peak height velocity. Correlations were analyzed with the chi-square test and Cramer V and Somers delta correlations. RESULTS: Six hundred and forty-five hand radiographs (an average of 5 for each girl with idiopathic scoliosis) and 11,517 epiphyses were scored. The rate of concordance between TW3 stages F, G, and I for the thumb proximal phalangeal epiphysis and those for all of the epiphyses of the ulnar 4 digits were 72.5%, 72.5%, and 89.9%, respectively. The overall concordance rate (including all epiphyses) was 71.3%, with a very high Cramer V correlation and significance (p < 0.01). High interchangeability was demonstrated for the TOCI and SSMS stages, supported by a high Somers delta correlation (>0.8) with significance (p < 0.05). CONCLUSIONS: The TOCI is highly practical for clinical use, and its stages are highly interchangeable with those of the SSMS. CLINICAL RELEVANCE: The TOCI could serve as a simplified "marker" of skeletal maturity on hand radiographs and minimize the learning-curve problems associated with the SSMS in a busy clinical practice. PMID- 29975276 TI - What's Important: Foundations of Orthopaedics-The "Multiple-of-Three Rule": Where Is the Evidence? PMID- 29975277 TI - Universal Access Results in More Equitable Hip Fracture Treatment: Commentary on an article by Kanu Okike, MD, MPH, et al.: "Association Between Race and Ethnicity and Hip Fracture Outcomes in a Universally Insured Population". PMID- 29975278 TI - Dupuytren Disease: Is Collagenase Better Than Needling?: Commentary on an article by Joakim Stromberg, MD, et al.: "Percutaneous Needle Fasciotomy Versus Collagenase Treatment for Dupuytren Contracture. A Randomized Controlled Trial with a Two-Year Follow-up". PMID- 29975280 TI - Assessment of Glycemic Variability May Be the Next Step in Optimizing Patients for Total Joint Arthroplasty: Commentary on an article by Noam Shohat, MD, et al.: "Increased Postoperative Glucose Variability Is Associated with Adverse Outcomes Following Total Joint Arthroplasty". PMID- 29975279 TI - What's New in Orthopaedic Trauma. PMID- 29975281 TI - Difference in carotid intima-media thickness between pre and postmenopausal women. AB - OBJECTIVES: To examine whether carotid intima-media thickness (CIMT), the prevalence of increased CIMT, and the presence of carotid plaque differ according to menopausal status. METHODS: In this analytical cross-sectional study, we enrolled 61 premenopausal women and 61 postmenopausal women. We matched the two groups for age. Participants were classified as either premenopausal or postmenopausal according to menstrual history and follicular-stimulating hormone level. Two skilled radiologists measured CIMT and carotid plaque in all participants by using B-mode ultrasound. RESULTS: The mean age was 49.25 +/- 2.0 years. The mean number of years since menopause in the postmenopausal group was 1.9 +/- 0.92 years. After adjusted analysis, the mean CIMT of the common carotid artery of postmenopausal women was significantly higher than that of premenopausal women, with a mean difference of 0.068 mm (95% confidence interval 0.023, 0.113). There was no significant association between number of years since menopause and mean CIMT. Although the prevalence of increased CIMT and the presence of carotid plaque were significantly higher in the postmenopausal group than in the premenopausal group according to crude analysis, this difference was not statistically significant after adjusted analysis. Multiple linear regression analysis for assessing potential risk factors for the alteration of mean CIMT showed that only menopausal status and body mass index were independently associated factors. CONCLUSIONS: Our findings indicate that postmenopausal status is a significant factor of high mean CIMT. These findings add to the growing evidence showing that menopause transition is a critical period for subclinical atherosclerosis development. PMID- 29975282 TI - Association between metabolic profiles in urine and bone mineral density of pre- and postmenopausal Chinese women. AB - OBJECTIVE: In the present study, we aimed to characterize the pathological development of menopausal osteoporosis, as well as to explore potential biomarkers and metabolic pathways involved in osteoporosis. METHODS: Urine samples from 322 female participants categorized by menopause status and different bone conditions were collected and analyzed based on a gas chromatography-mass spectrometry (GC-MS) approach. Multivariate and univariate statistical analyses were carried out for urinary metabolomic profile characterization and comparison. RESULTS: Seventeen metabolites in the low bone mineral density (BMD) groups were clearly differentiated from those in normal BMD groups. Among these 17 differentiating metabolites, taurine, beta-alanine, and 5 hydroxycaproic acid were found to be potential biomarkers of osteoporosis. The taurine metabolic pathway and the beta-alanine metabolic pathway were found to be related to menopause and bone loss. CONCLUSIONS: Based on the GC-MS metabolomic platform, four typical pathological phases during the progression of postmenopausal osteoporosis were described. Several differentiating metabolites and metabolic pathways were found to be closely related to the pathology of postmenopausal osteoporosis. Our results provided a solid foundation for further studies on early diagnosis and pathomechanistic evaluation. PMID- 29975283 TI - Effect of combined circuit exercise on arterial stiffness in hypertensive postmenopausal women: a local public health center-based pilot study. AB - OBJECTIVE: Postmenopausal women have increased arterial stiffness compared with premenopausal women. Regular physical activity including aerobic and resistance exercises are recommended to lower cardiovascular disease risk and to enhance musculoskeletal health in these women. This study examined the effect of combined circuit exercise on arterial stiffness in hypertensive postmenopausal women. Furthermore, it ascertained whether performing this exercise program is feasible in local public health centers with better accessibility than research and commercial facilities. METHODS: Among 24 hypertensive postmenopausal women, 16 finished this study in either the control (n = 8) or exercise (n = 8) group. Except for one participant who withdrew from the study due to the difficulty of the exercise program, seven participants withdrew due to reasons unrelated to the study. Circuit-type exercise (aerobic- and resistance-combined) program was applied to the exercise group, 60 min/d and 3 d/wk for 12 weeks under supervision. Brachial-ankle pulse wave velocity was measured to assess arterial stiffness. RESULTS: In response to the combined exercise, brachial-ankle pulse wave velocity was significantly reduced in the hypertensive women (-0.7 m/s; P < 0.05). Weight, body mass index, and total cholesterol level were also significantly decreased after the exercise program (-2.1 kg, -0.8 kg/m, and -16 mg/dL, respectively; P < 0.05). In addition, changes in arterial stiffness were related to body adiposity, blood pressure, and blood lipid alterations (r = 0.61 0.70; P < 0.01). CONCLUSIONS: Circuit combined exercise is an effective intervention to improve arterial stiffness in hypertensive postmenopausal women, and is feasible in local public health centers. PMID- 29975284 TI - To the Editor. PMID- 29975285 TI - Endometrial cancer in the elderly: does patient age influence the choice of treatment interventions and do age-related treatment choices impact survival? PMID- 29975286 TI - In Reply. PMID- 29975287 TI - Apolipoprotein E4 genotype in combination with poor metabolic profile is associated with reduced cognitive performance in healthy postmenopausal women: implications for late onset Alzheimer's disease. AB - OBJECTIVE: We hypothesized the association of metabolic profile on cognition in postmenopausal women will be greater among ApoE4 carriers compared with noncarriers. METHODS: Metabolic biomarkers and measures of global cognition, executive functions, and verbal memory, collected among postmenopausal females, were used in this analysis. Clustering analyses of metabolic biomarkers revealed three phenotypes: healthy, predominantly hypertensive, and poor metabolic with (borderline normal laboratory values). General linear models tested whether an association of metabolic cluster with cognition differed by ApoE4 genotype. RESULTS: In the total sample of 497 women, verbal memory was lower in the poor metabolic cluster (P = 0.04). Among ApoE4+ women, performance in all cognitive domains was lowest in the poor metabolic cluster. Differences in executive functions among metabolic clusters were detected only in ApoE4+ women (P value for interaction = 0.003). CONCLUSIONS: In a general population of postmenopausal women, association between poor metabolic profile with reduction in cognitive performance is more apparent in women who carry an ApoE4 allele. These data indicate a window of opportunity for interventions to reverse the trajectory of the preclinical phase of Alzheimer's disease. PMID- 29975288 TI - To the Editor. PMID- 29975289 TI - Letter From Editor July 2018. PMID- 29975290 TI - Significance of Serum Human Epididymis Protein 4 and Cancer Antigen 125 in Distinguishing Type I and Type II Epithelial Ovarian Cancers. AB - OBJECTIVE: The objective of this study was to assess the effectiveness of human epididymis protein 4 (HE4) and cancer antigen 125 (CA125), and risk of ovarian malignancy algorithm (ROMA) in identifying type I and type II epithelial ovarian cancers (EOCs). METHODS: A cross-sectional diagnostic study was conducted of 499 Thai women older than 18 years who had clinically diagnosed pelvic masses and underwent elective surgery at our hospital between July 2012 and July 2014. Preoperative serum HE4 and CA125 levels were measured, and postoperative pathologic slides were reviewed. RESULTS: Of 499 Thai women enrolled in this study, 357 were noncancerous (NC), 79 had type I EOCs (EOCs-I) and 63 had type II (EOCs-II). Risk of ovarian malignancy algorithm revealed significantly better performance than HE4 and CA125 in discriminating between NC and EOCs-I (receiver operating characteristic curve and area under the curve [ROC-AUC]: ROMA, 0.86; HE4, 0.80; and CA125, 0.77), and NC and EOCs-II (ROC-AUC: ROMA, 0.97; HE4, 0.95; and CA125, 0.93). In differentiation between EOCs-I and EOCs-II (setting EOC-II as reference), ROMA yielded a better performance than HE4 and CA125 (ROC-AUC: ROMA, 0.83; HE4, 0.82; and CA125, 0.77); however, CA125 and HE4 showed higher sensitivity (CA125, 77.8%; HE4, 76.2%), whereas ROMA had the highest specificity (79.8%). CONCLUSIONS: In women who present with pelvic masses, ROMA performed very well in distinguishing between noncancer lesions and EOCs but the combined HE4 and CA125 test was more effective in predicting EOC types. PMID- 29975291 TI - Efficacy of Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery in the Treatment of Recurrent Uterine Sarcoma. AB - OBJECTIVE: Uterine sarcomas (USs) are characterized by poor response to systemic chemotherapy and high recurrence rates. This study evaluates whether the use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) confers survival benefit in comparison with conventional treatment modalities in patients with recurrent US. METHODS/MATERIALS: A retrospective analysis of patients with recurrent US at a single institution for an 11-year study period was performed. All women with a pathologic diagnosis of leiomyosarcoma, adenosarcoma, endometrial stromal sarcoma, or undifferentiated US were identified. Overall and disease-free survival was estimated using Kaplan-Meier method. Comparisons between the study groups were performed with the log-rank test and Cox regression. RESULTS: A total of 26 patients were identified. Five patients received chemotherapy and/or radiotherapy without surgical intervention, 14 patients underwent surgery alone or a combination of surgery and adjuvant systemic chemotherapy, and 7 patients received cytoreductive surgery with HIPEC. There was no treatment-related mortality in any group, and only 1 patient had grade III-IV surgical complications. Median disease-free survival was 2.4 months for patients with nonsurgical treatments, 5.3 months for patients treated with conventional surgery, and 11.3 months for patients treated with HIPEC. Median overall survival was 35.9 months for patients treated with conventional surgery and 43.8 months for patients treated with HIPEC. CONCLUSIONS: Our study is the first to compare survival outcomes of HIPEC versus conventional therapies for recurrent US and is suggestive of treatment benefit. Further studies with more patients and longer follow-up to evaluate the role of HIPEC in management of this disease are warranted. PMID- 29975292 TI - What's New in Pediatric Orthopaedic Trauma: The Lower Extremity. AB - BACKGROUND: Skeletal trauma is a primary tenet of pediatric orthopaedics. Many high-quality studies have been published over the last few years with substantial relevance to the clinical practice of pediatric orthopaedic trauma. Because of the volume of literature on the subject, this review excludes upper extremity trauma and focuses on the publications affecting the lower extremity. METHODS: An electronic search of the PubMed database was performed utilizing keywords for pediatric lower extremity trauma: pelvic injuries, femur fractures, tibial shaft fractures, femur fractures, ankle fractures, and foot fractures. All 835 papers related to the treatment of pediatric orthopaedic trauma of the lower extremity published from January 1, 2012 to July 31, 2017 were reviewed, yielding 25 papers that were believed to contribute significant findings to the profession. RESULTS: Of the 25 papers selected for presentation within this review, 8 related to tibial shaft injuries, 6 involved the pelvis, 5 involved femur fractures, 4 related to ankle injuries, 2 involved foot injuries, and 1 regarding trauma and venous thromoembolism. The level of evidence for these studies were either level III or IV. CONCLUSIONS: Higher-grade pediatric pelvic fractures do not correlate with increased severity of splenic or hepatic injuries. Successful union of femur fractures in older children can be obtained by surgeon preferred method of surgical management. Pediatric tibia shaft fractures should be managed conservatively in most cases; however, fractures with >20% of displacement and associated fibula fractures have a 40% risk of requiring delayed surgical stabilization. Vigilance remains the sin qua non regarding identification and appropriate management of compartment syndrome and venous thromboemobolism in children. Many Salter-Harris I distal fibula fractures are now believed to be ligamentous injury and can be treated as such. Calcaneous fractures remain uncommon in pediatrics, but minimally invasive approaches of surgical reduction and fixation may reduce complications in management. LEVEL OF EVIDENCE: Level IV. PMID- 29975293 TI - National Databases in Pediatric Orthopaedic Surgery: A Comparison of Demographics, Procedures, and Outcomes. AB - BACKGROUND: Large national databases have been increasingly used in recent years to determine the rate of adverse events and identify factors associated with altered surgical outcomes. This can be especially useful to evaluate rare events such as 30-day mortality. Despite differences between national pediatric databases, there have been no comparison studies in the pediatric orthopaedic population. METHODS: The Healthcare Cost and Utilization Project's Kids' Inpatient Database (KID) along with the American College of Surgeons National Surgical Quality Improvement Program Pediatric (NSQIP Pediatric) databases were queried to identify common pediatric orthopaedic procedures for humeral fractures, scoliosis, slipped capital femoral epiphysis, and femoral fractures during a single year. Clinical characteristics and complications in the 2 databases were compared using Student t test, chi, or Fisher' exact test. RESULTS: In total, 26,978 patients in the KID and 5186 patients in the NSQIP Pediatric databases were identified. Large differences were observed between the databases in identical procedure categories with respect to age, race, sex, and length of stay. Regardless of procedure, NSQIP Pediatric had statistically higher reported rates of cumulative complications. Surgical site infections and sepsis were consistently observed to be at least twice as common in the NSQIP Pediatric database in comparison to the KID. Overall, complication rates ranged from <1% in humeral fractures to >100% in neuromuscular scoliosis. CONCLUSIONS: Clinically and statistically significant differences exist between the KID and NSQIP Pediatric databases. Clinicians and researchers who utilize large databases must understand the differences in data import, quality control, and population sampling in order to provide adequate representation of the population as a whole. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 29975294 TI - Biomechanical and Clinical Comparative Study of the New Elastic Stable Intramedullary Nailing "MJ-FLEX Orthofix". AB - BACKGROUND: The objectives of this study were first to compare the results of osteosynthesis with standard Metaizeau (MS) nails versus Metaizeau Junior Flex or MJF Orthofix (MJF) in terms of the stability of long-bone fractures in children, and to study the preoperative and postoperative safety of these new nails. We also carried out an analysis by computer modeling of a femur, in order to compare the biomechanical stability of the 2 nails. The interest in the MJF nails lies in the improvements they bring in terms of stability for long-bone fractures in pediatric patients, as well as the simplification of the surgical procedure. METHODS: A study by numerical computer modeling of a femur was conducted to compare the biomechanical stability of the 2 assemblies with MS versus MJF nails. A retrospective single-center study of 137 fractures treated with MS and MJF was added to this biomechanical study. The onset of angular misalignment during follow-up was identified by radiographic measurements. RESULTS: The biomechanical study showed greater stiffness of MJF in the frontal and sagittal plane and in torsion for modeled comminuted and simple transverse fractures. Use of MJF nails significantly reduced the risk of frontal and sagittal misalignment, by a factor of 5 and 12, respectively. The amplitude of this misalignment was also significantly reduced by 30% in the frontal plane with the MJF nail. The use of MJF compared with MS significantly diminished not only the quantity of preoperative radiation by 66% but also operative time by 30%. The complication rate in our population was 33.4% with a 6-fold lower risk of complications with MJF. CONCLUSIONS: MJF nails provide greater stability in the frontal and sagittal plane with regard to both the onset and amplitude of misalignment in the treatment of long-bone fractures in children. This improvement was confirmed by the biomechanical study. Preoperative and postoperative safety was also better with these new nails, and surgery was easier. PMID- 29975295 TI - Shoulder Complex Mechanics in Adolescent Idiopathic Scoliosis and Their Relation to Patient-perceived Function. AB - BACKGROUND: Proper contribution of the scapulothoracic joint is necessary for adequate shoulder complex function. Associations between trunk shape and abnormal scapular kinematics and subsequent shoulder dysfunction have been established; however, the extent of shoulder dysfunction in adolescent idiopathic scoliosis (AIS) is still poorly understood. The purpose of this study was to perform a comprehensive analysis of scapular kinematics during multiplanar arm motion in patients with AIS and compare kinematics and patient-reported function with that of a typically developing cohort. METHODS: Typically developing adolescents (n=33) and patients with AIS (n=26) with no history of spine or shoulder surgery were recruited for this study. A 3-dimensional optoelectronic motion capture system was used to analyze scapular kinematics in 4 positions: rest, full abduction, forward reach, and hand to spine. Subjects in each group also completed the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire as a measure of patient-reported function. RESULTS: The convex shoulders of the patients with AIS exhibited deficits in scapular upward rotation and posterior tilt in all positions and reduced protraction range of motion during reaching. The AIS group also reported worse patient-perceived shoulder function than the typically developing group; however, this dysfunction was not related to specific scapular kinematic patterns. CONCLUSIONS: Patients with AIS show alterations in scapular kinematics that are associated with shoulder pathology. Despite displaying an unaffected ability to place the hand in space, the underlying joint mechanics place these adolescents at risk for future pathology. Accordingly, consideration of scapulothoracic and glenohumeral joint function is warranted in the treatment of AIS. LEVEL OF EVIDENCE: Level III-cross-sectional comparison. PMID- 29975296 TI - Trends in Pediatric ACL Reconstruction From the PHIS Database. AB - BACKGROUND: Previous studies have suggested that anterior cruciate ligament (ACL) reconstruction surgeries are being performed with increased frequency in children and adolescents. The purpose of this study was to evaluate the trend in the frequency of ACL reconstructions normalized by total orthopaedic surgeries at pediatric hospitals nationwide. METHODS: The Pediatric Health Information System (PHIS) database was queried for patients age 18 years or younger who underwent orthopaedic surgery at any of the PHIS-participating hospitals 2004-2014. The subset of patients who had been treated with ACL reconstruction were identified using Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) procedure codes. The yearly rate was expressed as the number of ACL reconstructions per 1000 orthopaedic surgeries, and a linear model was used to fit the data to illustrate the relative trend. RESULTS: In total, 470,126 orthopaedic surgeries, including 15,231 ACL reconstructions, were performed for patients 18 years or younger at 27 pediatric hospitals. ACL reconstructions were performed at a yearly rate of 32.4 per 1000 orthopaedic surgeries. Between 2004 and 2014, the number of ACL reconstructions increased 5.7 fold, whereas orthopaedic surgeries increased 1.7-fold; there was a 2.8-fold increase in ACL reconstructions relative to total pediatric orthopaedic surgeries. The 10-year relative fold increase was nearly equivalent across sexes, and the increasing trend in ACL reconstructions relative to orthopaedic surgeries was also seen across age groups. CONCLUSIONS: The number of ACL reconstructions performed for children and adolescents in pediatric hospitals nationwide markedly increased by nearly 3 times relative to orthopaedic surgeries over a recent 10 year period. LEVEL OF EVIDENCE: Level IV. PMID- 29975297 TI - A Comparison of Transphyseal Neck-Head Tunneling and Multiple Epiphyseal Drilling on Femoral Head Healing Following Ischemic Osteonecrosis: An Experimental Investigation in Immature Pigs. AB - BACKGROUND: Two operative procedures are currently advocated to stimulate the necrotic femoral head healing in children with Legg-Calve-Perthes disease: transphyseal neck-head tunneling (TNHT) and multiple epiphyseal drilling (MED). The purpose of this study was to compare the bone healing and physeal function after treatment with TNHT or MED in a piglet model of ischemic osteonecrosis. METHODS: Eighteen piglets were induced with osteonecrosis by surgically placing a ligature tightly around the right femoral neck. One week later, the piglets were assigned to 1 of 3 treatment groups (n=6/group): (1) local nonweight bearing only (NWB), (2) TNHT plus NWB, or (3) MED plus NWB. The unoperated left femoral heads were used as normal controls. The animals were euthanized at 8 weeks after osteonecrosis induction. Histologic, histomorphometric, radiographic, microcomputed tomography (CT), and calcein-labeling assessments were performed. Statistical analysis included a 1-way ANOVA. RESULTS: Micro-CT analyses showed higher femoral head bone volume in the MED group compared with the TNHT and the NWB groups (P<0.01). The MED group had a higher mean trabecular number (P<0.001) and new bone formation (P=0.001) based on calcein-labeling parameters compared with the TNHT and the NWB groups. In addition, the osteoclast number per bone surface was lower in the MED group compared with the NWB group (P=0.001). Histologic and micro-CT assessments of the proximal femoral physis revealed a larger physeal disruption at the site of physeal drilling in the TNHT group compared with the MED group. However, no significant differences in physeal elongation (P=0.61) and femoral neck length (P=0.31) were observed between the treatment groups. CONCLUSIONS: MED produced a higher bone volume and stimulated greater bone formation than the TNHT or the NWB alone. Both procedures did not produce a significant physeal growth disturbance during the study period. CLINICAL RELEVANCE: This preclinical study provides evidence that MED produces more favorable bone healing than the TNHT in a large animal model of Legg-Calve Perthes disease. PMID- 29975298 TI - How Do the Mechanical Demands of Cycling Affect the Information Content of the EMG? AB - PURPOSE: The persistence of phase-related information in EMG signals can be quantified by its entropic half-life (EnHL). It has been proposed that the EnHL would increase with the demands of a movement task, and thus increase as the pedaling power increased during cycling. However, simulation work on the properties of EMG signals suggests that the EnHL depends on burst duration and duty cycle in the EMG that may not be related to task demands. This study aimed to distinguish between these alternate hypotheses. METHODS: The EnHL was characterized for 10 muscles from nine cyclists cycling at a range of powers (35 to 260 W) and cadences (60-140 rpm) for the raw EMG, phase-randomized surrogate EMG, EMG intensity, and the principal components describing the muscle coordination patterns. RESULTS: There was phase-related information in the raw EMG signals and EMG intensities that was related to the EMG burst duration, duty cycle pedaling cadence, and power. The EnHL for the EMG intensities of the individual muscles (excluding quadriceps) and for the coordination patterns decreased as cycling power and cadence increased. CONCLUSIONS: The EnHL provide information on the structure of the motor control signals and their constituent motor unit action potentials, both within and between muscles, rather than on the mechanical demands of the cycling task per se. PMID- 29975299 TI - Sport and Triad Risk Factors Influence Bone Mineral Density in Collegiate Athletes. AB - PURPOSE: Athletes in weight-bearing sports may benefit from higher bone mineral density (BMD). However, some athletes are at risk for impaired BMD with female athlete triad (Triad). The purpose of this study is to understand the influence of sports participation and Triad on BMD. We hypothesize that athletes in high impact and multidirectional loading sports will have highest BMD, whereas nonimpact and low-impact sports will have lowest BMD. Triad risk factors are expected to reduce BMD values independent of sports participation. METHODS: Two hundred thirty-nine female athletes participating in 16 collegiate sports completed dual-energy x-ray absorptiometry (DXA) scans to measure BMD z-scores of the lumbar spine (LS) and total body (TB). Height and weight were measured to calculate body mass index (BMI). Triad risk assessment variables were obtained from preparticipation examination. Mean BMD z-scores were compared between sports and by sport category (high-impact, multidirectional, low-impact, and nonimpact). Multivariable regression analyses were performed to identify differences of BMD z scores accounting for Triad and body size/composition. RESULTS: Athlete populations with lowest average BMD z-scores included synchronized swimming (LS, 0.34; TB, 0.21) swimming/diving (LS, 0.34; TB, -0.06), crew/rowing (LS, 0.27; TB, 0.62), and cross-country (LS, 0.29; TB, 0.91). Highest values were in gymnastics (LS, 1.96; TB, 1.37), volleyball (LS, 1.90; TB, 1.74), basketball (LS, 1.73; TB, 1.99), and softball (LS, 1.68; TB, 1.78). All Triad risk factors were associated with lower BMD z-scores in univariable analyses; only low BMI and oligomenorrhea/amenorrhea were associated in multivariable analyses (all P < 0.05). Accounting for Triad risk factors and body size/composition, high-impact sports were associated with higher LS and TB BMD z-scores and nonimpact sports with lower LS and TB BMD z-scores compared to low-impact sport (all P < 0.05). CONCLUSIONS: Both sport type and Triad risk factors influence BMD. Athletes in low-impact and nonimpact sports and athletes with low BMI and oligomenorrhea/amenorrhea are at highest risk for reduced BMD. PMID- 29975300 TI - Reducing Impact Loading in Runners: A One-Year Follow-up. AB - : Increased vertical impact loading during running has been associated with a variety of running related injuries including stress fractures, patellofemoral pain, and plantar fasciitis. PURPOSE: The purpose of this study was to examine the acute and long-term effect of a gait retraining program aimed at teaching runners with high impact loading to run softer. METHODS: Nineteen runners with high tibial shock (TS) first underwent a control period of eight sessions of treadmill running over 2 wk, progressing from 15 to 30 min. This was followed by eight sessions of gait retraining over 2 wk using the identical treadmill protocol. Real-time feedback of TS was provided as the participant ran. Feedback was gradually removed during the last four sessions. Variables of interest included peak TS, vertical impact peak and vertical average loading rate, and vertical instantaneous loading rate. These variables were assessed at intervals following the retraining and at a 1-yr follow-up. RESULTS: All variables of interest were significantly reduced post-retraining (P < 0.001). TS was reduced by 32%, vertical impact peak by 21%, vertical instantaneous loading rate by 27%, and vertical average loading rate by 25%. All variables continued to be significantly reduced at a 1-yr follow-up. CONCLUSIONS: Impact loading can be reduced through gait retraining and the results persist at least 1 yr. As impact loading is associated with injury, this simple intervention may provide a powerful method of reducing musculoskeletal injury risk in runners. PMID- 29975301 TI - Differences within Elite Female Tennis Players during an Incremental Field Test. AB - PURPOSE: To compare technical and physiological responses between junior and professional female players during an incremental field test to exhaustion specific to tennis. METHODS: Twenty-seven female players (n = 14 and 13 for juniors and professionals, respectively) completed an incremental field test to exhaustion specific to tennis, which consisted of hitting alternatively forehand and backhand strokes at increasing ball frequency (ball machine) every minute. Ball accuracy and ball velocity were determined by radar and video analysis for each stroke, in addition to cardiorespiratory responses (portable gas analyzer). RESULTS: The stage corresponding to the second ventilatory threshold (+20.0%, P = 0.027), time to exhaustion (+18.9%, P = 0.002) and maximum oxygen uptake (+12.4%, P = 0.007) were higher in professionals than in juniors. The relative percentage of maximal HR was lower at both the first (-4.7%, P = 0.014) and the second ( 1.3%, P = 0.018) ventilatory thresholds in professionals. Backhand ball velocity was the only technical parameter that displayed larger (+7.1%, P = 0.016) values in professionals. CONCLUSIONS: Compared with juniors, female professional tennis players possess higher exercise capacity, maximal and submaximal aerobic attributes along with faster backhand stroke velocities during an incremental field test specific to tennis. PMID- 29975302 TI - Early Motor Unit Conduction Velocity Changes to High-Intensity Interval Training versus Continuous Training. AB - PURPOSE: Moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) are associated with different adjustments in motor output. Changes in motor unit (MU) peripheral properties may contribute to these adjustments, but this is yet to be elucidated. This study evaluated early changes in MU conduction velocity (MUCV) and MU action potential amplitude after 2 wk of either HIIT or MICT. METHODS: Sixteen men were assigned to either an MICT group or HIIT group (n = 8 each), and participated in six training sessions over 14 d. HIIT: 8 to 12 * 60-s intervals at 100% peak power output. Moderate-intensity continuous training: 90 to 120 min continuous cycling at ~65% VO2peak. Preintervention and postintervention, participants performed maximal voluntary contractions (MVC) and submaximal (10%, 30%, 50%, and 70% of MVC) isometric knee extensions while high-density EMG was recorded from the vastus medialis (VM) and vastus lateralis (VL) muscles. The high-density EMG was decomposed into individual MU by convolutive blind-source separation and tracked preintervention and postintervention. RESULTS: Both training interventions induced changes in MUCV, but these changes depended on the type of training (P < 0.001). The HIIT group showed higher values of MUCV after training at all torque levels (P < 0.05), MICT only displayed changes in MUCV at low torque levels (10%-30% MVC, P < 0.002). There were no changes in MU action potential amplitude for either group (P = 0.2). CONCLUSIONS: Two weeks of HIIT or MICT elicit differential changes in MUCV, likely due to the contrasting load and volume used in such training regimes. This new knowledge on the neuromuscular adaptations to training has implications for exercise prescription. PMID- 29975303 TI - The Respiratory Compensation Point and the Deoxygenation Break Point Are Not Valid Surrogates for Critical Power and Maximum Lactate Steady State. PMID- 29975304 TI - Is Ischemic Preconditioning Feasible to Improve Performance at Moderate Altitude? PMID- 29975305 TI - Response. PMID- 29975307 TI - Alternatives to excisional therapy: a clinical review of our current options to conservatively manage symptomatic leiomyomas. AB - PURPOSE OF REVIEW: This article provides a clinical review of the alternatives to traditional excisional surgical therapies for uterine leiomyomas, such as myomectomy or hysterectomy. RECENT FINDINGS: In this review, currently available hormonal medications will be briefly discussed. Then, nonhormonal medical therapy will be addressed with respect to mechanism of action, safety, and efficacy. Finally, the risk-benefit profile of nonexcisional procedures for management of leiomyomas will be addressed. SUMMARY: This provides an update on the information available for more conservative options for symptomatic leiomyoma management. PMID- 29975308 TI - Predatory Publishing Revisited. PMID- 29975309 TI - Simulation With Advanced Care Providers in a Nurse Residency Program. AB - As many hospitals are implementing residency programs for new graduate nurses, the utilization of high-fidelity simulation has become common. This pilot program compared simulation with participation of only new graduate nurses and new graduates with advanced care providers. Results found a statistically significant increase in knowledge of differing roles and skills in simulations that included both groups. Nursing professional development practitioners will find this helpful in designing residency programs for new graduate nurses. PMID- 29975310 TI - Prelicensure Employment and Student Nurse Self-Efficacy: Corrigendum. PMID- 29975311 TI - Instrument Development and Testing for Selection of Nursing Preceptors. AB - The purpose of this pilot study was to develop and test a preceptor selection instrument for validity and reliability. Using a valid and reliable instrument to help identify and select an appropriate nurse preceptor supports the success of both the preceptor and the new nurse graduate. The 14-item Cotter Preceptor Selection Instrument was developed to assess attributes of potential preceptor candidates. Use of a robust and user-friendly instrument can provide nursing leadership with a consistent, measurable, and collaborative process for selecting preceptors. PMID- 29975312 TI - Introducing Mindfulness Practices for Self-Care: Outcomes of a Brief Education Session. AB - Nurses' self-reported lack of self-care and work-related stress prompted professional educators to offer a 15-minute mindfulness experiential learning session during the facility's annual professional development forums. Nurses were taught and practiced mindfulness (e.g., meditation, imagery), designed to empower them to be present in the moment with a sense of clarity and compassion. Outcomes measured were nurses' self-reported practice benefit and interest in learning about and using mindfulness practices. Five hundred forty-five nurses attended the session. Most nurses (71%) reported benefit/great benefit from the session. Guided imagery and the mindful moment were the most frequently selected practices nurses would use and learn. Nursing professional development practitioners can incorporate mindfulness experiential learning opportunities into their existing education offerings. PMID- 29975313 TI - Promoting Learning Using Case-Based Strategies in Nursing Professional Development. AB - Realistic situations can be used to develop a variety of learning activities, including case reports, standard and evolving case studies, and problem-based learning. Most case-based strategies are aimed at promoting learner interaction, problem solving, and collaborative learning. This article provides a description and discussion of how each can be applied. Hints for developing the different types of cases are included, followed by specific examples. PMID- 29975314 TI - The Design of an Evidence-Based Competency Model. AB - A nursing professional practice model is designed to provide a framework for how nursing practices, communicates, leads, collaborates, and provides the highest quality of care as individuals navigate the complex healthcare system. An infrastructure for learning, competency, and performance needs to be integrated into this model as a foundation for accelerating business and clinical initiatives, promoting standardization, and sharing successful practices. This article describes the process that a large healthcare system used to develop a 5 year strategy whose outcomes resulted in professional and foundational competency domains, assumptions about their use, and future work to align and embed these competencies into the current environment. It provides a road map for nursing professional development practitioners to identify evidenced-based competencies which reflect the professional practice model and then use it as a framework to impart the knowledge, skills, and judgment required for practicing professional nurses. PMID- 29975315 TI - Learning Style Preferences of Practicing Nurses. AB - Nursing professional development practitioners are encouraged to consider incorporating preferred learning styles into professional development programs. However, conclusive evidence about preferred learning styles does not exist. This study describes the preferred learning styles of nursing staff. Results showed that learning style preferences existed and were correlated with satisfaction, years of experience, and gender. The results can be used to plan and deliver professional development opportunities that are engaging and promote retention of learning. PMID- 29975316 TI - Interprofessional Education: Insights From a Cohort of Nursing Students. AB - The central research questions of this study sought to understand the experiences of nursing students participating in an interprofessional simulation experience. This study used a nonrandom, purposive sample of 75 nursing students from one Midwestern university. Conventional content analysis was used to analyze the data. Five primary themes emerged from the data: (a) benefits of interprofessional collaboration, (b) communication, (c) "real-life" learning, (d) increased self-confidence, and (e) intraprofessional collaboration. The results of this study reveal the value of participation in interprofessional simulation activities and emphasize the need for continued development and implementation of such activity into nursing education. PMID- 29975317 TI - Preparing Nurse Leaders in Nursing Professional Development: Legal and Ethical Issues for Nursing Professional Development Leaders. PMID- 29975318 TI - Stages of Transition and Transition Shock. PMID- 29975319 TI - A Tool for Teaching Six Mindfulness Strategies. PMID- 29975320 TI - Column Editor Introduction: Column Editor Introduction. PMID- 29975321 TI - Nursing Professional Development: Our Spheres of Expansion. PMID- 29975322 TI - Educating and Supporting Preceptors. PMID- 29975323 TI - A Unique, Hybrid Approach to the Clinical Immersion Experience. AB - Through clinical immersion experiences (IEs), prelicensure nursing students work with a registered nurse preceptor to experience their schedule and patient assignment. IEs can have advantages for the practice and academic partners and individual students. However, there are also challenges to providing IEs, particularly for healthcare organizations. Collaborative planning and results are reported of a promising IE model, the hybrid immersion experience, which addressed the disadvantages and resulted in positive outcomes for all stakeholders. PMID- 29975324 TI - Tool Development and Testing for Selection of Nursing Preceptors. PMID- 29975326 TI - A Few Initial Thoughts on Receiving the Baton. PMID- 29975325 TI - Passing the Baton. PMID- 29975327 TI - Assessment of Infraorbital Hypesthesia Following Orbital Floor and Zygomaticomaxillary Complex Fractures Using a Novel Sensory Grading System. AB - PURPOSE: Introduction of a novel sensory grading system to assess the incidence and long-term recovery of infraorbital hypesthesia following orbital floor and inferior orbital rim fractures. METHODS: Patients who presented for evaluation of orbital floor and/or zygomaticomaxillary complex (ZMC) fractures between January 2015 and April 2016 were analyzed. Two-point subjective infraorbital sensory grading in 5 discrete anatomic areas was performed. Fractures were repaired based on traditional criteria; hypesthesia was not an indication for surgery. The sensory grading system was repeated a mean 21.7 months (range 18-28) after initial fracture. RESULTS: Sixty-two patients (mean 41.8 years) participated in the initial symptom grading, and 42 patients (67.7%) completed the 2-year follow up. Overall, 20 of 42 patients (47.6%) had some infraorbital hypesthesia. There were fewer with isolated orbital floor fractures versus ZMC fractures (31.8% vs. 68.4%; p = 0.019). Two years postinjury, 9.1% and 40.0% with isolated floor and ZMC fractures, respectively, had persistent sensory disturbance (p = 0.0188). Of patients with sensory disturbance on presentation, 71.4% with isolated floor fractures and 38.5% with ZMC fractures experienced complete sensory recovery (p = 0.1596). Patients with isolated floor fractures had improved recovery after surgery (100% vs. 33.3% recovery; p = 0.0410). Patients with ZMC fractures showed no difference in sensory prognosis between those repaired and observed. CONCLUSIONS: In this pilot study, isolated orbital floor fractures carried a good infraorbital sensory prognosis, further improved by surgical repair. Zygomaticomaxillary complex fractures portended a worse long-term sensory outcome, unaffected by management strategy. This study validates the novel sensory grading system in post-fracture analysis. PMID- 29975328 TI - Analysis of Internet Review Site Comments for Spine Surgeons: How Office Staff, Physician Likeability, and Patient Outcome Are Associated With Online Evaluations. AB - STUDY DESIGN: Observational study. OBJECTIVE: To evaluate how online patient comments will affect website ratings for spine surgeons. SUMMARY OF BACKGROUND DATA: With the ever-growing utilization of physician review websites, healthcare consumers are assuming more control over whom they choose for care. We evaluated patient feedback and satisfaction scores of spine surgeons using comments from three leading physician rating websites: Healthgrades.com, Vitals.com, Google.com. This is the largest review of online comments and the largest review of spine surgeon comments. METHODS: From the North American Spine Society (NASS) membership directory, 210 spine surgeons practicing in Florida (133 orthopedic trained; 77 neurosurgery trained) with online comments available for review were identified, yielding 4701 patient comments. These were categorized according to subject: (1) surgeon competence, (2) surgeon likeability/character, (3) office staff, ease of scheduling, office environment. Type 1 and 2 comments were surgeon dependent factors whereas type 3 comments were surgeon-independent factors. Patient comments also reported a score (1-5), 5 being the most favorable and 1 being the least favorable. RESULTS: There were 1214 (25.8%) comments from Healthgrades, 2839 (60.4%) from Vitals, and 648 (13.8%) from Google. 89.9% (4225) of comments pertained to surgeon outcomes and likeability (comment type 1 and 2), compared with 10.1% (476) surgeon-independent comments (comment type 3) (P < 0.0001). There was a significantly higher number of favorable ratings associated with surgeon-dependent comments (types 1 and 2) compared with surgeon-independent comments (type 3). Surgeon-independent comments were associated with significantly lower scores compared with comments regarding surgeon-dependent factors on all review sites. CONCLUSION: Spine surgeons are more likely to receive favorable reviews for factors pertaining to outcomes, likeability/character, and negative reviews based on ancillary staff interactions, billing, and office environment. Surgeons should continue to take an active role in modifying factors patients perceive as negative, even if not directly related to the physician. LEVEL OF EVIDENCE: 3. PMID- 29975329 TI - Coronal Imbalance after Three-column Osteotomy in Thoracolumbar Congenital Kyphoscoliosis: Incidence and Risk Factors. AB - STUDY DESIGN: Retrospective radiographical clinical study. OBJECTIVE: To investigate the incidence and risk factors of coronal imbalance (CI) after three column osteotomy (3-CO) in patients with thoracolumbar congenital kyphoscoliosis (CKS). SUMMARY OF BACKGROUND DATA: The incidence and risk factors of postoperative CI have been reported in adolescent idiopathic and degenerative lumbar scoliosis. However, limited data exists for patients with CKS after 3-CO. METHODS: We reviewed a consecutive series of patients with CKS who underwent posterior-only 3-CO. Coronal curve patterns were classified according to absolute C7 translation values into: Type A, C7 translation < 30 mm; Type B, C7 translation >= 30 mm and C7 plumb line (C7PL) shifted to the concave side of the main curve; and Type C, C7 translation >= 30 mm and C7PL shifted to the convex side. CI was defined as C7 translation on either side >= 30 mm. According to C7 translation at the latest follow-up, patients was subdivided into an imbalanced group and a balanced group. RESULTS: One-hundred-thirty patients (mean age: 17.7 +/- 5.2 years) were recruited. The mean follow-up was 41.3 +/- 18.5 months. Twenty-six patients (20%) were identified as having CI at the latest follow-up. Compared with the balanced group, the imbalanced group had a larger proportion of preoperative Type C pattern, higher main curve correction, and greater lowest instrumented vertebra (LIV) tilt before and after surgery. Multiple logistic regression showed that risk factors for CI were preoperative type C pattern, preoperative LIV tilt >= 23.5 degrees and immediate postoperative LIV tilt >= 12.3 degrees . CONCLUSION: The incidence of CI in patients with CKS after 3-CO was 20%. A preoperative type C pattern, preoperative LIV tilt >= 23.5 degrees , and immediate postoperative LIV tilt >= 12.3 degrees were found to be associated with CI at the latest follow-up. LEVEL OF EVIDENCE: 3. PMID- 29975330 TI - Loss of Pelvic Incidence Correction after Long Fusion Using Iliac Screws for Adult Spinal Deformity: Cause and Effect on Clinical Outcome. AB - STUDY DESIGN: Retrospective observational cohort study. OBJECTIVE: To determine change in pelvic incidence (PI) and loss of correction after long fusion with iliac screws, the effect of iliac screw loosening, and global alignment according to postoperative PI. SUMMARY OF BACKGROUND DATA: Posterior long fixation and fusion of the thoracic to the ilium is one of the most common surgical treatments for adult spinal deformity (ASD). Long fusion to the sacrum with iliac screws decreases the PI by 3.9 degrees after surgery. PI decreases once by long fusion with iliac screws. However, if the iliac screw loosens, PI may cause correction loss and return to the preoperative PI. METHODS: We retrospectively reviewed the cases of 69 consecutive patients with ASD. Their mean age (SD) was 70.5 (7.3) years, 12% were male. PI was evaluated preoperatively, early- and 1-year postoperatively. We compared change in PI with and without loosening of iliac screws, spinopelvic parameters according to 1 year-postoperative PI. RESULTS: PI decreased significantly from 51.8 degrees (9.3 degrees ) to 48.1 degrees (9.5 degrees ) early postoperatively (P < 0.01). PI increased significantly from 48.1 degrees (9.5 degrees ) to 49.6 degrees (9.7 degrees ) within a year postoperatively (P < 0.01). Significant loss of PI correction (2.3 degrees , P < 0.01) occurred within a year after surgery in patients with iliac screw loosening and was significantly different from the PI loss in those without screw loosening (53.9 degrees , 48.2 degrees , P = 0.03). Pelvic tilt, sacral slope, C7 sagittal vertical axis, global tilt, and T1 pelvic angle were significantly smaller in the group with PI < 50 degrees postoperatively at 1 year compared with the group with PI > 50 degrees . CONCLUSIONS: Although PI decreases after long fusion surgery with iliac screws, significant correction loss appears within a year. Loosening of iliac screws may exacerbate this loss. Patients with PI < 50 degrees postoperatively were able to maintain better global alignment. LEVEL OF EVIDENCE: 3. PMID- 29975331 TI - Dexmedetomidine Preconditioning Ameliorates Inflammation and Blood-Spinal Cord Barrier Damage after Spinal Cord Ischemia-Reperfusion Injury by Down-Regulation High Mobility Group Box 1-Toll-Like Receptor 4-Nuclear Factor kappaB Signaling Pathway. AB - STUDY DESIGN: To evaluate the effect of Dexmedetomidine (Dex) on the inflammatory response and the integrity of blood-spinal cord barrier (BSCB) after spinal cord ischemia-reperfusion injury (SCIRI). OBJECTIVE: To investigate the role of Dex in spinal cord I/R, particularly in the high mobility group box 1-toll-like receptor 4-nuclear factor kappaB (HMGB1-TLR4-NF-kappaB) pathway and the integrity of BSCB. SUMMARY OF BACKGROUND DATA: High mobility group box 1 (HMGB1) has been identified as a key mediator for the inflammatory response after spinal cord injury. Toll like receptor 4-nuclear factor kappaB (TLR4-NF-kappaB) signaling pathway is the downstream of HMGB1. Dex preconditioning could protect the spinal cord from I/R injury by inhibiting HMGB1 and stabilizing the integrity of BSCB. But its underlying mechanism is not fully understood. METHODS: Forty-eight male Japanese white rabbits were randomly assigned to three groups (16 rabbits / group): sham, I/R and Dex + I/R. The hind-limb motor function was assessed at 12 h intervals for 48 h after reperfusion using the modified Tarlov scale score. The expression of HMGB1, TLR4, NF-kappaB and tumor necrosis factor alpha (TNF-alpha) was evaluated by RT-PCR and Western blot. The permeability of BSCB was examined via Evans blue (EB) extravasation. RESULTS: Compared with sham group, spinal cord I/R increased the expression of HMGB1, TLR4, NF-kappaB and TNF-alpha as well as the permeability of BSCB (P < 0.05). Spinal cord I/R induced the decline of the score of hind-limb motor function (P < 0.01).Preconditioning with Dex attenuated the up regulation of the express of HMGB1, TLR4, NF-kappaB, TNF-alpha and stabilized the permeability of BSCB (P < 0.05). Dex preconditioning also improved the hiatopathological outcome and the motor function (P < 0.01). CONCLUSION: Dex preconditioning may inhibit the inflammatory response and stabilize the integrity of BSCB at least partially by inhibiting the HMGB1-TLR4-NF-kappaB signaling pathway to protect spinal cord from ischemia/reperfusion injury. LEVEL OF EVIDENCE: 2. PMID- 29975332 TI - Help for Future Research: Lessons Learned in Trial Design, Recruitment, and Delivery From the "hELP" Study. PMID- 29975333 TI - Human Papillomavirus Correlates With Histologic Anal High-Grade Squamous Intraepithelial Lesions in Hispanics With HIV. AB - OBJECTIVE: To estimate the magnitude of association between anal infection with high-risk human papilloma virus (HR-HPV) types and severity of biopsy-confirmed histopathological anal squamous intraepithelial lesions (SILs) among a clinic based sample of HIV-infected adults in Puerto Rico. METHODS: This cross-sectional study analyzed data from medical records of adult patients who visited a specialized anal neoplasia clinic from June 2015 to December 2017 (n = 239); sociodemographics, behavioral risk factors, medical history, clinical data, and pathology reports were collected. The magnitude of association between anal HR HPV and severity of anal SIL, adjusted for potential confounders, was assessed using a multinomial logistic model. RESULTS: A 78.7% of patients had anal HR-HPV infection, 43.9% had histopathological low-grade SIL (LSIL), and 37.7% had histopathological high-grade SIL (HSIL). The prevalence of anal HR-HPV infection was 63.6% among patients with no anal SIL, 70.5% for those with LSIL and 95.6% for those with HSIL. After adjusting for different predictors, patients with anal HR-HPV infection were more likely to have HSIL (odds ratio, 11.0; 95% confidence interval, 3.2-37.2) than those without anal HR-HPV infection, whereas no significant excess was observed for LSIL (odds ratio, 1.4; 95% confidence interval, 0.6-3.1). CONCLUSIONS: This study showed a strong association between anal HR-HPV infection and HSIL. Likewise, a high prevalence of anal HR-HPV infection and presence of anal SIL was observed among HIV-infected individuals. Our result highlights the importance of screening for anal HR-HPV infection and anal SIL and optimizing strategies for HPV vaccination in HIV-infected individuals. PMID- 29975334 TI - Long-Term Outcomes of Women With Recurrent Vulvovaginal Candidiasis After a Course of Maintenance Antifungal Therapy. AB - OBJECTIVES: Data about long-term clinical outcome after a course of maintenance fluconazole in those with recurrent vulvovaginal candidiasis (RVVC) is lacking. We aimed to determine the rate of recurrence at a minimum of 6 months after completion of maintenance therapy. METHODS: A retrospective analysis of women with Candida albicans RVVC from January 2008 to January 2017 was performed using chart review to obtain information about recurrence after maintenance therapy. Patients were considered resolved if they had no further episodes of candidiasis, sporadic with less than 3 episodes yearly and ongoing with greater than 3 episodes yearly. RESULTS: Approximately 1,672 patients with C. albicans vaginal isolates were identified. Of these, 201 met the criteria for RVVC. The mean age was 40.4 years; 151 (77.4%) were white, 133 (66.2%) had comorbid vulvar conditions, and 76 (37.8%) had a risk factor for vulvovaginal candidiasis. One hundred twenty complete charts were further analyzed. The mean length of follow up after discontinuing maintenance therapy was 39.9 months. After the initial course, 23 (19.2%), 21 (17.5%), and 76 (63.3%) were resolved, sporadic and ongoing, respectively. Risk factors, comorbid vulvar conditions, obesity, menopause status, and length of therapy were not associated with relapse. Age 40 or older was associated with relapse (p = .018). Of the 201 total patients with RVVC, 22 (10.9%) of patients self-reported at least 1 adverse event. The most common was gastrointestinal symptoms (8 [4%]). CONCLUSIONS: Although RVVC can be controlled, relapse is common after an initial course of maintenance fluconazole. Ongoing maintenance remains the most effective treatment option. PMID- 29975335 TI - Cervical Cytology and Histology After Solid Organ Transplant: A Longitudinal Cohort Study. AB - OBJECTIVES: The ideal frequency of cervical cancer screening in women with solid organ transplants (SOTs) remains to be determined. We aimed to assess the longitudinal rates of cytologic and histologic cervical abnormalities in women after SOT. METHODS: We retrospectively reviewed health records of women aged 18 to 60 years who received their first kidney, liver, pancreas, or combination transplant at Mayo Clinic (Rochester, Minnesota) from 1995 through 2011. Patient demographics, cervical cytology and histology, and high-risk human papillomavirus (hrHPV) testing data were abstracted. All women included in the study had documentation of at least 1 cervical cytologic assessment after SOT. Cumulative incidence of abnormal cytology or histology was estimated using the Kaplan-Meier method. RESULTS: In total, 459 women (mean age at SOT, 43.9 years) were included in the study. Pre-SOT cytology was benign in 226 (97.4%) of 232 patients with available results. During follow-up, 9 women had cervical intraepithelial neoplasia grade 3 or higher (CIN3) histology. The cumulative incidence of CIN3 was 0.2% (95% confidence interval [CI], 0%-0.6%) at 1 year after SOT, 0.7% (95% CI, 0%-1.5%) at 2 years, 1.9% (95% CI, 0.5%-3.3%) at 5 years, and 3.1% (95% CI, 0.4%-5.7%) at 10 years. At the time of the first post-SOT cervical cytology, a greater proportion of women who were hrHPV positive had abnormal findings compared with hrHPV-negative women (10/15 [66.7%] vs 1/71 [1.4%]; p < .001). CONCLUSIONS: The cumulative incidence of CIN3 in the first 5 years after SOT approximates the level of risk for which annual cytologic assessment has been recommended. PMID- 29975337 TI - Partners of Individuals with Borderline Personality Disorder: A Systematic Review of the Literature Examining Their Experiences and the Supports Available to Them. AB - Over a third of individuals with borderline personality disorder (BPD) are in long-term romantic partnerships, yet little is known about the experiences of their partners. Because difficulties in interpersonal relationships are a hallmark of BPD, it is especially important to understand the support needs of their romantic partners. This systematic review investigates the experiences of romantic partners of adult individuals with BPD and the interventions designed to support them. Twenty-two articles were found, 13 of which pertained to partner experiences and 9 to interventions. Thematic analysis was used to identify three main themes in the descriptions of partners' experiences: emotional challenges, dual roles as both a romantic partner and parental/therapeutic figure, and lack of control. The available interventions, which consisted of educational and skills-based programs with limited efficacy data, addressed only a small portion of the subthemes identified in the literature describing partners' experiences. The discrepancy between the needs identified in the partner-experience literature and the interventions available suggests a need to develop and evaluate more partner-oriented programming. Such programming should use psychoeducation, peer support, and individual- and relationship-based skills development to address and therefore improve the experiences of partners of individuals with BPD. PMID- 29975338 TI - Compassion and Loving-Kindness Meditation: An Overview and Prospects for the Application in Clinical Samples. AB - OBJECTIVES: This article presents a brief overview of the empirical evidence of well-established mindfulness interventions and an in-depth review of less established compassion-based interventions (CBIs) and loving-kindness meditation (LKM). Definitions, cognitive and physiological mechanisms, and methods of assessment are discussed. METHOD: A literature review using the databases Google Scholar, PsycINFO, and PubMed was conducted. RESULTS: Whereas the efficacy of mindfulness-based stress reduction and mindfulness-based cognitive therapy has been documented in many trials, only seven randomized, controlled trials have been completed on CBIs and LKM. In these trials, CBIs were effective in treating psychotic disorders, affective disorders with psychotic features, major depressive disorder, eating disorders, and patients with suicide attempts in the past year; LKM was effective in treating chronic pain; and a combination of both was effective for borderline personality disorder. A larger number of nonrandomized studies indicate that CBIs and LKM may be effective in treating a wide range of clinical conditions, including depression, anxiety disorders, chronic pain, and posttraumatic stress disorder. CONCLUSIONS: Further studies are needed to confirm the promising effects of CBIs and LKM. Preliminary evidence suggests that both approaches might be beneficial across various clinical populations. Future studies need to clarify whether these approaches might be options as stand-alone treatments or as adjuncts or augmentation of evidence based methods in psychotherapy. PMID- 29975339 TI - Conceptualization, Assessment, and Treatment of Traumatic Stress in First Responders: A Review of Critical Issues. AB - First responders are regularly confronted with exposure to traumatic events, including potentially life-threatening situations as well as the grave injuries and deaths of colleagues and civilians. Evidence indicates that the prevalence of posttraumatic stress disorder (PTSD) is substantially higher among first responders than the general population. This article provides information about the outpatient trauma services at McLean Hospital's LEADER (Law Enforcement, Active Duty, Emergency Responder) program to assist clinicians who encounter these first responders in their practices or who are specifically interested in working with this patient population. We begin by synthesizing the literature on the prevalence of PTSD in first responders following work-related exposure to traumatic stress, and by addressing the occupation-specific risk factors and the third-variable risk factors that may contribute to potentiated risk. We then discuss assessment strategies and treatment options used in our program, which is tailored for individuals who are dealing with mental health issues stemming from occupation-specific traumatic-stress exposure. We also address the unique challenges of treating traumatized first responders with more complex issues such as traumatic stress exposure across the lifespan and safety issues, including acute suicidality. We conclude by discussing notable gaps in the literature, including the need to investigate why and how women present with different PTSD symptoms than men and how these differences need to be taken into account in determining appropriate treatment for women. PMID- 29975340 TI - Ambushed by Memories of Trauma: Memory-Processing Interventions in an Adolescent Boy with Nocturnal Dissociative Episodes. PMID- 29975336 TI - Depression and Anxiety in Heart Failure: A Review. AB - LEARNING OBJECTIVES: After participating in this activity, learners should be better able to:* Identify the relationships between depression, anxiety, and heart failure (HF).* Assess methods for accurately diagnosing depression and anxiety disorders in patients with HF.* Evaluate current evidence for treatment of anxiety and depression in patients with HF. BACKGROUND: In patients with heart failure (HF), depression and anxiety disorders are common and associated with adverse outcomes such as reduced adherence to treatment, poor function, increased hospitalizations, and elevated mortality. Despite the adverse impact of these disorders, anxiety and depression remain underdiagnosed and undertreated in HF patients. METHODS: We performed a targeted literature review to (1) identify associations between depression, anxiety, and HF, (2) examine mechanisms mediating relationships between these conditions and medical outcomes, (3) identify methods for accurately diagnosing depression and anxiety disorders in HF, and (4) review current evidence for treatments of these conditions in this population. RESULTS: Both depression and anxiety disorders are associated with the development and progression of HF, including increased rates of mortality, likely mediated through both physiologic and behavioral mechanisms. Given the overlap between cardiac and psychiatric symptoms, accurately diagnosing depression or anxiety disorders in HF patients can be challenging. Adherence to formal diagnostic criteria and utilization of a clinical interview are the best courses of action in the evaluation process. There is limited evidence for the efficacy of pharmacologic and psychotherapy in patients with HF. However, cognitive-behavioral therapy has been shown to improve mental health outcomes in patients with HF, and selective serotonin reuptake inhibitors appear safe in this cohort. CONCLUSIONS: Depression and anxiety disorders in HF patients are common, underrecognized, and linked to adverse outcomes. Further research to improve detection and develop effective treatments for these disorders in HF patients is badly needed. PMID- 29975341 TI - A Brief Overview of Advances in LGBT Mental Health Advocacy in Lebanon. PMID- 29975342 TI - A Cost Reimbursement Model for Hepatitis C Treatment Care Coordination. AB - OBJECTIVE: To estimate the cost of delivering a hepatitis C virus care coordination program at 2 New York City health care provider organizations and describe a potential payment model for these currently nonreimbursed services. DESIGN: An economic evaluation of a hepatitis C care coordination program was conducted using micro-costing methods compared with macro-costing methods. A potential payment model was calculated for 3 phases: enrollment to treatment initiation, treatment initiation to treatment completion, and a bonus payment for laboratory evidence of successful treatment outcome (sustained viral response). SETTING: Two New York City health care provider organizations. PARTICIPANTS: Care coordinators and peer educators delivering care coordination services were interviewed about time spent on service provision. De-identified individual-level data on study participant utilization of services were also used. INTERVENTION: Project INSPIRE is an innovative hepatitis C care coordination program developed by the New York City Department of Health and Mental Hygiene. MAIN OUTCOME MEASURES: Average cost per participant per episode of care for 2 provider organizations and a proposed payment model. RESULTS: The average cost per participant at 1 provider organization was $787 ($522 nonoverhead cost, $264 overhead) per episode of care (5.6 months) and $656 ($429 nonoverhead cost, $227 overhead, 5.7 months) at the other one. The first organization had a lower macro costing estimate ($561 vs $787) whereas the other one had a higher macro-costing estimate ($775 vs $656). In the 3-phased payment model, phase 1 reimbursement would vary between the provider organizations from approximately $280 to $400, but reimbursement for both organizations would be approximately $220 for phase 2 and approximately $185 for phase 3. CONCLUSIONS: The cost of this 5.6-month care coordination intervention was less than $800 including overhead or less than $95 per month. A 3-phase payment model is proposed and requires further evaluation for implementation feasibility. Project INSPIRE's HCV care coordination program provides good value for a cost of less than $95 per participant per month. The payment model provides an incentive for successful cure of hepatitis C with a bonus payment; using the bonus payment to support HCV tele-mentoring expands HCV treatment capacity and empowers more primary care providers to treat their own patients with HCV. PMID- 29975343 TI - Local Health Departments' Engagement in Addressing Health Disparities: The Effect of Health Informatics. AB - CONTEXT: Health disparities and health inequities can lead to poor health outcomes. However, health disparities continue to persist in communities across the United States, presenting a crucial public health challenge. Persisting budget cuts and workforce challenges tend to hinder local health departments' (LHDs') ability to assess and address health disparities. OBJECTIVES: To examine the extent to which LHDs' use of informatics effects their engagement in strategies and activities addressing health disparities. METHODS: Data from the 2016 Profile of LHDs were used in examining the association of informatics with 9 activities addressing health disparities/inequities. RESULTS: Fifty-nine percent of LHDs used data and described health disparities in their jurisdiction, and 12% conducted original research to link health disparities to differences in social or environmental conditions. Less than 40% of LHDs prioritized resources for the reduction of health disparities. LHDs that implemented information systems had increased odds of describing the disparities in their jurisdiction (P < .01) and having prioritized resources for the reduction of disparities (P < .01). Per capita expenditures, participation in a national accreditation program process, and a larger LHD population were also positively associated with 7 of 9 activities for addressing health disparities/inequities. CONCLUSIONS: As LHDs advance efforts to reduce health disparities and inequities, leadership will find informatics a useful strategy. National initiatives aimed to boost LHDs' engagement in the reduction of disparities might benefit from our findings, positing a positive influence of informatics. PMID- 29975345 TI - CHOROIDAL THICKNESS, VASCULAR FACTORS, AND AGE-RELATED MACULAR DEGENERATION: The ALIENOR Study. AB - PURPOSE: To study the associations of subfoveal choroidal thickness with vascular risk factors and age-related macular degeneration. METHODS: Two hundred sixty-one participants of the Alienor study had gradable enhanced-depth imaging optical coherence tomography scans of the macula and available data on vascular and genetic risk factors (assessed through face-to-face interview and fasting blood samples) and age-related macular degeneration status (assessed from retinal photographs and optical coherence tomography). Subfoveal choroidal thickness was measured manually on one horizontal scan passing through the fovea. RESULTS: In a multivariate mixed linear model, subfoveal choroidal thickness was independently associated with age greater than 80 years (-21.77 MUm, P = 0.02), axial length ( 21.77 MUm, P < 0.0001), heavy smoking (>=20 pack-years: -24.89 MUm, P = 0.05), fasting blood glucose higher than 7 mmol/L (-53.17 MUm, P = 0.02), and lipid lowering treatment (+18.23, P = 0.047). After multivariate adjustment for age, sex, axial length, and vascular and genetic risk factors, subfoveal choroidal thickness was thinner in eyes with central hyperpigmentation (-45.39 MUm, P = 0.006), central hypopigmentation (-44.99 MUm, P = 0.001), and central pigmentary abnormalities (-44.50 MUm, P = 0.001), but not in eyes with late age-related macular degeneration (-18.05 MUm, P = 0.33) or soft drusen. CONCLUSION: These findings indicate a relationship between vascular risk factors and choroidal thinning and suggest an early involvement of the choroid in the pathogenesis of age-related macular degeneration. PMID- 29975344 TI - PHACOEMULSIFICATION CATARACT SURGERY WITH PROPHYLACTIC INTRAVITREAL BEVACIZUMAB FOR PATIENTS WITH COEXISTING DIABETIC RETINOPATHY: A Meta-Analysis. AB - PURPOSE: To evaluate the clinical effectiveness of intravitreal bevacizumab (IVB) injection combined with cataract surgery in the treatment of patients with cataract and coexisting diabetic retinopathy (DR). METHODS: Pertinent comparative studies were identified through systemic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register up to March 1, 2016. Outcome measures included corrected distance vision acuity, central macular thickness, and progression of DR and maculopathy. A meta-analysis was performed using RevMan (Cochrane Collaboration, Oxford, United Kingdom). RESULTS: Six studies describing a total of 283 eyes were identified. The meta-analysis results showed that corrected distance vision acuity measured at 1 month and 3 months after cataract surgery was significantly better in the IVB groups than in the control groups (P < 0.00001 and P = 0.01), whereas the corrected distance vision acuity at 6 months did not vary significantly between the 2 groups (P = 0.24). Similarly, the central macular thickness at 1, 3, and 6 months after surgery was significantly thinner in the IVB groups than in the control groups (P = 0.01, P = 0.0004, and P = 0.01, respectively). At 6 months, the progression of postoperative DR and maculopathy occurred more frequently in the control group than in the IVB group (P = 0.0001 and P < 0.0001, respectively). CONCLUSION: Our meta-analysis indicates that cataract surgery combined with IVB seems to be an effective treatment in patients with coexisting DR in the short term (up to 6 months). More randomized, prospective, and large-sample-sized trials are needed to evaluate the long-term effects of IVB at the time of cataract surgery in patients with DR. PMID- 29975346 TI - The Potential of Glycemic Control and Body Weight Change as Early Markers for Pancreatic Cancer in Patients With Long-standing Diabetes Mellitus: A Case Control Study. AB - OBJECTIVES: The aim of this study was to characterize the role of glycemic control and weight change as markers for pancreatic cancer (PaC) in patients with long-standing diabetes. METHODS: We conducted case-control analyses in patients with long-standing diabetes (>2 years) in the United Kingdom-based Clinical Practice Research Datalink. Cases were patients with PaC matched to control subjects on variables including age, sex, and diabetes duration. We compared glycated hemoglobin (HbA1c) levels, blood glucose levels, and weight change before cancer detection (matched date) between cases and control subjects to assess associations between the potential markers and PaC. RESULTS: Cases were more likely than control subjects to have high HbA1c levels. The adjusted odds ratio (aOR) was 4.94 (95% confidence interval [CI], 3.52-6.94) for HbA1c of 64.0 mmol/mol or greater compared with HbA1c of 47.5 mmol/mol or less within 6 months before cancer detection and within >1 to 2 years, 2.66 (95% CI, 2.00-3.54). Weight loss was also more common in cases, with an aOR of 15.40 (95% CI, 10.65 22.26) for loss of 15.0% body weight or greater compared with stable weight. The aOR for patients with both weight loss of 15.0% or greater and high HbA1c at 2 years or less before diagnosis was 60.97 (95% CI, 35.87-103.65), compared with patients with neither. CONCLUSIONS: Poor glycemic control and weight loss, particularly in combination, may be useful early markers for PaC in patients with long-standing diabetes. PMID- 29975348 TI - Spatial Distribution of Pancreatic Stones in Chronic Pancreatitis. AB - OBJECTIVES: The aim of this study was to establish a standard to describe the spatial distribution of pancreatic stones in chronic pancreatitis (CP). METHODS: Two hundred forty-seven CP patients with pancreatic stones from June to December 2012 were enrolled. Two-dimensional images from coronal projection of 3 dimensional computed tomography images of pancreatic stones were gained. The number (n) of all stones and the geometric standard deviation (sigma) of distances between the centroid of all stones and the centroids of every stone that represented the spatial distribution nonuniformity were calculated by Stone Reconstruction and Identification Programming System. RESULTS: The mean value of n and sigma were 13.6 and 22.5; n > 13.6 and sigma > 22.5 were determined as "multistones" and "nonuniform," respectively. Compared with alcoholic CP, idiopathic CP was less prone to multistones (odds ratio [OR], 0.310) and more prone to nonuniform (OR, 3.247). Pancreatic pseudocyst (OR, 2.211) in CP course was a risk factor of multistones, whereas diabetes mellitus in first-/second /third-degree relatives (OR, 0.382) was a protective factor. Age at diagnosis of pancreatic stones (OR, 1.022) was a risk factor of nonuniformity. CONCLUSIONS: Compared with idiopathic CP, alcoholic CP patients were prone to more pancreatic stones that distribute more uniformly. PMID- 29975349 TI - Adverse Oncologic Impact of New-Onset Diabetes Mellitus on Recurrence in Resected Pancreatic Ductal Adenocarcinoma: A Comparison With Long-standing and Non Diabetes Mellitus Patients. AB - OBJECTIVES: Diabetes mellitus (DM) is prevalent with pancreatic ductal adenocarcinoma (PDAC). Importantly, new-onset DM is characteristic of the disease and could be an early sign of PDAC. The clinical outcome of PDAC with new-onset DM may differ from that in patients without DM or long-standing DM. METHODS: We retrospectively reviewed medical records of PDAC patients who underwent curative resection between 2006 and 2014. New-onset DM was defined as a diagnosis of DM within 24 months before the diagnosis of PDAC. Survival analysis and Cox regression were performed to evaluate oncologic outcomes. RESULTS: No significant differences in clinical characteristics were found in 3 groups. Overall survival of patients with new-onset DM was worse than non-DM (22 vs 33 months, P = 0.039). New-onset DM was highly associated with early recurrence (hazard ratio, 1.451; 95% confidence interval, 1.054-1.999; P = 0.022). Poor oncologic outcome of new onset DM was more pronounced in low T stage patients (overall survival in low vs high T stage, 33 vs 18 months; P = 0.129). CONCLUSIONS: Pancreatic ductal adenocarcinoma with new-onset DM has worse oncologic outcomes than non-DM or long standing DM. These results suggest that new-onset DM represents aggressive tumor biology, especially in the early stage of PDAC. PMID- 29975347 TI - Systemic Depletion of Nerve Growth Factor Inhibits Disease Progression in a Genetically Engineered Model of Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: In patients with pancreatic ductal adenocarcinoma (PDAC), increased expression of proinflammatory neurotrophic growth factors (eg, nerve growth factor [NGF]) correlates with a poorer prognosis, perineural invasion, and, with regard to NGF, pain severity. We hypothesized that NGF sequestration would reduce inflammation and disease in the KPC mouse model of PDAC. METHODS: Following biweekly injections of NGF antibody or control immunoglobulin G, beginning at 4 or 8 weeks of age, inflammation and disease stage were assessed using histological, protein expression, and quantitative polymerase chain reaction analyses. RESULTS: In the 8-week anti-NGF group, indicators of neurogenic inflammation in the dorsal root ganglia (substance P and calcitonin gene-related peptide) and spinal cord (glial fibrillary acidic protein) were significantly reduced. In the 4-week anti-NGF group, TRPA1 mRNA in dorsal root ganglia and spinal phosphorylated ERK protein were elevated, but glial fibrillary acidic protein expression was unaffected. In the 8-week anti-NGF group, there was a 40% reduction in the proportion of mice with microscopic perineural invasion, and no macrometastases were observed. CONCLUSIONS: Anti-NGF treatment beginning at 4 weeks may increase inflammation and negatively impact disease. Treatment starting at 8 weeks (after disease onset), however, reduces neural inflammation, neural invasion, and metastasis. These data indicate that NGF impacts PDAC progression and metastasis in a temporally dependent manner. PMID- 29975350 TI - A Novel Approach for Therapeutic Delivery to the Rodent Pancreas Via Its Arterial Blood Supply. AB - OBJECTIVES: Endovascular techniques can now access the arterial blood supply of the pancreas in humans to enable therapeutics to reach the gland in high concentrations while concurrently avoiding issues related to non-targeted delivery. However, there is no way to replicate this in small animals. In a rat model, we therefore developed a novel non-terminal technique to deliver therapeutics to different regions of the pancreas, via its arterial blood supply. METHODS: In female Wistar rats, selective branches of the celiac artery were temporarily ligated, depending on the region of the pancreas being targeted. Trypan blue dye was then administered as a surrogate marker for a therapeutic agent, via the celiac artery, and its staining/distribution throughout the pancreas determined. Postoperatively, animals were monitored daily, and serum was evaluated for markers of pancreatitis, liver, and metabolic function. RESULTS: Using this technique, we could selectively target the head, body/tail, or entire gland of the pancreas, via its arterial blood supply, with minimal nontarget staining. Following the procedure, all animals recovered with no evidence of pancreatitis or liver/metabolic dysfunction. CONCLUSIONS: Our study demonstrates a novel technique that can be used to selectively deliver therapeutics directly to the rat pancreas in a safe manner with full recovery of the animal. PMID- 29975351 TI - A Clinical Model for the Early Diagnosis of Acute Pancreatitis in the Emergency Department. AB - OBJECTIVE: This study aimed to develop a diagnostic model that predicts acute pancreatitis (AP) risk before imaging. METHODS: Emergency department patients with serum lipase elevated to 3 times the upper limit of normal or greater were identified retrospectively (September 1, 2013-August 31, 2015). An AP diagnosis was established by expert review of full hospitalization records. Candidate predictors included demographic and clinical characteristics at presentation. Using a derivation set, a multivariable logistic regression model and corresponding point-based scoring system was developed to predict AP. Discrimination accuracy and calibration were assessed in a separate validation set. RESULTS: In 319 eligible patients, 182 (57%) had AP. The final model (area under curve, 0.92) included 8 predictors: number of prior AP episodes; history of cholelithiasis; no abdominal surgery (prior 2 months); time elapsed from symptom onset; pain localized to epigastrium, of progressively worsening severity, and severity level at presentation; and extent of lipase elevation. At a diagnostic risk threshold of 8 points or higher (>=99%), the model identified AP with a sensitivity of 45%, and a specificity and a positive predictive value of 100%. CONCLUSIONS: In emergency department patients with lipase elevated to 3 times the upper limit of normal or greater, this model helps identify AP risk before imaging. Prospective validation studies are needed to confirm diagnostic accuracy. PMID- 29975352 TI - Impact of the Controlling Nutritional Status Score on the Prognosis After Curative Resection of Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: The controlling nutritional status (CONUT) score is a useful tool to evaluate immune-nutritional status. This study aimed to investigate the impact of the CONUT score on short- and long-term outcomes after curative resection of pancreatic ductal adenocarcinoma (PDAC). METHODS: Consecutive 344 PDAC patients receiving pancreatectomy without neoadjuvant therapy were examined retrospectively. After the best predictive value of the CONUT score for survival was identified, association between the CONUT score and long-term outcomes was evaluated using log-rank tests and a Cox regression model. Then correlations between the CONUT score and postoperative complications were analyzed. RESULTS: The optimal cutoff value of the CONUT score was 4. The high CONUT score group showed significantly lower overall survival than the low CONUT score group (P = 0.002). In contrast, no significant difference in recurrence-free survival was found (P = 0.43). A multivariate analysis demonstrated that high CONUT score had an independent association with overall survival (hazard ratio, 1.64; P = 0.003). The CONUT score showed no association with postoperative pancreatic fistula, Clavien-Dindo grade, or postoperative hospital stay. CONCLUSION: The CONUT score had an independent association with survival in patients with PDAC after pancreatectomy and was not associated with recurrence or postoperative complications. PMID- 29975353 TI - Pathologic Evaluation of Surgical Margins in Pancreatic Cancer Specimens Using Color Coding With Tissue Marking Dyes. AB - OBJECTIVES: Processing of pancreatoduodenectomy specimens is not standardized; the clinical impact of pathologic surgical margins remains controversial. We used the color-coding method using tissue-marking dyes to evaluate margin status of resected specimens to assess its association with postoperative recurrence. METHODS: We developed a unified processing approach to assess pancreatoduodenectomy specimens. Five surgical margins of resected pancreatic specimens were marked with 5 colors. Microscopic resection margin distance (RMD) from margin closest to the tumor was evaluated for each surgical margin. Forty patients assessed using nonunified protocols, and 98 patients assessed using unified protocols were included. RESULTS: The frequency of tumors with RMD of 1 mm or less in posterior margin was significantly lower and that in portal vein/superior mesenteric vein margin was significantly higher in unified protocol group than in nonunified protocol group (P < 0.001). In unified protocol group, tumors with RMD of 1 mm or less correlated with locoregional recurrence (P = 0.025) and recurrence-free survival (P = 0.030). Multivariate analysis revealed that tumor size and lymph node metastasis were independent indicators for disease recurrence. CONCLUSIONS: Resection margin distance of 1 mm or less was a predictor for disease recurrence, particularly for locoregional recurrence. Early detection of small-sized tumors without lymph node metastasis is necessary for improved clinical outcomes in pancreas cancers. PMID- 29975354 TI - Short-term Outcomes of Laparoscopic Versus Open Treatment of Internal Enteric Fistulae: A Logistic Regression Analysis. AB - Although laparoscopy improves outcomes for common general surgical procedures, its role in complex colorectal procedures is not clearly defined. We sought to evaluate whether laparoscopy retains its short-term benefits when used for treatment of complex intra-abdominal fistulae. A retrospective analysis was conducted including patients undergoing surgeries for enteric fistulas over a 7 year period. The chi tests, the Fisher exact tests, and Student t tests were used. Logistic regression models were used to assess the relationship between outcome and predictors. A total of 74 patients (31 open, 43 laparoscopic) were included. There was no difference in age, sex, body mass index, and comorbidities between the 2 groups. The laparoscopic group had significantly shorter length of stay, estimated blood loss, and significantly lower incidence of major complications compared with open group. Our findings suggest that laparoscopy is safe and retains its short-term benefits for treatment of complex colorectal and small bowel procedures. PMID- 29975355 TI - Multimodal Treatment Strategies for Esophageal Perforation. AB - PURPOSE: Esophageal perforation constitutes a potentially life-threatening condition, and this study aimed to evaluate the indications and outcome for the different treatment modalities. PATIENTS AND METHODS: In total, 43 patients with esophageal perforation were considered for this retrospective analysis. Age, sex, length of hospital stay and intensive care treatment, in-hospital mortality, localization of perforation and etiology, treatment modality, and 90-day morbidity were analyzed. RESULTS: Most patients suffered from Boerhaave syndrome and from iatrogenic esophageal perforation. In total, 63% of patients (26/41) received successful nonoperative treatment, whereas 36% required additional surgery. Two patients (5%) underwent primary surgery. In all cases no esophagectomy was necessary. In-hospital mortality was 7%. During the 90-day follow-up 1 patient with stenosis required repetitive dilatations. CONCLUSIONS: Initial endoscopic treatment, either by stent or by endosponge, alone or combined with an additional operative treatment, seems feasible in patients suffering from esophageal perforation. In all patients, there was no need for esophagectomy. PMID- 29975356 TI - Lessons Learned From a Faulty Transoral Endoscopic Thyroidectomy Vestibular Approach. AB - BACKGROUND: Transoral endoscopic thyroidectomy via vestibular approach (TOETVA) is currently considered the most promisingly scarless approach to the thyroid and has gained more acceptance. MATERIALS AND METHODS: We described a case of faulty TOETVA. RESULTS: The faulty TOETVA resulted in pneumomediastinum, diffuse subcutaneous emphysema, prolonged surgery, and anesthesia. CONCLUSIONS: The important technical considerations during TOETVA, including the use of external retraction, the identification of the subplatysmal plane of dissection, CO2 insufflation settings, the learning curve, and patient selection, were described and discussed. PMID- 29975357 TI - Uniportal Thoracoscopic Approach For Pulmonary Hydatid Cyst: Preliminary Results. AB - PURPOSE: Pulmonary hydatid cyst is a preventable parasitary disease with high prevalence in low-medium income countries. Thoracoscopic approach is seen in the literature as small-case groups and multiple-port incisions are observed in these studies. Unlike other thoracoscopic approaches for the surgical treatment, we describe the single-port technique for the first time in our study. We attempt to compare the clinical outcomes and preliminary results of patients with pulmonary hydatid cyst treated with either minimally invasive or thoracotomy. METHODS: The medical records of 66 patients undergoing surgery for pulmonary hydatid cyst disease between January 2013 and July 2017 were reviewed. The number of patients who underwent thoracotomy was 48, whereas 18 were managed by single-port video assisted thoracoscopic surgery. Variables statistically compared between the 2 groups were age, diameter of the cystic, operation time, volume and duration of the drainage, postoperative complications, length of stay, duration of narcotic analgesic usage, and pain score. RESULTS: Thoracoscopic approach was superior to conventional thoracotomy in terms of operation time, drainage volume, time to drain removal, hospital stay, narcotic analgesic treatment duration, and postoperative pain scores. All thoracoscopic procedures were concluded successfully, and conversion to open surgery was not required. No postoperative mortality was seen in either group. During the follow-up period, no recurrence was encountered in either group. CONCLUSIONS: Uniportal thoracoscopic approach is a safe option for the treatment of hydatid cyst disease. It can be used as an alternative to thoracotomy, depending on the size and location of the lesion. PMID- 29975358 TI - A Simple Method to Aid Safe Resection Margin During Sleeve Gastrectomy in Patients With Incidental Gastric Lesions. AB - In contrast to colonic tattooing, data on dye-marking before gastric operations are scarce. A simple method of gastric tattooing before sleeve gastrectomy (SG) is presented. SG, under tattoo guidance has never been reported. Submucosa of the lesion is injected with 1 to 2 mL of carbon particles (Spot, PA) 24 hours before SG. At surgery, serosal dye stain is identified and stapling achieved with care to remove all dye-stained segment. Dye spread on the serosal surface differed significantly. However, as all the dye-stained segments were avoidable during stapling, 2 neuroendocrine tumors, 2 leiomyomas, and 1 benign ulcer were resected with clear histologic margins. The method presented herein may decrease the need for operative gastroscopy, mucosal resection, or laparoscopic gastrotomy in a number of patients. Because of the problem of the dye spreading, its utilization may be inappropriate in lesions that are closer to the minor curvature and incisura angularis in particular. PMID- 29975359 TI - Editorial. AB - no summary. PMID- 29975360 TI - Clinical picture, pathogenesis and psychometric assessment of negative symptoms of schizophrenia. AB - Negative symptoms of schizophrenia constitute a serious diagnostic and therapeutic problem. They substantially account for the impairment of health, social functioning and quality of life whereas treatment is difficult. In this paper the development of the concept of schizophrenia and negative symptoms is presented. The models of positive and negative symptoms, introduced in the 1980's by Timothy Crow and Nancy Andreasen, and William Carpenter's concept of so-called deficit syndrome with the criteria of the division of negative symptoms into the primary and secondary, are discussed. Current views on the pathogenesis of negative symptoms are shown with reference to neuroimaging studies, neurotransmitter alterations, neuropsychological deficits, genetic, immunological and epidemiological studies. A subsection is devoted to the diagnostics tools for negative symptoms. Chronologically, they are divided into scales of the 1st and 2nd generation. The first generation includes: the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Positive and Negative Syndrome Scale (PANSS), the Schedule for the Deficit Syndrome (SDS), and the Proxy for Deficit Syndrome. The second generation scales, developed as a result of the recommendation by American experts in 2006, include: the Brief Negative Syndrome Scale (BNSS) and the Clinical Assessment Interview for Negative Symptoms (CAINS), also the self-assessment scales: the Motivation and Pleasure Scale - Self Report (MAP-SR) and the Self-assessment of Negative Symptoms (SNS). The BNSS and the SNS scales, whose Polish versions were elaborated in the Department of Adult Psychiatry of Poznan University of Medical Sciences, are discussed in-depth. PMID- 29975361 TI - Schizophrenia as a disorder of embodied self. AB - Theories of schizophrenia propose numerous mechanisms underlying development of this disorder, yet the account including satisfactory etiological explanation is still lacking. Current trend is to indicate core, basic factors which may further give rise to whole diversity of symptoms. Experimental data and patients' reports show that such key factor may be selfexperience disturbed on a basic, pre reflective level, which can then lead to many higher-order symptoms. In this article we review and analyze these data, as well as the most influential cognitive theories focusing on mechanisms influencing the clinical picture of schizophrenia and giving rise to the anomalous experience of embodied self. These approaches pay attention to different, but complementary aspects of experience, such as body schema and body image, sense of ownership and sense of agency, or hyperreflexivity and diminished self-affection. Predictive coding approach is also introduced - the theory which, by appealing to the disturbance in a process of neural prediction, complements previous accounts and links various cognitive functions by means of single common predictive mechanism. Although very broad in its possible meanings, the self appears to be a concept of high explanatory value, grasping in the single framework many schizophrenic symptoms - these observable on neural, low-level of information processing, as well as on the level of phenomenology of subjective experience. Such approach appears to be valuable and useful for both research and practice. PMID- 29975362 TI - Schizophrenia and sense of coherence. AB - OBJECTIVES: The purpose of the study was to investigate the dependence between the sense of coherence (SOC) and symptomatic improvement as it is the determinant of recovery process of patients with schizophrenia spectrum disorders. METHODS: The group of 134 patients was surveyed. 118 of them suffered from paranoid schizophrenia and 16 suffered from schizoaffective disorders, all were hospitalized in psychiatric clinics. Mean age was 36.22 years (SD = 8.51). Research was based on the Orientation to Life Questionnaire by A. Antonovsky. The level of psychopathological symptoms intensity was investigated twice, at the start and at the end of hospitalization with the Positive and Negative Syndrome Scale (PANSS). The rate of recovery was the margin between psychopathological symptoms intensification at the beginning and at the end of hospitalization. RESULTS: The analysis show that higher sense of comprehensibility (SOCCOM) favors lesser intensity of negative symptoms and overall psychiatric symptomatology in PANSS while starting the hospitalization. Also patients with higher level of sense of coherence (SOC) show less negative symptoms escalation during hospital admission. Results show that higher level of sense of coherence (SOC) and higher level of sense of comprehensibility (SOCCOM) coexist with lesser difference in the intensification of psychopathological symptoms. CONCLUSIONS: This article tries to show the role of sense of coherence in the recovery process among people with schizophrenic disorders. Coexistence of higher sense of coherence with greater negative symptoms and psychopathological symptoms can be perceived as an insight to the illness, which can be recognized as an expression of recovery. PMID- 29975363 TI - The Cognitive Screening Scale for Schizophrenia (CSSS). Part 1. Design and structure of the scale. AB - OBJECTIVES: This paper presents the construction of the CSSS - a short screening scale intended for diagnosis of cognitive deficits among people with schizophrenia. METHODS: 160 persons (124 with schizophrenia and 36 healthy controls) were tested using the initial version of the CSSS scale consisting of 11 subscales. Correlation analysis between the subscales' results was carried out, as well as confirmatory factor analysis, internal consistency analysis of the scale, IRT (item response theory) analysis of the items' difficulty, and analysis of the scale's accuracy as a classifier. RESULTS: One factor (overall cognitive efficiency) explains 37% of the variance of the subscales' results. The scale has satisfactory internal consistency (Cronbach's alfa = 0.83). Subjects with schizophrenia achieved significantly lower scores than healthy subjects. The area under the ROC curve (AUC) for discriminating between subjects with schizophrenia and healthy subjects was 0.83. Cut-off point of 16 raw points is 86% sensitive and has 70% specificity. CONCLUSIONS: The form of the tool that has been achieved as a result of presented analyses suggests that this scale has a potential to fulfil the assumed goals, which will be tested during continuing validation studies. PMID- 29975364 TI - The Cognitive Screening Scale for Schizophrenia (CSSS) - Part 2: Validity of the Scale. AB - OBJECTIVES: The present study is focused on further validation procedure of the CSSS - short screening scale designed for fast detection of persons with cognitive impairment and coexisting psychosocial disorders that demand deeper neuropsychological diagnosis and rehabilitation. METHODS: 67 subjects with schizophrenia and 36 healthy controls were examined with the CSSS, BACS, PANSS, and the Global Assessment of Functioning (GAF). Relationships between the CSSS score, age and education were tested with simple linear regression in groups of 124 subjects with schizophrenia and 36 healthy controls. RESULTS: Numerous statistically significant (p< 0.05) relationships between the CSSS and the BACS subtests, and the CSSS and the PANSS subscales were observed. The corrected CSSS score differs GAF ? 70 group from GAF >70 group. CONCLUSIONS: The CSSS is a short method with satisfactory validity, that is adequate to the assumed goals and might be promising with respect to further development. PMID- 29975365 TI - The difficulties of secondary prophylaxis of cervical cancer in women suffering from paranoid schizophrenia - a case study. AB - Cervical cancer constitutes 5.32% of all malignant neoplasm cases, it is the sixth most common condition of the cancer type and it is an important problem because of its medical, epidemiological and social implications. The aim of primary prophylaxis is to reduce the number of new cases, while secondary prophylaxis is to provide early diagnoses and treatment of cancer cases. The aim of this work is to present the case of 55-year-old woman treated with chronic paranoid schizophrenia whose gynecologist refused to collect biological material for cytological evaluation. The patient was diagnosed with carcinoma planoepitheliale (G2), then treated surgically and qualified for adjuvant radiological treatment. Despite the good mental state and a psychiatrists' statement (treating the patient for many years) of the absence of contraindications for hospitalization, a gynecologist-oncologist refused to admit the patient to the ward in fear of a threat to other patients and decided on outpatient palliative treatment of the patient. Finally, radiologist-oncologist performed the complete cycle of irradiation in order to cure the patient. While looking for possible reasons of cervical cancer development in individuals with psychotic disorders, all the possible carcinogenic factors have to be taken into account. Nulliparous women and virgins treated for mental illness must not be denied screening examinations related to cervical cancer. Despite the changes, also related to the implementation of the mental health program, people with mental disorders with underlying physical illness are still stigmatized, even by a higher medical personnel. Moreover, mentally ill patients are denied proper treatment in accordance with the current state of medical knowledge. PMID- 29975367 TI - The effects of psychological help on assertive behaviors in family members of schizophrenia patients. AB - OBJECTIVES: The aim of this study was to determine the relationship between the use (or lack thereof) of psychological help among family members of schizophrenia patients, and their expression of assertive behavior in relation to their relatives suffering from the illness. METHODS: The study group consisted of 34 people who run the household with their loved ones - schizophrenia patients. In the study we used the Social Competence Questionnaire (KKS) by Matczak, and the Coping Inventory for Stressful Situations (CISS) in the Polish adaptation by Wrzesniewski et al. Socio-demographic data were collected through a self-designed survey. RESULTS: There was a relationship between a general tendency to avoid action in a problem situation and a tendency to seek social diversion in order to cope with stress. Assertive behavior was also found to correlate with a tendency to engage in substitute activities. Greater willingness to display assertive behavior was observed in subjects who revealed a tendency to avoid thinking about the problem and seeking active solutions in a stressful situation. The analyses also showed that younger people who coped with stress by revealing an avoidant coping style exhibited a more assertive behavior. CONCLUSIONS: Our study did not confirm the link between the use of psychological assistance by the relatives of schizophrenia patients and their expression of assertive behavior in relation to the patient. However, it proved important that younger people who coped with stress by means of avoidance-oriented strategies manifested a greater propensity for assertive behavior. PMID- 29975366 TI - The reasons for use of cannabinoids and stimulants in patients with schizophrenia. AB - OBJECTIVES: Both cannabinoids and psychoactive substances from the group of stimulants can have a significant effect on the induction, course and treatment of severe mental illness. They also can be treated as self-medication. Many patients feel subjective benefits of using psychoactive substances in the areas of social competence, to cope with side effects of neuroleptics, stress accompanying mental illness or to control its symptoms. Our research tries to explain the causes of taking psychoactive substances by patients with schizophrenia. METHODS: A total of 50 schizophrenia patients using cannabinoids, including 25 of them using also stimulants, took part in our research. They filled out questionnaires about the causes of drug use and subjectively perceived mental complaints. We analyzed medical documentation. RESULTS: It was found that subjects using both cannabinoids and stimulants pointed to spirituality as a cause significantly more often than subjects taking only cannabinoids. Marijuana and hashish were significantly more often taken to improve social relations. In both groups, the most common reasons were: curiosity, the need to relax, problem solving, improving relationships, and remedy for 'shyness'. In the group using only cannabinoids, it was observed that people who felt misunderstood often smoked marijuana to solve problems. Individuals using stimulants often complained of poor concentration. CONCLUSIONS: Ignorance of the consequences of using psychoactive substances in people at risk of schizophrenia or in those already ill is an additional risk factor. The results may indicate an increased demand for psychoeducation and social support regarding many areas of life of patients suffering from schizophrenia. PMID- 29975368 TI - ADHD - the scourge of the 21st century? AB - Currently, attention deficit hyperactivity disorder (ADHD) is intensively studied by world medical community, its understanding expands, for example, it has now been diagnosed not only in children but also in adults. On the other hand, ADHD raises a number of discussions on the need of its treatment and, if there is a need, how it shall be treated, it is doubtful whether this disorder overall exists, because its "morphological component" has not been identified so far, and all the symptoms of ADHD, including anxiety, concentration difficulties, motor hyperactivity, cognitive disorders or social disadaptation, can be found in a number of mental disorders and somatic diseases. Modern attention, emotional and behavioral changes can be considered as a result of changing human social portrait. Those who question ADHD existence argue that this disorder is likely temperament and parenting matter, rather than the illness, and that the diagnosis and treatment of this illness can be a matter invented by doctors and pharmacists, the aim of which is to tame individuals disregarding public standards of conduct and get the maximum profit from medicines in the treatment of this illness. Due to the fact that ADHD is diagnosed more often, it is even called the twenty-first-century scourge. In this article we will review the historical aspect of formation of ADHD diagnosis, illness etiology, comorbidity with other mental and somatic diseases as well as treatment necessity and opportunities, paying attention to adult ADHD as well. PMID- 29975369 TI - ADHD as a risk factor for obesity. Current state of research. AB - Obesity is now a major health concern in both children and adults. According to research from the past 15 years, one of the factors that increase the risk of obesity may be attentiondeficit hyperactivity disorder (ADHD). Not all the studies, however, provide unambiguous results. This literature review aims to systematize the results of previous studies on the risk of obesity in people with ADHD. It included articles addressing the issue of relationship between ADHD and obesity published in the years 2004-2016. Finally, 31 surveys fulfilling the selection criteria were qualified for the review. Analysis of the available sources leads to the conclusion that ADHD is a significant risk factor for obesity, which is especially visible in the adult population. Of the disorders associated with ADHD, the greatest modulating impact on the relationship between obesity and ADHD had oppositional defiant disorder, conduct disorder and emotional overeating. Pharmacological treatment, comorbid conditions, but also age and sex must remain important factors controlled in subsequent studies. Future research should focus on more systematic testing of hypotheses explaining the comorbidity of ADHD and obesity. PMID- 29975370 TI - The controversy around the diagnosis of selective mutism - a critical analysis of three cases in the light of modern research and diagnostic criteria. AB - The position of selective mutism disorder - SM - has been modified in the last edition of the classification of mental disorders DSM-5. It was removed from "Disorders of childhood and adolescence" and placed in "Anxiety disorders". This caused two important changes in the interpretation of the symptoms of selective mutism. It highlighted anxious etiology of the disorder and also open the possibility to diagnose selective mutism in adults as a special category of anxiety disorders. The aim of this study was to present three different cases concerning the diagnostic difficulties of selective mutism (the child, the teenager and the persons who became adult during our observation) regarding current views on SM. In this study we presented the current view on the etiology, course and available therapies for selective mutism. Owing to updating the clinical knowledge about SM and describing three cases, we highlighted the controversies around the diagnosis and treatment of this disorder. Selective mutism might be a preliminary diagnosis, often leading to the diagnosis of other disorders of diverse etiology and course. Among the psychiatric aspects of the disorder, the 'anxiety component' of SM is crucial. In individuals with selective mutism, developmental disorders, social cognition and neurocognition deficits or dysfunctions of auditory processing often coexist. The severity and the type of comorbidities may determine the future course of the illness and the final effects of the therapy. PMID- 29975371 TI - The prevalence of mental disorders among children and youth staying in residential institutions, children's homes - a review of epidemiological studies. AB - Emergence of mental health problems in childhood can seriously affect further development of a man and thus hamper his adaptation to adult life. Children in residential institutions may be particularly vulnerable at risk of abnormal mental development, this includes so-called 'children's homes'. In the article we present an overview of the few studies carried out so far in the European residential institutions, including children's homes, over the years 1940-2011 in the UK, Germany, Romania, and Poland. Firstly, we briefly describe a classic research carried out in the world in the 1940s among children from children's homes. Secondly, we present a study conducted in the UK among children and youth from different age groups staying in residential institutions, including children's homes. Then we focus on studies carried out among children and adolescents form German residential institutions and on a group of preschool children from Romanian children's homes. At the end of the article we describe the first epidemiological study carried out in Poland on the population of children and young people staying in children's homes in Warsaw. The review of researches shows that children from day-care facilities are a population with a high prevalence of psychiatric disorder. Children and youth staying in residential institutions probably require specialized psychiatric, psychological and psychotherapeutic care. PMID- 29975372 TI - Conservative management strategies and stress level in children and adolescents with idiopathic scoliosis. AB - OBJECTIVES: The objective of the study was to evaluate the stress level in children and adolescents with idiopathic scoliosis (IS) treated conservatively using the Dobosiewicz Method (DoboMed) approach in correlation with the clinical parameters and brace therapy. METHODS: The study group (SG) comprised 63 patients (54 girls), in mean age 14.7 years. DoboMed approach was used in all studied patients (31 of them had also a brace (orhosis)). The clinical analysis included also body mass index (BMI) z-scores, age at diagnosis, spinal curvature location and the duration of brace correction. The patients completed the Bad Sobernheim Stress Questionnaire Deformity (BSSQ-Deformity) and Bad Sobernheim Stress Questionnaire Brace (BSSQ-Brace) questionnaires twice, ie., at the beginning and at the end of the hospitalization. RESULTS: IS patients experienced low or moderate deformity-related stress (58.7% and 36.5% respectively). A significantly higher stress level (BSSQ-Deformity) was revealed in the combination therapy group compared to kinesiotherapy group (p<0.05). In brace wearers, the orthosis related was higher than the deformity-related stress (p<0.0001). A significant correlation was observed between the BSSQ-Deformity score vs. age, BMI z-score and number of hospitalizations (p<0.05). Deformity stress level was significantly related to the Cobb's angle in both analyzing subgroups. CONCLUSIONS: Stress level in IS patients is related to the severity of the disease irrespectively to the method of treatment. Brace wearing is a factor provoking and increasing stress level. Stress level related to bracing is higher than trunk deformity related. Higher stress levels were significantly correlated with age, BMI z-score and number of hospitalizations. Complex therapy should include also psychological support for young patients with IS. PMID- 29975373 TI - Temperament traits in 4-year-old children born prematurely - may they suggest a threat for mental functioning? AB - OBJECTIVES: The aim of the study was to assess emotional functioning and identification of temperamental traits in 4-year-old children born prematurely with birth weight =< 1500 grams. The second aim was evaluation of autism spectrum disorders frequency in this group of children. METHODS: Eighty-six 4-year-old children born prematurely (gestational age =< 32 weeks, birth weight =< 1500 grams) were evaluated. All children underwent physical examination (with the assessment of motor function, vision and hearing), anthropometric measurements and psychomotor tests: Leiter International Performance Scale P-93, Children Vocabulary Test (TSD), temperament questionnaire (EAS-C), and CAST questionnaire. Parents were asked to fill in questionnaires assessing socio-economic conditions of the family and children attendance in kindergarten or early development support. RESULTS: In the EAS-C questionnaire hyperactivity and reduced emotionality were significantly more common comparing to population. Children with lower gestational age and lower birth weight were characterized with low emotionality score. Children with the CAST score ? 12 points were significantly smaller at birth, more often suffered from retinopathy of prematurity and had poorer results in neurodevelopmental tests - Leiter scale, Children Vocabulary Test. CONCLUSIONS: Children born prematurely are at greater risk of the occurrence of hyperactivity and autism spectrum symptoms. Detection of emotional disorders in children born prematurely is essential to implement the therapeutic support as early as possible. PMID- 29975374 TI - Hospitalizations due to alcohol intoxication among children and adolescents - data from one clinical hospital in Poland. AB - OBJECTIVES: To determine the frequency of hospitalizations due to alcohol intoxication (AI) at the Pediatric Health Center, and to attempt to identify factors contributing to the occurrence of intoxication in the population of children and adolescents. METHODS: Medical documentation of 227 patients hospitalized due to AI. 108 (48%) patients were girls and 119 (52%) patients were boys. The mean age of the study group was 14.9 years +/-2.1. Data regarding patients, their families and the circumstances of intoxication underwent analysis. RESULTS: Alcohol intoxication constituted 2.8% of all hospitalizations. The number of hospitalizations between 2000 and 2011 showed an increasing tendency with some fluctuations within years. Spirits were predominant alcohol beverages. Over 10% of patients required a short-term hospital stay at the Department of Anesthesiology and Intensive Care. In 13% of children, coexisting medicine or drug intoxication was observed and 10% of patients presented with alcohol-related injury to the head or extremities. Risky sexual behaviors were noted in 25% of girls. The majority of children were raised by two parents who had received primary education. Alcoholism was present in over 20% of the families. In single-parent families, fathers were more frequently absent and a lack of a regular source of income was more often related to mothers. CONCLUSIONS: There are no uniform standards of multi-specialist medical care for children hospitalized due to AI. Identification of children consuming alcohol is recommended. It should be done by primary physicians, pediatricians, teachers and psychologists. Minor patients hospitalized due to AI should be provided with a long-term and comprehensive care. PMID- 29975376 TI - Investigating the autophagy pathway in silver@gold core-shell nanoparticles treated cells using surface-enhanced Raman scattering. AB - Previous studies have shown that nanoparticles can induce autophagy, and the main approach for investigating autophagy induced by nanoparticles is via traditional methods such as TEM and biochemical assay. These methods measurements suffer from the disadvantages of complicated experimental processes, cell destruction, as well as lack of characterization of individual stages of the autophagy pathway. Surface-enhanced Raman scattering (SERS) has been extensively used in biological applications. With the combination of SERS and chemometric methods, such as principal component analysis-linear discriminant analysis (PCA-LDA), identification and distribution mapping of endosomes and lysosomes in the endocytosis of Au nanoparticles has been achieved by segregating the spectra from complex SERS data sets in the previous study. In this study, silver@gold core shell nanoparticles (Ag@Au NPs) were synthesized by reduction of gold ions on the surface of the silver nanoparticles, and the autophagy induced by Ag@Au NPs was studied with Ag@Au NPs serving both as an autophagy inducer and as a high performance SERS substrate. Pro-survival autophagy induced by Ag@Au NPs was proved by the western blot assay, flow cytometry and fluorescent staining. Furthermore, the autophagy pathway in Ag@Au NPs-treated cells was first elucidated by SERS combined with a modified reference-based PCA-LDA methodology. This study provides a feasible way of using SERS to elucidate the autophagy pathway induced by nanoparticles. PMID- 29975375 TI - Validation of the Polish version of the Penn Alcohol Craving Scale (PACS). AB - OBJECTIVES: The conducted studies were aimed at making a Polish adaptation of the Penn Alcohol Craving Scale (PACS) by B. Flannery and co-workers. The Scale is a self-assessment method, it comprises 5 statements, and is designed to assess alcohol craving experienced by a patient in a week prior to the examination. METHODS: 550 patients with diagnosed alcohol dependence syndrome were examined, and the final analysis included results of 510 persons. The examined group consisted of 396 men and 114 women. The study was made in the 3rd week of their alcohol treatment. There were used: the PENN Craving Scale, the Alcohol Dependence Development Scale (SRUA) (the part in which craving is dealt with), a clinical interview with specially prepared questions about alcohol craving experienced last month and last week, and the Yale-Brown Obsessive Compulsive Intense Drinking Scale. RESULTS: The Polish version of the Penn Scale is characterised by very good psychometric properties - it is a reliable and valid tool. The exploratory and confirmatory factor analyses have proved the existence of one factor. The internal consistency, assessed on the basis of Cronbach's alpha, equalled 0.89. The method displays statistically significant (majority p < 0.0010) relationships with levels of craving experienced last year, last month, and last week before the examination, and also with total score on the Yale-Brown Scale. CONCLUSIONS: The effects of the conducted adaptation works on the Penn Scale speak for recommending the method for scientific research and use in therapeutic practice. PMID- 29975377 TI - High-capacitance Ti3C2Tx MXene obtained by etching submicron Ti3AlC2 grains grown in molten salt. AB - Submicron Ti3AlC2 grains are grown in molten salt. Etching the grains gives rise to small-sized Ti3C2Tx MXene particulates with capacitance more than twice that of the large ones derived from conventional high-temperature synthesis. Detailed electrochemical, structural, and spectroscopic studies demonstrate that increased capacitance predominantly originates from a decrease in the lateral size of the small Ti3C2Tx MXene particulates. PMID- 29975378 TI - Directed ortho C-H borylation catalyzed using Cp*Rh(iii)-NHC complexes. AB - Cp*Rh(NHC) complexes with bulky chiral bidentate NHC-carboxylate ligands were efficiently synthesized and fully characterized including solid-state structures. These unprecedented rhodium(iii) complexes demonstrated high selectivity in pyridine-directed ortho-C-H borylation of arenes under mild conditions. PMID- 29975379 TI - Correction: Model molecules to classify CHO hydrogen-bonds. AB - Correction for 'Model molecules to classify CHO hydrogen-bonds' by Amol M. Vibhute et al., Chem. Commun., 2018, 54, 4629-4632. PMID- 29975380 TI - Random mixed-metal Co1-xNix single-chain magnets with simultaneous azide, carboxylate and tetrazolate bridges. AB - This paper reports the magnetic properties of a series of isomorphous metal organic frameworks based on random heterometallic Co1-xNix chains with simultaneous azide, carboxylate and tetrazolate bridges. All the mixed-metal compounds show intrachain FM interactions, field-induced metamagnetism, and SCM like slow magnetic relaxation. These behaviors are quite different from the parent Co(ii) and Ni(ii) materials, and even a small amount of metal replacement can cause significant magnetic changes. The static properties such as AF ordering, metamagnetic critical field and the hysteresis parameters show complicated composition dependence. Most interestingly, the mixed-metal systems can show a higher blocking temperature than the Co(ii) compound, suggesting that the randomly distributed metal ions have synergistic effects on slow relaxation of magnetization. This is phenomenologically associated with the competitive effects of Deltatau and tauo. PMID- 29975381 TI - Design concepts in absorbance optical systems for analytical ultracentrifugation. AB - Analytical ultracentrifugation is a powerful technique for analyzing particles in solution, and has proved valuable for a wide range of applications in chemistry, biochemistry and material sciences for many years. The field is presently seeing a resurgence of instrument development from commercial and academic groups. To date, no modern optical modeling techniques have ever been applied to the basic imaging properties of the optical system in analytical ultracentrifugation. In this manuscript we provide a contextual framework for the application of such techniques, including an overview of the essential optical principles. The existing commercial and open source detection systems are evaluated for imaging performance, highlighting the limitations of chromatic aberration for broadband acquisitions. These results are the inspiration for a new mirror-based design, free of chromatic aberration. Our findings present a path forward for continued development in imaging and detector technology, where improved data quality will now push the limits of detection and resolution of analytical ultracentrifugation for years to come. PMID- 29975382 TI - Supramolecular chemotherapeutic drug constructed from pillararene-based supramolecular amphiphile. AB - Based on the host-guest interaction between a CPT-conjugated prodrug amphiphile (CPT-ss-Py) and a water-soluble pillar[5]arene (P5), a GSH-responsive supramolecular chemotherapeutic drug (P5?CPT-ss-Py) was fabricated. Through this supramolecular formulation, internalization and anticancer efficacy were greatly increased. PMID- 29975383 TI - Microfabricated devices for oral drug delivery. AB - Oral administration of drugs is most convenient for patients and therefore the ultimate goal when developing new medication. The physical barriers in the body, low pH of the stomach and degradation by enzymes in the gastrointestinal tract are a few of the obstacles to succeeding with oral drug delivery. Microfabricated devices show promise to overcome some of these hindrances and thereby improve the bioavailability of drugs after oral administration. There is an increasing focus on microfabricated oral drug delivery systems, and so far there have been three main groups of designs: patch-like structures, microcontainers and microwells. Here, we review the newest development in top-down microfabricated devices for oral drug delivery with coverage of the aspects of design, choice of material and fabrication techniques. Furthermore, the drug loading techniques and methods for testing are discussed. In addition, we discuss the future perspectives for microfabricated devices. PMID- 29975384 TI - Liquid-liquid phase separation and evaporation of a laser-trapped organic-organic airborne droplet using temporal spatial-resolved Raman spectroscopy. AB - Chemical reactions in aerosol particles can occur between the reactive components of the particle or between the particle and its surrounding media. The fate of atmospheric aerosols depends on the environment, the composition and the distribution of components within a particle. It could be very interesting to see how a liquid aerosol particle behaves in ambient air if the particle is composed of mixed chemicals. Do the chemical components remain homogeneously mixed within a particle or separate as the mixed liquid is aerosolized? How do the chemicals within a droplet separate and interact with the air? In this paper, a single microdroplet formed from an organic-organic mixture of diethyl phthalate (DEPh) and glycerol was investigated using laser-trapped position-resolved temporal Raman spectroscopy. For the first time, we were able to directly observe the gradient distributions of the two chemicals at different positions within such an airborne droplet, their time-resolved processes of liquid-liquid phase separation, and changes of the physical microstructure and chemical micro composition in the droplet. The results revealed that DEPh migrated to the surface and formed an outer layer and glycerol was more concentrated in the interior of the droplet, DEPh evaporated faster than glycerol, and both organic chemicals within the mixed droplet evaporated faster than either of them within their pure droplets. This technique also provides a new method for studying the fine structure and chemical reactions of different molecules taking place inside a particle and at the interface of a particle with the surrounding microenvironment. PMID- 29975385 TI - The promise of antireflective gold electrodes for optically monitoring the electro-deposition of single silver nanoparticles. AB - The interest in nano-objects has recently dramatically increased in all fields of science, and electrochemistry is no exception. As a consequence, in situ and operando visualization of electrochemical processes is needed at the nanoscale. Herein, we propose a new interferometric microscopy based on an antireflective thin metal electrode layer. The technique is coupled to electrochemistry in a model example: the electro-deposition of Ag metallic nanoparticles (NPs). This challenges the current opto-electrochemical methods and even those relying on nano-impact detection. Indeed, the sensitivity allows the dynamic in situ visualization of the electrochemical growth and dissolution of individual Ag NPs, whose size was tracked dynamically down to 15 nm in diameter. The use of microelectrodes provides interesting quantitative analysis of the NPs, from optically resolved arrays of single NPs to condensed arrays of (unresolved) NPs. Particularly, the optical analysis of all the individual NPs allows the reconstruction of optical voltammograms similar to the electrochemical ones. Finally, the NP dissolution-redeposition is also investigated. PMID- 29975386 TI - Tubular J-aggregates of a new thiacarbocyanine Cy5 dye for the far-red spectral region - a spectroscopic and cryo-transmission electron microscopy study. AB - The aggregation behavior of a phenol-substituted thiacarbocyanine Cy5 dye (5 chloro-2-[5-[5-chloro-3-(4-sulfobutyl)-3H-benzothiazol-2-ylidene]-3-phenyl-penta 1,3-dienyl]-3-(4-sulfobutyl)-benzothiazol-3-ium hydroxide, inner salt, triethylammonium salt) in aqueous solution is investigated using steady-state absorption, linear dichroism, and fluorescence spectroscopies, as well as cryogenic transmission electron microscopy (cryo-TEM). By increasing the concentration, the dye self-assembles in pure water into dimers and H-aggregates, the latter being uniform particles of ~2.6 nm size. In the presence of NaCl, two different types of J-aggregates are observed depending on salt concentration (varied from 10 to 100 mM). At low salt concentration (10 mM) a J-aggregate of extended mono-layered sheets prevails, which disappears after a few days, whereas a second type of J-aggregate emerges. Generally, the latter dominates in matured solutions in particular at high salt concentration and seems to be the thermodynamically stable species. This J-aggregate shows three perpendicularly polarized absorption bands and fluoresces in the far-red at around 800 nm. The most intensive and very narrow (fwhm of 238 cm-1) absorption band is centered at 796 nm. Cryo-TEM reveals uniform nanotubes of ~7 nm diameter and micrometer length. They represent the first tubular cyanine dye J-aggregates that are active in the far-red. Moreover, the studied dye is a prime example of cyanine dyes showing two self-assembly pathways that lead to different species of J-aggregates with distinct optical and morphological properties. PMID- 29975387 TI - Characterization of a new heteropolysaccharide from green guava and its application as an alpha-glucosidase inhibitor for the treatment of type II diabetes. AB - Psidium guajava fruit is a subtropical fruit, functional food and traditional medicine for the adjuvant treatment of diabetes mellitus in China. To investigate the active components responsible for its health benefits, a novel heteropolysaccharide GP70-3 was purified by water extraction, ethanol precipitation and column chromatography. Structural characterization of GP70-3 was elucidated for the first time by monosaccharide composition assay, Fourier transform-infrared spectroscopy (FT-IR), methylation analysis, gas chromatography coupled with mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). The data revealed that GP70-3 contained a backbone of 1->3,6) linked beta-d-Galp, 1->5)-linked alpha-l-Araf, 1->6)-linked beta-d-Galp and 1->3) linked beta-d-Galp, branched with 1->2,3,5)-linked alpha-l-Araf, 1->3)-linked alpha-l-Araf, 1->3)-linked alpha-l-Rhap, 1->3)-linked beta-d-GlcpA, 1->3)-linked beta-d-GalpA and terminated with ->1)-linked beta-d-Galp. Advanced structure studies showed GP70-3 consisted of irregular flakes with rounded-spherical pores. Moreover, GP70-3 exhibited outstanding alpha-glucosidase inhibitory activity in vitro, with an IC50 value of 2.539 +/- 0.144 MUM, which was 1867 times higher than that of the positive control acarbose (IC50 value of 4.744 +/- 0.026 mM). Therefore, consumption of guava polysaccharides may be beneficial as an alpha glucosidase inhibitor for reducing the postprandial blood glucose level and treating type II diabetes. PMID- 29975388 TI - Origin of fast oxide ion diffusion along grain boundaries in Sr-doped LaMnO3. AB - The prospect of significantly enhanced oxide ion diffusion along grain boundaries in Sr-doped LaMnO3 (LSM) was investigated by means of density functional theory calculations applied to a Sigma5 (3 1 0)[0 0 1] grain boundary. The structure of the grain boundary was optimized by rigid body translation, and segregation energies were calculated for oxygen vacancies and Sr-acceptors. Two potentially fast diffusion paths were identified along the grain boundary core based on the interconnectivity between neighbouring sites with a strong tendency for segregation of oxygen vacancies. The migration barriers for these paths, obtained with the nudged elastic band method, amounted to about 0.6 eV. Based on the obtained migration barriers and concentrations of oxygen vacancies for the relevant core sites, the grain boundary diffusion coefficient was estimated to be enhanced by 3 to 5 orders of magnitude relative to the bulk in the temperature range 500-900 degrees C. Space-charge effects were determined to be quite insignificant for the transport properties of LSM grain boundaries. PMID- 29975389 TI - Copper-catalyzed cyclization of 2-cyanobenzaldehydes and 2-isocyanoacetates: an efficient strategy for the synthesis of substituted 1-aminoisoquinolines. AB - A Cu(acac)2-catalyzed cyclization reaction of 2-cyanobenzaldehydes with 2 isocyanoacetates has been successfully developed providing an efficient strategy for the synthesis of substituted 1-aminoisoquinolines. The reaction proceeds smoothly under mild conditions with high efficiency, and might provide an alternative strategy for the synthesis of 1-aminoisoquinoline containing molecules. PMID- 29975390 TI - Preparation, characterization, and catalytic performances of a pyrazine dicarboxylate-bridging rare-earth-containing polytungstoarsenate aggregate for selective oxidation of thiophenes and deep desulfurization of model fuels. AB - A new polytungstoarsenate, K6LiH6[Ce4(H2O)14(pzdc)(H2pzdc)As3W29O103].22H2O (1) (H2pzdc = 2,3-pyrazinedicarboxylic acid), was synthesized via a conventional aqueous solution method. In this synthetic approach, the organic ligand pyrazine dicarboxylate acid was introduced into the arsenotungstate system. The synthesized compound 1 was well characterized using elemental analysis, IR spectroscopy, UV-vis spectroscopy, thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), and single-crystal X-ray diffraction. The catalytic activity of compound 1 was tested in acetonitrile to oxidize organosulfur compounds (benzothiophene (BT) and dibenzothiophene (DBT)) with hydrogen peroxide as an oxidant at room temperature. Two substrates were oxidized to their corresponding sulfones with high conversion and selectivity. Taking advantage of this remarkable catalytic move, the 1/H2O2/CH3CN system was further utilized in the oxidation of model fuels (MF) including a mixture of BT and DBT in octane. As a result, the organosulfur compounds in the model fuels were fully converted into their corresponding sulfones. Furthermore, the fluorescence properties of 1 were also investigated. PMID- 29975392 TI - The Importance of End-of-Life Conversations. PMID- 29975391 TI - Aging, Frailty, and Resilience. PMID- 29975393 TI - Drugs to Treat Depression. PMID- 29975394 TI - Insomnia: Will Medication Bring Rest? AB - Acute and chronic insomnia are common and difficult clinical problems that contribute to and are consequences of other mental and physical health problems. It is tempting to treat insomnia with medications for rapid relief; however, these medications have significant side effects that add health burden and may cause tolerance and dependency. First-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBT-I); however, this is less frequently prescribed than benzodiazepine and non-benzodiazepine sedative hypnotic agents. Prudent primary care and mental health clinicians should screen for insomnia using valid and reliable tools when clients report sleep difficulties. When screening is positive, further assessment with a sleep diary is warranted. The primary treatment for insomnia is CBT-I, and pharmacological treatment may provide temporary support for no more than 2 to 4 weeks. Non-benzodiazepine hypnotic agents, histamine blocking medications, dual orexin receptor antagonists, and over-the-counter herbal supplements may serve as adjuncts. [Journal of Psychosocial Nursing and Mental Health Services, 56(7), 9-14.]. PMID- 29975395 TI - Music as a Healing Art in Dementia Care. AB - Music is an easily accessible and stimulating medium that can be enjoyed alone or with others, even in the context of severe dementia. The power of music to improve the lives of individuals with dementia, as well as their caregivers, is becoming increasingly recognized as more research is focused on underlying neural relationships and evidence-based music interventions. Nurses and other health professionals can be instrumental in designing and implementing music-based interventions and expanding needed research to promote music as a healing art in dementia care. [Journal of Psychosocial Nursing and Mental Health Services, 56(7), 15-18.]. PMID- 29975396 TI - Perspectives of Frailty Among African American Men and Women. AB - Frailty is a syndrome of impaired homeostasis and poor response to stressors leading to adverse health outcomes. The aim of the current study was to explore lay perspectives about frailty among African American adults. Thirteen men and women participated in two focus groups. Content analysis yielded six themes: (a) Physical Impairment With Loss of Independence; (b) Can Happen to Anyone, At Any Age, At Any Time; (c) Mind-Body Connection; (d) Affects All Aspects of Life; (e) Positive Attitude and Prayer Guard Against Frailty; and (f) Be In Tune and Stay Connected. Findings suggest psychological and social factors, including a positive attitude and spirituality, are linked to physical function and well being in aging and are influential in frailty. Culturally tailored interventions that focus not only on promoting physical function but also address psychological, social, and spiritual domains may foster the resilience needed to prevent or alleviate frailty in African American individuals. [Journal of Psychosocial Nursing and Mental Health Services, 56(7), 20-29.]. PMID- 29975397 TI - Women's Mental Health After Retirement. AB - The aim of the current study was to examine mental health outcomes in retired women and determine whether relationships existed among mental health outcomes, sociodemographic characteristics, and type of retirement (i.e., voluntary or forced). A cross-sectional study was conducted with 80 women ages 55 and older residing in five southeastern states. Women had retired at least part-time from working outside of the home. Sociodemographic variables, diagnosis of depression, diagnosis of cognitive impairment, and health-related quality of life were assessed. Women with forced retirement had worse mental health compared to those who retired voluntarily. Minority women had higher rates of forced retirement compared with White women. Poorer mental health outcomes for women with forced retirement suggest the need for careful consideration of this transition as a socially determined health factor for retired women, especially minority women. Clinicians need to assess women for mental health indicators during the transition to retirement and provide educational and therapeutic resources to promote mental health during the transition from working life to retirement. [Journal of Psychosocial Nursing and Mental Health Services, 56(7), 37-45.]. PMID- 29975399 TI - "Royal Poinciana on Pink Cloth" by Veronica Benning. PMID- 29975398 TI - Resilience in Baccalaureate Nursing Students: An Exploration. AB - The purpose of the current study was to explore resilience in senior-level baccalaureate nursing students. Twenty-seven participants completed an online questionnaire assessing three stressors that pertained to marriage or divorce, death or loss of family members or close friends, and extreme financial hardship in the past 1 year. Resilience was measured using the 25-item Connor-Davidson Resilience Scale (CD-RISC-25) and one open-ended question about the experience of resilience. Mean CD-RISC-25 score was 73.26 (SD = 10.7; range = 45 to 96); only 33.3% of the sample was considered resilient (score >80). Qualitative data described academic stressors and support resources for resilience. Study findings underscore the relevance of resilience in nursing students. Nurse educators must help nursing students develop resilience to better prepare them for academic success and ensure a smooth transition into their professional nursing role. [Journal of Psychosocial Nursing and Mental Health Services, 56(7), 46-55.]. PMID- 29975401 TI - Predictive factors of survival in a surgical series of metastatic epidural spinal cord compression and complete external validation of 8 multivariate models of survival in a prospective North American multicenter study. AB - BACKGROUND: This study was designed to identify preoperative predictors of survival in surgically treated patients with metastatic epidural spinal cord compression (MESCC), to examine how these predictors are related to 8 prognostic models, and to perform the first full external validation of these models in accordance with the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. METHODS: One hundred forty two surgically treated patients with MESCC were enrolled in a prospective, multicenter North American cohort study and were followed for 12 months or until death. Cox regression was used. Noncollinear predictors with < 10% missing data, with >= 10 events per stratum, and with P < .05 in a univariate analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi prognostic scoring systems (PSSs), Tomita PSS, modified Bauer PSS, van der Linden PSS, Bartels model, Oswestry Spinal Risk Index, and Bollen PSS, this study examined calibration graphically, discrimination with Harrell c-statistics, and survival stratified by risk groups with the Kaplan-Meier method and log-rank test. RESULTS: The following were significant in the univariate analysis: type of primary tumor, sex, organ metastasis, body mass index, preoperative radiotherapy to MESCC, physical component (PC) of the 36-Item Short Form Health Survey, version 2 (SF-36v2), and EuroQol 5-Dimension (EQ-5D) Questionnaire. Breast, prostate and thyroid primary tumor (HR: 2.9; P =.0005), presence of organ metastasis (hazard ratio (HR): 2.0; P = .005) and SF-36v2 PC (HR: 0.95; P < .0001) were associated with survival in multivariable analysis. Predicted prognoses poorly matched observed values on calibration plots; Bartels model calibration slope was 0.45. Bollen PSS (0.61; 95% CI: 0.58-0.64) and Bartels model (0.68; 95% CI: 0.65-0.71) had the lowest and highest c-statistics, respectively. CONCLUSIONS: The primary tumor type (breast, prostate, or thyroid), an absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival for surgical MESCC patients. These results are in keeping with current models. This full external validation of 8 prognostic PSSs or model of survival in surgical MESCC patients has revealed that calibration is poor, especially for long-term survivors, whereas discrimination is possibly helpful. PMID- 29975402 TI - Different infusion durations for preventing platinum-induced hearing loss in children with cancer. AB - BACKGROUND: Platinum-based therapy, including cisplatin, carboplatin or oxaliplatin, or a combination of these, is used to treat a variety of paediatric malignancies. Unfortunately, one of the most important adverse effects is the occurrence of hearing loss or ototoxicity. In an effort to prevent this ototoxicity, different platinum infusion durations have been studied. This review is the second update of a previously published Cochrane review. OBJECTIVES: To assess the effects of different durations of platinum infusion to prevent hearing loss or tinnitus, or both, in children with cancer. Secondary objectives were to assess possible effects of these infusion durations on: a) anti-tumour efficacy of platinum-based therapy, b) adverse effects other than hearing loss or tinnitus, and c) quality of life. SEARCH METHODS: We searched the electronic databases Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 15 March 2018), MEDLINE (PubMed) (1945 to 15 March 2018) and Embase (Ovid) (1980 to 15 March 2018). In addition, we handsearched reference lists of relevant articles and we assessed the conference proceedings of the International Society for Paediatric Oncology (2009 up to and including 2017) and the American Society of Pediatric Hematology/Oncology (2014 up to and including 2017). We scanned ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; apps.who.int/trialsearch) for ongoing trials (searched on 12 March 2018 and 13 March 2018 respectively). SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing different platinum infusion durations in children with cancer. Only the platinum infusion duration could differ between the treatment groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, 'Risk of bias' assessment and GRADE assessment of included studies, and data extraction including adverse effects. Analyses were performed according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We identified one RCT and no CCTs; in this update no additional studies were identified. The RCT (total number of children = 91) evaluated the use of a continuous cisplatin infusion (N = 43) versus a one-hour bolus cisplatin infusion (N = 48) in children with neuroblastoma. For the continuous infusion, cisplatin was administered on days one to five of the cycle, but it is unclear if the infusion duration was a total of five days. Risk of bias was present. Only results from shortly after induction therapy were provided. No clear evidence of a difference in hearing loss (defined as asymptomatic and symptomatic disease combined) between the different infusion durations was identified as results were imprecise (risk ratio (RR) 1.39, 95% confidence interval (CI) 0.47 to 4.13, low-quality evidence). Although the numbers of children were not provided, it was stated that tumour response was equivalent in both treatment arms. With regard to adverse effects other than ototoxicity, we were only able to assess toxic deaths. Again, the confidence interval of the estimated effect was too wide to exclude differences between the treatment groups (RR 1.12, 95% CI 0.07 to 17.31, low-quality evidence). No data were available for the other outcomes of interest (i.e. tinnitus, overall survival, event-free survival and quality of life) or for other (combinations of) infusion durations or other platinum analogues. AUTHORS' CONCLUSIONS: Since only one eligible RCT evaluating the use of a continuous cisplatin infusion versus a one-hour bolus cisplatin infusion was found, and that had methodological limitations, no definitive conclusions can be made. It should be noted that 'no evidence of effect', as identified in this review, is not the same as 'evidence of no effect'. For other (combinations of) infusion durations and other platinum analogues no eligible studies were identified. More high-quality research is needed. PMID- 29975403 TI - Effect of exercise on metabolic syndrome in black women by family history and predicted risk of breast cancer: The FIERCE Study. AB - BACKGROUND: This study examined the effects of supervised and home-based exercise interventions on changes in metabolic syndrome (MetS) according to breast cancer risk (high vs low) in black women enrolled in the Focused Intervention on Exercise to Reduce Cancer (FIERCE) trial. METHODS: Postmenopausal, obese, metabolically unhealthy black women, 45 to 65 years old, were randomized to supervised aerobic exercise (73 women), home-based walking-based exercise (69 women), or a control arm (71 women). Participants in the exercise arms underwent a 6-month intervention with study assessments conducted at the baseline and 6 months. The primary outcome measure was MetS (fasting glucose, waist circumference, blood pressure, serum triglycerides, and high-density lipoprotein [HDL]). The intervention effects on MetS, stratified by breast cancer risk as measured by the family history of breast cancer and model-based projected breast cancer risk, were examined with intent-to-treat analyses using generalized estimating equation models. RESULTS: Among women with a family history of breast cancer, the exercise arms had lower mean MetS z scores, which suggested an improvement in the metabolic profile, than controls at 6 months (controls, + 0.55; home-based arm, -0.97, P < .01; supervised arm, -0.89, P < .01). Stratified analyses by projected breast cancer risk suggested similar but statistically nonsignificant findings, with those at high risk having more favorable changes in the MetS z score in the exercise arms versus the control arm. These changes were primarily attributable to changes in blood pressure, triglycerides, and HDL. CONCLUSIONS: Short-term aerobic activity regimens may improve the metabolic profile and thereby reduce breast cancer risk in obese, metabolically unhealthy black women at high risk for cancer. (c) 2018 American Cancer Society. PMID- 29975400 TI - Gut microbiota-immune-brain interactions in chemotherapy-associated behavioral comorbidities. AB - Increasing scientific attention is focused on the gut-brain axis, including the ability of the gastrointestinal (GI) tract to modulate central nervous system function. Changes in the intestinal microbiome can influence affective-like behavior, cognitive performance, fatigue, and sleep in rodents and humans. Patients with cancer who are receiving chemotherapy experience similar negative behavioral changes and concurrent GI symptoms. These chemotherapy comorbidities can be long-lasting and may reduce patients' quality of life and motivation to comply with treatment. This review summarizes the clinical and preclinical evidence supporting a role for the intestinal microbiome in mediating behavioral comorbidities through peripheral immune activation in patients with cancer who are receiving chemotherapy. In addition, evidence suggesting that targeted modification of the intestinal microbiome during cancer treatment could ameliorate associated behavioral comorbidities is reviewed. PMID- 29975405 TI - Dabigatran, Rivaroxaban, and Warfarin in the Oldest Adults with Atrial Fibrillation in Taiwan. AB - OBJECTIVES: To compare the effectiveness and safety of reduced-dose dabigatran, reduced-dose rivaroxaban, and warfarin in individuals aged 85 and older with atrial fibrillation (AF). DESIGN: Retrospective cohort study. SETTING: Taiwan National Health Insurance claims database, 2011~2015. PARTICIPANTS: Individuals with AF aged 85 and older (mean 88.6) with incident use of oral anticoagulants between June 1, 2012 and May 31, 2015 (N=4,722; dabigatran 110 mg, n=1,489; rivaroxaban 15 mg/10 mg, n=1,736; warfarin, n=1,497). MEASUREMENTS: Clinical outcomes included all-cause death, cardiovascular death, ischemic stroke, acute myocardial infarction, arterial embolism or thrombosis, intracranial hemorrhage, and gastrointestinal hemorrhage needing transfusion. Propensity score-matched analysis was performed, and the marginal proportional hazards model was used to estimate the relative risk of various clinical outcomes in a matched dabigatran warfarin cohort (n=1,180 in each group) and a rivaroxaban-warfarin cohort (n=1,207 in each group) RESULTS: Mean follow-up was 6.6 months for the overall population. Dabigatran group participants had lower risks of all-cause death (hazard ratio (HR)=0.59, 95% confidence interval (CI)=0.45-0.77) and cardiovascular death (HR=0.45, 95% CI=0.30-0.68) than warfarin group participants. Rivaroxaban users also had lower risks of all-cause death (HR=0.61, 95% CI=0.47-0.79) and cardiovascular death (HR=0.52, 95% CI=0.35-0.75) than warfarin users. Dabigatran users also had a lower risk of intracranial hemorrhage than warfarin users (HR=0.31, 95% CI=0.10-0.97). CONCLUSION: Individuals with AF aged 85 and older who used reduced-dose dabigatran or reduced-dose rivaroxaban had statistically significantly lower all-cause mortality and cardiovascular mortality than those who used warfarin. Reduced-dose dabigatran was also associated with lower risk of intracranial hemorrhage than warfarin. PMID- 29975404 TI - Long-term outcomes of partial prostate treatment with magnetic resonance imaging guided brachytherapy for patients with favorable-risk prostate cancer. AB - BACKGROUND: Partial prostate treatment has emerged as a potential method for treating patients with favorable-risk prostate cancer while minimizing toxicity. The authors previously demonstrated poor rates of biochemical disease control for patients with National Comprehensive Cancer Network (NCCN) intermediate-risk disease using partial gland treatment with brachytherapy. The objective of the current study was to estimate the rates of distant metastasis and prostate cancer specific mortality (PCSM) for this cohort. METHODS: Between 1997 and 2007, a total of 354 men with clinical T1c disease, a prostate-specific antigen (PSA) level < 15 ng/mL, and Gleason grade <=3 + 4 prostate cancer underwent partial prostate treatment with brachytherapy to the peripheral zone under 0.5-Tesla magnetic resonance guidance. The cumulative incidences of metastasis and PCSM for the NCCN very low-risk, low-risk, and intermediate-risk groups were estimated. Fine and Gray competing risk regression was used to evaluate clinical factors associated with time to metastasis. RESULTS: A total of 22 patients developed metastases at a median of 11.0 years (interquartile range, 6.9-13.9 years). The 12-year metastasis rates for patients with very low-risk, low-risk, and intermediate-risk disease were 0.8% (95% confidence interval [95% CI], 0.1% 4.4%), 8.7% (95% CI, 3.4%-17.2%), and 15.7% (95% CI, 5.7%-30.2%), respectively, and the 12-year PCSM estimates were 1.6% (95% CI, 0.1%-7.6%), 1.4% (95% CI, 0.1% 6.8%), and 8.2% (95% CI, 1.9%-20.7%), respectively. On multivariate analysis, NCCN risk category (low risk: hazard ratio, 6.34 [95% CI, 1.18-34.06; P = .03] and intermediate risk: hazard ratio, 6.98 [95% CI, 1.23-39.73; P = .03]) was found to be significantly associated with the time to metastasis. CONCLUSIONS: Partial prostate treatment with brachytherapy may be associated with higher rates of distant metastasis and PCSM for patients with intermediate-risk disease after long-term follow-up. Treatment of less than the full gland may not be appropriate for this cohort. PMID- 29975407 TI - Cancer patterns in Hmong in Minnesota, 2000 to 2012. AB - BACKGROUND: Minnesota has the second largest Hmong population in the United States. The objective of the current study was to estimate the cancer incidence among Hmong individuals in Minnesota between 2000 and 2012 to determine targets for screening and interventions. METHODS: Cancer cases in Minnesota between 2000 and 2012 were obtained from the Minnesota Cancer Surveillance System, and proportional incidence ratios (PIRs) were calculated. The 2000 and 2010 US Census reports were used to obtain total population estimates. Age-adjusted cancer incidence rates (AAR) and 95% confidence intervals (95% CIs) were calculated for Hmong individuals, Asian/Pacific Islander individuals, and all Minnesotans using direct method and Poisson regression. RESULTS: Compared with all Minnesotans, the Hmong had elevated PIRs and AARs for malignancies related to infections, including nasopharyngeal, stomach, liver, and cervical cancers. The AAR ratios in Hmong versus all Minnesotans were found to be significantly increased for nasopharyngeal (AAR, 15.90; 95% CI, 9.48-26.68), stomach (AAR, 2.99; 95% CI, 2.06 4.33), liver (AAR, 1.77; 95% CI, 1.04-3.02), and cervical (AAR, 3.88; 95% CI, 2.61-5.77) cancers. The AARs in Hmong versus all Minnesotans were significantly lower for all-cause cancer (AAR, 0.39; 95% CI, 0.35-0.44); cancers of the breast, lung, and colorectum; melanoma; and non-Hodgkin lymphoma. Compared with Asian/Pacific Islander individuals, the rates in Hmong were significantly higher for melanoma and cervical cancer, with AAR ratios of 2.23 (95% CI, 1.09-4.56) and 1.59 (95% CI, 1.01-2.49), respectively. CONCLUSIONS: Compared with all Minnesotans, the Hmong have an increased incidence of cancers related to infectious agents. These findings indicate a need for cancer prevention and screening programs in this population. PMID- 29975406 TI - Statistical justification of expansion cohorts in phase 1 cancer trials. AB - BACKGROUND: Phase I cancer trials increasingly incorporate dose-expansion cohorts (DECs), reflecting a growing demand to acquire more information about investigational drugs. Protocols commonly fail to provide a sample-size justification or analysis plan for the DEC. In this study, we develop a statistical framework for the design of DECs. METHODS: We assume the maximum tolerated dose (MTD) for the investigational drug has been identified in the dose escalation stage of the trial. We use the 80% lower confidence bound and the 90% upper confidence bound for the response and toxicity rates, respectively, as decision thresholds for the dose-expansion stage. We calculate the operating characteristics with reference to prespecified minimum effective response rates and maximum safe DLT rates. RESULTS: We apply our framework to specify a system of DEC plans. The design comprises three components: 1) the number of subjects enrolled at the MTD, 2) the minimum number of responses necessary to indicate provisional drug efficacy, and 3) the maximum number of dose-limiting toxicities (DLTs) permitted to indicate drug safety. We demonstrate our method in an application to a cancer immunotherapy trial. CONCLUSIONS: Our simple and practical tool enables creation of DEC designs that appropriately address the safety and efficacy objectives of the trial. PMID- 29975408 TI - Effectiveness of chimeric antigen receptor T cells may be impaired by prior chemotherapy. PMID- 29975410 TI - First person: Derek Raghavan, MD, PhD: Renowned physician-scientist leads the creation of an innovative cancer center. PMID- 29975409 TI - Declines in death from colorectal cancer in europe deemed major success. PMID- 29975411 TI - Reply to Radiation therapy does not increase survival in addition to standard androgen deprivation therapy for metastatic prostate cancer: An old, faded picture? PMID- 29975413 TI - Pragmatic approaches to address expansion cohort design. PMID- 29975412 TI - Putting the life in lifestyle: Lifestyle choices after a diagnosis of cancer predicts overall survival. AB - BACKGROUND: The aim of this study was to examine predictors of health behaviors over time and the link between health behaviors and survival after a diagnosis of advanced cancer. METHODS: Patients with a diagnosis of advanced cancer were administered a battery of questionnaires measuring optimism, depressive symptoms, physical activity, intake of fruits and vegetables, and alcohol and tobacco use over an 18-month period. Analyses included generalized linear mixed models and Cox regression survival analyses. RESULTS: Of the 334 patients enrolled in the study, the mean age at cancer diagnosis was 62 years; the majority were male (62.3%) and white (91%). Twenty percent of the patients reported using alcohol, 19% reported using tobacco, 19% reported eating fewer fruits and vegetables than recommended by the Centers for Disease Control and Prevention and 28% reported physical inactivity after the diagnosis of advanced cancer. Clinical levels of depressive symptoms were associated with lower intake of fruits and vegetables (t = 2.67, P = .007) and physical inactivity (t = 2.11, P = .035). Dispositional optimism was positively associated with physical activity (t = -2.16, P = .031) and a lower frequency of tobacco use (Z = -2.42, P = .015). Multivariate analyses revealed that after adjusting for demographic variables (age and sex), depressive symptoms, and disease-specific factors (diagnosis, tumor size, cirrhosis, vascular invasion, and number of lesions), alcohol use (chi2 = 4.1186, P = .042) and physical inactivity (chi2 = 5.6050, P = .018) were linked to an poorer survival. CONCLUSIONS: Greater dissemination and implementation of effective interventions to reduce alcohol use and increase physical activity in cancer patients are recommended. PMID- 29975414 TI - High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma. AB - BACKGROUND: It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses. METHODS: In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy. RESULTS: Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group (hazard ratio, 0.24; P = .002 and 0.28, P = .001, respectively). Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months; P = .0003). This advantage was maintained in the HD group versus the nonhypophysitis group (P = .02). Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group. CONCLUSIONS: Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs. PMID- 29975415 TI - Radiation therapy does not increase survival in addition to standard androgen deprivation therapy for metastatic prostate cancer: An old, faded picture? PMID- 29975416 TI - Toxicities and outcomes: Do steroids matter? PMID- 29975417 TI - Patient factors associated with sperm cryopreservation among at-risk adolescents newly diagnosed with cancer. AB - BACKGROUND: Although survivors of adolescent-onset cancers are at risk of infertility, the majority desire children. Fertility preservation options are available for adolescents, but sperm banking remains underused. To the authors' knowledge, patient factors that influence decisions to bank sperm are poorly understood. METHODS: A cross-sectional study of 146 adolescent males who were newly diagnosed with cancer and who completed surveys within 1 week of treatment initiation was performed. Participants, 65% of whom were white, were aged 13 to 21 years (mean, 16.49 years; standard deviation, 2.02 years) and were at risk of infertility secondary to impending gonadotoxic treatment. Participating institutions included 8 leading pediatric oncology centers across the United States and Canada. RESULTS: Of the patients approached, approximately 80.6% participated. Parent recommendation to bank (odds ratio [OR], 4.88; 95% confidence interval [95% CI], 1.15-20.71 [P = .03]), higher Tanner stage (OR, 4.25; 95% CI, 1.60-11.27 [P < .01]), greater perceived benefits (OR, 1.41; 95% CI, 1.12-1.77 [P < .01]), and lower social barriers to banking (OR, 0.88; 95% CI, 0.81-0.96 [P < .01]) were found to be associated with adolescent collection attempts, whereas meeting with a fertility specialist (OR, 3.44; 95% CI, 1.00 11.83 [P = .05]), parent (OR, 3.02; 95% CI, 1.12-8.10 [P = .03]) or provider (OR, 2.67; 95% CI, 1.05-6.77 [P = .04]) recommendation to bank, and greater adolescent self-efficacy to bank (OR, 1.16; 95% CI, 1.01-1.33 [P = .03]) were found to be associated with successful sperm banking. CONCLUSIONS: Adolescents' perceived benefits of sperm banking, higher Tanner stage, and parent recommendation were associated with collection attempts, whereas perceived social barriers decreased this likelihood. Successful banking was associated with greater adolescent self efficacy, parent and provider recommendation to bank, and consultation with a fertility specialist. Providers should consult with both adolescents and parents regarding fertility preservation, and interventions should be tailored to address barriers to sperm banking while promoting its benefits. PMID- 29975418 TI - The effects of Plantago major seed gum on steady and dynamic oscillatory shear rheology of sunflower oil-in-water emulsions. AB - : The effects of Plantago major seed (PMS) gum on the rheological properties of the sunflower oil-based emulsions (steady shear flow and dynamic oscillatory rheology) were investigated. The results of steady shear flow experiments showed that the shear stress-shear rate, apparent viscosity-shear rate, and shear stress time data were well fitted with Herschel-Bulkley, Carreau, and Tiu-Bogar models, respectively, and showed the highest R2 and the lower root mean square error within different models. The strain and frequency sweep data indicated that all emulsions showed weak gel-like behavior, which showed stable interactions and entanglements in the emulsion structure. CoX-Merz rule was applied to investigate the relationship between complex viscosity (eta*) and apparent viscosity (etaa ). In all emulsions containing PMS gum, eta* > eta a and they did not obey from this rule. PRACTICAL APPLICATIONS: The rheological properties of emulsion are critical features in stabilization of emulsion based products. The PMS gum can potentially be used in producing and stabilization of emulsion based products and effects of this gum on in oil in water emulsion can be useful in development of plant originated hydrocolloids in foods. PMID- 29975419 TI - Low-molecular-mass hyaluronan induces pulmonary inflammation by up-regulation of Mcl-1 to inhibit neutrophil apoptosis via PI3K/Akt1 pathway. AB - Although low-molecular-mass hyaluronan (LMMHA) has been implicated in pulmonary inflammatory diseases, the signalling pathway of LMMHA (200 000 molecular weight) that initiates the inflammatory response in lung is still unknown. In this study, we evaluate the role of phosphoinositide 3-kinase (PI3K) and its downstream signalling pathway in LMMHA-induced lung inflammatory responses. Our results indicate that pharmacological inhibition of PI3K or genetic deletion of Akt1 enhances neutrophil apoptosis, attenuates neutrophil influx into the lungs of mice and diminishes the expression of pro-inflammatory factors such as interleukin-6, keratinocyte cell-derived chemokine and pro-matrix metalloproteinase-9 in bronchoalveolar lavage fluid after intratracheal administration of LMMHA. More importantly, we found that PI3K/Akt1 participates in LMMHA-induced inflammatory responses, which are mainly mediated by the myeloid leukaemia cell differentiation protein (Mcl-1). Our study suggests that LMMHA induced significantly increased levels of inflammatory factors in bronchoalveolar lavage fluid and activation of the PI3K/Akt1 pathway, which up-regulates the expression of the anti-apoptotic protein Mcl-1 and inhibits the activation of caspase-3, thereby suppressing neutrophil apoptosis to trigger lung inflammation. These findings reveal a novel molecular mechanism underlying sterile inflammation and provides a new potential target for the treatment of pulmonary disease. PMID- 29975420 TI - Topography and neighborhood crowding can interact to shape species growth and distribution in a diverse Amazonian forest. AB - Abiotic constraints and biotic interactions act simultaneously to shape communities. However, these community assembly mechanisms are often studied independently, which can limit understanding of how they interact to affect species dynamics and distributions. We develop a hierarchical Bayesian neighborhood modeling approach to quantify the simultaneous effects of topography and crowding by neighbors on the growth of 124,704 individual stems >=1 cm DBH for 1,047 tropical tree species in a 25-ha mapped rainforest plot in Amazonian Ecuador. We build multi-level regression models to evaluate how four key functional traits (specific leaf area, maximum tree size, wood specific gravity and seed mass) mediate tree growth response to topography and neighborhood crowding. Tree growth is faster in valleys than on ridges and is reduced by neighborhood crowding. Topography and crowding interact to influence tree growth in ~10% of the species. Specific leaf area, maximum tree size and seed mass are associated with growth responses to topography, but not with responses to neighborhood crowding or with the interaction between topography and crowding. In sum, our study reveals that topography and neighborhood crowding each influence tree growth in tropical forests, but act largely independently in shaping species distributions. While traits were associated with species response to topography, their role in species response to neighborhood crowding was less clear, which suggests that trait effects on neighborhood dynamics may depend on the direction (negative/positive) and degree of symmetry of biotic interactions. Our study emphasizes the importance of simultaneously assessing the individual and interactive role of multiple mechanisms in shaping species dynamics in high diversity tropical systems. PMID- 29975421 TI - Causal models: Specification, fitting, reporting, and interpretation. PMID- 29975422 TI - Assessing gastrointestinal motility in healthy horses comparing auscultation, ultrasonography and an acoustic gastrointestinal surveillance biosensor: a randomised, blinded, controlled crossover proof of principle study. AB - BACKGROUND: Auscultation and ultrasonography are noninvasive techniques used to assess gastrointestinal motility in horses. Recently, noninvasive acoustic gastrointestinal surveillance (AGIS) biosensors evaluating intestinal motility have been validated in humans. OBJECTIVES: To compare AGIS to auscultation and ultrasonography for detecting decreased motility after xylazine administration. STUDY DESIGN: Randomised, blinded, controlled cross-over proof of principle study. METHODS: Six healthy horses were evaluated under fasted and nonfasted conditions and randomly assigned to receive treatment with 0.4 mg/kg xylazine or an equivalent volume of 0.9% NaCl intravenously. After a 48-h washout period, the process was repeated with the alternate treatment. Motility was assessed pre and posttreatment. Borborygmi were assessed in each abdominal quadrant and graded on a scale of 0-3, with 3 being continuous borborygmi. Duodenal, jejunal and caecal contractions were assessed ultrasonographically in consistent locations. Four AGIS biosensors were applied in standardised locations (duodenum, caecum, ventral midline, right dorsal colon). The biosensors measure acoustic signals and data were recorded in transport metric. Data were analysed using cross-classified multilevel random effects logistic regression including area under the receiver operator characteristic curve (AUC ROC). Sensitivity, specificity and accuracy were calculated for each modality. RESULTS: All three modalities detected a reduction in gastrointestinal motility following xylazine administration with AUC ROC being 0.85, 0.84 and 0.86 for auscultation, ultrasonography and AGIS respectively. The sensitivity, specificity and accuracy for auscultation was 88, 71 and 75%; for ultrasonography was 67, 63 and 64%; and for AGIS was 69, 70 and 70%, respectively. MAIN LIMITATIONS: The study was performed in normal healthy horses and application of this device to clinical patients warrants further investigation. CONCLUSIONS: In this proof of principle study, AGIS was able to discriminate between horses given xylazine from those given 0.9% NaCl with comparable accuracy as auscultation and ultrasonography. The Summary is available in Spanish - see Supporting Information. PMID- 29975425 TI - ICS 2018 Philadelphia Scientific Programme. PMID- 29975424 TI - Emotion Recognition Biases in Alcohol Use Disorder. AB - BACKGROUND: Alcohol use disorder (AUD) has been associated with impairments in cognitive and emotional function, including difficulty identifying emotional facial expressions. However, it is unclear whether these deficits are associated with alcohol consumption or related anxious and depressive symptoms. METHODS: We compared the recognition of emotional faces expressing happiness, surprise, sadness, fear, anger, and disgust in 19 AUD participants and 19 healthy volunteers using the Cambridge Neuropsychological Test Automated Battery Emotion Recognition Task. We analyzed group differences in response latency, accuracy, and misidentification patterns (as defined by the tendency to mislabel facial expressions as exhibiting specific emotions). To assess whether misidentification patterns were associated with drinking severity, we also examined associations with alcohol consumption over the past 90 days. RESULTS: There were no differences in response latency or accuracy between groups. However, there were group differences in misidentification patterns. While controls tended to misidentify emotional expressions as happy, those with AUD tended to misidentify expressions as angry or disgusted. In AUD participants, the degree to which individuals were biased toward anger or disgust was positively correlated with the number of drinks they consumed in the past 90 days but was not associated with depression or anxiety scores. CONCLUSIONS: Our findings suggest that individuals with AUD have a bias toward misidentifying emotional facial expressions as hostile, which is not mediated by associated mood changes. This provides further evidence of disrupted social cognition in AUD. PMID- 29975423 TI - Comparative study of chemical composition and active components against alpha glucosidase of various medicinal parts of Morus alba L. AB - Morus alba L has long been used as fodder and as a traditional medicine. The different parts of M. alba (Cortex Mori, Ramulus Mori, Folium Mori and Fructus Mori) have different bioactivities; however, most current evidence is focused on anti-diabetic properties. In spite of their widespread use, few studies have compared the chemical composition and activity against alpha-glucosidase of the various medicinal parts of M. alba. In this study, we developed an HPLC method for simultaneous quality control and discrimination of Cortex Mori, Ramulus Mori, Folium Mori and Fructus Mori using 13 marker compounds. We found that quercetin, morin, kuwanon G, sanggenon C, morusin, mulberroside A and rutin were chemically distinct among the various medicinal parts of M. alba. A spectrum-effect relationship method was established to compare alpha-glucosidase inhibitory activity of various batches of samples to determine the activity of the primary active components against alpha-glucosidase. Taken together with molecular docking data, we found that prenylated flavonoids (morin, sanggenon C, kuwanon G and morusin), flavonols (kaempferol, quercetin, rutin and isoquercitrin) and alkaloids (1-deoxynojirimycin) were small molecule alpha-glucosidase inhibitory ingredients. In conclusion, we laid a solid foundation for effective substance identification in various parts of M. alba, and simultaneously provided a basis for their quality control. PMID- 29975426 TI - Differences in caesarean rates across women's socio-economic status by diverse obstetric indications: Cross-sectional study. AB - BACKGROUND: The existing inconsistent association between the caesarean rate and maternal socio-economic status (SES) may be the result of a failure to examine the association across indications for caesarean. This study examined the variation in caesarean rates by maternal SES across diverse obstetric indications. METHODS: Data on demographics, education, insurance status, medical conditions, and obstetric characteristics needed to classify deliveries according to Robson's 10 obstetric-groups were extracted from the 2015 US birth certificate data (n = 3 988 733). Multivariable log-binomial regression was used to analyse the data adjusting for confounders. RESULTS: The caesarean rate was 34.1% for women with high SES and 26.8% for those with low SES. After adjustment for confounders, the rate was similar between women with graduate degrees and those who did not complete high school (relative risk (RR) 1.0, 95% confidence interval (CI) 0.9, 1.1). However, different rates of caesareans across SES were observed for particular obstetric-indications. Notably, women with graduate education compared to those who did not complete high school were more likely to have a caesarean (RR 3.0, 95% CI 2.9, 3.1) for a low-risk condition (group 1: nulliparous women with single, cephalic, >=37 gestational weeks, and spontaneous labour). Women with private insurance were more likely to have a caesarean in almost all obstetric groups, compared to those without private insurance or Medicaid. CONCLUSION: Examining the overall caesarean rate obscures the relationship between SES and the use of caesarean for particular obstetric indications. The unequal utilisation of caesareans across SES highlights overuse and potential underuse of the caesareans among American women. PMID- 29975428 TI - Response regarding "Good practices for observational studies of maternal weight and weight gain during pregnancy". PMID- 29975427 TI - A 22-Year Follow-Up (Range 16 to 23) of Original Subjects with Baseline Alcohol Use Disorders from the Collaborative Study on Genetics of Alcoholism. AB - BACKGROUND: Recent reports indicate higher-than-expected problematic drinking in older populations. However, few data describe how to predict which older individuals are most likely to demonstrate alcohol-related problems, including those with earlier alcohol use disorders (AUDs). These analyses evaluate predictors of alcohol outcomes in individuals with earlier AUDs in the Collaborative Study on Genetics of Alcoholism (COGA). METHODS: Original COGA participants with baseline AUDs at about age 40 were interviewed 13 to 26 years later and placed into clinically derived outcome categories. Chi-square and analysis of variance evaluated baseline differences across 4 outcome groups, with significant items entered into binary logistic regression backwards elimination analyses predicting outcomes. RESULTS: Low-Risk Drinkers (N = 100) at follow-up were predicted by baseline higher levels of response to alcohol (high LRs), lower histories of alcohol treatment, experience with fewer types of illicit drugs, and were more likely to have been widowed. At follow-up, Problem Drinkers (N = 192) differed from High-Risk Drinkers (N = 93) who denied multiple alcohol problems by exhibiting baseline lower LRs, higher Sensation Seeking, and a higher proportion who were widowed. Abstinent (N = 278) outcomes were predicted by a history of higher baseline AUD treatments, higher alcohol problems, lower usual drinks, as well as older age and European American heritage. Thirty-four subjects (4.9%) could not be classified and were not included in these analyses. CONCLUSIONS: These results generated from AUD individuals from both treatment and nontreatment settings reinforce low probabilities of recent Low-Risk Drinking in individuals with AUDs, but also suggest many individuals with AUDs demonstrate good outcomes 2 decades later. PMID- 29975430 TI - Dual Roles of Li3 N as an Electrode Additive for Li-Excess Layered Cathode Materials: A Li-Ion Sacrificial Salt and Electrode-Stabilizing Agent. AB - Li2 CO3 -passivated Li3 N with high stability is prepared by aging Li3 N powder in dry air, and is then used as an electrode additive for a Li(Li0.18 Ni0.15 Co0.15 Mn0.52 )O2 (LLMO) cathode material. The material shows a large irreversible capacity of 800 mA h g-1 during the first charge, with the formation of a Li2 N intermediate product. Acting as a Li+ sacrificial salt for a LLMO(+)/graphite(-) Li-ion battery, 2 wt % Li3 N results in a 10 % increase in discharge capacity. The Li2 N intermediate product reacts with the electrolyte, forming a uniform and regular surface film on the cathode. Moreover, chemical bonding between LLMO and N improves the electrode stability, resulting in excellent electrochemical performance. PMID- 29975429 TI - On-Chip Screening of a Glycomimetic Library with C-Type Lectins Reveals Structural Features Responsible for Preferential Binding of Dectin-2 over DC SIGN/R and Langerin. AB - A library of mannose- and fucose-based glycomimetics was synthesized and screened in a microarray format against a set of C-type lectin receptors (CLRs) that included DC-SIGN, DC-SIGNR, langerin, and dectin-2. Glycomimetic ligands able to interact with dectin-2 were identified for the first time. Comparative analysis of binding profiles allowed their selectivity against other CLRs to be probed. PMID- 29975431 TI - Thermoelectric Performance of IV-VI Compounds with Octahedral-Like Coordination: A Chemical-Bonding Perspective. AB - Thermoelectric materials provide a challenge for materials design, since they require optimization of apparently conflicting properties. The resulting complexity has favored trial-and-error approaches over the development of simple and predictive design rules. In this work, the thermoelectric performance of IV VI chalcogenides on the tie line between GeSe and GeTe is investigated. From a combination of optical reflectivity and electrical transport measurements, it is experimentally proved that the outstanding performance of IV-VI compounds with octahedral-like coordination is due to the anisotropy of the effective mass tensor of the relevant charge carriers. Such an anisotropy enables the simultaneous realization of high Seebeck coefficients, due to a large density-of states effective mass, and high electrical conductivity, caused by a small conductivity effective mass. This behavior is associated to a unique bonding mechanism by means of a tight-binding model, which relates band structure and bond energies; tuning the latter enables tailoring of the effective mass tensor. The model thus provides atomistic design rules for thermoelectric chalcogenides. PMID- 29975432 TI - Systematic identification of long non-coding RNAs during pollen development and fertilization in Brassica rapa. AB - The importance of long non-coding RNAs (lncRNAs) in plant development has been established, but a systematic analysis of lncRNAs expressed during pollen development and fertilization has been elusive. We performed a time series of RNA seq experiments at five developmental stages during pollen development and three different time points after pollination in Brassica rapa and identified 12 051 putative lncRNAs. A comprehensive view of dynamic lncRNA expression networks underpinning pollen development and fertilization was provided. B. rapa lncRNAs share many common characteristics of lncRNAs: relatively short length, low expression but specific in narrow time windows, and low evolutionary conservation. Gene modules and key lncRNAs regulating reproductive development such as exine formation were uncovered. Forty-seven cis-acting lncRNAs and 451 trans-acting lncRNAs were revealed to be highly coexpressed with their target protein-coding genes. Of particular importance are the discoveries of 14 lncRNAs that were highly coexpressed with 10 function-known pollen-associated coding genes. Fifteen lncRNAs were predicted as endogenous target mimics for 13 miRNAs, and two lncRNAs were proved to be functional target mimics for miR160 after experimental verification and shown to function in pollen development. Our study provides the systematic identification of lncRNAs during pollen development and fertilization in B. rapa and forms the foundation for future genetic, genomic, and evolutionary studies. PMID- 29975433 TI - Congenital inferior sinus venosus defect associated with pulmonary valve stenosis: A late presentation of a rare disease. AB - Congenital inferior sinus venosus defect (SVD) is a rare congenital heart disease. Proper diagnosis of this disease is challenging and requires understanding of cardiac hemodynamics. Here, we discuss a patient with a late presentation of combined congenital inferior SVD associated with congenital pulmonary stenosis. PMID- 29975434 TI - Free-Standing 2D Hexagonal Aluminum Nitride Dielectric Crystals for High Performance Organic Field-Effect Transistors. AB - The existence of defects and traps in a transistor plays an adverse role on efficient charge transport. In response to this challenge, extensive research has been conducted on semiconductor crystalline materials in the past decades. However, the development of dielectric crystals for transistors is still in its infancy due to the lack of appropriate dielectric crystalline materials and, most importantly, the crystal morphology required by the gate dielectric layer, which is also crucial for the construction of high-performance transistor as it can greatly improve the interfacial quality of carrier transport path. Here, a new type of dielectric crystal of hexagonal aluminum nitride (AlN) with the desired 2D morphology of combing thin thickness with large lateral dimension is synthesized. Such a suitable morphology in combination with the outstanding dielectric properties of AlN makes it promising as a gate dielectric for transistors. Furthermore, ultrathin 2,6-diphenylanthracene molecular crystals with only a few molecular layers can be prepared on AlN crystal via van der Waals epitaxy. As a result, this all-crystalline system incorporating dielectric and semiconductor crystals greatly enhances the overall performance of a transistor, indicating the importance of minimizing defects and preparing high-quality semiconductor/dielectric interface in a transistor configuration. PMID- 29975435 TI - Adsorption and Quantification of Volatile Organic Compounds (VOCs) by using Hybrid Magnetic Nanoparticles. AB - The ability of Fe3 O4 magnetic nanoparticles decorated with perylene bisimides to adsorb aromatic volatile organic compounds (VOCs) is reported. We have used DFT D3 calculations to anticipate the strong ability of the electron-poor perylene bisimide to form noncovalent complexes with electron-rich aromatic rings belonging to the VOC family. Subsequently, we synthesized a hybrid magnetic nanomaterial based on bisimide perylene dopamine and iron oxide nanoparticles. This material was used to fill a sorbent tube to study its ability to adsorb aromatic VOCs. We connected two tubes in series filled with the hybrid nanoparticles. The analysis of the front and back tubes was performed by thermal desorption (TD) coupled with capillary gas chromatography (GC)/flame ionization detector (FID). Adsorption values (defined as %VOCs found in the back tube) were determined for a series of aromatic VOCs and compared with the DFT binding energies. The tubes can be desorbed and reutilized more than 200 times without losing their properties. PMID- 29975436 TI - Ammonia-weighted imaging by chemical exchange saturation transfer MRI at 3 T. AB - Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT) weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations. PMID- 29975437 TI - Prevalence of allergy to human seminal fluid among women with allergy to male dog and sensitization to Can f 5. PMID- 29975438 TI - Highly Conducting Polythiophene Thin Films with Less Ordered Microstructure Displaying Excellent Thermoelectric Performance. AB - Polythiophene (PTh) with highly regular molecular structure is synthesized as nearly amorphous thin films by electrochemical methods in a BFEE/DTBP mixed medium (BFEE = boron fluoride ethyl ether; DTBP = 2,6-di-tert-butypyridine). The doping level and film morphology of PTh are modulated through adjusting the current density applied during the polymerization process. A combined analysis with solid-state NMR, FT-IR, and Raman spectra reveals the molecular structural regularity of the resulted PTh films, which leads to the highest electrical conductivity up to 700 S cm-1 for films obtained under an optimized current density of 1 mA cm-2 . By applying the self-heating 3omega-method, thermal conductivities are measured along the in-plane direction. A highly reduced Lorenz number of 6.49 * 10-9 W Omega K-2 and low lattice thermal conductivity of 0.21 W m-1 K-1 were extracted based on the analyses of the electrical and thermal conductivities according to the Wiedemann-Franz Law; the former is about one third of the Sommerfeld value. Finally, the maximized ZT value can reach up to 0.10 under room temperature, which shows that the highly conducting polymers with less ordered structure is the practical direction for developing organic thermoelectric materials. PMID- 29975439 TI - MiR-5702 suppresses proliferation and invasion in non-small-cell lung cancer cells via posttranscriptional suppression of ZEB1. AB - MiRNAs have emerged as important players in tumorigenesis and progression. MiR 5702 is a newly identified miRNA; the exact role of which has not been reported. Here, we found that miR-5702 was significantly decreased in the carcinoma tissues of non-small cell lung cancer (NSCLC) patients and NSCLC cell lines. Then, our results showed that the miR-5702 mimic induced apoptosis and inhibited proliferation and invasion in A549 cells. In contrast, the miR-5702 inhibitor reduced apoptosis and increased proliferation and invasion in A549 cells. Furthermore, bioinformatics and 3'-UTR luciferase reporter assays identified that oncogene zinc finger E-box-binding homeobox 1 (ZEB1) is a target gene of miR 5702. Western blotting analysis showed that miR-5702 overexpression suppressed, and miR-5702 knockdown promoted the expression of ZEB1 protein. Finally, the ZEB1 siRNA exhibited a similar effect to the miR-5702 mimic on expression of ZEB1 and its downstream genes, cell apoptosis, cell proliferation, and cell invasion, and it could antagonize the alternations in ZEB1 expression and cell behaviors by the miR-5702 inhibitor. In conclusion, miR-5702 may function as a tumor suppressor in NSCLC, which suppresses proliferation and invasion NSCLC cells via posttranscriptional suppression of ZEB1. PMID- 29975441 TI - VIGNETTE. PMID- 29975440 TI - The effect of astaxanthin and cadmium on rat erythrocyte G6PD, 6PGD, GR, and TrxR enzymes activities in vivo and on rat erythrocyte 6PGD enzyme activity in vitro. AB - In this study, the effects of astaxanthin (AST) that belongs to carotenoid family and cadmium (Cd), which is an important heavy metal, on rat erythrocyte G6PD, 6PGD, GR, and TrxR enzyme activities in vivo and on rat erythrocyte 6PGD enzyme activity in vitro were studied. In in vitro studies, 6PGD enzyme was purified from rat erythrocytes with 2',5'-ADP Sepharose4B affinity chromatography. Results showed inhibition of enzyme by Cd at IC50 ; 346.5 MUM value and increase of 6PGD enzyme activity by AST. In vivo studies showed an increase in G6PD, 6PGD, and GR enzyme activities (P ? 0.05) and no chance in TrxR enzyme activity by AST. Cd ion inhibited G6PD, 6PGD, and GR enzyme activities (P ? 0.05) and also decreased TrxR enzyme activity (P ? 0.05). AST + Cd group G6PD enzyme activity was statistically low compared with control group (P ? 0.05). 6PGD and TrxR enzyme activities decreased without statistical significance (P ? 0.05); however, GR enzyme activity increased statistically significantly (P ? 0.05). PMID- 29975442 TI - Needs of individuals recovering from a first episode of mental illness: A scoping review. AB - Central to the role of mental health clinicians is the assessment of needs. A number of assessment tools have been used to evaluate the needs of individuals diagnosed with a mental illness. These tools have largely been developed for people with a severe and persistent mental illness and may not be suitable for individuals who are recovering from a first episode of mental illness. The aims of this review were therefore to identify the needs experienced by individuals recovering from a first episode of mental illness; determine what tools have been used to evaluate these needs; and explore whether existing tools adequately reflect the needs described in the literature. Twenty-one articles were included, comprising articles which identified needs (n = 10), needs assessment tools (n = 1), or articles which identified both needs and a needs assessment tool (n = 10). Results indicate that individuals who have been admitted to a specialized mental health unit and are recovering from a first episode of mental illness may experience an extensive range of needs, spanning emotional, psychological, social, informational, functional, practical, and relationship needs. Four established needs assessment tools were found to have been used to evaluate these needs; however, these do not appear to represent all needs discovered in this review, were mostly developed for populations with a long-term mental illness, and may not be suitable for assessing the needs of individuals recovering from a first episode of mental illness following a presentation to a specialized mental health unit. PMID- 29975444 TI - GSH/GSSG redox couple plays central role in aryl hydrocarbon receptor-dependent modulation of cytochrome P450 1A1. AB - The redox regulation of aryl hydrocarbon receptor (AHR) target genes such as the best characterized, cytochrome P450 1A1 (CYP1A1) has not been known. Therefore the aim of this study was to explore how cellular redox state can influence on AHR-dependent modulation of CYP1A1 transcription and enzyme activities. Male BALB/c albino mice, HepG2 cells, and human hepatoma cell line (HepG2-XRE-Luc) carrying CYP1A1 response elements were exposed to suggested endogenous ligand of AHR,6-formylindolo[3,2-b] carbazole (FICZ) alone or in combination with, buthionine-(S,R)-sulfoximine (BSO) or N-acetyl-l-cysteine (NAC). A clear link between CYP1A1 transcription and enzyme activity and changes in the glutathione/oxidised glutathione (GSH/GSSG) redox couple was shown. In vivo and in vitro findings demonstrated that the time course of AHR activation/inhibition is characterized by an increase/decrease in the GSH/GSSG ratio. Based on these findings, we propose that many environmental pollutants and oxidants by alteration in the intracellular redox potential may interfere with the normal function of AHR target genes. PMID- 29975443 TI - Safety and efficacy of chronic suppressive azole therapy for endemic fungal infections in solid organ transplant recipients. AB - BACKGROUND: Although the research is limited, treatment guidelines recommend lifelong suppressive azole therapy for disseminated endemic fungal infection (EFI) after solid organ transplantation (SOT). Suppressive azole therapy may prevent EFI recurrence at the risk of hepatotoxicity and drug interactions. We present real-world safety and effectiveness data of chronic suppressive azole therapy for EFI in SOT recipients over a 10-year period at a single comprehensive transplant center. METHODS: A retrospective analysis was conducted of SOT recipients diagnosed with EFI from January 1, 2005, to May 1, 2015. Chronic suppressive azole therapy was defined as treatment for more than 12 months after diagnosis. Effectiveness of suppression was defined as preventing EFI reactivation. Safety endpoints included adverse reactions and drug interactions. RESULTS: Over a 10-year period, 28 SOT recipients were diagnosed with EFI: 16 histoplasmosis, 9 blastomycosis, and 3 coccidioidomycosis. Eighteen (64%) patients were treated with chronic suppressive azole therapy for a median length of 36 months (range 15-90). One patient had an adverse drug interaction requiring azole discontinuation. There were no episodes of azole-related hepatotoxicity, toxicity from antirejection medication, or EFI reactivation. CONCLUSIONS: Chronic suppressive azole therapy was safe and effective in preventing reactivation of EFI in SOT recipients. PMID- 29975445 TI - Antiapoptotic effects of vitamins C and E against cypermethrin-induced oxidative stress and spermatogonial germ cell apoptosis. AB - Toxicological studies have demonstrated the relation between use of agrochemicals and fertility issues within males. Thus, the present study aimed to elucidate the propensity of cypermethrin (CYP) in bringing testicular germ cell apoptosis and effective attenuation by vitamins C and E in caprines. Reproductive toxicity of CYP was evaluated using histomorphological, cytological, and biochemical changes in the testicular germ cells in dose-dependent (1, 5, 10 MUg/mL) and time dependent (4, 6, 8 h) manner. Histological and ethidium bromide/acridine orange fluorescence staining exhibited that vitamins C and E (0.5 and 1.0 mM) successfully diminished the CYP-induced testicular germ cells apoptosis. CYP exposure along with vitamins C and E supplementation also resulted in significantly increased ferric reducing antioxidant power activity along with the antioxidant enzymes, namely catalase, superoxide dismutase, and glutathione-s transferase, and decreased lipid peroxidation in testicular germ cells. Thus, vitamins C and E ameliorated CYP-induced testicular germ cell apoptosis, thereby preventing spermatogonial cells degeneration and male infertility. PMID- 29975446 TI - Patients' experiences of isolation in psychiatric inpatient care: Insights from a meta-ethnographic study. AB - Historically, people with mental ill-health have been isolated from society. Although mental health care has moved from closed to more open forms of care, in many societies care is still provided in locked wards, and people with mental ill health are sometimes secluded from their fellow patients, families, friends, and visitors. The aim of this study was to illuminate patients' experiences of isolation in psychiatric inpatient care. A systematic review of qualitative research was conducted, and the key findings were subjected to meta-ethnographic synthesis. The findings were twofold: 'being admitted to prison' and 'having access to shelter'. The experience of isolated care as prison-like symbolizes patients' longing for freedom and feeling restricted and limited by rules, stripped of rights, abandoned, controlled, powerless, and unsupported. In contrast, the experience of isolation as shelter symbolizes safety and the opportunity to regain control over one's own situation. A stigmatizing public view holds that people with mental ill-health are dangerous and unpredictable and, therefore, unsafe to themselves and others. Being placed in isolation because these fears contribute to self-stigma among patients. Promoting a sheltered experience in which isolation is used with respect for patients and the reasons are made explicit may encourage recovery. A shift in emphasis in ward culture from observation to engagement is needed to reduce blame, shift patient experiences from prison to shelter, and to support autonomy as a therapeutic intervention. PMID- 29975447 TI - Oxidative stress-induced renal telomere shortening as a mechanism of cyclosporine induced nephrotoxicity. AB - Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine-A exerts its nephrotoxic side effects via induction of oxidative stress-induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine-A treatment significantly (P < 0.05) enhanced renal malondialdehyde, 8-hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine-A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine-induced oxidative stress, indicating the potential mechanism of cyclosporine-induced nephrotoxicity. PMID- 29975448 TI - Control over Electrochemical Water Oxidation Catalysis by Preorganization of Molecular Ruthenium Catalysts in Self-Assembled Nanospheres. AB - Oxygen formation through water oxidation catalysis is a key reaction in the context of fuel generation from renewable energies. The number of homogeneous catalysts that catalyze water oxidation at high rate with low overpotential is limited. Ruthenium complexes can be particularly active, especially if they facilitate a dinuclear pathway for oxygen bond formation step. A supramolecular encapsulation strategy is reported that involves preorganization of dilute solutions (10-5 m) of ruthenium complexes to yield high local catalyst concentrations (up to 0.54 m). The preorganization strategy enhances the water oxidation rate by two-orders of magnitude to 125 s-1 , as it facilitates the diffusion-controlled rate-limiting dinuclear coupling step. Moreover, it modulates reaction rates, enabling comprehensive elucidation of electrocatalytic reaction mechanisms. PMID- 29975449 TI - Diversity of piRNA expression patterns during the ontogeny of the German cockroach. AB - The Piwi-interacting RNA (piRNA) system is an evolutionarily conserved mechanism involved in the control of transposable elements and maintenance of genomic stability, especially in germ line cells and in early embryo stages. However, relevant particularities, both in mechanism and function, exist across species among metazoans and even within the insect class. As a member of the scarcely studied hemimetabolan group, Blattella germanica can be a suitable reference model to study insect evolution. We present the results of a stringent process of identification and study of expressed piRNAs for B. germanica across 11 developmental stages, ranging from unfertilized egg to nymphs and adult female. Our results confirm the dual origin of piRNA in this species, with a majority of them being generated from the primary pathway, and a smaller but highly expressed set of sequences participating in the secondary ("ping-pong") reamplification pathway. An intriguing partial complementarity in expression is observed between the piRNA of the two biogenesis pathways, with those generated in the secondary pathway being quite restricted to early embryo stages. In addition, many piRNAs are exclusively expressed in late embryo and nymphal stages. These observations point at piRNA functions beyond the role of transposon control in early embryogenesis. Our work supports the view of a more complex scenario, with different sets of piRNAs acting in different times and having a range of functions wider than previously thought. PMID- 29975450 TI - Intermolecular amination of allylic and benzylic alcohols leads to effective inhibitions of acetylcholinesterase enzyme and carbonic anhydrase I and II isoenzymes. AB - In this study, we aimed to determine the inhibition effects of novel synthesized sulfamates (2a-g), sulfonamides (3b-f), carbonyl sulfonamides (3h and i), and carbonyl sulfamates (4h and 4i), which were tested against two human cytosolic carbonic anhydrase I and II isozymes (hCA I and II) and acetylcholinesterase (AChE) enzyme. For inhibition properties of allylic sulfamates, the half maximal inhibitory concentration (IC50 ) and inhibition constant (Ki ) were calculated for each novel compounds. The allylic sulfamates showed that Ki values are in the range of 187.33-510.31 pM for hCA I, 104.22-290.09 pM against hCA II, and 12.73 103.63 pM against AChE. The results demonstrated that all newly synthesized compounds had shown effective inhibition against hCA I and II isoenzymes and AChE enzyme. PMID- 29975451 TI - Alleviation by abscisic acid of Al toxicity in rice bean is not associated with citrate efflux but depends on ABI5-mediated signal transduction pathways. AB - Under conditions of aluminum (Al) toxicity, which severely inhibits root growth in acidic soils, plants rapidly alter their gene expression to optimize physiological fitness for survival. Abscisic acid (ABA) has been suggested as a mediator between Al stress and gene expression, but the underlying mechanisms remain largely unknown. Here, we investigated ABA-mediated Al-stress responses, using integrated physiological and molecular biology approaches. We demonstrate that Al stress caused ABA accumulation in the root apex of rice bean (Vigna umbellata [Thunb.] Ohwi & Ohashi), which positively regulated Al tolerance. However, this was not associated with known Al-tolerance mechanisms. Transcriptomic analysis revealed that nearly one-third of the responsive genes were shared between the Al-stress and ABA treatments. We further identified a transcription factor, ABI5, as being positively involved in Al tolerance. Arabidopsis abi5 mutants displayed increased sensitivity to Al, which was not related to the regulation of AtALMT1 and AtMATE expression. Functional categorization of ABI5-mediated genes revealed the importance of cell wall modification and osmoregulation in Al tolerance, a finding supported by osmotic stress treatment on Al tolerance. Our results suggest that ABA signal transduction pathways provide an additional layer of regulatory control over Al tolerance in plants. PMID- 29975452 TI - MiR-106b regulates the apoptosis and tumorigenesis of hepatocellular carcinoma via targeting Zinc finger and BTB domain-containing protein 7A (Zbtb7a). AB - MicroRNAs play vital regulatory roles in various type of tumorigenesis. We aimed to explore the functional microRNAs that might play as therapeutic targets in hepatocellular carcinoma (HCC). In this study, our results revealed that microRNA 106b was significantly increased in HCC tumor tissues. However, miR-106b knockdown remarkably suppressed the growth and increased the apoptosis of Hub-7 HCC cells. Biological analysis indicated that miR-106b directly targeted toZinc finger and BTB domain-containing protein 7A (Zbtb7a) to regulate the apoptosis of Hub-7 cells. Extensively, Zbtb7a overexpression reversed Huh-7 cell apoptosis and growth in vitro. Furthermore, in vivo studies confirmed that miR-106b inhibition or Zbtb7a overexpression retarded the growth of Hub-7 xenograft tumor in nude mice. In conclusion, we provide the evidence for the regulatory role of miR-106b in HCC, which is causally linked to targeting of Zbtb7a. This study may provide miR-106b as a potential therapeutic strategy for HCC. PMID- 29975453 TI - Addressing the Challenges to Identification in Gas Chromatography by Increased Resolution and Enhanced Detection Modalities. AB - In the past 15+ years, gas chromatography (GC) has undergone a renaissance in its implementation on the basis of the "disruptive" technology of comprehensive two dimensional gas chromatography (GC*GC). With a foundation based upon a two-column GC separation approach, GC*GC significantly alters the classical multidimensional gas chromatography (MDGC) method by employing very fast separation on a second dimension (2 D) after a conventional one-dimensional (i.e., single column; 1D) column separation. This allows the experimentalist to apply the advantages of multidimensionality to the total sample rather than to just discrete zones of the 1D separation that characterizes MDGC. This requires a new "language" to describe GC*GC separations, applied to the first dimension (1 D) and 2 D, and consideration of the modulation processes that define the transfer of analyte from the 1 D to the 2 D. The present review is based on the FACS Foundation lectureship of the author given at the 17th Asian Chemical Congress of the Federation of Asian Chemical Societies (FACS). The award lecture and this manuscript is based on material deriving largely from research in the area of MDGC and GC*GC separations of the author. PMID- 29975454 TI - Effects of intracameral injection of epinephrine and 2% lidocaine on pupil diameter, intraocular pressure, and cardiovascular parameters in healthy cats. AB - OBJECTIVES: To investigate the effects of the intracameral injection of epinephrine and two doses of 2% lidocaine on pupil diameter (PD), intraocular pressure (IOP), heart rate (HR), and mean arterial pressure (MAP) in healthy cats. METHODS: Five treatment groups were formed (10 cats/each). Animals received 0.2 mL of epinephrine, 0.2 or 0.3 mL of 2% lidocaine, or 0.2 mL of BSS. Cats were anesthetized, and all solutions were injected intracamerally. PD, IOP, HR, and MAP were assessed at baseline, following anterior chamber paracentesis (T0), and at every 5 minutes, until anesthesia was terminated (T60). PD and IOP continued to be assessed for 2 additional hours during recovery from anesthesia. In another group, cats were not anesthetized and one of the eyes was treated with one drop of 0.5% tropicamide to check for maximal pupil diameter. RESULTS: Faster onset and longer duration of sufficient mydriasis (>10 mm) were observed in epinephrine treatment group, when comparing with cats treated with both doses of lidocaine. Eyes treated with epinephrine achieved the largest maximum pupil diameter (mm) when comparing with eyes treated with 0.3 mL of lidocaine (11.01 +/- 0.16), tropicamide (10.66 +/- 0.17), and 0.2 mL of lidocaine (10.23 +/- 0.12) (P < .0001). In all groups, IOP decreased significantly at T0, but tended to return to baseline at T60. HR and MAP did not change significantly during time and among treatments. CONCLUSIONS: The intracameral injection of 0.2 mL of 1:100 000 epinephrine and 0.3 mL of 2% lidocaine can be used as an alternative to tropicamide in healthy cats. Both treatments produced satisfactory and long lasting mydriasis without adverse effects on IOP, HR, and MAP. PMID- 29975455 TI - Rab-H1b is essential for trafficking of cellulose synthase and for hypocotyl growth in Arabidopsis thaliana. AB - Cell-wall deposition of cellulose microfibrils is essential for plant growth and development. In plant cells, cellulose synthesis is accomplished by cellulose synthase complexes located in the plasma membrane. Trafficking of the complex between endomembrane compartments and the plasma membrane is vital for cellulose biosynthesis; however, the mechanism for this process is not well understood. We here report that, in Arabidopsis thaliana, Rab-H1b, a Golgi-localized small GTPase, participates in the trafficking of CELLULOSE SYNTHASE 6 (CESA6) to the plasma membrane. Loss of Rab-H1b function resulted in altered distribution and motility of CESA6 in the plasma membrane and reduced cellulose content. Seedlings with this defect exhibited short, fragile etiolated hypocotyls. Exocytosis of CESA6 was impaired in rab-h1b cells, and endocytosis in mutant cells was significantly reduced as well. We further observed accumulation of vesicles around an abnormal Golgi apparatus having an increased number of cisternae in rab h1b cells, suggesting a defect in cisternal homeostasis caused by Rab-H1b loss function. Our findings link Rab GTPases to cellulose biosynthesis, during hypocotyl growth, and suggest Rab-H1b is crucial for modulating the trafficking of cellulose synthase complexes between endomembrane compartments and the plasma membrane and for maintaining Golgi organization and morphology. PMID- 29975457 TI - Enhancing the Secretion of a Glyco-Engineered Anti-CD20 scFv-Fc Antibody in Hairy Root Cultures. AB - Hairy root (HR) cultures represent an attractive platform for the production of heterologous proteins, due to the possibility of secreting the molecule of interest in the culture medium. The main limitation is the low accumulation yields of heterologous proteins. The aim of this study is to enhance the accumulation of a tumor-targeting antibody with a human-compatible glycosylation profile in HR culture medium. To this aim, the authors produce Nicotiana benthamiana HR cultures expressing the red fluorescent protein (RFP) to easily screen for different auxins able to induce heterologous protein secretion in the medium. The hormone 2,4-dichlorophenoxyacetic acid (2,4-D) is found to induce high accumulation levels (334 mg L-1 ) of RFP in the culture medium. The same protocol is used to improve the secretion of the tumor-targeting, CD20-specific 2B8-FcDeltaXF recombinant antibody from glyco-engineered DeltaXTFT N. benthamiana HR cultures. The addition of 2,4-D determine a 28-fold increase of the accumulation of fully functional 2B8-FcDeltaXF in the culture medium, at levels of ~16 mg L-1 . Antibody N-glycosylation profiling reveal the prominent occurrence of GnGn structures and low levels of xylose- and fucose-containing counterparts. This result is the first example of the expression of an engineered anti-CD20 antibody with a scFv-Fc format at high levels in HR. PMID- 29975456 TI - Tunable Water-Soluble Supramolecular Polymers by Visible-Light-Regulated Host Guest Interactions. AB - The development of artificial self-assembling systems with dynamic photo regulation features in aqueous solutions has drawn great attention owing to the potential applications in fabricating elaborate biological materials. Here we demonstrate the fabrication of water-soluble cucurbit[8]uril (CB[8])-mediated supramolecular polymers by connecting the fluorinated azobenzene (FAB) containing monomers through host-enhanced heteroternary pi-pi stacking interactions. Benefiting from the unique visible-light-induced E->Z photoisomerization of the FAB photochromophores, the encapsulation behaviors between the CB[8] macrocycle and the monomers could be regulated upon visible light irradiation, resulting in the depolymerization of such CB[8]-mediated supramolecular polymers. PMID- 29975458 TI - A Cobalt-Based Metal-Organic Framework as Cocatalyst on BiVO4 Photoanode for Enhanced Photoelectrochemical Water Oxidation. AB - A metal-organic framework (MOF)-modified bismuth vanadate (BiVO4 ) photoanode is fabricated by an ultrathin sheet-induced growth strategy, where ultrathin cobalt oxide sheets act as a metal source for the in situ synthesis of Co-based MOF poly[Co2 (benzimidazole)4 ] (denoted [Co2 (bim)4 ]) nanoparticles on the surface of BiVO4 . [Co2 (bim)4 ] with small particle size and high dispersion can serve as a promising cocatalyst to accept holes transferred from BiVO4 and boost surface reaction kinetics for photoelectrochemical (PEC) water oxidation. The photocurrent density of a [Co2 (bim)4 ]-modified BiVO4 photoanode can achieve 3.1 mA cm-2 under AM 1.5G illumination at 1.23 V versus the reversible hydrogen electrode (RHE), which is better than those of pristine and cobalt-based inorganic materials-modified BiVO4 photoanodes. [Co2 (bim)4 ], with porosity and abundant metal sites, exhibits a high surface charge-separation efficiency (83 % at 1.2 V versus RHE), leading to the enhanced PEC activity. This work will bring new insight into the development of MOF materials as competent cocatalysts for PEC water splitting applications. PMID- 29975459 TI - Self-Assembly and Stabilization of Hybrid Cowpea Chlorotic Mottle Virus Particles under Nearly Physiological Conditions. AB - Capsids of the cowpea chlorotic mottle virus (CCMV) hold great promise for use as nanocarriers in vivo. A major drawback, however, is the lack of stability of the empty wild-type virus particles under physiological conditions. Herein, the assembly behavior and stability under nearly physiological conditions of protein based block copolymers composed of the CCMV capsid protein and two hydrophobic elastin-like polypeptides are reported. UV/Vis spectroscopy studies, dynamic light-scattering analysis, and TEM measurements demonstrate that both hybrid variants form stable capsids at pH 7.5, physiological NaCl concentration, and 37 degrees C. The more hydrophobic variant also remains stable in a cell culture medium. These engineered, hybrid CCMV capsid particles can therefore be regarded as suitable candidates for in vivo applications. PMID- 29975460 TI - In vitro metabolism of selected bioactive compounds of Eurycoma longifolia root extract to identify suitable markers in doping control. AB - Eurycoma longifolia Jack (Tongkat Ali, Simaroubaceae) is a medicinal plant endemic to South-East Asia. For centuries, different parts of the plant have been used as a natural remedy to treat fever, hypertension, or sexual insufficiency. Today, Eurycoma longifolia preparations are commercially available and advertised to enhance athletic performance and muscle strength. Several studies have demonstrated a testosterone-boosting effect that might be caused by the release of free testosterone from the sex-hormone-binding globulin. To date, many phytochemical constituents of Eurycoma longifolia root extracts have been identified and physiological effects have been examined, while studies on their biotransformation and monitoring are still lacking. Within this study, eurycomalide C, eurycomalactone, 5,6-dehydro-eurycomalactone, longilactone, 14,15beta-dihydroklaieanone, 11-dehydroklaieanone, 9-hydroxycanthin-6-one, and 9 methoxycanthin-6-one isolated from E. longifolia root were incubated with liver microsomes. Respective metabolites were analyzed by liquid chromatography-tandem (high-resolution) mass spectrometry. The compounds were chosen based on their potential androgenic effects (estimated by in vitro assays), their concentrations in plant extracts, and presumptive metabolic pathways. Hydroxylated phase I metabolites were only observed for 5,6-dehydro-eurycomalactone, 11 dehydroklaieanone, 9-hydroxycanthin-6-one, and 9-methoxycanthin-6-one. Moreover, an O-demethylated metabolite of 9-methoxycanthin-6-one was found. Besides, the glucuronide of 9-hydroxycanthin-6-one was detected after in vitro glucuronidation using liver microsomes. The in vitro generated metabolites were comparable to that detected in urine and serum after a single ingestion of either 9 methoxycanthin-6-one or an Eurycoma longifolia root extract. Hence, 9 methoxycanthin-6-one, its glucuronide, and the glucuronide of its O-demethylated biotransformation product are proposed to be the most suitable targets for detection of 9-methoxycanthin-6-one or Tongkat Ali application in urine and serum. PMID- 29975461 TI - HPV RNA in situ hybridization can inform cervical cytology-histology correlation. AB - BACKGROUND: In situ hybridization for human papillomavirus (HPV) messenger RNA (HPV RNA ISH) recently was introduced as an ancillary tool in the diagnosis of cervical squamous intraepithelial lesions, and can aid in the distinction between low-grade squamous intraepithelial lesions (LSILs) versus reactive/negative biopsies. Prior work has shown that up to one-half of cases originally diagnosed as LSIL are reclassified as negative/reactive by expert consensus review of morphology, and negative HPV RNA ISH results most often correlate with an expert diagnosis of negative/reactive. Given that LSIL overdiagnoses on biopsy may result in the erroneous clinical impression that a cervical lesion has been sampled appropriately, the authors proposed that HPV RNA ISH can inform cytology histology correlation for challenging LSIL biopsies. METHODS: A total of 92 cervical biopsies originally diagnosed as LSIL were reviewed by 3 gynecologic pathologists and reclassified based on consensus opinion of morphology. ISH was performed for high-risk and low-risk HPV E6/E7 mRNA. Prior/concurrent cytology results were collected. RESULTS: Based on expert consensus morphologic review, 49% of biopsies (45 of 92 biopsies) originally diagnosed as LSIL were reclassified as negative, 6.5% (6 of 92 biopsies) were reclassified as high-grade squamous intraepithelial lesion, and 44.5% (41 of 92 biopsies) were maintained as LSIL. The majority of LSIL biopsies reclassified as negative (80%; 36 of 45 biopsies) were HPV RNA negative, whereas 93% of LSIL biopsies (39 of 41 biopsies) and 100% of high-grade squamous intraepithelial lesion biopsies were HPV RNA positive. CONCLUSIONS: LSIL often is overdiagnosed by morphology on biopsy, potentially leading to the false impression that a lesion identified on cytology has been sampled. Performing RNA ISH on biopsies decreases histologic LSIL overdiagnosis, and potentially can prompt further sampling when there is cytology histology discordance. Cancer (Cancer Cytopathol) 2018. (c) 2018 American Cancer Society. PMID- 29975462 TI - Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: A randomized double-blind placebo-controlled study in Japan. AB - AIMS/INTRODUCTION: Diabetic polyneuropathy is one of the most frequent diabetic complications, and impairs patients' quality of life. We evaluated the efficacy and safety of ranirestat (40 mg/day) in patients with diabetic polyneuropathy. MATERIALS AND METHODS: This was a multicenter, placebo-controlled, randomized double-blind, parallel-group, phase III study in which 557 patients were randomly assigned to either the ranirestat or placebo group and assessed for 52 weeks. The co-primary end-points were the changes in tibial motor nerve conduction velocity and total modified Toronto Clinical Neuropathy Score as a measure of clinical symptoms. RESULTS: There was a significant increase in tibial motor nerve conduction velocity in the ranirestat group compared with the placebo group. The difference between groups in the change at last observation was 0.52 m/s (P = 0.021). Increases in nerve conduction velocity in the ranirestat group were found not only in the tibial motor nerves, but also in the median motor nerves, proximal median sensory nerves and distal median sensory nerves. No significant differences in modified Toronto Clinical Neuropathy Score or safety parameters were found between the two groups. CONCLUSIONS: Ranirestat (40 mg/day) was well tolerated and improved nerve conduction velocity. Regarding symptoms and signs, no detectable benefits over the placebo were observed in the ranirestat group during the 52 weeks of treatment. PMID- 29975463 TI - CytoTECHnology: The benefits of technology in teaching. PMID- 29975464 TI - Primary Sjogren's Syndrome. PMID- 29975465 TI - Recombinant Production of Mussel Byssus Inspired Proteins. AB - Mussel byssus, the holdfast of mussels, has attracted much attention due to the mechanical gradient properties of its threads and the robust and flexible adhesion to various substrates, features that originate mainly from mussel byssus proteins and could be used in potential applications in biomedicine. However, the applications have been impeded owing to the difficulties concerning the extraction of the natural materials, that is, proteins. Recent advances in recombinant production provide a novel approach to generate mussel byssus inspired proteins, even with the opportunities for scale-up production. Here, we review the recently investigated mussel byssus inspired proteins produced by biotechnological approaches and applications thereof with particular emphasis on adhesion and coatings. PMID- 29975466 TI - Structural changes arising from different thawing protocols on cryopreserved human allograft's aortic valve leaflets. AB - BACKGROUND: The aim of our experimental work was to assess the impact and morphological changes that arise during different thawing protocols on human aortic valve (AV) leaflets resected from cryopreserved aortic root allografts (CARAs). OBJECTIVES: Two thawing protocols were tested: 1. CARAs were thawed at a room temperature (23 degrees C); 2. CARAs were placed directly into a water bath at a temperature of 37 degrees C. After all the samples were thawed, non-coronary AV leaflets were sampled from each specimen and fixed in a 4% formaldehyde solution before they were sent for morphological analysis. MATERIAL AND METHODS: All the samples were washed in distilled water for 5 min and dehydrated in a graded ethanol series (70%, 85%, 95%, and 100%) for 5 min at each level. The tissue samples were then immersed in 100% hexamethyldisilazane (HMDS) for 10 min, and then air-dried in an exhaust hood at room temperature. Processed samples were mounted on stainless steel stubs and coated with gold. Histological analysis was performed with the use of an electron microscope on a scanning mode operating at 25 kV - BS 301. RESULTS: Thawing protocol 1 (room temperature at 23 degrees C): 6 (100%) samples showed loss of the endothelial covering of the basal membrane with no damage to the basal lamina. Thawing protocol 2 (water bath at 37 degrees C): 5 (83%) samples showed loss of the endothelial covering of the basal membrane with no damage to the basal lamina. One (17%) sample showed loss of the endothelial covering the basal membrane with significant damage to the basal membrane. CONCLUSIONS: Based on our experimental work, we can clearly conclude that cryopreserved AV leaflet allografts show identical structural changes at different rates of thawing. PMID- 29975467 TI - Diffusion and perfusion MR patterns of central nervous system lymphomas. AB - BACKGROUND: Central nervous system lymphomas (CNSLs) are rare tumors which may show variable appearance in standard magnetic resonance imaging (MRI) depending on their origin (primary or secondary) or patients' immunological status. OBJECTIVES: The aim of the study was to analyze imaging patterns of different CNSLs, using diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). MATERIAL AND METHODS: Our material consisted of 16 CNSLs (14 primary, 2 secondary, 13 immunocompetent, 3 immunodeficient) which underwent magnetic resonance (MR) examinations including DWI and T2* dynamic susceptibility contrast (DSC) perfusion (without a preload in 13 cases, with a preload in 3 subjects). In DWI, apparent diffusion coefficient (ADC), and in PWI, parameters of relative cerebral blood volume (rCBV), relative peak height (rPH) and relative percentage of signal recovery (rPSR) were analyzed within the entire tumor (mean values) and in regions with minimal diffusion (ADCmin) and maximal perfusion values (rCBVmax, rPHmax, rPSRmax). RESULTS: All CNSLs showed low values of ADCmean (0.70 * 10-3), ADCmin (0.54 * 10-3), rCBVmean (0.80), rCBVmax (1.27), rPHmean (1.05), rPHmax (1.59), as well as high values of rPSRmean (1.99) and rPSRmax (2.41). There were no significant differences in rCBVmax, as well as in all ADC, rPH and rPSR values between primary and secondary CNSLs or between tumors in immunocompetent and immunodeficient patients. Dynamic susceptibility contrast PWI with a preload resulted in significantly higher rCBV, rPH and lower rPSR values. CONCLUSIONS: Despite various MR appearances, both primary and secondary CNSLs in immunocompetent and immunodeficient patients show very typical patterns of restricted diffusion and hypoperfusion with signal intensity curves returning above the baseline. Dynamic susceptibility contrast perfusion without a preload is recommended. PMID- 29975468 TI - Modulation of 4-aminopyridine-induced neuronal activity and local pO(2)in rat hippocampal slices by changing the flow rate of the superfusion medium. AB - The brain slice preparation is the most frequently used tool for testing of pharmacological agents on the neuronal excitability. However in the absence of blood circulation in vitro, the tissue oxygenation strongly depends on the experimental conditions. It is well established that both hypoxia as well as hyperoxia can modulate the neuronal network activity. Thereby changes in tissue oxygen level during experiment may affect the final result. In the present study we investigated the effect of oxygenation on seizure susceptibility in the hippocampal slice preparation using 4-aminopyridine (4-AP) model of ictogenesis in inmature rats. We found that changing the medium perfusion rate in the range of 1-5 ml/min greatly affects the tissue oxygenation, amplitude and frequency of 4-AP-induced synchronous neuronal activity. The decrease in the flow rate as well as substitution of the oxygen in the extracellular medium with nitrogen causes a strong reduction of 4-AP-induced synchronous neuronal discharges. Our results demonstrate a significant linear correlation between the power of 4-AP-induced neuronal activity and the oxygen level in slice tissue. Also we demonstrated that the presence of medium flow is a necessary condition to support the constant level of the slice oxygenation. These data suggest that the oxygen supply of the brain slice strongly depends on experimental protocol and could modulate in vitro neuronal network excitability which should be taken into consideration when planning epilepsy-related studies. PMID- 29975469 TI - [REDUCED RESPONSE OF NATURAL KILLER LYMPHOCYTES TO TOLL-LIKE RECEPTOR 3 STIMULATION IN CHILDREN WITH RECURRENT INFECTIONS.] AB - In this study, we examined the activation of natural killer(NK)-lymphocytes mediated by Toll-like receptor 3(TLR3), in the group of children with recurrent infections and the group of children with invasive bacterial infections. We examined level of CD69 (marker, of activation) expression on NK - lymphocytes after incubation with TLR3 ligand. There was a significant decrease in the level of an activation marker - 36,3+/-4,4% in the group of children with recurrent infections, compared with a control group of healthy children (56,5+/-4,9%) and the group of children with invasive bacterial infections (55,9+/-4,4%). Also, decreased was an activation potential of NK-lymphocytes - 24,9+/-L4,5% which was calculated as the difference between the percentage of CD69+ NK - lymphocytes after incubation and spontaneous value (without the addition of activator). There were no correlations between markers of TLR3 mediated activation of NK-cells and the age. Thus, the ability to activate NK - lymphocyte mediated by TLR3, independent of age and reduced in the group of children with recurrent infections. Reduced activation of NK-lymphocytes may contribute to increased susceptibility to viral infections and bacterial complications. PMID- 29975470 TI - Disorders of carbohydrate metabolism in experimental brain injury. AB - In experimental heavy closed brain injury (mortality infive days - 86%) it is shown that from the first hours the violations of carbohydrate metabolism in the form of triad were formed: the marked hyperglycemia (3.3-3.6 times), hyperinsulinemia (2.4-3.2 times) and insulin resistance (HOMA-indexes increased to 8.0-11.7 times). These changes were caused by a decrease in tissue sensitivity to insulin and were accompanied by decrease in functional activity of the pancreatic beta-cells. In total it is possible to consider these changes as a pentad of the typical disorders of carbohydrate metabolism at brain injury. PMID- 29975471 TI - [PATHOLOGICAL CHANGES DEVELOPMENT IN THE HEART WITH UNDERLYING CONVULSIVE SYNDROME MODEL OF VARIOUS ETIOLOGIES.] AB - The basic mechanisms of myocardial damage were determined experimentally in case of electroconvulsive (n = 30) and corazole (n = 20) induced seizures in Wistar rats by histochemical, pathological, electron microscopy and biochemical methods. It has been founded that pathological changes in the myocardium underlying with electroconvulsive and corazole induced seizures have unidirectional origin; nevertheless electrocohvulsive model has more intensity. It has been shown that structural base of myocardial pathology development results in parallel changes of microvessels and contractile myocardium with the main focus on development of contractile changes of cardiomyocytes and intramuscular capillaries spasm, which causes blood flow impairment and reducing supply of oxygen to the working cells. Structural changes in the myocardium develop due to energy shifts which have been elucidated by confirmed decrease SDG in cardiac activity (control 2,65+/-0,03 act. Units; electroconvulsive model 2,15+/-0,02 act. Units; and corazole model 2,25+/-0,02 act. Units), and increased - LDH (control 2,20+/-0,01 act. Units. electroconvulsive model 2,55+/-0,01 act. Units; corazole model 2,45+/-0,01 act. Units.) histochemically, showing evidence of hypoxia progression in the myocardium tissue. It has been also shown processes of increasing degradation as well as reducing synthesis of ATP biochemically(43% electroconvulsive model and 41% corazole model). All this results indicate the presence of hypoenergetics in case of elec- troconvulsive and corazole experimental models of seizures. The received results of complex researches allow considering that adequate and rational treatment and prevention of seizures (large and small epilepsy) requires anticonvulsants choose as well as drug correction of the most affected parts of energy metabolism via afitihypoxants and antioxidants administration. Key words: electroconvulsive and carozole convulsive syn- dromes; heart; metabolism; structure; pathogenesis. PMID- 29975472 TI - [REDUCING RESISTANCE TO ACID HEMOLYSIS BY IRON-CONTAINED DRUG INCREASES THE LEVEL OF HEMOGLOBIN IN THE ERYTHROCYTES OF AGING ANIMALS.] AB - In experiments in vivo we studied the effect of chronic iron-contained drug (Urfuhem) supplemention on the level of hemoglobin (Hb) in the blood of aging rats. To establish the biochemical mechanisms of drug action it were determined the parameters of oxidative/nitrosative stress and the hydrogei sulfide level in plasma and erythrocytes, the level of non-heme iron in plasma and erythrocytes sensitivity to acid hemolysis. It was found that in aging rats the drug significantly increases the Hb content of red blood cells and reduces its resistance to acid hemolysis. After the drug supplemention the rate of superoxide anion-radical (*0(2)(-)) generation in erythrocytes and stable hydrogen peroxide (H(2)0(2)) content both in plasma and erythrocytes, were down-regulated. The drug did not reduce the high levels of generation of the hydroxyl radical (*OH) and high levels of excess NO de novo synthesis by iNOS in erythrocytes but reduced the pools of nitrate anion(NO(3)(-))a its reutilization for NO synthesis. After thei drug supplemention the rate of constitutine NO synthesis by cNOS in aging rats plasma was up-regulated perhaps by cNOS coupling. The results indicate that the reason for increasing the permeability of the proton (H*) in red blood cells that causes the acid hemolysis in aging fats after the drug supplemention can be change in the balance of levels of oxidative and nitrosative stress in red blood cells in favor of the latter, and that toxic, OH generation is not at the expense of the classical Fenton reaction in the presence of iron ions (Fe(2+)); but due to the formation and decomposition of peroxynitrie (ON0O(-)). PMID- 29975473 TI - [SUBUNIT SPECIFIC MODULATION OF GLYCINE RECEPTORS BY GINKGOLIC ACID.] AB - Ginkgo biloba extract is a multicomponent pharmacological agent widely used in neurological disorders therapy. It was shown that ginkgolic acid, a constituent of lipophylic Ginkgo biloba extract, has numerous biological activities. In the present study we have focused on the features of ginkgolic acid action on alphal and alpha2 glycine receptors that make part of the inhibitory system of the brain. Using whole-cell configuration of patch-clamp recording we analysed effects of ginkgolic acid on different subunits of glycine receptors. Experiments were performed on cultured Chinese hamster ovary cells (CHO cells), transfected with alphal and alpha2 glycine receptor subunits. Ionic currents were induced by the fast application of different glycine concentrations. After 20-40 sec of pre treatment with ginkgolic acid (25MUM) currents mediated by al glycine receptors reversibly increased from 364+/-49 pA, (n=34) to 846+/-134 pA, (n=34). EC(50) for glycine has changed from 36+/-6 MUM (control) to 17+/-2 MUM. In contrast, the application of ginkgolic acid on glycine receptors formed by alpha2 subunits did not provoke potentiation. Our results demonstrate that ginkgolic acid is a subunit specific modulator of glycine receptors. The mechanisms of the ginkgolic acid action on glycine receptors require further investigation. PMID- 29975474 TI - [INFLUENCE OF INTERMITTENT NORMOBARIC HYPOXIA ON CARDIOVASCULAR SYSTEM AND HEMODYNAMIC PARAMETERS OF CHILDREN LIVED AT RADIATION CONTAMINATED TERRITORIES.] AB - The effect of intermittent normobaric hypoxia (INH) of sanogenic level on the state of the cardiovascular system in 120 children aged from 12 to 17 years was studied. Children were divided into 3 groups. The 1st control group consisted of 20 persons (practically healthy ones), the 2nd group, a group of comparison, included 50 persons, and there were 50 persons in the 3rd group - a main group. Examined patients of two studied groups received the standard therapy, and those of the 3rd group - the seances of intermittent, normobaric hypoxia additionally to standard therapy. Systolic arterial pressure was significantly decreased in the rest from 108,2+/-1,9 to 103,8+/-1,1 mm Hg in children of the main group. Comparing the heart rate, systolic arterial pressure and diastolic arterial pressure their statistically decreased values by 9,3 min(-1), 8,36 and 7,84 mm Hg were revealed at 10 minutes of orthostatic, respectively. Autonomic supplying the activity of cardiovascular system with normal type of reaction was 34 % higher than that of the comparison group. It indicates an the improvement in hemodynamics and an increase in adaptation capabilities of the autonomic nervous system. PMID- 29975475 TI - [IMPACT OF EMOTIONAL STRESS ON THE IMMUNE SYSTEM INDICES AMONG RESIDENTS OF RADIATION CONTAMINATED AREAS.] AB - The aim of this research is to study special characteristics of immune system functioning among residents of the areas contaminated with radionuclides, under conditions of additional emotional load. We examined 350 people, including a group of radiation free areas residents (control group, 150 people) and a group of residents living in the areas of enhanced radiation monitoring (IV radiation zone, the density of soil contamination with isotopes (137)Cs 1-5 Ki/km(2), 200 people). All examined are the students of Cherkassy State University, aged 18-24 years, at the time of research didn't have any acute diseases. The role of additional stress factor (additional emotional load) was fulfilled by winter examination session. The first analysis of immune system indices was carried out in the interval between examination sessions, the second 2 after the first exam, the third - after the last exam, the fourth - after two weeks recovery period. Indicators of cellular immunity were determined by immunophenotyping and dyeing on Romanowsky-Giemsa. The level of immunoglbulins in blood serum was determined by radial immunodiffusion on Mancini. The level of cortisol in blood serum was determined-by immunoenzyme method. We determined that leukogram redistribution in favor of granulocyte fractions can be observed in the analyzed group in the intersession period, and also the reduction of the relative and absolute number of lymphocytes expressing antigens CD3, CD5, CD4 and CD 16. Also, all examined had reduced immunoregulatory index CD4(+)/CD8(+) and increased concentration of serum immunoglobulin G. Emotional stress increased earlier revealed tendencies. As a result the relative(23.41+/-1.01%) and absolute (0.28+/-0.02x10(9)/) number of T cells with the phenotype CD4(+), and immunoregulatory index (1.04+/-0.03) reached values lower than homeostatic norm. These indicators also show the longest period of recovery. Dynamics of the analyzed indices in session and recovery periods gives a reason to believe that mechanisms of adaptation and deadaptation are better displayed for thymus-dependent cells. Additional short term stress factor intensifies immuno-suppression caused by living in radiation contaminated areas, and creates the basis for regular monitoring of health status of the population that suffered from the combined stress and for implementing preventive measures during the recovery period. PMID- 29975476 TI - [DEPENDENCE OF LEVEL OF MYELOPEROXIDASE OF PLASMA OF BLOOD ON FUNCTIONAL STATE OF NEUTROPHILS AT ACUTE INFARCT OF MYOCARDIUM.] AB - The purpose of this work was to define dependence of maintenance of myeloperoxidase (MPO) in plasma of blood of patients by the acute infarct of myocardium from the state of oxygen metabolism of neutrophils, which was estimated on activity of myeloperoxidases, superoxid-anion and catalase in cells and on maintenance by peroxigens. 19 is inspected practically healthy volunteers and 56 patients with the the acute infarct of myocardium. The got results testify that maintenance of MPO in plasma of blood of patients with acute infarct of myocardium depends on the functional state of neutrophils, which, in its turn, is related to the clinical features of patients. Low maintenance is associated exceptionally with low activity of MPO of neutrophils, and also other oxygen radicals. High maintenance of MPO in plasma accompanied low or high activity of MPO of neutrophils and is pathognomonic for patients with the acute infarct of myocardium. PMID- 29975477 TI - [CORRECTION OF HEART RATE VARIABILITY USING DIAPHRAGMATIC BREATHING MODE BIOFEEDBACK IN HEALTHY PEOPLE.] AB - The research is an attempt to explain the use of portable computer devices aiming to correct heart rate variability (HRV) of healthy young men. According to the data, used deep diaphragmatic breathing in mode of biofeedback harmonizes breathing and blood circulation which positively affects the body's adaptive potential. However, developers present the portable instruments of biofeedback primarily as a means of psychological relaxation. The aim of this study is to determine whether such devices are able to significantly affect heart rate variability and how long this effect lasts. There were 30 males aged 18 to 20 years that participated in this study. They were randomly divided into three equal groups with up to 10 people in each of them. Members of the first group were doing breathing exercises using a portable biofeedback StressEraser device, the second group used Em-Wave2, and the third one used hardware and software system MyCalmBeat. Each session lasted from 10 to 15 minutes. There were 10 sessions held daily in the morning. HRV was recorded by remote heart rate monitor Polar RS800CX and software Polar ProTrainer5. 5-minutes' stationary segments of the curve chest electrocardiogram removal were used in order to calculate the HRV indexes. It was found that 15 minutes deep breathing in mode of biofeedback significantly affects the heart rate variability of healthy young people. In particular, it increases the overall heart rate variability according to the statistical and spectral analysis. It was established that in all 3 groups of experiment participants the spectral curve low-range "Low frequency" (LF) suffered the major shifts. These shifts reflect the activity level of the sympathetic autonomic nervous system (ANS) as well as vascular-motor center according to the conventional interpretation. It was found that all three groups suffered a specific weight decrease of Very Low Frequency (VLF)% respectively 11.8+/-2.2%;(p <0,01); 6.6 +/- 2.8%; (p <0,02) and 6.8 +/- 2.4% (p <0,05). This means that activity redistribution between different regulatory components of heart rate occurred in favour of the peripheral ANS parts. Heart rate variability changes of this kind remained valid for at least one month after the experiment. The greatest influence on heart rate variability was observed in the group of people who used the device StressEraser. PMID- 29975478 TI - [EFFECT OF L-ARGININE - NO ON PROOXIDANT-ANTIOXIDANT BALANCE IN ERYTHROCYTES OF RATS UNDER ALCOHOL INTOXICATION.] AB - It was shown changes in the activity of antioxidant enzymes (superoxide dismutase, catalase) and NO-synthase (NOS), in the content. of stable metabolic products of nitric oxide and levels of lipid peroxidation products in erythrocytes of rats under alcoholic intoxication. It was shown that animals with alcohol intoxication under of the admission of the main substrate NOS - L arginine activity of antioxidant protection enzymes was increased in twice on the fond of TBA-positive products decrease contents. Established in hemolisate red blood cells in rats with alcohol inrotoxication value of total NOS activity decreases by 65% compared to control. Not selective inhibitor Nto-nitro-L arginine methyl ester (L-NAME), which is a structural analog of L-arginine, reduced output level of total NOS activity by 23.4% in the control and 25% under conditions of pathology. The consumption of rats L-arginine NOS total activity increased in the two study groups. The results testify that L-arginine has antioxidant properties, whereas L-NAME exerts a slightly stabilizing influence. PMID- 29975479 TI - [VOLTAGE-GATED CALCIUM CHANNELS: CLASSIFICATION AND PHARMACOLOGICAL PROPERTIES (PART I).] AB - Calcium influx though voltage-gated calcium channels mediate a huge amount of physiological events and cellular responses. Numerous scientific reports indicate that calcium channels are involved in synaptic transmission, neurotransmitter release, regulation of gene expression, cellular membrane voltage oscillations, pacemaker activity, secretion of specific substances from nerve and secretory cells, morphological differentiation, activation of calcium-dependent enzymes, etc. This review represents the modern classification, molecular structure, physiological and pharmacological properties of voltage-gated calcium channels expressed in mammalian cells. PMID- 29975480 TI - [INSULIN-LIKE GROWTH FACTOR 1 UNDER CONDITIONS OF THE BRAIN VASCULAR DISEASES.] AB - The system insulin-like growth factors (IGF) occupies an important place in the development and growth of the central nervous system (CNS). Gene expression of insulin-like growth factor I (IGF-1) and IGF-1 receptor are represented in all parts of the brain and are heavily concentrated in the cerebral vessels. IGF-1 is involved in neuro-, angiogenesis, in the stimulation of cell proliferation, and repair responses to damage for both the central and peripheral nervous system. IGF- 1 exerts antioxidant, anti-inflammatory and protective effects on the CNS. The review discusses the importance and the role of IGF-I in vascular diseases of the brain, in particular, aneurysms, the ischemic stroke, the aneurysmal subarachnoid hemorrhage, as well as neuroprotection. PMID- 29975481 TI - Parents' views on preparation to care for extremely premature infants at home. AB - AIM: To gain insight into the post-discharge experiences of parents in relation to the adequacy of preparation for caring for extremely premature infants at home. METHOD: A narrative approach was drawn on to facilitate data collection, through face-to-face semi-structured interviews with 14 parents of extremely premature infants. FINDINGS: Constant comparative analysis was used to allow the emergence of five key research themes - emotional and mental health of parents, uncertain outcomes, ongoing health needs of the baby, educational needs of health professionals, and parental support and preparation for transition home. CONCLUSION: Parental experience of being discharged home with a premature baby can be emotionally challenging and necessitates a range of support mechanisms to help them to cope with this period of transition. Health professionals can direct parents to appropriate counselling services, resources and peer support groups. Tailored education is needed for community-based health professionals, such as health visitors, to equip them to support parents practically and emotionally during the transition home and beyond. In addition, health professionals can learn much from parents about what is needed to support them. PMID- 29975482 TI - Nursing Leadership in ACO Payment Reform. AB - Accountable Care Organizations (ACOs) are a promising new model for payment reform in the complex and fragmented health care system in the United States. Nursing vision and leadership are essential for the success of an organization participating in an ACO. By understanding the political, financial, and cultural facilitators and barriers to change, as well as models for helping organizations transition toward change (e.g., Kotter Model of Change Management), nurses have the potential to be leaders in health care change. PMID- 29975483 TI - Cost Analysis of an Advanced Practice Registered Nurse Transitional Care Model for Cardiac Patients. AB - Interest in care transitions has intensified in light of emphasis placed on hospital readmissions. This study provides a comparative analysis of the costs of providing transitional care through a program for cardiac patients against hospital readmission costs. The advanced practice registered nurse-managed BRIDGE model reduced health care costs associated with readmissions that were in excess of program costs. On average, there was a per-patient savings of $4,944 in avoided readmissions within 30 days of hospital discharge. Over the duration of the program, this equates to a $306,537 savings in patients with acute coronary syndrome. Nurse practitioners have a unique, holistic, and supportive approach to providing care that may make them ideal for the transitional care setting. PMID- 29975484 TI - A Leadership Development Program Through Mentorship for Clinical Nurses in Turkey. AB - Mentoring programs can enhance nursing satisfaction, improve retention, ensure optimal patient outcomes, and may have a positive organizational effect in developing leadership skills in nursing. In this study, the effects of a formal mentoring program were explored on a sample of 18 professional nurse leaders (nine mentors and nine proteges) at a university hospital in Turkey. After receiving a formal mentoring training program, mentors and proteges were paired with each other for a 6-month monitoring period. An overall assessment revealed both mentors and proteges perceived benefits from the mentoring program. The formal mentoring program created positive change in leadership behaviors for both mentors and proteges and contributed toward relational job learning for mentors and personal skill development for proteges. Suggestions are provided for the integration of formal mentoring programs into the organizational culture. PMID- 29975485 TI - Election 2016: Where Are We with the Affordable Care Act? AB - As this election campaign, like many, has been more about personality than policy, it is important to remember that positions on policy are the real substance of election outcomes. Although health care is ranking lower than other national issues in the minds of voters, it remains a vital topic. Nurses need to stay informed on this important issue, especially regarding the policy proposals from both parties and candidates PMID- 29975486 TI - Why We Should Be Paying Attention to the Evolving World Of Staffing Technology Solutions. AB - Staffing solutions are evolving at remarkable speed. It no longer takes large, complicated, technical teams to create powerful, reliable, high-quality solutions. Today's cloud-based solutions can be implemented in hours and configured as fast as an organization can tolerate. These new, well-designed systems are highly intuitive and adopted rapidly. Data can be displayed in different ways for different users with different responsibilities. Upgrades are no longer big, costly events; they are done automatically. Large outlays for licensing fees and big start-up costs are also things of the past. PMID- 29975487 TI - Nurses and the Ethics of Big Data. AB - As we move toward a value-based health care system and payment models based on individual performance of providers, nurses are faced with a dilemma. Should we as a profession actively pursue the development of individual nurse performance metrics, analysis, benchmarks, and practice standards, similar to those being implemented for physicians? Or should we wait until these metrics are imposed by payers and policymakers with little or no input from nurses? PMID- 29975488 TI - Searching for Meaning in Times of Uncertainty. PMID- 29975489 TI - Trends in Nursing Care Efficiency From 2007 to 2011 on Acute Nursing Units. AB - Improving the efficiency of health care is a national priority. The purpose of this study was to estimate trends in the efficiency of nursing care. Specifically, the baseline and rate of change in efficiency in the association between select hospital and nursing unit characteristics (e.g., nurse staffing levels) and indicators of patient safety (e.g., fall rates and hospital-acquired pressure ulcer rates) was investigated. A small but significant improvement in efficiency for non-Magnet(r) hospitals and units with increased RN hours per patient day was found. Trends in efficiency varied by unit type, with medical units showing the greatest improvement. In general, efficiency improved most in health care settings having the greatest opportunity for improvement. PMID- 29975490 TI - Strategies for Improving Patient Throughput in an Acute Care Setting Resulting in Improved Outcomes: A Systematic Review. AB - Patient throughput allows for the efficient flow of patients through the hospital, ensuring timely and appropriate level of care. Evidence supports the implementation of hospital-wide patient throughput initiatives. Hospitals who have prioritized patient throughput have realized improvements in quality patient care, patient satisfaction, as well as a positive financial impact. Hospitals have implemented various patient throughput strategies; however, a standard process or methodology has not been identified. Evidence-based research is needed to create a framework to guide hospitals in implementing patient throughput strategies. PMID- 29975491 TI - Enhancing Nurse Faculty Retention Through Quality Work Environments: A Photovoice Project. AB - The literature is rich with evidence that a nurse's work environment impacts his or her experience of factors related to turnover intent. However, one area of inquiry that has received little attention is the work environment of nursing faculty. The aim of this study was to gain an understanding of participants' lived experiences related to work environment quality and it's link with retention; use the knowledge gained to construct a definition of quality work environments from a nursing faculty perspective; and formulate grassroots recommendations that can serve as a stimulant for change within organizations. To achieve these aims, a participatory action research method, photovoice, was employed. Using this framework, nursing faculty were empowered to collect data using photography and construct meaning and recommendations for change. PMID- 29975492 TI - The Mediating Role of Psychological Contract Violation Between Psychological Contract Breach And Nurses' Organizational Attitudes. AB - This study draws on psychological contract theory, according to which organizational members reciprocate detrimental treatment they perceive with negative work-related attitudes and behaviors. Organizational attitudes were predicted by both breach and violation. This study demonstrates the importance of psychological contract breach and violation to nurses. Nursing administrators and leaders are advised to monitor and balance the expectations of nurses. They should recognize the importance of the interpretive process leading to feelings of betrayal and anger, thus providing the opportunity to manage perceptions of breach. PMID- 29975493 TI - Ambulatory Care Nurse-Sensitive Indicators Series: Patient Engagement as a Nurse Sensitive Indicator In Ambulatory Care. AB - Ambulatory care registered nurses (RNs) have a pivotal role in educating, encouraging, motivating, and supporting patients to be engaged in their care and achieve their health care goals. To improve health outcomes, patients need to be engaged in attaining these goals. RNs are instrumental in this process and well controlled studies will demonstrate their impact on helping patient's engage in their care. PMID- 29975494 TI - Want to Create Jobs and Drive Economic Growth? Invest In Nursing and Global Health Workforce. AB - The High-Level Commission on Health Employment and Economic Growth was created by the United Nations to tackle the projected global shortfall of health care workers. The Commission developed recommendations addressing job creation, gender and women's rights, education, training and skills, health service delivery and organization, technology, and crises and humanitarian settings. The Commission report is an opportunity for nurse leaders, key stakeholders, and advocates in our nation to continue to champion heath workforce issues. The timing is right as we anticipate a new presidential administration and state, federal, and local leadership in 2017. PMID- 29975495 TI - Photo Identification on a Medical-Surgical Unit Improves Communication Resulting in Positive Patient Outcomes. AB - Creating an environment that allows for ease of communication is imperative to meet the demands of health care that is focused on quality, safety, and outcomes. As a way to improve the communication between and identification of nursing staff by the interprofessional team, a process was created to aide in timely identification and communication between health care members. Enhanced communication can result in an increase in Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores for patient satisfaction in responsiveness, communication with nurses, and bathroom help. PMID- 29975496 TI - Gunter Blobel (1936-2018) PMID- 29975497 TI - Effects of Strengthening Cigarette Pack Warnings on Attention and Message Processing: A Systematic Review AB - The current study sought to examine the impact of strengthening cigarette pack warnings on attention, message processing, and perceived effectiveness, through a systematic review of longitudinal observational studies. The review included 22 studies (N = 81,824 participants). Strengthened warnings increased attention to warnings, recall of warnings, and thinking about the health risks of smoking. Strengthened warnings also increased several perceived effectiveness outcomes, including perceptions that warnings reduce smoking and motivate quitting. Strengthened cigarette pack warnings achieve their goal of attracting attention and enhancing motivation to act. Strengthening warning policies should be a priority for tobacco control globally. PMID- 29975498 TI - Antioxidant defense capacity of ovarian tissue after vitrification in a metal closed system. AB - OBJECTIVE: The present study analyzed the quality of bovine ovarian tissue after vitrification in a metal closed chamber, in terms of putative changes in tissue viability (lactate dehydrogenase -LDH- release), anti-oxidant defenses, and redox parameters caused by cryopreservation. METHODS: Small and large fragmented bovine ovarian tissue specimens were vitrified in a metal chamber. After rewarming, tissue samples were fixed or cultured for 48 hours. Glutathione (GSH), protein sulfhydryl content, Total Radical Trapping Antioxidant Potential (TRAP), and lactate dehydrogenase were analyzed immediately after rewarming and after tissue culture. RESULTS: No changes in antioxidant parameters or viability of rewarmed tissue samples were found immediately or 48h after vitrification. The method of vitrification in a metal closed chamber used in this study preserved the quality of bovine ovarian tissue. Furthermore, our data showed that the size of the tissue specimens did not affect post-vitrification biochemical viability parameters. CONCLUSIONS: We believe that the vitrification methodology employed in the present study is safe and effective, and should be evaluated for use in humans. PMID- 29975499 TI - Toughening Elastomers Using a Mussel-Inspired Multiphase Design. AB - It is a challenge to simultaneously achieve high stretchability, high modulus, and recoverability of polymers. Inspired by the multiphase structure of mussel byssus cuticles, we circumvent this dilemma by introducing a deformable microphase-separated granule with rich coordination into a ductile rubber network. The granule can serve as an additional cross-link to improve the modulus, while the sacrificial, reversible coordination can dissociate and reconstruct continuously during stretching to dissipate energy. The elastomer with such a bioinspired multiphase structure exhibits over a 10-fold increase in toughness compared to the original sample. We envision that this work offers a novel yet facile biomimetic route toward high-performance elastomers. PMID- 29975500 TI - Mg2Nb34O87 Porous Microspheres for Use in High-Energy, Safe, Fast-Charging, and Stable Lithium-Ion Batteries. AB - M-Nb-O compounds are advanced anode materials for lithium-ion batteries (LIBs) due to their high specific capacities, safe operating potentials, and high cycling stability. Nevertheless, the found M-Nb-O anode materials are very limited. Here, Mg2Nb34O87 is developed as a new M-Nb-O material. Mg2Nb34O87 porous microspheres (Mg2Nb34O87-P) with primary-particle sizes of 30-100 nm are fabricated based on a solvothermal method. Mg2Nb34O87 has an open 3 * 4 * infinity Wadsley-Roth shear structure and a large unit-cell volume, leading to its largest Li+ diffusion coefficients among all the developed M-Nb-O anode materials. In situ X-ray diffraction analyses reveal its high structural stability and intercalating characteristic. These architectural, conductivity, and structural advantages in Mg2Nb34O87-P lead to its most significant intercalation pseudocapacitive contribution (87.7% at 1.1 mV s-1) among the existing M-Nb-O anode materials and prominent rate capability (high reversible capacities of 338 mAh g-1 at 0.1C and 230 mAh g-1 at 10C). Additionally, this new material exhibits a safe operating potential (~1.68 V), an ultrahigh initial Coulombic efficiency (94.8%), and an outstanding cycling stability (only 6.9% capacity loss at 10C over 500 cycles). All of these evidences indicate that Mg2Nb34O87-P is an ideal anode material for high-energy, safe, fast-charging, and stable LIBs. PMID- 29975501 TI - Dried Blood Spheroids for Dry-State Room Temperature Stabilization of Microliter Blood Samples. AB - It is well-known that 2D dried blood spots on paper offer a facile sample collection, storage, and transportation of blood. However, large volume requirements, possible analyte instability, and difficult sample recovery plague this method, lowering confidence in analyte quantification. For the first time, we demonstrate a new approach using 3D dried blood spheroids for stabilization of small volume blood samples, mitigating these effects without cold storage. Blood spheroids form on hydrophobic paper, preventing interaction between the sample and paper substrate, eliminating all chromatographic effects. Stability of the enzyme alanine transaminase and labile organic compounds such as cocaine and diazepam were also shown to increase in the spheroid by providing a critical radius of insulation. On-surface analysis of the dried blood spheroids using paper spray mass spectrometry resulted in sub-ng/mL limits of detection for all illicit drugs tested, representing 1 order of magnitude improvement compared with analysis from 2D dried blood spots. PMID- 29975502 TI - Fast and Sensitive Colloidal Quantum Dot Mid-Wave Infrared Photodetectors. AB - Colloidal quantum dots (CQDs) with a band gap tunable in the mid-wave infrared (MWIR) region provide a cheap alternative to epitaxial commercial photodetectors such as HgCdTe (MCT) and InSb. Photoconductive HgTe CQD devices have demonstrated the potential of CQDs for MWIR photodetection but face limitations in speed and sensitivity. Recently, a proof-of-concept HgTe photovoltaic (PV) detector was realized, achieving background-limited infrared photodetection at cryogenic temperatures. Using a modified PV device architecture, we report up to 2 orders of magnitude improvement in the sensitivity of the HgTe CQD photodetectors. A solid-state cation exchange method was introduced during device fabrication to chemically modify the interface potential, leading to an order of magnitude improvement of external quantum efficiency at room temperature. At 230 K, the HgTe CQD photodetectors reported here achieve a sensitivity of 109 Jones with a cutoff wavelength between 4 and 5 MUm, which is comparable to that of commercial photodetectors. In addition to the chemical treatment, a thin-film interference structure was devised using an optical spacer to achieve near unity internal quantum efficiency upon reducing the operating temperature. The enhanced sensitivity of the HgTe CQD photodetectors reported here should motivate interest in a cheap, solution-processed MWIR photodetector for applications extending beyond research and military defense. PMID- 29975503 TI - Modification of Extracellular Vesicles by Fusion with Liposomes for the Design of Personalized Biogenic Drug Delivery Systems. AB - Extracellular vesicles (EVs) are recognized as nature's own carriers to transport macromolecules throughout the body. Hijacking this endogenous communication system represents an attractive strategy for advanced drug delivery. However, efficient and reproducible loading of EVs with therapeutic or imaging agents still represents a bottleneck for their use as a drug delivery system. Here, we developed a method for modifying cell-derived EVs through their fusion with liposomes containing both membrane and soluble cargoes. The fusion of EVs with functionalized liposomes was triggered by polyethylene glycol (PEG) to create smart biosynthetic hybrid vectors. This versatile method proved to be efficient to enrich EVs with exogenous lipophilic or hydrophilic compounds, while preserving their intrinsic content and biological properties. Hybrid EVs improved cellular delivery efficiency of a chemotherapeutic compound by a factor of 3-4, as compared to the free drug or the drug-loaded liposome precursor. On one side, this method allows the biocamouflage of liposomes by enriching their lipid bilayer and inner compartment with biogenic molecules. On the other side, the proposed fusion strategy enables efficient EV loading, and the pharmaceutical development of EVs with adaptable activity and drug delivery property. PMID- 29975504 TI - Selective Laser-Assisted Synthesis of Tubular van der Waals Heterostructures of Single-Layered PbI2 within Carbon Nanotubes Exhibiting Carrier Photogeneration. AB - The electronic and optical properties of two-dimensional layered materials allow the miniaturization of nanoelectronic and optoelectronic devices in a competitive manner. Even larger opportunities arise when two or more layers of different materials are combined. Here, we report on an ultrafast energy efficient strategy, using laser irradiation, which allows bulk synthesis of crystalline single-layered lead iodide in the cavities of carbon nanotubes by forming cylindrical van der Waals heterostructures. In contrast to the filling of van der Waals solids into carbon nanotubes by conventional thermal annealing, which favors the formation of inorganic nanowires, the present strategy is highly selective toward the growth of monolayers forming lead iodide nanotubes. The irradiated bulk material bearing the nanotubes reveals a decrease of the resistivity as well as a significant increase in the current flow upon illumination. Both effects are attributed to the presence of single-walled lead iodide nanotubes in the cavities of carbon nanotubes, which dominate the properties of the whole matrix. The present study brings in a simple, ultrafast and energy efficient strategy for the tailored synthesis of rolled-up single layers of lead iodide (i.e., single-walled PbI2 nanotubes), which we believe could be expanded to other two-dimensional (2D) van der Waals solids. In fact, initial tests with ZnI2 already reveal the formation of single-walled ZnI2 nanotubes, thus proving the versatility of the approach. PMID- 29975505 TI - Fast Charge Extraction in Perovskite-Based Core-Shell Nanowires. AB - Realizing nanostructured interfaces with precise architectural control enables one to access properties unattainable using bulk materials. In particular, a nanostructured interface ( e. g., a core-shell nanowire) between two semiconductors leads to a short charge separation distance, such that photoexcited charge carriers can be more quickly and efficiently collected. While vapor-phase growth methods are used to synthesize uniform core-shell nanowire arrays of semiconductors such as Si and InP, more general strategies are required to produce related structures composed of a broader range of materials. Herein, we employ anodic aluminum oxide templates to synthesize CH3NH3PbI3 perovskite core-copper thiocyanate shell nanowire arrays employing a combination of electrodeposition and solution casting methods. Using scanning electron microscopy, powder X-ray diffraction, and time-resolved photoluminescence spectroscopy, we confirm the target structure and show that adopting a core-shell nanowire architecture accelerates the rate of charge quenching by nearly 3 orders of magnitude compared to samples with only an axial junction. Subsequently, we fit decay curves to a triexponential function to attribute fast quenching in core shell nanowires to charge extraction by the copper thiocyanate nanotubes, as opposed to recombination within the perovskite nanowires. Dramatic improvements to charge extraction speed and efficiency result from the substantially reduced charge separation distance and increased interfacial area achieved via the core shell nanowire array architecture. PMID- 29975506 TI - A Transferable, Sample-Independent Calibration Procedure for Trapped Ion Mobility Spectrometry (TIMS). AB - Ion mobility spectrometry-mass spectrometry (IMS-MS) determines momentum transfer cross sections of ions to elucidate their structures. Recent IMS methods employ electrodynamic fields or nonstationary buffer gases to separate ions. These methods require a calibration procedure to determine ion mobilities from the experimental data. This applies in particular to trapped IMS (TIMS), a novel IMS method with reported high resolving powers. Here, we report the first systematic assessment of the accuracy and the limitations of mobility calibration in TIMS. Our data show that the currently used TIMS calibration approach reproduces drift tube mobilities to approximately 1% (95th percentile). Furthermore, we develop a transferable and sample-independent calibration procedure for TIMS. The central aspects of our approach are (1) a calibration function derived from a solution to the Boltzmann transport equation and (2) calibration constants based on a Taylor expansion of instrument properties (TEIP). The key advantage of our calibration approach over current ones is its transferability: one equation and one set of parameters are sufficient to calibrate ion mobilities for various instrument settings, compound classes, or charge states. Our approach is transferable over time and sufficiently accurate (~1-2%) for structure-elucidation purposes. While we develop our calibration procedure specifically for TIMS, the approach we take is generic in nature and can be applied to other IMS systems. PMID- 29975507 TI - Supramolecular Switching of Ion-Transport in Nanochannels. AB - Noncovalent approaches to achieve smart ion-transport regulation in artificial nanochannels have garnered significant interest in the recent years because of their advantages over conventional covalent routes. Herein, we demonstrate a simple and generic approach to control the surface charge in mesoporous silica nanochannels by employing pi-electron-rich charged motifs (pyranine-based donors) to interact with the surface of mesoporous silica modified with pi-electron deficient motifs (viologen-based acceptors) through a range of noncovalent forces, namely, charge-transfer, electrostatic, and hydrophobic interactions. The extent of each of these interactions was independently controlled by molecular design and pH, while employing them in a synergistic or antagonistic fashion to modulate the binding affinity of the charged motifs. This enabled the precise control of the surface charge of the nanochannels to achieve multiple ion transport states. PMID- 29975508 TI - Digestion-Free Analysis of Peptides from 30-year-old Formalin-Fixed, Paraffin Embedded Tissue by Mass Spectrometry Imaging. AB - Formalin-fixed neuroendocrine tissues from American cockroaches ( Periplaneta americana) embedded in paraffin more than 30 years ago were recently analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI), to reveal the histological localization of more than 20 peptide ions. These represented protonated, and other cationic species of, at least, 14 known neuropeptides. The characterization of peptides in such historical samples was made possible by a novel sample preparation protocol rendering the endogenous peptides readily amenable to MSI analysis. The protocol comprises brief deparaffinization steps involving xylene and ethanol, and is further devoid of conventional aqueous washing, buffer incubations, or antigen retrieval steps. Endogenous secretory peptides that are typically highly soluble are therefore retained in-tissue with this protocol. The method is fully "top-down", that is, without laborious in situ enzymatic digestion that typically disturbs the detection of low-abundance endogenous peptides by MSI. Peptide identifications were supported by accurate mass, on-tissue tandem MS analyses, and by earlier MALDI-MSI results reported for freshly prepared P. americana samples. In contrast to earlier literature accounts stating that MALDI-MSI detection of endogenous peptides is possible only in fresh or freshly frozen tissues, or exceptionally, in formalin-fixed, paraffin-embedded (FFPE) material of less than 1 year old, we demonstrate that MALDI-MSI works for endogenous peptides in FFPE tissue of up to 30 years old. Our findings put forward a useful method for digestion-free, high throughput analysis of endogenous peptides from FFPE samples and offer the potential for reinvestigating archived and historically interesting FFPE material, such as those stored in hospital biobanks. PMID- 29975509 TI - Improved Triboelectric Nanogenerator Output Performance through Polymer Nanocomposites Filled with Core-shell-Structured Particles. AB - Core-shell-structured BaTiO3-poly( tert-butyl acrylate) (P tBA) nanoparticles are successfully prepared by in situ atom transfer radical polymerization of tert butyl acrylate ( tBA) on BaTiO3 nanoparticle surface. The thickness of the P tBA shell layer could be controlled by adjusting the feed ratio of tBA to BaTiO3. The BaTiO3-P tBA nanoparticles are introduced into poly(vinylidene fluoride) (PVDF) matrix to form a BaTiO3-P tBA/PVDF nanocomposite. The nanocomposites keep the flexibility of the PVDF matrix with enhanced dielectric constant (~15@100 Hz) because of the high permittivity of inorganic particles and the ester functional groups in the P tBA. Furthermore, the BaTiO3-P tBA/PVDF nanocomposites demonstrate the inherent small dielectric loss of the PVDF matrix in the tested frequency range. The high electric field dielectric constant of the nanocomposite film was investigated by polarization hysteresis loops. The high electric field effective dielectric constant of the nanocomposite is 26.5 at 150 MV/m. The output current density of the nanocomposite-based triboelectric nanogenerator (TENG) is 2.1 MUA/cm2, which is above 2.5 times higher than the corresponding pure PVDF-based TENG. PMID- 29975510 TI - Dynamics of Cellulose Nanocrystal Alignment during 3D Printing. AB - The alignment of anisotropic particles during ink deposition directly affects the microstructure and properties of materials manufactured by extrusion-based 3D printing. Although particle alignment in diluted suspensions is well described by analytical and numerical models, the dynamics of particle orientation in the highly concentrated inks typically used for printing via direct ink writing (DIW) remains poorly understood. Using cellulose nanocrystals (CNCs) as model building blocks of increasing technological relevance, we study the dynamics of particle alignment under the shear stresses applied to concentrated inks during DIW. With the help of in situ polarization rheology, we find that the time period needed for particle alignment scales inversely with the applied shear rate and directly with the particle concentration. Such dependences can be quantitatively described by a simple scaling relation and qualitatively interpreted in terms of steric and hydrodynamic interactions between particles at high shear rates and particle concentrations. Our understanding of the alignment dynamics is then utilized to estimate the effect of shear stresses on the orientation of particles during the printing process. Finally, proof-of-concept experiments show that the combination of shear and extensional flow in 3D printing nozzles of different geometries provides an effective means to tune the orientation of CNCs from fully aligned to core-shell architectures. These findings offer powerful quantitative guidelines for the digital manufacturing of composite materials with programmed particle orientations and properties. PMID- 29975511 TI - One-Pot Synthesis of Highly Dispersible Fluorescent Nanodiamonds for Bioconjugation. AB - Fluorescent nanodiamonds (FNDs) have been attracting much attention as promising therapeutic agents and probes for bioimaging and nanosensing. For their biological applications, several hydrophilizing methods to enhance FND colloidal stability have been developed to suppress their aggregation and the nonspecific adsorption to biomolecules in complex biomedical environments. However, these methods involve several complicated synthetic and purification steps, which prohibit the use of FNDs for bioapplications by biologists. In this study, we describe a simple one-pot FND hydrophilization method that comprises coating of the surface of the nanoparticles with COOH-terminated hyperbranched polyglycerol (HPG-COOH). HPG-COOH-coated FNDs (FND-HPG-COOHs) were found to exhibit excellent dispersibility under physiological conditions despite the thinness of the 5 nm HPG-COOH layer. Biotinylated FND-HPG-COOHs specifically captured avidin molecules in the absence of nonspecific protein adsorption. Moreover, we demonstrated that FND-HPG-COOHs conjugated with antibodies can be used to selectively target integrins in fixed HeLa cells. In addition, intracellular temperature changes were measured via optically detected magnetic resonance using FND-HPG-COOHs conjugated with mitochondrial localization signal peptides. Our one-pot synthetic method will encourage the broad use of FNDs among molecular and cellular biologists and pave the way for extensive biological and biomedical applications of FNDs. PMID- 29975512 TI - Development of Cell-Based Sentinels for Nitric Oxide: Ensuring Marker Expression and Unimodality. AB - We generated "sentinel" bacteria that respond to the biomarker nitric oxide (NO) and produce a homogeneous and strong fluorescent response. Our dual-plasmid system consists of a signal "relay" vector that employs an NO-responsive promoter that amplifies the native signal (via expression of T7 Polymerase (T7Pol)) to a second vector responsible for GFP expression. Importantly, to achieve an optimal "sentinel" response, we developed strategies that balance the transcriptional load within cells by altering (i) translation and (ii) activity of the T7Pol. Our optimized genetic circuitry was then used to transform commensal E. coli Nissle, as a proof-of-concept toward an ingestible cell-based sensor for Crohn's disease (CD) that, in turn, is marked by elevated levels of intestinal NO. Thus, the "biosensors" demonstrated here may serve as a simple diagnostic tool, contrasting the standard of care including colonoscopies or biopsies. PMID- 29975513 TI - Homeotropic Self-Alignment of Discotic Liquid Crystals for Nanoporous Polymer Films. AB - Nanostructured polymer films with continuous, membrane-spanning pores from polymerizable hexagonal columnar discotic liquid crystals (LCs) were fabricated. A robust alignment method was developed to obtain homeotropic alignment of columns between glass surfaces by adding a small amount of a tri(ethylene glycol) modified analogue of the mesogen as a dopant that preferentially wets glass. The homeotropic LC alignment was fixated via a photoinitiated free radical copolymerization of a high-temperature tolerant trisallyl mesogen with a divinyl ester. Removal of the hydrogen-bonded template from the aligned columns afforded a nanoporous network with pores of nearly 1 nm in diameter perpendicular to the surface, and without noticeable collapse of the nanopores. The effect of pore orientation was demonstrated by an adsorption experiment in which homeotropic film showed a threefold increase in the initial uptake rate of methylene blue compared to planarly aligned films. PMID- 29975514 TI - Lysine Propionylation To Boost Sequence Coverage and Enable a "Silent SILAC" Strategy for Relative Protein Quantification. AB - Quantification in proteomics largely relies on the incorporation of stable isotopes, with protocols that either introduce the label through metabolic incorporation or chemical tagging. Most methods rely on the use of trypsin and/or LysC to generate labeled peptides. Although alternative proteases can enhance proteome coverage, generic quantitative methods that port over to such enzymes are lacking. Here we describe a quantification strategy amenable to most proteases, which involves propionylation of metabolically labeled lysine, using a "silent stable isotope labeling by amino acids in cell culture (SILAC)" strategy that reveals isotopic labels on second-stage mass spectrometry (MS2) fragmentation in a tandem mass tag (TMT)-like manner. We selectively propionylated lysine residues prior to digestion to generate pure ArgC-like digestion for trypsin and novel ArgN-like digestions for LysargiNase, by restricting digestion at lysine. The modification offers highly complementary sequence coverage, and even enhanced protein identification rates in certain situations (GluC digestion). Propionylated lysine residues were present in the majority of identified peptides generated from digests of cell lysates and led to the consistent release of an intense cyclic imine reporter ion at mass-to-charge ratio ( m/ z) 140 using higher-energy collisional dissociation. We grew A549 cells in media containing either l-1-13C-lysine or l-6-13C-lysine, to generate proteins that share the same accurate mass when paired. Peptides were indistinguishable on the first-stage mass spectrometry (MS1) level and, upon fragmentation, released reporter ions at m/ z 140 and m/ z 141, without otherwise affecting sequence ion mass. The quantification approach is independent of the number of peptide lysines and offers a new strategy for quantitative proteomics. PMID- 29975515 TI - Fully Dispersed Rh Ensemble Catalyst To Enhance Low-Temperature Activity. AB - Minimizing the use of precious metal catalysts is important in many applications. Single-atom catalysts (SACs) have received much attention because all of the metal atoms can be used for surface reactions. However, SACs cannot catalyze some important reactions that require ensemble sites. Here, Rh catalysts were prepared by treating 2 wt % Rh/CeO2 hydrothermally at 750 degrees C for 25 h. Nearly 100% dispersion was obtained, but the surface Rh atoms were not isolated (denoted as ENS). They catalyzed the oxidation of C3H6 or C3H8 at low temperatures, but these oxidations did not occur on the Rh SAC. When the simultaneous oxidation of CO, C3H6, and C3H8 was performed, the T20 (temperature at conversion 20%) for CO oxidation increased significantly from 40 degrees C for sole CO oxidation to 180 degrees C on SAC due to the competitive adsorption of hydrocarbons. However, T20 increased much less on ENS, from 60 to 100 degrees C. ENS exhibited superior activity for low-temperature oxidation. During hydrothermal treatment for 25 h, the Rh size initially increased from 2.3 to 6.7 nm then decreased to 0.9 nm. The surface hydroxyl groups formed on the catalyst surface help detach Rh atoms from Rh clusters, while preventing the reaggregation of dispersed Rh atoms into Rh clusters. This fully dispersed catalyst would have maximum atom-efficiency while catalyzing various surface reactions. PMID- 29975517 TI - Dual Carbon-Chlorine Isotope Analysis Indicates Distinct Anaerobic Dichloromethane Degradation Pathways in Two Members of Peptococcaceae. AB - Dichloromethane (DCM) is a probable human carcinogen and frequent groundwater contaminant and contributes to stratospheric ozone layer depletion. DCM is degraded by aerobes harboring glutathione-dependent DCM dehalogenases; however, DCM contamination occurs in oxygen-deprived environments, and much less is known about anaerobic DCM metabolism. Some members of the Peptococcaceae family convert DCM to environmentally benign products including acetate, formate, hydrogen (H2), and inorganic chloride under strictly anoxic conditions. The current study applied stable carbon and chlorine isotope fractionation measurements to the axenic culture Dehalobacterium formicoaceticum and to the consortium RM comprising DCM degrader Candidatus Dichloromethanomonas elyunquensis. Degradation associated carbon and chlorine isotope enrichment factors (epsilonC and epsilonCl) of -42.4 +/- 0.70/00 and -5.3 +/- 0.10/00, respectively, were measured in D. formicoaceticum cultures. A similar epsilonCl of -5.2 +/- 0.10/00, but a substantially lower epsilonC of -18.3 +/- 0.20/00, were determined for Ca. Dichloromethanomonas elyunquensis. The epsilonC and epsilonCl values resulted in distinctly different dual element C-Cl isotope correlations (LambdaC/Cl = Deltadelta13C/Deltadelta37Cl) of 7.89 +/- 0.12 and 3.40 +/- 0.03 for D. formicoaceticum and Ca. Dichloromethanomonas elyunquensis, respectively. The distinct LambdaC/Cl values obtained for the two cultures imply mechanistically distinct C-Cl bond cleavage reactions, suggesting that members of Peptococcaceae employ different pathways to metabolize DCM. These findings emphasize the utility of dual carbon-chlorine isotope analysis to pinpoint DCM degradation mechanisms and to provide an additional line of evidence that detoxification is occurring at DCM-contaminated sites. PMID- 29975516 TI - Identification of a Water-Coordinating HER2 Inhibitor by Virtual Screening Using Similarity-Based Scoring. AB - Human epidermal growth factor receptor 2 (HER2) is a validated breast cancer drug target for small molecule inhibitors that target the ATP-binding pocket of the kinase domain. In this work, a large-scale virtual screen was performed to a novel homology model of HER2, in a hypothesized "fully active" state, that considered water-mediated interactions during the prioritization of compounds for experimental testing. This screen led to the identification of a new inhibitor with micro molar affinity and potency ( Kd = 7.0 MUM, IC50 = 4.6 MUM). Accompanying molecular dynamics simulations showed that inhibitor binding likely involves water coordination through an important water-mediated network previously identified in our laboratory. The predicted binding geometry also showed a remarkable overlap with the crystallographic poses for two previously reported inhibitors of the related Chk1 kinase. Concurrent with the HER2 studies, we developed formalized computational protocols that leverage solvated footprints (per-residue interaction maps that include bridging waters) to identify ligands that can "coordinate" or "displace" key binding site waters. Proof-of-concept screens targeting HIVPR and PARP1 demonstrate that molecules with high footprint overlap can be effectively identified in terms of their coordination or displacement patterns relative to a known reference. Overall, the procedures developed as a result of this study should be useful for researchers targeting HER2 and, more generally, for any protein in which the identification of compounds that exploit binding site waters is desirable. PMID- 29975518 TI - Determination and Comparison of 4'- O-Methylpyridoxine Analogues in Ginkgo biloba Seeds at Different Growth Stages. AB - The antivitamin B6, 4'- O-methylpyridoxine (MPN); its glucoside, 4'- O methylpyridoxine-5'-glucoside (MPNG); and vitamin B6 compounds, including pyridoxal (PL), pyridoxamine, pyridoxine, pyridoxal-5'-phosphate (PLP), and pyridoxamine-5'-phosphate, exist in Ginkgo biloba seeds, which are widely used as food and medicine. This work aimed to determine the MPN analogues in G. biloba seeds at different growth stages in terms of cultivars and ages of trees. The highest total MPN contents of 249.30, 295.62, and 267.85 MUg/g were obtained in the mature stages of three selected G. biloba samples. The total contents of vitamin B6 compounds decreased significantly in the entire growth period of the three samples. Principal-component analysis revealed that MPN and MPNG were important contributors in the MPN-analogue metabolism of G. biloba seeds. The influence of the cultivar on the content and composition of MPN analogues was greater than that of the age of the G. biloba tree. PMID- 29975519 TI - A Pseudotetrahedral Uranium(V) Complex. AB - A series of uranium amides were synthesized from N, N, N cyclohexyl(trimethylsilyl)lithium amide [Li][N(TMS)Cy] and uranium tetrachloride to give U(NCySiMe3) x(Cl)4- x, where x = 2, 3, or 4. The diamide was isolated as a bimetallic, bridging lithium chloride adduct ((UCl2(NCyTMS)2)2-LiCl(THF)2), and the tris(amide) was isolated as the lithium chloride adduct of the monometallic species (UCl(NCyTMS)3-LiCl(THF)2). The tetraamide complex was isolated as the four-coordinate pseudotetrahedron. Cyclic voltammetry revealed an easily accessible reversible oxidation wave, and upon chemical oxidation, the UV amido cation was isolated in near-quantitative yields. The synthesis of this family of compounds allows a direct comparison of the electronic structure and properties of isostructural UIV and UV tetraamide complexes. Spectroscopic investigations consisting of UV-vis, NIR, MCD, EPR, and U L3-edge XANES, along with density functional and wave function calculations, of the four-coordinate UIV and UV complexes have been used to understand the electronic structure of these pseudotetrahedral complexes. PMID- 29975520 TI - Engineering a Protein Binder Specific for p38alpha with Interface Expansion. AB - Protein binding specificities can be manipulated by redesigning contacts that already exist at an interface or by expanding the interface to allow interactions with residues adjacent to the original binding site. Previously, we developed a strategy, called AnchorDesign, for expanding interfaces around linear binding epitopes. The epitope is embedded in a loop of a scaffold protein, in our case a monobody, and then surrounding residues on the monobody are optimized for binding using directed evolution or computational design. Using this strategy, we have increased binding affinities by >100-fold, but we have not tested whether it can be used to control protein binding specificities. Here, we test whether AnchorDesign can be used to engineer a monobody that binds specifically to the mitogen-activated protein kinase (MAPK) p38alpha but not to the related MAPKs ERK2 and JNK. To anchor the binding interaction, we used a small (D) docking motif from the mitogen-activated protein kinase kinase (MAP2K) MKK6 that interacts with similar affinity with p38alpha and ERK2. Our hypothesis was that by embedding the motif in a larger protein that we could expand the interface and create contacts with residues that are not conserved between p38alpha and ERK2. Molecular modeling was used to inform insertion of the D motif into the monobody, and a combination of phage and yeast display were used to optimize the interface. Binding experiments demonstrate that the engineered monobody binds to the target surface on p38alpha and does not exhibit detectable binding to ERK2 or JNK. PMID- 29975521 TI - Splicing Nanoparticles-Based "Click" SERS Could Aid Multiplex Liquid Biopsy and Accurate Cellular Imaging. AB - Here, a completely new readout technique, so-called "Click" SERS, has been developed based on Raman scattered light splice derived from nanoparticle (NP) assemblies. The single and narrow (1-2 nm) emission originating from triple bond containing reporters undergoes dynamic combinatorial output, by means of controllable splice of SERS-active NPs analogous to small molecule units in click chemistry. Entirely different to conventional "sole code related to sole target" readout protocol, the intuitional, predictable and uniquely identifiable "Click" SERS is relies on the number rather than the intensity of combinatorial emissions. By this technique, 10-plex synchronous biomarkers detection under a single scan, and accurate cellular imaging under double exposure have been achieved. "Click" SERS demonstrated multiple single band Raman scattering could be an authentic optical analysis method in biomedicine. PMID- 29975522 TI - Refining Defect States in W18O49 by Mo Doping: A Strategy for Tuning N2 Activation towards Solar-Driven Nitrogen Fixation. AB - Photocatalysis may provide an intriguing approach to nitrogen fixation, which relies on the transfer of photoexcited electrons to the ultrastable N=N bond. Upon N2 chemisorption at active sites (e.g., surface defects), the N2 molecules have yet to receive energetic electrons toward efficient activation and dissociation, often forming a bottleneck. Herein, we report that the bottleneck can be well tackled by refining the defect states in photocatalysts via doping. As a proof of concept, W18O49 ultrathin nanowires are employed as a model material for subtle Mo doping, in which the coordinatively unsaturated (CUS) metal atoms with oxygen defects serve as the sites for N2 chemisorption and electron transfer. The doped low-valence Mo species play multiple roles in facilitating N2 activation and dissociation by refining the defect states of W18O49: (1) polarizing the chemisorbed N2 molecules and facilitating the electron transfer from CUS sites to N2 adsorbates, which enables the N=N bond to be more feasible for dissociation through proton coupling; (2) elevating defect-band center toward the Fermi level, which preserves the energy of photoexcited electrons for N2 reduction. As a result, the 1 mol % Mo-doped W18O49 sample achieves an ammonia production rate of 195.5 MUmol gcat-1 h-1, 7-fold higher than that of pristine W18O49. In pure water, the catalyst demonstrates an apparent quantum efficiency of 0.33% at 400 nm and a solar-to-ammonia efficiency of 0.028% under simulated AM 1.5 G light irradiation. This work provides fresh insights into the design of photocatalyst lattice for N2 fixation and reaffirms the versatility of subtle electronic structure modulation in tuning catalytic activity. PMID- 29975523 TI - pseudo[1]Catenane-Type Pillar[5]thiacrown Whose Planar Chiral Inversion is Triggered by Metal Cation and Controlled by Anion. AB - Chiral inversion of single molecules has been a challenging task because chirality information controls structures and functions of various molecules, artificial nanostructures, DNA, and proteins. Herein we present a pseudo[1]catenane-type molecule whose planar chiral inversion is driven by a metal ion under the control of anions for the first time. Considering an in-out equilibrium of a fused thiacrown and the soft metal binding, pillar[5]thiacrown ( rac-L) was synthesized. Two planar-chiral enantiomers of rac-L ( in-pS-L and in pR-L) were isolated and the absolute configuration was determined by circular dichroism and single crystal X-ray analysis. The in-pS-L recognizes Hg2+ to trigger the chiral inversion to out-pR-L, to our surprise; it takes place only in the presence of ClO4- or NO3- among the anions used. In the mercury(II) perchlorate complex solution, anion-exchange from ClO4- to I- or removal of Hg2+ by addition of S2- makes the system reversible. The crystallographic approach reveals that the anions act as coordination mode-directing species ( endo- or exo coordination) which play a decisive role on the chiral inversion. For instance, the week coordinating ClO4- allows Hg2+ to locate inside the thiacrown ( endo coordination) which causes the chiral inversion from in-pS-L to out-pR-L due to the expansion of the thiacrown unit upon endo-mode complexation. Oppositely, the strong coordinating I- takes Hg2+ out of the thiacrown ( exo-coordination) without large conformational changes of the thiacrown, resulting in no chiral inversion. A series of experimental works was also accomplished with the other enantiomer in-pR-L, which afforded identical results. Consequently, the chiral inversion is governed by steric factors that arise from the coordination modes depending on the coordinating ability of anions. This work demonstrates the first chiral inversion induced by combination of metal ion and anion and presents a new perspective on the supramolecular coordination chemistry of pillar[ n]arenes. PMID- 29975524 TI - Transcriptome Analysis Reveals Potential Antioxidant Defense Mechanisms in Antheraea pernyi in Response to Zinc Stress. AB - The growth and development of the Chinese oak silkworm, Antheraea pernyi, are strongly influenced by environmental conditions, including heavy metal pollution. An excess of heavy metals causes cellular damage through the production of free radical reactive oxygen species. In this study, transcriptome analysis was performed to investigate global gene expression when A. pernyi was exposed to zinc infection. With RNA sequencing (RNA-Seq), a total of 25 795 510 and 38 158 855 clean reads were obtained from zinc-treated and control fat body libraries, respectively. We identified 2399 differential expression genes (DEGs) (1845 upregulated and 544 downregulated genes) in the zinc-treated library. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that these DEGs were related to the peroxisome pathway that was associated with antioxidant defense. Our results suggest that fat bodies of A. pernyi constitute a strong antioxidant defense against heavy metal contamination. PMID- 29975525 TI - Interaction of Chemical Pesticides and Their Formulation Ingredients with Microbes Associated with Plants and Plant Pests. AB - Chemical pesticides and their formulation ingredients can have unintended effects on microbes associated with plants and plant pests. These effects can be due to direct effects on the microbes or to effects on crops or weeds that subsequently affect the microbes. In addition to fungicides, some insecticides, herbicides, and formulation compounds are toxic to plant pathogenic microbes, as well as to potentially beneficial microbes, such as those that infect insect pests. These chemicals, especially herbicides, can also indirectly affect microbes through their effects on crops and weeds. For example, glyphosate strongly impairs shikimic acid pathway-based plant defenses to microbial diseases in glyphosate susceptible plants, significantly increasing its efficacy as an herbicide. Some herbicides induce plant defenses against plant pathogens. For a complete understanding of integrated pest management and overall cost/benefit of pesticide use, much more information is needed on microbial/pesticide interactions. PMID- 29975526 TI - Alkali-Driven Disassembly and Reassembly of Molecular Niobium Oxide in Water. AB - Counterions are deemed "spectators" in aqueous solutions of cationic or anionic molecular metal-oxo clusters. While pH and concentration drive aqueous metal speciation as a first approximation, the important effect of counterions is usually overlooked and never considered in standard Pourbaix databases. Alkali counterions for polyoxometalate (POM) clusters control solubility with distinct periodic trends, but evidence for alkali control over speciation is ambiguous. Here we show that a simple Nb-POM, [Nb10O28]6- ({Nb10}), converts to oligomers of (H xNb24O72)(24- x)- ({Nb24}) upon adding only alkali chloride salts, even in buffered neutral solutions. Raman and X-ray scattering reveal that the rate of {Nb10} to {Nb24} conversion increases with alkali cation radius and cation concentration. Cation-bridged oligomers of {Nb24} y ( y = 2,4) are defined by comparing experimental to computed small-angle X-ray scattering spectra. Computational studies and mass spectrometry indicate that the alkalis open the compact {Nb10} cluster in conjunction with protonation of a heptamer {Nb7} intermediate, in which alkali-{Nb10} association at key locations on the cluster initiates the reaction. Computation also explains the alkali periodic trend for {Nb10} to {Nb24} conversion; larger alkalis more effectively destabilize {Nb10}. This periodic trend asserts the hypothesis that Nb-cluster speciation near neutral pH is driven by the alkali cations in the absence of added base or acid. The extremely high solubility of these 3.5 nm polyoxoanion assemblies-2 M Nb at near neutral pH-is both surprising and exploitable for aqueous synthesis of niobate thin films or nanomaterials used in energy and microelectronics applications. PMID- 29975527 TI - Synthetic beta-Barrel by Metal-Induced Folding and Assembly. AB - The de novo construction of repeat proteins has received much attention from biologists and chemists, yet that of a beta-barrel structure, one of the most well-known classes, has not been accomplished to date. Here, we report the first chemical construction of a beta-barrel tertiary structure with a pore through a combination of peptide folding and metal-directed self-assembly. Coordination of zinc salts to an eight-residue peptide fragment bearing beta-strand- and loop forming sequences resulted in a beta-barrel in which six-stranded cylindrical antiparallel beta-sheets formed a hydrophobic pore with a specific shape. PMID- 29975528 TI - Cyclopentadienone Formation from beta,gamma-Unsaturated Cyclopentenones and Its Application in Diels-Alder Reactions. AB - We report that alpha-acyloxy-beta,gamma-unsaturated cyclopentenones were used as starting substrates to make various trisubstituted cyclopentadienones. The substrates are easily available in one step from our previously developed protocol, and the potential of this cyclopentadienone formation method was demonstrated in a series of Diels-Alder reactions, forming dimerization products, dimethyl phthalate derivatives, and polyaryl benzene compounds. PMID- 29975529 TI - Discovery of 5-Cyano-6-phenylpyrimidin Derivatives Containing an Acylurea Moiety as Orally Bioavailable Reversal Agents against P-Glycoprotein-Mediated Mutidrug Resistance. AB - P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has become a major obstacle in successful cancer chemotherapy, which attracted much effort to develop clinically useful compounds to reverse MDR. Here, we designed and synthesized a novel series of derivatives with a 5-cyano-6-phenylpyrimidine scaffold and evaluated their potential reversal activities against MDR. Among these compounds, 55, containing an acylurea appendage, showed the most potent activity in reversing paclitaxel resistance in SW620/AD300 cells. Further studies demonstrated 55 could increase accumulation of PTX, interrupt ABCB1-mediated Rh123 accumulation and efflux, stimulate ABCB1 ATPase activity, and especially have no effect on CYP3A4 activity, which avoid drug interaction caused toxicity. More importantly, 55 significantly enhanced the efficacy of PTX against the SW620/AD300 cell xenograft without obvious side effects for orally intake. Given all that, the pyrimidine-acylurea based ABCB1 inhibitor may be a promising lead in developing new efficacious ABCB1-dependent MDR modulator. PMID- 29975530 TI - Investigating Polyoxometalate-Protein Interactions at Chemically Distinct Binding Sites. AB - In this study, a combined molecular docking (rigid and flexible) and all-atom molecular dynamics simulations technique have been employed to investigate interactions of 1:1 Zr-containing Keggin polyoxometalate (ZrK) with four chemically distinct cleavage sites [Arg114-Leu115 (site 1), Ala257-Asp258 (site 2), Lys313-Asp314 (site 3), and Cys392-Glu393 (site 4)] of human serum albumin (HSA). The ZrK-HSA complexations were analyzed using electrostatic potentials, the chemical nature of amino acid residues, binding free energies, and secondary structures as parameters. They suggested that ZrK binds in a rather distinct manner to different cleavage sites, and its association was dominated by hydrogen bonding, both direct and solvent mediated, and electrostatic interactions, as suggested experimentally. The computed binding free interaction energies (-57.5, 24.2, -50.8, and -91.2 kJ/mol for sites 1, 2, 3, and 4, respectively) predicted the existence of one major binding site (site 4) and three minor binding sites (site 1, site 2, and site 3). The strong exothermicity of the binding was also supported by isothermal calorimetry experiments. Additionally, the binding of ZrK did not alter the overall alpha-helical secondary structure of HSA, which was in line with experimental observation. Furthermore, hydrolysis of the peptide bonds of the substrate was found to retain its overall structure. These results have provided a deeper understanding of the complex ZrK interactions with proteins, and they will lead to the design of the next generation of catalytically active polyoxometalates with improved hydrolytic activities. PMID- 29975531 TI - Steered Molecular Dynamics Simulation in Rational Drug Design. AB - Conventional de novo drug design is time consuming, laborious, and resource intensive. In recent years, emerging in silico approaches have been proven to be critical to accelerate the process of bringing drugs to market. Molecular dynamics (MD) simulations of single molecule and molecular complexes have been commonly applied to achieve accurate binding modes and binding energies of drug receptor interactions. A derivative of MD, namely, steered molecular dynamics (SMD), has been demonstrated as a promising tool for rational drug design. In this paper, we review various studies over the last 20 years using SMD simulations, thus paving the way to determine the relationship between protein structure and function. In addition, the paper highlights the use of SMD simulation for in silico drug design. We also aim to establish an understanding on the key interactions which play a crucial role in the stabilization of peptide ligand interfaces, the binding and unbinding mechanism of the ligand-protein complex, the mechanism of ligand translocating via membrane, and the ranking of different ligands on receptors as therapeutic candidates. PMID- 29975532 TI - Bioactive Phenolic Components from the Twigs of Atalantia buxifolia. AB - Five new compounds named buxifoximes A-C (1-3), buxifobenzoate (4), and 7- O-(7' peroxygeranyl) coumarin (5), together with 25 known compounds, were identified from the twigs of Atalantia buxifolia. Compounds 1-3 are unique secondary metabolites with the aldoxime functionality. The structures of the isolates were determined on the basis of spectroscopic data analyses, and the structure of 1 was confirmed by an X-ray single-crystallographic analysis. With respect to bioactivity, antidengue virus, anti-inflammatory, and cytotoxic activities of all purified compounds were tested and evaluated. Compound 1 showed a significant anti-inflammatory effect by inhibiting superoxide anion generation with an IC50 value of 4.8 +/- 0.7 MUM. Among the acridone alkaloids, 5-hydroxy- N methylseverifoline (23) exhibited antidengue activity (IC50 = 5.3 +/- 0.4 MUM), and atalaphyllinine (20) demonstrated cytotoxicity (IC50 = 6.5 +/- 0.0 MUM) against the human liver cancer cell line, HepG2. PMID- 29975534 TI - Theoretical Studies on the Catalytic Cycle of Histidine Acid Phosphatases Revealing an Acid Proof Mechanism. AB - After reporting the mechanisms of purple acid phosphatases against acid environments and alkaline phosphatases against alkaline environments, in the present work, we continued investigating the relationship between catalytic structures of histidine acid phosphatases (HAPs) and acid environments. On the basis of the comparison of the crystal structures of several HAP members, a series of models were constructed and calculated using density functional theory. Our calculations describe a complete catalytic cycle of HAPs, including a free stage and a catalytic reaction stage. This cycle reveals a definite mechanism for HAPs to survive in acidic environments, which can be used to nicely interpret acidic pH optima of HAPs. It also suggests that a free water molecule from a solvent should be the nucleophile for hydrolyzing the phosphohistidine intermediate. Our studies are focused on the biological significance of enzymatic mechanisms and raise two concrete criteria: the logic-complete catalytic cycle and the evolutional relation with family members and molecular environments. PMID- 29975535 TI - Building Next-Generation Li-ion Capacitors with High Energy: An Approach beyond Intercalation. AB - Hybridization of two prominent electrochemical energy storage systems, such as high-energy Li-ion batteries and high-power supercapacitors into a single system, tends to deliver high-energy and high-power capabilities; such systems are often called Li-ion capacitors (LICs). The utilization of battery-type electrodes, which undergo a traditional intercalation process, in LICs provides the necessary energy; however, their limited reversible capacities and higher redox potentials (except graphite and hard carbon) hinder achieving high values. Using materials that can undergo either alloying or conversion or both together with Li, rather than intercalation, is an attractive approach to achieve high energy without compromising both power capability and cyclability. This Perspective discusses the possibility of using high-capacity, exhibiting relatively lower redox potential than transition metal-based intercalation hosts, low-cost materials in conversion and alloying reactions with Li, along with prelithiation strategies (Aravindan, V.; Lee, Y.-S.; Madhavi, S. Best Practices for Mitigating Irreversible Capacity Loss of Negative Electrodes in Li-Ion Batteries. Adv. Energy Mater. 2017, 7, 1602607). Future prospects on working with alloying and conversion-type materials are discussed in detail. PMID- 29975536 TI - Dual-Mode Imaging Guided Multifunctional Theranosomes with Mitochondria Targeting for Photothermally Controlled and Enhanced Photodynamic Therapy in Vitro and in Vivo. AB - Photodynamic therapy (PDT) is commonly restricted by inefficient tumor selectivity during clinical study. Hence, a mitochondria-targeting multifunctional nanocarrier "theranosome (TNS)" was developed for near-infrared fluorescent (NIRF) imaging and photoacoustic (PA) imaging. What's more, the TNS can also enhance PDT efficacy. In this work, chlorin e6 (Ce6) undertakes reactive oxygen generation and fluorescence emission. Ce6 was quenched when being encapsulated into TNS together with IR780 iodide. When exposed under 808 nm NIR light, IR780 from the TNS can be photobleached; thus, the phototoxicity of Ce6 can be activated. The IR780 induced hyperthermia damaged tumor cells to perform photothermal therapy (PTT) effect. Then lysosomes disruption under PTT facilitated PDT effect induced by Ce6 through enhanced cytoplasmic delivery. Moreover, in vitro subcellular uptake experiments showed that triphenylphosphonium (TPP) group attached to the IR780/Ce6 TNS (ICT) could promote mitochondria targeting capacity. It can lead to PDT induced oxidizing damage to the mitochondria by mitochondrial membrane potential decreasing and cell apoptosis eventually. In in vivo antitumor studies, the TPP/IR780/Ce6 TNS (TICT) substantially repressed tumor growth in nude mice. Besides, we did not find any obvious side effects to normal tissues and organs. The results suggested the TICT conjugate provided a dual NIRF/PA tumor imaging modalities with spatial resolution and superior imaging contrast. This study offered an improved phototherapy for potential theranostic application. PMID- 29975537 TI - Synthesis of Substituted 4 H-Thiochromen-4-imines via Copper-Catalyzed Cyclization Cascades of o-Bromobenzothioamides with Terminal Alkynes. AB - A series of ( E)- N-aryl-4 H-thiochromen-4-imines has been conveniently obtained through a cascade reaction between o-bromobenzothioamides and terminal alkynes. This novel approach probably involved an initial generation of benzothietane-2 imine intermidates via an intramolecular Ullmann reaction under CuI/L-proline cocatalysis and alkaline conditions followed by imine alkynylation, ring opening, and cyclization sequences to provide the unexpected 4 H-thiochromen-4-imines rather than isothiochromans. PMID- 29975538 TI - Mass Spectrometry Reveals the Direct Action of a Chemical Chaperone. AB - Despite their fundamental biological importance and therapeutic potential, the interactions between chemical chaperones and proteins remain difficult to capture due to their transient and nonspecific nature. Using a simple mass spectrometric assay, we are able to follow the interactions between proteins and the chemical chaperone trimethylamine- N-oxide (TMAO). In this manner, we directly observe that the counteraction of TMAO and the denaturant urea is driven by the exclusion of TMAO from the protein surface, whereas the surfactant lauryl dimethylamine- N oxide cannot be displaced. Our results clearly demonstrate a direct chaperoning mechanism for TMAO, corroborating extensive computational studies, and pave the way for the use of nondenaturing mass spectrometry and related techniques to study chemical chaperones in molecular detail. PMID- 29975539 TI - Size-Selective Carbon Clusters as Obstacles to Graphene Growth on a Metal. AB - Chemical vapor deposition (CVD) on metals is so far the best suited method to produce high-quality, large-area graphene. We discovered an unprecedentedly large family of small size-selective carbon clusters that form together with graphene during CVD. Using scanning tunneling microscopy (STM) and density functional theory (DFT), we unambiguously determine their atomic structure. For that purpose, we use grids based on a graphene moire and a dilute atomic lattice that unambiguously reveal the binding geometry of the clusters. We find that the observed clusters bind in metastable configurations on the substrate, while the thermodynamically stable configurations are not observed. We argue that the clusters are formed under kinetic control and establish that the evolution of the smallest clusters is blocked. They are hence products of surface reactions in competition with graphene growth, rather than intermediary species to the formation of extended graphene, as often assumed in the literature. We expect such obstacles to the synthesis of perfect graphene to be ubiquitous on a variety of metallic surfaces. PMID- 29975540 TI - Endocytic Selective Toxicity of Rhodamine 6G nanoGUMBOS in Breast Cancer Cells. AB - Herein, we report on the role of endocytosis in the selective chemotherpeutic toxicity of rhodamine 6G (R6G) based nanomaterials, i.e., nanoGUMBOS, that are derived from a group of uniform materials based on organic salts (GUMBOS). Evaluation of cellular uptake in the presence and absence of endocytosis inhibitors suggests nanoGUMBOS internalization via clathrin-mediated endocytosis in cancer cells and reveals lack of endocytic internalization in normal cells. Results from characterization of these nanomaterials suggest that endocytic internalization in cancer cells leads to nanoGUMBOS dissociation within the endosomal environment. This ultimately results in selective cytotoxicity of the nanoGUMBOS for cancer cells with no toxicity toward normal cells under examined conditions. Following examination of the selectivity mechanism, in vivo investigations were performed to examine potential therapeutic properties of these nanoparticles. Remarkably, nanoGUMBOS treatment using a mouse xenograft model reduced the tumor volume by 50% suggesting retention of in vitro therapeutic properties in vivo. These results corroborate the selective behavior of nanoGUMBOS and demonstrate their in vivo therapeutic effects, providing further insight into the possible use of these nanomaterials as potential chemotherapeutic agents. PMID- 29975541 TI - Enhanced Acidity of Acetic and Pyruvic Acids on the Surface of Water. AB - Understanding the acid-base behavior of carboxylic acids on aqueous interfaces is a fundamental issue in nature. Surface processes involving carboxylic acids such as acetic and pyruvic acids play roles in (1) the transport of nutrients through cell membranes, (2) the cycling of metabolites relevant to the origin of life, and (3) the photooxidative processing of biogenic and anthropogenic emissions in aerosols and atmospheric waters. Here, we report that 50% of gaseous acetic acid and pyruvic acid molecules transfer a proton to the surface of water at pH 2.8 and 1.8 units lower than their respective acidity constants p Ka = 4.6 and 2.4 in bulk water. These findings provide key insights into the relative Bronsted acidities of common carboxylic acids versus interfacial water. In addition, the work estimates the reactive uptake coefficient of gaseous pyruvic acid by water to be gammaPA = 0.06. This work is useful to interpret the interfacial behavior of pyruvic acid under low water activity conditions, typically found in haze aerosols, clouds, and fog waters. PMID- 29975542 TI - Importance of OCT2 and MATE1 for the Cimetidine-Metformin Interaction: Insights from Investigations of Polarized Transport in Single- And Double-Transfected MDCK Cells with a Focus on Perpetrator Disposition. AB - Cimetidine decreases the renal clearance of metformin by inhibition of renal tubular cation transport, and the underlying molecular mechanisms are still not fully understood. We investigated polarized metformin transport without and with the addition of cimetidine as well as polarized cimetidine transport in double transfected MDCK-OCT2-MATE1 cells that mimic organic cation transport processes in proximal renal tubule cells and in MDCK vector control and single-transfected MDCK-OCT2 and MDCK-MATE1 cells. At all tested concentrations (1, 10, 100 MUM), the intracellular accumulation of cimetidine after administration to the basal compartment was considerably higher in MDCK-OCT2 cells compared to that in all other cells ( p < 0.001). Whereas cimetidine transcellular, basal-to-apical transport was only slightly higher in MDCK-OCT2 cells, the presence of MATE1 in the apical membrane caused a pronounced translocation of cimetidine in both single- and double-transfected cells ( p < 0.001). Transcellular, basal-to-apical metformin net transport was reduced by 89.1, 74.5, and 91.0% in MDCK-OCT2-MATE1 cells after the addition of cimetidine (100 MUM) to the basal, the apical, or both compartments ( p < 0.001). In MDCK-MATE1 and MDCK-OCT2-MATE1 cells, transcellular net transport of metformin was inhibited by cimetidine with IC50 values of 8.0 and 6.6 MUM, respectively. Our data confirm the relevance of MATE1 and suggest the relevance of OCT2 for the cimetidine-metformin interaction, primarily because OCT2 mediates uptake of the perpetrator cimetidine into renal proximal tubular cells and thereby to the site of the metformin exporter MATE1. This work supports the notion that a thorough understanding of transporter mediated drug-drug interactions may require investigations on the impact of transporters on cellular uptake and transcellular transport of victim as well as perpetrator drugs. PMID- 29975543 TI - Polymeric Nanoparticles Limit the Collective Migration of Cellular Aggregates. AB - Controlling the propagation of primary tumors is fundamental to avoiding the epithelial to mesenchymal transition process leading to the dissemination and seeding of tumor cells throughout the body. Here we demonstrate that nanoparticles (NPs) limit the propagation of cell aggregates of CT26 murine carcinoma cells used as tumor models. The spreading behavior of these aggregates incubated with NPs is studied on fibronectin-coated substrates. The cells spread with the formation of a cell monolayer, the precursor film, around the aggregate. We study the effect of NPs added either during or after the formation of aggregates. We demonstrate that, in both cases, the spreading of the cell monolayer is slowed down in the presence of NPs and occurs only above a threshold concentration that depends on the size and surface chemistry of the NPs. The density of cells in the precursor films, measured by confocal microscopy, shows that the NPs stick cells together. The mechanism of slowdown is explained by the increase in cell-cell interactions due to the NPs adsorbed on the membrane of the cells. The present results demonstrate that NPs can modulate the collective migration of cells; therefore, they may have important implications for cancer treatment. PMID- 29975544 TI - Kinetic Growth Regimes of Hydrothermally Synthesized Potassium Tantalate Nanoparticles. AB - A general mathematical kinetic growth model is proposed on the basis of observed growth regimes of hydrothermally synthesized KTaO3 nanoparticles from electron microscopy studies on the surface morphology and surface chemistry. Secondary electron imaging demonstrated that there are two dominant growth mechanisms: terrace nucleation, where the surfaces are rough, and terrace growth, where surfaces are smooth. In the proposed model based upon standard step-flow growth, the rates of both mechanisms are established to be dependent on the chemical potential change of the growth environment-terrace nucleation dominates with larger negative chemical potential, and terrace growth dominates with smaller negative chemical potential. This analysis illustrates the importance of ending a synthesis in a regime of low negative chemical potential in order to achieve smooth well-faceted nanoparticles. PMID- 29975545 TI - Adsorption and Denaturation of Structured Polymeric Nanoparticles at an Interface. AB - Nanoparticles (NPs) have been widely applied in fields as diverse as energy conversion, photovoltaics, environment remediation, and human health. However, the adsorption and trapping of NPs interfaces is still poorly understood, and few studies have characterized the kinetics quantitatively. In many applications, such as drug delivery, understanding NP interactions at an interface is essential to determine and control adsorption onto targeted areas. Therapeutic NPs are especially interesting because their structures involve somewhat hydrophilic surface coronas, to prevent protein adsorption, and much more hydrophobic core phases. We initiated this study after observing aggregates of nanoparticles in dispersions where there had been exposure of the dispersion to air interfaces. Here, we investigate the evolution of NP attachment and structural evolution at the air-liquid interface over time scales from 100 ms to 10s of seconds. We document three distinct stages in NP adsorption. In addition to an early stage of free diffusion and a later one with steric adsorption barriers, we find a hitherto unrealized region where the interfacial energy changes due to surface "denaturation" or restructuring of the NPs at the interface. We adopt a quantitative model to calculate the diffusion coefficient, adsorption rate and barrier, and extent of NP hydrophobic core exposure at different stages. Our results deepen the fundamental understanding of the adsorption of structured NPs at an interface. PMID- 29975546 TI - Total Synthesis and Absolute Stereochemical Assignment of the Insecticidal Metabolites Yaequinolones J1 and J2. AB - A highly stereocontrolled total synthesis of (-)-yaequinolone J1 and (+) yaequinolone J2 was accomplished using an Evans auxiliary to establish a syn-diol unit in an acyclic appendage to a preformed benzopyran core bearing a homoprenyl group. The first total synthesis of a complex member of this family of 3,4 dioxygenated 3,4-dihydro 4-aryl quinolin-2-(1 H)-ones also allowed the assignment of absolute stereochemistry, thereby suggesting the same for several members of this family of biogenetically related alkaloids hitherto reported with relative configurations of stereogenic carbons for some and absolute assignments relying on empirical data for others. PMID- 29975547 TI - Catalytic C-N and C-H Bond Activation: ortho-Allylation of Benzoic Acids with Allyl Amines. AB - A facile insertion of ruthenium into aromatic C-H and allylic C-N bonds are the key steps in a [Ru( p-cymene)Cl2]2-catalyzed ortho-C-H allylation of benzoic acids. This protocol allows drawing on the large pool of allylic amines for state of-the-art ortho-functionalizations of arenes, turning neutral amines into leaving groups. Concise syntheses of biologically active compounds provide further evidence of the synthetic potential of this methodology. PMID- 29975548 TI - Influence of Multistep Surface Passivation on the Performance of PbS Colloidal Quantum Dot Solar Cells. AB - The performance of devices containing colloidal quantum dot (CQD) films is strongly dependent on the surface chemistry of the CQDs they contain. Multistep surface treatments, which combine two or more strategies, are important for creating films with high carrier mobility that are well passivated against trap states and oxidation. Here, we examine the effect of a number of these surface treatments on PbS CQD films, including cation exchange to form PbS/CdS core/shell CQDs, and solid-state ligand-exchange treatments with Cl, Br, I, and 1,2 ethanedithiol (EDT) ligands. Using laboratory-based and synchrotron-radiation excited X-ray photoelectron spectroscopy (XPS), we examine the compositions of the surface layer before and after treatment, and correlate this with the performance data and stability in air. We find that halide ion treatments may etch the CQD surfaces, with detrimental effects on the air stability and solar cell device performance caused by a reduction in the proportion of passivated surface sites. We show that films made up of PbS/CdS CQDs are particularly prone to this, suggesting Cd is more easily etched from the surface than Pb. However, by choosing a less aggressive ligand treatment, a good coverage of passivators on the surface can be achieved. We show that halide anions bind preferentially to surface Pb (rather than Cd). By isolating the part of XPS signal originating from the topmost surface layer of the CQD, we show that air stability is correlated with the total number of passivating agents (halide + EDT + Cd) at the surface. PMID- 29975549 TI - Biomechanical Strength of Rotator Cuff Repairs: A Systematic Review and Meta regression Analysis of Cadaveric Studies. AB - BACKGROUND: Biomechanical cadaveric studies of rotator cuff repair (RCR) have shown that transosseous equivalent and double-row anchored repairs are stronger than other repair constructs. PURPOSE: To identify technical and procedural parameters that most reliably predict biomechanical performance of RCR constructs. STUDY DESIGN: Systematic review. METHODS: The authors systematically searched the EMBASE and PubMed databases for biomechanical studies that measured RCR performance in cadaveric specimens. The authors performed a meta-regression on the pooled data set with study outcomes (gap formation, failure mode, and ultimate failure load) as dependent variables and procedural parameters (eg, construct type, number of suture limbs) as covariates. Stratification by covariates was performed. An alpha level of .05 was used. RESULTS: Data from 40 eligible studies were included. Higher number of suture limbs correlated with higher ultimate failure load (beta = 38 N per limb; 95% CI, 28 to 49 N) and less gap formation (beta = -0.6 mm per limb; 95% CI, -1 to -0.2 mm). Other positive predictors of ultimate failure load were number of sutures, number of mattress stitches, and use of wide suture versus standard suture. When controlling for number of suture limbs, we found no significant differences among single-row anchored, double-row anchored, transosseous equivalent, and transosseous repairs. Higher number of suture limbs and transosseous equivalent repair both increased the probability of catastrophic construct failure. CONCLUSION: This study suggests that the number of sutures, suture limbs, and mattress stitches in a RCR construct are stronger predictors of overall strength than is construct type. There is a need to balance increased construct strength with higher risk of type 2 failure. PMID- 29975550 TI - Phenotypical heterogeneity in responder and nonresponder male ApoE*3Leiden.CETP mice. AB - The metabolic syndrome (MetS) is a major health issue worldwide and is associated with obesity, insulin resistance, and hypercholesterolemia. Several animal models were used to describe the MetS; however, many of them do not mimic well the MetS pathophysiology in humans. The ApoE*3Leiden.CETP mouse model overcomes part of this limitation, since they have a humanised lipoprotein metabolism and a heterogeneous response to MetS, similar to humans. The reported heterogeneity among them and their common classification refer to responder (R) and nonresponder (NR) mice; R mice show increased body weight, cholesterol, and triglycerides levels, whereas NR mice do not show this expected phenotype when fed a Western type diet. To define better the differences between R and NR mice, we focused on feeding behavior, body weight gain, glucose tolerance, and lipid parameters, and on an extensive pathological examination along with liver histology analysis. Our data confirmed that R mice resemble the pathological features of the human MetS: obesity, dysplipidemia, and glucose intolerance. NR mice do not develop the full dysmetabolic phenotype because of a severe inflammatory hepatic condition, which may heavily affect liver function. We conclude that R and NR mice are metabolically different and that NR mice have indications of severely impaired liver function. Hence, it is critical to identify and separate the respective mice to decrease data heterogeneity. Clinical chemistry and histological analysis should be used to confirm retrospectively the animals' classification. Moreover, we point out that NR mice may not be an appropriate control for studies involving ApoE*3Leiden.CETP R mice. NEW & NOTEWORTHY When compared with some other animal models, ApoE*3Leiden.CETP mice are better models to describe the metabolic syndrome. However, there is phenotypic heterogeneity between "responder" and "nonresponder" mice, the latter showing some evidence of hepatic pathology. A full phenotypic characterization and eventually postmortem analysis of the liver are warranted. PMID- 29975551 TI - Environmental Impact on Maternal Breastfeeding Behavior. PMID- 29975552 TI - Children with Intellectual Disability Are Vulnerable to Overweight and Obesity: A Cross-Sectional Study among Chinese Children. AB - BACKGROUND: The epidemic of childhood obesity has been well documented in typically developing child populations, while situations among children with intellectual disabilities (ID) remain unclear. METHODS: A cross-sectional study was conducted among 524 Chinese children with ID (males: 68.9%, mean age: 12.2 years) in Hong Kong in 2015. Children's height and weight were measured at school. Parents, in the presence of their children, completed a self-administered questionnaire at home about the children's physical activity (PA), eating habits, and sleep duration in a typical week as well as parenting practices regarding children's eating, PA, and their sociodemographic characteristics. RESULTS: Of the participants, 31.3% were overweight or obese, which was higher than their typical counterparts (18.7%-19.9%). Multivariate logistic regression analyses revealed that overweight and obesity in children with ID were linked to their comorbidity with autism, maternal overweight and obesity, parenting practices with less pressure to eat more, children having shorter sleep duration, longer periods of sedentary behavior, and higher intake frequencies of sweetened beverages, fried food, meats, fish, and eggs. CONCLUSIONS: Children with ID are vulnerable to being overweight or obese. Identified risk factors in this study highlight a multifaceted approach to the involvement of parents as well as the modification of some children's questionable behaviors to help them achieve a healthy weight. PMID- 29975553 TI - Current and emerging treatment options for endometriosis. AB - INTRODUCTION: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors including age and patient preference, reproductive plans, intensity of pain, severity of disease and incidence of adverse effects. Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that are currently available or are under investigation for the treatment of endometriosis highlighting on-going clinical trials. Expert opinion: Almost all of the available treatment options for endometriosis suppress ovarian function and are not curative. Combined oral contraceptives and progestins are commonly administered to these patients in order to ameliorate pain symptoms. Gonadotropin releasing hormone-agonists are prescribed when first-line therapies are ineffective, not tolerated or contraindicated. Aromatase inhibitors should be reserved only for women who are refractory to other treatments. Amongst the drugs under development, gonadotropin-releasing hormone antagonists have shown the most promising results. Presently, are a number of potential therapies currently in pre-clinical or early clinical studies which may alter treatment strategies in the future although further studies are necessary. PMID- 29975554 TI - Integrity of the Untorn Articular-Sided Tendon in Bursal-Sided Partial-Thickness Rotator Cuff Tear: A Comparative Study of Apoptotic Activity in Torn and Untorn Layers. AB - BACKGROUND: Conversion to full-thickness tear in partial-thickness rotator cuff tears (PTRCTs) is based on the quality and thickness of the normal-looking untorn rotator cuff layer. However, whether the untorn tendon is a healthy tissue remains to be elucidated. PURPOSE: To compare the apoptotic gene expression of the untorn articular layer with the torn bursal layer in PTRCTs. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon tissues were harvested from 20 patients undergoing arthroscopic surgery for partial-thickness rotator cuff repair. As a control group, the tissues were harvested during intramedullary nail fixation in 10 proximal humeral fractures. In the experimental group, the samples were harvested from 2 sites: the torn bursal-sided tendon and the untorn articular-sided tendon. Hematoxylin and eosin (H&E) staining was conducted for basic histological evaluation, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was used to detect apoptosis of tissue cells. The expression of caspase 3, 8, and 9 was confirmed immunohistochemically. Western blot analysis was used to assay the caspase activities. RESULTS: In H&E staining, the direction of collagen bundles in untorn tendon was disoriented when compared with those of control tendon. However, the shape of the nuclei was not different, although the nuclei of the untorn tendon showed apoptosis in the TUNEL staining similar to those of the torn tendon. The immunohistochemical staining of caspase 3, 8, and 9 was increased concomitantly in untorn and torn tendons. All of the caspase activities in the untorn articular layer and torn bursal layer were significantly higher than in controls ( P < .05). However, no significant differences were found between the two layers ( P > .05). CONCLUSION: The study demonstrates that apoptotic gene expression is increased not only in the torn bursal layer but also in the untorn articular layer of PTRCTs. CLINICAL RELEVANCE: The untorn articular layer of PTRCTs is abnormal, which triggers postoperative pain and further rotator cuff tears. Therefore, treatment of the abnormal untorn articular layer is essential in bursal-sided PTRCTs. PMID- 29975555 TI - Cardiovascular Events Following Treatment Initiation with Atypical Antipsychotic Medications in Publicly Insured U.S. Youth. AB - OBJECTIVE: To assess the risk of incident cardiovascular events that led to hospitalizations or emergency department visits following atypical antipsychotic (AAP) treatment initiation in youth according to dose, duration of use, and concomitant use of leading psychotropic medication classes. METHODS: We used computerized Medicaid claims to conduct a retrospective cohort study of youth (5 20 years) who initiated AAP treatment. AAP use was operationalized in a time dependent manner according to current vs. former use, average daily dose (in risperidone dose equivalents), and duration of use. In a secondary analysis, concomitant use of (1) stimulants and (2) serotonin-reuptake inhibitors (SSRI/SNRIs) with AAPs was also assessed. To account for confounding, disease risk score methodology was used in discrete time failure models. RESULTS: There were 74,700 youth who initiated AAP treatment (average follow-up = 24.8 months). During follow-up, the risk of cardiovascular events was significantly greater during current than former AAP use (RR = 1.55, 95% CI = 1.09-2.21). Furthermore, for current users of AAPs, the risk of cardiovascular events intensified with average daily dose (RR = 2.04, 95% CI = 1.11-3.77 for >3.75 mg/day vs. <=1.25 mg/day). The risk of cardiovascular events did not significantly differ according to duration of AAP use. In AAP-treated youth, concomitant SSRI/SNRI use was associated with an increased risk of cardiovascular events (RR = 1.61, 95% CI = 1.01-2.57). By contrast, stimulant use concomitant with AAPs was not significantly associated with an increased risk of cardiovascular events. CONCLUSIONS: In publicly insured U.S. youth, current AAP use was associated with an increased risk of incident cardiovascular events, which intensified with increasing dose and with concomitant SSRI/SNRI use. Prudent interpretation of these findings suggests that further research is needed to identify youth subpopulations with the greatest risk of developing AAP treatment-emergent cardiovascular events. PMID- 29975556 TI - A Word to the Wise: Adolescent Reactions to Parental Communication about Weight. AB - BACKGROUND: With high rates of adolescent obesity, many parents are talking to adolescents about their body weight. Parental "weight talk" is linked with adverse health behaviors in youth, but we know little about what parents say in these conversations. Using a weight loss treatment-seeking sample of adolescents, the present study assessed adolescents' emotional reactions to words their parents use to describe their weight and preferred language for these interactions. METHODS: Adolescents enrolled in a national weight loss camp (N = 148) completed a questionnaire assessing their preferences for, and emotional reactions to, parental use of 18 words to describe their body weight. RESULTS: Findings showed a diverse range of weight language used by parents, with many words inducing negative emotional reactions of embarrassment, shame, and sadness in adolescents. Emotional responses to weight language varied according to adolescents' gender, BMI, and experience of weight-teasing from family members. CONCLUSIONS: Findings underscore the need to carefully consider language; parents should avoid making assumptions about what language to use in conversations with adolescents about their weight. Educating parents how to identify negative weight talk may help promote more supportive parental communication about weight-related health. PMID- 29975557 TI - Epidemiology of Upper Extremity Injuries in NCAA Men's and Women's Ice Hockey. AB - BACKGROUND: Ice hockey is a physically demanding sport where athletes are susceptible to a variety of injuries. Several studies reported the overall injury rates in ice hockey; however, there is a paucity of information on upper extremity (UE) injuries among collegiate ice hockey players. PURPOSE: To describe the epidemiology of UE injuries among collegiate male and female ice hockey players with NCAA (National Collegiate Athletic Association) injury surveillance data from 2004-2005 to 2013-2014. STUDY DESIGN: Descriptive epidemiology study. METHODS: Data were obtained from the NCAA Injury Surveillance Program for all UE injuries sustained during the academic years 2004-2005 to 2013-2014. Injury rates, rate ratios (RRs), and injury proportion ratios were reported with 95% CIs. RESULTS: During the 10 years studied, the overall rate of UE injuries for men was higher than that for women (236 vs 125 injuries per 100,000 athlete exposures [AEs]; RR, 1.89; 95% CI, 1.67-2.15). UE injuries sustained during either pre- or postseason were approximately 3 times higher for men than for women (preseason: 149 vs 53 per 100,000 AEs; RR, 2.83; 95% CI, 1.69-4.74; postseason: 143 vs 49 per 100,000 AEs; RR, 2.91; 95% CI, 1.33-6.38). The overall injury rate was highest during the regular season (men: 257 per 100,000 AEs; 95% CI, 242-272; women: 143 per 100,000 AEs; 95% CI, 126-160). Additionally, the injury rate for men and women was higher during competition than practice (men: 733 vs 83 per 100,000 AEs; 95% CI, 687-780 and 75-92; women: 303 vs 64 per 100,000 AEs; 95% CI, 259-348 and 52-76). The most common injury observed was acromioclavicular joint sprain (men, 29.1%; women, 13.8%). For both groups, acromioclavicular joint injuries accounted for most non-time loss, moderate time loss (2-13 days), and severe time loss (>=14 days) injuries. CONCLUSION: Men and women sustained a significant number of UE injuries playing collegiate ice hockey during the period studied, with acromioclavicular joint sprain being the most common UE injury and the one that most frequently led to significant time loss. These data may provide insight for future injury prevention and guide improvements in training. PMID- 29975558 TI - The safety of DPP-4 inhibitor and SGLT2 inhibitor combination therapies. AB - INTRODUCTION: Type 2 diabetes (T2D), a multifactorial and chronic disease, requires in an elevated percentage of patients the association of several antidiabetic drugs to achieve optimal glycemic control. Dipeptidyl peptidase-4 inhibitors (DPP-4i) and sodium-glucose cotransporter inhibitors (SGLT2i) are new classes of oral antidiabetic drugs developed over the last years. Areas covered: This paper summarizes the safety of DPP-4i and SGLT2i combination therapies. Relevant studies were identified through searches in PubMed. Expert opinion: DPP4i and SGLT2i are antidiabetic drugs that lower blood glucose without causing hypoglycaemia or weight increase. More importantly, cardiovascular trials have clearly demonstrated the cardiovascular safety of DPP4i and a reduction in cardiovascular events with SGLT2i (empagliflozin and canagliflozin). Therefore, the association of both therapeutic groups could be an attractive option to achieve optimal blood glucose control in T2D because of their complementary mechanism of action. Clinical trials evaluating the combination of SGLT2i and DPP4i show that the co-administration of these drugs in fixed-dose combinations in comparison to separate tablets does not carry additional safety concerns that each individual drug, but increases therapeutic effects. Therefore, this antidiabetic combination is a safe and effective therapy for patients with T2D. PMID- 29975559 TI - Further Support for the Involvement of Genetic Variants Related to the Serotonergic Pathway in the Antidepressant Response in Children and Adolescents After a 12-Month Follow-Up: Impact of the HTR2A rs7997012 Polymorphism. AB - OBJECTIVE: Fluoxetine is an effective and well-tolerated pharmacological treatment for children and adolescents with major depressive disorder (MDD). However, a high percentage of patients do not respond. There is a substantial genetic contribution to this variable clinical outcome. Based on previous genetic results of our group and given the lack of pharmacogenetics studies of antidepressant response with a long follow-up period, we evaluated the influence of single nucleotide polymorphisms (SNPs) in genes related to the serotonergic pathway on remission and recovery in children and adolescents diagnosed with MDD after 12 months of initiating fluoxetine treatment. METHODS: The assessment was performed in 46 patients. All of them were visited at least once a month during the 12-month follow-up. Psychiatrists interviewed patients and their parents to explore clinical improvement. A total of 75 genotyped SNPs in 10 candidate genes were included in the genetic association analysis with remission and recovery. Bonferroni correction for multiple testing was applied to avoid false positive results. RESULTS: The HTR2A rs7997012 SNP was significantly associated after Bonferroni correction with clinical improvement. Particularly, the homozygotes for the major allele (GG) showed the highest percentage of remitters and the highest score reductions on the Clinical Global Impressions-Severity (CGI-S) scale. Moreover, although the results were on the border of statistical significance, the GG homozygotes also tended to experience fewer readmissions during the follow-up period Conclusions: These results provide more evidence of the involvement of genetic variants related to the serotonergic pathway in the antidepressant response. Studies with larger cohorts are needed to integrate all relevant variants into clinical predictors of antidepressant response. PMID- 29975560 TI - The use of hemodynamics to predict mortality in patients undergoing primary PCI for ST-elevation myocardial infarction. AB - INTRODUCTION: Challenges remain in predicting mortality and severe myocardial dysfunction in patients undergoing primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). Areas covered: Cardiogenic shock is associated with a high mortality rate. Less well characterized are patients who are not in cardiogenic shock but will die from pump failure as a result of a STEMI. There is a long history of using hemodynamics to risk stratify patients with acute MI with the Killip class being shown to provide prognostic information in the prereperfusion, thrombolytic and PPCI eras. Recent studies have identified low systolic blood pressure (SBP), elevated heart rate, elevated left ventricular end diastolic pressure (LVEDP), and low SBP/LVEDP ratio as hemodynamic parameters associated with early mortality in patients undergoing PPCI. Although infrequently used, prognostic information can be obtained from right heart catheterization in the setting of STEMI with the best-studied parameters being cardiac power, pulmonary capillary wedge pressure (PCWP), cardiac output, right atrial pressure/PCWP ratio, and pulmonary artery pulsatility index. Expert commentary: Hemodynamic parameters measured at the time of PPCI provide important prognostic information. Whether hemodynamics can be used to determine which patients benefit from early initiation of mechanical support remains to be determined. PMID- 29975561 TI - Using Situation Awareness and Workload to Predict Performance in Submarine Track Management: A Multilevel Approach. AB - OBJECTIVE: Examine the extent to which subjective workload and situation awareness (SA) can predict variance in performance at the between- and within person levels of analysis in a simulated submarine track management task. BACKGROUND: SA and workload are crucial constructs in human factors that are conceptualized as states that change within individuals over time. Thus, a change in an individual's subjective workload or SA over the course of performing a task should be predictive of their subsequent performance (within-person effects). However, there is little empirical evidence for this. METHOD: Participants monitored displays to track the behaviors of contacts in relationship to their own ship (Ownship) and landmarks. The Situational Awareness Global Assessment Technique measured SA, and the Air Traffic Workload Input Technique measured subjective workload. RESULTS: When a participant's subjective workload rating increased, their subsequent performance decreased, but there was no evidence for within-person effects of SA on performance. We replicated prior between-person level effects of SA; participants with higher SA performed better than those with lower SA. CONCLUSION: Change in an individual's subjective workload rating (but not SA) was predictive of their subsequent performance. Because an increase in SA should increase the extent to which operators hold the knowledge required to perform subsequent tasks, further research is required to examine SA effects on performance at the within-person level. APPLICATION: Adapting automation is more likely to produce optimal outcomes if based on measurement of operator states that predict future task performance, such as workload. PMID- 29975562 TI - Is it time to be concerned about the effects of e-cigarettes on cardiovascular health? PMID- 29975563 TI - One-Year Prospective Study of Liver Function Tests in Children and Adolescents on Second-Generation Antipsychotics: Is There a Link with Metabolic Syndrome? AB - OBJECTIVE: To analyze liver function tests (LFT), weight, metabolic syndrome (MetS) and at risk of meeting MetS criteria (AR-MetS) in children and adolescents on antipsychotics (AP) during a year-long follow-up. METHODS: Two hundred sixteen patients, AP naive or quasi-naive (<30 days on AP), were included. Total bilirubin, the enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), weight and other parameters of MetS were measured at baseline, and at 3, 6 and 12 months, while patients remained on the same AP. RESULTS: At baseline, patients (mean age: 14.1 +/- 3.1 years; 60.2% male) were on risperidone (N = 143), olanzapine (N = 37), or quetiapine (N = 36), although the sample decreased over time to 67 patients at 12 months (risperidone N = 46, olanzapine N = 10, and quetiapine N = 11). Around 3% of patients had ALT/AST levels that were at least twice the upper limit of normal (ULN) at 3 and 6 months; whereas roughly 19% of patients had ALP levels that were at least twice the ULN in at least one assessment after baseline, but had no clinical symptoms. From baseline to 6 months, significant increases were observed in ALT levels in the whole sample (p = 0.005), whereas ALP increased only in patients on risperidone. Patients showed significant weight gain, and more individuals met criteria for MetS and AR-MetS over time (from baseline: 2.8% and 8.3%, to 1 year: 10.5% and 23.9%, respectively). There was a trend-level group effect in global ALT across time (p = 0.076). Patients with MetS showed higher ALT concentrations (28.9 [18.4-39.4] U/L) than AR-MetS (20.4 [8.5-32.2] U/L), and no-AR-MetS (19.2 [8.4-29.9] U/L). CONCLUSIONS: Less than 3% of children and adolescents on AP during 1-year follow-up showed an increase in ALT or AST levels in one or more of the assessments, and none of these increases was of clinical significance. Patients with MetS and AR-MetS increased during this period, and the possible role of ALT levels to monitor these patients deserves further study. PMID- 29975564 TI - US budget impact of increased payer adoption of the Flexitouch advanced pneumatic compression device in lymphedema patients with advanced chronic venous insufficiency and multiple infections. AB - AIMS: To assess the budget impact to a US commercial health plan of providing access to the Flexitouch (FLX) advanced pneumatic compression device (Tactile Medical) to lymphedema (LE) patients with either comorbid chronic venous insufficiency (CVI) or frequent infections. METHODS: Budget impact was calculated over 2 years for a hypothetical US payer with 10-million commercial members. Model inputs were derived from published sources and from a case-matched analysis of Blue Health Intelligence (BHI) claims data for the years 2012-2016. To calculate the budget impact, the Status Quo budget (i.e. total cost for LE and sequelae-related medical treatment) was compared to the budget under each of three Alternate Payer Policy scenarios which assumed that a sub-set of patients was redistributed from their initial treatment groups to a group that received FLX. Model outputs included cumulative payer costs, net budget impact, and breakeven point. Sensitivity analyses were performed to assess the impact of model inputs on results. RESULTS: Increasing access to FLX yielded a favorable budget impact in every scenario. For LE patients with comorbid CVI, the three alternate scenarios resulted in cumulative 2-year budget impacts of -$52,841, $173,317, and -$375,601, respectively. For LE patients with comorbid frequent infections, the three alternate scenarios resulted in cumulative 2-year budget impacts of -$192,729, -$259,339, and -$613,179, respectively. LIMITATIONS: Use of claims data assumes accurate coding and does not allow one to control for disease severity or treatment adherence. Also, the distribution of patients between treatment arms was determined using claims data from a specific payer organization, and could differ for health plans with different coverage policies. CONCLUSIONS: While previous studies have illustrated cost savings with adoption of FLX, US commercial health plans may also achieve tangible cost savings by expanding access to FLX for LE patients with comorbid CVI and multiple infections. PMID- 29975565 TI - Cardiovascular responses to cold and submaximal exercise in patients with coronary artery disease. AB - Regular year-round exercise is recommended for patients with coronary artery disease (CAD). However, the combined effects of cold and moderate sustained exercise, both known to increase cardiac workload, on cardiovascular responses are not known. We tested the hypothesis that cardiac workload is increased, and evidence of ischemia would be observed during exercise in the cold in patients with CAD. Sixteen men (59.3 +/- 7.0 yr, means +/- SD) with stable CAD each underwent 4, 30 min exposures in a randomized order: seated rest and moderate intensity exercise [walking, 60%-70% of max heart rate (HR)] performed at +22 degrees C and -15 degrees C. Systolic brachial blood pressure (SBP), HR, electrocardiogram (ECG), and skin temperatures were recorded throughout the intervention. Rate pressure product (RPP) and ECG parameters were obtained. The combined effects of cold and submaximal exercise were additive for SBP and RPP and synergistic for HR when compared with rest in a neutral environment. RPP (mmHg.beats/min) was 17% higher during exercise in the cold (18,080 +/- 3540) compared with neutral (15,490 +/- 2,940) conditions ( P = 0.001). Only a few ST depressions were detected during exercise but without an effect of ambient temperature. The corrected QT interval increased while exercising in the cold compared with neutral temperature ( P = 0.023). Recovery of postexercise blood pressure was similar regardless of temperature. Whole body exposure to cold during submaximal exercise results in higher cardiac workload compared with a neutral environment. Despite the higher RPP, no signs of myocardial ischemia or abnormal ECG responses were observed. The results of this study are useful for planning year-round exercise-based rehabilitation programs for stable CAD patients. PMID- 29975566 TI - Folic acid supplementation improves vascular endothelial function, yet not skin blood flow during exercise in the heat, in patients with heart failure. AB - Heart failure (HF) patients are susceptible to heat strain during exercise, secondary to blunted skin blood flow (SkBF) responses, which may be explained by impaired nitric oxide (NO)-dependent vasodilation. Folic acid improves vascular endothelial function and SkBF through NO-dependent mechanisms in healthy older individuals and patients with cardiovascular disease. We examined the effect of folic acid supplementation (5 mg/day for 6 wk) on vascular function [brachial artery flow-mediated dilation (FMD)] and SkBF responses [cutaneous vascular conductance (CVC)] during 60 min of exercise at a fixed metabolic heat production (300 WHprod) in a 30 degrees C environment in 10 patients with HF (New York Heart Association Class I-II) and 10 healthy controls (CON). Serum folic acid concentration increased in HF [preintervention (pre): 1.4 +/- 0.2; postintervention (post): 8.9 +/- 6.7 ng/ml, P = 0.01] and CON (pre: 1.3 +/- 0.6; post: 5.2 +/- 4.9 ng/ml, P = 0.03). FMD improved by 2.1 +/- 1.3% in HF ( P < 0.01), but no change was observed in CON postintervention ( P = 0.20). During exercise, the external workload performed on the cycle ergometer to attain the fixed level of heat production for exercise was similar between groups (HF: 60 +/ 13; CON: 65 +/- 20 external workload, P = 0.52). Increases in CVC during exercise were similar in HF (pre: 0.89 +/- 0.43; post: 0.83 +/- 0.45 au/mmHg, P = 0.80) and CON (pre: 2.01 +/- 0.79; post: 2.03 +/- 0.72 au/mmHg, P = 0.73), although the values were consistently lower in HF for both pre- and postintervention measurement intervals ( P < 0.05). These findings demonstrate that folic acid improves vascular endothelial function in patients with HF but does not enhance SkBF during exercise at a fixed metabolic heat production in a warm environment. PMID- 29975567 TI - Directional sensitivity of dynamic cerebral autoregulation in squat-stand maneuvers. AB - Dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (BP), is usually modeled as a linear mechanism. We tested the hypothesis that dynamic CA can display nonlinear behavior resulting from differential efficiency dependent on the direction of BP changes. Cerebral blood velocity (CBV) (transcranial Doppler), heart rate (HR) (three-lead ECG), continuous BP (Finometer), and end-tidal CO2 (capnograph) were measured in 10 healthy young subjects during 15 squat-stand maneuvers (SSM) with a frequency of 0.05 Hz. The protocol was repeated with a median (interquartile range) of 44 (35-64) days apart. Dynamic CA was assessed with the autoregulation index (ARI) obtained from CBV step responses estimated with an autoregressive moving-average model. Mean BP, HR, and CBV were different (all P < 0.001) between squat and stand, regardless of visits. ARI showed a strong interaction ( P < 0.001) of SSM with the progression of transients; in general, the mean ARI was higher for the squat phase compared with standing. The changes in ARI were partially explained by concomitant changes in CBV ( P = 0.023) and pulse pressure ( P < 0.001), but there was no evidence that ARI differed between visits ( P = 0.277). These results demonstrate that dynamic CA is dependent on the direction of BP change, but further work is needed to confirm if this finding can be generalized to other physiological conditions and also to assess its dependency on age, sex and pathology. PMID- 29975568 TI - Perinatal short-chain fructooligosaccharides program intestinal microbiota and improve enteroinsular axis function and inflammatory status in high-fat diet-fed adult pigs. AB - Perinatal nutrition programs physiologic and metabolic functions, with consequences on the susceptibility to develop metabolic diseases in adulthood. The microbiota represents a key factor of such programming. We investigated whether perinatal prebiotic [short-chain fructooligosaccharides (scFOS)] supplementation improved adult metabolic health in association with microbiota changes in pigs used as human model. Sows were supplemented with scFOS or not during the end of gestation and the entire lactation, and offspring received scFOS accordingly during 1 mo after weaning. Pigs were then fed a standard diet for 5 mo, followed by a high-fat diet for 3 mo once adults. Perinatal scFOS supplementation induced a persistent modulation of the composition of the fecal microbiota in adulthood, notably by increasing the Prevotella genus. Meanwhile, scFOS animals displayed improved capacity to secrete glucagon-like peptide-1 and improved pancreas sensitivity to glucose without any changes in peripheral insulin sensitivity. Perinatal scFOS supplementation also increased ileal secretory IgA secretion and alkaline phosphatase activity and decreased TNF-alpha expression in adipose tissue. In conclusion, perinatal scFOS supplementation induced long-lasting modulation of intestinal microbiota and had beneficial consequences on the host physiology in adulthood. Our results highlight the key role of perinatal nutrition on later microbiota and host metabolic adaptation to an unbalanced diet.-Le Bourgot, C., Ferret-Bernard, S., Apper, E., Taminiau, B., Cahu, A., Le Normand, L., Respondek, F., Le Huerou-Luron, I., Blat, S. Perinatal short-chain fructooligosaccharides program intestinal microbiota and improve enteroinsular axis function and inflammatory status in high-fat diet-fed adult pigs. PMID- 29975569 TI - A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats. AB - Reduced fetal nutrition and rapid postnatal growth accelerates the aging phenotype in many organ systems; however, effects on the immune system are unclear. We addressed this by studying the thymus from a rat model of developmental programming. The recuperated group was generated by in utero protein restriction, followed by cross-fostering to control-fed mothers, and were then compared with controls. Fat infiltration and adipocyte size increased with age ( P < 0.001) and in recuperated thymi ( P < 0.05). Cortex/medulla ratio decreased with age ( P < 0.001) and decreased ( P < 0.05) in 12-mo recuperated thymi. Age-associated decreases in thymic-epithelial cell ( P < 0.01) and thymocyte markers ( P < 0.01) were observed in both groups and was decreased ( P < 0.05) in recuperated thymi. These data demonstrate effects of developmental programming upon thymic involution. The recuperated group had longer thymic telomeres than controls ( P < 0.001) at 22 d and at 3 mo, which was associated with increased expression of telomere-length maintenance molecules [telomerase RNA component ( Terc; P < 0.01), P23 ( P = 0.02), and Ku70 and Ku80 ( P < 0.01)]. By 12 mo, recuperated offspring had shorter thymic telomeres than controls had ( P < 0.001) and reduced DNA damage-response markers [( DNA-PKcs, Mre11 ( P < 0.01), Xrcc4 ( P = 0.02), and gamma-H2ax ( P < 0.001], suggesting failure of earlier compensatory responses. Our results suggest that low birth weight with rapid postnatal growth results in premature thymic maturation, resulting in accelerated thymic aging. This could lead to increased age-associated vulnerability to infection.-Tarry-Adkins, J. L., Aiken, C. E., Ashmore, T. J., Fernandez-Twinn, D. S., Chen, J.-H., Ozanne, S. E. A suboptimal maternal diet combined with accelerated postnatal growth results in an altered aging profile in the thymus of male rats. PMID- 29975570 TI - Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes. AB - Chronic exposure of tubular renal cells to high glucose contributes to tubulointerstitial changes in diabetic nephropathy. In the present study, we identified a new fibrosis gene called galectin-1 (Gal-1), which is highly expressed in tubular cells of kidneys of type 1 and type 2 diabetic mouse models. Gal-1 protein and mRNA expression showed significant increase in kidney cortex of heterozygous Akita+/- and db/db mice compared with wild-type mice. Mouse proximal tubular cells exposed to high glucose showed significant increase in phosphorylation of Akt and Gal-1. We cloned Gal-1 promoter and identified the transcription factor AP4 as binding to the Gal-1 promoter to up-regulate its function. Transfection of cells with plasmid carrying mutations in the binding sites of AP4 to Gal-1 promoter resulted in decreased protein function of Gal-1. In addition, inhibition of Gal-1 by OTX-008 showed significant decrease in p Akt/AP4 and protein-promoter activity of Gal-1 and fibronectin. Moreover, down regulation of AP4 by small interfering RNA resulted in a significant decrease in protein expression and promoter activity of Gal-1. We found that kidney of Gal-1 /- mice express very low levels of fibronectin protein. In summary, Gal-1 is highly expressed in kidneys of type 1 and 2 diabetic mice, and AP4 is a major transcription factor that activates Gal-1 under hyperglycemia. Inhibition of Gal 1 by OTX-008 blocks activation of Akt and prevents accumulation of Gal-1, suggesting a novel role of Gal-1 inhibitor as a possible therapeutic target to treat renal fibrosis in diabetes.-Al-Obaidi, N., Mohan, S., Liang, S., Zhao, Z., Nayak, B. K., Li, B., Sriramarao, P., Habib, S. L. Galectin-1 is a new fibrosis protein in type 1 and type 2 diabetes. PMID- 29975574 TI - IMPACT OF RAMADAN FASTING ON THYROID STATUS AND QUALITY OF LIFE IN PATIENTS WITH PRIMARY HYPOTHYROIDISM: A PROSPECTIVE COHORT STUDY FROM KARACHI, PAKISTAN. AB - OBJECTIVE: Ramadan is the ninth month in the lunar calendar, during which Muslims fast from predawn to sunset and major changes occur in their dietary, sleep, and physical activity patterns. Most patients with hypothyroidism are unable to comply with the proper timings of levothyroxine (LT4) administration. The objective of the study was to determine the change in thyroid-stimulating hormone (TSH) level and quality of life (QOL) before and after Ramadan in patients with primary hypothyroidism. METHODS: This prospective cohort study included adult patients on stable doses of LT4 who fasted for at least 20 days during the month of Ramadan in the Islamic year 1437 Hijri (June/July 2016). Baseline characteristics and TSH levels were recorded on all consenting patients within 6 weeks prior to Ramadan. Post-Ramadan TSH was tested within 1 to 2 weeks after Eid ul-Fitr. RESULTS: During the study period, 64 patients with hypothyroidism were enrolled, of which 58 were female. The mean age of participants was 44.2 +/- 13.2 years. Average daily dose of LT4 was 95.3 +/- 35.4 MUg. On average, patients fasted for 26.5 days and missed a dose of LT4 on 1.27 days. Mean TSH pre-Ramadan was 2.37 +/- 1.35 mIU/L, and post-Ramadan, it was 4.69 +/- 3.87 mIU/L. Mean difference between TSH pre- and post-Ramadan was 2.32 +/- 3.80 mIU/L ( P<.001). However, the difference in TSH was not significantly different between those who were compliant with meals and LT4 interval versus those who were not (compliant, 2.04 mIU/L; noncompliant, 3.15 mIU/L; P = .30). Overall, an increase in QOL scores in the domains of physical health, psychological health, and social relationships was observed after Ramadan. CONCLUSION: We observed statistically significant changes in TSH concentrations after the month of Ramadan in hypothyroid patients who fasted. The change in TSH was not affected by timing of LT4 intake and interval from meal. ABBREVIATIONS: AKUH = Aga Khan University Hospital; LT4 = levothyroxine; QOL = quality of life; TSH = thyroid-stimulating hormone. PMID- 29975571 TI - Continued Improvements in Quadriceps Strength and Biomechanical Symmetry of the Knee After Postoperative Anterior Cruciate Ligament Reconstruction Rehabilitation: Is It Time to Reconsider the 6-Month Return-to-Activity Criteria? AB - CONTEXT: Patients who undergo anterior cruciate ligament reconstruction (ACLR) present with strength and biomechanical deficits at return to activity (RTA). Deficits in strength and biomechanical symmetry impair function during activity and may predispose patients to subsequent injury. OBJECTIVE: To compare strength and biomechanical function in patients with ACLR at RTA and more than 12 months post-ACLR. DESIGN: Descriptive laboratory study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 20 participants (12 females, 8 males; age = 21.40 +/- 5.60 years, height = 171.3 +/- 10.2 cm, mass = 73.21 +/- 19.41 kg) who had undergone ACLR and were cleared to RTA were recruited. INTERVENTION(S): Strength was measured during knee extension and evaluated by the isometric and isokinetic quadriceps index. Biomechanical function was evaluated using symmetry values for sagittal-plane knee-joint rotations, changes in sagittal-plane knee-joint rotation, knee-extension moments, and changes in knee-extension moment that were recorded during a single-legged forward hop. MAIN OUTCOME MEASURE(S): Self-reported function was measured using the International Knee Documentation Committee Subjective Knee Evaluation Form. Participants were assessed at RTA (212.25 +/- 28.11 days) and more than 12 months post-ACLR (556.25 +/- 230.89 days). RESULTS: At RTA, strength and biomechanical values were less than 80% symmetric. We observed improvements from RTA to more than 12 months post-ACLR for the isometric quadriceps index ( F1,18 = 29.22, P < .001), isokinetic quadriceps index ( F1,18 = 10.88, P = .004), sagittal-plane knee-joint rotations ( F1,19 = 9.58, P = .006), change in sagittal-plane knee joint rotations ( F1,19 = 7.83, P = .01), knee-extension moments ( F1,19 = 5.73, P = .03), change in knee-extension moments ( F1,19 = 21.10, P < .001), and self perceived function ( F1,19 = 11.50, P = .003). Of the 7 variables that showed improvement at more than 12 months post-ACLR, only 3 met the recommended criteria (>=90%). CONCLUSIONS: Patients with ACLR showed asymmetry in strength and biomechanics at RTA. These asymmetries, along with self-perceived function, improved over time. However, despite improvements in strength and biomechanics at RTA, asymmetries of more than 10% were still present more than 12 months post ACLR. PMID- 29975572 TI - Reliability and Validity of a 1-Person Technique to Measure Humeral Torsion Using Ultrasound. AB - CONTEXT: Knowledge of the bilateral difference in humeral torsion (HT) enables clinicians to implement appropriate interventions for soft tissue restrictions of the shoulder to restore rotational motion and reduce injury risk. Whereas the current ultrasound method for measuring HT requires 2 assessors, a more efficient 1-person technique (1PT) may be of value. OBJECTIVE: To determine if a 1PT is a reliable and valid alternative to the established 2-person technique (2PT) for indirectly measuring HT using ultrasound. DESIGN: Descriptive laboratory study. SETTING: Biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: A convenience sample of 16 volunteers (7 men, 9 women; age = 26.9 +/- 6.8 years, height = 172.2 +/- 10.7 cm, mass = 80.0 +/- 13.3 kg). MAIN OUTCOME MEASURE(S): We collected the HT data using both the 1PT and 2PT from a total of 30 upper extremities (16 left, 14 right). Within-session intrarater reliability (intraclass correlation coefficient; ICC [3,1]) and standard error of measurement (SEM) were assessed for both techniques. Simple linear regression and Bland Altman analysis were used to examine the validity of the 1PT when compared with the established 2PT. RESULTS: The 1PT (ICC [3,1] = 0.992, SEM = 0.8 degrees ) and 2PT (ICC [3,1] = 0.979, SEM = 1.1 degrees ) demonstrated excellent within session intrarater reliability. A strong linear relationship was demonstrated between the HT measurements collected with both techniques ( r = 0.963, r2 = 0.928, F1,28 = 361.753, P < .001). A bias of -1.2 degrees +/- 2.6 degrees was revealed, and the 95% limits of agreement indicated the 2 techniques can be expected to vary from -6.3 degrees to 3.8 degrees . CONCLUSIONS: The 1PT for measuring HT using ultrasound was a reliable and valid alternative to the 2PT. By reducing the number of testers involved, the 1PT may provide clinicians with a more efficient and practical means of obtaining these valuable clinical data. a. PMID- 29975575 TI - Predictors and Clinical Outcomes of Treatment Intensification in Patients With Type 2 Diabetes Uncontrolled on Basal Insulin in a Real-World Setting. AB - OBJECTIVE: To understand factors associated with intensification of basal insulin therapy and treatment impact on clinical outcomes in patients with type 2 diabetes (T2D). METHODS: In this retrospective, observational study of the Practice Fusion electronic health record database, eligible patients were adults with T2D, >=1 basal insulin prescription and office visit in the 6 months before a glycated hemoglobin A1c (A1C) test >7.0% (index date), and no other injectable prescriptions in the 12 months before the index date. Patients were categorized to intensifiers with injectables (rapid-acting insulin [RAI], glucagon-like peptide-1 receptor agonist [GLP-1 RA], or other injectables) or nonintensifiers with injectables (including no change, adding an oral antidiabetes drug, or changing basal insulin dose). Principal outcomes were A1C change, hypoglycemia incidence, and change in body weight. RESULTS: Among 14,653 patients, 2,121 (14.5%) and 12,532 (85.5%) were categorized as intensifiers and nonintensifiers with injectables, respectively. Compared with nonintensifiers, intensifiers were more likely to have an endocrinologist as the prescribing physician (odds ratio [OR], 2.52 [95% confidence interval (CI), 2.16 to 2.94]), hypertension (OR, 1.26 [95% CI, 1.08 to 1.47]), higher baseline A1C (OR, 1.22 [95% CI, 1.17 to 1.26]), obesity (OR, 1.17 [95% CI, 1.01 to 1.36]), and higher body mass index (OR, 1.02 [95% CI, 1.01 to 1.03]). In GLP-1 RA intensifiers, the baseline use of dipeptidyl peptidase-4 inhibitors increased the likelihood of intensification. GLP-1 RA intensifiers had equivalent glycemic control to RAI or other injectables, with a nonsignificantly lower risk of hypoglycemia and reduction in body weight. CONCLUSION: Addition of GLP-1 RA to basal insulin may be an effective strategy for overcoming clinical inertia with injectable therapy in patients with T2D. ABBREVIATIONS: A1C = glycated hemoglobin A1c; BMI = body mass index; CI = confidence interval; DCSI = Diabetes Complications Severity Index; DPP-4 = dipeptidyl peptidase-4; EHR = electronic health record; GLP-1 RA = glucagon-like peptide-1 receptor agonist; ICD-9-CM = International Classification of Diseases Ninth Revision-Clinical Modification; ICD-10-CM = International Classification of Diseases-Tenth Revision-Clinical Modification; OAD = oral antidiabetes drug; OR = odds ratio; RAI = rapid-acting insulin; SGLT-2 = sodium-glucose cotransporter-2; T2D = type 2 diabetes. PMID- 29975573 TI - Balance- and Strength-Training Protocols to Improve Chronic Ankle Instability Deficits, Part I: Assessing Clinical Outcome Measures. AB - CONTEXT: Functional rehabilitation may improve the deficits associated with chronic ankle instability (CAI). OBJECTIVE: To determine if balance- and strength-training protocols improve the balance, strength, and functional performance deficits associated with CAI. DESIGN: Randomized controlled clinical trial. SETTING: Athletic training research laboratory. PATIENTS OR OTHER PARTICIPANTS: Participants were 39 volunteers with CAI, which was determined using the Identification of Functional Ankle Instability Questionnaire. They were randomly assigned to 1 of 3 groups: balance-training protocol (7 males, 6 females; age = 23.5 +/- 6.5 years, height = 175.0 +/- 8.5 cm, mass = 72.8 +/- 10.9 kg), strength-training protocol (8 males, 5 females; age = 24.6 +/- 7.7 years, height = 173.2 +/- 9.0 cm, mass = 76.0 +/- 16.2 kg), or control (6 males, 7 females; age = 24.8 +/- 9.0 years, height = 175.5 +/- 8.4 cm, mass = 79.1 +/- 16.8 kg). INTERVENTION(S): Each group participated in a 20 minute session, 3 times per week, for 6 weeks. The control group completed a mild to moderately strenuous bicycle workout. MAIN OUTCOME MEASURE(S): Participants completed baseline testing of eccentric and concentric isokinetic strength in each ankle direction (inversion, eversion, plantar flexion, and dorsiflexion) and the Balance Error Scoring System (BESS), Star Excursion Balance Test (SEBT), and side-hop functional performance test. The same variables were tested again at 6 weeks after the intervention. Two multivariate repeated-measures analyses of variance with follow-up univariate analyses were conducted. The alpha level was set a priori at .05. RESULTS: We observed time-by-group interactions in concentric ( P = .02) and eccentric ( P = .01) inversion, eccentric eversion ( P = .01), concentric ( P = .001) and eccentric ( P = .03) plantar flexion, BESS ( P = .01), SEBT ( P = .02), and side hop ( P = .004). With pairwise comparisons, we found improvements in the balance- and strength-training protocol groups in concentric and eccentric inversion and concentric and eccentric plantar flexion and the BESS, SEBT, and side hop (all P values = .001). Only the strength training protocol group improved in eccentric eversion. The control group did not improve in any dependent variable. CONCLUSIONS: Both training protocols improved strength, balance, and functional performance. More clinicians should incorporate hop-to-stabilization exercises into their rehabilitation protocols to improve the deficits associated with CAI. PMID- 29975576 TI - Thoracic Outlet Syndrome: A Unique Presentation of a Primary Intrathoracic Goiter. PMID- 29975577 TI - PREDICTION OF NONDIAGNOSTIC RESULTS IN FINE-NEEDLE ASPIRATION OF THYROID NODULES: UTILITY OF ON-SITE GROSS VISUAL ASSESSMENT OF SPECIMENS FOR LIQUID-BASED CYTOLOGY. AB - OBJECTIVE: To explore a comprehensive approach for on-site gross visual assessments of liquid-based cytology (LBC) specimens of thyroid nodules and determine morphologic criteria that help predict nondiagnostic rates. METHODS: Two-hundred nodules from 165 patients who underwent fine-needle aspiration (FNA) at our hospital were included in this prospectively designed, retrospective analysis. Specimens were visually assessed on-site for three morphologic categories (specimen color, specimen volume, and particle count) using a 5-point grading. RESULTS: Twenty-two nodules (11%) showed nondiagnostic results. Regarding specimen color, nondiagnostic rates tended to be higher in grades 1 (75%) and 5 (100%) than in grades 2 (18%), 3 (8%), or 4 (17%), with a significant difference between grade 1 and grade 3 ( P = .003). For specimen volume, nondiagnostic results were significantly more common in grade 1 (33%) and 5 (33%) than in grades 3 (5%) or 4 (1%) ( P<.005). There was a significant negative correlation between the grading of the particle count and the nondiagnostic rate (Spearman rho = -1.000; P<.001). The sensitivity and specificity in the prediction of nondiagnostic results were 77% and 76%, respectively, at the optimal cutoff value of 2 (grade 2 or lower). CONCLUSION: Particle count was an important morphologic criterion that helped predict nondiagnostic rates in LBC specimens of thyroid nodules, and the specimen color and volume were also useful adjuncts. In routine practice, on-site gross visual assessment followed by resampling (if necessary) may potentially help reduce the rates of nondiagnostic results, repeat FNAs, and the number of unnecessary needle passes. ABBREVIATIONS: FNA = fine-needle aspiration; LBC = liquid-based cytology; ROC = receiver operating characteristic; US = ultrasonography. PMID- 29975578 TI - ASPIRIN FOR PRIMARY PREVENTION IN PATIENTS WITH TYPE 2 DIABETES. PMID- 29975579 TI - Nonalcoholic Fatty Liver Disease and Risk of Diabetes: A Prospective Study in China. AB - OBJECTIVE: We aimed to investigate whether liver steatosis severity affects the risk of developing diabetes in a large cohort study. METHODS: We prospectively examined the association in 41,650 Chinese adults with negative hepatitis-B surface antigen who were free of alcohol consumption, diabetes, and liver cirrhosis at baseline. Cox proportional models were used to estimate the risk of diabetes after a mean of 3.6 years of follow-up. Nonalcoholic fatty liver disease (NAFLD) was assessed with hepatic ultrasonography. Elevated alanine transaminase (ALT) was defined as ALT concentrations >19 and >30 U/L in females and males, respectively. Diabetes was defined as a fasting glucose 37.0 mmol/L or treatment with hypoglycemic medication. RESULTS: Liver steatosis severity was significantly associated with higher risks of developing diabetes (adjusted hazard ratio [HR] for severe vs. without NAFLD = 2.66, 95% confidence interval [CI]: 2.17-3.25, P trend<.001) and impaired fasting glucose (fasting glucose between 5.6 and 6.9 mmol/L, adjusted HR = 1.36, 95% CI: 1.16-1.59, P-trend<.001), as well as a faster increase rate of fasting glucose concentrations ( P-trend<.001), during 3.6 years of follow-up. Elevated ALT was also associated with incident diabetes (HR = 1.12, 95% CI: 1.02-1.22), adjusting for NAFLD and other covariates. CONCLUSION: We observed a dose-response relationship between liver steatosis severity and increased diabetes risk, and ALT may predict incident diabetes independently of NAFLD. ABBREVIATIONS: ALT = alanine transaminase; BP = blood pressure; CI = confidence interval; HCV = hepatitis C virus; HR = hazard ratio; IFG = impaired fasting glucose; NAFLD = nonalcoholic fatty liver disease; ULN = upper limit of normal. PMID- 29975580 TI - DIFFERENTIAL REGULATION OF 11beta-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVITY IN PATIENTS WITH DIFFERING ETIOLOGIES OF HYPOPITUITARISM. AB - OBJECTIVE: Pituitary patients with different etiologies of hypopituitarism exhibit differing phenotypes, despite similar replacement therapy strategies. We hypothesized that differential regulation of the isoenzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which mediates the net autocrine conversion of cortisone to cortisol in adipose tissues and liver, may play a role. METHODS: We studied 11beta-HSD1 activity (using urine cortisol/cortisone metabolites ratio) in 36 hypopituitary patients with treated craniopharyngiomas, treated remitted Cushing disease, and treated nonfunctioning pituitary adenomas + prolactinomas on and off growth hormone (GH) replacement. RESULTS: 11beta-HSD1 activity was higher in subjects with craniopharyngioma both on and off GH, as evidenced by increased tetrahydrocortisol to tetrahydrocortisone metabolite ratios compared to other diagnostic groups, but there was no difference in body mass index, insulin levels, serum hormone measurements, or hydrocortisone dose between groups. CONCLUSION: Craniopharyngiomas are associated with enhanced 11beta-HSD1 activity compared to other diagnostic hypopituitary groups, and this may contribute to the adverse phenotypic and metabolic features seen in this condition. ABBREVIATIONS: BMI = body mass index; Em = cortisone metabolites; Fm = cortisol metabolites; GH = growth hormone; 11beta-HSD1 = 11beta-hydroxysteroid dehydrogenase type 1; IGF-1 = insulin-like growth factor 1; NFPA = nonfunctioning pituitary adenoma; THE = tetrahydrocortisone; THF = tetrahydrocortisol. PMID- 29975581 TI - Evaluation of Cardiovascular Risk With Arterial Stiffness in Patients with Nonfunctioning Pituitary Adenoma. AB - OBJECTIVE: Nonfunctioning pituitary adenoma (NFPA) accounts for 30% of all pituitary adenomas, and its incidence has been increasing compared to previous years. Increased risk of cardiovascular effects shown in recent studies is noteworthy in patients with NFPA diagnosis, but the number of studies on the subject is limited. In this study, we aimed to assess possible cardiovascular effects and risk via arterial stiffness measurements in patients diagnosed with NFPA. METHODS: We performed arterial stiffness measurements for 30 patients diagnosed with NFPA and 30 healthy volunteers and compared the results to explore the relationship between arterial stiffness parameters, hormone levels, and adenoma size. RESULTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), central SBP, central DBP, augmentation index corrected for a heart rate of 75 beats per minute (AIx@75), and pulse wave velocity (PWV) values of the patients with NFPA diagnosis were significantly higher than the control group. PWV was found to have a significant and negative correlation with growth hormone and insulin-like growth factor 1 (IGF-1). A significant and positive correlation was found between adenoma median short-axis length and PWV. IGF-1 was found to have a significant and negative correlation with adenoma median long- and short-axis length. In multivariate linear regression analysis, we found that IGF-1 was an independent predictor of PWV. CONCLUSION: Both arterial stiffness parameters such as AIx@75 and PWV and peripheral SBP, DBP, and MBP values were found to be high in NFPA patients with no cardiovascular risk factors. Our findings suggest increased cardiovascular effect and risk in patients with NFPA diagnosis, and therefore, we recommend that patients are monitored closely in this respect. ABBREVIATIONS: ACTH = adrenocorticotropic hormone; AIx@75 = augmentation index corrected for a heart rate of 75 beats per minute; BMI = body mass index; CVD = cardiovascular disease; DBP = diastolic blood pressure; FSH = follicle-stimulating hormone; GH = growth hormone; HT = hypertension; IGF-1 = insulin-like growth factor 1; LH = luteinizing hormone; MBP = mean blood pressure; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; PP = pulse pressure; PWA = pulse wave analysis; PWV = pulse wave velocity; SBP = systolic blood pressure; TSH = thyroid stimulating hormone. PMID- 29975582 TI - Breakthrough Cancer Pain Influences General Activities and Pain Management: A Comparison of Patients with and without Breakthrough Cancer Pain. AB - BACKGROUND: Breakthrough cancer pain (BTcP) is a predictor of interference with general activities and poor pain management. The extent of this influence has not yet been determined. OBJECTIVE: This study aimed to investigate the influence of BTcP on general activities, and pain management in patients with controlled background pain. DESIGN: Single-center prospective observational study. SETTING/SUBJECTS: The study cohort comprised 258 consecutive patients (female, 40.0%; mean age, 64.5 years) who had received opioid medication for cancer pain for over 2 weeks. MEASUREMENTS: A recommended diagnostic algorithm was used to quantitate and compare interference with general activities, average background pain intensity over the previous 24 hours (24h-PI), and achievement of personalized pain goals (PPGs) (24h-PI<=PPG) of 119 patients with and 139 patients without BTcP. RESULTS: Interference with general activities, 24h-PI, and PPG scores [mean (standard deviation)] in patients with BTcP were 2.8 (2.2), 3.0 (1.7), and 1.8 (1.4), respectively, which are all significantly higher than for those without BTcP [1.3 (2.0), p < 0.01; 1.7 (1.6), p < 0.01; 1.5 (1.3), p = 0.03], respectively. A significantly smaller percentage of patients with BTcP than without BTcP achieved their PPGs (36.1% vs. 67.6%, p < 0.01). CONCLUSIONS: BTcP has a negative impact on general activities and pain management. Healthcare providers should recognize that management of BTcP is important in improving general activities and management of cancer pain. PMID- 29975583 TI - Diagnostic Accuracy of Prehospital Tele-Electrocardiography in Acute Coronary Syndrome. AB - BACKGROUND: Tele-electrocardiography (tele-ECG) is a powerful ally in the screening of acute ischemic lesions. INTRODUCTION: Evidence that confirms the correlation between the diagnosis of acute coronary syndrome (ACS) determined in the prehospital setting and the confirmation of the diagnosis in the hospital setting is scarce. This study compares the presumed diagnosis of ACS in the prehospital setting based on electrocardiographic changes, such as ST-segment deviation, with the diagnosis confirmed in a hospital setting. MATERIALS AND METHODS: Retrospective, cross-sectional analysis of medical records of patients who sought emergency ambulance services of a distinguished public healthcare service in the city of Porto Alegre from September 2013 to August 2014. Data were collected from tele-ECG recordings and medical records available at the database of the Secretary of Health. The study was based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: Among the 1,338 prehospital examinations performed, a total of 250 admissions in tertiary hospitals were registered. There was a significant agreement (p < 0.01) of 71% of the electrocardiographic changes identified in the prehospital setting with the diagnosis of ACS confirmed in the hospital setting. These changes were more prevalent in men (p = 0.048) and in patients aged 60 years or older (p = 0.006). DISCUSSION: The tele-ECG allows the early diagnosis of ACS, reducing the delay to definitive treatment, be it reperfusion, chemical, or mechanical therapy. CONCLUSIONS: Seventy-two percent of the prehospital diagnosis of ACS based on electrocardiographic changes was later confirmed in the hospital setting. PMID- 29975584 TI - Consistent and Reproducible Direct Ink Writing of Eutectic Gallium-Indium for High-Quality Soft Sensors. AB - Given the need for stretchable sensors, many studies have been conducted on eutectic gallium-indium, which has superior properties as a conductive ink. However, it has remained a challenge to manufacture sensors in a consistent and reproducible manner because conventional mold-based fabrication still depends highly on manual techniques. To overcome this limitation, the direct ink writing was used in this study, focusing on improving the stability of writing by exploring issues related to failure and ensuring the consistency of the microchannel by selecting appropriate process variables, including the syringe material. As a result, multiple sensors produced under the same manufacturing conditions had similar behaviors. This fabrication technique improved the accuracy of manufacturing a microchannel, and its behavior was predicted successfully by a simple mathematical model, which was confirmed by nondestructive inspections of the microchannel. In developing a one-piece glove type sensor without an assembly process, the efficiency of the fabrication technique was also emphasized. PMID- 29975585 TI - A New Spiral-Type Inflatable Pure Torsional Soft Actuator. AB - Soft robot has become a hot topic recently due to its distinct advantages over traditional rigid robots such as high deformability and good impact resistance. However, the coupled deflections of flexile materials bring challenges to soft robotic research in many aspects such as kinematic modeling, dynamic analysis, and control. Besides, unwanted deformations might enlarge external dimensions of soft robots, causing a reduction in the efficiency and bringing about unexpected or harmful contacts with surrounding environments that will significantly affect the robots' performance. In this study, we propose a new inflatable soft actuator driven by two spiral chambers twined with fibers for the first time. A key feature of this actuator is that it possesses a pure and high-efficient torsional motion with no bending and extension movements when works without load, which reduces the difficulties of theoretical analysis and control to some extent. Kinematic model is established by combining virtual work principle and elastic strain energy function for nonlinear flexible materials. The new soft torsional actuator module is carefully designed and fabricated, of which both the kinematic property and output torque are investigated experimentally. Results show that the module exhibits good linearity with air pressure ranging from 35 to 100 kPa, and can provide a torsion angle of up to 110 degrees with an angular displacement accuracy of +/-2 degrees in empty loaded conditions; the maximum output torque reaches 0.026 N.m with the corresponding air pressure of 100 kPa. Finally, three soft robots are assembled by utilizing this new, inflatable, pure, soft torsional actuator, and successfully carry out different manipulating tasks. This work might provide some insights into the design of linear soft actuators without coupled deformations in future. PMID- 29975586 TI - Linking Education to Action: A Program to Increase Research Participation Among African American Women. AB - BACKGROUND: Underrepresentation of African American women as research participants contributes to health disparities. Contemporary studies have focused on clinical trial (CT) participation; epidemiologic and genetic studies utilizing medical records and/or biological samples have received less attention. In partnership with The Links, Incorporated (The Links), a national service organization of professional African American women, this study sought to examine attitudes regarding chart review (CR) studies, genetic studies/biobanking (GEN), and CTs; develop; and evaluate an online education-to-action program. METHODS: In phase 1, focus groups were convened with members of The Links to inform the content and format of the program. Phases 2 and 3 involved designing and evaluating the program, respectively. RESULTS: Thirty-four women across three focus groups shared attitudes and perceptions regarding research and provided guidance for program development. Subsequently, 244 women completed the program (77% response rate), including pre- and post-assessments. Participants indicating that they "definitely" or "probably" (responses combined) intend to participate in research increased from 36.5% to 69.3% (pre/post-program). Agreement with the statement "research in the U.S. is ethical" increased (52.9% to 74.4%) as did factual knowledge regarding each of the study types. There was a decrease in reporting "little or no understanding" of study types (Pre/Post: GEN: 66%/24.9%, CR: 62.9%/18.4%, CTs: 40.7%/15.5%). Pre-program, few were "very positive" about the study types (14.3% GEN, 15.0% CR, 28.6% CTs); post-program ratings increased and equalized (42.8% GEN, 43.0% CR, 42.5% CTs). CONCLUSIONS: An online education to-action program targeting professional African American women improved knowledge, perceptions of ethics, and intent to participate in biomedical research. PMID- 29975587 TI - Oral and Cloacal Helicobacter Detection in Wild and Captive Orinoco Crocodiles (Crocodylus intermedius) in Venezuela. AB - Helicobacter species can colonize digestive tract of animals and humans and have been associated with gastrointestinal diseases; however, this genus has not been studied in crocodiles. Our objective was to detect by PCR Helicobacter genus and Helicobacter pylori in oral and cloacal swabs from Orinoco crocodiles of two wild (Cojedes River System and Capanaparo River) and two captive breeding centers (CBCs; Masaguaral Ranch and UNELLEZ) populations. Bacterial DNA was found in 100% of oral samples (10 wild and 10 captives), and in the 95% of cloacal samples (10 wild and 9 captives). In wild populations, Helicobacter spp. was not detected, whereas in CBCs, Helicobacter was detected in 10% of the oral samples, and 66.7% of cloacal samples. H. pylori was detected in two Orinoco crocodiles. Two cloacal non-pylori Helicobacter amplicons were sequenced, showing low similarity (<=97%) to Helicobacter sequences reported. This is the first report of Helicobacter species, including H. pylori in Crocodylus intermedius from CBCs. PMID- 29975588 TI - Physiological comparison of intensity-controlled, isocaloric intermittent and continuous exercise. AB - VO2 fluctuations are argued to be an important mechanism underpinning chronic adaptations following interval training. We compared the effect of exercise modality, continuous vs. intermittent realized at a same intensity, on electrical muscular activity, muscular oxygenation and on whole body oxygen uptake. Twelve participants (24 +/- 5 years; VO2peak: 43 +/- 6 mL. min-1.kg-1) performed (i) an incremental test to exhaustion to determine peak work rate (WRpeak); two randomized isocaloric exercises at 70%WRpeak; (ii) 1 bout of 30 min; (iii) 30 bouts of 1 min work intercepted with 1 min passive recovery. For electromyography, only the CON exercise showed change for the vastus lateralis root-mean-square (+6.4 +/- 5.1%, P < .01, 95%CI 3.2, 8.3) and mean power frequency (-5.2 +/- 4.8, P < .01, 95%CI -8.2, -3.5). Metabolic fluctuations (i.e. Oxygen Fluctuation Index and HHb Fluctuation Index) were higher in the intermittent modality, while post-exercise blood lactate concentrations (4.80 +/- 1.50 vs. 2.32 +/- 1.21 mM, respectively, for the CON and INT, P < .01, 95%CI 1.72, 3.12) and the time spent over 90% of VO2 target (1644 +/- 152 vs. 356 +/- 301 sec, respectively, for the CON and INT, P < .01, 95%CI 1130, 1446) were higher in the continuous modality. In conclusion, despite a similar energy expenditure and intensity, intermittent and continuous exercises showed two very different physiological responses. The intermittent modality would lead to a larger recruitment of fast twitch fibres that are less mitochondria-equipped and therefore may be more likely respondent to mitochondrial adaptations. In addition, this modality induces greater metabolic variations, a stimulus who could lead to mitochondrial development. PMID- 29975589 TI - Immune nutrition and exercise: Narrative review and practical recommendations. AB - Evidence suggests that periods of heavy intense training can result in impaired immune cell function, and whether this leaves elite athletes at greater risk of infections and upper respiratory symptoms (URS) is still debated. There is some evidence that episodes of URS do cluster around important periods of competition and intense periods of training. Since reducing URS, primarily from an infectious origin, may have implications for performance, a large amount of research has focused on nutritional strategies to improve immune function at rest and in response to exercise. Although there is some convincing evidence that meeting requirements of high intakes in carbohydrate and protein and avoiding deficiencies in nutrients such as vitamin D and antioxidants is integral for optimal immune health, well-powered randomised controlled trials reporting improvements in URS beyond such intakes are lacking. Consequently, there is a need to first understand whether the nutritional practices adopted by elite athletes increases their risk of URS. Second, promising evidence in support of efficacy and mechanisms of immune-enhancing nutritional supplements (probiotics, bovine colostrum) on URS needs to be followed up with more randomised controlled trials in elite athletes with sufficient participant numbers and rigorous procedures with clinically relevant outcome measures of immunity. PMID- 29975590 TI - Regulation of Sexual Commitment and Gametocytogenesis in Malaria Parasites. AB - Sexual differentiation of malaria parasites from the asexual blood stage into gametocytes is an essential part of the life cycle, as gametocytes are the form that is taken up by the mosquito host. Because of the essentiality of this process for transmission to the mosquito, gametocytogenesis is an extremely attractive target for therapeutic interventions. The subject of this review is the considerable progress that has been made in recent years in elucidating the molecular mechanisms governing this important differentiation process. In particular, a number of critical transcription factors and epigenetic regulators have emerged as crucial elements in the regulation of commitment. The identification of these factors has allowed us to understand better than ever before the events occurring prior to and during commitment to sexual development and offers potential for new therapeutic interventions. PMID- 29975591 TI - Blindness and Human Brain Plasticity. AB - Early blindness causes fundamental alterations of neural function across more than 25% of cortex-changes that span the gamut from metabolism to behavior and collectively represent one of the most dramatic examples of plasticity in the human brain. The goal of this review is to describe how the remarkable behavioral and neuroanatomical compensations demonstrated by blind individuals provide insights into the extent, mechanisms, and limits of human brain plasticity. PMID- 29975593 TI - Considerations for the governance of gene drive organisms. AB - Governance is a broader and more flexible concept than statute-driven regulations as it incorporates components outside the latter's remit. Considerations of governance are critical in the development of emerging biotechnologies such as gene drive organisms. These have been proposed or are being developed to address public and environmental health issues not addressed easily by conventional means. Here, we consider how the concept of governance differs from statute driven regulation with reference to the role each may play in the development of gene drive organisms. First, we discuss existing statute-based regulatory systems. Second, we consider whether novel risks or different concerns derive from gene drive organisms, concentrating on characteristics that contribute to public health or environmental risk and uncertainties that may affect risk perceptions. Third, we consider public engagement, outlining how existing statute driven regulatory systems and other governance mechanisms may provide opportunities for constructive interactions. Finally, we provide some observations that may help address science- and values-based concerns in a governance space larger than that of statute-driven regulatory systems. PMID- 29975594 TI - Should Waist Circumference Cutoffs in the Context of Cardiometabolic Risk Factor Assessment be Specific to Sex, Age, and BMI? AB - OBJECTIVE: A sex-specific standard waist circumference (WC) is widely used to determine cardiometabolic risk across ages even though aging impacts the link between fat distribution and cardiometabolic risk. The objective was to propose WC thresholds that better predict metabolic abnormalities according to sex, age, and body mass index (BMI) categories. METHODS: First, receiver operating characteristic analyses were performed to identify optimal age (20-49, 50-64, and 65-80 years) and BMI (normal weight, overweight, obese I, and obese II+) specific WC thresholds to correctly identify at-risk individuals, that is, presenting >=2 cardiometabolic risk factors of metabolic syndrome (n = 23,482; NHANES 2007 2014). Second, cross-validation analyses (n = 18,686; NHANES 1999-2006) were used to validate these WC optimal thresholds. Univariate logistic regression models with WC as an independent predictor were performed to quantify odds of being at risk for each age and BMI subgroups. RESULTS: When age and BMI categories were considered in the identification of optimal WC thresholds, sensitivity to correctly identify at-risk individuals significantly improved. CONCLUSIONS: Our results indicate that the use of WC thresholds that are specific to age and BMI subcategories significantly increases the capacity to accurately identify at-risk individuals. They would thus be highly appropriate for clinicians in the context of efficient cardiometabolic risk assessment and intervention recommendations. PMID- 29975592 TI - Linking V1 Activity to Behavior. AB - A long-term goal of visual neuroscience is to develop and test quantitative models that account for the moment-by-moment relationship between neural responses in early visual cortex and human performance in natural visual tasks. This review focuses on efforts to address this goal by measuring and perturbing the activity of primary visual cortex (V1) neurons while nonhuman primates perform demanding, well-controlled visual tasks. We start by describing a conceptual approach-the decoder linking model (DLM) framework-in which candidate decoding models take neural responses as input and generate predicted behavior as output. The ultimate goal in this framework is to find the actual decoder-the model that best predicts behavior from neural responses. We discuss key relevant properties of primate V1 and review current literature from the DLM perspective. We conclude by discussing major technological and theoretical advances that are likely to accelerate our understanding of the link between V1 activity and behavior. PMID- 29975595 TI - Minimally Invasive Surgical Approach for Posterior Tracheopexy to Treat Severe Tracheomalacia: Lessons Learned from Initial Case Series. AB - BACKGROUND/PURPOSE: Posterior tracheopexy directly addresses membranous tracheal intrusion in severe tracheomalacia (TM). We have previously reported our experience of posterior tracheopexy through open approach in a large series of patients. This study aimed to review lessons learned from our initial series posterior tracheopexy through the video-assisted or robotic video-assisted thoracoscopic approach. METHODS: We retrospectively reviewed our single institution experience on all patients who underwent video-assisted or robotic video-assisted posterior tracheopexy for treatment of symptomatic TM between October 2016 and February 2018. RESULTS: Ten patients underwent video-assisted (n = 4) or robotic video-assisted (n = 6) thoracoscopic posterior tracheopexy (age range: 8 months-19 years). One patient, the youngest in our cohort, had a type C esophageal atresia repair; none of the other patients had undergone prior thoracic operations. All had symptomatic TM; 1 patient with tracheostomy dependence also had severe distal bronchomalacia, including segmental airways. Postoperatively, patients were hospitalized 3-7 days, with 1-2 days for ICU observation. Improved respiratory symptoms were noted in 9/10 patients following the operation. The 1 patient with preexisting tracheostomy had reduced ventilator dependence but remained hospitalized with ongoing respiratory symptoms. CONCLUSIONS: The thoracoscopic approach for posterior tracheopexy, while challenging, can be applied to a select cohort of children with severe TM. Thoracoscopic surgery with robotic assistance can eliminate some technical limitations of the video-assisted approach by providing an easier platform for more complicated suturing angles. PMID- 29975596 TI - Projected Behavioral Impacts of Global Climate Change. AB - The projected behavioral impacts of global climate change emanate from environmental changes including temperature elevation, extreme weather events, and rising air pollution. Negative affect, interpersonal and intergroup conflict, and possibly psychological distress increase with rising temperature. Droughts, floods, and severe storms diminish quality of life, elevate stress, produce psychological distress, and may elevate interpersonal and intergroup conflict. Recreational opportunities are compromised by extreme weather, and children may suffer delayed cognitive development. Elevated pollutants concern citizens and may accentuate psychological distress. Outdoor recreational activity is curtailed by ambient pollutants. Limitations and issues in need of further investigation include the following: lack of data on direct experience with climate change rather than indirect assessments related to projected changes; poor spatial resolution in environmental exposures and behavioral assessments; few rigorous quasi-experimental studies; overreliance on self-reports of behavioral outcomes; little consideration of moderator effects; and scant investigation of underlying psychosocial processes to explain projected behavioral impacts. Expected final online publication date for the Annual Review of Psychology Volume 70 is January 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 29975597 TI - Educational Disparities in Risk for Metabolic Syndrome. AB - BACKGROUND: The objective of this study was to evaluate the relationship between educational level as a surrogate marker of socioeconomic status and the risk of developing metabolic syndrome (MetS). METHODS: Study subjects were 1915 Korean adults (1193 women and 722 men) who participated in a cohort study. Educational level was categorized into two groups: (1) high education (more than 12 years of education), and (2) low education (less than 12 years of education). MetS was defined according to diagnostic criteria of the National Cholesterol Education Program (NCEP-III) and the International Diabetes Federation (IDF). Multiple logistic regression analysis and Cox proportional hazard analysis were performed to evaluate cross-sectional and prospective association between MetS or MetS components and educational level after adjusting for covariates. RESULTS: The overall prevalence of MetS at baseline was 15.0% in women and 20.4% in men. Incidence of MetS over 4.52 years was 16.6 per 1000 person-year in women and 27.6 per 1000 person-year in men. The prevalence and incidence of MetS were higher in the low educational group than those in the high educational group in both sexes. At baseline, the risk of MetS (odds ratio [OR]: 1.63, 95% confidence interval [CI]: 1.05-2.53 for NCEP criteria; OR: 2.30, 95% CI: 1.41-3.76 for IDF criteria) and abdominal obesity (OR: 2.62, 95% CI: 1.75-3.93) were higher in less educated women compared with those in more educated women. In men, there was no association between Mets or MetS components and educational level. Over 4.6 years of follow-up, the risk of developing MetS in women in the low education group (hazard ratio [HR]: 1.95, 95% CI: 1.12-3.50 for NCEP criteria; HR: 2.36, 95% CI: 1.14-4.86 for IDF criteria) was significantly higher than that in the high education group. In men, low education significantly increased the risk of developing impaired fasting glucose (HR: 1.95, 95% CI: 1.12-3.40). CONCLUSION: An inverse association between educational level and MetS was found in Korean women, suggesting that socioeconomic disparities might increase the risk of MetS development, especially in women. PMID- 29975598 TI - Analysis of Exposure to Solar and Galactic Cosmic Radiations of Flights Representative of the European International Air Traffic. AB - This study analyzed the impact of galactic and solar cosmic rays on ambient dose equivalent during airline travel. A high statistic of flights are considered, which is representative of European international air traffic. Flight paths are based on the Eurocontrol Demand Data Repository and consider realistic flight plans with and without regulations or updated with radar data from the Central Flow Management Unit. Ambient dose equivalent during flights was investigated during quiet solar periods and extreme solar flare events. Thus, the statistical analyses presented here take into account route characteristics (departure, arrival, continent, etc.) and space weather conditions. The findings of this work show the important influence of flight path, particularly the latitude, which drives the cutoff rigidity variations. Moreover, dose values vary drastically during ground level enhancement events, with the route path (latitude, longitude and altitude) and the phasing of the solar event. This study highlights the importance of monitoring these solar events and developing a physical approach to obtain reliable assessment of ambient dose equivalents. PMID- 29975599 TI - Intensity of End-of-Life Care for Patients with Hematologic Malignancies and the Role of Race/Ethnicity. AB - BACKGROUND: Racial/ethnic minority patients with nonhematologic malignancies (non HM) have lower rates of hospice care, advance directive use, and palliative care utilization than non-Hispanic white (NHW) patients. Less is known regarding racial/ethnic minority patients with hematologic malignancies (HM). OBJECTIVES: To study hospital utilization among racial/ethnic minority patients with HM and compare end-of-life outcome measures to patients with non-HM. METHODS: We performed a retrospective cohort study (2010-2015) using electronic health records from an integrated academic health center to study differences in hospital utilization patterns and documentation of advance care planning between patients with HM and non-HM. In the subgroup with hematologic malignancy, we examined outcomes associated with racial/ethnic minority status. RESULTS: Among all patients in the last 30 days of life, those with HM had higher rates of inpatient care (odds ratio [OR], 1.96; 95% CI: 1.74-2.20; p < 0.001) and intensive care unit (ICU) care (OR, 3.50; 95% CI: 3.05-4.03; p < 0.001). Patients with HM were more likely to die in a hospital (OR, 2.75; 95% CI: 2.49-3.04; p < 0.001) than those with non-HM. Furthermore, during the last 30 days of life, among patients with HM, racial/ethnic minority patients were more likely to have more than one emergency room visit (OR, 6.81; 95% CI: 1.34-33.91; p = 0.02), 14+ days of inpatient care (OR, 1.60; 95% CI: 1.08-2.35; p = 0.02), longer stays in the ICU (OR, 1.26; 95% CI: 1.04-1.52; p = 0.02), and lower rates of advance directive documentation (OR, 0.60; 95% CI: 0.44-0.82; p < 0.01) than NHWs. CONCLUSION: Our findings suggest that racial/ethnic minority patients with HM have higher utilization of care at the end-of-life and lower rates of advance directives compared with NHW patients. PMID- 29975601 TI - Effect of quantity and quality of pre-exercise carbohydrate meals on central fatigue. AB - Both the quantity and quality of pre-exercise carbohydrate (CHO) meals have been shown to improve endurance performance. However, their role in attenuating central fatigue (CF) is inconclusive. The use of neurophysiological techniques, such as voluntary activation (VA) and the central activation ratio (CAR), alongside maximum voluntary contraction (MVC) and sustained MVC (sMVC) can provide information on CF. Hence, the objective of this study was to investigate the effects of isocaloric pre-exercise meals: 1) a high versus low quantity of CHO and 2) a high quantity of CHO with a high versus low glycemic index (GI) on MVC, VA, and CAR following a 90-min run. The high and low quantity of CHO was 1.5 and 0.8 g/kg body wt, respectively, and high and low GI was ~75 and ~40, respectively. Blood insulin, serotonin, tryptophan, and gaseous exchange were also measured. High CHO preserved sMVC, VA, CAR, and serotonin postrunning with greater CHO oxidation and insulin response, whereas in low CHO, greater reductions in sMVC, VA, and CAR were accompanied by higher serotonin and fat oxidation with lower insulin response. These observations indicate central involvements. Meanwhile, high GI CHO better preserved force (sMVC), CAR, and tryptophan with greater CHO oxidation and insulin response compared with low GI. The findings of this study suggest that pre-exercise meals with varying quantity and quality of CHO can have an effect on CF, where greater CHO oxidation and insulin response found in both high CHO and high GI lead to attenuation of CF. NEW & NOTEWORTHY This paper examined the effects of carbohydrate interventions (high and low: quantity and quality wise) on central activity during prolonged exercise using mainly neurophysiological techniques along with gaseous exchange and blood insulin, serotonin, and tryptophan data. PMID- 29975600 TI - Exercise preconditioning diminishes skeletal muscle atrophy after hindlimb suspension in mice. AB - The aim of the present study was to investigate whether short-term, concurrent exercise training before hindlimb suspension (HLS) prevents or diminishes both soleus and gastrocnemius atrophy and to analyze whether changes in mitochondrial molecular markers were associated. Male C57BL/6 mice were assigned to control at 13 +/- 1 wk of age, 7-day HLS at 12 +/- 1 wk of age (HLS), 2 wk of exercise training before 7-day HLS at 10 +/- 1 wk of age (Ex+HLS), and 2 wk of exercise training at 11 +/- 1 wk of age (Ex) groups. HLS resulted in a 27.1% and 21.5% decrease in soleus and gastrocnemius muscle weight-to-body weight ratio, respectively. Exercise training before HLS resulted in a 5.6% and 8.1% decrease in soleus and gastrocnemius weight-to-body weight ratio, respectively. Exercise increased mitochondrial biogenesis- and function-associated markers and slow myosin heavy chain (SMHC) expression, and reduced fiber-type transitioning marker myosin heavy chain 4 (Myh4). Ex+HLS revealed decreased reactive oxygen species (ROS) and oxidative stress compared with HLS. Our data indicated the time before an atrophic setting, particularly caused by muscle unloading, may be a useful period to intervene short-term, progressive exercise training to prevent skeletal muscle atrophy and is associated with mitochondrial biogenesis, function, and redox balance. NEW & NOTEWORTHY Mitochondrial dysfunction is associated with disuse-induced skeletal muscle atrophy, whereas exercise is known to increase mitochondrial biogenesis and function. Here we provide evidence of short-term concurrent exercise training before an atrophic event protecting skeletal muscle from atrophy in two separate muscles with different, dominant fiber-types, and we reveal an association with the adaptive changes of mitochondrial molecular markers to exercise. PMID- 29975602 TI - Acquisition of motor memory determines the interindividual variability of learning-induced plasticity in the primary motor cortex. AB - Acquisition of new motor skills induces plastic reorganization in the primary motor cortex (M1). Previous studies have demonstrated the increases in the M1 excitability through motor skill learning. However, this M1 reorganization is highly variable between individuals even though they improve their skill performance through the same training protocol. To reveal the source of this interindividual variability, we examined the relationship between an acquisition of memory-guided feedforward movements and the learning-induced increases in the M1 excitability. Twenty-eight subjects participated in experiment 1. We asked subjects to learn a visuomotor tracking task. The subjects controlled a cursor on a PC monitor to pursue a target line by performing ankle dorsiflexion and plantar flexion. In experiment 1, we removed the online visual feedback provided by the cursor movement once every six trials, which enabled us to assess whether the subjects could perform accurate memory-guided movements. Motor-evoked potentials (MEP) were elicited in the tibialis anterior muscle by transcranial magnetic stimulation of the relevant M1 before and after the learning of the visuomotor tracking task and after half the trials. We found that the MEP amplitude was increased along with the improvement in memory-guided movements. In experiment 2 ( n = 10), we confirmed this relationship by examining whether the improvement in memory-guided movements induces increases in MEP amplitude. The results of this study indicate that the plastic reorganization of the M1 induced by the learning of a visuomotor skill is associated with the acquisition of memory-guided movements. NEW & NOTEWORTHY Acquisition of novel motor skills increases excitability of the primary motor cortex (M1). We recently reported that the amount of increases in the M1 excitability is highly variable between individuals even though they learned the same skill to the similar extent, yet the sources of this interindividual variability still remain unclear. The present study revealed that this interindividual variability is associated with whether individuals acquire a motor memory, which enables them to produce accurate memory-guided movements. PMID- 29975603 TI - Coordination of hamstrings is individual specific and is related to motor performance. AB - The torque-sharing strategies between synergistic muscles may have important functional consequences. This study involved two experiments. The first experiment ( n = 22) aimed 1) to determine the relationship between the distribution of activation and the distribution of torque-generating capacity among the heads of the hamstring, and 2) to describe individual torque-sharing strategies and to determine whether these strategies are similar between legs. The second experiment ( n = 35) aimed to determine whether the distribution of activation between the muscle heads affects endurance performance during a sustained submaximal knee flexion task. Surface electromyography (EMG) was recorded from biceps femoris (BF), semimembranosus (SM), and semitendinosus (ST) during submaximal isometric knee flexions. Torque-generating capacity was estimated by measuring muscle volume, fascicle length, pennation angle, and moment arm. The product of the normalized EMG amplitude and the torque-generating capacity was used as an index of muscle torque. The distributions of muscle activation and of torque-generating capacity were not correlated significantly (all P > 0.18). Thus, there was a torque imbalance between the muscle heads (ST torque > BF and SM torque; P < 0.001), the magnitude of which varied greatly between participants. A significant negative correlation was observed between the imbalance of activation across the hamstring muscles and the time to exhaustion ( P < 0.001); i.e., the larger the imbalance of activation across muscles, the lower the muscle endurance performance. Torque-sharing strategies between the heads of the hamstrings are individual specific and related to muscle endurance performance. Whether these individual strategies play a role in hamstring injury remains to be determined. NEW & NOTEWORTHY The distribution of activation among the heads of the hamstring is not related to the distribution of torque generating capacity. The torque-sharing strategies within hamstring muscles vary greatly between individuals but are similar between legs. Hamstring coordination affects endurance performance; i.e., the larger the imbalance of activation across the muscle heads, the lower the muscle endurance. PMID- 29975604 TI - The Central Nervous System Modulates the Neuromechanical Delay in a Broad Range for the Control of Muscle Force. AB - Force is generated by muscle units according to the neural activation sent by motor neurons. The motor unit is therefore the interface between the neural coding of movement and the musculotendinous system. Here we propose a method to accurately measure the latency between an estimate of the neural drive to muscle and force. Further, we systematically investigate this latency, that we refer to as the neuromechanical delay (NMD), as a function of the rate of force generation. In two experimental sessions, eight men performed isometric finger abduction and ankle dorsiflexion sinusoidal contractions at three frequencies and peak-to-peak amplitudes [0.5,1,1.5 (Hz); 1,5,10 of maximal force (%MVC)], with a mean force of 10% MVC. The discharge timings of motor units of the first dorsal interosseous (FDI) and tibialis anterior (TA) muscle were identified by high density surface EMG decomposition. The neural drive was estimated as the cumulative discharge timings of the identified motor units. The neural drive predicted 80 +/- 0.4% of the force fluctuations and consistently anticipated force by 194.6 +/- 55 ms (average across conditions and muscles). The NMD decreased non-linearly with the rate of force generation (R2 = 0.82 +/- 0.07; exponential fitting) with a broad range of values (from 70 to 385 ms) and was 66 +/- 0.01 ms shorter for the FDI than TA (P<0.001). In conclusion, we provided a method to estimate the delay between the neural control and force generation and we showed that this delay is muscle-dependent and is modulated within a wide range by the central nervous system. PMID- 29975605 TI - Interindividual and regional relationship between cerebral blood flow and glucose metabolism in the resting brain. AB - Studies of the resting brain measurements of cerebral blood flow (CBF) show large interindividual and regional variability, but the metabolic basis of this variability is not fully established. The aim of the present study was to reassess regional and interindividual relationships between cerebral perfusion and glucose metabolism in the resting brain. Regional quantitative measurements of CBF and cerebral metabolic rate of glucose (CMRglc) were obtained in 24 healthy young men using dynamic [15O]H2O and [18F]fluorodeoxyglucose positron emission tomography (PET). Magnetic resonance imaging measurements of global oxygen extraction fraction (gOEF) and metabolic rate of oxygen ([Formula: see text]) were obtained by combined susceptometry-based sagittal sinus oximetry and phase contrast mapping. No significant interindividual associations between global CBF, global CMRglc, and [Formula: see text] were observed. Linear mixed model analysis showed a highly significant association of CBF with CMRglc regionally. Compared with neocortex significantly higher CBF values than explained by CMRglc were demonstrated in infratentorial structures, thalami, and mesial temporal cortex, and lower values were found in the striatum and cerebral white matter. The present study shows that absolute quantitative global CBF measurements appear not to be a valid surrogate measure of global cerebral glucose or oxygen consumption, and further demonstrates regionally variable relationship between perfusion and glucose metabolism in the resting brain that could suggest regional differences in energy substrate metabolism. NEW & NOTEWORTHY Using method-independent techniques the study cannot confirm direct interindividual correlations of absolute global values of perfusion with oxygen or glucose metabolism in the resting brain, and absolute global perfusion measurements appear not to be valid surrogate measures of cerebral metabolism. The ratio of both perfusion and oxygen delivery to glucose metabolism varies regionally, also when accounting for known methodological regional bias in quantification of glucose metabolism. PMID- 29975606 TI - Lessons from the Incursion of Myrtle Rust in Australia. AB - Austropuccinia psidii (myrtle rust) is a globally invasive neotropical rust of the Myrtaceae that came into international prominence following extensive damage to exotic Eucalyptus plantations in Brazil in the 1970s and 1980s. In 2005, myrtle rust established in Hawaii (USA), and over the past 12 years has spread from the Americas into Asia, the Pacific, and South Africa. Myrtle rust was detected in Australia in 2010, and the response and ultimately unsuccessful eradication attempt was a lesson to those concerned about the threat of exotic pests and diseases to Australia's environment. Seven years following establishment, we are already observing the decline of many myrtaceous species and severe impacts to native plant communities. However, the recently developed Myrtle rust in Australia draft action plan identified that there is no nationally coordinated response strategy for the environmental dimensions of this threat. Recent reviews have identified a greater need for involvement from environmental agencies in biosecurity preparedness, response, and resourcing, and we believe this approach needs to extend to the management of invasive environmental pathogens once they establish. PMID- 29975607 TI - CRISPR Crops: Plant Genome Editing Toward Disease Resistance. AB - Genome editing by sequence-specific nucleases (SSNs) has revolutionized biology by enabling targeted modifications of genomes. Although routine plant genome editing emerged only a few years ago, we are already witnessing the first applications to improve disease resistance. In particular, CRISPR-Cas9 has democratized the use of genome editing in plants thanks to the ease and robustness of this method. Here, we review the recent developments in plant genome editing and its application to enhancing disease resistance against plant pathogens. In the future, bioedited disease resistant crops will become a standard tool in plant breeding. PMID- 29975608 TI - Wheat Blast: Past, Present, and Future. AB - The devastating wheat blast disease first emerged in Brazil in 1985. The disease was restricted to South America until 2016, when a series of grain imports from Brazil led to a wheat blast outbreak in Bangladesh. Wheat blast is caused by Pyricularia graminis-tritici ( Pygt), a species genetically distinct from the Pyricularia oryzae species that causes rice blast. Pygt has high genetic and phenotypic diversity and a broad host range that enables it to move back and forth between wheat and other grass hosts. Recombination is thought to occur mainly on the other grass hosts, giving rise to the highly diverse Pygt population observed in wheat fields. This review brings together past and current knowledge about the history, etiology, epidemiology, physiology, and genetics of wheat blast and discusses the future need for integrated management strategies. The most urgent current need is to strengthen quarantine and biosafety regulations to avoid additional spread of the pathogen to disease-free countries. International breeding efforts will be needed to develop wheat varieties with more durable resistance. PMID- 29975609 TI - Understanding Cytoskeletal Dynamics During the Plant Immune Response. AB - The plant cytoskeleton is a dynamic framework of cytoplasmic filaments that rearranges as the needs of the cell change during growth and development. Incessant turnover mechanisms allow these networks to be rapidly redeployed in defense of host cytoplasm against microbial invaders. Both chemical and mechanical stimuli are recognized as danger signals to the plant, and these are perceived and transduced into cytoskeletal dynamics and architecture changes through a collection of well-recognized, previously characterized players. Recent advances in quantitative cell biology approaches, along with the powerful molecular genetics techniques associated with Arabidopsis, have uncovered two actin-binding proteins as key intermediaries in the immune response to phytopathogens and defense signaling. Certain bacterial phytopathogens have adapted to the cytoskeletal-based defense mechanism during the basal immune response and have evolved effector proteins that target actin filaments and microtubules to subvert transcriptional reprogramming, secretion of defense related proteins, and cell wall-based defenses. In this review, we describe current knowledge about host cytoskeletal dynamics operating at the crossroads of the molecular and cellular arms race between microbes and plants. PMID- 29975610 TI - Advance Care Planning: Senior Center Members' Perceptions of a Death Over Dinner Event. PMID- 29975611 TI - Not Your Grandma's Advance Care Planning: Preparing (Ourselves) for a Systems Based Approach. PMID- 29975612 TI - Grieve and Light a Virtual Candle. PMID- 29975613 TI - Development and Pilot Testing of a Motivational Interview for Engagement in Advance Care Planning. PMID- 29975614 TI - Competence and Its Conundrums: A Call for Clinical Wisdom. PMID- 29975615 TI - Dream of a Dying Man. PMID- 29975616 TI - The Night of 1000 Stevies. PMID- 29975617 TI - You Poor Thing. PMID- 29975618 TI - The Group: Seven Widowed Fathers Reimagine Life. PMID- 29975619 TI - Potential Technology Development for Palliative Care. PMID- 29975620 TI - Deprescribing and Tapering Benzodiazepines #355. PMID- 29975621 TI - Deprescribing Cholinesterase Inhibitors at the End of Life #354. PMID- 29975622 TI - Ten Tips Palliative Care Pharmacists Want the Palliative Care Team to Know When Caring for Patients. AB - As palliative care (PC) moves upstream in the course of serious illness and the development of drugs and their indications rapidly expand, PC providers must understand common drug indications and adverse effects to ensure safe and effective prescribing. Pharmacists, experts in the nuances of medication management, are valuable resources and colleagues for PC providers. This article will offer PC providers 10 useful clinical pharmacy tips that PC pharmacists think all PC providers should know for safe and effective symptom management. Close collaboration with or addition of a trained pharmacist to your PC team can improve clinical care for all PC patients. PMID- 29975623 TI - Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. AB - PURPOSE: Follicular lymphoma (FL) is curable by involved-field radiotherapy (IFRT) in < 50% of patients with stage I to II disease. We hypothesized that adding systemic therapy to IFRT would improve long-term progression-free survival (PFS). PATIENTS AND METHODS: A multicenter randomized controlled trial enrolled patients with stage I to II low-grade FL after staging computed tomography scans and bone marrow biopsies. 18F-labeled fluorodeoxyglucose-positron emission tomography (PET) was not mandatory. Patients were randomly assigned to either arm A (30 Gy IFRT alone) or arm B (IFRT plus six cycles of cyclophosphamide, vincristine, and prednisolone [CVP]). From 2006, rituximab was added to arm B (R CVP). RESULTS: Between 2000 and 2012, 150 patients were enrolled, 75 per arm. In arm B, 44 patients were allocated to receive CVP and 31 were allocated to receive R-CVP. At randomization, 75% had stage I, the median age was 57 years, 52% were male, and 48% were PET staged. With a median follow-up of 9.6 years (range, 3.1 to 15.8 years), PFS was superior in arm B (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = .033). Ten-year PFS rates were 59% (95% CI, 46% to 74%) and 41% (95% CI, 30% to 57%) for arms B and A, respectively. Patients in arm B who received R CVP had markedly superior PFS compared with contemporaneous patients in arm A (hazard ratio, 0.26; 95% CI, 0.07 to 0.97; P = .045). Fewer involved regions ( P = .047) and PET staging ( P = .056) were associated with better PFS. Histologic transformation occurred in four and 10 patients in arms B and A, respectively ( P = .1). Ten deaths occurred in arm A versus five in arm B, but overall survival was not significantly different ( P = .40; 87% and 95% at 10 years, respectively). CONCLUSION: Systemic therapy with R-CVP after IFRT reduced relapse outside radiation fields and significantly improved PFS. IFRT followed by immunochemotherapy is more effective than IFRT in early-stage FL. PMID- 29975624 TI - Progression-Free Survival as a Surrogate End Point for Overall Survival in First Line Diffuse Large B-Cell Lymphoma: An Individual Patient-Level Analysis of Multiple Randomized Trials (SEAL). AB - Purpose Overall survival (OS) is the definitive and best-established primary efficacy end point to evaluate diffuse large B-cell lymphoma (DLBCL) therapies, but it requires prolonged follow-up. An earlier end point assessed post-treatment would expedite clinical trial conduct and accelerate patient access to effective new therapies. Our objective was to formally evaluate progression-free survival (PFS) and PFS at 24 months (PFS24) as surrogate end points for OS in first-line DLBCL. Patients and Methods Individual patient data were analyzed from 7,507 patients from 13 multicenter randomized controlled trials of active treatment in previously untreated DLBCL, published after 2002, with sufficient PFS data to predict treatment effects on OS. Trial-level surrogacy examining the correlation of treatment effect estimates of PFS/PFS24 and OS was evaluated using both linear regression ( R2WLS) and Copula bivariable ( R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula >= 0.80 and neither < 0.7, with lower-bound 95% CI > 0.60. Results Trial-level surrogacy for PFS was strong ( R2WLS = 0.83; R2Copula = 0.85) and met the predefined criteria for surrogacy. At the patient level, PFS strongly correlated with OS. The surrogate threshold effect had a hazard ratio of 0.89. Surrogacy was consistent across comparisons with or without rituximab and with rituximab maintenance trials. Trial-level surrogacy for PFS24 was relatively strong ( R2WLS = 0.77; R2Copula = 0.78) but did not meet prespecified criteria. At the patient level, PFS24 significantly correlated with OS. The surrogate threshold effect had an odds ratio of 1.51. Conclusion This large pooled analysis of individual patient data supports PFS as a surrogate end point for OS in future randomized controlled trials evaluating chemoimmunotherapy in DLBCL. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before OS results are mature. PMID- 29975626 TI - Bactibilia in women affected with diseases of the biliary tract and pancreas. A STROBE guidelines-adherent cross-sectional study in Southern Italy. AB - PURPOSE: Bile is a hepatobiliary lipid-rich sterile solution, and its colonization by microorganisms defines the condition of bactibilia. In this study, we aimed to assess the bile microbiological flora and its potential link with comorbidity in women. METHODOLOGY: We performed a microbiologic investigation on 53 female patients with biliopancreatic diseases who granted consent, and we analysed the data using a MATLAB platform. RESULTS: We found that the most frequent disease associated with bactibilia was pancreas head carcinoma (PHC) (P=0.0015), while the least frequent disease was gall bladder carcinoma (GBC) (P=0.0002). The most common microorganisms were Pseudomonas spp. (P<0.0001) and Escherichia coli (P<0.0001). In particular Pseudomonas spp. and E. coli were negatively correlated to PHC presence and positively correlated to CCA by both univariate and multivariate analysis. CONCLUSIONS: Gram-negative bacteria have been linked to a tumour-associated inflammatory status. In the last 30 years, the analysis of mortality rate in Italy for PHC and GBC shows an increasing and a decreasing trend, respectively. Although this study targeted only 53 patients and does not reflect the frequency of diagnosis in a Southern Italian population, the decrease in GBC may raise the suggestion ofnon-adherence to a Mediterranean diet that may have become more prevalent in Southern Italy since the 1990s. PMID- 29975628 TI - Transport of AOPP-Albumin into Human Alveolar Epithelial A549 Cell. AB - PURPOSE: Alveolar clearance of proteins, such as albumin, plays an essential role in recovery from lung injuries. Albumin is known to be oxidized by reactive oxygen species (ROS), leading to generation of advanced oxidation protein products (AOPP)-albumin in the alveolar lining fluid. In this study, we aimed to characterize the uptake of FITC-labeled AOPP-albumin (FITC-AOPP-albumin) into human alveolar epithelial cell line, A549. METHODS: FITC-AOPP-albumin uptake into A549 cells and its effect of ROS generation was evaluated using fluorescence spectrometer and flow cytometry, respectively. RESULTS: FITC-AOPP-albumin was taken up by A549 cells in a time- and temperature-dependent fashion, and showed saturation kinetics with a Km value of 0.37 mg/mL. The uptake of FITC-AOPP albumin was suppressed by phenylarsine oxide, a clathrin-mediated endocytosis inhibitor, but not by indomethacin and nystatin, caveolae-mediated endocytosis inhibitors, or 5-(N-ethyl-N-isopropyl) amiloride, a macropinocytosis inhibitor. AOPP-albumin induced ROS generation in A549 cells, suggesting that alveolar clearance of AOPP-albumin should be important to prevent further ROS generation. CONCLUSION: AOPP-albumin is transported into alveolar epithelial cells through clathrin-mediated endocytosis, which may be important to prevent further ROS generation. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29975627 TI - Fluoroquinolone resistance in Salmonella: insights by whole-genome sequencing. AB - Fluoroquinolone (FQ)-resistant Salmonella spp. were listed by the WHO in 2017 as priority pathogens for which new antibiotics were urgently needed. The overall global burden of Salmonella infections is high, but differs per region. Whereas typhoid fever is most prevalent in South and South-East Asia, non-typhoidal salmonellosis is prevalent across the globe and associated with a mild gastroenteritis. By contrast, invasive non-typhoidal Salmonella cause bloodstream infections associated with high mortality, particularly in sub-Saharan Africa. Most Salmonella strains from clinical sources are resistant to first-line antibiotics, with FQs now being the antibiotic of choice for treatment of invasive Salmonella infections. However, FQ resistance is increasingly being reported in Salmonella, and multiple molecular mechanisms are already described. Whole-genome sequencing (WGS) is becoming more frequently used to analyse bacterial genomes for antibiotic-resistance markers, and to understand the phylogeny of bacteria in relation to their antibiotic-resistance profiles. This mini-review provides an overview of FQ resistance in Salmonella, guided by WGS studies that demonstrate that WGS is a valuable tool for global surveillance. PMID- 29975629 TI - Effect of a two-day extensive continuing medical education course on participants' knowledge of clinical and operative urology. AB - OBJECTIVE: Continuing Medical Education (CME) is an established method for facilitating the lifelong learning and developing knowledge, skills and attitudes to ensure delivery of a medical care which is up-to-date, evidence based, safe and patient-centered. An extensive 2 day urology course was conducted to meet the needs of learners. The purpose of the current study was to measure the effect of this CME activity on the knowledge of the participants. MATERIAL AND METHODS: This quasi-experimental, single group pre-, and post-test study measured the gain in learning as a result of the two-day extensive CME course conducted by the section of Urology at Department of Surgery, the Aga Khan University, Karachi Pakistan. Gain in knowledge, defined as the difference between the pre-test and the post-test scores, was taken as a measure of course effectiveness. The test comprised of 40 one-best type carefully constructed multiple choice questions (MCQs). Item analyses were also performed. RESULTS: Forty-five out of a total of 70 participants from within and outside the city completed both pre and post tests and were included in the study. The mean age of the subjects was 33.3+6.7 years. Of these 45 participants, 68.9% (n=31) of them were trainees at different levels. Mean gain in knowledge was 12.7+/-6.8% (p<0.01; 95% CI: 4.17-5.79). Mean test scores improved significantly from 37.8+/-11.3% to 50.3+/-10.8%. Difference in pre and post scores due to age, gender, practice type or years since start of training was not significant. The reliability of the test using Cronbach's alpha was 0.634. CONCLUSION: CME sessions when designed and delivered carefully are effective means of increasing the knowledge significantly. Pre- and post-test is a reliable and valid strategy to measure gain in participants' knowledge. PMID- 29975630 TI - Patterns of management of translocation renal cell carcinoma. AB - OBJECTIVE: Translocation renal cell carcinoma (TRCC) represents 1% to 5% of all cases of renal cell carcinoma (RCC), with the highest frequency among children and young adults. Management of these tumors is ill defined. We sought to characterize clinicopathological features of TRCC and patterns of medical and surgical management in a middle eastern health institute. MATERIAL AND METHODS: Clinical and pathological data of 23 patients from a single institution diagnosed with TRCC between January 2005 and July 2017 were retrospectively reviewed. We dichotomized patients based on demographics, methods of surgical approach and pathologic tumor stage. We then evaluated the methods of medical management for metastatic disease and response to treatment based on cancer-specific survival (CSS) and progression-free survival (PFS). RESULTS: The median age at diagnosis was 37 years. Fifteen (65%) patients were male. Most of the patients were diagnosed incidentally (65%) during abdominal imaging for other reasons. The mean tumor size was 9 cm, 47% of the patients had pathologic >= T3 stage. Eleven patients had lymph node dissection for clinically enlarged lymph nodes, 7 of which (64%) had lymph node metastasis. Partial nephrectomies were performed for three tumors. Eight patients had metastasis (34.7%), and 3 of them had metastasis at the time of diagnosis. Six patients received sunitinib for the treatment of metastatic disease, one patient had complete response, 4 patients had stable disease and one had disease progression. Three patients died during follow-up period because of development of metastasis at postoperative 4 (n=1), and 21 (n=1) months, and cerebral hemorrhage (n=1). The mean follow-up period was 35 months and 3-year disease-free survival was 75%. CONCLUSION: TRCC is rarely seen but carries significant risk of disease progression with potential response to targeted therapy. PMID- 29975631 TI - Brain metastases from prostate cancer: A single-center experience. AB - OBJECTIVE: Metastases from prostate cancer to the brain are very unusual and very few case series have been reported in the literature. Present study was performed to assess the proportion of brain metastasis from prostate cancer among other brain metastasis in men, to evaluate the distribution, pattern and magnetic resonance imaging (MRI) appearance of these metastatic lesions, and prognosis of brain metastasis in patients with prostate cancer. MATERIAL AND METHODS: Between January 2010 and November 2016, 339 males who had received radiotherapy at our department were retrospectively reviewed. After the first evaluation of patients data, we reviewed only the patients with brain metastases from prostate cancer. We evaluated MRI characteristics of metastatic brain lesions and characteristics of the patients, tumor and treatment modalities. RESULTS: Ten of 339 patients (2.9%) had brain metastases from prostate cancer. Sixty percent of the patients had pure intraparenchymal metastasis, 20% of the patients had pure extensive dural metastasis and 20% of them had both. Seventy-five percent of the patients with intraparenchymal metastasis had multiple metastatic lesions. The median prostate specific antigen (PSA) level was 49.40 ng/mL and the Gleason score was >=7 in all patients. Sixty percent of the patients had distant metastasis at the time of the diagnosis of prostate cancer. Median survival time in patients with brain metastasis was 4.5 months. CONCLUSION: Lesions of brain metastasis from prostate cancer had a large variety of imaging presentation and it is very difficult to distinguish them from the other brain metastasis originating from other types of cancer. Presence of a disseminated disease, high PSA level and high Gleason score can be useful parameters for the prediction of brain metastasis from prostate cancer. PMID- 29975632 TI - Comparison of uropathogens and antibiotic susceptibility patterns in catheterized ambulant middle-aged and elderly Nigerian patients with bladder outlet obstruction. AB - OBJECTIVE: Advanced age is one of the notable risk factors for catheter associated urinary tract infections (CAUTIs), and differences between middle aged and elderly men with CAUTIs is poorly understood. This study aimed at comparing the pattern of urinary pathogens and antibiotic susceptibility in ambulant catheterized middle-aged and elderly Nigerian men. MATERIAL AND METHODS: One hundred and fifty-four patients catheterized for >48 hours had provided clean catch mid-stream urine samples for microscopic analysis, culture and sensitivity tests. Eighty-two men aged <65, and 72 men aged >=65 years matched for age, level of education, occupation and marital status were compared. RESULTS: Prevalence of CAUTIs among middle-aged men was middle-aged men was higher than the elderly (90.2% and 80.6% respectively) but this was not statistically significant (p=0.086). CAUTIs in middle-aged men with suprapubic catheters were significantly more frequent than those with urethral catheters (p=0.000). The prevalence of CAUTIs in middle-aged men with urethral stricture was different from other causes of bladder outlet obstruction (p=0.004). Men with indwelling catheters longer than 2 weeks had higher CAUTIs (p=0.000). Escherichia coli was the commonest pathogen in both groups while nitrofurantoin was the most sensitive drug. CONCLUSION: There are differential rates of CAUTIs in both the middle-aged men and the elderly with bladder outlet obstruction in our environment. The knowledge of the common pathogens and the antibiotic susceptibility will prevent irrational antibiotic use. Middle-aged men had higher prevalence of CAUTIs when Proteus spp. was the infectious agent. However, E. coli was the commonest pathogen of CAUTIs in all men. Also, middle- aged men with suprapubic catheters had higher rates of CAUTIs. Nitrofurantoin was the best drug in all men with CAUTIs but elderly men had higher rates of multi-resistance. PMID- 29975633 TI - Evaluation of the results of dorsolateral buccal mucosal augmentation urethroplasty. AB - OBJECTIVE: Evaluation of the results of dorsolateral buccal mucosal augmentation urethroplasty in patients with a long- segment urethral strictures. MATERIAL AND METHODS: Twenty male patients who underwent urethroplasty in our clinic between November 2015 and January 2017 were evaluated. The outcomes of single-stage dorsolateral buccal mucosal augmentation urethroplasty were retrospectively evaluated. Patients were followed-up at 2nd-3rd weeks, 3rd and 6th months after the operation. RESULTS: Mean age of the patients was 59.45+/-13.6 years. Mean length of the strictures was 4.59+/-1.99 cm (3-11 cm) and mean length of buccal mucosal graft (BMG) was 6.8+/-1.98 cm (5-13 cm). Mean duration of operation was 149.25+/-47.39 minutes (95-270 min) and mean blood loss was calculated as 165.5+/ 63.05 mL (75-280 mL). The success rate of dorsolateral buccal mucosal augmentation urethroplasty was calculated as 85% after a mean follow-up of 7.38+/ 2.6 months. There were no perioperative or postoperative complications in the urethroplasty region or the mouth except one patient. Three patients who were found to have a decline in the maximum voiding rate in the postoperative 3rd month were included in the dilation program. CONCLUSION: Single-stage dorsolateral buccal mucosal augmentation urethroplasty is a surgical option to be used in the treatment of long segment urethral strictures with high success and low complication rates in experienced hands. PMID- 29975634 TI - Management of obturator nevre injury during pelvic lymph node dissection. AB - OBJECTIVE: Obturator nerve injuries may be seen during pelvic lymph node dissection in oncological surgery and although not common it is an important complication. According to the shape and location of the injury, tingling and loss of sensation may develop on the inner surface of the leg, together with loss of motor function of the adductor muscles. In this study an evaluation was made of these complications encountered in our clinic and the management strategies applied to these patients. MATERIAL AND METHODS: The data were retrospectively reviewed of 843 patients who underwent open radical retropubic prostatectomy between January 2002 and May 2016. To confirm obturator nerve palsy, electrophysiological investigation (ENG-EMG) was performed immediately postoperatively and 3 weeks later. RESULTS: A total of 6 obturator nerve injuries occurred during pelvic lymphadenectomy (0.7%). Reapproximation end to end with sutures was applied in 3 case and sural nerve graft in 1. In the other 2 patients, just clips were placed and these were removed early during the operation. After the treatment period, neurotropic medications or physiotherapy were given in some cases according to the neurological examinations. CONCLUSION: Obturator nerve injury can be prevented by having a comprehensive knowledge of pelvic anatomy, and avoiding the use of electrocautery during lymph node dissection. The repair should be performed as soon as possible, with a tension free reapproximation of the ends, using electrophysiological tests with a multidisciplinary approach and benefit should be taken from physiotherapy and medical treatment when needed. PMID- 29975635 TI - DNA fragmentation index and human papilloma virus in males with previous assisted reproductive technology failures. AB - OBJECTIVE: This study was designed to evaluate the prevalence of Human Papilloma Virus (HPV) in semen and document the cycle outcomes in couples with previous intra-cytoplasmic sperm injection (ICSI) failures. MATERIAL AND METHODS: One hundred and seventeen couples with at least two ICSI attempts were included in the study. HPV infection in semen and DNA fragmentation in samples were analyzed by commercially available kits. The percentage of spermatozoa with fragmented DNA (DNA fragmentation index: DFI) was determined during fluorescence microscopic examination as previously described. The cycle outcomes of couples with or without HPV infected male partners were recorded. RESULTS: According to our results, the prevalence of HPV was 7.7% in asymptomatic males with at least two previous ICSI failures. The increased DFI (>30%) was observed in 82.9% of the cases. In HPV-positive cases significantly lower number of good quality embryos were obtained. The implantation and pregnancy rates were similar in infected and non-infected males (p>0.05). The early miscarriage rate was slightly higher in HPV- positive group (33% vs. 10%, p>0.05). CONCLUSION: In cases with previous ICSI failures, the prevalence of HPV infection in semen is not higher than previously reported infertile populations. The reproductive outcome might be impaired in HPV-positive semen due to lower number of good quality embryos, which needs to be clarified by further large population-based studies. PMID- 29975636 TI - Alveolar echinococcosis in a dog; analysis of clinical and histological findings and molecular identification of Echinococcus multilocularis. AB - Echinococcus multilocularis is a zoonotic tapeworm of medical and veterinary importance that occasionally infects accidental intermediate hosts causing severe disease or even death. In dogs, alveolar echinococcosis has been reported mainly in central Europe and Canada. The paper presents clinical, biochemical and histological signs of alveolar echinococcosis in a dog from Slovakia and the results of mitochondrial nad1 gene analysis. In 2016, 11-years old Siberian husky female suffering from inappetence was presented to the Veterinary Clinic in Zilina. Biochemical blood examination and blood count showed only minor changes, but abdominal ultrasonography showed the hepatomegaly and the presence of nonhomogeneous hypodense lobulated formation in the left liver lobe. Histological and molecular examinations of excided tissue confirmed the diagnosis of alveolar echinococcosis of the liver. BLAST analysis of E. multilocularis nad1 gene revealed that the nucleotide sequence did not exactly match the previously identified M1 (AJ237639) and/or M2 genotype (AJ237640). In total, two single nucleotide polymorphisms (SNPs) occurred within overlapping region of nad1 gene. In the discussion, clinical and laboratory findings of the infection in other dog patients are compared and the possibilities of diagnosis and therapy of the disease are discussed. PMID- 29975637 TI - Does apicortin, a characteristic protein of apicomplexan parasites and placozoa, occur in Eumetazoa? AB - Apicortin is a characteristic protein of apicomplexan parasites which has recently been identified in their free-living cousins, chromerids as well. The placozoan Trichoplax adhaerens is the only animal possessing this protein and apicortin is one of its most abundant proteins. The recently published transcriptome of the cnidarian Porites astreoides contains an apicortin-like sequence. Other cnidarians do not have it, thus it is its first occurrence not only in this phylum but also in Eumetazoa. However, its translated amino acid sequence is more similar to apicomplexan apicortins than to that of T. adhaerens, the GC ratio is much higher than either the genome-wide GC ratio of P. astreoides or that of the placozoan apicortin gene, and phylogenetic analyses suggest that this apicortin has an apicomplexan origin. Although these data might be indicative for a horizontal gene transfer event, we should be cautious to state it; it is more probable that it is a contamination from a gregarine, a marine Apicomplexa. Thus T. adhaerens remains the only animal where the presence of apicortin is proved. PMID- 29975638 TI - First molecular evidence of Thelohanellus wallagoi Sarkar, 1985 (Myxozoa) from economically important food fish, freshwater shark Wallago attu (Siluridae) in India. AB - The freshwater shark Wallago attu (Bl. and Schn.) is a frequent silurid in the River Ganga and one of the most commercially exploit fish in India. In a survey on its infection with myxosporeans, spore type belongs to Thelohanellus species was found in the gills, kidney and intestine respectively. Through morphological and molecular investigations, we identified the spore as Thelohanellus wallagoi Sarkar, 1985. They were pyriform in valvular view and slim in sutural view, and had one pyriform polar capsule with four to five turns. The spores measured 8.0 * 4.0 * 2.3 MUm. T. wallagoi developed in small cysts in the gill lamellae, whereas cyst and scattered spores of T. wallagoi were also found in the kidney and intestine respectively. The 18S rDNA sequence of T. wallagoi isolates recovered from gills, kidney and intestine were found similar to each other and differed from any other Thelohanellus species available in GenBank and validated its status after 32 years of original description. Phylogenetic analysis signified that T. wallagoi was placed sister to Myxobolus species in the clade that indicated the polyphyletic nature of the genus Thelohanellus. PMID- 29975639 TI - A new coccidian parasite (Apicomplexa: Eimeriidae: Eimeria) from the southern black racer, Coluber constrictor priapus (Reptilia: Ophidia: Colubridae) from Arkansas, USA. AB - Between April 2012 and October 2017, 18 southern black racers, Coluber constrictor priapus, were collected from nine counties of Arkansas (n = 13) and McCurtain County, Oklahoma (n = 5) and their faeces examined for coccidian parasites. One of 18 (6%) C. c. priapus harboured an eimerian that we describe here as new. Oocysts of Eimeria dunni sp. nov. were subspheroidal with a lightly pitted bi-layered wall measuring L * W 24.0 * 21.1 and L/W ratio of 1.2. A micropyle was absent but an oocyst residuum and polar granule were present. Sporocysts were ovoidal and measured 11.9 * 8.1 with L/W of 1.5. A Stieda body was present but substieda and parastieda bodies were absent. The sporocyst residuum was composed of medium-sized granules aligned along perimeter of sporocyst or in a dispersed mass. This represents the first valid eimerian reported from the southern black racer. PMID- 29975640 TI - Further study on Procamallanus (Spirocamallanus) pintoi (Kohn et Fernandes, 1988) (Nematoda: Camallanidae) in Corydoras paleatus and Corydoras micracanthus (Siluriformes: Callichthyidae) from Salta, Argentina, with a key to congeneric species from Neotropical Realm. AB - This study describes the morphology of Procamallanus (Spirocamallanus) pintoi (Kohn et Fernandes, 1988), isolated from the intestine of Corydoras micracanthus Regan, 1912 and C. paleatus (Jenyns, 1842) (both Callichthyidae, Siluriformes) from Bermejo and Juramento River basins, respectively, province of Salta, Argentina. This is the first record of P. (S.) pintoi in C. micracanthus from Northwestern Argentina. The light and scanning electron microscopy observations of P. (S.) pintoi, revealed a few previously unreported morphological details of the cephalic region, vulva and caudal region of males. In addition, morphometric variability was observed in, mainly body size, glandular oesophagus length and position of the vulva between present specimens and those described in previous studies. A key to the species of Procamallanus (Spirocamallanus) from the Neotropical Realm is proposed. PMID- 29975641 TI - Morphological and molecular study of Neorhadinorhynchus nudus (Harada, 1938) (Acanthocephala: Cavisomidae) from Auxis thazard Lacepede (Perciformes: Scombridae) in the South China Sea. AB - In the present study, Neorhadinorhynchus nudus (Harada, 1938) is reported from the frigate tuna Auxis thazard (Lacepede) (Perciformes: Scombridae), in the South China Sea for the first time. The detailed morphology of N. nudus was studied using light and scanning electron microscopy based on the newly collected material. The results showed some morphometric variability between our specimens and previous studies, including the number of hooks per longitudinal row and the size of copulatory bursa and eggs. Our SEM observations also revealed all proboscis hooks emerged from elevated round rims on proboscis surface. In addition, N. nudus was firstly characterised using molecular methods by sequencing and analysing the ribosomal ITS and mitochondrial cox1 regions. There is no nucleotide divergence found in the ITS sequences, but a low level of nucleotide variability detected in the cox1 regions (the level of intraspecific nucleotide variability being 0.75% to 2.54%). The DNA sequence data obtained herein will indeed be a useful reference for rapid and accurate species identification of Neorhadinorhynchus. PMID- 29975642 TI - Epidemiological and genetic characterization of larval stages of Fasciola gigantica in snail intermediate hosts in Karnataka State, India. AB - Fasciolosis in ruminants in India is caused by the liver fluke Fasciola gigantica. Radix (Lymnaea) spp. are known to carry the infective stages of this parasite. Understanding the seasonal prevalence of F. gigantica infection in the intermediate host is of extreme importance in order to elucidate the transmission dynamics of the parasite. So the present study was designed to determine the bioclimatic distribution of larval stages of F. gigantica in Radix spp. snails as well as to explore the genetic diversity of F. gigantica in three geographical regions (Deccan plateau, Western Ghats and coastal region) of Karnataka. The lymnaeid snails were sampled (n = 2077) for a period of one year (June 2015 to May 2016) at 24 sites. The snails were morphologically identified and the infection status was established through cercarial shedding and nested polymerase chain reaction (PCR) based technique targeting second internal transcribed spacers (ITS-2) of nuclear ribosomal DNA. The sensitivity of PCR (8.2%) for detection of F. gigantica infection within snail is significantly higher than cercarial shedding (4.3%) with an overall prevalence of 5.1%. The prevalence of infection was higher in winter than in the rainy and summer seasons (6.2% instead of 4.6% and 4.3% respectively). Deccan plateau (5.8%) showed a higher prevalence of infection compared to Western Ghats (5.2%) and Coastal region (3.6%). The sequencing ITS-2 region permitted the identification of the parasite as F. gigantica which is having high implication in studying the population genetic structure of the parasite in the country. In conclusion, overall results indicated that Radix spp. snails harboured F. gigantica developmental stages throughout the year and nested PCR was found to be sensitive and specific for detection of F. gigantica infection in snails compared to routine parasitological techniques. PMID- 29975643 TI - Anti-Neospora caninum antibodies in feral cats on the Island of Fernando de Noronha, Brazil. AB - Neospora caninum is a protozoan responsible for abortions, stillbirths (mainly among cattle) and neuromuscular diseases in dogs. Its importance in wild species and its impact on the environmental preservation of different ecosystems have been little described. This study aimed to investigate the presence of anti-N. caninum antibodies in feral cats on the island of Fernando de Noronha and contribute epidemiological data on this disease in these animals and its impact on the environmental preservation of the island. Serum samples from 257 feral cats on the island were analyzed through the Neospora agglutination test (NAT) to search for anti-Neospora caninum antibodies. Among the 257 serum samples analyzed, 8 (3.11%) were positive in the NAT. The antibody titers were 20 in seven animals (87.5%) and 40 in one animal (12.5%). These results demonstrate that feral cats are exposed to infection by N. caninum on the island of Fernando de Noronha, at a low frequency. Greater knowledge on this infection in this animal species in this insular environment is important for elucidating its impact on the conservation of species and the maintenance of this parasite on the island. PMID- 29975644 TI - Endoparasites in Limnonectes magnus (Anura, Dicroglossidae) from Samar Island, Philippines with description of a new species of Aplectana (Nematoda, Cosmocercidae). AB - Aplectana samarensis sp. nov. (Ascaridida, Cosmocercidae) from the intestines of Limnonectes magnus (Anura, Dicroglossidae) is described and illustrated. Aplectana samarensis sp. nov. represents the 53rd species assigned to the genus and the 6th species reported from the Oriental region. It is easily separated from the 5 species previously reported from the region by the presence of a gubernaculum and the distribution pattern of male caudal papillae: A. macintoshii has an irregular pattern, no precloacal papillae in rows; both A. akhrami and A. dubrajpuri lack a gubernaculum; A. duttaphryni has 3 pairs of precloacal papillae forming 2 rows; A. ranae has 7 pairs of precloacal papillae forming 2 rows; A. samarensis sp. nov. has 4 pairs of precloacal papillae in 2 rows. In addition to the new species, individuals of Falcaustra dubia and Pseudoacanthocephalus bufonis as well as cestode plerocercoids were also found. PMID- 29975645 TI - Ascaridia galli isolates with ITS1-5.8rRNA-ITS2 fragment homologous to Ascaridia columbae. AB - Ascaridia (A.) galli is one of the most commonly occurring nematodes in poultry worldwide, often in hens and broiler chickens. The infection with Ascaridia galli in free-range chickens was even 70%. There is not much information about A. galli genetic features. The present study was conducted to assess the genetic diversity of A. galli isolated from hens in Poland by analyzing the nucleotide sequence of the region ITS1-5.8rRNA-ITS2 and to define its homology within the family Ascaridiidae. Adult A. galli were collected from the intestines of naturally infected hens from two flocks of free-run laying hens from the Wielkopolska region in Poland. From all parasites an identical ITS1-5.8rRNA-ITS2 sequence was obtained, which was homologous in 99% with A. columbae (JQ995321.1) sequence. The high homology sequences of A. galli (KX683286) from Poland and A. columbae (JQ995321.1) isolate from the USA, support the observations of other authors suggesting that A. galli and A. columbae might be closely related. It is the first whole ITS1-5.8rRNA-ITS2 of A. galli in the GenBank database, so there is not enough data for detailed phylogenetic analysis of A. galli. Detailed genetic analysis is necessary to get better insight into the birds' Ascaridia species. PMID- 29975646 TI - Molecular phylogenetic position of Haplometroides intercaecalis (Digenea, Plagiorchiidae). AB - Three valid species of Haplometroides Odhner, 1910 parasitise snakes and amphisbaenians from South America. This study provides additional data on morphometric and molecular phylogenetic position inferred from the nuclear ribosomal gene 28S (partial). DNA sequences were isolated from Haplometroides intercaecalis Silva, Ferreira and Strussmann, 2007 found in one specimen of Phalotris matogrossensis Lema, D'Agostini and Cappellari, 2005. Five digenean specimens were recovered from the esophagus of this snake, and four specimens were used for morphometrical studies and one specimen for molecular analysis. Phylogenetic analysis using maximum likelihood and Bayesian methods was conducted with sequences available for the order Plagiorchiida and its phylogenetic position places H. intercaecalis among the brachycoeliids Brachycoelium (Dujardin, 1845) Stiles and Hassall, 1898 and Parabrachycoelium Perez-Ponce de Leon, Mendoza-Garfias, Razo-Mendivil and Parra-Olea, 2011, and the mesocoeliid Mesocoelium Odhner, 1910, not closely related to plagiorchids as expected. Due to morphological differences among these families, it may be necessary to create a new family to accommodate Haplometroides spp. However, more genera/taxa as well as other molecular markers should be added in future studies to confirm our results and resolve this matter. This is the first phylogenetic positioning of digeneans of the genus Haplometroides, contributing to the systematic analysis of the helminthological biodiversity of Neotropical snakes. PMID- 29975647 TI - Dirofilaria repens infection as a cause of intensive peripheral microfilariemia in a Polish patient: process description and cases review. AB - Dirofilariasis is a parasitic disease of dogs and other carnivores transmitted mainly by the mosquitoes of the genera Culex, Aedes, Anopheles. Full life cycle of the Dirofilaria nematodes in humans is extremely rarely observed, usually lacking species determination at the molecular level. We report fully documented unusual clinical manifestation of subcutaneous dirofilariasis with intensive microfilariemia in peripheral blood revealed by the Knott's concentration technique. The identification of the Dirofilaria repens nematode was based on typical morphological findings for adult gravid female nematode found in the histopathological preparations. The morphology of microfilariae obtained from patient's peripheral blood was also typical for D. repens. The final identification was confirmed by the molecular analysis of microfilariae collected from the blood. PMID- 29975648 TI - Comparison of sensitivity of two primer sets for the detection of Toxoplasma gondii DNA in wildlife. AB - Toxoplasma gondii, a coccidian parasite known to infect almost all warm-blooded animals, is the cause of one of the most common zoonotic parasitic diseases. The aim of the study is to determine whether the 529 bp fragment or the TGR1E gene is more useful target for PCR identification of T. gondii, for common use. The brains of 221 carnivores and omnivores collected between 2013 and 2015 from north eastern Poland were examined for the presence of this parasite. The DNA was extracted and then amplified using specific primers. Positive results were obtained in 24% of brain samples using the TGR1E target and 19% using the 529 bp sequence. The results demonstrate that both TGR1E and 529 bp repeat element are suitable for detecting T. gondii DNA in wildlife animals, and the combination of two methods is necessary to obtain reliable results. PMID- 29975649 TI - Molecular characterization of Theileria spp. in livestock and the first report on the occurrence of Theileria sp. OT3 in Iran. AB - Theileria lestoquardi, T. ovis, and T. annulata are recognized as major causative agents for ovine and cattle theileriosis in Iran, respectively. Recently, there have been reports on the presence of Theileria spp. (Theileria sp. OT1, Theileria sp. OT3, and Theileria sp.). In this study, 37 blood samples were collected from sheep and cattle with clinically suspected Theileria infection in the Northwest of Iran. The samples were analyzed using a light microscope. DNA samples were amplified via nested-polymerase chain reaction (PCR) of 18S rRNA gene. The amplicons were digested with HpaII, following restriction fragment length polymorphism (RFLP) and sequenced to reconfirm Theileria species. The microscopic examination indicated that 4 out of 37 (10.8%) blood samples were infected with Theileria spp. Based on the nested PCR-RFLP and sequencing data, 5.4%, 13.5%, and 27% of blood samples were infected with Theileria sp. OT3, T. ovis, and T. annulata, respectively. The pairwise distance matrix of Theileria sp. OT3 showed 99.8-100% identity and 0-0.2% divergence in comparison with the registered sequences. The present study is the first report of Theileria sp. OT3 in Iran. To the evaluate evolution of Theileria spp. and providing resultant genetic data, further research with a larger sample is necessary in the region. PMID- 29975650 TI - First identification of Echinococcus multilocularis in golden jackals in Croatia. AB - Alveolar echinococcosis, caused by the tapeworm Echinococcus multilocularis, is one of the world's most dangerous zoonosis and an emerging disease with growing incidence in humans. The disease has been reported in new areas and host species in the last two decades, and the primary hosts of the parasite - red fox, golden jackal and grey wolf - are expanding their distribution in Europe. Here we report the morphological and molecular identification of Echinococcus multilocularis tapeworms in one of 29 carcasses of adult golden jackals in Croatia, where the only previous report of the parasite was in red foxes in 2016. These results suggest that alveolar echinococcosis should be treated as an emerging disease in Croatia. PMID- 29975651 TI - Screening of Cercopithifilaria bainae and Hepatozoon canis in ticks collected from dogs of Northeastern Brazil. AB - Rhipicephalus sanguineus sensu lato (s.l.) is one of the most widespread ixodid ticks and is a competent vector of several vector-borne pathogens of veterinary and medical concern. For instance, this tick species transmits nematodes of the genus Cercopithifilaria and protozoa of the genus Hepatozoon to carnivores, including dogs. Here we investigated the occurrence of Cercopithifilaria spp. and Hepatozoon spp. in a population of ticks collected from naturally infested dogs living in rural areas of Northeastern Brazil. From August 2016 to June 2017, 758 tick specimens (mean ticks per month = 68.9 +/- 71.4) were sampled from 75 dogs (mean ticks per dog = 10.11 +/- 5.2) and dissected under a stereomicroscope in order to visualize Cercopithifilaria spp. larvae and Hepatozoon spp. oocysts and sporocysts. R. sanguineus s.l. was the only species collected, peaking in September (n = 273) and decreasing in February 2017 (n = 39). Different larval stages of Cercopithifilaria bainae were identified in 7 out of 758 (0.93%) ticks. In addition, 4 specimens (0.53%) were positive for oocysts and free sporocysts of Hepatozoon canis. The identity of both species of parasites was molecularly confirmed. These results account for the predominance of R. sanguineus (s.l.) in domestic dogs from rural locations of the study area, as well as for the presence C. bainae and H. canis in these tick populations. PMID- 29975652 TI - Systemic oxidative stress in Suffolk and Santa Ines sheep experimentally infected with Haemonchus contortus. AB - The mechanisms responsible for the imbalance between oxidants and antioxidants in sheep infected with Haemonchus contortus are not well established. This study aimed to prove the hypothesis that oxidative stress occurring during infection by H. contortus varies according to breed, and that the parasite burden correlates with hypoalbuminaemia and anaemia. Thus, after deworming and confirming the absence of infection, two different sheep breeds, Suffolk (n = 15) and Santa Ines (n = 22), were orally inoculated with a single dose of 5,000 L3 of H. contortus. The egg counts per gram of faeces (EPG), packed cell volume (PCV) and concentrations of several plasma markers of oxidative stress (lipid peroxidation, albumin, uric acid, total bilirubin, total antioxidant capacity [TAC], total oxidant concentration [TOC] and the oxidative stress index [OSI]) were quantified before (control group) and during the experimental infection (28, 34 and 42 days post-inoculation). In both breeds, TOC increased at 28 days and TAC increased at 42 days. In Suffolk sheep, there was a positive correlation of EPG with oxidant components (28 days) and a negative correlation of EPG with PCV (42 days). In Santa Ines sheep, there was a positive correlation of EPG with bilirubin (r = 0.492; p = 0.020). H. contortus infection caused oxidative stress, which varied according to the breed. Parasite burden was not associated with hypoalbuminaemia, whereas there was a negative correlation with PCV. This research provides the first evidence that the antioxidant status contributes more to the resilience to H. contortus in Santa Ines sheep compared to Suffolk sheep. PMID- 29975653 TI - Human case of Fasciola gigantica-like infection, review of human fascioliasis reports in Nepal, and epidemiological analysis within the South Central Asia. AB - The diagnosis of a 22 year-old male patient from Kerabari, Morang District, Nepal led to the review of human fascioliasis cases and analysis of the epidemiological situation in that country not included in the WHO fascioliasis map. Symptom onset one month before egg detection and normal levels of ALT and AST did not agree with the 3-4-month migratory period of fascioliasis. A shorter acute phase may happen when the main biliary duct is reached by the migratory juveniles directly from the intestinal lumen. The causal agent was ascribed to F. gigantica-like worms after considering adult fluke morphology, altitude of the patient's infection area, fasciolid characteristics in the neighbouring Bangladesh, and lymnaeid snail vector species known in Nepal and in the patient's infection area. Previous reports of human infection by Fasciola in Nepal are reviewed. The patient in question proved to be the twelfth case and the first in whom a F. gigantica-like infection is reported. In Nepal, the wide geographical distribution of livestock fascioliasis, with high prevalences in buffaloes, cattle and goats, and the reports of Fasciola-infected schoolchildren close to the capital Kathmandu, give rise to concern on the situation in remote rural areas in a country where most of the population lives in rural areas. Moreover, the climate change impact in Nepal remembers Pakistan, where human fascioliasis emergence has been related to climate change and man-made irrigation. All in all, the present analysis suggests that human infection by Fasciola may be underestimated in Nepal. PMID- 29975654 TI - Ten new species of Brueelia Keler, 1936 (Phthiraptera: Ischnocera: Philopteridae) from nuthatches (Aves: Passeriformes: Sittidae), tits and chickadees (Paridae), and goldcrests (Regulidae). AB - Ten new species of chewing lice in the genus Brueelia Keler, 1936, are described from hosts in the families Paridae, Regulidae, and Sittidae. They are: Brueelia johnsoni n. sp. from Poecile sclateri eidos (Peters, 1927); Brueelia juniperi n. sp. from Baeolophus ridgwayi ridgwayi (Richmond, 1902); Brueelia kabulica n. sp. from Sitta tephronota tephronota Sharpe, 1872; Brueelia mpumalangensis n. sp. from Melaniparus niger niger (Vieillot, 1818); Brueelia nazae n. sp. from Parus cinereus caschmirensis Hartert, 1905; Brueelia oxyrhyncha n. sp. from Sitta nagaensis nagaensis Godwin-Austen, 1874; Brueelia picea. sp. from Parus major excelsus Buvry, 1857; Brueelia ragusica n. sp. from Sitta neumayer neumayer Michahelles, 1830; Brueelia regulicida n. sp. from Regulus calendula grinnelli Palmer, 1897; Brueelia sittacola n. sp. from Sitta carolinensis carolinensis Latham, 1790. Brueelia regulicida is the first Brueelia-complex louse to be described from the host family Regulidae. Collectively, the Brueelia of parid, regulid, and sittid hosts show two peculiar patterns. Firstly, lice on closely related hosts appear to be distantly related. Secondly, lice on most hosts in these families appear to be more closely related to lice on other host families than to each other. This contradicts the traditional view that Brueelia-complex lice on closely related hosts are themselves closely related. Potentially, the tendency of the hosts to participate in mixed-species feeding flocks may explain some of these patterns. PMID- 29975655 TI - Morphological and molecular characterization of Paramphistomum epiclitum of small ruminants. AB - Morphological and molecular identification can pave the way to design the most effective control measures against the Paramphistomum epiclitum in small ruminants. Morphology of the flukes had described the features of Paramphistomum genus. Body was conical with concave ventral and convex dorsal surface, tegumental spines all around the body in the immature stage, terminal funnel shape oral sucker, sub-terminal acetabulum, blind caeca with a serpentine course touching the anterior level of the acetabulum. Vitelline glands were at the lateral margins of the body extended from the pharynx to the posterior sucker. Testes were lobed and tandem, wavy post-testicular uterus and genital pore behind intestinal bifurcation. Sequence analyses of internal transcribed spacer (ITS)-2+ (PCR products of approximately 500 bp) of 10 flukes yielded 2 genotypes, Navsari isolate 1 and 2. In BLAST analysis, ITS-2+ genotypes were 97.3-99% similar with published sequences (KF564870, JF834888, KF642983 and JX678254) of P. epiclitum of Paramphistomatidae. Two genotypes depicted 4 single nucleotide polymorphisms (NPs) in the form of transitions (C-T at 10 and 18; G-A at 255; A-G at 367 locus), 1 triple NPs (CGT-GAA between 21-23 loci) and missing A base at codon 40 in the genotype 1. Average AT and GC content was 49.61% and 50.38%, respectively. Trees topology inferred by Neighbor Joining and Maximum Likelihood methods of ITS2+ of trematodes were similar, with small difference of bootstrap values. Navsari genotypes formed a tight cluster with the P. epiclitum, originated from different location with high bootstrap value and 0.004-0.011 estimated evolutionary divergence. PMID- 29975656 TI - Descriptions of Acanthocephalus parallelcementglandatus (Echinorhynchidae) and Neoechinorhynchus (N.) pennahia (Neoechinorhynchidae) (Acanthocephala) from amphibians and fish in Central and Pacific coast of Vietnam, with notes on N. (N.) longnucleatus. AB - Three species of acanthocephalans are described from fishes caught in the Pacific coast off eastern Vietnam and from amphibians in the midlands in 2016: (1) Acanthocephalus parallelcementglandatus Amin, Heckmann, Ha, 2014 (Echinorhynchidae), described from 1 male specimen is now fully described from males and females collected from 2 species of amphibians, the similar frog Hylarana attigua Inger, Orlov, Darevsky and the odorous frog Odorrana sp. Fei, Ye, Huang (Ranidae) in Huong Thuy, Hue City and Chu Yang Sin Park, central Vietnam, respectively, as well as from the needlefish Tylosurus sp. Cocco (Belonidae) in Binh Thuan in the Pacific South. The allotype female is designated. Neoechinorhynchus (N.) pennahia Amin, Ha, Ha, 2011 described from 1 female specimen is now fully described from males and females collected from the Toli shad (Chinese herring), Tenualosa toli (Valenciennes) (Clupeidae) in the Pacific north coast off Haiphong. The allotype male is designated. One specimen of Neoechinorhynchus (Neoechinorhynchus) longnucleatus Amin, Ha, Ha, 2011 is also reported from the common ponyfish, Leiognathus equulus (Forssskal) (Leiognathidae) in the Pacific south coast of Nha Trang and its ecology briefly discussed. PMID- 29975657 TI - The discovery of Lepeophtheirus acutus Heegaard, 1943 (Copepoda: Caligidae) from two new elasmobranch hosts in the Mediterranean Sea, and a comparative redescription of Lepeophtheirus rhinobati Luque, Chaves et Cezar, 1998. AB - In this study, supplementary information on the morphology of the siphonostomatoid copepod Lepeophtheirus acutus Heller, 1865 is given based on new material collected from the ventral body surface and mouth cavity of common guitarfish, Rhinobatos rhinobatos (Linnaeus) and from the branchial cavity of bull ray, Aetomylaeus bovinus (Geoffroy Saint-Hilaire) caught in Iskenderun Bay, Turkey. This is the first report of L. acutus from Mediterranean waters. Key diagnostic characters of both sexes are reported, supported by light and scanning electron microscopy observations. In addition, Lepeophtheirus rhinobati Luque, Chaves et Cezar, 1998, which is closely related to L. acutus and has been reported from the same host genus, Rhinobatos, is reexamined based on paratypes stored in the collections of the United States National Museum of Natural History. Some of the key diagnostic characters which were incompletely known or lacking in the original description of both sexes of L. rhinobati are redescribed and/or presented for the first time. PMID- 29975658 TI - Morphological and phylogenetic characterization of a novel Unicauda species, infecting the kidney of Astyanax altiparanae (Teleostei: Characidae) in Brazil. AB - During a parasitological survey of Astyanax altiparanae captured in the Mogi Guacu river, Pirassununga, state of Sao Paulo, Brazil, a new species of myxozoa was observed infecting the kidney of 30 of 42 specimens. Plasmodia of the new myxozoa, referred to herein as Unicauda whippsi n. sp. were spherical and varied from 450 to 1000 MUm in length. The mature spore was elongated and measured 11 +/ 1.2 (10-12) MUm long by 5.4 +/- 0.6 (4.7-7.2) MUm wide. Polar capsules of unequal length with the filament coiled 7-9 times and a unique caudal process characteristic of the genus Unicauda, were recorded. Phylogenetic analysis demonstrated that U. whippsi n. sp. clustered with members of the genus Unicauda and Myxobolus, confirming it's placement within the family Myxobolidae. This is the first record of a species of Unicauda infecting characiform fish, as well as the first registered occurrence of species of this genus in South America. PMID- 29975659 TI - Assessment of oxidative/nitrosative stress biomarkers and DNA damage in Haemonchus contortus, following exposure to zinc oxide nanoparticles. AB - Drug resistance in helminth parasites has incurred several difficulties to livestock industry and ranked among the top public health concerns. Therefore, seeking for new agents to control parasites is an urgent strategy. In the recent years, metallic nanoparticles have been considerably evaluated for anthelmintic effects. The current research was conducted to assess possible anthelmintic impacts of zinc oxide nanoparticles (ZnO-NPs) on a prevalent gastrointestinal nematode, H. contortus. Moreover, several biomarkers of oxidative/nitrosative stress and DNA damage were measured. Various concentrations of the nanoparticle were prepared and incubated with the worms for 24 hours. The parasite mobility, mortality rate, antioxidant enzymes activities (SOD, Catalase and GSH-Px), lipid peroxidation, total antioxidant status as well as nitric oxide (NO) contents and DNA damage were determined. ZnO-NPs exerted significant wormicidal effects via induction of oxidative/nitrosative stress and DNA damage. Conclusively, ZnO-NPs can be utilized as a novel and potential agent to control and treatment of helminth parasitic infections. PMID- 29975660 TI - First molecular identification of an agent of diplostomiasis, Diplostomum pseudospathaceum (Niewiadomska 1984) in the United Kingdom and its genetic relationship with populations in Europe. AB - Trematode genus Diplostomum comprises of parasitic species which cause diplostomiasis, the 'white eye' disease in fish and heavy infection can result in mortality. The increasing availability of DNA sequences of accurately identified Diplostomum species on public data base presently enables the rapid identification of species from novel sequences. We report the first molecular evidence of the occurrence of D. pseudospathaceum in the United Kingdom. Two gene regions, nuclear internal transcribed spacer cluster (ITS1-5.8S-ITS2) and mitochondrial cytochrome c oxidase subunit 1 (cox1) of cercariae from infected aquatic snails, Lymnaea stagnalis collected in several locations in Southern England were sequenced. Phylogenetic analysis based on both sequenced genes revealed that the novel sequences were D. pseudospathaceum. Molecular diversity analysis of published D. pseudospathaceum cox1 sequences from seven countries in Europe and the novel sequences from the present study revealed high diversity, but low nucleotide divergence and a lack of gene differentiation between the populations. Haplotype network analysis depicted a star-like pattern and revealed a lack of geographic structure in the population. Fixation indices confirmed gene flow between populations and we suspect high levels of dispersal facilitated by highly mobile second intermediate (fish) and definitive (piscivorous birds) host may be driving gene flow between populations. Neutrality tests and mismatch distribution indicated recent population growth/expansion for D. pseudospathaceum in Europe. PMID- 29975661 TI - Activation and activity of glycosylated KLKs 3, 4 and 11. AB - Human kallikrein-related peptidases 3, 4, 11, and KLK2, the activator of KLK3/PSA, belong to the prostatic group of the KLKs, whose major physiological function is semen liquefaction during the fertilization process. Notably, these KLKs are upregulated in prostate cancer and are used as clinical biomarkers or have been proposed as therapeutic targets. However, this potential awaits a detailed characterization of these proteases. In order to study glycosylated prostatic KLKs resembling the natural proteases, we used Leishmania (LEXSY) and HEK293 cells for secretory expression. Both systems allowed the subsequent purification of soluble pro-KLK zymogens with correct propeptides and of the mature forms. Periodic acid-Schiff reaction, enzymatic deglycosylation assays, and mass spectrometry confirmed the glycosylation of these KLKs. Activation of glycosylated pro-KLKs 4 and 11 turned out to be most efficient by glycosylated KLK2 and KLK4, respectively. By comparing the glycosylated prostatic KLKs with their non-glycosylated counterparts from Escherichia coli, it was observed that the N-glycans stabilize the KLK proteases and change their activation profiles and their enzymatic activity to some extent. The functional role of glycosylation in prostate-specific KLKs could pave the way to a deeper understanding of their biology and to medical applications. PMID- 29975662 TI - Sphingolipids in early viral replication and innate immune activation. AB - In this review, we summarize the mechanisms by which sphingolipids modulate virus multiplication and the host innate immune response, using a number of host-virus systems as illustrative models. Sphingolipids exert diverse functions, both at the level of the viral life cycle and in the regulation of antiviral immune responses. Sphingolipids may influence viral replication in three ways: by serving as (co)receptors during viral entry, by modulating virus replication, and by shaping the antiviral immune response. Several studies have demonstrated that sphingosine kinases (SphK) and their product, sphingosine-1-phosphate (S1P), enhance the replication of influenza, measles, and hepatitis B virus (HBV). In contrast, ceramides, particularly S1P and SphK1, influence the expression of type I interferon (IFN-I) by modulating upstream antiviral signaling and enhancing dendritic cell maturation, differentiation, and positioning in tissue. The synthetic molecule alpha-galactosylceramide has also been shown to stimulate natural killer cell activation and interferon (IFN)-gamma secretion. However, to date, clinical trials have failed to demonstrate any clinical benefit for sphingolipids in the treatment of cancer or HBV infection. Taken together, these findings show that sphingolipids play an important and underappreciated role in the control of virus replication and the innate immune response. PMID- 29975663 TI - Total yield of reactive species originating from an atmospheric pressure plasma jet in real time. AB - It is now well established that plasma-induced reactive species are key agents involved in many biochemical reactions. This work reports on the formation of plasma reactive species in an acidified ferrous sulfate (Fricke) solution interacting with an atmospheric pressure plasma jet (APPJ). A yield of ferric (Fe3+) ions measured using in situ absorption spectroscopy was attributed to the formation of plasma reactive species provided and/or originated in the solution. The results indicated that the number of reactive species formed was proportional to plasma frequency and voltage. However, the Fe3+ yield per pulse decreased with increased frequency. To obtain a better understanding of the processes and species involved in the chemical reactions due to plasma exposure, Fe3+ yields were calculated and compared to the experimental data. At higher frequencies, there was insufficient time to complete all the reactions before the next pulse reached the solution; at lower frequencies, the Fe3+ yield was higher because of the relatively longer time available for reactions to occur. In addition, the comparison between DNA damage levels and Fe3+ yields was investigated under different experimental conditions in order to verify the usefulness of both the Fricke solution and the DNA molecule as a probe to characterize APPJs. PMID- 29975664 TI - Robust EOG-based saccade recognition using multi-channel blind source deconvolution. AB - Human activity recognition (HAR) is a research hotspot in the field of artificial intelligence and pattern recognition. The electrooculography (EOG)-based HAR system has attracted much attention due to its good realizability and great application potential. Focusing on the signal processing method of the EOG-HAR system, we propose a robust EOG-based saccade recognition using the multi-channel convolutional independent component analysis (ICA) method. To establish frequency domain observation vectors, short-time Fourier transform (STFT) is used to process time-domain EOG signals by applying the sliding window technique. Subsequently, we apply the joint approximative diagonalization of eigenmatrix (JADE) algorithm to separate the mixed signals and choose the "clean" saccadic source to extract features. To address the problem of permutation ambiguity in a case with a six-channel condition, we developed a constraint direction of arrival (DOA) algorithm that can automatically adjust the order of eye movement sources according to the constraint angle. Recognition experiments of four different saccadic EOG signals (i.e. up, down, left and right) were conducted in a laboratory environment. The average recognition ratios over 13 subjects were 95.66% and 97.33% under the between-subjects test and the within-subjects test, respectively. Compared with "bandpass filtering", "wavelet denoising", "extended infomax algorithm", "frequency-domain JADE algorithm" and "time-domain JADE algorithm, the recognition ratios obtained relative increments of 4.6%, 3.49%, 2.85%, 2.81% and 2.91% (within-subjects test) and 4.91%, 3.43%, 2.21%, 2.24% and 2.28% (between-subjects test), respectively. The experimental results revealed that the proposed algorithm presents robust classification performance in saccadic EOG signal recognition. PMID- 29975665 TI - Dental fluorosis and associated risk factors in early adolescents in India. AB - Background Dental fluorosis has a negative impact on the facial esthetics of adolescents and is a worldwide oral health concern. Objective To assess the prevalence and associated risk factors for dental fluorosis in early adolescents in India. Methods This was a cross-sectional study carried out on 800 adolescent school children selected from the Jhabua and Dhar districts of Madhya Pradesh, India. The children were in the of 12-15-year age group. A total of eight schools from both Jhabua and Dhar districts were included in the study. A self administered questionnaire collected information on demographic characteristics, oral hygiene practices and various risk factors for dental fluorosis. Water samples were collected from each zone and sent to a laboratory for water fluoride estimation. Dental fluorosis was assessed using the Dean index. Chi-squared (chi2) and logistic regression analysis were performed. Results The overall prevalence of dental fluorosis was found to be 40.5% in early adolescents. The prevalence of dental fluorosis was found to be 45% in the Jhabua district and 36% in the Dhar district. The water fluoride content was found to be the strongest predictor for dental fluorosis followed by the method of water storage. Conclusion Dental fluorosis affects a large number of adolescents in both the Jhabua and Dhar districts of Madhya Pradesh. Effective policies focusing on oral health education and prevention of dental fluorosis need to be drafted. PMID- 29975666 TI - The relationship between metabolic syndrome, cytokines and physical activity in obese youth with and without Prader-Willi syndrome. AB - BACKGROUND: The objective of this study was to examine the associations between adiposity, metabolic syndrome (MetS), cytokines and moderate-to-vigorous physical activity (MVPA) in youth with Prader-Willi syndrome (PWS) and non-syndromic obesity (OB). METHODS: Twenty-one youth with PWS and 34 with OB aged 8-15 years participated. Measurements included body composition, blood pressure, fasting blood markers for glucose control, lipids and inflammation and MVPA. Group differences for adiposity, MetS, blood parameters and MVPA were determined using independent t-tests and chi-square (chi2) analyses. Bivariate correlations and analysis of variance (ANOVA) examined the associations between adiposity, MetS severity, cytokines and MVPA. RESULTS: PWS presented similar percentage of body fat (%), lower body mass index (BMI) z-scores, insulin resistance, triglycerides, MetS severity, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and MVPA and higher high-density lipoprotein (HDL) and adiponectin (ADP) than OB. Fewer PWS presented MetS based on BMI z-score (61.9% vs. 91.2%) and glucose (14.3% vs. 44.1%) compared to OB. In all youth, MetS severity was significantly associated with body fat %, ADP, interleukin-6 (IL-6) and TNF-alpha and also with CRP in PWS, but associations became non-significant for CRP and IL-6 when controlling for body fat %. In PWS, those with low MVPA had significantly higher TNF-alpha than those with high MVPA (1.80+/-0.45 vs. 1.39+/-0.26 pg/mL). CONCLUSIONS: Although PWS presented better cardiometabolic profiles than OB and lower MetS risk, associations between body fat, MetS and cytokines were somewhat similar for both groups, with the exception of CRP. Results suggest a potential role for MVPA related to MetS and inflammation and extend associations shown in OB to PWS. PMID- 29975667 TI - Urinary bisphenol-A levels in children with type 1 diabetes mellitus. AB - BACKGROUND: Bisphenol-A (BPA) is one of the most abundantly produced chemicals globally. Concerns have been raised about BPA's possible role in the pathogenesis of type 1 diabetes mellitus (T1DM). The main aim of the current study was to evaluate the possible association between BPA exposure and T1DM. The second aim was to investigate children's possible BPA exposure routes in Turkey. METHODS: A total of 100 children aged between 5 and 18 years including 50 children with T1DM and 50 healthy children were included. Urinary BPA levels of all children were measured using high-performance liquid chromatography. Mothers of children enrolled in the study were also requested to complete a survey that included questions on the sociodemographic characteristics, medical history and possible BPA exposure routes of their children. RESULTS: In the T1DM group, urinary BPA levels were slightly higher compared to the control group, but this difference was not significant (p=0.510). However, there was an inverse relationship between current urinary BPA levels and birth weight. It was found that the use of plastic kettles and the consumption of dairy products in plastic boxes significantly increased the urinary BPA concentrations in all subjects. CONCLUSIONS: Although there was no significant association between urinary BPA levels and T1DM, we found an inverse relationship between current urinary BPA levels and birth weight. This finding might be important for prenatal exposure, and further prospective research must be conducted. Also, the use of plastic kettles, which has not been mentioned much in the literature before, was found to be an important exposure route for BPA. PMID- 29975668 TI - Air pollution exposure during pregnancy and spontaneous abortion and stillbirth. PMID- 29975669 TI - Empirical Bayesian approach to testing multiple hypotheses with separate priors for left and right alternatives. PMID- 29975670 TI - Gabapentin and NMDA receptor antagonists interacts synergistically to alleviate allodynia in two rat models of neuropathic pain. AB - Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects. PMID- 29975671 TI - Tracing dividing stem cells. PMID- 29975672 TI - "Hot Seat" Simulation Model for Conflict Resolution: A Pilot Study. AB - BACKGROUND: Unresolved conflicts in health care threaten both clinician morale and quality of patient care. We piloted a training model that targeted clinicians' conflict resolution skills. METHODS: Sixty clinicians from local hospitals were randomized into an intervention group (n = 30), completing a 3 hour conflict resolution training session, and a control group (n = 30) without training. The training included facilitated practice with actors, coaching, and feedback. Evaluation of 60 participants' conflict resolution skills was done in videotaped simulations with actors portraying interprofessional colleagues. Global ratings and checklist items developed for assessing clinicians' performance mirrored steps in the conflict communication model. RESULTS: The intervention group's performance exceeded the control group on global scores, 7.2 of 10 (SD = 1.6) versus 5.6 (SD = 1.5), p < .05, and checklist scores, 9.3 of 11 (SD = 2.9) versus 7.9 (SD = 1.5), p < .05. Two checklist items showed statistically significant differences: (1) subjects opened the dialogue on a neutral ground before jumping into conflict discussions (intervention: 97% and control: 73%, p < .05) and (2) subjects elicited the colleague's story before sharing their own story (intervention: 70% and control: 27%, p < .05). CONCLUSIONS: The pilot results suggest that a health care-specific approach to conflict resolution can be effectively taught through facilitated practice, coaching, and feedback. PMID- 29975674 TI - Notes from the Field: Adverse Event Associated with Unintentional Exposure to the Brucella abortus RB51 Vaccine - Oregon, December 2017. PMID- 29975673 TI - Radiological Changes Associated with New Bone Formation Following Osteotome Sinus Floor Elevation (OSFE): A Retrospective Study of 40 Patients with 18-Month Follow Up. AB - BACKGROUND Osteotome sinus floor elevation (OSFE) is used to increase the bone volume at the site of the maxillary sinus through the transalveolar approach, and may require support with bone grafting. The aim of this retrospective study was to evaluate the radiological changes associated with new bone formation following OSFE during an 18-month follow-up period. MATERIAL AND METHODS Forty patients (including 51 implants) underwent OSFE with final dental reconstruction with a single crown, six months after surgery. Of the 51 dental implants, 24 were implanted with bone grafts, and 27 were implanted without bone grafts. All patients were reviewed using preoperative cone beam computed tomography (CBCT) and panoramic radiographs in postoperative follow-up immediately after OSFE, at six-month follow-up, at 12-month follow-up, and at 18-month follow-up. The degree of new bone formation following OSFE was measured by endo-sinus bone gain (ESBG) in the digital radiographs, and the related factors were analyzed. RESULTS At 18 month follow-up, the mean ESBG was 2.55+/-2.24 mm (range, 0.1-8.6 mm). Partial correlation analysis showed that there was no significant correlation between residual bone height (RBH) and ESBG (partial correlation coefficient -0.143) (P=0.328). There were significant positive correlations between the implant protrusion length (IPL) and ESBG (partial correlation coefficient 0.560) (P=0.000), and whether to perform bone grafts and ESBG (partial correlation coefficient 0.596) (P=0.000). CONCLUSIONS Following OSFE combined with a short implant, the IPL and the performance of bone grafts were significantly associated with new bone formation. PMID- 29975675 TI - Notes from the Field: HIV Testing in Health Care Facilities - Lesotho, 2017. PMID- 29975676 TI - QuickStats: Percentage of Injury Deaths* That Occurred in the Decedent's Home for the Five Most Common Causes? of Injury DeathS - United States, 2016. PMID- 29975677 TI - Measles-Rubella Supplementary Immunization Activity Readiness Assessment - India, 2017-2018. AB - In 2013, during the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR), the 11 SEAR countries* adopted goals to eliminate measles and control rubella and congenital rubella syndrome by 2020? (1). To accelerate progress in India (2,3), a phasedS nationwide supplementary immunization activity (SIA) using measles-rubella vaccine and targeting approximately 410 million children aged 9 months-14 years commenced in 2017 and will be completed by first quarter of 2019. To ensure a high-quality SIA, planning and preparation were monitored using a readiness assessment tool adapted from the WHO global field guide** (4) by the India Ministry of Health and Family Welfare. This report describes the results and experience gained from conducting SIA readiness assessments in 24 districts of three Indian states (Andhra Pradesh, Kerala, and Telangana) during the second phase of the SIA. In each selected area, assessments were conducted 4-6 weeks and 1-2 weeks before the scheduled SIA. At the first assessment, none of the states and districts were on track with preparations for the SIA. However, at the second assessment, two (67%) states and 21 (88%) districts were on track. The SIA readiness assessment identified several preparedness gaps; early assessment results were immediately communicated to authorities and led to necessary corrective actions to ensure high-quality SIA implementation. PMID- 29975678 TI - Chagas Disease Surveillance Activities - Seven States, 2017. AB - Chagas disease, a potentially life-threatening disease caused by the protozoan parasite Trypanosoma cruzi, has become a concern in the United States as a result of human emigration from Latin America where Chagas disease is endemic (1). It is estimated that as many as 8 million people living in Mexico, and Central and South America have Chagas disease.* Most cases of Chagas disease in the United States are chronic infections; however, rare cases of acute congenital infections and autochthonous vectorborne transmission have been reported (2). To understand how data are collected and used, a review of state-level public health surveillance for Chagas disease was conducted through semistructured interviews with health officials in six states (Arizona, Arkansas, Louisiana, Mississippi Tennessee, and Texas) where Chagas disease is reportable and one (Massachusetts) where it was previously reportable. States implemented surveillance in response to blood donor screening for Chagas disease and to identify the route of disease transmission. Many states reported primarily chronic cases and had limited ability to respond to local transmission because acute cases were infrequently reported. Surveillance remains important in states with large populations of immigrants or frequent travelers from countries with endemic disease and for states with a risk for local transmission. Surveillance efforts can also help increase awareness among providers and assist in linking patients with Chagas disease to treatment to help prevent cardiac and gastrointestinal complications. PMID- 29975679 TI - Evaluation of Occupational Exposure Limits for Heat Stress in Outdoor Workers - United States, 2011-2016. AB - Heat stress, an environmental and occupational hazard, is associated with a spectrum of heat-related illnesses, including heat stroke, which can lead to death. CDC's National Institute for Occupational Safety and Health (NIOSH) publishes recommended occupational exposure limits for heat stress (1). These limits, which are consistent with those of the American Conference of Governmental Industrial Hygienists (ACGIH) (2), specify the maximum combination of environmental heat (measured as wet bulb globe temperature [WBGT]) and metabolic heat (i.e., workload) to which workers should be exposed. Exposure limits are lower for workers who are unacclimatized to heat, who wear work clothing that inhibits heat dissipation, and who have predisposing personal risk factors (1,2). These limits have been validated in experimental settings but not at outdoor worksites. To determine whether the NIOSH and ACGIH exposure limits are protective of workers, CDC retrospectively reviewed 25 outdoor occupational heat-related illnesses (14 fatal and 11 nonfatal) investigated by the Occupational Safety and Health Administration (OSHA) from 2011 to 2016. For each incident, OSHA assessed personal risk factors and estimated WBGT, workload, and acclimatization status. Heat stress exceeded exposure limits in all 14 fatalities and in eight of 11 nonfatal illnesses. An analysis of Heat Index data for the same 25 cases suggests that when WBGT is unavailable, a Heat Index screening threshold of 85 degrees F (29.4 degrees C) could identify potentially hazardous levels of workplace environmental heat. Protective measures should be implemented whenever the exposure limits are exceeded. The comprehensive heat-related illness prevention program should include an acclimatization schedule for newly hired workers and unacclimatized long-term workers (e.g., during early-season heat waves), training for workers and supervisors about symptom recognition and first aid (e.g., aggressive cooling of presumed heat stroke victims before medical professionals arrive), engineering and administrative controls to reduce heat stress, medical surveillance, and provision of fluids and shady areas for rest breaks. PMID- 29975680 TI - Drosophila melanogaster establishes a species-specific mutualistic interaction with stable gut-colonizing bacteria. AB - Animals live together with diverse bacteria that can impact their biology. In Drosophila melanogaster, gut-associated bacterial communities are relatively simple in composition but also have a strong impact on host development and physiology. It is generally assumed that gut bacteria in D. melanogaster are transient and their constant ingestion with food is required to maintain their presence in the gut. Here, we identify bacterial species from wild-caught D. melanogaster that stably associate with the host independently of continuous inoculation. Moreover, we show that specific Acetobacter wild isolates can proliferate in the gut. We further demonstrate that the interaction between D. melanogaster and the wild isolated Acetobacter thailandicus is mutually beneficial and that the stability of the gut association is key to this mutualism. The stable population in the gut of D. melanogaster allows continuous bacterial spreading into the environment, which is advantageous to the bacterium itself. The bacterial dissemination is in turn advantageous to the host because the next generation of flies develops in the presence of this particularly beneficial bacterium. A. thailandicus leads to a faster host development and higher fertility of emerging adults when compared to other bacteria isolated from wild-caught flies. Furthermore, A. thailandicus is sufficient and advantageous when D. melanogaster develops in axenic or freshly collected figs, respectively. This isolate of A. thailandicus colonizes several genotypes of D. melanogaster but not the closely related D. simulans, indicating that the stable association is host specific. This work establishes a new conceptual model to understand D. melanogaster-gut microbiota interactions in an ecological context; stable interactions can be mutualistic through microbial farming, a common strategy in insects. Moreover, these results develop the use of D. melanogaster as a model to study gut microbiota proliferation and colonization. PMID- 29975681 TI - COBRAme: A computational framework for genome-scale models of metabolism and gene expression. AB - Genome-scale models of metabolism and macromolecular expression (ME-models) explicitly compute the optimal proteome composition of a growing cell. ME-models expand upon the well-established genome-scale models of metabolism (M-models), and they enable a new fundamental understanding of cellular growth. ME-models have increased predictive capabilities and accuracy due to their inclusion of the biosynthetic costs for the machinery of life, but they come with a significant increase in model size and complexity. This challenge results in models which are both difficult to compute and challenging to understand conceptually. As a result, ME-models exist for only two organisms (Escherichia coli and Thermotoga maritima) and are still used by relatively few researchers. To address these challenges, we have developed a new software framework called COBRAme for building and simulating ME-models. It is coded in Python and built on COBRApy, a popular platform for using M-models. COBRAme streamlines computation and analysis of ME-models. It provides tools to simplify constructing and editing ME-models to enable ME-model reconstructions for new organisms. We used COBRAme to reconstruct a condensed E. coli ME-model called iJL1678b-ME. This reformulated model gives functionally identical solutions to previous E. coli ME-models while using 1/6 the number of free variables and solving in less than 10 minutes, a marked improvement over the 6 hour solve time of previous ME-model formulations. Errors in previous ME-models were also corrected leading to 52 additional genes that must be expressed in iJL1678b-ME to grow aerobically in glucose minimal in silico media. This manuscript outlines the architecture of COBRAme and demonstrates how ME-models can be created, modified, and shared most efficiently using the new software framework. PMID- 29975682 TI - mTOR acts as a pivotal signaling hub for neural crest cells during craniofacial development. AB - mTOR is a highly conserved serine/threonine protein kinase that is critical for diverse cellular processes in both developmental and physiological settings. mTOR interacts with a set of molecules including Raptor and Rictor to form two distinct functional complexes, namely the mTORC1 and mTORC2. Here, we used novel genetic models to investigate functions of the mTOR pathway for cranial neural crest cells (NCCs), which are a temporary type of cells arising from the ectoderm layer and migrate to the pharyngeal arches participating craniofacial development. mTOR deletion elicited a proliferation deficit and excessive apoptosis of post-migratory NCCs, leading to growth arrest of the facial primordia along with midline orofacial clefts. Furthermore, NCC differentiation was impaired. Thus, NCC derivatives, such as skeletons, vasculatures and neural tissues were either rudimentary or malformed. We further demonstrate that disruption of mTOR caused P53 hyperactivity and cell cycle arrest in cranial NCCs, and lowering P53 activity by one copy reduction attenuated the severity of craniofacial phenotype in NCC-mTOR knockout mice. Remarkably, NCC-Rptor disruption caused a spectrum of defects mirroring that of the NCC-mTOR deletion, whereas NCC-Rictor disruption only caused a mild craniofacial phenotype compared to the mTOR and Rptor conditional knockout models. Altogether, our data demonstrate that mTOR functions mediated by mTORC1 are indispensable for multiple processes of NCC development including proliferation, survival, and differentiation during craniofacial morphogenesis and organogenesis, and P53 hyperactivity in part accounts for the defective craniofacial development in NCC mTOR knockout mice. PMID- 29975683 TI - rbpms2 functions in Balbiani body architecture and ovary fate. AB - The most prominent developmental regulators in oocytes are RNA-binding proteins (RNAbps) that assemble their targets into ribonucleoprotein granules where they are stored, transported and translationally regulated. RNA-binding protein of multiple splice forms 2, or Rbpms2, interacts with molecules that are essential to reproduction and egg patterning, including bucky ball, a key factor for Bb formation. Rbpms2 is localized to germ granules in primordial germ cells (PGCs) and to the Balbiani body (Bb) of oocytes, although the mechanisms regulating Rbpms2 localization to these structures are unknown. Using mutant Rbpms2 proteins, we show that Rbpms2 requires distinct protein domains to localize within germ cells and somatic cells. Accumulation and localization to subcellular compartments in the germline requires an intact RNA binding domain. Whereas in zebrafish somatic blastula cells, the conserved C-terminal domain promotes localization to the bipolar centrosomes/spindle. To investigate Rbpms2 functions, we mutated the duplicated and functionally redundant zebrafish rbpms2 genes. The gonads of rbpms2a;2b (rbpms2) mutants initially contain early oocytes, however definitive oogenesis ultimately fails during sexual differentiation and, rbpms2 mutants develop as fertile males. Unlike other genes that promote oogenesis, failure to maintain oocytes in rbpms2 mutants was not suppressed by mutation of Tp53. These findings reveal a novel and essential role for rbpms2 in oogenesis. Ultrastructural and immunohistochemical analyses revealed that rbpms2 is not required for the asymmetric accumulation of mitochondria and Buc protein in oocytes, however its absence resulted in formation of abnormal Buc aggregates and atypical electron-dense cytoplasmic inclusions. Our findings reveal novel and essential roles for rbpms2 in Buc organization and oocyte differentiation. PMID- 29975684 TI - Bases of antisense lncRNA-associated regulation of gene expression in fission yeast. AB - Antisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2 sensitivite lncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase gene ctt1 revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT. Interestingly, expression of this asXUT was also activated in wild-type cells upon oxidative stress, concomitant to ctt1 induction, indicating a potential attenuation feedback. This attenuation correlates with asXUT abundance, it is transcriptional, characterized by low RNAPII-ser5 phosphorylation, and it requires an histone deacetylase activity and the conserved Set2 histone methyltransferase. Finally, we identified Dicer as another RNA processing factor acting on ctt1 induction, but independently of Exo2. We propose that asXUTs could modulate the expression of their paired-sense genes when it exceeds a critical threshold, using a conserved mechanism independent of RNAi. PMID- 29975685 TI - Depression and Post Traumatic Stress amongst female sex workers in Soweto, South Africa: A cross sectional, respondent driven sample. AB - BACKGROUND: Sex workers in South Africa are exposed to high levels of violence, yet little is known about their mental health needs. This study aims to understanding the prevalence of depression and post-traumatic stress disorder (PTSD) and their risk factors amongst female sex worker (FSWs) in Soweto, South Africa. METHODS: A cross-sectional, respondent-driven sampling (RDS) survey enrolled 508 FSWs. Raw and RDS adjusted data were analyzed using a chi-squared test of association and multinomial regression for risk factors associated with depression and PTSD. FINDINGS: Symptoms of severe depression were prevalent amongst 68.7%, PTSD was 39.6%, and 32.7% suffered from comorbid PTSD and depression. Experiencing >=3 kinds of violence increased the likelihood of comorbidity (RRR4.11, 95% CI 1.52-11.12,p = 0.005). Internalised stigma increased the likelihood of one mental health condition (RRR1.25, 95% CI 1.10-1.42,p = 0.001), higher self-esteem was associated with independent (RRR1.14, 95% CI 1.05 1.25,p = 0.002) and comorbid conditions (RRR1.17, 95% CI 1.07-1.27,p = 0.001). CONCLUSION: Our findings highlight the sizable burden of treatable mental health conditions among FSWs in Soweto. This was driven by multiple exposures to violence, sex work related discrimination and overall moderate levels of self esteem masking defence mechanisms. This suggests the urgent need to design and integrate services geared to the mental health needs for this population. PMID- 29975686 TI - Building flux capacity: Citizen scientists increase resolution of soil greenhouse gas fluxes. AB - Though citizen science programs have been broadly successful in diverse scientific fields, their adoption has lagged in some disciplines, including soil science and ecosystem ecology. Collaborations with citizen scientists may be viewed as a conundrum in these disciplines, which often require substantial labor and technical experience; citizen scientists could improve sampling capacity but may reduce sample quality or require training and oversight prior to and while performing specialized tasks. To demonstrate the feasibility of incorporating citizen scientists into soil biogeochemistry research, we conducted a proof-of concept study in high-elevation meadows of the Sierra Nevada in California. A collaboration between university researchers and citizen scientists allowed us to assess spatial and diel patterns of soil greenhouse gas (GHG) fluxes with an intensity and frequency that would otherwise be beyond the capacity of a typical research laboratory. This collaboration with citizen scientists increased our sampling intensity by over 700% while only doubling the sampling error relative to that of full-time researchers. With training and support from project scientists, citizen scientists collected data that demonstrate spatial independence of carbon dioxide, methane, and nitrous oxide at scales between 1 m and 175 m. Additionally, we found a lack of temporal variation over a 24-h period for all three GHGs. Citizen scientists participating in this one-day event reported levels of satisfaction commensurate with longer-term, immersive campaigns. The place-based event also proved an effective tool for teaching intangible concepts of soil biogeochemistry and promoting local conservation. Despite perceived barriers to entry, this study demonstrates the mutual benefits of citizen science collaborations in soil science and ecosystem ecology, encouraging adoption by disciplines that have been slow to take advantage of such collaborations. Short-term, local citizen science events can provide meaningful experiences for area residents and teach global biogeochemical cycles in a place based context. PMID- 29975687 TI - Earthquake prediction model using support vector regressor and hybrid neural networks. AB - Earthquake prediction has been a challenging research area, where a future occurrence of the devastating catastrophe is predicted. In this work, sixty seismic features are computed through employing seismological concepts, such as Gutenberg-Richter law, seismic rate changes, foreshock frequency, seismic energy release, total recurrence time. Further, Maximum Relevance and Minimum Redundancy (mRMR) criteria is applied to extract the relevant features. A Support Vector Regressor (SVR) and Hybrid Neural Network (HNN) based classification system is built to obtain the earthquake predictions. HNN is a step wise combination of three different Neural Networks, supported by Enhanced Particle Swarm Optimization (EPSO), to offer weight optimization at each layer. The newly computed seismic features in combination with SVR-HNN prediction system is applied on Hindukush, Chile and Southern California regions. The obtained numerical results show improved prediction performance for all the considered regions, compared to previous prediction studies. PMID- 29975688 TI - Genetic basis and evolution of rapid cycling in railway populations of tetraploid Arabidopsis arenosa. AB - Spatially structured plant populations with diverse adaptations provide powerful models to investigate evolution. Human-generated ruderal habitats are abundant and low-competition, but are challenging for plants not adapted to them. Ruderal habitats also sometimes form networked corridors (e.g. roadsides and railways) that allow rapid long-distance spread of successfully adapted variants. Here we use transcriptomic and genomic analyses, coupled with genetic mapping and transgenic follow-up, to understand the evolution of rapid cycling during adaptation to railway sites in autotetraploid Arabidopsis arenosa. We focus mostly on a hybrid population that is likely a secondary colonist of a railway site. These mountain railway plants are phenotypically similar to their cosmopolitan cousins. We thus hypothesized that colonization primarily involved the flow of adaptive alleles from the cosmopolitan railway variant. But our data shows that it is not that simple: while there is evidence of selection having acted on introgressed alleles, selection also acted on rare standing variation, and new mutations may also contribute. Among the genes we show have allelic divergence with functional relevance to flowering time are known regulators of flowering, including FLC and CONSTANS. Prior implications of these genes in weediness and rapid cycling supports the idea that these are "evolutionary hotspots" for these traits. We also find that one of two alleles of CONSTANS under selection in the secondary colonist was selected from rare standing variation in mountain populations, while the other was introgressed from the cosmopolitan railway populations. The latter allele likely arose in diploid populations over 700km away, highlighting how ruderal populations could act as allele conduits and thus influence local adaptation. PMID- 29975689 TI - HIV-1 diversity among young women in rural South Africa: HPTN 068. AB - BACKGROUND: South Africa has one of the highest rates of HIV-1 (HIV) infection world-wide, with the highest rates among young women. We analyzed the molecular epidemiology and evolutionary history of HIV in young women attending high school in rural South Africa. METHODS: Samples were obtained from the HPTN 068 randomized controlled trial, which evaluated the effect of cash transfers for school attendance on HIV incidence in women aged 13-20 years (Mpumalanga province, 2011-2015). Plasma samples from HIV-infected participants were analyzed using the ViroSeq HIV-1 Genotyping assay. Phylogenetic analysis was performed using 200 pol gene study sequences and 2,294 subtype C reference sequences from South Africa. Transmission clusters were identified using Cluster Picker and HIV TRACE, and were characterized using demographic and other epidemiological data. Phylodynamic analyses were performed using the BEAST software. RESULTS: The study enrolled 2,533 young women who were followed through their expected high school graduation date (main study); some participants had a post-study assessment (follow-up study). Two-hundred-twelve of 2,533 enrolled young women had HIV infection. HIV pol sequences were obtained for 94% (n = 201/212) of the HIV infected participants. All but one of the sequences were HIV-1 subtype C; the non C subtype sequence was excluded from further analysis. Median pairwise genetic distance between the subtype C sequences was 6.4% (IQR: 5.6-7.2). Overall, 26% of study sequences fell into 21 phylogenetic clusters with 2-6 women per cluster. Thirteen (62%) clusters included women who were HIV-infected at enrollment. Clustering was not associated with study arm, demographic or other epidemiological factors. The estimated date of origin of HIV subtype C in the study population was 1958 (95% highest posterior density [HPD]: 1931-1980), and the median estimated substitution rate among study pol sequences was 1.98x10-3 (95% HPD: 1.15x10-3-2.81x10-3) per site per year. CONCLUSIONS: Phylogenetic analysis suggests that multiple HIV subtype C sublineages circulate among school age girls in South Africa. There were no substantive differences in the molecular epidemiology of HIV between control and intervention arms in the HPTN 068 trial. PMID- 29975690 TI - Paxillin phosphorylation at serine 273 and its effects on Rac, Rho and adhesion dynamics. AB - Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signalling proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly. Paxillin is known to bind to a GIT1-betaPIX-PAK1 complex, which increases the local activation of the small GTPase Rac. To understand quantitatively the behaviour of this system and how it relates to adhesion assembly/disassembly, we developed a mathematical model describing the dynamics of the small GTPases Rac and Rho as determined by paxillin S273 phosphorylation. Our model revealed that the system possesses bistability, where switching between uninduced (active Rho) and induced (active Rac) states can occur through a change in rate of paxillin phosphorylation or PAK1 activation. The bistable switch is characterized by the presence of memory, minimal change in the levels of active Rac and Rho within the induced and uninduced states, respectively, and the limited regime of monostability associated with the uninduced state. These results were validated experimentally by showing the presence of bimodality in adhesion assembly and disassembly rates, and demonstrating that Rac activity increases after treating Chinese Hamster Ovary cells with okadaic acid (a paxillin phosphatase inhibitor), followed by a modest recovery after 20 min washout. Spatial gradients of phosphorylated paxillin in a reaction-diffusion model gave rise to distinct regions of Rac and Rho activities, resembling polarization of a cell into front and rear. Perturbing several parameters of the model also revealed important insights into how signalling components upstream and downstream of paxillin phosphorylation affect dynamics. PMID- 29975691 TI - Forelimb musculature and osteological correlates in Sauropodomorpha (Dinosauria, Saurischia). AB - This contribution presents the forelimb muscular arrangement of sauropodomorph dinosaurs as inferred by comparisons with living archosaurs (crocodiles and birds) following the Extant Phylogenetic Bracket approach. Forty-one muscles were reconstructed, including lower limb and manus musculature, which prior information available was scarce for sauropodomorphs. A strong emphasis was placed on osteological correlates (such as tubercles, ridges and striae) and comparisons with primitive archosauromorphs are included in order to track these correlates throughout the clade. This should help to elucidate how widespread among other archosaurian groups are these osteological correlates identified in Sauropodomorpha. The ultimate goal of this contribution was to provide an exhaustive guide to muscular identification in fossil archosaurs and to offer solid anatomical bases for future studies based on osteology, myology, functional morphology and systematics. PMID- 29975692 TI - The spleen microbiota of small wild mammals reveals distinct patterns with tick borne bacteria. AB - BACKGROUND: Wild mammals serve as reservoirs for a variety of microbes and play an important role in the enzootic cycles of these microbes. Some of them are vector-borne bacteria in the genera Anaplasma, Ehrlichia and Rickettsia of the order Rickettsiales, which can cause febrile illnesses in human beings as well as animals. Anaplasma spp., Ehrlichia spp. and many spotted fever group (SFG) Rickettsia spp. are transmitted to mammalian hosts by tick vectors during blood meals. As a powerful sequencing method, the next generation sequencing can reveal the complexity of bacterial communities in humans and animals. Compared with limited studies on blood microbiota, however, much fewer studies have been carried out on spleen microbiota, which is very scarce in wild mammals. Chongming Island is the third biggest island in China. It was unclear whether there were any vector-borne bacteria in Chongming Island. In the present study, we explored the bacterial microbiota in the spleens of wild mice and shrews from the rural areas of Chongming Island and investigated the prevalence of vector-borne bacteria. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNAs were extracted from the spleen samples of 35 mice and shrews. The 16S rDNA V3-V4 regions of the DNA extracts were amplified by PCR and subjected to the 16S rDNA-targeted metagenomic sequencing on an Illumina MiSeq platform. All the 35 spleen samples obtained data with sufficient coverage (99.7-99.9%) for analysis. More than 1,300,000 sequences were obtained after quality control and classified into a total of 1,967 operational taxonomic units (OTUs) clustered at 97% similarity. The two most abundant bacterial phyla were Firmicutes and Proteobacteria according to the analysis of rarefied sequences. Among the bacterial communities detected in this study, Anaplasma, Rickettsia and Coxiella were adjacently clustered by hierarchical analysis. Significant differences in many bacterial features between Anaplasma-positive and Anaplasma-negative samples were identified by LEfSe analysis and Wilcoxon rank-sum test, suggesting that the Anaplasma-infection of small wild mammals was associated with a specific pattern of spleen microbiota. CONCLUSIONS/SIGNIFICANCE: Our study has comprehensively characterized the complex bacterial profiles in the spleens of wild mice and shrews from Chongming Island, Shanghai city. This work has revealed distinct spleen bacterial communities associated with tick-borne bacteria in wild animals. The detection of tick-borne bacteria highlights the risk of contracting pathogens with public health importance upon tick-exposure in the studied areas. PMID- 29975693 TI - Quantum theory of mass potentials. AB - Probabilistic formalism of quantum mechanics is used to quantitatively link the global scale mass potential with the underlying electrical activity of excitable cells. Previous approaches implemented methods of classical physics to reconstruct the mass potential in terms of explicit physical models of participating cells and the volume conductor. However, the multiplicity of cellular processes with extremely intricate mixtures of deterministic and random factors prevents the creation of consistent biophysical parameter sets. To avoid the uncertainty inherent in physical attributes of cell ensembles, we undertake here a radical departure from deterministic equations of classical physics, instead applying the probabilistic reasoning of quantum mechanics. Crucial steps include: (1) the relocation of the elementary bioelectric sources from a cellular to a molecular level; (2) the creation of microscale particle models in terms of a non-homogenous birth-and-death process. To link the microscale processes with macroscale potentials, time-frequency analysis was applied for estimation of the empirical characteristic functions for component waveforms of electroencephalogram (EEG), eye-blink electromyogram (EMG), and electrocardiogram (ECG). We describe universal models for the amplitude spectra and phase functions of functional components of mass potentials. The corresponding time domain relationships disclose the dynamics of mass potential components as limit distribution functions produced by specific microscale transients. The probabilistic laws governing the microscale machinery, founded on an empirical basis, are presented. Computer simulations of particle populations with time dependent transition probabilities reveal that hidden deterministic chaos underlies development of the components of mass potentials. We label this kind of behaviour "transient deterministic chaos". PMID- 29975694 TI - Prioritizing core areas, corridors and conflict hotspots for lion conservation in southern Africa. AB - Conservation of large carnivores, such as the African lion, requires preservation of extensive core habitat areas, linkages between them, and mitigation of human wildlife conflict. However, there are few rigorous examples of efforts that prioritized conservation actions for all three of these critical components. We used an empirically optimized resistance surface to calculate resistant kernel and factorial least cost path predictions of population connectivity and conflict risk for lions across the Kavango-Zambezi Transfrontier Conservation Area (KAZA) and surrounding landscape. We mapped and ranked the relative importance of (1) lion dispersal areas outside National Parks, (2) corridors between the key areas, and (3) areas of highest human-lion conflict risk. Spatial prioritization of conservation actions is critical given extensive land use redesignations that are reducing the extent and increasing the fragmentation of lion populations. While our example focuses on lions in southern Africa, it provides a general approach for rigorous, empirically based comprehensive conservation planning based on spatial prioritization. PMID- 29975695 TI - Genetic diversity, phylogeography and molecular clock of the Lutzomyia longipalpis complex (Diptera: Psychodidae). AB - BACKGROUND: The Lutzomyia longipalpis complex has a wide but discontinuous distribution in Latin America, extending throughout the Neotropical realm between Mexico and northern Argentina and Uruguay. In the Americas, this sandfly is the main vector of Leishmania infantum, the parasite responsible for Visceral Leishmaniasis (VL). The Lu. longipalpis complex consists of at least four sibling species, however, there is no current consensus on the number of haplogroups, or on their divergence. Particularly in Argentina, there have been few genetic analyses of Lu. longipalpis, despite its southern expansion and recent colonization of urban environments. The aim of this study was to analyze the genetic diversity and structure of Lu. longipalpis from Argentina, and to integrate these data to re-evaluate the phylogeography of the Lu. longipalpis complex using mitochondrial markers at a Latin American scale. METHODOLOGY/PRINCIPAL FINDINGS: Genetic diversity was estimated from six sites in Argentina, using a fragment of the ND4 and the 3' extreme of the cyt b genes. Greatest genetic diversity was found in Tartagal, Santo Tome and San Ignacio. There was high genetic differentiation of Lu. longipalpis in Argentina using both markers: ND4 (FST = 0.452, p < 0.0001), cyt b (FST = 0.201, p < 0.0001). Genetic and spatial Geneland analyses reveal the existence of two primary genetic clusters in Argentina, cluster 1: Tartagal, Santo Tome, and San Ignacio; cluster 2: Puerto Iguazu, Clorinda, and Corrientes city. Phylogeographic analyses using ND4 and cyt b gene sequences available in GenBank from diverse geographic sites suggest greater divergence than previously reported. At least eight haplogroups (three of these identified in Argentina), each separated by multiple mutational steps using the ND4, are differentiated across the Neotropical realm. The divergence of the Lu. longipalpis complex from its most recent common ancestor (MRCA) was estimated to have occurred 0.70 MYA (95% HPD interval = 0.48-0.99 MYA). CONCLUSIONS/SIGNIFICANCE: This study provides new evidence supporting two Lu. longipalpis genetic clusters and three of the total eight haplogroups circulating in Argentina. There was a high level of phylogeographic divergence among the eight haplogroups of the Lu. longipalpis complex across the Neotropical realm. These findings suggest the need to analyze vector competence, among other parameters intrinsic to a zoonosis, according to vector haplogroup, and to consider these in the design and surveillance of vector and transmission control strategies. PMID- 29975696 TI - Impact of a national deworming campaign on the prevalence of soil-transmitted helminthiasis in Uganda (2004-2016): Implications for national control programs. AB - BACKGROUND: Soil-transmitted Helminths and Anemia potentially reduce and retard cognitive and physical growth in school-age children with great implications for national control programs in Africa. After 13 years of deworming and limited health education campaigns, a study was undertaken to evaluate the impact of deworming interventions on the prevalence and intensity of soil-transmitted helminthic infections in school-age children in Uganda. METHODOLOGY: A cross sectional study was carried out in six regions of Uganda, where two districts were randomly selected per region based on the ecological zones in the country. Included in the study were the districts; Mpigi and Nakasongola from the Central; Nakapiripirit and Kotido from Karamoja; Arua and Yumbe from West Nile; Gulu and Alebtong from the North; Kaliro and Mbale from the East; Hoima and Bundibugyo in the West. Five schools were randomly selected from each district and in each school 50 children aged 6-14 years were randomly selected. Stool samples were taken each child and examined for the presence of helminthic infections. A short pretested questionnaire was administered to each participant to obtain their knowledge, attitude, and practice relating to STH infections, their control. General observations were made on environmental sanitation in the schools. The location of each school was geo-referenced using a GPS machine (Garmin(r)GPSMAP62, Garmin Ltd, Southampton, UK). RESULTS: In total, 4,285 children were assessed including 719(16.82%) from central region, 718(16.80%) from eastern region, 719 (16.82%) from northern region, 689 (18.82%) from Karamoja region, 717(16.77%) from West Nile region and 723(16.91%) from western region. The average age of the children was 12.6 years with a standard deviation, SD 1.8 years and the minimum age was 6 years and upper age limit of 12 years. The percentage of boys (50.1%) and girls (49.9%) was comparable. 8.8% (95% CI; 8.0 9.7) were infected with at least any one STH species. Hookworm was the most prevalent (7.7%; 95% CI; 6.9-8.5) followed by whipworms (Trichuris trichiura) (1.3%; 95% CI; 1.0-1.7) and roundworms (Ascaris lumbricoides) (0.5%; 95% CI; 0.3 0.7). Some children had Schistosoma mansoni, 13.0% (95% CI; 12.0-14.0). All the children knew what soil transmitted helminths were (62.8%, 95% CI: 61.3-64.2) and most common knowledge of information were from; home (39%, 95% CI: 37.1-40.8), media (radio& newspaper)(11%, 95% CI: 9.8-12.2), school(65.7%, 95% CI: 63.9-67.5) and friends(11.5%, 95% CI: 10.3-12.7). Majority were aware of how one gets infected with soil transmitted helminths through; eating contaminated food (77.5%, 95% CI: 76.0-79.1), walking barefoot (59.6%, 95% CI: 57.8-61.5), drinking contaminated water (52.9%, 95% CI: 51.0-54.8), playing in dirty places (21.8%, 95% CI: 20.2-23.3) and dirty hands (2.3%, 95% CI: 1.7-2.9). CONCLUSION: Semi annual deworming campaigns have proved effective in significantly reducing helminthic infections in most of the districts in Uganda. Regular evaluations are vital to assess impact of the interventions and guide programme implementation. Our data shows that the prevalence of infection has been reduced to a level where STH morbidity is no longer of public health importance in most districts surveyed. PMID- 29975697 TI - Multilocus microsatellite typing (MLMT) reveals host-related population structure in Leishmania infantum from northeastern Italy. AB - BACKGROUND: Visceral leishmaniasis (VL) caused by Leishmania infantum is an ongoing health problem in southern Europe, where dogs are considered the main reservoirs of the disease. Current data point to a northward spread of VL and canine leishmaniasis (CanL) in Italy, with new foci in northern regions previously regarded as non-endemic. METHODOLOGY/PRINCIPAL FINDINGS: Multilocus microsatellite typing (MLMT) was performed to investigate genetic diversity and population structure of L. infantum on 55 samples from infected humans, dogs and sand flies of the E-R region between 2013 and 2017. E-R samples were compared with 10 L. infantum samples from VL cases in other Italian regions (extra E-R) and with 52 strains within the L. donovani complex. Data displayed significant microsatellite polymorphisms with low allelic heterozygosity. Forty-one unique and eight repeated MLMT profiles were recognized among the L. infantum samples from E-R, and ten unique MLMT profiles were assigned to the extra E-R samples. Bayesian analysis assigned E-R samples to two distinct populations, with further sub-structuring within each of them; all CanL samples belonged to one population, genetically related to Mediterranean MON-1 strains, while all but one VL cases as well as the isolate from the sand fly Phlebotomus perfiliewi fell under the second population. Conversely, VL samples from other Italian regions proved to be genetically similar to strains circulating in dogs. CONCLUSIONS/SIGNIFICANCE: A peculiar epidemiological situation was observed in northeastern Italy, with the co-circulation of two distinct populations of L. infantum; one population mainly detected in dogs and the other population detected in humans and in a sand fly. While the classical cycle of CanL in Italy fits well into the data obtained for the first population, the population found in infected humans exhibits a different cycle, probably not involving a canine reservoir. This study can contribute to a better understanding of the population structure of L. infantum circulating in northeastern Italy, thus providing useful epidemiologic information for public health authorities. PMID- 29975698 TI - SAFlex: A structural alphabet extension to integrate protein structural flexibility and missing data information. AB - In this paper, we describe SAFlex (Structural Alphabet Flexibility), an extension of an existing structural alphabet (HMM-SA), to better explore increasing protein three dimensional structure information by encoding conformations of proteins in case of missing residues or uncertainties. An SA aims to reduce three dimensional conformations of proteins as well as their analysis and comparison complexity by simplifying any conformation in a series of structural letters. Our methodology presents several novelties. Firstly, it can account for the encoding uncertainty by providing a wide range of encoding options: the maximum a posteriori, the marginal posterior distribution, and the effective number of letters at each given position. Secondly, our new algorithm deals with the missing data in the protein structure files (concerning more than 75% of the proteins from the Protein Data Bank) in a rigorous probabilistic framework. Thirdly, SAFlex is able to encode and to build a consensus encoding from different replicates of a single protein such as several homomer chains. This allows localizing structural differences between different chains and detecting structural variability, which is essential for protein flexibility identification. These improvements are illustrated on different proteins, such as the crystal structure of an eukaryotic small heat shock protein. They are promising to explore increasing protein redundancy data and obtain useful quantification of their flexibility. PMID- 29975699 TI - Functional reorganization of the conceptual brain system after deafness in early childhood. AB - The neurodevelopmental consequences of deafness on the functional neuroarchitecture of the conceptual system have not been intensively investigated so far. Using functional magnetic resonance imaging (fMRI), we therefore identified brain areas involved in conceptual processing in deaf and hearing participants. Conceptual processing was probed by a pictorial animacy decision task. Furthermore, brain areas sensitive to observing verbal signs and to observing non-verbal visual hand actions were identified in deaf participants. In hearing participants, brain areas responsive to environmental sounds and the observation of visual hand actions were determined. We found a stronger recruitment of superior and middle temporal cortex in deaf compared to hearing participants during animacy decisions. This region, which forms auditory cortex in hearing people according to the sound listening task, was also activated in deaf participants, when they observed sign language, but not when they observed non-verbal hand actions. These results indicate that conceptual processing in deaf people more strongly depends on language representations compared to hearing people. Furthermore, additionally enhanced activation in visual and motor areas of deaf versus hearing participants during animacy decisions and a more frequent report of visual and motor features in the property listing task suggest that the loss of the auditory channel is partially compensated by an increased importance of visual and motor information for constituting object knowledge. Hence, our results indicate that conceptual processing in deaf compared to hearing people is more strongly based on the language system, complemented by an enhanced contribution of the visuo-motor system. PMID- 29975700 TI - Comparative transcriptome profiling of Blumeria graminis f. sp. tritici during compatible and incompatible interactions with sister wheat lines carrying and lacking Pm40. AB - Blumeria graminis f. sp. tritici (Bgt) is an obligate biotrophic fungus that causes wheat powdery mildew, which is a devastating disease in wheat. However, little is known about the pathogenesis of this fungus, and differences in the pathogenesis of the same pathogen at various resistance levels in hosts have not been determined. In the present study, leaf tissues of both Pm40-expressing hexaploid wheat line L658 and its Pm40-deficient sister line L958 were harvested at 0 (without inoculation), 6, 12, 24, 48 and 72 hours post-inoculation (hpi) with Bgt race 15 and then subjected to RNA sequencing (RNA-seq). In addition, we also observed changes in fungal growth morphology at the aforementioned time points. There was a high correlation between percentage of reads mapped to the Bgt reference genome and biomass of the fungus within the leaf tissue during the growth process. The percentage of mapped reads of Bgt in compatible interactions was significantly higher (at the p<0.05 level) than that of reads in incompatible interactions from 24 to 72 hpi. Further functional annotations indicated that expression levels of genes encoding H+-transporting ATPase, putative secreted effector proteins (PSEPs) and heat shock proteins (HSPs) were significantly up regulated in compatible interactions compared with these levels in incompatible interactions, particularly at 72 hpi. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that genes involved in the endocytosis pathway were also enriched in compatible interactions. Overall, genes encoding H+ transporting ATPase, PSEPs and HSPs possibly played crucial roles in successfully establishing the pathogenesis of compatible interactions during late stages of inoculation. The study results also indicated that endocytosis is likely to play a potential role in Bgt in establishing compatible interactions. PMID- 29975701 TI - Identification of a gene-expression predictor for diagnosis and personalized stratification of lupus patients. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a wide spectrum of clinical manifestations and degrees of severity. Few genomic biomarkers for SLE have been validated and employed to inform clinical classifications and decisions. To discover and assess the gene-expression based SLE predictors in published studies, we performed a meta-analysis using our established signature database and a data similarity-driven strategy. From 13 training data sets on SLE gene-expression studies, we identified a SLE meta signature (SLEmetaSig100) containing 100 concordant genes that are involved in DNA sensors and the IFN signaling pathway. We rigorously examined SLEmetaSig100 with both retrospective and prospective validation in two independent data sets. Using unsupervised clustering, we retrospectively elucidated that SLEmetaSig100 could classify clinical samples into two groups that correlated with SLE disease status and disease activities. More importantly, SLEmetaSig100 enabled personalized stratification demonstrating its ability to prospectively predict SLE disease at the individual patient level. To evaluate the performance of SLEmetaSig100 in predicting SLE, we predicted 1,171 testing samples to be either non-SLE or SLE with positive predictive value (97-99%), specificity (85%-84%), and sensitivity (60-84%). Our study suggests that SLEmetaSig100 has enhanced predictive value to facilitate current SLE clinical classification and provides personalized disease activity monitoring. PMID- 29975702 TI - The effects of plasma chromium on lipid profile, glucose metabolism and cardiovascular risk in type 2 diabetes mellitus. A case - control study. AB - BACKGROUND: The study was aimed at determining the effect of plasma chromium concentration on the metabolism of glucose, and lipids and their subsequent cardiovascular risk in patients with type 2 diabetes in the Bolgatanga district of Ghana. MATERIAL AND METHODS: Fasting blood glucose and lipids profile were determined by enzymatic assay using the BT 5000(r) Random Access Chemistry Analyzer. Fasting serum insulin and High sensitive C-reactive protein were determined by ELISA, a solid phase direct sandwich immunoassay method. HOMA-IR, which is based on fasting blood sample for insulin and glucose concentrations measured in a single blood sample, was used to calculate insulin resistance. Plasma chromium was measured using an atomic Absorption Spectrometer. RESULTS: Patientswith diabeteshad significantly (p<0.0001) increased LDL, TC, TG, VLDL, insulin, CRP and HOMAIR and a significantly reduced plasma chromium (p<0.0001) (0.53+/- 0.02MUg/l and 0.11+/-0.01MUg/l control and case respectively). Low Cr (p <=0.001) was associated with high blood pressure, obesity and lipid dysregulation. Plasma Cr significantly correlated negatively with blood pressure and LDL. CONCLUSION: Lower plasma Cr level was associated with hyperglycaemia, hyperinsulinemia, hypertension, insulin resistance and high inflammation marker HsCRP. PMID- 29975703 TI - Comparison of latent tuberculosis infection screening strategies before tumor necrosis factor inhibitor treatment in inflammatory arthritis: IGRA-alone versus combination of TST and IGRA. AB - This study aims to compare the latent tuberculosis infection (LTBI) screening strategy of interferon-gamma release assay (IGRA)-alone and in combination with tuberculin skin tests (TSTs) before the initiation of tumor necrosis factor (TNF) inhibitor treatment in patients with inflammatory arthritis. Between January 2011 and June 2017, we enrolled 476 patients who were followed up for >=1 year after the TNF inhibitor initiation in a tertiary referral center in South Korea. Inflammatory arthritis comprised rheumatoid arthritis in 266 (55.9%) and ankylosing spondylitis in 210 (44.1%) patients. The following strategies were used for LTBI screening during the study period: (i) from January 2011 to October 2014, the combination of TST and QuantiFERON-TB Gold In-Tube (QFT-GIT); (ii) between November 2014 and February 2015, QFT-GIT-alone and (iii) since March 2015, either the combination of TST and QFT-GIT or QFT-GIT-alone depending on the attending physician's choice. We compared the screening strategies of QFT-GIT alone and in combination with TST. Overall, 338 (71.0%) patients received LTBI screening tests using the combination of TST and QFT-GIT, and 138 (29.0%) received QFT-GIT-alone. In addition, the LTBI tests were positive in 159 (47.0%) of 338 patients using the combination tests, and 43.8% (148/338) required LTBI treatment. Meanwhile, the LTBI tests were positive in 32.6% (45/138) of QFT-GIT alone patients, and 30.4% (42/138) required LTBI treatment. Among 338 patients who received combination tests, 2 patients developed active tuberculosis within 1 year after the TNF inhibitor initiation. Of patients who received QFT-GIT-alone, no patient developed tuberculosis. In conclusion, among patients who received QFT GIT-alone, the number of patients who required LTBI treatment declined compared to the TST and QFT-GIT combination, and none developed active tuberculosis within 1 year, suggesting that QFT-GIT-alone could be a potential screening strategy for diagnosing LTBI in patients with inflammatory arthritis in South Korea. PMID- 29975704 TI - Arsenic level in toenails is associated with hearing loss in humans. AB - Arsenic (As) pollution in drinking water is a worldwide health risk for humans. We previously showed hearing loss in young people who live in areas of As polluted drinking water and in young mice orally treated with As. In this study, we epidemiologically examined associations between As levels in toenails and hearing in 145 Bangladeshi aged 12-55 years in 2014. Levels of As in toenails, but not those in urine, were shown to be significantly correlated with hearing loss at 4 kHz [odds ratio (OR) = 4.27; 95% confidence interval (CI): 1.51, 12.05], 8 kHz (OR = 3.91; 95% CI: 1.47, 10.38) and 12 kHz (OR = 4.15; 95% CI: 1.55, 11.09) by multivariate analysis with adjustments for age, sex, smoking and BMI. Our experimental study further showed a significant association between As levels in inner ears and nails (r = 0.8113, p = 0.0014) in mice orally exposed to As, suggesting that As level in nails is a suitable index to assess As level in inner ears. Taken together, the results of our study suggest that As level in nails could be a convenient and non-invasive biomarker for As-mediated hearing loss in humans. PMID- 29975705 TI - Using risk of bias domains to identify opportunities for improvement in food- and nutrition-related research: An evaluation of research type and design, year of publication, and source of funding. AB - PURPOSE: This retrospective cross-sectional study aimed to identify opportunities for improvement in food and nutrition research by examining risk of bias (ROB) domains. METHODS: Ratings were extracted from critical appraisal records for 5675 studies used in systematic reviews conducted by three organizations. Variables were as follows: ROB domains defined by the Cochrane Collaboration (Selection, Performance, Detection, Attrition, and Reporting), publication year, research type (intervention or observation) and specific design, funder, and overall quality rating (positive, neutral, or negative). Appraisal instrument questions were mapped to ROB domains. The kappa statistic was used to determine consistency when multiple ROB ratings were available. Binary logistic regression and multinomial logistic regression were used to predict overall quality and ROB domains. FINDINGS: Studies represented a wide variety of research topics (clinical nutrition, food safety, dietary patterns, and dietary supplements) among 15 different research designs with a balance of intervention (49%) and observation (51%) types, published between 1930 and 2015 (64% between 2000-2009). Duplicate ratings (10%) were consistent (kappa = 0.86-0.94). Selection and Performance domain criteria were least likely to be met (57.9% to 60.1%). Selection, Detection, and Performance ROB ratings predicted neutral or negative quality compared to positive quality (p<0.001). Funder, year, and research design were significant predictors of ROB. Some sources of funding predicted increased ROB (p<0.001) for Selection (interventional: industry only and none/not reported; observational: other only and none/not reported) and Reporting (observational: university only and other only). Reduced ROB was predicted by combined and other only funding for intervention research (p<0.005). Performance ROB domain ratings started significantly improving in 2000; others improved after 1990 (p<0.001). Research designs with higher ROB were nonrandomized intervention and time series designs compared to RCT and prospective cohort designs respectively (p<0.001). CONCLUSIONS: Opportunities for improvement in food and nutrition research are in the Selection, Performance, and Detection ROB domains. PMID- 29975706 TI - Capacity to conduct health research among NGOs in Malawi: Diverse strengths, needs and opportunities for development. AB - BACKGROUND: The role of non-governmental organisations (NGOs) in health research has attracted growing attention. NGOs are important service providers and advocates in international health, and conducting research can help NGOs to strengthen these service delivery and advocacy activities. However, capacity to conduct research varies among NGOs. There is currently limited evidence on NGOs' research capacity that can explain why capacity varies or indicate potential areas for support. We examined NGOs' capacity to conduct research, identifying factors that affect their access to the funds, time and skills needed to undertake research. METHODS: We examined research capacity through qualitative case studies of three NGOs in Malawi, including one national and two international NGOs. Data were generated through interviews and focus groups with NGO staff, observation of NGO activities, and document reviews. RESULTS: Availability of funding, skills and time to conduct research varies considerably between the case NGOs. Access to these resources is affected by internal processes such as sources of funding and prioritisation of research, and by the wider environment and external relationships, including the nature of donor support. Constraints include limited ability to apply for research funding, a perception that donors will not support research costs, lack of funding to hire or train research staff, and prioritisation of service delivery over research in funding proposals and staff schedules. CONCLUSION: The findings suggest strategies for NGOs and for donors interested in supporting NGOs' research capacity. Above all, the findings reinforce the importance of initial capacity assessments to identify organisational needs and opportunities. In addition, the need for time and funding as well as skills suggests that strengthening NGOs' research capacity will often require more than research training. PMID- 29975707 TI - A multi-centre investigation of delivering national guidelines on exercise training for men with advanced prostate cancer undergoing androgen deprivation therapy in the UK NHS. AB - BACKGROUND: National guidelines (NICE-CG175) recommended 12 weeks of supervised exercise training for men treated with androgen deprivation therapy (ADT) for prostate cancer to counter debilitating adverse effects of castration. As with other chronic conditions where exercise is indicated, it is uncertain if these services are being delivered in the health services. The aim of this multi-centre investigation was to examine what exercise referral is currently available for men on ADT as provided by the NHS and if a supervised, individually-tailored exercise training package (as per the national NICE guidelines CG175) is embedded within prostate cancer care. METHODS: A multi-centre investigation of current National Health Service (NHS) care involving a web-based survey of NHS prostate cancer care, five focus groups involving 26 men on ADT and 37 semi-structured interviews with healthcare professionals (HCPs) involved in the management of prostate cancer. Descriptive statistics and thematic analysis evaluated quantitative and qualitative data, respectively. Qualitative methods followed COREQ standards. RESULTS: HCPs and men on ADT asserted that medical castration has a serious and debilitating impact on many features of men's quality of life. There is support for exercise training programmes as part of cancer care and patients would support their initiation soon after diagnosis. Involving the Multidisciplinary Team (MDT) is proposed as key to this. Critically, traditional values in oncology would need to be overcome for widespread acceptance. Specialist further training for HCPs around behaviour change support could encourage this. Given that these schemes are seen as a fundamental part of cancer care, it is felt the NHS should commission and support provision. 79 representatives of 154 NHS trusts (51%) provided survey data on current delivery: only 17% could provide supervised exercise as per CG175. CONCLUSIONS: Evidence based national exercise guidelines are not being delivered to men on ADT as intended. Traditional values in oncology and the need for NHS financial support are seen as major barriers to provision of current best practice guidelines. Despite this both HCPs and men on ADT are in favour of such programmes being a fundamental part of their cancer care. PMID- 29975708 TI - B lymphocytes can be activated to act as antigen presenting cells to promote anti tumor responses. AB - Immune evasion by tumors includes several different mechanisms, including the inefficiency of antigen presenting cells (APCs) to trigger anti-tumor T cell responses. B lymphocytes may display a pro-tumoral role but can also be modulated to function as antigen presenting cells to T lymphocytes, capable of triggering anti-cancer immune responses. While dendritic cells, DCs, are the best APC population to activate naive T cells, DCs or their precursors, monocytes, are frequently modulated by tumors, displaying a tolerogenic phenotype in cancer patients. In patients with cervical cancer, we observed that monocyte derived DCs are tolerogenic, inhibiting allogeneic T cell activation compared to the same population obtained from patients with precursor lesions or cervicitis. In this work, we show that B lymphocytes from cervical cancer patients respond to treatment with sCD40L and IL-4 by increasing the CD80+CD86+ population, therefore potentially increasing their ability to activate T cells. To test if B lymphocytes could actually trigger anti-tumor T cell responses, we designed an experimental model where we harvested T and B lymphocytes, or dendritic cells, from tumor bearing donors, and after APC stimulation, transplanted them, together with T cells into RAG1-/- recipients, previously injected with tumor cells. We were able to show that anti-CD40 activated B lymphocytes could trigger secondary T cell responses, dependent on MHC-II expression. Moreover, we showed that dendritic cells were resistant to the anti-CD40 treatment and unable to stimulate anti-tumor responses. In summary, our results suggest that B lymphocytes may be used as a tool for immunotherapy against cancer. PMID- 29975709 TI - A qualitative study exploring patient motivations for screening for lung cancer. AB - BACKGROUND: Low-dose computed tomography (LDCT) of the chest for lung cancer screening of heavy smokers was given a 'B' rating by the U.S. Preventive Services Task Force (USPSTF) in 2013, and gained widespread insurance coverage in the U.S. in 2015. Lung cancer screening has since had low uptake. However, for those that do choose to screen, little is known about patient motivations for completing screening in real-world practice. OBJECTIVE: To explore the motivations for screening-eligible patients to screen for lung cancer. METHODS: Semi-structured qualitative interviews were conducted with 20 LDCT screen-completed men and women who were members of an integrated mixed-model healthcare system in Washington State. From June to September 2015, participants were recruited and individual interviews performed about motivations to screen for lung cancer. Audio-recorded interviews were transcribed and analyzed using inductive content analysis by three investigators. RESULTS: Four primary themes emerged as motivations for completing LDCT lung cancer screening: 1) trust in the referring clinician; 2) early-detection benefit; 3) low or limited harm perception; and 4) friends or family with advanced cancer. CONCLUSION: Participants in our study were primarily motivated to screen for lung cancer based on perceived benefit of early detection, absence of safety concerns, and personal relationships. Our findings provide new insights about patient motivations to screen, and can potentially be used to improve lung cancer screening uptake and shared decision-making processes. PMID- 29975710 TI - Variation in physiological host range in three strains of two species of the entomopathogenic fungus Beauveria. AB - Knowledge of the host range of a biocontrol agent (BCA) is fundamental. Host range determines the BCA's economic potential, as well as the possible risk for non-target organisms. Entomopathogenic fungal strains belonging to the genus Beauveria are widely used as BCA, but our knowledge of their physiological host range is only partial. The aim of this study was to improve our understanding of the physiological host range of three Beauveria strains belonging to two species, B. hoplocheli and B. bassiana. We performed laboratory mortality bioassays to assess their pathogenicity and virulence against nine insect pests, belonging to three orders: Lepidoptera, Coleoptera and Diptera. Mortality rate, mean survival time and mycosis rate were used to estimate virulence. Pathogenicity was assessed as the capacity to cause a disease and induce mortality. Virulence was assessed as the severity of the disease based on mortality rate, mean survival time and mycosis rate. The results of this study revealed significant differences in the physiological host range of the three Beauveria strains tested. The three strains were pathogenic to all Diptera and Lepidoptera species tested. In the case of the Coleoptera, only the B. hoplocheli strain was pathogenic to the white grub Hoplochelus marginalis and only the B. bassiana strains were pathogenic to Alphitobius diaperinus. The B. hoplocheli strain was less virulent on Lepidoptera and Diptera than the two B. bassiana strains. The latter both exhibited very similar virulence patterns. The fact that B. hoplocheli and B. bassiana strains have different host ranges means that they can be used as BCA to target different pests. Impacts on non-target insects across multiple orders cannot be ruled out in the absence of ecological host range studies. PMID- 29975711 TI - Effects of naturally-produced lovastatin on feed digestibility, rumen fermentation, microbiota and methane emissions in goats over a 12-week treatment period. AB - Twenty male Saanen goats were randomly assigned to four levels of lovastatin supplementation and used to determine the optimal dosage and sustainability of naturally produced lovastatin from fermentation of palm kernel cake (PKC) with Aspergillus terreus on enteric methane (CH4) mitigation. The effects on ruminal microbiota, rumen fermentation, feed digestibility and health of animal were determined over three measuring periods (4-, 8- and 12-weeks) and the accumulation of lovastatin in tissues was determined at the end of the experiment. The diets contained 50% rice straw, 22.8% concentrates and 27.2% of various proportions of untreated or treated PKC to achieve the target daily intake level of 0 (Control), 2, 4 or 6 mg lovastatin/kg body weight (BW). Enteric CH4 emissions per dry matter intake (DMI), decreased significantly (P<0.05) and equivalent to 11% and 20.4%, respectively, for the 2 and 4 mg/kg BW groups as compared to the Control. No further decrease in CH4 emission thereafter with higher lovastatin supplementation. Lovastatin had no effect on feed digestibility and minor effect on rumen microbiota, and specifically did not reduce the populations of total methanogens and Methanobacteriales (responsible for CH4 production). Similarly, lovastatin had little effect on rumen fermentation characteristics except that the proportion of propionate increased, which led to a decreasing trend (P<0.08) in acetic: propionate ratio with increasing dosage of lovastatin. This suggests a shift in rumen fermentation pathway to favor propionate production which serves as H+ sink, partly explaining the observed CH4 reduction. No adverse physiological effects were noted in the animals except that treated PKC (containing lovastatin) was less palatable at the highest inclusion level. Lovastatin residues were detected in tissues of goats fed 6 mg lovastatin/kg BW at between 0.01 to 0.03 MUg/g, which are very low. PMID- 29975712 TI - Taste and odor preferences following Roux-en-Y surgery in humans. AB - It is well established that bariatric surgery, the most effective method to achieve long-term weight loss in obese subjects, reverses enhanced preference and intake of sweet/fatty foods. Although taste and odor preference changes following bariatric surgery have been previously described, their time course and relationship to weight loss remains an issue. The aim of this study was to determine the relationship between taste and odor preference changes and successful weight loss following bariatric surgery. A cross-sectional study was performed on 195 human subjects with body mass index (BMI) above 30 (at least class I obesity), who were scheduled to receive (n = 54) or had previously received (n = 141) Roux-en-Y gastric bypass (RYGB). A Self-Assessment Manikin test was used to measure each participant's affective reaction (ranging from pleasure to displeasure) to a variety of food-related and odor-related pictures. Results confirmed earlier reports about changes in sweet/fatty foods preference after surgery and revealed a shift in preference toward less calorie-dense foods. Relatedly, endorsements of "favorite" foods were mostly sweet/fatty foods in subjects awaiting surgery but were shifted toward more healthy choices, particularly vegetables, in subjects post-RYGB surgery. However, food preference ratings trended toward pre-surgical levels as the time since surgery increased. Answers to open-ended questions about why their diet changed post-surgery revealed that changes in cravings, rather than changes in taste per se, were the major factor. Surprisingly, patients rating a coffee taste as more pleasing after surgery had a lower post-surgical BMI. No associations of odors with change in BMI were apparent. Results showed that following bariatric surgery taste preferences are significantly altered and that these changes correlate with lowered BMI. However, these changes fade as time since surgery lengthens. These results may suggest diagnostic criteria to identify people at risk for less than optimal changes in BMI following bariatric surgery. PMID- 29975713 TI - Genetics instability of wtAAV2 genome and AAV promoter activities in the Baculovirus/Sf9 cells system. AB - The human Adeno-Associated Virus serotype 2 (wtAAV2) is a common non-pathological virus and its recombinant form (rAAV) is widely used as gene therapy vector. Although rAAVs are routinely produced in the Baculovirus/Sf9 cell system, wtAAV2 has never been studied in this context. We tried to produce wtAAV2 in the baculovirus/Sf9 cell system hypothesizing that the wtAAV2 may be considered as a normal recombinant AAV transgene. Through our attempts to produce wtAAV2 in Baculovirus/Sf9, we found that wtAAV2 p5 promoter, which controls the expression of large Rep proteins in mammalian cells, was active in this system. p5 promoter activity in the baculovirus/Sf9 cell system leads to the expression of Rep78 that finally excises wtAAV2 genome from the baculovirus genome during the earliest phases of baculovirus stock production. Via p5 promoter expression kinetics and strand specific RNA-Seq analysis of wtAAV2, rAAV and Rep2/Cap2 cassettes in the baculovirus context we could demonstrate that wtAAV2 native promoters, p5, p19 and p40 are all active in the context of the baculovirus system and lead to the expression of different proteins and peptides. In addition, this study has proven that the baculovirus brings at least some of the helper functions needed in the AAV replication/life cycle. PMID- 29975714 TI - Design and application of an MR reference phantom for multicentre lung imaging trials. AB - INTRODUCTION: As there is an increasing number of multicentre lung imaging studies with MRI in patients, dedicated reference phantoms are required to allow for the assessment and comparison of image quality in multi-vendor and multi centre environments. However, appropriate phantoms for this purpose are so far not available commercially. It was therefore the purpose of this project to design and apply a cost-effective and simple to use reference phantom which addresses the specific requirements for imaging the lungs with MRI. METHODS: The phantom was designed to simulate 4 compartments (lung, blood, muscle and fat) which reflect the specific conditions in proton-MRI of the chest. Multiple phantom instances were produced and measured at 15 sites using a contemporary proton-MRI protocol designed for an in vivo COPD study at intervals over the course of the study. Measures of signal- and contrast-to-noise ratio, as well as structure and edge depiction were extracted from conventionally acquired images using software written for this purpose. RESULTS: For the signal to noise ratio, low intra-scanner variability was found with 4.5% in the lung compartment, 4.0% for blood, 3.3% for muscle and 3.7% for fat. The inter-scanner variability was substantially higher, with 41%, 32%, 27% and 32% for the same order of compartments. In addition, measures of structure and edge depiction were found to both vary significantly among several scanner types and among scanners of the same model which were equipped with different gradient systems. CONCLUSION: The described reference phantom reproducibly quantified image quality aspects and detected substantial inter-scanner variability in a typical pulmonary multicentre proton MRI study, while variability was greater in lung tissue compared to other tissue types. Accordingly, appropriate reference phantoms can help to detect bias in multicentre in vivo study results and could also be used to harmonize equipment or data. PMID- 29975715 TI - Characterization of crop residues from false banana /Ensete ventricosum/ in Ethiopia in view of a full-resource valorization. AB - False banana /Ensete ventricosum [Welw.] Cheesman/ is exploited as a food crop in Ethiopia where it represents an important staple food. The plant is harvested and large amounts of biomass residues are originated, mainly from the pseudo stem (i.e., fiber bundles obtained from the leaf sheaths after being scrapped to produce starchy food) and the inflorescence stalk. These materials were studied in relation to their summative chemical composition, composition of lignin, lipophilic and polar extracts. Moreover, their structural characteristics, in view of their valorization, were scrutinized. The analytical studies were performed with the aid of FTIR, GC/MS, Py-GC/MS and SEM. The fiber bundles are aggregates of mainly long and slender fibers with low ash, extractives and lignin contents (3.8%. 4.4% and 10.5% respectively) and high holocellulose and alpha cellulose contents (87.5% and 59.6% respectively). The hemicelluloses in the fibers are mostly highly acetylated xylans and the lignin is of the H-type (H:G:S, 1:0.7:0.8). This lignin composition is in line with the FTIR peaks at 1670 cm-1 and 1250 cm-1.The inflorescence stalk has high ash content (12.3% in the main stalk and 24.6% in fines) with a major proportion of potassium, high extractives (25.9%), and low lignin and alpha-cellulose contents (5.8% and 17.9% respectively). The stalk includes numerous starch granules in the cellular structure with the predominant presence of parenchyma. The potential valorization routes for these materials are clearly different. The fiber bundles could be used as a fiber source for paper pulp production with the possibility of a prior hemicelluloses removal while the inflorescence stalk has nutritional value for food and fodder. Furthermore, it can also be used for sugar fermentation products. PMID- 29975716 TI - Anal HPV infection and correlates in HIV-infected patients attending a Sexually Transmitted Infection clinic in Brazil. AB - OBJECTIVE: To estimate the prevalence of anal HPV infection, genotype distribution, intraepithelial neoplasia (AIN) and correlates in a cohort of HIV infected patients attending at Sexually Transmitted Infections (STI) clinic in Brazil. STUDY DESIGN: A descriptive analysis was performed which includes, demographic, behavioral and clinical data. Anal specimens from HIV-positive men and women were collected during a regular visit and they were used for cytology and histopathology tests, as well as for HPV molecular identification. RESULTS: A total of 223 patients (143 females and 80 males) were enrolled in the study and, HPV was identified in 68.6% of the sample. The frequency of HR-HPV, HPV16/18 and multiple HPV infection were similar in both groups. The upstream regulatory region (URR) sequencing was carried out in 38 samples identified as HPV16 positive, and European variants were the most frequent (69.2%), followed by Africans (25.6%) and Asiatic-Americans (5.1%). Having more than 20 sexual partners was associated with multiple HPV infection (p = 0.000) while, anal sex and the first intercourse before 15 years of age was a risk factor for any HPV infection (p = 0.001). Being MSM (men who have sex with men) was a risk factor for any HPV and multiple infections (p = 0.002). The CD4 count >500 cells/mm3 was a protective factor for the HPV16/18 (p = 0.048) and multiple infections (p = 0.023), and the undetectable viral load and HAART treatment were both protective for any HPV (p = 0.010), HR-HPV (p = 0.091) and multiple infections (p = 0.006). Abnormal anoscopy was found in 23.7% (53/223) of the total number of patients, and this was significantly associated with all types of investigated HPV infections (p<0.0001). CONCLUSIONS: In this study, anal HPV infection was common among young HIV-positive men and women, particularly in MSM. Anal cancer screening in patients at risk, such as those who are HIV-positive, and mainly those with anal HPV infection and a history of STI, will increase the likelihood of detecting anal intraepithelial neoplasia. PMID- 29975717 TI - Influence of seasonal variation on in vitro fertilization success. AB - OBJECTIVE: To evaluate the influence of seasonal variation on in vitro fertilization (IVF) outcome in a large cohort population. METHODS & MATERIALS: A total of 5,765 IVF cycles conducted in Sheba medical center between 2013 and 2016 were retrospectively analyzed. The treatment cycles included 4214 ovarian stimulation and ovum pick up (OPU) cycles of which 3020 resulted in fresh embryo transfer and 1551 vitrified- warmed cycles of which1400 resulted in warmed embryo transfer. Cycles were assigned to seasons according to the date of OPU for fresh embryo transfer cycles or according to the date of embryo warming for vitrified warmed embryo transfer cycles. RESULTS: There were no statistically significant differences between the calendar months or seasons concerning the number of oocytes retrieved or fertilization rate in the fresh cycles. Throughout the 4 years of the study, the monthly clinical pregnancy rate fluctuated between 18.2% and 27.9% per fresh embryo transfer (mean 23.3%) and between 17.7% and 29.4% per vitrified warmed embryo transfer (mean 23%). These fluctuations did not follow any specific seasonal pattern. CONCLUSIONS: Our study did not demonstrate any significant influence of the calendar months or seasons on the clinical pregnancy rates of fresh or vitrified warmed embryo transfers. It might be speculated that the complete pharmaceutical control of the ovarian and endometrial function, as well as the homogeneous treatments, procedures and laboratory equipment used during the study period have lowered the influence of seasonal effect on IVF treatment outcome. PMID- 29975718 TI - Agricultural land use among mestizo colonist and indigenous populations: Contrasting patterns in the Amazon. AB - This paper compares land use patterns of mestizo colonists and indigenous populations in the central Ecuadorian Amazon, based on data from a household survey covering mestizo colonist, Kichwa and Shuar households. As expected, colonists mostly engage in commercial agriculture and cattle ranching, but there are substantial differences in land use patterns between the Shuar and the Kichwa. The Shuar engage in cash cropping and cattle ranching, and on average, devote even more land to agricultural uses than mestizo colonists in this sample. In contrast, the Kichwa engage more in subsistence crop production and less in commercial agriculture. Such different patterns appear related to local conditions, earlier migratory and settlement patterns, and the level of exposure to markets. The implications of this for policy are explored in the conclusions. PMID- 29975719 TI - Spatial and topical imbalances in biodiversity research. AB - The rapid erosion of biodiversity is among the biggest challenges human society is facing. Concurrently, major efforts are in place to quantify changes in biodiversity, to understand the consequences for ecosystem functioning and human wellbeing, and to develop sustainable management strategies. Based on comprehensive bibliometric analyses covering 134,321 publications, we report systematic spatial biases in biodiversity-related research. Research is dominated by wealthy countries, while major research deficits occur in regions with disproportionately high biodiversity as well as a high share of threatened species. Similarly, core scientists, who were assessed through their publication impact, work primarily in North America and Europe. Though they mainly exchange and collaborate across locations of these two continents, the connectivity among them has increased with time. Finally, biodiversity-related research has primarily focused on terrestrial systems, plants, and the species level, and is frequently conducted in Europe and Asia by researchers affiliated with European and North American institutions. The distinct spatial imbalances in biodiversity research, as demonstrated here, must be filled, research capacity built, particularly in the Global South, and spatially-explicit biodiversity data bases improved, curated and shared. PMID- 29975720 TI - Development of third generation anti-EGFRvIII chimeric T cells and EGFRvIII expressing artificial antigen presenting cells for adoptive cell therapy for glioma. AB - Glioblastoma multiforme (GBM) is the most aggressive and deadly form of adult brain cancer. Despite of many attempts to identify potential therapies for this disease, including promising cancer immunotherapy approaches, it remains incurable. To address the need of improved persistence, expansion, and optimal antitumor activity of T-cells in the glioma milieu, we have developed an EGFRvIII specific third generation (G3-EGFRvIII) chimeric antigen receptor (CAR) that expresses both co-stimulatory factors CD28 and OX40 (MR1-CD8TM-CD28-OX40 CD3zeta). To enhance ex vivo target specific activation and optimize T-cell culturing conditions, we generated artificial antigen presenting cell lines (aAPC) expressing the extracellular and transmembrane domain of EGFRvIII (EGFRVIIIDelta654) with costimulatory molecules including CD32, CD80 and 4-1BBL (EGFRVIIIDelta654 aAPC and CD32-80-137L-EGFRVIIIDelta654 aAPC). We demonstrate that the highest cell growth was achieved when G3-EGFRvIII CAR T-cells were cocultured with both co-stimulatory aAPCs and with exposure to EGFRvIII (CD32-80 137L-EGFRVIIIDelta654 aAPCs) in culturing periods of three to six weeks. G3 EGFRvIII CAR T-cells showed an increased level of IFN-gamma when cocultured with CD32-80-137L-EGFRVIIIDelta654 aAPCs. Evaluation of G3-EGFRvIII CAR T-cells in an orthotropic human glioma xenograft model demonstrated a prolonged survival of G3 EGFRvIII CAR treated mice compared to control mice. Importantly, we observed survival of G3-EGFRvIII CAR T-cells within the tumor as long as 90 days after implantation in low-dose and single administration, accompanied by a marked tumor stroma demolition. These findings suggest that G3-EGFRvIII CAR cocultured with CD32-80-137L-EGFRVIIIDelta654 aAPCs warrants itself as a potential anti-tumor therapy strategy for glioblastoma. PMID- 29975722 TI - An open-source tool for analysis and automatic identification of dendritic spines using machine learning. AB - Synaptic plasticity, the cellular basis for learning and memory, is mediated by a complex biochemical network of signaling proteins. These proteins are compartmentalized in dendritic spines, the tiny, bulbous, post-synaptic structures found on neuronal dendrites. The ability to screen a high number of molecular targets for their effect on dendritic spine structural plasticity will require a high-throughput imaging system capable of stimulating and monitoring hundreds of dendritic spines in various conditions. For this purpose, we present a program capable of automatically identifying dendritic spines in live, fluorescent tissue. Our software relies on a machine learning approach to minimize any need for parameter tuning from the user. Custom thresholding and binarization functions serve to "clean" fluorescent images, and a neural network is trained using features based on the relative shape of the spine perimeter and its corresponding dendritic backbone. Our algorithm is rapid, flexible, has over 90% accuracy in spine detection, and bundled with our user-friendly, open-source, MATLAB-based software package for spine analysis. PMID- 29975721 TI - Dual effects of leptin in perioperative gas exchange of morbidly obese patients. AB - Leptin has shown positive effects on respiratory function in experimental settings. The role of leptin on perioperative respiratory function in morbidly obese patients has not been established. We performed a retrospective analysis of morbidly obese patients undergoing laparoscopic sleeve gastrectomy. Fasting serum leptin and interleukin (IL)-6 were measured preoperatively, and arterial blood gases were obtained pre- and postoperatively. Outcome variables were arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and differences in PaO2 and PaCO2 between pre- and postoperative values (DeltaPaO2, DeltaPaCO2; postoperative minus preoperative). Patients with lower (<40 MUg/L) and higher (>=40 MUg/L) leptin levels were compared. Bravais Pearson's correlation, multiple linear regression, and logistic regression analysis were performed. A total of 112 morbidly obese patients were included. Serum leptin was significantly higher in females than in males (42.86+/-12.89 vs. 30.67+/-13.39 MUg/L, p<0.0001). Leptin was positively correlated with body mass index (r = 0.238; p = 0.011), IL-6 (r = 0.473; p<0.0001), and DeltaPaO2 (r = 0.312; p = 0.0008). Leptin was negatively correlated with preoperative PaO2 (r = 0.199; p = 0.035). Preoperative PaO2 was lower, DeltaPaCO2 was smaller, and DeltaPaO2 was greater in the high leptin group than in the low leptin group. In multiple regression analysis, leptin was negatively associated with preoperative PaO2 (estimate coefficient = -0.147; p = 0.023). In logistic regression analysis, leptin was associated with improved DeltaPaO2 (odds ratio [OR] = 1.104; p = 0.0138) and DeltaPaCO2 (OR = 0.968; p = 0.0334). Leptin appears to have dual effects related to perioperative gas exchange in obese patients undergoing bariatric surgery. It is associated with worse preoperative oxygenation but improved respiratory function after surgery. PMID- 29975723 TI - The effectiveness of an on-line training program for improving knowledge of fire prevention and evacuation of healthcare workers: A randomized controlled trial. AB - BACKGROUND: Hospitals are vulnerable to fires and the evacuation process is challenging. However, face-to-face fire prevention and evacuation training may take healthcare workers' time away from patient care; therefore, effective on line training may be warranted. We carried out and examined the effectiveness of an on-line education and training of fire prevention and evacuation training for healthcare workers in China by a randomized controlled trial using convenience sampling from five public hospitals in China. METHODS: A total of 128 participants were recruited between December 2014 and March 2015. The authors built a webpage that included the informed consent statement, pre-test questionnaire, video training, and post-test questionnaire. After completing the pre-test questionnaire, participants were randomly assigned to watch the intervention video (basic response to a hospital fire) or the control video (introduction to volcanic disasters). A 45-item questionnaire on knowledge of fire prevention and evacuation was administered before and after the video watching. This questionnaire were further divided into two subscales (25-item generic knowledge of fire response and 20-item hospital-specific knowledge of fire prevention and evacuation). One point was awarded for each correct answer. RESULTS: Half of the participants (n = 64, 50%) were randomized into the intervention group and the remaining 64 (50%) were randomized into the control group. For generic knowledge of fire prevention and evacuation, those in the intervention group improved significantly (from 16.16 to 20.44, P < 0.001) while the scores of those in the control group decreased significantly (from 15.27 to 13.70, P = 0.03). For hospital-specific knowledge of fire prevention and evacuation, those in the intervention group (from 10.75 to 11.33, P = 0.15) and the control group (from 10.38 to 10.16, P = 0.54) had insignificant change. For total score, those in the intervention group improved significantly (from 26.91 to 31.77, P < 0.001) while those in the control group decreased insignificantly (from 25.64 to 23.86, P = 0.07). After the intervention, the difference between the scores of the intervention group and the control group on all three knowledge areas of fire prevention and evacuation (generic, hospital-specific, and total) were significant (all Ps < 0.05). CONCLUSIONS: An on-line fire training program delivered via educational video can effectively improve healthcare workers' knowledge of fire prevention and evacuation. TRIAL REGISTRATION: Clinicaltrials.gov NCT02438150. PMID- 29975724 TI - The microstructure of white feathers predicts their visible and near-infrared reflectance properties. AB - Research on the optical properties of animal integuments, including fur, feather, skin and cuticle, has focussed almost exclusively on animal-visible wavelengths within the narrow range of 300-700 nm. By contrast, the near-infrared (NIR) portion of direct sunlight, spanning 700-2600 nm, has been largely ignored despite its potentially important thermal consequences. We quantified variation in visible and NIR reflectance and transmission for white body contour feathers of 50 bird species, and examined how well they are predicted by feather macro- and micro-structural morphology. Both visible and NIR reflectance of the feathers varied substantially across species. Larger, thicker, and sparser feathers that are characteristic of larger species, and feathers with rounder barbs and more closely spaced barbules, had high average reflectance, particularly within avian visible wavelengths (300-700 nm). Feathers with rounder barbs and more closely situated barbules also had high average reflectance, particularly for NIR wavelengths. Barb roundness and barbule density were the only predictors of NIR reflectance after accounting for variation in visible reflectance and body size. Our results highlight the potential for adaptive variation in NIR reflectance mediated by feather structure, which may inform the design of functional materials to control light and heat. PMID- 29975725 TI - Role of critical elements in botulinum neurotoxin complex in toxin routing across intestinal and bronchial barriers. AB - The highly potent botulinum neurotoxin serotype A (BoNT/A) inhibits neurotransmitter release at neuromuscular junctions resulting in flaccid muscle paralysis, respiratory arrest and death. In order to reach their neuronal cell targets, BoNT/A must cross epithelial cell barriers lining the intestines and airways. The toxin is produced as a large protein complex comprised of the neurotoxin and non-toxic neurotoxin-associated proteins (NAPs). Although NAPs are known to protect the toxin from harsh environments, their role in the movement of BoNT/A across epithelial barriers has not been fully characterized. In the current study, movement of the toxin across epithelial cells was examined macroscopically using a sensitive near infrared fluorescence transcytosis assay and microscopically using fluorescently labeled toxin and confocal microscopy. The studies show that the BoNT/A complex internalizes more rapidly than the pure toxin. The studies also show that one NAP protein, hemaglutinin 33 (Hn33), enhanced both the binding and movement of a deactivated recombinant botulinum neurotoxin A (DrBoNT) across epithelial cell monolayers and that the toxin associates with Hn33 on the cell surface. Collectively, the data demonstrate that, in addition to their protective role, NAPs and Hn33 play an important role in BoNT/A intoxication. PMID- 29975727 TI - Sequential cooperative spectrum sensing in the presence of dynamic Byzantine attack for mobile networks. AB - Cooperative spectrum sensing (CSS) is envisaged as a powerful approach to improve the utilization of scarce radio spectrum resources, but it is threatened by Byzantine attack. Byzantine attack has been becoming a popular research topic in both academia and industry due to the demanding requirements of security. Extensive research mainly aims at mitigating the negative effect of Byzantine attack on CSS, but with some strong assumptions, such as attackers are in minority or trusted node(s) exist for data fusion, while paying little attention to a mobile scenario. This paper focuses on the issue of designing a general and reliable reference for CSS in a mobile network. Instead of the previously simplified attack, we develop a generic Byzantine attack model from sophisticated behaviors to conduct various attack strategies and derive the condition of which Byzantine attack makes the fusion center (FC) blind. Specifically, we propose a robust sequential CSS (SCSS) against dynamic Byzantine attack. Our proposed method solves the unreliability of the FC by means of delivery-based assessment to check consistency of individual sensing report, and innovatively reuses the sensing information from Byzantines via a novel weight allocation mechanism. Furthermore, trust value (TrV) ranking is exploited to proceed with a sequential test which generates a more accurate decision about the presence of phenomenon with fewer samples. Lastly, we carry out simulations on comparison of existing data fusion technologies and SCSS under dynamic Byzantine attack, and results verify the theoretical analysis and effectiveness of our proposed approach. We also conduct numerical analyses to demonstrate explicit impacts of secondary user (SU) density and mobility on the performance of SCSS. PMID- 29975726 TI - Isotopic turnover rates and diet-tissue discrimination depend on feeding habits of freshwater snails. AB - Estimates of animal diets and trophic structure using stable isotope analysis are strongly affected by diet-tissue discrimination and tissue turnover rates, yet these factors are often unknown for consumers because they must be measured using controlled-feeding studies. Furthermore, these parameters may be influenced by diet quality, growth, and other factors. We measured the effect of dietary protein content on diet-tissue discrimination and tissue turnover in three freshwater snail species. We fed lettuce to individually housed snails (n = 450 per species) for ten weeks, then half were switched to a high-protein diet. Isotopic values of muscle and gonad tissue were assessed at 48 and 80 days post diet change. Snail discrimination factors varied by diet (low-protein > high protein) and usually differed among species for both N and C, although species had similar carbon discrimination when fed the low-protein diet. Carbon turnover rates were similar among species for a given tissue type, but nitrogen turnover varied more among species. In addition, diet affected growth of species differently; some species grew larger on high-protein (H. trivolvis) while others grew larger on low-protein diet (Lymnaea spp.). These differences among species in growth influenced turnover rates, which were faster in the species with the highest growth rate following the diet switch from low to high-protein. Thus, growth is one of the main processes that affects tissue turnover, but growth and feeding preference did not affect diet-tissue discrimination, which was greater on low-protein than high-protein diets for all species regardless of growth performance. These results suggest that diet might influence two key parameters of stable isotope analysis differently. PMID- 29975728 TI - Association of infant formula composition and anthropometry at 4 years: Follow-up of a randomized controlled trial (BeMIM study). AB - The relationships between nutrition, metabolic response, early growth and later body weight have been investigated in human studies. The aim of this follow-up study was to assess the long-term effect of infant feeding on growth and to study whether the infant metabolome at the age of 4 months might predict anthropometry at 4 years of age. The Belgrade-Munich infant milk trial (BeMIM) was a randomized controlled trial in which healthy term infants received either a protein-reduced infant formula (1.89 g protein/100 kcal) containing alpha-lactalbumin enriched whey and long-chain polyunsaturated fatty acids (LC-PUFA), or a standard formula (2.2 g protein/100 kcal) without LC-PUFA, focusing on safety and suitability. Non randomized breastfed infants were used as a reference group. Of the 259 infants that completed the BeMIM study at the age of 4 months (anthropometry assessment and blood sampling), 187 children participated in a follow-up visit at 4 years of age. Anthropometry including weight, standing height, head circumference, and percent body fat was determined using skinfolds (triceps, subscapular) and bioelectrical impedance analysis. Plasma metabolite concentration, collected in samples at the age of 4 months, was measured using flow-injection tandem mass spectrometry. A linear regression model was applied to estimate the associations between each metabolite and growth with metabolites as an independent variable. At 4 years of age, there were no significant group differences in anthropometry and body composition between formula groups. Six metabolites (Asn, Lys, Met, Phe, Trp, Tyr) measured at 4 months of age were significantly associated with changes in weight-for-age z-score between 1 to 4 months of age and BMI-for-age z-score (Tyr only), after adjustment for feeding group. No correlation was found between measured metabolites and long-term growth (up to 4 years of age). No long-term effects of early growth patterns were shown on anthropometry at 4 years of age. The composition of infant formula influences the metabolic profile and early growth, while long-term programming effects were not observed in this study. PMID- 29975730 TI - Environmental factors effecting the germination and seedling emergence of two populations of an aggressive agricultural weed; Nassella trichotoma. AB - Nassella trichotoma (Nees) Hack. ex Arechav. (Serrated tussock) is an aggressive globally significant weed to agricultural and natural ecosystems. Herbicide resistant populations of this C3 perennial weed have emerged, increasing the need for effective wide-scale cultural control strategies. A thorough seed ecology study on two spatially distinct populations of N. trichotoma was conducted on this weed to identify differences in important environmental factors (drought, salinity, alternating temperature, photoperiod, burial depth, soil pH, artificial seed aging, and radiant heat) which influence seed dormancy. Seeds were collected from two spatially distinct populations; Gnarwarre (38 O 9' 8.892'' S, 144 O 7' 38.784'' E) and Ingliston (37O 40' 4.44'' S, 144 O 18' 39.24'' E) in December 2016 and February 2017, respectively. Twenty sterilized seeds were placed into Petri dishes lined with a single Whatman(r) No. 10 filter paper dampened with the relevant treatments solution and then incubated under the identified optimal alternating temperature and photoperiod regime of 25 degrees C/15 degrees C (light/dark, 12h/12h). For the burial depth treatment, 20 seeds were placed into plastic containers (10cm in diameter and 6cm in depth) and buried to the relevant depth in sterilized soil. All trials were monitored for 30 days and germination was indicated by 5mm exposure of the radicle and emergence was indicated by the exposure of the cotyledon. Each treatment had three replicates for each population, and each treatment was repeated to give a total of six replicates per treatment, per population. Nassella trichotoma was identified to be non photoblastic, with germination (%) being similar under alternating light and dark and complete darkness conditions. With an increase of osmotic potential and salinity, a significant decline in germination was observed. There was no effect of pH on germination. Exposure to a radiant heat of 120 degrees C for 9 minutes resulted in the lowest germination in the Ingliston population (33%) and the Gnarwarre population (60%). In the burial depth treatment, the Ingliston population and the Gnarwarre population had highest emergence of 75% and 80%, respectively at a depth of 1cm. Variation between the two populations was observed for the burial depth treatments; Gnarwarre had greater emergence than Ingliston from the 4cm burial depth, while Ingliston had greater emergence at the soil surface than Gnarwarre. The Gnarwarre population had greater overall germination than Ingliston, which could be attributed to the greater seed mass (0.86mg compared to 0.76mg, respectively). This study identifies that spatial variations in N. trichotoma's seed ecology are present between spatially distinct populations. PMID- 29975729 TI - Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B. AB - BACKGROUND/AIMS: The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. METHODS: One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. RESULTS: We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 * 10-6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27-7.63) at 11q12.1, rs171941 (P = 3.52*10 6, OR = 3.69, 95% CI = 2.13-6.42) at 5q14.1, and rs6462008 (P = 3.40*10-6, OR = 0.34, 95% CI = 0.22-0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. CONCLUSIONS: To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology. PMID- 29975731 TI - Non-nutritive sweeteners possess a bacteriostatic effect and alter gut microbiota in mice. AB - Non-nutritive sweeteners (NNSs) are widely used in various food products and soft drinks. There is growing evidence that NNSs contribute to metabolic dysfunction and can affect body weight, glucose tolerance, appetite, and taste sensitivity. Several NNSs have also been shown to have major impacts on bacterial growth both in vitro and in vivo. Here we studied the effects of various NNSs on the growth of the intestinal bacterium, E. coli, as well as the gut bacterial phyla Bacteroidetes and Firmicutes, the balance between which is associated with gut health. We found that the synthetic sweeteners acesulfame potassium, saccharin and sucralose all exerted strong bacteriostatic effects. We found that rebaudioside A, the active ingredient in the natural NNS stevia, also had similar bacteriostatic properties, and the bacteriostatic effects of NNSs varied among different Escherichia coli strains. In mice fed a chow diet, sucralose increased Firmicutes, and we observed a synergistic effect on Firmicutes when sucralose was provided in the context of a high-fat diet. In summary, our data show that NNSs have direct bacteriostatic effects and can change the intestinal microbiota in vivo. PMID- 29975732 TI - Fast score test with global null estimation regardless of missing genotypes. AB - In genome-wide association studies (GWASs) for binary traits (or case-control samples) in the presence of covariates to be adjusted for, researchers often use a logistic regression model to test variants for disease association. Popular tests include Wald, likelihood ratio, and score tests. For likelihood ratio test and Wald test, maximum likelihood estimation (MLE), which requires iterative procedure, must be computed for each single nucleotide polymorphism (SNP). In contrast, the score test only requires MLE under the null model, being lower in computational cost than other tests. Usually, genotype data include missing genotypes because of assay failures. It loses computational efficiency in the conventional score test (CST), which requires null estimation by excluding individuals with missing genotype for each SNP. In this study, we propose two new score tests, called PM1 and PM2, that use a single global null estimator for all SNPs regardless of missing genotypes, thereby enabling faster computation than CST. We prove that PM2 and CST have an equivalent asymptotic power and that the power of PM1 is asymptotically lower than that of PM2. We evaluate the performance of the proposed methods in terms of type I error rates and power by simulation studies and application to real GWAS data provided by the Alzheimer's Disease Neuroimaging Initiative (ADNI), confirming our theoretical results. ADNI GWAS application demonstrated that the proposed score tests improve computational speed about 6-18 times faster than the existing tests, CST, Wald tests and likelihood ratio tests. Our score tests are general and applicable to other regression models. PMID- 29975733 TI - De novo characterization of the Baphicacanthus cusia(Nees) Bremek transcriptome and analysis of candidate genes involved in indican biosynthesis and metabolism. AB - Baphicacanthus cusia (Nees) Bremek is an herb widely used for the clinical treatment of colds, fever, and influenza in Traditional Chinese Medicine. The roots, stems and leaves can be used as natural medicine, in which indigo and indirubin are two main active ingredients. In this study, quantification of indigo, indirubin, indican and adenosine among various tissues of B. cusia was conducted using HPLC-DAD. Leaves have significantly higher contents than stems and roots (380.66, 315.15, 20,978.26, 4323.15 MUg/g in leaves, 306.36, 71.71, 3,056.78, 139.45 MUg/g in stems, and 9.31, 7.82, 170.45, 197.48 MUg/g in roots, respectively). De novo transcriptome sequencing of B. cusia was performed for the first time. The sequencing yielded 137,216,248, 122,837,394 and 140,240,688 clean reads from leaves, stems and roots respectively, which were assembled into 51,381 unique sequences. A total of 33,317 unigenes could be annotated using the databases of Nr, Swiss-Prot, KEGG and KOG. These analyses provided a detailed view of the enzymes involved in indican backbone biosynthesis, such as cytochrome P450, UDP-glycosyltransferase, glucosidase and tryptophan synthase. Analysis results showed that tryptophan synthase was the candidate gene involved in the tissue-specific biosynthesis of indican. We also detected sixteen types of simple sequence repeats in RNA-Seq data for use in future molecular mark assisted breeding studies. The results will be helpful in further analysis of B. cusia functional genomics, especially in increasing biosynthesis of indican through biotechnological approaches and metabolic regulation. PMID- 29975734 TI - Stereosonic vision: Exploring visual-to-auditory sensory substitution mappings in an immersive virtual reality navigation paradigm. AB - Sighted people predominantly use vision to navigate spaces, and sight loss has negative consequences for independent navigation and mobility. The recent proliferation of devices that can extract 3D spatial information from visual scenes opens up the possibility of using such mobility-relevant information to assist blind and visually impaired people by presenting this information through modalities other than vision. In this work, we present two new methods for encoding visual scenes using spatial audio: simulated echolocation and distance dependent hum volume modulation. We implemented both methods in a virtual reality (VR) environment and tested them using a 3D motion-tracking device. This allowed participants to physically walk through virtual mobility scenarios, generating data on real locomotion behaviour. Blindfolded sighted participants completed two tasks: maze navigation and obstacle avoidance. Results were measured against a visual baseline in which participants performed the same two tasks without blindfolds. Task completion time, speed and number of collisions were used as indicators of successful navigation, with additional metrics exploring detailed dynamics of performance. In both tasks, participants were able to navigate using only audio information after minimal instruction. While participants were 65% slower using audio compared to the visual baseline, they reduced their audio navigation time by an average 21% over just 6 trials. Hum volume modulation proved over 20% faster than simulated echolocation in both mobility scenarios, and participants also showed the greatest improvement with this sonification method. Nevertheless, we do speculate that simulated echolocation remains worth exploring as it provides more spatial detail and could therefore be more useful in more complex environments. The fact that participants were intuitively able to successfully navigate space with two new visual-to-audio mappings for conveying spatial information motivates the further exploration of these and other mappings with the goal of assisting blind and visually impaired individuals with independent mobility. PMID- 29975735 TI - Quercetin prevents rhinovirus-induced progression of lung disease in mice with COPD phenotype. AB - Acute exacerbations are the major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Rhinovirus, which causes acute exacerbations may also accelerate progression of lung disease in these patients. Current therapies reduces the respiratory symptoms and does not treat the root cause of exacerbations effectively. We hypothesized that quercetin, a potent antioxidant and anti-inflammatory agent with antiviral properties may be useful in treating rhinovirus-induced changes in COPD. Mice with COPD phenotype maintained on control or quercetin diet and normal mice were infected with sham or rhinovirus, and after 14 days mice were examined for changes in lung mechanics and lung inflammation. Rhinovirus-infected normal mice showed no changes in lung mechanics or histology. In contrast, rhinovirus-infected mice with COPD phenotype showed reduction in elastic recoiling and increase in lung inflammation, goblet cell metaplasia, and airways cholinergic responsiveness compared to sham-infected mice. Interestingly, rhinovirus-infected mice with COPD phenotype also showed accumulation of neutrophils, CD11b+/CD11c+ macrophages and CD8+ T cells in the lungs. Quercetin supplementation attenuated rhinovirus-induced all the pathologic changes in mice with COPD phenotype. Together these results indicate that quercetin effectively mitigates rhinovirus-induced progression of lung disease in a mouse model of COPD. Therefore, quercetin may be beneficial in the treatment of rhinovirus-associated exacerbations and preventing progression of lung disease in COPD. PMID- 29975736 TI - Pessimistic expectations and poorer experiences: The role of (low) extraversion in anticipated and experienced enjoyment of social interaction. AB - Given research suggesting that social interactions are beneficial, it is unclear why individuals lower in extraversion engage less in social interactions. In this study, we test whether individuals lower in extraversion reap fewer hedonic rewards from social interactions and explore social psychological processes that explain their experiences. Before participants socialized, we measured extraversion, state positive affect, cognitive capacity, and expectations about the social interactions. After participants socialized with one another, we measured state positive affect and cognitive capacity again as well as fear of negative evaluation and belief in limited cognitive capacity. Participants also rated the social skillfulness of each interaction partner. We found that less extraverted individuals expect to feel worse after socializing. However, all but those extremely low in extraversion (17% of sample) actually experience an increase in positive affect after socializing. Surprisingly, those low in extraversion did not show reduced cognitive capacity after socializing. Although they are more likely to believe that cognitive capacity is limited and to be fearful of negative evaluation, these characteristics did not explain the social experience of those low in extraversion. PMID- 29975737 TI - 'That's how we help each other': Community savings groups, economic empowerment and HIV risk among female sex workers in Iringa, Tanzania. AB - Female sex workers (FSW) are a socially and economically marginalized population heavily affected by HIV. Community empowerment approaches focus on FSW taking collective action to address structural barriers to their health and have demonstrated effectiveness in reducing HIV risk. This study examines the potential for community savings groups (locally called michezo) among FSW in Iringa, Tanzania to reduce HIV risk and promote economic and community empowerment. We conducted 27 in-depth interviews (IDIs) with 15 FSW over time and 4 focus group discussions (FGDs) with 35 FSW participating in michezo, and 10 key informant interviews (KIIs) with group collectors. Content analysis was used to identify salient themes around participants' sex work and financial realities; the role of savings groups in their lives and work; and experiences with social cohesion associated with group participation. Michezo were described as providing a safety net for times of financial need, allowing FSW to create greater financial security for themselves and their families. Participation in the groups was also reported to facilitate both individual agency, resulting in members' ability to negotiate condom use and be selective about clients, and a sense of collective identity and solidarity. Participants described group challenges including high mobility and low income of FSW making it difficult for women to fulfill their financial obligations to the group. As a result, participants reported preferences for joining michezo whose members were perceived as more stable (e.g. older, married, from more established venues). Group collectors and members were eager to have michezo formally registered and become recognized by the broader community. Findings indicate that savings groups promote individual agency to reduce sexual risk behaviors and foster community empowerment among FSW. The groups hold potential as an empowerment strategy to enable sex workers to address structural sources of HIV vulnerability and help them achieve socioeconomic inclusion. PMID- 29975738 TI - Tonsil-derived mesenchymal stem cell-embedded in situ crosslinkable gelatin hydrogel therapy recovers postmenopausal osteoporosis through bone regeneration. AB - We investigated therapeutic potential of human tonsil-derived mesenchymal stem cells (TMSC) subcutaneously delivered to ovariectomized (OVX) mice for developing more safe and effective therapy for osteoporosis. TMSC were isolated from tonsil tissues of children undergoing tonsillectomy, and TMSC-embedded in situ crosslinkable gelatin-hydroxyphenyl propionic acid hydrogel (TMSC-GHH) or TMSC alone were delivered subcutaneously to the dorsa of OVX mice. After 3 months, three-dimensionally reconstructed micro-computed tomographic images revealed better recovery of the femoral heads in OVX mice treated with TMSC-GHH. Serum osteocalcin and alkaline phosphatase were also recovered, indicating bone formation only in TMSC-GHH-treated mice, and absence in hypercalcemia or other severe macroscopic deformities showed biocompatibility of TMSC-GHH. Additionally, visceral fat reduction effects by TMSC-GHH further supported their therapeutic potential. TMSC provided therapeutic benefits toward osteoporosis only when embedded in GHH, and showed potential as a supplement or alternative to current therapies. PMID- 29975739 TI - Sema3a inhibits the differentiation of Raw264.7 cells to osteoclasts under 2Gy radiation by reducing inflammation. AB - Astronauts and cancer patients receive different types of radiation, and radiation decreases bone strength and leads to radiation-induced osteoporosis. This effect is attributed to the activation of osteoclasts. Our aim was to study the effect of Sema3a on the differentiation of the murine macrophage cell line Raw264.7 into osteoclasts upon irradiation. Raw264.7 cells were divided into four groups: A, receiving no radiation; B, receiving no radiation + 50ngng/ml Sema3a; C, receiving 2Gy radiation; and D, receiving 2Gy radiation +50ngng/ml Sema3a. After treatment, cells were subjected to a proliferation assay, migration assay, live and apoptosis assay, and an ROS assay, along with analyses of bone resorption activity, TRAP staining and RT-PCR to assess the effect of Sema3a on Raw264.7 cells under 2Gy radiation. Sema3a inhibited the proliferation of Raw264.7 cells and showed statistical significance at a concentration of 100ngng/ml (P<0.05). Under 2Gy radiation, cell migration was reduced (P<0.05). In addition, 2Gy radiation resulted in more apoptotic cells, a higher level of ROS, larger bone resorption lacunae and more Trap-positive cells (p<0.05), and radiation increased CSTK, NFAT, TRAP-5b, Rankl/OPG, IL-1, IL-6, TNFa and P53 gene expression (P<0.05). Sema3a had an inhibitory effect on the differentiation of Raw264.7 cells and the migration and activity of osteoclasts upon irradiation but did not affect ROS. Sema3a also decreased the expression of CSTK, NFAT, TRAP-5b, Rankl/OPG, IL-1, IL-6 and TNFa on the 3rd and 7th days after irradiation (p<0.05), whereas P53 expression was increased (P<0.05). Sema3a reduced the inflammation induced by radiation and negatively regulated osteoclast differentiation. Sema3a promoted Raw264.7 cell apoptosis after irradiation, indicating that Sema3a could be a potential therapeutic target for radiation induced osteoporosis. PMID- 29975740 TI - PASI: A novel pathway method to identify delicate group effects. AB - Pathway analysis is a common approach in diverse biomedical studies, yet the currently-available pathway tools do not typically support the increasingly popular personalized analyses. Another weakness of the currently-available pathway methods is their inability to handle challenging data with only modest group-based effects compared to natural individual variation. In an effort to address these issues, this study presents a novel pathway method PASI (Pathway Analysis for Sample-level Information) and demonstrates its performance on complex diseases with different levels of group-based differences in gene expression. PASI is freely available as an R package. PMID- 29975741 TI - Storage stability of liposomes stored at elevated subzero temperatures in DMSO/sucrose mixtures. AB - Cryopreservation of biological materials is predominantly done using liquid nitrogen, and its application involves high maintenance costs and the need for periodical refilling of liquid nitrogen. Stable storage in mechanical freezers at -80 degrees C would eliminate these issues and allow for shipment of frozen specimens using dry ice. In this work, the possibility of increasing the storage temperature of cryopreserved samples to -80 degrees C by using combinations of DMSO and sucrose has been studied. Preservation efficacy was studied by measuring stability of liposomes encapsulated with carboxyfluorescein during storage at 150, -80 and -25 degrees C for up to three months. Thermal and molecular mobility properties of the different DMSO-sucrose formulations were measured using differential scanning calorimetry, whereas hydrogen bonding interactions of the formulations were probed by Fourier transform infrared spectroscopy. It was found that addition of sucrose to DMSO solutions increases the Tg, and decreases molecular mobility in the glassy state at a particular temperature. Although it was expected that storage above or close to Tg at -80 degrees C would affect liposome stability, stability was found to be similar compared to that of samples stored at -150 degrees C. Higher molecular mobility in the glassy state could not be associated with faster CF-leakage rates. Distinct differences in storage stability at -25 degrees C, far above Tg, were found among the sucrose/DMSO formulations, which were explained by the differences in permeability of sucrose and DMSO resulting in different levels of osmotic stress in the formulations. PMID- 29975742 TI - Salivary gland carcinoma: Prediction of cancer death risk based on apparent diffusion coefficient histogram profiles. AB - We evaluated apparent diffusion coefficient (ADC) histogram parameters for predicting the outcomes of patients with salivary gland carcinoma. Diffusion weighted MR imaging was performed in 20 patients with salivary gland carcinoma, and ADCs were determined using b-values of 500 and 1000 s/mm2. ADC histogram parameters (mean, median, percentage tumor area with distinctive ADC values [pADC], skewness, and kurtosis) were analyzed. The patients were followed for 5 136 months after primary surgery. The ADC histogram parameters and T (pT), N(pN), and M categories of the primary tumors were assessed for the prognostic importance using Cox proportional hazards models, logistic regression analysis, and receiver operating characteristic (ROC) analysis. Cohen's d was determined for evaluating the importance of differences in the parameters between two patient groups with different outcomes. Six patients died of cancer (DOC) within 3 years after the primary surgery. Cox proportional hazards models indicated that ADC mean (95% CI = 0.494-0.977, p = 0.034), ADC median (95% CI = 0.511-0.997, p = 0.048), pADC with extremely low (<0.6 mm2/s) ADC (95% CI = 1.013-1.082, p = 0.007), kurtosis (95% CI = 1.166-7.420, p = 0.023), and pN classification (95% CI = 1.196-4.836, p = 0.012) were important factors of cancer death risk. ROC analyses indicated that the pADC <0.6 *10-3 mm2/s was the best prognostic predictor (p <0.001; AUC = 0.929) among the ADC and TNM classification parameters that were significant in a univariate logistic regression analysis. Cohen's d values between the DOC and survived patients for the ADC mean, ADC median, pADC with extremely low ADC, and kurtosis were 1.06, 1.04, 2.12, and 1.13, respectively. These results suggest that ADC histogram analysis may be helpful for predicting the outcomes of patients with salivary gland carcinoma. PMID- 29975743 TI - Apparent ileal digestibility of Maillard reaction products in growing pigs. AB - The absorption of Maillard reaction products (MRP) from dietary origin has been linked to the occurrence of chronic diseases. The aim of the present study was to determine the effects of toasting time of rapeseed meal (RSM) and the processing method of the diets (pelleting and extrusion) that included RSM on the apparent ileal digestibility (AID) of total lysine, fructosyl-lysine (FL), carboxymethyl lysine (CML), carboxyethyl-lysine (CEL), lanthionine (LAN) and lysinoalanine (LAL) in growing pigs. The study consisted of a 2*3 factorial design with toasting time of RSM (60, 120 min) and diet processing method (mash, pelleted, extruded) as factors. Fifty growing pigs were individually fed one of the experimental diets for 4.5 consecutive days. Following euthanasia, samples of digesta were collected from the terminal 1.5 m of the small intestine. Increasing the toasting time of RSM increased the contents of FL, CML and CEL, whereas the additional effects of the diet processing methods were relatively small. Lysinoalanine and lanthionine were not detected in the diets; therefore, digestibility of these compounds could not be determined. The contents of FL, CML and CEL in the ileal chyme were positively correlated to their contents in the diets. The AID of the MRP from thermally-treated RSM were overall low and were not related to their contents in the diets. The AID of FL ranged between -8.5 and 19.1%, whilst AID of CML and CEL ranged from -0.2 to 18.3 and 3.6 to 30%, respectively. In conclusion, thermal treatments have clear effects on the contents of MRP in the diets. These compounds have relatively low digestibility in growing pigs. PMID- 29975744 TI - Cyclosporine-insensitive mode of cell death after prolonged myocardial ischemia: Evidence for sarcolemmal permeabilization as the pivotal step. AB - A prominent theory of cell death in myocardial ischemia/reperfusion (I/R) posits that the primary and pivotal step of irreversible cell injury is the opening of the mitochondrial permeability transition (MPT) pore. However, the predominantly positive evidence of protection against infarct afforded by the MPT inhibitor, Cyclosporine A (CsA), in experimental studies is in stark contrast with the overall lack of benefit found in clinical trials of CsA. One reason for the discrepancy might be the fact that relatively short experimental ischemic episodes (<1 hour) do not represent clinically-realistic durations, usually exceeding one hour. Here we tested the hypothesis that MPT is not the primary event of cell death after prolonged (60-80 min) episodes of global ischemia. We used confocal microcopy in Langendorff-perfused rabbit hearts treated with the electromechanical uncoupler, 2,3-Butanedione monoxime (BDM, 20 mM) to allow tracking of MPT and sarcolemmal permeabilization (SP) in individual ventricular myocytes. The time of the steepest drop in fluorescence of mitochondrial membrane potential (DeltaPsim)-sensitive dye, TMRM, was used as the time of MPT (TMPT). The time of 20% uptake of the normally cell-impermeable dye, YO-PRO1, was used as the time of SP (TSP). We found that during reperfusion MPT and SP were tightly coupled, with MPT trending slightly ahead of SP (TSP-TMPT = 0.76+/-1.31 min; p = 0.07). These coupled MPT/SP events occurred in discrete myocytes without crossing cell boundaries. CsA (0.2 MUM) did not reduce the infarct size, but separated SP and MPT events, such that detectable SP was significantly ahead of MPT (TSP -TMPT = -1.75+/-1.28 min, p = 0.006). Mild permeabilization of cells with digitonin (2.5-20 MUM) caused coupled MPT/SP events which occurred in discrete myocytes similar to those observed in Control and CsA groups. In contrast, deliberate induction of MPT by titration with H2O2 (200-800 MUM), caused propagating waves of MPT which crossed cell boundaries and were uncoupled from SP. Taken together, these findings suggest that after prolonged episodes of ischemia, SP is the primary step in myocyte death, of which MPT is an immediate and unavoidable consequence. PMID- 29975745 TI - What's in a tide pool? Just as much food web network complexity as in large open ecosystems. AB - Understanding the fundamental laws that govern complex food web networks over large ecosystems presents high costs and oftentimes unsurmountable logistical challenges. This way, it is crucial to find smaller systems that can be used as proxy food webs. Intertidal rock pool environments harbour particularly high biodiversity over small areas. This study aimed to analyse their food web networks to investigate their potential as proxies of larger ecosystems for food web networks research. Highly resolved food webs were compiled for 116 intertidal rock pools from cold, temperate, subtropical and tropical regions, to ensure a wide representation of environmental variability. The network properties of these food webs were compared to that of estuaries, lakes and rivers, as well as marine and terrestrial ecosystems (46 previously published complex food webs). The intertidal rock pool food webs analysed presented properties that were in the same range as the previously published food webs. The niche model predictive success was remarkably high (73-88%) and similar to that previously found for much larger marine and terrestrial food webs. By using a large-scale sampling effort covering 116 intertidal rock pools in several biogeographic regions, this study showed, for the first time, that intertidal rock pools encompass food webs that share fundamental organizational characteristics with food webs from markedly different, larger, open and abiotically stable ecosystems. As small, self-contained habitats, intertidal rock pools are particularly tractable systems and therefore a large number of food webs can be examined with relatively low sampling effort. This study shows, for the first time that they can be useful models for the understanding of universal processes that regulate the complex network organization of food webs, which are harder or impossible to investigate in larger, open ecosystems, due to high costs and logistical difficulties. PMID- 29975746 TI - Shaping pre-modern digital terrain models: The former topography at Charlemagne's canal construction site. AB - The use of remote sensing techniques to identify (geo)archaeological features is wide spread. For archaeological prospection and geomorphological mapping, Digital Terrain Models (DTMs) on based LiDAR (Light Detection And Ranging) are mainly used to detect surface and subsurface features. LiDAR is a remote sensing tool that scans the surface with high spatial resolution and allows for the removal of vegetation cover with special data filters. Archaeological publications with LiDAR data in issues have been rising exponentially since the mid-2000s. The methodology of DTM analyses within geoarchaeological contexts is usually based on "bare-earth" LiDAR data, although the terrain is often significantly affected by human activities. However, "bare-earth" LiDAR data analyses are very restricted in the case of historic hydro-engineering such as irrigation systems, mills, or canals because modern roads, railway tracks, buildings, and earth lynchets influence surface water flows and may dissect the terrain. Consequently, a "natural" pre-modern DTM with high depth accuracy is required for palaeohydrological analyses. In this study, we present a GIS-based modelling approach to generate a pre-modern and topographically purged DTM. The case study focuses on the landscape around the Early Medieval Fossa Carolina, a canal constructed by Charlemagne and one of the major medieval engineering projects in Europe. Our aim is to reconstruct the pre-modern relief around the Fossa Carolina for a better understanding and interpretation of the alignment of the Carolingian canal. Our input data are LiDAR-derived DTMs and a comprehensive vector layer of anthropogenic structures that affect the modern relief. We interpolated the residual points with a spline algorithm and smoothed the result with a low pass filter. The purged DTM reflects the pre-modern shape of the landscape. To validate and ground-truth the model, we used the levels of recovered pre-modern soils and surfaces that have been buried by floodplain deposits, colluvial layers, or dam material of the Carolingian canal. We compared pre-modern soil and surface levels with the modelled pre-modern terrain levels and calculated the overall error. The modelled pre-modern surface fits with the levels of the buried soils and surfaces. Furthermore, the pre-modern DTM allows us to model the most favourable course of the canal with minimal earth volume to dig out. This modelled pathway corresponds significantly with the alignment of the Carolingian canal. Our method offers various new opportunities for geoarchaeological terrain analysis, for which an undisturbed high-precision pre-modern surface is crucial. PMID- 29975747 TI - Relationship between alcohol co-ingestion and outcome in profenofos self poisoning - A prospective case series. AB - INTRODUCTION: The importance of alcohol co-ingestion for outcome in organophosphorus (OP) insecticide self-poisoning has only been studied for the relatively hydrophilic dimethyl insecticide, dimethoate. We aimed to assess the effect of alcohol in acute poisoning with the lipophilic S-alkyl OP insecticide, profenofos. METHODOLOGY: Demographic and clinical data, including an alcohol history, were prospectively collected from all cases of acute poisoning with agricultural profenofos EC50 presenting to two Sri Lankan hospitals over seven years. RESULTS: Of 1859 patients with acute OP insecticide self-poisoning, 243 (13.1%) reported ingestion of profenofos (male 182/243, 74.9%). Alcohol co ingestion was reported by 64/243 (26.3%). All patients reporting alcohol co ingestion were male (64/64 [100%] vs 118/179 [65.9%] not reporting alcohol ingestion, p<0.001). More patients reporting alcohol co-ingestion died (10/64 [15.6%] vs 10/179 [5.6%]; p = 0.013) and required intubation (13/64 [20.3%] vs 16/179 [8.9%], p = 0.016) compared to those who did not co-ingest alcohol. Using multi-logistic regression, controlling for the estimated dose ingested, age (OR 11.1 [2.5 to 48.9] for age > 35 years vs <=35 years) and alcohol co-ingestion (OR 3.1 [1.2 to 7.9]) were independently associated with increased risk of death. Increased risk of intubation was independently associated with age (OR 3.2 [1.6 to 6.6] for age > 35 years vs <=35 years) and alcohol co-ingestion (OR 3.2 [1.6 to 6.4]). CONCLUSION: A history of alcohol co-ingestion, as well as older age, is independently associated with worse outcome in patients' self-poisoned with profenofos. PMID- 29975748 TI - Teaching hospital alternatives for Veterans Health Administration facilities: A Google Maps proximity study. AB - The United States Veterans Health Administration (VHA) serves more than 9 million enrolled Veterans each year. Although most of the care that the VHA sponsors is delivered within its own facilities, there has been a call for "privatizing" some or all of these services. Under such an arrangement, the Department of Veterans Affairs would pay non-VHA providers to deliver care in facilities open to the general public. Privatization is hotly contested on political grounds and is not resolved. Yet the question whether the VHA should be privatized cannot be resolved without first establishing that this policy change is even feasible. One potential obstacle to privatization would be the lack of nearby alternative facilities to deliver care. To assess for the presence of this impediment, we used Google Maps to measure the travel time between 167 VA hospitals and the teaching hospital nearest to each of them. We determined that the mean travel time between VA hospitals and their nearest teaching hospital was approximately 18 minutes with a median of 10 minutes. All but nine VA facilities were within two hours' travel, and these nine within ten minutes' travel to a tertiary care, nonteaching hospital. These data do not definitively resolve the privatization debate, of course, but do refute the assertion that inpatient VA services cannot be privatized because replacement hospitals are too far away. As shown, that is simply not the case. PMID- 29975750 TI - Determination of sulfachloropyridazine residue levels in feathers from broiler chickens after oral administration using liquid chromatography coupled to tandem mass spectrometry. AB - Several antimicrobials are routinely used by the poultry farming industry on their daily operations, however, researchers have found for some antimicrobials that their residues persist for longer periods in feathers than they do in edible tissues, and at higher concentrations, as well. But this information is not known for other classes of antimicrobials, such as the sulfonamides. Therefore, this work presents an accurate and reliable analytical method for the detection of sulfachloropyridazine (SCP) in feathers and edible tissues from broiler chickens. This method was also validated in-house and then used to study the depletion of sulfachloropyridazine in those matrices. The experimental group comprised 54 broiler chickens, who were raised under controlled conditions and then treated with a commercial formulation of 10% sulfachloropyridazine for 5 days. Samples were analyzed via LC-MS/MS, using 13C6-sulfamethazine (SMZ-13C6) as an internal standard. Aromatic sulfonic acid solid phase extraction (SPE) cartridges were used to clean up the samples. The Limit of Detection (LOD) for this method was set at 10 MUg kg-1 on feathers and liver; and at 5 MUg kg-1 on muscle. Within the range of 10-100 MUg kg-1, the calibration curves for all matrices presented a determination coefficient greater than 0.96. Our results show, with a 95% confidence level, that sulfachloropyridazine persisted in feathers for up to 55 days after ceasing treatment, and its concentrations were higher than in edible tissues. In consequence, to avoid re-entry of antimicrobial residues into the food-chain, we recommend monitoring and inspecting animal diets that contain feather derivatives, such as feathers meals, because they could be sourced from birds that might have been medicated with sulfachloropyridazine. PMID- 29975749 TI - The effect of depressive symptoms on cognition in patients with fibromyalgia. AB - BACKGROUND: Fibromyalgia (FM) patients frequently complain of cognitive problems, but it remains unclear whether these cognitive complaints can be attributed to a dysfunction of the central nervous system or if they can be explained by other factors associated with the disease, such as depression, anxiety and sleep dysfunction. METHODS: One hundred and ten patients with FM were compared with thirty-three patients diagnosed with a depressive disorder (DD) and fifty healthy controls (HC). Several measures of attention and executive functions were used to make these comparisons and the patients were also asked to complete questionnaires on depression, anxiety and sleep quality. Univariate analyses of covariance (ANCOVA) were performed to identify and control confounders and multiple linear models were used to examine the effects of fibromyalgia and depression on cognitive measures. RESULTS: FM and HC differed significantly with respect to depression, anxiety and sleep dysfunction, whereas FM and DD did not differ in terms of symptoms of depression and anxiety. However, FM was associated with a worse quality of sleep than DD. Comparisons of cognitive performance between groups showed that short-term and working memory and inattention measures were only associated with symptoms of depression, whereas selective attention was associated with both depression and fibromyalgia, and processing speed, cognitive flexibility and inhibitory control showed a significant interaction between depression and fibromyalgia. Moreover, cognitive flexibility and inhibition abilities were specifically associated with FM. CONCLUSION: FM patients show a cluster of cognitive impairment in the attentional and executive domains, although some of the symptoms observed could be explained by the severity of the symptoms of depression, while others seem to depend on the effects of fibromyalgia. Implications of the findings for the understanding and management of cognitive impairment of FM patients are discussed. PMID- 29975752 TI - The increased purchase of asthma medication for individuals born preterm seems to wane with age: A register-based longitudinal national cohort study. AB - INTRODUCTION: Preterm birth is associated with increased risk of respiratory symptoms in childhood, often treated with asthma medication. We designed a follow up study to previous research and investigated whether the association of gestational age with purchasing asthma medication diminishes in adulthood. METHODS: We conducted a register-based study of a national cohort of all infants born in Denmark in 1980-2009 evaluating longitudinal data on individually prescribed asthma medication (both inhaled beta-2 receptor agonist and different controller treatment over 2-year periods) available from 1995-2011. We analyzed the effect of gestational age considering age, birth year, and perinatal variables using logistic regression with a Generalized Estimating Equations model. All data were unambiguously linked through the Civil Registration System. RESULTS: We included 1,819,743 individuals in our study population. We found an inverse dose-response relationship between gestational age and asthma medication in earlier age-groups with a gradual decrease in odds ratios with increasing age and loss of statistical significance in early adulthood (18-31 years). For our oldest generations, there was a significant effect of gestational age (p-value = 0.04), which became insignificant when adjusting for confounding and mediating factors (p = 0.44). There were significant interactions between gestational age and age (p<0.0001) and gestational age and birth year, but these were most important during childhood (0-11 years) and for our youngest generations (born after 1995). CONCLUSION: The strong association between gestational age and purchase of prescription asthma medication weakens with age into early adulthood, in consistence with the results from our previous study. The risk for purchasing medication to treat asthma-like symptoms was higher in more recent birth years, but the effect of gestational age was small beyond 11 years of age. Gestational age per se did not seem to be significant for the development of asthma-like symptoms: most of its effect could be explained by other perinatal factors. PMID- 29975751 TI - PIK3CA missense mutations promote glioblastoma pathogenesis, but do not enhance targeted PI3K inhibition. AB - BACKGROUND: Glioblastoma (GBM) is the most common adult primary brain tumor. Multimodal treatment is empiric and prognosis remains poor. Recurrent PIK3CA missense mutations (PIK3CAmut) in GBM are restricted to three functional domains: adaptor binding (ABD), helical, and kinase. Defining how these mutations influence gliomagenesis and response to kinase inhibitors may aid in the clinical development of novel targeted therapies in biomarker-stratified patients. METHODS: We used normal human astrocytes immortalized via expression of hTERT, E6, and E7 (NHA). We selected two PIK3CAmut from each of 3 mutated domains and induced their expression in NHA with (NHARAS) and without mutant RAS using lentiviral vectors. We then examined the role of PIK3CAmut in gliomagenesis in vitro and in mice, as well as response to targeted PI3K (PI3Ki) and MEK (MEKi) inhibitors in vitro. RESULTS: PIK3CAmut, particularly helical and kinase domain mutations, potentiated proximal PI3K signaling and migration of NHA and NHARAS in vitro. Only kinase domain mutations promoted NHA colony formation, but both helical and kinase domain mutations promoted NHARAS tumorigenesis in vivo. PIK3CAmut status had minimal effects on PI3Ki and MEKi efficacy. However, PI3Ki/MEKi synergism was pronounced in NHA and NHARAS harboring ABD or helical mutations. CONCLUSION: PIK3CAmut promoted differential gliomagenesis based on the mutated domain. While PIK3CAmut did not influence sensitivity to single agent PI3Ki, they did alter PI3Ki/MEKi synergism. Taken together, our results demonstrate that a subset of PIK3CAmut promote tumorigenesis and suggest that patients with helical domain mutations may be most sensitive to dual PI3Ki/MEKi treatment. PMID- 29975753 TI - Inhibition of NF-kappaB signaling in IKKbetaF/F;LysM Cre mice causes motor deficits but does not alter pathogenesis of Spinocerebellar ataxia type 1. AB - Spinocerebellar Ataxia type 1 (SCA1) is a fatal neurodegenerative genetic disease that is characterized by pronounced neuronal loss and gliosis in the cerebellum. We have previously demonstrated microglial activation, measured as an increase in microglial density in cerebellar cortex and an increase in the production of pro inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), in the cerebellum of the ATXN1[82Q] transgenic mouse model of SCA1. To examine the role of activated state of microglia in SCA1, we used a Cre-Lox approach with IKKbetaF/F;LysM Cre mice intended to reduce inflammatory NF-kappaB signaling, selectively in microglia. ATXN1[82Q];IKKbetaF/F;LysM Cre mice showed reduced cerebellar microglial density and production of TNFalpha compared to ATXN1[82Q] mice, yet reducing NF-kappaB did not ameliorate motor impairments and cerebellar cellular pathologies. Unexpectedly, at 12 weeks of age, control IKKbetaF/F;LysM Cre mice showed motor deficits equal to ATXN1[82Q] mice that were dissociated from any obvious neurodegenerative changes in the cerebellum, but were rather associated with a developmental impairment that presented as a retention of climbing fiber synaptic terminals on the soma of Purkinje neurons. These results indicate that NF-kappaB signaling is required for increase in microglial numbers and TNF-alpha production in the cerebella of ATXN1[82Q] mouse model of SCA1. Furthermore, these results elucidate a novel role of canonical NF-kappaB signaling in pruning of surplus synapses on Purkinje neurons in the cerebellum during development. PMID- 29975754 TI - Development and psychometric properties of short form of central sensitization inventory in participants with musculoskeletal pain: A cross-sectional study. AB - BACKGROUND: The central sensitization inventory (CSI) comprises 25 items and is commonly used to measure somatic and emotional symptoms related to central sensitization symptoms. CSI was developed as an easy-to-administer screening instrument for patients at high risk of developing central sensitization in whom it was essential to quickly evaluate the condition. The purpose of the present study was to develop a short form of CSI and evaluate its psychometric properties using a contemporary approach called Rasch analysis. METHODS: A total of 505 patients with musculoskeletal disorders were recruited in this study. The CSI, pain intensity, pain interference, and the health-related quality of life (QOL) were evaluated for each participant. The original CSI items were consecutively analyzed using the Rasch model. Successive Rasch analyses were performed until a final set of items satisfied the model fit requirements. We also analyzed the psychometric properties of the original and short forms of CSI. RESULTS: Four consecutive Rasch analyses identified the removable items. Finally, the shortest questionnaire obtained that maintained the correct psychometric properties based on the Rasch model contained only 9 items (CSI-9). Rasch analysis showed that the CSI-9 had acceptable internal consistency, exhibited unidimensionality, had no notable differential item functioning, and was functional on the category rating scale. CONCLUSIONS: The nine-item short form of CSI has acceptable psychometric properties and is suitable for use for patients with musculoskeletal pain. Thus, the CSI-9 can be used as a brief instrument to evaluate central sensitization. PMID- 29975755 TI - Acceptance of different design exergames in elders. AB - For promoting the successful aging of elderly residents of Chang Gung Silver Village in Taiwan, five interactive exergames were developed to promote the well being of the elderly. The exergames included both physical games and cognitive games, and were implemented using various computer-based technologies in the Chang Gung Silver Village. The exergames were trialed by 39 elderly residents (15 male, 24 female; mean age 79.5 +/- 17.5 years) of Chang Gung Silver Village. Following the trials, the participants were requested to complete a Technology Acceptance Model 2 (TAM2) questionnaire. The results showed that the perceived playfulness and perceived usefulness of the exergames were significantly related to the users' usage behavior and intention to use for both the physical games and the cognitive games. However, a relationship between the output quality of the game and the usage behavior was apparent only in the case of the cognitive exergames. Finally, the impact of social influence on the intention to use and the usage behavior was more pronounced for the physical exergames. Overall, the results revealed that the acceptance of exergames by the elderly depends not so much on the awareness of fun in using the game, but the perceived usefulness of the related physical and cognitive abilities. PMID- 29975756 TI - Multiple cardiovascular risk factors in adolescents from a middle-income country: Prevalence and associated factors. AB - Multiple cardiovascular risk factors are directly related to the severity of atherosclerosis, even in children and adolescents. In this context accurate assessment of risk factors at the individual level play a decisive role in cardiovascular disease (CVD) prevention. The objective of this study was to estimate the prevalence of cardiovascular risk factors, the frequency of their coexistence in individuals, and identify possible determinants associated with this coexistence in Brazilian adolescents. A cross-sectional study with 1170 students (12-17 years) from public and private schools of a large city was conducted. In addition to family history, modifiable cardiovascular risk factors were assessed including: tobacco use, alcohol consumption, sedentary lifestyle, overweight/obesity, increased waist circumference, and high blood pressure (office and home). We built a linear regression model to identify determinants associated with increasing number of modifiable risk factors. Mean study population age was 14.7+/-1.6 years, 67% were enrolled in public schools and 33% in private ones. The majority of the adolescents had at least two risk factors (68.9%), more than 10% had more than 4 risk factors, and in only 6.7% of the sample no risk factor was identified. Family history of CVD (beta-coefficient = 1.20; 95%CI 1.07-1.34; p<0.001), increasing age (beta-coefficient = 0.08; 95%CI 0.04-0.11; p<0.001), and being enrolled in private schools (beta-coefficient = 0.16; 95%CI 0.02-0.30; p = 0.023) were directly associated with the modifiable CV risk factors. In conclusion, the prevalence of multiple cardiovascular risk factors was high in the population of adolescents studied. School based interventions should be addressed to change this scenario. PMID- 29975757 TI - Rehabilitation strategy for hip fracture, focused on behavioral psychological symptoms of dementia for older people with cognitive impairment: A nationwide Japan rehabilitation database. AB - The aim is to investigate the relationship between a positive outcome on rehabilitation after hip fracture and behavioral psychological symptoms of dementia (BPSD) transition during rehabilitation. This study is a retrospective cohort study based on the Japan Rehabilitation Database. We recruited 756 subjects 65 years of age or older from 31 hospitals in the database. All subjects were in the hospital as patients undergoing rehabilitation for hip fracture. Functional independence measure (FIM), walking ability, Mini-Mental State Examination (MMSE), and BPSD were measured both at the beginning and at the end of rehabilitation. MMSE for 23 or under was defined as the cognitive-impaired group. MMSE for 24 or over was used as the cognitively intact group. Cognitive impaired participants were divided into four groups: participants presented no BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (-/-)), participants presented BPSD at the beginning of rehabilitation but resolved at the end of rehabilitation (Group (+/-)), participants had no BPSD at the beginning of rehabilitation but appeared at the end of rehabilitation (Group (-/+)) and participants had sign of BPSD both at the beginning of rehabilitation and at the end of rehabilitation (Group (+/+)). The endpoints were waking ability, FIM gain. As results, one hundred thirty-seven cognitive-impaired older people patients out of 471 (29.1%) suffered from BPSD at the beginning of rehabilitation. FIM gains in cognitively intact group, Group (-/-), Group (+/-), Group (-/+) and Group (+/+) were 24.8 +/- 18.7, 17.5 +/- 16.9, 27.3 +/- 19.7, 17.8 +/- 12.2 and 12.2 +/- 17.2, respectively. The Group (+/-) was significantly connected to a positive outcome for rehabilitation. The present study suggested that the management of BPSD can lead to better functional recovery during rehabilitation. PMID- 29975758 TI - Understanding plastome evolution in Hemiparasitic Santalales: Complete chloroplast genomes of three species, Dendrotrophe varians, Helixanthera parasitica, and Macrosolen cochinchinensis. AB - Santalales is a large order, with over 2200 species, most of which are root or aerial (stem) hemiparasites. In this study, we report the newly assembled chloroplast genome of Dendrotrophe varians (140,666 bp) in the family Amphorogynaceae and the cp genomes of Helixanthera parasitica (124,881 bp) and Macrosolen cochinchinensis (122,986 bp), both in the family Loranthaceae. We compared the cp genomes of 11 Santalales including eight currently available cp genomes. Santalales cp genomes are slightly or not reduced in size (119-147 kb), similar to other hemiparasitic species, when compared with typical angiosperm cp genomes (120-170 kb). In a phylogeny examining gene content, the NADH dehydrogenase gene group is the only one among eight functional gene groups that lost complete functionally in all examined Santalales. This supports the idea that the functional loss of ndh genes is the initial stage in the evolution of the plastome of parasitic plants, but the loss has occurred independently multiple times in angiosperms, while they are not found in some parasites. This suggests that the functional loss of ndh genes is not essential for the transition from autotroph to parasite. We additionally examined the correlation between gene content and type of parasitism (obligate/facultative and stem/root parasites) of all hemiparasitic species in which cp genomes have been reported to date. Correlation was not found in any types of parasitism. PMID- 29975759 TI - Automated TruTip nucleic acid extraction and purification from raw sputum. AB - Automated nucleic acid extraction from primary (raw) sputum continues to be a significant technical challenge for molecular diagnostics. In this work, we developed a prototype open-architecture, automated nucleic acid workstation that includes a mechanical homogenization and lysis function integrated with heating and TruTip purification; optimized an extraction protocol for raw sputum; and evaluated system performance on primary clinical specimens. Eight samples could be processed within 70 min. The system efficiently homogenized primary sputa and doubled nucleic acid recovery relative to an automated protocol that did not incorporate sample homogenization. Nucleic acid recovery was at least five times higher from raw sputum as compared to that of matched sediments regardless of smear or culture grade, and the automated workstation reproducibly recovered PCR detectable DNA to at least 80 CFU mL-1 raw sputum. M. tuberculosis DNA was recovered and detected from 122/123 (99.2%) and 124/124 (100%) primary sputum and sediment extracts, respectively. There was no detectable cross-contamination across 53 automated system runs and amplification or fluorescent inhibitors (if present) were not detectable. The open fluidic architecture of the prototype automated workstation yields purified sputum DNA that can be used for any molecular diagnostic test. The ability to transfer TruTip protocols between personalized, on-demand pipetting tools and the fully automated workstation also affords public health agencies an opportunity to standardize sputum nucleic acid sample preparation procedures, reagents, and quality control across multiple levels of the health care system. PMID- 29975760 TI - Detection of PrPres in peripheral tissue in pigs with clinical disease induced by intracerebral challenge with sheep-passaged bovine spongiform encephalopathy agent. AB - Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to pigs via intracerebral inoculation. A clear link has been established between the consumption of products of bovine origin contaminated with the BSE agent and the development of variant Creutzfeldt-Jakob disease in humans. Small ruminants can also naturally develop BSE, and sheep-adapted BSE (Sh-BSE) propagates more efficiently than cattle BSE in pigs and in mouse models expressing porcine prion protein. In addition, Sh-BSE shows greater efficiency of transmission to human models than original cow BSE. While infectivity and/or abnormal PrP accumulation have been reported in the central nervous system in BSE-infected pigs, the ability of the agent to replicate in peripheral tissues has not been fully investigated. We previously characterized the presence of prions in a panel of tissues collected at the clinical stage of disease from pigs experimentally infected with Sh-BSE. Western blot revealed low levels of PrPres accumulation in lymphoid tissues, nerves, and skeletal muscles from 4 of the 5 animals analysed. Using protein misfolding cyclic amplification (PMCA), which we found to be 6 log fold more sensitive than direct WB for the detection of pig BSE, we confirmed the presence of the Sh-BSE agent in lymphoid organs, nerves, ileum, and striated muscles from all 5 inoculated pigs. Surprisingly, PrPres positivity was also detected in white blood cells from one pig using this method. The presence of infectivity in lymphoid tissues, striated muscles, and peripheral nerves was confirmed by bioassay in bovine PrP transgenic mice. These results demonstrate the ability of BSE-derived agents to replicate efficiently in various peripheral tissues in pigs. Although no prion transmission has been reported in pigs following oral BSE challenge, our data support the continuation of the Feed Ban measure implemented to prevent entry of the BSE agent into the feed chain. PMID- 29975761 TI - Evaluation of temperature induction in focal ischemic thermocoagulation model. AB - The thermocoagulation model, which consists of focal cerebral ischemia with craniectomy, is helpful in studying permanent ischemic brain lesions and has good reproducibility and low mortality. This study analyzed the best conditions for inducing a focal ischemic lesion by thermocoagulation. We investigated parameters such as temperature and thermal dissipation in the brain tissue during induction and analyzed real-time blood perfusion, histological changes, magnetic resonance imaging (MRI), and motor behavior in a permanent ischemic stroke model. We used three-month-old male Wistar rats, weighing 300-350 g. In the first experiment, the animals were divided into four groups (n = 5 each): one sham surgery group and three ischemic lesion groups having thermocoagulation induction (TCI) temperatures of 200 degrees C, 300 degrees C, and 400 degrees C, respectively, with blood perfusion (basal and 30 min after TCI) and 2,3,5-Triphenyl-tetrazolium chloride (TTC) evaluation at 2 h after TCI. In the second experiment, five groups (n = 5 each) were analyzed by MRI (basal and 24 h after TCI) and behavioral tests (basal and seven days after TCI) with the control group added for the surgical effects. The MRI and TTC analyses revealed that ischemic brain lesions expressively evolved, especially at TCI temperatures of 300 degrees C and 400 degrees C, and significant motor deficits were observed as the animals showed a decrease frequency of movement and an asymmetric pattern. We conclude that a TCI temperature of 400 degrees C causes permanent ischemic stroke and motor deficit. PMID- 29975762 TI - Plasmodium sporozoites can invade hepatocytic cells independently of the Ephrin receptor A2. AB - Sporozoite forms of the malaria parasite Plasmodium are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. In previous studies, two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the Scavenger Receptor BI (SR-BI), were shown to play an important role during entry of Plasmodium sporozoites into hepatocytic cells. In contrast to HCV entry, which requires both CD81 and SR-BI together with additional host factors, CD81 and SR BI operate independently during malaria liver infection, as sporozoites can use CD81 and/or SR-BI, depending on the Plasmodium species, to invade hepatocytes. However, the molecular function of CD81 and SR-BI during parasite entry remains unknown. Another HCV entry factor, the Ephrin receptor A2 (EphA2), was recently reported to play a key role as a host cell entry factor during malaria liver infection. Here, we investigated the contribution of EphA2 during CD81-dependent and SR-BI-dependent sporozoite infection. Using small interfering RNA (siRNA) and antibodies against EphA2, combined with direct detection of parasites by flow cytometry or microscopy, we show that blocking EphA2 has no significant impact on P. yoelii or P. berghei host cell infection, irrespective of the entry route. Thus, our findings argue against an important role of EphA2 during malaria liver infection. PMID- 29975763 TI - Relationship of spinal alignment with muscular volume and fat infiltration of lumbar trunk muscles. AB - Fat infiltration and atrophy of lumbar muscles are related to spinal degenerative conditions and may cause functional deficits. Spinal alignment exerts biomechanical influence on lumbar intervertebral discs and joints. Our objective was to evaluate if spinopelvic parameters correlate with the lumbar muscle volume and fat infiltration. This is an observational, prospective and cross-sectional study. Ninety-three asymptomatic adult aged 20-40 years were included. Lumbar lordosis (LL), thoracic kyphosis (TK), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), thoracolumbar alignment (TL), sagittal vertical axis (SVA), C2 pelvic angle (CPA), spinosacral angle (SSA), lack of lordosis (PI-LL), L1S1 and T1S1 length were measured on panoramic spine radiographs. Lumbar axial T1 weighted and In- and Out-Phase images were obtained on 1.5T MRI scanner and were used to extract the muscle volumes and fat fractions of multifidus, erector spinae, and psoas. All muscle volumes were higher in men than women (p<0.05). The fat fraction was higher in the multifidus and erector spinae in women (p<0.05). Multifidus volume was weakly correlated with PT (R = 0.22), PI (R = 0.22), LL (R = 0.34) and CPA (R = 0.29). Erectors spinae volume were correlated with CPA (R = 0.21). Psoas volume correlated with TK (R = 0.21), TL (R = 0.27) and SVA (R = 0.23). The lumbar muscle volumes showed a moderated correlation with T1S1 length (R = 0.55 to 0.62). Spinopelvic parameters showed correlation with lumbar muscle volumes but not with muscle fat infiltration on asymptomatic young adults. PMID- 29975764 TI - Evolution of patients' socio-behavioral characteristics in the context of DAA: Results from the French ANRS CO13 HEPAVIH cohort of HIV-HCV co-infected patients. AB - BACKGROUND: Direct-acting antivirals (DAA) have dramatically increased HCV cure rates with minimal toxicity in HIV-HCV co-infected patients. This study aimed to compare the socio-behavioral characteristics of patients initiating pegylated interferon (PEG-IFN)-based HCV treatment with those of patients initiating DAA based treatment. METHODS: ANRS CO13 HEPAVIH is a national multicenter prospective cohort started in 2005, which enrolled 1,859 HIV-HCV co-infected patients followed up in French hospital outpatient units. Both clinical/biological and socio-behavioral data were collected during follow-up. We selected patients with socio-behavioral data available before HCV treatment initiation. RESULTS: A total of 580 patients were included in this analysis. Of these, 347 initiated PEG-IFN based treatment, and 233 DAA-based treatment. There were significant differences regarding patient mean age (45 years+/-6 for the PEG-IFN group vs. 52 years+/-8 for the DAA group, p<0.001), unstable housing (21.4% vs. 11.2%, p = 0.0016), drug use (44.7% vs. 29.6%, p = 0.0003), regular or daily use of cannabis (24.3% vs. 15.6%, p = 0.0002), a history of drug injection (68.9% vs 39.0%, p<0.0001) and significant liver fibrosis (62.4% vs 72.3%, p = 0.0293). In multivariable analysis, patients initiating DAA-based treatment were older than their PEG-IFN based treatment counterparts (aOR = 1.17; 95%CI [1.13; 1.22]). Patients receiving DAA treatment were less likely to report unstable housing (0.46 [0.24; 0.88]), cannabis use (regular or daily use:0.50 [0.28; 0.91]; non-regular use: 0.41 [0.22; 0.77]), and a history of drug injection (0.19 [0.12; 0.31]). CONCLUSION: It is possible that a majority of patients who had socio-economic problems and/or a history of drug injection and/or a non-advanced disease stage were already treated for HCV in the PEG-IFN era. Today, patients with unstable housing conditions are prescribed DAA less frequently than other populations. As HCV treatment is prevention, improving access to DAA remains a major clinical and public health strategy, in particular for individuals with high-risk behaviors. PMID- 29975765 TI - Reappraisal of the systematics of Microglanis cottoides (Siluriformes, Pseudopimelodidae), a catfish from southern Brazil. AB - The southern region of Brazil is characterized by high species diversity and endemism of freshwater fishes distributed across geographically isolated river basins. Microglanis cottoides has a widespread range across these river basins and occurs in sympatry with other endemic species of the genus (e.g. M. cibelae, M. eurystoma, and M. malabarbai). Herein we tested the monophyly of M. cottoides and presented for the first time information about the molecular phylogeny of species in the genus. The results suggest that M. cottoides currently forms a non monophyletic group which includes populations endemic to the Uruguay River basin that are more closely related to M. malabarbai, and excludes M. cibelae, found to be nested within M. cottoides. Based on an integrative approach using morphological and molecular data, we propose M. cibelae as a junior synonym of M. cottoides, and the populations of the Uruguay River basin previously assigned to M. cottoides in fact belong to M. malabarbai. Our molecular phylogeny shows that M. cottoides is sister to M. parahybae, which is also a coastal species, and M. malabarbai is sister of M. garavelloi, both endemic to inland river basins. The time-calibrated phylogeny indicates that the separation between inland and the coastal clades occurred in the Tertiary period, and that the species within the coastal basins diverged in the Pliocene, which overlaps with the diversification times estimated for the two inland species as well. This pattern of diversification corroborates some previous studies with other fishes from the same region. PMID- 29975766 TI - Alternative splicing of helicase-like transcription factor (Hltf): Intron retention-dependent activation of immune tolerance at the feto-maternal interface. AB - Hltf is regulated by intron retention, and global Hltf-deletion causes perinatal lethality from hypoglycemia. In heart, full-length Hltf is a transcriptional regulator of Hif-1alpha that controls transport systems. Thus, we tested the hypothesis that Hltf deletion from placenta caused or exacerbated neonatal hypoglycemia via Hif-1alpha regulation of nutrient transporters. RNA-seq data analyses identified significant changes in transcript expression and alternative splicing (AS) in E18.5 placentome. iPathwayGuide was used for gene ontology (GO) analysis of biological processes, molecular functions and cellular components. Elim pruning algorithm identified hierarchical relationships. The methylome was interrogated by Methyl-MiniSeq Epiquest analysis. GO analysis identified gene enrichment within biological processes. Protein expression was visualized with immunohistochemistry. Although two Hltf mRNA isoforms are quantifiable in most murine tissues, only the truncated Hltf isoform is expressed in placenta. The responsible intron retention event occurs in the absence of DNA methylation. iPathwayGuide analysis identified 157 target genes of 11,538 total genes with measured expression. These were obtained using a threshold of 0.05 for statistical significance (p-value) and a long fold change of expression with absolute value of at least 0.6. Hltf deletion altered transcription of trophoblast lineage-specific genes, and increased transcription of the Cxcr7 (p = 0.004) gene whose protein product is a co-receptor for human and simian immunodeficiency viruses. Concomitant increased Cxcr7 protein was identified with immunolabeling. Hltf deletion had no effect on transcription or site-specific methylation patterns of Hif-1alpha, the major glucose transporters, or System A amino acid transporters. There was no measureable evidence of uteroplacental dysfunction or fetal compromise. iPathGuide analysis revealed Hltf suppresses cytolysis (10/21 genes; p-value 1.900e-12; p-value correction: Elim pruning; GO:019835) including the perforin-granzyme pathway in uterine natural killer cells. Our findings 1) prove the truncated Hltf protein isoform is a transcription factor, 2) establish a functional link between AS of Hltf and immunosuppression at the feto-maternal interface, 3) correlate intron retention with the absence of DNA methylation, and 4) underscore the importance of differential splicing analysis to identify Hltf's functional diversity. PMID- 29975767 TI - With some risk-taking and luck: A veterinarian's adventures in viral immunology. PMID- 29975768 TI - Correction: System steganalysis with automatic fingerprint extraction. AB - [This corrects the article DOI: 10.1371/journal.pone.0195737.]. PMID- 29975769 TI - Efficacy of different revision procedures for infected megaprostheses in musculoskeletal tumour surgery of the lower limb. AB - PURPOSE: The incidence of recurrent infections in patients following one or two stage revision for infected megaprostheses after resection of bone tumours was investigated. The difference between retaining at least one well fixed stem and a complete removal of the megaprosthesis during a two stage revision was also analysed. METHODS: 627 patients who experienced a replacement of a musculoskeletal tumour by megaprostheses were recorded. An infection occurred in 83 of 621 patients available for follow-up. 61 patients underwent one stage revision, and 16 patients two stage revision for the first revision surgery. In the entire study period, two stage revision was performed 32 times (first, second, and third revision). RESULTS: The cumulative incidence analysis showed a reinfection probability after one stage revision of 18% at one year, 30% at two years, 39% at five years, 46% at ten years, and 56% at 15 years. After two stage revision, a reinfection probability of 28% at two years, and 48% at five years was calculated. Cumulative incidence curves did not differ significantly (Gray's test; p = 0.51) between one and two stage revision (with and without complete removal of the stems). In two stage revision (n = 32), a statistically significant difference in infection rates between patients treated with complete removal of the megaprosthesis (n = 18) including anchorage stems and patients with at least one retained stem (n = 14) was shown (Fisher's exact test, p = 0.029). CONCLUSION: Two stage revisions with complete removal of the megaprosthesis showed the best results among limb salvage procedures for the treatment of infected megaprosthesis. PMID- 29975770 TI - Twin-twin transfusion syndrome screening and diagnosis in the United States: A triangulation design of patient experiences. AB - OBJECTIVE: Using patient-reported experiences, this study: 1) quantitatively evaluated TTTS screening trends, 2) examined screening and diagnostic experiences using a mixed methods approach, and 3) determined gaps in clinical care experiences. DESIGN: This was a cross-sectional study. Data was collected using a self-report, retrospective survey. A triangulation design was used to validate quantitative survey data with thematically analyzed qualitative data. SETTING: Participants were recruited through social media and national foundations and completed the survey online. PARTICIPANTS: Participants were 312 women who completed a TTTS pregnancy in the United States, representing the largest survey of participants who have experienced TTTS. METHODS: Descriptive statistics and bivariate analyses were conducted. Multivariate logistic regression examined predictors of ultrasound frequency. Qualitative data were initially coded by hand and checked using qualitative software. RESULTS: The percentages of participants reporting guideline recommended screening, including identification of pregnancy type by gestational week 13 and timely receipt of ultrasounds, increased over time. However, 44.6% of participants diagnosed in recent years (2014 and later), reported that prior to TTTS diagnosis, they did not receive biweekly or more frequent ultrasounds. Three patient-reported provider practices were related to receiving ultrasounds at the recommended frequency: (1) determining MCDA status prior to gestational week 14, (2) providing participants with early warnings about the risk of TTTS to their pregnancies after MCDA status had been determined, and (3) referring participants to a Maternal-Fetal Medicine Specialist after MCDA identification, as validated by qualitative data. Our qualitative data revealed gaps in effective clinical care experiences among OB/GYN and specialist providers. CONCLUSION: These findings indicate screening and diagnosis for TTTS, as reported by patients, is improving in the United States; however, further efforts are required to ensure all patients receive appropriate screening, education and a team-based approach to comprehensive and supportive clinical care. PMID- 29975772 TI - Correction: Treatment outcomes and HPV characteristics for an institutional cohort of patients with anal cancer receiving concurrent chemotherapy and intensity-modulated radiation therapy. AB - [This corrects the article DOI: 10.1371/journal.pone.0194234.]. PMID- 29975771 TI - Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. AB - Eliciting broadly neutralizing antibodies (bnAbs) targeting envelope (Env) is a major goal of HIV vaccine development, but cross-clade breadth from immunization has only sporadically been observed. Recently, Xu et al (2018) elicited cross reactive neutralizing antibody responses in a variety of animal models using immunogens based on the epitope of bnAb VRC34.01. The VRC34.01 antibody, which was elicited by natural human infection, targets the N terminus of the Env fusion peptide, a critical component of the virus entry machinery. Here we precisely characterize the functional epitopes of VRC34.01 and two vaccine-elicited murine antibodies by mapping all single amino-acid mutations to the BG505 Env that affect viral neutralization. While escape from VRC34.01 occurred via mutations in both fusion peptide and distal interacting sites of the Env trimer, escape from the vaccine-elicited antibodies was mediated predominantly by mutations in the fusion peptide. Cryo-electron microscopy of four vaccine-elicited antibodies in complex with Env trimer revealed focused recognition of the fusion peptide and provided a structural basis for development of neutralization breadth. Together, these functional and structural data suggest that the breadth of vaccine-elicited antibodies targeting the fusion peptide can be enhanced by specific interactions with additional portions of Env. Thus, our complete maps of viral escape both delineate pathways of resistance to these fusion peptide-directed antibodies and provide a strategy to improve the breadth or potency of future vaccine-induced antibodies against Env's fusion peptide. PMID- 29975773 TI - GPCR-bigrams: Enigmatic signaling components in oomycetes. PMID- 29975774 TI - Correction: Evidence of Cognitive Dysfunction after Soccer Playing with Ball Heading Using a Novel Tablet-Based Approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0057364.]. PMID- 29975775 TI - Neisseria gonorrhoeae employs two protein inhibitors to evade killing by human lysozyme. AB - The bacterial pathogen Neisseria gonorrhoeae (Gc) infects mucosal sites rich in antimicrobial proteins, including the bacterial cell wall-degrading enzyme lysozyme. Certain Gram-negative bacteria produce protein inhibitors that bind to and inhibit lysozyme. Here, we identify Ng_1063 as a new inhibitor of lysozyme in Gc, and we define its functions in light of a second, recently identified lysozyme inhibitor, Ng_1981. In silico analyses indicated that Ng_1063 bears sequence and structural homology to MliC-type inhibitors of lysozyme. Recombinant Ng_1063 inhibited lysozyme-mediated killing of a susceptible mutant of Gc and the lysozyme-sensitive bacterium Micrococcus luteus. This inhibitory activity was dependent on serine 83 and lysine 103 of Ng_1063, which are predicted to interact with lysozyme's active site residues. Lysozyme co-immunoprecipitated with Ng_1063 and Ng_1981 from intact Gc. Ng_1063 and Ng_1981 protein levels were also increased in Gc exposed to lysozyme. Gc lacking both ng1063 and ng1981 was significantly more sensitive to killing by lysozyme than wild-type or single mutant bacteria. When exposed to human tears or saliva, in which lysozyme is abundant, survival of Delta1981Delta1063 Gc was significantly reduced compared to wild-type, and survival was restored upon addition of recombinant Ng_1981. Delta1981Delta1063 mutant Gc survival was additionally reduced in the presence of human neutrophils, which produce lysozyme. We found that while Ng_1063 was exposed on the surface of Gc, Ng_1981 was both in an intracellular pool and extracellularly released from the bacteria, suggesting that Gc employs these two proteins at multiple spatial barriers to fully neutralize lysozyme activity. Together, these findings identify Ng_1063 and Ng_1981 as critical components for Gc defense against lysozyme. These proteins may be attractive targets for antimicrobial therapy aimed to render Gc susceptible to host defenses and/or for vaccine development, both of which are urgently needed against drug-resistant gonorrhea. PMID- 29975776 TI - Prognostic role of FUT8 expression in relation to p53 status in stage II and III colorectal cancer. AB - The expression of fucosyltransferase 8, an enzyme responsible for core fucosylation encoded by FUT8, influences tumor biology and correlates with patient prognosis in several solid cancers. We hypothesized that p53 alteration modifies prognostic associations of FUT8 expression in colorectal cancer (CRC), since FUT8 has recently been identified as a direct transcriptional target of wild-type p53. Utilizing multiple datasets of microarray and RNA sequence of CRC, FUT8 mRNA was found to be highly expressed in wild-type p53 tumors (n = 382) compared to those of mutant p53 (n = 437). Prognostic values of FUT8 expression in conjunction with the p53 status for disease-free survival (DFS) were analyzed using two independent cohorts of stage II and III CRC after curative surgery, including the immunohistochemistry (IHC) cohort (n = 123) and the microarray cohort (n = 357). In both cohorts, neither FUT8 expression nor the p53 status was associated with DFS. Strikingly, positive expression of FUT8 protein was significantly associated with better DFS only in tumors with negative p53, while it had no prognostic impact in tumors with positive p53 in the IHC cohort. Although not statistically significant, a similar prognostic trend was observed in the microarray cohort when patients were stratified by the p53 status. Our results suggest that the prognostic values of FUT8 expression on DFS may be modified by the p53 status, and the expression of FUT8 protein can be a prognostic biomarker for patients with stage II and III CRC. PMID- 29975777 TI - Correction: Combination of ultrasound and rtPA enhances fibrinolysis in an In Vitro clot system. AB - [This corrects the article DOI: 10.1371/journal.pone.0188131.]. PMID- 29975778 TI - Correction: Buoyancy effects in stagnation-point flow of Maxwell fluid utilizing non-Fourier heat flux approach. AB - [This corrects the article DOI: 10.1371/journal.pone.0192685.]. PMID- 29975779 TI - Physiological processes and gross energy budget of the submerged longline cultured Pacific oyster Crassostrea gigas in a temperate bay of Korea. AB - Physiological processes and gross energy budget of the longline-cultured Pacific oyster Crassostrea gigas were investigated in Geoje-Hansan Bay, Korea during two entire culturing periods. Based on physiological measurements of food consumption, feces production, ammonium excretion, and respiration from July 2008 to February 2009 and from July 2013 to February 2014, scope for growth appeared to be positive during most of the culturing period, except for one period with extremely high temperatures (up to 25 degrees C). Estimates of physiological energy production matched well with tissue energy increment measured by gross biochemical composition during the culturing period, suggesting that the oysters might adjust their physiological performance to relatively low concentrations of suspended particulate matter in the bay to optimize energy acquisition. Such an adaptive adjustment includes an increased absorption of energy and a reduced loss of metabolic and excretory energy, resulting in positive production under high culturing density. Using physiological measurements, we further assessed the feedback effects of the longline aquaculture of oysters on the bay system. Ecological efficiency, estimated by a series of energetic efficiencies at the whole bay level, was low compared with Lindeman's law of trophic efficiency. Biodeposition and ammonia excretion rates in this study were relatively low compared with other intertidal plastic bag cultures. These results indicate that the cultured oysters might have only minor effects on benthic and pelagic environments of the bay. Overall, our results suggest that the adaptive physiological performance of oysters and consequently weak feedback effects on ambient habitats should facilitate sustainable longline aquaculture in the bay for a prolonged period without severe habitat deterioration. PMID- 29975780 TI - Sensitivity of vegetation to climate variability and its implications for malaria risk in Baringo, Kenya. AB - The global increase in vector borne diseases has been linked to climate change. Seasonal vegetation changes are known to influence disease vector population. However, the relationship is more theoretical than quantitatively defined. There is a growing demand for understanding and prediction of climate sensitive vector borne disease risks especially in regions where meteorological data are lacking. This study aimed at analyzing and quantitatively assessing the seasonal and year to-year association between climatic factors (rainfall and temperature) and vegetation cover, and its implications for malaria risks in Baringo County, Kenya. Remotely sensed temperature, rainfall, and vegetation data for the period 2004-2015 were used. Poisson regression was used to model the association between malaria cases and climatic and environmental factors for the period 2009-2012, this being the period for which all datasets overlapped. A strong positive relationship was observed between the Normalized Difference Vegetation Index (NDVI) and monthly total precipitation. There was a strong negative relationship between NDVI and minimum temperature. The total monthly rainfall (between 94 181mm), average monthly minimum temperatures (between 16-21 degrees C) and mean monthly NDVI values lower than 0.35 were significantly associated with malaria incidence rates. Results suggests that a combination of climatic and vegetation greenness thresholds need to be met for malaria incidence to be significantly increased in the county. Planning for malaria control can therefore be enhanced by incorporating these factors in malaria risk mapping. PMID- 29975781 TI - The VTI1A-TCF4 colon cancer fusion protein is a dominant negative regulator of Wnt signaling and is transcriptionally regulated by intestinal homeodomain factor CDX2. AB - Sequencing of primary colorectal tumors has identified a gene fusion in approximately 3% of colorectal cancer patients of the VTI1A and TCF7L2 genes, encoding a VTI1A-TCF4 fusion protein containing a truncated TCF4. As dysregulation of the Wnt signaling pathway is associated with colorectal cancer development and progression, the functional properties and transcriptional regulation of the VTI1A-TCF4 fusion protein may also play a role in these processes. Functional characteristics of the VTI1A-TCF4 fusion protein in Wnt signaling were analyzed in NCI-H508 and LS174T colon cancer cell lines. The NCI H508 cell line, containing the VTI1A-TCF7L2 fusion gene, showed no active Wnt signaling, and overexpression of the VTI1A-TCF4 fusion protein in LS174T cells along with a Wnt signaling luciferase reporter plasmid showed inhibition of activity. The transcriptional regulation of the VTI1A-TCF4 fusion gene was investigated in LS174T cells where the activity of the VTI1A promoter was compared to that of the TCF7L2 promoter, and the transcription factor CDX2 was analyzed for gene regulatory activity of the VTI1A promoter through luciferase reporter gene assay using colon cancer cell lines as a model. Transfection of LS174T cells showed that the VTI1A promoter is highly active compared to the TCF7L2 promoter, and that CDX2 activates transcription of VTI1A. These results suggest that the VTI1A-TCF4 fusion protein is a dominant negative regulator of the Wnt signaling pathway, and that transcription of VTI1A is activated by CDX2. PMID- 29975782 TI - Comparative transcriptome analysis provides global insight into gene expression differences between two orchid cultivars. AB - The orchids GL and YL are two cultivars of Cymbidium longibracteatum. YL displays an obviously yellowing rhizome and yellow leaves, while GL ('Longchangsu') shows dark green leaves and greenish rhizome. But the molecular mechanism for the differences between the two cultivars is poorly understood. In the present study, we showed that the structure of chloroplasts was significantly damaged in YL. Biochemical analysis uncovered the contents of chlorophyll a, chlorophyll b, total chlorophyll and carotenoid were notably decreased in YL. Using RNA-Seq technology, more than 38 million clean reads were generated in each pool, and 116,422 unigenes were assembled de novo. 6,660 unigenes with differential expression patterns (FDR<=0.01 and |log2 ratio|>=1) were totally identified between the two cultivars. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed unigenes (DEGs) suggested 33 KEGG pathways were notably enriched, including biological processes such as "phenylpropanoid biosynthesis", "phagosome", "starch and sucrose metabolism", "drug metabolism cytochrome P450", "fatty acid elongation", and "flavone and flavonol biosynthesis". Further analysis revealed that chlorophyll degeneration related unigene (c48794_g1) and flavonoid biosynthesis related unigenes (c16388_g1, c48963_g1, c63571_g1, c4492_g1, c52282_g1, c78740_g1, c4645_g1) were up-regulated while carotenoid biosynthesis related unigene (c7212_g1) were down-regulated in YL. Additionally, six of NAC, R2R3-MYB, bHLH transcription factors (c42861_g1, c105949_g1, c61265_g1, c42659_g1, c82171_g1, c19158_g1) might be involved in regulation of pigment biosynthesis. The chlorophyll degeneration and the flavonoid biosynthesis related unigenes up-regulation together with the carotenoid biosynthesis related unigenes down-regulation may contribute to the yellowing phenotype of YL. PMID- 29975783 TI - Symbiotic organisms search algorithm for the unrelated parallel machines scheduling with sequence-dependent setup times. AB - This paper addresses the problem of makespan minimization on unrelated parallel machines with sequence dependent setup times. The symbiotic organisms search (SOS) algorithm is a new and popular global optimization technique that has received wide acceptance in recent years from researchers in continuous and discrete optimization domains. An improved SOS algorithm is developed to solve the parallel machine scheduling problem. Since the standard SOS algorithm was originally developed to solve continuous optimization problems, a new solution representation and decoding procedure is designed to make the SOS algorithm suitable for the unrelated parallel machine scheduling problem (UPMSP). Similarly, to enhance the solution quality of the SOS algorithm, an iterated local search strategy based on combining variable numbers of insertion and swap moves is incorporated into the SOS algorithm. More so, to further improve the SOS optimization speed and performance, the longest processing time first (LPT) rule is used to design a machine assignment heuristic that assigns processing machines to jobs based on the machine dynamic load-balancing mechanism. Subsequently, the machine assignment scheme is incorporated into SOS algorithms and used to solve the UPMSP. The performances of the proposed methods are evaluated by comparing their solutions with other existing techniques from the literature. A number of statistical tests were also conducted to determine the variations in performance for each of the techniques. The experimental results showed that the SOS with LPT (SOS-LPT) heuristic has the best performance compared to other tested method, which is closely followed by SOS algorithm, indicating that the two proposed algorithms' solution approaches are reasonable and effective for solving large scale UPMSPs. PMID- 29975785 TI - Remembering Reminiscence. PMID- 29975788 TI - Feasibility of a Family-Centered Hospital Intervention. AB - Approximately one half of the 40 million family caregivers in the United States are regularly performing medical/nursing tasks, with very little training from clinicians. The goal of the current project was to encourage health care and social service professionals to proactively engage family caregivers as partners in care. The phases of the Professional Partners Supporting Family Caregivers project and results of an intervention are presented. Five hospitals were selected to develop a family-centered intervention. Patients' and family caregivers' hospital experience was examined, as well as nurses' perception of their work environment specific to care of older adults and caregivers. The sample included five intervention sites in which patients, family caregivers, and nurses provided baseline post-intervention data. The four comparison sites included post-intervention data from patients, family caregivers, and nurses. The family-centered intervention shows promise in improving patients' hospital experience and nurses' perception of caring for older adults and their families. [Journal of Gerontological Nursing, 43(6), 9-16.]. PMID- 29975784 TI - SliC is a surface-displayed lipoprotein that is required for the anti-lysozyme strategy during Neisseria gonorrhoeae infection. AB - Lysozymes are nearly omnipresent as the first line of immune defense against microbes in animals. They exert bactericidal action through antimicrobial peptide activity and peptidoglycan hydrolysis. Gram-negative bacteria developed several weapons to battle lysozymes, including inhibitors of c-type lysozymes in the MliC/PliC family and the Neisseria adhesin complex protein (ACP). Until the recent discovery of ACP, no proteinaceous lysozyme inhibitors were reported for the genus Neisseria, including the important human pathogen N. gonorrhoeae. Here, we describe a previously unrecognized gonococcal virulence mechanism involving a protein encoded by the open reading frame ngo1063 that acts to counteract c-type Iysozyme and provides a competitive advantage in the murine model of gonorrhea. We named this protein SliC as a surface-exposed lysozyme inhibitor of c-type lysozyme. SliC displays low overall primary sequence similarity to the MliC/PliC inhibitors, but we demonstrate that it has a parallel inhibitory mechanism. Our studies provide the first evidence that bacterial proteinaceous lysozyme inhibitors protect against host lysozyme during infection based on lack of attenuation of the DeltasliC mutant in lysozyme knock-out mice, and that the conserved residues involved in lysozyme inhibition, S83 and K103, are functionally indispensable during infection in wild type mice. Recombinant SliC completely abrogated the lytic activity of human and chicken c-type lysozymes, showing a preference towards human lysozyme with an IC50 of 1.85 MUM and calculated KD value of 9.2 +/- 1.9 MUM. In contrast, mutated SliC bearing S83A and K103A substitutions failed to protect fluorescein-labeled cell-wall from lysozyme-mediated hydrolysis. Further, we present data revealing that SliC is a surface-displayed lipoprotein released in membrane vesicles that is expressed throughout all phases of growth, in conditions relevant to different niches of the human host, and during experimental infection of the murine genital tract. SliC is also highly conserved and expressed by diverse gonococcal isolates as well as N. meningitidis, N. lactamica, and N. weaveri. This study is the first to highlight the importance of an anti-lysozyme strategy to escape the innate immune response during N. gonorrhoeae infection. PMID- 29975790 TI - The mental health of mothers and fathers during pregnancy and early parenthood after successful oocyte donation treatment: A nested case-control study. AB - INTRODUCTION: The aim of this study was to compare the mental health problems between parents after oocyte donation treatment, after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with own gametes and after naturally conceiving (NC). MATERIAL AND METHODS: This is a prospective, longitudinal questionnaire study. The study group consisted of 26 oocyte donation mothers and their matched IVF/ICSI (n = 52) and NC (n = 52) controls. Matching was performed according to mother's age, parity, type of pregnancy, and number of returned questionnaires. The parents filled-in the General Health Questionnaire (GHQ-36) at gestational weeks 18-20 (T1), and at 2 months (T2) and 12 months (T3) after the childbirth. RESULTS: Full response rate (T1-T3) for oocyte donation mothers was 76.9% and for oocyte donation fathers was 73.1%. At T1, no significant differences were found between groups in depression, anxiety, sleeping difficulties, or social dysfunction, but they differed at T2 and T3 in anxiety (T2, P = .02; T3, P = .01), in sleeping difficulties (T2, P = .02; T3, P = .04) and in social dysfunction (T2, P = .01; T3, P = .04). Oocyte donation mothers showed less anxiety than NC mothers (T2, T3), and fewer sleeping difficulties and less social dysfunction than IVF/ICSI (T2, T3) and NC mothers (T2). Mental health problems of oocyte donation fathers did not differ from those of IVF/ICSI and NC control fathers at T1-T3. CONCLUSIONS: Oocyte donation mothers showed fewer mental health symptoms in early parenthood compared with IVF/ICSI and NC mothers. No differences were found among mothers during pregnancy and among fathers at any time point. PMID- 29975791 TI - A partially linear proportional hazards model for current status data. AB - For analyzing current status data, a flexible partially linear proportional hazards model is proposed. Modeling flexibility is attained through using monotone splines to approximate the baseline cumulative hazard function, as well as B-splines to accommodate nonlinear covariate effects. To facilitate model fitting, a computationally efficient and easy to implement expectation maximization algorithm is developed through a two-stage data augmentation process involving carefully structured latent Poisson random variables. Asymptotic normality and the efficiency of the spline estimator of the regression coefficients are established, and the spline estimators of the nonparametric components are shown to possess the optimal rate of convergence under suitable regularity conditions. The finite-sample performance of the proposed approach is evaluated through Monte Carlo simulation and it is further illustrated using uterine fibroid data arising from a prospective cohort study on early pregnancy. PMID- 29975792 TI - Frontline Science: Targeted expression of a dominant-negative high mobility group A1 transgene improves outcome in sepsis. AB - High mobility group (HMG) proteins are a family of architectural transcription factors, with HMGA1 playing a role in the regulation of genes involved in promoting systemic inflammatory responses. We speculated that blocking HMGA1 mediated pathways might improve outcomes from sepsis. To investigate HMGA1 further, we developed genetically modified mice expressing a dominant negative (dn) form of HMGA1 targeted to the vasculature. In dnHMGA1 transgenic (Tg) mice, endogenous HMGA1 is present, but its function is decreased due to the mutant transgene. These mice allowed us to specifically study the importance of HMGA1 not only during a purely pro-inflammatory insult of endotoxemia, but also during microbial sepsis induced by implantation of a bacterial-laden fibrin clot into the peritoneum. We found that the dnHMGA1 transgene was only present in Tg and not wild-type (WT) littermate mice, and the mutant transgene was able to interact with transcription factors (such as NF-kappaB), but was not able to bind DNA. Tg mice exhibited a blunted hypotensive response to endotoxemia, and less mortality in microbial sepsis. Moreover, Tg mice had a reduced inflammatory response during sepsis, with decreased macrophage and neutrophil infiltration into tissues, which was associated with reduced expression of monocyte chemotactic protein-1 and macrophage inflammatory protein-2. Collectively, these data suggest that targeted expression of a dnHMGA1 transgene is able to improve outcomes in models of endotoxin exposure and microbial sepsis, in part by modulating the immune response and suggest a novel modifiable pathway to target therapeutics in sepsis. PMID- 29975793 TI - Validation of an LC-MS/MS method for simultaneous determination of icotinib and its four major circulating metabolites in human plasma and its application in a pharmacokinetic study. AB - In this study, a simple and sensitive LC-MS/MS method was developed and validated for simultaneous determination of icotinib and its four circulating metabolites in human plasma. The analytes were extracted with acetonitrile and separated on a C18 column using 2 mm ammonium acetate containing 0.2% formic acid and acetonitrile as mobile phase. The analytes were introduced into the mass spectrometer via an electrospray ionization source operated in positive ion mode. Precursor-to-product transitions were optimized to be m/z 392.2 -> 304.1 for icotinib, m/z 424.1 -> 278.2 for M1 and M2, m/z 408.2 -> 320.1 for M3, m/z 410.2 > 322.1 for M4 and m/z 394.4 -> 278.1 for IS. The assay showed good linearity over the concentration ranges of 0.1-600 ng/mL for icotinib and 0.1-200 ng/mL for metabolites, with correlation coefficients >0.994 (r > 0.994). The LLOQ was 0.1 ng/mL for each analyte. The intra- and inter-day precisions (RSD) were <=12.98% while the accuracy (RE) ranged from -8.76 to 12.01%. No significant matrix effect was observed. The validated method was successfully applied for the pharmacokinetic study of icotinib and its four circulating metabolites in human plasma after oral administration of icotinib at a single dose of 125 mg. PMID- 29975794 TI - Mast cells and immunoexpression of FGF-1 and Ki-67 in rat subcutaneous tissue following the implantation of Biodentine and MTA Angelus. AB - AIM: To compare the formation of fibrous capsules around Biodentine and MTA Angelus implants as well as the participation of fibroblast growth factor-1 (FGF 1) and mast cells in the tissue response to these endodontic materials. METHODOLOGY: Sixty polyethylene tubes filled with Biodentine or MTA, and empty tubes (control group) were implanted into the dorsal subcutaneous tissues of male rats. After 7, 15, 30 and 60 days, the specimens were embedded in paraffin and the number of fibroblasts and mast cells was quantified in the sections stained with Masson's trichrome or Alcian Blue, respectively. FGF-1 and Ki-67 were detected by immunohistochemistry, and the number of immunolabelled cells was computed. The collagen content was estimated in the picrosirius red-stained sections. The data were subjected to two-way ANOVA followed by Tukey's test (P <= 0.05). RESULTS: The capsules were associated with a significant increase (P < 0.0001) in the number of fibroblasts and mast cells, and in the collagen content over time. A significant decrease (P < 0.0001) in the immunoexpression of FGF-1 and Ki-67 was observed in all groups from the 7th-60th day. At 60 days, the number of fibroblasts (P = 0.0226) and the collagen content (P < 0.0001) were significantly greater in MTA than Biodentine specimens, while the greatest number of mast cells and FGF-1-immunolabelled cells was observed in Biodentine specimens (P < 0.0001). A significant difference in Ki-67 immunoexpression was not detected between specimens of Biodentine and MTA. CONCLUSIONS: The collagen-rich capsule formed slowly around Biodentine in comparison with MTA. FGF-1 and mast cells participated in capsule remodelling, stimulating fibroblast proliferation and subsequent collagen production, in response to subcutaneous implants. PMID- 29975795 TI - Increased risk of all-cause mortality associated with domperidone use in Parkinson's patients: a population-based cohort study in the UK. AB - AIMS: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all-cause mortality associated with domperidone exposure in PD. METHODS: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987-2011). The first recorded PD diagnosis defined index date. Time-dependent Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti-Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non-PD patients. RESULTS: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two-fold increase in all-cause mortality (HRadj = 2.00, 95% confidence interval [CI]: 1.64-2.45), as compared to patients never exposed to domperidone. All-cause mortality risk was highest in those starting domperidone in the previous month [HRadj = 2.97, 95% CI: 2.06-4.27]. When compared to matched non-PD patients, PD was associated with a 43% increased risk of all-cause mortality, yet this increased to a 2.4-fold increased risk among PD patients currently using domperidone. CONCLUSION: Current use of domperidone was associated with a two-fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone. PMID- 29975796 TI - Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies. AB - AIMS: The aim of this study was to determine clinical variables associated with posaconazole exposure among adult patients with haematological malignancies who received posaconazole tablets for prophylaxis of invasive fungal infections (IFIs). METHODS: The study population included adult patients with haematological malignancies who received posaconazole delayed-release tablets for prophylaxis of IFIs after induction chemotherapy for acute leukaemia or graft-versus-host disease (GVHD) complicating hematopoietic stem cell transplantation (HSCT) in the period January 2016-December 2017. RESULTS: Sixty-six consecutive patients with 176 posaconazole Cmin were included for evaluation in the study. Subtherapeutic posaconazole concentrations (< 0.7 mg l-1 ) were observed at least once in 33.3% of patients (22/66), and overall in 17.0% of therapeutic drug monitoring (TDM) episodes (30/176). At multilevel linear regression, use of PPIs (P = 0.008), use of intermediate or high dose steroids (>0.7 mg kg-1 daily) (P = 0.022) and male gender (P = 0.025) were significantly associated with decreased Cmin , whereas time from starting therapy (P = 0.032) was associated with increased Cmin in our patient population. CONCLUSION: Posaconazole exposure during treatment with delayed-released tablet formulation may be affected by the use of PPIs and/or of intermediate or high dose steroids. PMID- 29975797 TI - Sex-specific patterns of reproductive senescence in a long-lived reintroduced raptor. AB - For many species, there is evidence that breeding performance changes as an individual ages. In iteroparous species, breeding performance often increases through early life and is expected to level out or even decline (senesce) later in life. An individual's sex and conditions experienced in early life may also affect breeding performance and how this changes with age. Long-term monitoring of individuals from reintroduced populations can provide unique opportunities to explore age-related trends in breeding performance that might otherwise be logistically challenging. We used a unique dataset from a reintroduced population of white-tailed eagles Haliaeetus albicilla in Scotland, which has been intensively monitored since their initial reintroduction in 1975, to study age- and sex-specific trends in two measures of breeding performance. This monitoring provided data on the breeding performance of known individuals ranging in age from 3 to 26 years. We also explored changes in breeding performance in relation to early life experience (i.e., whether they were released or fledged in the wild). Breeding performance increased with age in early life in a similar manner for both sexes. We found stronger evidence for senescence in breeding performance in males than females. However, late-life female breeding success was associated with early life experience, while male senescent trends were not apparently impacted by conditions experienced during early life. Sexual differences in senescence mean that older males are less likely to breed successfully compared to older females, and this may influence females' mate changes later in life. This difference may suggest a linked sexual difference in survival rates or the possibility of proactive partner change by females in later life in this typically monogamous biparental species. PMID- 29975798 TI - Single-fiber F waves compared with conventional surface F waves, and their utility in detecting early diabetic neuropathy. AB - INTRODUCTION: The single-fiber F-wave (SFF-wave) technique assesses the entire length of single motor fibers using a concentric needle. Herein we investigated the utility of this approach in the detection of early diabetes-related neuropathy, and compared it with the use of conventional surface F waves (CF waves). METHODS: Sixteen patients with diabetes and either no neuropathy or mild neuropathy were assessed and compared with 16 age- and height-matched control participants. RESULTS: Both CF and SFF waves were abnormal in all 5 patients who had mild neuropathy. However, SFF waves demonstrated subclinical abnormalities in 7 of 11 patients (64%) with no neuropathy, whereas only 2 of these patients (18%) had prolonged CF waves. Minimum F-wave latency was comparable between techniques, but maximum SFF-wave latency was more frequently prolonged, as these delayed motor units were better isolated, rather than buried among summated CF-wave responses. DISCUSSION: SFF waves highlight the segmental involvement in diabetic neuropathy, and use of the SFF-wave technique detects more abnormalities than with CF waves. Muscle Nerve 58: 665-670, 2018. PMID- 29975799 TI - The 'top 100' drugs and classes in England: an updated 'starter formulary' for trainee prescribers. AB - AIMS: Prescribing is a complex skill required of doctors and, increasingly, other healthcare professionals. Use of a personal formulary can help to develop this skill. In 2006-9, we developed a core list of the 100 most commonly prescribed drugs. Our aim in the present study was to update this 'starter formulary' to ensure its continued relevance for prescriber training. METHODS: We analysed large contemporary primary and secondary care datasets to identify the most frequently prescribed medicinal products. Items were classified into natural groups, broadly following their British National Formulary classification. The resulting drug groups were included in the core list if they comprised >=0.1% prescriptions in both settings or >=0.2-0.3% prescriptions in one setting. Drugs from emergency guidelines that did not qualify by prescribing frequency completed the list. RESULTS: Over 1 billion primary care items and approximately 1.8 million secondary care prescriptions were analysed. The updated list comprises 81 drug groups commonly prescribed in both settings; six from primary care; seven from secondary care; and six from emergency guidelines. Eighty-eight per cent of the formulary was unchanged. Notable changes include entry of newer anti epileptics and dipeptidyl peptidase-4 inhibitors and exit of phenytoin and thiazolidinediones. CONCLUSIONS: The relative stability of the core drug list over 9 years and the current update ensure that learning based on this list remains relevant to practice. Trainee prescribers may be encouraged to use this 'starter formulary' to develop a sound basis of prescribing knowledge and skills that they can subsequently apply more widely. PMID- 29975800 TI - Cascade Reactions in Tunable Lamellar Micro- and Mesopores for C=C Bond Coupling and Hydrocarbon Synthesis. AB - Two-dimensional MFI zeolite nanosheets contain Bronsted acid sites partially confined at the intercept between micro- and mesopores. These acid sites exhibit exceptional reactivities and stabilities for C=C bond coupling and ring-closure reactions that transform light aldehydes to aromatics. These sites are much more effective than those confined within the micropores of MFI crystallites and those unconfined on H4 SiW12 O40 clusters or mesoporous aluminosilicate Al-MCM-41. The partially confined site environment solvates and stabilizes the transition states of the kinetically relevant steps during aromatization. PMID- 29975801 TI - Ionizable Amino-Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino-Alcohols for Tissue Selective mRNA Delivery. AB - The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI. Adopting tertiary amino-alcohols to initiate ROP of lactones allows to control polymer molecular weight and obtain amino-polyesters with narrow molecular weight distribution, exhibiting batch-to-batch consistency. All of which highlight the potential for clinical translation of APEs for systemic mRNA delivery and demonstrate the importance of employing controlled polymerization in the design of new polymeric nanomaterials to improve in vivo nucleic acid delivery. PMID- 29975802 TI - WITHDRAWN: Techniques to ascertain correct endotracheal tube placement in neonates. AB - BACKGROUND: The success rate of correct endotracheal tube (ETT) placement for junior medical staff is less than 50% and accidental oesophageal intubation is common. Rapid confirmation of correct tube placement is important because tube malposition is associated with serious adverse outcomes including hypoxaemia, death, pneumothorax and right upper lobe collapse.ETT position can be confirmed using chest radiography, but this is often delayed; hence, a number of rapid point-of-care methods to confirm correct tube placement have been developed. Current neonatal resuscitation guidelines advise that correct ETT placement should be confirmed by the observation of clinical signs and the detection of exhaled carbon dioxide (CO2). Even though these devices are frequently used in the delivery room to assess tube placement, they can display false-negative results. Recently, newer techniques to assess correct tube placement have emerged (e.g. respiratory function monitor), which have been claimed to be superior in the assessment of tube placement. OBJECTIVES: To assess various techniques for the identification of correct ETT placement after oral or nasal intubation in newborn infants in either the delivery room or neonatal intensive care unit compared with chest radiography. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library 2012, Issue 4), MEDLINE (January 1996 to June 2014), EMBASE (January 1980 to Juen 2014) and CINAHL (January 1982 to June 2014). We searched clinical trials registers and the abstracts of the Society for Pediatric Research and the European Society for Pediatric Research from 2004 to 2014. We did not apply any language restrictions. SELECTION CRITERIA: We planned to include randomised and quasi-randomised controlled trials and cluster trials that compared chest radiography with clinical signs, respiratory function monitors, exhaled CO2 detectors or ultrasound for the assessment of correct ETT placement either in the delivery room or the neonatal intensive care unit. DATA COLLECTION AND ANALYSIS: Two review authors independently evaluated the search results against the selection criteria. We did not perform data extraction and 'Risk of bias' assessments because we identified no studies that met our inclusion criteria. MAIN RESULTS: We did not identify any studies meeting the criteria for inclusion in this review. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine the most effective technique for the assessment of correct ETT placement either in the delivery room or the neonatal intensive care unit. Randomised clinical trials comparing either of these techniques with chest radiography are warranted. PMID- 29975803 TI - Phase Modulation of (1T-2H)-MoSe2/TiC-C Shell/Core Arrays via Nitrogen Doping for Highly Efficient Hydrogen Evolution Reaction. AB - Tailoring molybdenum selenide electrocatalysts with tunable phase and morphology is of great importance for advancement of hydrogen evolution reaction (HER). In this work, phase- and morphology-modulated N-doped MoSe2 /TiC-C shell/core arrays through a facile hydrothermal and postannealing treatment strategy are reported. Highly conductive TiC-C nanorod arrays serve as the backbone for MoSe2 nanosheets to form high-quality MoSe2 /TiC-C shell/core arrays. Impressively, continuous phase modulation of MoSe2 is realized on the MoSe2 /TiC-C arrays. Except for the pure 1T-MoSe2 and 2H-MoSe2 , mixed (1T-2H)-MoSe2 nanosheets are achieved in the N MoSe2 by N doping and demonstrated by spherical aberration electron microscope. Plausible mechanism of phase transformation and different doping sites of N atom are proposed via theoretical calculation. The much smaller energy barrier, longer H?Se bond length, and diminished bandgap endow N-MoSe2 /TiC-C arrays with substantially superior HER performance compared to 1T and 2H phase counterparts. Impressively, the designed N-MoSe2 /TiC-C arrays exhibit a low overpotential of 137 mV at a large current density of 100 mA cm-2 , and a small Tafel slope of 32 mV dec-1 . Our results pave the way to unravel the enhancement mechanism of HER on 2D transition metal dichalcogenides by N doping. PMID- 29975804 TI - Comparison between radiofrequency ablation and chemical neurolysis of thoracic splanchnic nerves for the management of abdominal cancer pain, randomized trial. AB - BACKGROUND: Radiofrequency ablation (RFA) of the splanchnic nerves has been reported as a predictable and safe technique for abdominal pain management. We compare between RFA and chemical neurolysis of bilateral thoracic splanchnic nerves in the management of refractory cancer pain. METHODS: The study was conducted on 60 patients aged >=18 years who suffered from abdominal pain (visceral pain, VAS >=4) due to upper abdominal cancers. Participants were randomized into two groups. Group I (RF): 30 participants received a bilateral splanchnic nerve block at T10 and T11 levels using RFA. Group II (alcohol): 30 participants received a bilateral splanchnic nerve block at T11 using alcohol. Pain relief was assessed using VAS (0-10) and total daily oral opioid consumption (primary outcome). RESULTS: Significant reductions of VAS and global perceived effect satisfaction scores (GPES) were observed in both groups compared to baseline levels (p < 0.001); Group I had the largest reduction. MST consumption and QOL scores improved significantly in both groups (p < 0.001). Oral opioid consumption started to reduce at the end of the first post-interventional week for Group I, 0.00 (0-45 mg), and at the end of the second post-interventional week for Group II, 20.00 (0-135 mg). No major complications were recorded in either group. CONCLUSION: Simultaneous bilateral pain block of splanchnic nerves at the levels of T10 and T11 using RFA is more effective than using alcohol at a single level of T11 in cancer patients presenting with upper abdominal pain. The RFA intervention acted faster, provided longer duration analgesia, worked in a higher proportion of patients and had a better safety profile than the alcohol intervention. SIGNIFICANCE: Radiofrequency ablation of the splanchnic nerves is safe and effective for relieving upper abdominal cancer pain. PMID- 29975805 TI - Spinel Structural Disorder Influences Solar-Water-Splitting Performance of ZnFe2 O4 Nanorod Photoanodes. AB - Zinc spinel ferrite, ZnFe2 O4 (ZFO), is an emerging photoanode material for photoelectrochemical (PEC) solar fuel production. However, a lack of fundamental insight into the factors limiting the photocurrent has prevented substantial advance in its performance. Herein, it is found that ZFO nanorod array photoelectrodes with varying crystallinity exhibit vastly different PEC properties. Using a sacrificial hole scavenger (H2 O2 ), spatially defined carrier generation, and electrochemical impedance spectroscopy, it is shown that ZFO with a relatively poor crystallinity but a higher spinel inversion degree (due to cation disorder) exhibits superior photogenerated charge separation efficiency and improved majority charge carrier transport compared to ZFO with higher crystallinity and a lower inversion degree. Conversely, the latter condition leads to better charge injection efficiency. Optimization of these factors, and the addition of a nickel-iron oxide cocatalyst overlayer, leads to a new benchmark solar photocurrent for ZFO of 1.0 mA cm-2 at 1.23 V versus reversible hydrogen electrode (RHE) and 1.7 mA cm-2 at 1.6 V versus RHE. Importantly, the observed correlation between the cation disorder and the PEC performance represents a new insight into the factors important to the PEC performance of the spinel ferrites and suggests a path to further improvement. PMID- 29975806 TI - Tenofovir alafenamide associated fatal lactic acidosis in an autologous hematopoietic stem cell transplant recipient. AB - Fatal lactic acidosis has been reported while on the treatment with Nucleoside/nucleotide analogues (NA) for the treatment of hepatitis B, C and HIV. No cases of such a complication have been reported in hematopoietic stem cell transplant (HSCT) recipients. We present a 65-year male who underwent autologous HSCT for the treatment of multiple myeloma. Prior to transplant he was started on single agent tenofovir alafenamide (TAF) for treatment of resolved hepatitis B infection. He presented few weeks later with severe lactic acidosis. Other causes of lactic acidosis were excluded. The patient died of multi-organ failure despite stopping TAF and aggressive supportive care. The case demonstrates the need for increased awareness of this potential complication of NA treatment in the course of transplantation. PMID- 29975807 TI - Towards complete identification of allergens in Jack Jumper (Myrmecia pilosula) ant venom and their clinical relevance: An immunoproteomic approach. AB - BACKGROUND: The venomous stings of Jack Jumper ant (JJA; species of the Myrmecia pilosula taxonomic group) are a significant public health issue in parts of south eastern and south-western Australia, causing anaphylaxis in approximately 3% of the population. Three allergenic peptides, Myr p 1, Myr p 2 and Myr p 3, and one histamine-releasing peptide, pilosulin 5, have been fully described, but there are at least 5 additional high molecular weight IgE-binding components that have not been identified. OBJECTIVE: To identify IgE-binding components in JJA venom (JJAV) and to relate the IgE recognition of these components to relevant clinical parameters. METHODS: Identification of IgE-binding components and determination of their sensitizing prevalence was performed using SDS-PAGE immunoblot assay and sera from 90 patients with confirmed allergy to JJAV. Tandem mass spectrometry was used for identification of novel JJAV components fractionated by size exclusion chromatography (SEC) and SDS-PAGE. RESULTS: Using SDS-PAGE immunoblot, 10 IgE-binding bands were identified in JJAV, two of which were recognized by 81% and 47% of the population studied. Mass spectrometry identified 17 novel JJAV proteins, including 2 glycoproteins, and confirmed the presence of 4 known Myr p and pilosulin peptides in JJAV. Most of the newly identified IgE-binding proteins were enzymes, including phospholipase A2 , hyaluronidase, arginine kinase and dipeptidyl peptidase IV. Correlations were found between recognition of certain IgE-binding bands with JJAV-specific IgE titre by ImmunoCAP, intradermal test threshold and treatment-related issues. CONCLUSIONS AND CLINICAL RELEVANCE: This study has for the first time revealed the identity of various proteins with IgE binding capacity in the venom of JJA and demonstrated their clinical relevance in the diagnosis and treatment of JJAV allergy. PMID- 29975808 TI - High ambient levels of grass, weed and other pollen are associated with asthma admissions in children and adolescents: A large 5-year case-crossover study. AB - BACKGROUND: Pollen is an important aeroallergen that triggers asthma exacerbations in children, but we know little about the impact of different pollen types in cities with varying climatic conditions and pollen seasons. OBJECTIVES: We aimed to assess the role of ambient level of different types of pollen on a large time series of child and adolescent asthma hospitalizations in Sydney, Australia. METHODS: Childhood asthma hospitalization and the daily ambient pollen concentrations of different species were collected in South-West Sydney. With a bidirectional case-crossover design, we fitted conditional logistic regression models to measure the associations between instantaneous and up to 3 days lagged effects of pollen concentrations on asthma hospitalizations after controlling for potential confounders and testing for interactions. RESULTS: A total of 2098 children, more boys (59.7%) and 2-5 years old (62.6%), were hospitalized due to asthma. The geometric mean concentration of Cupressus, 7.88 [5.02] grains/m3 , was the highest during the study period. The increase from 75th to 90th percentile of grass (OR = 1.037, 95% CI 1.005-1.070), weed other than Plantago species (OR = 1.053, 95% CI 1.009-1.098) and unclassified pollen (OR = 1.034, 95% CI 1.010-1.058) were significantly associated with the odds of asthma hospitalizations. Boys were at greater risk of asthma exacerbations associated with grass (OR = 1.046, 95% CI 1.003-1.090) and unclassified pollen (OR = 1.041, 95% CI 1.010-1.073). There was evidence of effect modification by age groups for Cupressus, conifer, total tree and total pollen. CONCLUSIONS: Although boys are more vulnerable to grass pollen, weed, and other pollen are also important triggers of asthma exacerbations in all children and adolescents. These findings are important for urban green space planning and the development of pollen monitoring systems for families with children at risk of asthma exacerbations during peak pollen seasons. PMID- 29975809 TI - Lithium Silicide Surface Enrichment: A Solution to Lithium Metal Battery. AB - The propensity of lithium dendrite formation during the charging process of lithium metal batteries is linked to inhomogeneity on the lithium surface layer. The high reactivity of lithium and the complex surface structure of the native layer create "hot spots" for fast dendritic growth. Here, it is demonstrated that a fundamental restructuring of the lithium surface in the form of lithium silicide (Lix Si) can effectively eliminate the surface inhomogeneity on the lithium surface. In situ optical microscopic study is carried out to monitor the electrochemical deposition of lithium on the Lix Si-modified lithium electrodes and the bare lithium electrode. It is observed that a much more uniform lithium dissolution/deposition on the Lix Si-modified lithium anode can be achieved as compared to the bare lithium electrode. Full cells paring the modified lithium anode with sulfur and LiFePO4 cathodes show excellent electrochemical performances in terms of rate capability and cycle stability. Compatibility of the anode enrichment method with mass production process also offers a practical way for enabling lithium metal anode for next-generation lithium batteries. PMID- 29975810 TI - Unrecognized pre-transplant disseminated Coxiella burnetti infection diagnosed in a post-transplant heart-kidney recipient. AB - To the best of our knowledge, we report the first case of pre-transplant unrecognized disseminated Coxiella burnetii infection, unmasked in the post transplant period leading to both heart and kidney allograft dysfunction. A 59 year old man with a history of simultaneous heart-kidney transplantation due to end stage heart failure from severe aortic regurgitation (AR) and cryoglobulinemic immune complex mediated concentric necrotizing glomerulonephritis (GN), presents with a history of intermittent fevers and fatigue. Prior to transplantation he was treated for multiple episodes of culture negative endocarditis requiring bio-prosthetic valve replacement. Evaluation of fever included a transesophageal echocardiogram (TEE) that revealed a large hyperechoic mass on the anterior mitral leaflet with perforation, severe mitral regurgitation and moderate AR. Blood cultures were negative at that time. Owing to development of allograft mitral and aortic valve insufficiency, he underwent allograft bio-prosthetic mitral valve (MV) replacement and aortic valvuloplasty 2 years following his transplantation. Pathologic examination of the allograft mitral valve demonstrated fibrinopurulent exudate with degenerating bacterial organisms, consistent with vegetation and myxoid degenerative changes. Due to a high suspicion for native heart C. burnetii prosthetic valve endocarditis prior to transplantation, we re-evaluated the native explanted heart histopathology, as well as the explanted allograft MV. Cardiac allograft and native MV were positive for C. burnetii by real-time PCR. C. burnetii serology was consistent with persistent infection as well. PMID- 29975811 TI - Psychological therapies for the treatment of mental disorders in low- and middle income countries affected by humanitarian crises. AB - BACKGROUND: People living in humanitarian settings in low- and middle-income countries (LMICs) are exposed to a constellation of stressors that make them vulnerable to developing mental disorders. Mental disorders with a higher prevalence in these settings include post-traumatic stress disorder (PTSD) and major depressive, anxiety, somatoform (e.g. medically unexplained physical symptoms (MUPS)), and related disorders. A range of psychological therapies are used to manage symptoms of mental disorders in this population. OBJECTIVES: To compare the effectiveness and acceptability of psychological therapies versus control conditions (wait list, treatment as usual, attention placebo, psychological placebo, or no treatment) aimed at treating people with mental disorders (PTSD and major depressive, anxiety, somatoform, and related disorders) living in LMICs affected by humanitarian crises. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR), the Cochrane Central Register of Controlled Trials (Wiley), MEDLINE (OVID), Embase (OVID), and PsycINFO (OVID), with results incorporated from searches to 3 February 2016. We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov to identify any unpublished or ongoing studies. We checked the reference lists of relevant studies and reviews. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing psychological therapies versus control conditions (including no treatment, usual care, wait list, attention placebo, and psychological placebo) to treat adults and children with mental disorders living in LMICs affected by humanitarian crises. DATA COLLECTION AND ANALYSIS: We used standard Cochrane procedures for collecting data and evaluating risk of bias. We calculated standardised mean differences for continuous outcomes and risk ratios for dichotomous data, using a random-effects model. We analysed data at endpoint (zero to four weeks after therapy); at medium term (one to four months after therapy); and at long term (six months or longer). GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) was used to assess the quality of evidence for post-traumatic stress disorder (PTSD), depression, anxiety and withdrawal outcomes. MAIN RESULTS: We included 36 studies (33 RCTs) with a total of 3523 participants. Included studies were conducted in sub-Saharan Africa, the Middle East and North Africa, and Asia. Studies were implemented in response to armed conflicts; disasters triggered by natural hazards; and other types of humanitarian crises. Together, the 33 RCTs compared eight psychological treatments against a control comparator.Four studies included children and adolescents between 5 and 18 years of age. Three studies included mixed populations (two studies included participants between 12 and 25 years of age, and one study included participants between 16 and 65 years of age). Remaining studies included adult populations (18 years of age or older).Included trials compared a psychological therapy versus a control intervention (wait list in most studies; no treatment; treatment as usual). Psychological therapies were categorised mainly as cognitive-behavioural therapy (CBT) in 23 comparisons (including seven comparisons focused on narrative exposure therapy (NET), two focused on common elements treatment approach (CETA), and one focused on brief behavioural activation treatment (BA)); eye movement desensitisation and reprocessing (EMDR) in two comparisons; interpersonal psychotherapy (IPT) in three comparisons; thought field therapy (TFT) in three comparisons; and trauma or general supportive counselling in two comparisons. Although interventions were described under these categories, several psychotherapeutic elements were common to a range of therapies (i.e. psychoeducation, coping skills).In adults, psychological therapies may substantially reduce endpoint PTSD symptoms compared to control conditions (standardised mean difference (SMD) -1.07, 95% confidence interval (CI) -1.34 to -0.79; 1272 participants; 16 studies; low-quality evidence). The effect is smaller at one to four months (SMD -0.49, 95% CI -0.68 to -0.31; 1660 participants; 18 studies) and at six months (SMD -0.37, 95% CI 0.61 to -0.14; 400 participants; five studies). Psychological therapies may also substantially reduce endpoint depression symptoms compared to control conditions (SMD -0.86, 95% CI -1.06 to -0.67; 1254 participants; 14 studies; low-quality evidence). Similar to PTSD symptoms, follow-up data at one to four months showed a smaller effect on depression (SMD -0.42, 95% CI -0.63 to -0.21; 1386 participants; 16 studies). Psychological therapies may moderately reduce anxiety at endpoint (SMD -0.74, 95% CI -0.98 to -0.49; 694 participants; five studies; low-quality evidence) and at one to four months' follow-up after treatment (SMD 0.53, 95% CI -0.66 to -0.39; 969 participants; seven studies). Dropout rates are probably similar between study conditions (19.5% with control versus 19.1% with psychological therapy (RR 0.98 95% CI 0.82 to 1.16; 2930 participants; 23 studies, moderate quality evidence)).In children and adolescents, we found very low quality evidence for lower endpoint PTSD symptoms scores in psychotherapy conditions (CBT) compared to control conditions, although the confidence interval is wide (SMD -1.56, 95% CI -3.13 to 0.01; 130 participants; three studies;). No RCTs provided data on major depression or anxiety in children. The effect on withdrawal was uncertain (RR 1.87 95% CI 0.47 to 7.47; 138 participants; 3 studies, low quality evidence).We did not identify any studies that evaluated psychological treatments on (symptoms of) somatoform disorders or MUPS in LMIC humanitarian settings. AUTHORS' CONCLUSIONS: There is low quality evidence that psychological therapies have large or moderate effects in reducing PTSD, depressive, and anxiety symptoms in adults living in humanitarian settings in LMICs. By one to four month and six month follow-up assessments treatment effects were smaller. Fewer trials were focused on children and adolescents and they provide very low quality evidence of a beneficial effect of psychological therapies in reducing PTSD symptoms at endpoint. Confidence in these findings is influenced by the risk of bias in the studies and by substantial levels of heterogeneity. More research evidence is needed, particularly for children and adolescents over longer periods of follow-up. PMID- 29975813 TI - Corrections. PMID- 29975812 TI - Asymmetric Segregation of Aged Spindle Pole Bodies During Cell Division: Mechanisms and Relevance Beyond Budding Yeast? AB - Asymmetric cell division generates cell diversity and contributes to cellular aging and rejuvenation. Here, we review the molecular mechanisms enabling budding yeast to recognize spindle pole bodies (SPB, centrosome equivalent) based on their age, and guide their non-random mitotic segregation: SPB inheritance requires the distinction of old from new SPBs and is regulated by the SPB inheritance network (SPIN) and the mitotic exit network (MEN). The SPIN marks the pre-existing SPB as old and the MEN recognizes these marks translating them into spindle orientation. We next revisit other molecules and structures that partition depending on their age rather than their abundance at mitosis as, for example, DNA, centrosomes, mitochondria, and histones in yeast and other systems. The recurrence of this differential behavior suggests a functional significance for numerous cell types, which we then discuss. We conclude that non-random segregation may facilitate asymmetric cell fate determination and thereby indirectly aging and rejuvenation. Also see the video abstract here: https://youtu.be/1sQ4rAomnWY. PMID- 29975814 TI - Corrections. PMID- 29975815 TI - Hepatology highlights. PMID- 29975816 TI - The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation. AB - BACKGROUND: CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). METHODS: This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. RESULTS: Overall, 690 transplant episodes were included (allogeneic [n = 310]; autologous [n = 380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45 days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient = 0.21, estimated incremental daily cost USD $500; P = 0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient = 0.13, USD $699 vs $613, or $24 892 per transplant episode; P = 0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. CONCLUSIONS: Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients. PMID- 29975817 TI - A Protein-Based Encapsulation System with Calcium-Controlled Cargo Loading and Detachment. AB - Protein-based encapsulation systems have a wide spectrum of applications in targeted delivery of cargo molecules and for chemical transformations in confined spaces. By engineering affinity between cargo and container proteins it has been possible to enable the efficient and specific encapsulation of target molecules. Missing in current approaches is the ability to turn off the interaction after encapsulation to enable the cargo to freely diffuse in the lumen of the container. Separation between cargo and container is desirable in drug delivery applications and in the use of capsids as catalytic nanoparticles. We describe an encapsulation system based on the hepatitis B virus capsid in which an engineered high-affinity interaction between cargo and capsid proteins can be modulated by Ca2+ . Cargo proteins are loaded into capsids in the presence of Ca2+ , while ligand removal triggers unbinding inside the container. We observe that confinement leads to hindered rotation of cargo inside the capsid. Application of the designed container for catalysis was also demonstrated by encapsulation of an enzyme with beta-glucosidase activity. PMID- 29975818 TI - Using XCAVATOR and EXCAVATOR2 to Identify CNVs from WGS, WES, and TS Data. AB - Copy Number Variants (CNVs) are structural rearrangements contributing to phenotypic variation but also associated with many disease states. In recent years, the identification of CNVs from high-throughput sequencing experiments has become a common practice for both research and clinical purposes. Several computational methods have been developed so far. In this unit, we describe and give instructions on how to run two read count-based tools, XCAVATOR and EXCAVATOR2, which are tailored for the detection of both germline and somatic CNVs from different sequencing experiments (whole-genome, whole-exome, and targeted) in various disease contexts and population genetic studies. (c) 2018 by John Wiley & Sons, Inc. PMID- 29975819 TI - beta-Cyclodextrin as a Precursor to Holey C-Doped g-C3 N4 Nanosheets for Photocatalytic Hydrogen Generation. AB - A green, template-free and easy-to-implement strategy was developed to access holey g-C3 N4 (GCN) nanosheets doped with carbon. The protocol involves heating dicyandiamide with beta-cyclodextrin (betaCD) prior to polymerization. The local symmetry of the GCN skeleton is broken, yielding CxGCN (x corresponds to the initial amount of betaCD used) with pores and a distorted structure. The electronic, emission, optical and textural properties of the best-performing material, C2GCN, were significantly modified as compared to bulk GCN. The spectroscopic and luminescent features of C2GCN show the characteristic pi-pi* electronic transition of GCN, accompanied by much stronger n-pi* electronic transitions owing to the porous and distorted network. These new electronic transitions, along with the presence of additional carbon synergistically contributed to enhanced visible light absorption and restrained recombination of electron-hole pairs. Steady-state and time-resolved photoluminescence showed an effective quench of the fluorescence emission, accompanied by a decrease of fluorescence lifetime of C2GCN (2.20 ns) in comparison with GCN (5.85 ns), owing to the delocalization of electron and holes to new recombination centers. The photocatalytic activity of C2GCN was attributed to efficient charge carrier separation and improved visible-light absorbing ability. As result, C2GCN exhibited ~5 times higher photocatalytic H2 generation under visible light than bulk GCN. PMID- 29975821 TI - Intrauterine Devices. PMID- 29975820 TI - Controlling Nerve Growth with an Electric Field Induced Indirectly in Transparent Conductive Substrate Materials. AB - Innovative neurostimulation therapies require improved electrode materials, such as poly(3,4-ethylenedioxythiophene) (PEDOT) polymers or IrOx mixed ionic electronic conductors and better understanding of how their electrochemistry influences nerve growth. Amphibian neurons growing on transparent films of electronic (metal) conductors and electronic-ionic conductors (polymers and semiconducting oxides) are monitored. Materials are not connected directly to the power supply, but a dipole is created wirelessly within them by electrodes connected to the culture medium in which they are immersed. Without electrical stimulation neurons grow on gold, platinum, PEDOT-polystyrene sulfonate (PEDOT PSS), IrOx , and mixed oxide (Ir-Ti)Ox , but growth is not related to surface texture or hydrophilicity. Stimulation induces a dipole in all conductive materials, but neurons grow differently on electronic conductors and mixed valence mixed-ionic conductors. Stimulation slows, but steers neurite extension on gold but not on platinum. The rate and direction of neurite growth on PEDOT PSS resemble that on glass, but on IrOx and (Ir-Ti)Ox neurites grow faster and in random directions. This suggests electrochemical changes induced in these materials control growth speed and direction selectively. Evidence that the electric dipole induced in conductive material controls nerve growth will impact electrotherapies exploiting wireless stimulation of implanted material arrays, even where transparency is required. PMID- 29975822 TI - [PYRIDOXAL-5-PHOSPHATE RESTORES HYDROGEN SULFIDE SYNTHES AND REDOX STATE OF HEART AND BLOOD VESSELS TISSUE IN OLD ANIMALS]. AB - It was shown the alterations in hydrogen sulfide (H(2)S) metabolism and the development of oxidative and nitrozative stress in cardiovascular system by aging. The administration of pyridoxal-5-phosphate as cofactor of H(2)S synthesizing enzymes restored endogenous H(2)S level and redox state in the heart and aorta tissues. Under these conditions, the following indicators of oxidative stress were significantly decreased in heart and aorta tissues: superoxide generation rate (.0(2)(-)) and hydroxyl (.OH) anion radicals, compared with significantly elevated levels of these parameters in old animals. We also found the reduction of non-enzymatic (diene conjugates and malonic dialdehyde) and enzymatic (uric acid, LTC(4) and TxB(2)) lipid oxidation products levels in old rats under H(2)S synthesis stimulation that confirms the restriction of oxidative stress. An important consequence of endogenous synthesis stimulation of hydrogen sulfide during aging is a decrease of nitrozative stress, such as iNOS activity and nitrate reductase, as well as recovery of constitutive NO synthase activity, indicating the importance of this gas transmitter in cardiovascular system. Thus, stimulation of hydrogen sulfide endogenous synthesis contributed to reduced production of reactive oxygen species (oxidative stress) and nitrogen (nitrozative stress) in heart and aorta tissues with aging. The presence of a pronounced antioxidant effect and modulating influence of pyridoxal-5- phosphate in the redox state of heart tissue and blood vessels during aging suggests cardioprotective properties of the substance and prospects for future research. PMID- 29975824 TI - Probiotic strains of lactobacilli and bifidobacteria alter pro- and anti inflammatory cytokines production in rats with monosodium glutamate-induced obesity. AB - The aim of this study was to investigate the effect of probiotic strains of Lactobacillus casei IMV B-7280, Bifidobacterium animalis VKL, B. animalis VKB on the pro- and anti-inflammatory cytokines production in Wistar male rats with monosodium glutamate (MSG)-induced obesity. It was established that neonatal administration of MSG to rats leads to increasing levels of the interleukin (IL) 1beta and IL-12, and to decreasing ofthe IL-4, IL-10 and tumor growthfactor (TGF) beta levels in the bloodserum. After administration of the B. animalis VKL - B. animalis VKB - L. casei IMV B-7280 composition to obese rats the level of the IL lP in blood serum wasn't differ from that in the obese rats, that didn't receive of the probiotic bacteria. But there was no statistically signifcant difference comparing with intact rats. The level of the IL-12B p4O in blood serum was decreased under influence of the B. animalis VKL - B. animalis VKB - L. casei IMV B-7280 composition (18.9%, p < 0.05) and B. animalis VKL (10.5%, p < 0.05) compared with obese rats, not receiving probiotic bacteria, but remained higher than in intact animals. After administration to obese rats ofthe B. animalis VKL B. animalis VKB - L. casei IMV B-7280 composition the levels ofthe IL-4, IL- 10 and TGF-beta increased in blood serum comparing with obese rats, not receiving probiotic bacteria. The level of the IL-10 also increased under influence of the B. animalis VKB, and IL-4 - under influence of the L. casei IMVB-7280. Our results suggest that these probiotic bacteria and probiotic composition are able to down-regulation the inflammation in rats with MSG-induced obesity but the strongest anti-inflammatory effects have probiotic composition. The ability of lactobacilli and bifdobacteria to alter the pro- and anti-inflammatory cytokines production, opens perspectives to create new treatments for obesity and metabolic syndrome based on probiotics. PMID- 29975823 TI - [EFFECT OF CURCUMIN ON MITOCHONDRIAL FUNCTION OF CARDIOMYOCYTES WITH DOXORUBICIN INDUCED OXIDATIVE STRESS]. AB - We studied the effect of curcumin on the cardiomyocytes viability, processes of oxidative phosphorylation in the mitochondria of cardiomyocytes, their pro- and antioxidant balance in doxorubicin-induced oxidative stress. It has been revealed that administration of doxorubicin to rats led to a significant increase in the secondary products of lipid peroxidation (TBARS) in mitochondria by 21 and H(2)0(2) by 76%, reduction of the enzymatic activity of mitochondrial Mn-SOD by 14% and intensified catalase activity by 80% compared with the control. After combined use of doxorubicin and curcumin the content of TBARS and H(2)0(2) increased by 14 and 26%, respectively, the enzymatic activity of catalase decreased by 28%, and mitochondrial Mn-SOD activity intensified by 9%. During the incubation with doxorubicin, the number of live cells decreased by 30.4% and the number of necrotic cells increased by 30.4% relative to control. Coadministration of doxorubicin and curcumin led to augmented cell viability by 8%, while the number of necrotic cells reduced by 8% compared with the use of doxorubicin only. In assessing the parameters of mitochondrial respiration in rats that received injections of doxorubicin active breathing index (V(3)) fell by 43.8%, the oxidation rate of the contingency of phosphorylation (V(3)/V(4)(ATp)) decreased by 47% and phosphorylation efficiency index (ADP/O) also declined by 31.7% respectively compared with the control. The combined use of doxorubicin and curcumin improved the indicators of mitochondrial respiration compared to using only doxorubicin: V(3) raised by 25%, V(3)/V(4)(ATP)by 18% and ADP/O by 12% respectively. PMID- 29975825 TI - [AGE AND SEX FEATURES OF BONE MINERAL DENSITY IN RATS]. AB - In vivo assessment of bone mineral density (BMD) and bone mineral content (BMC) indices gives an objective description of the possible rates of bone loss during aging and various diseases, as well as response to treatment by various drugs, affecting bone metabolism. This study was conducted on 376 Wistar rats of both genders, divided into 12 age groups using the method of dual-energy X-ray absorptiometry. Studying the parameters of BMD and BMC depending on age and sex has found no bone mass opeak) in rats of both sexes. Bone mineral density indices were increased in both male and female rats during growing, more pronounced in males. These differences are noted in all age groups of animals. Moreover, we have established age and gender particularities of BMC indices in different parts of the skeleton. In female rats, a significant increase of BMD and BMC parameters have been detected in age from 1.5 to 2 months (33%), from 2 to 3 months - by 12.5%. In males, the increase of BMD indices was found to happen 1 month later and it was less pronounced (from 2 to 3 months - 27%, from 4 to 5 months - 5%). In other age periods, the dynamics of BMD indices had only an upward trend, but significant differences different groups were not established. Our results of BMD and BMC indices and their age and gender features can be used for further research in osteology as reference data for modeling of experimental osteoporosis in rats and study of response to the use of different antiosteoporotic drugs. PMID- 29975826 TI - [ANALYSIS OF gamma-GLUTAMYL CARBOXYLASE GENE rs2592551 POLYMORPHISM ASSOCIATION WITH ISCHEMIC ATHEROTHROMBOTIC STROKE]. AB - The results of gamma-glutamyl carboxylase gene rs2592551 polymorphism determining in 170 patients with ischemic atherothrombotic stroke and 124 subjects without acute cerebrovascular disease (control group) have been evaluated. Obtained results revealed that rs2592551 polymorphism was related to ischemic stroke in Ukrainian population. The risk for this disease in patients with T/T genotype was higher than in major C-allele carriers (odds ratio (OR) = 3.117; 95% confidence interval (CI) = 1.016-9.566; P = 0.047). After dividing patients into subgroups, formed by the presence of certain risk factors for atherosclerosis, similar association has been established for women and non-smokers. At the same time, the heterozygous genotype (C/T) in females had significantly protective effect against ischemic stroke development when compared to C/C and T/T genotypes (OR = 0.460; 95% CI 0.213-0.994; P = 0.048). Statistical significance of these results persisted even after adjustment for age, body mass index, smoking and hypertension. PMID- 29975827 TI - [THE EFFECT OF OF POLY(ADP-RIBOSE) POLYMERASE INHIBITOR 4-HYDROXY-QUINAZOLINE ON DEATH OF IMMUNE CELLS UNDER IMMUNE COMPLEX-MEDIATED INJURY IN MICE]. AB - The influence of poly(ADP-ribose) polymerase (PARP) in- hibitor 4 hydroxyquinazoline (4-HQ) on the level of DNA damage and on the death of thymic and lymph node cells in mouse model of immune complex injury was investigated to reveal its possible cytoprotective effect. As shown by comet assay, DNA damage index of immune cells was increased 4,0 times in mice with immune complex mediated pathology induced by a long-term immunization of CBA mice with bovine serum albumin (BSA), P<0,001. The percentage of thymic cells with strong DNA damage was increased to 77% under immunization (compared to 1,5% in control mice) and the percentage of such cells from lymph nodes was increased to 80% (compared to 0% in control), in both cases P< 0,001. Genotoxic stress was reduced by treatment of immunized mice with 4-HQ: the percentage of lymphocytes with strong DNA damage was significantly decreased that promoted increase in the amount of cells having intact DNA. PARP inhibition exerted a strong cytoprotective effect: viability of thymus and lymph node cells was increased mainly due to reduced level of necrosis. So, our results suggest that PARP may be involved in thymic and lymph node cell damage in immune complex mediated pathology and give evidence that inhibition of this enzyme may constitute a perspective target in immune complex diseases prevention and therapy. PMID- 29975828 TI - [CHANGES IN RHEOGRAPHIC INDICATORS OF SHIN IN ATHLETES OF DIFFERENT KINDS OF SPORTS]. AB - We determined the changes of time, amplitude and derivatives of these indicators of rheovasograms of shin in sportsmen of youth age and high level of skills engaged in volleyball, athletics and wrestling with sports experience at least 3 years. We determined significant differences in the value of time, amplitude and derivatives of these indicators ofrheovazograms of shin in males youth age, depending on the impact of intense exercise. The volleyball players compared to youth who do not exercise, reliably large values of the overall tone of the arteries (11,2%), arteries of large diameter (8,2%), arteries of medium and small diameters (13,5%), time ascending part of rheovazograms (2%) and a slow passage (5,9%) and less dycrotycs index (17%), duration ofrheographic wave (3,7%), time descending part of rheovazograms (10%). The persons of control group had higher values of baseline impedance than wrestlers (9,9%) and athletes (13,7%) and all amplitude indicators rheograms of the shin than athletes (average 12-15%) and wrestlers (22-23%). The size and volume of blood flow to the arteries of the extremities adapted to the metabolic needs of the relevant muscles. In volleyball players compared to the athletes, a lower duration of rheographic wave (10%), time of downlink part of the rheograms (12,7%), the base impedance (17,2%), amplitude of the systolic wave (17%) and rapid blood filling (21%), all indicators tone of arteries (12,2-16,9%) and greater value of time of rising part of rheograms (3,5%) and slow blood filling (5,9%). Wrestlers compared to the athletes have a lower duration of rheographic wave (6,1%), time of downlink part of the rheograms (6,1%), the amplitude of the systolic wave (9,3%), compared with volleyball players set lower values of average speed of fast blood filling (15,6%), tone of arteries with different diameters (15-16,5%), all amplitude indicators (20-28%), time slow blood filling (9,7%), ascending parts rheogram (10,3%). Thus, the level ofphysical activity and especially muscle activity has a significant effect on the performance of regional blood flow. PMID- 29975829 TI - [CHANGES OF NORMALIZED SPECTRAL POWER OF ELECTROENCEPHALOGRAM RHYTHMS OF HARD-OF HEARING CHILDREN AND TEENAGERS]. AB - We showed that a cortical maturation rhythms of people with hard-of-hearing is the subject to the same laws as the background rhythm persons normally hear: with age on the background EEG in the people with hard-of-hearing is a gradual increase in alpha-rhythm, but still normalized spectral power of the alpha- rhythm on the background's EEG of teenagers with hard-of-hearing remains below the similar indicators adolescents normally, and greater representation of slow waves. It was found that the background's EEG of teenagers with hard-of-hearing observed moving focus of alpha-occipital activity in the parietal cortex, which is not observed in the hard-of-hearing children. It can be associated with an increased activity in the limbic system on the background of bark tone in the hard-of-hearing children. PMID- 29975830 TI - [EFFECT OF NMDA-RECEPTOR BLOCKERS ON THE DYNAMICS OF INTRAOCULAR PRESSURE IN RABBITS]. AB - Experiments on rabbits with a model of acute temporary ocular hypertension created by intragastric administration of water (100 ml/kg) have been performed. It was found that intravenous administration or instillation into the eye of blocker of NMDA-receptor 1-adamantylethyloxy-3-morpholino-2- propanol hydrochloride (Ademol) unlike amantadine sulfate results in a significant decrease in intraocular pressure (IOP). It was also discovered that such ocular hypotensive effect takes place in animals with unchanged ophthalmotonus. Taking into account neuroretinoprotective and hypotensive ocular hypotensive properties of Ademol this drug appears to be perspective in the treatment of ischemic disorders of the retina and optic nerve, especially under the conditions of increased IOP. PMID- 29975831 TI - [DIPROSPAN, LONGIDAZA AND THEIR COMBINED ACTION AGAINST FIBROSIS CAUSED BY MECHANICAL INJURY OF THE INTERVERTEBRAL DISCS IN RATS]. AB - The formation of connective tissue changes in the spinal canal of rats, caused by the method of intervertebral disc ruptures, in association with a mixture of epidural injection of longidaza and diprospan has been researched. Simultaneous injection of hialuronidase and betamethasone in composition of diprospan and longidaza, revealed a high synergistic effect and anti-fibrotic activity. Combined antifibrosis action of these two drugs is stronger than the sum of the actions of the two drugs in their separate use. Reducion of the maximum thickness of the fibrous layer was 49%, compared with the reference value and reduction of the total area of the fibrous formation was 46%. In our opinion, due to anti inflammatory effects and the ability to reduce epidural scar adhesion, this complex is promising for its therapeutic use in treatment of spinal epidural fibrosis. PMID- 29975832 TI - [PHYSIOLOGICAL RELATIONSHIP OF ERYTHROCYNE ANTIGENS WITH INDICATORS OF HORSE SPERMOGRAM]. AB - The possible presence of the physiological relationship of erythrocyte antigens of the A, C, D, K alleles of the blood group systems in the examined horses of the Ukrainian selection with the spermogram major parameters has been demonstrated. It has been found that when investigating ad/bcm and dg/cgm alleles of the blood group system D in the stallions, there was the physiological tendency of the decrease in the semen activity on average less than 5 points; at the presence of ad/cgm, ad/d, ad/ de, ad/dk, bcm/d, bcm/de, bcm/dg bcm/dk cegm/cgm, cegm/d, cegm/dg, cegm/dk cgm/ceg, cgm/cgm, cgm/dg, cgm/dk de/ cgm, de/dk dg/di, dk/d, dk/de, dk/dk alleles the spermogram of the average quality with the activity of the semen on average from 5 to 7 points was obtained; at the presence of bcm/cgm, dg/dk, de/d, egm/d, cgm/de alleles high parameters of semen activity, more than 7 points, were received. The tendency of the increase in the semen concentration was revealed in the examined stallions having a/- allele of the blood group C. The possible decrease in the semen concentration in the stallions having a/-allele of the blood group K was shown. The alleles of the blood group system D had the highest statistical impact on the volume of the ejaculate, the activity, concentration and the number of pathological forms of semen, the correlation coefficient was 0,36; 0,31; 0, 43 and 0,27, respectively. At the same time it has been found out that the alleles of the blood group systems A,C and K had the coefficient of correlation with the examined parameters of the semen at the level of not more than 0,07. PMID- 29975833 TI - [CHANGES OF LIFETIME MORPHOLOGICAL PARAMETERS OF THE RETINA ON THE BACKGROUND OF CORRECTION OF LIPID METABOLISM IN PATIENTSWITH TYPE 2 DIABETES MELLITUS]. AB - The functional changes of retina morphological parameters of macular zone were investigated under condition of long term action of fenofibrate, 145 mg in patients with diabetes mellitus type 2. Dynamic observation of certain ophthalmologic (visual acuity, macular thickness zone) and system functional parameters (lipid fractions content in serum) in long-term use of this medical drug in 20 patients with diabetes type 2 and DMO for 8 months. In this period we revealed some positive changes in the functional state of the macular area: increase of visual acuity, decrease of macula thickness and the improvement of the lipid profile in blood serum. PMID- 29975835 TI - Computational Design of Functional Amyloid Materials with Cesium Binding, Deposition, and Capture Properties. AB - Amyloid materials are gaining increasing attention as promising materials for applications in numerous fields. Computational methods have been successfully implemented to investigate the structures of short amyloid-forming peptides, yet their application in the design of functional amyloid materials is still elusive. Here, we developed a computational protocol for the design of functional amyloid materials capable of binding to an ion of interest. We applied the protocol in a test case involving the design of amyloid materials with cesium ion deposition and capture properties. As part of the protocol, we used an optimization-based design model to introduce mutations at non-beta-sheet residue positions of an amyloid designable scaffold. The designed amino acids introduced to the scaffold mimic how amino acids bind to cesium ions according to experimentally resolved structures and also aim at energetically stabilizing the bound conformation of the pockets. The optimum designs were computationally validated using a series of simulations and structural analysis to select the top designed peptides, which are predicted to form fibrils with cesium ion binding properties for experimental testing. Experiments verified the amyloid-forming properties of the selected top designed peptides, as well as the cesium ion deposition and capture properties by the amyloid materials formed. This study demonstrates the first, to the best of our knowledge, computational design protocol to functionalize amyloid materials for ion binding properties and suggests that its further advancement can lead to novel, highly promising functional amyloid materials of the future. PMID- 29975834 TI - [MUSCLE FATIGUE: FACTORS OF DEVELOPMENT AND WAYS OF CORRECTION]. AB - The data regarding the analysis of the physiological and biochemical mechanisms of muscle fatigue and ways to prevent it are summarized. The effect of the most common endogenous and exogenous antioxidants in the biochemical processes in muscle fatigue was analyzed. It is shown that biocompatible, non-toxic water soluble C(60) fullerenes, which possess powerful antioxidative properties, promise great prospects in the correction of skeletal muscle fatigue caused by the destructive action of free radicals. PMID- 29975837 TI - Porous NaTi2(PO4)3/C Hierarchical Nanofibers for Ultrafast Electrochemical Energy Storage. AB - NaTi2(PO4)3 (NTP) with a sodium superionic conductor three-dimensional (3D) framework is a promising anode material for sodium-ion batteries (SIBs) because of its suitable potential and stable structure. Although its 3D structure enables high Na-ion diffusivity, low electronic conductivity severely limits NTP's practical application in SIBs. Herein, we report porous NTP/C nanofibers (NTP/C NFs) obtained via an electrospinning method. The NTP/C-NFs exhibit a high reversible capacity (120 mA h g-1 at 0.2 C) and a long cycling stability (a capacity retention of ~93% after 700 cycles at 2 C). Furthermore, sodium-ion full cells and hybrid sodium-ion capacitors have also been successfully assembled, both of which exhibit high-rate capabilities and remarkable cycling stabilities because of the high electronic/ionic conductivity and impressive structural stability of NTP/C-NFs. The results show that the nanoscale-tailored NTP/C-NFs could deliver new insights into the design of high-performing and highly stable anode materials for room-temperature SIBs. PMID- 29975838 TI - Tyrosinase-Mediated Bioconjugation. A Versatile Approach to Chimeric Macromolecules. AB - We present a method for tyrosine-selective and reversible bioconjugation; tyrosines are enzymatically converted into catechols and in situ "clicked" onto boronic acids. Importantly, our process selectively produces catechols and avoids quinones, thereby improving the control over the chemical identity of the products. We have conjugated boronic acid-containing hyaluronic acid (HyA) to peptides bearing tyrosines in variable number and position; the use of tagging peptides for the provision of well exposed tyrosine residues-in our case the hemagglutinin-derived HA-tag-makes our approach applicable to virtually any protein; we have demonstrated this concept by conjugating HA-tagged ovalbumin to HyA, thereby also showing the feasibility of producing chimeric proteoglycans. A caveat of this appproach is that, although the formation of boronic esters does not affect the biological recognition of substrates (ovalbumin and HyA), the introduction of catechols may alter some of their biological properties: for example, only after tyrosinase treatment ovalbumin directly induced dendritic cell maturation, either alone or as a HyA conjugate. PMID- 29975836 TI - Probing Intermolecular Interactions within the Amyloid beta Trimer Using a Tethered Polymer Nanoarray. AB - Amyloid oligomers are considered the most neurotoxic species of amyloid aggregates. Spontaneous assembly of amyloids into aggregates is recognized as a major molecular mechanism behind Alzheimer's disease and other neurodegenerative disorders involving protein aggregation. Characterization of such oligomers is extremely challenging but complicated by their transient nature. Previously, we introduced a flexible nanoarray (FNA) method enabling us to probe dimers assembled by the amyloid beta (14-23) [Abeta (14-23)] peptide. The study presented herein modifies and enhances this approach to assemble and probe trimers of Abeta (14-23). A metal-free click chemistry approach was used, in which dibenzocyclooctyne (DBCO) groups were incorporated at selected sites within the FNA template to click Abeta (14-23) monomers at their terminal azide groups. Atomic force microscopy (AFM) force spectroscopy was employed to characterize the assemblies. The force measurement data demonstrate that the dissociation of the trimer undergoes a stepwise pattern, in which the first monomer dissociates at the rupture force ~48 +/- 2.4 pN. The remaining dimer ruptures at the second step at a slightly larger rupture force (~53 +/- 3.2 pN). The assembled trimer was found to be quite dynamic, and transient species of this inherently dynamic process were identified. PMID- 29975839 TI - Rational Design of Mononuclear Iron Porphyrins for Facile and Selective 4e-/4H+ O2 Reduction: Activation of O-O Bond by 2nd Sphere Hydrogen Bonding. AB - Facile and selective 4e-/4H+ electrochemical reduction of O2 to H2O in aqueous medium has been a sought-after goal for several decades. Elegant but synthetically demanding cytochrome c oxidase mimics have demonstrated selective 4e-/4H+ electrochemical O2 reduction to H2O is possible with rate constants as fast as 105 M-1 s-1 under heterogeneous conditions in aqueous media. Over the past few years, in situ mechanistic investigations on iron porphyrin complexes adsorbed on electrodes have revealed that the rate and selectivity of this multielectron and multiproton process is governed by the reactivity of a ferric hydroperoxide intermediate. The barrier of O-O bond cleavage determines the overall rate of O2 reduction and the site of protonation determines the selectivity. In this report, a series of mononuclear iron porphyrin complexes are rationally designed to achieve efficient O-O bond activation and site-selective proton transfer to effect facile and selective electrochemical reduction of O2 to water. Indeed, these crystallographically characterized complexes accomplish facile and selective reduction of O2 with rate constants >107 M-1 s-1 while retaining >95% selectivity when adsorbed on electrode surfaces (EPG) in water. These oxygen reduction reaction rate constants are 2 orders of magnitude faster than all known heme/Cu complexes and these complexes retain >90% selectivity even under rate determining electron transfer conditions that generally can only be achieved by installing additional redox active groups in the catalyst. PMID- 29975840 TI - Dihydromyricetin Inhibits Lead-Induced Cognitive Impairments and Inflammation by the Adenosine 5'-Monophosphate-Activated Protein Kinase Pathway in Mice. AB - Dihydromyricetin (DHM), a natural flavonoid derived from the medicinal and edible plant Ampelopsis grossedentata, exhibits antioxidant, antiapoptosis, antitumor, and anti-inflammatory bioactivities. This study evaluated the effects of DHM on Pb-induced neurotoxicity and explored the underlying mechanisms. DHM significantly ameliorated behavioral impairments of Pb-induced mice. It decreased the levels of lipid peroxidation and protein carbonyl and increased the activities of superoxide dismutase and catalase in the brains. DHM suppressed Pb induced apoptosis, as indicated by the decreased levels of Bax and cleaved caspase-3. DHM also decreased inflammatory cytokines in the brains of Pb-treated mice. DHM decreased amyloid-beta (Abeta) level and nuclear factor-kappaB nuclear translocation. Moreover, DHM induced the adenosine 5'-monophosphate-activated protein kinase (AMPK) phosphorylation and inhibited the activation of p38, Toll like receptor 4, myeloid differentiation factor 88, and glycogen synthase kinase 3. Collectively, this is the first report indicating that DHM could improve Pb induced cognitive functional impairment by preventing oxidative stress, apoptosis, and inflammation and that the protective effect was mediated partly through the AMPK pathway. PMID- 29975841 TI - Optical Activation of TrkA Signaling. AB - Nerve growth factor/tropomyosin receptor kinase A (NGF/TrkA) signaling plays a key role in neuronal development, function, survival, and growth. The pathway is implicated in neurodegenerative disorders including Alzheimer's disease, chronic pain, inflammation, and cancer. NGF binds the extracellular domain of TrkA, leading to the activation of the receptor's intracellular kinase domain. As TrkA signaling is highly dynamic, mechanistic studies would benefit from a tool with high spatial and temporal resolution. Here we present the design and evaluation of four strategies for light-inducible activation of TrkA in the absence of NGF. Our strategies involve the light-sensitive protein Arabidopsis cryptochrome 2 and its binding partner CIB1. We demonstrate successful recapitulation of native NGF/TrkA functions by optical induction of plasma membrane recruitment and homo interaction of the intracellular domain of TrkA. This approach activates PI3K/AKT and Raf/ERK signaling pathways, promotes neurite growth in PC12 cells, and supports survival of dorsal root ganglion neurons in the absence of NGF. This ability to activate TrkA using light bestows high spatial and temporal resolution for investigating NGF/TrkA signaling. PMID- 29975842 TI - Carbon Nanotube Film Gate in Vacuum Electronic Devices. AB - A superaligned carbon nanotube (SACNT) film can act as an ideal gate electrode in vacuum electronics due to its low secondary electron emission, high electron transparency, ultrasmall thickness, highly uniform electric field, high melting point, and high mechanical strength. We used a SACNT film as the gate electrode in a thermionic emission electron tube and field emission display prototype. The SACNT film gate in a thermionic emission electron tube shows a larger amplification factor. A triode tube with the SACNT film gate is used in an audio amplification circuit. The SACNT film gate electrode in field emission devices shows better field uniformity. The field emission display prototype is demonstrated to dynamically display Chinese characters. PMID- 29975843 TI - Characterization of Carboxylated Cellulose Nanocrytals Isolated through Catalyst Assisted H2O2 Oxidation in a One-Step Procedure. AB - A green and facile method was designed to isolate a type of cellulose nanocrystal (CNC) with carboxylated surfaces from native cellulose materials. Because isolation and modification processes of cellulosic particles are generally performed separately using harmful chemicals and multiple steps, the one-pot approach employed in this work is interesting from both an economical and ecological point of view. The reaction is carried out by adding hydrogen peroxide as an oxidant and copper(II) sulfate as a catalyst in acidic medium under mild thermal conditions. The charge content of the carboxylated CNC is about 1.0 mmol g-1, measured by a conductometric titration. Fourier transform infrared spectroscopy also proved the presence of carboxyl groups on the CNC particles. Atomic force microscopy along with optical polarized microscopy readily showed a rod shape morphology for the cellulosic particles. An average length of 263 nm and width of 23 nm were estimated by transmission electron microscopy. Dynamic laser scattering on carboxylated CNC suspensions by adding salt confirmed that nanoparticles are electrostatically stable. Carboxylated CNCs were furthermore characterized by solid carbon-13 nuclear magnetic resonance and X-ray spectroscopy. PMID- 29975844 TI - High Mobility HgTe Microstructures for Quantum Spin Hall Studies. AB - The topic of two-dimensional topological insulators has blossomed after the first observation of the quantum spin Hall (QSH) effect in HgTe quantum wells. However, studies have been hindered by the relative fragility of the edge states. Their stability has been a subject of both theoretical and experimental investigation in the past decade. Here, we present a new generation of high quality (Cd,Hg)Te/HgTe-structures based on a new chemical etching method. From magnetotransport measurements on macro- and microscopic Hall bars, we extract electron mobilities MU up to about 400 * 103 cm2/(V s), and the mean free path lambdamfp becomes comparable to the sample dimensions. The Hall bars show quantized spin Hall conductance, which is remarkably stable up to 15 K. The clean and robust edge states allow us to fabricate high quality side-contacted Josephson junctions, which are significant in the context of topological superconductivity. Our results open up new avenues for fundamental research on QSH effect as well as potential applications in spintronics and topological quantum computation. PMID- 29975845 TI - Determination Method and Size Dependence of Interfacial Tension between Nanoparticles and a Solution. AB - Interfacial tension plays an important role in the processes of preparation, research, and application of nanomaterials. Because the interfacial tension is fairly difficult to be determined by experiments, it is still unclear about the effect of particle size on interfacial tension. In this paper, we proposed a method to determine the interfacial tensions and its temperature coefficients by determining the electrode potential of the nanoparticle electrode. Nano-Au with different radii (from 0.9 to 37.4 nm) in an aqueous solution was taken as a research system; we determined the interfacial tension and its temperature coefficient of the interface and discussed the size dependence. At the same time, we found surprisingly that this method can also be applied to determine the Tolman length and the atomic radius. The results show that the particle size of nano-Au has remarkable influences on the interfacial tension and its temperature coefficient. As the particle size decreases, the interfacial tension and the absolute value of its temperature coefficient increase. With the decrease of radius, the influences of the particle size on the interfacial tension and its temperature coefficient become more significant, whereas the influences can be neglected when the radius exceeds 10 nm. In addition, the results also show that the Tolman length is a negative value, and temperature has little effect on the Tolman length. This research can provide a new method to conveniently and reliably determine the interfacial tension on interfaces between nanoparticles and solutions, the temperature coefficients, the Tolman lengths, and the atomic radii; and the size dependences can provide important references for preparation, research, and application of nanomaterials. PMID- 29975846 TI - The Topmost Water Structure at a Charged Silica/Aqueous Interface Revealed by Heterodyne-Detected Vibrational Sum Frequency Generation Spectroscopy. AB - Despite recent significant advances in interface-selective nonlinear spectroscopy, the topmost water structure at a charged silica surface is still not clearly understood. This is because, for charged interfaces, not only interfacial molecules at the topmost layer but also a large number of molecules in the electric double layer are probed even with second-order nonlinear spectroscopy. In the present study, we studied water structure at the negatively charged silica/aqueous interface at pH 12 using heterodyne-detected vibrational sum frequency generation spectroscopy, and demonstrated that the spectral component of the topmost water can be extracted by examining the ionic strength dependence of the Imchi(2) spectrum. The obtained Imchi(2) spectrum indicates that the dominant water species in the topmost layer is hydrogen-bonded to the negatively charged silanolate at the silica surface with one OH group. There also exists minor water species that weakly interacts with the oxygen atom of a siloxane bridge or the remaining silanol at the silica surface, using one OH group. The ionic strength dependence of the Imchi(2) spectrum indicates that this water structure of the topmost layer is unchanged in a wide ionic strength range from 0.01 to 2 M. PMID- 29975847 TI - Materials by Design for Stiff and Tough Hairy Nanoparticle Assemblies. AB - Matrix-free polymer-grafted nanocrystals, called assembled hairy nanoparticles (aHNPs), can significantly enhance the thermomechanical performance of nanocomposites by overcoming nanoparticle dispersion challenges and achieving stronger interfacial interactions through grafted polymer chains. However, effective strategies to improve both the mechanical stiffness and toughness of aHNPs are lacking given the general conflicting nature of these two properties and the large number of molecular parameters involved in the design of aHNPs. Here, we propose a computational framework that combines multiresponse Gaussian process metamodeling and coarse-grained molecular dynamics simulations to establish design strategies for achieving optimal mechanical properties of aHNPs within a parametric space. Taking poly(methyl methacrylate) grafted to high aspect-ratio cellulose nanocrystals as a model nanocomposite, our multiobjective design optimization framework reveals that the polymer chain length and grafting density are the main influencing factors governing the mechanical properties of aHNPs, in comparison to the nanoparticle size and the polymer-nanoparticle interfacial interactions. In particular, the Pareto frontier, that marks the upper bound of mechanical properties within the design parameter space, can be achieved when the weight percentage of nanoparticles is above around 60% and the grafted chains exceed the critical length scale governing transition into the semidilute brush regime. We show that theoretical scaling relationships derived from the Daoud-Cotton model capture the dependence of the critical length scale on graft density and nanoparticle size. Our established modeling framework provides valuable insights into the mechanical behavior of these hairy nanoparticle assemblies at the molecular level and allows us to establish guidelines for nanocomposite design. PMID- 29975848 TI - Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis. AB - Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S HH) signaling cascade. Shh is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular Sostdc1, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating Sostdc1, resulting in cleft palate and defective osteogenesis. PMID- 29975849 TI - A Functionally Graded PICN Material for Biomimetic CAD-CAM Blocks. AB - The objective of this study was to introduce a functionally graded (FG) polymer infiltrated ceramic network (PICN) block, characterized by a gradient of mechanical properties, as a biomimetic material for computer-aided design and manufacturing (CAD-CAM) prostheses. FG-PICN blocks were manufactured from a slurry of glass-ceramic powder, which was subsequently centrifuged and sintered. The ceramic network was infiltrated with urethane dimethacrylate and polymerized under high temperature-pressure. Blocks were sectioned into 9 layers, and each layer was subsequently cut into 3 samples. Samples were loaded into a 3-point bending device and tested for flexural strength, flexural load energy, and flexural modulus. The volume percentage of glass-ceramic, hardness, and brittleness index were also measured and scanning electron microscopy (SEM) observations were performed. Katana translucent zirconia (HT-ZIR) and e.max-CAD (EMX) were tested for comparison. Flexural strength, flexural load energy, and Weibull modulus of FG-PICN were shown to increase from the first (enamel-like zone) to the ninth layer (dentin-like zone), while, on the contrary, flexural modulus, hardness, brittleness index, and ceramic volume percentage decreased. SEM characterization highlighted a higher porosity in layer 9 than in layer 1. Flexural strength of the dentin-like zone (372.7 +/- 27.8 MPa) was similar to EMX and lower than HT-ZIR. Flexural modulus was shown to vary from 41.9 +/- 5.1 to 28.6 +/- 2.0 GPa from surface to depth. Flexural load energy in the dentin-like zone (27.1 +/- 4.9 mJ) was significantly superior to EMX and HT-ZIR. Hardness gradient was shown to be close to tooth tissues. This work introduces FG-PICN blocks, with a gradient of mechanical and optical properties through the entire thickness of the block designed to mimic dental tissues. FG-PICN demonstrated a favorable gradient of flexural strength, elastic modulus, and, most of all, flexural load energy and hardness compared to other CAD-CAM materials, which can promote the biomechanical behavior of single-unit restorations on teeth and implants. PMID- 29975850 TI - Letter to the editor: Remembering Steve Hebert (1946-2008). PMID- 29975851 TI - System dynamics of active and passive postural changes: Insights from principal dynamic modes analysis of baroreflex loop. AB - The baroreflex being a key modulator of cardiovascular control ensures adequate blood pressure regulation under orthostatic stress which otherwise may cause severe hypotension. Contrary to conventional baroreflex sensitivity indices derived across a-priori traditional frequency bands, the present study is aimed at proposing new indices for the assessment of baroreflex drive which follows active (supine to stand-up) and passive (supine to head-up tilt) postural changes. To achieve this, a novel system identification approach of principal dynamic modes (PDM) was utilized to extract data-adaptive frequency components of closed-loop interactions between beat-to-beat interval and systolic blood pressure recorded from 10 healthy humans. We observed that the gain of low-pass global PDM of cardiac arm (:feedback reflex loop, mediated by pressure sensors to adjust heart rate in response to arterial blood pressure), and 0.2 Hz global PDM of mechanical arm (:feed-forward pathways, originating changes in arterial blood pressure in response to heart rate variations) may function as potential markers to distinguish active and passive orthostatic tests in healthy subjects. PMID- 29975852 TI - Bi-dimensional multiscale entropy: Relation with discrete Fourier transform and biomedical application. AB - The multiscale entropy (MSE1D) measure is now widely used to quantify the complexity of time series. The development of complexity measures for images is also a long-standing goal. Recently, the bi-dimensional version of MSE1D has been proposed (MSE2D) to analyze images. The interpretation of MSE2D curves and the applications to real data are still emergent. Because the coarse-graining step in the MSE2D computation changes the frequency content of the image, we hypothesized a possible dependence between MSE2D and the discrete Fourier transform (DFT). To analyze this dependence, synthetic as well as biomedical images are analyzed. Our results reveal that i) the profile of MSE2D is sensitive to both the amplitude and phase of the DFT; ii) MSE2D could find applications in the biomedical field. This work brings valuable information for MSE2D interpretation and opens possibilities to study images from an entropy point of view through spatial scales. PMID- 29975853 TI - Letter regarding the article "Detecting atrial fibrillation by deep convolutional neural networks" by Xia et al. PMID- 29975854 TI - Migration resistance of esophageal stents: The role of stent design. AB - OBJECTIVE: Stenting is one of the major treatments for malignant esophageal cancer. However, stent migration compromises clinical outcomes. A flared end design of the stent diminishes its migration. The goal of this work is to quantitatively characterize stent migration to develop new strategies for better clinical outcomes. METHODS: An esophageal stent with flared ends and a straight counterpart were virtually deployed in an esophagus with asymmetric stricture using the finite element method. The resulted esophagus shape, wall stress, and migration resistance force of the stent were quantified and compared. RESULTS: The lumen gain for both the flared stent and the straight one exhibited no significant difference. The flared stent induced a significantly larger contact force and thus a larger stress onto the esophagus wall. In addition, more migration resistance force was required to pull the flared stent through the esophagus. This force was inversely related to the occurrence rate of stent migration. A doubled strut diameter also increased the migration resistance force by approximately 56%. An increased friction coefficient from 0.1 to 0.3 also boosted the migration resistance force by approximately 39%. SUMMARY: The mechanical advantage of the flared stent was unveiled by the significantly increased contact force, which provided the anchoring effect to resist stent migration. Both the strut diameter and friction coefficient positively correlated with the migration resistance force, and thus the occurrence of stent migration. PMID- 29975855 TI - Discrimination of skin cancer cells using Fourier transform infrared spectroscopy. AB - Fourier transform infrared (FTIR) spectroscopy is a highly versatile tool for cell and tissue analysis. Modern commercial FTIR microspectroscopes allow the acquisition of good-quality hyperspectral images from cytopathological samples within relatively short times. This study aims at assessing the abilities of FTIR spectra to discriminate different types of cultured skin cell lines by different computer analysis technologies. In particular, 22700 single skin cells, belonging to two non-tumoral and two tumoral cell lines, were analysed. These cells were prepared in three different batches that included each cell type. Different spectral preprocessing and classification strategies were considered, including the current standard approaches to reduce Mie scattering artefacts. Special care was taken for the optimisation, training and evaluation of the learning models in order to avoid possible overfitting. Excellent classification performance (balanced accuracy between 0.85 and 0.95) was achieved when the algorithms were trained and tested with the cells from the same batch. When cells from different batches were used for training and testing the balanced accuracy reached values between 0.35 and 0.6, demonstrating the strong influence of sample preparation on the results and comparability of cell FTIR spectra. A deep study of the most optimistic results was performed in order to identify perturbations that influenced the final classification. PMID- 29975856 TI - Numerical simulation of thermal water delivery in the human nasal cavity. AB - This work describes an extensive numerical investigation of thermal water delivery for the treatment of inflammatory disorders in the human nasal cavity. The numerical simulation of the multiphase air-droplets flow is based upon the Large Eddy Simulation (LES) technique, with droplets of thermal water described via a Lagrangian approach. Droplet deposition is studied for different sizes of water droplets, corresponding to two different thermal treatments, i.e. aerosol and inhalation. Numerical simulations are conducted on a patient-specific anatomy, employing two different grid sizes, under steady inspiration at two breathing intensities. The results are compared with published in vivo and in vitro data. The effectiveness of the various thermal treatments is then assessed qualitatively and quantitatively, by a detailed analysis of the deposition patterns of the droplets. Discretization effects on the deposition dynamics are addressed. The level of detail of the present work, together with the accuracy afforded by the LES approach, leads to an improved understanding of how the mixture of air-water droplets is distributed within the nose and the paranasal sinuses. PMID- 29975857 TI - Effect of ultrasound on bone fracture healing: A computational bioregulatory model. AB - Bone healing is a complex biological procedure in which several cellular actions, directed by biochemical and mechanical signals, take place. Experimental studies have shown that ultrasound accelerates bone ossification and has a multiple influence on angiogenesis. In this study a mathematical model predicting bone healing under the presence of ultrasound is demonstrated. The primary objective is to account for the ultrasound effect on angiogenesis and more specifically on the transport of the Vascular Endothelial Growth Factor (VEGF). Partial differential equations describing the spatiotemporal evolution of cells, growth factors, tissues and ultrasound acoustic pressure and velocity equations determining the development of the blood vessel network constitute the present model. The effect of the ultrasound characteristics on angiogenesis and bone healing is investigated by applying different boundary conditions of acoustic pressure at the periosteal region of the bone model, which correspond to different intensity values. The results made clear that ultrasound enhances angiogenesis mechanisms during bone healing. The proposed model could be regarded as a step towards the monitoring of the effect of ultrasound on bone regeneration. PMID- 29975858 TI - Hierarchical core decomposition of RING structure as a method to capture novel functional residues within RING-type E3 ligases: a structural systems biology approach. AB - BACKGROUND: Increasing amounts of evidence strongly suggest that mutations located in RING (Really Interesting New Gene) domains of E3 ligases are involved in cancer development. Despite the existence of many experimentally defined E3 RING structures, there are still many RING mutations in the Catalog of Somatic Mutations in Cancer (COSMIC), with an unknown structural or functional significance, which are usually substitutions of amino acids with no conservation at the corresponding position. The core decomposition of networks has long been used in systems biology but never utilized in protein structure networks to identify a tolerant "core" to peripheral structure changes or failures, a region that is usually not easy to be determined with high accuracy through classical 3D protein structure analyses. METHOD: A new structure decomposition method that utilizes network analysis and computational thermodynamic measures of fold stability changes upon amino acids alterations is proposed. RESULTS: In particular, by successively pruning the entire RING structure network of three cancer-associated E3s (BRCA1, MDM2, and cIAP2), a ''core'' for each RING domain is left. Interestingly, substitutions of ''core'' residues are associated with cancers according to COSMIC catalog. Unexpectedly, 80% of the residues located in the ''core'' RING subnetworks are non-conserved within E3 RING domains. To validate the predictions, the function of the identified RING ''core'' amino acids as well as the effects of their substitutions on E3 Ub ligase activity were mined from the literature and investigated by computational tools and in vitro Ub ligase assays. CONCLUSIONS: This method could be widely applicable as a source of novel functional RING residues, non-conserved in E3s, for which substitutions could be deleterious. PMID- 29975859 TI - The effect of childhood trauma on blood transcriptome expression in major depressive disorder. AB - Childhood trauma (CT) increases the likelihood of developing severe mental illnesses, such as major depressive disorder (MDD), during adulthood. Several studies have suggested an inflammatory immune system dysregulation as a biological mediator; however, the molecular mechanisms underlying this relationship remain largely undetermined. Moreover, different types of CT, in particular, emotional abuse and neglect, confer a higher risk of developing MDD, and recent meta-analyses showed that each CT can be associated with different pro inflammatory biomarkers. However, no studies using a hypothesis-free approach have been performed. For this reason, we carried out a reanalysis of transcriptome data from a large mRNA sequencing dataset to investigate different types of CT in MDD patients. Gene expression analysis followed by principal component and gene-set enrichment analyses were carried out to identify genes and pathways differentially expressed in 368 patients who experienced four different types of CT (sexual abuse, physical abuse, emotional abuse and neglect). Expression analysis of single genes revealed a significant association between the neglect CT and the MED22 gene (p = 1.11 * 10-6; FDR = 0.016). Furthermore, analyses of the principal components of expression data support a dysregulation of cytokine system pathways, such as interferon (IFN) alpha/beta and gamma signaling, as a consequence of emotional abuse in depressed patients. Our results corroborate the hypothesis that specific types of CT affect distinct molecular pathways, and in particular, emotional abuse and neglect exert the strongest impact on gene expression in MDD. PMID- 29975860 TI - A simulation impact evaluation of a cigarette excise tax increase on licit and illicit cigarette consumption and tax revenue in 36 European countries. AB - OBJECTIVES: To assess the impact of a simulated 10% tax-induced cigarette price increase on licit and illicit consumption and tax revenues in 36 European countries. METHODS: Employing panel data for licit and illicit cigarette consumption, fixed effects regression models were applied for different income clusters. RESULTS: Total cigarette consumption dropped by about 3.1% as a result of the simulated tax-induced price increase. Annual illicit cigarette consumption increased by 1.52%, (95% confidence interval: 0.21, 2.83), while annual licit cigarette consumption decreased by 4.61% (95% confidence interval: -6.51, -2.72) in the observed 36 European countries. With total consumption decreasing by about 8%, the Czech Republic, Latvia, Lithuania, Poland and Slovakia were affected the most by the price hike. More specifically, licit consumption in these countries decreased by 18.43% (95% confidence interval: -19.91, -16.95) while illicit use increased by 10.99% (95% confidence interval: 6.01, 15.96). Moreover, the overall annual tobacco tax revenue increased by US$14.69 billion in the simulation. CONCLUSION: Results of the study suggest that European policy makers continue to implement tobacco taxation policies to control smoking prevalence and national health care expenditures. At the same time, efforts to kerb contraband activities along EU Eastern borders should be intensified. PMID- 29975861 TI - Prevalence and predictors of parental concern for children's weight from 2002 to 2012. AB - OBJECTIVES: Public health initiatives to increase parental awareness about children's obesity have become more prominent in the past decade. These initiatives may contribute to increased concern in parents for their children's weight, even if their children are at a healthy weight. The aim of the present study was to document trends in parental (N = 365; 67.9% female) concern for their children's weight from 2002 to 2012 using surveys on health and eating behaviors. STUDY DESIGN: Participants (N = 365) were parents who completed surveys in 2002 and were followed up in 2012 as part of a longitudinal epidemiological study of eating attitudes and behavior. METHODS: McNemar's test and logistic regression models estimated changes in and predictors of parental concern. RESULTS: In 2002, 36.5% of participants indicated concern for their children's weight, which rose to 54.4% in 2012. Parents of overweight children were more likely to report concern than parents of average-weight children at baseline and 10-year follow-up. However, concern increased significantly even among parents of average-weight children, rising from 28.7% to 41.6% (McNemar's test statistic: 8.20, P = .002). Secondary analyses revealed that parents' baseline drive for thinness predicted increased likelihood of concern in these parents (odds ratio: 1.10, P = .04). CONCLUSION: Findings support the need for future research to examine consequences of societal messages about pediatric obesity. PMID- 29975862 TI - Acculturation, resilience, and the mental health of migrant youth: a cross country comparative study. AB - OBJECTIVES: Using data from an international collaborative research project on youth resilience in the context of migration, this study aims to investigate how different acculturation patterns (i.e. integration, assimilation, separation and marginalization) influence the mental health of migrant youth, and whether resilience might function as a mediator in the association between acculturation and mental health. STUDY DESIGN: A cross-sectional pilot study conducted in six countries employing a common survey questionnaire. METHODS: The study sample was 194 youths aged 10-17 years (median = 13.6) from six countries (Australia, Canada, China, New Zealand, South Africa, and United Kingdom) and included cross border and internal migrants. Mental health and well-being was measured by the Warwick-Edinburgh Mental Well-Being Scale (WEMWBS). Resilience was measured by the Child and Youth Resilience Measure-28 (CYRM-28). Acculturation was assessed using the Acculturation, Habits, and Interests Multicultural Scale for Adolescents (AHIMSA). Multivariate regression and path analysis were performed to examine the hypothesized mediation model. RESULTS: Resilience scores correlated strongly with mental health and well-being. Acculturation exerted no significant direct effects on the mental health of migrant youths. Nevertheless, compared to youths who were integration-oriented, assimilation-oriented youths tended to exhibit lower levels of resilience, resulting in poorer mental health. Compared to youths from other countries, migrant youths from China also reported lower levels of resilience, which led to poorer mental health outcome. CONCLUSION: Acculturation plays a significant role in the mental health of migrant youth, with different acculturative orientations exhibiting different influences through the mediation effect of resilience. Fostering resilience and facilitating integration-oriented acculturation are recommended public health strategies for migrant youth. PMID- 29975863 TI - Potential prophylactic effect of recombinant bovine somatotropin (rbST) in sheep with experimentally induced hyperketonemia. AB - Hyperketonemia in sheep is associated with a disease known as pregnancy toxemia. The purposes of this study were to (1) induce hyperketonemia by infusion with D beta-hydroxybutyrate (D-BHB) in eighteen healthy, non-pregnant, non-lactating ewes, (2) to evaluate the metabolic pathways in which recombinant bovine somatotropin (rbST) may be involved, and (3) to evaluate the possible benefits of preventive rbST therapy on the metabolic profiles of the sheep. The sheep were intravenously infused with a D-BHB solution over 2 h. Three days prior to the infusion, one group (n = 9) was injected with a single dose of 160 mg rbST, and the other group (n = 9) was injected with saline as a control. Blood samples were collected and metabolic profiles were analyzed every 20 min during the infusion and at 15, 30, 60, 120, 180, and 240 min post-infusion. Hyperketonemia was successfully achieved, demonstrated by serum BHB concentrations of 3.9 and 3.0 mmol/L in the rbST and control groups, respectively, without the presence of clinical signs. An increase in peripheral insulin resistance was observed after infusion but not during the infusion, in the rbST group. Higher glucose concentrations were observed in the rbST group post-infusion, suggesting a positive impact of D-BHB on gluconeogenesis. Our data suggest that prophylactic treatment with rbST may be useful in sheep to reduce the risk of PT. PMID- 29975864 TI - The effects of cation-pi and anion-pi interactions on halogen bonds in the [N?X?N]+ complexes: A comprehensive theoretical study. AB - The effects of ion-pi interaction on the [N?X?N]+ halogen bond have been investigated by placement of monovalent ions on a pyridine ring plane of the complexes. The structural and electronic properties of the complexes have been studied via the density functional theory (DFT), quantum theory of atoms in molecules (QTAIM), non-covalent interaction (NCI) index and the nuclear magnetic resonance (NMR) calculations. The evaluation of halogen bonds in bis(pyridine)halonium complexes reveals the existence of two factors, ion-pi interactions and intermolecular N?N distance, which play the important roles on the formation and stability of these quaternary complexes. The complexes are made via halogen bonding, where anti-cooperativity effect between two halogen bonds can be a reason for the change in quaternary complexes. The cation-pi interaction decreases the total binding energy |DeltaE|, while anion-pi interaction increases that. The trend in the |DeltaE| values are Ag+ < Au+ < Cu+ < py2X+ < Br-< Cl- < F and is not changed by the methods of calculations. The spin-spin coupling constants 2XJN?N increase in the following order 15N?Cl+?15N > 15N?Br+?15N > 15N?I+?15N, as it similarly observes for the |DeltaE| and the cooperativity and synergetic energies (Ecoop and Esyn). According to AIM and NMR analysis, 1JN?X and 1XJN?X have opposite signs in closed and shared shell XBs. The obtained potential curves can be applied as valuable data to describe the effect of ion-pi interaction on the improving of the three-center-four-electron [N?X?N]+ complexes reactivity. PMID- 29975865 TI - Molecular dynamics simulation of G-actin interacting with PAMAM dendrimers. AB - Understanding the interactions of dendrimers as drug/gene delivery vectors with proteins is important for functional optimization. Here, atomistic molecular dynamics simulations are employed to study the interactions between six positively-charged polyamidoamine dendrimers of the second generation (G2 PAMAM) and G-actin. We find that the structure of G-actin is relatively stable after dendrimers' binding. PAMAM dendrimers also do not significantly change the secondary structure of G-actin. Furthermore, we find the formation of dendrimer actin complex is mainly driven by electrostatic interactions. Moreover, we suggest the secondary structure change of local domains of G-actin is probably responsible to the inhibition of actin polymerization. PMID- 29975866 TI - Physical properties of cubic BaGeO3 perovskite at various pressure using first principle calculations for energy renewable devices. AB - The electronic, optical and thermoelectric analyses of BaGeO3 perovskite have been done by using density functional theory (DFT) based Trans and Blaha modified Becke and Johnson (TB-mBJ) approach. The applied pressure (up to 30 GPa) has been found tailoring the band gap from indirect to direct bandgap (at 20 GPa), within the visible region, revealing renewable energy applications of the studied perovskite. The applied pressure improves mechanical stability by increasing ductility. Furthermore, optical properties are illustrated by computing dielectric constants, refraction, absorption, optical conductivity and optical loss factor for suggesting optoelectronic applications. The maximum peaks shifting to higher energy, due to increasing pressure indicate a blue shift. Finally, the calculated thermal and electrical conductivities, See-beck coefficient, power factor, Hall coefficient, specific heat capacity, susceptibility and electron densities are also elaborated for thermoelectric applications by using BoltzTraP code. PMID- 29975873 TI - Thermal nanometrology using piezoresistive SThM probes with metallic tips. AB - In this paper we present design and application of novel piezoresistive scanning thermal microscopy (SThM) probes. The proposed probe integrates a piezoresistive deflection sensor and thermally active, resistive nanosize tip. Manufacturing technology includes standard silicon MEMS/CMOS processing and sophisticated postprocessing using Focus Ion Beam milling. Authors also describe dedicated measurement technique in order to perform quantitative nanoscale thermal probing. Performance of the developed thermal probes is validated by test scans (topography and temperature distribution) of silicon nanoresistors supplied with current. PMID- 29975874 TI - Characterization of single-atom catalysts by EELS and EDX spectroscopy. AB - Fitted with a field emission source, aberration-corrected optics and an energy dispersive X-ray detector of large solid angle, a modern analytical TEM can generate a current density high enough to chemically identify a single metal atom within a fraction of a second, if the atom remains stationary within the electron probe. However, atom motion will occur if the atomic binding energy is too low, the specimen temperature too high, or the electron accelerating voltage above a certain threshold. We discuss such motion in terms of thermal diffusion, beam induced sputtering and beam-assisted surface migration. Calculations based on a Rutherford-scattering approximation suggest that when atomic displacement is possible, it drastically reduces the analytical signal and signal/noise ratio. For certain elements, electron energy-loss spectroscopy (EELS) provides a higher detectability than energy-dispersive X-ray (EDX) but suffers from the same problem of atomic displacement. PMID- 29975875 TI - Postural control before and after cerebrospinal fluid shunt surgery in idiopathic normal pressure hydrocephalus. AB - OBJECTIVES: This study aimed to confirm whether cerebrospinal fluid (CSF) shunting for idiopathic normal-pressure hydrocephalus (iNPH) improves postural instability, and to investigate the relationship between postural control and gait ability. PATIENTS AND METHODS: Twenty-three iNPH patients and 18 age-matched healthy controls (HC) were examined using the timed up and go (TUG) test and a force platform for calculating the center of pressure (COP) trajectory during voluntary multidirectional leaning and quiescent standing. We determined the patients' TUG values and COP trajectories before and after shunt surgery. RESULTS: Postural sway was greater in iNPH patients before shunt surgery and the TUG value was lower in iNPH patients before shunt surgery than in HC. Voluntary COP movements were significantly improved in iNPH patients at 1 week post surgery, but no significant changes in quiescent standing were found between pre- and post-surgery. Significant correlations were found between the TUG value and voluntary COP movements in iNPH patients before and after surgery, but no significant correlations were observed between the TUG value and quiescent standing. CONCLUSION: Our results indicate that CSF shunting in iNPH patients may improve voluntary postural control and reduce the risk of falling. Impaired voluntary COP control in iNPH patients may reflect the underlying pathophysiological mechanisms of balance disturbance in iNPH. PMID- 29975876 TI - Modeling prognostic factors for poor neurological outcome in conservatively treated patients with intracerebral hemorrhage: A focus on TNF-alpha. AB - OBJECTIVE: Prognostic models for Intracerebral hemorrhage (ICH), mainly based on clinical evaluation, have remained inherently confounded by subjective scoring assessments and limited accuracy. In this study, we aimed at assessing the risk for poor outcome after ICH based on peripheral biochemical markers (TNF-alpha, glutamate and glucose) and radiological variables (both at admission and five days after patient's care), for modeling purposes of prognostication. PATIENTS AND METHODS: The defined initial variables of fifty non-comatose conservatively treated ICH patients without severe complications during the hospitalization process (as intraventricular bleeding, or hematoma expansion) were aligned with the evaluated parameters during re-evaluation (3 months later). A comprehensive statistical approach has been applied by using different modeling strategies for prediction of their functional status and outcome. RESULTS: Higher blood plasma glutamate, TNF-alpha and initial ICH volume at admission, as well as higher volumes of ICH and perihematomal edema after five days of care were significantly more likely associated with the poor outcome. Nevertheless, in all of the constructed models, TNF-alpha was estimated as the only significant predictive risk factor, thus outperforming the capacity of the initial ICH volume and the radiological variables after 5 days, both in terms of prognostication of the functional status and the 3-month neurological outcome. The constructed canonical variable that has fairly marked off the different outcomes was also mainly weighed by the admission TNF-alpha levels. For the first time, we have carefully developed probability functions for the neurological outcome as a response to the admission TNF-alpha levels; TNF-alpha levels >110.35 pg/mL were assessed as an optimal cutoff point fairly identifying patients who will fall into the group with poor outcome. CONCLUSIONS: TNF-alpha based models and admission TNF-alpha screening might be appropriate as a key component that assists more objective prognostication and management of patient's care in clinical decision making, as rapid initial diagnosis and concentrated management are crucial for secondary prevention of further devastating neurological impairments after ICH. PMID- 29975877 TI - Wnt proteins as modulators of synaptic plasticity. AB - Dynamic changes in the structure and function of synapses in response to the environment, termed synaptic plasticity, are the cellular basis of learning and memory. At excitatory synapses, activation of NMDA receptors by glutamate leads to calcium influx triggering intracellular pathways that promote the trafficking of AMPA receptors to the post-synaptic membrane and actin remodeling. New evidence shows that Wnt secreted proteins, known for their role in synapse development, are essential for early stages of long-term potentiation, a form of plasticity that increases synaptic strength. Here, we review recent progress in this area and the significance of Wnt signaling to synaptic plasticity in health and disease. PMID- 29975878 TI - Impact of the Spanish smoking legislation among smokers: A longitudinal study with biomarkers in Barcelona (Spain). AB - BACKGROUND: The aim of this study is to assess the impact of the Spanish tobacco control legislation on smoking behavior and salivary cotinine concentration among smokers. METHODS: We used data from a longitudinal study, before (2004-2005) and after (2013-2014) the implementation of the two national smoking bans (in 2006 and 2011), in a representative sample of adults (>=16 years old) from Barcelona (Spain). We only analyzed a subsample of continuing smokers (n = 116). We conducted a survey on smoking behavior and obtained saliva sample for cotinine analyses. For this report, we analyzed a subsample of continuing smokers (n = 116). We calculated geometric means (GM). RESULTS: Among continuing smokers, salivary cotinine concentration significantly increased by 28.7% (GM from 91.7 ng/ml to 117.3 ng/ml, p = 0.015) after the implementation of the two Spanish smoke-free bans. Nonetheless, no pattern of change was observed in the self reported number of cigarettes smoked daily. CONCLUSIONS: Our study shows a significant increase in the salivary cotinine concentration among adult continuing smokers after both Spanish legislations. This increase could be due to differences in smoking topography (increase in the depth of inhalation when smoking) along with changes in the type of tobacco smoked (increase in smoking roll-your-own cigarettes or mixed use of roll-your-own and manufactured cigarettes). Our results suggest the need to extend tobacco control policies, focusing on the reduction of use of any type of tobacco product and implementing better treatment to help smokers stop smoking. PMID- 29975879 TI - Comparing cigarette and e-cigarette dependence and predicting frequency of smoking and e-cigarette use in dual-users of cigarettes and e-cigarettes. AB - INTRODUCTION: The 4-item Patient-Reported Outcomes Measurement Information System Nicotine Dependence Item Bank is a psychometrically sound measure for assessing cigarette (PROMIS) and e-cigarette dependence (PROMIS-E). We evaluated whether dual-users of cigarettes and e-cigarettes self-report experiencing different levels of dependence on each product. We subsequently examined whether cigarette and e-cigarette dependence are associated with the frequency of using each product in dual-users. METHODS: Dual-users completed an online survey in Summer 2017 (n = 326; 49.7% male, 85.3% White, mean age 38.17 [13.08] years). Measurement invariance of the PROMIS and PROMIS-E was evaluated. Mean differences in cigarette and e-cigarette dependence then were examined. The correlation between cigarette and e-cigarette dependence also was examined. Finally, one-way MANOVA was used to evaluate how cigarette and e-cigarette dependence relate to past-month frequency of e-cigarette use and cigarette smoking. RESULTS: The PROMIS and the PROMIS-E were scalar measurement invariant, and, on average, dual users reported stronger dependence on cigarettes than on e-cigarettes. Cigarette and e-cigarette dependence were related, yet distinct constructs (r = 0.35), suggesting that dual-users can discriminate between dependence on each product. Stronger cigarette dependence predicted more frequent past-month smoking and less frequent past-month vaping. Stronger e-cigarette dependence predicted more frequent past-month vaping and less frequent smoking. CONCLUSIONS: Overall, dual users reported stronger dependence on cigarettes than on e-cigarettes. However, dependence on each product was associated with increased use of each respective product and with less frequent use of the other product. Future research using the PROMIS can evaluate how potential FDA regulations could reduce nicotine dependence across products. PMID- 29975880 TI - Short message service (SMS) reminders improve treatment attendance in alcohol dependence, but are less effective for patients high in impulsivity. AB - BACKGROUND AND AIMS: Poor attendance increases the likelihood of relapse in alcohol dependence treatment. Evidence for improved attendance rates following introduction of short message service (SMS) appointment reminders is available in other health care domains. Patients high in impulsivity, characterized by a lack of planning, may particularly benefit from reminders. The study investigated the impact of SMS reminders on outpatient treatment attendance for alcohol dependence, and whether effects were moderated by impulsivity. DESIGN: Prospective natural history study, with historical case control. Alcohol dependent outpatients attending treatment received SMS appointment reminders (n = 102). These were compared to a historical control group (n = 91) treated prior to the introduction of SMS (totalling 1149 scheduled sessions). SETTING: A metropolitan university hospital alcohol and drug outpatient clinic. PARTICIPANTS: 193 alcohol-dependent patients participated in a 12-week cognitive behavioral therapy (CBT) program with a treatment goal of abstinence. MEASUREMENTS: Trait impulsivity, severity of dependence, psychological distress at baseline. Attendance at each scheduled session. FINDINGS: SMS reminders significantly increased probability of session attendance (0.90 versus 0.84, p = .02). The effect was qualified by a significant SMS x Impulsivity interaction whereby reminders became less effective with increasing patient impulsivity (p = .003). CONCLUSIONS: SMS appointment reminders improve treatment attendance for alcohol-dependent outpatients. More impulsive patients benefited less from reminders, suggesting their non-attendance may be related more to motivational factors. PMID- 29975881 TI - Picomolar sensitive and SNP-selective "Off-On" hairpin genosensor based on structure-tunable redox indicator signals. AB - A robust and sensitive electrochemical assay for chrononocoulometric detection of nucleic acids at a single nucleotide polymorphism (SNP) level has been developed. The assay exploits hybridization-induced conformational switching of gold tethered TP53-specific 33-mer and truncated 20-mer hairpin DNA probes and methylene blue (MB) as an intercalating redox indicator. We show that by fine tuning of MB-DNA intercations the enhanced binding of MB to hybrids formed with a cancer-biomarker sequence can be achieved, and that results in robust "off-on" sensing of hybridization, while the stem-loop probe design allows minimized, independent of the DNA length background signals. Both DNA probes were sensitive to the presence of SNP in the targeted DNA sequence already at 10 pM. DNA levels, and the robust "off-on" discrimination of 10 pM perfectly-matched DNA from 50 nM SNP-containing DNA was achieved by time-adjusted chronocoulometry. This label free hairpin DNA strategy allows systematic design of DNA assays for fast, robust and inexpensive genetic analysis in excessive mixtures of structurally-related DNA sequences and was used for specific analysis of prostate-cancer-realted cellular microRNA in total RNA samples isolated from LNCaP and BPH1 cells. PMID- 29975882 TI - Developmental trajectories of math anxiety during adolescence: Associations with STEM career choice. AB - The purpose of this study was to determine if there were distinct developmental trajectories of math anxiety during adolescence and if these trajectories predicted later STEM career choice. The study also evaluated whether the trajectories varied in relation to gender and race/ethnicity. Data were drawn from Longitudinal Study of American Youth-younger cohort that consisted of 3116 nationally representative sample of 7th grade students (48% Female, 70% European American) that were followed for 7 years. The results revealed four heterogeneous math anxiety trajectory groups: consistently low (34.68%), decreasing (23.72%), increasing (21.90%), and consistently high (20.12%). Trajectories varied with regard to race/ethnicity but not gender. Membership in consistently low or decreasing trajectory predicted later STEM career choice. The findings suggest that preventive interventions may benefit from targeting math anxiety during adolescence. PMID- 29975883 TI - Exergetic performance prediction of solar air heater using MLP, GRNN and RBF models of artificial neural network technique. AB - In the present study three different types of neural models: multi-layer perceptron (MLP), generalized regression neural network (GRNN) and radial basis function (RBF) has been used to predict the exergetic efficiency of roughened solar air heater. The experiments were conducted at NIT Jamshedpur, India, using two different types of absorber plate: arc shape wire rib roughened with relative roughness height 0.0395, relative roughness pitch 10 and angle of attack 60 degrees , and smooth absorber plates for 7 days. Total 210 data sets were collected from the experiments. Mass flow rate, relative humidity, wind speed, ambient air temperature, inlet air temperature, mean air temperature, average plate temperature and solar intensity were selected as input parameters in input layer to estimate the exergetic efficiency. In the first part of study, MLP model has been used. In this model 10-20 neurons with LM learning algorithm were used in hidden layer for optimal model selection. It has been found that LM-18 is an optimal model. In second part, GRNN model was used. The GRNN model was simulated experimentally at different spread constants and found that keeping spread constant as 1.5, optimal results have been obtained. In the third part, RBF model was used. For optimal model, 1-5 spread constant at interval of 0.5 have been used. It has been found that by taking spread constant 3.5, best results are obtained. In the last part of the study, all neural models are compared on the basis of statistical error analysis. It has been found that RBF model is better than GRNN and MLP models due to lowest value of RMSE and MAE and highest value of R2 and ME. After RBF model, GRNN model performs better results as compared to MLP model. It has been found that the values of RMSE, MAE and R2 were 0.001652, 2.86E 04 and 0.99999 respectively for RBF model. PMID- 29975884 TI - Granulated cork as biosorbent for the removal of phenol derivatives and emerging contaminants. AB - This study evaluated the ability of cork to adsorb a broad range of phenolic, pharmaceutical and cosmetic compounds: phenol, 2-chlorophenol, 2-nitrophenol, 2,4 dichlorophenol, pentachlorophenol carbamazepine, naproxen, ketoprofen, diclofenac, triclosan, and methyl paraben. The effect of variables such as the compound concentrations and the amount of cork were studied resulting in a highly pH dependence in the case of phenolic compounds. Maximum removal percentages and uptake values of 75% (1.61 mg/g) for 2,4-dichlorophenol, 55% (1.25 mg/g) for 2 nitrophenol, 45% (1.47 mg/g) for 2-chlorophenol, 20% (0.63 mg/g) for phenol, and 100% for pentachlorophenol, were obtained for a 30 mg L-1 solution at pH 6, showing that the adsorption process increased with greater electronegativity of the phenolic substituting group. Removal percentages and uptakes of 82% (3.56 mg/g) for naproxen, 57% (2.31 mg/g) for ketoprofen, 50% (1.84 mg/g) for carbamazepine, 50% (1.78 mg/g) for methyl paraben, 100% for sodium diclofenac, and 100% for triclosan, were obtained using 5 mg of cork and a 1 mg L-1 solution of each compound. The adsorption process was almost complete after 30 min for all the micropollutants. Experimental equilibrium data were analysed by Freundlich and Langmuir adsorption models. Cork has proved to be an effective sorbent for the removal of phenols and emerging contaminants from contaminated waters and is a readily available material that can be acquired at minimal or no cost in cork producing areas. PMID- 29975885 TI - Review - Bacteria and their extracellular polymeric substances causing biofouling on seawater reverse osmosis desalination membranes. AB - Biofouling in seawater reverse osmosis (SWRO) membranes is a critical issue faced by the desalination industry worldwide. The major cause of biofouling is the irreversible attachment of recalcitrant biofilms formed by bacteria and their extracellular polymeric substances (EPS) on membrane surfaces. Transparent exopolymer particles (TEP) and protobiofilms are recently identified as important precursors of membrane fouling. Despite considerable amount of research on SWRO biofouling, the control of biofouling still remains a challenge. While adoption of better pretreatment methods may help in preventing membrane biofouling in new desalination setups, it is also crucial to effectively disperse old, recalcitrant biofilms and prolong membrane life in operational plants. Most current practices employ the use of broad spectrum biocides and chemicals that target bacterial cells to disperse mature biofilms, which are evidently inefficient. EPS, being known as the strongest structural framework of biofilms, it is essential to breakdown and disintegrate the EPS components for effective biofilm removal. To achieve this, it is necessary to understand the chemical composition and key elements that constitute the EPS of major biofouling bacterial groups in multi species, mature biofilms. However, significant gaps in understanding the complexity of EPS are evident by the failure to achieve effective prevention and mitigation of fouling in most cases. Some of the reasons may be difficulty in sampling membranes from fully operational full-scale plants, poor understanding of microbial communities and their ecological shifts under dynamic operational conditions within the desalination process, selection of inappropriate model species for laboratory-scale biofouling studies, and the laborious process of extraction and purification of EPS. This article reviews the novel findings on key aspects of SWRO membrane fouling and control measures with particular emphasis on the key sugars in EPS. As a novel strategy to alleviate biofouling, future control methods may be aimed towards specifically disintegrating and breaking down these key sugars rather than using broad spectrum chemicals such as biocides that are currently used in the industry. PMID- 29975886 TI - Development and evaluation of MTLSER and QSAR models for predicting polyethylene water partition coefficients. AB - Current study was aimed to make further improvements in measuring low density polyethylene (LDPE) -water partition coefficient (KPE-w) for organic chemicals. Modified theoretical linear solvation energy relationship (MTLSER) model and quantitative structure activity relationship (QSAR) model were developed for predicting KPE-w values from chemical descriptors. With the MTLSER model, alpha (average molecular polarizability), MU (dipole moment) and q- (net charge of the most negative atoms) as significant variables were screened. With the QSAR model, main control factors of KPE-w values, such as CrippenLogP (Crippen octanol-water partition coefficient), CIC0 (neighborhood symmetry of 0-order) and GATS2p (Geary autocorrelation-lag2/weighted by polarizabilities) were studied. As per our best knowledge, this is the first attempt to predict polymer-water partition coefficient using the MTLSER model. Statistical parameters, correlation coefficient (R2) and cross-validation coefficients (Q2) were ranging from 0.811 to 0.951 and 0.761 to 0.949, respectively, which indicated that the models appropriately fit the results, and also showed robustness and predictive capacity. Mechanism interpretation suggested that the main factors governing the partition process between LDPE and water were the molecular polarizability and hydrophobicity. The results of this study provide an excellent tool for predicting log KPE-w values of most common hydrophobic organic compounds, within the applicability domains to reduce experimental cost and time for innovation. PMID- 29975887 TI - Efficiency of various sewage sludges and their biochars in improving selected soil properties and growth of wheat (Triticum aestivum). AB - Due to increasing demand of P fertilizers and gradual decrease in P resources, recyclable P is the focus of researchers in recent years. Sewage sludge (SS) is a municipal waste that contains appreciable amounts of P and probably other nutrients. In present study, the effects of various SS and their biochars (450 degrees C for 2 h) were investigated on soil properties and P uptake in wheat (Triticum aestivum) with and without P fertilizer. The biomass of plants and grain yield were significantly increased with application of SS and their biochars as compared to the control treatment either without or with P application. Moreover, there was significant interaction between treatments and P application for the concentration of K, and P in shoots and roots of wheat. Shoot P concentration was not significantly affected with SS than biochars whereas root P concentration was higher in SS treatments than respective biochars. Higher increase in Olsen's P concentration was observed in populated area sludge applied soil as compared to disposal sludge and their biochars. Overall, it is observed that SS application increased the wheat yield and P concentrations in plants than control depending upon SS types whereas biochar application decreased the P concentration in roots. Grain yield and P concentration in shoots were not significantly affected for the treatment with P fertilizers than without P. Sewage sludge and their biochars might be a potential source of P but further research is needed to recommend the use of modified SS-biochars as source of available P for crops. PMID- 29975888 TI - Effects of soil erosion on agro-ecosystem services and soil functions: A multidisciplinary study in nineteen organically farmed European and Turkish vineyards. AB - This multidisciplinary research work evaluated the effects of soil erosion on grape yield and quality and on different soil functions, namely water and nutrient supply, carbon sequestration, organic matter recycling, and soil biodiversity, with the aim to understand the causes of soil malfunctioning and work out a proper strategy of soil remediation. Degraded areas in nineteen organically farmed European and Turkish vineyards resulted in producing significantly lower amounts of grapes and excessive concentrations of sugar. Plants suffered from decreased water nutrition, due to shallower rooting depth, compaction, and reduced available water capacity, lower chemical fertility, as total nitrogen and cation exchange capacity, and higher concentration of carbonates. Carbon storage and organic matter recycling were also depressed. The general trend of soil enzyme activity mainly followed organic matter stock. Specific enzymatic activities suggested that in degraded soils, alongside a general slowdown in organic matter cycling, there was a greater reduction in decomposition capacity of the most recalcitrant forms. The abundance of Acari Oribatida and Collembola resulted the most sensitive indicator of soil degradation among the considered microarthropods. No clear difference in overall microbial richness and evenness were observed. All indices were relatively high and indicative of rich occurrence of many and rare microbial species. Dice cluster analyses indicated slight qualitative differences in Eubacterial and fungal community compositions in rhizosphere soil and roots in degraded soils. This multidisciplinary study indicates that the loss of soil fertility caused by excessive earth movement before planting, or accelerated erosion, mainly affects water nutrition and chemical fertility. Biological soil fertility is also reduced, in particular the ability of biota to decompose organic matter, while biodiversity is less affected, probably because of the organic management. Therefore, the restoration of the eroded soils requires site-specific and intensive treatments, including accurately chosen organic matrices for fertilization, privileging the most easily decomposable. Restoring soil fertility in depth, however, remain an open question, which needs further investigation. PMID- 29975889 TI - The environmental impact of dairy production on poorly drained soils under future climate scenarios for Ireland. AB - The environmental impact of dairy production in Ireland has been widely studied and it is known that regional differences in management and impact are driven by climate. Climate change projections for Ireland predict increasing temperature, change in rainfall patterns and decreasing in solar radiation, varying by agroclimatic region. This study evaluated the environmental impacts of low-cost, grass-based, rotational-grazing dairy production on poorly drained soils under climate change. The Dairy_sim model was used to determine the theoretical optimum dairy system management for five different locations in Ireland assuming a poorly drained soil resource under baseline (1981-2000) and future climate scenarios (2041-2060, high and low emissions scenarios). An optimum system was defined as having maximum grass production and grazed grass in the diet, minimum necessary silage, minimum imported feed, minimum housing days and a very small silage surplus. Life cycle assessment was then used to quantify the environmental impacts (climate change, eutrophication and acidification) for all scenarios. The dairy production systems were predicted to be more productive in the future, with climate change impacts per unit milk reduced or the same, acidification impacts reduced and eutrophication impacts reduced. The absolute emissions driving climate change and eutrophication were predicted to significantly increase for the future low emission scenario, and emissions driving acidification were predicted to slightly increase. The predictions indicate that system adaptation to mitigate absolute emissions are needed rather than just policies that focus on impacts per unit output. PMID- 29975890 TI - Implementation of an automated beach water quality nowcast system at ten California oceanic beaches. AB - Fecal indicator bacteria like Escherichia coli and entercococci are monitored at beaches around the world to reduce incidence of recreational waterborne illness. Measurements are usually made weekly, but FIB concentrations can exhibit extreme variability, fluctuating at shorter periods. The result is that water quality has likely changed by the time data are provided to beachgoers. Here, we present an automated water quality prediction system (called the nowcast system) that is capable of providing daily predictions of water quality for numerous beaches. We created nowcast models for 10 California beaches using weather, oceanographic, and other environmental variables as input to tuned regression models to predict if FIB concentrations were above single sample water quality standards. Rainfall was used as a variable in nearly every model. The models were calibrated and validated using historical data. Subsequently, models were implemented during the 2017 swim season in collaboration with local beach managers. During the 2017 swim season, the median sensitivity of the nowcast models was 0.5 compared to 0 for the current method of using day-to-week old measurements to make beach posting decisions. Model specificity was also high (median of 0.87). During the implementation phase, nowcast models provided an average of 140 additional days per beach of updated water quality information to managers when water quality measurements were not made. The work presented herein emphasizes that a one-size fits all approach to nowcast modeling, even when beaches are in close proximity, is infeasible. Flexibility in modeling approaches and adaptive responses to modeling and data challenges are required when implementing nowcast models for beach management. PMID- 29975891 TI - Enhancing biomethanation from dairy waste activated biomass using a novel EGTA mediated microwave disintegration. AB - A novel approach to explore the impact of calcium specific chelant - Ethylene glycol tetra acetic acid (EGTA) on deflocculation followed by biomass disintegration using microwave (MW) was investigated. In the first phase of the study, the EGTA dosage of 0.012 g/g suspended solids (SS) was found to be optimal for disassociating the biomass. Subsequent disintegration of biomass in microwave (EGTA-MW) yielded a biomass lysis and solids reduction of about 39.7% and 30.5%. EGTA-MW disintegration reduces the amount of specific energy required to disintegrate the biomass from 18,900 kJ/kg TS to 13,500 kJ/kg TS, when compared to control. The impact of EGTA-MW disintegration on anaerobic digestion was also evident from its methane yield (235.3 mL/g VS) which was 36.2% higher than control. An economic assessment of this study provides a net profit of 8.48 ?/ton in EGTA-MW and highly endorsed for biomass disintegration. PMID- 29975892 TI - Recovery of sulfuric acid aqueous solution from copper-refining sulfuric acid wastewater using nanofiltration membrane process. AB - We used a nanofiltration (NF) membrane process to produce purified aqueous sulfuric acid from copper-refining sulfuric acid wastewater. Wastewater generated from a copper-refining process was used to explore the membrane performances and acid stabilities of six commercial NF membranes. A combination of permeate flux, sulfate permeation, and metal ion rejection clearly showed that two polyamide membranes and a polyacrylonitrile-based membrane achieved recovery of a purified sulfuric acid solution. Acid-stability and long-term performance tests showed that the polyamide membranes were unsuitable for copper-refining wastewater treatment because of their low acid stabilities. In contrast, the polyacrylonitrile-based composite membrane showed excellent acid stability, and gave greater than 90% metal ion rejection, with the exception of calcium ions, for 430 d. We also evaluated the recovery performance in 1 ton/d pilot-scale process using wastewater from copper-refining process; 90% metal ion rejection was achieved, with the exception of calcium ions, even at 95% recovery rate. PMID- 29975893 TI - Identification of urban drinking water supply patterns across 627 cities in China based on supervised and unsupervised statistical learning. AB - Urbanization, one of the predominant trends of the 21st century, places great stress on urban water supply networks. This paper aimed to identify the most important variables driving urban water supply patterns in China, a region which has seen rapid urban growth in the last few decades. In addition, a principal component analysis-informed urban water sustainability index was developed in order to benchmark cities. The research involved applying statistical learning and other analytical methods to 12 years of urban water supply data for 627 cities across China. The findings were as follows: (1) PCA showed that approximately 46.8% of variability in the data could be explained by two principal components. Component 1 (37.26%) was more closely associated with variables related to water supply and sale, supply pipelines, and water supply finance. C2 (9.51%) was clearly related to urban water prices and average per capita water use. (2) Random forest and XGBoost algorithms were effective in classifying cities according to their region, with model testing accuracies of 87.69% and 88.32% respectively. (3) Chinese cities have consistently suffered water loss/leakage rates above 20% since 2001, and water prices are closely associated with leakage. (4) China's urban water sustainability has increased by just 3.56% between 2001 and 2013; Southwest China saw the highest growth rate in urban water supply sustainability. The implications of our research effort will be useful for decision makers in water-stressed urban areas around the world who are seeking novel insights in how to leverage statistical learning techniques to gain insights into urban drinking water supply patterns. PMID- 29975894 TI - How to improve threatened species management: An Australian perspective. AB - Targeted threatened species management is a central component of efforts to prevent species extinction. Despite the development of a range of management frameworks to improve conservation outcomes over the past decade, threatened species management is still commonly characterised as ad hoc. Although there are notable successes, many management programs are ineffective, with relatively few species experiencing improvements in their conservation status. We identify underlying factors that commonly lead to ineffective and inefficient management. Drawing attention to some of the key challenges, and suggesting ways forward, may lead to improved management effectiveness and better conservation outcomes. We highlight six key areas where improvements are needed: 1) stakeholder engagement and communication; 2) fostering strong leadership and the development of achievable long-term goals; 3) knowledge of target species' biology and threats, particularly focusing on filling knowledge gaps that impede management, while noting that in many cases there will be a need for conservation management to proceed initially despite knowledge gaps; 4) setting objectives with measurable outcomes; 5) strategic monitoring to evaluate management effectiveness; and 6) greater accountability for species declines and failure to recover species to ensure timely action and guard against complacency. We demonstrate the importance of these six key areas by providing examples of innovative approaches leading to successful species management. We also discuss overarching factors outside the realm of management influence that can help or impede conservation success. Clear recognition of factors that make species' management more straightforward - or more challenging - is important for setting realistic management objectives, outlining strategic action, and prioritising resources. We also highlight the need to more clearly demonstrate the benefit of current investment, and communicate that the risk of under-investment is species extinctions. Together, improvements in conservation practice, along with increased resource allocation and re-evaluation of the prioritisation of competing interests that threaten species, will help enhance conservation outcomes for threatened species. PMID- 29975895 TI - Holistic water quality dynamics in rural artificial shallow water bodies. AB - The water environment in diversely used rural artificial water bodies is generally varied with seasonal and diurnal changes, stability of which is significant in water resources management. Understanding of interaction among different water quality parameters that depend on their diurnal variations is the concern of this study. A rural homestead pond used for aquaculture in Bangladesh and a micro-dam used as an irrigation tank for paddy farming in Japan are chosen for contrasting the analysis of data. The observed data series of four typical water quality parameters exhibits the diurnal variations, which are primarily inferred to be driven by solar radiation and complex bio-chemical interactions. The study proposes a stochastic differential equation model to represent holistic water quality dynamics based on continuous measurements. The water quality parameters are considered as temporally continuous Markov process, where their individual effects on each parameter are evaluated in a specific time step and immediately reflected to the next observation. The model parameters are calibrated and the stability is discussed based on the eigenvalues of model parameters. The result mostly shows the mean reverting properties for dissolved oxygen and water temperature, while pH and oxidation reduction potential are rather depend on other parameters or external disturbance. PMID- 29975896 TI - Flood susceptibility in rural settlements in remote zones: The case of a mountainous basin in the Sierra-Costa region of Michoacan, Mexico. AB - Maps of natural hazards are essential for the prevention or mitigation of disasters. The Nexpa River mountainous basin is in the Sierra-Costa region of the state of Michoacan, Mexico. The dispersed rural settlements in the basin, accessed through a network of mainly minor roads and tracks, are highly vulnerable in cases of catastrophic hydrometeorological events. Our study aimed to map flood zones and assess flood susceptibility in the basin on the basis of geopedology, topography, land cover and land use, to assess the vulnerability of local rural settlements and their network of roads and tracks. The land morphology was mapped and the weighted overlay technique was applied in a geographic information system to generate maps of susceptibility to flooding. Our results showed that 13% of settlements and 7% of the communication network are within flood zones. Maps based on environmental factors showed low to medium susceptibility to flooding. These methods are useful and effective for zones with little or no hydrometeorological information, and they can provide a robust source of information for decision makers regarding land planning to mitigate flood vulnerability. PMID- 29975897 TI - The case of conflicting Finnish peatland management - Skewed representation of nature, participation and policy instruments. AB - Peatlands that are close to a natural state are rich in biodiversity and are significant carbon storages. Simultaneously, peat resources are of interest to industry, which leads to competing interests and tensions regarding the use and management of peatlands. In this case study, we studied knowledge-management interactions through the development of participation and the resulting representation of nature (how nature was described), as well as the proposed and implemented conservation policy instruments. We focused on the years 2009-2015, when peatland management was intensively debated in Finland. We did an interpretative policy analysis using policy documents (Peatland Strategy; Government Resolution; Proposal for Conservation Programme) and environmental legislation as central data. Our results show how the representation of nature reflected the purpose of the documents and consensus of participants' values. The representation of nature changed from skewed use of ecosystem services to detailed ecological knowledge. However, simultaneously, political power changed and the planned supplementation programme for peatland conservation was not implemented. The Environment Protection Act was reformulated so that it prohibited the use of the most valuable peatlands. Landowners did not have the chance to fully participate in the policy process. Overall, the conservation policy instruments changed to emphasize voluntariness but without an adequate budget to ensure sufficient conservation. PMID- 29975898 TI - Combined effects of polyacrylamide and nanomagnetite amendment on soil and water quality, Khorasan Razavi, Iran. AB - Nanotechnology is increasingly being used to remediate polluted soil and water. However, few studies are available assessing the potential of nanoparticles to bind surface particles, decrease erosion, and minimize the loading of water pollutants from agricultural surface discharge. To investigate this potential, we treated in situ field plots with two practical surface application levels of anionic polyacrylamide (PAM only) with and without nanomagnetite (PAM-NM), examined soil physical properties, and evaluated the impact of this amendment on contaminant sorption and soil erosion control. Polyacrylamide and PAM-NM treatments resulted in 32.2 and 151.9 fold reductions in Mn2+, 1.8 and 2.7 fold for PO43--P, and 2.3 and 1.6 fold for NH4+-N, respectively, compared to the control. Thus, we found that the combination of PAM and NM, had an important inhibitory effect on NH4+-N and PO43--P transport from soil-pollutants which can contribute substantially to the eutrophication of surface water bodies. Additionally, since the treatment, especially at a high concentration of NM, was effective at reducing Mn2+concentrations in the runoff water, the combination of PAM and NM may be important for mitigating potential risks associated with Mn2+ toxicity. Average sediment contents in the runoff monitored during the rainfall simulation were reduced by 3.6 and 4.2 fold for the low and high concentration PAM-NM treatments when compared to a control. This treatment was only slightly less effective than the PAM-only applications (4.9 and 5.9 fold, respectively). We report similar findings for turbidity of the runoff (2.6-3.3 fold for PAM only and 1.8-2.3 fold for PAM-NM) which was caused by the effects of both PAM and NM on the binding of surface particles corresponding to an increase in aggregate size and stability. Findings from this field-based study show that PAM-modified NM adsorbents can be used to both inhibit erosion and control contaminant transport. PMID- 29975899 TI - Response of carbon uptake to abiotic and biotic drivers in an intensively managed Lei bamboo forest. AB - Lei bamboo (Phyllostachys praecox) is widely distributed in southeastern China. We used eddy covariance to analyze carbon sequestration capacity of a Lei bamboo forest (2011-2013) and to identify the seasonal biotic and abiotic determinants of carbon fluxes. A machine learning algorithm called random forest (RF) was used to identify factors that affected carbon fluxes. The RF model predicted well the gross ecosystem productivity (GEP), ecosystem respiration (RE) and net ecosystem exchange (NEE), and displayed variations in the drivers between different seasons. Mean annual NEE, RE, and GEP were -105.2 +/- 23.1, 1264.5 +/- 45.2, and 1369.6 +/- 52.5 g C m-2, respectively. Climate warming increased RE more than GEP when water inputs were not limiting. Summer drought played little role in suppressing GEP, but low soil moisture contents suppressed RE and increased the carbon sink during drought in the summer. The most important drivers of NEE were soil temperature in spring, summer, and winter, and photosynthetically active radiation in autumn. Air and soil temperature were important drivers of GEP in all seasons. PMID- 29975900 TI - Manganese and iron recovery from groundwater treatment sludge by reductive acid leaching and hydroxide precipitation. AB - In this study, the recovery of manganese (Mn) and iron (Fe) from groundwater treatment sludge through reductive acid leaching and hydroxide precipitation was investigated. Maximum leached Mn (100%) was obtained using sulfuric acid and hydrogen peroxide at 25 degrees C. Leached Mn and Fe decreased with the increase in the solid-liquid ratio. Leaching time had minimal effect on Mn and Fe leaching beyond 5 min, while agitation rate had minimal effect beyond 150 rpm. At 25 degrees C, the rate-limiting step of Mn leaching was diffusion through inert solid components of the sludge, composed mainly of insoluble sand particles. Fe leaching was governed by diffusion through the insoluble components of the sludge, including the unreacted manganese dioxide (MnO2). Maximum precipitation of Fe and separation from Mn in the leachate through addition of potassium hydroxide occurred at pH 4.0. The results demonstrated that reductive acid leaching and hydroxide precipitation is an effective means of recovering Mn and Fe from groundwater treatment sludge. The applicability of the recovered Mn for nickel ion removal from aqueous solution was also explored in the study. Highest nickel ion uptake by the MnO2 synthesized from the recovered Mn was at 111.67 mg g-1, even exceeding the adsorption capacities of previously studied nickel adsorbents. PMID- 29975901 TI - Development and characterization of iron-pectin beads as a novel system for iron delivery to intestinal cells. AB - Iron deficiency is the most common nutritional deficit worldwide. The goal of this work was to obtain iron-pectin beads by ionic gelation and evaluate their physiological behavior to support their potential application in the food industry. The beads were firstly analyzed by scanning electronic microscopy, and then physical-chemically characterized by performing swelling, thermogravimetric, porosimetry, Mossbauer spectroscopy and X-ray fluorescence analyses, as well as by determining the particle size. Then, physiological assays were carried out by exposing the beads to simulated gastric and intestinal environments, and determining the iron absorption and transepithelial transport into Caco-2/TC7 cells. Iron-pectin beads were spherical (diameter 1-2 mm), with high density (1.29 g/mL) and porosity (93.28%) at low pressure, indicating their high permeability even when exposed to low pressure. Swelling in simulated intestinal medium (pH 8) was higher than in simulated gastric medium. The source of iron [FeSO4 (control) or iron-pectin beads] did not have any significant effect on the mineral absorption. Regarding transport, the iron added to the apical pole of Caco-2/TC7 monolayers was recovered in the basal compartment, and this was proportional with the exposure time. After 4 h of incubation, the transport of iron arising from the beads was significantly higher than that of the iron from the control (FeSO4). For this reason, iron-pectin beads appear as an interesting system to overcome the low efficiency of iron transport, being a potential strategy to enrich food products with iron, without altering the sensory properties. PMID- 29975902 TI - Diamond nanoparticles suppress lateral growth of bacterial colonies. AB - Diamond nanoparticles (DNPs) of various types have been recently reported to possess antibacterial properties. Studies have shown a decrease of the colony forming ability on agar plates of the bacteria that had been previously co incubated with DNPs in the suspension. Before plating, bacteria with DNPs were adequately diluted in order to obtain a suitable number of colony forming units. However, residual DNPs were still present on an agar plate, concentrated on the surface during the plating process; this introduces a potential artifact which might affect colony growth. The effect of DNPs remaining on the surface, alongside growing bacteria, has not been previously investigated. In this work, we present the experiments designed to investigate the effect of DNPs on bacterial survival and on the growth of the bacterial colony on a solid media. We employed Escherichia coli and Bacillus subtilis as models of Gram-negative and Gram-positive bacteria, respectively, and Proteus mirabilis as a model of bacterium exhibiting swarming motility on the surfaces. We analyzed the number, area, and weight of bacterial colonies grown on the agar surface covered with DNPs. We did not observe any bactericidal effect of such applied DNPs. However, in all bacterial species used in this work, we observed the appreciable reduction of colony area, which suggests that DNPs obstruct either bacterial growth or motility. The most obvious effect on colony growth was observed in the case of motile P. mirabilis. We show that DNPs act as the mechanical barrier blocking the lateral colony growth. PMID- 29975903 TI - Immobilization of trypsin onto Fe3O4@SiO2 -NH2 and study of its activity and stability. AB - The preparation of biocatalysts based on immobilized trypsin is of great importance for proteomic research, industrial applications and organic synthesis. Here in, we have developed a facile method to immobilize trypsin on magnetic nanoparticles. Fe3O4 nanoparticles were synthesized by co-precipitating Fe2+and Fe3+in an ammonia solution and then coated by silicon dioxides were developed by sol-gel method. The silica-coated Fe3O4 nanoparticles were further modified with 3-aminopropyltriethoxysilane, resulting in attaching of primary amine groups on the surface of the particles. Trypsin from porcine pancrease was then immobilized on the magnetic core-shell particles by using glutaraldehyde as a cross-linker. The synthesis steps and characterizations of immobilized trypsin were examined by FT-IR, XRD, TGA, EDX and SEM. The results showed that the enzyme immobilization increased the enzyme activity in different pHs and temperatures, without any changes in the optimum pH and temperature for enzyme activity. The Kinetic results showed that the enzyme immobilization decreased and increased Vmax and Km values, respectively. The stability results showed that the enzyme immobilization improved trypsin thermostability in the absence and presence of 10% (v/v) of the used solvents (DMF, THF, DMSO, ACN and 1, 4-Dioxane). The reusability results indicated that the immobilized enzyme maintained 85% of its activity after 6 periods of activity. PMID- 29975904 TI - Highly dispersed lithium doped mesoporous silica nanospheres regulating adhesion, proliferation, morphology, ALP activity and osteogenesis related gene expressions of BMSCs. AB - Lithium (Li) doped mesoporous silica nanospheres (LMSNs) were synthesized by incorporation of 5 wt% Li into mesoporous silica nanospheres (MSNs) using sol-gel method. The results showed that LMSNs with a mean size of approximate 300 nm exhibited uniform and highly dispersed spherical morphology, which was similar to the morphology of MSNs. Moreover, the degradability of MSNs was significantly increased after the incorporation of Li, and LMSNs could release both silicon (Si) and Li ions in a sustained manner. Due to the release of Li ions, LMSNs showed higher stimulatory effects on the attachment and proliferation of bone marrow mesenchymal stem cells (BMSCs) than MSNs. In addition, LMSNs could also enhance the ALP activity of BMSCs as well as improving osteogenesis related genes (OPN, ALP, Runx2 and OCN) expression of BMSCs. In summary, LMSNs have shown the capability of being a carrier of biologically active ions, which exhibit great potential in bone repair/regeneration applications. PMID- 29975905 TI - Fractal properties of biophysical models of pericellular brushes can be used to differentiate between cancerous and normal cervical epithelial cells. AB - Fractal behavior is found on the topographies of pericellular brushes on the surfaces of model healthy and cancerous cells, using dissipative particle dynamics models and simulations. The influence of brush composition, chain stiffness and solvent quality on the fractal dimension is studied in detail. Since fractal dimension alone cannot guarantee that the brushes possess fractal properties, their lacunarity was obtained also, which is a measure of the space filling capability of fractal objects. Soft polydisperse brushes are found to have larger fractal dimension than soft monodisperse ones, under poor solvent conditions, in agreement with recent experiments on dried cancerous and healthy human cervical epithelial cells. Additionally, we find that image resolution is critical for the accurate assessment of differences between images from different cells. The images of the brushes on healthy model cells are found to be more textured than those of brushes on model cancerous cells, as indicated by the larger lacunarity of the former. These findings are helpful to distinguish monofractal behavior from multifractality, which has been found to be useful to discriminate between immortal, cancerous and normal cells in recent experiments. PMID- 29975906 TI - Investigation of different core-shell toward Janus morphologies by variation of surfactant and feeding composition: A study on the kinetics of DOX release. AB - Composite particles with two individual hydrophilic parts were synthesized via seeded emulsion polymerization. As first part, nearly-monodisperse ethylene glycol dimethacrylate (EGDMA)-crosslinked poly(acrylic acid) (PAA) particles were synthesized by distillation precipitation polymerization (DPP). These particles were used as seeds in emulsion polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA). Effects of type of surfactant, monomers/seed weight ratio and amount of shell crosslinker on the synthesized composite particles' morphology were studied. Different morphologies consisting of core-shell, Janus type, raspberry-like and porous core-shell structures were investigated by variations of polymerization parameters. Different structures were chosen as drug carriers and subjected to DOX loading and release system. Results showed that amount of drug loading and extent of release were strongly dependent on the structure of carriers whereas for all carriers, DOX was released more rapid. Kinetics of release was evaluated by different mathematical models to investigate the release mechanism through composite particles. Results showed that only Korsmeyer-Peppas model fitted the drug release data and other ones were inappropriate in this field. PMID- 29975907 TI - Reusable anionic sulfonate functionalized nanofibrous membranes for cellulase enzyme adsorption and separation. AB - Poly (vinyl alcohol-co-ethylene) nanofibrous membranes (PVA-co-PE NFM) were successfully modified by sodium-3-sulfobenzoate to become negatively charged with sulfonate groups, and the sulfonated (PVA-co-PE) nanofiber membrane SS (PVA-co-PE NFM) was used in non-covalent adsorption of cellulases via electrostatic attraction. The modified NFM showed excellent adsorption to the enzyme molecules due to the incorporated static charge interaction with the fibers, high open porosity and ultrahigh surface areas of the nanofibers. Such unique morphology and chemical structures lead to the adsorption capacity of 130 mg g-1 and reusability for 5 cycles without significant change in catalytic functions. The morphology changes of the nanofibrous membranes were observed by using a scanning electron microscopy, and chemical structures of the membranes were characterized by using FTIR and water contact angle measurements. SS (PVA-co-PE NFM) is a promising solid support media for enzyme immobilization, and the immobilized enzymes can be applied in industrial applications. PMID- 29975908 TI - Bacterial cellulose hydrogel loaded with lipid nanoparticles for localized cancer treatment. AB - The use of hybrid materials, where a matrix sustains nanoparticles controlling the release of the chemotherapeutic drug, could be beneficial for the treatment of primary tumors prior or after surgery. This localized chemotherapy would guarantee high drug concentrations at the tumor site while precluding systemic drug exposure minimizing undesirable side effects. We combined bacterial cellulose hydrogel (BC) and nanostructured lipid carriers (NLCs) including doxorubicin (Dox) as a drug model. NLCs loaded with cationic Dox (NLCs-H) or neutral Dox (NLCs-N) were fully characterized and their cell internalization and cytotoxic efficacy were evaluated in vitro against MDA-MB-231 cells. Thereafter, a fixed combination of NLCs-H and NLCs-N loaded into BC (BC-NLCs-NH) was assayed in vivo into an orthotopic breast cancer mouse model. NLCs-H showed low encapsulation efficiency (48%) and fast release of the drug while NLCs-N showed higher encapsulation (97%) and sustained drug release. Both NLCs internalized via endocytic pathway, while allowing a sustained release of the Dox, which in turn rendered IC50 values below of those of free Dox. Taking advantage of the differential drug release, a mixture of NLCs-N and NLCs-H was encapsulated into BC matrix (BC-NLCs-NH) and assayed in vivo, showing a significant reduction of tumor growth, metastasis incidence and local drug toxicities. PMID- 29975909 TI - Soft nanoparticles charge expression within lipid membranes: The case of amino terminated dendrimers in bilayers vesicles. AB - Interactions of charged nanoparticles with model bio-membranes provide important insights about the soft interaction involved and the physico-chemical parameters that influence lipid bilayers stability, thus providing key features of their cytotoxicity effects onto cellular membranes. With this aim, the self-assembly processes between polyamidoamine dendrimers (generation G = 2.0 and G = 4.0) and dipalmitoylphosphatidylcholine (DPPC) lipids were investigated by means of Zeta potential analysis, x-rays, Raman and quasielastic light scattering experiments. Raman scattering data evidenced that dendrimers penetration produce a perturbation of the DPPC vesicles alkyl chains. A linear increase of liposome zeta-potential with increasing PAMAM concentration evidenced that only a fraction of the dendrimers effective charge contributes to the expression of the charge at the surface of the DPPC liposome. The linear region of the zeta-potential extends toward higher PAMAM concentrations as the dendrimer generation decreases from G = 4.0 to G = 2.0. Further increase in PAMAM concentration, outside of the linear region, causes a perturbation of the bilayer characterized by the loss in multilamellar correlation and the increase of DPPC liposome hydrodynamic radius. The findings of our investigation help to rationalize the effect of nanoparticles electrostatic interaction within lipid vesicles as well as to provide important insights about the perturbation of lipid bilayers membrane induced by nanoparticles inclusion. PMID- 29975910 TI - Fabrication of tannic acid/poly(N-vinylpyrrolidone) layer-by-layer coating on Mg based metallic glass for nerve tissue regeneration application. AB - For improving recovery rates and functional outcomes in large nerve defects, a nerve guide conduit, in addition to topographic, physical and chemical cues should provide contact guidance and adequate mechanical support for cell migration and axon outgrowth. Among biomaterials, magnesium (Mg) metal has potential to support nerve regeneration owing to its electrical conductivity, biodegradation and ability to be formed into wires, filaments and ribbons. However, rapid degradation of magnesium can pose a challenge. Mg-based metallic glasses with desirable features including favorable biocompatibility, proper biodegradation and good mechanical properties are a good alternative to crystalline Mg alloys. This study investigates the biocorrosion and biocompatibility of Mg-Zn-Ca metallic glass ribbon with Mg70Zn26Ca4 composition. For controlling biocorrosion, layer-by-layer coating of tannic acid/ poly(N vinylpyrrolidone) was applied on Mg70Zn26Ca4 ribbon and characterized by SEM and FTIR. Immersion and potentiodynamic polarization test results indicated that coating significantly improved the corrosion resistance of Mg70Zn26Ca4. Schwann cells were selected for the cytocompatibility evaluation of samples due to their key role in peripheral nerve regeneration and ability to repair spinal cord injuries. The MTT assay and cell morphology results showed good biocompatibility for Mg70Zn26Ca4 metallic glass as a promising candidate for nerve regeneration and implantable nervous prosthetic devices. PMID- 29975911 TI - Perceptible isotopic effect in 3D-framework of alpha-glycine at low temperatures. AB - Glycine, the most fundamental amino acid, albeit studied for many decades, has kept researchers captivated with interesting structural variations relevant to important biological, astrophysical and technological applications. We report here a noticeable effect of deuteration on the three dimensional hydrogen bonding network of alpha-glycine using low temperature infrared absorption studies in a wide spectral range, corroborated with Raman scattering studies. These systematic studies in the range 300-4.2 K have demonstrated a relatively compact assembly of glycine molecules in the three dimensional bilayered structure of hydrogenated glycine (gly-h) at low temperatures. This is inferred from a remarkable temperature effect in the weak intra-bilayer hydrogen bond ~ along the b-axis, which strengthens upon cooling. A pronounced increase in the intensity of NH3 torsional and NH stretching modes has been observed. This is accompanied with a large rate of stiffening and softening respectively of these modes upon cooling and a change in slope across 210 K and 80 K. In contrast, the D---O hydrogen bond lengths in fully deuterated isotope (gly-d), as estimated using empirical correlation, show that the weak intra-bilayer hydrogen bond is not strengthened upon cooling down to 180 K, whereas the stronger intra-layer hydrogen bonds in the ac-plane become further strong. The ND3 torsional vibrations show no temperature effect. This implies a relatively stable two dimensional layered structure formed by strongly hydrogen bonded glycine sheets in the ac-plane. Below 180 K, similar qualitative trends have been obtained for the hydrogen bond lengths in the two isotopes. In addition, temperature induced variation of the characteristic "indicator" band of zwitterionic gly-h and gly-d has also been reported. PMID- 29975912 TI - Spectroscopic properties analyses and laser characterization simulation of Er3+,Eu3+:YAP single crystal. AB - Er,Eu:YAlO3 (abbr. as Er,Eu:YAP) crystal was grown by the Czochralski technique for the first time. Its absorption and fluorescence spectra as well as the fluorescence decay curves were measured and investigated. The spectral parameters including absorption cross-section and emission cross-section were calculated. It is found that the crystal has short lifetimes at 4I13/2 and 4I11/2 levels, large absorption cross-section at 974 nm and 790 nm, and large stimulated emission cross-section at 2704 nm. The co-dopant Eu3+ decreases the fluorescence lifetime of 4I11/2 level from 400 MUs to 59.35 MUs, and thus inhibits the self-termination effect of ~2.7 MUm in some degree. We develop a theoretical model that simulates the laser characteristics of Er,Eu:YAP crystal numerically. Based on Er3+-Eu3+ energy level diagrams, the rate equation model was built and discussed. It was found that: when the pump rate increases gradually, the laser quantum efficiency reaches to its upper limit with a fixed value 2-p2, and this value is 1.35 for Er,Eu:YAP crystal. The results show that Er,Eu:YAP crystal is an excellent material candidate for ~2.7 MUm laser. PMID- 29975913 TI - Structural characterization and evaluation of municipal wastewater sludge (biosolids) from two rural wastewater treatment plants in East Texas, USA. AB - Wastewater sludge (or) biosolids collected from two rural wastewater treatment plants (NWWTP, LWWTP) in East Texas, USA were characterized and evaluated via inductively coupled plasma optical emission spectrometry, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), thermogravimetric analysis, X-ray diffraction, Fourier transform infrared spectroscopy (FTIR), and ion chromatography. The proximate organic and inorganic compositions and spectroscopic characteristics of sewage sludge were determined. The results show that the concentrations of toxic metals Cd, Cr, Cu, Mo, Ni, Pb, Hg, and Zn meet USEPA guideline recommendations for land applications. Notably, metals concentrations in biosolids from NWWTP (Mn (700 +/- 83) > Zn (422.5 +/- 35.4 ppm) > Ba (319.5 +/- 87 ppm) > Cu (240 +/- 27 ppm) > B (107 +/- 14 ppm) > V (24 +/- 3.3 ppm) > Cr (20 +/- 3.3 ppm) > Ni (16.7 +/- 2.0 ppm) > Pb (16.8 +/- 1.1 ppm) > As (11.99 +/- 1.27 ppm) > Co (7.6 +/- 0.7 ppm) > Mo (6.4 +/- 1.4 ppm) > Hg (0.55 +/- 0.24 ppm) > Cd (0.130 +/- 0.109 ppm)) and LWWTP follow similar trends. Macro elements concentrations in LWWTP follow the trend P (19,648 +/- 169) > Fe (22,688 +/- 2110) > Ca (9372 +/- 163) > S (9010 +/- 1009) > Al (12,538 +/- 2116) > K (3514 +/- 550) > Mg (33,370 +/- 502) > Na (1511 +/- 472). The Br-, NO3-, NO2-, F , Cl-, and SO42- concentrations meet USEPA guidelines. Whereas biosolid particle sizes were in the range ~20 MUm to 500 MUm mineralogical results show quartz and vermiculite to be major constituents with abundancies 12.94%, and 10.87% w/wt, respectively. PMID- 29975914 TI - Preparation and photophysical properties of thienothiophene functionalized difluoroboron bis-beta-diketonate complexes. AB - A series of six new thienothiophene functionalized difluoroboron bis-beta diketonates were synthesized and characterized. Their photophysical properties were investigated by UV-vis absorption, fluorescence spectroscopy and the method of CIE chromaticity in solution and powders. The results showed that these difluoroboron complexes yielded a blue-green emission at 474-500 nm in DMF solution and emitted a green to yellow emission at 541-587 nm in powders. Especially, the complex 3c showed the stronger fluorescence intensity, much higher quantum yield (Phiu = 0.89) in DMF solution and larger Stokes shifts (?lambdastokes = 149 nm), longer lifetime value (tau = 3.54 ns) in powders as compared to other complexes. The CIE coordinate of the complex 3c was positioned in an ideal orange-yellow region of the chromaticity diagram. Meanwhile, their electrochemical properties were also studied by the cyclic voltammetry; the HOMO, LUMO energy levels and energy band gaps were determined from the onset oxidation and reduction potentials. PMID- 29975915 TI - Identification of native charge-transfer status of p-aminothiolphenol adsorbed on noble metallic substrates by surface-enhanced infrared absorption (SEIRA) spectroscopy. AB - p-Aminothiophenol (PATP) is a preferred molecule in research on surface-enhanced Raman scattering (SERS) because of its unique characteristics of high spectral activity, easily induced charge-transfer (CT), and sensitivity to molecular structural changes. However, some aspects are still unclear, such as the initial steady state of PATP on noble metallic substrates without strong additional excitation with incident and/or induced electromagnetic radiation. Information about the initial steady state, especially the intrinsic CT state, is of great importance to elucidate the dynamic processes of CT and/or molecular structural changes under additional excitation. To investigate the native state of an adsorbed molecule, a suitable probe method that does not disrupt the native state of the whole system, including both molecules and substrates, is required. SERS is not applied in this context because of its use of high-energy visible and near infrared light. Herein, a low-energy probe method, surface-enhanced infrared absorption (SEIRA) spectroscopy, is employed as a suitable method for studying the native adsorption state of PATP on silver nanoisland films. The molecular structure and adsorption state were investigated. The intrinsic CT state received particular attention by analyzing the CT-related vibration of B2 modes. Using Fourier transform infrared (FTIR), transmission SEIRA and reflection SEIRA spectroscopy, we explained why the relative intensities of some bands were different under different conditions. A quasi-standing orientation of PATP adsorbed on the substrates was also confirmed. More importantly, we demonstrated that there is no perceptible CT between PATP and silver nanoisland films; in contrast, CT generally occurs in a disruptive manner in SERS. Density functional theory (DFT) calculations and the selection rules for infrared (IR) transmission and reflection-absorption spectroscopy were used to analyze the spectra throughout the paper. SEIRA proved to be an effective technique to explore the native adsorption state of molecules without the excessive external disturbance induced by excitation. The results are very important in providing insight into molecules in surface-interface chemistry, enhanced spectroscopy and photoelectronics. PMID- 29975916 TI - Silver (Ag) nanoparticles enhanced luminescence properties of Dy3+ ions in borotellurite glasses for white light applications. AB - In the present work, the structural and optical properties of borotellurite glasses co-doped with Dy3+ ions and Ag nanoparticles were investigated. From HR TEM analysis, the average Ag nanoparticle diameter was calculated as 13.7 +/- 1 nm. The negative sign of the bonding parameter explored the ionic nature of metal ligand (DyO) bonds. The emission spectra exhibited three emission bands in blue, yellow and red regions corresponding to 4F9/2 -> 6H15/2, 4F9/2 -> 6H13/2 and 4F9/2 -> 6H11/2 transitions, respectively. The Yellow/Blue (Y/B) ratio of optimal BTD0.5A glass was found to be 1.881 and this low Y/B ratio indicated the fact that Dy3+ ions were located in higher symmetrical ligand environment. The CCT values are found to vary from 3717 to 3800 K and hence the present glasses may emit cool white light when excited with UV lamp. The radiative parameters were calculated for all the emission transitions by using JO theory. The decay curves are found to show non-exponential behavior for all the studied glasses. The obtained results were discussed in detail and compared with similar reported glasses. PMID- 29975917 TI - Non-invasive study of natural dyes on historical textiles from the collection of Michelangelo Guggenheim. AB - A selection of historical textile fragments from the Venetian art dealer Moise Michelangelo Guggenheim collection, ranging from XV to XVIII century, has been investigated by means of non-invasive techniques in order to reveal the coloring materials. Imaging was preliminarily used to visually investigate the selected artwork fragments in order to investigate their structure and conservation conditions; Fiber Optics Reflectance Spectroscopy (FORS) allowed recognizing the main natural dyestuffs, such as indigotin and anthraquinones-based compounds, except the yellow ones, difficultly identifiable when using this non-invasive technique. Collected spectroscopic data have been also elaborated by using a clustering algorithm that permitted to group collected spectra on the basis of similar properties and evidencing their inflection point wavelength as the most influencing feature. PMID- 29975918 TI - A novel jointly colorimetric and fluorescent sensor for Cu2+ recognition and its complex for sensing S2- by a Cu2+ displacement approach in aqueous media. AB - In this work, a simple and easily synthesized Schiff-based derivative colorimetric and fluorescent sensor (1), 4-dimethylamino-benzoic acid (2 imidazole formaldehyde)-hydrazide, was obtained for the detection of Cu2+ and S2 . The compound 1 exhibited dual spectral responses to Cu2+, that is, vivid color change and fluorescence enhancement in the presence of Cu2+. The detection limits were valued as 0.46 MUM and 15 nM according to absorption and fluorescent response, respectively. Both of them are below the World Health Organization (WHO) guidelines for drinking water (31.5 MUM). In addition, the ensemble (1 Cu2+) selectively and sensitively detected a low concentration of S2-. As the addition of S2- instantly removed Cu2+ from the ensemble (1-Cu2+) resulting in a color change from yellow to colorless and a "turn-off" fluorescent response. The detection limit for S2- was estimated as 0.12 MUM (from fluorescent method) and 0.68 MUM (from absorption method), respectively, each of which was also lower than the maximum allowable level of S2- (15 MUM) in drinking water defined by the WHO. The binding process was confirmed via UV-vis absorption, fluorescence measurements, 1H NMR, mass spectroscopy and density functional theory calculation. What's more, successful practical application of test paper is used to inspect the S2- which means the convenient and rapid assay in real samples can be achieved. PMID- 29975919 TI - Basics and applications of analytical molecular and biomolecular spectroscopy. PMID- 29975920 TI - The effect of prenatal exposure to Ramadan on children's height. AB - We examine the effect of prenatal exposure to Ramadan on children's height by sex, age, region, and the degree of religiosity. Since Ramadan rotates on solar calendars, we pool demographic and health survey data from numerous developing countries to increase the number of birth years and fairly control for potential seasonal effects. Our results suggest that Ramadan-induced nutritional stress during early- and mid-gestation may negatively affect the height of 3 and 4 years old Muslim male children. The effect tends to be stronger in West Africa and Central Asia. It also tends to be stronger in more religious countries. We do not detect consistent negative effects on height in female children. PMID- 29975921 TI - MiR-137 Suppresses Triple-Negative Breast Cancer Stemness and Tumorigenesis by Perturbing BCL11A-DNMT1 Interaction. AB - BACKGROUND/AIMS: Triple negative breast cancer (TNBC) is resistant to conventional chemotherapy due to high proportions of cancer stem cells (CSCs). The aim of this study is to unravel the miR-137-mediated regulatory mechanism of B-cell lymphoma/leukemia 11A (BCL11A) in TNBC. METHODS: A corhort of 34 TNBC tumor tissues and paired adjacent normal tissues, as well as 25 non-TNBC tumor tissues and paired adjacent normal tissues were collected post-operatively from patients with breast cancer. Q-PCR was performed to determine the mRNA levels of miR-137 and BCL11A in breast tissues and cell lines. Bioinformatics analysis and dual luciferase reporter assay were used to verify the direct interaction between miR-137 and BCL11A. After up-/down-regulation of BCL11A, miR-137, or DNMT1 via lentiviral transduction in TNBC cell lines SUM149 and MDA-MB-231 cells, Q-PCR and Western blot assays were used to detect the expression levels of BCL11A, DNA methyltransferases 1 (DNMT1), and Islet-1 (ISL1). Mammosphere assay was conducted to assess tumorosphere formation ability of cells, coupled with flow cytometry to determine the percentage of breast cancer stem cells. Co-immunoprecipitation assay was used to determine the interaction between BCL11A and DNMT1. Xenograft tumorigenesis assay was performed to monitor tumor formation in vivo. RESULTS: BCL11A was highly expressed in TNBC, whereas miR-137 was significantly lower in both TNBC tissues and cell lines. miR-137 suppressed BCL11A expression at both mRNA and protein levels by directly targeting its 3'UTR. In both SUM149 and MDA MB-231 cells, overexpression of miR-137 or knockdown of BCL11A reduced the number of tumoroshperes and the percentage of cancer stem cells in vitro, and inhibited tumor development in vivo. Furthermore, BCL11A interacted with DNMT1 in TNBC cells. Silencing of either BCL11A or DNMT1 impaired cancer stemness and tumorigenesis of TNBC via suppressing ISL1 expression both in vitro, and in vivo. CONCLUSIONS: By perturbing BCL11A-DNMT1 interaction, miR-137 impairs cancer stemness and suppresses tumor development in TNBC. PMID- 29975922 TI - Survival Benefit of Germline BRCA Mutation is Associated with Residual Disease in Ovarian Cancer. AB - BACKGROUND/AIMS: Prognostic value of germline BRCA1 or BRCA2 (gBRCA1/2) mutations in epithelial ovarian cancer (EOC) remains controversial, especially in the estimation of long-term survival. We previously reported the largest study of gBRCA1/2 mutation prevalence in Chinese EOC patients. The aim of this study is to further illustrate the correlation of residual disease and survival in BRCA associated EOC in China. METHODS: In the current cohort consisting of 615 cases from the Chinese EOC genome-wide association study, we evaluated the association between gBRCA1/2 mutation and clinical outcomes. RESULTS: Overall, we did not find any significant difference between gBRCA1/2 mutation carriers and non carriers in both progression-free survival (PFS) and overall survival (OS) (19.3 vs. 18.1 months and 77.2 vs. 73.2 months, P=0.528 and 0.147, HR 0.93 and 0.79, 95%CI 0.74-1.17 and 0.57-1.09, respectively). However, within three years after diagnosis, mutation carriers showed a longer OS than non-carriers (P=0.018, HR 0.53, 95%CI 0.31-0.90). Such a survival advantage decreased along with the extension of follow-up time. Quite interestingly, in the subgroup of patients with gross residual disease, mutation carriers had a longer survival than non carriers (18.5 vs. 15.1 months and 68.5 vs. 54.3 months, P=0.046 and 0.038, HR 0.74 and 0.65, 95% CI 0.55-1.00 and 0.43-0.98, for PFS and OS respectively). CONCLUSIONS: Our findings provided the evidence that gBRCA1/2 mutation was not associated with survival in Chinese EOC patients, which possibly attributed to more than 37% of the patients without gross residual disease. Survival benefit of gBRCA1/2 mutation was prominent in ovarian cancer patients with gross residual disease. PMID- 29975923 TI - Let-7d Inhibits Growth and Metastasis in Breast Cancer by Targeting Jab1/Cops5. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) regulate the expressions of cancer-related genes, and are involved in the development and progression of various human cancers. Here, we performed further analyses to determine whether let-7d is functionally linked to Jab1 in breast cancer. METHODS: In situ hybridization and immunohistochemical analyses were used to determine the level of let-7d and Jab1 in breast cancer clinical specimens and its correlation with clinicopathological data. Let-7d overexpressing breast cancer cell lines combined with mouse models bearing cell-derived xenografts were used to assess the functional role of let-7d both in vitro and in vivo. RESULTS: In this study, we found that let-7d was downregulated in breast cancer tissues, coupled with the elevations of Jab1 protein expressions, compared with paired adjacent noncancerous breast tissues. Let-7d overexpression significantly suppressed the proliferation and invasion in MCF-7 and MDA-MB-231 cells. Dual luciferase reporter assay indicated that Jab1 was the direct target of let-7d. Stepwise studies from in vitro and in vivo experiments indicated that let-7d overexpression inhibited cell growth and decreased Jab1 expressions in breast cancer cells and nude mice tumor tissues. Statistical analyses demonstrated that breast cancer patients with low levels of let-7d or high levels of Jab1 had a significant correlation with worse prognosis. CONCLUSION: These findings provide novel insights into molecular mechanism of let 7d and Jab1 in tumor development and progression of breast cancer, and thus let 7d/Jab1 are novel potential therapeutic targets for breast cancer patients. PMID- 29975924 TI - Alpha-Lipoic Acid Protects Human Aortic Endothelial Cells Against H2O2-Induced Injury and Inhibits Atherosclerosis in Ovariectomized Low Density Lipoprotein Receptor Knock-Out Mice. AB - BACKGROUND/AIMS: Diseases caused by atherosclerosis are the leading causes of death in postmenopausal women, owing to the loss of estradiol. Hormone replacement therapy (HRT) provides short-term beneficial effects in the treatment of cardiovascular disease for postmenopausal women but may increase the risk of stroke and gynecological cancer. Therefore, a substitute for HRT is urgently in needed. METHODS: In this study, we examined the effectiveness of alpha-lipoic acid (ALA), a natural potent antioxidant, in preventing the development and progression of atherosclerosis in the low density lipoprotein receptor deficient (Ldlr-/-) mouse model, using western blot analysis, immunohistochemistry, Oil-red O, elastin staining and TUNEL assay. We also examined the protective effect of ALA in human aortic endothelial cells (HAECs) against H2O2-induced oxidative injury, using western blotting, immunofluorescence staining, and monocyte adhesion assay. RESULTS: We showed that ALA treatment significantly reduced the atherosclerosis induced by ovariectomy and high fat diet in the Ldlr-/- mouse model and restored expression of estrogen receptors (ERalpha and ERbeta), which reduced the progression of atherosclerosis. Moreover, ALA treatment attenuated monocyte adhesion, suppressed cellular apoptosis, and eliminated excessive generation of intracellular reactive oxygen species (ROS) by reducing the protein levels of ROS-generating enzymes Nox4 and p22phox, as well as inhibiting NF kappaB activation in HAECs stimulated by H2O2. CONCLUSIONS: ALA could provide a potential treatment for atherosclerosis in postmenopausal patients. PMID- 29975925 TI - Direct Oral Anticoagulants in Nonvalvular Atrial Fibrillation: Practical Considerations on the Choice of Agent and Dosing. AB - Direct or new oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, have recently revolutionized the field of antithrombotic therapy for stroke and systemic embolism prevention in nonvalvular atrial fibrillation (NVAF). Randomized controlled trials have shown that these agents have at least comparable efficacy with vitamin K antagonists along with superior safety, at least in what concerns intracranial hemorrhage. As a result, NOACs are indicated as first-line anticoagulation therapy for NVAF patients with at least one risk factor for stroke or systemic embolism. The rapid introduction, however, of NOACs in a field dominated for decades by vitamin antagonists and the variety of agents and dosing schemes may create difficulties in decision making. In the present article, we attempt to determine a practical approach to the choice of agent and dose in different clinical scenarios by considering not only the results of seminal randomized trials and post hoc analyses but also data from real-world patient populations as well as the recently available possibility of rapid NOAC reversal. PMID- 29975926 TI - Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway. AB - BACKGROUND/AIMS: Leupaxin (LPXN) is a member of the paxillin protein family. Several studies have reported that LPXN regulates cancer development; however, the role of LPXN in bladder cancer remains unknown. METHODS: The expression of LPXN in bladder cancer cells and tissues was determined by real-time PCR, western blotting, and immunohistochemistry, respectively. The biological role of LPXN in bladder cancer cell proliferation, invasion, and angiogenesis was explored both in vitro and in vivo. RESULTS: LPXN expression was elevated in bladder cancer tissues and cell lines compared to adjacent non-tumor tissues and normal urothelial cells. High LPXN expression was correlated with large tumor size, advanced tumor stage, and poor survival in bladder cancer patients. Overexpression of LPXN significantly promoted the proliferation, invasion, and angiogenesis of bladder cancer cells, while suppressing LPXN had the opposite effects. The impact on tumor progression was abolished by inhibiting PI3K/ AKT signaling pathway. We further demonstrated that LPXN probably up-regulated S100P via the PI3K/AKT pathway. CONCLUSIONS: LPXN may facilitate bladder cancer progression by upregulating the expression of S100P via PI3K/AKT pathway. These results provide a novel insight into the role of LPXN in tumorigenesis and progression of bladder cancer and potential therapeutic target of bladder cancer. PMID- 29975927 TI - Erratum. PMID- 29975929 TI - Erratum. PMID- 29975928 TI - A Preliminary Investigation of PVT1 on the Effect and Mechanisms of Hepatocellular Carcinoma: Evidence from Clinical Data, a Meta-Analysis of 840 Cases, and In Vivo Validation. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) remains a difficult problem that significantly affects the survival of the afflicted patients. Accumulating evidence has demonstrated the functions of long non-coding RNA (lncRNA) in HCC. In the present study, we aimed to explore the potential roles of PVT1 in the tumorigenesis and progression of HCC. METHODS: In this study, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was applied to detect the differences between PVT1 expression in HCC tissues and cell lines. Then, the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were searched to confirm the relationship between PVT1 expression and HCC. Moreover, a meta-analysis comprising TCGA, GEO, and RT-qPCR was applied to estimate the expression of PVT1 in HCC. Then, cell proliferation was evaluated in vitro. A chicken chorioallantoic membrane (CAM) model of HCC was constructed to measure the effect on tumorigenicity in vivo. To further explore the sponge microRNA (miRNA) of PVT1 in HCC, we used TCGA, GEO, a gene microarray, and target prediction algorithms. TCGA and GEO and the gene microarray were used to select the differentially expressed miRNAs, and the different target prediction algorithms were applied to predict the target miRNAs of PVT1. RESULTS: We found that PVT1 was markedly overexpressed in HCC tissue than in normal liver tissues based on both RT-qPCR and data from TCGA, and the overexpression of PVT1 was closely related to the gender and race of the patient as well as to higher HCC tumor grades. Also, a meta-analysis of 840 cases from multiple sources (TCGA, GEO and the results of our in-house RT-qPCR) showed that PVT1 gained moderate value in discriminating HCC patients from normal controls, confirming the results of RT qPCR. Additionally, the upregulation of PVT1 could promote HCC cell proliferation in vitro and vivo. Based on the competing endogenous RNA (ceRNA) theory, the PVT1/miR-424-5p/INCENP axis was finally selected for further research. The in silico prediction revealed that there were complementary sequences between PVT1 and miR-424-5p as well as between miR-424-5p and INCENP. Furthermore, a negative correlation trend was found between miR-424-5p and PVT1 based on RT-qPCR, whereas a positive correlation trend was found between PVT1 and INCENP based on data from TCGA. Also, INCENP small interfering RNA (siRNA) could significantly inhibit cell proliferation and viability. CONCLUSIONS: We hypothesized that PVT1 could affect the biological function of HCC cells via targeting miR-424-5p and regulating INCENP. Focusing on the new insight of the PVT1/miR-424-5p/INCENP axis, this study provides a novel perspective for HCC therapeutic strategies. PMID- 29975930 TI - Plastrum Testudinis Extracts Promote BMSC Proliferation and Osteogenic Differentiation by Regulating Let-7f-5p and the TNFR2/PI3K/AKT Signaling Pathway. AB - BACKGROUND/AIMS: Plastrum testudinis extracts (PTE) show osteoprotective effects on glucocorticoid-induced osteoporosis in vivo and in vitro. However, the underlying molecular mechanism of PTE in promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is unclear. METHODS: BMSC proliferation was investigated using the Cell Counting Kit-8 assay. BMSC differentiation and osteogenic mineralization were assayed using alkaline phosphatase and Alizarin red staining, respectively. The mRNA expression levels of Let-7f-5p, Tnfr2, Traf2, Pi3k, Akt, beta-catenin, Gsk3beta, Runx2, and Ocn were measured using real time quantitative polymerase chain reaction. Protein levels of TNFR2, TRAF2, p-PI3K, p-AKT, p-beta-CATENIN, and p-GSK3beta were analyzed by western blotting. The functional relationship of Let-7f-5p and Tnfr2 was determined by luciferase reporter assays. RESULTS: The optimum concentration for PTE was 30 MUg/ml. PTE significantly promoted BMSC osteogenic differentiation and mineralization after 7 and 14 days in culture, respectively. The combination of PTE and osteogenic induction exhibited significant synergy. PTE upregulated Let-7f-5p, beta-catenin, Runx2, and Ocn mRNA expression, and downregulated Tnfr2, Traf2, Pi3k, Akt, and Gsk3beta mRNA expression. PTE inhibited TNFR2, TRAF2, and p beta-CATENIN protein expression, and promoted p-PI3K, p-AKT, and p-GSK3beta protein expression. In addition, Tnfr2 was a functional target of Let-7f-5p in 293T cells. CONCLUSIONS: Our results suggested that PTE may promote BMSC proliferation and osteogenic differentiation via a mechanism associated with the regulation of Let-7f-5p and the TNFR2/PI3K/AKT signaling pathway. PMID- 29975931 TI - Effects of Curcumin on Epidermal Growth Factor in Proliferative Vitreoretinopathy. AB - BACKGROUND/AIMS: Proliferative vitreoretinopathy (PVR) is a common refractory eye disease that causes blindness and occurs after retinal detachment or retinal reattachment. Epidermal growth factor (EGF) has been shown to play an important role in the migration and proliferation of retinal pigment epithelium (RPE) cells, which promote PVR. Curcumin inhibits RPE cell proliferation, but it is not known whether it participates in the formation of PVR. Curcumin regulates the biological functions of EGF, which plays important roles in the development of PVR. This study aimed to evaluate the effect of curcumin on the regulation of EGF in PVR. METHODS: Rabbit RPE cells were cultured, and EGF expression was detected by immunocytochemistry. MTT assay was conducted to determine cell proliferation induced by different concentrations of EGF. Immunocytochemical staining was used to detect EGF expression after treatment with curcumin at varying concentrations. Real-time PCR (RT-PCR) and western blot analysis were used to detect the concentrations of EGF mRNA and protein after treatment with curcumin. After RPE cells and curcumin were injected into experimental rabbit eyes, the cornea, aqueous humor, lens, and vitreous opacity were observed and recorded simultaneously by indirect ophthalmoscopy, fundus color photography, and B ultrasonography. The vitreous body was extracted, and the EGF content in the vitreous humor was measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: At each time point (24, 48, and 72 h), cell proliferation gradually increased with increasing EGF concentrations (0, 3, 6, and 9 ng/mL) in a dose dependent manner. Cell proliferation between EGF concentrations of 9 and 12 ng/mL were no different, which suggested that 9 ng/mL EGF was the best concentration to use to stimulate RPE cell proliferation in vitro. Under all EGF concentrations (0, 3, 6, 9, and 12 ng/mL), RPE cell proliferation increased with time (from 24 to 72 h), suggesting a time-effect relationship. Curcumin downregulated EGF expression in RPE cells, which also indicated time-effect and dose-effect relationships. The best curcumin concentration for the inhibition of EGF expression was 15 ug/mL. RT-PCR and western blot analyses indicated that the EGF mRNA and expression of the protein in RPE cells treated with curcumin significantly decreased with time. Ocular examinations revealed that the vitreous opacity was lower and the proliferative membrane was thinner in the curcumin group compared with the control group. The PVR grade and the incidence of retinal detachment were significantly lower in the experimental group than in the control group. ELISA results showed that the EGF content in vitreous humor was higher in the control group than in the curcumin group. The curcumin and control groups were significantly different at each time point. CONCLUSION: Curcumin inhibited RPE cell proliferation by downregulating EGF and thus effectively inhibited the initiation and development of PVR. PMID- 29975933 TI - TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma. AB - BACKGROUND/AIMS: TNF-alpha receptor-associated factor (TRAF)-interacting protein with a forkhead-associated (FHA) domain (TIFA) may mediate the impact of TRAF on the development of lung cancer. The current study was conducted to investigate the expression of TIFA in lung adenocarcinoma and its potential role in the regulation of cancer cell proliferation and migration, and its influence on patient survival. METHODS: Specimens of lung adenocarcinoma tissues and their adjacent normal lung tissues were obtained from 116 patients who underwent surgical resection of lung cancer. The expression of TIFA in the lung tissues was examined by immunohistochemistry, immunoblotting, and real-time RT-PCR in four different lung cancer cell lines and one normal bronchial epithelial cell line (BEAS-2B). TIFA was silenced by RNAi technique, and cell proliferation was then assessed by the CCK8 method. Furthermore, cell migration was determined by wound healing trans-well and wound-healing migration assays. Additionally, cell-cycle arrest and apoptosis were assessed by flow cytometry analysis. RESULTS: TIFA was positively detected in 63 (54.3%) out of 116 lung adenocarcinoma specimens, which was significantly higher than the respective rate established in normal tissues adjacent to the tumor (30.1%, p < 0.05). The overall survival rate was significantly lower in the patients with positive TIFA expression than that in the patients with negative TIFA expression (p < 0.05). TIFA was also highly expressed in the lung cancer cell lines (H1299, H1975, and HCC827) tested. It is noteworthy that siRNA suppressed the expression of TIFA, which contributed to the attenuation of cell proliferation and migration, but promoted cell-cycle arrest and apoptosis. Furthermore, the silencing of TIFA caused upregulation of p53, p21, and cleaved-caspase-3, but downregulation of Bcl-2, cyclin D1, and CDK4, as well as phosphorylation of IKKbeta, IkappaB, and p65. CONCLUSIONS: TIFA may serve as a biomarker in the prediction of lung adenocarcinoma. Furthermore, TIFA may modulate lung cancer cell survival and proliferation through regulating the synthesis of apoptosis-associated proteins. PMID- 29975932 TI - miR-100 Reverses Cisplatin Resistance in Breast Cancer by Suppressing HAX-1. AB - BACKGROUND/AIMS: Breast cancer (BC) is the most common cancer in women worldwide. Despite great advancements in cancer therapy in recent years, surgery and chemotherapy are still the mainstays of BC treatment. However, cancer cells usually develop mechanisms to evade cell death induced by chemotherapy. Thus, strategies are needed to reverse the chemoresistance of cancer cells. METHODS: We established cisplatin-resistant BC models in MDA-MB-231 and MCF-7 BC cell lines through long-term exposure to cisplatin. Quantitative reverse transcription PCR was used to examine the expression of microRNA (miR)-100. MTT cell viability assays were performed to determine cell viability. Regulation of hematopoietic cell-specific protein 1-associated protein X-l (HAX-1) targeted by miR-100 was confirmed by western blotting and luciferase reporter assays. The mitochondrial membrane potential and apoptosis were measured by flow cytometry. Release of cytochrome c from the mitochondria into the cytoplasm, HAX-1 expression, and activation of caspase-9 and caspase-3 were detected by western blotting. RESULTS: A clear decrease in miR-100 expression was observed in cisplatin-resistant MDA-MB 231 and MCF-7 cells (MDA-MB-231/R and MCF-7/R). Overexpression of miR-100 increased the sensitivity of MDA-MB-231/R and MCF-7/R cells to cisplatin treatment and promoted cisplatin-induced mitochondrial apoptosis by targeting HAX 1 gene. CONCLUSIONS: MiR-100 targeted HAX-1 to increase the chemosensitivity of BC by mediating the mitochondrial apoptosis pathway. PMID- 29975934 TI - Transcriptome Profiling of Panc-1 Spheroid Cells with Pancreatic Cancer Stem Cells Properties Cultured by a Novel 3D Semi-Solid System. AB - BACKGROUND/AIMS: Pancreatic cancer remains one of the deadliest human malignancies, the lethality of which may be attributed to the presence of pancreatic cancer stem cells (PCSCs), a small subpopulation of cells existing within pancreatic tumor with high carcinogenesis. Therefore, it is crucial to establish an efficient enrichment and culture system of PCSCs and identify the key genes involved in the regulation of PCSCs. The three-dimensional (3D) liquid suspension mammosphere culture system has been established for enrichment and culture of PCSCs in vitro as the cell spheres are likely to originate from individual cell clone, but it has been challenged because the cell spheroids could be a result of cell aggregation. METHODS: We optimized the existing culture system by adding methylcellulose to create a 3D semi-solid system which prevented the non-specific aggregation. Then we identified the CSC properties of Panc-1 spheroid cells cultured by this system by detecting the genes associated with stemness and by evaluation of the tumorigenicity in vitro and in vivo through invasion, migration and xenograft experiments methods. Subsequently, we performed high-throughput sequencing (HTS) of the Panc-1 spheroid cells. RESULTS: We confirmed the PCSCs properties and high malignancy of the Panc-1 spheroid cells enriched by our novel 3D semi-solid system both in vitro and in vivo. Hundreds of mRNA, microRNA (miRNA) and dozens of long non-coding RNA (LncRNA) were identified to be differentially regulated in PCSCs-like Panc-1 spheroid cells compared with their parental cells by HTS. CONCLUSIONS: Our results demonstrate an efficient enrichment and culture system for Panc-1 spheroid cells with the PCSCs properties. The differentially expressed genes and their targets identified by the HTS of the Panc-1 spheroid cells can serve as new potential biomarkers for pancreatic cancer diagnosis and targeted therapy. PMID- 29975935 TI - Expressional and Functional Characterization of Intracellular pH Regulators and Effects of Ethanol in Human Oral Epidermoid Carcinoma Cells. AB - BACKGROUND/AIMS: To functionally characterize intracellular pH (pHi) regulating mechanisms, such as Na+-H+ exchanger (NHE) and Na+-HCO3- co-transporter (NBC), and further examine effects of ethanol on the pHi regulating mechanism in human oral epidermoid carcinoma (OEC-M1) cells. METHODS: OEC-M1 cells were a gift from Tri-Service General Hospital. Changes of pHi were detected by microspectrofluroimetry with a pH-sensitive fluorescent dye, BCECF. Isoforms of transporters were examined by Western blot technique. RESULTS: i) the steady state pHi value shifted from alkaline (7.35~7.49) to acidic (7.0~7.03) following acid/base impacts; ii) in HEPES-buffer system, pHi recovery following induced acidification was totally blocked by either removing [Na]o+ or adding HOE 694 (a NHE1 specific inhibitor), which demonstrates existence of NHE1; iii) in HCO3-/CO2 buffer system, the pHi recovery following induced-acidification was entirely blocked by either removing [Na]o+ or adding HOE 694 plus DIDS (a NBC specific inhibitor), which suggests existence of Na+- and HCO3-dependent acid-extruder, i.e. NBC; iv) the isoforms of the two acid extruders were NHE1, NBCn1, NBCe1 and NDCBE; v) ethanol (10-1000 mM) showed a biphasic and concentration-dependent effect on resting pHi (i.e. increase then decrease) by changing the activity of NHE1 and NBC accordingly; vi) treatment with ethanol for 24 hr (> 300 mM) significantly inhibited the expression of NHE1, NBCn1 and NDCBE, while up-regulated NBCe1. CONCLUSIONS: Ethanol affects pHi in a concentration-dependent manner by changing function and expression of NHE1 and NBC isoforms in OEC-M1 cells. PMID- 29975936 TI - Clinical Characteristics and Surgical Treatment for Inguinal Endometriosis in Young Women of Reproductive Age. AB - AIM: To study the characteristics and surgical treatment of inguinal endometriosis (IEM), which can occur in women of reproductive age. METHODS: Patients who underwent groin surgery at the Hiroshima City Funairi Citizens Hospital between 2004 and 2017 were retrospectively examined. Patients with IEM were divided into 3 groups based on the site of occurrence as follows: at a hernia sac or hydrocele of Nuck's canal (type I), round ligament (type II), or subcutaneous area (type III). Clinical characteristics were compared among groups. RESULTS: Of 2,798 patients investigated, 28 were pathologically diagnosed as having IEM with 15, 10, and 3 classified as type I, II, and III respectively. All patients presented with a mass (median 20 mm) and/or bulge that mainly occurred at the right inguinal region. Sixteen patients presented with inguinal pain associated with menstruation. While the groups did not differ in terms of most clinical characteristics, the lack of a preoperative diagnosis of IEM occurred more frequently for type I than for types II and III. CONCLUSIONS: Because IEM-type I might be underdiagnosed preoperatively, complete resection of a hernia sac or hydrocele of Nuck's canal with subsequent pathological examination is required for women of reproductive age with an inguinal disease. PMID- 29975937 TI - Digital Image Analysis with Fully Connected Convolutional Neural Network to Facilitate Hysteroscopic Fibroid Resection. AB - AIMS: The study aimed to determine the accuracy of deep neural network in identifying the plane between myoma and normal myometrium. METHODS: On the images of surgery, different structures were signed and annotated for the training phase. After the appropriate training of the deep neural network with 4,688 images from that training set, 1,600 formerly unseen images were used for testing. Indication for surgery was heavy menstrual bleeding and hysteroscopic finding was submucous fibroid. Operative intervention was fibroid resection. Recorded videos of transcervical resection of myoma in 13 cases were used for the study. Different filters and procedures were applied by the fully convolutional neural network (FCNN) for identifying previously annotated structures. RESULTS: Previously manually annotated images and the manually drawn bitmasks were used for training the applied FCNN and then this pre-trained network was used for automatic segmentation of normal myometrium in an unseen video frame. The segmentation pixel-wise accuracy achieved the 86.19% considering the Hausdorff metric. CONCLUSION: Using deep learning technique in analyzing process of endoscopic video frame could help in real-time identification of structures while performing endoscopic surgery. PMID- 29975938 TI - Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. AB - BACKGROUND/AIMS: Melatonin has been demonstrated to protect cardiac microvascular endothelial cells (CMECs) against ischemia/reperfusion injury (IRI). Autophagy plays different roles in the heart during ischemia and reperfusion. The AMP activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway is associated with autophagy. This study sought to explore whether melatonin regulates CMEC autophagy through the AMPK/mTOR signaling pathway. METHODS: The effects of melatonin in IRI were investigated in vivo rat models and in vitro neonatal CMECs. Myocardial infarct size was achieved by Evans blue and triphenyltetrazolium chloride staining. The severity of cell injury was evaluated by cell vitality and lactate dehydrogenase (LDH) release assays, and autophagy was evaluated by transmission electron microscopy and the assessment of autophagy related gene expression, such as that of Beclin 1 and light chain 3-II. RESULTS: In vivo, melatonin markedly reduced infarcted area, improved cardiac function and decreased LDH release. However, the AMPK activator AICAR and the mTOR inhibitor rapamycin reduced the protective effects of melatonin on IRI. In vitro, Beclin1 and light chain 3-II protein were found to be down-regulated and autophagosomes were found to be reduced in response to melatonin, together with an increase in cell vitality and a decrease in LDH. Treatment with AICAR or rapamycin ablated the benefit observed with melatonin treatment. CONCLUSIONS: Melatonin played an important and protective role in CMECs by inhibiting autophagy against IRI via the AMPK/mTOR system. PMID- 29975939 TI - Histone Acetyltransferase Mof Affects the Progression of DSS-Induced Colitis. AB - BACKGROUND/AIMS: Histone acetylation has been demonstrated to be associated with inflammation response. Histone acetyltransferase (HAT) Mof, specifically acetylating lysine 16 of histone H4 (H4K16), has been reported to regulate T cell differentiation. In addition, it has been suggested that acetylation of H4K16 is associated with the inflammatory response. We evaluated the role and potential mechanism of Mof in the development of experimental colitis. METHODS: We used Mof conditional knockout mice to study the role of Mof in dextran sulfate sodium (DSS)-induced colitis and detected the differential expression of genes due to Mof deficiency involved in the inflammatory response, particularly the Th17 signaling pathway, by western blotting, quantitative PCR and RNA sequencing (RNA seq). RESULTS: A significant elevation of Mof was observed in colonic tissues of mice with DSS-induced colitis. Mof deficiency alleviated the severity of DSS- induced colitis in mice. We found that Th17 signaling pathway associated genes, including Il17a, Il22, RORgammat, RORalpha, Stat3, TGF-beta 1, and Il6, were downregulated in colon tissues with Mof deficiency. RNA-seq data analysis suggested that 68 genes were related to inflammatory response processing and 47 genes were downregulated in Mof defective colon tissues. CONCLUSION: Our study demonstrated that HAT Mof is involved in the development of colitis, and the lack of Mof ameliorates DSS-induced colitis in mice. PMID- 29975941 TI - Epidemiology and Genetic Diversity of Rotavirus in Kunming, China, in 2015. AB - Group A rotavirus (RVA) is a serious public problem in China, with a prevalence of 29.7% in diarrhea cases under 5 years of age. A total of 1,224 fecal specimens were collected in 2015 from children under 5 years of age with acute gastroenteritis in Kunming, China, for detection and characterization of rotavirus. The prevalence of RVA was 28.5%. The frequency of RVA detection was greatest (52%) among children aged 7-12 months. The following strains were the most common types: G9P(8) (58.2%), G3P(8) (14.9%), and G1P(8) (6.9%). The following strains were uncommon types: G3P(4), G8P(9), and G9P(4) (1.1%); G1P(4), G2P(8), and G4P(8) (0.9%); G2P(6), G3P(9), G4P(6), and G9P(6) (0.6%); and G4P(4) (0.3%). G3G1P(8) (5.2%), G1G2P(4) (0.9%), G1G9P(8) (0.6%), and G2P(4)P(8) (0.3%) were mixed types. This study documents the molecular epidemiology, genetics, and diversity of rotavirus strains in children under 5 years of age in Kunming, China, and suggests that it may be important to offer RVA vaccination and scientific evidence to stop and control RVA-related diarrhea. PMID- 29975940 TI - Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines. AB - Different liver cell types are endowed with immunological properties, including cell-intrinsic innate immune functions that are important to initially control pathogen infections. However, a full landscape of expression and functionality of the innate immune signaling pathways in the major human liver cells is still missing. In order to comparatively characterize these pathways, we purified primary human hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells (LSEC), and Kupffer cells (KC) from human liver resections. We assessed mRNA and protein expression level of the major innate immune sensors, as well as checkpoint-inhibitor ligands in the purified cells, and found Toll-like receptors (TLR), RIG-I-like receptors, as well as several DNA cytosolic sensors to be expressed in the liver microenvironment. Amongst the cells tested, KC were shown to be most broadly active upon stimulation with PRR ligands emphasizing their predominant role in innate immune sensing the liver microenvironment. By KC immortalization, we generated a cell line that retained higher innate immune functionality as compared to THP1 cells, which are routinely used to study monocyte/macrophages functions. Our findings and the establishment of the KC line will help to understand immune mechanisms behind antiviral effects of TLR agonists or checkpoint inhibitors, which are in current preclinical or clinical development. PMID- 29975942 TI - An Analysis of Skin Prick Tests to Latex and Patch Tests to Rubber Additives and other Causative Factors among Dental Professionals and Students with Contact Dermatoses. AB - BACKGROUND: Dental workers often experience unwanted allergic and nonallergic skin reactions resulting in different contact dermatoses (e.g., contact urticaria, irritant and allergic contact dermatitis) that are often attributed to rubber gloves. OBJECTIVE: To examine allergic and nonallergic contact dermatoses by different methods amongst dental professionals and dental students, more specifically, reactions to natural rubber latex (NRL), rubber additives, and other causative factors. METHODS: In this cross-sectional study we surveyed a total of 444 subjects (dentists, assistants, technicians, and students); 200 agreed to be tested to latex by the standard skin prick test (SPT) and prick-by prick test, of whom 107 were patch tested to rubber additives (mercapto mix, thiuram mix, carba mix, and N-isopropyl-N-phenyl-4-phenylenediamine [IPPD]). RESULTS: Skin lesions appeared significantly more frequently with longer work experience (p = 0.002; V = 0.181), frequent glove changes (p < 0.001; V = 0.310), and hand washing (p < 0.001; V = 0.263), and in subjects with a history of allergies (atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and others) (p < 0.001; V = 0.183). Positive SPTs to latex occurred in 14/200 subjects (7%), of whom 5/14 subjects (35.7%) were also positive in prick-by-prick tests. Patch tests were positive in 5/104 subjects (4.8%) (mercapto mix 1%, thiuram mix 1.9%, and carba mix 1.9%). CONCLUSION: Only a small number of our subjects were allergic to latex (7%) or rubber additives (4.8%). Thus, self reported contact dermatoses (during NRL product use) in dental professionals and students are not commonly caused by allergies to latex and rubber additives, as is often assumed, but by other factors. PMID- 29975943 TI - Apigenin Retards Atherogenesis by Promoting ABCA1-Mediated Cholesterol Efflux and Suppressing Inflammation. AB - BACKGROUND/AIMS: The development of atherosclerosis is accompanied by escalating inflammation and lipid accumulation within blood vessel walls. ABCA1 plays a crucial role in mediating cholesterol efflux from macrophages, which protects against atherogenesis. This research was designed to explore the effects and underlying mechanisms of apigenin (4', 5, 7-trihydroxyflavone) on ABCA1-mediated cellular cholesterol efflux and LPS-stimulated inflammation in RAW264.7 macrophages and apoE-/- mice. METHODS: Expression of genes or proteins was examined by RT-PCR or western blot analysis. Liquid scintillation counting was used to detect percent cholesterol efflux. Cellular cholesterol content was measured using HPLC assay. The secretion levels of pro-inflammatory cytokines were quantified by ELISA assay. Atherosclerotic lesion sizes were determined with Oil Red O staining. The contents of macrophages and smooth muscle cells in atherosclerotic lesion were evaluated using immunohistochemistry. Plasma TC, TG, HDL-C and LDL-C levels in apoE-/- mice were evaluated using commercial test kits. RESULTS: Apigenin potently increased ABCA1 expression through miR-33 repression in a dose- and time-dependent manner. Treatment with apigenin significantly increased ABCA1-mediated cholesterol efflux, and reduced TC, FC and CE levels in macrophage-derived foam cells. In LPS-treated macrophages, the expression levels of TLR-4, MyD88 and p-IkappaB-alpha as well as nuclear NF-kappaB p65 were decreased by the addition of apigenin. Moreover, apigenin markedly decreased secretion levels of several pro-inflammatory cytokines. Lastly, in LPS-challenged apoE-/- mice, apigenin administration augmented ABCA1 expression, decreased the contents of macrophages and smooth muscle cells in atherosclerotic lesion, reduced miR-33, TLR-4, and NF-kappaB p65 levels, improved plasma lipid profile and relieved inflammation, which results in less atherosclerotic lesion size. CONCLUSIONS: Taken together, these results suggest that apigenin may attenuate atherogenesis through up-regulating ABCA1-mediated cholesterol efflux and inhibiting inflammation. PMID- 29975945 TI - Egr-1 Maintains NSC Proliferation and Its Overexpression Counteracts Cell Cycle Exit Triggered by the Withdrawal of Epidermal Growth Factor. AB - In adult mammals, neural stem cells (NSCs) reside in specialized niches at the level of selected CNS regions, such as the subventricular zone (SVZ). The signaling pathways that reg-ulate NSC proliferation and differentiation remain poorly understood. Early growth response protein 1 (Egr-1) is an important transcription factor, widely studied in the adult mammalian brain, mediating the activation of target genes by a variety of extracellular stimuli. In our study, we aimed at testing how Egr-1 regulates adult NSCs derived from mouse SVZ and, in particular, the interplay between Egr-1 and the proliferative factor EGF. We demonstrate that Egr-1 expression in NSCs is induced by growth factor stimulation, and its level decreases after EGF deprivation or by using AG1478, an inhibitor of the EGF/EGFR signaling pathway. We also show that Egr-1 overexpression rescues the cell proliferation decrease observed either after EGF removal or upon treatment with AG1478, suggesting that Egr-1 works downstream of the EGF pathway. To better understand this mechanism, we investigated targets downstream of both the EGF pathway and Egr-1, and found that they regulate genes involved in NSC proliferation, such as cell cycle regulators, cyclins, and cyclin dependent kinase inhibitors. PMID- 29975944 TI - LncRNA LINC00311 Promotes the Proliferation and Differentiation of Osteoclasts in Osteoporotic Rats Through the Notch Signaling Pathway by Targeting DLL3. AB - BACKGROUND/AIMS: Osteoporosis is a commonly occurring condition marked by a loss of bone density. Previous evidence has highlighted the roles played by microRNAs as potential treatment tools for the disease. At present, the influence of long non-coding RNAs (lncRNAs) on the progression of osteoporosis remains largely unclear. Thus, an investigation was conducted into the target relationship between LINC00311, which has been reported to be highly expressed in osteoporosis, and delta-like 3 (DLL3), which is involved in the Notch signaling pathway, in connection with a series of bioinformatic methods. An osteoporotic rat model was established by means of ovariectomy (OVX) to evaluate the influence exerted by DLL3-binding LINC00311 on osteoclasts through the Notch signaling pathway. METHODS: Osteoclasts were extracted from osteoporotic rats and transfected with the LINC00311-vector, shRNA-LINC00311, Notch activator, or a combination of the Notch activator and LINC00311-vector. Western blotting and RT qPCR techniques were applied to determine the expression levels of LINC00311, DLL3, Notch1, Notch2, Jagged1, Hes-1 and TRAP in tissues and cells, while cell activity was detected by MTT assay. The cell cycle as well as the rate of apoptosis was detected by flow cytometry. The successfully established osteoporotic rats were designated into the OVX-siRNA, OVX-LINC00311 and OVX control groups to observe the effects of LINC00311 on the proliferation and differentiation of osteoclasts. RESULTS: Cells transfected with the LINC00311 vector exhibited increased expression levels of Notch2 and TRPA as well as increased cell activity, while decreased expression levels of DLL3, Notch1, Jagged1 and Hes-1, along with a decreased cell apoptosis rate, were observed. The opposite tendencies of these parameters were observed in the cells treated with shRNA-LINC00311. A key observation was made when the Notch signaling pathway was activated, in that the cell activity was decreased while the rate of apoptosis increased. In comparison with the OVX-control group, the expression levels of LINC00311, Notch2 and TRAP as well as the positive expression rate of TRAP all exhibited reductions, while those of DLL3, Jagged1 and Notch1 were elevated in the OVX-siRNA group. Compared with those in the sham group, in the OVX-control and OVX-LINC00311 groups, LINC00311 and the expression levels of Notch2 and TRAP were increased; however, decreased levels of DLL3, Jagged1 and Notch1 were noted. CONCLUSIONS: Taken together, the key findings of the present study suggest that LINC00311 induces proliferation and inhibits apoptosis of osteoclasts via the regulation of the Notch signaling pathway by inhibiting DLL3 expression, ultimately demonstrating that LINC00311 and its target gene DLL3 may serve as independent factors in cases of osteoporosis. PMID- 29975946 TI - Decreased Hepatic Lactotransferrin Induces Hepatic Steatosis in Chronic Non Alcoholic Fatty Liver Disease Model. AB - BACKGROUND/AIMS: Non-alcoholic fatty liver disease (NAFLD) is an emerging metabolic disease. Although it leads to severe hepatic diseases including steatohepatitis, cirrhosis, and hepatic cancer, little is known about therapy to prevent and cure hepatic steatosis, the first step of NAFLD. We conducted this investigation to unveil the mechanism of hepatic steatosis. METHODS: We established a novel chronic NAFLD mouse model through whole body irradiation and verified the model through histological and biochemical analysis. To find molecular mechanism for hepatic steatosis, we analyzed hepatic transcriptomic profiles in this model and selected target molecule. To induce the expression of lactotransferrin (Ltf) and regulate the NAFLD, growth hormone (GH) and coumestrol was introduced to hepatocyte and mice. The universal effect of coumestrol was confirmed by administration of coumestrol to NAFLD mouse model induced by high fructose, high-fat, and MCD diet. RESULTS: It was observed that decreased hepatic Ltf expression led to excessive hepatic lipid accumulation in NAFLD mouse. Furthermore, we found that GH was decreased in irradiated mice and functioned as an upstream regulator of Ltf expression. It was observed that GH could stimulate Ltf expression and prevent uptake of dietary lipids in hepatocytes, leading to rescue of NAFLD. Finally, we suggested that coumestrol, a kind of isoflavonoid, could be used as an inducer of hepatic Ltf expression through cooperation with the GH signaling pathway both in vitro and in vivo. CONCLUSIONS: Hepatic Ltf prevents hepatic steatosis through inhibition of dietary lipid uptake in radiation-induced NAFLD mouse model. We also suggest coumestrol as a drug candidate for prevention of NAFLD. PMID- 29975947 TI - Klf4 Alleviates Lipopolysaccharide-Induced Inflammation by Inducing Expression of MCP-1 Induced Protein 1 to Deubiquitinate TRAF6. AB - BACKGROUND/AIMS: Inflammation is an essential component of innate immunity against pathogens, but is tightly regulated, such as by Kruppel-like factor 4 (Klf4), to prevent injury. Klf4 also regulates macrophage polarization, although the mechanisms underlying both functions are poorly understood. The aim of this study was to investigate whether and how Klf4 prevents unregulated inflammation. METHODS: The bone marrow-derived macrophages and RAW264.7 cell line were used. Quantitative real-time PCR was used to determine inflammatory cytokines (IL 1beta, TNF-alpha, IL-6 and MCP-1), Klf4 and MCPIP1 transcript levels. Extraction of nuclear and cytoplasmic proteins and Immunoblotting were used to determine Klf4, MCPIP1, relative kinases from NF-kappaB pathway and K63-linked polyubiquitins expression in nucleus and cytoplasm separately. Dual luciferase reporter assay was used to analyze whether Klf4 mediate MCPIP1 transcription. Immunoprecipitation was used to determine the protein interaction among Klf4, MCPIP1, TRAF6 and K63-linked polyubiquitins. Secretion of IL-1beta and TNF-alpha into sera in mice was measured by Enzyme-linked immunosorbent assay. RESULTS: We found that exposure to lipopolysaccharides suppresses Klf4 expression, even as it induces release of pro-inflammatory cytokines. Strikingly, Klf4 overexpression significantly lowered cytokine secretion and NF-kappaB signaling in the cytoplasm following exposure to lipopolysaccharide, even though Klf4 was exclusively nuclear. The cytoplasmic effects are likely mediated by MCP-1 induced protein 1 (MCPIP1), a deubiquitinase and a key modulator of inflammation that accumulates both in the nucleus and cytoplasm in response to Klf4. Indeed, binding between MCPIP1 and K63 polyubiquitins is attenuated in macrophages overexpressing Klf4, suggesting that MCPIP1 is an intermediator induced by Klf4 in the nucleus to remove K63 polyubiquitins from TRAF6 in the cytoplasm, and thereby impede NF kappaB and inflammatory signaling. Importantly, Klf4 overexpression in mice alleviated sepsis symptoms following exposure to lipopolysaccharides. CONCLUSION: The data highlight Klf4 as an essential MCPIP1-dependent modulator of innate immunity that protects against excessive and self-destructive inflammation. PMID- 29975948 TI - Antiestrogenic Activity of the Xi-Huang Formula for Breast Cancer by Targeting the Estrogen Receptor alpha. AB - BACKGROUND/AIMS: The Xi-Huang (XH) formula has been used for breast cancer treatment in traditional Chinese medicine (TCM) since 1740. In this study, we show that, XH extract could suppress the growth of breast cancer cells in vitro and in vivo, and that it preferentially inhibits cell growth of estrogen receptor positive (ER+) breast cancer cells. Presently, little is known about the potential mechanism of XH and our studies aim to elucidate its mechanism in breast cancer treatment. METHODS: Network-based systems biology and molecular docking analyses were performed to predict explicit targets of XH and active ingredients in XH. The effects of XH on cell viability, cell cycle, apoptosis in different breast cancer cell lines were analyzed in vitro. A model of transplanted tumors on nude mice was used to study the anticancer effect in vivo. Various techniques, including western blotting, reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence, co-immunoprecipitation and immunohistochemical were utilized to assess the expression of targets of XH in vitro and in vivo. RNA sequencing (RNA-seq) was performed to study the gene targets of XH. Furthermore, we analyzed of protein-ligand binding reactions by isothermal titration calorimetry (ITC). RESULTS: Using network-based systems biology and molecular docking analyses, we predicted that the major targets of XH were ERalpha and HSP90. Moreover, we found that, XH mediated its anti-cancer effects by promoting the disassociation of ERalpha and HSP90, resulting in the degradation of ERalpha and blockade of transport of ERalpha to the nucleus. XH also caused the dissociation of ERalpha and other oncoproteins via binding to HSP90. Some of the active ingredients in XH share a common cyclopentane hydrogen skeleton and were predicted to target ERalpha based on the structural similarity. CONCLUSIONS: XH, which has been used since 1740, has antiestrogenic effects in breast cancer via the targeting of ERalpha. PMID- 29975949 TI - Clinical and Genetic Characteristics Analysis of Korean Patients with Stargardt Disease Using Targeted Exome Sequencing. AB - PURPOSE: To investigate genetic mutations in Korean patients with Stargardt disease (STGD) using exome sequencing, and to analyze the correlations between genetic mutations and clinical phenotypes. METHODS: Peripheral venous blood was obtained from 24 clinically diagnosed Korean STGD patients, followed by extraction of genomic DNAs. Using exome sequencing we investigated gene mutations for the adenosine triphosphate-binding cassette, subfamily A, member 4 (ABCA4) elongation of very-long-chain fatty acids 4 (ELOVL4), and prominin 1 (PROM1), and confirmed gene mutations by the direct sequencing of polymerase chain reaction products. RESULTS: ABCA4 mutations were confirmed in 17 of 24 patients, and 12 novel mutations were identified. ELOVL4 and PROM1 gene mutations were not identified in this study. We also identified 16 previously reported mutations related to STGD1. In patients whose disease symptoms occurred before 20 years of age, visual acuity was poorer and atrophic flecks were more frequently found. In addition, more ABCA4 mutations were found in patients who had choroidal silence or atrophic flecks. CONCLUSIONS: Novel ABCA4 gene mutations were found in Korean patients with STGD1. This study will facilitate better understanding of the relationships between ABCA4 gene mutations and clinical symptoms in Korean patients. PMID- 29975950 TI - High-Grade T1 on Re-Transurethral Resection after Initial High-Grade T1 Confers Worse Oncological Outcomes: Results of a Multi-Institutional Study. AB - INTRODUCTION: The aim of this multicenter study was to investigate the prognostic impact of residual T1 high-grade (HG)/G3 tumors at re-transurethral resection (TUR of bladder tumor) in a large multi-institutional cohort of patients with primary T1 HG/G3 bladder cancer (BC). PATIENTS AND METHODS: The study period was from January 2002 to -December 2012. A total of 1,046 patients with primary T1 HG/G3 and who had non-muscle invasive BC (NMIBC) on re-TUR followed by adjuvant intravesical Bacillus Calmette-Guerin (BCG) therapy with maintenance were included. Endpoints were time to disease recurrence, progression, and overall and cancer-specific death. RESULTS: A total of 257 (24.6%) patients had residual T1 HG/G3 tumors. The presence of concomitant carcinoma in situ, multiple and large tumors (> 3 cm) at first TUR were associated with residual T1 HG/G3. Five-year recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS) were 17% (CI 11.8-23); 58.2% (CI 50.7 65); 73.7% (CI 66.3-79.7); and 84.5% (CI 77.8-89.3), respectively, in patients with residual T1 HG/G3, compared to 36.7% (CI 32.8-40.6); 71.4% (CI 67.3-75.2); 89.8% (CI 86.6-92.3); and 95.7% (CI 93.4-97.3), respectively, in patients with NMIBC other than T1 HG/G3 or T0 tumors. Residual T1 HG/G3 was independently associated with RFS, PFS, OS, and CSS in multivariable analyses. CONCLUSIONS: Residual T1 HG/G3 tumor at re-TUR confers worse prognosis in patients with primary T1 HG/G3 treated with maintenance BCG. Patients with residual T1 HG/G3 for primary T1 HG/G3 are very likely to fail BCG therapy alone. PMID- 29975951 TI - Unilateral Left Deep Brain Stimulation of the Caudal Zona Incerta Is Equally Effective on Voice Tremor as Bilateral Stimulation: Evidence from 7 Patients with Essential Tremor. AB - BACKGROUND/AIMS: Deep brain stimulation (DBS) is less effective on voice tremor than arm tremor, and it is generally assumed that successful voice tremor treatment requires bilateral DBS and possibly more precise thalamic stimulation. However, recent findings suggest that these assumptions should be reconsidered. OBJECTIVES: To evaluate whether unilateral DBS targeting the caudal zona incerta (cZi) may be sufficient to alleviate voice tremor in patients with essential tremor, or whether bilateral stimulation is needed. METHODS: Seven patients with voice tremor off stimulation were evaluated during bilateral stimulation using their clinical settings, and during unilateral left stimulation in iterations with increasing stimulation amplitude. Two expert listeners assessed voice tremor severity in all samples in a blinded procedure. RESULTS: Six patients had comparable or better effects with unilateral left stimulation compared to bilateral stimulation. For the seventh patient, unilateral DBS at a slightly higher amplitude achieved similar results as bilateral DBS. Overall, high amplitude stimulation did not appear to be beneficial on voice tremor. CONCLUSIONS: Unilateral left and bilateral cZi-DBS had comparable effects on voice tremor in the investigated group of 7 patients. This finding suggests that the assumption that bilateral DBS is required to treat voice tremor may need to be reconsidered. PMID- 29975952 TI - Pros and Cons of the New Edition of TNM Classification of Head and Neck Squamous Cell Carcinoma. AB - The TNM classification is a worldwide standard staging system used to define the extent of cancer and is a major prognostic factor in predicting the outcome of patients. The TNM Classification of Malignant Tumours, 8th edition, has been used since January 1, 2018. In the area of head and neck cancer major modifications were produced: important updated T and N modification for oral cavity and nasopharyngeal cancer, the introduction of clinical and pathological stages for neck disease, and a new HPV-16-positive HNSCC classification. While until a few years ago the TNM staging system classified prognostic risk groups based on tumour size, the 8th edition responds to the need to categorize the prognosis of patients with similarly sized tumours but with very different clinical and biological behaviour. This review details TNM changes and the clinical need for these modifications, valuating possible limits in daily applicability. PMID- 29975953 TI - Thalidomide in Combination with Chemotherapy in Treating Elderly Patients with Acute Myeloid Leukemia. AB - BACKGROUND: Currently, the treatment decisions in elderly patients with acute myeloid leukemia (AML) are difficult and remain controversial. This study aims to evaluate the effect of thalidomide plus chemotherapy on elderly patients with AML. METHODS: 70 elderly AML patients (median age 71 years) were enrolled into this prospective study and randomly assigned to either the control arm (PC, n = 35) or the investigational arm (TPC, n = 35). Patients in the PC arm received a non-intensive regimen composed of cytarabine, aclarubicin and G-CSF (CAG) chemotherapy for induction of remission, and patients in the TPC arm received in addition thalidomide at a maximum dose of 200 mg/day. RESULTS: After 2 courses of induction therapy, complete response rate of TPC and PC arms was 54.3% and 57.1%, respectively (p = 0.810). At the last follow-up, the Kaplan-Meier estimate showed that the median overall survival (OS) and event-free survival (EFS) in patients in the PC arm was inferior to those of patients in the TPC arm. Using a stratified Cox model adjusted for randomized treatment, patients receiving thalidomide plus chemotherapy were shown to derive some survival benefit in both OS and EFS. Overall, the hematological and non-hematological toxicity were similar between the 2 treatment arms. CONCLUSIONS: Thalidomide in combination with chemotherapy is an alternative treatment option for elderly patients with AML. PMID- 29975954 TI - Language Exposure of Preterm Infants in the Neonatal Unit: A Systematic Review. AB - BACKGROUND: Elevated sound levels and low language exposures of preterm infants (< 37 weeks) cared for in the neonatal unit contribute to poorer growth, cognition, language and motor outcomes. These delays can have lasting effects on childhood development and continue throughout adult life. Whilst recommendations have been established for appropriate sound exposure levels in neonatal units, very little is known about the optimal level of language exposure. OBJECTIVES: To examine the evidence regarding language exposure, both measured (observational) and prescribed (interventional), in preterm infants (< 37 weeks) cared for in neonatal units and to identify optimal exposure levels to promote neurodevelopment. SEARCH METHODS: An electronic search of English-language articles with an open date range was conducted in the PubMed, MEDLINE, Joanna Briggs, CINAHL and Cochrane databases and in Google Scholar. The criteria were limited to original research studies of preterm infants (< 37 weeks) in which language was either measured as it naturally occurred in the neonatal unit environment or through a language intervention. RESULTS: The search produced a total of 2,367 articles, 49 of which were related to language. A full-text review of these articles identified 10 eligible studies and 6 studies from reference searches. CONCLUSIONS: Preterm infants experience low levels of language exposure and high sound exposures in neonatal units. There is a lack of conclusive evidence to recommend an optimal level of language exposure to support improved neurodevelopmental outcomes in preterm infants. Further research from large, good quality clinical trials is required before clear direction can be provided to inform clinical practice. PMID- 29975956 TI - Endovascular Management of a Rare Case of Pediatric Vertebral Artery Mycotic Aneurysm: A Case Report. AB - Pediatric posterior-circulation aneurysms are uncommon, difficult-to-treat lesions associated with significant morbidity and mortality. Infections and trauma are important risk factors in children. Here, we present a 10-year-old boy with a lower respiratory tract infection, rapidly progressive right-neck swelling, and weakness of the right upper limb. Imaging revealed a partially thrombosed right vertebral-artery pseudoaneurysm with multiple cavitory lung lesions. Subsequent laboratory work-up showed underlying primary immunodeficiency disorder (chronic granulomatous disease). The aneurysm was successfully managed by parent-artery occlusion. The child made a complete recovery without neurological sequelae. PMID- 29975955 TI - A Simple Method for Normalization of Aortic Contractility. AB - Vascular contractile function changes in proliferative vascular diseases, e.g. atherosclerosis, and is documented using isolated blood vessels; yet, many laboratories differ in their approach to quantification. Some use raw values (e.g., mg, mN); others use a "percentage of control agonist" approach; and others normalize by blood vessel characteristic, e.g. length, mass, etc. A lack of uniformity limits direct comparison of contractility outcomes. To address this limitation, we developed a simple 2-step normalization method: (1) measure blood vessel segment length (mm), area (mm2) and calculate volume (mm3); then, (2) normalize isometric contraction (mN) by segment length and volume. Normalized aortic contractions but not raw values were statistically different between normal chow and high-fat diet-fed mice, supporting the practical utility and general applicability of normalization. It is recommended that aortic contractions be normalized to segment length and/or volume to reduce variability, enhance efficiency, and to foster universal comparisons across isometric myography platforms, laboratories, and experimental settings. PMID- 29975957 TI - Positive Association between Preoperative Total Testosterone Levels and Risk of Positive Surgical Margins by Prostate Cancer: Results in 476 Consecutive Patients Treated Only by Radical Prostatectomy. AB - OBJECTIVE: To evaluate preoperative total testosterone (TT) as a predictor of positive surgical margins (PSM) in prostate cancer (PCA). PATIENTS AND METHODS: During the period from November 2014 to July 2017, preoperative TT was measured in 476 PCA patients undergoing only radical prostatectomy (RP) and including all risk classes. Surgical margins were stated negative, focal positive (single and less than 1 mL), and multifocal positive (more than 1). The risk of TT and clinical factors associated with the risk of PSM (focal or multifocal versus negative) was evaluated by the multinomial logistic regression model. RESULTS: Overall, PSM were detected in 149 cases (31.3%), which included 99 patients with focal cancer invasion (20.8%) and 50 subjects with multifocal cancer invasion (10.5%). In univariate analysis, PSM associated with higher median levels of TT and prostate-specific antigen than controls. Multifocal PSM associated with higher rates of high-risk PCA (42%) than focal (22.2%) or control cases (18.3%). In multivariate analysis, TT was the only independent factor positively associated with the risk of focal PSM when compared to controls (OR 1.002; p = 0.035). TT (OR 1.003; p = 0.002) and high-risk PCA (OR 1.002; p = 0.047) were independent factors, which positively associated with the risk of multifocal PSM when compared to controls. Risk models were computed. CONCLUSIONS: In a large and contemporary cohort of patients elected to primary RP, TT was an -independent positive factor associated with the risk of focal and multifocal PSM. TT associated with aggressive PCA biology. PMID- 29975958 TI - Distinguishing Subgroups Based on Psychomotor Functioning among Patients with Major Depressive Disorder. AB - BACKGROUND: Retardation and agitation are symptoms of major depressive disorder (MDD), and their presence could play a role in determining clinically meaningful depressive subtypes such as nonmelancholic depression (NMD) and melancholic depression (MD). In this project, we explored whether three depression subgroups (NMD, MD with psychotic symptoms, and MD without psychotic symptoms) could be distinguished based on objective measures of psychomotor functioning. METHODS: Sixty-nine patients with MDD underwent extensive clinical and psychomotor testing prior to treatment with electroconvulsive therapy. Psychomotor functioning was assessed subjectively using the Core Assessment of Psychomotor Change (CORE) and objectively by means of both 24-h actigraphy and performance on a fine motor drawing task. RESULTS: The daytime activity levels measured by actigraphy were significantly lower (F = 7.1, p = 0.0004) in MD patients both with and without psychotic symptoms than in those with NMD. No objective psychomotor variable was able to distinguish between melancholic patients with and those without psychotic symptoms. CONCLUSIONS: The depression subtypes NMD, MD with psychotic symptoms, and MD without psychotic symptoms are not marked by increasing psychomotor retardation, possibly because psychomotor disturbance in MD with psychotic symptoms often consists of agitation rather than retardation, or a mixture of the two. However, psychomotor functioning as measured by actigraphy can be used to distinguish between NMD patients and MD patients. PMID- 29975959 TI - Testicular Preservation in 46 XY Denys-Drash Syndrome: A Report of Two Cases. AB - Denys Drash Syndrome (DDS) is a rare combination of genital and urinary anomalies that are mostly associated with malignancy. We report 2 patients who presented with genital ambiguity and were diagnosed as 46-XY DDS. During the discussion of the management plan, parents preferred to keep the gonads to preserve its endocrinal function for future sexual development. However, both patients developed primary hypogonadism at puberty and required testosterone supplementation. Persevering gonads in such patients had no endocrinal benefits but put the patients at risk of malignant transformation. PMID- 29975960 TI - Evaluation of Factors Affecting Lymph Node Metastasis in Clinical Stage I-II Epithelial Ovarian Cancer. AB - BACKGROUND: Systematic lymphadenectomy is useful for accurate staging of early stage ovarian cancer and has obvious prognostic value. Accurate staging may prevent unnecessary postoperative chemotherapy. The aim of this study was to evaluate the rate of lymph node involvement and factors affecting it in clinically early-stage epithelial ovarian cancer (EOC; stages I, II). PATIENTS AND METHODS: The study included 163 patients who underwent surgery at our hospital between January 2004 and April 2017 and who were diagnosed with early stage EOC based on preoperative and intraoperative examination. Patient data were retrospectively analyzed. The rate of lymph node involvement and factors affecting it were analyzed. RESULTS: Of 163 patients, 21 (12.9%) had lymph node metastasis, whereas 16 (16.3%) of 98 patients who underwent comprehensive lymphadenectomy had lymph node metastasis. According to the univariate results for patients undergoing any type of lymphadenectomy, the rate of positive lymph nodes was significantly higher (37.1%) in those with bilateral ovarian involvement (p < 0.001). The rate was significantly higher in patients with positive intraabdominal fluid cytology (25.9%; p < 0.001), serous histology (20.5%; p = 0.02), and grade 3 disease (33.3%; p < 0.001). In multivariate logistic regression analysis, the rate was significantly higher in patients with bilateral adnexal involvement (p = 0.012). The risk of positive lymph nodes was significantly higher in patients with grade 3 disease (p = 0.016). CONCLUSION: Comprehensive lymphadenectomy increases the detection rate for metastatic lymph nodes in patients with clinically early-stage EOC. The rate of lymph node involvement is significantly higher in grade 3 tumors, serous cytology, bilateral adnexal involvement, and positive intraabdominal fluid cytology. PMID- 29975961 TI - Methodologic Assessment of the Systematic Reviews of Ophthalmic Adverse Drug Reactions Published in Ophthalmology Journals: A Systematic Review. AB - PURPOSE: This systematic review aims to characterize and review the methodology of the systematic reviews reporting ophthalmic adverse drug reactions. METHODS: This systematic review followed the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-analyses guide. MEDLINE and EMBASE databases were searched, by all Ophthalmology journals. All systematic reviews reporting ophthalmic adverse drug reactions in the last decade were included. Data on methodology were extracted. Methodological quality was assessed through A MeaSurement Tool to Assess systematic Reviews 2 scale. Descriptive analysis was performed. RESULTS: Twenty-one systematic reviews were identified. Almost 60% of the systematic reviews reported non-ophthalmic drugs. Nine (43%) systematic reviews did not follow any recommendation. A search filter was not applied in 48% systematic reviews. Observational data was the source of information most included. The methodological quality was assessed in 57% systematic reviews. A meta-analysis was performed in 57% systematic reviews. The protocol's elaboration, the explanation of the sources of information and the list of excluded articles were the domains less performed in the systematic reviews. CONCLUSION: The systematic reviews reporting ophthalmic adverse drug reactions diverged in some methodological aspects. Such an issue deserves further investigation, since discrepancies may lead to biased conclusions and, consequently, impact clinical and/or regulatory decisions. PMID- 29975962 TI - Oral Cancer Treatment: Still an Indication for Elective Neck Dissection? AB - INTRODUCTION: Oral squamous cell carcinoma has a high incidence and, although elective neck dissection is recommended, the removed nodes frequently present without metastasis. This surgical approach causes disabilities and increases possible surgical complications. OBJECTIVE: To evaluate the possibility of a watchful waiting approach in oral cancer. METHODS: We compared 78 patients with clinical and pathological node metastases and their counterparts with pathological node metastases but without evident clinical neck disease. Therefore, we provided a theoretical comparison between the patients who had an elective neck dissection and those who waited until a clinically positive node was evident. RESULTS: The prognostic factor rates were similar between the groups. Their regional recurrence and mortality rates had no statistical differences. CONCLUSION: A watchful waiting policy could be applied to selected oral cancer patients who can undergo a very close follow-up. This option would be more cost-effective and less harmful than elective neck dissection. PMID- 29975963 TI - Bony and Cartilaginous Tissues in Lumbosacral Lipomas. AB - PURPOSE: It is well known that bony and cartilaginous tissues can be present in lumbosacral lipomas; however, the relationship between their presence and clinical features has not been demonstrated. METHODS: Five (10.4%) out of 48 patients had osteochondral tissues in lipomas. We retrospectively analyzed the clinical, neuroradiological, and histological findings of these patients. RESULTS: Five (45.5%) of 11 patients with dorsal and transitional type lipomas had osteochondral tissues, while none with caudal and filar type lipomas had these tissues. Presurgical imaging demonstrated that the osteochondral tissue was located in a large subcutaneous lipoma dorsal to the bifid vertebral column. Histologically, mature bone with hematopoietic marrow and hyaline cartilage were observed in 3 and 2 patients, respectively. CONCLUSIONS: The high incidence of association of osteochondral tissues with dorsal and transitional type lipomas is thought to be the result of primary neurulation failure with invasion of mesenchymal tissues. Caudal and filar type lipomas, resulting from secondary neurulation failure, thus did not have osteochondral tissue. PMID- 29975964 TI - The Respiratory System in Autoimmune Vascular Diseases. AB - The respiratory system may be involved in all types of systemic vasculitis with varying significance and frequency. ANCA-associated vasculitis, including granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis, affects the respiratory tract more commonly than other vasculitis types. Granulomatosis with polyangiitis is always associated with upper or lower respiratory tract involvement. Pulmonary and ENT involvements are the hallmark feature of the disease and are present in 90 and 80% of cases, respectively, with frequent skin or gastrointestinal involvement. In about 10% of cases, the lung is the only organ affected. Eosinophilic granulomatosis with polyangiitis is always associated with hypereosinophilia and asthma which usually precedes the systemic manifestations by several years; however, onset of asthma and of the vasculitis may be concomitant. Parenchymal infiltrates may be migratory and rapidly resolve upon corticosteroid treatment. Diffuse alveolar hemorrhage and renal failure are typical features of microscopic polyangiitis. The former is the leading manifestation of anti-glomerular basement membrane disease and is usually part of a pulmonary-renal syndrome. Takayasu arteritis has a distinct clinical presentation due to pulmonary arteritis and may present with massive hemoptysis, chest pain, and rarely symptoms of pulmonary hypertension. Behcet disease is the most common cause of pulmonary artery aneurysm and can also cause in situ thrombosis of the pulmonary arteries. Corticosteroids and immunosuppressive agents are the mainstay of treatment. In conclusion, systemic vasculitis is a frequent cause of respiratory system involvement with diverse manifestations of distinct severity and outcome. PMID- 29975965 TI - Association of Thyroid Function With the Estimated Glomerular Filtration Rate in a Large Chinese Euthyroid Population. AB - BACKGROUND/AIMS: We aimed to explore whether thyroid function within a normal range is associated with the estimated glomerular filtration rate (eGFR) and the incidence of chronic kidney disease (CKD) in a large Chinese population. METHODS: We conducted a cross-sectional study that included 10,859 euthyroid individuals who underwent an annual regular health checkup in Jiangsu Province Official Hospital between August 2012 and August 2013. We measured the thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) levels using a Roche modular analytics E170 and then calculated the eGFR using the Chinese modified Modification of Diet in Renal Disease (CMDRD) equation. RESULTS: In multiple linear regression models, TSH was negatively associated with eGFR after adjusting for confounding factors (beta = -0.072, P = 1.994*10-22). The significance remained in both males and females. No significant association was observed between FT4 and eGFR. In the logistic regression model, we did not observe significant associations of TSH or FT3 with CKD. Participants in the highest quartile of FT4 versus the lowest quartile (reference) had an increased risk of CKD (OR = 1.763, P = 0.012). The risk of CKD was more pronounced in females with the highest quartile of FT4 (OR = 2.424, P = 0.029). CONCLUSION: Our findings suggest that TSH is associated with eGFR in euthyroid individuals and that higher FT4 is associated with an increased risk of CKD. More cohort studies are warranted to confirm whether the association is causal. PMID- 29975966 TI - PET and Neck Ultrasound for the Detection of Cervical Lymphadenopathy in Patients with Lung Cancer and Mediastinal Lymphadenopathy. AB - BACKGROUND: Cervical lymph nodes are frequently involved in patients with lung cancer and indicate inoperability. Some guidelines recommend neck ultrasound (NUS) in patients with bulky mediastinal lymphadenopathy. Positron emission tomography (PET) is indicated for patients with potentially curable disease. OBJECTIVES: We aimed to assess the diagnostic yield of NUS and the diagnostic accuracy of PET for cervical lymphadenopathy in this group with a high pre-test probability of N3 disease. METHODS: Records of all patients with lung cancer who underwent an NUS over a consecutive 5-year period were reviewed. Only patients with mediastinal lymphadenopathy on computerised tomography (CT) were included. The diagnostic accuracy of PET was assessed with NUS-guided fine needle aspiration cytology used as the reference test. RESULTS: During the study period, 123 patients met the inclusion criteria. Malignant cervical lymphadenopathy was confirmed in 49/123 (39.8% [95% CI 31.1-49.1]). PET-CT had a specificity of 81.1%, sensitivity of 87.5%, negative predictive value of 96.8% and positive predictive value of 50% for the detection of cervical lymphadenopathy, and it contributed no additional staging information in the neck area. Overall, PET led to a change in management in only 2.2% of cases. CONCLUSION: A significant proportion of patients with lung cancer and mediastinal lymphadenopathy have cervical lymphadenopathy detected by NUS. In this group of patients, PET offers minimal additional value in staging and management. PMID- 29975967 TI - Impact of Patient-Prosthesis Mismatch following Aortic Valve Replacement on Long Term Survival and Quality of Life. AB - BACKGROUND: The impact of patient-prosthesis mismatch (PPM) after aortic valve replacement (AVR) on long-term survival and quality of life (QoL) remains controversial. The objective of this study was to evaluate the impact of PPM on long-term survival and QoL in a large cohort of patients treated with isolated stented biological AVR in a single-center experience. METHODS: We analyzed data of 632 consecutive patients following isolated stented biological AVR between 2007 and 2012 at our institution. We evaluated the QoL (393 evaluable patients) using the Short Form 12-item Health Survey (SF-12) questionnaire via telephone call and the impact of PPM on long-term survival (533 evaluable patients) by Kaplan-Meier's estimate. RESULTS: Severe PPM (<0.65 cm2/m2) had a negative impact on physical component summary (PCS) score (SF-12) compared with patients with moderate or no PPM (p = 0.014), while the mental component summary (MCS) score (SF-12) was not affected by the degree of PPM (p = 0.133). Long-term survival was not different among the three different PPM groups investigated (p = 0.75). CONCLUSION: Severity of PPM demonstrated no influence on long-term survival and MCS score (SF-12), but it was associated with a lower PCS score (SF 12) in patients with severe PPM. PMID- 29975968 TI - Etiology and Prognosis of Severe Ventriculomegaly Diagnosed at Late Gestation. AB - OBJECTIVES: We sought to assess the causes and outcomes of severe VM diagnosed de novo after 24 weeks of gestation where a mid-trimester anomaly scan was described as normal. METHODS: Multicenter retrospective study of five European fetal medicine centers. The inclusion criteria were normal anatomy at the mid trimester scan, uni/bilateral finding of posterior ventricle measuring >= 15 mm after 24 weeks with neonatal and postnatal pediatric and/or neurological assessment data. RESULTS: Of 74 potentially eligible cases, 10 underwent termination, the outcome was missing in 19 cases and there was 1 neonatal death. Therefore, 44 formed the study cohort with a median gestation at diagnosis of 32 + 0 weeks (25 + 6 - 40 + 5). VM was unilateral in five cases. Agenesis of the corpus callosum (ACC) and grade III/IV intraventricular hemorrhage (IVH) accounted for 14 cases each. ACC was isolated in 9 fetuses. Obstructive abnormalities included 5 arachnoid and 1 cavum velum interpositum cyst. Four fetuses had an associated suspected or confirmed genetic condition, 2 congenital infections, 1 abnormal cortical development and the etiology was unknown in 3/44. Postnatal assessment at median 20 months (3 - 96) showed 22/44 (50 %) normal, 7 (16 %) mildly abnormal and 15 (34 %) severely abnormal neurodevelopmental outcomes. CONCLUSION: One half of babies with severe VM diagnosed after 24 weeks have normal infant outcome with ACC and IVH representing the most common causes. Etiology is the most important factor affecting the prognosis of fetuses with severe VM diagnosed at late gestation. PMID- 29975969 TI - Ultrasound-Assisted Tumor Surgery in Breast Cancer - A Prospective, Randomized, Single-Center Study (MAC 001). AB - PURPOSE: Breast-conserving therapy is associated with a risk of tumor-involved margins. For intraoperative orientation, non- palpable or indistinctly palpable lesions are wire-marked prior to surgery. Ultrasound-guided surgery has the potential to reduce the number of tumor-involved margins. In the MAC 001 trial we evaluated ultrasound-guided breast-conserving surgery compared to wire-guided surgery with regard to free tumor margins, duration of surgery and resection volume. MATERIALS AND METHODS: In this randomized, prospective, single-center controlled trial, patients with ductal invasive breast cancer were recruited for either ultrasound-guided or wire localization surgery. Primary outcomes were tumor-free resection margins, the reoperation rate and the resection volume in each group. The results were analyzed by intention to treat. The trial was registered under ClinicalTrials.gov NCT02222675. RESULTS: 56 patients were assessed, and 47 patients were evaluated in the trial. 93 % (25/27) of the patients in the ultrasound arm had an R0 reoperation compared to 65 % (13/20) in the wire localization control arm. This result was statistically significant (p = 0.026). No statistical difference was found for the resection volume or the duration of surgery between the two arms. No major complication was seen in either arm. CONCLUSION: Ultrasound-assisted breast surgery significantly increases the possibility of tumor-free margins and therefore reduces the risk of reoperations. Breast surgeons should be trained in ultrasound and ultrasound should be available in every breast surgery operating room. PMID- 29975970 TI - Ultrasound Markers in Fetal Hydronephrosis to Predict Postnatal Surgery. AB - PURPOSE: Parents confronted with the finding of antenatal hydronephrosis (ANH) are particularly interested in whether their baby will need postnatal surgery. The objective of this study was to predict ANH requiring surgery on the basis of the fetal anteroposterior renal pelvic diameter (APRPD) and the Society for Fetal Urology (SFU) grading system. MATERIALS AND METHODS: The medical records of 179 patients with the finding of ANH were reviewed retrospectively. ANH was graded according to the SFU grading system. Prenatal ultrasound examinations were correlated to postnatal outcome, which was divided into three groups: prenatal resolution, conservative management and surgical treatment. RESULTS: 58 (32.4 %) cases were classified as prenatal resolution, 89 (49.7 %) babies were assigned to the conservative outcome group and 32 (17.9 %) patients needed surgical repair. Postnatal surgery was best predicted in the second trimester (area under the receiver operating characteristics curve: 0.839) by an APRPD cut-off of 8.3 mm (sensitivity: 77.8 %; specificity: 85.7 %; PPV of 53.9 %, NPV of 94.7 %). The combination of the parameters "progression of SFU grade" and SFU grade 3 or 4 achieved a sensitivity of 84.4 % and a specificity of 80.3 % for the prediction of surgery. CONCLUSION: Second-trimester APRPD is a useful parameter for predicting the risk for postnatal surgery. The SFU grade should be assessed in every prenatal ultrasound examination as some further risk estimates can be made based on its dynamics over time. PMID- 29975971 TI - Use of Ultrasound in the Diagnostic Work-Up of Adult Intussusception - A Multicenter Retrospective Analysis. AB - PURPOSE: To evaluate the use of ultrasound (US) in the diagnostic work-up of adult intussusception (AI). METHODS: This multicenter study includes 26 consecutive patients diagnosed with AI between January 2010 and November 2017. A retrospective chart analysis was conducted with a focus on abdominal US findings and diagnostic accuracy of different imaging modalities (ultrasound, computed tomography (CT), magnetic resonance imaging). If available, surgical and pathological findings served as the gold standard (76.9 %). US examiners certified according to DEGUM grade 2 or 3 were classified as experts. Otherwise, they were regarded to have basic skills. RESULTS: During diagnostic work-up, 92.3 % underwent abdominal US. US was the first-line imaging modality in 88.5 % of cases. The accuracy regarding the detection of AI (85 %), correct localization (95 %) and detection of complications (100 %) was excellent and comparable with CT (81 %, 90.5 %, and 91.7 %) when performed by experts. 72.7 % of tumorous lead points were detected by experienced examiners. In contrast, AI was detected in only 45.5 % of cases by examiners with basic skills. AI was diagnosed prior to surgery in all patients. CONCLUSION: US is reliable in the diagnostic work-up of AI when performed by experienced examiners with high-quality equipment. US, CT and MRI should be used in a complementary fashion since combination provides excellent sensitivity regarding the detection and correct localization of AI as well as the detection of complications. The impact of real-time imaging is illustrated by supplementary videos. PMID- 29975972 TI - A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression. AB - INTRODUCTION: Randomized, double-blind, placebo-controlled trials were developed to draw rather unbiased conclusions regarding the efficacy of antidepressants in the treatment of a major depressive episode (internal validity), mostly with the purpose of formal approval of new compounds in this indication. However, at the same time, data suggest that the very process of randomization and blinded administrations of placebo will have a significant impact on the efficacy of the antidepressant tested and therefore may limit the external validity of results obtained from this type of studies. Therefore, there is an urgent need to systematically study the impact of randomization/placebo control/blinding on patient population, efficacy, tolerability, and external validity in the psychopharmacological treatment of patients with a major depressive episode. METHODS: To develop a study design that allows the systematic exploration of the impact of trial design on characteristics of included patient population and outcome. RESULTS: We propose a study design including sample size calculation and statistical analysis in which patients with a major depressive episode are randomized to 3 distinct study designs that differ with regard to control, randomization, and blindness. DISCUSSION: The results of the proposed study design may have substantial consequences when it comes to how to best interpret the results of traditional randomized, double-blind, placebo-controlled trials in the acute treatment of major depressive disorder. Furthermore, they may lead to the implementation of new study designs that may be more suitable for assessing the effectiveness of new antidepressant compounds in everyday clinical practice. PMID- 29975974 TI - [Morphological patterns of hypoxic brain damage in MRI]. PMID- 29975973 TI - Severe Vitamin D3 Deficiency in the Majority of Patients with Diabetic Foot Ulcers. AB - Diabetic foot ulcers are a severe complication in patients with diabetes mellitus. Vitamin D is associated with impaired beta-cell function and insulin resistance, and is necessary for wound healing and bone metabolism. We measured the serum concentrations of 25-hydroxyvitamin D3 in 104 patients (63 inpatients, 41 outpatients) with diabetic foot ulcers and compared them to 99 healthy humans (control) and 103 patients with diabetes mellitus type 2 without diabetic foot ulcers. Calcium, creatinine, and parathyroid hormone were measured in patients with diabetic foot ulcers. The data were analysed together with glycosylated hemoglobin A1c and the severity of diabetic foot lesions according to the Armstrong classification. Levels of 25-hydroxyvitamin D3 were lower (11.8+/-11.3 ng/ml, p<0.001) in patients with diabetic foot ulcers (mean age 70+/-12 years) than in the control group (27.2+/-12.2 ng/ml). No difference was found between in and outpatients. Fifty-eight (55.8%) of patients with diabetic foot ulcers had a severe 25-hydroxyvitamin D3 deficiency with levels below 10 ng/ml. Only 12% of the patients had 25-hydroxyvitamin D3 levels above 20 ng/ml. Secondary hyperparathyroidism was found in 27.9% of patients and 11.5% of the patients were hypocalcemic. There was a negative correlation (r=-0.241) (p<00.1) between Armstrong classification and 25-hydroxyvitamin D3 status. In conclusion, patients with diabetic foot syndrome are at high risk of 25-hydroxyvitamin D3 deficiency. Thus, any patient with diabetic foot syndrome should undergo 25-hydroxyvitamin D3 measurement and supplementation, if values are found to be decreased. PMID- 29975975 TI - Median arcuate ligament syndrome - imaging presentation and interdisciplinary management. PMID- 29975977 TI - ? PMID- 29975976 TI - Prostate Artery Embolization: Indication, Technique and Clinical Results. AB - BACKGROUND: Prostate artery embolization (PAE) is a new embolization therapy to treat benign prostate syndrome (BPS). MATERIALS AND METHODS: This review article presents the rationale and impact mechanism of PAE, criteria for patient selection, and discusses the anatomy of prostate arteries. The study results are seen in the context of complications and clinical partners. RESULTS: Important preconditions for successful prostate artery embolization are a strict indication, precise knowledge of the anatomy of the pelvic arteries and advanced interventional-radiological skills. Several studies showed that urological parameters after prostate artery embolization improve at a similar level as for established post-surgical treatments. At the same time, it could be proven that prostate artery embolization has no impact on erectile function and is associated with a relatively low complication rate. CONCLUSION: PAE is increasingly developing to an alternative for the established surgical treatments in BPS patients. KEY POINTS: . PAE is a new embolization method for treating BPS and represents an alternative to classic urological surgical procedure such as TURP.. . Due to the low caliber of the prostate artery (0.5 - 2 mm), the presence of anatomical variations, and the arteriosclerosis seen in most older men, PAE is a technically challenging embolization method.. . In patients with a high postoperative bleeding risk in classic urological surgical treatment concepts, PAE is a very gentle alternative method.. CITATION FORMAT: . Teichgraber U, Aschenbach R, Diamantis I et al. Prostate Artery Embolization: Indication, Technique and Clinical Results. Fortschr Rontgenstr 2018; 190: 847 - 855. PMID- 29975978 TI - ? PMID- 29975979 TI - Definition, Classification and Diagnosis of Diabetes Mellitus. AB - Aim of recommendations like this one issued by the German Diabetes Association is to provide the GP and diabetologist and his team with information he needs for his daily practice. These recommendations are updated annually. They are written by a group of experts, but they are not evidence based guidelines. This specific recommendation for diabetes diagnosis briefly describes the diabetes types and the different options for diagnosis. Also the caveats and the practical procedure are presented. PMID- 29975980 TI - Practical Recommendations for Glucose Measurement, Glucose Monitoring and Glucose Control in Patients with Type 1 or Type 2 Diabetes in Germany. PMID- 29975981 TI - Bilateral Asymmetry of Nutrient Foramen Position in Forearm Bones: Implications for its Use in Sorting Commingled Remains. AB - Commingling is frequently encountered in cases examined by the Committee on Missing Persons in Cyprus, and pair-matching is routinely used as a preliminary segregation method. Here we examine the degree of bilateral asymmetry in nutrient foramen position of the radius and ulna to determine whether nutrient foramen position may be useful in visual and/or ostetometric pair-matching. Differences in nutrient foramen position between left-right pairs from the same individual were compared with differences in nutrient foramen position between different individuals. Bilateral asymmetry in nutrient foramen position was found to be high, indicating that it is not a reliable trait for pair-matching. Bilateral asymmetry and between-person variation were found to differ between the two bones examined, suggesting that nutrient foramen position in other long bones should also be tested. PMID- 29975982 TI - The Influence of Body Size on the Expression of Sexually Dimorphic Morphological Traits. AB - Skeletal sexual dimorphism manifests as size or shape differences between males and females in a population. Certain dimorphic traits are used in sex estimation methods, and populational variation in the expression of these traits can result in inaccurate sex estimation. However, the underlying causes of variation in trait expression remain unclear. This study explores body size, which also exhibits sexual dimorphism, as a potential factor influencing trait expression. To test this, skeletons of 209 individuals of varying body size were analyzed, and morphological traits were scored according to the Walker (2008), Klales et al. (2012), and Rogers (1999) sex estimation methods. Statistical analyses found significant correlations between body size parameters and expression of traits, with stature explaining more relative variance in trait expression than body mass. However, the relationships are weak and few in number, suggesting that body size has a minimal impact on the expression of these morphological traits. PMID- 29975983 TI - The Kodak Syndrome: Risks and Opportunities Created by Decentralization of Forensic Capabilities. AB - Forensic science laboratories are being challenged by the expanding decentralization of forensic capabilities, particularly for digital traces. This study recommends laboratories undertake digital transformations to capitalize on the decentralization movement, develop a more comprehensive understanding of crime and security-relevant problems, and play a more central role in problem solving collaboratively with law enforcement organizations and other stakeholders. A framework for the bilateral transfer of information and knowledge is proposed to magnify the impact of forensic science laboratories on abating crime, strengthening security, and reinforcing the criminal justice system. To accomplish digital transformations, laboratories require personnel with different expertise, including investigative reasoning, knowledge codification, data analytics, and forensic intelligence. Ultimately, this study encourages managers, educators, researchers, and policymakers to look beyond the usefulness of forensic results for solving individual investigations, and to realize the value of combined forensic knowledge and intelligence for developing broader strategies to deal with crime in digitalized society. PMID- 29975984 TI - Multivariate Global Sensitivity Analysis Based on Distance Components Decomposition. AB - In this article, a new set of multivariate global sensitivity indices based on distance components decomposition is proposed. The proposed sensitivity indices can be considered as an extension of the traditional variance-based sensitivity indices and the covariance decomposition-based sensitivity indices, and they have similar forms. The advantage of the proposed sensitivity indices is that they can measure the effects of an input variable on the whole probability distribution of multivariate model output when the power of distance 060 years of age; after exclusions, we included 2,088 men in the final analysis. We categorized the study participants into three groups according to AUDIT score: low risk (0-7), intermediate risk (8-14), and high risk (>=15 points). RESULTS: Among the study population, 17.0% of the men were high-risk drinkers, who had the highest mean waist circumference, systolic and diastolic blood pressure (BP), fasting plasma glucose (FPG), and triglyceride (TG) levels. The overall prevalence of MetS was 41.9% in the elderly men, and it was significantly higher in the group with high (48.3%) versus low (31.9%) AUDIT scores. The prevalence of MetS components (elevated BP, high FPG, high TG, and low high-density lipoprotein cholesterol) was associated with a high AUDIT score. The odds ratios (95% confidence interval) of the high-risk group for MetS, elevated BP, and high TG were 1.40 (1.03-1.89), 1.82 (1.28- 2.60), and 1.77 (1.30-2.41) after adjustment for confounding variables. CONCLUSION: AUDIT score was correlated with most MetS components in elderly Korean men. PMID- 29975999 TI - Deastringent Peel Extracts of Persimmon (Diospyros kaki Thunb. cv. Cheongdo Bansi) Protect Neuronal PC-12 and SH-SY5Y Cells against Oxidative Stress. AB - The peel of astringent persimmon (Diospyros kaki Thunb. cv. Cheongdo-Bansi) is a by-product of dried persimmon (gotgam). We investigated if deastringent peel extracts of persimmon cv. Cheongdo-Bansi had antioxidative and neuroprotective properties. Two different extracts were prepared: thermally and nonthermally treated persimmon peel extracts (TPE and NTPE, respectively). Both TPE and NTPE were fractionated sequentially in n-hexane, chloroform, ethyl acetate, n-butanol, and water. The TPE and NTPE ethyl acetate fractions had the highest total phenolic and flavonoid contents as well as antioxidant capacities among all the fractions. Pretreatment of neuronal PC-12 and SH-SY5Y cells with the TPE and NTPE ethyl acetate fractions increased cell viability after exposure to oxidative stress. The ethyl acetate fraction of TPE attenuated oxidative stress inside both PC-12 and SH-SY5Y cells more effectively than that of NTPE. Furthermore, the TPE and NTPE ethyl acetate fractions inhibited acetylcholinesterase and butyrylcholinesterase. Analysis of ultra-high-performance liquid chromatography electrospray ionization-tandem mass spectrometry results revealed gallic acid, kaempferol, kaempferol-3-O-galactoside, kaempferol-3-O-glucoside, quercetin, quercetin-3-O-galactoside, quercetin-3-O-galactoside-2'-O-gallate, and quercetin 3-O-glucoside as the major phenolics of the TPE and NTPE ethyl acetate fractions. Taken together, these results suggest that the ethyl acetate fraction of deastringent persimmon peel is rich in antioxidants and has potential as a functional food to reduce oxidative stress. PMID- 29976001 TI - Association between Possibility of Purchasing Cigarettes and E-cigarette Experience among Korean Adolescent Smokers. AB - Background: To aim of this study was to examine the association between perceived possibility of purchasing cigarettes and e-cigarette experience among adolescents who currently smoke cigarettes. METHODS: Data were derived from the Korea Youth Risk Behavior Web-Based Survey; a total of 29,169 current smokers participated. The dependent variable was e-cigarette experience in the previous month. Analyses included chi2 test and survey logistic regression. RESULTS: A perceived easy possibility of purchasing cigarettes increased the odds of e-cigarette experience (odds ratio, 1.19; 95% confidence interval, 1.07-1.33) compared to when it was perceived as impossible. An easy possibility of purchasing cigarettes increased the odds of e-cigarettes experience among males aged 12-15 or 17 years compared to when it was impossible to purchase cigarettes. CONCLUSION: A perceived easy possibility of purchasing cigarettes was more likely to increase e-cigarette experience among adolescents. Laws restricting adolescents' access to e cigarettes must be strengthened. PMID- 29976002 TI - Associations between urinary monohydroxy polycyclic aromatic hydrocarbons metabolites and Framingham Risk Score in Chinese adults with low lung function. AB - Previous studies have reported an association of exposure to polycyclic aromatic hydrocarbons (PAHs) with lung function decline or cardiovascular diseases, or reduced lung function with 10-year cardiovascular (CV) risk. We analyzed risk factors for the 10-year Framingham CV risk using multiple logistic regression, and examined the mediational effect of reduced lung function on the association between exposure to PAHs and FRS using the post-exploratory structural equation modeling. Participants (n = 2268) were drawn from the Wuhan residents at baseline from the Wuhan-Zhuhai Cohort Study. They completed the physical examination, measurements of lung function and urinary monohydroxylated-PAHs (OH-PAHs). In all individuals, we found a dose-response relationship of PAHs exposure, forced expiratory volume in 1s (FEV1) or forced vital capacity (FVC) with the 10-year CV risk. The proportions of FEV1 and FVC mediation effects in association of PAH exposure with the10-year CV risk were 35% and 24%, respectively. The findings indicated that PAHs exposure or reduced lung function increased the 10-year CV risk. Impaired lung function may partly contribute to increase in the 10-year CV risk regarding exposure to PAHs. PMID- 29976003 TI - How can salicylic acid and jasmonic acid mitigate salt toxicity in soybean plants? AB - This research was undertaken to assess the impact of 1mM salicylic acid (SA) and 0.5mM jasmonic acid (JA) on alleviation of oxidative, ionic and osmotic stresses of different levels of salinity (0, 4, 7, 10 dS m-1 NaCl, respectively). Salinity increased the contents of glycine betaine, proline, soluble sugars, proteins and the activities of peroxidase, catalase, superoxide dismutase, ascorbate peroxidase, and the amount of malondialdehyde and sodium ion of soybean leaves, but decreased the leaf water content, membrane stability index, potassium and calcium ions, chlorophylls content, chlorophyll stability index, plant biomass and seed yield. Foliar spray of JA reduced Na+ entry to the cells, while enhancing the glycine betaine and soluble proteins content, antioxidant enzymes activity, membrane stability index and leaf water content. This treatment had no effect on potassium and the calcium ions content, chlorophyll contents, chlorophyll stability index, soluble sugars, plant biomass and seed yield. In contrast, SA enriched the leaf cells with potassium and calcium ions under different levels of salt stress and increased glycine betaine, soluble sugars, proteins, antioxidant enzymes, leaf water content, membrane stability index, chlorophyll content and chlorophyll stability index, but reduced proline content. These superiorities of SA treatment led to considerable improvement in plant biomass (10%) and seed yield (17%) of soybean. PMID- 29976004 TI - Hematological, physiological and genotoxicological effects of Match 5% EC insecticide on Biomphalaria alexandrina snails. AB - Freshwater snails are used as brilliant biomarkers of aquatic ecosystem pollution by chemical compounds. The objective of this study is to highlight the ecotoxicological impacts of the insecticide Match 5%EC (its active ingredient is lufenuron 5% EC) on Biomphalaria alexandrina snails the intermediate host of Schistosoma mansoni in Egypt. The present investigation recorded a remarkable molluscicidal effect of lufenuron 5% EC on these snails and there was a decrease in total number of their hemocytes after exposure. Three morphologically distinct populations of circulating hemocytes were identified (round small cells, granulocytes and hyalinocytes) and results showed that some hyalinocytes had a shrunk nucleus and some were degenerated. Significant increase of transaminases (ALT and AST), while, a decrease of the total protein and albumin content in hemolymph was recorded. The results of alkaline comet assay in the present study demonstrated that lufenuron 5% EC has a genotoxic effect especially when its concentration increases. It can be concluded that Biomphalaria alexandrina snails can be used as bio monitor to screen the deleterious effects of lufenuron 5% EC insecticide as a cause of the environmental pollution, and this insecticide can be used in controlling schistosomiasis because of its molluscicidal effects on B. alexandrina snails. PMID- 29976005 TI - Comparative studies on muscle microstructure and ultrastructure of Mythimna separata Walker treated with wilforgine and chlorantraniliprole. AB - We attempted to elucidate the comparative effects between wilforgine and chlorantraniliprole on the microstructure/ultrastructure of muscle tissue in Mythimna separate larvae. The typical toxicity symptoms of M. separata larvae upon wilforgine treatment was feeding cessation and flaccid paralysis, whereas feeding cessation and contraction paralysis were the main poisoning symptoms wrought by chlorantraniliprole. Light-microscopy observations showed that the microstructure of muscle tissue could be damaged by wilforgine and chlorantraniliprole, and the death of insects was associated with muscle lesions. Muscle tissue was loose after wilforgine treatment but constricted muscle tissue was observed upon chlorantraniliprole treatment. Transmission electron microscopy showed that wilforgine and chlorantraniliprole could disrupt endomembranes and plasma membranes. These results suggest that wilforgine can induce microstructural and ultrastructural changes in the muscles of M. separata larvae; the sites of action are proposed to be calcium receptors or channels in the muscular system. PMID- 29976006 TI - A critical review on speciation, mobilization and toxicity of lead in soil microbe-plant system and bioremediation strategies. AB - Lead accumulation in soils is of serious concern in agricultural production due to the harmful effects on soil microflora, crop growth and food safety. In soil, speciation of lead greatly affects its bioavailability and thus its toxicity on plants and microbes. Many plants and bacteria have evolved to develop detoxification mechanisms to counter the toxic effect of lead. Factors influencing the lead speciation include soil pH, organic matter, presence of various amendments, clay minerals and presence of organic colloids and iron oxides. Unlike, other metals little is known about the speciation and mobility of lead in soil. This review focuses on the speciation of lead in soil, its mobility, toxicity, uptake and detoxification mechanisms in plants and bacteria and bioremediation strategies for remediation of lead contaminated repositories. PMID- 29976007 TI - Use of Ethylenediurea (EDU) in identifying indicator cultivars of Indian clover against ambient ozone. AB - Three clover (Trifolium alexandrium L.) cultivars (Bundel, Wardan and JHB-146) were assessed for their responses to ambient ozone (O3) with respect to growth, physiological and biochemical parameters at two rural sites (R1 and R2) using ethylenediurea (EDU). EDU solution (300ppm) was applied as soil drench, 10 days after germination (DAG) at an interval of 10 days up to 80 DAG. The average O3 concentrations were 52.76 and 60.86 ppb at R1 and R2 sites, respectively during the experimental period. Ambient O3 induced visible symptoms in all the cultivars at both the sites, with more at R2 site having high ambient O3 levels. Visible injury was observed first in non-EDU treated plants of Wardan at R2 site. Wardan also showed maximum reduction in leaf injury under EDU treatment at both the sites with more at R2. Under EDU treatment, better adaptation to ambient O3 at initial age of observation and higher acquisition of resources at later ages of observation at both the sites led to better physiological and biochemical adaptations in Wardan. Bundel retained more biomass in shoot as is reflected with higher shoot/root ratio and thus focused more on repair and defense. Shoot/root ratio of JHB-146 did not respond to EDU treatment and thus showed insignificant variations except at initial age of observation at R1 site. This study clearly suggests that Wardan and Bundel are sensitive to ambient O3 and can be used as bioindicator species in areas having higher O3 levels using EDU as a research tool. PMID- 29976008 TI - Genes coding for transporters showed a rapid and sharp increase in their expression in response to lead, in the aquatic fern (Salvinia minima Baker). AB - Salvinia minima was assessed for its ability to accumulate lead (Pb) by exposing it to concentrations of 40uM Pb(NO3)2 during 24h. At the same time, the expression levels were quantified, of four genes coding for transporters: SmABCC (ABCC-MRP), SmATPase (ATPase-P3A), SmNhaD (Type-Na+/H+) and SmABCG (ABCG-WBC). In the absence of lead, S. minima had very low expression of those genes, when plants were exposed to the metal however, those genes showed a rapid (in just three hours or less) and sharp increase (up to 60 times) in their expression, particularly the SmNhaD (Type-Na+/H+) gene. This sharp increase in expression levels of the genes studied, occurred at the same time that the plant accumulated the highest content of lead in its tissues. The first two genes, are apparently implicated in detoxification and lead accumulation mechanisms, while the other two genes are apparently involved in maintaining cell balance (homeostatic control) and membrane integrity. Our results confirmed that S. minima is efficient for phytoremediation of water bodies contaminated by lead, as it is efficient in accumulating this metal in its tissues (bioconcentration factor; BCF) values greater than 1000, in short times of exposure. More importantly, our data on the expression profiles of four genes coding for transporters, represent a first sight scenario of the molecular basis for understanding the different mechanism of detoxification, apparently present in this aquatic fern. PMID- 29976009 TI - Genotoxic effects of olive oil wastewater on sunflower. AB - The aim of this study is to determine in detail the genotoxic effects of Olive Oil Wastewater (OOWW) on sunflower. For this reason, different concentrations of OOWW (1/1,1/10,1/100) were applied as irrigation water to sunflowers at different times (3-day, 5-day, 10-day). In the plants taken during these times, RAPD-based genomic template stability (GTS) assays and gene expression (transcriptomic) levels of different free radical scavenging enzyme genes (SOD, CAT, SOD2, GST, GPX, APX), protein repair/chaperoning genes (HSP26, HSP70, HSP83), N metabolism gene (GS) and apoptotic genes (BAX, BCL2, BCLXL, CYT-C, XIAP) were compared to the those of the control (OOWW-free) group. As a result; The GTS rates seemed to be fairly lower than the control and therefore the OOWW was likely to cause significant damage to the DNA's nucleotide and genomic structure, and the GTS value increased inversely proportional when the OOWW concentration was reduced from 1/1 to 1/10, and after a 10-day application, it seemed to be partly healing. In transcriptomic analysis; all OOWW experiments caused a free radical threat, and especially in 5-day OOWW applications, this raised significantly almost all expressions of antioxidants, protein repair, N metabolism, and apoptotic genes. So, the damages of 5-day OOWW treatments were found to be relatively more than those of 3-day treatments. Regarding 10-day transcriptomic data; a partial repair was found. Additionally, it was determined that the values of B, F, Al, Mn, Ni, Cr, As, Se, Cd, Pb and total polyphenols were high in OOWW. Our findings were also supported by plant images and various heavy metals' and OOWW polyphenols' toxicity results. Our results pointed to key findings in OOWW genotoxicology. PMID- 29976010 TI - Platinum uptake, distribution and toxicity in Arabidopsis thaliana L. plants. AB - Platinum (Pt) occurs at very low levels in parent rock and soils in unpolluted areas, however concentrations of this element in urban areas is steadily increasing. At the levels recorded in urban environments, Pt is not yet phytotoxic, but it already poses a threat to human health, particularly when present in airborne particulate matter. In this study an attempt was made to evaluate Pt(II) uptake, distribution and toxicity in Arabidopsis thaliana L. plants. Arabidopsis thaliana plants were hydroponically grown with increasing Pt(II) concentrations in the range of 0.025-100uM. Pt(II) was taken up by the roots and translocated to the rosette. At lower Pt(II) concentrations (<= 2.5MUM) hormesis was recorded, plant growth was stimulated, the efficiency of the photosynthetic apparatus improved and biomass accumulation increased. Higher Pt(II) concentrations were phytotoxic, causing growth inhibition, impairment of the photosynthetic apparatus, membrane injuries and a reduction in biomass accumulation. Exposure of A. thaliana to Pt(II) also resulted in an increased content of phytochelatins throughout the plant and glutathione in the rosette. Uptake and translocation of Pt(II) to harvestable organs of A. thaliana suggests that species of higher biomass accumulation from the Brassicaceae family can probably be used for the phytoextraction of Pt-polluted sites. PMID- 29976012 TI - Fine structure of oviducal epithelium of Xenopus laevis in relation to its role in secreting egg envelopes. AB - During passage through the oviduct, the egg of Xenopus laevis acquires the following substances or envelopes: electron-dense particles in the vitelline coat, the prefertilization layer in and around the vitelline coat, and four layers of jelly. Both gross anatomical observation and light and scanning or transmission electron microscopic observations of various levels of oviduct revealed that the first two are produced in the pars recta 1 and 2 portions, and that jelly layers 1-4 are added in the pars convoluta 1-4 respectively. The relative lengths of these portions were 0-0.044, 0.044-0,055, 0.055-0.52, 0.52 0.70, 0.70-0.87 and 0.87-1.00 from anterior to posterior. Along the whole length of the oviduct, the epithelium was comprised of ciliated cells and various types of secretory cells. Except for the pars recta 1 portion, there were two or three types of secretory cells in each portion of the oviduct, indicating that the structure of each stratum of the egg envelope is formed by an interaction of products from the specific types of secretory cells in each portion of the oviduct. PMID- 29976011 TI - Insights into citric acid-induced cadmium tolerance and phytoremediation in Brassica juncea L.: Coordinated functions of metal chelation, antioxidant defense and glyoxalase systems. AB - Cadmium (Cd) is a serious environmental threat because it accumulates in plants from soil and is subsequently transported into the food cycle. Increased Cd uptake in plants disrupts plant metabolism and hampers crop growth and development. Therefore, remediation of Cd from soil and enhancing plant tolerance to metal toxicity is vital. In the present study, we investigated the function of different doses of citric acid (CA) on Cd toxicity in terms of metal accumulation and stress tolerance in mustard (Brassica juncea L.). Brassica juncea seedlings (12-day-old) were treated with Cd (0.5mMCd and 1.0mM CdCl2) alone and in combination with CA (0.5mM and 1.0mM) in a semi-hydroponic medium for three days. Cadmium accumulation in the roots and shoots of the mustard seedlings increased in a dose-dependent manner and was higher in the roots. Increasing the Cd concentration led to reduced growth, biomass, water status, and chlorophyll (chl) content resulting from increased oxidative damage (elevated malondialdehyde, MDA content; hydrogen peroxide, H2O2 level; superoxide, O2*- generation; lipoxygenase, LOX activity; and methylglyoxal, MG content) and downregulating of the major enzymes of the antioxidant defense and glyoxalase systems. Under Cd stress, both doses of CA improved the growth of the plants by enhancing leaf relative water content (RWC) and chl content; reducing oxidative damage; enhancing the pool of ascorbate (AsA) and glutathione (GSH) and the activities of the antioxidant enzymes (ascorbate peroxidase, APX; monodehydroascorbate reductase, MDHAR; dehydroascorbate reductase, DHAR; glutathione reductase, GR; glutathione peroxidase, GPX; superoxide dismutase, SOD; catalase, CAT); improving the performance of the glyoxalase system (glyoxalase I, Gly I and glyoxalase II, Gly II activity); and increasing the phytochelatin (PC) content. Exogenous CA also increased the root and shoot Cd content and Cd translocation from the roots to the shoots in a dose-dependent manner. Our findings suggest that CA plays a dual role in mustard seedlings by increasing phytoremediation and enhancing stress tolerance through upregulating the antioxidant defense and glyoxalase systems. PMID- 29976013 TI - Fine structure of antennal putative thermo-/hygrosensilla of adult Rhodnius prolixus Stal (Hemiptera: Reduviidae). AB - At least five nonporous sensilla with inflexible sockets (npsensilla) occur on each antenna of both sexes of adult Rhodnius prolixus. Externally the sensillum appears as a short, rounded peg set into a pit surrounded by a depression. A very electron-dense material occurs in the peg lumen and the inner aspect of the pit. Filamentous extensions of this material radiate into the overlying outlets. Each sensillum is innervated by three neurons with unbranched dendrites. Two dendrites extend to the peg tip and distally are covered by a dendritic sheath. The portion of these dendrites within the sheath contains a large number of microtubules. The third dendrite terminates near the base of the dentritic sheath and partially wraps around the other two dendrites. Three sheath cells are associated with each sensillum. Based on similarities in structure with sensilla of known function it is probable that the np-sensilla of R. prolixus are thermo-/hygrosensilla responding to cold, dryness and wetness. The sensilla have a number of structural similarities with insect rectal sheath cells known to absorb atmospheric water by electroosmosis. Possibly this process leads to volumetric alterations of cuticular elements associated with the dendrites and ultimately to mechanotransduction. PMID- 29976014 TI - Fine structure of the micropylar cell and its change during oocyte maturation in the chum salmon, Oncorhynchus keta. AB - In the ovarian follicle, the micropylar cell (MPC) is distinguished from neighboring granulosa cells by its larger cell size and its thick cytoplasmic process. The micropylar cell body fits into a shallow depression (micropylar vestibule) on the outer surface of the egg envelope; its process extends through the micropylar canal, which extends from the bottom of the vestibule through the full thickness of the zona pellucida interna. At its distal end, the cell process expands into a bulb which fits into an indentation of the ooplasmic surface immediately beneath the inner opening of the micropylar canal. Intermediate and desmosomelike junctions establish an intimate association between MPC process and oocyte. Various kinds of organelles and inclusions in the MPC show a characteristic pattern of cytoplasmic distribution; rough endoplasmic reticulum with markedly dilated cisternae is found exclusively in the main cell body, while microtubules and thin filaments are observed in the cytoplasmic process. Immediately before or during the breakdown of the germinal vesicle in the intrafollicular oocyte, the cytoplasmic process of the MPC gradually decreases in length and begins to withdraw from the micropylar canal. At the same time, the ooplasmic surface protrudes outward to form a papilla in the canal. The intimate MPC-oocyte association disappears during formation of the ooplasmic papilla. Hydration of the oocyte apparently occurs at the final stage of maturation and probably participates in papilla formation. Although the MPC undergoes degenerative changes as ovulation draws near, it remains attached to the inner surface of the granulosa cell layer even after its association with the oocyte has completely disappeared. We speculate that the micropyle develops during fish oogenesis through the combined activity of the MPC and neighboring granulosa cells. It appears that the cell body of the micropylar cell and nearby granulosa cells exert mechanical pressure on the external surface of the growing oocyte and thus participate in formation of the micropylar vestibule. The cytoplasmic process of the MPC evidently forms a passive barrier to deposition of material for the egg envelope in the animal pole, thereby resulting in formation of the micropylar canal. PMID- 29976015 TI - Functional organization of battery cell complexes in tentacles of Hydra attenuata. AB - Ultrastructural and light microscopic observations on the organization of thick and thin regions of hydra's tentacles, made on serial sections and on whole fixed, plastic-embedded tentacles, reveal the existence of two levels of anatomical order in the tentacle ectoderm: (1) The battery-cell complex (BCC), composed of a single epitheliomuscular cell (EMC) and its content of enclosed nematocytes and neurons; and (2) the battery cell complex ring (BCC ring), an arrangement of 4 or more BCCs into larger units organized as rings around the circumference of the tentacle. All EMCs of the distal tentacle appear to contain batteries of nematocytes, and are, therefore, called "battery cells." Apart from battery cell complexes and migrating nematocytes, there are no other cell types in the tentacle ectoderm. Battery cells are composed of three distinct regions: the cell body, peripheral attenuated extensions and myonemes. Thick tentacle bands are composed of cell bodies, whereas thin bands are made up of attenuated extensions. Myonemes contribute to both thick and thin regions. It was confirmed that each battery cell has several myonemes, which appear to interdigitate with myonemes of other more proximal and distal battery cells, but not with battery cells of the same BCC ring. Nematocytes have several basal processes. Some processes insert between myonemes and contact the mesoglea; other processes insert into cuplike extensions of myonemes, and are connected to myonemal cups by desmosomal junctions. These observations are discussed in relation to mechanical and electrical aspects of tentacular contraction and bending. PMID- 29976016 TI - Fine structure and classification of shrimp hemocytes. AB - The structure of hemocytes from two species of penaeid shrimp was examined by light and electron (TEM) microscopy. Hemocytes from the two species are indistinguishable and are classified as either agranular, small-granule, or large granule hemocytes. Agranular hemocytes are the smallest of the hemocytes, lack granules, compose only 5-10% of the circulating hemocytes, and are nonrefractile when examined by light microscopy. Small-granule hemocytes are the most abundant type of hemocyte (75% of all hemocytes), appear nonrefractile, and contain a variable number (1-40) of granules (0.4 MUm diameter). Large-granule hemocytes compose 10-20% of the hemocytes. They are filled with granules (0.8 MUm in diameter) that are highly refractile when examined by light microscopy and are electron-dense when examined by TEM. Our classification scheme is based solely on the absence or presence and relative size of granules. Features used by other researchers, such as cell size, shape, and staining properties, were not used because these features are subtle and/or subjective. The proposed classification is compared with schemes developed for other decapods, and its usefulness and limitations are discussed. This scheme will serve as a basis for further studies on the maturation and physiological function(s) or crustacean hemocytes. PMID- 29976017 TI - Fat distribution in the skin of bottlenose dolphins (Tursiops truncatus and Tursiops gilli). AB - Frozen sections stained with Oil-red-O and semithin (0.5 MUm) plastic sections stained with toluidine blue revealed an abundance of fat globules of various sizes in all strata of the epidermis of bottlenose dolphins (Tursiops truncatus and T. gilli). The fat was rather evenly distributed but sometimes appeared as circumscribed areas of heavier concentration involving hundreds of cells (as seen in a single plane). Occasionally, there were smaller groups of epidermal cells heavily loaded with lipid. The dermis presented a unique phenomenon in the presence of abundant extracellular fat distributed among the collagen bundles as droplets of various sizes or as larger, irregularly shaped lipid particles that seemed to conform to the spaces between collagen bundles. These lipid particles were sometimes seen to be closely applied to the dermal surface of the stratum basale. Equally unusual was the presence of lipid particles of various sizes and shapes in the lumen of some of the vessels of the dermal papillae. Granular cells resembling mast cells were commonly seen in the papillary dermis and some were closely associated with lipid particles. Blood vessels of the reticular dermis tended to have collections of lipid droplets in the loose connective tissue often found adjacent to the tunica adventitia. It is postulated that the extracellular dermal lipids (probably mainly triglycerides) are broken down to free fatty acids that diffuse into the basal layer of the epidermis and are there resynthesized into triglycerides. Possible uses for the epidermal lipids are discussed. PMID- 29976018 TI - Fine structure of spermatozoa of some labidognath spiders (Filistatidae, Segestriidae, Dysderidae, Oonopidae, Scytodidae, Pholcidae; Araneae; Arachnida) with remarks on spermiogenesis. AB - The present study reports on the spermiogenesis and spermatozoa of seven labidognath spiders: Filistata insidiatrix (Filistatidae), Segestria senoculata (Segestriidae), Dysdera sp., Harpactea hombergi (Dysderidae), Oonops domesticus (Oonopidae), Scytodes thoracica (Scytodidae), and Pholcus phalangioides (Pholcidae). Filistata insidiatrix is the first cribellate spider whose spermatology is described electron microscopically. A common characteristic of the spermatozoa of the cribellate spider and the remaining species, often referred to as haplogyne spiders, is the coiling process that occurs at the end of spermiogenesis. As a result of coiling, an elongated spermatid is converted into a lens-shaped structure with the flagellum bearing a 9 * 2 + 3 axoneme becoming incorporated into the cell body. Remarkable differences regarding the main components (shape of nucleus, acrosomal vacuole, implantation fossa, and centriolar complex) probably reflect systematic relationships. The formation of sperm capsules and sperm balls is described for the first time in detail. Sperm capsules occur in Filistata, in which numbers of individual spermatozoa are grouped together by a common secretory envelope established in the distal vas deferens. In contrast, in the sperm balls, two (Harpactea) or four (Segestria, Dysdera, Seytodes) spermatids fuse completely at the end of spermiogenesis. These sperm balls, considered unique in the animal kingdom, are also provided with an envelope. A further peculiarity not reported previously is the occurrence of a large vesicular area in the sperm balls of Dysdera and Harpactea; this area is also found in Oonops, which, however, possesses individual spermatozoa. Components of the spermatozoa such as the acrosomal vacuole, part of the nucleus, and the axoneme protrude into this area and are thus secondarily covered with a membrane. A detailed study of the individual spermatozoa of Pholcus phalangioides completes earlier investigations and stresses the exceptional position of the genus in comparison to that of other spiders. PMID- 29976019 TI - Fine structure of the statocyst sensilla of the mysid shrimp Neomysis integer (Leach, 1814) (Crustacea, Mysidacea). AB - The fine structure of the statocyst sensilla of Neomysis integer was investigated. The statocyst contains about 35 sensilla, which are composed of two bipolar sensory cells, nine enveloping cells, and a seta. The sensory cells consist of an axon, a perikaryon, and a dendrite. The dendrite contains a proximal segment with a ciliary rootlet and at least one basal body, and a distal segment with a ciliary axoneme (9 * 2 + 0) at its base. The distal segment extends along the peripheral wall of the seta and is in close contact with the wall of the hair shaft. The enveloping cells surround the proximal and distal segments of the dendrite. The innermost enveloping cell contains a scolopale rod. It surrounds the receptor lymph cavity and secretes flocculent material into this cavity. From the tip of the cell a dendritic sheath, which encloses the distal segment of the dendrite, emerges. A peculiar feature of the second enveloping cell is the presence of a scolopale-like rod, which is more slender and less pronounced than in the first enveloping cell. The seta consists of three parts: a socket, a tubular midpart, and a gutter-like apical part, the tip of which penetrates into the statolith. The seta shows over its full length a bilaterally symmetrical axis that is coplanar with the plane in which the seta is bent toward the statolith. The structure of the seta and the position of the distal segments provide morphological evidence for directional sensitivity of the sensilla and for the magnitude of shear on the setal wall being an adequate stimulus. PMID- 29976020 TI - Formation of the pronephros and pronephric duct rudiment in the Mexican axolotl. AB - In the Mexican axolotl (Ambystoma mexicanum), the pronephros begins to form at the four-somite stage. It is initially continuous with the posterior-lateral region of somite 2 and the lateral margin of somites 3 and 4. By the seven-somite stage, the pronephros has become compacted, and the cells are now morphologically distinct from the somitic cells. At this stage, a mass of loosely connected cells, apparently originating from the lateral mesoderm, is seen below somites 4 and 5. By the eight-somite stage, these presumptive duct cells have migrated dorsally to the duct path and are found below somites 5-7. By the nine-somite stage they have begun to migrate caudally. PMID- 29976021 TI - Follicular placenta and embryonic growth of the viviparous four-eyed fish (Anableps). AB - In the four-eyed fish, Anableps (Atheriniformes, Anablepidae), eggs are fertilized and embryos develop to term within the ovarian follicles. Development is highly matrotrophic. During gestation, the largest term embryo of A. anableps examined had grown to a total length of 51 mm and attained a dry weight of 149 mg. The postfertilization weight increase is 298,000%. The largest term embryo of A. dowi examined had grown to a total length of 77 mm and attained a dry weight of 910 mg. The postfertilization weight increase is 843,000%. Embryonic weight increases result from nutrient transfer across the follicular placenta. This structure is formed by apposition of the maternal follicular epithelium to absorptive surface cells of the embryo's pericardial trophoderm. The latter, a ventral ramification of the pericardial somatopleure, replaces the yolk sac during early gestation. The external surface of the pericardial trophoderm develops hemispherical projections, termed vascular bulbs. Within each bulb, the vascular plexus of the trophoderm expands to form a blood sinus. Cells of the external surface of the bulbs possess microplicae. Microvilli are absent. During middle to late gestation, the juxtaembryonic follicular epithelium differentiates into two regions. One region consists of shallow, pitlike depressions within which vascular bulbs interdigitate in a "ball and socket" arrangement. Follicular pits are formed by the curvilinear distortion of the apical surfaces of follicle cells. The second region in contact with the dorsal and lateral surfaces of the embryo, is comprised of villous extensions of the hypertrophied follicular epithelium. In both regions, follicle cells appear to constitute a transporting rather than a secretory epithlium. In terms of percentage of weight increase, the follicular placenta of Anableps appears to be the most efficient adaptation for maternal-embryonic nutrient transfer in teleost fishes and closely approaches the efficiency (1.2 * 106 %) of oophagy and embryonic cannibalism in lamnoid sharks. PMID- 29976022 TI - In situ manifestations of nonself recognition between incrusting sponges. AB - The present study investigates the morphological aspects of nonself recognition between three incrusting sponge species living in contact. Two types of association have been observed: nonmerging fronts and epizoism. In two of the three combinations studied, Hymeniacidon sanguinea/Halichondria panicea and Halichondria panicea/Ophlitaspongia seriata, nonself contacts consisted of either epizoism or of nonmerging fronts. In contrast, only nonmerging fronts were observed between Hymeniacidon sanguinea and Ophlitaspongia seriata. In the two types of associations, the main phenomenon consists of the isolation of the foreign sponges by a spongin barrier secreted by the partners in the zone of contact. The microscpic structure and the thickness of the barrier vary according to the type of association and the species paired, but they are clearly defined for a given combination. The conditions required for the establishment of epizoism and the existence of a natural xenogeneic tolerance between sponges are discussed. PMID- 29976023 TI - Mineral content of the organ of Bellonci in the marine amphipod Gammarus setosus. AB - Calcium is demonstrated by energy and wavelength dispersive X-ray microanalysis to be the major component of the granules that fill the fuselli of the organ of Bellonci in Gammarus setosus. The presence of calcium was confirmed by chelation with EDTA and by other cytochemical techniques. X-ray microanalysis indicated the simultaneous presence of iron in the region of the fuselli occupied by the calcium granules, but this could not be confirmed by cytochemical means in resin embedded tissue by light or transmission electron microscopy. PMID- 29976024 TI - Modifications of the fertilized egg surface following the cortical reaction in Limulus polyphemus L. as viewed with the scanning electron microscope. AB - In the development of the horseshoe crab, Limulus polyphemus, the fertilized egg undergoes a complicated cleavage (Stages 1-3) resulting in blastoderm formation (Stage 4). Stage 1 involves intralecithal cleavage and consists of nine discrete surface modifications (events) which have been briefly described with light microscopy by Brown and Barnum ('83). Since in Stage 1 the cortical reaction (events 1-4) has already been examined with ultrastructural methods, the objectives of the present study were to examine with scanning electron microscopy: (1) the first two of three intermittent granulations (events 5 and 7), and (2) the associated events characterized by smooth surfaces (events 4, 6, and 8). The first granulation occurs 2 1/2 to 3 hours after fertilization (22 degrees C) and lasts approximately 1 1/2 hours. The second granulation appears approximately 5 hours after fertilization and lasts about 3 hours. The dynamic changes that occur during the two granulations involve the transformation of a smooth appearing embryonic surface, liberally coated with microvilli, into a granule-dominated surface on which microvilli are greatly reduced in number. Also of considerable interest are the numerous projections which begin to appear on the surface near the end of the second granulation (event 7) and dominate the surface of the following smooth step stage (event 8). Hypotheses on the significance of these dynamic changes and surface modifications involve relationships to the cell cycle, possible mechanisms for membrane storage, and secretory function. PMID- 29976025 TI - Intricate sutures as fractal curves. AB - The study of fractal dimensionality for complex sutures in deer skulls and ammonites reveals their extremely long and elaborate lengths in relation to the defined areas they bound. These sutures often show various scales of self similarity (where the parent pattern is elaborated in miniature, again and again), and empirical fractal dimensions calculated lie between one and two. In the scaling elaborations of Cervid sutures, some elaborations seem isolated from the continuous suture. Small "islands" are seen in similar theoretical fractal curves as well. The evolutionary and developmental specialization of intricate sutures improves the bonds; such fitness is essential owing to extraordinary stresses. Autocorrelation (where nearby sides or elaborations tend to resemble a basic pattern and, therefore, resemble one another) of the elaborations of the sutures serves to lengthen the boundaries and theoretically enhances the development of self-similar patterns. When autocorrelation and self-similarity in the sutures are favored by an evolutionary process plastic enough to elaborate intricate form, ensuring fitness, and natural selection does not directly limit the lengths while concomitantly defining the bounded areas, then the intricacy is manifest as fractal phenomena, and practically described as such. PMID- 29976026 TI - Microcirculation in mouse spleen (nonsinusal) studied by means of corrosion casts. AB - Corrosion casts of mouse spleen, examined by scanning electron microscopy, enabled vascular pathways of the arterial, intermediate, and venous circulations to be traced over considerable distances. The arterial tree is surrounded by white pulp immediately upon entering at the hilus, and relatively few arterioles extend into red pulp. A profusion of capillaries is present in both periarterial lymphatic sheaths and lymphatic nodules, arranged as bifurcating systems (rather than anastomosing networks) terminating in the marginal sinus (MS) and marginal zone (MZ). The MS, which is situated between white pulp and MZ, consists of a discontinuous layer of flattened anastomosing spaces which are up to six times as large as those in rat spleen. Extensive filling of the entire MZ took place before appreciable filling of surrounding red pulp occurred. Capillary terminations in red pulp are always continuous with reticular meshwork, i.e., no evidence for a "closed" circulation was found. Casts of the venous origins support the classification "pulp venules" rather than "venous sinuses" and show major morphological differences from the richly anastomosing system of sinuses in rat. In the subcapsular region of mouse spleen large anastomosing veins ramify over the surface, with reticular meshwork occupying extensive areas between adjacent veins. For in vivo microscopy this arrangement offers advantages over that found in rat spleen (accompanying paper), where almost the entire surface is densely covered with venous sinuses. PMID- 29976027 TI - Immunocytochemical study of the hyperglycemic hormone (CHH)-producing system in the eyestalk of the crayfish Astacus leptodactylus during larval and postlarval development. AB - Immunocytochemical investigation of the eyestalks of the larval and postlarval stages of the crayfish Astacus letodactylus, using an anti-Astacus-CHH serum, shows that immunopositive staining starts in the immediate posthatching larval stage, in neurosecretory cells of the medulla terminalis ganglionic X-organ (MTGX), in an MTGX-sinus gland tract, and in part of the axon terminals of the sinus gland. The number of these immunopositive cells increases during postlarval development. Neurosecretory granules belonging to distinct axon terminals of the neurohemal region show immunostaining. The mean diameter of the stained granules increases during postlarval development. The hemolymph glucose concentration in adult crayfish increases after injection of larval eyestalks. PMID- 29976028 TI - Microcirculation in rat spleen (sinusal), studied by means of corrosion casts, with particular reference to the intermediate pathways. AB - Blood vessels and their connections in rat spleen were traced over considerable distances by scanning electron microscopy of microcorrosion casts prepared by injection of minimal amounts of casting material. The periarterial lymphatic sheath and lymphatic nodules are highly developed, containing an abundance of capillaries which terminate in the marginal sinus (MS) and marginal zone (MZ). The MS, which consists of a series of discontinuous flattened vascular spaces interconnected by short capillaries, shows circumferential filling followed by flow radially outward into the MZ. Contrary to the generally accepted view, many venous sinuses begin as open-ended tubes at the MS or MZ, allowing free entry of blood into the venous system, thereby bypassing the reticular meshwork of the red pulp. The majority of arterial capillaries terminate in the reticular meshwork ("open" circulation), but evidence for direct connections between capillaries and venous sinuses ("closed" circulation) was also obtained. Casts of the subcapsular region reveal an elaborate system of venous sinuses in fan-shaped arrays, superimposed on an extensive network of capillaries draining into flattened reticular spaces; such casts provide a three-dimensional map useful in interpreting light microscopic observations of red cell flow in vivo. Sphincter like constrictions in venous sinuses, at points of connection with larger sinuses, indicate that these are possible sites for control of intrasplenic flow distribution. PMID- 29976029 TI - Histochemical and biochemical studies of the hepatopancreas peroxidase of the freshwater crayfish, Cambarus robustus. AB - Crayfish are among the few invertebrate species reported to possess endogenous peroxidase activity. The enzyme is found within the hepatopancreas, the principal digestive and absorptive organ of the crustacean body. Cambarus robustus, a species found in abundance in the streams of western New York, was used in this study. Homogenates of 18 hepatopancreases were assayed for peroxidase activity using guaiacol as the substrate. Although present in all organs, peroxidase activity displayed a greater than 50-fold difference between the two extremes (0.05-;2.72 units/mg protein). Histochemical examination using diaminobenzidine revealed peroxidase activity within a line of cells extending along the distal two-thirds of the lengths of all hepatopancreatic tubules. The cells function to synthesize the enzyme, sequester it within vacuoles of increasing size, and eventually secrete it into the tubule lumen. Since the tubule is constantly renewed by distal mitotic activity and concomitant proximal exfoliation, this histochemical technique permits not only the examination of the ontogeny of this peroxidase-positive cell line, but also offers additional insight into the mechanism of hepatopancreatic tubule renewal. PMID- 29976030 TI - Gross and fine structure of the antennal circulatory organ in cockroaches (Blattodea, Insecta). AB - The antennal circulatory organ of Periplaneta americana and Blaberus craniifer was investigated by light and electron microscopy. This organ consists of two pulsatile ampullae located near the antennal base which are interconnected by a large transverse muscle and associated blood vessels which run into the antennae. Diastole is caused simultaneously in both ampullae by the transverse muscle. Systole is produced passively by the elasticity of the wall of the ampullae and minute accessory tendons. Both elastic structures contain fine unbanded extracellular filaments. The antennal vessels possess two distinct regions: a proximal convoluted region lying within the hemocoel of the head and a narrower distal region running through the antenna and opening near the antennal apex. The length of the proximal portion increases markedly during ontogeny in correlation with the growing antenna. Its wall consists of a high-prismatic epithelium ensheathed by a thick layer of collagen fibrils. The structure of the wall cells is comparable to that found in some salt transporting epithelia: it shows a polar organization with basal infoldings, a large number of mitochondria, and typical arrangement of the junctions or mitochondrial-scalariform junctional complexes. The possible physiological function of this epithelium in ionic or osmoregulation of the hemolymph entering the antenna is discussed. The wall of the distal vessel region consists of a flat single-layered epithelium and seems to be specialized only for delivery of hemolymph to antennae. The structure and function of the antennal heart in cockroaches is compared to that found in other insects. PMID- 29976031 TI - Morphology of the head skeleton and muscles of the mosquito, Culiseta inornata (Williston) (Diptera: Culicidae). AB - The objectives of this research were to investigate the morphology of the head skeleton and muscles of the female mosquito, Culiseta inornata (Williston). The skeletal parts were examined after maceration in KOH. The attachments of muscles were determined by dissection. Observations were made with the aid of a dissecting microscope at 70* and lower. Each skeletal part and muscle is illustrated and described. Conclusions regarding the skeleton are as follows: (1) the clypeal area is composed of an anteclypeus and postclypeus, (2) the suture between the anteclypeus and postclypeus is rigid and cannot function as a hinge, (3) the dorsal wall of the labrum terminates at its union with the anteclypeus, (4) the dorsal and epipharyngeal walls of the labrum are united apically, (5) the gena and postclypeus are not separated by a suture, and (6) the labellum is composed of three segments and the furca, of some authors, is absent. Twenty-five muscles were identified, and the origin, insertion, and action of each is described. The tormo-epipharyngalis muscle is attached anterior to the cibarium and fulcral plates. Its origin is on the clypeal apodeme and the insertion is on the epipharynx. This result confirms earlier reports and disagrees with some recent authors. The maxillary teeth are not designed to draw the fascicle into the tissues, but the cervical and leg muscles accomplish the probing process during feeding on a host. An undescribed muscle of the mandible is reported. PMID- 29976032 TI - Gut Bacterial Diversity of Insecticide-Susceptible and -Resistant Nymphs of the Brown Planthopper Nilaparvata lugens Stal (Hemiptera: Delphacidae) and Elucidation of Their Putative Functional Roles. AB - Knowledge about the gut bacterial communities associated with insects is essential to understand their roles in the physiology of the host. In the present study, the gut bacterial communities of a laboratory-reared insecticide susceptible (IS), and a field-collected insecticide-resistant (IR) population of a major rice pest, the brown planthopper Nilaparvata lugens, were evaluated. The deep-sequencing analysis of the V3 hypervariable region of the 16S rRNA gene was performed using Illumina and the sequence data were processed using QIIME. The toxicological bioassays showed that compared with the IS population, IR population exhibited 7.9-, 6.7-, 14.8-, and 18.7-fold resistance to acephate, imidacloprid, thiamethoxam, and buprofezin, respectively. The analysis of the alpha diversity indicated a higher bacterial diversity and richness associated with the IR population. The dominant phylum in the IS population was Proteobacteria (99.86%), whereas the IR population consisted of Firmicutes (46.06%), followed by Bacteroidetes (30.8%) and Proteobacteria (15.49%). Morganella, Weissella, and Enterococcus were among the genera shared between the two populations and might form the core bacteria associated with N. lugens. The taxonomic-to-phenotypic mapping revealed the presence of ammonia oxidizers, nitrogen fixers, sulfur oxidizers and reducers, xylan degraders, and aromatic hydrocarbon degraders in the metagenome of N. lugens. Interestingly, the IR population was found to be enriched with bacteria involved in detoxification functions. The results obtained in this study provide a basis for future studies elucidating the roles of the gut bacteria in the insecticide resistance associated symbiotic relationship and on the design of novel strategies for the management of N. lugens. PMID- 29976033 TI - Craniofacial Polyostotic Fibrous Dysplasia Initially Diagnosed in a Primary Care Unit. AB - Fibrous dysplasia (FD) is a non-malignant bone tumor that typically behaves as a slow and indolent growing mass lesion. We report the case of a female patient presenting with headache and facial deformity and later diagnosed with polyostotic fibrous dysplasia (PFD). A 29-year-old woman visited Mealhada Primary Health Care Unit complaining of headache, nasal congestion, and hyposmia for several weeks. She also presented with facial deformity and painful swelling of the upper left orbit. X-ray imaging revealed a suspicious opacity in the left frontal sinus and a right shift of the nasal septum. Computed tomography and bone scintigraphy later confirmed a tumor involving the ethmoid and frontal bone. The patient was referred to the neurosurgery and otorhinolaryngology departments of a central hospital and the suspected diagnosis of PFD was confirmed. A watchful waiting approach with regular imaging screenings was proposed and accepted by the patient, who is now free of symptoms and more acceptant of the benign condition of her tumor. With this case, we aim to make family physicians more aware of this rare but relevant condition that can be difficult to diagnose. FD is a rare but benign tumor that occurs mainly in adolescents and young adults. Symptoms depend on the location and type of the tumor and include facial deformity, vision changes, nasal congestion, and headache. No clear guidelines exist for its treatment, and options include monitoring the progression of the tumor, in addition to medical or surgical approaches. PMID- 29976034 TI - Relationship between Marital Status and Metabolic Syndrome in Korean Middle-Aged Women: The Sixth Korea National Health and Nutrition Examination Survey (2013 2014). AB - BACKGROUND: This study aimed to investigate the relationship between marital status and the incidence of metabolic syndrome in Korean middle-aged women. METHODS: Based on data from the sixth Korea National Health and Nutrition Examination Survey (2013-2014), 3,225 women aged 40-69 years were subjected to the analysis. Marital status was categorized as married, unmarried, separated, widowed, or divorced. The odds ratios (ORs) for metabolic syndrome were calculated based on marital status. After adjustment for age, income level, education level, alcohol intake, smoking status, leisure physical activity, menopause status, daily calories, and fat intake, changes in the OR for metabolic syndrome based on marital status were examined by multivariate logistic regression analysis. RESULTS: The OR for metabolic syndrome in the widowed group to the married group was 4.818 (95% confidence interval [CI], 3.861-6.002; P<0.001) and that after adjustment of age, economic level, education level, alcohol intake, smoking status, physical activity, menopause status, total daily calories, and fat intake was 2.141 (CI, 1.432-3.199; P<0.001), both of which were statistically significant. The OR for metabolic syndrome in the unmarried group to the married group was 0.246 (CI, 0.141-0.431; P<0.001) after adjustment of all components. On the contrary, the ORs of the separated group and the divorced group to the married group were not significant. CONCLUSION: In comparison with the married middle-aged group, the widowed middle-aged group tended to have a higher risk of metabolic syndrome, which is speculated to be related to socioeconomic factors and health behavior. PMID- 29976035 TI - Plasma Levels of K18 Fragments Do Not Correlate with Alcoholic Liver Fibrosis. AB - Background/Aims: Noninvasive markers of liver fibrosis in alcoholic liver disease (ALD) are crucial to establish early intervention. Previous studies have suggested that plasma levels of cleaved keratin-18 (K18; M30) fragments can predict the severity of liver disease. The aim of this study was to correlate plasma M30 levels with stages of liver fibrosis in ALD. Methods: Patients with ALD (n=139, 79.1% males) and liver histology were included, and plasma samples were collected to quantify plasma M30 levels. Patients were stratified into five groups by fibrosis stage (F0=14; F1=15; F2=35; F3=17; and F4=58) according to the Kleiner score. Differences between groups were evaluated using the chi-square test or analysis of variance. Trends by fibrosis stage were calculated by logistic regression analysis, and sensitivity, specificity and positive and negative predictive values were determined. Results: There were no significant differences in M30 levels among fibrosis stages. The correlation between plasma M30 levels and fibrosis was poor (Pearson's correlation coefficient=0.13, Spearman rho=0.20 [p=0.02]), and M30 levels did not correlate with alcohol specific histological features. However, significant correlations of M30 levels with aspartate aminotransferase (Spearman rho=0.653, p<0.001) and alanine aminotransferase (Spearman rho=0.432, p<0.001) were found. M30 levels of >200 U/L reveal a sensitivity for predicting cirrhosis of 84.5% with a negative predictive value of 73.5%. Conclusions: Plasma M30 levels are often elevated in ALD and correlate with serum transaminases but do not reflect fibrosis. The usefulness as a prognostic marker awaits evaluation in prospective studies. PMID- 29976036 TI - Evaluation of high resolution computed tomography findings of cystic fibrosis. AB - Background/Aims: Morphological changes due to lung disease in patients with cystic fibrosis (CF) were evaluated using high resolution computed tomography (HRCT), and the HRCT scores obtained using the Bhalla scoring system were correlated with those obtained using clinical and laboratory indicators. Methods: Medical records of 28 children with CF who underwent chest CT in Department of Pediatric Allergy and Immunology, Cukurova University Balcali Hospital between March 2011 and January 2016 were retrospectively reviewed. Demographic data and physical examination, respiratory cultures, pulmonary function tests, and chest HRCT findings were evaluated. Patients were divided into the following two groups according to their forced expiratory volume in the first second (FEV1) values: normal FEV1 (>= 80% of predicted values) and low FEV1 (< 80% of predicted values). Deep throat or sputum cultures were evaluated for the presence of Pseudomonas aeruginosa (PsA) and other bacteria. HRCT scans were scored using the Bhalla scoring system. Results: No significant correlation was found between the Bhalla scores and sex, age group, or height percentiles. Significant relationships were found between the Bhalla score and weight (p = 0.036) and body mass index (BMI) (p = 0.032) percentiles below the third percentile, bacterial growth in the sputum/ deep throat cultures (p = 0.009), and presence of PsA (p = 0.004). Moreover, a significant correlation was found between the Bhalla score and FEV1 (r = -0.315, p = 0.0272), forced vital capacity (FVC; r = -0.381, p = 0.0178), forced expiratory flow between 25% and 75% of FVC (r = -0.229, p = 0.0431), and BMI (r = -3.368, p = 0.050). Conclusions: Chest HRCT is an important diagnostic tool for the pulmonary evaluation of children with CF. PMID- 29976037 TI - Primary Gastric Small Cell Carcinoma: A Case Identified as a Large Subepithelial Tumor from Invisible State in 6 Months. AB - Primary gastric small cell carcinoma (GSCC) is a rare cancer with a very aggressive behavior and a poor prognosis because of the high rate of metastases. It is usually found in far advanced stage. We experienced a case of GSCC which had developed into a large subepithelial tumor (SET) from invisible state in a short period. A 65-year-old man consulted our hospital because of early gastric cancer. He underwent endoscopic submucosal dissection for the early gastric cancer at high body posterior wall. After 6 months, the follow-up endoscopy showed a large newly developed SET-like lesion with central ulceration at the gastric cardia. Endoscopic biopsy revealed GSCC. Total gastrectomy was performed. One out of the 26 perigastric lymph nodes had a metastasis. He received 6 cycles of adjuvant chemotherapy with etoposide and cisplatin. He is still in good health 12 months after operation. PMID- 29976038 TI - Fetal weight estimation by ultrasound: development of Indian population-based models. AB - Purpose: Existing ultrasound-based fetal weight estimation models have been shown to have high errors when used in the Indian population. Therefore, the primary objective of this study was to develop Indian population-based models for fetal weight estimation, and the secondary objective was to compare their performance against established models. Methods: Retrospectively collected data from 173 cases were used in this study. The inclusion criteria were a live singleton pregnancy and an interval from the ultrasound scan to delivery of <=7 days. Multiple stepwise regression (MSR) and lasso regression methods were used to derive fetal weight estimation models using a randomly selected training group (n=137) with cross-products of abdominal circumference (AC), biparietal diameter (BPD), head circumference (HC), and femur length (FL) as independent variables. In the validation group (n=36), the bootstrap method was used to compare the performance of the new models against 12 existing models. Results: The equations for the best-fit models obtained using the MSR and lasso methods were as follows: log10(EFW)=2.7843700+0.0004197(HC*AC)+0.0008545(AC*FL) and log10(EFW)=2.38 70211110+0.0074323216(HC)+0.0186555940(AC)+0.0013463735(BPD*FL)+0.0004519715 (HC*FL), respectively. In the training group, both models had very low systematic errors of 0.01% (+/-7.74%) and -0.03% (+/-7.70%), respectively. In the validation group, the performance of these models was found to be significantly better than that of the existing models. Conclusion: The models presented in this study were found to be superior to existing models of ultrasound-based fetal weight estimation in the Indian population. We recommend a thorough evaluation of these models in independent studies. PMID- 29976039 TI - Association between anti-citrullinated alpha enolase antibodies and clinical features in a cohort of patients with rheumatoid arthritis: a pilot study. AB - In recent years several antibodies against citrullinated peptides (ACPAs) have been identified in patients with rheumatoid arthritis (RA) and their pathogenic, diagnostic and prognostic significance is under intense investigation. Among ACPAs, those targeting citrullinated alpha enolase (anti-CEP1) have been identified in RA but data about their ability to predict the development of erosive disease are conflicting. Furthermore, no data are currently available concerning their possible association with extra-articular manifestations (EAMs) in RA. The aim of this study was to investigate the prevalence and significance of anti-CEP1 from a prognostic point of view. In this pilot study we confirmed that anti-CEP1 Abs are associated with higher prevalence of bone erosions, but we also provided the first evidence of an association between anti-CEP1 Abs and RA interstitial lung disease (ILD). These results provide the basis to investigate the association between anti-CEP1 Abs and EAMs in larger cohorts of RA patients to possibly confirm its role as biomarker for RA-ILD. PMID- 29976040 TI - Low body mass index in long standing rheumatoid arthritis: relation to RA disease activity and functional indices. AB - The aim of the work was to study the relationship between the body mass index (BMI) in longstanding rheumatoid arthritis (RA) and RA disease activity and functional indices. This study included 105 RA patients. For all patients, we recorded the presence of erosions on radiographs, the presence of subcutaneous nodules (SCN), the 28-tender joint count (TJC), 28-swollen joint count (SJC) scores, the visual analogue scale (VAS), physicians' global assessments (PhGA), the erythrocyte sedimentation rate (ESR), and the rheumatoid factor (RF). The disease activity index (DAS28) and BMI were calculated and current treatment was recorded. Patients were divided into two groups: group I: BMI 25. Group I included 32 (30.5%) patients, whereas group II included 73 (69.5%) patients. There were statistically significant differences between the two groups regarding each of the following: SJC (p=0.006), erosions (p=0.006), DAS28 (p=0.016) and PhGA (p=0.007). All were higher in group I (underweight and normal) than in group II (overweight and obese). No statistically significant differences emerged regarding age (p=0.11), smoking (p=0.69), disease duration (p=0.46), TJC (p=0.14), SCN (p=1.00), HAQ (p=0.26), VAS (p=0.16), ESR (p=0.25), RF (p=0.54) and steroid cumulative dose (p=0.08). Low BMI in longstanding RA patients may indicate more active and erosive disease and it may be considered as a poor prognostic factor. PMID- 29976041 TI - The use of rituximab in idiopathic inflammatory myopathies: description of a monocentric cohort and review of the literature. AB - Rituximab (RTX), a chimeric monoclonal antibody targeted against CD20, has been used to treat refractory inflammatory myopathies (IIM). The primary objective of this study was to retrospectively assess the efficacy of RTX in reducing disease activity in patients with IIM refractory to conventional therapy. Secondary aim was the evaluation of adverse events (AE) during the treatment period. We examined 26 patients with a diagnosis of IIM, referred to our Rheumatology Unit and treated with RTX for active refractory disease. Patients were treated with RTX 1000 mg i.v., twice, with a 2-week interval. RTX treatment was associated with a significant reduction of creatine kinase (p=0.001) after six months compared to the baseline, an improved muscular strength measured with MMT8 (p<0.001) and a reduction of the extramuscular activity of the disease measured with MYOACT (p<0.001). In particular, RTX improved DM skin rash, arthritis and pulmonary manifestations. Autoantibody positivity (in particular antisynthetase, anti- SRP and antiRo/SSA), and a disease duration <36 months at the moment of the treatment are associated with a better response rate. Treatment with RTX was also associated with a reduction of the mean daily dose of steroids needed to control disease activity (p=0.002). Our results have confirmed that RTX is efficacious in the treatment of refractory IIM. Ad hoc controlled trials are needed to better clarify the specific subset of patients who may better respond to the treatment and the optimal therapeutic schedule. PMID- 29976042 TI - Antibodies to extractable nuclear antigens (ENAS) in systemic lupus erythematosus patients: correlations with clinical manifestations and disease activity. AB - The aim was to explore possible correlations of antibodies to extractable nuclear antigens (ENA) with clinical manifestations and disease activity indices in systemic lupus erythematosus (SLE) patients. A total of 70 consecutive SLE patients (64 females) were included. Disease activity was assessed by SLE activity index (SLEDAI), and British Isles Lupus Assessment Group (BILAG). Anti Ro/SSA correlated positively with, headache (r=0.24, p=0.04), blurring of vision (r=0.25, p=0.03) and SLEDAI (r=0.25, p=0.04) and negatively with C3 (r=-0.35, p=0.003). Anti-Ro/SSA correlated with anti La/SSB antibodies (r=0.69, p<0.001), but not with anti-DNA, anti-RNP and anti-Sm antibodies. Anti-La/SSB antibodies correlated with headache (r=0.26, p=0.03), SLEDAI (r=0.25, p=0.03) and negatively with C3 (r=-0.34, p=0.004). Anti-La/SSB did not correlate with anti-RNP or anti Sm antibodies. Anti-Sm antibodies correlated with disease duration (r=0.34, p=0.003), 24 hours urinary proteins (r=0.31, p=0.008), SLEDAI (r=0.31, p=0.009), BILAG renal score (r=0.29, p=0.02) and negatively with age at onset (r=-0.27, p=0.02), WBCs (r=-0.29, p=0.014) and C4 (r=-0.25, p=0.049). In multivariate analyses, anti-Ro/SSA antibodies remained associated with headache, blurring of vision and C3 and anti-La/SSB antibodies remained associated with C3 and with headache. Anti-Sm antibodies were independently associated with disease duration and total SLEDAI scores, while anti-RNP antibodies remained significantly associated with BILAG mucocutaneous scores only. Antibodies to ENAs are associated with clinical aspects of SLE and may play a role in the assessment of disease activity. Insight into these ENAs may lead to new approaches to diagnostic testing, accurate evaluation of disease activity and lead to target approach for SLE. PMID- 29976043 TI - Determinants of occupational multisite musculoskeletal disorders: a cross sectional study among 254 patients. AB - The aim was to describe the profile of workers with occupational multi-site musculoskeletal disorders (MSMSD) and study the relationship between these lesions and socio-professional factors. This is a cross-sectional study involving 254 subjects with occupational musculoskeletal disorders (MSD), identified in the Department of Occupational Medicine at the University Hospital of Mahdia, in Tunisia, over a period of 10 years from 2005 to 2014. The study population was subdivided into two groups; mono-site MSD and multi-site (>=2 sites) groups. Data collection was based on a questionnaire prepared beforehand and covered the description of sociodemographic and professional characteristics. To study psychosocial constraints at work, we have used the Karasek questionnaire. MS-MSD was correlated to the number of dependent children (p=0.02), job/place of work (p=0.00), qualification (p=0.02), taking a rest period (p=0.03), decision latitude (p=0.00), mental demands (p=0.002), social support (p=0.00) and job stress (p=0.04). After binary logistic regression, MS-MSD depended significantly on the number of dependent children (p=0.013; OR=0,33; IC=0,17-0,83), working spouse (p=0.05; OR=0.35; IC=0.12-0.99), job/place of work (p=0.00; OR=4.16; IC=1.95-8.88), qualification (p=0.008; OR=0.28; IC=0.11-0.72), taking a break during work (p=0.04; OR=3.10; IC=1.04-9.22) and social support (p=0.00; OR=7,1; IC=1,9-25,3). When individual risk factors are fixed, the prevention of MS-MSD must target modifiable levers, related to the professional environment of the employees. PMID- 29976044 TI - Macrophage activation syndrome in adult systemic lupus erythematosus: report of seven adult cases from a single Italian rheumatology center. AB - The aim was to describe the macrophage activation syndrome (MAS), a life threatening syndrome characterized by excessive immune activation that can be triggered by conditions affecting immune homeostasis, in a cohort of adult Italian patients with systemic lupus erythematosus (SLE). This was a monocentric retrospective evaluation. The utility of the H-score, developed to estimate the individual risk of having reactive MAS in adult patients, was assessed. Among 511 patients with SLE, 7 cases (1.4%) of MAS (all females) were identified and their medical records reviewed. In all cases, MAS was simultaneous to the onset of SLE. All patients had fever, lymphadenopathy, hematological involvement, and high titer of anti-dsDNA antibodies. Workup for infections and malignancies was negative. In all cases, the H-score was higher than the cut-off suggested for the classification of reactive MAS. All cases required hospital admission, and 2 patients were admitted to the intensive care unit. Most patients were treated successfully with high doses of corticosteroids and with immunosuppressive drugs, whereas the full therapeutic regimen developed for primary hemophagocytic lymphohistiocytosis HLH was used only in one case. No death from MAS was observed. MAS is a rare and severe disorder that complicated the onset of SLE in our cohort. The H-score may be useful in the classification of these patients. PMID- 29976045 TI - Coexistence of sarcoidosis and Hashimoto thyroiditis. AB - Sarcoidosis is a chronic, inflammatory disease with unknown cause characterized by non-caseating granuloma formations. It can present with bilateral hilar lymphadenopathy, skin lesions, eye involvement and locomotor system findings. Hashimoto thyroiditis is an organ-specific autoimmune disease characterized by increased autoantibody synthesis. Sarcoidosis can involve different endocrine glands. Thyroid gland involvement may lead to increased thyroid function disorders and autoantibodies. Herein, we report an 80-year-old female patient with sarcoidosis and Hashimoto coexistence. PMID- 29976046 TI - Pulmonary cavitary lesions may be one of the presenting features in Ig A nephropathy. AB - Immunoglobulin A (Ig A) nephropathy is the most frequent primary glomerulonephritis. Renal limited disease is the most widespread clinical form of the disease. Pulmonary involvement may also be seen concomitantly and capillaritis with pulmonary hemorrhage is the most frequent pulmonary involvement. In this paper, for the first time in literature, we describe an Ig A nephropathy patient with multiple pulmonary cavities as one of the presenting features of the disease. Also, no other etiology for the cavities was found other than Ig A nephropathy. Herein, possible pathogenesis might be capillaritis or deposition of immune complexes. As a result, it should be kept in mind that pulmonary cavity may be the presenting feature of Ig A nephropathy especially with other frequent signs of the disease. PMID- 29976047 TI - Acute myocarditis as a revealing clue of complete Kawasaki disease. AB - Not available. PMID- 29976048 TI - The real evidence for polymyalgia rheumatic as a paraneoplastic syndrome. AB - Not available. PMID- 29976049 TI - The real evidence for polymyalgia rheumatic as a paraneoplastic syndrome. AB - Not available. PMID- 29976050 TI - RETRACTION: Pain in systemic sclerosis. AB - To our readers: With deep regrets, we inform that the article Pain in systemic sclerosis (DOI: https:// doi.org/10.4081/reumatismo.2014.764), which has been published in Reumatismo (2014; 66(1): 44-47), contains verbatim text plagiarized from another paper. The manuscript must be considered as retracted.On behalf of the Editorial Board of Reumatismo, I apologize to the Author of the manuscript whose text was plagiarized by Stisi et al. that this was not picked up in the peer review process. I also apologize to the affected journal for the violation of copyright due to plagiarism. Reumatismo is uncompromising in its commitment to scientific integrity. When credible evidence of misconduct is brought to our attention, our commitment to the scientific record and to our readership requires immediate notification. Reumatismo is increasingly employing sophisticated software to detect plagiarism. Other journals use similar tools. Authors should be aware that most journals routinely employ plagiarism detection software, and that any plagiarism is likely to be detected.Marco A. CimminoEditor-in ChiefReumatismo. PMID- 29976051 TI - An Impedance-Transduced Chemiresistor with a Porous Carbon Channel for Rapid, Nonenzymatic, Glucose Sensing. AB - A new type of chemiresistor, the impedance-transduced chemiresistor (ITCR), is described for the rapid analysis of glucose. The ITCR exploits porous, high surface area, fluorine-doped carbon nanofibers prepared by electrospinning of fluorinated polymer nanofibers followed by pyrolysis. These nanofibers are functionalized with a boronic acid receptor and stabilized by Nafion to form the ITCR channel for glucose detection. The recognition and binding of glucose by the ITCR is detected by measuring its electrical impedance at a single frequency. The analysis frequency is selected by measuring the signal-to-noise ( S/ N) for glucose detection across 5 orders of magnitude, evaluating both the imaginary and real components of the complex impedance. On the basis of this analysis, an optimal frequency of 13 kHz is selected for glucose detection, yielding an S/ N ratio of 60-100 for [glucose] = 5 mM using the change in the total impedance, Delta Z. The resulting ITCR glucose sensor shows a rapid analysis time (<8 s), low coefficient of variation for a series of sensors (<10%), an analysis range of 50 MUM to 5 mM, and excellent specificity versus fructose, ascorbic acid, and uric acid. These metrics for the ITCR are obtained using a sample size as small as 5 MUL. PMID- 29976052 TI - Flavoalkaloids with a Pyrrolidinone Ring from Chinese Ancient Cultivated Tea Xi Gui. AB - Chinese Xi-Gui tea is one ancient cultivated variety of Camellia sinensis var. assamica. At present, it is used for producing expensive and elite tea in China. Five new flavoalkaloids, (-)-6-(5''' S)- N-ethyl-2-pyrrolidinone-epicatechin-3- O gallate (ester-type catechins pyrrolidinone E, etc-pyrrolidinone E, 1), (-)-6 (5''' R)- N-ethyl-2-pyrrolidinone-epicatechin-3- O-gallate (etc-pyrrolidinone F, 2) (-)-8-(5''' S)- N-ethyl-2-pyrrolidinone-epicatechin-3- O-gallate (etc pyrrolidinone G, 3a), (-)-8-(5''' S)- N-ethyl-2-pyrrolidinone-catechin-3- O gallate (etc-pyrrolidinone I, 4a), (-)-8-(5''' R)- N-ethyl-2-pyrrolidinone catechin-3- O-gallate (etc-pyrrolidinone J, 4b), and one new naturally occurring natural product (-)-8-(5''' R)- N-ethyl-2-pyrrolidinone-epicatechin-3- O-gallate (etc-pyrrolidinone H, 3b) together with the known flavoalkaloids etc pyrrolidinones A-D (5, 6, 7a, and 7b) were detected and isolated from Xi-Gui green tea. Their structures were identified by comprehensive NMR spectroscopic analyses. Absolute configurations of 1-3 were established by comparison of the CD analyses with epicatechin-3- O-gallate (ECG). Compounds 1-4 were evaluated for their protection against high glucose induced cell senescence on human umbilical vein endothelia cells (HUVECs) and showed significant protection effects ( p < 0.01) at both 1.0 and 10 MUM. A discussion on the possible evolution of tea plants divergent from related food plants on the basis of phytochemical view is also provided. PMID- 29976053 TI - Methylene Blue Analogues with Marginal Monoamine Oxidase Inhibition Retain Antidepressant-like Activity. AB - Methylene blue (MB) possesses diverse medical applications. Among these, MB presents with antidepressant-like effects in animals and has shown promise in clinical trials for the treatment of mood disorders. As an antidepressant, MB may act via various mechanisms which include modulation of the nitric oxide cyclic guanosine monophosphate (NO-cGMP) cascade, enhancement of mitochondrial respiration and antioxidant effects. MB is also, however, a high potency inhibitor of monoamine oxidase (MAO) A, which most likely contributes to its antidepressant effect, but also to its adverse effects profile (e.g., serotonin toxicity). The latter has raised the question whether it is possible to design out the MAO inhibition properties of MB yet retaining its clinically useful attributes. This study explores this idea further by characterizing five newly synthesized low MAO-A active MB analogues and examining their antidepressant-like properties in the acute forced swim test (FST) in rats, with comparison to imipramine and MB. The results show that all five analogues exhibit antidepressant-like properties in the FST without confounding effects on locomotor activity. The magnitude of these effects is comparable to those of imipramine and MB. Moreover, these newly synthesized MB analogues are markedly less potent MAO-A inhibitors (IC50 = 0.518-4.73 MUM) than MB (IC50 = 0.07 MUM). We postulate that such lower potency MAO-A inhibitors may present with a reduced risk of adverse effects associated with MAO-A inhibition. While low level MAO-A inhibition still may produce an antidepressant effect, we posit that other MB related mechanisms may underlie their antidepressant effects, thereby representing a novel group of antidepressant compounds. PMID- 29976054 TI - Mechanically Robust Magnetic Fe3O4 Nanoparticle/Polyvinylidene Fluoride Composite Nanofiber and Its Application in a Triboelectric Nanogenerator. AB - Mechanically robust composite nanofibers (NFs) with enhanced magnetic properties were made from polyvinylidene fluoride (PVDF) and Fe3O4 nanoparticles (NPs) by an electrospinning method. At up to 11.3 wt %, Fe3O4 NPs were embedded randomly in the PVDF NFs, but when the content exceeded 17 wt %, the NPs aggregated on the NF surfaces. Magnetization of the composite NFs consistently increased with the increasing Fe3O4 NP content. The mechanical strength of the Fe3O4 NP/PVDF composite NF was enhanced by a dispersion strengthening mechanism. A triboelectric nanogenerator was made from the composite, which showed enhanced output performance with the Fe3O4 NP content less than 11.3 wt %, but the performance degraded at higher content. These results were attributed to the electret doping effect and surface aggregation of the Fe3O4 NPs on the NFs, respectively. PMID- 29976055 TI - Peptide-Loaded Microgels as Antimicrobial and Anti-Inflammatory Surface Coatings. AB - Here we report on covalently immobilized poly(ethyl acrylate- co-methacrylic acid) microgels loaded with the host defense peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR), which is derived from human heparin cofactor II, as well as its poly(ethylene glycol)-conjugated (PEGylated) version, KYE28PEG. Peptide loading and release, as well as the consequences of these processes on the microgel and peptide properties, were studied by in situ ellipsometry, confocal microscopy, zeta potential measurements, and circular dichroism spectroscopy. The results show that the microgel-peptide interactions are electrostatically dominated, thus promoted at higher microgel charge density, while PEGylation suppresses peptide binding. PEGylation also enhances the alpha helix induction observed for KYE28 upon microgel incorporation. Additionally, peptide release is facilitated at physiological salt concentration, particularly so for KYE28PEG, which illustrates the importance of electrostatic interactions. In vitro studies on Escherichia coli show that the microgel-modified surfaces display potent antifouling properties in both the absence and presence of the incorporated peptide. While contact killing dominates at low ionic strength for the peptide-loaded microgels, released peptides also provide antimicrobial activity in bulk at a high ionic strength. Additionally, KYE28- and KYE28PEG loaded microgels display anti-inflammatory effects on human monocytes. Taken together, these results not only show that surface-bound microgels offer an interesting approach for local drug delivery of host defense peptides but also illustrate the need to achieve high surface loads of peptides for efficient biological effects. PMID- 29976056 TI - Design of Experiments Methodology to Build a Multifactorial Statistical Model Describing the Metabolic Interactions of Alcohol Dehydrogenase Isozymes in the Ethanol Biosynthetic Pathway of the Yeast Saccharomyces cerevisiae. AB - Multifactorial approaches can quickly and efficiently model complex, interacting natural or engineered biological systems in a way that traditional one-factor-at a-time experimentation can fail to do. We applied a Design of Experiments (DOE) approach to model ethanol biosynthesis in yeast, which is well-understood and genetically tractable, yet complex. Six alcohol dehydrogenase (ADH) isozymes catalyze ethanol synthesis, differing in their transcriptional and post translational regulation, subcellular localization, and enzyme kinetics. We generated a combinatorial library of all ADH gene deletions and measured the impact of gene deletion(s) and environmental context on ethanol production of a subset of this library. The data were used to build a statistical model that described known behaviors of ADH isozymes and identified novel interactions. Importantly, the model described features of ADH metabolic behavior without explicit a priori knowledge. The method is therefore highly suited to understanding and optimizing metabolic pathways in less well-understood systems. PMID- 29976057 TI - alpha-Amylase@Ferria: Magnetic Nanocomposites with Enhanced Thermal Stability for Starch Hydrolysis. AB - The present study is devoted to the development of a new class recyclable magnetic catalytic nanocomposites for starch hydrolysis. alpha-Amylase was entrapped within a magnetite-derived xerogel matrix in a course of a room temperature sol-gel transition, leading to enzyme immobilization within the pores of a rigid magnetic matrix. For hybrid organo-inorganic composites with enzyme mass fractions less than 10 wt %, no enzyme leaching was observed. At 80 degrees C, the amylase@ferria composite demonstrates catalytic activity on the level of 10 units/mg and the starch hydrolysis rate comparable to free enzyme, while at 90 degrees C, the activity of amylase@ferria is at least twice higher than that of free amylase as a result of higher thermal stability of the composite. Entrapped amylase showed excellent stability and lost only 9% of its activity after 21 days of storage in a buffer solution, while free enzyme was totally inactivated after 17 days. The material can be used as either a magnetically separable reusable catalyst or a catalytic ceramic coating with at least 10 cycles of use. PMID- 29976058 TI - Inhibition of Epigallocatechin-3-gallate/Protein Interaction by Methyl-beta cyclodextrin in Myofibrillar Protein Emulsion Gels under Oxidative Stress. AB - Nowadays, natural antioxidants abundant in polyphenols have been widely used to substitute synthetic antioxidants in meat products. In general, high doses of natural antioxidants are required to provide comparative antioxidant effects as synthetic antioxidants. Noticeably, the qualities of meat products can be jeopardized due to interactions between polyphenols and myofibrillar proteins (MPs). In this study, methyl-beta-cyclodextrin was used to increase the polyphenol loading amount by preventing interactions between polyphenols and proteins. Solubility, electrophoresis, fluorescence spectroscopy, and surface hydrophobicity analyses indicated that methyl-beta-cyclodextrin could dose dependently inhibit epigallocatechin-3-gallate-induced attacks on MPs under oxidative stress. Gel strength, cooking loss, confocal laser scanning microscopy, dynamic rheological testing, and Raman spectrum during gelation were further analyzed to investigate the effects of methyl-beta-cyclodextrin on the qualities of epigallocatechin-3-gallate-treated emulsion gel. Methyl-beta-cyclodextrin addition prevented modification of the secondary structure of MPs caused by epigallocatechin-3-gallate. In consequence, the gel and emulsifying properties of MPs were significantly improved. Moreover, beta-cyclodextrins could partly inhibit oxidative attacks on MPs and thus increase their solubility. These results indicated that methyl-beta-cyclodextrin addition effectively enhanced epigallocatechin-3-gallate loading capacity in meat products. PMID- 29976059 TI - Using Single-Cell Amperometry and Intracellular Vesicle Impact Electrochemical Cytometry To Shed Light on the Biphasic Effects of Lidocaine on Exocytosis. AB - Single cell amperometry and intracellular vesicle impact electrochemical cytometry were used to examine whether lidocaine can regulate neurotransmitter release or storage for PC12 cells to explain the biphasic effects whereby it can protect neurons and improve cognitive outcome at low concentration, but can cause neurotoxicity at high concentration. We show that lidocaine affects the behavior of PC12 cell exocytosis in a concentration dependent way, which exactly corresponds to its biphasic effects. At a relatively high concentration, it shows a much narrower pore size and a longer-duration fusion pore with less monoamine released than control cells. However, at a relatively low concentration, the fusion pore is open even longer than at high concentration, and with more monoamine released than control cells. Furthermore, intracellular vesicle impact electrochemical cytometry was used to confirm that lidocaine did not change the catecholamine content of the vesicles. These data provide a mechanism for the observed biphasic effects of the drug and suggest that lidocaine influences exocytosis through multiple mechanisms. PMID- 29976060 TI - Enhancing Oral Bioavailability of Cyclic RGD Hexa-peptides by the Lipophilic Prodrug Charge Masking Approach: Redirection of Peptide Intestinal Permeability from a Paracellular to Transcellular Pathway. AB - Hydrophilic peptides constitute most of the active peptides. They mostly permeate via tight junctions (paracellular pathway) in the intestine. This permeability mechanism restricts the magnitude of their oral absorption and bioavailability. We hypothesized that concealing the hydrophilic residues of the peptide using the lipophilic prodrug charge masking approach (LPCM) can improve the bioavailability of hydrophilic peptides. To test this hypothesis, a cyclic N-methylated hexapeptide containing Arg-Gly-Asp (RGD) and its prodrug derivatives, masking the Arg and Asp charged side chains, were synthesized. The library was evaluated for intestinal permeability in vitro using the Caco-2 model. Further investigation of metabolic stability ex vivo models in rat plasma, brush border membrane vesicles (BBMVs), and isolated CYP3A4 microsomes and pharmacokinetic studies was performed on a selected peptide and its prodrug (peptide 12). The parent drug analogues were found to have a low permeability rate in vitro, corresponding to atenolol, a marker for paracellular permeability. Moreover, palmitoyl carnitine increased the Papp of peptide 12 by 4-fold, indicating paracellular permeability. The Papp of the prodrug derivatives was much higher than that of their parent peptides. For instance, the Papp of the prodrug 12P was 20-fold higher than the Papp of peptide 12 in the apical to basolateral (AB) direction. Whereas the permeability in the opposite direction (BA of the Caco-2 model) was significantly faster than the Papp AB, indicating the involvement of an efflux system. These results were corroborated when verapamil, a P-gp inhibitor, was added to the Caco-2 model and increased the Papp AB of prodrug 12P by 3-fold. The prodrug 12P was stable in the BBMVs environment, yet degraded quickly (less than 5 min) in the plasma into the parent peptide 12. Pharmacokinetic studies in rats showed an increase in the bioavailability of peptide 12 > 70-fold (from 0.58 +/- 0.11% to 43.8 +/- 14.9%) after applying the LPCM method to peptide 12 and converting it to the prodrug 12P. To conclude, the LPCM approach converted the absorption mechanism of the polar peptides from a paracellular to transcellular pathway that tremendously affects their oral bioavailability. The LPCM method provides a solution for the poor bioavailability of RGD cyclohexapeptides and paves the way for other active hydrophilic and charged peptides with poor oral bioavailability. PMID- 29976061 TI - Synthetic Pathway for the Production of Olivetolic Acid in Escherichia coli. AB - Type III polyketide synthases (PKS IIIs) contribute to the synthesis of many economically important natural products, most of which are currently produced by direct extraction from plants or through chemical synthesis. Olivetolic acid (OLA) is a plant secondary metabolite sourced from PKS III catalysis, which along with its prenylated derivatives has various pharmacological activities. To demonstrate the potential for microbial cell factories to circumvent limitations of plant extraction or chemical synthesis for OLA, here we utilize a synthetic approach to engineer Escherichia coli for the production of OLA. In vitro characterization of polyketide synthase and cyclase enzymes, OLA synthase and OLA cyclase, respectively, validated their requirement as enzymatic components of the OLA pathway and confirmed the ability for these eukaryotic enzymes to be functionally expressed in E. coli. This served as a platform for the combinatorial expression of these enzymes with auxiliary enzymes aimed at increasing the supply of hexanoyl-CoA and malonyl-CoA as starting and extender units, respectively. Through combining OLA synthase and OLA cyclase expression with the required modules of a beta-oxidation reversal for hexanoyl-CoA generation, we demonstrate the in vivo synthesis of olivetolic acid from a single carbon source. The integration of additional auxiliary enzymes to increase hexanoyl-CoA and malonyl-CoA, along with evaluation of varying fermentation conditions enabled the synthesis of 80 mg/L OLA. This is the first report of OLA production in E. coli, adding a new example to the repertoire of valuable compounds synthesized in this industrial workhorse. PMID- 29976062 TI - Improved LC/MS Methods for the Analysis of Metal-Sensitive Analytes Using Medronic Acid as a Mobile Phase Additive. AB - Phosphorylated compounds and organic acids with multiple carboxylate groups are commonly observed to have poor peak shapes and signal in LC/MS experiments. The poor peak shape is caused by the presence of trace metals, particularly iron, contributed from a variety of sources within the chromatographic system. To ameliorate this problem, different solvent additives were investigated to reduce the amount of metal in the flow path to achieve better analytical performance for these metal-sensitive compounds. Here, we introduce the use of a solvent additive that can significantly improve the peak shapes and signal of metal-sensitive metabolites for LC/MS analysis. Moreover, the additive is shown to be amenable for other metal-sensitive applications, such as the analysis of phosphopeptides and polar phosphorylated pesticides, where the instruments could be used in either positive or negative analysis mode. PMID- 29976063 TI - Triplet Energy Transfer Governs the Dissociation of the Correlated Triplet Pair in Exothermic Singlet Fission. AB - Singlet fission is a spin-allowed process of exciton multiplication that has the potential to enhance the efficiency of photovoltaic devices. The majority of studies to date have emphasized understanding the first step of singlet fission, where the correlated triplet pair is produced. Here, we examine separation of correlated triplet pairs. We conducted temperature-dependent transient absorption on 6,3-bis(tri isopropylsilylethynyl)pentacene (TIPS-Pn) films, where singlet fission is exothermic. We evaluated time constants to show that their temperature dependence is inconsistent with an exclusively thermally activated process. Instead, we found that the trends can be modeled by a triplet-triplet energy transfer. The fitted reorganization energy and electronic coupling agree closely with values calculated using density matrix renormalization group quantum chemical theory. We conclude that dissociation of the correlated triplet pair to separated (but spin-entangled) triplet excitons in TIPS-Pn occurs by triplet triplet energy transfer with a hopping time constant of approximately 3.5 ps at room temperature. PMID- 29976064 TI - Bioluminescent Probe for Detection of Starvation-Induced Pantetheinase Upregulation. AB - Pantetheinase, a glycosylphosphatidylinositol (GPI) anchored enzyme, overexpresses in intestine, liver, and kidney with various biological functions such as its linkage to the inflammation and some metabolic diseases. It can hydrolyze pantetheine to cysteamine, an antioxidant, and pantothenic acid (Vitamin B5) that is an essential component of coenzyme A (CoA). Until now, very few analytic methods were developed for this enzyme, hampering the further investigation of its biological functions. In this work, we report the design, synthesis, and biological examination of a highly sensitive bioluminogenic probe for pantetheinase with a limit of detection of 1.14 ng/mL. Furthermore, animal experiments validated that our probe can be applied to detect the endogenous pantetheinase activity. To the best of our knowledge, this is the first bioluminogenic probe achieving the detection of pantetheinase level in vivo. PMID- 29976065 TI - Fabrication of an Effective Avermectin Nanoemulsion Using a Cleavable Succinic Ester Emulsifier. AB - In this study, a new emulsifier precursor was prepared via esterification of avermectin with succinic anhydride. The chemical structure of the product was confirmed to be monosubstituted avermectin. After neutralization with triethanolamine, it exhibited adequate emulsification ability for avermectin. Avermectin was then encapsulated in nanoparticles in the nanoemulsion with a high drug loading up to 60 wt % and high stability. The nanoemulsion of nanoparticles that serves as a carrier of avermectin shows highly efficient pesticide characteristics, including low surface tension, high affinity to leaves, and improved photostability. In the presence of esterase or under strongly basic conditions, the ester bonds of the emulsifier can be hydrolyzed, and the encapsulated avermectin molecules can be released in an accelerated manner. The nanoemulsion exhibited improved insecticidal effect compared with commercial emulsifiable concentrate, which was attributed to the cleavage of ester bonds of the emulsifier by esterase in vivo. PMID- 29976066 TI - Structural Modifications of DPPC Bilayers upon Inclusion of an Antibacterial Cationic Bolaamphiphile. AB - The emergence of antibiotic-resistant bacterial strains has fostered fundamental research to develop alternative antimicrobial strategies. Among the several systems proposed so far, the association complexes (nanoplexes) formed by transcription factor decoys (TFDs), i.e., short oligonucleotides targeting a crucial bacterial transcription factor, and a bolaform cationic amphiphile, 10,10'-(dodecane-1,12-diyl)-bis-(9-amino-1,2,3,4-tetrahydroacridinium) chloride (12-bis-THA), have demonstrated their potential in vitro and in vivo. The application of these nanoplexes is hampered by a scarce colloidal stability, which can be addressed by including the bolaamphiphile in a liposomal carrier, which is then associated to the TFD. The present study reports an investigation on the effects of 12-bis-THA on the structure of synthetic lipid bilayers to assess the morphology of the mixed assemblies, gain insight into the location of the host within the bilayer, and determine the loading capacity of the carrier. Our results demonstrate that 12-bis-THA promptly inserts within 1,2-dipalmitoyl- sn-glycero-3-phosphocholine (DPPC) bilayers, bending its C-12 spacer chain to adopt a conelike shape and shifting the gel-liquid crystalline transition of the chains to lower temperatures. The host liposomal structure is retained for a bolaamphiphile concentration of up to 3.2% mol to DPPC, whereas higher concentrations lead to the destabilization by means of a detergency-like mechanism, with the simultaneous existence of different lamellar-based structures, such as liposomes, bicelles, and rafts, in which DPPC and 12-bis-THA could be present in different molar ratios. Overall, these results shed light on the interaction of the bolaamphiphile with a lipid bilayer and provide valuable insight to better formulate the antimicrobial amphiphile in liposomal carriers to circumvent the colloidal instability of nanoplexes. PMID- 29976067 TI - Direct Visualization of Photomorphic Reaction Dynamics of Plasmonic Nanoparticles in Liquid by Four-Dimensional Electron Microscopy. AB - Liquid-cell electron microscopy (LC-EM) provides a unique approach for in situ imaging of morphology changes of nanocrystals in liquids under electron beam irradiation. However, nanoscale real-time imaging of chemical and physical reaction processes in liquids under optical stimulus is still challenging. Here, we report direct observation of photomorphic reaction dynamics of gold nanoparticles (AuNPs) in water by liquid-cell four-dimensional electron microscopy (4D-EM) with high spatiotemporal resolution. The photoinduced agglomeration, coalescence, and fusion dynamics of AuNPs at different temperatures are studied. At low laser fluences, the AuNPs show a continuous aggregation in several seconds, and the aggregate size decreases with increasing fluence. At higher fluences close to the melting threshold of AuNPs, the aggregates further coalesced into nanoplates. While at fluences far above the melting threshold, the aggregates fully fuse into bigger NPs, which is completed within tens of nanoseconds. This liquid-cell 4D-EM would also permit study of other numerical physical and chemical reaction processes in their native environments. PMID- 29976068 TI - Concise Synthesis of (-)-Cycloclavine and (-)-5- epi-Cycloclavine via Asymmetric C-C Activation. AB - To illustrate the synthetic significance of C-C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (-) cycloclavine and (-)-5- epi-cycloclavine, which is enabled by an asymmetric Rh catalyzed "cut-and-sew" transformation between benzocyclobutenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C-N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate scope with high enantioselectivity (94-99% e.e.). The C-C activation based strategy employed here is anticipated to have further implications for syntheses of other natural products that contain complex fused or bridged rings. PMID- 29976069 TI - Effects of Mechanical Stimuli on Profilin- and Formin-Mediated Actin Polymerization. AB - Self-assembling actin filaments not only form the basis of the cytoskeleton network in cells but also are utilized as nanosized building blocks to make novel active matter in which the dynamic polymerization and depolymerization of actin filaments play a key role. Formins belong to a main family of actin nucleation factors that bind to the barbed end of actin filaments and regulate actin polymerization through an interaction with profilin. Due to actomyosin contractility and relative rotation between formin and actin filaments, formin dependent actin polymerization is subject to force and rotation constraints. However, it remains unclear how force and rotation constraints affect formin dependent actin polymerization in the presence of profilin. Here, we show that for rotation-unconstrained actin filaments, elongation is accelerated by both force and profilin. The combined effect leads to surprisingly fast actin elongation that can approach the diffusion-limited rate at forces of a few piconewtons. The elongation of rotation-constrained filaments is also accelerated by profilin but is insensitive to applied force. We show that FH2, the main actin binding domain, plays the primary mechanosensing role. Together, the findings not only significantly advance our understanding of the mechanochemical regulation of formin-mediated actin polymerization in cells but also can potentially be utilized to make novel actin-based active matter. PMID- 29976071 TI - Reconfirmation of "Art" in Organic Synthesis. PMID- 29976070 TI - Techno-Functional Properties of Crude Extracts from the Green Microalga Tetraselmis suecica. AB - A mild fractionation process to extract functional biomolecules from green microalgae was implemented. The process includes bead milling, centrifugation, and filtration with several membrane cut-offs. For each fraction, the corresponding composition was measured, and the surface activity and gelation behavior were determined. A maximum protein yield of 12% was obtained in the supernatant after bead milling and between 3.2 and 11.7% after filtration. Compared to whey protein isolate, most of the algae fractions exhibited comparable or enhanced functionality. Surface activity for air-water and oil water interfaces and gelation activities were notably superior for the retentate fractions compared to the permeates. It is proposed that such functionality in the retentates is due to the presence of hydrophobic compounds and molecular complexes exhibiting a similar behavior as Pickering particles. We demonstrated that excellent functionality can be obtained with crude fractions, requiring minimum processing and, thus, constituting an interesting option for commercial applications. PMID- 29976072 TI - Synthesis of Antibiotics and Related Molecules. PMID- 29976073 TI - Clinical-endoscopic relevance of incidental colorectal lesions detected by PET CT. AB - AIM: to determine the proportion of incidental colon lesions detected by PET-CT and their correlation with the endoscopic and histological findings. In addition, to determine the maximum standardized uptake value (SUVmax) that can discriminate between benign and malignant lesions in our series of cases. METHODS: this was a retrospective study of 3,000 patients evaluated by PET-CT for staging or response to treatment of primary neoplasms, between 2011 and 2015. Patients with incidental uptake in the colon were included in the study. Exclusion criteria included an incomplete, poorly prepared or abandoned colonoscopy, inflammatory bowel disease and treatment with metformin. RESULTS: the study cohort comprised 71 patients evaluated by PET-CT and subsequently analyzed by endoscopy; 69% were male with a mean age of 65.77 +/- 11.2. The rate of incidental colon lesions found by PET-CT was 1.73%, with 52 incidental colonic uptakes reported in 50 patients. The location of the uptake was the rectum (19.23%), sigmoid colon (34.62%), descending colon (13.46%), transverse colon (1.9%), ascending colon (19.23%), cecum (9.62%) and ileocolic anastomosis (1.92%). Thirty-five pathological colonoscopies (71.15%) were identified: the findings included five neoplasms (13.51%), two inflammatory lesions (5.4%) and 30 adenomatous polyps (81.1%). Significant differences were found between neoplastic SUVmax (11.7 g/ml; p = 0.03) and polyps (9.26 g/ml; p = 0.04) in relation to inflammatory lesions and normal endoscopies (6.05 g/ml). There were no differences in terms of the size of the polyps, nor the presence or absence of high grade dysplasia (p = 0.12 and 0.33). Both PET-CT and endoscopy proved consistent for locating lesions (k 0.90; CI 95% 0.86-0.93). CONCLUSION: there is a good correlation between the findings identified by PET-CT and the endoscopic study. In our study, a SUVmax > 11 g/ml suggests a malignant pathology, which aids the prioritization of an endoscopic study. PMID- 29976074 TI - Factors associated with complications during endoscopic esophageal dilation. AB - BACKGROUND: endoscopic dilation is considered as the treatment of choice for esophageal strictures. However, there are no studies in our region that have assessed the safety of the procedure. OBJECTIVE: to assess the safety of esophageal dilation and the factors associated with the development of complications. MATERIALS AND METHODS: a retrospective cohort was studied. All patients referred for esophageal dilation between January 2015 and June 2017 were included in the study. A complication rate was obtained and the association between nonadherence to the "rule of 3" and the development of complications was determined. Other predictive factors associated with complication development were also analyzed. RESULTS: a total of 164 patients that underwent 474 dilations were included in the study. Surgical anastomosis stricture was the most prevalent etiology. A total of six complications occurred, including three perforations (0.63%), two bleeding events (0.42%) and one episode of significant pain that required post-procedure observation (0.21%). Endoscopic esophageal dilation without adherence to the "rule of 3" was not associated with a higher risk of complications. Balloon dilation was the only predictive factor for complications. CONCLUSIONS: esophageal dilation is a safe procedure. Nonadherence to the "rule of 3" does not appear to be associated with a higher risk of complications, including esophageal perforation. PMID- 29976075 TI - An Analysis of Recruitment Efficiency for an End-of-Life Advance Care Planning Randomized Controlled Trial. AB - BACKGROUND: Optimizing recruitment efficiency is an important strategy to address the resource limitations that typically constrain clinical research. Surprisingly, little empiric data exist to guide research teams attempting to recruit a difficult population into similar studies. Our objective was to investigate factors associated with enrollment into an advance care planning interventional trial. METHODS: This study used secondary data of patients with advanced cancer receiving treatment at an academic medical center in central Pennsylvania who were referred to a randomized controlled trial of an advance care planning intervention. Enrolled participants were compared to nonparticipants with regard to age, gender, race, season of recruitment, elapsed time between recruitment stage, distance to study site, and number of recruitment calls. RESULTS: Of the 1988 patients referred, 200 participants were enrolled yielding a recruitment efficiency of 10%. Two-thirds of all enrolled participants were recruited with 1 or less phone calls, whereas only 5% were enrolled after 3 calls. There were no statistically significant differences in enrollment based on gender ( P = .88) or elapsed time between recruitment contacts ( P = .22). However, nonparticipants were slightly older ( P = .02). CONCLUSIONS: Our finding that individuals were more likely to enroll within the first 3 phone calls suggests that recruitment efforts should be focused on making initial contacts with potential participants, rather than continuing attempts to those who are unable to be contacted easily. Researchers could optimize their recruitment strategy by periodically performing similar analyses, comparing differences between participants and nonparticipants. PMID- 29976076 TI - Urine markers of podocyte dysfunction: a review of podocalyxin and nephrin in selected glomerular diseases. AB - Urinary podocalyxin and nephrin are urine markers of podocyte dysfunction that may reflect the integrity of kidney's filtration barrier. Studies on their respective roles in glomerular diseases are still underway. However, the isolated and unsystematic manner in which they are being studied does not permit proper identification of their roles in each glomerular disease. As such, there is little or no appreciation of what research has already achieved and what remains to be achieved as the research direction is not clearly defined. We explored the recent studies and outlined the major findings regarding the value of both biomarkers in each of the three glomerular disease entities. Our review covered diabetic nephropathy, membranous nephropathy and IgA nephropathy. PMID- 29976077 TI - Exogenous phytase and xylanase exhibit opposing effects on real-time gizzard pH in broiler chickens. AB - 1. The current study was conducted to evaluate the influence of high phytase doses and xylanase, individually and in combination, on performance, blood inositol and real-time gastric pH in broilers fed wheat-based diets. 2. In a 42-d experiment, a total of 576 male Ross 308 broiler chicks were allocated to 4 dietary treatments. Treatments consisted of a 2 * 2 factorial arrangement, with 500 or 2500 FTU/kg phytase and 0 or 16 000 BXU/kg xylanase, fed in two phases (starter 0-21; grower 21-42 d). Heidelberg pH capsules were administered to 8 birds from each treatment group, pre- and post-diet phase change, with readings captured over a 5.5-h period. 3. At 21 and 42 d, birds fed 500 FTU/kg phytase without xylanase had on average 127 and 223 g lower weight gain than all other treatments, respectively (P < 0.05). At 21 d, feed conversion ratio (FCR) was reduced (P < 0.01) by 2500 FTU/kg phytase or xylanase; however, 42-d FCR was unaffected by enzyme treatment. Inositol content of plasma was twice that of the erythrocyte (P < 0.001), with 2500 FTU/kg phytase tending to increase (P = 0.07) inositol content in both blood fractions. 4. Across all treatments, capsule readings ranged from pH 0.54 to 4.84 in the gizzard of broilers. Addition of 2500 FTU/kg phytase to the grower diet reduced (P < 0.05) average gizzard pH from 2.89 to 1.69, whilst feeding xylanase increased (P < 0.001) gizzard pH from 2.04 to 2.40. In contrast, digital probe measurements showed no effect of xylanase on gizzard pH, while addition of 2500 FTU/kg phytase increased (P = 0.05) pH compared to 500 FTU/kg phytase with or without xylanase. 5. These findings suggested that xylanase and high phytase doses have opposite effects on real-time gastric pH, while similarly improving performance of broilers. PMID- 29976078 TI - Comparison of single- and multi-strain probiotics effects on broiler breeder performance, egg production, egg quality and hatchability. AB - 1. This study was conducted to investigate the effect of multi-strain probiotic (containing Lactobacillus acidophilus 2.5 * 107 cfu/g, Lactobacillus casei 2.5 * 107 cfu/g, Bifidobacterium thermophilum 2.5 * 107 cfu/g and Enterococcus faecium 2.5 * 107 cfu/g) and single-strain probiotic (Pediococcus acidilactici 1 * 1010 cfu/g) on broiler breeder performance and gastrointestinal health. 2. A completely randomised trial was conducted using 300 broiler breeder hens (Ross 308) aged 51 weeks old which were randomly allocated to 1 of 5 dietary treatments with 6 replicates per treatment in a 10 week trial. Treatments included (1) the basal diet a negative control, (2) basal diet supplemented with 0.1 g/kg multi strain probiotic (MS), (3) basal diet supplemented with 0.1 g/kg single-strain probiotic (SS), (4) basal diet supplemented with 0.1 g/kg of both of probiotics (MS+ SS) and (5) positive control basal diet supplemented with 0.5 g/kg oxytetracycline antibiotic (OX). 3. Body weight, egg production, yolk weight, eggshell thickness and weight, Haugh unit, fertility and hatchability were determined. Results showed that dietary treatments had no significant effect on total hen house or total hatching egg production, egg weight, yolk colour index, shell weight, mortality, body weight, fertility, hatchability, oviduct and stroma weight or number of large and small yellow follicles (P > 0.05). None of the jejunum morphological parameters, apparent ileal digestibility of protein and ileal Lactobacillus population were influenced by supplemental probiotics (P > 0.05), although ileum Escherichia coli count was reduced by inclusion of dietary probiotics (P < 0.05). 4. It was concluded that although both probiotic treatments reduced coliforms, they did not improve broiler breeder performance or gastrointestinal tract (GIT) function. PMID- 29976079 TI - The Association Between Abdominal Aortic Aneurysms With Cardiovascular and Noncardiovascular Diseases. PMID- 29976080 TI - Effects of Celastrus orbiculatus on Epithelial Mesenchymal Transition in Gastric Mucosal Epithelial Cells by Inhibiting Lgr5 Expression from Rats with Gastric Precancerous Lesions. AB - The extract of Celastrus orbiculatus (COE) has been shown to possess anti Helicobacter pylori (H. pylori) activity and anticancer effects in vitro and in vivo. However, the molecular mechanism by which COE on precancerous lesions of gastric cancer (PLGC) has not been fully elucidated so far. The purpose of this study is to evaluate the effect and mechanism of COE in the rat model of PLGC, after the rat model of PLGC was successfully constructed. The effects of COE in gastric mucosa of rats with PLGC were tested using routine pathology and a transmission electron microscope (TEM) analysis. The protein and mRNA expression levels of epithelial mesenchymal transition (EMT) markers (E-cadherin, N-cadherin and Vimentin) and leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) were detected adopting techniques of immunohistochemistry (IHC), real-time PCR (RT-PCR) and western blot assays. The body weight of PLGC rats was significantly higher in the COE group than that in the untreated group. The process of PLGC was significantly reversed after COE treatment, shown by observing the changes of histopathological morphology and ultrastructure. Gastric mucosal epithelial cells in COE high dose (COE-H) group showed significantly higher expression levels of E-cadherin, and lower expression levels of N cadherin, Vimentin and Lgr5 than those of the untreated group. COE could suppress the spatial distribution of Lgr5[Formula: see text] cell changes in PLGC rats. These findings suggested that the therapeutic mechanisms of COE in treating PLGC might be related with its effects on reversing the EMT process and inhibiting Lgr5 expression. PMID- 29976081 TI - Curcuminoids Induce Reactive Oxygen Species and Autophagy to Enhance Apoptosis in Human Oral Cancer Cells. AB - Numerous studies support the use of herbal medicine or natural products for chemotherapy in human cancers. Reports have associated curcumin (CUR), dimethoxy curcumin (DMC) and bisdemethoxycurcumin (BDMC) with numerous biological activities including anticancer activities, but no available information have shown that these induced apoptotic cell death and autophagy in human oral cancer cells. In the present study, we investigated the effect of CUR, DMC and BDMC on the cell viability, apoptotic cell death, reactive oxygen species (ROS), Ca[Formula: see text], mitochondria membrane potential (MMP) and caspase activities using flow cytometry assay and autophagy by monodansylcadaverine (MDC) and acridine orange (AO) staining in human oral cancer SAS cells. Results indicated that CUR, DMC and BDMC decreased total viable cell number through the induction of cell autophagy and apoptosis in SAS cells. Cells were pretreated with N-acetyl-cysteine (NAC), 3-methyladenine (3MA), rapamycin and carbobenzoxy valyl-alanyl-aspartyl-[O-methyl]-fluoro-methylketone (Z-VAD-fmk) and then were treated with CUR, DMC and BDMC that led to increased total viable cell number when compared to CUR, DMC and BDMC treatments only. Results indicated induced apoptotic cell death through ROS, mitochondria-dependent pathway and induction of cell autophagy. Based on those observations, we suggest that CUR, DMC and BDMC could be used as a potential anticancer agent in human oral cancer. PMID- 29976082 TI - Therapeutic Effect of Glycyrrhizin Arginine Salt on Rat Cholestatic Cirrhosis and its Mechanism. AB - To investigate the therapeutic effect of glycyrrhizin arginine salt on rat cholestatic cirrhosis, we subjected male Sprague Dawley rats to common bile duct ligation for 14 days and treated them with distilled water (model group), arginine, or a low or high dose of glycyrrhizin arginine salt by gavage. A sham operated group was used as a control group. Treatment with glycyrrhizin arginine salt substantially improved animal growth rates, reduced the ratio of liver weight to body weight and decreased total bilirubin, aspartate aminotransferase, 8-isoprostane and malondialdehyde compared with the values measured in the model group. The progress of liver fibrosis, as detected by hematoxylin and eosin and Masson's trichrome staining, was slower in the glycyrrhizin arginine salt groups than in the model group or the arginine group. Reductions of bile salt pool size, hepatic hydroxyproline content and fibrosis score were also seen in the glycyrrhizin arginine salt groups compared with the model group. Furthermore, glycyrrhizin arginine salt significantly reduced the expression of transforming growth factor [Formula: see text]1 (TGF-[Formula: see text]1), [Formula: see text]-smooth muscle actin, tumor necrosis factor-[Formula: see text] and matrix metalloproteinases 2 and 9. Glycyrrhizin arginine salt also inhibited the expression of [Formula: see text]-SMA and matrix metalloproteinases 2 and 9 in response to TGF-[Formula: see text]1 in LX-2 cells and primary rat hepatic stellate cells and mitigated the cytotoxicity induced by rat bile in HepG2 cells and primary rat hepatocytes. PMID- 29976083 TI - Panax notoginseng for Inflammation-Related Chronic Diseases: A Review on the Modulations of Multiple Pathways. AB - Panax notoginseng (P. notoginseng) is a well-known and commonly used Chinese herbal medicine in Asian countries. As one of the major species in the Panax genus, it has a distinct chemical composition and medical application compared with other species. P. notoginseng attracts attention and interest due to its potential therapeutic effects not only on blood diseases, but also other kinds of human chronic disorders. This paper critically reviewed the latest advance of knowledge on the pharmacological effects of P. notoginseng on a variety of chronic diseases including inflammatory bowel disease, arthritis, ischemia, atherosclerosis, Alzheimer disease and trauma, as well as hyperlipidemia, diabetes, and so on. As inflammation is considered the fundamental factor involved in the pathogenesis of chronic diseases, our review therefore focuses on understanding the involvement of classical inflammatory pathways underlying the mechanism of action of P. notoginseng. Potential clinical application was also discussed. Furthermore, by combining with network pharmacology, we introduced the major bioactive components of P. notoginseng, analyzed their cellular targets and associated signaling pathways. In conclusion, this review identified inflammatory pathway as the key signaling for determining the efficacy of P. notoginseng on chronic diseases. It is speculated that P. notoginseng is a multi-targeted agent with an anti-inflammatory property in the adjuvant and alternative treatment of human chronic diseases. PMID- 29976084 TI - Flos Magnoliae Inhibits Chloride Secretion via ANO1 Inhibition in Calu-3 Cells. AB - Flos Magnoliae (FM, Chinese name: Xin-yi) is an oriental medicinal herb commonly used for symptomatic relief from allergic rhinitis, sinusitis, and headache, including in traditional Chinese and Korean medicine formulations. FM inhibits histamine release from mast cells and cytokine secretion from T cells. However, the mechanism of action of FM on the anoctamin-1 (ANO1) ion channel, which is responsible for nasal hypersecretion in allergic rhinitis, has not been elucidated. Therefore, in this study, we investigated the effect of a 30% ethanolic extract of FM (FMEtOH) and its chemical constituents on ANO1 activity. We used high-performance liquid chromatography analysis to identify five major chemical constituents of FMEtOH: vanillic acid, tiliroside, eudesmin, magnolin, and fargesin. Using a conventional whole-cell patch clamp method, we found that FMEtOH (30, 100, and 300[Formula: see text][Formula: see text]g/mL) and its chemical constituent tiliroside inhibited ANO1 activity in ANO1-overexpressing HEK293T cells. In addition, we found that the treatment of the airway epithelial cell line Calu-3 with interleukin 4 significantly increased Ca[Formula: see text] activated Cl[Formula: see text] current (ICaCC), but not cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride current (ICFTR). FMEtOH and tiliroside specifically inhibited ICaCC. Thus, in this study, we identified a novel mechanism underlying the alleviation of allergic rhinitis by FMEtOH. Our results indicate that FMEtOH and its chemical constituent tiliroside are promising and potent agents for the prevention and treatment of allergic rhinitis. PMID- 29976085 TI - Kaempferol's Protective Effect on Ethanol-Induced Mouse Primary Hepatocytes Injury Involved in the Synchronous Inhibition of SP1, Hsp70 and CYP2E1. AB - The mechanism of ethanol-induced hepatotoxicity was complicated, accompanied by the over-expressions of the cytochrome P450 2E1 (CYP2E1), heat shock protein 70 (Hsp70) and the nuclear factor specificity protein 1 (SP1). Kaempferol (Kaem) could protect the ethanol-induced hepatotoxicity likely by inhibiting the CYP2E1 expression and activity. This study investigated the protective mechanism(s) of kaempferol on ethanol-induced toxicity by dynamic alteration of SP1, Hsp70 and CYP2E1 among the nucleus and different organelles in hepatocytes. After ethanol treatment alone and co-incubation hepatocytes with kaempferol, protein levels of CYP2E1, Hsp70, and SP1 were determined in vitro (western blotting and immunofluorescence). Hepatocytes' viability was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) methods. Glutathione (GSH) levels were evaluated for ethanol-induced oxidative stress. In the ethanol-treated hepatocytes, kaempferol decreased protein levels of CYP2E1 in both microsome and mitochondria, cytosolic Hsp70 and SP1 in nuclear and cytosol, and the oxidative stress and increased the cell viability compared to those of ethanol group. Collectively, our findings propose that the protective mechanism of kaempferol is involved in the synchronous, early and persistent inhibitions of mitochondrial and microsomal CYP2E1, cytosolic Hsp70 and nuclear and cytosolic SP1 in mouse primary hepatocytes' injury induced by ethanol. PMID- 29976087 TI - Sildenafil and calcitonin gene-related peptide dilate intradural arteries: A 3T MR angiography study in healthy volunteers. AB - Background Sildenafil and calcitonin gene-related peptide are vasoactive substances that induce migraine attacks in patients. The intradural arteries are thought to be involved, but these have never been examined in vivo. Sildenafil is the only migraine-inducing compound for which cephalic, extracranial artery dilation is not reported. Here, we investigate the effects of sildenafil and calcitonin gene-related peptide on the extracranial and intradural parts of the middle meningeal artery. Methods In a double-blind, randomized, three-way crossover, placebo-controlled head-to-head comparison study, MR-angiography was recorded in healthy volunteers at baseline and twice after study drug (sildenafil/ calcitonin gene-related peptide/saline) administration. Circumferences of extracranial and intradural middle meningeal artery segments were measured using semi-automated analysis software. The area under the curve for circumference change was compared using paired t-tests between study days. Results Twelve healthy volunteers completed the study. The area under the curveBaseline-120min was significantly larger on both the sildenafil and the calcitonin gene-related peptide day in the intradural middle meningeal artery (calcitonin gene-related peptide, p = 0.013; sildenafil, p = 0.027) and the extracranial middle meningeal artery (calcitonin gene-related peptide, p = 0.0003; sildenafil, p = 0.021), compared to placebo. Peak intradural middle meningeal artery dilation was 9.9% (95% CI [2.9-16.9]) after sildenafil (T30min) and 12.5% (95% CI [8.1-16.8]) after calcitonin gene-related peptide (T30min). Peak dilation of the extracranial middle meningeal artery after calcitonin gene related peptide (T30min) was 15.7% (95% CI [11.2-20.1]) and 18.9% (95% CI [12.8 24.9]) after sildenafil (T120min). Conclusion An important novel finding is that both sildenafil and calcitonin gene-related peptide dilate intradural arteries, supporting the notion that all known pharmacological migraine triggers dilate cephalic vessels. We suggest that intradural artery dilation is associated with headache induced by calcitonin gene-related peptide and sildenafil. PMID- 29976088 TI - Risk-Based HIV Testing at Los Angeles County Men's Central Jail. AB - Incarcerated populations tend to be disproportionately affected by HIV and sexually transmitted infections (STIs), and men who have sex with men (MSM) are an especially high-risk subset of these populations. Despite the Centers for Disease Control and Prevention's recommendations for universal HIV screening, a lack of resources and high inmate turnover make it difficult to implement such guidelines in jails. From September 2013 to May 2016, the Infection Control Unit of the Los Angeles County Jail used existing resources to implement a voluntary, risk-based HIV educational and screening program targeting MSM inmates during early incarceration. The results revealed a high percentage of previously unknown HIV infections (8.5% = 57 of the 671 tested) and some unknown non-HIV STI cases. In the absence of resources for universal HIV screening, the risk-based approach is a sustainable and cost-effective approach for improving HIV surveillance in the correctional setting. PMID- 29976086 TI - Galectin-12 is Involved in Corn Silk-Induced Anti-Adipogenesis and Anti-Obesity Effects. AB - Obesity is a significant risk factor for various diseases. It is a clinical condition caused by the excessive accumulation of fat, which has a negative impact on human health. Galactin-12 is an adipocyte-expressed protein and possesses adipocyte-inducing activity. We investigated the expression level of candidate proteins involved in galactin-12-mediated adipocyte differentiation pathway. We performed a high-throughput screening assay to monitor galectin-12 promoter activity using 105 traditional Chinese herbs. Corn silk extract and [Formula: see text]-sitosterol reduced the expression of galactin-12 promoter in 3T3-L1 cells. In addition, corn silk extract and [Formula: see text]-sitosterol decreased the level of lipid droplets and downregulated the gene and protein expression level of C/EBP[Formula: see text], C/EBP[Formula: see text], PPAR[Formula: see text], Ap2, and adipsin in 3T3-L1 pre-adipocytes via AKT and ERK1/2 inhibition. In vivo study with the oral administration of corn silk extract and [Formula: see text]-sitosterol in a mouse model showed a significant weight reduction and decrease in adipocytes in several organs such as the liver and adipose tissue. Taken together, corn silk extract and [Formula: see text] sitosterol may effectively reduce pre-adipocyte differentiation by inhibiting galectin-12 activity and exerting anti-obesity effects. These findings highlight the potential use of corn silk extract and [Formula: see text]-sitosterol as potential candidates for the prevention and treatment of obesity. PMID- 29976089 TI - The Impact of School Nurses in Kentucky Public High Schools. AB - The purpose of this study was to examine the relationship between school nurse presence and graduation rates, absenteeism, and American College Test (ACT) scores. A state-wide survey of all public high schools was undertaken (participation rate of 99.1%). Survey data obtained from individual high schools provided information on the employment status of school nurses. In addition to nurse presence determined by the survey, open-access electronic databases were used to determine graduation rates, absenteeism, ACT scores, money spent per pupil, gender, race-ethnicity proportion, and incarceration data. Study findings showed a possible relationship between students attending schools with a full time nurse and significantly higher graduation rates, lower absenteeism, and higher ACT scores. The study results suggest that school nurses may contribute not just to health outcomes but to improved academic and economic outcomes as well. Of course, future work is needed to confirm these assertions. PMID- 29976091 TI - A scoping review of rehabilitation interventions for survivors of head and neck cancer. AB - PURPOSE: The objectives of this scoping review were to summarize, understand, and disseminate findings from a broad body of literature on rehabilitation interventions used with survivors of head and neck cancer. METHOD: Searches were conducted in six databases. Inclusion criteria were studies of adult head and neck cancer survivors with a predefined primary rehabilitation outcome as a result of an intervention. Excluded were studies not written in English, opinion papers, or studies where the intervention was not carried out by a rehabilitation healthcare service. A second level, full-text review of the studies was conducted. A thematic analysis was used to examine and combine study findings. RESULTS: A total of 3804 results were retrieved from all sources resulting in 39 papers that were analyzed. The thematic analysis of the included papers represented interventions focusing on swallowing and nutrition, speech, physical therapy, assistive devices, complementary and alternative modalities, comprehensive interdisciplinary programs, and preventive rehabilitation programs. CONCLUSION: This review has provided an overview of the scope of rehabilitation interventions available for survivors of head and neck cancer and preliminary information about their efficacy. This is foundational information for the development and refinement of rehabilitation interventions and programs for head and neck cancer survivors. Implications for Rehabilitation The existing evidence suggests that survivors of head and neck cancer can benefit from early screening of potential rehabilitation needs and being involved in preventive rehabilitation programs pre-surgery when possible. Rehabilitation programs should consider swallowing interventions for patients as evidence reports improved swallowing function, decreased pain and discomfort, and reduced duration of feeding tube use. Rehabilitation programs should consider nutritional interventions after radiotherapy: Patients benefited from stabilized weights, improved nutritional status, and an improved quality of life. Physical exercise interventions demonstrated improvements in physical function, muscular endurance, range of motion, overall quality of life, and showed reductions in pain, and fatigue. PMID- 29976090 TI - PARK7 modulates autophagic proteolysis through binding to the N-terminally arginylated form of the molecular chaperone HSPA5. AB - Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10). In this mechanism, TNFSF10 induces the N-terminal arginylation (Nt-arginylation) of the endoplasmic reticulum (ER)-residing molecular chaperone HSPA5/BiP/GRP78, leading to cytosolic accumulation of Nt-arginylated HSPA5 (R-HSPA5). In parallel, TNFSF10 induces the oxidation of PARK7. Oxidized PARK7 acts as a co-chaperone-like protein that binds the ER-derived chaperone R-HSPA5, a member of the HSPA/HSP70 family. By forming a complex with PARK7 (and possibly misfolded protein cargoes), R-HSPA5 binds SQSTM1 through its Nt-Arg, facilitating self-polymerization of SQSTM1 and the targeting of SQSTM1-cargo complexes to phagophores. The 3-way interaction among PARK7, R HSPA5, and SQSTM1 is stabilized by the Nt-Arg residue of R-HSPA5. PARK7-deficient cells are impaired in the targeting of R-HSPA5 and SQSTM1 to phagophores and the removal of Ub-conjugated cargoes. Our results suggest that PARK7 functions as a co-chaperone for R-HSPA5 to modulate autophagic removal of misfolded protein cargoes generated by oxidative stress. PMID- 29976092 TI - Helicobacter pylori drug resistance: therapy changes and challenges. AB - INTRODUCTION: Helicobacter pylori is a Gram-negative bacterium that causes chronic gastritis, dyspepsia, peptic ulcers, and gastric cancer. Over half the world's population is infected with H. pylori, with higher prevalence in developing countries. Areas covered: In this review, current guidelines on H. pylori therapy, such as the Toronto consensus statement, the Maastricht V/Florence consensus report, and the American College of Gastroenterology guidelines, are compared. Also, we analyzed reports of antimicrobial resistance of H. pylori published in PubMed in the last years to determine current antimicrobial resistance worldwide. Expert commentary: Although H. pylori antimicrobial resistance varies by geographic area, its prevalence has been increasing over time, causing therapy failures and low eradication rates. To best optimize the management of H. pylori infection, H. pylori therapy should be based on patterns of local and individual antimicrobial resistance, if possible. PMID- 29976093 TI - Spontaneous childbirth-related mental images among pregnant women: a mixed-method study. AB - BACKGROUND: Mental imagery may reflect the present, past or future. Childbirth is often anticipated with joy but also in some cases with fear, which may negatively impact on the childbirth experience. So far, research on birth-related mental imagery in pregnancy is lacking. This study aimed to investigate in detail the phenomenology of spontaneous childbirth-related mental images and the association between main imagery characteristics (valence, positive/negative percentage ratio and impact on behaviour and decision-making) and fear of childbirth. METHODS: A concurrent triangulation mixed methods design was employed. Thirty-seven nulliparous, French-speaking women, aged >= 18 years in their third trimester of pregnancy completed self-report questionnaires assessing fear of childbirth, spontaneous use of mental imagery, prenatal depression and trait anxiety, and participated in a mental imagery interview to assess spontaneous childbirth related mental images. Women with a prenatal diagnosis of malformation were excluded. RESULTS: All participants reported having spontaneous mental images of their impending childbirth. The images captured were rich in detail and included a variety of sensory modalities. More positive mental images were associated with less fear of childbirth (r = -0.533, p = .008) and women who had a higher proportion of negative mental images had a higher fear of childbirth (r = 0.428, p = .005). The impact of the most negative mental images on behaviour and decision-making was positively correlated with fear of childbirth (r = 0.342, p = .038). CONCLUSION: Our results indicate that negative spontaneous childbirth related imagery is associated with fear of childbirth. Intervention techniques could be developed that focus on enhancing positive childbirth-related mental images during pregnancy and thus fostering a more positive childbirth experience. PMID- 29976094 TI - The Cumulative Incidence of Self-Reported Suicide-Related Thoughts and Attempts in Young Canadians. AB - OBJECTIVE: To estimate the cumulative incidence of self-reported suicide-related thoughts (SRTs) and suicide attempts (SAs) in males and females from 11 to 25 years of age in Canada. METHODS: A cohort study was conducted by linking cycles 2 to 8 from the National Longitudinal Survey of Children and Youth, a representative survey of Canadians aged 11 to 25 years conducted from 1996 to 2009. The 11- to 25-year cumulative incidence of self-reported SRTs and SAs (with suicidal intent) was estimated in males and females using a novel application of a counting process approach to account for discontinuous risk intervals between survey cycles. RESULTS: The risk of SRTs was 29% (95% confidence interval [CI], 26% to 31%) in females and 19% (95% CI, 16% to 23%) in males. The risk of SAs was 16% (95% CI, 14% to 19%) in females and 7% (95% CI, 6% to 8%) in males. Over 70% of SRTs and SAs first occur between 11 and 16 years of age and 30% between 11 and 13 years of age, respectively. CONCLUSIONS: The risk of SRTs and SAs is high in young Canadians, with most events first occurring in early to mid-adolescence and possibly earlier. Females are at a higher risk compared to males. This research underscores the need for better longitudinal surveillance of SRTs and SAs in the population. A counting process framework could be useful for future research using existing longitudinal surveys suffering from design limitations relating to gaps in respondent follow-up. Furthermore, these findings have implications for younger SRT and SA risk management by clinicians and earlier implementation of suicide prevention programs. PMID- 29976095 TI - Materials and techniques for percutaneous retrieval of intravascular foreign bodies. AB - The presence of an intravascular foreign body represents a well-known risk of serious complications. While in the past surgical removal of intravascular foreign body was the most common intervention, nowadays a percutaneous approach in the retrieval of an intravascular foreign body is widely accepted as the first line technique. In the literature, many case reports describe different techniques and materials. This article summarizes and illustrates the main materials and techniques currently applied for percutaneous retrieval of intravascular foreign body, providing a simplified tool with different interventional possibilities, adaptable to different clinical situations. PMID- 29976096 TI - Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes? AB - Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on treatment hsCRP concentrations <=2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent. PMID- 29976097 TI - Predicting post treatment client satisfaction between behavioural activation for depression delivered either in-person or via home-based telehealth. AB - Introduction Treatment engagement, adherence, cancellations and other patient centric data are important predictors of treatment outcome. But often these data are only examined retrospectively. In this investigation, we analysed data from a clinical trial focused on innovative delivery of depression treatment to identify which patients are likely to prefer either in-home or in-person treatment based on pre-treatment characteristics. Methods Patient satisfaction was assessed in a trial of individuals with depression treated using identical behavioural activation therapy protocols in person or through videoconferencing to the home ( N = 87 at post treatment: 42 in-person and 45 in-home participants). The Client Satisfaction Questionnaire was administered at the end of the treatment. A Tobit regression model was used to assess moderation using treatment assignment. Regression lines were generated to model treatment satisfaction as a function of treatment assignment and to identify whether and where the groups intersected. We examined the distributions of the contributing moderators to the subsets of participants above and below the intersection point to identify differences. Results While no significant differences in patient satisfaction were observed between the two groups, or between patients receiving treatment by different providers, baseline characteristics of the sample could be used to differentiate those with a preference for traditional, in-office care from those preferring in home care. Discussion Participants who were more likely to prefer in-home care were characterized by larger proportions of veterans and lower-ranked enlisted service members. They also had more severe symptoms at baseline and less formal education. Understanding client reactions when selecting treatment modality may allow for a more satisfying patient experience. PMID- 29976098 TI - A psychometric comparison of anxiety-relevant attention measures. AB - BACKGROUND AND OBJECTIVES: Preferential attention to threat, emotional response inhibition, and attentional control each purportedly play a key role in anxiety disorders. Divergent psychometric properties among attention measures may produce differential detection of anxiety-related associations and treatment-related changes. However, no studies have directly compared the psychometric properties of these attention measures in the same sample. DESIGN: Eighty-five young adults (M = 19.41 years, SD = 1.47, 48 Females) completed a cognitive task battery and a subset of 60 participants (M = 19.42 years, SD = 1.48, 33 Females) completed the task battery again approximately two weeks later. METHOD: To assess preferential attention to threat, emotional response inhibition, and attentional control, the cognitive task battery included a dot-probe task, emotion and gender Stroop tasks, and a flanker task. Tasks varied in how attention was directed and if emotional stimuli were included. Internal consistency and test-retest reliability were compared across measures. RESULTS: Within the same sample, internal consistency and reliability differed across attention measures. Explicit attention measures (emotional Stroop and flanker) exhibited stronger internal consistency and greater test-retest reliability compared to implicit measures (dot-probe and gender Stroop). CONCLUSIONS: These results inform clinical research using attention measures to assess anxiety-related differences and treatment response. PMID- 29976100 TI - Effects of binge alcohol consumption on sleep and inflammation in healthy volunteers. AB - Objective Alcohol is a hypnotic that modifies immune function, specifically the cytokines interferon gamma (IFN-gamma) and interleukin 2 (IL-2). We evaluated the association between unscheduled napping and acute alcohol-induced augmentation of IFN-gamma and IL-2 expression. Methods In this prospective, observational pilot study, volunteers completed questionnaires on sleep quality, alcohol use, and hangover characteristics. Actigraph recordings began three nights before and continued for four nights after study initiation. Napping was recorded by actigraphy and self-reporting. A weight-based dose of 100-proof vodka was consumed, and the blood alcohol content (BAC) and phytohemagglutinin-M stimulated cytokine level were measured before and 20 minutes, 2 hours, and 5 hours after binge consumption. Results Ten healthy volunteers participated (mean age, 34.4 +/ 2.3 years; mean body mass index, 23.9 +/- 4.6 kg/m2; 60% female). The mean 20 minute BAC was 137.7 +/- 40.7 mg/dL. Seven participants took an unscheduled nap. The ex vivo IFN-gamma and IL-2 levels significantly increased at all time points after binge consumption in the nappers, but not in the non-nappers. Conclusion Augmented IFN-gamma and IL-2 levels are associated with unscheduled napping after binge alcohol consumption. Further studies are needed to clarify the associations among alcohol consumption, sleep disruption, and inflammatory mediators. PMID- 29976102 TI - US Medical Information Websites Benchmarking: How Is the Industry Fairing in Usability? AB - OBJECTIVES: This study of 23 US-based biopharmaceutical medical information (MI) websites was conducted to assess usability and identify best practices and areas of potential improvement. METHODS: In this systematic review, websites were evaluated from June 22-November 1, 2016, and awarded points based on content, functionality, and navigation (maximum score of 42). Low-, mid-, and high-range usability scores were <=13, 14-27, >=28, respectively. RESULTS: Mean scores were 7 of 17, 4 of 10, and only 5 of 15 criteria for content, functionality, and navigation. The mean usability score across all websites was 15 of 42 criteria. Larger companies generally had a higher mean usability score. A minor trend was also observed with regard to usability score and industry size (r2 = 0.3). Only 2 websites scored high, whereas 13 scored in the mid- and 8 in the lower range of usability. Overall, websites scored low when pertaining to presence of novel content type, search engine optimization, presence of social media, and MI services offered. Overall site architecture, presence of self-certification, and mobile compatibility scored fairly well across the industry. CONCLUSION: The majority of websites scored in the low to midrange, which suggests an industry wide opportunity for improvement. In order to meet the evolving needs of health care professionals, MI websites need to be optimized for content, navigation, and functionality. Ensuring MI websites are discoverable through search engines and improving the level of MI services offered was also deemed to be important features to incorporate into a given MI website optimization strategy. PMID- 29976101 TI - The role of the chronic care model in promoting the management of the patient with rare liver disease. AB - INTRODUCTION: The chronic care model (CCM) provides a holistic approach for managing chronic illnesses. Patients with rare liver diseases (RLD) have complex needs, impaired quality of life and often life-threatening complications. Most RLD meet the criteria for a long-term chronic condition and should be viewed through the prism of CCM. We aimed to ascertain whether the CCM has been considered for the frequently-encountered RLD. METHODS: MEDLINE(r)/PubMed(r)/Cochrane/EMBASE were searched to identify publications relating to the use of the CCM for the management of six RLD. We identified 33 articles eligible for inclusion. RESULTS: Six, eleven, one, thirteen, two and zero studies, discussed individual components of the CCM for autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cirrhosis (PSC), Wilsons disease (WD), alpha-1 antitrypsin deficiency (A1AD) and lysosomal acid lipase deficiency (LALd) respectively. We have not identified studies using the full CCM for any of the aforementioned RLD. DISCUSSION: Unlike in common chronic conditions e.g. diabetes, there has been limited consideration of the use of CCM (or its components) for the management of RLD. This may reflect a reluctance of the clinical community to view these diseases as chronic or lack of healthcare policy investment in rare diseases in general. PMID- 29976103 TI - Bioresponsive functional nanogels as an emerging platform for cancer therapy. AB - INTRODUCTION: Bioresponsive nanogels with a crosslinked three-dimensional structure and an aqueous environment that undergo physical or chemical changes including swelling and dissociation in response to biological signals such as mild acidity, hyperthermia, enzymes, reducing agents, reactive oxygen species (ROS), and adenosine-5'-triphosphate (ATP) present in tumor microenvironments or inside cancer cells have emerged as an appealing platform for targeted drug delivery and cancer therapy. Areas covered: This review highlights recent designs and development of bioresponsive nanogels for facile loading and triggered release of chemotherapeutics and biotherapeutics. The in vitro and in vivo antitumor performances of drug-loaded nanogels are discussed. Expert opinion: Bioresponsive nanogels with an excellent stability and safety profile as well as fast response to biological signals are unique systems that mediate efficient and site-specific delivery of anticancer drugs, in particular macromolecular drugs like proteins, siRNA and DNA, leading to significantly enhanced tumor therapy compared with the non-responsive counterparts. Future research has to be directed to the development of simple, tumor-targeted and bioresponsive multifunctional nanogels, which can be either constructed from natural polymers with intrinsic targeting ability or functionalized with targeting ligands. We anticipate that rationally designed nanotherapeutics based on bioresponsive nanogels will become available for future clinical cancer treatment. ABBREVIATIONS: AIE, aggregation induced emission; ATP, adenosine-5'-triphosphate; ATRP, atom transfer radical polymerization; BSA, bovine serum albumin; CBA, cystamine bisacrylamide; CC, Cytochrome C; CDDP, cisplatin; CT, computed tomography; DC, dendritic cell; DiI, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate; DOX, doxorubicin; dPG, dendritic polyglycerol; DTT, dithiothreitol; EAMA, 2-(N,N diethylamino)ethyl methacrylate; EPR, enhanced permeability and retention; GrB, granzyme B; GSH, glutathione tripeptide; HA, hyaluronic acid; HAase, hyaluronidases; HCPT, 10-Hydroxycamptothecin; HEP, heparin; HPMC, hydroxypropylmethylcellulose; LBL, layer-by-layer; MTX, methotrexate; NCA, N carboxyanhydride; OVA, ovalbumin; PAH, poly(allyl amine hydrochloride); PBA, phenylboronic acid; PCL, polycaprolactone; PDEAEMA, poly(2-diethylaminoethyl methacrylate); PDGF, platelet derived growth factor; PDPA, poly(2 (diisopropylamino)ethyl methacrylate); PDS, pyridyldisulfide; PEG, poly(ethylene glycol); PEGMA, polyethyleneglycol methacrylate; PEI, polyethyleneimine; PHEA, poly(hydroxyethyl acrylate); PHEMA, poly(2-(hydroxyethyl) methacrylate; PNIPAM, poly(N-isopropylacrylamide); PMAA, poly(methacrylic acid); PPDSMA, poly(2 (pyridyldisulfide)ethyl methacrylate); PTX, paclitaxel; PVA, poly(vinyl alcohol); QD, quantum dot; RAFT, reversible addition-fragmentation chain transfer; RGD, Arg Gly-Asp peptide; ROP, ring-opening polymerization; ROS, reactive oxygen species; TMZ, temozolomide; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VEGF, vascular endothelial growth factor. PMID- 29976104 TI - Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction. AB - INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) continues to be a major challenge for clinicians. Many crucial aspects of the syndrome remain unclear, including the exact pathophysiology, early diagnosis, and treatment. Patients with HFpEF are often asymptomatic late into the disease process, and treatment with medications commonly used in heart failure with reduced ejection fraction (HFrEF) has not been proven to be beneficial. In addition, the confusion of similar terms with HFpEF, such as diastolic heart failure, and diastolic dysfunction (DD), has led to a misunderstanding of the true scope of HFpEF. Areas covered: In this review, authors highlight the differences in terminology and critically review the current knowledge on the underlying mechanisms, diagnosis, and latest treatment strategies of HFpEF. Expert commentary: While significant advances have been made in the understanding of HFpEF, the definitive diagnosis of HFpEF continues to be difficult. The development of improved and standardized methods for detecting DD has shown promise in identifying early HFpEF. However, even with early detection, there are few treatment options shown to provide mortality benefit warranting further investigation. PMID- 29976105 TI - Quality of Life and Its Predictors Among Nursing Students in Saudi Arabia. AB - PURPOSE: This study investigated the quality of life (QOL) and its predictors among nursing students in a university in Saudi Arabia. DESIGN: A descriptive, cross-sectional design. METHOD: A convenience sample of 175 baccalaureate nursing students from a university in Saudi Arabia was surveyed in this study. Using the WHOQOL-BREF and a sociodemographic sheet, the QOL and its predictors among Saudi nursing students were investigated. FINDINGS: The respondents reported a mean score of 4.09 ( SD = 0.71) and 4.02 ( SD = 0.87) for their overall perceptions of QOL and health, respectively. The psychological and physical health of these students had the highest and poorest QOL perception, respectively. Gender, academic year level, community type, and monthly family income exerted a multivariate effect on the four domains of QOL. CONCLUSION: The study underscores the need to ensure the highest level of health and well-being among nursing students while they are undergoing training for their professional roles as nurses. The findings should be utilized by policymakers in nursing institutions in Saudi Arabia in creating policies centered on the holistic development of nursing students in the country. PMID- 29976106 TI - Equine pericardium-covered stenting in post-traumatic pseudoaneurysm of cavernous internal carotid artery. AB - We report a case of traumatic intracranial carotid artery pseudoaneurysm treated with an equine pericardium-covered stent. The patient was admitted to the Emergency Department after sustaining severe polytrauma in a motor vehicle accident. A cavernous carotid pseudoaneurysm was detected after an episode of massive epistaxis that required emergent nasal packing. Treatment with parent vessel sacrifice was ruled out after an unfavourable balloon test occlusion. We opted for an equine pericardium-covered stent as a means to immediately seal the wall defect in the setting of massive bleeding secondary to an unstable lesion. We describe the potential benefits and drawbacks of these prostheses and the technical difficulties encountered in this particular case. To our best knowledge, this is the first published case report on a post-traumatic intracranial internal carotid artery pseudoaneurysm successfully treated with an equine pericardium-covered stent. PMID- 29976107 TI - Unexpected occlusion of the contralateral transverse sinus after stenting for idiopathic intracranial hypertension. AB - A woman in her thirties with intracranial hypertension underwent stenting of the right transverse-sigmoid (TS) junction with resolution of the pressure gradient. Due to persisting symptoms at follow-up, she underwent a repeat study showing a patent right TS stent but the non-dominant left transverse sinus, patent on initial studies, was now completely occluded. According to the positive feedback loop hypothesis, stenting of the right transverse sinus should have resulted in a reduction in intracranial pressures (confirmed by post-stenting lumbar puncture), but also an increase in left transverse sinus diameter, opposed to the occlusion seen on venography. This unexpected finding can be explained by the positive feedback loop hypothesis if a revision is made accounting for intramural venous pressures as an opposing force of venous sinus stenosis, as venous outflow obstruction in the dominant venous sinus pathway provided an increased intramural venous pressure in the non-dominant sinus facilitating patency against extramural pressures. PMID- 29976108 TI - Usefulness of contrast-enhanced and TOF MR angiography for follow-up after low profile stent-assisted coil embolization of intracranial aneurysms. AB - BACKGROUND: Low-profile, self-expandable stents are used to treat wide-neck aneurysms located on the smaller distal intracranial arteries. This study aimed to assess the usefulness of time-of-flight (TOF) and contrast-enhanced (CE) magnetic resonance angiography (MRA) for follow-up after LEO Baby stent (LBS) assisted coil embolization. METHODS: Twenty-four aneurysms treated with LBS assisted coil embolization were evaluated. Researchers reviewed TOF MRA and CE MRA images in terms of occlusion and stent patency. Aneurysm occlusion was graded according to Raymond-Roy classification as follows: total occlusion (grade 1), residual neck (grade 2), and residual aneurysm (grade 3). Stent patency was scored as follows: occlusion (1), stenosis (2), and normal (3). Interobserver and intermodality agreement values were determined by weighted kappa (kappa) statistics. RESULTS: Intermodality and interobserver values of TOF MRA and CE MRA with digital subtraction angiography (DSA) were perfect (kappa = 1.00, p < 0.001) in terms of aneurysm occlusion. Rate of stent occlusion and stenosis in DSA, TOF, and MRA, respectively, were as follows: 0 and 12.5%, 16.6 and 70.8%, and 0 and 62.5%. Intermodality agreement values of TOF MRA and CE MRA with DSA were insignificant in terms of stent patency (kappa = 0.065, p = 0.27; kappa = 0.158, p = 0.15, respectively). Interobserver agreement was substantial in both TOF MRA (kappa = 0.71, p < 0.001) and CE MRA (kappa = 0.64, p = 0.001). CONCLUSIONS: Both TOF and CE MRA techniques have strong concordance with DSA for the detection of aneurysm occlusion status. CE MRA can be used as a first-line noninvasive imaging modality due to its superiority to TOF MRA with respect to the visualization of in-stent signals. PMID- 29976110 TI - Modelling the cost-effectiveness of tofacitinib for the treatment of rheumatoid arthritis in the United States. AB - BACKGROUND AND OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, debilitating disease affecting an estimated 1.5 million patients in the US. The condition is associated with a substantial health and economic burden. An economic model was developed to evaluate the cost-effectiveness of tofacitinib (a novel oral Janus kinase inhibitor) versus biologic therapies commonly prescribed in the US for the treatment of RA. METHODS: A cost-utility model was developed whereby sequences of treatments were evaluated. Response to treatment was modeled by HAQ change, and informed by a network meta-analysis. Mortality, resource use and quality of life were captured in the model using published regression analyses based on HAQ score. Treatment discontinuation was linked to response to treatment and to adverse events. Patients were modeled as having had an inadequate response to methotrexate (MTX-IR), or to a first biologic therapy (TNFi-IR). RESULTS: The tofacitinib strategy was associated with cost savings compared with alternative treatment sequences across all modeled scenarios (i.e. in both the MTX-IR and TNFi-IR scenarios), with lifetime cost savings per patient ranging from $65,205 to $93,959 (2015 costs). Cost savings arose due to improved functioning and the resulting savings in healthcare expenditure, and lower drug and administration costs. The tofacitinib strategies all resulted in an increase in quality-adjusted life years (QALYs), with additional QALYs per patient ranging from 0.01 to 0.22. CONCLUSIONS: Tofacitinib as a second-line therapy following methotrexate failure and as a third-line therapy following a biologic failure produces lower costs and improved quality of life compared with the current pathway of care. PMID- 29976109 TI - Does narrative medicine education improve nursing students' empathic abilities and academic achievement? A randomised controlled trial. AB - Objective To determine the effectiveness of a narrative medicine educational intervention on the empathic abilities and academic achievement of Chinese nursing students. Methods A cluster randomised controlled trial was conducted between January 2015 and July 2017. Six class clusters (two controls, four interventions) comprising 180 nursing students were included in this trial. After pre-tests to obtain baseline measurements, two control classes (Group 1) attended regular medical education courses, two intervention classes (Group 2) received theoretical narrative medicine education for 1 term, and two intervention classes (Group 3) received narrative medicine education that integrated theory with practice for 2 terms. The empathic ability and academic achievement of the groups were compared, and longitudinal changes in empathic ability were measured. Results Students in Group 3 showed higher empathic ability and academic achievement than students in Group 1. Empathic ability was measured at six time points and showed between-group differences. The empathy scores of students in Group 3 increased abruptly after the two-term intervention. Conclusions Narrative medicine education that combines theory with practice is an effective strategy for improving nursing students' empathic ability and academic achievement. PMID- 29976111 TI - Community-acquired bacterial pneumonia in adult HIV-infected patients. AB - INTRODUCTION: Despite active antiretroviral therapy (ART), community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality among human immunodeficiency virus (HIV)-infected patients and incurs high health costs. Areas covered: This article reviews the most recent publications on bacterial CAP in the HIV-infected population, focusing on epidemiology, prognostic factors, microbial etiology, therapy, and prevention. The data discussed here were mainly obtained from a non-systematic review using Medline, and references from relevant articles. Expert commentary: HIV-infected patients are more susceptible to bacterial CAP. Although ART improves their immune response and has reduced CAP incidence, these patients continue to present increased risk of pneumonia in part because they show altered immunity and because immune activation persists. The risk of CAP in HIV-infected patients and the probability of polymicrobial or atypical infections are inversely associated with the CD4 cell count. Mortality in HIV-infected patients with CAP ranges from 6% to 15% but in well-controlled HIV-infected patients on ART the mortality is low and similar to that seen in HIV negative individuals. Vaccination and smoking cessation are the two most important preventive strategies for bacterial CAP in well-controlled HIV-infected patients on ART. PMID- 29976112 TI - Possible mechanisms behind cardiac troponin elevations. AB - Cardiac-specific troponins are elevated in blood following cardiac injury and are the preferred diagnostic biomarkers when acute myocardial infarction is suspected clinically. Cardiac troponin (cTn) elevations are also observed in clinical conditions without obvious connection to cardiac injury. Irrespective of the underlying condition, cTn elevation is linked to a poor prognosis, even if the elevation is stable over time. Here, we explore mechanisms that may lead to cTn elevations, including necrosis, apoptosis, necroptosis, cell wounds and decreased clearance. The aim is to broaden the perspective of how we interpret unexpected cTn elevations in patients. The cTn elevations may not be able to serve as direct proof of myocardial necrosis especially in the absence of a clear-cut reason for its release. Abbreviations: AMI: acute myocardial infarction; cTn: cardiac troponin; cTnI: cardiac troponin I; cTnT: cardiac troponin T; MLKL: mixed lineage kinase domain-like; TUNEL: terminal deoxynucleotidyl transferase nick end labeling. PMID- 29976113 TI - Bilateral root resorption of maxillary first permanent molars by unerupted second molars associated with orthodontic distalisation. AB - Root resorption is a common but undesirable side-effect of orthodontic treatment. It is a well-recognised phenomenon largely associated with impacted or unerupted teeth and in most cases, is mild and does not affect longevity of the affected teeth. This case report of a medically fit and healthy Caucasian boy who was undergoing orthodontic treatment at the Eastman Dental Hospital, UCLH (EDH) for management of his severe hypodontia, presents an unusual incident of bilateral resorption of his maxillary first permanent molars by the unerupted second molars. The near end-of treatment radiographs showed that both upper second molars were mesio-angularly impacted and resorbing the first molars; however, the patient reported no associated signs or symptoms. Bilateral Cone Beam Computed Tomography radiographs were requested for the posterior maxillary arch in the area of the molar dentitions and extensive root resorption affecting the first molars caused by the crown of the mesio-angularly impacted second molars was evident. This unusual bilateral root resorption of maxillary first molars associated with unerupted second molars is an uncommon presentation, with no similar case reports found in the literature. Great emphasis should be placed on informed valid consent and potentially making the patient aware of the small but potential risk of resorption of erupted terminal molars where orthodontic molar distalisation is considered. PMID- 29976114 TI - Aryl hydrocarbon receptor/IL-22/Stat3 signaling pathway is involved in the modulation of intestinal mucosa antimicrobial molecules by commensal microbiota in mice. AB - Compelling evidence demonstrates the crucial role of the commensal microbiota in host physiology and the detrimental effects of its perturbations following antibiotic treatment. However, the effects of commensal microbiota on intestinal mucosa antimicrobial molecules have not been elucidated systematically. Here, we investigate the impacts of antibiotic-induced depletion and subsequent restoration of the intestinal microbiota on the murine antimicrobial molecules in intestinal mucosa. Our results demonstrate that depletion of commensal microbiota leads to intestinal mucosa atrophy and reduction of antimicrobial molecules, including lysozyme, regenerating islet-derived protein 3 gamma (RegIIIgamma), and cryptdin 5 mRNA, whereas subsequent reconstitution of intestinal microbiota by fecal microbiota transplantation (FMT) rescues mucosa morphology and antimicrobials. Importantly, our study shows that down-regulation of aryl hydrocarbon receptor (AhR), interleukin-22 (IL-22), and phosphorylated Stat3 (p Stat3) is associated with decreased antimicrobials, which might mediate the antibiotic-associated intestinal mucosa injury. Last, exogenous activation of the AhR/IL-22/Stat3 signaling pathway with the AhR agonist 6-formylindolo(3,2 b)carbazole (Ficz) rescued antimicrobial molecule levels markedly after antibiotic treatment to levels similar to those following reconstitution of intestinal microbiota by FMT. Together, our results demonstrate that the AhR/IL 22/Stat3 signaling pathway is involved in the modulation of intestinal mucosa antimicrobial molecules by commensal microbiota and suggest this pathway as a promising target in the treatment of antibiotic-associated gut barrier damage. PMID- 29976115 TI - Delayed Phonological Encoding in Stuttering: Evidence from Eye Tracking. AB - Stuttering is a multifactorial disorder that is characterized by disruptions in the forward flow of speech believed to be caused by differences in the motor and linguistic systems. Several psycholinguistic theories of stuttering suggest that delayed or disrupted phonological encoding contributes to stuttered speech. However, phonological encoding remains difficult to measure without controlling for the involvement of the speech-motor system. Eye-tracking is proposed to be a reliable approach for measuring phonological encoding duration while controlling for the influence of speech production. Eighteen adults who stutter and 18 adults who do not stutter read nonwords under silent and overt conditions. Eye-tracking was used to measure dwell time, number of fixations, and response time. Adults who stutter demonstrated significantly more fixations and longer dwell times during overt reading than adults who do not stutter. In the silent condition, the adults who stutter produced more fixations on the nonwords than adults who do not stutter, but dwell-time differences were not found. Overt production may have resulted in additional requirements at the phonological and phonetic levels of encoding for adults who stutter. Direct measurement of eye-gaze fixation and dwell time suggests that adults who stutter require additional processing that could potentially delay or interfere with phonological-to-motor encoding. PMID- 29976116 TI - Targeted Multiplex Gene Expression Profiling to Measure High-Fat Diet and Metformin Effects on Fetal Gene Expression in a Mouse Model. AB - BACKGROUND: Maternal obesity and excessive gestational weight gain (GWG) are associated with delivery of a large-for-gestational-age infant. We used a high fat diet (HFD) mouse model to separate the effect of maternal obesity from excessive GWG on fetal growth. Our objective was to identify fetal gene expression changes in an HFD and control diet (CD) mouse model with and without metformin exposure. STUDY DESIGN: Normal weight timed-pregnant (Female Friend virus B) strain mice were allocated on day e0.5 to receive HFD or CD and either plain water or metformin (2.5 mg/mL in drinking water). Dams were euthanized on day e17.5 and fetal livers harvested and frozen at -80 degrees C. RNA was extracted and hybridized to a customized 96-gene Nanostring panel focused on angiogenesis, inflammation, and growth gene expression. Fetal liver gene expression was compared between metformin and plain water groups using analysis of variance. Significant differences in gene expression, defined by a false discovery controlled q value <0.01, were then analyzed using Ingenuity pathway analysis (IPA). RESULTS: In HFD-fed dams, compared to controls, the metformin treated group had significantly lower fetal weight and 39 differentially expressed liver genes; 15 (38%) were in the growth/angiogenesis gene expression network. IPA predicted that fetal liver gene upregulation associated with metformin exposure is a result of metformin inhibition of the common upstream regulator, phosphatase and tensin homolog ( PTEN). CONCLUSIONS: Metformin-exposed fetuses from dams fed HFD and CD have significant gene expression differences in genes specific to growth and angiogenesis pathways in the fetal liver. Diet alone did not alter fetal liver gene expression. PMID- 29976117 TI - Scoping Review: Social Determinants of Young Children's Participation in the United States. AB - Optimal child development is supported by services, policies, a social determinants of health (SDOH) frame, and meaningful participation (as defined by the International Classification of Functioning, Disability, and Health-Children and Youth [ICF-CY]). This scoping review describes the social determinants that may affect the participation of young children aged 0 to 3 years with developmental disabilities (DD) in the United States. Scoping review of studies including U.S. children with DD aged 0 to 3 years, from 2000 to 2016, were used. 5/979 studies met inclusion criteria. Two researchers independently coded studies to align them with both ICF-CY and SDOH. Studies found determinants of participation stemming from the child (e.g., individual) and multiple contexts: immediate, community, and policy. The emergent literature continues to primarily focus on child determinants but suggests participation of young children with DD is affected by social determinants stemming from the community and policy contexts. The literature underrepresents children from racial/ethnic minority backgrounds. PMID- 29976118 TI - The role of mitochondria in anchoring dynein to the cell cortex extends beyond clustering the anchor protein. AB - Organelle distribution is regulated over the course of the cell cycle to ensure that each of the cells produced at the completion of division inherits a full complement of organelles. In yeast, the protein Num1 functions in the positioning and inheritance of two essential organelles, mitochondria and the nucleus. Specifically, Num1 anchors mitochondria as well as dynein to the cell cortex, and this anchoring activity is required for proper mitochondrial distribution and dynein-mediated nuclear inheritance. The assembly of Num1 into clusters at the plasma membrane is critical for both of its anchoring functions. We have previously shown that mitochondria drive the assembly of Num1 clusters and that these mitochondria-assembled Num1 clusters serve as cortical attachment sites for dynein. Here we further examine the role for mitochondria in dynein anchoring. Using a GFP-alphaGFP nanobody targeting system, we synthetically clustered Num1 on eisosomes to bypass the requirement for mitochondria in Num1 cluster formation. Utilizing this system, we found that mitochondria positively impact the ability of synthetically clustered Num1 to anchor dynein and support dynein function even when mitochondria are no longer required for cluster formation. Thus, the role of mitochondria in regulating dynein function extends beyond simply concentrating Num1; mitochondria likely promote an arrangement of Num1 within a cluster that is competent for dynein anchoring. This functional dependency between mitochondrial and nuclear positioning pathways likely serves as a mechanism to order and integrate major cellular organization systems over the course of the cell cycle. PMID- 29976119 TI - Language processing fluency and verbal working memory in prelingually deaf long term cochlear implant users: A pilot study. AB - OBJECTIVE: Verbal working memory (WM) is more strongly correlated with spoken language skills in prelingually deaf, early-implanted cochlear implant (CI) users than in normal-hearing (NH) peers, suggesting that CI users access WM in order to support and compensate for their slower, more effortful spoken language processing. This pilot study tested the feasibility and validity of a dual-task method for establishing the causal role of WM in basic language processing (lexical access speed) in samples of 9 CI users (ages 8-26 years) and 9 NH peers. METHODS: Participants completed tests of lexical access speed (rapid automatized picture naming test and lexical decision test) under two administration conditions: a standard condition and a dual-task WM condition requiring participants to hold numerals in WM during completion of the lexical access speed tests. RESULTS: CI users showed more dual-task interference (decline in speed during the WM condition compared to the standard condition) than NH peers, indicating that their lexical access speed was more dependent on engagement of WM resources. Furthermore, dual-task interference scores were significantly correlated with several measures of speed-based executive functioning (EF), consistent with the hypothesis that the dual-task method reflects the involvement of EF in language processing. CONCLUSION: These pilot study results support the feasibility and validity of the dual-task WM method for investigating the influence of WM in the basic language processing of CI users. Preliminary findings indicate that CI users are more dependent on the use of WM as a compensatory strategy during slow-effortful basic language processing than NH peers. PMID- 29976121 TI - Normative performance of healthy older individuals on the Modified Mini-Mental State (3MS) examination according to ethno-racial group, gender, age, and education level. AB - OBJECTIVE: To present normative performance data on the Modified Mini-Mental State (3MS) examination for healthy community-dwelling older individuals according to gender, age, education level, and ethno-racial group. METHOD: More than 19,000 generally healthy older men and women without a diagnosis of dementia were recruited from the general population in Australia and the U.S. for the ASPirin in Reducing Events in the Elderly (ASPREE) study. The 3MS exam was administered as part of the baseline screening and individuals scoring above 77 were eligible to participate. RESULTS: The sample comprised 16,360 Australian whites, 1080 U.S. whites, 895 African-Americans and 316 Hispanic/Latinos. The median age of participants was 74 years (range 65-98), with an average of 12 years of education and 56% were female. Increasing age and fewer years of completed education were associated with lower scores on the 3MS. Women scored higher than men in most age and education categories. Differences across ethno racial groups were found. With factor analysis, four factors were identified which accounted for 35% of the between-person variance in 3MS scores for white Australians. CONCLUSIONS: This large cohort of older individuals provides some of the most comprehensive 3MS normative data to be generated for whites (Australian and U.S.), Hispanic/Latinos and African-Americans, by age, gender, and educational attainment. These findings will serve as important reference standards for monitoring cognitive function in generally healthy older individuals, becoming increasingly important as this fraction of the population increases. PMID- 29976123 TI - Ultrastructural changes in red blood cells in aortic dissection patients under extracorporeal circulation: Atomic force microscopy study. AB - PURPOSE: During extracorporeal circulation in heart surgery, blood is exposed to non-physiological conditions, such as high shear stress, foreign surfaces, turbulence, and hypothermia. These factors cause damage to the red blood cells, which is manifested by immediate and delayed hemolysis or some changes in the mechanical properties of red blood cells, defined as sublethal trauma. Unfortunately, sublethal trauma is hard to detect, and there is not enough morphological evidence regarding red blood cell sublethal trauma. In this study, red blood cell sublethal trauma was observed after extracorporeal circulation by describing ultrastructural changes in red blood cell membranes using atomic force microscopy and scanning electron microscopy. METHODS: Venous blood (2 mL) was collected into heparin tubes from preoperative, intraoperative and postoperative aortic dissection patients for comparison with blood from healthy patients. The red blood cell morphological study (malformations percentage, diameter, height, concavity, and roughness) was performed with scanning electron microscopy and atomic force microscopy. RESULTS: Scanning electron microscopy and atomic force microscopy imaging analysis revealed that the red blood cell shape changed during extracorporeal circulation and that the red blood cell malformation percentage in the postoperative group was higher than those in the preoperative and intraoperative groups. Most morphological parameters had no obvious changes, except roughness (Ra and Rq) in aortic dissection patients. Atomic force microscopy quantitative analysis indicated that the roughness of red blood cell membranes increased during extracorporeal circulation. CONCLUSIONS: This study demonstrates that ultrastructural morphological damage occurs to red blood cells membranes due to extracorporeal circulation in aortic dissection patients. In addition, we provided a new parameter (Ra and Rq) to evaluate red blood cell sublethal trauma. PMID- 29976122 TI - One-year experience with ex vivo lung perfusion: Preliminary results from a single center. AB - OBJECTIVE: To enlarge the donor pool for lung transplantation, an increasing number of extended criteria donor lungs are used. However, in more than 50% of multi-organ donors the lungs are not used. Ex vivo lung perfusion offers a unique possibility to evaluate and eventually recondition the injured donor lungs. The aim of our study was to assess the enlargement of the donor pool and the outcome with extended criteria donor lungs after ex vivo lung perfusion. PATIENTS AND METHODS: Data were prospectively collected in our lung transplant database. We compared the results of lung transplants after ex vivo lung perfusion with those after conventional cold static preservation. In total, 11 extended criteria donor lungs processed with ex vivo lung perfusion and 41 cold static preservation lungs transplanted consecutively between May 2016 and May 2017 were evaluated. Normothermic ex vivo lung perfusion was performed according to the Toronto protocol for 4 h. Cold static preservation lungs were stored in low-potassium dextran solution. RESULTS: Ex vivo lung perfusion lungs before procurement had significantly lower PaO2/FiO2 (P/F) ratios and more X-ray abnormalities. There were no statistically significant differences for pre-donation ventilation time, smoking history, or sex. After reconditioning with ex vivo lung perfusion, 9 out of 11 processed lungs were considered suitable and successfully transplanted. The mean postoperative ventilation time and in-hospital stay were not significantly different in ex vivo lung perfusion and cold static preservation recipients. CONCLUSION: Ex vivo lung perfusion can safely be used in the evaluation of lungs initially considered not suitable for transplantation. The primary outcome was not negatively affected and normothermic ex vivo lung perfusion is a useful tool to increase the usage of potentially transplantable lungs. PMID- 29976124 TI - Hemodialysis during cardiopulmonary resuscitation in patients with severe metabolic acidosis. AB - BACKGROUND/AIMS: Severe metabolic acidosis during cardiopulmonary resuscitation is an important and yet unresolved issue. The potential use of hemodialysis for severe metabolic acidosis during cardiopulmonary resuscitation was investigated. METHODS: Acute hemodialyses between January 2012 and April 2017 were reviewed for patients with concomitant hemodialysis and cardiopulmonary resuscitation. In addition, MEDLINE was searched for similar reports. Data were extracted from hospital records. RESULTS: Two patients (36M, 70F) were found to study, without similar reports in MEDLINE. Cardiac arrests (in-hospital) occurred due to severe metabolic acidosis in both patients (due to ethylene glycol and metformin intoxications, respectively). Return of spontaneous circulation could not be obtained within the first 28 and 30 min of cardiopulmonary resuscitation only, whereas both patients had return of spontaneous circulation following at least 45 min of concomitant hemodialysis and cardiopulmonary resuscitation. One patient (70F) was discharged with good neurological outcome, but the other died. CONCLUSION: The addition of high-efficiency hemodialysis during cardiopulmonary resuscitation may contribute to the return of spontaneous circulation in patients with severe metabolic acidosis due to intoxication. PMID- 29976126 TI - Evaluation of the effects of a polyglycolic acid-collagen tube in the regeneration of facial nerve defects in rats. AB - PURPOSE: The purpose of this study was to assess the utility of a polyglycolic acid-collagen tube and to investigate its possible application in the field of facial nerve reconstruction. METHODS: Wistar rats were used in this study. In the operation, a periauricular incision was made to expose the buccal and marginal branches of the facial nerve. Gaps of 10 mm were created by resection of a part of the nerve into the marginal branches and the buccal branch of the left facial nerve. The left marginal branch gap was bridged with a 10-mm polyglycolic acid collagen tube or an autograft. At 12 weeks after the operation, nerve regeneration was assessed based on clinical, histopathological, and electrophysiological evaluations. RESULT: The functional recovery of the vibrissal muscle was observed with the polyglycolic acid-collagen tube. However, the functional recovery obtained with the use of the polyglycolic acid-collagen tube was inferior to that obtained with an autograft. CONCLUSION: We found that polyglycolic acid-collagen tubes could be applied in facial nerve gap reconstruction. However, further improvements will be necessary to achieve results that are equivalent to those obtained with autografts. PMID- 29976125 TI - Risk stratification with longitudinal neutrophil to lymphocyte ratio assessment after left ventricular assist device implantation. AB - INTRODUCTION: Inflammatory processes are well-characterized risk factors in cardiovascular disease including advanced heart failure. Previous studies have utilized individual white cell subtypes in risk analysis, and a recent study has focused on the efficacy of the neutrophil-to-lymphocyte ratio in evaluating negative outcomes following left ventricular assist device implantation. To investigate the interaction between the left ventricular assist device and white cell counts, we assessed longitudinal changes in neutrophil-to-lymphocyte ratio following left ventricular assist device implantation. METHODS: This retrospective study included 100 patients who underwent left ventricular assist device implantation between 2012 and 2013. The neutrophil-to-lymphocyte ratio was calculated prior to left ventricular assist device implantation, daily for the first 30 postoperative days, and at the first two postoperative outpatient visits. Preoperative demographic and clinical data were collected for all patients. RESULTS: The mean neutrophil-to-lymphocyte ratio immediately before left ventricular assist device implantation was 5.2 +/- 4.9. After surgery, the neutrophil-to-lymphocyte ratio decreased asymptotically, from a peak of 29.2 on postoperative day 1 to 4.1 at the second outpatient visit ( p < 0.001). Lack of improvement in the neutrophil-to-lymphocyte ratio at postoperative day 10 was associated with increased length of stay, right heart failure, and a trend toward worsened survival. CONCLUSION: Our results indicate a significant inflammatory response to implantation of the left ventricular assist device, a known effect. The magnitude of this response may be effectively and easily monitored over time using the neutrophil-to-lymphocyte ratio. In general, approximately 30 days is required for the neutrophil-to-lymphocyte ratio to return to preoperative levels. After several months, the neutrophil-to-lymphocyte ratio improves to below preoperative levels. It is possible that this reduction reflects the reversal of various heart failure-mediated inflammatory processes following left ventricular assist device implantation. PMID- 29976127 TI - Force induced piezoelectric effect of polyvinylidene fluoride and polyvinylidene fluoride-co-trifluoroethylene nanofibrous scaffolds. AB - Polyvinylidene fluoride and its co-polymer with trifluoroethylene are promising biomaterials for supporting nerve regeneration processes because of their proven biocompatibility and piezoelectric properties that could stimulate cell ingrowth due to electrical activity upon mechanical deformation. This study reports the piezoelectric effect of electrospun polyvinylidene fluoride scaffolds in response to mechanical loading. An impact test machine was used to evaluate the generation of electrical voltage upon application of an impact load. Scaffolds were produced via electrospinning from polyvinylidene fluoride and polyvinylidene fluoride-co trifluoroethylene with concentrations of 10-20 wt% dissolved in N,N dimethylformamide (DMF) and acetone (6:4). The structural and thermal properties of scaffolds were analyzed using Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry, respectively. The piezoelectric response of the scaffolds was induced using a custom-made manual impact press machine. Impact forces between 0.4 and 14 N were applied. Fourier Transform Infrared Spectroscopy and Differential Scanning Calorimetry results demonstrated the piezoelectric effect of the electrospun polyvinylidene fluoride and polyvinylidene fluoride-co trifluoroethylene scaffolds. All the scaffolds exhibited a piezoelectric polar beta-phase formation. Their thermal enthalpies were higher than the value of the initial materials and exhibited a better tendency of crystallization. The electrospun scaffolds exhibited piezoelectric responses in form of voltage by applying impact load. Polyvinylidene fluoride-co-trifluoroethylene scaffolds showed higher values in the range of 6-30 V as compared to pure polyvinylidene fluoride. Here, the mechanically induced electrical impulses measured were between 2.5 and 8 V. Increasing the impact forces did not increase the piezoelectric effect. The results demonstrate the possibility of producing electrospun polyvinylidene fluoride and polyvinylidene fluoride-co trifluoroethylene scaffolds as nerve guidance with piezoelectric response. Further experiments must be carried out to analyze the piezoelectricity at dynamic conditions. PMID- 29976128 TI - Development of an automated liver perfusion system: The benefit of a hemofilter. AB - INTRODUCTION:: Liver perfusion machines are close to becoming a reality in the transplantation field. However, depending on the techniques used and the goals pursued, their application is limited in the research field. Here, we present the entire development of a perfusion system with self-made engineering, completely autonomous controls, and a high degree of versatility that allows the design of different studies on liver functionality. METHODS:: A user-friendly interface permits real-time monitoring and remote control by the devices within the circuit. Centrifugal pumps allow the perfusate enter the organ with controlled pressures and flows at both hepatic artery and portal vein. The implementation of a hemofilter as a novel tool permits to control and maintain homeostasis. Peristaltic pumps adjust pH, extraction rate, and total volume by means of sensors. RESULTS:: Real-time monitoring facilitates liver functionality assessment. The controlled system shows rapid stabilization and quick responses to changes during 6 h of perfusion experiments. Furthermore, the integration of a hemofilter helps the system to eliminate toxic waste and maintain homeostasis. DISCUSSION:: The machine provides the basis of a perfusion system with autonomous controls and the implementation of a hemofilter that enables a more efficient control of hemostasis. Moreover, the developed hardware and software are subjected to further tuning for additional purposes such as pathophysiologic studies, suboptimal grafts recovery, or recellularization of decellularized scaffolds among others. PMID- 29976129 TI - Patterns of poisoning exposure at different ages: the 2015 annual report of the Australian Poisons Information Centres. AB - OBJECTIVES: To characterise the types of calls received by Australian Poisons Information Centres (PICs) in Australia, and to analyse poisoning exposures by age group, circumstances of exposure, and the types of substances involved. Design, setting: Retrospective analysis of call records from all four Australian PICs (national coverage). MAIN OUTCOME MEASURES: Basic demographic information; exposure circumstances, substance types involved in each age group; recommendations for management (eg, stay at home, go to hospital). RESULTS: There were 204 906 calls to Australian PICs in 2015, 69.0% from the general public, 27.9% from health professionals; 16.2% of calls originated from hospitals. 170 469 calls (including re-calls about an exposure) related to 164 363 poison exposure events; 64.4% were unintentional, 18.1% were the consequences of medication error, and 10.7% involved deliberate self-poisoning. Most exposures were of 20-74-year-old adults (40.1%) or 1-4-year-old toddlers (36.0%). The PICs advised callers to stay at home for 67.4% of exposures, and to present to hospital for 10.9%. The most common substances involved in exposures overall were household cleaners (10.2%) and paracetamol-containing analgesics (7.3%). Exposures of infants and toddlers were most frequently to household cleaning substances (17.8%, 15.3% respectively) and personal care items (6.6%, 7.3%); callers were usually advised to stay at home (88.5%, 86.4%). Deliberate self poisoning (49.1%) and hospital referral (23.9%) were most frequent for adolescents. Exposures of adults (20-74 years) frequently involved psychotropic pharmaceuticals (17.8%) or painkillers (15.1%). Exposures in adults over 74 were typically medication errors involving cardiovascular (23.6%), anticoagulant (4.6%), or antidiabetic (4.1%) medications. CONCLUSIONS: Poisoning is a significant public health problem throughout life, but the nature of the hazards differs markedly between age groups. PIC data could inform strategic public health interventions that target age-specific poisoning hazards. PMID- 29976130 TI - The true price of sugar-sweetened disease: political inertia requires renewed, strategic action. PMID- 29976131 TI - Population awareness of tobacco-related harms: implications for refreshing graphic health warnings in Australia. PMID- 29976132 TI - Overcoming the data drought: exploring general practice in Australia by network analysis of big data. AB - OBJECTIVES: To investigate the organisation and characteristics of general practice in Australia by applying novel network analysis methods to national Medicare claims data. DESIGN: We analysed Medicare claims for general practitioner consultations during 1994-2014 for a random 10% sample of Australian residents, and applied hierarchical block modelling to identify provider practice communities (PPCs). PARTICIPANTS: About 1.7 million patients per year. MAIN OUTCOME MEASURES: Numbers and characteristics of PPCs (including numbers of providers, patients and claims), proportion of bulk-billed claims, continuity of care, patient loyalty, patient sharing. RESULTS: The number of PPCs fluctuated during the 21-year period; there were 7747 PPCs in 2014. The proportion of larger PPCs (six or more providers) increased from 32% in 1994 to 43% in 2014, while that of sole provider PPCs declined from 50% to 39%. The median annual number of claims per PPC increased from 5000 (IQR, 40-19 940) in 1994 to 9980 (190-23 800) in 2014; the proportion of PPCs that bulk-billed all patients was lowest in 2004 (21%) and highest in 2014 (29%). Continuity of care and patient loyalty were stable; in 2014, 50% of patients saw the same provider and 78% saw a provider in the same PPC for at least 75% of consultations. Density of patient sharing in a PPC was correlated with patient loyalty to that PPC. CONCLUSIONS: During 1994 2014, Australian GP practice communities have generally increased in size, but continuity of care and patient loyalty have remained stable. Our novel approach to the analysis of routinely collected data allows continuous monitoring of the characteristics of Australian general practices and their influence on patient care. PMID- 29976133 TI - A population-based comparison of the post-operative outcomes of open and laparoscopic appendicectomy in children. AB - OBJECTIVE: To assess and compare the post-operative outcomes of open and laparoscopic appendicectomy in children. DESIGN: Record linkage analysis of administrative hospital (Admitted Patient Data Collection) and emergency department (Emergency Department Data Collection) data.Participants, setting: Children under 16 years of age who underwent an appendicectomy in a public or private hospital in New South Wales between January 2002 and December 2013. MAIN OUTCOME MEASURES: Association between type of appendicectomy and post-operative complications within 28 days of discharge, adjusted for patient characteristics and type of hospital. RESULTS: Of 23 961 children who underwent appendicectomy, 19 336 (81%) had uncomplicated appendicitis and 4625 (19%) had appendicitis complicated by abscess, perforation, or peritonitis. The proportion of laparoscopic appendicectomies increased from 11.8% in 2002 to 85.8% in 2013. In cases of uncomplicated appendicitis, laparoscopic appendicectomy was associated with more post-operative complications (mostly symptomatic re-admissions or emergency department presentations) than open appendicectomy (7.4% v 5.8%), but with a reduced risk of post-operative intestinal obstruction (adjusted odds ratio [aOR], 0.59; 95% CI, 0.36-0.97). For cases of complicated appendicitis, the risk of wound infections was lower for laparoscopic appendicectomy (aOR, 0.67; 95% CI, 0.50-0.90), but not the risks of intestinal obstruction (aOR, 0.97; 95% CI, 0.62 1.52) or intra-abdominal abscess (aOR, 1.06; 95% CI, 0.72-1.55). CONCLUSION: Post appendicectomy outcomes were similar for most age groups and hospital types. Children with uncomplicated appendicitis have lower risk of post-operative bowel obstruction after laparoscopic appendicectomy than after open appendicectomy, but may be discharged before their post-operative symptoms have adequately resolved. PMID- 29976134 TI - Development and validation of a MEDLINE search filter/hedge for degenerative cervical myelopathy. AB - BACKGROUND: Degenerative cervical myelopathy (DCM) is a common condition with many unmet clinical needs. Pooled analysis of studies is an important tool for advancing medical understanding. This process starts with a systematic search of the literature. Identification of studies in DCM is challenged by a number of factors, including non-specific terminology and index terms. Search filters or HEDGEs, are search strings developed and validated to optimise medical literature searches. We aimed to develop a search filter for DCM for the MEDLINE database. METHODS: The diagnostic test assessment framework of a "development dataset" and seperate "validation dataset" was used. The development dataset was formed by hand searching four leading spinal journals (Spine, Journal of Neurosurgery Spine, Spinal Cord and Journal of Spinal Disorders and Techniques) in 2005 and 2010. The search filter was initially developed focusing on sensitivity and subsequently refined using NOT functions to improve specificity. One validation dataset was formed from DCM narrative and systematic review articles and the second, articles published in April of 1989, 1993, 1997, 2001, 2005, 2009, 2013 and 2017 retrieved via the search MeSH term 'Spine'. Metrics of sensitivity, specificity, precision and accuracy were used to test performance. RESULTS: Hand searching identified 77/1094 relevant articles for 2005 and 55/1199 for 2010. We developed a search hedge with 100% sensitivity and a precision of 30 and 29% for the 2005 and 2010 development datasets respectively. For the selected time periods, EXP Spine returned 2113 publications and 30 were considered relevant. The search filter identified all 30 relevant articles, with a specificity of 94% and precision of 20%. Of the 255 references listed in the narrative index reviews, 225 were indexed in MEDLINE and 165 (73%) were relevant articles. All relevant articles were identified and accuracy ranged from 67 to 97% over the three reviews. Of the 42 articles returned from 3 recent systematic reviews, all were identified by the filter. CONCLUSIONS: We have developed a highly sensitive hedge for the research of DCM. Whilst precision is similarly low as other hedges, this search filter can be used as an adjunct for DCM search strategies. PMID- 29976135 TI - Repeat emergency department visits by nursing home residents: a cohort study using health administrative data. AB - BACKGROUND: Nursing home (NH) residents are frequent users of emergency departments (ED) and while prior research suggests that repeat visits are common, there is little data describing this phenomenon. Our objectives were to describe repeat ED visits over one year, identify risk factors for repeat use, and characterize "frequent" ED visitors. METHODS: Using provincial administrative data from Ontario, Canada, we identified all NH residents 65 years or older who visited an ED at least once between January 1 and March 31, 2010 and then followed them for one year to capture all additional ED visits. Frequent ED visitors were defined as those who had 3 or more repeat ED visits. We used logistic regression to estimate risk factors for any repeat ED visit and for being a frequent visitor and Andersen-Gill regression to estimate risk factors for the rate of repeat ED visits. RESULTS: In a cohort of 25,653 residents (mean age 84.5 (SD = 7.5) years, 68.2% female), 48.8% had at least one repeat ED visit. Residents who experienced a repeat ED visit were generally similar to others but they tended to be slightly younger, have a higher proportion male, and a higher proportion with minimal cognitive or physical impairment. Risk factors for a repeat ED visit included: being male (adjusted odds ratio 1.27, (95% confidence interval 1.19-1.36)), diagnoses such as diabetes (AOR 1.28 (1.19-1.37)) and congestive heart failure (1.26 (1.16-1.37)), while severe cognitive impairment (AOR 0.92 (0.84-0.99)) and 5 or more chronic conditions (AOR 0.82 (0.71-0.95)) appeared protective. Eleven percent of residents were identified as frequent ED visitors, and they were more often younger then 75 years, male, and less likely to have Alzheimer's disease or other dementias than non-frequent visitors. CONCLUSIONS: Repeat ED visits were common among NH residents but a relatively small group accounted for the largest number of visits. Although there were few clear defining characteristics, our findings suggest that medically complex residents and younger residents without cognitive impairments are at risk for such outcomes. PMID- 29976136 TI - FC_analysis: a tool for investigating atomic force microscopy maps of force curves. AB - BACKGROUND: The collection and analysis of Atomic Force Microscopy force curves is a well-established procedure to obtain high-resolution information of non topographic data from any kind of sample, including biological specimens. In particular, these analyses are commonly employed to study elasticity, stiffness or adhesion properties of the samples. Furthermore, the collection of several force curves over an extended area of the specimens allows reconstructing maps, called force volume maps, of the spatial distribution of the mechanical properties. Coupling these maps with the conventional high-resolution topographic reconstruction of the sample's surface, provides a deeper insight on the sample composition from the structural and nanomechanical point of view. RESULTS: In this paper we present the open source software package FC_analysis that automatically analyses single force curves or entire force volume maps to yield the corresponding elasticity and deformability images. The principal characteristic of the FC_analysis is a large adaptability to the various experimental setups and to different analysis methodologies. For instance, the user can provide custom values for the detector sensitivity, scanner-z sensitivity, cantilever's elastic constant and map's acquisition modality and can choose between different analysis methodologies. Furthermore, the software allows the optimization of the fitting parameters and gives direct control on each step of the analysis procedure. Notably, to overcome a limitation common to many other analysis programs, FC_analysis can be applied to a rectangular portion of the image, allowing the analysis of inhomogeneous samples. Finally, the software allows reconstructing a Young's modulus map at different penetration depths, enabling the use of modern investigation tools such as the force tomography. CONCLUSIONS: The FC_analysis software aims to become a useful tool for the analysis of force curves maps collected using custom or commercial Atomic Force Microscopes, and is especially useful in those cases for which the producer doesn't release a dedicated software. PMID- 29976137 TI - Medical treatment of cystic echinococcosis: systematic review and meta-analysis. AB - BACKGROUND: Cystic echinococcosis (CE) is a well-known neglected parasitic disease. However, evidence supporting the four current treatment modalities is inadequate, and treatment options remain controversial. The aim of this work is to analyse the available data to answer clinical questions regarding medical treatment of CE. METHODS: A thorough electronic search of the relevant literature without language restrictions was carried out using PubMed (Medline), Cochrane Central Register of Controlled Trials, BioMed, Database of Abstracts of Reviews of Effects, and Cochrane Plus databases up to February 1, 2017. All descriptive studies reporting an assessment of CE treatment and published in a peer-reviewed journal with available full-text were considered for a qualitative analysis. Randomized controlled trials were included in a quantitative meta-analysis. We used the standard methodological procedures established by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. RESULTS: We included 33 studies related to the pharmacological treatment of CE in humans. Of these, 22 studies with levels of evidence 2 to 4 were qualitatively analysed, and 11 randomized controlled trials were quantitatively analysed by meta-analysis. CONCLUSIONS: Treatment outcomes are better when surgery or PAIR (Puncture, Aspiration, Injection of protoscolicidal agent and Reaspiration) is combined with benzimidazole drugs given pre- and/or post-operation. Albendazole chemotherapy was found to be the primary pharmacological treatment to consider in the medical management of CE. Nevertheless, combined treatment with albendazole plus praziquantel resulted in higher scolicidal and anti-cyst activity and was more likely to result in cure or improvement relative to albendazole alone. PMID- 29976138 TI - A more comprehensive investigation of disability and associated factors among older adults receiving home-based care in rural Dongguan, China. AB - BACKGROUND: No previous study has evaluated disability in older persons according to the International Classification of Functioning, Disability and Health Framework guidelines. We conducted a more comprehensive investigation of disability and associated factors among older adults receiving home-based care in rural Dongguan, a city in the central Guangdong Province of Southern China. METHODS: A total of 819 individuals aged >=60 years were recruited from Dongguan home-based care system of via a two-stage selection process. We interviewed participants and assessed their ability level using the Ability Assessment for Older Adults, which defined by a combination of activity of daily living, sensory perception, mental status and social involvement. Conditional probability and Logistic regression approaches were used to assess the strength of association between each pair of conditions. Factors significantly associated with disability were identified via chi2 tests and multinomial ordinal logistic regression. RESULTS: Of the 819 included participants (mean age 87 +/-4.7 years), 75.5% were female, 76.7% had any disability, and 62.3% had a mild disability. The occurrence of any deficits significantly increased the likelihood of the co-occurrence of other deficits (odds ratio [OR] > 1, P < 0.05), with the lowest prevalence odds ratio observed among individuals with sensory and communication deficiency (OR: 2.99; 95% confidence interval [CI]: 2.21-4.05). Multivariable ordinal logistic regression analysis indicated that physical activity (OR: 0.96; 95% CI: 0.93 0.99), sedentary behavior (OR: 1.25; 95% CI: 1.13-1.38), not watching television (OR: 1.7; 95% CI: 1.07-2.72) and age (OR: 1.09; 95% CI: 1.02-1.17) were significantly associated with disability. CONCLUSIONS: Impairment of ADL, sensory perception, mental status or social involvement increased the likelihood of risk of the co-occurrence of other deficits. Comprehensive disability among older adults receiving home-based care is associated with age, sedentariness, physical activity and TV viewing. PMID- 29976139 TI - Influence of food matrix type on extracellular products of Vibrio parahaemolyticus. AB - BACKGROUND: Two strains of Vibrio parahaemolyticus (ATCC 17802 and 33847) in shrimp, oyster, freshwater fish, pork, chicken and egg fried rice were evaluated for production of hemolysin and exoenzymes of potential importance to the pathogenicity of this bacterium. RESULTS: The two strains of V. parahaemolyticus produced hemolysin, gelatinase, caseinase, phospholipase, urease, DNase and amylase in selected food matrices. Significantly higher (p < 0.05) hemolytic activity was produced by V. parahaemolyticus in egg fried rice > shrimp > freshwater fish > chicken > oyster > pork. But the exoenzyme activities were not consistent with the hemolytic activity profile, being significantly higher (p < 0.05) in shrimp > freshwater fish > chicken > oyster > pork > egg fried rice. Filtrates of V. parahaemolyticus from shrimp, freshwater fish and chicken given intraperitoneally to adult mice induced marked liver and kidney damage and were highly lethal compared with the filtrates of V. parahaemolyticus from oyster > egg fried rice > pork. CONCLUSION: From in vitro and in vivo tests, it appears that the food matrix type has a significant impact on the activity of extracellular products and the pathogenicity of V. parahaemolyticus. From a food safety aspect, it is important to determine which food matrices can stimulate V. parahaemolyticus to produce additional extracellular factors. This is the first report of non-seafood including freshwater fish and chicken contaminated with V. parahaemolyticus to have been shown to be toxic to mice in vivo. PMID- 29976140 TI - Red cell distribution width and red cell distribution width to total serum calcium ratio as major predictors of severity and mortality in acute pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) is associated with considerable morbidity and mortality. Current severity scores include multiple variables and some of them are only complete within 48 h of admission. Red cell distribution width (RDW) is a simple and routine parameter that seems to be related to inflammatory status. Our aims were to evaluate the diagnostic value of RDW in severity and mortality of AP comparing with other prognostic scoring systems. METHODS: Retrospective case-control study of a total of 312 patients with AP admitted between 2014 and 2016. Patients with severe AP (cases) were compared with patients with mild AP (controls) in the 1:1 proportion. Additionally, a comparison between survivor and nonsurvivor AP patients was performed. Diagnosis and severity of AP were defined according to the revised Atlanta classification 2012. Variables evaluated included demographics, comorbidities, hospital stay, laboratorial parameters, arterial blood gas analysis, prognostic scores within 24 h of admission (Ranson, BISAP and Modified Marshall) and mortality. RESULTS: Included 91 cases of severe AP, most males (58.2% vs 51.6%; p = 0.228) with mean age of 64.8 +/- 16.3 years (vs 67.9 +/- 13.7; p = 0.239). RDW0h was higher in patients with severe AP (14.6 +/- 1.3 vs 12.7 +/- 0.5; p < 0.001), as well as RDW0h-to-serum calcium ratio (1.8 +/- 0.3 vs 1.3 +/- 0.1; p < 0.001). After multivariate and ROC curve analysis, RDW0h (AUROC: 0.960; p < 0.001) and RDW0h-to-serum calcium ratio (AUROC: 0.973; p < 0.001) were the major predictors of severe AP for a cut-off value of 13.0 (S: 92.7%; Sp: 84.3%) and 1.4 (S: 96.3%; Sp: 84.3%), respectively. These factors were superior to prognostic scores, such as Ranson (AUROC: 0.777; p < 0.001; cut-off: 3.0), BISAP (AUROC: 0.732; p < 0.001; cut-off: 2.0) and Modified Marshall (AUROC: 0.756; p < 0.001; cut-off: 1.0). The mortality rate was 8.8% (16/182), all cases associated with severe AP (17.6%; 16/91). RDW0h and RDW0h-to-serum calcium ratio were higher in nonsurvivor AP patients (15.3 +/- 1.4 vs 13.5 +/- 1.3; p < 0.001 and 2.0 +/- 0.3 vs 1.6 +/- 0.3; p < 0.001, respectively). In multivariate and ROC curve analysis, RDW0h (AUROC: 0.842; p < 0.001; cut-off: 14.0), RDW24h (AUROC: 0.848; p < 0.001; cut-off: 13.8) and RDW0h-to-serum calcium ratio (AUROC: 0.820; p < 0.001; cut-off: 1.7) were independent predictors for AP mortality, superior to conventional prognostic scoring systems Ranson (AUROC: 0.640; p = 0.003; cut off:3.0), BISAP (AUROC: 0.693; p = 0.017; cut-off: 2.0) and Modified Marshall (AUROC: 0.806; p < 0.001; cut-off:1.0). CONCLUSIONS: RDW is a simple routine parameter, available at admission. This AP cohort showed that RDW0h > 13.0 and RDW0h-to-total serum calcium ratio > 1.4 were excellent predictors for severity and RDW0h > 14.0 and RDW0h-to-total serum calcium ratio > 1.7 were very-good predictors for mortality, being superior to conventional prognostic scoring systems. PMID- 29976141 TI - 18F-FDG PET/CT may be a suitable method for preoperative diagnosis and evaluation of Chinese older patients with hilar cholangiocarcinoma. AB - BACKGROUND: As the most common cholangiocarcinoma, hilar cholangiocarcinoma (HCCA) is a challenge in hepatobiliary surgery and causes a very poor prognosis. This study was designed to explore whether 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) may be a suitable method for preoperative diagnosis and evaluation of Chinese older patients with hilar cholangiocarcinoma. METHODS: This study enrolled 53 patients (>= 65 years) with HCCA. 18F-FDG PET/CT scan was performed in all patients within one week before operation. RESULTS: 18F-FDG PET/CT identified the tumors in all patients (100%). There were 48 patients (90.6%) with the same Bismuth-Corlette classifications determined by 18F-FDG PET/CT and operative pathology, whereas Bismuth-Corlette classifications of 5 patients (9.4%) were underestimated by 18F-FDG PET/CT compared with that determined by operative pathology. 18F-FDG PET/CT identified 19 patients (sensitivity: 67.9%) in 28 patients with lymph node metastases, and 22 patients (specificity: 88.0%) in 25 patients without lymph node metastases, with an accuracy of 77.4%. 18F-FDG PET/CT identified 8 patients (sensitivity: 47.1%) in 17 patients with liver, peritoneal or other distant metastases, and 35 patients (specificity: 97.2%) in 36 patients without liver, peritoneal or other distant metastases, with an accuracy of 81.1%. 18F-FDG PET/CT identified 17 patients (sensitivity: 73.9%) in 23 patients with unresectable tumors, and 24 patients (specificity: 80.0%) in 30 patients with resectable tumors, with an accuracy of 77.4%. CONCLUSIONS: 18F-FDG PET/CT may be a suitable method for preoperative diagnosis and evaluation, and offer valuable information for effective operation in Chinese older patients with HCCA. PMID- 29976142 TI - Diversity, evolution, and function of myriapod hemocyanins. AB - BACKGROUND: Hemocyanin transports O2 in the hemolymph of many arthropod species. Such respiratory proteins have long been considered unnecessary in Myriapoda. As a result, the presence of hemocyanin in Myriapoda has long been overlooked. We analyzed transcriptome and genome sequences from all major myriapod taxa - Chilopoda, Diplopoda, Symphyla, and Pauropoda - with the aim of identifying hemocyanin-like proteins. RESULTS: We investigated the genomes and transcriptomes of 56 myriapod species and identified 46 novel full-length hemocyanin subunit sequences in 20 species of Chilopoda, Diplopoda, and Symphyla, but not Pauropoda. We found in Cleidogona sp. (Diplopoda, Chordeumatida) a hemocyanin-like sequence with mutated copper-binding centers, which cannot bind O2. An RNA-seq approach showed markedly different hemocyanin mRNA levels from ~ 6 to 25,000 reads per kilobase per million reads. To evaluate the contribution of hemocyanin to O2 transport, we specifically studied the hemocyanin of the centipede Scolopendra dehaani. This species harbors two distinct hemocyanin subunits with low expression levels. We showed cooperative O2 binding in the S. dehaani hemolymph, indicating that hemocyanin supports O2 transport even at low concentration. Further, we demonstrated that hemocyanin is > 1500-fold more highly expressed in the fertilized egg than in the adult. CONCLUSION: Hemocyanin was most likely the respiratory protein in the myriapod stem-lineage, but multiple taxa may have independently lost hemocyanin and thus the ability of efficient O2 transport. In myriapods, hemocyanin is much more widespread than initially appreciated. Some myriapods express hemocyanin only at low levels, which are, nevertheless, sufficient for O2 supply. Notably, also in myriapods, a non-respiratory protein similar to insect storage hexamerins evolved from the hemocyanin. PMID- 29976143 TI - Antarctic yeasts: analysis of their freeze-thaw tolerance and production of antifreeze proteins, fatty acids and ergosterol. AB - BACKGROUND: Microorganisms have evolved a number of mechanisms to thrive in cold environments, including the production of antifreeze proteins, high levels of polyunsaturated fatty acids, and ergosterol. In this work, several yeast species isolated from Antarctica were analyzed with respect to their freeze-thaw tolerance and production of the three abovementioned compounds, which may also have economic importance. RESULTS: The freeze-thaw tolerance of yeasts was widely variable among species, and a clear correlation with the production of any of the abovementioned compounds was not observed. Antifreeze proteins that were partially purified from Goffeauzyma gastrica maintained their antifreeze activities after several freeze-thaw cycles. A relatively high volumetric production of ergosterol was observed in the yeasts Vishniacozyma victoriae, G. gastrica and Leucosporidium creatinivorum, i.e., 19, 19 and 16 mg l- 1, respectively. In addition, a high percentage of linoleic acid with respect to total fatty acids was observed in V. victoriae (10%), Wickerhamomyces anomalus (12%) and G. gastrica (13%), and a high percentage of alpha linoleic acid was observed in L. creatinivorum (3.3%). CONCLUSIONS: Given these results, the abovementioned yeasts are good candidates to be evaluated for use in the production of antifreeze proteins, fatty acids, and ergosterol at the industrial scale. PMID- 29976145 TI - BARCOSEL: a tool for selecting an optimal barcode set for high-throughput sequencing. AB - BACKGROUND: Current high-throughput sequencing platforms provide capacity to sequence multiple samples in parallel. Different samples are labeled by attaching a short sample specific nucleotide sequence, barcode, to each DNA molecule prior pooling them into a mix containing a number of libraries to be sequenced simultaneously. After sequencing, the samples are binned by identifying the barcode sequence within each sequence read. In order to tolerate sequencing errors, barcodes should be sufficiently apart from each other in sequence space. An additional constraint due to both nucleotide usage and basecalling accuracy is that the proportion of different nucleotides should be in balance in each barcode position. The number of samples to be mixed in each sequencing run may vary and this introduces a problem how to select the best subset of available barcodes at sequencing core facility for each sequencing run. There are plenty of tools available for de novo barcode design, but they are not suitable for subset selection. RESULTS: We have developed a tool which can be used for three different tasks: 1) selecting an optimal barcode set from a larger set of candidates, 2) checking the compatibility of user-defined set of barcodes, e.g. whether two or more libraries with existing barcodes can be combined in a single sequencing pool, and 3) augmenting an existing set of barcodes. In our approach the selection process is formulated as a minimization problem. We define the cost function and a set of constraints and use integer programming to solve the resulting combinatorial problem. Based on the desired number of barcodes to be selected and the set of candidate sequences given by user, the necessary constraints are automatically generated and the optimal solution can be found. The method is implemented in C programming language and web interface is available at http://ekhidna2.biocenter.helsinki.fi/barcosel . CONCLUSIONS: Increasing capacity of sequencing platforms raises the challenge of mixing barcodes. Our method allows the user to select a given number of barcodes among the larger existing barcode set so that both sequencing errors are tolerated and the nucleotide balance is optimized. The tool is easy to access via web browser. PMID- 29976144 TI - Novel proteome and acetylome of Bemisia tabaci Q in response to Cardinium infection. AB - BACKGROUND: It has become increasingly clear that symbionts have crucial evolutionary and ecological ramifications for their host arthropods. However, little is known whether these symbiont infections influence the proteome and lysine acetylome of their host arthropods. Here we performed experiments to investigate the proteomes and acetylomes of Cardinium-infected (C*+) and uninfected (C-) Bemisia tabaci Q with identical backgrounds, through the combination of affinity enrichment and high-resolution LC-MS/MS analysis. RESULTS: Of the 3353 proteins whose levels were quantitated in proteome, a total of 146 proteins dividing into 77 up-regulated and 69 down-regulated proteins were discovered to be differentially expressed as having at least a 1.2-fold change when C*+ strain was compared with C- strain. Furthermore, a total of 528 lysine acetylation sites in 283 protein groups were identified, among which 356 sites in 202 proteins were quantified. The comparison of acetylomes revealed 30 sites in 26 lysine acetylation proteins (Kac) were quantified as up-regulated targets and 35 sites in 29 Kac proteins were quantified as down-regulated targets. Functional analysis showed that these differentially expressed proteins and Kac proteins were mainly involved in diverse physiological processes related to development, immune responses and energy metabolism, such as retinol metabolism, methane metabolism and fatty acid degradation. Notably, protein interaction network analyses demonstrated widespread interactions modulated by protein acetylation. CONCLUSION: Here we show the proteome and acetylom of B. tabaci Q in response to the symbiont Cardinium infection. This is the first study to utilize the tool of acetylome analysis for revealing physiological responses of arthropods to its symbiont infection, which will provide an important resource for exploring the arthropod-symbiont interaction. PMID- 29976146 TI - Towards integrated surveillance of zoonoses: spatiotemporal joint modeling of rodent population data and human tularemia cases in Finland. AB - BACKGROUND: There are an increasing number of geo-coded information streams available which could improve public health surveillance accuracy and efficiency when properly integrated. Specifically, for zoonotic diseases, knowledge of spatial and temporal patterns of animal host distribution can be used to raise awareness of human risk and enhance early prediction accuracy of human incidence. METHODS: To this end, we develop a spatiotemporal joint modeling framework to integrate human case data and animal host data to offer a modeling alternative for combining multiple surveillance data streams in a novel way. A case study is provided of spatiotemporal modeling of human tularemia incidence and rodent population data from Finnish health care districts during years 1995-2012. RESULTS: Spatial and temporal information of rodent abundance was shown to be useful in predicting human cases and in improving tularemia risk estimates in 40 and 75% of health care districts, respectively. The human relative risk estimates' standard deviation with rodent's information incorporated are smaller than those from the model that has only human incidence. CONCLUSIONS: These results support the integration of rodent population variables to reduce the uncertainty of tularemia risk estimates. However, more information on several covariates such as environmental, behavioral, and socio-economic factors can be investigated further to deeper understand the zoonotic relationship. PMID- 29976147 TI - Endometrial tuberculosis among patients undergoing endometrial biopsy at Tikur Anbesa specialized hospital, Addis Ababa, Ethiopia. AB - BACKGROUND: Female genital tuberculosis (FGTB) is known to cause severe tubal disease leading to infertility and its incidence closely parallels with the overall prevalence of tuberculosis (TB) in a community. Its magnitude is underreported because diagnosis is difficult and requires invasive techniques. In this study we determined the prevalence of endometrial tuberculosis and characterized isolates among women who underwent endometrial biopsy for evaluation of various conditions at a Tikur Anbessa Specialized Hospital (TAHS), Addis Ababa, Ethiopia. METHODS: A cross sectional study was conducted on 152 consecutive gynecologic patients who underwent endometrial biopsy for different gynecologic diseases. Endometrial tissue taken for routine histopathology examination was shared after informed consent was obtained from the patient and subjected to polymerase chain reaction (PCR) and culture for Mycobacterium tuberculosis (Mtb). RESULTS: The prevalence of endometrial TB in this study by IS1081PCR was 4.6% (7/152) while culture proven endometrial TB was 2.6% (4/152). However, histological examination identified only 2/152 (1.3%) endometrial tuberculosis. While all culture proven TB samples were also PCR positive for Mtb, only one histologic proven endometrial TB was culture and PCR positive. All of the four isolates by culture were M. tuberculosis. CONCLUSION: This study has shown that the magnitude of endometrial TB is fairly high in gynecologic patients visiting outpatient departments for various complaints and PCR detects more cases than culture or Histopathology. PMID- 29976148 TI - Genetic etiologies of the electrical status epilepticus during slow wave sleep: systematic review. AB - BACKGROUND: Electrical status epilepticus during slow-wave sleep (ESESS) which is also known as continuous spike-wave of slow sleep (CSWSS) is type of electroencephalographic (EEG) pattern which is seen in ESESS/CSWSS/epilepsy aphasia spectrum. This EEG pattern can occur alone or with other syndromes. Its etiology is not clear, however, brain malformations, immune disorders, and genetic etiologies are suspected to contribute. We aimed to perform a systematic review of all genetic etiologies which have been reported to associate with ESESS/CSWSS/epilepsy-aphasia spectrum. We further aimed to identify the common underlying pathway which can explain it. To our knowledge, there is no available systematic review of genetic etiologies of ESESS/CSWSS/epilepsy-aphasia spectrum. MEDLINE, EMBASE, PubMed and Cochrane review database were searched, using terms specific to electrical status epilepticus during sleep or continuous spike-wave discharges during slow sleep or epilepsy-aphasia spectrum and of studies of genetic etiologies. These included monogenic mutations and copy number variations (CNVs). For each suspected dosage-sensitive gene, further studies were performed through OMIM and PubMed database. RESULTS: Twenty-six studies out of the 136 identified studies satisfied our inclusion criteria. I51 cases were identified among those 26 studies. 16 studies reported 11 monogenic mutations: SCN2A (N = 6), NHE6/SLC9A6 (N = 1), DRPLA/ ATN1 (N = 1), Neuroserpin/SRPX2 (N = 1), OPA3 (N = 1), KCNQ2 (N = 2), KCNA2 (N = 5), GRIN2A (N = 34), CNKSR2 (N = 2), SLC6A1 (N = 2) and KCNB1 (N = 5). 10 studies reported 89 CNVs including 9 recurrent ones: Xp22.12 deletion encompassing CNKSR2 (N = 6), 16p13 deletion encompassing GRIN2A (N = 4), 15q11.2-13.1 duplication (N = 15), 3q29 duplication (N = 11), 11p13 duplication (N = 2), 10q21.3 deletion (N = 2), 3q25 deletion (N = 2), 8p23.3 deletion (N = 2) and 9p24.2 (N = 2). 68 of the reported genetic etiologies including monogenic mutations and CNVs were detected in patients with ESESS/CSWSS/epilepsy aphasia spectrum solely. The most common underlying pathway was channelopathy (N = 56). CONCLUSIONS: Our review suggests that genetic etiologies have a role to play in the occurrence of ESESS/CSWSS/epilepsy-aphasia spectrum. The common underlying pathway is channelopathy. Therefore we propose more genetic studies to be done for more discoveries which can pave a way for proper drug identification. We also suggest development of common cut-off value for spike-wave index to ensure common language among clinicians and researchers. PMID- 29976149 TI - Trans-arterial radioembolization for intermediate-advanced hepatocellular carcinoma: a budget impact analysis. AB - BACKGROUND: Trans-arterial radio-embolization (TARE) is an emerging treatment for the management of hepatocellular carcinoma (HCC). TARE may compete with systemic chemotherapy, sorafenib, in intermediate stage patients with prior chemoembolization failure or advanced patients with tumoral macrovascular invasion with no extra-hepatic spread and good liver function. We performed a budget impact analysis (BIA) evaluating the expected changes in the expenditure for the Italian Healthcare Service within scenarios of increased utilization of TARE in place of sorafenib over the next five years. METHODS: Starting from patient level data from three oncology centres in Italy, a Markov model was developed to project on a lifetime horizon survivals and costs associated to matched cohorts of intermediate-advanced HCC patients treated with TARE or sorafenib. The initial model has been integrated with epidemiological data to perform a BIA comparing the current scenario with 20 and 80% utilization rates for TARE and sorafenib, respectively, with increasing utilization rates of TARE of 30, 40 and 50% over the next 1, 3 and 5 years. RESULTS: Compared to the current scenario, progressively increasing utilization rates of TARE over sorafenib in the next 5 years is expected to save globally about 7 million Euros. CONCLUSIONS: Radioembolization can be considered a valuable treatment option for patients with intermediate-advanced HCC. These findings enrich the evidence about the economic sustainability of TARE in comparison to standard systemic chemotherapy within the context of a national healthcare service. PMID- 29976150 TI - 3-O-Acetyloleanolic acid inhibits VEGF-A-induced lymphangiogenesis and lymph node metastasis in an oral cancer sentinel lymph node animal model. AB - BACKGROUND: Sentinel lymph node metastasis is a common and early event in the metastatic process of head and neck squamous cell carcinoma (HNSCC) and is the most powerful prognostic factor for survival of HNSCC patients. 3-O acetyloleanolic acid (3AOA), a pentacyclic triterpenoid compound isolated from seeds of Vigna sinensis K., has been reported to have potent anti-angiogenesis and anti-tumor activities. However, its effects on tumor-related lymphangiogenesis and lymph node metastasis are not yet understood. METHODS: The in vitro inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis were investigated via in vitro experiments using mouse oral squamous cell carcinoma (SCCVII) cells and human lymphatic microvascular endothelial cells (HLMECs). The in vivo inhibitory effects of 3AOA on VEGF-A-induced lymphangiogenesis and sentinel lymph node metastasis were investigated in an oral cancer sentinel lymph node (OCSLN) animal model. RESULTS: 3AOA inhibited tumor-induced lymphangiogenesis and sentinel lymph node metastasis in an OCSLN animal model, and reduced expression of VEGF-A, a lymphangiogenic factor in hypoxia mimetic agent CoCl2-treated SCCVII cells. 3AOA inhibited proliferation, tube formation, and migration of VEGF-A-treated HLMECs. The lymphatic vessel formation that was stimulated in vivo in a by VEGF-A Matrigel plug was reduced by 3AOA. 3AOA suppressed phosphorylation of vascular endothelial growth factor (VEGFR) -1 and - 2 receptors that was stimulated by VEGF-A. In addition, 3AOA suppressed phosphorylation of the lymphangiogenesis-related downstream signaling factors PI3K, FAK, AKT, and ERK1/2. 3AOA inhibited tumor growth, tumor-induced lymphangiogenesis, and sentinel lymph node metastasis in a VEGF-A-induced OCSLN animal model that was established using VEGF-A overexpressing SCCVII cells. CONCLUSION: 3AOA inhibits VEGF-A-induced lymphangiogenesis and sentinel lymph node metastasis both in vitro and in vivo. The anti-lymphangiogenic effects of 3AOA are probably mediated via suppression of VEGF-A/VEGFR-1 and VEGFR-2 signaling in HLMECs, and can be a useful anti-tumor agent to restrict the metastatic spread of oral cancer. PMID- 29976151 TI - Epidemiology of Ventilator-Associated Pneumonia, microbiological diagnostics and the length of antimicrobial treatment in the Polish Intensive Care Units in the years 2013-2015. AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is a common nosocomial infection in intensive care units (ICUs). The objective of this study was to describe the epidemiology and microbiology of VAP in Polish ICUs from 2013 to 2015, as well as to understand how these depended on the diagnostic methods used to identify VAP pathogens and the clinical strategy for VAP treatment. METHODS: This observational study was carried out in seven Polish adult ICUs. VAP surveillance was based on the European Healthcare-associated Infections Surveillance Network recommendations and was defined as pneumonia occurring more than 48 h after receiving mechanical ventilation, with symptom onset 3 days or more after the hospital stay. Depending on the microbiological diagnostic method, VAP cases were classified as PNEU-1 (positive quantitative culture from minimally contaminated lower respiratory tract specimen such as broncho-alveolar lavage, protected brush or distal protected aspirate) or other VAP cases. RESULTS: The incidence of VAP was 8.0% and the incidence density: 12.3/1000 ventilator days. Microbiological diagnosis was made using PNEU-1 in 80 cases (39%); over the study duration, the proportion of cases diagnosed with PNEU-1 increased from 14 to 60% (p < 0.001). The predominant etiologic agents causing VAP were Enterobacteriaceae (32.6%) and non-fermenting Gram-negative bacteria (27.6%). The causative microbe varied significantly depending on the diagnostic method: in cases diagnosed using PNEU-1, Staphylococcus aureus (21.3%) and Klebsiella pneumoniae (12.5%) were the dominant organisms, whereas in other VAP cases, Acinetobacter baumannii (23.8%) was commonly observed. The length of antibiotic treatment in cases diagnosed with PNEU-1 was shorter than for other VAP cases (7.2 vs. 9.1 days, p < 0.005), as was the duration of hospitalization (49 vs. 51.8 days, p < 0.001). Antibiotic resistance was a particular concern for A.baumannii isolates, which were highly resistance to imipenem (70.6%) and meropenem or doripenem (52.9%). K. pneumoniae isolates demonstrated resistance to ampicillin (90.3%), ceftazidime (71.0%) and third-generation cephalosporins (74.2%). CONCLUSION: A change over time was observed in the microbiological diagnostic methods used for patients with VAP. A. baumannii was observed mainly in VAP cases diagnosed using substandard methods (non-PNEU-1). The duration of treatment for VAP patients diagnosed properly using PNEU-1 was shorter. PMID- 29976152 TI - A novel locus on mouse chromosome 7 that influences survival after infection with tick-borne encephalitis virus. AB - BACKGROUND: Tick-borne encephalitis (TBE) is the main tick-borne viral infection in Eurasia. Its manifestations range from inapparent infections and fevers with complete recovery to debilitating or fatal encephalitis. The basis of this heterogeneity is largely unknown, but part of this variation is likely due to host genetic. We have previously found that BALB/c mice exhibit intermediate susceptibility to the infection of TBE virus (TBEV), STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, carrying 12.5% of the STS genome on the background of the BALB/c genome is even more susceptible than BALB/c. Importantly, mouse orthologs of human TBE controlling genes Oas1b, Cd209, Tlr3, Ccr5, Ifnl3 and Il10, are in CcS-11 localized on segments derived from the strain BALB/c, so they are identical in BALB/c and CcS-11. As they cannot be responsible for the phenotypic difference of the two strains, we searched for the responsible STS-derived gene-locus. Of course the STS-derived genes in CcS-11 may operate through regulating or epigenetically modifying these non-polymorphic genes of BALB/c origin. METHODS: To determine the location of the STS genes responsible for susceptibility of CcS-11, we analyzed survival of TBEV-infected F2 hybrids between BALB/c and CcS-11. CcS-11 carries STS-derived segments on eight chromosomes. These were genotyped in the F2 hybrid mice and their linkage with survival was tested by binary trait interval mapping. We have sequenced genomes of BALB/c and STS using next generation sequencing and performed bioinformatics analysis of the chromosomal segment exhibiting linkage with TBEV survival. RESULTS: Linkage analysis revealed a novel suggestive survival controlling locus on chromosome 7 linked to marker D7Nds5 (44.2 Mb). Analysis of this locus for polymorphisms between BALB/c and STS that change RNA stability and genes' functions led to detection of 9 potential candidate genes: Cd33, Klk1b22, Siglece, Klk1b16, Fut2, Grwd1, Abcc6, Otog, and Mkrn3. One of them, Cd33, carried a nonsense mutation in the STS strain. CONCLUSIONS: The robust genetic system of recombinant congenic strains of mice enabled detection of a novel suggestive locus on chromosome 7. This locus contains 9 candidate genes, which will be focus of future studies not only in mice but also in humans. PMID- 29976153 TI - Comparison of qPCR and culture methods for group B Streptococcus colonization detection in pregnant women: evaluation of a new qPCR assay. AB - BACKGROUND: Streptococcus Group B (GBS) colonization in pregnant women is the most important risk factor for newborn disease due to vertical transmission during delivery. GBS colonization during pregnancy has been implicated as a leading cause of perinatal infections. Traditionally, pregnant women are screened for GBS between 35 and 37 weeks of gestation. However, antenatal culture-based screening yields no information on GBS colonization status and offers low predictive value for GBS colonization at delivery. Numerous assays have been evaluated for GBS screening in an attempt to validate a fast and efficient method. The aim of this study was to compare bacteria isolation by culture and two qPCR techniques, targeting sip and cfb genes, respectively, for detecting colonizing GBS. METHODS: Cultures - the gold-standard technique, a previous qPCR technique targeting the sip gene, and a new proposed qPCR assay targeting the cfb gene were evaluated as diagnostic tools on 320 samples. RESULTS: Considering cultures as the gold standard, the evaluated qPCR method detected 75 out of 78 samples, representing a sensitivity of 93.58% (95% confidence interval (CI), 90.89-96.27) and specificity of 94.62% (95% CI, 91.78-97.46). However, an additional analysis was performed for true positives that included not only samples showing positives by culture but samples showing positive for both qPCR assays. The sensitivity and specificity were recalculated including these discrepant samples and a total of 89 samples were considered as positive, giving a prevalence of 27.81%. With this new analysis, the qPCR targeting the cfb gene showed a sensitivity of 95.5% (95% CI, 88.65-98.59) and specificity of 99.13% (95% CI, 96.69-99.97). CONCLUSIONS: The new qPCR method is a sensitive and specific assay for detecting GBS colonization and represents a valuable tool for identifying candidates for intrapartum antibiotic prophylaxis. Cultures should be retained as the reference and the routine technique because of its specificity and cost analysis ratio, but it would be convenient to introduce PCR techniques to check negative culture samples or when an urgent detection is required to reduce risk of infection among infants. PMID- 29976154 TI - Docetaxel facilitates lymphatic-tumor crosstalk to promote lymphangiogenesis and cancer progression. AB - BACKGROUND: Infiltration into lymphatic vessels is a critical step in breast cancer metastasis. Lymphatics undergo changes that facilitate metastasis as a result of activation of the cells lining lymphatic vessels, lymphatic endothelial cells (LECs). Inhibition of activation by targeting VEGFR3 can reduce invasion toward lymphatics. To best benefit patients, this approach should be coupled with standard of care that slows tumor growth, such as chemotherapy. Little is known about how chemotherapies, like docetaxel, may influence lymphatics and conversely, how lymphatics can alter responses to therapy. METHODS: A novel 3D in vitro co-culture model of the human breast tumor microenvironment was employed to examine the contribution of LECs to tumor invasion and viability with docetaxel and anti-VEGFR3, using three cell lines, MDA-MB-231, HCC38, and HCC1806. In vivo, the 4T1 mouse model of breast carcinoma was used to examine the efficacy of combinatorial therapy with docetaxel and anti-VEGFR3 on lymph node metastasis and tumor growth. Lymphangiogenesis in these mice was analyzed by immunohistochemistry and flow cytometry. Luminex analysis was used to measure expression of lymphangiogenic cytokines. RESULTS: In vitro, tumor cell invasion significantly increased with docetaxel when LECs were present; this effect was attenuated by inhibition of VEGFR3. LECs reduced docetaxel-induced cell death independent of VEGFR3. In vivo, docetaxel significantly increased breast cancer metastasis to the lymph node. Docetaxel and anti-VEGFR3 combination therapy reduced lymph node and lung metastasis in 4T1 and synergized to reduce tumor growth. Docetaxel induced VEGFR3-dependent vessel enlargement, lymphangiogenesis, and expansion of the LEC population in the peritumoral microenvironment, but not tumor-free stroma. Docetaxel caused an upregulation in pro-lymphangiogenic factors including VEGFC and TNF-alpha in the tumor microenvironment in vivo. CONCLUSIONS: Here we present a counter-therapeutic effect of docetaxel chemotherapy that triggers cancer cells to elicit lymphangiogenesis. In turn, lymphatics reduce cancer response to docetaxel by altering the cytokine milieu in breast cancer. These changes lead to an increase in tumor cell invasion and survival under docetaxel treatment, ultimately reducing docetaxel efficacy. These docetaxel-induced effects can be mitigated by anti-VEGFR3 therapy, resulting in a synergism between these treatments that reduces tumor growth and metastasis. PMID- 29976155 TI - The relation of secondary sex ratio and miscarriage history with Toxoplasma gondii infection. AB - BACKGROUND: Toxoplasma gondii is a protozoan parasite with worldwide distribution, infecting a broad-range of humans and warm-blooded animals. In the current study, role of this parasite on secondary sex ratio and risk of miscarriage was investigated. METHODS: In this cross-sectional study, 850 cord blood samples were collected in Tehran, Iran, 2014-2015. Enzyme-linked immunosorbent assay (ELISA) was used to assess anti-Toxoplasma IgG in samples. Information such as sex of the neonates and age, number of previous pregnancies and history of miscarriage of the mothers were recorded in questionnaires. Logistic regression analysis was used to assess the possible relationship between the latent toxoplasmosis and the highlighted parameters. RESULTS: Logistic regression analysis showed that the odds of having a male neonate in seropositive women is nearly 64% higher than that in seronegative women (OR = 1.64, CI95 = 1.16-2.33, P = 0.005). The odds ratio of having male neonate increased to 2.10 (CI95 = 1.24-3.57, P = 0.006) in high-titer seropositive women, compared to that in seronegative control group. The odds of having a miscarriage history was approximately two and a half times greater in seropositive women than in seronegative ones (OR = 2.45, CI95 = 1.56-3.87, P < 0.001). The odds ratio of having miscarriage increased to 2.76 (CI95 = 1.61-4.73, P < < .001) in low-titer seropositive women, compared to that in seronegative control group. CONCLUSION: Results of the current study have shown that T. gondii infection affects secondary sex ratio in human offspring and can be addressed as one of the major miscarriage causes in women. PMID- 29976156 TI - Survival of HIV infected patients on maintenance hemodialysis in Cameroon: a comparative study. AB - BACKGROUND: There are conflicting reports on the impact of HIV in the era of combined antiretroviral (c-ART) on survival of patient with ESKD. We aimed to compare the one-year survival of HIV positive patients to that of their HIV negative counterparts with ESKD on maintenance haemodialysis in Cameroon. METHODS: This was a retrospective cohort study conducted in the haemodialysis units of the Douala and Yaounde General Hospitals. All HIV positive patients treated by maintenance haemodialysis between January 2007 and March 2015 were included. A comparative group of HIV negative patients with ESKD were matched for age, sex, co morbidities, year of dialysis initiation and haemodialysis unit. Relevant data at the time of haemodialysis initiation and during the first year of haemodialysis was noted. Survival was analysed using the Kaplan Meier and Cox regression hazard ratio estimator. A p value < 0.05 was considered statistically significant. RESULTS: A total of 57 patients with HIV and 57 without HIV were included. Mean age was 46.25 +/- 11.41 years, and 52.6% were females in both groups. HIV nephropathy (50.9%) was the main presumed aetiology of ESKD in the HIV group, while chronic glomerulonephritis (33.3%) and diabetes (21.1%) were the main aetiologies in the HIV negative group. At initiation of dialysis, the median CD4 count was 212 cell/mm3 (IQR; 138-455) and 77.2% were receiving c-ART. The proportion of patients who initiated dialysis with a temporary venous catheter was similar in both groups (p = 0.06). After one year on haemodialysis, survival rate was lower in the HIV positive group compared to the HIV negative group (61.4%/78.9%, HR: 2.05; 95% CI: 1.03-4.08; p = 0.042).Kaplan Meier survival curve was in direction of a lower survival in HIV positive group (p = 0.052). CONCLUSION: The one year survival of HIV positive patients on maintenance haemodialysis in Cameroon seems to be lower compared to their HIV negative counterparts. PMID- 29976157 TI - Outcome of inflammatory breast cancer in Moroccan patients: clinical, molecular and pathological characteristics of 219 cases from the National Oncology Institute (INO). AB - BACKGROUND: Usually misdiagnosed, Inflammatory Breast Cancer (IBC) is the most aggressive form of non-metastatic breast cancer. This orphan disease is more frequent in North Africa. Despite intensive treatment, the survival rate remains very low. METHODS: We have retrospectively studied all breast cancer cases diagnosed at the National Oncology Institute (INO), Rabat between 2005 and 2010. We have collected 219 cases of women with metastatic and non-metastatic IBC. Data have been obtained from patients' personal medical files over a follow-up period of 5 years. We have described IBC's clinicopathological features and analyzed its clinical outcome using SPSS software. HR (hazard Ratio) was calculated using Cox regression analysis. RESULTS: The frequency of IBC cases is 4.05%. The majority of our patients (65.3%) were under 50 years old. The most prevalent molecular subtype was Luminal A (38.7%) followed by Luminal B HER2+ (27.9%) and Triple negative (21.6%). During the follow-up period, 72 patients (32.9%) had recurrence and 40 patients (18.3%) died. The 3-year OS (Overall Survival) and EFS (Event Free Survival) of non-metastatic patients were 70.4 and 46.5% respectively, while in the metastatic disease, the 3-year OS was only 41.9%. In non-metastatic women, we observed a higher rate of EFS associated to Selective estrogen receptor modulation treatment (p = 0.01), and a lower rate EFS in triple negative breast cancer patients (p = 0.02). In univariate analysis, we found that EFS rate is lower in patients presenting Triple Negative tumors when compared to other molecular subtypes (HR: 3.54; 95%CI: 1.13-11.05; p = 0.02). We also found that Selective estrogen receptor modulation treatment is associated with higher EFS rate (HR: 0.48; 95%CI: 0.07-0.59; p = 0.01). CONCLUSIONS: IBC in Morocco shows similar characteristics to those in North African countries; however, survival rates are still the highest when compared with neighboring countries. Collaborative studies with prospective aspects are warranted to establish the epidemiological profile and understand the high frequencies of IBC in North Africa. More studies on molecular markers are also needed to improve IBC patients' management and eventually their survival rate. PMID- 29976159 TI - MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells. AB - BACKGROUND: Although MASTL (microtubule-associated serine/threonine kinase-like) is a key mitotic kinase that regulates mitotic progression through the inactivation of tumor suppressor protein phosphatase 2A (PP2A), the antitumor mechanism of MASTL targeting in cancer cells is still unclear. METHODS: MASTL expression was evaluated by using breast cancer tissue microarrays and public cancer databases. The effects of MASTL depletion with siRNAs were evaluated in various breast cancer cells or normal cells. Various methods, including cell viability, cell cycle, soft agar, immunoblotting, immunofluorescence, PP2A activity, live image, and sphere forming assay, were used in this study. RESULTS: This study showed the oncosuppressive mechanism of MASTL targeting that promotes mitotic catastrophe through PP2A activation selectively in breast cancer cells. MASTL expression was closely associated with tumor progression and poor prognosis in breast cancer. The depletion of MASTL reduced the oncogenic properties of breast cancer cells with high MASTL expression, but did not affect the viability of non-transformed normal cells with low MASTL expression. With regard to the underlying mechanism, we found that MASTL inhibition caused mitotic catastrophe through PP2A activation in breast cancer cells. Furthermore, MASTL depletion enhanced the radiosensitivity of breast cancer cells with increased PP2A activity. Notably, MASTL depletion dramatically reduced the formation of radioresistant breast cancer stem cells in response to irradiation. CONCLUSION: Our data suggested that MASTL inhibition promoted mitotic catastrophe through PP2A activation, which led to the inhibition of cancer cell growth and a reversal of radioresistance in breast cancer cells. PMID- 29976158 TI - Differential expression of hsa-miR-221, hsa-miR-21, hsa-miR-135b, and hsa-miR-29c suggests a field effect in oral cancer. AB - BACKGROUND: The theory of field effect suggests that the tumor-adjacent area, besides histopathologically normal, undergoes genetic and epigenetic changes that can eventually affect epithelial homeostasis, predisposing the patient to cancer development. One of the many molecular changes described in cancer are microRNAs (miRNAs), which regulates the expression of important genes during carcinogenesis. Thus, the aim of this study was to investigate the field effect in oral cancer. METHODS: We investigated the differential expression profile of four miRNAs (hsa-miR-221, hsa-miR-21, hsa-miR-135b, and hsa-miR-29c) in cancerous oral tissue, in tumor-adjacent tissue and and in non-cancerous tissue samples from healthy volunteers. RESULTS: Our results showed significant overexpression profiles of all four studied miRNAs in cancerous oral tissue compared to non cancerous samples, as well as in tumor-adjacent tissue compared to cancer-free tissue. No significant difference was found when comparing the expression profile of cancerous and tissue-adjacent tissue groups. We found a negative correlation between the expression of hsa-miR-21 expression and STAT3 in oral squamous cell carcinoma. CONCLUSION: These results suggest that the tissue adjacent to cancer cannot be considered a normal tissue because its molecular aspects are significantly altered. Our data corroborates the hypothesis of field cancerization. PMID- 29976161 TI - A randomized trial comparing the pharmacology of magnesium sulfate when used to treat severe preeclampsia with serial intravenous boluses versus a continuous intravenous infusion. AB - BACKGROUND: Magnesium sulfate is the preferred pharmacological intervention for the prevention and treatment of eclamptic seizures in pregnancy. Pain associated with intramuscular injections and the need for an electronic infusion pump for use intravenously represent significant barriers to broader utilization. We hypothesize that an alternative regimen based on serial intravenous (IV) boluses can produce serum concentrations comparable to those produced by a continuous infusion. METHODS: An open-label randomized trial was performed at two hospitals in Egypt. Women with severe preeclampsia were eligible and enrolled between January 2015 and February 2016. Two hundred subjects were randomized by random numbers generated centrally in distinct blocks and stratified by study site. They were assigned to a continuous infusion arm, (4 g loading dose with 1 g/hr. continuous infusion) or a serial IV bolus arm, (6 g loading dose with 2 g bolus every 2 h using a Springfusor(r) pump). Sparsely sampled magnesium serum concentrations were collected, nonlinear mixed effect modeling was conducted and Monte Carlo simulations were used to generate 200 simulated subjects in each treatment arm. The simulated populations were used to determine area under the concentration-time curve (AUC) as a measure of total drug exposure and compared. RESULTS: Simulated area under the magnesium serum concentration-time curve was significantly higher in the serial IV bolus arm than in the continuous infusion arm (1107 +/- 461 mmol*min /L vs. 1010 +/- 398 mmol*min /L, (P = 0.02)). Four percent of women in the serial bolus arm considered the treatment unacceptable or very unacceptable compared to 2% in the continuous infusion arm, (P = 0.68). CONCLUSIONS: Serial IV boluses achieve serum magnesium concentrations statistically significantly higher but clinically comparable to those achieved with a continuous infusion and offer a third option for the administration of MgSO4 to women with preeclampsia that may reduce barriers to utilization. TRIAL REGISTRATION: Trial no. NCT02091401, March 17, 2014. PMID- 29976160 TI - Identification of ANKDD1B variants in an ankylosing spondylitis pedigree and a sporadic patient. AB - BACKGROUND: Ankylosing spondylitis (AS) is a debilitating autoimmune disease affecting tens of millions of people in the world. The genetics of AS is unclear. Analysis of rare AS pedigrees might facilitate our understanding of AS pathogenesis. METHODS: We used genome-wide linkage analysis and whole-exome sequencing in combination with variant co-segregation verification and haplotype analysis to study an AS pedigree and a sporadic AS patient. RESULTS: We identified a missense variant in the ankyrin repeat and death domain containing 1B gene ANKDD1B from a Han Chinese pedigree with dominantly inherited AS. This variant (p.L87V) co-segregates with all male patients of the pedigree. In females, the penetrance of the symptoms is incomplete with one identified patient out of 5 carriers, consistent with the reduced frequency of AS in females of the general population. We further identified a distinct missense variant affecting a conserved amino acid (p.R102L) of ANKDD1B in a male from 30 sporadic early onset AS patients. Both variants are absent in 500 normal controls. We determined the haplotypes of four major known AS risk loci, including HLA-B*27, 2p15, ERAP1 and IL23R, and found that only HLA-B*27 is strongly associated with patients in our cohort. CONCLUSIONS: Together these results suggest that ANKDD1B variants might be associated with AS and genetic analyses of more AS patients are warranted to verify this association. PMID- 29976162 TI - Animal experimental research design in critical care. AB - BACKGROUND: Limited translational success in critical care medicine is thought to be in part due to inadequate methodology, study design, and reporting in preclinical studies. The purpose of this study was to compare reporting of core features of experimental rigor: blinding, randomization, and power calculations in critical care medicine animal experimental research. We hypothesized that these study design characteristics were more frequently reported in 2015 versus 2005. METHODS: We performed an observational bibliometric study to grade manuscripts on blinding, randomization, and power calculations. Chi-square tests and logistic regression were used for analysis. Inter-rater agreement was assessed using kappa and Gwet's AC1. RESULTS: A total of 825 articles from seven journals were included. In 2005, power estimations were reported in 2%, randomization in 35%, and blinding in 20% (n = 482). In 2015, these metrics were included in 9, 47, and 36% of articles (n = 343). The increase in proportion for the metrics tested was statistically significant (p < 0.001, p = 0.002, and p < 0.001). CONCLUSIONS: Only a minority of published manuscripts in critical care medicine journals reported on recommended study design steps to increase rigor. Routine justification for the presence or absence of blinding, randomization, and power calculations should be considered to better enable readers to assess potential sources of bias. PMID- 29976163 TI - LTR-retrotransposon transcriptome modulation in response to endotoxin-induced stress in PBMCs. AB - BACKGROUND: Human Endogenous Retroviruses (HERVs) and Mammalian apparent LTR retrotransposons (MaLRs) represent the 8% of our genome and are distributed among our 46 chromosomes. These LTR-retrotransposons are thought to be essentially silent except in cancer, autoimmunity and placental development. Their Long Terminal Repeats (LTRs) constitute putative promoter or polyA regulatory sequences. In this study, we used a recently described high-density microarray which can be used to study HERV/MaLR transcriptome including 353,994 HERV/MaLR loci and 1559 immunity-related genes. RESULTS: We described, for the first time, the HERV transcriptome in peripheral blood mononuclear cells (PBMCs) using a cellular model mimicking inflammatory response and monocyte anergy observed after septic shock. About 5.6% of the HERV/MaLR repertoire is transcribed in PBMCs. Roughly one-tenth [5.7-13.1%] of LTRs exhibit a putative constitutive promoter or polyA function while one-quarter [19.5-27.6%] may shift from silent to active. Evidence was given that some HERVs/MaLRs and genes may share similar regulation control under lipopolysaccharide (LPS) stimulation conditions. Stimulus-dependent response confirms that HERV expression is tightly regulated in PBMCs. Altogether, these observations make it possible to integrate 62 HERVs/MaLRs and 26 genes in 11 canonical pathways and suggest a link between HERV expression and immune response. The transcriptional modulation of HERVs located close to genes such as OAS2/3 and IFI44/IFI44L or at a great distance from genes was discussed. CONCLUSION: This microarray-based approach revealed the expression of about 47,466 distinct HERV loci and identified 951 putative promoter LTRs and 744 putative polyA LTRs in PBMCs. HERV/MaLR expression was shown to be tightly modulated under several stimuli including high-dose and low-dose LPS and Interferon-gamma (IFN-gamma). HERV incorporation at the crossroads of immune response pathways paves the way for further functional studies and analyses of the HERV transcriptome in altered immune responses in vivo such as in sepsis. PMID- 29976165 TI - Efficacy of indoor air purification in treating Artemisia (mugwort) pollen allergic rhinitis: study protocol for a randomised controlled trial. AB - BACKGROUND: Allergic rhinitis (AR) is a worldwide health problem. Allergen avoidance is strongly recommended for AR patients. Air purification can reduce concentrations of particles in indoor air, including those of allergens. Air purifiers have been recommended by clinicians for AR patients, but few studies have focused on the removal of airborne allergens from home environments. Such studies have been limited by a lack of blinding, small samples, or a failure to measure allergen levels, disease activity, or a combination of these factors. This study investigates the efficacy of a high-efficiency air purifier in reducing disease activity in the homes of AR patients sensitive to the allergens produced by Artemisia (mugwort) pollen. METHODS: This is a randomized, double blind, clinical controlled trial that will test active and inactive versions of an air purifier (Atmosphere(r); Amway China). Sixty AR patients sensitive to the allergens produced by Artemisia pollen will be assigned randomly to two groups of equal numbers. All patients will undergo a 4-week treatment period and a 4-week observation period. Evaluation will be conducted at baseline (day 0) and on days 7, 14, 21, 28, and 56. The primary outcome measure will be the difference in visual analog scale scores from baseline. Secondary outcomes will be changes from baseline in nasal symptoms, allergy symptom scores, responses to the Rhinoconjunctivitis Quality of Life Questionnaire, Epworth Sleepiness Scale scores, and tolerability scores for the air purifier. Side effects of treatment will be recorded. DISCUSSION: Reducing exposure to allergens can reduce the risk of conditions such as AR. We hypothesise that AR patients sensitive to the allergens produced by Artemisia pollen will not suffer symptoms in a pollen-free environment. AR patients can remove pollen from their homes using air purifiers, decreasing the risk of symptoms. We expect that our study results will provide reliable evidence for determining the effects of air-purification therapy. TRIAL REGISTRATION: ChiCTR-INR-17012481 . (Retrospectively registered 26 August 2017). PMID- 29976164 TI - Bulk tumour cell migration in lung carcinomas might be more common than epithelial-mesenchymal transition and be differently regulated. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is one mechanism of carcinoma migration, while complex tumour migration or bulk migration is another best demontrated by tumour cells invading blood vessels. METHODS: Thirty cases of non-small cell lung carcinomas were used for identifying genes responsible for bulk cell migration, 232 squamous cell and adenocarcinomas to identify bulk migration rates. Genes expressed differently in the primary tumour and in the invasion front were regarded as relevant in migration and further validated in 528 NSCLC cases represented on tissue microarrays (TMAs) and metastasis TMAs. RESULTS: Markers relevant for bulk cancer cell migration were regulated differently when compared with EMT: Twist expressed in primary tumour, invasion front, and metastasis was not associated with TGFbeta1 and canonical Wnt, as Slug, Snail, and Smads were negative and beta-Catenin expressed membraneously. In the majority of tumours, E-Cadherin was downregulated at the invasive front, but not absent, but, coexpressed with N-Cadherin. Vimentin was coexpressed with cytokeratins at the invasion site in few cases, whereas fascin expression was seen in a majority. Expression of ERK1/2 was downregulated, PLCgamma was only expressed at the invasive front and in metastasis. Brk and Mad, genes identified in Drosophila border cell migration, might be important for bulk migration and metastasis, together with invadipodia proteins Tks5 and Rab40B, which were only upregulated at the invasive front and in metastasis. CXCR1 was expressed equally in all carcinomas, as opposed to CXCR2 and 4, which were only expressed in few tumours. CONCLUSION: Bulk cancer cell migration seems predominant in AC and SCC. Twist, vimentin, fascin, Mad, Brk, Tsk5, Rab40B, ERK1/2 and PLCgamma are associated with bulk cancer cell migration. This type of migration requires an orchestrated activation of proteins to keep the cells bound to each other and to coordinate movement. This hypothesis needs to be proven experimentally. PMID- 29976166 TI - Determinants of utilisation rates of preventive health services: evidence from Chile. AB - BACKGROUND: Preventive health services play a vital role in population health. However, access to such services is not always equitably distributed. In this article, we examine the barriers affecting utilisation rates of preventive health services, using Chile as a case study. METHODS: We conducted a cross-sectional study analysing secondary data from 206,132 Chilean adults, taken from the 2015 National Socioeconomic Characterisation Survey of the Government of Chile. We carried out logistic regressions to explore the relationship between the dependent variable use of preventive services and various demographic and socioeconomic variables. RESULTS: Categories more likely to use preventive services were women (OR=1.16; 95%CI: 1.11-1.21) and inactive people (OR=1.41; 95%CI: 1.33-1.48). By contrast, single individuals (OR= 0.85 ; 95%CI: 0.80-0.91) and those affiliated with the private healthcare provider (OR= 0.89; 95%CI: 0.81 0.96) had fewer odds of undertaking preventive exams. CONCLUSIONS: The findings underline the necessity of better information campaigns on the availability and necessity of preventive health services, addressing health inequality in accessing health services, and tackling lifestyle-related health risks. This is particularly important in countries - such as Chile - characterised by high income inequality and low utilisation rates of preventive health services. PMID- 29976167 TI - A new device-aided cognitive function test, User eXperience-Trail Making Test (UX TMT), sensitively detects neuropsychological performance in patients with dementia and Parkinson's disease. AB - BACKGROUND: A newer generation neuropsychological tests can take advantage of touch screen and mobile technology. We have developed a new Android application termed "User eXperience-Trail Making Test (UX-TMT)" for neurocognitive assessment and training. This study investigated the utility, including the reliability and the validity, of the UX-TMT as a screening test for cognitive decline in adults. METHODS: A total of 84 individuals aged 27-86 years were divided into three groups; healthy controls ([HC] n = 29), people with Parkinson's disease (PD; n = 28), and people with mild cognitive impairment (MCI) and dementia (MCI&D; n = 27). We examined the distributions of the scores and the time required, and the effects of age and group on these distributions. We analyzed internal consistency and convergent validity in all samples and applied receiver operator characteristic (ROC) analysis to determine a cutoff score that could differentiate the MCI & D group from the HC group. RESULTS: 97.6% of the participants completed all of the tasks, and the average total test time required for UX-TMT was 428.8 (+/- 109.1) s in the HC, 542.0 (+/- 168.7) s in the PD, and 777.5 (+/- 256.1) s in the MCI&D groups, respectively. The MCI&D group showed significantly lower UX-TMT scores and longer total time in completing the task than the HC group. In an ROC analysis, a score of 21 showed high sensitivity (.83) and specificity (.92), and the UX-TMT score plus age improved sensitivity to .96. Additionally, the UX-TMT scores showed significant correlation with the Mini-Mental State Examination (Japanese version) scores (r = .77, p = .001), and Cronbach's alpha (.71-.83) indicated acceptable internal consistency. CONCLUSION: The UX-TMT demonstrated high reliability and validity to detect cognitive decline in Japanese adults, highlighting its utility as a screening tool for epidemiological and clinical research. PMID- 29976168 TI - Stress begets stress: the association of adverse childhood experiences with psychological distress in the presence of adult life stress. AB - BACKGROUND: Adverse childhood experiences (ACES) have been linked to poor health and well-being outcomes, including poor mental health such as psychological distress. Both ACEs and psychological distress pose a significant public health burden, particularly in low to middle income countries. Contemporaneous stress events in adulthood may also impact psychological distress. The aims of this study were to describe the prevalence of ACEs and psychological distress and to assess the separate and cumulative effect of ACEs on psychological distress, while accounting for the effect of adult stress. METHODS: In this cross-sectional study, we used retrospectively measured ACEs from a sample of 1223 young adults aged between 22 and 23 years (52% female) from the Birth to Twenty Plus Study. Psychological distress and adult life stress were measured with a six-month recall period. Hierarchical logistic regression was employed to assess the associations between the exposures and outcome. RESULTS: Nearly 90% of the sample reported at least one ACE and 28% reported psychological distress. The median number of ACEs reported was three (range 0-11). After accounting for demographic and socio-economic factors, all ACEs were individually associated with psychological distress except for parental divorce and unemployment. The individual ACEs increased the odds of PD by between 1.42 and 2.79 times. Compared to participants experiencing no ACEs, those experiencing one to five ACEs were three times more likely to report psychological distress (AOR 3.2 95% CI: 1.83 5.63), while participants who experienced six or more ACEs had nearly eight times greater odds of reporting psychological distress (AOR 7.98 95% CI: 4.28-14.91). Interaction analysis showed that in the absence of adult life stress, the effect of low ACEs compared to high ACEs on PD was not significantly different. DISCUSSION AND CONCLUSION: The prevalence of ACEs in this young adult population is high, similar to other studies in young adult populations. A significant direct association exists between ACEs and psychological distress. Adult life stress seems to be a mediator of this relationship. Interventions targeted at psychological distress should address both early life adversity and contemporary stress. PMID- 29976169 TI - Participant, peer and PEEP: considerations and strategies for involving people who have used illicit substances as assistants and advisors in research. AB - BACKGROUND: The Peer Engagement and Evaluation Project (PEEP) aimed to engage, inspire, and learn from peer leaders who represented voices of people who use or have used illicit substances, through active membership on the 'Peeps' research team. Given the lack of critical reflection in the literature about the process of engaging people who have used illicit substances in participatory and community-based research processes, we provide a detailed description of how one project, PEEP, engaged peers in a province-wide research project. METHODS: By applying the Peer Engagement Process Evaluation Framework, we critically analyze the intentions, strategies employed, and outcomes of the process utilized in the PEEP project and discuss the implications for capacity building and empowerment among the peer researchers. This process included: the formation of the PEEP team; capacity building; peer-facilitated data collection; collaborative data analysis; and, strengths-based approach to outputs. RESULTS: Several lessons were learned from applying the Peer Engagement Process Evaluation Framework to the PEEP process. These lessons fall into themes of: recruiting and hiring; fair compensation; role and project expectations; communication; connection and collaboration; mentorship; and peer-facilitated research. CONCLUSION: This project offers a unique approach to engaging people who use illicit substances and demonstrates how participation is an important endeavor that improves the relevance, capacity, and quality of research. Lessons learned in this project can be applied to future community-based research with people who use illicit substances or other marginalized groups and/or participatory settings. PMID- 29976170 TI - Changes in (risk) behavior and HPV knowledge among Dutch girls eligible for HPV vaccination: an observational cohort study. AB - BACKGROUND: Implementation of human papillomavirus (HPV) vaccination raised concerns that vaccination could lead to riskier sexual behavior. This study explored how possible differences in sexual behavior and HPV knowledge developed over time between HPV-vaccinated and unvaccinated girls. METHODS: A random sample of 19,939 girls (16-17 year olds) eligible for the catch-up HPV vaccination campaign in the Netherlands was invited for a longitudinal study with questionnaires every 6 months over a two-year follow-up period. Possible differences over time between vaccinated and unvaccinated participants were studied using generalized equations estimation (GEE). RESULTS: A total of 2989 girls participated in round one, of which 1574 participated (52.7%) in the final 5th round. Vaccinated girls were more likely to live in more urban areas (OR 1.28, 95%CI 1.10-1.47) and to use alcohol (OR 1.46, 95%CI 1.24-1.70) and contraceptives (OR 1.69, 95%CI 1.45-1.97). Vaccinated and unvaccinated girls showed comparable knowledge on HPV, HPV vaccination, and transmission. Vaccinated girls were more likely to be sexually active (OR 1.19, 95%CI 1.02-1.39), and this difference increased over time (OR for interaction 1.06, 95%CI 1.00-1.12). However, they had a slightly lower number of lifetime sexual partners (mean difference - 0.20, 95%CI -0.41-0.00). Vaccinated girls were less likely to use a condom with a steady partner (aOR 0.71, 95%CI 0.56-0.89). However, the difference between vaccinated and unvaccinated girls with regard to condom use with casual or steady partner(s) did not significantly change over time. CONCLUSION: Overall, we did not find indications that vaccination influenced sexual behavior in girls during 2 years of follow-up. The few differences found may be related to existing disparities in the socio-demographic characteristics of the young population pointing to the importance and improvement of education with regard to safe sex practices. Our findings do not suggest that vaccination status is associated with changes in sexual risk behavior and thus it is unlikely that this might influence the effectiveness of the vaccination program. PMID- 29976171 TI - Group B streptococcus late-onset disease,contaminated breast milk and mothers persistently GBS negative: report of 3cases. AB - BACKGROUND: Human milk is fundamental for its nutritional properties and to protect newborns, but it is not sterile and can sometime transmit bacteria. Few anecdotal cases suggest that breast milk could be a possible source of group B Streptococcus (GBS) late onset disease, although the pathogenesis is not entirely understood. CASE PRESENTATION: We report 3 cases of GBS late onset disease in full-term newborns. Fresh breast milk cultures yielded GBS, but mothers of neonates had no signs of mastitis and remained persistently GBS negative at rectovaginal site. CONCLUSIONS: Breast milk containing group B Streptococcus can be a risk factor for late onset disease. The persistent negative maternal GBS status supports the assumption that newborns, colonised in the throat, could be the initial source of GBS, while the mammary gland could act as a GBS replication site. It is unclear whether a low bacterial load may represent only contamination rather than true milk infection. PMID- 29976172 TI - Validation of a high performance functional assay for individual radiosensitivity in pediatric oncology: a prospective cohort study (ARPEGE). AB - BACKGROUND: Approximately 900 children/adolescents are treated with radiotherapy (RT) every year in France. However, among the 80% of survivors, the cumulative incidence of long-term morbidity - including second malignancies - reach 73.4% thirty years after the cancer diagnosis. Identifying a priori the subjects at risk for RT sequelae is a major challenge of paediatric oncology. Individual radiosensitivity (IRS) of children/adolescents is unknown at this time, probably with large variability depending on the age when considering the changes in metabolic functions throughout growth. We previously retrospectively showed that unrepaired DNA double strand breaks (DSB) as well a delay in the nucleoshuttling of the pATM protein were common features to patients with RT toxicity. We aim to validate a high performance functional assay for IRS prospectively. METHODS/DESIGN: ARPEGE is a prospective open-label, non-randomized multicentre cohort study. We will prospectively recruit 222 children/adolescents who require RT as part of their routine care and follow them during 15 years. Prior RT we will collect blood and skin samples to raise a primary dermal fibroblast line to carry out in blind the IRS assay. As a primary objective, we will determine its discriminating ability to predict the occurrence of unusual early skin, mucous or hematological toxicity. The primary endpoint is the measurement of residual double-strand breaks 24 h after ex vivo radiation assessed with indirect immunofluorescence (gammaH2AX marker). Secondary endpoints include the determination of pATM foci at 10 min and 1 h (pATM marker) and micronuclei at 24 h. In parallel toxicity including second malignancies will be reported according to NCI-CTCAE v4.0 reference scale three months of the completion of RT then periodically during 15 years. Confusion factors such as irradiated volume, skin phototype, previous chemotherapy regimen, smoking, comorbities (diabetes, immunodeficiency, chronic inflammatory disease...) will be reported. DISCUSSION: ARPEGE would be the first study to document the distribution of IRS in the pediatric subpopulation. Screening hypersensitive patients would be a major step forward in the management of cancers, opening a way to personalized pediatric oncology. TRIAL REGISTRATION: ID-RCB number: 2015-A00975-44, ClinicalTrials.gov Identifier: NCT02827552 Registered 7/6/2016. PMID- 29976173 TI - Integrating use of point-of-care circulating cathodic antigen rapid diagnostic tests by community health workers during mass drug administration campaigns to improve uptake of praziquantel treatment among the adult population at Kome Island, North-Western Tanzania: a cluster randomized community trial. AB - BACKGROUND: The major drawback of the community-based mass drug administration (MDA) approach against schistosomiasis is that treatment is offered blindly without testing for the targeted infection. This partly contributes to the low treatment coverage. One approach to overcome this limitation is to introduce a diagnostic component in the treatment approach. This will improve drug uptake and compliance to treatment. This study is conducted to assess the feasibility and acceptability of integrating point-of-care Circulating Cathodic Antigen (POC-CCA) test to community-based directed MDA in improving treatment coverage and compliance with treatment among adults. METHODS: This is a randomized control community trial in which 30 clusters were randomly assigned to either an intervention or control arm to evaluate two interventions on treatment coverage and compliance with treatment. In each cluster, 150 adult participants were enrolled. Community Health Workers (CHW) in both arms were trained on all aspects of praziquantel (PZQ) distribution and management of mild side effects. In the intervention arm, CHWs had additional training on how to use POC-CCA to diagnose intestinal schistosomiasis. In the intervention arm, participants were tested using POC-CCA test for presence of intestinal schistosomiasis and treated based on test results, while in the control arm, participants were treated with PZQ without testing. The primary outcome measure was the proportion of participants provided with PZQ between the two arms and geographical clusters. Secondary outcomes were prevalence of S. mansoni infection based on the POC-CCA test conducted by CHWs, ability of CHWs to use the POC-CCA test accurately and safely and community acceptability of the POC-CCA test results from CHWs. Both quantitative and qualitative techniques have been used to collect data at study endpoint. DISCUSSION: The study will generate evidence on the importance of integrating a diagnostic component into the community directed MDA conducted by CHWs. Findings will generate discussion on the current MDA policy and practice in Tanzania. TRIAL REGISTRATION: PACTR201804003343404 (25/4/2018). PMID- 29976174 TI - The effectiveness of Dutch Cell Dogs in correctional facilities in the Netherlands: a study protocol of a quasi-experimental trial. AB - BACKGROUND: Many former inmates recidivate, resulting in high costs for societies worldwide. Evidence based treatment practices may not work in prisons, due to detainees' lacking motivation, impaired well-being, and an unsafe group environment. One attempt to improve social group climate and well-being is the use of Prison-based Animal Programs (PAP). Using a quasi-experimental design, the aim of the current study is to examine the effectiveness of one such PAP in the Netherlands: Dutch Cell Dogs (DCD). METHODS/DESIGN: Participants (N = 256) from 12 justice centers, including psychiatric, juvenile and adult facilities, will be recruited. Half of the sample (n = 128) will receive DCD training after voluntarily signing up (intervention group); The other half (n = 128) will be recruited to participate in the research and receive treatment-as-usual (TAU/Ccomparison group). Factors related to psychosocial functioning (e.g., self esteem, empathy, self-control, life satisfaction, attention) and general therapeutic factors (i.e., therapeutic alliance, treatment motivation), expected to contribute to treatment success, will be assessed to measure the effectiveness of DCD. In addition, behavioral problems will be measured as well as recidivism rates. Questionnaires and neuropsychological tests will be employed to measure aforementioned outcome variables. Moreover, physiological data, based on heart rate and cortisol measures, will be collected to provide insight into the functioning of participants' physiological stress response and to determine whether stress reduction occurs over time. Multimethod data collection will occur at pre-training (T1), at 1-month (halfway training/T2), at 2-months (end training/T3), and 6-months after the end of the training (follow up/T4). DISCUSSION: This is the first study to examine the effectiveness of a widely implemented PAP in the Netherlands. Challenges associated with conducting the proposed study are typical for practice based research in correctional settings (e.g., a demanding workload of staff, lack of motivation to participate in research). Study results on the effects of a PAP will have an impact on inmates, justice centers, and municipalities across the Netherlands. TRIAL REGISTRATION: Retrospectively registered. The Netherlands National Trial Register TC = 6894 . PMID- 29976175 TI - Epidemiology and clinical characteristics of acute respiratory tract infections among hospitalized infants and young children in Chengdu, West China, 2009-2014. AB - BACKGROUND: Acute respiratory infection (ARI) is the leading cause of morbidity and mortality in pediatric patients worldwide and imposes an intense pressure on health care facilities. Data on the epidemiology profiles of ARIs are scarce in the western and rural areas of China. The purpose of the current study is to provide data on the presence of potential pathogens of ARIs in hospitalized children in Chengdu, west China. METHODS: Respiratory specimens were obtained from hospitalized patients (under 6 years old) with ARIs in a local hospital in Chengdu. Eight respiratory viruses were identified by PCR and 6 respiratory bacteria by biochemical reactions and Analytical Profile Index (API). Pathogens profiles, clinical characteristics and seasonality were analyzed. RESULTS: Fifty one percent of patients were identified with at least one respiratory pathogen. Human rhinovirus (HRV) (23%), Respiratory syncytial virus (RSV) (22.7%) was the most commonly identified viruses, with Klebsiella pneumoniae (11.5%) the most commonly identified bacterium in the study. The presences of more than one pathogen were found, and multiple viral, bacterial, viral/bacterial combinations were identified in 14.9, 3.3 and 13.9% of patients respectively. Respiratory viruses were identified throughout the year with a seasonal peak in December February. Pathogens profiles and clinical associations were different between infants (< 1 year of age) and older children (> 1 year of age). Infants with ARIs were more likely to have one or more viruses than older children. Infants identified with multiple pathogens had significantly higher proportions of tachypnea than infants that were not. CONCLUSIONS: This study demonstrated that viral agents were frequently found in hospitalized children with ARI in Chengdu during the study period. This study gives us better information on the pathogen profiles, clinical associations, co-infection combinations and seasonal features of ARIs in hospitalized children, which is important for diagnoses and treatment of ARIs, as well as implementation of vaccines in this area. Moreover, future efforts in reducing the impact of ARIs will depend on programs in which available vaccines, especially vaccines on RSV, HRV and S. pneumoniae could be employed in this region and new vaccines could be developed against common pathogens. PMID- 29976176 TI - Generalized arterial calcification of infancy with a novel ENPP1 mutation: a case report. AB - BACKGROUND: Generalized Arterial Calcification of Infancy (GACI) is a heritable ectopic mineralization disorder resulting in diffuse arterial calcifications and/or stenosis, mostly caused by mutations in the ENPP1 gene. Here we present a case report of GACI in a male infant with a new familial mutation of the ENPP1 gene and the clinical outcome after biphosphonates therapy. CASE PRESENTATION: The clinical presentation was characterized by a severe early-onset of hypertension refractory to multiple therapy. To investigate this atypical hypertension, a renal Doppler ultra-sonography was performed and diffuse echo bright arteries were detected; then a low-dose whole-body computed tomography demonstrated extensive arterial calcifications, suggesting GACI. A novel homozygous mutation c.784A > G (p.Ser262Gly) was detected in the ENPP1 gene. The infant was administered four courses of bisphosphonates: arterial calcifications were found to decrease but severe refractory hypertension was persistent. Although GACI can be a rapidly fatal illness and frequently results in death in infancy, the patient was 24 months of age at the time of writing this report. CONCLUSIONS: Three points of interest: the first one is to remind clinicians of this rare and atypical etiology in neonates with severe hypertension and in fetuses with cardiomyopathy and non-immune hydrops fetalis. The second point is the identification of a novel mutation in the ENPP1 gene associated with a clinical presentation of GACI. The third point is the fairly favourable outcome of our patient after bisphosphonates therapy, with calcifications regression but not hypertension. PMID- 29976177 TI - The prevalence, burden and risk factors associated with bronchial asthma in commonwealth of independent states countries (Ukraine, Kazakhstan and Azerbaijan): results of the CORE study. AB - BACKGROUND: In the Commonwealth of Independent States (CIS) countries epidemiology of Bronchial Asthma (BA) is poorly characterized. The objective of this analysis is to present the prevalence, burden and risk factors associated with BA in the CIS countries as part of the CORE study (Chronic Obstructive REspiratory diseases). METHODS: A total of 2842 adults (>=18 years) were recruited (964 in Kiev, Ukraine, 945 in Almaty, Kazakhstan, and 933 in Baku, Azerbaijan) in 2013-2015 during household visits. A two-step cluster random sampling strategy was used. All respondents were interviewed about respiratory symptoms, smoking, medical history. Two definitions were used: (i) "doctor diagnosed asthma" when the respondent reported that he/she had ever been diagnosed with BA by a doctor, (ii) "wheezing symptoms" (when the respondent reported wheezing at the ATS Respiratory Symptoms Questionnaire during the study) using GINA (2012) recommendations. Chi-square tests were used to assess differences in proportions. Binary logistic regression was used to estimate odds ratios (OR) and 95% CI for association between risk factors and BA. RESULTS: Prevalence of "doctor diagnosed asthma" was 12.5, 19.0 and 26.8 per 1000 persons, and prevalence of "wheezing symptoms" was 74.4, 254.8 and 123.4 per 1000 in Ukraine, Kazakhstan, and Azerbaijan, respectively. Statistically significant relationship with "wheezing symptoms" was shown for smoking (OR 1.99 (CI 1.22 3.27) in Ukraine, 2.08 (CI 1.54-2.81) in Kazakhstan, 8.01 (CI 5.24-12.24) in Azerbaijan); overweight/obesity (OR: 1.66 (CI 1.02-2.72); 1.94 (CI 1.44-2.62); 1.77 (CI 1.18-2.68), respectively) and dusty work (OR: 3.29 (CI 1.57-6.89); 1.68 (CI 1.18-2.39); 2.36 (CI 1.56-3.59), respectively), and for tuberculosis in Azerbaijan (OR: 10.11 (CI 3.44-29.69)). Co-morbidities like hypertension, cardiovascular diseases, abnormal blood lipids and a history of pneumonia occurred significantly (p < 0.05) more frequently in respondents with BA compared to those without BA across all participating countries. CONCLUSION: In CIS countries (Ukraine, Kazakhstan and Azerbaijan) the prevalence of doctor diagnosed asthma was significantly lower compared to prevalence of wheezing symptoms underlining that BA is likely to be underreported in these countries. The information provided in this paper will be helpful for healthcare policy makers in CIS countries to instruct BA management strategies and to allocate healthcare resources accordingly. PMID- 29976178 TI - Study protocol of the RaPS study: novel risk adapted prevention strategies for people with a family history of colorectal cancer. AB - BACKGROUND: People aged 40-60 years with a family history (FH) of colorectal cancer (CRC) in 1st degree relatives (FDRs) have a 2- to 4-fold increased risk of CRC compared to the average risk population. Therefore, experts recommend starting CRC screening earlier for this high-risk group. However, information on prevalence of relevant colonoscopic findings in this group is sparse, and no risk adapted screening offers are implemented in the German health care system. For example, screening colonoscopy is uniformly offered from age 55 on, regardless of family history. Thus, we initiated a multicenter epidemiological study - the RaPS study (Risk adapted prevention strategies for colorectal cancer) - with the following aims: to determine the prevalence of having a FH of CRC in FDR in the German population aged 40-54 years; to investigate the prevalence of colorectal neoplasms among people with a FDR; and to develop risk-adapted prevention strategies for this high-risk group based on the collected information. METHODS/DESIGN: A random sample of 160.000 persons from the general population aged 40-54 years from the catchment areas of three study centers in Germany (Dresden, Munich and Stuttgart) are contacted to assess FH of CRC by an online questionnaire. Those with a FH of CRC in FDRs are invited to the study centers for individual consultation regarding CRC prevention. Participants are asked to donate blood and stool samples and medical records of colonoscopies will be obtained. Prevalence of CRC and its precursors will be evaluated. Furthermore, genetic, epigenetic and proteomic biomarkers in blood and microbiomic biomarkers in stool will be investigated. Risk markers and their eligibility for risk adapted screening offers will be examined. DISCUSSION: This study will provide data on the prevalence of colorectal neoplasms among persons with a FH of CRC in the age group 40-54 years, which will enable us to derive evidence based screening strategies for this high-risk group. TRIAL REGISTRATION: This trial was registered retrospectively in the German Clinical Trials Register (DRKS) on 29th of December 2016: German Clinical Trials Register DRKS-ID: DRKS00007842 . PMID- 29976179 TI - CDC42 controls the activation of primordial follicles by regulating PI3K signaling in mouse oocytes. AB - BACKGROUND: In mammalian females, progressive activation of dormant primordial follicles in adulthood is crucial for the maintenance of the reproductive lifespan. Misregulated activation of primordial follicles leads to various ovarian diseases, such as premature ovarian insufficiency (POI). Although recent studies have revealed that several functional genes and pathways, such as phosphoinositide 3-kinase (PI3K) signaling, play roles in controlling the activation of primordial follicles, our understanding of the molecular networks regulating the activation progress is still incomplete. RESULTS: Here, we identify a new role for cell division cycle 42 (CDC42) in regulating the activation of primordial follicles in mice. Our results show that CDC42 expression increases in oocytes during the activation of primordial follicles in the ovary. Disruption of CDC42 activity with specific inhibitors or knockdown of Cdc42 expression significantly suppresses primordial follicle activation in cultured mouse ovaries. Conversely, the follicle activation ratio is remarkably increased by overexpression of CDC42 in ovaries. We further demonstrate that CDC42 governs the process of primordial follicle activation by binding to phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (p110beta) and regulating the expression levels of PTEN in oocytes. Finally, we extend our study to potential clinical applications and show that a short-term in vitro treatment with CDC42 activators could significantly increase the activation rates of primordial follicles in both neonatal and adult mouse ovaries. CONCLUSION: Our results reveal that CDC42 controls the activation of primordial follicles in the mammalian ovary and that increasing the activity of CDC42 with specific activators might improve the efficiency of in vitro activation approaches, opening avenues for infertility treatments. PMID- 29976180 TI - Promoting quality use of medicines in South-East Asia: reports from country situational analyses. AB - BACKGROUND: Irrational use of medicines is widespread in the South-East Asia Region (SEAR), where policy implementation to encourage quality use of medicines (QUM) is often low. The aim was to determine whether public-sector QUM is better in SEAR countries implementing essential medicines (EM) policies than in those not implementing them. METHODS: Data on six QUM indicators and 25 EM policies were extracted from situational analysis reports of 20 country (2-week) visits made during 2010-2015. The average difference (as percent) for the QUM indicators between countries implementing versus not implementing specific policies was calculated. Policies associated with better (> 1%) QUM were included in regression of a composite QUM score versus total number of policies implemented. RESULTS: Twenty-two policies were associated with better (> 1%) QUM. Twelve policies were associated with 3.6-9.5% significantly better use (p < 0.05), namely: standard treatment guidelines; formulary; a government unit to promote QUM; continuing health worker education on prescribing by government; limiting over-the-counter (OTC) availability of systemic antibiotics; disallowing public sector prescriber revenue from medicines sales; not charging fees at the point of care; monitoring advertisements of OTC medicines; public education on QUM; and a good drug supply system. There was significant correlation between the number of policies implemented out of 22 and the composite QUM score (r = 0.71, r2 = 0.50, p < 0.05). CONCLUSIONS: Country situational analyses allowed rapid data collection that showed EM policies are associated with better QUM. SEAR countries should implement all such policies. PMID- 29976181 TI - Involving the employer to enhance return to work among patients with stress related mental disorders - study protocol of a cluster randomized controlled trial in Swedish primary health care. AB - BACKGROUND: Work-related stress has become a major challenge for social security and health care systems, employers and employees across Europe. In Sweden, sickness absence particularly due to stress-related disorders has increased excessively in recent years, and the issue of how to improve sustainable return to work in affected employees is high up on the political agenda. The literature on interventions for return to work in patients with common mental disorders is still inconclusive. This randomized controlled trial (RCT) aims to contribute with knowledge about how physicians and rehabilitation coordinators in primary health care can involve the employer in the rehabilitation of patients with stress-related disorders. The objective is to evaluate whether the early involvement of the patient's employer can reduce the time for return to work compared to treatment as usual. A process study will complete the RCT with information about what prerequisites primary health caregivers need to succeed with this endeavor. METHODS: Twenty-two primary care centers were randomized to either intervention or control group. At the intervention centers, physicians and rehabilitation coordinators underwent training, providing them with both knowledge and practical tools to involve the employer in rehabilitation. At the patient level, employed patients with an ICD-10 F43 diagnosis were eligible for participation (n=132). Difference in proportion of patients on full- or part-time sick leave at three, six and 12 months after inclusion will be investigated. Register data, logbooks and interviews with coordinators and physicians at both intervention and control centers will be used for process evaluation. DISCUSSION: Although the issue of how to tackle work-related stress can be recognized all across Europe, Sweden face an urgent need to curb the disproportional increase of stress-related disorders in the sick-leave statistics. Since physicians are limited by time constraints, the rehabilitation coordinator may be a helpful resource to take this contact. The current study will contribute to knowledge about how this collaboration can be organized to facilitate employer involvement and reduce time to return to work among patients suffering from work related stress. TRIAL REGISTRATION: Registered on 1 November 2016, ClinicalTrials.gov, NCT03022760 . PMID- 29976182 TI - Participatory action research to identify a package of interventions to promote postpartum family planning in Burkina Faso and the Democratic Republic of Congo. AB - BACKGROUND: The YAM DAABO study ("your choice" in Moore) takes place in Burkina Faso and the Democratic Republic of Congo. It has the objective to identify a package of postpartum family planning (PPFP) interventions to strengthen primary healthcare services and determine its effectiveness on contraceptive uptake during the first year postpartum. This article presents the process of identifying the PPFP interventions and its detailed contents. METHODS: Based on participatory action research principles, we adopted an inclusive process with two complementary approaches: a bottom-up formative approach and a circular reflective approach, both of which involved a wide range of stakeholders. For the bottom-up component, we worked in each country in three formative sites and used qualitative methods to identify barriers and catalysts to PPFP uptake. The results informed the package design which occurred during the circular reflective approach - a research workshop gathering service providers, members of both country research teams, and the WHO coordination team. RESULTS: As barriers and catalysts were found to be similar in both countries and with the view to scaling up our strategy to other comparable settings, we identified a common package of six low-cost, low-technology, and easily-scalable interventions that addressed the main service delivery obstacles related to PPFP: (1) refresher training of service providers, (2) regularly scheduled and strengthened supportive supervision of service providers, (3) enhanced availability of services 7 days a week, (4) a counseling tool, (5) appointment cards for women, and (6) invitation letters for partners. CONCLUSIONS: Our research strategy assumes that postpartum contraceptive uptake can be increased by supporting providers, enhancing the availability of services, and engaging women and their partners. The package does not promote any modern contraceptive method over another but prioritizes the importance of women's right to information and choice regarding postpartum fertility options. The effectiveness of the package will be studied in the experimental phase. If found to be effective, this intervention package may be relevant to and scalable in other parts of Burkina Faso and the DRC, and possibly other Sub-Saharan countries. TRIAL REGISTRATION: Retrospectively registered in the Pan African Clinical Trials Registry ( PACTR201609001784334 , 27 September 2016). PMID- 29976183 TI - Papillary thyroid carcinoma with pleomorphic tumor giant cells in a pregnant woman - a case report. AB - BACKGROUND: Papillary thyroid carcinoma with pleomorphic tumor giant cells (PTC PC) is characterized by the occurrence of bizarre, pleomorphic cells within a small area of a conventional PTC. The histologic distinction between PTC-PC and PTC's with a focal anaplastic thyroid cancer (ATC) component (denoted in the 2004 WHO classification as "papillary thyroid carcinoma with spindle and giant cell carcinoma", PTC-SGC) is debated, however the prognosis is thought to be different (excellent for PTC-PC, poor for PTC-SGC). Therefore, this diagnostic challenge is significant for any endocrine pathologist to recognize. Herein, we report the histological and clinical workup of a PTC-PC case, with particular focus on the molecular analyses that facilitated the establishment of the final diagnosis. CASE PRESENTATION: The patient was a pregnant, 28-year-old female presenting with a 30 mm conventional PTC, with focal areas with undifferentiated cells exhibiting exaggerated nuclear pleomorphism. No foci of extrathyroidal extension, angioinvasion or lymph node engagement were seen. Immunohistochemical analyses revealed the pleomorphic cells exhibiting retained differentiation. Molecular genetic analyses demonstrated a codon V600 missense mutation of the BRAF gene, but no TP53 or TERT promoter mutations. The absence of an aggressive phenotype in addition to the lack of mutations in two major ATC-related genes led to the diagnosis of a PTC-PC. Postoperative MRI showed no evidence of metastatic disease. Radioiodine ablation was performed seven months post-operatively, and a SPECT-CT imaging did not show signs of residual tissue. She is well and without signs of disease 16 months post-operatively. CONCLUSIONS: PTC-PC is a differential diagnosis to PTC-SGC that mandates careful considerations. Taken together with previous publications, PTC-PC seems to be histologically similar to PTC-SGC, but clinically distinct. Even so, the distinction is not easily made given the different therapeutic consequences for each individual patient. This is the first report that includes molecular genetics to aid in finalizing the diagnosis. Exclusion of mutations in TP53 and the TERT promoter could be considered as an adjunct tool when assessing papillary thyroid cancer with focal pleomorphism. PMID- 29976184 TI - Youth at-risk for serious mental illness: methods of the PROCAN study. AB - BACKGROUND: Most mental disorders begin in adolescence; however, there are gaps in our understanding of youth mental health. Clinical and policy gaps arise from our current inability to predict, from amongst all youth who experience mild behavioural disturbances, who will go on to develop a mental illness, what that illness will be, and what can be done to change its course and prevent its worsening to a serious mental illness (SMI). There are also gaps in our understanding of how known risk factors set off neurobiological changes that may play a role in determining who will develop a SMI. Project goals are (i) to identify youth at different stages of risk of SMI so that intervention can begin as soon as possible and (ii) to understand the triggers of these mental illnesses. METHOD: This 2-site longitudinal study will recruit 240 youth, ages 12 25, who are at different stages of risk for developing a SMI. The sample includes (a) healthy individuals, (b) symptom-free individuals who have a first-degree relative with a SMI, (c) youth who are experiencing distress and may have mild symptoms of anxiety or depression, and (d) youth who are already demonstrating attenuated symptoms of SMI such as bipolar disorder or psychosis. We will assess, every 6 months for one year, a wide range of clinical and psychosocial factors to determine which factors can be used to predict key outcomes. We will also assess neuroimaging and peripheral markers. We will develop and validate a prediction algorithm that includes demographic, clinical and psychosocial predictors. We will also determine if adding biological markers to our algorithm improves prediction. DISCUSSION: Outcomes from this study include an improved clinical staging model for SMI and prediction algorithms that can be used by health care providers as decision-support tools in their practices. Secondly, we may have a greater understanding of clinical, social and cognitive factors associated with the clinical stages of development of a SMI, as well as new insights from neuroimaging and later neurochemical biomarker studies regarding predisposition to SMI development and progression through the clinical stages of illness. PMID- 29976185 TI - Preparedness and response against diseases with epidemic potential in the European Union: a qualitative case study of Middle East Respiratory Syndrome (MERS) and poliomyelitis in five member states. AB - BACKGROUND: EU Decision 1082/2013/EU on serious cross-border health threats provides a legal basis for collaboration between EU Member States, and between international and European level institutions on preparedness, prevention, and mitigation in the event of a public health emergency. The Decision provides a context for the present study, which aims to identify good practices and lessons learned in preparedness and response to Middle East Respiratory Syndrome (MERS) (in UK, Greece, and Spain) and poliomyelitis (in Poland and Cyprus). METHODS: Based on a documentary review, followed by five week-long country visits involving a total of 61 interviews and group discussions with experts from both the health and non-health sectors, this qualitative case study has investigated six issues related to preparedness and response to MERS and poliomyelitis: national plans and overall preparedness capacity; training and exercises; risk communication; linking policy and implementation; interoperability between the health and non-health sectors; and cross-border collaboration. RESULTS: Preparedness and response plans for MERS and poliomyelitis were in place in the participating countries, with a high level of technical expertise available to implement them. Nevertheless, formal evaluation of the responses to previous public health emergencies have sometimes been limited, so lessons learned may not be reflected in updated plans, thereby risking mistakes being repeated in future. The nature and extent of inter-sectoral collaboration varied according to the sectors involved, with those sectors that have traditionally had good collaboration (e.g. animal health and food safety), as well as those that have a financial incentive for controlling infectious diseases (e.g. agriculture, tourism, and air travel) seen as most likely to have integrated public health preparedness and response plans. Although the formal protocols for inter-sectoral collaboration were not always up to date, good personal relations were reported within the relevant professional networks, which could be brought into play in the event of a public health emergency. Cross-border collaboration was greatly facilitated if the neighbouring country was a fellow EU Member State. CONCLUSIONS: Infectious disease outbreaks remain as an ongoing threat. Efforts are required to ensure that core public health capacities for the full range of preparedness and response activities are sustained. PMID- 29976186 TI - Quality of health care in adolescents and adults with disorders/differences of sex development (DSD) in six European countries (dsd-LIFE). AB - BACKGROUND: To investigate the association between the structural quality of care and patient satisfaction with care in individuals with disorders/ differences of sex development (DSD). METHODS: A multicenter cross-sectional comparative study was conducted in 14 clinics in six European countries. We assessed the level of structural quality of care in each center using a self-constructed measure (Center Score) and the level of participant satisfaction with care using the customer satisfaction questionnaire (CSQ-4) and an adopted version of the Youth Health Care - Satisfaction, Utilization & Needs (YHC-SUN-SF). Data were obtained from individuals with Turner Syndrome (261), Klinefelter Syndrome (173), 46, XX congenital adrenal hyperplasia (190) and XY-DSD (257). RESULTS: We found large variations between the scores for structural quality of care both within a diagnostic group and within a country; the overall association between participant satisfaction with the center score was significant. CONCLUSIONS: Comparative effectiveness research across Europe can lead to more insight on beneficial structures and processes and the overall strategy to care for people with rare diseases in general and specific conditions such as disorders/ differences of sex development. Appreciation of higher levels of structural quality of the centers in this study supports the concept of comprehensive care. TRIAL REGISTRATION: German Clinical Trials Register: Registration identification number: DRKS00006072 , date of registration April 17th, 2014. DRKS00006072 (German Clinical Trials Register). PMID- 29976187 TI - Phenolic profile, anti-inflammatory, antinociceptive, anti-ulcerogenic and hepatoprotective activities of Pimenta racemosa leaves. AB - BACKGROUND: Pimenta racemosa tree has many traditional uses where its leaves are used as herbal tea for treatment of flatulence, gastric disorder, osteoarthritis, colds and fever in addition to its analgesic and anti-inflammatory activities. So, this study aimed to isolate phenolic constituents of 80% aqueous methanol extract (AME) of leaves and evaluate its biological activities. METHODS: The defatted AME was chromatographed and structures of the isolated compounds were elucidated using UV, NMR spectroscopy and UPLC-ESI-MS analysis. Antioxidant activity was investigated using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity. Anti-inflammatory activity was evaluated using carrageenan - induced paw oedema, while antinociceptive activity was determined by chemical and thermal stimuli. Anti-ulcerogenic effect of AME against gastric damage induced by ethanol in Wister male albino rats was evaluated. Also, hepatoprotective activity was investigated through determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) following oral administration of paracetamol. Both of Anti-ulcerogenic and hepatoprotective activities (125, 250 and 500 mg/kg b.wt.) were supported by histopathological examinations. RESULTS: Gallic acid (1), methyl gallate (2), avicularin (3), quercetin 3-O-beta-D-arbinopyranoside (4), quercetin 3-O-beta-D-glucopyranoside (5), quercetrin (6), cynaroside (7), strictinin (8), castalagin (9), grandinin (10) quercetin (11) and ellagic acid (12) were isolated. AME showed significant radical scavenging activity (SC50 = 4.6 MUg/mL), promising anti-inflammatory effect through inhibition of oedema and antinociceptive activity by reduction in number of writhes after acetic acid injection and prolongation of reaction time towards the thermal stimulus. AME reduced the gastric mucosal lesions compared with ethanol control and ranitidine groups, ALT at the three doses and AST only at 125 and 250 mg/kg b.wt., when compared with paracetamol group. The results were confirmed by histopathological studies. CONCLUSION: P. racemosa leaves are rich in phenolic compounds and showed significant biological activities. PMID- 29976188 TI - Impact of a structured yoga program on blood pressure reduction among hypertensive patients: study protocol for a pragmatic randomized multicenter trial in primary health care settings in Nepal. AB - BACKGROUND: Hypertension control remains a major global challenge. The behavioral approaches recommended for blood pressure reduction are stress reduction, increased exercise and healthy dietary habits. Some study findings suggest that yoga has a beneficial effect in reducing blood pressure. However, the role of yoga on blood pressure has received little attention in existing health care practices in developing countries. This study will be conducted in primary health care facilities in Nepal to assess the effectiveness of a pragmatic yoga intervention to complement standard practice in further reducing blood pressure. METHODS: This will be multicentric, two arms, randomized, nonblinded, pragmatic trial. It will be conducted in seven District Ayurveda Health Centers (DAHCs) in Nepal between July 2017 and June 2018. The study participants will consist of hypertensive patients with or without antihypertensive medication attending to the outpatient department (OPD). One hundred and forty participants will be randomized to treatment or control groups by using a stratified block randomization. At the study site, the treatment arm participants will receive an intervention consisting of five days of structured yoga training and practice of the same package at home with a recommendation of five days a week for the following 90 days. Both the intervention and control groups will receive two hours of health education on lifestyle modifications. The primary outcome of this trial will be the change in systolic blood pressure and it will be assessed after 90 days of the intervention. DISCUSSION: This study will establish the extent to which a yoga intervention package can help reduce blood pressure in hypertensive patients. If proven effective, study findings may be used to recommend the governing bodies and other stakeholders for the integration of yoga in the national healthcare system for the treatment and control of hypertension. TRIAL REGISTRATION: Clinical Trial Registry- India (CTRI); CTRI Reg. No- CTRI/2017/02/007822 . Registered on 10/02/2017. PMID- 29976189 TI - New recommendation and coverage of low-dose computed tomography for lung cancer screening: uptake has increased but is still low. AB - BACKGROUND: In 2013, the US Preventive Services Task Force (USPSTF) issued recommendations for low-dose computed tomography for lung cancer screening (LDCT LCS), but there continues to be a dearth of information on the adoption of LDCT LCS in healthcare systems. Using a multilevel perspective, our study aims to assess referrals for LDCT-LCS and identify facilitators and barriers to adoption following recent policy changes. METHODS: A retrospective analysis of electronic medical record data from patients aged 55-80 years with no history of lung cancer who visited a primary care provider in a large healthcare system in California during 2010-2016 (1,572,538 patient years). Trends in documentation of smoking history, number of eligible patients, and lung cancer screening orders were assessed. Using Hierarchical Generalized Linear Models, we also evaluated provider-level and patient-level factors associated with lung cancer screening orders among 970 primary care providers and 12,801 eligible patients according to USPSTF guidelines between January 1st, 2014 and December 31st, 2016. RESULTS: Documentation of smoking history to determine eligibility (59.2% in 2010 to 77.8% in 2016) and LDCT-LCS orders (0% in 2010 to 7.3% in 2016) have increased since USPSTF guidelines. Patient factors associated with increased likelihood of lung cancer screening orders include: younger patient age (78-80 vs. 55-64 years old: OR, 0.4; 95% CI, 0.3-0.7), Asian race (vs. Non-Hispanic White: OR, 1.6; 95% CI, 1.1-2.4), reported current smoking (vs. former smoker: OR, 1.7; 95% CI, 1.4-2.0), no severe comorbidity (severe vs. no major comorbidity: OR = 0.2, 95% CI = 0.1 0.3; moderate vs. no major comorbidity: OR = 0.5; 95% CI = 0.4-0.7), and making a visit to own primary care provider (vs. other primary care providers: OR, 2.4; 95% CI, 1.7-3.4). Appropriate referral for lung cancer screening varies considerably across primary care providers. Provider factors include being a female physician (vs. male: OR, 1.6; 95% CI, 1.1-2.3) and receiving medical training in the US (foreign vs. US medical school graduates: OR = 0.4, 95% CI = 0.3-0.7). CONCLUSIONS: Future interventions to improve lung cancer screening may be more effective if they focus on accurate documentation of smoking history and target former smokers who do not regularly see their own primary care providers. PMID- 29976190 TI - Perceptions of traditional Chinese medicine for chronic disease care and prevention: a cross-sectional study of Chinese hospital-based health care professionals. AB - BACKGROUND: In China, demands for disease prevention and health care and the prevalence of chronic non-communicable diseases have increased. TCM and general hospitals are increasingly utilizing TCM strategies for chronic non-communicable disease care and prevention. This study aimed to investigate health care professionals' (HCPs') perceptions of TCM for prevention, their TCM knowledge, and their abilities to provide such services in TCM and general hospitals. METHODS: This cross-sectional study investigated Chinese medicine hospitals and Chinese medicine departments in general hospitals in five Chinese cities. A self designed questionnaire used to study 400 HCPs focused on basic demographic data, the demand for and effects of TCM for prevention and treatment, and their perceptions of such service implementation. The data analysis included chi squared tests and descriptive and multi-factor analyses. RESULTS: The 335 HCP respondents comprised 230 (68.7%) females and 105 (31.3%) males, 75.5% of whom overall had knowledge of TCM preventive and health care services. Respondents older than 40 years (28.6%) had greater knowledge of and satisfaction with TCM for preventive and health care services than younger respondents. Moreover, 97.7% of the older respondents were clearly willing to provide TCM preventive services for chronic diseases, 67.8% of whom indicated that their hospitals already provided TCM for prevention and treatment. According to the chi-squared test results, the TCM service characteristics in hospitals, hospital outlooks regarding TCM and TCM development in hospitals were the primary factors affecting the respondents' perceptions of TCM for chronic disease care and prevention. The multivariate analysis showed high satisfaction as significantly associated with older providers and those with lengthier work experience, particularly among those who worked in hospitals that provided typical TCM services and had positive attitudes towards TCM. CONCLUSION: The study HCPs had relatively satisfactory knowledge of and positive attitudes towards TCM for chronic disease care and prevention and would use it in practice. Their perceptions and satisfaction levels correlated closely with the successful application of TCM for preventive care and treatment in hospitals. While the use of TCM for prevention and treatment was well developed in some hospitals, further improvements are warranted. PMID- 29976192 TI - Normal serum alanine aminotransferase and non-alcoholic fatty liver disease among Korean adolescents: a cross-sectional study using data from KNHANES 2010-2015. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is complicated disease and increasing worldwide. Previously, many studies of NALFD prevalences have used alanine aminotransferase (ALT) of > 40 U/L to define NAFLD, although that is too high to be reliable among adolescents. This study aimed to define the upper normal limit of ALT among Korean adolescents, and use it to estimate the prevalence of NAFLD, based on data from the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: Data were obtained from 1785 healthy adolescents (916 boys and 869 girls, 10-18 years old) who participated in the KNHANES during 2010-2015. The International Diabetes Federation metabolic syndrome criteria for adolescents were used to exclude participants with metabolic syndrome components. Furthermore, participants who previously had diseases related to low HDL levels, high TG levels, diabetes, or very low/high body mass index and hepatitis B were excluded. The 95th percentiles level of ALT from healthy participants were evaluated. The definition of NAFLD was overweight status (>=85th percentile of body mass index) plus elevated ALT levels (95th percentile). RESULTS: The upper normal ALT were 24.1 U/L for boys and 17.7 U/L for girls. Based on these values, the estimated prevalences of NAFLD in 2015 were 8.9% among adolescents. CONCLUSION: Defining the upper normal limit of ALT can be adjusted for each sex and ethnics in the general population. ALT laboratory thresholds used for children should be re-examined. The physicians should be aware not to underdiagnose NAFLD patient even ALT level is < 40 U/L. PMID- 29976191 TI - "They can rest at home": an observational study of patients' quality of sleep in an Australian hospital. AB - BACKGROUND: Poor sleep is known to adversely affect hospital patients' recovery and rehabilitation. The aim of the study was to investigate the perceived duration and quality of patient sleep and identify any environmental factors associated with patient-reported poor sleep in hospital. METHOD: A cross sectional study was conducted involving 15 clinical units within a 672-bed tertiary-referral hospital in Australia. Semi-structured interviews to determine perceptions of sleep quantity and quality and factors that disturb nocturnal sleep were conducted with patients and nursing staff. Environmental noise, light and temperature were monitored overnight, with concurrent logging of noise sources by observers. RESULTS: Patients reported a mean reduction in hospital sleep duration, compared to home, of 1.8 h (5.3 vs. 7.1 h; p < 0.001). The proportions of patients reporting their sleep quality to be poor/very poor, fair and of good quality were 41.6, 34.2 and 24.2% respectively. Patients reported poorer sleep quality than nurses (p < 0.05). Patients, nurses and observers all reported the main factors associated with poor sleep as clinical care interventions (34.3%) and environmental noise (32.1%). Noise levels in all 15 clinical areas exceeded WHO recommended levels of < 30 dB [A] by 36.7 to 82.6%, with peak noise levels of 51.3 to 103.3 dB (A). CONCLUSION: Hospital in-patients are exposed to factors which reduce the duration and quality of their sleep. These extrinsic factors are potentially modifiable through behaviour change and reconfiguration of the clinical environment. The findings from this study provided the foundation for a quality improvement project currently underway to improve patients' sleep. PMID- 29976193 TI - A haven of green space: learning from a pilot pre-post evaluation of a school based social and therapeutic horticulture intervention with children. AB - BACKGROUND: Research suggests outdoor activity in green spaces is important for children's mental, emotional and social wellbeing. A recognised green space intervention is "Social and Therapeutic Horticulture" (STH). We discuss findings from a pilot STH intervention, "A Haven of Green Space" conducted in North West England. The target group were school children aged 9-15 years experiencing behavioural, emotional and social difficulties. This exploratory study aims to assess the mental wellbeing of the children pre- and post-intervention, and assess the value of the evaluation methods and "Five Ways to Wellbeing" evaluation framework. METHODS: The intervention involved 6 monthly sessions with two horticulturists and a psychotherapist. Sessions were participatory with the development of selected greenspaces at each school directed by the children. Evaluation was situated in the "Five Ways to Wellbeing" framework, using a mixed methods pre- post-evaluation design. Existing public mental health evaluation methodologies were adapted for use with school children: Mental Well Being Impact Assessment (MWIA) and Wellbeing Check Cards. The MWIA was analysed qualitatively identifying over-arching themes. The quantitative wellbeing check cards were analysed by mean score comparison. RESULTS: Results were collected from 36 children across the three participating schools, and suggest that the Haven Green Space intervention was associated with improved mental wellbeing. MWIA factors relating to mental wellbeing ("emotional wellbeing" and "self-help") were positively impacted in all three schools. However, findings from the wellbeing check cards challenge this, with worsening scores across many domains. CONCLUSIONS: A key study limitation is the pilot nature of the intervention and challenges in adapting evaluation methods to context and age-range. However, results indicate that group based socially interactive horticulture activities facilitated by trained therapists are associated with positive impacts upon the mental and emotional wellbeing of children experiencing behavioural, emotional and social difficulties. Further research is needed to verify this, and to support using the "Five Ways" in intervention development and evaluation. Finally, we recommend continued efforts to develop age-appropriate evaluation methods. PMID- 29976194 TI - Correction to: A systematic review of stakeholder views of selection methods for medical schools admission. AB - Following publication of the original article [1], the author report typographical errors in the. PMID- 29976195 TI - Fentanyl-contaminated drugs and non-fatal overdose among people who inject drugs in Baltimore, MD. AB - BACKGROUND: The opioid crisis remains a major public health issue in the US and beyond. Despite rapid rises in fentanyl-related mortality nationally, little is known about the role of fentanyl in the occurrence of non-fatal overdose among people who use drugs. We examined the prevalence of non-fatal overdose and perceived fentanyl exposure among syringe services program (SSP) clients and modeled the correlates of non-fatal overdose. METHODS: Data were drawn from a cross-sectional survey of 203 SSP clients in Baltimore, MD recruited in 2016. Logistic regression models were used to identify the correlates of experiencing non-fatal overdose in the past 12 months. RESULTS: The majority (65%) was male, 52% were black, 41% were white, and 37% were homeless. Almost all (97%) used heroin, 64% injected heroin with cocaine (i.e., speedball), and many used other types of drugs. Half (53%) perceived fentanyl presence in their drugs either half, most or all of the time. Lifetime and past 12 month prevalence of non-fatal overdose were 58 and 31%, respectively. Independent correlates of non-fatal overdose in the past 12 months were perceiving fentanyl in drugs more than half the time (aOR = 2.79; 95% CI = 1.00-4.68), speedball injection (aOR = 2.80, 95% CI = 1.26-6.23), non-prescription buprenorphine use (aOR = 6.37; 95% CI = 2.86 14.17), and homelessness (aOR = 3.07; 95% CI = 1.28-7.39). CONCLUSIONS: These data demonstrate that SSP clients are at high-risk of overdose, some of which is likely attributable to fentanyl exposure. Addressing the rising fentanyl epidemic will require comprehensive and innovative strategies that attend to drug use patterns and structural factors such as homelessness. PMID- 29976196 TI - Cancer prevalence in Pakistan: meta-analysis of various published studies to determine variation in cancer figures resulting from marked population heterogeneity in different parts of the country. AB - BACKGROUND: Pakistan's population is ethnically diverse with distinct ethnic groups inhabiting various parts of the country. Cancer statistics obtained from specific regions populated by distinct ethnic groups may vary considerably. There is no national cancer registry. To determine whether there are indeed significant statistical differences in cancer incidence and prevalence, data was recorded from different parts of Pakistan based on the ethnic composition of the population in those parts. METHODS: Ten papers (original articles) on cancer incidence and prevalence in Pakistan published in the last two decades were selected from PubMed and Google Scholar. Meta-analysis of findings of these studies was performed using Meta-analysis of Observational Studies in Epidemiology (MOOSE) checklist. chi2-based I2 test was used for evaluating heterogeneity and Forest plots were generated for calculating unadjusted prevalence estimates. Oral, gastric, prostate, breast, and colorectal cancers were selected for meta-analysis. I2 values of 75% or greater indicated high heterogeneity. RESULTS: All five types of cancer selected for meta-analysis (performed on studies carrying similar statistical weights) showed extremely high heterogeneity with I2 values of 99.7% for oral cancer, 98.6% for prostate cancer, 98.3% for gastric cancer, 99.8% for breast cancer, and 85.4% for colorectal cancer. p values for all cancers were highly statistically significant. CONCLUSIONS: Our findings show that the prevalence rates of different cancer types demonstrate marked variation in different studies depending on the place of origin of the study and dominant ethnic group in that region, and these variations are highly statistically significant. A national cancer registry needs to be established as soon as possible. PMID- 29976197 TI - Sex-specific effects of perinatal dioxin exposure on eating behavior in 3-year old Vietnamese children. AB - BACKGROUND: We previously reported that perinatal dioxin exposure increased autistic traits in children living in dioxin-contaminated areas of Vietnam. In the present study, we investigated the impact of dioxin exposure on children's eating behavior, which is often altered in those with developmental disorders. METHODS: A total of 185 mother-and-child pairs previously enrolled in a birth cohort in dioxin-contaminated areas participated in this survey, conducted when the children reached 3 years of age. Perinatal dioxin exposure levels in the children were estimated using dioxin levels in maternal breast milk after birth. Mothers were interviewed using the Children's Eating Behaviour Questionnaire (CEBQ). A multiple linear regression model was used to analyze the association between dioxin exposure and CEBQ scores, after controlling for covariates such as location, parity, maternal age, maternal education, maternal body mass index, family income, children's gestational age at delivery, and children's age at the time of the survey. A general linear model was used to analyze the effects of sex and dioxin exposure on CEBQ scores. RESULTS: There was no significant association between most dioxin congeners or toxic equivalencies of polychlorinated dibenzo-p dioxins/furans (TEQ-PCDDs/Fs) and CEBQ scores in boys, although significant associations between some eating behavior sub-scores and 1,2,3,4,6,7,8,9 octachlorodibenzofuran were observed. In girls, there was a significant inverse association between levels of TEQ-PCDFs and enjoyment of food scores and between levels of TEQ-PCDFs and TEQ-PCDDs/Fs and desire to drink scores. Two pentachlorodibenzofuran congeners and 1,2,3,6,7,8-hexachlorodibenzofuran were associated with a decreased enjoyment of food score, and seven PCDF congeners were associated with a decreased desire to drink score. The adjusted mean enjoyment of food score was significantly lower in children of both sexes exposed to high levels of TEQ-PCDFs. There was, however, a significant interaction between sex and TEQ-PCDF exposure in their effect on desire to drink scores, especially in girls. CONCLUSIONS: Perinatal exposure to dioxin can influence eating behavior in children and particularly in girls. A longer follow-up study would be required to assess whether emotional development that affects eating styles and behaviors is related to dioxin exposure. PMID- 29976198 TI - FlashFry: a fast and flexible tool for large-scale CRISPR target design. AB - BACKGROUND: Genome-wide knockout studies, noncoding deletion scans, and other large-scale studies require a simple and lightweight framework that can quickly discover and score thousands of candidate CRISPR guides targeting an arbitrary DNA sequence. While several CRISPR web applications exist, there is a need for a high-throughput tool to rapidly discover and process hundreds of thousands of CRISPR targets. RESULTS: Here, we introduce FlashFry, a fast and flexible command line tool for characterizing large numbers of CRISPR target sequences. With FlashFry, users can specify an unconstrained number of mismatches to putative off targets, richly annotate discovered sites, and tag potential guides with commonly used on-target and off-target scoring metrics. FlashFry runs at speeds comparable to commonly used genome-wide sequence aligners, and output is provided as an easy to-manipulate text file. CONCLUSIONS: FlashFry is a fast and convenient command line tool to discover and score CRISPR targets within large DNA sequences. PMID- 29976199 TI - Assessing Plasmodium falciparum transmission in mosquito-feeding assays using quantitative PCR. AB - BACKGROUND: Evaluating the efficacy of transmission-blocking interventions relies on mosquito-feeding assays, with transmission typically assessed by microscopic identification of oocysts in mosquito midguts; however, microscopy has limited throughput, sensitivity and specificity. Where low prevalence and intensity mosquito infections occur, as observed during controlled human malaria infection studies or natural transmission, a reliable method for detection and quantification of low-level midgut infection is required. Here, a semi-automated, Taqman quantitative PCR (qPCR) assay sufficiently sensitive to detect a single oocyst midgut infection is described. RESULTS: Extraction of genomic DNA from Anopheles stephensi midguts using a semi-automated extraction process was shown to have equivalent extraction efficiency to manual DNA extraction. An 18S Plasmodium falciparum qPCR assay was adapted for quantitative detection of P. falciparum midgut oocyst infection using synthetic DNA standards. The assay was validated for sensitivity and specificity, and the limit of detection was 0.7 genomes/uL (95% CI 0.4-1.6 genomes/uL). All microscopy-confirmed oocyst infected midgut samples were detected by qPCR, including all single-oocyst positive midguts. The genome number per oocyst was assessed 8-9 days after feeding assay using both qPCR and droplet digital PCR and was 3722 (IQR: 2951-5453) and 3490 (IQR: 2720-4182), respectively. CONCLUSIONS: This semi-automated qPCR method enables accurate detection of low-level P. falciparum oocyst infections in mosquito midguts, and may improve the sensitivity, specificity and throughput of assays used to evaluate candidate transmission-blocking interventions. PMID- 29976200 TI - ART manipulation after controlled ovarian stimulation may not increase the risk of abnormal expression and DNA methylation at some CpG sites of H19,IGF2 and SNRPN in foetuses: a pilot study. AB - BACKGROUND: To examine the effects of IVF, ICSI and FET, as well as in vitro culture, on the safety of offspring, this study was conducted from the perspective of genetic imprinting to investigate whether assisted reproductive technology would influence the parental and maternal imprinting genes. METHODS: Eighteen foetuses were collected from multifoetal reduction and divided into 6 groups: multifoetal reduction after IVF fresh transferred D3 embryos (n = 3), multifoetal reduction after IVF frozen transferred D3 embryos (n = 3), multifoetal reduction after IVF frozen transferred D5 embryos (n = 3), multifoetal reduction after ICSI fresh transferred D3 embryos (n = 3), multifoetal reduction after ICSI frozen transferred D3 embryos (n = 3), and multifoetal reduction after controlled ovarian hyperstimulation (COH) (n = 3). The imprinted genes H19, IGF2 and SNRPN were selected for analysis. The expression and DNA methylation at some CpG sites of H19, IGF2, and SNRPN were examined using real-time quantitative polymerase chain reaction (PCR) and pyrosequencing. RESULTS: There were no significant differences in the mRNA expression levels among the groups. The mean percentage of H19 methylation (eight CpG sites), IGF2 methylation (five CpG sites) and SNRPN methylation (nine CpG sites) did not differ significantly. CONCLUSIONS: The results suggest that ARTs after controlled ovarian stimulation (IVF, ICSI, cryopreservation and duration of in vitro culture) may not increase the risk of abnormal expression and DNA methylation at some CpG sites of H19, IGF2 and SNRPN in foetuses. Further study with strict design, expanded sample size and CpG sites is essential. PMID- 29976201 TI - Serum and thyroid tissue level of let-7b and their correlation with TRAb in Graves' disease. AB - BACKGROUND: Abnormal microRNAs (miRNAs) were reported to be involved in the mechanism of Graves' disease (GD). Dysregulated miRNAs may be overlapping in different cells and can be secreted to circulation. We chose miRNAs which were previously reported to be differentially expressed in peripheral blood mononuclear cells (PBMCs) in patients with GD with different disease stage, detected the expression of those miRNAs in serum, corroborated the findings in thyroid tissue, and validated the target gene in vitro to investigate the possible role of circulating miRNAs in GD. METHODS: A total of 54 individuals with untreated GD, 12 individuals with GD in remission and 14 disease-free controls were enrolled. The expression of miR-142-3p, miR-154-3p, miR-431-3p, miR 590-5p, and let-7b was detected in the serum. Ten thyroid tissue samples from patients with GD and six disease-free thyroid samples were used for further validation. The potential target genes were identified and validated in vitro. RESULTS: miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b were present in serum and two of them (miR-142-3p and let-7b) were significantly increased in serum of patients with untreated GD (for serum miR-142-3p, P = 0.033, for serum let-7b, P = 0.026) and gradually decreased to normal levels in patients with GD in remission. Correlation analysis showed that let-7b level was strongly correlated with TRAb level (r = 0.305, P = 0.001). let-7b directly inhibited promyelocytic leukemia zinc finger (PLZF) expression and increased the expression of TSHR in thyroid cells in vitro. Furthermore, let-7b levels in GD thyroid tissue were found to be inversely correlated with PLZF levels (r = - 0.849, P = 0.033). Decreased PLZF and increased TSHR was validated in thyroid tissue in patients with GD. CONCLUSIONS: The present study confirmed that a portion of miRNAs in PBMCs were also presented and differentially expressed in serum and thyroid tissue. Upregulated in all these three compartments, let-7b may be used as a disease biomarker and therapeutic targets in patients with GD. Circulating let-7b had a strong correlation with disease severity and let-7b may participate in the production of TRAb via targeting PLZF in patients with GD. PMID- 29976202 TI - The exon 19-deleted EGFR undergoes ubiquitylation-mediated endocytic degradation via dynamin activity-dependent and -independent mechanisms. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is closely implicated in cancer, and sequencing analyses have revealed a high mutation rate of EGFR in lung cancer. Recent advances have provided novel insights into the endocytic regulation of wild-type EGFR, but that of mutated EGFR remains elusive. In the present study, we aim to investigate the endocytic degradation of a frequently occurred exon 19-deleted mutant in lung cancer. METHODS: The EGF-induced endocytic degradation of EGFR was examined in a panel of lung cancer cells using immunoblotting. The subcellular distribution of internalized EGFR was investigated using immunofluorescence and confocal microscopy. The effects of dynamin were assessed using its small molecule inhibitors, while the influence of RTN3 was tested using shRNA-mediated knockdown. Finally the ubiquitylation status of EGFR mutant was studied using immunoprecipitation under steady state and tyrosine kinase inhibitor-treated conditions. RESULTS: EGF induced various rates of EGFR endocytic degradation in lung cancer cells. Interestingly, the exon 19 deletion mutant is constantly internalized and sorted to lysosome for degradation, and this process is independent of dynamin activity. EGF stimulation and HSP90 inhibition further enhance the endocytic degradation of the exon 19 deletion mutant, in a dynamin activity-dependent and -independent manner, respectively. Albeit with different modes of internalization, the uptake of the exon 19-deleted EGFR is mediated through receptor ubiquitylation. CONCLUSIONS: The internalized EGFR mutant is constantly routed through endosome to lysosome for degradation. The endocytosis of EGFR mutant occurs through both dynamin activity-dependent and -independent mechanisms. Our findings gain novel insights into the endocytic regulation of mutated EGFR and may have potential clinical implications. PMID- 29976203 TI - Pain as a risk factor for substance use: a qualitative study of people who use drugs in British Columbia, Canada. AB - BACKGROUND: People who use drugs have a significantly higher prevalence of chronic non-cancer pain compared to the general population, yet little is known about how various policy, economic, physical, and social environments may serve as risk or protective factors in the context of concurrent pain and substance use. Therefore, this study sought to explore perspectives, risks, and harms associated with pain among people who use drugs. METHODS: Thirteen focus group interviews were held across British Columbia, Canada, from July to September 2015. In total, 83 people who had lived experience with substance use participated in the study. Using an interpretive description approach, themes were conceptualized according to the Rhodes' Risk Environment and patient centered care frameworks. RESULTS: Participants described how their experiences with inadequately managed pain in various policy, economic, physical, and social environments reinforced marginalization, such as restrictive policies, economic vulnerability, lack of access to socio-physical support systems, stigma from health professionals, and denial of pain medication leading to risky self medication. Principles of patient-centered care were often not upheld, from a lack of recognition of patients as experts in understanding their unique pain needs and experiences, to an absence of shared power and decision-making, which often resulted in distrust of the patient-provider relationship. CONCLUSIONS: Various risk environments and non-patient-centered interactions may contribute to an array of health and social harms in the context of inadequately managed pain among people who use drugs. PMID- 29976204 TI - Trends of Plasmodium falciparum prevalence in two communities of Muheza district North-eastern Tanzania: correlation between parasite prevalence, malaria interventions and rainfall in the context of re-emergence of malaria after two decades of progressively declining transmission. AB - BACKGROUND: Although the recent decline of malaria burden in some African countries has been attributed to a scale-up of interventions, such as bed nets (insecticide-treated bed nets, ITNs/long-lasting insecticidal nets, LLINs), the contribution of other factors to these changes has not been rigorously assessed. This study assessed the trends of Plasmodium falciparum prevalence in Magoda (1992-2017) and Mpapayu (1998-2017) villages of Muheza district, North-eastern Tanzania, in relation to changes in the levels of different interventions and rainfall patterns. METHODS: Individuals aged 0-19 years were recruited in cross sectional surveys to determine the prevalence of P. falciparum infections in relation to different malaria interventions deployed, particularly bed nets and anti-malarial drugs. Trends and patterns of rainfall in Muheza for 35 years (from 1981 to 2016) were assessed to determine changes in the amount and pattern of rainfall and their possible impacts on P. falciparum prevalence besides of those ascribed to interventions. RESULTS: High prevalence (84-54%) was reported between 1992 and 2000 in Magoda, and 1998 and 2000 in Mpapayu, but it declined sharply from 2001 to 2004 (from 52.0 to 25.0%), followed by a progressive decline between 2008 and 2012 (to <= 7% in both villages). However, the prevalence increased significantly from 2013 to 2016 reaching >= 20.0% in 2016 (both villages), but declined in the two villages to <= 13% in 2017. Overall and age specific P. falciparum prevalence decreased in both villages over the years but with a peak prevalence shifting from children aged 5-9 years to those aged 10-19 years from 2008 onwards. Bed net coverage increased from < 4% in 1998 to > 98% in 2001 and was >= 85.0% in 2004 in both villages; followed by fluctuations with coverage ranging from 35.0 to <= 98% between 2008 and 2017. The 12-month weighted anomaly standardized precipitation index showed a marked rainfall deficit in 1990-1996 and 1999-2010 coinciding with declining prevalence and despite relatively high bed net coverage from 2000. From 1992, the risk of infection decreased steadily up to 2013 when the lowest risk was observed (RR = 0.07; 95% CI 0.06-0.08, P < 0.001), but it was significantly higher during periods with positive rainfall anomalies (RR = 2.79; 95% CI 2.23-3.50, P < 0.001). The risk was lower among individuals not owning bed nets compared to those with nets (RR = 1.35; 95% CI 1.22-1.49, P < 0.001). CONCLUSIONS: A decline in prevalence up to 2012 and resurgence thereafter was likely associated with changes in monthly rainfall, offset against changing malaria interventions. A sustained surveillance covering multiple factors needs to be undertaken and climate must be taken into consideration when relating control interventions to malaria prevalence. PMID- 29976205 TI - Socioeconomic disparities in abdominal obesity over the life course in China. AB - BACKGROUND: Abdominal obesity has become an important public health issue in China. Socioeconomic disparities are thought to be closely related to the prevalence of abdominal obesity. Exploring socioeconomic disparities in abdominal obesity over the life course in China could inform the design of new interventions to prevent and control abdominal obesity. METHODS: The China Health and Nutrition Survey (CHNS) was a prospective household-based study involving seven rounds of surveys between 1993 and 2011. Twenty three thousand, two hundred and forty-three individuals were followed up over an 18-year period. The mixed effects models with random intercepts were used to assess the effects on abdominal obesity. Six key socioeconomic indicators, with age and age-squared added to the models, were used to identify socioeconomic disparities in abdominal obesity over the adult life course. RESULTS: Prevalence of abdominal obesity increased non-linearly with age over the adult life course. Abdominal obesity was more prevalent in younger than older birth cohorts. Positive period effects on the prevalence of abdominal obesity were substantial from 1993 to 2011, and were stronger among males than females. Prevalence of abdominal obesity was higher among ethnic Han Chinese and among the married [coefficient (95% confidence intervals): 0.03(0.003, 0.057) and 0.035(0.022, 0.047), respectively], and was lower among males [coefficient (95% confidence intervals): - 0.065(- 0.075, 0.055)]. A higher-level of urbanization and higher household income increased the probability of abdominal obesity [coefficient (95% confidence intervals): 0.160(0.130, 0.191), 3.47E- 4 (2.23E- 4, 4.70E- 4), respectively], while individuals with more education were less likely to experience abdominal obesity [coefficient (95% confidence intervals): - 0.222 (- 0.289, - 0.155)] across adulthood. CONCLUSIONS: In China, abdominal obesity increased substantially in more recent cohorts. And people with lower educational attainment, with higher household income, or living in more urbanized communities may be the disadvantaged population of abdominal obesity over the adult life course. Effective interventions targeting the vulnerable population need to be developed. PMID- 29976206 TI - Review of the possible association between thyroid and breast carcinoma. AB - BACKGROUND: Thyroid and breast cancer are two of the malignant diseases with highest incidence in females. Based on clinical experience, breast and thyroid cancer often occur metachronously or synchronously. Therefore, thyroid and breast cancer might share some common etiological factors. The relationship between these diseases has attracted substantial attention, and because these two glands are both regulated by the hypothalamic-pituitary axis, such a relationship is not surprising. A study of this relationship will be useful for obtaining a better understanding of the mechanism by which these two malignancies co-occur. MAIN BODY: This study reviewed the progress in research on the roles of iodine intake, folate metabolism, obesity, gonadal hormones, and thyroid hormone in thyroid and breast cancer. These studies evaluating the etiological roles of these factors in linking breast and thyroid cancer might also improve our understanding and identify new therapeutic approaches, such as sodium/iodide symporter-mediated radioiodine therapy and thyroid-stimulating hormone receptor antagonists, for breast cancer. In addition, some specific treatments for each cancer, such as radiotherapy for breast cancer or radioactive iodine therapy for thyroid cancer, might be risk factors for secondary malignances, including breast and thyroid cancer. CONCLUSIONS: Studies of the precise relationship between the co occurrence of breast and thyroid cancer will certainly improve our understanding of the biological behaviors of these two malignancies and direct evidence-based clinical practice. PMID- 29976207 TI - Introduction of F446I mutation in the K13 propeller gene leads to increased ring survival rates in Plasmodium falciparum isolates. AB - BACKGROUND: Mutations in the Plasmodium falciparum k13 gene are associated with artemisinin (ART) resistance. However, it is unclear whether the F446I mutation, the most prevalent allele at the China-Myanmar border and north of Myanmar, is associated with ART resistance. Therefore, the aim of this study was to investigate the role of this mutation in ART resistance by generating transgenic parasites expressing the F446I mutant allele. METHODS: The transgenic parasites carrying the F446I or C580Y mutation in both 3D7 and FCC1/HN isolates were generated by single crossing-over recombination and verified using PCR and gene sequencing. The ring-stage survival assay of 0-3 h (RSA0-3 h) was used to evaluate ART susceptibility of the transgenic parasites in vitro. RESULTS: Four transgenic parasite lines named 3D7F446I mut, 3D7C580Y mut, FCC1/HNF446I mut and FCC1/HNC580Y mut were successfully generated. These parasite lines showed no changes in the expression level of k13 when compared with their parent parasite isolates. However, introduction of the F446I mutation in k13 of the 3D7 and FCC1/HN isolates led to elevated ring survival rates detected using RSA0-3 h when subjected to both 700 and 20 nM concentrations of dihydroartemisinin. The survival rates were similar to those detected in the parasite lines with the C580Y mutation. CONCLUSIONS: Insertion of the F446I mutation in k13 led to increased ring survival, suggesting that this mutation may be associated with ART resistance and could be used as a molecular marker for monitoring ART-resistant parasites. The results also highlights the importance of surveillance of F446I mutants for containing the resistant parasite. PMID- 29976208 TI - Prognostic factors in patients with metastatic spine tumors derived from lung cancer-a novel scoring system for predicting life expectancy. AB - BACKGROUND: Recently, molecule-targeting and bone-modifying agents have improved the treatment outcomes of lung cancer-derived metastatic spine tumors. Therefore, the prognostic factors for such tumors were examined, and novel scoring systems for predicting the life expectancy of patients with such tumors were proposed. METHODS: In 207 patients with lung cancer-derived metastatic spine tumors (surgery 49; conservative therapy 158), we retrospectively examined the factors that influenced the post-treatment survival time (age, sex, the affected site, pathology, general condition, the number of extraspinal bone metastases, the number of spinal metastases, the presence/absence of major internal organ metastasis, paralysis state, the total Tokuhashi score, the serum alkaline phosphatase level, the serum carcinoembryonic antigen level, molecule-targeting drug treatment, and bone-modifying agent treatment). Based on the results, we devised novel scoring systems for predicting the prognosis of such patients. RESULTS: Univariate analyses showed that the pathology of the primary lung tumor, the patient's general condition and paralysis state, and the presence/absence of molecule-targeting drug treatment significantly influenced survival. We performed a Cox regression analysis of these four factors and developed criteria for a novel scoring system based on the patient's general condition and paralysis state, which exhibited significance in the regression analysis. A retrospective review indicated that the consistency rate between predicted life expectancy and actual survival was 67.3%. When criteria based on the four factors that exhibited significance in the univariate analyses were adopted, the consistency rate was 76.2%. CONCLUSION: The patient's general condition and paralysis state, the pathology of the primary lung tumor, and molecule-targeting drug treatment influenced survival among patients with lung cancer-derived metastatic spine tumors. Novel scoring systems based on these four factors were proposed. PMID- 29976209 TI - Gene expression pattern of TCR repertoire and alteration expression of IL-17A gene of gammadelta T cells in patients with acute myocardial infarction. AB - BACKGROUND: gammadelta T cells are associated with the pathogenesis of coronary atherosclerotic heart disease, but the relationship between the development of acute myocardial infarction (AMI) and gammadelta T cells is not clear. So we attempt to investigate the expression pattern and clonality of T cell receptor (TCR) repertoire of gammadelta T cells in AMI patients, analyze the expression levels of regulatory genes Foxp3 and IL-17A, and characterize the correlation between gammadelta T cells and the pathogenesis of AMI. METHODS: 25 patients diagnosed with ST-segment-elevation AMI were enrolled and 14 healthy individuals were recruited as the controls. RT-PCR and GeneScan were used to analyze the complementarity-determining region 3 sizes of TCR gammadelta repertoire genes in sorted gammadelta T cells from peripheral blood mononuclear cells (PBMCs). RQ-PCR was used to detect the gene expression levels of Foxp3, IL-17A and TCR Vgamma subfamilies in sorted gammadelta T cells. All the patients were followed up for recordings of clinical endpoints. RESULTS: The mRNA gene expression levels of TCR Vgamma1, Vgamma2, and Vgamma3 subfamilies in AMI patients were significantly higher than those in healthy controls. The expression pattern was Vgamma1 > Vgamma2 > Vgamma3 in AMI patients, while Vgamma1 > Vgamma3 > Vgamma2 in healthy controls. The significantly restricted expression of TCR Vdelta subfamilies were also found in AMI patients. The expression frequencies of TCR Vdelta7 and TCR Vdelta6 in AMI patients were significantly lower than those in healthy controls. The high clonal expansion frequencies of the TCR Vdelta8, Vdelta4 and Vdelta3 were determined in AMI patients. High expression of Foxp3 gene was found in AMI PBMCs, while high expression of IL-17A was found in AMI gammadelta+ cells. CONCLUSIONS: Restrictive expression of TCR gammadelta repertoire and alteration expression of IL-17A gene are the important characteristics of gammadelta T cells in AMI patients, which might be related to the immune response and clinical outcome. gammadelta T cells might play a key role in the pathological progress of AMI and associated with the IL-17A mediated pathway. PMID- 29976210 TI - Sheep models for evaluation of novel patch and prosthesis material in vascular surgery: tips and tricks to avoid possible pitfalls. AB - BACKGROUND: In vascular surgery, novel synthetic prosthesis materials for patch angioplasties, interpositions, bypasses and shunts are continuously under development and optimization. The characteristics of an ideal vascular prosthesis would display long-term patency, biocompatibility, durability, low porosity, lack of stich hole bleeding, ease of handling, kink resistance, infection resistance and reasonable costs. The aim of this study was to establish and report a reliable sheep model including potential pitfalls where those parameters could be analyzed. Before surgery, sheep were acclimatized for 4-8 weeks, during which parasite infections were treated and blood and serum parameters monitored. Twenty four sheep underwent surgery, and carotid patch-angioplasties (n = 12), graft interpositions (n = 6) or arteriovenous prosthetic shunts (n = 6) were implanted. Half of the animals in each group were sacrificed after 2 weeks and the other half after 8 weeks. The implants were analyzed for patency, endothelialization, thrombogenicity and biocompatibility by clinical observation, blood flow measurement and pathological and histopathological (H&E, EvG) as well as immunohistochemical (Ki67, CD31) evaluations. RESULTS: Health monitoring of the sheep revealed a parasitic burden with endoparasites in all animals. Some animals showed thereby infestations in the bile duct causing fibrotic cholangitis with calcifications in the liver. In addition, sarcosporidia were detected in histopathological specimen of the heart in all animals. Parasitic burden correlated with blood counts and serum bilirubin levels. Both were significantly reduced by albendazole treatment within the acclimatization time. Patches, interposition grafts, and straight shunts were successfully implanted bilaterally in all animals. The total average operation time was 136 +/- 21 min. Most animals (23/24) showed good patency rates and general condition after implantation. Pathological and histopathological/immunohistochemical analyses were suitable to determine thrombogenicity, endothelialization, cellular/fibroblastic proliferation, biocompatibility, inflammatory cell infiltration, and thickness of neointima in the prosthesis material. CONCLUSIONS: We have developed a suitable experimental protocol with standardized and successful anesthesia- and surgical procedures for patch-angioplasty, graft interposition, and arteriovenous prosthetic shunts. This sheep model allows testing of new prosthetic materials for biocompatibility, thrombogenicity, and endothelialization. PMID- 29976211 TI - How can we teach medical students to choose wisely? A randomised controlled cross over study of video- versus text-based case scenarios. AB - BACKGROUND: The Choosing Wisely campaign highlights the importance of clinical reasoning abilities for competent and reflective physicians. The principles of this campaign should be addressed in undergraduate medical education. Recent research suggests that answering questions on important steps in patient management promotes knowledge retention. It is less clear whether increasing the authenticity of educational material by the inclusion of videos further enhances learning outcome. METHODS: In a prospective randomised controlled cross-over study, we assessed whether repeated video-based testing is more effective than repeated text-based testing in training students to choose appropriate diagnostic tests, arrive at correct diagnoses and identify advisable therapies. Following an entry exam, fourth-year undergraduate medical students attended 10 weekly computer-based seminars during which they studied patient case histories. Each case contained five key feature questions (items) on the diagnosis and treatment of the presented patient. Students were randomly allocated to read text cases (control condition) or watch videos (intervention), and assignment to either text or video was switched between groups every week. Using a within-subjects design, student performance on video-based and text-based items was assessed 13 weeks (exit exam) and 9 months (retention test) after the first day of term. The primary outcome was the within-subject difference in performance on video-based and text-based items in the exit exam. RESULTS: Of 125 eligible students, 93 provided data for all three exams (response rate 74.4%). Percent scores were significantly higher for video-based than for text-based items in the exit exam (76.2 +/- 19.4% vs. 72.4 +/- 19.1%, p = 0.026) but not the retention test (69.2 +/- 20.2% vs. 66.4 +/- 20.3%, p = 0.108). An additional Bayesian analysis of this retention test suggested that video-based training is marginally more effective than text-based training in the long term (Bayes factor 2.36). Regardless of presentation format, student responses revealed a high prevalence of erroneous beliefs that, if applied to the clinical context, could place patients at risk. CONCLUSION: Repeated video-based key feature testing produces superior short-term learning outcome compared to text-based testing. Given the high prevalence of misconceptions, efforts to improve clinical reasoning training in medical education are warranted. The Choosing Wisely campaign lends itself to being part of this process. PMID- 29976213 TI - Astrocytic gap junction inhibition by carbenoxolone enhances the protective effects of ischemic preconditioning following cerebral ischemia. AB - BACKGROUND: Stroke is the second leading cause of death worldwide and the most common cause of adult-acquired disability in many nations. Thus, attenuating the damage after ischemic injury and improving patient prognosis are of great importance. We have indicated that ischemic preconditioning (IP) can effectively reduce the damage of ischemia reperfusion and that inhibition of gap junctions may further reduce this damage. Although we confirmed that the function of gap junctions is closely associated with glutamate, we did not investigate the mechanism. In the present study, we aimed to clarify whether the blockade of cellular communication at gap junctions leads to significant reductions in the levels of glutamate released by astrocytes following cerebral ischemia. METHODS: To explore this hypothesis, we utilized the specific blocking agent carbenoxolone (CBX) to inhibit the opening and internalization of connexin 43 channels in an in vitro model of oxygen-glucose deprivation/re-oxygenation (OGD/R), following IP. RESULTS: OGD/R resulted in extensive astrocytic glutamate release following upregulation of hemichannel activity, thus increasing reactive oxygen species (ROS) generation and subsequent cell death. However, we observed significant increases in neuronal survival in neuron-astrocyte co-cultures that were subjected to IP prior to OGD/R. Moreover, the addition of CBX enhanced the protective effects of IP during the re-oxygenation period following OGD, by means of blocking the release of glutamate, increasing the level of the excitatory amino acid transporter 1, and downregulating glutamine expression. CONCLUSIONS: Our results suggest that combined use of IP and CBX represents a novel therapeutic strategy to attenuate damage from cerebral ischemia with minimal adverse side effects. PMID- 29976212 TI - Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain. AB - BACKGROUND: Neuroinflammation and microglial activation have been implicated in both alcohol use disorders (AUD) and fetal alcohol spectrum disorders (FASD). Chemokine monocyte chemoattractant protein 1 (MCP-1) and its receptor C-C chemokine receptor type 2 (CCR2) are critical mediators of neuroinflammation and microglial activation. FASD is the leading cause of mental retardation, and one of the most devastating outcomes of FASD is the loss of neurons in the central nervous system (CNS). The underlying molecular mechanisms, however, remain unclear. We hypothesize that MCP-1/CCR2 signaling mediates ethanol-induced neuroinflammation and microglial activation, which exacerbates neurodegeneration in the developing brain. METHODS: C57BL/6 mice and mice deficient of MCP-1 (MCP-1 /-) and CCR2 (CCR2-/-) were exposed to ethanol on postnatal day 4 (PD4). Neuroinflammation, and microglial activation, and neurodegeneration in the brain were evaluated by immunohistochemistry and immunoblotting. A neuronal and microglial co-culture system was used to evaluate the role of microglia and MCP 1/CCR2 signaling in ethanol-induced neurodegeneration. Specific inhibitors were employed to delineate the involved signaling pathways. RESULTS: Ethanol-induced microglial activation, neuroinflammation, and a drastic increase in the mRNA and protein levels of MCP-1. Treatment of Bindarit (MCP-1 synthesis inhibitor) and RS504393 (CCR2 antagonist) significantly reduced ethanol-induced microglia activation/neuroinflammation, and neuroapoptosis in the developing brain. MCP-1-/ and CCR2-/- mice were more resistant to ethanol-induced neuroapoptosis. Moreover, ethanol plus MCP-1 caused more neuronal death in a neuron/microglia co culture system than neuronal culture alone, and Bindarit and RS504393 attenuated ethanol-induced neuronal death in the co-culture system. Ethanol activated TLR4 and GSK3beta, two key mediators of microglial activation in the brain and cultured microglial cells (SIM-A9). Blocking MCP-1/CCR2 signaling attenuated ethanol-induced activation of TLR4 and GSK3beta. CONCLUSION: MCP-1/CCR2 signaling played an important role in ethanol-induced microglial activation/neuroinflammation and neurodegeneration in the developing brain. The effects may be mediated by the interaction among MCP-1/CCR2 signaling, TLR4, and GSK3beta. PMID- 29976214 TI - The role of deep hypothermic circulatory arrest in surgery for renal or adrenal tumor with vena cava thrombus: a single-institution experience. AB - BACKGROUND: The aim of this study was to review our experience in managing renal or adrenal tumors with level III or IV inferior vena cava thrombus by using deep hypothermic circulatory arrest (DHCA), and to evaluate survival outcomes. METHODS: Between September 2004 and March 2016, we treated 33 patients with renal or adrenal malignancy tumor and thrombus extending into the inferior vena cava. Patients were identified according to radiographic records and operative findings. Clinicopathological and operative characteristics were recorded, and comparisons of clinical and operative characteristics through DHCA were performed. A Cox regression model was used to determine predictors of perioperative mortality. RESULTS: Twenty-one out of 33 patients with level III (n = 15), level IV (n = 5), or level II (n = 1) renal or adrenal tumors were treated surgically through cardiopulmonary bypass (CPB) with DHCA, and 12 patients with level II or III tumors were treated surgically through normothermic CPB. Three complications were observed, and one death occurred perioperatively, owing to multiple organ failure. The overall perioperative mortality was 4.7%. There were significant differences in the clinicopathological characteristics, operative duration, estimated blood loss, transfusions and hospital stay depending on use of DHCA. Multivariate analysis indicated that the operative duration (OR, 3.78; P < 0.001), estimated blood loss (OR, 1.08; P = 0.02), and transfusion (OR, 2.13; P = 0.038) during/after surgery were positively associated with higher mortality and morbidity. DHCA failed to reach statistical significance (P = 0.378). CONCLUSIONS: Use of CPB and DHCA to treat renal or adrenal tumors allows for complete tumor resection, especially at the T4 stage. Although it can cause physical damage, this technique does not increase operative risk and is a relatively safe approach. PMID- 29976215 TI - Patient-reported outcome measures used in patients with primary sclerosing cholangitis: a systematic review. AB - BACKGROUND: Primary Sclerosing Cholangitis (PSC) is a rare chronic, cholestatic liver condition in which patients can experience a range of debilitating symptoms. Patient reported outcome measures (PROMs) could provide a valuable insight into the impact of PSC on patient quality of life and symptoms. A previous review has been conducted on the quality of life instruments used in liver transplant recipients. However, there has been no comprehensive review evaluating PROM use or measurement properties in PSC patients' to-date. The aim of the systematic review was to: (a) To identify and categorise which PROMs are currently being used in research involving the PSC population (b) To investigate the measurement properties of PROMs used in PSC. METHODS: A systematic review of Medline, EMBASE and CINAHL, from inception to February 2018, was undertaken. The methodological quality of included studies was assessed using the Consensus-based Standards for selection of health Measurement Instruments (COSMIN) checklist. RESULTS: Thirty-seven studies were identified, which included 36 different PROMs. Seven PROMs were generic, 10 disease-specific, 17 symptom-specific measures and 2 measures on dietary intake. The most common PROMs were the Short form-36 (SF-36) (n = 15) and Chronic liver disease questionnaire (CLDQ) (n = 6). Only three studies evaluated measurement properties, two studies evaluated the National Institute of Diabetes Digestive and Kidney Diseases Liver Transplant (NIDDK-QA) and one study evaluated the PSC PRO; however, according to the COSMIN guidelines, methodological quality was poor for the NIDDK-QA studies and fair for the PSC PRO study. CONCLUSION: A wide variety of PROMs have been used to assess health related quality of life and symptom burden in patients with PSC; however only two measures (NIDDK-QA and PSC PRO) have been formally validated in this population. The newly developed PSC PRO requires further validation in PSC patients with diverse demographics, comorbidities and at different stages of disease; however this is a promising new measure with which to assess the impact of PSC on patient quality of life and symptoms. PMID- 29976216 TI - Acceptability and stakeholders perspectives on feasibility of using trained psychologists and health workers to deliver school-based sexual and reproductive health services to adolescents in urban Accra, Ghana. AB - BACKGROUND: Adolescent sexual and reproductive health is recognized as a key developmental issue of international concern. However, adolescents' access to sexual and reproductive health (SRH) information and services is largely inadequate in sub-Saharan Africa. With increasing enrollment in schools, this could be an avenue to reach adolescents with SRH information and services. This study was therefore conducted to assess the acceptability and stakeholders' perspectives on the feasibility of using health workers and trained psychologists to provide school-based SRH services in Ghana. METHODS: Fourteen (14) focus group discussions (N = 136) were conducted; 8 among adolescents aged 12-17 years (4 boys, 4 girls groups), 4 among parents (2 males, 2 females groups) and two among mixed teacher groups. We also conducted 18 in-depth interviews with teachers, managers of schools, health workers, clinical psychologists, as well as adolescent SRH program managers in the Ghana Health Service, Ghana Education Service, UNICEF, UNESCO and National Population Council, Ghana. We audio-recorded all interviews and took field notes. Interviews were transcribed and transcripts imported into NVivo 11 for analysis using grounded theory approach to qualitative data analysis. RESULTS: Many respondents reported that it was challenging for parents and/or teachers to provide adolescents with SRH information. For this reason, they agreed that it was a good idea to have health workers and psychologists provide SRH information and services to adolescents in school. Although, there was general agreement about providing SRH services in school, many of the respondents disagreed with distribution of condoms in schools as they believed that availing condoms would encourage adolescents to experiment with sex. While majority of respondents thought it was acceptable to use psychologists and health workers to provide school-based sexual and reproductive health to adolescents, some teachers and education managers thought the implementation of such a program would oppose practical challenges. Key among the challenges were how to pay for the services that health workers and trained psychologists will render, and the availability of psychologists to cater for all schools. CONCLUSION: Stakeholders believe it is feasible and acceptable to use trained psychologists and health workers to deliver school-based SRH information and services in the Ghanaian school context. However, provisions must be made to cater for financial and other logistical considerations in the implementation of school-based SRH programs. PMID- 29976217 TI - A prospective study on the microbiological examination of secretions from the paranasal sinuses in horses in health and disease. AB - BACKGROUND: Diagnostics in equine sinusitis can be challenging and often require a combination of different imaging tools to ascertain its underlying aetiology. The bacterial flora of healthy and diseased paranasal sinuses, respectively, has only sporadically been assessed in horses. The objectives of this study were to determine whether assessment of microbiological features of secretions from the paranasal sinuses displays a useful diagnostic tool in equine sinusitis to distinguish between different aetiologies. Secretion samples from 50 horses with sinusitis and from 10 healthy horses were taken transendoscopically from the drainage angle of the nasomaxillary aperture using a guidable Swing Tip catheter. Bacteria found in healthy and diseased equine sinuses were compared. Endoscopic samples in all healthy and 19 diseased horses were compared with samples taken directly from the affected sinus after trephination. RESULTS: Eleven of the 14 horses with primary sinusitis revealed growth of Streptococcus equi ssp. zooepidemicus, with three samples yielding pure cultures. Anaerobes were found in 15 out of 26 samples from horses with dental sinusitis. Healthy sinuses revealed mainly alpha-haemolytic streptococci and coagulase-negative staphylococci or showed no growth. Enterobacteriaceae were found more frequently in secondary sinusitis. There were significant differences in the bacterial composition and diversity (P < 0.05) between primary sinusitis, dental sinusitis and healthy controls. The correlation between endoscopic and trephination samples was satisfying. CONCLUSIONS: Microbiological examination of secretions from horses with sinusitis collected transendoscopically can help to distinguish between primary and dental sinusitis. Therefore, it may display a feasible ancillary diagnostic tool, but does not replace a meticulous examination procedure including diagnostic imaging. PMID- 29976218 TI - Neurocognitive and somatic stabilization in pediatric patients with severe Mucopolysaccharidosis Type I after 52 weeks of intravenous brain-penetrating insulin receptor antibody-iduronidase fusion protein (valanafusp alpha): an open label phase 1-2 trial. AB - BACKGROUND: Mucopolysaccharidosis (MPS) Type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, alpha-L-iduronidase (IDUA), and a majority of patients present with severe neurodegeneration and cognitive impairment. Recombinant IDUA does not cross the blood-brain barrier (BBB). To enable BBB transport, IDUA was re-engineered as an IgG-IDUA fusion protein, valanafusp alpha, where the IgG domain targets the BBB human insulin receptor to enable transport of the enzyme into the brain. We report the results of a 52-week clinical trial on the safety and efficacy of valanafusp alpha in pediatric MPSI patients with cognitive impairment. In the phase I trial, 6 adults with attenuated MPSI were administered 0.3, 1, and 3 mg/kg doses of valanafusp alpha by intravenous (IV) infusion. In the phase II trial, 11 pediatric subjects, 2-15 years of age, were treated for 52 weeks with weekly IV infusions of valanafusp alpha at 1, 3, or 6 mg/kg. Assessments of adverse events, cognitive stabilization, and somatic stabilization were made. Outcomes at 52 weeks were compared to baseline. RESULTS: Drug related adverse events included infusion related reactions, with an incidence of 1.7%, and transient hypoglycemia, with an incidence of 6.4%. The pediatric subjects had CNS involvement with a mean enrollment Development Quotient (DQ) of 36.1+/-7.1. The DQ, and the cortical grey matter volume of brain, were stabilized by valanafusp alpha treatment. Somatic manifestations were stabilized, or improved, based on urinary glycosaminoglycan levels, hepatic and spleen volumes, and shoulder range of motion. CONCLUSION: Clinical evidence of the cognitive and somatic stabilization indicates that valanafusp alpha is transported into both the CNS and into peripheral organs due to its dual targeting mechanism via the insulin receptor and the mannose 6 phosphate receptor. This novel fusion protein offers a pharmacologic approach to the stabilization of cognitive function in MPSI. TRIAL REGISTRATION: Clinical Trials.Gov, NCT03053089 . Retrospectively registered 9 February, 2017; Clinical Trials.Gov, NCT03071341 . Registered 6 March, 2017. PMID- 29976219 TI - Quantitation of the latent HIV-1 reservoir from the sequence diversity in viral outgrowth assays. AB - BACKGROUND: The ability of HIV-1 to integrate into the genomes of quiescent host immune cells, establishing a long-lived latent viral reservoir (LVR), is the primary obstacle to curing these infections. Quantitative viral outgrowth assays (QVOAs) are the gold standard for estimating the size of the replication competent HIV-1 LVR, measured by the number of infectious units per million (IUPM) cells. QVOAs are time-consuming because they rely on culturing replicate wells to amplify the production of virus antigen or nucleic acid to reproducibly detectable levels. Sequence analysis can reduce the required number of culture wells because the virus genetic diversity within the LVR provides an internal replication and dilution series. Here we develop a Bayesian method to jointly estimate the IUPM and variant frequencies (a measure of clonality) from the sequence diversity of QVOAs. RESULTS: Using simulation experiments, we find our Bayesian approach confers significantly greater accuracy over current methods to estimate the IUPM, particularly for reduced numbers of QVOA replicates and/or increasing actual IUPM. Furthermore, we determine that the improvement in accuracy is greater with increasing genetic diversity in the sample population. We contrast results of these different methods applied to new HIV-1 sequence data derived from QVOAs from two individuals with suppressed viral loads from the Rakai Health Sciences Program in Uganda. CONCLUSIONS: Utilizing sequence variation has the additional benefit of providing information on the contribution of clonality of the LVR, where high clonality (the predominance of a single genetic variant) suggests a role for cell division in the long-term persistence of the reservoir. In addition, our Bayesian approach can be adapted to other limiting dilution assays where positive outcomes can be partitioned by their genetic heterogeneity, such as immune cell populations and other viruses. PMID- 29976220 TI - Treatment of simple bone cysts using endoscopic curettage: a case series analysis. AB - BACKGROUND: Endoscopic curettage is considered applicable for the treatment of simple bone cysts with the expectation that it might be less invasive than open curettage. In this study, we investigated the efficacy of endoscopic curettage for the treatment of simple bone cysts. The goal was to investigate the incidence of cyst recurrence and bone healing after endoscopic curettage. Moreover, complications and functionality at the final follow-up were evaluated. METHODS: From 2003 to 2014, 37 patients with simple bone cysts underwent endoscopic curettage. Twenty-four were male and 13 were female, with a mean age of 14.7 years. Endoscopic curettage was performed with the support of an arthroscope via 7-8 mm holes penetrated by cannulated drills with a small incision. The cysts underwent curettage using angled curettes, rongeurs, and an electrical shaver until the normal bone was observed in the medullary cavity. To investigate the bone healing after endoscopic curettage, we evaluated the consolidation of the cyst at the final evaluation (Modified Neer Classification) and the time to solid union after operation, which was defined as the sufficient thickness of the cortical bone to prevent fracture and allow physical activities. RESULTS: Recurrence occurred in seven patients (18.9%). A log-rank analysis revealed that contact with the physis was associated with recurrence (p = 0.006). Among 31 patients (83.7%), the consolidation of cyst was considered healed at the final X ray follow-up period, and in these patients, the mean time taken for solid union of cortical bone thinning was 4.0 months (standard deviation, 2.4). With regard to major complications of endoscopic curettage, a transient radial nerve palsy and two postoperative fractures occurred. The former problem was managed conservatively and the latter problems by transient internal fixation; these problems were managed without any further complications. All patients had a good postoperative function. CONCLUSIONS: Endoscopic curettage might be a useful alternative as it is a minimally invasive procedure for the treatment of simple bone cysts. Considering the relatively smaller size of this study, further investigation should be necessary for deducing the reliable conclusion. PMID- 29976221 TI - Stochastic lattice-based modelling of malaria dynamics. AB - BACKGROUND: The transmission of malaria is highly variable and depends on a range of climatic and anthropogenic factors. In addition, the dispersal of Anopheles mosquitoes is a key determinant that affects the persistence and dynamics of malaria. Simple, lumped-population models of malaria prevalence have been insufficient for predicting the complex responses of malaria to environmental changes. METHODS AND RESULTS: A stochastic lattice-based model that couples a mosquito dispersal and a susceptible-exposed-infected-recovered epidemics model was developed for predicting the dynamics of malaria in heterogeneous environments. The It[Formula: see text] approximation of stochastic integrals with respect to Brownian motion was used to derive a model of stochastic differential equations. The results show that stochastic equations that capture uncertainties in the life cycle of mosquitoes and interactions among vectors, parasites, and hosts provide a mechanism for the disruptions of malaria. Finally, model simulations for a case study in the rural area of Kilifi county, Kenya are presented. CONCLUSIONS: A stochastic lattice-based integrated malaria model has been developed. The applicability of the model for capturing the climate-driven hydrologic factors and demographic variability on malaria transmission has been demonstrated. PMID- 29976222 TI - Assessing patients' acceptance of their medication to reveal unmet needs: results from a large multi-diseases study using a patient online community. AB - BACKGROUND: Patients with chronic conditions are required to take long-term treatments for their disease itself or to prevent any potential health risks. Measuring patient acceptance of their medication should help to better understand and predict patients' behavior toward treatment. This study aimed to describe the level of patient acceptance toward various long-term treatments in real life using an online patient community. METHODS: This was an observational, cross sectional study conducted through the French Carenity platform. All Carenity patient members were invited to complete an online questionnaire including the 25 item ACCEptance by the Patients of their Treatment (ACCEPT(c)) questionnaire. ACCEPT(c) measures patient acceptance toward their medication and includes one general acceptance dimension (Acceptance/General) and six treatment-attribute specific dimensions (scores 0-100; lowest to highest acceptance): Acceptance/Medication Inconvenience, Acceptance/Long-term Treatment, Acceptance/Regimen Constraints, Acceptance/Side effects, Acceptance/Effectiveness, and Acceptance/Numerous Medications. Patients included in the analysis were treated adults experiencing any chronic diseases and who responded to at least one ACCEPT(c) item. RESULTS: Among the 4193 patients included in the analysis, more than 270 chronic diseases were represented, amidst which 19 included more than 30 patients. Mean ACCEPT(c) Acceptance/General score for those 19 diseases were 61.2 (SD = 31.9) for type 1 diabetes, 59.8 (SD = 32.3) for asthma, 56.3 (SD = 34.3) for hypertension, 52.0 (SD = 32.2) for chronic obstructive pulmonary disease, 51.7 (SD = 27.0) for epilepsy, 50.1 (SD = 33.1) for bipolar disorder, 49.9 (SD = 33.1) for type 2 diabetes, 48.6 (SD = 31.6) for multiple sclerosis, 46.1 (SD = 34.5) for Crohn's disease/ulcerative colitis, 44.3 (SD = 31.5) for depression, 42.8 (SD = 31.5) for lupus, 42.3 (SD = 33.0) for arthrosis, 41.8 (SD = 32.6) for Parkinson's disease, 40.5 (SD = 32.2) for rheumatoid arthritis, 38.6 (SD = 31.7) for breast cancer, 36.4 (SD = 36.4) for myocardial infarction, 35.8 (SD = 32.0) for ankylosing spondylitis, 34.1 (SD = 32.3) for psoriasis, and 33.7 (SD = 31.7) for fibromyalgia. CONCLUSIONS: This first of its kind study enabled ACCEPT(c) data to be collected in real life for a variety of chronic diseases. These data may help in evaluating and interpreting levels of acceptance in future studies and provide valuable insights about patient priorities and current unmet needs. PMID- 29976223 TI - Impact of female gender and perspectives of pregnancy on admission in residency programs. AB - BACKGROUND: Motherhood is a demanding part of any women's life. Female interns could encounter difficulties during selection for residency program according to their plans of conceiving. Our aim is to explore the influence of female gender on the selection process of residency programs. METHOD: A cross sectional study was conducted in 2016 at a University Hospital in Beirut, Lebanon. Female residents and chief of departments were interviewed about the impact of the timing of motherhood during residency on the interview for admission. The questionnaire reviewed concerns among female Lebanese medical residents as well as the head of departments revolving around the choice of opting for motherhood and the decision of integrating into a residency program while juggling motherhood responsibilities. RESULTS: Eighty nine female residents and 22 head of department agreed to participate in this study. During the interviews for residency acceptance, 29 residents (34.5%) were directly asked about their family and motherhood plans; 9% of them did not reveal their intention. 35% of the residents thought that this subject could affect the program directors' decision. 47% of residents felt that having pregnant colleagues would add to their workload, and almost half of them (46%) believed that pregnant colleagues showed less productivity. 45% of program directors stated that it was an important factor taken into consideration during the interview, and 68% believed that residents tended to choose their specialty according to their life priorities. CONCLUSION: Pregnancy during residency training represents major challenges for female residents and their program directors. Rules and laws designed to set a balance between career and personal life are required to improve women's ability to participate equally in the workforce. PMID- 29976224 TI - Transforaminal endoscopic discectomy versus conventional microdiscectomy for lumbar discherniation: a systematic review and meta-analysis. AB - BACKGROUND: The open microdiscectomy is the most common surgical procedure for the decompression of radiculopathy caused by lumbar disk herniation. To date, a variety of minimally invasive (MI) techniques have been developed. In the last decades, endoscopic techniques have been developed to perform discectomy. The transforaminal endoscopic discectomy (TED) with posterolateral access evolved out of the development of endoscopic techniques. METHODS: A systematic literature search was performed using the PubMed, EMBASE, and Cochrane Library databases for trials written in English. The randomized trials and observational studies that met our inclusion criteria were subsequently included. Two reviewers respectively extracted data and estimated the risk of bias. All statistical analyses were performed using Review Manager 5.3. RESULTS: Five prospective and four retrospective studies involving 1527 patients were included. The results of the meta-analysis indicated that there were significant differences between the two groups in length of hospital stay (MD = - 8.41, 95% CI - 10.26, - 6.56; p value < 0.00001). However, there were no significant differences in the leg visual analog scale (VAS) scores, the Oswestry Disability Index (ODI) scores, and the incidence of complications and recurrence. CONCLUSIONS: The transforaminal endoscopic discectomy is superior to open microdiscectomy in the length of hospital stay. However, there were no differences in leg pain, functional recovery, and incidence of complications between TED and MD in treating LDH. PMID- 29976225 TI - Use of withdrawal management services among people who use illicit drugs in Vancouver, Canada. AB - BACKGROUND: For many individuals with substance use disorders, the entry point for addiction treatment can be through withdrawal management (e.g. detoxification) services. However, little is known about the factors that predict withdrawal management service use among people who use illicit drugs (PWUD). Using data derived from two prospective cohorts of PWUD, we conducted a longitudinal data analysis of factors associated with use of withdrawal management services. METHODS: Individuals participating in two cohorts of PWUD were prospectively followed between December 2005 and May 2016 in Vancouver, Canada. Bivariate and multivariate generalized estimating equations were used to examine factors associated with use of withdrawal management services. RESULTS: Out of a total of 2001 participants, 339 (16.9%) individuals reported having been to a withdrawal management centre in the previous 6 months at some point during the study period. In multivariate analyses, male sex (adjusted odds ratio [AOR]: 1.62, 95% Confidence Interval [CI]: 1.17-2.24), homelessness (AOR: 1.86, 95% CI: 1.45-2.38), binge use of any substance (AOR: 1.34, 95% CI: 1.08-1.67), having attended a supervised injection facility (AOR: 1.66, 95% CI: 1.3-2.11), and having accessed other addiction medicine treatment or supports (other than withdrawal management services or opioid agonist therapy; AOR: 3.34, 95% CI: 2.64 4.22) were positively associated with having accessed withdrawal management services, whereas older age (AOR: 0.81, 95% CI: 0.7-0.94) was negatively associated with the outcome. CONCLUSIONS: This study identified specific factors associated with accessing withdrawal management services. Current evidence suggests a need to re-examine the provision of withdrawal management services. Consideration needs to be given to redesigning access to care and bridging to evidence-based addiction treatment, particularly for highly vulnerable subpopulations, identified in this study as females and older people. PMID- 29976226 TI - Mediation analysis to understand genetic relationships between habitual coffee intake and gout. AB - BACKGROUND: Increased coffee intake is associated with reduced serum urate concentrations and lower risk of gout. Specific alleles of the GCKR, ABCG2, MLXIPL, and CYP1A2 genes have been associated with both reduced coffee intake and increased serum urate in separate genome-wide association studies (GWAS). The aim of this study was to determine whether these single nucleotide polymorphisms (SNPs) influence the risk of gout through their effects on coffee consumption. METHODS: This research was conducted using the UK Biobank Resource. Data were available for 130,966 European participants aged 40-69 years. Gout status and coffee intake were tested for association with four urate-associated SNPs: GCKR (rs1260326), ABCG2 (rs2231142), MLXIPL (rs1178977), and CYP1A2 (rs2472297). Multiple regression and path analysis were used to examine whether coffee consumption mediated the effect of the SNPs on gout risk. RESULTS: Coffee consumption was inversely associated with gout (multivariate adjusted odds ratio (95% confidence interval (CI)) for any coffee consumption 0.75 (0.67-0.84, P = 9 * 10-7)). There was also evidence of a dose-effect with multivariate adjusted odds ratio (95% CI) per cup consumed per day of 0.85 (0.82-0.87, P = 9 * 10-32). The urate-increasing GCKR, ABCG2, MLXIPL, and CYP1A2 alleles were associated with reduced daily coffee consumption, with the strongest associations for CYP1A2 (beta -0.30, P = 8 * 10-40), and MLXIPL (beta -0.17, P = 3 * 10-8), and weaker associations for GCKR (beta -0.07, P = 3 * 10-10) and ABCG2 (beta -0.09, P = 2 * 10-9). The urate-increasing GCKR and ABCG2 alleles were associated with gout (multivariate adjusted p < 5 * 10-8 for both), but the urate-increasing MLXIPL and CYP1A2 alleles were not. In mediation analysis, the direct effects of GCKR and ABCG2 accounted for most of the total effect on gout risk, with much smaller indirect effects mediated by coffee consumption. CONCLUSION: Coffee consumption is inversely associated with risk of gout. Although alleles at several SNPs associate with both lower coffee consumption and higher risk of gout, these SNPs largely influence gout risk directly, rather than indirectly through effects on coffee consumption. PMID- 29976227 TI - Open-label randomized controlled trial to compare wound dressings for patients undergoing hip and knee arthroplasty: study protocol for a randomized controlled trial. AB - BACKGROUND: Surgical wounds are covered to prevent bleeding, absorb the exudates, and provide a barrier against external contamination. Currently, in our hospital, after orthopedic surgery, traditional occlusive dressing of sterile gauze and non woven hypoallergenic adhesive tape is placed. Some of the newest dressings have been shown to reduce the incidence of blisters compared with traditional dressing or colloid adhesive dressings. However, there are no comparative evaluations between the different types of dressings and their contribution to the overall results of the healing process. METHODS/DESIGN: This is a randomized, controlled, open-label trial to compare five types of dressings used in total knee and hip arthroplasty surgical wounds. A total of 550 patients will be randomly allocated to one of the following dressings: (1) traditional occlusive dressing, (2) Aquacel Surgical(r), (3) Mepilex(r) Border Post-Op, (4) OpSite Post-Op Visible, or (5) UrgoTul(r) Absorb Border. The dressing assigned is placed right after surgery. Patients will be followed up to 14 days after surgery when the dressing is definitively removed and will be tracked up to 3 months to record any late complications. During the immediate postoperative period and patient hospitalization and at the ambulatory visits after discharge, every time that the dressing is changed, nurses perform the study assessments. The main study outcome will be the percentage of patients with skin integrity at all times when the dressing has been changed. Skin integrity is a composite of the absence of blisters, erosion, erythema, maceration, swelling, wound dehiscence, and purulent exudates. Secondary outcomes include time to first change of dressing; percentage of patients with presence/absence of blisters, erosion, erythema, maceration, swelling, wound dehiscence, and purulent exudates; number of dressing changes needed; days of hospital stay; and nurse and patient satisfaction. Differences in the main variable between each treatment group and group 1 will be tested by means of a chi-squared test or Fisher's exact test. Subgroup analyses of diabetic and non-diabetic patients, patients with a body mass index of more than 30 or not more than 30, and type of surgery (hip or knee) are planned. DISCUSSION: The results of this study will be useful for clinical decision making by giving information on the contribution of the dressings studied to the outcome of the wound and may also show which dressing offers better results depending on the characteristics of patients. TRIAL REGISTRATION: This trial has been registered at ClinicalTrials.gov ( NCT03190447 ). Retrospectively registered on 16 June 2017. PMID- 29976228 TI - Intermittent screening and treatment with artemether-lumefantrine versus intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in pregnancy: a facility-based, open-label, non-inferiority trial in Nigeria. AB - BACKGROUND: The spread of SP resistance may compromise the effectiveness of intermittent preventive treatment of malaria in pregnancy (MiP) with sulfadoxine pyrimethamine (IPTp-SP) across Africa. However, there is no recommended alternative medicine for IPTp or alternative strategy for prevention of MiP. This poses problems for the prevention of MiP. This study investigated, whether screening with a rapid diagnostic test for malaria at routine antenatal clinic attendances and treatment of only those who are positive (intermittent screening and treatment) with artemether-lumefantrine is as effective and safe as IPTp-SP in pregnant women. METHODS: During antenatal clinic sessions at the General Hospital Calabar, Nigeria, held between October 2013 and November 2014, 459 pregnant women were randomized into either the current standard IPTp-SP or intermittent screening and treatment with artemether-lumefantrine (ISTp-AL). All women received a long-lasting insecticide-treated net at enrolment. Study women had a maximum of four scheduled visits following enrolment. Haemoglobin concentration and peripheral parasitaemia were assessed in the third trimester (36-40 weeks of gestation). Birth weight was documented at delivery or within a week for babies delivered at home. RESULTS: In the third trimester, the overall prevalence of severe anaemia (Hb < 8 g/dl) and moderate (8-10.9 g/dl) anaemia was 0.8 and 27.7%, respectively, and was similar in both treatment groups (p = 0.204). The risk of third-trimester severe anaemia did not differ significantly between both treatment arms (risk difference - 1.75% [95% CI - 4.16 to 0.66]) although the sample was underpowered for this outcome due to several participants being unavailable to give a blood sample. The risk of third-trimester maternal parasitaemia was significantly lower in the ISTp-AL arm (RD - 3.96% [95% CI - 7.76 to - 0.16]). The risk of low birthweight was significantly lower in the ISTp AL arm after controlling for maternal age, gravidity and baseline parasitaemia (risk difference - 1.53% [95% CI - 1.54 to - 1.15]). Women in the ISTp-AL arm complained of fever more frequently compared to women in the IPTp-SP arm (p = 0.022). CONCLUSIONS: The trial results suggest that in an area of high malaria transmission with moderate sulfadoxine-pyrimethamine resistance, ISTp with artemether-lumefantrine may be an effective strategy for controlling malaria in pregnancy. Trial registration PACTR, PACTR201308000543272. Registered 29 April 2013, http://www.pactr.org/ATMWeb/appmanager/atm/atmregistry?dar=true&tNo=PACTR20130800 543272. PMID- 29976229 TI - Syndecan-1 induction in lung microenvironment supports the establishment of breast tumor metastases. AB - BACKGROUND: Syndecan-1 (Sdc1), a cell surface heparan sulfate proteoglycan normally expressed primarily by epithelia and plasma cells, is aberrantly induced in stromal fibroblasts of breast carcinomas. Stromal fibroblast-derived Sdc1 participates in paracrine growth stimulation of breast carcinoma cells and orchestrates stromal extracellular matrix fiber alignment, thereby creating a migration and invasion-permissive microenvironment. Here, we specifically tested the role of stromal Sdc1 in metastasis. METHODS: The metastatic potential of the aggressive mouse mammary carcinoma cell lines, 4T1 and E0776, was tested in wild type and genetically Sdc1-deficient host animals. Metastatic lesions were characterized by immunohistochemical analysis. RESULTS: After orthotopic inoculation, the lung metastatic burden was reduced in Sdc1-/- animals by 97% and more than 99%, in BALB/cJ and C57BL/6 animals, respectively. The difference in metastatic efficiency was maintained when the tumor cells were injected into the tail vein, suggesting that host Sdc1 exerts its effect during later stages of the metastatic cascade. Co-localization studies identified Sdc1 expression in stromal fibroblasts within the metastatic microenvironment and in normal airway epithelial cells but not in other cells (endothelial cells, alpha-smooth muscle actin positive cells, leucocytes, macrophages). The Ki67 proliferation index and the rate of apoptosis of the metastatic tumor cells were diminished in Sdc1-/- vs. Sdc1+/+ animals, and leucocyte density was indistinguishable. Sdc1-mediated metastatic efficiency was abolished when the animals were housed at a thermoneutral ambient temperature of 31 degrees C, suggesting that the host Sdc1 effect on metastasis requires mild cold stress. CONCLUSIONS: In summary, Sdc1 is induced in the lung microenvironment after mammary carcinoma cell dissemination and promotes outgrowth of metastases in a temperature-dependent manner. PMID- 29976230 TI - (Arg)9-SH2 superbinder: a novel promising anticancer therapy to melanoma by blocking phosphotyrosine signaling. AB - BACKGROUND: Melanoma is a malignant tumor with high misdiagnosis rate and poor prognosis. The bio-targeted therapy is a prevailing method in the treatment of melanoma; however, the accompanying drug resistance is inevitable. SH2 superbinder, a triple-mutant of the Src Homology 2 (SH2) domain, shows potent antitumor ability by replacing natural SH2-containing proteins and blocking multiple pY-based signaling pathways. Polyarginine (Arg)9, a powerful vector for intracellular delivery of large molecules, could transport therapeutic agents across cell membrane. The purpose of this study is to construct (Arg)9-SH2 superbinder and investigate its effects on melanoma cells, expecting to provide potential new approaches for anti-cancer therapy and overcoming the unavoidable drug resistance of single-targeted antitumor agents. METHODS: (Arg)9 and SH2 superbinder were fused to form (Arg)9-SH2 superbinder via genetic engineering. Pull down assay was performed to identify that (Arg)9-SH2 superbinder could capture a wide variety of pY proteins. Immunofluorescence was used to detect the efficiency of (Arg)9-SH2 superbinder entering cells. The proliferation ability was assessed by MTT and colony formation assay. In addition, wound healing and transwell assay were performed to evaluate migration of B16F10, A375 and A375/DDP cells. Moreover, apoptosis caused by (Arg)9-SH2 superbinder was analyzed by flow cytometry-based Annexin V/PI. Furthermore, western blot revealed that (Arg)9-SH2 superbinder influenced some pY-related signaling pathways. Finally, B16F10 xenograft model was established to confirm whether (Arg)9-SH2 superbinder could restrain the growth of tumor. RESULTS: Our data showed that (Arg)9-SH2 superbinder had the ability to enter melanoma cells effectively and displayed strong affinities for various pY proteins. Furthermore, (Arg)9-SH2 superbinder could repress proliferation, migration and induce apoptosis of melanoma cells by regulating PI3K/AKT, MAPK/ERK and JAK/STAT signaling pathways. Importantly, (Arg)9-SH2 superbinder could significantly inhibit the growth of tumor in mice. CONCLUSIONS: (Arg)9-SH2 superbinder exhibited high affinities for pY proteins, which showed effective anticancer ability by replacing SH2-containing proteins and blocking diverse pY-based pathways. The remarkable ability of (Arg)9-SH2 superbinder to inhibit cancer cell proliferation and tumor growth might open the door to explore the SH2 superbinder as a therapeutic agent for cancer treatment. PMID- 29976231 TI - Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines. AB - BACKGROUND: Hydroxychloroquine (HCQ) retinopathy may be more common than previously recognized; recent ophthalmology guidelines have revised recommendations from ideal body weight (IBW)-based dosing to actual body weight (ABW)-based dosing. However, contemporary HCQ prescribing trends in the UK remain unknown. METHODS: We examined a UK general population database to investigate HCQ dosing between 2007 and 2016. We studied trends of excess HCQ dosing per ophthalmology guidelines (defined by exceeding 6.5 mg/kg of IBW and 5.0 mg/kg of ABW) and determined their independent predictors using multivariable logistic regression analyses. RESULTS: Among 20,933 new HCQ users (78% female), the proportions of initial HCQ excess dosing declined from 40% to 36% using IBW and 38% to 30% using ABW, between 2007 and 2016. Among these, 47% of women were excess-dosed (multivariable OR 12.52; 95% CI 10.99-14.26) using IBW and 38% (multivariable OR 1.98; 95% CI,1.81-2.15) using ABW. Applying IBW, 37% of normal and 44% of obese patients were excess-dosed; however, applying ABW, 53% of normal and 10% of obese patients were excess-dosed (multivariable ORs = 1.61 and 0.1 (reference = normal); both p < 0.01). Long-term HCQ users showed similar excess dosing. CONCLUSION: A substantial proportion of HCQ users in the UK, particularly women, may have excess HCQ dosing per the previous or recent weight-based guidelines despite a modest decline in recent years. Over half of normal-BMI individuals were excess-dosed per the latest guidelines. This implies the potential need to reduce dosing for many patients but also calls for further research to establish unifying evidence-based safe and effective dosing strategies. PMID- 29976232 TI - Immature-like molecular expression patterns in the hippocampus of a mouse model of dementia with Lewy body-linked mutant beta-synuclein. AB - AIM: Maturation abnormalities of the brain cells have been suggested in several neuropsychiatric disorders, including schizophrenia, bipolar disorder, autism spectrum disorders, and epilepsy. In this study, we examined the expression patterns of neuronal maturation markers in the brain of a mouse model of dementia with Lewy body-linked mutant beta-synuclein (betaS), especially in the hippocampus, to explore whether such brain abnormalities occur in neurodegenerative disorders as well. METHODS: Quantitative PCR (qPCR) and immunohistochemical analyses were performed using the hippocampus of 14-month-old P123H betaS transgenic (Tg) mice to evaluate the expression of molecular markers for maturation of dentate granule cells. RESULTS: Based on qPCR results, expression of Tdo2 and Dsp (markers of mature granule cells) was decreased and that of Drd1a (a marker of immature granule cells) was increased in the hippocampus of P123H betaS Tg mice compared to that in wild-type controls. Immunohistochemical analysis revealed decreased expression of mature granule cell markers Calb1 and Gria1, along with increased expression of the microglial marker Iba1, in the hippocampal dentate gyrus region of P123H betaS Tg mice. P123H betaS Tg mice exhibited immature-like neuronal molecular expression patterns and microgliosis in the hippocampus. Pseudo-immaturity of dentate granule cells, associated with neuroinflammation, may be a shared endophenotype in the brains of at least a subgroup of patients with neuropsychiatric disorders and neurodegenerative diseases. PMID- 29976233 TI - Gastric versus postpyloric enteral nutrition in elderly patients (age >= 75 years) on mechanical ventilation: a single-center randomized trial. AB - BACKGROUND: The risk of ventilator-associated pneumonia (VAP) is reduced when postpyloric enteral nutrition (EN) is administered compared to when gastric EN is administered in specific populations. In the present study, we tested the hypothesis that postpyloric EN is superior to gastric EN in reducing the incidence of VAP in elderly patients (age >= 75 years) who are admitted to the intensive care unit (ICU) and require mechanical ventilation. METHODS: We performed a single-center randomized clinical trial involving elderly patients (age >= 75 years) who were admitted to the ICU and required mechanical ventilation. The patients were randomly assigned to either the postpyloric EN group or the gastric EN group. The primary outcome was the VAP rate. RESULTS: Of the 836 patients screened, 141 patients were included in the study (70 in the postpyloric EN group and 71 in the gastric EN group). The patients in the postpyloric EN group were 82.0 (75.0-99.0) years old (male 61.4%), and those in the gastric EN group were 82.0 (75.0-92.0) years old (male 63.4%). The Acute Physiology and Chronic Health Evaluation II scores were 28.09 +/- 6.75 in the postpyloric EN group and 27.80 +/- 7.60 in the gastric EN group (P = 0.43). VAP was observed in 8 of 70 patients (11.4%) in the postpyloric EN group and in 18 of 71 patients (25.4%) in the gastric EN group, which resulted in a significant between-group difference (OR 0.38, 95% CI 0.15-0.94; P = 0.04). In the postpyloric EN group, there were significant reductions in vomiting (12 patients in the postpyloric EN group vs 29 patients in the gastric EN group; OR 0.30, 95% CI 0.14-0.65; P = 0.002) and abdominal distension (18 patients in the postpyloric EN group vs 33 patients in the gastric EN group; OR 0.40, 95% CI 0.20-0.81; P = 0.01). No significant differences were observed between the two groups regarding mortality and other secondary outcomes. CONCLUSIONS: Our study demonstrated that, compared with gastric EN, postpyloric EN reduced the VAP rate among elderly patients who were admitted to the ICU and required mechanical ventilation. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-16008485 . Registered on 17 May 2016. PMID- 29976234 TI - WASH Benefits Bangladesh trial: system for monitoring coverage and quality in an efficacy trial. AB - BACKGROUND: Researchers typically report more on the impact of public health interventions and less on the degree to which interventions were followed implementation fidelity. We developed and measured fidelity indicators for the WASH Benefits Bangladesh study, a large-scale efficacy trial, in order to identify gaps between intended and actual implementation. METHODS: Community health workers (CHWs) delivered individual and combined water, sanitation, handwashing (WSH) and child nutrition interventions to 4169 enrolled households in geographically matched clusters. Households received free enabling technologies (insulated water storage container; sani-scoop, potty, double-pit, pour-flush latrine; handwashing station, soapy-water storage bottle), and supplies (chlorine tablets, lipid-based nutrient supplements, laundry detergent sachets) integrated with parallel behavior-change promotion. Behavioral objectives were drinking treated, safely stored water, safe feces disposal, handwashing with soap at key times, and age-appropriate nutrition behaviors. We administered monthly surveys and spot-checks to households from randomly selected clusters for 6 months early in the trial. If any fidelity measures fell below set benchmarks, a rapid response mechanism was triggered. RESULTS: In the first 3 months, functional water seals were detected in 33% (14/42) of latrines in the sanitation only arm; 35% (14/40) for the combined WSH arm; and 60% (34/57) for the combined WSH and Nutrition arm, all falling below the pre-set benchmark of 80%. Other fidelity indicators met the 65 to 80% uptake benchmarks. Rapid qualitative investigations determined that households concurrently used their own latrines with broken water seals in parallel with those provided by the trial. In consultation with the households, we closed pre-existing latrines without water seals, increased the CHWs' visit frequency to encourage correct maintenance of latrines with water seals, and discouraged water-seal removal or breakage. At the sixth assessment, 86% (51/59) of households were in sanitation only; 92% (72/78) in the combined WSH; and 93% (71/76) in the combined WSH and Nutrition arms had latrines with functional water seals. CONCLUSIONS: An intensive implementation fidelity monitoring and rapid response system proved beneficial for this efficacy trial. To implement a routine program at scale requires further research into an adaptation of fidelity monitoring that supports program effectiveness. TRIAL REGISTRATION: WASH Benefits Bangladesh: ClinicalTrials.gov, ID: NCT01590095 . Registered on 30 April 2012. PMID- 29976235 TI - The roles of neutrophil serine proteinases in idiopathic inflammatory myopathies. AB - BACKGROUND: Dermatomyositis and polymyositis are the best known idiopathic inflammatory myopathies (IIMs). Classic histopathologic findings include the infiltration of inflammatory cells into muscle tissues. Neutrophil serine proteinases (NSPs) are granule-associated enzymes and play roles in inflammatory cell migration by increasing the permeability of vascular endothelial cells. In this study, we aimed to find the roles of NSPs in pathogenesis of IIMs. METHODS: RNA and DNA were isolated to measure the relative expression of NSPs and their methylation levels. The expression of NSPs in serum and muscle tissues was tested by enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence, respectively. Serum from patients was used to culture the human dermal microvascular endothelial cells (HDMECs), and then we observed the influence of serum on expression of VE-cadherin, endothelial cell tube formation, and transendothelial migration of peripheral blood mononuclear cells (PBMCs). RESULTS: We found that the expression of NSPs was increased in PBMCs, serum, and muscle tissues of IIM patients; these NSPs were hypomethylated in the PBMCs of patients. Serum NSPs were positively correlated with clinical indicators of IIM patients, including lactic dehydrogenase, erythrocyte sedimentation rate, C reactive protein, immunoglobulin G, immunoglobulin M, and immunoglobulin A. Patients with anti-Jo-1, with anti-Ro-52, or without interstitial lung disease had lower levels of proteinase 3. Serum NSPs degraded the VE-cadherin of HDMECs, and serum NSP application increased the permeability of HDMECs. CONCLUSIONS: Our studies indicate, for the first time, that NSPs play an important role in muscle inflammatory cell infiltration by increasing the permeability of vascular endothelial cells in IIM patients. PMID- 29976236 TI - Obesity, hypertension and diuretic use as risk factors for incident gout: a systematic review and meta-analysis of cohort studies. AB - BACKGROUND: Gout treatment remains suboptimal. Identifying populations at risk of developing gout may provide opportunities for prevention. Our aim was to assess the risk of incident gout associated with obesity, hypertension and diuretic use. METHODS: We conducted a systematic review and meta-analysis of prospective and retrospective cohort studies in adults (age >= 18 years) from primary care or the general population, exposed to obesity, hypertension or diuretic use and with incident gout as their outcome. RESULTS: A total of 9923 articles were identified: 14 met the inclusion criteria, 11 of which contained data suitable for pooling in the meta-analysis. Four articles were identified for obesity, 10 for hypertension and six for diuretic use, with four, nine and three articles included respectively for each meta-analysis. Gout was 2.24 times more likely to occur in individuals with body mass index >= 30 kg/m2 (adjusted relative risk 2.24 (95% confidence interval) 1.76-2.86). Hypertensive individuals were 1.64 (1.34-2.01) and 2.11 (1.64-2.72) times more likely to develop gout as normotensive individuals (adjusted hazard ratio and relative risk respectively). Diuretic use was associated with almost 2.5 times the risk of developing gout compared to no diuretic use (adjusted relative risk 2.39 (1.57-3.65)). CONCLUSIONS: Obesity, hypertension and diuretic use are risk factors for incident gout, each more than doubling the risk compared to those without these risk factors. Patients with these risk factors should be recognised by clinicians as being at greater risk of developing gout and provided with appropriate management and treatment options. PMID- 29976237 TI - Evaluation of alpha-tubulin, detyrosinated alpha-tubulin, and vimentin in CTCs: identification of the interaction between CTCs and blood cells through cytoskeletal elements. AB - BACKGROUND: Circulating tumor cells (CTCs) are the major players in the metastatic process. A potential mechanism of cell migration and invasion is the formation of microtentacles in tumor cells. These structures are supported by alpha-tubulin (TUB), detyrosinated alpha-tubulin (GLU), and vimentin (VIM). In the current study, we evaluated the expression of those cytoskeletal proteins in CTCs. METHODS: Forty patients with breast cancer (BC) (16 early and 24 metastatic) were enrolled in the study. CTCs were isolated using the ISET platform and stained with the following combinations of antibodies: pancytokeratin (CK)/VIM/TUB and CK/VIM/GLU. Samples were analyzed with the ARIOL platform and confocal laser scanning microscopy. RESULTS: Fluorescence quantification revealed that the ratios CK/TUB, CK/VIM, and CK/GLU were statistically increased in MCF7 compared with more aggressive cell lines (SKBR3 and MDA-MB-231). In addition, all of these ratios were statistically increased in MCF7 cells compared with metastatic BC patients' CTCs (p = 0.0001, p = 0.0001, and p = 0.003, respectively). Interestingly, intercellular connections among CTCs and between CTCs and blood cells through cytoskeleton bridges were revealed, whereas microtentacles were increased in patients with CTC clusters. These intercellular connections were supported by TUB, VIM, and GLU. Quantification of the examined molecules revealed that the median intensity of TUB, GLU, and VIM was significantly increased in patients with metastatic BC compared with those with early disease (TUB, 62.27 vs 11.5, p = 0.0001; GLU, 6.99 vs 5.29, p = 0.029; and VIM, 8.24 vs 5.38, p = 0.0001, respectively). CONCLUSIONS: CTCs from patients with BC aggregate to each other and to blood cells through cytoskeletal protrusions, supported by VIM, TUB, and GLU. Quantification of these molecules could potentially identify CTCs related to more aggressive disease. PMID- 29976238 TI - Emergency Department disposition decisions and associated mortality and costs in ICU patients with suspected infection. AB - BACKGROUND: Following emergency department (ED) assessment, patients with infection may be directly admitted to the intensive care unit (ICU) or alternatively admitted to hospital wards or sent home. Those admitted to the hospital wards or sent home may experience future deterioration necessitating ICU admission. METHODS: We used a prospectively collected registry from two hospitals within a single tertiary care hospital network between 2011 and 2014. Patient information, outcomes, and costs were stored in the hospital data warehouse. Patients were categorized into three groups: (1) admitted directly from the ED to the ICU; (2) initially admitted to the hospital wards, with ICU admission within 72 hours of initial presentation; or (3) sent home from the ED, with ICU admission within 72 hours of initial presentation. Using multivariable logistic regression, we sought to compare outcomes and total costs between groups. Total costs were evaluated using a generalized linear model. RESULTS: A total of 657 patients were included; of these, 338 (51.4%) were admitted directly from the ED to the ICU, 246 (37.4%) were initially admitted to the wards and then to the ICU, and 73 (11.1%) were initially sent home and then admitted to the ICU. In-hospital mortality was lowest among patients admitted directly to the ICU (29.5%), as compared with patients admitted to the ICU from wards (42.7%) or home (61.6%) (P < 0.001). As compared with direct ICU admission, disposition to the ward was associated with an adjusted OR of 1.75 (95% CI, 1.22-2.50; P < 0.01) for mortality, and disposition home was associated with an adjusted OR of 4.02 (95% CI, 2.32-6.98). Mean total costs were lowest among patients directly admitted to the ICU ($26,748), as compared with those admitted from the wards ($107,315) and those initially sent home ($71,492) (P < 0.001). Cost per survivor was lower among patients directly admitted to the ICU ($37,986) than either those initially admitted to the wards ($187,230) or those sent home ($186,390) (P < 0.001). CONCLUSIONS: In comparison with direct admission to the ICU, patients with suspected infection admitted to the ICU who have previously been discharged home or admitted to the ward are associated with higher in-hospital mortality and costs. PMID- 29976239 TI - Next-generation sequencing profiling of mitochondrial genomes in gout. AB - BACKGROUND: Accumulating evidence implicates mitochondrial DNA (mtDNA) alleles, which are independent of the nuclear genome, in disease, especially in human metabolic diseases. However, this area of investigation has lagged behind in researching the nuclear alleles in complex traits, for example, in gout. METHODS: Next-generation sequencing was utilized to investigate the relationship between mtDNA alleles and phenotypic variations in 52 male patients with gout and 104 age matched male non-gout controls from the Taiwan Biobank whole-genome sequencing samples. Differences from a reference sequence (GRCh38) were identified. The sequence kernel association test (SKAT) was applied to identify gout-associated alleles in mitochondrial genes. The tools Polymorphism Phenotyping, Sorting Intolerant From Tolerant (SIFT), Predict the pathology of Mutations (PMUT), Human Mitochondrial Genome Database (mtDB), Multiple Alignment using Fast Fourier Transform (MAFFT), and Mammalian Mitochondrial tRNA Genes (Mamit-tRNA) were used to evaluate pathogenicity of alleles. Validation of selected alleles by quantitative polymerase chain reaction of single nucleotide polymorphisms (qPCR SNPs) was also performed. RESULTS: We identified 456 alleles in patients with gout and 640 alleles in non-gout controls with 274 alleles shared by both. Mitochondrial genes were associated with gout, with MT-CO3, MT-TA, MT-TC, and MT TT containing potentially pathogenic gout-associated alleles and displaying evidence of gene-gene interactions. All heteroplasmy levels of potentially pathogenic alleles exceeded metabolic thresholds for pathogenicity. Validation assays confirmed the next-generation sequencing results of selected alleles. Among them, potentially pathogenic MT-CO3 alleles correlated with high-density lipoprotein (HDL) levels (P = 0.034). CONCLUSION: This study provided two scientific insights. First, this was the most extensive mitochondrial genomic profiling associated with gout. Second, our results supported the roles of mitochondria in gout and HDL, and this comprehensive analysis framework can be applied to other diseases in which mitochondrial dysfunction has been implicated. PMID- 29976240 TI - Controlled efficacy trial confirming toltrazuril resistance in a field isolate of ovine Eimeria spp. AB - BACKGROUND: Coccidiosis due to Eimeria spp. infections in lambs causes increased mortality and substantial production losses, and anticoccidials are important for control of the infection. Anticoccidial resistance has been reported in poultry and swine, and we recently described reduced toltrazuril efficacy in ovine Eimeria spp. in some Norwegian sheep farms using a newly developed faecal oocyst count reduction test (FOCRT). The aim of the present study was to use a controlled efficacy trial to assess the efficacy of toltrazuril against a field isolate suspected of being resistant. METHODS: Twenty lambs, 17-22 days old and raised protected against exposure to coccidia, were infected with a field isolate of 100,000 Eimeria spp. oocysts. This isolate was obtained from a farm with a previously calculated drug efficacy of 56% (95% confidence interval: -433.9 to 96.6%). At day 7 post-infection, 10 of the lambs were orally treated with 20 mg/kg toltrazuril (Baycox Sheep vet., Bayer Animal Health), while the other 10 lambs (controls) were given physiological saline. Clinical examinations were conducted, and weight gains recorded. Daily faecal samples were scored for diarrhoea on a scale from 1 to 5, and oocyst excretion was determined using a modified McMaster technique. Oocysts were morphologically identified to species level. At 17-24 days post-infection, the lambs were euthanized and necropsied. RESULTS: The tested Eimeria isolate was resistant against toltrazuril, and resistance was seen in both pathogenic and non-pathogenic species. In addition, no significant differences in faecal score, growth, gross pathology or histological changes were identified between the two groups. The pathogenic E. ovinoidalis was the dominant species, and no significant difference in the individual prevalence of E. ovinoidalis post-treatment was found between treated (66.9%) and control lambs (61.9%). Other species identified included E. crandallis/weybridgensis, E. parva, E. marsica, E. faurei, E. pallida, E. ahsata and E. bakuensis. CONCLUSIONS: This study confirms toltrazuril resistance in ovine Eimeria spp.; in addition, the data support the use of FOCRT as an appropriate tool for field evaluation of anticoccidial efficacy. Due to limited anticoccidial treatment alternatives, these findings may have important implications for the sheep industry, particularly in northern Europe. PMID- 29976241 TI - Symptomatic bilateral pulmonary embolism without deep venous thrombosis in an adolescent following arthroscopic anterior cruciate ligament reconstruction: a case report and review of the literature. AB - BACKGROUND: Venous thromboembolism, specifically pulmonary embolism, is a rare complication following elective pediatric orthopedic surgery. Bilateral pulmonary embolism with associated pulmonary hemorrhage/infarct without concomitant deep vein thrombosis has never been reported following routine anterior cruciate ligament reconstruction in an adolescent. CASE PRESENTATION: A 16-year-old white girl presented with acute onset shortness of breath and pleuritic chest pain 6 days following elective anterior cruciate ligament reconstruction. After performing a thorough work-up, she was diagnosed as having provoked bilateral pulmonary embolism with associated pulmonary hemorrhage without concomitant deep vein thrombosis. She was treated successfully with 3 months of anticoagulation therapy with daily Lovenox (enoxaparin) injections. CONCLUSIONS: Symptomatic bilateral pulmonary embolism may have a good prognosis if it is diagnosed early and treated appropriately. It is important to appreciate the risk of provoked thromboembolic events in healthy adolescents undergoing arthroscopic knee surgery. PMID- 29976242 TI - DDIT4 promotes gastric cancer proliferation and tumorigenesis through the p53 and MAPK pathways. AB - BACKGROUND: Gastric cancer (GC) is one of the most common malignancies worldwide, particularly in China. DNA damage-inducible transcript 4 (DDIT4) is a mammalian target of rapamycin inhibitor and is induced by various cellular stresses; however, its critical role in GC remains poorly understood. The present study aimed to investigate the potential relationship and the underlying mechanism between DDIT4 and GC development. METHODS: We used western blotting, real-time polymerase chain reaction, and immunohistochemical or immunofluorescence to determine DDIT4 expression in GC cells and tissues. High-content screening, cell counting kit-8 assays, colony formation, and in vivo tumorigenesis assays were performed to evaluate cell proliferation. Flow cytometry was used to investigate cell apoptosis and cell cycle distribution. RESULTS: DDIT4 was upregulated in GC cells and tissue. Furthermore, downregulating DDIT4 in GC cells inhibited proliferation both in vitro and in vivo and increased 5-fluorouracil-induced apoptosis and cell cycle arrest. In contrast, ectopic expression of DDIT4 in normal gastric epithelial cells promoted proliferation and attenuated chemosensitivity. Further analysis indicated that the mitogen-activated protein kinase and p53 signaling pathways were involved in the suppression of proliferation, and increased chemosensitivity upon DDIT4 downregulation. CONCLUSION: DDIT4 promotes GC proliferation and tumorigenesis, providing new insights into the role of DDIT4 in the tumorigenesis of human GC. PMID- 29976243 TI - Acute catatonia on medical wards: a case series. AB - BACKGROUND: Catatonia is a behavioral syndrome which presents with an inability to move normally. It is associated with mood disorders and schizophrenia, as well as with medical and neurological conditions. It is an expression of the severity of the underlying condition. The awareness of catatonia among general medical doctors and even psychiatrists is poor. It is often seen as an historical diagnosis. Because of this, catatonia is often not recognized. If patients in catatonic states are not diagnosed, their condition is likely to progress with a risk of increased morbidity and potentially fatal outcomes. CASE PRESENTATION: We present a case series of three acutely unwell, frail, elderly medical patients (a 65-year-old Irish woman, a 75-year-old Irish woman, and a 68-year-old Irish woman) with a background of longstanding well-controlled psychiatric illnesses, who developed acute catatonia while being treated for medical conditions in a general medical in-patient setting. CONCLUSIONS: Catatonia is common in acute medical settings but is underdiagnosed due to the low awareness of the condition among both general medical doctors and psychiatrists. Within a short time period, we diagnosed and successfully treated three acutely unwell patients in acute medical settings. We would like to increase the awareness of catatonia among medical doctors. PMID- 29976245 TI - Health system barriers influencing perinatal survival in mountain villages of Nepal: implications for future policies and practices. AB - BACKGROUND: This paper aims to examine the health care contexts shaping perinatal survival in remote mountain villages of Nepal. Health care is provided through health services to a primary health care level-comprising district hospital, village health facilities and community-based health services. The paper discusses the implications for future policies and practice to improve health access and outcomes related to perinatal health. The study was conducted in two remote mountain villages in one of the most remote and disadvantaged mountain districts of Nepal. The district is reported to rank as the country's lowest on the Human Development Index and to have the worst child survival rates. The two villages provided a diversity of socio-cultural and health service contexts within a highly disadvantaged region. METHODS: The study findings are based on a qualitative study of 42 interviews with women and their families who had experienced perinatal deaths. These interviews were supplemented with 20 interviews with health service providers, female health volunteers, local stakeholders, traditional healers and other support staff. The data were analysed by employing an inductive thematic analysis technique. RESULTS: Three key themes emerged from the study related to health care delivery contexts: (1) Primary health care approach: low focus on engagement and empowerment; (2) Quality of care: poor acceptance, feeling unsafe and uncomfortable in health facilities; and (3) Health governance: failures in delivering health services during pregnancy and childbirth. CONCLUSIONS: The continuing high perinatal mortality rates in the mountains of Nepal are not being addressed due to declining standards in the primary health care approach, health providers' professional misbehaviour, local health governance failures, and the lack of cultural acceptance of formalised care by the local communities. In order to further accelerate perinatal survival in the region, policy makers and programme implementers need to immediately address these contextual factors at local health service delivery points. PMID- 29976244 TI - Activities of stromal and immune cells in HPV-related cancers. AB - The immune system is composed of immune as well as non-immune cells. As this system is a well-established component of human papillomavirus- (HPV)-related carcinogenesis, high risk human papillomavirus (hrHPV) prevents its routes and mechanisms in order to cause the persistence of infection. Among these mechanisms are those originated from stromal cells, which include the cancer-associated fibroblasts (CAFs), the myeloid-derived suppressor cells (MDSCs) and the host infected cells themselves, i.e. the keratinocytes. These types of cells play central role since they modulate immune cells activities to create a prosperous milieu for cancer development, and the knowledge how such interactions occur are essential for prognostic assessment and development of preventive and therapeutic approaches. Nevertheless, the precise mechanisms are not completely understood, and this lack of knowledge precluded the development of entirely efficient immunotherapeutic strategies for HPV-associated tumors. As a result, an intense work for attaining how host immune response works, and developing of effective therapies has been applied in the last decade. Based on this, this review aims to discuss the major mechanisms of immune and non-immune cells modulated by hrHPV and the potential and existing immunotherapies involving such mechanisms in HPV related cancers. It is noticed that the combination of immunotherapies has been demonstrated to be essential for obtaining better results, especially because the possibility of increasing the modulating capacity of the HPV-tumor microenvironment has been shown to be central in strengthening the host immune system. PMID- 29976246 TI - Role of (myo)fibroblasts in the development of vascular and connective tissue structure of the C38 colorectal cancer in mice. AB - BACKGROUND: It remains unclear if the vascular and connective tissue structures of primary and metastatic tumors are intrinsically determined or whether these characteristics are defined by the host tissue. Therefore we examined the microanatomical steps of vasculature and connective tissue development of C38 colon carcinoma in different tissues. METHODS: Tumors produced in mice at five different locations (the cecal wall, skin, liver, lung, and brain) were analyzed using fluorescent immunohistochemistry, electron microscopy and quantitative real time polymerase chain reaction. RESULTS: We found that in the cecal wall, skin, liver, and lung, resident fibroblasts differentiate into collagenous matrix producing myofibroblasts at the tumor periphery. These activated fibroblasts together with the produced matrix were incorporated by the tumor. The connective tissue development culminated in the appearance of intratumoral tissue columns (centrally located single microvessels embedded in connective tissue and smooth muscle actin-expressing myofibroblasts surrounded by basement membrane). Conversely, in the brain (which lacks fibroblasts), C38 metastases only induced the development of vascularized desmoplastic tissue columns when the growing tumor reached the fibroblast-containing meninges. CONCLUSIONS: Our data suggest that the desmoplastic host tissue response is induced by tumor-derived fibrogenic molecules acting on host tissue fibroblasts. We concluded that not only the host tissue characteristics but also the tumor-derived fibrogenic signals determine the vascular and connective tissue structure of tumors. PMID- 29976247 TI - WASH Benefits Bangladesh trial: management structure for achieving high coverage in an efficacy trial. AB - BACKGROUND: Water, sanitation, and hygiene (WASH) efficacy trials deliver interventions to the target population under optimal conditions to estimate their effects on outcomes of interest, to inform subsequent selection for inclusion in routine programs. A systematic and intensive approach to intervention delivery is required to achieve the high-level uptake necessary to measure efficacy. We describe the intervention delivery system adopted in the WASH Benefits Bangladesh study, as part of a three-paper series on WASH Benefits Intervention Delivery and Performance. METHODS: Community Health Workers (CHWs) delivered individual and combined WASH and nutrition interventions to 4169 enrolled households in geographically matched clusters. Households were provided with free enabling technologies and supplies, integrated with parallel behaviour-change promotion. Behavioural objectives were drinking treated, safely stored water, safe feces disposal, handwashing with soap at key times, and age-appropriate nutrition behaviours (birth to 24 months). The intervention delivery system built on lessons learned from prior WASH intervention effectiveness, implementation, and formative research studies. We recruited local CHWs, residents of the study villages, through transparent merit-based selection methods, and consultation with community leaders. CHW supervisors received training on direct intervention delivery, then trained their assigned CHWs. CHWs in turn used the technologies in their own homes. Each CHW counseled six to eight intervention households spread across a 0.2-2.2-km radius, with a 1:12 supervisor-to-CHW ratio. CHWs met monthly with supervisor-trainers to exchange experiences and adapt technology and behaviour-change approaches to evolving conditions. Intervention uptake was tracked through fidelity measures, with a priori benchmarks necessary for an efficacy study. RESULTS: Sufficient levels of uptake were attained by the fourth intervention assessment month and sustained throughout the intervention period. Periodic internal CHW monitoring resulted in discontinuation of a small number of low performers. CONCLUSIONS: The intensive intervention delivery system required for an efficacy trial differs in many respects from the system for a routine program. To implement a routine program at scale requires further research on how to optimize the supervisor-to-CHW-to-intervention household ratios, as well as other program costs without compromising program effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCC01590095 . Registered on 2 May 2012. PMID- 29976249 TI - Metagenomic analysis of basal ice from an Alaskan glacier. AB - BACKGROUND: Glaciers cover ~ 10% of land but are among the least explored environments on Earth. The basal portion of glaciers often harbors unique aquatic microbial ecosystems in the absence of sunlight, and knowledge on the microbial community structures and their metabolic potential is very limited. Here, we provide insights into the microbial lifestyle present at the base of the Matanuska Glacier, Alaska. RESULTS: DNA and RNA were extracted from samples of the Matanuska Glacier basal ice. Using Illumina MiSeq and HiSeq sequencing, we investigated the microbial diversity with the metagenomic shotgun reads and 16S ribosomal RNA data. We further assembled 9 partial and draft bacterial genomes from the metagenomic assembly, and identified key metabolic pathways such as sulfur oxidation and nitrification. Collectively, our analyses suggest a prevalence of lithotrophic and heterotrophic metabolisms in the subglacial microbiome. CONCLUSION: Our results present the first metagenomic assembly and bacterial draft genomes for a subglacial environment. These results extend our understanding of the chemical and biological processes in subglacial environments critically influenced by global climate change. PMID- 29976248 TI - Sex differences in the traumatic stress response: PTSD symptoms in women recapitulated in female rats. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) affects men and women differently. Not only are women twice as likely as men to develop PTSD, they experience different symptoms and comorbidities associated with PTSD. Yet the dearth of preclinical research on females leaves a notable gap in understanding the underlying neuropathology of this sex difference. METHODS: Using two standard measures of PTSD-like responses in rats, the acoustic startle response (ASR) and dexamethasone suppression test (DST), we tested the effects of traumatic stress in adult male and female rats using two rodent models of PTSD, single prolonged stress and predator exposure. We then examined the neural correlates underlying these responses with cFos and glucocorticoid receptor immunohistochemistry in brain regions implicated in the traumatic stress response. RESULTS: We now report that adult male and female rats across two models of PTSD show consistent sex specific responses that recapitulate fundamental differences of PTSD in men and women. Trauma-exposed males showed the well-established hyper-responsive phenotype of enhanced ASR and exaggerated negative feedback control of the hypothalamic-pituitary-adrenal axis, while the same traumatic event had little effect on these same measures in females. Dramatic sex differences in how trauma affected cFos and glucocorticoid receptor expression in the brain lend further support to the idea that the trauma response of male and female rats is fundamentally different. CONCLUSIONS: Two standard measures, ASR and DST, might suggest that females are resilient to the effects of traumatic stress, but other measures make it clear that females are not resilient, but simply respond differently to trauma. The next important question to answer is why. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience. The divergent effects of trauma in the brains of males and females begin to shed light on the neurobiological underpinnings of these sex differences, paving the way for improved diagnostics and therapeutics that effectively treat both men and women. PMID- 29976250 TI - Use of ECMO in ARDS: does the EOLIA trial really help? PMID- 29976251 TI - Achieving optimal technology and behavioral uptake of single and combined interventions of water, sanitation hygiene and nutrition, in an efficacy trial (WASH benefits) in rural Bangladesh. AB - BACKGROUND: Uptake matters for evaluating the health impact of water, sanitation and hygiene (WASH) interventions. Many large-scale WASH interventions have been plagued by low uptake. For the WASH Benefits Bangladesh efficacy trial, high uptake was a prerequisite. We assessed the degree of technology and behavioral uptake among participants in the trial, as part of a three-paper series on WASH Benefits Intervention Delivery and Performance. METHODS: This study is a cluster randomized trial comprised of geographically matched clusters among four districts in rural Bangladesh. We randomly allocated 720 clusters of 5551 pregnant women to individual or combined water, sanitation, handwashing, and nutrition interventions, or a control group. Behavioral objectives included; drinking chlorine-treated, safely stored water; use of a hygienic latrine and safe feces disposal at the compound level; handwashing with soap at key times; and age-appropriate nutrition behaviors (pregnancy to 24 months) including a lipid-based nutrition supplement (LNS). Enabling technologies and behavior change were promoted by trained local community health workers through periodic household visits. To monitor technology and behavioral uptake, we conducted surveys and spot checks in 30-35 households per intervention arm per month, over a 20-month period, and structured observations in 324 intervention and 108 control households, approximately 15 months after interventions commenced. RESULTS: In the sanitation arms, observed adult use of a hygienic latrine was high (94-97% of events) while child sanitation practices were moderate (37-54%). In the handwashing arms, handwashing with soap was more common after toilet use (67-74%) than nonintervention arms (18-40%), and after cleaning a child's anus (61-72%), but was still low before food handling. In the water intervention arms, more than 65% of mothers and index children were observed drinking chlorine treated water from a safe container. Reported LNS feeding was > 80% in nutrition arms. There was little difference in uptake between single and combined intervention arms. CONCLUSIONS: Rigorous implementation of interventions deployed at large scale in the context of an efficacy trial achieved high levels of technology and behavioral uptake in individual and combined WASH and nutrition intervention households. Further work should assess how to achieve similar uptake levels under programmatic conditions. TRIAL REGISTRATION: WASH Benefits Bangladesh: ClinicalTrials.gov, identifier: NCT01590095 . Registered on April 30, 2012. PMID- 29976252 TI - Systematic review of resilience-enhancing, universal, primary school-based mental health promotion programs. AB - BACKGROUND: Wellbeing and resilience are essential in preventing and reducing the severity of mental health problems. Equipping children with coping skills and protective behavior can help them react positively to change and obstacles in life, allowing greater mental, social and academic success. This systematic review studies the implementation and evaluation of universal, resilience-focused mental health promotion programs based in primary schools. METHODS: A systematic review of literature used five primary databases: PsycINFO; Web of Science; PubMed; Medline; Embase and The Cochrane Library; and keywords related to (a) health education, health promotion, mental health, mental health promotion, social and emotional wellbeing; (b) school health service, student, schools, whole-school; (c) adolescent, child, school child, pre-adolescent; (d) emotional intelligence, coping behavior, emotional adjustment, resilienc*, problem solving, to identify relevant articles. Articles included featured programs that were universally implemented in a primary school setting and focused on teaching of skills, including coping skills, help-seeking behaviors, stress management, and mindfulness, and were aimed at the overall goal of increasing resilience among students. RESULTS: Of 3087 peer-reviewed articles initially identified, 475 articles were further evaluated with 11 reports on evaluations of 7 school-based mental health promotion programs meeting the inclusion criteria. Evaluation tools used in program evaluation are also reviewed, with successful trends in evaluations discussed. Encouraging results were seen when the program was delivered by teachers within the schools. Length of programing did not seem important to outcomes. Across all 7 programs, few long-term sustained effects were recorded following program completion. CONCLUSIONS: This review provides evidence that mental health promotion programs that focus on resilience and coping skills have positive impacts on the students' ability to manage daily stressors. PMID- 29976253 TI - Potent O-antigen-deficient (rough) mutants of Salmonella Typhimurium secreting Lawsonia intracellularis antigens enhance immunogenicity and provide single immunization protection against proliferative enteropathy and salmonellosis in a murine model. AB - The obligate intracellular pathogen Lawsonia intracellularis (LI), the etiological agent of proliferative enteropathy (PE), poses a substantial economic loss in the swine industry worldwide. In this study, we genetically engineered an O-antigen-deficient (rough) Salmonella strain secreting four selected immunogenic LI antigens, namely OptA, OptB, LfliC, and Lhly. The genes encoding these antigens were individually inserted in the expression vector plasmid pJHL65, and the resultant plasmids were transformed into the ?asd ?lon ?cpxR ?rfaL Salmonella Typhimurium (ST) strain JOL1800. The individual expression of the selected LI antigens in JOL1800 was validated by an immunoblotting assay. We observed significant (P < 0.05) induction of systemic IgG and mucosal IgA responses against each LI antigen or Salmonella outer membrane protein in mice immunized once orally with a mixture of four JOL1800-derived strains. Further, mRNA of IL-4 and IFN-gamma were highly upregulated in splenic T cells re-stimulated in vitro with individual purified antigens. Subsequently, immunized mice showed significant protection against challenge with 106.9 TCID50 LI or 2 * 109 CFU of a virulent ST strain. At day 8 post-challenge, no mice in the immunized groups showed the presence of LI-specific genomic DNA (gDNA) in stool samples, while 50% of non-immunized mice were positive for LI-specific gDNA. Further, all the immunized mice survived the virulent ST challenge, compared to a 20% mortality rate observed in the control mice. Collectively, the constructed rough ST-based LI vaccine candidate efficiently elicited LI and ST-specific humoral and cell mediated immunity and conferred proper dual protection against PE and salmonellosis. PMID- 29976254 TI - Impact of prehospital medical evacuation (MEDEVAC) transport time on combat mortality in patients with non-compressible torso injury and traumatic amputations: a retrospective study. AB - BACKGROUND: In combat operations, patients with traumatic injuries require expeditious evacuation to improve survival. Studies have shown that long transport times are associated with increased morbidity and mortality. Limited data exist on the influence of transport time on patient outcomes with specific injury types. The objective of this study was to determine the impact of the duration of time from the initial request for medical evacuation to arrival at a medical treatment facility on morbidity and mortality in casualties with traumatic extremity amputation and non-compressible torso injury (NCTI). METHODS: We completed a retrospective review of MEDEVAC patient care records for United States military personnel who sustained traumatic amputations and NCTI during Operation Enduring Freedom between January 2011 and March 2014. We grouped patients as traumatic amputation and NCTI (AMP+NCTI), traumatic amputation only (AMP), and neither AMP nor NCTI (Non-AMP/NCTI). Analysis was performed using chi squared tests, Fisher's exact tests, Cochran-Armitage Trend tests, Shapiro-Wilks tests, Wilcoxon and Kruskal-Wallis techniques and Cox proportional hazards regression modeling. RESULTS: We reviewed 1267 records, of which 669 had an injury severity score (ISS) of 10 or greater and were included in the analysis. In the study population, 15.5% sustained only amputation injuries (n=104, AMP only), 10.8% sustained amputation and NCTI (n=72, AMP+NCTI), and 73.7% did not sustain either an amputation or an NCTI (n=493, Non-AMP/NCTI). AMP+NCTI had the highest mortality (16.7%) with transport time greater than 60 min. While the AMP+NCTI group had decreasing survival with longer transport times, AMP and Non AMP/NCTI did not exhibit the same trend. CONCLUSIONS: A decreased transport time from the point of injury to a medical treatment facility was associated with decreased mortality in patients who suffered a combination of amputation injury and NCTI. No significant association between transport time and outcomes was found in patients who did not sustain NCTI. Priority for rapid evacuation of combat casualties should be given to those with NCTI. PMID- 29976256 TI - Expression of Concern to: Does ovary need D-chiro-inositol? PMID- 29976255 TI - Ablation of tau causes an olfactory deficit in a murine model of Parkinson's disease. AB - Parkinson's disease is diagnosed upon the presentation of motor symptoms, resulting from substantial degeneration of dopaminergic neurons in the midbrain. Prior to diagnosis, there is a lengthy prodromal stage in which non-motor symptoms, including olfactory deficits (hyposmia), develop. There is limited information about non-motor impairments and there is a need for directed research into these early pathogenic cellular pathways that precede extensive dopaminergic death in the midbrain. The protein tau has been identified as a genetic risk factor in the development of sporadic PD. Tau knockout mice have been reported as an age-dependent model of PD, and this study has demonstrated that they develop motor deficits at 15-months-old. We have shown that at 7-month-old tau knockout mice present with an overt hyposmic phenotype. This olfactory deficit correlates with an accumulation of alpha-synuclein, as well as autophagic impairment, in the olfactory bulb. This pathological feature becomes apparent in the striatum and substantia nigra of 15-month-old tau knockout mice, suggesting the potential for a spread of disease. Initial primary cell culture experiments have demonstrated that ablation of tau results in the release of alpha-synuclein enriched exosomes, providing a potential mechanism for disease spread. These alterations in alpha synuclein level as well as a marked autophagy impairment in the tau knockout primary cells recapitulate results seen in the animal model. These data implicate a pathological role for tau in early Parkinson's disease. PMID- 29976257 TI - Differences in gene mutations according to gender among patients with colorectal cancer. AB - BACKGROUND: The incidence, site distribution, and mortality rates of patients with colorectal cancer differ according to gender. We investigated gene mutations in colorectal patients and wanted to examine gender-specific differences. METHODS: A total of 1505 patients who underwent surgical intervention for colorectal cancer were recruited from March 2000 to January 2010 at Taipei Veterans' General Hospital and investigated for gene mutations in K-ras, N-ras, H ras, BRAF, loss of 18q, APC, p53, SMAD4, TGF-beta, PIK3CA, PTEN, FBXW7, AKT1, and MSI. RESULTS: There were significant differences between male and female patients in terms of tumor location (p < 0.0001) and pathological stage (p = 0.011). The female patients had significantly more gene mutations in BRAF (6.4 vs. 3.3%, OR 1.985, p = 0.006), TGF-beta (4.7 vs. 2.5%, OR 1.887, p = 0.027), and revealed a MSI-high status (14.0 vs. 8.3%, OR 1.800, p = 0.001) than male patients. Male patients had significantly more gene mutations in N-ras (5.1 vs. 2.3%, OR 2.227, p = 0.012); however, the significance was maintained only for mutations in BRAF (OR 2.104, p = 0.038), MSI-high status (OR 2.003 p = 0.001), and N-ras (OR 3.000, p = 0.010) after the groups were divided by tumor site. CONCLUSION: Gene mutations in BRAF, MSI-high status, and N-ras differ according to gender among patients with colorectal cancer. PMID- 29976258 TI - Laboulbeniales (Fungi: Ascomycota) infection of bat flies (Diptera: Nycteribiidae) from Miniopterus schreibersii across Europe. AB - BACKGROUND: Bat flies (Diptera: Nycteribiidae and Streblidae) are obligate, blood sucking ectoparasites of bats with specialized morphology, life-cycle and ecology. Bat flies are occasionally infected by different species of Laboulbeniales (Fungi: Ascomycota), microscopic fungal ectoparasites belonging to three genera: Arthrorynchus spp. are restricted to the Eastern Hemisphere, while species of Gloeandromyces and Nycteromyces occur on Neotropical bat flies. Little is known about the distribution and host specificity of Arthrorynchus spp. on bat flies. In this study, we focused on sampling bat flies from the cave-dwelling bat species Miniopterus schreibersii. Bat and ectoparasite collection took place in Albania, Croatia, Hungary, Italy, Portugal, Slovakia, Spain and Switzerland. Flies were inspected for Laboulbeniales infections. RESULTS: Six hundred sixty seven bat flies of five species were collected: Nycteribia latreillii, N. pedicularia, N. schmidlii, Penicillidia conspicua, and P. dufourii. Laboulbeniales infection was observed on 60 specimens (prevalence = 9%). Two Laboulbeniales species, Arthrorhynchus eucampsipodae and A. nycteribiae, were present on three bat fly species. All observations of A. eucampsipodae were on N. schmidlii, and A. nycteribiae was present on P. conspicua and P dufourii. Arthrorhynchus eucampsipodae is, for the first time, reported from Slovakia and Spain. Arthrorhynchus nycteribiae represents a new country record for Portugal and Slovakia. There were no significant differences among infection rates in different countries. Females of N. schmidlii showed a higher infection rate than males with an observable trend (P = 0.0502). No sex differences in infection rate for P. conspicua and P. dufourii were detected. Finally, thallus density was significantly lower in N. schmidlii compared to P. conspicua and P. dufourii. CONCLUSIONS: With this study, we contribute to the knowledge of the geographical distribution and host specificity of Laboulbeniales fungi associated with ectoparasitic bat flies within Europe. We discuss parasite prevalence and host specificity in the light of our findings and the available literature. Penicillidia conspicua is unambiguously the main host species for A. nycteribiae based on our and previous findings. Differences in parasite intensity and sex biased infections of the fungi are possible depending on the species. PMID- 29976259 TI - Outbreak of Escherichia coli O157 Phage Type 32 linked to the consumption of venison products. AB - In September 2015, an outbreak of Escherichia coli Phage Type 32 with an indistinguishable multi locus variable number tandem repeat analysis profile was identified in Scotland. Twelve cases were identified; nine primary cases, two secondary and one asymptomatic case. Extensive food history investigations identified venison products containing wild venison produced by a single food business operator as the most likely source of the outbreak. Of the nine primary cases, eight had consumed venison products, and one case had not eaten venison themselves but had handled and cooked raw venison in the household. This was the first reported outbreak of Shiga toxin-producing Escherichia coli (STEC) linked to venison products in the UK, and was also notable due to the implicated products being commercially produced and widely distributed. In contrast, previous venison outbreaks reported from other countries have tended to be smaller and related to individually prepared carcases. The outbreak has highlighted some important knowledge gaps in relation to STEC in venison that are currently been investigated via a number of research studies. PMID- 29976260 TI - How Consistent are Genetic Factors in Explaining Leisure-Time Physical Activity and Sport Participation? The Portuguese Healthy Families Study. AB - This study investigates how consistent genetic factors are, as measured by heritability estimates (h2), in the leisure-time physical activity index (LTPAI) and sport participation index (SPI) from early (10-14 yrs) to late adolescence (15-19 yrs). The sample comprises 12,385 subjects from 3,378 Portuguese nuclear families. Height and weight were measured and body mass index (BMI) was calculated, and the LTPAI and SPI were estimated by questionnaire. Socioeconomic status (SES) was assessed by parental occupation. Analyses were done using S.A.G.E. software. Our results showed that h2 estimates for the LTPAI and SPI in the two age groups (10-14 yrs and 15-19 yrs) were stable: for the LTPAI, h2 = 0.297 and 0.322, respectively; and for the SPI, h2 = 0.413 and 0.428, respectively. Sibling correlations and environmental correlations are higher in the younger age group for both the LTPAI and the SPI. Spousal correlations are higher in the younger age group for the LTPAI and lower for the SPI than the older group. Parent-offspring correlations are similar in both age groups for the LTPAI and SPI. In conclusion, the influence of genetic factors on physical activity and sport participation remains stable across age in adolescence. However, variation in sibling correlations - in particular, environmental correlations - was observed. These findings suggest that shared/non-shared environmental factors express different degrees of importance across age. Future intervention programs aiming to promote change in behaviors need to consider these results to bring about positive changes in physical activity and sport participation behaviors within the family setting. PMID- 29976261 TI - Assessing the relative validity of a new, web-based, self-administered 24 h dietary recall in a French-Canadian population. AB - OBJECTIVE: To assess the relative validity of a new, web-based, self-administered 24 h dietary recall, the R24W, for assessment of energy and nutrient intakes among French Canadians. DESIGN: Each participant completed a 3d food record (FR) and the R24W on three occasions over a 4-week period. Intakes of energy and of twenty-four selected nutrients assessed by both methods were compared. SETTING: Quebec City metropolitan area. SUBJECTS: Fifty-seven women and fifty men (mean (sd) age: 47.2 (13.3) years). RESULTS: Equivalent proportions of under-reporters were found with the R24W (15.0%) and the FR (23.4%). Mean (sd) energy intake from the R24W was 7.2% higher than that from the FR (10 857 (3184) kJ/d (2595 (761) kcal/d) v. 10 075 (2971) kJ/d (2408 (710) kcal/d); P<0.01). Significant differences in mean nutrient intakes between the R24W and the FR ranged from 54.8% (i.e. lower value with R24W) for niacin to +40.0% (i.e. higher value with R24W) for alcohol. Sex- and energy-adjusted deattenuated correlations between the two methods were significant for all nutrients except Zn (range: 0.35-0.72; P<0.01). Cross-classification demonstrated that 40.0% of participants were classified in the same quartile with both methods, while 40.0% were classified in the adjacent quartile and only 3.6% were grossly misclassified (1st v. 4th quartile). Analysis of Bland-Altman plots revealed proportional bias between the two assessment methods for 8/24 nutrients. CONCLUSIONS: These data suggest that the R24W presents an acceptable relative validity as compared with the FR for estimating usual dietary intakes in a cohort of French Canadians. PMID- 29976262 TI - Qualitative study on identification of common coping strategies practised by Indigenous Peoples (Orang Asli) in Peninsular Malaysia during periods of food insecurity. AB - OBJECTIVE: To examine the types of coping strategies practised by Indigenous women or Orang Asli (OA) in Peninsular Malaysia during times of food shortage and to determine the level of severity for food insecurity that will trigger each specific coping strategy. DESIGN: A qualitative case study was conducted. Pertinent information about each type of coping strategy was gathered by in-depth interviews. To gauge the level of severity for each of the coping strategies, focus group discussions (FGD) were held. Thematic analysis was used for data analysis. SETTING: OA villages in the states of Kelantan, Pahang, Perak and Selangor, Malaysia. SUBJECTS: Sixty-one OA women from three ethnic groups (Senoi, Proto-Malay and Negrito) for in-depth interviews and nineteen OA women from the Proto-Malay ethnic group for three FGD. RESULTS: The findings identified twenty nine different coping strategies and these were divided into two main themes: food consumption (sub-themes of food consumption included dietary changes, diversification of food sources, decreasing the number of people and rationing) and financial management (sub-themes of financial management included increasing household income, reducing expenses for schooling children and reducing expenses on daily necessities). Three levels of severity were derived: less severe, severe and very severe. CONCLUSIONS: This information would enable local authorities or non-governmental organisations to more precisely target and plan interventions to better aid the OA communities needing assistance in the areas of food sources and financial management. PMID- 29976263 TI - Preliminary evaluation of the Healthy Savings Program: a novel health insurance based wellness programme to encourage healthy food purchases. AB - OBJECTIVE: To examine level of participation and satisfaction with the Healthy Savings Program (HSP), a programme that provides price discounts on healthier foods. DESIGN: For Study 1, a survey was distributed to a random sample of adults who were invited to participate in a version of the HSP that provided a discount for the purchase of fresh produce and discounts on other healthier foods. In Study 2, interviews were conducted with a convenience sample of adults invited to participate in a version of the HSP that provided price discounts on specific products only (no fresh produce discount). SETTING: The HSP is provided to all employer-based insurance plan members of a large health plan. Employers can choose to enhance the version of the HSP that their employees receive by paying for a weekly discount on fresh produce. SUBJECTS: Employees in employer groups that received the enhanced HSP (Study 1) and employees in an employer group (Study 2) that received the standard HSP. RESULTS: Among survey respondents in Study 1, 69.3 % reported using the HSP card. Most were satisfied with the fresh produce discount and ease of use of the HSP card. Satisfaction was lower for selection of participating stores, amounts of discounts and selection of discounted products. In Study 2, barriers to the use of the HSP card cited included the limited number of participating stores and the limited selection of discounted products. CONCLUSIONS: Satisfaction with some elements of the HSP was high while other elements may need improvement to increase programme use. PMID- 29976264 TI - Evaluation and comparison of the National Tuberculosis (TB) Surveillance System in Ireland before and after the introduction of the Computerised Electronic Reporting System (CIDR). AB - We evaluated and compared the completeness, timeliness, simplicity, usefulness and flexibility between the former National Tuberculosis (TB) Surveillance System (NTBSS) and the newer Computerised Infectious Disease Reporting System (CIDR). Completeness was assessed by examining the field completion of key variables and median time from diagnosis to notification was calculated to evaluate timeliness. Differences between the two systems on completeness and timeliness were statistically assessed using chi2 and Wilcoxon rank-sum test, respectively. An online questionnaire on simplicity, flexibility and usefulness was sent to key stakeholders. Time and diagnosis-related variables were more complete in NTBSS, while variables on drug susceptibility, HIV and laboratory tests were more complete in CIDR (P < 0.05). The median time notification interval increased significantly in CIDR (P < 0.05). Stakeholders thought that CIDR is simpler (37.5%), more useful (41.7%) and more flexible (29.2%) than NTBSS. This study demonstrated that CIDR did not improve data completeness and decreased timeliness of notification. Simplicity, usefulness and flexibility were improved but qualitative methods should be applied to further explore these results. PMID- 29976265 TI - Using a distributed lag non-linear model to identify impact of temperature variables on haemorrhagic fever with renal syndrome in Shandong Province. AB - Haemorrhagic fever with renal syndrome (HFRS) is transmitted to humans mainly by rodents and this transmission could be easily influenced by meteorological factors. Given the long-term changes in climate associated with global climate change, it is important to better identify the effects of meteorological factors of HFRS in epidemic areas. Shandong province is one of the most seriously suffered provinces of HFRS in China. Daily HFRS data and meteorological data from 2007 to 2012 in Shandong province were applied. Quasi-Poisson regression with the distributed lag non-linear model was used to estimate the influences of mean temperature and Diurnal temperature range (DTR) on HFRS by sex, adjusting for the effects of relative humidity, precipitation, day-of-the-week, long-term trends and seasonality. A total of 6707 HFRS cases were reported in our study. The two peaks of HFRS were from March to June and from October to December, particularly, the latter peak in 2012. The estimated effects of mean temperature and DTR on HFRS were non-linear. The immediate and strong effect of low temperature and high DTR on HFRS was found. The lowest temperature -8.86 degrees C at lag 0 days indicated the largest related relative risk (RRs) with the reference (14.85 degrees C), respectively, 1.46 (95% CI 1.11-1.90) for total cases, 1.33 (95% CI 1.00-1.78) for the males and 1.76 (95% CI 1.12-2.79) for the females. Highest DTR was associated with a higher risk on HFRS, the largest RRs (95% CI) were obtained when DTR = 15.97 degrees C with a reference at 8.62 degrees C, with 1.26 (0.96 1.64) for total cases and 1.52 (0.97-2.38) for the female at lag 0 days, 1.22 (1.05-1.41) for the male at lag 5 days. Non-linear lag effects of mean temperature and DTR on HFRS were identified and there were slight differences for different sexes. PMID- 29976266 TI - Using formative research with older adults to inform a community physical activity programme: Get Healthy, Get Active. AB - : AimThe purpose of this formative study was to explore current knowledge and attitudes towards physical activity, as well as perceived barriers, facilitators and opportunities for physical activity participation among older adults living in the community. The findings have subsequently informed the design, delivery and recruitment strategies of a local community physical activity intervention programme which forms part of Sport England's national Get Healthy, Get Active initiative. BACKGROUND: There is a growing public health concern regarding the amount of time spent in sedentary and physical activity behaviours within the older adult population. METHODS: Between March and June 2016, 34 participants took part in one of six focus groups as part of a descriptive formative study. A homogenous purposive sample of 28 community dwelling white, British older adults (six male), aged 65-90 years (M=78, SD=7 years) participated in one of five focus group sessions. An additional convenience pragmatic sub-sample of six participants (three male), aged 65-90 years (M=75, SD=4 years), recruited from an assisted living retirement home participated in a sixth focus group. Questions for focus groups were structured around the PRECEDE stage of the PRECEDE-PROCEDE model of health programme design, implementation and evaluation. Questions addressed knowledge, attitudes and beliefs towards physical activity, as well as views on barriers and opportunities for physical activity participation. All data were transcribed verbatim. Thematic analysis was then conducted with outcomes represented as pen profiles.FindingsConsistent views regarding both the potential physical and psychosocial benefits of physical activity were noted regardless of living status. The themes of, opportunities and awareness for physical activity participation, cost, transport, location and season/weather varied between participants living in an assisted living retirement home and community dwelling older adults. Further comparative research on the physical activity requirements of older adults living in assisted living versus community settings are warranted. PMID- 29976267 TI - Single nucleotide polymorphisms in the growth hormone and IGF type-1 (IGF1) genes associated with carcass traits in Santa Ines sheep. AB - Polymorphisms in the growth hormone (GH) and IGF type-1 (IGF1) genes have been associated with the economic traits in farm animals, including BW of some sheep breeds. However, it remains unknown if these polymorphisms also affect carcass traits in sheep. Thus, we aimed to identify polymorphisms in the GH and IGF1 genes in Santa Ines sheep in order to describe their allelic and genotypic frequencies as well as to test the hypotheses that they are associated with the carcass traits. Fragments of 4550 bp (IGF1) and 1194 bp (GH) were sequenced in up to 191 lambs. In all, 18 polymorphisms were identified in the IGF1 and 21 in the GH gene. The IGF1 polymorphisms rs430457475, rs412470350, rs409110739 and rs400113576 showed an additive effect on the internal carcass length (-0.9265+/ 0.4223), rump girth (-2.9285+/-1.1473), rib yield (-1.0003+/-0.4588) and neck weight (-0.0567+/-0.0278), respectively. In addition, the polymorphisms rs58957314 in the GH affected the rib weight (-0.4380+/-0.1272) and rib yield ( 2.2680+/-0.6970), loin weight (-0.1893+/-0.0516) and loin yield (-0.9423+/ 0.3259), palette weight (-0.2265+/-0.0779) and palette yield (-0.9424+/-0.4184), leg weight (-0.3960+/-0.1375), neck weight (-0.0851+/-0.0394) and carcass finishing score (-0.1700+/-0.0839). These results allow us to conclude that there are polymorphisms in the IGF1 and GH genes associated with carcass traits in Santa Ines sheep, which can provide important information for marker-assisted selection. PMID- 29976268 TI - Assessing epidemiology of leprosy and socio-economic distribution of cases. AB - Leprosy still represents a serious health problem in a number of countries, including Brazil. Although leprosy has been associated with poverty for a long time, it is still difficult to accurately define this relationship. Here, we evaluated in an endemic municipality the progress from 1995 to 2015 of epidemiological indicators to establish if there were any strong associations between social indicators and the occurrence of leprosy. An ecological study was conducted using the SINAN database (Brazilian leprosy-national notifiable diseases information system) in combination with georeferencing of leprosy cases. The georeferencing used the ArcGis programme and occurrence of cases was evaluated in relation to the Health Vulnerability Index (HVI), an indicator that categorises socio-economic and sanitation factors. The data identified a marked decrease in the overall prevalence of leprosy, a reduction in the new case detection rate and a reduction in the number of cases with grade 2 disabilities (albeit with transient peaks in 2007 and 2015). Logistic regression analysis showed association of detection rates with elevated HVI. Thus, while the epidemiological indicators point to the elimination of leprosy, there is evidence of hidden cases and an association between higher rates of leprosy detection and greater social vulnerability remain. PMID- 29976269 TI - Genetic (co)variances between milk mineral concentration and chemical composition in lactating Holstein-Friesian dairy cows. AB - Milk mineral concentration is important from both the perspective of processing milk into dairy products and its nutritive value for human consumption. Precise estimates of genetic parameters for milk mineral concentration are lacking because of the considerable resources required to collect vast phenotypes quantities. The milk concentration of calcium (Ca), potassium (K), magnesium (Mg), sodium (Na) and phosphorus (P) in the present study was quantified from mid IR spectroscopy on 12 223 test-day records from 1717 Holstein-Friesian cows. (Co)variance components were estimated using random regressions to model both the additive genetic and within-lactation permanent environmental variances of each trait. The coefficient of genetic variation averaged across days-in-milk (DIM) was 6.93%, 3.46%, 6.55%, 5.20% and 6.68% for Ca, K, Mg, Na and P concentration, respectively; heritability estimates varied across lactation from 0.31+/-0.05 (5 DIM) to 0.67+/-0.04 (181 DIM) for Ca, from 0.18+/-0.03 (60 DIM) to 0.24+/-0.05 (305 DIM) for K, from 0.08+/-0.03 (15 DIM) to 0.37+/-0.03 (223 DIM) for Mg, from 0.16+/-0.03 (30 DIM) to 0.37+/-0.04 (305 DIM) for Na and from 0.21+/-0.04 (12 DIM) to 0.57+/-0.04 (211 DIM) for P. Genetic correlations within the same trait across different DIM were almost unity between adjacent DIM but weakened as the time interval between pairwise compared DIM lengthened; genetic correlations were weaker than 0.80 only when comparing both peripheries of the lactation. The analysis of the geometry of the additive genetic covariance matrix revealed that almost 90% of the additive genetic variation was accounted by the intercept term of the covariance functions for each trait. Milk protein concentration and mineral concentration were, in general, positively genetically correlated with each other across DIM, whereas milk fat concentration was positively genetically correlated throughout the entire lactation with Ca, K and Mg; the genetic correlation with fat concentration changed from negative to positive with Na and P at 243 DIM and 50 DIM, respectively. Genetic correlations between somatic cell score and Na ranged from 0.38+/-0.21 (5 DIM) to 0.79+/-0.18 (305 DIM). Exploitable genetic variation existed for all milk minerals, although many national breeding objectives are probably contributing to an indirect positive response to selection in milk mineral concentration. PMID- 29976270 TI - Individual and food environmental factors: association with diet. AB - OBJECTIVE: To examine the associations of individual and food environmental factors with fruit and vegetable (F&V) intake in a city in a low-to-middle-income country (LMIC). DESIGN: Cross-sectional. SETTING: Representative sample of the Brazilian Primary Care service known as the Health Academy Program (HAP) in Belo Horizonte, a Brazilian city. SUBJECTS: Using a conceptual model as a guide, individual and food environment data were obtained through: (i) face-to-face interviews with participants aged 20 years or older; and (ii) F&V food store audits. A broad set of individual, household, and community and consumer nutrition environment variables was investigated. Multilevel linear regression was used to quantify area-level variations in F&V intake and to estimate associations with the factors. RESULTS: Eighteen HAP centres were selected and 2944 participants and 336 food stores were included. F&V intake varied between contexts, being higher in areas with better socio-economic conditions and food store quality, such as specialised F&V markets. Individual-level factors, including age, income, food insecurity, stage of change, self-efficacy and decisional balance, were significantly associated with F&V intake. After controlling for individual-level characteristics, greater F&V intake was also associated with higher quality of food stores. CONCLUSIONS: In one of the first studies to comprehensively assess the food environment in an LMIC, individual level factors accounted for the largest variation in F&V intake; however, the food environment was also important, because area-level variables explained 10.5 % of the F&V intake variation. The consumer nutrition environment was more predictive of healthy eating than was the community nutrition environment. The findings suggest new possibilities for interventions. PMID- 29976271 TI - Carotid Artery Atherosclerosis: A Review on Heritability and Genetics. AB - Carotid atherosclerosis (CAS) is associated with increased cardiovascular risk, and therefore, assessing the genetic versus environmental background of CAS traits is of key importance. Carotid intima-media-thickness and plaque characteristics seem to be moderately heritable, with remarkable differences in both heritability and presence or severity of these traits among ethnicities. Although the considerable role of additive genetic effects is obvious, based on the results so far, there is an important emphasis on non-shared environmental factors as well. We aimed to collect and summarize the papers that investigate twin and family studies assessing the phenotypic variance attributable to genetic associations with CAS. Genes in relation to CAS markers were overviewed with a focus on genetic association studies and genome-wide association studies. Although the role of certain genes is confirmed by studies conducted on large populations and meta-analyses, many of them show conflicting results. A great focus should be on future studies elucidating the exact pathomechanism of these genes in CAS in order to imply them as novel therapeutic targets. PMID- 29976272 TI - Seasonal variation of Pseudomonas aeruginosa in culture positive otitis externa in South East England. AB - Otitis externa is the inflammation of the external auditory canal. The disease is common and shows a seasonal variation with a greater incidence in warmer months. Pseudomonas aeruginosa is a common pathogen in otitis externa and in this retrospective study, we show a corresponding seasonal variation in the proportional incidence of P. aeruginosa isolates from otitis externa in South East England. In total 7770 patients were diagnosed with otitis externa over a period of 9 years from January 2008 to December 2016. P. aeruginosa was isolated from 2802 patients (proportional incidence of 36%). Incidence was higher in the months of August, September and October and in patients between 5 and 15 years of age. We postulate a combination of increased contact with water during warm weather in the holiday season and increased rainfall in the preceding season as a putative mechanism for the seasonal trends. PMID- 29976273 TI - Mental health problems, benefits and tackling discrimination. AB - SummaryPoverty is strongly associated with mental illness. Access to state benefits can be a lifeline for people with mental health problems in times of hardship and can assist them on their journey of recovery. However, benefit application processes can discriminate against those with mental illness and can result in individuals unjustly missing out on support. Clinical evidence from mental health professionals can ameliorate these challenges and ensure that people get access to financial help.Declaration of interestDr Billy Boland is on the advisory board of the Money and Mental Health Policy Institute. PMID- 29976275 TI - Midterm Follow-up of Coronary Artery Bypass Grafting with 64-Slice Multi-detector Computed Tomography: Identification of Risk Factors Affecting Graft Patency. AB - To identify the risk factors that are associated with the midterm coronary artery bypass grafting (CABG) functionality by assessing patency of left internal mammary artery (LIMA) graft and saphenous vein (SV) graft with 64-slice multi detector computed tomography (64-MDCT).Methods Patients who underwent CABG operation and postoperative 64-MDCT follow-up examinations from August 2012 to December 2015 were included. The graft patent status was classified into patent and poor patent according to MDCT findings predominantly on 3D reconstructed images by two radiologists. The clinical data and imaging findings of the patients were collected and compared between the patent group and poor patent group. Univariate analysis and the multivariate logistic regression analysis were performed to identify the risk factors that affect graft patency.Results Among 341 patients in the study, there were 330 LIMA grafts [326 anastomosed to the left anterior descending artery (LAD), 4 to right coronary artery (RCA)] and 564 SV grafts (SVG) [100 anastomosed to the diagonal branch (D), 226 to the obtuse marginal branch (OM), and 238 to the RCA territory]. The approximal vessel stenosis exceeding 90% occurred in 268 of 292 patent LIMA grafts, and in 1 of 34 poor patent grafts (chi 2=167, P<0.001). The patency rate was higher when SVG was anastomosed to OM (85.4%) or RCA territory (81.9%) than to D (69.0%) (chi 2=15.471, P=0.004). The proximal target vessel stenosis < 90% (OR= 0.015, 95% CI: 0.01-0.14, P=0.000) was independently associated with the closure risk of LIMA grafts, the dyslipidemia (OR= 1.52, 95% CI: 1.0-2.5, P=0.048), history of diabetes (OR = 1.28, 95% CI : 0.90-2.26, P=0.045) and typical angina symptoms (OR=1.81, 95% CI :1.33-4.15, P=0.003) were independently associated with the closure risk of SVG. Conclusions The proximal LAD stenosis less than 90% was adversely associated with graft patency in LIMA recipients; dyslipidemia, diabetes and angina symptoms were associated with the midterm failure in SVG recipients. The choice of the target anastomosis sites may affect the patency of SVG. PMID- 29976274 TI - Effects of Nesting Material on the Toxicologic Assessment of Cyclophosphamide in Crl:CD1(ICR) Mice. AB - The provision of nesting material benefits mice by reducing cold stress, improving feed conversion, increasing litter size, and improving adaptive immunity. The effects of toxins are sensitive to environmental changes, and the introduction of novel items can alter results in some toxicologic studies. We hypothesized that nesting material would reduce stress and positively alter immunologic parameters in Crl:CD1(ICR) mice, thus changing typical results from a well-studied immunomodulating drug, cyclophosphamide. A 13-wk study assessed the following treatments in a factorial design (n = 4; 32 cages total): nesting (0 or 10 g) and drug (50 mg/kg cyclophosphamide or 10 mL/kg saline; IP weekly). Detailed examinations and body weights were recorded weekly, and nests were scored twice weekly. Fecal pellets were collected at 0, 4, 6, and 12 wk for analysis of corticosterone metabolites. At study termination, clinical pathology and immune parameters were collected, a necropsy performed, and lymphoid organs and adrenal glands were submitted for histopathology. All expected results due to cyclophosphamide were observed. Nesting reduced the proportion of mice with piloerection, and body weights were highest in saline-nested male mice. No differences in hematology, clinical chemistry, or absolute lymphocyte counts were observed. Corticosterone metabolites in all nested groups were not different from baseline levels but all nonnested groups had higher levels than baseline. Nested cyclophosphamide-treated groups had significantly lower corticosterone levels than nonnested cyclophosphamide-treated groups. This study illustrates that nesting material does not alter the results of a standard toxicology study of cyclophosphamide but alleviates study-related stress and improves mouse welfare. PMID- 29976276 TI - Irrationality of Allogeneic Red Blood Cell Transfusion in Intraoperative Cell Salvage Patients: a Retrospective Analysis. AB - Objective Although intraoperative cell salvage (ICS) has been widely used to reduce the demand for allogeneic blood transfusion, patients who use ICS approach still have not completely avoided chances of blood transfusion. This study aims to investigate the rate of allogeneic red blood cell(RBC) transfusion in patients receiving ICS, and to evaluate irrationality of allogeneic RBC transfusion and its risk factors.Methods Medical records of all patients associated with ICS approach from January 2013 to July 2014 were retrospectively reviewed. Theoretical hemoglobin level after reinfusion of salvaged RBC at the end of operations was estimated. Irrational transfusion was defined as initiating allogeneic transfusion with theoretical hemoglobin above 100 g/L. The clinical variables, including the surgical department, gender, age, body weight, ratio of blood loss to estimated blood volume(EBV), salvaged blood volume and preoperative hemoglobin level were subsequently compared between patients who received rational transfusion and those did not. Logistic regression was performed to identify the risk factors for irrationality of allogeneic RBC transfusion in these patients.Results Of 1487 patients with ICS approach in this study, the rate of allogeneic RBC transfusion was 31.4%(467/1487), and the rate of irrational allogeneic RBC transfusion was 26.0% (341/1313). Patients with irrational transfusion were younger (t=4.656, P<0.001), with lower body weight (t=3.910, P<0.001) and slightly lower preoperative HGB level (t=2.822, P=0.005) than those with rational transfusion, but had significantly larger salvaged blood volume (U= 10.926, P<0.001) and higher ratio of blood loss to EBV (U=-17.067, P<0.001), disregarding whether they preoperatively met anemia criteria or not (U=-1.396, P=0.163). Preoperative hemoglobin level (OR=1.975, P=0.005) and the ratio of blood loss/EBV (OR=5.392, P<0.001) were independent risk factors leading to the irrational allogeneic RBC transfusion.Conclusions The irrationality of allogeneic RBC transfusion existed in ICS patients, which may be associated with the preoperative hemoglobin level and the ratio of blood loss to EBV. Determining the HGB levels before transfusion is required to avoid unnecessary blood administration. Doctors should keep their knowledge in blood management updated and improve their awareness of rational transfusion for a better patients care. PMID- 29976277 TI - Effects of Short-term High Dose Atorvastatin on Left Ventricular Remodeling in Patients with First Time Attack of Anterior Acute Myocardial Infarction. AB - Objects The aim of this trial was to evaluate the effect of short-term high-dose atorvastatin therapy on levels of high-sensitivity C-reactive protein (hs-CRP), malonaldehyde (MDA), endothelin-1(ET-1), matrix metalloproteinases (MMPs), and left ventricular (LV) remodeling in patients with first time attack of acute anterior myocardial infarction (AAMI) .Methods A hundred and three patients with first time attack of AAMI who underwent successful primary percutaneous coronary intervention were randomized to receive atorvastatin 40 mg once daily for 1 week followed by 20 mg once daily (intensive treatment group, IT group, n=49), or atorvastatin 20 mg once daily (standard treatment group, ST group, n=54). Plasma levels of hs-CRP, MDA, ET-1, MMP-2 and MMP-9 were measured on admission, at 1 week, 2 weeks and 6 months follow up and compared between the IT group and ST group. Echocardiography was performed on admission, at 2 week, and 1 year follow up. The left ventricular end-diastolic volume (LVEDV), left ventricular end systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were measured at each echocardiographic examination and compared between the IT group and ST group.Results Plasma levels of hs-CRP (F=7.718, P=0.009), ET-1 (F=7.882, P=0.006), MMP-9 (F=4.834, P=0.028) and pro-BNP (F=4.603, P=0.032) were significantly lower at 1 week after initial onset of AAMI in the IT group compared with the ST group. The changes of LVEDV, LVESV, and LVEF at the 1 year follow-up from the admission did not differ between the IT group and the ST group (t=0.722, P=0.444; t=1.228, P=0.221; t=1.354, P=0.187, repectively).Conclusions Short-term high-dose atorvastatin treatment for AAMI was associated with lower hs CRP, ET-1 and MMP-9 levels compared to the standard dose treatment. However, this beneficial effect is not likely to related to the left ventricular remodeling. PMID- 29976278 TI - A Cohort Study of Incidences and Risk Factors for Thromboembolic Events in Patients with Idiopathic Membranous Nephropathy. AB - Objective The aims of this study were to assess incidences and characteristics of arterial thromboembolic events (ATEs) and venous thromboembolic events (VTEs) in Chinese patients with idiopathic membranous nephropathy (IMN), and to identify the predisposing risk factors of them.Methods A total of 766 consecutive Chinese patients with IMN were enrolled in this retrospective cohort study. The cumulative incidences of newly diagnosed ATEs and VTEs were calculated using Kaplan-Meier methods. Univariable risk prediction model analysis followed by multivariable survival analysis was used to evaluate the potential risk factors of ATE and VTE.Results At 0.5, 1, 2, 3, and 5 years after biopsy diagnosis of IMN, the cumulative incidence of newly diagnosed ATEs were 4.3%, 5.7%, 6.3%, 7.1%, and 8.0%, and of newly diagnosed VTEs were 5.9%, 6.8%, 6.9%, 7.0%, and 7.2%, respectively. In 78 ATEs events (71 patients), cardiovascular diseases, thrombotic ischemic stroke (IS) and peripheral artery disease accounted for 50%, 45% and 5% respectively; in 60 VTEs events(53 patients), the deep vein thrombosis, renal vein thrombosis and pulmonary embolism accounted for 60%, 13% and 27% respectively. At the time of event, 42.1% patients with ATEs and 81.5% patients with VTEs were at nephrotic syndrome(NS) status (chi 2=18.1, P<0.001). Severe proteinuria, aging, smoking, hypertension and prior ATE history were associated with ATEs. Aging was demonstrated as the independent risk factor for ATEs (P=0.001), and hypoalbuminemia was the dominant independent risk factor for VTEs (P=0.03). Conclusions Patients with IMN have increased incidences of ATEs and VTEs, and most of events occurred within the first 6 months of the disease. IS was very common in ATEs in our cohort. Severe proteinuria and classic risk factors for atherosclerosis were associated with onset of ATEs. Hypoalbuminemia independently predicted VTEs. Risks of both ATEs and VTEs were particularly high in the status of NS, particularly VTEs. PMID- 29976279 TI - Cortical Thinning Pattern of Bulbar- and Spinal-onset Amyotrophic Lateral Sclerosis: a Surface-based Morphometry Study. AB - Objective The precise cortical thinning pattern has not been elucidated for onset subtypes of amyotrophic lateral sclerosis (ALS). The current study aimed to investigate the altered cortical thickness signatures of the bulbar-onset and spinal-onset ALS using surface-based morphometry, and the correlation between the cortical thickness of positive brain regions and clinical variables of the patients.Methods MR structural images were obtained from 65 ALS patients (15 bulbar-onset, 50 spinal-onset) and 65 normal controls (NCs) on a 3.0T MRI system. The structural images were segmented into gray matter and white matter based on DARTEL method and the central cortical surfaces were reconstructed using projection-based thickness method. The surface-based morphometry was performed to identify the alteration of cortical thickness in overall ALS patients, bulbar onset ALS patients and spinal-onset ALS patients comparing to the NCs. The correlation analysis was applied between the clinical variables and the mean cortical thickness of the abnormal brain regions with age and sex as covariates.Results The cortex thinning of ALS patients was located in the left precentral gyrus, left postcentral gyrus, right gyrus rectus and right medial precentral gyrus. The bulbar-onset ALS (ALS-bulbar) presented motor cortex thinning of left precentral gyrus and right supplementary motor cortex, and the spinal-onset ALS (ALS-spinal) suffered from extra-motor cortex thinning of left posterior insula and right gyrus rectus. In ALS patients, the thickness of right gyrus rectus was negatively correlated to disease duration (r=-0.311, P=0.013), the thickness of right precentral gyrus was positively correlated to the score of ALS functional rating score-revise (ALSFRS-R) (r=0.271, P=0.032). The thickness of motor cortices in ALS-bulbar were not correlated to disease duration and ALSFRS-R score; the thickness of extra-motor cortices in ALS-spinal were negatively correlated to the disease duration (left insula, r=-0.409, P=0.004; right gyrus rectus, r=-0.351, P=0.014).Conclusion The findings suggested that bilateral motor cortex thinning presented in bulbar-onset ALS and extra-motor cortex thinning presented in spinal-onset ALS. The motor cortex thinning may be the intrinsic pathophysiological change that associated to the disease disability, and extra-motor cortex thinning may be secondary pathophysiological change that associated to disease duration. PMID- 29976280 TI - Effect of Red Ginseng Extract on the Pharmacokinetics of Aspirin Metabolite in Sprague Dawley Rats. AB - Objective To investigate whether red ginseng extract can affect the pharmacokinetics of aspirin in Sprague Dawley (SD) rats.Methods Totally, 12 male SD rats were randomly and uniformly divided into the aspirin group (aspirin 10.42 mg.kg -1) and the combined group (red ginseng extraction 0.5 mg.g -1 + aspirin 10.42 mg.kg -1). After intragastric administration of drugs, blood samples (0.5 ml once) were drawn from orbit at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 10 and 12 hours after dosing. Plasma concentration of salicylic acid (metabolite of aspirin) was detected with ultraviolet-visible high performance liquid chromatography (HPLC). The reliability of the procedure was verified with respect to specificity, linearity, accuracy, precision, extraction recovery and matrix effect, and stability. Pharmacokinetics of salicylic acid was evaluated by using non-compartmental model. Results The method was proved to be validated. Compared with the aspirin group, area under the curve (AUC 0-t) and maximum concentration of salicylic acid in rats of the combined group increased obviously (P<0.01), while clearance rate (CLz/F) decreased clearly (P<0.05).Conclusion The in vivo study showed that red ginseng extract can help the internal absorption of aspirin, and delay the in vivo metabolism of aspirin. PMID- 29976281 TI - Relationship Between Traditional Chinese Medicine(TCM)Constitution and TCM Syndrome in the Diagnosis and Treatment of Chronic Diseases. AB - Chronic diseases are global threats to human health. By applying the traditional Chinese medicine (TCM) theory of body constitution to the treatment of chronic diseases, and comprehensively identifying and differentiating the syndrome, disease, and constitution, TCM can be fully used in the diagnosis and treatment of chronic diseases. In this manner, population-based and evidence-based modern medicine can organically align with the individual-focused and speculation-based TCM, with subsequent benefits for the control of chronic diseases, reducing their burden on human health. PMID- 29976282 TI - A Literature Review of Antithrombotic Therapy for Patients of Venous Thromboembolic Events with Comorbidity of Coronary Heart Disease. AB - Patients with venous thromboembolism (VTE) and concurrent coronary heart disease (CHD) are not rare in clinic. The main challenge in the treatment for these patients is that the antithrombotic therapies for VTE and CHD are different from each other, but the combination of the two therapeutic strategies would increase the risk of bleeding. There is a need to optimize the antithrombotic therapeutic scheme on the basis of individual conditional, in order to balance the therapeutic effects and the bleeding risk. This article discussed the appropriate antithrombotic therapy when balancing the effectiveness and the risk in different circumstance of concurrence of VTE and CHD, such as combining anticoagulation therapy, dual antiplatelet therapy (DAPT), triple antithrombotic therapy (TAT), thrombolytic therapy and extending therapy, in order to provide safe, standard and effective therapeutic schemes for the clinical management of these patients. In the meantime, this article also provides perspectives regarding the application of novel non-vitamin K anticoagulants (NOACs) and the assessment tools of bleeding risk. PMID- 29976283 TI - Successful Resuscitation with Extracorporeal Membrane Oxygenation in a Case with Prolonged Cardiac Arrest. AB - This case study describes a 25-year-old patient who had a witnessed cardiac arrest in the medical intensive care unit. The patient received 107 minutes of cardiopulmonary resuscitation before the veno-arterial extracorporeal membrane oxygenation was initiated. During extracorporeal life support, the patient's cardiac function improved. The patient was weaned from extracorporeal membrane oxygenation on day 6 and was discharged without physical and neurological complications on day 28. The successful resuscitation in this case attributed to high-quality CCPR and timely ECMO support. PMID- 29976284 TI - Early Diagnosis of Recurrent Optic Neuritis Using Contrast-Enhanced T2 Fluid attenuated Inversion Recovery Imaging: a Case Report. AB - The diagnosis of the recurrent optic neuritis is commonly established clinically, and sometimes it could be challenging because the involved optic nerve does not always show significant enhancement on conventional contrast enhanced-T1 weighted imaging (CE-T1WI). In this paper, we reported a middle-aged female with early diagnosis of recurrent optic neuritis using contrast-enhanced T2 fluid-attenuated inversion recovery imaging (CE-T2FLAIR). The involved optic nerve presented evident enhancement on CE-T2FLAIR and no enhancement on CE-T1WI. This case suggested that the CE-T2FLAIR may be a useful diagnostic tool specifically for the recurrent optic neuritis in clinical practice. PMID- 29976285 TI - Fatal or Irreversible Bleeding and Ischemic Events With Rivaroxaban in Acute Coronary Syndrome. AB - BACKGROUND: Net clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact. OBJECTIVES: A comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact. METHODS: In the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding. RESULTS: Rivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: -11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient years of exposure in the group taking 2.5 mg orally twice per day. CONCLUSIONS: Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965). PMID- 29976286 TI - Ischemia and Bleeding on the Horns of a Dilemma: Do Only Hard Endpoints Count? PMID- 29976287 TI - Global Prospective Safety Analysis of Rivaroxaban. AB - BACKGROUND: The efficacy of direct oral anticoagulants (DOACs) for stroke prevention in patients with atrial fibrillation (AF) has been established in clinical trials. However, well-conducted, prospective, real-world observational studies of the safety and effectiveness of DOACs are needed. OBJECTIVES: This study sought to assess the real-world safety profile of rivaroxaban through a pooled analysis of patients with AF enrolled in the XANTUS (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation) program worldwide. METHODS: A pre-planned pooled analysis of the XANTUS, XANAP (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia), and XANTUS-EL (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region) registries was performed. Patients with AF newly starting rivaroxaban for stroke prevention were followed for 1 year. Primary outcomes were treatment-emergent major bleeding, adverse events (AEs)/serious AEs, and all-cause death. Secondary outcomes included treatment-emergent thromboembolic events and nonmajor bleeding. Major outcomes were centrally adjudicated. RESULTS: Overall, 11,121 patients were included (mean age 70.5 +/- 10.5 years; female 42.9%). Comorbidities included heart failure (21.2%), hypertension (76.2%), and diabetes (22.3%). Event rates were: events/100 patient years: major bleeding 1.7 (95% confidence interval [CI]: 1.5 to 2.0; lowest: Latin America 0.7; highest: Western Europe, Canada, and Israel 2.3); all-cause death 1.9 (95% CI: 1.6 to 2.2; lowest: Eastern Europe 1.5; highest: Latin America, Middle East, and Africa 2.7); and stroke or systemic embolism 1.0 (95% CI: 0.8 to 1.2; lowest: Latin America 0; highest: East Asia 1.8). One-year treatment persistence was 77.4% (lowest: East Asia 66.4%; highest: Eastern Europe 84.4%). CONCLUSIONS: This large, prospective, real-world analysis in 11,121 patients from 47 countries showed low bleeding and stroke rates in rivaroxaban treated patients with AF, with low treatment discontinuation in different regions of the world. Results were broadly consistent across regions. (Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation [XANTUS]; NCT01606995; Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Latin America and EMEA Region [XANTUS-EL]; NCT01800006; and Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation in Asia [XANAP]; NCT01750788). PMID- 29976288 TI - Stroke Prevention in Atrial Fibrillation: What Is Real World, and What Do Real World Data Reveal? PMID- 29976290 TI - Low-Density Lipoprotein Triglycerides: Widening the Atherogenic Landscape in CVD Risk Assessment. PMID- 29976289 TI - Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease. AB - BACKGROUND: Hypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL TG. OBJECTIVES: The aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study. METHODS: Fasting plasma RLP C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored. RESULTS: RLP-C and LDL TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 * 10-8). CONCLUSIONS: RLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy. PMID- 29976291 TI - Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction. AB - BACKGROUND: Vasopressor agents could have certain specific effects in patients with cardiogenic shock (CS) after myocardial infarction, which may influence outcome. Although norepinephrine and epinephrine are currently the most commonly used agents, no randomized trial has compared their effects, and intervention data are lacking. OBJECTIVES: The goal of this paper was to compare in a prospective, double-blind, multicenter, randomized study, the efficacy and safety of epinephrine and norepinephrine in patients with CS after acute myocardial infarction. METHODS: The primary efficacy outcome was cardiac index evolution, and the primary safety outcome was the occurrence of refractory CS. Refractory CS was defined as CS with sustained hypotension, end-organ hypoperfusion and hyperlactatemia, and high inotrope and vasopressor doses. RESULTS: Fifty-seven patients were randomized into 2 study arms, epinephrine and norepinephrine. For the primary efficacy endpoint, cardiac index evolution was similar between the 2 groups (p = 0.43) from baseline (H0) to H72. For the main safety endpoint, the observed higher incidence of refractory shock in the epinephrine group (10 of 27 [37%] vs. norepinephrine 2 of 30 [7%]; p = 0.008) led to early termination of the study. Heart rate increased significantly with epinephrine from H2 to H24 while remaining unchanged with norepinephrine (p < 0.0001). Several metabolic changes were unfavorable to epinephrine compared with norepinephrine, including an increase in cardiac double product (p = 0.0002) and lactic acidosis from H2 to H24 (p < 0.0001). CONCLUSIONS: In patients with CS secondary to acute myocardial infarction, the use of epinephrine compared with norepinephrine was associated with similar effects on arterial pressure and cardiac index and a higher incidence of refractory shock. (Study Comparing the Efficacy and Tolerability of Epinephrine and Norepinephrine in Cardiogenic Shock [OptimaCC]; NCT01367743). PMID- 29976292 TI - Norepinephrine as a First-Line Inopressor in Cardiogenic Shock: Oversimplification or Best Practice? PMID- 29976293 TI - Association of IL-8 With Infarct Size and Clinical Outcomes in Patients With STEMI. AB - BACKGROUND: Little is known about the role of interleukin (IL)-8 in patients with acute ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: The aims of this study were to evaluate, in STEMI patients, the temporal profile of IL-8 and possible associations with left ventricular (LV) function and remodeling, infarct size, microvascular obstruction, myocardial salvage, and future clinical events. METHODS: A total of 258 patients with STEMI were included. Blood samples were drawn before and immediately after percutaneous coronary intervention (PCI), at day 1, and after 4 months. Cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were registered during 12 months' follow-up and all-cause mortality after median 70 months' follow-up. RESULTS: Patients with IL-8 levels greater than the median measured both immediately after PCI and at day 1 had larger final infarct size, lower LV ejection fraction, larger increase in LV end-diastolic volume, and higher frequency of microvascular obstruction. After multivariate adjustment, high IL-8 levels at day 1 were associated with an increased risk of developing a large MI and having reduced LV ejection fraction at 4 months, also after adjustment for peak troponin value. Patients with IL-8 levels in the highest quartile measured at all sampling points were more likely to have a clinical event during the first 12 months after the MI and had lower overall survival during long-term follow-up. CONCLUSIONS: High levels of circulating IL-8 were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI, suggesting IL-8 as a future therapeutic target based on its important role in post-infarction inflammation. PMID- 29976294 TI - Understanding and Targeting Inflammation in Acute Myocardial Infarction: An Elusive Goal. PMID- 29976295 TI - Neoplasia and the Heart: Pathological Review of Effects With Clinical and Radiological Correlation. AB - The intersection of oncological and cardiovascular diseases is an increasingly recognized phenomenon. This recognition has led to the emergence of cardio oncology as a true subspecialty. This field is not simply limited to primary cardiac tumors or complications of chemotherapeutic medications. Rather, it also encompasses metastatic cardiovascular complications and secondary cardiovascular effects of the underlying neoplasia. This review will broadly cover primary and metastatic cardiac neoplasms, as well as secondary cardiovascular effects of extracardiac neoplasia (e.g., amyloidosis, carcinoid valvulopathy, and chemotherapeutic cardiotoxicities). PMID- 29976296 TI - The Cardiologist and the Cancer Patient: Challenges to Cardio-Oncology (or Onco Cardiology) and Call to Action. PMID- 29976297 TI - FcgammaRIIa: A New Cardiovascular Risk Marker. PMID- 29976298 TI - Physical Activity to Reduce Weight and Cardiovascular Events: A Wrong Focus Regarding a Shiver Contention. PMID- 29976299 TI - Reply: Physical Activity to Reduce Weight and Cardiovascular Events: A Wrong Focus Regarding a Shiver Contention. PMID- 29976300 TI - Thoracic Aortic Calcification: Diagnostic, Prognostic, and Management Considerations. AB - Thoracic aortic calcification (TAC) is associated with adverse cardiovascular outcomes, and for the cardiovascular imager, is predominantly encountered in 4 settings: 1) incidentally, for example, during a coronary artery calcium scan; 2) as part of dedicated screening; 3) in the evaluation of an embolic event; or 4) in procedural planning. This review focuses on TAC in these contexts. Within atherosclerosis, TAC is common, variable in extent, and begins in the intima with a patchy distribution. In metabolic disorders, aortitis, and radiation-associated cardiovascular disease, calcification preferentially involves the media and is often more concentric. As an incidental finding, atherosclerotic TAC provides limited incremental discriminative value, and current data do not support screening. After an embolic event, the demonstration of thoracic atheroma provides diagnostic clarity, but has limited treatment implications. Before any procedure, the plan often changes if the most severe form of TAC, a porcelain aorta, is discovered. PMID- 29976301 TI - Losing Track by Tracking Speckles. PMID- 29976302 TI - The Authors Reply. PMID- 29976303 TI - Changing Paradigms for Bioprosthetic Valves: Yearly Surveillance Echocardiographic Studies Early Post-Op and Routine Anticoagulation. PMID- 29976304 TI - Will Cardiac Magnetic Resonance Change the Management of Severe Aortic Stenosis Patients? PMID- 29976305 TI - Comparing Cardiac Magnetic Resonance-Guided Versus Angiography-Guided Treatment of Patients With Stable Coronary Artery Disease: Results From a Prospective Randomized Controlled Trial. AB - OBJECTIVES: The purpose of this study was the prospective and randomized evaluation of cardiovascular endpoints and quality of life in patients with stable coronary artery disease comparing a cardiac magnetic resonance (CMR)-based management strategy with a coronary angiography-based approach. BACKGROUND: Evidence from trials prospectively evaluating the role of CMR in clinical pathways and decision processes is limited. METHODS: Patients with symptomatic CAD were randomized to diagnostic coronary angiography (group 1) or adenosine stress CMR (group 2). The primary endpoint was the composite of cardiac death and nonfatal myocardial infarction. Quality of life was assessed using the Seattle Angina Questionnaire at baseline and during follow-up. RESULTS: Two hundred patients were enrolled. In group 1, 45 revascularizations (45.9%) were performed. In group 2, 27 patients (28.1%) were referred to revascularization because of ischemia on CMR. At 12-month follow-up, 7 primary events occurred: 3 in group 1 (event rate 3.1%) and 4 in group 2 (event rate 4.2%), with no statistically significant difference (p = 0.72). Within the next 2 years, 6 additional events could be observed, giving 4 events in group 1 and 9 events in group 2 (event rate 4.1% vs. 9.4%; p = 0.25). Group 2 showed significant quality-of-life improvement after 1 year in comparison to group 1. CONCLUSIONS: A CMR-based management strategy for patients with stable coronary artery disease was safe, reduced revascularization procedures, and resulted in better quality of life at 12-month follow-up, though noninferiority could not be proved. Optimal timing for reassessment remains to be investigated. (Magnetic Resonance Adenosine Perfusion Imaging as Gatekeeper of Invasive Coronary Intervention [MAGnet]; NCT02580851). PMID- 29976307 TI - Caring for Each Other While We Care for Others. PMID- 29976306 TI - Magnetic Resonance Perfusion Imaging to Guide Management of Patients With Stable Ischemic Heart Disease. PMID- 29976308 TI - Emergency Nurses and Code Lavender. PMID- 29976309 TI - Response to Lenaghan Preventing ED Violence article. PMID- 29976310 TI - Response to Delgadillo Sexual Assault Nurse Examiner article. PMID- 29976311 TI - Nonurgent Visits to Emergency Departments in Iran and the Health System Research Agenda: A Call for Action. PMID- 29976312 TI - Acute Pain Management Amid an Opioid Crisis. PMID- 29976313 TI - Clinical Practice Guideline: Prevention of Blood Specimen Hemolysis in Peripherally-Collected Venous Specimens. PMID- 29976314 TI - Social Networking by Emergency Nurses. PMID- 29976315 TI - Decreasing Malpractice Risk in the Emergency Department. PMID- 29976316 TI - This One is Scary. PMID- 29976317 TI - Avoid Insulin-Related Adverse Events When Treating Hyperkalemia. PMID- 29976319 TI - "Say BOO to the FLU!" Introduction of the Seasonal Influenza Peer Vaccination Programme in the Emergency Department and AMAU. PMID- 29976320 TI - A Clinic on the Edge of Genocide. PMID- 29976321 TI - Pediatric Phlebotomy: Taking the Bite Out of Dracula. PMID- 29976322 TI - Reducing LWBS Rates With a Focused Friendly Face Out Front. PMID- 29976323 TI - Neoliberal welfare reform and single parents' mental health. PMID- 29976324 TI - A painful lesson: are we repeating previous mistakes in pain management? PMID- 29976325 TI - The growing threat of China's HIV epidemic. PMID- 29976326 TI - Public transport and the promotion of unhealthy food and drink. PMID- 29976327 TI - Effects of restrictions to Income Support on health of lone mothers in the UK: a natural experiment study. AB - BACKGROUND: In the UK, lone parents must seek work as a condition of receiving welfare benefits once their youngest child reaches a certain age. Since 2008, the lower age limit at which these Lone Parent Obligations (LPO) apply has been reduced in steps. We used data from a nationally representative, longitudinal, household panel study to analyse the health effects of increased welfare conditionality under LPO. METHODS: From the Understanding Society survey, we used data for lone mothers who were newly exposed to LPO when the age cutoff was reduced from 7 to 5 years in 2012 (intervention group 1) and from 10 to 7 years in 2010 (intervention group 2), as well as lone mothers who remained unexposed (control group 1) or continuously exposed (control group 2) at those times. We did difference-in-difference analyses that controlled for differences in the fixed characteristics of participants in the intervention and control groups to estimate the effect of exposure to conditionality on the health of lone mothers. Our primary outcome was the difference in change over time between the intervention and control groups in scores on the Mental Component Summary (MCS) of the 12-item Short-Form Health Survey (SF-12). FINDINGS: The mental health of lone mothers declined in the intervention groups compared with the control groups. For intervention group 1, scores on the MCS decreased by 1.39 (95% CI 1.29 to 4.08) compared with control group 1 and by 2.29 (0.00 to 4.57) compared with control group 2. For intervention group 2, MCS scores decreased by 2.45 ( 0.57 to 5.48) compared with control group 1 and by 1.28 (-1.45 to 4.00) compared with control group 2. When pooling the two intervention groups, scores on the MCS decreased by 2.13 (0.10 to 4.17) compared with control group 1 and 2.21 (0.30 to 4.13) compared with control group 2. INTERPRETATION: Stringent conditions for receiving welfare benefits are increasingly common in high-income countries. Our results suggest that requiring lone parents with school-age children toseek work as a condition of receiving welfare benefits adversely affects their mental health. FUNDING: UK Medical Research Council, Scottish Government Chief Scientist Office, and National Health Service Research Scotland. PMID- 29976328 TI - Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study. AB - BACKGROUND: Interest in the use of cannabis and cannabinoids to treat chronic non cancer pain is increasing, because of their potential to reduce opioid dose requirements. We aimed to investigate cannabis use in people living with chronic non-cancer pain who had been prescribed opioids, including their reasons for use and perceived effectiveness of cannabis; associations between amount of cannabis use and pain, mental health, and opioid use; the effect of cannabis use on pain severity and interference over time; and potential opioid-sparing effects of cannabis. METHODS: The Pain and Opioids IN Treatment study is a prospective, national, observational cohort of people with chronic non-cancer pain prescribed opioids. Participants were recruited through community pharmacies across Australia, completed baseline interviews, and were followed up with phone interviews or self-complete questionnaires yearly for 4 years. Recruitment took place from August 13, 2012, to April 8, 2014. Participants were asked about lifetime and past year chronic pain conditions, duration of chronic non-cancer pain, pain self-efficacy, whether pain was neuropathic, lifetime and past 12 month cannabis use, number of days cannabis was used in the past month, and current depression and generalised anxiety disorder. We also estimated daily oral morphine equivalent doses of opioids. We used logistic regression to investigate cross-sectional associations with frequency of cannabis use, and lagged mixed effects models to examine temporal associations between cannabis use and outcomes. FINDINGS: 1514 participants completed the baseline interview and were included in the study from Aug 20, 2012, to April 14, 2014. Cannabis use was common, and by 4-year follow-up, 295 (24%) participants had used cannabis for pain. Interest in using cannabis for pain increased from 364 (33%) participants (at baseline) to 723 (60%) participants (at 4 years). At 4-year follow-up, compared with people with no cannabis use, we found that participants who used cannabis had a greater pain severity score (risk ratio 1.14, 95% CI 1.01-1.29, for less frequent cannabis use; and 1.17, 1.03-1.32, for daily or near-daily cannabis use), greater pain interference score (1.21, 1.09-1.35; and 1.14, 1.03 1.26), lower pain self-efficacy scores (0.97, 0.96-1.00; and 0.98, 0.96-1.00), and greater generalised anxiety disorder severity scores (1.07, 1.03-1.12; and 1.10, 1.06-1.15). We found no evidence of a temporal relationship between cannabis use and pain severity or pain interference, and no evidence that cannabis use reduced prescribed opioid use or increased rates of opioid discontinuation. INTERPRETATION: Cannabis use was common in people with chronic non-cancer pain who had been prescribed opioids, but we found no evidence that cannabis use improved patient outcomes. People who used cannabis had greater pain and lower self-efficacy in managing pain, and there was no evidence that cannabis use reduced pain severity or interference or exerted an opioid-sparing effect. As cannabis use for medicinal purposes increases globally, it is important that large well designed clinical trials, which include people with complex comorbidities, are conducted to determine the efficacy of cannabis for chronic non-cancer pain. FUNDING: National Health and Medical Research Council and the Australian Government. PMID- 29976329 TI - Service user involvement in radiotherapy and oncology education; the patient perspective. AB - INTRODUCTION: The Health & Care Professions Council (HCPC) recently mandated the integration of the service-user voice into all aspects of allied healthcare education in the UK. However, the potential benefits and harms of this integration to service users are largely unknown. This study aimed to determine service user perspectives on relaying their personal experience of the cancer treatment pathway to students in an undergraduate Radiotherapy and Oncology programme. METHODS: A qualitative study was conducted where seven patients led educational sessions with students and were interviewed (1:1) 1 week later using an iterative semi-structured format. RESULTS: Unanimously, the primary motivation for participation was the opportunity for patients to tell their unique story to positively influence the future behaviour and understanding of student healthcare professionals. Patients experiencing significant cancer-related psychological trauma reported reacting more emotionally to the experience but also reported particularly positive benefits from their participation, including therapeutic healing. CONCLUSION: Findings highlight the array of benefits to service users associated with teaching in allied healthcare education. Post traumatic growth (PTG) may also potentially occur through this type of intervention in certain participants and this warrants further investigation in future studies. PMID- 29976330 TI - An investigation into the incidence of pain flare in patients undergoing radiotherapy for symptomatic bone metastases. AB - INTRODUCTION: External Beam Radiotherapy (EBRT) is a recognised intervention for symptomatic pain relief from bone metastases. Pain flare is a reported EBRT toxicity, described in 16-41% of steroid-naive patients. This study aimed to determine incidence and duration of pain flare amongst patients within one Oncology Centre. METHODS: Patients receiving EBRT for bone metastases were recruited to a prospective cohort study. Baseline pain scores and a daily pain/analgesia diary were recorded during EBRT and for 14 days thereafter. Pain flare was defined as a two-point increase on a pain scale or 25% increase in analgesia intake, with a return to baseline. RESULTS: Of the thirty-two participants, 69% (n = 22) completed the diary. 41% (n = 9) patients experienced pain flare, the median duration being 3 days. Of the evaluable patients, 55% (n = 12) were male, 45% (n = 9) female. The median age was 73 years (range 40-83). The common primary sites of disease were Breast (32%) and Prostate (32%), with other sites making up the remaining 36%. The most frequent EBRT site was the spine (63%), with other treatment sites including pelvis (23%) and extremities (14%). EBRT regimes were restricted to 20 Gy in 5 treatments, received by 32% (n = 7) of patients and 8 Gy in 1 treatment (68% (n = 14)). Of these two regimes, pain flare was reported by 29% and 47% respectively. CONCLUSION: Pain flare is a common toxicity of EBRT for bone metastases. Taking the small sample size into consideration, the incidence and duration of pain flare in patients within this single-centre study are comparable with those found in international studies. PMID- 29976331 TI - Establishment of image quality for MRI of the knee joint using a list of anatomical criteria. AB - INTRODUCTION: The Commission of the European Communities published image quality criteria for imaging modalities. However, none were established for magnetic resonance imaging (MRI). Such criteria are warranted due to the complexity and health and safety risks associated with MRI. The purpose of this study was to establish image quality criteria for MRI examinations of the knee, providing harmonisation of image quality, improving practice and reducing risks. METHODS: Image quality criteria were established following a literature review and validation by experts. The evaluation of the quality of randomly selected MR images (n = 10) with normal findings was performed by Maltese radiographers working at a local MRI institution. The visualisation of the developed anatomical criteria was performed by rating the visibility of each criterion using visual grading analysis. RESULTS: Results of the Friedman and Binomial tests on image quality rating scores, highlighted those anatomical criteria for each scan plane which scored significantly lower (p <= 0.05) than the threshold score of 3. This score was identified as the score below which anatomical structures would not be sufficiently visualised to enable adequate diagnosis. CONCLUSION: A set of image quality anatomical criteria have been successfully developed to provide image quality standards enabling the visualisation of the complex anatomical structures of the knee joint. This concept can be applied to other MRI examinations. PMID- 29976332 TI - Medical imaging and informed consent - Can radiographers and patients agree upon a realistic best practice? AB - INTRODUCTION: For radiographers, gaining informed consent with our patients represents a challenging undertaking. Reconciling the need to gain meaningful consent with time pressures represents one challenge, as does differing expectations of how risk communication should be undertaken. Different methods and thresholds of risk disclosure are considered, with the aim of finding a realistic best practice. METHODS: A cross-sectional study of radiographers and members of the public was undertaken. Participants were asked their preferences for how they would like to receive ionising radiation risk information. This included the health care professional(s) most suited to provide the information, the media through which the information was delivered, and the technique for delivering the information. In addition, participants were asked to consider hypothetical scenarios in which they were a patient receiving an ionising radiation examination, and to give the threshold of ionising radiation cancer risk which they would consider material. These scenarios considered variations in the cancer-onset time, and the accuracy of the test. RESULTS: One hundred and twenty-one (121) radiographer participants and one hundred and seventy two (172) members of the public met the inclusion criteria and completed the survey. There was strong agreement in the most appropriate media, and person, to disclose risk, as well as what represents a significant risk. There was considerable agreement in risk delivery technique. However, some of the agreed-upon strategies may be challenging to achieve in clinical practice. CONCLUSION: Radiographers and patients fundamentally agree upon risk communication strategies, but implementing some strategies may prove clinically challenging. PMID- 29976333 TI - Evaluation of an equilibrium phase free-breathing dynamic contrast-enhanced MRI prototype sequence compared to traditional breath-held MRI acquisition in liver oncology patients. AB - INTRODUCTION: Magnetic Resonance Imaging (MRI) is a commonly used for diagnosing metastatic liver disease. When patients are unable to achieve the necessary arrested respiration required during image acquisition, image artefacts occur that affect image quality and diagnostic value. The main contribution of this study is the evaluation of a novel prototype technique that allows a specific sub group of patients to breathe freely throughout the acquisition of dynamic contrast enhanced equilibrium phase MRI of the liver. METHODS: The study compared a traditional single phase of arrested respiration T1-weighted (T1W) fat saturated (FatSat) volumetric interpolated breath-hold sequence (VIBE) with a novel free-breathing T1W 3D Radial VIBE prototype sequence. A cohort of patients (n = 30) with known hepatic metastases who demonstrated difficulty in complying with the instructions for arrested inspiration were scanned. Both sets of data were compared for diagnostic quality using a Likert scale questionnaire by specialist Oncology Radiologists (n = 2). RESULTS: Higher scores for all image quality criteria, including the presence of artefact (2.6 +/- 0.57; p < 0.001), lesion conspicuity (2.9 +/- 0.35; p < 0.001) and visibility of intra-hepatic vessels (2.8 +/- 0.37; p < 0.001) were found using the free-breathing sequence (13.5 +/- 1.94; p < 0.001 t = 13.31; df 29; p < 0.001) than the breath hold phase (8.1 +/- 2.06), confirmed with kappa (k-0.023; p-0.050). CONCLUSIONS: The results demonstrated a 39.5% improvement in overall image quality using the T1W 3D Radial VIBE prototype sequence, and have the potential to improve patient experience and reduce image artefacts during MRI imaging of this sub-group of patients. PMID- 29976334 TI - Newly qualified radiographers' perceptions of their abnormality detection abilities and the associated training they received at undergraduate level. AB - INTRODUCTION: Abnormality detection system use across National Health Service (NHS) hospitals is widespread with radiographer participation considered as fundamental to the role. The "red dot" system is evolving towards the preliminary clinical evaluation (PCE) system. Newly qualified radiographers will be expected to be able to provide accurate descriptive comments. Confidence and training issues may hinder implementation of the PCE system. METHOD: An online quantitative survey approach was used. Participants were sought from 24 major trauma centres (MTC) across England. The sample frame was defined as radiographers who had been qualified less than 2 years. Approval to approach was granted by all local Research & Development departments. Cross-tabulation and correlational statistical analyses were undertaken. RESULTS: Approval to approach radiographers was granted in 17 of the 24 MTCs yielding 85 participants, 63 females and 22 males. The large majority are confident with their red dot skills. Strong correlation exists between university training and PCE confidence. However, almost a third of participants are not confident in describing abnormalities. Thirty percent of participants thought PCE training at university was not suitable, and 55% thought PCE training on placement was not suitable. CONCLUSION: While red dot training at university and placement is considered suitable as it positively affects confidence, participants' views on PCE training are more variable. At university PCE training positively influences confidence in describing abnormalities, but commenting training on placement is recognised as an area for improvement. A larger study is suggested to gain further understanding of any issues hindering widespread PCE implementation. PMID- 29976335 TI - Participatory action research into implementing open access in musculoskeletal X ray: Management and staff perspectives. AB - INTRODUCTION: Neighbouring Trusts have implemented open access (walk-in) services to shorten waiting times in x-ray. Despite this, staff perceptions of their effectiveness have not yet been studied. This study forms the initial baseline evaluation phase of wider participatory action research investigating the implementation of an open access service for general practitioner musculoskeletal x-ray referrals. Staff perceptions regarding effectiveness of the current service were gathered, including their opinions regarding the effectiveness of open access services. METHODS: Qualitative data were obtained via three semi structured interviews with radiology management and two (cross-site) staff focus groups over a 2 month period. Template analysis was used to interpret the data with the aid of NVIVO 11 to facilitate analysis. RESULTS: Template analysis uncovered several drivers for changing the current service including waiting times, external pressures, patient choice and administrative delays. 'Flexibility' was the key theme to arise during discussion regarding the effectiveness of the current service. Potential for improved access was highlighted as a major benefit to the implementation of open access, however 'workload', 'staffing' and 'communication' were all identified as potential barriers to its implementation. CONCLUSION: Although several staff members were satisfied with current service several drivers for change were identified that need to be addressed in order to truly deliver a service that fulfils the patients' needs. Results will inform the wider participatory action research that will investigate the barriers to implementing an open access service and identify whether this is indeed a suitable method of addressing the drivers for change. PMID- 29976336 TI - Agreement between expert thoracic radiologists and the chest radiograph reports provided by consultant radiologists and reporting radiographers in clinical practice: Review of a single clinical site. AB - INTRODUCTION: To compare the clinical chest radiograph (CXR) reports provided by consultant radiologists and reporting radiographers with expert thoracic radiologists. METHODS: Adult CXRs (n = 193) from a single site were included; 83% randomly selected from CXRs performed over one year, and 17% selected from the discrepancy meeting. Chest radiographs were independently interpreted by two expert thoracic radiologists (CTR1/2).Clinical history, previous and follow-up imaging was available, but not the original clinical report. Two arbiters compared expert and clinical reports independently. Kappa (K), Chi Square (chi2) and McNemar tests were performed to determine inter-observer agreement. RESULTS: CTR1 interpreted 187 (97%) and CTR2 186 (96%) CXRs, with 180 CXRs interpreted by both experts. Radiologists and radiographers provided 93 and 87 of the original clinical reports respectively. Consensus between both expert thoracic radiologists and the radiographer clinical report was 70 (CTR1; K = 0.59) and 70 (CTR2; K = 0.62), and comparable to agreement between expert thoracic radiologists and the radiologist clinical report (CTR1 = 76, K = 0.60; CTR2 = 75, K = 0.62). Expert thoracic radiologists agreed in 131 cases (K = 0.48). There was no difference in agreement between either expert thoracic radiologist, when the clinical report was provided by radiographers or radiologists (CTR1 chi = 0.056, p = 0.813; CTR2 chi = 0.014, p = 0.906), or when stratified by inter-expert agreement; radiographer McNemar p = 0.629 and radiologist p = 0.701. CONCLUSION: Even when weighted with chest radiographs reviewed at discrepancy meetings, content of CXR reports from trained radiographers were indistinguishable from content of reports issued by radiologists and expert thoracic radiologists. PMID- 29976337 TI - Effective lifetime radiation risk for a number of national mammography screening programmes. AB - BACKGROUND AND PURPOSE: The performance of mammography screening programmes is focussed mainly on breast cancer detection rates. However, when the benefits and risks of mammography are considered, the risk of radiation-induced cancer is calculated for only the examined breast using Mean Glandular Dose (MGD). The risk from radiation during mammography is often described as low or minimal. This study aims to evaluate the effective lifetime risk from full field digital mammography (FFDM) for a number of national screening programmes. MATERIAL AND METHODS: Using an ATOM phantom, radiation doses to multiple organs were measured during standard screening mammography. Sixteen FFDM machines were used and the effective lifetime risk was calculated across the female lifespan for each machine. Once the risks were calculated using the phantom, the total effective lifetime risk across 48 national screening programmes was then calculated; this assumed that all these programmes use FFDM for screening. RESULTS: Large differences exist in effective lifetime risk, varying from 42.21 [39.12-45.30] cases/106 (mean [95% CI]) in the Maltese screening programme to 1099.67 [1019.25 1180.09] cases/106 for high breast cancer risk women in the United States of America. These differences are mainly attributed to the commencement age of screening mammography and the time interval between successive screens. CONCLUSIONS: Effective risk should be considered as an additional parameter for the assessment of screening mammography programme performance, especially for those programmes which recommend an early onset and more frequent screening mammography. PMID- 29976338 TI - Assistant radiographer practitioners: Creating capacity or challenging professional boundaries? AB - INTRODUCTION: Over the last 2 decades the assistant radiographer practitioner (ARP) role has been introduced into NHS diagnostic imaging departments as a strategy to expand the workforce and create capacity. This skill mix initiative has not been implemented in a standardised way and there is limited knowledge of the current role scope within general radiography (X-Ray). METHOD: An electronic survey of ARPs working within UK diagnostic imaging departments was conducted. Both open and closed questions sought information regarding basic demographic data (age category; gender; geographic region), scope of practice (patient groups; anatomical regions; imaging outside of the diagnostic imaging department), limitations placed on practice, supervision and additional roles. RESULTS: A total of 108 responses, including 13 trainees, were received. Most sites employ three or less ARPs in general radiography (n = 43/66; 65.2%), although 11 sites have five (range 1-15). The majority undertake imaging of both adults and children (n = 85/108; 78.7%), although limitations on age were described. Their scope of practice covers a broad anatomical range and included some non-ambulant patients. The level of supervision varied with some sites empowering ARPs to check the referral prior to examination (n = 25) or images post acquisition (n = 32) (both n = 20/66; chi2 = 16.003; 1df; p = 0.000). CONCLUSION: ARPs are helping to maintain capacity in imaging departments but we suggest there is further scope for expansion. The practice described by the post holders suggests that many are working beyond the scope envisaged by the radiography professional body. PMID- 29976339 TI - "It's all in the history": A service evaluation of the quality of radiological requests in acute imaging. AB - INTRODUCTION: The aim of this service evaluation project was to assess the quality of clinical details provided in radiological requests. METHODS: A retrospective review of adult inpatient and emergency department radiological requests over a seven-day period was performed, using the local Clinical Radiological Information System (CRIS). Requests for plain film, CT, MRI and Ultrasound were assessed for the inclusion of a clinical question, lateralisation/localisation of signs or symptoms if required, and relevant past medical/surgical history if available. RESULTS: 1548 imaging requests were analysed. 76% asked a specific clinical question. 74% of requests requiring localisation provided this. Of those cases with relevant past medical or surgical history available, 49% mentioned this. Emergency department (ED) requests provided localisation when required in 81% of cases compared to 62% of in patients (p < 0.05). However, in-patient requests contained relevant past history in 53% of cases compared to 40% for ED requests (p = 0.00096). Compared to plain film requests, those for CT, MRI and Ultrasound studies were more complete in respect to inclusion of a clinical question (88% versus 72%, p < 0.05), localisation if required (83% versus 71%, p = 0.0007) and pertinent clinical history (67% versus 42%, p < 0.05). Requests from the weekend more often included a clinical question (83% vs 75%, p = 0.00054) and localisation if needed (84% vs 71%, p = 0.00188) compared with weekday requests. CONCLUSION: This large-scale service evaluation project shows that the quality of clinical details in requests for radiological investigations requires improvement, particularly in regard to inclusion of relevant past medical and surgical history. PMID- 29976340 TI - Is a nurse consultant impact toolkit relevant and transferrable to the radiography profession? An evaluation project. AB - INTRODUCTION: Consultant posts were developed to strengthen strategic leadership whilst maintaining front line service responsibilities and clinical expertise. The nursing profession has attempted to develop tools to enable individuals to evaluate their own practice and consider relevant measurable outcomes. This study evaluated the feasibility of transferring such a nursing 'toolkit' to another health profession. METHOD: This evaluation was structured around a one-day workshop where a nurse consultant impact toolkit was appraised and tested within the context of consultant radiographic practice. The adapted toolkit was subsequently validated using a larger sample at a national meeting of consultant radiographers. RESULTS: There was broad agreement that the tools could be adopted for use by radiographers although several themes emerged in relation to perceived gaps within the nursing template, confirming the initial exercise. This resulted in amendments to the original scope and a proposed new evaluation tool. CONCLUSION: The impact toolkit could help assess individual and collaborat ive role impact at a local and national level. The framework provides consultant radiographers with an opportunity to understand and highlight the contribution their roles have on patients, staff, their organisation and the wider profession. PMID- 29976341 TI - Is there a role for simulation based education within conventional diagnostic radiography? A literature review. AB - INTRODUCTION: Simulation based education is advancing, but is there a role for it in Diagnostic Radiography? The aim of this literature review was to understand the use of simulation within conventional diagnostic radiography education to raise awareness of this pedagogical approach. Objectives were to identify the prevalence and stage of delivery in education; understand the variation of simulation and learning objectives informing its use; and review the perceptions of those using simulation in education and practice. METHODS: The literature review used a systematic search strategy. Library Plus, CINAHL, ScienceDirect, Medline and Google Scholar were reviewed resulting in 703 articles. Inclusion and exclusion criteria were applied with initial review of title and abstract resulting in 22 articles. Fifteen articles were selected following full text review. RESULTS: Simulation was used for both pre-and post-registration education. Themes included inter-professional education, use of computer software and improving patient/practitioner interactions. Increased confidence and understanding of professional roles were common outcomes. CONCLUSION: Simulation is a valuable pedagogical approach for diagnostic radiography education. Staff training and careful implementation of each stage is required to achieve desired learning outcomes. PMID- 29976342 TI - RE: Effective lifetime radiation risk for a number of national mammography screening programmes. PMID- 29976343 TI - RE: Effective lifetime radiation risk for a number of national mammography screening programmes. PMID- 29976344 TI - The use of gadolinium-based contrast agents in Ghana with a focus on residual intracranial gadolinium deposition. AB - INTRODUCTION: The aim of the survey was to identify current practice of the use of gadolinium-based contrast agents (GBCAs) in the wake of recent reports on gadolinium deposition in the brain following repeated administration of GBCAs. METHOD: A total of 13 facilities in Ghana with magnetic resonance imaging (MRI) departments were contacted via email with a two-page questionnaire. RESULTS: A response rate of 69.2% (n = 9) was achieved. Gadodiamide (Omniscan) was the most commonly used GBCA. Slightly more than half of respondents were aware of residual deposition of GBCAs in the brain. Majority of the respondents were aware of GBCA deposition in individuals with abnormal renal function, but not aware of its deposition in those with normal renal function. A great majority of the respondents do not record the type and dose of GBCA after each intravenous administration, and such information is not provided in MRI reports. More than half of the respondents do not check eGFR prior to the administration of GBCA even when a high-risk agent is used. CONCLUSION: Gadodiamide (Omniscan) a high risk agent remains the most commonly used GBCA in Ghana. Awareness of current findings of GBCA deposition in the brain following repeated doses are not encouraging as revealed in this study. The need to adopt international standard guidelines into practice cannot be overemphasized in order to reduce the potential long-term effect of this deposition. PMID- 29976345 TI - Knowledge and practices of radiographers regarding infection control in radiology departments in Malawi. AB - INTRODUCTION: Adherence to standard infection control precautions (SICP) by radiographers is critical in combating healthcare associated infections (HAIs). Therefore, radiographers need to have adequate knowledge and practices of infection control if they are to contain the magnitude of HAIs. METHODS: Purposive, all-inclusive sampling was used to recruit 62 radiographers from four government referral hospital in Malawi. Radiographers' knowledge and practices of infection control were determined using a self-administered questionnaire. Data collection was carried out in January 2017. Descriptive (e.g. mean and standard deviation) and inferential (Chi2 test) statistics were generated using an MS Excel VBA application. RESULTS: The majority of the respondents (84%) were between 20 and 39 years of age. The study results revealed that radiographers in the four hospitals had mean infection control score (percentage) of 76.8 +/- 12.6 for knowledge and a mean infection control score of 65.3 +/- 16.1 for practice. A slight significant association between age and knowledge (p < 0.05; Cramer's V 0.26) was found in that radiographers between 40 and 59 years of age (majority of the sample) obtained higher knowledge scores than those 20-39 years of age. CONCLUSION: Given the results, further training is required regarding infection control among radiographers in radiology departments in Malawi. A guideline for infection control, specifically contextualised to be used by radiographers in radiology departments in Malawi, should be developed and implemented to enhance adherence to SICP in these departments. PMID- 29976346 TI - Curricula, attributes and clinical experiences of radiography programs in four European educational institutions. AB - INTRODUCTION: The aim of this study was to compare radiography curricula, teaching/learning strategies, skill development, clinical practice outcomes and research development delivered by four European educational institutions. METHODS: This study was carried out in two phases: the first focused on curricula analysis; the second involved online questionnaires to ascertain data from two key-informants: students who had recently completed their bachelor thesis and teaching-staff. Questionnaires were designed to capture teaching and learning strategies, skill acquisition and outcomes of clinical practice and research. Descriptive statistics and thematic analysis were performed according to the nature of the questions. RESULTS: The European Credits Transfer System dedicated per core subject area (natural sciences, clinical practice, research, imaging technology, humanities) differed between institutions. Students classified technical, practical and communication skills as the most important, teaching staff highlighted also critical thinking. The students defined as "very good" their experience in radiography (58.5%) and computed-tomography (45%). Magnetic resonance imaging practice was considered "Average" by 53% of the UK-students and "Good" by the other European students (40%). According to 71% (55/78) of the students, research work contributed to the development of critical/reflective thinking. CONCLUSIONS: The four radiography programs presented variations in curricula, contact-hours, clinical experience and outcomes. Research units allowed the participant-students to develop their critical thinking capabilities. The outcomes from clinical practice differ across the institutions, mainly due to differences in background and access to specialities. Further work is necessary to assess the real impact of different radiography programs on professional and academic mobility across Europe. PMID- 29976348 TI - A Wave of Change in Medical School Education. PMID- 29976347 TI - Image interpretation: Experiences from a Singapore in-house education program. AB - INTRODUCTION: The aim of this study is to take a longitudinal approach to assess the value of an in-house program developed in a Singapore hospital over a two year period. METHODS: Radiographers (n = 48) consented to take part in the study. The control group (CG: n = 40) continued with normal working practice whilst the remaining 'additional training group' (ATG: n = 8) participated in the hospital's in-house image interpretation program. Upon completion, all participants were assessed using a RadBench(r) test bank. All participants then continued to work in their normal clinical practice; however the ATG received regular peer support to reinforce learning and aid further development. One year later, the same populations were invited to sit another RadBench(r) assessment. RESULTS: The mean accuracy of both groups was very similar at phase one (70v71%). The ATG demonstrated higher mean sensitivity (83v72%) but the CG higher mean specificity (68v56%). One year later, with continued mentor support, the ATG demonstrated a marked improvement in mean accuracy over CG (86v70%) largely driven by a marked increase in mean specificity from 56 to 87%. 43% of the ATG could deliver exceptional standards for accuracy, sensitivity and specificity, ready and able to provide reliable preliminary clinical evaluation, versus none of the CG. CONCLUSION: In-house programmes could be a cost effective approach to skills development and ideally suited to preceptorship and new employee orientation in order to assess, develop and monitor image interpretation performance. PMID- 29976349 TI - Quantification of Right Ventricular Electromechanical Dyssynchrony in Relation to Right Ventricular Function and Clinical Outcomes in Children with Repaired Tetralogy of Fallot. AB - BACKGROUND: Electromechanical dyssynchrony occurs ubiquitously following tetralogy of Fallot (TOF) repair, manifesting electrically as a wide QRS duration and mechanically as a right-sided septal/apical flash. Early septal activation and prestretch of the right ventricular (RV) basal lateral wall followed by its postsystolic shortening contributes to inefficient RV mechanics. However, a right sided septal flash is a dichotomous finding, and the severity of RV dyssynchrony as a continuous spectrum in relationship to RV dysfunction and clinical outcomes in patients with repaired TOF has not been studied. The aim of this study was to quantify the severity of electromechanical dyssynchrony in relation to RV remodeling and clinical outcomes in a pediatric cohort following TOF repair. METHODS: A retrospective analysis was performed in 81 children with RV volume loading after TOF repair, aged 13.6 +/- 2.9 years, and compared with 50 matched control subjects. RESULTS: Patients had higher RV basal-lateral prestretch and postsystolic strain amplitude and duration, RV mechanical dispersion, and basal lateral-septal wall delay compared with control subjects (P < .001 for all). All intra-RV dyssynchrony timing parameters were associated with reduced cardiac magnetic resonance-derived RV ejection fraction and/or echocardiography-derived RV longitudinal strain. Prestretch duration as a percentage of total shortening time and RV basal lateral-to-midseptal delay were independently associated with RV dysfunction. Postsystolic strain amplitude was higher in patients with ventricular arrhythmias compared with arrhythmia-free patients (7.8% [4.2%-13%] vs 2.0% [0%-12.5%], P = .03). CONCLUSION: RV prestretch duration, postsystolic strain, and RV lateral-septal delay quantify RV electromechanical dyssynchrony severity and reflect the underlying pathophysiology. The prestretch duration percentage and RV basal lateral-to-midseptal delay were independently associated with RV dysfunction, potentially providing a clinical tool to quantify RV electromechanical dyssynchrony. PMID- 29976351 TI - How to Implement ASE Guideline Standards into Your Lab. PMID- 29976350 TI - The Importance of Understanding the Technology that Serves Us. PMID- 29976352 TI - Building Diversity One Citation at a Time. PMID- 29976353 TI - Ambition. PMID- 29976354 TI - Re: "Management of Incidental Liver Lesions on CT: A White Paper of the ACR Incidental Findings Committee". PMID- 29976355 TI - Radiologist Revenue Change Following Multiple-Procedure Payment Reduction Modification. PMID- 29976356 TI - Author's Reply. PMID- 29976357 TI - Management of Coronary Artery Aneurysms. AB - Aneurysmal dilation of coronary arteries is observed in up to 5% of patients undergoing coronary angiography. Due to their poorly elucidated underlying mechanisms, their variable presentations, and the lack of largescale outcome data on their various treatment modalities, coronary artery aneurysms and coronary ectasia pose a challenge to the managing clinician. This paper aims to provide a succinct review of aneurysmal coronary disease, with a special emphasis on the challenges associated with its interventional treatment. PMID- 29976358 TI - Outcomes After Left Main Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting According to Lesion Site: Results From the EXCEL Trial. AB - OBJECTIVES: The authors sought to determine the extent to which the site of the left main coronary artery (LM) lesion (distal bifurcation versus ostial/shaft) influences the outcomes of revascularization with percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). BACKGROUND: Among 1,905 patients with LM disease and site-assessed SYNTAX scores of <32 randomized in the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, revascularization with PCI and CABG resulted in similar rates of the composite primary endpoint of death, myocardial infarction (MI), or stroke at 3 years. METHODS: Outcomes from the randomized EXCEL trial were analyzed according to the presence of angiographic core laboratory-determined diameter stenosis >=50% involving the distal LM bifurcation (n = 1,559; 84.2%) versus disease isolated to the LM ostium or shaft (n = 293; 15.8%). RESULTS: At 3 years, there were no significant differences between PCI and CABG for the primary composite endpoint of death, MI, or stroke for treatment of both distal LM bifurcation disease (15.6% vs. 14.9%, odds ratio [OR]: 1.08, 95% confidence interval [CI]: 0.81 to 1.42; p = 0.61) and isolated LM ostial/shaft disease (12.4% vs. 13.5%, OR: 0.90, 95% CI: 0.45 to 1.81; p = 0.77) (pinteraction = 0.65). However, at 3 years, ischemia-driven revascularization occurred more frequently after PCI than CABG in patients with LM distal bifurcation disease (13.0% vs. 7.2%, OR: 2.00, 95% CI: 1.41 to 2.85; p = 0.0001), but were not significantly different in patients with disease only at the LM ostium or shaft (9.7% vs. 8.4%, OR: 1.18, 95% CI: 0.52 to 2.69; p = 0.68) (pinteraction = 0.25). CONCLUSIONS: In the EXCEL trial, PCI and CABG resulted in comparable rates of death, MI, or stroke at 3 years for treatment of LM disease, including those with distal LM bifurcation disease. Repeat revascularization rates during follow-up after PCI compared with CABG were greater for lesions in the distal LM bifurcation but were similar for disease isolated to the LM ostium or shaft. PMID- 29976360 TI - Left Main Revascularization: One Size Does Not Fit All. PMID- 29976359 TI - Outcomes After Coronary Stenting or Bypass Surgery for Men and Women With Unprotected Left Main Disease: The EXCEL Trial. AB - OBJECTIVES: The aim of the present study was to assess outcomes after coronary artery bypass grafting surgery (CABG) and percutaneous coronary intervention (PCI) according to sex in a large randomized trial of patients with unprotected left main disease. BACKGROUND: In the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial, sex had a significant interaction effect with revascularization strategy, and women had an overall higher mortality when treated with PCI than CABG. METHODS: The EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial was a multinational randomized trial that compared PCI with everolimus-eluting stents and CABG in patients with unprotected left main disease. The primary endpoint was the composite of all-cause death, myocardial infarction, or stroke at 3 years. RESULTS: Of 1,905 patients randomized, 1,464 (76.9%) were men and 441 (23.1%) were women. Compared with men, women were older; had higher prevalence rates of hypertension, hyperlipidemia, and diabetes; and were less commonly smokers but had lower coronary anatomic burden and complexity (mean SYNTAX score 24.2 vs. 27.2, p < 0.001). By multivariate analysis, sex was not independently associated with either the primary endpoint (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 0.82 to 1.48; p = 0.53) or all-cause death (HR: 1.39; 95% CI: 0.92 to 2.10; p = 0.12) at 3 years. At 30 days, all-cause death, myocardial infarction, or stroke had occurred in 8.9% of woman treated with PCI, 6.2% of women treated with CABG, 3.6% of men treated with PCI, and 8.4% of men treated with CABG (p for interaction = 0.003). The 3-year rate of the composite primary endpoint was 19.7% in women treated with PCI, 14.6% in women treated with CABG, 13.8% in men treated with PCI, and 14.7% in men treated with CABG (p for interaction = 0.06). These differences were driven by higher periprocedural rates of myocardial infarction in women after PCI and in men after CABG. CONCLUSIONS: In patients with unprotected left main disease in the EXCEL trial, sex was not an independent predictor of adverse outcomes after revascularization. However, women undergoing PCI had a trend toward worse outcomes, a finding related to associated comorbidities and increased periprocedural complications. Further studies are required to determine the optimal revascularization modality in women with complex coronary artery disease. PMID- 29976362 TI - Left Main Bifurcation Angioplasty: Are 2 Stents One Too Many? PMID- 29976361 TI - Long-Term Clinical Outcomes and Optimal Stent Strategy in Left Main Coronary Bifurcation Stenting. AB - OBJECTIVES: This study sought to investigate the long-term clinical effects of stent generation and stent strategy for left main coronary artery (LMCA) bifurcation lesion treatment. BACKGROUND: Limited data are available to assess long-term clinical outcomes after stenting, including use of current-generation drug-eluting stent (C-DES) for treatment of LMCA bifurcation lesions. METHODS: A total of 1,353 patients who were recorded in 2 multicenter real-world registries were treated by either early-generation drug-eluting stent (E-DES) (n = 889) or C DES (n = 464). Primary endpoint was major adverse cardiovascular events (MACE). MACE was defined as a composite of cardiac death or myocardial infarction, stent thrombosis, and target lesion revascularization rates during 3-year follow-up. The authors further performed propensity-score adjustment for clinical outcomes. RESULTS: During 3-year follow-up, the overall MACE rate was 8.7%. Use of a 1 stent strategy resulted in better clinical outcomes than use of a 2-stent strategy (4.7% vs. 18.6%, hazard ratio [HR]: 3.71; 95% confidence interval [CI]: 2.55 to 5.39; p < 0.001). Use of C-DES resulted in a lower MACE rate compared with using E-DES (4.6% vs. 10.9%, HR: 0.55; 95% CI: 0.34 to 0.89; p = 0.014), especially for the 2-stent strategy. For patients with C-DES, the presence of chronic kidney disease and pre-intervention side branch diameter stenosis >=50% were significant independent predictors of MACE. CONCLUSIONS: Intervention of LMCA bifurcation lesions using DES implantation demonstrated acceptable long-term clinical outcomes, especially in C-DES patients. Use of a 1-stent strategy resulted in better clinical benefits than using a 2-stent strategy. PMID- 29976363 TI - Debris Heterogeneity Across Different Valve Types Captured by a Cerebral Protection System During Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: This study investigated differences between transcatheter heart valve (THV) types and regarding debris captured by a cerebral embolic protection system (Claret Medical Sentinel, Santa Rosa, California). BACKGROUND: Differences of THV types and cerebral injury after transcatheter aortic valve replacement (TAVR) are not well understood. METHODS: A total of 246 patients pooled from 2 prospective studies (SENTINEL [Cerebral Protection in Transcatheter Aortic Valve Replacement] trial, N = 100; SENTINEL-H [Histopathology of Embolic Debris Captured During Transcatheter Aortic Valve Replacement] trial, N = 146) were included in the analysis. Histopathologic assessment and histomorphometric analyses of debris were compared with THV types. Analyses were differentiated by particle size (>=150, >=500, and >=1,000 MUm), particle count, total particle area, and maximum of largest dimension. Only commercially available THVs were included: 16% Evolut R (EvR), 15% Lotus, 59% SAPIEN 3 (S3), and 10% SAPIEN XT (XT). RESULTS: Particles were captured in 99% of patients. There was a significantly higher amount of debris related to the vascular bed (valve tissue, arterial wall, calcification) in EvR patients compared with S3 patients; 53% of all patients irrespective of valve type had at least 1 particle >=1 mm. Larger particles (>=500 and >=1,000 MUm) were significantly more frequent in EvR than XT and S3 patients. Lotus patients with particles >=1,000 MUm were significantly more frequent than in S3 patients. Particle count, total particle area, and maximum of largest dimension were significantly higher in both Lotus and EvR patients compared with S3 and XT. CONCLUSIONS: Debris was captured in 99% of patients, of whom 53% had at least 1 particle of debris >1 mm. The number and size of particles captured during a procedure in which EvR or Lotus THV was used were higher and larger than with a Sapien THV. Regardless, embolic debris, including large particles, is universal across valve types and provides mechanistic support for the potential benefit of using cerebral embolic protection in all TAVR procedures. PMID- 29976364 TI - Embolic Protection Devices in Transcatheter Aortic Valve Replacement: Measuring Treasure or Treasuring Measure? PMID- 29976366 TI - Commentary on Optimal Treatment Strategy for Tandem Stroke. PMID- 29976367 TI - Single Transseptal Puncture for Left Atrial Appendage Closure and Mitral Valvuloplasty With Total Cerebrovascular Protection in a Patient With Acute Embolic Cerebral Ischemia. PMID- 29976365 TI - Carotid Stenting With Antithrombotic Agents and Intracranial Thrombectomy Leads to the Highest Recanalization Rate in Patients With Acute Stroke With Tandem Lesions. AB - OBJECTIVES: The aim of this study was to identify the optimal endovascular approach in patients with acute stroke with tandem lesions. BACKGROUND: At present, there is no consensus about the ideal technical strategy for the endovascular treatment of patients with acute ischemic stroke with tandem lesions of the extracranial internal carotid artery (ICA) and intracranial cerebral arteries. METHODS: This was an international, multicenter registry with a total of 482 patients with acute ischemic stroke and tandem lesions. Patients were treated by intracranial thrombectomy as well as 1 of the following 4 strategies: 1) acute carotid artery stenting of the extracranial ICA with antithrombotic agents; 2) acute carotid artery stenting of the extracranial ICA without antithrombotic agents; 3) balloon angioplasty of the extracranial ICA; and 4) intracranial thrombectomy alone. The main outcome endpoints of the study were the degree of recanalization and the 90-day clinical outcome. The safety endpoints were symptomatic intracerebral hemorrhage and all causes of mortality at 90 days. RESULTS: Using univariate analysis, the rates of successful reperfusion (modified Thrombolysis in Cerebral Infarction grades 2B and 3) and favorable clinical outcome after 90 days were significantly higher after acute carotid stenting with antithrombotic therapy and thrombectomy compared with the group with thrombectomy alone. After adjusting for confounding variables, acute stenting with antithrombotic therapy was independently associated with successful recanalization (odds ratio: 2.4; 95% confidence interval: 1.25 to 4.59; p = 0.008). The rates of symptomatic intracerebral hemorrhage and 90-day mortality were comparable among all 4 treatment groups. CONCLUSIONS: Acute stenting of the extracranial ICA with antithrombotic therapy in combination with intracranial thrombectomy is associated with higher recanalization rates in treatment of patients with acute stroke with tandem lesions. PMID- 29976368 TI - The IMPACTOR-CTO Trial. PMID- 29976369 TI - Procedural Success and Clinical Outcome of the Portico Transcatheter Aortic Valve Using the Left Subclavian Artery as Primary Access. PMID- 29976370 TI - Telomeres in the Clinic, Not on TV. PMID- 29976371 TI - Hey Goglexiri, Do I Have Coronary Artery Disease? PMID- 29976372 TI - Estimated Cardiorespiratory Fitness Assessment as a Patient Vital Sign. PMID- 29976373 TI - Understanding the Patterns of Multimorbidity. PMID- 29976374 TI - Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes. AB - Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit. PMID- 29976375 TI - Bilateral Sustained Nephrograms After Parenteral Administration of Iodinated Contrast Material: A Potential Biomarker for Acute Kidney Injury, Dialysis, and Mortality. AB - OBJECTIVE: To determine whether persistent bilateral global nephrograms are associated with acute kidney injury (AKI), dialysis, and mortality. PATIENTS AND METHODS: All patients who underwent (1) contrast-enhanced computed tomography (CT) or cardiac catheterization with iohexol between January 1, 2000, and December 31, 2014, and (2) noncontrast abdominal CT in the subsequent 24+/-6 hours were identified. Patients without preprocedure and postprocedure creatinine measurements or who received additional contrast material were excluded. Nephrograms were identified by radiologist review and CT attenuation measurements. Univariate and multivariate analyses were performed to determine nephrogram risk factors. Acute kidney injury (defined as a creatinine level of >=0.5 mg/dL or Kidney Disease: Improving Global Outcomes stages 1-3), dialysis, and mortality proportions were compared between patients with and without bilateral global nephrograms using the Fisher's exact test. RESULTS: A total of 123 patients met all inclusion criteria. The proportion of patients with a nephrogram was 37.4% (n=46), with a higher proportion following interventional (67% [18 of 30]) vs diagnostic (27.3% [9 of 33]) catheterization or contrast enhanced computed tomography (31.7% [19 of 60]). Age (P=.002), chronic kidney disease (P=.05), and acute hypotension or shock (P=.02) were significant risk factors for nephrogram development. Patients with nephrogram had significantly higher rates of AKI (37.0% [17 of 46] vs 5.2% [4 of 77]; odds ratio [OR], 10.7 [95% CI, 3.31-34.5]; P<.001), dialysis (17.4% [8 of 46] vs 1.3% [1 of 77]; OR, 16.0 [95% CI, 1.93-133]; P=.001), and mortality (15.2% [7 of 46] vs 1.3% [1 of 77]; OR, 13.6 [1.62-115]; P=.003) than patients without nephrogram. CONCLUSION: The presence of persistent bilateral global nephrograms suggests an increased risk of AKI, dialysis, and mortality when compared with patients whose kidneys fully eliminated the contrast material. PMID- 29976376 TI - Opioid-Induced Adrenal Insufficiency. AB - One in 10 Americans experience chronic pain. Although opioids do play a role in the management of pain, long-term opioid use may lead to adverse effects. Endocrine-related adverse effects have been described but remain poorly recognized. Opioid-induced adrenal insufficiency occurs because of suppression of hypothalamic-pituitary-adrenal communication and may be challenging to diagnose but has been reported in 9% to 29% of patients receiving long-term opiate therapy. Little data exist to guide case detection and patient management. Treatment includes cessation of opiates (the inciting factor) if possible and glucocorticoid replacement. PMID- 29976377 TI - Additional Safety Considerations Before Prescribing Opioids to Manage Restless Legs Syndrome. PMID- 29976378 TI - In Reply-Additional Safety Considerations Before Prescribing Opioids to Manage Restless Legs Syndrome. PMID- 29976379 TI - An Outbreak of Brodifacoum Coagulopathy Due to Synthetic Marijuana in Central Illinois. PMID- 29976380 TI - End-Stage Renal Disease Risk in Different Glomerulonephropathies. PMID- 29976381 TI - In Reply-End-Stage Renal Disease Risk in Different Glomerulonephropathies. PMID- 29976382 TI - Chorea and Calcifications: Atypical Presentation of Microscopic Polyangiitis. PMID- 29976383 TI - Endometrial Adenocarcinoma, Endometrioid Type. PMID- 29976384 TI - Henry David Thoreau's Final Journey: Minnesota. PMID- 29976385 TI - Minnesota Birds and Flora by Emily Wilson. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 29976386 TI - 2016 ASSH Presidential Address: Teaching Hands-Pass It On. PMID- 29976387 TI - Commentary on "Immediate Versus Overnight-Delayed Digital Replantation: Comparative Retrospective Cohort Study of Survival Outcomes". PMID- 29976388 TI - Development of a Risk Stratification Scoring System to Predict General Surgical Complications in Hand Surgery Patients. AB - PURPOSE: Avoidance of postoperative complications is important to both patients and surgeons. In an attempt to optimize postoperative outcomes, a risk stratification scoring system has been created to aid in optimizing risk factors for general surgical complications in hand surgery patients. METHODS: Patients were identified who underwent hand procedures as part of the American College of Surgeons National Surgical Quality Improvement Program. Independent risk factors associated with postoperative complications within 30 days of surgery were identified and used to develop a point-scoring system to estimate the relative risk for sustaining complications. For validation, the system was tested on a subset of patients from the database who had undergone hand surgery. RESULTS: A total of 49,272 patients were identified as having undergone hand surgery from 2005 to 2015. The incidence of postoperative complications within 30 days of hand surgery was 2.3%. Risk factors associated with postoperative complications were male sex, tobacco abuse, congestive heart failure, anemia (male hematocrit less than 42; female less than 38), elevated creatinine (greater than 1.3 mg/dL), hypoalbuminemia (less than 3.5 g/dL), and hyponatremia (less than 135 mEq/L). Point scores derived for each of these factors were: hypoalbuminemia, +5; congestive heart failure, +2; anemia, +2; elevated creatinine, +2; male sex, +1; tobacco abuse, +1; and hyponatremia, +1. In the validation cohort, patients categorized as low-risk (0-3) using the point-scoring system had a 2.4% rate of 30-day complications; patients categorized as medium risk (4-7) had a 10.4% complication rate (relative risk = 4.3; 95% confidence interval, 3.1-5.9 compared with low risk) and high risk (>=8), 28.9% (relative risk = 11.9; 95% confidence interval, 9.0-15.7). CONCLUSIONS: This point-scoring system predicts risk for general postoperative complications after hand surgery. These data may help surgeons identify areas of clinical concern with patients to reduce the risk for sustaining postoperative complications. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 29976389 TI - Letter Regarding "Perioperative Celecoxib and Postoperative Opioid Use in Hand Surgery: A Prospective Cohort Study". PMID- 29976390 TI - Response to "Letter Regarding 'Perioperative Celecoxib and Postoperative Opioid Use in Hand Surgery: A Prospective Cohort Study'". PMID- 29976391 TI - Letter Regarding "Outcomes of Isolated Radial Osteotomy for Volar Distal Radioulnar Joint Instability Following Radial Malunion in Children". PMID- 29976392 TI - Response to "Letter Regarding 'Outcomes of Isolated Radial Osteotomy for Volar Distal Radioulnar Joint Instability Following Radial Malunion in Children'". PMID- 29976393 TI - Application of thermal stability difference to remove flammutoxin in fungal immunomodulatory protein, FIP-fve, extract from Flammulina velutipes. AB - Fungal immunomodulatory protein (FIP-fve) is a potential functional food ingredient. However, undesirable component flammutoxin (FTX) would occur in the extracted fraction of FIP-fve. In this paper, an application of heating processing instead of the intensive separation process was employed in fractionation of FIP-fve, meanwhile, exclusion of FTX was reached. Contents of FIP-fve and FTX were monitored by HPLC-UV-ESI-MS. Both FIP-fve and FTX had higher thermal stability in a lower concentration solution. Cold water could effectively extract FIP-fve and FTX from fresh mushroom without acetic acid and disulfide bond breaking agent beta-mercaptoethanol commonly used in biochemical studies. Heating cold water extract contained 580 MUg/mL FIP-fve and 452 MUg/mL FTX at 60 degrees C for 5 min could effectively exclude FTX and remain 75% of FIP-fve. Adding 0.1 M trehalose or 20% ethanol did not significantly alter the stability of both proteins. The method developed is an applicable procedure for preparing FIP-fve solution free of FTX. PMID- 29976394 TI - Synergic effect of curcumin and its structural analogue (Monoacetylcurcumin) on anti-influenza virus infection. AB - Curcumin (Cur), a polyphenolic compound extracted from spice and common food colourant turmeric, contains versatile bio-activities. Monoacetylcurcumin (MAC), a structural analogue of Cur, differs from Cur by acetyl modification, but retains enone groups. Comparative analysis revealed MAC effectively inhibited influenza virus infection (IAV) to a similar extent as, if not superior to, curcumin. Both compounds mildly reduced viral NA activity. Surprisingly, unlike Cur, the MAC inhibition of IAV did not occur through the blocking of HA activity. However, MAC strongly dampened Akt phosphorylation, the prerequisite signalling for efficient IAV propagation. A much stronger inhibition effect on IAV infection was observed when MAC treatment was in combination with Cur. Collectively, MAC demonstrated clear antiviral activity, and likely inhibited IAV via multiple mechanisms that were not identical to Cur. Importantly, Cur and MAC in combination synergistically inhibited IAV infection. PMID- 29976395 TI - Mulberry leaf extract inhibit hepatocellular carcinoma cell proliferation via depressing IL-6 and TNF-alpha derived from adipocyte. AB - Epidemiological studies have revealed that obesity and being overweight are associated with increased cancer risk. Adipose tissue is regarded as an endocrine organ that secretes proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), which are related to the progression of hepatocellular carcinoma (HCC). In this study, adipocytes from 3T3-L1 cells were induced and stained with Oil Red O, which revealed marked intracellular lipid accumulation. Adding 15% conditioned medium (CM) from adipogenic -differentiated 3T3-L1 cells, which contained adipocyte-derived factors, to a culture medium of HepG2 cells was discovered to promote cell proliferation by a factor of up to 1.3 compared with the control. Mulberry leaf extract (MLE), with major components including chlorogenic acid and neochlorogenic acid, was revealed to inhibit CM promoted HepG2 cell proliferation. The inhibitory effect of MLE on the proliferation of the signal network was evaluated. Expression of the CM-activated IkappaB/NFkappaB, STAT3, and Akt/mTOR pathways were reduced when MLE was administered. Although adipocyte-derived factors are complex, administrating anti TNF-alpha and anti-IL-6 revealed that MLE blocks signal activation promoted by TNF-alpha and IL-6. Taken together, these results demonstrated that MLE targets the proliferation signal pathway of the inflammatory response of adipocytes in HCC and could be to prevent obesity-mediated liver cancer. PMID- 29976396 TI - Elemental profile and oxygen isotope ratio (delta18O) for verifying the geographical origin of Chinese wines. AB - The elemental profile and oxygen isotope ratio (delta18O) of 188 wine samples collected from the Changji, Mile, and Changli regions in China were analyzed by inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma optical emission spectroscopy (ICP-OES) and isotope ratio mass spectrometry (IRMS), respectively. By combining the data of delta18O and the concentration data of 52 elements, the analysis of variance (ANOVA) technique was firstly applied to obtain the important descriptors for the discrimination of the three geographical origins. Ca, Al, Mg, B, Fe, K, Rb, Mn, Na, P, Co, Ga, As, Sr, and delta18O were identified as the key explanatory factors. In the second step, the key elements were employed as input variables for the subsequent partial least squares discrimination analysis (PLS-DA) and support vector machine (SVM) analyses. Then, cross validation and random data splitting (training set: test set = 70:30, %) were performed to avoid the over-fitting problem. The average correct classification rates of the PLS-DA and SVM models for the training set were both 98%, while for the test set, these values were 95%, 97%, respectively. Thus, it was suggested that the combination of oxygen isotope ratio (delta18O) and elemental profile with multi-step multivariate analysis is a promising approach for the verification of the considered three geographical origins of Chinese wines. PMID- 29976397 TI - Combination of on-line desalting and HPLC-UV-ESI-MS for simultaneous detection and identification of FIP-fve and flammutoxin in Flammulina velutipes. AB - A rapid analytical approach, on-line desalting HPLC-UV-ESI-MS method, for the analysis of FIP-fve and flammutoxin (FTX), two important bioactive proteins in the fruiting bodies of Flammulina velutipes, was developed. In this study, a highly efficient desalting method is provided using molecular weight cut-off centrifugal filtration and on-line desalting. Sample preparation followed by an on-line desalting HPLC-UV-ESI-MS system was employed for simultaneous desalting and detection and identification of FIP-fve and FTX. Results indicated that using trifluoroacetic acid as a modifier on a C18 reversed-phase column renders effective separation. ESI-MS revealed that the apparent molecular masses of FIP fve and FTX were 12,749.1 Da and 21,912.5 Da, respectively. Eleven milligrams of FIP-fve was obtained from 100 g of fresh fruiting bodies, and UV detection was performed at 280 nm using bovine serum albumin as the standard protein. The calibration curve was linear in the concentration range of 0.29-4.69 mg/mL (r2 = 0.9999). FTX and a series of degradation products were isolated from F. velutipes using 35% saturated ammonium sulfate on a DEAE cellulose column. The complete identification of FTX and a series of degradation products were carried out by precipitation of various ammonium sulfate concentrations (0-45%, 45-65% and 65 90%), in-gel trypsin digestion, and MS analysis with combined database search. The molecular weights of FTX and a series of degradation products were 29,957.2 Da, 27,480.2 Da, 26,512.5 Da, and 21,912.5 Da. PMID- 29976398 TI - Improvement of nutritional components and in vitro antioxidative properties of soy-powder yogurts using Lactobacillus plantarum. AB - This research was the first to demonstrate changes in nutritional compositions (isoflavone and CLA) from the 50% methanol extracts of soy-powder milk (SPM) and soy-powder yogurt (SPY) through fermentation using Lactobacillus plantarum S48 and P1201 strains. The radical scavenging activities and protective effects against oxidative stress in LLC-PK1 cells were also investigated. The average physicochemical characteristics including acidity and viable cell number as well as beta-glucosidase activity increased with 0.2 -> 0.7%, 7.5 -> 9.8 log cfu/mL, and 0.0 3 -> 1.75 U/g in SPYs. Total average isoflavones were considerably reduced (3180.3 -> 2018.3 MUg/g) with the increase of aglycone contents (191.8 -> 770.2 MUg/g), especially, daidzein exhibited the most remarkable increase rate (98.6 -> 460.9 MUg/g; > 4.8 times) during fermentation. The CLA and total phenolics also increased with significant differences (ND -> 1.6 mg/g; 2.4 -> 3.6 mg/GAE/g) between SPM and SPY. Interestingly, the cis-9, trans-11 CLA showed approximately 90% in total content. Moreover, the scavenging capacities against three radicals markedly increased with about 30% in SPYs, as the following order: ABTS > hydroxyl > DPPH. The protective effects on oxidative stress (pyrogallol: O2-, SNP: NO, and SIN-1: ONOO-) were also observed high cell viabilities (>10%) under LLC-PK1 cellular system. Our results suggest that SPY may be utilized as a potent source regarding natural antioxidants and beneficial components for health food and medical uses. PMID- 29976399 TI - Resveratrol protects muscle cells against palmitate-induced cellular senescence and insulin resistance through ameliorating autophagic flux. AB - Skeletal muscle, a highly metabolic tissue, is particularly vulnerable to increased levels of saturated free fatty acids (FFAs). The role of autophagy in saturated FFAs-induced cellular senescence and insulin resistance in skeletal muscle remains unclear. Therefore, the present study was aimed to explore autophagic flux in cellular senescence and insulin resistance induced by palmitate in muscle cells, and whether resveratrol limited these responses. Our results showed that palmitate induced cellular senescence in both myoblasts and myotubes. In addition, palmitate delayed differentiation in myoblasts and inhibited expression of insulin-stimulated p-AKTSer473 in myotubes. The accumulations of autophagosome assessed by tandem fluorescent-tagged LC3 demonstrated that autophagic flux was impaired in both palmitate-treated myoblasts and myotubes. Resveratrol protected muscle cells from palmitate-induced cellular senescence, apoptosis during differentiation, and insulin resistance via ameliorating autophagic flux. The direct influence of autophagic flux on development of cellular senescence and insulin resistance was confirmed by blockage of autophagic flux with chloroquine. In conclusion, impairment of autophagic flux is crucial for palmitate-induced cellular senescence and insulin resistance in muscle cells. Restoring autophagic flux by resveratrol could be a promising approach to prevent cellular senescence and ameliorate insulin resistance in muscle. PMID- 29976400 TI - Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells. AB - Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARgamma), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate-activated protein kinase (AMPK) dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in beta oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 beta (GSK3beta), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD). PMID- 29976401 TI - Effects of vitamin B-6 supplementation on oxidative stress and inflammatory response in neonatal rats receiving hyperoxia therapy. AB - Hyperoxia is often used in the treatment of neonates. However, protracted use of hyperoxia leads to significant morbidity. The purpose of this study was to evaluate the effects of vitamin B-6 supplementation on oxidative stress and inflammatory responses in neonatal rats undergoing hyperoxia therapy. The study consisted of 2 parts: a survival study and a vitamin B-6 efficacy study for 16 days. Neonatal rats were randomly divided into either the control group, B-6 group (subcutaneously injected with 90 mg/kg/d of pyridoxal 5'-phosphate [PLP]), O2 group (treated with 85% oxygen), or O2 + B-6 group (simultaneously treated with 85% oxygen and 90 mg/kg/d PLP). After the survival study was done, the vitamin B-6 efficacy study was performed with duplicate neonatal rats sacrificed on the 3rd, 6th, 9th, and 16th day. Serum inflammatory cytokines, tissue pathology, and malondialdehyde (MDA) levels were measured. In the survival study, the survival rate of neonatal rats in the control, B-6, O2, and O2 + B-6 group on the 16th day were 100%, 100%, 25%, and 62.50%, respectively. The efficacy study showed lung polymorphonuclear granulocyte (PMN) and macrophage infiltration, increased liver hemopoiesis, and higher MDA levels in liver homogenates at days 3 through 16 in the O2 group. Vitamin B-6 supplementation considerably increased serum inflammatory cytokines in either the 6th or 9th day and decreased liver MDA level before the 6th day. These results indicate that neonatal rats receiving hyperoxia treatment suffered divergent serum inflammatory responses and were in increased liver oxidative stress. Vitamin B-6 supplementation seemed to improve survival rates, change systemic inflammatory response, and decrease liver oxidative stress while neonatal rats were under hyperoxia treatment. PMID- 29976402 TI - Production of functional peptides with inhibition ability against angiotensin I Converting enzyme using P. pastoris expression system. AB - To obtain the angiotension-I converting enzyme inhibitor (ACEI), a fusion ACEI polypeptide encoded with 8 DNA sequences of GPL, GPM, IKW, IVY, IRPVQ, IWHHT, IYPRY and IAPG, which were selected and designed and cloned into pGAPZalphaC and then transformed into Pichia pastoris SMD1168H. After 3 days induction, the fraction with highest ACEI activity was expressed and purified using a Ni SepharoseTM 6 Fast Flow. The IC50 of recombinant ACEI polypeptide was 88.2 MUM. A 128-fold increase of ACEI activity (0.69 MUM) was obtained after pepsin digestion, which was equivalent to 0.022 MUM of captopril. Reverse phase HPLC indicated all the 8 peptides contained in ACEI-hydrolysate after pepsin digestion. PMID- 29976403 TI - A feasible and practical 1H NMR analytical method for the quality control and quantification of bioactive principles in Lycii Fructus. AB - Lycii Fructus, a solanaceous drug, is widely used as functional foods and in Traditional Chinese Medicine. Samples collected from different regions of China have been found to be not identical in chemical compositions which might affect the biological activities. Although many chromatographic and spectrometric methods have been reported to determine the concentration of betaine and other bioactive amino acids, disturbance resulted from other polar substances with low UV-absorbance and expensive mass facilities reduced the applicability of these techniques. In the present study, the strong cation exchange solid phase extraction procedure incorporated with 1H NMR was successfully developed as a rapid and reliable method that can simultaneously determine betaine, citric acid, threonine, alanine, and proline in various Lycii Fructus. In addition, ERETIC 2 method based on PULCON principle was also applied and compared with conventional method. This feasible and practical method offers a very powerful tool for the quality control of commercial Lycii Fructus from different sources. PMID- 29976404 TI - Quantitative and qualitative analyses of cytotoxic triterpenoids in the rhizomes of Anemone raddeana using HPLC and HPLC-ESI-Q/TOF-MS. AB - Anemone raddeana Regel, a Traditional Chinese Medicine, has been demonstrated to possess cytotoxicity and anti-inflammatory activities. The purpose of this study is to establish analytical methods to identify and quantify the major active constituents in Anemone raddeana. A high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (HPLC-ESI-Q/TOF-MS) was used to identify the components in the title plant material. To quantify the major components, a HPLC-UV method was developed and validated. The results showed that 37 compounds were identified based on the MS data and retention times. The contents of eight main bioactive compounds were determined by HPLC simultaneously. These methods could be used to effectively evaluate the quality of A. raddeana and provide a valuable reference for further study. In addition, the cytotoxicity activity of the different fractions of A. raddeana was determined. Hederacolchiside A1 (f) showed promising activity against ten human cancer cell lines with IC50 values from 0.29 to 3.48 MUM. PMID- 29976405 TI - Comprehensive quality evaluation and comparison of Angelica sinensis radix and Angelica acutiloba radix by integrated metabolomics and glycomics. AB - Angelica radix (Danggui in Chinese) used in China and Japan is derived from two species of Angelica, namely Angelica sinensis and Angelica acutiloba, respectively. The differences in quality between A. sinensis radix (ASR) and A. acutiloba radix (AAR) should be therefore investigated to guide the medicinal and dietary applications of these two species. Secondary metabolites and carbohydrates have been demonstrated to be the two major kinds of bioactive components of Danggui. However, previously, quality comparison between ASR and AAR intensively concerned secondary metabolites but largely overlooked carbohydrates, thus failing to include or take into consideration an important aspect of the holistic quality of Danggui. In this study, untargeted/targeted metabolomics and glycomics were integrated by multiple chromatography-based analytical techniques for qualitative and quantitative characterization of secondary metabolites and carbohydrates in Danggui so as to comprehensively evaluate and compare the quality of ASR and AAR. The results revealed that not only secondary metabolites but also carbohydrates in ASR and AAR were different in type and amount, which should collectively contribute to their quality difference. By providing more comprehensive chemical information, the research results highlighted the need to assess characteristics of both carbohydrates and secondary metabolites for overall quality evaluation and comparison of ASR and AAR. PMID- 29976406 TI - Simultaneous analysis of 23 illegal adulterated aphrodisiac chemical ingredients in health foods and Chinese traditional patent medicines by ultrahigh performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - This paper presents an application of ultra high-performance liquid chromatography-quadrupole-TOF high resolution mass spectrometry (UHPLC-Q-TOF HRMS) for simultaneous analysis of 23 illegal adulterated aphrodisiac type chemical ingredients in health foods and Chinese Traditional Patent Medicines (CTPMs). The mass spectrometer was operated in Information Dependent Acquisition (IDA) mode, which provides crucial information for the elemental composition analysis, structure elucidation and quantitative analysis simultaneously. Quantitative analysis was performed using the peak areas of the precursor ions in the XICs. The method validation included assessment of selectivity, sensitivity, calibration curve, accuracy, precision, recovery, matrix effect and stability. The results show good linear relationship with the concentrations of the analytes over wide concentration ranges (e.g., 0.05-10 MUg/g for sildenafil) as all the fitting coefficients of determination r2 are >0.9984. The detection limits (LODs) were in the range of 0.002-0.1 MUg/g. The recoveries were able to reach 82.5 103.6%, while the matrix effects ranged from 87.7 to 109.3%. The intra- and inter day accuracies were in the range of 82.3-113.8%, while the intra- and inter-day precision ranged from 0.4 to 13.6%. Among 40 batches of health foods and 32 batches of CTPMs (including 28 capsules, 32 tablets, 10 liquid and 2 pills) samples, 28 batches of heath foods were positive. The detected chemical ingredients involved sildenafil, tadalafil, aildenafil and sulfoaildenafil. This method can be used for the screening, identification and quantification of illegal adulterated aphrodisiac chemical ingredients in health foods and CTPMs. Moreover, the LC-Q-TOF MS is very useful to structural elucidation of unknown compound. PMID- 29976407 TI - Investigation of aflatoxins contamination in herbal materia medica in a Taiwan pharmaceutical factory. AB - During the years 2005-2016, a total of 1067 samples for 24 types of herbal materia medica were investigated for the presence of aflatoxins (AFs) using immunoaffinity column cleanup and HPLC-coupled to a fluorescence detector after post-column derivatization. AFs were detected in 373 (35%) out of the total samples. Among them, Platycladi Semen (65% for total AFs and 79% for AFB1), Corydalis Rhizoma (53% for total AFs and 32% for AFB1), Corni Fructus (3% for total AFs), Coicis Semen (3% for total AFs and AFB1), Nelumbinis Semen (6% for total AFs and 9% for AFB1), Arecae Semen (18% for AFB1), Polygalae Radix (5% for total AFs and AFB1), and Cassiae Semen (25% for total AFs and 38% for AFB1) exceeded the official limits of 5 and 10 MUg/kg, for AFB1 and total AFs (the sum of AFB1, AFB2, AFG1, and AFG2), respectively, set by the Taiwan government. We concluded that Platycladi Semen, Corydalis Rhizoma, and Cassiae Semen are the most commonly contaminated by AFs. PMID- 29976408 TI - Comparative study of two different chromatographic approaches for quantitation of hydrocortisone acetate and pramoxine hydrochloride in presence of their impurities. AB - In the present study, we compare the performance of two reversed-phase liquid chromatographic approaches using different eluents either conventional hydro organic eluent or micellar one for simultaneous estimation of hydrocortisone acetate and pramoxine hydrochloride in presence of their degradants and process related impurities; hydrocortisone and 4-butoxyphenol, respectively. For conventional reversed-phase liquid chromatography (RPLC), separation of the studied compounds was completed on an Inertsil ODS 3-C18 column (150 mm * 4.6 mm, 5 MUm particle size) with a mobile phase consists of 50 mM phosphate buffer (pH 5.0): acetonitrile (50: 50, v/v). For micellar liquid chromatography (MLC), an Eclipse XDB-C8 column (150 mm * 4.6 mm, 5 MUm particle size) was chosen for the separation with a green mobile phase consists of 0.15 M sodium dodecyl sulfate, 0.3% triethylamine and 10% n-butanol in 20 mM orthophosphoric acid (pH 5.0). Both methods were extended to analyze hydrocortisone acetate and pramoxine hydrochloride in their co-formulated cream. RPLC was superior to MLC with regard to sensitivity for the estimation of impurities. While, MLC represents an eco friendly, less hazardous and biodegradable approach. Furthermore, the direct injection of the cream to the system without the need to laborious samples pretreatment, excessive amount of analysis time and/or use of large amount of toxic organic solvents is one of the outstanding advantages of MLC. PMID- 29976409 TI - Enantioseparation of phenothiazines through capillary electrophoresis with solid phase extraction and polymer based stacking. AB - This study developed a sensitive method involving capillary electrophoresis (CE) coupled with ultraviolet absorption for the simultaneous separation of chiral phenothiazine drugs at nanomolar concentration levels. The method consists of hydroxypropyl-gamma-cyclodextrin (Hp-gamma-CD) as a chiral selector and poly (diallyldimethylammonium chloride) (PDDAC)-based CE. Five pairs of d,l phenothiazines were baseline separated using a background electrolyte containing 0.9% PDDAC, 5 mM Hp-gamma-CD, and 100 mM tris(hydroxymethyl)aminomethane (Tris) formate (pH 3.0). The five pairs were successfully stacked on the basis of the difference in viscosity between the PDDAC-containing background electrolyte and the sample solution, with almost no loss of resolution. The combination of a solid-phase extraction and PDDAC-mediated CE can efficiently improve the sensitivity of the phenothiazine enantiomers. Under optimal conditions, calibration graphs displayed the linear range between 6 and 1500 nM, with relative standard deviation values lower than 3.5% (n = 5). Detection limit ranged from 2.1 to 6.3 nM for target analytes, and 607- to 1555-fold enhancement was achieved. The practicality of using the proposed method to determine five pairs of d,l-phenothiazines in urine is also validated, in which recoveries between recoveries of all phenothiazines from urine ranged from 89% to 101%. PMID- 29976410 TI - Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. AB - Flavonoids luteolin and quercetin can inhibit growth and metastasis of cancer cells. In our previous report, luteolin and quercetin was shown to block Akt/mTOR/c-Myc signaling. Here, we found luteolin and quercetin reduced protein level and transactivation activity of RPS19 in A431-III cells, which is isolated from parental A431 (A431-P) cell line. Further investigation the inhibitory mechanism of luteolin and quercetin on RPS19, we found c-Myc binding sites on RPS19 promoter. The Akt inhibitor LY294002, mTOR inhibitor rapamycin and c-Myc inhibitor 10058-F4 significantly suppressed RPS19 expression and transactivation activities. Overexpression and knockdown of c-Myc in cancer cells show RPS19 expression was regulated by c-Myc. Furthermore, Knockdown and overexpression of RPS19 was used to analyze of the function of RPS19 in cancer cells. The epithelial-mesenchymal transition (EMT) markers and metastasis abilities of cancer cells were also regulated by RPS19. These data suggest that luteolin and quercetin might inhibit metastasis of cancer cells by blocking Akt/mTOR/c-Myc signaling pathway to suppress RPS19-activated EMT signaling. PMID- 29976411 TI - Characterization of titanium dioxide and zinc oxide nanoparticles in sunscreen powder by comparing different measurement methods. AB - Numerous consumer products, such as cosmetics, contain nanoparticles (NPs) of titanium dioxide (TiO2) or zinc oxide (ZnO); however, this raises questions concerning the safety of such additives. Most of these products do not indicate whether the product includes NPs. In this study, we characterized metal oxide NPs according to size, shape, and composition as well as their aggregation/agglomeration characteristics. In order to comprehend quickly the characterization of metal oxide NPs, we employed single particle inductively coupled plasma (SP-ICPMS) to help quantify the size of metal oxide NPs; then, we use transmission electron microscopy (TEM) to corroborate the results. The crystal size and structure was measured by X-ray diffraction (XRD), there are two crystal phase of TiO2 NPs in sunscreen powder showed in XRD. However, SP-ICPMS proved highly effective in determining the size of NPs, the results of which remarkably good agreement with the TEM measurements. Pre-treatment included a conventional copper grid (requiring sample dilution) to evaluate the size, shape and composition of primary particles or plastic embedding (without the need for sample dilution) to evaluate the aggregate/aggregation of native NOAAs. The proposed method is an effective and fast approach to the characterization of oxide NPs in cosmetic sunscreen powder. These findings outline an alternative approach to the analysis of NPs in powder-form matrix. PMID- 29976412 TI - Benefaction of probiotics for human health: A review. AB - Humans are a unique reservoir of heterogeneous and vivacious group of microbes, which together forms the human-microbiome superorganism. Human gut serves as a home to over 100-1000 microbial species, which primarily modulate the host internal environment and thereby, play a major role in host health. This spectacular symbiotic relationship has attracted extensive research in this field. More specifically, these organisms play key roles in defense function, eupepsia along with catabolism and anabolism, and impact brain-gut responses. The emergence of microbiota with resistance and tolerance to existing conventional drugs and antibiotics has decreased the drug efficacies. Furthermore, the modern biotechnology mediated nano-encapsulated multiplex supplements appear to be high cost and inconvenient. Henceforth, a simple, low-cost, receptive and intrinsic approach to achieve health benefits is vital in the present era. Supplementation with probiotics, prebiotics, and synbiotics has shown promising results against various enteric pathogens due to their unique ability to compete with pathogenic microbiota for adhesion sites, to alienate pathogens or to stimulate, modulate and regulate the host's immune response by initiating the activation of specific genes in and outside the host intestinal tract. Probiotics have also been shown to regulate fat storage and stimulate intestinal angiogenesis. Hence, this study aims to underline the possible beneficial impact of probiotics for human health and medical sectors and for better lifestyle. PMID- 29976413 TI - Recent progress in natural dietary non-phenolic bioactives on cancers metastasis. AB - From several decades ago to now, cancer continues to be the leading cause of death worldwide, and metastasis is the major cause of cancer-related deaths. For health benefits, there is a great desire to use non-chemical therapy such as nutraceutical supplementation to prevent pathology development. Over 10,000 different natural bioactives or phytochemicals have been known that possessing potential preventive or supplementary effects for various diseases including cancer. Previously, the in vitro and in vivo anti-invasive and anti-metastatic activities of phenolic acids, monophenol, polyphenol and their derivatives and flavonoids and their derivatives have been reviewed. However, a vast number of natural dietary compounds other than phenolics have been demonstrated to potentially possess the ability to inhibit the invasion and metastasis of various cancers. In this review, we summarize the studies in recent decade on in vitro and in vivo effects and molecular mechanisms of natural bioactives, excluding the phenolics in food, in cancer invasion and metastasis. By combining this review of non-phenolics with the previous phenolics reviews, the puzzle for the contribution of natural dietary bioactives on cancer invasive or/and metastatic progress will be almost complete and more clear. PMID- 29976414 TI - Pyrrole-protein adducts - A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity. AB - Pyrrolizidine alkaloids (PAs) are phytotoxins identified in over 6000 plant species worldwide. Approximately 600 toxic PAs and PA N-oxides have been identified in about 3% flowering plants. PAs can cause toxicities in different organs particularly in the liver. The metabolic activation of PAs is catalyzed by hepatic cytochrome P450 and generates reactive pyrrolic metabolites that bind to cellular proteins to form pyrrole-protein adducts leading to PA-induced hepatotoxicity. The mechanisms that pyrrole-protein adducts induce toxicities have not been fully characterized. Methods for qualitative and quantitative detection of pyrrole-protein adducts have been developed and applied for the clinical diagnosis of PA exposure and PA-induced liver injury. This mini-review addresses the mechanisms of PA-induced hepatotoxicity mediated by pyrrole-protein adducts, the analytical methods for the detection of pyrrole-protein adducts, and the development of pyrrole-protein adducts as the mechanism-based biomarker of PA exposure and PA-induced hepatotoxicity. PMID- 29976415 TI - Lactic acid bacteria-fermented product of green tea and Houttuynia cordata leaves exerts anti-adipogenic and anti-obesity effects. AB - Obesity is associated with higher risks of developing diabetes and cardiovascular disease. Green tea, rich in polyphenolic compounds such as epigallocatechin gallate (EGCG) and epigallocatechin (EGC), has been shown to display anti-obesity effects. Houttuynia cordata leaves have also been shown to exhibit anti-obesity effects due to their chlorogenic acid content. Lactic acid bacteria are able to increase the production of polyphenolic compounds. This study aims to develop a novel anti-obesity fermentation product by combining H. cordata leaf tea with green tea, using Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101) for fermentation due to the advantages of bioconverting the polyphenolic compounds. The regulation of adipogenesis factors and the anti-obesity effect of the NTU 101 fermented tea were evaluated in an in vitro 3T3-L1 pre-adipocyte model and an in vivo obese rat model, respectively. The results show that the NTU 101-fermented tea, which contained higher EGCG, EGC, and chlorogenic acid levels than unfermented tea, was able to inhibit the lipogenesis of mature 3T3-L1 adipocytes by the stimulation of lipolysis. Furthermore, the body weight gain, body fat pad, and feeding efficiency of obese rats, induced with a high fat diet, were decreased by the oral administration of NTU 101-fermented tea. The significant anti-obesity effect was probably due to lipolysis. However, NTU 101 bacteria cells and EGCG may also act as functional ingredients to contribute to the anti obesity effects of NTU 101-fermented products. PMID- 29976416 TI - 4-O-Caffeoylquinic acid as an antioxidant marker for mulberry leaves rich in phenolic compounds. AB - Mulberry (Morus alba L.) leaves are widely used as herbal tea to prevent heat stroke. Potential chemical markers of the antioxidant properties and its correlation with harvesting times and leaf location were explored in this study. A 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay guided isolation of mulberry leaves extract provided five phenolic compounds: 5-O-caffeoylquinic acid (1), 4-O-caffeoylquinic acid (2), gastrodin (3), isoquercetin (4) and rutin (5). The 50% radical-scavenging concentrations (SC50) of these compounds were 32.76 +/- 0.27, 11.41 +/- 0.48, 404.30 +/- 4.92, 10.63 +/- 0.96, and 10.57 +/- 0.61 MUg/mL, respectively. Chromatographic fingerprinting allowed content analysis of 1-5 in samples over a 12-month period. Compounds 1-5 were abundance in apical leaves (0-10 cm) in January and February at temperatures < 20 degrees C. Contents of 2 and 5 were highest in these months and were strongly correlated to the antioxidant property. Therefore, we suggested that the mulberry leaves harvested during January and February have high yield of 4-O-caffeoylquinic acid and this compound can be used as antioxidative marker in mulberry leaves. PMID- 29976417 TI - Concentrations of perfluoroalkyl substances in foods and the dietary exposure among Taiwan general population and pregnant women. AB - This study quantified five perfluorocarboxylic acids (PFCAs) and two perfluorosulfonic acids in cereals, meats, seafood, eggs, pork liver, and milk in Taiwan using ultra-performance liquid chromatography-tandem mass spectrometry and evaluated the dietary exposure of the general population and pregnant women using per capita consumption and a questionnaire, respectively. Perfluorooctanoic acid (PFOA) and PFCAs of 10-12 carbons were found in almost all of the samples in considerable concentrations in rice and pork liver, reaching as high as 283 ng/g (PFOA in pork liver); the levels are two to three orders of magnitude higher than previous reports. Perfluorooctane sulfonate (PFOS), the most frequently mentioned perfluoroalkyl substance, was rarely detected in many food items (detection frequencies <20% in rice, flour, pork, chicken, salmon, squid, eggs, and milk) at <0.4 ng/g, except for beef, pork liver and some seafood (detection frequencies: 100%, GMs: 0.05-3.52 ng/g). Compared to populations in Western countries, people in Taiwan are exposed to much more perfluorohexanoic acid, PFOA, perfluorodecanoic acid, and perfluoroundecanoic acid (11.2, 85.1, 44.2, and 4.45 ng/kg b.w./day, respectively), mainly due to the higher contaminations in food. The exposure of 8.0 MUg PFOA/person/day in the 95 percentile of pregnant women was due to their frequent consumption of pork liver. PMID- 29976418 TI - Malpractice Litigation After Arthroscopy. AB - Litigation after arthroscopic surgery can be avoided by making the correct diagnosis and mindfully conducting one's surgical practice. PMID- 29976419 TI - Arthroscopic Versus Open Ankle Arthrodesis. PMID- 29976420 TI - Author Reply to "Arthroscopic Versus Open Ankle Arthrodesis". PMID- 29976422 TI - Editorial Commentary: Pursuit of Value-Based Care for SLAP Lesions: More Work to Be Done. AB - Type II SLAP tears are considered the most common type of SLAP lesions. However, the management of type II SLAP tears in middle-aged patients is challenging because recent evidence suggests that there is a high prevalence of type II SLAP lesions in the asymptomatic middle-aged shoulder. Treatment options for type II SLAP lesions in middle-aged patients may include biceps tenodesis, SLAP repair, or nonoperative treatment. Value-based research suggests that biceps tenodesis is the preferred cost-effective treatment modality in middle-aged patients. However, the treatment of type II SLAP lesions in younger patients is more nuanced, and isolated type II SLAP lesions in middle-aged patients are a rare, frequently misdiagnosed, and overtreated entity. As such, more work is needed to better understand the health economics of SLAP treatment across different age groups and activity levels. PMID- 29976421 TI - Editorial Commentary: Drilling Is Never Easy Nor Without Danger in the Shoulder Region. AB - Drilling anatomic tunnels when performing coracoclavicular reconstruction might jeopardize the medial cortex of the coracoid process. PMID- 29976423 TI - Editorial Commentary: Computed Tomography-based Analysis of the Arthroscopic Latarjet Procedure Suggests Graft Positioning Is More Variable than Expected. AB - The Latarjet operation is one of the most successful techniques for the treatment of recurrent anterior shoulder instability, which has recently been translated into the arthroscopic field. Several studies suggest that its arthroscopic variant is safe and reproducible and report promising short-term and mid-term results. Some authors claim that, in addition to less soft tissue damage, positioning of the coracoid graft is more accurate during arthroscopic control. There is currently no evidence of superiority of the arthroscopic or the open technique. As with the open procedure, the arthroscopic Latarjet operation requires a substantial learning curve; therefore the arthroscopic technique should be reserved for experienced arthroscopists treating a large number of shoulder instabilities. PMID- 29976424 TI - Editorial Commentary: What's in a Name: Is There a Difference Between Incomplete and Partial Rotator Cuff Repairs? AB - For the treatment of large to massive rotator cuff repairs, not all partial repairs are equivalent. The technique of rotator cuff repair in large to massive rotator cuff tears matters. By using mobilization techniques to mobilize the rotator cuff to obtain anatomic or near anatomic coverage, double-row techniques to increase footprint coverage, and medial mobilization to decrease tension on the repair, exposure of the humeral head can be minimized, which can improve outcomes. PMID- 29976425 TI - Editorial Commentary: Get Ready to Download the i-Cuff App: Developing the Rotator Cuff Irreparability Equation. AB - Despite extensive published literature on rotator cuff repair, it can still be difficult to predict surgical reparability. We understand that larger chronic tears with fatty infiltration are associated with a greater risk of irreparability. However, it can be difficult to accurately determine the odds of irreparability on a patient-specific level. Several ubiquitous preoperative variables can be incorporated into an "irreparability equation" to more accurately predict if the rotator cuff can be repaired, which could be of tremendous benefit to both the patient and surgeon. PMID- 29976426 TI - Editorial Commentary: Is the Cure Worse Than the Disease? Harvesting Autologous Osteochondral Transfer Plugs for Treatment of Lesions of the Elbow. AB - For autologous osteochondral transfer procedures for osteochondritis dessicans of the elbow, surgeons usually use the knee or ribs as donor sites. This procedure is not without donor site complications. Finding local donor sites is important to reducing the overall morbidity of this procedure. PMID- 29976427 TI - Editorial Commentary: Hip Arthroscopy in a Military Population: Are the Results Comparable to an Athletic Population? AB - Hip pain is common in the military population and has led to an increase in hip arthroscopy as a means of therapeutic treatment. Return to duty (RTD) is the measure by which military surgeons tend to judge their outcomes; could the servicemember "get back in the fight?" Return to play (RTP) is a common metric in sports medicine for assessing the effectiveness of a surgical intervention. The results of prior studies of RTD hip arthroscopy in the US military population have been underwhelming when compared with RTP in athletic cohorts. This discrepancy in outcomes likely has more to do with the differences in RTD and RTP as outcome measures than any surgeon, pathology, or demographic factors. PMID- 29976428 TI - Editorial Commentary: Should Proximal Hamstring Surgery Make You Nervous? AB - In recent times, there has been an increased awareness of high-grade proximal hamstring injuries, many of which are now being managed surgically. Yet, surgical treatment of these injuries is challenging and carries potential risks of serious neurologic complications. Indeed, it is likely that postoperative neurologic complications are under-recognized. As such, knowledge of the intimate anatomic relation of the pudendal nerve and other neural structures around the proximal hamstring is essential and should provide a road map for safer and more successful surgery. PMID- 29976429 TI - Editorial Commentary: Hip Radiographic Measurement: It Takes More Than One. AB - The success of hip arthroscopy is based on selecting the right patient. Radiographic measurements are commonly used in the diagnosis of femoroacetabular impingement and other hip pathologies that are treated with hip arthroscopy. Unfortunately, there is not one measurement. For proper patient selection, it is critical to assess for dysplasia and the level of osteoarthritis. The final diagnosis and the decision to proceed with hip arthroscopy should be based on a global evaluation of the joint using different radiographic views and parameters. PMID- 29976430 TI - Editorial Commentary: Ligamentum Teres Tears: What Are We Chasing? Could Posterior Bony Impingement Cause Midsubstance Tears? AB - In addition to traumatic events such as hip dislocations, bony impingement can result in partial or complete tears of the ligamentum teres. The understanding of the biomechanical function, structural and mechanical properties of the ligament teres, and the reasons for tears is still evolving, and we should continue to look out for unusual appearances. Obviously, the clinical relevance of the findings can be debated. PMID- 29976431 TI - Editorial Commentary: Femoroacetabular Impingement and Evidence: Are We There Yet? AB - Femoroacetabular impingement has been established as an impactful cause of hip pain and dysfunction in the young active individual. Improving evidence from well conducted studies will continue to refine indications and outcomes and perhaps lead to more questions, such as: "How was the capsule managed?" "What was the patient compliance rate with rehabilitation?" "What was the impact of surgical morphology correction on clinical outcome?" "Did cartilage status impact clinical outcome?" and "Was there a noticeable learning curve reflected in outcomes?" These are all important questions that should be addressed in future studies. PMID- 29976432 TI - Editorial Commentary: Smarter Than a Sixth Grader? Hip Arthroscopists, Check Your Training at the Door. AB - Literacy is one of the best predictors of an individual's health, and providing effective, patient-centered communication to our less literate patients has become a challenge for the entire medical community. The internet has become patients' first-line source of medical information, and as caretakers of musculoskeletal medicine, it is orthopaedists' responsibility to provide high quality, patient-centric resources that are simple and clear. When creating our own practice or institution's websites, we must check our training and technicality at the door to create resources that are easily readable and digestible. PMID- 29976433 TI - Editorial Commentary: Managing Excessive Posterior Slope in Anterior Cruciate Ligament Reconstruction: Where Do We Draw the Line? AB - When an anterior cruciate ligament (ACL) reconstruction fails, surgeons often rush to critique graft placement, graft choice, size, and fixation amongst other factors. One often-overlooked but important risk factor for noncontact failure of ACL reconstruction is tibial alignment. Although the deleterious effects of varus and valgus malalignment have been well established, recent research calls attention to excess posterior tibial slope as an underappreciated risk factor for failure of ACL reconstruction. PMID- 29976434 TI - Editorial Commentary: Looking Outside the Box With Ultrasound in an Anterior Cruciate Ligament-Deficient Knee: Welcome to Surgery 2.0. AB - Perspectives on the anterolateral ligament have changed greatly since the first articles were published that cast doubt on the existence of this structure. The current debate is centered on how to best analyze it. Surgeons are increasingly focusing on the knee's secondary restraints. It is important to understand that magnetic resonance imaging is not the only imaging modality available to us. PMID- 29976435 TI - Editorial Commentary: Can We Really See the Calcified Cartilage Layer When Debriding Focal Cartilage Defects? AB - Cell-based cartilage restoration techniques have made huge leaps in recent years; however, many hurdles still lay ahead, one of which is the fundamental task of preparing the cartilage lesion site. Although it is one of the first skills an arthroscopist learns during training, it seems that current techniques and instrumentation still yield inconsistent results, which can hinder patient outcomes. PMID- 29976436 TI - Editorial Commentary: Proficiency-Based Training: Are We Ready for a New Way to Train and Test Orthopaedic Surgeons? AB - Orthopaedic training has followed an apprentice/mentorship pathway of training throughout its history. This method of training is entrenched in Medicine and is the foundation for our current residency/fellowship method of attaining the appropriate training and credentialing of physicians and surgeons to safely care for our patients. Over the past 2 decades, the use of proficiency-based training has been shown to be effective in general surgery, cardiac surgery, vascular and plastic surgery, and now with the Copernicus project, in shoulder arthroscopy. Combining proficiency-based training with the rapid advances in virtual reality technology will allow surgeons to become competent with the surgical skills needed for surgery before ever touching a patient. PMID- 29976437 TI - Editorial Commentary: The Quest to Prevent Knee Anterior Cruciate Ligament Bone Tunnel Widening Continues. AB - The exploration of methods to improve healing of a tendon graft in a bone tunnel in anterior cruciate ligament reconstruction has been a subject of basic and translational research for over 30 years. It is well recognized that the graft attachment site to the bone represents the "weak link" in the early healing period. We as clinicians search for methods to augment healing of the tendon graft in the bone tunnel. Agents and techniques that improve osteoinduction may improve healing. Implanted chondrocytes may promote tendon-to-bone healing by participating in new bone formation or, alternatively, by providing signaling molecules that stimulate local or distant endogenous cells. Tracking of cell fate after implantation will be required to further delineate biologic mechanisms. PMID- 29976438 TI - Editorial Commentary: Outside the Scope of Practice-Wrong-Site Surgery Should NEVER Happen. AB - Malpractice lawsuits involving arthroscopic surgical procedures are relatively common. Fortunately, many of them are avoidable. Wrong-site surgery results in a successful verdict for the plaintiff all the time, so it needs to be avoided. Deep venous thrombosis, another common reason for lawsuits, especially after knee arthroscopy, can be stratified based on risk factors and managed accordingly. Effective communication is the arthroscopist's best defense against potential lawsuits. PMID- 29976440 TI - The death of low-dose oral theophylline for COPD? PMID- 29976439 TI - Editorial Commentary: To Cyst or Not to Cyst: Shoulder SLAP Lesions With Concomitant Spinoglenoid Notch Ganglion Cysts. AB - When a patient presents with shoulder pain and the workup reveals a spinoglenoid notch cyst, it is presumed by most to be related to an intra-articular SLAP tear. When managing this condition cyst excision has been advocated to alleviate suprascapular nerve pressure and also perhaps minimize recurrence assuming that the SLAP has also been treated. Cyst excision can endanger the suprascapular nerve and takes additional operating room time. The question is whether repairing the SLAP and therefore removing the starting point for the cyst would be adequate as the only surgical management. My preference is to leave the operating room with some indication that the pressure on the suprascapular nerve has been dealt with by at least decompressing the cyst. But on the basis of recent published experience, we may need to re-evaluate this. PMID- 29976441 TI - Pulmonary tuberculosis in Pope Clement XI. PMID- 29976442 TI - Swabbing for science. PMID- 29976443 TI - Hypoxia and eosinophilia in a patient with difficult asthma. PMID- 29976444 TI - Pan-tuberculosis regimens: re-framing the argument. PMID- 29976445 TI - Isoniazid-resistant, rifampicin-susceptible tuberculosis in India. PMID- 29976446 TI - RSV prevention in infancy and asthma in later life. PMID- 29976447 TI - RSV prevention in infancy and asthma in later life. PMID- 29976448 TI - RSV prevention in infancy and asthma in later life. PMID- 29976450 TI - Corrections. PMID- 29976451 TI - Health systems for prosperity and solidarity: Tallinn 2018. PMID- 29976449 TI - RSV prevention in infancy and asthma in later life - Authors' reply. PMID- 29976453 TI - ICD-11: a brave attempt at classifying a new world. PMID- 29976452 TI - Turning Brexit uncertainties into public health advancement. PMID- 29976454 TI - Robot-assisted versus open cystectomy. PMID- 29976455 TI - Is organ preservation in rectal cancer ready for prime time? PMID- 29976456 TI - Preprints with The Lancet: joining online research discussion platforms. PMID- 29976457 TI - Offline: Defending the left hand of the state. PMID- 29976458 TI - Hepatitis C-infected organ transplants offer hope. PMID- 29976459 TI - Alzheimer's disease research: the future of BACE inhibitors. PMID- 29976460 TI - Gun violence research in the USA: the CDC's impasse. PMID- 29976461 TI - Wendy Barclay: a contagious enthusiasm for the influenza virus. PMID- 29976462 TI - Spanish influenza redux: revisiting the mother of all pandemics. PMID- 29976463 TI - Medical research in war-torn Syria: medical students' perspective. PMID- 29976464 TI - Five actions to rescue children in Syria. PMID- 29976465 TI - Protecting children against Japanese encephalitis in Bali, Indonesia. PMID- 29976466 TI - Infected necrotising pancreatitis: antibiotic administration remains the first step. PMID- 29976467 TI - Alpha-chain disease: a lymphomagenesis model. PMID- 29976468 TI - Infected necrotising pancreatitis: antibiotic administration remains the first step - Authors' reply. PMID- 29976469 TI - Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. AB - BACKGROUND: Radical cystectomy is the surgical standard for invasive bladder cancer. Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity. We aimed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot assisted cystectomy. METHODS: The RAZOR study is a randomised, open-label, non inferiority, phase 3 trial done in 15 medical centres in the USA. Eligible participants (aged >=18 years) had biopsy-proven clinical stage T1-T4, N0-N1, M0 bladder cancer or refractory carcinoma in situ. Individuals who had previously had open abdominal or pelvic surgery, or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded. Patients were centrally assigned (1:1) via a web-based system, with block randomisation by institution, stratified by type of urinary diversion, clinical T stage, and Eastern Cooperative Oncology Group performance status, to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion. Treatment allocation was only masked from pathologists. The primary endpoint was 2-year progression-free survival, with non inferiority established if the lower bound of the one-sided 97.5% CI for the treatment difference (robotic cystectomy minus open cystectomy) was greater than 15 percentage points. The primary analysis was done in the per-protocol population. Safety was assessed in the same population. This trial is registered with ClinicalTrials.gov, number NCT01157676. FINDINGS: Between July 1, 2011, and Nov 18, 2014, 350 participants were randomly assigned to treatment. The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients. 17 (10%) of 176 patients in the robotic cystectomy group did not have surgery and nine (5%) patients had a different surgery to that they were assigned. 21 (12%) of 174 patients in the open cystectomy group did not have surgery and one (1%) patient had robotic cystectomy instead of open cystectomy. Thus, 302 patients (150 in the robotic cystectomy group and 152 in the open cystectomy group) were included in the per-protocol analysis set. 2-year progression-free survival was 72.3% (95% CI 64.3 to 78.8) in the robotic cystectomy group and 71.6% (95% CI 63.6 to 78.2) in the open cystectomy group (difference 0.7%, 95% CI -9.6% to 10.9%; pnon-inferiority=0.001), indicating non inferiority of robotic cystectomy. Adverse events occurred in 101 (67%) of 150 patients in the robotic cystectomy group and 105 (69%) of 152 patients in the open cystectomy group. The most common adverse events were urinary tract infection (53 [35%] in the robotic cystectomy group vs 39 [26%] in the open cystectomy group) and postoperative ileus (33 [22%] in the robotic cystectomy group vs 31 [20%] in the open cystectomy group). INTERPRETATION: In patients with bladder cancer, robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival. Increased adoption of robotic surgery in clinical practice should lead to future randomised trials to assess the true value of this surgical approach in patients with other cancer types. FUNDING: National Institutes of Health National Cancer Institute. PMID- 29976471 TI - Schistosomiasis detected during appendectomy. PMID- 29976470 TI - Long-term outcomes of clinical complete responders after neoadjuvant treatment for rectal cancer in the International Watch & Wait Database (IWWD): an international multicentre registry study. AB - BACKGROUND: The strategy of watch and wait (W&W) in patients with rectal cancer who achieve a complete clinical response (cCR) after neoadjuvant therapy is new and offers an opportunity for patients to avoid major resection surgery. However, evidence is based on small-to-moderate sized series from specialist centres. The International Watch & Wait Database (IWWD) aims to describe the outcome of the W&W strategy in a large-scale registry of pooled individual patient data. We report the results of a descriptive analysis after inclusion of more than 1000 patients in the registry. METHODS: Participating centres entered data in the registry through an online, highly secured, and encrypted research data server. Data included baseline characteristics, neoadjuvant therapy, imaging protocols, incidence of local regrowth and distant metastasis, and survival status. All patients with rectal cancer in whom the standard of care (total mesorectal excision surgery) was omitted after neoadjuvant therapy were eligible to be included in the IWWD. For the present analysis, we only selected patients with no signs of residual tumour at reassessment (a cCR). We analysed the proportion of patients with local regrowth, proportion of patients with distant metastases, 5 year overall survival, and 5-year disease-specific survival. FINDINGS: Between April 14, 2015, and June 30, 2017, we identified 1009 patients who received neoadjuvant treatment and were managed by W&W in the database from 47 participating institutes (15 countries). We included 880 (87%) patients with a cCR. Median follow-up time was 3.3 years (95% CI 3.1-3.6). The 2-year cumulative incidence of local regrowth was 25.2% (95% CI 22.2-28.5%), 88% of all local regrowth was diagnosed in the first 2 years, and 97% of local regrowth was located in the bowel wall. Distant metastasis were diagnosed in 71 (8%) of 880 patients. 5-year overall survival was 85% (95% CI 80.9-87.7%), and 5-year disease specific survival was 94% (91-96%). INTERPRETATION: This dataset has the largest series of patients with rectal cancer treated with a W&W approach, consisting of approximately 50% data from previous cohort series and 50% unpublished data. Local regrowth occurs mostly in the first 2 years and in the bowel wall, emphasising the importance of endoscopic surveillance to ensure the option of deferred curative surgery. Local unsalvageable disease after W&W was rare. FUNDING: European Registration of Cancer Care financed by European Society of Surgical Oncology, Champalimaud Foundation Lisbon, Bas Mulder Award granted by the Alpe d'Huzes Foundation and Dutch Cancer Society, and European Research Council Advanced Grant. PMID- 29976472 TI - Conflict in Ukraine and a ticking bomb of HIV. PMID- 29976473 TI - The fourth joint conference of BHIVA with BASHH. PMID- 29976474 TI - Modeling the effects of telephone nursing on healthcare utilization. AB - BACKGROUND: Telephone nursing is the first line of contact for many care-seekers and aims at optimizing the performance of the healthcare system by supporting and guiding patients to the correct level of care and reduce the amount of unscheduled visits. Good statistical models that describe the effects of telephone nursing are important in order to study its impact on healthcare resources and evaluate changes in telephone nursing procedures. OBJECTIVE: To develop a valid model that captures the complex relationships between the nurse's recommendations, the patients' intended actions and the patients' health seeking behavior. Using the model to estimate the effects of telephone nursing on patient behavior, healthcare utilization, and infer potential cost savings. METHODS: Bayesian ordinal regression modeling of data from randomly selected patients that received telephone nursing. Inference is based on Markov Chain Monte Carlo (MCMC) methods, model selection using the Watanabe-Akaike Information Criteria (WAIC), and model validation using posterior predictive checks on standard discrepancy measures. RESULTS AND CONCLUSIONS: We present a robust Bayesian ordinal regression model that predicts three-quarters of the patients' healthcare utilization after telephone nursing and we found no evidence of model deficiencies. A patient's compliance to the nurse's recommendation varies and depends on the recommended level of care, its agreement with and level of the patient's prior intention, and the availability of different care options at the time. The model reveals a risk reducing behavior among patients and the effect of the telephone nursing recommendation is 7 times higher than the effect of the patient's intended action prior to consultation if the recommendation is the highest level of care. But the effect of the nurse's recommendation is lower, or even non-existing, if the recommendation is self-care. Telephone nursing was found to have a constricting effect on healthcare utilization, however, the compliance to nurse's recommendation is closely tied to perceptions of risk, emphasizing the importance to address caller's needs of reassurance. PMID- 29976475 TI - In Reply to McClelland III and Jaboin. PMID- 29976476 TI - In Regard to Chi et al. PMID- 29976477 TI - In Reply to Roos et al. PMID- 29976478 TI - Erratum to: Mohan R, Held KD, Story MD, et al. Proceedings of the National Cancer Institute Workshop on Charged Particle Radiobiology. Int J Radiat Oncol Biol Phys 2018;100:816-831. PMID- 29976479 TI - GI Cancers-Modulating the Modern Management of Gastrointestinal Malignancies: A Look at Liver Metastases, Rectal Cancer, Esophagogastric Cancer, and Anal Cancer. PMID- 29976480 TI - In the Eye of the Maximal Storm: Surgery Versus Radiation? PMID- 29976482 TI - Organ Preservation in Sinonasal Malignancies Through Particle Therapy. PMID- 29976481 TI - Reluctant Induction Followed by Proton Beam Therapy, If Practicable. PMID- 29976483 TI - Time to Rethink Our Strategy With a Preoperative Intensification Approach. PMID- 29976484 TI - Preoperative Radiation Therapy for Locally Advanced Sinus Malignancies. PMID- 29976485 TI - Intra-arterial Chemoradiation Therapy as an Option for Maxillary Sinus Cancers. PMID- 29976486 TI - Carl Mansfield, MD, ScD, FACR, FASTRO (1928-2018). PMID- 29976487 TI - Radiation Therapy Research: A Global Analysis 2001-2015. AB - Radiation therapy is a core modality of cancer treatment; however, concerns have been expressed regarding its underutilization and its lack of prioritization as a research domain relative to other cancer treatment modalities, despite its rapid technical evolution. It is therefore important to understand, from a public policy perspective, the evolution of global radiation therapy research, to identify strengths, weaknesses, and opportunities. This study used a bibliometric approach to undertake a quantitative analysis of global radiation therapy research published between 2001 and 2015 and available in the Web of Science (Wos) database, with particular focus on the 25 leading research-active countries. A total of 62,550 radiation therapy research articles from 127 countries, published in 2531 international journals, were analyzed. The United States was responsible for 32.3% of these outputs, followed by Japan (8.0%) and Germany (7.7%). Nearly half of all publications related to preparation and delivery of radiation therapy, combined-modality regimens, and dose fractionation studies. Health services research, palliative care, and quality of life studies represented only 2%, 5%, and 4% of all research outputs, respectively. Countries varied significantly in their commitment to different research domains, and trial related publications represented only 5.1% of total output. Research impact was analyzed according to 3 different citation scores, with research outputs from Denmark, The Netherlands, and the United States consistently the highest ranked. Globally, radiation therapy publication outputs continue to increase but lag behind other spheres of cancer management. The types of radiation therapy research undertaken appear to be regionally patterned, and there is a clear disconcordance between the volume of research output from individual countries and its citation impact. Greater support for radiation therapy research in low- and middle-income countries is required, including international collaboration. The study findings are expected to provide the requisite knowledge to guide future radiation therapy research programs. PMID- 29976488 TI - Scholarly Publishing and the Metric System. PMID- 29976489 TI - The Resident Individual Development Plan as a Guide for Radiation Oncology Mentorship. PMID- 29976490 TI - A Window to Internet-based Information Seeking of US Fourth-Year Medical Students: Are Radiation Oncology Residency Program Websites Comprehensive? PMID- 29976491 TI - RECORDS: improved Reporting of montE CarlO RaDiation transport Studies. PMID- 29976492 TI - Radiation Therapy for Solitary Plasmacytoma and Multiple Myeloma: Guidelines From the International Lymphoma Radiation Oncology Group. AB - PURPOSE: To develop guidelines for the work-up and radiation therapy (RT) management of patients with plasma cell neoplasms. METHODS AND MATERIALS: A literature review was conducted covering staging, work-up, and RT management of plasma cell neoplasms. Guidelines were developed through consensus by an international panel of radiation oncologists with expertise in these diseases, from the International Lymphoma Radiation Oncology Group. RT volume definitions are based on the International Commission on Radiation Units and Measurements. RESULTS: Plasma cell neoplasms account for approximately one-fifth of mature B cell neoplasms in the United States. The majority (~95%) are diagnosed as multiple myeloma, in which there has been tremendous progress in systemic therapy approaches with novel drugs over the last 2 decades, resulting in improvements in disease control and survival. In contrast, a small proportion of patients with plasma cell neoplasms present with a localized plasmacytoma in the bone, or in extramedullary (extraosseous) soft tissues, and definitive RT is the standard treatment. RT provides long-term local control in the solitary bone plasmacytomas and is potentially curative in the extramedullary cases. This guideline reviews the diagnostic work-up, principles, and indications for RT, target volume definition, treatment planning, and follow-up procedures for solitary plasmacytoma. Specifically, detailed recommendations for RT volumes and dose/fractionation are provided, illustrated with specific case scenarios. The role of palliative RT in multiple myeloma is also discussed. CONCLUSIONS: The International Lymphoma Radiation Oncology Group presents a standardized approach to the use and implementation of definitive RT in solitary plasmacytomas. The modern principles outlining the supportive role of palliative RT in multiple myeloma in an era of novel systemic therapies are also discussed. PMID- 29976493 TI - Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1. AB - PURPOSE: Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but in vitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1. METHODS AND MATERIALS: We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4 Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist. RESULTS: Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and DeltaHU/Gy (RBE) (endpoint 2): P = .049 and P = .00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P = .018; median score, 3 of 9 for protons and 1.5 of 9 for photons). CONCLUSIONS: Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important in vivo as well as in vitro. PMID- 29976494 TI - Proton Stereotactic Radiosurgery for Brain Metastases: A Single-Institution Analysis of 370 Patients. AB - PURPOSE: To report the first series of proton stereotactic radiosurgery (SRS) for the treatment of patients with single or multiple brain metastases, including failure patterns, survival outcomes, and toxicity analysis. METHODS AND MATERIALS: This was a single-institution, retrospective study of 815 metastases from 370 patients treated with proton SRS between April 1991 and November 2016. Cumulative incidence estimates of local failure, distant brain failure, and pathologically confirmed radionecrosis and Kaplan-Meier estimates of overall survival were calculated. Fine and Gray and Cox regressions were performed to ascertain whether clinical and treatment factors were associated with the described endpoints. RESULTS: The median follow-up from proton SRS was 9.2 months. The 6- and 12-month estimates of local failure, distant brain failure, and overall survival were 4.3% (95% confidence interval [CI] 3.0%-5.9%) and 8.5% (95% CI 6.7%-10.6%), 39.1% (95% CI 34.1%-44.0%) and 48.2% (95% CI 43.0%-53.2%), and 76.0% (95% CI 71.3%-80.0%) and 51.5% (95% CI 46.3%-56.5%), respectively. The median survival was 12.4 months (95% CI 10.8-14.0 months) after proton SRS. The most common symptoms were low-grade fatigue (12.5%), headache (10.0%), motor weakness (6.2%), seizure (5.8%), and dizziness (5.4%). The rate of pathologically confirmed radionecrosis at 12 months was 3.6% (95% CI 2.0%-5.8%), and only target volume was associated on multivariate analysis (subdistribution hazard ratio 1.13, 95% CI 1.0-1.20). CONCLUSIONS: To the best of our knowledge, this is the first reported series of proton SRS for the management of brain metastases. Moderate-dose proton SRS is well tolerated and can achieve good local control outcomes, comparable to those obtained with conventional photon SRS strategies. Although proton SRS remains resource-intensive, future strategies evaluating its selective utility in patients who would benefit most from integral dose reduction should be explored. PMID- 29976495 TI - Proton Therapy for Brain Metastases: A Question of Value. PMID- 29976496 TI - Phosphatidylinositol-3-Kinase Mutations Are Associated With Increased Local Failure in Brain Metastases Treated With Radiation. AB - PURPOSE: To determine whether phosphatidylinositol-3-kinase (PI3K) mutations confer suboptimal local control after radiation therapy (RT) for brain metastases. METHODS AND MATERIALS: We retrospectively reviewed 259 patients with brain metastases treated with RT during the period 2004 to 2017 for whom tumor genetic data (MSK-IMPACT) were available for primary or metastatic lesions. Associations between clinical factors, PI3K mutations status, and local failure (LF) were evaluated with univariate and multivariate competing risks regression. RESULTS: A total of 112 patients received whole brain radiation therapy (WBRT) to a median dose of 30 Gy in 10 fractions, and 147 patients received stereotactic radiosurgery (SRS) to 338 lesions; 276 lesions were treated with single fraction SRS (median dose 21 Gy) and 76 lesions over 3 to 5 fractions SRS (median dose 30 Gy). PI3K mutations were present in 36 WBRT patients (32%) and 44 SRS patients (30%). For WBRT, patients with PI3K mutations (hazard ratio 2.67, P < .001) were found to be at higher risk for LF on multivariable analysis, and the 1-year cumulative incidence of LF was 50% (95% confidence interval [CI] 32%-65%) for patients with PI3K mutations versus 26% (95% CI 17%-37%) for patients without PI3K mutations. For SRS lesions, while PI3K mutations positivity was not statistically significantly associated with LF, higher rate of LF was observed: 1 year LF cumulative incidence of 11% (95% CI 6%-17%) for patients with PI3K mutations versus 5% (95% CI 3%-9%) for patients without PI3K mutations. CONCLUSION: Patients with PI3K mutations are at higher risk for LF for brain metastases after RT. Novel therapeutic strategies to improve treatment outcomes in these patients should be considered. PMID- 29976497 TI - Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases. AB - PURPOSE: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM). METHODS AND MATERIALS: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed. RESULTS: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes. CONCLUSIONS: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor. PMID- 29976499 TI - Cost-Effectiveness Analysis of Intensity Modulated Radiation Therapy Versus Proton Therapy for Oropharyngeal Squamous Cell Carcinoma. AB - PURPOSE: To compared the cost-effectiveness of intensity modulated proton beam therapy (PBT) and intensity modulated radiation therapy (IMRT) in the management of stage III-IVB oropharynx cancer (OPC). METHODS AND MATERIALS: A Markov model was constructed to compare IMRT with PBT for a 65-year-old patient with stage IVA OPSCC. We assumed PBT led to a 25% reduction in long-term xerostomia, short-term dysgeusia, and the need for gastrostomy tube. Fewer dental complications were also expected with PBT. Incremental cost-effectiveness ratios (ICERs) were calculated, and value of information analyses were performed. The societal willingness-to-pay was defined as $100K per quality-adjusted life year (QALY). RESULTS: The ICERs for PBT for favorable human papillomavirus (HPV)-positive OPC were $288,000/QALY and $390,000/QALY in the payer perspective (PP) and societal perspective, respectively. Under nearly every scenario, PBT was not cost effective, with ICERs above $150,000/QALY in the PP. The ICERs for HPV-negative OPC were typically greater than $250K/QALY in both perspectives. For HPV-positive patients, the ICER was less than $100,000/QALY in the PP only in younger patients who experienced a 50% reduction in both xerostomia and gastrostomy use. On probabilistic sensitivity analyses, there were 0% and 0.4% probabilities that PBT was cost-effective for 65- and 55-year old patients, respectively. The value of information was zero or negligible for all ages and perspectives at willingness to-pay of $100,000/QALY and only meaningful in the PP for younger patients at a willingness-to-pay of $150,000/QALY. CONCLUSIONS: Intensity modulated proton beam therapy was only cost-effective in the PP if assumed to achieve profound reductions in long-term morbidity for younger patients; it was never cost effective in the societal perspective. Prospective data are needed (and may be valuable) to better characterize the comparative toxicities of these treatments but are unlikely to change this calculation, except potentially in the most favorable cohort of patients. PMID- 29976498 TI - The Children's Oncology Group Radiation Oncology Discipline: 15 Years of Contributions to the Treatment of Childhood Cancer. AB - PURPOSE: Our aim was to review the advances in radiation therapy for the management of pediatric cancers made by the Children's Oncology Group (COG) radiation oncology discipline since its inception in 2000. METHODS AND MATERIALS: The various radiation oncology disease site leaders reviewed the contributions and advances in pediatric oncology made through the work of the COG. They have presented outcomes of relevant studies and summarized current treatment policies developed by consensus from experts in the field. RESULTS: The indications and techniques for pediatric radiation therapy have evolved considerably over the years for virtually all pediatric tumor types, resulting in improved cure rates together with the potential for decreased treatment-related morbidity and mortality. CONCLUSIONS: The COG radiation oncology discipline has made significant contributions toward the treatment of childhood cancer. Our discipline is committed to continuing research to refine and modernize the use of radiation therapy in current and future protocols with the goal of further improving the cure rates and quality of life of children with cancer. PMID- 29976500 TI - Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results From a Multi-institutional Consortium Study. AB - PURPOSE: Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity. METHODS AND MATERIALS: The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding. RESULTS: The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P < .01 by chi2 test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048). CONCLUSIONS: To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment. PMID- 29976501 TI - A Randomized Phase 2 Trial of Consolidation Chemotherapy After Preoperative Chemoradiation Therapy Versus Chemoradiation Therapy Alone for Locally Advanced Rectal Cancer: KCSG CO 14-03. AB - PURPOSE: Preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME) in locally advanced rectal cancer is the standard of care. To date, the role of consolidation chemotherapy after CRT has rarely been addressed through randomized trials. This study aimed to evaluate the efficacy of CRT followed by consolidation chemotherapy compared with CRT alone. METHODS AND MATERIALS: This study enrolled patients with adenocarcinoma of the rectum and cT3 or cT4 disease with any N category and no metastasis. In arm A (control arm), we planned CRT (50.4 Gy in 28 fractions) with capecitabine followed by TME. In arm B, 2 cycles of capecitabine and oxaliplatin were administered 1 week after the completion of CRT before TME (capecitabine, 1700 mg/m2 per day from day 1 to 14, and oxaliplatin, 100 mg/m2 on day 1, every 3 weeks). The downstaging rate (the proportion of ypT0 to ypT2 and ypN0M0) was the primary endpoint, which was to be tested with a 1-sided type I error of 15% and with 85% power. RESULTS: From September 2014 to February 2016, 110 patients (56 in arm A and 54 in arm B) were randomized and 108 (55 in arm A and 53 in arm B) started CRT. TME was conducted per protocol in 96 patients (52 in arm A and 44 in arm B). In arms A and B, downstaging was achieved in 21.2% and 36.4% (P = .077), respectively, and the pathologic complete response rate was 5.8% and 13.6% (P = .167), respectively. Grade >=3 adverse events occurred in 3.6% of patients in arm A and 9.4% of patients in arm B during the preoperative treatment phase and in 1.9% and 9.0%, respectively, during the postoperative recovery phase. CONCLUSIONS: Consolidation chemotherapy with 2 cycles of capecitabine and oxaliplatin demonstrated a marginal improvement in the downstaging rate. However, a phase 3 trial of this strategy is discouraged because of the high dropout rate and safety issues. PMID- 29976503 TI - Longitudinal Evaluation of Lung Function in Patients With Advanced Non-Small Cell Lung Cancer Treated With Concurrent Chemoradiation Therapy. AB - PURPOSE: In lung cancer patients, radiation therapy modifies lung architecture, resulting in functional deterioration, which worsens symptoms and reduces quality of life. METHODS AND MATERIALS: A multicenter, prospective, longitudinal study was conducted in a cohort of patients with locally advanced and oligometastatic non-small cell lung cancer treated with concurrent chemoradiation therapy (CCRT). A wide array of pulmonary function tests (forced spirometry, body plethysmography, impulse oscillometry, carbon monoxide diffusing capacity, fraction of exhaled nitric oxide, arterial blood gases, and 6-minute walk test) were used to evaluate lung function at baseline; after radiation therapy; and at 6, 12, 24, and 48 weeks after CCRT. Relative changes in test results (percentages) were estimated at the aforementioned intervals and compared with baseline results. RESULTS: Thirty-seven patients completed the follow-up and were included in the analysis. After CCRT, patients showed a maximum decline in lung volumes as follows: (1) 31% in forced expiratory volume in the first second after 24 weeks (P = .008), (2) 9.6% in forced vital capacity after 48 weeks (P = .04), and (3) 15.1% in total lung capacity after 48 weeks (P = .0015). Similarly, at 12 weeks after CCRT, patients showed a 21.8% decrease in carbon monoxide diffusing capacity (P = .002). Increases were found in total airway resistance (respiratory system resistance at 5 Hz), frequency dependence of resistance (change in respiratory system resistance at 5 Hz-respiratory system resistance at 20 Hz, P = .012), and reactance (P = .0003 for respiratory system reactance at 5 Hz and P = .001 for reactance area), which together indicate small-airway dysfunction. CONCLUSIONS: The longitudinal evaluation of lung function through pulmonary function tests detects CCRT-induced damage before the appearance of clinical symptoms associated with CCRT lung toxicity. PMID- 29976502 TI - Baseline Albumin-Bilirubin (ALBI) Score in Western Patients With Hepatocellular Carcinoma Treated With Stereotactic Body Radiation Therapy (SBRT). AB - PURPOSE: To assess the baseline albumin-bilirubin (ALBI) score as a predictor of toxicity and survival in a prospective cohort of Western patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) in 2 prospective trials. METHODS AND MATERIALS: The study included 102 patients with Child-Pugh class A liver disease who received 6-fraction SBRT for HCC. Univariate and multivariable logistic regression investigated factors associated with toxicity, defined as an increase in Child-Pugh score >= 2 within 3 months of SBRT. Univariate and multivariable Cox regression analyses investigated factors predictive of overall survival (OS). The ALBI score was analyzed as a continuous and binary variable in separate analyses. RESULTS: On multivariable analysis of toxicity, including the ALBI score as a continuous variable, the ALBI score (odds ratio [OR] per 0.1-unit increase, 1.51; 95% confidence interval [CI] 1.23-1.85; P = .00074), mean liver dose (OR, 1.31; 95% CI 1.02-1.68; P = .036), and dose received by 800 cm3 of normal liver (OR, 1.10; 95% CI 1.01-1.20; P = .028) were significant. When the ALBI score was included as a dichotomous variable, the ALBI grade remained a significant predictor of toxicity (OR, 7.44; 95% CI 2.34-23.70; P = .00069). On multivariable analysis of OS, including the ALBI score as a continuous variable, the ALBI score (hazard ratio [HR] per 0.1-unit increase, 1.09; 95% CI 1.03-1.17; P = .004), tumor thrombus (HR, 1.94; 95% CI 1.23-3.07; P = .004), and treatment in trial 1 versus trial 2 (HR, 1.92; 95% CI 1.23-3.03; P = .004) were significant. Similarly, when the ALBI score was included as a binary variable, the ALBI grade, tumor thrombus, and trial were significant predictors of OS. When the ALBI score was considered, the Child-Pugh score (A6 vs A5) was not significant in multivariable models analyzing toxicity or survival. Concordance statistics indicated models containing the ALBI score were superior to those containing the Child-Pugh score. CONCLUSIONS: The baseline ALBI score was more discriminating than the Child-Pugh score in predicting OS and toxicity in patients with Child-Pugh class A liver disease. The ALBI score should be used as a factor for stratification in future HCC SBRT trials. PMID- 29976504 TI - Clinical and Dosimetric Factors Predicting Grade >=2 Radiation Pneumonitis After Postoperative Radiotherapy for Patients With Non-Small Cell Lung Carcinoma. AB - PURPOSE: To identify clinical and dosimetric factors that would predict grade >=2 radiation pneumonitis (RP) for patients undergoing postoperative radiation therapy (PORT) for non-small cell lung cancer (NSCLC); and to use the factors identified to generate a predictive model to quantify risk of RP in such patients. METHODS AND MATERIALS: We retrospectively reviewed radiation therapy, radiographic, and clinical data from 199 patients who had received PORT, with or without chemotherapy, for NSCLC. Potential associations between dosimetric and clinical factors and RP were evaluated in univariate and multivariate Cox regression hazard models and competing risk analysis. Kaplan-Meier analysis was used to estimate overall survival and the cumulative incidence of RP, and receiver operating characteristic curve analysis to identify cutpoints for variables found to influence RP risk. The endpoint was grade >=2 RP (symptomatic, requiring steroids or limiting instrumental activities of daily living). RESULTS: Thirty-seven patients (19%) developed grade >=2 RP. Patient-related factors, type of surgery or chemotherapy, and radiation therapy-related factors were not associated with grade >=2 RP; only lung V10 > 30% and lung V20 > 20% predicted grade >=2 RP. Risk groupings were as follows: high risk, V10 > 30% and V20 > 20% (24 of 72 patients, 33%); intermediate risk, V10 > 30% and V20 <= 20% or V10 <= 30% and V20 > 20% (6 of 26 patients, 23%); and low risk, V10 <= 30% and V20 <= 20% (6 of 101 patients, 6%) (P < .0001). In a subgroup analysis of patients who had had lobectomy, corresponding incidences of RP were as follows: high risk, 20 of 59 (34%); intermediate risk, 5 of 22 (23%); and low risk, 6 of 70 (9%) (P = .001). CONCLUSIONS: The lung dose-volume variables V10 and V20 predicted risk of grade >=2 RP among patients who underwent PORT for NSCLC. PMID- 29976505 TI - Radiation Therapy Quality Assurance (RTQA) of Concurrent Chemoradiation Therapy for Locally Advanced Non-Small Cell Lung Cancer in the PROCLAIM Phase 3 Trial. AB - PURPOSE: Chemoradiation therapy trials of different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation therapy quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM trial evaluating 2 different chemoradiation therapy regimens. The RTQA results were evaluated from the PROCLAIM study, and the impact of irradiation deviations on efficacy outcomes was investigated. METHODS AND MATERIALS: The study was conducted from 2008 to 2014. Review of the irradiation plan was mandated for all patients. Real-time review was performed prior to irradiation start for the first enrolled patient at each site and randomly in 20% of additional patients, with non-real-time review in the remainder. The RTQA criteria evaluated included planning target volume coverage, dose homogeneity, volume of lung receiving >=20 Gy, and maximum point dose to spinal cord. RESULTS: Major RTQA violations occurred in 40 of 554 patients, treated at 28 sites. Seven sites treated >=2 patients with major violations. Stage IIIB disease and larger planning target volume were observed more frequently in patients with major violations. Major violations were more prevalent in sites treating either <6 patients or >15 patients. Patients treated at sites enrolling >=2 patients with major violations (n = 86) had lower median overall survival (21.1 months vs 29.8 months; hazard ratio, 1.442) and progression-free survival (7.3 months vs 11.3 months; hazard ratio, 1.345) than patients treated at sites without major violations. These findings remained significant for overall survival on multivariate analysis. CONCLUSIONS: Major violations in treatment plans were uncommon in the PROCLAIM study, possibly reflecting mandatory RTQA. The RTQA violations were more frequent in patients requiring more complex chemoradiation therapy plans. Poorer observed outcomes at centers with multiple major violations are hypothesis generating. PMID- 29976506 TI - Acute Hospital Encounters in Cancer Patients Treated With Definitive Radiation Therapy. AB - PURPOSE: Acute hospital encounters in patients undergoing curative-intent radiation therapy (RT) have not previously been well characterized. Understanding acute visit patterns among RT patients yields insights for risk assessments and cancer urgent care clinics that could decrease hospitalization rates and reduce health care costs. This study aims to identify patient, disease-site, and treatment characteristics associated with emergency department visits and inpatient admissions in cancer patients treated with definitive RT. METHODS AND MATERIALS: A retrospective cohort study was conducted using data from a quaternary-care cancer center. The cohort was defined as all consecutive patients aged >= 18 years who began RT between July 1, 2011, and December 31, 2013; were without metastases; and were treated with curative intent. An acute encounter was defined as an emergency department visit or inpatient admission during RT or within 30 days after the conclusion of RT. RESULTS: Among 1852 unique RT courses, 666 RT courses (36.0%) involved at least 1 acute encounter, and a total of 1418 acute encounters were identified. RT courses with at least 1 acute encounter corresponded to patients more likely to be on their second (odds ratio [OR], 1.96; P < .001) or third (OR, 3.82; P < .05) RT course and undergoing concurrent chemotherapy (OR, 6.38; P < .001). Among the RT courses with at least 1 acute encounter, the most common disease site was thoracic (22.8%), followed by head and/or neck (22.2%) and gastrointestinal (18.3%). Central nervous system tumors had the greatest proportion of RT courses with acute encounters (77.1%). CONCLUSIONS: In this retrospective analysis, more than one-third of curative intent RT courses were associated with at least 1 acute hospital encounter during or shortly after irradiation. Given that acute encounters varied by patient, disease-site, and treatment characteristics, these findings can inform targeted preventive measures to reduce cancer-related acute hospital encounters and guide improved management protocols. PMID- 29976507 TI - Decorin-Modified Umbilical Cord Mesenchymal Stem Cells (MSCs) Attenuate Radiation Induced Lung Injuries via Regulating Inflammation, Fibrotic Factors, and Immune Responses. AB - PURPOSE: To evaluate the therapeutic effects of decorin (DCN)-modified mesenchymal stem cells (MSCs) on radiation-induced lung injuries (RILIs) and to clarify the underlying mechanisms. METHODS AND MATERIALS: Umbilical cord-derived mesenchymal stem cells (MSCs) were modified with Ad(E1-).DCN to generate DCN expressing MSCs (DCN-modified MSCs [MSCs.DCN]). In an experimental mouse model of RILI, MSCs.DCN and MSCs.Null [MSCs modified with Ad(E1-).Null] were intravenously engrafted at 6 hours or 28 days after irradiation. The therapeutic effects on lung inflammation and fibrosis were evaluated by histopathologic analysis at 28 days and 3 months after irradiation. Inflammatory cytokines and chemokines were analyzed in both sera and lung tissues, and subtypes of T lymphocytes including regulatory T cells (Tregs) were analyzed in the peripheral blood and spleen. RESULTS: Both MSC treatments could alleviate histopathologic injuries by reducing lymphocyte infiltration, decreasing apoptosis, increasing proliferation of epithelial cells, and inhibiting fibrosis in the later phase. However, treatment with MSCs.DCN resulted in much more impressive therapeutic effects. Moreover, we discovered that MSC treatment reduced the expression of chemokines and inflammatory cytokines and increased the expression of anti-inflammatory cytokines in both the peripheral blood and local pulmonary tissues. An important finding was that MSCs.DCN were much more effective in inducing interferon-gamma expression, inhibiting collagen type III alpha1 expression in pulmonary tissues, and decreasing the proportion of Tregs. Furthermore, our data suggested that treatment during the acute phase (6 hours) after irradiation evoked much stronger responses both in attenuating inflammation and in inhibiting fibrosis than in the later phase (28 days). CONCLUSIONS: MSCs.DCN could attenuate acute inflammation after irradiation and significantly inhibit later fibrosis. Likewise, DCN enhanced the functions of MSCs by targeting profibrotic factors and Tregs. PMID- 29976508 TI - Acute Epithelial Toxicity Is Prognostic for Improved Prostate Cancer Response to Radiation Therapy: A Retrospective, Multicenter, Cohort Study. AB - PURPOSE: To test the hypothesis that increased acute toxicity, measured using subdomains reflective of epithelial cell damage, will be associated with reduced late biochemical failure, as a surrogate for tumor radiosensitivity. METHODS AND MATERIALS: The study design was retrospective, with discovery and validation cohorts involving routinely collected data. Eligible patients had prostate cancer, underwent radiation therapy with curative intent, and had acute toxicity assessed prospectively. The discovery cohort was from a single institution. Genitourinary and gastrointestinal acute toxicity related to epithelial cell damage (hematuria, dysuria, proctitis, or mucus) were related to freedom from late biochemical failure (FFBF; nadir + 2). The validation cohort was from two separate institutions. RESULTS: In all, 503 patients were included in the discovery cohort and 658 patients in the validation cohort. In the validation cohort, patients with acute radiation toxicity reflecting epithelial damage had a longer FFBF on both univariate (hazard ratio [HR] 0.37; P = .004) and multivariate (HR 0.45; P = .035) analysis. The impact of acute toxicity on late FFBF seemed to be greater in patients treated with androgen deprivation (HR 0.19) than in those without (HR 0.48). CONCLUSION: Patients reporting acute radiation toxicity reflective of epithelial cell damage during definitive radiation therapy for prostate cancer have significantly longer FFBF, consistent with an underlying genetic link between normal tissue and tumor radiosensitivity. PMID- 29976509 TI - The Biology of SBRT: LQ or Something New? PMID- 29976510 TI - Micro-imaging of Brain Cancer Radiation Therapy Using Phase-contrast Computed Tomography. AB - PURPOSE: Experimental neuroimaging provides a wide range of methods for the visualization of brain anatomic morphology down to subcellular detail. Still, each technique-specific detection mechanism presents compromises among the achievable field-of-view size, spatial resolution, and nervous tissue sensitivity, leading to partial sample coverage, unresolved morphologic structures, or sparse labeling of neuronal populations and often also to obligatory sample dissection or other sample invasive manipulations. X-ray phase contrast imaging computed tomography (PCI-CT) is an experimental imaging method that simultaneously provides micrometric spatial resolution, high soft-tissue sensitivity, and ex vivo full organ rodent brain coverage without any need for sample dissection, staining or labeling, or contrast agent injection. In the present study, we explored the benefits and limitations of PCI-CT use for in vitro imaging of normal and cancerous brain neuromorphology after in vivo treatment with synchrotron-generated x-ray microbeam radiation therapy (MRT), a spatially fractionated experimental high-dose radiosurgery. The goals were visualization of the MRT effects on nervous tissue and a qualitative comparison of the results to the histologic and high-field magnetic resonance imaging findings. METHODS AND MATERIALS: MRT was administered in vivo to the brain of both healthy and cancer-bearing rats. At 45 days after treatment, the brain was dissected out and imaged ex vivo using propagation-based PCI-CT. RESULTS: PCI-CT visualizes the brain anatomy and microvasculature in 3 dimensions and distinguishes cancerous tissue morphology, necrosis, and intratumor accumulation of iron and calcium deposits. Moreover, PCI-CT detects the effects of MRT throughout the treatment target areas (eg, the formation of micrometer-thick radiation-induced tissue ablation). The observed neurostructures were confirmed by histologic and immunohistochemistry examination and related to the micro magnetic resonance imaging data. CONCLUSIONS: PCI-CT enabled a unique 3D neuroimaging approach for ex vivo studies on small animal models in that it concurrently delivers high-resolution insight of local brain tissue morphology in both normal and cancerous micro-milieu, localizes radiosurgical damage, and highlights the deep microvasculature. This method could assist experimental small animal neurology studies in the postmortem evaluation of neuropathology or treatment effects. PMID- 29976511 TI - Dosimetric Evaluation of Incorporating Patient Geometric Variations Into Adaptive Plan Optimization Through Probabilistic Treatment Planning in Head and Neck Cancers. AB - PURPOSE: Four-dimensional (4D) adaptive radiation therapy (ART) treatment planning is an alternative to the conventional margin-based treatment planning approach. In 4D ART, interfraction patient geometric variations, gathered from computed tomography (CT) or cone beam CT (CBCT) images acquired during the patient treatment course, are directly incorporated into the adaptive plan optimization using a probabilistic treatment planning method. The goal of the present planning study was to evaluate the dosimetric differences between 4D ART and conventional margin-based adaptive planning strategies for head and neck cancers. In addition, we examined whether the dose differences achieved with 4D ART would translate into clinically relevant toxicity reductions using the existing normal tissue complication probability (NTCP) models. METHODS AND MATERIALS: For 18 head and neck cancer patients, the treatment plans were retrospectively generated for 4 different treatment strategies, including a solely image guided radiation therapy (IGRT) strategy (IGRT-only), 2 conventional adaptive treatment planning strategies using 3- and 0-mm planning target volume (PTV) margins, and the 4D ART strategy. In the IGRT-only strategy, a conventional 3-mm PTV margin treatment plan was applied for the entire treatment course. In the 2 conventional adaptive strategies, 2 new treatment plans were generated during the treatment course using diagnostic planning CT scans acquired after the 10th and 22nd fractions. The 4D ART followed the same adaptive schedule, except that the 4D adaptive plan was generated using 5 CBCT images acquired during the 5 most recent treatment fractions. For each strategy, the actual delivered dose for the entire treatment course was constructed by calculating the daily doses on 35 CBCT scans, deforming back to the pretreatment planning CT scan, and accumulating over all 35 fractions. The target coverage was evaluated using the percentage of target volume receiving >=100% of the prescription dose (V100%) and the minimum dose to 99% of the target volume (D99). It was considered adequate if the V100% was >=95% and the dose deficit in D99 was <=2 Gy (with respect to the prescription dose). For each strategy, the dose received by the organs at risk (OARs) was also evaluated, and the corresponding NTCP values were subsequently calculated using 3 NTCP models. RESULTS: Adequate target coverage was achieved for the primary clinical target volume (CTV1) and elective nodal CTV (CTV2) with a 3-mm PTV margin, regardless of adaptation. The 3-mm ART plan reduced the OAR mean dose by 1 to 2 Gy compared with the IGRT-only plan. The 0-mm ART plan further reduced the OAR dose by another 2 to 3 Gy at the expense of target coverage: 3 and 1 patient had V100% <95%, and 6 and 5 patients had a >2 Gy dose deficit in D99 for the CTV1 and CTV2, respectively. Use of 4D ART improved target coverage and attained OAR sparing similar to that with 0-mm ART. The number of patients with V100% <95% and >2 Gy D99 deficit decreased to 0 and 0 for CTV1 and 0 and 2 for CTV2, respectively. The NTCP calculations suggested that 4D ART could benefit a substantial portion of patients compared with IGRT-only because 17 and 12 patients had >=5% and >=10% NTCP reductions for parotid toxicity and 18 and 3 patients had >=5% and >=10% NTCP reductions for swallowing toxicity, respectively. CONCLUSIONS: Compared with margin-based adaptive planning strategies, 4D ART provides a better balance between target coverage and OAR sparing. NTCP estimation predicted for theoretical clinical benefits that warrant further clinical validation. PMID- 29976512 TI - In Reply to Yilmaz et al. PMID- 29976513 TI - In Regard to Chen et al. PMID- 29976514 TI - In Regard to Palmer et al. PMID- 29976515 TI - How to be ready for the next influenza pandemic. PMID- 29976516 TI - Towards rubella elimination in Japan. PMID- 29976517 TI - Rotavirus vaccine: a single birth dose? PMID- 29976518 TI - Corrections. PMID- 29976519 TI - Mass screening for hepatitis B and C and HIV in sub-Saharan Africa. PMID- 29976520 TI - Testing for gonorrhoea should routinely include the pharynx. PMID- 29976521 TI - Genetic characterisation of Neisseria gonorrhoeae resistant to both ceftriaxone and azithromycin. PMID- 29976522 TI - Emergence of recalcitrant dermatophytosis in India. PMID- 29976523 TI - Gametocytocidal drugs: taking the population perspective. PMID- 29976524 TI - Chronic Chagas disease: therapeutic protocols and efficacy endpoints. PMID- 29976526 TI - Neglecting childhood tuberculosis "a human rights violation". PMID- 29976525 TI - Appropriate comparisons of tuberculosis latency structures with empiric data. PMID- 29976527 TI - WHO launches Essential Diagnostics List. PMID- 29976530 TI - Spreading the blame, finding the solutions. PMID- 29976531 TI - Kerion celsi caused by Trichophyton tonsurans in a child. PMID- 29976533 TI - Gabapentin versus dexchlorpheniramine as treatment for uremic pruritus: a randomised controlled trial. AB - BACKGROUND: Uremic pruritus is a common symptom in chronic renal failure patients with undefined pathophysiology. Initial treatment involves topical therapy mainly in the form of moisturizers, however, in many cases, this is not sufficient to relieve itching. Systemic adjuvant therapy is therefore necessary, which commonly includes oral antihistamines, with limited success. Positive effects have been reported for gabapentin. OBJECTIVES: To evaluate the efficacy and safety of gabapentin vs. dexchlorpheniramine in reducing uremic pruritus. MATERIALS & METHODS: A randomized, controlled, double-blinded clinical trial for haemodialysis patients with persistent pruritus was performed. Pre-randomisation, cold cream was used for 15 days by 71 participants. Those with pruritus who remained in the study (60 patients) were randomised to receive gabapentin (30 patients; GABA group) or dexchlorpheniramine (30 patients; DEX group) for 21 days. The primary outcome was the decrease in pruritus score and improvement in quality of life. RESULTS: After cold cream use, the participants demonstrated a 37.5% median reduction in Visual Analogue Scale (p<0.01) and a 50% reduction in Quality of Life in Dermatology (DLQI) score (p<0.01). There was an additional reduction of pruritus in both groups (p<0.01), with no difference between the two (p>0.7). The median DLQI was reduced from 2 to 1 in the GABA group and from 2 to 0 in the DEX group. Nineteen patients (32%) reported mild/moderate side effects without differences between the groups. CONCLUSIONS: Uremic pruritus was reduced upon treatment with gabapentin or dexchlorpheniramine with good safety profiles; no difference was observed between the two treatments. PMID- 29976532 TI - Sickle SCANTM (BioMedomics) fulfills analytical conditions for neonatal screening of sickle cell disease. AB - Sickle SCANTM is a rapid, qualitative, point-of-care lateral flow immunoassay for the identification of AS, AC, SS/Sbeta0thal, SC and CC/Cbeta0thal phenotype. We evaluated this test under the conditions encountered in the French newborn screening (NBS) program for sickle cell disease: a total of 104 dried blood spots (DBSs) were tested with an HPLC reference method and then with the Sickle SCANTM device. Sickle SCANTM identified the hemoglobin (Hb) phenotype correctly on 96% of cases. In the four non-concordant cases, the antibody anti-HbS cross-reacted with HbE (n=2), HbD (n=1) or HbX (n=1). There were no false negative. In order to test Sickle SCANTM's sensitivity to low levels of HbA and HbS in the presence of high HbF levels, we selected another 21 DBS cards with low percentages of HbA (0.6-4.2%) and HbS (2.0-6.9%). HbA and HbS were always detected when present at levels of more than 1% and 2%, respectively. Sickle SCANTM appears to be an accurate point-of-care method for the identification of newborns with SCD trait. The device meets the criteria for sickle cell disease NBS programs in endemic countries with poor access to laboratory equipment. PMID- 29976534 TI - Granulomatous pigmented purpuric dermatosis containing Propionibacterium acnes. PMID- 29976535 TI - Stevens-Johnson and Lyell syndromes in children in a hospital setting in Lome, Togo, from 2000 to 2015. AB - OBJECTIVE: The aim of this study was to document the profile of children with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN, also called Lyell syndrome) in hospital settings in Lome, Togo. METHOD: This descriptive retrospective study examined the records of children aged 0 to 15, seen and/or hospitalized in the dermatology department of CHU-SO Lome and diagnosed with SJS/TEN between 2000 and 2015. RESULTS: Records were identified for 14 children with these diagnoses during the study period. Their average age was 10.9 +/- 3.9 years. The average time between taking the apparently causal medication and the onset of symptoms was 10.5 days (range: 4 to 21 days). SJS accounted for 64.3% of the cases. Six children with SJS and one with TEN had ocular involvement. Antibacterial sulfonamides were the main drug involved for 43% of children, followed by anticonvulsants for 14/3%. CONCLUSION: Our results show that SJS/TEN is rare but serious in children. The antibacterial sulfonamides used for the treatment of malaria and anticonvulsants are their most frequent cause. PMID- 29976536 TI - Do informal caregivers of demented patients refuse clinic comprehensive medico psycho-social assessment? Prevalence and reasons for refusal. AB - OBJECTIVE: Caregivers do not usually use services that could alleviate their burden. The objectives were to determine the refusal's prevalence and the reasons why informal caregivers of demented patients refuse clinic medico-psycho-social assessment in the first day care hospital dedicated to caregivers in France. METHODS: Caregivers of patients hospitalized in geriatric ward were prospectively asked to fill in a questionnaire (demographic data, risk for depression and caregiver burden (Zarit scale) about their willingness to benefit from a clinic checkup. If caregivers refused eleven close questions were asked. Characteristics of the caregivers were compared according to the caregivers' agreement or refusal to the clinic checkup. RESULTS: Seventy-seven caregivers (mean age (standard deviation): 68.2 (11.5)) were included: 68.8% of women, 51.9% of children and 35.1% of spouses, mean Zarit scale score was 32.8 (8.8)/88. Clinic checkup was accepted by 28 caregivers. Agreement was associated with exhaustion (p<0.001), depression (p=0.003), memory complaints (p<0.001) and higher burden (p=0.008). Reasons for refusal were mostly the belief that support was sufficient (67.3%) and good self-perceived health (44.9%). Nearly 1/4 of caregivers though that the clinic checkup would be useless. CONCLUSION: Two third of caregivers refused the evaluation because subjective feeling of good physiological and psychological health and that currently provided support was sufficient. Studies to address caregivers 'needs should be conducted. PMID- 29976538 TI - Lichen aureus with involvement of the hands and feet responding well to tripterygium glycosides. PMID- 29976537 TI - Trichostasis spinulosa arising in isolated collagenoma of the scalp. PMID- 29976539 TI - Virginal breast hypertrophy: clinicopathological similarities between virginal breast hypertrophy and diffuse dermal angiomatosis of the breast. PMID- 29976541 TI - Identification of frailty by the use of the SEGAm scale (part A) in geriatrical consultation. AB - : At present, it is recognized that screening for frailty in the elderly is a major public health issue. Numerous scales have emerged for the purpose of detecting/measuring frailty. METHODS: A prospective, observational study was performed in subjects aged over 75 years, coming from the first neuro-geriatric consultation, from July 3, 2017 to August 18, 2017, included in the CHU Rouen, and benefiting from frailty screening through the use of the grid SEGAm (part A); this correlated with the subjective opinion of the nurse. RESULTS: 58 patients were included, with an average age of 82.1+/-3.87 (extreme age: 75-95) and a slight female predominance (37 subjects, 63.8%). The mean Charlson score was 2.31+/-1.75. Home helpers were present for 34 patients. The elderly were in a couple for 35 patients. The mean weight of the series is 74.5+/-14.67. The mean BMI of the series is 26.85+/-4.79. The mean MMSE score is 22.8+/-3.28. Non-frail elderly subjects, according to the SEGAm scale, represent 45 patients, while the frail elderly represent 13 patients (22.4%). The average SEGAm score is 6.3+/ 3.59. SEGAm achievement time is about 6.2 min. According to the feeling of the nursing team, 36 elderly patients (62%) were not frail, 15 elderly patients (26%) were frail, while 7 elderly patients were very frail (12%). Cohen's kappa was estimated at 0.56 (IC95: 0.33-0.79). Thus the agreement, according to Cohen's kappa, is estimated as average. CONCLUSION: The SEGAm score appears to be a suitable outpatient score. It is easy to use, allows an overall assessment of the patient and is not time consuming. The objective of this work is to be able to develop at best frailty consultations or even a day hospital, the real objective of the main hospitals. PMID- 29976540 TI - Efficacy and tolerance of photodynamic therapy for vulvar Paget's disease: a multicentric retrospective study. AB - BACKGROUND: Extra-mammary Paget's disease is a rare form of intraepithelial adenocarcinoma with a variable pattern of invasion, sometimes associated with distant malignancy. Vulvar Paget's disease (VPD) represents 1% of all vulvar cancers. Standard treatment is surgical excision, however, the recurrence rate is high and surgery leads to anatomical, functional, and sexual morbidity. Some case series suggest efficacy of photodynamic (PDT) as treatment for this indication. OBJECTIVES: Our aim was to assess the efficacy and tolerance of PDT in women suffering from VPD. MATERIALS & METHODS: A retrospective study was conducted on all patients suffering from VPD, treated with PDT at six hospitals in France. Clinical data, histopathological reports at diagnosis, therapeutic history, PDT schedule, tolerance, and clinical response were reported. RESULTS: Thirteen women were included, with a mean age of 70.1 years. Ten women had an in situ disease, two had <1-mm dermal involvement, and one had adnexal involvement. All PDT courses were carried out using the same light source and photosensitizing agent. Complete response was achieved in two patients (15%) and partial response in five patients (38%). Five patients (38%) had stable disease and one (7%) had progressive disease. Ten of the 13 patients underwent pain evaluation; in six cases (60%), pain was described as moderate to intense. CONCLUSION: PDT appears to be a therapeutic option for patients with VPD, with a response rate similar to that of other therapies usually recommended, such as surgery and imiquimod. There is a need to harmonise PDT procedures and pain assessment. PMID- 29976542 TI - Herpes zoster complicated by unilateral pleural effusion. PMID- 29976543 TI - Multiple warty dyskeratomas of the scalp: report of a new case and literature review. PMID- 29976544 TI - Eosinophilia and systemic symptoms with transient ageusia: a drug reaction caused by zonisamide. PMID- 29976545 TI - Longitudinal melanonychia in adults and children: a clinical and histopathological review of Korean patients. PMID- 29976546 TI - Persistent neutrophilic scarring alopecia triggered by anti-TNF blockade for Crohn's disease. PMID- 29976547 TI - Cetuximab-induced epidermolysis revealed by multiple erosions. PMID- 29976548 TI - Ultrasound in rural India: a failure of the best intentions. AB - The Pre-Conception and Pre-Natal Diagnostic Techniques Act was written to prevent societally unacceptable harms including intentional sex selection. The pragmatism required to enforce this law has profound effects on the ability of rural Indians to access diagnostic ultrasonography. In so doing, it may have inadvertently placed a heavier burden on the poorest and worsened health inequity in India, creating serious ethical and justice concerns. It is time to re-examine and update the law such that diagnostic ultrasonography is widely available in even the most peripheral primary health and community health centres. Shorter, more accessible ultrasonography training courses should be offered; collaboration between radiologists and rural practitioners and facilities should be encouraged. Finally, modern ultrasound machines can carefully record all images via a "silent observer" modality. With some modifications to previously used silent observer modalities, this technology allows both greater access and better policing of potential misuse of ultrasound technology. PMID- 29976549 TI - Emergency care in rural settings: Can doctors be ethical and survive? AB - We describe below the pressures of running a small private hospital in an underserved rural area, while providing emergency healthcare for victims of poisonous stings, accidents, and other acute health conditions. Both ethics and law demand that payment is not asked for upfront in emergency cases. Yet patients and their families often fail to pay normal dues for months or even years. It is disturbing to encounter such behaviour even in villages; and doctors in small communities are easy prey. In these conditions can one be true to ethical principles and ensure one's own survival? PMID- 29976550 TI - Audiovisual informed consent process in vaccine trials: Experience from North India. AB - Audiovisual (AV) recording of the informed consent process in a clinical or vaccine trial to document the consent process of participants (especially from vulnerable populations), ensures preservation of their rights and well-being. This paper describes the AV consent process during a phase III rotavirus vaccine trial among healthy infants in Chandigarh and examines its effects. Out of 155 parents/guardians of participating infants who were contacted to be a part of the study, 50 were reluctant to participate in the study trial (not necessarily in the AV consenting process). Among 105 parents/guardians of participating infants who expressed initial willingness to participate in the trial, all agreed to undergo the AV consenting process; and 100 finally consented to participate and were enrolled in the study. So, the participation rate was 64.5% (100/155) among those who were contacted, and 95.2% (100/105) among those who underwent AV consenting process. AV recordings of these 100 patient representatives were transcribed and later translated into English for a thematic analysis of the text. A total of 105 queries were raised by 55 participants. All queries were patiently listened to and addressed, allaying most fears, especially those related to adverse events following intervention. The AV process ensured transparency and accountability of the investigators, responsive referral mechanism in case of adverse events, building an initial rapport with the participant, complete vaccination of the trial subjects, and provision for free private care consultation depending upon the willingness of the parents. These benefits of the AV consent process might have led to a higher participation rate. PMID- 29976552 TI - Seven days in medicine: 27 June to 3 July 2018. PMID- 29976551 TI - Bleak future for pre- and paraclinical postgraduates in India. AB - In a bid to encourage medical graduates to opt for postgraduation in pre- and paraclinical courses, the Odisha Government, in January 2018, hiked the stipend for students pursuing these courses in state-run medical colleges. The state government also announced additional financial assistance of Rs 18,000 per month for pre- and paraclinical postgraduate students, along with the stipend money. The state's Health and Family Welfare Minister, Pratap Jena, said this would be applicable to both in-service and direct postgraduate students. This announcement in the newspapers gave rise to much discussion in the social media. PMID- 29976553 TI - Beet the Best? AB - RATIONALE: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. OBJECTIVE: To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. METHODS AND RESULTS: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2+/-57.3 s for the exercise plus placebo group (n=13) and by 180.3+/-46.6 s for the exercise plus beetroot juice group (n=11; P<=0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, -0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6+/-12.1 and 53.3+/-19.6 m ( P<=0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to large effect sizes over exercise plus placebo changes. CONCLUSIONS: Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524. PMID- 29976555 TI - Validation of the Kutcher Adolescent Depression Scale in a Caribbean student sample. AB - BACKGROUND: Research on depression among Caribbean children has been limited by a lack of valid and reliable measures. We addressed this problem by exploring the internal consistency reliability and the concurrent and discriminant validity of the Kutcher Adolescent Depression Rating Scale (KADS) among a wide cross-section of the student population attending elementary schools in Jamaica and Barbados. METHODS: Students enrolled in grade 6 in a cross-section of schools in Jamaica and Barbados were invited to participate in the study. Schools included a balance of government-funded public schools and privately funded preparatory schools. All schools that were invited to participate accepted, and all grade 6 classrooms in each school were sampled. The following instruments were administered to the students during the fall semester of 2015: KADS, Adolescent Depression Rating Scale (ADRS), major depression disorder subscale of the Revised Children's Anxiety and Depression Scale (RCADS), and state and trait anxiety visual analogue scales. RESULTS: In total, 759 children (376 girls [49.5%] and 363 boys [47.8%]; in 20 cases [2.6%], sex was missing) with a mean age of 10.7 (standard deviation 0.66) years (median 11.0 yr) took part in the study. Overall, the KADS had an acceptable degree of reliability (alpha = 0.76). The instrument had reasonably good concurrent validity, as evidenced by strong correlations with scores on the ADRS (r = 0.62) and the major depression disorder subscale of the RCADS (r = 0.61). It had acceptable discriminant validity, as shown through low correlations with the state and trait anxiety visual analogue scales (r = 0.21 and 0.18, respectively). This pattern of results suggests that a large part (37%) of the variance underlying the KADS assesses depression, and a smaller degree of the variance (3%-4%) measures a conceptually similar but distinct concept. INTERPRETATION: The KADS is a reliable and valid measure for assessing depressive symptoms among Jamaican and Barbadian elementary school students. The sample may not be representative of all Caribbean children. PMID- 29976556 TI - Cannabis based drugs should be rescheduled to make research and prescribing easier, says chief medical officer. PMID- 29976557 TI - How I treat primary mediastinal B-cell lymphoma. AB - The World Health Organization now recognizes primary mediastinal B-cell lymphoma (PMBCL) as a unique clinical and biologic entity. PMBCL is distinct from other B cell non-Hodgkin lymphoma subtypes and has features that overlap with classical Hodgkin lymphoma, including a peak incidence in the adolescent and young adult population, mediastinal presentation of disease, and molecular alterations in JAK2 and programmed death ligands. Because PMBCL is rare, there are few prospective clinical trials to guide therapy, resulting in no single standard of care. Given the long life expectancy of survivors of PMBCL, treatment approaches must balance maximizing cure while minimizing long-term toxicity. In this article, I review my approach to the treatment of PMBCL, incorporating data from adult and pediatric studies, as well as recent advances in our understanding of the molecular basis of PMBCL. PMID- 29976558 TI - Comparing the usability of paediatric weight estimation methods: a simulation study. AB - OBJECTIVE: Estimating weight is essential in order to prepare appropriate sized equipment and doses of resuscitation drugs in cases where children are critically ill or injured. Many methods exist with varying degrees of complexity and accuracy. The most recent version of the Advanced Paediatric Life Support (APLS) course has changed their teaching from an age-based calculation method to the use of a reference table. We aimed to evaluate the potential implications of this change. METHOD: Using a bespoke online simulation platform we assessed the ability of acute paediatric staff to apply different methods of weight estimation. Comparing the time taken, rate and magnitude of errors were made using the APLS single and triple age-based formulae, Best Guess and reference table methods. To add urgency and an element of cognitive stress, a time-based competitive component was included. RESULTS: 57 participants performed a total of 2240 estimates of weight. The reference table was the fastest (25 (22-28) vs 35 (31-38) to 48 (43-51) s) and most preferred, but errors were made using all methods. There was no significant difference in the percentage accuracy between methods (93%-97%) but the magnitude of errors made was significantly smaller using the three APLS formulae 10% (6.5-21) compared with reference table (69% (34 133)) mainly from month/year table confusion. CONCLUSION: In this exploratory study under psychological stress none of the methods of weight estimation were free from error. Reference tables were the fastest method and also had the largest errors and should be designed to minimise the risk of picking errors. PMID- 29976559 TI - META: A Novel Method for Evaluating Pediatric Scoring Systems for Implementation. PMID- 29976560 TI - A PIM-CHK1 signaling pathway regulates PLK1 phosphorylation and function during mitosis. AB - Although the kinase CHK1 is a key player in the DNA damage response (DDR), several studies have recently provided evidence of DDR-independent roles of CHK1, in particular following phosphorylation of its S280 residue. Here, we demonstrate that CHK1 S280 phosphorylation is cell cycle-dependent and peaks during mitosis. We found that this phosphorylation was catalyzed by the kinase PIM2, whose protein expression was also increased during mitosis. Importantly, we identified polo-like kinase 1 (PLK1) as a direct target of CHK1 during mitosis. Genetic or pharmacological inhibition of CHK1 reduced the activating phosphorylation of PLK1 on T210, and recombinant CHK1 was able to phosphorylate T210 of PLK1 in vitro Accordingly, S280-phosphorylated CHK1 and PLK1 exhibited similar specific mitotic localizations, and PLK1 was co-immunoprecipitated with S280-phosphorylated CHK1 from mitotic cell extracts. Moreover, CHK1-mediated phosphorylation of PLK1 was dependent on S280 phosphorylation by PIM2. Inhibition of PIM proteins reduced cell proliferation and mitotic entry, which was rescued by expressing a T210D phosphomimetic mutant of PLK1. Altogether, these data identify a new PIM-CHK1 PLK1 phosphorylation cascade that regulates different mitotic steps independently of the CHK1 DDR function.This article has an associated First Person interview with the first author of the paper. PMID- 29976561 TI - Complexes of alpha6beta4 integrin and vimentin act as signaling hubs to regulate epithelial cell migration. AB - We find that clusters of beta4 integrin, organized into distinct puncta, localize along vimentin filaments within lamellipodia at the cell edge of A549 cells, as assessed by interferometric photoactivated localization microscopy. Moreover, puncta and vimentin filaments exhibit a dynamic interplay in live cells, as viewed by structured-illumination microscopy, with beta4 integrin puncta that associate with vimentin persisting for longer than those that do not. Interestingly, in A549 cells beta4 integrin regulates vimentin cytoskeleton organization. When beta4 integrin is knocked down there is a loss of vimentin filaments from lamellipodia. However, in these conditions, vimentin filaments instead concentrate around the nucleus. Although beta4 integrin organization is unaffected in vimentin-deficient A549 cells, such cells move in a less-directed fashion and exhibit reduced Rac1 activity, mimicking the phenotype of beta4 integrin-deficient A549 cells. Moreover, in vimentin-deficient cells, Rac1 fails to cluster at sites enriched in alpha6beta4 integrin heterodimers. The aberrant motility of both beta4 integrin and vimentin-deficient cells is rescued by expression of active Rac1, leading us to propose that complexes of beta4 integrin and vimentin act as signaling hubs, regulating cell motility behavior. PMID- 29976562 TI - An Outward-Facing Aromatic Amino Acid Is Crucial for Signaling between the Membrane-Spanning and Nucleotide-Binding Domains of Multidrug Resistance Protein 1 (MRP1; ABCC1). AB - The 190-kDa human MRP1 is an ATP-binding cassette multidrug and multiorganic anion efflux transporter. The 17 transmembrane helices of its three membrane spanning domains, together with its two nucleotide binding domains (NBDs), form a stabilizing network of domain-domain interactions that ensure substrate binding in the cytoplasm is efficiently coupled to ATP binding and hydrolysis to effect solute efflux into the extracellular milieu. Here we show that Ala substitution of Phe583 in an outward-facing loop between the two halves of the transporter essentially eliminates the binding of multiple organic anions by MRP1. Conservative substitutions with Trp and Tyr had little or no effect. The F583A mutation also caused a substantial increase in orthovanadate-induced trapping of azidoADP by the cytoplasmic NBDs of MRP1, although the binding of ATP was unaffected. These observations indicate that the loss of the aromatic side chain at position 583 impairs the release of ADP and thus effectively locks the transporter in a low-affinity solute binding state. Phe583 is the first outward facing amino acid in MRP1 found to be critical for its transport function. Our data provide evidence for long-range coupling, presumably via allosteric interaction, between this outward-facing region of MRP1 and both the solute binding and nucleotide binding regions of the transporter. Cryoelectron microscopy structural and homology models of MRP1 indicate that the orientation of the Phe583 side chain is altered by ATP binding but are currently unable to provide insights into the molecular mechanism by which this long-range signaling is propagated. PMID- 29976564 TI - Innovations in the psychosocial treatment of youth with anxiety disorders: implications for a stepped care approach. AB - Anxiety disorders are highly prevalent among children and adolescents and frequently result in impairments across multiple domains of life. While psychosocial interventions, namely cognitive-behavioural therapy (CBT), have been found to be highly effective in treating these conditions, significant numbers of youth simply do not have access to these evidence-based interventions, and of those who do, a substantial proportion (up to 40%) fail to achieve remission. Thus, there is a pressing need for innovation in both the delivery of evidence based treatments and efforts to enhance treatment outcomes for those who do not respond to standard care. This paper reviews current innovations attempting to address these issues, including evidence for brief, low-intensity approaches to treatment; internet delivered CBT and brief, high-intensity CBT. Moreover, we propose a model of stepped care delivery of evidence-based mental health interventions for children and youth with anxiety. In general, a stepped care approach begins with a lower intensity, evidence-based treatment that entails minimal therapist involvement (ie, brief, low-intensity self-help or internet delivered CBT) and then proceeds to more intensive treatments with greater therapist involvement (ie, brief high-intensity CBT), but only for those individuals who show a poor response at each step along the way. Future research is needed in order to evaluate such a model, and importantly, to identify predictors and moderators of response at each step, in order to inform an evidence-based, fully-integrated stepped care approach to service delivery. PMID- 29976554 TI - Virological and Immunological Outcomes of Coinfections. AB - SUMMARYCoinfections involving viruses are being recognized to influence the disease pattern that occurs relative to that with single infection. Classically, we usually think of a clinical syndrome as the consequence of infection by a single virus that is isolated from clinical specimens. However, this biased laboratory approach omits detection of additional agents that could be contributing to the clinical outcome, including novel agents not usually considered pathogens. The presence of an additional agent may also interfere with the targeted isolation of a known virus. Viral interference, a phenomenon where one virus competitively suppresses replication of other coinfecting viruses, is the most common outcome of viral coinfections. In addition, coinfections can modulate virus virulence and cell death, thereby altering disease severity and epidemiology. Immunity to primary virus infection can also modulate immune responses to subsequent secondary infections. In this review, various virological mechanisms that determine viral persistence/exclusion during coinfections are discussed, and insights into the isolation/detection of multiple viruses are provided. We also discuss features of heterologous infections that impact the pattern of immune responsiveness that develops. PMID- 29976566 TI - Circulating PIWI-Interacting RNAs piR-5937 and piR-28876 Are Promising Diagnostic Biomarkers of Colon Cancer. AB - Background: The early detection of colon cancer is one of the main prerequisites for successful treatment and mortality reduction. Circulating PIWI-interacting RNAs (piRNA) were recently identified as novel promising biomarkers. The purpose of the study was to assess the profiles of piRNAs in blood serum of colon cancer patients with the aim to identify those with high diagnostic potential.Methods: Blood serum samples from 403 colon cancer patients and 276 healthy donors were included in this 3-phase biomarker study. Large-scale piRNA expression profiling was performed using Illumina small RNA sequencing. The diagnostic potential of selected piRNAs was further validated on independent training and validation sets of samples using RT-qPCR.Results: In total, 31 piRNAs were found to be significantly deregulated in serum of cancer patients compared with healthy donors. Based on the levels of piR-5937 and piR-28876, it was possible to differentiate between cancer patients and healthy donors with high sensitivity and specificity. Moreover, both piRNAs exhibited satisfactory diagnostic performance also in patients with stage I disease and enabled detection of colon cancer with higher sensitivity than currently used biomarkers CEA and CA19-9. Finally, the expression of analyzed piRNAs in blood restored significantly 1 month after the surgical resection.Conclusions: Based on our findings, piRNAs are abundant in human blood serum. Furthermore, their levels in colon cancer have been observed to be significantly deregulated. However, their involvement in carcinogenesis must be further established.Impact: piRNAs could serve as promising noninvasive biomarkers for early detection of colon cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 1019-28. (c)2018 AACR. PMID- 29976563 TI - Allergen Delivery Inhibitors: A Rationale for Targeting Sentinel Innate Immune Signaling of Group 1 House Dust Mite Allergens through Structure-Based Protease Inhibitor Design. AB - Diverse evidence from epidemiologic surveys and investigations into the molecular basis of allergenicity have revealed that a small cadre of "initiator" allergens promote the development of allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Pre-eminent among these initiators are the group 1 allergens from house dust mites (HDM). In mites, group 1 allergens function as cysteine peptidase digestive enzymes to which humans are exposed by inhalation of HDM fecal pellets. Their protease nature confers the ability to activate high gain signaling mechanisms which promote innate immune responses, leading to the persistence of allergic sensitization. An important feature of this process is that the initiator drives responses both to itself and to unrelated allergens lacking these properties through a process of collateral priming. The clinical significance of group 1 HDM allergens in disease, their serodominance as allergens, and their IgE-independent bioactivities in innate immunity make these allergens interesting therapeutic targets in the design of new small-molecule interventions in allergic disease. The attraction of this new approach is that it offers a powerful, root-cause-level intervention from which beneficial effects can be anticipated by interference in a wide range of effector pathways associated with these complex diseases. This review addresses the general background to HDM allergens and the validation of group 1 as putative targets. We then discuss structure-based drug design of the first-in-class representatives of allergen delivery inhibitors aimed at neutralizing the proteolytic effects of HDM group 1 allergens, which are essential to the development and maintenance of allergic diseases. PMID- 29976568 TI - Malnutrition and Mortality in Frail and Non-Frail Older Adults Undergoing Aortic Valve Replacement. AB - Background -Older adults undergoing aortic valve replacement are at risk for malnutrition. The association between pre-procedural nutritional status and midterm mortality has yet to be determined. Methods -The FRAILTY-AVR prospective multi-center international cohort study was conducted between 2012-2017 in 14 centers in 3 countries. Patients >=70 years of age who underwent transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) were eligible. The Mini Nutritional Assessment-Short Form (MNA-SF) was assessed by trained observers pre-procedure, with scores <=7 of 14 considered malnourished and 8-11 of 14 considered at-risk for malnutrition. The Short Performance Physical Battery (SPPB) was simultaneously assessed to measure physical frailty, with scores <=5 of 12 considered severely frail and 6-8 of 12 considered mildly frail. The primary outcome was 1-year all-cause mortality and the secondary outcome was 30-day composite mortality or major morbidity. Multivariable regression models were used to adjust for potential confounders. Results -There were 1,158 patients (727 TAVR and 431 SAVR) with 45% females, a mean age of 81.3 years, a mean body mass index of 27.5 kg/m2, and a mean Society of Thoracic Surgeons-Predicted Risk of Mortality (STS-PROM) of 5.1%. Overall, 8.7% of patients were classified as malnourished and 32.8% were at-risk for malnutrition. MNA-SF scores were moderately correlated with SPPB scores (Spearman R=0.31, P<0.001). There were 126 deaths in the TAVR group (19.1 per 100 patient-years) and 30 deaths in the SAVR group (7.5 per 100 patient-years). Malnourished patients had a nearly 3-fold higher crude risk of 1-year mortality compared with those with normal nutritional status (28% vs 10%, P<0.001). After adjustment for frailty, STS-PROM, and procedure type, pre-procedural nutritional status was a significant predictor of 1-year mortality (OR 1.08 per MNA-SF point, 95% CI 1.01 1.16) and of the 30-day composite safety endpoint (OR 1.06 per MNA-SF point, 95% CI 1.00 to 1.12). Conclusions -Pre-procedural nutritional status is associated with mortality in older adults following aortic valve replacement. Clinical trials are needed to determine whether pre- and post-procedural nutritional interventions can improve clinical outcomes in these vulnerable patients. PMID- 29976569 TI - SMAD4 Prevents Flow Induced Arterial-Venous Malformations by Inhibiting Casein Kinase 2. AB - Background -Hereditary Hemorrhagic Telangiectasia (HHT) is an inherited vascular disorder that causes arterial-venous malformations (AVMs). Mutations in the genes encoding Endoglin (ENG) and Activin-receptor-like kinase 1 (AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with Juvenile Polyposis/HHT syndrome that involves AVMs. SMAD4 is a downstream effector of Transforming growth factor-beta (TGFbeta)/Bone morphogenetic protein (BMP) family ligands that signal via Activin like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial specific Alk1 deletion induce AVMs in mouse models as a result of increased PI3K/AKT signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K/AKT pathway activation. Methods -We generated a tamoxifen-inducible, postnatal endothelial-specific Smad4 mutant mice (Smad4iDeltaEC). Results -We found that loss of endothelial Smad4 resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1 and SMAD4 dependent manner. Smad4iDeltaEC endothelial cells in AVMs displayed increased PI3K/AKT signaling, and pharmacological PI3K inhibitors or endothelial Akt1 deletion both rescued AVM formation in Smad4iDeltaEC mice. BMP9 induced SMAD4 inhibited Casein Kinase 2 (CK2) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in Smad4iDeltaEC mice. Conclusions -Our study reveals SMAD4 as an essential effector of BMP9-10/ALK1 signaling that affects AVM pathogenesis via regulation of CK2 expression and PI3K/AKT1 activation. PMID- 29976570 TI - Crystal structure and pH-dependent allosteric regulation of human beta ureidopropionase, an enzyme involved in anticancer drug metabolism. AB - beta-Ureidopropionase (betaUP) catalyzes the third step of the reductive pyrimidine catabolic pathway responsible for breakdown of uracil-, thymine- and pyrimidine-based antimetabolites such as 5-fluorouracil. Nitrilase-like betaUPs use a tetrad of conserved residues (Cys233, Lys196, Glu119 and Glu207) for catalysis and occur in a variety of oligomeric states. Positive co-operativity toward the substrate N-carbamoyl-beta-alanine and an oligomerization-dependent mechanism of substrate activation and product inhibition have been reported for the enzymes from some species but not others. Here, the activity of recombinant human betaUP is shown to be similarly regulated by substrate and product, but in a pH-dependent manner. Existing as a homodimer at pH 9, the enzyme increasingly associates to form octamers and larger oligomers with decreasing pH. Only at physiological pH is the enzyme responsive to effector binding, with N-carbamoyl beta-alanine causing association to more active higher molecular mass species, and beta-alanine dissociation to inactive dimers. The parallel between the pH and ligand-induced effects suggests that protonation state changes play a crucial role in the allosteric regulation mechanism. Disruption of dimer-dimer interfaces by site-directed mutagenesis generated dimeric, inactive enzyme variants. The crystal structure of the T299C variant refined to 2.08 A resolution revealed high structural conservation between human and fruit fly betaUP, and supports the hypothesis that enzyme activation by oligomer assembly involves ordering of loop regions forming the entrance to the active site at the dimer-dimer interface, effectively positioning the catalytically important Glu207 in the active site. PMID- 29976567 TI - T1-REDEEM: A Randomized Controlled Trial to Reduce Diabetes Distress Among Adults With Type 1 Diabetes. AB - OBJECTIVE: To compare the effectiveness of two interventions to reduce diabetes distress (DD) and improve glycemic control among adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Individuals with T1D (n = 301) with elevated DD and HbA1c were recruited from multiple settings and randomly assigned to OnTrack, an emotion-focused intervention, or to KnowIt, an educational/behavioral intervention. Each group attended a full-day workshop plus four online meetings over 3 months. Assessments occurred at baseline and 3 and 9 months. Primary and secondary outcomes were change in DD and change in HbA1c, respectively. RESULTS: With 12% attrition, both groups demonstrated dramatic reductions in DD (effect size d = 1.06; 78.4% demonstrated a reduction of at least one minimal clinically important difference). There were, however, no significant differences in DD reduction between OnTrack and KnowIt. Moderator analyses indicated that OnTrack provided greater DD reduction to those with initially poorer cognitive or emotion regulation skills, higher baseline DD, or greater initial diabetes knowledge than those in KnowIt. Significant but modest reductions in HbA1c occurred with no between-group differences. Change in DD was modestly associated with change in HbA1c (r = 0.14, P = 0.01), with no significant between-group differences. CONCLUSIONS: DD can be successfully reduced among distressed individuals with T1D with elevated HbA1c using both education/behavioral and emotion-focused approaches. Reductions in DD are only modestly associated with reductions in HbA1c. These findings point to the importance of tailoring interventions to address affective, knowledge, and cognitive skills when intervening to reduce DD and improve glycemic control. PMID- 29976571 TI - Altered Mental Status at High Altitude. AB - Intrathecal baclofen pumps are commonly used in pediatric patients with spastic cerebral palsy. Baclofen binds to gamma-aminobutyric acid receptors to inhibit both monosynaptic and polysynaptic reflexes at the spinal cord level. The blockade stops the release of excitatory transmitters and thereby decreases muscle contraction. It is commonly used for lower limb spasticity and has been shown to improve postural ability and functional status. The US Food and Drug Administration has approved baclofen for the treatment of spasticity of cerebral or spinal origin in adult and pediatric patients 4 years or older. Various complications of baclofen pumps are described in the literature. Immediately after surgery, problems from infection can arise and range from superficial skin infections to meningitis and bacteremia. Another early complication includes cerebrospinal fluid leak that can be observed by notable swelling beneath the lumbar incision. Additional problems that arise later are usually from the mechanics of the pump and catheter. Pump-related complications include failure, migration, and flipping. Catheter-related complications include disconnection, occlusion, fracture, or kink. Most of these complications typically lead to baclofen withdrawal, although there are a few case reports of overdose due to mechanical causes. Here we describe 2 cases of individuals experiencing complications of excessive baclofen exposure after significant changes in the atmospheric pressure due to travel involving ambient altitude change. These cases reflect the need to discuss this potential complication with families and patients with baclofen pumps before travel to high elevations. PMID- 29976572 TI - Clinical Implications of the Revised AAP Pediatric Hypertension Guidelines. AB - BACKGROUND AND OBJECTIVES: New pediatric hypertension definitions were recently published in a clinical practice guideline (CPG). We evaluated the impact of the CPG, compared with the previous guideline ("Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents"), on the prevalence of hypertension and associations with target organ damage (TOD) in high-risk youth. METHODS: Participants (10-18 years old) undergoing an evaluation of the cardiovascular effects of obesity and type 2 diabetes mellitus in youth were studied. Blood pressure was categorized according to the 2 guidelines as normal, elevated, and hypertension (stages 1 and 2). Measures of TOD (carotid artery intima-media thickness, pulse wave velocity, left ventricular mass, and diastolic function) were obtained. Associations between blood pressure categories and TOD and the sensitivity of hypertension classification in identifying TOD were evaluated. RESULTS: Data were available for 364 participants (65% female sex; 15.1 +/- 2.1 years of age). Hypertension was identified in 8% and 13% as defined in the Fourth Report and CPG, respectively (P = .007). The 2 guidelines revealed similar associations with TOD; however, the CPG demonstrated improved sensitivity of TOD detection in hypertensive participants. For example, the proportion of participants with an abnormal left ventricular mass categorized as hypertensive increased from 20% to 31% as defined in the Fourth Report and CPG, respectively (P < .001). CONCLUSIONS: Incorporation of the CPG increased the prevalence of pediatric hypertension in a population of high-risk youth and improved the sensitivity of TOD identification in hypertensive participants. PMID- 29976573 TI - A Specific Probe Substrate for Evaluation of CYP4A11 Activity in Human Tissue Microsomes and a Highly Selective CYP4A11 Inhibitor: Luciferin-4A and Epalrestat. AB - The specificity of cytochrome P450 4A11 (CYP4A11) against luciferin-4A O demethylation in human liver microsomes (HLMs) and human renal microsomes (HRMs) and selectivity of CYP4A11 inhibition by epalrestat were investigated. Kinetic analysis of luciferin-4A O-demethylation yielded Vmax and S50 values of 39.7 pmol/min per milligram protein and 43.2 MUM for HLMs (Hill coefficient 1.24) and 39.4 pmol/min per milligram protein and 33.8 MUM for HRMs (Hill coefficient 1.34), respectively. Among the selective CYP inhibitors tested, HET0016 (CYP4 inhibitor) exclusively inhibited luciferin-4A O-demethylation by HLMs and HRMs. Furthermore, anti-CYP4A11 antibody nearly abolished the activity of both tissue microsomes. Luciferin-4A O-demethylase activity of HLMs was significantly correlated with lauric acid omega-hydroxylase activity, a marker of CYP4A11 activity (r = 0.904, P < 0.0001). Next, effects of epalrestat on CYP-mediated drug oxidations were examined. Epalrestat showed the most potent inhibition against CYP4A11 (IC50 = 1.82 MUM) among the 17 recombinant enzymes tested. The inhibitory effect of epalrestat on CYP4A11 was at least 10-fold stronger than those on CYP4F2, CYP4F3B, and CYP4F12. For known CYP4 inhibitors, in contrast, HET0016 inhibited the activities of CYP4A11 and CYP4F2 (IC50 = 0.0137-0.0182 MUM); 17-octadecynoic acid reduced activities of CYP4A11, CYP4F2, CYP4F3B, and CYP4F12 to a similar extent (IC50 = 5.70-17.7 MUM). Epalrestat selectively and effectively inhibited the CYP4A11 activity of HLMs (IC50 = 0.913 MUM) and HRMs (IC50 = 0.659 MUM). These results indicated that luciferin-4A O-demethylase activity is a good CYP4A11 marker of HLMs and HRMs, and that epalrestat is a more selective CYP4A11 inhibitor compared with known CYP4 inhibitors. PMID- 29976574 TI - Replication Stress Drives Constitutive Activation of the DNA Damage Response and Radioresistance in Glioblastoma Stem-like Cells. AB - Glioblastoma (GBM) is a lethal primary brain tumor characterized by treatment resistance and inevitable tumor recurrence, both of which are driven by a subpopulation of GBM cancer stem-like cells (GSC) with tumorigenic and self renewal properties. Despite having broad implications for understanding GSC phenotype, the determinants of upregulated DNA-damage response (DDR) and subsequent radiation resistance in GSC are unknown and represent a significant barrier to developing effective GBM treatments. In this study, we show that constitutive DDR activation and radiation resistance are driven by high levels of DNA replication stress (RS). CD133+ GSC exhibited reduced DNA replication velocity and a higher frequency of stalled replication forks than CD133- non-GSC in vitro; immunofluorescence studies confirmed these observations in a panel of orthotopic xenografts and human GBM specimens. Exposure of non-GSC to low-level exogenous RS generated radiation resistance in vitro, confirming RS as a novel determinant of radiation resistance in tumor cells. GSC exhibited DNA double strand breaks, which colocalized with "replication factories" and RNA: DNA hybrids. GSC also demonstrated increased expression of long neural genes (>1 Mbp) containing common fragile sites, supporting the hypothesis that replication/transcription collisions are the likely cause of RS in GSC. Targeting RS by combined inhibition of ATR and PARP (CAiPi) provided GSC-specific cytotoxicity and complete abrogation of GSC radiation resistance in vitro These data identify RS as a cancer stem cell-specific target with significant clinical potential.Significance: These findings shed new light on cancer stem cell biology and reveal novel therapeutics with the potential to improve clinical outcomes by overcoming inherent radioresistance in GBM. Cancer Res; 78(17); 5060-71. (c)2018 AACR. PMID- 29976576 TI - Simultaneous inhibition of FXR and TGR5 exacerbates atherosclerotic formation. AB - Simultaneous activation of bile acid receptors farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5) by INT-767 significantly reduces atherosclerotic formation. In this study, we investigated the effect of simultaneous inactivation of these bile acid receptors in atherosclerosis and which bile acid receptor mediates the anti-atherogenic effect of INT-767. To investigate the role of simultaneous inactivation of FXR and TGR5 in vivo, we generated LDL receptor knockout (LDLR) KO mice with FXR and TGR5 dual deficiency, which exhibited severe atherosclerosis and aortic inflammation through nuclear factor kappaBeta activation. The lipid-lowering effects of INT-767 were completely blocked by FXR single deficiency but not TGR5 single deficiency. INT 767 was able to block atherosclerotic formation and decrease levels of aortic cytokines and chemokines in LDLR KO mice under either FXR or TGR5 single deficiency. Dual deficiency of FXR and TGR5 completely blocked the anti atherogenic and anti-inflammatory effects of INT-767 in LDLR KO mice. We demonstrated that 1) FXR and TGR5 dual deficiency exacerbated the development of atherosclerosis and 2) the anti-atherogenic effect of INT-767 requires the anti inflammatory effect but not the lipid-lowering effect through the simultaneous activation of FXR and TGR5. Our results indicate that dual activation of FXR and TGR5 is a promising strategy for treating atherosclerosis. PMID- 29976575 TI - IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. AB - The tumor microenvironment (TME) plays a major role in the pathogenesis of multiple cancer types, including upper-gastrointestinal (GI) cancers that currently lack effective therapeutic options. Cancer-associated fibroblasts (CAF) are an essential component of the TME, contributing to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. Through an unbiased approach, we have established that IL-6 mediates cross-talk between tumor cells and CAF not only by supporting tumor cell growth, but also by promoting fibroblast activation. As a result, IL-6 receptor (IL6Ralpha) and downstream effectors offer opportunities for targeted therapy in upper-GI cancers. IL-6 loss suppressed tumorigenesis in physiologically relevant three-dimensional (3D) organotypic and 3D tumoroid models and murine models of esophageal cancer. Tocilizumab, an anti-IL6Ralpha antibody, suppressed tumor growth in vivo in part via inhibition of STAT3 and MEK/ERK signaling. Analysis of a pan-cancer TCGA dataset revealed an inverse correlation between IL-6 and IL6Ralpha overexpression and patient survival. Therefore, we expanded evaluation of tocilizumab to head and neck squamous cell carcinoma patient-derived xenografts and gastric adenocarcinoma xenografts, demonstrating suppression of tumor growth and altered STAT3 and ERK1/2 gene signatures. We used small-molecule inhibitors of STAT3 and MEK1/2 signaling to suppress tumorigenesis in the 3D organotypic model of esophageal cancer. We demonstrate that IL6 is a major contributor to the dynamic cross-talk between tumor cells and CAF in the TME. Our findings provide a translational rationale for inhibition of IL6Ralpha and downstream signaling pathways as a novel targeted therapy in oral-upper-GI cancers.Significance: These findings demonstrate the interaction of esophageal cancer and cancer-associated fibroblasts through IL-6 signaling, providing rationale for a novel therapeutic approach to target these cancers. Cancer Res; 78(17); 4957-70. (c)2018 AACR. PMID- 29976577 TI - Response by Liberman et al to Letter Regarding Article, "Misdiagnosis of Cerebral Vein Thrombosis in the Emergency Department". PMID- 29976578 TI - Letter by Zhao et al Regarding Article, "Misdiagnosis of Cerebral Vein Thrombosis in the Emergency Department". PMID- 29976581 TI - Response by Dowlatshahi et al to Letter Regarding Article, "Predicting Intracerebral Hemorrhage Expansion With Noncontrast Computed Tomography: The BAT Score". PMID- 29976579 TI - Letter by Zheng and Niu Regarding Article, "Cerebrovascular Accidents During Mechanical Circulatory Support: New Predictors of Ischemic and Hemorrhagic Strokes and Outcome". PMID- 29976582 TI - To Treat or Not to Treat? AB - Background and Purpose- The 2015 updated US Food and Drug Administration alteplase package insert altered several contraindications. We thus explored clinical factors influencing alteplase treatment decisions for patients with minor stroke. Methods- An expert panel selected 7 factors to build a series of survey vignettes: National Institutes of Health Stroke Scale (NIHSS), NIHSS area of primary deficit, baseline functional status, previous ischemic stroke, previous intracerebral hemorrhage, recent anticoagulation, and temporal pattern of symptoms in first hour of care. We used a fractional factorial design (150 vignettes) to provide unconfounded estimates of the effect of all 7 main factors, plus first-order interactions for NIHSS. Surveys were emailed to national organizations of neurologists, emergency physicians, and colleagues. Physicians were randomized to 1 of 10 sets of 15 vignettes, presented randomly. Physicians reported the subjective likelihood of giving alteplase on a 0 to 5 scale; scale categories were anchored to 6 probabilities from 0% to 100%. A conjoint statistical analysis was applied. Results- Responses from 194 US physicians yielded 156 with complete vignette data: 74% male, mean age 46, 80% neurologists. Treatment mean probabilities for individual vignettes ranged from 6% to 95%. Treatment probability increased from 24% for NIHSS score =1 to 41% for NIHSS score =5. The conjoint model accounted for 25% of total observed response variance. In contrast, a model accounting for all possible interactions accounted for 30% variance. Four of the 7 factors accounted jointly for 58% of total relative importance within the conjoint model: previous intracerebral hemorrhage (18%), recent anticoagulation (17%), NIHSS (13%), and previous ischemic stroke (10%). Conclusions- Four main variables jointly account for only a small fraction (<15%) of the total variance related to deciding to treat with intravenous alteplase, reflecting high variability and complexity. Future studies should consider other variables, including physician characteristics. PMID- 29976583 TI - Response by Izzy et al to Letter Regarding Article, "Cerebrovascular Accidents During Mechanical Circulatory Support: New Predictors of Ischemic and Hemorrhagic Stroke and Outcome". PMID- 29976584 TI - Quantitative Lesion Water Uptake in Acute Stroke Computed Tomography Is a Predictor of Malignant Infarction. AB - Background and Purpose- Early selection of patients with acute middle cerebral artery infarction at risk for malignant edema is critical to initiate timely decompressive surgery. Net water uptake (NWU) per brain volume is a quantitative imaging biomarker of space-occupying ischemic edema which can be measured in computed tomography. We hypothesize that NWU in early infarct lesions can predict development of malignant edema. The aim was to compare NWU in acute brain infarct against other common predictors of malignant edema. Methods- After consecutive screening of single-center registry data, 153 patients with acute proximal middle cerebral artery occlusion fulfilled the inclusion criteria. A total of 29 (18.2%) patients developed malignant edema defined as end point in follow-up imaging leading to decompressive surgery and death as a direct implication of mass effect. Early infarct lesion volume and NWU were quantified in multimodal admission computed tomography; time from symptom onset to admission imaging was recorded. Results- Mean time from onset to admission imaging was equivalent between patients with and without malignant infarcts (mean+/-SD: 3.3+/-1.4 hours and 3.3+/-1.7 hours, respectively). Edematous tissue expansion by NWU within infarct lesions occurred across all patients in this cohort (NWU: 9.1%+/-6.8%; median, 7.9%; interquartile range, 8.8%; range, 0.1%-35.6%); 7.0% (+/-5.2) in nonmalignant and 18.0% (+/-5.7) in malignant infarcts. Based on univariate receiver operating characteristic curve analysis, NWU >12.7% or an edema rate >3.7% NWU/h identified malignant infarcts with high discriminative power (area under curve, 0.93+/-0.02). In multivariate binary logistic regression, the probability of malignant infarct was significantly associated with early infarct volume and NWU. Conclusions- Computed tomography-based quantitative NWU in early infarct lesions is an important surrogate marker for developing malignant edema. Besides volume of early infarct, the measurements of lesion water uptake may further support identifying patients at risk for malignant infarction. PMID- 29976585 TI - Letter by Jiang and Peng Regarding Article, "Predicting Intracerebral Hemorrhage Expansion With Noncontrast Computed Tomography: The BAT Score". PMID- 29976586 TI - Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno Associated Viral Vector. AB - BACKGROUND: After injury, mesenchymal progenitors in the kidney interstitium differentiate into myofibroblasts, cells that have a critical role in kidney fibrogenesis. The ability to deliver genetic material to myofibroblast progenitors could allow new therapeutic approaches to treat kidney fibrosis. Preclinical and clinical studies show that adeno-associated viruses (AAVs) efficiently and safely transduce various tissue targets in vivo; however, protocols for transduction of kidney mesenchymal cells have not been established. METHODS: We evaluated the transduction profiles of various pseudotyped AAV vectors expressing either GFP or Cre recombinase reporters in mouse kidney and human kidney organoids. RESULTS: Of the six AAVs tested, a synthetic AAV called Anc80 showed specific and high-efficiency transduction of kidney stroma and mesangial cells. We characterized the cell specificity, dose dependence, and expression kinetics and showed the efficacy of this approach by knocking out Gli2 from kidney mesenchymal cells by injection of Anc80-Cre virus into either homozygous or heterozygous Gli2-floxed mice. After unilateral ureteral obstruction, the homozygous Gli2-floxed mice had less fibrosis than the Gli2 heterozygotes had. We observed the same antifibrotic effect in beta-catenin floxed mice injected with Anc80-Cre virus before obstructive injury, strongly supporting a central role for canonical Wnt signaling in kidney myofibroblast activation. Finally, we showed that the Anc80 synthetic virus can transduce the mesenchymal lineage in human kidney organoids. CONCLUSIONS: These studies establish a novel method for inducible knockout of floxed genes in mouse mesangium, pericytes, and perivascular fibroblasts and are the foundation for future gene therapy approaches to treat kidney fibrosis. PMID- 29976587 TI - Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin. AB - BACKGROUND: Expression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO. METHODS: We evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation. RESULTS: Reduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis. CONCLUSIONS: These data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin's antifibrotic action in the kidney. PMID- 29976588 TI - Diagnostic Accuracy and Utility of FluoroType MTBDR, a New Molecular Assay for Multidrug-Resistant Tuberculosis. AB - Most cases of multidrug-resistant (MDR) tuberculosis (TB) are never diagnosed (328,300 of the ~490,000 cases in 2016 were missed). The Xpert MTB/RIF assay detects resistance only to rifampin, despite ~20% of rifampin-resistant cases being susceptible to isoniazid (a critical first-line drug). Consequently, many countries require further testing with the GenoType MTBDRplus assay. However, MTBDRplus is not recommended for use on smear-negative specimens, and thus, many specimens require culture-based drug susceptibility testing. Furthermore, MTBDRplus requires specialized expertise, lengthy hands-on time, and significant laboratory infrastructure and interpretation is not automated. To address these gaps, we evaluated the accuracy of the FluoroType MTBDR (FluoroType) assay. Sputa from 244 smear-positive and 204 smear-negative patients with presumptive TB (Xpert MTB positive, n = 343) were tested. Culture and MTBDRplus on isolates served as reference standards (for active TB and MDR-TB, respectively). Sanger sequencing and MTBDRplus, both of which were performed on sputa, were used to resolve discrepancies. The sensitivity of FluoroType for the detection of M. tuberculosis complex was 98% (95% confidence interval [CI], 95 to 99%) and 92% (95% CI, 84 to 96%) for smear-positive and smear-negative specimens, respectively (232/237 versus 90/98 specimens; P < 0.009). The sensitivity and specificity for smear-negative specimens were 100% and 97%, respectively, for rifampin resistance; 100% and 98%, respectively, for isoniazid resistance; and 100% and 100%, respectively, for MDR-TB. FluoroType identified 98%, 97%, and 97% of the rpoB, katG, and inhA promoter mutations, respectively. FluoroType has excellent sensitivity with sputa equivalent to that of MTBDRplus with the isolates and can provide rapid drug susceptibility testing for rifampin and isoniazid. In addition, the capacity of FluoroType to simultaneously identify virtually all mutations in the rpoB, katG, and inhA promoter may be useful for individualized treatment regimens. PMID- 29976589 TI - Prevalence and Genomic Structure of Bacteriophage phi3 in Human-Derived Livestock Associated Methicillin-Resistant Staphylococcus aureus Isolates from 2000 to 2015. AB - Whereas the emergence of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) clonal complex 398 (CC398) in animal husbandry and its transmission to humans are well documented, less is known about factors driving the epidemic spread of this zoonotic lineage within the human population. One factor could be the bacteriophage phi3, which is rarely detected in S. aureus isolates from animals but commonly found among isolates from humans, including those of the human-adapted methicillin-susceptible S. aureus (MSSA) CC398 clade. The proportion of phi3-carrying MRSA spa-CC011 isolates, which constitute presumptively LA-MRSA within the multilocus sequence type (MLST) clonal complex 398, was systematically assessed for a period of 16 years to investigate the role of phi3 in the adaptation process of LA-MRSA to the human host. For this purpose, 632 MRSA spa-CC011 isolates from patients of a university hospital located in a pig farming-dense area in Germany were analyzed. Livestock-associated acquisition of MRSA spa-CC011 was previously reported as having increased from 1.8% in 2000 to 29.4% in 2014 in MRSA-positive patients admitted to this hospital. However, in this study, the proportion of phi3-carrying isolates rose only from 1.1% (2000 to 2006) to 3.9% (2007 to 2015). Characterization of the phi3 genomes revealed 12 different phage types ranging in size from 40,712 kb up to 44,003 kb, with four hitherto unknown integration sites (genes or intergenic regions) and several modified bacterial attachment (attB) sites. In contrast to the MSSA CC398 clade, phi3 acquisition seems to be no major driver for the readaptation of MRSA spa CC011 to the human host. PMID- 29976590 TI - Multicenter Evaluation of the Etest Gradient Diffusion Method for Ceftolozane Tazobactam Susceptibility Testing of Enterobacteriaceae and Pseudomonas aeruginosa. AB - Ceftolozane-tazobactam (C/T) is a novel beta-lactam-beta-lactamase inhibitor combination antibiotic approved by the U.S. Food and Drug Administration in 2014 for the treatment of complicated intra-abdominal infections (in combination with metronidazole) and complicated urinary tract infections. In this study, we evaluated the performance of the C/T Etest, a gradient diffusion method. C/T Etest was compared to broth microdilution (BMD) for 51 Enterobacteriaceae challenge isolates and 39 Pseudomonas aeruginosa challenge isolates at three clinical sites. Essential agreement (EA) between the methods ranged from 47 to 49/51 (92.2 to 96.1%) for the Enterobacteriaceae, and categorical agreement (CA) ranged from 49 to 51/51 (96.1 to 100.0%). EA and CA for P. aeruginosa were 100% at all sites. The C/T Etest was also compared to BMD for susceptibility testing on 966 clinical isolates (793 Enterobacteriaceae, including 167 Klebsiella pneumoniae and 159 Escherichia coli isolates, in addition to 173 P. aeruginosa isolates) collected at four clinical sites. EA between Etest and BMD was 96.9% for Enterobacteriaceae isolates and 98.8% for P. aeruginosa isolates. Within the Enterobacteriaceae, isolates from each species examined had >96% CA. For the clinical isolates, no very major errors were identified but two major errors were found (one for K. pneumoniae and one for Providencia rettgeri). By BMD, 47.0% of Enterobacteriaceae and 46.2% of P. aeruginosa challenge strains were nonsusceptible to C/T by CLSI breakpoint criteria; 8.2% of clinical Enterobacteriaceae isolates and 12.1% of clinical P. aeruginosa isolates were nonsusceptible to C/T by CLSI breakpoint criteria. In conclusion, Etest is accurate and reproducible for C/T susceptibility testing of Enterobacteriaceae and P. aeruginosa. PMID- 29976591 TI - Whole-Genome Sequence Analysis of Multidrug-Resistant Campylobacter Isolates: a Focus on Aminoglycoside Resistance Determinants. AB - A whole-genome sequencing (WGS) approach was conducted in order to identify the molecular determinants associated with antimicrobial resistance in 12 multidrug resistant Campylobacter jejuni and Campylobacter coli isolates, with a focus on aminoglycoside resistance determinants. Two variants of a new aminoglycoside phosphotransferase gene [aph(2")-Ii1 and aph(2")-Ii2 ] putatively associated with gentamicin resistance were found. In addition, the following new genes were identified for the first time in Campylobacter: a lincosamide nucleotidyltransferase gene [lnu(G)], likely associated with lincomycin resistance, and two resistance enzyme genes (spw and apmA) similar to those found in Staphylococcus aureus, which may confer spectinomycin and gentamicin resistance, respectively. A C1192T mutation of the 16S rRNA gene that may be involved in spectinomycin resistance was also found in a C. coli isolate. Genes identified in the present study were located either on the bacterial chromosome or on plasmids that could be transferred naturally. Their role in aminoglycoside resistance remains to be supported by genetic studies. Regarding the other antimicrobial agents studied, i.e., ampicillin, ciprofloxacin, erythromycin, and tetracycline, a perfect correlation between antimicrobial phenotypes and genotypes was found. Overall, our data suggest that WGS analysis is a powerful tool for identifying resistance determinants in Campylobacter and can disclose the full genetic elements associated with resistance, including antimicrobial compounds not tested routinely in antimicrobial susceptibility testing. PMID- 29976592 TI - Metagenomics for Clinical Infectious Disease Diagnostics Steps Closer to Reality. AB - Metagenomics approaches based on shotgun next-generation sequencing hold promise for infectious disease diagnostics. Despite substantial challenges that remain, work done over the past few years justifies excitement about the potential for these approaches to transform how clinical pathogen identification and analysis are performed. In an article in this issue of the Journal of Clinical Microbiology, M. I. Ivy et al. (J Clin Microbiol 56:e00402-18, 2018, https://doi.org/10.1128/JCM.00402-18) have applied a shotgun metagenomics approach to the diagnosis of prosthetic joint infections directly from synovial fluid. The results from this work demonstrate both the potentials and challenges of this approach applied in the clinical microbiology laboratory. PMID- 29976593 TI - Histopathological Diagnosis of Prosthetic Joint Infection: Does a Threshold of 23 Neutrophils Do Better than Classification of the Periprosthetic Membrane in a Prospective Multicenter Study? AB - No gold standard exists for histopathological diagnosis of a prosthetic joint infection (PJI). The historical criterion considers the presence of neutrophil infiltration upon examination of periprosthetic tissue. Morawietz et al. proposed a classification of periprosthetic membranes (Morawietz et al., Clin Pathol 59:591-597, 2006, https://doi.org/10.1136/jcp.2005.027458) and a more recently described classification with a new cutoff value of 23 neutrophils in 10 high power fields (Morawietz et al., Histopathology 54:847-853, 2009. https://doi.org/10.1111/j.1365-2559.2009.03313.x). We performed a multicenter prospective study, which compared both methods for the diagnosis of PJI. All suspicions of PJI (n = 264) between December 2010 and March 2012 in seven centers were prospectively included. Five perioperative specimens were collected per patient for cultures, and one was collected for histology. Diagnosis of PJI was made according to the Infectious Diseases Society of America (IDSA) guidelines. Histopathological analysis classified the patients according to the threshold of 23 neutrophils and according to the classification of Morawietz. Performances of both methods were compared by using clinical and/or bacteriological criteria as the gold standard. Among 264 patients with suspected PJI, a diagnosis of infection was confirmed in 215 and unconfirmed in 49 patients. Histopathological analysis was available for 150 confirmed PJI and 40 unconfirmed PJI cases. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 78.7%, 90.0%, 96.7%, 52.9%, and 81.1%, respectively, for the Morawietz classification, and 82.0%, 90.0%, 96.9%, 57.1%, and 83.7%, respectively, for the 23-neutrophil threshold. The new algorithm using a threshold of 23 neutrophils can be proposed as a new gold standard for the histopathological diagnosis of PJI. PMID- 29976594 TI - Development and Optimization of Metagenomic Next-Generation Sequencing Methods for Cerebrospinal Fluid Diagnostics. AB - The purpose of this study was to develop and optimize different processing, extraction, amplification, and sequencing methods for metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) specimens. We applied mNGS to 10 CSF samples with known standard-of-care testing (SoC) results (8 positive and 2 negative). Each sample was subjected to nine different methods by varying the sample processing protocols (supernatant, pellet, neat CSF), sample pretreatment (with or without bead beating), and the requirement of nucleic acid amplification steps using DNA sequencing (DNASeq) (with or without whole-genome amplification [WGA]) and RNA sequencing (RNASeq) methods. Negative extraction controls (NECs) were used for each method variation (4/CSF sample). Host depletion (HD) was performed on a subset of samples. We correctly determined the pathogen in 7 of 8 positive samples by mNGS compared to SoC. The two negative samples were correctly interpreted as negative. The processing protocol applied to neat CSF specimens was found to be the most successful technique for all pathogen types. While bead beating introduced bias, we found it increased the detection yield of certain organism groups. WGA prior to DNASeq was beneficial for defining pathogens at the positive threshold, and a combined DNA and RNA approach yielded results with a higher confidence when detected by both methods. HD was required for detection of a low-level-positive enterovirus sample. We demonstrate that NECs are required for interpretation of these complex results and that it is important to understand the common contaminants introduced during mNGS. Optimizing mNGS requires the use of a combination of techniques to achieve the most sensitive, agnostic approach that nonetheless may be less sensitive than SoC tools. PMID- 29976595 TI - Risk Factors for Colistin Resistance among Gram-Negative Rods and Klebsiella pneumoniae Isolates. AB - Infections due to colistin-resistant (Colr) Gram-negative rods (GNRs) and colistin-resistant Klebsiella pneumoniae isolates in particular result in high associated mortality and poor treatment options. To determine the risk factors for recovery on culture of Colr GNRs and ColrK. pneumoniae, analyses were chosen to aid decisions at two separate time points: the first when only Gram stain results are available without any bacterial species information (corresponding to the Colr GNR model) and the second when organism identification is performed but prior to reporting of antimicrobial susceptibility testing results (corresponding to the ColrK. pneumoniae model). Cases were retrospectively analyzed at a major academic hospital system from 2011 to 2016. After excluding bacteria that were intrinsically resistant to colistin, a total of 28,512 GNR isolates (4,557 K. pneumoniae isolates) were analyzed, 128 of which were Colr (i.e., MIC > 2 MUg/ml), including 68 of which that were ColrK. pneumoniae In multivariate analysis, risk factors for Colr GNRs were neurologic disease, residence in a skilled nursing facility prior to admission, receipt of carbapenems in the last 90 days, prior infection with a carbapenem-resistant organism, and receipt of ventilatory support (c-statistic = 0.81). Risk factors for ColrK. pneumoniae specifically were neurologic disease, residence in a skilled nursing facility prior to admission, receipt of carbapenems in the last 90 days, receipt of an anti-methicillin-resistant Staphylococcus aureus antimicrobial in the last 90 days, and prior infection with a carbapenem-resistant organism (c-statistic = 0.89). A scoring system derived from these models can be applied by providers to guide empirical antimicrobial therapy in patients with infections with suspected Colr GNR and ColrK. pneumoniae isolates. PMID- 29976597 TI - Sharing patient data: understanding anonymisation. PMID- 29976596 TI - Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden. AB - OBJECTIVE: To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception. DESIGN: Population based historical cohort study using nationwide health registers. SETTING: Sweden, 2003-15. PARTICIPANTS: 2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes. MAIN OUTCOME MEASURES: Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels. RESULTS: 122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for >=9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for >=9.1% (1.68, 0.85 to 3.33). CONCLUSION: Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only. PMID- 29976599 TI - Directed migration: Cells navigate by extracellular vesicles. AB - Directional cell motility toward a chemical gradient, chemotaxis, is critical during inflammation, embryogenesis, and cancer metastasis. In this issue, Kriebel et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201710170) demonstrate that the key cAMP chemoattractant for Dictyostelium discoideum amoebas is synthesized within and released from extracellular vesicles to promote chemotaxis. PMID- 29976601 TI - Complete Genome Sequence of Escherichia coli Phage vB_EcoS Sa179lw, Isolated from Surface Water in a Produce-Growing Area in Northern California. AB - We report here the whole-genome sequence of a novel Escherichia coli phage, vB_EcoS Sa179lw, isolated from surface water collected in a produce-growing area. With the presence of a putative eae-like gene that was associated with previous non-O157 Shiga toxin-producing E. coli outbreaks, this phage is a candidate for the study of virulence gene transfer. PMID- 29976602 TI - Draft Genome Sequence of Pectobacterium atrosepticum PB72 and Complete Genome Sequence of the Specific Bacteriophage PP90. AB - We present the draft genome sequence of Pectobacterium atrosepticum strain PB72 infecting potatoes in Russia. PB72 is similar to the previously reported strain 21A. Considering potential biocontrol of this pathogen, an infectious bacteriophage was isolated and characterized. Phage vB_PatP_PP90 is a lytic podovirus of narrow host range belonging to the KP34virus genus. PMID- 29976600 TI - Variations in 24-Hour BP Profiles in Cohorts of Patients with Kidney Disease around the World: The I-DARE Study. AB - BACKGROUND AND OBJECTIVES: Ambulatory BP is increasingly recognized as a better measure of the risk for adverse outcomes related to hypertension, an important comorbidity in patients with CKD. Varying definitions of white-coat and masked hypertension have made it difficult to evaluate differences in prevalence of these BP patterns across CKD cohorts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The International Database of Ambulatory BP in Renal Patients collaborative group established a large database of demographic, clinical, and ambulatory BP data from patients with CKD from cohorts in Italy, Spain, the Chronic Renal Insufficiency Cohort (CRIC) and the African American Study of Kidney Disease and Hypertension Cohort Study (AASK) in the United States, and the CKD Japan Cohort (CKD-JAC). Participants (n=7518) with CKD were included in the present analyses. Cutoffs for defining controlled BP were 140/90 mm Hg for clinic and 130/80 mm Hg for 24-hour ambulatory BP. RESULTS: Among those with controlled clinic BP, compared with CKD-JAC, AASK participants were more likely to have masked hypertension (prevalence ratio [PR], 1.21; 95% confidence interval [95% CI], 1.04 to 1.41) whereas CRIC (PR, 0.82; 0.72 to 0.94), Italian (PR, 0.73; 0.56 to 0.95), and Spanish participants (PR, 0.75; 0.64 to 0.88) were less likely. Among those with elevated clinic BP, AASK participants were more likely to have sustained hypertension (PR, 1.22; 95% CI, 1.13 to 1.32) whereas Italian (PR, 0.78; 0.70 to 0.87) and Spanish participants (PR, 0.89; 0.82 to 0.96) were less likely, although CRIC participants had similar prevalence as CKD-JAC. Prevalence of masked and sustained hypertension was elevated in males, patients with diabetes, participants on four or more antihypertensives, and those with moderate to-severe proteinuria. CONCLUSIONS: In a large, multinational database, the prevalence of masked and sustained hypertension varied across cohorts independent of important comorbidities. PMID- 29976603 TI - Draft Genome Sequences of Three Salmonella enterica Serovar 4,[5],12:i:- Strains and One S. enterica Serovar Typhimurium Strain, Isolated in Brazil. AB - Draft genomes of three Salmonella enterica 4,[5],12:i:- (STi) strains isolated from human infections were obtained using Illumina sequencing. They were negative for the fljBA operon but positive for hin, and k-mer analyses revealed their identity as S. enterica 4,[5],12:i:- 08-1736 and S Typhimurium. A draft S Typhimurium sequence is described for comparison. PMID- 29976604 TI - Genomic Analysis of a Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Circulating in Pig Farms in West China. AB - Porcine reproductive and respiratory syndrome virus (PRRSV), which leads to tremendous economic losses worldwide, is currently one of the most threatening viruses for the swine industry. However, PRRSV outbreaks in West China are rarely reported, even though the virus has remained active for a long time across the country. In this study, we report an outbreak of the highly pathogenic PRRSV strain QTX, isolated from a pig farm located in Ningxia, a province in West China. PMID- 29976605 TI - Genome Sequences of Listeria Phages Induced from Lysogenic Isolates of Listeria monocytogenes from Seafood and a Seafood Processing Environment in Thailand. AB - We report here the complete genome sequences of three Listeria phages (PSU-VKH LP019, PSU-VKH-LP040, and PSU-VKH-LP041), which were newly induced from lysogenic isolates of Listeria monocytogenes from seafood and a seafood processing environment in Thailand. The three phages show circularly permuted double stranded DNA genomes with sizes of 38.6, 39.6, and 48.3 kb. PMID- 29976606 TI - Complete Genome Sequences of Zika Virus Strains Used for the Formulation of CBER/FDA RNA Reference Reagents and Lot Release Panels for Nucleic Acid Technology Testing. AB - We report here the complete genome sequences of two Zika virus strains (FSS13025 and PRVABC59) used for formulation of CBER/FDA RNA reference reagents and lot release panels for use with nucleic acid technology (NAT) testing. PMID- 29976607 TI - Draft Genome Sequence of Klebsiella pneumoniae Strain ICIS-278_PBV, Isolated from the Feces of a Healthy 59-Year-Old Man from Orenburg, Russia. AB - This report describes the draft genome sequence of Klebsiella pneumoniae strain ICIS-278_PBV, isolated from the feces of a healthy 59-year-old man from Orenburg, Russia. The size of the genome was 5,584,615 bp (57.2% G+C content). Annotation revealed 5,302 coding sequences, including 5,254 proteins, 23 rRNA genes, and 81 tRNA genes. PMID- 29976608 TI - Complete Genome Sequence Analysis of an Imported Dengue Virus Serotype 1 Strain from Myanmar. AB - It has been determined that recent dengue virus epidemics in Yunnan, China, originated from Southeast Asian strains. Here, we report the first complete genome sequence and molecular characterization of the imported dengue virus serotype 1 strain YNPE1. Phylogenetic analysis revealed that strain YNPE1 belonged to genotype I. PMID- 29976609 TI - Draft Genome Sequence of Bioactive Strain Streptomyces sp. SMS_SU21, Isolated from Soil Sediment of the Sundarbans Mangrove Ecosystem. AB - Streptomyces sp. SMS_SU21 possesses strong antimicrobial activity and antioxidant potential. This strain was isolated from the Sundarbans mangrove ecosystem, and its draft genome comprises 7,449,420 bp with 6,680 open reading frames. Genome analysis of strain SMS_SU21 provides insight into its secondary metabolite arsenal and reveals the gene clusters putatively responsible for its bioactive potential. PMID- 29976610 TI - Complete Genome Sequence of Lactobacillus paracasei EG9, a Strain Accelerating Free Amino Acid Production during Cheese Ripening. AB - Lactobacillus paracasei EG9 is a strain isolated from well-ripened cheese and accelerates free amino acid production during cheese ripening. Its complete genome sequence was determined using the PacBio RS II platform, revealing a single circular chromosome of 2,927,257 bp, a G+C content of 46.59%, and three plasmids. PMID- 29976611 TI - Genome Sequence of Geobacillus thermoleovorans SGAir0734, Isolated from Singapore Air. AB - The thermophilic bacterium Geobacillus thermoleovorans was isolated from a tropical air sample collected in Singapore. The genome was sequenced on the PacBio RS II platform and consists of one chromosome with 3.6 Mb and one plasmid with 75 kb. The genome comprises 3,509 protein-coding genes, 88 tRNAs, and 27 rRNAs. PMID- 29976612 TI - Complete Genome Sequence of the Bacterium Serratia marcescens SGAir0764, Isolated from Singapore Air. AB - Serratia marcescens strain SGAir0764 was isolated from a tropical air sample collected in Singapore. The complete genome, sequenced on the PacBio RS II platform, consists of one chromosome with 5.1 Mb and one plasmid with 76.4 kb. Genome annotation predicts 4,723 protein-coding genes, 89 tRNAs, and 22 rRNAs. PMID- 29976613 TI - Genome Sequence of Bacillus velezensis SGAir0473, Isolated from Tropical Air Collected in Singapore. AB - Bacillus velezensis strain SGAir0473 (Firmicutes) was isolated from tropical air collected in Singapore. Its genome was assembled using short reads and single molecule real-time sequencing and comprises one chromosome with 4.18 Mb. The genome consists of 3,937 protein-coding genes, 86 tRNAs, and 27 rRNAs. PMID- 29976614 TI - Genome Sequence of Pantoea ananatis SGAir0210, Isolated from Outdoor Air in Singapore. AB - Pantoea ananatis SGAir0210 was isolated from outdoor air collected in Singapore. The genome was assembled from long reads generated by single-molecule real-time sequencing complemented with short reads. The genome size was approximately 4.81 Mb, with 4,303 protein-coding genes, 80 tRNAs, and 22 rRNAs identified. PMID- 29976615 TI - Terroristic sniper shot ocular injuries: military and police casualties: case series. AB - INTRODUCTION: Sniper shot ocular injuries (SSOI) are rare and result in poor ocular outcomes due to high energy transfer both to the eye and the adjacent brain. To our knowledge, no reports of such injuries in terms of outcomes have been previously described in the literature. The aim of this case series was to describe the treatment performed and ocular outcomes of such injuries. METHODS: Five cases of terroristic SSOIs referred to Gulhane Military Medical Academy Department of Ophthalmology between 22 July 2015 and 30 January 2017 were reviewed. Comparisons were made between the location and mechanism of injury, initial and final ocular signs, interventions and additional extraocular injuries. RESULTS: Two cases were of police officers and the remaining were Turkish military soldiers. All of our cases were injured in urban district by terrorist snipers hidden in apartments. Four individuals were injured in the right eye and the other was injured bilaterally. Initial visual acuities (VA) ranged from no light perception (NLP) to 0.0 with logMAR. Final VA raised to 0.0 in three patients whereas in two of NLP patients it remained the same. Mean Ocular Trauma Score was 2.2. Two eyes necessitated evisceration and the others underwent vitrectomy surgery. CONCLUSIONS: The prognosis of SSOI is unpredictable and is highly dependent on the trajectory and energy deposition. Primary evisceration or enucleation should be reserved to severely ruptured globe cases with no chance of globe-saving procedures. If the globe remains intact, retinal and vitreal damage should be repaired. Due to risk of associated intracranial injury, all patients should be referred for neurosurgical opinion. PMID- 29976616 TI - Lost productivity among military personnel with cardiovascular disease. AB - OBJECTIVE: Cardiovascular disease (CVD) is associated with significant productivity loss among all occupational groups. However, the increased occupational requirements of military personnel pose physical and psychological demands that could lead to greater lost productivity of CVD. The aim of this study was to determine the economic cost of lost productivity of military patients with CVD. METHODS: A prospective cross-sectional study was undertaken on all military patients attending a specialist CVD clinic in Tehran, Iran. All participants were interviewed using face-to-face questioning using a Valuation of Lost Productivity questionnaire. Data captured included paid and unpaid time lost due to CVD, military job characteristics and their work environment. Ordered logistic regression was used to examine the determinants of lost productivity. RESULTS: The mean time of lost productivity was 118 hours over a 3-month period, of which 70 and 48 hours were paid and unpaid work, respectively. The average cost per patient of total lost productivity was estimated to be US$303 over a 3 month period. CONCLUSIONS: CVDs are associated with significant lost productivity among military personnel. There is a statistically significant relation between some military occupation characteristics and lost productivity from CVD. Level of income, teamwork and physical activity have the greatest effects on lost productivity. Military workers who were suffering from other chronic conditions (in addition to CVD) were four times more likely to lose productivity. A supportive work environment should be created for military personnel with emphasis on developing teamwork, improving worker's attitudes towards disease and giving priority to workers with comorbidities. PMID- 29976620 TI - Margaret McCartney: Getting the abstract in perspective. PMID- 29976618 TI - ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes. AB - In patients with diabetes, impaired activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the plasma metalloprotease that cleaves highly thrombogenic von Willebrand factor multimers, is a major risk factor of cardiovascular events. Here, using Adamts13-/- mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. Adamts13-/- mice experienced a shorter life span than their diabetic wild-type littermates. It was surprising that animal death was not related to the occurrence of detectable thrombotic events. The lack of ADAMTS13 drastically increased the propensity for ventricular arrhythmias during dobutamine-induced stress in diabetic mice. Cardiomyocytes of diabetic Adamts13-/- mice exhibited an aberrant distribution of the ventricular gap junction connexin 43 and increased phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII), and with the consequent CaMKII-induced disturbance in Ca2+ handling, which underlie propensity for arrhythmia. In vitro, thrombospondin 1 (TSP1) promoted, in a paracrine manner, CaMKII phosphorylation in murine HL-1 cardiomyocytes, and ADAMTS13 acted to inhibit TSP1-induced CaMKII activation. In conclusion, the deficiency of ADAMTS13 may underlie the onset of lethal arrhythmias in diabetes through increased CaMKII phosphorylation in cardiomyocytes. Our findings disclose a novel function for ADAMTS13 beyond its antithrombotic activity. PMID- 29976617 TI - CD4 T Cells Reactive to Hybrid Insulin Peptides Are Indicators of Disease Activity in the NOD Mouse. AB - We recently established that hybrid insulin peptides (HIPs), formed in islet beta cells by fusion of insulin C-peptide fragments to peptides of chromogranin A or islet amyloid polypeptide, are ligands for diabetogenic CD4 T-cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity. MHC class II tetramers were used to investigate the presence, phenotype, and function of HIP-reactive and insulin reactive T cells in NOD mice. Insulin-reactive T cells encounter their antigen early in disease, but they express FoxP3 and therefore may contribute to immune regulation. In contrast, HIP-reactive T cells are proinflammatory and highly diabetogenic in an adoptive transfer model. Because the frequency of antigen experienced HIP-reactive T cells increases over progression of disease, they may serve as biomarkers of autoimmune diabetes. PMID- 29976621 TI - Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain. AB - Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain. PMID- 29976619 TI - Up-front rituximab maintenance improves outcome in patients with follicular lymphoma: a collaborative Nordic study. AB - The introduction of the anti-CD20 antibody rituximab in combination with chemotherapy (R-chemo) has improved the prognosis of patients with follicular lymphoma (FL). During the last decade, the addition of a maintenance treatment with rituximab (MR) after R-chemo has been tested with the hope of further improving the outcome of these patients. Using 2 independent population-based cohorts, we investigated the effect of up-front MR on time related end points as well as the risk of histological transformation (HT). FL patients were included if they: (1) completed first-line induction treatment with R-chemo, (2) were alive after induction treatment and eligible for MR, and (3) had no evidence of HT at this time point. The training cohort consisted of 733 Danish patients of whom 364 were consolidated with MR; 369 were not. Patients receiving MR more often had advanced clinical stage (90% vs 78%), high Follicular Lymphoma International Prognostic Index (FLIPI) score (64% vs 55%), and bone marrow infiltration (49% vs 40%). Those consolidated with MR had an improved 5-year overall survival (OS; 89% vs 81%; P = .001) and progression-free survival (PFS; 72% vs 60%; P < .001). In the training cohort, MR was associated with a reduction of HT risk (P = .049). Analyses of an independent validation cohort of 190 Finnish patients confirmed the favorable impact of MR on 5-year OS (89% vs 81%; P = .046) and PFS (70% vs 57%; P = .005) but did not find a reduced risk of HT. The present population-based data suggest that the outcome of patients with FL has improved after consolidation of R-chemo with MR. PMID- 29976622 TI - Grid-cell activity on linear tracks indicates purely translational remapping of 2D firing patterns at movement turning points. AB - Grid cells in rodent medial entorhinal cortex are thought to play a critical role for spatial navigation. When the animal is freely moving in an open arena the firing fields of each grid cell tend to form a hexagonal lattice spanning the environment. For movements along a linear track the cells seem to respond differently. They show multiple firing fields that are not periodically arranged and whose shape and position change when the running direction is reversed. In addition, peak firing rates vary widely from field to field. Measured along one running direction only, firing fields are, however, compatible with a slice through a two-dimensional hexagonal pattern. It is an open question, whether this is also true if left-ward and right-ward runs are jointly considered. By analyzing data from fifteen male Long-Evans rats, we show that a single hexagonal firing pattern explains the linear-track data if translational shifts of the pattern are allowed at the movement turning points. A rotation or scaling of the grid is not required. The agreement is further improved if the peak firing rates of the underlying 2D grid fields can vary from field to field, as suggested by recent studies. These findings have direct consequences for experiments using linear tracks in virtual reality.SIGNIFICANCE STATEMENTVarious types of neurons support spatial navigation. Their response properties are often studied in reduced settings and might change when the animal can freely explore its environment. Grid cells in rodents, for example, exhibit seemingly irregular firing fields when animal movement is restricted to a linear track but highly regular patterns in two-dimensional arenas. We show that a cell's linear-track responses for both, left-wards and right-wards running directions can be explained as cuts through a single hexagonal pattern if translational remapping is allowed at movement turning points; neither rotations nor scale transformations are needed. These results provide a basis to quantify grid-cell activity in 1D virtual-reality and could help to detect and categorize grid cells without experiments in 2D environments. PMID- 29976623 TI - Synaptopathy in the Aging Cochlea: Characterizing Early-Neural Deficits in Auditory Temporal Envelope Processing. AB - Aging listeners, even in the absence of overt hearing loss measured as changes in hearing thresholds, often experience impairments processing temporally complex sounds such as speech in noise. Recent evidence has shown that normal aging is accompanied by a progressive loss of synapses between inner hair cells and auditory nerve fibers. The role of this cochlear synaptopathy in degraded temporal processing with age is not yet understood. Here, we used population envelope following responses, along with other hair cell- and neural-based measures from an age-graded series of male and female CBA/CaJ mice to study changes in encoding stimulus envelopes. By comparing responses obtained before and after the application of the neurotoxin ouabain to the inner ear, we demonstrate that we can study changes in temporal processing on either side of the cochlear synapse. Results show that deficits in neural coding with age emerge at the earliest neural stages of auditory processing and are correlated with the degree of cochlear synaptopathy. These changes are seen before losses in neural thresholds and particularly affect the suprathreshold processing of sound. Responses obtained from more central sources show smaller differences with age, suggesting compensatory gain. These results show that progressive cochlear synaptopathy is accompanied by deficits in temporal coding at the earliest neural generators and contribute to the suprathreshold sound processing deficits observed with age.SIGNIFICANCE STATEMENT Aging listeners often experience difficulty hearing and understanding speech in noisy conditions. The results described here suggest that age-related loss of cochlear synapses may be a significant contributor to those performance declines. We observed aberrant neural coding of sounds in the early auditory pathway, which was accompanied by and correlated with an age-progressive loss of synapses between the inner hair cells and the auditory nerve. Deficits first appeared before changes in hearing thresholds and were largest at higher sound levels relevant to real world communication. The noninvasive tests described here may be adapted to detect cochlear synaptopathy in the clinical setting. PMID- 29976624 TI - Gating of Sensory Input at Subcortical and Cortical Levels during Grasping in Humans. AB - Afferent input from the periphery to the cortex contributes to the control of grasping. How sensory input is gated along the ascending sensory pathway and its functional role during gross and fine grasping in humans remain largely unknown. To address this question, we assessed somatosensory-evoked potential components reflecting activation at subcortical and cortical levels and psychophysical tests at rest, during index finger abduction, precision, and power grip. We found that sensory gating at subcortical level and in the primary somatosensory cortex (S1), as well as intracortical inhibition in the S1, increased during power grip compared with the other tasks. To probe the functional relevance of gating in the S1, we examined somatosensory temporal discrimination threshold by measuring the shortest time interval to perceive a pair of electrical stimuli. Somatosensory temporal discrimination threshold increased during power grip, and higher threshold was associated with increased intracortical inhibition in the S1. These novel findings indicate that humans gate sensory input at subcortical level and in the S1 largely during gross compared with fine grasping. Inhibitory processes in the S1 may increase discrimination threshold to allow better performance during power grip.SIGNIFICANCE STATEMENT Most of our daily life actions involve grasping. Here, we demonstrate that gating of afferent input increases at subcortical level and in the primary somatosensory cortex (S1) during gross compared with fine grasping in intact humans. The precise timing of sensory information is critical for human perception and behavior. Notably, we found that the ability to perceive a pair of electrical stimuli, as measured by the somatosensory temporal discrimination threshold, increased during power grip compared with the other tasks. We propose that reduced afferent input to the S1 during gross grasping behaviors diminishes temporal discrimination of sensory processes related, at least in part, to increased inhibitory processes within the S1. PMID- 29976625 TI - Quantitative Association of Anatomical and Functional Classes of Olfactory Bulb Neurons. AB - Juxtaglomerular cells (JGCs) of the olfactory bulb (OB) glomerular layer (GL) play a fundamental role in olfactory information processing. Their variability in morphology, physiology, and connectivity suggests distinct functions. The quantitative understanding of population-wise morphological and physiological properties and a comprehensive classification based on quantitative parameters, however, is still lacking, impeding the analysis of microcircuits. Here, we provide multivariate clustering of 95 in vitro sampled cells from the GL of the mouse (male or female C57BL/6) OB and perform detailed morphological and physiological characterization for the seven computed JGC types. Using a classifier based on a subselection of parameters, we identified the neuron types in paired recordings to characterize their functional connectivity. We found that 4 of the 7 clusters comply with prevailing concepts of GL cell types, whereas the other 3 represent own distinct entities. We have labeled these entities horizontal superficial tufted cell (hSTC), vertical superficial tufted cell, and microglomerular cell (MGC): The hSTC is a tufted cell with a lateral dendrite that much like mitral cells and tufted cells receives excitatory inputs from the external tufted cell but likewise serves as an excitatory element for glomerular interneurons. The vertical superficial tufted cell, on the other hand, represents a tufted cell type with vertically projecting basal dendrites. We further define the MGC, characterized by a small dendritic tree and plateau action potentials. In addition to olfactory nerve-driven and external tufted cell driven interneurons, these MGCs represent a third functionally distinct type, the hSTC driven interneurons. The presented correlative analysis helps to bridge the gap between branching patterns and cellular functional properties, permitting the integration of results from in vivo recordings, advanced morphological tools, and connectomics.SIGNIFICANCE STATEMENT The variance of neuron properties is a feature across mammalian cerebral circuits, contributing to signal processing and adding computational robustness to the networks. It is particularly noticeable in the glomerular layer of the olfactory bulb, the first site of olfactory information processing. We provide the first unbiased population-wise multivariate analysis to correlate morphological and physiological parameters of juxtaglomerular cells. We identify seven cell types, including four previously described neuron types, and identify further three distinct classes. The presented correlative analysis of morphological and physiological parameters gives an opportunity to predict morphological classes from physiological measurements or the functional properties of neurons from morphology and opens the way to integrate results from in vivo recordings, advanced morphological tools, and connectomics. PMID- 29976626 TI - Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. AB - Cocaine-associated cues and contexts can precipitate drug seeking in humans and in experimental animals. Glutamatergic synapses in the core subcompartment of the nucleus accumbens (NAcore) undergo transient potentiation in response to presenting drug-associated cues. The NAcore contains two populations of medium spiny neurons (MSNs) that differentially express D1 or D2 dopamine receptors. By recording the ratio of AMPA and NMDA glutamate receptor currents (AMPA/NMDA ratio) from MSNs in NAcore tissue slices, we endeavored to understand which subpopulation of MSNs was undergoing transient potentiation. Transgenic female and male mice differentially expressing fluorescent reporters in D1 or D2 MSNs were withdrawn for 2-3 weeks after being trained to self-administer cocaine. In some mice, discrete cocaine-conditioned cues were isolated from the drug associated context via extinction training, which causes rodents to refrain from drug seeking in the extinguished context. By measuring AMPA/NMDA ratios in the drug context with or without contextual or discrete cues, and with or without extinction training, we made the following three discoveries: (1) mice refraining from cocaine seeking in the extinguished context showed selective elevation in AMPA/NMDA ratios in D2 MSNs; (2) without extinction training, the drug-associated context selectively increased AMPA/NMDA ratios in D1 MSNs; (3) mice undergoing cue-induced cocaine seeking after extinction training in the drug-associated context showed AMPA/NMDA ratio increases in both D1 and D2 MSNs. These findings reveal that the NAcore codes drug seeking through transient potentiation of D1 MSNs, and that refraining from cocaine seeking in an extinguished context is coded through transient potentiation of D2 MSNs.SIGNIFICANCE STATEMENT Relapse is a primary symptom of addiction that can involve competition between the desire to use drugs and the desire to refrain from using drugs. Drug-associated cues induce relapse, which is correlated with transiently potentiated glutamatergic synapses in the nucleus accumbens core. We determined which of two cell populations in the accumbens core, D1-expressing or D2-expressing neurons, undergo transient synaptic potentiation. After being trained to self-administer cocaine, mice underwent withdrawal, some with and others without extinguishing responding in the drug-associated context. Extinguished mice showed transient potentiation in D2-expressing neurons in the extinguished environment, and all mice engaged in context-induced or cue-induced drug seeking showed transient potentiation of D1 expressing neurons. A simple binary engram in accumbens for seeking drugs and refraining from drugs offers opportunities for cell-specific therapies. PMID- 29976627 TI - Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain. AB - Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (MPhis) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral MPhis. Furthermore, AT2R activation in MPhis triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (MPhis) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This MPhi-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions. PMID- 29976628 TI - Potential of Protein-based Anti-metastatic Therapy with Serpins and Inter alpha Trypsin Inhibitors. AB - In this review we summarize the principles of anti-metastatic therapy with selected serpin family proteins, such as pigment epithelial-derived factor (PEDF) and maspin, as well as inter alpha-trypsin inhibitor (IalphaIs) light chains (bikunin) and heavy chains (ITIHs). Case-by-case, antimetastatic activity may be dependent or independent of the protease-inhibitory activity of the corresponding proteins. We discuss the incidence of target deregulation in different tumor entities, mechanisms of deregulation, context-dependent functional issues as well as in vitro and in vivo target validation studies with transfected tumor cells or recombinant protein as anti-metastatic agents. Finally, we comment on possible clinical evaluation of these proteins in adjuvant therapy. PMID- 29976629 TI - The Dual PI3K/mToR Inhibitor Omipalisib/GSK2126458 Inhibits Clonogenic Growth in Oncogenically-transformed Cells from Neurocutaneous Melanocytosis. AB - BACKGROUND: Omipalisib has been found to affect the viability of cancer cells. However, its effect on clonogenicity - a feature of cancer stem cells, is not clear. Cells isolated from neurocutaneous melanocytosis (NCM) patients' lesions grow clonogenically. The aim of this study was to investigate the effect of omipalisib treatment on clonogenic growth of NCM cells in vitro. MATERIALS AND METHODS: Clonogenic growth efficiency was evaluated by colony formation assays with or without specific growth factors. Activation of MEK and Akt was determined by immunoblots. Colony formation and cell viability were assessed upon pharmacological inhibition of MEK, Akt and mToR. RESULTS: Clonogenicity appeared to depend on bFGF and IGF1signaling through ERK and Akt. Omipalisib treatment prevented colony formation and induced autophagic cell death. CONCLUSION: Signaling through Akt is important for survival of clonogenic cells in NCM, and omipalisib treatment as a monotherapy or in combination with MEK162 could be an effective therapeutic strategy to inhibit clonogenic growth. PMID- 29976630 TI - Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response. AB - Sepantronium bromide (YM-155) is believed to elicit apoptosis and mitotic arrest in tumor cells by reducing (BIRC5, survivin) mRNA. In this study, we monitored changes in survivin mRNA and protein after treating MDA-MB-231 cells with YM-155 concurrent with evaluation of whole transcriptomic (WT) mRNA and long intergenic non-coding RNA at 2 time points: 8 h sub-lethal (83 ng/mL) and 20 h at the LC50 (14.6 ng/mL). The data show a tight association between cell death and the precipitating loss of survivin protein and mRNA (-2.67 fold-change (FC), p<0.001) at 20 h, questioning if the decline in survivin is attributed to cell death or drug impact. The meager loss of survivin mRNA was overshadowed by enormous differential change to the WT in both magnitude and significance for over 2000 differentially up/down-regulated transcripts: (+22 FC to -12 FC, p<0.001). The data show YM-155 to up-regulate transcripts in control of circadian rhythm (NOCT, PER, BHLHe40, NFIL3), tumor suppression (SIK1, FOSB), histone methylation (KDM6B) and negative feedback of NF-kappa B signaling (TNFAIP3). Down-regulated transcripts by YM-155 include glucuronidase (GUSBP3), numerous micro-RNAs, DNA damage repair elements (CENPI, POLQ, RAD54B) and the most affected system was the ataxia-telangiectasia mutated (ATM)/Fanconi anemia E3 monoubiquitin ligase core complexes (FANC transcripts - A/B/E/F/G/M), FANC2, FANCI, BRCA1, BRCA2, RAD51, PALB2 gene and ATR (ATM- and Rad3-Related) pathway. In conclusion, these findings suggest that a primary target of YM-155 is the loss of replicative DNA repair systems. PMID- 29976631 TI - Frequency of Mismatch Repair Protein Deficiency in a Puerto Rican Population with Colonic Adenoma and Adenocarcinoma. AB - BACKGROUND/AIM: Microsatellite instability (MSI) results from genetic alterations involving the mismatch repair (MMR) genes MLH1, PSM2, MSH2, and MSH6. MSI has been implicated in both sporadic CRC and Lynch syndrome. The aim of the study was to assess the frequency of alterations in MMR protein expression in both primary colorectal cancer and precursor lesions among Puerto Rican patients. PATIENTS AND METHODS: A retrospective study of 84 Puerto Rican patients was performed to assess the frequency of MMR protein expression alterations in both primary CRC and precursor lesions using tissue microarray and immunohistochemistry. RESULTS: The loss of expression of both MLH1 and PMS2 proteins was present in 6.3% of adenomas, 9.1% of adenomas with high-grade dysplasia and 9.4% of colon adenocarcinomas. Negative nuclear staining for both MSH2 and MSH6 proteins was found in 2.4% of colon adenocarcinomas. CONCLUSION: When compared to prior reports, this study suggests a lower frequency of MSI among the Puerto Rican population. The higher prevalence of MLH1 mutations correlates with previous studies of protein expression among the Hispanic community including Colombian, Uruguay and Brazilian populations. PMID- 29976632 TI - Glioblastoma Multiforme: Fewer Tumor Copy Number Segments of the SGK1 Gene Are Associated with Poorer Survival. AB - BACKGROUND/AIM: Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system. The serum and glucocorticoid-regulated kinase SGK1 gene is required for the growth and survival of GBM stem-like cells under both normoxic and hypoxic conditions. It has been reported that oxygenation significantly affects cellular genetic expression; 30% of the genes required in hypoxia were not required under normoxic conditions. Therefore, we examined SGK1 expression to determine if it may be a novel potential drug target for GBM. MATERIALS AND METHODS: We assessed the association between SGK1 and glioblastoma patient overall survival using the GBM cohort in TCGA (The Cancer Genome Atlas) database (TCGA-GBM). To access and analyze the data we used the UCSC Xena browser (https://xenabrowser.net). Survival data of the GBM subgroup were extracted for analysis and generation of Kaplan-Meier curves for overall survival. The best cut off was identified by methods described in the R2 web-based application (http://r2.amc.nl). RESULTS: We analyzed patient survival by tumor SGK1 copy number segments after removal of common germ-line copy-number variants (CNVs). Copy number segments (log2 tumor/normal) <=0.009700 were associated with significantly poorer survival (p=0.016). CONCLUSION: Increased median overall survival associated with increased SGK1 copy number segments may be a reflection of better tumor oxygenation. Therefore, besides being a drug target, SGK1 may also be a prognostic marker. Among molecular tumor markers, only the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene has shown a significant association with survival in patients with GBM. PMID- 29976633 TI - Comparative Secretome Profiling and Mutant Protein Identification in Metastatic Prostate Cancer Cells by Quantitative Mass Spectrometry-based Proteomics. AB - BACKGROUND: Secreted proteins play an important role in promoting cancer (PCa) cell migration and invasion. Proteogenomics helps elucidate the mechanism of diseases, discover therapeutic targets, and generate biomarkers for diagnosis through protein variations. MATERIALS AND METHODS: We carried out mass a spectrometry-based proteomic analysis of the conditioned media (CM) from two human prostate cancer cell lines, belonging to different metastatic sites, to identify potential metastatic and/or aggressive factors. RESULTS: We identified a total of 598 proteins, among which 561 were quantified based on proteomic analysis. Among the quantified proteins, 128 were up-regulated and 83 were down regulated in DU145/PC3 cells. Six mutant peptides were identified in the CM of prostate cancer cell lines using proteogenomics approach. CONCLUSION: This is the first proteogenomics study in PCa aiming at exploring a new type of metastatic factor, which are mutant peptides, predicting a novel biomarker of metastatic PCa for diagnosis, prognosis and drug targeting. PMID- 29976634 TI - Comparing Clonality Between Components of Combined Hepatocellular Carcinoma and Cholangiocarcinoma by Targeted Sequencing. AB - BACKGROUND/AIM: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a very rare type of tumor, comprising these two different components in a single mass. Although several studies have determined the genetic characteristics of cHCC-CC, next-generation sequencing (NGS) data for comparing clonality of cHCC-CC are currently unavailable. MATERIALS AND METHODS: Four cHCC-CC cases were selected and HCC, CC and normal components from each case were separately micro-dissected. DNA and RNA were isolated from each sample and sequenced by Oncomine Comprehensive Panel interrogating 143 cancer genes using the Ion S5 XL sequence platform. Genetic features of HCC and CC from each patient were compared. RESULTS: All cases successfully produced NGS data. Two cases demonstrated different mutations in their HCC and CC components (biclone), while two cases shared the same mutations in the two components (monoclone). Single nucleotide polymorphisms (SNPs) of TP53 (4/4) and phosphatase and tensin homolog (PTEN) (1/4), and gene amplifications of mesenchymal-epithelial transition factor (MET) (1/4), c-MYC (1/4), and cyclin-dependent kinase 6 (CDK6) (1/4) were found in the CC component. In the HCC component, SNPs of TP53 (3/4), PTEN (1/4) and catenin beta 1 (CTNNB1) (1/4) and cyclin D1 (CCND1) amplification (1/4) were detected. Two biclonal cases showed a histologically distinct border between HCC and CC components with or without intermediate cell foci. Two monoclonal cases showed a histologically ambiguous border between HCC and CC components with more intermingled pattern than biclonal cases. CONCLUSION: Based on our study, cHCC-CC can be genetically divided into biclonal and monoclonal forms. Therefore, separate sequencing of each component of cHCC-CC is recommended for exact molecular classification and targeted therapy. PMID- 29976635 TI - Identification and Quantification of Heterogeneously-methylated DNA Fragments Using Epiallele-sensitive Droplet Digital Polymerase Chain Reaction (EAST-ddPCR). AB - BACKGROUND/AIM: DNA methylation plays an important role in the initiation and propagation of carcinogenesis; however, the role of heterogeneously methylated epialleles is currently not well studied, also due to the lack of sensitive, unbiased and high throughput methods. Here, a newly developed droplet digital PCR (ddPCR)-based method was evaluated regarding its ability to quantify such heterogeneously methylated epialleles with sufficient analytical sensitivity and specificity. MATERIALS AND METHODS: Genomic DNA from blood leukocytes and bone marrow aspirate of an 8-year old male with B-cell acute lymphoblastic leukemia (B ALL) and from normal and malignant prostate cell lines were analysed using ddPCR. RESULTS: By using these DNA samples, the specificity of an applied set of fluorescence-labeled probes was demonstrated as a proof of concept. CONCLUSION: All individual heterogeneously-methylated epialleles were quantifiable by a set of fluorescence-labeled probes with complementary sequences to epialleles in a closed-tube and high-throughput manner. The new method named epiallele-sensitive droplet digital PCR (EAST-ddPCR) may give new insights in the generation and regulation of epialleles and may help in finding new biomarkers for the diagnosis of benign und malignant diseases. PMID- 29976636 TI - Overexpression of FGFR1 Promotes Peritoneal Dissemination Via Epithelial-to Mesenchymal Transition in Gastric Cancer. AB - BACKGROUND: Peritoneal dissemination (PD) is one of the most common causes of cancer-related mortality in gastric cancer (GC). We aimed to identify PD associated genes and investigate their role in GC. MATERIALS AND METHODS: We identified FGFR1 as a putative PD-associated gene using a bioinformatics approach. The biological significance of FGFR1 in epithelial-to-mesenchymal transition (EMT) was evaluated according to the correlation with genes that participated in EMT and FGFR1 knockdown experiments. The associations between FGFR1 expression and the clinicopathological features were examined. RESULTS: FGFR1 expression positively correlated with SNAI1, VIM and ZEB1 expression, and negatively correlated with CDH1 expression. Knockdown of FGFR1 suppressed the malignant phenotype of GC cells. High FGFR1 expression significantly correlated with the peritoneal lavage cytology and synchronous PD positivity as well as poor prognosis. CONCLUSION: High FGFR1 expression was associated with PD via promotion of EMT and led to a poor prognosis of GC patients. PMID- 29976637 TI - Pre-operative Plasma miR-21-5p Is a Sensitive Biomarker and Independent Prognostic Factor in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgical Resection. AB - Blood plasma microRNAs (miRNAs) are emerging as a clinically useful tool for non invasive detection and prognosis estimation in various cancer types including pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to provide an independent validation of circulating miRNAs identified in previous studies as diagnostic and/or prognostic biomarkers in PDAC. Based on the literature search, 6 miRNAs were chosen as candidates for independent validation; miR-21-5p, miR-375, miR-155, miR-17-5p, miR-126-5p and miR-1290. Validation of these miRNAs was performed in a cohort of 25 patients with PDAC undergoing surgical resection and 24 healthy donors. Plasma levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of all tested miRNA in blood plasma of PDAC patients in comparison to healthy controls with miR-21-5p showing the highest analytical performance (p<0.001; AUC>0.99). Increased levels of miR-21-5p (p=0.045) and miR-375 (p=0.013) were significantly associated with overall survival. Multivariate analysis demonstrated that miR-21 5p is a significant unfavorable prognostic factor independent on other clinical variables including adjuvant chemotherapy (hazard ratio 2.95; 95% CI 1.06-8.18; p=0.038). Our preliminary data indicate promising diagnostic and prognostic utility of plasma miR-21-5p in PDAC patients. PMID- 29976638 TI - Leptin Receptor Antagonists' Action on HDAC Expression Eliminating the Negative Effects of Leptin in Ovarian Cancer. AB - BACKGROUND/AIM: A common finding in cancer cells is the overexpression of histone deacetylases (HDACs), leading to altered expression and activity of numerous proteins involved in carcinogenesis. Considering that leptin can modulate the levels of HDACs, we hypothesised that leptin receptor antagonists can alter HDAC expression. MATERIALS AND METHODS: HDAC expression in cells exposed to leptin and leptin receptor antagonists (SHLA and Lan2) were evaluated in ovarian epithelial (OVCAR-3, CaOV3) and folliculoma (COV434, KGN) cells. RESULTS: Higher HDAC expression was found in epithelial compared to folliculoma cells. Leptin increased class I and II HDACs only in OVCAR-3 cells, and SHLA was more potent then Lan-2. In folliculoma cells, leptin only increased class II HDAC expression, Lan-2 was more potent than SHLA in the COV434 and neither antagonist affected the KGN cells. CONCLUSION: SHLA and Lan2 eliminate the negative effects of leptin on HDAC expression in a cell-type-dependent manner. This is the first report testing leptin receptor blockers as HDAC inhibitors in ovarian cancer cells. PMID- 29976639 TI - Proteomic Analysis of Pelvic Autonomic Nerve in Nerve-sparing Radical Hysterectomy for Cervical Carcinoma. AB - BACKGROUND/AIM: This study was designed to identify candidate proteins which can be used for visualization of pelvic autonomic nerve during nerve-sparing surgery. MATERIALS AND METHODS: Both soft tissue and vesical branch of the inferior hypogastric nerve from five women were collected during surgery. These 10 tissue specimens were analysed using liquid chromatography-mass spectrometry (LC-MS) and Human Protein Atlas (HPA) for protein expression. The existence of nerve fibres was confirmed using haematoxylin and eosin (H&E) and anti-S-100 staining. RESULTS: A total of 413 proteins were detected. There were three proteins (isoform 1 of fibronectin, protein S100-A8 and A9) which implied a relation with pelvic autonomic nerve. In nerve tissue from one case, the existence of nerve fibre was not confirmed. CONCLUSION: Further large studies are expected to present more nerve-specific candidate proteins which can be used for the easy and safe identification of autonomic nerves. PMID- 29976640 TI - A Comprehensive Method for Detecting Fusion Genes in Paediatric Brain Tumours. AB - BACKGROUND: Fusion genes driving tumourigenesis have drawn the attention of researchers and oncologists. Despite the importance of such molecular alterations, there are no comprehensive reproducible methods for detecting fusion genes. MATERIALS AND METHODS: Nineteen paediatric brain tumours of five types, namely pilocytic astrocytoma, oligodendroglioma, anaplastic astrocytoma, glioblastoma and, ganglioglioma, were examined to detect fusion genes using a pyrosequencing-based method following RNA isolation, cDNA synthesis and real-time polymerase chain reaction. RESULTS: Our method successfully detected KIAA1549-v raf murine sarcoma viral oncogene homolog B1 (BRAF) fusion in 14 out of 19 patients suffering from five types of paediatric brain tumours providing information on fusion breakpoints within 2 h. CONCLUSION: A comprehensive method for detecting fusion genes in paediatric brain tumours was evaluated. This method identified KIAA1549-BRAF fusion variants quickly. Our results may help researchers interested in the role of fusion genes in tumourigenesis. PMID- 29976641 TI - Anti-HIV-1 Activity of Lactic Acid in Human Cervicovaginal Fluid. AB - Women of reproductive age with a Lactobacillus-dominated vaginal microbiota have a reduced risk of acquiring and transmitting HIV and a vaginal pH of ~4 due to the presence of ~1% (wt/vol) lactic acid. While lactic acid has potent HIV virucidal activity in vitro, whether lactic acid present in the vaginal lumen inactivates HIV has not been investigated. Here we evaluated the anti-HIV-1 activity of native, minimally diluted cervicovaginal fluid obtained from women of reproductive age (n = 20) with vaginal microbiota dominated by Lactobacillus spp. Inhibition of HIVBa-L was significantly associated with the protonated form of lactic acid in cervicovaginal fluid. The HIVBa-L inhibitory activity observed in the <3-kDa acidic filtrate was similar to that of the corresponding untreated native cervicovaginal fluid as well as that of clarified neat cervicovaginal fluid subjected to protease digestion. These ex vivo studies indicate that protonated lactic acid is a major anti-HIV-1 metabolite present in acidic cervicovaginal fluid, suggesting a potential role in reducing HIV transmission by inactivating virus introduced or shed into the cervicovaginal lumen.IMPORTANCE The Lactobacillus-dominated vaginal microbiota is associated with a reduced risk of acquiring and transmitting HIV and other sexually transmitted infections (STIs). Lactic acid is a major organic acid metabolite produced by lactobacilli that acidifies the vagina and has been reported to have inhibitory activity in vitro against bacterial, protozoan, and viral STIs, including HIV infections. However, the anti-HIV properties of lactic acid in native vaginal lumen fluids of women colonized with Lactobacillus spp. have not yet been established. Our study, using native cervicovaginal fluid from women, found that potent and irreversible anti-HIV-1 activity is significantly associated with the concentration of the protonated (acidic, uncharged) form of lactic acid. This work advances our understanding of the mechanisms by which vaginal microbiota modulate HIV susceptibility and could lead to novel strategies to prevent women from acquiring HIV or transmitting the virus during vaginal intercourse and vaginal birth. PMID- 29976642 TI - Sad1 Spatiotemporally Regulates Kinetochore Clustering To Ensure High-Fidelity Chromosome Segregation in the Human Fungal Pathogen Cryptococcus neoformans. AB - Kinetochore clustering, frequently observed in yeasts, plays a key role in genome organization and chromosome segregation. In the absence of the metaphase plate arrangement, kinetochore clustering in yeast species is believed to facilitate timely kinetochore-microtubule interactions to achieve bivalent attachments of chromosomes during metaphase. The factors determining the dynamics of kinetochore clustering remain largely unknown. We previously reported that kinetochores oscillate between an unclustered and a clustered state during the mitotic cell cycle in the basidiomycetous yeast Cryptococcus neoformans Based on tubulin localization patterns, while kinetochore clustering appears to be microtubule dependent, an indirect interaction of microtubules with kinetochores is expected in C. neoformans In this study, we sought to examine possible roles of the SUN KASH protein complex, known to form a bridge across the nuclear envelope, in regulating kinetochore clustering in C. neoformans We show that the SUN domain protein Sad1 localizes close to kinetochores in interphase as well as in mitotic cells. Sad1 is nonessential for viability in C. neoformans but is required for proper growth and high-fidelity chromosome segregation. Further, we demonstrate that the onset of kinetochore clustering is significantly delayed in cells lacking Sad1 compared to wild-type cells. Taken together, this study identifies a novel role of the SUN domain protein Sad1 in spatiotemporal regulation of kinetochore clustering during the mitotic cell cycle in C. neoformansIMPORTANCE The linker of nucleoskeleton and cytoskeleton (LINC) complex is present in fungi, animals, and plants. It performs diverse functions in animals, and its role(s) have recently been explored in plants. In ascomycetous yeast species, the role of the LINC complex in spindle pole body function and telomere clustering during meiosis has been determined. However, nothing is known about the LINC complex in the fungal phylum of Basidiomycota. In this study, we identified the role of the LINC complex in kinetochore dynamics as well as in nuclear migration in a basidiomycetous yeast, Cryptococcus neoformans, a human pathogen. Unlike most other yeast species, kinetochores remain unclustered during interphase but gradually cluster during mitosis in C. neoformans We report that the LINC complex is required for timely onset of kinetochore clustering and high-fidelity chromosome segregation in C. neoformans Thus, our study identifies a novel factor required for kinetochore clustering during mitosis in yeast species. PMID- 29976643 TI - Taxon-Driven Functional Shifts Associated with Storm Flow in an Urban Stream Microbial Community. AB - Urban streams are susceptible to stormwater and sewage inputs that can impact their ecological health and water quality. Microbial communities in streams play important functional roles, and their composition and metabolic potential can help assess ecological state and water quality. Although these environments are highly heterogenous, little is known about the influence of isolated perturbations, such as those resulting from rain events on urban stream microbiota. Here, we examined the microbial community composition and diversity in an urban stream during dry and wet weather conditions with both 16S rRNA gene sequencing across multiple years and shotgun metagenomics to more deeply analyze a single storm flow event. Metagenomics was used to assess population-level dynamics as well as shifts in the microbial community taxonomic profile and functional potential before and after a substantial rainfall. The results demonstrated general trends present in the stream under storm flow versus base flow conditions and also highlighted the influence of increased effluent flow following rain in shifting the stream microbial community from abundant freshwater taxa to those more associated with urban/anthropogenic settings. Shifts in the taxonomic composition were also linked to changes in functional gene content, particularly for transmembrane transport and organic substance biosynthesis. We also observed an increase in relative abundance of genes encoding degradation of organic pollutants and antibiotic resistance after rain. Overall, this study highlighted some differences in the microbial community of an urban stream under storm flow conditions and showed the impact of a storm flow event on the microbiome from an environmental and public health perspective.IMPORTANCE Urban streams in various parts of the world are facing increased anthropogenic pressure on their water quality, and storm flow events represent one such source of complex physical, chemical, and biological perturbations. Microorganisms are important components of these streams from both ecological and public health perspectives. Analysis of the effect of perturbations on the stream microbial community can help improve current knowledge on the impact such chronic disturbances can have on these water resources. This study examines microbial community dynamics during rain-induced storm flow conditions in an urban stream of the Chicago Area Waterway System. Additionally, using shotgun metagenomics we identified significant shifts in the microbial community composition and functional gene content following a high rainfall event, with potential environment and public health implications. Previous work in this area has focused on specific genes/organisms or has not assessed immediate storm flow impact. PMID- 29976645 TI - Fusobacterium Genomics Using MinION and Illumina Sequencing Enables Genome Completion and Correction. AB - Understanding the virulence mechanisms of human pathogens from the genus Fusobacterium has been hindered by a lack of properly assembled and annotated genomes. Here we report the first complete genomes for seven Fusobacterium strains, as well as resequencing of the reference strain Fusobacterium nucleatum subsp. nucleatum ATCC 25586 (total of seven species; total of eight genomes). A highly efficient and cost-effective sequencing pipeline was achieved using sample multiplexing for short-read Illumina (150 bp) and long-read Oxford Nanopore MinION (>80 kbp) platforms, coupled with genome assembly using the open-source software Unicycler. Compared to currently available draft assemblies (previously 24 to 67 contigs), these genomes are highly accurate and consist of only one complete chromosome. We present the complete genome sequence of F. nucleatum subsp. nucleatum ATCC 23726, a genetically tractable and biomedically important strain and, in addition, reveal that the previous F. nucleatum subsp. nucleatum ATCC 25586 genome assembly contains a 452-kb genomic inversion that has been corrected using our sequencing and assembly pipeline. To enable genomic analyses by the scientific community, we concurrently used these genomes to launch FusoPortal, a repository of interactive and downloadable genomic data, genome maps, gene annotations, and protein functional analyses and classifications. In summary, this report provides detailed methods for accurately sequencing, assembling, and annotating Fusobacterium genomes, while focusing on using open source software to foster the availability of reproducible and open data. This resource will enhance efforts to properly identify virulence proteins that may contribute to a repertoire of diseases that includes periodontitis, preterm birth, and colorectal cancer.IMPORTANCEFusobacterium spp. are Gram-negative, oral bacteria that are increasingly associated with human pathologies as diverse as periodontitis, preterm birth, and colorectal cancer. While a recent surge in F. nucleatum research has increased our understanding of this human pathogen, a lack of complete genomes has hindered the identification and characterization of associated host-pathogen virulence factors. Here we report the first eight complete Fusobacterium genomes sequenced using an Oxford Nanopore MinION and Illumina sequencing pipeline and assembled using the open-source program Unicycler. These genomes are highly accurate, and seven of the genomes represent the first complete sequences for each strain. In summary, the FusoPortal resource provides a publicly available resource that will guide future genetic, bioinformatic, and biochemical experiments to characterize this genus of emerging human pathogens. PMID- 29976644 TI - FusoPortal: an Interactive Repository of Hybrid MinION-Sequenced Fusobacterium Genomes Improves Gene Identification and Characterization. AB - Here we present FusoPortal, an interactive repository of Fusobacterium genomes that were sequenced using a hybrid MinION long-read sequencing pipeline, followed by assembly and annotation using a diverse portfolio of predominantly open-source software. Significant efforts were made to provide genomic and bioinformatic data as downloadable files, including raw sequencing reads, genome maps, gene annotations, protein functional analysis and classifications, and a custom BLAST server for FusoPortal genomes. FusoPortal has been initiated with eight complete genomes, of which seven were previously only drafts that ranged from 24 to 67 contigs. We have showcased that the genomes in FusoPortal provide accurate open reading frame annotations and have corrected a number of large (>3-kb) genes that were previously misannotated due to contig boundaries. In summary, FusoPortal (http://fusoportal.org) is the first database of MinION-sequenced and completely assembled Fusobacterium genomes, and this central Fusobacterium genomic and bioinformatic resource will aid the scientific community in developing a deeper understanding of how this human pathogen contributes to an array of diseases, including periodontitis and colorectal cancer.IMPORTANCE In this report, we describe a hybrid MinION whole-genome sequencing pipeline and the genomic characteristics of the first eight Fusobacterium strains deposited in the FusoPortal database. This collection of highly accurate and complete genomes drastically improves upon previous multicontig assemblies by correcting and newly identifying a significant number of open reading frames. We believe that the availability of this resource will result in the discovery of proteins and molecular mechanisms used by an oral pathogen, with the potential to further our understanding of how Fusobacterium nucleatum contributes to a repertoire of diseases, including periodontitis, preterm birth, and colorectal cancer. PMID- 29976646 TI - The 5' Untranslated Region of the EFG1 Transcript Promotes Its Translation To Regulate Hyphal Morphogenesis in Candida albicans. AB - Extensive 5' untranslated regions (UTR) are a hallmark of transcripts determining hyphal morphogenesis in Candida albicans The major transcripts of the EFG1 gene, which are responsible for cellular morphogenesis and metabolism, contain a 5' UTR of up to 1,170 nucleotides (nt). Deletion analyses of the 5' UTR revealed a 218 nt sequence that is required for production of the Efg1 protein and its functions in filamentation, without lowering the level and integrity of the EFG1 transcript. Polysomal analyses revealed that the 218-nt 5' UTR sequence is required for efficient translation of the Efg1 protein. Replacement of the EFG1 open reading frame (ORF) by the heterologous reporter gene CaCBGluc confirmed the positive regulatory importance of the identified 5' UTR sequence. In contrast to other reported transcripts containing extensive 5' UTR sequences, these results indicate the positive translational function of the 5' UTR sequence in the EFG1 transcript, which is observed in the context of the native EFG1 promoter. It is proposed that the 5' UTR recruits regulatory factors, possibly during emergence of the native transcript, which aid in translation of the EFG1 transcript.IMPORTANCE Many of the virulence traits that make Candida albicans an important human fungal pathogen are regulated on a transcriptional level. Here, we report an important regulatory contribution of translation, which is exerted by the extensive 5' untranslated regulatory sequence (5' UTR) of the transcript for the protein Efg1, which determines growth, metabolism, and filamentation in the fungus. The presence of the 5' UTR is required for efficient translation of Efg1, to promote filamentation. Because transcripts for many relevant regulators contain extensive 5' UTR sequences, it appears that the virulence of C. albicans depends on the combination of transcriptional and translational regulatory mechanisms. PMID- 29976648 TI - Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial. AB - Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1 month of zopiclone on OSA severity, sleepiness and alertness in patients with low-moderate respiratory arousal thresholds without major overnight hypoxaemia.69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea-hypopnoea index (AHI) 22+/-11 events.h-1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5 mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729).The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups ( 5.9+/-10.2 versus -2.4+/-5.5 events.h-1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different.1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology. PMID- 29976647 TI - Transporters MRP1 and MRP2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration during Streptococcus pneumoniae Lung Infection. AB - Streptococcus pneumoniae remains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we use in vitro biotinylation and neutrophil transmigration and in vivo murine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection with S. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity.IMPORTANCEStreptococcus pneumoniae is a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid in S. pneumoniae elimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia. PMID- 29976649 TI - Nonadherence with inhaled preventer therapy in severe asthmatic patients on long term omalizumab. PMID- 29976652 TI - Pharmacists and medication adherence in asthma: a systematic review and meta analysis. AB - The Lancet Asthma Commission highlighted that non-adherence remains a persistent barrier within asthma care. Medical consultations remain pivotal in addressing non-adherence, but interest in additional adherence support from pharmacists is increasing. This systematic review and meta-analysis aims to evaluate how effective pharmacist-led interventions are in improving medication adherence in adults with asthma.Studies were included if they had adult participants with asthma, pharmacist-led or collaborative care interventions, randomised controlled trial designs comparing interventions with usual pharmacist care, and a medication adherence outcome. We analysed adherence data using the standardised mean difference (d) and the remaining data were synthesised narratively.From 1159 records, 11 were included in the narrative synthesis and nine in the meta analysis. The meta-analysis for adherence produced a medium effect size of d=0.49 (se=0.08, 95% CI 0.35-0.64, p<0.0001) with low statistical heterogeneity.In line with the Perceptions and Practicalities Approach, interventions targeted to address both the perceptions and practicalities that influence individual motivation and ability to adhere were more effective. Contextual factors (country and healthcare setting) were also influential. Our findings suggest that with adequate remuneration and integration into asthma care, pharmacists can help improve adherence in asthma. PMID- 29976650 TI - Dyspnoea in patients receiving noninvasive ventilation for acute respiratory failure: prevalence, risk factors and prognostic impact: A prospective observational study. AB - Dyspnoea is a frequent and intense symptom in intubated patients, but little attention has been paid to dyspnoea during noninvasive mechanical ventilation in the intensive care unit (ICU).The objectives of this study were to quantify the prevalence, intensity and prognostic impact of dyspnoea in patients receiving noninvasive ventilation (NIV) for acute respiratory failure (ARF) based on secondary analysis of a prospective observational cohort study in patients who received ventilatory support for ARF in 54 ICUs in France and Belgium. Dyspnoea was measured by a modified Borg scale.Among the 426 patients included, the median (interquartile range) dyspnoea score was 4 (3-5) on admission and 3 (2-4) after the first NIV session (p=0.001). Dyspnoea intensity >=4 after the first NIV session was associated with the Sequential Organ Failure Assessment Score (odds ratio (OR) 1.12, p=0.001), respiratory rate (OR 1.03, p=0.032), anxiety (OR 1.92, p=0.006), leaks (OR 2.5, p=0.002) and arterial carbon dioxide tension (OR 0.98, p=0.025). Dyspnoea intensity >=4 was independently associated with NIV failure (OR 2.41, p=0.001) and mortality (OR 2.11, p=0.009), but not with higher post-ICU burden and altered quality of life.Dyspnoea is frequent and intense in patients receiving NIV for ARF and is associated with a higher risk of NIV failure and poorer outcome. PMID- 29976653 TI - REM-associated sleep apnoea: prevalence and clinical significance in the HypnoLaus cohort. AB - This study determined the prevalence of rapid eye movement (REM) related sleep disordered breathing (REM-SDB) in the general population and investigated the associations of REM-SDB with hypertension, metabolic syndrome, diabetes and depression.Home polysomnography (PSG) recordings (n=2074) from the population based HypnoLaus Sleep Cohort (48.3% men, 57+/-11 years old) were analysed. The apnoea-hypopnoea index was measured during REM and non-REM sleep (as REM-AHI and NREM-AHI, respectively). Regression models were used to explore the associations between REM-SDB and hypertension, diabetes, metabolic syndrome and depression in the entire cohort and in subgroups with NREM-AHI <10 events.h-1 and total AHI <10 events.h-1The prevalence of REM-AHI >=20 events.h-1 was 40.8% in the entire cohort. An association between increasing REM-AHI and metabolic syndrome was found in the entire cohort and in both the NREM-AHI and AHI subgroups (p trend=0.014, <0.0001 and 0.015, respectively). An association was also found between REM-AHI >=20 events.h-1 and diabetes in both the NREM-AHI <10 events.h-1 (odds ratio (OR) 3.12 (95% CI 1.35-7.20)) and AHI <10 events.h-1 (OR 2.92 (95% CI 1.12-7.63)) subgroups. Systolic and diastolic blood pressure were positively associated with REM-AHI >=20 events.h-1REM-SDB is highly prevalent in our middle to-older age sample and is independently associated with metabolic syndrome and diabetes. These findings suggest that an increase in REM-AHI could be clinically relevant. PMID- 29976654 TI - Role of C1q-binding anti-HLA antibodies as a predictor of lung allograft outcome. AB - Presence of anti-human leukocyte antigen donor-specific antibodies (DSAs) is associated with poor outcome after lung transplantation. Currently, DSAs are detected using the Luminex technique, which may be overly sensitive. The new C1q assay allows for the exclusive detection of complement (C1q)-binding antibodies, involved in antibody-mediated rejection. We investigated whether early detection of complement-binding DSAs is associated with chronic lung allograft dysfunction (CLAD) and survival.From 2009 to 2012, lung transplant recipients from three transplantation centres were screened for the presence of DSA and their complement-binding capacity during the 6-12 months post-transplantation in a stable condition.The analysis included 168 patients. The 3-year rates of freedom from CLAD and graft survival were lower for patients with complement-binding DSAs (33.6% and 53.7%, respectively), as compared with patients with non-complement binding DSAs (61.9% and 77.4%, respectively) and patients without DSA (70% and 84.9%, respectively) (p<0.001 and p=0.001, respectively). Detection of complement binding DSA was associated with a risk of graft loss that was nearly tripled after adjustment for clinical, functional, histological and immunological factors (hazard ratio 2.98, 95% CI 1.33-6.66; p=0.008).Assessment of the C1q-binding capacity of DSA appears to be useful in identifying stable lung transplant recipients at high risk of lung allograft loss. PMID- 29976655 TI - Rhinovirus is the most common virus and rhinovirus-C is the most common species in paediatric intensive care respiratory admissions. PMID- 29976656 TI - Macitentan reduces progression of TGF-beta1-induced pulmonary fibrosis and pulmonary hypertension. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease with an unknown cause. Two drugs, nintedanib and pirfenidone, have been shown to slow, but not stop, disease progression. Pulmonary hypertension (PH) is a frequent complication in IPF patients and is associated with poor prognosis. Macitentan is a dual endothelin receptor antagonist that is approved for pulmonary arterial hypertension treatment. We hypothesised that using macitentan to treat animals with pulmonary fibrosis induced by adenoviral vector encoding biologically active transforming growth factor-beta1 (AdTGF-beta1) would improve the PH caused by chronic lung disease and would limit the progression of fibrosis.Rats (Sprague Dawley) which received AdTGF-beta1 were treated by daily gavage of macitentan (100 mg.kg-1.day-1), pirfenidone (0.5% food admix) or a combination from day 14 to day 28. Pulmonary artery pressure (PAP) was measured before the rats were killed, and fibrosis was subsequently evaluated by morphometric measurements and hydroxyproline analysis.AdTGF-beta1 induced pulmonary fibrosis associated with significant PH. Macitentan reduced the increase in PAP and both macitentan and pirfenidone stopped fibrosis progression from day 14 to day 28. Macitentan protected endothelial cells from myofibroblast differentiation and apoptosis whereas pirfenidone only protected against fibroblast-to-myofibroblast differentiation. Both drugs induced apoptosis of differentiated myofibroblasts in vitro and in vivoOur results demonstrate that dual endothelin receptor antagonism was effective in both PH and lung fibrosis whereas pirfenidone only affected fibrosis. PMID- 29976651 TI - Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: a multinational point prevalence study of hospitalised patients. AB - Pseudomonas aeruginosa is a challenging bacterium to treat due to its intrinsic resistance to the antibiotics used most frequently in patients with community acquired pneumonia (CAP). Data about the global burden and risk factors associated with P. aeruginosa-CAP are limited. We assessed the multinational burden and specific risk factors associated with P. aeruginosa-CAP.We enrolled 3193 patients in 54 countries with confirmed diagnosis of CAP who underwent microbiological testing at admission. Prevalence was calculated according to the identification of P. aeruginosa Logistic regression analysis was used to identify risk factors for antibiotic-susceptible and antibiotic-resistant P. aeruginosa CAP.The prevalence of P. aeruginosa and antibiotic-resistant P. aeruginosa-CAP was 4.2% and 2.0%, respectively. The rate of P. aeruginosa CAP in patients with prior infection/colonisation due to P. aeruginosa and at least one of the three independently associated chronic lung diseases (i.e. tracheostomy, bronchiectasis and/or very severe chronic obstructive pulmonary disease) was 67%. In contrast, the rate of P. aeruginosa-CAP was 2% in patients without prior P. aeruginosa infection/colonisation and none of the selected chronic lung diseases.The multinational prevalence of P. aeruginosa-CAP is low. The risk factors identified in this study may guide healthcare professionals in deciding empirical antibiotic coverage for CAP patients. PMID- 29976657 TI - Combination Attenuation Offers Strategy for Live Attenuated Coronavirus Vaccines. AB - With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2'O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2'O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2'O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2'O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2'O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2'O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines. PMID- 29976659 TI - Ancient evolutionary origin and positive selection of the retroviral restriction factor Fv1 in muroid rodents. AB - The laboratory mouse Fv1 gene encodes a retroviral restriction factor that mediates resistance to murine leukemia viruses (MLVs). Sequence similarity between Fv1 and the gag protein of the murine endogenous retrovirus-L (MuERV-L) family of ERVs suggests that Fv1 was co-opted from an ancient provirus. Previous evolutionary studies found Fv1 orthologs only in the Mus genus. Here, we describe identification of orthologous Fv1 sequences in several species belonging to multiple families of rodents outside of the genus Mus We show that these Fv1 orthologs are in the same region of conserved synteny, between the genes Miip and Mfn2, suggesting a minimum insertion time of 45 million years for the ancient progenitor of Fv1 Our analysis also reveals that Fv1 was not detectable or heavily mutated in some lineages in the superfamily Muroidea, while, in concert with previous findings in the Mus genus, we found strong evidence of positive selection of Fv1 in the African clade in the subfamily Muridae Residues identified as evolving under positive selection include those that have been previously found to be important for restriction of multiple retroviral lineages. Taken together these findings suggest that the evolutionary origin of Fv1 substantially predates Mus evolution, that the rodent Fv1 has been shaped by lineage-specific differential selection pressures, and that Fv1 has long been evolving under positive selection in the rodent family Muridae, supporting a defensive role that significantly antedates exposure to MLVs.IMPORTANCE Retroviruses have adapted to living in concert with their hosts throughout vertebrate evolution. Over the years, the study of these relationships revealed the presence of host proteins called restriction factors that inhibit retroviral replication in host cells. The first of these restriction factors to be identified, the Fv1 gene found in mice, was thought to have originated in the genus Mus In this study, we utilized genome database searches and DNA sequencing to identify Fv1 copies in multiple rodent lineages. Our findings suggest a minimum insertion time of 45 million years into the genome of rodents for the ancestral progenitor of Fv1 While Fv1 is not detectable in some lineages, we also identified full-length orthologs showing signatures of a molecular "arms race" in a family of rodent species indigenous to Africa. This finding suggests that Fv1 in these species has been co-evolving with unidentified retroviruses for millions of years. PMID- 29976658 TI - Strand-Specific Dual RNA Sequencing of Bronchial Epithelial Cells Infected with Influenza A/H3N2 Viruses Reveals Splicing of Gene Segment 6 and Novel Host-Virus Interactions. AB - Host-influenza virus interplay at the transcript level has been extensively characterized in epithelial cells. Yet, there are no studies that simultaneously characterize human host and influenza A virus (IAV) genomes. We infected human bronchial epithelial BEAS-2B cells with two seasonal IAV/H3N2 strains, Brisbane/10/07 and Perth/16/09 (reference strains for past vaccine seasons) and the well-characterized laboratory strain Udorn/307/72. Strand-specific RNA sequencing (RNA-seq) of the infected BEAS-2B cells allowed for simultaneous analysis of host and viral transcriptomes, in addition to pathogen genomes, to reveal changes in mRNA expression and alternative splicing (AS). In general, patterns of global and immune gene expression induced by the three IAVs were mostly shared. However, AS of host transcripts and small nuclear RNAs differed between the seasonal and laboratory strains. Analysis of viral transcriptomes showed deletions of the polymerase components (defective interfering-like RNAs) within the genome. Surprisingly, we found that the neuraminidase gene undergoes AS and that the splicing event differs between seasonal and laboratory strains. Our findings reveal novel elements of the host-virus interaction and highlight the importance of RNA-seq in identifying molecular changes at the genome level that may contribute to shaping RNA-based innate immunity.IMPORTANCE The use of massively parallel RNA sequencing (RNA-seq) has revealed insights into human and pathogen genomes and their evolution. Dual RNA-seq allows simultaneous dissection of host and pathogen genomes and strand-specific RNA-seq provides information about the polarity of the RNA. This is important in the case of negative-strand RNA viruses like influenza virus, which generate positive (complementary and mRNA) and negative-strand RNAs (genome) that differ in their potential to trigger innate immunity. Here, we characterize interactions between human bronchial epithelial cells and three influenza A/H3N2 strains using strand-specific dual RNA-seq. We focused on this subtype because of its epidemiological importance in causing significant morbidity and mortality during influenza epidemics. We report novel elements that differ between seasonal and laboratory strains highlighting the complexity of the host-virus interplay at the RNA level. PMID- 29976660 TI - Upregulation of MicroRNA 711 Mediates HIV-1 Vpr Promotion of Kaposi's Sarcoma Associated Herpesvirus Latency and Induction of Pro-proliferation and Pro survival Cytokines by Targeting the Notch/NF-kappaB-Signaling Axis. AB - Coinfection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) often leads to AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The interaction between HIV and KSHV plays a pivotal role in the progression of these malignancies. We have previously demonstrated that, by upregulating miR-942-5p, HIV-1 viral protein R (Vpr) inhibits KSHV lytic replication by targeting IkappaBalpha to activate the NF-kappaB signaling (Q. Yan, C. Shen, J. Qin, W. Li, M. Hu, H. Lu, D. Qin, J. Zhu, S. J. Gao, C. Lu, J Virol 90:8739-8753, 2016). Here, we show that Vpr inactivates Notch signaling, resulting in inhibition of KSHV lytic replication and induction of pro proliferative and -survival cytokines, including interleukin-2 (IL-2), TIMP-1, IGF-1, and NT-4. Mechanistically, Vpr upregulates miR-711, which directly targets the Notch1 3' untranslated region. Suppression of miR-711 relieved Notch1 and reduced Vpr inhibition of KSHV lytic replication and Vpr induction of pro proliferation and -survival cytokines, while overexpression of miR-711 exhibited the opposite effect. Finally, overexpression of Notch1 reduced Vpr induction of NF-kappaB activity by promoting IkappaBalpha promoter activity. Our novel findings reveal that by upregulating miR-711 to target Notch1, Vpr silences Notch signaling to activate the NF-kappaB pathway by reducing IkappaBalpha expression, leading to inhibition of KSHV lytic replication and induction of pro proliferation and -survival cytokines. Therefore, the miR-711/Notch/NF-kappaB axis is important in the pathogenesis of AIDS-related malignancies and could be an attractive therapeutic target.IMPORTANCE HIV-1 infection significantly increases the risk of KS and PEL in KSHV-infected individuals. Our previous study has shown that HIV-1 Vpr regulates the KSHV life cycle by targeting IkappaBalpha to activate NF-kappaB signaling through upregulating cellular miR-942-5p. In this study, we have further found that Vpr inactivates Notch signaling to promote KSHV latency and production of pro-proliferation and -survival cytokines. Another Vpr upregulated cellular microRNA, miR-711, participates in this process by directly targeting Notch1. As a result, Notch1 upregulation of the IkappaBalpha promoter activity is attenuated, resulting in reduced levels of IkappaBalpha transcript and protein. Overall, these results illustrate an alternative mechanism of HIV-1 Vpr regulation of KSHV latency and aberrant cytokines through the miR 711/Notch/NF-kappaB axis. Our novel findings further demonstrate the role of an HIV-1-secreted regulatory protein in the KSHV life cycle and KSHV-related malignancies. PMID- 29976661 TI - Crystal Structure of the Dimerized N Terminus of Porcine Circovirus Type 2 Replicase Protein Reveals a Novel Antiviral Interface. AB - Two replicase (Rep) proteins, Rep and Rep', are encoded by porcine circovirus (PCV) ORF1; Rep is a full ORF1 transcript, and Rep' is a truncated transcript generated by splicing. These two proteins are crucial for the rolling-circle replication (RCR) of PCV. The N-terminal sequences of Rep and Rep' are identical and interact to form homo- or heterodimers. The three types of dimers perform different functions during replication. A structural examination of the interfacing termini has not been performed. In this study, a crystal structure of dimerized Rep protein N termini was resolved at 2.7 A. The dimerized protein was maintained by nine intermolecular hydrogen bonds and 15 pairs of hydrophobic interactions. The amino acid residue Ile37 participates in 11 of the hydrophobic interactions, mostly with its side chain. To find the predominant sites for protein dimerization and virus replication, a series of mutant proteins and virus replicons were generated by alanine substitution. Of all the single amino acid substitutions, the mutation at Ile37 showed the greatest effect on protein dimerization and virus replication. A double mutation at Leu35 and Ile37 almost eliminated protein dimerization and had the greatest negative effect on virus replication. These studies demonstrate that Leu35 and Ile37 are the most important residues for protein dimerization and are crucial for virus replication. Our results also show that PCV replication can be decreased by disrupting the dimerization of Rep or Rep' at the N terminus, suggesting that the structural interface responsible for dimerization offers a promising antiviral target.IMPORTANCE Porcine circovirus type 2 (PCV2) is one of the most economically damaging pathogens affecting the swine industry. Although vaccines have been available for more than 10 years, the virus still remains prevalent. More effective strategies for disease prevention are clearly required. The Rep and Rep' proteins of the virus have identical N-terminal regions that interact with each other, allowing the formation of homo- or heterodimers. The heterodimer has crucial functions during different stages of viral replication. Here, we resolved the crystal structure of the Rep (Rep') dimerization domain. The individual residues involved in the intermolecular interaction were visualized in the protein structure, and several interactions were verified by mutant analysis. Our studies show that disrupting the interaction decreases viral replication, thus revealing a new target for the design of antiviral agents. PMID- 29976662 TI - Extracellular Vesicles Released by Herpes Simplex Virus 1-Infected Cells Block Virus Replication in Recipient Cells in a STING-Dependent Manner. AB - Herpes simplex virus 1 (HSV-1)-infected cells release extracellular vesicles (EVs) that deliver to uninfected cells viral factors and host components, such as the stimulator of interferon genes (STING), which activates type I interferon upon foreign DNA sensing. The functions of EVs released by HSV-1-infected cells have remained unknown. Here, we describe a procedure to separate the EVs from HSV 1 virions that is based on an iodixanol/sucrose gradient. STING, along with the EV markers CD63 and CD9, was found in light-density fractions, while HSV components accumulated in heavy-density fractions. HSV-1 infection stimulated the release of EVs from the cells. The EVs derived from infected cells, but not from uninfected cells, activated innate immunity in recipient cells and suppressed viral gene expression and virus replication. Moreover, only the EVs derived from infected cells stimulated the expression of a subset of M1-type markers in recipient macrophages. Conversely, EVs derived from STING-knockdown cells failed to stimulate the expression of these M1-type markers, they activated innate immune responses to a lesser extent in recipient cells, and they did not sustain the inhibition of virus replication. These data suggest that STING from the EV donor cells contributes to the antiviral responses in cells receiving EVs from HSV-1-infected cells. Perturbations in the biogenesis of EVs by silencing CD63 or blocking the activity of the neutral spingomyelinase-2 (nSMase-2) increased the HSV-1 yields. Overall, our data suggest that the EVs released from HSV-1-infected cells negatively impact the infection and could control the dissemination of the virus.IMPORTANCE Extracellular vesicles (EVs) are released by all types of cells as they constitute major mechanism of intercellular communication and have the capacity to alter the functions of recipient cells despite their limited capacity for cargo. How the EVs released by HSV-infected cells could alter the surrounding microenvironment and influence the infection currently remains unknown. The cargo of EVs reflects the physiological state of the cells in which they were produced, so the content of EVs originating from infected cells is expected to be substantially different from that of healthy cells. Our studies indicate that the EVs released by HSV-1-infected cells carry innate immune components such as STING and other host and viral factors; they can activate innate immune responses in recipient cells and inhibit HSV-1 replication. The implication of these data is that the EVs released by HSV-1-infected cells could control HSV-1 dissemination promoting its persistence in the host. PMID- 29976663 TI - PARP1 Stabilizes CTCF Binding and Chromatin Structure To Maintain Epstein-Barr Virus Latency Type. AB - Epstein Barr virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is posttranslationally modified by the host enzyme PARP1. PARP1, or poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD+ onto acceptor proteins, including itself, histone proteins, and CTCF. PARylation of CTCF by PARP1 can affect CTCF's insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Thus, we predicted that pharmacological inhibition with PARP1 inhibitors would affect EBV latency type through a chromatin-specific mechanism. Here, we show that PARP1 and CTCF colocalize at specific sites throughout the EBV genome and provide evidence to suggest that PARP1 acts to stabilize CTCF binding and maintain the open chromatin landscape at the active Cp promoter during type III latency. Further, PARP1 activity is important in maintaining latency type-specific viral gene expression. The data presented here provide a rationale for the use of PARP inhibitors in the treatment of EBV-associated cancers exhibiting type III latency and ultimately could contribute to an EBV-specific treatment strategy for AIDS-related or posttransplant lymphomas.IMPORTANCE EBV is a human gammaherpesvirus that infects more than 95% of individuals worldwide. Upon infection, EBV circularizes as an episome and establishes a chronic, latent infection in B cells. In doing so, the virus utilizes host cell machinery to regulate and maintain the viral genome. In otherwise healthy individuals, EBV infection is typically nonpathological; however, latent infection is potentially oncogenic and is responsible for 1% of human cancers. During latent infection, EBV expresses specific sets of proteins according to the given latency type, each of which is associated with specific types of cancers. For example, type III latency, in which the virus expresses its full repertoire of latent proteins, is characteristic of AIDS-associated and posttransplant lymphomas associated with EBV infection. Understanding how viral latency type is regulated at the chromatin level may reveal potential targets for EBV-specific pharmacological intervention in EBV-associated cancers. PMID- 29976664 TI - The 5' Untranslated Region of the Capsid Protein 2 Gene of Mink Enteritis Virus Is Essential for Its Expression. AB - Mink enteritis virus (MEV), as a parvovirus, is among the smallest of the animal DNA viruses. The limited genome leads to multifunctional sequences and complex gene expression regulation. Here, we show that the expression of viral capsid protein 2 (VP2) of MEV requires its 5' untranslated regions (5' UTR) which promote VP2 gene expression at both transcriptional and translational levels. The expression of VP2 was inhibited in several common eukaryotic expression vectors. Our data showed that the 5' UTR of VP2 enhanced capsid gene transcription but not increased stability or promotes nucleocytoplasmic export of VP2 mRNA. Analysis of the functions of 5' UTR fragments showed that the proximal region (nucleotides [nt] 1 to 270; that is, positions +1 to +270 relative to the transcription initiation site, nt 2048 to 2317 of MEV-L) of 5' UTR of VP2 was necessary for VP2 transcription and also promoted the activity of P38 promoter. Unexpectedly, further analysis showed that deletion of the distal region (nt 271 to 653) of the 5' UTR of VP2 almost completely abolished VP2 translation in the presence of P38, whereas the transcription was still induced significantly. Furthermore, using a luciferase reporter bicistronic system, we identified that the 5' UTR had an internal ribosome entry site-like function which could be enhanced by NS1 via the site at nt 382 to 447. Mutation of the 5' UTR in the MEV full-length clones further showed that the 5' UTR was required for VP2 gene expression. Together, our data reveal an undiscovered function of 5' UTR of MEV VP2 in regulating viral gene expression.IMPORTANCE MEV, a parvovirus, causes acute enteritis in mink. In the present report, we describe an untranslated sequence-dependent mechanism by which MEV regulates capsid gene expression. Our results highlight the roles of untranslated sequences in regulating the transcriptional activity of P38 promoter and translation of capsid genes. These data also reveal the possibility of an unusual translation mechanism in capsid protein expression and the multiple functions of nonstructural protein. A better understanding of the gene expression regulation mechanism of this virus will help in the design of new vaccines and targets for antiviral agents against MEV. PMID- 29976665 TI - The Apical Region of the Herpes Simplex Virus Major Capsid Protein Promotes Capsid Maturation. AB - The herpesvirus capsid assembles in the nucleus as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown, but it is dependent upon activation of the VP24 internal protease. Scaffold cleavage triggers angularization of the shell and its decoration with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and mature angularized capsid, the apical region of the major capsid protein (VP5) is surface exposed. We investigated whether the VP5 apical region contributes to intracellular transport dynamics following entry into primary sensory neurons and also tested the hypothesis that conserved negatively charged amino acids in the apical region contribute to VP26 acquisition. To our surprise, neither hypothesis proved true. Instead, mutation of glutamic acid residues in the apical region delayed viral propagation and induced focal capsid accumulations in nuclei. Examination of capsid morphogenesis based on epitope unmasking, capsid composition, and ultrastructural analysis indicated that these clusters consisted of procapsids. The results demonstrate that, in addition to established events that occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis and maturation.IMPORTANCE Herpesviruses assemble capsids and encapsidate their genomes by a process that is unlike those of other mammalian viruses but is similar to those of some bacteriophage. Many important aspects of herpesvirus morphogenesis remain enigmatic, including how the capsid shell matures into a stable angularized configuration. Capsid maturation is triggered by activation of a protease that cleaves an internal protein scaffold. We report on the fortuitous discovery that a region of the major capsid protein that is exposed on the outer surface of the capsid also contributes to capsid maturation, demonstrating that the morphogenesis of the capsid shell from its procapsid precursor to the mature angularized form is dependent upon internal and external components of the megastructure. PMID- 29976666 TI - Hepacivirus A Infection in Horses Defines Distinct Envelope Hypervariable Regions and Elucidates Potential Roles of Viral Strain and Adaptive Immune Status in Determining Envelope Diversity and Infection Outcome. AB - Hepacivirus A (also known as nonprimate hepacivirus and equine hepacivirus) is a hepatotropic virus that can cause both transient and persistent infections in horses. The evolution of intrahost viral populations (quasispecies) has not been studied in detail for hepacivirus A, and its roles in immune evasion and persistence are unknown. To address these knowledge gaps, we first evaluated the envelope gene (E1 and E2) diversity of two different hepacivirus A strains (WSU and CU) in longitudinal blood samples from experimentally infected adult horses, juvenile horses (foals), and foals with severe combined immunodeficiency (SCID). Persistent infection with the WSU strain was associated with significantly greater quasispecies diversity than that observed in horses who spontaneously cleared infection (P = 0.0002) or in SCID foals (P < 0.0001). In contrast, the CU strain was able to persist despite significantly lower (P < 0.0001) and relatively static envelope diversity. These findings indicate that envelope diversity is a poor predictor of hepacivirus A infection outcomes and could be dependent on strain-specific factors. Next, entropy analysis was performed on all E1/E2 genes entered into GenBank. This analysis defined three novel hypervariable regions (HVRs) in E2, at residues 391 to 402 (HVR1), 450 to 461 (HVR2), and 550 to 562 (HVR3). For the experimentally infected horses, entropy analysis focusing on the HVRs demonstrated that these regions were under increased selective pressure during persistent infection. Increased diversity in the HVRs was also temporally associated with seroconversion in some horses, suggesting that these regions may be targets of neutralizing antibody and may play a role in immune evasion.IMPORTANCE Hepacivirus C (hepatitis C virus) is estimated to infect 150 million people worldwide and is a leading cause of cirrhosis and hepatocellular carcinoma. In contrast, its closest relative, hepacivirus A, causes relatively mild disease in horses and is frequently cleared. The relationship between quasispecies evolution and infection outcome has not been explored for hepacivirus A. To address this knowledge gap, we examined envelope gene diversity in horses with resolving and persistent infections. Interestingly, two strain specific patterns of quasispecies diversity emerged. Persistence of the WSU strain was associated with increased quasispecies diversity and the accumulation of amino acid changes within three novel hypervariable regions following seroconversion. These findings provided evidence that envelope gene mutation is influenced by adaptive immune pressure and may contribute to hepacivirus persistence. However, the CU strain persisted despite relative evolutionary stasis, suggesting that some hepacivirus strains may use alternative mechanisms to persist in the host. PMID- 29976667 TI - Bub1 Facilitates Virus Entry through Endocytosis in a Model of Drosophila Pathogenesis. AB - In order to establish productive infection and dissemination, viruses usually evolve a number of strategies to hijack and/or subvert the host defense systems. However, host factors utilized by the virus to facilitate infection remain poorly characterized. In this work, we found that Drosophila melanogaster deficient in budding uninhibited by benzimidazoles 1 (bub1), a highly conserved subunit of the kinetochore complex regulating chromosome congression (1), became resistant to Drosophila C virus (DCV) infection, evidenced in increased survival rates and reduced viral loads, compared to the wild-type control. Mechanistic analysis further showed that Bub1 also functioned in the cytoplasm and was essentially involved in clathrin-dependent endocytosis of DCV and other pathogens, thus limiting pathogen entry. DCV infection potentially had strengthened the interaction between Bub1 and the clathrin adaptor on the cell membrane. Furthermore, the conserved function of Bub1 was also verified in a mammalian cell line. Thus, our data demonstrated a previously unknown function of Bub1 that could be hijacked by pathogens to facilitate their infection and spread.IMPORTANCE In this work, we identify for the first time that the nuclear protein Bub1 (budding uninhibited by benzimidazoles 1), a highly conserved subunit of the kinetochore complex regulating chromosome congression, has a novel and important function on the cell membrane to facilitate the virus to enter host cells. Bub1 deficiency empowers the host to have the ability to resist viral infection in Drosophila and a human cell line. Bub1 is involved in the virus entry step through regulating endocytosis. The DCV capsid protein can recruit Bub1, and DCV infection can strengthen the interaction between Bub1 and a clathrin-dependent endocytosis component. The restricted entry of vesicular stomatitis virus (VSV) and Listeria monocytogenes in bub1-deficient flies and cell lines was also observed. Therefore, our data implicate a previously unknown function of Bub1 that can be hijacked by pathogens to facilitate their entry, and Bub1 may serve as a potential antiviral therapy target for limiting viral entry. PMID- 29976669 TI - Adenovirus E1A Activation Domain Regulates H3 Acetylation Affecting Varied Steps in Transcription at Different Viral Promoters. AB - How histone acetylation promotes transcription is not clearly understood. Here, we confirm an interaction between p300 and the adenovirus 2 large E1A activation domain (AD) and map the interacting regions in E1A by observing colocalization at an integrated lacO array of fusions of LacI-mCherry to E1A fragments with YFP p300. Viruses with mutations in E1A subdomains were constructed and analyzed for kinetics of early viral RNA expression and association of acetylated H3K9, K18, K27, TBP, and RNA polymerase II (Pol II) across the viral genome. The results indicate that this E1A interaction with p300 is required for H3K18 and H3K27 acetylation at the E2early, E3, and E4 promoters and is required for TBP and Pol II association with the E2early promoter. In contrast, H3K18/27 acetylation was not required for TBP and Pol II association with the E3 and E4 promoters but was required for E4 transcription at a step subsequent to Pol II preinitiation complex assembly.IMPORTANCE Despite a wealth of data associating promoter and enhancer region histone N-terminal tail lysine acetylation with transcriptional activity, there are relatively few examples of studies that establish causation between these histone posttranslational modifications and transcription. While hypoacetylation of histone H3 lysines 18 and 27 is associated with repression, the step(s) in the overall process of transcription that is blocked at a hypoacetylated promoter is not clearly established in most instances. Studies presented here confirm that the adenovirus 2 large E1A protein activation domain interacts with p300, as reported previously (P. Pelka, J. N. G. Ablack, J. Torchia, A. S. Turnell, R. J. A. Grand, J. S. Mymryk, Nucleic Acids Res 37:1095 1106, 2009, https://doi.org/10.1093/nar/gkn1057), and that the resulting acetylation of H3K18/27 affects varied steps in transcription at different viral promoters. PMID- 29976668 TI - Preadaptation of Simian Immunodeficiency Virus SIVsmm Facilitated Env-Mediated Counteraction of Human Tetherin by Human Immunodeficiency Virus Type 2. AB - The host restriction factor tetherin inhibits virion release from infected cells and poses a significant barrier to successful zoonotic transmission of primate lentiviruses to humans. While most simian immunodeficiency viruses (SIV), including the direct precursors of human immunodeficiency virus type 1 (HIV-1) and HIV-2, use their Nef protein to counteract tetherin in their natural hosts, they fail to antagonize the human tetherin ortholog. Pandemic HIV-1 group M and epidemic group O strains overcame this hurdle by adapting their Vpu and Nef proteins, respectively, whereas HIV-2 group A uses its envelope (Env) glycoprotein to counteract human tetherin. Whether or how the remaining eight groups of HIV-2 antagonize this antiviral factor has remained unclear. Here, we show that Nef proteins from diverse groups of HIV-2 do not or only modestly antagonize human tetherin, while their ability to downmodulate CD3 and CD4 is highly conserved. Experiments in transfected cell lines and infected primary cells revealed that not only Env proteins of epidemic HIV-2 group A but also those of a circulating recombinant form (CRF01_AB) and rare groups F and I decrease surface expression of human tetherin and significantly enhance progeny virus release. Intriguingly, we found that many SIVsmm Envs also counteract human as well as smm tetherin. Thus, Env-mediated tetherin antagonism in different groups of HIV-2 presumably stems from a preadaptation of their SIVsmm precursors to humans. In summary, we identified a phenotypic trait of SIVsmm that may have facilitated its successful zoonotic transmission to humans and the emergence of HIV-2.IMPORTANCE HIV-2 groups A to I resulted from nine independent cross-species transmission events of SIVsmm to humans and differ considerably in their prevalence and geographic spread. Thus, detailed characterization of these viruses offers a valuable means to elucidate immune evasion mechanisms and human specific adaptations determining viral spread. In a systematic comparison of rare and epidemic HIV-2 groups and their simian SIVsmm counterparts, we found that the ability of Nef to downmodulate the primary viral entry receptor CD4 and the T cell receptor CD3 is conserved, while effects on CD28, CD74, and major histocompatibility complex class I surface expression vary considerably. Furthermore, we show that not only the Env proteins of HIV-2 groups A, AB, F, and I but also those of some SIVsmm isolates antagonize human tetherin. This finding helps to explain why SIVsmm has been able to cross the species barrier to humans on at least nine independent occasions. PMID- 29976671 TI - CD32+ and PD-1+ Lymph Node CD4 T Cells Support Persistent HIV-1 Transcription in Treated Aviremic Individuals. AB - A recent study conducted in blood has proposed CD32 as the marker identifying the "elusive" HIV reservoir. We have investigated the distribution of CD32+ CD4 T cells in blood and lymph nodes (LNs) of HIV-1-uninfected subjects and viremic untreated and long-term-treated HIV-1-infected individuals and their relationship with PD-1+ CD4 T cells. The frequency of CD32+ CD4 T cells was increased in viremic compared to treated individuals in LNs, and a large proportion (up to 50%) of CD32+ cells coexpressed PD-1 and were enriched within T follicular helper (Tfh) cells. We next investigated the role of LN CD32+ CD4 T cells in the HIV reservoir. Total HIV DNA was enriched in CD32+ and PD-1+ CD4 T cells compared to CD32- and PD-1- cells in both viremic and treated individuals, but there was no difference between CD32+ and PD-1+ cells. There was no enrichment of latently infected cells with inducible HIV-1 in CD32+ versus PD-1+ cells in antiretroviral therapy (ART)-treated individuals. HIV-1 transcription was then analyzed in LN memory CD4 T cell populations sorted on the basis of CD32 and PD-1 expression. CD32+ PD-1+ CD4 T cells were significantly enriched in cell-associated HIV RNA compared to CD32- PD-1- (averages of 5.2-fold in treated individuals and 86.6 fold in viremics), CD32+ PD-1- (2.2-fold in treated individuals and 4.3-fold in viremics), and CD32- PD-1+ (2.2-fold in ART-treated individuals and 4.6-fold in viremics) cell populations. Similar levels of HIV-1 transcription were found in CD32+ PD-1- and CD32- PD-1+ CD4 T cells. Interestingly, the proportion of CD32+ and PD-1+ CD4 T cells negatively correlated with CD4 T cell counts and length of therapy. Therefore, the expression of CD32 identifies, independently of PD-1, a CD4 T cell population with persistent HIV-1 transcription and coexpression of CD32 and PD-1, the CD4 T cell population with the highest levels of HIV-1 transcription in both viremic and treated individuals.IMPORTANCE The existence of long-lived latently infected resting memory CD4 T cells represents a major obstacle to the eradication of HIV infection. Identifying cell markers defining latently infected cells containing replication-competent virus is important in order to determine the mechanisms of HIV persistence and to develop novel therapeutic strategies to cure HIV infection. We provide evidence that PD-1 and CD32 may have a complementary role in better defining CD4 T cell populations infected with HIV-1. Furthermore, CD4 T cells coexpressing CD32 and PD-1 identify a CD4 T cell population with high levels of persistent HIV-1 transcription. PMID- 29976670 TI - Localized Induction of Wild-Type and Mutant Alpha-Synuclein Aggregation Reveals Propagation along Neuroanatomical Tracts. AB - Misfolded alpha-synuclein (alphaS) may exhibit a number of characteristics similar to those of the prion protein, including the apparent ability to spread along neuroanatomical connections. The demonstration for this mechanism of spread is largely based on the intracerebral injections of preaggregated alphaS seeds in mice, in which it cannot be excluded that diffuse, surgical perturbations and hematogenous spread also contribute to the propagation of pathology. For this reason, we have utilized the sciatic nerve as a route of injection to force the inoculum into the lumbar spinal cord and induce a localized site for the onset of alphaS inclusion pathology. Our results demonstrate that mouse alphaS fibrils (fibs) injected unilaterally in the sciatic nerve are efficient in inducing pathology and the onset of paralytic symptoms in both the M83 and M20 lines of alphaS transgenic mice. In addition, a spatiotemporal study of these injections revealed a predictable spread of pathology to brain regions whose axons synapse directly on ventral motor neurons in the spinal cord, strongly supporting axonal transport as a mechanism of spread of the alphaS inducing, or seeding, factor. We also revealed a relatively decreased efficiency for human alphaS fibs containing the E46K mutation to induce disease via this injection paradigm, supportive of recent studies demonstrating a diminished ability of this mutant alphaS to undergo aggregate induction. These results further demonstrate prion-like properties for alphaS by the ability for a progression and spread of alphaS inclusion pathology along neuroanatomical connections.IMPORTANCE The accumulation of alpha-synuclein (alphaS) inclusions is a hallmark feature of Parkinson's disease (PD) and PD-related diseases. Recently, a number of studies have demonstrated similarities between the prion protein and alphaS, including its ability to spread along neuroanatomical tracts throughout the central nervous system (CNS). However, there are caveats in each of these studies in which the injection routes used had the potential to result in a widespread dissemination of the alphaS-containing inocula, making it difficult to precisely define the mechanisms of spread. In this study, we assessed the spread of pathology following a localized induction of alphaS inclusions in the lumbar spinal cord following a unilateral injection in the sciatic nerve. Using this paradigm, we demonstrated the ability for alphaS inclusion spread and/or induction along neuroanatomical tracts within the CNS of two alphaS-overexpressing mouse models. PMID- 29976673 TI - Mouse Norovirus infection reduces the surface expression of MHC class I proteins and inhibits CD8+ T cell recognition and activation. AB - Human Noroviruses are highly infectious, single stranded RNA (ssRNA) viruses and the major cause of non-bacterial gastroenteritis worldwide. With the discovery of Murine Norovirus (MNV) and the introduction of an effective model for norovirus infection and replication, knowledge about infection mechanisms and its impact on the host immune response has progressed. A major player in the immune response against viral infections is the group of major histocompatibility complex (MHC) class I proteins, which present viral antigen to immune cells. We have observed that MNV interferes with the antigen presentation pathway in infected cells by reducing the surface expression of MHC class I proteins. We have shown that MNV infected dendritic cells or macrophages have a reduced surface expression of MHC class I proteins compared to uninfected and bystander cells. Transcriptional analysis revealed that this defect is not due to decreased amount of mRNA, but is reflected at the protein level. A defect we have identified to be mediated via the MNV NS3 protein. Significantly, treatment of MNV-infected cells with the endocytic recycling inhibitor Dynasore completely restored the surface expression of MHC class I, whereas treatment with the proteasome inhibitor MG132 partly restored the surface expression of MHC class I. These observations indicate a role of endocytic recycling and proteasome-mediated degradation of the protein. Importantly, we show that due to the reduced surface expression of MHC class I proteins, antigen presentation is inhibited, resulting in the inability of CD8+ T cells to become activated in the presence of MNV infected cells.IMPORTANCE Human Noroviruses (HuNoV) are the major cause of non-bacterial gastroenteritis worldwide and cause a great burden on patients and health systems every year. So far, no antiviral treatment or vaccine is available. We show that MNV evades the host immune response by reducing the amount of MHC class I proteins displayed on the cell surface. This reduction leads to a decrease in viral antigen presentation and interferes with the CD8+ T cell response. CD8+ T cells respond to foreign antigen by activating cytotoxic pathways and inducing immune memory to the infection. By evading this immune response MNV is able to replicate efficiently in the host and cells are impaired in their ability to respond to consecutive infections. These findings have a major impact on our understanding of how Noroviruses interact with the host immune response and manipulate immune memory. PMID- 29976672 TI - Roles of the Phosphorylation of Herpes Simplex Virus 1 UL51 at a Specific Site in Viral Replication and Pathogenicity. AB - Herpes simplex virus 1 (HSV-1) UL51 is a phosphoprotein that functions in the final envelopment in the cytoplasm and viral cell-cell spread, leading to efficient viral replication in cell cultures. To clarify the mechanism by which UL51 is regulated in HSV-1-infected cells, we focused on the phosphorylation of UL51. Mass spectrometry analysis of purified UL51 identified five phosphorylation sites in UL51. Alanine replacement of one of the identified phosphorylation sites in UL51, serine 184 (Ser-184), but not the other identified phosphorylation sites, significantly reduced viral replication and cell-cell spread in HaCaT cells. This mutation induced membranous invaginations adjacent to the nuclear membrane, the accumulation of primary enveloped virions in the invaginations and perinuclear space, and mislocalized UL34 and UL31 in punctate structures at the nuclear membrane; however, it had no effect on final envelopment in the cytoplasm of HaCaT cells. Of note, the alanine mutation in UL51 Ser-184 significantly reduced the mortality of mice following ocular infection. Phosphomimetic mutation in UL51 Ser-184 partly restored the wild-type phenotype in cell cultures and in mice. Based on these results, we concluded that some UL51 functions are specifically regulated by phosphorylation at Ser-184 and that this regulation is critical for HSV-1 replication in cell cultures and pathogenicity in vivoIMPORTANCE HSV-1 UL51 is conserved in all members of the Herpesviridae family. This viral protein is phosphorylated and functions in viral cell-cell spread and cytoplasmic virion maturation in HSV-1-infected cells. Although the downstream effects of HSV-1 UL51 have been clarified, there is a lack of information on how this viral protein is regulated as well as the significance of the phosphorylation of this protein in HSV-1-infected cells. In this study, we show that the phosphorylation of UL51 at Ser-184 promotes viral replication, cell cell spread, and nuclear egress in cell cultures and viral pathogenicity in mice. This is the first report to identify the mechanism by which UL51 is regulated as well as the significance of UL51 phosphorylation in HSV-1 infection. Our study may provide insights into the regulatory mechanisms of other herpesviral UL51 homologs. PMID- 29976674 TI - DNA Polymerase Sequences of New World Monkey Cytomegaloviruses: Another Molecular Marker with Which To Infer Platyrrhini Systematics. AB - Over the past few decades, a large number of studies have identified herpesvirus sequences from many mammalian species around the world. Among the different nonhuman primate species tested so far for cytomegaloviruses (CMVs), only a few were from the New World. Seeking to identify CMV homologues in New World monkeys (NWMs), we carried out molecular screening of 244 blood DNA samples from 20 NWM species from Central and South America. Our aim was to reach a better understanding of their evolutionary processes within the Platyrrhini parvorder. Using PCR amplification with degenerate consensus primers targeting highly conserved amino acid motifs encoded by the herpesvirus DNA polymerase gene, we characterized novel viral sequences from 12 species belonging to seven genera representative of the three NWM families. BLAST searches, pairwise nucleotide and amino acid sequence comparisons, and phylogenetic analyses confirmed that they all belonged to the Cytomegalovirus genus. Previously determined host taxa allowed us to demonstrate a good correlation between the distinct monophyletic clades of viruses and those of the infected primates at the genus level. In addition, the evolutionary branching points that separate NWM CMVs were congruent with the divergence dates of their hosts at the genus level. These results significantly expand our knowledge of the host range of this viral genus and strongly support the occurrence of cospeciation between these viruses and their hosts. In this respect, we propose that NWM CMV DNA polymerase gene sequences may serve as reliable molecular markers with which to infer Platyrrhini phylogenetics.IMPORTANCE Investigating evolutionary processes between viruses and nonhuman primates has led to the discovery of a large number of herpesviruses. No study published so far on primate cytomegaloviruses has extensively studied New World monkeys (NWMs) at the subspecies, species, genus, and family levels. The present study sought to identify cytomegalovirus homologues in NWMs and to decipher their evolutionary relationships. This led us to characterize novel viruses from 12 of the 20 primate species tested, which are representative of the three NWM families. The identification of distinct viruses in these primates not only significantly expands our knowledge of the host range of this viral genus but also sheds light on its evolutionary history. Phylogenetic analyses and molecular dating of the sequences obtained support a virus-host coevolution. PMID- 29976675 TI - Vaccination with the Conserved Caveolin-1 Binding Motif in Human Immunodeficiency Virus Type 1 Glycoprotein gp41 Delays the Onset of Viral Infection and Provides Partial Protection in Simian/Human Immunodeficiency Virus-Challenged Cynomolgus Macaques. AB - We have previously reported that the CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, elicits peptide specific antibodies. Here, we have investigated the cellular immune response and the protective efficacy against a simian/human immunodeficiency virus (SHIV162P3) challenge. In addition to the CBD1 peptide, peptides overlapping the caveolin binding-motif (CBM) (622IWNNMTWMQW631 or 622IWNNMTW628) were fused to a Gag-p24 T helper epitope for vaccination. All immunized cynomolgus macaques responded to a cocktail peptide immunization by inducing specific T cells and the production of high-titer CBD1/CBM peptide-specific antibodies. Six months after the fourth vaccine boost, six control and five vaccinated animals were challenged weekly by repeated exposure to SHIV162P3 via the mucosal rectal route. All control animals were infected after 1 to 3 challenges with SHIV, while among the five vaccinated monkeys, three became infected after a delay compared to control; one was infected after the eighth viral challenge, and one remained uninfected even after the ninth SHIV challenge. Immunized animals maintained a CD4 T cell count, and their central memory CD4 T cells were less depleted than in the control group. Furthermore, SHIV challenge stimulates antigen-specific memory T cell response in vaccinated macaques. Our results indicate that peptides derived from the CBM region can be immunogenic and provide protection against SHIV infection in cynomolgus monkeys.IMPORTANCE In HIV-1-producing cells, gp41 exists in a complexed form with caveolin-1, an interaction most probably mediated by the caveolin-1 binding motif. This sequence is highly conserved in every single HIV-1 isolate, thus suggesting that there is constant selective pressure to preserve this sequence for a specific function in the HIV infectious cycle. Consequently, the CBM sequence may represent the "Achilles' heel" of HIV-1 in the development of an efficient vaccine. Our results demonstrate that macaques immunized with the CBM-based peptides displayed a delay in the onset of viral infection and CD4 depletion, as well as a significant induction of antigen-specific memory T cell response, which is essential for the control of HIV/SIV infections. Finally, as HIV-infected individuals lack anti-CBM immune responses, CBM-based vaccines could have applications as a therapeutic vaccine in AIDS patients. PMID- 29976676 TI - Feline Leukemia Virus (FeLV) Disease Outcomes in a Domestic Cat Breeding Colony: Relationship to Endogenous FeLV and Other Chronic Viral Infections. AB - Exogenous feline leukemia virus (FeLV) is a feline gammaretrovirus that results in a variety of disease outcomes. Endogenous FeLV (enFeLV) is a replication defective provirus found in species belonging to the Felis genus, which includes the domestic cat (Felis catus). There have been few studies examining interaction between enFeLV genotype and FeLV progression. We examined point-in-time enFeLV and FeLV viral loads, as well as occurrence of FeLV/enFeLV recombinants (FeLV-B), to determine factors relating to clinical disease in a closed breeding colony of cats during a natural infection of FeLV. Coinfections with feline foamy virus (FFV), feline gammaherpesvirus 1 (FcaGHV-1), and feline coronavirus (FCoV) were also documented and analyzed for impact on cat health and FeLV disease. Correlation analysis and structural equation modeling techniques were used to measure interactions among disease parameters. Progressive FeLV disease and FeLV B presence were associated with higher FeLV proviral and plasma viral loads. Female cats were more likely to have progressive disease and FeLV-B. Conversely, enFeLV copy number was higher in male cats and negatively associated with progressive FeLV disease. Males were more likely to have abortive FeLV disease. FFV proviral load was found to correlate positively with higher FeLV proviral and plasma viral load, detection of FeLV-B, and FCoV status. Male cats were much more likely to be infected with FcaGHV-1 than female cats. This analysis provides insights into the interplay between endogenous and exogenous FeLV during naturally occurring disease and reveals striking variation in the infection patterns among four chronic viral infections of domestic cats.IMPORTANCE Endogenous retroviruses are harbored by many animals, and their interactions with exogenous retroviral infections have not been widely studied. Feline leukemia virus (FeLV) is a relevant model system to examine this question, as endogenous and exogenous forms of the virus exist. In this analysis of a large domestic cat breeding colony naturally infected with FeLV, we documented that enFeLV copy number was higher in males and inversely related to FeLV viral load and associated with better FeLV disease outcomes. Females had lower enFeLV copy numbers and were more likely to have progressive FeLV disease and FeLV-B subtypes. FFV viral load was correlated with FeLV progression. FFV, FcaGHV-1, and FeLV displayed markedly different patterns of infection with respect to host demographics. This investigation revealed complex coinfection outcomes and viral ecology of chronic infections in a closed population. PMID- 29976678 TI - Probing Zika Virus Neutralization Determinants with Glycoprotein Mutants Bearing Linear Epitope Insertions. AB - Zika virus (ZIKV) glycoproteins are the primary target of the humoral immune response. In this study, we explored the capacity of these glycoproteins to tolerate insertion of linear epitope sequences and the potential of antibodies that bind these epitopes to inhibit infection. We first created a panel of ZIKV mutants with the FLAG epitope inserted in the premembrane (prM) and envelope (E) glycoprotein regions. The insertion locations were based on the results of our recent transposon insertional mutagenesis screen. Although FLAG insertions in prM greatly impaired viral fitness, this sequence was tolerated in numerous surface exposed E protein sites. We observed that mutants bearing FLAG epitopes in E domains I and II and the E domain I-II hinge region were all neutralized by FLAG antibody; however, the neutralization sensitivity varied highly. We measured the antibody binding efficiency and found that this closely matched the pattern of neutralization sensitivity. We determined that E glycosylation did not affect antibody binding to a nearby epitope or its capacity to serve as a neutralization target. Although we could not generate infectious viruses with FLAG epitope insertions in a buried region of E protein domain III, we found that the V5 epitope could be inserted at this site without greatly impacting fitness. Furthermore, this virus was efficiently neutralized by V5 antibodies, highlighting that even buried epitopes can function as neutralization targets. Finally, we analyzed the timing of antibody neutralization activity during cell entry and found that all antibodies blocked a step after cell attachment.IMPORTANCE Zika virus (ZIKV) infections are associated with severe birth defects and neurological disease. The structure of the mature ZIKV particle reveals a virion surface covered by the envelope glycoprotein, which is the dominant target of the humoral immune response. It is unclear if all regions of the envelope protein surface or even buried epitopes can function as neutralization targets. To test this, we created a panel of ZIKV mutants with epitope insertions in different regions of the envelope protein. In characterizing these viruses, we found that the strength of antibody binding to an epitope is the major determinant of the neutralization potential of an antibody, that even a buried region of the envelope protein can be efficiently targeted, and that the sole potential envelope glycan does not impact nearby epitope antibody binding and neutralization. Furthermore, this work provides important insights into our understanding of how antibodies neutralize ZIKV. PMID- 29976677 TI - Targeting the HIV-1 Spike and Coreceptor with Bi- and Trispecific Antibodies for Single-Component Broad Inhibition of Entry. AB - Protection against acquiring human immunodeficiency virus (HIV) infection may not require a vaccine in the conventional sense, because broadly neutralizing antibodies (bNAbs) alone prevent HIV infection in relevant animal challenge models. Additionally, bNAbs as therapeutics can effectively suppress HIV replication in infected humans and in animal models. Combinations of bNAbs are generally even more effective, and bNAb-derived multivalent antibody-like molecules also inhibit HIV replication both in vitro and in vivo To expand the available array of multispecific HIV inhibitors, we designed single-component molecules that incorporate two (bispecific) or three (trispecific) bNAbs that recognize HIV Env exclusively, a bispecific CrossMAb targeting two epitopes on the major HIV coreceptor, CCR5, and bi- and trispecifics that cross-target both Env and CCR5. These newly designed molecules displayed exceptional breadth, neutralizing 98 to 100% of a 109-virus panel, as well as additivity and potency compared to those of the individual parental control IgGs. The bispecific molecules, designed as tandem single-chain variable fragments (scFvs) (10E8fv N6fv and m36.4-PRO 140fv), displayed median 50% inhibitory concentration (IC50s) of 0.0685 and 0.0131 MUg/ml, respectively. A trispecific containing 10E8-PGT121 PGDM1400 Env-specific binding sites was equally potent (median IC50 of 0.0135 MUg/ml), while a trispecific molecule targeting Env and CCR5 simultaneously (10E8Fab-PGDM1400fv-PRO 140fv) demonstrated even greater potency, with a median IC50 of 0.007 MUg/ml. By design, some of these molecules lacked Fc-mediated effector function; therefore, we also constructed a trispecific prototype possessing reconstituted CH2-CH3 domains to restore Fc receptor binding capacity. The molecules developed here, along with those described previously, possess promise as prophylactic and therapeutic agents against HIV.IMPORTANCE Broadly neutralizing antibodies (bNAbs) prevent HIV infection in monkey challenge models and suppress HIV replication in infected humans. Combinations of bNAbs are more effective at suppression, and antibody-like molecules engineered to have two or three bNAb combining sites also inhibit HIV replication in monkeys and other animal models. To expand the available array of multispecific HIV inhibitors, we designed single-component molecules that incorporate two (bispecific) or three (trispecific) bNAb binding sites that recognize the HIV envelope glycoprotein (Env) or the HIV coreceptor (CCR5) or that cross-target both Env and CCR5. Several of the bi- and trispecific molecules neutralized most viruses in a diverse cross-clade panel, with greater breadth and potency than those of the individual parental bNAbs. The molecules described here provide additional options for preventing or suppressing HIV infection. PMID- 29976681 TI - Encouraging international medical students to stay in the UK. PMID- 29976679 TI - Engineered Dengue Virus Domain III Proteins Elicit Cross-Neutralizing Antibody Responses in Mice. AB - Dengue virus is the most globally prevalent mosquito-transmitted virus. Primary infection with one of four cocirculating serotypes (DENV-1 to -4) causes a febrile illness, but secondary infection with a heterologous serotype can result in severe disease, due in part to antibody-dependent enhancement of infection (ADE). In ADE, cross-reactive but nonneutralizing antibodies, or subprotective levels of neutralizing antibodies, promote uptake of antibody-opsonized virus in Fc-gamma receptor-positive cells. Thus, elicitation of broadly neutralizing antibodies (bNAbs), but not nonneutralizing antibodies, is desirable for dengue vaccine development. Domain III of the envelope glycoprotein (EDIII) is targeted by bNAbs and thus is an attractive immunogen. However, immunization with EDIII results in sera with limited neutralization breadth. We developed "resurfaced" EDIII immunogens (rsDIIIs) in which the A/G strand epitope that is targeted by bNAb 4E11 is maintained but less desirable epitopes are masked. RsDIIIs bound 4E11, but not serotype-specific or nonneutralizing antibodies. One rsDIII and, unexpectedly, wild-type (WT) DENV-2 EDIII elicited cross-neutralizing antibody responses against DENV-1 to -3 in mice. While these sera were cross-neutralizing, they were not sufficiently potent to protect AG129 immunocompromised mice at a dose of 200 MUl (50% focus reduction neutralization titer [FRNT50], ~1:60 to 1:130) against mouse-adapted DENV-2. Our results provide insight into immunogen design strategies based on EDIII.IMPORTANCE Dengue virus causes approximately 390 million infections per year. Primary infection by one serotype causes a self limiting febrile illness, but secondary infection by a heterologous serotype can result in severe dengue syndrome, which is characterized by hemorrhagic fever and shock syndrome. This severe disease is thought to arise because of cross reactive, non- or poorly neutralizing antibodies from the primary infection that are present in serum at the time of secondary infection. These cross-reactive antibodies enhance the infection rather than controlling it. Therefore, induction of a broadly and potently neutralizing antibody response is desirable for dengue vaccine development. Here, we explore a novel strategy for developing immunogens based on domain III of the E glycoprotein, where undesirable epitopes (nonneutralizing or nonconserved) are masked by mutation. This work provides fundamental insight into the immune response to domain III that can be leveraged for future immunogen design. PMID- 29976682 TI - Introduction to a Compendium on Regenerative Cardiology. PMID- 29976683 TI - Cell-Based Therapy in Cardiac Regeneration: An Overview. PMID- 29976680 TI - Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus Induced Immunosuppression. AB - AIDS-related human cytomegalovirus retinitis remains the leading cause of blindness among untreated HIV/AIDS patients worldwide. To study mechanisms of this disease, we used a clinically relevant animal model of murine cytomegalovirus (MCMV) retinitis with retrovirus-induced murine AIDS (MAIDS) that mimics the progression of AIDS in humans. We found in this model that MCMV infection significantly stimulates ocular suppressor of cytokine signaling 1 (SOCS1) and SOCS3, host proteins which hinder immune-related signaling by cytokines, including antiviral type I and type II interferons. The present study demonstrates that in the absence of retinal disease, systemic MCMV infection of mice without MAIDS, but not in mice with MAIDS, leads to mild stimulation of splenic SOCS1 mRNA. In sharp contrast, when MCMV is directly inoculated into the eyes of retinitis-susceptible MAIDS mice, high levels of intraocular SOCS1 and SOCS3 mRNA and protein are produced which are associated with significant intraocular upregulation of gamma interferon (IFN-gamma) and interleukin-6 (IL-6) mRNA expression. We also show that infiltrating macrophages, granulocytes, and resident retinal cells are sources of intraocular SOCS1 and SOCS3 protein production during development of MAIDS-related MCMV retinitis, and SOCS1 and SOCS3 mRNA transcripts are detected in retinal areas histologically characteristic of MCMV retinitis. Furthermore, SOCS1 and SOCS3 are found in both MCMV-infected cells and uninfected cells, suggesting that these SOCS proteins are stimulated via a bystander mechanism during MCMV retinitis. Taken together, our findings suggest a role for MCMV-related stimulation of SOCS1 and SOCS3 in the progression of retinal disease during ocular, but not systemic, MCMV infection.IMPORTANCE Cytomegalovirus infection frequently causes blindness in untreated HIV/AIDS patients. This virus manipulates host cells to dysregulate immune functions and drive disease. Here, we use an animal model of this disease to demonstrate that cytomegalovirus infection within eyes during retinitis causes massive upregulation of immunosuppressive host proteins called SOCS. As viral overexpression of SOCS proteins exacerbates infection with other viruses, they may also enhance cytomegalovirus infection. Alternatively, the immunosuppressive effect of SOCS proteins may be protective against immunopathology during cytomegalovirus retinitis, and in such a case SOCS mimetics or overexpression treatment strategies might be used to combat this disease. The results of this work therefore provide crucial basic knowledge that contributes to our understanding of the mechanisms of AIDS-related cytomegalovirus retinitis and, together with future studies, may contribute to the development of novel therapeutic targets that could improve the treatment or management of this sight threatening disease. PMID- 29976687 TI - Extracellular Vesicles and the Application of System Biology and Computational Modeling in Cardiac Repair. AB - Recent literature suggests that extracellular vesicles (EVs), secreted from most cells and containing cell-specific cargo of proteins, lipids, and nucleic acids, are major driver of intracellular communication in normal physiology and pathological conditions. The recent evidence on stem/progenitor cell EVs as potential therapeutic modality mimicking their parental cell function is exciting because EVs could possibly be used as a surrogate for the stem cell-based therapy, and this regimen may overcome certain roadblocks identified with the use of stem/progenitor cell themselves. This review provides a comprehensive update on our understanding on the role of EVs in cardiac repair and emphasizes the applications of stem/progenitor cell-derived EVs as therapeutics and discusses the current challenges associated with the EV therapy. PMID- 29976686 TI - Enhancement Strategies for Cardiac Regenerative Cell Therapy: Focus on Adult Stem Cells. AB - The idiom heart of the matter refers to the focal point within a topic and, with regard to health and longevity, the heart is truly pivotal for quality of life. Societal trends worldwide continue toward increased percent body fat and decreased physical activity with coincident increases in chronic diseases including cardiovascular disease as the top global cause of death along with insulin resistance, accelerated aging, cancer. Although long-term survival rates for cardiovascular disease patients are grim, intense research efforts continue to improve both prevention and treatment options. Pharmacological interventions remain the predominant interventional strategy for mitigating progression and managing symptoms, but cellular therapies have the potential to cure or even mediate remission of cardiovascular disease. Adult stem cells are the most studied cellular therapy in both preclinical and clinical investigation. This review will focus on the advanced therapeutic strategies to augment products and methods of delivery, which many think heralds the future of clinical investigations. Advanced preclinical strategies using adult stem cells are examined to promote synergism between preclinical and clinical research, streamline implementation, and improve this imminent matter of the heart. PMID- 29976688 TI - RNA Therapeutics in Cardiovascular Disease. AB - Noncoding RNAs have been shown to exert important physiological and pathophysiological functions. Various studies suggest that modulating noncoding RNAs may provide a therapeutic option. Noncoding RNAs comprise small RNAs, mainly microRNAs, and long noncoding RNAs. MicroRNAs postranscriptionally regulate gene expression pattern by binding to the 3'untranslated region of a given target mRNA, thereby blocking protein translation or inducing its degradation. Long noncoding RNAs on the contrary have more diverse functions acting as epigenetic regulators, molecular scaffolds, or decoys. In this article, we summarize examples of microRNAs and long noncoding RNAs, which might be promising novel targets for treatment of cardiovascular diseases, such as heart failure, acute myocardial infarction, fibrosis, as well as atherosclerosis. Furthermore, we give insights into the available tools to inhibit or overexpress noncoding RNAs and discuss the challenges for translation. Strategies for improving RNA therapeutics and reducing toxicity, for example, by augmenting tissue specificity or cellular uptake will be discussed. PMID- 29976684 TI - New Paradigms in Cell Therapy: Repeated Dosing, Intravenous Delivery, Immunomodulatory Actions, and New Cell Types. AB - Perhaps the most important advance in the field of cell therapy for heart disease has been the recognition that all stem/progenitor cells (both adult and embryonic) fail to engraft in the heart to a significant extent and thus work via paracrine mechanisms. This fundamental advance has led to 4 new paradigms that are discussed in this review and that may importantly shape, or even revolutionize, the future of the field: (1) repeated cell therapy, (2) intravenous cell therapy, (3) immunomodulatory actions of cell therapy, and (4) new cell types. Because virtually all of our current knowledge of cell therapy is predicated on the effects of a single cell dose, the idea that the full therapeutic effects of a cell product require repeated doses is disruptive and has far-reaching implications. For example, inadequate dosing (single-dose protocols) may be responsible, at least in part, for the borderline or disappointing results obtained to date in clinical trials; furthermore, future studies (both preclinical and clinical) may need to incorporate repeated cell administrations. Another disruptive idea, supported by emerging preclinical and clinical evidence, is that intravenously injected cells can produce beneficial effects on the heart, presumably via release of paracrine factors in extracardiac organs or endocrine factors into the systemic circulation. Intravenous administration would obviate the need for direct delivery of cells to the heart, making cell therapy simpler, cheaper, safer, more scalable, and more broadly available, even on an outpatient basis. Although the mechanism of action of cell therapy remains elusive, there is compelling in vitro evidence that transplanted cells modulate the function of various immune cell types via release of paracrine factors, such as extracellular vesicles, although in vivo evidence is still limited. Investigation of the new paradigms reviewed herein should be a top priority because it may profoundly transform cell therapy and finally make it a reality. PMID- 29976689 TI - At the Heart of Genome Editing and Cardiovascular Diseases. PMID- 29976691 TI - Can We Engineer a Human Cardiac Patch for Therapy? AB - Some of the most significant leaps in the history of modern civilization-the development of article in China, the steam engine, which led to the European industrial revolution, and the era of computers-have occurred when science converged with engineering. Recently, the convergence of human pluripotent stem cell technology with biomaterials and bioengineering have launched a new medical innovation: functional human engineered tissue, which promises to revolutionize the treatment of failing organs including most critically, the heart. This compendium covers recent, state-of-the-art developments in the fields of cardiovascular tissue engineering, as well as the needs and challenges associated with the clinical use of these technologies. We have not attempted to provide an exhaustive review in stem cell biology and cardiac cell therapy; many other important and influential reports are certainly merit but already been discussed in several recent reviews. Our scope is limited to the engineered tissues that have been fabricated to repair or replace components of the heart (eg, valves, vessels, contractile tissue) that have been functionally compromised by diseases or developmental abnormalities. In particular, we have focused on using an engineered myocardial tissue to mitigate deficiencies in contractile function. PMID- 29976692 TI - Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions. AB - Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products. PMID- 29976685 TI - New Myocyte Formation in the Adult Heart: Endogenous Sources and Therapeutic Implications. AB - Death of adult cardiac myocytes and supportive tissues resulting from cardiovascular diseases such as myocardial infarction is the proximal driver of pathological ventricular remodeling that often culminates in heart failure. Unfortunately, no currently available therapeutic barring heart transplantation can directly replenish myocytes lost from the injured heart. For decades, the field has struggled to define the intrinsic capacity and cellular sources for endogenous myocyte turnover in pursuing more innovative therapeutic strategies aimed at regenerating the injured heart. Although controversy persists to this day as to the best therapeutic regenerative strategy to use, a growing consensus has been reached that the very limited capacity for new myocyte formation in the adult mammalian heart is because of proliferation of existing cardiac myocytes but not because of the activity of an endogenous progenitor cell source of some sort. Hence, future therapeutic approaches should take into consideration the fundamental biology of myocyte renewal in designing strategies to potentially replenish these cells in the injured heart. PMID- 29976693 TI - Stem Cell Therapy for Hypoplastic Left Heart Syndrome: Mechanism, Clinical Application, and Future Directions. AB - Hypoplastic left heart syndrome is a type of congenital heart disease characterized by underdevelopment of the left ventricle, outflow tract, and aorta. The condition is fatal if aggressive palliative operations are not undertaken, but even after the complete 3-staged surgical palliation, there is significant morbidity because of progressive and ultimately intractable right ventricular failure. For this reason, there is interest in developing novel therapies for the management of right ventricular dysfunction in patients with hypoplastic left heart syndrome. Stem cell therapy may represent one such innovative approach. The field has identified numerous stem cell populations from different tissues (cardiac or bone marrow or umbilical cord blood), different age groups (adult versus neonate-derived), and different donors (autologous versus allogeneic), with preclinical and clinical experience demonstrating the potential utility of each cell type. Preclinical trials in small and large animal models have elucidated several mechanisms by which stem cells affect the injured myocardium. Our current understanding of stem cell activity is undergoing a shift from a paradigm based on cellular engraftment and differentiation to one recognizing a primarily paracrine effect. Recent studies have comprehensively evaluated the individual components of the stem cells' secretomes, shedding new light on the intracellular and extracellular pathways at the center of their therapeutic effects. This research has laid the groundwork for clinical application, and there are now several trials of stem cell therapies in pediatric populations that will provide important insights into the value of this therapeutic strategy in the management of hypoplastic left heart syndrome and other forms of congenital heart disease. This article reviews the many stem cell types applied to congenital heart disease, their preclinical investigation and the mechanisms by which they might affect right ventricular dysfunction in patients with hypoplastic left heart syndrome, and finally, the completed and ongoing clinical trials of stem cell therapy in patients with congenital heart disease. PMID- 29976690 TI - Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes as Models for Cardiac Channelopathies: A Primer for Non-Electrophysiologists. AB - Life threatening ventricular arrhythmias leading to sudden cardiac death are a major cause of morbidity and mortality. In the absence of structural heart disease, these arrhythmias, especially in the younger population, are often an outcome of genetic defects in specialized membrane proteins called ion channels. In the heart, exceptionally well-orchestrated activity of a diversity of ion channels mediates the cardiac action potential. Alterations in either the function or expression of these channels can disrupt the configuration of the action potential, leading to abnormal electrical activity of the heart that can sometimes initiate an arrhythmia. Understanding the pathophysiology of inherited arrhythmias can be challenging because of the complexity of the disorder and lack of appropriate cellular and in vivo models. Recent advances in human induced pluripotent stem cell technology have provided remarkable progress in comprehending the underlying mechanisms of ion channel disorders or channelopathies by modeling these complex arrhythmia syndromes in vitro in a dish. To fully realize the potential of induced pluripotent stem cells in elucidating the mechanistic basis and complex pathophysiology of channelopathies, it is crucial to have a basic knowledge of cardiac myocyte electrophysiology. In this review, we will discuss the role of the various ion channels in cardiac electrophysiology and the molecular and cellular mechanisms of arrhythmias, highlighting the promise of human induced pluripotent stem cell-cardiomyocytes as a model for investigating inherited arrhythmia syndromes and testing antiarrhythmic strategies. Overall, this review aims to provide a basic understanding of the electrical activity of the heart and related channelopathies, especially to clinicians or research scientists in the cardiovascular field with limited electrophysiology background. PMID- 29976694 TI - Meta-Analysis of Cell Therapy Studies in Heart Failure and Acute Myocardial Infarction. AB - Heart failure (HF) is one of the leading causes of death worldwide and has reached epidemic proportions in most industrialized nations. Despite major improvements in the treatment and management of the disease, the prognosis for patients with HF remains poor with approximately only half of patients surviving for 5 years or longer after diagnosis. The poor prognosis of HF patients is in part because of irreparable damage to cardiac tissue and concomitant maladaptive changes associated with the disease. Cell-based therapies may have the potential to transform the treatment and prognosis of HF through regeneration or repair of damaged cardiac tissue. Accordingly, numerous phase I and II randomized clinical trials have tested the clinical benefits of cell transplant, mostly autologous bone marrow-derived mononuclear cells, in patients with HF, ischemic heart disease, and acute myocardial infarction. Although many of these trials were relatively small, meta-analyses of cell-based therapies have attempted to apply rigorous statistical methodology to assess the potential clinical benefits of the intervention. As a prelude to larger phase III trials, meta-analyses, therefore, remain the obvious means of evaluating the available clinical evidence. Here, we review the different meta-analyses of randomized clinical trials that evaluate the safety and potential beneficial effect of cell therapies in HF and acute myocardial infarction spanning nearly 2 decades since the first pioneering trials were conducted. PMID- 29976695 TI - 11C-DPA-713 versus 18F-GE-180: A preclinical comparison of TSPO-PET tracers to visualize acute and chronic neuroinflammation in a mouse model of ischemic stroke. AB - Neuroinflammation plays a key role in neuronal injury following ischemic stroke. Positron emission tomography (PET) imaging of translocator protein 18 kDa (TSPO) permits longitudinal, non-invasive visualization of neuroinflammation in both pre clinical and clinical settings. Many TSPO tracers have been developed, however it is unclear which tracer is the most sensitive and accurate for monitoring the in vivo spatiotemporal dynamics of neuroinflammation across applications. Hence, there is a need for head-to-head comparisons of promising TSPO-PET tracers across different disease states. Accordingly, the aim of this study was to directly compare two promising second-generation TSPO tracers; 11C-DPA-713 and 18F-GE-180, for the first time at acute and chronic time-points following ischemic stroke. Methods: Following distal middle cerebral artery occlusion (dMCAO) or sham surgery, mice underwent consecutive PET/CT imaging with 11C-DPA-713 and 18F-GE 180 at 2, 6, and 28 days after stroke. T2-weighted magnetic resonance (MR) images were acquired to enable delineation of ipsilateral (infarct) and contralateral brain regions of interest (ROIs). PET images were analyzed by calculating % injected dose per gram (%ID/g) in MR-guided ROIs. Standardized uptake value ratios were determined using the contralateral thalamus as a pseudo-reference region (SUVTh). Ex vivo autoradiography and immunohistochemistry were performed to verify in vivo findings. Results: Significantly increased tracer uptake was observed in the ipsilateral compared to contralateral ROI (SUVTh, 50-60 min summed data) at acute and chronic time-points using 11C-DPA-713 and 18F-GE-180. Ex vivo autoradiography confirmed in vivo findings demonstrating increased TSPO tracer uptake in infarcted versus contralateral brain tissue. Importantly, a significant correlation was identified between microglial/macrophage activation (CD68 immunostaining) and 11C-DPA-713-PET signal, that was not evident with 18F GE-180. No significant correlations were observed between TSPO-PET and activated astrocytes (GFAP immunostaining). Conclusion: Both 11C-DPA-713 and 18F-GE-180-PET enable detection of neuroinflammation at early and chronic time-points following cerebral ischemia in mice. 11C-DPA-713-PET reflects the extent of microglial activation in infarcted dMCAO mouse brain tissue more accurately compared to 18F GE-180, and appears to be slightly more sensitive. These results highlight the potential of 11C-DPA-713 for tracking microglial activation in vivo after stroke, and warrants further investigation in both pre-clinical and clinical settings. PMID- 29976696 TI - Insights into Trace Metal Metabolism in Health and Disease from PET: "PET Metallomics". AB - Essential trace metals such as copper, zinc, iron, and manganese perform critical functions in cellular and physiologic processes including catalytic, regulatory, and signaling roles. Disturbed metal homeostasis is associated with the pathogenesis of diseases such as dementia, cancer, and inherited metabolic abnormalities. Intracellular pathways involving essential metals have been extensively studied but whole-body fluxes and transport between different compartments remain poorly understood. The growing availability of PET scanners and positron-emitting isotopes of key essential metals, particularly 64Cu, 63Zn, and 52Mn, provide new tools with which to study these processes in vivo. This review highlights opportunities that now present themselves, exemplified by studies of copper metabolism that are in the vanguard of a new research front in molecular imaging: "PET metallomics." PMID- 29976697 TI - 68Ga-PSMA-11 PET/CT in Primary and Recurrent Prostate Carcinoma: Implications for Radiotherapeutic Management in 121 Patients. AB - The present study analyzed the impact of Gallium-68 (68Ga)-labeled prostate specific membrane antigen-HBED-CC (68Ga-PSMA-11) positron-emission tomography (PET)/computed tomography (CT) on radiotherapeutic management in a large cohort of men with primary or recurrent disease. Methods: This study investigated 121 men with carcinoma of the prostate who underwent 68Ga-PSMA-11 PET/CT as well as conventional imaging. 50 patients were treatment naive, 11 had persistent prostate-specific antigen (PSA) soon after surgery and 60 presented with recurrent PSA following definitive therapy. Changes in TNM classification of malignant tumors (TNM) stage and radiotherapeutic management after 68Ga-PSMA-11 imaging were compared to results achieved with conventional imaging. Results: In total, a change in TNM stage and radiotherapeutic management was observed for 49 patients (40.5%) and 62 patients (51.2%), respectively. In treatment naive patients, a change in TNM stage and radiotheraeutic plan occurred in 26.0% and 44.0% of the cohort respectively. For patients with PSA persistence or recurrence, TNM and radiotherapeutic management changed in 50.7% and 56.3% respectively. Conclusion:68Ga-PSMA-11 PET/CT may shortly become an indispensable tool for detecting prostate cancer lesions in treatment-naive patients as well as in men with recurrent disease or persistent PSA and seems to be very helpful in personalizing radiotherapeutic management to the individual patients' distribution of disease. PMID- 29976698 TI - Characterization of Noise and Resolution for Quantitative 177Lu SPECT/CT with xSPECT Quant. AB - Quantitative SPECT/CT imaging forms the basis for internal dosimetry in molecular radiotherapies. While the conversion from counts to activity is typically performed based on conversion factors individually measured by each site, a recently introduced commercially available reconstruction (xSPECT Quant) offers a standardized and traceable calibration of SPECT/CT systems. The aim of this work was to assess the characteristics of xSPECT Quant in combination with 177Lu as one of the most important radionuclides used in molecular radiotherapies and to compare it to a widely used ordered subset expectation maximization reconstruction (Flash3D). Methods: In a series of 177Lu-filled phantom measurements, several important features were investigated for xSPECT Quant and Flash3D: Noise behavior and accuracy of the activity determination were evaluated in a large cylinder. Recovery coefficients were assessed in a hot-sphere phantom with and without background. Additionally, the resolutions were determined in a line source phantom as well as in a matched-filter resolution analysis of the hot sphere-cold-background phantom. Results: Both reconstruction algorithms improve the spatial resolution at the cost of noise build-up. Despite its slower convergence, Flash3D features a more efficient recovery. Although resolution recovery methods are applied within both reconstructions, partial volume errors - namely activity overestimation in the object center and spill-out of counts from the object edges - remain of relevance. In contrast to Flash3D where only the total number of updates (iterations*subsets) plays a role, the exact subdivision into iterations and subsets affected all characteristics of xSPECT Quant (optimum: 1 subset). The optimal trade-off between noise build-up and resolution improvement was found for 48 iterations and 1 subset, resulting in a quantitative accuracy of 1.2% in the Jaszczak cylinder (xSPECT Quant cross-calibrated to the dose calibrator). Conclusion: If the reconstruction parameters are chosen with care, both examined reconstructions can provide absolute quantitative SPECT images with high image quality (sub-centimeter resolution at an acceptable noise build-up) as well as high quantitative accuracy (given a well-calibrated Flash3D conversion from counts to activity concentration). With its standardized (and traceable) activity determination, xSPECT Quant dispenses with site-specific calibration protocols, enabling a reliable activity determination comparable across sites, which is especially useful for multi-centric molecular radiotherapy studies. PMID- 29976699 TI - Cats deserve more attention. PMID- 29976702 TI - What do you think of advanced level nurses? PMID- 29976700 TI - China lifts ban on UK beef imports. PMID- 29976704 TI - Should universities do more for mental health? PMID- 29976706 TI - How technology can help livestock farming. PMID- 29976708 TI - Going Dutch: a new kind of chicken farming. AB - Josh Loeb explains how a chicken farm in the Netherlands is optimising animal welfare and empowering sustainability. PMID- 29976710 TI - Disease surveillance in England and Wales, June 2018. PMID- 29976711 TI - Feline research: where have we come from and where are we going? PMID- 29976712 TI - Bacterial isolation and antimicrobial susceptibility trends: why these are important and how they can be used. PMID- 29976713 TI - Cats on farms in the United Kingdom: numbers and preventive care. PMID- 29976714 TI - Eosinophilic keratitis in horses. PMID- 29976716 TI - We need to question over treatment. PMID- 29976717 TI - Domestic cat neutering to preserve the Scottish wildcat. PMID- 29976718 TI - Why has it taken so long to improve cat care? AB - Claire Bessant argues that although great strides have been made in understanding the clinical needs of cats, the veterinary sector has been slow to make progress in improving their wellbeing in veterinary clinics, and more needs to be done to meet the welfare needs of cats. PMID- 29976719 TI - Clinicians must be humble. PMID- 29976720 TI - Why I use a cat-friendly clinic. AB - Rachael Humber explains why she thinks all cat owners should use a cat-friendly clinic. PMID- 29976733 TI - Hermit crabs (Pagurus bernhardus) use visual contrast in self-assessment of camouflage. AB - Animals can make use of camouflage to reduce the likelihood of visual detection or recognition and thus improve their chances of survival. Background matching, where body colouration is closely matched to the surrounding substrate, is one form of camouflage. Hermit crabs have the opportunity to choose their camouflage independently of body colouration as they inhabit empty gastropod shells, making them ideal to study their choice of camouflage. We used 3D-printed artificial shells of varying contrasts against a grey substrate to test whether hermit crabs prefer shells that they perceive as less conspicuous. Contrast-minimising shells were chosen for Weber contrasts stronger than -0.5. However, in looming experiments, animals responded to contrasts as weak as -0.2, indicating that while they can detect differences between shells and the background, they are only motivated to move into those shells when the alternatives contrast strongly. This suggests a trade-off between camouflage and vulnerability introduced by switching shells. PMID- 29976734 TI - Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. AB - The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment free remission in chronic myeloid leukemia patients with a deep molecular response (BCR-ABL1IS <=0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4 78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6 versus 48.6%, respectively; P=0.0126 by the log rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904). PMID- 29976735 TI - Preclinical human models and emerging therapeutics for advanced systemic mastocytosis. AB - Mastocytosis is a term used to denote a group of rare diseases characterized by an abnormal accumulation of neoplastic mast cells in various tissues and organs. In most patients with systemic mastocytosis, the neoplastic cells carry activating mutations in KIT Progress in mastocytosis research has long been hindered by the lack of suitable in vitro models, such as permanent human mast cell lines. In fact, only a few human mast cell lines are available to date: HMC 1, LAD1/2, LUVA, ROSA and MCPV-1. The HMC-1 and LAD1/2 cell lines were derived from patients with mast cell leukemia. By contrast, the more recently established LUVA, ROSA and MCPV-1 cell lines were derived from CD34+ cells of non mastocytosis donors. While some of these cell lines (LAD1/2, LUVA, ROSAKIT WT and MCPV-1) do not harbor KIT mutations, HMC-1 and ROSAKIT D816V cells exhibit activating KIT mutations found in mastocytosis and have thus been used to study disease pathogenesis. In addition, these cell lines are increasingly employed to validate new therapeutic targets and to screen for effects of new targeted drugs. Recently, the ROSAKIT D816V subclone has been successfully used to generate a unique in vivo model of advanced mastocytosis by injection into immunocompromised mice. Such a model may allow in vivo validation of data obtained in vitro with targeted drugs directed against mastocytosis. In this review, we discuss the major characteristics of all available human mast cell lines, with particular emphasis on the use of HMC-1 and ROSAKIT D816V cells in preclinical therapeutic research in mastocytosis. PMID- 29976736 TI - Radiation exposure from computerized tomography and risk of childhood leukemia: Finnish register-based case-control study of childhood leukemia (FRECCLE). AB - The only well-established risk factors for childhood leukemia are high-dose ionizing radiation and Down syndrome. Computerized tomography is a common source of low-dose radiation. In this study, we examined the magnitude of the risk of childhood leukemia after pediatric computed tomography examinations. We evaluated the association of computed tomography scans with risk of childhood leukemia in a nationwide register-based case-control study. Cases (n=1,093) were identified from the population-based Finnish Cancer Registry and three controls, matched by gender and age, were randomly selected for each case from the Population Registry. Information was also obtained on birth weight, maternal smoking, parental socioeconomic status and background gamma radiation. Data on computed tomography scans were collected from the ten largest hospitals in Finland, covering approximately 87% of all pediatric computed tomography scans. Red bone marrow doses were estimated with NCICT dose calculation software. The data were analyzed using exact conditional logistic regression analysis. A total of 15 cases (1.4%) and ten controls (0.3%) had undergone one or more computed tomography scans, excluding a 2-year latency period. For one or more computed tomography scans, we observed an odds ratio of 2.82 (95% confidence interval: 1.05 - 7.56). Cumulative red bone marrow dose from computed tomography scans showed an excess odds ratio of 0.13 (95% confidence interval: 0.02 - 0.26) per mGy. Our results are consistent with the notion that even low doses of ionizing radiation observably increase the risk of childhood leukemia. However, the observed risk estimates are somewhat higher than those in earlier studies, probably due to random error, although unknown predisposing factors cannot be ruled out. PMID- 29976737 TI - Idelalisib impairs T-cell-mediated immunity in chronic lymphocytic leukemia. PMID- 29976738 TI - Trisomy 12 chronic lymphocytic leukemia expresses a unique set of activated and targetable pathways. AB - Although +12 chronic lymphocytic leukemia comprises about 20% of cases, relatively little is known about its pathophysiology. These cases often demonstrate atypical morphologic and immunophenotypic features, high proliferative rates, unmutated immunoglobulin heavy chain variable region genes, and a high frequency of NOTCH1 mutation. Patients with +12 chronic lymphocytic leukemia have an intermediate prognosis, and show higher incidences of thrombocytopenia, Richter's transformation, and other second cancers. Despite these important differences, relatively few transcriptional profiling studies have focused on identifying dysregulated pathways that characterize +12 chronic lymphocytic leukemia, and most have used a hierarchical cytogenetic classification in which cases with more than one recurrent abnormality are categorized according to the abnormality with the poorest prognosis. In this study, we sought to identity protein-coding genes whose expression contributes to the unique pathophysiology of +12 chronic lymphocytic leukemia. To exclude the likely confounding effects of multiple cytogenetic abnormalities on gene expression, our +12 patient cohort had +12 as the sole abnormality. We profiled samples obtained from 147 treatment-naive patients. We compared cases with +12 as the sole cytogenetic abnormality to cases with sole del(13q), del(11q), or diploid cytogenetics using independent discovery (n=97) and validation (n=50) sets. We demonstrate that chronic lymphocytic leukemia cases with +12 as the sole abnormality express a unique set of activated pathways compared to other cytogenetic subtypes. Among these pathways, we identify the NFAT signaling pathways and the immune checkpoint molecule, NT5E (CD73), which may represent new therapeutic targets. PMID- 29976739 TI - Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the YARS2 gene. PMID- 29976740 TI - Transmission of diffuse large B cell lymphoma by an allogeneic stem-cell transplant. PMID- 29976741 TI - Development of angiotensin II (1-7) analog as an oral therapeutic for the treatment of chemotherapy-induced myelosuppression. PMID- 29976742 TI - Novel lineage depletion preserves autologous blood stem cells for gene therapy of Fanconi anemia complementation group A. AB - A hallmark of Fanconi anemia is accelerated decline in hematopoietic stem and progenitor cells (CD34 +) leading to bone marrow failure. Long-term treatment requires hematopoietic cell transplantation from an unaffected donor but is associated with potentially severe side-effects. Gene therapy to correct the genetic defect in the patient's own CD34+ cells has been limited by low CD34+ cell numbers and viability. Here we demonstrate an altered ratio of CD34Hi to CD34Lo cells in Fanconi patients relative to healthy donors, with exclusive in vitro repopulating ability in only CD34Hi cells, underscoring a need for novel strategies to preserve limited CD34+ cells. To address this need, we developed a clinical protocol to deplete lineage+(CD3+, CD14+, CD16+ and CD19+) cells from blood and marrow products. This process depletes >90% of lineage+cells while retaining >=60% of the initial CD34+cell fraction, reduces total nucleated cells by 1-2 logs, and maintains transduction efficiency and cell viability following gene transfer. Importantly, transduced lineage- cell products engrafted equivalently to that of purified CD34+ cells from the same donor when xenotransplanted at matched CD34+ cell doses. This novel selection strategy has been approved by the regulatory agencies in a gene therapy study for Fanconi anemia patients (NCI Clinical Trial Reporting Program Registry ID NCI-2011-00202; clinicaltrials.gov identifier: 01331018). PMID- 29976743 TI - Safety of obinutuzumab alone or combined with chemotherapy for previously untreated or relapsed/refractory chronic lymphocytic leukemia in the phase IIIb GREEN study. AB - The safety of obinutuzumab, alone or with chemotherapy, was studied in a non randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade >=3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade >=3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade >=3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943). PMID- 29976744 TI - Prognostic factors of Erdheim-Chester disease: a nationwide survey in Japan. AB - Erdheim-Chester disease is a rare histiocytosis with insufficient clinical data. To clarify the clinical features and prognostic factors of Erdheim-Chester disease, we conducted a nationwide survey to collect the detailed data of 44 patients with Erdheim-Chester disease in Japan. The median age of onset of the participants was 51 (range: 23-76) years, and the median number of involved organs per patient was 4 (range: 1-11). The existence of central nervous system disease was correlated with older age (P=0.033), the presence of cardiovascular lesions (P=0.015), and an increased number of involved organs (P=0.0042). The median survival from the onset was 10.4 years, and >3.0 mg/dL C-reactive protein level at onset was associated with worse outcome (median survival, 14.6 vs. 7.4 years; P=0.0016). In a multivariate analysis, age >60 years (hazard ratio, 25.9; 95% confidence interval, 2.82-237; P=0.0040) and the presence of digestive organ involvement (hazard ratio, 4.74; 95% confidence interval, 1.05-21.4; P=0.043) were correlated with worse survival. Fourteen patients had available histological samples of Erdheim- Chester disease lesions. BRAFV600E mutation was detected in 11 patients (78%) by Sanger sequencing. A correlation between BRAF mutation status and clinical factors was not observed. Our study revealed that age and digestive organ involvement influence the outcome of Erdheim-Chester disease patients, and an inflammatory marker, such as C-reactive protein, might reflect the activity of this inflammatory myeloid neoplasm. PMID- 29976745 TI - BCR-ABL1 genomic DNA PCR response kinetics during first-line imatinib treatment of chronic myeloid leukemia. AB - Accurate quantification of minimal residual disease during treatment of chronic myeloid leukaemia guides clinical decisions. The conventional minimal residual disease method, RQ-PCR for BCR-ABL1 mRNA, reflects a composite of the number of circulating leukemic cells and the BCR-ABL1 transcripts per cell. BCR-ABL1 genomic DNA only reflects leukemic cell number. We used both methods in parallel to determine the relative contribution of the leukemic cell number to molecular response. BCR-ABL1 DNA PCR and RQ-PCR were monitored up to 24 months in 516 paired samples from 59 newly-diagnosed patients treated with first-line imatinib in the TIDEL-II study. In the first 3 months of treatment BCR-ABL1 mRNA values declined more rapidly than DNA. By 6 months the two measures aligned closely. The expression of BCR-ABL1 mRNA was normalized to cell number to generate an expression ratio. The expression of e13a2 BCR-ABL1 was lower than that of e14a2 transcripts at multiple time points during treatment. BCR-ABL1 DNA was quantifiable in 48% of samples with undetectable BCR-ABL1 mRNA, resulting in minimal residual disease being quantifiable for an additional 5-18 months (median 12 months). These parallel studies show for the first time that the rapid decline in BCR-ABL1 mRNA over the first 3 months of treatment is due to a reduction in both cell number and transcript level per cell, whereas beyond 3 months falling levels of BCR-ABL1 mRNA are predominantly due to depletion of leukaemic cells. PMID- 29976746 TI - Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. AB - As part of the UK NCRI AML17 trial, adult patients with acute myeloid leukemia in remission could be randomized to receive the mammalian target of rapamycin inhibitor everolimus, sequentially with post-induction chemotherapy. Three hundred and thirty-nine patients were randomised (2:1) to receive everolimus or not for a maximum of 84 days between chemotherapy courses. The primary endpoint was relapse-free survival. At 5 years there was no difference in relapse-free survival [29% versus 40%; odds ratio 1.19 (0.9-1.59) P=0.2], cumulative incidence of relapse [60% versus 54%: odds ratio 1.12 (0.82-1.52): P=0.5] or overall survival [45% versus 58%: odds ratio 1.3 (0.94-1.81): P=0.11]. The independent Data Monitoring Committee advised study termination after randomization of 339 of the intended 600 patients because of excess mortality in the everolimus arm without any evidence of beneficial disease control. The delivery of the everolimus dose was variable, but there was no evidence of clinical benefit in patients with adequate dose delivery compared with no treatment. This study suggests that the addition of mammalian target of rapamycin inhibition to chemotherapy provides no benefit. PMID- 29976747 TI - MDM2- and FLT3-inhibitors in the treatment of FLT3-ITD acute myeloid leukemia, specificity and efficacy of NVP-HDM201 and midostaurin. AB - Prognosis for FLT3-ITD positive acute myeloid leukemia with high allelic ratio (>0.5) is poor, particularly in relapse, refractory to or unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting both the mutated FLT3 receptor and cellular p53 inhibitors might be a promising treatment option for this poor risk leukemia subset. We therefore assessed MDM2 and FLT3 inhibitors as well as cytotoxic compounds used for conventional induction treatment as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. Acute myeloid leukemia cells represented all major morphologic and molecular subtypes with normal karyotype, including FLT3-ITD (>0.5) and FLT3 wild type, NPM1 mutant and NPM1 wild type, as well as TP53 mutant and TP53 wild type cell lines. Acute myeloid leukemia cells with mutated or deleted TP53 were resistant to MDM2- and FLT3-inhibitors. FLT3-ITD positive TP53 wild type acute myeloid leukemia cells were significantly more susceptible to FLT3-inhibitors than FLT3-ITD negative TP53 wild type cells. The presence of a NPM1 mutation reduced the susceptibility of TP53 wild type acute myeloid leukemia cells to the MDM2 inhibitor NVP-HDM201. Moreover, the combined use of MDM2- and FLT3 inhibitors was superior to single agent treatment, and the combination of midostaurin and NVP-HDM201 was as specific and effective against FLT3-ITD positive TP53 wild type cells as the combination of midostaurin with conventional induction therapy. In summary, the combined use of the MDM2 inhibitor NVP-HDM201 and the FLT3 inhibitor midostaurin was a most effective and specific treatment to target TP53 and NPM1 wild type acute myeloid leukemia cells with high allelic FLT3-ITD ratio. These data suggest that the combined use of NVP-HDM201 and midostaurin might be a promising treatment option particularly in FLT3-ITD positive acute myeloid leukemia relapsed or refractory to conventional therapy. PMID- 29976748 TI - CD16+NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice. AB - Patients with acute myeloid leukemia (AML) often relapse after initial therapy because of persistence of leukemic stem cells that frequently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16+ NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxicity; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell-mediated cytotoxicity, which we utilized in combination with an anti-CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16+ NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cytotoxicity against CD123+ leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16+NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradiated CD16+NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16+NK-92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML. PMID- 29976751 TI - Skin cancer: smartphone diagnostic apps may offer false reassurance, warn dermatologists. PMID- 29976749 TI - Traumatic knee pain in a child. PMID- 29976752 TI - Discovery and engineering of enhanced SUMO protease enzymes. AB - Small ubiquitin-like modifier (SUMO) is commonly used as a protein fusion domain to facilitate expression and purification of recombinant proteins, and a SUMO specific protease is then used to remove SUMO from these proteins. Although this protease is highly specific, its limited solubility and stability hamper its utility as an in vitro reagent. Here, we report improved SUMO protease enzymes obtained via two approaches. First, we developed a computational method and used it to re-engineer WT Ulp1 from Saccharomyces cerevisiae to improve protein solubility. Second, we discovered an improved SUMO protease via genomic mining of the thermophilic fungus Chaetomium thermophilum, as proteins from thermophilic organisms are commonly employed as reagent enzymes. Following expression in Escherichia coli, we found that these re-engineered enzymes can be more thermostable and up to 12 times more soluble, all while retaining WT-or-better levels of SUMO protease activity. The computational method we developed to design solubility-enhancing substitutions is based on the RosettaScripts application for the macromolecular modeling suite Rosetta, and it is broadly applicable for the improvement of solution properties of other proteins. Moreover, we determined the X-ray crystal structure of a SUMO protease from C. thermophilum to 1.44 A resolution. This structure revealed that this enzyme exhibits structural and functional conservation with the S. cerevisiae SUMO protease, despite exhibiting only 28% sequence identity. In summary, by re-engineering the Ulp1 protease and discovering a SUMO protease from C. thermophilum, we have obtained proteases that are more soluble, more thermostable, and more efficient than the current commercially available Ulp1 enzyme. PMID- 29976753 TI - N6-Methyladenosine-binding proteins suppress HIV-1 infectivity and viral production. AB - The internal N6-methyladenosine (m6A) modification of cellular mRNA regulates post-transcriptional gene expression. The YTH domain family proteins (YTHDF1-3 or Y1-3) bind to m6A-modified cellular mRNAs and modulate their metabolism and processing, thereby affecting cellular protein translation. We previously reported that HIV-1 RNA contains the m6A modification and that Y1-3 proteins inhibit HIV-1 infection by decreasing HIV-1 reverse transcription activity. Here, we investigated the mechanisms of Y1-3-mediated inhibition of HIV-1 infection in target cells and the effect of Y1-3 on viral production levels in virus-producing cells. We found that Y1-3 protein overexpression in HIV-1 target cells decreases viral genomic RNA (gRNA) levels and inhibits both early and late reverse transcription. Purified recombinant Y1-3 proteins preferentially bound to the m6A modified 5' leader sequence of gRNA compared with its unmodified RNA counterpart, consistent with the strong binding of Y1-3 proteins to HIV-1 gRNA in infected cells. HIV-1 mutants with two altered m6A modification sites in the 5' leader sequence of gRNA exhibited significantly lower infectivity than WT, replication competent HIV-1, confirming that these sites alter viral infection. HIV-1 produced from cells in which endogenous Y1, Y3, or Y1-3 proteins were knocked down singly or together had increased viral infectivity compared with HIV-1 produced in control cells. Interestingly, we found that Y1-3 proteins and HIV-1 Gag protein formed a complex with RNA in HIV-1-producing cells. Overall, these results indicate that Y1-3 proteins inhibit HIV-1 infection and provide new insights into the mechanisms by which the m6A modification of HIV-1 RNA affects viral replication. PMID- 29976754 TI - Structural basis of VHH-mediated neutralization of the food-borne pathogen Listeria monocytogenes. AB - Listeria monocytogenes causes listeriosis, a potentially fatal food-borne disease. The condition is especially harmful to pregnant women. Listeria outbreaks can originate from diverse foods, highlighting the need for novel strategies to improve food safety. The first step in Listeria invasion is internalization of the bacteria, which is mediated by the interaction of the internalin family of virulence factors with host cell receptors. A crucial interaction for Listeria invasion of the placenta, and thus a target for therapeutic intervention, is between internalin B (InlB) and the receptor c-Met. Single-domain antibodies (VHH, also called nanobodies, or sdAbs) from camel heavy chain antibodies are a novel solution for preventing Listeria infections. The VHH R303, R330, and R326 all bind InlB with high affinity; however, the molecular mechanism behind their mode of action was unknown. We demonstrate that despite a high degree of sequence and structural diversity, the VHH bind a single epitope on InlB. A combination of gentamicin protection assays and florescent microscopy establish that InlB-specific VHH inhibit Listeria invasion of HeLa cells. A high resolution X-ray structure of VHH R303 in complex with InlB showed that the VHH binds at the c-Met interaction site on InlB, thereby acting as a competitive inhibitor preventing bacterial invasion. These results point to the potential of VHH as a novel class of therapeutics for the prevention of listeriosis. PMID- 29976755 TI - TMPRSS11A activates the influenza A virus hemagglutinin and the MERS coronavirus spike protein and is insensitive against blockade by HAI-1. AB - The influenza virus hemagglutinin (HA) facilitates viral entry into target cells. Cleavage of HA by host cell proteases is essential for viral infectivity, and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease (TTSP) TMPRSS2 has been identified as an HA activator in cell culture and in the infected host. However, it is less clear whether TMPRSS2-related enzymes can also activate HA for spread in target cells. Moreover, the activity of cellular serine protease inhibitors against HA activating TTSPs is poorly understood. Here, we show that TMPRSS11A, another member of the TTSP family, cleaves and activates the influenza A virus (FLUAV) HA and the Middle East respiratory syndrome coronavirus spike protein (MERS-S). Moreover, we demonstrate that TMPRSS11A is expressed in murine tracheal epithelium, which is a target of FLUAV infection, and in human trachea, suggesting that the protease could support FLUAV spread in patients. Finally, we show that HA activation by the TMPRSS11A-related enzymes human airway tryptase and DESC1, but not TMPRSS11A itself, is blocked by the cellular serine protease inhibitor hepatocyte growth factor activator inhibitor type-1 (HAI-1). Our results suggest that TMPRSS11A could promote FLUAV spread in target cells and that HA-activating TTSPs exhibit differential sensitivity to blockade by cellular serine protease inhibitors. PMID- 29976757 TI - Interaction via the N terminus of the type IV secretion system (T4SS) protein VirB6 with VirB10 is required for VirB2 and VirB5 incorporation into T-pili and for T4SS function. AB - Many bacterial pathogens employ multicomponent protein complexes such as type IV secretion systems (T4SSs) to transfer virulence factors into host cells. Here we studied the interaction between two essential T4SS components: the very hydrophobic inner membrane protein VirB6, which may be a component of the translocation channel, and VirB10, which links the inner and outer bacterial membranes. To map the interaction site between these two T4SS components, we conducted alanine scanning and deleted six-amino acid stretches from the N terminal periplasmic domain of VirB6 from Brucella suis Using the bacterial two hybrid system to analyze the effects of these alterations on the VirB6-VirB10 interaction, we identified the amino acid regions 16-21 and 28-33 and Leu-18 in VirB6 as being required for this interaction. SDS-PAGE coupled with Western blotting of cell lysates and native PAGE of detergent-extracted membrane proteins revealed that the corresponding VirB6 residues in Agrobacterium tumefaciens (Phe 20 and amino acids 18-23 and 30-35) modulate the stability of both VirB6 and VirB5. However, the results from immuno-EM and super-resolution microscopy suggested that these regions and residues are not required for membrane association or for polar localization of VirB6. The six-amino acid deletions in the N terminus of VirB6 abolished pilus formation and virulence of A. tumefaciens, and the corresponding deletions in the VirB6 homolog TraD from the plasmid pKM101-T4SS abrogated plasmid transfer. Our results indicate that specific residues of the VirB6 N-terminal domain are required for VirB6 stabilization, its interaction with VirB10, and the incorporation of VirB2 and VirB5 into T-pili. PMID- 29976756 TI - Legionella pneumophila effector Lem4 is a membrane-associated protein tyrosine phosphatase. AB - Legionella pneumophila is a Gram-negative pathogenic bacterium that causes severe pneumonia in humans. It establishes a replicative niche called Legionella containing vacuole (LCV) that allows bacteria to survive and replicate inside pulmonary macrophages. To hijack host cell defense systems, L. pneumophila injects over 300 effector proteins into the host cell cytosol. The Lem4 effector (lpg1101) consists of two domains: an N-terminal haloacid dehalogenase (HAD) domain with unknown function and a C-terminal phosphatidylinositol 4-phosphate binding domain that anchors Lem4 to the membrane of early LCVs. Herein, we demonstrate that the HAD domain (Lem4-N) is structurally similar to mouse MDP-1 phosphatase and displays phosphotyrosine phosphatase activity. Substrate specificity of Lem4 was probed using a tyrosine phosphatase substrate set, which contained a selection of 360 phosphopeptides derived from human phosphorylation sites. This assay allowed us to identify a consensus pTyr-containing motif. Based on the localization of Lem4 to lysosomes and to some extent to plasma membrane when expressed in human cells, we hypothesize that this protein is involved in protein-protein interactions with an LCV or plasma membrane-associated tyrosine phosphorylated host target. PMID- 29976758 TI - Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks. AB - During the biosynthesis of chondroitin/dermatan sulfate (CS/DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two epimerases, dermatan sulfate epimerases 1 (DS-epi1) and 2 (DS-epi2). Previous in vitro studies indicated that without association with other enzymes, DS-epi1 activity produces structures that have only a few adjacent iduronic acid units. In vivo, concomitant with epimerization, dermatan 4-O-sulfotransferase 1 (D4ST1) sulfates the GalNAc adjacent to iduronic acid. This sulfation facilitates DS-epi1 activity and enables the formation of long blocks of sulfated iduronic acid-containing domains, which can be major components of CS/DS. In this report, we used recombinant enzymes to confirm the concerted action of DS-epi1 and D4ST1. Confocal microscopy revealed that these two enzymes colocalize to the Golgi, and FRET experiments indicated that they physically interact. Furthermore, FRET, immunoprecipitation, and cross-linking experiments also revealed that DS-epi1, DS epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. In conclusion, the iduronic acid-forming enzymes operate in complexes, similar to other enzymes active in glycosaminoglycan biosynthesis. This knowledge shed light on regulatory mechanisms controlling the biosynthesis of the structurally diverse CS/DS molecule. PMID- 29976759 TI - High-density lipoprotein inhibits serum amyloid A-mediated reactive oxygen species generation and NLRP3 inflammasome activation. AB - Serum amyloid A (SAA) is a high-density apolipoprotein whose plasma levels can increase more than 1000-fold during a severe acute-phase inflammatory response and are more modestly elevated in chronic inflammation. SAA is thought to play important roles in innate immunity, but its biological activities have not been completely delineated. We previously reported that SAA deficiency protects mice from developing abdominal aortic aneurysms (AAAs) induced by chronic angiotensin II (AngII) infusion. Here, we report that SAA is required for AngII-induced increases in interleukin-1beta (IL-1beta), a potent proinflammatory cytokine that is tightly controlled by the Nod-like receptor protein 3 (NLRP3) inflammasome and caspase-1 and has been implicated in both human and mouse AAAs. We determined that purified SAA stimulates IL-1beta secretion in murine J774 and bone marrow derived macrophages through a mechanism that depends on NLRP3 expression and caspase-1 activity, but is independent of P2X7 nucleotide receptor (P2X7R) activation. Inhibiting reactive oxygen species (ROS) by N-acetyl-l-cysteine or mito-TEMPO and inhibiting activation of cathepsin B by CA-074 blocked SAA mediated inflammasome activation and IL-1beta secretion. Moreover, inhibiting cellular potassium efflux with glyburide or increasing extracellular potassium also significantly reduced SAA-mediated IL-1beta secretion. Of note, incorporating SAA into high-density lipoprotein (HDL) prior to its use in cell treatments completely abolished its ability to stimulate ROS generation and inflammasome activation. These results provide detailed insights into SAA mediated IL-1beta production and highlight HDL's role in regulating SAA's proinflammatory effects. PMID- 29976760 TI - 'In a blink of an eye your life can change': experiences of players sustaining a rugby-related acute spinal cord injury. AB - BACKGROUND: Though rare, rugby union carries a risk for serious injuries such as acute spinal cord injuries (ASCI), which may result in permanent disability. Various studies have investigated injury mechanisms, prevention programmes and immediate medical management of these injuries. However, relatively scant attention has been placed on the player's experience of such an injury and the importance of context. AIM: The aim of this study was to explore the injury experience and its related context, as perceived by the catastrophically injured player. METHODS: A qualitative approach was followed to explore the immediate, postevent injury experience. Semi-structured interviews were conducted with 48 (n=48) players who had sustained a rugby-related ASCI. RESULTS: Four themes were derived from the data. Participants described the context around the injury incident, which may be valuable to help understand the mechanism of injury and potentially minimise risk. Participants also described certain contributing factors to their injury, which included descriptions of foul play and aggression, unaccustomed playing positions, pressure to perform and unpreparedness. The physical experience included signs and symptoms of ASCI that is important to recognise by first aiders, fellow teammates, coaches and referees. Lastly, participants described the emotional experience which has implications for all ASCI first responders. SIGNIFICANCE: All rugby stakeholders, including players, first responders, coaches and referees, may gain valuable information from the experiences of players who have sustained these injuries. This information is also relevant for rugby safety initiatives in shaping education and awareness interventions. PMID- 29976763 TI - Dozens of US doctors charged in "historic" fraud crackdown. PMID- 29976762 TI - Lateral plasma membrane compartmentalization links protein function and turnover. AB - Biological membranes organize their proteins and lipids into nano- and microscale patterns. In the yeast plasma membrane (PM), constituents segregate into a large number of distinct domains. However, whether and how this intricate patchwork contributes to biological functions at the PM is still poorly understood. Here, we reveal an elaborate interplay between PM compartmentalization, physiological function, and endocytic turnover. Using the methionine permease Mup1 as model system, we demonstrate that this transporter segregates into PM clusters. Clustering requires sphingolipids, the tetraspanner protein Nce102, and signaling through TORC2. Importantly, we show that during substrate transport, a simple conformational change in Mup1 mediates rapid relocation into a unique disperse network at the PM Clustered Mup1 is protected from turnover, whereas relocated Mup1 actively recruits the endocytic machinery thereby initiating its own turnover. Our findings suggest that lateral compartmentalization provides an important regulatory link between function and turnover of PM proteins. PMID- 29976764 TI - FDA advisers were paid $10 000 to $1.9m for future industry work. PMID- 29976765 TI - Gene Regulatory Variation in Drosophila melanogaster Renal Tissue. AB - Genetic variation influencing levels of gene expression is abundant in natural populations, and may exert its effects through complex mechanisms that depend on an organism's genetic background and the tissue in which expression is measured. We investigated natural variation in gene expression in the Malpighian tubules of three inbred Drosophila melanogaster strains and their F1 hybrids. One of the strains was from a population in the species' ancestral range (Zambia), while the other two were from a more recently derived population (Sweden). Although closely related, the two Swedish strains differed greatly in terms of their expression inheritance when hybridized with the Zambian strain, with one Swedish strain showing a large excess of genes with recessive expression inheritance, as well as a large number of genes with overdominant inheritance. Although most expression variation could be attributed to trans-regulation, there were ~200 genes that showed allele-specific expression differences in each of the between-population hybrids, indicating that cis-regulation contributes as well. The cis-regulated genes were enriched with cytochrome P450 genes, and the upstream regions of six of these genes were incorporated into transgenic reporter gene constructs to test their effects on expression. Differential expression was observed for five of the six reporter genes in the Malpighian tubule, suggesting that a large proportion of cis-regulatory variation lies directly upstream of the affected gene. In most cases, the differential expression was specific to the Malpighian tubule or greater in this tissue than in the rest of the body, highlighting the importance of single-tissue studies of gene expression variation. PMID- 29976761 TI - Proteolytic ectodomain shedding of membrane proteins in mammals-hardware, concepts, and recent developments. AB - Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery. PMID- 29976767 TI - MicroRNA-199a-3p and MicroRNA-199a-5p Take Part to a Redundant Network of Regulation of the NOS (NO Synthase)/NO Pathway in the Endothelium. AB - Objective- Members of the microRNA (miR)-199a family, namely miR-199a-5p and miR 199a-3p, have been recently identified as potential regulators of cardiac homeostasis. Also, upregulation of miR-199a expression in cardiomyocytes was reported to influence endothelial cells. Whether miR-199a is expressed by endothelial cells and, if so, whether it directly regulates endothelial function remains unknown. We investigate the implication of miR-199a products on endothelial function by focusing on the NOS (nitric oxide synthase)/NO pathway. Approach and Results- Bovine aortic endothelial cells were transfected with specific miRNA inhibitors (locked-nucleic acids), and potential molecular targets identified with prediction algorithms were evaluated by Western blot or immunofluorescence. Ex vivo experiments were performed with mice treated with antagomiRs targeting miR-199a-3p or -5p. Isolated vessels and blood were used for electron paramagnetic resonance or myograph experiments. eNOS (endothelial NO synthase) activity (through phosphorylations Ser1177/Thr495) is increased by miR 199a-3p/-5p inhibition through an upregulation of the PI3K (phosphoinositide 3 kinase)/Akt (protein kinase B) and calcineurin pathways. SOD1 (superoxide dismutase 1) and PRDX1 (peroxiredoxin 1) upregulation was also observed in locked nucleic acid-treated cells. Moreover, miR-199a-5p controls angiogenesis and VEGFA (vascular endothelial growth factor A) production and upregulation of NO dependent relaxation were observed in vessels from antagomiR-treated mice. This was correlated with increased circulated hemoglobin-NO levels and decreased superoxide production. Angiotensin infusion for 2 weeks also revealed an upregulation of miR-199a-3p/-5p in vascular tissues. Conclusions- Our study reveals that miR-199a-3p and miR-199a-5p participate in a redundant network of regulation of the NOS/NO pathway in the endothelium. We highlighted that inhibition of miR-199a-3p and -5p independently increases NO bioavailability by promoting eNOS activity and reducing its degradation, thereby supporting VEGF induced endothelial tubulogenesis and modulating vessel contractile tone. PMID- 29976766 TI - Serum Amyloid A Is an Exchangeable Apolipoprotein. AB - Objective- SAA (serum amyloid A) is a family of acute-phase reactants that have proinflammatory and proatherogenic activities. SAA is more lipophilic than apoA-I (apolipoprotein A-I), and during an acute-phase response, <10% of plasma SAA is found lipid-free. In most reports, SAA is found exclusively associated with high density lipoprotein; however, we and others have reported SAA on apoB (apolipoprotein B)-containing lipoproteins in both mice and humans. The goal of this study was to determine whether SAA is an exchangeable apolipoprotein. Approach and Results- Delipidated human SAA was incubated with SAA-free human lipoproteins; then, samples were reisolated by fast protein liquid chromatography, and SAA analyzed by ELISA and immunoblot. Both in vitro and in vivo, we show that SAA associates with any lipoprotein and does not remain in a lipid-free form. Although SAA is preferentially found on high-density lipoprotein, it can exchange between lipoproteins. In the presence of CETP (cholesterol ester transfer protein), there is greater exchange of SAA between lipoproteins. Subjects with diabetes mellitus, but not those with metabolic syndrome, showed altered SAA lipoprotein distribution postprandially. Proteoglycan-mediated lipoprotein retention is thought to be an underlying mechanism for atherosclerosis development. SAA has a proteoglycan-binding domain. Lipoproteins containing SAA had increased proteoglycan binding compared with SAA free lipoproteins. Conclusions- Thus, SAA is an exchangeable apolipoprotein and increases apoB-containing lipoproteins' proteoglycan binding. We and others have previously reported the presence of SAA on low-density lipoprotein in individuals with obesity, diabetes mellitus, and metabolic syndrome. We propose that the presence of SAA on apoB-containing lipoproteins may contribute to cardiovascular disease development in these populations. PMID- 29976768 TI - Influence of a Coronary Artery Disease-Associated Genetic Variant on FURIN Expression and Effect of Furin on Macrophage Behavior. AB - Objective- Genome-wide association studies have revealed a robust association between genetic variation on chromosome 15q26.1 and coronary artery disease (CAD) susceptibility; however, the underlying biological mechanism is still unknown. The lead CAD-associated genetic variant (rs17514846) at this locus resides in the FURIN gene. In advanced atherosclerotic plaques, furin is expressed primarily in macrophages. We investigated whether this CAD-associated variant alters FURIN expression and whether furin affects monocyte/macrophage behavior. Approach and Results- A quantitative reverse transcription polymerase chain reaction analysis showed that leukocytes from individuals carrying the CAD risk allele (A) of rs17514846 had increased FURIN expression. A chromatin immunoprecipitation assay revealed higher RNA polymerase II occupancy in the FURIN gene in mononuclear cells of individuals carrying this allele. A reporter gene assay in transiently transfected monocytes/macrophages indicated that the CAD risk allele had higher transcriptional activity than the nonrisk allele (C). An analysis of isogenic monocyte cell lines created by CRISPR (clustered regularly interspaced short palindromic repeats)-mediated genome editing showed that isogenic cells with the A/A genotype for rs17514846 had higher FURIN expression levels than the isogenic cells with the C/C genotype. An electrophoretic mobility shift assay exhibited preferential binding of a nuclear protein to the risk allele. Studies of monocytes/macrophages with lentivirus-mediated furin overexpression or shRNA (short hairpin RNA)-induced furin knockdown showed that furin overexpression promoted monocyte/macrophage migration, increased proliferation, and reduced apoptosis whereas furin knockdown had the opposite effects. Conclusions- Our study shows that the CAD-associated genetic variant increases FURIN expression and that furin promotes monocyte/macrophage migration and proliferation while inhibiting apoptosis, providing a biological mechanism for the association between variation at the chromosome 15q26.1 locus and CAD risk. PMID- 29976769 TI - Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. AB - Objective- Gut microbiota-dependent metabolites, in particular trimethylamine N oxide (TMAO), have recently been reported to promote atherosclerosis and thrombosis. Here, we examined for the first time the relation of TMAO and the risk of incident cardiovascular events in patients with recent first-ever ischemic stroke in 2 independent prospective cohorts. Moreover, the link between TMAO and proinflammatory monocytes as a potential contributing factor for cardiovascular risk in stroke patients was studied. Approach and Results- In a first study (n=78), higher TMAO plasma levels were linked with an increased risk of incident cardiovascular events including myocardial infarction, recurrent stroke, and cardiovascular death (fourth quartile versus first quartile; hazard ratio, 2.31; 95% CI, 1.25-4.23; P<0.01). In the second independent validation cohort (n=593), high TMAO levels again heralded marked increased risk of adverse cardiovascular events (fourth quartile versus first quartile; hazard ratio, 5.0; 95% CI, 1.7-14.8; P<0.01), and also after adjustments for cardiovascular risk factors including hypertension, diabetes mellitus, LDL (low-density lipoprotein) cholesterol, and estimated glomerular filtration rate (hazard ratio, 3.3; 95% CI, 1.2-10.9; P=0.04). A significant correlation was also found between TMAO levels and percentage of proinflammatory intermediate CD14++CD16+ monocytes ( r=0.70; P<0.01). Moreover, in mice fed a diet enriched with choline to increase TMAO synthesis, levels of proinflammatory murine Ly6Chigh monocytes were higher than in the chow-fed control group (choline: 9.2+/-0.5*103 per mL versus control: 6.5+/-0.5*103 per mL; P<0.01). This increase was abolished in mice with depleted gut microbiota (choline+antibiotics: 5.4+/-0.7*103 per mL; P<0.001 versus choline). Conclusions- The present study demonstrates for the first time a graded relation between TMAO levels and the risk of subsequent cardiovascular events in patients with recent prior ischemic stroke. Our data support the notion that TMAO related increase of proinflammatory monocytes may add to elevated cardiovascular risk of patients with increased TMAO levels. PMID- 29976771 TI - Hepatocyte-Specific SR-BI Gene Transfer Corrects Cardiac Dysfunction in Scarb1 Deficient Mice and Improves Pressure Overload-Induced Cardiomyopathy. AB - Objective- We investigated the hypothesis that HDL (high-density lipoprotein) dysfunction in Scarb1-/- mice negatively affects cardiac function both in the absence and in the presence of pressure overload. Second, we evaluated whether normalization of HDL metabolism in Scarb1-/- mice by hepatocyte-specific SR-BI (scavenger receptor class B, type I) expression after E1E3E4-deleted adenoviral AdSR-BI (E1E3E4-deleted adenoviral vector expressing SR-BI protein in hepatocytes) transfer abrogates the effects of total body SR-BI deficiency on cardiac structure and function. Approach and Results- Transverse aortic constriction (TAC) or sham operation was performed at the age of 14 weeks, 2 weeks after saline injection or after gene transfer with AdSR-BI or with the control vector Adnull. Mortality rate in Scarb1-/- TAC mice was significantly increased compared with wild-type TAC mice during 8 weeks of follow-up (hazard ratio, 2.02; 95% CI, 1.14-3.61). Hepatocyte-specific SR-BI gene transfer performed 2 weeks before induction of pressure overload by TAC potently reduced mortality in Scarb1-/- mice (hazard ratio, 0.329; 95% CI, 0.180-0.600). Hepatocyte-specific SR-BI expression abrogated increased cardiac hypertrophy and lung congestion and counteracted increased myocardial apoptosis and interstitial and perivascular fibrosis in Scarb1-/- TAC mice. Scarb1-/- sham mice were, notwithstanding the absence of detectable structural heart disease, characterized by systolic and diastolic dysfunction and hypotension, which were completely counteracted by AdSR-BI transfer. Furthermore, AdSR-BI transfer abrogated increased end-diastolic pressure and diastolic dysfunction in Scarb1-/- TAC mice. Increased oxidative stress and reduced antioxidant defense systems in Scarb1-/- mice were rescued by AdSR-BI transfer. Conclusions- The detrimental effects of SR BI deficiency on cardiac structure and function are nullified by hepatocyte specific SR-BI transfer, which restores HDL metabolism. PMID- 29976770 TI - CRISPR-Cas9-Mediated Epitope Tagging Provides Accurate and Versatile Assessment of Myocardin-Brief Report. AB - Objective- Unreliable antibodies often hinder the accurate detection of an endogenous protein, and this is particularly true for the cardiac and smooth muscle cofactor, MYOCD (myocardin). Accordingly, the mouse Myocd locus was targeted with 2 independent epitope tags for the unambiguous expression, localization, and activity of MYOCD protein. Approach and Results- 3cCRISPR (3 component clustered regularly interspaced short palindromic repeat) was used to engineer a carboxyl-terminal 3*FLAG or 3*HA epitope tag in mouse embryos. Western blotting with antibodies to each tag revealed a MYOCD protein product of ~150 kDa, a size considerably larger than that reported in virtually all publications. MYOCD protein was most abundant in some adult smooth muscle-containing tissues with surprisingly low-level expression in the heart. Both alleles of Myocd are active in aorta because a 2-fold increase in protein was seen in mice homozygous versus heterozygous for FLAG-tagged Myocd. ChIP (chromatin immunoprecipitation) quantitative polymerase chain reaction studies provide proof-of-principle data demonstrating the utility of this mouse line in conducting genome-wide ChIP-seq studies to ascertain the full complement of MYOCD-dependent target genes in vivo. Although FLAG-tagged MYOCD protein was undetectable in sections of adult mouse tissues, low-passaged vascular smooth muscle cells exhibited expected nuclear localization. Conclusions- This report validates new mouse models for analyzing MYOCD protein expression, localization, and binding activity in vivo and highlights the need for rigorous authentication of antibodies in biomedical research. PMID- 29976772 TI - Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production Through Interleukin-1alpha and Cathepsin G. AB - Objective- Coronary artery thrombosis can occur in the absence of plaque rupture because of superficial erosion. Erosion-prone atheromata associate with more neutrophil extracellular traps (NETs) than lesions with stable or rupture-prone characteristics. The effects of NETs on endothelial cell (EC) inflammatory and thrombogenic properties remain unknown. We hypothesized that NETs alter EC functions related to erosion-associated thrombosis. Approach and Results- Exposure of human ECs to NETs increased VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) mRNA and protein expression in a time- and concentration-dependent manner. THP-1 monocytoid cells and primary human monocytes bound more avidly to NET-treated human umbilical vein ECs than to unstimulated cells under flow. Treatment of human ECs with NETs augmented the expression of TF (tissue factor) mRNA, increased EC TF activity, and hastened clotting of recalcified plasma. Anti-TF-neutralizing antibody blocked NET-induced acceleration of clotting by ECs. NETs alone did not exhibit TF activity or acceleration of clotting in cell-free assays. Pretreatment of NETs with anti interleukin (IL)-1alpha-neutralizing antibody or IL-1Ra (IL-1 receptor antagonist)-but not with anti-IL-1beta-neutralizing antibody or control IgG blocked NET-induced VCAM-1, ICAM-1, and TF expression. Inhibition of cathepsin G, a serine protease abundant in NETs, also limited the effect of NETs on EC activation. Cathepsin G potentiated the effect of IL-1alpha on ECs by cleaving the pro-IL-1alpha precursor and releasing the more potent mature IL-1alpha form. Conclusions- NETs promote EC activation and increased thrombogenicity through concerted action of IL-1alpha and cathepsin G. Thus, NETs may amplify and propagate EC dysfunction related to thrombosis because of superficial erosion. PMID- 29976773 TI - Induced pluripotent stem cell-derived endothelial cells promote angiogenesis and accelerate wound closure in a murine excisional wound healing model. AB - Chronic wounds are a major complication in patients with cardiovascular diseases. Cell therapies have shown potential to stimulate wound healing, but clinical trials using adult stem cells have been tempered by limited numbers of cells and invasive procurement procedures. Induced pluripotent stem cells (iPSCs) have several advantages of other cell types, for example they can be generated in abundance from patients' somatic cells (autologous) or those from a matched donor. iPSCs can be efficiently differentiated to functional endothelial cells (iPSC-ECs). Here, we used a murine excisional wound model to test the pro angiogenic properties of iPSC-ECs in wound healing. Two full-thickness wounds were made on the dorsum of NOD-SCID mice and splinted. iPSC-ECs (5 * 105) were topically applied to one wound, with the other serving as a control. Treatment with iPSC-ECs significantly increased wound perfusion and accelerated wound closure. Expression of endothelial cell (EC) surface marker, platelet endothelial cell adhesion molecule (PECAM-1) (CD31), and pro-angiogenic EC receptor, Tie1, mRNA was up-regulated in iPSC-EC treated wounds at 7 days post-wounding. Histological analysis of wound sections showed increased capillary density in iPSC-EC wounds at days 7 and 14 post-wounding, and increased collagen content at day 14. Anti-GFP fluorescence confirmed presence of iPSC-ECs in the wounds. Bioluminescent imaging (BLI) showed progressive decline of iPSC-ECs over time, suggesting that iPSC-ECs are acting primarily through short-term paracrine effects. These results highlight the pro-regenerative effects of iPSC-ECs and demonstrate that they are a promising potential therapy for intractable wounds. PMID- 29976774 TI - A highly significant association between Cathepsin S gene polymorphisms rs12068264 and chronic obstructive pulmonary disease susceptibility in Han Chinese population. AB - Cathepsin S (CTSS) and Sirtuin-1 (SIRT1) played crucial roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the associations between the polymorphisms of CTSS as well as SIRT1 and COPD in Asian population remain elusive. In the present study, one single nucleotide polymorphism (SNP) in rs12068264 was discovered (in 385 individuals) to be associated with the susceptibility of COPD in a Chinese Han population. The genotyping was performed using improved multiplex ligase detection reaction (iMLDR) technique. Subjects with T allele of rs12068264 in CTSS gene had an increased risk of COPD (T compared with C: odds ratio (OR) = 1.351, 95% confidence interval (95% CI): 1.008 1.811, P=0.044) compared with C allele. Subjects with TT genotype at rs12068264 had a higher risk of COPD in a recessive model (TT compared with TC + CC: OR = 2.30, 95% CI: 1.06-4.989, P=0.035). Compared with the C variant of rs12068264, the homozygous carriers of the TT genotype had higher procalcitonin (PCT) levels. Finally, haplotype analysis demonstrated that the SNPs in the CTSS and SIRT1 gene had no statistical differences between patients with COPD and the controls. In conclusion, the genetic polymorphisms of CTSS were associated with the susceptibility of COPD in a Chinese Han population, which may be helpful in understanding genetic mechanisms underlying the pathogenesis of COPD. PMID- 29976776 TI - Getting to transplant in Hodgkin lymphoma: BVB. PMID- 29976777 TI - The FLIPI nowadays: validation and modification. PMID- 29976778 TI - CEP: a new beta2 integrin ligand in inflamed tissue. PMID- 29976775 TI - Comprehensive assessment for miRNA polymorphisms in hepatocellular cancer risk: a systematic review and meta-analysis. AB - MiRNA polymorphisms had potential to be biomarkers for hepatocellular cancer (HCC) susceptibility. Recently, miRNA single nucleotide polymorphisms (SNPs) were reported to be associated with HCC risk, but the results were inconsistent. We performed a systematic review with a meta-analysis for the association of miRNA SNPs with HCC risk. Thirty-seven studies were included with a total of 11821 HCC patients and 15359 controls in this meta-analysis. We found hsa-mir-146a rs2910164 was associated with a decreased HCC risk in the recessive model (P=0.017, OR = 0.90, 95% confidence interval (CI) = 0.83-0.98). While hsa-mir 34b/c rs4938723 was related with an increased HCC risk in the co-dominant model (P=0.016, odds ratio (OR) = 1.19, 95%CI = 1.03-1.37). When analyzing the Hepatitis B virus (HBV)-related HCC risk, hsa-mir-196a-2 rs11614913 was associated with a decreased HBV-related HCC risk in the co-dominant and allelic models. And hsa-mir-149 rs2292832 was found to be associated with a decreased HBV related HCC risk in the dominant and recessive models. In conclusion, hsa-mir 146a rs2910164 and hsa-mir-34b/c rs4938723 could be biomarkers for the HCC risk while hsa-mir-196a-2 rs11614913 and hsa-mir-149 rs2292832 had potential to be biomarkers for HBV-related HCC risk. PMID- 29976779 TI - HLH: genomics illuminates pathophysiological diversity. PMID- 29976780 TI - Phenotyping rare hepcidin deficiency. PMID- 29976781 TI - T-cell prolymphocytic leukemia negative for surface CD3 and CD45. PMID- 29976782 TI - Concurrent JAK2 mutation and isolated del(5q) associated with marrow fibrosis and small hypo/monolobated megakaryocytes. PMID- 29976783 TI - Clinical and echocardiographic follow-up of patients following surgical heart valve repair or replacement: a tertiary centre experience. AB - International best practice guidelines recommend lifelong follow-up of patients that have undergone valve repair or replacement surgery and provide recommendations on the utilization of echocardiography during follow-up. However, such follow-up regimes can vary significantly between different centres and sometimes within the same centre. We undertook this study to determine the patterns of clinical follow-up and use of transthoracic echocardiography (TTE) amongst cardiologists in a large UK tertiary centre. In this retrospective study, we identified patients that underwent heart valve repair or replacement surgery in 2008. We used local postal codes to identify patients within our hospital's follow-up catchment area. We determined the frequency of clinical follow-up and use of transthoracic echocardiography (TTE) during the 9-year follow-up period (2009-2016 inclusive). Of 552 patients that underwent heart valve surgery, 93 (17%) were eligible for local follow-up. Of these, the majority (61/93, 66%) were discharged after their 6-week post-operative check-up with no further follow-up. Of the remaining 32 patients, there was remarkable heterogeneity in follow-up regimes and use of TTE. This variation did not correlate with the prosthesis type. In summary, the frequency of clinical follow-up and use of echocardiography is highly variable in contemporary practice. Many patients are inappropriately discharged back to their family doctor with no plans for hospital follow-up. These data further support the creation of dedicated specialist heart valve clinics to optimize patient care, ensure rational use of TTE and optimize adherence with best practice guidelines. PMID- 29976784 TI - Vision and visual potential for perifoveal retinoblastoma after optical coherence tomographic-guided sequential laser photocoagulation. AB - BACKGROUND/AIMS: To assess tumour control, vision and anatomical visual potential in eyes with perifoveal retinoblastoma treated by sequential photocoagulation from the antifoveal tumour edge inwards, avoiding treatment near the fovea. Patients were monitored for tumour control, foveal and perifoveal anatomy at each treatment session by optical coherence tomography (OCT) and treated for amblyopia when the other eye had better vision. METHODS: Eyes with perifoveal retinoblastoma treated between 1 January 2011 and 31 May 2017 with laser therapy after chemotherapy for juxtafoveal (fovea clear of tumour but <3000 um from tumour edge) or foveolar retinoblastoma (tumour underlying fovea) were retrospectively reviewed for tumour control without recurrence, anatomical success (foveal pit preservation and/or restoration with >=500 um perifoveal retina free of tumour and scar) and functional success (acceptable (>0.1 decimal) or good (>0.3 decimal) visual acuity (VA)). RESULTS: Twenty-two eyes (14 juxtafoveal, 8 foveolar tumours) of 20 patients (19 bilateral, 1 familial and 11 females) were included. No juxtafoveal tumour had tumour recurrence, and 13/14 patients showed foveal pit preservation with >=500 um of perifoveal retina tumour free. Foveolar tumours had significant worse anatomical outcomes: failure to restore foveal pit or perifoveal retina (8/8, p=0.001) and tumour recurrences (5/8, p=0.001). Functional success with acceptable VA was achieved in 12/14 juxtafoveal and 5/8 foveal tumours eyes (p=0.01). Amblyopia therapy data were insufficient to evaluate impact on VA. CONCLUSIONS: Anatomical visual potential and functional vision were better in juxtafoveal than foveolar retinoblastoma treated with foveal-sparing laser photocoagulation guided by OCT. The role of amblyopia therapy requires a prospective study. PMID- 29976785 TI - Adherence and long-term growth outcomes: results from the easypodTM connect observational study (ECOS) in paediatric patients with growth disorders. AB - OBJECTIVE: The easypod connect observational study (ECOS) assessed treatment adherence among paediatric patients receiving growth hormone (GH) via the easypod electronic injection device. DESIGN: ECOS was an open-label, observational, longitudinal study conducted in 24 countries between 2010 and 2016, enrolling children treated with GH. METHODS: The primary endpoint was the rate of treatment adherence during 5 years of follow-up. Impact of adherence on growth outcomes was assessed using Spearman's product-moment correlations. RESULTS AND CONCLUSIONS: Overall, 1190 patients had easypod data available for >=3 months; most patients had GH deficiency (75%); 606 of these patients were GH naive at baseline. Over the first year of monitoring, the median rate of adherence was 93.7% among patients overall and >93.0% in GH-naive patients, irrespective of the treatment indication. Clinically meaningful improvements in growth rates were observed after 1 year of treatment across all GH indications. Adherence decreased with increasing treatment duration, but the overall median adherence rate remained high after 3 years of follow-up: 87.2% (n = 409), 75.5% after 4 years (n = 143) and 70.2% after 5 years (n = 43). Statistically significant correlations between adherence and 1-year change in height standard deviation score (P < 0.001 for patients overall) and height velocity (P < 0.001) were observed. CONCLUSIONS: ECOS produced accurate, real-time adherence data in a large population of GH treated children over 5 years of follow-up. Using the easypod connect system, physicians can potentially identify patients with inadequate adherence and poor response to treatment, enabling them to take appropriate action to help them maximise the benefits of GH treatment. PMID- 29976787 TI - Change is in the Wind: What research tells us about the future of dental hygiene. PMID- 29976788 TI - Interest in Dental Hygiene Therapy: a study of dental hygienists in Maine. AB - Purpose: The purpose of this study was to assess the awareness of registered dental hygienists (RDHs), licensed in the state of Maine, regarding the midlevel dental hygiene therapist (DHT) provider model and to gather data regarding the degree of interest in enrolling in a DHT program.Methods: A quantitative cross sectional study design with a non-probability purposive sampling of actively practicing RDHs in the state of Maine (n=1,284) was utilized for the web-based survey. Survey questions included awareness in the passage of DHT legislation, level of interest pursuing education and licensure in this midlevel provider model. Data was collected over a three-week period. Descriptive statistics and thematic analysis were used for data analysis.Results: Response rate was 21% (n=268). Sixty-five percent of respondents expressed interest in enrolling in a DHT program and 40% of those respondents stated a willingness to enroll in a DHT program within the coming year. Although willing to travel 25-50 miles, a majority of respondents preferred programs incorporating online components combined with clinical training completed in nearby communities. Themes emerging from the open-ended question regarding DHT program feasibility and appeal included: convenience, flexibility, cost/affordability, and independent or collaborative practice.Conclusion: Study outcomes indicated interest exists among Maine RDHs regarding the DHT provider role and enrollment in a DHT program. Although there are no DHT programs currently being offered in the New England states, results suggest further investigation is warranted regarding the development of a DHT program in the Northeastern United States. PMID- 29976790 TI - Variations in Periodontal Diagnosis Among Clinicians: dental hygienists' experiences and perceived barriers. AB - Purpose: Research indicates clinicians face barriers when attempting to utilize evidence-based protocols for periodontal disease and periodontal disease diagnosis often varies between dental providers. The purpose of this study was to identify and better understand dental hygienists' perceived barriers and experiences during the process of diagnosing periodontal disease in clinical practice.Methods: This study used a qualitative design and a purposive sample of dental hygienists (n=20). Utilizing a virtual video-conferencing platform, participants logged into focus group sessions to discuss their experiences with diagnosing periodontal disease in clinical practice. Focus group sessions were recorded and transcribed. Thematic analysis involved the use of inductive coding to draw themes from the data.Results: Dental hygienists reported being responsible for periodontal disease diagnosis, and that they utilized similar classification systems, and agreed with colleagues' periodontal disease diagnoses. However, participants reported the lack of a standardized periodontal classification system was confusing when communicating outside of their dental practice and described both intrinsic and extrinsic barriers to diagnosing disease. A common theme expressed by participants was that patients' lack of acceptance of their periodontal disease status and inability to fund treatment interfered with providing an evidence-based diagnosis and treatment plan. Newly licensed dental hygienists felt somewhat prepared to diagnose periodontal disease upon completion of their education but reported increased confidence in their skills and knowledge with years of practice and continuing education.Conclusion: Study data indicates dental hygienists feel the lack of a standardized periodontal classification system causes confusion and inconsistencies when communicating with other oral health care providers outside of their clinical practice setting, and dental hygienists face barriers when diagnosing periodontal disease. These findings may be instrumental in assisting educators in preparing students for clinical practice. PMID- 29976789 TI - Food Security and Unmet Dental Care Needs in Adults in the United States. AB - Purpose: Low food security is potentially related to poor dental health and unmet dental care needs. Food security has become a significant public health concern in the United States (U.S.) since the Great Recession beginning in 2007. The purpose of this study is to determine the association between low food security and unmet dental care need in adults in the U.S.Methods: A cross-sectional design with data from the National Health and Nutrition Examination Survey (NHANES) 2011 2012 was used for the study to measure unmet dental care need. The study population included 4,845 adults, ages 20 years and above. Chi square tests and logistic regressions were conducted for the statistical analysis.Results: Overall, 47% of participants had unmet dental care need and 16% were found to have low food security. A higher percentage of adults with low food security had unmet dental care need (70.0% vs. 41.0%; p < .000) as compared to adults with full food security. In adjusted analysis, adults with low food security were more likely to have unmet dental care need as compared to participants with full food security (Adjusted Odds Ratio, 1.58 [95% CI: 1.18, 2.12; p <.01]).Conclusions: A significant association between low food security and unmet dental care need was identified among adults in the United States. Dental professionals routinely provide community educational programs and regularly query patients about food intake due to its impact on oral and overall health. It is important for dental professionals to be able to discuss community food resource options or refer patients to social service providers to assist individuals with low food security. PMID- 29976791 TI - Polypharmacy and Off-label Drug Use in Dentistry: knowledge, attitudes and practices of California dental hygienists. AB - Purpose: This study examined the knowledge, attitudes, and practices of dental hygienists, licensed in the state of California, regarding polypharmacy and off label drug use for purposes in dentistry.Methods: A cross-sectional design was used to assess the knowledge, attitudes, and practices (KAP) related to off-label drug use and polypharmacy via an online survey tool. The study sample included licensed dental hygienists, who were members of the Long Beach and Tri-County Dental Hygienists' Associations located in Southern California (n=360). Descriptive statistics were used to assess the participant characteristics. ANOVA was used to assess differences in knowledge, attitudes and practices when compared to three key variables: highest academic/professional degree, experience and license type.Results: One hundred seven electronic surveys (n=107) were returned for a 34% response rate. Over half of respondents (53%) held an associates' degree for their license, most (72%) worked in a general dentistry setting and 46% had practiced 15 years or less. Regarding knowledge of polypharmacy and off-label drug use, the results demonstrated very low knowledge, with 25% of the respondents unable to answer any of the knowledge questions correctly. No significant differences in practices related to off-label drugs or polypharmacy were found based on type of licensure, highest degree achieved, or years of experience. However, participants holding a baccalaureate degree or higher were significantly more confident (p=.011) in discussing polypharmacy with patients and colleagues.Conclusion: Participants showed a general low-level of knowledge related to polypharmacy and off-label drug use in dentistry regardless of their level of education, years of experience, or type of dental hygiene licensure; indicating a need for increased pharmacology content in both entry level dental hygiene programs and continuing education courses. PMID- 29976786 TI - Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? AB - Sepsis is a highly lethal and urgent unmet medical need. It is the result of a complex interplay of several pathways, including inflammation, immune activation, hypoxia, and metabolic reprogramming. Specifically, the regulation and the impact of the latter have become better understood in which the highly catabolic status during sepsis and its similarity with starvation responses appear to be essential in the poor prognosis in sepsis. It seems logical that new interventions based on the recognition of new therapeutic targets in the key metabolic pathways should be developed and may have a good chance to penetrate to the bedside. In this review, we concentrate on the pathological changes in metabolism, observed during sepsis, and the presumed underlying mechanisms, with a focus on the level of the organism and the interplay between different organ systems. PMID- 29976792 TI - Educational and Clinical Experiences in Administering Local Anesthesia: a study of dental and dental hygiene students in California. AB - Purpose: The purpose of this study was to examine the differences in educational preparation and practical educational experiences between dental and dental hygiene students in the administration of local anesthesia (LA) and management of LA related complications in the state of California.Methods: Course instructors responsible for teaching LA or the program directors of the 6 dental schools and 29 dental hygiene programs in California (n=35) were invited to participate in this study. A computer-based descriptive survey, a comparative checklist of LA instruction requirements and semi-structured interviews were used for the data collection. Descriptive statistics were used to analyze results.Results: Eighteen LA course instructors or program directors participated in the study for a response rate of 51%. One respondent was from a dental school while 17 were from dental hygiene programs. The majority of the dental hygiene (n=16) respondents reported teaching 12 types of intraoral injections; the dental school respondent reported teaching seven injection types. Fewer student-to-student injection experiences per injection type were required by the dental school (n=7) than the dental hygiene schools (n=12) and the dental school did not indicate a minimum number of student-to-patient injection requirements for graduation. Analysis of a checklist of required elements of LA instruction and individual syllabi revealed common elements of all courses; students are expected to choose the proper local anesthetic, identify the proper injection type, and manage any LA complications. The majority of the interview participants perceived that dental hygiene students had more educational preparation in LA than their dental student cohorts and that dental hygienists were educationally prepared to administer LA safely without direct supervision.Conclusions: Dental hygiene students in California programs appear to be well prepared through their education experiences to administer and manage complications related to local anesthesia. Consideration should be given to supporting changing the supervision requirements for the administration of local anesthesia by dental hygienists licensed in the state of California. PMID- 29976793 TI - Dental Hygienists' Readiness to Screen for Intimate Partner Violence in the State of Texas. AB - Purpose: Limited data document dental hygienists' preparedness for intimate partner violence (IPV) screening and response. The aim of this study was to assess dental hygienists' readiness to screen for IPV and provide baseline information for the realization of action toward addressing IPV.Methods: The Domestic Violence Healthcare Provider Survey (DVHPS) instrument was distributed online to all members of the Texas Dental Hygienists' Association (n=1100). Four hundred fifteen emails were opened and 114 (n=114) surveys were returned for 28% response rate. This validated survey measures six scales: perceived self efficacy, fear of offending patients, victim personality/traits, professional role resistance, perceptions of victim disobedience causing IPV, and psychiatric support. Descriptive statistics were used to calculate mean scores for each scale. Specific criteria were applied to interpret the level of readiness based on the scale scores.Results: A little more than one quarter of the respondents (28%) reported having had course content related to IPV as students in their dental hygiene program curriculum, while 27% reported completing continuing education on IPV. A significant proportion of participants, 40%, were uncertain if routine IPV screening was within their professional role. They did not perceive self-efficacy in their screening capabilities (m=3.08 with 5.0 as the strongest), however they reported possessing a strong knowledge regarding IPV victims' personality/traits and did not blame the victims (m=1.92 and 1.48 respectively with 1.0 as the strongest).Conclusion: Results confirm earlier studies indicating the need for IPV training for oral health care professionals. Specifically, there is an evident need for training to increase dental hygienists' self-efficacy regarding IPV screening. Dental hygienists play a critical role in IPV screening and should be prepared to face the challenges presented by IPV and be available to meet the needs of IPV victims through referral to the appropriate support services. PMID- 29976794 TI - DNA-induced liquid phase condensation of cGAS activates innate immune signaling. AB - The binding of DNA to cyclic GMP-AMP synthase (cGAS) leads to the production of the secondary messenger cyclic GMP-AMP (cGAMP), which activates innate immune responses. We have shown that DNA binding to cGAS robustly induced the formation of liquidlike droplets in which cGAS was activated. The disordered and positively charged cGAS N terminus enhanced cGAS-DNA phase separation by increasing the valencies of DNA binding. Long DNA was more efficient in promoting cGAS liquid phase separation and cGAS enzyme activity than short DNA. Moreover, free zinc ions enhanced cGAS enzyme activity both in vitro and in cells by promoting cGAS DNA phase separation. These results demonstrated that the DNA-induced phase transition of cGAS promotes cGAMP production and innate immune signaling. PMID- 29976796 TI - High thermal conductivity in cubic boron arsenide crystals. AB - The high density of heat generated in power electronics and optoelectronic devices is a critical bottleneck in their application. New materials with high thermal conductivity are needed to effectively dissipate heat and thereby enable enhanced performance of power controls, solid-state lighting, communication, and security systems. We report the experimental discovery of high thermal conductivity at room temperature in cubic boron arsenide (BAs) grown through a modified chemical vapor transport technique. The thermal conductivity of BAs, 1000 +/- 90 watts per meter per kelvin meter-kelvin, is higher than that of silicon carbide by a factor of 3 and is surpassed only by diamond and the basal plane value of graphite. This work shows that BAs represents a class of ultrahigh thermal conductivity materials predicted by a recent theory, and that it may constitute a useful thermal management material for high-power density electronic devices. PMID- 29976795 TI - Juno observations of spot structures and a split tail in Io-induced aurorae on Jupiter. AB - Jupiter's aurorae are produced in its upper atmosphere when incoming high-energy electrons precipitate along the planet's magnetic field lines. A northern and a southern main auroral oval are visible, surrounded by small emission features associated with the Galilean moons. We present infrared observations, obtained with the Juno spacecraft, showing that in the case of Io, this emission exhibits a swirling pattern that is similar in appearance to a von Karman vortex street. Well downstream of the main auroral spots, the extended tail is split in two. Both of Ganymede's footprints also appear as a pair of emission features, which may provide a remote measure of Ganymede's magnetosphere. These features suggest that the magnetohydrodynamic interaction between Jupiter and its moon is more complex than previously anticipated. PMID- 29976797 TI - Unusual high thermal conductivity in boron arsenide bulk crystals. AB - Conventional theory predicts that ultrahigh lattice thermal conductivity can only occur in crystals composed of strongly bonded light elements, and that it is limited by anharmonic three-phonon processes. We report experimental evidence that departs from these long-held criteria. We measured a local room-temperature thermal conductivity exceeding 1000 watts per meter-kelvin and an average bulk value reaching 900 watts per meter-kelvin in bulk boron arsenide (BAs) crystals, where boron and arsenic are light and heavy elements, respectively. The high values are consistent with a proposal for phonon-band engineering and can only be explained by higher-order phonon processes. These findings yield insight into the physics of heat conduction in solids and show BAs to be the only known semiconductor with ultrahigh thermal conductivity. PMID- 29976798 TI - Experimental observation of high thermal conductivity in boron arsenide. AB - Improving the thermal management of small-scale devices requires developing materials with high thermal conductivities. The semiconductor boron arsenide (BAs) is an attractive target because of ab initio calculation indicating that single crystals have an ultrahigh thermal conductivity. We synthesized BAs single crystals without detectable defects and measured a room-temperature thermal conductivity of 1300 watts per meter-kelvin. Our spectroscopy study, in conjunction with atomistic theory, reveals that the distinctive band structure of BAs allows for very long phonon mean free paths and strong high-order anharmonicity through the four-phonon process. The single-crystal BAs has better thermal conductivity than other metals and semiconductors. Our study establishes BAs as a benchmark material for thermal management applications and exemplifies the power of combining experiments and ab initio theory in new materials discovery. PMID- 29976800 TI - Erratum for the Report "Aging and neurodegeneration are associated with increased mutations in single human neurons" by M. A. Lodato, R. E. Rodin, C. L. Bohrson, M. E. Coulter, A. R. Barton, M. Kwon, M. A. Sherman, C. M. Vitzthum, L. J. Luquette, C. N. Yandava, P. Yang, T. W. Chittenden, N. E. Hatem, S. C. Ryu, M. B. Woodworth, P. J. Park, C. A. Walsh. PMID- 29976802 TI - News at a glance. PMID- 29976801 TI - Science Advances advancing. PMID- 29976803 TI - Polio outbreaks in the DRC threaten eradication effort. PMID- 29976799 TI - A liquid phase of synapsin and lipid vesicles. AB - Neurotransmitter-containing synaptic vesicles (SVs) form tight clusters at synapses. These clusters act as a reservoir from which SVs are drawn for exocytosis during sustained activity. Several components associated with SVs that are likely to help form such clusters have been reported, including synapsin. Here we found that synapsin can form a distinct liquid phase in an aqueous environment. Other scaffolding proteins could coassemble into this condensate but were not necessary for its formation. Importantly, the synapsin phase could capture small lipid vesicles. The synapsin phase rapidly disassembled upon phosphorylation by calcium/calmodulin-dependent protein kinase II, mimicking the dispersion of synapsin 1 that occurs at presynaptic sites upon stimulation. Thus, principles of liquid-liquid phase separation may apply to the clustering of SVs at synapses. PMID- 29976804 TI - Lawmakers ask NIH and CDC charities for more on donors. PMID- 29976805 TI - Optical interferometers sharpen views of the sky. PMID- 29976806 TI - Biologists raise alarm over changes to biopiracy rules. PMID- 29976807 TI - Proposed DOE test reactor sparks controversy. PMID- 29976808 TI - Hidden conflicts? PMID- 29976809 TI - Is FDA's revolving door open too wide? PMID- 29976810 TI - Broad interests reap benefits for science. PMID- 29976811 TI - America's lost dogs. PMID- 29976812 TI - A new brain circuit in feeding control. PMID- 29976813 TI - Molecular movies filmed at conical intersections. PMID- 29976814 TI - The search for ancient DNA heads east. PMID- 29976815 TI - Chromatin domains rich in inheritance. PMID- 29976816 TI - The dynamic art of growing COF crystals. PMID- 29976817 TI - Autonomous vehicles: No driver...no regulation? PMID- 29976818 TI - Single-crystal x-ray diffraction structures of covalent organic frameworks. AB - The crystallization problem is an outstanding challenge in the chemistry of porous covalent organic frameworks (COFs). Their structural characterization has been limited to modeling and solutions based on powder x-ray or electron diffraction data. Single crystals of COFs amenable to x-ray diffraction characterization have not been reported. Here, we developed a general procedure to grow large single crystals of three-dimensional imine-based COFs (COF-300, hydrated form of COF-300, COF-303, LZU-79, and LZU-111). The high quality of the crystals allowed collection of single-crystal x-ray diffraction data of up to 0.83-angstrom resolution, leading to unambiguous solution and precise anisotropic refinement. Characteristics such as degree of interpenetration, arrangement of water guests, the reversed imine connectivity, linker disorder, and uncommon topology were deciphered with atomic precision-aspects impossible to determine without single crystals. PMID- 29976819 TI - A single-photon switch and transistor enabled by a solid-state quantum memory. AB - Single-photon switches and transistors generate strong photon-photon interactions that are essential for quantum circuits and networks. However, the deterministic control of an optical signal with a single photon requires strong interactions with a quantum memory, which has been challenging to achieve in a solid-state platform. We demonstrate a single-photon switch and transistor enabled by a solid state quantum memory. Our device consists of a semiconductor spin qubit strongly coupled to a nanophotonic cavity. The spin qubit enables a single 63-picosecond gate photon to switch a signal field containing up to an average of 27.7 photons before the internal state of the device resets. Our results show that semiconductor nanophotonic devices can produce strong and controlled photon photon interactions that could enable high-bandwidth photonic quantum information processing. PMID- 29976820 TI - Observation of an environmentally insensitive solid-state spin defect in diamond. AB - Engineering coherent systems is a central goal of quantum science. Color centers in diamond are a promising approach, with the potential to combine the coherence of atoms with the scalability of a solid-state platform. We report a color center that shows insensitivity to environmental decoherence caused by phonons and electric field noise: the neutral charge state of silicon vacancy (SiV0). Through careful materials engineering, we achieved >80% conversion of implanted silicon to SiV0 SiV0 exhibits spin-lattice relaxation times approaching 1 minute and coherence times approaching 1 second. Its optical properties are very favorable, with ~90% of its emission into the zero-phonon line and near-transform-limited optical linewidths. These combined properties make SiV0 a promising defect for quantum network applications. PMID- 29976822 TI - Tandem catalysis for asymmetric coupling of ethylene and enynes to functionalized cyclobutanes. AB - Transformation of simple precursors into structurally complex cyclobutanes, present in many biologically important natural products and pharmaceuticals, is of considerable interest in medicinal chemistry. Starting from 1,3-enynes and ethylene, both exceptionally inexpensive starting materials, we report a cobalt catalyzed route to vinylcyclobutenes, as well as the further enantioselective addition of ethylene to these products to form complex cyclobutanes with all carbon quaternary centers. These reactions can proceed in discrete stages or in a tandem fashion to achieve three highly selective carbon-carbon bond formations in one pot using a single chiral cobalt catalyst. PMID- 29976821 TI - Imaging CF3I conical intersection and photodissociation dynamics with ultrafast electron diffraction. AB - Conical intersections play a critical role in excited-state dynamics of polyatomic molecules because they govern the reaction pathways of many nonadiabatic processes. However, ultrafast probes have lacked sufficient spatial resolution to image wave-packet trajectories through these intersections directly. Here, we present the simultaneous experimental characterization of one photon and two-photon excitation channels in isolated CF3I molecules using ultrafast gas-phase electron diffraction. In the two-photon channel, we have mapped out the real-space trajectories of a coherent nuclear wave packet, which bifurcates onto two potential energy surfaces when passing through a conical intersection. In the one-photon channel, we have resolved excitation of both the umbrella and the breathing vibrational modes in the CF3 fragment in multiple nuclear dimensions. These findings benchmark and validate ab initio nonadiabatic dynamics calculations. PMID- 29976823 TI - Biological uptake and reversible scavenging of zinc in the global ocean. AB - Zinc (Zn) is a key micronutrient for marine phytoplankton, with a global distribution that is similar to silicic acid. The processes that govern this relationship, despite the very different biological cycling of Zn and silica, remain poorly understood. Here, we use diagnostic and mechanistic models to show that only a combination of Southern Ocean biological uptake and reversible scavenging of Zn onto sinking particles can explain the observations. The distinction between organic and adsorbed Zn can also reconcile the vertical distribution and mass balance of Zn isotopes, which previously appeared at odds. This holistic understanding explains the Zn deficiencies observed throughout the low-latitude ocean and implies a greater sensitivity of the marine Zn cycle to climate-driven changes in organic matter cycling than previously recognized. PMID- 29976824 TI - Regulation of feeding by somatostatin neurons in the tuberal nucleus. AB - The tuberal nucleus (TN) is a surprisingly understudied brain region. We found that somatostatin (SST) neurons in the TN, which is known to exhibit pathological or cytological changes in human neurodegenerative diseases, play a crucial role in regulating feeding in mice. GABAergic tuberal SST (TNSST) neurons were activated by hunger and by the hunger hormone, ghrelin. Activation of TNSST neurons promoted feeding, whereas inhibition reduced it via projections to the paraventricular nucleus and bed nucleus of the stria terminalis. Ablation of TNSST neurons reduced body weight gain and food intake. These findings reveal a previously unknown mechanism of feeding regulation that operates through orexigenic TNSST neurons, providing a new perspective for understanding appetite changes. PMID- 29976828 TI - The road less traveled. PMID- 29976826 TI - Ancient goat genomes reveal mosaic domestication in the Fertile Crescent. AB - Current genetic data are equivocal as to whether goat domestication occurred multiple times or was a singular process. We generated genomic data from 83 ancient goats (51 with genome-wide coverage) from Paleolithic to Medieval contexts throughout the Near East. Our findings demonstrate that multiple divergent ancient wild goat sources were domesticated in a dispersed process that resulted in genetically and geographically distinct Neolithic goat populations, echoing contemporaneous human divergence across the region. These early goat populations contributed differently to modern goats in Asia, Africa, and Europe. We also detect early selection for pigmentation, stature, reproduction, milking, and response to dietary change, providing 8000-year-old evidence for human agency in molding genome variation within a partner species. PMID- 29976829 TI - Prospective daily review of discharge medications by pharmacists: Effects on measures of safety and efficiency. AB - PURPOSE: Results of a pilot project to improve the safety and efficiency of the discharge process by adding daily pharmacist review and preparation of discharge medication orders to an existing discharge medication reconciliation workflow are reported. SUMMARY: Due to patient capacity issues, the pharmacy department of a large tertiary medical center implemented changes to the existing medication discharge workflow. A steering committee was established, with subgroups responsible for workflow development, electronic medical record enhancement, and data collection designated. Patients admitted to 5 hospitalist services, 1 otolaryngology service, and 1 gynecology service were included in pilot testing of a new discharge workflow over a 7-week period. The new workflow included pharmacist daily prospective preparation of discharge medication orders by "pending" (i.e., managing all aspects of) orders for providers to sign. After implementation, a 22% relative reduction (p = 0.046) in pharmacist-identified medication-related problems was documented. Additionally, the proportion of discharges occurring before noon was increased on all services involved in the pilot project, including a significant increase (from 19% to 23%, p = 0.001) on the hospitalist services. Challenges identified during the pilot project included suboptimal initial provider acceptance and added pharmacist workload. On average, an additional 16.2 minutes of pharmacist time per patient was required for ordering of discharge medications throughout a patient stay. CONCLUSION: Implementation of a discharge process that incorporated pharmacist pending of discharge medication orders throughout the patient stay improved measures of safety and efficiency of the discharge process. PMID- 29976830 TI - Evaluation of a transitional care pharmacist intervention in a high-risk cardiovascular patient population. AB - PURPOSE: The utility of a transitions-of-care (TOC) pharmacist intervention focused on improving the quality and safety of the medication process for high risk cardiovascular patients was evaluated. METHODS: A quality-improvement initiative was developed for patients with heart failure or acute coronary syndrome followed longitudinally at a hospital's outpatient cardiovascular clinic. The TOC pharmacist intervention occurred either before a patient's outpatient cardiovascular clinic appointment or during a hospitalization. The major outcome analyzed was the number of unplanned hospital readmissions within 30 days. Additional endpoints evaluated included the time to healthcare utilization, number of medication discrepancies identified, percentage of therapeutic recommendations accepted by a provider, number of medication access issues resolved, patient cost savings, patient satisfaction, and mean time spent on an intervention by the pharmacist per patient encounter. RESULTS: A total of 118 patients received the TOC pharmacist intervention. A total of 516 medication discrepancies were identified and corrected, with 55.6% of discrepancies involving cardiovascular medications. A total of 244 recommendations for therapeutic optimization were provided, with an 81% provider acceptance rate and a 100% patient satisfaction rate. Fifty-five patients were provided with medication cost savings, and medication-access issues were resolved for 8 patients. A TOC pharmacist spent means of 98 and 73 minutes on patient education and coordination of care during inpatient and ambulatory encounters, respectively. The 30-day hospital readmission rate for patients with heart failure was reduced by 20%. CONCLUSION: A TOC pharmacist intervention improved the quality and safety of care across both inpatient and ambulatory settings for high-risk cardiovascular patients at our institution. PMID- 29976825 TI - The evolutionary history of dogs in the Americas. AB - Dogs were present in the Americas before the arrival of European colonists, but the origin and fate of these precontact dogs are largely unknown. We sequenced 71 mitochondrial and 7 nuclear genomes from ancient North American and Siberian dogs from time frames spanning ~9000 years. Our analysis indicates that American dogs were not derived from North American wolves. Instead, American dogs form a monophyletic lineage that likely originated in Siberia and dispersed into the Americas alongside people. After the arrival of Europeans, native American dogs almost completely disappeared, leaving a minimal genetic legacy in modern dog populations. The closest detectable extant lineage to precontact American dogs is the canine transmissible venereal tumor, a contagious cancer clone derived from an individual dog that lived up to 8000 years ago. PMID- 29976831 TI - Brain Perfusion Measurements Using Multidelay Arterial Spin-Labeling Are Systematically Biased by the Number of Delays. AB - BACKGROUND AND PURPOSE: Multidelay arterial spin-labeling is a promising emerging method in clinical practice. The effect of imaging parameters in multidelay arterial spin-labeling on estimated cerebral blood flow measurements remains unknown. We directly compared 3-delay versus 7-delay sequences, assessing the difference in the estimated transit time and blood flow. MATERIALS AND METHODS: This study included 87 cognitively healthy controls (78.7 +/- 3.8 years of age; 49 women). We assessed delay and transit time-uncorrected and transit time corrected CBF maps. Data analysis included voxelwise permutation-based between sequence comparisons of 3-delay versus 7-delay, within-sequence comparison of transit time-uncorrected versus transit time-corrected maps, and average CBF calculations in regions that have been shown to differ. RESULTS: The 7-delay sequence estimated a higher CBF value than the 3-delay for the transit time uncorrected and transit time-corrected maps in regions corresponding to the watershed areas (transit time-uncorrected = 27.62 +/- 12.23 versus 24.58 +/- 11.70 mL/min/100 g, Cohen's d = 0.25; transit time-corrected = 33.48 +/- 14.92 versus 30.16 +/- 14.32 mL/min/100 g, Cohen's d = 0.23). In the peripheral regions of the brain, the estimated delay was found to be longer for the 3-delay sequence (1.52408 +/- 0.25236 seconds versus 1.47755 +/- 0.24242 seconds, Cohen's d = 0.19), while the inverse was found in the center of the brain (1.39388 +/- 0.22056 seconds versus 1.42565 +/- 0.21872 seconds, Cohen's d = 0.14). Moreover, 7-delay had lower hemispheric asymmetry. CONCLUSIONS: The results of this study support the necessity of standardizing acquisition parameters in multidelay arterial spin-labeling and identifying basic parameters as a confounding factor in CBF quantification studies. Our findings conclude that multidelay arterial spin-labeling sequences with a high number of delays estimate higher CBF values than those with a lower number of delays. PMID- 29976827 TI - The prehistoric peopling of Southeast Asia. AB - The human occupation history of Southeast Asia (SEA) remains heavily debated. Current evidence suggests that SEA was occupied by Hoabinhian hunter-gatherers until ~4000 years ago, when farming economies developed and expanded, restricting foraging groups to remote habitats. Some argue that agricultural development was indigenous; others favor the "two-layer" hypothesis that posits a southward expansion of farmers giving rise to present-day Southeast Asian genetic diversity. By sequencing 26 ancient human genomes (25 from SEA, 1 Japanese Jomon), we show that neither interpretation fits the complexity of Southeast Asian history: Both Hoabinhian hunter-gatherers and East Asian farmers contributed to current Southeast Asian diversity, with further migrations affecting island SEA and Vietnam. Our results help resolve one of the long standing controversies in Southeast Asian prehistory. PMID- 29976832 TI - Noncontrast Head CT in Children: National Variation in Radiation Dose Indices in the United States. AB - BACKGROUND AND PURPOSE: Radiologists should manage the radiation dose for pediatric patients to maintain reasonable diagnostic confidence. We assessed the variation in estimated radiation dose indices for pediatric noncontrast head CT in the United States. MATERIALS AND METHODS: Radiation dose indices for single phase noncontrast head CT examinations in patients 18 years of age and younger were retrospectively reviewed between July 2011 and June 2016 using the American College of Radiology CT Dose Index Registry. We used the reported volume CT dose index stratified by patient demographics and imaging facility characteristics. RESULTS: The registry included 295,296 single-phase pediatric noncontrast head CT studies from 1571 facilities (56% in male patients and 53% in children older than 10 years of age). The median volume CT dose index was 33 mGy (interquartile range = 22-47 mGy). The volume CT dose index increased as age increased. The volume CT dose index was lower in children's hospitals (median, 26 mGy) versus academic hospitals (median, 32 mGy) and community hospitals (median, 40 mGy). There was a lower volume CT dose index in level I and II trauma centers (median, 27 and 32 mGy, respectively) versus nontrauma centers (median, 40 mGy) and facilities in metropolitan locations (median, 30 mGy) versus those in suburban and rural locations (median, 41 mGy). CONCLUSIONS: Considerable variation in the radiation dose index for pediatric head CT exists. Median dose indices and practice variations at pediatric facilities were both lower compared with other practice settings. Decreasing dose variability through proper management of CT parameters in pediatric populations using benchmarks generated by data from registries can potentially decrease population exposure to ionizing radiation. PMID- 29976833 TI - Impact of Focal White Matter Damage on Localized Subcortical Gray Matter Atrophy in Multiple Sclerosis: A 5-Year Study. AB - BACKGROUND AND PURPOSE: It is unclear to what extent subcortical gray matter atrophy is a primary process as opposed to a result of focal white matter damage. Correlations between WM damage and atrophy of subcortical gray matter have been observed but may be partly attributable to indirect relationships between co occurring processes arising from a common cause. Our aim was to cross-sectionally and longitudinally characterize the unique impact of focal WM damage on the atrophy of connected subcortical gray matter regions, beyond what is explainable by global disease progression. MATERIALS AND METHODS: One hundred seventy-six individuals with MS and 47 healthy controls underwent MR imaging at baseline and 5 years later. Atrophy and lesion-based disruption of connected WM tracts were evaluated for 14 subcortical gray matter regions. Hierarchic regressions were applied, predicting regional atrophy from focal WM disruption, controlling for age, sex, disease duration, whole-brain volume, and T2-lesion volume. RESULTS: When we controlled for whole-brain volume and T2-lesion volume, WM tract disruption explained little additional variance of subcortical gray matter atrophy and was a significant predictor for only 3 of 14 regions cross sectionally (DeltaR2 = 0.004) and 5 regions longitudinally (DeltaR2 = 0.016). WM tract disruption was a significant predictor for even fewer regions when correcting for multiple comparisons. CONCLUSIONS: WM tract disruption accounts for a small percentage of atrophy in connected subcortical gray matter when controlling for overall disease burden and is not the primary driver in most cases. PMID- 29976835 TI - Managing the risk from interactions with herbal medicines. PMID- 29976834 TI - Primary Angioplasty without Stenting for Symptomatic, High-Grade Intracranial Stenosis with Poor Circulation. AB - BACKGROUND AND PURPOSE: Although the Stenting versus Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study demonstrated a high incidence of perioperative complications for Intracranial Atherosclerotic disease (ICAD) treatments with stent placement, some studies have shown that submaximal angioplasty with an undersized balloon limits the risks of perioperative complications, suggesting that intervention may remain an alternative option for ICAD if perioperative complications are minimized. We sought to evaluate clinical and angiographic outcomes after primary angioplasty without stent placement in patients with symptomatic, high-grade intracranial stenosis and poor antegrade flow who were refractory to medical therapy. MATERIALS AND METHODS: All cases with high-grade, symptomatic intracranial stenosis and poor antegrade flow treated with intracranial angioplasty without stent placement at Xuanwu Hospital, Capital Medical University, from January 2010 to December 2016, were retrospectively reviewed. The main outcomes included the changes in antegrade flow and residual stenosis and any stroke or death within 1 month. We also evaluated functional outcomes, stroke, and restenosis in patients on follow-up. RESULTS: Thirty-five patients (mean age, 64.3 years) were included, and the mean follow-up time was 9.7 months. The average preprocedural stenosis was 88.4%. The immediate, average postprocedure stenosis rate was 25.3%, and the average postprocedural stenosis rate at last angiographic follow-up was 34.7%. The primary end point of major stroke or death at 30 days was observed in 1 patient (1/35, 2.9%), and no patient had intraprocedural complications. The incidence of stroke or death at the last follow-up was 2.9%, which was superior to the results of the medical and stent-placement arms of the SAMMPRIS study. Severe restenosis was observed in 3 (3/25, 12%) patients but without any symptoms. CONCLUSIONS: In this retrospective series, primary balloon angioplasty was an effective treatment option for symptomatic intracranial stenosis with a high risk of stroke. PMID- 29976836 TI - Flavodiiron-Mediated O2 Photoreduction Links H2 Production with CO2 Fixation during the Anaerobic Induction of Photosynthesis. AB - Some microalgae, such as Chlamydomonas reinhardtii, harbor a highly flexible photosynthetic apparatus capable of using different electron acceptors, including carbon dioxide (CO2), protons, or oxygen (O2), allowing survival in diverse habitats. During anaerobic induction of photosynthesis, molecular O2 is produced at photosystem II, while at the photosystem I acceptor side, the reduction of protons into hydrogen (H2) by the plastidial [FeFe]-hydrogenases primes CO2 fixation. Although the interaction between H2 production and CO2 fixation has been studied extensively, their interplay with O2 produced by photosynthesis has not been considered. By simultaneously measuring gas exchange and chlorophyll fluorescence, we identified an O2 photoreduction mechanism that functions during anaerobic dark-to-light transitions and demonstrate that flavodiiron proteins (Flvs) are the major players involved in light-dependent O2 uptake. We further show that Flv-mediated O2 uptake is critical for the rapid induction of CO2 fixation but is not involved in the creation of the micro-oxic niches proposed previously to protect the [FeFe]-hydrogenase from O2 By studying a mutant lacking both hydrogenases (HYDA1 and HYDA2) and both Flvs (FLVA and FLVB), we show that the induction of photosynthesis is strongly delayed in the absence of both sets of proteins. Based on these data, we propose that Flvs are involved in an important intracellular O2 recycling process, which acts as a relay between H2 production and CO2 fixation. PMID- 29976837 TI - The Microtubule-Associated Protein IQ67 DOMAIN5 Modulates Microtubule Dynamics and Pavement Cell Shape. AB - The dynamic arrangement of cortical microtubules (MTs) plays a pivotal role in controlling cell growth and shape formation in plants, but the mechanisms by which cortical MTs are organized to regulate these processes are not well characterized. In particular, the dynamic behavior of cortical MTs is critical for their spatial organization, yet the molecular mechanisms controlling MT dynamics remain poorly understood. In this study, we used the puzzle piece-shaped pavement cells of Arabidopsis (Arabidopsis thaliana) leaves as a model system in which to study cortical MT organization. We isolated an ethyl methanesulfonate mutant with reduced interdigitation of pavement cells in cotyledons. This line carried a mutation in IQ67 DOMAIN5 (IQD5), which encodes a member of the plant specific IQ motif protein family. Live-cell imaging and biochemical analyses demonstrated that IQD5 binds to MTs and promotes MT assembly. MT-depolymerizing drug treatment and in vivo MT dynamics assays suggested that IQD5 functions to stabilize MTs. Hence, our findings provide genetic, cell biological, and biochemical evidence that IQD5 regulates MT dynamics that affect MT organization and subsequent cell shape formation. PMID- 29976838 TI - When maternal periconceptional diet affects neurological development, it's time to think. PMID- 29976839 TI - RalA signaling may reveal the true nature of 3T3-L1 adipocytes as a model for thermogenic adipocytes. PMID- 29976840 TI - Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. AB - Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1 12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 A, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable. PMID- 29976841 TI - Personalized disease signatures through information-theoretic compaction of big cancer data. AB - Every individual cancer develops and grows in its own specific way, giving rise to a recognized need for the development of personalized cancer diagnostics. This suggested that the identification of patient-specific oncogene markers would be an effective diagnostics approach. However, tumors that are classified as similar according to the expression levels of certain oncogenes can eventually demonstrate divergent responses to treatment. This implies that the information gained from the identification of tumor-specific biomarkers is still not sufficient. We present a method to quantitatively transform heterogeneous big cancer data to patient-specific transcription networks. These networks characterize the unbalanced molecular processes that deviate the tissue from the normal state. We study a number of datasets spanning five different cancer types, aiming to capture the extensive interpatient heterogeneity that exists within a specific cancer type as well as between cancers of different origins. We show that a relatively small number of altered molecular processes suffices to accurately characterize over 500 tumors, showing extreme compaction of the data. Every patient is characterized by a small specific subset of unbalanced processes. We validate the result by verifying that the processes identified characterize other cancer patients as well. We show that different patients may display similar oncogene expression levels, albeit carrying biologically distinct tumors that harbor different sets of unbalanced molecular processes. Thus, tumors may be inaccurately classified and addressed as similar. These findings highlight the need to expand the notion of tumor-specific oncogenic biomarkers to patient specific, comprehensive transcriptional networks for improved patient-tailored diagnostics. PMID- 29976842 TI - A new genus of Asiatic short-tailed shrew (Soricidae, Eulipotyphla) based on molecular and morphological comparisons. AB - Blarinellini is a tribe of soricine shrews comprised of nine fossil genera and one extant genus. Blarinelline shrews were once widely distributed throughout Eurasia and North America, though only members of the Asiatic short-tailed shrew genus Blarinella currently persist (mostly in southwestern China and adjacent areas). Only three forms of Blarinella have been recognized as either species or subspecies. However, recent molecular studies indicated a strikingly deep divergence within the genus, implying the existence of a distinct genus-level lineage. We sequenced the complete mitochondrial genomes and one nuclear gene of three Asiatic short-tailed and two North American shrews and analyzed them morphometrically and morphologically. Our molecular analyses revealed that specimens ascribed to B. griselda formed two deeply diverged lineages, one a close relative to B. quadraticauda, whereas the other - comprised of topotype specimens from southern Gansu - diverged from other Blarinella in the middle Miocene (ca. 18.2 million years ago (Ma), 95% confidence interval=13.4-23.6 Ma). Although the skulls were similarly shaped in both lineages, we observed several diagnostic characteristics, including the shape of the upper P4. In consideration of the molecular and morphological evidence, we recognize B. griselda as the sole species of a new genus, namely, Pantherina gen. nov. Interestingly, some characteristics of Pantherina griselda are more similar to fossil genera, suggesting it represents an evolutionarily more primitive form than Blarinella. Recognition of this new genus sheds light on the systematics and evolutionary history of the tribe Blarinellini throughout Eurasia and North America. PMID- 29976843 TI - Current understanding on the roles of gut microbiota in fish disease and immunity. AB - Intensive aquaculture has increased the severity and frequency of fish diseases. Given the functional importance of gut microbiota in various facets of host physiology, modulation of this microbiota is a feasible strategy to mitigate emerging diseases in aquaculture. To achieve this, a fundamental understanding of the interplay among fish health, microbiota, and invading pathogens is required. This mini-review focuses on current knowledge regarding the associations between fish diseases, dysbiosis of gut microbiota, and immune responses. Furthermore, updated research on fish disease from an ecological perspective is discussed, including colonization resistance imposed by commensals and strategies used by pathogens to overcome resistance. We also propose several directions for future research, such as exploration of the causal links between fish diseases and specific taxa, and identification of universal gut microbial biomarkers for rapid disease diagnosis. PMID- 29976844 TI - Tail regeneration reduction in lizards after repetitive amputation or cauterization reflects an increase of immune cells in blastemas. AB - Lizards are key amniote models for studying organ regeneration. During tail regeneration in lizards, blastemas contain sparse granulocytes, macrophages, and lymphocytes among the prevalent mesenchymal cells. Using transmission electron microscopy to examine scarring blastemas after third and fourth sequential tail amputations, the number of granulocytes, macrophages, and lymphocytes increased at 3-4 weeks in comparison to the first regeneration. An increase in granulocytes and agranulocytes also occurred within a week after blastema cauterization during the process of scarring. Blood at the third and fourth regeneration also showed a significant increase in white blood cells compared with that under normal conditions and at the first regeneration. The extracellular matrix of the scarring blastema, especially after cauterization, was denser than that in the normal blastema and numerous white blood cells and fibroblasts were surrounded by electron-pale, fine fibrinoid material mixed with variable collagen fibrils. In addition to previous studies, the present observations support the hypothesis that an increase in inflammation and immune reactions determine scarring rather than regeneration. These new findings verify that an immune reaction against mesenchymal and epidermal cells of the regenerative blastema is one of the main causes for the failure of organ regeneration in amniotes. PMID- 29976845 TI - In-Line Inspection Tool with Eddy Current Instrumentation for Fatigue Crack Detection. AB - Eddy current transducer with sensing coils placed orthogonally and connected in differential mode was introduced to evaluate fatigue cracks in clad pipeline circumferential welds. A dedicated embedded electronic hardware was developed to drive the transducer and measure the electrical complex impedance of the coils, and was specifically designed for operation under autonomous in-line inspection tool. In the laboratory experiments, an automated inspection was performed with the goal to evaluate transducer’s detectability, and different scanning speed was tested to reproduce in service situation. The results have confirmed that the introduced eddy current transducer is a potential solution for fatigue crack detection in clad circumferential weld root, while the hardware developed presented a reasonable SNR reaching the data rate required to be incorporated in an autonomous in-line inspection tool. PMID- 29976847 TI - Variations of Major Product Derived from Conversion of 5-Hydroxymethylfurfural over a Modified MOFs-Derived Carbon Material in Response to Reaction Conditions. AB - In recent years, the conversion of 5-hydroxymethylfurfural (HMF) into 5 ethoxymethylfurfural (EMF) and ethyl levulinate (EL) has become an attractive biomass transformation route due to their potential applications in the energy and chemical industries. In this study, we have developed an effective method to prepare a catalyst for this reaction. Sulfonic-acid-functionalized carbon nanomaterials (C-SO3H), prepared from the direct pyrolysis of Metal-Organic Frameworks (MOFs) precursor Cu-benzene-1,3,5-tricarboxylate (Cu-BTC) followed by acidification with sulfuric acid, show excellent catalytic activity with a total yield higher than 90%. It is interesting that, different from the previous catalysts, a different major product—EMF or EL—can be selectively obtained by controlling the reaction temperature and time. PMID- 29976846 TI - 1,10-Secoguaianolides from Artemisia austro-yunnanensis and Their Anti Inflammatory Effects. AB - Seven 1,10-secoguaianolides 1-7, including a new one (compound 1), were isolated from Artemisia austro-yunnanensis and identified by HRESIMS and other spectroscopic methods. Their anti-inflammatory effects were evaluated by the model of LPS-induced RAW264.7 cells in vitro. Bioassay results showed that six of them (1-4, 6 and 7), with the exception of 5, produce some cytotoxicity on RAW264.7 cells at its high dosage, can significantly decrease the release of NO, TNF-α, IL-1β, IL-6 and PGE2 in a dose dependent manner, and down regulate the expression of proteins iNOS and COX-2. The mechanism study indicated they regulated the NF-κB dependent transcriptional activity through decreasing the phosphorylation of NF-κB. Further, the relationship between their structures and cytokines to anti-inflammatory were studied by PCA and discussed. PMID- 29976848 TI - Differences in Falls between Older Adult Participants in Group Exercise and Those Who Exercise Alone: A Cross-Sectional Study Using Japan Gerontological Evaluation Study (JAGES) Data. AB - This study examined the difference in falls between older adults who participated in group exercise and those who exercised alone. We used cross-sectional data from the Japan Gerontological Evaluation Study. Data were obtained from functionally independent residents aged 65 years or older across 30 municipalities in Japan (n = 19,257). Logistic regression analysis was performed with experience of multiple falls over the past year as the dependent variable and type of exercise as the independent variable. Respondents were divided into three groups according to how they performed exercise: (1) non-exercisers (NE, no exercise), (2) those who only exercised alone (IE, individual exercise), and (3) those whose exercise included participation in group exercise (GE, group exercise). In total, 887 (4.6%) respondents reported multiple falls. After adjustment for 10 possible confounders, the GE group had an odds ratio (OR) for falls of 0.75 (95% confidence intervals 0.60-0.95) compared with the IE group. After adjustment for physiological factors and a psychological factor, the OR for the GE group increased slightly; however, an association between falls and exercise type was indicated. Older adults who participate in group exercise may receive additional benefits related to falls prevention compared with those who exercise alone. PMID- 29976849 TI - Genotypic Diversity Is Independent of Pathogenicity in Colombian Strains of Cryptococcus neoformans and Cryptococcus gattii in Galleria mellonella. AB - Cryptococcosis is a potentially fatal opportunistic mycosis that affects the lungs and central nervous system. It has been suggested that certain strains of C. neoformans/C. gattii may have the potential to be more virulent according to the molecular type. This study aims to investigate the association between virulence in the G. mellonella model and genotypic diversity of Colombian clinical and environmental isolates of C. neoformans/C. gattii. A total of 33 clinical and 12 environmental isolates were selected according to their geographical origin and sequence types (STs). Pathogenicity was determined using the G. mellonella model, and the cell and capsular size before and after inoculation was determined. For C. neoformans, virulence in G. mellonella revealed that death occurred on average on day 6 (p < 0.05) and that ST5C, 6C, 25C and 71C were the most virulent. In C. gattii, death occurred at 7.3 days (p < 0.05), and ST47C, 58C, 75A and 106C were the most virulent. Capsular size increased for both species after passage in G. mellonella. In conclusion, the pathogenicity of Cryptococcus strains in the G. mellonella invertebrate model is independent of molecular type or pathogenicity factor, even within the same ST, but it is possible to find variable degrees of pathogenicity. PMID- 29976850 TI - SoEasy: A Software Framework for Easy Hardware Control Programming for Diverse IoT Platforms. AB - Many Internet of Things (IoT) applications are emerging and evolving rapidly thanks to widespread open-source hardware platforms. Most of the high-end open source IoT platforms include built-in peripherals, such as the universal asynchronous receiver and transmitter (UART), pulse width modulation (PWM), general purpose input output (GPIO) ports and timers, and have enough computation power to run embedded operating systems such as Linux. However, each IoT platform has its own way of configuring peripherals, and it is difficult for programmers or users to configure the same peripheral on a different platform. Although diverse open-source IoT platforms are widespread, the difficulty in programming those platforms hinders the growth of IoT applications. Therefore, we propose an easy and convenient way to program and configure the operation of each peripheral using a user-friendly Web-based software framework. Through the implementation of the software framework and the real mobile robot application development along with it, we show the feasibility of the proposed software framework, named SoEasy. PMID- 29976851 TI - Nonlinear Flow Sensor Calibration with an Accurate Syringe. AB - Flow sensors are required for monitoring patients on mechanical ventilation and in respiratory research. Proper calibration is important for ensuring accuracy and can be done with a precision syringe. This procedure, however, becomes complex for nonlinear flow sensors, which are commonly used. The objective of the present work was to develop an algorithm to allow the calibration of nonlinear flow sensors using an accurate syringe. We first noticed that a power law equation could properly fit the pressure-flow relationship of nonlinear flow sensors. We then developed a software code to estimate the parameters for this equation using a 3 L syringe (calibration syringe). Finally, we tested the performance of a calibrated flow sensor using a different 3 L syringe (testing syringe) and a commercially available spirometer. After calibration, the sensor had a bias ranging from −1.7% to 3.0% and precision from 0.012 L to 0.039 L for volumes measured with the 3 L testing syringe. Calibrated sensor performance was at least as good as the commercial sensor. This calibration procedure can be done at the bedside for both clinical and research purposes, therefore improving the accuracy of nonlinear flow sensors. PMID- 29976853 TI - Reactive Oxygen and Nitrogen Species Regulate Key Metabolic, Anabolic, and Catabolic Pathways in Skeletal Muscle. AB - Reactive oxygen and nitrogen species (RONS) are important cellular regulators of key physiological processes in skeletal muscle. In this review, we explain how RONS regulate muscle contraction and signaling, and why they are important for membrane remodeling, protein turnover, gene expression, and epigenetic adaptation. We discuss how RONS regulate carbohydrate uptake and metabolism of skeletal muscle, and how they indirectly regulate fat metabolism through silent mating type information regulation 2 homolog 3 (SIRT3). RONS are causative/associative signaling molecules, which cause sarcopenia or muscle hypertrophy. Regular exercise influences redox biology, metabolism, and anabolic/catabolic pathways in skeletal muscle in an intensity dependent manner. PMID- 29976852 TI - The Association of Vitamin D Levels with Common Pregnancy Complications. AB - The association between vitamin D deficiency and various adverse pregnancy outcomes has been extensively investigated in recent years. The pregnant woman is the only source of vitamin D for the foetus. The main sources of vitamin D for pregnant women are sunlight, fortified dairy products, oily fish and dietary supplements. Vitamin D deficiency during pregnancy has been associated with some adverse neonatal outcomes as well as an increased risk of late pregnancy complications. The outcomes of the published studies investigating preeclampsia and gestational diabetes mellitus vary with some large trials suggesting a potential positive effect of vitamin D supplementation during pregnancy on the decreased risk of these complications. Research also suggests a possible connection between lower vitamin D concentrations and increased risk of preterm labour. In our manuscript, we aim to review the existing literature regarding the prevalence of vitamin D deficiency during pregnancy, the factors associated with vitamin D deficiency, and possible pregnancy complications arising from it. PMID- 29976854 TI - Bacterial Lipopolysaccharide Increases Serotonin Metabolism in Both Medial Prefrontal Cortex and Nucleus Accumbens in Male Wild Type Rats, but Not in Serotonin Transporter Knockout Rats. AB - It is well known that bacterial lipopolysaccharides (LPS) both increases proinflammatory cytokines and produces sickness behavior, including fatigue and anhedonia (i.e., the inability to experience pleasure). Previously, we have shown that intraperitoneally (i.p.) administered LPS increased extracellular monoamine metabolite levels in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), which was completely, or at least partly, prevented by pretreatment with a triple reuptake inhibitor that also blocks the serotonin (5-HT) transporter (SERT). This suggests indirectly, that LPS may enhance SERT transporter activity, and consequently, increase removal of 5-HT from the synaptic cleft, and increase metabolism of 5-HT. In the present study, we focus more specifically on the role of SERT in this increased metabolism by using rats, that differ in SERT expression. Therefore, the effects of an intraperitoneal LPS injection on extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were investigated by in vivo microdialysis in the NAc and mPFC of wild type (SERT+/+), heterozygous (SERT+/−) and knockout (SERT−/−) rats. Here, we show that LPS-induced 5-HIAA formation in male rats, is significantly increased in SERT+/+ rats in both the NAc and mPFC, whereas this increase is partly or totally abolished in SERT+/− and SERT−/− rats, respectively. Thus, the present study supports the hypothesis that systemic LPS in male rats increases SERT function and consequently enhances 5-HT uptake and metabolism in both the NAc and mPFC. PMID- 29976855 TI - Targeting FRET-Based Reporters for cAMP and PKA Activity Using AKAP79. AB - Fluorescence resonance energy transfer (FRET)-based sensors for 3′ 5′cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) allow real-time imaging of cAMP levels and kinase activity in intact cells with high spatiotemporal resolution. The development of FRET-based sensors has made it possible to directly demonstrate that cAMP and PKA signals are compartmentalized. These sensors are currently widely used to dissect the organization and physiological function of local cAMP/PKA signaling events in a variety of cell systems. Fusion to targeting domains has been used to direct the sensors to a specific subcellular nanodomain and to monitor cAMP and PKA activity at specific subcellular sites. Here, we investigate the effects of using the A-kinase anchoring protein 79 (AKAP79) as a targeting domain for cAMP and PKA FRET-based reporters. As AKAP79 interacts with PKA itself, when used as a targeting domain, it can potentially impact on the amplitude and kinetics of the signals recorded locally. By using as the targeting domain wild type AKAP79 or a mutant that cannot interact with PKA, we establish that AKAP79 does not affect the amplitude and kinetics of cAMP changes or the level of PKA activity detected by the sensor. PMID- 29976856 TI - Reliability of Orthodontic Miniscrews: Bending and Maximum Load of Different Ti 6Al-4V Titanium and Stainless Steel Temporary Anchorage Devices (TADs). AB - Temporary anchorage devices (TADs) have been introduced into orthodontic clinical practice in order to allow tooth movements while avoiding strain on adjacent teeth. Miniscrews are available in the market with different diameters and materials. Accordingly, the purpose of the present report was to measure and compare the forces to bend and fracture different mini implants. Ti-6Al-4V titanium and stainless steel TADs of different manufacturers (Spider ScrewHDC; Mini Implants-Leone; Benefit-Orteam; Storm-Kristal) were evaluated. Two different diameters (1.5 mm and 2.0 mm) were tested. The sample included 10 unused specimens for each group, blocked in an Instron Universal Testing Machine, and a shear load was applied at the neck of the miniscrew. The force to bend the miniscrew was measured at 0.1 mm and 0.2 mm deflections. Also, the maximum force before screw fracture was recorded. Data were submitted for statistical analysis. Results showed significantly higher forces for 2.0 mm than 1.5 mm screws, both at 0.1 mm and 0.2 mm deflections and at maximum load. Moreover, no significant differences were reported between titanium and stainless steel miniscrews of equal diameters. PMID- 29976857 TI - Comparative Chloroplast Genome Analyses of Species in Gentiana section Cruciata (Gentianaceae) and the Development of Authentication Markers. AB - Gentiana section Cruciata is widely distributed across Eurasia at high altitudes, and some species in this section are used as traditional Chinese medicine. Accurate identification of these species is important for their utilization and conservation. Due to similar morphological and chemical characteristics, correct discrimination of these species still remains problematic. Here, we sequenced three complete chloroplast (cp) genomes (G. dahurica, G. siphonantha and G. officinalis). We further compared them with the previously published plastomes from sect. Cruciata and developed highly polymorphic molecular markers for species authentication. The eight cp genomes shared the highly conserved structure and contained 112 unique genes arranged in the same order, including 78 protein-coding genes, 30 tRNAs, and 4 rRNAs. We analyzed the repeats and nucleotide substitutions in these plastomes and detected several highly variable regions. We found that four genes (accD, clpP, matK and ycf1) were subject to positive selection, and sixteen InDel-variable loci with high discriminatory powers were selected as candidate barcodes. Our phylogenetic analyses based on plastomes further confirmed the monophyly of sect. Cruciata and primarily elucidated the phylogeny of Gentianales. This study indicated that cp genomes can provide more integrated information for better elucidating the phylogenetic pattern and improving discriminatory power during species authentication. PMID- 29976858 TI - Human Pathogenic Paecilomyces from Food. AB - Paecilomyces spp. and Byssochlamys spp. are heat-resistant fungi important to industry because they can cause food and beverage spoilage, incurring economic loss. The consequences of food or beverage fungal colonization is the loss of nutritional value, structure and taste, and the possibility of producing toxic secondary metabolites that may result in medical problems. Furthermore, these fungi can infect animals and humans and it is unknown if contaminated foods may be fomites. P. variotii is the principal agent of food spoilage or contamination and it is most frequently associated with human hyalohyphomycosis with clinical manifestations including peritonitis, cutaneous and disseminated infections, among others. Byssochlamys spp. had not been identified as a cause of systemic infection until the case of a dog with a fungal infection, after immunosuppressive therapy. P. variotii has clinical importance because it causes severe infection in immunosuppressed patients and also because the number of immunocompetent infected patients is increasing. This review draws attention to the ability of these species to grow at high temperatures, to colonize food products, and to cause human disease. PMID- 29976860 TI - Study on the Performance of Nano-Titanium Nitride-Coated Stainless Steel Electrodes in Electro-Fenton Systems. AB - The electro-Fenton (EF) process is a type of electrochemical oxidation process; ·OH radicals are generated on the cathode using electricity and decolorize dye wastewaters. Most studies on EF systems in the past have focused on the operating parameters of this process. In recent years, the influence of electrode performance on the EF process has begun to receive more attention. In this study, direct nitridation was used to prepare titanium nitride powders, which were thereafter coated on an SUS304 stainless steel substrate. The performance of this system in the treatment of rhodamine B dye wastewaters via the EF process was investigated. The experimental methods used in this work include: (1) scanning electron microscopy (SEM); (2) X-ray diffraction (XRD); (3) electrochemical Tafel curves; (4) linear sweep voltammetry (LSV); (5) and cyclic voltammetry (CV). It was shown that high-purity TiN can be formed at nitriding temperatures above 900 °C, and the strength of the (111) crystal plane increases with the increase in nitriding temperature; the TiN coating effectively activates the reactive surface of the electrode owing to its porous structure. In terms of corrosion resistance, the corrosion potential and corrosion current of the TiN 1000 °C/SUS304 electrode were 116.94 mV and 205 nA/cm2, respectively, and the coating had a coating porosity of 0.89 × 10−7. As compared with SUS304 stainless steel, the TiN 1000 °C/SUS304 composite electrode had a significantly greater degree of corrosion resistance and exhibited higher redox activity in LSV tests. This composite electrode could achieve a decolorization rate of 49.86% after 30 min, and 94.46% after 120 min. In summary, the TiN 1000 °C/SUS304 composite electrode is very stable and has excellent decolorization efficacy in the EF process. Our findings will serve as a useful reference for future studies on EF electrodes. PMID- 29976859 TI - Isolation of Adipose-Derived Stem/Stromal Cells from Cryopreserved Fat Tissue and Transplantation into Rats with Spinal Cord Injury. AB - Adipose tissue contains multipotent cells known as adipose-derived stem/stromal cells (ASCs), which have therapeutic potential for various diseases. Although the demand for adipose tissue for research use remains high, no adipose tissue bank exists. In this study, we attempted to isolate ASCs from cryopreserved adipose tissue with the aim of developing a banking system. ASCs were isolated from fresh and cryopreserved adipose tissue of rats and compared for proliferation (doubling time), differentiation capability (adipocytes), and cytokine (hepatocyte growth factor and vascular endothelial growth factor) secretion. Finally, ASCs (2.5 × 106) were intravenously infused into rats with spinal cord injury, after which hindlimb motor function was evaluated. Isolation and culture of ASCs from cryopreserved adipose tissue were possible, and their characteristics were not significantly different from those of fresh tissue. Transplantation of ASCs derived from cryopreserved tissue significantly promoted restoration of hindlimb movement function in injured model rats. These results indicate that cryopreservation of adipose tissue may be an option for clinical application. PMID- 29976861 TI - Anti-Influenza A Viral Butenolide from Streptomyces sp. Smu03 Inhabiting the Intestine of Elephas maximus. AB - Actinobacteria are a phylum of bacteria known for their potential in producing structurally diversified natural products that are always associated with a broad range of biological activities. In this paper, using an H5N1 pseudo-typed virus drug screening system combined with a bioassay guided purification approach, an antiviral butanolide (1) was identified from the culture broth of Streptomyces sp. SMU03, a bacterium isolated from the feces of Elephas maximus in Yunnan province, China. This compound displayed broad and potent activity against a panel of influenza viruses including H1N1 and H3N2 subtypes, as well as influenza B virus and clinical isolates with half maximal inhibitory concentration values (IC50) in the range of 0.29 to 12 µg/mL. In addition, 1 was also active against oseltamivir-resistant influenza virus strain of A/PR/8/34 with NA-H274Y mutation. Studies on the detailed modes of action suggested that 1 functioned by interfering with the fusogenic process of hemagglutinin (HA) of influenza A virus (IAV), thereby blocking the entry of virus into host cells. Furthermore, the anti IAV activity of 1 was assessed with infected BALB/c mice, of which the appearance, weight, and histopathological changes in the infected lungs were significantly alleviated compared with the no-drug-treated group. Conclusively, these results provide evidence that natural products derived from microbes residing in animal intestines might be a good source for antiviral drug discovery. PMID- 29976862 TI - Controlling the 3D Electromagnetic Coupling in Co-Sputtered Ag-SiO2 Nanomace Arrays by Lateral Sizes. AB - Ag-SiO2 nanomace arrays were prepared on a two-dimensional ordered colloidal (2D) polystyrene sphere template by co-sputtering Ag and SiO2 in a magnetron sputtering system. The lateral size of the nanomaces and the distance between the neighbor nanomaces were controlled by adjusting the etching time of the 2D template. The nanomaces were composed of SiO2-isolated Ag nanoparticles, which produced surface-enhanced Raman scattering (SERS) enhancement, and 3D hot spots were created between the neighbor nanomaces. When the distance between the nanomaces was sufficiently large, triangle-shaped nanostructures on silicon substrate were observed, which also contributed to the enhancement of the SERS signals. The finite-difference time-domain (FDTD) method was used to calculate the electromagnetic field distributions in the Ag-SiO2 nanomace arrays, which generated physical reasons for the change of the SERS signals. PMID- 29976863 TI - Effect of PDLA and Amide Compounds as Mixed Nucleating Agents on Crystallization Behaviors of Poly (l-lactic Acid). AB - The improvement of the rate of crystallization and crystallinity of poly (l lactic acid) (PLLA) is one of the key performance elements for PLLA to perform better at the higher temperature than its heat deflection temperature (around 60 °C). The organic nucleating agent compounds are one of the interesting choice as they can offer the clarity of products. On the other hand, the nucleated PLLA can be prepared using a low molecular weight poly (d-lactic acid) (PDLA). The aim of this work was to explore the effect of an unsaturated amide compound and PDLA as single and mixed nucleating agents used for PLLA. The crystallization rate and kinetics were investigated and compared for the synthetic unsaturated amide compound (N,N′-ethylenebis (10-undecenamide) (EBU)) and commercial hydrazide compound (tetramethylenedicarboxylic dibenzoylhydrazide (TMC-306)). PLLA samples was prepared by melt-mixing with TMC or EBU incorporated with peroxide. The influence of different nucleating agents loading on thermal properties, crystallization behaviors, and rheological properties of PLLA were explored by differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA). The results showed that the addition of EBU or TMC 0.5 phr could pronouncedly increase the crystallinity of PLLA from 3.80% to 24.84% and 8.61%, respectively. The crystallization peak appeared at 112.3 °C in the cooling scan at the rate 7 °C/min when addition EBU and peroxide into PLLA. This indicated that EBU acted as an efficient nucleating agent for PLLA. In isothermal crystallization run at 110 °C, it was found that the overall crystallization rate of nucleated PLLA with TMC or EBU was much faster than neat PLLA. The crystallization half-time indicated that the existence of TMC or EBU could slightly decrease to 2.90 and 1.96 min, respectively compared to neat PLLA (4.60 min). Finally, a low molecular weight PDLA with different contents between 3 and 7 wt % was added in PLLA with EBU and peroxide to investigate the effect of mixed nucleating agents. The crystallization rate of the incorporation of PDLA/EBU/peroxide into PLLA was discussed with the proposed crystallization mechanism. The results revealed the stereocomplex temperature peak at 207 °C as well as normal melting temperature of PLLA. The kinetics of growth crystallization, the crystallization half-time of PLLA at 110 °C was reduced from 4.60 min to 1.96 min (when adding EBU alone) and to 2.62 min (when using mixed PDLA and EBU). PMID- 29976864 TI - Effects of Ventilation Improvement on Measured and Perceived Indoor Air Quality in a School Building with a Hybrid Ventilation System. AB - Ventilation system design and operation may significantly affect indoor air quality (IAQ). The aims of this case study were to investigate the functionality of a supply air fan-assisted hybrid ventilation system in a newly built school building with reported IAQ problems and to determine the effects of ventilation improvement on measured and perceived IAQ. The ventilation system function was researched simultaneously with IAQ measurements, with an analysis of total volatile organic compounds (TVOC), single volatile organic compounds (VOCs), and indoor mycobiota, and with questionnaires about perceived IAQ. At the baseline, an operational error of the ventilation system was found, which prevented the air from coming into the classrooms, except for short periods of high carbon dioxide (CO2) concentrations. After the ventilation operation was improved, a significant change in indoor mycobiota was found; the dominant, opportunistic human pathogenic species Trichoderma citrinoviride found in settled dust in the classroom before the improvement was no longer detected. In addition, the concentrations of CO2, TVOC, and some single VOCs, especially toluene and decamethylcyclopentasiloxane, decreased. The analysis of the questionnaire results indicated that the perceptions of unpleasant odors and stuffy air decreased, although a statistically significant improvement in perceived IAQ was not observed. The results provided evidence that the properly controlled hybrid ventilation system operating in mechanical supply mode provided adequate ventilation and was effective in decreasing the concentrations of some indoor generated pollutants. With simple ventilation adjustments, microbiological exposure from building structures might be prevented. PMID- 29976865 TI - Phloretin as a Potent Natural TLR2/1 Inhibitor Suppresses TLR2-Induced Inflammation. AB - Toll-like receptor 2 (TLR2) responses are involved in various inflammatory immune disorders. Phloretin is a naturally occurring dietary flavonoid that is abundant in fruit. Here, we investigated whether the anti-inflammatory activity of phloretin is mediated through TLR2 pathways, and whether phloretin acts as an inhibitor of TLR2/1 heterodimerization using the TLR2/1 agonist Pam3CSK4. We tested the effects of phloretin on tumor necrosis factor (TNF)-α production induced by various TLRs using known TLR-specific agonists. Phloretin significantly inhibited Pam3CSK4-induced TRL2/1 signaling in Raw264.7 cells compared to TLR signaling induced by the other agonists tested. Therefore, we further tested the effects of phloretin in human embryonic kidney (HEK) 293-hTLR2 cells induced by Pam3CSK4, and confirmed that phloretin has comparable inhibition of TLR2/1 heterodimerization to that induced by the known TLR2 inhibitor CU CPT22. Moreover, phloretin reduced the secretion of the inflammatory cytokines TNF-α and interleukin (IL)-8 in Pam3CSK4-induced HEK293-hTLR2 cells, whereas it did not significantly reduce these cytokines under Pam2CSK4-induced activation. Western blot results showed that phloretin significantly suppressed Pam3CSK4-induced TLR2 and NF-κB p65 expression. The molecular interactions between phloretin and TLR2 were investigated using bio-layer interferometry and in silico docking. Phloretin bound to TLR2 with micromolar binding affinity, and we proposed a binding model of phloretin at the TLR2-TLR1 interface. Overall, we confirmed that phloretin inhibits the heterodimerization of TLR2/1, highlighting TLR2 signaling as a therapeutic target for treating TLR2-mediated inflammatory immune diseases. PMID- 29976866 TI - Potential Mechanism of Action of Cyclosporin A in Human Dermal Fibroblasts Transcriptomic Analysis of CYPs. AB - Effect of cyclosporin A (CsA) in a therapeutic concentration, on the expression of cytochrome P450 genes (CYPs), was investigated in normal human dermal fibroblast cells. The expression of 57 genes, encoding cytochrome P450 isoforms, was estimated using the microarray method. Amongst 396 normalized fluorescence signals related to cytochrome P450 activity, only 91 were strictly connected to CYPs and were analyzed using two methods: a self-organizing feature map of artificial neural networks and typical statistical analysis with significance level at p ≤ 0.05. Comparing the samples from fibroblasts cultured with CsA and those cultured without, up-regulated changes of CYP19A1, 1B1, 7A1, 7F1, 17A1 and down-regulated 2D6 gene expression were observed. The mRNAs with increased changes were in the same neuron of the self-organizing feature map. All distinguished CYPs encode monooxygenases, which plays an important role in steroids biosynthesis and metabolism. Based on the obtained results, we can conclude that CsA in therapeutic concentration changes the expression profile of CYPs in human dermal fibroblasts, especially affecting genes linked to steroids synthesis and/or metabolism. It shows the potential mechanism of action of CsA in human dermal fibroblast cells. PMID- 29976867 TI - Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti Adhesives by Molecular Simulation-The Example of FimH. AB - Located at the tip of type I fimbria of Escherichia coli, the bacterial adhesin FimH is responsible for the attachment of the bacteria to the (human) host by specifically binding to highly-mannosylated glycoproteins located on the exterior of the host cell wall. Adhesion represents a necessary early step in bacterial infection and specific inhibition of this process represents a valuable alternative pathway to antibiotic treatments, as such anti-adhesive drugs are non intrusive and are therefore unlikely to induce bacterial resistance. The currently available anti-adhesives with the highest affinities for FimH still feature affinities in the nanomolar range. A prerequisite to develop higher affinity FimH inhibitors is a molecular understanding of the FimH-inhibitor complex formation. The latest insights in the formation process are achieved by combining several molecular simulation and traditional experimental techniques. This review summarizes how molecular simulation contributed to the current knowledge of the molecular function of FimH and the importance of dynamics in the inhibitor binding process, and highlights the importance of the incorporation of dynamical aspects in (future) drug-design studies. PMID- 29976868 TI - Coating Dependent In Vitro Biocompatibility of New Fe-Si Nanoparticles. AB - Magnetic nanoparticles offer multiple utilization possibilities in biomedicine. In this context, the interaction with cellular structures and their biological effects need to be understood and controlled for clinical safety. New magnetic nanoparticles containing metallic/carbidic iron and elemental silicon phases were synthesized by laser pyrolysis using Fe(CO)5 vapors and SiH4 gas as Fe and Si precursors, then passivated and coated with biocompatible agents, such as l-3,4 dihydroxyphenylalanine (l-DOPA) and sodium carboxymethyl cellulose (CMC-Na). The resulting magnetic nanoparticles were characterized by XRD, EDS, and TEM techniques. To evaluate their biocompatibility, doses ranging from 0-200 µg/mL hybrid Fe-Si nanoparticles were exposed to Caco2 cells for 24 and 72 h. Doses below 50 μg/mL of both l-DOPA and CMC-Na-coated Fe-Si nanoparticles induced no significant changes of cellular viability or membrane integrity. The cellular internalization of nanoparticles was dependent on their dispersion in culture medium and caused some changes of F-actin filaments organization after 72 h. However, reactive oxygen species were generated after exposure to 25 and 50 μg/mL of both Fe-Si nanoparticles types, inducing the increase of intracellular glutathione level and activation of transcription factor Nrf2. At nanoparticles doses below 50 μg/mL, Caco2 cells were able to counteract the oxidative stress by activating the cellular protection mechanisms. We concluded that in vitro biological responses to coated hybrid Fe-Si nanoparticles depended on particle synthesis conditions, surface coating, doses and incubation time. PMID- 29976869 TI - The Perturbation of Pulmonary Surfactant by Bacterial Lipopolysaccharide and Its Reversal by Polymyxin B: Function and Structure. AB - After inhalation, lipopolysaccharide (LPS) molecules interfere with a pulmonary surfactant, a unique mixture of phospholipids (PLs) and specific proteins that decreases surface tension at the air-liquid interphase. We evaluated the behaviour of a clinically used modified porcine pulmonary surfactant (PSUR) in the presence of LPS in a dynamic system mimicking the respiratory cycle. Polymyxin B (PxB), a cyclic amphipathic antibiotic, is able to bind to LPS and to PSUR membranes. We investigated the effect of PxB on the surface properties of the PSUR/LPS system. Particular attention was paid to mechanisms underlying the structural changes in surface-reducing features. The function and structure of the porcine surfactant mixed with LPS and PxB were tested with a pulsating bubble surfactometer, optical microscopy, and small- and wide-angle X-ray scattering (SAXS/WAXS). Only 1% LPS (w/w to surfactant PLs) prevented the PSUR from reaching the necessary low surface tension during area compression. LPS bound to the lipid bilayer of PSUR and disturbed its lamellar structure by swelling. The structural changes were attributed to the surface charge unbalance of the lipid bilayers due to LPS insertion. PxB acts as an inhibitor of structural disarrangement induced by LPS and restores original lamellar packing, as detected by polarised light microscopy and SAXS. PMID- 29976870 TI - Association of Infant Eczema with Childhood and Adult Asthma: Analysis of Data from the 1958 Birth Cohort Study. AB - The influence of early life exposures on later life disease has for some time provided clues to modifiable risk factors of disease. The “atopic march” is thought to play a role in the progression of allergic diseases and may offer an opportunity to lower asthma’s health and socioeconomic burden, although evidence remains controversial. We aimed to examine the relationship between early life eczema and asthma later in life. Using the National Child Development Study, we examined infant eczema and childhood and adult asthma. Data related to asthma or wheezing bronchitis were available for 13,503 (73%; 95% CI 72-74), 11,503 (61%; 95% CI 60-61), 12,524 (68%; 95% CI 67 69), 11,194 (60%; 95% CI 60-60), 9377 (51%; 95% CI 51-51), and 9760 (53%; 95% CI 52-53) subjects at ages 11, 16, 23, 33, 44, and 50 years, respectively. Logistic regression models were fitted to examine each wave separately before and after adjusting for a range of potential confounders. Generalised estimating equation (GEE) methods were undertaken to examine the associations after pooling all data from questionnaires. The prevalence of self-reported asthma in those that had previously reported infant eczema ranged from 1.0%; 95% CI 0.9-1.4 (age 44 years) to 2.2%; 95% CI 2.1-2.3 (age 33 years). Participants with infant eczema had a 2-3 fold increased risk of reporting asthma in childhood and adulthood; this was 1.6 times at age 44 years when using spirometry measures. Similar effect sizes were observed in the GEE models when considering all participants (OR 2.9; 95% CI 2.6 3.2). Childhood and adult asthma were consistently associated with infant eczema both by using the self-reported data and lung measures. PMID- 29976871 TI - Dengue Virus Induces the Release of sCD40L and Changes in Levels of Membranal CD42b and CD40L Molecules in Human Platelets. AB - Platelets are considered as significant players in innate and adaptive immune responses. The adhesion molecules they express, including P-selectin, CD40L, and CD42b, facilitate interactions with many cellular effectors. Upon interacting with a pathogen, platelets rapidly express and enhance their adhesion molecules, and secrete cytokines and chemokines. A similar phenomenon occurs after exposure of platelets to thrombin, an agonist extensively used for in vitro activation of these cells. It was recently reported that the dengue virus not only interacts with platelets but possibly infects them, which triggers an increased expression of adhesion molecule P-selectin as well as secretion of IL-1β. In the present study, surface molecules of platelets like CD40L, CD42b, CD62P, and MHC class I were evaluated at 4 h of interaction with dengue virus serotype 2 (DENV 2), finding that DENV-2 induced a sharp rise in the membrane expression of all these molecules. At 2 and 4 h of DENV-2 stimulation of platelets, a significantly greater secretion of soluble CD40L (sCD40L) was found (versus basal levels) as well as cytokines such as GM-CSF, IL-6, IL-8, IL-10, and TNF-α. Compared to basal, DENV-2 elicited more than two-fold increase in these cytokines. Compared to the thrombin-induced response, the level generated by DENV-2 was much higher for GM-CSF, IL-6, and TNF-α. All these events induced by DENV end up in conspicuous morphological changes observed in platelets by confocal microscopy and transmission electron microscopy, very different from those elicited by thrombin in a more physiological scenery. PMID- 29976872 TI - In Overweight or Obese Pregnant Women, Maternal Dietary Factors are not Associated with Fetal Growth and Adiposity. AB - The aim of our study was to evaluate associations between maternal dietary factors and fetal growth and adiposity in overweight and obese women. Women randomised to the ‘Standard Care’ group of the LIMIT trial were included. Maternal dietary factors including Healthy Eating Index, total energy, fat, carbohydrates, protein, glycaemic load and index were measured using the Harvard semi-quantitative Food Frequency questionnaire at time of study entry, 28 and 36 weeks’ gestation. Fetal ultrasound measurements of biometry and adiposity were obtained at 28 and 36 weeks’ gestation. Linear regression models were used to associate between dietary factors and fetal growth and adiposity measurements. There were 721 women included in this exploratory analysis. A 10 unit increase in the log total energy was associated with a reduction in mid-thigh lean mass by 4.94 mm at 28 weeks (95% CI −9.57 mm, −0.32 mm; p = 0.036) and 7.02 mm at 36 weeks (95% CI −13.69 mm, −0.35 mm; p = 0.039). A 10 unit increase in Healthy Eating Index score was associated with a reduced mean subscapular skin fold measure at 28 weeks by 0.17 mm (95% CI −0.32 mm, −0.03 mm; p = 0.021). We did not identify consistent associations between maternal diet and measures of fetal growth and adiposity in overweight and obese women. PMID- 29976873 TI - Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide Stimulated Cultures. AB - An increasing body of evidence postulates that microglia are the main mediators of inflammation-related disorders, including depression. Since activated microglia produce a wide range of pro- and anti-inflammatory factors, the modulation of M1/M2 microglial polarization by antidepressants may be crucial in the treatment of depression. The current paper aimed to investigate the impact of tianeptine on the microglia’s viability/death parameters, and on M1/M2 microglial activation in response to lipopolysaccharide (LPS) stimulation. Furthermore, the molecular mechanisms via which tianeptine affected the LPS evoked changes were investigated. The results revealed that tianeptine had partially protective effects on the changes in microglia viability/death evoked by LPS. Tianeptine attenuated microglia activation by decreasing the expression of cluster of differentiation 40 (CD40), and major histocompatibility complex class II (MHC II) markers, as well as the release of pro-inflammatory factors: interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α), and chemokine CC motif ligand 2 (CCL2), and the production of nitric oxide and reactive oxygen species. In contrast, we did not observe an impact of tianeptine on M2 microglia measured by IL-4, IL-10, TGF-β, and insulin-like growth factor 1 (IGF-1) expression. Moreover, we demonstrated an inhibitory effect of tianeptine on the LPS-induced activation of the nucleotide-binding oligomerization domain-like (NOD-like) receptor pyrin-containing 3 inflammasome (NLRP3) inflammasome subunits, NLRP3 and caspase-1, as well as the ability of tianeptine to reduce Toll-like receptor 4 (TLR4) levels, as well as the phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2) and of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Collectively, we demonstrated that tianeptine has protective properties and inhibits M1 polarization, thus attenuating the production of inflammatory mediators. Moreover, we found that M1 microglia suppression may be related to the NLRP3 inflammasome and TLR4 signaling. These findings suggest that a better understanding of the multifaceted mechanisms of tianeptine action on microglia may increase the effectiveness of therapy, where inflammation is a central hallmark. PMID- 29976874 TI - Utility of Two-Dimensional Difference Gel Electrophoresis in Diagnosis of Multiple Sclerosis. AB - Two-dimensional difference gel electrophoresis (2D-DIGE) has been used for identification of possible biomarkers in the cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients. However, in different studies inconsistent results have been obtained. We wanted to analyze the diagnostic value of 2D-DIGE in early MS patients by comparing protein patterns between single and pooled samples of MS patients and controls. CSF samples of 20 MS patients and 10 control subjects were processed with 2D-DIGE. The so obtained protein patterns were analyzed with DeCyder 6.5 software, whereby we described variation of patterns presented in one gel as well as between different gels. Even when running single samples of patients of the same group in one gel, variation of protein patterns was high. The number of identified spots with different protein level varied between 4 and 30, depending on which sample batches were compared. We did not find a consistent pattern throughout all possible batch combinations. The inter individual variation of protein expression as well as the susceptibility of 2D DIGE for methodological variations makes use of 2D-DIGE as a diagnostic tool for MS and for detection of possible candidate biomarkers difficult, since detected proteins vary depending on which samples are compared. PMID- 29976875 TI - Zinc Deficiency among Lactating Mothers from a Peri-Urban Community of the Ecuadorian Andean Region: An Initial Approach to the Need of Zinc Supplementation. AB - Zinc is an important mineral for biological and physiological processes. Zinc deficiency (ZD) is one of the most common micronutrient deficiencies worldwide and a crucial determinant of pregnancy outcomes and childhood development. Zinc levels and the zinc supplementation rate among lactating women have not been assessed neither in Ecuador nor in the Andean region. We conducted a pilot study including 64 mothers of infants between eight days to seven months old from a primary care center located in Conocoto, a peri-urban community of Quito, Ecuador. The mothers were interviewed and a fasting blood sample was taken to determine plasma zinc levels. The prevalence of ZD was calculated and compared with the prevalence of ZD among Ecuadorian non-pregnant non-lactating women, and the sample was analysed considering zinc supplementation during pregnancy. The prevalence of ZD among the participants was 81.3% (95% CI: 71.7-90.9), higher than the reported among non-pregnant non-lactating women (G2 = 18.2; p < 0.05). Zinc supplementation rate was 31.2%. No significant differences were found comparing the groups considering zinc supplementation. The insights obtained from this study encourage extending studies to document zinc levels and its interactions among breastfeeding women in areas with a high prevalence of ZD in order to determine the need of zinc supplementation. PMID- 29976876 TI - Development of Dermal Films Containing Miconazole Nitrate. AB - This study aims to develop new antifungal dermal films based on their mechanical properties (elongation, adhesion, behaviour towards vapour moisture) and the in vitro availability of miconazole nitrate, used as a pharmaceutical active ingredient in various concentrations. The three polymeric films prepared were translucent or shiny, with the surface of 63.585 cm2, 0.20-0.30 mm thickness, and content of miconazole nitrate of 3.931 or 15.726 mg·cm2. The mechanical resistance and elongation tests demonstrated that the two films based on hydroxyethyl cellulose (HEC) polymer were more elastic than the one prepared with hydroxypropyl methylcellulose (HPMC). The vapour water absorption and vapour water loss capacity of the films revealed that the HPMC film did not dry very well in the process of preparation by the evaporation of the solvent technique, unlike the HEC films that jellified more evenly in water and had higher drying capacity at 40 °C. The in vitro availability of miconazole nitrate from dermal films was evaluated using the Franz diffusion cell method, through a synthetic membrane (Ø 25 mm × 0.45 µm) and acceptor media with pH 7.4 (phosphate buffer and sodium lauryl sulphate 0.045%), resulting a release rate of up to 70%. PMID- 29976877 TI - Effects of Low Energy Availability on Reproductive Functions and Their Underlying Neuroendocrine Mechanisms. AB - It is known that metabolic disturbances suppress reproductive functions in females. The mechanisms underlying metabolic and nutritional effects on reproductive functions have been established based on a large body of clinical and experimental data. From the 1980s to 1990s, it was revealed that disrupted gonadotropin-releasing hormone (GnRH) secretion is the main cause of reproductive impairments in metabolic and nutritional disorders. From the late 1990s to early 2000s, it was demonstrated that, in addition to their primary functions, some appetite- or metabolism-regulating factors affect GnRH secretion. Furthermore, in the early 2000s, kisspeptin, which is a potent positive regulator of GnRH secretion, was newly discovered, and it has been revealed that kisspeptin integrates the effects of metabolic status on GnRH neurons. Recent studies have shown that kisspeptin mediates at least some of the effects of appetite- and metabolism-regulating factors on GnRH neurons. Thus, kisspeptin might be a useful clinical target for treatments aimed at restoring reproductive functions in individuals with metabolic or nutritional disturbances, such as those who exercise excessively, experience marked weight loss, or suffer from eating disorders. This paper presents a review of what is currently known about the effects of metabolic status on reproductive functions and their underlying mechanisms by summarizing the available evidence. PMID- 29976878 TI - Assessment of Microbiological Safety of Water in Public Swimming Pools in Guangzhou, China. AB - This study assessed microbiological safety of water from public swimming pools in Guangzhou, China. Water samples from 39 outdoor municipal swimming pools were collected from late June to early September, 2013 and subjected to detection of protozoa (Giardia and Cryptosporidium) and bacteria (Pseudomonas aeruginos, total coliforms, E. coli, E. coli O157, Shigella, and Salmonella). Cryptosporidium and Giardia were both detected in 5 (12.8%) swimming pools. Total coliforms were detected in 4 (10.3%) samples with concentrations ranging from 1.3 to 154.0 MPN/100 mL while E. coli was detected in 4 (10.3%) samples with concentrations ranging from 0.5 to 5.3 MPN/100 mL. P. aeruginosa was detected in 27 (69.2%) samples but E. coli O157, Shigella and Salmonella were not detected. Among these swimming pools, 9 (23%) met the Chinese National Standard of residual chlorine levels and 24 (62%) were tested free of residual chlorine at least once. The multi-locus sequence typing (MLST) analysis showed that all P. aeruginosa isolates belonged to new sequence types (STs) with dominant ST-1764 and ST-D distributed in different locations within the area. Some P. aeruginosa strains were resistant to medically important antibiotics. Results indicate potential public health risks due to the presence of microbiological pathogens in public swimming pools in this area. PMID- 29976880 TI - Hybrid Top-Down/Bottom-Up Fabrication of a Highly Uniform and Organized Faceted AlN Nanorod Scaffold. AB - As a route to the formation of regular arrays of AlN nanorods, in contrast to other III-V materials, the use of selective area growth via metal organic vapor phase epitaxy (MOVPE) has so far not been successful. Therefore, in this work we report the fabrication of a highly uniform and ordered AlN nanorod scaffold using an alternative hybrid top-down etching and bottom-up regrowth approach. The nanorods are created across a full 2-inch AlN template by combining Displacement Talbot Lithography and lift-off to create a Ni nanodot mask, followed by chlorine based dry etching. Additional KOH-based wet etching is used to tune the morphology and the diameter of the nanorods. The resulting smooth and straight morphology of the nanorods after the two-step dry-wet etching process is used as a template to recover the AlN facets of the nanorods via MOVPE regrowth. The facet recovery is performed for various growth times to investigate the growth mechanism and the change in morphology of the AlN nanorods. Structural characterization highlights, first, an efficient dislocation filtering resulting from the ~130 nm diameter nanorods achieved after the two-step dry-wet etching process, and second, a dislocation bending induced by the AlN facet regrowth. A strong AlN near band edge emission is observed from the nanorods both before and after regrowth. The achievement of a highly uniform and organized faceted AlN nanorod scaffold having smooth and straight non-polar facets and improved structural and optical quality is a major stepping stone toward the fabrication of deep UV core-shell-based AlN or AlxGa1-xN templates. PMID- 29976879 TI - The Many Faces of Amphipathic Helices. AB - Amphipathic helices (AHs), a secondary feature found in many proteins, are defined by their structure and by the segregation of hydrophobic and polar residues between two faces of the helix. This segregation allows AHs to adsorb at polar-apolar interfaces such as the lipid surfaces of cellular organelles. Using various examples, we discuss here how variations within this general scheme impart membrane-interacting AHs with different interfacial properties. Among the key parameters are: (i) the size of hydrophobic residues and their density per helical turn; (ii) the nature, the charge, and the distribution of polar residues; and (iii) the length of the AH. Depending on how these parameters are tuned, AHs can deform lipid bilayers, sense membrane curvature, recognize specific lipids, coat lipid droplets, or protect membranes from stress. Via these diverse mechanisms, AHs play important roles in many cellular processes. PMID- 29976881 TI - Overview on the Mycotoxins Incidence in Serbia in the Period 2004-2016. AB - With an average annual production of 6.9 M tonnes and 2.5 M tonnes of maize and wheat respectively, Serbia is one of the main grain producers and exporters in Europe. Cereals are also the major staple food in Serbian diet. In view of the high cereal consumption, for human and animal nutrition, the presence of mycotoxins entails a high public health risk of chronic exposure to mycotoxins. This study provides an overview of the incidence of predominant mycotoxins, mainly in cereal and dairy products, in Serbia, in the 2004-2016, using data reported in the scientific literature. The study demonstrated that the total prevalence of aflatoxins was 62.9% (n = 12,517) with 26.2% of the samples exceeding the EU limits during this period. Results obtained for T-2/HT-2 (n = 523), deoxynivalenol (n = 2907), fumonisins (n = 998), zearalenone (n = 689) and ochratoxin A (n = 740) indicated the prevalence of 45.5%, 42.9%, 63.3%, 39.3% and 28.1%, respectively. For these mycotoxins, the EU limits were less frequently exceeded. Comprehensive collection and analysis of all accessible information reviewed in this paper showed moderate incidence and prevalence of mycotoxins in Serbia, with an exception of the 2012 drought year and the 2014 flood year. PMID- 29976882 TI - A High-Precision CMOS Temperature Sensor with Thermistor Linear Calibration in the (-5 degrees C, 120 degrees C) Temperature Range. AB - A high-precision Complementary Metal-Oxide-Semiconductor (CMOS) temperature sensor for (−5 °C, 120 °C) temperature range is designed and analyzed in this investigation. The proposed design is featured with a temperature range selection circuit so that the thermistor linear circuit automatically switches to a corresponding calibration loop in light of the temperature range besides the analysis of the calibration method. It resolves the problem that the temperature range of a single thermistor temperature sensor is too small. Notably, the output of the proposed design also attains a high linearity. The measurement results in a thermal chamber justifying that the output voltage is 1.96 V to 4.15 V, the maximum linearity error ≤1.4%, and the worst temperature error ≤1.1 °C in the temperature range of −5 °C to 120 °C. PMID- 29976883 TI - Improving Hydrophilicity and Inducing Bone-Like Apatite Formation on PPBES by Polydopamine Coating for Biomedical Application. AB - Copoly(phthalazinone biphenyl ether sulfone) (PPBES) as a commercially available polyarylether is a promising orthopaedic implant material because its mechanical properties are similar to bone. However, the bioinert surface of polyarylether causes some clinical problems after implantation, which limits its application as an implant material. In this study, the surface of PPBES was modified by a biomineralization method of polydopamine-assisted hydroxyapatite formation (pHAF) to enhance its cytocompatibility. Polydopamine (PDA) coating, inspired by the adhesion mechanism of mussels, can readily endow PPBES with high hydrophilicity and the ability to integrate via the bone-like apatite coating. PPBES and PDA coated PPBES were evaluated by scanning electronic microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurement. The water contact angles were reduced significantly after coating with PDA. PDA was successfully synthesized on PPBES and more PDA was obtained by increasing the temperature. Bone-like apatite on PPBES (apatite-coated PPBES) was confirmed by SEM and transmission electron microscopy (TEM). The cytotoxicity of pristine PPBES and apatite-coated PPBES were characterized by culturing of NIH-3T3 cells. Bone-like apatite synthesized by pHAF could further enhance cytocompatibility in vitro. This study provides a promising alternative for biofunctionalized PPBES with improved cytocompatibility for bone implant application. PMID- 29976884 TI - First-Principles Investigation on the Electronic and Mechanical Properties of Cs Doped CH3NH3PbI3. AB - Methylammonium lead iodide, CH3NH3PbI3, is currently a front-runner as light absorber in hybrid solar cells. Despite the high conversion efficiency, the stability of CH3NH3PbI3 is still a major obstacle for commercialization application. In this work, the geometry, electronic structure, thermodynamic, and mechanical property of pure and Cs-doped CH3NH3PbI3 have been systematically studied by first-principles calculations within the framework of the density functional theory (DFT). Our studies suggest that the (CH3NH3)+ organic group takes a random orientation in perovskite lattice due to the minor difference of orientation energy. However, the local ordered arrangement of CH3NH3+ is energetic favorable, which causes the formation of electronic dipole domain. The band edge states of pure and Cs-doped CH3NH3PbI3 are determined by (PbI6)− group, while A-site (CH3NH3)+ or Cs+ influences the structural stability and electronic level through Jahn-Teller effect. It has been demonstrated that a suitable concentration of Cs can enhance both thermodynamic and mechanical stability of CH3NH3PbI3 without deteriorating the conversion efficiency. Accordingly, this work clarifies the nature of electronic and mechanical properties of Cs-doped CH3NH3PbI3, and is conducive to the future design of high efficiency and stable hybrid perovskite photovoltaic materials. PMID- 29976886 TI - Hydrophilic and Hydrophobic Mesoporous Silica Derived from Rice Husk Ash as a Potential Drug Carrier. AB - This work describes the preparation of mesoporous silica by the green reaction of rice husk ash (RHA) with glycerol, followed by the modification and the potential use as a drug carrier. The reaction was carried out at 215 °C for 2 h. The solution was further hydrolyzed with deionized water and aged for various times (24, 48, 120, 360, 528 and 672 h) before calcinations at 500 °C for 24 h. Further treatment of prepared mesoporous silica was performed using trimethylmethoxysilane (TMMS) to obtain hydrophobic Mesoporous silica. For all synthesized silicas, silica contents were as high as 95 wt %, whereas organic residues were less than 3 wt %. RHA-glycerol showed the highest specific surface area with smallest pore diameter (205.70 m2/g, 7.46 nm) when aged for 48 h. The optimal hydrolysis-ageing period of 120 h resulted in 500.7 m2/g specific surface area, 0.655 cm3/g pore volume and 5.23 nm pore diameter. The surface modification of RHA-glycerol occurred through the reaction with TMMS as confirmed by FTIR (Fourier-transform infrared spectroscopy). Ibuprofen was selected as a model drug for the adsorption experiments. The adsorption under supercritical CO2 was carried out at isothermal temperature of 40 °C and 100 bar; % ibuprofen loading of TMMS modified mesoporous silica (TMMS-g-MS) was 6 times less than that of mesoporous silica aged for 24 h (MS-24h) due to the hydrophobic nature of modified mesoporous silica, not surface and pore characteristics. The release kinetics of ibuprofen-loaded mesoporous silicas were also investigated in vitro. The release rate of ibuprofen-loaded MS-24h was much faster than that of ibuprofen-loaded TMMS-g-MS, but comparable to the crystalline ibuprofen. The slower release rate was attributed to the diffusion control and the stability of hydrophobic nature of modified silica. This would allow the design of a controlled release drug delivery system. PMID- 29976885 TI - Para-probiotics for Preterm Neonates-The Next Frontier. AB - Current evidence supports the use of probiotics in preterm neonates for prevention of necrotizing enterocolitis, mortality and late onset sepsis. Despite the strong evidence, the uptake of this intervention has not been universal due to concerns including probiotic sepsis, pro-inflammatory response and transmission of antibiotic resistance. Critically ill extremely preterm neonates with potentially compromised gut integrity are at higher risk of probiotic sepsis due to translocation. In most countries, probiotics are sold as food supplements with poor quality control. The traditional definition of probiotics as “live microorganisms” has been challenged as many experts have questioned the importance of viability in the context of the beneficial effects of probiotics. Paraprobiotics (ghost probiotics), are defined as non-viable microbial cells (intact or broken) or crude cell extracts (i.e., with complex chemical composition), which, when administered (orally or topically) in adequate amounts, confer a benefit on the human or animal consumer. Current evidence indicates that paraprobiotics could be safe alternatives to probiotics in preterm neonates. High-quality pre-clinical and clinical studies including adequately powered randomised controlled trials (RCTs) are warranted in preterm neonates to explore this new frontier. PMID- 29976888 TI - Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways. AB - It is hypothesized that the uremic toxin indoxyl sulfate (IS) plays a role in the pathogenesis of renal anemia. To further explore that hypothesis, we examined the effects of IS on reactive oxygen species (ROS) production, levels of reduced glutathione (GSH), and erythrocyte death (eryptosis) in red blood cells (RBC) from healthy controls (CON-RBC) and hemodialyzed patients (HD-RBC), respectively. RBC were incubated either in either TRIS-Glc-BSA buffer or IS at concentrations of 0.01, 0.09, and 0.17 mM, respectively. We measured ROS generation (expressed as % of DCFH-DA positive RBC), eryptosis (expressed as % of annexin-V positive RBC), and GSH levels after 6, 12, and 24 h. When incubated in buffer, ROS production was approximately seven-fold higher at all time points HD-RBC when compared to CON-RBC. Incubation with IS increased ROS production in CON-RBS dose dependently up to 10-fold. Eryptosis in buffer-incubated HD-RBC was up to seven fold higher as compared to COB-RBC. Incubation of CON-RBC with IS increased the eryptosis rate dose-dependently up to 6-fold. Pretreatment of CON-RBC with the organic anion transporter 2 (OAT2) specific inhibitor ketoprofen or with NADPH oxidase inhibitor diphenyleneiodonium-Cl blunted the IS effect on both ROS production and eryptosis induction. While GSH levels in HD-RBC were reduced when compared to CON-RBC, they were not affected by IS incubation. In summary, IS increases ROS generation and eryptosis in CON-RBC by an activity dependent of the IS influx through OAT2, and NADPH oxidase activity-dependent, and a GSH independent mechanism. These findings lend support to a putative role of IS in the pathogenesis of renal anemia. PMID- 29976887 TI - In Vitro Anti-Cholinesterase and Antioxidant Activity of Extracts of Moringa oleifera Plants from Rivers State, Niger Delta, Nigeria. AB - This study evaluated Moringa oleifera extracts from two locations in Niger Delta for in vitro anti-cholinesterase and antioxidant activities. Methanolic, aqueous and ethanolic extracts of Moringa oleifera were evaluated for inhibition of acetylcholinesterase (AChE) activity, antioxidant properties, and total phenolic and flavonoid contents using standard procedures. M. oleifera extracts possessed significant and concentration dependent AChE inhibitory activity for methanolic, aqueous, and ethanolic extracts. For the most potent extracts, the percentage AChE inhibition/IC50 (µg/mL) values were Moringa oleifera root methanolic extracts (MORME): ~80%/0.00845; Moringa oleifera root ethanolic extract 1 (MOREE1): ~90%/0.0563; Moringa oleifera root ethanolic extract 2 (MOREE2): ~70%/0.00175; and Moringa oleifera bark ethanolic extract (MOBEE): ~70%/0.0173. The descending order of AChE inhibitory potency of plant parts were: root > bark > leaf > flowers > seed. All M. oleifera methanolic extracts at a concentration of 1000 µg/mL displayed significant (p < 0.05-0.001) DPPH radical scavenging activity, with values of ~20-50% of that of ascorbic acid. The total phenolic content and total flavonoid content (TPC/TFC) of MORME, Moringa Oju bark methanolic extract (MOBME), MOREE1, MOREE2 and Moringa leaf ethanolic leaf extract (MLEE) were (287/254), (212/113), (223/185), (203/343) and (201/102) mg gallic acid equivalents/g and quercetin equivalents/g, respectively. There was an inverse correlation between plant extract AChE inhibition and total phenolic (p < 0.0001) and total flavonoid contents (p < 0.0012). In summary, this study revealed 5 of 19 extracts of M. oleifera that have potent in vitro anti cholinesterase and antioxidant activities. PMID- 29976889 TI - Effect of Squat Exercises on Lung Function in Elderly Women with Sarcopenia. AB - We explored whether a mechanically-assisted squat exercise improved muscle mass, muscle function, and pulmonary function in elderly women with or without sarcopenia. In total, 76 community-dwelling elderly subjects (>60 years of age) were screened. We ultimately included 30 subjects who completed more than 80% of the six-week course of mechanically-assisted squat exercises (three days per week, 30 min per day). We measured body composition, lung function, knee extensor strength, hand grip strength, and the 3-min walk distance (3MWD) before and after the exercise program. Subjects with sarcopenia had poor hand grip strength and knee extensor strength, and a slow walking speed. Their lung function parameters, including forced vital capacity (FVC), was lower than those of the controls. After six weeks of squat exercises, the hand grip strength, knee extensor strength, and 3MWD increased significantly in both groups. Appendicular skeletal muscle mass and leg lean mass were increased in subjects without sarcopenia. The FVC (L) increased significantly only in the sarcopenia group (p = 0.019). The mechanically-assisted squat exercise program increased muscle function and lung function, including FVC, in patients with sarcopenia. Muscle mass increased in subjects without sarcopenia. PMID- 29976890 TI - Discovery of Matrinic Thiadiazole Derivatives as a Novel Family of Anti-Liver Fibrosis Agents via Repression of the TGFbeta/Smad Pathway. AB - A series of novel matrinic thiadiazole derivatives were designed, synthesized and evaluated for their inhibitory effect on COL1A1 promotor. The SAR indicated that: (i) the introduction of a thiadiazole on the 11-side chain was beneficial for activity; (ii) a 12-N-benzyl moiety was favorable for activity. Among them, compound 6n displayed a high activity with an inhibitory rate of 39.7% at a concentration of 40 μM. It also effectively inhibited the expression of two representative collagen proteins (COL1A1 and α-SMA) on both the mRNA and protein levels and showed a high safety profile in vivo, indicating its great promise as an anti-liver fibrosis agent. Further study indicated that it might repress hepatic fibrogenesis via the TGFβ/Smad pathway. This study provided powerful information for further strategic optimization and the top compound 6n was selected for further study as an ideal liver fibrosis lead for next investigation. PMID- 29976891 TI - "Chocolate" Gold Nanoparticles-One Pot Synthesis and Biocompatibility. AB - The chemical synthesis of nanoparticles can involve and generate toxic materials. Here, we present for the first time, a one pot direct route to synthesize gold nanoparticles (AuNPs) using natural cacao extract as both a reducing and stabilizing agent. The nanoparticles were characterized by UV-visible spectroscopy (UV-VIS), dynamic light scattering (DLS), and transmission electron microscopy (TEM); and have excellent biocompatibility with human primary dermal fibroblasts. PMID- 29976892 TI - Effects of Railway Elevation, Operation of a New Station, and Earthquakes on Railway Noise Annoyance in Kumamoto, Japan. AB - This study investigated the effects of railway elevation, operation of a new station, and earthquakes on railway noise annoyance in two areas along a conventional railway line (CRL) adjacent to the Kyushu Shinkansen line: the north area with the CRL elevation and the south area with the operation of the new station, both of which occurred in March 2016. In April 2016, Kumamoto region was struck by a series of large earthquakes, prompting their inclusion in this study, as frequent aftershocks with loud ground rumbling might make people more sensitive to railway noise and vibration. Socioacoustic surveys were performed in both areas before and after the earthquakes. Because very few respondents in the north area reported that they were “highly annoyed,” further analysis was conducted on data from the south area. The exposure-annoyance relationship was found to be significantly higher in 2017 than in 2011 despite lower noise exposure. Multiple logistic regression analysis showed that Lden, noise sensitivity, and serious damage by the earthquakes in addition to the operation of the new station significantly affected the annoyance in both detached and apartment houses. However, when the earthquakes caused minimal damage, they did not significantly affect annoyance. PMID- 29976893 TI - General Practitioners' Views on the Acceptability and Applicability of Using Quality Indicators as an Intervention to Reduce Unnecessary Prescription of Antibiotics in Four South American Countries. AB - As part of the quality improvement program “Health Alliance for Prudent Prescribing, Yield And Use of anti-microbial Drugs In the Treatment of respiratory tract infections” (HAPPY AUDIT) South America, we planned to implement an intervention based on the use of quality indicators as a means to influence General Practitioners’ (GPs) prescribing decision. Knowledge on the acceptability and applicability of an intervention is crucial to decide whether the intervention is suitable and will achieve the expected outcomes. This study explores GPs’ views about the acceptability and applicability of using quality indicators as an intervention to influence their prescribing decision in patients with suspected Respiratory Tract Infections (RTIs) across four countries in South-America. In March 2015, GPs that were participating in HAPPY AUDIT South America were invited to participate in focus groups. A discussion guide covering the domains acceptability and applicability was used. Data was analyzed through systematic text condensation with an inductive approach. 171 GPs were invited and 48% participated. Acceptability ranged from totally acceptable to slightly acceptable. This spectrum of GPs views on acceptability was influenced by themes concerning applicability. In conclusion, there is a positive attitude towards the use of quality indicators. Nonetheless, applicability challenges have to be taken into consideration and solved if we are to achieve a large effect with the implementation of this intervention. PMID- 29976895 TI - Microbiological Parameters in the Primary Production of Berries: A Pilot Study. AB - The primary production of fresh soft fruits was considered to be a suspected critical point for the contamination of frozen berries that were responsible for the large 2013-2014 Hepatitis A virus (HAV) outbreak in Europe. In this study, an Italian berries’ production area was studied for its agro-technical characteristics, and the fresh fruits were analyzed for the presence of enteric viruses (HAV and Norovirus (NoV) genogroup I and genogroup II (GGI and GGII)), the enumeration of hygienic quality parameters, and the prevalence of bacterial pathogens. A total of 50 producers were sampled, who specialized in the exclusive or shared cultivation of berries. Escherichia coli was detected in two blackberry samples, whereas HAV and Norovirus were not detected. The samples were negative for Salmonella spp., Listeria monocytogenes, and Shiga toxin-producing Escherichia coli (STEC). The farms’ attributes were not associated with positive samples, apart from the presence of E. coli and the aerobic mesophilic bacteria for blackberry that were statistically correlated. In blueberries, the high aerobic mesophilic count could likely be associated with the resistance of the outer layer to handling. However, the two pathogens (Salmonella spp. and STEC) and the targeted viruses (HAV, NoV GGI and GGII) were not detected, highlighting the low risk of foodborne pathogens and viral contamination at the primary production stage of the berry food chain in the area considered in this pilot study. PMID- 29976894 TI - Biological Activities and Safety of Citrus spp. Essential Oils. AB - Citrus fruits have been a commercially important crop for thousands of years. In addition, Citrus essential oils are valuable in the perfume, food, and beverage industries, and have also enjoyed use as aromatherapy and medicinal agents. This review summarizes the important biological activities and safety considerations of the essential oils of sweet orange (Citrus sinensis), bitter orange (Citrus aurantium), neroli (Citrus aurantium), orange petitgrain (Citrus aurantium), mandarin (Citrus reticulata), lemon (Citrus limon), lime (Citrus aurantifolia), grapefruit (Citrus × paradisi), bergamot (Citrus bergamia), Yuzu (Citrus junos), and kumquat (Citrus japonica). PMID- 29976896 TI - Urinary Inorganic Arsenic Concentration and Gestational Diabetes Mellitus in Pregnant Women from Arica, Chile. AB - Introduction: The association of total arsenic exposure with impaired glucose tolerance and gestational diabetes has been shown; however, evidence regarding urinary inorganic arsenic in pregnant women is still limited. Our aim was to evaluate the association between urinary inorganic arsenic concentration and gestational diabetes among pregnant women living in Arica, Chile. Methods: Cross sectional study of pregnant women receiving care at primary health centers in urban Arica. The exposure was urinary inorganic arsenic concentration, while gestational diabetes was the outcome. The association was evaluated using multiple logistic regression models adjusted by age, education level, ethnicity, and pre-pregnancy body mass index. Results: 244 pregnant women were surveyed. The median urinary inorganic arsenic was 14.95 μg/L, and the prevalence of gestational diabetes was 8.6%. After adjusting, we did not find a significant association between gestational diabetes and inorganic arsenic exposure tertiles (Odds ratio (OR) 2.98, 95% CI = 0.87-10.18), (OR 1.07, 95% CI = 0.26-4.33). Conclusion: This study did not provide evidence on the relationship between urinary inorganic arsenic concentration and gestational diabetes. Further research is needed to elucidate the factors underlying this association. PMID- 29976897 TI - A Blade Defect Diagnosis Method by Fusing Blade Tip Timing and Tip Clearance Information. AB - Blade tip timing (BTT) technology is considered the most promising method for blade vibration measurements due to the advantages of its simplicity and non contact measurement capacity. Nevertheless, BTT technology still suffers from two problems, which are (1) the requirements of domain expertise and prior knowledge of BTT signals analysis due to severe under-sampling; and (2) that the traditional BTT method can only judge whether there is a defect in the blade but it cannot judge the severity and the location of the defect. Thus, how to overcome the above drawbacks has become a big challenge. Aiming at under-sampled BTT signals, a feature learning method using a convolutional neural network (CNN) is introduced. In this way, some new fault-sensitive features can be adaptively learned from raw under-sampled data and it is therefore no longer necessary to rely on prior knowledge. At the same time, research has found that tip clearance (TC) is also very sensitive to the blade state, especially regarding defect severity and location. A novel analysis method fusing TC and BTT signals is proposed in this paper. The goal of this approach is to integrate tip clearance information with tip timing information for blade fault detection. The method consists of four key steps: First, we extract the TC and BTT signals from raw pulse data; second, TC statistical features and BTT deep learning features will be extracted and fused using the kernel principal component analysis (KPCA) method; then, model training and selection are carried out; and finally, 16 sets of experiments are carried out to validate the feasibility of the proposed method and the classification accuracy achieves 95%, which is far higher than the traditional diagnostic method. PMID- 29976898 TI - Associations of Family Demands and Work-Life Conflict with Musculoskeletal Disorders among Korean Workers. AB - Although family-related demands play a role in the effect of psychosocial work characteristics on health, research on work-related health has neglected the family domain. The aim of the present study was to identify the effects of family demands and work-life conflict (WLC) on musculoskeletal disorders (MSDs) among Korean workers. We analyzed data from the nationally representative Korean Working Conditions Survey conducted with 50,007 workers in 2014. Logistic regression analyses stratified by gender were performed to identify gender differences, and interaction terms including WLCs and key covariates were also incorporated. Childcare demands (odds ratio (OR), 1.16) were related to MSD only in male workers, whereas homemaking (OR, 1.09) and eldercare (OR, 1.26) demands were related to MSDs only in female workers. WLC was also associated with MSDs among both male (OR, 1.50) and female (OR, 1.55) workers. We found no gender difference in the effect of WLC on MSDs (p = 0.91). Moreover, childcare demands may exacerbate the effect of WLC on MSDs. Our data suggest that family demands and WLC could be important targets of workplace interventions to prevent MSDs, and future research should evaluate the role of family demands and WLC as stressors in the workplace. PMID- 29976899 TI - A Cost-Benefit Analysis of the Official Development Assistance Project on Maternal and Child Health in Kwango, DR Congo. AB - A project on maternal and child health (MCH) was conducted by the Korea International Cooperation Agency to reduce maternal and child mortality rates in Kwango, Democratic Republic of Congo (DRC). The objective of this study was to evaluate the costs and benefits of the MCH project, which was under Official Development Assistance for a period of 3 years from 2014 to 2016. The study conducted a cost-benefit analysis (CBA) using a benefit-cost ratio (BCR). The costs were the total costs incurred in implementing the MCH project. The benefits of the MCH project were estimated as the monetary values of the reduction in maternal mortality rates and the mortality rates of infants and children aged under 5 years. The adjusted costs that converted the time value for 2016 were estimated as USD 1,969,532 as part of the CBA. The benefits of reduced maternal mortality and the mortality of infants and children aged under 5 years were estimated as USD 681,416, USD 4,332,376, and USD 1,710,184, respectively, in monetary terms. The total benefits were estimated as USD 6,723,976 and the BCR was calculated at 3.41. In addition, the benefits were estimated by the different economic assumptions through a sensitivity analysis. The MCH project was economically satisfied under the most conservative assumptions. PMID- 29976900 TI - The Accuracy of the Detection of Body Postures and Movements Using a Physical Activity Monitor in People after a Stroke. AB - BACKGROUND: In stroke rehabilitation not only are the levels of physical activity important, but body postures and movements performed during one’s daily life are also important. This information is provided by a new one-sensor accelerometer that is commercially available, low-cost, and user-friendly. The present study examines the accuracy of this activity monitor (Activ8) in detecting several classes of body postures and movements in people after a stroke. METHODS: Twenty-five people after a stroke participated in an activity protocol with either basic activities or daily-life activities performed in a laboratory and/or at home. Participants wore an Activ8 on their less-affected thigh. The primary outcome was the difference in registered time for the merged class “upright position” (standing/walking/running) between the Activ8 and the video recording (the reference method). Secondary analyses focused on classes other than “upright position”. RESULTS: The Activ8 underestimated the merged class “upright position” by 3.8% (775 s). The secondary analyses showed an overestimation of “lying/sitting” (4.5% (569 s)) and of “cycling” (6.5% (206 s)). The differences were lowest for basic activities in the laboratory and highest for daily-life activities at home. CONCLUSIONS: The Activ8 is sufficiently accurate in detecting different classes of body postures and movements of people after a stroke during basic activities and daily-life activities in a laboratory and/or at home. PMID- 29976901 TI - Improving Air-Stability and Performance of Bulk Heterojunction Polymer Solar Cells Using Solvent Engineered Hole Selective Interlayer. AB - In bulk heterojunction polymer solar cells (BHJ-PSCs), poly(3,4 ethylenedioxythiophene) doped with poly(styrene sulfonate) (PEDOT:PSS) is the most commonly used hole selective interlayer (HSIL). However, its acidity, hygroscopic nature, and the use of indium tin oxide (ITO) etching can degrade the overall photovoltaic performance and the air-stability of BHJ-PSCs. Solvent engineering is considered as a facile approach to overcome these issues. In this work, we engineered the HSIL using ethanol (ET) treated PEDOT:PSS to simultaneously enhance the photovoltaic performance properties and air-stability of the fabricated devices. We systematically investigated the influence of ET on the microstructural, morphological, interfacial characteristics of modified HSIL and photovoltaic characteristics of BHJ-PSCs. Compared with the BHJ-PSC with pristine PEDOT:PSS, a significant enhancement of power conversion efficiency (~17%) was witnessed for the BHJ-PSC with PEDOT:PSS-ET (v/v, 1:0.5). Consequently, the BHJ-PSC with PEDOT:PSS-ET (v/v, 1:0.5) as HSIL exhibited remarkably improved air-stability. PMID- 29976902 TI - The Chemical Composition and Functional Properties of Essential Oils from Four Species of Schisandra Growing Wild in the Qinling Mountains, China. AB - The aim of this study was to investigate the chemical composition and functional properties of the essential oils from the plants Schisandra grandiflora (Wall.) Hook. f. et Thoms, Schisandra rubriflora (Franch). Rehd. et Wils., Schisandra sphenanthera Rehd. et Wils., and Schisandra propinqua (Wall.) Baill var. sinensis Oliv. collected in the Qinling Mountains. Under the optimum conditions of the ultrasonic-assisted extraction method, the extraction yields were 7.51% (S. grandiflora), 6.91% (S. rubriflora), 6.11% (S. sphenanthera), and 5.88% (S. propinqua). A total of 86 components were identified from four species of Schisandra and 16 components were shared among the essential oils of all samples with different contents. However, some components were identified only in a certain plant, for example, β-caryophyllen (S. grandiflora), α bulnesene (S. rubriflora), and α-Chamigrene (S. propinqua). Terpenoids (sesquiterpenes and oxygenated sesquiterpenes), accounting for 73.87-82.08% of the total compounds, were the main components. Meanwhile, the antioxidant activities of the essential oils were evaluated through three free radical scavenging assays and a reducing power assay, which were related to the contents of the individual bioactive composition. These results provide a phytochemical foundation for the use of four species, and for the further study of the identification of Schisandra species. PMID- 29976903 TI - Formation of 6-, 8- and 10-Shogaol in Ginger through Application of Different Drying Methods: Altered Antioxidant and Antimicrobial Activity. AB - Gingerols and shogaols are compounds found in ginger (Zingiber officinale Roscoe); shogaols are found in lower concentration than gingerols but exhibit higher biological activities. This work studied the effects of different drying methods including open sun drying (OSD) solar tunnel drying (STD) and hot air drying (HAD) with various temperature on the formation of six main active compounds in ginger rhizomes, namely 6-, 8-, and 10-gingerols and 6-, 8-, and 10 shogaols, as well as essential oil content. Antioxidant and antimicrobial activity of dried ginger was also evaluated. High performance liquid chromatography (HPLC) analysis showed that after HAD with variable temperature (120, 150 and 180 °C), contents of 6-, 8-, and 10-gingerols decreased, while contents of 6-, 8-, and 10-shogaol increased. High formation of 6-, 8-, and 10 shogaol contents were observed in HAD (at 150 °C for 6 h) followed by STD and OSD, respectively. OSD exhibited high content of essential oil followed by STD and HAD method. Ginger-treated with HAD exhibited the highest DPPH (IC50 of 57.8 mg/g DW) and FRAP (493.8 µM of Fe(II)/g DM) activity, compared to STD and OSD method. HAD ginger exhibited potent antimicrobial activity with lower minimum inhibition concentration (MIC) value against bacteria strains followed by STD and OSD, respectively. Ginger extracts showed more potent antimicrobial activity against Gram positive bacteria than Gram negative bacteria strains. Result of this study confirmed that conversion of gingerols to shogaols was significantly affected by different drying temperature and time. HAD at 150 °C for 6 h, provides a method for enhancing shogaols content in ginger rhizomes with improving antioxidant and antimicrobial activities. PMID- 29976904 TI - Highly Efficient and Sustainable Spent Mushroom Waste Adsorbent Based on Surfactant Modification for the Removal of Toxic Dyes. AB - The treatment of wastewater always demands eco-friendly and cost-efficient adsorbents. In this paper, spent mushroom waste (SMW) was modified by a cationic surfactant (cetyltrimethylammonium bromide, CTAB) to eliminate toxic dyes. A characterization of adsorbents confirmed that CTAB was successfully embedded into the SMW structure. The spent mushroom waste, modified by CTAB (SMWC), exhibited an excellent adsorption capacity of 249.57 mg·g−1, 338.67 mg·g−1, and 265.01 mg·g−1 for the Direct red 5B (DR5B), Direct blue 71 (DB71), and Reactive black (RB5) dyes, respectively. Batch experiments indicated that the dye adsorption of SMWC depended mainly on pH, dye concentration, temperature, and ionic strength. The adsorption isotherm could be fitted to the Langmuir model and described by the pseudo-second-order kinetic model. The dye adsorption mechanism was dominated mostly by the chemosorption of the dyes and the SMWC surface. Thermodynamic parameters showed that the adsorption was endothermic and spontaneous. SMWC could successfully remove over 90% of dyes from various water samples. This can be considered a feasible waste resource utility, since it meets both the ecological and the economic requirements for auspicious industrial applications. PMID- 29976905 TI - A Triton X-100-Based Microemulsion for the Removal of Hydrophobic Materials from Works of Art: SAXS Characterization and Application. AB - The removal of hydrophobic materials from a porous support, such as wax stains on wall paintings, is particularly challenging. In this context, traditional methods display several drawbacks. The limitations of these methods can be overcome by amphiphile-based aqueous nanostructured fluids, such as micellar solutions and microemulsions. In this study, a microemulsion for the removal of wax spots from artistic surfaces was formulated. The nanostructured fluid includes a non-ionic surfactant, i.e., Triton X-100, and two apolar solvents, namely p-xylene and n nonane. The solvents were selected on the basis of solubility tests of three waxes in several organic solvents. The nanostructured fluid was characterized by means of small-angle X-rays scattering (SAXS) and the information about micelle structure was used to understand the interaction between the microemulsion and the selected waxes. The microemulsion was then tested during the restoration of the frescoes in the Major Chapel of the Santa Croce Basilica in Florence, Italy. After some preliminary tests on fresco mockups reproduced in the laboratory, the nanostructured fluid was successfully used to clean some wax deposits from the real paintings, hardly removable with traditional physico-mechanical methods. PMID- 29976907 TI - Fatigue Performance of Different Thickness Structure Combinations of Hot Mix Asphalt and Cement Emulsified Asphalt Mixtures. AB - Cement emulsified asphalt mixture (CEAM) is widely used in asphalt pavement for its environmental virtues. However, a CEAM layer can influence fatigue performance of asphalt pavement because of higher air voids of CEAM in contrast to hot mix asphalt (HMA). Therefore, it is common to use HMA and CEAM structure combinations for improving the fatigue performance. In this work, three different thickness structure combinations of HMA (AC-10) and CEAM (AC-16) were designed, in which HMA and CEAM were used as top layer and bottom layer, respectively. The fatigue performance of the three combinations was studied. The fatigue equations of the combinations were established and the rational combination was recommended. The distributions of the internal voids in the combinations were studied with X-ray computed tomography (X-ray CT); and the correlation between the fatigue life and the void ratios were analyzed. Artificial neural network (ANN) was employed to predict the fatigue life of each combination. The results show that the fatigue life of the combinations is inversely proportional to the stress ratio level and environment temperature. The optimal combination is the structure with 40 mm HMA and 40 mm CEAM. The internal void ratio of CEAM is higher than that of HMA. A thinner HMA and thicker CEAM structure can result in higher void ratios and lower fatigue life of the combinations. The prediction results of ANN are similar to the experimental results. The obtained results can potentially guide the design of cement emulsified asphalt pavement structures. PMID- 29976908 TI - Stress Concentration and Mechanical Strength of Cubic Lattice Architectures. AB - The continuous design of cubic lattice architecture materials provides a wide range of mechanical properties. It makes possible to control the stress magnitude and the local maxima in the structure. This study reveals some architectures specifically designed to reach a good compromise between mass reduction and mechanical strength. Decreased local stress concentration prevents the early occurrence of localized plasticity or damage, and promotes the fatigue resistance. The high performance of cubic architectures is reported extensively, and structures with the best damage resistance are identified. The fatigue resistance and S-N curves (stress magnitude versus lifetime curves) can be estimated successfully, based on the investigation of the stress concentration. The output data are represented in two-dimensional (2D) color maps to help mechanical engineers in selecting the suitable architecture with the desired stress concentration factor, and eventually with the correct fatigue lifetime. PMID- 29976906 TI - Novel Food Processing and Extraction Technologies of High-Added Value Compounds from Plant Materials. AB - Some functional foods contain biologically active compounds (BAC) that can be derived from various biological sources (fruits, vegetables, medicinal plants, wastes, and by-products). Global food markets demand foods from plant materials that are “safe”, “fresh”, “natural”, and with “nutritional value” while processed in sustainable ways. Functional foods commonly incorporate some plant extract(s) rich with BACs produced by conventional extraction. This approach implies negative thermal influences on extraction yield and quality with a large expenditure of organic solvents and energy. On the other hand, sustainable extractions, such as microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), high-pressure assisted extraction (HPAE), high voltage electric discharges assisted extraction (HVED), pulsed electric fields assisted extraction (PEF), supercritical fluids extraction (SFE), and others are aligned with the “green” concepts and able to provide raw materials on industrial scale with optimal expenditure of energy and chemicals. This review provides an overview of relevant innovative food processing and extraction technologies applied to various plant matrices as raw materials for functional foods production. PMID- 29976909 TI - Sensitive Detection of Escherichia coli O157:H7 in Food Products by Impedimetric Immunosensors. AB - In this work, the development of an impedimetric label-free immunosensor for the detection of Escherichia coli O157:H7 is reported. Different immobilization techniques of monoclonal anti-E. coli were tested, in order to reach the very low limit of detections. The comparison between the immobilization procedures underlined the advantages of the oriented procedure and the use of a dendrimer, which allowed for immobilizing a higher number of antibody units, reaching a very high sensitivity. However, the use of activated ferrocene as electron transferring mediator, which improved the electrical properties of the system, resulted in a very low limit of detection equal to 3 cfu/mL. This immunosensor was used to analyze milk and meat samples obtaining a good agreement with the results of the ELISA methods. PMID- 29976911 TI - Mechanical Properties and Carbonation Durability of Engineered Cementitious Composites Reinforced by Polypropylene and Hydrophilic Polyvinyl Alcohol Fibers. AB - Herein, the mechanical properties and carbonation durability of engineered cementitious composites (ECC) were studied. For the cost-efficient utilization of ECC materials, different types of specimens were cast with polypropylene (PP) and hydrophilic polyvinyl alcohol (HPVA) fibers. The compressive strength, Poisson’s ratio, strength-deflection curves, cracking/post-cracking strength, impact index, and tensile strain-stress curves of two types of ECC materials, with differing fiber contents of 0 vol %, 1 vol %, 1.5 vol %, and 2 vol %, were investigated with the use of compressive tests, four-point bending tests, drop-weight tests, and uniaxial tensile tests. In addition, the matrix microstructure and failure morphology of the fiber in the ECC materials were studied by scanning electron microscopy (SEM) analysis. Furthermore, carbonation tests and characterization of steel corrosion after carbonization were employed to study durability resistance. The results indicated that for both PP fiber- and HPVA fiber-reinforced ECCs, the compressive strength first increases and then decreases as fiber content increases from 0 vol % to 2 vol %, reaching a maximum at 1 vol % fiber content. The bending strength, deformation capacity, and impact resistance show significant improvement with increasing fiber content. The ECC material reinforced with 2 vol % PP fiber shows superior carbonized durability with a maximum carbonation depth of only 0.8 mm. PMID- 29976910 TI - Beet Stalks and Leaves (Beta vulgaris L.) Protect Against High-Fat Diet-Induced Oxidative Damage in the Liver in Mice. AB - Some flavonoids identified in beet stalks can help the antioxidant endogenous defenses during a chronic inflammation process. The current study investigates the effect of polyphenols present in beet stalks and leaves on liver oxidative damage in mice fed a high-fat diet (HF). The control (CT) or HF diet groups were supplemented with dehydrated beet stalks and leaves (SL) or beet stalk and leaf ethanolic extract (EX). In terms of Vitexin-rhaminoside equivalents (VRE), EX groups received ~5.91 mg of VRE·100 g−1 diet, while the SL groups received ~3.07 mg VRE·100 g−1 diet. After 8 weeks, we evaluated fasting blood glucose; cholesterol, hepatic Malondialdehyde (MDA) levels and hepatic Glutathione (GSH), Glutathione peroxidase (GPx), Glutathione reductase (GR) and Superoxide dismutase (SOD) activity. Dehydrated beet stalks and leaves (HFSL) attenuated the deleterious effects of a HF diet on lipid metabolism, reduced fasting blood glucose levels, ameliorated cholesterol levels and reduced GPx and GR activities (p < 0.05) compared to the HF group. However; the addition of ethanolic extract from beet stalks and leaves was unable (p > 0.05) to prevent the liver damage caused by HF diet in mice. The presence of flavonoids, such as Vitexin derivatives in beet stalks and leaves can help the liver damage induced by HF diet. PMID- 29976913 TI - Using Farm Animal Welfare Protocols as a Base to Assess the Welfare of Wild Animals in Captivity-Case Study: Dorcas Gazelles (Gazella dorcas). AB - There is a lack of protocols specifically developed for the assessment of welfare of wild animals in captivity, even when it is known that providing good standards of welfare is important. The aim of this study was the development and the application of a protocol for the assessment of welfare in captive dorcas gazelles. The protocol was mainly developed taking into account the protocol for the assessment of welfare in cattle from the Welfare Quality® project, the available literature of the biology of this species and the Husbandry Guidelines developed for captive breeding and management of this species. The protocol was specifically developed for dorcas gazelles and included four principles, 10 criteria and 23 animal and environmental-based indicators. To test its utility, this protocol was applied to five different groups of gazelles from three different zoos. Its application made possible to detect areas for improvement in all groups assessed. PMID- 29976912 TI - Acid Assisted Organosolv Delignification of Beechwood and Pulp Conversion towards High Concentrated Cellulosic Ethanol via High Gravity Enzymatic Hydrolysis and Fermentation. AB - BACKGROUND: Future biorefineries will focus on converting low value waste streams to chemical products that are derived from petroleum or refined sugars. Feedstock pretreatment in a simple, cost effective, agnostic manner is a major challenge. METHODS: In this work, beechwood sawdust was delignified via an organosolv process, assisted by homogeneous inorganic acid catalysis. Mixtures of water and several organic solvents were evaluated for their performance. Specifically, ethanol (EtOH), acetone (AC), and methyl- isobutyl- ketone (MIBK) were tested with or without the use of homogeneous acid catalysis employing sulfuric, phosphoric, and oxalic acids under relatively mild temperature of 175 °C for one hour. RESULTS: Delignification degrees (DD) higher than 90% were achieved, where both AC and EtOH proved to be suitable solvents for this process. Both oxalic and especially phosphoric acid proved to be good alternative catalysts for replacing sulfuric acid. High gravity simultaneous saccharification and fermentation with an enzyme loading of 8.4 mg/gsolids at 20 wt.% initial solids content reached an ethanol yield of 8.0 w/v%. CONCLUSIONS: Efficient delignification combining common volatile solvents and mild acid catalysis allowed for the production of ethanol at high concentration in an efficient manner. PMID- 29976914 TI - Ag2O on ZrO2 as a Recyclable Catalyst for Multicomponent Synthesis of Indenopyrimidine Derivatives. AB - We describe the synthesis of silver loaded on zirconia and its use as an efficient catalyst for a one-pot three-component reaction to synthesize 11 indenopyrimidine derivatives, of which 7 are new compounds. The procedure involves substituted benzaldehydes, indane-1,3-dione, and guanidinium hydrochloride, with ethanol as solvent. The proposed green protocol at room temperature is simple and efficient, giving excellent yields (90-96%) in short reaction times (<30 min). The protocol works well according to the green chemistry principles with respect to high atom economy, no need for column separation, and reusability of the catalyst, which are attractive features. XRD, TEM, SEM, and BET analysis were used to characterize the catalyst materials. PMID- 29976915 TI - Dog Ecology and Rabies Knowledge of Owners and Non-Owners in Sanur, A Sub District of the Indonesian Island Province of Bali. AB - This study gained an understanding of dog demographics, owner behaviour, and knowledge, attitudes and practices relating to rabies in three villages in Sanur, Bali, providing insights for an intervention to improve responsible dog ownership. A combination of a census of all dogs, street surveys of roaming dogs, and a Knowledge, Attitude and Practices (KAP) survey was used to study both dogs and people. A total of 6009 dogs were recorded, of which only 3.3% appeared to be unowned; unowned dogs had poorer welfare and were more likely to be wary of attempted approaches by people. The source of dogs, method of confinement used by owners, and whether dogs were sterilised differed between three breed types; purebred dogs, mixed breed, and Bali dogs (native breed). Three variables were found to have significant effects on the chances of not being vaccinated: age, dog type, and confinement. A mean of 3.81 roaming dogs per km of street surveyed was recorded along 28 sub-village routes. Responses to attitude statements showed that most people had a positive attitude towards dogs and vaccination and did not agree with culling. Knowledge of appropriate bite treatment and symptoms of rabies in dogs was good. PMID- 29976916 TI - Multi-Band Up-Converted Lasing Behavior in NaYF4:Yb/Er Nanocrystals. AB - Random lasers have attracted great interests and extensively investigation owing to their promising applications. Here, we explored unambiguously the multi-band up-converted random lasing from NaYF4:Yb,Er nanocrystals (NCs). NaYF4:Yb,Er NCs exhibit high effective up-conversion luminescence when they are excited by continuous wave 980 nm laser. We investigated a planar microcavities approach wherein the NaYF4:Yb,Er NCs showed up-converted lasing behavior. The optical pumping of NaYF4:Yb,Er NCs by 980 nm pulsed laser excitation exhibited multi-band lasing. The NaYF4:Yb,Er NCs showed multi-band lasing emission with a line width of 0.2 nm at 540 nm and 0.4 nm at 660 nm. This research promotes potential application in bioimaging and biomedical fields. PMID- 29976917 TI - Relationship between Atherogenic Indices and Carotid Intima-Media Thickness in Prediabetes: A Cross-Sectional Study from Central India. AB - Prediabetes is the precursor stage of diabetes mellitus and is also considered to be a risk factor for the development of cardiovascular disease. Atherogenic indices have been used for assessment of risk for cardiovascular disease development. To date, there is no data on evaluating the relationship between atherogenic indices (cardiac risk ratio (CRR), atherogenic coefficient (AC), and atherogenic index of plasma (AIP)) and carotid intima-media thickness (CIMT) in prediabetes. Hence, we aimed to determine atherogenic indices (CRR, AC, and AIP) and CIMT in prediabetic subjects and then sought to evaluate the relationship between them. A total of 400 human subjects were included in the present study, out of which 200 were prediabetic subjects and 200 were normal healthy control subjects. For each subject, CRR, AC, and AIP were calculated from routine lipid parameters and carotid intima-media thickness was measured as well. Atherogenic indices, that is, CRR, AC, and AIP, were significantly increased in prediabetic subjects as compared to the controls (5.87 +/- 0.87 vs. 4.23 +/- 0.50, p < 0.001; 4.87 +/- 0.87 vs. 3.23 +/- 0.50, p < 0.001; and 0.29 +/- 0.07 vs. 0.09 +/- 0.09, p < 0.001, respectively). Moreover, a significant and positive correlation was observed between CIMT and AIP (r = 0.529, p < 0.01), CRR (r = 0.495, p < 0.01), and AC (r = 0.495, p < 0.01). Prediabetic subjects present abnormalities in atherogenic indices and CIMT, which indicate a greater propensity of prediabetes for the development of cardiovascular disease. Hence, atherogenic indices can be used in addition to routine lipid parameters for the better assessment of subclinical atherosclerosis in prediabetic subjects. PMID- 29976918 TI - Effect of Preformed or De Novo Anti-HLA Antibodies on Function and Graft Survival in Kidney Transplant Recipients. AB - BACKGROUND Donor-specific antibodies (DSA), directed against human leucocyte antigens (HLA), are associated with increased risk for graft rejection in kidney transplantation. Anti-HLA antibodies detection by LuminexTM present high sensitivity and accuracy, but its interpretation after transplantation is not completely clear. The aim of this study was to evaluate the impact of anti-HLA antibodies, preformed or de novo, on renal function, graft survival, and incidence of antibody-mediated acute rejection (AMR). MATERIAL AND METHODS A retrospective cohort of 86 kidney transplant recipients was divided into 3 groups according to the presence of anti-HLA antibodies before transplantation: donor specific antibodies (DSA+, n=15), non-DSA (non-DSA, n=39), and negative pre transplant panel reactive antibodies (PRA) that became positive after transplantation (PRA-, n=22). Forty-nine recipients with negative PRA pre- and post-transplantation were excluded. Antibody specificity and intensity of fluorescence (MFI) and their relationship with renal function, proteinuria, AMR, and graft failure were evaluated. RESULTS Among patients who completed 1 year of follow-up, there was no significant difference in serum creatinine, estimated glomerular filtration rate, or proteinuria. AMR incidence was 9.5% in the DSA group, 2.3% in the non-DSA group, and 9.1% in the PRA- group. There was no correlation between fluorescence intensity and/or antibodies class (I or II) with increased risk of AMR. Thirteen grafts failed within 1 year post-transplant, there were 9 deaths due to infection, and only 1 due to AMR (PRA- group, DSA de novo at 3 months). CONCLUSIONS In contrast to previous reports, we did not find a correlation between incidence of AMR and MFI intensity in this series. PMID- 29976919 TI - Duodenocolostomy as Treatment of Ileus in Short Bowel Syndrome: A Case Report. AB - BACKGROUND Short bowel syndrome (SBS) is a malabsorption syndrome that results from an extensive intestinal resection or repeated small bowel resections. Postoperative small bowel obstruction is a well-known complication of abdominal surgeries requiring readmission and reoperation after failed conservative management. A combination of the above factors poses a clinical challenge for surgeons due to lack of applicable treatment options. CASE REPORT A 68-year-old man underwent repetitive laparotomies and multiple small bowel resections for an incarcerated inguinal hernia, resulting in SBS. Postoperative small bowel obstruction resulting from an anastomotic stricture near the ligament of Treitz made the patient unable to sustain oral nutrition. During reoperation, insufficient jejunum length and extensive intraabdominal adhesions led us to perform a primary side-to-side duodenocolonic anastomosis, which is an unusual treatment option. After a long but uncomplicated postoperative course, the patient was able to ingest solid foods and was discharged in healthy condition with parental nutritional support. CONCLUSIONS Duodenocolostomy can be a treatment of last resort in patients with limited surgical treatment options and can lead to a significant improvement of their quality of life. PMID- 29976921 TI - Direct comparison of ten quantitative fecal immunochemical tests for hemoglobin stability in colorectal cancer screening. AB - OBJECTIVES: To systematically investigate and directly compare, for the first time, the sample stability of a large number of quantitative fecal immunochemical tests (FITs) at different storage conditions. METHODS: Stool samples were obtained from participants of the German screening colonoscopy program between 2005 and 2010. After an initial FIT-based hemoglobin (Hb) measurement, stool samples were kept frozen at -80 degrees C until analysis. Twenty randomly selected participants with initial measurements ranging from 10 to 100 MUg Hb/g feces were included. Ten quantitative FITs were investigated in parallel. A defined stool amount was extracted using each manufacturer's brand-specific fecal sampling device and stored at 5 degrees C, 20 degrees C, and 35 degrees C, respectively. After 1, 4, 5, and 7 days, the samples were analyzed blinded. Median fecal Hb concentrations and positivity rates were calculated. RESULTS: Mean age of the participants was 67 years (range: 56-80 years) and 60% were male. The most advanced finding at screening colposcopy was advanced adenoma in five and non-advanced adenoma in eight cases. Hyperplastic polyps were found in two participants and five participants were without any findings. At 5 degrees C storage temperature, almost all FITs showed fairly stable results throughout the 7-day observation period. At 20 degrees C, most FITs still showed fairly stable results over 4 days, whereas positivity rates significantly declined from day 4 on for most FITs at 35 degrees C. Major differences regarding the sample stability between FITs were observed. CONCLUSION: FIT-specific Hb decay according to ambient temperature and time period between sampling and test evaluation requires careful consideration in the design of FIT-based screening programs. PMID- 29976920 TI - Astragalus Polysaccharide Inhibits Ionizing Radiation-Induced Bystander Effects by Regulating MAPK/NF-kB Signaling Pathway in Bone Mesenchymal Stem Cells (BMSCs). AB - BACKGROUND This study investigated the effect of Astragalus polysaccharides (APS) on radiation-induced bystander effects (RIBE) in human bone mesenchymal stem cells (BMSCs) induced by irradiated A549 cells. MATERIAL AND METHODS A549 cells were irradiated with 2 Gy X-rays to obtain conditioned medium. BMSCs were incubated with the conditioned medium or APS. The levels of reactive oxygen species (ROS) and TGF-beta were detected by ELISA. Cell survival, genomic instability, and DNA damages were detected by CCK-8 assay, colony formation assay, the micronucleus test and immunofluorescence assay, respectively. The protein and phosphorylation protein expression of p38, c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase (ERK1/2), P65, and cyclooxygenase-2 (COX-2) in bystander effect cells were detected by Western blot. RESULTS The expression of COX-2 and ROS increased following stimulation with conditioned medium; this effect was inhibited by pre-exposing the cells to APS. BMSCs growth and colony formation rate decreased following stimulation with conditioned medium; this effect was suppressed by pre-exposing the cells to APS. In addition, the micronucleus rate and 53BP1 foci number increased after treatment with conditioned medium; this increase in BMSCs was inhibited by APS. The levels of phosphorylated p38, JNK, ERK1/2, NF-kappaB P65, and COX-2 proteins were increased by conditioned medium but were decreased by pre-treatment with APS. CONCLUSIONS RIBE in BMSCs induced by the irradiated A549 was mediated by the ROS in the conditioned medium and might be related to MAPK/NF-kappaB signal pathways in BMSCs. APS may block RIBE through regulating the MAPK/NF-kappaB pathway. PMID- 29976922 TI - Feeders facilitate telomere maintenance and chromosomal stability of embryonic stem cells. AB - Feeder cells like mouse embryonic fibroblasts (MEFs) have been widely applied for culture of pluripotent stem cells, but their roles remain elusive. Noticeably, ESCs cultured on the feeders display transcriptional heterogeneity. We investigated roles of feeder cells by examining the telomere maintenance. Here we show that telomere is longer in mESCs cultured with than without the feeders. mESC cultures without MEF feeders exhibit telomere loss, chromosomal fusion, and aneuploidy with increasing passages. Notably, feeders facilitate heterogeneous transcription of 2-cell genes including Zscan4 and telomere elongation. Moreover, feeders produce Fstl1 that together with BMP4 periodically activate Zscan4. Interestingly, Zscan4 is repressed in mESCs cultured in 2i (inhibitors of Mek and Gsk3beta signaling) media, associated with shorter telomeres and increased chromosome instability. These data suggest the important role of feeders in maintaining telomeres for long-term stable self-renewal and developmental pluripotency of mESCs. PMID- 29976924 TI - Medium- and high-intensity rTMS reduces psychomotor agitation with distinct neurobiologic mechanisms. AB - Definitive data are lacking on the mechanism of action and biomarkers of repetitive transcranial magnetic stimulation (rTMS) for the treatment of depression. Low-intensity rTMS (LI-rTMS) has demonstrated utility in preclinical models of rTMS treatments but the effects of LI-rTMS in murine models of depression are unknown. We examined the behavioral and neurobiologic changes in olfactory bulbectomy (OB) mice with medium-intensity rTMS (MI-rTMS) treatment and fluoxetine hydrochloride. We then compared 10-Hz rTMS sessions for 3 min at intensities (measured at the cortical surface) of 4 mT (LI-rTMS), 50 mT (medium intensity rTMS [MI-rTMS]), or 1 T (high-intensity rTMS [HI-rTMS]) 5 days per week over 4 weeks in an OB model of agitated depression. Behavioral effects were assessed with forced swim test; neurobiologic effects were assessed with brain levels of 5-hydroxytryptamine, brain-derived neurotrophic factor (BDNF), and neurogenesis. Peripheral metabolomic changes induced by OB and rTMS were monitored through enzyme-linked immunosorbent assay and ultrapressure liquid chromatography-driven targeted metabolomics evaluated with ingenuity pathway analysis (IPA). MI-rTMS and HI-rTMS attenuated psychomotor agitation but only MI rTMS increased BDNF and neurogenesis levels. HI-rTMS normalized the plasma concentration of alpha-amino-n-butyric acid and 3-methylhistidine. IPA revealed significant changes in glutamine processing and glutamate signaling in the OB model and following MI-rTMS and HI-rTMS treatment. The present findings suggest that MI-rTMS and HI-rTMS induce differential neurobiologic changes in a mouse model of agitated depression. Further, alpha-amino-n-butyric acid and 3 methylhistidine may have utility as biomarkers to objectively monitor the response to rTMS treatment of depression. PMID- 29976923 TI - ATR is a multifunctional regulator of male mouse meiosis. AB - Meiotic cells undergo genetic exchange between homologs through programmed DNA double-strand break (DSB) formation, recombination and synapsis. In mice, the DNA damage-regulated phosphatidylinositol-3-kinase-like kinase (PIKK) ATM regulates all of these processes. However, the meiotic functions of the PIKK ATR have remained elusive, because germline-specific depletion of this kinase is challenging. Here we uncover roles for ATR in male mouse prophase I progression. ATR deletion causes chromosome axis fragmentation and germ cell elimination at mid pachynema. This elimination cannot be rescued by deletion of ATM and the third DNA damage-regulated PIKK, PRKDC, consistent with the existence of a PIKK independent surveillance mechanism in the mammalian germline. ATR is required for synapsis, in a manner genetically dissociable from DSB formation. ATR also regulates loading of recombinases RAD51 and DMC1 to DSBs and recombination focus dynamics on synapsed and asynapsed chromosomes. Our studies reveal ATR as a critical regulator of mouse meiosis. PMID- 29976925 TI - Photonic crystal cavities from hexagonal boron nitride. AB - Development of scalable quantum photonic technologies requires on-chip integration of photonic components. Recently, hexagonal boron nitride (hBN) has emerged as a promising platform, following reports of hyperbolic phonon polaritons and optically stable, ultra-bright quantum emitters. However, exploitation of hBN in scalable, on-chip nanophotonic circuits and cavity quantum electrodynamics (QED) experiments requires robust techniques for the fabrication of high-quality optical resonators. In this letter, we design and engineer suspended photonic crystal cavities from hBN and demonstrate quality (Q) factors in excess of 2000. Subsequently, we show deterministic, iterative tuning of individual cavities by direct-write EBIE without significant degradation of the Q factor. The demonstration of tunable cavities made from hBN is an unprecedented advance in nanophotonics based on van der Waals materials. Our results and hBN processing methods open up promising avenues for solid-state systems with applications in integrated quantum photonics, polaritonics and cavity QED experiments. PMID- 29976926 TI - Zika Virus Replication in Dorsal Root Ganglia Explants from Interferon Receptor1 Knockout Mice Causes Myelin Degeneration. AB - Zika virus (ZIKV) is a neurotropic agent that targets the developing fetal brain in women infected during pregnancy. In addition to the developing central nervous system, ZIKV has been recently shown to infect cells of the peripheral nervous system (PNS), highlighting its potential to cause acute peripheral neuropathies in adults, such as Guillain-Barre Syndrome (GBS). Here we show that myelinating dorsal root ganglia (DRG) explants obtained from interferon-alpha/beta receptor knock-out mice are productively infected by ZIKV. Virus replication is cytopathic in both peripheral neurons and myelinating Schwann cells leading to myelin disruption. These results confirm and extend previous observations suggesting that the PNS is indeed a potential site of ZIKV infection, replication and cytopathicity. PMID- 29976927 TI - Genome-Wide Determination of Gene Essentiality by Transposon Insertion Sequencing in Yeast Pichia pastoris. AB - In many prokaryotes but limited eukaryotic species, the combination of transposon mutagenesis and high-throughput sequencing has greatly accelerated the identification of essential genes. Here we successfully applied this technique to the methylotrophic yeast Pichia pastoris and classified its conditionally essential/non-essential gene sets. Firstly, we showed that two DNA transposons, TcBuster and Sleeping beauty, had high transposition activities in P. pastoris. By merging their insertion libraries and performing Tn-seq, we identified a total of 202,858 unique insertions under glucose supported growth condition. We then developed a machine learning method to classify the 5,040 annotated genes into putatively essential, putatively non-essential, ambig1 and ambig2 groups, and validated the accuracy of this classification model. Besides, Tn-seq was also performed under methanol supported growth condition and methanol specific essential genes were identified. The comparison of conditionally essential genes between glucose and methanol supported growth conditions helped to reveal potential novel targets involved in methanol metabolism and signaling. Our findings suggest that transposon mutagenesis and Tn-seq could be applied in the methylotrophic yeast Pichia pastoris to classify conditionally essential/non essential gene sets. Our work also shows that determining gene essentiality under different culture conditions could help to screen for novel functional components specifically involved in methanol metabolism. PMID- 29976928 TI - Juvenile bovine bone is an appropriate surrogate for normal and reduced density human bone in biomechanical testing: a validation study. AB - Orthopaedic research necessitates accurate and reliable models of human bone to enable biomechanical discoveries and translation into clinical scenarios. Juvenile bovine bone is postulated to be a potential model of normal human bone given its dimensions and comparatively reduced ethical restrictions. Demineralisation techniques can reduce bone density and alter bone properties, and methods to model osteoporotic bone using demineralised juvenile bovine bone are investigated. Juvenile bovine long bones were quantitatively CT scanned to assess bone density. Demineralisation using hydrochloric acid (0.6, 1.2 and 2.4 M) was performed to create different bone density models which underwent biomechanical validation for normal and osteoporotic bone models. All long bones were found to have comparable features to normal human bone including bone density (1.96 +/- 0.08 gcm-3), screw insertion torque and pullout strength. Demineralisation significantly reduced bone density and pullout strength for all types, with 0.6 M hydrochloric acid creating reductions of 25% and 71% respectively. Juvenile bovine bone is inexpensive, easy to source and not subject to extensive ethical procedures. This study establishes for the first time, the use of its long bones as surrogates for both normal and osteoporotic human specimens and offers preliminary validation for its use in biomechanical testing. PMID- 29976929 TI - Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome. AB - Wolfram syndrome (WS) is a rare autosomal recessive disorder caused by mutations in the WFS1 (Wolframin1) gene. The syndrome first manifests as diabetes mellitus, followed by optic nerve atrophy, deafness, and neurodegeneration. The underlying mechanism is believed to be a dysregulation of endoplasmic reticulum (ER) stress response, which ultimately leads to cellular death. Treatment with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to normalize ER stress response in several in vitro and in vivo models. Early chronic intervention with the GLP-1 receptor agonist liraglutide starting before the onset of metabolic symptoms prevented the development of glucose intolerance, improved insulin and glucagon secretion control, reduced ER stress and inflammation in Langerhans islets in Wfs1 mutant rats. Thus, treatment with GLP-1 receptor agonists might be a promising strategy as a preventive treatment for human WS patients. PMID- 29976930 TI - Mouse MRI shows brain areas relatively larger in males emerge before those larger in females. AB - Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI's ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders. PMID- 29976931 TI - Zebrafish mutants and TEAD reporters reveal essential functions for Yap and Taz in posterior cardinal vein development. AB - As effectors of the Hippo signaling cascade, YAP1 and TAZ are transcriptional regulators playing important roles in development, tissue homeostasis and cancer. A number of different cues, including mechanotransduction of extracellular stimuli, adhesion molecules, oncogenic signaling and metabolism modulate YAP1/TAZ nucleo-cytoplasmic shuttling. In the nucleus, YAP1/TAZ tether with the DNA binding proteins TEADs, to activate the expression of target genes that regulate proliferation, migration, cell plasticity, and cell fate. Based on responsive elements present in the human and zebrafish promoters of the YAP1/TAZ target gene CTGF, we established zebrafish fluorescent transgenic reporter lines of Yap1/Taz activity. These reporter lines provide an in vivo view of Yap1/Taz activity during development and adulthood at the whole organism level. Transgene expression was detected in many larval tissues including the otic vesicles, heart, pharyngeal arches, muscles and brain and is prominent in endothelial cells. Analysis of vascular development in yap1/taz zebrafish mutants revealed specific defects in posterior cardinal vein (PCV) formation, with altered expression of arterial/venous markers. The overactivation of Yap1/Taz in endothelial cells was sufficient to promote an aberrant vessel sprouting phenotype. Our findings confirm and extend the emerging role of Yap1/Taz in vascular development including angiogenesis. PMID- 29976932 TI - Cellular dissection of malaria parasite invasion of human erythrocytes using viable Plasmodium knowlesi merozoites. AB - Plasmodium knowlesi, a zoonotic parasite causing severe-to-lethal malaria disease in humans, has only recently been adapted to continuous culture with human red blood cells (RBCs). In comparison with the most virulent human malaria, Plasmodium falciparum, there are, however, few cellular tools available to study its biology, in particular direct investigation of RBC invasion by blood-stage P. knowlesi merozoites. This leaves our current understanding of biological differences across pathogenic Plasmodium spp. incomplete. Here, we report a robust method for isolating viable and invasive P. knowlesi merozoites to high purity and yield. Using this approach, we present detailed comparative dissection of merozoite invasion (using a variety of microscopy platforms) and direct assessment of kinetic differences between knowlesi and falciparum merozoites. We go on to assess the inhibitory potential of molecules targeting discrete steps of invasion in either species via a quantitative invasion inhibition assay, identifying a class of polysulfonate polymer able to efficiently inhibit invasion in both, providing a foundation for pan-Plasmodium merozoite inhibitor development. Given the close evolutionary relationship between P. knowlesi and P. vivax, the second leading cause of malaria-related morbidity, this study paves the way for inter-specific dissection of invasion by all three major pathogenic malaria species. PMID- 29976933 TI - Efficient production of human interferon beta in the white of eggs from ovalbumin gene-targeted hens. AB - Transgenic chickens could potentially serve as bioreactors for commercial production of recombinant proteins in egg white. Many transgenic chickens have been generated by randomly integrating viral vectors into their genomes, but transgene expression has proved insufficient and/or limited to the initial cohort. Herein, we demonstrate the feasibility of integrating human interferon beta (hIFN-beta) into the chicken ovalbumin locus and producing hIFN-beta in egg white. We knocked in hIFN-beta into primordial germ cells using a CRISPR/Cas9 protocol and then generated germline chimeric roosters by cell transplantation into recipient embryos. Two generation-zero founder roosters produced hIFN-beta knock-in offspring, and all knock-in female offspring produced abundant egg-white hIFN-beta (~3.5 mg/ml). Although female offspring of the first generation were sterile, their male counterparts were fertile and produced a second generation of knock-in hens, for which egg-white hIFN-beta production was comparable with that of the first generation. The hIFN-beta bioactivity represented only ~5% of total egg-white hIFN-beta, but unfolding and refolding of hIFN-beta in the egg white fully recovered the bioactivity. These results suggest that transgene insertion at the chicken ovalbumin locus can result in abundant and stable expression of an exogenous protein deposited into egg white and should be amenable to industrial applications. PMID- 29976934 TI - Integument CYP genes of the largest genome-wide cytochrome P450 expansions in triatomines participate in detoxification in deltamethrin-resistant Triatoma infestans. AB - Insect resistance to chemical insecticides is attributed to a combination of different mechanisms, such as metabolic resistance, knockdown resistance, and the cuticular resistance or penetration factor. The insect integument offers an efficient barrier against contact insecticides and its role as penetration factor has been previously reported; however, there is no information about its potential function in the metabolic resistance. Cytochrome P450 genes (CYP) are highly expressed in the fat body of several insects and thus play a key role in their metabolic resistance. Here, we describe new members that belong to the highly genome-wide expanded CYP3093A and CYP4EM subfamilies in the Chagas disease vectors Rhodnius prolixus and Triatoma infestans. We modeled the docking of deltamethrin in their active site and detected differences in some amino acids between both species that are critical for a correct interaction with the substrate. We also knocked down the two constitutively most expressed genes in the integument of resistant T. infestans nymphs (CYP3093A11 and CYP4EM10) in order to find clues on their participation in deltamethrin resistance. This is the first report on the role of the insect integument in detoxification events; although these two CYP genes do not fully explain the resistance observed in T. infestans. PMID- 29976935 TI - Modeling erythrocyte electrodeformation in response to amplitude modulated electric waveforms. AB - We present a comprehensive theoretical-experimental framework for quantitative, high-throughput study of cell biomechanics. An improved electrodeformation method has been developed by combing dielectrophoresis and amplitude shift keying, a form of amplitude modulation. This method offers a potential to fully control the magnitude and rate of deformation in cell membranes. In healthy human red blood cells, nonlinear viscoelasticity of cell membranes is obtained through variable amplitude load testing. A mathematical model to predict cellular deformations is validated using the experimental results of healthy human red blood cells subjected to various types of loading. These results demonstrate new capabilities of the electrodeformation technique and the validated mathematical model to explore the effects of different loading configurations on the cellular mechanical behavior. This gives it more advantages over existing methods and can be further developed to study the effects of strain rate and loading waveform on the mechanical properties of biological cells in health and disease. PMID- 29976936 TI - Attentional state and brain processes: state-dependent lateralization of EEG profiles in horses. AB - Lateralization of brain functions has been suggested to provide individuals with advantages, such as an increase of neural efficiency. The right hemisphere is likely to be specialized for processing attention for details and the left hemisphere for categorization of stimuli. Thus attentional processes actually may underlie lateralization. In the present study, we hypothesized that the attentional state of horses could be reflected in the lateralization of brain responses. We used i) a recently developed attention test to measure horses' visual attentional responses towards a standardized stimulus and ii) a recently developed portable EEG telemetric tool to measure brain responses. A particular emphasis was given to the types of waves (EEG power profile) and their side of production when horses were either attentive towards a visual stimulus or quiet standing. The results confirmed that a higher attentional state is associated with a higher proportion of gamma waves. There was moreover an interaction between the attentional state, the hemisphere and the EEG profile: attention towards the visual stimulus was associated with a significant increase of gamma wave proportion in the right hemisphere while "inattention" was associated with more alpha and beta waves in the left hemisphere. These first results are highly promising and contribute to the large debate on functional lateralization. PMID- 29976937 TI - Next generation sequencing identifies novel disease-associated BEST1 mutations in Bestrophinopathy patients. AB - Bestinopathies are a spectrum of retinal disorders associated with mutations in BEST1 including autosomal recessive bestrophinopathy (ARB) and autosomal dominant Best vitelliform macular dystrophy (BVMD). We applied whole-exome sequencing on four unrelated Indian families comprising eight affected and twelve unaffected individuals. We identified five mutations in BEST1, including p.Tyr131Cys in family A, p.Arg150Pro in family B, p.Arg47His and p.Val216Ile in family C and p.Thr91Ile in family D. Among these, p.Tyr131Cys, p.Arg150Pro and p.Val216Ile have not been previously reported. Further, the inheritance pattern of BEST1 mutations in the families confirmed the diagnosis of ARB in probands in families A, B and C, while the inheritance of heterozygous BEST1 mutation in family D (p.Thr91Ile) was suggestive of BVMD. Interestingly, the ARB families A and B carry homozygous mutations while family C was a compound heterozygote with a mutation in an alternate BEST1 transcript isoform, highlighting a role for alternate BEST1 transcripts in bestrophinopathy. In the BVMD family D, the heterozygous BEST1 mutation found in the proband was also found in the asymptomatic parent, suggesting an incomplete penetrance and/or the presence of additional genetic modifiers. Our report expands the list of pathogenic BEST1 genotypes and the associated clinical diagnosis. PMID- 29976938 TI - Novel biomineralization strategy in calcareous foraminifera. AB - This work shows that calcareous benthic foraminifera are capable of agglutinating sedimentary particles also. In particular, we focus on Melonis barleeanus. Traditionally considered a calcareous species, our data revealed the presence of minute (~3 MUm) sedimentary particles (silicate grains) inside the chamber walls of the examined shells. These particles were arranged in a definitive and systematic pattern, and the similar grain chemical characterization and size suggested a relatively high degree of selectivity in both modern and fossil specimens. Based on these results, we propose that M. barleeanus is capable of agglutinating sedimentary particles during the formation of a new chamber. The analysis of other calcareous foraminiferal species (e.g., Cassidulina neoteretis, Lobatula lobatula, Nonionella stella) did not reveal the presence of silicate grains in the shell of the specimens analyzed confirming this to be a characteristic of M. barleeanus. Considering that the isotopic and chemical composition of this species is widely used in paleoclimatic and paleoceanographic reconstructions, we used a mixing model to better constrain the influence of sedimentary particles on M. barleeanus delta18O data. Our model showed that the calcite delta18O would increase by ~0.9-20/00 if 10 wt% of feldspars (i.e., anorthite, albite, orthoclase) and quartz, respectively, were included in the analyzed shell. Based on these results, we emphasize that it is of paramount importance to consider M. barleeanus unusual biomineralization strategy during the interpretation of geological records and to investigate the presence of similar processes in other calcareous foraminiferal species. PMID- 29976939 TI - Chronotype and social jetlag influence human circadian clock gene expression. AB - We examined the relationships between chronotype or social jetlag and clock gene expression. Twenty-four young men [Chronotype: morningness, n = 8; intermediate, n = 8, eveningness, n = 8], aged 27 +/- 2 years old (mean +/- SE), completed two trials in a randomized order: (1) a Friday trial and (2) a Monday trial. In both trials, hair follicle cells were collected to evaluate the expression of clock genes over a 24-hour period at 4-hour intervals. There was a significant main effect of time on the expression of NR1D1, NR1D2, and PER3 (P < 0.001) in the morningness group, but not in the eveningness group. Changes in the peak time of expression of NR1D1 (r = 0.434, P = 0.034), NR1D2 (r = 0.481, P = 0.017), and PER3 (r = 0.457, P = 0.025) from the Friday to Monday trials were positively correlated with social jetlag (SJL) time. Our findings indicate that there was no change in the patterns of clock gene expression between workdays and the day after the holiday in the morningness group, and that SJL time influences the peak time of clock gene expression, moving it from the early to late workday, after a holiday. PMID- 29976940 TI - Fluidically Switchable Metasurface for Wide Spectrum Absorption. AB - Metasurfaces, owing to their attractive features, provide a wide range of potential applications. Electromagnetic absorbers based on metasurfaces have significantly improved responses compared to the earlier absorbers made from composite materials. Active metasurfaces, in contrast to the passive designs, can exhibit multifunctional characteristics without repeated fabrication. This paper presents a fluidically-reconfigurable active metasurface that provides switchable wide spectrum absorption. The proposed design is comprised of liquid-metal encased dielectric substrates, sandwiched between the top resistive pattern and bottom ground plane. With precise control of the liquid metal flow, the structure can exhibit wide absorption bandwidth switching between two frequency regimes. Further, the proposed metasurface has a significant advantage of displaying polarization-insensitive behaviour, unlike the previous fluidically-reconfigured structures. The design has been investigated by illustrating surface current distributions and several parametric variations. Finally, the proposed structure was fabricated using laser etching, and experimentally validated. This work has paved the way towards the realization of reconfigurable metasurfaces with multifunctional characteristics, thus showing great potential in microfluidic technology for diverse applications. PMID- 29976943 TI - Lipoblastoma-like tumor of the vulva: a clinicopathologic, immunohistochemical, fluorescence in situ hybridization and genomic copy number profiling study of seven cases. AB - Lipoblastoma-like tumor of the vulva was first described as a benign mesenchymal neoplasm of adipocytic differentiation having features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma. Prior studies of lipoblastoma-like tumor have evaluated PLAG1, HMGA2, and RB1 immunohistochemistry and DDIT3 rearrangement status, with results supporting its distinction from lipoblastoma and myxoid liposarcoma. However, absent RB1 expression was reported in a majority of tested cases, suggesting that lipoblastoma-like tumor may have underlying 13q alterations and be related to RB1-deleted soft tissue tumors. To further understand the molecular genetics of lipoblastoma-like tumor, we examined 7 cases by RB1 immunohistochemistry, DDIT3 and PLAG1 break apart FISH probes, RB1 enumeration FISH probe, and genomic copy number analysis by microarray. Patient age ranged from 21 to 56 years (median 35 years). Clinical follow up was available for 5 patients (71%) ranging 3-264 months (median 74 months). Microscopically, lipoblastoma-like tumor formed large lobules separated by thin and/or thick bands of fibrous tissue and had a prominent network of thin-walled vessels. Each tumor was predominantly composed of spindle cells and lipoblasts with variable quantities of mature adipocytes. RB1 immunohistochemistry exhibited a heterogeneous or "mosaic" pattern of weak and negative nuclear expression in all seven cases. DDIT3 and PLAG1 FISH were negative in each case. No evidence of RB1 regional gain or loss was identified by FISH. Genomic copy number analysis by chromosomal microarray showed a normal diploid profile in six tumors (86%). One tumor had copy number abnormalities consisting of an 11.9 megabase deletion from 1p13.3 to 1p11.2 and monosomy 14. Although lipoblastoma-like tumor has features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma, it is genetically different from these tumors. Furthermore, lipoblastoma-like tumor does not appear to have structural abnormalities of 13q resulting in deletion of RB1. PMID- 29976944 TI - Role of columnar cell lesions in breast carcinogenesis: analysis of chromosome 16 copy number changes by multiplex ligation-dependent probe amplification. AB - Columnar cell lesions have been proposed as precursor lesions of low-grade breast cancer. The molecular characteristic of low-grade breast neoplasia is whole-arm loss of chromosome 16q. Copy number changes of 6 genes on 16p and 20 genes on 16q were analysed by multiplex ligation-dependent probe amplification in 165 lesions of 103 patients. Twenty-three columnar cell lesions and 19 atypical ducal hyperplasia lesions arising in columnar cell lesions were included, as well as cases of usual ductal hyperplasia, blunt duct adenosis, ductal carcinoma in situ, lobular neoplasia and invasive carcinoma. Usual ductal hyperplasia and blunt duct adenosis lacked whole-arm losses of 16q. In contrast, columnar cell lesions without atypia, columnar cell lesions with atypia, atypical ductal hyperplasia, low-grade ductal carcinoma in situ and low-grade invasive carcinomas increasingly harboured whole-arm losses of 16q (17%, 27%, 47% and 57%, respectively). However, no recurrent losses in specific genes could be identified. In several patients, columnar cell lesions and atypical ductal hyperplasia harboured similar losses as related ductal carcinoma in situ or invasive carcinomas within the same breast. There were indications for 16q breakpoints near the centromere. Whole-arm gains on 16p were relatively scarce and there was no relation between whole-arm gains of 16p and progression of lesions of the low-grade breast neoplasia family. In conclusion, columnar cell lesions (with and without atypia) often harbour whole arm losses of 16q, which underlines their role as precursors in low-grade breast carcinogenesis, in contrast with usual ductal hyperplasia and blunt duct adenosis. However, no recurrent losses in specific genes could be identified, pointing to minor events in multiple tumour suppressor genes rather than major events in a single 16q gene contributing to low-grade breast carcinogenesis. PMID- 29976942 TI - Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening. AB - Protein-protein interactions (PPIs) represent important and promising therapeutic targets that are associated with the regulation of various molecular pathways, particularly in cancer. Although they were once considered "undruggable," the recent advances in screening strategies, structure-based design, and elucidating the nature of hot spots on PPI interfaces, have led to the discovery and development of successful small-molecule inhibitors. In this report, we are describing an integrated high-throughput and computational screening approach to enable the discovery of small-molecule PPI inhibitors of the anti-apoptotic protein, Mcl-1. Applying this strategy, followed by biochemical, biophysical, and biological characterization, nineteen new chemical scaffolds were discovered and validated as Mcl-1 inhibitors. A novel series of Mcl-1 inhibitors was designed and synthesized based on the identified difuryl-triazine core scaffold and structure-activity studies were undertaken to improve the binding affinity to Mcl 1. Compounds with improved in vitro binding potency demonstrated on-target activity in cell-based studies. The obtained results demonstrate that structure based analysis complements the experimental high-throughput screening in identifying novel PPI inhibitor scaffolds and guides follow-up medicinal chemistry efforts. Furthermore, our work provides an example that can be applied to the analysis of available screening data against numerous targets in the PubChem BioAssay Database, leading to the identification of promising lead compounds, fuelling drug discovery pipelines. PMID- 29976945 TI - Physiological and genetic characterization of calcium phosphate precipitation by Pseudomonas species. AB - Microbial biomineralization is a widespread phenomenon. The ability to induce calcium precipitation around bacterial cells has been reported in several Pseudomonas species but has not been thoroughly tested. We assayed 14 Pseudomonas strains representing five different species for the ability to precipitate calcium. Calcium phosphate precipitated adjacent to the colonies of all the Pseudomonas strains tested and also precipitated on the surface of colonies for several of the Pseudomonas strains assayed. The precipitate was commonly precipitated as amorphous calcium phosphate, however seven of the 14 Pseudomonas strains tested precipitated amorphous apatite in agar adjacent to the colonies. Out of the seven Pseudomonas strains that precipitated amorphous apatite, six are plant pathogenic. The formation of amorphous apatite was commonly observed in the area of the agar where amorphous calcium phosphate had previously formed. A transposon mutagenesis screen in Pseudomonas syringae pv. tomato DC3000 revealed genes involved in general metabolism, lipopolysaccharide and cell wall biogenesis, and in regulation of virulence play a role in calcium precipitation. These results shed light on the common ability of Pseudomonas species to perform calcium precipitation and the underlying genetic regulation involved in biomineralization. PMID- 29976946 TI - Glacial Inception in Marine Isotope Stage 19: An Orbital Analog for a Natural Holocene Climate. AB - The Marine Isotope Stage 19c (MIS19c) interglaciation is regarded as the best orbital analog to the Holocene. The close of MIS19c (~777,000 years ago) thus serves as a proxy for a contemporary climate system unaffected by humans. Our global climate model simulation driven by orbital parameters and observed greenhouse gas concentrations at the end of MIS19c is 1.3 K colder than the reference pre-industrial climate of the late Holocene (year 1850). Much stronger cooling occurs in the Arctic, where sea ice and year-round snow cover expand considerably. Inferred regions of glaciation develop across northeastern Siberia, northwestern North America, and the Canadian Archipelago. These locations are consistent with evidence from past glacial inceptions and are favored by atmospheric circulation changes that reduce ablation of snow cover and increase accumulation of snowfall. Particularly large buildups of snow depth coincide with presumed glacial nucleation sites, including Baffin Island and the northeast Canadian Archipelago. These findings suggest that present-day climate would be susceptible to glacial inception if greenhouse gas concentrations were as low as they were at the end of MIS 19c. PMID- 29976947 TI - A multifunctional DNA nano-scorpion for highly efficient targeted delivery of mRNA therapeutics. AB - The highly efficient cancer cell targeted delivery plays an important role in precise targeted therapies. Herein, a multifunctional DNA nano-scorpion nanostructure (termed AptDzy-DNS) functioned with aptamers and DNAzyme is developed for highly efficient targeted delivery of mRNA therapeutics in gene therapy. The designed AptDzy-DNS is self-assembled with specific aptamers as "scorpion stingers" for targeting tumor cell and DNAzymes as "scorpion pincers" for targeted gene therapy by cleaving mRNA into fragments. The as-prepared AptDzy DNS can effectively distinguish cancer cells from normal cells by specific cross talking between aptamers on AptDzy-DNS and overexpressed cell-surface receptors. In the process of gene therapy, by reacting with Mg2+-dependent DNAzyme on AptDzy DNS, the mRNA oligonucleotide in cancer cell is auto-cleaved into broken strand, failing to be translated into corresponding protein. Following, the downregulation protein can block cancer cell growth and realize highly efficient targeted therapies. The results demonstrate that the multifunctional AptDzy-DNS shows promise for targeted cancer cell discrimination, highly efficient targeted delivery of mRNA therapeutics in gene therapy. Thus, this developed strategy provides impressive improvement on gene targeted therapy and paves the way for application of AptDzy-DNS in human cancer targeted therapies. PMID- 29976948 TI - Neonatal corticosterone mitigates autoimmune neuropsychiatric disorders associated with streptococcus in mice. AB - Increased glucocorticoid concentrations have been shown to favor resilience towards autoimmune phenomena. Here, we addressed whether experimentally induced elevations in circulating glucocorticoids mitigate the abnormalities exhibited by an experimental model of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). This is a pathogenic hypothesis linking repeated exposures to Group-A-beta-hemolytic streptococcus (GAS), autoantibodies targeting selected brain nuclei and neurobehavioral abnormalities. To persistently elevate glucocorticoid concentrations, we supplemented lactating SJL/J mice with corticosterone (CORT; 80 mg/L) in the drinking water. Starting in adolescence (postnatal day 28), developing offspring were exposed to four injections - at bi-weekly intervals - of a GAS homogenate and tested for behavioral, immunological, neurochemical and molecular alterations. GAS mice showed increased perseverative behavior, impaired sensorimotor gating, reduced reactivity to a serotonergic agonist and inflammatory infiltrates in the anterior diencephalon. Neonatal CORT persistently increased circulating glucocorticoids concentrations and counteracted these alterations. Additionally, neonatal CORT increased peripheral and CNS concentrations of the anti-inflammatory cytokine IL 9. Further, upstream regulator analysis of differentially expressed genes in the striatum showed that the regulatory effect of estradiol is inhibited in GAS treated mice and activated in GAS-treated mice exposed to CORT. These data support the hypothesis that elevations in glucocorticoids may promote central immunomodulatory processes. PMID- 29976950 TI - Candida tolerates and persists. PMID- 29976949 TI - Innate and adaptive immune dysregulation in critically ill ICU patients. AB - This study aimed to evaluate whether ICU patients who developed persistent critical illness displayed an immune profile similar to an aged immune phenotype and any associations with patient outcomes. Twenty two critically ill ICU patients (27-76 years, 15 males), at day 5 of mechanical ventilation, and 22 healthy age-matched controls (27-77 years, 13 males) were recruited. Frequency and phenotype of innate and adaptive immune cells and telomere length in peripheral blood mononuclear cells (PBMCs) were measured. An elevated granulocyte count (p < 0.0001), increased numbers of immature granulocytes (p < 0.0001), increased CD16++ve monocytes (p = 0.003) and CD14+ve HLADRdim/low monocytes (p = 0.004) and lower NK cell numbers (p = 0.007) were observed in ICU patients compared to controls. Critically ill patients also had lower numbers of total T lymphocytes (p = 0.03), naive CD4 T cells (p = 0.003) and PTK7+ve recent thymic emigrants (p = 0.002), and increased senescent CD28-ve CD57+ve CD4 T cells (p = 0.02), but there was no difference in PBMC telomere length. Regulatory immune cell frequency was affected with reduced circulating CD19+veCD24hiCD38hi regulatory B cells (p = 0.02). However, only a raised neutrophil:lymphocyte ratio and reduced frequency of CD14+ve HLADRdim/low monocytes were associated with poor outcomes. We conclude that persistent critical illness results in changes to immune cell phenotype only some of which are similar to that seen in physiological ageing of the immune system. PMID- 29976951 TI - High-throughput imaging flow cytometry by optofluidic time-stretch microscopy. AB - The ability to rapidly assay morphological and intracellular molecular variations within large heterogeneous populations of cells is essential for understanding and exploiting cellular heterogeneity. Optofluidic time-stretch microscopy is a powerful method for meeting this goal, as it enables high-throughput imaging flow cytometry for large-scale single-cell analysis of various cell types ranging from human blood to algae, enabling a unique class of biological, medical, pharmaceutical, and green energy applications. Here, we describe how to perform high-throughput imaging flow cytometry by optofluidic time-stretch microscopy. Specifically, this protocol provides step-by-step instructions on how to build an optical time-stretch microscope and a cell-focusing microfluidic device for optofluidic time-stretch microscopy, use it for high-throughput single-cell image acquisition with sub-micrometer resolution at >10,000 cells per s, conduct image construction and enhancement, perform image analysis for large-scale single-cell analysis, and use computational tools such as compressive sensing and machine learning for handling the cellular 'big data'. Assuming all components are readily available, a research team of three to four members with an intermediate level of experience with optics, electronics, microfluidics, digital signal processing, and sample preparation can complete this protocol in a time frame of 1 month. PMID- 29976952 TI - Comparison between renal denervation and metoprolol on the susceptibility of ventricular arrhythmias in rats with myocardial infarction. AB - Ventricular arrhythmias (VAs) are the leading cause of sudden cardiac death in patients with myocardial infarction (MI). We sought to compare effects of renal denervation (RDN) and metoprolol on VAs after MI. Fifty-four male Sprague-Dawley rats underwent ligation of left anterior descending coronary artery to induce MI, while 6 rats served as Control. Metoprolol was given 20 mg/kg/day for 5 weeks after MI surgery. RDN/Sham-RDN procedure was performed at 1 week after MI. At 5 weeks after MI, electrical programmed stimulation (EPS) was performed in all groups for evaluation of VAs. After EPS, heart and kidneys were harvested. Compared with MI group, RDN and metoprolol significantly decreased the incidence of VAs, and RDN is superior to metoprolol. Compared with metoprolol group, Masson staining showed that RDN significantly reduced the myocardial fibrosis. Both RDN and metoprolol decreased the protein expression of connexin43 (Cx43) compared with MI group, while only RDN lighted this decrease remarkably. Immunohistochemical staining of Tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) revealed that RDN and metoprolol had similar effect on reducing densities of sympathetic nerve in infarction border zone. According to this study, RDN is more effective in reducing VAs than metoprolol in ischemic cardiomyopathy model. PMID- 29976953 TI - Threshold for neural tube defect risk by accumulated singleton loss-of-function variants. PMID- 29976954 TI - Preparation of Anti-Human Podoplanin Monoclonal Antibody and its application in Immunohistochemical Diagnosis. AB - Podoplanin (PDPN), a 38 kDa transmembrane sialoglycoprotein from human, is expressed in lymphatic endothelial cells but not in vascular endothelial cells, and has been considered as a specific marker of lymph. In this study, the gene encoding the extracellular part of PDPN (ePDPN) was synthesized and used to expressed fusion protein ePDPN-His and GST-ePDPN, respectively, in E.coli. The purified GST-ePDPN fusion protein was mixed with QuickAntibody-Mouse5W adjuvant to immune mice, and the antiserum titer was determined by indirect ELISA. A stable cell line named 5B3 generating anti-PDPN monoclonal antibody (mAb) was obtained by hybridoma technology. The isotype of 5B3 cell line was IgG2b, and the chromosome number was 102 +/- 4. The 5B3 mAb was purified successfully from ascites fluid through Protein G column, and its affinity constant was 2.94 * 108 L/mol. Besides, excellent specificity of the 5B3 mAb was further demonstrated in ELISA, western blot and immunohistochemistry experiments, suggesting that 5B3 mAb displays similar application value to D2-40, a commercial available antibody. Hence, the current study provides conclusive guidelines for preparation of other mAbs and their applications in immunohistochemistry diagnosis. PMID- 29976956 TI - Synthetic antigen-binding fragments (Fabs) against S. mutans and S. sobrinus inhibit caries formation. AB - Streptococcus mutans and Streptococcus sobrinus are the main causative agents of human dental caries. Current strategies for treating caries are costly and do not completely eradicate them completely. Passive immunization using nonhuman antibodies against Streptococcal surface antigens has shown success in human trials, however they often invoke immune reactions. We used phage display to generate human antigen-binding fragments (Fabs) against S. mutans and S. sobrinus. These Fabs were readily expressed in E. coli and bound to the surface S. mutans and S. sobrinus. Fabs inhibited sucrose-induced S. mutans and S. sobrinus biofilm formation in vitro and a combination of S. mutans and S. sobrinus Fabs prevented dental caries formation in a rat caries model. These results demonstrated that S. mutans and S. sobrinus Fabs could be used in passive immunization strategies to prevent dental caries. In the future, this strategy may be applied towards a caries therapy, whereby Fabs are topically applied to the tooth surface. PMID- 29976955 TI - Tissue and exosomal miRNA editing in Non-Small Cell Lung Cancer. AB - RNA editing in microRNAs has been recently proposed as a novel biomarker in cancer. Here, we investigated RNA editing by leveraging small-RNA sequencing data from 87 NSCLC (Non-Small Cell Lung Cancer) samples paired with normal lung tissues from The Cancer Genome Atlas (TCGA) combined with 26 plasma-derived exosome samples from an independent cohort. Using both the editing levels and microRNA editing expression, we detected deregulated microRNA editing events between NSCLC tumor and normal tissues. Interestingly, and for the first time, we also detected editing sites in the microRNA cargo of circulating exosomes, providing the potential to non-invasively discriminate between normal and tumor samples. Of note, miR-411-5p edited in position 5 was significantly dysregulated in tissues as well as in exosomes of NSCLC patients, suggesting a potential targetome shift relevant to lung cancer biology. PMID- 29976957 TI - Old origin of a protective endogenous retrovirus (enJSRV) in the Ovis genus. AB - Sheep, the Jaagsiekte sheep retrovirus (JSRV) and its endogenous forms (enJSRVs) are a good model to study long-time relationships between retroviruses and their hosts. Taking advantage of 76 whole genome resequencing data of wild and domestic Ovis, we investigated the evolution of this relationship. An innovative analysis of re-sequencing data allowed characterizing 462 enJSRVs insertion sites (including 435 newly described insertions) in the Ovis genus. We focused our study on endogenous copies inserted in the q13 locus of chromosome 6 (6q13). Those copies are known to confer resistance against exogenous JSRV thanks to alleles bearing a mutation in the gag gene. We characterized (i) the distribution of protective and non-protective alleles across Ovis species and (ii) the copy number variation of the 6q13 locus. Our results challenged the previous hypothesis of fixation and amplification of the protective copies in relation with domestication, and allowed building a new model for the evolution of the 6q13 locus. JSRV would have integrated the 6q13 locus after the Ovis-Capra divergence (5-11 MYA) and before the Ovis diversification (2.4-5 MYA). The protective mutation in the enJSRV 6q13 copy appeared shortly after its insertion and was followed by genomic amplifications, after the divergence between Pachyform lineage on one side and the Argaliform and moufloniform lineages on the other (2.4-5 MYA). Considering the potential selective advantage of the protective mutation, its fixation in both sheep and its closest wild relative Ovis orientalis may be due to natural selection before domestication from O. orientalis populations. PMID- 29976958 TI - Evolutionary consequences of epigenetic inheritance. PMID- 29976959 TI - Cross-scale neutral ecology and the maintenance of biodiversity. AB - One of the first successes of neutral ecology was to predict realistically-broad distributions of rare and abundant species. However, it has remained an outstanding theoretical challenge to describe how this distribution of abundances changes with spatial scale, and this gap has hampered attempts to use observed species abundances as a way to quantify what non-neutral processes are needed to fully explain observed patterns. To address this, we introduce a new formulation of spatial neutral biodiversity theory and derive analytical predictions for the way abundance distributions change with scale. For tropical forest data where neutrality has been extensively tested before now, we apply this approach and identify an incompatibility between neutral fits at regional and local scales. We use this approach derive a sharp quantification of what remains to be explained by non-neutral processes at the local scale, setting a quantitative target for more general models for the maintenance of biodiversity. PMID- 29976960 TI - Obesity cutoff values in Korean men with motor complete spinal cord injury: body mass index and waist circumference. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: To determine the obesity cutoff values for body mass index (BMI) and waist circumference (WC) in Korean men with motor complete spinal cord injury (SCI). SETTING: Tertiary level hospital in Seoul, Korea. METHODS: BMI (kg/m2) was calculated and WC (cm) was measured in each participant in the supine position. Percentage of total body fat (%) was determined using whole-body dual-energy X-ray absorptiometry. Receiver operating characteristic curves were generated to determine the obesity cutoff values for BMI and WC. The optimal cutoff values were determined using the Youden index. Identified cutoff values were compared with those of 195 age- and BMI-matched men in the general population (GP), obtained from the Korea National Health and Nutrition Examination Survey. RESULTS: This study included 52 Korean men with motor complete SCI. A BMI of 20.2 kg/m2 and WC of 81.3 cm were identified as obesity cutoff values in Korean men with motor complete SCI. The area under the curve (AUC) was 0.928, specificity was 100%, and sensitivity was 84.8% according to the ROC curve of BMI for participants. AUC was 0.964, specificity was 100%, and sensitivity was 84.8% in the ROC curve of WC for participants. A BMI of 22.5 kg/m2 and WC of 85.5 cm were identified as obesity cutoff values in age- and BMI matched men in the GP. CONCLUSIONS: The obesity cutoff values in Korean men with motor complete SCI that were determined in this study were lower than those of the Korean GP and western people with SCI. PMID- 29976961 TI - Modeling the distributions of tegu lizards in native and potential invasive ranges. AB - Invasive reptilian predators can have substantial impacts on native species and ecosystems. Tegu lizards are widely distributed in South America east of the Andes, and are popular in the international live animal trade. Two species are established in Florida (U.S.A.) - Salvator merianae (Argentine black and white tegu) and Tupinambis teguixin sensu lato (gold tegu) - and a third has been recorded there- S. rufescens (red tegu). We built species distribution models (SDMs) using 5 approaches (logistic regression, multivariate adaptive regression splines, boosted regression trees, random forest, and maximum entropy) based on data from the native ranges. We then projected these models to North America to develop hypotheses for potential tegu distributions. Our results suggest that much of the southern United States and northern Mexico probably contains suitable habitat for one or more of these tegu species. Salvator rufescens had higher habitat suitability in semi-arid areas, whereas S. merianae and T. teguixin had higher habitat suitability in more mesic areas. We propose that Florida is not the only state where these taxa could become established, and that early detection and rapid response programs targeting tegu lizards in potentially suitable habitat elsewhere in North America could help prevent establishment and abate negative impacts on native ecosystems. PMID- 29976962 TI - Structural determination of bilayer graphene on SiC(0001) using synchrotron radiation photoelectron diffraction. AB - In recent years there has been growing interest in the electronic properties of 'few layer' graphene films. Twisted layers, different stacking and register with the substrate result in remarkable unconventional couplings. These distinctive electronic behaviours have been attributed to structural differences, even if only a few structural determinations are available. Here we report the results of a structural study of bilayer graphene on the Si-terminated SiC(0001) surface, investigated using synchrotron radiation-based photoelectron diffraction and complemented by angle-resolved photoemission mapping of the electronic valence bands. Photoelectron diffraction angular distributions of the graphene C 1s component have been measured at different kinetic energies and compared with the results of multiple scattering simulations for model structures. The results confirm that bilayer graphene on SiC(0001) has a layer spacing of 3.48 A and an AB (Bernal) stacking, with a distance between the C buffer layer and the first graphene layer of 3.24 A. Our work generalises the use of a versatile and precise diffraction method capable to shed light on the structure of low-dimensional materials. PMID- 29976963 TI - Hypoxia promotes breast cancer cell invasion through HIF-1alpha-mediated up regulation of the invadopodial actin bundling protein CSRP2. AB - Hypoxia is a common feature of solid tumours that promotes invasion and metastatic dissemination. Invadopodia are actin-rich membrane protrusions that direct extracellular matrix proteolysis and facilitate tumour cell invasion. Here, we show that CSRP2, an invadopodial actin bundling protein, is upregulated by hypoxia in various breast cancer cell lines, as well as in pre-clinical and clinical breast tumour specimens. We functionally characterized two hypoxia responsive elements within the proximal promoter of CSRP2 gene which are targeted by hypoxia-inducible factor-1 (HIF-1) and required for promoter transactivation in response to hypoxia. Remarkably, CSRP2 knockdown significantly inhibits hypoxia-stimulated invadopodium formation, ECM degradation and invasion in MDA-MB 231 cells, while CSRP2 forced expression was sufficient to enhance the invasive capacity of HIF-1alpha-depleted cells under hypoxia. In MCF-7 cells, CSRP2 upregulation was required for hypoxia-induced formation of invadopodium precursors that were unable to promote ECM degradation. Collectively, our data support that CSRP2 is a novel and direct cytoskeletal target of HIF-1 which facilitates hypoxia-induced breast cancer cell invasion by promoting invadopodia formation. PMID- 29976964 TI - Publisher Correction: Learning by neural reassociation. AB - In the version of this article initially published, equation (10) contained cos Theta instead of sin Theta as the bottom element of the right-hand vector. The error has been corrected in the HTML and PDF versions of the article. PMID- 29976965 TI - Exposure to podophyllotoxin inhibits oocyte meiosis by disturbing meiotic spindle formation. AB - Podophyllotoxin is used as medical cream which is widely applied to genital warts and molluscum contagiosum. Although previous study showed that podophyllotoxin had minimal toxicity, it was forbidden to use during pregnancy since it might be toxic to the embryos. In present study we used mouse as the model and tried to examine whether podophyllotoxin exposure was toxic to oocyte maturation, which further affected embryo development. Our results showed that podophyllotoxin exposure inhibited mouse oocyte maturation, showing with the failure of polar body extrusion, and the inhibitory effects of podophyllotoxin on oocytes was dose depended. Further studies showed that the meiotic spindle formation was disturbed, the chromosomes were misaligned and the fluorescence signal of microtubule was decreased, indicating that podophyllotoxin may affect microtubule dynamics for spindle organization. Moreover, the oocytes which reached metaphase II under podophyllotoxin exposure also showed aberrant spindle morphology and chromosome misalignment, and the embryos generated from these oocytes showed low developmental competence. We also found that the localization of p44/42 MAPK and gamma-tubulin was disrupted, which further confirmed the effects of podophyllotoxin on meiotic spindle formation. In all, our results indicated that podophyllotoxin exposure could affect mouse oocyte maturation by disturbing microtubule dynamics and meiotic spindle formation. PMID- 29976966 TI - The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio: In support of an investment strategy to improve the public health of the nation through perinatal research. PMID- 29976967 TI - The uncertain fate of the National Institutes of Health (NIH) pediatric research portfolio. AB - BACKGROUND: The amount of federal dollars allocated to improving the health of our pediatric population can serve as an indicator of the priority placed on child well-being. Although Congress has established novel mechanisms that marginally increase pediatric research funding, the pediatric research portfolio is facing an increasingly uncertain fate. METHODS: This work examines pediatric, perinatal and pediatric research initiative (PRI) spending using data collected by the NIH that uses the novel research, condition and disease categorization system. Further, this work reports on recent policy developments in pediatric biomedical research and offers recommendations to insulate this portfolio from future uncertainty. RESULTS: Federal support for pediatric research has declined with average annual growth rates of NIH pediatric spending dropping from 12.8% (FY 1998-2003) to 1.7% (FY 2004-2015). After taking into account Biomedical Research and Development Price Index growth, the pediatric research portfolio's purchasing power has declined by 15.9% (FY 2004-2015). CONCLUSION: Federal support for pediatric biomedical research has plateaued in nominal terms and declined significantly in real terms. Future congressional action will be necessary to protect gains and to expand the capacity of the pediatric portfolio. PMID- 29976968 TI - Dobutamine treatment reduces inflammation in the preterm fetal sheep brain exposed to acute hypoxia. AB - BACKGROUND: Impaired cerebral autoregulation in preterm infants makes circulatory management important to avoid cerebral hypoxic-ischemic injury. Dobutamine is frequently used as inotropic treatment in preterm neonates, but its effects on the brain exposed to cerebral hypoxia are unknown. We hypothesized that dobutamine would protect the immature brain from cerebral hypoxic injury. METHODS: In preterm (0.6 gestation) fetal sheep, dobutamine (Dob, 10 MUg/kg/min) or saline (Sal) was infused intravenously for 74 h. Two hours after the beginning of the infusion, umbilical cord occlusion (UCO) was performed to produce fetal asphyxia (Sal+UCO: n = 9, Dob+UCO: n = 7), or sham occlusion (Sal+sham: n = 7, Dob+sham: n = 6) was performed. Brains were collected 72 h later for neuropathology. RESULTS: Dobutamine did not induce cerebral changes in the sham UCO group. UCO increased apoptosis and microglia density in white matter, hippocampus, and caudate nucleus, and astrocyte density in the caudate nucleus. Dobutamine commenced before UCO reduced microglia infiltration in the white matter, and microglial and astrocyte density in the caudate. CONCLUSION: In preterm hypoxia-induced brain injury, dobutamine decreases neuroinflammation in the white matter and caudate, and reduces astrogliosis in the caudate. Early administration of dobutamine in preterm infants for cardiovascular stabilization appears safe and may be neuroprotective against unforeseeable cerebral hypoxic injury. PMID- 29976970 TI - Clinical utility of endomyocardial biopsies in the diagnosis of arrhythmogenic right ventricular cardiomyopathy in children. AB - BACKGROUND: Histomorphometry of endomyocardial biopsies is one component of arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis, although there is a need for stricter diagnostic criteria for this disease in pediatrics. The clinical utility of biopsy analysis as a component of ARVC diagnosis was evaluated in pediatric patients. METHODS: Histomorphometric analysis of fibrofatty infiltrate was completed on pediatric right ventricular endomyocardial biopsy samples. Myocardial replacement by fat and fibrosis was quantified. ARVC diagnosis was established using the 2010 ARVC Task Force criteria, with the biopsy measures compared across various ARVC diagnoses (definite, borderline, possible, or no ARVC). Receiver-operating characteristic (ROC) curve analysis was also completed using biopsy measures. RESULTS: The greatest proportion of fat, fibrosis, and myocardial replacement was in the definite ARVC cohort, and was significantly larger than for the other diagnosis cohorts. ROC curve analysis (with the biopsy analysis removed from the diagnostic classification) produced cutoff values of 15 and 25% myocardial replacement, which is lower than current adult diagnosis criteria. CONCLUSION: We propose modifications in pediatric major and minor biopsy diagnosis criteria to allow for improved sensitivity. This study suggests that biopsy analysis in children is most significant for subjects with a more severe disease presentation. PMID- 29976969 TI - Effects of antenatal betamethasone on preterm human and mouse ductus arteriosus: comparison with baboon data. AB - BACKGROUND: Although studies involving preterm infants <=34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results. METHODS: We used preterm baboons, mice, and humans (<=276/7 weeks gestation) to examine betamethasone's effects on ductus gene expression and constriction both in vitro and in vivo. RESULTS: In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone's effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born <=256/7 weeks gestation, betamethasone's contractile effects were only apparent when prostaglandin signaling was inhibited, whereas at 26-27 weeks gestation, betamethasone's contractile effects were apparent even in the absence of prostaglandin inhibitors. CONCLUSIONS: We speculate that betamethasone's contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone's effects vary according to the infant's developmental age at birth. PMID- 29976971 TI - The effects of sleeping position, maternal smoking and substance misuse on the ventilatory response to hypoxia in the newborn period. AB - BACKGROUND: Maternal smoking, substance misuse in pregnancy and prone sleeping increase the risk of sudden infant death syndrome (SIDS). We examined the effect of maternal smoking, substance misuse and sleeping position on the newborn response to hypoxia. METHODS: Infants born between 36 and 42 weeks of gestational age underwent respiratory monitoring in the prone and supine sleeping position before and during a hypoxic challenge. Minute ventilation (MV) and end-tidal carbon dioxide (ETCO2) levels were assessed. RESULTS: Sixty-three infants were studied: 22 controls, 23 whose mothers smoked and 18 whose mothers substance misused and smoked. In the supine position, baseline MV was higher and ETCO2 levels were lower in infants of substance-misusing mothers compared to controls (p = 0.015, p = 0.017, respectively). Infants of substance-misusing mothers had a lower baseline MV and higher ETCO2 levels in the prone position (p = 0.005, p = 0.004, respectively). When prone, the rate of decline in minute ventilation in response to hypoxia was greater in infants whose mothers substance-misused and smoked compared to controls (p = 0.002) and infants of smoking mothers (p = 0.016). CONCLUSION: The altered response to hypoxia in the prone position of infants whose mothers substance-misused and smoked in pregnancy may explain their increased vulnerability to SIDS. PMID- 29976972 TI - Basal levels of 17-hydroxyprogesterone can distinguish children with isolated precocious pubarche. AB - BACKGROUND: Basal levels of androgens, in particular 17-hydroxyprogesterone (17OHP), are widely debated as predictors of non-classical congenital adrenal hyperplasia (NCCAH) among patients with precocious pubarche (PP). Many authors have recommended the use of adrenocorticotropic hormone (ACTH) stimulation test in children with PP. The aim of our study was to identify clinical and biochemical predictors of NCCAH in children with PP. METHODS: We conducted a prospective study of 92 patients with PP undergoing an ACTH stimulation test. We tested the association of basal clinical and biochemical parameters with NCCAH diagnosis. Patients were suspected to have NCCAH if their stimulated 17OHP plasma levels were >10 ng/mL. In these patients, the diagnosis was confirmed by genetic test. RESULTS: Seven (7.6%) patients resulted having NCCAH. The best basal biochemical predictor for NCCAH was 17OHP level >2 ng/mL. In fact, a basal 17OHP level >2 ng/mL had 100% (95% confidence interval (CI), 59.04-100) sensitivity and 93% (95% CI, 85.3-97.37) specificity. The area under the receiver-operating characteristic curve for 17OHP was 0.99 (95% CI, 0.98-1.007). CONCLUSIONS: Basal 17OHP cut-off of 2 ng/mL was very effective in predicting NCCAH among our patients with PP. Assay-specific cut-off would probably be the best strategy to avoid unnecessary ACTH test. PMID- 29976973 TI - Vitamin D receptor gene (FokI, TaqI, BsmI, and ApaI) polymorphisms in children with urinary tract infection. AB - BACKGROUND: Little is known about the genetic background of urinary tract infection (UTI) in children. METHODS: In this study, vitamin D receptor (VDR) gene polymorphisms were compared between 60 children with UTI (case group) and 60 healthy children (control group). DNA extraction, polymerase chain reaction, and the restriction fragment length polymorphism methods were used to perform the genetic analysis. RESULTS: There was a significant difference between the case and control groups for VDR gene, ApaI and Bsml, polymorphisms (P < 0.05). The frequency of VDR Bb, bb, Aa, and aa genotypes, and the b and a alleles in the case group was significantly higher than that in the control group (P < 0.05). A significant difference was also found between lower UTI and acute pyelonephritis groups for the VDR Apal and Bsml genotypes (P < 0.05). There was no significant difference between children with first UTI and those with more than one UTI for VDR gene polymorphisms (P > 0.05). CONCLUSION: This study showed that there is a significant relationship between VDR gene, Apal and Bsml, polymorphisms and UTI in children. The results indicate that these polymorphisms may play a role in pathogenesis of UTI. PMID- 29976974 TI - Defining pharyngeal contractile integral during high-resolution manometry in neonates: a neuromotor marker of pharyngeal vigor. AB - BACKGROUND: Pharyngeal contractility is critical for safe bolus propulsion. Pharyngeal contractile vigor can be measured by Pharyngeal Contractile Integral (PhCI): product of mean pharyngeal contractile amplitude, length, and duration. We characterized PhCI in neonates and examined the hypothesis that PhCI differs with mode of stimulation. METHODS: Nineteen neonates born at 38.6 (34-41) weeks gestation were evaluated at 42.9 (40.4-44.0) weeks postmenstrual age using high resolution manometry (HRM). PhCI was calculated using: (a) Conventional and (b) Automated Swallow Detection algorithm (ASDA) methods. Contractility metrics of all pharyngeal regions were examined using mixed statistical models during spontaneous and adaptive state (pharyngeal and oral stimulus) swallowing. RESULTS: PhCI of oral stimuli swallows were distinct from pharyngeal stimuli and spontaneous swallows (P < 0.05). Correlation between conventional and ASDA methods was high (P < 0.001). PhCI increased with swallows for pharyngeal stimulation (P < 0.05) but remained stable for swallows with oral stimulation. PhCI differed between proximal and distal pharynx (P < 0.001). CONCLUSIONS: PhCI is a novel reliable metric capable of distinguishing (1) proximal and distal pharyngeal activity, (2) effects of oral and pharyngeal stimulation, and (3) effects of prolonged stimulation. Changes in pharyngeal contractility with maturation, disease, and therapies can be examined with PhCI. PMID- 29976975 TI - FOXC1 plays a crucial role in the growth of pancreatic cancer. AB - IGF-1R signaling controls various vital cellular functions and this signaling is deregulated in many cancers, including pancreatic cancer. Several efforts have mainly focused on inhibiting the IGF-1R signaling cascade. The outcomes of these focused preclinical studies have been positive, whereas clinical trials of IGF-1R inhibitors in pancreatic cancer have failed, raising the questions about this therapeutic approach. This necessitates a better understanding of the role of IGF 1R signaling in pancreatic cancer. We investigated the impact of IGF-1R signaling on crucial transcription factors and identified the FOXC1 as one of the crucial regulator of IGF-1R signaling. We employed genetic approaches to overexpress and silence FOXC1 in pancreatic cancer cells. Our results demonstrate that IGF-1R and FOXC1 seem to positively regulate each other. Further, FOXC1 increased the metastatic abilities of pancreatic cancer cells by enhancing cell proliferation, migration, invasion, epithelial-to-mesenchymal transition, and angiogenesis. The data from xenograft experiments further established the importance of FOXC1 in pancreatic tumorigenesis. In conclusion, FOXC1 is a potent oncogenic transcription factor, which promotes pancreatic cancer growth and metastasis. Thus, targeting FOXC1 could be a potential therapeutic strategy against pancreatic cancer. PMID- 29976976 TI - Comparison of methods for transcriptome imputation through application to two common complex diseases. AB - Transcriptome imputation has become a popular method for integrating genotype data with publicly available expression data to investigate the potentially causal role of genes in complex traits. Here, we compare three approaches (PrediXcan, MetaXcan and FUSION) via application to genome-wide association study (GWAS) data for Crohn's disease and type 1 diabetes from the Wellcome Trust Case Control Consortium. We investigate: (i) how the results of each approach compare with each other and with those of standard GWAS analysis; and (ii) how variants in the models used by the prediction tools compare with variants previously reported as eQTLs. We find that all approaches produce highly correlated results when applied to the same GWAS data, although for a subset of genes, mostly in the major histocompatibility complex, the approaches strongly disagree. We also observe that most associations detected by these methods occur near known GWAS risk loci. PrediXcan and MetaXcan's models for predicting expression more consistently recapitulate known effects of genotype on expression, suggesting they are more robust than FUSION. Application of these transcriptome imputation approaches to summary statistics from meta-analyses in Crohn's disease and type 1 diabetes detects 53 significant expression-Crohn's disease associations and 154 significant expression-type 1 diabetes associations, providing insight into biology underlying these diseases. We conclude that while current implementations of transcriptome imputation typically detect fewer associations than GWAS, they nonetheless provide an interesting way of interpreting association signals to identify potentially causal genes, and that PrediXcan and MetaXcan generally produce more reliable results than FUSION. PMID- 29976977 TI - Genome-wide copy number variation analysis identifies novel candidate loci associated with pediatric obesity. AB - Obesity is a multifactorial condition that is highly heritable. There have been ~60 susceptibility loci identified, but they only account for a fraction of cases. As copy number variations (CNVs) have been implicated in the etiology of a multitude of human disorders including obesity, here, we investigated the contribution of rare (<1% population frequency) CNVs in pediatric cases of obesity. We genotyped 67 such individuals, including 22 with co-morbid developmental delay and prioritized rare CNVs at known obesity-associated loci, as well as, those impacting genes involved in energy homeostasis or related processes. We identified clinically relevant or potentially clinically relevant CNVs in 15% (10/67) of individuals. Of these, 4% (3/67) had 16p11.2 microdeletions encompassing the known obesity risk gene SH2B1. Notably, we identified two unrelated probands harboring different 6p22.2 microduplications encompassing SCGN, a potential novel candidate gene for obesity. Further, we identified other biologically relevant candidate genes for pediatric obesity including ARID5B, GPR39, PTPRN2, and HNF4G. We found previously reported candidate loci for obesity, and new ones, suggesting CNV analysis may assist in the diagnosis of pediatric obesity. PMID- 29976978 TI - Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. AB - Medical genomics research performed in diverse population facilitates a better understanding of the genetic basis of developmental disorders, with regional implications for community genetics. Autosomal recessive mitochondrial complex I deficiency (MCID) accounts for a constellation of clinical features, including encephalopathies, myopathies, and Leigh Syndrome. Using whole-exome sequencing, we identified biallelic missense variants in NDUFV1 that encodes the 51-kD subunit of complex I (NADH dehydrogenase) NDUFV1. Mapping the variants on published crystal structures of mitochondrial complex I demonstrate that the novel c.1118T > C (p.(Phe373Ser)) variant is predicted to diminish the affinity of the active pocket of NDUFV1 for FMN that correlates to an early onset of debilitating MCID symptoms. The c.1156C > T (p.(Arg386Cys)) variant is predicted to alter electron shuttling required for energy production and correlate to a disease onset in childhood. NDUFV1 c.1156C > T (p.(Arg386Cys)) represents a founder variant in South Asian populations that have value in prioritizing this variant in a population-specific manner for genetic diagnostic evaluation. In conclusion, our results demonstrate the advantage of analyzing population specific sequences to understand the disease pathophysiology and prevalence of inherited risk variants in the underrepresented populations. PMID- 29976979 TI - Peniazaphilin A, a new azaphilone derivative produced by Penicillium sp. CPCC 400786. AB - A new azaphilone derivative, named peniazaphilin A (1) and one known isocoumarin, (R)-3-methyl-6-hydroxy-8-methoxy-3,4-dihydroisocoumarin (2) were isolated from the fungus Penicillium sp. CPCC 400786. Their structures were elucidated by means of extensive spectroscopic analysis. The absolute configuration of 2 was established by circular dichroism for the first time. Compounds 1 and 2 exhibited weak anti-HIV activities with the IC50 values of 60.4 and 69.3 MUM, respectively. PMID- 29976980 TI - Electron heating in rf capacitive discharges at atmospheric-to-subatmospheric pressures. AB - Electron heating is a fundamental and multidisciplinary phenomenon in partially ionized gases, from the planet's ionosphere to laboratory-scale plasmas. Plasmas produced at ambient or reduced pressures have recently shown potential for scientific and industrial applications. However, electron heating, which is strongly coupled to the physicochemical properties of these plasmas, has been poorly understood. We experimentally found the rapid structural transition from non-local to local electron heating in collisional radio-frequency discharges at atmospheric-to-subatmospheric pressures. As the gas pressure decreased from 760 to 200 Torr, the time-averaged electron density increased from 1.3 * 1012 to 1.3 * 1013 cm-3, and the electron temperature decreased from 2.5 to 1.1 eV at the maximum allowable discharge current in the abnormal alpha-mode in the plasma bulk. The spatiotemporal evolution of the electron temperature clearly shows that the electron temperature increases uniformly throughout the bulk plasma region during sheath expansion and collapse at 760 Torr, but the electron heating weakens with sheath collapse as the gas pressure decreases. PMID- 29976981 TI - Improving of hydrolases biosythesis by solid-state fermentation of Penicillium camemberti on rapeseed cake. AB - The study show usefulness of rapeseed cake, rich in fats and proteins byproduct generated after oil production, which may be used as a microbial medium for lipase and protease biosynthesis. Of 26 different filamentous fungi screened by solid-state fermentation, Penicillium camemberti AM83 was found to abundantly produce lipase and protease. Various process parameters were then optimized to maximize lipase and protease secretion, including carbon and nitrogen source, C/N ratio, metal ions, temperature, moisture content, initial pH, and inoculum size. Lipase production increased approximately 11.2-fold in solid-state cultures on rapeseed cake supplemented with lactose and calcium chloride, alkalinized to pH 8, hydrated to 80%, and inoculated with 1.2 * 106 spores/mL. Similarly, protease production increased approximately 8.4-fold in optimized cultures inoculated with 3.2 * 108 spores/mL, and grown on rapeseed cake with lactose and ammonium sulfate at pH 9 and moisture content 60%. The results highlight the potential economic value of solid-state fermentation on rapeseed cake to produce industrial hydrolases. PMID- 29976982 TI - Melatonin alleviates low-sulfur stress by promoting sulfur homeostasis in tomato plants. AB - Despite involvement of melatonin (MT) in plant growth and stress tolerance, its role in sulfur (S) acquisition and assimilation remains unclear. Here we report that low-S conditions cause serious growth inhibition by reducing chlorophyll content, photosynthesis and biomass accumulation. S deficiency evoked oxidative stress leading to the cell structural alterations and DNA damage. In contrast, MT supplementation to the S-deprived plants resulted in a significant diminution in reactive oxygen species (ROS) accumulation, thereby mitigating S deficiency induced damages to cellular macromolecules and ultrastructures. Moreover, MT promoted S uptake and assimilation by regulating the expression of genes encoding enzymes involved in S transport and metabolism. MT also protected cells from ROS induced damage by regulating 2-cysteine peroxiredoxin and biosynthesis of S compounds. These results provide strong evidence that MT can enhance plant tolerance to low-S-induced stress by improving S uptake, metabolism and redox homeostasis, and thus advocating beneficial effects of MT on increasing the sulfur utilization efficiency. PMID- 29976983 TI - Universal geometric frustration in pyrochlores. AB - Materials with the pyrochlore/fluorite structure have diverse technological applications, from magnetism to nuclear waste disposal. Here we report the observation of structural instability present in the pyrochlores A2Zr2O6O' (A = Pr, La) and Yb2Ti2O6O', that exists despite ideal stoichiometry, ideal cation ordering, the absence of lone pair effects, and a lack of magnetic order. Though these materials appear to have good long-range order, local structure probes find displacements, of the order of 0.01 nm, within the pyrochlore framework. The pattern of displacements of the A2O' sublattice mimics the entropically-driven fluxional motions characteristic of and well-known in the silica mineral beta cristobalite. The universality of such displacements within the pyrochlore structure adds to the known structural diversity and explains the extreme sensitivity to composition found in quantum spin ices and the lack of ferroelectric behavior in pyrochlores. PMID- 29976984 TI - Paleosecular variation recorded by Quaternary lava flows from Guadeloupe Island. AB - Paleomagnetic directional data were obtained from fourteen 0 to 2 Ma old lava flows at Basse-Terre Island (Guadeloupe, French West Indies). Five reversed polarity flows are consistent with their Matuyama age between 1.6-1.5 Ma and 875 790 ka while the ages of the other nine normal polarity units tie them to the Olduvai subchron and the Brunhes Chron. These directions have been combined with previous results obtained from Basse-Terre Island. The overall mean direction (D = -1.2 degrees , I = 31.4 degrees , alpha95 = 3.3 degrees ) obtained from the 39 non-transitional flows from Basse-Terre Island is indistinguishable from the expected geocentric axial dipole value (D = 0 degrees , I = 29.8 degrees ). The dispersion measured from the angular standard deviation of the Virtual Geomagnetic Poles (VGPs) was found to be close to, but smaller than the predictions of geomagnetic models. Together with further directions from the nearby Martinique Island, the 45 directions obtained within the Brunhes chron provide the most robust estimate of the statistical distribution of paleosecular variation (PSV) at this latitude. The sequence of directions shows episodes of high amplitude secular variation that are coeval with several geomagnetic events including the last reversal documented by five transitional directions. Finally, three lava flows have recorded a transitional behavior which could be link to two excursions, the Laguna del Sello (at ~340 ka) and the Pringle Falls (at ~210 ka) events. PMID- 29976985 TI - Ewing sarcoma. PMID- 29976986 TI - A biomimetic chiral-driven ionic gate constructed by pillar[6]arene-based host guest systems. AB - Inspired by glucose-sensitive ion channels, herein we describe a biomimetic glucose-enantiomer-driven ion gate via the introduction of the chiral pillar[6]arene-based host-guest systems into the artificial nanochannels. The chiral nanochannels show a high chiral-driven ionic gate for glucose enantiomers and can be switched "off" by D-glucose and be switched "on" by L-glucose. Remarkably, the chiral nanochannel also exhibited a good reversibility toward glucose enantiomers. Further research indicates that the switching behaviors differed due to the differences in binding strength between chiral pillar[6]arene and glucose enantiomers, which can lead to the different surface charge within nanochannel. Given these promising results, the studies of chiral-driven ion gates may not only give interesting insight for the research of biological and pathological processes caused by glucose-sensitive ion channels, but also help to understand the origin of the high stereoselectivity in life systems. PMID- 29976987 TI - Association of meteorological factors and air NO2 and O3 concentrations with acute exacerbation of elderly chronic obstructive pulmonary disease. AB - We studied the combined effect of air pollutant concentrations and meteorological factors [e.g., temperature and atmospheric pressure (AP)] on the acute exacerbation of coronary obstructive pulmonary disease (COPD) in 277 older patients with COPD (240 men and 37 women; average age, 75.3 +/- 9.3 years). Average air pollutant concentrations, AP, temperature, and relative humidity corresponding to each of the 7 days before the date of hospitalisation were identified as the case and the two other weekly averages, 4 and 8 weeks prior to admission, were considered the controls. During the warming-up season, COPD exacerbation more likely occurred on days of temperature increase or AP decrease than on other days. Increments in CO, NO2 and O3 concentrations were significantly associated with 5%, 11% and 4% increases in COPD exacerbation risks, respectively. During the cooling-down season, increments in PM10 concentrations were significant risk factors; the exacerbation likely occurred on days of temperature decreases than on other days. Air pollution with increased NO2, CO, O3 and PM10 concentrations and continual temperature changes (colder during cooling-down seasons or hotter during warning-up seasons) were associated with acute exacerbation of COPD in older patients. PMID- 29976988 TI - Developing a conceptual, reproducible, rubric-based approach to consent and result disclosure for genetic testing by clinicians with minimal genetics background. AB - PURPOSE: In response to genetic testing being widely ordered by nongenetics clinicians, the Consent and Disclosure Recommendations (CADRe) Workgroup of the Clinical Genome Resource (ClinGen; clinicalgenome.org ) developed guidance to facilitate communication about genetic testing and efficiently improve the patient experience. Considering ethical, legal, and social implications, and medical factors, CADRe developed and pilot tested two rubrics addressing consent for genetic testing and results disclosure. The CADRe rubrics allow for adjusting the communication approach based on circumstances specific to patients and ordering clinicians. METHODS: We present results of a formative survey of 66 genetics clinicians to assess the consent rubric for nine genes (MLH1, CDH1, TP53, GJB2, OTC; DMD, HTT, and CYP2C9/VKORC1). We also conducted interviews and focus groups with family and patient stakeholders (N = 18), nongenetics specialists (N = 27), and genetics clinicians (N = 32) on both rubrics. RESULTS: Formative evaluation of the CADRe rubrics suggests key factors on which to make decisions about consent and disclosure discussions for a "typical" patient. CONCLUSION: We propose that the CADRe rubrics include the primary issues necessary to guide communication recommendations, and are ready for pilot testing by nongenetics clinicians. Consultation with genetics clinicians can be targeted toward more complex or intensive consent and disclosure counseling. PMID- 29976989 TI - Blue light excited retinal intercepts cellular signaling. AB - Photoreceptor chromophore, 11-cis retinal (11CR) and the photoproduct, all-trans retinal (ATR), are present in the retina at higher concentrations and interact with the visual cells. Non-visual cells in the body are also exposed to retinal that enters the circulation. Although the cornea and the lens of the eye are transparent to the blue light region where retinal can absorb and undergo excitation, the reported phototoxicity in the eye has been assigned to lipophilic non-degradable materials known as lipofuscins, which also includes retinal condensation products. The possibility of blue light excited retinal interacting with cells; intercepting signaling in the presence or absence of light has not been explored. Using live cell imaging and optogenetic signaling control, we uncovered that blue light-excited ATR and 11CR irreversibly change/distort plasma membrane (PM) bound phospholipid; phosphatidylinositol 4,5 bisphosphate (PIP2) and disrupt its function. This distortion in PIP2 was independent of visual or non-visual G-protein coupled receptor activation. The change in PIP2 was followed by an increase in the cytosolic calcium, excessive cell shape change, and cell death. Blue light alone or retinal alone did not perturb PIP2 or elicit cytosolic calcium increase. Our data also suggest that photoexcited retinal-induced PIP2 distortion and subsequent oxidative damage incur in the core of the PM. These findings suggest that retinal exerts light sensitivity to both photoreceptor and non-photoreceptor cells, and intercepts crucial signaling events, altering the cellular fate. PMID- 29976990 TI - Genome Sequencing and analyses of Two Marine Fungi from the North Sea Unraveled a Plethora of Novel Biosynthetic Gene Clusters. AB - Marine Fungi are potent secondary metabolite producers. However, limited genetic information are available their biosynthetic gene clusters (BGCs) and their biotechnological applications. To overcome this lack of information, herein, we used next-generation sequencing methods for genome sequencing of two marine fungi, isolated from the German Wadden Sea, namely Calcarisporium sp. KF525 and Pestalotiopsis sp. KF079. The assembled genome size of the marine isolate Calcarisporium sp. KF525 is about 36.8 Mb with 60 BGCs, while Pestalotiopsis sp. KF079 has a genome size of 47.5 Mb harboring 67 BGCs. Of all BGCs, 98% and 97% are novel clusters of Calcarisporium sp. and Pestalotiopsis sp., respectively. Only few of the BGCs were found to be expressed under laboratory conditions by RNA-seq analysis. The vast majority of all BGCs were found to be novel and unique for these two marine fungi. Along with a description of the identified gene clusters, we furthermore present important genomic features and life-style properties of these two fungi. The two novel fungal genomes provide a plethora of new BGCs, which may have biotechnological applications in the future, for example as novel drugs. The genomic characterizations will provide assistance in future genetics and genomic analyses of marine fungi. PMID- 29976991 TI - Reconstructing the sediment concentration of a giant submarine gravity flow. AB - Submarine gravity flows are responsible for the largest sediment accumulations on the planet, but are notoriously difficult to measure in action. Giant flows transport 100s of km3 of sediment with run-out distances over 2000 km. Sediment concentration is a first order control on flow dynamics and deposit character. It has never been measured directly nor convincingly estimated in large submarine flows. Here we reconstruct the sediment concentration of a historic giant submarine flow, the 1929 "Grand Banks" event, using two independent approaches, each validated by estimates of flow speed from cable breaks. The calculated average bulk sediment concentration of the flow was 2.7-5.4% by volume. This is orders of magnitude higher than directly-measured smaller-volume flows in river deltas and submarine canyons. The new concentration estimate provides a test case for scaled experiments and numerical simulations, and a major step towards a quantitative understanding of these prodigious flows. PMID- 29976993 TI - Potential invasion of exotic ambrosia beetles Xyleborus glabratus and Euwallacea sp. in Mexico: A major threat for native and cultivated forest ecosystems. AB - We analyze the invasive potential of two Asian ambrosia beetles, Xyleborus glabratus and Euwallacea sp., into Mexico and the southern United States. The fungal symbionts of these beetles have been responsible for damage to trees of the family Lauraceae, including Persea americana and other non-cultivated tree species on both coasts of the United States. We estimate their potential threat using ecological niche modeling and spatial multi-criteria evaluation protocols to incorporate plant and beetle suitabilities as well as forest stress factors across Mexico. Mexico contains higher climatic and habitat suitability for X. glabratus than for Euwallacea sp. Within this country, the neotropical region is most vulnerable to invasion by both of these species. We also identify a corridor of potential invasion for X. glabratus along the Gulf of Mexico coast where most Lauraceae and native Xyleborus species are present; dispersal of either X. glabratus or Euwallacea sp. into this region would likely lead to major disease spread. However, the overall potential damage that these beetles can cause may be a function of how many reproductive hosts and how many other ambrosia beetles are present, as well as of their capacity to disperse. This work can also alert relevant managers and authorities regarding this threat. PMID- 29976992 TI - DNA methylation landscape of the genes regulating D-serine and D-aspartate metabolism in post-mortem brain from controls and subjects with schizophrenia. AB - The spatio-temporal regulation of genes involved in the synthesis and degradation of D-serine and D-aspartate such as serine racemase (SR), D-amino acid oxidase (DAO), G72 and D-aspartate oxidase (DDO), play pivotal roles in determining the correct levels of these D-amino acids in the human brain. Here we provide a comprehensive analysis of mRNA expression and DNA methylation status of these genes in post-mortem samples from hippocampus, dorsolateral prefrontal cortex, and cerebellum from patients with schizophrenia and non-psychiatric controls. DNA methylation analysis was performed at an ultradeep level, measuring individual epialleles frequency by single molecule approach. Differential CpG methylation and expression was detected across different brain regions, although no significant correlations were found with diagnosis. G72 showed the highest CpG and non-CpG methylation degree, which may explain the repression of G72 transcription in the brain regions considered here. Conversely, in line with the sustained SR mRNA expression in the analyzed areas, very low methylation levels were detected at this gene's regulatory regions. Furthermore, for DAO and DDO, our single-molecule methylation approach demonstrated that analysis of epiallele distribution was able to detect differences in DNA methylation representing area specific methylation signatures, which are likely not detectable with targeted or genome-wide classic methylation analyses. PMID- 29976994 TI - A window of opportunity for cooperativity in the T Cell Receptor. AB - The T-cell antigen receptor (TCR) is pre-organised in oligomers, known as nanoclusters. Nanoclusters could provide a framework for inter-TCR cooperativity upon peptide antigen-major histocompatibility complex (pMHC) binding. Here we have used soluble pMHC oligomers in search for cooperativity effects along the plasma membrane plane. We find that initial binding events favour subsequent pMHC binding to additional TCRs, during a narrow temporal window. This behaviour can be explained by a 3-state model of TCR transition from Resting to Active, to a final Inhibited state. By disrupting nanoclusters and hampering the Active conformation, we show that TCR cooperativity is consistent with TCR nanoclusters adopting the Active state in a coordinated manner. Preferential binding of pMHC to the Active TCR at the immunological synapse suggests that there is a transient time frame for signal amplification in the TCR, allowing the T cells to keep track of antigen quantity and binding time. PMID- 29976996 TI - Male rutting calls synchronize reproduction in Serengeti wildebeest. AB - Tightly synchronized reproduction in vast wildebeest herds underpins the keystone role this iconic species plays in the Serengeti. However, despite decades of study, the proximate synchronizing mechanism remains unknown. Combining a season long field experiment with simple stochastic process models, we show that females exposed to playback of male rutting vocalizations are over three times more synchronous in their expected time to mating than a control group isolated from all male stimuli. Additionally, predictions of both mating and calving synchrony based on the playback group were highly consistent with independent data on wildebeest mating and calving synchrony, while control-based predictions were inconsistent with the data. Taken together, our results provide the first experimental evidence that male rutting vocalizations alone could account for the highly synchronized reproduction observed in Serengeti wildebeest. Given anthropogenically driven losses in many areas, a mechanistic understanding of synchrony can highlight additional risks declining wildebeest populations may face. PMID- 29976995 TI - Sir-2.1 mediated attenuation of alpha-synuclein expression by Alaskan bog blueberry polyphenols in a transgenic model of Caenorhabditis elegans. AB - Misfolding and accumulation of cellular protein aggregates are pathological hallmarks of aging and neurodegeneration. One such protein is alpha-synuclein, which when misfolded, forms aggregates and disrupts normal cellular functions of the neurons causing Parkinson's disease. Nutritional interventions abundant in pharmacologically potent polyphenols have demonstrated a therapeutic role for combating protein aggregation associated with neurodegeneration. The current study hypothesized that Alaskan bog blueberry (Vaccinum uliginosum), which is high in polyphenolic content, will reduce alpha-synuclein expression in a model of Caenorhabditis elegans (C. elegans). We observed that blueberry extracts attenuated alpha-synuclein protein expression, improved healthspan in the form of motility and restored lipid content in the transgenic strain of C. elegans expressing human alpha-synuclein. We also found reduced gene expression levels of sir-2.1 (ortholog of mammalian Sirtuin 1) in blueberry treated transgenic animals indicating that the beneficial effects of blueberries could be mediated through partial reduction of sirtuin activity. This therapeutic effect of the blueberries was attributed to its xenohormetic properties. The current results highlight the role of Alaskan blueberries in mediating inhibition of sir-2.1 as a novel therapeutic approach to improving pathologies of protein misfolding diseases. Finally, our study warrants further investigation of the structure, and specificity of such small molecules from indigenous natural compounds and its role as sirtuin regulators. PMID- 29976997 TI - Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology. AB - Pharmaceutical agents despite their efficacy to treat disease can cause additional unwanted cardiovascular side effects. Cardiotoxicity is characterized by changes in either the function and/or structure of the myocardium. Over recent years, functional cardiotoxicity has received much attention, however morphological damage to the myocardium and/or loss of viability still requires improved detection and mechanistic insights. A human 3D cardiac microtissue containing human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), cardiac endothelial cells and cardiac fibroblasts was used to assess their suitability to detect drug induced changes in cardiac structure. Histology and clinical pathology confirmed these cardiac microtissues were morphologically intact, lacked a necrotic/apoptotic core and contained all relevant cell constituents. High-throughput methods to assess mitochondrial membrane potential, endoplasmic reticulum integrity and cellular viability were developed and 15 FDA approved structural cardiotoxins and 14 FDA approved non-structural cardiotoxins were evaluated. We report that cardiac microtissues provide a high-throughput experimental model that is both able to detect changes in cardiac structure at clinically relevant concentrations and provide insights into the phenotypic mechanisms of this liability. PMID- 29976998 TI - Phasic and sustained interactions of multisensory interplay and temporal expectation. AB - Every moment organisms are confronted with complex streams of information which they use to generate a reliable mental model of the world. There is converging evidence for several optimization mechanisms instrumental in integrating (or segregating) incoming information; among them are multisensory interplay (MSI) and temporal expectation (TE). Both mechanisms can account for enhanced perceptual sensitivity and are well studied in isolation; how these two mechanisms interact is currently less well-known. Here, we tested in a series of four psychophysical experiments for TE effects in uni- and multisensory contexts with different levels of modality-related and spatial uncertainty. We found that TE enhanced perceptual sensitivity for the multisensory relative to the best unisensory condition (i.e. multisensory facilitation according to the max criterion). In the latter TE effects even vanished if stimulus-related spatial uncertainty was increased. Accordingly, computational modelling indicated that TE, modality-related and spatial uncertainty predict multisensory facilitation. Finally, the analysis of stimulus history revealed that matching expectation at trial n-1 selectively improves multisensory performance irrespective of stimulus related uncertainty. Together, our results indicate that benefits of multisensory stimulation are enhanced by TE especially in noisy environments, which allows for more robust information extraction to boost performance on both short and sustained time ranges. PMID- 29977000 TI - Synergy of AERONET and MODIS AOD products in the estimation of PM2.5 concentrations in Beijing. AB - Satellite aerosol optical depth (AOD) is widely used to estimate particulate matter with aerodynamic diameter <=2.5 um (PM2.5) mass concentrations. Polar orbiting satellite retrieval 1-2 times each day is frequently affected by cloud, snow cover or misclassification of heavy pollution. Novel methods are therefore required to improve AOD sampling. Sunphotometer provides much more AODs than satellite at a fixed point. Furthermore, much of the aerosol pollution is regional. Both factors indicate that sunphotometer has great potential for PM2.5 concentration estimation. The spatial representativeness of the Aerosol Robotic Network (AERONET) AOD at Beijing site is investigated by linear regression analysis of 13-year daily paired AODs at each grid from Moderate Resolution Imaging Spectroradiometer (MODIS) on Aqua and Beijing AERONET. The result suggests a good correlation for the whole Beijing Administrative region, with regional mean correlation coefficient exceeding 0.73. Pixel AODs are then estimated from AERONET AOD using linear equations, which are verified to have the same accuracy as that of MODIS AOD. Either AOD from MODIS retrieval or estimation from AERONET AOD in the absence of MODIS pixel AOD is finally used to predict PM2.5 concentration. Daily AOD sampling in average is enhanced by 59% in winter when MODIS AODs are very limited. More importantly, synergy of AERONET and MODIS AOD is able to improve the estimation of regional mean PM2.5 concentrations, which indicates this method would play a significant role in monitoring regional aerosol pollution. PMID- 29976999 TI - Genotype-phenotype correlation in Becker muscular dystrophy in Chinese patients. AB - Large deletions and duplications are the most frequent causative mutations in Becker muscular dystrophy (BMD), but genetic profile varied greatly among reports. We performed a comprehensive molecular investigation in 95 Chinese BMD patients. All patients were divided into three subtypes: normal muscle strength (type 1) in 18 cases, quadriceps myopathy (type 2) in 20 cases, and limb-girdle weakness (type 3) in 57 cases. Nineteen cases (20.0%) had small mutations and 76 cases (80.0%) had major rearrangements, including 67 cases (70.5%) of exonic deletions and 9 cases (9.5%) of exonic duplications. We identified 50 cases (65.8%) of in-frame mutations, and 26 cases (34.2%) of frame-shift mutations. The frequency of deletion in exons 13-19 was 30.6% in type 1 patients, 9.7% in type 2 patients, and 10.4% in type 3 patients. The frequency of deletion in exons 45-55 was 28.6% in type 1 patients, 40.8% in type 2, and 50.0% in type 3 patients. All major rearrangements of DMD gene in type 1 patients were also observed in type 3 patients. Our study suggested that frame-shift mutation was not rare in Chinese BMD patients. Although no difference was observed on the forms of DMD gene mutations among the three types of patients, the mutation in proximal region of DMD gene has higher frequency for patients without weakness. Effect of exon skipping for DMD depends on the size and location of the mutation. Additional studies are required to determine whether exon-skipping strategies in proximal region of DMD gene could yield more functional dystrophin. PMID- 29977001 TI - A new nonlinear method for calculating growing degree days. AB - Precise calculations of growing degree days (GDD) are an important component in crop simulation models and managerial decisions. Traditional methods for calculating GDD assume linear developmental responses to temperature and cannot precisely account for the delay in growth or development at temperatures above the optimal temperature (Topt). A new nonlinear method for calculating GDD was developed. Variations in the prediction of the dates since sowing to various developmental stages and performance measures for describing the accumulation of dry matter by GDD for two widely planted crops (corn and wheat) were used to evaluate the new method in comparison with the traditional methods. The new method predicted the dates of the developmental stages more precisely (date variations reduced by 1 d), and the errors for the predictions of the accumulation of dry matter for winter wheat and corn were smaller. The method was most promising for spring wheat. The new method was more stable and more precise than traditional methods, especially when Topt was lower than the maximum air temperature. PMID- 29977003 TI - REDCap: web-based software for all types of data storage and collection. PMID- 29977002 TI - Reuse of malaria rapid diagnostic tests for amplicon deep sequencing to estimate Plasmodium falciparum transmission intensity in western Uganda. AB - Molecular techniques are not routinely employed for malaria surveillance, while cross-sectional, community-based parasite surveys require significant resources. Here, we describe a novel use of malaria rapid diagnostic tests (RDTs) collected at a single facility as source material for sequencing to esimtate malaria transmission intensity across a relatively large catchment area. We extracted Plasmodium falciparum DNA from RDTs, then amplified and sequenced a region of the apical membrane antigen 1 (pfama1) using targeted amplicon deep sequencing. We determined the multiplicity of infection (MOI) for each sample and examined associations with demographic, clinical, and spatial factors. We successfully genotyped 223 of 287 (77.7%) of the samples. We demonstrated an inverse relationship between the MOI and elevation with individuals presenting from the highest elevation villages harboring infections approximately half as complex as those from the lowest (MOI 1.85 vs. 3.51, AOR 0.25, 95% CI 0.09-0.65, p = 0.004). This study demonstrates the feasibility and validity of using routinely-collected RDTs for molecular surveillance of malaria and has real-world utility, especially as the cost of high-throughpout sequencing continues to decline. PMID- 29977004 TI - Apatinib, a selective VEGFR2 inhibitor, improves the delivery of chemotherapeutic agents to tumors by normalizing tumor vessels in LoVo colon cancer xenograft mice. AB - Tumor vascular normalization has been proposed as a therapeutic strategy for malignant neoplasms, which can also interpret the synergistic effect of anti angiogenesis agents combined with chemotherapy. Apatinib (Apa), a highly selective VEGFR2 inhibitor, attracts much attentions due to its encouraging anticancer activity, especially in the clinical trials of combined treatment. In this study, we investigated whether Apa could promote vascular normalization in tumor in a certain time window. Mice bearing LoVo colon cancer xenograft were orally administrated Apa (150 mg kg-1 per day) for 5, 7, 10, or 12 days. Apa significantly inhibited tumor growth and decreased the microvessel density. Using multi-photon microscopy and electron microscopy, we found that Apa improved tumor vessel morphology by pruning distorted vessel branches and decreased the gap between endothelial cells after a 7-day treatment. Furthermore, Apa decreased vessel leakage and increased pericyte coverage on vascular endothelial cells, suggesting that tumor vessels were more mature and integrated. The intratumoral distribution of adriamycin (ADR) in Apa group was improved from day 7 to 10 without change in plasma drug concentration. Tumor blood perfusion was also increased in this window, and the expression of hypoxia induced factor 1alpha was downregulated, suggesting the effect of Apa on alleviating tumor hypoxic micro environment. In conclusion, Apa may improve the effective perfusion of tumor vessels and increase the intratumoral distribution of ADR in a certain time window via normalizing tumor vessels. This normalization window (7 to 10 days of treatment) may contribute to develop a regimen of combined medication in clinic use of Apa. PMID- 29977005 TI - ClC-3 promotes angiotensin II-induced reactive oxygen species production in endothelial cells by facilitating Nox2 NADPH oxidase complex formation. AB - Recent evidence suggests that ClC-3, a member of the ClC family of Cl- channels or Cl-/H+ antiporters, plays a critical role in NADPH oxidase-derived reactive oxygen species (ROS) generation. However, the underling mechanisms remain unclear. In this study we investigated the effects and mechanisms of ClC-3 on NADPH oxidase activation and ROS generation in endothelial cells. Treatment with angiotensin II (Ang II, 1 MUmol/L) significantly elevated ClC-3 expression in cultured human umbilical vein endothelial cells (HUVECs). Furthermore, Ang II treatment increased ROS production and NADPH oxidase activity, an effect that could be significantly inhibited by knockdown of ClC-3, and further enhanced by overexpression of ClC-3. SA-beta-galactosidase staining showed that ClC-3 silencing abolished Ang II-induced HUVEC senescence, whereas ClC-3 overexpression caused the opposite effects. We further showed that Ang II treatment increased the translocation of p47phox and p67phox from the cytosol to membrane, accompanied by elevated Nox2 and p22phox expression, which was significantly attenuated by knockdown of ClC-3 and potentiated by overexpression of ClC-3. Moreover, overexpression of ClC-3 increased Ang II-induced phosphorylation of p47phox and p38 MAPK in HUVECs. Pretreatment with a p38 inhibitor SB203580 abolished ClC-3 overexpression-induced increase in p47phox phosphorylation, as well as NADPH oxidase activity and ROS generation. Our results demonstrate that ClC-3 acts as a positive regulator of Ang II-induced NADPH oxidase activation and ROS production in endothelial cells, possibly via promoting both Nox2/p22phox expression and p38 MAPK-dependent p47phox/p67phox membrane translocation, then increasing Nox2 NADPH oxidase complex formation. PMID- 29977006 TI - A novel endoscopic classification for craniopharyngioma based on its origin. AB - Endoscopic endonasal approach for craniopharyngioma (CP) resection provides a wide view and direct observation of hypothalamus and origin of tumor. Under endoscopy, 92 CPs were classified into 2 types: Peripheral and Central, according to its relation to pituitary stalk. Peripheral type was further divided into 3 subtypes: Hypothalamic stalk, Suprasellar stalk and Intrasellar stalk CP, according to the different origin site along hypothalamus-pituitary axis. Peripheral type arisen from the stalk but expanded and grown laterally in an exophytic pattern, accounting for 71.7% of all CPs, preservation rate of stalk was higher (76.0%). Central type grew within and along pituitary stalk and located strictly in the midline. The pituitary stalk was hardly preserved (only15.4%). Hypothalamic stalk CPs (n = 36, 54.6%) developed from the junction of hypothalamus and stalk, hypothalamus damage was found in all of this subtype after surgery. Suprasellar stalk CPs (n = 14, 21.2%) originated from the lower portion of stalk and displaced hypothalamus upward rather than infiltrated it. Intrasellar stalk CPs (n = 16, 24.2%) arose from the subdiaphragma portion of the stalk, with less hypothalamus damage. Recoginzing the origin of CP is helpful to understand its growth pattern and relation to hypothalamus, which is critical in planning the most appropriate surgical approach and degree of excision. PMID- 29977007 TI - Repetitive transcranial magnetic stimulation reveals a causal role of the human precuneus in spatial updating. AB - As we move through an environment, the positions of surrounding objects relative to our body constantly change, with some objects even leaving our field of view. As a consequence, maintaining orientation requires spatial updating, the continuous monitoring of self-motion cues to update external locations within an egocentric frame of reference. While previous research using functional magnetic resonance imaging has implicated the precuneus in spatial updating, direct evidence for this claim is missing. To address this important question, we applied theta burst repetitive transcranial magnetic stimulation (rTMS) over the precuneus to induce a "virtual lesion". Following stimulation, participants were tested in a large-scale virtual environment in which they had to use visual self motion information to keep track of the position of virtual objects. Compared to sham stimulation, rTMS affected working memory traces for object locations. Critically, rTMS further impaired the ability to update these locations whenever participants experienced simulated movement. As this effect could not be explained by working memory deficits alone, we conclude that visual spatial updating relies on the construction of updated representations of egocentric object locations within the precuneus. Together, these findings establish the precuneus as performing key computations for the formation of cognitive maps. PMID- 29977008 TI - Microorganisms facilitate uptake of dissolved organic nitrogen by seagrass leaves. AB - Microorganisms play a critical role in nitrogen cycling by mineralising dissolved organic nitrogen (DON) compounds into bioavailable inorganic forms (DIN). Although DIN is crucial for seagrass growth, the hypothesis that seagrass leaf associated-microorganisms could convert DON to forms available for plant uptake has never been tested. We conducted a laboratory-based experiment in which seagrass (Posidonia sinuosa) leaves were incubated with 15N-amino acids (aa), with and without associated microorganisms. Samples were collected after 0.5, 2, 6 and 12 h. Both bulk stable isotope and nanoscale secondary ion mass spectrometry (NanoSIMS) analysis showed high accumulation of 15N within seagrass leaf tissues with an associated microbiota, but not in plants devoid of microorganisms. These results significantly change our understanding of the mechanisms of seagrass nitrogen use and provide evidence that seagrass microbiota increase nitrogen availability for uptake by seagrass leaves by mineralising aa, thus enhancing growth and productivity of these important coastal ecosystems. PMID- 29977010 TI - Fuzzy Union to Assess Climate Suitability of Annual Ryegrass (Lolium multiflorum), Alfalfa (Medicago sativa) and Sorghum (Sorghum bicolor). AB - The Law of the Minimum is often implemented using t-norm or fuzzy intersection. We propose the use of t-conorm or fuzzy union for climate suitability assessment of a grass species using annual ryegrass (Lolium multiflorum Lam.) as an example and evaluate the performance for alfalfa (Medicago sativa L.) and sorghum (Sorghum bicolor L.). The ORF and ANDF models, which are fuzzy logic systems based on t-conorm and t-norm between temperature and moisture conditions, respectively, were developed to assess the quality of climate conditions for crops. The parameter values for both models were obtained from existing knowledge, e.g., the EcoCrop database. These models were then compared with the EcoCrop model, which is based on the t-norm. The ORF model explained greater variation (54%) in the yield of annual ryegrass at 84 site-years than the ANDF model (43%) and the EcoCrop model (5%). The climate suitability index of the ORF model had the greatest likelihood of occurrence of annual ryegrass compared to the other models. The ORF model also had similar results for alfalfa and sorghum. We emphasize that the fuzzy logic system for climate suitability assessment can be developed using knowledge rather than presence-only data, which can facilitate more complex approaches such as the incorporation of biotic interaction into species distribution modeling. PMID- 29977011 TI - Management options and parental voice in the treatment of trisomy 13 and 18. PMID- 29977009 TI - Enhanced bacterial mutualism through an evolved biofilm phenotype. AB - Microbial communities primarily consist of multiple species that affect one another's fitness both directly and indirectly. This study showed that the cocultivation of Paenibacillus amylolyticus and Xanthomonas retroflexus exhibited facultative mutualistic interactions in a static environment, during the course of which a new adapted phenotypic variant of X. retroflexus appeared. Although the emergence of this variant was not directly linked to the presence of P. amylolyticus, its establishment in the coculture enhanced the productivity of both species due to mutations that stimulated biofilm formation. The mutations were detected in genes encoding a diguanylate cyclase predicted to synthesise cyclic-di-GMP. Examinations of the biofilm formed in cocultures of P. amylolyticus and the new variant of X. retroflexus revealed a distinct spatial organisation: P. amylolyticus only resided in biofilms in association with X. retroflexus and occupied the outer layers. The X. retroflexus variant therefore facilitated increased P. amylolyticus growth as it produced more biofilm biomass. The increase in X. retroflexus biomass was thus not at the expense of P. amylolyticus, demonstrating that interspecies interactions can shape diversification in a mutualistic coculture and reinforce these interactions, ultimately resulting in enhanced communal performance. PMID- 29977012 TI - Making a business case for a model of regionalization with neonatologist availability at all facilities: one institution's financial tell-all. PMID- 29977013 TI - NTproBNP as a surrogate biomarker for early screening of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia. AB - OBJECTIVE: Pulmonary hypertension (PH) is a known complication of bronchopulmonary dysplasia (BPD). This study aimed to determine the utility of serial N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels in the screening of BPD associated PH (BPD-PH) in preterm infants. STUDY DESIGN: Infants with birth weight <1500 g and <30 week corrected gestational age (CGA) were followed with serial NTproBNP levels and echocardiograms (ECHO). They were divided into control, BPD and BPD-PH groups. Statistical analyses included repeated measures analysis of variance and receiver operator curve (ROC) generation. RESULTS: Infants in the BPD-PH and BPD group had significantly elevated NTproBNP levels as compared to the control group. ROC curves for NTproBNP at 28 weeks CGA provided a cut-point of 2329 pg/ml and 578.1 pg/ml for detection of BPD-PH and BPD, respectively. CONCLUSIONS: NTproBNP appears to be a good screening tool to determine the onset of BPD-PH as early as 28 weeks CGA. PMID- 29977015 TI - Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors. AB - Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we used a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs. Unbiased clustering and kinase enrichment analysis identified rapid induction of phospho proteins associated with endocytosis by the wild type G-CSFR only; while G-CSFR mutants showed abnormal kinetics of canonical Stat3, Stat5, and Mapk phosphorylation, and aberrant activation of Bruton's Tyrosine Kinase (Btk). Mutant-G-CSFR-expressing cells displayed enhanced sensitivity (3-5-fold lower IC50) for ibrutinib-based chemical inhibition of Btk. Primary murine progenitor cells from G-CSFR-Q741x knock-in mice validated activation of Btk by the mutant receptor and retrovirally transduced human CD34+ umbilical cord blood cells expressing mutant receptors displayed enhanced sensitivity to Ibrutinib. A significantly lower clonogenic potential was displayed by both murine and human primary cells expressing mutated receptors upon ibrutinib treatment. Finally, a dramatic synergy was observed between ibrutinib and ruxolinitib at lower dose of the individual drug. Altogether, these data demonstrate the strength of unsupervised proteomics analyses in dissecting oncogenic pathways, and suggest repositioning Ibrutinib for therapy of myeloid leukemia bearing CSF3R mutations. Phospho-tyrosine data are available via ProteomeXchange with identifier PXD009662. PMID- 29977014 TI - The small molecule drug diminazene aceturate inhibits liver injury and biliary fibrosis in mice. AB - There is no established medical therapy to treat biliary fibrosis resulting from chronic inflammation in the biliary tree. We have recently shown that liver specific over-expression of angiotensin converting enzyme 2 (ACE2) of the renin angiotensin system (RAS) ameliorated liver fibrosis in mice. Diminazene aceturate (DIZE), a small molecule drug approved by the US Food and Drug Administration, which is used to treat human trypanosomiasis, has been shown to have antifibrotic properties by enhancing ACE2 activity. In this study we sought to determine the therapeutic potential of DIZE in biliary fibrosis using bile duct ligated and multiple drug resistant gene-2 knockout mice. Additionally, human hepatic stellate (LX-2) and mouse Kupffer (KUP5) cell lines were used to delineate intracellular pathways. DIZE treatment, both in vivo and in vitro, markedly inhibited the activation of fibroblastic stellate cells which was associated with a reduced activation of Kupffer cells. Moreover, DIZE-inhibited NOX enzyme assembly and ROS generation, activation of profibrotic transcription factors including p38, Erk1/2 and Smad2/3 proteins and proinflammatory and profibrotic cytokine release. These changes led to a major reduction in biliary fibrosis in both models without affecting liver ACE2 activity. We conclude that DIZE has a potential to treat biliary fibrosis. PMID- 29977016 TI - Genetic predisposition to B-cell acute lymphoblastic leukemia at 14q11.2 is mediated by a CEBPE promoter polymorphism. AB - Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Genome-wide association studies have shown variation at 14q11.2 influences ALL risk. We sought to decipher causal variant(s) at 14q11.2 and the mechanism of tumorigenesis. We show rs2239630 G>A resides in the promoter of the CCAT enhancer binding protein epsilon (CEBPE) gene. The rs2239630-A risk allele is associated with increased promotor activity and CEBPE expression. Depletion of CEBPE in ALL cells reduces cell growth, correspondingly CEBPE binds to the promoters of electron transport and energy generation genes. RNA-seq in CEBPE depleted cells demonstrates CEBPE regulates the expression of genes involved in B-cell development (IL7R), apoptosis (BCL2), and methotrexate resistance (RASS4L). CEBPE regulated genes significantly overlapped in CEBPE depleted cells, ALL blasts and IGH-CEBPE translocated ALL. This suggests CEBPE regulates a similar set of genes in each, consistent with a common biological mechanism of leukemogenesis for rs2239630 associated and CEBPE translocated ALL. Finally, we map IGH-CEBPE translocation breakpoints in two cases, implicating RAG recombinase activity in their formation. PMID- 29977017 TI - Assay to rapidly screen for immunoglobulin light chain glycosylation: a potential path to earlier AL diagnosis for a subset of patients. PMID- 29977018 TI - Cytogenetic abnormalities in monoclonal gammopathy of undetermined significance. PMID- 29977019 TI - The Life Skills of Older Americans: Association with Economic, Psychological, Social, and Health Outcomes. AB - Studies of children and adolescents indicate that success in life is determined in part by attributes such as conscientiousness, emotional stability and sense of control, independently of childhood socioeconomic status and cognitive ability. Less is known about the role of these characteristics at older ages. This study investigated the relationship of five life skills - conscientiousness, emotional stability, persistence, optimism and sense of control - with a range of outcomes in 8,843 participants (mean age 72.57 years) in the Health and Retirement Study, a representative study of older Americans. More life skills were associated with greater wealth and income, better emotional wellbeing, stronger social relationships, less loneliness, better health, fewer chronic illnesses and impaired activities of daily living, better mobility and less obesity, after controlling for childhood socioeconomic status and current cognitive ability. Longitudinally, more life skills predicted emotional wellbeing, less loneliness and more prosocial behavior, better health and mobility over a 4 year period. Associations were independent of gender, ethnicity, family background, education and cognitive ability. The number of attributes was important rather than any single life skill. Life skills continue to matter at advanced ages, and fostering these characteristics in older adults may pay dividends in terms of later life health and wellbeing. PMID- 29977020 TI - Altmetric analysis of contemporary dental literature. PMID- 29977021 TI - Clinical skills of a new foundation dentist: the expectations of dental foundation education supervisors. PMID- 29977023 TI - The ultimate guide to restoration longevity in England and Wales. Part 5: crowns: time to next intervention and to extraction of the restored tooth. PMID- 29977022 TI - Are UK graduates equipped with the skill set required to meet the demands of the UK's edentulous population? AB - As the UK witnesses a decline in the number of edentulous adults, there is a simultaneous reduction in the number of cases available to undergraduate dental students for the teaching of complete dentures. When edentulous adults are unable to function with conventional complete dentures, particularly pertaining to the mandibular denture, an implant-supported mandibular overdenture has been evidenced as the gold standard for edentulous patients. The evidence in favour of mandibular implant-supported overdentures is one of the most robust evidence bases for any clinical treatment and similarly it has been shown that undergraduate students are equally as capable in the provision of implant supported overdentures as experienced prosthodontists. Yet there appears to be a disparity in the General Dental Council's undergraduate learning outcomes pertaining to care for edentulous adults. Furthermore, the UK seems to be falling behind in this respect in comparison to our European, American and Australian colleagues. This review looks at the evidence for the provision of implant supported overdentures in the setting of the undergraduate dental curriculum, the potential barriers within this teaching forum and how well prepared UK undergraduates are for the clinical management of edentulous patients in the future. PMID- 29977024 TI - Effects of climate and potential policy changes on heating degree days in current heating areas of China. AB - Based on climate simulations over East Asia from a high-resolution regional climate model under RCP4.5 and 8.5 scenarios, we examine the impact of future climate change and heating policy changes on energy demand in current central heating areas over China using the heating degree days (HDD) and the number of the heating days (NHD) with different base temperature as the indices. Based on current heating policy in China, significant decreases of NHDs are projected, with larger decreases under RCP8.5 than RCP4.5. This decrease of NHDs would cause a northward shift of the decadal heating boundary line, with significant implications for infrastructure planning and development. Changing the heating policy currently in practice to one used in Europe and USA would cause an immediate jump in NHDs and in HDDs; as warming progresses in the future, these effects attenuate with time in an approximately linear trend under the two scenarios. Under RCP8.5, by 2050, the effects of warming climate would dominate over the heating policy change, and heating demand would be lower than the present day HDD and continue to decrease until the end of the century. Energy demand and the number of the heating days during peak winter shows no dependence on heating policy, as the policy-induced increase of energy demand would occur primarily during warmer months of the year. In addition, the indices are further weighted by population, and results show that increases in both HDDs and NHDs can be found in parts of northern China due to the increased population there by the end of the 21st century. PMID- 29977025 TI - Biomimetic materials assembled on a photovoltaic cell as a novel biosensing approach to cancer biomarker detection. AB - This work describes for the first time the integration of Dye Sensitized Solar Cell (DSSC) technology in biosensors and biomimetic materials, opening doors towards a new dimension of autonomous screening devices that may be used in point of-care, with zero-power requirements. DSSCs are fabricated with a counter electrode (CE) of polypyrrole (PPy) that was made responsive to a specific protein by biomimetic material (BM) technology. Carcinogenic embryonic antigen (CEA) was selected as target protein. The resulting BM-PPy film acted as biomimetic artificial antibody for CEA. Rebinding of CEA into this film changed its intrinsic electrical properties and the subsequent electrical output of the DSSC using it as CE. The quantity of CEA in solution was deduced by I-V and electrochemical impedance spesctroscopy (EIS). Linear responses to CEA were observed down to 0.25 pg/mL, with 0.13 pg/mL detection limit. Control films of PPy (prepared without CEA in the electropolymerization step) confirmed the ability of the BM material to recognize the target protein. Accurate results were obtained in the analysis of urine samples. Further developments into this ground breaking self-powered biosensor will display a huge impact in point-to-care medical applications, which may be extended to other fields of knowledge. PMID- 29977026 TI - Author Correction: Dorsal hippocampus contributes to model-based planning. AB - In the version of this article initially published, the green label in Fig. 1c read "rightward choices" instead of "leftward choices." The error has been corrected in the HTML and PDF versions of the article. PMID- 29977028 TI - Source localisation and its uncertainty quantification after the third DPRK nuclear test. AB - The International Monitoring System is being set up aiming to detect violations of the Comprehensive Nuclear-Test-Ban Treaty. Suspicious radioxenon detections were made by the International Monitoring System after the third announced nuclear test conducted by the Democratic People's Republic of Korea (DPRK). In this paper, inverse atmospheric transport and dispersion modelling was applied to these detections, to determine the source location, the release term and its associated uncertainties. The DPRK nuclear test site was found to be a likely source location, though a second likely source region in East Asia was found by the inverse modelling, partly due to the radioxenon background from civilian sources. Therefore, techniques to indirectly assess the influence of the radioxenon background are suggested. In case of suspicious radioxenon detections after a man-made explosion, atmospheric transport and dispersion modelling is a powerful tool for assessing whether the explosion could have been nuclear or not. PMID- 29977027 TI - ATR is required to complete meiotic recombination in mice. AB - Precise execution of recombination during meiosis is essential for forming chromosomally-balanced gametes. Meiotic recombination initiates with the formation and resection of DNA double-strand breaks (DSBs). Cellular responses to meiotic DSBs are critical for efficient repair and quality control, but molecular features of these remain poorly understood, particularly in mammals. Here we report that the DNA damage response protein kinase ATR is crucial for meiotic recombination and completion of meiotic prophase in mice. Using a hypomorphic Atr mutation and pharmacological inhibition of ATR in vivo and in cultured spermatocytes, we show that ATR, through its effector kinase CHK1, promotes efficient RAD51 and DMC1 assembly at RPA-coated resected DSB sites and establishment of interhomolog connections during meiosis. Furthermore, our findings suggest that ATR promotes local accumulation of recombination markers on unsynapsed axes during meiotic prophase to favor homologous chromosome synapsis. These data reveal that ATR plays multiple roles in mammalian meiotic recombination. PMID- 29977029 TI - Dietary methionine deficiency affects oxidative status, mitochondrial integrity and mitophagy in the liver of rainbow trout (Oncorhynchus mykiss). AB - The low levels of methionine in vegetable raw materials represent a limit to their use in aquafeed. Methionine is considered as an important factor in the control of oxidative status. However, restriction of dietary methionine has been shown to reduce generation of mitochondrial oxygen radicals and thus oxidative damage in liver. Here, we aim to evaluate the effect of dietary methionine deficiency in hepatic oxidative status in rainbow trout and identify the underlying mechanisms. Fish were fed for 6 weeks diets containing two different methionine concentrations: deficient (MD, Methionine Deficient diet) or adequate (CTL, control diet). At the end of the experiment, fish fed the MD diet showed a significantly lower body weight and feed efficiency compared to fish fed the CTL diet. Growth reduction of the MD group was associated to a general mitochondrial defect and a concomitant decrease of the oxidative status in the liver. The obtained results also revealed a sharp increase of mitochondrial degradation through mitophagy in these conditions and emphasized the involvement of the PINK1/PARKIN axis in this event. Collectively, these results provide a broader understanding of the mechanisms at play in the reduction of oxidant status upon dietary methionine deficiency. PMID- 29977030 TI - Magnetic resonance imaging evidence of hippocampal structural changes in patients with primary biliary cholangitis. AB - INTRODUCTION: Behavioral symptoms are commonly reported by patients with primary biliary cholangitis (PBC). In other patient populations, symptoms are commonly associated with hippocampal volume reduction linked to neuroinflammation (inferred from regional iron deposition), as demonstrated by magnetic resonance imaging (MRI). We hypothesized that PBC patients would exhibit reduced volume and increased iron deposition of the hippocampus. METHODS: Seventeen female non cirrhotic PBC patients and 17 age/gender-matched controls underwent 3-Tesla T1 weighted MRI and quantitative susceptibility mapping (QSM; an indicator of iron deposition). The hippocampus and its subfields were segmented from T1 images using Freesurfer, and susceptibility of the whole hippocampus was calculated from QSM images. Volume and susceptibility were compared between groups, and associations with PBC-40 score and disease indicators (years since diagnosis, Fibroscan value, alkaline phosphatase level, clinical response to ursodeoxycholic acid (UDCA)) were investigated. RESULTS: PBC patients exhibited significantly reduced hippocampal volume (p = 0.023) and increased susceptibility (p = 0.048). Subfield volumes were reduced for the subiculum, molecular layer, granule cell layer of the dentate gyrus and CA4 (p < 0.05). Fibroscan value was significantly correlated with PBC-40 (Spearman's rho = 0.499; p = 0.041) and disease duration (Spearman's rho = 0.568; p = 0.017). DISCUSSION: Our findings suggest hippocampal changes occur early in the disease course of PBC, similar in magnitude to those observed in major depressive disorder and neurodegenerative diseases. TRANSLATIONAL IMPACT: Clinical management of PBC could include early interventional strategies that promote hippocampal neurogenesis that may beneficially impact behavioral symptoms and improve quality of life. PMID- 29977032 TI - Effects of an FcgammaRIIA polymorphism on leukocyte gene expression and cytokine responses to anti-CD3 and anti-CD28 antibodies. AB - The low affinity Fcgamma receptor, FcgammaRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcgammaR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype. Our analysis revealed that the levels of four cytokines (IFNgamma, IL-12, IL-2, TNFalpha) and global gene expression patterns differed between all three genotype classes. Surprisingly, the heterozygotes showed suboptimal T cell activation compared to cells from individuals homozygous for the higher-affinity FcgammaRIIA allele (GG; Arg/Arg). The results of this study demonstrate that IgG response varies among all rs1801274 genotype classes and results in profound differences in both cytokine responses and gene expression patterns in blood leukocytes. Because even heterozygotes showed dampened global responses, our data may provide insight into the heterogeneity of outcomes in cytokine release assays and immunotherapy efficacy. PMID- 29977031 TI - A Mouse Model of Schnyder Corneal Dystrophy with the N100S Point Mutation. AB - Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disease in humans, characterized by abnormal deposition of cholesterol and phospholipids in cornea caused by mutations in the UbiA prenyltransferase domain containing 1 (UBIAD1) gene. In this study, we generated a mouse line carrying Ubiad1 N100S point mutation using the CRISPR/Cas9 technique to investigate the pathogenesis of SCD. In vivo confocal microscopy revealed hyper-reflective dot-like deposits in the anterior cornea in heterozygotes and homozygotes. No significant change was found in corneal epithelial barrier function or wound healing. Electron microscopy revealed abnormal mitochondrial morphology in corneal epithelial, stromal, and endothelial cells. Mitochondrial DNA copy number assay showed 1.27 +/- 0.07 fold change in homozygotes versus 0.98 +/- 0.05 variation in wild type mice (P < 0.05). Lipidomic analysis indicated abnormal metabolism of glycerophosphoglycerols, a lipid class found in mitochondria. Four (34:1, 34:2, 36:2, and 44:8) of the 11 glycerophosphoglycerols species identified by mass spectrometry showed a significant increase in homozygous corneas compared with heterozygous and wild-type mouse corneas. Unexpectedly, we did not find a difference in the corneal cholesterol level between different genotypes by filipin staining or lipidomic analysis. The Ubiad1N100S mouse provides a promising animal model of SCD revealing that mitochondrial dysfunction is a prominent component of the disease. The different phenotype in human and mouse may due to difference in cholesterol metabolism between species. PMID- 29977033 TI - Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation. AB - Post-hoc subgroup analysis of the negative trial of interleukin-1beta receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030.7 etag/ml, +/-SEM 7,411.1). In total 11 rare (minor allele frequency <5%) pathogenic or likely pathogenic variants causal for the monogenic disorders of Familial Hemophagocytic Lymphohistiocytosis, atypical Hemolytic Uremic Syndrome, Familial Mediterranean Fever, and Cryopyrin-associated Periodic Fever were identified. In these conditions, seven of the identified variants are currently targeted with IL1RA and four with anti-C5 antibody. Gene-targeted precision medicine may benefit this subgroup of patients with septic shock and pathogenic immune variation. PMID- 29977034 TI - Social learning from conspecifics and humans in dog puppies. AB - Social learning is especially advantageous for young individuals because it reduces the risks of trial-and-error learning, while providing an efficient way of acquiring information. Whereas adult dogs are known to excel in social learning skills, the ontogeny of this process has been mainly overlooked. The focus of our study was to investigate whether the capacity of social learning is already developed in dogs at an early age. We tested 8-week-old dog puppies on their ability to learn socially to open a puzzle box baited with food and on their capacity to retain the acquired information in their memory. Puppies were tested with conspecific and human demonstrators. We further investigated on whether demonstrations performed by their mother or by an unfamiliar conspecific model affected puppies' learning trend differently. We found that social learning skills are present in 8 weeks old puppies and they remembered this experience for 1 hour. Puppies learned to solve the task from both conspecific and human demonstrators, thereby endorsing dogs' flexibility in learning from different social partners. Unexpectedly, puppies were more likely to learn from unfamiliar conspecifics than from their mother, probably as a result of greater attention payed to the demonstration performed by the unfamiliar model. PMID- 29977036 TI - Modelling the metabolism: allometric relationships between total daily energy expenditure, body mass, and height. AB - BACKGROUND/OBJECTIVES: Accurately predicting energy requirements form a critical component for initializing dynamic mathematical models of metabolism. The majority of such existing estimates rely on linear regression models that predict total daily energy expenditure (TDEE) from age, gender, height, and body mass, however, there is evidence these predictors obey a power function. SUBJECTS/METHODS: Baseline, free-living TDEE measured by doubly labeled water (DLW) in 20 studies with no overlapping subjects were obtained from the core lab at the University of Chicago and the University of Wisconsin-Madison (N = 2501 adults, 628 males, 1873 females). Linear regression models of log-transformed equations of the form: [Formula: see text] and [Formula: see text] were developed to determine the values of the exponents of body mass (M (kg)) and height (H (cm)) along with a gender effect (Sex). A nonlinear curve fit was performed to develop a power model that also includes age [Formula: see text]. RESULTS: The power for body mass, beta1 = 0.45 and the power for height was beta2 = 1.52 in the database with both genders combined. Adding gender reduced these to beta1 = 0.43 and beta2 = 1.04. All terms were significant (p < 0.01) except for height when including gender. The powers for height in the additive gender-specific models were both closer to 1 and the power for body mass was similar across all models ranging between 0.41 and 0.57. CONCLUSIONS: A nonlinear scaling relationship was found to hold for body mass and needs to be considered when adjusting TDEE for body mass or predicting human energy requirements as a function of body mass especially in individuals with obesity. PMID- 29977035 TI - A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis. AB - OBJECTIVES: Adsorptive granulomonocytapheresis (GMA) with the Adacolumn has been introduced as a non-pharmacologic treatment for ulcerative colitis (UC). However, a subset of patients who might respond well to GMA needs to be targeted. This study was conducted at three IBD centers to determine factors affecting the efficacy of GMA in patients with moderately-to-severely active UC. METHODS: From January 2008 to December 2017, a total of 894 active episodes (first attack or relapse) in 593 patients were treated with GMA. Clinical remission was defined as normal stool frequency and no rectal bleeding. Multiple clinical and laboratory parameters at entry were considered for efficacy assessment. RESULTS: Clinical remission was achieved during 422 (47%) of the 894 treatment cases. In the multivariate analysis, predictors for favorable response to GMA were age <=60 years, UC duration <1 year, Mayo endoscopic subscore 2 (vs. 3), steroid naive UC, and biologic naive UC. Clinical remission rate was 70% in patients with four of the five factors, 52% in patients with three factors, 46% in patients with two factors, 39% in patients with one factor, and 18% in patients with none of these factors. Overall, the clinical remission rate was significantly higher in patients with a greater number of the five predictors (P < 0.0001). CONCLUSIONS: GMA appeared to be effective in steroid naive and biologic naive patients with short duration of UC. Elderly patients (>60 years) and those with severe endoscopic activity did not respond well to GMA. Additional, well designed, prospective, controlled trials should strengthen our findings. PMID- 29977037 TI - Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2-/ mice by diminishing senescence of cholangiocytes. AB - Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. The aim of this study was to determine the effects of genetic depletion of SR in Mdr2-/- mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. 12 wk SR-/-, Mdr2-/-, and SR-/-/Mdr2-/- mice with corresponding wild-type mice were used for the in vivo studies. Immunohistochemistry or immunofluorescence was performed in liver sections for (i) biliary expression of SR; (ii) hematoxylin and eosin; (iii) intrahepatic biliary mass by CK-19; (iv) fibrosis by Col1a1 and alpha-SMA; (v) senescence by SA-beta-gal and p16; and (vi) angiogenesis by VEGF-A and CD31. Secretin (Sct) and TGF-beta1 levels were measured in serum and cholangiocyte supernatant by ELISA. In total liver, isolated cholangiocytes or HSCs, we evaluated the expression of fibrosis markers (FN-1 and Col1a1); senescence markers (p16 and CCL2); microRNA 125b and angiogenesis markers (VEGF-A, VEGFR-2, CD31, and vWF) by immunoblots and/or qPCR. In vitro, we measured the paracrine effect of cholangiocyte supernatant on the expression of senescent and fibrosis markers in human hepatic stellate cells (HHSteCs). The increased level of ductular reaction, fibrosis, and angiogenesis in Mdr2-/- mice was reduced in SR-/ /Mdr2-/- mice. Enhanced senescence levels in cholangiocytes from Mdr2-/- mice were reversed to normal in SR-/-/Mdr2-/- mice. However, senescence was decreased in HSCs from Mdr2-/- mice but returned to normal values in SR-/-/Mdr2-/- mice. In vitro treatment of HHSteCs with supernatant from cholangiocyte lacking SR (containing lower biliary levels of Sct-dependent TGF-beta1) have decreased fibrotic reaction and increased cellular senescence. Sct-induced TGF-beta1 secretion was mediated by microRNA 125b. Our data suggest that differential modulation of angiogenesis-dependent senescence of cholangiocytes and HSCs may be important for the treatment of liver fibrosis in cholangiopathies. PMID- 29977038 TI - Long-term HEV carriers without antibody seroconversion among eligible immunocompetent blood donors. AB - Hepatitis E virus (HEV) is emerging as a potential threat to the safety of blood transfusions. In many countries and regions endemic for HEV, such as China, blood donors are not routinely tested for HEV infection. In this study, 11747 eligible blood donors were screened for anti-HEV immunoglobulin M (IgM)/immunoglobulin G (IgG) and HEV RNA and antigen in China. Twenty-four donors who were positive for both HEV antigen and RNA were followed for >= 70 days, and none of these donors reported clinical hepatitis or illness. At least 1 follow-up sample was provided by 17 donors, including 10 with viremia and/or antigenemia for >= 70 days and 3 with antigen and RNA positivity for >90 days. Fourteen of the 17 donors did not present with an obvious serologic response during the follow-up period. These results differed from previous reports, in which viremia lasted for 68 days and elicited an antibody response. These donors showed atypical HEV infection progression that differed from that of hepatitis E patients. The presence of these donors presents a challenge for transfusion transmission screening. PMID- 29977039 TI - Early phosphoproteomic changes for adverse outcome pathway development in the fathead minnow (Pimephales promelas) brain. AB - Adverse outcome pathways (AOPs) are conceptual frameworks that organize and link contaminant-induced mechanistic molecular changes to adverse biological responses at the individual and population level. AOPs leverage molecular and high content mechanistic information for regulatory decision-making, but most current AOPs for hormonally active agents (HAAs) focus on nuclear receptor-mediated effects only despite the overwhelming evidence that HAAs also activate membrane receptors. Activation of membrane receptors triggers non-genomic signaling cascades often transduced by protein phosphorylation leading to phenotypic changes. We utilized label-free LC-MS/MS to identify proteins differentially phosphorylated in the brain of fathead minnows (Pimephales promelas) aqueously exposed for 30 minutes to two HAAs, 17alpha-ethinylestradiol (EE2), a strong estrogenic substance, and levonorgestrel (LNG), a progestin, both components of the birth control pill. EE2 promoted differential phosphorylation of proteins involved in neuronal processes such as nervous system development, synaptic transmission, and neuroprotection, while LNG induced differential phosphorylation of proteins involved in axon cargo transport and calcium ion homeostasis. EE2 and LNG caused similar enrichment of synaptic plasticity and neurogenesis. This study is the first to identify molecular changes in vivo in fish after short-term exposure and highlights transduction of rapid signaling mechanisms as targets of HAAs, in addition to nuclear receptor-mediated pathways. PMID- 29977040 TI - Modeling SNP array ascertainment with Approximate Bayesian Computation for demographic inference. AB - Single nucleotide polymorphisms (SNPs) in commercial arrays have often been discovered in a small number of samples from selected populations. This ascertainment skews patterns of nucleotide diversity and affects population genetic inferences. We propose a demographic inference pipeline that explicitly models the SNP discovery protocol in an Approximate Bayesian Computation (ABC) framework. We simulated genomic regions according to a demographic model incorporating parameters for the divergence of three well-characterized HapMap populations and recreated the SNP distribution of a commercial array by varying the number of haploid samples and the allele frequency cut-off in the given regions. We then calculated summary statistics obtained from both the ascertained and genomic data and inferred ascertainment and demographic parameters. We implemented our pipeline to study the admixture process that gave rise to the present-day Mexican population. Our estimate of the time of admixture is closer to the historical dates than those in previous works which did not consider ascertainment bias. Although the use of whole genome sequences for demographic inference is becoming the norm, there are still underrepresented areas of the world from where only SNP array data are available. Our inference framework is applicable to those cases and will help with the demographic inference. PMID- 29977041 TI - Aerosol trace metal leaching and impacts on marine microorganisms. AB - Metal dissolution from atmospheric aerosol deposition to the oceans is important in enhancing and inhibiting phytoplankton growth rates and modifying plankton community structure, thus impacting marine biogeochemistry. Here we review the current state of knowledge on the causes and effects of the leaching of multiple trace metals from natural and anthropogenic aerosols. Aerosol deposition is considered both on short timescales over which phytoplankton respond directly to aerosol metal inputs, as well as longer timescales over which biogeochemical cycles are affected by aerosols. PMID- 29977042 TI - BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma. AB - Glioblastoma multiforme (GBM) is a highly vascularized and aggressive brain tumor, with a strong ability to disseminate and invade the surrounding parenchyma. In addition, a subpopulation of GBM stem cells has been reported to possess the ability to transdifferentiate into tumor-derived endothelial cells (TDECs), supporting the resistance to anti-angiogenic treatments of newly formed blood vessels. Bone Morphogenetic Protein 9 (BMP9) is critically involved in the processes of cancer cell differentiation, invasion and metastasis, representing a potential tool in order to impair the intrinsic GBM aggressiveness. Here we demonstrate that BMP9 is able to trigger the activation of SMADs in patient derived GBM cells, and to strongly inhibit proliferation and invasion by reducing the activation of PI3K/AKT/MAPK and RhoA/Cofilin pathways, respectively. Intriguingly, BMP9 treatment is sufficient to induce a strong differentiation of GBM stem-like cells and to significantly counteract the already reported process of GBM cell transdifferentiation into TDECs not only in in vitro mimicked TDEC models, but also in vivo in orthotopic xenografts in mice. Additionally, we describe a strong BMP9-mediated inhibition of the whole angiogenic process engaged during GBM tumor formation. Based on these results, we believe that BMP9, by acting at multiple levels against GBM cell aggressiveness, can be considered a promising candidate, to be further developed, for the future therapeutic management of GBM. PMID- 29977043 TI - Porcine Alveolar Macrophage-like cells are pro-inflammatory Pulmonary Intravascular Macrophages that produce large titers of Porcine Reproductive and Respiratory Syndrome Virus. AB - Lung inflammation is frequently involved in respiratory conditions and it is strongly controlled by mononuclear phagocytes (MNP). We previously studied porcine lung MNP and described a new population of cells presenting all the features of alveolar macrophages (AM) except for their parenchymal location, that we named AM-like cells. Herein we showed that AM-like cells are macrophages phagocytosing blood-borne particles, in agreement with a pulmonary intravascular macrophages (PIM) identity. PIM have been described microscopically long time ago in species from the Laurasiatheria superorder such as bovine, swine, cats or cetaceans. We observed that PIM were more inflammatory than AM upon infection with the porcine reproductive and respiratory syndrome virus (PRRSV), a major swine pathogen. Moreover, whereas PRRSV was thought to mainly target AM, we observed that PIM were a major producer of virus. The PIM infection was more correlated with viremia in vivo than AM infection. Finally like AM, PIM-expressed genes were characteristic of an embryonic monocyte-derived macrophage population, whose turnover is independent of bone marrow-derived hematopoietic precursors. This last observation raised the interesting possibility that AM and PIM originate from the same lung precursor. PMID- 29977044 TI - Spontaneous reactivation of latent HIV-1 promoters is linked to the cell cycle as revealed by a genetic-insulators-containing dual-fluorescence HIV-1-based vector. AB - Long-lived latently HIV-1-infected cells represent a barrier to cure. We developed a dual-fluorescence HIV-1-based vector containing a pair of genetic insulators flanking a constitutive fluorescent reporter gene to study HIV-1 latency. The protective effects of these genetic insulators are demonstrated through long-term (up to 394 days) stable fluorescence profiles in transduced SUP T1 cells. Analysis of 1,941 vector integration sites confirmed reproduction of HIV-1 integration patterns. We sorted monoclonal cells representing latent HIV-1 infections and found that both vector integration sites and integrity of the vector genomes influence the reactivation potentials of latent HIV-1 promoters. Interestingly, some latent monoclonal cells exhibited a small cell subpopulation with a spontaneously reactivated HIV-1 promoter. Higher expression levels of genes involved in cell cycle progression are observed in these cell subpopulations compared to their counterparts with HIV-1 promoters that remained latent. Consistently, larger fractions of spontaneously reactivated cells are in the S and G2 phases of the cell cycle. Furthermore, genistein and nocodazole treatments of these cell clones, which halted cells in the G2 phase, resulted in a 1.4-2.9-fold increase in spontaneous reactivation. Taken together, our HIV-1 latency model reveals that the spontaneous reactivation of latent HIV-1 promoters is linked to the cell cycle. PMID- 29977045 TI - Large-scale production of megakaryocytes in microcarrier-supported stirred suspension bioreactors. AB - Megakaryocytes (MKs) are the precursors of platelets (PLTs) and may be used for PLT production in vivo or in vitro, as well as a source for PLT-derived growth factors. Induced pluripotent stem cells represent an unlimited cell source for the in vitro production of MKs. This study aimed at developing an effective, xeno free and scalable system to produce high numbers of MKs. In particular, microcarrier beads-assisted stirred bioreactors were evaluated as a means of improving MK yields. This method resulted in the production of 18.7 * 107 MKs per 50 ml medium. Laminin-coated microcarriers increased MK production per iPSC by up to 10-fold. MKs obtained in this system showed typical features of mature MKs and were able to produce PLTs in vitro and in vivo. To increase safety, MKs produced in the bioreactors were irradiated; a procedure that did not affect their capability to form proPLTs and PTLs after transfusion. In vitro generated MKs represent a promising alternative to donor PLTs and open the possibility for the development of innovative MK-based cell therapies. PMID- 29977046 TI - Metastable phase formation of Pt-X (X = Ir, Au) thin films. AB - The dependence of phase formation and mechanical properties on the chemical composition has been investigated for Pt-Ir and Pt-Au combinatorial thin films. The formation of a single, metastable Pt-Ir solid solution has been observed for all experimental compositions and temperatures. Upon Ir addition to Pt the experimentally determined changes in lattice parameter and Young's modulus display rule of mixture behavior which is in good agreement with our ab initio data. Whereas, in the Pt-Au system, the single metastable solid solution decomposes into two phases as the growth temperature is raised to >=600 degrees C. The lattice parameters in the dual phase region are independent of chemical composition. The substrate temperature and chemical composition dependent phase formation in Pt-Ir and Pt-Au thin films can be rationalized based on CALPHAD (CALculation of PHAse Diagrams) results combined with estimations of the activation energy required for surface diffusion: The metastable phase formation during film growth is caused by kinetic limitations, where Ir atoms (in Pt-Ir) need to overcome an up to factor 6 higher activation energy barrier than Au (in Pt-Au) to enable surface diffusion. PMID- 29977048 TI - Ecological influence of sediment bypass tunnels on macroinvertebrates in dam fragmented rivers by DNA metabarcoding. AB - Sediment bypass tunnels (SBTs) are guiding structures used to reduce sediment accumulation in reservoirs during high flows by transporting sediments to downstream reaches during operation. Previous studies monitoring the ecological effects of SBT operations on downstream reaches suggest a positive influence of SBTs on riverbed sediment conditions and macroinvertebrate communities based on traditional morphology-based surveys. Morphology-based macroinvertebrate assessments are costly and time-consuming, and the large number of morphologically cryptic, small-sized and undescribed species usually results in coarse taxonomic identification. Here, we used DNA metabarcoding analysis to assess the influence of SBT operations on macroinvertebrates downstream of SBT outlets by estimating species diversity and pairwise community dissimilarity between upstream and downstream locations in dam-fragmented rivers with operational SBTs in comparison to dam-fragmented (i.e., no SBTs) and free-flowing rivers (i.e., no dam). We found that macroinvertebrate community dissimilarity decreases with increasing operation time and frequency of SBTs. These factors of SBT operation influence changes in riverbed features, e.g. sediment relations, that subsequently effect the recovery of downstream macroinvertebrate communities to their respective upstream communities. Macroinvertebrate abundance using morphologically-identified specimens was positively correlated to read abundance using metabarcoding. This supports and reinforces the use of quantitative estimates for diversity analysis with metabarcoding data. PMID- 29977047 TI - A new approach of gene co-expression network inference reveals significant biological processes involved in porcine muscle development in late gestation. AB - The integration of genetic information in the cellular and nuclear environments is crucial for deciphering the way in which the genome functions under different physiological conditions. Experimental techniques of 3D nuclear mapping, a high flow approach such as transcriptomic data analyses, and statistical methods for the development of co-expressed gene networks, can be combined to develop an integrated approach for depicting the regulation of gene expression. Our work focused more specifically on the mechanisms involved in the transcriptional regulation of genes expressed in muscle during late foetal development in pig. The data generated by a transcriptomic analysis carried out on muscle of foetuses from two extreme genetic lines for birth mortality are used to construct networks of differentially expressed and co-regulated genes. We developed an innovative co expression networking approach coupling, by means of an iterative process, a new statistical method for graph inference with data of gene spatial co-localization (3D DNA FISH) to construct a robust network grouping co-expressed genes. This enabled us to highlight relevant biological processes related to foetal muscle maturity and to discover unexpected gene associations between IGF2, MYH3 and DLK1/MEG3 in the nuclear space, genes that are up-regulated at this stage of muscle development. PMID- 29977049 TI - Increased risk for inflammatory bowel disease in congenital hypothyroidism supports the existence of a shared susceptibility factor. AB - Loss-of-function mutations in dual oxidase (DUOX) 2 are the most common genetic variants found in congenital hypothyroidism (CH), and similar mutations have been recently reported in few very-early-onset inflammatory bowel disease (IBD) patients without CH. If DUOX2 variants indeed increase susceptibility for IBD, the enrichment of DUOX2 mutation carriers among CH patients should be reflected in higher risk for developing IBD. Using a database containing health insurance claims data for over 230 million patients in the United States, 42,922 subjects with CH were identified based on strict inclusion criteria using diagnostic codes. For subgroup analysis, CH patients with pharmacy records were stratified as transient or permanent CH based on the absence or presence of levothyroxine treatment, respectively. Patients were matched to an equal-sized, age- and gender matched non-CH group. Compared to controls, CH patients had a 73% higher overall IBD prevalence (0.52% vs 0.30%; P < 0.0001). The CH-associated relative risk was higher for indeterminate or ulcerative colitis than Crohn's disease. Patients with transient CH had higher odds for IBD (OR 2.39 (95% CI 1.77-3.23) than those with permanent CH (1.69 (95% CI 1.31-2.18). We conclude that patients with CH are at an increased risk of developing IBD. The risk was highest for patients with transient CH, for which partial defects in the DUOX2 system are a particularly common finding. PMID- 29977050 TI - A call for a global 'bigger' data approach to Alzheimer disease. PMID- 29977052 TI - The evolution of adaptiveness: balancing speed and evidence. PMID- 29977053 TI - Concerns, challenges and promises of high-content analysis of 3D cellular models. PMID- 29977051 TI - Principles for targeting RNA with drug-like small molecules. AB - RNA molecules are essential for cellular information transfer and gene regulation, and RNAs have been implicated in many human diseases. Messenger and non-coding RNAs contain highly structured elements, and evidence suggests that many of these structures are important for function. Targeting these RNAs with small molecules offers opportunities to therapeutically modulate numerous cellular processes, including those linked to 'undruggable' protein targets. Despite this promise, there is currently only a single class of human-designed small molecules that target RNA used clinically - the linezolid antibiotics. However, a growing number of small-molecule RNA ligands are being identified, leading to burgeoning interest in the field. Here, we discuss principles for discovering small-molecule drugs that target RNA and argue that the overarching challenge is to identify appropriate target structures - namely, in disease causing RNAs that have high information content and, consequently, appropriate ligand-binding pockets. If focus is placed on such druggable binding sites in RNA, extensive knowledge of the typical physicochemical properties of drug-like small molecules could then enable small-molecule drug discovery for RNA targets to become (only) roughly as difficult as for protein targets. PMID- 29977054 TI - New genomic drivers identified. PMID- 29977055 TI - FGF2 causes genomic instability. PMID- 29977056 TI - The multidomain flavodiiron protein from Clostridium difficile 630 is an NADH:oxygen oxidoreductase. AB - Flavodiiron proteins (FDPs) are enzymes with a minimal core of two domains: a metallo-beta-lactamase-like, harbouring a diiron center, and a flavodoxin, FMN containing, domains. FDPs are O2 or NO reducing enzymes; for many pathogens, they help mitigate the NO produced by the immune system of the host, and aid survival during fluctuating concentrations concentrations of oxygen. FDPs have a mosaic structure, being predicted to contain multiple extra domains. Clostridium difficile, a threatening human pathogen, encodes two FDPs: one with the two canonical domains, and another with a larger polypeptide chain of 843 amino acids, CD1623, with two extra domains, predicted to be a short-rubredoxin-like and an NAD(P)H:rubredoxin oxidoreductase. This multi-domain protein is the most complex FDP characterized thus far. Each of the predicted domains was characterized and the presence of the predicted cofactors confirmed by biochemical and spectroscopic analysis. Results show that this protein operates as a standalone FDP, receiving electrons directly from NADH, and reducing oxygen to water, precluding the need for extra partners. CD1623 displayed negligible NO reductase activity, and is thus considered an oxygen selective FDP, that may contribute to the survival of C. difficile in the human gut and in the environment. PMID- 29977058 TI - Cultural engagement predicts changes in cognitive function in older adults over a 10 year period: findings from the English Longitudinal Study of Ageing. AB - There is increasing evidence that leading an active, socially engaged lifestyle might protect against cognitive decline. The arts have been proposed as potentially beneficial activities due to their combination of cognitive complexity and mental creativity. Yet it remains uncertain which types of arts engagement and what level of engagement is required for potential benefits to accrue. This study therefore explored the association between three types of cultural engagement (visiting museums/galleries/exhibitions, going to the theatre/concert/opera and going to the cinema) and change in cognitive function over 10 years amongst adults aged over 52. Our participants (n = 3,445), drawn from the English Longitudinal Study of Ageing, were assessed in 2004/5 and 2014/15. We measured memory and semantic fluency at baseline and follow-up, analysing results using ordinary least squares regression models. Independent of demographic, health and social confounders, visiting museums/galleries/exhibitions and going to the theatre/concert/opera were associated with a lesser decline in cognitive function. Sensitivity analyses confirmed effects were unaffected by considerations of mobility or dementia diagnoses. However, going to the cinema was found to hold little effect for cognitive preservation. Overall, our results suggest that more frequent cultural engagement is associated with more marked effects, but even annual engagement may be protective. PMID- 29977059 TI - Ewing sarcoma. AB - Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment related toxicity, overall survival and quality of life. PMID- 29977060 TI - Contactless Fluid Manipulation in Air: Droplet Coalescence and Active Mixing by Acoustic Levitation. AB - Acoustic manipulation by an ultrasonic phased array provides an entirely new approach to processes such as coalescence, mixing, separation, and evaporation occurring in the generation of new materials, physical property measurement, the biomedical industry, etc. However, to date, ultrasonic phased arrays have not been fully investigated for applications in fluid manipulation. This paper provides contactless coalescence and mixing techniques for droplets in air by controlling the acoustic potential by using an ultrasonic phased array. We focused on mode oscillation to propose an efficient mixing technique for liquid without contact. A comparison of mixing performance between cases with mode oscillation and without mode oscillation showed that the flow induced by mode oscillation promotes droplet mixing. Our paper demonstrates the feasibility of contactless coalescence and mixing as a first step in fluid manipulation with a phased array. PMID- 29977061 TI - Author Correction: Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. AB - Change history: In this Letter, the surname of author Efi E. Massasa was misspelled 'Massassa'. This error has been corrected online. PMID- 29977062 TI - Author Correction: RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/6. AB - In this Letter, the surname of author Lena Vlaminck was misspelled 'Vlaeminck'. In addition, author Kris Vleminckx should have been associated with affiliation 16 (Center for Medical Genetics, Ghent University, Ghent, Belgium). These have been corrected online. PMID- 29977057 TI - Age at first birth in women is genetically associated with increased risk of schizophrenia. AB - Previous studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health. PMID- 29977064 TI - Anticoagulants impact on innate immune responses and bacterial survival in whole blood models of Neisseria meningitidis infection. AB - Neisseria meningitidis (meningococcus) causes invasive diseases such as meningitis or septicaemia. Ex vivo infection of human whole blood is a valuable tool to study meningococcal virulence factors and the host innate immune responses. In order to consider effects of cellular mediators, the coagulation cascade must be inhibited to avoid clotting. There is considerable variation in the anticoagulants used among studies of N. meningitidis whole blood infections, featuring citrate, heparin or derivatives of hirudin, a polypeptide from leech saliva. Here, we compare the influence of these three different anticoagulants, and additionally Mg/EGTA, on host innate immune responses as well as on viability of N. meningitidis strains isolated from healthy carriers and disease cases, reflecting different sequence types and capsule phenotypes. We found that the anticoagulants significantly impact on cellular responses and, strain dependently, also on bacterial survival. Hirudin does not inhibit complement and is therefore superior over the other anticoagulants; indeed hirudin-plasma most closely reflects the characteristics of serum during N. meningitidis infection. We further demonstrate the impact of heparin on complement activation on N. meningitidis and its consequences on meningococcal survival in immune sera, which appears to be independent of the heparin binding antigens Opc and NHBA. PMID- 29977063 TI - Human IgM monoclonal antibodies block HIV-transmission to immune cells in cervico vaginal tissues and across polarized epithelial cells in vitro. AB - The importance of natural IgM antibodies in protection against infections is still emerging and these antibodies have a potential role in the maintenance of homeostasis through clearance of apoptotic bodies, complement-dependent mechanisms, inflammation and exclusion of misfolded proteins. Natural IgM act as a first line of defence against unknown hazardous factors and are present in most vertebrates. We investigated the functional capacity of anti-HIV-1 IgM monoclonal antibodies, from a combinatorial Fab library derived from healthy individuals, and evaluated their protective role in inhibiting HIV-1 in vitro when passing across the human mucosal epithelial barrier. Primary HIV-1 isolates were efficiently transmitted over the tight polarized epithelial cells when added to their apical surface. Efficient inhibition of HIV-1 transmission was achieved when anti-HIV-1 IgM monoclonal antibodies were added to the basolateral side of the cells. Two of these human IgM MoAbs had the ability to neutralize HIV and reduced infection of dendritic cells in primary cervico-vaginal tissue biopsies in vitro. This indicates a potential role of natural IgM antibodies in the reduction of HIV-1 transmission in mucosal tissues and improve our understanding of how natural IgM antibodies against a neutralizing epitope could interfere with viral transmission. PMID- 29977065 TI - Visual Osteoclast Fusion via A Fluorescence Method. AB - Osteoclasts are multinucleated giant cells. Fusion is an essential element in the formation of osteoclasts. However, the exact cellular events and mechanisms remain largely unknown because of limited and insufficient methods for observing fusion process. In this work, a fluorescence reporter strategy was established to monitor osteoclast fusion. After fusing with cells expressing Cre recombinase, those cells with double fluorescence switch its expression from red to green fluorescent protein. The effect of RANKL and PTH on osteoclast fusion were both quantitatively and visually detected utilizing this strategy. Furthermore, a combination of this strategy with a technique of fluorescence-activated cell sorting revealed two different populations of fused osteoclasts, tdTomato+ GFP+ cells (TG cells) and GFP+ cells (G cells). The results argue for the potential of combining this technique with other bio-technologies to gain more information about osteoclast fusion. Overall, these data demonstrated that this visual fluorescence switch strategy is useful for further analysis of osteoclast fusion mechanisms. PMID- 29977066 TI - The frontal skull Hounsfield unit value can predict ventricular enlargement in patients with subarachnoid haemorrhage. AB - Hydrocephalus is a common complication following subarachnoid haemorrhage (SAH) arising from spontaneous aneurysm rupture. The Hounsfield unit (HU) value from computed tomography scans may reflect bone mineral density, which correlates with body mass index, which in turn is related to post-SAH ventricle size changes. We herein investigated potential associations between frontal skull HU values and ventricle size changes after SAH. HU values from four different areas in the frontal bone were averaged to minimize measurement errors. The bicaudate index and Evans ratio were measured using both baseline and follow-up CT images. CT images with bicaudate index >0.2 and Evans ratio >0.3 simultaneously were defined as indicating ventriculomegaly. We included 232 consecutive patients with SAH due to primary spontaneous aneurysm rupture, who underwent clipping over almost a 9 year period at a single institution. The first tertile of frontal skull HU values in older patients (>=55 years) was an independent predictor of ventriculomegaly after SAH, as compared to the third tertile in younger patients (hazard ratio, 4.01; 95% confidence interval 1.21-13.30; p = 0.023). The lower frontal skull HU value independently predicted ventricular enlargement post-SAH, due to the potential weak integrity of subarachnoid trabecular structures in younger patients. PMID- 29977067 TI - Ventromedial hypothalamic nucleus in regulation of stress-induced gastric mucosal injury in rats. AB - Previous studies showed that restraint water-immersion stress (RWIS) increases the expression of Fos protein in the ventromedial hypothalamic nucleus (VMH), indicating the VMH involving in the stress-induced gastric mucosal injury (SGMI). The present study was designed to investigate its possible neuro-regulatory mechanisms in rats receiving either VMH lesions or sham surgery. The model for SGMI was developed by restraint and water (21 +/- 1 degrees C) immersion for 2 h. Gastric mucosal injury index, gastric motility, gastric acid secretion and Fos expression in the hypothalamus and brainstem were examined on the 15th postoperative day in RWIS rats. Gastric mucosal injury in VMH-lesioned rats was obviously aggravated compared to the control. Gastric acidity under RWIS was obviously higher in VMH-lesioned rats than that in sham rats. Meantime, the VMH lesioned rats exhibited marked increases in the amplitude of gastric motility in the VMH lesions group after RWIS. In VMH-lesioned rats, Fos expression significantly increased in the dorsal motor nucleus of the vagus (DMV), the nucleus of the solitary tract (NTS), the area postrema (AP), the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) in response to RWIS. These results indicate that VMH lesions can aggravate the stress-induced gastric mucosal injury through the VMH-dorsal vagal complex (DVC)-vagal nerve pathway. PMID- 29977068 TI - Modelling microglial function with induced pluripotent stem cells: an update. AB - It is becoming increasingly apparent that microglia, the immune cells of the CNS, and their peripheral counterparts, macrophages, have a major role in normal physiology and pathology. Recent technological advances in the production of particular cell types from induced pluripotent stem cells have led to an interest in applying this methodology to the production of microglia. Here, we discuss recent advances in this area and describe how they will aid our future understanding of microglia. PMID- 29977070 TI - Author Correction: Dogs and humans respond to emotionally competent stimuli by producing different facial actions. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29977069 TI - CAP modifies the structure of a model protein from thermophilic bacteria: mechanisms of CAP-mediated inactivation. AB - Cold atmospheric plasma (CAP) has great potential for sterilization in the food industry, by deactivation of thermophilic bacteria, but the underlying mechanisms are largely unknown. Therefore, we investigate here whether CAP is able to denature/modify protein from thermophilic bacteria. We focus on MTH1880 (MTH) from Methanobacterium thermoautotrophicum as model protein, which we treated with dielectric barrier discharge (DBD) plasma operating in air for 10, 15 and 20 mins. We analysed the structural changes of MTH using circular dichroism, fluorescence and NMR spectroscopy, as well as the thermal and chemical denaturation, upon CAP treatment. Additionally, we performed molecular dynamics (MD) simulations to determine the stability, flexibility and solvent accessible surface area (SASA) of both the native and oxidised protein. PMID- 29977071 TI - Using machine learning tools for protein database biocuration assistance. AB - Biocuration in the omics sciences has become paramount, as research in these fields rapidly evolves towards increasingly data-dependent models. As a result, the management of web-accessible publicly-available databases becomes a central task in biological knowledge dissemination. One relevant challenge for biocurators is the unambiguous identification of biological entities. In this study, we illustrate the adequacy of machine learning methods as biocuration assistance tools using a publicly available protein database as an example. This database contains information on G Protein-Coupled Receptors (GPCRs), which are part of eukaryotic cell membranes and relevant in cell communication as well as major drug targets in pharmacology. These receptors are characterized according to subtype labels. Previous analysis of this database provided evidence that some of the receptor sequences could be affected by a case of label noise, as they appeared to be too consistently misclassified by machine learning methods. Here, we extend our analysis to recent and quite substantially modified new versions of the database and reveal their now extremely accurate labeling using several machine learning models and different transformations of the unaligned sequences. These findings support the adequacy of our proposed method to identify problematic labeling cases as a tool for database biocuration. PMID- 29977072 TI - Comparison of the expression of cluster of differentiation (CD)39 and CD73 between propofol- and sevoflurane-based anaesthesia during open heart surgery. AB - High expression of cluster of differentiation (CD)39 and CD73 has cardio protective effects. We hypothesised that the expression of CD39 and CD73 would differ between propofol- and volatile anaesthetic-based anaesthesia in patients undergoing open heart surgery (OHS). The objective of this prospective randomized trial was to compare the changes in CD39 and CD73 levels in CD4+ T cells between propofol- and sevoflurane-based anaesthesia during OHS. The study randomly allocated 156 patients undergoing OHS to a propofol or sevoflurane group. Blood was obtained preoperatively and up to 48 hours after weaning from cardiopulmonary bypass (CPB). The expression levels of CD39 and CD73 in circulating CD4+ T cells, serum cytokines and other laboratory parameters were analysed. The primary outcome was the expression of CD39 and CD73 on CD4+ T cells. Demographic data and perioperative haemodynamic changes did not show significant differences between the two groups. The expression of CD39 and CD73 in the sevoflurane group was significantly lower than in the propofol group (P < 0.001). Other laboratory findings including cardiac enzymes and cytokine levels, did not show significant intergroup differences. Propofol attenuated the decrease in CD39 and CD73 in circulating CD4+ T cells compared to sevoflurane-based anaesthesia during OHS. PMID- 29977073 TI - Role of endocannabinoids in the hippocampus and amygdala in emotional memory and plasticity. AB - Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 ug/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 ug/0.5 ul intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA. PMID- 29977076 TI - Tumor-associated neutrophils correlate with poor prognosis in diffuse large B cell lymphoma patients. PMID- 29977074 TI - The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. AB - The ability of ketamine administration to activate prefrontal glutamate neurotransmission is thought to be a key mechanism contributing to its transient psychotomimetic effects and its delayed and sustained antidepressant effects. Rodent studies employing carbon-13 magnetic resonance spectroscopy (13C MRS) methods have shown ketamine and other N-methyl-D-aspartate (NMDA) receptor antagonists to transiently increase measures reflecting glutamate-glutamine cycling and glutamate neurotransmission in the frontal cortex. However, there are not yet direct measures of glutamate neurotransmission in vivo in humans to support these hypotheses. The current first-level pilot study employed a novel prefrontal 13C MRS approach similar to that used in the rodent studies for direct measurement of ketamine effects on glutamate-glutamine cycling. Twenty-one participants (14 healthy and 7 depressed) completed two 13C MRS scans during infusion of normal saline or subanesthetic doses of ketamine. Compared to placebo, ketamine increased prefrontal glutamate-glutamine cycling, as indicated by a 13% increase in 13C glutamine enrichment (t = 2.4, p = 0.02). We found no evidence of ketamine effects on oxidative energy production, as reflected by 13C glutamate enrichment. During ketamine infusion, the ratio of 13C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale (r = -0.54, p = 0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects. PMID- 29977075 TI - Sex differences in neuroimmunity as an inherent risk factor. AB - Identifying and understanding the sources of inherent risk to neurodevelopmental disorders is a fundamental goal of neuroscience. Being male or being exposed to inflammation early in life are two known risk factors, but they are only infrequently associated with each other. Cellular and molecular mechanisms mediating the masculinization of the brain in animal models reveal a consistent role for inflammatory signaling molecules and immune cells in the healthy male brain. Why this is so remains in the realm of speculation but may have its origins in the maternal immune system. Masculinization of the brain occurs during a restricted critical period that begins in utero and overlaps with the sensitive period during which maternal immune activation negatively impacts the developing brain. The convergence of maleness and early life inflammation as risk factors for neuropsychiatric disorders compels us to consider whether sexual differentiation of the brain in males creates an inherent and greater risk than that experienced by females. PMID- 29977077 TI - Bio-based products control black rot (Xanthomonas campestris pv. campestris) and increase the nutraceutical and antioxidant components in kale. AB - Black rot of crucifers, (Xanthomonas campestris pv. campestris) is the principal yield-limiting and destructive pathogen of cruciferous crop worldwide. In order to validate a bio-based control alternative for this disease, whey, lime sulfur, biofertilizer, Bordeaux mixture or raw milk were applied to kale (Brassica oleracea var. acephala) plants. The disease control was achieved by most of the tested products. Milk-based products (raw milk and whey) and biofertilizer reduced the severity by 44 and 56% in the field. Antioxidants, crude fibber, crude protein and lipid contents and kale yield were verified in the five treatments on the leaves with and without X. campestris pv. campestris inoculation. In the absence of the pathogen (non-inoculated), lime sulfur and Bordeaux mixture improved plant nutritional value compared to organic treatments, nevertheless milk-based products and biofertilizer improved the evaluated variables more than the control. However, on leaves inoculated with X. campestris pv. campestris raw milk increased antioxidant activity, crude protein and fiber contents, whereas biofertilizer increased kale yield, lipid and antioxidant contents. Milk-based products and biofertilizer were further evaluated in greenhouse trials to determinate the activity of defense-related enzymes and lignin content. Biofertilizer treatment resulted in increased phenylalanine ammonia lyase, catalase, peroxidase activities and lignin content. Hence, the application of milk-based products and biofertilizer are promising to control black rot of crucifers and also improves food quality by boosting nutritional values and antioxidant activity. PMID- 29977078 TI - Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community. AB - Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child's seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as "effective" versus those rated "ineffective". Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as "effective", with no clear differences between extracts perceived as "effective" and "ineffective". Contrary to family's expectations, most samples contained low concentrations of cannabidiol, while Delta9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy. PMID- 29977079 TI - Rbpj direct regulation of Atoh7 transcription in the embryonic mouse retina. AB - In vertebrate retinal progenitor cells, the proneural factor Atoh7 exhibits a dynamic tissue and cellular expression pattern. Although the resulting Atoh7 retinal lineage contains all seven major cell types, only retinal ganglion cells require Atoh7 for proper differentiation. Such specificity necessitates complex regulation of Atoh7 transcription during retina development. The Notch signaling pathway is an evolutionarily conserved suppressor of proneural bHLH factor expression. Previous in vivo mouse genetic studies established the cell autonomous suppression of Atoh7 transcription by Notch1, Rbpj and Hes1. Here we identify four CSL binding sites within the Atoh7 proximal regulatory region and demonstrate Rbpj protein interaction at these sequences by in vitro electromobility shift, calorimetry and luciferase assays and, in vivo via colocalization and chromatin immunoprecipitation. We found that Rbpj simultaneously represses Atoh7 transcription using both Notch-dependent and independent pathways. PMID- 29977080 TI - A prospective, randomized, double-blind, placebo-controlled trial of acute postoperative pain treatment using opioid analgesics with intravenous ibuprofen after radical cervical cancer surgery. AB - This study assessed the efficacy and tolerability of intravenous ibuprofen in the improvement of post-operative pain control and the reduction of opioid usage. Patients were randomly divided into placebo, ibuprofen 400 mg and ibuprofen 800 mg groups. All patients received patient-controlled intravenous morphine analgesia after surgery. The first dose of study drugs was administered intravenously 30 min before the end of surgery and then every 6 hours, for a total of 8 doses after surgery. The primary endpoint of this study was the mean amount of morphine used during the first 24 hours after surgery. Morphine use was reduced significantly in the ibuprofen 800 mg group compared with the placebo group (P = 0.04). Tramadol use was reduced significantly in the ibuprofen 400 mg and ibuprofen 800 mg groups compared with the placebo group (P < 0.01). The area under the curve of visual analog scale pain ratings was not different between groups. Safety assessments and side effects were not different between the three groups. Intravenous ibuprofen 800 mg was associated with a significant reduction in morphine requirements, and it was generally well tolerated for postoperative pain management in patients undergoing radical cervical cancer surgery. PMID- 29977082 TI - Quantification of radioactivity by planar gamma-camera images, a promoted method of absorbed dose in the thyroid after iodine-131 treatment. AB - Iodine-131 (131I) is an essential and widely used radioisotope in thyroid diseases and animal experiments. Planar imaging has been considered the most popular method for 131I thyroid uptake radioactive activity quantification. The ROI defining section is essential and can affect the accuracy of quantitative results. However, a consistent method has not been proposed. In this study, a UC ROI defining method based on ULWL setting and colour display grade was applied. Three steps were performed: image acquisition of five standard activity models and obtaining the exact value that the counts per radioactive activity contributes to the ROI; image acquisition of 20 rat thyroids and obtaining the counts of the ROI (thyroid); and calculating the rat thyroid radioactive activity and comparing these values with the true values. The accuracy of quantification activity of 131I in rat thyroid reached 2.62% +/- 0.41%. The mean quantification within 5% could be achieved in 19 of 20 rat thyroids. No significant difference existed between calculated thyroid 131I activity and true values with a paired matched-test (t = -0.384, P = 0.706 > 0.05). The results indicated that with the UC-ROI defining method, more accurate thyroid uptake 131I radioactive activity quantification by SPECT planar imaging can be achieved in vivo rat study. PMID- 29977083 TI - Optimal schedule of home blood-pressure measurements for the diagnosis of hypertension. AB - Various home blood-pressure (HBP) measurement schedules were compared to determine the optimal schedule of HBP measurement for the diagnosis of hypertension. Out of 319 individuals who were suspected of having hypertension based on office BP measurements and who did not take antihypertensive drugs, 157 individuals who completed 42 HBP measurements over 7 days and who had a valid 24 h ambulatory blood pressure (ABP) measurement were included in this analysis. We evaluated five HBP measurement schedules to determine the optimal HBP measurement schedule for the diagnosis of hypertension. The cumulatively averaged HBP from 5 to 6 measurement days showed a Pearson correlation coefficient of >0.990 compared to HBP averaged for 6 or 7 days depending on the method. The intraclass correlation coefficient of the cumulatively averaged HBP measurements compared with the 24-h ABP measurement was excellent (>=0.75) from the average of three measurement days and increased steadily with increasing averaged days of HBP measurements. Compared with a diagnosis using a 24-h ABP measurement, the diagnostic sensitivity, specificity, and positive and negative predictive values of HBP measurements were not different among the five methods. The diagnostic agreement of cumulatively averaged HBP measurements was nearly perfect (kappa >= 0.9) from the average of five measurement days compared with a diagnosis based on HBP measurements averaged for 6 or 7 days and diagnosis based on averaged HBP measurements of previous days. We suggest obtaining HBP measurements over 5 days or more, in the morning and evening, taking two or more measurements per occasion, and averaging all of the readings as the optimal schedule of HBP measurement for the diagnosis of hypertension. PMID- 29977081 TI - Low-Frequency Raman Spectroscopy of Few-Layer 2H-SnS2. AB - We investigated interlayer phonon modes of mechanically exfoliated few-layer 2H SnS2 samples by using room temperature low-frequency micro-Raman spectroscopy. Raman measurements were performed using laser wavelengths of 441.6, 514.4, 532 and 632.8 nm with power below 100 MUW and inside a vacuum chamber to avoid photo oxidation. The intralayer Eg and A1g modes are observed at ~206 cm-1 and 314 cm 1, respectively, but the Eg mode is much weaker for all excitation energies. The A1g mode exhibits strong resonant enhancement for the 532 nm (2.33 eV) laser. In the low-frequency region, interlayer vibrational modes of shear and breathing modes are observed. These modes show characteristic dependence on the number of layers. The strengths of the interlayer interactions are estimated by fitting the interlayer mode frequencies using the linear chain model and are found to be 1.64 * 1019 N . m-3 and 5.03 * 1019 N . m-3 for the shear and breathing modes, respectively. PMID- 29977084 TI - Red but not dead. PMID- 29977085 TI - Stratospheric order mutants. PMID- 29977086 TI - A book for every trunk. PMID- 29977087 TI - Surfing the genomic new wave. PMID- 29977088 TI - Stop messing with old-growth forests. PMID- 29977089 TI - Organoselenium-Based Entry into Versatile, alpha-(2-Tributylstannyl)vinyl Amino Acids in Scalemic Form: A New Route to Vinyl Stannanes. PMID- 29977090 TI - Moving Object Detection Using a Parallax Shift Vector Algorithm. AB - There are various algorithms currently in use to detect asteroids from ground based observatories, but they are generally restricted to linear or mildly curved movement of the target object across the field of view. Space based sensors in high inclination, low Earth orbits can induce significant parallax in a collected sequence of images, especially for objects at the typical distances of asteroids in the inner Solar System. This results in a highly non-linear motion pattern of the asteroid across the sensor, which requires a more sophisticated search pattern for detection processing. Both the classical pattern matching used in ground based asteroid search and the more sensitive matched filtering and synthetic tracking techniques, can be adapted to account for highly complex parallax motion. A new shift vector generation methodology is discussed along with its impacts on commonly used detection algorithms, processing load, and responsiveness to asteroid track reporting. The matched filter, template generator, and pattern matcher source code for the software described herein are available via GitHub. PMID- 29977091 TI - The Maser Emitting Structure and Time Variability of the SIS Lines J = 14 - 13 and 15 - 14 in IRC+10216. AB - We present new high angular resolution interferometer observations of the upsilon = 0 J = 14 - 13 and 15 - 14 SiS lines towards IRC+10216, carried out with CARMA and ALMA. The maps, with angular resolutions of ?0?"25and0?"55, reveal (1) an extended, roughly uniform, and weak emission with a size of ?0?"5, (2) a component elongated approximately along the East-West direction peaking at ?0?"13and0?"17 at both sides of the central star, and (3) two blue- and red shifted compact components peaking around 0?"07 to the NW of the star. We have modeled the emission with a 3D radiation transfer code finding that the observations cannot be explained only by thermal emission. Several maser clumps and one arc-shaped maser feature arranged from 5 to 20R? from the central star, in addition to a thin shell-like maser structure at ? 13R? are required to explain the observations. This maser emitting set of structures accounts for 75% of the total emission while the other 25% is produced by thermally excited molecules. About 60% of the maser emission comes from the extended emission and the rest from the set of clumps and the arc. The analysis of a time monitoring of these and other SiS and 29SiS lines carried out with the IRAM 30 m telescope from 2015 to present suggests that the intensity of some spectral components of the maser emission strongly depends on the stellar pulsation while other components show a mild variability. This monitoring evidences a significant phase lag of ? 0.2 between the maser and NIR light-curves. PMID- 29977092 TI - Infinitesimal Probabilities. AB - Non-Archimedean probability functions allow us to combine regularity with perfect additivity. We discuss the philosophical motivation for a particular choice of axioms for a non-Archimedean probability theory and answer some philosophical objections that have been raised against infinitesimal probabilities in general. 1 Introduction2 The Limits of Classical Probability Theory 2.1 Classical probability functions 2.2 Limitations 2.3 Infinitesimals to the rescue?3 NAP Theory 3.1 First four axioms of NAP 3.2 Continuity and conditional probability 3.3 The final axiom of NAP 3.4 Infinite sums 3.5 Definition of NAP functions via infinite sums 3.6 Relation to numerosity theory4 Objections and Replies 4.1 Cantor and the Archimedean property 4.2 Ticket missing from an infinite lottery 4.3 Williamson's infinite sequence of coin tosses 4.4 Point sets on a circle 4.5 Easwaran and Pruss5 Dividends 5.1 Measure and utility 5.2 Regularity and uniformity 5.3 Credence and chance 5.4 Conditional probability6 General Considerations 6.1 Non-uniqueness 6.2 InvarianceAppendix . PMID- 29977093 TI - Carbon Dioxide Solubilities in Decanoic Acid-Based Hydrophobic Deep Eutectic Solvents. AB - The solubility of CO2 in hydrophobic deep eutectic solvents (DESs) has been measured for the first time. Six different hydrophobic DESs are studied in the temperature range from 298 to 323 K and at CO2 pressures up to 2 MPa. The results are evaluated by comparing the solubility data with existing hydrophilic DESs and currently applied physical solvents and fluorinated ionic liquids. The DESs are prepared by mixing decanoic acid with a quaternary ammonium salt with different halide anions and alkyl chain lengths. The measured CO2 solubilities are similar to those found in renowned fluorinated ILs, while the heats of CO2 absorption are in the range of nonpolar solvents. The presented DESs show good potential to be used as CO2 capture agents. PMID- 29977094 TI - The Role of Men's Childbearing Intentions in Father Involvement. AB - An expanding body of research has investigated factors that influence fathers' involvement with their children. Generally overlooked has been the role of pregnancy intentions on men's fathering behaviors. In this study, the authors used nationally representative data from men interviewed in the 2002 and 2006 2010 National Survey of Family Growth to examine relationships between fathers' pregnancy intentions and multiple aspects of their parental involvement. Using propensity score methods to control for confounding, they found that men were less likely to live with a young child from a mistimed than intended pregnancy and that among nonresident fathers, mistimed pregnancies were associated with lower levels of visitation and consequently reduced participation in caregiving and play. Among both resident and nonresident fathers, mistimed pregnancies were also associated with lower self-appraisals of fathering quality when compared with intended pregnancies; for nonresident fathers, however, this association was moderated by other involvement. PMID- 29977095 TI - A self-organising biomimetic collagen/nano-hydroxyapatite-glycosaminoglycan scaffold for spinal fusion. AB - The use of spinal fusion surgery as a treatment for degenerative spinal conditions and chronic back pain is increasing. However, this technique requires use of a bone grafting material to fuse the vertebrae, traditionally autologous bone, which consists of an optimal combination of osteogenic cell precursors, extracellular matrix proteins and mineral components. To date, this remains the 'gold standard' material but its supply is limited and is associated with a number of clinical and ethical difficulties; consequently, various combinations of cells with biological scaffold materials have been tested but have failed to achieve fusion rates even comparable to autologous bone. We successfully fabricated a novel collagen-based scaffold using self-organising atelocollagen combined with nano-hydroxyapatite and chondroitin sulphate, cross-linked by microbial transglutaminase. The scaffold was characterised using a range of imaging, chemical composition and thermal analysis techniques. It was found to exhibit appropriate stiffness and suitable pore size for the adhesion, growth and differentiation of MSCs. The low toxicity makes it suitable for clinical application, and its slow degradation profile would enable the scaffold to promote bone growth over an extended period. This material therefore shows promise for clinical use in spinal fusion and other procedures requiring the use of bone grafts. PMID- 29977096 TI - Terrestrial effects of moderately nearby supernovae. AB - Recent data indicate one or more moderately nearby supernovae in the Early Pleistocene, with additional events likely in the Miocene. This has motivated more detailed computations, using new information about the nature of supernovae and the distances of these events to describe in more detail the sorts of effects that are indicated at the Earth. This short communication/review is designed to describe some of these effects so that they may possibly be related to changes in the biota around these times. PMID- 29977097 TI - Electrochemical Atom Transfer Radical Polymerization in Miniemulsion with a Dual Catalytic System. AB - An electrochemical approach was used to control atom transfer radical polymerization (ATRP) of n-butyl acrylate (BA) in miniemulsion. Electropolymerization required a dual catalytic system, composed of an aqueous phase catalyst and an organic phase catalyst. This allowed shuttling the electrochemical stimulus from the working electrode (WE) to the continuous aqueous phase and to the dispersed monomer droplets. As aqueous phase catalysts, the hydrophilic Cu complexes with the ligands N,N-bis( 2-pyridylmethyl)-2 hydroxyethylamine (BPMEA), 2,2'-bipyridine (bpy), and tris(2-pyridylmethyl)amine (TPMA) were tested. As organic phase catalysts, the hydrophobic complexes with the ligands bis(2-pyridylmethyl)-octadecylamine (BPMODA) and bis[2-(4-methoxy-3,5 dimethyl)-pyridylmethyl]octadecylamine (BPMODA*) were evaluated. Highest rates and best control of BA electropolymerization were obtained with the water-soluble Cu/BPMEA used in combination with the oil-soluble Cu/BPMODA*. The polymerization rate could be further enhanced by changing the potential applied at the WE. Differently from traditional ATRP systems, reactivity of the dual catalytic system did not depend on the redox potential of the catalysts but instead depended on the hydrophobicity and partition coefficient of the aqueous phase catalyst. PMID- 29977098 TI - Electrochemically Mediated Reversible Addition-Fragmentation Chain-Transfer Polymerization. AB - An electrochemically mediated reversible addition-fragmentation chain-transfer polymerization (eRAFT) of (meth)acrylates was successfully carried out via electroreduction of either benzoyl peroxide (BPO) or 4-bromobenzenediazonium tetrafluoroborate (BrPhN2+) which formed aryl radicals, acting as initiators for RAFT polymerization. Direct electroreduction of chain transfer agents was unsuccessful since it resulted in the formation of carbanions by a two-electron transfer process. Reduction of BrPhN2+ under a fixed potential showed acceptable control, but limited conversion due to the generation of a passivating organic layer grafted on the working electrode surface. However, using fixed current conditions, easier to implement than fixed potential conditions, conversions > 80% were achieved. Well-defined homopolymers and block copolymers with a broad range of targeted degrees of polymerization were prepared. PMID- 29977099 TI - Harnessing the interaction between surfactant and hydrophilic catalyst to control eATRP in miniemulsion. AB - In contrast with previous accounts, it is reported that a single, strongly hydrophilic Cu complex can control an electrochemically mediated atom transfer radical polymerization (eATRP) in oil-in-water miniemulsion in the presence of anionic surfactants, such as sodium dodecyl sulfate (SDS). The anionic surfactant interacted strongly with cationic copper complexes, enabling controlled polymerization by a combination of "interfacial" and "ion-pair" catalysis, whereby ion pairs transport the catalyst to the monomer droplets. The ion-pair system was assembled in situ by mixing commercially available reagents (NaBr, SDS, and traditional hydrophilic copper complexes). Polymer purification was very facile because after reaction >99% of the hydrophilic copper complexes spontaneously left the hydrophobic polymer particles. PMID- 29977100 TI - A practical guide to big data. AB - Big Data is increasingly prevalent in science and data analysis. We provide a short tutorial for adapting to these changes and making the necessary adjustments to the academic culture to keep Biostatistics truly impactful in scientific research. PMID- 29977102 TI - Tridentate Phosphine Ligands Bearing Aza-Crown Ether Lariats. AB - Crown ethers are useful macrocycles that act as size-selective binding sites for alkali metals. These frameworks have been incorporated into a number of macromolecular assemblies that use simple cations as reporters and/or activity triggers. Incorporating crown ethers into secondary coordination sphere ligand frameworks for transition metal chemistry will lead to new potential methods for controlling bond formation steps, and routes that couple traditional ligand frameworks with these moieties are highly desirable. Herein we report the syntheses of a family of tridentate phosphine complexes bearing tethered aza crown ethers (lariats) designed to modularize the variation of aza-crown size, lariat length, and distal phosphine substituents, followed by the synthesis and solid-state structures of Mo(III) complexes bearing cations in the pendent crown ethers. PMID- 29977101 TI - Group testing case identification with biomarker information. AB - Screening procedures for infectious diseases, such as HIV, often involve pooling individual specimens together and testing the pools. For diseases with low prevalence, group testing (or pooled testing) can be used to classify individuals as diseased or not while providing considerable cost savings when compared to testing specimens individually. The pooling literature is replete with group testing case identification algorithms including Dorfman testing, higher-stage hierarchical procedures, and array testing. Although these algorithms are usually evaluated on the basis of the expected number of tests and classification accuracy, most evaluations in the literature do not account for the continuous nature of the testing responses and thus invoke potentially restrictive assumptions to characterize an algorithm's performance. Commonly used case identification algorithms in group testing are considered and are evaluated by taking a different approach. Instead of treating testing responses as binary random variables (i.e., diseased/not), evaluations are made by exploiting an assay's underlying continuous biomarker distributions for positive and negative individuals. In doing so, a general framework to describe the operating characteristics of group testing case identification algorithms is provided when these distributions are known. The methodology is illustrated using two HIV testing examples taken from the pooling literature. PMID- 29977103 TI - High Fidelity Virtual Reality Orthognathic Surgery Simulator. AB - Surgical simulators are powerful tools that assist in providing advanced training for complex craniofacial surgical procedures and objective skills assessment such as the ones needed to perform Bilateral Sagittal Split Osteotomy (BSSO). One of the crucial steps in simulating BSSO is accurately cutting the mandible in a specific area of the jaw, where surgeons rely on high fidelity visual and haptic cues. In this paper, we present methods to simulate drilling and cutting of the bone using the burr and the motorized oscillating saw respectively. Our method allows low computational cost bone drilling or cutting while providing high fidelity haptic feedback that is suitable for real-time virtual surgery simulation. PMID- 29977104 TI - Functional Decline and Emotional Elder Abuse: A Population-Based Study of Older Korean Adults. AB - Objectives: Elder abuse is an increasingly prevalent issue in South Korea. The current study examines the association between functional impairment and emotional abuse victimization in Korean adults 65 and older. We also examines the mediating roles of diverse aspects of family resources (i.e., older adult's self esteem, family cohesion, family assistance, contact with friends/neighbors, and participation in social activities) in the aforementioned association. Methods: We analyzed 9,691 community-dwelling older Koreans from a population-based survey of the 2009 Survey of Elderly Care and Welfare Need. We conducted a path analysis to analyze the mediational hypothesis. Results: About 11% of the study sample reported experiencing emotional abuse by a family member in the past year (n = 1,082). The results of the mediational analysis showed that greater ADL/IADL limitations were associated with a) reduced self-esteem and b) receiving more assistance from family, which were ultimately associated with increased risk of emotional abuse victimization. Discussion: Elder abuse is a family crisis that may occur as a result of maladaptation to the heightened long-term care needs of older family members. Practitioners should take into account older adults' vulnerability in terms of the loss of adaptive resources in the face of functional decline. This study further supports the importance of relieving the burden of family caregivers to avoid the incidence of emotional elder abuse. PMID- 29977106 TI - Competing influences of anthropogenic warming, ENSO, and plant physiology on future terrestrial aridity. AB - The 2011-2016 Californian drought illustrates that drought-prone areas do not always experience relief once a favorable phase of El Nino-Southern Oscillation (ENSO) returns. In the 21st century, such an expectation is unrealistic in regions where global warming induces an increase in terrestrial aridity larger than the aridity changes driven by ENSO variability. This premise is also flawed in areas where precipitation supply cannot offset the global warming-induced increased evaporative demand. Here, atmosphere-only experiments are analyzed to identify land regions in which aridity is currently sensitive to ENSO, and where projected future changes in mean aridity exceed the range caused by ENSO variability. Insights into the drivers of these aridity changes are obtained in simulations with incremental addition of three different factors to current climate: ocean warming, vegetation response to elevated CO2 levels, and intensified CO2 radiative forcing. The effect of ocean warming overwhelms the range of ENSO-driven temperature variability worldwide, increasing potential evapotranspiration (PET) in most ENSO-sensitive regions. Additionally, ~39% of the regions currently sensitive to ENSO receive less precipitation in the future, independent of the ENSO phase. Aridity increases consequently in 67-72% of the ENSO-sensitive area. When both radiative and physiological effects are considered, the area affected by aridity rises to 75-79% when using PET-derived measures of aridity, but declines to 41% when total soil moisture aridity indicator is employed. This reduction mainly occurs because plant stomatal resistance increases under enhanced CO2 concentrations, which results in improved plant water use efficiency, and hence reduced evapotranspiration and soil desiccation. Imposing CO2-invariant stomatal resistance may overestimate future drying in PET-derived indices. PMID- 29977105 TI - Live Imaging Mitochondrial Transport in Neurons. AB - Mitochondria are among a cell's most vital organelles. They not only produce the majority of the cell's ATP but also play a key role in Ca2+ buffering and apoptotic signaling. While proper allocation of mitochondria is critical to all cells, it is particularly important for the highly polarized neurons. Because mitochondria are mainly synthesized in the soma, they must be transported long distances to be distributed to the far-flung reaches of the neuron-up to 1 m in the case of some human motor neurons. Furthermore, damaged mitochondria can be detrimental to neuronal health, causing oxidative stress and even cell death, therefore the retrograde transport of damaged mitochondria back to the soma for proper disposal, as well as the anterograde transport of fresh mitochondria from the soma to repair damage, are equally critical. Intriguingly, errors in mitochondrial transport have been increasingly implicated in neurological disorders. Here, we describe how to investigate mitochondrial transport in three complementary neuronal systems: cultured induced pluripotent stem cell-derived neurons, cultured rat hippocampal and cortical neurons, and Drosophila larval neurons in vivo. These models allow us to uncover the molecular and cellular mechanisms underlying transport issues that may occur under physiological or pathological conditions. PMID- 29977107 TI - alpha-Vinylic Amino Acids: Occurrence, Asymmetric Synthesis and Biochemical Mechanisms. AB - This report presents an overview of the family of naturally occurring 'vinylic' amino acids, namely those that feature a C-C double bond directly attached to the alpha-carbon, along the side chain. Strategies that have been brought to bear on the stereocontrolled synthesis of these olefinic amino acids are surveyed. The mechanistic diversity by which such 'vinylic triggers' can be actuated in a PLP (pyridoxal phosphate) enzyme active site is then highlighted by discussions of vinylglycine (VG), its substituted congeners, particularly AVG [4E-(2' aminoethoxy)vinylglycine], and a naturally occurring VG-progenitor, SMM (S methylmethionine). PMID- 29977108 TI - Collaboration in Action: Measuring and Improving Contracting Performance in the University of California Contracting Network. AB - In 2013, the University of California, Biomedical Research, Acceleration, Integration, and Development (UC BRAID) convened a regional network of contracting directors from the five University of California (UC) health campuses to: (i) increase collaboration, (ii) operationalize and measure common metrics as a basis for performance improvement efforts, and (iii) identify and implement best practices to maintain a competitive edge in the field of biomedical research. This article summarizes an 18-month examination of performance metrics across the five campuses, including methods for data collection and harmonization agreed upon by the UC contracting offices. Some of the most striking, and previously unmeasured, results demonstrate that master agreements are a highly effective and successful strategy for significantly shortening the average time to completion of contract terms. Interestingly, clinical research organizations (CROs) significantly increase the time required to negotiate a contract. Results also point to the intra- and inter-organizational dependencies affecting time to contract execution. Systematic and transparent data collection among UC stakeholders is necessary to continue improvements to the system. However, data collection is only one component of the larger need to develop shared technology both within and between institutions. This study demonstrates that collaboration and sharing of contract terms is an effective way to reduce study activation time, but the greatest improvements will be driven by the sharing of data and technology tools. PMID- 29977109 TI - A Posterior Approach to Laparoscopic Sacrospinous Ligament Suspension. AB - Background and Objectives: Laparoscopic sacrospinous ligament suspension, as commonly performed, is associated with extensive stripping, high risk of intraoperative bleeding, and prolonged operative time. We explore the safety and feasibility of posterior laparoscopic approach sacrospinous ligament suspension (LPASLS) in the treatment of pelvic organ prolapse (POP). Methods: We retrospectively analyzed the clinical data of 9 patients with symptomatic POP treated intraoperatively with LPASLS at the Women's and Children's Health Centre, The Third Affiliated Hospital of Chongqing Medical University, between November 2016 and July 2017. Regular follow-up was performed at 1, 3, and 6 months after the operation. Subjective cure was considered as the absence of any postoperative subjective symptoms, and objective cure was considered as a postoperative POP-Q grade of 0. Results: All operations were completed successfully. The operative time ranged from 90 to 140 (mean, 117.78 +/- 20.01) minutes, and the mean suspension time was about 30 minutes. The intraoperative estimated blood loss ranged from 30 to 100 (range, 54.9 +/- 24.2) mL, and pelvic vascular injury occurred in 1 patient. Postoperative sacrococcygeal pain occurred in 5 patients, and Visual Analog Scale scores ranged from 3 to 4 (mean, 3.4 +/- 0.5). The symptom disappeared without any treatment after 3-4 d. Patients were followed up for 3-10 (mean, 6.3 +/- 2.1) months, and the subjective and objective cure rates were both 100%. Conclusion: LPASLS is safe and feasible and may be considered as an alternative approach to traditional laparoscopic sacrospinous ligament suspension. PMID- 29977110 TI - A Sling Technique for Laparoscopic Resection of Segment Seven of the Liver. AB - Introduction: As the incidence of liver cancer continues to increase in the setting of cirrhosis, parenchyma-sparing liver resection is increasingly necessary. A technique is described that involves using a sling made from 1-inch wide packing gauze to retract and rotate the liver to divide the right triangular and coronary ligaments and mobilize segment 7. The right lobe is rotated anteriorly and counterclockwise, allowing access and parenchymal transection of segment 7 under ultrasonographic guidance. Case Presentation: Seven patients with tumors in segment 7 underwent resection with the technique described above: 4 had Child's A cirrhosis and hepatocellular carcinoma (HCC), 1 had metastatic colon cancer, 1 had an adenoma, and 1 had a symptomatic hemangioma. Tumor size ranged between 2.5 and 7.7 cm. Blood loss during resection was between 150 and 500 mL. No patients required transfusion as a result of surgery. With the exception of 1 patient with Clostridium difficile colitis, the average hospital stay was 3.8 days. Management and Outcome: Parenchyma-sparing laparoscopic resection of segment 7 is feasible and can be safely performed using a sling for intracorporal hepatic retraction, manipulation, and positioning. Given the risk of HCC recurrence, laparoscopic liver resection may also be better suited for subsequent salvage liver transplant because of less perihepatic adhesions. PMID- 29977111 TI - Novel Method of 3-Dimensional Graphical Representation for Proteins and Its Application. AB - In this article, we propose a 3-dimensional graphical representation of protein sequences based on 10 physicochemical properties of 20 amino acids and the BLOSUM62 matrix. It contains evolutionary information and provides intuitive visualization. To further analyze the similarity of proteins, we extract a specific vector from the graphical representation curve. The vector is used to calculate the similarity distance between 2 protein sequences. To prove the effectiveness of our approach, we apply it to 3 real data sets. The results are consistent with the known evolution fact and show that our method is effective in phylogenetic analysis. PMID- 29977112 TI - High Frequency of Extractable Nuclear Autoantibodies in Wheat-Related Disorders. AB - Background and aims: There has been broad interest to explore the presence of autoimmunity among wheat-sensitive individuals, but neither the pathogenesis nor the relevance has been established. In this study, we evaluated the frequencies and levels of autoantibodies, which are important biomarkers of autoimmunity, in subjects with wheat-related disorders and controls. Anti-nuclear antibodies (ANA) and the specific ones against extractable nuclear antigens (ENA) were investigated. Methods: A total of 713 subjects who showed symptoms related to wheat ingestion were addressed to Vibrant America Clinical Laboratory from December 2015 to November 2017. Serum samples were collected from all subjects and tested with a wheat protein antibody panel (IgG and IgA to 18 proteins at the peptide level) and an autoantibody panel (ANA by immunofluorescence analysis and 10 ENA antibodies). Retrospective analysis was completed using de-identified clinical data and test results. Results: In the retrospective analysis, 38 (5%) were seropositive in a Celiac Disease panel, 491 (83%) were seropositive in a wheat protein antibody panel "Wheat Zoomer," and 84 (12%) were seronegative in both panels. Anti-nuclear antibodies were detected in similar portions of the celiac disease subjects (13%), the Wheat Zoomer-positive subjects (12%), and seronegative controls (15%), which is also very close to the reported occurrence of ANA positivity (15%) in the healthy population. The prevalence of anti-ENA was reported to be less than 2% in the general population; however, our study found it to be much higher in the celiac disease subjects (29%) and the wheat-sensitive subjects (27%), compared with a smaller proportion of seronegative controls (19%). The prevalence of anti-histone was especially prominent among the celiac disease subjects (73%) and the Wheat Zoomer-positive subjects (60%). Conclusions: High proportions of wheat-related disease subjects carry ENA antibodies that are important specific biomarkers of autoimmunity. PMID- 29977113 TI - Change in Breast Cancer Screening Knowledge is Associated With Change in Mammogram Intention in Mexican-Origin Women After an Educational Intervention. AB - Purpose: To determine the relationship between breast cancer screening knowledge and intent to receive a mammogram within 6 months in a sample of Mexican-origin women living in El Paso, Texas. Methods: A total of 489 uninsured Mexican-origin women were assigned to treatment or control and completed surveys at pre- and postintervention. Pre-post associations between breast cancer screening knowledge and intent were tested. Results: Participants were on average were 56.7 years of age and spoke primarily Spanish (92.6%). Most of the samples had not had a mammogram in 3 or more years (51.6%) and 14.6% had never had a mammogram. At baseline, the majority intended to be screened for breast cancer within the next 6 months (93.4%). At postintervention, half of the intervention group changed their 6-month intent to be screened for breast cancer from likely to unlikely. Change in intent was associated with a change in knowledge of risk of having a first child by the age of 30 and breast cancer being rare after the age of 70. Discussion: Intent to be screened for breast cancer in Mexican-origin women may be influenced by the type of knowledge. Conclusions: Change in screening knowledge may influence perceived risk that influences intention to be screened. PMID- 29977114 TI - "Getting Under the Hood" of Neuronal Signaling in Caenorhabditis elegans. AB - Caenorhabditis elegans is a powerful model to study the neural and biochemical basis of behavior. It combines a small, completely mapped nervous system, powerful genetic tools, and a transparent cuticle, allowing Ca++ imaging without the need for dissection. However, these approaches remain one step removed from direct pharmacological and physiological characterization of individual neurons. Much can still be learned by "getting under the hood" or breaching the cuticle and directly studying the neurons. For example, we recently combined electrophysiology, Ca++ imaging, and pharmacological analysis on partially dissected ASH nociceptors showing that serotonin (5-HT) potentiates depolarization by inhibiting Ca++ influx. This study challenges the tacit assumption that Ca++ transient amplitudes and depolarization strength are positively correlated and has validated a new paradigm for interpreting Ca++ signals. Bypassing the cuticle was critical for the success of these experiments, not only for performing electrical recordings but also for the acute and reversible application of drugs. By contrast, drug soaking or mutating genes can produce long-term effects and compensatory changes, potentially confounding interpretations significantly. Therefore, direct studies of the physiological response of individual neurons should remain a critical objective, to provide key molecular insights complementing global Ca++ imaging neural network studies. PMID- 29977115 TI - Social Hierarchy Representation in the Primate Amygdala Reflects the Emotional Ambiguity of Our Social Interactions. AB - Group living can help individuals defend against predators and acquire nutrition. However, conflicts between group members can arise (food sharing, mating, etc), requiring individuals to know the social status of each member to promote survival. In our recent paper, we sought to understand how the brain represents the social status of monkeys living in the same colony. Primates learn the social status of their peers through experience, including observation and direct interactions, just like they learn the rewarding or aversive nature of stimuli that predict different types of reinforcement. Group members may thereby be viewed as differing in value. We found in the amygdala, a brain area specialized for emotion, a neural representation of social hierarchy embedded in the same neuronal ensemble engaged in the assignment of motivational significance to previously neutral stimuli. Interestingly, we found 2 subpopulations of amygdala neurons encoding the social status of individuals in an opposite manner. In response to a stimulus, one population encodes similarly appetitive nonsocial images and dominant monkeys as well as aversive nonsocial stimuli and submissive monkeys. The other population encodes the opposite pattern later in time. This mechanism could reflect the emotional ambiguity we face in social situations as each interaction is potentially positive (eg, food access, protection, promotion) or negative (eg, aggression, bullying). PMID- 29977116 TI - Circulating MicroRNAs as Biomarkers in Diffuse Large B-cell Lymphoma: A Pilot Prospective Longitudinal Clinical Study. AB - Objectives: Diffuse large B-cell lymphoma (DLBCL) is highly heterogeneous in terms of phenotype and treatment response in patients. These characteristics make the prognosis difficult to establish and hinder the use of new personalized treatments in clinical practice. In this context, there is currently a need to define new biomarkers enabling a better definition of DLBCL subtypes, prognosis evaluation, and an overview of the resistance to chemotherapeutics. The aim of this study was to evaluate the use of microRNAs found in plasma from patients with DLBCL as biomarkers of tumor evolution in these patients. Method: For this purpose, a plasma biobank was created with samples from patients with DLBCL. The evolution of the level of selected microRNAs during treatment has been studied. A total of 19 patients with DLBCL were included in this pilot mono-centered study and a total of 68 samples were analyzed. Results: The first step of this study was the selection of the microRNAs to be quantified in all the samples of the biobank and that could potentially be used as biomarkers. To this end, quantification of 377 microRNAs was performed on the plasma samples of 2 selected patients with DLBCL and 1 healthy donor with no history of cancer. Among the 377 microRNAs evaluated, 7 were selected and analyzed in the entire biobank. Conclusions: This study highlighted 5 circulating microRNAs whose plasma levels would be worth further investigating for the characterization of DLBCL evolution in patients. MiR-21 and miR-197 had a significant higher plasmatic level in patients with tumors unresponsive to treatment. With a higher plasma level in patients with complete remission, miR-19b, miR-20a, and miR-451 could enable to differentiate, at the remission review, patients with residual tumor, from patients with complete remission. PMID- 29977117 TI - Short-Term Outcomes in Treatment of Knee Osteoarthritis With 4 Bone Marrow Concentrate Injections. AB - Background: Preliminary research suggests that bone marrow concentrate (BMC), which contains mesenchymal stem cells and platelets, is a promising treatment for knee osteoarthritis. The aim of this study was to build on this preliminary research by reporting the short-term progress of 15 patients (20 knees) with knee osteoarthritis through 4 BMC treatments. Methods: Patients underwent four sequential BMC treatments with mean injection times of 13.80 days after the first treatment, 21.40 days after the second treatment, and 33.50 days after the third treatment. The last follow-up was conducted a mean 86 days after the first treatment. Baseline and posttreatment outcomes of resting pain, active pain, lower functionality scale, and overall improvement percentage were compared after each treatment. Results: Patients experienced statistically significant improvements in active pain and functionality score after the first treatment. Additionally, patients experienced a mean decrease in resting pain after the first treatment, yet outcomes were not statistically significant until after the second treatment. On average, patients experienced an 84.31% decrease in resting pain, a 61.95% decrease in active pain, and a 55.68% increase in functionality score at the final follow-up. Patients also reported a mean 67% total overall improvement at study conclusion. Outcomes at the final follow-up after the fourth treatment were statistically significant compared to outcomes at baseline, after first treatment, after second treatment, and after third treatment. Conclusions: These results are promising, and additional research with a larger sample size and longer follow-up is needed to further examine the treatment effectiveness of multiple BMC injections for knee osteoarthritis. PMID- 29977118 TI - Safety and Predictive Factors of Short-Term Efficacy of a Single Injection of Mannitol-Modified Cross-Linked Hyaluronic Acid in Patients with Trapeziometacarpal Osteoarthritis. Results of a Multicentre Prospective Open Label Pilot Study (INSTINCT Trial). AB - Purpose: To assess safety and search predictive factors of efficacy of a single intra-articular injection of a mannitol-modified hyaluronic acid (HA) viscosupplement, in patients having trapeziometacarpal (TMC) osteoarthritis (OA). Methods: Patients with symptomatic TMC OA, not adequately relieved by analgesic therapy and/or by the use of a thumb splint, were included in a 3-month prospective multicentre open-label trial. All underwent plain radiographs with the Kapandji incidences allowing the Dell radiological grade assessment (1-4). Primary end point was the variation between injection (D0) and day 90 (D90) of the thumb pain (11-point Likert scale). Treatment consisted in a single injection of 0.6 to 1 mL of a viscosupplement made of a cross-linked HA combined with mannitol. All injections were performed under imaging guidance. Predictive factors of pain decrease were studied in univariate and multivariate analysis. Results: A total of 122 patients (76% women, mean age 60, mean disease duration 36 months) were included and 120 (98%) were assessed at 3 months. The TMC OA was of Dell's grade 1, 2, 3, and 4 in 23%, 36.8%, 36.8%, and 3.5% of cases, respectively. At D0, the average (SD) pain level was 6.5 +/- 1.6 without significant difference between Dell groups (P = .21). At day 90, pain decreased from 6.5 +/- 1.6 to 3.9 +/- 2.5 (difference -2.7 +/- 2.5; -42%; P < .0001) without significant difference between Dell grade (P = .055), despite a seemingly smaller number of responders in stage 2 patients. The average analgesic consumption decreased in more than 1 out of 2 patients. In multivariate analysis, no predictor of response was identified. There was no safety issue. All adverse events (11%) were transient increase in pain during or following HA administration and resolved without sequel within 1 to 7 days. Conclusions: This study suggests that a single course of HANOX-M-XL injection is effective in relieving pain in patients with TMC OA, without safety concern. Patients with advanced stage of OA benefit the treatment as much as those with mild or moderate OA. PMID- 29977119 TI - Total Knee Arthroplasty for Chronic Anterior Knee Dislocation. AB - Background: The occurrence of chronic knee dislocation is rare. To the best of our knowledge, total knee arthroplasty for treatment of chronic anterior knee dislocation has not been reported. Method: This report describes 3 cases of chronic anterior knee dislocation treated by total knee arthroplasty. Results: Three female patients with chronic anterior knee dislocation were treated by hinged prosthesis total knee arthroplasty using the Insall rectus snip approach. At a mean of 17 months (range, 12-24 months) of follow-up, all patients showed a painless stable prosthesis and expressed satisfaction with the results. Conclusions: Total knee arthroplasty for chronic anterior knee dislocation is a challenging procedure. The Insall rectus snip approach with quadriceps release and constrained prosthesis is recommended. PMID- 29977120 TI - A Single-Centre Experience on the Management of Adenosarcoma: A Successful Report of an Integrated Medical and Surgical Approach. AB - Adenosarcomas are the rarest form of uterine sarcomas, and clinical experience with their management is still limited. Here, we reported 7 patients with uterine adenosarcoma referred to our institution, focusing on main pathologic features, their medical history, and long-term follow-up. Among these patients, we provided a detailed description of the medical history of a 49-year-old woman with advanced uterine adenosarcoma with sarcomatous overgrowth who presented a brilliant radiologic and pathologic response after 3 cycles of epirubicin and ifosfamide, ultimately achieving an extraordinary long-term outcome through an integrated surgical and medical approach. Our single-centre experience would suggest that aggressive uterine adenosarcomas with sarcomatous overgrowth are sensitive to standard epirubicin and ifosfamide and that an integrated approach, both medical and surgical, could be considered in clinical practice, again emphasizing the relevant role of multidisciplinary management for this extremely rare disease. PMID- 29977121 TI - Development and Optimization of a Fluorescent Imaging System to Detect Amyloid beta Proteins: Phantom Study. AB - Alzheimer disease is the most common form of dementia, affecting more than 5 million people in the United States. During the progression of Alzheimer disease, a particular protein begins to accumulate in the brain and also in extensions of the brain, ie, the retina. This protein, amyloid-beta (Abeta), exhibits fluorescent properties. The purpose of this research article is to explore the implications of designing a fluorescent imaging system able to detect Abeta proteins in the retina. We designed and implemented a fluorescent imaging system with a range of applications that can be reconfigured on a fluorophore to fluorophore basis and tested its feasibility and capabilities using Cy5 and CRANAD-2 imaging probes. The results indicate a promising potential for the imaging system to be used to study the Abeta biomarker. A performance evaluation involving ex vivo and in vivo experiments is planned for future study. PMID- 29977122 TI - PCR-based detection of Plasmodium falciparum in saliva using mitochondrial cox3 and varATS primers. AB - Background: Sampling of saliva for diagnosing Plasmodium falciparum infections is a safe, non-invasive alternative to sampling of blood. However, the use of saliva presents a challenge because lower concentrations of parasite DNA are present in saliva compared to peripheral blood. Therefore, a sensitive method is needed for detection of parasite DNA in saliva. This study utilized two recently reported "ultra-sensitive" PCR assays based on detection of the P. falciparum mitochondrial cox3 gene and the multi-copy nuclear varATS gene. The ultra sensitive assays have an advantage over standard 18S rRNA gene-based PCR assay as they target genes with higher copy numbers per parasite genome. Stored saliva DNA samples from 60 Cameroonian individuals with infections previously confirmed by 18S rRNA gene PCR in peripheral blood were tested with assays targeting the cox3 and varATS genes. Results: Overall, the standard 18S rRNA gene-based PCR assay detected P. falciparum DNA in 62% of the stored saliva DNA samples, whereas 77 and 68% of the samples were positive with assays that target the cox3 and varATS genes, respectively. Interestingly, the ultra-sensitive assays detected more P. falciparum infections in stored saliva samples than were originally detected by thick-film microscopy (41/60 = 68%). When stratified by number of parasites in the blood, the cox3 assay successfully detected more than 90% of infections using saliva when individuals had > 1000 parasites/MUl of peripheral blood, but sensitivity was reduced at submicroscopic parasitemia levels. Bands on electrophoresis gels were distinct for the cox3 assay, whereas faint or non specific bands were sometimes observed for varATS and 18S rRNA that made interpretation of results difficult. Assays could be completed in 3.5 and 3 h for the cox3 and varATS assays, respectively, whereas the 18S rRNA gene assays required at least 7 h. Conclusions: This study demonstrates that a PCR assay targeting the cox3 gene detected P. falciparum DNA in more saliva samples than primers for the 18S rRNA gene. Non-invasive collection of saliva in combination with the proposed cox3 primer-based PCR assay could potentially enhance routine testing of P. falciparum during disease surveillance, monitoring, and evaluation of interventions for malaria elimination. PMID- 29977123 TI - Water-limited vegetated ecosystems driven by stochastic rainfall: feedbacks and bimodality. AB - In arid or semi-arid ecosystems, water availability is one of the primary controls on vegetation growth. When subsurface water resources are unavailable, the vegetation growth is dictated by the rainfall, and the random nature of the rainfall arrivals and quantities induces a probability distribution of soil moisture and vegetation biomass via the coupled dynamic equations of biomass balance and water balance. We have previously obtained an exact solution for these distributions under certain conditions, and shown that the mapping of rainfall variability to observed biomass variability can be successfully applied to a field site. Here, we expand upon our earlier theoretical work to show how the dynamics can give rise to more complicated, bimodal (and multimodal) structures in the biomass distribution when positive feedbacks between growth and water availability are included. We also derive some new analytical results for the crossing properties of this system, which enable us to determine on what time scale the effects of these feedbacks will be felt, and, relatedly, how long the system will take to cross between different modes. PMID- 29977124 TI - Nematic liquid crystals on curved surfaces: a thin film limit. AB - We consider a thin film limit of a Landau-de Gennes Q-tensor model. In the limiting process, we observe a continuous transition where the normal and tangential parts of the Q-tensor decouple and various intrinsic and extrinsic contributions emerge. The main properties of the thin film model, like uniaxiality and parameter phase space, are preserved in the limiting process. For the derived surface Landau-de Gennes model, we consider an L2-gradient flow. The resulting tensor-valued surface partial differential equation is numerically solved to demonstrate realizations of the tight coupling of elastic and bulk free energy with geometric properties. PMID- 29977125 TI - Exact eigenstates of a nanometric paraboloidal emitter and field emission quantities. AB - The progress in field emission theory from its initial Fowler-Nordheim form is centred on the transmission coefficient. For the supply (of electrons) function one still uses the constant value due to a supply of plane-waves states. However, for emitting tips of apex radius of 1-5 nm this is highly questionable. To address this issue, we have solved the Schrodinger equation in a sharp paraboloidally shaped quantum box. The Schrodinger equation is separable in the rotationally parabolic coordinate system and we hence obtain the exact eigenstates of the system. Significant differences from the usual Cartesian geometry are obtained. (1) Both the normally incident and parallel electron fluxes are functions of the angle to the emitter axis and affect the emission angle. (2) The WKB approximation fails for this system. (3) The eigenfunctions of the nanoemitter form a continuum only in one dimension while complete discretization occurs in the other two directions. (4) The parallel electron velocity vanishes at the apex which may explain the recent spot-size measurements in near-field scanning electron microscopy. (5) Competing effects are found as the tip radius decreases to 1 nm: The electric field increases but the total supply function decreases so that possibly an optimum radius exists. PMID- 29977126 TI - A no-go theorem for theories that decohere to quantum mechanics. AB - To date, there has been no experimental evidence that invalidates quantum theory. Yet it may only be an effective description of the world, in the same way that classical physics is an effective description of the quantum world. We ask whether there exists an operationally defined theory superseding quantum theory, but which reduces to it via a decoherence-like mechanism. We prove that no such post-quantum theory exists if it is demanded that it satisfy two natural physical principles: causality and purification. Causality formalizes the statement that information propagates from present to future, and purification that each state of incomplete information arises in an essentially unique way due to lack of information about an environment. Hence, our result can be viewed either as evidence that the fundamental theory of Nature is quantum or as showing in a rigorous manner that any post-quantum theory must abandon causality, purification or both. PMID- 29977127 TI - How realistic are painted lightnings? Quantitative comparison of the morphology of painted and real lightnings: a psychophysical approach. AB - Inspired by the pioneer work of the nineteenth century photographer, William Nicholson Jennings, we studied quantitatively how realistic painted lightnings are. In order to answer this question, we examined 100 paintings and 400 photographs of lightnings. We used our software package to process and evaluate the morphology of lightnings. Three morphological parameters of the main lightning branch were analysed: (i) number of branches Nb, (ii) relative length r, and (iii) number of local maxima (peaks) Np of the turning angle distribution. We concluded: (i) Painted lightnings differ from real ones in Nb and Np. (ii) The r-values of painted and real lightnings vary in the same range. (iii) 67 and 22% of the studied painted and real lightnings were non-bifurcating (Nb = 1, meaning only the main branch), the maximum of Nb of painted and real lightnings is 11 and 51, respectively, and painted bifurcating lightnings possess mostly 2-4 branches, while real lightnings have mostly 2-10 branches. To understand these findings, we performed two psychophysical experiments with 10 test persons, whose task was to guess Nb on photographs of real lightnings which were flashed for short time periods Deltat = 0.5, 0.75 and 1 s (characteristic to lightnings) on a monitor. We obtained that (i) test persons can estimate the number of lightning branches quite correctly if Nb <= 11. (ii) If Nb > 11, its value is strongly underestimated with exponentially increasing difference between the real and estimated numbers. (iii) The estimation is independent of the flashing period Deltat of lightning photos/pictures. (iv) The estimation is more accurate, if skeletonized lightning pictures are flashed, rather than real lightning photos. These findings explain why artists usually illustrate lightnings with branches not larger than 11. PMID- 29977128 TI - Force appropriation of nonlinear structures. AB - Nonlinear normal modes (NNMs) are widely used as a tool for developing mathematical models of nonlinear structures and understanding their dynamics. NNMs can be identified experimentally through a phase quadrature condition between the system response and the applied excitation. This paper demonstrates that this commonly used quadrature condition can give results that are significantly different from the true NNM, in particular, when the excitation applied to the system is limited to one input force, as is frequently used in practice. The system studied is a clamped-clamped cross-beam with two closely spaced modes. This paper shows that the regions where the quadrature condition is (in)accurate can be qualitatively captured by analysing transfer of energy between the modes of the system, leading to a discussion of the appropriate number of input forces and their locations across the structure. PMID- 29977129 TI - An asymptotic higher-order theory for rectangular beams. AB - A direct asymptotic integration of the full three-dimensional problem of elasticity is employed to derive a consistent governing equation for a beam with the rectangular cross section. The governing equation is consistent in the sense that it has the same long-wave low-frequency behaviour as the exact solution of the original three-dimensional problem. Performance of the new beam equation is illustrated by comparing its predictions against the results of direct finite element computations. Limiting behaviours for beams with large (and small) aspect ratios, which can be established using classical plate theories, are recovered from the new governing equation to illustrate its consistency and also to illustrate the importance of using plate theories with the correctly refined boundary conditions. The implications for the correct choice of the shear correction factor in Timoshenko's beam theory are also discussed. PMID- 29977130 TI - An algorithm to explore entanglement in small systems. AB - A quantum state's entanglement across a bipartite cut can be quantified with entanglement entropy or, more generally, Schmidt norms. Using only Schmidt decompositions, we present a simple iterative algorithm to maximize Schmidt norms. Depending on the choice of norm, the optimizing states maximize or minimize entanglement, possibly across several bipartite cuts at the same time and possibly only among states in a specified subspace. Recognizing that convergence but not success is certain, we use the algorithm to explore topics ranging from fermionic reduced density matrices and varieties of pure quantum states to absolutely maximally entangled states and minimal output entropy of channels. PMID- 29977131 TI - Critical curvature localization in graphene. I. Quantum-flexoelectricity effect. AB - Here, we report the discovery of a new, curvature-localizing, subcritical buckling mode that produces shallow-kink corrugation in multi-layer graphene. Our density functional theory (DFT) analysis reveals the mode configuration-an approximately 2 nm wide boundary layer of highly localized curvature that connects two regions of uniformly but oppositely sheared stacks of flat atomic sheets. The kink angle between the two regions is limited to a few degrees, ensuring elastic deformation. By contrast, a purely mechanical model of sandwich structures shows progressive supercritical curvature localization spread over a 50-100 nm wide boundary layer. Our effective-locality model of electromechanics reveals that coupling between atomic-layer curvature and electric-charge polarization, i.e. quantum flexoelectricity, leads to emergence of a boundary layer in which curvature is focused primarily within a 0.86 nm fixed band width. Both DFT and the model analyses show focused distributions of curvature and polarization exhibiting oscillating decay within the approximately 2 nm wide boundary layer. The results show that dipole-dipole interaction lowers the potential energy with such a distribution. Furthermore, this model predicts peak polarization density approximately 0.12 e- nm-1 for 3 degrees tilt angle. This high polarization concentration can be controlled by macroscopic deformation and is expected to be useful in studies of selective graphene-surface functionalization for various applications. PMID- 29977132 TI - Bond graph modelling of the cardiac action potential: implications for drift and non-unique steady states. AB - Mathematical models of cardiac action potentials have become increasingly important in the study of heart disease and pharmacology, but concerns linger over their robustness during long periods of simulation, in particular due to issues such as model drift and non-unique steady states. Previous studies have linked these to violation of conservation laws, but only explored those issues with respect to charge conservation in specific models. Here, we propose a general and systematic method of identifying conservation laws hidden in models of cardiac electrophysiology by using bond graphs, and develop a bond graph model of the cardiac action potential to study long-term behaviour. Bond graphs provide an explicit energy-based framework for modelling physical systems, which makes them well suited for examining conservation within electrophysiological models. We find that the charge conservation laws derived in previous studies are examples of the more general concept of a 'conserved moiety'. Conserved moieties explain model drift and non-unique steady states, generalizing the results from previous studies. The bond graph approach provides a rigorous method to check for drift and non-unique steady states in a wide range of cardiac action potential models, and can be extended to examine behaviours of other excitable systems. PMID- 29977133 TI - Treatment Patterns and Survival among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France. AB - Objective: To describe real-world treatment patterns and outcomes for patients with advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy in the United Kingdom, Spain, Germany, and France. Methods: Physicians completed a web-based medical record abstraction for adult patients with advanced STS (other than Kaposi's sarcoma or gastrointestinal stromal tumor) who received >=1 line of systemic therapy. Clinical characteristics, treatments, tumor responses, and mortality data were recorded. Results: A total of 130 physicians provided data for 807 patients. Patients' mean age at advanced STS diagnosis was 57.1 (+/ 12.3) years; 59% were male. The most commonly identified histologic categories were leiomyosarcoma (28%), liposarcoma (13%), and rhabdomyosarcoma (11%). Overall, 57% of patients received only 1 line of therapy, 32% received 2 lines of therapy, and 11% received >=3 lines of therapy. The most common first-line regimens were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%), and ifosfamide (4%). Median overall survival from start of treatment was estimated to be 17.6 months (95% confidence interval, 15.6-19.0 months). Conclusions: In real-world clinical practice, advanced STS is most commonly treated with older therapies in the United Kingdom, Spain, Germany, and France. New therapies that improve overall survival in advanced STS are needed. PMID- 29977134 TI - Continuous production process of retroviral vector for adoptive T- cell therapy. AB - Adoptive T-Cell therapy is being considered as a promising method for cancer treatment. In this approach, patient's T cells are isolated, modified, expanded, and administered back to the patient. Modifications may include adding specific T cell receptors (TCR) or chimeric antigen receptors (CAR) to the isolated cells by using retroviral vectors. PG13 cells, derivatives of NIH3T3 mouse fibroblasts, are being used to stably produce retroviral vectors that transduce the T cells. PG13 cells are anchorage-dependent cells that grow in roller bottles or cell factories and lately also in fixed bed bioreactors to produce the needed viral vector. To scale up viral vector production, PG13 cells were propagated on microcarriers in a stirred tank bioreactor utilizing an alternating tangential flow perfusion system. Microcarriers are 10 um - 0.5 mm beads that support the attachment of cells and are suspended in the bioreactor that provides controlled growth conditions. As a result, growth parameters, such as dissolved oxygen concentration, pH, and nutrients are monitored and continuously controlled. There were no detrimental effects on the specific viral vector titer or on the efficacy of the vector in transducing the T cells of several patients. Viral vector titer increased throughout the 11 days perfusion period, a total of 4.8 * 1011 transducing units (TU) were obtained with an average titer of 4.4 * 107 TU/mL and average specific productivity of 10.3 (TU) per cell, suggesting that this method can be an efficient way to produce large quantities of active vector suitable for clinical use. PMID- 29977135 TI - IS FUNCTIONAL OUTCOME BETTER AFTER ARTHROPLASTY FOR TROCHANTERIC FRACTURES IN OLDER ADULTS? AB - Objectives: This article evaluated functional recovery and mortality after surgery to repair trochanteric fracture with regard to treatment technique through one year of follow-up. Method: Eighty consecutive patients with trochanteric fractures were divided into two groups according to treatment technique (osteosynthesis and arthroplasty). We evaluated patient data including age, sex, time to surgery, total hospital stay, transfusion volume, and functional status according to FIM (Functional Independence Measure) scores. Scores for FIM were assessed three times: prior to fracture, six months after surgery, and one year after surgery. Results: Patients who received osteosynthesis had shorter hospital stays than arthroplasty patients. The arthroplasty group had significantly higher functional independence six months after surgery, while no difference was detected one year after surgery. Patient age, transfusion volume, and FIM scores were detected as significant predictors of mortality. Conclusion: Trochanteric fractures lead to unavoidable functional loss, although this can be reduced in the short term by treating with arthroplasty instead of osteosynthesis. Age, transfusion and functional situation predict one-year mortality for patients with trochanteric fractures. The patient's functional situation must be considered when choosing treatment for trochanteric fractures in order to reduce patient morbidity. Level of Evidence II; Therapeutic prospective study. PMID- 29977136 TI - TWO CLASSIFICATIONS FOR SURGICAL WOUND HEMATOMA AFTER TOTAL HIP REPLACEMENT. AB - Objective: To determine the reliability of two classification methods for wound hematoma after total hip replacement. Methods: This prospective cohort study was conducted on patients who underwent total hip replacement for hip osteoarthritis between May 2014 and April 2015. Epidemiological, surgical, and functional data were assessed. Two experienced hip surgeons evaluated 75 pictures of wounds taken 24 hours after surgery. Both evaluators performed the analysis twice, with a 6 week interval between the two analyses. The subjective classification was divided into four different categories describing the hematoma: absent, mild, moderate, and severe. The objective classification was derived from mathematical calculation of the area of the hematoma using a grid superimposed on a picture of the wound. Results: The subjective classification demonstrated an intra-rater agreement of more than 70%, while kappa values showed poor to moderate inter rater reliability. The objective classification based on mathematical measurements of the hematoma area was more reliable, with good to excellent intra and inter-rater reliability. Conclusion: The objective classification demonstrated higher intra- and inter-rater reliability. The classification methods used in this study could serve as a useful instrument for orthopedic surgeons, researchers, and health care providers when assessing wound hematomas after total hip replacement. Level of Evidence II; Development of diagnostic criteria on consecutive patients (with universally applied reference ''gold'' standard). PMID- 29977137 TI - AGREEMENT IN DIAGNOSIS OF KNEE INJURIES BY ORTHOPEDISTS WITH CLINICAL EXPERIENCE IN KNEE TREATMENT. AB - Objective: To analyze the level of agreement in diagnosing knee injury among orthopedists with clinical experience in knee treatment. Method: An online questionnaire was used to analyze the ability of orthopedic knee surgeons to diagnose intra-articular knee injuries using MRI, the importance given to this test in their clinical practice, and the agreement between these diagnoses and the radiology report. Results: The study participants considered MRI an important tool for clarifying inconclusive diagnoses and surgical planning. The level of agreement between the surgeons and the radiologist was considered to be very slight for posterior cruciate ligament injuries, collateral ligament injuries, and chondral injuries, and was considered slight for anterior cruciate ligament and meniscus injuries. Conclusion: A diagnosis of intra-articular knee injury must be based on the patient history, physical examination, and radiological imaging (MRI) in order to provide a complete approach to the patient. Level of Evidence III; Clinical study. PMID- 29977138 TI - INFLUENCE OF JOINT HIPERMOBILITY ON POSTOPERATIVE RESULTS OF KNEE SURGERY. AB - Objective: To evaluate the prevalence of joint hypermobility in patients undergoing knee surgery to treat traumatic injury to the meniscus and anterior cruciate ligament, and the influence of this hypermobility on postoperative results. Methods: This prospective study assessed joint hypermobility in patients who underwent surgical reconstruction of the anterior cruciate ligament (ACL), partial meniscectomy, or a procedure combining ACL reconstruction and partial meniscectomy during the period 2011-2015. The Beighton score was used to evaluate joint hypermobility and Tegner activity scale for postoperative assessment. Results: A total of 242 patients underwent surgery during the study period: 107 to treat ACL injuries, 75 to treat ACL injuries associated with meniscus injuries, and 60 to treat meniscus injuries. Of the total, 45 patients had joint hypermobility. We found no association between joint hypermobility and sex or type of injury. Postoperative Tegner scale results were not influenced by the presence of joint hypermobility. Conclusion: No association was found between joint hypermobility and the evaluated variables (gender and type of specific injury), and hypermobility did not have a negative impact on postoperative outcomes. Level of Evidence IV; Case series. PMID- 29977139 TI - FACTORS ASSOCIATED WITH THE DEVELOPMENT OF EARLY INFECTION AFTER SURGICAL TREATMENT OF FRACTURES. AB - Objective: Infection after the internal fixation of fractures is a major complication. Early infection is particularly challenging, because it occurs when the fracture is not yet united. The objective of this study is to identify possible factors related to the development of early infection in patients treated with internal fixation for fractures. Method: This retrospective observational study analyzed 24 patients with long bone fractures who underwent internal fixation and developed infections in the post-operatory period. The infections were classified as early (diagnosis in the first two weeks after surgery) or late (diagnosis after 2 weeks). Results: Of the 24 patients studied, 11 (46%) developed early infections and 13 (54%) were diagnosed with late infections. The early infection group was significantly younger (37.8 versus 53.1 [p = 0.05]) and underwent more surgeries prior to internal fixation (1.2 versus 0.2 [p < 0.00]). Conclusion: Risk factors for the development of early infection in the postoperative period should be considered when treating patients with internal fracture fixation in order to diagnose this condition as early as possible. Level of Evidence IV; Case series. PMID- 29977140 TI - RELATIONSHIP BETWEEN BONE MINERAL DENSITY AND BODY COMPOSITION IN ELDERLY. AB - Objective: To evaluate the association between bone mineral density (BMD) and body composition in healthy older adults at different skeletal sites. Methods: We analyzed 87 medical records and BMD along with the body composition of men ranging from 60 to 87 years of age (mean: 68.5, standard deviation: 6.5). Inclusion criteria were normal BMD values (T-score greater than or equal to -1.0) and body mass index within normal or overweight range (18.5 to 29.5 kg/m2). Body composition was evaluated using bone densitometry with dual-energy X-ray absorptiometry (DEXA) in a LUNAR-DPX apparatus. Results: Greater lean mass, fat mass, and soft tissue was associated with better BMD values in older adults, and higher age was associated with poorer BMD. Conclusion: Body composition (lean and fat masses and soft tissue) in older men is positively associated with BMD at all body sites (arms, legs, and trunk). Level of Evidence II; Prognostic studies - Investigating the effect of a patient characteristic on the outcome of disease. PMID- 29977141 TI - MODIFIED DEGA OSTEOTOMY IN TREATING DEVELOPMENTAL DYSPLASIA OF THE HIP. AB - Objective: To retrospectively evaluate the preliminary postoperative results of modified Dega-type acetabular osteotomy to treat developmental dysplasia of the hip, confirming the efficacy and reproducibility of this technique. Methods: This retrospective study included patients older than 18 months. A total of 19 hips underwent modified Dega osteotomy. Results: Satisfactory results were obtained, with an average decrease of the acetabular index from 39.2 to 20.6 degrees. The final average center edge angle was 29.6 degrees. Hip joint congruence was reestablished in all cases, and as of this writing, only one case developed necrosis in the femoral head during follow-up. Conclusion: Modified Dega osteotomy demonstrated good initial results, as well as the potential for use in treating developmental dysplasia of the hip. Level of Evidence IV; Case series. PMID- 29977142 TI - ANALYSIS OF MEDICAL ASSISTANCE PROVIDED TO SPECTATORS AT THE 2014 FIFA WORLD CUP MATCHES. AB - Objective: Several studies have already described the main injuries to soccer players during FIFA World Cup events; however, little is known about the main reasons spectators require medical assistance during these matches. The aim of this study is to assess the number of cases and main reasons spectators required medical assistance during the 2014 World Cup matches in Brazil. Methods: Data were collected from spectators who received medical assistance on all game days, and factors related to the assistance provided were analyzed. Results: Medical assistance was given to spectators in a total of 6,222 cases during the 64 games played in Brazil, an average of 97.2 times per game. The total number of spectators removed from the stadiums by ambulance was 167, a mean of 2.6 removals per game. The main reasons spectators required medical assistance during the World Cup games were headache, gastrointestinal problems, and trauma. Conclusions: Most spectators required medical assistance during the World Cup games for headache, gastrointestinal problems, and trauma; this information is fundamental to develop new prevention strategies and plan medical assistance for large-scale events. Level of Evidence IV; Case series. PMID- 29977143 TI - ARCADE OF FLEXOR DIGITORUM SUPERFICIALIS MUSCLE: ANATOMICAL STUDY AND CLINICAL IMPLICATIONS. AB - Objective: The arcade of the flexor digitorum superficialis muscle (FDS) is an anatomical structure which has not yet been widely studied and is a site of nerve compression. The aim of this study was to analyze the arcade of the FDS muscle and its relations with the median and anterior interosseous nerves through anatomic dissections. Method: Fifty arms from 25 adult cadavers (21 males and 4 females) were dissected; 18 were previously preserved in formalin and glycerin and 7 fresh specimens were dissected in the Laboratory of Anatomy. Results: The arcade of the superficial flexor muscle was identified in all dissected limbs. The radial and humeral heads were present in all specimens, and the ulnar head in 16 (32%). We identified two varieties of the arcade structure: a fibrous arcade in 32 specimens (64%), and a muscular arcade in 11 specimens (22%). In 4 specimens (8%) the arcade was very fine and so transparent that the nerve could be seen within the arcade. In 3 forearms the arcade was considered irregular because of discontinuity between the fibers that comprised this structure. Conclusion: The fibrous arcade of the FDS muscle may be a potential cause of nerve compression of the median and interosseous anterior nerves. Level of Evidence IV; Case series. PMID- 29977144 TI - EFFECT OF THE P.A.R.Q.V.E ON RHIZARTHRITIS. AB - Objective: To evaluate the effect of a clinical management program involving education on hand function in patients with rhizarthritis. Methods: One hundred and eight patients with rhizarthritis and multiple arthritis (191 hands with clinical and radiographic rhizarthritis) followed for two years as part of an educational program on osteoarthritis were administered the SF-36, DASH, and HAQ questionnaires and measured for the strength of their palmar grip, pulp to pulp pinch, key (lateral) pinch, and tripod pinch at the time of inclusion and after 24 months. Age, race, level and frequency of physical activity, sex, body mass index, percentage of body fat, and degree of osteoarthritis were correlated to the test outcomes. Results: Women improved less than men on the HAQ (p=0.037). Each 1% reduction in fat percentage increased the chance of HAQ score improvement by 9.2% (p=0.038). Physical activity did not influence improvement in the parameters evaluated (p>0.05). Palmar grip improvement was affected by age and presence of rhizarthritis (p<0.05); patients with unilateral rhizarthritis improved 5.3 times more than patients without the disease (p=0.015), while improvement in palmar grip strength decreased 6.8% per year (p=0.004). Pulp pinch grip strength improved more in women than in men (p=0.018). Conclusion: Patients with rhizarthritis and multiple arthritis improved quality of life and grip strength through clinical treatment, an educational program, and fat loss. Level of Evidence II; Retrospective study. PMID- 29977145 TI - HOW DO BOARD-CERTIFIED HAND SURGEONS MANAGE CARPAL TUNNEL SYNDROME? A NATIONAL SURVEY. AB - Objective: To evaluate tendencies in the planning, diagnosis, and treatment of carpal tunnel syndrome (CTS) by Brazilian hand surgery specialists. Methods: This cross-sectional study was performed at the 36th Brazilian Hand Surgery Congress. We prepared a questionnaire about preferences in the management of CTS, and board certified hand surgeons that attended the congress were asked to fill out the questionnaires. A total of 174 questionnaires were analyzed. Results: Electromyography examination is used by most surgeons. Night splinting is the most commonly used conservative treatment option. Half of the surgeons utilized prophylactic antibiotics. Most of the interviewees conduct inpatient surgery in the operating room and prefer intravenous regional anesthesia. Most of surgeons use the standard open technique associated with proximal release of the antebrachial fascia and do not perform neurolysis. Compressive dressings are most commonly used for 7 days. Conclusion: The approach to CTS among Brazilian hand surgeons with regard to pre-, intra-, and post-operatory conduct is consistent with the international literature. However, there is a need to reflect and conduct new studies on non-surgical treatment involving local corticosteroid injection, use of prophylactic antibiotics, hospital admission, and type of anesthesia in order to provide more cost-effective approach to surgical treatment for CTS. Level of Evidence V; Expert opinion. PMID- 29977146 TI - PROPOSAL TOMOGRAPHIC CLASSIFICATION FOR INTRA-ARTICULAR DISTAL RADIUS FRACTURES. AB - Objective: The objective of this study was to present a proposal tomographic classification for intra-articular distal radius fractures. Methods: This descriptive study was based on observing tomographic images from 74 patients with distal radius fractures. The cases were grouped by similarity according to the presence of several parameters which determine fracture complexity; the results of the descriptive analysis were transcribed as tomographic classification. Results: The proposal tomographic classification for intra-articular distal radius fractures comprised three major groups and nine sub-groups, which are organized by increasing severity according to the presence of spacing between articular fragments, angulation, loss of radial height, cortical depression, and associated dislocation. Conclusion: This proposal tomographic classification for intra-articular distal radius fractures can help professionals indicate therapeutic options. Level of Evidence IV; Case series. PMID- 29977147 TI - EVALUATION OF A BONE REINFORCEMENT TECHNIQUE USING FINITE ELEMENT ANALYSIS. AB - Objectives: To compare the results of a simulated fall on the greater trochanter in the proximal portion of a synthetic femur before and after femoral reinforcement with tricalcium phosphate bone cement (TP) and polymethyl methacrylate (PMMA), using finite element analysis (FEA). Methods: Using two synthetic proximal femurs, a FEA simulating a fall on the greater trochanter was performed, using the Bi-directional Evolutionary Structural Optimization (BESO) program. For this analysis, the femurs were filled with TP and PMMA after perforations were created in the trochanteric region and neck. The results were compared with the strength values obtained from testing the control specimen, a synthetic bone without reinforcement. Results: FEA showed a value of 600 N prior to reinforcement. After cementing with PMMA, the load increased by 57.5% (945 N), and by 53% (920 N) after cementing with TP. Conclusion: Synthetic femurs gained resistance to fracture-causing forces in a simulated fall on the trochanter after bone reinforcement with PMMA and TP. Level of Evidence III; Experimental study. PMID- 29977148 TI - EFFICACY OF TRANEXAMIC ACID IN REDUCING BLOOD LOSS IN TOTAL KNEE ARTHROPLASTY. AB - Objective: To evaluate the efficacy of tranexamic acid in reducing blood loss in total knee arthroplasty by examining the existing literature. Method: This literature review investigated the use of tranexamic acid in knee arthroplasty. The search was performed in the Pubmed, Science Direct, Google Scholar, and Lilacs databases over a 20-year period using the keywords: "knee arthroplasty, tranexamic acid, and efficacy". Only randomized clinical trials published between 2000 and 2016 in English, Spanish, or Portuguese were accepted, and only trials which scored above 3 on the Jadad scale were selected. Results: A total of 7 randomized clinical trials met the inclusion criteria, with a sample of 948 patients. Conclusion: The use of tranexamic acid in total knee arthroplasty (unilateral or bilateral) reduces perioperative and postoperative blood loss more than other available antifibrinolytics. With this reduction in total blood loss and the need for blood transfusions without any increase in side effects, the use of tranexamic acid can be considered safe and effective in controlling bleeding after knee arthroplasties. Level of Evidence II; Systematic review. PMID- 29977149 TI - COULD OZONE TREATMENT BE A PROMISING ALTERNATIVE FOR OSTEOMYELITIS? AN EXPERIMENTAL STUDY. AB - Objective: The aim of the present study was to investigate the biochemical and histopathological impact of ozone treatment in an experimental model of osteomyelitis in rats. Methods: A total of 24 adult male Sprague-Dawley rats (3 months old, each weighing 300 to 400 g) were randomly allocated into three groups. Group I (n=8) served as a control and received no interventions or medications. In Group II (n=8), osteomyelitis was induced in the femur and no treatment was applied. Group III (n=8) received intraperitoneal ozone treatment for 3 weeks after the formation of osteomyelitis in the femur. Serum samples were taken to assess total antioxidant capacity (TAC), protein carbonyl content (PCO), and lactate dehydrogenase (LDH). Bone specimens obtained from the femur were histopathologically evaluated for inflammation, necrosis, osteomyelitis, and abscess formation. Results: Serum TAC levels were notably higher (p<0.001), while LDH levels were lower (p=0.002) in Group III than Group II. No significant difference was detected between groups with respect to PCO level. Similarly, Group III displayed more favorable histopathological outcomes with respect to osteomyelitis (p=0.008), inflammation (p=0.001), necrosis (p=0.022), and abscess formation (p=0.022). Conclusion: Ozone may be a useful adjunct treatment for osteomyelitis. Further studies in animals and humans are needed to clarify and confirm these preventive effects, understand the underlying pathophysiology, and establish guidelines. Level of Evidence II; Prospective comparative study. PMID- 29977150 TI - METHOD FOR REMOVING BROKEN PROXIMAL FEMORAL NAILS USING EXISTING SCREW HOLE. AB - The use of intramedullary nailing to treat proximal femoral fractures has increased in recent years. Nail breakage is a rare complication of intramedullary nailing of the femur, and generally occurs at the non-united fracture site. Removal of the distal fragment of a broken nail is a challenging problem. In this article, the authors describe the methods used to remove strongly fixed broken intramedullary nails. Level of Evidence IV; Case series. PMID- 29977152 TI - Restoring Inflammatory Mediator Balance after Sofosbuvir-Induced Viral Clearance in Patients with Chronic Hepatitis C. AB - This study aimed at analyzing circulating levels of inflammatory and profibrogenic cytokines in patients with hepatitis C virus (HCV) chronic infection undergoing therapy with direct-acting antiviral agents (DAA) and correlating these immune biomarkers with liver disease status. We studied 88 Brazilian monoinfected chronic hepatitis C patients receiving interferon- (IFN-) free sofosbuvir-based regimens for 12 or 24 weeks, followed-up before therapy initiation and three months after the end of treatment. Liver disease was determined by transient elastography, in addition to APRI and FIB-4 indexes. Analysis of 30 immune mediators was carried out by multiplex or enzymatic immunoassays. Sustained virological response rate was 98.9%. Serum levels of cytokines were increased in HCV-infected patients when compared to control group. CCL-2, CCL-3, CCL-4, CXCL-8, CXCL-10, IL-1beta, IL-15, IFN-gamma, IL-4, IL-10, TGF-beta, FGFb, and PAI-1 decreased significantly after antiviral therapy, reaching values similar to noninfected controls. TGF-beta and suPAR levels were associated with fibrosis/cirrhosis. Also, we observed amelioration in hepatic parameters after DAA treatment. Together, our results suggest that viral control induced by IFN-free DAA therapy restores inflammatory mediators in association with improvement in liver function. PMID- 29977151 TI - The Kat in the HAT: The Histone Acetyl Transferase Kat6b (MYST4) Is Downregulated in Murine Macrophages in Response to LPS. AB - Epigenetic modulators, including histone methylases, demethylases, and deacetylases, have been implicated previously in the regulation of classical and alternative macrophage activation pathways. In this study, we show that the histone acetyl transferase (HAT) Kat6B (MYST4) is strongly suppressed (>80%) in macrophages by lipopolysaccharide (LPS) (M1 activation), while Kat6A, its partner in the MOZ/MORF complex, is reciprocally upregulated. This pattern of expression is not altered by LPS together with the adenosine receptor agonist NECA (M2d activation). This is despite the observation that miR-487b, a putative regulator of Kat6B expression, is mildly stimulated by LPS, but strongly suppressed by LPS/NECA. Other members of the MYST family of HATs (Kat5, Kat7, and Kat8) are unaffected by LPS treatment. Using the pLightswitch 3'UTR reporter plasmid, the miR-487b binding site in the Kat6b 3'UTR was found to play a role in the LPS mediated suppression of Kat6B expression, but other as-yet unidentified factors are also involved. As Kat6B is a HAT that has the potential to modulate gene expression by its effects on chromatin accessibility, we are continuing our studies into the potential roles of this epigenetic modulator in macrophage activation pathways. PMID- 29977154 TI - When east meets west: a qualitative study of barriers and facilitators to evidence-based practice in Hunan China. AB - Background: Research into evidence-based practice has been extensively explored in nursing and there is strong recognition that the organizational context influences implementation. A range of barriers has been identified; however, the research has predominantly taken place in Western cultures, and there is little information about factors that influence evidence-based practice in China. The purpose of this study was to explore barriers and facilitators to evidence-based practice in Hunan province, a less developed region in China. Methods: A descriptive qualitative methodology was employed. Semi-structured interviews were conducted with staff nurses, head nurses and directors (n = 13). Interviews were translated into English and verified for accuracy by two bilingual researchers. Both Chinese and English data were simultaneously analyzed for themes related to factors related to the evidence to be implemented (Innovation), nurses' attitudes and beliefs (Potential Adopters), and the organizational setting (Practice Environment). Results: Barriers included lack of available evidence in Chinese, nurses' lack of understanding of what evidence-based practice means, and fear that patients will be angry about receiving care that is perceived as non traditional. Nurses believed evidence-based practice was to be used when clinical problems arose, and not as a routine way to practice. Facilitators included leadership support and the pervasiveness of web based social network services such as Baidu () for easy access to information. Conclusion: While several parallels to previous research were found, our study adds to the knowledge base about factors related to evidence-based practice in different contextual settings. Findings are important for international comparisons to develop strategies for nurses to provide evidence-based care. PMID- 29977153 TI - CD38 Deficiency Promotes Inflammatory Response through Activating Sirt1/NF-kappaB Mediated Inhibition of TLR2 Expression in Macrophages. AB - CD38 was first identified as a lymphocyte-specific antigen and then has been found to be widely expressed in a variety of cell types. The functions of CD38 are involved in numerous biological processes including immune responses. Here, we showed the downregulations of both TLR2 mRNA and protein in macrophages from CD38-/- mice and in CD38 knockdown RAW264.7 cells. Several NF-kappaB-binding motifs in the promoter region of the TLR2 gene were identified by the bioinformatics analysis and were confirmed by the luciferase activity assay with the different truncated TLR2 promoters. CD38 deficiency resulted in the reduction of NF-kappaB p65 and acetyl-NF-kappaB p65 (Ac-p65) levels as determined by Western blot. The expression of Sirt1 did not change, but an increased activity of Sirt1 was observed in CD38-deficient macrophages. Inhibition of the Sirt1/NF kappaB signaling pathway resulted in downregulation of TLR2 expression in RAW264.7 cells. However, re-expression of CD38 in the knockdown clones reversed the effect on Sirt1/NF-kappaB/TLR2 signaling, which is NAD-dependent. Moreover, the inflammatory cytokines including G-CSF, IL-1alpha, IL-6, MCP-1, MIP-1alpha, and RANTES were increased in CD38 knockdown RAW264.7 cells. Taken together, our data demonstrated that CD38 deficiency enhances inflammatory response in macrophages, and the mechanism may be partly associated with increased Sirt1 activity, which promoted NF-kappaB deacetylation and then inhibited expression of the TLR2 gene. Obviously, our study may provide an insight into the molecular mechanisms in CD38-mediated inflammation. PMID- 29977155 TI - Physical and mental determinants of dropout and retention among nursing students: protocol of the SPRiNG cohort study. AB - Background: The shortage of nursing professionals is of growing concern. The causes of this include the demanding physical and mental workload, leading to a dropout of nurses that may start during their education. However, it is unclear to what extent nursing students already perceive a physical and mental workload leading to health problems during their nursing education and placement, and to what extent these health problems cause students to dropout from nursing education. Very few prospective cohort studies have investigated protective and risk factors in relation to dropout and retention among nursing students. Methods: Three cohorts of third-year nursing students will be followed for 2.5 years. Students will be enrolled from the Bachelor of Nursing program of the Rotterdam University of Applied Sciences. At baseline, students will receive a self-administered questionnaire. Primary outcome is dropout from nursing education and dropout from the nursing profession. Data on dropout from nursing education will be retrieved from the student administration on a yearly basis. Dropout from the nursing profession will be measured one year after graduation, using the self-reported questionnaire. Secondary outcomes are presenteeism and sick leave (during internship/work). In addition to student characteristics, the questionnaire asks about physical and mental internship/work characteristics, personal and behavioral factors, and experienced physical and mental burden.Main aims of this study are to determine: 1) the prevalence and incidence rates of dropout, 2) the protective and risk factors, and early indicators of dropout, and 3) the interaction between these factors and the indicators. Discussion: Data analysis of a large, prospective cohort study with regard to determinants of dropout and retention of nursing students and newly graduated nurses is in progress. Findings emerging from this study can be used to develop a predictive model to identify the first indicators of dropout from nursing education and nursing profession, for which targeted interventions can be deployed. PMID- 29977156 TI - The expression of protease-activated receptors in esophageal carcinoma cells: the relationship between changes in gene expression and cell proliferation, apoptosis in vitro and growing ability in vivo. AB - Background: Protease-activated receptors (PARs) are a family of four G protein coupled receptors expressed widely in many types of cells. PAR1, 2, and 4 have been shown to play an important role in many of the physiological activities of cells and many types of cancer cells. Esophageal carcinoma has become the fourth most common clinically diagnosed cancer and one of the top three leading causes of cancer-related deaths in China. The functions and expression patterns of PAR1, 2, and 4 in esophageal carcinoma have not published previously. Methods: Here, we systematically studied the expression of PAR1, 2, and 4 in clinical esophageal carcinoma patients and determined their role in esophageal carcinoma in vivo and in vitro through the overexpression or knockdown of PAR1, 2, and 4. Results: We found that the expression of PAR1 and 2 expressed higher in esophageal carcinoma than in the paracarcinoma tissues on clinical patients. PAR1 and 2 enhanced cell proliferation both in vivo and in vitro and reduced apoptosis to strengthen cancer cell vitality in TE-1 cells. In contrast, the expression of PAR4 expressed decreased in esophageal carcinoma, and its expression induced apoptosis in vivo and vitro. Conclusion: In our previous studies and the present study, we noted that the expression of PAR1, 2, and 4 was almost absent in different stages of esophageal carcinoma. PAR1 and 2 might be potential molecular markers for esophageal carcinoma, and PAR4 might be an effective treatment target for esophageal carcinoma prevention and treatment. PMID- 29977157 TI - Harmine, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor induces caspase-mediated apoptosis in neuroblastoma. AB - Background: Neuroblastoma (NB) is an early childhood malignancy that arises from the developing sympathetic nervous system. Harmine is a tricyclic beta-carboline alkaloid isolated from the harmal plant that exhibits both cytostatic and cytotoxic effects. Harmine is capable of blocking the activities of dual specificity tyrosine phosphorylation-regulated kinase (DYRK) family proteins and mitogen-activated protein kinase. These kinases promote proliferation and inhibit apoptosis. Methods: Four human NB cell lines were used to study the effects of harmine treatment: SKNBE and KELLY (MYCN-amplified) as well as SKNAS and SKNFI (MYCN non-amplified). The anti-cancer properties of harmine were examined by RealTime-Glo MT cell viability assays, caspase activity assays, PARP cleavage using Western blot analysis, and flow cytometry-based Annexin V detection. A molecular interaction model of harmine bound to the DYRK2 family kinase was generated by computational docking using X-ray structures. NB tumors from human patients were profiled for DYRK mRNA expression patterns and clinical correlations using the R2 platform. Results: The IC50 values for harmine after 72 h treatment were 169.6, 170.8, and 791.7 MUM for SKNBE, KELLY, and SKNFI, respectively. Exposure of these NB cell lines to 100 MUM of harmine resulted in caspase-3/7 and caspase-9 activation as well as caspase-mediated PARP cleavage and Annexin V-positive stained cells, as early as 24 h after treatment, clearly suggesting apoptosis induction, especially in MYCN-amplified cell lines. Elevated DYRK2 mRNA levels correlated with poor prognosis in a large cohort of NB tumors. Conclusion: Harmine is a known inhibitor of DYRK family kinases. It can induce apoptosis in NB cell lines, which led us to investigate the clinical correlations of DYRK family gene expression in NB tumors. The patient results support our hypothesis that DYRK inhibition by harmine and the subsequent triggering of caspase-mediated apoptosis might present a novel approach to NB therapy. PMID- 29977158 TI - MiR-218 regulates epithelial-mesenchymal transition and angiogenesis in colorectal cancer via targeting CTGF. AB - Background: Endothelial-to-mesenchymal transition (EMT) and angiogenesis play important roles in colorectal cancer (CRC) development. Connective tissue growth factor (CTGF) has been reported to promote several kinds of cancer progression and miR-218 has been identified as a tumor suppressor miRNA. However, little is known about the function of miR-218 in CRC. Here we investigated the effects of miR-218 on EMT and angiogenesis process in CRC cells. As well, the relation between miR-218 and CTGF was identified. The mechanism of miR-218's function was illustrated. Methods: CRC cell lines were transfected with miR-218 mimics. Proliferation, migration and angiogenesis were identified by MTT assay, Transwell assay, colony formation assay and tube formation assay. Protein and mRNA expression levels of associated genes were measured by Western blotting and RT PCR. Dual luciferase assay was used to determine the relation of miR-218 and CTGF. Results: miR-218 was down-regulated in CRC cell lines and over expression of miR-218 could significantly inhibit EMT and angiogenesis. CTGF was a direct target of miR-218. Up regulation of CTGF level after miR-218 transfection could sufficiently rescue the suppression effects on EMT and angiogenesis. Conclusion: miR-218 directly targets CTGF and inhibits its expression, leading to suppression on EMT and angiogenesis of CRC cells. miR-218 might be used as potential therapeutic strategy for CRC treatment. PMID- 29977159 TI - The association of semaphorin 5A with lymph node metastasis and adverse prognosis in cervical cancer. AB - Background: Semaphorin 5A has been linked to tumor growth, invasion, and metastasis in pancreatic cancer. However, the role of semaphorin 5A in cervical cancer is not known. Our aim is to investigate the prognostic value of semaphorin 5A and its potential role in lymphangiogenesis and invasion in cervical cancer. Methods: In this study, pathological features and clinical data of 232 cervical cancer patients were retrospectively reviewed. Semaphorin 5A protein and mRNA expression was detected by immunohistochemistry and quantitative real-time reverse transcription-polymerase chain reaction, respectively. In vitro, we determined the role and mechanistic pathways of semaphorin 5A in tumor progression in cervical carcinoma cell lines. Results: Semaphorin 5A expression was significantly higher in stage IIb tumors than in stage Ia, Ib, and IIa tumors. High semaphorin 5A expression was significantly associated with pelvic lymph node metastasis, lymphovascular permeation, and poor survival. Semaphorin 5A induced lymphangiogenesis through a plexin-B/Met/vascular endothelial growth factor-C pathway. Semaphorin 5A also increased cervical cancer cell invasion by stimulating the expression and activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 via PI3K/AKT and plexin-B3. Conclusion: Our findings indicate that semaphorin 5A may represent a poor prognostic biomarker and anti-metastasis therapeutic target in cervical cancer. PMID- 29977161 TI - Extended thromboprophylaxis with betrixaban: a new standard for acute medically ill patients. PMID- 29977160 TI - Cost-effectiveness of colorectal cancer screening in Ukraine. AB - Background: Colorectal cancer is one of the most common cancers worldwide and is associated with high mortality when detected at a later stage. There is a paucity of studies from low and middle income countries to support the cost-effectiveness of colorectal cancer screening. We aim to analyze the cost-effectiveness of colorectal cancer screening compared to no screening in Ukraine, a lower-middle income country. Methods: We developed a deterministic Markov cohort model to assess the cost-effectiveness of three colorectal cancer screening strategies [fecal occult blood test (FOBT) every year, flexible sigmoidoscopy with FOBT every 5 years, and colonoscopy every 10 years] compared to no screening. We modeled outcomes in terms of cost per quality-adjusted life-years (QALYs) over a lifetime time horizon. We performed sensitivity analyses on treatment adherence, test characteristics and costs. Analyses were conducted from the perspective of the Ministry of Health of Ukraine. Results: The base-case lifetime cost effectiveness analysis showed that all three screening strategies were cost saving compared to no screening, and among the three strategies, colonoscopy every 10 years was the dominant strategy compared to no screening with standard adherence to treatment. When decreased adherence to treatment was modeled, colonoscopy every 10 years was the most cost-effective strategy with an incremental cost-effectiveness ratio of $843 per QALY compared with no screening. Conclusion: Our findings indicate that colorectal cancer screening can save money and improve health compared to no screening in Ukraine. Colonoscopy every 10 years is superior to the other screening modalities evaluated in this study. This knowledge can be used to concentrate efforts on developing a national screening program in Ukraine. PMID- 29977162 TI - Highlights: burden of venous thromboembolism and role of extended-duration thromboprophylaxis in acute medically ill patients. PMID- 29977163 TI - Reducing the burden of venous thromboembolism in the acute medically ill population with extended-duration thromboprophylaxis. AB - Hospitalized acute medically ill patients are vulnerable to venous thromboembolism (VTE), known as hospital-acquired thrombosis (HAT). The elevated risk of HAT is usually due to a combination of factors, with immobility and a prothrombotic state due to acute illness being the most frequent. The HAT risk persists well after hospital discharge, with more than half of events occurring after patient release. These HAT events may be fatal, and patients who survive the initial event may be subject to VTE recurrence, chronic discomfort from post thrombotic syndrome and, although rare, may develop chronic thrombo-embolic pulmonary hypertension, which is often debilitating. The risk of HAT can be reduced with effective thromboprophylaxis. Current guidelines recommend thromboprophylaxis with subcutaneous heparin, low molecular weight heparin (LMWH) or fondaparinux for at-risk acute medically ill patients, but reports of real world practice indicated that some patients do not receive protection in the short-term as outlined by the guidelines. Previous studies that have assessed extended thromboprophylaxis for 4-5 weeks with LMWH or direct oral anticoagulants in medically ill patients found they did not offer a net clinical benefit; any demonstrated efficacy was outweighed by the significantly increased risk of major haemorrhage. Therefore, there is an ongoing need for improved VTE prevention without increasing the risk of bleeding. In the APEX trial, conducted in an acute medically ill population, betrixaban provided a significant reduction in VTE events after 35 to 42 days of treatment compared with short-term enoxaparin without an increase in major bleeding. PMID- 29977164 TI - Pharmacological properties of betrixaban. AB - Venous thromboembolism (VTE) in acute medically ill patients is a leading cause of in-hospital morbidity and mortality. A majority of these VTE events occur post discharge, and patients remain at increased VTE risk for up to 3 months post discharge. Recent clinical trials of extended-duration thromboprophylaxis with enoxaparin, rivaroxaban, and apixaban in acute medically ill patients did not demonstrate a net clinical benefit compared with in-hospital thromboprophylaxis, and were shown to be associated with higher risks of major bleeding. Betrixaban is a new direct oral anticoagulant (DOAC) with a different pharmacokinetic profile than other DOACs. Betrixaban has the longest half-life among the DOAC class, with a terminal half-life of 35-45 h and an effective half-life of 19-27 h. Betrixaban has a low peak-to-trough ratio compared with other anticoagulants and a predictable duration of drug exposure, leading to overall consistent anticoagulant effect over 24 h. Betrixaban is mainly cleared via the hepatobiliary system and therefore not contraindicated in patients with severe renal insufficiency. Betrixaban was recently approved for the indication of extended thromboprophylaxis in the United States based on the APEX trial of betrixaban 80 mg once daily for 35-42 days compared with low molecular weight heparin enoxaparin for 10 +/- 4 days in hospitalized acute medically ill patients. This study demonstrated that extended-duration betrixaban reduced VTE compared with standard-duration enoxaparin in acute medically ill patients, without increased risk of major bleeding. This patient population at risk of VTE may benefit from extended prophylaxis, ensuring continuum of care from in hospital to post-discharge. PMID- 29977165 TI - Betrixaban for prevention of venous thromboembolism in acute medically ill patients. AB - Venous thromboembolism (VTE) is a common, potentially preventable cause of morbidity and mortality among acute medically ill patients. More than half of VTE events in this population occur after hospital discharge. Thus, providing extended-duration VTE prophylaxis from in-hospital through the post-discharge continuum may improve the quality of care in patients at risk of VTE. Betrixaban is a new oral, once-daily factor Xa inhibitor approved by the United States (US) Food and Drug Administration (FDA) for extended-duration prophylaxis of VTE in acute medically ill patients. The clinical efficacy and safety of betrixaban in acute medically ill patients perceived to be at high risk for VTE were evaluated in a large, randomized, double-blind, active-controlled, multinational clinical trial [Acute Medically Ill VTE Prevention With Extended Duration Betrixaban (APEX)]. Patients were randomized to receive subcutaneous enoxaparin (10 +/- 4 days) or oral betrixaban (35-42 days) plus matching placebos. The primary efficacy outcome was a composite of asymptomatic proximal deep vein thrombosis and symptomatic VTE; the primary safety measure was major bleeding. Extended duration betrixaban reduced VTE events without an increase in major bleeding in the modified intent-to-treat analysis. Post hoc analyses of the APEX trial provided further evidence to support the efficacy and safety of betrixaban in reducing all-cause ischaemic stroke, fatal or irreversible ischaemic or bleeding events, as well as reducing VTE-related rehospitalization. In summary, analyses of the APEX study demonstrated a positive benefit-risk profile for extended prophylaxis of VTE with betrixaban in acute medically ill patients. This is likely to have important public health and health economic implications. PMID- 29977167 TI - ABRF Proteome Informatics Research Group (iPRG) 2016 Study: Inferring Proteoforms from Bottom-up Proteomics Data. AB - This report presents the results from the 2016 Association of Biomolecular Resource Facilities Proteome Informatics Research Group (iPRG) study on proteoform inference and false discovery rate (FDR) estimation from bottom-up proteomics data. For this study, 3 replicate Q Exactive Orbitrap liquid chromatography-tandom mass spectrometry datasets were generated from each of 4 Escherichia coli samples spiked with different equimolar mixtures of small recombinant proteins selected to mimic pairs of homologous proteins. Participants were given raw data and a sequence file and asked to identify the proteins and provide estimates on the FDR at the proteoform level. As part of this study, we tested a new submission system with a format validator running on a virtual private server (VPS) and allowed methods to be provided as executable R Markdown or IPython Notebooks. The task was perceived as difficult, and only eight unique submissions were received, although those who participated did well with no one method performing best on all samples. However, none of the submissions included a complete Markdown or Notebook, even though examples were provided. Future iPRG studies need to be more successful in promoting and encouraging participation. The VPS and submission validator easily scale to much larger numbers of participants in these types of studies. The unique "ground-truth" dataset for proteoform identification generated for this study is now available to the research community, as are the server-side scripts for validating and managing submissions. PMID- 29977168 TI - Operational Characterization of Pressure Regulating Valves. AB - The functionality of pressure regulating valves (PRVs) is important for proper uniformity and efficiency of irrigation during center pivot irrigation, especially when the center pivot operates on sloping terrain. In practice, the regulated pressure at the PRV outlet is slightly influenced by its inlet pressure, the flow rate through it, and hysteresis effects. The objectives of this work were (a) to evaluate operational characteristics of PRVs based on requirements stated by ISO 10522 (1993) and (b) to model the regulated pressure as a function of inlet pressure and flow rate through the valve considering hysteresis. We carried out tests to evaluate regulation uniformity, regulation curve, hysteresis, and the regulated pressure as function of flow rate and inlet pressure. The following three models of PRVs were evaluated: 10 PSI, 15 PSI, and 20 PSI. For each model, three samples were tested under increasing and decreasing conditions of inlet pressure, within the range from 49.03 to 784.53 kPa, with increments of 49.03 kPa. In addition, flow rates were tested within the range of 0 and 4 m3 h-1. From the gathered data, models to predict outlet pressure as a function of inlet pressure and flow rate were fitted. PMID- 29977166 TI - Solid Organ Transplantation for HIV-Infected Individuals. AB - Purpose of Review: The prevalence of end-stage organ disease is increasing among HIV-infected (HIV+) individuals. Individuals with well-controlled HIV on antiretroviral therapy (ART), without active opportunistic infections or cancer, and with specified minimum CD4 cell counts are appropriate transplant candidates. Infectious disease clinicians can improve access to transplantation for these patients and optimize management pre- and post-transplant. Recent Findings: Clinical trials and registry-based studies demonstrate excellent outcomes for select HIV+ kidney and liver transplant recipients with similar patient and graft survival as HIV-uninfected patients. Elevated allograft rejection rates have been observed in HIV+ individuals; this may be related to a dysregulated immune system or drug interactions. Lymphocyte-depleting immunosuppression has been associated with lower rejection rates without increased infections using national registry data. Hepatitis C virus (HCV) coinfection has been associated with worse outcomes, however improvements are expected with direct-acting antivirals. Summary: Solid organ transplantation should be considered for HIV+ individuals with end-stage organ disease. Infectious disease clinicians can optimize ART to avoid pharmacoenhancers, which interact with immunosuppression. The timing of HCV treatment (pre- or post-transplant) should be discussed with the transplant team. Finally, organs from HIV+ donors can now be considered for HIV+ transplant candidates, within research protocols. PMID- 29977169 TI - Update on the Treatment of Metastatic Urothelial Carcinoma. AB - Platinum-based combination chemotherapy has been the standard of care in the first-line treatment of metastatic urothelial carcinoma (mUC). Treatment of metastatic disease following progression on platinum-based regimens has evolved significantly in the last few years. Clinical trials are currently ongoing to determine how best to use and sequence these treatments. In this minireview, we will review current first-line treatment options in both cisplatin fit and cisplatin unfit patients and advances in first- and second-line treatments including chemotherapy and immunotherapy. This review reports key findings from the clinical trials especially highlighting the importance of PD-1 and PD-L1 inhibitors in the treatment of bladder/urothelial carcinomas. PMID- 29977170 TI - Control of Cryptococcus Gattii Biofilms by an Ethanolic Extract of Cochlospermum Regium (Schrank) Pilger Leaves. AB - Cryptococcus gattii is an etiologic agent of cryptococcosis and a serious disease that affects immunocompromised and immunocompetent patients worldwide. The therapeutic arsenal used to treat cryptococcosis is limited to a few antifungal agents, and the ability of C. gattii to form biofilms may hinder treatment and decrease its susceptibility to antifungal agents. The objective of this study was to evaluate the antifungal and antibiofilm activities of an ethanolic extract of Cochlospermum regium (Schrank) Pilger leaves against C. gattii. The antifungal activity was assessed by measuring the minimum inhibitory concentration (MIC) using the broth microdilution technique and interaction of the extract with fluconazole was performed of checkerboard assay. The antibiofilm activity of the extract was evaluated in 96-well polystyrene microplates, and the biofilms were quantified by counting colony forming units. The extract showed antifungal activity at concentrations of 62.5 to 250 MUg/mL and when the extract was evaluated in combination with fluconazole, C. gattii was inhibited at sub-MIC levels. The antibiofilm activity of the extract against C. gattii was observed both during biofilm formation and on an already established biofilm. The results showed that the ethanolic extract of the leaves of C. regium shows promise for the development of antifungal drugs to treat cryptococcosis and to combat C. gattii biofilms. PMID- 29977171 TI - Antibacterial and Antibiofilm Activities of Cinnamomum Sp. Essential Oil and Cinnamaldehyde: Antimicrobial Activities. AB - To assess the activities of essential oils derived from the trunk bark of Cinnamomum zeylanicum (EOCz) and Cinnamomum cassia (EOCc) as well as cinnamaldehyde on bacterial biofilms of clinical interest. Antimicrobial activity was assessed by the broth microdilution method to determine minimum inhibitory concentrations (MICs). Antibiofilm activity was assessed by quantifying the biomass and determining the number of viable cells. The chemical composition of the essential oils was determined. The results showed that the major component of EOCz and EOCc was cinnamaldehyde. For the assayed substances, biofilm biomasses were reduced by up to 99.9%, and Streptococcus pyogenes, Pseudomonas aeruginosa, and Escherichia coli biofilms were sensitive to all of the concentrations and substances analysed. In cell viability tests, 2 mg/ml of cinnamaldehyde reduced the number of viable cells by 5.74 Log CFU/ml. EOCz, EOCc, and cinnamaldehyde exhibited antimicrobial and antibiofilm activities. This work describes substances with potential use against infections caused by bacterial biofilms. PMID- 29977172 TI - T-Bet Is Dependent on Stat-4 Inhibiting Acute Colitis but Not Stat-1 Using L4 Somatic Antigen of Heligmosomoides polygyrus. AB - Helminths may alter the immunoinflammatory reactions of colitis. Proteins derived from H. polygyrus have prospective therapy for colitis. The goal of this study was to interpret the protective mechanisms of L4 somatic antigen (LSA) from Heligmosomoides polygyrus against an inflammatory response to the pathogenesis of DNBS-induced colitis. Colitis was actuated in mice by rectal instillation of DNBS. The mice were randomly divided into five groups containing control, DNBS alone, and three groups, with different doses of LSA (50, 100, and 200 MUg/mL), respectively. Mice initiated colitis by rectal administration of DNBS and after that were immunized with LSA for 14 days. Mice treated with LSA inhibited wasting disease compared with DNBS only group. The percentages of cells producing IFN gamma were reduced by LSA treatment. The level of T lymphocytes CD4+IFN-gamma+ cells in the LPL was significantly diminished by LSA at both 100 and 200 MUg/mL groups (p<0.05). The mRNA expression of T-bet was significantly declined in LSA immunized mice, but not RORgamma-T mRNA, whereas GATA-3 expression tended to increase. The activation of STAT-4 significantly reduced LSA-treated mice but not STAT-1. It can be concluded that T-bet is required for optimal production of IFN gamma in colitis. PMID- 29977173 TI - Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors. AB - High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2 targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [99mTc]Tc(CO)3 using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [125I]I DARPin 9_29 and [99mTc]Tc(CO)3-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 +/- 0.7 %ID/g and 2.9 +/- 0.7 %ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 +/- 0.09 %ID/g and 0.30 +/- 0.05 %ID/g, respectively. Retention of [125I]I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [99mTc]Tc(CO)3 DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29. PMID- 29977174 TI - Everyday Activities for Children with Mitochondrial Disorder: A Retrospective Chart Review. AB - Background: Engagement in everyday activities is important for the health and wellbeing of children. Children with mitochondrial disorders have impaired energy production leading to limitations in activity. It is unknown which activities these children perform and if the nature of activities of low-functioning children differs from average-functioning children. Therefore, this pilot study explored the activities reported in patient records of a heterogeneous group of children with genetically confirmed mitochondrial disorders. Methods: A retrospective qualitative directed content analysis by health care professionals reported activities (as part of their professional reasoning obligations) in hospital patient records of children with mitochondrial disorder. Results: Seventeen patient records, presenting notes on capacities and performed activities, showed an overview of everyday activities that covered the categories: self-care, house chores, therapy, school, computing, hobby, play, sports, and mobility/transport. The activity categories of low-functioning children did not differ from average-functioning children, although descriptions of specific activities differed between groups. Conclusion: This pilot exploration indicates that the types of activities that children with mitochondrial disorders perform are not necessarily linked to the child's impairments. However, differences in levels of independence, assistive device usage, and energy costs seem to exist. Future research should address the child's perspective on, and meaning of, activity performances. PMID- 29977176 TI - Comparative Profiling of MicroRNAs Reveals the Underlying Toxicological Mechanism in Mice Testis Following Carbon Ion Radiation. AB - This study investigated the toxicity of heavy ion radiation to mice testis by microRNA (miRNA) sequencing and bioinformatics analyses. Testicular indices and histology were measured following enterocoelia irradiation with a 2 Gy carbon ion beam, with the testes exhibiting the most serious injuries at 4 weeks after carbon ion radiation (CIR) exposure. Illumina sequencing technology was used to sequence small RNA libraries of the control and irradiated groups at 4 weeks after CIR. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses implicated differential miRNAs in the regulation of target genes involved in metabolism, development, and reproduction. Here, 8 miRNAs, including miR-34c-5p, miR-138, and 6 let-7 miRNA family members previously reported in testis after radiation, were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) to validate miRNA sequencing data. The differentially expressed miRNAs described here provided a novel perspective for the role of miRNAs in testis toxicity following CIR. PMID- 29977177 TI - X-Ray Imaging is Essential for Contemporary Chiropractic and Manual Therapy Spinal Rehabilitation: Radiography Increases Benefits and Reduces Risks. AB - To remedy spine-related problems, assessments of X-ray images are essential to determine the spine and postural parameters. Chiropractic/manual therapy realignment of the structure of the spine can address a wide range of pain, muscle weakness, and functional impairments. Alternate methods to assess such spine problems are often indirect and do not reveal the root cause and could result in a significant misdiagnosis, leading to inappropriate treatment and harmful consequences for the patient. Radiography reveals the true condition and alignment of the spine; it eliminates guesswork. Contemporary approaches to spinal rehabilitation, guided by accurate imaging, have demonstrated superiority over primitive treatments. Unfortunately, there are well-meaning but misguided activists who advocate elimination or minimization of exposures in spine radiography. The radiation dose employed for a plain radiograph is very low, about 100 times below the threshold dose for harmful effects. Rather than increasing risk, such exposures would likely stimulate the patient's own protection systems and result in beneficial health effects. Spine care guidelines need to be revised to reflect the potential benefits of modern treatments and the lack of health risks from low X-ray doses. This would encourage routine use of radiography in manual spine therapy, which differs from common pharmacologic pain relief practice. PMID- 29977179 TI - EN ISO 15189, the Standard for Accreditation in Laboratory Medicine. PMID- 29977175 TI - The Lowest Radiation Dose Having Molecular Changes in the Living Body. AB - We herein attempted to identify the lowest radiation dose causing molecular changes in the living body. We investigated the effects of radiation in human cells, animals, and humans. DNA double-strand breaks (DSBs) formed in cells at gamma- or X-ray irradiation doses between 1 mGy and 0.5 Gy; however, the extent of DSB formation differed depending on the cell species. The formation of micronuclei (MNs) and nucleoplasmic bridges (NPBs) was noted at radiation doses between 0.1 and 0.2 Gy. Stress-responsive genes were upregulated by lower radiation doses than those that induced DNA DSBs or MN and NPBs. These gamma- or X-ray radiation doses ranged between approximately 10 and 50 mGy. In animals, chromosomal aberrations were detected between 50 mGy and 0.1 Gy of low linear energy transfer radiation, 0.1 Gy of metal ion beams, and 9 mGy of fast neutrons. In humans, DNA damage has been observed in children who underwent computed tomography scans with an estimated blood radiation dose as low as 0.15 mGy shortly after examination. The frequencies of chromosomal translocations were lower in residents of high background areas than in those of control areas. In humans, systemic adaptive responses may have been prominently expressed at these radiation doses. PMID- 29977180 TI - Clinical Utility of Anti-Tissue Transglutaminase Antibodies for Diagnosis and Monitoring of Coeliac Disease in Children and Adolescents. AB - : Identification of tissue transglutaminase (tTG) as a major target antigen of IgA anti-endomysial antibodies and detection of auto-antibodies against tTG in the serum pointed out a new direction in the serologic diagnosis of coeliac disease. Clinical utility of determination of anti-tTGIgA antibodies, with recombinant human tTG used as antigen, was evaluated for the diagnosis of coeliac disease and monitoring the adherence to the diet in children and adolescents. Patients: The study was performed in 169 patients aged 2-24 years, including 42 children (26 girls, 16 boys, mean age 8.01 +/- 5.69, range 2-18) with newly diagnosed coeliac disease (CD) (group I), 60 patients (39 females, 21 males, mean age 15.68 +/- 4.74, range 5-24) with CD recognized at least 3 years before entering the study, non-compliants with gluten-free diet (group II) and 67 children (34 girls, 33 boys, mean age 6,28+/- 4.48, range 2-16) suspected of malabsorption, in whom diagnosis of CD had been excluded. Methods: Serum samples were taken from all patients and tested for total IgA, anti-endomysial IgA (IgAEmA) or IgG autoantibodies (IgGEmA), only in cases with IgA deficiency, by indirect immunofluorescence method and anti-tTGIgA antibodies by ELISA. Results: [Table: see text] Strong significant associations between anti-tTGIgA present in the serum and IgAEmA (Kendall tau 0.7748, p<0.0001) and good correlation between the levels of anti-tTGIgA and IgAEmA (r=0,488, p=0.001) were found in group I. We have not shown the relationship between the presence of both types of antibodies in patients of group II (Kendall tau 0.2102, p=0.0937). However, a good significant correlation between the levels of these parameters was observed (r=0,813, p<0,0001). Anti-tTGIgA concentration was nificantly higher in patients of group I compared to group II (38.35 U/ml v. 23.13 U/ml, p=0,0356). The sensitivity of anti- tTGIgA test in group I was 88.1%, in group II - 91.7% while specificity reached 97%. Conclusions: Determination of anti-tTGIgA shows high sensitivity (88.1%) and specificity (97%) for the detection of coeliac disease. This test can be used alternatively with the immunofluorescent IgAEmA in diagnosis of coeliac disease, and also as a marker of compliance with gluten-free diet. However, both IgAEmA and anti-tTGIgA tests do not reach 100% sensitivity and specificity for diagnosis and nitoring of celiac disease. Therefore small intestinal biopsy is still recommended as a ? gold standard?. PMID- 29977178 TI - The Effect of Pulsed Electric Field on Expression of ECM proteins: Collagen, Elastin, and MMP1 in Human Dermal Fibroblasts. AB - Electrical stimulation of tissues has many uses in pain management, antibacterial treatment, and wound healing. The electric field stimulates epidermal migration and increases fibroblast cell proliferation. Here we show the effects of electrical field (EF) stimulation of human dermal fibroblasts (HDF) on the expression of collagen, elastin, and collagenase (MMP1; matrix metalloproteinase 1). The effects of EF stimulation are evaluated in terms of changes in cell morphology and extracellular matrix (ECM) protein expression, defined as intracellular concentration of collagen, elastin, and MMP1. HDF are stimulated in a bioreactor using square wave voltage pulses for up to 24 h. The pulse voltage (0-10V), pulse bias (0, +), pulse time (10-1000 ms), and rest time (0.1-10 s) were varied. We show that expression of collagen, elastin, and MMP1 increases in response to applied EF. The intracellular concentration of ECM proteins more than doubles depending on stimulation conditions with a threshold of effective stimulation above 3V/cm. The short time voltage pulses used for EF stimulation are more effective, while the rest time between pulses has a small effect on intracellular concentration of collagen, MMP1 and elastin. The previously studied HDF stimulation with chemical factors (i.e. TNF-alpha, TGF-beta) shows negative correlation between concentration of collagen and MMP1. Contrary to that observation, we show that EF stimulation causes increase in the intracellular concentration of both collagen and MMP1. We also demonstrate that the transdermal stimulation of HDF in subcutaneous tissue is possible, thus it might be utilized in the future to improve the wound healing and tissue regeneration process. PMID- 29977181 TI - ISO 15189:2003 - From Theory into Practice. PMID- 29977182 TI - Practical Application of ISO 15189 by Accreditation Bodies -: A comparison with ISO/IEC 17025. PMID- 29977183 TI - Pre and Post Examination Aspects. AB - After a long-standing tradition of analytical quality and analytical quality control programs, most medical laboratories that are aware of the need for total quality management, are experiencing new systems designed to assure quality throughout the entire total testing process, from the pre-analytical to the post analytical steps. The availability of a new International Standard, ISO 15189:2003, specifically developed and designed to satisfy the requirements for quality management and competence in medical laboratories, should promote the harmonization of accreditation programs at an international level, and implementation of an effective quality system at a local level. The importance of the pre- and post-analytical phases are well recognized in the new International Standard and, therefore, efforts to comply with this standard might assure an approach that safeguards and continuously improves total quality in medical laboratories. PMID- 29977184 TI - ISO 15190:2003 Medical Laboratories - Requirements for Safety. AB - ISO 15190:2003 is a new standard developed by the International Organization for Standardization to address the safety aspects of medical laboratories. It is directly linked to the ISO 15189:2003, the standard for quality and competence. It provides a framework for a safety program based upon the principles of quality management, including designation of responsibilities and authorities, regular audits, and continuous improvement. PMID- 29977185 TI - ISO 15189:2003 - Its Importance for the Enlarged Europe. PMID- 29977186 TI - ISO 15189:2003 and Evidence Based Laboratory Medicine. PMID- 29977187 TI - Frequency-Dependent Changes of the Resting BOLD Signals Predicts Cognitive Deficits in Asymptomatic Carotid Artery Stenosis. AB - "Asymptomatic" carotid artery stenosis (aCAS) patients usually have cognitive impairment in the domains of executive, psychomotor speed, and memory function. However, the pathophysiology of this impairment in aCAS patients is still unclear. In this study, amplitude of low-frequency fluctuation (ALFF) method was used based on resting-state blood oxygenation level dependent (BOLD) signals, to investigate local brain activity in 19 aCAS patients and 24 healthy controls, aimed to explore this pathophysiology mechanism. We analyzed this intrinsic activity in four individual frequency bands: Slow-2 (0.198-0.25 Hz), Slow-3 (0.073-0.198 Hz), Slow-4 (0.027-0.073 Hz), and Slow-5 (0.01-0.027 Hz). The aCAS related ALFF changes were mainly distributed in (1) cortical midline structure, including bilateral dorsomedial prefrontal (dmPFC), cingulate cortex (CC) and precuneus (PCu); (2) hippocampus and its adjacent structures, including bilateral hippocampus, thalamus and medial temporal regions. We found these spatial patterns were frequency-dependent. Significant interaction between frequency and group was found distributed in left putamen, triangle part of inferior temporal and bilateral precentral/postcentral gyrus when Slow-4 and Slow-5 were considered. The delay recall ability of aCAS patient was significantly positive correlated to the mean ALFF in dmPFC within Slow-4 band and the mean ALFF in the bilateral hippocampus within Slow-3 band, respectively. We also found the Montreal Cognitive Assessme score of aCAS patient was significantly positive correlated to the mean ALFF in right fusiform and parahippocampus within Slow-3 band. Furthermore, we built the automatic diagnosis and prediction models based on support vector machine (SVM) and back propagation neural network (BPNN), respectively. Both two types of models could achieve relatively competent performance, which meant the frequency-dependent changes in ALFF could not only reveal the pathophysiology mechanism of cognitive impairment of aCAS, but also could be used as neuroimaging marker in the analysis of cognition impairment for aCAS patients. PMID- 29977188 TI - Nucleus Accumbens Dopamine D1-Receptor-Expressing Neurons Control the Acquisition of Sign-Tracking to Conditioned Cues in Mice. AB - Following repeated pairings, the reinforcing and motivational properties (incentive salience) of a reward can be transferred onto an environmental stimulus which can then elicit conditioned responses, including Pavlovian approach behavior to the stimulus (a sign-tracking response). In rodents, acquisition of sign-tracking in autoshaping paradigms is sensitive to lesions and dopamine D1 receptor antagonism of the nucleus accumbens (NAc) of the ventral striatum. However, currently, the possible roles of dorsal striatal subregions, as well as of the two major striatal neuron types, dopamine D1-/D2-expressing medium spiny neurons (MSNs), in controlling the development of conditioned responses is still unclear and warrants further study. Here, for the first time, we used a transgenic mouse line combined with striatal subregion-specific AAV virus injections to separately express tetanus toxin in D1-/D2- MSNs in the NAc, dorsomedial striatum, and dorsolateral striatum, to permanently block neurotransmission in these neurons during acquisition of an autoshaping task. Neurotransmission blocking of NAc D1-MSNs inhibited the acquisition of sign tracking responses when the initial conditioned response for each conditioned stimulus presentation was examined, confirming our initial hypothesis. These findings suggest that activity in NAc D1-MSNs contributes to the attribution of incentive salience to conditioned stimuli. PMID- 29977189 TI - Decoding Inner Speech Using Electrocorticography: Progress and Challenges Toward a Speech Prosthesis. AB - Certain brain disorders resulting from brainstem infarcts, traumatic brain injury, cerebral palsy, stroke, and amyotrophic lateral sclerosis, limit verbal communication despite the patient being fully aware. People that cannot communicate due to neurological disorders would benefit from a system that can infer internal speech directly from brain signals. In this review article, we describe the state of the art in decoding inner speech, ranging from early acoustic sound features, to higher order speech units. We focused on intracranial recordings, as this technique allows monitoring brain activity with high spatial, temporal, and spectral resolution, and therefore is a good candidate to investigate inner speech. Despite intense efforts, investigating how the human cortex encodes inner speech remains an elusive challenge, due to the lack of behavioral and observable measures. We emphasize various challenges commonly encountered when investigating inner speech decoding, and propose potential solutions in order to get closer to a natural speech assistive device. PMID- 29977190 TI - The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondrial Biogenesis in Aging Yeast. AB - Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondrial biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology. PMID- 29977191 TI - C57BL/6 and Swiss Webster Mice Display Differences in Mobility, Gliosis, Microcavity Formation and Lesion Volume After Severe Spinal Cord Injury. AB - Spinal cord injuries (SCI) are neuropathologies causing enormous physical and emotional anguish as well as irreversibly disabilities with great socio/economic burdens to our society. The availability of multiple mouse strains is important for studying the underlying pathophysiological response after SCI. Although strain differences have been shown to directly affect spontaneous functional recovery following incomplete SCI, its influence after complete lesion of the spinal cord is unclear. To study the influence of mouse strain on recovery after severe SCI, we first carried out behavioral analyses up to 6 weeks following complete transection of the spinal cord in mice with two different genetic backgrounds namely, C57BL/6 and Swiss Webster. Using immunohistochemistry, we then analyzed glial cell reactivity not only at different time-points after injury but also at different distances from the lesion epicenter. Behavioral assessments using CatWalkTM and open field analyses revealed increased mobility (measured using average speed) and differential forelimb gross sensory response in Swiss Webster compared to C57BL/6 mice after complete transection of the spinal cord. Comprehensive histological assessment revealed elevated microglia/macrophage reactivity and a moderate increase in astrogliosis in Swiss Webster that was associated with reduced microcavity formation and reduced lesion volume after spinal cord transection compared to C57BL/6 mice. Our results thus suggest that increased mobility correlates with enhanced gliosis and better tissue protection after complete transection of the spinal cord. PMID- 29977192 TI - Microglia Activation and Immunomodulatory Therapies for Retinal Degenerations. AB - A chronic pro-inflammatory environment is a hallmark of retinal degenerative diseases and neurological disorders that affect vision. Inflammatory responses during retinal pathophysiology are orchestrated by microglial cells which constitute the resident immune cell population. Following activation, microglia cells lose their ramified protrusions, proliferate and rapidly migrate to the damaged areas and resolve tissue damage. However, sustained presence of tissue stress primes microglia to become overreactive and results in the excessive production of pro-inflammatory mediators that favor retinal degenerative changes. Consequently, interventions aimed at overriding microglial pro-inflammatory and pro-oxidative properties may attenuate photoreceptor demise and preserve retinal integrity. We highlight the positive effects of ligands for the translocator protein 18 kDa (TSPO) and the cytokine interferon beta (IFN-beta) in modulating microgliosis during retinal pathologies and discuss their plausible mechanisms of action. PMID- 29977193 TI - Principles of Functional Circuit Connectivity: Insights From Spontaneous Activity in the Zebrafish Optic Tectum. AB - The brain is continuously active, even in the absence of external stimulation. In the optic tectum of the zebrafish larva, this spontaneous activity is spatially organized and reflects the circuit's functional connectivity. The structure of the spontaneous activity displayed patterns associated with aspects of the larva's preferences when engaging in complex visuo-motor behaviors, suggesting that the tectal circuit is adapted for the circuit's functional role in detecting visual cues and generating adequate motor behaviors. Further studies in sensory deprived larvae suggest that the basic structure of the functional connectivity patterns emerges even in the absence of retinal inputs, but that its fine structure is affected by visual experience. PMID- 29977194 TI - Long-Range, Border-Crossing, Horizontal Axon Radiations Are a Common Feature of Rat Neocortical Regions That Differ in Cytoarchitecture. AB - Employing wide-field optical imaging techniques supported by electrophysiological recordings, previous studies have demonstrated that stimulation of a spatially restricted area (point) in the sensory periphery results in a large evoked neuronal activity spread in mammalian primary cortices. In rats' primary cortices, such large evoked spreads extend diffusely in multiple directions, cross cortical cytoarchitectural borders and can trespass into other unimodal sensory areas. These point spreads are supported by a spatially matching, diffuse set of long-range horizontal projections within gray matter that extend in multiple directions and cross borders to interconnect different cortical areas. This horizontal projection system is in addition to well-known area-to-area clustered projections to defined targets through white matter. Could similar two projection cortical systems also be found in cortical regions that differ in their cytoarchitectural structure? To address this question, an adeno-associated viral vector expressing green fluorescent protein (GFP) was injected as an anterograde tract tracer into granular somatosensory cortex (trunk area), dysgranular cortex (somatosensory dysgranular zone and extrastriate cortex) and agranular motor cortex (MCx). Irrespective of the injection site the same two projection systems were found, and their quantification revealed a close similarity to findings in primary sensory cortices. Following detailed reconstruction, the diffuse horizontal axon radiation was found to possess numerous varicosities and to include short, medium and long axons, the latter extending up to 5.2 mm. These "proof of concept" findings suggest that the similarity of the two projection systems among different cortical areas could potentially constitute a canonical motif of neocortical organization. PMID- 29977195 TI - Pain Input After Spinal Cord Injury (SCI) Undermines Long-Term Recovery and Engages Signal Pathways That Promote Cell Death. AB - Pain (nociceptive) input caudal to a spinal contusion injury increases tissue loss and impairs long-term recovery. It was hypothesized that noxious stimulation has this effect because it engages unmyelinated pain (C) fibers that produce a state of over-excitation in central pathways. The present article explored this issue by assessing the effect of capsaicin, which activates C-fibers that express the transient receptor potential vanilloid receptor-1 (TRPV1). Rats received a lower thoracic (T11) contusion injury and capsaicin was applied to one hind paw the next day. For comparison, other animals received noxious electrical stimulation at an intensity that engages C fibers. Both forms of stimulation elicited similar levels of c-fos mRNA expression, a cellular marker of nociceptive activation, and impaired long-term behavioral recovery. Cellular assays were then performed to compare the acute effect of shock and capsaicin treatment. Both forms of noxious stimulation increased expression of tumor necrosis factor (TNF) and caspase-3, which promotes apoptotic cell death. Shock, but not capsaicin, enhanced expression of signals related to pyroptotic cell death [caspase-1, inteleukin-1 beta (IL-1beta)]. Pyroptosis has been linked to the activation of the P2X7 receptor and the outward flow of adenosine triphosphate (ATP) through the pannexin-1 channel. Blocking the P2X7 receptor with Brilliant Blue G (BBG) reduced the expression of signals related to pyroptotic cell death in contused rats that had received shock. Blocking the pannexin-1 channel with probenecid paradoxically had the opposite effect. BBG enhanced long-term recovery and lowered reactivity to mechanical stimulation applied to the girdle region (an index of chronic pain), but did not block the adverse effect of nociceptive stimulation. The results suggest that C-fiber input after injury impairs long-term recovery and that this effect may arise because it induces apoptotic cell death. PMID- 29977196 TI - Effects of Transcutaneous Vagus Nerve Stimulation (tVNS) on the P300 and Alpha Amylase Level: A Pilot Study. AB - Recent research suggests that the P3b may be closely related to the activation of the locus coeruleus-norepinephrine (LC-NE) system. To further study the potential association, we applied a novel technique, the non-invasive transcutaneous vagus nerve stimulation (tVNS), which is speculated to increase noradrenaline levels. Using a within-subject cross-over design, 20 healthy participants received continuous tVNS and sham stimulation on two consecutive days (stimulation counterbalanced across participants) while performing a visual oddball task. During stimulation, oval non-targets (standard), normal-head (easy) and rotated head (difficult) targets, as well as novel stimuli (scenes) were presented. As an indirect marker of noradrenergic activation we also collected salivary alpha amylase (sAA) before and after stimulation. Results showed larger P3b amplitudes for target, relative to standard stimuli, irrespective of stimulation condition. Exploratory post hoc analyses, however, revealed that, in comparison to standard stimuli, easy (but not difficult) targets produced larger P3b (but not P3a) amplitudes during active tVNS, compared to sham stimulation. For sAA levels, although main analyses did not show differential effects of stimulation, direct testing revealed that tVNS (but not sham stimulation) increased sAA levels after stimulation. Additionally, larger differences between tVNS and sham stimulation in P3b magnitudes for easy targets were associated with larger increase in sAA levels after tVNS, but not after sham stimulation. Despite preliminary evidence for a modulatory influence of tVNS on the P3b, which may be partly mediated by activation of the noradrenergic system, additional research in this field is clearly warranted. Future studies need to clarify whether tVNS also facilitates other processes, such as learning and memory, and whether tVNS can be used as therapeutic tool. PMID- 29977197 TI - Fatigue Influences the Recruitment, but Not Structure, of Muscle Synergies. AB - The development of fatigue elicits multiple adaptations from the neuromuscular system. Muscle synergies are common patterns of neuromuscular activation that have been proposed as the building blocks of human movement. We wanted to identify possible adaptations of muscle synergies to the development of fatigue in the upper limb. Recent studies have reported that synergy structure remains invariant during the development of fatigue, but these studies did not examine isolated synergies. We propose a novel approach to characterise synergy adaptations to fatigue by taking advantage of the spatial tuning of synergies. This approach allows improved identification of changes to individual synergies that might otherwise be confounded by changing contributions of overlapping synergies. To analyse upper limb synergies, we applied non-negative matrix factorization to 14 EMG signals from muscles of 11 participants performing isometric contractions. A preliminary multidirectional task was used to identify synergy directional tuning. A subsequent fatiguing task was designed to fatigue the participants in their synergies' preferred directions. Both tasks provided virtual reality feedback of the applied force direction and magnitude, and were performed at 40% of each participant's maximal voluntary force. Five epochs were analysed throughout the fatiguing task to identify progressive changes of EMG amplitude, median frequency, synergy structure, and activation coefficients. Three to four synergies were sufficient to account for the variability contained in the original data. Synergy structure was conserved with fatigue, but interestingly synergy activation coefficients decreased on average by 24.5% with fatigue development. EMG amplitude did not change systematically with fatigue, whereas EMG median frequency consistently decreased across all muscles. These results support the notion of a neuromuscular modular organisation as the building blocks of human movement, with adaptations to synergy recruitment occurring with fatigue. When synergy tuning properties are considered, the reduction of activation of muscle synergies may be a reliable marker to identify fatigue. PMID- 29977198 TI - The Complex Nature of Hippocampal-Striatal Interactions in Spatial Navigation. AB - Decades of research have established the importance of the hippocampus for episodic and spatial memory. In spatial navigation tasks, the role of the hippocampus has been classically juxtaposed with the role of the dorsal striatum, the latter of which has been characterized as a system important for implementing stimulus-response and action-outcome associations. In many neuroimaging paradigms, this has been explored through contrasting way finding and route following behavior. The distinction between the contributions of the hippocampus and striatum to spatial navigation has been supported by extensive literature. Convergent research has also underscored the fact that these different memory systems can interact in dynamic ways and contribute to a broad range of navigational scenarios. For example, although familiar routes may often be navigable based on stimulus-response associations, hippocampal episodic memory mechanisms can also contribute to egocentric route-oriented memory, enabling recall of context-dependent sequences of landmarks or the actions to be made at decision points. Additionally, the literature has stressed the importance of subdividing the striatum into functional gradients-with more ventral and medial components being important for the behavioral expression of hippocampal-dependent spatial memories. More research is needed to reveal how networks involving these regions process and respond to dynamic changes in memory and control demands over the course of navigational events. In this Perspective article, we suggest that a critical direction for navigation research is to further characterize how hippocampal and striatal subdivisions interact in different navigational contexts. PMID- 29977199 TI - Alpha Phase Synchronization of Parietal Areas Reflects Switch-Specific Activity During Mental Rotation: An EEG Study. AB - Action selection is typically influenced by the history of previously selected actions (the immediate motor history), which is apparent when a selected action is switched from a previously selected one to a new one. This history dependency of the action selection is even observable during a mental hand rotation task. Thus, we hypothesized that the history-dependent interaction of actions might share the same neural mechanisms among different types of action switching tasks. An alternative hypothesis is that the history dependency of the mental hand rotation task might involve a distinctive neural mechanism from the general action selection tasks so that the reported observation with the mental hand rotation task in the previously published literature might lack generality. To refute this possibility, we compared neural activity during action switching in the mental hand rotation with the general action switching task which is triggered by a simple visual stimulus. In the experiment, to focus on temporal changes in whole brain oscillatory activity, we recorded electroencephalographic (EEG) signals while 25 healthy subjects performed the two tasks. For analysis, we examined functional connectivity reflected in EEG phase synchronization and analyzed temporal changes in brain activity when subjects switched from a previously selected action to a new action. Using a clustering-based method to identify functional connectivity reflected in time-varying phase synchronization, we identified alpha-power inter-parietal synchronization that appears only during switching of the selected action, regardless of the hand laterality in the presented image. Moreover, the current study revealed that for both tasks the extent of this alpha-power inter-parietal synchronization was altered by the history of the selected actions. These findings suggest that alpha-power inter parietal synchronization is engaged as a form of switching-specific functional connectivity, and that switching-related activity is independent of the task paradigm. PMID- 29977200 TI - Experience Replay Using Transition Sequences. AB - Experience replay is one of the most commonly used approaches to improve the sample efficiency of reinforcement learning algorithms. In this work, we propose an approach to select and replay sequences of transitions in order to accelerate the learning of a reinforcement learning agent in an off-policy setting. In addition to selecting appropriate sequences, we also artificially construct transition sequences using information gathered from previous agent-environment interactions. These sequences, when replayed, allow value function information to trickle down to larger sections of the state/state-action space, thereby making the most of the agent's experience. We demonstrate our approach on modified versions of standard reinforcement learning tasks such as the mountain car and puddle world problems and empirically show that it enables faster, and more accurate learning of value functions as compared to other forms of experience replay. Further, we briefly discuss some of the possible extensions to this work, as well as applications and situations where this approach could be particularly useful. PMID- 29977201 TI - Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis. AB - People with Down syndrome (DS) are at high risk for developing Alzheimer disease (AD). Neuropathology consistent with AD is present by 40 years of age and dementia may develop up to a decade later. In this review, we describe metabolic and vascular neuroimaging studies in DS that suggest these functional changes are a key feature of aging, linked to cognitive decline and AD in this vulnerable cohort. FDG-PET imaging in DS suggests systematic reductions in glucose metabolism in posterior cingulate and parietotemporal cortex. Magentic resonance spectroscopy studies show consistent decreases in neuronal health and increased myoinositol, suggesting inflammation. There are few vascular imaging studies in DS suggesting a gap in our knowledge. Future studies would benefit from longitudinal measures and combining various imaging approaches to identify early signs of dementia in DS that may be amenable to intervention. PMID- 29977202 TI - Cannabigerol Action at Cannabinoid CB1 and CB2 Receptors and at CB1-CB2 Heteroreceptor Complexes. AB - Cannabigerol (CBG) is one of the major phytocannabinoids present in Cannabis sativa L. that is attracting pharmacological interest because it is non psychotropic and is abundant in some industrial hemp varieties. The aim of this work was to investigate in parallel the binding properties of CBG to cannabinoid CB1 (CB1R) and CB2 (CB2R) receptors and the effects of the compound on agonist activation of those receptors and of CB1-CB2 heteroreceptor complexes. Using [3H] CP-55940, CBG competed with low micromolar Ki values the binding to CB1R and CB2R. Homogeneous binding in living cells, which is only technically possible for the CB2R, provided a 152 nM Ki value. Also interesting, CBG competed the binding of [3H]-WIN-55,212-2 to CB2R but not to CB1R (Ki: 2.7 versus >30 MUM). The phytocannabinoid modulated signaling mediated by receptors and receptor heteromers even at low concentrations of 0.1-1 MUM. cAMP, pERK, beta-arrestin recruitment and label-free assays in HEK-293T cells expressing the receptors and treated with endocannabinoids or selective agonists proved that CBG is a partial agonist of CB2R. The action on cells expressing heteromers was similar to that obtained in cells expressing the CB2R. The effect of CBG on CB1R was measurable but the underlying molecular mechanisms remain uncertain. The results indicate that CBG is indeed effective as regulator of endocannabinoid signaling. PMID- 29977204 TI - Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397. AB - Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating intracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopaminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopamine-dependent hyperactivity in mice lacking the dopamine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopamine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous in vitro and in vivo findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on intracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation. PMID- 29977203 TI - CXCR7 Targeting and Its Major Disease Relevance. AB - Chemokine receptors are the target of small peptide chemokines. They play various important roles in physiological and pathological processes. CXCR7, later renamed ACKR3, is a non-classical seven transmembrane-spanning receptor whose function as a signaling or non-signaling scavenger/decoy receptor is currently under debate. Even for cell signaling mechanisms, there has been inconsistency on whether CXCR7 couples to G-proteins or beta-arrestins. Several reasons may contribute to this uncertainty or controversy. In one hand, it has been neglected that CXCR7 has more than five natural ligands and unfortunately, most of the prior research only studied SDF-1 (CXCL12) and/or I-TAC (CXCL11); on the other hand, there are mounting evidence supporting ligand and tissue bias for receptor signaling, but limited such information is available for CXCR7. In this review we focus on summarizing the endogenous and exogenous ligands of CXCR7, the main diseases related to CXCR7 and the biased signaling events happening on CXCR7. These three aspects of CXCR7 pharmacologic properties may explain why the contradicting opinions of whether CXCR7 is a signaling or non-signaling receptor exist. Further, potential new direction and perspective for the study of CXCR7 biology and pharmacology are highlighted. PMID- 29977205 TI - Pharmacist-Led Intervention to Enhance Medication Adherence in Patients With Acute Coronary Syndrome in Vietnam: A Randomized Controlled Trial. AB - Background: Patient adherence to cardioprotective medications improves outcomes of acute coronary syndrome (ACS), but few adherence-enhancing interventions have been tested in low-income and middle-income countries. Objectives: We aimed to assess whether a pharmacist-led intervention enhances medication adherence in patients with ACS and reduces mortality and hospital readmission. Methods: We conducted a randomized controlled trial in Vietnam. Patients with ACS were recruited, randomized to the intervention or usual care prior to discharge, and followed 3 months after discharge. Intervention patients received educational and behavioral interventions by a pharmacist. Primary outcome was the proportion of adherent patients 1 month after discharge. Adherence was a combined measure of self-reported adherence (the 8-item Morisky Medication Adherence Scale) and obtaining repeat prescriptions on time. Secondary outcomes were (1) the proportion of patients adherent to medication; (2) rates of mortality and hospital readmission; and (3) change in quality of life from baseline assessed with the European Quality of Life Questionnaire - 5 Dimensions - 3 Levels at 3 months after discharge. Logistic regression was used to analyze data. Registration: ClinicalTrials.gov (NCT02787941). Results: Overall, 166 patients (87 control, 79 intervention) were included (mean age 61.2 years, 73% male). In the analysis excluding patients from the intervention group who did not receive the intervention and excluding all patients who withdrew, were lost to follow-up, died or were readmitted to hospital, a greater proportion of patients were adherent in the intervention compared with the control at 1 month (90.0% vs. 76.5%; adjusted OR = 2.77; 95% CI, 1.01-7.62) and at 3 months after discharge (90.2% vs. 77.0%; adjusted OR = 3.68; 95% CI, 1.14-11.88). There was no significant difference in median change of EQ-5D-3L index values between intervention and control [0.000 (0.000; 0.275) vs. 0.234 (0.000; 0.379); p = 0.081]. Rates of mortality, readmission, or both were 0.8, 10.3, or 11.1%, respectively; with no significant differences between the 2 groups. Conclusion: Pharmacist-led interventions increased patient adherence to medication regimens by over 13% in the first 3 months after ACS hospital discharge, but not quality of life, mortality and readmission. These results are promising but should be tested in other settings prior to broader dissemination. PMID- 29977207 TI - Topical TWEAK Accelerates Healing of Experimental Burn Wounds in Mice. AB - The interaction of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (Fn14) participates in inflammatory responses, fibrosis, and tissue remodeling, which are central in the repair processes of wounds. Fn14 is expressed in main skin cells including dermal fibroblasts. This study was designed to explore the therapeutic effect of TWEAK on experimental burn wounds and the relevant mechanism underlying such function. Third-degree burns were introduced in two BALB/c mouse strains. Recombinant TWEAK was administrated topically, followed by the evaluation of wound areas and histologic changes. Accordingly, the downstream cytokines, inflammatory cell infiltration, and extracellular matrix synthesis were examined in lesional tissue. Moreover, the differentiation markers were analyzed in cultured human dermal fibroblasts upon TWEAK stimulation. The results showed that topical TWEAK accelerated the healing of burn wounds in wild-type mice but not in Fn14 deficient mice. TWEAK strengthened inflammatory cell infiltration, and exaggerated the production of growth factor and extracellular matrix components in wound areas of wild-type mice. Moreover, TWEAK/Fn14 activation elevated the expression of myofibroblastic differentiation markers, including alpha-smooth muscle actin and palladin, in cultured dermal fibroblasts. Therefore, topical TWEAK exhibits therapeutic effect on experimental burn wounds through favoring regional inflammation, cytokine production, and extracellular matrix synthesis. TWEAK/Fn14 activation induces the myofibroblastic differentiation of dermal fibroblasts, partially contributing to the healing of burn wounds. PMID- 29977208 TI - Trimebutine Promotes Glioma Cell Apoptosis as a Potential Anti-tumor Agent. AB - Gliomas are the most common primary brain tumors with a usually fatal malignancy. They are associated with a poor prognosis although multiple therapeutic options have been available. Trimebutine is one of the prokinetic agents and it has been mainly used for treatment of disorders of the gastrointestinal (GI) tract such as irritable bowel syndrome. However, its effects on glioma cells remain unknown. Here, we used various concentrations of trimebutine to treat SHG44, U251, and U 87 MG human glioma/glioblastoma cells. And combined experiments of MTT, colony formation assay, and wound healing assay, as well as western blot and immunofluorescence staining were used to evaluate the effects of trimebutine on glioma cells. The results demonstrated that trimebutine significantly inhibited cell viability and colony formation. A significant inhibition of glioma cell migration was also indicated by wound healing assay. In addition, trimebutine promoted cell apoptosis and induced Bcl-2 downregulation, accompanied with Bax upregulation. Both immunofluorescence staining and western blot results showed that trimebutine increased the level of active Caspase-3. Moreover, trimebutine reduced the activation of both AKT and ERK signaling pathways. In subcutaneous U 87 MG cell xenograft tumors in nude mice, trimebutine significantly inhibited tumor growth. More TUNEL-positive apoptotic cells in tumor sections were observed in trimebutine-treated mice when compared to the vehicle control. Reduced Bcl-2 and upregulated Bax, as well as perturbed p-AKT and p-ERK signaling pathways were also observed in trimebutine-treated xenograft tissues. Our combined data indicated that trimebutine may be potentially applied for the clinical management of glioma/glioblastoma. PMID- 29977206 TI - Interplay of miRNAs and Canonical Wnt Signaling Pathway in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma is one of the leading causes of cancer death worldwide and the activation of canonical Wnt signaling pathway is universal in hepatocellular carcinoma patients. MicroRNAs are found to participate in the pathogenesis of hepatocellular carcinoma by activating or inhibiting components in the canonical Wnt signaling pathway. Meanwhile, transcriptional activation of microRNAs by canonical Wnt signaling pathway also contributes to the occurrence and progression of hepatocellular carcinoma. Pharmacological inhibition of hepatocellular carcinoma pathogenesis and other cancers by microRNAs are now in clinical trials despite the challenges of identifying efficient microRNAs candidates and safe delivery vehicles. The focus of this review is on the interplay mechanisms between microRNAs and canonical Wnt signaling pathway in hepatocellular carcinoma, and a deep understanding of the crosstalk will promote to develop a better management of this disease. PMID- 29977209 TI - Src Plays an Important Role in AGE-Induced Endothelial Cell Proliferation, Migration, and Tubulogenesis. AB - Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway. PMID- 29977211 TI - Multimodal Treatment With ECT for Identity Integration in a Patient With Dissociative Identity Disorder, Complex Post-traumatic Stress Disorder, and Major Depressive Disorder: A Rare Case Report. AB - The legitimacy and etiology of Dissociative Identity Disorder (DID) remains a controversial topic within Psychiatry. The two schools of thought are the Post Traumatic Model (PTM) and the Socio-Cognitive Model (SCM). This case highlights the validity of PTM in an individual who suffered severe and prolonged physical, psychological, and sexual abuse from 2 years old through adulthood. The reported abuse was corroborated and proven on two separate occasions via medical professionals/rape kit and the police. This resulted in the incarceration of one of her abusers. The only way for the patient to cope with the trauma she suffered was to dissociate, which resulted in the development of four full identity alters. In addition to being diagnosed with DID, the patient has been diagnosed with Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), and chronic suicidality. Unable to manage the suicidal ideations and MDD after nearly 10 years of therapy and psychiatric medications, the patient was referred for Electroconvulsive Therapy (ECT). Upon receiving ECT weekly for 2 years, the patient reported having "lost the others." As ECT progressed she went from having four alters to no alters and at the time of this report only being able to vaguely hear alter #4. With the integration of these alters she had access to the memories and pain that the alters had protected her from. Prior to losing the alters, her long-term memory was impaired by dissociative processes. Her long term memory was also impaired because when one of the alters was in control of consciousness only that alter remembered what had happened during that time, unless that alter shared what had happened with one or more of the others. It is unclear if frequent ECT was the catalyst that lead to the integration of her alters however, integration finally began following prolonged ECT. This case highlights the importance of the PTM as an etiological description for DID and the importance of mental health providers further studying and researching the effects of ECT on patients with chronic MDD, PTSD, and suicidal intent, especially if these are comorbid with DID. PMID- 29977210 TI - AltitudeOmics: Baroreflex Sensitivity During Acclimatization to 5,260 m. AB - Introduction: Baroreflex sensitivity (BRS) is essential to ensure rapid adjustment to variations in blood pressure (BP). Little is known concerning the adaptive responses of BRS during acclimatization to high altitude at rest and during exercise. Methods: Twenty-one healthy sea-level residents were tested near sea level (SL, 130 m), the 1st (ALT1) and 16th day (ALT16) at 5,260 m using radial artery catheterization. BRS was calculated using the sequence method (direct interpretation of causal link between BP and heartrate). At rest, subjects breathed a hyperoxic mixture (250 mmHg O2, end tidal) to isolate the preponderance of CO2 chemoreceptors. End-tidal CO2 varied from 20 to 50 mmHg to assess peripheral chemoreflex. Rebreathing provoked incremental increase in CO2, increasing BP to assess baroreflex. During incremental cycling exercise to exhaustion, subjects breathed room air. Results: Resting BRS decreased in ALT1 which was exacerbated in ALT16. This decrease in ALT1 was reversible upon additional inspired CO2, but not in ALT16. BRS decrease during exercise was greater and occurred at lower workloads in ALT1 compared to SL. At ALT16, this decrease returned toward SL values. Discussion/Conclusion: This study is the first to report attenuated BRS in acute hypoxia, exacerbated in chronic hypoxia. In ALT1, hypocapnia triggered BRS reduction whilst in ALT16 resetting of chemoreceptor triggered BRS reduction. The exercise BRS resetting was impaired in ALT1 but normalized in ALT16. These BRS decreases indicate decreased control of BP and may explain deteriorations of cardiovascular status during exposure to high altitude. PMID- 29977212 TI - Adolescent Basic Facial Emotion Recognition Is Not Influenced by Puberty or Own Age Bias. AB - Basic facial emotion recognition is suggested to be negatively affected by puberty onset reflected in a "pubertal dip" in performance compared to pre- or post-puberty. However, findings remain inconclusive. Further, research points to an own-age bias, i.e., a superior emotion recognition for peer faces. We explored adolescents' ability to recognize specific emotions. Ninety-five children and adolescents, aged 8-17 years, judged whether the emotions displayed by adolescent or adult faces were angry, sad, neutral, or happy. We assessed participants a priori by pubertal status while controlling for age. Results indicated no "pubertal dip", but decreasing reaction times across adolescence. No own-age bias was found. Taken together, basic facial emotion recognition does not seem to be disrupted during puberty as compared to pre- and post-puberty. PMID- 29977213 TI - Are Manipulation Checks Necessary? AB - Researchers are concerned about whether manipulations have the intended effects. Many journals and reviewers view manipulation checks favorably, and they are widely reported in prestigious journals. However, the prototypical manipulation check is a verbal (rather than behavioral) measure that always appears at the same point in the procedure (rather than its order being varied to assess order effects). Embedding such manipulation checks within an experiment comes with problems. While we conceptualize manipulation checks as measures, they can also act as interventions which initiate new processes that would otherwise not occur. The default assumption that manipulation checks do not affect experimental conclusions is unwarranted. They may amplify, undo, or interact with the effects of a manipulation. Further, the use of manipulation checks in mediational analyses does not rule out confounding variables, as any unmeasured variables that correlate with the manipulation check may still drive the relationship. Alternatives such as non-verbal and behavioral measures as manipulation checks and pilot testing are less problematic. Reviewers should view manipulation checks more critically, and authors should explore alternative methods to ensure the effectiveness of manipulations. PMID- 29977215 TI - Effects of Face and Background Color on Facial Expression Perception. AB - Detecting others' emotional states from their faces is an essential component of successful social interaction. However, the ability to perceive emotional expressions is reported to be modulated by a number of factors. We have previously found that facial color modulates the judgment of facial expression, while another study has shown that background color plays a modulatory role. Therefore, in this study, we directly compared the effects of face and background color on facial expression judgment within a single experiment. Fear-to-anger morphed faces were presented in face and background color conditions. Our results showed that judgments of facial expressions was influenced by both face and background color. However, facial color effects were significantly greater than background color effects, although the color saturation of faces was lower compared to background colors. These results suggest that facial color is intimately related to the judgment of facial expression, over and above the influence of simple color. PMID- 29977214 TI - Category-Based Learning About Deviant Outgroup Members Hinders Performance in Trust Decision Making. AB - The present research examines whether individuation and categorization processes influence trust decisions about strangers at first and across repeated interactions. In a partial replication of the study reported by Canadas et al. (2015), participants played an adaptation of the multi-round trust game paradigm and had to decide whether or not to cooperate with unknown partners. Gender (Study 1a) and ethnicity (Studies 1b, 2, and 3) served to create distinct social categories among the game partners, whose reciprocation rates were manipulated at group and individual levels. At the group level, two social groups (i.e., ingroup vs. outgroup) were associated with opposite reciprocation rates (i.e., high vs. low reciprocation rate). At the individual level, consistency was manipulated by altering the reciprocation rate of one out of four members of each social group. That is, there was one inconsistent individual in each group showing a pattern of reciprocation opposite to the group reciprocation rate. Our data, contrary to Canadas et al.'s (2015) findings, suggested that ingroup partners were individuated given that participants made their decisions to cooperate with the trustees according to their individual reciprocation rate and independently of the group reciprocation rate. In contrast, decisions about outgroup partners (i.e., men in Study 1a and Blacks in Studies 1b, 2, and 3) were affected by category-based thinking. At the same time, in comparison with ingroup, greater cooperation was observed with ethnic outgroups but not with gender outgroups. The consistency of our results with the previous literature on social categorization and across the three experiments seems to indicate they are reliable, supporting the hypothesis that categorization and individuation processes guide trust decision-making, promoting individuation mainly for ingroup and categorization among outgroup members. PMID- 29977216 TI - The Drivers of Heuristic Optimization in Insect Object Manufacture and Use. AB - Insects have small brains and heuristics or 'rules of thumb' are proposed here to be a good model for how insects optimize the objects they make and use. Generally, heuristics are thought to increase the speed of decision making by reducing the computational resources needed for making decisions. By corollary, heuristic decisions are also deemed to impose a compromise in decision accuracy. Using examples from object optimization behavior in insects, we will argue that heuristics do not inevitably imply a lower computational burden or lower decision accuracy. We also show that heuristic optimization may be driven by certain features of the optimization problem itself: the properties of the object being optimized, the biology of the insect, and the properties of the function being optimized. We also delineate the structural conditions under which heuristic optimization may achieve accuracy equivalent to or better than more fine-grained and onerous optimization methods. PMID- 29977217 TI - Involuntary Entry Into Consciousness From the Activation of Sets: Object Counting and Color Naming. AB - High-level cognitions can enter consciousness through the activation of certain action sets and the presentation of external stimuli ("set-based entry," for short). Set-based entry arises in a manner that is involuntary and systematic. In the Reflexive Imagery Task, for example, subjects are presented with visual objects and instructed to not think of the names of the objects. Involuntary subvocalizations arise on roughly 80% of the trials. We examined whether or not set-based entry can also occur in the case of involuntary counting. Subjects in Experiment 1A were instructed to not count the number of objects presented in an array. Involuntary counting arose on a high proportion of the trials (a mean proportion of ~0.90) for stimulus arrays having 2-5 objects, and such counting arose less frequently across trials when the array consisted of 6-10 objects (a mean proportion of ~0.21). The data from Experiment 1B revealed that, when people choose to perform Set X, they also experience thoughts about an unselected Set (Set Y). Subjects were trained on one set (e.g., to "color name") and then, when presented with stimuli, were given the choice to perform the trained set or a novel set. Consistent with theories proposing that the conscious contents represent several potential action plans, subjects were equally likely to experience set-related imagery or set-unrelated imagery. Our findings regarding set-based entry are relevant to many subfields of psychology and neuroscience (e.g., the study of high-level mental processes, attention, imagery, and action control). PMID- 29977218 TI - Parent-Child Cohesion, Basic Psychological Needs Satisfaction, and Emotional Adaptation in Left-Behind Children in China: An Indirect Effects Model. AB - This study aimed to validate an indirect effects model of parent-child cohesion in emotional adaptation (i.e., loneliness and depression) via basic psychological needs satisfaction in Chinese left-behind children as well as the applicability of the model to both genders. A cross-sectional study was conducted and included 1,250 children aged between 9 and 12 years (635 left-behind children and 615 non left-behind children) from rural primary schools. The results showed that: (1) relative to non-left-behind children, left-behind children exhibited significantly higher loneliness and depression scores and greater disadvantages involving father-child cohesion, mother-child cohesion, and psychological needs satisfaction. (2) Father- and mother-child cohesion were significantly negatively correlated with loneliness and depression and significantly positively correlated with psychological needs satisfaction in left-behind children. (3) Through structural equation modeling showed that psychological needs satisfaction partially mediated the relationship between parent-child cohesion and emotional outcomes in left-behind children. (4) Through multi-group analyses showed significant gender differences in structural weighting between parent-child cohesion and emotional adaptation, in that parent-child cohesion in left-behind boys was a stronger negative predictor of unfavorable emotional outcomes relative to that observed in left-behind girls, while psychological needs satisfaction in left-behind girls was a stronger negative predictor of unfavorable emotional outcomes relative to that observed in left-behind boys. The implications of these findings for interventions directed at Chinese left-behind children were discussed. PMID- 29977219 TI - Behavioral Inhibition Underlies the Link Between Interoceptive Sensitivity and Anxiety-Related Temperamental Traits. AB - Interoceptive sensitivity (IS) is a biologically determined, constitutional trait of an individual. High IS has been often associated with proneness to anxiety. This association has been explained by elevated autonomic responsiveness in anxious individuals. However, in a heartbeat discrimination task (discrimination of heartbeats' simultaneity to an external stimulus) low cardiac responsiveness has accompanied enhanced performance. The relation between these factors seems task dependent, and cannot comprehensively explain the link between IS and anxiety. We explored for additional explanatory factors for this link. More specifically, we studied which anxiety-related temperamental traits most strongly predict IS in the discrimination task. Compatibly with earlier findings, IS was positively associated with individual trait anxiety and also other related traits such as negative affect, emotional intensity, and introversion. Interestingly, behavioral inhibition was the temperamental trait that most strongly predicted high IS, and, in fact, accounted for its significant associations with the other anxiety-related temperamental traits. Good performance on heartbeat discrimination task may reflect adaptive attentional control abilities in behaviorally inhibited individuals. These results can improve our understanding of how IS and other traits together determine the personality and wellbeing of a human individual. PMID- 29977220 TI - Parent-Child Relationships and Resilience Among Chinese Adolescents: The Mediating Role of Self-Esteem. AB - The present study primarily aimed to examine whether self-esteem serves as a mediator in the associations between parent-child relationships, including parental support and parent-child conflict, and resilience among adolescents. Three hundred and four Chinese adolescents were surveyed with questionnaires and structural equation modeling was adopted to test the mediational hypothesis. The results indicated that the associations between parent-child relationships and adolescent resilience were primarily mediated by self-esteem and that parental support was more robustly linked with adolescent resilience than parent adolescent conflict. The current study also tested a competitive mediational model in which resilience was the mediator and self-esteem was the outcome variable, and observed that this model was also well-established but inferior to the hypothesized mediational model. These findings extend our insight into the mechanisms underlying the associations among parent-child relationships, self esteem, and resilience among adolescents and suggest that adolescent resilience promotion programs should focus on improving parental support in a family context and developing individual self-esteem. PMID- 29977221 TI - Effects of Mindfulness-Based Stress Reduction on Depression in Adolescents and Young Adults: A Systematic Review and Meta-Analysis. AB - Background: Mindfulness as a positive mental health intervention approach has been increasingly applied to address depression in young people. This systematic review and meta-analysis evaluated the effects of mindfulness-based stress reduction (MBSR) in the treatment of depression among adolescents and young adults. Methods: Electronic databases and references in articles were searched. Randomized controlled trials (RCTs) evaluating MBSR and reporting outcomes for depressive symptoms among young people aged 12 to 25 years were included. Data extraction and risk of bias assessment were conducted by two reviewers independently. Hedges' g with a 95% confidence interval was calculated to represent intervention effect. Results: Eighteen RCTs featuring 2,042 participants were included in the meta-analysis. Relative to the control groups (e.g., no treatment, treatment as usual, or active control), MBSR had moderate effects in reducing depressive symptoms at the end of intervention (Hedges' g = 0.45). No statistically significant effects were found in follow-up (Hedges' g = 0.24) due to a lack of statistical power. Meta-regression found that the average treatment effect might be moderated by control condition, treatment duration, and participants' baseline depression. Conclusion: MBSR had moderate effects in reducing depression in young people at posttest. Future research is needed to assess the follow-up effects of MBSR on depressive symptoms among adolescents and young adults. PMID- 29977222 TI - Different Subcomponents of Executive Functioning Predict Different Growth Parameters in Mathematics: Evidence From a 4-Year Longitudinal Study With Chinese Children. AB - Executive functioning (EF), an umbrella term used to represent cognitive skills engaged in goal-directed behaviors, has been found to be a unique predictor of mathematics performance. However, very few studies have examined how the three core EF subcomponents (inhibition, shifting, and working memory) predict the growth parameters (intercept and slope) in mathematics skills and even fewer studies have been conducted in a non-Western country. Thus, the purpose of this study was to examine how inhibition, shifting, and working memory predict the growth parameters in arithmetic accuracy and fluency in a group of Chinese children (n = 179) followed from Grade 2 (mean age = 97.89 months) to Grade 5 (mean age = 133.43 months). In Grade 2, children were assessed on measures of nonverbal IQ, number sense, speed of processing, inhibition, shifting, and working memory. In addition, in Grades 2-5, they were assessed on arithmetic accuracy and fluency. Results of structural equation modeling showed that nonverbal IQ, speed of processing, and number sense predicted the intercept in arithmetic accuracy, while working memory was the only EF subcomponent to predict the slope (rate of growth) in arithmetic accuracy. In turn, number sense, speed of processing, inhibition, and shifting were significant predictors of the intercept in arithmetic fluency. None of the EF subcomponents predicted the slope in arithmetic fluency. Our findings reinforce those of previous studies in North America and Europe showing that EF contributes to mathematics performance over and above other key predictors of mathematics, and suggest that different EF subcomponents may predict different growth parameters in mathematics. PMID- 29977223 TI - Psychopathological Features of Bipolar Depression: Italian Validation of the Bipolar Depression Rating Scale (I-BDRS). AB - Background: Aim of the study was the validation of the Bipolar Disorder Rating Scale (BDRS) in an Italian population. Secondary aim was the evaluation of differences between unipolar and bipolar depression and between bipolar I and II depressed patients. Method: 125 Bipolar Disorder and 60 Major Depressive Disorder patients were administered an Italian translation of the BDRS (I-BDRS), Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Temperament and Character Inventory Revised (TCI-R). Results: I-BDRS showed considerable validity and reliability. Factor analysis found 3 subscales, two linked to depressive symptoms and one to mixed symptoms. Measures concerning depression (MADRS and HAM-D) were positively related to the I-BDRS's subscales, but mostly to the two subscales measuring depression. In mixed symptoms, the mean of the bipolar group was significantly higher than the unipolar group suggesting that the BDRS was able to distinguish between unipolar and bipolar depressed patients. Conclusion: I-BDRS is a valid scale for the measurement of depression in BD patients, with a notable internal consistency (Cronbach's alpha 0.82), a significant consistency between items/total (Cronbach's alpha from 0.80 to 0.82) and positive correlation with other scales (MADRS r = 0.67, p < 0.001; HDRS r = 0.81, p < 0.001; YMRS r = 0.46 p < 0.0001). The mixed state sub-scale shows usefulness in differentiating bipolar from unipolar patients. I-BDRS could be a sensitive tool, both in pure depression and in mixed states, and could be used in the everyday screening and treatment of Bipolar Disorder. PMID- 29977224 TI - Neuromodulatory Inputs to Motoneurons Contribute to the Loss of Independent Joint Control in Chronic Moderate to Severe Hemiparetic Stroke. AB - In chronic hemiparetic stroke, increased shoulder abductor activity causes involuntary increases in elbow, wrist, and finger flexor activation, an abnormal muscle coactivation pattern known as the flexion synergy. Recent evidence suggests that flexion synergy expression may reflect recruitment of contralesional cortico-reticulospinal motor pathways following damage to the ipsilesional corticospinal tract. However, because reticulospinal motor pathways produce relatively weak post-synaptic potentials in motoneurons, it is unknown how preferential use of these pathways could lead to robust muscle activation. Here, we hypothesize that the descending neuromodulatory component of the ponto medullary reticular formation, which uses the monoaminergic neurotransmitters norepinephrine and serotonin, serves as a gain control mechanism to facilitate motoneuron responses to reticulospinal motor commands. Thus, inhibition of the neuromodulatory component would reduce flexion synergy expression by disfacilitating spinal motoneurons. To test this hypothesis, we conducted a pre clinical study utilizing two targeted neuropharmacological probes and inert placebo in a cohort of 16 individuals with chronic hemiparetic stroke. Test compounds included Tizanidine (TIZ), a noradrenergic alpha2 agonist and imidazoline ligand selected for its ability to reduce descending noradrenergic drive, and Isradipine, a dihyropyridine calcium-channel antagonist selected for its ability to post-synaptically mitigate a portion of the excitatory effects of monoamines on motoneurons. We used a previously validated robotic measure to quantify flexion synergy expression. We found that Tizanidine significantly reduced expression of the flexion synergy. A predominantly spinal action for this effect is unlikely because Tizanidine is an agonist acting on a baseline of spinal noradrenergic drive that is likely to be pathologically enhanced post stroke due to increased reliance on cortico-reticulospinal motor pathways. Although spinal actions of TIZ cannot be excluded, particularly from Group II pathways, our finding is consistent with a supraspinal action of Tizanidine to reduce descending noradrenergic drive and disfacilitate motoneurons. The effects of Isradipine were not different from placebo, likely related to poor central bioavailability. These results support the hypothesis that the descending monoaminergic component of the ponto-medullary reticular formation plays a key role in flexion synergy expression in chronic hemiparetic stroke. These results may provide the basis for new therapeutic strategies to complement physical rehabilitation. PMID- 29977225 TI - Role of Chemokines in Thyroid Cancer Microenvironment: Is CXCL8 the Main Player? AB - Tumor-related inflammation does influence the biological behavior of neoplastic cells and ultimately the patient's outcome. With specific regard to thyroid cancer, the issue of tumor-associated inflammation has been extensively studied and recently reviewed. However, the role of chemokines, which play a crucial role in determining the immuno-phenotype of tumor-related inflammation, was not addressed in previous reviews on the topic. Experimental evidence shows that thyroid cancer cells actively secrete a wide spectrum of chemokines and, at least for some of them, solid scientific data support a role for these immune-active molecules in the aggressive behavior of the tumor. Our proposal for a review article on chemokines and thyroid cancer stems from the notion that chemokines, besides having the ability to attract and maintain immune cells at the tumor site, also produce several pro-tumorigenic actions, which include proangiogenetic, cytoproliferative, and pro-metastatic effects. Studies taking into account the role of CCL15, C-X-C motif ligand 12, CXCL16, CXCL1, CCL20, and CCL2 in the context of thyroid cancer will be reviewed with particular emphasis on CXCL8. The reason for focusing on CXCL8 is that this chemokine is the most studied one in human malignancies, displaying multifaceted pro-tumorigenic effects. These include enhancement of tumor cells growth, metastatization, and angiogenesis overall contributing to the progression of several cancers including thyroid cancer. We aim at reviewing current knowledge on the (i) ability of both normal and tumor thyroid cells to secrete CXCL8; (ii) direct/indirect pro tumorigenic effects of CXCL8 demonstrated by in vitro and in vivo studies specifically performed on thyroid cancer cells; and (iii) pharmacologic strategies proven to be effective for lowering CXCL8 secretion and/or its effects on thyroid cancer cells. PMID- 29977226 TI - Impact of Altered Mineral Metabolism on Pathological Cardiac Remodeling in Elevated Fibroblast Growth Factor 23. AB - Clinical and experimental studies indicate a possible link between high serum levels of fibroblast growth factor 23 (FGF23), phosphate, and parathyroid hormone (PTH), deficiency of active vitamin D (1,25D) and klotho with the development of pathological cardiac remodeling, i.e., left ventricular hypertrophy and myocardial fibrosis, but a causal link has not been established so far. Here, we investigated the cardiac phenotype in klotho hypomorphic (kl/kl) mice and Hyp mice, two mouse models of elevated FGF23 levels and klotho deficiency, but differing in parameters of mineral metabolism, by using histology, quantitative real-time PCR, immunoblot analysis, and serum and urine biochemistry. Additionally, the specific impact of calcium, phosphate, PTH, and 1,25D on hypertrophic growth of isolated neonatal rat cardiac myocytes was investigated in vitro. Kl/kl mice displayed high serum Fgf23 levels, increased relative heart weight, enhanced cross-sectional area of individual cardiac myocytes, activated cardiac Fgf23/Fgf receptor (Fgfr) 4/calcineurin/nuclear factor of activated T cell (NFAT) signaling, and induction of pro-hypertrophic NFAT target genes including Rcan1, bMHC, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) as compared to corresponding wild-type (WT) mice. Investigation of fibrosis-related molecules characteristic for pathological cardiac remodeling processes demonstrated ERK1/2 activation and enhanced expression of Tgf-beta1, collagen I, and Mmp2 in kl/kl mice than in WT mice. In contrast, despite significantly elevation of serum and cardiac Fgf23, and reduced renal klotho expression, Hyp mice showed no signs of pathological cardiac remodeling. Kl/kl mice showed enhanced serum calcium and phosphate levels, while Hyp mice showed unchanged serum calcium levels, lower serum phosphate, and elevated serum iPTH concentrations compared to corresponding WT mice. In cultured cardiac myocytes, treatment with both calcium or phosphate significantly upregulated endogenous Fgf23 mRNA expression and stimulated hypertrophic cell growth and expression of pro-hypertrophic genes. The treatment with PTH induced hypertrophic cell growth only, and stimulation with 1,25D had no significant effects. In conclusion, our data indicate that Hyp mice, in contrast to kl/kl mice appear to be protected from pathological cardiac remodeling during conditions of high FGF23 levels and klotho deficiency, which may be due, at least in part, to differences in mineral metabolism alterations, i.e., hypophosphatemia and lack of hypercalcemia. PMID- 29977227 TI - Mechanisms Underlying the Synergistic Action of Insulin and Growth Hormone on IGF I and -II Expression in Grass Carp Hepatocytes. AB - In mammals, insulin is known to modify growth hormone (GH)-induced IGF-I expression at the hepatic level, which also contributes to the functional crosstalk between energy homeostasis and somatotropic axis. However, the studies on the comparative aspects of this phenomenon are limited and the mechanisms involved have not been fully characterized. Using a serum-free culture of grass carp hepatoctyes, the functional interaction between GH and insulin on hepatic expression of IGF-I and -II was examined in a fish model. In carp hepatocytes, GH could up-regulate IGF-I and -II mRNA expression via the JAK2/STAT5, MEK/ERK and PI3K/Akt pathways. These stimulatory effects were mimicked by insulin via activation of the PI3K/Akt but not MEK/ERK and P38 MAPK cascades. Although insulin did not activate JAK2 and STAT5 at hepatocyte level, insulin-induced IGF I and -II mRNA expression were highly dependent on the normal functioning of JAK2/STAT5 pathway. In parallel experiments, insulin co-treatment was found to markedly enhance IGF-I and -II responses induced by GH and these potentiating effects were mediated by insulin receptor (InsR) but not IGF-I receptor. Interestingly, co-treatment with GH also enhanced insulin-induced InsR phosphorylation with a current elevation in protein:protein interaction between GH receptor and phosphorylated InsR and these stimulatory effects were noted with further enhancement in STAT5, ERK1/2 and Akt phosphorylation at hepatocyte level. Consistent with these findings, the potentiating effects of GH and insulin co treatment on IGF-I and -II mRNA expression were found to be suppressed/abolished by inhibiting JAK2/STAT5, MEK/ERK and PI3K/Akt but not P38 MAPK pathways. These results, as a whole, suggest that insulin and GH can act in a synergistic manner in the carp liver to up-regulate IGF-I and -II expression through protein:protein interaction at the receptor level followed by potentiation in post-receptor signaling. PMID- 29977228 TI - Circadian Regulation of Glutamate Transporters. AB - L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS). This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases. Increasing evidence indicates glutamate transporters are controlled by the circadian system in direct and indirect manners, so in this contribution we focus on the mechanisms of circadian regulation (transcriptional, translational, post translational and post-transcriptional regulation) of glutamate transport in neuronal and glial cells, and their consequence in brain function. PMID- 29977229 TI - Diagnostic Aspects of Veterinary and Human Aspergillosis. AB - The genus Aspergillus is composed of more than 300 species, a fraction of which are involved in animal or human infections mostly following environmental exposure. Various risk factors (i.e., immunosuppression, tuberculosis) have been recognized for human whereas for veterinary infections, unhygienic management, trauma, anatomical conformation of the skull, or suspected immunological deficiencies have been suggested. In animals, aspergillosis is mostly sporadic but in some circumstance such as infections on poultry farms may involve the whole flock. Since the high prevalence of immunosuppression in human patients has not been mirrored in veterinary medicine, and although to the best of our knowledge, no comprehensive data on the prevalence of aspergillosis in animals has been published, their epidemiology has not changed during the last decades. The impact of these infections may be economic or if they are incurable, sentimental. The objective of the first part is to describe the diagnosis of the main clinical entities caused by Aspergillus spp. in animals. It includes disseminated canine aspergillosis, canine and feline sino-nasal and sino-orbital aspergillosis, guttural pouch mycosis in horses, mycotic abortion in cattle, mycotic keratitis in horses, and avian aspergillosis. When pathogenesis and clinical aspects are relevant for diagnosis-they will be addressed as well. The second part deals with human aspergillosis, which is a multifaceted disease, manifested in a spectrum of clinical entities affecting one or more organs. Diagnosis is based on the clinical manifestation, supported and confirmed by laboratory means, involving the classical approach of demonstrating the etiological agent in the clinical specimens and in culture. Noncultural methods, such as antigen detection and/or molecular assays to detect fungal nucleic acids or protein profiles, are used as well. The isolation and identification of the fungus allows the determination of its susceptibility to antifungal drugs. Thus, antifungal susceptibility testing maybe considered as part of the diagnostic process, which is of relevance for management of the infection. In this review article, the part dealing with diagnostic aspects of aspergillosis in humans concentrates on susceptibility testing of Aspergillus spp. to antifungal drugs and drug combinations. The technologies and methods of susceptibility testing are described and evaluated. PMID- 29977230 TI - Exposure to Arsenic Alters the Microbiome of Larval Zebrafish. AB - Exposure to environmental toxins such as heavy metals can perturb the development and stability of microbial communities associated with human or animal hosts. Widespread arsenic contamination in rivers and riparian habitats therefore presents environmental and health concerns for populations living near sources of contamination. To investigate how arsenic affects host microbiomes, we sequenced and characterized the microbiomes of twenty larval zebrafish exposed to three concentrations of arsenic that are found in contaminated water-low (10 ppb), medium (50 ppb), and high (100 ppb) for 20 days. We found that even a small concentration of arsenic changed the overall microbial composition, structure and diversity of microbial communities, causing dysbiosis in developing larval zebrafish microbiota. In addition, we found that a high concentration of arsenic also increased the abundance of a class 1 integron, an integrase-dependent system facilitating the horizontal transfer of genes conferring resistance to heavy metals and antibiotics. PMID- 29977231 TI - Endoplasmic Reticulum Stress Mediated MDRV p10.8 Protein-Induced Cell Cycle Arrest and Apoptosis Through the PERK/eIF2alpha Pathway. AB - In this study, the mechanism of Muscovy duck reovirus (MDRV) p10.8 protein induced pathogenesis was investigated, with a focus on endoplasmic reticulum (ER) stress. In chicken embryo fibroblasts cell lines (DF1), pCI-neo-flg-p10.8 protein transfection increased the phosphorylation (p-) levels of PERK and eIF2alpha as shown by Western blotting analysis and led to the dissociation of BiP from PERK as shown by co-immunoprecipitation (Co-IP) analysis. Results of treatment with both ER stress activator and inhibitor further confirmed that p10.8 protein induced ER stress. Subsequently, using flow cytometry analysis, it was also found that p10.8 protein induced cell cycle arrest during the G0/G1 phase. Furthermore, p10.8 transfection increased the phosphorylation levels of PERK and eIF2alpha, and reduced the expression levels of CDK2, CDK4, and Cyclin E according to Western blotting analysis. Treatment with ER stress activator and ER stress inhibitor after p10.8 protein transfection in DF1 cells further indicated that p10.8 protein induced ER stress, which resulted in cell cycle arrest. The results of knockdown of either PERK or eIF2alpha genes further confirmed that p10.8 protein-induced ER stress led to cell cycle arrest through the PERK/eIF2alpha pathway. Further results showed that p10.8 protein induced ER stress and apoptosis in DF1 cells. The expression levels of p-PERK, p-eIF2alpha, CHOP, cleaved-Caspase12, and cleaved-Caspase3 were increased by p10.8 protein. Test results of treatment with each of Tunicamycin, TUDCA and knockdown of PERK, and eIF2alpha, confirmed that p10.8 protein induced ER stress involving apoptosis via the PERK/eIF2alpha pathway. In conclusion, MDRV p10.8 protein induced ER stress that caused cell cycle arrest and apoptosis through the PERK/eIF2alpha pathway. PMID- 29977232 TI - Enhanced Triacylglycerol Production With Genetically Modified Trichosporon oleaginosus. AB - Mitochondrial pyruvate dehydrogenase (PDH) is important in the production of lipids in oleaginous yeast, but other yeast may bypass the mitochondria (PDH bypass), converting pyruvate in the cytosol to acetaldehyde, then acetate and acetyl CoA which is further converted to lipids. Using a metabolic model based on the oleaginous yeast Yarrowia lipolytica, we found that introduction of this bypass to an oleaginous yeast should result in enhanced yield of triacylglycerol (TAG) on substrate. Trichosporon oleaginosus (formerly Cryptococcus curvatus) is an oleaginous yeast which can produce TAGs from both glucose and xylose. Based on the sequenced genome, it lacks at least one of the enzymes needed to complete the PDH bypass, acetaldehyde dehydrogenase (ALD), and may also be deficient in pyruvate decarboxylase and acetyl-CoA synthetase under production conditions. We introduced these genes to T. oleaginosus in various combinations and demonstrated that the yield of TAG on both glucose and xylose was improved, particularly at high C/N ratio. Expression of a phospholipid:diacyltransferase encoding gene in conjunction with the PDH bypass further enhanced lipid production. The yield of TAG on xylose (0.27 g/g) in the engineered strain approached the theoretical maximum yield of 0.289 g/g. Interestingly, TAG production was also enhanced compared to the control in some strains which were given only part of the bypass pathway, suggesting that these genes may contribute to alternative routes to cytoplasmic acetyl CoA. The metabolic model indicated that the improved yield of TAG on substrate in the PDH bypass was dependent on the production of NADPH by ALD. NADPH for lipid synthesis is otherwise primarily supplied by the pentose phosphate pathway (PPP). This would contribute to the greater improvement of TAG production from xylose compared to that observed from glucose when the PDH bypass was introduced, since xylose enters metabolism through the non-oxidative part of the PPP. Yield of TAG from xylose in the engineered strains (0.21-0.27 g/g) was comparable to that obtained from glucose and the highest so far reported for lipid or TAG production from xylose. PMID- 29977233 TI - Study of Bacterial Community Composition and Correlation of Environmental Variables in Rambla Salada, a Hypersaline Environment in South-Eastern Spain. AB - We studied the bacterial community in Rambla Salada in three different sampling sites and in three different seasons and the effect of salinity, oxygen, and pH. All sites samples had high diversity and richness (Rr > 30). The diversity indexes and the analysis of dendrograms obtained by DGGE fingerprint after applying Pearson's and Dice's coefficient showed a strong influence of sampling season. The Pareto-Lorenz (PL) curves and Fo analysis indicated that the microbial communities were balanced and despite the changing environmental conditions, they can preserve their functionality. The main phyla detected by DGGE were Bacteroidetes (39.73%), Proteobacteria (28.43%), Firmicutes (8.23%), and Cyanobacteria (5.14%). The majority of the sequences corresponding to uncultured bacteria belonged to Bacteroidetes phylum. Within Proteobacteria, the main genera detected were Halothiobacillus and Roseovarius. The environmental factors which influenced the community in a higher degree were the salinity and oxygen. The bacteria belonging to Bacteroidetes and Proteobacteria were positively influenced by salinity. Nevertheless, bacteria related to Alpha- and Betaproteobacteria classes and phylum Firmicutes showed a positive correlation with oxygen and pH but negative with salinity. The phylum Cyanobacteria were less influenced by the environmental variables. The bacterial community composition of Rambla Salada was also studied by dilution-to-extinction technique. Using this method, 354 microorganisms were isolated. The 16S sequences of 61 isolates showed that the diversity was very different to those obtained by DGGE and with those obtained previously by using classic culture techniques. The taxa identified by dilution-to-extinction were Proteobacteria (81.92%), Firmicutes (11.30%), Actinobacteria (4.52%), and Bacteroidetes (2.26%) phyla with Gammaproteobacteria as predominant class (65.7%). The main genera were: Marinobacter (38.85%), Halomonas (20.2%), and Bacillus (11.2%). Nine of the 61 identified bacteria showed less than 97% sequence identity with validly described species and may well represent new taxa. The number of bacteria in different samples, locations, and seasons were calculated by CARD-FISH, ranging from 54.3 to 78.9% of the total prokaryotic population. In conclusion, the dilution-to-extinction technique could be a complementary method to classical culture based method, but neither gets to cultivate the major taxa detected by DGGE. The bacterial community was influenced significantly by the physico-chemical parameters (specially the salinity and oxygen), the location and the season of sampling. PMID- 29977234 TI - Is There a Role for Hematopoietic Growth Factors During Sepsis? AB - Sepsis is a complex syndrome characterized by simultaneous activation of pro- and anti-inflammatory processes. After an inflammatory phase, patients present signs of immunosuppression and possibly persistent inflammation. Hematopoietic growth factors (HGFs) are glycoproteins that cause immune cells to mature and/or proliferate. HGFs also have a profound effect on cell functions and behavior. HGFs play crucial role in sepsis pathophysiology and were tested in several clinical trials without success to date. This review summarizes the role played by HGFs during sepsis and their potential therapeutic role in the Management of sepsis-related immune disturbances. PMID- 29977235 TI - Deficiencies in Natural Killer Cell Numbers, Expansion, and Function at the Pre Neoplastic Stage of Pancreatic Cancer by KRAS Mutation in the Pancreas of Obese Mice. AB - The combined/synergistic effect of genetic mutation of KRAS in the pancreas and obesity, a life-style factor on suppression of natural killer (NK) cells at the pre-neoplastic stage of pancreatic cancer has not been investigated and is the subject of this report. Obese mice with KRAS (KC) mutation in the pancreas fed with high-fat calorie diet (HFCD) exhibit severe deficiencies in the NK cell expansion and function at the pre-neoplastic stage of pancreatic cancer. Decreased NK cell-mediated cytotoxicity is observed in the peripheral blood, spleen, pancreas, and peri-pancreatic adipose tissue in obese KC mice, whereas in bone marrow an increased NK cell-mediated cytotoxicity is observed when compared to lean WT mice fed with control diet (CD). Obese KC mice on HFCD demonstrated the least ability to expand NK cells or induce NK cell-mediated cytotoxicity when compared to the other groups of mice. Indeed, the following profile WT/CD > WT/HFCD > KC/CD > KC/HFCD was seen for the ability to expand NK cells or mediate cytotoxicity among four groups of mice in spleen, peripheral blood, pancreas, and peri-pancreatic adipose tissue. Sorted NK cells from the splenocytes of four groups of mice also exhibited the same profiles for the cytotoxicity as the unsorted splenocytes, and a decreased IFN-gamma secretion could be seen in cultures of NK cells from KC mice fed with either CD or HFCD. Cultures of NK cells with autologous monocytes from obese KC mice fed with HFCD exhibited decreased cytotoxicity and IFN-gamma secretion, whereas cultures of allogeneic NK cells from WT mice fed with CD with osteoclasts of obese mice fed with HFCD demonstrated decreased cytotoxicity but augmented IFN-gamma secretion. Increased IL-6 along with decreased IFN-gamma and cell-mediated cytotoxicity by the NK cells, within NK-adipose tissue of KC/HFCD mice, may provide safe microenvironment for the expansion of pancreatic tumors. PMID- 29977236 TI - Mycobacterium tuberculosis Invasion of the Human Lung: First Contact. AB - Early immune responses to Mycobacterium tuberculosis (Mtb) invasion of the human lung play a decisive role in the outcome of infection, leading to either rapid clearance of the pathogen or stable infection. Despite their critical impact on health and disease, these early host-pathogen interactions at the primary site of infection are still poorly understood. In vitro studies cannot fully reflect the complexity of the lung architecture and its impact on host-pathogen interactions, while animal models have their own limitations. In this study, we have investigated the initial responses in human lung tissue explants to Mtb infection, focusing primarily on gene expression patterns in different tissue resident cell types. As first cell types confronted with pathogens invading the lung, alveolar macrophages, and epithelial cells displayed rapid proinflammatory chemokine and cytokine responses to Mtb infection. Other tissue-resident innate cells like gamma/delta T cells, mucosal associated invariant T cells, and natural killer cells showed partially similar but weaker responses, with a high degree of variability across different donors. Finally, we investigated the responses of tissue-resident innate lymphoid cells to the inflammatory milieu induced by Mtb infection. Our infection model provides a unique approach toward host-pathogen interactions at the natural port of Mtb entry and site of its implantation, i.e., the human lung. Our data provide a first detailed insight into the early responses of different relevant pulmonary cells in the alveolar microenvironment to contact with Mtb. These results can form the basis for the identification of host markers that orchestrate early host defense and provide resistance or susceptibility to stable Mtb infection. PMID- 29977237 TI - Phenotype, Function, and Mobilization of 6-Sulfo LacNAc-Expressing Monocytes in Atopic Dermatitis. AB - Mononuclear phagocytes (MPs) are important immune regulatory cells in atopic dermatitis (AD). We previously identified 6-sulfo LacNAc-expressing monocytes (slanMo) as TNF-alpha- and IL-23-producing cells in psoriatic skin lesions and as inducers of IFN-gamma-, IL-17-, and IL-22-producing T cells. These cytokines are also upregulated in AD and normalize with treatment, as recently shown for dupilumab-treated patients. We here asked for the role of slanMo in AD. Increased numbers of slanMo were found in AD skin lesions. In difference to other MPs in AD, slanMo lacked expression of FcERI, CD1a, CD14, and CD163. slanMo from blood of patients with AD expressed increased levels of CD86 and produced IL-12 and TNF alpha at higher amounts than CD14+ monocytes and myeloid dendritic cells. While CD14+ monocytes from patients with AD revealed a reduced IL-12 production, we observed no difference in the cytokine production comparing slanMo in AD and healthy controls. Interestingly, experimentally induced mental stress, a common trigger of flares in patients with AD, rapidly mobilized slanMo which retained their high TNF-alpha-producing capacity. This study identifies slanMo as a distinct population of inflammatory cells in skin lesions and as proinflammatory blood cells in patients with AD. slanMo may, therefore, represent a potent future target for treatment of AD. PMID- 29977238 TI - In Vitro Evolution of Antibodies Inspired by In Vivo Evolution. AB - In vitro generation of antibodies often requires variable domain sequence evolution to adapt the protein in terms of affinity, specificity, or developability. Such antibodies, including those that are of interest for clinical development, may have their origins in a diversity of immunoglobulin germline genes. Others and we have previously shown that antibodies of different origins tend to evolve along different, preferred trajectories. Apart from substitutions within the complementary determining regions, evolution may also, in a germline gene-origin-defined manner, be focused to residues in the framework regions, and even to residues within the protein core, in many instances at a substantial distance from the antibody's antigen-binding site. Examples of such germline origin-defined patterns of evolution are described. We propose that germline gene-preferred substitution patterns offer attractive alternatives that should be considered in efforts to evolve antibodies intended for therapeutic use with respect to appropriate affinity, specificity, and product developability. We also hypothesize that such germline gene-origin-defined in vitro evolution hold potential to result in products with limited immunogenicity, as similarly evolved antibodies will be parts of conventional, in vivo-generated antibody responses and thus are likely to have been seen by the immune system in the past. PMID- 29977239 TI - The US Military Commitment to Vaccine Development: A Century of Successes and Challenges. AB - The US military has been a leading proponent of vaccine development since its founding. General George Washington ordered the entire American army to be variolated against smallpox after recognizing the serious threat that it posed to military operations. He did this on the recommendation from Dr. John Morgan, the physician-in-chief of the American army, who wrote a treatise on variolation in 1776. Although cases of smallpox still occurred, they were far fewer than expected, and it is believed that the vaccination program contributed to victory in the War of Independence. Effective military force requires personnel who are healthy and combat ready for worldwide deployment. Given the geography of US military operations, military personnel should also be protected against diseases that are endemic in potential areas of conflict. For this reason, and unknown to many, the US military has strongly supported vaccine research and development. Four categories of communicable infectious diseases threaten military personnel: (1) diseases that spread easily in densely populated areas (respiratory and dysenteric diseases); (2) vector-borne diseases (disease carried by mosquitoes and other insects); (3) sexually transmitted diseases (hepatitis, HIV, and gonorrhea); and (4) diseases associated with biological warfare. For each category, the US military has supported research that has provided the basis for many of the vaccines available today. Although preventive measures and the development of drugs have provided some relief from the burden of malaria, dengue, and HIV, the US military continues to fund research and development of prophylactic vaccines that will contribute to force health protection and global health. In the past few years, newly recognized infections with Zika, severe acute respiratory syndrome, Middle East respiratory syndrome viruses have pushed the US military to fund research and fast track clinical trials to quickly and effectively develop vaccines for emerging diseases. With US military personnel present in every region of the globe, one of the most cost-effective ways to maintain military effectiveness is to develop vaccines against prioritized threats to military members' health. PMID- 29977240 TI - Interferon Signaling Is Frequently Downregulated in Melanoma. AB - Immune checkpoint inhibitors that block the programmed cell death protein 1/PD-L1 pathway have significantly improved the survival of patients with advanced melanoma. Immunotherapies are only effective in 15-40% of melanoma patients and resistance is associated with defects in antigen presentation and interferon signaling pathways. In this study, we examined interferon-gamma (IFNgamma) responses in a large panel of immune checkpoint inhibitor-naive melanoma cells with defined genetic drivers; BRAF-mutant (n = 11), NRAS-mutant (n = 10), BRAF/NRAS wild type (n = 10), and GNAQ/GNA11-mutant uveal melanomas (UVMs) (n = 8). Cell surface expression of established IFNgamma downstream targets PD-L1, PD L2, HLA-A, -B, and -C, HLA-DR, and nerve growth factor receptor (NGFR) were analyzed by flow cytometry. Basal cellular expression levels of HLA-A, -B, -C, HLA-DR, NGFR, and PD-L2 predicted the levels of IFNgamma-stimulation, whereas PD L1 induction was independent of basal expression levels. Only 13/39 (33%) of the melanoma cell lines tested responded to IFNgamma with potent induction of all targets, indicating that downregulation of IFNgamma signaling is common in melanoma. In addition, we identified two well-recognized mechanisms of immunotherapy resistance, the loss of beta-2-microglobulin and interferon gamma receptor 1 expression. We also examined the influence of melanoma driver oncogenes on IFNgamma signaling and our data suggest that UVM have diminished capacity to respond to IFNgamma, with lower induced expression of several targets, consistent with the disappointing response of UVM to immunotherapies. Our results demonstrate that melanoma responses to IFNgamma are heterogeneous, frequently downregulated in immune checkpoint inhibitor-naive melanoma and potentially predictive of response to immunotherapy. PMID- 29977242 TI - Pivotal Role of IL-22 Binding Protein in the Epithelial Autoregulation of Interleukin-22 Signaling in the Control of Skin Inflammation. AB - Disruption of skin homeostasis can lead to inflammatory cutaneous diseases resulting from the dysregulated interplay between epithelial keratinocytes and immune cells. Interleukin (IL)-22 signaling through membrane-bound IL-22 receptor 1 (IL-22R1) is crucial to maintain cutaneous epithelial integrity, and its malfunction mediates deleterious skin inflammation. While IL-22 binding protein (IL-22BP) binds IL-22 to suppress IL-22 signaling, how IL-22BP controls epithelial functionality to prevent skin inflammation remains unclear. Here, we describe the pivotal role of IL-22BP in mediating epithelial autoregulation of IL 22 signaling for the control of cutaneous pathogenesis. Unlike prominent expression of IL-22BP in dendritic cells in lymphoid tissues, epidermal keratinocytes predominantly expressed IL-22BP in the skin in the steady state, whereas its expression decreased during the development of psoriatic inflammation. Deficiency in IL-22BP aggravates psoriasiform dermatitis, accompanied by abnormal hyperproliferation of keratinocytes and excessive cutaneous inflammation as well as enhanced dermal infiltration of granulocytes and gammadeltaT cells. Furthermore, IL-22BP abrogates the functional alternations of keratinocytes upon stimulation with IL-22. On the other hand, treatment with IL-22BP alleviates the severity of cutaneous pathology and inflammation in psoriatic mice. Thus, the fine-tuning of IL-22 signaling through autocrine IL 22BP production in keratinocytes is instrumental in the maintenance of skin homeostasis. PMID- 29977241 TI - Nonallergic Asthma and Its Severity: Biomarkers for Its Discrimination in Peripheral Samples. AB - Asthma is a complex and heterogeneous respiratory disorder characterized by chronic airway inflammation. It has generally been associated with allergic mechanisms related to type 2 airway inflammation. Nevertheless, between 10 and 33% of asthmatic individuals have nonallergic asthma (NA). Several targeted treatments are in clinical development for patients with Th2 immune response, but few biomarkers are been defined for low or non-Th2-mediated inflammation asthma. We have recently defined by gene expression a set of genes as potential biomarkers of NA, mainly associated with disease severity: IL10, MSR1, PHLDA1, SERPINB2, CHI3L1, IL8, and PI3. Here, we analyzed their protein expression and specificity using sera and isolated peripheral blood mononuclear cells (PBMCs). First, protein quantification was carried out using ELISA (in sera) or Western blot (proteins extracted from PBMCs by Trizol procedure), depending on the biomarker in 30 healthy controls (C) subjects and 30 NA patients. A receiver operating characteristic curve analysis was performed by using the R program to study the specificity and sensitivity of the candidate biomarkers at a gene- and protein expression level. Four kinds of comparisons were performed: total NA group vs C group, severe NA patients vs C, moderate-mild NA patients vs C, and severe NA patients vs moderate-mild NA patients. We found that all the single genes showed good sensitivity vs specificity for some phenotypic discrimination, with CHI3L1 and PI3 exhibiting the best results for C vs NA: CHI3L1 area under the curve (AUC) (CI 95%): 0.95 (0.84-1.00) and PI3 AUC: 0.99 (0.98-1.00); C vs severe NA: PI3 AUC: 1 (0.99-1.00); and C vs moderate-mild NA: CHI3L1 AUC: 1 (0.99 1.00) and PI3 AUC: 0.99 (0.96-1.00). However, the results for discriminating asthma disease and severity with protein expression were better when two or three biomarkers were combined. In conclusion, individual genes and combinations of proteins have been evaluated as reliable biomarkers for classifying NA subjects and their severity. These new panels could be good diagnostic tests. PMID- 29977243 TI - Dephosphorylated Polymerase I and Transcript Release Factor Prevents Allergic Asthma Exacerbations by Limiting IL-33 Release. AB - Background: Asthma is a chronic inflammatory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). IL-33 is considered as one of the most critical molecules in asthma pathogenesis. IL-33 is stored in nucleus and passively released during necrosis. But little is known about whether living cells can release IL-33 and how this process is regulated. Objective: We sought to investigate the role of polymerase I and transcript release factor (PTRF) in IL-33 release and asthma pathogenesis. Methods: Ovalbumin (OVA)-induced asthma model in PTRF+/- mice were employed to dissect the role of PTRF in vivo. Then, further in vitro experiments were carried out to unwind the potential mechanism involved. Results: In OVA asthma model with challenge phase, PTRF+/- mice showed a greater airway hyper-reaction, with an intense airway inflammation and more eosinophils in bronchoalveolar lavage fluid (BALF). Consistently, more acute type 2 immune response in lung and a higher IL-33 level in BALF were found in PTRF+/- mice. In OVA asthma model without challenge phase, airway inflammation and local type 2 immune responses were comparable between control mice and PTRF+/- mice. Knockdown of PTRF in 16HBE led to a significantly increased level of IL-33 in cell culture supernatants in response to LPS or HDM. Immunoprecipitation assay clarified Y158 as the major phosphorylation site of PTRF, which was also critical for the interaction of IL-33 and PTRF. Overexpression of dephosphorylated mutant Y158F of PTRF sequestered IL-33 in nucleus together with PTRF and limited IL-33 extracellular secretion. Conclusion: Partial loss of PTRF led to a greater AHR and potent type 2 immune responses during challenge phase of asthma model, without influencing the sensitization phase. PTRF phosphorylation status determined subcellular location of PTRF and, therefore, regulated IL-33 release. PMID- 29977244 TI - Lysosomal Cathepsin Release Is Required for NLRP3-Inflammasome Activation by Mycobacterium tuberculosis in Infected Macrophages. AB - Lysosomal cathepsin B (CTSB) has been proposed to play a role in the induction of acute inflammation. We hypothesised that the presence of active CTSB in the cytosol is crucial for NLRP3-inflammasome assembly and, consequently, for mature IL-1beta generation after mycobacterial infection in vitro. Elevated levels of CTSB was observed in the lungs of mice and rabbits following infection with Mycobacterium tuberculosis (Mtb) H37Rv as well as in plasma from acute tuberculosis patients. H37Rv-infected murine bone marrow-derived macrophages (BMDMs) displayed both lysosomal leakage, with release of CTSB into the cytosol, as well as increased levels of mature IL-1beta. These responses were diminished in BMDM infected with a mutant H37Rv deficient in ESAT-6 expression. Pharmacological inhibition of cathepsin activity with CA074-Me resulted in a substantial reduction of both mature IL-1beta production and caspase-1 activation in infected macrophages. Moreover, cathepsin inhibition abolished the interaction between NLRP3 and ASC, measured by immunofluorescence imaging in H37Rv-infected macrophages, demonstrating a critical role of the enzyme in NLRP3-inflammasome activation. These observations suggest that during Mtb infection, lysosomal release of activated CTSB and possibly other cathepsins inhibitable by CA07-Me is critical for the induction of inflammasome-mediated IL-1beta processing by regulating NLRP3-inflammasome assembly in the cytosol. PMID- 29977245 TI - Roles of Myeloid and Lymphoid Cells in the Pathogenesis of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is currently the third largest cause of human mortality in the world after stroke and heart disease. COPD is characterized by sustained inflammation of the airways, leading to destruction of lung tissue and declining pulmonary function. The main risk factor is known to be cigarette smoke currently. However, the strategies for prevention and treatment have not altered significantly for many years. A growing body of evidences indicates that the immune system plays a pivotal role in the pathogenesis of COPD. The repeated and progressive activation of immune cells is at least in part the source of this chronic inflammation. In this review paper, we have conducted an extensive literature search of the studies of immune cells in COPD patients. The objective is to assess the contributions of different immune cell types, the imbalance of pro/anti-inflammatory immune cells, such as M1/M2 macrophages, Tc1/Tc10, and Th17/Treg, and their mediators in the peripheral blood as well as in the lung to the pathogenesis of COPD. Therefore, understanding their roles in COPD development will help us find the potential target to modify this disease. This review focuses predominantly on data derived from human studies but will refer to animal studies where they help understand the disease in humans. PMID- 29977247 TI - Concurrent Overexpression of OsGS1;1 and OsGS2 Genes in Transgenic Rice (Oryza sativa L.): Impact on Tolerance to Abiotic Stresses. AB - Glutamine synthetase (GS) is a key enzyme involved in the nitrogen metabolism of higher plants. Abiotic stresses have adverse effects on crop production and pose a serious threat to global food security. GS activity and expression is known to be significantly modulated by various abiotic stresses. However, very few transgenic overexpression studies of GS have studied its impact on abiotic stress tolerance. GS is also the target enzyme of the broad spectrum herbicide Glufosinate (active ingredient: phosphinothricin). In this study, we investigated the effect of concurrent overexpression of the rice cytosolic GS1 (OsGS1;1) and chloroplastic GS2 (OsGS2) genes in transgenic rice on its tolerance to abiotic stresses and the herbicide Glufosinate. Our results demonstrate that the co overexpression of OsGS1;1 and OsGS2 isoforms in transgenic rice plants enhanced its tolerance to osmotic and salinity stress at the seedling stage. The transgenic lines maintained significantly higher fresh weight, chlorophyll content, and relative water content than wild type (wt) and null segregant (ns) controls, under both osmotic and salinity stress. The OsGS1;1/OsGS2 co overexpressing transgenic plants accumulated higher levels of proline but showed lower electrolyte leakage and had lower malondialdehyde (MDA) content under the stress treatments. The transgenic lines showed considerably enhanced photosynthetic and agronomic performance under drought and salinity stress imposed during the reproductive stage, as compared to wt and ns control plants. The grain filling rates of the transgenic rice plants under reproductive stage drought stress (64.6 +/- 4.7%) and salinity stress (58.2 +/- 4.5%) were significantly higher than control plants, thereby leading to higher yields under these abiotic stress conditions. Preliminary analysis also revealed that the transgenic lines had improved tolerance to methyl viologen induced photo oxidative stress. Taken together, our results demonstrate that the concurrent overexpression of OsGS1;1 and OsGS2 isoforms in rice enhanced physiological tolerance and agronomic performance under adverse abiotic stress conditions, apparently acting through multiple mechanistic routes. The transgenic rice plants also showed limited tolerance to the herbicide Glufosinate. The advantages and limitations of glutamine synthetase overexpression in crop plants, along with future strategies to overcome these limitations for utilization in crop improvement have also been discussed briefly. PMID- 29977249 TI - Forecasting Root-Zone Electrical Conductivity of Nutrient Solutions in Closed Loop Soilless Cultures via a Recurrent Neural Network Using Environmental and Cultivation Information. AB - In existing closed-loop soilless cultures, nutrient solutions are controlled by the electrical conductivity (EC) of the solution. However, the EC of nutrient solutions is affected by both growth environments and crop growth, so it is hard to predict the EC of nutrient solution. The objective of this study was to predict the EC of root-zone nutrient solutions in closed-loop soilless cultures using recurrent neural network (RNN). In a test greenhouse with sweet peppers (Capsicum annuum L.), data were measured every 10 s from October 15 to December 31, 2014. Mean values for every hour were analyzed. Validation accuracy (R2) of a single-layer long short-term memory (LSTM) was 0.92 and root-mean-square error (RMSE) was 0.07, which were the best results among the different RNNs. The trained LSTM predicted the substrate EC accurately at all ranges. Test accuracy (R2) was 0.72 and RMSE was 0.08, which were lower than values for the validation. Deep learning algorithms were more accurate when more data were added for training. The addition of other environmental factors or plant growth data would improve model robustness. A trained LSTM can control the nutrient solutions in closed-loop soilless cultures based on predicted future EC. Therefore, the algorithm can make a planned management of nutrient solutions possible, reducing resource waste. PMID- 29977246 TI - Hepatitis C Virus (HCV)-Apolipoprotein Interactions and Immune Evasion and Their Impact on HCV Vaccine Design. AB - With more than 71 million people chronically infected, hepatitis C virus (HCV) is one of the leading causes of liver disease and hepatocellular carcinoma. While efficient antiviral therapies have entered clinical standard of care, the development of a protective vaccine is still elusive. Recent studies have shown that the HCV life cycle is closely linked to lipid metabolism. HCV virions associate with hepatocyte-derived lipoproteins to form infectious hybrid particles that have been termed lipo-viro-particles. The close association with lipoproteins is not only critical for virus entry and assembly but also plays an important role during viral pathogenesis and for viral evasion from neutralizing antibodies. In this review, we summarize recent findings on the functional role of apolipoproteins for HCV entry and assembly. Furthermore, we highlight the impact of HCV-apolipoprotein interactions for evasion from neutralizing antibodies and discuss the consequences for antiviral therapy and vaccine design. Understanding these interactions offers novel strategies for the development of an urgently needed protective vaccine. PMID- 29977248 TI - Field-Based Metabolomics of Vitis vinifera L. Stems Provides New Insights for Genotype Discrimination and Polyphenol Metabolism Structuring. AB - Grape accumulates numerous polyphenols with abundant health benefit and organoleptic properties that in planta act as key components of the plant defense system against diseases. Considerable advances have been made in the chemical characterization of wine metabolites particularly volatile and polyphenolic compounds. However, the metabotyping (metabolite-phenotype characterization) of grape varieties, from polyphenolic-rich vineyard by-product is unprecedented. As this composition might result from the complex interaction between genotype, environment and viticultural practices, a field experiment was setting up with uniform pedo-climatic factors and viticultural practices of growing vines to favor the genetic determinism of polyphenol expression. As a result, UPLC-MS based targeted metabolomic analyses of grape stems from 8 Vitis vinifera L. cultivars allowed the determination of 42 polyphenols related to phenolic acids, flavonoids, procyanidins, and stilbenoids as resveratrol oligomers (degree of oligomerization 1-4). Using a partial least-square discriminant analysis approach, grape stem chemical profiles were discriminated according to their genotypic origin showing that polyphenol profile express a varietal signature. Furthermore, hierarchical clustering highlights various degree of polyphenol similarity between grape varieties that were in agreement with the genetic distance using clustering analyses of 22 microsatellite DNA markers. Metabolite correlation network suggested that several polyphenol subclasses were differently controlled. The present polyphenol metabotyping approach coupled to multivariate statistical analyses might assist grape selection programs to improve metabolites with both health-benefit potential and plant defense traits. PMID- 29977250 TI - TcMYC2a, a Basic Helix-Loop-Helix Transcription Factor, Transduces JA-Signals and Regulates Taxol Biosynthesis in Taxus chinensis. AB - The multitherapeutic taxol, which can be obtained from Taxus spp., is the most widely used anticancer drug. Taxol biosynthesis is significantly regulated by jasmonate acid (JA), one of the most important endogenous hormones in land plants. Nevertheless, the JA-inducing mechanism remains poorly understood. MYC2 is one of the key regulators of JA signal transfer and the biosynthesis of various secondary metabolites. Here, TcMYC2a was identified to contain a basic helix-loop-helix (bHLH)-leucine zipper domain, a bHLH-MYC_N domain, and a BIF/ACT like domain. TcMYC2a was also found to bind with TcJAZ3 in yeast, which was a homolog of Arabidopsis JASMONATE ZIM-domain JAZ proteins, indicating that TcMYC2a had a similar function to AtMYC2 of JA signal transduction. TcMYC2a was able to affect the expression of GUS reporter gene by binding with the T/G-box, G-box, and E-box, which were the key cis-elements of TASY and TcERF12/15 promoter. TcMYC2a overexpression also led to significantly increased expression of TASY, tat, dbtnbt, t13h, and t5h genes. Additionally, TcERF15, which played the positive role to regulate tasy gene, was up-regulated by TcMYC2a. All these results revealed that TcMYC2a can regulate taxol biosynthesis either directly or via ERF regulators depending on JA signaling transduction. PMID- 29977251 TI - Silencing the nosocomial pathogen Serratia marcescens by glyceryl trinitrate. AB - Background: Quorum sensing is a cell-to-cell communication system in bacteria that controls the production of virulence factors. Serratia marcescens is a causative agent of hospital-acquired infections that shows high resistance to antibiotics. This makes the treatment of these infections difficult. Quorum sensing regulates the production of virulence factors of S. marcescens such as prodigiosin, protease, swimming and swarming motilities and formation of biofilms. Inhibition of quorum sensing may be an alternative to antibiotic treatment to avoid emergence of resistance. Objectives: Testing the ability of glyceryl trinitrate to inhibit quorum sensing and virulence factors of Serratia marcescens. Methods: The inhibiting activities of sub-inhibitory concentration of glyceryl trinitrate against the quorum-sensing regulated violacein pigment in Chromobacterium violaceum CV026 was performed to evaluate the anti-quorum sensing effect of glyceryl trinitrate. The anti-virulence activity was assessed against prodigiosin, protease, biofilm formation in addition to swimming and swarming motilities. Results: Glyceryl trinitrate at at a concentration of 0.25 mg/ml produced significant inhibitory effects against violacein (67.01%), prodigiosin (82.67%), protease, swimming (36.72%) and swarming (79.31%) motilities and biofilm formation (87.83%). Conclusion: Glyceryl trinitrate is a quorum sensing and virulence inhibitor that may be useful in treatment of nosocomial infections caused by Serratia marcescens. PMID- 29977253 TI - Prevalence and risk factors for brucellosis in prolonged fever patients in post conflict Northern Uganda. AB - Background: Brucellosis is a disease with significant public and economic implications but strategies for controlling this disease remain problematic. Objectives: This study sought to determine the sero-prevalence of brucellosis in prolonged fever patients and to identify modifiable risk factors for the infection in humans in post conflict Northern Uganda. Methods: The study employed a cross-sectional method among prolonged fever patients who had visited selected health facilities in the study districts in Northern Uganda. Sero-prevalence of brucellosis was calculated for i-ELISA IgG/IgM. A structured questionnaire was used to obtain data on possible risk factors for brucellosis. Associations between sero-prevalence and risk factors were measured using the Odds Ratio. Results: Brucellosis was confirmed in 18.7% of the 251 patients that tested positive for the disease, with the rapid Brucella Plate Agglutination Test, and ages 10-84 years (median age 47+0.86). Sex (p = 0.001; OR 3.79; 95% CI 1.75 - 8.24), rearing livestock (p < 0.005; OR 8.44; 95% CI 2.84-25.03) and consumption of unpasteurised milk (p = 0.023; OR 2.57; 95% CI 1.14-5.80) were factors associated with brucellosis. Conclusion: Control of brucellosis in animals, training and sensitisation of the community on brucellosis is needed to stimulate action on human brucellosis control. PMID- 29977252 TI - Phenotypic and genotypic detection of antibiotic resistance of Pseudomonas aeruginosa isolated from urinary tract infections. AB - Bakground: Pseudomonas aeruginosa is a major nosocomial uropathogen. It can tolerate a wide variety of physical conditions and many antibiotics by different resistance mechanisms. Objectives: This study aimed to investigate the mechanisms of antibiotics resistance in uropathogenic P. aeruginosa clinical isolates. Methods: Two hundred sixty six urine samples were collected from Zagazig University Hospitals, Zagazig, Egypt. P. aeruginosa isolates were identified using standard microbiological tests. The sensitivity to different antibiotics was determined by disc diffusion method. Anti-microbial resistance mechanisms were investigated using phenotypic methods and confirmed by PCR. Results: Fifty P. aeruginosa isolates were recovered. All isolates were MDR and were resistant to amoxicillin/clavulinic, sulphamethaxzole/trimethoprim, doxycycline and ceftazidime. Phenotypic detection of resistance mechanisms revealed that all strains have efflux mechanism, outer membrane porins, and AmpC beta-lactamase; none of the strains showed ESBL activity and two of the imipenem resistant strains showed MbetaL activity. PCR analysis showed that all strains have MexAB R, OprD and AmpC genes, 42 strains had PSE gene, while VEB and VIM genes were not detected. Conclusion: The resistance rates in P. aeruginosa were higher than global values; this resistance was attributed to several mechanisms. This high resistance is alarming and necessitates applying strict antibiotic prescription policies. PMID- 29977254 TI - Stigma and increase of leprosy cases in SouthEast Sulawesi Province, Indonesia. PMID- 29977255 TI - Multidrug-resistant pattern of food borne illness associated bacteria isolated from cockroaches in meal serving facilities, Jimma, Ethiopia. AB - Introduction: An increase in the emergence and spread of multidrug-resistant (MDR) bacteria in recent years is becoming worrisome. Domestic cockroaches can play a significant role in the dissemination of such bacteria between the environment and human beings. This study aimed at determining anti-microbial resistance pattern of food borne illness associated bacteria identified from cockroaches trapped in restaurants and cafeterias. Methods: Trapped cockroaches were picked with surgical gloves, sealed in sterile plastic bags and transported to the Microbiology laboratory. Standard microbiological techniques were used to isolate and identify bacteria. Anti-microbial susceptibility testing was done using Kirby Bauer diffusion technique. Result: A total of five species of food borne illness associated bacteria were detected. Majority (57.1%) of the bacteria were isolated from the gut of cockroaches. More than 89% of the isolates were multi drug resistance (MDR). MDR was higher on gram positive bacteria. S. aureus showed 53.3% resistance against oxacillin(MRSA) and 33.3% against vancomycin. Conclusion: A very high percentage of MDR bacteria was seen in this study. Most of the bacteria tested were isolated from the gut of cockroaches. Potential factors associated with cockroaches that contributed to this high MDR rate of the isolates should be investigated in future. PMID- 29977256 TI - First studies showing high temephos resistance in Anopheles labranchiae (Diptera: Culicidae) from Tunisia. AB - Background: Despite the public health importance of Anopheles (An.) labranchiae, their resistance status to temephos insecticide has not, to our knowledge, been explored. Objectives: The present study was carried out to determine the temephos resistance status of field populations of An. labranchiae from Tunisia. Methods: Six field populations of An. labranchiae were collected as larvae from breeding sites of Northern and Central Tunisia. All the tests were carried out according to the WHO method. Results: Results reported that the majority of field populations showed low and medium resistance ratios (6.235 years). Overall, 255 (49%) used an illicit substance, (24% females and 63% males). Majority of substance users were youth (18-35 years) in both males (83.1%) and females (73.8%). Cannabis and methamphetamine were the most popular drugs in males (56.3% and 34.9%) and females (17.9% and 16.2%) with the highest rates being among the youth. Violence was common among both men (60.7%) and women (40.8%); among the violent, 67% of males and 35.6% of female used substances. Only 5.5% of drug users utilized formal drug rehabilitation services. Conclusion: Substance use and violence were high, yet only a small proportion of the patients utilised available drug rehabilitation services. This may have implications on psychotic relapses, morbidity and subsequent pressure on financial resources within the health care system. Efforts are needed to maximise utilisation of existing rehabilitative resources for these patients. PMID- 29977265 TI - Inflammatory cytokines and immune system modulation by aerobic versus resisted exercise training for elderly. AB - Background: Aging is characterized with immunosenescence associated with a hyper inflammatory state, characterized by elevated circulating levels of pro inflammatory mediators. Physical exercise is a potential strategy for improving the immune system dysfunction and chronic inflammation that accompanies aging. However, there is a need to differentiate between aerobic and resistance exercise training regarding human immune system and systemic inflammation among the elderly Saudi population. Objective: The aim of this study was to compare the impact of 6 months of aerobic versus resisted exercise training on inflammatory cytokines and immune system response among elderly. Material and methods: Sixty previously sedentary elderly subjects participated in this study, their age ranged from 61-66 years. All Subjects were randomly assigned to supervised aerobic exercise intervention group (group A, n=40) or resistance exercise group (group B, n=40). Number of CD3+,CD4+,CD8+ T cells count and CD4/CD8 ratio were quantified, IL-6, TNF-alpha and IL10 were measured before and after 6 months, at the end of the study. Results: The mean values of CD3+, CD4+ and CD8+ T cells count and IL-10 were significantly increased, whereas the mean values of CD4/CD8 ratio, IL-6 and TNF-alpha were significantly decreased in group (A) and group (B). Also; there were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. Conclusion: The current study provides evidence that aerobic exercise is more appropriate in modulating the immune system and inflammatory markers among the elderly population. PMID- 29977267 TI - Early diagnosis and intervention for autism spectrum disorder in Africa: insights from a case study. AB - Background: Globally the prevalence of autism spectrum disorder (ASD) has become more apparent. Prevalence on the African continent remains unknown. There is a call for further research into ASD in Africa as well as means to make early diagnosis and intervention possible. Objectives: The study aimed to raise awareness about ASD in Africa and encourage dialogue on possible intervention strategies for ASD in low resource settings. Methods: This was a qualitative mixed method case study. Literature regarding ASD in Africa was reviewed in order to provide context for the research and facilitate data reduction of the case study of Temple Grandin. The case study was conducted through a psychobiographical approach using Erikson's (1950/1973) theory of psychosocial development to interpret the life of Temple Grandin. The findings underwent further data reduction in order to focus on possible interventions for ASD. Results: Four primary interventions were found to be useful in facilitating development in an individual with ASD. Namely; speech therapy, creative endeavours, animals (human-animal interaction), and being mentored. Conclusion: Undiagnosed and untreated cases of ASD place undue psychosocial and economic burden on families and communities. Government support, by including ASD in health policies, is essential. Through creative adaptation of knowledge, communities may provide a valuable resource to ASD intervention strategies. PMID- 29977268 TI - Truncus arteriosus communis: report of three cases and review of literature. AB - Background: Truncus arteriosus communis (TAC) is a congenital heart defect in which the physiologic arterial common trunk was not divided into aorta and pulmonary artery trunk. Objectives: In this paper, we report on three observed cases from which we looked for (in conjunction with literature review) the different causes of TAC many of which have genetic origins. Methods: We collected three clinical files of fetuses having a TAC. Two of them were examinated after a medical termination of pregnancy motivated by severe cardiopathy. The malformation had been diagnosed based on different techniques: echocardiography, skeletal radiography, arteriography, fetal autopsy, karyotype and fluorescence in situ hybridization (FISH). Results: Imaging and fetopathological examination revealed the presence of TAC type 3 and 4 in the Van Praaghs classification. FISH analysis showed a 22q11.2 deletion in one fetus in favour of Digeorge syndrome. The karyotype analysis performed in two cases was normal. Conclusion: Truncus arteriosus is a rare pathology caused by numerous etiologies from which many of them have genetic origin. This malformation can be diagnosed early during prenatal period. Postmortem fetopathological examination allows a better diagnosis approach and eventually a genetic counseling in recurrent cases such as case of consanguinity. PMID- 29977269 TI - Outcome of caesarean section at the Edward Francis Small Teaching Hospital, Banjul The Gambia. AB - Background: Caesarean section is a very important procedure to decrease maternal and perinatal morbidity and mortality. Anecdotal evidence suggests that more than half of all caesarean sections done in The Gambia are done at the Edward Francis Small Teaching Hospital. Objective: The aim of the study was to determine the caesarean section rate at the Edward Francis Small teaching Hospital. The study also aimed to determine the socio-demographic factors associated with caesarean section and maternal and fetal outcomes of caesarean section at the hospital. Method: A retrospective review of all caesarean sections carried out at the Edward Francis Small Teaching Hospital from 1st January 2014 to 31st December 2014 was done. Data was extracted from patients' record. Descriptive statistics was done using Epi Info 7 statistical software. Results: The Caesarean section rate in the hospital is 24.0%. The commonest indications for caesarean section were previous caesarean section (20.6%) and cephalopelvic disproportion (20.2%). There were 21 maternal deaths (1.8%) and 71 fresh stillbirths (6.0%) in the study population. Conclusion: About a quarter of all deliveries in the hospital were caesarean sections most of which were done as emergencies. The commonest indications for caesarean section were cephalopelvic disproportion and previous caesarean section. PMID- 29977270 TI - Teaching obstetric ultrasound at Mulago Hospital - Kampala, Uganda. AB - Background: Mulago Hospital is a high volume referral hospital under the Makerere University School of Medicine and Health Sciences. Basic obstetric ultrasound is a useful skill that can aid patient care. Objectives: The purpose of the study was to assess the effectiveness of an intervention implemented to teach basic ultrasound skills to medical students and house officers at Mulago Hosptial, Kampala, Uganda. Methods: Forty participants, including medical students, junior house officers (JHOs), and senior house officers (SHOs) were enrolled in the study. A didactic and practical hands-on teaching session was evaluated using a pre- and post-test that was administered to all participants. Results: Participants included 12 medical students, 23 JHOs, and 5 SHOs. A significant difference in pre- and post-test scores was demonstrated in the medical students and JHOs (34% to 76%, p <0.0001) and this was retained when the results were stratified into the basic definitions and practical sections of the survey (33% to 71%, p<0.0001). The scores for the senior house officers had a mean increase of 2.3 points. Conclusion: This original teaching intervention is an effective method to improve knowledge and skills for medical students and house officers at Mulago Hospital in the area of basic obstetric ultrasound. PMID- 29977271 TI - Turkish University seniors' knowledge of and opinions on fertility and expectations of having children. AB - Background: In recent years the trend of postponement of child bearing has been increasing. Aim: To assess knowledge on fertility and expectations of having children in seniors at a Turkish University. Methods: The cross-sectional study sample (n=485) comprised senior students of the University in the branches of medicine, social sciences, and life sciences. Data were collected via a self administered questionnaire in 2015. Results: The mean age of the students was 23.03+/-1.93 and 98.1% were unmarried. 88.45% of these students wanted to have children in the future. A higher percentage of females planned parenthood in the future than males. Males desired more children than females. Most students wanted to have their first child at age 25-29. Males wanted to have their first and last child later than did females. In case of infertility, 74.4% of females and 54.2% of males stated that they can benefit from assisted reproduction techniques. Students overestimated the success rate of assisted reproduction techniques. The percentage of students who were aware of the age at which fertility begins to decline was low. Conclusion: The expectations of seniors at a Turkish university to have children in the future are high, with insufficient knowledge on fertility. PMID- 29977272 TI - Behavioural risk factors for sexually transmitted infections and health seeking behaviour of street youths in Ibadan, Nigeria. AB - Background: Street youths are faced with a number of health challenges that could be linked to their exposure to the risk elements, accessing medical care including motivation and /or ignorance to utilise available health care. Objective: This qualitative study therefore aimed at determining the behavioural risks for sexually transmitted infections (STIs) and health seeking behaviour of street youths in Ibadan. Methods: Sixteen focus group discussion (FGD) sessions were conducted among 160 street youths aged between 15-24 years. Result: The result showed that most of the respondents had low perception of risk of contracting STIs in spite of their risky behaviours which included multiple sexual partnering, sharing of personal effects, malnourishment and sexual harassment. Most of the street youth could not identify the various types however; Gonorrhea and HIV were commonly mentioned by them. The major treatment regimen for STIs was traditional remedies and drugs obtained from patent medicine vendors. Traditional remedies were preferred by most of the participants and considered to be more effective. Conclusion: Majority of the street youths were sexually active, engaged in high risk sexual behaviours and had inappropriately treated sexually transmitted infections. Development of risk reduction and appropriate sexual health interventions targeted at prevention and appropriate treatment is recommended. PMID- 29977274 TI - Responsible conduct of research. PMID- 29977273 TI - Approaches and strategies used in the training and supervision of Health Extension Workers (HEWs) delivering integrated community case management (iCCM) of childhood illness in Ethiopia: a qualitative rapid appraisal. AB - Background: Globally, preventable and treatable childhood conditions such as pneumonia, diarrhoea, malaria, malnutrition and newborn conditions still account for 75% of under-five mortality. To reduce the mortality rate from these conditions, Ethiopia launched an ambitious Health Extension Programme (HEP) in 2003. Trained Community Health Workers (CHWs), named Health Extension Workers (HEWs) were deployed to deliver a package of care which includes integrated Community Case-Management (iCCM) of common childhood diseases. Objectives: This qualitative study aimed to explore approaches and strategies used in the HEW training and supervision as part of an evaluation of the Catalytic Initiative to Save a Million Lives. Method: A qualitative rapid appraisal study using focus group discussions and in-depth interviews was conducted. Results: Training of HEWs followed a cascaded training of trainer approach supported by implementing partners under guidance of the Ministry of Health. A comprehensive planning phase enabled good coverage of districts and consistency in training approaches. Training was complemented by on-going supportive supervision. HEW motivation was enhanced through regular review meetings and opportunities for career progression. Conclusion: These findings describe a thorough approach to training and supervision of HEWs delivering iCCM in rural Ethiopia. Ongoing investments by partners will be critical for long-term sustainability. PMID- 29977275 TI - Health issues of concern to Africa and beyond: infections, NCDs and health systems inertia. PMID- 29977276 TI - A Classifier Graph Based Recurring Concept Detection and Prediction Approach. AB - It is common in real-world data streams that previously seen concepts will reappear, which suggests a unique kind of concept drift, known as recurring concepts. Unfortunately, most of existing algorithms do not take full account of this case. Motivated by this challenge, a novel paradigm was proposed for capturing and exploiting recurring concepts in data streams. It not only incorporates a distribution-based change detector for handling concept drift but also captures recurring concept by storing recurring concepts in a classifier graph. The possibility of detecting recurring drifts allows reusing previously learnt models and enhancing the overall learning performance. Extensive experiments on both synthetic and real-world data streams reveal that the approach performs significantly better than the state-of-the-art algorithms, especially when concepts reappear. PMID- 29977277 TI - EEG-Based Biometrics: Challenges And Applications. PMID- 29977278 TI - An Improved Multispectral Palmprint Recognition System Using Autoencoder with Regularized Extreme Learning Machine. AB - Multispectral palmprint recognition system (MPRS) is an essential technology for effective human identification and verification tasks. To improve the accuracy and performance of MPRS, a novel approach based on autoencoder (AE) and regularized extreme learning machine (RELM) is proposed in this paper. The proposed approach is intended to make the recognition faster by reducing the number of palmprint features without degrading the accuracy of classifier. To achieve this objective, first, the region of interest (ROI) from palmprint images is extracted by David Zhang's method. Second, an efficient normalized Gist (NGist) descriptor is used for palmprint feature extraction. Then, the dimensionality of extracted features is reduced using optimized AE. Finally, the reduced features are fed to the RELM for classification. A comprehensive set of experiments are conducted on the benchmark MS-PolyU dataset. The results were significantly high compared to the state-of-the-art approaches, and the robustness and efficiency of the proposed approach are revealed. PMID- 29977279 TI - State-of-the-Art Techniques to Causally Link Neural Plasticity to Functional Recovery in Experimental Stroke Research. AB - Current experimental stroke research faces the same challenge as neuroscience: to transform correlative findings in causative ones. Research of recent years has shown the tremendous potential of the central nervous system to react to noxious stimuli such as a stroke: Increased plastic changes leading to reorganization in form of neuronal rewiring, neurogenesis, and synaptogenesis, accompanied by transcriptional and translational turnover in the affected cells, have been described both clinically and in experimental stroke research. However, only minor attempts have been made to connect distinct plastic remodeling processes as causative features for specific behavioral phenotypes. Here, we review current state-of the art techniques for the examination of cortical reorganization and for the manipulation of neuronal circuits as well as techniques which combine anatomical changes with molecular profiling. We provide the principles of the techniques together with studies in experimental stroke research which have already applied the described methodology. The tools discussed are useful to close the loop from our understanding of stroke pathology to the behavioral outcome and may allow discovering new targets for therapeutic approaches. The here presented methods open up new possibilities to assess the efficiency of rehabilitative strategies by understanding their external influence for intrinsic repair mechanisms on a neurobiological basis. PMID- 29977280 TI - Effect of Group-Based Rehabilitation Combining Action Observation with Physiotherapy on Freezing of Gait in Parkinson's Disease. AB - Freezing of gait (FoG) is among the most disabling symptoms of Parkinson's disease (PD) patients. Recent studies showed that action observation training (AOT) with repetitive practice of the observed actions represents a strategy to induce longer-lasting effects compared with standard physiotherapy. We investigated whether AOT may improve FoG and mobility in PD, when AOT is applied in a group-based setting. Sixty-four participants with PD and FoG were assigned to the experimental (AO) or control groups and underwent a 45-minute training session, twice a week, for 5 weeks. AOT consisted in physical training combined with action observation whereas the control group executed the same physical training combined with landscape-videos observation. Outcome measures (FoG questionnaire, Timed Up and Go test, 10-meter walking test, and Berg balance scale) were evaluated before training, at the end of training, and 4 weeks later (FU-4w). Both groups showed positive changes in all outcome measures at posttraining assessment. Improvements in FoG questionnaire, Timed Up and Go test, and Berg balance scale were retained at FU-4w evaluation only in the AOT group. AOT group-based training is feasible and effective on FoG and motor performance in PD patients and may be introduced as an adjunctive option in PD rehabilitation program. PMID- 29977281 TI - Mu Suppression Is Sensitive to Observational Practice but Results in Different Patterns of Activation in Comparison with Physical Practice. AB - Research has shown the effectiveness of observational practice for motor learning, but there continues to be debate about the mechanisms underlying effectiveness. Although cortical processes can be moderated during observation, after both physical and observational practice, how these processes change with respect to behavioural measures of learning has not been studied. Here we compared short-term physical and observational practice during the acquisition and retention of a novel motor task to evaluate how each type of practice modulates EEG mu rhythm (8-13 Hz). Thirty healthy individuals were randomly assigned to one of three groups: (1) physical practice (PP), (2) observational practice (OP), and (3) no practice (NP) control. There were four testing stages: baseline EEG, practice, postpractice observation, and delayed retention. There was significant bilateral suppression of mu rhythm during PP but only left lateralized mu suppression during OP. In the postpractice observation phase, mu suppression was bilateral and larger after PP compared to that after OP. NP control showed no evidence of suppression and was significantly different to both the OP and PP groups. When comparing the three groups in retention, the groups did not differ with respect to tracing times, but the PP group showed fewer errors, especially in comparison to the NP group. Therefore, although the neurophysiological measures index changes in the OP group, which are similar but moderated in comparison to PP, changes in these processes are not manifest in observational practice outcomes when assessed in a delayed retention test. PMID- 29977283 TI - Effectiveness of Traditional Healers in Program to Control Leprosy in Nagan Raya District in Aceh. AB - Aceh Province had the highest rate of leprosy in Indonesia; in 2014, 436 new Multibacillary cases were reported. Nagan Raya was the District in Aceh with the highest number of cases; new cases in 2015 comprised 26 with Paucibacillary (PB) and 21 with Multibacillary (MB) with a total of 4.26% with Grade II disability. The phenomena of handling and treatment by the people in Nagan Raya involve treatment by traditional healers, "Tabib", to treat the leprosy, with treatments known as Peundang locally. The purpose of this study was to find out and to take steps to improve the effectiveness of the Tabib in controlling leprosy in Nagan Raya. The main object of this study, which used a quasi-experimental design, was to find out and to improve the treatment of leprosy patients by the Tabib who treat them there. Data was gathered using a questionnaire with an interview and the intervention was to provide training and a pocket book about leprosy and how to detect, control, and manage it there and the role that the Tabib can play in controlling leprosy in the future. The results of the study showed that there was a significant difference in knowledge about leprosy between the EG (Experimental Group) Tabib after they got the training including the pocket book and the Tabib in the Control Group (CG); i.e., that did not get any training nor the pocket book. Furthermore, after the training, there was also a significant difference in the attitude towards leprosy between the EG and the CG of Tabib. There was also a significant difference in the future role of the Tabibs to control the spread of leprosy between the EG and the CG. Based on these results, it is hoped that the District Health Department can implement a partnership model with the Tabib in Nagan Raya (and elsewhere) to use the pocket book with training to implement a program to control the spread of leprosy and also to always support the Tabib to improve their role in controlling and eliminating leprosy amongst the village people. PMID- 29977282 TI - Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder. AB - CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five) gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/-) mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/- mice. We found that Cdkl5 +/- mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/- mice show age related alterations in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/- mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder. PMID- 29977284 TI - Screening Biomarker as an Alternative to Endoscopy for the Detection of Early Gastric Cancer: The Combination of Serum Trefoil Factor Family 3 and Pepsinogen. AB - Objective: The serum pepsinogen test has limitation in its predictive power as a noninvasive biomarker for gastric cancer screening. We aimed to investigate whether the combination of TFF3 and pepsinogen could be an effective biomarker for the detection of gastric cancer even in the early stages. Methods: In total, 281 patients with early gastric cancer (EGC), who underwent endoscopic submucosal dissection in Korea, and 708 healthy individuals from Japan were enrolled in the derivation cohort. The validation cohort included 30 Korean patients with EGC and 30 Korean healthy control blood donors. Serum TFF3 levels were examined using enzyme-linked immunosorbent assay. Results: Using a cutoff of 6.73 ng/mL in the derivation cohort, the sensitivity of the combination of tests for EGC detection was superior (87.5%) to that of TFF3 (80.4%) or pepsinogen test alone (39.5%). Similarly, in the validation cohort, the sensitivity of TFF3 plus pepsinogen was higher (90.4%) than that of TFF3 (80.0%) or pepsinogen test alone (33.3%). Conclusion: The combination of serum TFF3 and pepsinogen is a more effective noninvasive biomarker for gastric cancer detection compared with pepsinogen or TFF3 alone, even in EGC. This trial is registered with NCT03046745. PMID- 29977285 TI - Persuasion, Adaptation, and Double Identity: Qualitative Study on the Psychological Impact of a Screen-Detected Colorectal Cancer Diagnosis. AB - The NHS Bowel Cancer Screening Programme (BCSP) is aimed at reducing colorectal cancer (CRC) mortality through early detection within a healthy population. This study explores how 5 people (three females) experience and make sense of their screen-detected diagnosis and the psychological implications of this diagnostic pathway. A biographical narrative interview method was used, and transcripts were analysed using a thematic analysis with a phenomenological lens. Themes specifically relating to posttreatment experience and reflections are reported here: Do it: being living proof, Resisting the threat of recurrence, Rationalising bodily change, and Continuing life-"carrying on normally." Participants described their gratefulness to the BCSP, motivating a strong desire to persuade others to be screened. Furthermore, participants professed a duality of experience categorised by the normalisation of life after diagnosis and treatment and an identification of strength post cancer, as well as a difficulty adjusting to the new changes in life and a contrasting identity of frailty. Understanding both the long- and short-term impacts of a CRC diagnosis through screening is instrumental to the optimisation of support for patients. The results perhaps highlight a particular target for psychological distress reduction, which could reduce the direct and indirect cost of cancer to the patient. PMID- 29977286 TI - Variations of Gastrocolic Trunk of Henle and Its Significance in Gastrocolic Surgery. AB - Due to the increasing incidence of gastrointestinal (GI) tumors, more and more importance is attached to radical resection and patients' survival, which requires adequate extent of resection and radical lymph node dissection. Blood vessels around the gastrointestinal tract, as anatomical landmarks for tumor resection and lymph node dissection, play a key role in the successful surgery and curative treatment of gastrointestinal tumors. In the isolation of subpyloric area or hepatic flexure of the colon for gastrectomy or right hemicolectomy, lymph node dissection and ligation are often performed at the head of the pancreas and superior mesenteric vein, during which even a minor inadvertent error may lead to unwanted bleeding. Among these blood vessels, the venous system composed of Henle's trunk and its tributaries is the most complex, which has a direct influence on the outcome and postoperative recovery of the patients. There are many variations of Henle's trunk, with complicated courses and various locations, attracting more and more researchers to study it and tried to analyze the influence of its variations on gastrointestinal surgeries. We characterized various variants and tributaries of Henle's trunk using autopsy, vascular casting, 3D CT reconstruction, intraoperative anatomy, and Hisense CAS system and summarized and analyzed the tributaries of Henle's trunk, to determine its influence on GI surgeries. PMID- 29977288 TI - Altered Salivary Alpha-Amylase Secretion in Patients with Ulcerative Colitis. AB - Purpose: Patients with ulcerative colitis (UC) frequently present with psychological disturbances as well as dysfunctions of autonomic nervous system (ANS). Salivary alpha-amylase (sAA) secretion is predominantly controlled by sympathetic nervous activity, while salivary fluid secretion is by parasympathetic nervous activity. Thus, it is speculated that alterations of salivary secretion may be addressed in UC populations. Methods: Thirty-five UC patients as well as 32 age- and sex-matched healthy controls were enrolled. Saliva samples before and after citric acid stimulation were collected from each participant, and salivary flow rate (SFR) was calculated accordingly. Western blotting and quantitative PCR were applied to measure the sAA level and sAA gene (AMY1) copy number, respectively. The psychological disorders, anxiety and depression, were evaluated by the scoring system of Hospital Anxiety and Depression Scale (HADS) for each participant. Results: We observed robustly increased prevalence of anxiety (p < 0.001) as well as depression (p < 0.001) in UC patients relative to controls. Interestingly, we detected elevated basal (p = 0.015) and stimulated (p = 0.021) sAA levels in the UC populations compared to controls. However, no differences were found for basal (p = 0.643) or stimulated (p = 0.402) SFR between the two study groups. Besides, AMY1 gene copy number was comparable between UC patients and controls. Conclusions: Our results reveal an overactivity of the sympathetic nervous system and a normal activity of the parasympathetic nervous system in the UC population. PMID- 29977287 TI - Noninvasive Assessment of Portal Hypertension in Advanced Chronic Liver Disease: An Update. AB - The assessment of portal hypertension is a relevant step in the evaluation of newly diagnosed advanced chronic liver disease (ACLD). The current gold standard includes the invasive evaluation of hepatic venous pressure gradient (HVPG) and endoscopy. However, noninvasive or minimally invasive techniques to assess portal hypertension have been proposed and well established. In the present manuscript, we review clinical studies on the use of noninvasive or minimally invasive techniques to assess portal hypertension in ACLD patients. PMID- 29977289 TI - SMAD4 Protein Expression Is Downregulated in Ileal Epithelial Cells from Patients with Crohn's Disease with Significant Inverse Correlation to Disease Activity. AB - Background: Small mothers against decapentaplegic (SMAD)4 and SMAD7 are key regulatory components in the immunosuppressive transforming growth factor- (TGF-) beta signaling pathway, which is defective in inflammatory bowel disease (IBD). SMAD4 may play an important role in the pathogenesis of IBD as indicated in experimental models of colitis. Aims: To examine the ileal expression levels of SMAD4 and to correlate these with CD disease activity. Methods: The material comprised 29 CD patients (13 with active disease, 16 in remission) and 9 asymptomatic patients referred for ileocolonoscopy as part of an adenoma surveillance program serving as controls. Patients were examined with ileocolonoscopy. Corresponding ileal biopsies were obtained for histological analysis and assessment of SMAD4 and SMAD7 protein expression by immunohistochemistry (IHC). Results: The protein expression of SMAD4 was significantly downregulated in ileal tissue sections from CD patients as compared to healthy controls (p < 0.001). Further, luminal SMAD4 expression was inversely correlated with endoscopic (rs = -0.315; p = 0.05) and histopathological activity (rs = -0.40; p = 0.013). Conclusions: The SMAD4 epithelial protein level was markedly downregulated in CD patients and inversely correlated with disease activity. This may contribute to defective mucosal TGF-beta signaling in active IBD. PMID- 29977291 TI - An Assessment of the Genotoxicity and Subchronic Toxicity of a Supercritical Fluid Extract of the Aerial Parts of Hemp. AB - A battery of toxicological studies was conducted on a supercritical CO2 extract of the aerial parts of the Cannabis sativa plant, containing approximately 25% cannabinoids. No evidence of genotoxicity was found in a bacterial reverse mutation test (Ames), in an in vitro mammalian chromosomal aberration test, or in an in vivo mouse micronucleus study. A 14-day repeated oral dose-range finding study conducted in Wistar rats at 1000, 2000, and 4000 mg/kg bw/day resulted in effects where a NOAEL could not be concluded. Based on those results, a 90-day repeated dose oral toxicity study was performed in rats using doses of 100, 360, and 720 mg/kg bw/day, followed by a 28-day recovery period for two satellite groups. Significant decreases in body weight, body weight gain, and differences in various organ weights compared to controls were observed. At the end of the recovery period, many of the findings were trending toward normal; thus, the changes appeared to be reversible. The NOAEL for the hemp extract in Hsd.Han Wistar rats was considered to be 100 mg/kg bw/day for males and 360 mg/kg bw/day for females. PMID- 29977290 TI - Prognostic Roles of Inflammatory Markers in Pancreatic Cancer: Comparison between the Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio. AB - Background/Objectives: This meta-analysis is aimed at investigating the prognostic roles of the inflammatory markers neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with pancreatic cancer. Methods: The correlations between high inflammatory marker expression levels and prognosis in 7105 patients with pancreatic cancer from 34 eligible studies were investigated. Additionally, subgroup analyses based on study location, tumor stage, treatment, and value cutoffs were performed. Results: High NLR and PLR values were considered to be 2.0-5.0 and 150-200, respectively. Using a random effects model, the estimated rates of high NLR and PLR were 0.379 (95% confidence interval [CI] 0.310-0.454) and 0.490 (95% CI 0.438-0.543), respectively. High NLRs were frequently found in patients with lower tumor stages and in those who underwent surgery. There were significant correlations between high NLR and PLR and poor survival rates (hazard ratio [HR] 1.737, 95% CI 1.502-2.009 and HR 1.143, 95% CI 1.037-1.259, resp.). Interestingly, the NLR and PLR had no prognostic value in patients who underwent chemoradiotherapy. Conclusion: Taken together, our results showed that inflammatory markers are useful for predicting prognosis in patients with pancreatic cancer. The NLR is a more suitable parameter for predicting prognosis regardless of the patient's condition. PMID- 29977294 TI - Prevalence of Anterior Dental Trauma and Its Associated Factors among Preschool Children Aged 3-5 Years in Khartoum City, Sudan. AB - Background: Traumatic dental injury (TDI) is a challenging public health problem. Its incidence and prevalence vary within countries, states, and different social groups. Aim: The purpose of this study was to determine the prevalence of traumatic dental injuries in primary incisors among 3-5-year-old Sudanese preschool children and associated factors such as age, sex, and size of overjet and anterior open bite. Materials and Methods: Descriptive cross-sectional study was carried out among 600 preschool children (3-5 years old) selected by multistage cluster technique from preschools located in Khartoum city, Sudan. The data regarding age, sex, causes, and treatment of TDI were collected from the mothers through structured interview questionnaire. Children were examined in an upright position, using mouth mirror and torch. A single examiner assessed the type of trauma, the tooth involved, and overbite/overjet. The data were analyzed statistically through descriptive analysis, and the chi-square test was used to compare between different variables with P < 0.05. Results: The prevalence of traumatic dental injuries (TDIs) was 18.5%. Enamel fractures were the most common type (74.8%), followed by enamel and dentin (11.7%). The maxillary central incisors were the most commonly affected teeth, and the home was most common place for TDI. The prevalence rate was 45% in boys and 55% in girls with a statistically significant difference (P=0.02). Conclusions: The prevalence of traumatic dental injuries to the primary anterior teeth among the Sudanese preschool children was relatively high (18.5%). Factors such as overjet size, overbite size, and lip competency were not significantly correlated with dental trauma among the studied population. PMID- 29977292 TI - Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review. AB - Apelin has been isolated from the bovine stomach extracts as an endogenous ligand of the previously orphan receptor APJ. Expression of the apelinergic system (apelin and APJ) was described in many organs where pleiotropic effects like regulation of food intake, body weight, or cardiovascular and immune function were described. Recent studies have shown that apelin also plays an important role in the regulation of female and male reproduction. Some data showed that the gene and protein of apelin/APJ are expressed in the hypothalamic-pituitary-gonad (HPG) axis tissue. Thus, apelin is synthesized locally in the hypothalamus, pituitary, ovaries, and testis of many species and has autocrine and/or paracrine effects. Most research indicates that apelin has an inhibitory effect on gonadotropin secretion and participates in the direct regulation of steroidogenesis, cell proliferation, and apoptosis in gonads. The article summarizes also results of a series of recent studies on the effect of apelin on reproduction pathology, like polycystic ovarian syndrome, endometriosis, and ovarian cancer. Many of these pathologies are still in critical need of therapeutic intervention, and recent studies have found that apelin can be targets in reproductive pathological states. PMID- 29977293 TI - TFF1 and TFF3 mRNAs Are Higher in Blood from Breast Cancer Patients with Metastatic Disease than Those without. AB - Introduction: Breast cancer metastasis occurs when tumor cells dissociate from the primary tumor and migrate to distant organs through the peripheral bloodstream or lymphatic drainage. Circulating tumor cells (CTCs) originate from primary sites or metastases and circulate in the patients' bloodstream. Molecular assays for the detection and molecular characterization of CTCs can serve as a liquid biopsy and can represent an alternative to invasive biopsies as a source of tumor tissue in the metastatic patients. Patients and Methods: We analyzed the presence of CTCs in the peripheral blood of 50 breast cancer patients by quantitative real-time reverse transcriptase polymerase chain reaction (RT-qPCR) to detect trefoil factor family (TFF) 1 and 3 genes. Results: We found significant difference in the level of both TFF1 and TFF3 mRNA in the blood of nonmetastatic versus metastatic breast cancer patients (p= 0.001 and p= 0.038, respectively). TFF1 mRNA was detected at higher levels in 34.6% of metastatic breast cancer patients as compared to 0% of nonmetastatic (p= 0.002). As regards TFF3 mRNA, it was detected at higher levels in 46.2% of metastatic breast cancer patients as compared to 4% of nonmetastatic (p= 0.026). Moreover, we found that the high level of both TFF1 and TFF3 mRNA was related to estrogen status of the patients. The detection of high level of TFF1 mRNA in CTCs was associated with bone metastases (77.8%), while that of TFF3 was related to lymph node involvement (75%) and lung metastases (68.8%). Conclusion: The combined measurement of both TFF1 and TFF3 mRNA level for differentiation of metastatic from nonmetastatic breast cancer gave 57.69% sensitivity and 83.3% specificity. PMID- 29977295 TI - Fabrication of AChE/SnO2-cMWCNTs/Cu Nanocomposite-Based Sensor Electrode for Detection of Methyl Parathion in Water. AB - The work highlights inhibition-based Acetylcholinesterase (AChE) fabrication using composite nanomaterial comprising tin oxide nanoparticles (SnO2) and carboxylated multiwalled carbon nanotubes (cMWCNTs) for detection of pesticide methyl parathion (MP) in water samples. Working electrode AChE/SnO2-cMWCNTs/Cu exhibited high sensitivity with a linearity range of 1.0 MUM to 160 MUM and a minimum detection limit of 0.1 MUM for MP in water. The fabricated electrode was found biocompatible and nontoxic which can be used to detect low concentrations of pesticide in water samples. The synergistic and facilitated electron transferring properties of SnO2-cMWCNTs/Cu made it an excellent support for immobilization of enzyme in sensing technology. The enzyme AChE was covalently immobilized with cMWCNTs using glutaraldehyde as crosslinking agent which has enhanced the storage stability and reusability of the method. The reusability attained was 30 times for 40 days when AChE/SnO2-cMWCNTs/Cu was stored at low temperature of 4 degrees C. Developed sensor showed excellent analytical recovery of pesticide in water sample with negligible effect of interfering species. Also, AChE/SnO2-cMWCNTs/Cu was easily reactivated simply by varying pH of phosphate buffer. This method is fast, reliable, and accurate showing successful development of amperometric biosensor for detection of MP in water sample. PMID- 29977296 TI - Design of Optical Sensor Membrane Based on Polymer Poly(methyl methacrylate) for Paracetamol Detection in Traditional Herbal Medicine. AB - Generally, regulation states that herbal medicines are remedies containing plants or preparation of plants as active ingredients only. Paracetamol is one of the drugs that is frequently added in herbal medicine to enhance the effect as an analgesic. The government regulation disallows chemical drugs contained in herbal medicine due to the toxic effect of uncontrolled consumption. On this study, the optical sensor membrane from polymer poly(methyl methacrylate) (PMMA) was synthesized by phase inversion method and was used to detect paracetamol in herbal medicine. PMMA was made in three different concentrations 5%, 7.5%, and 10% and was mixed with ferric chloride (FeCl3), Folin-Ciocalteu, and Nessler reagent as specific colorimetric reagents for paracetamol detection, with a ratio of solvent:reagent was 6:4; 7:3; and 8:2. The result of the experiment shows that PMMA-FeCl3 7.5% (7:3), PMMA-Folin 5% (6:4), and PMMA-Nessler 5% (6:4) give the best performance for paracetamol detection. Real herbal medicine samples were analyzed to confirm the practical application of this sensor, and the result shows good agreement with UV-Vis data. The results show that optical sensor membrane which has been developed can be used as new detection method of paracetamol for community application. PMID- 29977297 TI - In Vitro Culture of Single Bovine Embryos with Microwell Plates Made of Poly(dimethylsiloxane) Cured under Low Pressure. AB - Single embryo culture is useful for assessing the developmental competence of an embryo in detail. Recently, a device made of poly(dimethylsiloxane) (PDMS), which is biocompatible and nontoxic, has been widely used for culture various types of cells. However, PDMS plates are porous, causing the serious osmolality increment of the medium (over 600 mOsm/kg from Day 4 to Day 7). Here, we report that curing the PDMS under low pressure (LP-PDMS) greatly reduced the porosity, resulting in a constant osmolality of the medium. The blastocyst rate of single bovine embryos cultured with LP-PDMS microwell (MW) plates was the same as that of group cultured embryos (25 embryos/50 MUl droplet; control, P>0.05). These results indicate that MWs on a plate made of PDMS cured under low pressure can be successfully used for individual embryo culture. PMID- 29977298 TI - Frequency of Red Blood Cell Alloimmunization in Patients with Sickle Cell Disease in Palestine. AB - Background: Transfusion of red blood cells (RBC) is an essential therapeutic tool in sickle cell disease (SCD). Repeated RBC transfusions can cause alloimmunization which causes difficulty in cross-matching and finding compatible blood for transfusions. This study aimed to investigate the frequency of RBC alloimmunization and related risk factors among Palestinian SCD patients. Materials and Methods: A multicenter cross-sectional study on 116 previously transfused SCD patients from three centers in West Bank, Palestine. Demographic, medical data and history of transfusion were recorded. Blood samples were collected from transfused consenting SCD patients. Gel card method was used for antibody screening and identification. In all patients, autocontrol and direct antiglobulin (DAT) test were performed using polyspecific (anti-IgG + C3d) anti human globulin (AHG) gel cards for the detection of autoantibodies. Results: Of the SCD patients, 62 (53.4%) patients were HbSS and 54 (46.6%) patients were sickle beta-thalassemia (S/beta-thal). There were 53 (45.7%) females and 63 (54.3%) males. Mean age was 18.8 years (range 3-53 years). The frequency of RBC alloimmunization among SCD patients was 7.76%, with anti-K showing the highest frequency (33.3%) followed by anti-E (22.2%), anti-D (11.1%), anti-C (11.1%), and anti-c (11.1%). All reported IgG alloantibodies were directed against antigens in the Rh (66.7%) and Kell (33.3%) systems. Older ages of patients, increased number of blood units transfused, and splenectomy were the commonest risk factors for alloimmunization in our study. Conclusions: RBC alloimmunization rate among Palestinian SCD patients is low compared to neighboring countries and countries all over the world but still warrants more attention. Phenotyping of donors/recipients' RBC for Rh antigens and K1 (partial phenotype matching) before their first transfusion may reduce the incidence of alloimmunization. PMID- 29977299 TI - Patterns of Change in Metabolic Capabilities of Sediment Microbial Communities in River and Lake Ecosystems. AB - Information on the biodegradation potential of lake and river microbial communities is essential for watershed management. The water draining into the lake ecosystems often carries a significant amount of suspended sediments, which are transported by rivers and streams from the local drainage basin. The organic carbon processing in the sediments is executed by heterotrophic microbial communities, whose activities may vary spatially and temporally. Thus, to capture and apprehend some of these variabilities in the sediments, we sampled six sites: three from the Saint Clair River (SC1, SC2, and SC3) and three from Lake Saint Clair in the spring, summer, fall, and winter of 2016. Here, we investigated the shifts in metabolic profiles of sediment microbial communities, along Saint Clair River and Lake Saint Clair using Biolog EcoPlates, which test for the oxidation of 31 carbon sources. The number of utilized substrates was generally higher in the river sediments (upstream) than in the lake sediments (downstream), suggesting a shift in metabolic activities among microbial assemblages. Seasonal and site-specific differences were also found in the numbers of utilized substrates, which were similar in the summer and fall, and spring and winter. The sediment microbial communities in the summer and fall showed more versatile substrate utilization patterns than spring and winter communities. The functional fingerprint analyses clearly distinguish the sediment microbial communities from the lake sites (downstream more polluted sites), which showed a potential capacity to use more complex carbon substrates such as polymers. This study establishes a close linkage between physical and chemical properties (temperature and organic matter content) of lake and river sediments and associated microbial functional activities. PMID- 29977300 TI - Retracted: Prevalence of Bacteriuria and Antimicrobial Susceptibility Patterns among Diabetic and Nondiabetic Patients Attending at Debre Tabor Hospital, Northwest Ethiopia. AB - [This retracts the article DOI: 10.1155/2017/5809494.]. PMID- 29977301 TI - Fertility Outcomes following Laparoscopy-Assisted Hysteroscopic Fallopian Tube Cannulation: A Preliminary Study. AB - Objectives: To determine fertility outcomes following laparoscopy-guided hysteroscopic tubal cannulation for cornual obstruction. Study Design: A prospective cohort study in Life Institute for Endoscopy at Life Specialist Hospital Nnewi, Southeast Nigeria. Patients with unilateral or bilateral cornual tubal obstruction as the only cause of infertility were included. Outcome measures included successful tubal recanalization, procedural complications, conception rates (first spontaneous conception after the procedure), and live birth rates. Results: Forty-nine infertile women were assessed for eligibility, but 27 met the inclusion criteria. Of 27 women, 24 (88.9%) had bilateral cornual obstruction and 3 (11.1%) had unilateral obstruction. Only three (11.1%) patients had failed cannulation. Successful recanalization rate was 90.2% (46/51) per tube and 88.9% (24/27) per patient. In the 24 patients with successfully recanalization, six spontaneous pregnancies (25.0%) and two intrauterine insemination-assisted pregnancies (8.3%) occurred within first six months of follow-up. All the eight (100.0%) pregnancies were intrauterine. The overall conception rate and live birth rate was 33.3%. There were no pre- or postprocedural complications. Conclusion: Successful recanalization rate was 90.2% per tube and 88.9% per patient with a conception rate of 33.3%. Women with only cornual obstruction should be considered first for laparoscopy-assisted hysteroscopic cannulation before assisted reproduction. PMID- 29977302 TI - Isolated Knee Arthritis as Early and Only Symptom of Whipple's Disease. AB - We report a case of isolated Whipple's disease involving the knee of a 64-year old female patient who presented recurrent monoarthritis whose origin was not clear. Initially, the cause of the gradually invalidating symptoms was related to a meniscal lesion and a diffuse minor grade chondropathy, but pain and functional impairment suggested that more exams were needed. Biopsies were performed during arthroscopy. The histology showed highly inflammatory infiltrates with PAS staining negative for Tropheryma while PCR revealed the infection with Tropheryma whipplei. This, following the recommendation of a rheumatologist and infectious disease specialist, led to biopsies of the gastrointestinal tract and analysis of the cerebrospinal fluid that showed no other organ involvement. This confirms the scientific literature that an isolated monoarthritis without involvement of the gastrointestinal tract caused by this bacterium is rare but can occur as an early manifestation of potentially fatal systemic disease. Moreover, a review of the scientific literature showed the uncertainty about epidemiology of this rare disease, suggesting that more and specific data are required. PMID- 29977303 TI - Extensive Craniocervical Abscess after Transoral Ganglionic Local Opioid Analgesia at the Superior Cervical Ganglion for Atypical Trigeminal Neuralgia: Report of a Severely Complicated Case. AB - Ganglionic local opioid analgesia (GLOA) describes the application of low-dose opioids close to sympathetic as, for example, to the superior cervical ganglion. GLOA can be effective in different pain syndromes affecting the head and face region and has been considered to be a safe technique with few complications reported so far. We present the case of a patient who received a single, transoral GLOA for a refractory trigeminal neuralgia. The patient subsequently developed an extensive epidural abscess at the craniocervical junction, requiring ultimately transoral odontoid resection and dorsal stabilisation. This severe complication challenges the role of transoral infiltration therapies in analgetic medicine. PMID- 29977304 TI - Asymptomatic Pulmonary Artery Intimal Sarcoma with Chest Wall Metastasis as an Initial Manifestation: An Autopsy Case. AB - Pulmonary artery intimal sarcoma (PAIS) is a rare mesenchymal malignancy arising in the pulmonary trunk or proximal pulmonary artery and shows intraluminal growth. Clinical manifestations in PAIS are predominantly related to the pulmonary artery embolism, so cases with initial symptoms related to an extrapulmonary metastasis are unusual. The present report describes an 82-year old man without any cardiopulmonary symptoms who was detected with an abnormal shadow on chest radiography during a routine health checkup. Contrast medium enhanced chest computed tomography revealed an enhancing mass in the right pulmonary artery, pulmonary nodules, and a chest wall tumor corresponding to the abnormal shadow observed using chest radiography. A core needle biopsy for the chest wall tumor determined a pathological diagnosis of unclassified sarcoma. The patient was diagnosed with PAIS on the basis of clinical, radiological, and pathological correlations. He was scheduled to receive supportive care, but died of respiratory failure 1 year from the first visit. An autopsy revealed the pleomorphic sarcoma occupying the entire lumen of the right pulmonary artery with the only site of extrapulmonary metastasis in the chest wall. We should be aware of rare cases of asymptomatic PAIS found through routine health checkups. PMID- 29977305 TI - Xenogenic Implantation of Equine Synovial Fluid-Derived Mesenchymal Stem Cells Leads to Articular Cartilage Regeneration. AB - Horses are widely used as large animal preclinical models for cartilage repair studies, and hence, there is an interest in using equine synovial fluid-derived mesenchymal stem cells (SFMSCs) in research and clinical applications. Since, we have previously reported that similar to bone marrow-derived MSCs (BMMSCs), SFMSCs may also exhibit donor-to-donor variations in their stem cell properties; the current study was carried out as a proof-of-concept study, to compare the in vivo potential of equine BMMSCs and SFMSCs in articular cartilage repair. MSCs from these two sources were isolated from the same equine donor. In vitro analyses confirmed a significant increase in COMP expression in SFMSCs at day 14. The cells were then encapsulated in neutral agarose scaffold constructs and were implanted into two mm diameter full-thickness articular cartilage defect in trochlear grooves of the rat femur. MSCs were fluorescently labeled, and one week after treatment, the knee joints were evaluated for the presence of MSCs to the injured site and at 12 weeks were evaluated macroscopically, histologically, and then by immunofluorescence for healing of the defect. The macroscopic and histological evaluations showed better healing of the articular cartilage in the MSCs' treated knee than in the control. Interestingly, SFMSC-treated knees showed a significantly higher Col II expression, suggesting the presence of hyaline cartilage in the healed defect. Data suggests that equine SFMSCs may be a viable option for treating osteochondral defects; however, their stem cell properties require prior testing before application. PMID- 29977306 TI - Isolation and Characterization of Multipotent Turkey Tendon-Derived Stem Cells. AB - Tendon injuries are among the most common and severe hand injuries with a high demand for functional recovery. Stem cells have been identified and isolated from different species and a variety of tissues for the sake of regenerative medicine. Recently, turkey has been suggested as a potential new large animal model for flexor tendon-related research. However, turkey tissue-specific stem cells have not been investigated. Here, we presented the isolation and verification of tendon-derived stem cells (TDSCs) from 6- to 8-month-old heritage-breed turkey. TDSCs were isolated from turkey flexor tendon by plating nucleated cells at the determined optimal density. Approximately 4% of the nucleated cells demonstrated clonogenicity, high proliferation rate, and trilineage differentiation potential after induction culturing. These cells expressed surface antigens CD90, CD105, and CD44, but did not express CD45. There was a high level of gene expression of tenogenic markers in TDSCs, including mohawk, collagen type I, tenascin C, and elastin. Turkey TDSCs also expressed transcription factors PouV, Nanog, and Sox2, which are critically involved in the regulation of stemness. The successful isolation of tendon-derived stem cells from turkey was beneficial for future studies in tendon tissue engineering and would help in the development of new treatment for tendon diseases using this novel animal model. PMID- 29977307 TI - Evaluation of Oxidative Stress and Mitophagy during Adipogenic Differentiation of Adipose-Derived Stem Cells Isolated from Equine Metabolic Syndrome (EMS) Horses. AB - Mesenchymal stem cells (MSCs) are frequently used in both human and veterinary medicine because their unique properties, such as modulating the immune response and differentiating into multiple lineages, make them a valuable tool in cell based therapies. However, many studies have indicated the age-, lifestyle-, and disease-related deterioration of MSC regenerative characteristics. However, it still needs to be elucidated how the patient's health status affects the effectiveness of MSC differentiation. In the present study, we isolated mesenchymal stem cells from adipose tissue (adipose-derived mesenchymal stem cells (ASCs)) from horses diagnosed with equine metabolic syndrome (EMS), a common metabolic disorder characterized by pathological obesity and insulin resistance. We investigated the metabolic status of isolated cells during adipogenic differentiation using multiple research methods, such as flow cytometry, PCR, immunofluorescence, or transmission and confocal microscopy. The results indicated the impaired differentiation potential of ASCEMS. Excessive ROS accumulation and ER stress are most likely the major factors limiting the multipotency of these cells. However, we observed autophagic flux during differentiation as a protective mechanism that allows cells to maintain homeostasis and remove dysfunctional mitochondria. PMID- 29977308 TI - Autologous Stem Cell Therapy in Critical Limb Ischemia: A Meta-Analysis of Randomized Controlled Trials. AB - Objective: Critical limb ischemia (CLI) is the most dangerous stage of peripheral artery disease (PAD). Many basic researches and clinical treatment had been focused on stem cell transplantation for CLI. This systematic review was performed to review evidence for safety and efficacy of autologous stem cell therapy in CLI. Methods: A systematic literature search was performed in the SinoMed, PubMed, Embase, ClinicalTrials.gov, and Cochrane Controlled Trials Register databases from building database to January 2018. Results: Meta-analysis showed that cell therapy significantly increased the probability of ulcer healing (RR = 1.73, 95% CI = 1.45-2.06), angiogenesis (RR = 5.91, 95% CI = 2.49-14.02), and reduced the amputation rates (RR = 0.59, 95% CI = 0.46-0.76). Ankle-brachial index (ABI) (MD = 0.13, 95% CI = 0.11-0.15), TcO2 (MD = 12.22, 95% CI = 5.03 19.41), and pain-free walking distance (MD = 144.84, 95% CI = 53.03-236.66) were significantly better in the cell therapy group than in the control group (P < 0.01). Conclusions: The results of this meta-analysis indicate that autologous stem cell therapy is safe and effective in CLI. However, higher quality and larger RCTs are required for further investigation to support clinical application of stem cell transplantation. PMID- 29977311 TI - Antimicrobial and Antioxidant Activities of Natural Compounds. PMID- 29977310 TI - Efficacy and Safety of Traditional Chinese Medicine on Nonerosive Reflux Disease: A Meta-Analysis of Randomized Controlled Trials. AB - Objectives: Traditional Chinese medicine (TCM) therapy for nonerosive reflux disease (NERD) remains controversial. The aim of this study was to evaluate the efficacy and safety of TCM regimens in NERD treatment. Methods: Randomized controlled trials (RCTs) of TCM treatment for NERD through September 31, 2017, were systematically identified in PubMed, Wanfang Data, CNKI, VIP, CBM, Ovid, Web of Science, and Cochrane Library databases. Quality assessment was performed by employing the Cochrane Risk of Bias assessment tool. Results: A total of 725 and 719 patients in 14 RCTs were randomly divided into TCM alone and conventional Western medicine groups, respectively. The clinical total effective rate of the TCM group was markedly higher than that of the single proton pump inhibitors (PPIs) or Prokinetics therapy group (RR = 1.19, 95% CI = 1.07-1.31, and P = 0.0008), while it was comparable to that of the combination of PPIs and Prokinetics therapy group (RR = 1.14, 95% CI = 1.00-1.29, and P = 0.05). Compared with Western medicine group, the TCM group showed improved symptom relief through a reduced RDQ score (SMD = -0.91; 95% CI = -1.68--0.15; and P = 0.02). Additionally, TCM clearly decreased the recurrence rate (RR = 0.38, 95% CI = 0.28 0.52, and P < 0.00001). Adverse events, such as constipation, sickness, fever, abdominal distension, and stomach noise, were slight for both the TCM and Western medicine groups and disappeared after the easement of pharmacological intervention; in particular, TCM possessed fewer side effects. Conclusion: Compared with PPIs or Prokinetics therapy alone, TCM single therapy can better improve the clinical total effective rate and symptom relief and decrease the recurrence rate and adverse events in the treatment of NERD. Our results suggest that TCM will be a promising alternative therapy for NERD patients in the future. PMID- 29977312 TI - Acupuncture for Diarrhoea-Predominant Irritable Bowel Syndrome: A Network Meta Analysis. AB - Background: The objective of this study was to compare the efficacy and side effects of acupuncture, sham acupuncture, and drugs in the treatment of diarrhoea predominant irritable bowel syndrome. Methods: Randomized controlled trials (RCTs) assessing the effects of acupuncture and drugs were comprehensively retrieved from electronic databases (such as PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, VIP Database, and CBM) up to December 2017. Additional references were obtained from review articles. With document quality evaluations and data extraction, Network Meta-Analysis was performed using a random-effects model under a frequentist framework. Results: A total of 29 studies (n = 9369) were included; 19 were high-quality studies, and 10 were low-quality studies. NMA showed the following: (1) the ranking of treatments in terms of efficacy in diarrhoea-predominant irritable bowel syndrome is acupuncture, sham acupuncture, pinaverium bromide, alosetron = eluxadoline, ramosetron, and rifaximin; (2) the ranking of treatments in terms of severity of side effects in diarrhoea predominant irritable bowel syndrome is rifaximin, alosetron, ramosetron = pinaverium bromide, sham acupuncture, and acupuncture; and (3) the treatment of diarrhoea-predominant irritable bowel syndrome includes common acupoints such as ST25, ST36, ST37, SP6, GV20, and EX-HN3. Conclusion: Acupuncture may improve diarrhoea-predominant irritable bowel syndrome better than drugs and has the fewest side effects. Sham acupuncture may have curative effect except for placebo effect. In the future, it is necessary to perform highly qualified research to prove this result. Pinaverium bromide also has good curative effects with fewer side effects than other drugs. PMID- 29977309 TI - Extracellular Vesicles: A New Prospective in Crosstalk between Microenvironment and Stem Cells in Hematological Malignancies. AB - The bone marrow (BM) microenvironment in hematological malignancies (HMs) comprises heterogeneous populations of neoplastic and nonneoplastic cells. Cancer stem cells (CSCs), neoplastic cells, hematopoietic stem cells (HSCs), and mesenchymal stromal/stem cells (MSCs) are all components of this microenvironment. CSCs are the HM initiators and are associated with neoplastic growth and drug resistance, while HSCs are able to reconstitute the entire hematopoietic system; finally, MSCs actively support hematopoiesis. In some HMs, CSCs and neoplastic cells compromise the normal development of HSCs and perturb BM-MSCs. In response, "reprogrammed" MSCs generate a favorable environment to support neoplastic cells. Extracellular vesicles (EVs) are an important cell-to cell communication type in physiological and pathological conditions. In particular, in HMs, EV secretion participates to unidirectional and bidirectional interactions between neoplastic cells and BM cells. The transfer of EV molecular cargo triggers different responses in target cells; in particular, malignant EVs modify the BM environment in favor of neoplastic cells at the expense of normal HSCs, by interfering with antineoplastic immunity and participating in resistance to treatment. Here, we review the role of EVs in BM cell communication in physiological conditions and in HMs, focusing on the effects of BM niche EVs on HSCs and MSCs. PMID- 29977314 TI - ROS-Mediated Mitochondrial Pathway is Required for Manilkara Zapota (L.) P. Royen Leaf Methanol Extract Inducing Apoptosis in the Modulation of Caspase Activation and EGFR/NF-kappaB Activities of HeLa Human Cervical Cancer Cells. AB - Manilkara zapota (L.) P. Royen (family: Sapotaceae) is commonly called sapodilla, or locally known as ciku. The detailed mechanisms underlying Manilkara zapota leaf methanol extract against HeLa human cervical cancer cells have yet to be investigated. Therefore, our present study is designed to investigate the ability to induce apoptosis and the underlying mechanisms of Manilkara zapota leaf methanol extract inducing cytotoxicity in HeLa cells. The apoptotic cell death was assessed using Annexin V-propidium iodide staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential activities were measured using dichlorodihydrofluorescein diacetate and MitoLite Orange, respectively, by NovoCyte Flow Cytometer. Bax and Bcl-2 expression were evaluated using Enzyme-Linked Immunosorbent Assay. Caspase-3 activity was determined using a colorimetric assay. The associated biological interaction pathways were evaluated using quantitative real-time PCR. Our data showed that HeLa cells were relatively more sensitive to Manilkara zapota leaf methanol extract than other cancer cell lines studied. Overall analyses revealed that Manilkara zapota leaf methanol extract can inhibit the viability of HeLa cells, induce mitochondrial ROS generation, and inhibit nuclear factor-kappa B (NF-kappaB) and epidermal growth factor receptor (EGFR) transcriptional activities. Our results suggested that Manilkara zapota leaf methanol extract might represent a potential anticervical cancer agent. PMID- 29977313 TI - Acute Biochemical, Cardiovascular, and Autonomic Response to Hyperbaric (4 atm) Exposure in Healthy Subjects. AB - The aim of this study was to explore the effect of a hyperbaric environment alone on the cardiovascular system by ensuring elimination of factors that may mask the effect on hyperbaria. The research was performed in a hyperbaric chamber to eliminate the effect of physical activity and the temperature of the aquatic environment. Biochemical analysis and examination with the Task Force Monitor device were performed before and immediately after exposure. TFM was used for noninvasive examination of the cardiovascular system and the functional evaluation of the autonomic nervous system. Natriuretic peptides were measured as biochemical markers which were involved in the regulation of haemodynamic circulation vasoconstriction (urotensin II). L-arginine acted as a precursor of the level of the nitric oxide whereas angiotensin II and angiotensin (1-7) were involved in cardiac remodeling. The study group is comprised of 18 volunteers who were professional divers of similar age and experience. The results shown in our biochemical studies do not exceed reference ranges but a statistically significant increase indicates the hyperbaric environment is not without impact upon the human body. A decrease in HR, an increase in mBP, dBP, and TPR, and increase in parasympathetic heart nerves activity suggest an increase in heart afterload with a decrease in heart activity within almost one hour after hyperbaric exposure. Results confirm that exposure to a hyperbaric environment has significant impact on the cardiovascular system. This is confirmed both by changes in peptides associated with poorer cardiovascular outcomes, where a significant increase in the studied parameters was observed, and by noninvasive examination. PMID- 29977315 TI - Relationship between Tongue Temperature Estimated by Infrared Thermography, Tongue Color, and Cold-Heat Pathological Patterns: A Retrospective Chart Review Study. AB - Tongue diagnosis is a technique used to determine cold-heat pathologic patterns (CHPPs). Herein, we reviewed electronic medical records of tongue temperature measured using infrared thermography (IRT), tongue color (luminance, green/red, and blue/yellow balance), cold-heat pattern questionnaires (CHPQ), and body temperature for 134 women with gynecological problems (age, 38.97 +/- 11.49 years). The temperatures of seven tongue regions (root, center, tip, and both sides of the center and root) were determined, and the effects of age, regional differences, and their correlations with color parameters were examined. Factor analysis was conducted separately with the 10 cold pattern (CP) and 10 heat pattern (HP) items. Tongue temperature showed an age effect (beta; -0.198 to 0.210) and regional differences (both sides of the root > center and root > tip). Tongue temperature was positively correlated with luminance (r: 0.236-0.246), indicating that a higher temperature was associated with a brighter color. The factor analysis extracted two factors (cold sensitivity-pain and discharge complexion factors) from the CP items and three factors (heat sensation-pain, discharge-breath, and cold preference-thirst factors) from the HP items. Tongue temperature was negatively correlated with the discharge-complexion factor of CP and the discharge-breath factor of HP (r: -0.171 to -0.203), indicating that a lower tongue temperature may be a consequence of emission of excessive heat in HP and a lower blood perfusion in CP. Body temperature did not correlate with the CHPQ factor scores. In conclusion, tongue temperatures measured using IRT may be a partial indicator of CHPPs. PMID- 29977316 TI - In Vivo Antiplasmodial Activity of Two Sahelian Plant Extracts on Plasmodium berghei ANKA Infected NMRI Mice. AB - Up to now, the control of malaria remains a challenge. The World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) for uncomplicated malaria treatment. Despite this guideline, many people in Burkina Faso use herbal medicine as primary treatment against malaria. The aim of this study was to assess the in vivo activity of Guiera senegalensis J. F. Gmel and Bauhinia rufescens Lam. leaves extracts against Plasmodium berghei ANKA. A four-day treatment of leaves decoction of each plant was administrated orally to 7 groups of six NMRI (Naval Medical Research Institute) mice infected with Plasmodium berghei ANKA strain. The control group received distilled water as treatment while the treated groups each received daily 100, 250, and 500 mg extract/kg body weight. Thin blood smears were performed on day five and the percentage of reduction of parasitaemia was determined compared to the control. The percentages of reduction of the parasitaemia at the doses of 100, 250, and 500 mg extract/kg body weight were, respectively, 57.5%, 35.9%, and 44.9% for Guiera senegalensis and 50.6%, 22.2%, and 25.7% for Bauhinia rufescens. Our findings on antiplasmodial activity of these two plants justify the traditional use by local populations against malaria. Thus, the isolation of the active compounds from these two plants is suggested for possible antimalarial candidate drugs. PMID- 29977318 TI - Physical and Mental Effects of Bathing: A Randomized Intervention Study. AB - Showering is the most common form of bathing worldwide. Whole-body immersion bathing in warm water (~40 degrees C) is common in Japan and exerts sufficient hyperthermic action to induce vasodilatation and increase blood flow, supplying more oxygen and nutrients to the periphery. Cross-sectional studies report better subjective health status with an immersion bathing habit. This randomized controlled trial compared the effects on health of immersion bathing and shower bathing in 38 participants who received 2-week intervention of immersion bathing in warm water (40 degrees C) for 10 min (bathing intervention) followed by 2-week shower bathing without immersion (showering intervention) or vice versa (n = 19 each group). Visual analog scale scores were significantly better for fatigue, stress, pain, and smile and tended to be better for self-reported heath and skin condition after bathing intervention than after showering intervention. The SF-8 Health Survey showed significantly better general health, mental health, role emotional, and social functioning scores. Profile of Mood State scores were lower for stress, tension-anxiety, anger-hostility, and depression-dejection. Immersion bathing, but not shower bathing, exerts hyperthermic action that induces increased blood flow and metabolic waste elimination, which may afford physical refreshment. Immersion bathing should improve both physical and emotional aspects of quality of life. PMID- 29977317 TI - In Vitro Antioxidant Potential and Effect of a Glutathione-Enhancer Dietary Supplement on Selected Rat Liver Cytochrome P450 Enzyme Activity. AB - Background: There is considerable evidence that many people take dietary supplements including those of herbal origin as an alternative therapy to improve their health. One such supplement, with an amalgam of constituents, is CellGevity(r). However, the effect of this dietary supplement on drug metabolizing enzymes is poorly understood, as it has not been studied extensively. Therefore, we investigated the effect of CellGevity dietary supplement on selected rat liver microsomal cytochrome P450 (CYP) enzymes, the most common drug-metabolizing enzymes. We also determined the total antioxidant potential of this dietary supplement in vitro. Methods: To determine the antioxidant potential of CellGevity dietary supplement, 2,2-diphenyl-2-picryl hydrazyl (DPPH), total phenolic, and flavonoid assays were used after initial preparation of a solution form of the supplement (low dose, LD; 4 mg/kg and high dose, HD; 8 mg/kg). Rats received oral administration of these doses of the supplement for 7 days, after which the effect of the supplement on selected liver CYP enzymes was assessed using probe substrates and spectroscopic and high performance liquid chromatographic methods. Rats which received daily administration of 80 mg/kg of phenobarbitone and distilled water served as positive and negative controls, respectively. Results: The IC50 value of the supplement 0.34 +/- 0.07 mg/ml compared to 0.076 +/- 0.03 mg/ml of the BHT (positive control). The total phenolic content of the supplement at a concentration of 2.5 mg/ml was 34.97 g gallic acid equivalent (GAE)/100 g while its total flavonoid content at a concentration of 2.5 mg/ml was 6 g quercetin equivalent (QE)/100 g. The supplement significantly inhibited rat CYP2B1/2B2 (LDT 92.4%; HDT 100%), CYP3A4 (LDT 81.2%; HDT 71.7%), and CYP2C9 (LDT 21.7%; HDT 28.5%) while it had no significant inhibitory effect on CYPs 1A1/1A2, CYP1A2, and CYP2D6. Conclusion: CellGevity dietary supplement possesses moderate antioxidant activity in vitro and has an inhibitory effect on selected rat liver CYP enzymes, suggesting its potential interaction with drugs metabolized by CYP enzymes. PMID- 29977319 TI - The development and metamorphosis of the indirect developing acorn worm Schizocardium californicum (Enteropneusta: Spengelidae). AB - Background: Enteropneusts are benthic marine invertebrates that belong to the deuterostome phylum Hemichordata. The two main clades of enteropneusts are defined by differences in early life history strategies. In the Spengelidae and Ptychoderidae, development is indirect via a planktotrophic tornaria larva. In contrast, development in the Harrimanidae is direct without an intervening larval life history stage. Most molecular studies in the development and evolution of the enteropneust adult body plan have been carried out in the harrimanid Saccoglossus kowalevskii. In order to compare these two developmental strategies, we have selected the spengelid enteropneust Schizocardium californicum as a suitable indirect developing species for molecular developmental studies. Here we describe the methods for adult collecting, spawning and larval rearing in Schizocardium californicum, and describe embryogenesis, larval development, and metamorphosis, using light microscopy, immunocytochemistry and confocal microscopy. Results: Adult reproductive individuals can be collected intertidally and almost year-round. Spawning can be triggered by heat shock and large numbers of larvae can be reared through metamorphosis under laboratory conditions. Gastrulation begins at 17 h post-fertilization (hpf) and embryos hatch at 26 hpf as ciliated gastrulae. At 3 days post-fertilization (dpf), the tornaria has a circumoral ciliary band, mouth, tripartite digestive tract, protocoel, larval muscles and a simple serotonergic nervous system. The telotroch develops at 5 dpf. In the course of 60 days, the serotonergic nervous system becomes more elaborate, the posterior coeloms develop, and the length of the circumoral ciliary band increases. At the end of the larval stage, larval muscles disappear, gill slits form, and adult muscles develop. Metamorphosis occurs spontaneously when the larva reaches its maximal size (ca. 3 mm), and involves loss and reorganization of larval structures (muscles, nervous system, digestive tract), as well as development of adult structures (adult muscles, tripartite body organization). Conclusions: This study will enable future research in S. californicum to address long standing questions related to the evolution of axial patterning mechanisms, germ layer induction, neurogenesis and neural patterning, the mechanisms of metamorphosis, the relationships between larval and adult body plans, and the evolution of metazoan larval forms. PMID- 29977320 TI - Nut consumption and risk of metabolic syndrome and overweight/obesity: a meta analysis of prospective cohort studies and randomized trials. AB - Background: Nut consumption has been shown to reduce the risk of cardiovascular disease. However, its role in the prevention of metabolic disorders, such as metabolic syndrome (Mets) and overweight/obesity, remains controversial. We therefore conducted a meta-analysis to determine the association of nut consumption with Mets and overweight/obesity. Methods: Eligible studies were identified by searching the PubMed and Embase databases and by reviewing the references of relevant literatures. We used random effect models to pool the studies-specific risk ratio (RR) and weighted mean difference (WMD). Results: This meta-analysis included six prospective cohort studies with 420,890 subjects and 62 randomized feeding trials with 7184 participants. Among the cohort studies, the summary RR for every 1-serving/week increase in nut intake was 0.96 (95% confidence interval [CI]: 0.92 to 0.99; n = 3) for Mets, 0.97 (95% CI: 0.95 to 0.98; n = 2) for overweight/obesity, and 0.95 (95% CI: 0.89 to 1.02; n = 2) for obesity. Pooling of randomized trials indicated that nut consumption was related to a significant reduction in body weight (WMD: - 0.22 Kg, 95% CI: -0.40 to - 0.04), body mass index (WMD: - 0.16 Kg/m2, 95% CI: -0.31 to - 0.01), and waist circumference (WMD: - 0.51 cm, 95% CI: -0.95 to - 0.07). These findings remained stable in the sensitivity analysis, and no publication bias was detected. Conclusion: Nut consumption may be beneficial in the prevention of Mets and overweight/obesity. Additional prospective studies are needed to enhance these findings and to explore the metabolic benefits for specific subclasses of nut. PMID- 29977321 TI - Long-term effect of hand-arm vibration on thermotactile perception thresholds. AB - Background: Occupational exposure to hand-transmitted vibration (HTV) is known to cause neurological symptoms such as numbness, reduced manual dexterity, grip strength and sensory perception. The purpose of this longitudinal study was to compare thermotactile perception thresholds for cold (TPTC) and warmth (TPTW) among vibration exposed manual workers and unexposed white collar workers during a follow-up period of 16 years to elucidate if long-term vibration exposure is related to a change in TPT over time. Methods: The study group consisted of male workers at a production workshop at which some of them were exposed to HTV. They were investigated in 1992 and followed-up in 2008. All participants were physically examined and performed TPT bilaterally at the middle and distal phalanges of the second finger. Two different vibration exposure dosages were calculated for each individual, i.e. the individual cumulative lifetime dose (mh/s2) or a lifetime 8-h equivalent daily exposure (m/s2). Results: A significant mean threshold difference was found for all subjects of about 4-5 degrees C and 1-2 degrees C in TPTW and TPTC, respectively, between follow-up and baseline. No significant mean difference in TPTC between vibration exposed and non-exposed workers at each occasion could be stated to exist. For TPTW a small but significant difference was found for the right index finger only. Age was strongly related to thermotactile perception threshold. The 8-h equivalent exposure level (A (8)) dropped from about 1.3 m/s2 in 1992 to about 0.7 m/s2 in 2008. Conclusions: A lifetime 8-h equivalent daily exposure to hand-transmitted vibration less than 1.3 m/s2 does not have a significant effect on thermotactile perception. Age, however, has a significant impact on the change of temperature perception thresholds why this covariate has to be considered when using TPT as a tool for health screening. PMID- 29977322 TI - Deep breast pain during lactation: a case-control study in Sweden investigating the role of Candida albicans. AB - Background: Deep breast pain during lactation, with or without accompanying nipple pain and soreness continues to be anecdotally linked to infection by Candia albicans despite lack of robust evidence in the literature that Candida albicans is the cause of women's breast symptoms. Methods: A case-control study of breastfeeding women in Sweden with (n 35) and without (n 35) symptoms that may be attributable to Candida albicans was carried out. The symptoms were radiating, burning and penetrating or non-penetrating breast pain with or without associated nipple pain during or after breastfeeding. The primary aim of the study was to test the hypothesis that breastfeeding women with symptoms commonly associated with Candida albicans infection will have a growth of Candida albicans in their breast milk significantly more often than women without these symptoms. A secondary aim was comparison of breastfeeding self-efficacy, measured by the BSES SF (Breastfeeding Self Efficacy Scale -Short Form), between cases and controls. Results: None of the women in the control group and eight of the women in the case group showed a growth of Candida albicans in their breast milk (p < 0.01), which confirms the hypothesis. There were no statistically significant differences in severity or type of symptoms between those in the case group with and without growth of Candida albicans in their breast milk. Results of the BSES SF measurement showed no statistically significant differences between cases and controls. However, when analyses were stratified for parity, multiparous controls showed statistically significant higher scores for breastfeeding self-efficacy than multiparous cases. Conclusions: Neither clinical symptoms nor microbial cultivation appear to be reliable means for making a diagnosis of Candida albicans infection of the breast. Skilled breastfeeding consultants should offer support and help with positioning, attachment and identification of physical impediments to successful breastfeeding. Professionals should be aware that it is possible that uncertainty in the breastfeeding situation may to some extent account for mothers' breast symptoms. The ISRCTN (International Standard Randomised Controlled Trial Number) identity for this case-control study is ISRCTN88839993. The study was retrospectively registered on 30 November 2016. PMID- 29977323 TI - A transient transformation system for gene characterization in upland cotton (Gossypium hirsutum). AB - Background: Genetically modified cotton accounts for 64% of the world's cotton growing area (22.3 million hectares). The genome sequencing of the diploid cotton progenitors Gossypium raimondii and Gossypium arboreum as well as the cultivated Gossypium hirsutum has provided a wealth of genetic information that could be exploited for crop improvement. Unfortunately, gene functional characterization in cotton is lagging behind other economically important crops due to the low efficiency, lengthiness and technical complexity of the available stable transformation methods. We present here a simple, fast and efficient method for the transient transformation of G. hirsutum that can be used for gene characterization studies. Results: We developed a transient transformation system for gene characterization in upland cotton. Using beta-glucuronidase as a reporter for Agrobacterium-mediated transformation assays, we evaluated multiple transformation parameters such as Agrobacterium strain, bacterial density, length of co-cultivation, chemicals and surfactants, which can affect transformation efficiency. After the initial characterization, the Agrobacterium EHA105 strain was selected and a number of binary constructs used to perform gene characterization studies. 7-days-old cotton seedlings were co-cultivated with Agrobacterium and transient gene expression was observed 5 days after infection of the plants. Transcript levels of two different transgenes under the control of the cauliflower mosaic virus (CaMV) 35S promoter were quantified by real-time reverse transcription PCR (qRT-PCR) showing a 3-10 times increase over the levels observed in non-infected controls. The expression patterns driven by the promoters of two G. hirsutum genes as well as the subcellular localization of their corresponding proteins were studied using the new transient expression system and our observations were consistent with previously published results using Arabidopsis as a heterologous system. Conclusions: The Agrobacterium mediated transient transformation method is a fast and easy transient expression system enabling high transient expression and transformation efficiency in upland cotton seedlings. Our method can be used for gene functional studies such as promoter characterization and protein subcellular localization in cotton, obviating the need to perform such studies in a heterologous system such as Arabidopsis. PMID- 29977324 TI - A 13C isotope labeling method for the measurement of lignin metabolic flux in Arabidopsis stems. AB - Background: Metabolic fluxes represent the functional phenotypes of biochemical pathways and are essential to reveal the distribution of precursors among metabolic networks. Although analysis of metabolic fluxes, facilitated by stable isotope labeling and mass spectrometry detection, has been applied in the studies of plant metabolism, we lack experimental measurements for carbon flux towards lignin, one of the most abundant polymers in nature. Results: We developed a feeding strategy of excised Arabidopsis stems with 13C labeled phenylalanine (Phe) for the analysis of lignin biosynthetic flux. We optimized the feeding methods and found the stems continued to grow and lignify. Consistent with lignification profiles along the stems, higher levels of phenylpropanoids and activities of lignin biosynthetic enzymes were detected in the base of the stem. In the feeding experiments, 13C labeled Phe was quickly accumulated and used for the synthesis of phenylpropanoid intermediates and lignin. The intermediates displayed two different patterns of labeling kinetics during the feeding period. Analysis of lignin showed rapid incorporation of label into all three subunits in the polymers. Conclusions: Our feeding results demonstrate the effectiveness of the stem feeding system and suggest a potential application for the investigations of other aspects in plant metabolism. The supply of exogenous Phe leading to a higher lignin deposition rate indicates the availability of Phe is a determining factor for lignification rates. PMID- 29977325 TI - Common Interferences Removal from Dense Multichannel EEG Using Independent Component Decomposition. AB - To improve the spatial resolution, dense multichannel electroencephalogram with more than 32 leads has gained more and more applications. However, strong common interference will not only conceal the weak components generated from the specific isolated neural source, but also lead to severe spurious correlation between different brain regions, which results in great distortion on brain connectivity or brain network analysis. Starting from the fast independent component analysis algorithm, we first derive the mixing matrix of independent source components based on the baseline signals prior to tasks. Then, we identify the common interferences as those components whose mixing vectors span the minimum angles with respect to the unitary vector. By assuming that both the common interferences and their corresponding mixing vectors stay consistent during the entire experiment, we apply the demixing and mixing matrix to the task signals and remove the inferred common interferences. Subsequently, we validate the method using simulation. Finally, the index of global coherence is calculated for validation. It turns out that the proposed method can successfully remove the common interferences so that the prominent coherence of mu rhythms in motor imagery tasks is unmasked. The proposed method can gain wide applications because it reveals the true correlation between the local sources in spite of the low signal-to-noise ratio. PMID- 29977326 TI - Method for Calculating the Bending Angle of Puncture Needle in Preoperative Planning for Transjugular Intrahepatic Portal Systemic Shunt (TIPS). AB - Transjugular Intrahepatic Portal Systemic Shunt is a comprehensive interventional therapy for portal hypertension. During this intervention, puncturing from hepatic vein into portal vein is a difficult step. Selecting puncture needle with a proper bending angle is vital to accurate puncture. Thus, this prospective study provides a method to calculate the angle of the puncture needle using preinterventional contrast-enhanced CT imaging. According to the geometrical characteristics of puncture needle, Bezier curve equation was adopted to describe its bending part. By testing whether each point in a specific region satisfied the equation set of Bezier curves, the possible position of needle tip was obtained. Then, the bending angle of puncture needle was obtained by calculating curvature. The method was evaluated in 13 patients from 2 centers showing now a success rate of 100% and a duration of the procedure of 141 and 161 minutes. The method based on Bezier curve equation for calculating a proper bending angle of puncture needle was proven to be effective. And the clinical study is preliminary and additional work for clinical evaluation is necessary. PMID- 29977327 TI - A contemporary case series of Fournier's gangrene at a Swiss tertiary care center can scoring systems accurately predict mortality and morbidity? AB - Background: Fournier's gangrene (FG) is a life-threatening infection of the genital, perineal, and perianal regions with a morbidity range between 3 and 67%. Our aim is to report our experience in treatment of FG and to assess whether three different scoring systems can accurately predict mortality and morbidity in FG patients. Methods: All patients that were treated for FG at the Department of Urology of the University Hospital Basel between June 2012 and March 2017 were included and assessed retrospectively by chart review. Furthermore, we calculated Fournier's Gangrene Severity Index (FGSI), the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC), and the neutrophil-lymphocyte ratio (NLR) in every patient and assessed whether those scores correlate with the patients' morbidity and mortality. Results: Twenty patients were included, with a median (IQR) age of 66 (46-73) years. Fifteen of twenty (75%) patients required treatment on an intensive care unit, and three died (mortality rate: 15%). The mean FGSI, LRINEC, and NLR scores were 13.0, 9.3, and 45.3 for non-survivors and 7.7, 6.5, and 26 for survivors, respectively. None of the risk scores correlated significantly with mortality; however, all three significantly correlated with infection- and surgically-induced morbidity. Conclusions: In our series, Fournier's gangrene was associated with a mortality rate of 15% despite maximum multidisciplinary therapy at a specialized center. All risk scores were able to predict the morbidity of the disease in terms of local extent and the required surgical measures. PMID- 29977329 TI - Negative effect of hepatitis in overall and progression-free survival among patients with diffuse large B-cell lymphoma. AB - Background: Hepatitis B virus (HBV) is one of the most prevalent and serious infections worldwide. HBV reactivation is a serious complication for lymphoma patients who are being treated with rituximab-containing regimen. Since the impact of HBV has not been fully evaluated on the prognosis of diffuse large B cell lymphoma (DLBCL), this study examined the effect of the hepatitis infection on the progression-free survival (PFS) and overall survival (OS) in patients with DLBCL who received rituximab-containing chemotherapy. Methods: This retrospective cohort study was conducted at Princess Noorah Oncology Center, Jeddah by reviewing all medical records of 172 DLBCL diagnosed patients and recieved Rituximab-containing chemotherapy dated from January 2009 to February 2016. Results: Out of 172 patients, 53 were found positive in hepatitis serology. The 12 of those were HBsAg-positive and 41 were HBcAb-positive. Hepatitis reactivation was observed in 1% of the patients (i.e., 2 out of 172) and both of them were HBsAg-positive. Thus, the risk of hepatitis reactivation among the HBsAg-positive patients was 17% (i.e., 2 out of 12). The predicted 3-year PFS for HBsAg-positive and HBcAb-positive were 52% (+/- 8%), while 76% (+/- 4) for HBsAg negative and HBcAb-negative patients. On the other hand, the predicted 3-year OS for HBsAg and HBcAb-negative group is 93% (+/-3) while for HBsAg-positive and HBcAb-positive is 77% (+/-7), respectively. Conclusion: The present study demonstrated a low HBV reactivation rate of 1% exclusively in 2 patients with HBsAg-positive status diagnosed with DLBCL and receiving R-CHOP chemotherapy. PMID- 29977328 TI - Closed Or Open after Source Control Laparotomy for Severe Complicated Intra Abdominal Sepsis (the COOL trial): study protocol for a randomized controlled trial. AB - Background: Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods: The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score >= 3 or a World Society-of-Emergency-Surgery-Sepsis-Severity-Score >= 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health care resources. Discussion: Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration: ClinicalTrials.gov, NCT03163095. PMID- 29977330 TI - Tenofovir decrease hepatocellular carcinoma recurrence in chronic hepatitis B patients after liver resection. AB - Background: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are recommended as the first-line choices regarding the treatment of chronic hepatits B. The impact of the two antiviral agents on prognosis of Chronic hepatitis B (CHB) related hepatocellular carcinoma (HCC) remains to be explored. We aim to investigate whether CHB-related HCC patients receiving TDF and ETV have a different prognosis. Methods: 233 CHB-related compensated cirrhosis patients were divided into groups according to the nucleut(s)ide patients received. The results of TDF and ETV groups were reviewed and compared. The disease-free survival (DFS) and overall survival (OS) of both groups were analyzed and compared. Results: 233 CHB-related compensated cirrhosis patients from 2013 October to 2014 November were included in our study. 107 and 126 patients received TDF and ETV monotherapy, respectively. Child-Pugh score, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin level, status of hepatitis B e antigen (HBeAg) and serum HBV DNA level were compared between groups. DFS in TDF treatment group were significantly longer than it in ETV-treatment group (p < 0.05). multi-variant analysis indicated that TDF duration was significantly associated with lower probability of HCC development, (hazard ratio, 0.35; 95% confidence interval range, 0.33-0.84, p < 0.05). Conclusion: Anti-virus regimen containing TDF benefits for the prognosis of CHB-related liver cirrhosis patients. PMID- 29977332 TI - Manipulation of two regulatory genes for efficient production of chromomycins in Streptomyces reseiscleroticus. AB - Background: Regulatory genes play critical roles in natural product biosynthetic pathways. Chromomycins are promising anticancer natural products from actinomycetes. This study is aimed to create an efficient strain for production of these molecules by manipulating the regulatory genes. Results: A putative but silent chromomycin biosynthetic gene cluster was discovered in Streptomyces reseiscleroticus. Heterologous expression of the ketosynthase, chain length factor, and acyl carrier protein in Streptomyces lividans confirmed that they are responsible for the assembly of a decaketide. Two regulatory genes are present in this gene cluster, including SARP-type activator SrcmRI and PadR-like repressor SrcmRII. Either overexpression of SrcmRI or disruption of SrcmRII turned on the biosynthetic pathway of chromomycins. The production titers of chromomycin A3/A2 in R5 agar in these two strains reached 8.9 +/- 1.2/13.2 +/- 1.6 and 49.3 +/- 4.3/53.3 +/- 3.6 mg/L, respectively. An engineered strain was then constructed with both SrcmRII disruption and SrcmRI overexpression, which produced chromomycins A3 and A2 in R5 agar at 69.4 +/- 7.6 and 81.7 +/- 7.2 mg/L, respectively. Optimization of the culture conditions further increased the titers of chromomycins A3 and A2 respectively to 145.1 +/- 15.3 and 158.3 +/- 15.4 mg/L in liquid fermentation. Conclusions: This work revealed the synergistic effect of manipulation of pathway repressor and activator genes in the engineering of a natural product biosynthetic pathway. The resulting engineered strain showed the highest production titers of chromomycins by a strain of Streptomyces, providing an efficient way to produce these pharmaceutically valuable molecules. PMID- 29977331 TI - "The needs have clearly evolved as time has gone on.": A qualitative study to explore stakeholders' perspectives on the health needs of Syrian refugees in Greece following the 2016 European Union-Turkey agreement. AB - Background: By 2017, more than 500,000 Syrian refugees had passed through Greece seeking safety and asylum. Understanding how their health needs evolved over the refugee crisis in Greece and in relation to changing migration policy, and exploring the challenges involved in delivering their healthcare is timely as non governmental organizations (NGOs) transition health service provision to the Greek health authorities. Methods: We conducted a qualitative study to explore stakeholders' perspectives on delivering health services to Syrian refugees over the course of the humanitarian response in Greece from 2015 to 2017. Twenty-five in-depth interviews were conducted face-to-face or by Skype with healthcare providers, NGO staff, and organizational and government representatives involved in coordinating and managing healthcare for the Syrian refugee population in Greece. Following informed consent, interviews were audio-recorded or detailed summaries were manually recorded. Data were coded inductively to identify emerging themes. Results: Following the implementation of the European Union Turkey agreement in 2016, healthcare providers in refugee camps reported a shift from acute physical health issues to mental health disorders, and heightened risks of gender-based violence among Syrian refugees. Key challenges to service delivery included a narrow model of healthcare provision and insufficient referral mechanisms for social support and mental health services. Language and gender differences between refugees and healthcare providers, and a lack of privacy and space in clinics impeded the quality of care. Stakeholders observed deterioration in refugees' mental health in relation to longer periods spent in the camps. Many also emphasized that services for gender-based violence and mental health should be prioritized. Conclusion: This study provides stakeholders' perspectives on changes in refugee health needs over the course of the humanitarian response in Greece. With protracted encampment resulting from migration policy, addressing mental health disorders and gender-based violence should be prioritized, including psychosocial training for healthcare providers and strengthening referral mechanisms for specialized care. The findings also emphasize the importance of providing human-centered care and gender concordant services by incorporating female healthcare providers and interpreters into medical teams. Strategic communication and coordination is needed between NGOs and Greek health authorities to facilitate the transition of health service delivery to the Greek healthcare system and to improve access and quality of care for refugees. PMID- 29977333 TI - The Influence of Backpack Weight and Hip Belt Tension on Movement and Loading in the Pelvis and Lower Limbs during Walking. AB - The introduction of hip belts to backpacks has caused a shift of loading from the spine to the hips with reported improvements in musculoskeletal comfort. Yet the effects of different hip belt tensions on gait biomechanics remain largely unknown. The goal of this study was to assess the influence of backpack weight and hip belt tension on gait biomechanics. Data from optical motion capture and ground reaction forces (GRF) during walking were acquired in nine healthy male subjects (age 28.0 +/- 3.9 years). Six configurations of a commercial backpack were analyzed, that is, 15 kg, 20 kg, and 25 kg loading with 30 N and 120 N hip belt tension. Joint ranges of motion (ROM), peak GRF, and joint moments during gait were analyzed for significant differences by repeated measures of ANOVA with Bonferroni post hoc comparison. Increased loading led to a significant reduction of knee flexion-extension ROM as well as pelvis rotational ROM. No statistically significant effect of hip belt tension magnitudes on gait dynamics was found at any backpack weight, yet there was a trend of increased pelvis ROM in the transverse plane with higher hip belt tension at 25 kg loading. Further research is needed to elucidate the optimum hip belt tension magnitudes for different loading weights to reduce the risks of injury especially with higher loading. PMID- 29977334 TI - Changes in the microbial consortium during dark hydrogen fermentation in a bioelectrochemical system increases methane production during a two-stage process. AB - Background: Bioelectrochemical systems (BESs) are an innovative technology developed to influence conventional anaerobic digestion. We examined the feasibility of applying a BES to dark hydrogen fermentation and its effects on a two-stage fermentation process comprising hydrogen and methane production. The BES used low-cost, low-reactivity carbon sheets as the cathode and anode, and the cathodic potential was controlled at - 1.0 V (vs. Ag/AgCl) with a potentiostat. The operation used 10 g/L glucose as the major carbon source. Results: The electric current density was low throughout (0.30-0.88 A/m2 per electrode corresponding to 0.5-1.5 mM/day of hydrogen production) and water electrolysis was prevented. At a hydraulic retention time of 2 days with a substrate pH of 6.5, the BES decreased gas production (hydrogen and carbon dioxide contents: 52.1 and 47.1%, respectively), compared to the non-bioelectrochemical system (NBES), although they had similar gas compositions. In addition, a methane fermenter (MF) was applied after the BES, which increased gas production (methane and carbon dioxide contents: 85.1 and 14.9%, respectively) compared to the case when the MF was applied after the NBES. Meta 16S rRNA sequencing revealed that the BES accelerated the growth of Ruminococcus sp. and Veillonellaceae sp. and decreased Clostridium sp. and Thermoanaerobacterium sp., resulting in increased propionate and ethanol generation and decreased butyrate generation; however, unknowingly, acetate generation was increased in the BES. Conclusions: The altered redox potential in the BES likely transformed the structure of the microbial consortium and metabolic pattern to increase methane production and decrease carbon dioxide production in the two-stage process. This study showed the utility of the BES to act on the microbial consortium, resulting in improved gas production from carbohydrate compounds. PMID- 29977335 TI - Enhancing oil production and harvest by combining the marine alga Nannochloropsis oceanica and the oleaginous fungus Mortierella elongata. AB - Background: Although microalgal biofuels have potential advantages over conventional fossil fuels, high production costs limit their application in the market. We developed bio-flocculation and incubation methods for the marine alga, Nannochloropsis oceanica CCMP1779, and the oleaginous fungus, Mortierella elongata AG77, resulting in increased oil productivity. Results: By growing separately and then combining the cells, the M. elongata mycelium could efficiently capture N. oceanica due to an intricate cellular interaction between the two species leading to bio-flocculation. Use of a high-salt culture medium induced accumulation of triacylglycerol (TAG) and enhanced the contents of polyunsaturated fatty acids (PUFAs) including arachidonic acid and docosahexaenoic acid in M. elongata. To increase TAG productivity in the alga, we developed an effective, reduced nitrogen-supply regime based on ammonium in environmental photobioreactors. Under optimized conditions, N. oceanica produced high levels of TAG that could be indirectly monitored by following chlorophyll content. Combining N. oceanica and M. elongata to initiate bio-flocculation yielded high levels of TAG and total fatty acids, with ~ 15 and 22% of total dry weight (DW), respectively, as well as high levels of PUFAs. Genetic engineering of N. oceanica for higher TAG content in nutrient-replete medium was accomplished by overexpressing DGTT5, a gene encoding the type II acyl-CoA:diacylglycerol acyltransferase 5. Combined with bio-flocculation, this approach led to increased production of TAG under nutrient-replete conditions (~ 10% of DW) compared to the wild type (~ 6% of DW). Conclusions: The combined use of M. elongata and N. oceanica with available genomes and genetic engineering tools for both species opens up new avenues to improve biofuel productivity and allows for the engineering of polyunsaturated fatty acids. PMID- 29977336 TI - A non-linear model of hydrogen production by Caldicellulosiruptor saccharolyticus for diauxic-like consumption of lignocellulosic sugar mixtures. AB - Background: Caldicellulosiruptor saccharolyticus is an attractive hydrogen producer suitable for growth on various lignocellulosic substrates. The aim of this study was to quantify uptake of pentose and hexose monosaccharides in an industrial substrate and to present a kinetic growth model of C. saccharolyticus that includes sugar uptake on defined and industrial media. The model is based on Monod and Hill kinetics extended with gas-to-liquid mass transfer and a cybernetic approach to describe diauxic-like growth. Results: Mathematical expressions were developed to describe hydrogen production by C. saccharolyticus consuming glucose, xylose, and arabinose. The model parameters were calibrated against batch fermentation data. The experimental data included four different cases: glucose, xylose, sugar mixture, and wheat straw hydrolysate (WSH) fermentations. The fermentations were performed without yeast extract. The substrate uptake rate of C. saccharolyticus on single sugar-defined media was higher on glucose compared to xylose. In contrast, in the defined sugar mixture and WSH, the pentoses were consumed faster than glucose. Subsequently, the cultures entered a lag phase when all pentoses were consumed after which glucose uptake rate increased. This phenomenon suggested a diauxic-like behavior as was deduced from the successive appearance of two peaks in the hydrogen and carbon dioxide productivity. The observation could be described with a modified diauxic model including a second enzyme system with a higher affinity for glucose being expressed when pentose saccharides are consumed. This behavior was more pronounced when WSH was used as substrate. Conclusions: The previously observed co-consumption of glucose and pentoses with a preference for the latter was herein confirmed. However, once all pentoses were consumed, C. saccharolyticus most probably expressed another uptake system to account for the observed increased glucose uptake rate. This phenomenon could be quantitatively captured in a kinetic model of the entire diauxic-like growth process. Moreover, the observation indicates a regulation system that has fundamental research relevance, since pentose and glucose uptake in C. saccharolyticus has only been described with ABC transporters, whereas previously reported diauxic growth phenomena have been correlated mainly to PTS systems for sugar uptake. PMID- 29977338 TI - Characterization of chromosome composition of sugarcane in nobilization by using genomic in situ hybridization. AB - Background: Interspecific hybridization is an effective strategy for germplasm innovation in sugarcane. Nobilization refers to the breeding theory of development and utilization of wild germplasm. Saccharum spontaneum is the main donor of resistance and adaptive genes in the nobilization breeding process. Chromosome transfer in sugarcane is complicated; thus, research of different inheritance patterns can provide guidance for optimal sugarcane breeding. Results: Through chromosome counting and genomic in situ hybridization, we found that six clones with 80 chromosomes were typical S. officinarum and four other clones with more than 80 chromosomes were interspecific hybrids between S. officinarum and S. spontaneum. These data support the classical view that S. officinarum is characterized by 2n = 80. In addition, genomic in situ hybridization showed that five F1 clones were products of a 2n + n transmission and one F1 clone was the product of an n + n transmission in clear pedigree noble hybrids between S. officinarum and S. spontaneum. Interestingly, Yacheng 75-408 and Yacheng 75-409 were the sibling lines of the F1 progeny from the same parents but with different genetic transmissions. Conclusions: This is the first clear evidence of Loethers, Crystallina, Luohanzhe, Vietnam Niuzhe, and Nanjian Guozhe were typical S. officinarum by GISH. Furthermore, for the first time, we identified the chromosome transmission of six F1 hybrids between S. officinarum and S. spontaneum. These findings may provide a theoretical basis for germplasm innovation in sugarcane breeding and guidance for further sugarcane nobilization. PMID- 29977337 TI - Development of an emergency general surgery process improvement program. AB - Background: The Joint Trauma System has demonstrated improved outcomes through coordinated research and process improvement programs. With fewer combat trauma patients, our military American College of Surgeons level 2 trauma center's ability to maintain a strong trauma Process Improvement (PI) program has become difficult. As emergency general surgery (EGS) patients are similar to trauma patients, our Trauma and Acute Care Surgery (TACS) service developed an EGS PI program analogous to what is done in trauma. We describe the implementation of our novel EGS PI program and its effect on institutional PI proficiency. Methods: An EGS registry was developed in 2013. Inclusion criteria were based on AAST published literature. In 2015, EGS registrar and PI coordinator positions were developed and filled with existing trauma staff. A formal EGS PI program began January 1, 2016. Pre- and post-program data was compared to determine the effect including EGS PI events had on increasing yield into our trauma PI program. Results: In 2016, TACS saw 1001 EGS consults. Four hundred forty-four met criteria for registry inclusion. Eighty-two patients had 131 PI events; re admission within 30 days, unplanned therapeutic intervention, and unplanned ICU admission were the most common events. Capture of EGS PI events yielded a 49% increase compared with 2015. Conclusion: Overall patient volume and PI events post EGS PI program initiation exceeded those prior to implementation. These data suggest that extending trauma PI principles to EGS may be beneficial in maintaining inter-war military and/or lower volume trauma center readiness. PMID- 29977339 TI - High prevalence of irritable bowel syndrome-type symptoms in microscopic colitis: implications for treatment. AB - Background: Patients with microscopic colitis (MC) often present with abdominal pain and diarrhoea, and previous data suggest that there may be overlap between MC and irritable bowel syndrome (IBS). We evaluated the prevalence of IBS-type symptoms in patients with MC, and assess the impact of these symptoms on psychological health and quality of life. Methods: We conducted a cross-sectional survey of individuals with a histological diagnosis of MC, collecting demographic data, Rome III IBS-type symptoms, and mood, somatization, and quality of life data. Results: In total, 151 (31.6%) of 478 individuals with a new diagnosis of MC completed questionnaires, 52 (34.4%) of whom reported IBS-type symptoms. The commonest histological subtype was collagenous colitis (51.7%, n = 78), followed by lymphocytic colitis (39.1%, n = 59). Individuals with IBS-type symptoms had significantly higher levels of anxiety [Hospital Anxiety and Depression Scale (HADS) anxiety score 8.6 versus 5.1, p < 0.001], depression (HADS depression score 6.2 versus 3.6, p = 0.001), and somatoform-type behaviour (Patient Health Questionnaire 15 score 12.7 versus 8.0, p < 0.001) compared with individuals who did not. Those with IBS-type symptoms scored significantly worse across all domains of the 36-item Short Form questionnaire, except for physical functioning. Conclusions: More than one third of individuals with MC reported IBS-type symptoms, although whether this is due to ongoing inflammation is unclear. These individuals had higher levels of anxiety, depression, and somatization, and impaired quality of life. Identifying concomitant IBS in individuals with MC may have important implications for management decisions. PMID- 29977340 TI - Vedolizumab and early postoperative complications in nonintestinal surgery: a case-matched analysis. AB - Background: Vedolizumab (VDZ) is a gut-specific alpha4-beta7 integrin antagonist that has demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC). The safety of VDZ in the perioperative period remains unclear. The aim of this study was to evaluate postoperative complications and perioperative safety in VDZ-treated patients undergoing nonintestinal operations. Methods: A case matched study was performed at two inflammatory bowel disease (IBD) referral centers. Adult patients with CD and UC who underwent a nonintestinal surgical procedure during treatment with VDZ were included. Patients who had their last VDZ infusion up to 12 weeks before the procedure were considered exposed and were matched in a 1:1 ratio to patients without VDZ therapy, according to type of surgical procedure, age, and sex. The primary outcome was overall risk of early postoperative infectious complications (up to 30 days after surgery), readmissions, reoperations, surgical site infections, and other infections. The VDZ and control groups were subsequently compared using the Pearson chi2 test and Wilcoxon rank sum. Results: We identified 34 patients treated with VDZ who underwent 36 nonintestinal surgical procedures. These patients were matched with 36 control procedures. Postoperative complications were not different between the VDZ-treated and control cohorts for all outcomes analyzed: infectious complications occurred in 14% versus 8% (p = 0.45), superficial surgical site infections 6% versus 0% (p = 0.15), reoperations 6% versus 3% (p = 0.56) and readmissions 11% versus 6% (p = 0.37). Conclusions: VDZ-treated patients with IBD undergoing nonintestinal procedures did not have an increased risk of overall postoperative infections or other complications compared with matched controls. PMID- 29977341 TI - MRI features as a helpful tool to predict the molecular subgroups of medulloblastoma: state of the art. AB - Medulloblastoma is the most common malignant pediatric brain tumor. Medulloblastoma should not be viewed as a single disease, but as a heterogeneous mixture of various subgroups with distinct characteristics. Based on genomic profiles, four distinct molecular subgroups are identified: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. Each of these subgroups are associated with specific genetic aberrations, typical age of onset as well as survival prognosis. Magnetic resonance imaging (MRI) is performed for all patients with brain tumors, and has a key role in the diagnosis, surgical guidance and follow up of patients with medulloblastoma. Several studies indicate MRI as a promising tool for early detection of medulloblastoma subgroups. The early identification of the subgroup can influence the extent of surgical resection, radiotherapy and chemotherapy targeted treatments. In this article, we review the state of the art in MRI facilitated medulloblastoma subgrouping, with a summary of the main MRI features in medulloblastoma and a brief discussion on molecular characterization of medulloblastoma subgroups. The main focus of the article is MRI features that correlate with medulloblastoma subtypes, as well as features suggestive of molecular subgroups. Finally, we briefly discuss the latest trends in MRI studies and latest developments in molecular characterization. PMID- 29977342 TI - Combined walking outcome measures identify clinically meaningful response to prolonged-release fampridine. AB - Background: Gait impairment is common in multiple sclerosis (MS) and negatively impacts patients' health-related quality of life (HRQoL). Prolonged-release fampridine (PR-fam) improves walking speed, but it is unclear which walking measures are the most suitable for identifying treatment response. Our aim was to assess the effect of PR-fam and the outcome measures that best identify short- and long-term clinically meaningful response. Methods: We conducted a prospective study in 32 MS patients treated with PR-fam for a year. The assessments at 2 weeks, 3, 6 and 12 months included: timed 25-foot walk (T25FW), 6-minute walk test (6MWT), MS Walking Scale-12 (MSWS-12), a five-level version of the EuroQoL-5 dimensions, and accelerometry. PR-fam response was defined as an improvement in T25FW ?20%. Results: Twenty-five (78%) patients were considered responders after 2 weeks of PR-fam and improved significantly in all measures. Responders to T25FW and MSWS-12 (n = 19) showed a significant improvement in HRQoL and accelerometer data compared with responders only to T25FW (n = 6). At 1 year, 15/20 (75%) patients remained responders, but only those with permanent response to T25FW and MSWS-12 (n = 8; 53%) showed a significant improvement in 6MWT and HRQoL. Conclusion: The combination of T25FW and MSWS-12 identify better those patients with a clinically significant benefit of PR-fam. PMID- 29977343 TI - The meningeal and choroidal infiltration routes for leukocytes in stroke. AB - Stroke is a major health burden as it is a leading cause of morbidity and mortality worldwide. Blood flow restoration, through thrombolysis or endovascular thrombectomy, is the only effective treatment but is restricted to a limited proportion of patients due to time window constraint and accessibility to technology. Over the past two decades, research has investigated the basic mechanisms that lead to neuronal death following cerebral ischemia. However, the use of neuroprotective paradigms in stroke has been marked by failure in translation from experimental research to clinical practice. In the past few years, much attention has focused on the immune response to acute cerebral ischemia as a major factor to the development of brain lesions and neurological deficits. Key inflammatory processes after stroke include the activation of resident glial cells as well as the invasion of circulating leukocytes. Recent research on anti-inflammatory strategies for stroke has focused on limiting the transendothelial migration of peripheral immune cells from the compromised vasculature into the brain parenchyma. However, recent trials testing the blockage of cerebral leukocyte infiltration in patients reported inconsistent results. This emphasizes the need to better scrutinize how immune cells are regulated at the blood-brain interface and enter the brain parenchyma, and particularly to also consider alternative cerebral infiltration routes for leukocytes, including the meninges and the choroid plexus. Understanding how immune cells migrate to the brain via these alternative pathways has the potential to develop more effective approaches for anti-inflammatory stroke therapies. PMID- 29977345 TI - Tigecycline application in a 3-month-old infant with multiple drug resistant Klebsiella pneumonia: a case report. AB - Background: Tigecycline is an 'immature' antibiotic for children. We report the youngest surviving patient who received a complete tigecycline treatment, and no significant adverse effects occurred in the patient. Case presentation: The 3 month old infant suffered from a catheter-associated bloodstream infection by multiple drug resistant Klebsiella pneumoniae. Tigecycline was considered as a salvage therapy to control the severe sepsis. The therapy consisted of 3 mg/kg as a loading dose and 1.5 mg/kg Q12 h as a maintenance dose for 26 days. Conclusion: Current researches are limited in clinical trials directly focused on children. This therapeutic schedule might be safe for patients who are above 3 months old. PMID- 29977344 TI - Reliability and correlates of cross-sectional area of abductor hallucis and the medial belly of the flexor hallucis brevis measured by ultrasound. AB - Background: Weakness of the intrinsic foot muscles is thought to produce deformity, disability and pain. Assessing intrinsic foot muscles in isolation is a challenge; however ultrasound might provide a solution. The aims of this study were to assess the reproducibility of assessing the size of abductor halluces (AbH) and the medial belly of flexor hallucis brevis (FHBM) muscles, and identify their relationship with toe strength, foot morphology and balance. Methods: Twenty one participants aged 26-64 years were measured on two occasions for muscle cross-sectional area using a Siemens Acuson X300 Ultrasound System with 5 13 MHz linear array transducer. Great toe flexor strength was measured by pedobarography, the paper grip test and hand-held dynamometry. Foot morphology was assessed by foot length, truncated foot length, Foot Posture Index (FPI) and dorsal arch height. Balance was measured by the maximal step test. Intra-class correlation coefficients (ICC3,1) were used to evaluate intra-rater reliability. Pearson's correlation coefficients were performed to assess associations between muscle size and strength, morphology and balance measures. To account for the influence of physical body size, partial correlations were also performed controlling for truncated foot length. Results: Intra-rater reliability was excellent for AbH (ICC3,1 = 0.97) and FHBM (ICC3,1 = 0.96). Significant associations were found between cross-sectional area of AbH and great toe flexion force measured standing by pedobarography (r = .623, p = .003),), arch height measured sitting (r = .597, p = .004) and standing (r = .590, p = .005), foot length (r = .582, p = 006), truncated foot length (r = .580, p = .006), balance (r = .443, p = .044), weight (r = .662, p = .001), height (r = .559, p = .008), and BMI (r = .502, p = .020). Significant associations were found between cross sectional area of FHBM and FPI (r = .544, p = .011), truncated foot length (r = .483, p = .027) and foot length (r = .451, p = .040). Significant partial associations were found between AbH and great toe flexion force in standing by pedobarography (r = .562, p = .012) and FHBM and the FPI (r = .631, p = .003). Conclusions: Measuring the cross-sectional area of AbH and FHBM with ultrasound is reproducible. Measures of strength, morphology and balance appear to relate more to the size of AbH than FHBM. After controlling for physical body size, cross-sectional area of AbH remained a significant correlate of great toe flexor strength and might be a useful biomarker to measure early therapeutic response to exercise. PMID- 29977346 TI - N-Acetyl-glucosamine influences the biofilm formation of Escherichia coli. AB - Background: The intestinal mucous layer is a physical barrier that limits the contact between bacteria and host epithelial cells. There is growing evidence that microbiota-produced metabolites can also be specifically sensed by gut pathogens as signals to induce or repress virulence genes. Many E. coli, including adherent and invasive (AIEC) strains, can form biofilm. This property can promote their intestinal colonization and resistance to immune mechanisms. We sought to evaluate the impact of mucus-derived sugars on biofilm formation of E. coli. Results: We showed that the mucin sugar N-acetyl-glucosamine (NAG) can reduce biofilm formation of AIEC strain LF82. We demonstrated that the inactivation of the regulatory protein NagC, by addition of NAG or by mutation of nagC gene, reduced the biofilm formation of LF82 in static condition. Interestingly, real-time monitoring of biofilm formation of LF82 using microfluidic system showed that the mutation of nagC impairs the early process of biofilm development of LF82. Thus, NAG sensor NagC is involved in the early steps of biofilm formation of AIEC strain LF82 under both static and dynamic conditions. Its implication is partly due to the activation of type 1 fimbriae. NAG can also influence biofilm formation of other intestinal E. coli strains. Conclusions: This study highlights how catabolism can be involved in biofilm formation of E. coli. Mucus-derived sugars can influence virulence properties of pathogenic E. coli and this study will help us better understand the mechanisms used to prevent colonization of the intestinal mucosa by pathogens. PMID- 29977347 TI - Precision medicine applications in prostate cancer. AB - Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival. PMID- 29977348 TI - Should age impact breast cancer management in young women? Fine tuning of treatment guidelines. AB - Despite breast cancer being uncommon in young women, it is still the most frequent cancer diagnosed in women aged 15-39 years, and the leading cause of death in this age group in high-income countries, after accidents and self injury. The present review summarizes the most recent guidelines and offers an expert perspective on the many challenges associated with treatment of young women with breast cancer. We will especially focus on early breast cancer, exploring the specificities of the diagnostic process, imaging techniques, locoregional and systemic treatments, and the added value of dedicated multidisciplinary teams. Specific differences in adjuvant treatment between premenopausal and postmenopausal women, especially regarding endocrine therapy, will be addressed in detail. Research questions and current gaps in important fields, such as the paucity of age-specific data regarding antihuman epidermal growth factor receptor 2 (anti-HER2) therapy and gene panels such as OncotypeDX or MAMMAPRINT will be highlighted. A consistent part of this review is dedicated to the issues defining 'young women', such as fertility preservation, managing long-term side effects of oncological treatments and genetic counselling, by detailing current strategies and future perspectives. PMID- 29977349 TI - Immune-checkpoint inhibitors in melanoma and kidney cancer: from sequencing to rational selection. AB - Immune-checkpoint inhibitors (ICPIs), including antibodies against cytotoxic T lymphocyte associated antigen 4 and programmed cell death protein 1, have been shown to induce durable complete responses in a proportion of patients in the first-line and refractory setting in advanced melanoma and renal cell carcinoma. In fact, there are several lines of both targeted agents and ICPI that are now feasible treatment options. However, survival in the metastatic setting continues to be poor and there remains a need for improved therapeutic approaches. In order to enhance patient selection for the most appropriate next line of therapy, better predictive biomarkers of responsiveness will need to be developed in tandem with technologies to identify mechanisms of ICPI resistance. Adaptive, biomarker-driven trials will drive this evolution. The combination of ICPI with specific chemotherapies, targeted therapies and other immuno-oncology (IO) drugs in order to circumvent ICPI resistance and enhance efficacy is discussed. Recent data support the role for both targeted therapies and ICPI in the adjuvant setting of melanoma and targeted therapies in the adjuvant setting for renal cell carcinoma, which may influence the consideration of treatment on subsequent relapse. Approaches to select the optimal treatment sequences for these patients will need to be refined. PMID- 29977350 TI - Optimal management of luminal breast cancer: how much endocrine therapy is long enough? AB - Patients with early estrogen receptor-positive breast cancer are at continuous risk of relapse even after more than 10 years of follow up. Currently, no biomarker that identifies patients for early versus late recurrence, or one that selects patients or tumors for longer versus shorter durations of endocrine therapy (ET) is available and a crucial question is how to properly select patients who could be spared extended ET or those who require it. In the last 20 years more than 40,000 women were enrolled in randomized trials to answer the question of optimal duration of ET. According to the results of these studies extended adjuvant ET is more effective than standard 5 years of adjuvant ET. Extended ET in patients who remain premenopausal after 5 years of adjuvant tamoxifen is still tamoxifen for another 5 years. Extended ET with aromatase inhibitors (AIs) should be offered to postmenopausal women with substantial residual risk of relapse after completing 5 years of tamoxifen therapy. Extension of AI treatment to 10 years resulted in significantly better 5-year disease-free survival including disease recurrence local/distant or the occurrence of contralateral breast cancer events. Currently, new therapeutic targets are under investigation, but the beneficial effect of prolonged treatment for high-risk patients, identified by using multigenomic tests, remains unclear. Thus, further studies need to be performed to confirm the advantage of extended adjuvant ET in selected patients. PMID- 29977351 TI - Rucaparib in ovarian cancer: an update on safety, efficacy and place in therapy. AB - Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor and potent inhibitor of PARP1, PARP2 and PARP3 enzymes. Phase II and III trials have documented that rucaparib has single-agent antitumor activity in patients with high-grade ovarian carcinoma, with both BRCA-mutated (germline and somatic) and with homologous recombination deficiency (HRD). Rucaparib as a maintenance treatment showed increased progression-free survival in patients with ovarian carcinoma who achieved a response to platinum-based chemotherapy, with an acceptable safety profile. The approval of this drug, along with the companion diagnostic FoundationFocus CDxBRCA test represents an important new therapeutic option in the treatment of ovarian cancer. This article reviews the mechanisms of action, safety, pharmacokinetics and pharmacodynamics and indications for use of rucaparib as well as future trials. PMID- 29977352 TI - 5-fluorouracil and cardiotoxicity: a review. AB - Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity. PMID- 29977354 TI - IL-17A and GDF15 are able to induce epithelial-mesenchymal transition of lung epithelial cells in response to cigarette smoke. AB - Smoking is one of the primary causes of chronic obstructive pulmonary disease (COPD). Sustained active epithelial-mesenchymal transition (EMT) in COPD may explain the core pathophysiology of airway fibrosis and why lung cancer is so common among smokers. Interleukin (IL)-17A and growth/differentiation factor (GDF)15 have been reported to be biomarkers of COPD; however, the role of IL-17A and GDF15 in EMT remains unclear. The aim of the present study was to investigate the role of IL-17A and GDF15 in the pathogenesis of COPD. It was demonstrated that IL-17A and GDF15 are upregulated in patients with COPD, particularly those with a history of smoking. The results also revealed that IL-17A and GDF15 expression was negatively correlated with the epithelial marker epithelial cadherin and positively correlated with the mesenchymal marker vimentin. Furthermore, treatment with cigarette smoke extract or IL-17A induced GDF15 expression. Combined treatment with IL-17A and GDF15 induced EMT in human small epithelial HSAEpiC cells in vitro. Collectively, the results of the present study suggest that IL-17A and GDF15-induced EMT serves an important role in the pathology of COPD. PMID- 29977353 TI - Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives. AB - Brain metastases are the most common central nervous system tumors in adults, and incidence of brain metastases is increasing due to both improved diagnostic techniques (e.g. magnetic resonance imaging) and increased cancer patient survival through advanced systemic treatments. Outcomes of patients remain disappointing and treatment options are limited, usually involving multimodality approaches. Brain metastases represent an unmet medical need in solid tumor care, especially in breast cancer, where brain metastases are frequent and result in impaired quality of life and death. Challenges in the management of brain metastases have been highlighted in this review. Innovative research and treatment strategies, including prevention approaches and emerging systemic treatment options for brain metastases of breast cancer, are further discussed. PMID- 29977355 TI - Protective effects of nicorandil against cerebral injury in a swine cardiac arrest model. AB - The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100beta, tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100beta were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P<0.05). Additionally, NSE and S100beta levels were significantly lower in the nicorandil group compared with the control (P<0.05). Pathological examinations and electron microscopy indicated that nicorandil reduced brain tissue damage. TNF-alpha and IL-6 levels were significantly decreased in the nicorandil group compared with the control group (P<0.05). Furthermore, AQP-4 expression in brain tissue 6 h following ROSC was significantly lower in the nicorandil group compared with the control group (P<0.05). MDA and GSH levels in swine brain tissue decreased and increased, respectively, in the nicorandil group compared with the control group (P<0.05). The results of the present study demonstrate that nicorandil exerts a protective effect against brain injury following cardiac arrest by reducing oxidative damage, inflammatory responses and brain edema post ROSC. PMID- 29977356 TI - Smoking and drinking influence the advancing of ischemic stroke disease by targeting PTGS2 and TNFAIP3. AB - In the present study, we explored the influence of cigarette smoking and alcohol drinking on gene expression level and related functions and pathways on the development of ischemic stroke (IS) disease. The gene expression profile of E GEOD-22255 was obtained from 20 IS samples (7 patients without smoking or drinking history and 13 patients with smoking or drinking history) and 20 controls (9 normal controls without smoking or drinking history and 11 controls with smoking or drinking history). The correlation degree between gene expression and grouping were measured by significance analysis of microarray (SAM). Smoking or drinking-related DEGs were screened. GO functional and KEGG pathway enrichment analyses were processed. Based on the KEGG database, a pathway relationship network was constructed. DEGs in significant functions and pathways were inserted and regarded as key DEGs. Gene co-expression network was constructed based on the expression value of key genes. In total, 319 IS-related DEGs, which were induced by smoking and drinking, were screened and enriched in various functions and pathways, including inflammatory response, nuclear factor-kappaB (NF-kappaB) signaling pathway and influenza A. Pathway relationship network was constructed with 44 nodes and the hub node was the MAPK signaling pathway. After merging, 87 key DEGs were obtained. The gene co-expression network with 43 node edges was constructed and the hub node was prostaglandin-endoperoxide synthase 2. In IS patients, smoking and drinking may induce different expression of many genes, including PTGS2, TNFAIP3, ZFP36 and NFKBIZ. In addition, these genes participated in various pathways, such as inflammatory response. PMID- 29977357 TI - Propofol improves the function of natural killer cells from the peripheral blood of patients with esophageal squamous cell carcinoma. AB - Postoperative immunosuppression is associated with the recurrence and metastasis of esophageal squamous cell carcinoma (ESCC). Propofol is a commonly used intravenous anesthetic and has been reported to be associated with immunosuppression; however, little is known about its effect on innate immune cells during the postoperative period in patients with ESCC. The aim of the present study was to investigate the effects of propofol on the phenotype and cytotoxicity of natural killer (NK) cells derived from the peripheral blood of patients with ESCC. The percentage, phenotype and function of NK cells were compared between patients with ESCC and healthy volunteers using flow cytometry. NK cells were negatively sorted using magnetic beads and cocultured with propofol to assess changes in phenotype and function. The results revealed that the percentage of NK cells was significantly increased in the peripheral blood of patients with ESCC, while their activity and cytotoxicity were impaired. NK cells were successfully separated from peripheral blood in vitro and it was demonstrated that propofol enhanced their activity by influencing the expression of activating or inhibitory receptors. Furthermore, propofol was able to increase the cytotoxicity of NK cells from the peripheral blood of patients with ESCC. These results suggest that propofol is able to improve the function of NK cells in patients with ESCC and may therefore be an appropriate anesthetic for ESCC surgery. PMID- 29977358 TI - Establishment of a novel rat model of blast-related diffuse axonal injury. AB - Although studies concerning blast-related traumatic brain injury (bTBI) have demonstrated the significance of diffuse axonal injury (DAI), no standard models for this type of injury have been widely accepted. The present study investigated a mechanism of inducing DAI through real blast injury, which was achieved by performing instantaneous high-speed swinging of the rat head, thus establishing a stable animal model of blast DAI. Adult Sprague-Dawley rats weighing 150+/-10 g were randomly divided into experimental (n=16), control (n=10) and sham control (n=6) groups. The frontal, parietal and occipital cortex of the rats in the experimental group were exposed, whereas those of the control group were unexposed; the sham control group rats were anesthetized and attached to the craniocerebral blast device without experiencing a blast. The rats were subjected to craniocerebral blast injury through a blast equivalent to 400 mg of trinitrotoluene using an electric detonator. Biomechanical parameters, and physical and behavioural changes of the sagittal head swing were measured using a high-speed camera. Magnetic resonance imaging (MRI) scans were conducted at 2, 12, 24 and 48 h after craniocerebral injury, only the experimental group indicated brain stem injury. The rats were sacrificed immediately following the MRI at 48 h for pathological examination of the brain stem using haematoxylin and eosin staining. The results indicated that 14 rats (87.5%) in the experimental group exhibited blast DAI, while no DAI was observed in the control and sham control groups, and the difference between the groups was significant (P<0.05). The present results indicated that this experimental design may serve to provide a stable model of blast DAI in rats. PMID- 29977359 TI - A cynomolgus monkey model of carotid atherosclerosis induced by puncturing and scratching of the carotid artery combined with a high-fat diet. AB - Cardio-cerebrovascular disease is one of the three major causes of mortality in humans and constitutes a major socioeconomic burden. Carotid atherosclerosis (CAS) is a very common lesion of the arterial walls, which leads to narrowing of the arteries, in some cases occluding them entirely, increasing the risk of cardiovascular events. The aim of the present study was to evaluate a cynomolgus monkey model of carotid atherosclerosis (CAS) induced by puncturing and scratching combined with a high-fat diet. A total of 12 cynomolgus monkeys were randomly divided into four groups: A, puncturing and scratching carotid artery intimas + high-fat diet (n=3); B, puncturing and scratching carotid artery intimas + regular diet (n=3); C, high-fat diet only (n=3); and D, regular diet only (n=3). Blood was harvested at weeks 4, 6 and 8 and plasma lipid levels were assessed. At week 8, monkeys were sacrificed and carotid arteries were harvested for hematoxylin and eosin (H&E) staining to observe pathological changes. The results revealed that a high-fat diet led to increased plasma lipid levels and accelerated plaque formation. Carotid color Doppler ultrasonography was performed and, along with H&E staining, revealed plaque formation in group A. In summary, the results of the present study suggest that a cynomolgus monkey model of CAS model may be successfully constructed by puncturing and scratching of the carotid artery intimas in combination with a high-fat diet. PMID- 29977360 TI - Early growth response factor-1 DNA enzyme 1 inhibits the formation of abdominal aortic aneurysm in rats. AB - The aim of the present study was to characterize the effects of early growth response factor-1 DNA enzyme (EDRz) in a rat abdominal aortic aneurysm (AAA) model to determine the mechanism by which EDRz inhibits AAA and affects the formation of AAA by regulating the activity of matrix metalloproteinase (MMP)-2 and MMP-9. EDRz was transfected into the abdominal aorta of rats using the jetPRIME transfection reagent following infusion with elastase. Fluorescent microscopy, hematoxylin and eosin staining, ultrastructural analysis, reverse transcription-quantitative polymerase chain reaction, western blotting and immunohistochemical analysis were performed to characterize the response to EDRz. The EDRz group showed minimal aneurysm formation when compared with the control group, with significantly lower aortic diameter expansion (2.5+/-0.1 vs. 3.5+/ 0.1 mm; P<0.05). Early growth response factor 1 (Egr-1) mRNA and protein levels were significantly decreased in the EDRz group, as expected. The decrease in Egr 1 was accompanied by decreases in the mRNA and protein levels of MMP-2 and MMP-9 (P<0.05). Transfection of the Egr-1 specific synthetic DNA enzyme EDRz significantly reduced AAA following elastase infusion in rats, at least in part due to the decreased expression of downstream MMP-2 and MMP-9. PMID- 29977361 TI - Identification of differential modules in ankylosing spondylitis using systemic module inference and the attract method. AB - The objective of the present study was to identify differential modules in ankylosing spondylitis (AS) by integrating network analysis, module inference and the attract method. To achieve this objective, four steps were conducted. The first step was disease objective network (DON) for AS, and healthy objective network (HON) inference dependent on gene expression data, protein-protein interaction networks and Spearman's correlation coefficient. In the second step, module detection was performed by utilizing a clique-merging algorithm, which comprised of exploring maximal cliques by clique algorithm and refining or merging maximal cliques with a high overlap. The third part was seed module evaluation through module pair matches by Jaccard score and module correlation density (MCD) calculation. Finally, in the fourth step, differential modules between the AS and healthy groups were identified based on a gene set enrichment analysis-analysis of variance model in the attract method. There were 5,301 nodes and 28,176 interactions both in DON and HON. A total of 20 and 21 modules were detected for the AS and healthy group, respectively. Notably, six seed modules across two groups were identified with Jaccard score >=0.5, and these were ranked in descending order of differential MCD (DeltaC). Seed module 1 had the highest DeltaC of 0.077 and Jaccard score of 1.000. By accessing the attract method, one differential module between the AS group and healthy group was identified. In conclusion, the present study successfully identified one differential module for AS that may be a potential marker for AS target therapy and provide insights for future research on this disease. PMID- 29977362 TI - Mechanism of melatonin combined with calcium carbonate on improving osteoporosis in aged rats. AB - The effects of melatonin and calcium carbonate on aged rats with osteoporosis (OP) were assessed. Forty female Sprague-Dawley (SD) rats aged 15 months were randomly divided into a model group (group OP), melatonin group (group M), calcium carbonate group (group Ca) and melatonin combined with calcium carbonate group (group M+Ca), while 10 rats aged 3 months were set as the control group (group NC). The changes of bone density and bone mineral level of lumbar vertebra and bilateral femur in rats of each group were observed. The levels of serum calcium, phosphorus, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) in rats of each group were determined. Compared with those in group NC, bone density of lumbar vertebra and bilateral femur and bone mineral level were distinctly reduced, serum calcium and activities of SOD and GSH-Px were obviously decreased, and MDA content was remarkably increased in rats of groups OP, M and Ca; the differences were statistically significant (P<0.05 or P<0.01); compared with that in group OP, bone density of lumbar vertebra and bilateral femur and bone mineral level were remarkably increased, serum calcium and activities of SOD and GSH-Px were obviously increased, and MDA content was remarkably decreased in rats of groups M, Ca and M+Ca; the differences were statistically significant (P<0.05 or P<0.01); compared with those in groups M and Ca, bone density of lumbar vertebra and bilateral femur and bone mineral level were obviously elevated, serum calcium and activities of SOD and GSH-Px were evidently elevated, and MDA content was remarkably decreased in rats of group M+Ca; the differences were statistically significant (P<0.05). Melatonin and calcium carbonate can significantly improve antioxidative ability in rats with osteoporosis, increase bone density, elevate serum calcium level and reduce bone mineral loss, thus preventing and treating osteoporosis, and the combination displays more remarkable effects. PMID- 29977363 TI - Glycerol fructose combined with vitamin B6 is beneficial to postoperative recovery of patients with cerebral aneurysm. AB - The aim of the present study is to investigate whether glycerol fructose combined with vitamin B6 is beneficial to the postoperative recovery of patients with cerebral aneurysm (CA). A total of 134 patients receiving embolization of CA in the Central Hospital of Wuhan between February, 2013 and June, 2015 and were divided into observation and control groups according to the random number table method, with 67 cases in each group. The control was given vitamin B6 routine treatment, while the observation group received glycerol fructose on the basis of treatment in the control group. The incidence rate of postoperative complications after treatment, Glasgow coma scale (GCS) score, Barthel index score, and neurological fatigue index (NFI) score were compared between the two groups. After treatment, the GCS, Barthel index and NFI scores of patients in the observation were better than those in the control group (p<0.05), and the Barthel index score in the observation group was significantly higher than that in the control group (p<0.01). The mean flow velocity of middle cerebral artery (MCA) in the observation group after treatment was significantly different from that in the control group (p<0.05). As for complications, the incidence rates of postoperative cerebral vasospasm (1.49%), cerebral ischemia (1.49%), hematoma at puncture site (2.98%) and aneurysm rupture and hemorrhage (4.47%) in the observation group were lower than those of cerebral vasospasm (8.95%), cerebral ischemia (7.46%), hematoma at puncture site (8.95%) and aneurysm rupture and hemorrhage (10.44%) in the control group, and the differences were statistically significant (p<0.05). In conclusion, glycerol fructose combined with vitamin B6 can reduce the incidence rate of postoperative complications and improve patients self-care ability and quality of life. Therefore, it is beneficial to postoperative recovery and it is worthy of clinical application. PMID- 29977364 TI - Serum STLT-1 and bilirubin levels in patients with acute coronary syndrome and correlation with prognosis. AB - The serum triggering receptor expressed on myeloid cell (TREM)-like transcription factor-1 [soluble TREM-like transcript-1 (STLT-1)] and bilirubin levels were investigated in patients with acute coronary syndrome and the correlation with prognosis. A total of 125 patients of acute coronary syndrome admitted to the Department of Cardiology in People's Hospital of Rizhao were selected, including 45 cases with ST-segment elevation myocardial infarction (STEMI), 36 cases with non-ST-elevation myocardial infarction (NSTEMI) and 44 cases with unstable angina pectoris (UAP), while 48 subjects were enrolled as the normal control. The serum STLT-1 and bilirubin levels on admission and on the 3rd, 7th and 10th day after admission of patients in each group were respectively determined, the level changes of these two indicators in serum during the initial stage of acute coronary syndrome were analyzed, and their effects on prognosis of patients were analyzed. STLT-1 levels in groups STEMI, NSTEMI and UAP were higher than those in the normal control group, and serum levels of STLT-1 in groups STEMI and NSTEMI were higher than those in group UAP. Bilirubin levels in groups STEMI, NSTEMI and UAP were lower than those in the normal control group, and serum levels of bilirubin in groups STEMI and NSTEMI were lower than those in group UAP. The proportions of complications in patients of groups STEMI and NSTEMI were significantly higher than those in group UAP (P<0.05). The results showed that the timely and effective treatment administered to patients with acute coronary syndrome during the initial stage to reduce the level of STLT-1 in serum and enhance bilirubin to a relatively high level is conducive in ameliorating the prognosis of patients, which is of clinical significance. PMID- 29977365 TI - Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3-kinase/protein kinase B signaling. AB - Glioblastoma is the most common and malignant primary brain tumor. RWD domain containing 3 (RWDD3) has been previously reported to serve a promoting role in pituitary tumors. However, the exact role of RWDD3 in glioblastoma remains unclear. Therefore, the present study aimed to investigate the expression levels of RWDD3 in human glioblastoma tissues and cell lines, as well as to examine the regulatory mechanism of RWDD3 underlying glioblastoma growth and metastasis. The results revealed that RWDD3 was significantly upregulated in glioblastoma tissues compared with normal brain tissues, while high expression of RWDD3 was associated with a shorter survival time of glioblastoma patients. The expression levels of RWDD3 were also higher in the glioblastoma cell lines compared with the normal human astrocyte cell line. Subsequent to knockdown of RWDD3, the proliferation of glioblastoma U87 and U251 cells was significantly decreased, possibly due to the cell cycle arrest at G1 phase, as well as the increased cell apoptosis. Furthermore, downregulation of RWDD3 also suppressed U87 and U251 cell invasion by inhibiting the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9. Molecular mechanism investigation demonstrated that knockdown of RWDD3 significantly downregulated the activity of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Activation of PI3K/AKT signaling prevented the suppressive effects of RWDD3 downregulation on glioblastoma cell proliferation and migration, concurrent with increased protein levels of MMP2 and MMP9. In conclusion, the current study demonstrated for the first time that inhibition of RWDD3 expression inhibited glioblastoma progression, at least partly, via suppressing the PI3K/AKT signaling activity, and thus RWDD3 may be a novel potential therapeutic target for glioblastoma. PMID- 29977366 TI - Maternal lipids, BMI and IL-17/IL-35 imbalance in concurrent gestational diabetes mellitus and preeclampsia. AB - The objective of the present study was to investigate the role of blood glucose, lipid metabolism, body mass index (BMI), C-reactive protein (CRP) as well as an interleukin (IL)-17/IL-35 imbalance in the pathogenesis of concurrent gestational diabetes mellitus (GDM) and preeclampsia (PE) (DPE). The mRNA expression of forkhead box protein 3 (FoxP3), IL-35 [including Epstein-Barr virus-induced gene 3 (EBI3) and P35 subunits] and IL-17 in the peripheral blood mononuclear cells of patients with DPE (n=30), GDM (n=33), PE (n=33) and normal pregnancy (n=33) were determined by reverse transcription-quantitative polymerase chain reaction. The serum levels of IL-35, IL-17 and CRP were analyzed using ELISA. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) and fasting blood glucose (FBG) were also detected. The levels of low-density lipoprotein (LDL) were calculated using the Friedewald formula. Body weight and height were determined in order to calculate the BMI. It was observed that the levels of FBG were markedly elevated in patients with GDM, PE and DPE. In addition, significantly higher serum TG, TC, LDL and very LDL were detected in patients with GDM, PE and DPE compared with those in subjects with normal pregnancies. By contrast, the concentration of HDL was lower in the patient groups. In addition, higher BMI values were identified in patients with GDM, PE and DPE. A decreased expression of FoxP3, P35 and EBI3 mRNA, and an elevated expression of IL-17 in PBMCs was detected in patients with GDM, PE and DPE. In addition, higher serum levels of IL-17 and CRP, as well as lower levels of IL-35, were observed. Furthermore, in patients with DPE, positive correlations of diastolic blood pressure with IL-17 levels, BMI and TG, as well as IL-17 levels with BMI and proteinuria were identified. In conclusion, the present study indicated that abnormal maternal lipids, hyperglycemia, high BMI, high CRP and IL-17/IL-35 imbalance may have a role in the pathophysiology of DPE. Therefore, pregnant women and clinicians should be made aware that maternal hyperlipidaemia, hyperglycemia, high BMI, high CRP levels and IL-17/IL-35 imbalance may lead to DPE. PMID- 29977367 TI - Protective effect of Fructus corni polysaccharide on hippocampal tissues and its relevant mechanism in epileptic rats induced by lithium chloride-pilocarpine. AB - The aim of the present study was to investigate the potential effect of Fructus corni polysaccharide (PFC) on the hippocampus tissues in epileptic rats induced by lithium chloride-pilocarpine, and to explore the underlying mechanism. The epileptic rat models were established using lithium chloride-pilocarpine treatment. According to the dosage of PFC, the rat models were divided into three groups: The low-dose (100 mg/kg/day), middle-dose (200 mg/kg/day) and high-dose (300 mg/kg/day) groups. The intervention for rat models lasted for 24 days. Subsequently, the production levels of reactive oxygen species (ROS) and malondialdehyde (MDA), the activity of superoxide dismutase (SOD), the mitochondrial membrane potential and the expressions of mitogen-activated protein kinase [P-38, Janus kinase (JNK) and extracellular signal-regulated kinase 1/2], cytochrome-C and caspase-3 in hippocampal tissues were detected. In addition, the structure of the CA-1 region of the hippocampus was also observed. Compared with the control group, the production levels of ROS were increased and the mitochondrial membrane potential was decreased in the hippocampus tissues of rats in the model group. In addition, in the model group, it was observed that MDA content was increased, SOD activity was decreased, and the expressions of phosphorylated (p)-p38, p-JNK, cytochrome-c and caspase-3 were increased, compared with the control group. Furthermore, those abnormal variations of the indicators were reversed by the intervention of PFC. These findings suggest that PFC can ameliorate the secondary damage to the hippocampi of epileptic rats, and that the anti-oxidation and -apoptosis effects of PFC may be associated with the mechanism that provides a protective effect for hippocampal tissues. PMID- 29977368 TI - 2-Iodo-N-isopropyl-5-methoxybenzamide as a highly reactive and environmentally benign catalyst for alcohol oxidation. AB - Several N-isopropyliodobenzamides were evaluated as catalysts for the oxidation of benzhydrol to benzophenone in the presence of Oxone(r) (2KHSO5.KHSO4.K2SO4) as a co-oxidant at room temperature. A study on the substituent effect of the benzene ring of N-isopropyl-2-iodobenzamide on the oxidation revealed that its reactivity increased in the following order of substitution: 5-NO2 < 5-CO2Me, 3 OMe < 5-OAc < 5-Cl < H, 4-OMe < 5-Me < 5-OMe. The oxidation of various benzylic and aliphatic alcohols using a catalytic amount of the most reactive 5-methoxy derivative successfully resulted in moderate to excellent yields of the corresponding carbonyl compounds. The high reactivity of the 5-methoxy derivative at room temperature is a result of the rapid generation of the pentavalent species from the trivalent species during the reaction. 5-Methoxy-2-iodobenzamide would be an efficient and environmentally benign catalyst for the oxidation of alcohols, especially benzylic alcohols. PMID- 29977369 TI - Correlation effects and many-body interactions in water clusters. AB - Background: The quantum-chemical description of the interactions in water clusters is an essential basis for deriving accurate and physically sound models of the interaction potential for water to be used in molecular simulations. In particular, the role of many-body interactions beyond the two-body interactions, which are often not explicitly taken into account by empirical force fields, can be accurately described by quantum chemistry methods on an adequate level, e.g., random-phase approximation electron correlation methods. The relative magnitudes of the different interaction energy contributions obtained by accurate ab initio calculations can therefore provide useful insights that can be exploited to develop enhanced force field methods. Results: In line with earlier theoretical studies of the interactions in water clusters, it has been found that the main contribution to the many-body interactions in clusters with a size of up to N = 13 molecules are higher-order polarisation interaction terms. Compared to this, many-body dispersion interactions are practically negligible for all studied sytems. The two-body dispersion interaction, however, plays a significant role in the formation of the structures of the water clusters and their stability, since it leads to a distinct compression of the cluster sizes compared to the structures optimized on an uncorrelated level. Overall, the many-body interactions amount to about 13% of the total interaction energy, irrespective of the cluster size. The electron correlation contribution to these, however, amounts to only about 30% to the total many-body interactions for the largest clusters studied and is repulsive for all structures considered in this work. Conclusion: While this shows that three- and higher-body interactions can not be neglected in the description of water complexes, the electron correlation contributions to these are much smaller in comparison to the two-body electron correlation effects. Efficient quantum chemistry approaches for describing intermolecular interactions between water molecules may therefore describe higher body interactions on an uncorrelated Hartree-Fock level without a serious loss in accuracy. PMID- 29977370 TI - Cross-coupling of dissimilar ketone enolates via enolonium species to afford non symmetrical 1,4-diketones. AB - Due to their closely matched reactivity, the coupling of two dissimilar ketone enolates to form a 1,4-diketone remains a challenge in organic synthesis. We herein report that umpolung of a ketone trimethylsilyl enol ether (1 equiv) to form a discrete enolonium species, followed by addition of as little as 1.2-1.4 equivalents of a second trimethylsilyl enol ether, provides an attractive solution to this problem. A wide array of enolates may be used to form the 1,4 diketone products in 38 to 74% yield. Due to the use of two TMS enol ethers as precursors, an optimization of the cross-coupling should include investigating the order of addition. PMID- 29977371 TI - The first Pd-catalyzed Buchwald-Hartwig aminations at C-2 or C-4 in the estrone series. AB - A facile Pd-catalyzed C(sp2)-N coupling to provide a range of 2- or 4 [(subst.)phenyl]amino-13alpha-estrone derivatives has been achieved under microwave irradiation. The reactions were mediated with the use of Pd(OAc)2 as a catalyst and KOt-Bu as a base in the presence of X-Phos as a ligand. The desired products have been obtained in good to excellent yields. The nature and the position of the aniline substituent at the aromatic ring influenced the outcome of the couplings. 2-Amino-13alpha-estrone was also synthesized in a two-step protocol including an amination of 2-bromo-13alpha-estrone 3-benzyl ether with benzophenone imine and subsequent hydrogenolysis. PMID- 29977372 TI - Polysubstituted ferrocenes as tunable redox mediators. AB - A series of four ferrocenyl ester compounds, 1-methoxycarbonyl- (1), 1,1' bis(methoxycarbonyl)- (2), 1,1',3-tris(methoxycarbonyl)- (3) and 1,1',3,3' tetrakis(methoxycarbonyl)ferrocene (4), has been studied with respect to their potential use as redox mediators. The impact of the number and position of ester groups present in 1-4 on the electrochemical potential E1/2 is correlated with the sum of Hammett constants. The 1/1+ -4/4+ redox couples are chemically stable under the conditions of electrolysis as demonstrated by IR and UV-vis spectroelectrochemical methods. The energies of the C=O stretching vibrations of the ester moieties and the energies of the UV-vis absorptions of 1-4 and 1+ -4+ correlate with the number of ester groups. Paramagnetic 1H NMR redox titration experiments give access to the chemical shifts of 1+ -4+ and underline the fast electron self-exchange of the ferrocene/ferrocenium redox couples, required for rapid redox mediation in organic electrosynthesis. PMID- 29977373 TI - Preparation, structure, and reactivity of bicyclic benziodazole: a new hypervalent iodine heterocycle. AB - A new bicyclic organohypervalent iodine heterocycle derivative of benziodazole was prepared by oxidation of 2-iodo-N,N'-diisopropylisophthalamide with m chloroperoxybenzoic acid under mild conditions. Single crystal X-ray crystallography of this compound revealed a five-membered bis-heterocyclic structure with two covalent bonds between the iodine atom and the nitrogen atoms. This novel benziodazole is a very stable compound with good solubility in common organic solvents. This compound can be used as an efficient reagent for oxidatively assisted coupling of carboxylic acids with alcohols or amines to afford the corresponding esters or amides in moderate yields. PMID- 29977374 TI - Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines. AB - Herein, we describe a catalytic fluorooxygenation of readily accessible N allylcarboxamides via an I(I)/I(III) manifold to generate 2-oxazolines containing a fluoromethyl group. Catalysis is conditional on the oxidation competence of Selectfluor(r), whilst HF serves as both a fluoride source and Bronsted acid activator. The C(sp3)-F bond of the mono-fluoromethyl unit and the C(sp3)-O bond of the ring are aligned in a synclinal relationship thereby engaging in stabilising hyperconjugative interactions with vicinal, electron-rich sigma-bonds (sigmaC-C->sigma*C-F and sigmaC-H->sigma*C-O). This manifestation of the stereoelectronic gauche effect was established by X-ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class. PMID- 29977375 TI - Hypervalent iodine-mediated Ritter-type amidation of terminal alkenes: The synthesis of isoxazoline and pyrazoline cores. AB - Hypervalent iodine-mediated olefin functionalization provides a rapid gateway towards accessing both various heterocyclic cores and functional groups. In this regard, we have developed a Ritter-type alkene functionalization utilizing a PhI(OAc)2 ((diacetoxyiodo)benzene, PIDA)/Lewis acid combination in order to access isoxazoline and pyrazoline cores. Based on allyl ketone oximes and allyl ketone tosylhydrazones, we have developed an alkene oxyamidation and amido amidation protocol en route to accessing both isoxazoline and pyrazoline cores. Additionally, acetonitrile serves as both the solvent and an amine source in the presence of this PIDA/Lewis acid combination. This operationally straightforward and metal-free protocol provides an easy access to isoxazoline and pyrazoline derivatives. PMID- 29977376 TI - Imide arylation with aryl(TMP)iodonium tosylates. AB - Herein, we describe the synthesis of N-aryl phthalimides by metal-free coupling of potassium phthalimide with unsymmetrical aryl(TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the coupling reaction is compatible with electron-deficient and sterically encumbered aryl groups. PMID- 29977377 TI - Hypervalent iodine-guided electrophilic substitution: para-selective substitution across aryl iodonium compounds with benzyl groups. AB - The reactivity of benzyl hypervalent iodine intermediates was explored in congruence with the reductive iodonio-Claisen rearrangement (RICR) to show that there may be an underlying mechanism which expands the reasoning behind the previously known C-C bond-forming reaction. By rationalizing the hypervalent iodine's metal-like properties it was concluded that a transmetallation mechanism could be occurring with metalloid groups such as silicon and boron. Hypervalent iodine reagents such as Zefirov's reagent, cyclic iodonium reagents, iodosobenzene/BF3, and PhI(OAc)2/BF3 or triflate-based activators were tested. A desirable facet of the reported reaction is that iodine(I) is incorporated into the product thus providing greater atom economy and a valuable functional group handle for further transformations. The altering of the RICR's ortho-selectivity to form para-selective products with benzyl hypervalent iodine intermediates suggests a mechanism that involves hypervalent iodine-guided electrophilic substitution (HIGES). PMID- 29977378 TI - Hypervalent iodine(III)-mediated decarboxylative acetoxylation at tertiary and benzylic carbon centers. AB - The decarboxylative acetoxylation of carboxylic acids using a combination of PhI(OAc)2 and I2 in a CH2Cl2/AcOH mixed solvent is reported. The reaction was successfully applied to two types of carboxylic acids containing an alpha quaternary and a benzylic carbon center under mild reaction conditions. The resulting acetates were readily converted into the corresponding alcohols by hydrolysis. PMID- 29977380 TI - Selective carboxylation of reactive benzylic C-H bonds by a hypervalent iodine(III)/inorganic bromide oxidation system. AB - An oxidation system comprising phenyliodine(III) diacetate (PIDA) and iodosobenzene with inorganic bromide, i.e., sodium bromide, in an organic solvent led to the direct introduction of carboxylic acids into benzylic C-H bonds under mild conditions. The unique radical species, generated by the homolytic cleavage of the labile I(III)-Br bond of the in situ-formed bromo-lambda3-iodane, initiated benzylic carboxylation with a high degree of selectivity for the secondary benzylic position. PMID- 29977382 TI - Iodine(III)-mediated halogenations of acyclic monoterpenoids. AB - Five different halofunctionalizations of acyclic monoterpenoids were performed using a combination of a hypervalent iodine(III) reagent and a halide salt. In this manner, the dibromination, the bromo(trifluoro)acetoxylation, the bromohydroxylation, the iodo(trifluoro)acetoxylation or the ene-type chlorination of the distal trisubstituted double bond occurred with excellent selectivity and moderate to good yields. PMID- 29977381 TI - Synthetic avenues towards a tetrasaccharide related to Streptococcus pneumonia of serotype 6A. AB - Streptococcus pneumonia (SPn) is a Gram-positive bacterium which causes life threatening diseases. The bacteria protect themselves against non-specific host defence by an external polysaccharide (PS) capsule which bears a repeating unit, alpha-D-Galp(1->3)-alpha-D-Glcp(1->3)-alpha-L-Rhap(1->3)-D-Rib (SPn 6A). A closer look at the structure reveals the presence of alpha-linked galactose and glucose residues. The synthesis of these 1,2-cis glycosidic linkages are considered challenging particularly in the context of a one-pot oligosaccharide synthesis. We have synthesized the aforesaid tetrasaccharide (SPn 6A) based on both stepwise and sequential one-pot glycosylation reactions using easily accessible common building blocks; eventually similar overall yields were obtained in both cases. PMID- 29977379 TI - An overview of recent advances in duplex DNA recognition by small molecules. AB - As the carrier of genetic information, the DNA double helix interacts with many natural ligands during the cell cycle, and is amenable to such intervention in diseases such as cancer biogenesis. Proteins bind DNA in a site-specific manner, not only distinguishing between the geometry of the major and minor grooves, but also by making close contacts with individual bases within the local helix architecture. Over the last four decades, much research has been reported on the development of small non-natural ligands as therapeutics to either block, or in some cases, mimic a DNA-protein interaction of interest. This review presents the latest findings in the pursuit of novel synthetic DNA binders. This article provides recent coverage of major strategies (such as groove recognition, intercalation and cross-linking) adopted in the duplex DNA recognition by small molecules, with an emphasis on major works of the past few years. PMID- 29977383 TI - Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis. AB - The system of the hypervalent iodine(III) reagent FPID and (4-MeOC6H4)3P was successfully applied to solid-phase peptide synthesis and cyclic peptide synthesis. Four peptides with biological activities were synthesized through SPPS and the bioactive cyclic heptapeptide pseudostellarin D was obtained via solution phase peptide synthesis. It is worth noting that FPID can be readily regenerated after the peptide coupling reaction. PMID- 29977384 TI - One hundred years of benzotropone chemistry. AB - This review focuses on the chemistry of benzo-annulated tropones and tropolones reported since the beginning of the 20th century, which are currently used as tools by the synthetic and biological communities. PMID- 29977385 TI - Are dispersion corrections accurate outside equilibrium? A case study on benzene. AB - Modern approaches to modelling dispersion forces are becoming increasingly accurate, and can predict accurate binding distances and energies. However, it is possible that these successes reflect a fortuitous cancellation of errors at equilibrium. Thus, in this work we investigate whether a selection of modern dispersion methods agree with benchmark calculations across several potential energy curves of the benzene dimer to determine if they are capable of describing forces and energies outside equilibrium. We find the exchange-hole dipole moment (XDM) model describes most cases with the highest overall agreement with reference data for energies and forces, with many-body dispersion (MBD) and its fractionally ionic (FI) variant performing essentially as well. Popular approaches, such as Grimme-D and van der Waals density functional approximations (vdW-DFAs) underperform on our tests. The meta-GGA M06-L is surprisingly good for a method without explicit dispersion corrections. Some problems with SCAN+rVV10 are uncovered and briefly discussed. PMID- 29977386 TI - Stereoselective nucleophilic addition reactions to cyclic N-acyliminium ions using the indirect cation pool method: Elucidation of stereoselectivity by spectroscopic conformational analysis and DFT calculations. AB - In this study, six-membered N-acyliminium ions were generated by the "indirect cation pool" method and reacted with several nucleophiles. These reactions afforded disubstituted piperidine derivatives with high diastereoselectivities and good to excellent yields. The conformations of the obtained N-acyliminium ions were studied by low temperature NMR analyses and DFT calculations and were found to be consistent with the Steven's hypothesis. PMID- 29977387 TI - Rapid transformation of sulfinate salts into sulfonates promoted by a hypervalent iodine(III) reagent. AB - An alternative method for forming sulfonates through hypervalent iodine(III) reagent-mediated oxidation of sodium sulfinates has been developed. This transformation involves trapping reactive sulfonium species using alcohols. With additional optimization of the reaction conditions, the method appears extendable to other nucleophiles such as electron-rich aromatic systems or cyclic ethers through a ring opening pathway. PMID- 29977388 TI - Rhodium-catalyzed C-H functionalization of heteroarenes using indoleBX hypervalent iodine reagents. AB - The C-H indolation of heteroarenes was realized using the benziodoxolone hypervalent iodine reagents indoleBXs. Functionalization of the C-H bond in bipyridinones and quinoline N-oxides catalyzed by a rhodium complex allowed to incorporate indole rings into aza-heteroaromatic compounds. These new transformations displayed complete regioselectivity for the C-6 position of bipyridinones and the C-8 position of quinoline N-oxides and tolerated a broad range of functionalities, such as halogens, ethers, or trifluoromethyl groups. PMID- 29977389 TI - Investigations of alkynylbenziodoxole derivatives for radical alkynylations in photoredox catalysis. AB - The alkynylbenziodoxole derivatives are recently developed alkynylation reagents in organic synthesis, which demonstrate excellent radical alkynylation reactivity in photoredox catalysis reactions. Herein we report the synthesis of alkynylbenziodoxole derivatives with difluoro, monofluoro, monomethoxy, and dimethoxy substitution on the benziodoxole moiety, and investigated their radical alkynylation reactivity for the first time. A series of mechanistic experiments were conducted to study the radical acceptor and oxidative quencher reactivity of alkynylbenziodoxoles, in which unsubstituted alkynylbenziodoxoles played balancing roles in both processes, while electron-rich benziodoxole derivatives demonstrate synthetic advantages in some cases. PMID- 29977390 TI - Synthesis of pyrazolopyrimidinones using a "one-pot" approach under microwave irradiation. AB - A simple one-pot method for the microwave-assisted synthesis of substituted pyrazolo[1,5-a]pyrimidinones, a core scaffold in many bioactive and pharmaceutically relevant compounds, has been established. A variety of substituents was tolerated at the 2 and 5 positions, including functionalized aryls, heterocycles, and alkyl groups. PMID- 29977391 TI - A selective removal of the secondary hydroxy group from ortho-dithioacetal substituted diarylmethanols. AB - We present a successful deoxygenation reaction of ortho-1,3 dithianylaryl(aryl)methanols which enables a selective removal of the secondary hydroxy group in presence of the 1,3-dithianyl moiety under reductive conditions. This reaction proceeds well with ZnI2/Na(CN)BH3 in dichloroethane or benzene for both unsubstituted and substituted aryls (by electron-rich groups). This is leading to formyl-protected diarylmethanes with potential application in the synthesis of new pharmaceuticals and optoelectronic materials. This synthetic approach gives an access to a wide variety of functionalized ortho-1,3 dithianylaryl(aryl)methanes in 26-95% yields and is recommended for the substrates containing sulfur atoms, for which transition metal-induced reactions fail. PMID- 29977392 TI - London dispersion as important factor for the stabilization of (Z)-azobenzenes in the presence of hydrogen bonding. AB - The understanding and control of the light-induced isomerization of azobenzenes as one of the most important classes of molecular switches is crucial for the design of light-responsive materials using this entity. Herein, we present the stabilization of metastable (Z)-azobenzenes by London dispersion interactions, even in the presence of comparably stronger hydrogen bonds in various solvents. The Z->E isomerization rates of several N-substituted 4,4'-bis(4 aminobenzyl)azobenzenes were measured. An intramolecular stabilization was observed and explained by the interplay of intramolecular amide and carbamate hydrogen bonds as well as London dispersion interactions. Whereas in toluene, 1,4 dioxane and tert-butyl methyl ether the hydrogen bonds dominate, the variation in stabilization of the different substituted azobenzenes in dimethyl sulfoxide can be rationalized by London dispersion interactions. These findings were supported by conformational analysis and DFT computations and reveal low-energy London dispersion forces to be a significant factor, even in the presence of hydrogen bonds. PMID- 29977393 TI - A survey of chiral hypervalent iodine reagents in asymmetric synthesis. AB - The recent years have witnessed a remarkable growth in the area of chiral hypervalent iodine chemistry. These environmentally friendly, mild and economic reagents have been used in catalytic or stoichiometric amounts as an alternative to transition metals for delivering enantioenriched molecules. Varieties of different chiral reagents and their use for demanding asymmetric transformations have been documented over the last 25 years. This review highlights the contribution of different chiral hypervalent iodine reagents in diverse asymmetric conversions. PMID- 29977394 TI - Atom-economical group-transfer reactions with hypervalent iodine compounds. AB - Hypervalent iodine compounds, in particular aryl-lambda3-iodanes, have been used extensively as electrophilic group-transfer reagents. Even though these compounds are superior substrates in terms of reactivity and stability, their utilization is accompanied by stoichiometric amounts of an aryl iodide as waste. This highly nonpolar side product can be tedious to separate from the desired target molecules and significantly reduces the overall atom efficiency of these transformations. In this short review, we want to give a brief summary of recently developed methods, in which this arising former waste is used as an additional reagent in cascade transformations to generate multiple substituted products in one step and with high atom efficiency. PMID- 29977395 TI - Novel unit B cryptophycin analogues as payloads for targeted therapy. AB - Cryptophycins are naturally occurring cytotoxins with great potential for chemotherapy. Since targeted therapy provides new perspectives for treatment of cancer, new potent analogues of cytotoxic agents containing functional groups for conjugation to homing devices are required. We describe the design, synthesis and biological evaluation of three new unit B cryptophycin analogues. The O-methyl group of the unit B D-tyrosine analogue was replaced by an O-(allyloxyethyl) moiety, an O-(hydroxyethyl) group, or an O-(((azidoethoxy)ethoxy)ethoyxethyl) substituent. While the former two maintain cytotoxicity in the subnanomolar range, the attachment of the triethylene glycol spacer with a terminal azide results in a complete loss of activity. Docking studies of the novel cryptophycin analogues to beta-tubulin provided a rationale for the observed cytotoxicities. PMID- 29977396 TI - An unusual thionyl chloride-promoted C-C bond formation to obtain 4,4' bipyrazolones. AB - Dialkyl 5,5'-dioxo-4,4'-bipyrazole-4,4'-dicarboxylates are readily obtained by the reaction of 5-hydroxypyrazole-4-carboxylates in refluxing thionyl chloride. The obtained diesters can be transformed into the corresponding 4,4'-bipyrazoles via alkaline hydrolysis and subsequent decarboxylation. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a representative 5,5'-dioxo-4,4'-bipyrazole 4,4'-dicarboxylate was confirmed by X-ray crystal structure analysis. PMID- 29977397 TI - Oligonucleotide analogues with cationic backbone linkages. AB - Their unique ability to selectively bind specific nucleic acid sequences makes oligonucleotides promising bioactive agents. However, modifications of the nucleic acid structure are an essential prerequisite for their application in vivo or even in cellulo. The oligoanionic backbone structure of oligonucleotides mainly hampers their ability to penetrate biological barriers such as cellular membranes. Hence, particular attention has been given to structural modifications of oligonucleotides which reduce their overall number of negative charges. One such approach is the site-specific replacement of the negatively charged phosphate diester linkage with alternative structural motifs which are positively charged at physiological pH, thus resulting in zwitterionic or even oligocationic backbone structures. This review provides a general overview of this concept and summarizes research on four according artificial backbone linkages: aminoalkylated phosphoramidates (and related systems), guanidinium groups, S methylthiourea motifs, and nucleosyl amino acid (NAA)-derived modifications. The synthesis and properties of the corresponding oligonucleotide analogues are described. PMID- 29977398 TI - Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria. AB - N-Acylhomoserine lactones (AHLs) are important bacterial messengers, mediating different bacterial traits by quorum sensing in a cell-density dependent manner. AHLs are also produced by many bacteria of the marine Roseobacter group, which constitutes a large group within the marine microbiome. Often, specific mixtures of AHLs differing in chain length and oxidation status are produced by bacteria, but how the biosynthetic enzymes, LuxI homologs, are selecting the correct acyl precursors is largely unknown. We have analyzed the AHL production in Dinoroseobacter shibae and three Phaeobacter inhibens strains, revealing strain specific mixtures. Although large differences were present between the species, the fatty acid profiles, the pool for the acyl precursors for AHL biosynthesis, were very similar. To test the acyl-chain selectivity, the three enzymes LuxI1 and LuxI2 from D. shibae DFL-12 as well as PgaI2 from P. inhibens DSM 17395 were heterologously expressed in E. coli and the enzymes isolated for in vitro incubation experiments. The enzymes readily accepted shortened acyl coenzyme A analogs, N-pantothenoylcysteamine thioesters of fatty acids (PCEs). Fifteen PCEs were synthesized, varying in chain length from C4 to C20, the degree of unsaturation and also including unusual acid esters, e.g., 2E,11Z-C18:2-PCE. The latter served as a precursor of the major AHL of D. shibae DFL-12 LuxI1, 2E,11Z C18:2-homoserine lactone (HSL). Incubation experiments revealed that PgaI2 accepts all substrates except C4 and C20-PCE. Competition experiments demonstrated a preference of this enzyme for C10 and C12 PCEs. In contrast, the LuxI enzymes of D. shibae are more selective. While 2E,11Z-C18:2-PCE is preferentially accepted by LuxI1, all other PCEs were not, except for the shorter, saturated C10-C14-PCEs. The AHL synthase LuxI2 accepted only C14 PCE and 3-hydroxydecanoyl-PCE. In summary, chain-length selectivity in AHLs can vary between different AHL enzymes. Both, a broad substrate acceptance and tuned specificity occur in the investigated enzymes. PMID- 29977399 TI - [3 + 2]-Cycloaddition reaction of sydnones with alkynes. AB - This review covers all known examples of [3 + 2]-cycloaddition between sydnones and both terminal as well as internal alkynes/cycloalkynes taken from literature since its discovery by Huisgen in 1962 up to the current date. Except enumeration of synthetic applications it also covers mechanistic studies, catalysis, effects of substituents and reaction conditions influencing reaction rate and regioselectivity. PMID- 29977400 TI - Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines. AB - This review collects the recent developments in the synthesis of chiral 3 substituted 3-amino-2-oxindoles based on enantioselective catalytic nucleophilic additions to isatin imines published since the beginning of 2015. PMID- 29977401 TI - A three-armed cryptand with triazine and pyridine units: synthesis, structure and complexation with polycyclic aromatic compounds. AB - The aromatic nucleophilic substitution reaction based synthesis of a three-armed cryptand displaying 2,4,6-triphenyl-1,3,5-triazine units as caps and pyridine rings in the bridges, along with NMR, MS and molecular modelling-based structural analysis of this compound are reported. Appropriate NMR and molecular modelling investigations proved the formation of 1:1 host-guest assemblies between the investigated cryptand and some polynuclear aromatic hydrocarbons or their derivatives. PMID- 29977402 TI - Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions. AB - Within this study, we report about the design and biological characterization of novel cell-penetrating peptides (CPPs) with selective suborganelle-targeting properties. The nuclear localization sequence N50, as well as the nucleoli targeting sequence NrTP, respectively, were fused to a shortened version of the cell-penetrating peptide sC18. We examined cellular uptake, subcellular fate and cytotoxicity of these novel peptides, N50-sC18* and NrTP-sC18*, and found that they are nontoxic up to a concentration of 50 or 100 uM depending on the cell lines used. Moreover, detailed cellular uptake studies revealed that both peptides enter cells via energy-independent uptake, although endocytotic processes cannot completely excluded. However, initial drug delivery studies demonstrated the high versatility of these new peptides as efficient transport vectors targeting specifically nuclei and nucleoli. In future, they could be further explored as parts of newly created peptide-drug conjugates. PMID- 29977403 TI - Recent applications of chiral calixarenes in asymmetric catalysis. AB - The use of calixarenes in asymmetric catalysis is receiving increasing attention due to their tunable three-dimensional molecular platforms along with their easy syntheses and versatile modification at the upper and lower rims. This review summarizes the recent progress of synthesis and use of chiral calixarenes in asymmetric syntheses which emerged later than 2010. PMID- 29977404 TI - Three-component coupling of aryl iodides, allenes, and aldehydes catalyzed by a Co/Cr-hybrid catalyst. AB - The cobalt/chromium-catalyzed three-component coupling of aryl iodides, allenes, and aldehydes has been developed to afford multi-substituted homoallylic alcohols in a diastereoselective manner. Control experiments for understanding the reaction mechanism reveal that the cobalt catalyst is involved in the oxidative addition and carbometalation steps in the reaction, whereas the chromium salt generates highly nucleophilic allylchromium intermediates from allylcobalt species, without the loss of stereochemical information, to allow the addition to aldehydes. PMID- 29977405 TI - Enantioselective phase-transfer catalyzed alkylation of 1-methyl-7-methoxy-2 tetralone: an effective route to dezocine. AB - In order to prepare asymmetrically (R)-(+)-1-(5-bromopentyl)-1-methyl-7-methoxy-2 tetralone (3a), a key intermediate of dezocine, 17 cinchona alkaloid-derived catalysts were prepared and screened for the enantioselective alkylation of 1 methyl-7-methoxy-2-tetralone with 1,5-dibromopentane, and the best catalyst (C7) was identified. In addition, optimizations of the alkylation were carried out so that the process became practical and effective. PMID- 29977406 TI - Spectroelectrochemical studies on the effect of cations in the alkaline glycerol oxidation reaction over carbon nanotube-supported Pd nanoparticles. AB - The effects of the alkali cations Na+ and K+ were investigated in the alkaline electrochemical oxidation of glycerol over Pd nanoparticles (NPs) deposited on functionalized carbon nanotubes (CNTs). The electrocatalytic activity was assessed by cyclic voltammetry revealing a lower overpotential of glycerol oxidation for nitrogen-functionalized Pd/NCNTs compared with oxygen functionalized Pd/OCNTs. Whereas significantly lower current densities were observed for Pd/OCNT in NaOH than in KOH in agreement with stronger non-covalent interactions on the Pd surface, Pd/NCNT achieved an approximately three-times higher current density in NaOH than in KOH. In situ electrochemistry/IR spectroscopy was applied to unravel the product distribution as a function of the applied potential in NaOH and KOH. The IR spectra exhibited strongly changing band patterns upon varying the potential between 0.77 and 1.17 V vs RHE: at low potentials oxidized C3 species such as mesoxalate and tartronate were formed predominantly, and with increasing potentials C2 and C1 species originating from C-C bond cleavage were identified. The tendency to produce carbonate was found to be less pronounced in KOH. The less favored formation of highly oxidized C3 species and of carbonate is deduced to be the origin of the lower current densities in the cyclic voltammograms (CVs) for Pd/NCNT in KOH. The enhanced current densities in NaOH are rationalized by the presence of Na+ ions bound to the basic nitrogen species in the NCNT support. Adsorbed Na+ ions can form complexes with the organic molecules, presumably enhanced by the chelate effect. In this way, the organic molecules are assumed to be bound more tightly to the NCNT support in close proximity to the Pd NPs facilitating their oxidation. PMID- 29977407 TI - Cobalt-metalloid alloys for electrochemical oxidation of 5-hydroxymethylfurfural as an alternative anode reaction in lieu of oxygen evolution during water splitting. AB - The electrochemical water splitting commonly involves the cathodic hydrogen and anodic oxygen evolution reactions (OER). The oxygen evolution reaction is more energetically demanding and kinetically sluggish and represents the bottleneck for a commercial competitiveness of electrochemical hydrogen production from water. Moreover, oxygen is essentially a waste product of low commercial value since the primary interest is to convert electrical energy into hydrogen as a storable energy carrier. We report on the anodic oxidation of 5 hydroxymethylfurfural (HMF) to afford the more valuable product 2,5 furandicarboxylic acid (FDCA) as a suitable alternative to the oxygen evolution reaction. Notably, HMF oxidation is thermodynamically more favorable than water oxidation and hence leads to an overall improved energy efficiency for H2 production. In addition, contrary to the "waste product O2", FDCA can be further utilized, e.g., for production of polyethylene 2,5-furandicarboxylate (PEF), a sustainable polymer analog to polyethylene terephthalate (PET) and thus represents a valuable product for the chemical industry with potential large scale use. Various cobalt-metalloid alloys (CoX; X = B, Si, P, Te, As) were investigated as potential catalysts for HMF oxidation. In this series, CoB required 180 mV less overpotential to reach a current density of 55 mA cm-2 relative to OER with the same electrode. Electrolysis of HMF using a CoB modified nickel foam electrode at 1.45 V vs RHE achieved close to 100% selective conversion of HMF to FDCA at 100% faradaic efficiency. PMID- 29977408 TI - Two new 2-alkylquinolones, inhibitory to the fish skin ulcer pathogen Tenacibaculum maritimum, produced by a rhizobacterium of the genus Burkholderia sp. AB - Exploration of rhizobacteria of the genus Burkholderia as an under-tapped resource of bioactive molecules resulted in the isolation of two new antimicrobial 2-alkyl-4-quinolones. (E)-2-(Hept-2-en-1-yl)quinolin-4(1H)-one (1) and (E)-2-(non-2-en-1-yl)quinolin-4(1H)-one (3) were isolated from the culture broth of strain MBAF1239 together with four known alkylquinolones (2 and 4-6), pyrrolnitrin (7), and BN-227 (8). The structures of 1 and 3 were unambiguously characterized using NMR spectroscopy and mass spectrometry. Compounds 1-8 inhibited the growth of the marine bacterium Tenacibaculum maritimum, an etiological agent of skin ulcers in marine fish, offering new opportunities to develop antibacterial drugs for fish farming. PMID- 29977409 TI - Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination. AB - The reaction of enamine compounds with the Togni reagent in the presence of CuI afforded beta-trifluoromethylated enamine intermediates, which were converted directly to biologically interesting trifluoromethylated 2H-azirines by an iodosobenzene (PhIO)-mediated intramolecular azirination in a one-pot process. PMID- 29977410 TI - Vitamin D status and epigenetic-based mortality risk score: strong independent and joint prediction of all-cause mortality in a population-based cohort study. AB - Background: Vitamin D deficiency and insufficiency have been established to be strongly associated with increased overall mortality and deaths from specific aging-related diseases. Recently, an epigenetic "mortality risk score" (MS) based on whole blood DNA methylation at the 10 most prominent mortality-related cytosine-phosphate-guanine (CpG) sites has also been found to be highly related to all-cause mortality. This study aimed to explore whether vitamin D status, defined by serum 25-hydroxyvitamin D [25(OH)D] concentrations, is associated with the MS and to what extent both indicators are individually and jointly capable of predicting all-cause mortality in a general population sample of older adults. Results: The MS was derived from the blood DNA methylation profiles measured by Illumina Human Methylation 450K Beadchip, and serum 25(OH)D concentration was measured among 1467 participants aged 50-75 of the German ESTHER cohort study. There was no association between vitamin D status and the MS at baseline, but both metrics were prominently and independently associated with all-cause mortality during a median follow-up of 15.2 years. The combination of both indicators showed the potential to be a particularly strong prognostic index for all-cause mortality. Participants with vitamin D deficiency (< 30 nmol/L) and high MS (> 5 CpG sites with aberrant methylation) had almost sixfold mortality (hazard ratio 5.79, 95% CI 3.06-10.94) compared with participants with sufficient vitamin D (>= 50 nmol/L) and a low MS (0-1 CpG site with aberrant methylation). Conclusions: This study suggests that vitamin D and the MS are strong independent predictors of all-cause mortality in older adults. PMID- 29977411 TI - A Preliminary Study of microRNA-208b after Acute Myocardial Infarction: Impact on 6-Month Survival. AB - Introduction: miRNAs contribute to a variety of essential biological processes including development, proliferation, differentiation, and apoptosis. Circulating microRNAs are very stable and have shown potential as biomarkers of cardiovascular disease. microRNA-208b expression was increased in the blood of patients with acute myocardial infarction (AMI) and has been proposed as a biomarker for early diagnosis. In this pilot study, we investigate the potential of circulating miR-208b as a prognostic biomarker of 6-month survival in AMI patients. Methods: Plasma samples from 21 patients and 8 age- and gender-matched healthy adults were collected, and circulating levels of miR-208b were detected using quantitative real-time PCR. Results: miR-208b levels were higher in healthy control subjects (9.6-fold; P <= 0.05). Within the AMI patients, the levels of miR-208b were significantly lower in the survivor versus nonsurvivor group (fold change = 6.51 and 14.1, resp.; P <= 0.05). The Kaplan-Meier curve revealed that the 6-month survival time was significantly higher among AMI patients with a relative expression of miR-208b lower than 12.38. The hazard ratio (HR) for the relative expression of miR-208b (<12.38 was the reference) was 5.08 (95% CI: 1.13 22.82; P = 0.03). Conclusion: Our results showed that elevated miR-208b expression was associated with reduced long-term survival in AMI patients. These pilot data indicate the need for a large follow-up study to confirm whether miR 208b can be used as a predictor of 6-month survival time after AMI. PMID- 29977412 TI - Inhibition of the development of N-nitrosomethylbenzylamine-induced esophageal tumors in rats by strawberries and aspirin, alone and in combination. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of two subtypes of esophageal cancer, with high incidence and mortality rates in developing countries. OBJECTIVE: The current study investigated the potential chemoprotective effects of strawberries and aspirin against the development of rat esophageal papillomas, the precursors to ESCC. METHODS: Using a prevention model, we administered study diets to rats before, during, and after N nitrosomethylbenzylamine (NMBA) treatment. The effects of the four diets were evaluated: the control diet, 5% strawberry powder in the control diet, 0.01% aspirin in the drinking water, and the combination of strawberries and aspirin. At week 25, we euthanized all the rats and collected their esophagi to quantify tumor incidence, multiplicity, and burden, as well as for molecular analysis. RESULTS: Both strawberries and aspirin significantly decreased esophageal tumor multiplicity, with the combination causing the most robust suppression. Aspirin alone and the combination decreased the total tumor burden in the esophagus. None of the diets had a significant effect on tumor incidence or the expression of COX 1 and COX-2. Strawberries and aspirin, alone and in combination, significantly suppressed squamous epithelial cell proliferation (PCNA). CONCLUSIONS: Strawberries, aspirin, and their combination exhibit chemoprotective effects against NMBA-induced esophageal tumors in rats. PMID- 29977413 TI - Zoledronic acid exacerbates inflammation through M1 macrophage polarization. AB - Background: Zoledronic acid (Zol), one of the bisphosphonates, is frequently utilized for the treatment of osteoporosis and bone metastasis. However, the onset of medication-related osteonecrosis of the jaw (MRONJ) following dental treatments has become a serious issue. We reported previously that osteonecrosis can be induced by Zol and lipopolysaccharide (LPS) in vivo, suggesting the involvement of Zol in inflammation. Macrophages are divided into M1/M2 macrophages. M1 macrophages are involved in the induction and exacerbation of inflammation and express proinflammatory mediators including interleukin (IL)-1. On the other hand, M2 macrophages are associated with anti-inflammatory reactions through the expression of anti-inflammatory cytokines, such as IL-10. In the present study, we clarified the effects of Zol on M1/M2 macrophage polarization in vitro. Methods: Human monocytic THP-1 cells were polarized to macrophage-like cells by phorbol 12-myristate 13-acetate (PMA), and, after culturing for an additional 24 h with or without Zol, then polarized to M1 macrophages by LPS or to M2 macrophages by IL-4. Cell viability was examined by the WST-8 assay. Gene expression was confirmed by the real-time polymerase chain reaction. Protein expression was detected by western blotting and enzyme-linked immunosorbent assays. Results: Zol treatment upregulated the expression of IL-1beta mRNA and protein through NLRP3 inflammasome activation in LPS-treated THP-1 cells. Zol treatment did not affect the expression of IL-10, IL-1ra, or CD206 in IL-4 treated THP-1 cells. Conclusions: Zol enhanced LPS-induced M1, but not M2, macrophage polarization through the NLRP3 inflammasome-dependent pathway, resulting in the production of inflammatory cytokines in THP-1 cells. PMID- 29977414 TI - Parasitic Appendicitis: A Novel Laparoscopic Approach for the Prevention of Peritoneal Contamination. AB - Background/Aim: Although rare, parasitic infection can cause acute appendicitis and result in contamination of the peritonea during appendectomy. The goal of this study was to summarize our experiences with parasitic appendicitis and describe a novel laparoscopic technique to prevent contamination. Method: All patients diagnosed with acute appendicitis who underwent appendectomy between January 2016 and January 2017 were included in the study. All appendectomies were performed using the standard three-port laparoscopic method, and a video recording was made of each procedure. Following separation of the mesoappendix, a single endoloop was placed in the base of the appendix, and the appendix was then transected 3-4 mm above the clamp with the aid of a thermal cauterizing/sealing device. The appendix was extracted from the 10 mm trocar hole below the umbilicus and placed inside a bag prepared from a glove. After pathological confirmation of parasitic appendicitis, medical records were retrospectively analyzed in each case for whether peritoneal contamination had occurred or not. Results: Out of 97 appendectomies, parasitic infection was observed in 4 cases, as confirmed by pathological examination. In two of these patients, E. vermicularis was detected, while the other two were infected with Balantidium coli. Intraoperative contamination did not occur in any of the cases, and retrospective review of the video recordings indicated no peritoneal contamination. Conclusion: As a result of the coagulation and sealing effects of thermal devices, airtight seals were created on the residual appendiceal stumps, and consequently, no contamination was observed in any of the cases. PMID- 29977415 TI - A Review on Emerging and Reemerging of Infectious Diseases in Jordan: The Aftermath of the Syrian Crises. AB - The review aims to examine the emergence and reemergence of infectious diseases in Jordan, in parallel with the Syrian refugee crisis. Qualitative approach has been adopted for systematically examining the outcomes of the Syrian crisis, which resulted in emerging and reemerging infectious diseases. It has adhered that infectious diseases, including measles, tuberculosis, and cutaneous leishmaniasis, have hazardous effects on Syrian refugees along with the local population in Jordan. The threat of major infectious diseases is higher and alarming in Jordan. National health policies should be implemented to adhere the influence of infectious diseases as well as to reduce the extent of infectious diseases in Jordan. In the 21st century, Syrian conflict can be deliberated as one of the biggest humanitarian disasters. In this multifaceted emergency with devastating requirements and limitations, it has been found essential for dominant medical healthcare providers to develop medical strategies that are based on comprehensive understanding of the concerned context and the main medical requirements and susceptible groups. PMID- 29977416 TI - Development of Microsatellite Markers for the Nipa Palm Hispid Beetle, Octodonta nipae (Maulik). AB - The nipa palm hispid beetle, Octodonta nipae (Maulik) (Coleoptera: Chrysomelidae), is an important invasive pest on palm plants in southern China. Based on existing transcriptome data, polymorphism simple sequence repeat (SSR) loci were identified. In total, 1274 SSR loci were identified from 49919 unigenes. The majority of them contained mononucleotide, dinucleotide, and trinucleotide motifs (43.56%, 26.14%, and 28.18%), in which A/T (41.21%) and AT/TA (15.86%) were the most abundant motifs. 104 pairs of the SSR primers produced amplification bands of expected sizes in O. nipae, 80 pairs of SSR primers were tested randomly for polymorphism, 9 loci of them were validated to be polymorphic markers, and the number of alleles ranged from 2 to 3, with an average of 2.56 per locus. The population of Zhangzhou and Fuzhou was analyzed by the 9 loci (On1-On9). These SSR transcriptome data can provide invaluable resource for SSR development, population genetics research, invasion and expansion mechanism, paternity testing, and other research on O. nipae and its related species. PMID- 29977417 TI - Ear Involvement in Inflammatory Bowel Disease: A Review of the Literature. AB - Inflammatory bowel disease (IBD) is a multisystemic disease. The ear is a rare but recognized site of extraintestinal manifestations of IBD. In external ear, the more common manifestations of IBD are pyoderma gangrenosum, metastatic Crohn's disease and relapsing polychondritis and the treatment includes corticosteroids and anti-TNF agents. Sensorineural hearing loss (SNHL) is the most common ear disease in IBD and especially in patients with ulcerative colitis. In most cases of IBD patients with SNHL, the hearing loss is attributable to autoimmune inner ear disease (AIED). Diagnosis of AIED is based on clinical presentation, the demonstration of a progressive sensorineural hearing loss in periodic audiological tests, a response to immunosuppressive drugs and exclusion of other causes of SNHL. The only diagnostic test that is available for clinical use is the Otoblot test (Western blot for antibodies against 68 kD protein-inner ear antigens). Initial therapy is usually steroids, with a step up to anti-TNF-a therapy and cochlear implantations with failure of treatment. Furthermore, Cogan's syndrome, a chronic disease characterized by deafness, vertigo keratitis and aortitis, has been associated with IBD and mainly with Crohn's disease. PMID- 29977419 TI - Is There a Role for Diagonal Coronary Artery Stenting in Patients Undergoing Robotic Coronary Artery Bypass Graft Surgery? AB - Background: The efficacy of diagonal coronary artery stenting in patients undergoing robotic left internal thoracic artery-to-left anterior descending (LITA-to-LAD) anastomosis is not well defined. The objective of this study was to assess graft and stent patency in a single-stage hybrid revascularization with LITA-to-LAD anastomosis and PCI to a diagonal coronary artery. Methods: From 2004 to 2014, a total of 25 patients consented to robotic-assisted LITA harvesting and a small left anterior thoracotomy for off-pump coronary artery bypass anastomosis onto the LAD along with concomitant PCI to the diagonal coronary artery. PCI to the diagonal coronary artery was performed in the same fluoroscopy-equipped hybrid operating room. Results: Patients were on average 66 +/- 11 years with 32% female. Pre-operative characteristics of these patients included 8% with a grade 3 or 4 left ventricle, 16% with a recent MI, and 92% with CCS III/IV symptoms. There were no death, one patient required an intra-aortic balloon pump, and one patient required re-operation for bleeding. The average ICU stay was 1.1 +/- 0.53 days, and the average hospital stay was 4.6 +/- 2.4 days. Fitzgibbon Grade A LITA to-LAD patency at 6-month follow-up was 100%. As well, at 6-month follow-up the DES to the diagonal coronary artery had a patency rate of 96%. Conclusions: Single-stage hybrid revascularization strategy for bifurcating lesions of the LAD and diagonal coronary arteries with LITA-to-LAD anastomosis and PCI to a diagonal coronary artery appears to have acceptable clinical results with excellent 6 month angiographic patency results. PMID- 29977420 TI - Association Between Visceral Fat Accumulation and Exercise Tolerance in Non-Obese Subjects Without Diabetes. AB - Background: We examined the associations between visceral fat accumulation, presence of the components of metabolic syndrome (MetS), and exercise tolerance in non-obese subjects without diabetes. Methods: Seventy-four non-obese, non diabetic Japanese men were enrolled. The subjects were divided into the following two groups: non-obese subjects without any MetS risk factors (n = 38, Group A) and non-obese subjects with one or two MetS risk factors (n = 36, Group B). Anthropometric and metabolic parameters were measured. The response of heart rate (HR) and blood pressure (BP), and exercise tolerance were also evaluated with a cardiopulmonary exercise test using a bicycle ergometer. Results: The body mass index, abdominal circumference, visceral fat area, and homeostasis model assessment-insulin resistance, were significantly higher, while levels of anaerobic threshold and maximal oxygen uptake were significantly lower in Group B than in Group A. The levels of resting HR, resting BP, and BP at maximal exercise were significantly higher in Group B than in Group A. There were no significant differences in the HR at maximal exercise as well as the HR and BP after exercise between the two groups. The visceral fat area was significantly and negatively correlated with exercise tolerance. Multivariate linear regression analyses demonstrated that visceral fat area, but not abdominal circumference, was significantly and independently associated with maximal oxygen uptake. Conclusions: These data suggest that the visceral fat area is a significant determinant for exercise tolerance even in non-obese subjects without diabetes. PMID- 29977421 TI - The Characteristics and Trends in Adrenocortical Carcinoma: A United States Population Based Study. AB - Background: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Data on the incidence of ACC, however, are scarce and not recent. The purpose of this study was to characterize the tumor and the patients developing ACC over the last four decades using a large population based database. Methods: We identified all cases of ACC diagnosed between 1973 - 2014 from the Surveillance, Epidemiology, and End Results-18 registry. Descriptive analyses were used for all extracted demographic, clinical, pathological, therapeutic and survival data, and were compared between the four time periods of 1973 to 1984, 1985 to 1994, 1995 to 2004 and 2005 to 2014 using Chi-square tests for categorical variables and one-way analysis of variance for continuous variables. Results: There were a total of 2,014 cases of ACC between 1973 and 2014 with an age-adjusted incidence of 1.02 per million populations. The median age at diagnosis was 55 years with the majority of them being females and whites. The proportion of cases by different genders, races and age at diagnosis had not changed significantly over time. These malignancies were mostly the only primary malignancy, unilateral and of high grades at diagnosis. Surgical resection of the tumor remained the mainstay of treatment. However, there was a significant increase in the use of adjuvant radiotherapy, adjuvant chemotherapy and chemotherapy alone in recent times. The median survival time was 17 months, but continues to decrease in recent time periods. Conclusions: ACC continues to be a rare malignancy in the United States. However, most cases continue to be diagnosed only in advanced stages and are associated with poor survival. These findings underline the need for specific diagnostics tools with new and more effective treatment options. PMID- 29977418 TI - SGLT-2 Inhibitors and Cardiovascular Protection: Lessons and Gaps in Understanding the Current Outcome Trials and Possible Benefits of Combining SGLT 2 Inhibitors With GLP-1 Agonists. AB - Landmark trials on diabetes control have shown variable results in terms of cardiovascular benefits, with the majority showing a favorable effect of glycemic control on microvascular and, more recently, macrovascular complications. However, some trials pointed out a CV hazard with tight diabetes mellitus (DM) control. Most of those trials were assessing the impact of glycemic control, more than evaluating the effect of a certain medication. In the last decade, food and drugs administration (FDA) has mandated that all new hypoglycemic agents run a CV outcome trial (CVOT) for safety in order to grant and sustain approval. The most stunning results came from relatively new agents in the field of diabetes management, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the glucagon like peptide-1 agonists (GLP-1 agonists), details of these CVOTs will be addressed later in this document. SGLT2i effect on the cardiovascular system remains an area of extensive research. We aimed in this review to summarize what is the current evidence of cardiovascular protection upon using SGLT2i. Moreover, we wanted to raise a point that may be strongly adopted in the future, combining SGLT2i plus GLP-1 agonists, having a cardiovascular privilege in both molecules. PMID- 29977422 TI - Efficacy and Patient Satisfaction of Dipeptidyl Peptidase-4 Inhibitor After Switching From Once-Daily DPP-4 Inhibitor to Once-Weekly Regimen. AB - Background: We administered once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor (W) (used omarigliptin as W in this study) to patients with type 2 diabetes taking once-daily DPP-4 inhibitor (D), and investigated efficacy, safety and patient satisfaction before and after switching to W. Methods: W was administered to 182 patients with type 2 diabetes taking D (used sitagliptin as D in this study), who had been visiting our hospital on an outpatient basis; 164 (90.6%) of these patients requested to switch medications. Of these 164 patients, this study investigated 153 who requested to continue taking W. Hemoglobin A1c (HbA1c) levels, body weight, blood pressure and a questionnaire survey (Diabetes Treatment Satisfaction Questionnaire (DTSQ)) were evaluated in these patients. Results: Patient characteristics were as follows: age, 63.9 +/- 10.3; male/female ratio, 93:60; duration of diabetes, 14.9 +/- 7.7 years; and body mass index (BMI), 25.5 +/- 4.2 kg/m2. After switching to W, HbA1c levels changed from 7.41 +/- 0.7% to 7.36 +/- 0.9%, which was not statistically significant. Changes in body weight, BMI, and systolic and diastolic blood pressure were also not significant. On the DTSQ, satisfaction of Q1 significantly increased (P < 0.01). The score for lifestyle assessment did not significantly change, but compliance significantly improved (P < 0.001). Conclusion: This study revealed that 90% of patients taking D elected to switch to W. Moreover, patient satisfaction and compliance improved after switching to W. Increased satisfaction appeared to be influenced by improved blood glucose control, but was not associated with compliance. Switching from D to W did not affect HbA1c levels but improved patient adherence. PMID- 29977423 TI - Effect of Anagliptin on Glycemic and Lipid Profile in Patients With Type 2 Diabetes Mellitus. AB - Background: Anagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor expected to improve the lipid profile as well as glycemic control. However, findings from large-scale prospective trials have not been obtained. Methods: We performed a multicenter prospective trial in patients with type 2 diabetes receiving anagliptin to evaluate its effect on glycemic control and the lipid profile. A total of 95 patients received anagliptin at 200 mg twice daily. Markers of glucose and lipid metabolism were measured at baseline and after 12 and 24 weeks of administration, and the absolute changes and percent changes were determined. Results: Both HbA1c and plasma glucose were significantly decreased by anagliptin therapy. Regarding the lipid profile, total cholesterol (TC) showed a significant decrease at 12 weeks, while TC, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were significantly decreased at 24 weeks. Multivariate analysis revealed that female sex was an independent predictor of greater reduction of TC, LDL-C, and HDL-C, while a baseline TC level >= 200 mg/dL predicted greater reduction of TC and a baseline HDL-C level >= 40 mg/dL predicted greater reduction of LDL-C and HDL-C. Conclusions: This study suggested that anagliptin significantly reduced TC, LDL-C, and HDL-C levels, as well as improving glycemic control, particularly in female patients. PMID- 29977424 TI - Pretreatment Lymphocyte to Monocyte Ratio as a Prognostic Marker for Advanced Pulmonary Squamous Cell Carcinoma Treated With Chemotherapy. AB - Background: Lower lymphocyte to monocyte ratio (LMR), higher neutrophil to lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS) 2 have been demonstrated as independent prognostic markers for poor prognosis of advanced non small cell lung cancer (NSCLC). However, little is known about these three markers as prognostic markers for a specific histological subset of NSCLC, squamous cell carcinoma (SCC). This study aimed to evaluate the prognostic significance of LMR, NLR and mGPS for advanced SCC. Methods: We retrospectively collected 107 patients who met the following criteria: pathologically confirmed SCC, chemo-naive patients who had initiated first-line cytotoxic chemotherapy between September 2007 and February 2017 at our institution, and c-stage IIIB, IV or recurrence after curative-intent surgery or thoracic radiotherapy. In order to demonstrate these three markers as significant prognostic factors, we compared overall survival (OS) between two groups divided by LMR, NLR and mGPS 0 - 1 versus 2, and performed univariate and multivariate Cox proportional hazard analyses. Results: Groups with low LMR (< 2.07) and high NLR (>= 5.28) experienced shorter OS (LMR: 6.5 versus 15.6 months in median, P < 0.01; NLR: 8.2 versus 15.6 months, P < 0.01) than groups with high LMR (>= 2.07) and low NLR (< 5.28). However, no significant difference was detected in OS between mGPS 0 - 1 and 2 (13.0 versus 13.7 months, P = 0.61). As significant poor prognostic factors, our multivariate Cox hazard analysis detected ECOG PS 2 - 4 (hazard ration (HR): 3.09, 95% confidence interval (CI): 1.77 - 5.40; P < 0.01) and LMR < 2.07 (HR: 0.39, 95% CI: 0.21 - 0.79; P < 0.01). However, NLR was not selected in the multivariate analysis. Conclusion: LMR is an independent prognostic factor for advanced pulmonary SCC. Neither NLR nor mGPS is useful as prognostic factor for this histology. The optimal prognostic markers may differ from each subset of NSCLC. PMID- 29977425 TI - Unusual Features of Clear Cell Adenocarcinoma of the Female Urethra: A Case Report and Literature Review. AB - Background: There has been scarce information about clear cell adenocarcinoma of the urethra (CCAU), an extremely rare type of cancer. A few case reports show that CCAU tends to have similar clinical manifestation to the other urethral carcinomas, urethrocystoscopy can easily identify tumoral lesions in the urethra, and bloody drainage from the urethral meatus is often seen during physical exams. Methods: A 52-year-old woman presented with dysuria for 6 months. Urethrocystoscopy did not reveal abnormality, and there was no bloody vaginal drainage or bloody drainage from the urethral meatus during physical exams. Ultrasonography demonstrated a solid mass with well-defined margins located between the anterior vaginal wall and the posterior urethral wall. Computed tomography showed the mass with smooth margins at the level of vaginal fornix, and magnetic resonance imaging showed the same location of the tumor as ultrasonography. Results: Surgical removal of the tumor was successfully performed and histological and immunohistochemical analysis confirmed the final diagnosis of CCAU. Conclusion: Abnormality in urethrocystoscopy and bloody drainage during the physical exam were not found in this case, which is in contrast to the findings reported in literature. These unusual features add new knowledge about CCAU that deserves dissemination for improved CCAU diagnosis and management. PMID- 29977426 TI - Bofutsushosan Significantly Ameliorated Betamethasone-Induced Cushing's Syndrome. PMID- 29977427 TI - Summer Issue, 2018. PMID- 29977428 TI - Effect of Methylphenidate for Apathy on Visual Attention Scanning Behavior: a Pilot Study. AB - Background: The purpose of this pilot study was to explore the potential of eye tracking technology in monitoring symptoms and predicting outcomes in apathetic Alzheimer's disease (AD) patients treated with methylphenidate (MTP). Methods: Neuropsychological tests and eye-tracking measurements were completed at baseline and following at least four weeks of treatment with MTP (5-10 mg BID). Eye movements were measured while patients viewed novel and social stimuli. Cognition, behavior, and apathy were assessed using the Standardized Mini-Mental State Exam (sMMSE), Neuropsychiatric Inventory, and Apathy Evaluation Scale (AES), respectively. Results: Nine patients were included in the analysis (age: median=75, interquartile range=8; sMMSE: median=22, interquartile range=14). Spearman correlations showed that improvement on the AES was associated with increased visual attention towards novel stimuli (rho7=-0.809, p=.008). Additionally, lower baseline attention towards social images was associated with improvement on the AES (rho7=0.905, p=.001). Conclusions: Eye-tracking techniques can be developed as an objective and nonverbal method of monitoring symptoms and treatment outcomes in AD patients. PMID- 29977429 TI - Towards Consensus on Essential Components of Physical Examination in Primary Care based Memory Clinics. AB - Background: Primary care-based memory clinics were established to meet the needs of persons with memory concerns. We aimed to identify: 1) physical examination maneuvers required to assess persons with possible dementia in specialist supported primary care-based memory clinics, and 2) the best-suited clinicians to perform these maneuvers in this setting. Methods: We distributed in-person and online surveys of clinicians in a network of 67 primary care-based memory clinics in Ontario, Canada. Results: 90 surveys were completed for an overall response rate of 66.7%. Assessments of vital signs, gait, and for features of Parkinsonism were identified as essential by most respondents. There was little consensus on which clinician should be responsible for specific physical examination maneuvers. Conclusions: While we identified specific physical examination maneuvers deemed by providers to be both necessary and feasible to perform in the context of primary care-based memory clinics, further research is needed to clarify interprofessional roles related to the examination. PMID- 29977430 TI - The Lost Years: Delay Between the Onset of Cognitive Symptoms and Clinical Assessment at a Memory Clinic. AB - Background: Early assessment of cognitive symptoms is an issue in geriatrics. This study investigated the delay from the onset of cognitive symptoms to initial clinical assessment and its associations with patients' sociodemographic and clinical characteristics. Methods: This is a cross-sectional retrospective study using medical chart review of 316 patients referred for assessment to a university-affiliated memory clinic. Symptom duration was self-reported by patients/carers. Severity of symptoms assessed by the MoCA and FAST instruments was compared according to delay duration (>=3 years vs. <3 years) using chi squared tests. Logistic regression was used to determine the association between patients' characteristics and long symptom duration (>=3 years). Results: At the initial assessment, 29.4% of patients reported experiencing cognitive symptoms for >=3 years. They were more likely to have MoCA scores <=17 (47.8 vs. 34.1%; p=.023) and FAST scores >=5 (21.5 vs. 10.8%; p=.012). They were also significantly older than 75 years (75-84 yr: OR=2.22 [95%CI: 1.11-4.41]; >=85 yr: 4.36 [2.08-9.11]), presented more depressive symptoms (2.37 [1.40-4.02]), and were less likely to live alone (0.55 [0.31-0.96]). Conclusions: A significant proportion of patients had cognitive symptoms for years when initially assessed, which delayed diagnosis and management. Stigma, depression, and compensatory help from carers may contribute to this delay. PMID- 29977432 TI - #CGS2015: An Evaluation of Twitter Use at the Canadian Geriatrics Society Annual Scientific Meeting. AB - Background: Twitter is a microblogging platform increasingly used in medicine to overcome geographic barriers and promote international connections. Tweets, the 280-character microblogs, are catalogued by hashtags (#). This study evaluates and describes the participation, content, and impact of Twitter at the 2015 Canadian Geriatrics Society (CGS) Annual Scientific Meeting, during which #CGS2015 was the official conference hashtag. Methods: Twitter transcripts of #CGS2015 were obtained from Symplur to prospectively analyze tweets for content and quantitative metrics. TweetReach was used to retrospectively analyze tweets with the hashtag #CGS2014 from the 2014 meeting for growth analysis. The impact of Twitter on the conference experience was derived from questionnaires. Results: There were 1,491 #CGS2015 tweets, 40% of which were original. Tweet content was categorized into conference sessions (38.8%), networking (29.2%), resource sharing (17.6%), and conference promotion (14.3%). Of the 279 participants, 60% were non-Canadian. The questionnaire data from 86 respondents demonstrated generally positive experiences with Twitter, particularly with facilitating collegial interactions, resource sharing, and insight into sessions not attended live. The most cited drawback was divided attention when using personal devices. Analysis comparing #CGS2014 to #CGS2015 demonstrated increases in total participants (50 to 279), number of tweets (434 to 1,491) and impressions (155,600 to 943,825). Conclusions: Twitter engagement at the CGS 2015 annual meeting enabled international participation in networking, resource sharing, and online discussions of sessions. Future conferences may benefit from a workshop on Twitter basics for attendees and presenters. PMID- 29977431 TI - Guidelines for Gait Assessments in the Canadian Consortium on Neurodegeneration in Aging (CCNA). AB - Background: Motor and cognitive impairments are common among older adults and often co-exist, increasing their risk of dementia, falls, and fractures. Gait performance is an accepted indicator of global health and it has been proposed as a valid motor marker to detect older adults at risk of developing mobility and cognitive declines including future falls and incident dementia. Our goal was to provide a gait assessment protocol to be used for clinical and research purposes. Methods: Based on a consensus that identified common evaluations to assess motor cognitive interactions in community-dwelling older individuals, a protocol on how to evaluate gait in older adults for the Canadian Consortium on Neurodegeneration in Aging (CCNA) was developed. Results: The CCNA gait assessment includes preferred and fast pace gait, and dual-task gait that comprises walking while performing three cognitively demanding tasks: counting backwards by ones, counting backwards by sevens, and naming animals. This gait protocol can be implemented using an electronic-walkway, as well as by using a regular stopwatch. The latter approach provides a simple manner to evaluate quantitative gait performance in clinics. Conclusions: Establishing a standardized gait assessment protocol will help to assess motor-cognitive interactions in aging and neurodegeneration, to compare results across studies, and to feasibly implement and translate gait testing in clinics for detecting impending cognitive and mobility decline. PMID- 29977433 TI - National Dementia Strategies: What Should Canada Learn? AB - Background: In order to provide appropriate care for the aging population, many countries are adopting a National Dementia Strategy (NDS). On June 22, 2017, Canada announced it will become the 30th country to launch a NDS. In light of this announcement and as Canada prepares to develop its own NDS, we conducted this review to examine and compare the NDSs of the other previous 29 countries with Canadian government's policies to date. Methods: NDSs were compared according to their major priorities. The primary endpoints were the framework conditions and key actions outlined in the strategies. Secondary endpoints included the years active, involvement of stakeholders, funding, and implementation. Results: We were able to review and compare 25 of the 29 published NDSs. While the NDSs of each country varied, several major priorities were common among the strategies-increasing awareness of dementia, reducing its stigma, identifying support services, improving the quality of care, as well as improving training and education and promoting research. Conclusions: This review comprehensively lists and compares the NDSs of different countries. The results should be of great interest to policy-makers, health-care professionals and other key stakeholders involved in developing Canada's forthcoming NDS. We hope that policy-makers in Canada can review other NDSs, learn from their example, and develop an effective NDS for our country. PMID- 29977434 TI - Metastatic biphasic pleural mesothelioma presenting with cauda equina syndrome. AB - Patient with previous asbestos exposure on a watchful wait and watch regime presents acutely with cauda equina syndrome. Radiological imaging confirmed a mass with direct invasion of the spinal cord. Histology confirmed metastatic pleural mesothelioma. PMID- 29977435 TI - Ipilimumab cystic hypophysitis mimicking metastatic melanoma. AB - Ipilimumab is an immunotherapeutic agent used in the treatment of metastatic melanoma, and is known to cause hypophysitis in some patients. Magnetic resonance imaging of ipilimumab-induced hypophysitis typically shows diffuse enlargement of the pituitary gland with variable enhancement or enlargement of the infundibulum. This often produces a diagnostic dilemma as melanoma not uncommonly metastasizes to the pituitary gland due to the rich vascular plexus of the hypophyseal portal system, and has a similar imaging appearance to autoimmune hypophysitis. We present a case of a 49-year-old man with a Clark level 4 melanoma of the left calf with inguinal nodal metastases that was treated with resection and 2 cycles of ipilimumab, and subsequently developed a "cystic" pituitary mass. To our knowledge, all of the described cases of ipilimumab-induced hypophysitis to date have shown solid enhancement on imaging. Because metastatic melanoma to the pituitary gland often has internal hemorrhage that produces a "cystic" appearance, and ipilimumab-induced hypophysitis is typically a solidly enhancing abnormality, this presented a significant diagnostic and therapeutic dilemma. Our patient's symptoms, although significant, did not necessitate immediate surgical intervention, and a conservative approach of withholding the ipilimumab and administering therapeutic corticosteroids was pursued. The patient's symptoms abated and follow-up magnetic resonance imaging 1 month later showed near complete resolution of the pituitary abnormalities. As such, this is a unique case of ipilimumab-induced hypophysitis presenting as a "cystic" pituitary mass. PMID- 29977436 TI - Fugitive Chemicals and Environmental Justice: A Model for Environmental Monitoring Following Climate-Related Disasters. AB - The combination of population growth in areas of mixed (residential, commercial, and industrial) land use along U.S. waterfronts and the increasing frequency of devastating hurricanes and storm surges has led to community fears of widespread toxic chemical contamination resulting from accidental industrial or small business releases, particularly in the aftermath of an extreme weather event, such as a hurricane. Industrial waterfront communities, which are frequently environmental justice communities, contain numerous toxic chemical sources located in close proximity to residential housing, schools, daycare centers, playgrounds, and healthcare centers. Despite the longstanding concerns of community activists and researchers about the potential for "fugitive" chemicals to be released into floodwaters, there has been little coordinated research or action to develop environmental monitoring programs for disaster-affected communities. In the aftermath of Superstorm Sandy, a community-academic partnership was formed between the New York City Environmental Justice Alliance, UPROSE, The LifeLine Group, and the RAND Corporation. The collaboration, known as Grassroots Research to Action in Sunset Park (GRASP) has focused on identifying possible sources of chemical contamination, modeling the potential for chemical release into community areas and resulting exposure risks, and proactively developing actions for mitigating or preventing adverse community impacts. Through our ongoing work, we have identified barriers and drivers for community based environmental monitoring, and in doing so, we have developed a framework to overcome challenges. In this article, we describe this framework, which can be used by waterfront communities bracing to deal with the effects of future devastating weather disasters. PMID- 29977437 TI - Prenatal omega-3 LCPUFA and symptoms of allergic disease and sensitization throughout early childhood - a longitudinal analysis of long-term follow-up of a randomized controlled trial. AB - Background: Randomized controlled trials of prenatal omega (omega-3) long chain polyunsaturated fatty acid (LCPUFA) supplementation are suggestive of some protective effects on allergic sensitization and symptoms of allergic disease in childhood. Due to the nature of the atopic march, investigation of any effects of this prenatal intervention may be most informative when consistently assessed longitudinally during childhood. Methods: Follow-up of children (n = 706) with familial risk of allergy from the Docosahexaenoic Acid to Optimize Mother Infant Outcome (DOMInO) trial. The intervention group received fish oil capsules (900 mg of omega-3 LCPUFA) daily from <21 weeks' gestation until birth; the control group received vegetable oil capsules without omega-3 LCPUFA. This new longitudinal analysis reports previously unpublished data collected at 1 and 3 years of age. The allergic disease symptom data at 1, 3 and 6 years of age were consistently reported by parents using the "International Study of Asthma and Allergies in Childhood" (ISAAC) questionnaire. Sensitization was determined by skin prick test to age specific, common allergen extracts. Results: Changes over time in symptoms of allergic disease with sensitization (IgE-mediated) and sensitization did not differ between the groups; interaction p = 0.49, p = 0.10, respectively. Averaged across the 1, 3 and 6-year assessments, there were no significant effects of prenatal omega-3 LCPUFA supplementation on IgE-mediated allergic disease symptoms (adjusted relative risk 0.88 (95% CI 0.69, 1.12), p = 0.29) or sensitization (adjusted relative risk 0.97 (95% CI 0.82, 1.15), p = 0.76). Sensitization patterns to common allergens were consistent with the atopic march, with egg sensitization at 1 year strongly associated with house dust mite sensitization at 6 years, (p < 0.0001). Discussion: Although there is some evidence to suggest that maternal supplementation with 900mg omega-3 LCPUFA has a protective effect on early symptoms of allergic disease and sensitization in the offspring, we did not observe any differences in the progression of disease over time in this longitudinal analysis. Further investigation into the dose and timing of omega-3 LCPUFA supplementation, including long-term follow up of children using consistent outcome reporting, is essential to determine whether this intervention may be of benefit as a primary prevention strategy for allergic disease. Conclusion: Maternal supplementation with 900 mg of omega-3 LCPUFA did not change the progression of IgE-mediated allergic disease symptoms or sensitization throughout childhood from 1 to 6 years. Trial registration: Australian New Zealand Clinical Trials Registry (ACTRN); DOMInO trial ACTRN12605000569606, early childhood allergy follow up ACTRN12610000735055 and 6-year allergy follow up ACTRN12615000498594. PMID- 29977438 TI - Debates in Allergy Medicine: Does oral immunotherapy shorten the duration of milk and egg allergy? The pro argument. AB - The development of oral tolerance or food allergy is an active process, related to dynamic interactions between host immune cells, microbiome, dietary factors, and food allergens. Oral tolerance is the default immune response in the gut. A food allergy occurs when this process fails and a pathologic Th2 response is activated. Oral food immunotherapy (OIT) aims to restore immune tolerance in food allergic individuals. The stimulation of Tregs production seems to represent a crucial step in inducing long-term tolerance, but other mechanisms (e.g., the suppression of mast cell and basophil reactivity, changes in allergen-specific cells with regulatory markers) are involved. Several studies reported the efficacy of OIT in terms of "sustained unresponsiveness" (SU), an operational definition of immune tolerance. In successfully treated subjects, the ability to pass an oral food challenge 2 to 8 weeks after stopping the food allergen exposure seems to be conditioned by the treatment starting age, frequency, amount or type of food consumed, and by the duration of the maintenance phase. Based on the available data, the percentage of milk- and egg-allergic subjects achieving sustained unresponsiveness after an OIT ranges from 21% to 58,3%. A comprehensive understanding of mechanisms underlying the induction of oral tolerance with OIT, or natural tolerance to food allergens in healthy individuals, could potentially lead to advances in development of better treatment options for food allergic patients. PMID- 29977439 TI - Debates in Allergy Medicine: Oral immunotherapy shortens the duration of milk and egg allergy - the con argument. AB - Oral immunotherapy (OIT) has been shown to be effective for inducing desensitization in children with cow's milk and egg allergy. In contrast, there is limited evidence that OIT can induce tolerance or sustained unresponsiveness in food allergic patients. Sustained unresponsiveness, determined by a food challenge following a period of secondary avoidance, has been suggested to reflect a more enduring state of tolerance and is pertinent when considering the ability of OIT to shorten the duration of food allergy. While it has been shown that children who tolerate baked forms of egg and milk are more likely to develop tolerance compared to those who are allergic to baked forms of these foods, there is no convincing evidence that OIT using modified allergen in baked foods can hasten resolution of cow's milk and egg allergy. Instead, it is likely that baked milk and baked egg tolerant children represent a sub-phenotype of milk and egg allergy that is more likely to resolve spontaneously over time. PMID- 29977440 TI - CareHeroes Web and AndroidTM Apps for Dementia Caregivers: A Feasibility Study. AB - The purpose of the current feasibility study was to examine the use, utility, and areas for refinement of a newly developed web-based and AndroidTM application (app) (i.e., CareHeroes) with multiple features to support individuals caring for loved ones with Alzheimer's disease or other forms of dementia (AD). The study was performed over an 11-week period with triads of AD caregivers, assigned home care case managers, and primary care providers (PCP). The study involved quantitative and qualitative methodologies. Eleven AD caregivers (seven daughters, two sons, and two spouses), six case managers, and five PCPs participated. Data demonstrate participants were mostly satisfied with the multiple features and ability to access and use CareHeroes. Barriers for use include concerns about time constraints and not being familiar with technology. Although the study findings are promising, a longer term study to evaluate the impact of the CareHeroes app is indicated. PMID- 29977442 TI - Incidence, Etiology, and Outcomes of Altered Mental Status in the Perioperative Setting of Liver Transplantation. AB - Background: We examined neurologic consultations for altered mental status in perioperative liver transplant patients to determine the overall incidence, to assess the presumed etiology and the data reviewed to determine that etiology, and to assess outcomes. Methods: Retrospective chart review conducted for all 728 adult patients receiving orthotopic liver transplantation (OLT) between January 01, 2010, to June 30, 2014, with identification of 218 receiving neurology consults between 30 days pre-OLT and 90 days post-OLT, with review of all records necessary to determine initial findings and follow-up examination. Results: Seventy-three consults for 69 patients were identified, with 27 felt to be altered since a procedure, 20 with sudden-onset altered mentation, and 26 with gradual or waxing-waning course. A single underlying etiology was identified in only 19 cases, with multiple factors involved in all others, with metabolic, toxic, infectious, and structural etiologies most often implicated. There was no statistically significant difference in outcome for those with altered mental status consults versus the total OLT population, though the sudden-onset presentation group did show significantly increased mortality rates. Conclusions: This systematic study illustrates the variety of potential causes of altered mentation within the perioperative setting of liver transplantation. Workup including neuroimaging (preferably magnetic resonance imaging), infectious cultures, and expanded metabolic laboratory tests should be undertaken. PMID- 29977441 TI - Transatlantic Differences in Management of Carotid Stenosis: BRIDGing the Gap in StrokE Management (BRIDGE) Project. AB - Background and Purpose: Management of carotid stenosis remains controversial despite several trials evaluating carotid endarterectomy (CEA) and carotid angioplasty/stenting (CAS). We compared attitudes in the management of carotid stenosis between selected experts within Europe and North America. Methods: A 3 phase Delphi survey was e-mailed to select stroke experts from Europe (n = 390) and North America (n = 289). Those completing the initial survey were shown all responses after each survey round. Consensus was defined as >=80% agreement. Results: For phases 1, 2, and 3, response rates were 32%, 62%, and 73%, respectively. Overall, 100 (15%) of 679 participated in all 3 phases, 19% Europeans versus 9% North Americans (P = .0007). The European group reached consensus in 6 of 15 statements; The North American group reached consensus in 4 of 15. Ninety percentage of Europeans versus 70% of North Americans (P = .017) stated CEA is superior to CAS for symptomatic carotid stenosis. This difference was not significant in the final model (adjusted odds ratio: 3.72 [95% confidence interval: 0.95-14.5]). Sixty-nine percentage of North Americans agreed there is a stronger indication for CAS over CEA in patients younger than 65 years for symptomatic carotid stenosis, whereas 55% of Europeans (P = .023) disagreed. For asymptomatic carotid stenosis, when asked how likely they would recommend CAS, 62% North Americans said "sometimes" versus 60% of Europeans said "never" (P = .06). Conclusion: The majority of North American and European respondents did not consider the 2 procedures equivalent and seemed to indicate that CEA was preferred for the management of carotid stenosis. These findings need to be further explored to help establish evidence-based guidelines. PMID- 29977443 TI - Discontinuation of Postoperative Prophylactic Antibiotics After Noninstrumented Spinal Surgery: Results of a Quality Improvement Project. AB - Background: Numerous medical society guidelines recommend discontinuation of antibiotics at a maximum of 24 hours after noninstrumented spinal surgery, even when a drain is left in place. As a result of these recommendations, our institution's Neurosurgery Quality Improvement Committee decided to stop administering prolonged prophylactic systemic antibiotics (PPSAs) to patients with drains after noninstrumented spinal surgery. Methods: We retrospectively reviewed data for patients who had noninstrumented spinal surgery performed by a neurosurgeon at our institution between December 2012 and July 2014 (PPSA period) and December 2014 and July 2016 (non-PPSA period) and had a drain left in place postoperatively. In the PPSA period, patients received antibiotics until drain removal. In the non-PPSA period, patients received antibiotics for a maximum of 24 hours. Results: We identified 58 patients in the PPSA period and 55 in the non PPSA period. Discontinuation of PPSAs resulted in a nonsignificant increase in the frequency of surgical site infections (SSIs; 0% in the PPSA period vs 4% in the non-PPSA period; P = .24). Conclusion: After discontinuing PPSAs for patients with noninstrumented spinal procedures, as is recommended for quality improvement, we saw a nonsignificant increase in our rate of SSIs. Further monitoring of this population is warranted. PMID- 29977444 TI - Ischemic Stroke After Emergency Department Discharge for Symptoms of Transient Neurological Attack. AB - Background and Purpose: The significance of transient neurological attack (TNA) symptoms is unclear. We sought to determine the risk of ischemic stroke after discharge from the emergency department (ED) with a diagnosis consistent with symptoms of TNA. Methods: Using administrative claims data, we identified patients discharged from EDs in New York between 2006 and 2012 with a primary discharge diagnosis of a TNA symptom, defined as altered mental status, generalized weakness, and sensory changes. The primary outcome was ischemic stroke. We used Kaplan-Meier survival statistics to calculate cumulative rates, and Cox regression to compare stroke risk after TNA versus after transient ischemic attack (TIA; positive control) or renal colic (negative control) while adjusting for demographics and vascular risk factors. Results: Of 499 369 patients diagnosed with a TNA symptom and discharged from the ED, 7756 were hospitalized for ischemic stroke over a period of 4.7 (+/-1.9) years. At 90 days, the cumulative stroke rate was 0.29% (95% confidence interval [CI]: 0.28%-0.31%) after TNA symptoms versus 2.08% (95% CI: 1.89%-2.28%) after TIA and 0.03% (95% CI: 0.02%-0.04%) after renal colic. The hazard ratio (HR) of stroke was higher after TNA than after renal colic (HR: 2.13; 95% CI: 1.90-2.40) but significantly lower than after TIA (HR: 0.47; 95% CI: 0.44-0.50). Compared to TIA, TNA was less strongly associated with stroke among patients under 60 years of age compared to those over 60. Conclusions: Patients discharged from the ED with TNA symptoms faced a higher risk of ischemic stroke than patients with renal colic, but the magnitude of stroke risk was low, particularly compared to TIA. PMID- 29977445 TI - Artery of Percheron Infarct: 12 Cases and Their Complex Clinical Courses. AB - Strokes involving the artery of Percheron (AOP), an anatomic variant of thalamic vascular supply, are rare. Little is known about the inpatient hospital course for these patients. We retrospectively identified consecutive patients with AOP in their medical charts from a university-based tertiary care hospital from January 1, 2000, to August 15, 2017. A chart review identified demographics, transfer status, in-hospital versus community onset of stroke, emergency medical services (EMS) use, presenting signs/symptoms, time to radiologic diagnosis (from time of presentation to tertiary care hospital or from time of initial symptom onset in an already hospitalized patient), tissue plasminogen activator (tPA) use, intensive care unit (ICU) stays, intubation, length of stay (LOS), and discharge location. After radiologic inclusion/exclusion criteria were applied, 12 patients were included in the study. There were 7 men and 5 women, and the mean age (SD) was 68 (15). Seven were transfers, and 4 had an in-hospital stroke. Of the 8 community-onset strokes, 7 utilized EMS. Mental status changes occurred in 11 of 12 and ocular disturbances in all patients. Time to radiologic diagnosis averaged 1.9 (median = 1.1) days. One patient received tPA. Eight received care in the ICU. Four were intubated. Average LOS was 8.3 days. Four were discharged home, 3 entered inpatient rehabilitation facilities, and 5 entered skilled nursing facilities. In-hospital stroke status further complicates the already challenging diagnosis of AOP infarct, and clinicians must maintain a high suspicion for this rare stroke in order to quickly diagnose and intervene. PMID- 29977446 TI - Neurologic Complications of Acute Posterior Multifocal Placoid Pigment Epitheliopathy: A Case Series of 4 Patients. AB - Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a self limited idiopathic inflammatory ophthalmologic condition with characteristic funduscopic and fluorescein angiography findings. It is typically characterized by a flu-like prodrome followed by monocular or binocular vision loss. Often, prognosis is excellent with complete or near-complete recovery of vision. Rarely, however, APMPPE is associated with neurologic complications, including meningitis, cerebral vasculitis, and stroke. Treatment in patients with central nervous system (CNS) involvement involves steroids and ultimately other immunosuppressive therapy, as there can be significant resulting morbidity and mortality otherwise. Evidence or guidelines regarding duration of treatment are lacking. We present 4 patients diagnosed with APMPPE who demonstrate the spectrum of neurologic sequelae associated with APMPPE. The first 2 cases highlight cerebrospinal fluid lymphocytic pleocytosis as an indicator of active CNS inflammation and the potential utility of serial lumbar punctures (LPs) to guide treatment duration. Cases 3 and 4 demonstrate the neurovascular complications seen in CNS vasculitis. Case 4 also highlights the potential use of magnetic resonance vessel wall imaging (VWI) as a noninvasive means for disease surveillance and treatment guidance. This case series emphasizes the importance of recognition by neurologists of APMPPE as an entity associated with strokes and cerebral vasculitis in order to provide appropriate and timely treatment. Active CNS inflammation warrants continued aggressive immunosuppressant treatment, and we propose that serial LPs and/or magnetic resonance VWIs may be effective tools to guide disease surveillance and subsequent treatment duration. PMID- 29977447 TI - An Isolated Trigeminal Sensory Neuropathy. PMID- 29977448 TI - Infectious Temporal Lobe Encephalitis-Not Just Herpes! PMID- 29977449 TI - A Case of Dural Arteriovenous Fistula Mimicking a Cerebellar Tumor. PMID- 29977450 TI - Bow Hunter's Syndrome. PMID- 29977451 TI - Acute Sheehan Syndrome Manifesting as Unremitting Headache. PMID- 29977452 TI - Basilar Artery Thrombosis on Brain MRI. PMID- 29977453 TI - Pituitary Apoplexy With Bilateral Oculomotor Nerve Palsy. PMID- 29977454 TI - The Identification of Core Gene Expression Signature in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies, which causes serious financial burden worldwide. This study aims to investigate the potential mechanisms contributing to HCC and identify core biomarkers. The HCC gene expression profile GSE41804 was picked out to analyze the differentially expressed genes (DEGs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out using DAVID. We constructed a protein-protein interaction (PPI) network to visualize interactions of the DEGs. The survival analysis of these hub genes was conducted to evaluate their potential effects on HCC. In this analysis, 503 DEGs were captured (360 downregulated genes and 143 upregulated genes). Meanwhile, 15 hub genes were identified. GO analysis showed that the DEGs were mainly enriched in oxidative stress, cell cycle, and extracellular structure. KEGG analysis suggested the DEGs were enriched in the absorption, metabolism, and cell cycle pathway. PPI network disclosed that the top3 modules were mainly enriched in cell cycle, oxidative stress, and liver detoxification. In conclusion, our analysis uncovered that the alterations of oxidative stress and cell cycle are two major signatures of HCC. TOP2A, CCNB1, and KIF4A might promote the development of HCC, especially in proliferation and differentiation, which could be novel biomarkers and targets for diagnosis and treatment of HCC. PMID- 29977455 TI - Relevance of Alternative Routes of Kynurenic Acid Production in the Brain. AB - The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D-amino acids or by means of other enzymes as D-amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed. PMID- 29977457 TI - Harnessing Oxidative Stress as an Innovative Target for Cancer Therapy. PMID- 29977456 TI - Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway. AB - Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2. PMID- 29977459 TI - Inflammatory Web Catches Vessels. PMID- 29977460 TI - A Tug of War in the Periphery. PMID- 29977461 TI - Muscles Protect the Kidneys. PMID- 29977458 TI - Hydrogen Sulfide Alleviates Lipopolysaccharide-Induced Diaphragm Dysfunction in Rats by Reducing Apoptosis and Inflammation through ROS/MAPK and TLR4/NF-kappaB Signaling Pathways. AB - Diaphragm dysfunction is an important clinical problem worldwide. Hydrogen sulfide (H2S) is involved in many physiological and pathological processes in mammals. However, the effect and mechanism of H2S in diaphragm dysfunction have not been fully elucidated. In this study, we detected that the level of H2S was decreased in lipopolysaccharide- (LPS-) treated L6 cells. Treatment with H2S increased the proliferation and viability of LPS-treated L6 cells. We found that H2S decreased reactive oxygen species- (ROS-) induced apoptosis through the mitogen-activated protein kinase (MAPK) signaling pathway in LPS-treated L6 cells. Administration of H2S alleviated LPS-induced inflammation by mediating the toll-like receptor-4 (TLR-4)/nuclear factor-kappa B (NF-kappaB) signaling pathway in L6 cells. Furthermore, H2S improved diaphragmatic function and structure through the reduction of inflammation and apoptosis in the diaphragm of septic rats. In conclusion, these findings indicate that H2S ameliorates LPS-induced diaphragm dysfunction in rats by reducing apoptosis and inflammation through ROS/MAPK and TLR4/NF-kappaB signaling pathways. Novel slow-releasing H2S donors can be designed and applied for the treatment of diaphragm dysfunction. PMID- 29977463 TI - The Urgency and Impact of Cardiovascular Critical Care. PMID- 29977462 TI - Journal Editors Recognize Faisal Masud, M.D., for his Exceptional Guidance on this Issue Addressing Cardiovascular Critical Care. PMID- 29977464 TI - The Benefits of Enhanced Recovery After Surgery Programs and Their Application in Cardiothoracic Surgery. AB - The perioperative care of the surgical patient is undergoing a paradigm shift. Enhanced Recovery After Surgery (ERAS) programs are becoming the standard of care and best practice in many surgical specialties throughout the world. ERAS is a multimodal, multidisciplinary, evidence-based approach to care of the surgical patient that aims to optimize perioperative management and outcomes. Implementation, however, has been slow because it challenges traditional surgical doctrine. The key elements of ERAS Pathways strive to reduce the response to surgical stress, decrease insulin resistance, and maintain anabolic homeostasis to help the patient return to baseline function more quickly. Data suggest that these pathways have produced not only improvements in clinical outcome and quality of care but also significant cost savings. Large trials reveal an increase in 5-year survival and a decrease in immediate complication rates when strict compliance is maintained with all pathway components. Years of success using ERAS in colorectal surgery have helped to establish a body of evidence through a number of randomized controlled trials that encourage application of these pathways in other surgical specialties. PMID- 29977465 TI - Sepsis in a Panorama: What the Cardiovascular Physician Should Know. AB - Sepsis accounts for an estimated 30 million cases and 6 million deaths globally each year. According to a multidisciplinary task force convened by the Society of Critical Care Medicine and European Society of Intensive Care Medicine, sepsis is defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Sepsis is a medical emergency, so much so that the World Health Organization made it a global health priority. Since patients with cardiovascular diseases have unique risk factors for sepsis, prompt and accurate diagnosis is critical. In this regard, the sepsis-specific Sequential Organ Failure Assessment (SOFA) helps clinicians identify the organ dysfunction and predict outcomes. Sepsis management is grouped into specific interventions called bundles, and completion of each bundle element is time sensitive. The U.S. Centers for Medicaid and Medicare Services and some state-specific regulations have made compliance with these bundles reportable as a quality measure. The updated Surviving Sepsis Campaign Hour-1 bundle recommends that lactate measurement, blood cultures procurement, broad spectrum antibiotics administration, resuscitation with 30 mL/kg crystalloid, and vasopressor initiation for hypotension all be initiated within 1 hour of time zero, which is from the time of triage in the emergency department or from sepsis diagnosis. Septic shock is defined as hypotension with a mean arterial pressure less than 65 mm Hg, requiring vasopressors despite adequate fluid resuscitation and/or lactic acid levels above 2 mmol/L. Both fluid resuscitation and clinical re-evaluation with lactate measurement guide the fluid and vasopressor therapy. Specific guidelines exist for organ support that address mechanical ventilation, blood transfusions, vasopressor choices, and nutrition. PMID- 29977467 TI - The Role and Impact of Extracorporeal Membrane Oxygenation in Critical Care. AB - Use of extracorporeal membrane oxygenation (ECMO) has been exponentially increasing over the last decade and is now considered a mainstream lifesaving treatment modality in critical care medicine. However, the need for physician education, training, and experience remains imperative. Although ECMO has traditionally been used in end-stage lung disease and circulatory collapse, it is being adopted for use in right heart failure, as a bridge to heart and lung transplantation, and as rescue therapy for both sepsis and post-organ transplantation. The following article discusses indications, management, complications, and challenges of ECMO as well as our experience at the Houston Methodist DeBakey Heart & Vascular Center. PMID- 29977466 TI - How New Support Devices Change Critical Care Delivery. AB - Mechanical support devices are used to support failing cardiac, respiratory, or both systems. Since Gibbon developed the cardiopulmonary bypass in 1953, collaborative efforts by medical centers, bioengineers, industry, and the National Institutes of Health have led to development of mechanical devices to support heart, lung, or both. These devices are used as a temporary or long-term measures for acute collapse of circulatory system and/or respiratory failure. Patients are managed on these support devices as a bridge to recovery, bridge to long term devices, or bridge to transplant. The progress in development of these devices has improved mortality and quality of life in select groups of patients. Care of these patients requires a multidisciplinary team approach, which includes cardiac surgeons, critical care physicians, cardiologists, pulmonologists, nursing staff, and perfusionists. Using a team approach improves outcomes in these patients. PMID- 29977468 TI - Setting Expectations for ECMO: Improving Communication Between Clinical Teams and Decision Makers. AB - Transplant medicine is fraught with clinical-ethical issues. It is not uncommon to have ethicists on transplant teams to help navigate ethically complex cases and ethical questions. Clinical ethicists work in hospitals and/or other healthcare institutions identifying and addressing value-laden conflict and ethical uncertainties. As ethicists, we set out to describe our process and involvement in cases involving extracorporeal membrane oxygenation (ECMO). Our work centers on monitoring and optimizing communication among clinicians, families, and patients, with the goals of (1) aligning patient/family understanding of the nature and purpose of ECMO while encouraging realistic expectations for possible outcomes, and (2) proactively mitigating the moral distress of providers involved in complex ECMO cases. We close with recommendations for how to measure the impact of ethicists' involvement in ECMO cases. PMID- 29977469 TI - Telemedicine/Virtual ICU: Where Are We and Where Are We Going? AB - Intensive care unit telemedicine (tele-ICU) is technology enabled care delivered from off-site locations that was developed to address the increasing complexity of patients and insufficient supply of intensivists. Although tele-ICU deployment is increasing, it continues to cover only a small proportion of ICU patients. This is primarily due to expense, with first-year costs exceeding $50,000 per bed. Meta-analyses of outcomes indicate survival benefits and quality improvements, albeit with significant heterogeneity. Depending on the context, a wide range of estimated incremental cost-effectiveness ratios reflects variable effects on cost and outcomes, such as mortality or length of stay. Tele-ICUs may fit within a hybrid model of care to complement high-intensity ICU staff coverage. However, more research is required to foster consensus and determine best practices. This review summarizes data on tele-ICU structure, operations, outcomes, and costs. Evidence was extracted from meta-analyses, with secondary data from Cleveland Clinic's tele-ICU experience. PMID- 29977470 TI - Is 24/7 In-House Intensivist Staffing Necessary in the Intensive Care Unit? AB - Over the past few decades, an increasing number of studies have shown that intensivist-staffed intensive care units (ICUs) lead to overall economic benefits and improved patient outcomes, including shorter length of stay and lower rates of complications and mortality. This body of evidence has convinced advocacy groups to adopt this staffing model as a standard of care in the ICU so that more hospitals are offering around-the-clock intensivist coverage. Even so, opponents have pointed to high ICU staffing costs and a shortage of physicians trained in critical care as barriers to implementing this model. While these arguments may hold true in low-acuity, low-volume ICUs, evidence has shown that in high-acuity, high-volume centers such as teaching hospitals and tertiary care centers, the benefits outweigh the costs. This article explores the history of intensivists and critical care, the arguments for 24/7 ICU staffing, and outcomes in various ICU settings but is not intended to be a comprehensive review of all controversies surrounding continuous ICU staffing. PMID- 29977471 TI - Treatment of Platypnea-Orthodeoxia Syndrome in a Patient with Normal Cardiac Hemodynamics: A Review of Mechanisms with Implications for Management. AB - Platypnea-orthodeoxia syndrome is a rare entity characterized by dyspnea and hypoxemia in the sitting position and usually resolved by lying down. Although it is not well understood, it is thought to be associated with either intracardiac or extracardiac factors. Within the group of intracardiac etiologies, it typically occurs in the presence of right heart failure or elevated right-sided filling pressures. When right heart failure is absent, platypnea-orthodeoxia is thought to be due to either anatomic changes that produce a baffle-directing flow across an atrial defect or to posture-dependent right-to-left pressure gradients. We report this case of a patient with no prior diagnosis of heart failure who presented to our hospital with 6 months of New York Heart Association class IV dyspnea and recent paradoxical embolus across a patent foramen ovale (PFO). Platypnea-orthodeoxia syndrome was diagnosed clinically. Transesophageal echocardiography revealed bidirectional shunting across the PFO. In the catheterization laboratory, invasive hemodynamics showed normal right and left atrial pressures and normal pulmonary arterial pressures. An Amplatzer Cribiform occluder device (AGA Medical Corp.) was used to close the PFO, completely curing the patient's symptoms. This is a novel case of subacute-onset severe platypnea orthodeoxia associated with paradoxical embolus occurring while seated in the upright position. The cause of the patient's symptoms may have been progressive kyphosis or to increased pulmonary tidal volumes. Evaluation for platypnea orthodeoxia is important in cases of occult dyspnea because the condition may be cured by closing the anatomic defect, as it was in this case. PMID- 29977473 TI - A Giant Aortic Root Abscess. PMID- 29977472 TI - Adipositas Cordis: A Rare and Poorly Understood Cardiomyopathy. AB - Adipositas cordis is a rare cardiomyopathy characterized by diffuse fatty infiltration of the ventricular myocardium or interventricular septum. This occurs without myocardial cell destruction, unlike arrhythmogenic right ventricular cardiomyopathy. A 40-year-old obese woman was found to have a II/VI systolic murmur that worsened with standing. A transthoracic echocardiogram showed interventricular septal hypertrophy with a preserved left ventricular ejection fraction. Cardiac magnetic resonance imaging revealed a fatty mass in the interventricular septum. An endomyocardial biopsy revealed structurally normal myocytes with diffuse adipose cell infiltration and no evidence of malignant cells. Left and right cardiac catheterizations and stress echocardiography showed no abnormalities. This case shows the importance of considering a broad differential when approaching rare diseases. It also demonstrates the utility of noninvasive imaging and its impact on clinical decision making. PMID- 29977474 TI - A Case of Infected Mitral-Aortic Intervalvular Fibrosa Pseudoaneurysm. PMID- 29977475 TI - Continuous Venous-Venous-Hemodialysis versus Intermittent-Hemodialysis in Critically Ill Patients. AB - The column in this issue is supplied by Juan Jose Olivero, M.D., a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Training Program. Dr. Olivero obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas. PMID- 29977476 TI - Poet's Pen: Dante's Inferno, Canto I. AB - Dante Alighieri's Divine Comedy chronicles his journey through the afterlife in three cantiche-from hell (Inferno), to purgatory (Purgatorio), and finally to heaven (Paradiso)-each comprising 33 cantos. Writing in idiomatic Tuscan rather than the more common, but less widely understood, Latin, Dante is widely credited with establishing Italian as a literary language and opening up contemporary literature to a wider, less scholarly audience. He wrote his epic during his political exile from Florence, and completed it in 1320, just a year before his death. Henry Wadsworth Longfellow was the first American to translate the Divine Comedy into English, publishing this version in 1867. PMID- 29977477 TI - Dr. Phil's Art Corner: Alpha Centurion 9 and Shuttle Ready. AB - Philip Alexander, M.D., is a native Texan, retired physician, and accomplished musician and artist. After 41 years as an internal medicine physician, Dr. Phil retired from his practice in College Station in 2016. A lifelong musician and former music professor, he often performs as an oboe soloist for the Brazos Valley Symphony Orchestra. He began exploring visual art in 1980, evolving from pencil sketches-including an official White House portrait of President Ronald Reagan-to the computer-generated drawings featured in this journal. His images, which first appeared in this journal in the spring of 2012, are his own original creations. PMID- 29977478 TI - Essay on Being a Doctor: Dr. Edwards. AB - Through the generosity of Charles R. Millikan, D. Min., vice president for Spiritual Care and Values Integration, an annual award competition was established at Houston Methodist Hospital among the resident staff. To enter the writing competition, residents must submit a poem or essay of 1,000 words or less on the topic, "On Being a Doctor." A committee of seven was selected from Houston Methodist Hospital Education Institute to establish the judging criteria and select the winning entries. The following is the first-place winning entry for 2018; the second- and third-place entries will be published in the next two issues of this journal. PMID- 29977480 TI - An Artificial Neural Network Integrated Pipeline for Biomarker Discovery Using Alzheimer's Disease as a Case Study. AB - The field of machine learning has allowed researchers to generate and analyse vast amounts of data using a wide variety of methodologies. Artificial Neural Networks (ANN) are some of the most commonly used statistical models and have been successful in biomarker discovery studies in multiple disease types. This review seeks to explore and evaluate an integrated ANN pipeline for biomarker discovery and validation in Alzheimer's disease, the most common form of dementia worldwide with no proven cause and no available cure. The proposed pipeline consists of analysing public data with a categorical and continuous stepwise algorithm and further examination through network inference to predict gene interactions. This methodology can reliably generate novel markers and further examine known ones and can be used to guide future research in Alzheimer's disease. PMID- 29977479 TI - Discovery of Novel Functional Centers With Rationally Designed Amino Acid Motifs. AB - Plants are constantly exposed to environmental stresses and in part due to their sessile nature, they have evolved signal perception and adaptive strategies that are distinct from those of other eukaryotes. This is reflected at the cellular level where receptors and signalling molecules cannot be identified using standard homology-based searches querying with proteins from prokaryotes and other eukaryotes. One of the reasons for this is the complex domain architecture of receptor molecules. In order to discover hidden plant signalling molecules, we have developed a motif-based approach designed specifically for the identification of functional centers in plant molecules. This has made possible the discovery of novel components involved in signalling and stimulus-response pathways; the molecules include cyclic nucleotide cyclases, a nitric oxide sensor and a novel target for the hormone abscisic acid. Here, we describe the major steps of the method and illustrate it with recent and experimentally confirmed molecules as examples. We foresee that carefully curated search motifs supported by structural and bioinformatic assessments will uncover many more structural and functional aspects, particularly of signalling molecules. PMID- 29977481 TI - ctDNA and CTCs in Liquid Biopsy - Current Status and Where We Need to Progress. AB - We discuss the current status of liquid biopsy and its advantages and challenges with a focus on pre-analytical sample handling, technologies and workflows. The potential of circulating tumor cells and circulating tumor DNA is pointed out and an overview of corresponding technologies is given. PMID- 29977482 TI - Corrigendum to "A Gene Module-Based eQTL Analysis Prioritizing Disease Genes and Pathways in Kidney Cancer". AB - [This corrects the article DOI: 10.1016/j.csbj.2017.09.003.]. PMID- 29977483 TI - Acral myxoinflammatory fibroblastic sarcoma with hybrid features of hemosiderotic fibrolipomatous tumor occurring 10 years after renal transplantation. AB - Myxoinflammatory fibroblastic sarcoma is a rare malignant soft tissue neoplasm that typically arises on the distal extremities of adults. It usually behaves in a low-grade manner and its characteristic histology is of a lobulated proliferation of moderately atypical spindled to epithelioid cells, vacuolated cells, and enlarged or bizarre cells with prominent nucleoli, dispersed within myxoid stroma containing a mixed inflammatory cell infiltrate. The etiology of myxoinflammatory fibroblastic sarcoma remains unknown with no definite causal factors identified. We describe a case of myxoinflammatory fibroblastic sarcoma arising in the foot of a 77-year-old female, which rapidly recurred locally after initial excision and which arose 10 years after renal transplantation. The neoplasm also showed intermingled areas of hemosiderotic fibrolipomatous tumor. The patient also had multifocal areas of squamous cell carcinoma in situ of the foot and hand, in keeping with the clinical context of immune deficiency. This is the second case of myxoinflammatory fibroblastic sarcoma reported to occur after transplantation, but additionally shows hybrid features of hemosiderotic fibrolipomatous tumor, highlights immunocompromise/immunosuppressive therapy as a possible etiologic factor in their development, and adds to the growing number of myxoinflammatory fibroblastic sarcoma that has demonstrated aggressive behavior. PMID- 29977485 TI - Biotic- and abiotic-driven variations of the night-time sap flux of three co occurring tree species in a low subtropical secondary broadleaf forest. AB - Although several studies on the night-time water use of different plant species have been reported, comparative studies under the same climatic conditions of a region are scarce. This study aimed to analyse the inter- and intraspecific variations in night-time water use in relation to environmental factors and to tree morphological features to understand and elucidate the possible underlying mechanisms. The sap flow of three co-occurring tree species in a low subtropical secondary broadleaf forest in South China was monitored using Granier-style sap flux sensors. All examined environmental factors except wind speed exerted significant influence on the daytime sap flows of Schima superba, Castanopsis hystrix and Michelia macclurei, but the impacts of all factors, including wind speed, on the night-time sap flux were trivial. These results indicated that sap flow was mainly used for water recharge at night. The morphological features of the trees, except tree height, significantly affected the daytime water use, but no morphological features significantly affected the night-time water use. We found that night-time water recharge was strongly affected by the maximum flux density. A principal component analysis showed that there were more intraspecific than interspecific variations in water transport. The results also revealed that the night-time water use and the percentage of night/day (Qn/Qd) of photosynthetic stem species (C. hystrix and M. macclurei) were greater than those of non-photosynthetic stem species (S. superba). PMID- 29977484 TI - Raman Spectroscopy and Imaging for Cancer Diagnosis. AB - Raman scattering has long been used to analyze chemical compositions in biological systems. Owing to its high chemical specificity and noninvasive detection capability, Raman scattering has been widely employed in cancer screening, diagnosis, and intraoperative surgical guidance in the past ten years. In order to overcome the weak signal of spontaneous Raman scattering, coherent Raman scattering and surface-enhanced Raman scattering have been developed and recently applied in the field of cancer research. This review focuses on innovative studies of the use of Raman scattering in cancer diagnosis and their potential to transition from bench to bedside. PMID- 29977488 TI - Associations between shoot-level water relations and photosynthetic responses to water and light in 12 moss species. AB - In vascular plants, there is a clear coupling between traits related to water and traits related to carbon economics. For bryophytes this coupling has been little studied but is expected to be strong, because in these poikilohydric plants photosynthesis varies strongly with water availability. We hypothesized that there is a trade-off between water-holding and photosynthetic capacities for mosses, resulting in a limited spectrum of possible trait combinations. At one end of this spectrum, mosses would tend to stay wet and active for long periods but would have slow photosynthetic rates. At the other end, mosses would avoid external water and dry out quicker but would have high photosynthetic capacities. We determined the water relations (water-holding and -retention capacities), photosynthetic water- and light-response curves of shoots of 12 moss species and explored the associations between these traits and their distributions among the studied species. The results partly support our hypotheses, in that the water holding and water-retention capacities of mosses are positively related to each other and to the value and width of the optimal water-content range for photosynthesis. However, the photosynthetic capacities were specific to taxonomic groups, and the relationships between the water relations and the photosynthetic capacity are weak or inconsistent and depend strongly on the species used for analysis. The positive relationships between water-holding, water-retention and photosynthetic water-use capacities suggest two contrasting adaptations to avoid damage during dehydration: taking more time to 'prepare' or quick photosynthetic adjustment. However, the spectrum we hypothesized cannot be generalized for all mosses and defining a broader spectrum will require the extension of this study to a much larger number of species and including stand-level measurements of water loss and photosynthesis. PMID- 29977486 TI - Degradation of chlorophyll and synthesis of flavonols during autumn senescence the story told by individual leaves. AB - Autumn senescence of deciduous trees is characterized by chlorophyll degradation and flavonoid synthesis. In the present study, chlorophyll and flavonol contents were measured every morning and evening during the whole autumn with a non destructive method from individual leaves of Sorbus aucuparia, Acer platanoides, Betula pendula and Prunus padus. In most of the studied trees, the chlorophyll content of each individual leaf remained constant until a phase of rapid degradation commenced. The fast phase lasted only ~1 week and ended with abscission. In S. aucuparia, contrary to the other species, the chlorophyll content of leaflets slowly but steadily decreased during the whole autumn, but rapid chlorophyll degradation commenced only prior to leaflet abscission also in this species. An increase in flavonols commonly accompanied the rapid degradation of chlorophyll. The results may suggest that each individual tree leaf retains its photosynthetic activity, reflected by a high chlorophyll content, until a rapid phase of chlorophyll degradation and flavonoid synthesis begins. Therefore, in studies of autumn senescence, leaves whose chlorophyll content is decreasing and leaves with summertime chlorophyll content (i.e. the leaves that have not yet started to degrade chlorophyll) should be treated separately. PMID- 29977487 TI - Defence signalling marker gene responses to hormonal elicitation differ between roots and shoots. AB - Phytohormones such as jasmonic acid (JA), salicylic acid (SA), ethylene (ET) and abscisic acid (ABA) play a key role in regulation of plant immune responses to different attackers. Extensive research over recent years has led to the identification of molecular markers for specific hormonal-regulated defence pathways. However, most of our current knowledge on the regulation of plant immunity derives from studies focused on above-ground organs, mainly on the model plant Arabidopsis thaliana. Therefore, it is unclear whether the paradigms based on experiments on above-ground organs are entirely transferable to roots. Here, we used the non-model plant Brassica rapa to study the regulation dynamics of hormonal-related marker genes in both roots and shoots. These markers were identified in Arabidopsis shoots after elicitation of the JA-, SA-, ET- or ABA signalling pathways, and are commonly used to study induced responses. We assessed whether the regulation of those genes by hormonal elicitation differs between roots and shoots. To discern whether the differences in marker gene expression between roots and shoots are related to differences in hormone production or to differential responsiveness, we also measured actual hormone content in the treated tissue after elicitation. Our results show that some of the widely used markers did not show specific responsiveness to single hormone applications in B. rapa. We further found that hormonal elicitation led to different response patterns of the molecular markers in shoots and roots. Our results suggest that the regulation of some hormonal-related marker genes in B. rapa is organ specific and differs from the Arabidopsis-derived paradigms. PMID- 29977490 TI - Effects of Users' Familiarity With the Objects Depicted in Icons on the Cognitive Performance of Icon Identification. AB - This study investigated the effects of users' familiarity with the objects depicted in icons on the cognitive performance of icon identification. First, without knowing the specific semantic information of icons, 20 participants were required to search for target icons among visually similar distractors for 3-hour long training sessions across 1 week, during which their familiarity with different icons was manipulated by differential exposure frequencies. Half of the icons were presented 10 times more often than the other half. Subsequently, participants' abilities to recall corresponding semantic information when cued with associated target icons were tested after they had learned all the icons. The results showed that, in both the visual search task and the semantic information recall task, participants performed significantly better when the icons were more familiar. Importantly, the effects of icon complexity in the visual search task diminished as participants became familiar with the icons, and the beneficial effects of familiarity in the semantic information recall task were larger when the icons were complex. These findings have practical implications for icon design. When creating new icons for time critical user interfaces, icons should be kept as simple as possible and employ familiar, commonly used, graphics. PMID- 29977489 TI - Gist Perception of Image Composition in Abstract Artworks. AB - Most recent studies in experimental aesthetics have focused on the cognitive processing of visual artworks. In contrast, the perception of formal compositional features of artworks has been studied less extensively. Here, we investigated whether fast and automatic processing of artistic image composition can lead to a stable and consistent aesthetic evaluation when cognitive processing is minimized or absent. To this aim, we compared aesthetic ratings on abstract artworks and their shuffled counterparts in a gist experiment. Results show that exposure times as short as 50 ms suffice for the participants to reach a stable and consistent rating on how ordered and harmonious the abstract stimuli were. Moreover, the rating scores for the 50 ms exposure time exhibited similar dependencies on image type and self-similarity and a similar pattern of correlations between different rating terms, as the rating scores for the long exposure time (3,000 ms). Ratings were less consistent for the term interesting and inconsistent for the term pleasing. Our results are compatible with a model of aesthetic experience, in which the early perceptual processing of the formal aspects of visual artworks can lead to a consistent aesthetic judgment, even if there is no cognitive contribution to this judgment. PMID- 29977491 TI - Parallel Behind Your Head. AB - A miniature hair clip set-up presented to the first author gave inspiration for this study. After a number of studies investigating what is haptically perceived as parallel on horizontal, frontoparallel or midsagittal planes, the present study focusses on what is felt as parallel behind your head. The results show convincingly that also in this condition physically parallel is not the same as haptically parallel. Moreover, the deviations are large, idiosyncratic and in a direction predicted by assuming a biasing influence of an egocentric reference frame. PMID- 29977492 TI - Spatial Representation of the Workspace in Blind, Low Vision, and Sighted Human Participants. AB - It has been proposed that haptic spatial perception depends on one's visual abilities. We tested spatial perception in the workspace using a combination of haptic matching and line drawing tasks. There were 132 participants with varying degrees of visual ability ranging from congenitally blind to normally sighted. Each participant was blindfolded and asked to match a haptic target position felt under a table with their nondominant hand using a pen in their dominant hand. Once the pen was in position on the tabletop, they had to draw a line of equal length to a previously felt reference object by moving the pen laterally. We used targets at three different locations to evaluate whether different starting positions relative to the body give rise to different matching errors, drawn line lengths, or drawn line angles. We found no influence of visual ability on matching error, drawn line length, or line angle, but we found that early-blind participants are slightly less consistent in their matching errors across space. We conclude that the elementary haptic abilities tested in these tasks do not depend on visual experience. PMID- 29977493 TI - Formation of the initial kidney and mouth opening in larval amphioxus studied with serial blockface scanning electron microscopy (SBSEM). AB - Background: For early larvae of amphioxus, Kaji et al. (Zool Lett 2:2, 2016) proposed that mesoderm cells are added to the rim of the forming mouth, giving it the quality of a coelomoduct without homology to the oral openings of other animals. They depended in part on non-serial transmission electron microscopic (TEM) sections and could not readily put fine structural details into a broader context. The present study of amphioxus larvae is based largely on serial blockface scanning electron microscopy (SBSEM), a technique revealing TEM-level details within an extensive anatomical volume that can be reconstructed in three dimensions. Results: In amphioxus larvae shortly before mouth formation, a population of compact mesoderm cells is present at the posterior extremity of the first left somite. As development continues, the more dorsal of these cells give rise to the initial kidney (Hatschek's nephridium), while the more ventral cells become interposed between the ectoderm and endoderm in a localized region where the mouth will soon penetrate. SBSEM reveals that, after the mouth has opened, a majority of these mesoderm cells can still be detected, sandwiched between the ectoderm and endoderm; they are probably myoblasts destined to develop into the perioral muscles. Conclusions: SBSEM has provided the most accurate and detailed description to date of the tissues at the anterior end of amphioxus larvae. The present study supports the finding of Kaji et al. (2016) that the more dorsal of the cells in the posterior region of the first left somite give rise to the initial kidney. In contrast, the fate of the more ventral cells (called here the oral mesoderm) is less well understood. Although Kaji et al. (2016) implied that all of the oral mesoderm cells joined the rim of the forming mouth, SBSEM reveals that many of them are still present after mouth penetration. Even so, some of those cells go missing during mouth penetration and their fate is unknown. It cannot be ruled out that they were incorporated into the rim of the nascent mouth as proposed by Kaji et al. (2016). On the other hand, they might have degenerated or been shed from the larva during the morphogenetic interaction between the ectoderm and endoderm to form the mouth. The present SBSEM study, like Kaji et al. (2016), is based on static morphological data, and dynamic cell tracer experiments would be needed to decide among these possibilities. PMID- 29977495 TI - Assessment of Factors Influencing the Implementation of Biosecurity Measures on Pig Farms in the Western Highlands of Cameroon (Central Africa). AB - Biosecurity plays an irreplaceable role in preventing diseases and increasing productivity on farm. The main objective of this study was to characterize pig farming and investigate factors influencing biosecurity on pig farms in the western highlands of Cameroon. Data were collected from May to July 2017 using a questionnaire and observations. A technical scoring system was developed from the biosecurity measures. The results revealed that most farmers are males (76.29%), on average 47.82 +/- 10.34 years old, with secondary school level (53.61%). The most common husbandry system is extensive (73.22%). Over a total score of 93, measures with higher scores (>80) included "employees do not rear pigs at home," "animals of different age not in the same room," "unsold animals from market quarantined prior to reintroduction into the herd," "production materials not exchanged among farms," "piggeries clean every day," "disinfectants used," "pigs vaccinated," and "vaccination calendar respected." Those with the lowest score (<6) were "sanitary lock present," "use of herd specific clean coveralls and boots on farm," and "entry restriction sign post present." The biosecurity level was associated with production system, with the score 6.57 and 3.66 points lower for extensive and semi-intensive farms, respectively, than for intensive system. Farmer's age, gender, education level, and herd size did not affect the level of biosecurity. The results can be used to improve the general biosecurity status in pig herds in the country which in turn will lead, as observed elsewhere, to improved technical performance and economic gain. PMID- 29977494 TI - Contagious Bovine Pleuropneumonia: Seroprevalence and Risk Factors in Gimbo District, Southwest Ethiopia. AB - Contagious bovine pleuropneumonia (CBPP) is a highly contagious disease of cattle which is one of the great plagues which continues to devastate the cattle herds on which so many people are dependent in Africa. Cross-sectional study was conducted from October 2015 to August 2016 to determine the seroprevalence of CBPP in cattle and associated risk factors in Gimbo district, Southwest Ethiopia. A total of 384 serum samples were collected and tested for the presence of specific antibodies against Mycoplasma mycoides subspecies mycoides small colony (MmmSC), using a competitive enzyme-linked immunosorbent assay (cELISA). Univariable and multivariable logistic regression analysis were performed to determine the association between risk factors and seroprevalence of CBPP. An overall seroprevalence of CBPP was 8.1% (31/384) and it was ranging from 0% to 20% across different Peasant associations (PAs). The seroprevalence of CBPP among adult animals was 8.5% (25) and in young 6.6% (6), in good body condition animals 6.6% (18) and in poor 11.5% (13), in dry season 11.9% (20) and in rainy 5.1% (11), and in highland altitude 2.5% (3), midland 3.8% (5), and lowland 17.4% (23). Among the potential predisposing factors assessed, altitude was found significantly (p = 0.02, OR = 7.3) associated with the seroprevalence of contagious bovine pleuropneumonia and other risk factors had no significant (P > 0.05) influence. The present study showed that the overall seroprevalence of CBPP in Gimbo district was high and this indicates a need for intervening and implementing control measures to prevent further spread of the disease in the district through the use of better and coordinated vaccination program. PMID- 29977496 TI - Improved outcomes for papillary thyroid microcarcinoma care: active surveillance and case volume. PMID- 29977498 TI - Incidence, mechanisms and impact outcome of hyperglycaemia in severe scorpion envenomed patients. AB - Hyperglycaemia is often observed in severe scorpion-envenomed patients. It is due to a severe autonomic storm with a massive release of catecholamines, increased glucagon levels, cortisol levels, and either decreased insulin levels or insulin resistance. The presence of hyperglycaemia is an indicator of severity in this specific condition. Indeed, hyperglycaemia was associated with the severity of clinical manifestations of severe scorpion envenomation requiring intensive care unit (ICU) admission. In fact, the presence of hyperglycaemia was associated with the presence of respiratory failure, pulmonary oedema, haemodynamic instability, neurological failure, multisystem organ failure, and an increased mortality and ICU length of stay. As a consequence, we think the presence of hyperglycaemia in scorpion-envenomed patients at the emergency department prompts searching for presence of systemic manifestations or cardiorespiratory manifestations. As a consequence, the presence of hyperglycaemia can help screen severe patients at the emergency department. The current management of severe scorpion envenomation involves the admission and close surveillance in the ICU, where vital signs and continuous monitoring enable early initiation of therapy for life-threatening complications. The use of antivenom for scorpion stings remains controversial. All patients with pulmonary oedema should receive prazosin and possibly dobutamine, according the scorpion's species. Mechanical ventilation is usually used in severe cases. Insulin should be reserved for severe cases with confirmed excessive hyperglycaemia (>10 mmol/l). PMID- 29977497 TI - The value of fast-acting insulin aspart compared with insulin aspart for patients with diabetes mellitus treated with bolus insulin from a UK health care system perspective. AB - Background: Fast-acting insulin aspart is a new formulation of the rapid-acting insulin analogue insulin aspart and represents an advancement over current rapid acting insulin analogues in terms of onset of action and postprandial glucose control. The objective of the current analysis was to demonstrate the cost impact of prescribing fast-acting insulin aspart instead of insulin aspart, to highlight the value of fast-acting insulin aspart for the treatment of people with diabetes requiring mealtime insulin. Methods: A cost-impact analysis was conducted from the perspective of the UK National Health Service (NHS). The analysis excluded patients' out-of-pocket expenses, carers' costs and lost productivity. The time horizon of the analysis was 1 year, and no discounting was therefore applied. Results: The displacement of insulin aspart with fast-acting insulin aspart is cost neutral for the UK NHS. Fast-acting insulin aspart is at price parity to insulin aspart in terms of the vial and Penfill(r) cartridge and is available in the FlexTouch(r) pen at the same price as the insulin aspart FlexPen(r) (and thus cheaper than the insulin aspart FlexTouch(r) pen). Patients using the insulin aspart FlexPen(r) will be upgraded to the FlexTouch(r) pen device, which is preferred by patients and healthcare professionals, on switching to fast-acting insulin aspart, at no additional cost. Conclusions: Fast-acting insulin aspart offers additional clinical benefit but at no additional cost when compared with insulin aspart, and thus provides value to the UK NHS. PMID- 29977500 TI - Levothyroxine pseudo-malabsorption: testing and treatment in the outpatient setting. AB - Persistent elevation of thyroid stimulating hormone (TSH) is a common clinical problem in outpatient clinics treating patients with primary hypothyroidism. One challenge to practitioners involves predicaments where patients have an inadequate response to a seemingly appropriate dose of levothyroxine (L-T4). A patient's self-assessed compliance to hormone replacement therapy or verification refill history at the patient's pharmacy might not be a reliable form of confirmation of non-adherence to the drug by the patient, which has been referred to as "L-T4 pseudo-malabsorption." A fast and inexpensive tool to rule out true LT4 malabsorption and thereby properly diagnosing and ultimately successfully treat LT4 pseudo-malabsorption is available in the outpatient setting. This allows clinicians to identify which patients for individual support in adhering to their prescribed therapy and may also reduce unnecessary referrals for sub specialty care by endocrinologists. PMID- 29977499 TI - The role of mitogen-activated protein kinase-extracellular receptor kinase pathway in female fertility outcomes: a focus on pituitary gonadotropins regulation. AB - Mammalian reproduction systems are largely regulated by the secretion of two gonadotropins, that is, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The main action of LH and FSH on the ovary is to stimulate secretion of estradiol and progesterone, which play an important role in the ovarian function and reproductive cycle control. FSH and LH secretions are strictly controlled by the gonadotropin-releasing hormone (GnRH), which is secreted from the hypothalamus into the pituitary vascular system. Maintaining normal secretion of LH and FSH is dependent on pulsatile secretion of GnRH. Extracellular signal regulated kinase (ERK) proteins, as the main components of mitogen-activated protein kinase (MAPK) signaling pathways, are involved in the primary regulation of GnRH-stimulated transcription of the gonadotropins' alpha subunit in the pituitary cells. However, GnRH-stimulated expression of the beta subunit has not yet been reported. Furthermore, GnRH-mediated stimulation of ERK1 and ERK2 leads to several important events such as cell proliferation and differentiation. In this review, we briefly introduce the relationship between ERK signaling and gonadotropin secretion, and its importance in female infertility. PMID- 29977501 TI - Laparoscopic choledochoscopy with Ambu(r) aScope 3TM in the treatment of coledocholithiasis: a series of cases. AB - The progresses made in minimally invasive surgery, make it not only possible to perform isolated cholecystectomy, but also to provide a totally laparoscopic treatment of common bile duct lithiasis. In this approach, the use of choledochoscopy is indispensable for diagnostic and therapeutic success. This study describes the use of a disposable endoscope for choledochoscopy in the laparoscopic treatment of choledocholithiasis. We have analyzed the use of the Ambu(r) aScope 3TM disposable endoscope, normally used for bronchoscopy, in nine consecutive patients needing choledochoscopy in our Hospital. The patient average age was 78 years. Total clearance of the bile duct was obtained in seven patients. Bile duct vacuity was not obtained in two patients, but this is not attributed to equipment failure. There was one case of hemoperitoneum not related to equipment usage. This device is easy to use and looks promising for choledochoscopy in laparoscopic treatment of coledocholithiasis. PMID- 29977502 TI - Reduction of bilateral dislocation of TMJ and Rendu Osler Weber syndrome: case report and physiopathological model. AB - Temporomandibular joint dislocation (TMJ) is an infrequent clinical situation, representing 3% of all the human body's dislocations. The etiological factors reported are associated to alterations typical of the joint or of the muscular ligament apparatus, or to clinical conditions that may cause dislocation. We present the case of a 46-year-old patient with hereditary hemorrhagic telangiectasia with bilateral dislocation of the TMJ. There are several potential causes (antipsychotics, intubation, etc.) although the deposit of manganese in the basal ganglia that produce extrapyramidal symptoms could be the most consistent cause. PMID- 29977503 TI - A case of recurrent pneumatosis intestinalis. AB - Pneumatosis intestinalis (PI), defined as free gas in the bowel wall, is associated with autoimmune conditions, drugs, pulmonary disease and many other etiologies. Patients with findings of PI may have variable clinical presentations, ranging from asymptomatic to acute abdomen necessitating urgent surgery. Here, we present the case of an individual with recurrent PI whose suspected etiologies ultimately varied from benign to lethal between visits. We discuss the clinical management of each case, perform post-hoc application of a proposed treatment algorithm, and highlight areas for future research. PMID- 29977504 TI - Haemangiopericytoma of the greater omentum: a rare tumour requiring long-term follow-up. AB - Haemangiopericytomas (HPC) are highly vascularized tumours located in any part of the body where capillaries can be found. Since 2002, they have been re-classified under the umbrella 'extrapleural Solitary Fibrous Tumour (SFT)' and the term HPC is nowadays used to describe a growth pattern rather than a clinical entity. Their biological behaviour varies and they require a long-term follow-up since they may recur or metastasise several years after successful treatment. We present the case of a gentleman with HPC of the greater omentum initially appeared in 1998. HPC rarely develops in the greater omentum and only 20 cases have been described in the literature till today. Despite complete excision the mass re-appeared in 2011 and 2017, 13 and 19 years after initial treatment. Surgical management included en bloc excision of three lesions along with greater omentum. No further treatment was required. PMID- 29977506 TI - Gastric hibernoma: a novel location and presentation of a rare tumor. AB - We present a case of gastric hibernoma, an unusual tumor with a location novel to the literature. A 39-year-old female presented with one year of upper gastrointestinal bleeding and dysphagia. Gastroenterology performed an esophagogastroduodenoscopy with ultrasound and identified a 6 cm mass within the muscularis propria of the antrum. Computed tomography demonstrated a 9.7 * 7.8 * 4.8 cm3 heterogeneous antral mass with internal septa. A distal gastrectomy with Bilroth I gastroduodenostomy was performed with 4 cm proximal and 2 cm distal margins. Excision was appropriate to make the diagnosis, exclude malignancy, and remove a symptomatic mass. Hibernoma was confirmed by histopathology. These are rare tumors of brown fat named for their resemblance to the thermogenic tissue found in hibernating animals. They typically present as a slowly enlarging mass of the thigh or shoulder. To our knowledge, this is the first presentation of a hibernoma as a submucosal gastric mass. PMID- 29977505 TI - Abdominal hernia and the unexpected final diagnosis. AB - Mucinous neoplasm of the appendix are rare entities, among these, mucinous cystadenomas contribute to 31-34%. Cystadenomas often produce extensive dilatation of the appendix with epithelial atypia. Spontaneous perforation often occurs in 20%, leading to mucin distribution throughout the peritoneal cavity. Half of the patients are completely asymptomatic and are detected as an incidental diagnosis, others symptoms include a palpable mass, hernias, weight loss, peritonism or even intestinal obstruction. We present a case of a 71-year old female, she presented with a palpable mass in the upper abdomen. A ventral hernia was the most likely diagnosis and hernioplasty was planned. At surgery, a mucinous mass was discovered and mucous material was found free en the peritoneal cavity. Also, a perforated appendix and a mass in the cecum was found. Patient underwent full recovery. Pathology reported pseudomyxoma peritonei as the final diagnosis. PMID- 29977507 TI - Rare case of bleeding nipple hemangioma in a lactating mother. AB - Hemangiomas of nipple of the breast are rare lesions and are limited to case reports in the literature. Such pathology in a lactating mother are clearly a hindrance preventing the child from breastfeeding with its benefits. We report a rare case of a bleeding nipple hemangioma in a 24 years old lactating mother with the clinical, imaging and histopathological findings. PMID- 29977508 TI - Metastatic lobular breast carcinoma to the pancreas: a case report. AB - We report a case of a 72-year-old female, with an extensive breast cancer history, who presented with abdominal pain to her general practitioner. Cross sectional imaging demonstrated a lesion in the head of pancreas, which was not amenable to curative resection. Percutaneous biopsy was obtained, which demonstrated metastatic lobular breast cancer. This rare case highlights how previous medical histories may assist in final pathological diagnosis. PMID- 29977509 TI - External iliac vein aneurysm: a case report and review of the literature. AB - Iliac vein aneurysms are extremely rare, even amongst vein aneurysms. We discuss the case of a 26-year-old man with an external iliac vein aneurysm, likely secondary to iatrogenic vascular trauma in the neonatal period. It is the first reported case of an iliac vein aneurysm presenting with lower urinary tract symptoms. Attempts at endovenous management were unsuccessful and therefore the patient underwent open aneurysmectomy. A PubMed literature search revealed a total of nine case reports of iliac vein aneurysms published in English since 2011. We discuss the aetiology, presentation, investigation and management of iliac vein aneurysms and compare to our own case. PMID- 29977510 TI - Pharmacobezoar-a rare case presented as gastric outlet obstruction. AB - BEZOARS are retained concretions of indigestible foreign material that accumulate and conglomerate in the gastrointestinal tract, most commonly in the stomach. Prevalence of bezoar is 0.4%. Bezoars are classified in four categories: phytobezoars; trichobezoars; pharmacobezoars; lactobezoars. A 58-year-old man admitted with complains of pain abdomen and recurrent vomiting since last 3 months. Upper GI endoscopic biopsy reported-chronic gastritis with very occasional non-caseating epitheloid granuloma in lamina propria, no evidence of neoplasia? Crohn's disease. Keeping Crohn's as diagnosis patient was given mesalamine 400 mg tid by gastrophyscian. But patient did not respond so the patient was advised surgical management. Repeat UGI endoscopy revealed multiple pills (mesalamine) in the stomach with gastric outlet obstruction (GOO). Around 40 pills were extracted with the help of flower basket, and then patient develope GOO and underwent Laparoscopic gastrojejunostomy and truncal vagotomy. PMID- 29977511 TI - Bleb formation in small unruptured intracranial aneurysm as a predictor of early rupture. AB - Small unruptured aneurysms are thought to have a low risk of rupture, but the management of such lesions is still controversial. A 73-year-old man with a small anterior communication artery aneurysm, 4 mm in diameter, while on follow-up, developed an aneurysmal subarachnoid hemorrhage 2 weeks after the detection of a newly emerged bleb on the surface of the aneurysm. In conclusion, the formation of a bleb should be considered as a warning sign of an impending rupture, and treatment should be provided even for patients with small aneurysms. PMID- 29977512 TI - Heterotopic ossification following use of i-Factor for spinal fusion in Mucopolysaccharidosis 1: a case report. AB - Mucopolysaccharidosis is a rare group of genetic disorder which results in a complex of anomalies involving various systems. In Mucopolysaccharidosis 1 progressive thoracolumbar kyphosis is a common presentation which can result in instability and neurological deficit. Posterior spinal surgery is performed to correct deformity and obtain spinal fusion. Peptide enhanced bone graft substitute (i-FactorTM) is relatively a new component with proven efficacy to obtain early spinal fusion. An 8-year-old child with progressive high lumbar kyphosis due to Mucopolysaccharidosis 1 was admitted for Posterior spinal fusion with i-Factor bone graft substitute. Postoperatively patient had serous discharge from the wound which settled without intervention. A month after the surgery spinal radiographs revealed heterotopic ossification at the distal end of spinal construct in the paraspinal region. Patient remained asymptomatic and clinically well. PMID- 29977513 TI - An incredibly dilated Wirsung mimicking a sero-cystic neoplasm of the pancreatic head. AB - A diabetic patient who at a routine abdominal ultrasounds was found to have a very dilated pancreatic duct. Computed tomography (CT) scan diagnosed a sero cystic lesion of the pancreatic head. Gastroduodenoscopy discovered a duodenal hyperemic area, which was sampled. Biopsy demonstrated intramucosal vascular emboli from a neuroendocrine carcinoma positive for Chromogranin A and Somatostatin and negative for Gastrin. Cholangio-magnetic resonance imaging revealed that the sero-cystic lesion found at CT, was being mimicked by the enormously dilated pancreatic duct but suggested the possibility of an intraductal or ampullar neoplasm. Blood and urine tests were not helpful and an octreoscan was negative. The patient underwent surgery. Direct exploration confirmed the severe pancreatic duct dilation and a cephalic lesion requiring a pancreatoduodenectomy. Histology confirmed a neuroendocrine tumor infiltrating the duodenum. We conclude that despite modern sophisticated imaging and endoscopic techniques, the evaluation of bilio-pancreatic region can be challenging and can reserve surgical surprises. PMID- 29977514 TI - Perforation of a mesenteric Meckel's diverticulum. AB - Meckel's diverticulum is a remnant of the embryologic omphalomeseteric duct and is a common congenital anomaly found in ~2% of the population. The clinical significance of this anomaly is that the persistent diverticulum can lead to intestinal obstruction or diverticulitis and may contain ectopic tissue which can lead to bleeding, ulceration or perforation. The classic location of a Meckel's diverticulum has been described ~40 cm from the ileocecal valve on the antimesenteric side of the distal ileum. There have only been a few documented cases of a Meckel's diverticulum found on the mesenteric border of the ileum. In this report, we describe a patient who presented with a perforated Meckel's diverticulum which was found on the mesenteric border and performed a review to determine the significance of this finding. PMID- 29977515 TI - Unusual complication of bladder prolapse with subsequent diagnosis of urothelial carcinoma leading to a necrotizing soft tissue infection after radical cystectomy. AB - There is lack of information in the literature on long-term complications of suprapubic catheters. The most common complications include urinary tract infection, bladder calculi, urine leakage and neoplastic changes. We report a case of an unusual complication of bladder prolapse, with subsequent diagnosis of urothelial carcinoma, leading to a necrotizing soft tissue infection after a radical cystectomy in a patient with long-term catheterization and its management. Due to the rarity of this complication, its management has not been well studied. In this particular case, the logical indication was radical cystectomy due to the presence of bladder necrosis. PMID- 29977516 TI - Superficial femoral artery transection following penetrating trauma. AB - We describe a patient who sustained a penetrating injury to the posterior right lower extremity just above the popliteal region with transection of the superficial femoral artery (SFA) despite minimal evidence of active bleeding. An on-table angiogram identified flow in the SFA followed by the popliteal artery and into the trifurcation of the right lower extremity. Eventually, a second operation revealed transection followed by end-to-end anastomosis of SFA and stabilization of the patient. The findings of this case highlight the need for a high index of suspicion and persistent clinical investigation to identify vascular injuries in the absence of hard signs of vascular trauma. PMID- 29977517 TI - A rare case of giant cell lung carcinoma with intracardiac extension via the pulmonary vein and thrombus formation. AB - A 61-year-old man presented with dyspnea, left thoracic pain and productive cough. Chest computed tomography demonstrated a solid mass of the left upper lobe, 2.9 * 1.8 cm2 in size, which had irregular borders and appeared to infiltrate and totally occlude the upper left pulmonary vein extending up to the left atrium (LA) with thrombus formation. The patient underwent median sternotomy and left pneumonectomy, combined with LA thrombus resection under cardiopulmonary bypass (CPB) with bicaval cannulation. The LA was partially resected and the intracavitary thrombus was completely removed. The surgical margins were free of tumor cells. Episodes of embolism were not observed during surgery. The patient was successfully weaned from CPB. The postoperative course was uncomplicated. Pathological examination of the resected specimen revealed giant cell carcinoma. PMID- 29977518 TI - Rethinking the spectrum of mood disorders: implications for diagnosis and management - Proceedings of a symposium presented at the 30th Annual European College of Neuropsychopharmacology Congress, 4 September 2017, Paris, France. AB - The simultaneous occurrence of manic and depressive features has been recognized since classical times, but the term 'mixed state' was first used by Kraepelin at the end of the 19th century. From the 1980s, until the advent of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), psychiatric disorders were classified using a categorical approach. However, it was recognized that such an approach was too rigid to encompass the range of symptomatology encountered in clinical practice. Therefore, a dimensional approach was adopted in DSM-5, in which affective states are considered to be distributed across a continuum ranging from pure mania to pure depression. In addition, the copresence of symptoms of the opposite pole are captured using a 'with mixed features' specifier, applied when three or more nonoverlapping subthreshold symptoms of the opposite pole are present. Mixed features are common in patients with mood episodes, complicating the course of illness, reducing treatment response and worsening outcomes. However, research in this area is scarce and treatment options are limited. Current evidence indicates that antidepressants should be avoided for the treatment of bipolar mixed states. Evidence for bipolar mixed states supports the use of several second-generation antipsychotics, valproate and electroconvulsive therapy. One randomized controlled trial has demonstrated the efficacy of lurasidone, compared with placebo, in patients with major depressive disorder with mixed features, and there is limited evidence supporting the use of ziprasidone in such patients. Further research is required to determine whether other antipsychotic agents, or additional therapeutic approaches, might also be effective in this setting. PMID- 29977519 TI - Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial. AB - Background: A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice. Methods: The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine. Results: There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40-3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group (p = 0.014), and these were more likely to be cardiac symptoms. Conclusions: Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting. PMID- 29977523 TI - Declarations of conflicts of interest from the editors of the Journal of Global Health. PMID- 29977522 TI - Perioperative corticosteroid administration: a systematic review and descriptive analysis. AB - Background: Perioperative administration of corticosteroid is common and variable. Guidelines for perioperative corticosteroid administration before non cardiac non-transplant surgery in patients with current or previous corticosteroid use to reduce the risk of adrenal insufficiency are lacking. Perioperative use of corticosteroid may be associated with serious adverse events, namely hyperglycemia, infection, and poor wound healing. Objective: To determine whether perioperative administration of corticosteroids, compared to placebo or no intervention, reduces the incidence of adrenal insufficiency in adult patients undergoing non-cardiac surgery who were or are exposed to corticosteroids. Methods: We searched MEDLINE via Ovid and PubMed, EMBASE via Ovid, and the Cochrane Central Register of Controlled Trials, all from 1995 to January 2017. Selection criteria: We included randomized controlled trials (RCTs), cohort studies, case-studies, and systematic reviews involving adults undergoing non-cardiac non-transplant surgery and reporting the incidence of postoperative adrenal insufficiency. Data collection and analysis: Two authors independently assessed studies' quality and extracted data. A descriptive and bias assessment analysis was performed. Results: Two RCTs (total of 37 patients), five cohort studies (total of 462 patients), and four systematic reviews were included. Neither RCT showed a significant difference in the outcome. This result was like that of the five cohort studies. The quality of the evidence was low. Conclusion: The current use of perioperative corticosteroid supplementation to prevent adrenal insufficiency is not supported by evidence. Given the significant studies' limitations, it is not possible to conclude that perioperative administration of corticosteroids, compared to placebo, reduces the incidence of adrenal insufficiency. PMID- 29977520 TI - Psychiatric manifestations in Wilson's disease: possibilities and difficulties for treatment. AB - Wilson's disease (WD) is an inherited metabolic disorder related to disturbances of copper metabolism, and predominantly presents with liver and neuropsychiatric symptoms. In most cases it can be successfully treated with anti-copper agents, and both liver function and neuropsychiatric symptoms typically improve. Treatment guidelines for WD include recommendations for anti-copper treatment as well as for the treatment of liver failure symptoms. Recently, recommendations for treatment of the neurological symptoms of WD have also been proposed. Although most WD patients present with psychiatric symptoms at some stage of the disease, currently there are no guidelines for the treatment of the psychiatric manifestations. Treatment of the psychiatric symptoms of WD is often guided by general psychiatric experience, which typically glosses over the specificity of WD, and can result in severe neurological and/or hepatic complications. Here we review and discuss the possible treatments available for the mood disturbances, psychosis, behavioral and cognitive disorders that can occur in WD, as well as their efficacy. PMID- 29977525 TI - NEWS - AGENCIES. PMID- 29977521 TI - Be good, communicate, and collaborate: a qualitative analysis of stakeholder perspectives on adding a chiropractor to the multidisciplinary rehabilitation team. AB - Background: While chiropractors are integrating into multidisciplinary settings with increasing frequency, the perceptions of medical providers and patients toward adding chiropractors to existing healthcare teams is not well-understood. This study explored the qualities preferred in a chiropractor by key stakeholders in a neurorehabilitation setting. Methods: This qualitative analysis was part of a multi-phase, organizational case study designed to evaluate the planned integration of a chiropractor into a multidisciplinary rehabilitation team. The setting was a 62-bed rehabilitation specialty hospital located in the northeastern United States. Participants included patients, families, community members, and professional staff of the administrative, medical, nursing, and therapy departments. Data collection consisted of audiotaped, individual interviews and profession-specific focus groups guided by a semi-structured interview schedule. Transcripts were imported into a qualitative data analysis program for data analysis. An iterative coding process using thematic content analysis categorized key themes and domains. Results: Sixty participants were interviewed in June 2015, including 48 staff members, 6 patients, 4 family members, and 2 community members. Our analysis generated a conceptual model of The Preferred Chiropractor for Multidisciplinary Rehabilitation Settings composed of 5 domains and 13 themes. The central domain, Patient-Centeredness, or the provision of healthcare that is respectful, responsive, and inclusive of the patient's values, preferences, and needs, was mentioned in all interviews and linked to all other themes. The Professional Qualities domain highlighted clinical acumen, efficacious treatment, and being a safe practitioner. Interpersonal Qualities encouraged chiropractors to offer patients their comforting patience, familiar connections, and emotional intelligence. Interprofessional Qualities emphasized teamwork, resourcefulness, and openness to feedback as characteristics to enhance the chiropractor's ability to work within an interdisciplinary setting. Organizational Qualities, including personality fit, institutional compliance, and mission alignment were important attributes for working in a specific healthcare organization. Conclusions: Our findings provide an expanded view of the qualities that chiropractors might bring to multidisciplinary healthcare settings. Rather than labeling stakeholder perceptions as good, bad or indifferent as in previous studies, these results highlight specific attributes chiropractors might cultivate to enhance the patient outcomes and the experience of healthcare, influence clinical decision making and interprofessional teamwork, and impact healthcare organizations. PMID- 29977524 TI - NEWS - REGIONS. PMID- 29977526 TI - NEWS - RESOURCES. PMID- 29977527 TI - Calling for the next WHO Global Health Initiative: the use of disruptive innovation to meet the health care needs of displaced populations. PMID- 29977528 TI - Caution needed to avoid empty scale-up of Kangaroo Mother Care in low-income settings. PMID- 29977529 TI - Examining horizontal inequity and social determinants of inequality in facility delivery services in three South Asian countries. AB - Background: The utilization of maternal health care services has increased in many developing countries, but persistent wealth-related inequalities in use of maternal services remained an important public health issue. The paper examined the horizontal inequities and identified the key social determinants that can potentially explain such wealth-related inequalities in use of facility delivery services. Methods: The countries studied are Bangladesh, Pakistan and Nepal. We used horizontal inequity index to measure the horizontal inequity and decomposition of concentration index method to assess the contribution of different social determinants towards the wealth-related inequality. We have used household and women data from demographic and health surveys of Bangladesh (BDHS 2014), Pakistan (PDHS 2012-13) and Nepal (NDHS 2010-11). Results: All three countries showed pro-rich inequality in use of facility delivery services (Observed Concentration Index: Bangladesh = 0.235; Pakistan = 0.141; Nepal = 0.263). The study showed if the utilization were solely based on need factors there would have been little disparity between the rich and the poor (Need expected Concentration Index: Bangladesh = 0.004; Pakistan = 0.004; Nepal = 0.008). The use of facility delivery remained pro-rich in all three countries after taking the need factors into account (Horizontal inequity Index: Bangladesh = 0.231; Pakistan = 0.137; Nepal = 0.254). The decomposition analysis revealed that facility delivery is driven mostly by the social determinants of health rather than the individual health risk. Household socioeconomic condition, parental education, place of residence and parity emerged as the most important factors. Conclusions: Our study reiterates the importance of addressing social determinants of health in tackling wealth-related inequalities in use of facility delivery services. Health policy makers should acknowledge the importance of social determinants in determining individual health-seeking behaviour and accordingly set their strategies to improve access to facility delivery. PMID- 29977530 TI - Postnatal home visitation: Lessons from country programs operating at scale. AB - Background: Newborn mortality remains unacceptably high in many countries. Postnatal home visits (PNHVs) have been endorsed as a strategy for delivery of postnatal care (PNC) to reduce newborn mortality as well as to improve maternal outcomes. This paper reports on a review of coverage-related performance of such programs implemented at scale through government health services in Bangladesh, Ethiopia, Ghana, India, Indonesia, Malawi, Myanmar, Nepal, Pakistan, Rwanda, Sri Lanka and Uganda. Methods: We undertook a multi-country, mixed-method program review and used available survey and administrative data and key informant interviews to characterize performance of postnatal home visitation programs. In results presented in this paper, we have relied primarily on population-based surveys, notably Demographic and Health Surveys and Multi-Indicator Cluster Surveys. In addition, based on key informant interviews, we sought to understand the implementation challenges experienced delivering PNHVs, as well as responses to those challenges, in order to provide useful insights to countries to design home visitation programming when they can meet requirements for effective delivery at scale - and to identify other options when they cannot. Results: Contact coverage of PNC within 48 hours of birth following home birth (the group most prioritized in these programs) is below 10% in most of the countries reviewed; in no country does it exceed 20%. Most country programs have been unable to achieve PNHV contact coverage that would have any meaningful impact on newborn or maternal mortality. Country responses to disappointing performance have varied: some continued programming unchanged, some suspended attempts to provide PNHVs, and others modified their strategies for providing postnatal care (PNC). Conclusions: Policymakers and program managers need to consider seriously context and local feasibility when determining whether and how to use a strategy like PNHVs. At the global level, we need more than evidence of effectiveness (as determined through proof-of-concept trials) as a basis for formulating recommendations for how governments should provide services. We must also give serious attention to what can be learned from experience implementing at scale and place greater importance on feasibility of implementation in the real world. PMID- 29977531 TI - Perspectives and implications of the Improving Coverage Measurement Core Group's validation studies for household surveys. AB - Background: Formal validation studies are of critical importance in determining whether or not household survey questions are providing accurate information on what they intend to measure. These studies supplement an array of methods used to evaluate survey questions. Methods and Findings: This paper summarizes the methods used by the two major international household survey programmes - The Demographic and Health Surveys Program (DHS) and the Multiple Indicator Cluster Surveys (MICS) - to decide on possible modifications to the survey questions, nomenclature, tables, and interpretation of findings over time as additional information on the validity of the questions becomes available. Conclusions: Validation studies are most useful if they are conducted in a variety of different settings in low- and middle-income countries, preferably using representative samples and procedures that replicate DHS and MICS field conditions. Pilot tests, pre-tests in each country, feedback from interviewers and survey staff, and cognitive interviewing provide additional information about how well survey questions are understood and provide accurate information. The paper provides specific examples of changes that have been made in response to findings from validation studies and changes in international recommendations. PMID- 29977532 TI - The national and subnational prevalence of cataract and cataract blindness in China: a systematic review and meta-analysis. AB - Background: Cataract is the second leading cause of visual impairment and the first of blindness globally. However, for the most populous country, China, much remains to be understood about the scale of cataract and cataract blindness. We aimed to investigate the prevalence of cataract and cataract blindness in China at both the national and subnational levels, with projections till 2050. Methods: In this systematic review and meta-analysis, China National Knowledge Infrastructure (CNKI), Wanfang, Chinese Biomedicine Literature Database (CBM SinoMed), PubMed, Embase, and Medline were searched using a comprehensive search strategy to identify all relevant articles on the prevalence of cataract or cataract blindness in Chinese population published from January 1990 onwards. We fitted a multilevel mixed-effects meta-regression model to estimate the prevalence of cataract, and a random-effects meta-analysis model to pool the overall prevalence of cataract blindness. The United Nations Population Division (UNPD) data were used to estimate and project the number of people with cataract and cataract blindness from 1990 to 2050. According to different demographic and geographic features in the six geographic regions in China, the national numbers of people with cataract in the years 2000 and 2010 were distributed to each region. Results: In males, the prevalence of any cataract (including post surgical cases) ranged from 6.71% (95% CI = 5.06-8.83) in people aged 45-49 years to 73.01% (95% CI = 65.78-79.2) in elderly aged 85-89 years. In females, the prevalence of any cataract increased from 8.39% (95% CI = 6.36-10.98) in individuals aged 45-49 years to 77.51% (95% CI = 71.00-82.90) in those aged 85-89 years. For age-related cataract (ARC, including post-surgical cases), in males, the prevalence rates ranged from 3.23% (95% CI = 1.51-6.80) in adults aged 45-49 years to 65.78% (95% CI = 46.72-80.82) in those aged 85-89 years. The prevalence of ARC in females was 4.72% (95% CI = 2.22-9.76) in the 45-49 years age group and 74.03% (95% CI = 56.53-86.21) in the 85-89 years age group. The pooled prevalence rate of cataract blindness (including post-surgical cases) by best corrected visual acuity (BCVA)<0.05 among middle-aged and older Chinese was 2.30% (95% CI = 1.72-3.07), and those of cataract blindness by BCVA<0.10 and cataract blindness by presenting visual acuity (PVA)<0.10 were 2.56% (95% CI = 1.94-3.38) and 4.51% (95% CI = 3.53-5.75) respectively. In people aged 45-89 years, the number of any cataract cases was 50.75 million (95% CI = 42.17-60.37) in 1990 and 111.74 million (95% CI = 92.94-132.84) in 2015, and that of ARC rose from 35.77 million (95% CI = 19.81-59.55) in 1990 to 79.04 million (95% CI = 44.14-130.85) in 2015. By 2050, it is projected that the number of people (45-89 years of age) affected by any cataract will be 240.83 million (95% CI = 206.07-277.35), and that of those with ARC will be 187.26 million (95% CI = 113.17-281.23). During 2000 and 2010, South Central China consistently owed the most cases of any cataract, whereas Northwest China the least. Conclusions: The prevalence of cataract and cataract blindness in China was unmasked. In the coming decades, cataract and cataract blindness will continue to be a leading public-health issue in China due to the ageing population. Future work should be prioritized to the promotion of high-quality epidemiological studies on cataract. PMID- 29977533 TI - Whole genome sequencing reveals high clonal diversity of Escherichia coli isolated from patients in a tertiary care hospital in Moshi, Tanzania. AB - Background: Limited information regarding the clonality of circulating E. coli strains in tertiary care hospitals in low and middle-income countries is available. The purpose of this study was to determine the serotypes, antimicrobial resistance and virulence genes. Further, we carried out a phylogenetic tree reconstruction to determine relatedness of E. coli isolated from patients in a tertiary care hospital in Tanzania. Methods: E. coli isolates from inpatients admitted at Kilimanjaro Christian Medical Centre between August 2013 and August 2015 were fully genome-sequenced at KCMC hospital. Sequence analysis was done for identification of resistance genes, Multi-Locus Sequence Typing, serotyping, and virulence genes. Phylogeny reconstruction using CSI Phylogeny was done to ascertain E. coli relatedness. Stata 13 (College Station, Texas 77,845 USA) was used to determine Cohen's kappa coefficient of agreement between the phenotypically tested and whole genome sequence predicted antimicrobial resistance. Results: Out of 38 E. coli isolates, 21 different sequence types (ST) were observed. Eight (21.1%) isolates belonged to ST131; of which 7 (87.5.%) were serotype O25:H4. Ten (18.4%) isolates belonged to ST10 clonal complex; of these, four (40.0%) were ST617 with serotype O89:H10. Twenty eight (73.7%) isolates carried genes encoding beta-lactam resistance enzymes. On average, agreement across all drugs tested was 83.9%. Trimethoprim/sulphamethoxazole (co-trimoxazole) showed moderate agreement: 45.8%, kappa =15% and p = 0.08. Amoxicillin-clavulanate showed strongest agreement: 87.5%, kappa = 74% and p = 0.0001. Twenty-two (57.9%) isolates carried virulence factors for host cells adherence and 25 (65.7%) for factors that promote E. coli immune evasion by increasing survival in serum. The phylogeny analysis showed that ST131 clustering close together whereas ST10 clonal complex had a very clear segregation of the ST617 and a mix of the rest STs. Conclusion: There is a high diversity of E. coli isolated from patients admitted to a tertiary care hospital in Tanzania. This underscores the necessity to routinely screen all bacterial isolates of clinical importance in tertiary health care facilities. WGS use for laboratory-based surveillance can be an effective early warning system for emerging pathogens and resistance mechanisms in LMICs. PMID- 29977534 TI - Thymidylate synthase expression in primary colorectal cancer as a predictive marker for the response to 5-fluorouracil- and oxaliplatin-based preoperative chemotherapy for liver metastases. AB - In patients with colorectal liver metastases (CRLM), predictive markers for response to preoperative chemotherapy are lacking. The aim of the present study was to evaluate the expression of thymidylate synthase (TS) and excision repair cross-complementation group 1 (ERCC1) as predictive markers in CRLM. A total of 24 patients with CRLM were included in this study. Tumor response was evaluated using the tumor regression grade (TRG) and Response Evaluation Criteria in Solid Tumors (RECIST) methods. TS and ERCC1 expression in paired CRLM and primary lesions were assessed by immunohistochemistry. We analyzed correlations between i) the response to preoperative chemotherapy evaluated by TRG and RECIST, ii) TS and ERCC1 expression and the response evaluated by TRG and RESICT, and iii) TS and ERCC1 expression in matched pairs of primary tumor and CRLM. The preoperative chemotherapy response evaluated by TRG and RECIST was significantly associated (P=0.0005). The response based on RECIST criteria and TRG was significantly associated with TS expression in the primary tumor (P=0.0272, and P=0.0137, respectively). No correlations were detected between marker expression in the primary tumor and in CRLM for either TS or ERCC1 (P=0.371 and P=1.00, respectively). Our data suggested that TS expression in the primary tumor is a predictive marker of preoperative chemotherapy response in CRLM based on both TRG and RECIST methods. PMID- 29977535 TI - The relationship between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase, excision repair cross-complementation group 1 and class III beta-tubulin, and the therapeutic effect of S-1 or carboplatin plus paclitaxel in non-small-cell lung cancer. AB - Previous studies have reported that the expressions of specific proteins may predict the efficacy of chemotherapy agents for non-small cell lung cancer (NSCLC) patients. The present study evaluated the expression of proteins hypothesized to be associated with the effect of chemotherapeutic agents in 38 NSCLC patients with pathological stage II and IIIA. The subjects received carboplatin plus paclitaxel (CP) or S-1 as adjuvant chemotherapy following complete resection. The protein expressions evaluated were those of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phsphoribosyltransferase (OPRT), which were suspected to be associated with the effect of S-1 agents, excision repair cross-complementation group 1 (ERCC1), which was suspected to be associated with the effect of platinum-based agents, and class III beta-tubulin (TUBB3), which was suspected to be associated with the effect of taxane-based agents. The positive rate of TS was 55.3% (n=21/38), DPD was 57.9% (n=22/38), OPRT was 42.1% (n=16/38), ERCC1 was 47.4% (n=18/38) and TUBB3 was 44.7% (n=17/38). Among the patients who received S-1 adjuvant chemotherapy, TS-negative cases demonstrated a significantly better disease-free survival than positive cases. Thus, TS protein expression may have been a factor that predicted the effect of S-1 agent as adjuvant chemotherapy. PMID- 29977536 TI - Effective treatment of a platinum-resistant cutaneous squamous cell carcinoma case by EGFR pathway inhibition. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non melanoma skin cancer. Platinum-based regimens have been an integral part of palliative care for patients with locally advanced or metastatic disease. There is no evidence of efficacy for later lines of chemotherapy and no targeted therapy has been introduced as 'standard of care'. Here we report on the case of an elderly cSCC patient, resistant to conventional therapy, however successfully treated with anti-epidermal growth factor receptor (EGFR) agent (Cetuximab) in addition to a daily dose of Curcumin phospholipid. The patient responded to treatment and experienced no recurrence for 11 months with only minor skin related toxicity. To our knowledge, this is the first report of clinical evidence that an anti EGFR targeted therapy with a daily oral dose of Curcumin phospholipid is well tolerated and results in a highly effective disease control in a heavily pretreated cSCC patient. PMID- 29977537 TI - FIP1L1-PDGFRA fusion-negative hypereosinophilic syndrome with uncommon cardiac involvement responding to imatinib treatment: A case report. AB - Hypereosinophilic syndrome is a rare, chronic hematological disease characterized by a persistently elevated eosinophil count exceeding 1.5*109/l, following the exclusion of other potential etiologies. The systemic involvement of the disease causes tissue damage through eosinophil infiltration, and may affect various organs; cardiac complications are observed in 50-60% of cases, which are predominately attributed to endomyocardial fibrosis. The treatment is based initially on determining the presence of the FIP1L1-PDGFRA fusion. Patients with positive results for this mutation tend to achieve a complete response with imatinib treatment, which is thus the first line of treatment for this condition. However, patients who are negative for this mutation initially undergo treatment with corticosteroids. This study reports the case of a male 53-year-old patient diagnosed with hypereosinophilic syndrome in 2012, with negative results for the FIP1L1-PDGFRA mutation, and persistently high eosinophil levels, despite receiving the second line of standard treatment for this condition with hydroxyurea, and having already used corticosteroids without success. At the time of admission, the patient presented with acute decompensated heart failure due to severe mitral regurgitation, without any evidence of prior myocardial fibrosis or restrictive cardiomyopathy, and without suggestion of an associated ventricular hypertrophy. This clinical presentation is uncommon, as valvular involvement usually appears in the third stage of the development of cardiac involvement, and is usually associated with fibrosis and thrombotic events. Alternative therapeutic possibilities were evaluated due to the significant progression of the disease, and it was decided to attempt the use of imatinib, despite its use being preferably recommended for FIPIL1-PDGFRA-positive patients. The patient exhibited an evident and immediate response to imatinib, with normalization of the eosinophil count within 24 h of the first dose, which was maintained for at least the next 19 months. This clinical presentation is uncommon, as patients negative for FIPIL1-PDGFRA fusion do not frequently respond to imatinib treatment, and symptomatic heart failure usually appears in the third stage of disease progression. PMID- 29977538 TI - Gliomatosis peritonei with 18F-fluorodeoxyglucose accumulation and contrast enhancement secondary to immature teratoma: A case report. AB - Gliomatosis peritonei (GP) is a rare condition characterized by mature glial tissue implants widespread in the peritoneum, which is occasionally followed by treatment for immature teratoma (IM). The present study reported a case of GP with fluorodeoxyglucose (FDG) accumulation and contrast enhancement followed by treatment for IM. A 30-year-old female, 2-gravida and 0-para, underwent laparotomy with hysterectomy, bilateral salpingo-oophorectomy, and partial omentectomy followed by four cycles of chemotherapy with bleomycin, etoposide, and cisplatin for IM (Grade 2) of stage IIIC. At the 6-month follow-up, computed tomography (CT) revealed a 1-cm mass with contrast enhancement on splenic flexure. Positron-emission tomography (PET)/CT revealed intense FDG accumulation at the same site. Although alpha-fetoprotein, which was elevated preoperatively, remained normal, she was diagnosed with IM recurrence. The patient underwent three cycles of chemotherapy with paclitaxel, ifosfamide, and cisplatin, but the size, the degree of contrast enhancement and FDG accumulation of the mass did not change after chemotherapy. A diagnostic laparoscopy was performed. which revealed multiple small peritoneal implants, including a 1-cm mass at the splenic flexure. The 1-cm mass was dissected at the splenic flexure and some other implants. Mature well-differentiated glial tissue with non-atypia was identified in all tissue, and a diagnosis of GP was made. The patient is currently undergoing regular follow-up. Few reports are available regarding FDG-PET/CT imaging of GP. GP should be considered as the differential diagnosis of FDG-avid mass followed by IM therapy. A laparoscopic diagnosis is useful to obtain an accurate diagnosis of GP. PMID- 29977539 TI - Histiocytic sarcoma of the neck: A case report. AB - Histiocytic sarcoma (HS) is a term used to describe malignant hyperplasia of cells exhibiting morphological and immunophenotypical characteristics similar to those of mature cells, with expression of one or more tissue cell markers, excluding acute monocytic leukemia and primitive monocytic sarcoma. We herein describe a case of histiocytic sarcoma of the neck supported by histopathological and immunohistological evidence. A 53-year-old female patient of Chinese descent presented with a rapidly enlarging right neck mass. Imaging studies revealed multiple right cervical lymphadenectases with right jugular vein involvement. The tumor was composed of diffusely distributed large non-cohesive tumor cells, round or oval and focally spindle-shaped. The tumor cells were immunopositive for macrophage-associated antigen CD68 and lysosomes, mostly consistent with a diagnosis of HS. HS is very prone to systemic metastasis; therefore, early diagnosis and timely treatment are crucial. PMID- 29977540 TI - Implementation of cell-free tumor DNA sequencing from the cerebrospinal fluid to guide treatment in a patient with primary leptomeningeal melanoma: A case report. AB - Primary leptomeningeal melanoma (PLM) is a rare type of cancer that represents a major clinical and molecular diagnostic challenge. A definitive diagnosis requires consistent magnetic resonance imaging findings and cerebrospinal fluid (CSF) cytology. Due to the small number of malignant cells in the CSF, routine testing for mutations in the BRAF gene is difficult, which prevents the stratification of these patients to potentially beneficial therapies. We herein present the case of a 62-year old man with CSF cytology indicating PLM, where BRAF mutation testing, from cell-free (cf) tumor DNA isolated from the CSF and plasma was implemented to guide clinical decision making. Testing for BRAFV600E mutation from the CSF and plasma was technically feasible, yielded concordant results, and guided the treatment for this patient. This case suggests that mutation testing of cfDNA isolated from the CSF is technically feasible and may guide therapy in cases where a tissue diagnosis is not possible for PLM and other malignancies with defined oncogenic driver mutations. PMID- 29977541 TI - Quality of life and efficacy of temozolomide combined with whole-brain radiotherapy in patients with brain metastases from non-small-cell lung cancer. AB - The aim of the present study was to investigate the efficacy and life quality of temozolomide (TMZ) combined with whole-brain radiotherapy (WBRT) for patients with brain metastases (BM) from non-small-cell lung cancer (NSCLC). A total of 77 cases of patients with lung cancer and BM were selected and divided into two groups; the first group was administered WBRT with TMZ, and the second group was administered WBRT with placebo. The efficacy, overall survival (OS) and quality of life (QoL) were then compared between the two groups. There were no significant differences in toxicity between the two groups. However, the first group exhibited an advantage over the second group in terms of objective response and OS (P<0.5). Therefore, WBRT may improve the QoL of patients with BM. TMZ concomitantly with WBRT was well-tolerated and may be recommended for the treatment of BM from NSCLC. PMID- 29977542 TI - Expression and clinical significance of programmed death ligand 1 in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) has the highest incidence of all types of head and neck cancer in China. The present study aimed to investigate the association between the expression of programmed death ligand 1 (PD-L1) in NPC tissues and clinicopathological features, as well the outcomes for NPC patients. In addition, the association between tissue expression of PD-L1 and immune components in peripheral blood was assessed. The expression of PD-L1 was determined by immunohistochemistry, while immune indexes were determined by ELISA and flow cytometry. The positive expression rate of PD-L1 in NPC patients was 29.2%, and the PD-L1 expression levels were associated with distant metastasis (P=0.010) and the T-stage of the primary tumor (P=0.032). The expression of PD-L1 was associated with the distant metastasis-free survival of NPC patients (P=0.006). In addition, a statistically significant association of PD-L1 expression with Epstein-Barr virus viral capsid antigen IgA (EBV VCA-IgA; P=0.046) and with CD3 CD19+ cells (P=0.014) was identified. These results indicated that PD-L1 may be a potential prognostic biomarker for NPC patients, and that EBV VCA-IgA and CD3 CD19+ cells may be useful for predicting PD-L1 expression when its levels cannot be detected due to the lack of a tumor tissue sample. PMID- 29977544 TI - Atypical diffuse bilateral cystic lung changes secondary to erlotinib treatment in a patient with metastatic non-small cell lung carcinoma: A case report and literature review. AB - Erlotinib is a first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved in the first-line treatment of advanced non-small cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations. The response rate to erlotinib is ~60% and the incidence of erlotinib-induced interstitial lung disease (ILD) is ~1-4%. The Response Evaluation Criteria in Solid Tumours (RECIST) tool is commonly used to assess response to erlotinib; however, evaluation of response and subsequent progression in the presence of atypical cystic lung changes may be challenging. We herein present a rare case of diffuse cystic lung changes secondary to erlotinib treatment in a patient with EGFR mutation-positive metastatic NSCLC. Challenges in assessing atypical tumour response to erlotinib, pitfalls in using RECIST and differential diagnosis of TKI-related ILD are discussed in detail. PMID- 29977543 TI - Malignant psoas syndrome associated with gynecological malignancy: Three case reports and a review of the literature. AB - Malignant psoas syndrome (MPS) is a rare and unique cancer-associated syndrome caused by the malignant involvement of the psoas major muscle, and is characterized by ipsilateral lumbosacral plexopathy and painful hip flexion. The pain in MPS is often distressing and intractable, and there is no established effective treatment approach. Herein, the present study reports on three cases of MPS associated with gynecological malignancies, wherein symptom improvement was observed following chemotherapy or radiotherapy. Among 39 cases documented in the literature, female genital tract malignancies were the most frequent causes of MPS; however, the condition may be under-diagnosed, owing to the lack of general recognition. Considering the development of recent high-precision radiation therapy, palliative radiotherapy may serve an important role in the management of MPS. For physicians treating gynecological cancers, early detection of MPS is clinically important as this may allow patients to receive possible therapies and improve their quality of life in end-stage cancer. Further prospective studies should be performed to evaluate effective therapeutic approaches for MPS. PMID- 29977545 TI - Fibrous dysplasia of bone: Surgical management options and outcomes of 22 cases. AB - The surgical treatment for fibrous dysplasia (FD) of bone is problematic due to its variable clinical courses. And multifarious surgical treatment options have been reported while no consistent view can be reached. Therefore, we reviewed a series of 22 patients (11 males and 11 females; mean age 28.4 years, range 15-48 years) with FD between December 2011 and July 2015. Fourteen patients had monostotic fibrous dysplasia (MFD) and eight patients had polyostotic fibrous dysplasia (PFD) with nine lesions. All patients were followed up from 15 to 58 months with an average of 26.0 months. Functional and radiographic outcomes were recorded. In the MFD group, four patients were treated with curettage and bone grafting without internal fixation and nine were treated with curettage and bone grafting with internal fixations. Osteotomy and intramedullary (IM) nail was applied in one patient with serious deformity. In the PFD group, three deformity lesions were treated with osteotomy and proximal femoral nail anti-rotation (PFNA). IM were also applied in six large lesions to treat fracture or prevent deformity. One lesion in tibia were treated with only curettage and bone graft. No complication was observed in MFD group and satisfactory union and functional outcomes acquired during follow-up period. In the PFD group, the spiral blade cutting out from femoral head in PFNA was observed in one patient and treated with revision surgery. No other complication occurred, and satisfactory radiological and functional outcome were observed. The severity of both MFD and PFD are related to size, site and of the lesion. The goal of the surgery is to eliminate pain, correct deformity and treat pathological fracture. Curettage, bone grafting with internal fixation is recommended for treating large lesions with deformity or high pathological fracture risk. PFNA or IM nail is prior in osteotomy with better clinical outcome. PMID- 29977546 TI - Surgical outcome of extended liver resections for colorectal liver metastasis compared with standard liver resections. AB - Colorectal liver metastatic lesions sometimes invade adjacent organs. A hepatectomy is often extended to include the involved adjacent organ to achieve negative surgical margins. The purpose of the present retrospective study was to evaluate the surgical outcomes of extended liver resections and patients' prognoses. The medical records of 178 patients with colorectal liver metastasis who underwent liver resections in the Department of Gastroenterological Surgery at Osaka University Hospital (Suita, Japan), from 2000 to 2015 were reviewed. These patients were divided into two groups: the extended resection group (n=20) and the non-extended resection group (n=158). The disease-free and overall survival curves were estimated with the Kaplan-Meier method and analyzed with the log rank test. It was observed that the extended resection group had longer operation times and increased blood loss, however perioperative morbidity was similar. The organs resected most frequently were the diaphragm (n=10) and inferior vena cava (n=5). Overall survival rates in the extended resection group were lower compared with the non-extended resection group (5-year survival rates; 45.0 vs. 67.9%), however the difference was not significant. It was indicated that the aggressive hepatectomy combined with resection of adjacent organs was an acceptable treatment with low perioperative morbidity. The overall survival rate may not be inferior to that of simple hepatectomy. PMID- 29977547 TI - The clinical application of tumor markers in the screening of malignancies and interstitial lung disease of dermatomyositis/polymyositis patients: A retrospective study. AB - Objective: To examine the clinical utility of tumor markers in dermatomyositis/polymyositis patients in Taiwan. Method: Data were collected retrospectively from the database of Taichung Veterans General Hospital in Taiwan from 1998 to 2014. Patients who fulfilled Bohan and Peter criteria of dermatomyositis/polymyositis were recruited. Serum level of tumor markers including carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 125, carbohydrate antigen 19-9 and carbohydrate antigen 15-3 were measured. The occurrence of malignancies and interstitial lung disease was identified. The association of tumor markers with malignancies and interstitial lung disease was examined using Chi-square test or Fisher's exact test. Results: Among the enrolled 151 patients, 98 (64.9%) dermatomyositis and 53 (35.1%) polymyositis, a total of 15 malignancies were detected: breast ductal carcinoma (n = 4), bladder transitional cell carcinoma (n = 2), lung adenocarcinoma (n = 2), cervical intraepithelial neoplasia 3 and papillary squamous cell carcinoma (n = 2), colorectal (colon and rectal adenocarcinoma) (n = 2), uterine adenocarcinoma (n = 1), nasopharyngeal carcinoma (n = 1) and hematological malignancy (myelodysplastic with excess blast cells) (n = 1). Among the patients with malignancies, 13 (86.7%) had dermatomyositis, 2 (13.3%) polymyositis and 3 (20%) interstitial lung disease. The mean duration from dermatomyositis/polymyositis diagnosis to the occurrence of malignancies was 6.05 +/- 5.69 years. There was no significant association of raised tumor markers with the occurrence of malignancies (p > 0.085), while a significant association was observed between the elevated levels of carbohydrate antigen 15-3 and the presence of interstitial lung disease (p = 0.006). Conclusion: Tumor markers were not useful in malignancy screening or dermatomyositis/polymyositis patients in this tertiary center. The evaluation of the occurrence of malignancy in dermatomyositis/polymyositis patient should include a multidimensional approach. A raised level of carbohydrate antigen 15-3 may be a potential indicator of the presence of interstitial lung disease in dermatomyositis/polymyositis patients. PMID- 29977549 TI - No effects of mitomycin-C in primary trabeculectomies in Sweden. AB - Aim: To evaluate the results of a long-term follow-up after two different types of surgical techniques: trabeculectomy with or without mitomycin-C. Materials and methods: This study is a retrospective chart review of patients operated on with a primary trabeculectomy at the Eye Department of the Skaraborg Hospital, Skovde, Sweden. Complete success was defined as intraocular pressure ?18 mmHg (criterion 1) or intraocular pressure reduction ?30% (criterion 2) without eye drops postoperatively. Qualified success was defined using the same criteria (1 and 2), but patients were treated or untreated with eye-drops. Results: A total of 167 patients were included in this retrospective study, 83 patients in the no mitomycin-C group and 84 patients in the mitomycin-C-treated group. No significant difference was found in intraocular pressure reduction between the mitomycin-C and no-mitomycin-C group (t-test; p = 0.19). Complete success using criterion 1 was 66.2% in no-mitomycin-C and 62.8% in mitomycin-C (p = 0.88); success using criterion 2 was 76.6% in the no-mitomycin-C and 64.2% in the mitomycin-C group (p = 0.21). Qualified success using criterion 1 was 71.4% in the no-mitomycin-C and 74.4% in the mitomycin-C group (p = 0.84); success using criterion 2 was 80.0% in the no-mitomycin-C and 84.4% in the mitomycin-C group. All included patients were born in Sweden. Conclusion: Mitomycin-C seems to add no benefits to intraocular pressure reduction after primary trabeculectomies in a Swedish population. PMID- 29977548 TI - What matters in patient-centered medical home transformation: Whole system evaluation outcomes of the Brown Primary Care Transformation Initiative. AB - Objectives: Patient-centered medical home transformation initiatives for enhancing team-based, patient-centered primary care are widespread in the United States. However, there remain large gaps in our understanding of these efforts. This article reports findings from a contextual, whole system evaluation study of a transformation intervention at eight primary care teaching practice sites in Rhode Island. It provides a picture of system changes from the perspective of providers, staff, and patients in these practices. Methods: Quantitative/qualitative evaluation methods include patient, provider, and staff surveys and qualitative interviews; practice observations; and focus groups with the intervention facilitation team. Results: Patient satisfaction in the practices was high. Patients could describe observable elements of patient centered medical home functioning, but they lacked explicit awareness of the patient-centered medical home model, and their activation decreased over time. Providers' and staff's emotional exhaustion and depersonalization increased slightly over the course of the intervention from baseline to follow-up, and personal accomplishment decreased slightly. Providers and staff expressed appreciation for the patient-centered medical home as an ideal model, variously implemented some important patient-centered medical home components, increased their understanding of patient-centered medical home as more than specific isolated parts, and recognized their evolving work roles in the medical home. However, frustration with implementation barriers and the added work burden they associated with patient-centered medical home persisted. Conclusion: Patient centered medical home transformation is disruptive to practices, requiring enduring commitment of leadership and personnel at every level, yet the model continues to hold out promise for improved delivery of patient-centered primary care. PMID- 29977550 TI - Emerging themes in coping with lifetime stress and implication for stress management education. AB - Background: Adults with adverse childhood experiences and exposure to adverse life events experience a diverse array of physical, mental, and social health problems across their lifespan. Adult exposure to emotional trauma, physical injury, or other adverse life events may result in the development of post traumatic stress and post-traumatic stress disorder. Understanding individuals' response to stress and their coping strategies is as important as the stimulus or the causes of the stress for effective stress management interventions. Methods: This is a mixed quantitative and qualitative online survey study which explores the coping strategies to stress in adults with adverse childhood experiences and exposure to adverse life events through analysis of emerging themes from survey questionnaire responses of study participants. Results: Participants who respond to stress through adaptive coping focused either on problem-solving, 17.6% (32 out of 188), or on emotion-focused coping, 45.2% (85 out of 188). Participants engaged in problem-solving mainly through therapy such as counseling and other professional stress management, whereas those who chose emotion-focused coping used diverse strategies including practicing mindfulness, meditation, and yoga; using humor and jokes; seeking higher power or religious pursuits; engaging in physical or breathing exercises; and seeking social support. Participants who practiced maladaptive coping styles constituted 37.2% (70 out of 188) of respondents and resorted to avoidance of the stressful condition, withdrawal from a stressful environment, disengagement from stressful relationships, and use and abuse of drugs and/or alcohol. Conclusion: An understanding of emerging themes in coping strategies calls for collaborative and multidisciplinary approaches in the design, implementation, and execution of health education and promotion programs tailored to meet the diverse needs of priority populations. Stress management educators need to take into account the vulnerabilities of individuals who resort to maladaptive coping and institute evidence-based behavioral and social service intervention strategies, including life skills training, to prevent the consequences of maladaptive coping and to enhance the self-efficacy of individuals to cope more effectively with stress and stressful life events. PMID- 29977551 TI - Do primary care providers who prescribe more opioids have higher patient panel satisfaction scores? AB - Objectives: Opioid prescribing in the United States has tripled since 1999. At the same time, there has been increasing attention to patient satisfaction. It has been suggested that providers concerned about patient satisfaction may be more likely to treat pain with opioids. We examined primary care providers' opioid prescribing practices to determine if higher provider opioid prescribing was associated with higher patient satisfaction. Methods: For 77 primary care providers, we compared each provider's opioid prescription count and amount prescribed to each provider's patient panel satisfaction measures. Satisfaction measures were obtained from surveys following office visits and consisted of Likert-type scale answers concerning satisfaction for pain management and other provider satisfaction domains. Satisfaction surveys were generated independent of patient complaint of pain and had the aim of overall assessment of patient satisfaction with the provider and the healthcare system. We assessed the correlation between opioid prescribing and patient panel pain management satisfaction using linear regression models with and without adjustment for patient complexity. Results: We observed no statistically significant correlation between patient panel satisfaction with their provider and the quantity of opioids that the provider prescribed (R2 = 0.006; p = 0.52). There was also no correlation between patient panel satisfaction and the number of opioid prescriptions written by their provider (R2 = 0.005; p = 0.54). Additional multivariate analysis after adjusting for patient complexity also demonstrated no correlation of pain management satisfaction with opioids prescribed. Although the quantity of opioid prescriptions was not correlated with pain management satisfaction, several other patient satisfaction measures correlated significantly with pain management satisfaction. Conclusion: Primary care providers with a greater rate of opioid prescribing did not have higher patient panel satisfaction scores for pain management. In primary care, providers who want to improve patient satisfaction should focus on other components of patient care besides opioid-based pain management. PMID- 29977552 TI - Modulation of endoplasmic reticulum stress and the unfolded protein response in cancerous and noncancerous cells. AB - Objectives: The bio-field array is a device that generates a dielectrophoretic electromagnetic field when placed in a hypotonic saline solution and a direct current of approximately 3 A is applied. It is known that cell physiology is guided by bioelectrical properties, and there is a significant growth inhibition in cancerous (MDA-MB-231) cells that are grown in media that has been reconstituted with the saline that has been exposed to the bio-field array direct current dielectrophoretic electromagnetic field, alternatively there is no growth inhibition noted in noncancerous cells (MCF-10A) when grown in the bio-field array direct current dielectrophoretic electromagnetic field treated versus control media. Methods: To examine the basis for selective growth inhibition in human breast carcinoma, we employed cell death assays, cell cycle assays, microarray analysis and reverse transcription-quantitative polymerase chain reaction. Results: We found a large transcriptional reprogramming in the cell lines and of the genes affected, those involved in endoplasmic reticulum stress and the unfolded protein response pathways showed some of the most dramatic changes. Cancerous cells grown in media that has been reconstituted with a hypotonic saline solution that has been exposed to the bio-field array direct current dielectrophoretic electromagnetic field show a significant and strong upregulation of the apoptotic arms of the unfolded protein response while the noncancerous cells show a decrease in endoplasmic reticulum stress via microarray analyses and reverse transcription-quantitative polymerase chain reaction. Conclusion: The bio-field array shows potential to initiate apoptosis in cancerous cells while relieving cell stress in noncancerous cells in vitro. These studies lay a foundation for nurses to conduct future in vivo models for the possible development of future adjunct treatments in chronic disease. PMID- 29977553 TI - Racial/ethnic differences in HIV testing: An application of the health services utilization model. AB - This study applying the health services utilization model examined the importance of predisposing, enabling, and need variables to the social mechanisms explaining lifetime HIV testing across racial/ethnic groups. Data for the study were derived from the National Health Interview Survey (collected 2013-2014), our final sample numbering 18,574 adults. Four subsamples reflected race/ethnicity: 13,347 Whites, 2267 Blacks, 2074 Hispanics, and 886 Asians. Logistic regression established respondent odds of ever having received HIV testing. Further statistical testing evaluated race/ethnicity's potential moderating role in HIV testing. The findings generally support a role for Aday's predisposing, enabling, and need factors in explaining HIV testing. Across the four subsamples, female gender, older age, and sexual minority status consistently increased lifetime HIV testing. However, we found racial/ethnic differences in HIV testing's associations with these factors and others. Our study made a beginning in the effort to specify mechanisms leading to HIV testing-and reliable diagnosis-among four racial/ethnic groups. Understanding these mechanisms might multiply opportunities to raise testing rates for all, in turn reducing racial/ethnic disparities in HIV treatment. PMID- 29977554 TI - Cerebral small vessel disease in Indonesia: Lacunar infarction study from Indonesian Stroke Registry 2012-2014. AB - Background and Purpose: Stroke is the number one cause of morbidity and mortality in Indonesia. Lacunar infarction is one of cerebral small vessel disease spectrum. This study aimed to present stroke epidemiology in Indonesia and risk factors associated with cerebral small vessel disease. Methods: A multicenter prospective cross-sectional study of 18 hospitals in Indonesia was conducted using Stroke Case Report Form from 2012 to 2014. Stroke was diagnosed based on clinical findings confirmed with non-contrast computed tomography of the brain. Subjects were classified into two large groups: ischemic (lacunar and non lacunar) and hemorrhagic (intracranial and subarachnoid hemorrhage). Other risk factors were assessed on admission. Results: We enrolled 5411 patients, of whom 3627 (67.03%) had ischemic stroke and 1784 (32.97%) had hemorrhagic stroke. Male patients were prevalent in both large groups, although found less in subarachnoid hemorrhage group. Among patients with hemorrhagic stroke, 1603 (89.54%) of them had intracerebral hemorrhage and 181 (10.46%) had subarachnoid hemorrhage. From 3627 ischemic stroke patients, 1635 (45.07%) of them had lacunar infarction. We found that age above 55 years old, male gender, hypertension, dyslipidemia, and diabetes were important risk factors associated with lacunar stroke (p < 0.05). Conclusion: Ischemic stroke was the leading cause of stroke in Indonesia. In total, 45% of the total ischemic stroke patients had lacunar infarction. Important risk factors associated with lacunar infarction were hypertension, dyslipidemia, diabetes, age over 55, and male population. PMID- 29977555 TI - Outcome following open and endovascular intervention for carotid stump syndrome. AB - Carotid stump syndrome is defined as the persistence of retinal or cerebral ischaemic events with complete occlusion of the ipsilateral internal carotid artery. The aim of this retrospective cases series was to assess the outcomes for patients with carotid stump syndrome managed with surgical intervention. A series of 11 cases of carotid stump syndrome in nine patients presented to our tertiary vascular centre from October 2004 to February 2016. Indications for intervention were amaurosis fugax, transient ischaemic attacks and stroke. In total, 11 procedures were performed on nine patients including carotid angioplasty and stenting or carotid endarterectomy with patching. The mean follow-up period was 56.6 months. One patient suffered a myocardial infarction 30 days, post operatively, and one patient was lost to follow-up. In the remaining seven patients, there was a complete resolution of symptoms. There were no incidents of death, stroke, cranial nerve injury, wound haematoma or procedural bleeding. Surgical exclusion of carotid stumps combined with dual antiplatelet agents was found to be a safe and effective treatment method for carotid stump syndrome. PMID- 29977556 TI - An uncommon source for oesophageal foreign body: Fidget spinner. AB - Fidget spinner is a new handheld toy with potential choking and ingestion hazard. Our objectives are to describe clinical presentation of a child with fidget spinner ingestion and draw attention to danger associated with fidget spinner. A 3-year-old boy presented with painful swallowing and feeling of something stuck in the throat. A chest radiograph revealed a radiopaque foreign body with a disc like component. Rigid oesophagoscopy revealed a foreign object with disc battery and battery holder circuit board. Clinicians should consider the fidget spinner as one of many varieties of toys that has potential for button battery ingestion or aspiration. PMID- 29977557 TI - Magnetic resonance imaging findings of high-grade ductal carcinoma in situ of the male breast: A case report. AB - Ductal carcinoma in situ in men is incredibly rare and detection by conventional mammography and ultrasound is often challenging. We report an unusual case of a 50-year-old male, with no family history of breast cancer, who presented with an 8-year history of left-sided breast pain and recurrent bloody nipple discharge without any significant suspicious imaging features in mammography and targeted high-resolution ultrasound. Breast magnetic resonance imaging was performed as an adjunct modality. Magnetic resonance imaging findings revealed a suspicious retroareolar non-mass abnormality of segmental, linear and dendritic pattern, which was highly suspicious for a ductal carcinoma in situ. Stereotactic guided biopsy and subsequent mastectomy were consistent with pure high-grade ductal carcinoma in situ of the left breast. Overall, this case highlights the challenges in diagnosing ductal carcinoma in situ in men and demonstrates the importance for further investigating clinical suspicions of the male breast. PMID- 29977558 TI - Clostridium difficile colitis complicating Kawasaki disease in children: Two case reports. AB - Clostridium difficile infection is increasingly diagnosed in children with a wide clinical spectrum ranging from asymptomatic carriage to fulminant colitis. Symptomatic patients typically present with diarrhea, with or without blood, fever, and abdominal pain. Kawasaki disease, a vasculitis of unknown etiology, occurs primarily in young children. Establishing the diagnosis of Kawasaki disease can be challenging given the lack of a confirmatory diagnostic test or pathognomonic features as well as the appearance of symptoms over time rather than simultaneously. In addition, commonly occurring nonspecific associated symptoms, such as diarrhea and abdominal pain, may confound the clinical presentation. We present two cases of children with Kawasaki disease presenting with fever and Clostridium difficile colitis to illustrate the importance of keeping a high index of suspicion for Kawasaki disease. PMID- 29977559 TI - Pyoderma gangrenosum-like ulceration of the lower extremity secondary to sunitinib therapy: a case report. AB - Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used for the treatment of multiple different types of malignancies. Serious grade 3-4 adverse events occur in <10% of the patient population and usually improve with dose reduction. One of the more rarely reported side effects of sunitinib therapy is the development of pyoderma gangrenosum-like ulcerations in the lower extremities. These pyoderma gangrenosum-like ulcerations are difficult to treat and distinguish from similar-appearing dermatological diagnoses. We present a patient with refractory lung carcinoma and a past medical history of squamous cell carcinoma of the lower extremity, who developed a non-healing ulceration at the previous site of her skin cancer while undergoing therapy with sunitinib. At the time of the initial evaluation, the ulceration mimicked recurrent squamous cell carcinoma, posing a diagnostic challenge. Histopathological findings showed epidermal hyperplasia, ulceration, and dense acute inflammation. Despite meticulous wound care and treatment of infection, the ulcer only improved with cessation of sunitinib. PMID- 29977560 TI - Second-degree Atrioventricular Block: Conceptions and Misconceptions. PMID- 29977561 TI - Lingering effects of contraception management on feral mare (Equus caballus) fertility and social behavior. AB - Due to the extirpation of their natural predators, feral horse populations have expanded across the United States, necessitating their management. Contraception of females (mares) with porcine zona pellucida (PZP) is a popular option; however, effects to physiology and behavior can be substantial. On Shackleford Banks, North Carolina, USA, treated mares have exhibited cycling during the non breeding season and demonstrated decreased fidelity to the band stallion, but PZP's long-term effects on mare physiology and behavior remain largely unexplored. After the contraception program was suspended in this population, we examined how prior exposure to varying levels of PZP treatment impacted (1) foaling probability and foaling dates (a proxy for ovulatory cycling) from 2009 to 2014 and (2) mare fidelity to the band stallion and reproductive behavior during 2013 and 2015. Additionally, we evaluated the effects of time since the mares' last treatment on these factors. Mares receiving any level of prior PZP treatment were less likely to foal than were untreated mares. Among mares that received 1-3 PZP applications, foaling probability increased with time since last treatment before declining, at ~6 years post-treatment. Mares that received 4+ applications did not exhibit a significant increase in foaling probability with time since last treatment. Moreover, previously treated mares continued to conceive later than did untreated mares. Finally, mares previously receiving 4+ treatments changed groups more often than did untreated mares, though reproductive behavior did not differ with contraception history. Our results suggest that although PZP-induced subfertility and its associated behavioral effects can persist after the cessation of treatment, these effects can be ameliorated for some factors with less intense treatment. Careful consideration to the frequency of PZP treatment is important to maintaining more naturally functioning populations; the ability to manage populations adaptively may be compromised if females are kept subfertile for extended periods of time. PMID- 29977562 TI - Corrigendum to: Condition index monitoring supports conservation priorities for the protection of threatened grass-finch populations. AB - [This corrects the article DOI: 10.1093/conphys/cov025.][This corrects the article DOI: 10.1093/conphys/cov025.]. PMID- 29977563 TI - Evolution of plasticity in the city: urban acorn ants can better tolerate more rapid increases in environmental temperature. AB - Because cities contain high levels of impervious surfaces and diminished buffering effects of vegetation cover, urbanized environments can warm faster over the day and exhibit more rapid warming over space due to greater thermal heterogeneity in these environments. Whether organismal physiologies can adapt to these more rapid spatio-temporal changes in temperature rise within cities is unknown, and exploring these responses can inform not only how plastic and evolutionary mechanisms shape organismal physiologies, but also the potential for organisms to cope with urban development. Here, we examined how plasticity in thermal tolerance under faster and slower rates of temperature change might evolve in response to the more rapid spatio-temporal temperature rise in cities. We focused on acorn ants, a temperature-sensitive, ground-dwelling ant species that makes its home inside hollowed out acorns. We reared acorn ant colonies from urban and rural populations under a common garden design in the laboratory and assessed the thermal tolerances of F1 offspring workers using both fast (1 degrees C min-1) and slow (0.2 degrees C min-1) rates of temperature change. Relative to the rural population, the urban population exhibited higher heat tolerance when the temperature was increased quickly, providing evidence that temperature ramp-rate plasticity evolved in the urban population. This result was correlated with both faster rates of diurnal warming in urban acorn ant nest sites and greater spatial heterogeneity in environmental temperature across urban foraging areas. By contrast, rates of diurnal cooling in acorn ant nest sites were similar across urban and rural habitats, and correspondingly, we found that urban and rural populations responded similarly to variation in the rate of temperature decrease when we assessed cold tolerance. Our study highlights the importance of considering not only evolutionary differentiation in trait means across urbanization gradients, but also how trait plasticity might or might not evolve. PMID- 29977564 TI - Behavioural guidance of Chinook salmon smolts: the variable effects of LED spectral wavelength and strobing frequency. AB - Exploiting species-specific behavioural responses of fish to light is an increasingly promising technique to reduce the entrainment or impingement of fish that results from the diversion of water for human activities, such as hydropower or irrigation. Whilst there is some evidence that white light can be an effective deterrent for Chinook salmon smolts, the results have been mixed. There is a need to test the response of fish to different spectra and strobing frequencies to improve deterrent performance. We tested the movement and spatial response of groups of four fish to combinations of light-emitting diode (LED) spectra (red, green, blue and white light) during the day and night, and strobing frequencies (constant and 2Hz) during the day, using innovative LED technology intended as a behavioural guidance device for use in the field. Whilst strobing did not alter fish behaviour when compared to constant light, the red light had a repulsive effect during the day, with fish under this treatment spending significantly less time in the half of the arena closest to the behavioural guidance device compared to both the control and blue light. Importantly, this effect disappeared at night, where there were no differences in movement and space use found between spectra. There was some evidence of a potential attractive response of fish to the blue and green light during the day. Under these light treatments, fish spent the highest amount of time closest to the behavioural guidance device. Further tests manipulating the light intensity in the different spectra are needed to verify the mechanistic determinants of the observed behaviours. Results are discussed in reference to the known spectral sensitivities of the cone and rod photopigments in these fish, and further experiments are suggested to better relate the work to mitigating the effects on fish of infrastructure used for hydropower and irrigation. PMID- 29977565 TI - Rapid loss of seed viability in ex situ conserved wheat and barley at 4 degrees C as compared to -20 degrees C storage. AB - Genebanks aim to optimize their storage conditions in order to postpone seed ageing as long as possible. As most genebanks have a relatively short life history, empirical data about seed longevity during ex situ storage are almost absent. Based on seed characteristics, theoretical predictions indicate that cereal seeds can be stored without substantial loss of viability for time periods exceeding 100 years, even under temperatures of a few degrees above zero. Here we present the results of a germination study in wheat and barley, comparing genebank seed samples maintained at different temperatures for 23-33 years. Wheat and barley seed samples stored at -20 degrees C showed a mean germination of 94% and 90%, respectively, indicating no loss of the initial viability determined for the accessions prior to introduction in the collection. Seed samples maintained at 4 degrees C showed a mean germination of 62% for wheat and 75% for barley. In addition to the observed loss of viability, the 4 degrees C samples also showed a loss in vigour as the time period to reach their final germination was about twice as long compared to the -20 degrees C samples. A subset of the wheat accessions tested in 2011 were retested in 2017, showing further reduction in mean germination to 35% for the 4 degrees C samples, while the -20 degrees C samples remained stable at 95%. Several 4 degrees C samples were even close to a complete loss of viability. Considering that wheat and barley are generally regarded as good maintainers, the rapid loss of seed viability observed in the present study indicates that the ex situ seed storage of genetic resources at 4 degrees C should be treated with caution by genebanks, particularly when used for long-term conservation. PMID- 29977567 TI - Effects of changes in occupational stress on the depressive symptoms of Korean workers in a large company: a longitudinal survey. AB - Background: Prospective studies on occupational stress and depression among Korean workers are scarce. This study aimed to investigate the causal relationship between changes in occupational stress and the presence of depression. Methods: This study analyzed data from a survey conducted with workers in a large Korean company (2015-2016). Occupational stress was measured using the Korean Occupational Stress Scale, and depression was screened using the WHO-5 Well-being Index. The levels of occupational stress were grouped in quartiles based on subjects' occupational stress scores in 2015, and changes in occupational stress were measured using the score changes between the 2015 and 2016 surveys. Subjects were divided into four groups according to the presence or absence of depression in 2015 and 2016: a non-depressed group whose mental health did not change, a non-depressed group whose mental health deteriorated, a depressed group that continued to be depressed, and a depressed group whose symptoms of depression were alleviated. Logistic regression analysis was used to calculate the odds ratios (ORs) and confidence intervals (CIs) of the subjects' deterioration in mood or alleviation of depression by occupational stress levels and changes. Results: The OR for developing depressive symptoms was 2.51 (95% CI 1.46-4.33) and 2.73 (95% CI 1.39-5.36) in the third and the fourth quartiles of occupational stress, respectively, compared to the first quartile. When the occupational stress score increased by 1 point, the OR for increasing depressive symptoms was 1.07 (95% CI 1.04-1.10). There was no significant difference in the alleviation of depressive symptoms between the groups by level of occupational stress. However, when the occupational stress score decreased by 1 point, the OR for alleviating depressive symptoms was 1.08 (95% CI 1.05-1.11). Conclusion: The results showed that increased occupational stress increased the presence of depressive symptoms, and that reduced occupational stress suppressed the development of depressive symptoms. More attention should be paid to stress management among workers. PMID- 29977566 TI - Adapting medical guidelines to be patient-centered using a patient-driven process for individuals with sickle cell disease and their caregivers. AB - Background: Evidence-based guidelines for sickle cell disease (SCD) health maintenance and management have been developed for primary health care providers, but not for individuals with SCD. To improve the quality of care delivered to individuals with SCD and their caregivers, the main purposes of this study were to: (1) understand the desire for patient-centered guidelines among the SCD community; and (2) adapt guideline material to be patient-centered using community-engagement strategies involving health care providers, community -based organizations, and individuals with the disease. Methods: From May-December 2016, a volunteer sample of 107 individuals with SCD and their caregivers gave feedback at community forums (n = 64) and community listening sessions (n = 43) about technology use for health information and desire for SCD-related guidelines. A team of community research partners consisting of community stakeholders, individuals living with SCD, and providers and researchers (experts) in SCD at nine institutions adapted guidelines to be patient-centered based on the following criteria: (1) understandable, (2) actionable, and (3) useful. Results: In community forums (n = 64), almost all participants (91%) wanted direct access to the content of the guidelines. Participants wanted guidelines in more than one format including paper (73%) and mobile devices (79%). Guidelines were adapted to be patient-centered. After multiple iterations of feedback, 100% of participants said the guidelines were understandable, most (88%) said they were actionable, and everyone (100%) would use these adapted guidelines to discuss their medical care with their health care providers. Conclusions: Individuals with SCD and their caregivers want access to guidelines through multiple channels, including technology. Guidelines written for health care providers can be adapted to be patient-centered using Community-engaged research involving providers and patients. These patient-centered guidelines provide a framework for patients to discuss their medical care with their health care providers. PMID- 29977568 TI - The associations between work-related factors and temporomandibular disorders among female full-time employees: findings from the Fourth Korea National Health and Nutrition Examination Survey IV (2007-2009). AB - Background: The aim of this study was to investigate the association between work related factors and temporomandibular disorders (TMD) among female full-time employees using representative data from a national population-based survey. Methods: Data from the Fourth Korea National Health and Nutrition Examination Survey IV (2007-2009) were used to analyze 1,612 women. Complex samples logistic regression was applied for adjusting for general characteristics and work-related factors to examine the association between work-related factors and TMD. Results: The prevalence of TMD was 12.8% in this study population. With respect to age, educational status, marital status, problem drinking, exercise, and stress, there were statistically significant differences in the prevalence of TMD. In logistic regression analyses on complex samples, based on 40 h or less per week, odds ratios (ORs) for respondents who worked 40-48 working hours, 49-60 working hours, and more than 60 h were 1.16 (95% confidence interval (CI) 0.69-1.94), 1.41 (95% CI 0.79-2.54), and 2.43 (95% CI 1.29-4.59), after adjusting for general characteristics, working schedule, employment status, and occupation. Conclusions: This study found that long working hours were significantly associated with TMD in Korean female full-time employees. PMID- 29977571 TI - Application of light detection and ranging and ultrasonic sensors to high throughput phenotyping and precision horticulture: current status and challenges. AB - Ultrasonic and light detection and ranging (LiDAR) sensors have been some of the most deeply investigated sensing technologies within the scope of digital horticulture. They can accurately estimate geometrical and structural parameters of the tree canopies providing input information for high-throughput phenotyping and precision horticulture. A review was conducted in order to describe how these technologies evolved and identify the main investigated topics, applications, and key points for future investigations in horticulture science. Most research efforts have been focused on the development of data acquisition systems, data processing, and high-resolution 3D modeling to derive structural tree parameters such as canopy volume and leaf area. Reported applications of such sensors for precision horticulture were restricted to real-time variable-rate solutions where ultrasonic or LiDAR sensors were tested to adjust plant protection product or fertilizer dose rates according to the tree volume variability. More studies exploring other applications in site-specific management are encouraged; some that integrates canopy sensing data with other sources of information collected at the within-grove scale (e.g., digital elevation models, soil type maps, historical yield maps, etc.). Highly accurate 3D tree models derived from LiDAR scanning demonstrate their great potential for tree phenotyping. However, the technology has not been widely adopted by researchers to evaluate the performance of new plant varieties or the outcomes from different management practices. Commercial solutions for tree scanning of whole groves, orchards, and nurseries would promote such adoption and facilitate more applied research in plant phenotyping and precision horticulture. PMID- 29977569 TI - A novel integrated non-targeted metabolomic analysis reveals significant metabolite variations between different lettuce (Lactuca sativa. L) varieties. AB - Lettuce is an important leafy vegetable that represents a significant dietary source of antioxidants and bioactive compounds. However, the levels of metabolites in different lettuce cultivars are poorly characterized. In this study, we used combined GC * GC-TOF/MS and UPLC-IMS-QTOF/MS to detect and relatively quantify metabolites in 30 lettuce cultivars representing large genetic diversity. Comparison with online databases, the published literature, standards as well using collision cross-section values enabled putative identification of 171 metabolites. Sixteen of these 171 metabolites (including phenolic acid derivatives, glycosylated flavonoids, and one iridoid) were present at significantly different levels in leaf and head type lettuces, which suggested the significant metabolomic variations between the leaf and head types of lettuce are related to secondary metabolism. A combination of the results and metabolic network analysis techniques suggested that leaf and head type lettuces contain not only different levels of metabolites but also have significant variations in the corresponding associated metabolic networks. The novel lettuce metabolite library and novel non-targeted metabolomics strategy devised in this study could be used to further characterize metabolic variations between lettuce cultivars or other plants. Moreover, the findings of this study provide important insight into metabolic adaptations due to natural and human selection, which could stimulate further research to potentially improve lettuce quality, yield, and nutritional value. PMID- 29977570 TI - Genomic signatures of different adaptations to environmental stimuli between wild and cultivated Vitis vinifera L. AB - The application of population genetic methods in combination with gene mapping strategies can help to identify genes and mutations selected during the evolution from wild plants to crops and to explore the considerable genetic variation still maintained in natural populations. We genotyped a grapevine germplasm collection of 44 wild (Vitis vinifera subsp. sylvestris) and 48 cultivated (V. vinifera subsp. sativa) accessions at 54 K single-nucleotide polymorphisms (SNPs) to perform a whole-genome comparison of the main population genetic statistics. The analysis of Wright Fixation Index (FST) along the whole genome allowed us to identify several putative "signatures of selection" spanning over two thousand SNPs significantly differentiated between sativa and sylvestris. Many of these genomic regions included genes involved in the adaptation to environmental changes. An overall reduction of nucleotide diversity was observed across the whole genome within sylvestris, supporting a small effective population size of the wild grapevine. Tajima's D resulted positive in both wild and cultivated subgroups, which may indicate an ongoing balancing selection. Association mapping for six domestication-related traits was performed in combination with population genetics, providing further evidence of different perception and response to environmental stresses between sativa and sylvestris. PMID- 29977572 TI - Flower heads in Asteraceae-recruitment of conserved developmental regulators to control the flower-like inflorescence architecture. AB - Inflorescences in the Asteraceae plant family, flower heads, or capitula, mimic single flowers but are highly compressed structures composed of multiple flowers. This transference of a flower-like appearance into an inflorescence level is considered as the key innovation for the rapid tribal radiation of Asteraceae. Recent molecular data indicate that Asteraceae flower heads resemble single flowers not only morphologically but also at molecular level. We summarize this data giving examples of how rewiring of conserved floral regulators have led to evolution of morphological innovations in Asteraceae. Functional diversification of the highly conserved flower meristem identity regulator LEAFY has shown a major role in the evolution of the capitulum architecture. Furthermore, gene duplication and subsequent sub- and neofunctionalization of SEPALLATA- and CYCLOIDEA-like genes in Asteraceae have been shown to contribute to meristem determinacy, as well as flower type differentiation-key traits that specify this large family. Future challenge is to integrate genomic, as well as evolutionary developmental studies in a wider selection of Asteraceae species to understand the detailed gene regulatory networks behind the elaborate inflorescence architecture, and to promote our understanding of how changes in regulatory mechanisms shape development. PMID- 29977573 TI - The over-expression of a chrysanthemum gene encoding an RNA polymerase II CTD phosphatase-like 1 enzyme enhances tolerance to heat stress. AB - The enzyme RNAPII CTD phosphatase-like 1 is known as a transcriptional regulator of the plant response to various abiotic stresses. Here, the isolation of CmCPL1, a chrysanthemum (Chrysanthemum morifolium) gene encoding this enzyme is described. Its predicted 955 residue gene product includes the FCPH catalytic domain, two double-stranded RNA binding motifs, and a nuclear localization signal. A sub-cellular localization assay confirmed that CmCPL1 was expressed in the nucleus. CmCPL1 transcription was shown to be significantly inducible by heat stress. The over-expression and knockdown of CmCPL1, respectively, increased and diminished the tolerance of chrysanthemum to heat stress, which maybe dependent on the regulation of CmCPL1 and on the expression of downstream heat stress responsive genes. PMID- 29977574 TI - Genotyping-by-sequencing of Brassica oleracea vegetables reveals unique phylogenetic patterns, population structure and domestication footprints. AB - Brassica oleracea forms a diverse and economically significant crop group. Improvement efforts are often hindered by limited knowledge of diversity contained within available germplasm. Here, we employ genotyping-by-sequencing to investigate a diverse panel of 85 landrace and improved B. oleracea broccoli, cauliflower, and Chinese kale entries. Ultimately, 21,680 high-quality SNPs were used to reveal a complex and admixed population structure and clarify phylogenetic relationships among B. oleracea groups. Each broccoli landrace contained, on average, 8.4 times as many unique alleles as an improved broccoli and landraces collectively represented 81% of all broccoli-specific alleles. Commercial broccoli hybrids were largely represented by a single subpopulation identified within a complex population structure. Greater allelic diversity in landrace broccoli and 96.1% of SNPs differentiating improved cauliflower from landrace cauliflower were common to the larger pool of broccoli germplasm, supporting a parallel or later development of cauliflower due to introgression events from broccoli. Chinese kale was readily distinguished by principal coordinate analysis. Genotyping was accomplished with and without reliance upon a reference genome producing 141,317 and 20,815 filtered SNPs, respectively, supporting robust SNP discovery methods in neglected or unimproved crop groups that lack a reference genome. This work clarifies the population structure, phylogeny, and domestication footprints of landrace and improved B. oleracea broccoli using many genotyping-by-sequencing markers. Additionally, a large pool of genetic diversity contained in broccoli landraces is described which may enhance future breeding efforts. PMID- 29977575 TI - One down, one to go: coronary anomaly dual LAD blood supply with worsening chronic stable angina and 100% occluded left short LAD type IV variant. AB - Although rare, usually asymptomatic, and without concurrent disease, dual left anterior descending arteries (LAD) poses great challenges. We describe a 55-year old male with no history of coronary disease, who presented with worsening substernal chest pain with exertion, and was ruled out for myocardial infarction. On left heart catheterization and subsequent computed tomography angiogram, he was determined to have a dual LAD with a long LAD emerging from the right coronary artery. Moreover, this long LAD gave collaterals to a native long diagonal that ran parallel to this vessel from the left system and was chronically occluded. The long LAD, consistent with type IV classification, traveled in the anterior intraventricular groove to supply left ventricular myocardium; the chronically occluded long left native diagonal supplying lateral walls and apex is a unique variant. It is important to be aware of these anomalies to establish correct diagnoses and determine treatment options. PMID- 29977576 TI - Craniopharyngeal canal, morning glory disc anomaly and hypopituitarism: what do they have in common? AB - A 14-year-old girl with a history of mid-line defects, basal encephalocele and morning glory disc anomaly presented with untreated growth hormone deficiency, pubertal delay and hypothyroidism. She was found to have a large craniopharyngeal canal based on MRI scan. Craniopharyngeal canal is an uncommon condition that has not been well described in the pediatric population. Consideration of craniopharyngeal canal in the differential diagnosis for basal encephaloceles and understanding its presentation can impact medical decision making and follow-up for patients. PMID- 29977577 TI - Giant isolated intracardiac thrombus presenting as acute heart failure secondary to right ventricular outflow tract obstruction in a patient with renal carcinoma. AB - Right-sided intracardiac thrombi are potential causes of right ventricular (RV) failure, particularly when tricuspid or pulmonary obstruction occurs. In most cases, RV thrombus develops in patients with RV dysfunction and concomitant thrombosis in the systemic veins. However, RV thrombosis can rarely present as an isolated mass and despite preserved RV function, particularly in patients with thrombophilic states. In this report, we describe an unusual case of giant isolated RV thrombus presenting with acute RV failure secondary to dynamic RV outflow tract obstruction in a patient with renal carcinoma. Bedside echocardiography allowed a rapid assessment of the hemodynamic effects of the mass. The possibility of a thrombotic RV outflow obstruction should be considered in patients with acute RV failure, even in those with no evidence of thrombosis in the venous district. This may be particularly important in patients with prothrombotic states, where the effectiveness of routine thromboembolic prophylaxis could be reduced. PMID- 29977578 TI - Nonbacterial thrombotic endocarditis in a patient with primary antiphospholipid syndrome. AB - Nonbacterial thrombotic endocarditis (NBTE) is described in patients with mucin producing cancers and connective tissue disorders (usually SLE). We report NBTE in the setting of primary antiphospholipid antibody syndrome (APS). A 65-year-old female with APS was incidentally found to have thickened mitral leaflets on transthoracic echocardiogram with no signs of infection. Transesophageal echocardiogram (TEE) showed a mobile mitral mass (1.4 * 0.7 cm) and moderate mitral regurgitation. Differential diagnoses included bacterial endocarditis, NBTE, thrombus or tumor. Given the history of primary APS, the absence of fever and negative blood cultures, NBTE was considered. Low-molecular-weight heparin, hydroxychloroquine and corticosteroid were initiated. Repeat TEE in a week revealed shrinkage of the mass (0.6 * 0.7 cm), indicating an inflammatory nature. Lifelong anticoagulation is indicated regardless of embolism occurrence. Hydroxychloroquine and corticosteroids may have roles in the treatment. Determining and treating the underlying etiology is important. PMID- 29977579 TI - A case of recurrent transient global amnesia: don't forget the hippocampal punctuate diffusion restriction. AB - Transient global amnesia (TGA) is a syndrome characterized by reversible impairment of short-term memory. TGA itself is a benign disease, however, it is reasonable to investigate and exclude sinister causes of global amnesia; such as stroke or a seizure activity. A case of TGA is presented here with special emphasis on the typical TGA lesion that was detected on the patient's magnetic resonance imaging (MRI) of Brain. In patients with TGA, the typical MRI Brain finding is a tiny focus of diffusion restriction in the mesiotemporal lobe. This finding can potentially aid in early diagnosis and management of TGA. Although in overwhelming majority of cases, the TGA episode occurs only once, yet a second TGA episode can occur rarely. This patient, two years later, had a recurrence of TGA episode, albeit with a normal MRI brain, and without residual changes from prior episode. PMID- 29977580 TI - Persistent hiccup reflex activation as a complication of dental implant surgery: a case report. AB - Persistent hiccup can conceal life-threatening clinical conditions of highly heterogeneous nature. Here, we report a case of a persistent hiccup that has been temporally associated with dental implant insertion in a patient with paroxysmal atrial fibrillation. This 67-year-old patient underwent dental implant in area 36 and the procedure was performed without acute complications. A prolonged hiccup started ~48 h after the procedure: it failed to respond to several medications and it lasted for ~18 days, after which it spontaneously disappeared. Brain imaging and neurological examination were conducted in order to rule out organic conditions, even though all the investigations resulted to be negative. We suggest that the surgical procedure might have triggered a prolonged reflex activation. Knowledge about this complication of oral surgery procedure might be useful for avoiding unnecessary hospitalization or diagnostic tests. PMID- 29977581 TI - Skin lesions caused by Mycobacterium marinumin a patient with occupational exposure. AB - Mycobacterium marinum infections are associated with specific occupational risk factors and often have a delay to diagnosis. We present the case of a young tropical fish whole-sale worker presenting with skin lesions on the hand. PMID- 29977582 TI - Does Chronic Kidney Disease-Induced Cognitive Impairment Affect Driving Safety? AB - Purpose of Review: One of the principal mechanisms by which illness can affect driving safety is by impairing cognition. Nevertheless, despite the substantial evidence demonstrating cognitive impairment in chronic kidney disease (CKD), little is known about the effects of CKD on driving safety. Objective: Investigate the current national medical guidelines and research literature with respect to CKD and driving safety. Sources of Information: Medline, CINAHL, PEDro, Scopus as of August 2017. The most up to date national driving guidelines and available information provided by the provincial and territorial ministries of transportation across Canada. Findings: Fives studies of driving fitness in patients with CKD have been published with minimal data available for patients at early stages of the disease. Amongst these studies, only two come from an era when modern end stage renal disease therapies were routinely provided. The first study demonstrated that 40% of 186 surveyed patients on hemodialysis felt uncomfortable driving and that 1/3 of patients were involved in motor vehicle collisions (MVC) since starting dialysis. Of the patients who felt comfortable driving, more than 75% were found to be at increased driving risk. The second study reported that 15% of patients on hemodialysis were involved in MVCs over a three year span and that the "Am I A Safe Driver" assessment tool by the American Medical Association may not capture all patients at high driving risk. Despite these alarming numbers, national guidelines place few driving restrictions on this patient population and only 3 of 11 available provincial or territorial driving forms include kidney disease as a category that physicians should consider when assessing medical fitness to drive. Limitations: Our review is limited by the lack of randomized control studies evaluating the effects of CKD on driving safety. Implications: Our review demonstrates that driving safety in this patient population remains poorly understood. The limited evidence that does exist, however, suggests that these patients are at substantial risk for unsafe driving. Future research is necessary to determine the impact of CKD-associated cognitive impairment on driving risk, and to parse out the contributions of CKD and its various treatments to driving impairment. PMID- 29977583 TI - End-Stage Kidney Disease in Patients With Autosomal Dominant Polycystic Kidney Disease: A 12-Year Study Based on the Canadian Organ Replacement Registry. AB - Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, with afflicted patients often progressing to end-stage kidney disease (ESKD) requiring renal replacement therapy (RRT). As the timelines to ESKD are predictable over decades, it follows that ADPKD patients should be optimized regarding kidney transplantation, home dialysis therapies, and vascular access. Objectives: To examine the association of kidney transplantation, dialysis modalities, and vascular access in ADPKD patients compared with a matched, non-ADPKD cohort. Setting: Canadian patients from 2001 2012 excluding Quebec. Patients: All adult incident ESKD patients who received dialysis or a kidney transplant. Measurements: ADPKD as defined by the treating physician. Methods: ADPKD and non-ADPKD patients were propensity score (PS) matched (1:4) using demographics, comorbidities, and lab values. Conditional logistic regression and Cox proportional hazards models were used to examine associations with kidney transplantation (preemptive or any), dialysis modality (peritoneal, short daily, home, or in-center hemodialysis [HD]), vascular access (arteriovenous fistula [AVF], permanent or temporary central venous catheter [CVC]), and dialysis survival. Results: We matched 2120 ADPKD (99.9%) with 8283 non-ADPKD with no significant imbalances between the groups. ADPKD was significantly associated with preemptive kidney transplantation (odds ratio [OR] = 7.13, 95% confidence interval [CI] = 5.74-8.87), any kidney transplant (OR = 2.37, 95% CI = 2.14-2.63), and initial therapy of nocturnal daily HD (OR = 2.74, 95% CI = 1.38-5.44), whereas in-center intermittent HD was significantly less likely in the ADPKD population (OR = 0.59, 95% CI = 0.54-0.65). There was no difference in peritoneal dialysis (PD) as initial RRT but lower use of any PD among the ADPKD group (OR = 0.85, 95% CI = 0.77-0.95). ADPKD patients were significantly more likely to have an AVF (OR = 3.25, 95% CI = 2.79-3.79) and less likely to have either a permanent (OR 0.68, 95% CI 0.59-0.78) or temporary (OR = 0.49, 95% CI = 0.41-0.59) CVC as compared with the non-ADPKD cohort. Survival on either in-center HD or PD was better for ADPKD patients (HD: hazard ratio [HR] 0.48, 95% CI 0.44-0.53; PD: HR 0.73, 95% CI 0.60-0.88). Limitations: Conservative care patients were not captured; despite PS matching, the possibility of residual confounding remains. Conclusions: ADPKD patients were more likely to receive a kidney transplant, use home HD, dialyze with an AVF, and have better survival relative to non-ADPKD patients. Conversely, they were less likely to receive PD either as initial therapy or anytime during ESKD. This may be attributed to higher transplantation or clinical decision-making processes susceptible to education and intervention. PMID- 29977586 TI - Correction to: Physicochemical properties of M. longissimus dorsi of Korean native pigs. AB - [This corrects the article DOI: 10.1186/s40781-018-0163-y.]. PMID- 29977585 TI - Physical Activity in Patients Treated With Peritoneal Dialysis: A Systematic Review and Meta-analysis. AB - Background: Exercise has been shown to be of benefit in the general population and in patients with chronic diseases. Despite a lack of compelling evidence, patients with end-stage kidney disease (ESKD) treated with peritoneal dialysis (PD) are often discouraged from participating in exercise programs that include weight lifting due to concerns about the development of hernias and leaks. The actual effects of physical activity with or without structured exercise programs for patients on PD remain unclear. Objective: To determine the risks and benefits of physical activity in the ESKD population treated with PD. Design: Systematic review and meta-analysis. Setting: Included all studies that met our criteria regardless of country of origin. Patients: Adult patients with ESKD treated with PD. Measurements: Descriptive and quantitative analysis of our primary and secondary outcome variables. Methods: We searched MEDLINE, Embase, CINAHL, and Cochrane Central Register of Controlled Trials for observational and interventional studies examining the effects of physical activity in patients on PD. A systematic review and meta-analysis was conducted of the identified studies. The primary outcomes of interest included patient-centered outcomes of mental health, physical functioning, fatigue, quality of life, and adverse events. Secondary outcomes included nutritional measures, lipid profile, blood pressure changes, maximum heart rate, resting heart rate, maximal oxygen consumption, muscle development, cognitive function, and markers of inflammation. Results: Of 1828 studies identified by the literature search, 12 met the inclusion criteria including 6 interventional and 6 observational studies. There was limited information on the patient important outcomes. However, there is some evidence for improvements in burden of kidney disease, physical function, and some mental health measures with physical activity. Limitations: Lack of well designed randomized controlled trials impaired our ability to determine the benefits and risks of increasing physical activity. Conclusions: There is limited evidence of benefit with increased levels of physical activity in PD patients. Further research is needed to define the exercise program that is likely to be of most benefit to patients treated with PD. PMID- 29977584 TI - Gadolinium-Based Contrast Agents in Kidney Disease: A Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists. AB - Purpose of review: Use of gadolinium-based contrast agents (GBCA) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCA are absolutely contraindicated in AKI, category G4 and G5 CKD (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2), and dialysis-dependent patients is outdated and may limit access to clinically necessary contrast enhanced magnetic resonance imaging (MRI) examinations. This review and clinical practice guideline addresses the discrepancy between existing Canadian guidelines regarding use of GBCA in renal impairment and NSF. Sources of information: Published literature (including clinical trials, retrospective cohort series, review articles, and case reports), online registries, and direct manufacturer databases were searched for reported cases of NSF by class and specific GBCA and exposed patient population. Methods: A comprehensive review was conducted identifying cases of NSF and their association to class of GBCA, specific GBCA used, patient, and dose (when this information was available). Based on the available literature, consensus guidelines were developed by an expert panel of radiologists and nephrologists. Key findings: In patients with category G2 or G3 CKD (eGFR >= 30 and < 60 mL/min/1.73 m2), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with category G4 or G5 CKD (eGFR < 30 mL/min/1.73 m2) or on dialysis, administration of GBCA should be considered individually and alternative imaging modalities utilized whenever possible. If GBCA are necessary, newer GBCA may be administered with patient consent obtained by a physician (or their delegate) citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, those with category G4 or G5 CKD, or those on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCA. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCA is recommended. Limitations: Limited available literature (number of injections and use in renal impairment) regarding the use of gadoxetate disodium. Limited, but growing and generally high-quality, number of clinical trials evaluating GBCA administration in renal impairment. Limited data regarding the topic of Gadolinium deposition in the brain, particularly as it related to patients with renal impairment. Implications: In patients with AKI and category G4 and G5 CKD (eGFR < 30 mL/min/1.73 m2) and in dialysis-dependent patients who require GBCA-enhanced MRI, GBCA can be administered with exceedingly low risk of causing NSF when using macrocyclic agents and newer linear agents at routine doses. PMID- 29977587 TI - Relationship between body mass index, body image, and fear of negative evaluation: Moderating role of self-esteem. AB - This study examined the correlation between body mass index as independent variable, and body image and fear of negative evaluation as dependent variables, as well as the moderating role of self-esteem in these correlations. A total of 318 Malaysian young adults were conveniently recruited to do the self administered survey on the demographic characteristics body image, fear of negative evaluation, and self-esteem. Partial least squares structural equation modeling was used to test the research hypotheses. The results revealed that body mass index was negatively associated with body image, while no such correlation was found with fear of negative evaluation. Meanwhile, the negative correlation of body mass index with body image was stronger among those with lower self esteem, while a positive association of body mass index with fear of negative evaluation was significant only among individuals with low self-esteem. PMID- 29977588 TI - Spiritual health mediates the relationship between ego-strength and adjustment to heart disease. AB - This study aimed to investigate the mediating role of spiritual health in the relationship between ego-strength and adjustment to heart disease. In total, 327 patients with coronary artery disease (138 women, 189 men) completed the Ego Strength Scale, Adjustment to Illness Scale, and Spiritual Well-Being Scale. Results showed that both ego-strength and spiritual health had a significantly positive correlation with adjustment to heart disease. Results also revealed that spiritual health mediated the relationship between ego-strength and adjustment to heart disease. More improvement in adjustment to heart disease requires more improvement in patients' spiritual health as well as to ego-strength. PMID- 29977589 TI - Patient perceived changes in sexual dysfunction after initiation of natalizumab for multiple sclerosis. AB - Purpose: Sexual dysfunction is a common but often overlooked secondary symptom of multiple sclerosis (MS) and can be associated with a decreased health-related quality of life (HRQoL). Natalizumab is a disease-modifying therapy approved for the treatment of relapsing forms of MS. In addition to its efficacy, those using natalizumab have shown improvement in HRQoL parameters, including fatigue and cognition. The idea that improvement in fatigue may also correlate with improvement in sexual dysfunction is the impetus for this study. Methods: A single-center, open-label, single-arm, 24-week study was performed to evaluate perceived change in sexual dysfunction in MS patients treated with natalizumab. Adults with relapsing MS initiating natalizumab treatment and had a baseline level of sexual dysfunction were enrolled. The primary endpoint was change in the MS Intimacy and Sexuality Questionnaire-19 (MSISQ-19) score from baseline to week 24. Mean age of patients was 41 years, median disease duration was 7 years, and 73% of patients used at least one prior MS disease-modifying therapy. Results: Natalizumab-treated patients experienced improvement in sexual dysfunction within the first 24 weeks of starting therapy, as demonstrated by the primary subscale of the MSISQ-19 questionnaire (-0.6976, p = 0.02). Conclusions: Given the high prevalence of sexual dysfunction in MS patients and the significant impact it has on HRQoL, more research on this often overlooked symptom of MS could be very informative for patients that are deciding to initiate a new disease modifying therapy. PMID- 29977591 TI - Efficacy of a one-shot marbofloxacin treatment on acute pleuropneumonia after experimental aerosol inoculation of nursery pigs. AB - Background: Porcine pleuropneumonia, caused by Actinobacillus pleuropneumoniae, is a bacterial respiratory disease of swine. Acute outbreaks of the disease are often accompanied by high mortality and economic losses. As severe cases of the disease frequently require parenteral antibiotic treatment of the animals, the efficacy of a single, high dose of marbofloxacin was compared to a three-time application of a dose of enrofloxacin under experimental conditions. Methods: A blinded, controlled, randomized and blocked dose confirmation study was conducted to test the efficacy and safety of a single dose of 8 mg/kg marbofloxacin (160 mg/ml, Forcyl(r) Swine, Vetoquinol SA, France) to treat acute porcine pleuropneumonia after experimental aerosol inoculation of pigs with A. pleuropneumoniae serotype 2. The results were compared to a three consecutive day treatment of 2.5 mg/kg enrofloxacin and a mock (saline) treatment. Criteria for the assessment of efficacy were severity of lung lesions, bacteriological cure and the course of clinical disease after treatment. Results: Thirty six nursery pigs were divided into three treatment groups: marbofloxacin (T1), enrofloxacin (T2) and mock (T3). Statistically significant superiority (p < 0.05) of marbofloxacin and enrofloxacin compared to the mock-treated group was demonstrated for all efficacy criteria. The need of rescue euthanasia due to severity of symptoms was significantly reduced in both treatment groups (T1: 1 pig; T2: 0 pigs; vs. T3: 8 pigs). On day 6 after treatment initiation, clinical cure was observed in 10 (T1), 10 (T2) but only 1 of the piglets in T3. Extent of lung lesions (mean of lung lesion score T1: 3.9, T2: 6.0, T3: 21.1) and bacteriological isolation from lung tissue (on day 6 after treatment initiation: T1 = 0 pigs; T2 = 1 pig; T3 = all pigs) were also significantly reduced within both treatment groups. There were no adverse events linked to the drug administration and no injection site reactions were observed. Conclusions: Both applied antimicrobial treatments were proven safe and efficacious for the treatment of acute porcine pleuropneumonia. No statistically significant differences were detected between the antibiotic treatments. PMID- 29977592 TI - Walk with Me: a protocol for a pilot RCT of a peer-led walking programme to increase physical activity in inactive older adults. AB - Background: Levels of physical activity decline with age. Some of the most disadvantaged individuals in society, such as those from lower socio-economic position, are also the most inactive. Increasing physical activity levels, particularly among those most inactive, is a public health priority. Peer-led physical activity interventions may offer a model to increase physical activity in the older adult population. This study aims to test the feasibility of a peer led, multicomponent physical activity intervention in socio-economically disadvantaged community dwelling older adults. Methods: The Medical Research Council framework for developing and evaluating complex interventions will be used to design and test the feasibility of a randomised controlled trial (RCT) of a multicomponent peer-led physical activity intervention. Data will be collected at baseline, immediately after the intervention (12 weeks) and 6 months after baseline measures. The pilot RCT will provide information on recruitment of peer mentors and participants and attrition rates, intervention fidelity, and data on the variability of the primary outcome (minutes of moderate to vigorous physical activity measured with an accelerometer). The pilot trail will also assess the acceptability of the intervention and identify potential resources needed to undertake a definitive study. Data analyses will be descriptive and include an evaluation of eligibility, recruitment, and retention rates. The findings will be used to estimate the sample size required for a definitive trial. A detailed process evaluation using qualitative and quantitative methods will be conducted with a variety of stakeholders to identify areas of success and necessary improvements. Discussion: This paper describes the protocol for the 'Walk with Me' pilot RCT which will provide the information necessary to inform the design and delivery of a fully powered trial should the Walk with Me intervention prove feasible. Trial registration: ISRCTN Number ISRCTN23051918. Date of registration, November 18, 2015. PMID- 29977590 TI - Targeted disruption of the extracellular polymeric network of Pseudomonas aeruginosa biofilms by alginate oligosaccharides. AB - Acquisition of a mucoid phenotype by Pseudomonas sp. in the lungs of cystic fibrosis (CF) patients, with subsequent over-production of extracellular polymeric substance (EPS), plays an important role in mediating the persistence of multi-drug resistant (MDR) infections. The ability of a low molecular weight (Mn = 3200 g mol-1) alginate oligomer (OligoG CF-5/20) to modify biofilm structure of mucoid Pseudomonas aeruginosa (NH57388A) was studied in vitro using scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM) with Texas Red (TxRd(r))-labelled OligoG and EPS histochemical staining. Structural changes in treated biofilms were quantified using COMSTAT image analysis software of CLSM z-stack images, and nanoparticle diffusion. Interactions between the oligomers, Ca2+ and DNA were studied using molecular dynamics (MD) simulations, Fourier transform infrared spectroscopy (FTIR) and isothermal titration calorimetry (ITC). Imaging demonstrated that OligoG treatment (>=0.5%) inhibited biofilm formation, revealing a significant reduction in both biomass and biofilm height (P < 0.05). TxRd(r)-labelled oligomers readily diffused into established (24 h) biofilms. OligoG treatment (>=2%) induced alterations in the EPS of established biofilms; significantly reducing the structural quantities of EPS polysaccharides, and extracellular (e)DNA (P < 0.05) with a corresponding increase in nanoparticle diffusion (P < 0.05) and antibiotic efficacy against established biofilms. ITC demonstrated an absence of rapid complex formation between DNA and OligoG and confirmed the interactions of OligoG with Ca2+ evident in FTIR and MD modelling. The ability of OligoG to diffuse into biofilms, potentiate antibiotic activity, disrupt DNA-Ca2+-DNA bridges and biofilm EPS matrix highlights its potential for the treatment of biofilm-related infections. PMID- 29977593 TI - Cluster randomised controlled feasibility study of HENRY: a community-based intervention aimed at reducing obesity rates in preschool children. AB - Background: In the UK and beyond, public funding is used to commission interventions delivered in public health early years settings aimed at improving health and well-being and reducing inequalities in order to promote school readiness. This is a key setting for obesity prevention programmes, which are often commissioned despite the limited evidence base. The HENRY (Health, Exercise, Nutrition for the Really Young) programme is an 8-week programme delivered to parents of preschool children, designed to support families to optimise healthy weight behaviours. Early evidence suggests that it may be effective, but a robust evaluation using a randomised controlled design has not been conducted. This study begins this process by evaluating the feasibility of conducting a multi-centre definitive trial to evaluate the effectiveness and cost effectiveness of HENRY to prevent obesity in the early years. Methods: This is a multi-centre, open labelled, two group, prospective, cluster randomised, controlled, feasibility study aiming to recruit 120 parents from 12 children's centres, based in two local authority areas. Within each of the two local authorities, three centres will be randomised to HENRY and three will be randomised to a control arm of standard care (usual provision of services within children's centres). We will explore HENRY commissioning, provision and delivery and assess the feasibility of local authority, centre and parent recruitment, the processes and time required to train and certify staff to deliver the intervention, the potential sources (and associated risk) of contamination and the feasibility of the trial procedures. Research includes a process evaluation, feasibility of cost-effectiveness evaluation, with progression to the definitive trial judged against pre-defined criteria. Discussion: This feasibility study will support the decision to proceed to, and the design of, a future definitive trial, providing an evidence base of an approach to prevent childhood obesity, which has been deemed attractive to all stakeholders, including parents. Given the widespread adoption of the intervention, this has the potential to impact on public health in the UK and beyond. Trial registration: ClinicalTrials.gov Identifier NCT03333733 registered 6th November 2017Protocol date: 25th October 2017Protocol version: 4.0. PMID- 29977594 TI - Pheochromocytoma and Paraganglioma in Neurofibromatosis type 1: frequent surgeries and cardiovascular crises indicate the need for screening. AB - Background: Pheochromocytomas and Paragangliomas (PCC/PGL) are rare endocrine tumors that are mostly benign, but often hormone producing, causing significant morbidity and mortality due to excess catecholamine secretion and cardiovascular crises. It is estimated that 30% of PCC/PGL are due to germline mutations, including Neurofibromatosis type 1 (NF1). There is little published data describing the phenotype of NF1-associated PCC/PGL and there are no established recommendations for PCC/PGL screening in NF1. Methods: We conducted a retrospective chart review of 17 patients with NF1-associated PCC/PGL who received care at a large academic referral center between the years of 1992-2016. Results: Average age of diagnosis was 42 years old. Both genders were equally affected. Average tumor size was 3.9 cm. Nine patients were hypertensive; one had orthostatic hypotension; three had tachycardia; the remaining two patients had normal BP and HR. Most tumors were benign, unilateral adrenal tumors that were hormonally active. Two had metastatic disease. Six patients experienced cardiovascular crises; three of which occurred during elective surgeries for neurofibroma removal, and a fourth occurred during labor and delivery. Conclusion: These data highlight the importance of screening for PCC/PGL in NF1, especially prior to surgical procedures and pregnancy, labor and delivery as these events can trigger a cardiovascular crisis. Screening is easily accomplished with plasma or urine free fractionated metanephrine levels. PMID- 29977595 TI - Smart scaffolds in tissue regeneration. AB - Recent advances in biofabrication technologies and chemical synthesis approaches have enabled the fabrication of smart scaffolds that aim to mimic the dynamic nature of the native extracellular matrix. These scaffolds have paved the way for tissue regeneration in a dynamic and controllable manner. PMID- 29977596 TI - The directional migration and differentiation of mesenchymal stem cells toward vascular endothelial cells stimulated by biphasic calcium phosphate ceramic. AB - Osteoinductivity of porous calcium phosphate (CaP) ceramics has been widely investigated and confirmed, and it might be attributed to the rapid formation of the vascular networks after in vivo implantation of the ceramics. In this study, to explore the vascularization mechanism within the CaP ceramics, the migration and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) under the stimulation of porous biphasic calcium phosphate (BCP) ceramic with excellent osteoinductivity were systematically investigated. The results indicated that the directional migration of BMSCs toward BCP ceramic occurred when evaluated by using a transwell model, and the BMSCs migration was enhanced by the seeded macrophages on the ceramic in advance. Besides, by directly culturing BMSCs on BCP ceramic discs under both in vitro and in vivo physiological environment, it was found that the differentiation of BMSCs toward vascular endothelial cells (VECs) happened under the stimulation of BCP ceramic, as was confirmed by the up regulated gene expressions and protein secretions of VECs-related characteristic factors, including kinase insert domain receptor, von willebrand factor, vascular cell adhesion molecule-1 and cadherin 5 in the BMSCs. This study offered a possibility for explaining the origin of VECs during the rapid vascularization process after in vivo implantation of porous CaP ceramics and could give some useful guidance to reveal the vascularization mechanism of the ceramics. PMID- 29977598 TI - Comparative transcriptomic analysis of hematopoietic system between human and mouse by Microwell-seq. PMID- 29977597 TI - Vitamin D deficiency and risk of cardiovascular diseases: a narrative review. AB - Vitamin D, a fat-soluble prohormone, has wide-ranging roles in the regulation of many physiological processes through their interactions with the vitamin D receptors (VDR). It plays a major role in bones and calcium metabolism. Vitamin D deficiency is not uncommon and it has been associated with many health-related issues, including skeletal and non-skeletal complications. The association of low vitamin D and cardiovascular diseases and risk factors has been explored in both animal and human studies. However, studies and trials on the effect of vitamin D supplementation on cardiovascular risk factors and hypertension are conflicting with inconsistent results. Therefore, large, well-powered randomized controlled trials are warranted. If successful, supplementation with easy and low-cost vitamin D can impact our health positively. Here, we summarized the evidence for the association of vitamin D, cardiovascular diseases and risk factors, including coronary artery diseases, stroke, and hypertension, and mortality, with special consideration to resistant hypertension. PMID- 29977600 TI - A network of epigenomic and transcriptional cooperation encompassing an epigenomic master regulator in cancer. AB - Coordinated experiments focused on transcriptional responses and chromatin states are well-equipped to capture different epigenomic and transcriptomic levels governing the circuitry of a regulatory network. We propose a workflow for the genome-wide identification of epigenomic and transcriptional cooperation to elucidate transcriptional networks in cancer. Gene promoter annotation in combination with network analysis and sequence-resolution of enriched transcriptional motifs in epigenomic data reveals transcription factor families that act synergistically with epigenomic master regulators. By investigating complementary omics levels, a close teamwork of the transcriptional and epigenomic machinery was discovered. The discovered network is tightly connected and surrounds the histone lysine demethylase KDM3A, basic helix-loop-helix factors MYC, HIF1A, and SREBF1, as well as differentiation factors AP1, MYOD1, SP1, MEIS1, ZEB1, and ELK1. In such a cooperative network, one component opens the chromatin, another one recognizes gene-specific DNA motifs, others scaffold between histones, cofactors, and the transcriptional complex. In cancer, due to the ability to team up with transcription factors, epigenetic factors concert mitogenic and metabolic gene networks, claiming the role of a cancer master regulators or epioncogenes. Significantly, specific histone modification patterns are commonly associated with open or closed chromatin states, and are linked to distinct biological outcomes by transcriptional activation or repression. Disruption of patterns of histone modifications is associated with the loss of proliferative control and cancer. There is tremendous therapeutic potential in understanding and targeting histone modification pathways. Thus, investigating cooperation of chromatin remodelers and the transcriptional machinery is not only important for elucidating fundamental mechanisms of chromatin regulation, but also necessary for the design of targeted therapeutics. PMID- 29977599 TI - Cancer cell specific inhibition of Wnt/beta-catenin signaling by forced intracellular acidification. AB - Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/beta-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of beta-catenin, encouraging applications in treatment of cancers caused by APC and beta-catenin mutations. PMID- 29977601 TI - Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes. AB - Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS p values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways. We asked if the expressions of T2D-associated candidate genes from GWAS and literature are regulated by Nfatc4 in rat islets. Extensive in vitro silencing of Nfatc4 in rat islet cells displayed reduced expression of 16, and increased expression of four putative downstream T2D genes. Overall, our approach uncovers the mechanistic connection of NFATC4 with downstream targets including a previously unknown one, TCF7L2, and establishes the HiCc pathways' relationship to T2D. PMID- 29977603 TI - Remediation of adult black dental stains by phototherapy. AB - Introduction and aims: This study investigates the effects of the application of antimicrobial phototherapy on black-stained tooth surfaces. Key variables were area, color and time taken to reappearance of black stain following dental prophylaxis with and without antimicrobial phototherapy. Differences in bacterial composition of black stain (specifically Aggregatibacter actinomycetemcomitans, Tannerella forsythia, and Porphyromonas gingivalis) were analyzed. Material and methods: The phototherapy device used was GLOTM Science LLC, New York, America, emitting light at 475 nm and a power of 3 W. Light was applied in 2 cycles of 8 min on 31 volunteers. Microbial identification was carried out on DNA extracted from black plaque. This study is registered with ClinicalTrials.gov, number NCT03309748. Results: Following antimicrobial phototherapy, 64.5% of patients displayed reduced pigmentation area. Plaque color was lighter in 48.4% of subjects. Pigmentation area and depth of color returned to normal levels during the course of the study. Colonization by the three bacterial species decreased, although the changes were not statistically significant. We report a key novel finding showing elevated levels of colonization by Tannerella forsythia (83.9%) in adult black stain. Conclusions: Application of phototherapy results in a reduction in area, color and bacterial colonization of black plaque in adults. The changes were not found to be statistically significant, perhaps owing to the low illumination power of the home-whitening device. For the first time, we document the elevated presence of Tannerella forsythia in adult black stain. We also demonstrate the potential application of a commercially available home whitening device for black plaque treatment. PMID- 29977602 TI - Systems pharmacology using mass spectrometry identifies critical response nodes in prostate cancer. AB - In the United States alone one in five newly diagnosed cancers in men are prostate carcinomas (PCa). Androgen receptor (AR) status and the PI3K-AKT-mTOR signal transduction pathway are critical in PCa. After initial response to single drugs targeting these pathways resistance often emerges, indicating the need for combination therapy. Here, we address the question of efficacy of drug combinations and development of resistance mechanisms to targeted therapy by a systems pharmacology approach. We combine targeted perturbation with detailed observation of the molecular response by mass spectrometry. We hypothesize that the molecular short-term (24 h) response reveals details of how PCa cells adapt to counter the anti-proliferative drug effect. With focus on six drugs currently used in PCa treatment or targeting the PI3K-AKT-mTOR signal transduction pathway, we perturbed the LNCaP clone FGC cell line by a total of 21 treatment conditions using single and paired drug combinations. The molecular response was analyzed by the mass spectrometric quantification of 52 proteins. Analysis of the data revealed a pattern of strong responders, i.e., proteins that were consistently downregulated or upregulated across many of the perturbation conditions. The downregulated proteins, HN1, PAK1, and SPAG5, are potential early indicators of drug efficacy and point to previously less well-characterized response pathways in PCa cells. Some of the upregulated proteins such as 14-3-3 proteins and KLK2 may be useful early markers of adaptive response and indicate potential resistance pathways targetable as part of combination therapy to overcome drug resistance. The potential of 14-3-3zeta (YWHAZ) as a target is underscored by the independent observation, based on cancer genomics of surgical specimens, that its DNA copy number and transcript levels tend to increase with PCa disease progression. The combination of systematic drug perturbation combined with detailed observation of short-term molecular response using mass spectrometry is a potentially powerful tool to discover response markers and anti-resistance targets. PMID- 29977604 TI - Two sides of the same coin: A population genetics perspective on lethal mutagenesis and mutational meltdown. AB - The extinction of RNA virus populations upon application of a mutagenic drug is frequently referred to as evidence for the existence of an error threshold, above which the population cannot sustain the mutational load. To explain the extinction process after reaching this threshold, models of lethal mutagenesis have been proposed, in which extinction is described as a deterministic (and thus population size-independent) process. As a separate body of literature, the population genetics community has developed models of mutational meltdown, which focus on the stochastic (and thus population-size dependent) processes governing extinction. However, recent extensions of both models have blurred these boundaries. Here, we first clarify definitions in terms of assumptions, expectations, and relevant parameter spaces, and then assess similarities and differences. As concepts from both fields converge, we argue for a unified theoretical framework that is focused on the evolutionary processes at play, rather than dispute over terminology. PMID- 29977605 TI - Ancient DNA provides evidence of 27,000-year-old papillomavirus infection and long-term codivergence with rodents. AB - The long-term evolutionary history of many viral lineages is poorly understood. Novel sources of ancient DNA combined with phylogenetic analyses can provide insight into the time scale of virus evolution. Here we report viral sequences from ancient North American packrat middens. We screened samples up to 27,000 years old and found evidence of papillomavirus (PV) infection in Neotoma cinerea (Bushy-tailed packrat). Phylogenetic analysis placed the PV sequences in a clade with other previously published PV sequences isolated from rodents. Concordance between the host and virus tree topologies along with a correlation in branch lengths suggests a shared evolutionary history between rodents and PVs. Based on host divergence times, PVs have likely been circulating in rodents for at least 17 million years. These results have implications for our understanding of PV evolution and for further research with ancient DNA from Neotoma middens. PMID- 29977606 TI - Impact of donor chest radiography on clinical outcome after lung transplantation. AB - Background: Organ donation guidelines recommend a "clear" conventional bedside chest radiograph before lung transplantation despite only moderate accuracy for cardiopulmonary abnormalities. Purpose: To evaluate the influence of donor image interpretation on lung transplantation outcome in recipients by following early and late complications, one-year survival, and to correlate imaging findings and blood gas analysis with lung transplantation outcome in recipients. Material and Methods: In 35 lung donors from a single institution clinical reports and study reviews of imaging findings of the mandatory bedside chest radiographs and blood gas analyses were compared with clinical outcome in 38 recipients. Hospitalization time, peri- and postoperative complications, early complications (primary graft dysfunction, infection), 30-day and one-year survival, and forced expiratory volume in 1 s percentage of predicted normal value (FEV1%) at one-year follow-up were analyzed. Results: Findings in clinical reports and study reviews differed substantially, e.g. regarding reported decompensation, edema, infection, and atelectasis. No correlation was shown between imaging findings in clinical report or study review and blood gas analyses in the lung donors compared to postoperative outcome in recipients. Conclusion: The interpretation of the mandatory chest radiograph in its present form does not influence one-year outcome in lung transplantation. Larger imaging studies or a change in clinical routine including computed tomography may provide evidence for future guidelines. PMID- 29977607 TI - Clinical application and cases examples of a new treatment algorithm for treating thoracic and lumbar spine trauma. AB - Study design: Review of illustrative cases of a new algorithm to help in the treatment decision of thoracolumbar spine trauma. Objectives: To illustrate the use of the new algorithm for managing thoracic and lumbar spine trauma. Settings: Recently, a new algorithm for helping in the decision of the best treatment modality for thoracolumbar spine trauma (TLST) was published. The algorithm considers injury morphology, neurological status, clinical status (pain and disability), and also multimodal radiological evaluation (MMRE) in the decision for non-operative versus operative treatment for TLST. Injuries were classified in three groups: (1) stable injuries, (2) potentially unstable injuries/ delayed instability, or (3) clearly unstable injuries. Methods: Cases examples of the algorithm application were presented and discussed. Results: Stable injuries (minor fractures without instability) are non-surgically treated; potentially unstable injuries or associated with delayed instability may be initially managed non-surgically and operative treatment is an option, especially in the setting of important pain, deformity or a new neurological deficit. Clearly unstable injuries are treated surgically as soon as possible to avoid neurological worsening, severe pain, and/ or progressive spinal deformity. Conclusions: Clinical examples of TLST were presented, discussed and classified as stable, potentially unstable and clearly unstable injuries. Further studies addressing the reliability and safety of this algorithm are necessary. PMID- 29977608 TI - Cervicothoracic arachnoiditis-a rare complication of aneurysmal intracranial subarachnoid haemorrhage. AB - Introduction: Subarachnoid haemorrhage is a catastrophic condition which has significant morbidity and mortality, with mortality rate ranging between 8-67% and is associated with significant morbidity among the survivors. Arachnoiditis of the spinal cord is a very rare complication which can occur months to years after the subarachnoid haemorrhage. Case presentation: We report a case of cervicothoracic arachnoiditis following the subarachnoid haemorrhage secondary to posterior inferior cerebellar artery (PICA) aneurysm with posterior fossa AVM (arterio-venous malformation) causing dense paraplegia. Discussion: The haemorrhage that occurs into the fourth ventricle passes to the subarachnoid space via foramen of Magendie and Luschka. This subsequently induces inflammatory changes of the meninges predisposing to arachnoiditis. Early recognition and intervention may prevent this devastating complication or at least reduce the morbidity. PMID- 29977609 TI - Randomized trial of concentrated proanthocyanidins (PAC) for acute reduction of bacteriuria in male veterans with spinal cord injury utilizing clean intermittent catheterization. AB - Study design: This study was a double-blind, placebo-controlled trial of a concentrated PACs compound (36 mg/capsule), in veterans with SCI and neurogenic lower urinary tract dysfunction (NLUTD) requiring intermittent catheterization (IC) over a 15-day period. Objectives: The objective of this study was to evaluate the acute effects of concentrated proanthocyanidins (PACs) in the cranberry supplement ellura(r) on bacteriuria, leukocyturia, and subjective urine quality in catheter-dependent veterans with SCI. Setting: Spinal cord injury center (outpatient clinic and inpatient unit). Methods: Participants with positive urine bacterial colonization (>=50 K CFU/ml) were randomized to once daily concentrated PACs or identical placebo and followed with daily (in patients) or twice weekly (out-patients) urine cultures with colony forming units per milliliter (cfu/ml) range (bacteriuria), microscopic urine white blood cells per high-powered field (wbc/hpf) quantification (leukocyturia), and surveys assessing urine clarity, odor, color, sediment, and overall satisfaction. A repeated measure analysis of variance was used to compare treatment vs. control and evaluate serial trends. Results: A total of 13 male participants (7 randomized to concentrated PACs, 6 to placebo) completed the trial. There was no significant decrease over the study period in colony forming units per milliliter (cfu/ml) or log(wbc/hpf) in the treatment vs. the control group. Patients receiving concentrated PACs rated the clarity, odor, color, sediment, and overall satisfaction of their urine as insignificantly improved compared to placebo. Conclusions: Acutely, there was no reduction of bacteriuria and pyuria or improvement in subjective urine quality for SCI patients treated with daily concentrated PACs. PMID- 29977610 TI - Activation of the endoplasmic reticulum stress sensor IRE1alpha by the vaccine adjuvant AS03 contributes to its immunostimulatory properties. AB - The oil-in-water emulsion Adjuvant System 03 (AS03) is one of the few adjuvants used in licensed vaccines. Previous work indicates that AS03 induces a local and transient inflammatory response that contributes to its adjuvant effect. However, the molecular mechanisms involved in its immunostimulatory properties are ill defined. Upon intramuscular injection in mice, AS03 elicited a rapid and transient downregulation of lipid metabolism-related genes in the draining lymph node. In vitro, these modifications were associated with profound changes in lipid composition, alteration of endoplasmic reticulum (ER) morphology and activation of the unfolded protein response pathway. In vivo, treatment with a chemical chaperone or deletion of the ER stress sensor kinase IRE1alpha in myeloid cells decreased AS03-induced cytokine production and its capacity to elicit high affinity antigen-specific antibodies. In summary, our results indicate that IRE1alpha is a sensor for the metabolic changes induced by AS03 in monocytic cells and may constitute a canonical pathway that could be exploited for the design of novel vaccine adjuvants. PMID- 29977611 TI - Mini-hemagglutinin vaccination induces cross-reactive antibodies in pre-exposed NHP that protect mice against lethal influenza challenge. AB - Seasonal vaccines are currently the most effective countermeasure against influenza. However, seasonal vaccines are only effective against strains closely related to the influenza strains contained in the vaccine. Recently a new hemagglutinin (HA) stem-based antigen, the so-called "mini-HA", has been shown to induce a cross-protective immune response in influenza-naive mice and non-human primates (NHP). However, prior exposure to influenza can have a profound effect on the immune response to subsequent influenza infection and the protective efficacy of vaccination. Here we show that mini-HA, compared to a trivalent influenza vaccine (TIV), elicits a broadened influenza-specific humoral immune response in NHP previously exposed to influenza. Serum transfer experiments showed that antibodies induced by both mini-HA and seasonal vaccine protected mice against lethal challenge with a H1N1 influenza strain heterologous to the H1 HA included in the TIV. However, antibodies elicited by mini-HA showed an additional benefit of protecting mice against lethal heterosubtypic H5N1 influenza challenge, associated with H5 HA-specific functional antibodies. PMID- 29977612 TI - AS03 stresses out macrophages: Commentary on 'Activation of the endoplasmic reticulum stress sensor IRE1alpha by the vaccine adjuvant AS03 contributes to its immunostimulatory properties'. PMID- 29977613 TI - Mesangial cells, specialized renal pericytes and cytomegalovirus infectivity: Implications for HCMV pathology in the glomerular vascular unit and post transplant renal disease. AB - Background: Human Cytomegalovirus (HCMV) infection is problematic after kidney transplantation. Human mesangial cells along with human glomerular endothelial cells and podocytes constitute the renal glomerular vascular unit (GVU). HCMV infection of the GVU is poorly understood. Methods: GVU cells infectivity was analysed by microscopy and immunofluorescence. Cytokines profiles were measured by Luminex assays. Renal tissue analysis for HCMV infection was performed by immunohistochemistry. Results: Mesangial cells and glomerular endothelial cells but not podocytes were permissive for both lab adapted and clinical strains of HCMV. Luminex analysis of cytokines expressed by mesangial cells exposed to the SBCMV clinical strain was examined. A Tricell infection model of the GVU maintains >90% viability with a unique cytokine profile. Finally, we show alphaSMA stained mesangial cells permissive for HCMV in renal tissue from a transplant patient. Conclusions: HCMV infection of mesangial cells induces angiogenic and proinflammatory cytokines that could contribute to glomerular inflammation. PMID- 29977614 TI - Effect of Phenotypic Screening of Extracts and Fractions of Erythrophleum ivorense Leaf and Stem Bark on Immature and Adult Stages of Schistosoma mansoni. AB - Schistosomiasis is a disease caused by a flatworm parasite that infects people in tropical and subtropical regions of Sub-Saharan Africa, South America, China, and Southeast Asia. The reliance on just one drug for current treatment emphasizes the need for new chemotherapeutic strategies. The aim of this study was to determine the phenotypic effects of extracts and fractions of leaf and stem bark of Erythrophleum ivorense (family Euphorbiaceae), a tree that grows in tropical parts of Africa, on two developmental stages of Schistosoma mansoni, namely, postinfective larvae (schistosomula or somules) and adults. Methanol leaf and stem bark extracts of E. ivorense were successively fractionated with acetone, petroleum ether, ethyl acetate, and methanol. These fractions were then incubated with somules at 0.3125 to 100 MUg/mL and with adults at 1.25 MUg/mL. The acetone fractions of both the methanol leaf and bark of E. ivorense were most active against the somules whereas the petroleum ether fractions showed least activity. For adult parasites, the acetone fraction of methanol bark extract also elicited phenotypic changes. The data arising provide the first step in the discovery of new treatments for an endemic infectious disease using locally sourced African medicinal plants. PMID- 29977615 TI - Association of Genes in the High-Density Lipoprotein Metabolic Pathway with Polypoidal Choroidal Vasculopathy in Asian Population: A Systematic Review and Meta-Analysis. AB - Purpose: To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-related macular degeneration (AMD). Methods: We performed a literature search in EMBASE, PubMed, and Web of Science for genetic studies on 7 single nucleotide polymorphisms (SNPs) from 5 genes in the HDLMP including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), ATP-binding cassette transporter A1 (ABCA1), and ATP-binding cassette transporter G1 (ABCG1) in PCV. All studies were published before September 30, 2017, without language restriction. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of each polymorphism were estimated. We also compared the association profiles between PCV and AMD and performed a sensitivity analysis. Results: Our result is based on 43 articles. After excluding duplicates and articles without complete information, 7 studies were applicable to meta-analysis. 7 polymorphisms were meta-analyzed: CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919. We found that in Asian population, CETP rs3764261 (T allele; OR = 1.46; 95% CI: 1.28-1.665, P < 0.01), CETP rs2303790 (G allele; OR = 1.57; 95% CI: 1.258-1.96, P < 0.01), and ABCG1 rs57137919 (A allele; OR = 1.168; 95% CI: 1.016-1.343, P < 0.01) were significantly associated with PCV, and ABCG1 rs57137919 (A allele; OR = 1.208, 95% CI: 1.035-1.411, P < 0.01) has different effects in PCV and AMD. The other 4 polymorphisms in LIPC/LPL/ABCA1 had no significant association with PCV (P > 0.05). The sensitivity analysis validated the significance of our analysis. Conclusions: Our study revealed 7 polymorphisms in 5 genes. Among them, CETP (rs3764261/rs2303790) and ABCG1 (rs57137919) were the major susceptibility genes for PCV in Asian population and ABCG1 (rs57137919) showed allelic diversity between PCV and AMD. Since the size for PCV and AMD was small, we need to study these genes genotyping in larger samples. PMID- 29977616 TI - Myxoid Liposarcoma: Prognostic Factors and Metastatic Pattern in a Series of 148 Patients Treated at a Single Institution. AB - Objectives: The authors reported a retrospective study on myxoid liposarcomas (MLs), evaluating factors that may influence overall survival (OS), local recurrence-free survival (LRFS), metastasis-free survival (MFS), and analyzing the metastatic pattern. Methods: 148 MLs were analyzed. The sites of metastases were investigated. Results: Margins (p = 0.002), grading (p = 0,0479), and metastasis (p < 0,0001) were significant risk factors affecting overall survival (OS). Type of presentation (p = 0.0243), grading (p = 0,0055), margin (p = 0.0001), and local recurrence (0.0437) were risk factors on metastasis-free survival (MFS). Authors did not observe statistically significant risk factors for local recurrence-free survival (LRFS) and reported 55% extrapulmonary metastases and 45% pulmonary metastases. Conclusion: Margins, grading, presentation, local recurrence, and metastasis were prognostic factors. Extrapulmonary metastases were more frequent in myxoid liposarcoma. PMID- 29977617 TI - The Early Outcomes of Nurse Case Management in Patients with Acute Ischemic Stroke Treated with Intravenous Recombinant Tissue Plasminogen Activator: A Prospective Randomized Controlled Trial. AB - Background: Intravenous recombinant tissue plasminogen activator (i.v. rt-PA) is the milestone treatment for patients with acute ischemic stroke. Stroke Fast Track (SFT) facilitates time reduction, guarantees safety, and promotes good clinical outcomes in i.v. rt-PA treatment. Nursing case management is a healthcare service providing clinical benefits in many specific diseases. The knowledge about the efficacy of a nurse case management for Stroke Fast Track is limited. We aim to study the effect of nurse case management on clinical outcomes in patients with acute ischemic stroke involving intravenous recombinant tissue plasminogen activator (i.v. rt-PA) treatment. Methods: Seventy-six patients with acute ischemic stroke who received i.v. rt-PA treatment under Stroke Fast Track protocol of Thammasat University Hospital were randomized into two groups. One group was assigned to get standard care (control) while another group was assigned to get standard care under a nurse case management. The National Institute of Health Stroke Scale (NIHSS) at 24 hours after treatment between the control and the experimental groups was evaluated. Results: Time from triage to treatment in the experimental group was significantly faster than in the control group (mean = 39.02 and 59.37 minutes, respectively; p=.001). The NIHSS at 24 hours after treatment in the nurse case management group was significantly improved as compared to the control group (p=.001). No symptomatic intracranial hemorrhage (sICH) was detected at 24 hours after onset in both groups. Conclusion: The nurse case management should provide some benefits in the acute stroke system. Although the early benefit is demonstrated in our study, further studies are needed to ensure the long-term benefit and confirm its profit in patients with acute ischemic stroke. PMID- 29977618 TI - Microalbuminuria and Retinopathy among Hypertensive Nondiabetic Patients at a Large Public Outpatient Clinic in Southwestern Uganda. AB - Background: Routine testing of microalbuminuria and retinopathy is not done among patients with high blood pressure in resource-limited settings. We determined the prevalence of microalbuminuria and retinopathy and their risk factors among hypertensive patients at a large hospital in western Uganda. Methods: We consecutively recruited nondiabetic patients with hypertension at the outpatients' clinic over a period of 3 months. Spot urine samples were tested for urine albumin. Direct fundoscopy was done to assess retinal vasculature and optic disc for signs of hypertensive retinopathy. Logistic regression was done with retinopathy and microalbuminuria as primary outcomes. Results: We enrolled 334 patients and, of these, 208 (62.3%) were females, with median age of 55 years (range: 25-90). The prevalence of microalbuminuria was 59.3% (95% CI: 50.1-72.2) and that of retinopathy was 66.8% (95% CI: 58.6-76.5). The independent correlates of retinopathy and microalbuminuria were systolic blood pressure (SBP) > 140 mmHg (OR = 2.76, 95% CI: 1.29-5.93) and treatment with beta-blockers (OR = 2.16, 95% CI: 1.05-4.44). Use of ACEIs was unrelated to the study outcomes. Conclusion: The prevalence of retinopathy and microalbuminuria is high. Clinicians should aim for better control of blood pressure and routinely perform fundoscopy and urine albumin, especially for patients with poorly controlled blood pressure. PMID- 29977620 TI - Glucose Management during Insulinoma Resection Using Real-Time Subcutaneous Continuous Glucose Monitoring. AB - Insulinoma is a rare neuroendocrine tumor that causes hypoglycemia due to unregulated insulin secretion. Blood glucose management during insulinoma resection is therefore challenging. We present a case in which real-time subcutaneous continuous glucose monitoring (SCGM) in combination with intermittent blood glucose measurement was used for glycemic control during surgery for insulinoma resection. The SCGM system showed the trends and peak of interstitial glucose in response to glucose loading and the change of interstitial glucose before and after insulinoma resection. These data were helpful for adjusting the glucose infusion; therefore, we think that an SCGM system as a supportive device for glucose monitoring may be useful for glucose management during surgery. PMID- 29977619 TI - Transforming Growth Factor-beta Protects against Inflammation-Related Atherosclerosis in South African CKD Patients. AB - Background: Transforming growth factor-beta (TGF-beta) may inhibit the development of atherosclerosis. We evaluated serum levels of TGF-beta isoforms concurrently with serum levels of endotoxin and various inflammatory markers. In addition, we determined if any association exists between polymorphisms in the TGF-beta1 gene and atherosclerosis in South African CKD patients. Methods: We studied 120 CKD patients and 40 healthy controls. Serum TGF-beta1, TGF-beta2, TGF beta3, endotoxin, and inflammatory markers were measured. Functional polymorphisms in the TGF-beta1 genes were genotyped using a polymerase chain reaction-sequence specific primer method and carotid intima media thickness (CIMT) was assessed by B-mode ultrasonography. Results: TGF-beta isoforms levels were significantly lower in the patients with atherosclerosis compared to patients without atherosclerosis (p<0.001). Overall, TGF-beta isoforms had inverse relationships with CIMT. TGF-beta1 and TGF-beta2 levels were significantly lower in patients with carotid plaque compared to those without carotid plaque [TGF-beta1: 31.9 (17.2 - 42.2) versus 45.9 (35.4 - 58.1) ng/ml, p=0.016; and TGF-beta2: 1.46 (1.30 - 1.57) versus 1.70 (1.50 - 1.87) ng/ml, p=0.013]. In multiple logistic regression, age, TGF-beta2, and TGF-beta3 were the only independent predictors of subclinical atherosclerosis in CKD patients [age: odds ratio (OR), 1.054; 95% confidence interval (CI): 1.003 - 1.109, p=0.039; TGF beta2: OR, 0.996; 95% CI: 0.994-0.999, p=0.018; TGF-beta3: OR, 0.992; 95% CI: 0.985-0.999, p=0.029). TGF-beta1 genotypes did not influence serum levels of TGF beta1 and no association was found between the TGF-beta1 gene polymorphisms and atherosclerosis risk. Conclusion: TGF-beta isoforms seem to offer protection against the development of atherosclerosis among South African CKD patients. PMID- 29977621 TI - Endocarditis Caused by Gram-Negative Moraxella osloensis in an Immunocompetent Patient: First Case Report in Latin America. AB - This is a case report of infective endocarditis due to Moraxella osloensis. This study would be the fourth since the two latest episodes were described in 2015. The patient of this exposition is different from those previously described in the literature because it was a young adult, under 50 years of age, immunocompetent, with no comorbidities and no obvious focus of infection. PMID- 29977622 TI - Secret Sarcoma: A Cardiac Mass Disguised as Influenza. AB - This case presentation discusses an extremely rare diagnosis presenting with common symptoms, attributed to influenza, which were not investigated further when clear cardiac symptoms developed. The patient initially presented with symptoms consistent with influenza, but when orthopnea and dyspnea on exertion developed, these cardiac symptoms continued to be attributed to a postviral syndrome and were not further evaluated. Premature closure bias contributed to a delay in diagnosing a rare cardiac condition. The diagnostic momentum, or the continuing of a diagnostic label, occurred across multiple providers and settings. This case demonstrates the risk of premature closure and diagnostic momentum and reminds clinicians to reframe the differential diagnosis as more information on history or physical exam becomes available. PMID- 29977623 TI - Lethal End of Spectrum of Clots-Thrombotic Storm. AB - Thrombotic storm (TS) is a rare, acute, hypercoagulable state characterized by multiple thromboembolic events affecting at least two different areas of the vascular system/organs over a short period of time. Typical triggers include inflammation, infections, minor trauma, surgery, pregnancy, and the puerperium. A single thrombotic event can set off a number of thromboembolic events, often including unusual locations like hepatic, portal, or renal veins, skin (purpura fulminans), adrenal glands, and cerebral sinus venous thrombosis. Usually, younger female patients are affected; in some patients, there is an association with an autoimmune disorder like lupus erythematosus, and they show evidence of antiphospholipid antibodies or other phenotypic expressions of anticoagulation disorders. The majority of patients have no previous history of thromboembolism. As the diagnosis of thrombotic storm relies solely on clinical symptoms with a lack of specific diagnostic tests, this can result in a delay of diagnosis. The treatment consists of uninterrupted lifelong anticoagulation. Sometimes immunomodulatory therapies have been used. The distinction between extensive thrombotic events like Heparin Induced Thrombosis (HIT), Thrombotic Thrombocytopenic Purpura (TTP), Antiphospholipids Syndrome (APS), and TS can sometimes be difficult, and the etiology of TS remains uncertain. PMID- 29977624 TI - Aesthetic Rehabilitation of a Severe Dental Fluorosis Case with Ceramic Veneers: A Step-by-Step Guide. AB - The selection of an appropriate treatment plan for cases of dental fluorosis depends on the severity of the condition. Ceramic veneers are considered the treatment of choice for moderate to severe cases of fluorosis given the optimum aesthetics, wear resistance, biocompatibility, and long-term results of these veneers. This case report describes a step-by-step rehabilitation of fluorosed teeth, using ceramic veneers in a 26-year-old Yemeni male. The patient presented at the restorative dentistry clinics at King Saud University complaining of an unpleasant smile and generalized tooth discoloration. PMID- 29977625 TI - Maturogenesis of an Immature Dens Evaginatus Nonvital Premolar with an Apically Placed Bioceramic Material (EndoSequence Root Repair Material(r)): An Unexpected Finding. AB - Dens evaginatus is a dental developmental anomaly that arises due to the folding of the inner dental epithelium that leads to the formation of an additional cusp or tubercle on the occlusal surface of the affected tooth. This accessory tissue projection may carry with it a narrow and constricted pulp horn extension. Occasionally, the tubercle easily fractures, thus leading to microexposure of the pulp horn and eventual pulp necrosis. Often, the pulp necrosis occurs at a time the root development of the affected tooth is incomplete. Apexification with calcium hydroxide and mineral trioxide aggregates has been the mainstay of treatment options before root canal obturation in immature nonvital permanent teeth. Lately, regenerative endodontics (maturogenesis) is becoming one of the preferred treatment modalities to manage such teeth. The current case highlights the possibility of a bioceramic material (EndoSequence Root Repair Material, BC RRM-Fast Set PuttyTM, Brasseler, USA) which supposed to provide apical root closure (apexification) and could also induce continuation of root growth (maturogenesis). PMID- 29977626 TI - Removal of Implant and New Rehabilitation for Better Esthetics. AB - Tooth loss can result in loss of facial esthetics, in addition to its effect on mastication, swallowing, and speech. Adequate planning is required in order for the prosthetic treatment of the teeth and implants to be successful. Here, we present a clinical case demonstrating that improper positioning of an implant can make prosthetic rehabilitation unfeasible, necessitating new surgical and rehabilitation planning to achieve the desired esthetics. The patient had a missing right lateral incisor and cuspid, and a buccally directed implant. The preferred treatment regimen involved the removal of this implant and placement of another one more properly positioned distally and three dimensionally. The repositioning of the implant made rehabilitation treatment with a mesial cantilever possible. Due to esthetic considerations, gingival conditioning in the cantilever region was performed in the temporary prosthesis phase. The changes adopted in planning the surgery and rehabilitation resulted in good esthetics as well as functional outcomes. PMID- 29977627 TI - Restorative Management of Severe Localized Tooth Wear Using a Supraoccluding Appliance: A 5-Year Follow-Up. AB - This case report illustrates a novel conservative restorative management of a patient with bulimia nervosa who presented with severe localized upper palatal tooth wear and an anterior reverse overjet. This was achieved by using a localized bite raising or supraoccluding appliance, cemented on the lingual side of the lower anterior teeth to create interocclusal space, obviating the need for tooth reduction of the eroded upper palatal and incisal tooth surfaces. Surgical crown lengthening was performed to create a better aesthetic gingival architecture. All-ceramic restorations were provided on the upper anterior teeth to restore the tooth surface loss and provide a positive overbite and overjet. There was no complication or other observable biological change detected at the 5 year follow-up. The use of an appliance applying the supraoccluding technique, or Dahl concept, is a safe, conservative, and useful treatment option in the management of localized tooth wear. PMID- 29977628 TI - A Case of Hyperacute Severe Thrombocytopenia Occurring Less than 24 Hours after Intravenous Tirofiban Infusion. AB - Thrombocytopenia is defined as a condition where the platelet count is below the lower limit of normal (<150 G/L), and it is categorized as mild (100-149 G/L), moderate (50-99 G/L), and severe (<50 G/L). We present here a 79-year-old man who developed severe thrombocytopenia with a platelet count of 6 G/L, less than 24 hours after intravenous tirofiban infusion that was given to the patient during a percutaneous transluminal coronary angioplasty procedure with placement of 3 drug eluting stents. The patient's baseline platelet count was 233 G/L before the procedure. Based on the timeline of events during hospitalization and laboratory evidence, it was highly likely that the patient's thrombocytopenia was the result of tirofiban-induced immune thrombocytopenia, a type of drug-induced immune thrombocytopenia (DITP) which occurs due to drug-dependent antibody-mediated platelet destruction. Anticoagulant-mediated artefactual pseudothrombocytopenia was ruled out as no platelet clumping was seen on the peripheral blood smears. The treatment of DITP includes discontinuation of the causative drug; monitoring of platelet count recovery; or treatment of severe thrombocytopenia with glucocorticoids, IVIG, or platelet transfusions depending on the clinical presentation. The most likely causative agent of this patient's thrombocytopenia tirofiban-was discontinued, and the patient did not develop any signs of bleeding during the remainder of his hospital stay. His platelet count gradually improved to 24 G/L, and he was discharged on the sixth hospital day. PMID- 29977629 TI - Treatment Sequencing in a Chronic Lymphocytic Leukemia Patient with Central Nervous System Involvement. AB - Early-stage chronic lymphocytic leukemia (CLL) with neurologic involvement is a rare condition and should require a careful follow-up. Although no standard protocol exists for this condition, intrathecal chemotherapy, combined with systemic chemoimmunotherapy, has been used previously. This case describes the treatment of a patient with CLL and symptomatic compromise of the central nervous system. Our results suggest that a combination of chemotherapy, radiotherapy, and ibrutinib, administered sequentially over a 2-year period, led to a near-complete resolution of the cerebral spinal fluid neoplastic infiltration. Importantly, this response has been maintained with ibrutinib monotherapy for more than 12 months. PMID- 29977630 TI - Multiple Liver Nodules Mimicking Metastatic Disease as Initial Presentation of Multiple Myeloma. AB - Multiple myeloma is a malignant clonal proliferation of plasma cells in the bone marrow preceded by monoclonal gammopathy of undetermined significance. Initial presentation of multiple myeloma as extramedullary spread in soft tissues particularly in the liver is uncommon. We report a case of a 74-year-old African American female who presented with epigastric pain, hematemesis, elevated alkaline phosphatase, and gamma-glutamyl transferase. Initial impression was peptic ulcer disease; however, ultrasound and CT scan of the abdomen showed multiple liver nodules and perihepatic lymphadenopathy suggestive of metastatic disease. Biopsy of the liver nodules showed CD138 and kappa light chain restricted positive cells consistent with extramedullary spread of multiple myeloma to the liver. The patient achieved partial response after 6 months of treatment with Velcade, cyclophosphamide, and dexamethasone (VCD). Due to severe neutropenia from cyclophosphamide, regimen was switched to Velcade, Revlimid, and dexamethasone (VRD) which resulted to very good partial response in 1 year which eventually persisted after 4 years. No controlled prospective studies have defined the standard treatment for multiple myeloma with extramedullary spread particularly to the liver. Treatment of multiple myeloma with extramedullary disease follows guidelines for multiple myeloma. PMID- 29977631 TI - EBV Infection in XLP1 Manifested Solely by Behavioral Aggression and Effective Treatment Using Rituximab. AB - Patients with X-linked lymphoproliferative disease 1 (XLP1) are exquisitely susceptible to Epstein-Barr virus (EBV), with the first EBV infection often resulting in rapid death. In a manner not previously described, a 5-year-old patient with XLP1 presented solely with behavioral aggression, with no laboratory evidence of organ dysfunction or inflammation. Although EBV-IgM was negative, PCR confirmed the presence of EBV in both the blood and cerebrospinal fluid. MRI of the brain showed frontal lobe foci. After failure to eradicate his viremia with ganciclovir, rituximab was administered. EBV was eradicated from the blood after the second rituximab infusion and remained absent for 5 months, at which time he underwent hematopoietic stem cell transplant. Although EBV classically produces fulminant infection in patients with XLP1, this case demonstrates that EBV infection may be initially subtle. Acute change in behavior should prompt evaluation. This case also demonstrates the possible effectiveness of rituximab in the treatment of acute EBV infection. PMID- 29977632 TI - Intestinal Myiasis Caused by Sarcophaga spp. in Cusco, Peru: A Case Report and Review of the Literature. AB - Myiasis is the infestation by dipterous fly larvae in humans and animals. The larvae can infect living or necrotic tissue involving the skin, nasopharynx, genitourinary, and gastrointestinal tracts. The accidental ingestion of eggs causes infection of the intestinal tract. We report a case of intestinal myiasis caused by Sarcophaga spp. larvae in a two-year-old child from Limatambo province in the Cusco region of Peru. Live larvae were identified incidentally in this child's stool sample during the study screening for Strongyloides stercoralis. The child did not have any constitutional or abdominal symptoms. The morphological examination of the specimen under magnification revealed Sarcophaga spp. larvae. We performed a literature review of publications reporting intestinal myiasis caused by Sarcophaga spp. and discussed key aspects of this infestation. PMID- 29977633 TI - Inhaling Difluoroethane Computer Cleaner Resulting in Acute Kidney Injury and Chronic Kidney Disease. AB - Difluoroethane is the active ingredient in various computer cleaners and is increasingly abused by teenagers due to its ease of access, quick onset of euphoric effects, and lack of detectability on current urine drug screens. The substance has detrimental effects on various organ systems; however, its effects on the kidneys remain largely unreported. The following case report adds new information to the developing topic of acute kidney injury in patients abusing difluoroethane inhalants. In addition, it is one of the first to show a possible relationship between prolonged difluoroethane abuse and the development of chronic kidney disease in the absence of other predisposing risk factors. PMID- 29977634 TI - Unusual Case of a Torted Mesenteric Fibroid. AB - Extrauterine leiomyomas are very rare and present a clinical and diagnostic challenge due to their unusual growth patterns and behaviours. A 47-year-old woman was transferred to our tertiary specialist obstetrics and gynaecology hospital with acute abdominal pain and a palpable abdominal mass. She was taken immediately to theatre with the presumptive diagnosis of an ovarian torsion. Intraoperatively, a large necrotic mass originating from the mesentery and attachments to the bowel at the ileocaecal junction was noted. When converted to laparotomy due to limited access and poor visualisation, the uterus, ovaries, and tubes were found to be normal. A right partial hemicolectomy was performed with the assistance of the colorectal surgeon due to suspicion of bowel malignancy. Histology revealed a benign infarcted leiomyoma with adhesions to the adjacent ileum. The diagnosis of a primary torted mesenteric fibroid was made. PMID- 29977635 TI - Oncogenic Potential and Clinical Implications of Giant Endometrial Polyps: A Case Report and Literature Review. AB - Endometrial polyps exceeding 4 centimeters in length are exceedingly rare and are termed "giant polyps." We describe two patients that presented to our hospital with giant endometrial polyps. Clinical implications and oncologic potential of giant endometrial polyps are discussed. Risk factors of oncologic transformation include advanced age, menopausal status, obesity, diabetes, arterial hypertension, use of tamoxifen, and size greater than 1.0 centimeter. A literature review of all documented cases of giant endometrial polyps is presented and management strategies for counseling and polypectomy are reviewed. PMID- 29977636 TI - Renal Cell Carcinoma in a Horseshoe Kidney Treated with Laparoscopic Partial Nephrectomy. AB - Introduction: Horseshoe kidney is one of the most common congenital renal fusion anomalies. Due to its poor mobility and abnormal vasculature form, surgeons should pay close attention to all anatomical variations. Case Presentation: An 83 year-old woman was referred to our hospital because of left renal tumor in a horseshoe kidney incidentally found by her previous hospital. We performed laparoscopic partial nephrectomy. The pathological diagnosis was clear cell renal cell carcinoma. G2 INFalpha V-pT1a with a negative surgical margin. No evidence of recurrence has been noted, and the renal function is well preserved at 28 months after surgery. Conclusion: When performing laparoscopic partial nephrectomy for renal carcinoma, especially a horseshoe kidney, preoperative imaging is crucial for identifying the location of the renal vessels. PMID- 29977637 TI - Mediastinal Ectopic Pancreas with Abundant Endocrine Cells Coexisting with Mediastinal Cyst and Thymic Hyperplasia. AB - Mediastinal ectopic pancreas is a rare condition with only 28 cases reported in the literature. Here we report a 21-year-old female patient who presented with dyspnea and intermittent severe chest pain of 7 years' duration. Computerized tomography scan (CT-scan) of the chest revealed a mediastinal cyst. The cyst was resected and it demonstrated on histopathological examination the presence of pancreatic tissue with increased number of islets of Langerhans, coexistent with mediastinal cyst and thymic hyperplasia. We made a review of all previously reported cases of this entity. PMID- 29977638 TI - Aspirated Almond Masquerading as an Obstructing Endobronchial Mass Suspicious for Lung Cancer. AB - Foreign body aspiration is relatively rare in adults compared to children. In adults with delayed presentation, a history of choking is often absent, resulting in delayed diagnosis and significant morbidity. Common presenting features in adults include nonresolving cough with or without fever, hemoptysis, or wheezing and may mimic infectious, inflammatory, or neoplastic disorders. We present a case of a 64-year-old man with 80-pack-year smoking history who had a nonresolving left lower lobe infiltrate on chest radiograph after treatment for community-acquired pneumonia. His insidious-onset symptoms included cough, decreased exercise tolerance, and localized wheezing. Computed tomography of the chest showed a left lower lobe consolidation, with narrowing of the bronchus. Flexible bronchoscopy revealed a fleshy endobronchial mass, prompting endobronchial needle aspiration and biopsies, all of which revealed acute inflammation on rapid onsite evaluation. After multiple biopsies, a white pearly object with a detached brown cover was revealed; the object was found to be an aspirated almond. The almond and its peel were retrieved. The patient acknowledged that he had frequently eaten almonds in the supine position while recovering from a previous injury. His symptoms completely resolved at 3-month follow up, and he has ceased smoking and no longer consumes food while supine. PMID- 29977639 TI - Primary Angiosarcoma of the Breast after Bilateral Breast Reduction. AB - Angiosarcoma of the breast is a rare malignancy of endothelial cell origin, representing less than 1% of all breast malignancy. Primary angiosarcomas can occur in the setting of chronic lymphedema, but it also may occur spontaneously without any preceding treatment. Surgery is the primary therapeutic intervention for breast angiosarcomas with radiation and chemotherapy as adjuvant treatment. Angiosarcomas are aggressive and tend to have a high risk of local and metastatic recurrence. We present a case of primary angiosarcoma that developed in a patient who had bilateral breast reduction surgery in the past. PMID- 29977640 TI - Nerve Surgery to Treat Intractable Genitofemoral Neuropathic Pain following Laparoscopic Live Kidney Donation. AB - To date live laparoscopic donor nephrectomies (LLDN) are frequently performed. The most common complications entail bleeding, wound infection, and incisional hernia. Here we discuss a 50-year-old patient with a severe less known complication, namely, postoperative persistent neuropathic pain in the scrotum and left upper leg. Satisfactory pain control could not be obtained in 3 years of postoperative pain treatment which consisted of neuroleptic drugs, blocks of the L1/L2 dorsal roots with local anaesthetics, and pulsed radiofrequency lesioning. Exploratory laparoscopy was performed to assess the aspect of the genitofemoral nerve (GFN). A hemoclip used for the closure of the ureter at the time of nephrectomy was found in close relation to the GFN. The clip was removed and the GFN was subsequently cut proximal to the side of this clip. Soon after surgery the patient was completely pain-free and could return to his normal activities. Surgery should be considered in case of GFN neuropathic pain following LLDN. PMID- 29977641 TI - Evaluation of Tumor Viability for Primary and Bone Metastases in Metastatic Castration-Resistant Prostate Cancer Using Whole-Body Magnetic Resonance Imaging. AB - In contrast to bone scan and computed tomography (CT), which depend on osteoblastic response to detect bone metastasis, whole-body magnetic resonance imaging (WB-MRI) may be able to directly detect viable tumors. A 75-year-old male who had progressive metastatic prostate cancer during primary androgen deprivation therapy was referred to our hospital. Although bone scan and CT showed multiple bone metastases, WB-MRI suggested nonviable bone metastasis and viable tumor of the primary lesion. Prostate needle biopsy demonstrated viable prostate cancer cells from 10 of 12 cores. In contrast, CT-guided needle biopsy from bone metastasis of the lumbar vertebra revealed no malignant cells. Based on these findings, we reasoned that viable tumor cells inducing disease progression may primarily exist in the primary lesions and not in the metastatic lesions, and combined prostate radiotherapy and systemic hormonal therapy resulted in successful clinical response and disease control. The use of WB-MRI to detect viable disease lesions may enable us to design optimal treatment strategies for patients with metastatic castration-resistant prostate cancer. PMID- 29977642 TI - Rapid Identification and Simultaneous Quantification of Aristolochic Acids by HPLC-DAD and Confirmations by MS in Aristolochia chilensis Using a Limited Biomass. AB - Six aristolochic acids were identified in the Chilean species Aristolochia chilensis using high-performance liquid chromatography coupled to a diode array detector (HPLC-DAD) and subsequent confirmation with mass spectrometry (MS). The fractions of each signal were collected and injected directly into an Orbitrap mass detector model Q Exactive Focus (Thermo Scientific). The acids extraction was done with 0.10-0.50 g of lyophilized and pulverized sample and concentrated in Soxhlet extraction equipment. The liquid-liquid separations and a subsequent solid phase extraction (SPE) C18 were performed using 100 uL of the extract that contains the aristolochic acids present in the Aristolochia chilensis plant. The HPLC conditions used a single mobile phase acetonitrile : water (1 : 1) acidified with 0.1% acetic acid and an isocratic elution to 1 mL.min-1. The column InertSustain C18 250 * 4.6 mm and 3 um was used, the injection volume was 20 uL, and the time of run was reduced to 15 min. Calibration curves were constructed with r2 being 0.9997. The quantification limit for AAI was 0.138 +/- 0.010 ug/mL, and for AAII, it was 0.558 +/- 0.042 ug/mL. PMID- 29977643 TI - Retracted: Role of Wheat Based Diet on the Pathology of Necrotic Enteritis in Turkeys. AB - [This retracts the article DOI: 10.1155/2016/4381067.]. PMID- 29977645 TI - Screening for social determinants of health in clinical care: moving from the margins to the mainstream. AB - Background: Screening for the social determinants of health in clinical practice is still widely debated. Methods: A scoping review was used to (1) explore the various screening tools that are available to identify social risk, (2) examine the impact that screening for social determinants has on health and social outcomes, and (3) identify factors that promote the uptake of screening in routine clinical care. Results: Over the last two decades, a growing number of screening tools have been developed to help frontline health workers ask about the social determinants of health in clinical care. In addition to clinical practice guidelines that recommend screening for specific areas of social risk (e.g., violence in pregnancy), there is also a growing body of evidence exploring the use of screening or case finding for identifying multiple domains of social risk (e.g., poverty, food insecurity, violence, unemployment, and housing problems). Conclusion: There is increasing traction within the medical field for improving social history taking and integrating more formal screening for social determinants of health within clinical practice. There is also a growing number of high-quality evidence-based reviews that identify interventions that are effective in promoting health equity at the individual patient level, and at broader community and structural levels. PMID- 29977646 TI - A Prospective Look at the Link Between Frailty and Shoulder Function in Asymptomatic Elderly Individuals. AB - Introduction: The relationship between shoulder function and overall function in the elderly patients is not well understood. It is hypothesized that there is an increased tolerance of shoulder dysfunction in this population. The purpose of our study was to investigate and better understand the relationship between shoulder function, general musculoskeletal health, and frailty in the elderly patients. Materials and Methods: The dominant shoulders of 75 individuals aged >=65 years without known dominant shoulder pathology were assessed. Demographic data were collected. Functional evaluation was conducted by administering the Constant, American Shoulder and Elbow Surgeons (ASES), and the Short Musculoskeletal Function Assessment (SMFA) questionnaires. Shoulder range of motion and strength were measured and the Fried frailty phenotype was calculated. Mean age of the patients was 73.6 years. Sixty-seven percent of the patients were female. Mean body mass index was 31.2 kg/m2. Results: Twenty-eight percent of the patients reported the use of an assistive device for ambulation. As frailty increased among the 3 Fried frailty phenotypes (robust, prefrail, and frail), patients had statistically significant lower mean Constant scores (P < .0001), ASES scores (P < .0001), higher overall SMFA scores (P < .0001), and an increase in the use of assistive device for ambulation. Individuals who reported the use of an assistive device for ambulation had lower Constant and ASES scores (P < .0001 and P = .045, respectively) and higher overall SMFA scores (P < .0001). There was no evidence of correlation between body mass index and any of the other measures. Conclusions: Frailty and the use of an assistive device for ambulation correlate with poor shoulder function in patients who do not register shoulder complaints and have no known shoulder pathology. Level of Evidence: Level IV, Prognostic. PMID- 29977647 TI - The Eyes Have It: Eyelid Swelling and Rash in a 79-year-old Woman With Macular Degeneration. AB - Introduction: A 79-year-old woman with macular degeneration was referred to the Allergy/Immunology clinic for the evaluation of a potential allergy to anti vascular endothelial growth factor (anti-VEGF) treatments. The patient developed urticaria and eyelid swelling immediately following a retinal injection of aflibercept, which she had previously tolerated. She previously had allergic reactions following ranibizumab and bevacizumab injections. Injections of anti VEGF treatments were discontinued given concern for allergy with progression of the patient's disease. Objective: To assess the culprit medication(s) responsible for hypersensitivity reactions following anti-VEGF injections for macular degeneration. Methods: Medication records were reviewed for each retinal injection. All medications used in each procedure, including the anti-VEGF therapy (aflibercept), topical anesthetics (tetracaine and proparacaine hydrochloride), and antiseptic (povidine), were evaluated with skin testing. She was additionally tested for alternative anti-VEGF therapies (ranibizumab and bevacizumab) as she was thought to have allergies to these agents by prior history. A test dose challenge was completed for aflibercept, ranibizumab, and bevacizumab. Results: Skin prick and intradermal testing were negative to aflibercept, ranibizumab, bevacizumab, and povidine. Intradermal testing was positive to tetracaine and proparacaine hydrochloride. The patient passed test dose challenges to aflibercept, ranibizumab, and bevacizumab. Due to her positive hypersensitivity testing to 2 ester anesthetics, the patient underwent skin prick and intradermal testing to the amide anesthetic, lidocaine. This was negative and the patient tolerated a graded challenge to lidocaine. She was deemed to have an immunoglobulin E (IgE)-mediated hypersensitivity to ester-type local anesthetics. She successfully resumed anti-VEGF therapy with an amide local anesthetic. Conclusions: The reason for this consult was the concern for hypersensitivity to a biologic anti-VEGF medication. The culprit allergen, the local anesthetic, could have been overlooked without an assessment of all medications used during the procedure. This case highlights the importance of a thorough allergy evaluation of all medications used during procedures to determine the causative agent.Chief Complaint: Eyelid swelling and rash after ophthalmic procedures for macular degeneration. PMID- 29977644 TI - Primary sclerosing cholangitis: A review and update. AB - Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease of uncertain etiology characterized biochemically by cholestasis and histologically and cholangiographically by fibro-obliterative inflammation of the bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and/or hepatobiliary cancer, though the disease course can be highly variable. Despite clinical trials of numerous pharmacotherapies over several decades, safe and effective medical therapy remains to be established. Liver transplantation is an option for select patients with severe complications of PSC, and its outcomes are generally favorable. Periodic surveillance testing for pre- as well as post-transplant patients is a cornerstone of preventive care and health maintenance. Here we provide an overview of PSC including its epidemiology, etiopathogenesis, clinical features, associated disorders, surveillance, and emerging potential therapies. PMID- 29977648 TI - Description of Baseline Characteristics of Pediatric Allergic Asthma Patients Including those Initiated on Omalizumab. AB - Background: Indication of omalizumab in the United States was recently extended to include pediatric (6-11 years) uncontrolled moderate-to-severe allergic asthma patients. Objective: The purpose of this study was to describe baseline characteristics of this population from a real-world dataset. Methods: Allergic asthma patients and uncontrolled moderate-to-severe allergic asthma patients, aged 6-11 years, were identified in the Allergy Partners Network Electronic Medical Records (2007-2016). The index date for allergic asthma patients was the latest between the second asthma-related visit and the allergic status confirmation. Uncontrolled moderate-to-severe allergic asthma patients were stratified into omalizumab-exposed (index date) or omalizumab-unexposed (index date randomly generated) groups. Characteristics were evaluated during the 12 month preindex period. Results: A total of 5806 allergic asthma, 37 omalizumab exposed, and 2620 omalizumab-unexposed patients were selected (mean age approximately 9 years). Allergic asthma and omalizumab-unexposed patients were predominantly white (70.2% and 61.2%) whereas the majority of omalizumab-exposed were African Americans (62.2%). Mean immunoglobulin E was 782.0 IU/ml in allergic asthma patients (available in 2.2%), 1134.4 IU/ml in omalizumab-exposed (available in 100.0%), and 746.1 IU/ml in omalizumab-unexposed (available in 3.1%). Allergic asthma patients were less severe than omalizumab-exposed and omalizumab-unexposed based on the forced expiratory volume in 1 s as a percentage of predicted value (FEV1% predicted) and the Childhood Asthma Control Test (C ACT). FEV1% predicted was below normal (<80%) in 42.4% of omalizumab-exposed and 39.1% of omalizumab-unexposed patients, also 63.6% of omalizumab-exposed and 46.7% of omalizumab-unexposed had uncontrolled asthma (C-ACT score <20). In African American omalizumab-exposed patients, FEV1% predicted was below normal in 47.6% and 55.0% had uncontrolled asthma. Conclusions: In a real-world setting, pediatric patients with uncontrolled moderate-to-severe allergic asthma have a significant disease burden as shown by high rates of poor lung function, disease control, and symptoms. Currently available treatments could help improve disease management in this population. PMID- 29977649 TI - Fenugreek Anaphylaxis in a Pediatric Patient. AB - Fenugreek (Trigonella foenum-graecum) is a food product that belongs to the Leguminosae family along with other legumes. It has been used in India, Greece, and Egypt for culinary and medical purposes since ancient times, and today, fenugreek is used for flavoring foods, dyes, and drugs throughout the world. Many members of the Leguminosae family have been associated with allergies including soybean, green pea, and peanut. Fenugreek is also included in this family and may result in allergic reactions. Two cases of anaphylaxis have been described in children after ingestion of curry and pastes that contain fenugreek, although the true nature of the causative agent was unclear. We report the first case of fenugreek anaphylaxis in a pediatric patient defined by skin testing, immunoglobulin E ImmunoCAP assays, and clear ingestion. PMID- 29977651 TI - A needle in a haystack: Endoscopic removal of a foreign body from the infratemporal fossa. AB - Background: This report presented the case of a difficult-to-remove needle foreign body. The patient had a dental procedure in which a 30-gauge needle was lost in the gingival buccal sulcus. Several attempts at removal were unsuccessful. The patient presented to the otolaryngology clinic with trismus, pain with mastication, intermittent right otalgia, and numbness of the right cheek. Methods: The needle was finally localized in the infratemporal fossa and removed by using image guidance technology. Results: This case demonstrated an approach to a difficult-to-locate foreign body removal and the importance of intraoperative imaging in foreign body localization. Conclusion: Foreign bodies of the infratemporal fossa and posterior orbit are better removed via endoscopic than open technique. PMID- 29977650 TI - Amlodipine-induced angioedema: An unusual complication of a common medication. AB - Hypersensitivity reactions to dihydropyridine calcium channel blockers (CCB) are exceedingly rare, although sporadic reports of isolated angioedema seem to be gradually increasing in frequency. We present a case of angioedema likely triggered by amlodipine. PMID- 29977652 TI - Anti-inflammatory effect of wogonin on allergic responses in ovalbumin-induced allergic rhinitis in the mouse. AB - Background: Wogonin is commonly used for the treatment of allergic diseases. However, neither its precise effect in preventing allergic rhinitis (AR) nor its mechanism of action are known. Objectives: In this study, the effect of wogonin on allergic responses in ovalbumin (OVA) induced AR was investigated in mice. Methods: BALB/c mice were sensitized with intraperitoneal (i.p.) OVA and then challenged intranasally with OVA. Wogonin (10 and 30 mg/kg) was given to the treatment groups, and the effect of wogonin on the release of allergic inflammatory mediators, specifically OVA-specific immunoglobulin E (IgE) and inflammatory cytokines, was explored. Eosinophil infiltration and the levels of interleukin (IL) 5 and IL-13 were measured by immunohistochemistry. Results: In mice with AR, wogonin decreased OVA-specific IgE levels in serum, and the levels of the cytokines IL-4, IL-5, IL-13, eotaxin, and RANTES in nasal lavage fluid. Serum levels of IL-4, IL-5, and IL-13 were lower in both groups of wogonin pretreated mice than in the OVA group. A reduction in eosinophil infiltration of the nasal mucosa and inhibition of the expression of IL-5 and IL-13 were also noted in the treated groups. Conclusion: Wogonin induced antiallergic effects in a murine model of AR by decreasing the infiltration of eosinophils and levels of T-helper type 2 cytokines. Thus, wogonin merits consideration as a therapeutic agent for treating AR. PMID- 29977653 TI - Analysis of differential expression of protease-activated receptors in patients with allergic fungal rhinosinusitis. AB - Background: Ever since its characterization in the 1970s, allergic fungal rhinosinusitis (AFRS) has been the subject of much controversy, especially regarding its pathogenesis. In this study, we analyzed the differential expression of genes that encode protease-activated receptors (PAR) in patients with AFRS and patients with chronic rhinosinusitis, and tried to understand the pathogenic basis of this disease. Objective: To analyze the differential expression of PAR genes in patients with AFRS and in patients with chronic rhinosinusitis. Methods: Mucosa from ethmoid sinuses of 51 patients (tests and controls) was biopsied and evaluated for messenger RNA expression of PAR genes by using reverse transcriptase-polymerase chain reaction. Each of the four PAR genes, i.e., par1, par2, par3 and par4 was amplified, the final gene products were run on 1.8% agarose gel and analyzed by densitometry to calculate differential expression. The significance level was determined as p <= 0.05. Results: It was observed that the expressions of all four par genes were higher in the test samples compared with the controls, but statistical significance was achieved only for par1 (p=0.004) and par2 (p=0.05). Comparative expression of the four PAR genes was also performed within the test and control groups, and a statistically significant difference was seen between par1 and par2 (p=0.007), par1 and par3 (p=0.029), par1 and par4 (p=0.0001), par2 and par4 (p=0.002), and par3 and par4 (p=0.009) in the test group. In the control group as well, par1, par2, and par3 exhibited a higher expression compared with par4 but the difference was significant between par3 and par4 genes only. Conclusion: Patients with AFRS expressed increased levels of PAR genes in their nasal mucosa, and, of the four PAR genes, a higher expression of par1, par2, and par3 was observed in both the groups compared with par4. This information contributes toward our understanding of pathogenesis and possibly treatment of AFRS. PMID- 29977654 TI - Sinonasal epithelial-myoepithelial carcinoma: Report of a novel subsite and review of the literature. AB - Background: Epithelial-myoepithelial carcinoma (EMC) is a rare tumor of the major and minor salivary glands. Sinonasal EMC is extremely uncommon and hitherto not described within the frontal or ethmoid sinuses. Objective: To present a novel sinonasal subsite and review the literature regarding sinonasal EMC. Methods: A case of frontoethmoidal EMC was presented. A medical literature data base was queried from January 1, 1950, to August 8, 2017, for all reports of sinonasal EMC. Results: A 69-year-old man underwent combined open and endoscopic craniofacial resection of a right frontoethmoidal EMC, a previously undescribed primary location for this tumor. A comprehensive review of the literature revealed 13 additional cases of sinonasal EMC. Conclusion: EMC is an uncommon neoplasm typically found in the major salivary glands; occurrence in the nose or paranasal sinuses is extremely rare. EMC often follows an indolent clinical course, although, in a minority of cases, particularly in large tumors with nuclear atypia, more aggressive behavior may be observed. PMID- 29977655 TI - Diagnostic dilemmas of mechanical restriction of the medial rectus: A case report. AB - Background: Due to the proximity of the maxillary sinus and ethmoid sinuses to the orbit, inflammatory processes that originate in the sinonasal region have the potential to extend into the orbit. Objective: We presented a case of ptosis and restrictive strabismus of the medial rectus muscle. Methods: A case report with a literature review of possible diagnoses. Results: Biopsy, imaging, and laboratory evaluation by otolaryngology, ophthalmology, and rheumatology services were unable to identify the cause of the fibrosis after 22 months of follow-up. A response to oral steroids indicated an inflammatory process. Conclusion: Unilateral mechanical restriction of the medial rectus muscle is a rare complication of nasal disease. Inflammatory processes and iatrogenic injury are known to cause fibrosis of surrounding tissue. We presented a unique case of medial rectus fibrosis that did not meet the diagnostic criteria of recognized etiologies. PMID- 29977657 TI - Relationship Between Rhinitis, Asthma, and Eczema and the Presence of Sensitization in Young Swiss Adults. AB - Background: Rhinitis is a very common disease with allergies being the most frequent causative factor. It can co-occur together with asthma and eczema in atopic as well as in nonatopic patients. Objectives: To assess the prevalence of allergic sensitization within patient groups with rhinitis in consideration of the co-occurring disorders of asthma and eczema. Methods: Students of the third year of medical school completed an anonymous questionnaire on age, gender, and clinical symptoms, such as seasonal rhinitis, perennial rhinitis, asthma, and eczema, and underwent an ImmunoCAP Rapid test. We calculated the prevalence of sensitization within subgroups of patients reporting allergic disorders, such as rhinitis, asthma, and eczema. Results: Questionnaires and ImmunoCAP Rapid tests of 1513 medical students were analyzed. The participants' self-reported presence of seasonal/perennial rhinitis, asthma, and eczema was compared to the presence of sensitization. Data of 1467 subjects could be analyzed. Seasonal rhinitis was the most common symptom, followed by eczema, asthma, and perennial rhinitis. The participants were differentiated into 16 subgroups according to the combined clinical manifestations of the different symptoms and association to sensitization within subgroups. The prevalence of sensitization ranged from 18% in subjects reporting only eczema without any other symptom to 100% in those reporting to have asthma, seasonal/perennial rhinitis, and eczema together. In subjects reporting no sign or symptom at all, the prevalence of sensitization was 19%. Seasonal rhinitis was the strongest single predictor for sensitization with the highest proportion of sensitized participants in all symptom combinations (67%-100%), followed by perennial rhinitis (31%-100%), asthma (30%-100%), and eczema (18%-100%). Conclusion: Rhinitis most often is associated with allergen sensitization, and the probability of sensitization is substantially enhanced by co-occurrence of asthma. A careful assessment of clinical signs and symptoms is important and enables the selection of patients in whom targeted diagnostic analysis and therapy is appropriate.Trial registration: retrospectively registered by the Cantonal Ethics Committee Zurich on 22.01.2016; Nr: 08-2016. PMID- 29977658 TI - Effect of a Novel Photoelectrochemical Oxidation Air Purifier on Nasal and Ocular Allergy Symptoms. AB - Background: Photoelectrochemical oxidation (PECO) is a new air purification technology developed to reduce circulating indoor allergens. PECO removes particles as small as 0.1 nm with the destruction of organic matter otherwise not trapped by a traditional filter and removes volatile organic compounds. Objective: We hypothesized that with daily use, the device would reduce user nasal and ocular allergy total symptom scores (TSS) within 4 weeks. Methods: The study was performed among 46 individuals with self-reported allergies using a portable PECO air purifier. Self-reported TSS were calculated at baseline and weekly for 4 weeks following initiation of continuous use of the system. TSS was the sum of total nasal symptom scores (TNSS) and total ocular symptom scores (TOSS) for the week. Results: There was a statistically significant change in overall TSS from baseline to 4 weeks (10.1 at baseline and 4.35 postintervention) resulting in a mean difference of 5.75 (95% confidence interval [CI] 4.32-7.18; P < .0001). There was a statistically significant change in TNSS from baseline to 4 weeks (6.3 at baseline and 3.04 postintervention) resulting in a mean difference of 3.26 (95% CI 2.33-3.19; P < .0001). There was a statistically significant change in TOSS from baseline to 4 weeks (3.82 at baseline and 1.3 postintervention) resulting in a mean difference of 2.52 (95% CI 1.74-3.3; P < .0001). Conclusion: With the use of PECO air purification technology, TSS, TNSS, and TOSS decreased significantly. These improvements were consistent over the 4 week course of device use. PMID- 29977659 TI - Deep Gramulator: Improving Precision in the Classification of Personal Health Experience Tweets with Deep Learning. AB - Health surveillance is an important task to track the happenings related to human health, and one of its areas is pharmacovigilance. Pharmacovigilance tracks and monitors safe use of pharmaceutical products. Pharmacovigilance involves tracking side effects that may be caused by medicines and other health related drugs. Medical professionals have a difficult time collecting this information. It is anticipated that social media could help to collect this data and track side effects. Twitter data can be used for this task given that users post their personal health related experiences on-line. One problem with Twitter data, however, is that it contains a lot of noise. Therefore, an approach is needed to remove the noise. In this paper, several machine learning algorithms including deep neural nets are used to build classifiers that can help to detect these Personal Experience Tweets (PETs). Finally, we propose a method called the Deep Gramulator that improves results. Results of the analysis are presented and discussed. PMID- 29977656 TI - Autonomic nervous system dysfunction and sinonasal symptoms. AB - Background: The autonomic nervous system (ANS) richly innervates the nose and paranasal sinuses, and has a significant role in lower airway diseases, e.g., asthma. Nonetheless, its contribution to sinonasal symptoms is poorly understood. This review aimed to explore the complex relationship between the ANS and sinonasal symptoms, with reference to systemic diseases and triggers of ANS dysfunction. Methods: A review of articles published in English was conducted by searching medical literature databases with the key words "autonomic nervous system" and ("sinusitis" or "nose" or "otolaryngology"). All identified abstracts were reviewed, and, from these, relevant published whole articles were selected. Results: The ANS has a significant role in the pathophysiologic mechanisms that produce sinonasal symptoms. There was limited evidence that describes the relationship of the ANS in sinonasal disease with systemic conditions, e.g. hypertension. There was some evidence to support mechanisms related to physical and psychological stressors in this relationship. Conclusion: The role of ANS dysfunction in sinonasal disease is highly complex. The ANS sits within a web of multiple factors, including personality and psychological distress, that contribute to sinonasal symptoms. Further research will help to clarify the etiology of ANS dysfunction and its contribution to common systemic conditions. PMID- 29977660 TI - Prophylactic Hypogastric Artery Ligation during Placenta Percreta Surgery: A Retrospective Cohort Study. AB - Objective To evaluate if prophylactic hypogastric artery ligation (HAL) decreases surgical blood loss and blood products transfused. Study Design This is a retrospective cohort study comparing patients with placenta percreta undergoing prophylactic HAL at the time of cesarean hysterectomy versus those who did not. Data were presented as means +/- standard deviations, proportions, or medians with interquartile ranges. Demographic and clinical data were compared in the groups using Student's t -test for normally distributed data or the Mann Whitney U test for nonnormally distributed data. Fisher's exact test was used for proportions and categorical variables. Data are reported as significant where p was <0.05. Results There were 26 patients included in the control group with no HAL and 11 patients included in the study group. Estimated blood loss for the study group was 1,000 mL versus 800 mL in the control. Units of PRCBs transfused were 4.5 units in the study group versus 2 units for the control group. None of these measures were found to be statistically significant. Conclusion Our data suggest there was no benefit in the use of prophylactic HAL in decreasing surgical blood loss or amount of blood products transfused in patients who had a cesarean hysterectomy performed for placenta percreta. Precis Prophylactic HAL does not decrease blood loss during surgery for placenta percreta. PMID- 29977661 TI - Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature. AB - Background: Bone marrow transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively frequent but under-recognized and under-treated hematopoietic stem cell transplant (HSCT) complication that leads to significant post transplant morbidity and mortality. Classic TMA-defining laboratory abnormalities appear at different times in the course of TA-TMA development, with schistocytes often appearing later in the disease course. In some severe TMA cases, schistocytes may be absent due to increased endothelial permeability. Unfortunately, many clinicians continue to perceive the presence of schistocytes as an absolute requirement for TA-TMA diagnosis, which leads to delayed recognition and treatment of this potentially fatal transplant complication. Methods: Patient chart review and PubMed literature search using the term, "transplant-associated thrombotic microangiopathy". Case presentation: A 54-year old male IgG kappa multiple myeloma underwent a reduced intensity allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with fludarabine and melphalan. On day + 27, the patient developed acute kidney injury followed by repeated episodes of diarrhea and gastrointestinal bleeding attributed to graft versus host disease (GVHD) and cytomegalovirus (CMV) colitis. Repeated colonic biopsies suggested CMV infection and GVHD. Despite appropriate treatment with antiviral therapy and immunosuppressants, the patient's condition continued to deteriorate. He experienced concomitant anemia and thrombocytopenia as well as elevated lactate dehydrogenase and low haptoglobin levels, but a TA-TMA diagnosis was not made due to an absence of schistocytes on peripheral smear. The patient expired secondary to uncontrolled gastrointestinal bleeding. A post-mortem analysis of the resection specimen revealed extensive TMA involving numerous arteries and arterioles in the ileal and colonic submucosa as well as in the muscularis propria and deep lamina propria of the mucosa. Conclusions: TA-TMA can occur in the absence of peripheral blood schistocytes. Our experience underscores the importance of considering the diagnosis of intestinal TA-TMA in patients with refractory post-transplant diarrhea and GI bleeding, even if all classic features are not present. PMID- 29977662 TI - Robotic Remote Controlled Stereo Slit Lamp. AB - Purpose: Our purpose was to develop a robotic remotely operated stereo slit lamp system allowing three-dimensional stereo viewing and recording of the patient's examination via local area network, Internet, and satellite. Methods: A commercial slit lamp was modified to accept motors and servos to permit control of all optical and mechanical components of the device. The custom graphical user interface with dual high-resolution real-time stereoscopic imaging, control/position indicators, overview video, and audio were transmitted via local area network, Internet, and satellite. Under University of Miami Institutional Review Board authorization, Internet connectivity enabled multiple examiners to simultaneously view and control the slit lamp and to collaboratively discuss diagnosis and treatment options. The remote clinicians used a tablet, laptop, or desktop computer to view and control the slit lamp. Results: The network, Internet, satellite-connected system was controllable from the United States, Europe, and Canada while acquiring high-resolution, real-time video in all subjects. Control of the slit lamp through Ethernet, WiFi, and 4G exhibited total system latencies of 464 +/- 58, 483 +/- 64, and 870 +/- 66 milliseconds when transmitting within the continent, and Ethernet control exhibited a latency of 606 +/- 130 milliseconds when transmitting between continents. High- and low magnification images of healthy volunteers were acquired by a remote clinician. Conclusions: The robotic remotely operated stereo slit lamp system allows three dimensional stereo viewing and recording of the patient's examination via local area network, Internet, and satellite. Translational Relevance: The robotic remotely controlled stereo slit lamp system enables remote examination of human subjects. PMID- 29977664 TI - Distinctive facial features in idiopathic Moyamoya disease in Caucasians: a first systematic analysis. AB - Background: Craniofacial dysmorphic features are morphological changes of the face and skull which are associated with syndromic conditions. Moyamoya angiopathy is a rare cerebral vasculopathy that can be divided into Moyamoya syndrome, which is associated or secondary to other diseases, and into idiopathic Moyamoya disease. Facial dysmorphism has been described in rare genetic syndromes with associated Moyamoya syndrome. However, a direct relationship between idiopathic Moyamoya disease with dysmorphic facial changes is not known yet. Methods: Landmarks were manually placed on frontal photographs of the face of 45 patients with bilateral Moyamoya disease and 50 matched controls. After procrustes alignment of landmarks a multivariate, penalized logistic regression (elastic-net) was performed on geometric features derived from landmark data to classify patients against controls. Classifiers were visualized in importance plots that colorcode importance of geometric locations for the classification decision. Results: The classification accuracy for discriminating the total patient group from controls was 82.3% (P-value = 6.3*10-11, binomial test, a priori chance 50.2%) for an elastic-net classifier. Importance plots show that differences around the eyes and forehead were responsible for the discrimination. Subgroup analysis corrected for body mass index confirmed a similar result. Discussion: Results suggest that there is a resemblance in faces of Caucasian patients with idiopathic Moyamoya disease and that there is a difference to matched controls. Replication of findings is necessary as it is difficult to control all residual confounding in study designs such as ours. If our results would be replicated in a larger cohort, this would be helpful for pathophysiological interpretation and early detection of the disease. PMID- 29977665 TI - Mass Spectrometry-Inspired Degradation of Disinfection By-Product, 2,6-Dichloro 1,4-benzoquinone, in Drinking Water by Heating. AB - 2,6-Dichloro-1,4-benzoquinone (DCBQ), a highly toxic and carcinogenic disinfection by-product, was degraded during the electrospray process by elevating the source temperature. This unexpected finding inspired us to use heating to degrade DCBQs in drinking water. The results show that about 99% of DCBQs in the drinking water were degraded in one minute by heating to 100 degrees C with room light irradiation. Therefore, a conclusion can be drawn that heating enables the degradation of DCBQs in drinking water. PMID- 29977663 TI - Genetic Modifiers in Neurodegeneration. AB - PURPOSE OF REVIEW: To review the evidence for genetic modifier effects in the neurodegenerative diseases Huntington's Disease (HD), Frontotemporal Lobar Degeneration (FTLD), Alzheimer's Disease (AD), and Parkinson's Disease (PD). RECENT FINDINGS: Increasingly, we understand human disease genetics less through the lens of single-locus/single-trait effects, and more through that of polygenic contributions to disease risk. In addition, specific examples of genetic modifier effects of the chromosome 7 gene TMEM106B on various target genes including those causal for Mendelian classes of FTLD - GRN and c9orf72 - have emerged from both genetic cohort studies and mechanistic examinations of biological pathways. SUMMARY: Here, we summarize the literature reporting genetic modifier effects in HD, FTLD, AD, and PD. We further contextualize reported genetic modifier effects in these diseases in terms of insight they may lend to the concept of a polygenic landscape for the major neurodegenerative diseases. PMID- 29977666 TI - Chemistry for electron-induced nanofabrication. PMID- 29977667 TI - New 2D graphene hybrid composites as an effective base element of optical nanodevices. AB - For the first time, we estimated perspectives for using a new 2D carbon nanotube (CNT)-graphene hybrid nanocomposite as a base element of a new generation o optical nanodevices. The 2D CNT-graphene hybrid nanocomposite was modelled by two graphene monolayers between which single-walled CNTs with different diameters were regularly arranged at different distances from each other. Spectra of the real and imaginary parts of the diagonal elements of the surface conductivity tensor for four topological models of the hybrid nanocomposite have been obtained. The absorption coefficient for p-polarized and s-polarized radiation was calculated for different topological models of the hybrid nanocomposite. It was found that the characteristic peaks with high intensity appear in the UV region at wavelengths from 150 to 350 nm (related to graphene) and in the optical range from 380 to 740 nm irrespective of the diameter of the tubes and the distance between them. For waves corresponding to the most intense peaks, the absorption coefficient as a function of the angle of incidence was calculated. It was shown that the optical properties of the hybrid nanocomposite were approximately equal for both metallic and semiconductor nanotubes. PMID- 29977668 TI - Atomic-level characterization and cilostazol affinity of poly(lactic acid) nanoparticles conjugated with differentially charged hydrophilic molecules. AB - Nanotherapeutics is a promising field for numerous diseases and represents the forefront of modern medicine. In the present work, full atomistic computer simulations were applied to study poly(lactic acid) (PLA) nanoparticles conjugated with polyethylene glycol (PEG). The formation of this complex system was simulated using the reactive polarizable force field (ReaxFF). A full picture of the morphology, charge and functional group distribution is given. We found that all terminal groups (carboxylic acid, methoxy and amino) are randomly distributed at the surface of the nanoparticles. The surface design of NPs requires that the charged groups must surround the surface region for an optimal functionalization/charge distribution, which is a key factor in determining physicochemical interactions with different biological molecules inside the organism. Another important point that was investigated was the encapsulation of drugs in these nanocarriers and the prediction of the polymer-drug interactions, which provided a better insight into structural features that could affect the effectiveness of drug loading. We employed blind docking to predict NP-drug affinity testing on an antiaggregant compound, cilostazol. The results suggest that the combination of molecular dynamics ReaxFF simulations and blind docking techniques can be used as an explorative tool prior to experiments, which is useful for rational design of new drug delivery systems. PMID- 29977669 TI - Andreev spectrum and supercurrents in nanowire-based SNS junctions containing Majorana bound states. AB - Hybrid superconductor-semiconductor nanowires with Rashba spin-orbit coupling are arguably becoming the leading platform for the search of Majorana bound states (MBSs) in engineered topological superconductors. We perform a systematic numerical study of the low-energy Andreev spectrum and supercurrents in short and long superconductor-normal-superconductor junctions made of nanowires with strong Rashba spin-orbit coupling, where an external Zeeman field is applied perpendicular to the spin-orbit axis. In particular, we investigate the detailed evolution of the Andreev bound states from the trivial into the topological phase and their relation with the emergence of MBSs. Due to the finite length, the system hosts four MBSs, two at the inner part of the junction and two at the outer one. They hybridize and give rise to a finite energy splitting at a superconducting phase difference of pi, a well-visible effect that can be traced back to the evolution of the energy spectrum with the Zeeman field: from the trivial phase with Andreev bound states into the topological phase with MBSs. Similarly, we carry out a detailed study of supercurrents for short and long junctions from the trivial to the topological phases. The supercurrent, calculated from the Andreev spectrum, is 2pi-periodic in the trivial and topological phases. In the latter it exhibits a clear sawtooth profile at a phase difference of pi when the energy splitting is negligible, signalling a strong dependence of current-phase curves on the length of the superconducting regions. Effects of temperature, scalar disorder and reduction of normal transmission on supercurrents are also discussed. Further, we identify the individual contribution of MBSs. In short junctions the MBSs determine the current-phase curves, while in long junctions the spectrum above the gap (quasi-continuum) introduces an important contribution. PMID- 29977670 TI - Disorder-induced suppression of the zero-bias conductance peak splitting in topological superconducting nanowires. AB - We investigate the effect of three types of intrinsic disorder, including that in pairing energy, chemical potential, and hopping amplitude, on the transport properties through the superconducting nanowires with Majorana bound states (MBSs). The conductance and the noise Fano factor are calculated based on a tight binding model by adopting a non-equilibrium Green's function method. It is found that the disorder can effectively lead to a reduction in the conductance peak spacings and significantly suppress the peak height. Remarkably, for a longer nanowire, the zero-bias peak could be reproduced by weak disorder for a finite Majorana energy splitting. It is interesting that the shot noise provides a signature to discriminate whether the zero-bias peak is induced by Majorana zero mode or disorder. For Majorana zero mode, the noise Fano factor approaches zero in the low bias voltage limit due to the resonant Andreev tunneling. However, the Fano factor is finite in the case of a disorder-induced zero-bias peak. PMID- 29977671 TI - Interplay between pairing and correlations in spin-polarized bound states. AB - We investigate single and multiple defects embedded in a superconducting host, studying the interplay between the proximity-induced pairing and interactions. We explore the influence of the spin-orbit coupling on energies, polarization and spatial patterns of the bound (Yu-Shiba-Rusinov) states of magnetic impurities in a two-dimensional square lattice. We also address the peculiar bound states in the proximitized Rashba chain, resembling the Majorana quasiparticles, focusing on their magnetic polarization that has been recently reported by S. Jeon et al. (Science2017,358, 772). Finally, we study leakage of these polarized Majorana quasiparticles into side-attached nanoscopic regions and confront them with the subgap Kondo effect near to the singlet-doublet phase transition. PMID- 29977672 TI - Electrostatically actuated encased cantilevers. AB - Background: Encased cantilevers are novel force sensors that overcome major limitations of liquid scanning probe microscopy. By trapping air inside an encasement around the cantilever, they provide low damping and maintain high resonance frequencies for exquisitely low tip-sample interaction forces even when immersed in a viscous fluid. Quantitative measurements of stiffness, energy dissipation and tip-sample interactions using dynamic force sensors remain challenging due to spurious resonances of the system. Results: We demonstrate for the first time electrostatic actuation with a built-in electrode. Solely actuating the cantilever results in a frequency response free of spurious peaks. We analyze static, harmonic, and sub-harmonic actuation modes. Sub-harmonic mode results in stable amplitudes unaffected by potential offsets or fluctuations of the electrical surface potential. We present a simple plate capacitor model to describe the electrostatic actuation. The predicted deflection and amplitudes match experimental results within a few percent. Consequently, target amplitudes can be set by the drive voltage without requiring calibration of optical lever sensitivity. Furthermore, the excitation bandwidth outperforms most other excitation methods. Conclusion: Compatible with any instrument using optical beam deflection detection electrostatic actuation in encased cantilevers combines ultra-low force noise with clean and stable excitation well-suited for quantitative measurements in liquid, compatible with air, or vacuum environments. PMID- 29977673 TI - Nanoporous silicon nitride-based membranes of controlled pore size, shape and areal density: Fabrication as well as electrophoretic and molecular filtering characterization. AB - A new route will be presented for an all-parallel fabrication of highly flexible, freestanding membranes with well-defined porosity. This fabrication is based on arrays of well-defined Au nanoparticles (NPs) exhibiting a high degree of hexagonal order as obtained in a first step by a proven micellar approach. These NP arrays serve as masks in a second reactive ion etching (RIE) step optimized for etching Si and some important Si compounds (silicon oxide, silicon nitride) on the nanoscale. Application to commercially available silicon nitride membranes of well-defined thickness, delivers a diaphragm with millions of nanopores of intended and controlled size, shape, and areal density with narrow distributions of these parameters. Electrophoretic transport measurements indicated a very low flow resistance of these porous membranes in ionic solutions as expected theoretically. Size-selective separation of protein molecules was demonstrated by real-time fluorescence microscopy. PMID- 29977674 TI - Predicting the strain-mediated topological phase transition in 3D cubic ThTaN3. AB - The cubic ThTaN3 compound has long been known as a semiconductor with a band gap of approximately 1 eV, but its electronic properties remain largely unexplored. By using density functional theory, we find that the band gap of ThTaN3 is very sensitive to the hydrostatic pressure/strain. A Dirac cone can emerge around the Gamma point with an ultrahigh Fermi velocity at a compressive strain of 8%. Interestingly, the effect of spin-orbital coupling (SOC) is significant, leading to a band gap reduction of 0.26 eV in the ThTaN3 compound. Moreover, the strong SOC can turn ThTaN3 into a topological insulator with a large inverted gap up to 0.25 eV, which can be primarily attributed to the inversion between the d-orbital of the heavy element Ta and the p-orbital of N. Our results highlight a new 3D topological insulator with strain-mediated topological transition for potential applications in future spintronics. PMID- 29977675 TI - Robust midgap states in band-inverted junctions under electric and magnetic fields. AB - Several IV-VI semiconductor compounds made of heavy atoms, such as Pb1-x Sn x Te, may undergo band-inversion at the L point of the Brillouin zone upon variation of their chemical composition. This inversion gives rise to topologically distinct phases, characterized by a change in a topological invariant. In the framework of the k.p theory, band-inversion can be viewed as a change of sign of the fundamental gap. A two-band model within the envelope-function approximation predicts the appearance of midgap interface states with Dirac cone dispersions in band-inverted junctions, namely, when the gap changes sign along the growth direction. We present a thorough study of these interface electron states in the presence of crossed electric and magnetic fields, the electric field being applied along the growth direction of a band-inverted junction. We show that the Dirac cone is robust and persists even if the fields are strong. In addition, we point out that Landau levels of electron states lying in the semiconductor bands can be tailored by the electric field. Tunable devices are thus likely to be realizable, exploiting the properties studied herein. PMID- 29977676 TI - Colorimetric detection of Cu2+ based on the formation of peptide-copper complexes on silver nanoparticle surfaces. AB - We developed a colorimetric method for the rapid detection of copper ions (Cu2+) in aqueous solution. The detection of Cu2+ is based on coordination reactions of Cu2+ with casein peptide-functionalized silver nanoparticles (AgNPs), leading to a distinct color change of the solution from yellow to red. The developed method has a good detection limit of about 0.16 uM Cu2+ using 0.05 mL of AgNPs stock solution and a linearity in the range of 0.08-1.44 uM Cu2+ with a correlation coefficient of R2 = 0.973. The developed method is a useful tool for the detection of Cu2+ ions. Furthermore, it can be used for monitoring Cu2+ in water at concentrations below the safe limit for drinking water set by the World Health Organization. PMID- 29977677 TI - Preparation and morphology-dependent wettability of porous alumina membranes. AB - This article presents the preparation and study of the wetting properties of porous alumina membranes (PAMs) with a thickness of 25 to 75 MUm and with a different pore sizes. The fabrication process features, scanning electron microscopy and atomic force microscopy characterization results are presented. The comparative analysis of PAM surfaces (outer and inner) and the effect of morphology of these surfaces on the wetting properties are discussed. Both alumina surfaces show significant morphology-dependent wettability. Measurements of the interfacial contact angle were made on the as-fabricated amorphous membrane and after pore widening with a range of pore diameters from 25 to 100 nm. The possible applications of PAMs for various membrane technologies is shown. PMID- 29977678 TI - Tailoring polarization and magnetization of absorbing terahertz metamaterials using a cut-wire sandwich structure. AB - The permittivity and permeability of a cut-wire sandwich structure can be controlled by laterally shifting the upper and lower layers. The use of this process for designing specific application-oriented devices may lack clear-cut guidelines because the lateral misalignment will significantly change the permittivity and permeability simultaneously. Therefore, in this work, we designed, fabricated and characterized a cut-wire sandwich device capable of tailoring the polarization and magnetization separately, thereby providing a promising recipe for achieving specific application objectives, such as a high performance absorber. Accumulated charges effectively provided the polarization at the edge of cut-wires, and the surface current density on the cut-wires at top and bottom layers effectively generated the magnetization. By controlling and optimizing the geometrical configurations of the entire sandwich device (without lateral misalignment), the impedance could be matched to that of free space while generating a large imaginary part in the refractive index. This work characterizes the absorption performance of such sandwich structures in the terahertz regime. This mechanism could be further extended to other metamaterial devices in the terahertz and other frequency ranges because polarization and magnetization can now be selectively controlled in a straightforward manner. PMID- 29977680 TI - Electronic conduction during the formation stages of a single-molecule junction. AB - Single-molecule junctions are versatile test beds for electronic transport at the atomic scale. However, not much is known about the early formation steps of such junctions. Here, we study the electronic transport properties of premature junction configurations before the realization of a single-molecule bridge based on vanadocene molecules and silver electrodes. With the aid of conductance measurements, inelastic electron spectroscopy and shot noise analysis, we identify the formation of a single-molecule junction in parallel to a single-atom junction and examine the interplay between these two conductance pathways. Furthermore, the role of this structure in the formation of single-molecule junctions is studied. Our findings reveal the conductance and structural properties of premature molecular junction configurations and uncover the different scenarios in which a single-molecule junction is formed. Future control over such processes may pave the way for directed formation of preferred junction structures. PMID- 29977679 TI - Cr(VI) remediation from aqueous environment through modified-TiO2-mediated photocatalytic reduction. AB - Cr(VI) exhibits cytotoxic, mutagenic and carcinogenic properties; hence, effluents containing Cr(VI) from various industrial processes pose threat to aquatic life and downstream users. Various treatment techniques, such as chemical reduction, ion exchange, bacterial degradation, adsorption and photocatalysis, have been exploited for remediation of Cr(VI) from wastewater. Among these, photocatalysis has recently gained considerable attention. The applications of photocatalysis, such as water splitting, CO2 reduction, pollutant degradation, organic transformation reactions, N2 fixation, etc., towards solving the energy crisis and environmental issues are briefly discussed in the Introduction of this review. The advantages of TiO2 as a photocatalyst and the importance of its modification for photocatalytic reduction of Cr(VI) has also been addressed. In this review, the photocatalytic activity of TiO2 after modification with carbon based advanced materials, metal oxides, metal sulfides and noble metals towards reduction of Cr(VI) was evaluated and compared with that of bare TiO2. The photoactivity of dye-sensitized TiO2 for reduction of Cr(VI) was also discussed. The mechanism for enhanced photocatalytic activity was highlighted and attributed to the resultant properties, namely, effective separation of photoinduced charge carriers, extension of the light absorption range and intensity, increase of the surface active sites, and higher photostability. Advantages and limitations for photoreduction of Cr(VI) over modified TiO2 are depicted in the Conclusion. The various challenges that restrict the technology from practical applications in remediation of Cr(VI) from wastewater were addressed in the Conclusion section as well. The future perspectives of the field presented in this review are focused on the development of whole-solar-spectrum responsive, TiO2-coupled photocatalysts which provide efficient photocatalytic reduction of Cr(VI) along with their good recoverability and recyclability. PMID- 29977681 TI - Excitation of nonradiating magnetic anapole states with azimuthally polarized vector beams. AB - Nonradiating current configurations have been drawing the attention of the physics community for many years. It has been demonstrated recently that dielectric nanoparticles provide a unique platform to host such nonradiating modes, called "anapoles". Here we study theoretically the excitation of such exotic anapole modes in silicon nanoparticles using structured light. Alternative illumination configurations, properly designed, are able to unlock hidden behavior of scatterers. Particularly, azimuthally polarized focused beams enable us to excite ideal anapole modes of magnetic type in dielectric nanoparticles. Firstly, we perform the decomposition of this type of excitation into its multipolar content and then we employ the T-matrix method to calculate the far field scattering properties of nanoparticles illuminated by such beams. We propose several configuration schemes where magnetic anapole modes of simple or hybrid nature can be detected in silicon nanospheres, nanodisks and nanopillars. PMID- 29977682 TI - Cathodoluminescence as a probe of the optical properties of resonant apertures in a metallic film. AB - Here we present the results of an investigation of resonances of azimuthal trimer arrangements of rectangular slots in a gold film on a glass substrate using cathodoluminescence (CL) as a probe. The variation in the CL signal collected from specific locations on the sample as a function of wavelength and the spatial dependence of emission into different wavelength bands provides considerable insight into the resonant modes, particularly sub-radiant modes, of these apertures. By comparing our experimental results with electromagnetic simulations we are able to identify a Fabry-Perot mode of these cavities as well as resonances associated with the excitation of surface plasmon polaritons on the air-gold boundary. We obtain evidence for the excitation of dark (also known as sub-radiant) modes of apertures and aperture ensembles. PMID- 29977683 TI - Absence of free carriers in silicon nanocrystals grown from phosphorus- and boron doped silicon-rich oxide and oxynitride. AB - Phosphorus- and boron-doped silicon nanocrystals (Si NCs) embedded in silicon oxide matrix can be fabricated by plasma-enhanced chemical vapour deposition (PECVD). Conventionally, SiH4 and N2O are used as precursor gasses, which inevitably leads to the incorporation of ~10 atom % nitrogen, rendering the matrix a silicon oxynitride. Alternatively, SiH4 and O2 can be used, which allows for completely N-free silicon oxide. In this work, we investigate the properties of B- and P-incorporating Si NCs embedded in pure silicon oxide compared to silicon oxynitride by atom probe tomography (APT), low-temperature photoluminescence (PL), transient transmission (TT), and current-voltage (I-V) measurements. The results clearly show that no free carriers, neither from P- nor from B-doping, exist in the Si NCs, although in some configurations charge carriers can be generated by electric field ionization. The absence of free carriers in Si NCs <=5 nm in diameter despite the presence of P- or B-atoms has severe implications for future applications of conventional impurity doping of Si in sub-10 nm technology nodes. PMID- 29977684 TI - Robust topological phase in proximitized core-shell nanowires coupled to multiple superconductors. AB - We consider core-shell nanowires with prismatic geometry contacted with two or more superconductors in the presence of a magnetic field applied parallel to the wire. In this geometry, the lowest energy states are localized on the outer edges of the shell, which strongly inhibits the orbital effects of the longitudinal magnetic field that are detrimental to Majorana physics. Using a tight-binding model of coupled parallel chains, we calculate the topological phase diagram of the hybrid system in the presence of non-vanishing transverse potentials and finite relative phases between the parent superconductors. We show that having finite relative phases strongly enhances the stability of the induced topological superconductivity over a significant range of chemical potentials and reduces the value of the critical field associated with the topological quantum phase transition. PMID- 29977685 TI - Spatial Rabi oscillations between Majorana bound states and quantum dots. AB - Background: A Majorana bound state is a superconducting quasiparticle that is the superposition of particle and hole with equal amplitude. We propose a verification of this amplitude equality by analyzing the spatial Rabi oscillations of the quantum states of a quantum dot that is tunneling-coupled to the Majorana bound states. Results: We find two resonant Rabi driving energies that correspond to the energy splitting due to the coupling of two spatially separated Majorana bound states. The resulting Rabi oscillating frequencies from these two different resonant driving energies are identical for the Majorana bound states, while different for ordinary Andreev bound states. We further study a double-quantum-dot setup and find a nonlocal quantum correlation between them that is mediated by two Majorana bound states. This nonlocal correlation has the signature of additional resonant driving energies. Conclusion: Our method can be used to distinguish between Majorana bound states and Andreev bound states. It also gives a precise measurement of the energy splitting between two Majorana bound states. PMID- 29977686 TI - Optical near-field mapping of plasmonic nanostructures prepared by nanosphere lithography. AB - We introduce a simple, fast, efficient and non-destructive method to study the optical near-field properties of plasmonic nanotriangles prepared by nanosphere lithography. Using a rectangular Fourier filter on the blurred signal together with filtering of the lower spatial frequencies to remove the far-field contribution, the pure near-field contributions of the optical images were extracted. We performed measurements using two excitation wavelengths (532.1 nm and 632.8 nm) and two different polarizations. After the processing of the optical images, the distribution of hot spots can be correlated with the topography of the structures, as indicated by the presence of brighter spots at the apexes of the nanostructures. This technique is validated by comparison of the results to numerical simulations, where agreement is obtained, thereby confirming the near-field nature of the images. Our approach does not require any advanced equipment and we suggest that it could be applied to any type of sample, while keeping the measurement times reasonably short. PMID- 29977687 TI - Photoluminescence of CdSe/ZnS quantum dots in nematic liquid crystals in electric fields. AB - We have experimentally investigated the effect of the reorientation of a nematic liquid crystal (LC) in an electric field on the photoluminescence (PL) of CdSe/ZnS semiconductor quantum dots (QDs). To the LC with positive dielectric anisotropy, 1 wt % QDs with a core diameter of 5 nm was added. We compared the change of PL intensity and decay times of QDs in LC cells with initially planar or vertically orientated molecules, i.e., in active or passive LC matrices. The PL intensity of the QDs increases four-fold in the active LC matrix and only 1.6 fold in the passive LC matrix without reorientation of the LC molecules. With increasing electric field strength, the quenching of QDs luminescence occurred in the active LC matrix, while the PL intensity did not change in the passive LC matrix. The change in the decay time with increasing electric field strength was similar to the behavior of the PL intensity. The observed buildup in the QDs luminescence can be associated with the transfer of energy from LC molecules to QDs. In a confocal microscope, we observed the increase of particle size and the redistribution of particles in the active LC matrix with the change of the electric field strength. At the same time, no significant changes occurred in the passive LC matrix. With the reorientation of LC molecules from the planar in vertical position in the LC active matrix, quenching of QD luminescence and an increase of the ion current took place simultaneously. The obtained results are interesting for controlling the PL intensity of semiconductor QDs in liquid crystals by the application of electric fields. PMID- 29977688 TI - Sheet-on-belt branched TiO2(B)/rGO powders with enhanced photocatalytic activity. AB - TiO2(B) is usually adopted to construct phase junctions with anatase TiO2 for applications in photocatalysis to facilitate charge separation; its intrinsic photocatalytic activity, especially when in the form of one- or three-dimensional nanostructures, has been rarely reported. In this study, a sheet-on-belt branched TiO2(B) powder was synthesized with the simultaneous incorporation of reduced graphene oxide (rGO). The monophase, hierarchically nanostructured TiO2(B) exhibited a reaction rate constant 1.7 times that of TiO2(B)/rGO and 2.9 times that of pristine TiO2(B) nanobelts when utilized to assist the photodegradation of phenol in water under UV light illumination. The enhanced photocatalytic activity can be attributed to the significantly increased surface area and enhanced charge separation. PMID- 29977689 TI - Solid-state Stern-Gerlach spin splitter for magnetic field sensing, spintronics, and quantum computing. AB - We show conceptually that the edge of a two-dimensional topological insulator can be used to construct a solid-state Stern-Gerlach spin splitter. By threading such a Stern-Gerlach apparatus with a magnetic flux, Aharanov-Bohm-like interference effects are introduced. Using ferromagnetic leads, the setup can be used to both measure magnetic flux and as a spintronics switch. With normal metallic leads a switchable spintronics NOT-gate can be implemented. Furthermore, we show that a sequence of such devices can be used to construct a single-qubit SU(2)-gate, one of the two gates required for a universal quantum computer. The field sensitivity, or switching field, b, is related to the characteristic size of the device, r, through b = h/(2piqr2), with q being the unit of electric charge. PMID- 29977690 TI - Correlative electrochemical strain and scanning electron microscopy for local characterization of the solid state electrolyte Li1.3Al0.3Ti1.7(PO4)3. AB - Correlative microscopy has been used to investigate the relationship between Li ion conductivity and the microstructure of lithium aluminum titanium phosphate (Li1.3Al0.3Ti1.7(PO4)3, LATP) with high spatial resolution. A key to improvement of solid state electrolytes such as LATP is a better understanding of interfacial and ion transport properties on relevant length scales in the nanometer to micrometer range. Using common techniques, such as electrochemical impedance spectroscopy, only global information can be obtained. In this work, we employ multiple microscopy techniques to gain local chemical and structural information paired with local insights into the Li-ion conductivity based on electrochemical strain microscopy (ESM). Scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX) have been applied at identical regions to identify microstructural components such as an AlPO4 secondary phase. We found significantly lower Li-ion mobility in the secondary phase areas as well as at grain boundaries. Additionally, various aspects of signal formation obtained from ESM for solid state electrolytes are discussed. We demonstrate that correlative microscopy is an adjuvant tool to gain local insights into interfacial properties of energy materials. PMID- 29977691 TI - Evaluation of replicas manufactured in a 3D-printed nanoimprint unit. AB - Nanoimprint lithography has become a useful tool to prepare elements containing nanoscale features at quite reasonable cost, especially if the fabrication elements are created in the own laboratory. We have designed and fabricated a whole nanoimprint manufacturing system and analyzed the resulting surfaces using ad hoc packages developed on an open-software AFM image analysis suite. To complete the work, a number of polymers have been thoroughly studied in order to select the best material for this implementation. It turned out that the best alternative was not always the same, but depended on the application. A comparative study of the polymers, which takes into account the values and dispersion of numerous sample parameters, has been carried out. As a large number of samples was prepared, an automatized procedure for characterization of nanoimprint surfaces had to be set up. The procedure includes figures of merit for comparative purposes. Materials without the requirement of a solvent were found to be superior for most nanoimprint applications. A large dispersion of the samples was found. PMID- 29977692 TI - Interaction-tailored organization of large-area colloidal assemblies. AB - Colloidal lithography is an innovative fabrication technique employing spherical, nanoscale crystals as a lithographic mask for the low cost realization of nanoscale patterning. The features of the resulting nanostructures are related to the particle size, deposition conditions and interactions involved. In this work, we studied the absorption of polystyrene spheres onto a substrate and discuss the effect of particle-substrate and particle-particle interactions on their organization. Depending on the nature and the strength of the interactions acting in the colloidal film formation, two different strategies were developed in order to control the number of particles on the surface and the interparticle distance, namely changing the salt concentration and absorption time in the particle solution. These approaches enabled the realization of large area (~cm2) patterning of nanoscale holes (nanoholes) and nanoscale disks (nanodisks) of different sizes and materials. PMID- 29977694 TI - Light extraction efficiency enhancement of flip-chip blue light-emitting diodes by anodic aluminum oxide. AB - We produced an anodic aluminum oxide (AAO) structure with periodic nanopores on the surface of flip-chip blue light-emitting diodes (FC-BLEDs). The nanopores had diameters ranging from 73 to 85 nm and were separated by distances ranging from approximately 10 to 15 nm. The light extraction efficiency enhancement of the FC BLEDs subjected to different durations of the second pore-widening process was approximately 1.6-2.9%. The efficiency enhancement may be attributed to the following mechanism: periodic nanopores on the surface of FC-BLEDs reduce the critical angle of total reflection and effective energy transfer from a light emitter into a surface plasmon mode produced by AAO. PMID- 29977693 TI - Closed polymer containers based on phenylboronic esters of resorcinarenes. AB - Novel polymer nanospheres (p(SRA-B)) were prepared by cross-linking a sulfonated resorcinarene (SRA) with phenylboronic acid. p(SRA-B) shows good stability in water and can be used as a nanocontainer for the pH- and glucose-controlled substrate release. Fluorescent dyes (fluorescein, pyrene and 1,3,6,8 pyrenetetrasulfonic acid tetrasodium salt) were successfully loaded into p(SRA B). The release of dye is achieved by lowering the pH value to 3 or by adding glucose. PMID- 29977695 TI - Nanocomposites comprised of homogeneously dispersed magnetic iron-oxide nanoparticles and poly(methyl methacrylate). AB - Nanocomposites with a high, uniform loading of magnetic nanoparticles are very desirable for applications such as electromagnetic shielding and cancer treatment based on magnetically induced hyperthermia. In this study, a simple and scalable route for preparing nanocomposites with a high, uniform loading of magnetic nanoparticles is presented. The magnetic iron-oxide nanoparticles were functionalized with a methacrylate-based monomer that copolymerized in a toluene solution with the methyl methacrylate (MMA) monomer. The resulting suspension of magnetic nanoparticles decorated with poly(methyl methacrylate) (PMMA) chains in toluene were colloidal, even in the presence of a magnetic field gradient. Nanocomposites were precipitated from these suspensions. The transmission electron microscopy investigation of the prepared nanocomposites revealed that the magnetic nanoparticles were homogeneously dispersed in the PMMA matrix, even in amounts up to 53 wt %. The uniform dispersion of the nanoparticles in the PMMA matrix was attributed to the good solvation of the grafted PMMA chains from the magnetic nanoparticles by the PMMA chains of the matrix. The nanocomposites were superparamagnetic and exhibited large values for the saturation magnetization of up to 36 emu/g. Moreover, the nanocomposite with the largest amount of incorporated nanoparticles exhibited relatively large values for the specific power loss when subjected to alternating magnetic fields, giving this material great potential for the magnetically induced hyperthermia-based treatment of cancer. PMID- 29977696 TI - Nanoscale electrochemical response of lithium-ion cathodes: a combined study using C-AFM and SIMS. AB - The continuous demand for improved performance in energy storage is driving the evolution of Li-ion battery technology toward emerging battery architectures such as 3D all-solid-state microbatteries (ASB). Being based on solid-state ionic processes in thin films, these new energy storage devices require adequate materials analysis techniques to study ionic and electronic phenomena. This is key to facilitate their commercial introduction. For example, in the case of cathode materials, structural, electrical and chemical information must be probed at the nanoscale and in the same area, to identify the ionic processes occurring inside each individual layer and understand the impact on the entire battery cell. In this work, we pursue this objective by using two well established nanoscale analysis techniques namely conductive atomic force microscopy (C-AFM) and secondary ion mass spectrometry (SIMS). We present a platform to study Li-ion composites with nanometer resolution that allows one to sense a multitude of key characteristics including structural, electrical and chemical information. First, we demonstrate the capability of a biased AFM tip to perform field-induced ionic migration in thin (cathode) films and its diagnosis through the observation of the local resistance change. The latter is ascribed to the internal rearrangement of Li-ions under the effect of a strong and localized electric field. Second, the combination of C-AFM and SIMS is used to correlate electrical conductivity and local chemistry in different cathodes for application in ASB. Finally, a promising starting point towards quantitative electrochemical information starting from C-AFM is indicated. PMID- 29977697 TI - Sulfur-, nitrogen- and platinum-doped titania thin films with high catalytic efficiency under visible-light illumination. AB - Titanium dioxide photocatalysts have received a lot of attention during the past decades due to their ability to degrade various organic pollutants to CO2 and H2O, which makes them suitable for use in environmental related fields such as air and water treatment and self-cleaning surfaces. In this work, titania thin films and powders were prepared by a particulate sol-gel route, using titanium tetrachloride (TiCl4) as a precursor. Afterwards, the prepared sols were doped with nitrogen (ammonium nitrate, urea), sulfur (thiourea) and platinum (chloroplatinic acid), coated onto glass substrates by dip-coating, and thermally treated in a muffle furnace to promote crystallization. The resulting thin films were then characterized by various techniques (i.e., TGA-DSC-MS, XRD, BET, XPS, SEM, band gap measurements). The photocatalytic activity of the prepared thin films was determined by measuring the degradation rate of plasmocorinth B (PB), an organic pigment used in the textile industry, which can pose an environmental risk when expelled into wastewater. A kinetic model for adsorption and subsequent degradation was used to fit the experimental data. The results have shown an increase in photocatalytic activity under visible-light illumination of nonmetal and metal doped and co-doped titania thin films compared to an undoped sample. PMID- 29977698 TI - Free-radical gases on two-dimensional transition-metal disulfides (XS2, X = Mo/W): robust half-metallicity for efficient nitrogen oxide sensors. AB - The detection of single gas molecules is a highly challenging work because it requires sensors with an ultra-high level of sensitivity. By using density functional theory, here we demonstrate that the adsorption of a paramagnetic unpaired free radical gas (NO) on a monolayer of XS2 (X = Mo, W) can trigger the transition from semiconductor to half metal. More precisely, the single-layer XS2 (X = Mo, W) with NO adsorbed on it would behave like a metal in one spin channel while acting as a semiconductor in the other spin orientation. The half metallicity is robust and independent of the NO concentration. In contrast, no half-metallic feature can be observed after the adsorption of other free radical gases such as NO2. The unique change in electronic properties after the adsorption of NO on transition-metal sulfides highlights an effective strategy to distinguish NO from other gas species by experimentally measuring spin-resolved transmission. Our results also suggest XS2 (X = Mo, W) nanosheets can act as promising nanoscale NO sensors. PMID- 29977699 TI - Friction force microscopy of tribochemistry and interfacial ageing for the SiO x /Si/Au system. AB - Friction force microscopy was performed with oxidized or gold-coated silicon tips sliding on Au(111) or oxidized Si(100) surfaces in ultrahigh vacuum. We measured very low friction forces compared to adhesion forces and found a modulation of lateral forces reflecting the atomic structure of the surfaces. Holding the force microscopy tip stationary for some time did not lead to an increase in static friction, i.e., no contact ageing was observed for these pairs of tip and surface. Passivating layers from tip or surface were removed in order to allow for contact ageing through the development of chemical bonds in the static contact. After removal of the passivating layers, tribochemical reactions resulted in strong friction forces and tip wear. Friction, wear, and the re passivation by oxides are discussed based on results for the temporal development of friction forces, on images of the scanned area after friction force microscopy experiments, and on electron microscopy of the tips. PMID- 29977700 TI - Josephson effect in junctions of conventional and topological superconductors. AB - We present a theoretical analysis of the equilibrium Josephson current-phase relation in hybrid devices made of conventional s-wave spin-singlet superconductors (S) and topological superconductor (TS) wires featuring Majorana end states. Using Green's function techniques, the topological superconductor is alternatively described by the low-energy continuum limit of a Kitaev chain or by a more microscopic spinful nanowire model. We show that for the simplest S-TS tunnel junction, only the s-wave pairing correlations in a spinful TS nanowire model can generate a Josephson effect. The critical current is much smaller in the topological regime and exhibits a kink-like dependence on the Zeeman field along the wire. When a correlated quantum dot (QD) in the magnetic regime is present in the junction region, however, the Josephson current becomes finite also in the deep topological phase as shown for the cotunneling regime and by a mean-field analysis. Remarkably, we find that the S-QD-TS setup can support phi0 junction behavior, where a finite supercurrent flows at vanishing phase difference. Finally, we also address a multi-terminal S-TS-S geometry, where the TS wire acts as tunable parity switch on the Andreev bound states in a superconducting atomic contact. PMID- 29977701 TI - Nitrogen-doped carbon nanotubes coated with zinc oxide nanoparticles as sulfur encapsulator for high-performance lithium/sulfur batteries. AB - Nitrogen-doped carbon nanotubes coated with zinc oxide nanoparticles (ZnO@NCNT) were prepared via a sol-gel route as sulfur encapsulator for lithium/sulfur (Li/S) batteries. The electrochemical properties of the S/ZnO@NCNT composite cathode were evaluated in Li/S batteries. It delivered an initial capacity of 1032 mAh.g-1 at a charge/discharge rate of 0.2C and maintained a reversible capacity of 665 mAh.g-1 after 100 cycles. The coulombic efficiency of the cathode remains unchanged above 99%, showing stable cycling performance. X-ray photoelectron spectroscopy analysis confirmed the formation of S-Zn and S-O bonds in the composite. This indicates that an enhanced cycling and rate capability of the S/ZnO@NCNT composite could be ascribed to advantages of the ZnO@NCNT matrix. In the composite, the active ZnO-rich surfaces offer a high sulfur-bonding capability and the NCNT core acts as a conductive framework providing pathways for ion and electron transport. The as-prepared S/ZnO@NCNT composite is a promising cathode material for Li/S batteries. PMID- 29977702 TI - Toward the use of CVD-grown MoS2 nanosheets as field-emission source. AB - Densely populated edge-terminated vertically aligned two-dimensional MoS2 nanosheets (NSs) with thicknesses ranging from 5 to 20 nm were directly synthesized on Mo films deposited on SiO2 by sulfurization. The quality of the obtained NSs was analyzed by scanning electron and transmission electron microscopy, and Raman and X-ray photoelectron spectroscopy. The as-grown NSs were then successfully transferred to the substrates using a wet chemical etching method. The transferred NSs sample showed excellent field-emission properties. A low turn-on field of 3.1 V/MUm at a current density of 10 uA/cm2 was measured. The low turn-on field is attributed to the morphology of the NSs exhibiting vertically aligned sheets of MoS2 with sharp and exposed edges. Our findings show that the fabricated MoS2 NSs could have a great potential as robust high performance electron-emitter material for various applications such as microelectronics and nanoelectronics, flat-panel displays and electron-microscopy emitter tips. PMID- 29977704 TI - A zero-dimensional topologically nontrivial state in a superconducting quantum dot. AB - The classification of topological states of matter in terms of unitary symmetries and dimensionality predicts the existence of nontrivial topological states even in zero-dimensional systems, i.e., systems with a discrete energy spectrum. Here, we show that a quantum dot coupled with two superconducting leads can realize a nontrivial zero-dimensional topological superconductor with broken time-reversal symmetry, which corresponds to the finite size limit of the one-dimensional topological superconductor. Topological phase transitions corresponds to a change of the fermion parity, and to the presence of zero-energy modes and discontinuities in the current-phase relation at zero temperature. These fermion parity transitions therefore can be revealed by the current discontinuities or by a measure of the critical current at low temperatures. PMID- 29977703 TI - Multimodal noncontact atomic force microscopy and Kelvin probe force microscopy investigations of organolead tribromide perovskite single crystals. AB - In this work, methylammonium lead tribromide (MAPbBr3) single crystals are studied by noncontact atomic force microscopy (nc-AFM) and Kelvin probe force microscopy (KPFM). We demonstrate that the surface photovoltage and crystal photostriction can be simultaneously investigated by implementing a specific protocol based on the acquisition of the tip height and surface potential during illumination sequences. The obtained data confirm the existence of lattice expansion under illumination in MAPbBr3 and that negative photocarriers accumulate near the crystal surface due to band bending effects. Time-dependent changes of the surface potential occurring under illumination on the scale of a few seconds reveal the existence of slow ion-migration mechanisms. Lastly, photopotential decay at the sub-millisecond time scale related to the photocarrier lifetime is quantified by performing KPFM measurements under frequency-modulated illumination. Our multimodal approach provides a unique way to investigate the interplay between the charges and ionic species, the photocarrier-lattice coupling and the photocarrier dynamics in hybrid perovskites. PMID- 29977705 TI - Controllable one-pot synthesis of uniform colloidal TiO2 particles in a mixed solvent solution for photocatalysis. AB - This study reports on the controllable synthesis of uniform colloidal titanium dioxide (TiO2) particles and their photocatalytic applications toward rhodamine B (RhB) degradation. The monodispersed TiO2 particles were synthesized under mixed solvent conditions by sol-gel chemistry in a one-pot process. Varying the ratio of solvent composition, the concentration of surfactant and TiO2 precursor was used to control the particle diameter, degree of monodispersity and morphology. The modification of the calcination temperature affected the crystallinity and crystalline phase of the colloidal TiO2 particles. When uniform, amorphous TiO2 particles were calcined at an optimal temperature (500 degrees C), the final sample exhibited beneficial characteristics such as high anatase crystallinity with a mixed phase of anatase and rutile and relatively high surface area. The photocatalytic efficiency of the uniform TiO2 sample with high anatase crystallinity with mixed phase and high surface area was dramatically enhanced towards RhB degradation under UV-vis irradiation. We systemically discuss the relationship between the synthetic parameters in our synthesis and the properties of the final TiO2 products, as well as the crystalline properties and performance enhancement of TiO2 photocatalysts calcined at different temperatures. PMID- 29977706 TI - Magnetic properties of Fe3O4 antidot arrays synthesized by AFIR: atomic layer deposition, focused ion beam and thermal reduction. AB - Magnetic films of magnetite (Fe3O4) with controlled defects, so-called antidot arrays, were synthesized by a new technique called AFIR. AFIR consists of the deposition of a thin film by atomic layer deposition, the generation of square and hexagonal arrays of holes using focused ion beam milling, and the subsequent thermal reduction of the antidot arrays. Magnetic characterizations were carried out by magneto-optic Kerr effect measurements, showing the enhancement of the coercivity for the antidot arrays. AFIR opens a new route to manufacture ordered antidot arrays of magnetic oxides with variable lattice parameters. PMID- 29977708 TI - Cryochemical synthesis of ultrasmall, highly crystalline, nanostructured metal oxides and salts. AB - In the present investigation, the cryochemical approach was used for the improved synthesis of nanocrystalline metal oxides (e.g., NiO, Fe2O3, CeO2) and NaNO3 salt. It was shown that the solutions and sols can be treated with a liquid nitrogen stream (-196 degrees C) to increase the powder dispersity by 3-18 times and to increase their specific surface area by an order of magnitude. The proposed approach also reduces the agglomeration of the nanoparticles, and at the same time, results in NiO, Fe2O3 and CeO2 crystallite sizes of less than 10 nm (quantum dot size regime). The diameter of NaNO3 salt crystallites could also be reduced to <=50 nm by freezing in a liquid nitrogen atmosphere, which is a significant improvement over analogous salts obtained by traditional methods (average diameter 300-1000 nm). The characterization of the obtained nanopowders was carried out using X-ray diffraction, transmission electron microscopy, surface area measurements and diffusion aerosol spectrometry (DAS). It was determined that the addition of 3-15 wt % of NaF to the NaNO3 solution prior to its cryogenic treatment results in a further decrease in the particle size of the obtained crystalline salt. NaF creates a protective coating with a thickness of 2 3 nm on the surface of NaNO3 crystallites, preventing their association. The results obtained show that the cryochemical processing of the solutions during the preparation phase of production allows nanopowders to be obtained with improved morphological and textural characteristics without significant increase in technical development costs. PMID- 29977707 TI - Preparation of micro/nanopatterned gelatins crosslinked with genipin for biocompatible dental implants. AB - Background: Collagen is a basic component of the periodontium and plays an important role in the function of the periodontal unit. Therefore, coating with collagen/gelatin has been applied to enable dental implants to positively interact with peri-implant tissues. Although the micro/nanoscale topography is an important property of the surface of dental implants, smaller collagen/gelatin surface patterns have not been sufficiently developed. Furthermore, only few reports on the behavior of cells on gelatin surfaces with different patterns and sizes exist. In this study, we developed micro/nanometer-scaled gelatin surfaces using genipin crosslinking, with the aim of understanding the use of patterning in surface modification of dental implants. Results: Grooves, holes, and pillars, with widths or diameters of 2 um, 1 um, or 500 nm were fabricated using a combination of molding and genipin crosslinking of gelatin. The stability of the different gelatin patterns could be controlled by the degree of genipin crosslinking. The gelatin patterns at 20 mM concentration of genipin and 41% crosslinking maintained a stable, patterned shape for at least 14 days in a cell culture medium. A cell morphology study showed that the cells on groves were aligned along the direction of the grooves. In contrast, the cells on pillars and holes exhibited randomly elongated filopodia. The vinculin spots of the cells were observed on the top of ridges and pillars or the upper surface of holes. The results of a cell attachment assay showed that the number of surface-attached cells increased with increasing patterning of the gelatin surface. Unlike the cell attachment assay, the results of a cell proliferation assay showed that Saos 2 cells prefer grooves with diameters of approximately 2 um and 1 um and pillars with diameters of 1 um and heights of 500 nm. The number of cells on pillars with heights of 2 um was larger than those of the other gelatin surface patterns tested. Conclusion: These data support that a detailed design of the gelatin surface pattern can control both cell attachment and proliferation of Saos-2 cells. Thus, gelatin surfaces patterned using genipin crosslinking are now an available option for biocompatible material patterning. PMID- 29977709 TI - Increasing the performance of a superconducting spin valve using a Heusler alloy. AB - We have studied superconducting properties of spin-valve thin-layer heterostructures CoO x /F1/Cu/F2/Cu/Pb in which the ferromagnetic F1 layer was made of Permalloy while for the F2 layer we have taken a specially prepared film of the Heusler alloy Co2Cr1-x Fe x Al with a small degree of spin polarization of the conduction band. The heterostructures demonstrate a significant superconducting spin-valve effect, i.e., a complete switching on and off of the superconducting current flowing through the system by manipulating the mutual orientations of the magnetization of the F1 and F2 layers. The magnitude of the effect is doubled in comparison with the previously studied analogous multilayers with the F2 layer made of the strong ferromagnet Fe. Theoretical analysis shows that a drastic enhancement of the switching effect is due to a smaller exchange field in the heterostructure coming from the Heusler film as compared to Fe. This enables to approach an almost ideal theoretical magnitude of the switching in the Heusler-based multilayer with a F2 layer thickness of ca. 1 nm. PMID- 29977710 TI - Uniform cobalt nanoparticles embedded in hexagonal mesoporous nanoplates as a magnetically separable, recyclable adsorbent. AB - Novel hexagonal nanoplates (NPLs) comprised of mesoporous carbon containing imbedded magnetic Co nanoparticles (CoAl2O4 phase) are prepared through direct carbonization of polydopamine (PDA)-coated CoAl layered double hydroxide (LDH). A uniform PDA coating initially covers the surface of LDH by dopamine self polymerization under mild conditions. Well-dispersed Co nanoparticles are formed in the NPLs by the partial reduction of cobalt from Co2+ to Co0 with surface carbon during the heat treatment process. The surface morphology and specific surface area of the as-prepared NPLs can be tailored by adjusting the initial dopamine concentration and carbonization temperature. The mesoporous NPLs exhibit excellent sorption of rhodamine B (RhB) dye and fast magnetic separation in aqueous solution. Over 95% of RhB can be adsorbed within 2 min and the adsorption reaches equilibrium after about 30 min. The maximum adsorption capacity approaches 172.41 mg/g. After regeneration, this adsorbent can be recycled easily by magnetic separation and still possess good adsorption capacity for RhB removal, even after five cycles. PMID- 29977711 TI - SO2 gas adsorption on carbon nanomaterials: a comparative study. AB - Owing to their high stability against corrosive gases, carbon-based adsorbents are preferentially used for the adsorptive removal of SO2. In the present study, SO2 adsorption on different carbon nanomaterials namely carbon nanohorns (CNHs), multiwalled carbon nanotubes (MWNTs), single-walled carbon nanotubes (SWNTs) and vertically aligned carbon nanotubes (VACNTs) are investigated and compared against the adsorption characteristics of activated carbon and graphene oxide (GO). A comprehensive overview of the adsorption behavior of this family of carbon adsorbents is given for the first time. The relative influence of surface area and functional groups on the SO2 adsorption characteristics is discussed. The isosteric heat of adsorption values are calculated to quantify the nature of the interaction between the SO2 molecule and the adsorbent. Most importantly, while chemisorption is found to dominate the adsorption behavior in activated carbon, SO2 adsorption on carbon nanomaterials occurs by a physisorption mechanism. PMID- 29977712 TI - A visible-light-controlled platform for prolonged drug release based on Ag-doped TiO2 nanotubes with a hydrophobic layer. AB - In this work, a visible-light-controlled drug release platform was constructed for localized and prolonged drug release based on two-layer titania nanotubes (TNTs) fabricated using by an in situ voltage up-anodization process. The visible light photocatalytic activity is improved by loading Ag onto the TNTs by NaBH4 reduction. Then, the TNTs containing Ag nanoparticles were modified with dodecanethiol (NDM) to create a hydrophobic layer. To demonstrate the visible light-controlled drug release, the Zn2+ release behavior of the samples was investigated. In the initial 12 h, TNTs without NDM displayed a faster release rate with 29.4% Zn2+ release, which was more than three times that of the TNTs with NDM (8.7% Zn2+ release). Upon visible-light illumination, drug release from the sample coated with NDM was shown to increase due to the photocatalytic decomposition of NDM. The amount of released Zn2+ for this sample increased up to 71.9% within 12 h, indicating visible-light-controlled drug release. This drug release system may exhibit promising application as a localized, prolonged drug delivery platform. PMID- 29977713 TI - Direct AFM-based nanoscale mapping and tomography of open-circuit voltages for photovoltaics. AB - The nanoscale optoelectronic properties of materials can be especially important for polycrystalline photovoltaics including many sensor and solar cell designs. For thin film solar cells such as CdTe, the open-circuit voltage and short circuit current are especially critical performance indicators, often varying between and even within individual grains. A new method for directly mapping the open-circuit voltage leverages photo-conducting AFM, along with an additional proportional-integral-derivative feedback loop configured to maintain open circuit conditions while scanning. Alternating with short-circuit current mapping efficiently provides complementary insight into the highly microstructurally sensitive local and ensemble photovoltaic performance. Furthermore, direct open circuit voltage mapping is compatible with tomographic AFM, which additionally leverages gradual nanoscale milling by the AFM probe essentially for serial sectioning. The two-dimensional and three-dimensional results for CdTe solar cells during in situ illumination reveal local to mesoscale contributions to PV performance based on the order of magnitude variations in photovoltaic properties with distinct grains, at grain boundaries, and for sub-granular planar defects. PMID- 29977714 TI - Know your full potential: Quantitative Kelvin probe force microscopy on nanoscale electrical devices. AB - In this study we investigate the influence of the operation method in Kelvin probe force microscopy (KPFM) on the measured potential distribution. KPFM is widely used to map the nanoscale potential distribution in operating devices, e.g., in thin film transistors or on cross sections of functional solar cells. Quantitative surface potential measurements are crucial for understanding the operation principles of functional nanostructures in these electronic devices. Nevertheless, KPFM is prone to certain imaging artifacts, such as crosstalk from topography or stray electric fields. Here, we compare different amplitude modulation (AM) and frequency modulation (FM) KPFM methods on a reference structure consisting of an interdigitated electrode array. This structure mimics the sample geometry in device measurements, e.g., on thin film transistors or on solar cell cross sections. In particular, we investigate how quantitative different KPFM methods can measure a predefined externally applied voltage difference between the electrodes. We found that generally, FM-KPFM methods provide more quantitative results that are less affected by the presence of stray electric fields compared to AM-KPFM methods. PMID- 29977715 TI - Precision Spine Care: A New Era of Discovery, Innovation, and Global Impact. PMID- 29977717 TI - Evidence of an Inherited Predisposition for Spinal Cord Tumors. AB - Study Design: Retrospective study. Objectives: To determine familial clustering of primary spinal cord tumors using a statewide genealogy database. Methods: The Utah Population Database (UPDB) was queried using ICD-Oncology (International Classification of Diseases for Oncology) codes for primary spinal cord tumors. The hypothesis of disproportionate familial clustering was tested using the Genealogical Index of Familiality (GIF). The relative risks (RRs) in relatives were calculated using the ratio of observed spinal cord tumors to expected spinal cord tumors in relatives using estimated rates from the UPDB. The related clusters of spinal cord cancer cases with a significant excess number of spinal cord cancer cases descending from a common founder pair were identified using internal UPDB rates. Results: The analysis of the GIF for individual with tumors of the spinal cord showed excess close and distant relatedness (case GIF = 3.82; control mean GIF = 2.68; P = .068). Excess relatedness for spinal cord cancers was observed when only more distant relationships were considered (P = .019). The RRs for spinal cord tumors were elevated in second- and third-degree relatives but this did not reach statistical significance (RR = 2.9, P = .15, and RR = 2.0, P = .14). Multiple extended pedigrees with a significant excess of spinal cord cancer cases among the descendants were identified. Conclusions: The excess relatedness of tumor cases over controls in distant relationships, the higher RRs to distant relatives, and the discovery of high-risk pedigrees all suggest a familial predisposition to the development of spinal cord tumors. PMID- 29977716 TI - Solitary Osteochondroma of the Spine-A Case Series: Review of Solitary Osteochondroma With Myelopathic Symptoms. AB - Study Design: Case series and literature review. Objective: There is a growing body of literature supporting that osteochondroma of the spine may not be as rare as previously documented. The purpose of this study was to perform an updated review and present our experience with 4 cases of solitary osteochondroma of the spine, including surgical treatment and subsequent outcomes. Methods: A review of 4 cases and an updated literature review. Results: All 4 cases were diagnosed as solitary osteochondroma of the spine based on clinical and histopathologic findings. Majority of the lesions arose from the posterior column with one case showing extension into the middle column with clinical neurologic sequelae. Treatment strategies for all cases included complete marginal excision of the lesions using a posterior approach. All 4 cases showed no radiographic evidence of recurrence. The literature review yielded 132 cases of solitary osteochondroma and 17 case associated with multiple hereditary exostosis. Out of the 132 cases, 36 presented with myelopathic symptoms. Conclusion: Osteochondroma of the spine may not be as rare as previously reported. The best approach to treatment in almost all symptomatic cases include wide surgical excision of the tumor. This should include complete resection of the cartilaginous cap of the tumor in an effort to prevent recurrence. When excision is performed properly, the outcomes are excellent with very low recurrence of the tumor. PMID- 29977718 TI - General Health Adverse Events Within 30 Days Following Anterior Cervical Discectomy and Fusion in US Patients: A Comparison of Spine Surgeons' Perceptions and Reported Data for Rates and Risk Factors. AB - Study Design: Survey study and retrospective review of prospective data. Objectives: To contrast surgeons' perceptions and reported national data regarding the rates of postoperative adverse events following anterior cervical discectomy and fusion (ACDF) and to assess the accuracy of surgeons in predicting the impact of patient factors on such outcomes. Methods: A survey investigating perceived rates of perioperative complications and the perceived effect of patient risk factors on the occurrence of complications following ACDF was distributed to spine surgeons at the Cervical Spine Research Society (CSRS) 2015 Annual Meeting. The equivalent reported rates of adverse events and impacts of patient risk factors on such complications were assessed in patients undergoing elective ACDF from the National Surgical Quality Improvement Program (NSQIP). Results: There were 110 completed surveys from attending physicians at CSRS (response rate = 44%). There were 18 019 patients who met inclusion criteria in NSQIP years 2011 to 2014. The rates of 11 out of 17 (65%) postoperative adverse events were mildly overestimated by surgeons responding to the CSRS questionnaire in comparison to reported NSQIP data (overestimates ranged from 0.24% to 1.50%). The rates of 2 out of 17 (12%) postoperative adverse events were mildly underestimated by surgeons (range = 0.08% to 1.2%). The impacts of 5 out of 10 (50%) patient factors were overestimated by surgeons (range relative risk = 0.56 to 1.48). Conclusions: Surgeon estimates of risk factors for and rates of adverse events following ACDF procedures were reasonably nearer to national data. Despite an overall tendency toward overestimation, surgeons' assessments are roughly appropriate for surgical planning, expectation setting, and quality improvement initiatives. PMID- 29977719 TI - Preoperative Leg Pain Score Predicts Patient Satisfaction After Transforaminal Lumbar Interbody Fusion Surgery. AB - Study Design: Retrospective cohort study. Objectives: This study aims to determine the preoperative predictors of postoperative satisfaction in transforaminal lumbar interbody fusion (TLIF) surgery in order to improve management of patient groups at high risk of dissatisfaction. We retrospectively reviewed prospectively collected data on patients who underwent open TLIF in a tertiary hospital between 2008 and 2012 with 2-year follow-up and performed multivariate analysis for their preoperative variables. Methods: A multivariate regression analysis was performed for the 217 patients to identify preoperative predictors of postoperative satisfaction. Clinical outcomes were evaluated using Oswestry Disability Index (ODI), North American Spine Society (NASS) Neurogenic Symptom Score (NSS), 36-item Short-Form Survey (SF-36; mean Physical and Mental Health scores), numerical pain rating scale (NPRS) for pain, and NASS Questionnaire. Results: Significant improvements were seen in the postoperative ODI, NSS, SF-36, and NPRS scores at 2 years (P < .05). Eighty-six percent of the patients had their expectations of surgery met, and 94.7% of the patients were satisfied with the results of treatment at 2 years. From the multivariate regression model, patients with higher preoperative NPRS pain score (odds ratio = 1.323; 95% confidence interval = 1.071-1.633; P = .009) was more likely to be satisfied at 2 years. Conclusions: TLIF surgery provided significant health related quality-of-life scores and symptom improvement in terms of SF-36, ODI, NSS, and NPRS, with a high proportion of patients being satisfied with the results of surgery. Patients with higher preoperative NPRS leg pain were more likely to be satisfied at 2 years. Patient-reported satisfaction may be largely influenced by the improvement of radicular leg pain. PMID- 29977720 TI - Spinal Dural Repair: A Canadian Questionnaire. AB - Study Design: Questionnaire. Objectives: Iatrogenic dural tear is a complication of spinal surgery with significant morbidity and cost to the health care system. The optimal management is unclear, and therefore we aimed to survey current practices among Canadian practitioners. Methods: A questionnaire was administered to members of the Canadian Neurological Surgical Society designed to explore methods of closure of iatrogenic durotomy. Results: Spinal surgeons were surveyed anonymously with a 55% response rate (n = 91). For pinhole-sized tears, there is no agreement in the methods of closure, with a trend toward sealant fixation (36.7%). Medium- and large-sized tears are predominantly closed with sutures and sealant (67% and 80%, respectively). Anterior tears are managed without primary closure (40.2%), or using sealant alone (48%). Posterior tears are treated with a combination of sutures and sealant (73.8%). Nerve root tears are treated with either sealant alone (50%), or sutures and sealant (37.8%). Tisseal is the preferred sealant (79.7%) over alternatives. With the exception of pin-hole sized tears (39.5%) most respondents recommended bed rest for at least 24 hours in the setting of medium (73.2%) and large (89.1%) dural tears. Conclusions: This study elucidates the areas of uncertainty with regard to iatrogenic dural tear management. There is disagreement regarding management of anterior and nerve root tears, pinhole-sized tears in any location of the spine, and whether patients should be admitted to hospital or should be on bed rest following a pinhole-sized dural tear. There is a need for a robust comparative research study of dural repair strategies. PMID- 29977721 TI - Annulo-Nucleoplasty Using Disc-Fx in the Management of Degenerative Lumbar Disc Pathology: How Long Can the Effect Last? AB - Study Design: Prospective analysis. Objectives: To evaluate 2-year clinical outcomes in patients undergoing Disc-FX for the management of low back pain (LBP) due to degenerate disc (DD) or contained lumbar disc herniation (CLDH). To study salient factors that can potentially influence the clinical outcomes. Methods: We analyzed the prospectively collected data of 51 patients who underwent Disc-FX procedure for DD or CLDH, nonresponsive to 6 months of nonoperative treatment. Clinical outcome measures collected were visual analogue scale (VAS), Oswestry Disability Index (ODI), and MacNab scores. These preoperative values were compared with respective values at immediate, 6 months, 1 year, and 2 years postoperation. Minimum clinically important difference values for these outcomes in accordance with previously published data was used to evaluate the effectiveness of Disc-FX intervention. Results: Of 51 patients, 84% had DD and 16% had CLDH. Significant improvement (P < .01) in VAS and ODI scores was observed at all assessment periods compared to the respective preoperative values. Based on the MacNab scores, there was significant increase (P < .01) in the proportion of patients with excellent/good MacNab outcomes at each time point after the procedure; 78% achieving excellent/good outcomes at 2-year follow-up. Ease of access to the disc space was significantly influencing VAS, ODI, and MacNab scores at 1-year and 2-year follow-ups. VAS and MacNab scores were negatively influenced by high body mass index and smoking status at 6 and 12 months postoperation. Conclusions: Our data suggests that Disc-FX may be helpful in selected patients with symptomatic degenerative disc disease providing favorable outcomes lasting up to 2 years or more. The results were more favorable in patients with easier access to disc space. PMID- 29977722 TI - Lumbar Selective Nerve Root Block: Comparative Study Using Two Pharmacological Formulae. AB - Study Design: Retrospective cohort study. Objectives: The objective of the present study was to compare the effectiveness of 2 different pharmacological formulae in selective nerve root injections. Methods: We studied a series of 298 patients who received a selective nerve root injection and made a comparative study dividing them into 2 groups according to the drugs used. In group A, we used betamethasone 6 mg and lidocaine, while in group B, triamcinolone 60 mg and bupivacaine were used for the procedure. We evaluated the patients for a period of at least 8 months, assuming the need for surgical therapy as the failure of the procedure. Results: Both groups had 149 patients with similar etiological characteristics. Forty-seven patients (16%) required surgery to relieve pain with a similar distribution between groups (24 from group A and 23 from group B). Time between nerve root injection and surgery was 86.79 (14-360) days on average in group A and 75.76 (2-180) days in group B with no statistical difference (P = .67). Only one complication was documented, an anaphylactic shock in a patient in group B. Conclusions: Based on these results, we found no difference in the type of steroid or local anesthetic used for selective nerve root injections. PMID- 29977723 TI - Smoking Is an Independent Risk Factor of Reoperation Due to Recurrent Lumbar Disc Herniation. AB - Study Design: Retrospective cohort study. Objectives: The purpose of the present study is to determine if age, gender, smoking status, and body mass index (BMI) are significant risk factors of symptomatic recurrent lumbar disc herniation (rLDH) leading to reoperation. Methods: A cohort of 1378 consecutive patients who underwent discectomy for LDH from June 2010 to January 2015 at our institution were included. Patients who underwent reoperation due to rLDH prior to August 2015 were identified. Data on reoperations, age, gender, smoking status, and BMI were collected from our database. A comparison of age, gender, smoking status, and BMI was made between the controls (non-rLDH) and the cases (rLDH group). Binary logistic regression was performed to determine whether age, gender, smoking status, and BMI were independent risk factors for rLDH. Results: Patients in the non-rLDH group (48.2 years) were older than the rLDH group (44.7 years; P = .013). Gender distribution (54.8% vs 48.5% males; P = .222) and BMI (26.6 vs 26.6; P = .458) were similar between the 2 groups. A significantly higher prevalence of smokers was found in the rLDH group (33.1% vs 51.5%; P < .001). Binary logistic regression analysis showed that smoking was an independent risk factor of rLDH (odds ratio = 2.12; 95% confidence interval = 1.39-3.15; P < .001). Conclusions: Neither age, BMI, nor gender had any statistical significant association with the risk of rLDH. Smoking was associated with higher risk of reoperation due to rLDH. PMID- 29977724 TI - Utilization of Interspinous Devices Throughout the United States Over a Recent Decade: An Analysis of the Nationwide Inpatient Sample. AB - Study Design: Retrospective database study. Objectives: Analysis of economic and demographic data concerning interspinous device (ID) placement throughout the United States to improve value-based care and health care utilization. Methods: The National Inpatient Sample (NIS) database was queried for patients who underwent insertion of an interspinous process spinal stabilization device (ICD-9 CM 84.80) between 2008 and 2014 across 44 states. Demographic and economic data were obtained which included the annual number of surgeries, age, sex, insurance type, location, and frequency of routine discharge. The NIS database represents a 20% sample of discharges from US hospitals, which is weighted to provide national estimates. Results: There was a 73% decrease in ID implanted from 2008 to 2014. The mean cost associated with insertion of the device increased 28% from $13 653 in 2008 to $17 515 in 2014. The mean length of stay (LOS) increased from 1.8 to 2.4 days. Patients aged 45 to 64 years increased from 14.1% to 34.3% while patients aged 65 to 84 years decreased from 74.4% to 60.6%. By region, 34% of ID placement occurred in the South followed by 19.7% that occured in the Northeast. When stratifying by median income for patient zip code, the procedure was performed more in cities designated as higher rather than lower income areas (74.2% and 19.5%, respectively). Conclusions: Throughout the United States, there was a progressive decline in the insertion of interspinous spacers by 73% over the study period. The total costs for the procedure increased by 28% while the aggregate national charges decreased by 55.6% between 2008 and 2014. PMID- 29977725 TI - Risk Factors for Unplanned Reoperation Within 30 Days Following Elective Posterior Lumbar Spinal Fusion. AB - Study Design: Retrospective cohort study. Objectives: Unplanned reoperation following lumbar spinal fusion is detrimental to patients, providers, and health systems. The aim of this study was to identify risk factors associated with unplanned reoperation following elective posterior lumbar spinal fusion and assess the reasons for reoperation. Methods: A retrospective analysis of 22 151 patients from the American College of Surgeons National Surgical Quality Improvement Program data set between 2012 and 2015 was completed. The primary outcome measure was unplanned reoperation within 30 days. Secondary outcome measures were specific diagnoses and procedures associated with unplanned reoperation, as well as time to reoperation from initial procedure. Multiple stepwise logistic regression was employed to determine preoperative variables predictive of unplanned 30-day reoperation. Results: Patients with disseminated cancer (OR = 3.44, P = .0049), weight loss >10% in 6 months prior to surgery (OR = 3.26, P = .0276), bleeding disorders (OR = 1.92, P = .0049), American Society of Anesthesiologists score of 3 (OR = 1.46, P < .0001), body mass index of 35.0 to 39.9 (OR = 1.50, P = .0037), body mass index of >=40 (OR = 1.83, P < .0001), and multilevel fusion (OR = 1.24, P = .0069) exhibited increased odds of 30-day reoperation. The most common diagnosis associated with reoperation was postoperative infection (n = 121, 21.1% of reoperations). Conclusions: Predictors and causes of unplanned reoperation within 30 days following elective posterior lumbar spinal fusion are identifiable. In this study cohort, obesity, American Society of Anesthesiologists score, disseminated cancer, weight loss, bleeding disorders, and multilevel fusion were identified as significant risk factors for reoperation. Further research investigating risk factor modification on reoperation in elective posterior lumbar spinal fusion is warranted. PMID- 29977726 TI - Allograft Versus Demineralized Bone Matrix in Instrumented and Noninstrumented Lumbar Fusion: A Systematic Review. AB - Study Design: Systematic review. Objectives: The aim was to determine the fusion efficacy of allograft and demineralized bone matrix (DBM) in lumbar instrumented and noninstrumented fusion procedures for degenerative lumbar disorders. Methods: A literature search was conducted using the PubMed and Cochrane databases. To be considered, publications had to meet 4 criteria: patients were treated for a degenerative lumbar disorder, a minimum group size of 10 patients, use of allograft or DBM, and at least a 2-year follow-up. Data on the study population, follow-up time, surgery type, grafting material, fusion rates, and its definition were collected. Results: The search yielded 692 citations with 17 studies meeting the criteria including 4 retrospective and 13 prospective studies. Six studies used DBM and 11 employed allograft alone or in the combination with autograft. For the allograft, fusion rates ranged from 58% to 68% for noninstrumented and from 68% to 98% for instrumented procedures. For DBM, fusion rates were 83% for noninstrumented and between 60% and 100% for instrumented lumbar fusion procedures. Conclusions: Both allograft and DBM appeared to provide similar fusion rates in instrumented fusions. On the other hand, in noninstrumented procedures DBM was superior. However, a large variation in the type of surgery, outcomes collection, lack of control groups, and follow-up time prevented any significant conclusions. Thus, studies comparing the performance of allograft and DBM to adequate controls in large, well-defined patient populations and with a sufficient follow-up time are needed to establish the efficacy of these materials as adjuncts to fusion. PMID- 29977728 TI - ROC Solid: Receiver Operator Characteristic (ROC) Curves as a Foundation for Better Diagnostic Tests. PMID- 29977727 TI - Comparison of Lumbar Total Disc Replacement With Surgical Spinal Fusion for the Treatment of Single-Level Degenerative Disc Disease: A Meta-Analysis of 5-Year Outcomes From Randomized Controlled Trials. AB - Study Design: Meta-analysis. Objectives: To evaluate the long-term efficacy and safety of total disc replacement (TDR) compared with fusion in patients with functionally disabling chronic low back pain due to single-level lumbar degenerative disc disease (DDD) at 5 years. Methods: PubMed and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials reporting outcomes at 5 years for TDR compared with fusion in patients with single-level lumbar DDD. Outcomes included Oswestry Disability Index (ODI) success, back pain scores, reoperations, and patient satisfaction. All analyses were conducted using a random-effects model; analyses were reported as relative risk (RR) ratios and mean differences (MDs). Sensitivity analyses were conducted for different outcome definitions, high loss to follow-up, and high heterogeneity. Results: The meta-analysis included 4 studies. TDR patients had a significantly greater likelihood of ODI success (RR 1.0912; 95% CI 1.0004, 1.1903) and patient satisfaction (RR 1.13; 95% CI 1.03, 1.24) and a significantly lower risk of reoperation (RR 0.52; 95% CI 0.35, 0.77) than fusion patients. There was no association with improvement in back pain scores whether patients received TDR or fusion (MD -2.79; 95% CI -8.09, 2.51). Most results were robust to sensitivity analyses. Results for ODI success and patient satisfaction were sensitive to different outcome definitions but remained in favor of TDR. Conclusions: TDR is an effective alternative to fusion for lumbar DDD. It offers several clinical advantages over the longer term that can benefit the patient and reduce health care burden, without additional safety consequences. PMID- 29977729 TI - Treatment of choroidal neovascularization in a case of factor VIII deficiency: Ten-year follow-up. AB - An unusual case of choroidal neovascularization in a young female with factor VIII deficiency is presented. The treatment course lasted 23 months. A favourable treatment outcome with restoration of the original visual acuity was achieved. The eye remained stable until the last follow-up, 10 years following therapy. PMID- 29977730 TI - Eight-and-a-half syndrome: a rare potentially life-threatening disease. AB - Purpose: To report a case of eight-and-a-half syndrome presenting with a conjugate horizontal gaze palsy, an ipsilateral internuclear ophthalmoplegia, and an ipsilateral lower motor neuron-like facial palsy. Methods: A 56-year-old male who came in for limitation of extraocular muscle motion - wherein the only remaining movement is abduction of the left eye - and right-sided facial weakness. Magnetic resonance imaging revealed a well-defined lesion resembling a cavernoma, at the level of the ponto-medullary junction. Results: Eight-and-a half syndrome results from a lesion affecting the paramedian pontine reticular formation, the median longitudinal fasciculus, and the facial nerve fascicle on one side. In this case, a cavernoma at the level of the ponto-medullary junction was compressing the important pontine structures. Conclusion: Although eight-and a-half syndrome is most commonly caused by an infarction or demyelination, in rare instances, a space-occupying lesion at the level of the pons can be the etiology. It is of utmost importance to recognize the features of this disease entity to be able to exhaust the proper diagnostic exams, localize the lesion and determine the proper treatment regimen catered to each patient. PMID- 29977731 TI - Surgery for Triple Pathology of Giant Vestibular Schwannoma Associated with Carotid Artery Stenosis and Intracranial Aneurysm: Case Report. AB - Here we report the case of a 56-year-old woman who presented with a highly unusual combination of three pathologies, namely a giant left-sided vestibular schwannoma, severe stenosis of the left internal carotid artery, and a right anterior cerebral artery aneurysm. The chosen approach comprised three consecutive surgical procedures, namely (1) aneurysm embolization, (2) carotid stenosis stenting, and (3) vestibular schwannoma excision. This approach avoided complications and achieved a satisfactory functional outcome. To the best of our knowledge, this combination of three conditions has not been previously reported in the English-language literature. PMID- 29977732 TI - Management of donor site infections in split-thickness skin graft with water filtered infrared-A (wIRA). AB - Infection of donor sites in split-thickness skin grafts is one of the complications of skin transplantation. Nutrition status and associated diseases play important roles in healing of donor sites. There are different ways used to treat infected donor sites. Water-filtered infrared-A (wIRA), as a special form of heat radiation with a high tissue penetration and a low thermal load to the skin surface, can improve the healing of acute and chronic wounds both by thermal and thermic as well as by non-thermal and non-thermic effects. Water-filtered infrared-A (wIRA) increases tissue temperature, tissue oxygen partial pressure and tissue perfusion. These three factors are decisive for a sufficient supply of tissue with energy and oxygen and consequently also for wound healing and infection defense. This was confirmed in a case with a late severe healing disturbance of the donor sites after skin transplantation. PMID- 29977733 TI - Primary Cardiac B-Non-Hodgkin Lymphoma Disguised as a Pacemaker Endocarditis. AB - Background Pacemaker infections rates are high compared with the incidence of primary malignant cardiac tumors. However, they can look alike in diagnostics and patient presentation. Case Description We hereby report a rare case of a suspected pacemaker endocarditis which in fact turned out to be a primary cardiac B cell lymphoma. The lymphoma was removed surgically. Conclusion Sometimes we encounter the unexpected. Suboptimal preoperative diagnostics certainly lead to the faulty conclusion of an endocarditis. Nonetheless, even such an enhanced primary cardiac tumor can be resected with good clinical outcome and long-term survival. PMID- 29977734 TI - Successful Surgical Abdominal Aortic Debranching Preceding Stent Graft Implantation: A Case Report. AB - Background Acute endovascular aneurysm repair with stent grafts (thoracic endovascular aortic repair [TEVAR]) is safe and feasible. Case Description A 64 year-old female presented with a perforated aortic aneurysm of the thoracic descending aorta. Primary TEVAR resulted in good management of the perforation but a type Ib endoleakage remained postoperatively. To place another stent, abdominal debranching with saphenous vein bypass to the celiac trunk was required. In the same session, another endograft was inserted successfully. Conclusion Abdominal debranching is a safe alternative to open aortic repair in acute thoracic and abdominal aneurysms, instead of waiting for a custom-made device. PMID- 29977735 TI - Surgical Management of Pulmonary Mucormycosis in Third-Trimester Pregnancy. AB - Background Pulmonary mucormycosis is a rare fungal infection that carries a high mortality. Given the rarity of this disease, its management has not been well established. Case Description We report a 36-year-old female presenting with right middle and lower lobe pulmonary mucormycosis during the third trimester of pregnancy. Diagnosis was established using chest computed tomography followed by bronchoalveolar lavage and lung biopsy. Prompt initiation of amphotericin B and right middle and lower lobe lobectomy resulted in maternal survival and fetal viability. Conclusion This favorable outcome is attributed to extensive communication between treatment teams in addition to comprehensive surgical planning. PMID- 29977736 TI - Rupture of the Free Left Ventricular Wall: A Novel Approach for Reconstruction. AB - Background A rupture of the free wall of the left ventricle is a rarely seen complication of myocardial infarction and represents an absolute cardiac emergency. Case Description We hereby present a case of a 64-year-old patient with a rupture of the free left ventricular wall. The patient was treated in an emergent operation with a novel reconstruction method of the left ventricular wall and was discharged 30 days after the initial operation. Conclusion Left ventricular free wall rupture is rarely described in the literature, which might be because of high mortality in underdiagnosed cases. Therefore, early imaging by echo or computed tomography (CT) is essential for detecting this dangerous condition. Once diagnosed, urgent surgery is mandatory to save the life of the patient. PMID- 29977737 TI - Cardiac Graft from Donors with Extracorporeal Support-A Report of Two Cases. AB - The persistent global shortage of organ donors is still a major limitation for transplantation. Experiences of heart transplantation from donors with extracorporeal support are rare. Here, we report from two cases of donors who were supported by extracorporeal membrane oxygenation due to acute circulatory failure. In both cases, the direct postoperative course was uneventful and free from major complications. The patients were discharged to a rehabilitation clinic. Our experience suggests that the use of heart organ from carefully selected donors with extracorporeal support is possible and may lead to an excellent outcome. PMID- 29977738 TI - Notch Signaling and Immune Regulation in Alloimmunity. AB - Notch signaling plays a pivotal role in the differentiation and fate determination of T cells, B cells, dendritic cells (DCs) and innate lymphoid cells (ILCs). Recent gene-targeting and antibody approaches advanced our knowledge of the importance of Notch signaling in fine-tuning the peripheral immune response. Here we review current knowledge of the Notch pathway, focusing on solid organ transplant and graft-versus-host disease preclinical models, and discuss the potential of targeting Notch to suppress the immune response and improve transplant outcomes. PMID- 29977739 TI - Genome-wide Transcriptional Analysis of Oxidative Stress-related Genes and Pathways Induced by CdTe aqQDs in Mice. AB - Objective: Quantum dots (QDs) has widely applied in the field of science, whose potential toxic effect has increasingly become a focus concern we need pay attention to in public health. The purpose of this article was to explore the toxicity mechanism with oxidative damage from treatment with QDs at the molecular level through a gene microarray. Methods: Mice were administered aqueously synthesized cadmium telluride QDs (CdTe aqQDs) via intravenous tail injection of a 2 umol/kg solution (based on the molar mass of Cd), and their kidneys were collected at 1 day in strict accordance with the programs used for treated mice. We determined the hierarchical clustering of expression ratios, enriched gene ontology (GO) terms and signaling pathways through gene microarray analysis and bioinformatics analysis in kidney tissue and screened the key enzyme genes, which were verified by real-time quantitative polymerase chain reaction (real-time qPCR). Results: Compared to control group, 459 lncRNAs (197 down-regulated and 262 up-regulated) and 256 mRNAs (103 down-regulated and 153 up-regulated) were differentially expressed. According to biological processes in enriched GO terms, the response to a redox state played a significant role in the biological processes involved altered genes. Pathway analysis showed that the signaling pathways that involved cytochrome P450 (CYP450) enzymes had a close relationship with QDs. Among these signaling pathways, gene expression profiling revealed that selected differentially expressed mRNAs (CYP19A1, CYP1B1, CYP11A1, CYP11B2, and CYP17A1 in the kidney and CYP19A1 and CYP1B1 in the liver) were validated by real time qPCR, resulting in expression levels of CYP11A1, CYP11B2 and CYP17A1 in the kidney and CYP19A1 and CYP1B1 in the liver that were significantly increased, however in expression levels of CYP19A1 and CYP1B1 compared with control group in the kidney, there was no significant difference. Conclusions: Our results provide a foundation for and potential insight into the role of CYP450-related genes in QD-induced oxidative stress. QDs may produce a great deal of reactive oxygen species (ROS) by promoting high expression of CYP450 enzymes and accumulating steroid hormones, which may be an important toxicity mechanism for mediating oxidative stress and tissue damage. PMID- 29977740 TI - HAase-sensitive dual-targeting irinotecan liposomes enhance the therapeutic efficacy of lung cancer in animals. AB - Among all cancers, lung cancer is one of the most common and serious types of cancer. It is challenging for site-specific delivery of anticancer therapeutics to tumor cells. Herein, we developed a novel"smart" dual-targeting liposomal platform to respond to the highly expressed hyaluronidase (HAase) in the tumor microenvironment and improve tumor targeting and antitumor efficacy. Methods: In our design, the HA was used as a sensitive linker between a liposomal lipid and long chain PEG block to synthesize three functional conjugates in order to prepare"smart" liposomal platform modified with epidermal growth factor receptor (EGFR) antibody (GE11) and cell-penetrating peptide (TATp). Using irinotecan as a model therapeutic, evaluations were performed on the human lung adenocarcinoma A549 cells as well as the xenografted A549 cancer cells in nude mice. Results: The GE11/HA/TATp-irinotecan liposomes evidently increased the uptake of irinotecan and showed significant antitumor efficacy in the xenografted A549 cancer cells in nude mice by intravenous administration. The mechanisms were defined to be two aspects: GE11 exhibits high affinity for EGFR binding and the degradation of the HA by HAase results in the long-chain PEG removal and exposure of the previously hidden surface-attached TATp to enhance the target cell internalization. Conclusion: Our findings suggest that this functional liposomal platform may provide a novel strategy for treating lung cancers because of effective intracellular delivery. PMID- 29977741 TI - Near-Infrared Activated Release of Doxorubicin from Plasmon Resonant Liposomes. AB - Precise control of drug release from nanoparticles can improve efficacy and reduce systemic toxicity associated with administration of certain medications. Here, we combined two phenomena, photothermal conversion in plasmon resonant gold coating and thermal sensitivity of liposome compositions, to achieve a drug delivery system that rapidly releases doxorubicin in response to external stimulus. Methods: Thermosensitive liposomes were loaded with doxorubicin and gold-coated to produce plasmon resonant drug delivery system. Plasmon resonance facilitates release of contents upon near-infrared laser illumination, thus providing spatial and temporal control of the process. This controlled delivery system was compared to thermosensitive liposomes without gold coating and to the FDA-approved Doxil that was gold-coated to create a plasmon resonant coating. Release of doxorubicin from the gold-coated thermosensitive liposomes was further confirmed by tests of cell viability. Results: Upon laser illumination at 760 nm and 88 mW/cm2 power density, permeability of plasmon resonant liposomes increased by three orders of magnitude, from 70*10-12 to 60,000x10-12 cm/s. In control experiments, mild hyperthermia (42 degrees C) increased permeability of these thermosensitive liposomes to just 3,700*10-12 cm/s. Neither hyperthermia nor laser illumination elicit content release from Doxil or plasmon resonant Doxil obtained by gold coating. Laser-induced release of doxorubicin from plasmon resonant thermosensitive liposomes resulted in the loss of cell viability significantly greater than in any of the control groups. Conclusion: Combination of thermosensitive liposomes with plasmon resonant coating enables rapid, controlled release, not currently available in pharmaceutical formulations of anticancer drugs. PMID- 29977743 TI - Visualizing the molecular wave function in sigma-coordinated complexes. AB - The pi-complex theory developed by Michael J. S. Dewar in 1949 has had its most profound impact as part of the Dewar-Chatt-Duncanson model, a seminal and foundational contribution to the field of organometallic chemistry. Over time it has demonstrated its utility in systems far from those originally envisaged, including sigma-coordinated metal-complexes. This latter application is notable due to Dewar's original skepticism that his pi-complex theory could be extended to sigma-bonds. Separately it has previously been demonstrated that a one electron wave function. can be shown to satisfy an exact one-electron Schrodinger equation describing the motion of the single electron in the average field of the remaining electrons. To celebrate the centenary of his birth this paper seeks to demonstrate that sigma-coordinated metal-complexes present a perfect system to exemplify both the utility of the one-electron wave function and the power of the pi-complex theory. PMID- 29977742 TI - Ferumoxytol-based Dual-modality Imaging Probe for Detection of Stem Cell Transplant Rejection. AB - Purpose: Stem cell transplants are an effective approach to repair large bone defects. However, comprehensive techniques to monitor the fate of transplanted stem cells in vivo are lacking. Such strategies would enable corrective interventions at an early stage and greatly benefit the development of more successful tissue regeneration approaches. In this study, we designed and synthesized a dual-modality imaging probe (Feru-AFC) that can simultaneously localize transplanted stem cells and diagnose immune rejection-induced apoptosis at an early stage in vivo. Methods: We used a customized caspase-3 cleavable peptide-dye conjugate to modify the surface of clinically approved ferumoxytol nanoparticles (NPs) to generate the dual-modality imaging probe with fluorescence "light-up" feature. We labeled both mouse mesenchymal stem cells (mMSCs, matched) and pig mesenchymal stem cells (pMSCs, mismatched) with the probe and transplanted the labeled cells with biocompatible scaffold at the calvarial defects in mice. We then employed intravital microscopy (IVM) and magnetic resonance imaging (MRI) to investigate the localization, engraftment, and viability of matched and mismatched stem cells, followed by histological analyses to evaluate the results obtained from in vivo studies. Results: The Feru-AFC NPs showed good cellular uptake efficiency in the presence of lipofectin without cytotoxicity to mMSCs and pMSCs. The fluorescence of Feru-AFC NPs was turned on inside apoptotic cells due to the cleavage of peptide by activated caspase-3 and subsequent release of fluorescence dye molecules. Upon transplantation at the calvarial defects in mice, the intense fluorescence from the cleaved Feru-AFC NPs in apoptotic pMSCs was observed with a concomitant decrease in the overall cell number from days 1 to 6. In contrast, the Feru-AFC NP-treated mMSCs exhibited minimum fluorescence and the cell number also remained similar. Furthermore, in vivo MRI of the Feru-AFC NP-treated mMSC and pMSCs transplants could clearly indicate the localization of matched and mismatched cells, respectively. Conclusions: We successfully developed a dual-modality imaging probe for evaluation of the localization and viability of transplanted stem cells in mouse calvarial defects. Using ferumoxytol NPs as the platform, our Feru-AFC NPs are superparamagnetic and display a fluorescence "light-up" signature upon exposure to activated caspase-3. The results show that the probe is a promising tool for long-term stem cell tracking through MRI and early diagnosis of immune rejection induced apoptosis through longitudinal fluorescence imaging. PMID- 29977744 TI - Familial idiopathic pulmonary fibrosis in a young female. AB - Idiopathic pulmonary fibrosis is a chronic interstitial lung disease of unknown cause. In the past years there have been observations of clustering of pulmonary fibrosis in families, indicating the disease can be inherited. The most commonly identified mutations are mutations involving proteins from the telomerase complex and the surfactant system, where the mutations from the surfactant protein system are less identified. We report a rare care of familial IPF in a young female at the age of 34 years, in whom genetic testing shows two different heterozygous variants for the surfactant protein system as a probable cause of her interstitial lung disease. PMID- 29977745 TI - Multiple metachronous and synchronous malignancies with lung and thorax involvement. Report of two cases. AB - Multiple primary malignant neoplasms (MPMN) is an uncommon phenomenon, while the diagnosis of such conditions is very significant. Considering that the strategy of the treatment is determined by the histological type of the tumor, practitioners should be alert in order to avoid malpractices in cases of multiple metachronous or synchronous malignancies. In this article we report two rare cases of MPMN. The first patient suffered from three metachronous malignant neoplasms, specifically tonsillar, lung and breast cancer, while the second patient was diagnosed with four synchronous and metachronous malignant tumors, including renal and lung cancer, basaloid carcinoma and melanoma. Such cases are extremely rare in the clinical practice and poorly described in the literature. PMID- 29977746 TI - Interstitial lung disease and pre-capillary pulmonary hypertension in neurofibromatosis type 1. AB - Although previously reported, the existence of a neurofibromatosis (NF) associated diffuse lung disease (DLD) still lacks solid evidence. We report a case of a 68-year-old non-smoking female with NF1, pre-capillary pulmonary hypertension (PH) and an interstitial lung pattern. Initial findings included progressive dyspnea, hypoxemia and sparse centrilobular ground-glass micronodules on high-resolution computed tomography (HRCT). Further study demonstrated a severe defect in diffusing capacity for carbon monoxide (DLCO), macrophages on bronchoalveolar lavage and pre-capillary PH on right cardiac catheterization. Surgical biopsy revealed macrophage accumulation along bronchovascular bundles and alveolar spaces and type II pneumocytes hyperplasia. Given the absence of environmental exposure or new drugs, a NF-DLD was hypothesized. Pre-capillary PH was disproportionate to interstitial findings, so it was attributed to a NF1 vasculopathy. Treatment with triple sequential combined therapy was unsuccessful culminating in death 18 months later. This case adds HRCT and anatomopathological data suggesting NF-DLD as a distinct manifestation of the disease. PMID- 29977747 TI - A case of drug induced lung injury caused by levofloxacin eye drops. AB - A 78 year-old man, who received levofloxacin eye drops as a perioperative prophylactic antibacterial agent for cataract surgery, developed pyrexia and dyspnea, followed by respiratory failure. He was diagnosed as drug-induced lung injury due to levofloxacin, and the symptoms improved after the administration of corticosteroids and discontinuation of levofloxacin eye drops. The incidence of levofloxacin-induced lung injury is rare for its frequent prescription. Moreover, eye drops of it has never been reported to cause lung injury. We should be aware of eye drops as a causative dosage forms of drug-induced lung injury. PMID- 29977748 TI - Sarcoidosis presenting as Wallenberg syndrome and panuveitis. AB - Sarcoidosis is a multi-system disease with neurological involvement being one of the more rare manifestations. We report a case of a patient who presented with the lateral medullary syndrome and panuveitis as her initial manifestation of sarcoidosis. The patient's course was further complicated by renal involvement. Lacrimal gland and renal biopsies showed noncaseating granulomas without evidence of infection, establishing the diagnosis. Intracranial vertebral artery involvement was confirmed by brain imaging. Bilateral hilar lymphadenopathy with upper lobe predominant nodules on chest imaging was consistent with asymptomatic pulmonary involvement. Systemic steroid therapy is indicated for treatment of ocular sarcoidosis, with standard stroke management indicated for the treatment of lateral medullary syndrome. PMID- 29977749 TI - EGFR T790M mutation after chemotherapy for small cell lung cancer transformation of EGFR-positive non-small cell lung cancer. AB - In non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation, 50%-65% of cases acquire resistance after treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) because of an EGFR T790M point mutation and 3%-14% of these cases transformed to small cell lung cancer (SCLC). Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation. PMID- 29977750 TI - Liposteroid and methylprednisolone combination therapy for a case of idiopathic lung hemosiderosis. AB - Idiopathic pulmonary hemosiderosis (IPH) is a rare disease in children, with unknown etiology. The classical clinical triad is hemoptysis, hypochromic anemia and diffuse parenchymal infiltrations on chest X-ray. Liposteroid dexamethasone palmitate, which was developed in Japan, has shown good efficacy for IPH. We present the case of a patient with IPH, who suffered from a life-threatening respiratory dysfunction, and was rescued by a trial administration of liposteroid with methylprednisolone (mPSL). A 6-year-old girl was admitted to our hospital for repeated dyspnea and blood-stained sputum. She was diagnosed with IPH at the age of three-months by iron staining of gastric fluid and sputum studies. Her cumulative dose of steroids (equivalent to prednisolone (PSL)) was 1062 mg/kg. However, she could not achieve remission. We decided to initiate liposteroid therapy. We administered an infusion of liposteroid 0.8 mg/kg intravenously, for three consecutive days as a therapy for acute bleeding. After administration of liposteroid, she developed high fever with CRP elevation. We suspected that the inflammation was caused by palmitate, which is present as a lipo base in liposteroid. Hence, we added 2 mg/kg mPSL per day for 1 week. As a maintenance treatment, a single infusion of liposteroid was administered followed by mPSL administration for 6 days in every week. Her respiratory condition slowly improved. Tracheostomy was performed for airway management. She was shifted out of the ICU on the 34th day. Steroid is a key therapy for hemosiderosis. When IPH is diagnosed, oral prednisone therapy is initiated. Although this is effective, there are limitations due to significant adverse effects. Maintaining drug therapy is very important for IPH patients to keep the disease under control. Liposteroid has the same mechanism of action as dexamethasone. It has a Lipo base, palmitate, which could induce pro-inflammatory cytokine activation. We used mPSL to inhibit the inflammation following liposteroid administration. This was effective. A combination of liposteroid and mPSL administration was useful method of treatment for the patient. PMID- 29977751 TI - Emphysematous changes in hypersensitivity pneumonitis: A retrospective analysis of 12 patients. AB - Introduction: Emphysema is most commonly associated with smoking but also occurs in hypersensitivity pneumonitis (HP). The aim of this study was to further explore this relationship. Methods: A retrospective, computer-assisted search was performed to identify patients with HP seen at Mayo Clinic in Rochester, Minnesota, from January 1997 through February 2014. Demographic, clinical, and imaging features were analyzed. Patients were excluded if they had a smoking history of 10 pack-years or more. Results: Twelve patients (9 males) with HP and computed tomographic evidence of emphysema were identified. Ten were never smokers and 2 were ex-smokers. The median age at diagnosis was 47 (range, 29-77) years; median symptom duration was 2.2 (range, 0.2-13.4) years. The most common presenting symptoms were dyspnea (83%) and cough (67%). On pulmonary function testing, 6 patients (50%) had a restrictive defect, 2 (17%) had airflow obstruction, and 4 (33%) had an isolated reduction in diffusing capacity of lung for carbon monoxide. The severity of emphysema ranged from mild to severe to focal bullae. All patients had chronic hypersensitivity pneumonitis (CHP). Centrilobular emphysema was most commonly seen with coexistent paraseptal emphysema in 5 patients.Emphysema was most frequent in the upper lung but could be seen in any lobe. Conclusion: Emphysema can occur in patients with CHP independently of smoking history and exposure to specific types of antigens. Emphysematous changes seem to progress at a slower pace compare to reticulations/fibrosis. PMID- 29977752 TI - Multiple circular pleural metastases of renal cell carcinoma. AB - A 91-year-old woman was admitted with persistent pyrexia, anorexia and weight loss. A chest radiograph showed multiple circular masses of various sizes. Chest computed tomography revealed multiple pleural tumors without any lung lesion. The ultrasound-guided biopsy specimens demonstrated diffusely-proliferated tumor cells with clear or vacuolated cytoplasm, which were positive for CD10, PAX8, vimentin and CAM5.2, but were negative for mesothelial cell markers such as HBME 1 and thrombomodulin. These findings indicated metastatic clear cell carcinoma of the kidney, and a solitary renal tumor was observed on abdominal computed tomography. It has been reported that pleural metastases constituted 12% of patients with progressive renal cell carcinoma, and most of the pleural metastases occurred secondary to lung metastasis. This was a rare case of renal cell carcinoma with an unusual chest image via an intriguing metastatic pathway, which was limited to pleura. PMID- 29977753 TI - Lung cancer induced from chemotherapy a 20 years old case. AB - Lung cancer is diagnosed at a late stage although we have novel diagnostic tools. The association of smoking and other environmental factors are well known. However; there are cases where a malignancy is associated with previous radiation treatment. There is an association between radiotherapy treatment and cancer incidence. We present a case where lung cancer and laryngeal cancer was induced 20 years after radiation therapy of a hogkin lymphoma. PMID- 29977754 TI - Mitral stenosis due to rheumatic heart disease - A rare cause of massive hemoptysis. AB - Severe mitral valve stenosis caused by rheumatic heart disease presenting initially as massive hemoptysis has become a rare occurrence in contemporary western medicine. Massive hemoptysis can be due to multiple disease processes including airway diseases such as bronchiectasis, pulmonary parenchymal disease of infectious or autoimmune etiology, pulmonary AVM's, hematologic disorders, and numerous drugs and iatrogenic injuries. It is less associated with congestion from rheumatic heart disease due to the earlier detection and subsequent management of cardiac valve disease preventing the sequela of more severe disease. We describe a case of a 59 year-old woman with hemoptysis, who was found to have severe mitral stenosis consistent with rheumatic heart disease. We demonstrate the appearance of pulmonary venous congestion can be seen on bronchoscopic examination in severe mitral stenosis and discuss the significance of the Wilkins score to help guide management. PMID- 29977755 TI - Pneumocytic adenomyoepithelioma: A case providing support for the benignity of this extremely rare pulmonary neoplasm. AB - Pneumocytic adenomyoepithelioma is an extremely rare and poorly understood pulmonary neoplasm, so experience with this tumor is limited. Since the initial case series where the lesion was first proposed as a distinctive entity, only one additional report has been described. We present a case of pneumocytic adenomyoepithelioma with clinical and radiologic data that provide the first long term evidence of the benignity of this extremely rare pulmonary neoplasm. We also review the available literature surrounding pneumocytic adenomyoepitheliomas. Our case provides important new data on the behavior of this lesion, as imaging studies showed essentially stable or very slowly progressive disease over the course of approximately 9 years. Collectively, this rare and poorly described lesion appears to behave in an indolent or benign fashion, a notion that our case further supports. PMID- 29977756 TI - S. maltophilia pneumonia: A case report. AB - Case report of Community-acquired pneumonia in a male patient without co morbidities. Empiric antibiotic treatment did not resolve the clinical picture of productive cough, and a chest computerized tomography and sputum culture with antibiogram were performed, identifying S. maltophilia infection with sensitivity to levofloxacin and sulfamethoxazole/trimethoprim. Treatment with levofloxacin (500 mg/day for 15 days) resulted in resolution of the clinical picture. PMID- 29977757 TI - The role and safety of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis and management of infected bronchogenic mediastinal cysts in adults. AB - Bronchogenic and other duplication cysts are congenital abnormalities that can present at any age including adulthood years. They are usually asymptomatic and discovered incidentally on radiological imaging of the chest. They are commonly treated by surgical resection. Recently, endobronchial ultrasound has been used to assist in diagnosis when radiologic imaging is not definitive. Endobronchial ultrasound has been used rarely to drain infected cysts, a rare complication of the bronchogenic cyst. We present a unique case of an infected large bronchogenic cyst treated with endobronchial ultrasound drainage combined with conservative medical therapy. We also review the scarce available literature describing such an approach and its potential complications and add recommendations based on our experience in managing these anomalies. PMID- 29977758 TI - Epstein-Barr virus hepatitis can cause transient hepatopulmonary syndrome. AB - Introduction: Hepatopulmonary syndrome is commonly seen in the patients with chronic liver disease. Acute liver diseases are rarely associated with HPS. We have reported here a case of Transient HPS caused by Epstein-Barr virus hepatitis. Case report: The patient was a 31 years old man that came to hospital due to RUQ pain and yellowish skin. In examination the patient was tachypnic and O2 saturation was 71% with prominent JVP. ver enzyme and bilirubin were high. All viral hepatitis was negative except anti viral capsid antigen-antibody of EBV. In Blood gas PaO2 was 54 mmHg, O2 saturation 73% and alveolar-arterial gradient was 18 mmHg. Stress Echocardiography with saline injection reported pulmonary arterial pressure 32 cmHg with delayed opacification of left atrium. Conclusion: transient HPS can be manifestation in the acute hepatitis caused by EBV infection. PMID- 29977759 TI - Pulmonary strongyloidiasis causing septic shock in a patient with Crohn's disease. AB - A 58 years old male who was admitted to the intensive care unit for septic shock secondary to pneumonia, he has Crohn's disease currently treated with Vedolizumab and previously with infliximab. He was started on broad spectrum antibiotics and vasopressors for treatment of septic shock without improvement in the following days, sputum & blood cultures were negative. Bronchoscopy was done for non resolving pneumonia work up, broncheoalveolar lavage smears and cultures were negative for bacteria, tuberculosis and Fungi. Bronchial washings cytology showed filariform larvae and serology was positive for Strongyloides, He was started on ivermectin and his condition improved significantly. PMID- 29977760 TI - A fatal case of diffuse alveolar hemorrhage as the initial presentation of systemic lupus erythematosus: A case report and literature review. AB - Diffuse alveolar hemorrhage (DAH) is a rare fatal pulmonary complication of systemic lupus erythematosus (SLE). The clinical syndrome is characterized by hemoptysis, acute fall in hematocrit, hypoxemic respiratory failure, and diffuses pulmonary infiltrates. We describe a case of 23-year-old female who presented with Ludwig's angina that was complicated by diffuse alveolar hemorrhage as the initial presentation of undiagnosed systemic lupus erythematosus. A high index of suspicion is need for prompt diagnosis and treatment in order to avoid the high mortality associated with such cases. PMID- 29977762 TI - A rare case of pulmonary cement embolism in a lung transplant patient. AB - Pulmonary cement embolism (PCE) is a complication of percutaneous vertebral augmentation techniques. PCE in lung transplant patient population has not been reported. We report a case 57-year-old male patient with double lung transplant secondary to idiopathic pulmonary fibrosis presented with shortness of breath after vertebroplasty. CTA chest showed thin dense opacities within the bilateral pulmonary arteries consistent with pulmonary cement embolism. The patient was treated with therapeutic enoxaparin and remained stable at one year follow up. PMID- 29977761 TI - Alpha1 antitrypsin deficiency due to an homozygous PI* Null Q0Cairo mutation: Early onset of pulmonary manifestations and variability of clinical expression. AB - Alpha-1 antitrypsin deficiency is an autosomal, codominant disorder caused by mutations of the SERPINA1 gene. This genetic disorder is mainly associated with development of pulmonary emphysema and/or chronic liver disease and cirrhosis. Here we report a very rare alpha-1 antitrypsin Null Q0cairo homozygous mutation characterized by a complete absence of alpha-1 antitrypsin in the plasma, in a non-consanguineous Moroccan family. This mutation has been previously described in heterozygosis in only three cases worldwide: an Italian/Egyptian family and two Italian families (Zorzetto et al., 2005). The main clinical features in two members of this Moroccan family were the severity and precocity of bronchiectasis, quickly spreading and seriously limiting respiratory function and physical activity by the second decade of age. Moreover, the index case presented with many episodes of pulmonary infections concomitant with severe neutropenia. The third member of the family presented with ankylosing spondyloarthritis and developed panniculitis later but had no respiratory symptoms. The presence of this alpha-1-antitrypsin Q0cairo homozygous mutation could explain the severity of clinical manifestations. Moreover, our observations highlight a great variability of clinical expression for the same mutation: early severe bronchiectasis, panniculitis, rheumatologic manifestations. This study further underlines the importance of genotyping by whole SERPINA1 gene sequencing in addition to serum alpha-1 antitrypsin determination, to enable detection of alpha 1 antitrypsin deficiency due to rare genotypes. PMID- 29977763 TI - New hybrid method for trachea dilatation with rigid and flexible tools. AB - Trachea stenosis is observed either in benign or malignant situations. In cancer malignancy a tumor might obstruct the central airway in three different ways. Again granuloma tissue is usually observed after intubation or stent placement in order to manage a benign malformation of the trachea. In any case there are several tools and techniques that can be used either with surgery or endoscopically to manage such situation. We will focus on a hybrid technique in order to ventilate the patient while performing endoscopic management of granuloma tissue. PMID- 29977764 TI - Thoracic empyema and pectoral abscess resulting from attempting suicide by injection of benzene in the pleural cavity. AB - Background: Exposure to hydrocarbon compounds, such as benzene may cause injury to several organ systems. It occurs accidentally or intentionally by ingestion, inhalation, cutaneous exposure and either subcutaneous injection or intravenous injection. We report a patient who injected benzene into the left hemithorax and secondly attempted to commit suicide with paracetamol. Case presentation: A 52 year old man was admitted in the hospital because of an attempted suicide with an injection of benzene in the left hemithorax and ingestion of 50 tablets of 500 mg paracetamol. He developed a hydro-tensionpneumothorax due to inflammatory pleural effusion as a reaction to intrathoracic benzene. Therefore a chest-tube was inserted. A few days later he developed an empyema in the left lung and secondly a pectoral abscess, which required surgical debridement. After surgery, recovered fully and after 23 days of hospitalisation he was discharged to a psychiatric care facility. Conclusion: Hydrocarbon poisoning is either accidentally or intentionally and leads to thoracic pathology in rare cases. The most affected organ system is the respiratory system, and the cytotoxic effects of hydrocarbons can manifest as respiratory failure, pneumonitis and even acute respiratory distress syndrome (ARDS). PMID- 29977765 TI - Epithelioid angiosarcoma: A rare cause of pericarditis and pleural effusion. AB - Angiosarcomas are rare cancers accounting for less than 2% of all soft tissue sarcomas. We report the case of an unusual presentation of pleural epithelioid angiosarcoma in a patient with constrictive pericarditis and recurrent pleural effusion. A 62 year old smoker presented with acute chest pain. ECG showed diffuse elevation of ST segments in the precordial leads. After extensive evaluation, he was diagnosed with viral pericarditis and treated with colchicine. Two weeks later the patient presented to the emergency department with a large right pleural effusion. Evaluation of the pleural fluid obtained from a thoracentesis revealed an exudative effusion with negative microbial studies and no evidence of malignant cells. His pleural effusion re-accumulated rapidly, requiring repeated thoracenteses over several weeks. Medical thoracoscopy was performed and pleural biopsy revealed primary pleural epithelioid angiosarcoma. Staging PET scan revealed malignant enhancement of right pleura, pericardium, right iliac bone and right shoulder. He died suddenly within 6 weeks of diagnosis, prior to initiating palliative chemotherapy. Pleural angiosarcoma should be considered in the differential diagnosis of recurrent pleural effusions of unknown etiology. Negative cytology does not rule out the diagnosis; excisional biopsy is required. Reported risk factors include asbestos exposure, prior chest radiation, active smoking and history of complicated pleural tuberculosis. Pleural epithelioid angiosarcomas carry a very poor prognosis, with the majority of patients dying within months of diagnosis. PMID- 29977767 TI - Improved lung function and quality of life following guaifenesin treatment in a patient with chronic obstructive pulmonary disease (COPD): A case report. AB - We report improved lung function and quality of life following daily use of guaifenesin/dextromethorphan (Mucinex DM(r), Reckitt Benckiser) for the treatment of mucus-related symptoms in a patient with COPD, who presented with increasing dyspnea, progressive cough and chest congestion. PMID- 29977766 TI - Retinoic acid syndrome in a elderly male with psoriasis- A case report. AB - The retinoic acid derivatives are used for disorders of keratinization such as psoriasis. Retinoic acid syndrome is a cytokine release syndrome, commonly encountered in patients with acute promyelocytic leukaemia (APL). It is very rarely described in psoriasis seconday to use of retoind derivatives. Here we report a case of elderly male with psoriasis presenting with acitretin induced retinoic acid syndrome. PMID- 29977768 TI - Idiopathic pulmonary fibrosis patient supported with extracorporeal membrane oxygenation for 403 days while waiting for a lung transplant: A case report. AB - According to the Extracorporeal Life Support Organization, the average duration of veno-venous extracorporeal membrane oxygenation (V-V ECMO) in adults with acute respiratory failure is 10.5-13.5 days. Some patients on V-V ECMO may not recover in such a short period of time, and recently, there have been more reports of prolonged V-V ECMO. However, we do not know how long it is feasible to wait for native lung recovery or lung transplant (LTx) with the use of ECMO. We describe a patient with acute exacerbation of idiopathic pulmonary fibrosis supported by ECMO for 403 days while waiting for a LTx. In this case, we kept the patient awake, and he was communicating frequently with his family. We changed the membrane oxygenator 23 times and the cannula 10 times without complication. However, we terminated the treatment on day 403 of ECMO because there was no access site for cannula insertion due to blockage by a venous thrombotic occlusion, making it impossible to continue this bridge to lung transplantation. It has become possible to maintain patients on ECMO for extended periods of time, but it is difficult to manage ECMO for more than one year without the development of a more durable lung support system. PMID- 29977769 TI - Good's syndrome with clinical manifestation after thymectomy: A case report. AB - Good's syndrome is a rare condition of immunodeficiency that is characterized by thymoma and hypogammaglobulinemia. A 74-year-old Japanese woman underwent total thymothymectomy for type AB thymoma (2015 WHO classification). She developed recurrent infectious diseases caused by Escherichia coli (bacteremia), Streptococcus pneumoniae (pneumonia and bacteremia) and Pseudomonas aeruginosa (bacteremia) in the year after thymectomy. The serum levels of immunoglobulin were significantly low (IgG 157mg/dL), which suggested that her infectious diseases were associated with Good's syndrome. Although she began receiving intravenous immunoglobulin every four weeks, she died of pneumonia a week after the second administration of immunoglobulin. When physicians encounter patients with recurrent infection who have a medical history of thymoma, the detection of hypogammaglubulinemia can be a key clue to the diagnosis of Good's syndrome. PMID- 29977770 TI - An autopsy case of bird-related chronic hypersensitivity pneumonitis presenting with repeated acute exacerbation. AB - A 68-year-old woman was admitted to our hospital with a dry cough in 2010. Chest computed tomography showed the appearance of a nonspecific interstitial pneumonia (NSIP) pattern. Video-assisted thoracoscopic surgery (VATS) was performed, and the specimens prominently showed a usual interstitial pneumonia (UIP) pattern. She was diagnosed with bird-related chronic hypersensitivity pneumonitis (BRCHP) on the basis of the detection of antibodies to pigeon dropping extract in her serum and a history of using feather-filled duvets and indirect exposure to birds in her living environment. Even though she was treated with corticosteroids and immunosuppressants and recommended to avoid bird-related antigens, she had a progressive course with repeated acute exacerbation episodes and died of respiratory failure. The autopsy findings showed diffuse alveolar damage superimposed on UIP. Clinicians should be aware that BRCHP patients especially with histopathologically UIP pattern may experience acute exacerbation. PMID- 29977772 TI - Inhaled nitric oxide mitigates need for extracorporeal membrane oxygenation in a patient with refractory acute hypoxemic respiratory failure due to cardiac and pulmonary shunts. AB - We present a case of refractory acute hypoxemic respiratory failure due to influenza B pneumonia with concomitant large intra-atrial shunt (IAS) and severe pulmonary regurgitation in a patient with Saethre-Chotzen syndrome with prior pulmonary homograft placement. Our patient's hypoxemia improved with inhaled nitric oxide as an adjunct to mechanical ventilation without requiring extracorporeal membrane oxygenation, and eventually a percutaneous closure with a 30 mm CardioSeal patent foramen ovale closure device was accomplished. However, his peri-procedural hospital course was complicated by occluder device migration, which was retrieved with eventual surgical closure of the PFO. Nitric oxide has not demonstrated any statistically significant effect on mortality and only reported to transiently improved oxygenation in patients with hypoxemic respiratory failure. Our case demonstrates that inhaled nitric oxide may have a role in acute hypoxemic respiratory failure in a case with significant cardiac and pulmonary shunts. PMID- 29977771 TI - Esophagus lyomyoma diagnosed with convex endobronchial ultrasound (EBUS). AB - Esophageal lyomyoma are rare benign tumors of the esophagus and they remain usually undiagnosed until local compression symptoms occur in the esophagus. Gastroscopy or esophageal ultrasonography (EUS) are usually the methods of choice for diagnosis. Moreover; surgery is the solution for this entity. In our case we present diagnosis of esophageal lyomyoma using convex probe endobronchial ultrasound (EBUS) with a fine needle aspiration of 22G. PMID- 29977773 TI - Persistent cough - A rare presentation of hepatocellular carcinoma. AB - Coughing is a very common condition, accounting for frequent visits in general practice. In this case report, we found the cause of persisting cough to be hepatocellular carcinoma, located in close proximity to the diaphragm. After the tumor had been treated with chemoembolization the coughing disappeared. After the common causes for persistent cough has been ruled out, the clinician could consider other, rarer, conditions as the cause of the coughing, including affection of the diaphragm. PMID- 29977774 TI - Orthopnea and pulmonary hypertension. Treat the underlying disease. AB - We report the case of a patient with longstanding dyspnea upon reclining, who presented with severe right heart failure due to chronic alveolar hypoventilation. Bilateral diaphragmatic paresis was discovered. She recovered from her right ventricular failure with non-invasive mechanical ventilatory support. PMID- 29977775 TI - A unique case of a huge mixed squamous cell and glandular papilloma of non endobronchial origin with a peripheral growth. AB - We report a case of a huge solitary non-endobronchial pulmonary tumor in a 76 year-old male smoker. The tumor measured 11 * 10 * 8 cm. It was ill-defined, and it was located periphery of the right lower lobe with the subpleural cystic spaces. He underwent right lower lobectomy with mediastinal lymph node dissection and is free from tumor 30 months after surgery. Microscopically, it was composed of a proliferation of squamous and ciliated columnar epithelial cells with a few mucous cells. These cells were arranged in a papillary growth fashion extending along the fibrously thickened alveolar septa together with metaplastic bronchiolar and squamous epithelia displaying an usual interstitial pneumonia pattern. Although the histologic features of the tumor were that of a mixed squamous cell and glandular papilloma (MSCGP), it was peripherally located and showed a lepidic growth, and it was much larger than previously reported MSCGPs. It is possible that the tumor developed in association with bronchial metaplasia in the periphery of the lung, and then extended along the surface of the reconstructed air spaces, which resulted in its unique histologic appearance. Further investigations of respiratory papilloma are needed to clarify the pathogenesis of these lesions. PMID- 29977776 TI - Pulmonary inflammatory pseudotumor causing lung collapse responding to corticosteroid therapy. AB - Pulmonary inflammatory pseudotumor (PIP) is a rare benign tumor that represents less than one percent of all tumors found in the lungs. Despite the benign etiology, PIP can cause significant clinical problems due to its growth rate and potential to compromise adjacent pulmonary and thoracic structures. Complete surgical resection is the preferred therapy for PIP to prevent recurrence, however, this is not possible in some patients due to the size or location of the tumor. We present the case of an 18 year-old male presenting with PIP in the proximal left mainstem bronchus causing complete left lung collapse. Surgical resection was not possible due to tumor location, and therefore the patient was treated with corticosteroids with marked response. Corticosteroid use has for PIP has been described in few other situations, and this case demonstrates the potential for this therapeutic option in patients with PIP who have a contraindication to surgical resection. PMID- 29977777 TI - Pulmonary benign metastasizing leiomyoma: A case report. AB - Uterine leiomyoma is the most common benign gynecological tumor. Rarely, it has benign extra-uterine growth patterns, including benign metastasizing leiomyoma (BML), with lungs being the most common metastatic site. We present a case of a 47-year-old female who, 3 years prior to presentation, underwent abdominal supra cervical hysterectomy for benign leiomyoma. Approximately 6 months prior to presentation, she was seen for shortness of breath and chest pain. A CT of the chest revealed multiple new non-calcified pulmonary nodules bilaterally. PET/CT demonstrated mild FDG uptake in multiple lung nodules, with no significant extra thoracic sites of abnormal FDG uptake. A CT guided lung biopsy showed a low grade, smooth muscle tumor. Immunohistochemical staining was positive for smooth muscle actin and desmin, estrogen and progesterone receptor and was negative for CD117, HMB-45, CD34, pan cytokeratin and EMA. She underwent wedge resection of one of the nodules which confirmed the above findings. A cytogenetic analysis was also performed, which was consistent with pulmonary BML. She ultimately underwent left lower lobe resection and was started on a daily aromatase inhibitor. BML is a rare disease usually seen in women of reproductive age. The pathogenesis and treatment remain controversial. BML mostly tends to have an indolent course and a favorable outcome. PMID- 29977778 TI - Two cases of cavitary lung cancer with concomitant chronic infectious disease. AB - The existence of a lung cavity on chest radiographs suggests the presence of lung disease, including benign or malignant disease. Lung cancer, tuberculosis, and fungal infection are all known for developing lung cavity. In addition, there are some characteristic findings in the differential diagnosis of cavitary disease, although these cavitary diseases often coexist. Here, we report two cases that presented cavitary lung cancer with concomitant chronic infectious disease. One patient showed pulmonary aspergillosis and lung adenocarcinoma, the other patient showed Mycobacterium avium complex lung disease and lung adenocarcinoma. These chronic infectious diseases develop slowly, and clinicians often follow up over several months. To reduce the delay in diagnosis of malignancy, clinicians should aggressively collect the specimens from cavitary lesions and make a correct diagnosis when encountering lung cavity in diagnostic clinical imaging. PMID- 29977779 TI - Massive hemorrhage after inspection bronchoscopy for carcinoid tumor. AB - Carcinoid tumor is a neuroendocrine tumor that can arise in the bronchial tree and can be hypervascular. Here we describe a case of bronchial carcinoid tumor in a 34-year-old previously healthy male who presented with hemoptysis and right lung mass. Inspection bronchoscopy revealed bronchus intermedius endobronchial lesion and was complicated by urgent intubation and placement of endobronchial blocker for massive hemorrhage. Subsequent angiography with embolization of the bronchial artery supplying the mass resulted in control of bleeding. While massive hemorrhage has been described with biopsy of bronchial carcinoid tumor, this case suggests that careful planning for inspection bronchoscopy is needed when carcinoid tumor is suspected. PMID- 29977780 TI - Exacerbation of asthma due to inadvertent use of a dummy inhaler. AB - Asthma is a common airways disease. Fortunately most patients respond well to inhaled therapy. Regular use of a combination inhaler delivering corticosteroid and a long-acting beta-2 agonist, is the mainstay of treatment and allows asthmatics to live a relatively normal life. However, management of asthma depends not only on the choice of drug/inhaler but also on patient compliance and optimal inhaler technique. This report describes a patient who continued to deteriorate despite adhering to prescribed treatment and demonstrating a good inhaler technique. Unfortunately the combination inhaler she was taking inadvertently was a designated placebo device for a branded product. This error was identified and corrected only after she was admitted with an asthma attack. PMID- 29977781 TI - Ventilator associated pneumonia caused by Raoultella ornithinolytica in two immunocompetent trauma patients. AB - Infections with Raoultella ornithinolytica have recently been reported more frequently in the medical literature. This pathogen has the potential to cause many types of infections, including pneumonia. Here, we report the first two cases of ventilator-associated pneumonia (VAP) in trauma patients caused by Raoultella ornithinolytica. Both of these infections were successfully treated with antibiotics based on susceptibilities and the patients were able to be transferred out of the intensive care unit. PMID- 29977782 TI - "Exercise induced asthma" is not always asthma. AB - A 25 year old woman was referred to our center for further evaluation of an exercise-induced dyspnea. Moreover, the patient suffered from hoarseness and recurrent sinusitis and otitis. After initially finding nothing suspicious, a spiro-ergometry was performed. Interestingly, we saw a relevant limitation of the inspiratory flow-volume curve under maximal exercise load. Further evaluation (in particular the bronchoscopy and the resulting biopsies) led us to the final diagnosis of a granulomatosis with polyangiitis. After 4 weeks of an established therapy regime with prednisone and rituximab the prior detected subglottic stenosis and the inspiratory flow-volume curve limitation could no longer detected. We describe a rare differential diagnosis of an exercise-induced asthma and we underline the importance of a multimodal therapy concept. We highlight the critical nature of the flow-volume curve in spiro-ergometry under maximal exercise load. We recommend frequent follow-up control visits to monitor the subglottic stenosis. PMID- 29977783 TI - Community acquired multi drug resistant (MDR) Acinetobacter baumannii pneumonia in Malaysia - A case report. AB - Acinetobacter baumannii is an aerobic Gram-negative coccobacillus that is associated with hospital acquired pneumonia. There is increased reporting of emergent cases of community acquired multidrug resistance (MDR) acinetobacter associated with a higher mortality due to antibiotic resistance. Community acquired MDR acinetobacter pneumonia has not been reported in Malaysia. Here we report a case of a 19-year-old army officer who presented with fever and respiratory symptoms for 5 days. He had no known medical illness before and no history of hospitalization. Upon arrival, he was in septicaemic shock, requiring invasive ventilator support and renal replacement therapy in intensive care unit. Chest radiograph showed bilateral lung consolidations and bronchoscopy revealed haemoserous and greenish bronchiole secretion. He was treated with broad spectrum antibiotics and oseltamivir. Unfortunately he died on day 3 of hospital admission. His bronchial lavage culture came back positive for MDR Acinetobacter baumannii. This case illustrates that clinicians need to be aware that MDR Acinetobacter baumannii can cause severe community acquired pneumonia. We may need to consider this diagnosis in patients who do not respond to standard therapy. PMID- 29977784 TI - Right mainstem bronchoplasty 18 years following thoracic spinal implant surgery. AB - Thoracic spinal surgery has many complications ranging from surgical site infection, chronic pain, periarticular arthrosis, displacement of spinal screws and hardware migration to a lesser degree. Reports of spinal implants penetrating the aorta have been described in the literature, however to our knowledge, lower airway obstruction due to spinal hardware migration has not been reported. Here we describe a case of a patient presenting with a right main stem bronchial obstruction and pneumonia secondary to the migration of the surgical spinal hardware into the lower airway 18 years after his initial intervention. We describe our surgical approach, management and outcomes using bronchoscopy and open thoracotomy. Bronchial obstruction is not a common complication of thoracic spinal surgery, however in remote cases patients may present with rare consequences, it is therefore important to pay close attention to patients' clinical and surgical history since surgical complications may appear years after. PMID- 29977785 TI - Multiple myeloma causing interstitial pulmonary infiltrates and soft-tissue plasmacytoma. AB - Multiple Myeloma (MM) is a relatively rare disease and MM presenting outside the bone marrow, known as extramedullary myeloma (EMM), is rarer still. While the liver and CNS are most commonly affected in EMM, the lung parenchyma is an especially unusual site of involvement. We present the case of a 64-year-old male with known history of MM admitted with acute respiratory failure and a chest wall mass. Chest CT revealed patchy interstitial and alveolar opacities with no pulmonary masses or nodules. Bronchoalveolar lavage (BAL) was performed, with flow cytometry demonstrating monoclonal plasma cells expressing CD38, CD138 and CD56 with lambda light chain restriction. Fine Needle Aspiration of chest wall mass revealed CD138-positive cells as well. Review of the literature revealed only one other documented case of a patient presenting with both interstitial lung parenchymal involvement with MM as well as soft tissue plasmacytoma, with this occurring in a patient who had previously underwent stem cell transplant. To our knowledge, we report the first recorded case of this presentation in a patient without a history of stem cell transplantation. Furthermore, it demonstrates the utility of using BAL, rather than lung biopsy, to establish the diagnosis through less invasive means. PMID- 29977786 TI - Granulomatous response to invasive pulmonary aspergillosis in an immunotherapy naive host, a maladaptive response? AB - Pulmonary aspergillosis causes a wide spectrum of disease, ranging from asymptomatic airway colonization to severe invasive disease, contingent on the host's immune status and underlying pulmonary anatomy. The invasive form of aspergillosis is a rare occurrence in the immunocompetent population. Nevertheless, patients with a compromised innate immune response are at greatest risk. We present a case of a patient with known Crohn's disease who developed invasive pulmonary aspergillosis. His clinical picture was further complicated by an uncommon immune response characterized by the development of granulomas encasing the Aspergillus forms found on his lung biopsy, likely representing a maladaptive response, possibly related to the effects of his granulomatous disease in the lungs. He was successfully treated with antifungal therapy and video assisted thoracoscopic surgery with placement of thoracostomy tube drainage for a parapneumonic effusion. We will discuss the factors leading to his atypical presentation and clinical outcome. PMID- 29977787 TI - Organized blood clot masquerading as endobronchial tumor: A review of management and recent advances. AB - Central airway obstruction, a frequently encountered emergency, is usually associated with blood clots, tumors, foreign bodies or mucus plugs. Airway obstruction due to blood clots can be seen as a complication of lung malignancies, infections, bronchiectasis, arteriovenous malformations or pulmonary infarction. In patients with long standing blood clots, the thrombus gets organized and firmly adherent to the airway. The diagnosis is often misleading as these clots mimic tumors clinically and on imaging. Hemoptysis is the most common presenting symptom though many patients can be asymptomatic. Direct visualization with bronchoscopy is required to establish a diagnosis. Life threatening respiratory impairment is an indication for emergent clot retrieval. Management of these blood clots, especially when organized, is challenging. Initial attempts at removal should include suctioning, lavage or forceps extraction. When unsuccessful, further management options include balloon catheter dislodgement, use of topical thrombolytics, rigid bronchoscopy and cryoextraction. PMID- 29977788 TI - Diffusion-weighted magnetic resonance imaging-directed biopsy of a metastatic bone tumor: Lung adenocarcinoma with ALK rearrangement. AB - A previously healthy 44-year-old Japanese man with a 5-month history of lumbago presented to the emergency department with acute respiratory failure caused by pneumonia, and was immediately intubated. Computed tomography revealed a lung mass, pleural effusion, and multiple osteolytic lesions; however, the results of thoracentesis and bronchial brushing were not definitive. We performed a bone tumor biopsy guided by diffusion-weighted magnetic resonance imaging (DW-MRI) with mechanical ventilation, which enabled the diagnosis of ALK rearrangement positive lung adenocarcinoma. In the era of precision medicine requiring proper biological tissue collection, DW-MRI was critical for identifying the biopsy site safely and with high precision. PMID- 29977789 TI - Biopsy-proven recurrent, acute, familial hypersensitivity pneumonitis: A case report and literature review. AB - Hypersensitivity pneumonitis (HP) is characterized by inflammation of the lung parenchyma that is induced by exposure to an inhaled organic antigen. We present a case of recurrent, acute HP caused by repeated transient exposure to a down sleeping bag in a patient with a family history of chronic bird-associated hypersensitivity pneumonitis. The patient's recurrent symptoms, changes in physiology, and radiographic findings coincided with repeated exposure to this source. It was later confirmed that the patient's sister had also developed chronic HP from recurrent exposure to household birds. This case highlights recent studies implicating gene-exposure interactions in the development of HP. PMID- 29977790 TI - Short veno-venous extracorporeal membrane oxygenation assisted segmentectomy for second primary lung tumor in a patient with insufficient respiratory function for one lung ventilation. AB - Advances in extracorporeal membrane oxygenation (ECMO) have allowed safe performance of complex thoracic surgical procedures that were impossible before. Application of ECMO in general thoracic surgery is extremely rare, but allows life-saving procedures in patients in whom one-lung ventilation cannot be carried out safely. We present the case of a 66 year old man who underwent a challenging veno-venous ECMO assisted segmentectomy for a second primary lung cancer. One lung ventilation was not feasible due to previous lobectomy on the contralateral side and consequent lack of respiratory function. After the surgical procedure was completed the ECMO was removed and under stable conditions followed the immediate tracheal extubation. PMID- 29977791 TI - Teratoma-negative anti-NMDA receptor encephalitis presenting with a single generalized tonic-clonic seizure. AB - Herein, we describe a case report of anti-NMDA receptor encephalitis characterized by a single generalized tonic-clonic seizure and predominantly psychiatric symptoms, persisting long after EEG abnormalities had resolved. We discuss common presentations of anti-NMDA receptor encephalitis and advocate for the inclusion of this disease entity in the differential diagnosis of patients presenting with one generalized tonic-clonic seizure and prominent psychiatric symptoms. PMID- 29977792 TI - Seizure remission and improvement of neurological function in sialidosis with perampanel therapy. AB - A 15-year-old boy experienced myoclonic seizures for 3 years. He initially had occasional myoclonus, gradually progressive ataxia, tremors, and psychomotor and speech regression developed. Eventually, he exhibited nearly continuous myoclonus. He received treatment of sodium valproate, levetiracetam, clobazam, and phenobarbital, without efficacy. A ketogenic diet also proved ineffective. Adjunctive therapy with 4 mg/day of perampanel was started and was gradually titrated to 10 mg/day. The remission of myoclonic seizures was achieved within one month. The patient's neurological and cognitive functions improved to a certain degree during the following 20 months. Sialidosis was confirmed by the mutations of NEU1 gene. PMID- 29977793 TI - Lacosamide may improve cognition in patients with focal epilepsy: EpiTrack to compare cognitive side effects of lacosamide and carbamazepine. AB - Carbamazepine (CBZ) is a first generation anti-seizure drug, considered as first choice therapy in focal epilepsy but associated with cognitive side effects. Lacosamide (LCM) is a third-generation anti-seizure drug approved for treating focal epilepsy. This case series documented the comparable efficacy of LCM and CBZ as first add on treatments in patients affected by uncontrolled focal seizures. LCM showed an increase in EpiTrack scores, which measure cognitive abilities, at follow-up compared to CBZ. This preliminary data may represent the basis for future prospective studies aimed at comparing the long-term cognitive side effects of LCM and CBZ. PMID- 29977794 TI - Low-cost diagnostic test for susceptible and drug-resistant tuberculosis in rural Malawi. AB - Background: Rural settings where molecular tuberculosis diagnostics are not currently available need easy-to-use tests that do not require additional processing or equipment. While acid-fast bacilli (AFB) smear is the most common and often only tuberculosis diagnosis test performed in rural settings, it is labour intensive, has less-than-ideal sensitivity, and cannot assess tuberculosis drug susceptibility patterns. Objective: The objective of this study was to determine the feasibility of a multidrug-resistant (MDR) or extensively drug resistant (XDR)-tuberculosis coloured agar-based culture test (tuberculosis CX test), which can detect Mycobacterium tuberculosis growth and evaluate for drug susceptibility to isoniazid, rifampicin and a fluoroquinolone (i.e. ciprofloxacin) in approximately 14 days. Method: In this study, 101 participants were enrolled who presented to a rural health clinic in central Malawi. They were suspected of having active pulmonary tuberculosis. Participants provided demographic and clinical data and submitted sputum samples for tuberculosis testing using the AFB smear and tuberculosis CX-test. Results: The results showed a high level of concordance between the AFB smear (12 positive) and tuberculosis CX-test (13 positive); only one sample presented discordant results, with the molecular GeneXpert MTB/RIF(r) test confirming the tuberculosis CX-test results. The average time to a positive tuberculosis CX-test was 10 days. Of the positive samples, the tuberculosis CX-test detected no cases of drug resistance, which was later confirmed by the GeneXpert MTB/RIF(r). Conclusion: These findings demonstrate that the tuberculosis CX-test could be a reliable low-cost diagnostic method for active pulmonary tuberculosis in high tuberculosis burden rural areas. PMID- 29977796 TI - Simple ideas that work: Celebrating development in persons with profound intellectual and multiple disabilities. AB - Background: The purpose of this article is to share some lessons learnt by an interdisciplinary therapy team working with persons with profound intellectual and multiple disabilities (PIMD), implemented in diverse, low-income contexts over a period of 8 years. Objectives: The objective of all the activities described here was to provide increased stimulation and development opportunities for persons with PIMD within different settings (day care centre, residential centre or family home). Method: We used an iterative action-learning approach where we applied existing evidence in the given context, reflected on and adapted strategies in collaboration with stakeholders on a cyclical basis. We focussed on achieving our objectives through ongoing hands-on training of the carers involved with the clients as we felt that by providing them with the knowledge and skills needed, plus ongoing support, these programmes would be more sustainable. Findings: It took some time to put systems in place in care settings, but once they became part of the daily routine, they provided increased opportunities for learning for clients with PIMD. In addition, there were often marked changes in individual clients' communicative and physical functioning, which in turn encouraged carers to find new and different ways to interact with, and stimulate, the persons with PIMD in their care. Conclusion: Our hope is that parents and carers or professionals working in the field of PIMD in low-income contexts elsewhere may find one, some or all of these simple ideas useful in providing opportunities for learning, development and enjoyment for persons with PIMD. PMID- 29977795 TI - Detection of minority drug resistant mutations in Malawian HIV-1 subtype C positive patients initiating and on first-line antiretroviral therapy. AB - Background: Minority drug resistance mutations (DRMs) that are often missed by Sanger sequencing are clinically significant, as they can cause virologic failure in individuals treated with antiretroviral therapy (ART) drugs. Objective: This study aimed to estimate the prevalence of minor DRMs among patients enrolled in a Malawi HIV drug resistance monitoring survey at baseline and at one year after initiation of ART. Methods: Forty-one plasma specimens collected from HIV-1 subtype C-positive patients and seven clonal control samples were analysed using ultra-deep sequencing technology. Results: Deep sequencing identified all 72 DRMs detected by Sanger sequencing at the level of >=20% and 79 additional minority DRMs at the level of < 20% from the 41 Malawian clinical specimens. Overall, DRMs were detected in 85% of pre-ART and 90.5% of virologic failure patients by deep sequencing. Among pre-ART patients, deep sequencing identified a statistically significant higher prevalence of DRMs to nucleoside reverse transcriptase inhibitors (NRTIs) compared with Sanger sequencing. The difference was mainly due to the high prevalence of minority K65R and M184I mutations. Most virologic failure patients harboured DRMs against both NRTIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). These minority DRMs contributed to the increased or enhanced virologic failures in these patients. Conclusion: The results revealed the presence of minority DRMs to NRTIs and NNRTIs in specimens collected at baseline and virologic failure time points. These minority DRMs not only increased resistance levels to NRTIs and NNRTIs for the prescribed ART, but also expanded resistance to additional major first-line ART drugs. This study suggested that drug resistance testing that uses more sensitive technologies, is needed in this setting. PMID- 29977797 TI - The effect of synchronised metronome training: A case study in a single leg, below knee Paralympic sprinter. AB - Background: To optimise sprint performance, one needs to understand how motor control affects motor performance. Researchers have proposed that the Dynamic Systems Theory be adopted for explaining motor performance, skill acquisition and the development of pedagogical methods. Within this theory, the individual is seen as a complex system that functions as the interaction of many sub-systems. Entrained movements would be characterised by optimal sequencing, timing and grading of muscle activation. One of the identified control parameters for running is the rhythm in the coordination pattern. Objectives: The objectives of this study were twofold: firstly to investigate whether 6 weeks of timing and rhythmicity training using the computer-based Interactive MetronomeTM (IMTM) system improves motor timing and rhythmicity, and secondly to investigate whether such effects of IMTM influence the kinematic variables of a sprint. Methods: This study followed a semi-quantitative analysis case study approach using a Paralympic sprinter with a single below knee amputation participated in this study. Data for acceleration and maximal running velocity phases were collected using video recorders. Results and conclusions: As found by previous research, the IMTM programme improved the motor timing and rhythmicity of the athlete. However, in contrast to previous research, only minimal improvements, non significant improvements, were seen in the actual motor performance. This athlete was an older more established athlete and it is therefore recommended that these types of programmes should be followed by young participants in the more fundamental phases of their movement development, to show best results. PMID- 29977798 TI - A preliminary study on the establishment of an animal model of conjunctivochalasis. AB - AIM: To explore a feasible method on the establishment of an animal model of conjunctivochalasis (CCH). METHODS: Twelve clean-grade New Zealand white rabbits were divided into four groups (n=3/group): the control group (one received no interventions, and the others underwent subconjunctival injection of sterile water), the matrix metalloproteinases (MMPs) group (administered subconjunctival injection of MMP-3), the aging group (administered subcutaneous injection of D galactose), the tumor necrosis factor-alpha (TNF-alpha) solution group (administered eye drops of TNF-alpha). Anterior segment photography, conjunctival tissue light microscopy and transmission electron microscopy (TEM) were performed after 12wk. RESULTS: Among all groups, the MMPs group had the following changes: the looser connection between the inferior bulbar conjunctiva and sclera; the more disordered collagen fibers (Trichrome staining) and the broken elastic fibers (Aldehyde-fuchsin staining); the focal necrosis of fibroblasts (TEM). CONCLUSION: Administration of MMPs may be a feasible method for the establishment of an animal model of CCH. PMID- 29977800 TI - Bioinformatics analysis of microarray data to explore the key genes involved in HSF4 mutation-induced cataract. AB - AIM: To reveal the mechanisms of heat-shock transcription factor 4 (HSF4) mutation-induced cataract. METHODS: GSE22362, including 3 HSF4-null lens and 3 wild-type lens, was obtained from Gene Expression Omnibus database. After data preprocessing, the differentially expressed genes (DEGs) were identified using the limma package. Based on Database for Annotation, Visualization and Integrated Discovery (DAVID) tool, functional and pathway enrichment analyses were performed for the DEGs. Followed by protein-protein interaction (PPI) network was constructed using STRING database and Cytoscape software. Furthermore, the validated microRNA (miRNA)-DEG pairs were obtained from miRWalk2.0 database, and then miRNA-DEG regulatory network was visualized by Cytoscape software. RESULTS: A total of 176 DEGs were identified in HSF4-null lens compared with wild-type lens. In the PPI network, FBJ osteosarcoma oncogene (FOS), early growth response 1 (EGR1) and heme oxygenase (decycling) 1 (HMOX1) had higher degrees and could interact with each other. Besides, mmu-miR-15a-5p and mmu-miR-26a-5p were among the top 10 miRNAs in the miRNA-DEG regulatory network. Additionally, mmu-miR-26a 5p could target EGR1 in the regulatory network. CONCLUSION: FOS, EGR1, HMOX1, mmu miR-26a-5p and mmu-miR-15a-5p might function in the pathogenesis of HSF4 mutation induced cataract. PMID- 29977799 TI - Regulation of lipoxygenase-1 and Dectin-1 on interleukin-10 in mouse Aspergillus fumigatus keratitis. AB - AIM: To investigate the regulation of lipoxygenase (LOX)-1 and Dectin-1 on interleukin-10 (IL-10) production in mice with Aspergillus fumigatus (A. fumigatus) keratitis. METHODS: The corneas of C57BL/6 mice were pretreated with LOX-1 inhibitor Poly(I) or Dectin-1 siRNA separately before the infection of A. fumigatus. Polymerase chain reaction (PCR) and Western blot were used to detect the expression of IL-10. RESULTS: The mRNA and protein expressions of IL-10 were significantly increased in mice with A. fumigatus keratitis. Compared with the group pretreated with sterile water before infection, Poly(I) pretreatment suppressed IL-10 expression significantly. Compared with the group pretreated with scrambled siRNA before infection, Dectin-1 siRNA pretreatment significantly reduced IL-10 expression in response to A. fumigatus infection. CONCLUSION: LOX-1 and Dectin-1 regulate IL-10 production in mouse A. fumigatus keratitis. PMID- 29977801 TI - Knobloch syndrome caused by homozygous frameshift mutation of the COL18A1 gene in a Chinese pedigree. AB - AIM: To explore the clinical feature and genetic etiology of a Chinese Knobloch syndrome family. METHODS: Ocular examinations and magnetic resonance imagings (MRIs) were performed on the family. Whole exome sequencing was conducted on the two patients. Sanger sequencing was utilized to validate the presence of variation in the family as well as in 100 normal controls. Real-time quantitative polymerase chain reaction (PCR) was used to detect the expression level of COL18A1 in peripheral blood lymphocytes of the patients and normal carriers. RESULTS: The affected subjects presented with vision loss, exotropia, cataracts, retinal detachment, and other complications. A homozygous c.4759_4760delCT (p.Leu1587ValfsX72) mutation (rs398122391) in COL18A1 was identified in the two patients, cosegregating with the phenotypes, and did not be detected in 100 normal controls. This mutation caused significant decreased expression of COL18A1 mRNA in the patients. CONCLUSION: The findings strongly indicate that this mutation is the disease-causing mutation. Moreover, this is the first Knobloch syndrome pedigree reported in the Chinese population. PMID- 29977802 TI - Protective effects of ciliary neurotrophic factor on the retinal ganglion cells by injure of hydrogen peroxide. AB - AIM: To explore the effect of ciliary neurotrophic factor (CNTF) on retinal ganglion cell (RGC)-5 induced by hydrogen peroxide (H2O2). METHODS: After cell adherence, RGC-5 culture medium was changed to contain different concentrations of H2O2 from 50 to 150 umol/L at four time points (0.5, 1, 1.5 and 2h) to select the concentration and time point for H2O2 induced model. Two different ways of interventions for injured RGC-5 cells respectively were CNTF as an addition in the culture medium or recombinant lentiviral plasmid carrying CNTF gene transfecting bone mesenchymal stem cells (BMSCs) for co-culture with RGC-5. RESULTS: Compared to the control group, H2O2 led to RGC-5 death closely associated with concentrations and action time of H2O2 and we chose 125 umol/L and 2h to establish the H2O2-induced model. While CNTF inhibited the loss of RGC 5 cells obviously with a dose-dependent survival rate. Nevertheless two administration routes had different survival rate yet higher rate in recombinant lentiviral plasmid group but there were no statistically significant differences. CONCLUSION: Both the two administration routes of CNTF have effects on RGC-5 cells induced by H2O2. If their own advantages were combined, there may be a better administration route. PMID- 29977803 TI - Effect of Abeta protein on inhibiting proliferation and promoting apoptosis of retinal pigment epithelial cells. AB - AIM: To identify the effect and regulatory mechanism of amyloid beta (Abeta) protein on retinal pigment epithelial (RPE) cells in cell proliferation and apoptosis, and clarify Abeta role in the pathogenesis of age-related macular degeneration (AMD). METHODS: The model of Abeta25-35 protein cytotoxicity in RPE cell was successfully established to investigate the effect of Abeta protein on RPE cells in vitro. Based on Abeta protein, the specific inhibitors (HY-50682 or BAY11-7082) or activating agent (lipopolysaccharide) was used to analyze the regulatory mechanism of Abeta protein to RPE cells on cell proliferation and apoptosis by flow cytometry, real-time polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay and dual-luciferase reporter gene assay. RESULTS: The number of RPE cells, treated with Abeta25-35 from 0.3 to 60 umol/L, significantly reduce (P<0.01), and had the dose-dependent effect. Abeta protein 60 umol/L inhibits the G1/S phase transition (P<0.01) and down-regulated cyclin E mRNA level (P<0.01). Similarly, Abeta25-35 induced a significant increase of cell apoptosis, accompanied by the significantly higher level of activated caspase 3 protein. Furthermore, nuclear factor-kappaB (NF-kappaB) activity and phosphorylated Ikappa-Ba level would significantly lower in treated RPE cells. Using specific inhibitors or activating agent based on the Abeta, the cell numbers, NF-kappaB activity, phosphorylated Ikappa-Ba level, receptor for advanced glycation endproducts (RAGE) gene expression levels, cyclin E mRNA level and activated caspase 3 level had accordingly changed by different methods, confirming that RAGE/NF-kappaB signaling pathway involved in the regulation of Abeta protein on RPE cell apoptosis and proliferation. CONCLUSION: Abeta protein inhibits cell proliferation and activates apoptosis via inactivation of the RAGE/NF-kappaB signaling pathway in RPE cell. PMID- 29977804 TI - Protective effects of a novel drug RC28-E blocking both VEGF and FGF2 on early diabetic rat retina. AB - AIM: To investigate protective effects of a novel recombinant decoy receptor drug RC28-E on retinal damage in early diabetic rats. METHODS: The streptozotocin (STZ)-induced diabetic rats were randomly divided into 6 groups: diabetes mellitus (DM) group (saline, 3 uL/eye); RC28-E at low (0.33 ug/uL, 3 uL), medium (1 ug/uL, 3 uL), and high (3 ug/uL, 3 uL) dose groups; vascular endothelial growth factor (VEGF) Trap group (1 ug/uL, 3 uL); fibroblast growth factor (FGF) Trap group (1 ug/uL, 3 uL). Normal control group was included. At week 1 and 4 following diabetic induction, the rats were intravitreally injected with the corresponding solutions. At week 6 following the induction, apoptosis in retinal vessels was detected by TUNEL staining. Glial fibrillary acidic protein (GFAP) expression was examined by immunofluorescence. Blood-retinal barrier (BRB) breakdown was assessed by Evans blue assay. Ultrastructural changes in choroidal and retinal vessels were analyzed by transmission electron microscopy (TEM). Content of VEGF and FGF proteins in retina was measured by enzyme linked immunosorbent assay (ELISA). The retinal expression of intercellular cell adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha (TNF-alpha), VEGF and FGF genes was examined by quantitative polymerase chain reaction (qPCR). RESULTS: TUNEL staining showed that the aberrantly increased apoptotic cells death in diabetic retinal vascular network was significantly reduced by treatments of medium and high dose RC28-E, VEGF Trap, and FGF Trap (all P<0.05), the effects of medium and high dose RC28-E or FGF Trap were greater than VEGF Trap (P<0.01). GFAP staining suggested that reactive gliosis was substantially inhibited in all RC28-E and VEGF Trap groups, but the inhibition in FGF Trap group was not as prominent. Evans blue assay demonstrated that only high dose RC28-E could significantly reduce vascular leakage in early diabetic retina (P<0.01). TEM revealed that the ultrastructures in choroidal and retinal vessels were damaged in early diabetic retina, which was ameliorated to differential extents by each drug. The expression of VEGF and FGF2 proteins was significantly upregulated in early diabetic retina, and normalized by RC28-E at all dosages and by the corresponding Traps. The upregulation of ICAM-1 and TNF-alpha in diabetic retina was substantially suppressed by RC28-E and positive control drugs. CONCLUSION: Dual blockade of VEGF and FGF2 by RC28-E generates remarkable protective effects, including anti-apoptosis, anti-gliosis, anti-leakage, and improving ultrastructures and proinflammatory microenvironment, in early diabetic retina, thereby supporting further development of RC28-E into a novel and effective drug to diabetic retinopathy (DR). PMID- 29977806 TI - A new diagnostic model of primary open angle glaucoma based on FD-OCT parameters. AB - AIM: To build a clinical diagnostic model of primary open angle glaucoma (POAG) using the normal probability chart of frequency-domain optical coherence tomography (FD-OCT). METHODS: This is a cross-sectional study. Total 133 eyes from 133 healthy subjects and 99 eyes from 99 early POAG patients were included in the study. The retinal nerve fibre layer (RNFL) thickness parameters of optic nerve head (ONH) and RNFL3.45 scan were measured in one randomly selected eye of each subject using RTVue-100 FD-OCT. Then, we used these parameters to establish the diagnostic models. Four different diagnostic models based on two different area partition strategies on ONH and RNFL3.45 parameters, including ONH traditional area partition model (ONH-T), ONH new area partition model (ONH-N), RNFL3.45 traditional area partition model (RNFL3.45-T) and RNFL3.45 new area partition model (RNFL3.45-N), were built and tested by cross-validation. RESULTS: The new area partition models had higher area under the receiver operating characteristic (AROC; ONH-N: 0.990; RNFL3.45-N: 0.939) than corresponding traditional area partition models (ONH-T: 0.979; RNFL3.45-T: 0.881). There was no statistical difference among AROC of ONH-T, ONH-N, and RNFL3.45-N. Nevertheless, ONH-N was the simplest model. CONCLUSION: The new area partition models had higher diagnostic accuracy than corresponding traditional area partition models, which can improve the diagnostic ability of early POAG. In particular, the simplest ONH-N diagnostic model may be convenient for clinical application. PMID- 29977805 TI - Two-year outcomes of ab interno trabeculectomy with the Trabectome for Chinese primary open angle glaucoma: a retrospective multicenter study. AB - AIM: To evaluate the 2-year efficacy and safety of ab interno trabeculectomy with the Trabectome in Chinese primary open angle glaucoma (POAG) patients. METHODS: This was a multicenter, retrospective, observational study and included POAG patients with or without visually-significant cataracts. The Chinese patients were enrolled from three glaucoma centers and a group of comparable Japanese POAG patients was analyzed from our international Trabectome database. The patients received Trabectome or a combined surgery with phacoemulsification and intraocular lens implantation. The primary outcome was intraocular pressure (IOP) reduction. Secondary outcomes included reduction of glaucoma medications, surgical complications, and success at 2y. Success was defined as: 1) IOP<=21 mm Hg and at least 20% IOP reduction from baseline after 3mo at any two consecutive visits; 2) no additional glaucoma surgery required. RESULTS: A total of 42 Chinese POAG patients from three glaucoma centers were enrolled. Twelve patients underwent Trabectome surgery combined with phacoemulsification and intraocular lens implantation while the remainder underwent Trabectome surgery alone. Thirteen patients had a history of failed glaucoma surgery and were considered as complicated cases. In China data, the mean preoperative IOP was 21.4+/-1.23 mm Hg. The Trabectome lowered IOP to 17.9+/-1.8 mm Hg at 2y (P=0.05). The number of glaucoma medications also decreased significantly from a baseline of 2.0+/-0.9 to 1.1+/-0.8 at 2y post-surgery (P=0.04). The overall 2-year success rate was 78%, with patients undergoing combined surgery having a higher success rate compared with those undergoing Trabectome surgery alone (100% vs 76%). In Japan data, the mean preoperative IOP was 20.8+/-7.7 mm Hg. The Trabectome lowered IOP to 12.20+/ 2.0 mm Hg at 2y. The number of glaucoma medications also decreased significantly from a baseline of 2.1+/-0.9 to 3.4+/-0.6 at 2y post-surgery. In all patients, no major complications were seen. CONCLUSION: Surgery with the Trabectome appears to be an efficient and safe procedure in Chinese POAG patients in the long-term. PMID- 29977807 TI - Effect of the posterior corneal surface on total corneal astigmatism in patients with age-related cataract. AB - AIM: To explore the effect of the posterior astigmatism on total corneal astigmatism and evaluate the error caused by substituting the corneal astigmatism of the simulated keratometriy (simulated K) for the total corneal astigmatism in age-related cataract patients. METHODS: A total of 211 eyes with age-related cataract from 164 patients (mean age: 66.8+/-9.0y, range: 45-83y) were examined using a multi-colored spot reflection topographer, and the total corneal astigmatism was measured. The power vector components J0 and J45 were analyzed. Correlations between the magnitude difference of the simulated K and total cornea astigmatism (magnitude differenceSimK-Tca), anterior J0, and absolute meridian difference (AMD) between the anterior and posterior astigmatisms were calculated. To compare the astigmatism of the simulated K and total cornea both in magnitude and axial orientation, we drew double-angle plots and calculated the vector difference between the two measures using vector analysis. A corrective regression formula was used to adjust the magnitude of the simulated K astigmatism to approach that of the total cornea. RESULTS: The magnitude differenceSimK-Tca was positively correlated with the anterior corneal J0 (Spearman's rho= 0.539; P<0.001) and negatively correlated with the AMDR (Spearman's rho=-0.875, P<0.001). When the anterior J0 value was larger than 1.3 D or smaller than -0.8 D, the errors caused by determining the total corneal astigmatism with the karatometric calculation tended to be greater than 0.25 D. An underestimation by 16% was observed for against the rule (ATR) astigmatism and an overestimation by 9% was observed for with the rule (WTR) astigmatism when ignoring the posterior measurements. CONCLUSION: Posterior corneal astigmatism should be valued for more precise corneal astigmatism management, especially for higher ATR astigmatism of the anterior corneal surface. We suggest a 9% reduction in the magnitude of the simulated K in eyes with WTR astigmatism, and a 16% addition of the magnitude of the simulated K in eyes with ATR astigmatism. PMID- 29977808 TI - Comparison of immersion ultrasound and low coherence reflectometry for ocular biometry in cataract patients. AB - AIM: To compare the results of axial length (AL) biometry in cataract eyes by three methods: immersion B-ultrasound (IB) biometry, immersion A-ultrasound (IA) biometry and optical low coherence reflectometry. METHODS: In this prospective observational study of eyes with cataract AL measurements were performed using immersion ultrasound and optical low coherence reflectometry device. The results were evaluated using Bland-Altman analyses. The differences between both methods were assessed using the paired t-test, and its correlation was evaluated by Pearson coefficient. RESULTS: Eighty eyes of 80 patients (39 men and 41 women) for cataract surgery were included in the study. The values of AL could be got from all 80 eyes by IB and IA, the difference of AL measurements between IA and IB was of no statistical significance (P=0.97); the mean difference in AL measurements was -0.031 mm (P=0.26; 95%CI, -0.09 to 0.02); linear regression showed an excellent correlation (r=0.98, P<0.0001). Forty-five of eighty eyes with results of AL measurements, which can be obtained by three methods; the difference of AL measurements was of no statistical significance (IA vs IB, P=0.18; IA vs Lenstar, P=0.51; IB vs Lenstar, P=0.07); linear regression showed an excellent correlation (IA vs IB, r=0.99; IA vs Lenstar, r=0.96; IB vs Lenstar, r=0.96); Bland-Altman analysis also showed good agreement between the two methods [IA vs IB, 95% limits of agreement (LoA), -0.36 to 0.28 mm; IA vs Lenstar, 95% LoA, -0.65 to 0.69 mm; IB vs Lenstar, 95% LoA, -0.55 to 0.68 mm]. CONCLUSION: Measurements with the optical low coherence reflectometry correlated well with IB and IA. In the eyes with serious refractive medium opacity, the measurements of AL could not be achieved or existed deviations when using optical low coherence reflectometry device. Under such circumstances, we should choose IA or IB as the optimization method to obtain measurements, in order to get much more accurate results. PMID- 29977809 TI - Macular pigment and serum zeaxanthin levels with Goji berry supplement in early age-related macular degeneration. AB - AIM: To evaluate the efficacy of Goji berry supplementation on improving macular pigment, serum zeaxanthin levels and visual acuity in patients with early age related macular degeneration (AMD). METHODS: A total of 114 patients (aged from 51 to 92y, mean age 69.53+/-8.41y) with early AMD were enrolled in our prospective, randomized controlled study. The included patients were assigned randomly to the Goji group (n=57) with 25 g of Goji berries supplementation per day for 90d and the control group (n=57) with their normal diet for 90d. Macular pigment optical density (MPOD) was measured using heterochromatic flicker photometry (HFP). The levels of serum lutein (L)/zeaxanthin (Z) were analyzed using high-performance liquid chromatography (HPLC). MPOD, serum L/Z levels and best corrected visual acuity (BCVA) were recorded at baseline and 90d. RESULTS: In the Goji group, there were no statistically significant differences in the serum L levels between the baseline (0.199+/-0.149 umol/mL) and 90d (0.203+/ 0.181 umol/mL) (t=-0.186, P=0.850); however the serum Z levels were increased at 90d (0.101+/-0.087 umol/mL) compared with those at the baseline (0.029+/-0.032 umol/mL) (t=6.412, P<0.001). Patients treated with Goji berry for 90d showed an elevated MPOD (0.877+/-0.202 DU) from the baseline (0.731+/-0.205 DU) (t=-4.741, P=0.000). In contrast to the control group, the serum Z levels and MPOD were higher in the Goji group at 90d (both P<0.05). At 90d, patients with Goji berry supplementation had a relative decrease in BCVA (0.21+/-0.18 logMAR) compared with the baseline (0.27+/-0.20) (t=2.397, P=0.020). CONCLUSION: Overall, daily supplementation with Goji berry for 90d improves MPOD by increasing serum Z levels rather than serum L levels in early AMD patients. Goji berry may be an effective therapeutic intervention for preventing the progression of early AMD. PMID- 29977810 TI - The role of intravitreal ranubizumab in the treatment of familial exudative vitreoretinopathy of stage 2 or greater. AB - AIM: To evaluate the role of intravitreal ranubizumab (IVR) in the treatment of familial exudative vitreoretinopathy (FEVR) of stage 2 or greater either as primary or an ajunct to conventional treatments. METHODS: Retrospective, non controlled clinical study. Thirty patients (37 eyes) diagnosed with FEVR were enrolled. Twenty patients (66.67%) were male and 10 patients (33.33%) were female. Age ranged from 0.4 to 35 years old (median 3y). IVR was used either as primary or as a combined therapy according to the retinal neovasuclar activities. The follow up ranged from 1 to 57mo with mean 16.73+/-15.73 (median 11)mo. The treatment effect of retinal neovasuclar activites were recorded as well as the ocular and systemic side effects. RESULTS: Among 30 patients (37 eyes), 10 eyes received single IVR, 1 eye received 2 injections. Three eyes were treated with IVR and simutanous laser photocoagulation. Laser indirect ophthalmoscopy (LIO) was applied in 5 eyes 1mo after the primary IVR. Seven eyes were treated surgically following the primary IVR due to persistent retinal neovasuclar activities and retinal traction. IVR was used as combined treatment with vitrectomy in 11 eyes. Retinal neovascular regression was notified 1mo following the primary IVR in all eyes. Neither systemic nor ocular complications were recorded. CONCLUSION: IVR may be an effective modality in the treatment of FEVR either as primary or as an ajunct to the conventional therapies. The long term effect and safty of IVR still need further research. PMID- 29977811 TI - Short-term outcomes after the loading phase of intravitreal bevacizumab and subthreshold macular laser in non-center involved diabetic macular edema. AB - AIM: To compare the effectiveness of intravitreal bevacizumab and subthreshold macular photocoagulation (SMP), for the treatment of non-center involved diabetic macular edema (non-CI DME). METHODS: Prospective, randomized, controlled clinical study included patients with type 2 diabetes, non-CI DME and best-corrected visual acuity (BCVA) of 0.30 logMAR or better. Each eye was randomized into three groups: group 1, monthly intravitreal bevacizumab; group 2, single SMP; group 3, single SMP and monthly bevacizumab. Main outcome measures were BCVA, and macular thickness measured with optical coherence tomography as macular central subfield thickness (CST), macular area of greater thickness (MAGT) and total macular volume (TMV). Results were analyzed after 3mo. RESULTS: A total of 32 eyes were included. Group 3 improved in BCVA (0.19+/-0.16 to 0.12+/-0.14 logMAR; P=0.041) and in TMV (7.90+/-0.57 to 7.65+/-0.73 mm3; P=0.025). Group 1 improved in MAGT (325+/-26.26 to 298.20+/-44.85 um; P=0.022) and TMV (7.79+/-0.57 to 7.50+/-0.56 mm3, P=0.047). Group 2 didn't show significant improvement of any variable. CONCLUSION: The loading phase of bevacizumab as monotherapy or combined with SMP is superior to SMP as monotherapy in providing short-term visual and anatomical improvement in non-CI DME. PMID- 29977812 TI - Clinical observations of vitreoretinal surgery for four different phenotypes of X linked congenital retinoschisis. AB - AIM: To evaluate the outcomes of vitreoretinal surgery for four different phenotypes of X-linked retinoschisis (XLRS). METHODS: This study included thirty one eyes of 25 patients who developed XLRS with severe complications. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All of the patients underwent standard three-port pars plana vitrectomy. All of the eyes were divided into 4 groups before surgery according to a modified classification scheme, with the first three groups as follows: group A, with foveal cystic schisis; group B with macular lamellar schisis; and group C with foveolamellar changes. Peripheral schisis was not present in these 3 groups; however, group D was a complex group with both macular and peripheral changes. One year after surgery, we analyzed the best corrected visual acuity and postoperative anatomical and functional outcomes of these 4 groups. RESULTS: There were 7 eyes in group A (22.6%), 1 eye in group B (3.2%), 15 eyes in group C (48.4%) and 8 eyes in group D (25.8%). Postoperative anatomical and functional outcomes were satisfactory at the last visit, while the mean visual acuity was increased to 0.27+/-0.11, with a significant difference (t=-1.049, P=0.000) compared with the results before surgery (0.1+/-0.08). Visual acuity was improved in 23 eyes (74.2%). Complications were found in three eyes: two eyes with proliferative vitreoretinopathy and traction retinal detachment 10 and 12mo after surgery, respectively; and one eye with vitreous hemorrhage 15mo after surgery. These eyes were in groups C and D. The retinas remained attached in these 3 eyes after reoperation. CONCLUSION: We should pay greater attention to XLRS with foveolamellar changes because it is the most changeable phenotype. Once complications occur, vitreoretinal surgery can significantly improve visual acuity and restore the anatomic structure of the retina. PMID- 29977814 TI - Correlations between the optic nerve head morphology and ocular biometrics in highly myopic eyes. AB - AIM: To analyze peripapillary atrophy beta/gamma zone (PPA-beta/gamma) and the optic disc ovality index, and to assess their associations with the axial length (AL), refractive error, best corrected visual acuity (BCVA), choroidal thickness (CT), and age in highly myopic eyes. METHODS: This was a retrospective observational case series. The study included 667 patients consecutively examined for highly myopic eyes [spherical equivalent <=-6.0 diopters (D) and AL>=26 mm] with or without myopic retinopathy. Each patient went through a comprehensive ophthalmological examination that included spectral domain optical coherence tomography (SD-OCT) of the macula, A-mode ultrasonography, and a cycloplegic refraction test. The ovality index and PPA-beta/gamma area were measured from optic disc photographs. RESULTS: A significant association was seen between PPA beta/gamma area and the ovality index (P=0.000, r=-0.232). The PPA-beta/gamma area increased significantly with a longer AL, older age, worse BCVA, higher refractive error, and thinner choroid (P<0.01). The oval disc was significantly correlated with a longer AL, older age, worse BCVA, higher refractive error, larger PPA-beta/gamma area, and thinner choroid (P<0.01). CONCLUSION: The PPA beta/gamma zone and ovality index in highly myopic eyes show distinct associations with the AL, refractive error, BCVA, age, and CT. PMID- 29977813 TI - Short term effect of choroid thickness in the horizontal meridian detected by spectral domain optical coherence tomography in myopic children after orthokeratology. AB - AIM: To investigate choroidal thickness changes in the horizontal meridian after orthokeratology. METHODS: This is a prospective cross-sectional observed study. Subjects (n=30; 11.3+/-1.7y) with low-to-moderate myopia (-1.0 to -6.0 diopters), wore orthokeratology (Ortho-K) lenses for 3mo. Before and after Ortho-K, OCT scans were made through the fovea in the horizontal meridian. Choroid thickness around the fovea was acquired by custom software. The analyzed regions along the horizontal meridian were divided into 7 equal zones. Ocular parameters were measured by Lenstar LS 900 non-contact biometry. RESULTS: Only the right eye ocular parameters were analyzed in this study. Before Ortho-K, choroidal thickness along the horizontal meridian was 273.7+/-31.8 um in the temporal zone, 253.1+/-38.6 um in the macula zone, and 194.8+/-52.2 um in the nasal zone. After Ortho-K, the choroid was thicker in each horizontal zone (P<0.05). The increased thickness was greatest in the temporal zone (13.5+/-22.5 um) and least in the nasal zone (8.4+/-14.2 um). The axial length (AL) increased 0.02 mm (P>0.05). The choroid thickness change in each horizontal zone was negatively correlated with AL (r, -0.3 to -0.4; P<0.05) except one of the nasal zones. CONCLUSION: In myopic children, the thickness of the choroid is greatest in the temporal zone and thinnest in the nasal zone. After nightly Ortho-K for 3mo, the thickness increase along the horizontal meridian. The choroid thickness changes are negatively correlated with the change of AL. PMID- 29977815 TI - Aflibercept for diabetic macular oedema: a Meta-analysis of randomized controlled trials. AB - AIM: To evaluate the relative efficacy and safety of aflibercept for treatment of diabetic macular oedema (DMO). METHODS: A comprehensive search in MEDLINE, CENTRAL and EMBASE was undertaken for randomized controlled trials (RCTs) comparing intravitreal anti-vascular endothelial growth factor (anti-VEGF) versus another treatment. Primary outcome measures were proportion of patients with at least 15 letters of gain or loss on a logMAR visual acuity chart, and change in best corrected visual acuity (BCVA) and central macular thickness (CMT) from baseline. Safety outcomes were rates of death, thromboembolic events and any systemic or ocular serious adverse events. The final search was performed on November 2017. RESULTS: Four RCTs were included. Only one trial compared efficacy and safety of aflibercept with bevacizumab and ranibizumab over 1 or 2y. Three trials were included for Meta-analysis comprising 661 patients (331 in the aflibercept, and 330 in the photocoagulation group). Aflibercept was more efficacious compared to photocoagulation in the proportion of patients with at least 15 letters of improvement and worsening, and in improvement of BCVA and reduction in CMT at 1 or 2y. The safety estimates at 1 or 2y did not differ statistically. CONCLUSION: Aflibercept offers superior benefits over photocoagulation in improving and preserving vision, with no differences in safety. Further comparative effectiveness trials between aflibercept and other anti-VEGF agents will aid ophthalmologists in treatment decisions. PMID- 29977816 TI - The J-shape association of serum total IgE levels with age-related cataract. AB - AIM: To address the association between serum total IgE levels and age-related cataract in adults. METHODS: The study participants consisted of 1052 adults aged 40y or older in the Korean National Health and Nutrition Examination Survey 2010. We performed multivariable logistic regression analyses using the quartile cut points of total IgE levels. RESULTS: The odds ratios (ORs) for nuclear and any cataract with >=267 kU/L of serum IgE levels were 1.75 [95% confidence intervals (CI), 1.04-2.96] and 2.00 (95%CI, 1.22-3.27), respectively, comparing to 35-87 kU/L. Interestingly, participants with <=35 kU/L of IgE levels (OR, 1.67; 95%CI, 1.02-2.72) also had higher risk for any cataract than those with 35-87 kU/L. The risk for any cataract (OR, 1.48; 95%CI, 1.03-2.13) was higher in participants with high total IgE levels (>150 kU/L), comparing to normal participants. CONCLUSION: Our findings indicate a J-shaped relationship between serum IgE levels and age-related cataract. PMID- 29977817 TI - Refractive surgery: the most cost-saving technique in refractive errors correction. AB - AIM: To compare the lifetime and annual economic burden of spectacles, contact lenses, and refractive surgery in correction of refractive errors. METHODS: This is a cross-sectional study with convenience sampling which 120 patients were interviewed in a tertiary referral hospital in the Iranian health care system. The bottom-up based cost of illness approach was estimated using a face-to-face interview to assess the direct and indirect cost of different refractive errors correction of any correction technologies. RESULTS: Correction with spectacle imposes a total direct cost of US dollar (US$) 342.5 (+/-8.41) per year and US$9373.5 (+/-230.1) per lifetime to each patient. These figures for the contact lenses were obtained US$198.3 (+/-0.12) and US$5203.1 (+/-256.3) and for refractive surgery were obtained US$19.1 (+/-1.2) and US$568.1 (+/-64.6), respectively. Overall, based on age-adjusted prevalence rates, astigmatism had the highest share of refractive errors economic burden with a lifetime direct cost of slightly less than US$5.49 billion, while hyperopia and myopia imposed less than US$5.24 and 4.2 billion on patients, respectively. The annually imposed cost on each individual Iranian patient with refractive errors is US$308.5. CONCLUSION: Based on 18mo post refractive surgery course observation, which is generalized to whole life, refractive surgery significantly imposed much less cost compared with spectacles and contact lenses. Refractive errors among Iranians result in considerable economic burden. Using the refractive surgery instead of other two correction methods has the ability to reduce this economic loss in the future. PMID- 29977818 TI - Fruit and vegetable consumption and its relation to risk of asthenopia among Chinese college students. AB - AIM: To investigate the associations between fruit and vegetable consumption and risk of asthenopia among Chinese college students. METHODS: A total of 1022 students were selected from five universities by a multi-stage stratified cluster sampling method. They were surveyed via a self-administered questionnaire including socio-demographic features, dietary and lifestyle habits, eye-related symptoms, eye care habits and history of diseases. Ascertainment of asthenopia was based on participants' subjectively reported symptoms. The associations between fruit and vegetable intake with asthenopia risk were assessed using multivariate logistic regression analysis. RESULTS: There were no significant associations between total fruit and vegetable, total vegetable, or fruit and the risk of asthenopia. Higher intake of dark-green leafy vegetable was likely to be inversely associated with asthenopia risk [odd ratio (OR): 0.60; 95%CI: 0.37 0.97; Ptrend=0.21] after controlling for nondietary and dietary risk factors. Stratified analysis showed that the inverse association between dark-green leafy vegetable intake and asthenopia risk was limited to participants with suboptimal eyesight (OR: 0.45; 95%CI: 0.25-0.82; Ptrend=0.05), wearing glasses (OR: 0.35; 95%CI: 0.17-0.72; Ptrend=0.03) or using computer >=3h/d (OR: 0.48; 95%CI: 0.25 0.93; Ptrend=0.08). CONCLUSION: A higher consumption of dark-green leafy vegetable is associated with a lower asthenopia risk among college students with suboptimal eyesight and poor eye care habits. PMID- 29977819 TI - Clinical application of accommodating intraocular lens. AB - The present review describes recent advances in application of accommodating intraocular lenses (AIOLs). Standard monofocal intraocular lenses (MIOLs) only correct distance vision, while AIOLs are designed to allow both good distance vision and near vision, which is achieved through the contraction and relaxation of ciliary muscles by providing transformation of the axial movement or curvature of the lens. Thus, AIOLs may be a better choice for those patients who demand a higher level of visual performance. Since techniques to analyze the performance of AIOLs have not been standardized, and there is a variety of both subjective and objective methods, it is hard to measure the performance of these intraocular lenses. By evaluating advantages and disadvantages of various AIOLs, and introducing techniques for measurement the performance postoperative, this paper can provide some relative information on choosing the type of AIOLs in the clinic. PMID- 29977820 TI - Nanotechnology in retinal drug delivery. AB - Retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy (DR) are the leading causes of blindness in adults over the age of 50 years in the US. While most of those conditions do not have a cure, currently available treatment options attempt to prevent further vision loss. For many ophthalmic drugs, an efficient delivery system to provide maximum therapeutic efficacy and promote patient compliance remains an unmet medical need. An exploration of literature via PubMed spanning from 2007 to 2017 was conducted to identify studies that have evaluated nanotechnology as platforms for delivering therapeutic agents to the posterior segment of the eye where the retina is located. Until now, four routes that have been utilized for retinal drug delivery are the intravitreal, periocular, subretinal, and systemic routes. Intravitreal injections are now widely used in clinical practice due to their ability to directly target the back of the eye but are highly invasive procedures that may cause several complications, particularly with repeated uses over a short timespan. Nanotechnology shows great promise to revolutionize retinal drug delivery, offering many advantages such as a targeted delivery system towards the specific site of the retina as well as sustained delivery of therapeutic agents. In this review, specific eye anatomy and constraints on ocular drug administration are illustrated. Further, we list and highlight several examples of nanosystems, such as hydrogels, liposomes, dendrimers, and micelles, used via different drug delivery routes to treat various retinal diseases. PMID- 29977822 TI - Lateral rectus muscle recession and the vertical palpebral fissure height: to do or not to do inter-muscular septum dissection? AB - In this study, we aimed to evaluate changes of vertical palpebral fissure height (VPFH) after unilateral lateral rectus muscle recession. Twenty-five and twenty six patients who were candidates for lateral rectus muscle recession were assigned into "with" and "without" intermuscular septum dissection study arms. The VPFH was measured at one-day before surgery and in two weeks and three months, postoperatively. Three months after surgery, significant increase of VPFH was observed in both groups (Paired t-test; P=0.005). Also, less widening of VPFH was observed in "with intermuscular septum dissection" group (Change in VPFH in "with intermuscular septum dissection" vs "without intermuscular septum dissection" groups: 0.48 mm vs 1.34 mm; ANCOVA test; P<0.001). However, such results were not observed two weeks post-operatively (Change in VPFH in "with intermuscular septum dissection" vs "without intermuscular septum dissection" groups: -0.28 mm vs 0.28 mm; ANCOVA test; P=0.302). Intermuscular septum dissection is recommended in lateral rectus muscle recession to partially prevent the undesirable increment of VPFH. PMID- 29977821 TI - The measurement of time spent outdoors in child myopia research: a systematic review. AB - The purpose of this article is to summarize the methods most commonly used to measure time spent outdoors and provide a comprehensive review of time and activity recording methods with the aim of encouraging the development of new methods. PubMed, Embase and the Cochrane Library were searched from Jan. 1st, 1990 to Aug. 31th, 2017. Studies including the following specific terms: "outdoor", "outside", "outdoor activity", "outside activity", "outdoor time", "outside time", and "outdoor AND measurement of time spent outdoors" were considered for this review. In total, three kinds of outdoor time measurements were discussed. Questionnaires have the longest history and are the most thoroughly revised instruments for assessing time spent outdoors, but recall bias is their most substantial drawback. Global positioning system (GPS) tracking can distinguish between indoor and outdoor locations, but its utility is limited due to several factors such as subject compatibility. Light exposure measurement devices are newly emerging, but all of these devices require good subject cooperation. Further efforts and exploration are needed to develop better methods and new tools to record exposure to the outdoors in real time. Moreover, inventing a new device by combining two or more types of devices mentioned above and using the latest technology of en ergy supplementation and autoswitching may make the best use of the advantages and bypass the disadvantages of each tool. PMID- 29977823 TI - Reduction in interhemispheric functional connectivity in the dorsal visual pathway in unilateral acute open globe injury patients: a resting-state fMRI study. AB - This study investigated the changes in interhemispheric functional connectivity (FC) of the whole brain in open globe injury (OGI) patients, using voxel-mirrored homotopic connectivity (VMHC), and their relationships with clinical features. Totally, 16 male and 2 female acute OGI patients and 18 sex, age, and education matched healthy volunteers were enrolled in the study. All subjects were scanned through functional magnetic resonance imaging (fMRI). Receiver operating characteristic (ROC) curves analyses had been used to identify the VMHC in these brain areas could be used as biomarkers to distinguish OGI and from healthy control (HC). The mean VMHC values in multiple brain areas and clinical OGI manifestations were evaluated with a Pearson correlation analysis. OGI patients had significantly decreased VMHC in the bilateral calcarine/lingual/cuneus (BA18, 19, 30) and middle occipital gyrus (BA18, 19). The OGI patients had abnormal interhemispheric FC in the dorsal visual pathway, which may represent the pathophysiological mechanism that underlies acute vision loss after OGI. PMID- 29977824 TI - Fungal corneal endotheliitis: a series of case reports. PMID- 29977825 TI - Challenging treatment of bilateral multiple infection panuveitis in HIV/AIDS patients. PMID- 29977826 TI - Multispectral imaging in detecting early retinal pigment epithelial atrophy. PMID- 29977827 TI - Comment on "Anterior lamellar recession for management of upper eyelid cicatricial entropion and associated eyelid abnormalities". PMID- 29977828 TI - Made-on-demand, complex and personalized 3D-printed drug products. AB - Layer-by-layer fabrication of three dimensional (3D) objects from digital models is called 3D printing. This technology established just about three decades ago at the confluence of materials science, chemistry, robotics, and optics researches to ease the fabrication of UV-cured resin prototypes. The 3D technology was rapidly considered as a standard instrument in the aerospace, automotive, and consumer goods production factories. Nowadays, research interests in the 3D printed products have been raised and achieved ever-increasing traction in the pharmaceutical industry; so that, the first 3D printed drug product was approved by FDA in August 2015. This editorial summarizes the competitive advantages of the 3D printing for the made-on-demand, personalized and complex products, manufacturing of which establish opportunities for enhancing the accessibility, effectiveness, and safety of drugs. PMID- 29977829 TI - Biosynthesis of TiO2 and ZnO nanoparticles by Halomonas elongata IBRC-M 10214 in different conditions of medium. AB - Introduction: In the recent years, green synthesis is a novel method without some disadvantages of physical and chemical methods. In this approach, bacteria, archaebacteria, fungi, and plants may be applied without utilizing toxic and expensive materials for metal nanoparticles (MNPs) preparation. Methods: In this study, we used Taguchi method to obtain optimum conditions in titanium dioxide and zinc oxide nanoparticle (NPs) biosynthesis by Halomonas elongata IBRC-M 10214. Design and analysis of Taguchi experiments (an orthogonal assay and analysis of variance [ANOVA]) carried out by the Qualitek-4 software. Effects of TiO(OH)2, incubation temperature, and culturing time for synthesis of TiO2 NPs as well as ZnCl2 concentration, glucose concentration, and incubation temperature for the preparation of ZnO NPs were evaluated as the controllable factors with 3 levels. Characterization of TiO2 and ZnO NPs were determined by UV-Vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and dynamic light scattering (DLS) analysis. Also, the antimicrobial properties of these NPs were investigated based on agar diffusion assay of NPs dispersed in batch cultures using Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 43300 as multidrug-resistant (MDR) bacteria. Results: It was evaluated that TiO2 and ZnO NPs had respectively average diameter sizes of 104.63+/-27.75 and 18.11+/-8.93 nm with spherical shapes. In contrast to the TiO2 NPs without antibacterial activity, the ZnO NPs had antibacterial effects at 0.1 and 0.01 M of (ZnCl2). Conclusion: The ZnO NPs have the antibacterial effect that can be operative in the medicinal aspect for fighting against prominent MDR bacteria such as E. coli ATCC 25922 and S. aureus ATCC 43300. In total, this study presents a simple method in the biosynthesis of TiO2 and ZnO NPs with low the expense, eco-friendly, and high productivity properties. PMID- 29977830 TI - Design, fabrication, and implantation of tube-shaped devices for the treatment of salivary duct diseases. AB - Introduction: Starch-based materials were designed using a special extrusion die in order to obtain a tube-shaped device for application to salivary duct treatment in the field of endoscopy, i.e., sialendoscopy . Methods: Extrusion process was used to produce starch tubes. Mechanical properties of the dry tube before implantation were determined using an axial compression test. A finite element study was carried out to simulate the behavior of the hydrated tube under external axial pressure. Hydrolysis of these devices in a simulated salivary solution was studied, as well as its glycerol kinetics release. An animal short term implantation model for salivary ducts was proposed as a feasibility study for starch tube-shaped devices. Results: A continuous production of regular and size-controlled tubes was obtained. The very small diameter obtained, less than 2 mm, corresponds to the requirement of being insertable in a human salivary duct using sialendoscopy guidewire. Finite element analysis showed that the starch tube can still support an external pressure higher than 0.2 MPa without irreversible damage. After 4 days of implantation, the host response is encouraging and the inflammatory response for this type of procedure remains normal. Conclusion: These devices were adapted to sialendoscopic guidewires and able to be implanted in the salivary ducts of pigs. If a longer lasting tube is required, the crystallinity of the starch material should be improved. PMID- 29977831 TI - Drug nanocarrier agents based on starch-g-amino acids. AB - Introduction: In the recent decades, starch has been modified using different methods for the various forms of applications. Some new starch derivatives were prepared through a simple and convenient method in the grafting of amino acids: L alanine, L-leucine and L-phenyl alanine to starch. Methods: First, the amine groups of amino acids were protected using phthalic anhydride then the acidic side of amino acids were activated with chlorination using thionyl chloride, and the resultant acid chlorides were reacted with starch in aqueous media at room temperature. Results: Performing the various spectroscopy experiments on the obtained compounds showed that the new derivative of starch has been formed. The structure of all synthesized materials was determined and confirmed using common spectroscopy methods and their thermal behavior was examined using DSC experiment. Conclusion: New amino acid derivatives of starch and their nanocarriers successfully prepared through a simple and convenient method. The size of nanocarriers evaluated using DLS and TEM experiments. The spherical shape of particles shows that nanocarriers have been formed and the size of these particles are approximately 92, 137 and 97 nm. Performing the wettability test determined that all the resulted materials are soluble in water. Nanocarriers of the obtained modified starches were prepared using dialysis method and naproxen was utilized as a model drug molecule. The drug release dynamics in buffered solution were studied and investigation of the drug release mechanism showed that in case of L-alanine- and L-phenylalanine-modified starches, drug release followed the Fickian diffusion with a slight deviation. PMID- 29977833 TI - Mucin-1 aptamer-armed superparamagnetic iron oxide nanoparticles for targeted delivery of doxorubicin to breast cancer cells. AB - Introduction: Superparamagnetic iron oxide nanoparticles (SPIONs) can be functionalized with various agents (e.g., targeting and therapeutic agents) and used for targeted imaging/therapy of cancer. In the present study, we engineered doxorubicin (DOX)-conjugated anti-mucin -1 (MUC-1) aptamer (Ap)-armed PEGylated SPIONs for targeted delivery of DOX molecules to the breast cancer MCF-7 cells. Methods: The SPIONs were synthesized using the thermal decomposition method and modified by polyethylene glycol (PEG) to maximize their biocompatibility and minimize any undesired cytotoxicity effects. Subsequently, DOX molecules were loaded onto the SPIONs, which were further armed with amine-modified MUC-1 aptamer by EDC/NHS chemistry. Results: The morphologic and size analyses of nanoparticles (NPs) by transmission electron microscopy (TEM) and dynamic light scattering (DLS) revealed spherical and monodisperse MNPs with a size range of 5 64 nm. The FT-IR spectrophotometry and 1 HNMR analysis confirmed the surface modification of NPs. The cytotoxicity assay of the aptamer-armed MNPs exhibited a higher death rate in the MUC-1 over-expressing MCF-7 cells as compared to the MUC 1 under-expressing MDA-MB-231 cells. The flow cytometry analysis of the engineered Ap-armed SPIONs revealed a higher uptake as compared to the SPIONs alone. Conclusion: Based on our findings, the anti-MUC-1 Ap-armed PEGylated SPIONs loaded with DOX molecules could serve as an effective multifunctional theranostics for simultaneous detection and eradication of MUC-1-positive breast cancer cells. PMID- 29977832 TI - The assessment of metabolite alteration induced by -OH functionalized multi walled carbon nanotubes in mice using NMR-based metabonomics. AB - Introduction: There is a fundamental need to characterize multiwalled carbon nanotubes (MWCNTs) toxicity to guarantee their safe application. Functionalized MWCNTs have recently attracted special interest in order to enhance biocompatibility. The aim of the current work was to study the underlying toxicity mechanism of the -OH-functionalized MWCNTs (MWCNTs-OH), using the powerful NMR-based metabonomics technique. Methods: Following intraperitoneal single-injection of mice with 3 doses of MWCNTs-OH and one control, samples were collected at four time points during 22-days for NMR, biochemistry, and histopathology analysis. Metabolome profiling and pathway analysis were implemented by chemometrics tools and metabolome databases. Results: Based on the 1H-NMR data, metabolic perturbation induced by MWCNTs-OH were characterized by altered levels of steroid hormones, including elevated androgens, estrogens, corticosterone, and aldosterone. Moreover, increased L-lysine, aminoadipate, taurine and taurocholic acid and decreased biotin were observed in the high-dose group (1 mg.kg-1 B.W.) compared to the control. The findings also indicated that steroid hormone biosynthesis, lysine biosynthesis, and biotin metabolism are the most affected pathways by MWCNTs-OH. Conclusion: These pathways can reflect perturbation of energy, amino acids, and fat metabolism, as well as oxidative stress. The data obtained by biochemistry, metabonomics, and histopathology were in good agreement, proving that MWCNTs-OH was excreted within 24 h, through the biliary pathway. PMID- 29977834 TI - Reprogramming of mouse fibroblasts into neural lineage cells using biomaterials. AB - Introduction: Induced neural stem cells (iNSCs) have the ability of differentiation into neurons, astrocytes and oligodendrocytes. iNSCs are very useful in terms of research and treatment. The present study offers an idea that biomaterials could be one of the tools that could modulate reprogramming process in the fibroblasts. Methods: Gelatin biomaterials were fabricated into 3 types, including (i) gelatin, (ii) gelatin with 1 mg/mL hydroxyapatite, and (iii) gelatin with hydroxyapatite and pig brain. NIH/3T3 fibroblasts were cultured on each type of biomaterial for 7, 9 and 14 days. RT-PCR was performed to investigate the gene expression of the fibroblasts on biomaterials compared to the fibroblasts on tissue culture plates. PI3K/Akt signaling was performed by flow cytometry after 24 hours seeding on the biomaterials. The biomaterials were also tested with the human APCs and PDL cells. Results: The fibroblasts exhibited changes in the expression of the reprogramming factor; Klf?4 and the neural transcription factors; NFIa, NFIb and Ptbp1 after 9 days culture. The cultivation of fibroblasts on the biomaterials for 7 days showed a higher expression of the transcription factor SOX9. The expression of epigenetic genes; Kat2a and HDAC3 were changed upon the cultivation on the biomaterials for 9 days. The fibroblasts cultured on the biomaterials showed an activation of PI3K/Akt signaling. The human APCs and human PDL cells developed mineralization process on biomaterials Conclusion: Changes in the expression of Klf4, NFIa, NFIb, Ptbp1 and SOX9 indicated that fibroblasts were differentiated into an astrocytic lineage. It is possible that the well-designed biomaterials could work as powerful tools in the reprogramming process of fibroblasts into iNSCs. PMID- 29977836 TI - Neutrophil-Lymphocyte Ratio as a Prognostic Factor in Laryngeal Carcinoma. AB - Aim of this study; investigate whether neutrophils/lymphocyte ratio (NLR) could be used as a prognostic factor in larynx cancer. The correlation between preoperative peripheral blood NLR and age, gender, smoking, alcohol use, clinical stage and differentiation degree was examined. One hundered fourty-four patients in Dicle University Department of Otorhinolaryngology between the years of 2005 and 2014 were included in the study. Clinical and preoperative laboratory data of patients were screened retrospectively from archive files of otorhinolaryngology and the pathology results were screened retrospectively from archive files of pathology. The study was approved by the local ethics committee of the department and carried out in accordance with the declaration of Helsinki as amended in 2013. Statistical analyses were performed using the SPSS 15.0 software package for Windows (SPSS inc., Chicago, IL, USA). There was a significant difference between NLR and clinical stage (p = 0.003) smoking (p = 0,001) and alcohol use (p = 0.001). When NLR was analyzed in detail according to the degree of tumor differentiation; significant differences were observed between G1 and G2 (p = 0.007) and between G1 and G3 (p = 0.001). Light of these findings, NLR is a cheap and easily accessible marker which can be used as a prognostic faxtor in laryngeal cancer. It is thougkt to shed light on the studies which will be conducted with more patients. PMID- 29977837 TI - The Role of Hypertonic Saline in Monopolar Tonsillectomy in Pediatric Patients. AB - Looking for a simple and inexpensive method to reduce patients' pain during tonsillectomy. Bilateral tonsillectomy patients were enrolled and placed into different groups based on their admission numbers. Patients with odd numbers had electrical tonsillectomy on the right side with hypertonic saline injection into peritonsillar gap (group A) or electrical tonsillectomy on the left side without hypertonic saline injection (group B). Those with even numbers had electrical tonsillectomy on the left side with hypertonic saline injection into peritonsillar gap (group A) or electrical tonsillectomy on the right side without hypertonic saline injection (group B). Pain, operative bleeding, post-operation bleeding and operation time were evaluated. Injecting hypertonic saline into peritonsillar gap reduced pain caused by electrical tonsillectomy but did not impact operation or postoperative bleeding and operation time. While simple and economic, monopolar electrical tonsillectomy with the help of hypertonic saline injected into peritonsillar gap can effectively relieve patients from pain compared with surgeries without hypertonic saline injection. PMID- 29977835 TI - An update of the recombinant protein expression systems of Cyanovirin-N and challenges of preclinical development. AB - Introduction: Human immunodeficiency virus (HIV) is a debilitating challenge and concern worldwide. Accessibility to highly active antiretroviral drugs is little or none for developing countries. Production of cost-effective microbicides to prevent the infection with HIV is a requirement. Cyanovirin-N (CVN) is known as a promising cyanobacterial lectin, capable of inhibiting the HIV cell entry in a highly specific manner. Methods: This review article presents an overview of attempts conducted on different expression systems for the recombinant production of CVN. We have also assessed the potential of the final recombinant product, as an effective anti-HIV microbicide, comparing prokaryotic and eukaryotic expression systems. Results: Artificial production of CVN is a challenging task because the desirable anti-HIV activity (CVN-gp120 interaction) depends on the correct formation of disulfide bonds during recombinant production. Thus, inexpensive and functional production of rCVN requires an effective expression system which must be found among the bacteria, yeast, and transgenic plants, for the subsequent satisfying medical application. Moreover, the strong anti-HIV potential of CVN in trace concentrations (micromolar to picomolar) was reported for the in vitro and in vivo tests. Conclusion: To produce pharmaceutically effective CVN, we first need to identify the best expression system, with Escherichia coli, Pichia pastoris , Lactic acid bacteria and transgenic plants being possible candidates. For this reason, heterologous production of this valuable protein is a serious challenge. Since different obstacles influence clinical trials on microbicides in the field of HIV prevention, these items should be considered for evaluating the CVN activity in pre-clinical and clinical studies. PMID- 29977838 TI - Results of Hearing Outcome According to the Alloplastic Ossicular Prosthesis Materials. AB - The aim of this study is to compare the functional results and extrusion rates according to the type of ossciular alloplastic prosthesis. In this study, a retrospective analysis was performed. Sixty-one patients were involved in partial ossicular replacement (POR) cases and 70 patients were involved in total osscicular replacement (TOR) cases. In POR cases, Plastipore was used in 21 cases, hydroxyapatite in 20 cases, and titanium in 20 cases. In TOR cases, Plastipore was used in 20 cases, hydroxyapatite (HA) in 25 cases and titanium in 25 cases. We reviewed postoperative ABG (less than 20 dB or more than 20 dB) and the extrusion rate for more than 1 year follow-up period. In POR cases, ABG less than 20 dB were 71.4, 80.0, 85.0 % in plastipore, HA, and titanium prosthesis and in TOR cases, ABG less than 20 dB were 25.0, 28.0, 32.0 % in plastipore, HA, and titanium prostheses, respectively. In POR cases, extrusion rates (ER) were 9.5, 5.0, 5.0 % in plastipore, HA, and titanium prosthesis, respectively. In TOR cases, ER were 15.0, 8.0, 4.0 % in plastipore, HA, and titanium prosthesis, respectively. There were no significant differences in hearing gain results among plastipore, HA, and titanium in both POR and TOR cases, but the ER was significantly low in titanium. Clinically relatively better hearing gain and low rate of extrusion were found in titanium prosthesis and thus this material is recommended in cases of ossicular alloplastic replacement surgery. PMID- 29977839 TI - A Preliminary Attempt to Profile Tympanometric Measures in Infants Using High Frequency Probe Tones. AB - There is dearth of published data on high frequency tympanometric measures for infants in Indian context. Aim of present study was to profile Peak compensated static acoustic admittance (Ytm), Tympanometric peak pressure (TPP), Tympanometric width (TW) and Equivalent ear canal volume (Vea) in infants. Cross sectional study on 50 infants with present TEOAEs and with risk indicators for hearing loss. Tympanometry was performed using GSI-Tympstar for 678 and 1000 Hz probe tones. Descriptive statistics were used to determine mean, SD and minimum and maximum for both genders. Using 678 Hz, Ytm ranged from 0.09 to 1. 48 mmho (males) and 0.11 to 1.14 mmho (females), while with 1000 Hz ranged from 0.15 to 1.49 (males) and 0.13-1.61 mmho (females). Using 678 Hz, TPP ranged from -95 to 70 daPa (males) and -155 to 80 daPa (females), while with 1000 Hz ranged from -75 to 95 daPa (males) and -145 to 50 daPa (females). Using 678 Hz, TW ranged from 30 to 190 daPa (males) and 40-23 daPa (females), while with 1000 Hz ranged from 60 to 210 daPa (males) and 40-183 daPa (females). Using 678 Hz, Vea ranged from 0.11 to 1.7 mmho (males) and 0.14-2.5 mmho (females), while with 1000 Hz ranged from 0.14 to 2.0 mmho (males) and 0.14-3.6 mmho (males). This study was a preliminary attempt to profile the tympanic measures. Ytm values were lesser or similar to other studies, TPP and Vea values had lower and narrow range, while TW were more than previous studies. PMID- 29977840 TI - Aural Foreign Bodies Among Patients Presenting to Ibn Sina Teaching Hospital, Mukalla, Hadhramout Province, Yemen. AB - Objective: To describe the types of aural foreign bodies (FBs) among patients in Ibn Sina Teaching Hospital (ISTH) and to study the patient's symptoms, duration, complications and procedures used to extract them. Methods: A record based descriptive study was looked at patients with aural FBs at ISTH for 5 years between 2009 and 2015. The diagnosis of aural FBs was based on personal history, and otoscopic findings. The data were obtained from the records. Results: Patients with aural FBs were 154, (age 1-70 years). Inorganic aural FBs were 100 (65%) and 54 (35%) were organic. Unilateral purulent aural discharge was in 72 (46.75%) patients, pain in 27 (17.53%), ear bleeding in 12 (7.8%), conductive hearing loss and tinnitus each was 8 (5.19%) and itching in 7 (4.55%). Duration of symptoms was <1 week in 55 (35.7%) cases, 1-2 weeks in 64 (41.6%) and 2-4 weeks in 29 (18.8%). Forceps, syringing, hook and suction were the tools used for removal of the FBs, 56 (36.4%), 40 (26.0%), 36 (23.4%), 14 (9.1%) respectively. FBs were removed under G.A. were 30 (19%). Complications were otitis externa in 38 (24.7%) cases, tympanic membrane perforation in 29 (18.85%) and external meatus laceration in 28 (18.20%). Conclusion: The most common aural FBs found were inorganic (cotton tip, stone and eraser) and organic (fly, lice and bee). Complications were unilateral purulent discharge followed by pain and ear bleeding. FBs duration was from <1 to 4 weeks. The common procedures used were forceps, syringing, hook and suction. Particularly, organic vegetative FBs were removed under general anesthesia. PMID- 29977841 TI - Compensated Vestibular Dysfunction Post Cochlear Implantation in Children with Sensorineural Hearing Loss: A Prospective Study. AB - Children with sensorineural hearing loss have risk of surgically induced vestibular dysfunction post cochlear implantation due to instrumentation. It is clinically important to estimate the risk of vestibular loss post cochlear implant so the patient can be made fully aware of these risks when considering cochlear implantation. The aim of the study was to identify compensated vestibular dysfunction post cochlear implantation. Vestibular function was evaluated both pre and post CI using monothermal warm air caloric testing. Recordings were made using head band camera on SYNAPSYS Ulmer VNG software. 'Monothermal caloric asymmetry' (MCA) was depicted as 'unilateral weakness' based on the slow phase velocity of nystagmus. MCA of >15% was taken as evidence of canal paresis. The incidence of compensated vestibular dysfunction post CI surgery was found to be 16.66%. The results were statistically significant (p value 0.02) and indicated worsening of canal paresis indicative of vestibular dysfunction. Children for cochlear implantation should undergo evaluation of their vestibular system pre and post surgery. Caution should be exercised before planning bilateral cochlear implantation in the same sitting. PMID- 29977842 TI - Effect of Mastoid Drilling on Hearing of the Contralateral Normal Ear in Mastoidectomy. AB - To evaluate hearing of the contralateral normal ear before and after mastoidectomy in a longitudinal manner and to assess whether the hearing loss is transient or permanent and to find out the duration of temporary hearing loss. This was a clinical longitudinal observational study involving 50 patients with unilateral chronic suppurative otitis media requiring mastoidectomy operation over a period of 18 months after satisfying the inclusion criteria. During the part of the mastoidectomy surgery involving drilling of the mastoid bone, noise levels were recorded at multiple points in the surgery using a digital sound level meter. Postoperatively, beginning from Day 1 to Day 7, PTA and OAE of the contralateral ear were recorded for all patients. The patients were then followed up at 1, 3 and 6 months postoperatively, at which times PTA and OAE were repeated. There is an increase in the absence of High Frequency DPOAEs on the first and second postoperative days, but this increase is higher than that of Low Frequency DPOAEs and gradually returns to normal by 72 h. OAEs were found to be more sensitive at diagnosing and tracking the progress of affected patients. All affected ears only had a temporary postoperative hearing loss, primarily affecting the higher frequencies and returning to normal within 72 h. Drill generated noise and vibration during mastoidectomy operation is associated with a significant temporary shift in hearing thresholds of the contralateral normal ear in susceptible individuals, affecting the higher frequencies, and is best evaluated using DPOAEs. PMID- 29977843 TI - Safety of Carotid Canal during Transtympanic Dilatation of the Eustachian Tube: A Cadaver Pilot Study. AB - To assess the safety of Transtympanic balloon dilatation of the cartilaginous proximal Eustachian tube under endoscopic guidance as it relates to the integrity of the carotid canal in cadaver model. Endoscopic guided Transtympanic dilatations of the cartilaginous proximal end of the Eustachian tube were performed in 15 ears of 8 fresh frozen cadaver heads. CT scans were done before and after dilatation. Images were reviewed by two otologists and one radiologist. Balloon catheter placement and dilatation of the proximal Eustachian tube was feasible in all specimens. Endoscopic examination post dilatation showed a consistent increase in the aperture of the proximal cartilaginous tube in all ears. Review of CT images after dilatation showed no evidence of trauma to the carotid canal in all ears instrumented. Endoscopically guided Transtympanic dilatation of the proximal Eustachian tube is not associated with damage to the carotid canal in cadaver model. Level of Evidence: 4. PMID- 29977844 TI - Retro-Auricular Thyroidectomy: An Open Approach. AB - Distant access robot-assisted thyroidectomy has gained popularity in recent years. Adoption of distant access procedures has been limited by cost, need for specialized training and expertise. We report our preliminary clinical experience with our modification of the retro-auricular thyroidectomy approach that allows adequate exposure for thyroid lobectomy without robotic or endoscopic assistance. This is a retrospective chart review of ten patients who have undergone retro auricular thyroidectomies in the absence of robotic or endoscopic assistance. Ten patients were identified to have undergone this procedure over an 18-month period. All patients were female with average age 36 years (range 27-52). Six were right sided and 4 were left sided procedures. The average gland size was 4.2 cm (range 3.7-6 cm). The average nodule size was 2.1 cm (range 1.1-3.5 cm). The average operative time was 91 min (range 76-114 min). All patients had benign pathology on final histopathology. There were no conversions to open cervical thyroidectomy. Two patients had vocal cord paresis that resolved spontaneously. The average postoperative follow up was 3 months (range 1-7 months). Our technique for retro-auricular thyroidectomy is a safe, reproducible, and cost effective option for remote access thyroidectomy. PMID- 29977845 TI - Innovative Use of Tympanometry and Scintigraphy in Preoperative Assessment of the Patients with Chronic Otitis Media. AB - Normal middle ear volume indicates the well ventilated middle ear and subsequently the normal function of the Eustachian tube. We carried out preoperative assessment of the middle ear volume by tympanometry and scintigraphic evaluation of Eustachian tube patency in patients with unilateral otitis media. We correlated the middle ear volume and Eustachian tube patency in these patients. Prospective. A total of 58 patients with unilateral otitis media were studied. All patients underwent Eustachian tube scintigraphy. We categorized the patients as Group A with patent Eustachian tube and Group B with blocked Eustachian tube (ET). We assessed the equivalent middle ear volume (VeqME) in all patients and correlated it with ET patency. We also correlated the degree of hearing loss and intraoperative middle ear pathology in two groups. There is strong linear correlation between the ET patency and VeqME of the patients. Degree of hearing loss and the middle ear pathology is also found to be severe in patients with blocked ET and low VeqME. Preoperative assessment of patients with chronic otitis media should include the objective evaluation of middle ear volume and ET patency, as it is the reliable predictor of middle ear pathology. PMID- 29977847 TI - Inlay Butterfly Cartilage Tympanoplasty: Anatomic and Functional Results. AB - To evaluate anatomic/functional results of inlay butterfly cartilage tympanoplasty and compare those with the results of over-underlay perichondrium cartilage island or temporalis fascia tympanoplasties. Patients who operated for primary type 1 tympanoplasty (n = 78) with inlay butterfly cartilage (n = 25), over-underlay perichondrium-cartilage island (n = 36) or over-underlay temporalis fascia (n = 17) graft from January 2005 to January 2015 were included in the study. Age, gender, pre-/postoperative otoscopy findings/audiograms, and follow up time were obtained from the patient's file. Anatomic integrity rates of the tympanic membrane, the mean gains of air bone gap on pure tone audiogram at four frequencies (0.5, 1, 2, 4 kHz) and complications were reviewed parameters. Functional evaluation was made in patients with intact tympanic membrane. Anatomic integrity rates of the tympanic membrane was 92.00% for inlay butterfly cartilage tympanoplasty, 91.67% over-underlay perichondrium cartilage island tympanoplasty and 88.2% over-underlay fascia tympanoplasty. The mean gains of air bone gap on pure tone audiogram for the inlay butterfly cartilage, over-underlay perichondrium cartilage island and over-underlay fascia graft group were 11.28, 12.84 and 12.66 dB respectively. Inlay butterfly cartilage tympanoplasty is a reliable and simple technique with satisfactory outcomes in selected cases. The anatomic and functional results after inlay butterfly cartilage tympanoplasty are parallel to the results of over-underlay perichondrium-cartilage island or temporalis fascia tympanoplasties. PMID- 29977846 TI - Comparative Columellar Scar Analysis Between W Incisions and Inverted-V Incision in Open Technique Nasal Surgery. AB - A visible scar on the columella is undesirable result for both patient and surgeon. So it is one of the major disadvantage of open nose surgery. Different columellar incision types have been used in open technique of nasal surgery. In this prospective study, we compare W incisions and inverted-V columellar incisions with a scar assessment scale. In this prospective randomized study, open nasal surgery (open rhinoplasty and open technique septoplasty) were performed on 93 patients between November 2009 and July 2012. The inverted-V incision was used on 31 patients (24 males, 7 females). The "W" incision was used on 62 patients (40 males, 22 females). The entire surgical procedure was performed by a single surgeon. The columellar incision was closed using 6-0 interrupted polypropylene sutures. All sutures were removed on the seventh postoperative day. Scars were assessed at 6 moths, with 3 items scar assessment scale, we observed satisfactory scar, pigmentation, and notching. We compared both groups and found that the scar pigmentation, notching and scar formation are similar to each other. As a result of this study we concluded that the inverted-V incision or "W" incision might be a similar choice in open nasal surgery. PMID- 29977848 TI - Polypropylene in Endoscopic Dacryocystorhinostomy: A Novel Stent. AB - Endoscopic dacryocystorhinostomy (DCR) is usually done in cases of lacrimal apparatus obstruction. The common causes of failure are that of obstruction in the common canaliculus and closure of the rhinostomy site. To overcome these problems we use stents. Stents most commonly used are that of silicon which are expensive and not readily available. As an alternative, polypropylene (Prolene; Ethicon) is used as a stent which is cheaper and readily available. This study is done to evaluate the clinical efficacy and results of stenting with polypropylene suture material in endoscopic dacryocystorhinostomy. Fifty one endoscopic DCR operations were performed between July 2013 to December 2014. After creating an aperture in the medial wall of the lacrimal sac, 3/0 prolene was inserted from lower punctum to neo ostium. The prolene was left in the lacrimal sac for 3 weeks. The patients were followed up for 3 months. In our study, most of the patients belonged to the age group of 41-60 years (47%). There was female preponderance as 64.7% were females. 47 patients (92.2%) showed very good results. Two patients (3.9%) developed granuloma for which revision surgery was done. We lost 2 patients during follow up. This modification enables an easy, safe, effective and low-cost form of DCR. Prolene is cheaper and readily available. It might be used successfully in endoscopic dacryocystorhinostomy and is promising alternative to silicone stent intubations, especially in settings with limited resources. PMID- 29977849 TI - Evaluation of Various Laryngeal Pathologies: Videolaryngoscopy Versus Videolaryngostroboscopy. AB - Voice disorders are common in various laryngeal pathologies. The aim of this study is to evaluate the diagnostic value of videolaryngostroboscopy (VLSS) over videolaryngoscopy (VLS) in laryngeal pathologies. This was a prospective observational study. Detailed examination was carried out for 80 cases which presented with different laryngeal pathologies. Cases were evaluated on the basis of VLS and VLSS in the same sitting and diagnosed separately. Sensitivity, specificity, positive predictive value and negative predictive value were calculated to find out the relationship between diagnoses made by VLS and VLSS. The diagnostic value of VLSS is significant; it has 98.15% Sensitivity and 50% specificity over VLS in finding true vocal cord abnormalities. Around one third of the cases, i.e. 26 cases (32.50%) were misdiagnosed on VLS. Also, VLSS gave additional diagnosis in 6 cases (7.50%) which were missed on VLS. However, the diagnoses revealed by VLS and VLSS were same in 48 cases (60%). The diagnostic value of VLSS correlated with the type of laryngeal pathology. Through the present study, it has been deduced that VLSS is the superior modality for diagnosing laryngeal pathologies. It offers better visualisation of the finer aspects of the vocal cords. It has various advantages over VLS in terms of sensitivity and specificity. PMID- 29977850 TI - The Demographic Study of Otorhinolaryngological Trauma Among Patients with Head and Neck Trauma and Their Management in a Tertiary Care Centre. AB - The trauma has been increasing in frequency, especially in recent decades because of the higher number of automobile accidents and violence. The ear, nose and face region is the area in the body that is commonly involved in head and neck injury. Trauma to this region is often associated with mortality and varying degree of physical, functional and psychological damage. To study the demography, aetiology, clinical presentation, outcome of ENT trauma in our tertiary care centre and to compare our study with previous studies to see the changing trends with passage of time. A prospective study was conducted on 200 head and neck patients with ENT injuries during a period of 1 year from July 2014 to July 2015, who were admitted in ENT Department and Trauma Centre of Gajra Raja Medical College and J.A. Group of Hospital, Gwalior. Most of the patients were young adult males of age group 18-40 years (45, 22.5%) with a male:female ratio 1.78:1. Among them 53% patients were from rural area while 47% were from urban area. RTA is the most prevalent cause of ENT trauma (37%), followed by interpersonal violence (25%). 27% of the patients had facial injury and multiple region injury each. Among 200 patients 33% were managed conservatively on the other hand 66% patients required surgical interventions. Mortality rate was 8%. Among all 184 survivors 25.5% suffered from hearing loss, 14.5% had tympanic membrane perforation with hearing loss, 12% had pinna disfigurement, 10% had change in voice, 6.5% had permanent nasal deformity, 2% had facial nerve palsy. Young male adults were the most prevalent victims of ENT trauma, and Road traffic accidents were responsible for majority of the ENT injuries. Screening of all the patients with head and neck injuries for the presence of trauma in the ENT region should be introduced to enable early detection and therefore prevention of complications. PMID- 29977851 TI - Factors Affecting the Outcome of Stapes Surgery. AB - To study the outcome of stapes surgery based on the Clinical, Audiometry, and Surgical pre- and postoperative factors. This study is a prospective study of factors affecting the outcome of stapes surgery in otosclerosis patients. From February 2010 to June 2011, 57 patients of confirmed clinical otosclerosis were analysed. Out of them, 31 patients were included in our study as were available for follow-up. Clinical, audiometry and surgery-related parameters were included to assess the surgery outcome. Results were reported as suggested by AAO-HNS (American Association of Otolaryngology and Head and Neck Surgery) guidelines for stapes surgery, 1995. The paired t-test and analysis of variables test (ANOVA) were used to evaluate the results. A p value of <0.05 was considered significant. There was statistically significant improvement in ABG (air bone gap) closure at 3 months of surgery (p value <0.001). Among all cases, PTA BC (pure tone average bone conduction) at 3 months of surgery was found in the range of 7.5 dB to 43.75 dB. ABG closure was achieved in the range of 0 dB to 27.5 dB among all cases. Variables like gender, degree of hearing loss, type of footplate, sealing material, and piston diameter were definitely predicting the outcome of stapes surgery. Pure tone audiometry plays an important role to diagnose the otosclerosis, to evaluate degree and type of hearing loss and to assess hearing outcome after surgery. Our results may improve knowledge of predictive factors, providing the surgeon with useful information to plan surgery with a better case selection as well as to counsel the patient on the likelihood of success of the procedure. PMID- 29977852 TI - Doing Mastoidectomy Along with Tympanic Membrane Repair Reduces the Need for Revision Procedures: A Prospective Study. AB - To determine the role of cortical mastoidectomy on the results of tympanoplsty in tubotympanic type of chronic suppurative otitis media. A prospective, observational, interventional study was conducted from a period of October 2006 October 2008. This included 40 patients of either sex in the age group of 15-45 years having tubotympanic type of CSOM. Tympanoplasty with mastoidectomy was done in all the patients and they were followed up for graft acceptance and hearing impairment for 5 years to see the long term results. Per-operatively, the antrum was involved in 17, aditus in 11 and middle ear in 8 patients. Incus was necrosed in 10 cases and malleus and incus were absent in a single case. Mucoid discharge was found in the middle ear in 12 out of 40 patients. Mucoid discharge ears had antral mucosal hypertrophy in 100%, blocked aditus in 75% and middle ear mucosal hypertrophy in 58% cases; ossicular necrosis in 75% cases. 90% of the cases had graft accepted. In dry ears, graft take up rate was 89% and in ears with mucoid discharge it was 92%. Average air-bone-gap reduced to 13.90 dB as compared to average air-bone-gap (Av. AB Gap1) preoperatively of 38.62 dB. After 5 years, 83.5% patients had >10 dB improvement in hearing. We recommend opening of the mastoid if on inspection of middle ear one finds mucoid type of discharge. PMID- 29977853 TI - Otitis Media with Effusion (OME) in Urban Pediatric Population in a Tertiary Care Centre: A Clinical Study. AB - Otitis media with effusion (OME) is a common condition affecting children. It is one of the most common causes for reduced hearing in pediatric age group leading to various learning disabilities including delayed speech development. The aim of this study was to find out various epidemiological characteristics and risk factors for developing OME and various treatment modalities depending on the clinical features and their outcomes in urban pediatric population. A prospective comparative study was done in 100 children taken 50 as cases and 50 as controls for a period of 2 years. The risk factors, common presenting features and the examination and investigational findings (tympanometry) of the study condition were compared among the cases and controls. Among the 50 cases, 28 children were treated medically and 22 underwent surgical treatment in the form of Myringotomy and Grommet insertion. The patients were followed up-to 6 months in both groups. PMID- 29977854 TI - Juvenile Nasopharyngeal Angiofibroma: Our Experience in a Tertiary Hospital. AB - Nasopharyngeal angiofibroma is a highly vascular tumor seen typically in young adolescent males. It is an uncommon tumor accounting for less than 0.5% of all head and neck tumors. This peculiar tumor is thought to arise from the area of the sphenopalatine foramen and it classically presents with progressive nasal obstruction and epistaxis. This is a retrospective study of angiofibroma treated at our hospital over 3 years. The study discusses about clinical features, management options and the role of embolization in reducing the intra-operative blood loss. PMID- 29977855 TI - Radiological Anatomy of Inner Ear Malformation in Hearing Impaired Children and it's Correlation with Hearing Loss: A Hospital Based Observational Study. AB - To see the radiological anatomy of inner ear malformations in hearing impaired children. This study was a prospective observational study done at a tertiary care teaching hospital in north India. The included were children of 1-7 years with first time detected severe to profound SNHL. The evaluation of hearing was done by brainstem evoked response audiometry. Those with history of chronic suppurative otitis media and conductive hearing loss were excluded. The all included were undergone high resolution computed tomography of the tympano mastoid region. A written informed consent was taken. The institutional ethics committee approved the study protocol. We screened 130 children of 1-7 years of age with complaints of severe to profound hearing impairment (SNHL) by BERA. We excluded 38 and 14 children who had conductive hearing loss with or without CSOM and did not give consent, respectively. Among recruited 78 children, 47 (60.3%) had severe (71-90 dB) and 31 (39.7%) had profound (> 90 dB) SNHL. The majority of children (60/78, 76.9%) had a bilateral hearing impairment, only 18 (23.1%) had unilateral hearing impairment. The mean +/- SD of age was 3.9 +/- 1.3 years (95% CI = 3.6-4.2). The incidence of severe to profound SNHL was higher, though not statistically significant among the girls. Only 7.7% children with severe to profound SNHL were detected within first 2 years of life. Most of the children (92.3%) with severe to profound SNHL were detected after 2 years of age. Among 78 with severe to profound SNHL, 16 (20.5%) children had structural anomalies in their internal ears. Only 2 (6.9%) ears had single anomaly, others (27, 93.1%) had multiple anomalies. A maximum number of anomalies found in one ear were 5. The most common anomalies were found in the vestibule. The total number of anomalies were 115. Five children (6.4%) with severe to profound SNHL had craniofacial dysmorphism. Approximately 20% of children with severe to profound SNHL have congenital anomalies in their internal ears. It is crucial to know these anomalies before planning of CI. HRCT of tympano-mastoid is the first modality to know these anomalies. MRI should also be included to know the details of vestibulocochlear nerve. Since, the neurocognitive outcome would be the best if CI will be done as early as possible preferably around 1 year of age. Therefore, children must be screened at the appropriate age, firstly by OAE followed by BERA. PMID- 29977856 TI - Presentation of Lesions of Nose and Paranasal Sinuses at a Tertiary Care Center in Central India. AB - A variety of non-neoplastic and neoplastic conditions involve the nasal cavity, paranasal sinus and are fairly common presentation encountered in clinical practice. Sinonasal lesions are a common finding in all age groups. The lesion of nose and paranasal sinuses are very deceptive so, the presenting features, clinical examination, nasal endoscopy, radiodiagnosis and histopathology are employed conjointly to reach a diagnosis. This cross sectional study was conducted between November 2014 and September 2016. 150 patients with nasal or paranasal sinus lesions attending ENT OPD were included. Among 150 patients there was a male predominance in all lesion except malignant lesions and most of the patients 72 (48%) were in the age group 11- 30 years. Mean age of presentation for benign lesions was 33.64 years and of malignant lesions was 49.14 years. The study showed that 96 (64%) of the nose and PNS lesions were of inflammatory nature followed by 22 (15%) benign, 18 (12%) granulomatous and 14 (9%) malignant, Inflammatory polyp being the most common diagnosis. Haemangioma was the most common benign neoplastic lesion whereas in granulomatous lesions most common diagnosis was tuberculosis. The maximum lesions 74 (49%) were in maxillary antrum. The most common clinical presentation was nasal obstruction, with unilateral nasal obstruction seen in 84 (56%) cases and bilateral nasal obstruction in 50 (33.3%) cases. Angiofibroma 6 (4%) was exclusively seen in adolescent males. Olfactory neuroblastoma 4 (2.6%) was diagnosed in females with mean age of presentation of 30 years. Sinonasal lesions display a complex and interesting spectrum of clinical, radiological and histopathologic features. The non-neoplastic lesions are numerous, the morphologic variants of neoplasms are many and most of them present as polypoid masses which are impossible to distinguish clinically. Hence a proper workup including histopathological and radiological categorization is essential in the management of these lesions. PMID- 29977857 TI - Maximising Graft Take-Up in Type1 Tympanoplasty Using Peripheral Cartilage Ring and Perichondrium. AB - The aim of this study is to evaluate the results of closure of big central and subtotal perforation by Tympanoplasty using underlay technique with Composite graft of tragal perichondrium supported by a ring of cartilage peripherally. Our hypothesis was that the cartilage support offers an extremely reliable method for reconstruction of the tympanic membrane in cases of advanced middle ear pathology and Eustachian tube dysfunction and also revision cases. Prospective study of patients undergoing tympanoplasty in big central and subtotal perforation with graft supported by a ring of cartilage peripherally between June 2016 and August 2016. Hearing results were reported using four frequency (500, 1000, 2000 and 3000) pure tone average air-bone gap. During the study period, composite graft comprising of tragal perichondrium and peripheral ring of cartilage prepared from ipsilateral tragus was used for tympanic membrane reconstruction in 30 patients. Overall graft take rate was 93.33%. Complications included residual perforation in 6.67%. Cartilage ring support offers an extremely reliable method for reconstruction of tympanic membrane in cases of high-risk perforation (big central perforation, subtotal perforation, anterior perforation of tympanic membrane, revision cases). PMID- 29977858 TI - Comparison of Endonasal DCR Surgery Using Cautery and Surgical Blade Technique in Cases of Chronic Dacryocystitis. AB - Dacryocystitis is defined as inflammation of lacrimal sac. This can be congenital or acquired. Congenital dacryocystitis is commonly chronic while acquired dacryocystitis is acute and chronic both. Endonasal DCR surgery is the most commonly used treatment in chronic DCR but recent use of cautery technique in endonasal DCR surgery rather than traditional surgical blade technique has emerged with promising results with good success rate and fewer complications. PMID- 29977859 TI - Innovative Use of Insulated Microear Ball Probe Cautery in Creation of Nasal Mucosal Flap in EnDCR. AB - To study the outcome and complications of endoscopic endonasal dacryocystrhinostomy without stenting. Randomised prospective observational design. Tertiary academic centre. Seventy patients, clinically diagnosed as chronic dacryocystitis with nasolacrimal duct obstruction on the basis of syringing, were enrolled. Endoscopy was done for nasal pathology especially mucosal disease, hypertrophied turbinate, DNS. Seventy-eight eyes were operated with endoscopic-dacryocystorhinostomy along with additional surgeries and periodically followed up on OPD-basis at the end of 1st week, 2nd week, 1st month and 3rd month and evaluated clinically and by syringing (Ophthalmologist) and endoscopy done, wherever required. Insulated microear ball probe cautery was used to create nasal mucosal flap in all cases. Eleven patients underwent septal surgery along with one concha bullosa and one agger nasi removal (p < 0.05). Nil intraoperative complications (p < 0.05) and single postoperative complication noted (p < 0.05). Functional and anatomical patency found to be 100% at the end of 1st week, 98.7% at the end of 2nd week, 93.6% at end of 1st month and 91% at end of 3rd month. Nasal endoscopy showed restenosis in 1 patient at end of 2nd week, 4 patients at end of 1st month, 1 patient at the end of 3rd month along with granulation in 1 patient at the end of 3rd month. Revision surgery was done on 2 patients. Endoscopic dacryocystorhinostomy is safe and successful procedure for chronic dacryocystitis, due to nasolacrimal duct obstruction with less complications without stenting. The associated intranasal pathology, which might be the cause, can be corrected and bilateral dacryocystorhinostomy can be performed in single sitting reducing patient's morbidity and hospital stay. Use of cautery with insulated ball probe for making nasal mucosal flaps gives an precise and excellent blood less field. PMID- 29977860 TI - Post Stapedotomy Vestibular Deficit: Is CO2 Laser Better than Conventional Technique? A Non-randomized Controlled Trial. AB - The current standard of care for surgical management of Otosclerosis is small fenestra stapedotomy, which can be done by CO2 Laser assisted as well as conventional techniques. Vertigo is the commonest complication after stapes surgery. The use of CO2 Laser has been rising recently owing to its no touch principle, high precision and possibly lower risk of vertigo post operatively. To compare the post-operative vestibular deficit in patients of Otosclerosis having undergone small fenestra stapedotomy by conventional versus CO2 Laser assisted technique. 80 clinically diagnosed Otosclerosis patients fulfilling the inclusion criteria were enrolled. They underwent small fenestra stapedotomy by either conventional or CO2 Laser assisted technique. Vestibular function was assessed objectively by measuring sway velocity using modified clinical test of sensory interaction on balance by static posturography. Subjective measurement of balance was done using Vestibular balance subscore of Vertigo Symptom Score (VSS-sf-V). The outcome measures were compared pre-operatively and at first and fourth week post-operatively. All patients had vestibular deficit 1 week post-operatively in the form of increased sway velocity and symptom scores, which reduced by 4 weeks after Stapedotomy. The vestibular deficit in the two groups was similar at 1 week after surgery. 4 weeks after surgery, the sway velocity in conventional group was significantly greater than Laser group though there was no significant difference in the symptom scores. The use of CO2 Laser for Stapedotomy results in lesser post-operative vestibular deficit as compared to conventional method. PMID- 29977861 TI - Pyramidal Artery: An Artery to Pyramidal Lobe-A New Nomenclature. AB - Thyroid lobes are supplied by superior and inferior thyroid arteries. We dissected out a specific arterial pattern always present along with a well developed pyramidal lobe. Authors named this as "Pyramidal Artery". This may be a common unnoticed bleeding site during surgery. Thyroid anomalies are commonly observed as incidental finding during surgery. Presence of pyramidal lobe is the most common finding among other thyroid anomalies due to persistence of thyroglossal duct. Present study reported incidence of pyramidal lobe in 41.46% cases and pyramidal lobe branches off more frequently from left lobe than right. Special attention has to be paid during total thyroidectomy in order not to leave the thyroid tissue. Few such anatomical variations and surgical importance of vascular pattern in such cases is discussed in paper. PMID- 29977862 TI - Stapes Surgery Teaching Tool: A Simple, Stable and Successful Technique. AB - Stapes surgery is a highly skilled surgery among otological procedures and needs a good dexterity. To improve the skills one may need to do procedures using temporal bone dissections. We describe a procedure that is simple, inexpensive and improves the skills and can be done using easily available materials like disposable syringe, stapler pin and a forceps. PMID- 29977863 TI - Masson's Hemangioma of the Cheek: A Case Report. AB - We report a rare case of intravascular papillary endothelial hyperplasia (IPEH) of the cheek. This neoplasm, known as Masson's tumor, is an unusual vascular lesion of proliferating endothelial cells. It is usually confined to the lumen of preexisting vessels or vascular malformations. The principal significance of IPEH is its resemblance to a variety of benign and malignant diseases and possible misdiagnosis as such. Achieving a correct diagnosis is essential to avoid subjecting a patient to either unnecessarily aggressive or inadequate therapy. For this reason, awareness of this lesion is very important. PMID- 29977865 TI - Identification and Characterization of a Novel Palmitoyl Acyltransferase as a Druggable Rheostat of Dynamic Palmitoylome in L. donovani. AB - Palmitoylation has been recently identified as an important post-translational rheostat for controlling protein function in eukaryotes. However, the molecular machinery underlying palmitoylation remains unclear in the neglected tropical parasite, Leishmania donovani. Herein, we have identified a catalog of 20 novel palmitoyl acyltransferases (PATs) and characterized the promastigote-specific PAT (LdPAT4) containing the canonical Asp-His-His-Cys (DHHC) domain. Immunofluorescence analysis using in-house generated LdPAT4-specific antibody demonstrated distinct expression of LdPAT4 in the flagellar pocket of promastigotes. Using metabolic labeling-coupled click chemistry method, the functionality of this recombinant enzyme could be authenticated in E. coli strain expressing LdPAT4-DHHC domain. This was evident by the cellular uptake of palmitic acid analogs, which could be successfully inhibited by 2-BMP, a PAT specific inhibitor. Using CSS-Palm based in-silico proteomic analysis, we could predict up to 23 palmitoylated sites per protein in the promastigotes, and further identify distinctive palmitoylated protein clusters involved in microtubule assembly, flagella motility and vesicular trafficking. To highlight, proteins such as Flagellar Member proteins (FLAM1, FLAM5), Intraflagellar Transport proteins (IFT88), and flagellar motor assembly proteins including the Dynein family were found to be enriched. Furthermore, analysis of global palmitoylation in promastigotes using Acyl-biotin exchange purification identified a set of S-palmitoylated proteins overlapping with the in-silico proteomics data. The attenuation of palmitoylation using 2-BMP demonstrated several phenotypic alterations in the promastigotes including distorted morphology, reduced motility (flagellar loss or slow flagellar beating), and inefficient invasion of promastigotes to host macrophages. These analyses confirm the essential role of palmitoylation in promastigotes. In summary, the findings suggest that LdPAT4 acts as a functional acyltransferase that can regulate palmitoylation of proteins involved in parasite motility and invasion, thus, can serve as a potential target for designing chemotherapeutics in Visceral Leishmaniasis. PMID- 29977866 TI - Intestinal Inflammation in Chilean Infants Fed With Bovine Formula vs. Breast Milk and Its Association With Their Gut Microbiota. AB - Introduction: Compared to bovine formula (BF), breast milk (BM) has unique properties. In the newborn intestine, there is a homeostatic balance between the counterparts of the immune system, which allows a physiological inflammation, modulated by the gut microbiota. Many studies have attempted to understand the effect of BF vs. BM, and the changes in the gut microbiota, but few also focus on intestinal inflammation. Methods: We conducted a cohort study of newborn infants during their first 3 months. In stool samples taken at 1 and 3 months (timepoints T1 and T3), we quantified calprotectin, IL-8 and alpha1-antitrypsin by ELISA and we evaluated the expression of IL8 and IL1beta genes by RT-qPCR. To determine the microbiota composition, the 16S rRNA gene was amplified and sequenced using 454 pyrosequencing. Sequences were clustered into operational taxonomic units (OTUs). Results: In total 15 BM and 10 BF infants were enrolled. In the BM group, we found calprotectin and alpha1-antitrypsin levels were significantly elevated at T3 compared to T1; no differences were found between T1 and T3 in the BF group. A comparison between the BM and BF groups showed that calprotectin levels at T1 were lower in the BM than the BF group; this difference was not observed at T3. For IL-8 levels, we found no differences between groups. A gene expression analysis of the IL8 and IL1beta genes showed that infants from the BF group at T1 have a significantly increased expression of these markers compared to the BM group. Gut microbiota analyses revealed that the phylum Bacteroidetes was higher in BM than BF, whereas Firmicutes were higher in BF. A redundancy analysis and ANOVA showed BM has a community structure statistically different to BF at T1 but not at T3. Compared to BF, BM at T1 showed a higher representation of Enterococcus, Streptococcus, Enterobacter, Lactococcus, and Propionibacterium. Conclusions: We found a basal state of inflammation in the infants' intestine based on inflammation markers. One month after birth, infants receiving BF exhibited higher levels of inflammation compared to BM. PMID- 29977864 TI - Machine Learning and Radiogenomics: Lessons Learned and Future Directions. AB - Due to the rapid increase in the availability of patient data, there is significant interest in precision medicine that could facilitate the development of a personalized treatment plan for each patient on an individual basis. Radiation oncology is particularly suited for predictive machine learning (ML) models due to the enormous amount of diagnostic data used as input and therapeutic data generated as output. An emerging field in precision radiation oncology that can take advantage of ML approaches is radiogenomics, which is the study of the impact of genomic variations on the sensitivity of normal and tumor tissue to radiation. Currently, patients undergoing radiotherapy are treated using uniform dose constraints specific to the tumor and surrounding normal tissues. This is suboptimal in many ways. First, the dose that can be delivered to the target volume may be insufficient for control but is constrained by the surrounding normal tissue, as dose escalation can lead to significant morbidity and rare. Second, two patients with nearly identical dose distributions can have substantially different acute and late toxicities, resulting in lengthy treatment breaks and suboptimal control, or chronic morbidities leading to poor quality of life. Despite significant advances in radiogenomics, the magnitude of the genetic contribution to radiation response far exceeds our current understanding of individual risk variants. In the field of genomics, ML methods are being used to extract harder-to-detect knowledge, but these methods have yet to fully penetrate radiogenomics. Hence, the goal of this publication is to provide an overview of ML as it applies to radiogenomics. We begin with a brief history of radiogenomics and its relationship to precision medicine. We then introduce ML and compare it to statistical hypothesis testing to reflect on shared lessons and to avoid common pitfalls. Current ML approaches to genome-wide association studies are examined. The application of ML specifically to radiogenomics is next presented. We end with important lessons for the proper integration of ML into radiogenomics. PMID- 29977867 TI - MAP1981c, a Putative Nucleic Acid-Binding Protein, Produced by Mycobacterium avium subsp. paratuberculosis, Induces Maturation of Dendritic Cells and Th1 Polarization. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causative pathogen of chronic granulomatous enteropathy (Johne's disease) in animals, and has been focused on its association with various autoimmune diseases in humans, including Crohn's disease. The discovery of novel mycobacterial antigens and exploring their role in host immunity can contribute to the advancement of effective defense strategies including vaccines and diagnostic tools. In a preliminary study, we identified cellular extract proteins of MAP that strongly react with the blood of patients with Crohn's disease. In particular, MAP1981c, a putative nucleic acid-binding protein, showed high expression levels and strong reactivity to IgG and IgM in the sera of patients. Here, we investigated the immunological features of MAP1981c and focused on its interaction with dendritic cells (DCs), confirming its immunomodulatory ability. MAP1981c was shown to recognize Toll like receptor (TLR) 4, and induce DC maturation and activation by increasing the expression of co-stimulatory (CD80 and CD86) and MHC class I/II molecules and the secretion of pro-inflammatory cytokines (IL-6, IL-1beta, and TNF-alpha) in DCs. This DC activation by MAP1981c was mediated by downstream signaling of TLR4 via MyD88- and TRIF-, MAP kinase-, and NF-kappaB-dependent signaling pathways. In addition, MAP1981c-treated DCs activated naive T cells and induced the differentiation of CD4+ and CD8+ T cells to express T-bet, IFN-gamma, and/or IL 2, but not GATA-3 and IL-4, thus indicating that MAP1981c contributes to Th1-type immune responses both in vitro and in vivo. Taken together, these results suggest that MAP1981c is a novel immunocompetent antigen that induces DC maturation and a Th1-biased response upon DC activation, suggesting that MAP1981c can be an effective vaccine and diagnostic target. PMID- 29977868 TI - Integration of Transcriptomic and Proteomic Approaches Reveals the Temperature Dependent Virulence of Pseudomonas plecoglossicida. AB - Pseudomonas plecoglossicida is a facultative pathogen that is associated with diseases of multiple fish, mainly at 15-20 degrees C. Although fish disease caused by P. plecoglossicida has led to significant economic losses, the mechanisms of the temperature-dependent virulence are unclear. Here, we identify potential pathogenicity mechanisms and demonstrate the direct regulation of several virulence factors by temperature with transcriptomic and proteomic analyses, quantitative real-time PCR (qRT-PCR), RNAi, pyoverdine (PVD) quantification, the chrome azurol S (CAS) assay, growth curve measurements, a biofilm assay, and artificial infection. The principal component analysis, the heat map generation and hierarchical clustering, together with the functional annotations of the differentially expressed genes (DEGs) demonstrated that, under different growth temperatures, the animation and focus of P. plecoglossicida are quite different, which may be the key to pathogenicity. Genes involved in PVD synthesis and in the type VI secretion system (T6SS) are specifically upregulated at the virulent temperature of 18 degrees C. Silencing of the PVD-synthesis related genes reduces the iron acquisition, growth, biofilm formation, distribution in host organs and virulence of the bacteria. Silencing of the T6SS genes also leads to the reduction of biofilm formation, distribution in host organs and virulence. These findings reveal that temperature regulates multiple virulence mechanisms in P. plecoglossicida, especially through iron acquisition and T6SS secretion. Meanwhile, integration of transcriptomic and proteomic data provide us with a new perspective into the pathogenesis of P. plecoglossicida, which would not have been easy to catch at either the protein or mRNA differential analyses alone, thus illustrating the power of multi-omics analyses in microbiology. PMID- 29977869 TI - Characteristics and outcomes of patients with multiple myeloma : Data from a developing country. AB - Background: Multiple myeloma (MM) is a plasma cell disorder characterized by presence of monoclonal protein in serum or urine or both, increased bone marrow plasma cells, osteolytic lesion, hypercalcemia, and anemia. Several combination regimens are commonly recommended for treatment of multiple myeloma. The present study aimed at determining the characteristics and outcomes of patients with multiple myeloma treated at our centre. Methods: During July 2012 and December 2015, all patients with proven diagnosis of MM were included in this study. Data were collected from hospital information system. The characteristics and outcomes of all patients were analyzed. Progression- free survival and overall survival of patients were also estimated. Kaplan-Meier curves and Log-rank test were applied and SPSS Version19 was used for data analysis. Results: A total of 82 patients, with the median age of 51 years (Range: 23-64 yrs.) were available for final analysis. The number of patients with IgG and IgA type was 48 (58.5%) and 15(18.3%), respectively. There were 7 (8.5%) patients with non-secretory type. Most of the patients (n= 59; 71.9%) were treated with CTD regimen and 13 (15.8%) received bortezomib-based treatment. The median progression-free survival time was 30 months, and overall survival time was 48 months. The cumulative probability of survival at 36 months was 85%. Conclusion: Based on our results, the onset of multiple myeloma occurs in relatively younger age groups. A small number of patients received bortezomib due to cost issues. PFS and OS in our study were comparable with published literature. PMID- 29977870 TI - In vitro evaluation of decontamination effects on mechanical properties of fibrin membrane. AB - Background: Tissue engineering has been investigated as a potential method for healing traumatized tissues. Biomaterials are material devices or implants used to repair or replace native body tissues and organs. The present study was conducted to evaluate the effects of decontamination methods on biological/mechanical properties and degradation/adhesion test of the platelet rich fibrin (PRF) membranes to compare these properties with intact membranes as a biological biomaterial. Methods: The in vitro degradation tests were conducted by placing the equal sizes of (i) intact PRF membrane, (ii) PRF membrane sterilized by autoclave (iii), ultraviolet (UV), and (iiii) gamma irradiation in phosphate buffer solution on a shaker. The degradation profiles were expressed. Adhesion test was performed by counting adhered mouse fibroblast and sterilized fibrin membrane was compared to normal fibrin membrane by different sterilization methods. Results: The preliminary findings of sterilized PRF membranes showed that UV exposure (p<0.05) and autoclaved fibrin membranes (p<0.01) have significantly lower degradability compared to normal fibrin membranes. Gamma irradiation is similar to normal membrane in degradability. Cell adherence in all groups of fibrin membrane was significantly lower than the group without membrane, but there was no significant difference between intact and sterilized groups of fibrin membranes. Conclusion: Sterilization of fibrin membrane with different protocols does not have any adverse effects on cell adhesion; however, cell adherence is naturally very weak even in normal membranes. Also, it seems that ultraviolet ray polymerizes fibrin filaments and merges them to each other and increases the ability of fibrin membrane against degradation. Autoclaved fibrin membrane content proteins are denatured because of pressure and heat and show an increase in hardness and stability against degradation. PMID- 29977871 TI - Overuse and underuse of pulmonary CT angiography in patients with suspected pulmonary embolism. AB - Background: The aim of the present study was to evaluate the utilization and diagnostic yields of CT pulmonary angiography (CTPA)using the Revised Geneva score and Wells' criteria, in patients with suspected pulmonary embolism (PE). Methods: One hundred and twelve adult patients underwent CTPA for suspected PE were participated in this study. The outcome was positive or negative CTPA for PE. Revised Geneva and Wells' scores were calculated. The relationship between the results obtained rom these two scores and the available risk factors were compared. Descriptive analysis such as frequency and mean as well as analytical statistics including chi-square were done. The data analysis was performed using SPSS (v. 22). Results: In this study, according to the Wells' criteria calculated for the patients, 33.9% of the patients had low clinical, 56.3% intermediate and 9.8% high clinical probability. Among the 11 high clinical patients, 9(81.8%) were CTPA positive. Based on the revised Geneva score, 65 patients (58%) had low clinical, 36 (32.1%) intermediate and 11(9.8%) high clinical probability. Among the 1 high clinical patients, 8 were CTPA positive. Positive predictive value of the low clinical patients based on Wells' criteria and the revised Geneva score was 18.4% and 30.8%, respectively. Also, positive predictive value for high clinical probability of Wells' criteria and the revised Geneva score was 81.8% and 72.8% respectively. Conclusion: Under/overuse of CTPA in diagnosing PTE is a common problem especially in university hospitals. It is possible to avoid unnecessary CTPA requests using scholarly investigations and more accurate clinical risk assessments. PMID- 29977872 TI - The association of FokI and ApaI polymorphisms in vitamin D receptor gene with autoimmune thyroid diseases in the northwest of Iran. AB - Background: Some genetic factors are involved in the etiology of Hashimoto thyroiditis and Graves' disease as autoimmune thyroid diseases (AITDs). Effects of vitamin D receptor gene polymorphisms in AITDs development have already been investigated in some previous studies. However, no study has been done on the association between VDR FokI and ApaI polymorphisms and AITDs in an Iranian population. In this study, the possible effects of FokI and ApaI polymorphisms on AITDs were investigated in the population of northwest of Iran. Methods: A total of 121 AITDs adult patients and 117 healthy controls matched by age and sex in the same population were included in this study. FokI and ApaI polymorphisms were genotyped by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Chi-square test and odds ratio (OR) with 95% CI were used to analyze the data. Results: FokI and ApaI genotypes frequencies were not significantly different between the 2 groups (p= 0.06, p= 0.73, respectively). However, FokI "CC" and "CT" genotypes were related to AITDs risk (p= 0.03; OR= 3.75; 95% CI, 1.16-12.17 and p= 0.04; OR= 3.41; 95% CI, 1.03-11.28, respectively). Conclusion: These data suggest that FokI polymorphisms are involved in AITDs susceptibility in the population of northwest of Iran. PMID- 29977873 TI - A novel PKP2 mutation and intrafamilial phenotypic variability in ARVC/D. AB - Background: Arrhythmogenic ventricular cardiomyopathy (AVC) is an inherited cardiac disorder affecting 1 in 1000 individuals worldwide. The mean diagnosed age of disease is 31 years. In this article, an Iranian family reported that they were affected by ARVC due to a novel PKP2 mutation. Methods: Clinical evaluations, 12-lead ECG, CMR, and signal-averaged ECG were performed. After DNA extraction, genetic testing was done, and PCR-sequencing was applied to find causal mutations. Segregation analysis was also performed for the family. Results: ARVC criteria were documented in the patients. Genetic testing revealed a novel chain termination mutation (p.Tyr168Ter) in PKP2 gene; this mutation was transmitted from the mother to her 23-year-old son, but only the son was affected with ARVC. Conclusion: Modifier genes were indicated using interactome analysis of Plakophilin 2 protein (PKP2); they might have led to phenotypic variability through cellular mechanisms, such as nonsense-mediated mRNA decay. At least, 9 proteins were identified that might have affected Plakophilin 2 protein function, and consequently, rationalizing this intrafamilial phenotypic variability. This study highlighted the role of modifier genes involved in ARVC as well as the major role of PKP2 mutation in developing the disease in our population. PMID- 29977874 TI - Factors affecting the leadership effectiveness of hospital managers: A systematized review. AB - Background: Effective leadership is regarded as an important factor in organizational success. This study aimed at performing a systematic review on leadership effectiveness among hospital managers. Methods: A search was conducted in ScienceDirect, ProQuest, Web of Science, Ovid, and Scopus databases on the factors related to effectiveness of hospital managers' leadership during 1990 and 2016. The initial results included 2795 papers, but after further investigation and qualitative evaluation using CASP-19, a total of 8 papers were included in the systematic review. Then, summarizing, classification, and comparison were used for data analysis and synthesis. Results: From among the 8 investigated papers, 4 were conducted in different regions of the US and the other 4 studies were done in Canada, India, Turkey, and South Africa. The latest and oldest studies were conducted in 2016 and 1992, respectively. The papers included 4 reviews, 3 cross-sectional studies, and 1 qualitative study. Effective factors on the effectiveness of managers' leadership were identified and classified into 4 categories of self-management, people management, health services provision management, and nuclear management skills. Conclusion: Despite the emphasis of various studies on the existence of different effective factors on hospital managers' leadership, all these factors can be categorized as people management skills, self-management skills, nuclear management skills, and health services provision skills. PMID- 29977876 TI - Lipohypertrophy in Individuals with Type 2 Diabetes: Prevalence and Risk Factors. AB - Introduction: As well as its negative effect on the subcutaneous tissues, lipohypertrophy has negative effects on clinical data. The purpose of this study was to examine the frequency of lipohypertrophy, risk factors and perceived barriers preventing rotation in individuals with type 2 diabetes. Methods: This descriptive cross-sectional study was conducted at Diabetes Education Center and Endocrine and Metabolism Clinic of a university hospital and Diabetes Education and Monitoring Center in a private hospital in Turkey between June 2016- April 2017. The inclusion criteria were as follows; undergoing at least one year of insulin therapy, injecting insulin pens or syringes themselves, being over 18 years of age, making regular injection of insulin and being a patient with type 2 diabetes. Introductory information form was used to collect the data. The data were analyzed using descriptive statistics and chi-square analysis with SPSS version 16.0. Results: Factors influencing lipohypertrophy development were determined as follows; healthcare personnel who provide insulin education, duration of diabetes, the number of injection administered daily, needle length, the number of injection sites, insulin types, injection site rotation and intra site rotation and needle exchange frequency. In addition, the prevalence of lipohypertrophy was found to be higher in patients with hypoglycemia, unexplained hypoglycemia, and those with high BMI and A1C. Conclusion: It is recommended that diabetes education should be provided by the diabetes specialist nurses who have diabetes-specific certifications and / or education and who can provide full-time education. Randomized controlled interventional studies investigating how to prevent the lipohypertrophy development are also needed. PMID- 29977875 TI - Musculoskeletal Symptoms among Family Caregivers of Community-Dwelling Stroke Survivors in Nigeria. AB - Introduction: Caring for stroke survivors may be burdensome with adverse consequences on caregivers' physical health. This study examined the prevalence of musculoskeletal symptoms and associated factors among family caregivers of stroke survivors in Nigeria. Methods: A hospital-based cross-sectional study involving 90 stroke caregiver and stroke survivor dyads was conducted. Data on the participants' demographics and post-stroke duration were obtained. Seven-day prevalence of musculoskeletal symptoms among the caregivers and level of stroke survivors' disability were respectively assessed using the Nordic Musculoskeletal Questionnaire and Modified Rankin Scale. Prevalence of musculoskeletal symptoms was presented as percentages while participants' characteristics associated with prevalence of musculoskeletal symptoms were examined using inferential statistics. Results: Mean (SD) age of caregivers and stroke survivors was 33.2 (10.7) years and 58.9 (9.7) years respectively. Majority of the caregivers were females (61.1%), and children of the stroke survivors (58.9%). Prevalence of musculoskeletal symptoms was 82.2%. The low back was the most affected body region (72.2%) followed by the upper back (40%) while musculoskeletal symptoms in the wrist was least prevalent (3.3%). Female caregivers, caregivers of female stroke survivors and spousal caregivers had significantly higher prevalence of musculoskeletal symptoms compared to other categories of caregivers. Only 5 (5.6%) caregivers had however received any training on safe care giving methods while only 21 (28.4%) caregivers with musculoskeletal symptoms had received treatment. Conclusion: With the high prevalence of musculoskeletal symptoms among family caregivers of stroke survivors, effective preventive strategies including training and education as well as timely access to treatment would be required. PMID- 29977877 TI - Nurses' Information, Attitude and Practices towards Use of Physical Restraint in Intensive Care Units. AB - Introduction: Physical restraint may seem to be a useful and simple procedure to help the treatment but is a complex practice including physical, psychological, judicial, ethical and moral issues. Research was made on description basis in order to determine the knowledge, attitude and application levels of nurses working in critical care units about physical restraint applied on patients. Methods: The study was performed as a descriptive and correlation study. Working in ICUs, 158 nurses constituted the sampling. "Levels of Knowledge, Attitudes and Practices of Staff Regarding Physical Restraints Questionnaire" was used to collect data. Results: For information, attitude and practice scores, participants' scores were 7.1(1.7), 31.8 (4.6) and 36.6 (3.2), respectively. No association was found between information subscale, and age, professional years, working time in ICUs and weekly working hours. However, for attitude subscale, a negative and weak association was found between age (r=-0.229) and professional years (r=-0.174), and increasing these variables decreased attitude score. No association was found between attitude score, and working time in ICUs and weekly working hours. While there was no association between practice score, and age, professional years and working time in ICUs, the increase in weekly working hours (r=-0.243) was found to decrease practice score, and this association was found weak. Conclusion: In conclusion, we consider nurses' level of information is sufficient, but attitudes and practice were not at a positive level. It is recommendable that out of such conditions, novel approaches should be developed to decrease the use of physical restraint. PMID- 29977878 TI - The Effect of Cognitive-Behavioral Consultation on Sexual Function among Women: a Randomized Clinical Trial. AB - Introduction: Sexual dysfunction is one of the most common causes of family breakdowns. In recent years, various approaches have been proposed to resolve this issue. The present study was carried out in order to examine the effect of cognitive-behavioral consultation on sexual function among women who had referred to health centers in Hamadan. Method: A randomized clinical trial was conducted in two groups. It focused on 198 qualified women who had referred to selected health centers of Hamadan in 2016. The participants were selected by simple random sampling (99 people in each group).The intervention group received four 2 hour sessions of cognitive-behavioral group consultation. The required data were collected using a questionnaire of demographic characteristics and Female Sexual Function Index (FSFI). For ethical considerations, by the end of the study, sexual counseling for the control group was provided. To analyze the collected data, SPSS 13 was employed; t-test was used for independent samples. ANCOVA was also utilized. The significance level was set at 0.05. Results: The results showed that the two groups were not significantly different in terms of mean pretest scores in all domains, except for sexual satisfaction and total sexual function. However, after cognitive-behavioral consultation sessions, the intervention group experienced a significant increase in all behavioral domains and total sexual function as compared to the control group. Conclusion: Cognitive behavioral consultation among women can play a positive and effective role in improving sexual relationships. Therefore, the effectiveness of this type of consultation can be confirmed with more certainty. PMID- 29977879 TI - The Effect of Biofeedback on the Motor- Muscular Situation in Rehabilitation of Stroke Patients: a Randomized Controlled Trial. AB - Introduction: Stroke is the most common debilitating neurological disease in adults. Therefore, rehabilitation is a major consideration to reduce costs and relief disabilities. Biofeedback, a newly recommended method is claimed to be able to improve the consequences following stroke by enhancing the understanding of the psychological functions of the body. The purpose of this study was to investigate the effects of biofeedback on the motor- muscular situation in balance and ability to walk, muscle stiffness (spasticity), hand muscles strength of stroke patients. Methods: The present study was a randomized clinical trial done in 2016. The participants were randomly divided into 2 groups (case and control group). In the intervention group, biofeedback was performed. The check list of main variables, including balance and ability to walk, muscle stiffness (spasticity) and hand muscles strength was completed by a physician before the intervention and at the end of the intervention (16th session). The statistical analysis was conducted, using SPSS version 13. Results: The mean score of balance in intervention group versus control group showed significant differences. The results showed that by eliminating the effects of muscular strength before the intervention, this variable had made improvements and significant differences in both intervention and control groups after the intervention. Comparison of the average spasticity showed that spasticity evaluation score before and after the intervention revealed no significant difference between the two groups. Conclusion: Biofeedback therapy is a promising treatment modality for improving the motor-muscular situation of patients after stroke. PMID- 29977880 TI - Effectiveness of Text Messaging and Face to Face Training on Improving Knowledge and Quality of Life of Patients undergoing Hemodialysis: a Randomized Clinical Trial. AB - Background: The quality of life of patients undergoing hemodialysis is lower; to improve their living conditions, patients need further training. This study conducted to compare the effectiveness of two methods of text messaging and face to face education on knowledge and quality of life of patients under hemodialysis. Methods: Undergoing in a clinical trial study, 60 patients undergoing hemodialysis in Sina-teaching hospital of Tabriz, Iran were selected by convenience sampling and randomly allocated into three groups: two intervention groups: text massaging (P=20), face to face group (n=20) and one control group (n=20). Their knowledge and quality of life were assessed and compared by Chronic Hemodialysis Knowledge Survey (CHeKS) and Kidney Disease Quality of Life-short form (KDQOL-SF) questionnaires. Data were analyzed by SPSS version 13. Results: After intervention, the knowledge of text messaging and face to face groups were significantly more than the control group, but the quality of life scores after intervention had not any significant difference among the three groups. Intra-group comparisons showed that quality of life in face to face group have been significantly increased. Conclusion: Text messaging and face to face teaching were effective on improving knowledge of patients undergoing hemodialysis. However, the effectiveness of these methods on quality of life needs further evaluations in different setting for longer times in hemodialysis patients. PMID- 29977881 TI - The "Cooperative-Supportive" Intervention for Improving Mental Health Status among Pregnant Women. AB - Introduction: Maternal mental health during pregnancy has a major impact on fetal growth and consequently, child health. The objective of this study was to assess the effect of "Cooperative-Supportive" Intervention Program on Pregnancy. Methods: The present before and after interventional research was conducted on 114 pregnant women referring to Khoy health centers in 2014. Pregnant women were randomly divided into intervention (n=57) and control groups (n=57). The data collection tool in this research was the researcher-made questionnaire based on the Predisposing, Reinforcing and Enabling Constructs in Educational Diagnosis and Evaluation (PRECEDE) model which assessed the participants' predisposing, enabling, and reinforcing factors. The educational interventions for enhancing pregnant women's stress controlling skills were conducted and also practical pacifying lessons were held for the intervention group during five weeks with relaxation exercises. In order to assess health status among pregnant women, knowledge, attitude, depression, anxiety and self-efficacy were investigated by applying different scales and questioners. The questionnaires were completed before and after the interventional program. The data were analyzed, using suitable statistical tests. Results: After the intervention, the mean score of PRECEDE major components significantly increased and the total anxiety and depression scores decreased in the intervention group in comparison to those of the control group. Conclusion: The present study showed the positive impact of educational intervention programs based on PRECEED model and major components on reducing anxiety and depression, and finally mental health promotion in the studied population. PMID- 29977882 TI - The Effect of Pre-Discharge Training on the Quality of Life of Burn Patients. AB - Introduction: Many physical, psychological, social and economic complications have been reported after discharge, which have a negative impact on the quality of life of burn patients. The present research examines the effect of pre discharge training program on the life quality of patients with burns. Methods: This is a pre and post-experimental study with control group that was conducted in 2015 in teaching hospital Sina. The control group received the typical instructions upon being discharged from hospital while the experimental group received in-person training in the form of question-answer, pamphlets and a researcher-made instruction booklet. The patients' life quality was evaluated when they were being discharged, a month and then three months after they were discharged. Results: The result showed that the quality of life has a significant statistical difference across the three time points. And these differences are compared using Bonferroni's adjustment multiple comparisons indicating that pre discharge training affects the quality of life scores and this effect continues over time. Conclusion: The results show that the pre-discharge training has significantly improved the life quality among the burns patients. The improvement of life quality is also correlated with the quantitative variable of total body surface area percent (TBSA %). Thus, planning and designing in-discharge training programs based on the existing context, combined with training packages focusing on the patients' needs could be a very significant step in more successful implementation of the follow-up programs on the burn patients and improving their quality of life. PMID- 29977883 TI - Relationship between Oncology Nurses' Spiritual Wellbeing with Their Attitudes towards Spiritual Care Providing Based on Neuman System Model: Evidences from IRAN. AB - Introduction: Oncology nurses should create a balance in their personal and professional life to provide holistic care to patients. The more the awareness of spirituality in oncology nurses develops, the more obviously it manifests itself in their attitudes toward spiritual care. This study aimed to assess the relationship between oncology nurses' spiritual wellbeing, and their attitudes toward spiritual care based on Neumann's Systems Model. Methods: This descriptive correlational study tested the relationships of Neuman system-based model constructs, named oncology nurses antecedents, their spiritual wellbeing, and attitudes to spiritual care by using a causal model and path analysis. 130 oncology nurses from 12 Tehran hospitals completed the study questionnaires, having completed written informed consents. The study administration permission was approved by Urmia University of medical sciences ethical committee. The collected data were coded and entered to computer to be analyzed by SPSS 13. We used path analysis and multiple regressions for assessing the relationships among the variables of the hypothesized study model. Results: The model testing revealed, from four antecedents' predictors' variables, only age and spiritual wellbeing had a direct and meaningful relationship with oncology nurses' attitudes towards spiritual care. The nurses' antecedent and mediator variable, and spiritual wellbeing explained 32.5% of the variance in their attitudes towards spiritual care. Moreover, the nurses' spiritual wellbeing was found to have a positive relationship with their attitude to spiritual care (beta= 0.450). Conclusion: However, the study model and its constructs proved to be quite efficient in indicating oncology nurses' attitudes to spiritual care-related factors, but it is not a comprehensive model and other studies are required for its empirical testing. PMID- 29977884 TI - Transient Elastography for Significant Liver Fibrosis and Cirrhosis in Chronic Hepatitis B: A Meta-Analysis. AB - Background: The hepatitis B virus infection is a global health issue and the stage of liver fibrosis affects the prognosis in patients with chronic hepatitis B (CHB). We performed the meta-analysis describing diagnostic accuracy of transient elastography (TE) for predicting CHB-related fibrosis. Methods: We performed an adequate literature search to identify studies that assessed the diagnostic accuracy of TE in CHB patients using biopsy as reference standard. Hierarchical summary receiver-operating curves model and the bivariate mixed effects binary regression model were applied to generate summary receiver operating characteristic curves and pooled estimates of sensitivity and specificity. Results: The area under the summary receiver-operating curve for significant fibrosis and cirrhosis was 0.86 (95% confidence interval (CI): 0.83 0.89) and 0.92 (95% CI: 0.90-0.94), respectively. The sensitivity, specificity, and diagnostic odds ratio of TE for significant fibrosis were 0.78 (95% CI: 0.73 0.81, p < 0.01; I2 = 85.59%), 0.81 (95% CI: 0.77-0.84, p < 0.01; I2 = 88.20%), and 14.44 (95% CI: 10.80-19.31, p < 0.01; I2 = 100%) and for cirrhosis were 0.84 (95% CI: 0.80-0.88, p < 0.01; I2 = 76.67%), 0.87 (95% CI: 0.84-0.90, p < 0.01; I2 = 90.89%), and 36.63 (95% CI: 25.38-52.87, p < 0.01; I2 = 100%), respectively. The optimal cut-off values of TE were 7.25 kPa for diagnosing significant fibrosis and 12.4 kPa for diagnosing cirrhosis, respectively. Conclusion: TE is of great value in the detection of patients with CHB-related cirrhosis but has a suboptimal accuracy in the detection of significant fibrosis. PMID- 29977885 TI - Astragalus mongholicus (Fisch.) Bge Improves Peripheral Treg Cell Immunity Imbalance in the Children With Viral Myocarditis by Reducing the Levels of miR 146b and miR-155. AB - Viral myocarditis (VMC) is a common cardiac disease, however, there still lacks an effective therapeutic strategy for VMC. Astragalus mongholicus (Fisch.) Bge (AB), a Chinese herb with some functional metabolites, may have some pharmacological effects on VMC. AB ingredients were measured by a full-scan LCQ mass spectrum. We aimed to explore the effects of AB on the VMC children by investigating peripheral Treg cell homeostasis. A total of 68 VMC children were random and evenly assigned into an AG group (received 10-mL AB oral liquid daily), and a CG group (received placebo daily). Peripheral blood mononuclear cells (PBMC) were obtained from peripheral blood and Treg cells were isolated. The levels of miR-146b, miR-155, Treg immunity activity and myocarditis biomarkers were measured in Treg cells. There were four main components (sucrose, calycosin, Astragaloside IV and calycosin-7-glucoside) in AB. The cases sinus tachycardia, frequent premature ventricular contractions, and supraventricular tachycardia were significantly reduced in the AG group (P < 0.05). Meanwhile, the myocardial enzymes and cardiac function indexes were improved in the AG group when compared with the CG group (P < 0.05). The time of electrocardiogram recovery, symptom duration and hospital stay was shorter in the AG group than in the CG group (P < 0.05). The levels of miR-146b and miR-155 were higher in the CG group than in the AG group (P < 0.05). The levels of ROR-gammat (retinoic acid receptor-related orphan nuclear receptor gamma), FoxP3 (forkhead transcription factor), IL-10 (interleukin-11) and TGF-beta (transforming growth factor beta) were lower in the CG group than in the AG group (P < 0.05). In contrast, the levels of IL-17, IL-21, CK-MB (creatine kinase-MB), cTnI (cardiac troponin I), GrB (granzyme B), sFasL (soluble fas ligand) and caspase-3 were higher in the CG group than in the AG group (P < 0.05). Furthermore, the levels of ROR-gammat, FoxP3, IL-10, and TGF-beta were positively, whereas the levels of IL-17, IL-21, CK-MB, cTnI, GrB, sFasL and caspase-3 were negatively, associated with the levels of miR-146b and miR-155 (P < 0.05). AB treatment improved cardiac functions, peripheral Treg cell immunity imbalance in the children with VMC by reducing the levels of miR-146b and miR-155. PMID- 29977886 TI - Nutritional Status and Psychological Impairment in Rural Adolescent Girls: Pilot Data From "KOKAN" Region of Western India. AB - Background: Adolescence is a period during which psychological foundations are laid down as well as consolidated. Not much information is available on rural Indian adolescent girls and their psychological health. Methods: We did a pilot survey of psychological health of 80 adolescent girls residing at KOKAN region of western India. Psychological health was evaluated using Youth Paediatric Symptom Checklist (Y-PSC) consisting of 35 items with maximum score of 70. Girls with a score >30 were classified as psychologically impaired. In addition we also collected random blood sample and measured the micronutrients. Macronutrient intake was estimated by 24 h recall. Results: The mean age of the girls was 14 years with a standard deviation of 1.5. In all 35/76 (46.1%) could be classified as psychologically impaired. There was a high prevalence of micronutrient deficiencies with varying degrees. More than 65% were deficient in calcium, zinc and folic acid. About 22% were anemic and 36% were vitamin B1 deficient. More than 75% had a low recommended dietary allowance (RDA) of macronutrients. Those with poor serum calcium concentration had higher psychological score (p < 0.05). Fat and calcium intakes were inversely associated with psychological score (p < 0.05 and p < 0.001 respectively). Odds ratios for psychological impairment were significant for those with low calcium levels [1.47 (95% CI 1.21, 4.31)], and for those with low calcium intake 1.43 (1.08, 3.19) and low iron intake 3.04 (1.02, 9.26). Conclusion: Our pilot data has shown the urgent need to improve the nutrition of adolescent girls, which could improve their psychological health. PMID- 29977888 TI - Palladium and Platinum 2,4-cis-amino Azetidine and Related Complexes. AB - Seven N,N'-palladium(II) chloride complexes, one N,N'-palladium(II) acetate complex of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Two platinum(II) chloride N,N'-complexes of 2,4-cis-azetidines where prepared and analyzed by single crystal XRD. Computational analysis and determination of the %Vbur was examined conducted. A CNN' metallocyclic complex was prepared by oxidative addition of palladium(0) to an ortho bromo 2,4-cis-disubstituted azetidine and its crystal structure displays a slightly pyramidalized metal ligand orientation. PMID- 29977887 TI - HIV Stigma Reduction for Health Facility Staff: Development of a Blended- Learning Intervention. AB - Introduction: The effect of stigma on health and health inequity is increasingly recognized. While many medical conditions trigger stigmatization, the negative effects of HIV stigma are particularly well documented. HIV stigma undermines access, uptake, and adherence to both HIV prevention and treatment. People living with HIV face stigma in all aspects of their daily lives; however, stigma in the health system is particularly detrimental. A key component for health facility stigma-reduction interventions is participatory training of staff, often through several days of in-person training. Though this approach shows promise, it is time intensive and poses challenges for busy health facilities. In response, the DriSti study has developed a brief blended-learning approach to stigma reduction in Karnataka State, India. This paper describes the process and final content of the intervention development. The intervention is currently being tested. Final evaluation results will be published upon study completion. Methods: Grounded in behavior change strategies based on social cognitive theory principles that stress the importance of combining interpersonal interactions with specific strategies that promote behavior change, we used a three-phase approach to intervention development: (1) content planning-review of existing participatory stigma-reduction training activities; (2) story boarding-script development and tablet content production; and (3) pilot testing of tablet and in-person session materials. Results: The final intervention curriculum consists of three sessions. Two initial self-administered tablet sessions focus on stigma awareness, attitudes, fears of HIV transmission, and use of standard precautions. The third small group session covers the same material but includes skill building through role-play and testimony by a person living with HIV. A study team member administers the tablet sessions, explains the process, and is present throughout to answer questions. Conclusion: This paper describes the theoretical underpinning and process of developing the blended-learning curriculum content, and practical lessons learned.The approach covers three key drivers of HIV stigma stigma awareness, fear of HIV transmission, and attitudes. Developing video content for the self-directed learning is complex, requires a diverse set of people and skills, and presents unexpected opportunities for stigma reduction. Co facilitation of the in-person session by someone living with HIV is a critical component. PMID- 29977889 TI - Development of Efficient Protocols for Stable and Transient Gene Transformation for Wolffia Globosa Using Agrobacterium. AB - Members of the Wolffia genus are fascinating plants for many biologists as they are the smallest flowering plants on Earth and exhibit a reduced body plan that is of great interest to developmental biologists. There has also been recent interest in the use of these species for bioenergy or biorefining. Molecular and developmental studies have been limited in Wolffia species due to the high genome complexity and uncertainties regarding the stable genetic transformation. In this manuscript we present new protocols for both stable and transient genetic transformation for Wolffia globosa using Agrobacterium tumefaciens. For the transient transformation, we used Wolffia fronds whereas we used clusters for the stable transformation. As proof of concept we transformed two synthetic promoter constructs driving expression of the GUS marker gene, that have previously been used to monitor auxin and cytokinin output in a variety of species. Using these approaches we obtained a Transformation Efficiency (TE) of 0.14% for the stable transformation and 21.8% for the transient transformation. The efficiency of these two methods of transformation are sufficient to allow future studies to investigate gene function. This is the first report for successful stable transformation of W. globosa. PMID- 29977891 TI - One-Step Synthesis of Hexagonal Boron Nitrides, Their Crystallinity and Biodegradation. AB - Hexagonal boron nitrides (hBNs) have recently been investigated for several novel applications due to their unique properties such as biocompatibility, superhydrophobicity, electrical insulation, and thermal and chemical stability. In addition, their biodegradation products have recently reported to have therapeutic effect on certain cancer types. hBNs are easily synthesized from boron and nitrogen precursors at moderately low temperatures. However, crystallinity and yield vary depending on the type of precursor, reaction temperature, and duration. In this study, a simple one-step hBNs synthesis method is reported without a catalyst, which might be an undesired contaminant for biomedical applications. The influence of boron precursors (boric acid, colemanite, or boron trioxide) on hBNs crystallinity, stability, and biodegradation in suspensions containing oxidative and hydrolytic degradation agents is investigated with the aim of their possible application in biomedicine. We found that the choice of boron precursor is a critically important parameter controlling the hBNs crystallinity and dependently influencing the biodegradation rate. PMID- 29977890 TI - The Emerging Role of microRNAs in Aquaporin Regulation. AB - Aquaporins (AQPs) are membrane channels widely distributed in human tissues. AQPs are essential for water and energy homeostasis being involved in a broad range of pathophysiological processes such as edema, brain injury, glaucoma, nephrogenic diabetes insipidus, salivary and lacrimal gland dysfunction, cancer, obesity and related metabolic complications. Compelling evidence indicates that AQPs are targets for therapeutic intervention with potential broad application. Nevertheless, efficient AQP modulators have been difficult to find due to either lack of selectivity and stability, or associated toxicity that hamper in vivo studies. MicroRNAs (miRNAs) are naturally occurring small non-coding RNAs that regulate post-transcriptional gene expression and are involved in several diseases. Recent identification of miRNAs as endogenous modulators of AQP expression provides an alternative approach to target these proteins and opens new perspectives for therapeutic applications. This mini-review compiles the current knowledge of miRNA interaction with AQPs highlighting miRNA potential for regulation of AQP-based disorders. PMID- 29977892 TI - Incremental Shuttle Walking Test Distance Is Reduced in Patients With Pulmonary Hypertension in World Health Organisation Functional Class I. AB - Background: There is increasing interest in screening for and diagnosing pulmonary hypertension earlier in the course of disease. However, there is limited data on cardiopulmonary abnormalities in patients with pulmonary hypertension newly diagnosed in World Health Organization Function Class (WHO FC) I. Methods: Data were retrieved from the ASPIRE registry (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral center) for consecutive treatment naive patients diagnosed with pulmonary hypertension by cardiac catheterization between 2001 and 2010 who underwent incremental shuttle walk exercise testing. Results: Eight hundred and ninety-five patients were diagnosed with Group 1-5 pulmonary hypertension. Despite the absence of symptoms, patients in WHO FC I (n = 9) had a significant reduction in exercise capacity (Incremental shuttle walk distance percent predicted (ISWD%pred) 65 +/- 13%, Z score -1.77 +/- 1.05), and modest pulmonary hypertension with a median (interquartile range) pulmonary artery pressure 31(20) mmHg and pulmonary vascular resistance 2.1(8.2) Wood Units, despite a normal diffusion of carbon monoxide adjusted for age and sex (DLco)%pred 99 +/- 40%. Compared to patients in WHO FC I, patients in WHO FC II (n = 162) had a lower ISWD%pred 43 +/- 22 and lower DLco%pred 65 +/- 21%. Conclusion: Our results demonstrate that patients with newly diagnosed pulmonary hypertension with no or minimal symptomatic limitation have a significant reduction of exercise capacity. PMID- 29977893 TI - Peak MSC-Are We There Yet? AB - Human mesenchymal stem cells (hMSCs) are a critical raw material for many regenerative medicine products, including cell-based therapies, engineered tissues, or combination products, and are on the brink of radically changing how the world of medicine operates. Their unique characteristics, potential to treat many indications, and established safety profile in more than 800 clinical trials have contributed to their current consumption and will only fuel future demand. Given the large target patient populations with typical dose sizes of 10's to 100's of millions of cells per patient, and engineered tissues being constructed with 100's of millions to billions of cells, an unprecedented demand has been created for hMSCs. The fulfillment of this demand faces an uphill challenge in the limited availability of large quantities of pharmaceutical grade hMSCs for the industry-fueling the need for parallel rapid advancements in the biomanufacturing of this living critical raw material. Simply put, hMSCs are no different than technologies like transistors, as they are a highly technical and modular product that requires stringent control over manufacturing that can allow for high quality and consistent performance. As hMSC manufacturing processes are optimized, it predicts a future time of abundance for hMSCs, where scientists and researchers around the world will have access to a consistent and readily available supply of high quality, standardized, and economical pharmaceutical grade product to buy off the shelf for their applications and drive product development-this is "Peak MSC." PMID- 29977894 TI - A Review of the Use of Linear Programming to Optimize Diets, Nutritiously, Economically and Environmentally. AB - The "Diet Problem" (the search of a low-cost diet that would meet the nutritional needs of a US Army soldier) is characterized by a long history, whereas most solutions for comparable diet problems were developed in 2000 or later, during which computers with large calculation capacities became widely available and linear programming (LP) tools were developed. Based on the selected literature (52 papers), LP can be applied to a variety of diet problems, from food aid, national food programmes, and dietary guidelines to individual issues. This review describes the developments in the search for constraints. After nutritional constraints, costs constraints, acceptability constraints and ecological constraints were introduced. The 12 studies that apply ecological constraints were analyzed and compared in detail. Most studies have used nutritional constraints and cost constraints in the analysis of dietary problems and solutions, but such research begin showing weaknesses under situations featuring a small number of food items and/or nutritional constraints. Introducing acceptability constraints is recommended, but no study has provided the ultimate solution to calculating acceptability. Future possibilities lie in finding LP solutions for diets by combining nutritional, costs, ecological and acceptability constraints. LP is an important tool for environmental optimization and shows considerable potential as an instrument for finding solutions to a variety of very complex diet problems. PMID- 29977896 TI - Pre-calving Intravaginal Administration of Lactic Acid Bacteria Reduces Metritis Prevalence and Regulates Blood Neutrophil Gene Expression After Calving in Dairy Cattle. AB - Metritis affects up to 40% of dairy cows and it is usually treated with antibiotics. In spite of their advantages, there is an increased concern about antibiotic resistance leading to the research of alternative methods. The aim of this study was to evaluate the effects of a combination of lactic acid bacteria (LAB) on the prevalence of metritis and modulation of endometrial and neutrophil inflammatory markers in dairy cows. One hundred and thirty-five cows were enrolled 3 week before calving and randomly assigned to three treatments. Treatment groups were: (1) two intravaginal doses of LAB/wk during 3 week pre calving (vaginal, n = 45); (2) an intra-uterine dose, once 1 d after calving (uterine, n = 44); and (3) no intervention (CTRL, n = 45). Metritis was defined as body temperature > 39.5 degrees C and purulent vaginal discharge (> 50% pus), and diagnosed 6 d after calving. Blood samples were taken at d -14, -10, -7, -4, +1, +3, +6, and +14 relative to calving for non-esterified fatty acids (NEFA) analysis. At d -10, +1, +3, and +6 neutrophils were isolated from blood for gene expression analysis by RT-qPCR. Endometrium biopsies were taken from 30 cows, 15 from CTRL and 15 from the uterine group at d +1, +3, and +6 after calving for pro inflammatory markers analysis by NanoString(r). Vaginal treatment reduced metritis prevalence (6/45) up to 58% compared with CTRL group (14/45), but there was no difference between the uterine and CTRL group. Uterine and vaginal treatments reduced blood neutrophil gene expression. Expression of pro inflammatory markers in the endometrium did not differ between uterine and CTRL cows. Metritic cows expressed more C-X-C motif chemokine ligand 8 (CXCL8) and interleukin 1 beta (IL1B) at d 3 than healthy cows, whereas healthy cows expressed more CXCL8 at d 1 relative to calving in the endometrium. This study shows a promising potential of LAB probiotics as a preventive treatment against metritis in dairy cows. PMID- 29977895 TI - Evaluating Potential Biomarkers of Health and Performance in Veal Calves. AB - Veal calves undergo many challenges in the early stages of their life. Such challenges, including mixing procedures and transportation of calves to the veal farm, may have a negative influence on growth rate, feed intake, metabolism, immunity and disease susceptibility of calves. As a consequence, many hematological, physiological, metabolic and immunological parameters of stressed calves might be altered on arrival at the veal farm. Some of these response variables might be useful as biomarkers of performance of calves at the veal farm as they might provide information about an ongoing disease process, or may predict future diseases. Biomarkers might be helpful to group and manage calves in different risk categories after arrival. By adopting treatment decisions and protocols on a risk-group or individual basis, it would be possible to improve animal health and reduce both disease incidence and antibiotic use. Moreover, the use of biomarkers might be an economically feasible approach as some of them do not need invasive techniques and others can be measured in blood already taken during routine checks. Previous literature mainly assessed the physiological responses of calves to transportation. However, information on the link between on-farm arrival data and future health and performance of veal calves is limited. This review, therefore, examined a wide range of papers and aimed to identify potential biomarkers of future health and performance. PMID- 29977897 TI - Modeling Dynamic Human Behavioral Changes in Animal Disease Models: Challenges and Opportunities for Addressing Bias. AB - Over the past several decades, infectious disease modeling has become an essential tool for creating counterfactual scenarios that allow the effectiveness of different disease control policies to be evaluated prior to implementation in the real world. For livestock diseases, these models have become increasingly sophisticated as researchers have gained access to rich national livestock traceability databases, which enables inclusion of explicit spatial and temporal patterns in animal movements through network-based approaches. However, there are still many limitations in how we currently model animal disease dynamics. Critical among these is that many models make the assumption that human behaviors remain constant over time. As many studies have shown, livestock owners change their behaviors around trading, on-farm biosecurity, and disease management in response to complex factors such as increased awareness of disease risks, pressure to conform with social expectations, and the direct imposition of new national animal health regulations; all of which may significantly influence how a disease spreads within and between farms. Failing to account for these dynamics may produce a substantial layer of bias in infectious disease models, yet surprisingly little is currently known about the effects on model inferences. Here, we review the growing evidence on why these assumptions matter. We summarize the current knowledge about farmers' behavioral change in on-farm biosecurity and livestock trading practices and highlight the knowledge gaps that prohibit these behavioral changes from being incorporated into disease modeling frameworks. We suggest this knowledge gap can be filled only by more empirical longitudinal studies on farmers' behavioral change as well as theoretical modeling studies that can help to identify human behavioral changes that are important in disease transmission dynamics. Moreover, we contend it is time to shift our research approach: from modeling a single disease to modeling interactions between multiple diseases and from modeling a single farmer behavior to modeling interdependencies between multiple behaviors. In order to solve these challenges, there is a strong need for interdisciplinary collaboration across a wide range of fields including animal health, epidemiology, sociology, and animal welfare. PMID- 29977899 TI - Interaction of smoking with respiratory effects of occupational dust exposure: a prospective population study among Norwegian men. AB - Dust at work is associated with risk of respiratory symptoms, the population attributable fraction is 19, and smoking is an effect modifier http://ow.ly/w0RF30jUL2Z. PMID- 29977898 TI - Summary of the international clinical guidelines for the management of hospital acquired and ventilator-acquired pneumonia. AB - A summary of the evidence and recommendations made in the ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator associated pneumonia http://ow.ly/S3zA30iZfLa. PMID- 29977900 TI - Analysis of pulmonary features and treatment approaches in the COPA syndrome. AB - The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment. PMID- 29977901 TI - Prevalence and Risk Factors of Asthma and Allergy-Related Diseases among Adolescents (PERFORMANCE) study: rationale and methods. AB - Despite a considerable number of international reports on allergic diseases among children, information about the prevalence and risk factors of asthma and allergy related diseases among Indian adolescents is relatively sparse. The Prevalence and Risk Factors of Asthma and Allergy-Related Diseases among Adolescents (PERFORMANCE) study has been conceived to study the aetiology of asthma and allergic diseases including rhinoconjunctivitis, atopic eczema and food allergies among adolescents in West Bengal, India, using standardised methods and collaborations. The aims of the study are: 1) to estimate the prevalence and risk factors of asthma and allergic diseases among the adolescents residing in rural, suburban and urban areas of West Bengal; 2) to obtain information about the possible role of lifestyle factors (smoking, diet and physical activity) on the disease prevalence; and 3) to create a network for further investigation on social, environmental and genetic factors affecting the diseases. The PERFORMANCE study comprises two phases. The phase I study will investigate the prevalence and possible contributing factors of asthma and allergic diseases in a defined population. The phase II study will be performed as a follow-up of phase I to assess the incidence of asthma and allergic diseases. PMID- 29977903 TI - The Genetic Diversity and Geographic Differentiation of the Wild Soybean in Northeast China Based on Nuclear Microsatellite Variation. AB - In this study, the genetic diversity and population structure of 205 wild soybean core collections in Northeast China from nine latitude populations and nine longitude populations were evaluated using SSR markers. A total of 973 alleles were detected by 43 SSR loci, and the average number of alleles per locus was 22.628. The mean Shannon information index (I) and the mean expected heterozygosity were 2.528 and 0.879, respectively. At the population level, the regions of 42 degrees N and 124 degrees E had the highest genetic diversity among all latitudes and longitudes. The greater the difference in latitude was, the greater the genetic distance was, whereas a similar trend was not found in longitude populations. Three main clusters (1N, <41 degrees N-42 degrees N; 2N, 43 degrees N-44 degrees N; and 3N, 45 degrees N->49 degrees N) were assigned to populations. AMOVA analysis showed that the genetic differentiation among latitude and longitude populations was 0.088 and 0.058, respectively, and the majority of genetic variation occurred within populations. The Mantel test revealed that genetic distance was significantly correlated with geographical distance (r = 0.207, p < 0.05). Furthermore, spatial autocorrelation analysis showed that there was a spatial structure (omega = 119.58, p < 0.01) and the correlation coefficient (r) decreased as distance increased within a radius of 250 km. PMID- 29977902 TI - Prevention of aerosol isolation of nontuberculous mycobacterium from the patient's bathroom. AB - Reinfection of nontuberculous mycobacterium pulmonary disease may be caused by identical and not different genotypes http://ow.ly/62cH30krdpa. PMID- 29977904 TI - Medication Noncompliance among Patients with Chronic Diseases Attending a Primary Health Facility in a Periurban District in Ghana. AB - Background: Despite the growing interest in understanding the aetiology of chronic diseases, limited studies exist on medication noncompliance, especially, among periurban and rural dwellers in Ghana. In this study, we determined the prevalence of medication noncompliance and explored the medication intake behaviour of patients with chronic diseases. The relative influence of cost on medication noncompliance and the risk factors for noncompliance were also assessed. Methods: The design was a cross-sectional study of 200 patients from ages below 40 years to ages above 60 years sampled from the Offinso South Municipality, a periurban district of the Ashanti region of Ghana. Data collected through the administration of structured questionnaires was coded, cleaned, and analysed using the SPSS (v20) software programme. Descriptive and multivariate analyses using binary logistic regression were performed. Results: Medication noncompliance was high (55.5%), with patients living with HIV/AIDS and those with psychological disorders being the most noncompliant. Majority of patients took at least 2 medications (81.5%), did so twice daily (79.0%), did not experience side effects with intake (67.0%), considered their medication to be effective (88.5%), and were aware of the complications that could arise from noncompliance. The dominant route of medication intake was oral (86.8%) and a lesser proportion of patients (22.5%) took herbal preparation alongside their prescribed medications. The cost of medication did not prevent patients from adhering to their medication regimen as most of these drugs were covered by the National Health Insurance Scheme (NHIS). Age, duration of diagnosis and difficulty in remembering medication instructions were identified as significant predictors of noncompliance. Conclusion: Educating patients on the need to be compliant with their medication regimen, the complications that could arise from noncompliance and avoidance of intake of herbal medications during their treatment should form part of the clinical sessions organized for patients with chronic conditions. PMID- 29977905 TI - Effects of Roasting Temperature and Time on the Chemical Composition of Argan Oil. AB - This work aimed at assessing the effects of roasting temperature and duration on chemical composition of argan oil. Thus, argan oils extracted from almonds roasted at different temperatures (75-175 degrees C) and times (10-30 min) were analyzed and compared to a control. The physicochemical parameters (acidity, peroxide value, and absorbance at 232, 270 nm) increased slightly and the fatty acid composition did not show significant variation, regardless of roasting temperature and duration. The browning index increased significantly for temperatures greater than or equal to 100 degrees C. The tocopherols content significantly decreased with roasting temperature and time (from 977.9 to 305.2 mg/kg after roasting at 175 degrees C for 10 min). However, fluctuations are noted as a function of temperature. The phospholipids content increased with roasting temperature and time (from 0.198 % to 1.370 % after roasting at 175 degrees C for 30 min). The decrease in the tocopherols content would be due to their thermolability. The increase in phospholipids and tocopherols content could be explained by better extractability. The results obtained make it possible to conclude that a roasting at 125-150 degrees C / 10 min would allow the development of the organoleptic properties of the oil, notably its hazelnut flavour, without compromising its oxidative stability. PMID- 29977906 TI - Effects of Acidification and Preservatives on Microbial Growth during Storage of Orange Fleshed Sweet Potato Puree. AB - Orange Fleshed Sweet Potato (OFSP) puree, a versatile food ingredient, is highly perishable limiting its use in resource constrained environments. It is therefore important to develop shelf-stable puree. A challenge test study was carried out to determine the effect of combinations of chemical preservatives and acidification on microbial growth in stored puree. Puree was prepared and treated as follows: control (A); 0.05% potassium sorbate+0.05% sodium benzoate+1% citric acid (B); 0.1% potassium sorbate+0.1% sodium benzoate+1% citric acid (C); 0.2% potassium sorbate+0.2% sodium benzoate+1% citric acid (D); 1% citric acid (E). Samples were inoculated with Escherichia coli and Staphylococcus aureus at levels of 5.2 x 109 cfu/100g and 1.5 x 109 cfu/100g, respectively, before being evaluated during storage for 10 weeks at prevailing ambient temperature (15-25 degrees C) and refrigeration temperature (4 degrees C). Total aerobic counts, yeasts, and molds were also evaluated. E. coli and S. aureus counts declined significantly (p<0.05) by 4 log cycles in all puree treatments except for control and puree with only citric acid. Total viable count, yeasts, and molds were completely inhibited except for puree with only citric acid. Combination of chemical preservatives and acidification is effective in inhibiting pathogens and spoilage microorganisms in sweet potato puree. PMID- 29977907 TI - Nephrotoxicity Evaluation on Cisplatin Combined with 5-HT3 Receptor Antagonists: A Retrospective Study. AB - Objective: 5-HT3 receptor antagonist (ondansetron) has been reported to have nephrotoxic effect when combined with cisplatin in mice; however, little evidence exists in explaining its nephrotoxic effects on patients. The aim of this present study was to investigate whether 5-HT3 receptor antagonist could enhance or aggravate the incidence of cisplatin-induced nephrotoxicity in patients. Methods: We retrospectively reviewed 600 tumor patients which were treated with cisplatin (?60 mg/m2) as a first-time chemotherapy and combined with 5-HT3 receptor antagonist (i.e., ondansetron, tropisetron, or ramosetron, each kind of 5-HT3 receptor antagonist contains 200 cases) between January 2010 and December 2015. Cisplatin dosing, the baseline creatinine clearance, and other independent risk factors such as patient's age, sex, PS score, and weight associated with nephrotoxicity were evaluated in a multivariable model. Results: The incidence of Grade ? 2 serum creatinine elevation in cisplatin + ondansetron group was significantly higher than cisplatin + tropisetron group (P = 0.04), but no significant difference was found between cisplatin + ondansetron group and cisplatin + ramosetron group (P = 0.3). It was also found that cisplatin dosage and tumor type were independent risk factors in the development of nephrotoxicity. Conclusion: Higher cisplatin dosage and regular use of ondansetron combined with cisplatin are more likely to increase the incidence of nephrotoxicity; tropisetron showed the relatively mild effect on kidney function, suggesting that tropisetron is a preferable alternative in the process of cisplatin chemotherapy. PMID- 29977908 TI - Characterization of Atherosclerosis Formation in a Murine Model of Type IIa Human Familial Hypercholesterolemia. AB - A murine genetic model of LDL-cholesterol- (LDL-C-) driven atherosclerosis, based on complete deficiencies of both the LDL-receptor (Ldlr-/-) and key catalytic component of an apolipoprotein B-edisome complex (Apobec1-/-), which converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks. The general characteristics include the presence of high levels of LDL-C in plasma and macrophage-related fatty streak formation in the aortic tree, which progressively worsens with age. More specifically, plaque found in the aortic sinuses contains a lipid core with relatively high numbers of macrophages and a smooth muscle cell alpha-actin- and collagen-containing cap, which thins with age. These critical features of plaque progression suggest that the Ldlr-/-/Apobec1-/- mouse line presents a superior model of LDL-C-driven atherosclerosis. PMID- 29977909 TI - Sleep Quality of Functional Gastrointestinal Disorder Patients in Class-Three Hospitals: A Cross-Sectional Study in Tianjin, China. AB - Background: Functional gastrointestinal disorder (FGID) patients are influenced by anxiety, depression, and low sleep quality, which reduce the quality of their life. However, epidemiological data on the quality of sleep in FGID patients were lacking. This study aims to explore the sleep quality and influencing factors of the sleep quality in FGID patients. Methods: 1200 subjects, diagnosed as FGID in one of the six class-three hospitals in Tianjin, China, from January to December 2014, were recruited. The information about demographic information, the severity of clinical symptoms, psychological status (Zung self-rating depression scale), and sleep quality (evaluated with Pittsburgh sleep quality index) was gathered. Results: The questionnaires from 1117 participants were collected including 920 of functional dyspepsia (FD) patients, 77 of irritable bowel disease (IBS) patients, 26 of functional constipation (FC) patients, and 94 other FGID patients. The results showed that morbidity rate for FD patients who had sleep disorders was higher than those who suffered from IBS or FC (P < 0.001). The proportion of elderly patients suffering from low sleep quality was higher than that of middle-aged and young patients (P < 0.001). The binary logistic regression analysis showed that age, education, and the severity of FGID symptom were influencing factors for poor sleep quality in FGID patients. Conclusion: The issue of poor sleep quality in FGID patients in Tianjin area is prominent, and elderly patients suffer lower sleep quality than other FGID patients. Age, education, and the severity of FGID symptoms are critical influencing factors which result in a drop-in sleep quality. PMID- 29977910 TI - Novel Intravaginal Drug Delivery System Based on Molecularly PEGylated Lipid Matrices for Improved Antifungal Activity of Miconazole Nitrate. AB - The aim of this study was to investigate the potential of microparticles based on biocompatible phytolipids [Softisan(r) 154 (SF) (hydrogenated palm oil) and super refined sunseed oil (SO)] and polyethylene glycol- (PEG-) 4000 to improve intravaginal delivery of miconazole nitrate (MN) for effective treatment of vulvovaginal candidiasis (VVC). Lipid matrices (LMs) consisting of rational blends of SF and SO with or without PEG-4000 were prepared by fusion and characterized and employed to formulate MN-loaded solid lipid microparticles (SLMs) by melt-homogenization. The SLMs were characterized for physicochemical properties, anticandidal activity, and stability. Spherical discrete microparticles with good physicochemical properties and mean diameters suitable for vaginal drug delivery were obtained. Formulations based on SO:SF (1:9) and containing highest concentrations of PEG-4000 (4 %w/w) and MN (3.0 %w/w) were stable and gave highest encapsulation efficiency (83.05-87.75%) and inhibition zone diameter (25.87+/-0.94-26.33+/-0.94 mm) and significantly (p<0.05) faster and more powerful fungicidal activity regarding killing rate constant values (7.10 x 10-3-1.09 x 10-2 min-1) than commercial topical solution of MN (Fungusol(r)) (8.00 x 10-3 min-1) and pure MN sample (5.160 x 10-3 min-1). This study has shown that MN-loaded SLMs based on molecularly PEGylated lipid matrices could provide a better option to deal with VVC. PMID- 29977911 TI - FNDC4 Inhibits RANKL-Induced Osteoclast Formation by Suppressing NF-kappaB Activation and CXCL10 Expression. AB - FNDC4 acts as an anti-inflammatory factor on macrophages and improves mouse model of induced colitis. Considering osteoclast formation is characterized by the activation of inflammation-related pathways, we thus speculated that FNDC4 may play a pivotal role in this process. RT-qPCR analysis was performed to confirm the expression of osteoclast formation related genes in primary murine bone marrow macrophages (BMMs). RANKL-treated BMMs were cultured with FNDC4 to evaluate the effect of FNDC4 on osteoclast differentiation. TRAP staining and bone resorption pits assay were used to assess osteoclast formation and bone resorption, respectively. Luciferase assay and western blotting analysis were conducted to determine whether FNDC4 inhibited osteoclast formation via NF-kappaB signaling in RAW 264.7 cells. Furthermore, to identify gene signatures in FNDC4 treated BMMs and to use these to elucidate the underlying molecular mechanisms during osteoclast formation, we adopted a bioinformatics approach by downloading the GSE76172 gene expression profiling dataset from the Gene Expression Omnibus (GEO) database. FNDC4 inhibited RANKL-induced osteoclastogenesis and mature osteoclast resorptive function in a dose-dependent manner. Results of NF-kappaB luciferase assay suggested that FNDC4 could significantly suppress the RANKL induced NF-kappaB transcriptional activity. Based on the protein-protein interaction network, CXCL10 was identified as the differentially expressed gene with the highest connectivity degree (degree = 23); it was drastically downregulated in the presence of FNDC4, but supplementation of CXCL10 (10 ng/mL) partially ameliorated the FNDC4-induced inhibition of osteoclast formation. Taken together, we speculated that FNDC4 could suppress osteoclast formation via NF kappaB pathway and downregulation of CXCL10. PMID- 29977912 TI - Feasibility of Infrarenal Abdominal Aorta Balloon Occlusion in Pernicious Placenta Previa Coexisting with Placenta Accrete. AB - Objective: To evaluate the efficacy and safety of prophylactic balloon occlusion of the infrarenal abdominal aorta in pernicious placenta previa coexisting with placenta accrete. Methods: This retrospective study was performed in patients with placenta accreta complicated with pernicious placenta previa between January 2014 and December 2016 in Shengjing Hospital; 56 patients with a pathological diagnosis were included. The degree of placental invasion was evaluated by preoperative color Doppler ultrasonography and/or magnetic resonance imaging, and all patients in this study should undergo balloon occlusion preoperatively, which was a determination made by specific doctors. The control group consisted of 32 patients who underwent cesarean section alone, and the study group included 24 patients who underwent cesarean section with preoperative balloon occlusion. Prevention of hysterectomy was the primary outcome evaluated. The secondary outcomes include operative duration, estimated blood loss, blood transfusion, prothrombin time postoperatively, decrease in the hemoglobin level postoperatively, intensive care unit admission, pathological diagnosis, and total hospital stay (days), and these data were compared between the two groups. Additionally, the neonatal outcomes, premature delivery, Apgar scores at 1 minute and 5 minutes, neonatal birth weight, hospitalization, and mortality were compared. Results: There was a significant difference in the rate of hysterectomy between the two groups (p<0.05). However, no differences were observed between the groups in any other outcomes. Conclusion: The prophylactic use of infrarenal abdominal aortic balloon occlusion is an effective and safe option for treating pernicious placenta previa coexisting with placenta accreta. PMID- 29977913 TI - The Central Role of the Inflammatory Response in Understanding the Heterogeneity of Sepsis-3. AB - In sepsis-3, in contrast with sepsis-1, the definition "systemic inflammatory response" has been replaced with "dysregulated host response", and "systemic inflammatory response syndrome" (SIRS) has been replaced with "sequential organ failure assessment" (SOFA). Although the definition of sepsis has changed, the debate regarding its nature is ongoing. What are the fundamental processes controlling sepsis-induced inflammation, immunosuppression, or organ failure? In this review, we discuss the heterogeneity of sepsis-3 and address the central role of inflammation in the pathogenesis of sepsis. An unbalanced pro- and anti inflammatory response, inflammatory resolution disorder, and persistent inflammation play important roles in the acute and/or chronic phases of sepsis. Moreover, powerful links exist between inflammation and other host responses (such as the neuroendocrine response, coagulation, and immunosuppression). We suggest that a comprehensive evaluation of the role of the inflammatory response will improve our understanding of the heterogeneity of sepsis. PMID- 29977914 TI - Wee1 Inhibitor AZD1775 Combined with Cisplatin Potentiates Anticancer Activity against Gastric Cancer by Increasing DNA Damage and Cell Apoptosis. AB - Based on the mechanisms by which Wee1 inhibitor and cisplatin played their own role, a promising strategy of Wee1 inhibitor combined with cisplatin was proposed, which was investigated in gastric cancer (GC). Either Wee1 inhibitor AZD1775 or cisplatin alone had a certain inhibitory effect on in vitro cell proliferation; however, the inhibitory effect was more significant when AZD1775 combined with cisplatin in vitro and in vivo. The underlying mechanisms unveiled that the increased DNA damage indicated by increased gammaH2AX protein, as well as augmented cell apoptosis indicated by upregulated proapoptotic proteins, was responsible for the significant inhibitory effect of AZD1775 plus cisplatin. Moreover, compared to any single drug, in vitro cell migration and invasion abilities were further attenuated by AZD1775 combined with cisplatin. There were suggestive results that the potentiated cytotoxicity between AZD1775 and cisplatin deserved a deep exploration in the future. PMID- 29977915 TI - Impact of Leaf Development Stages on Polyphenolics Profile and Antioxidant Activity in Clausena lansium (Lour.) Skeels. AB - Clausena lansium (Lour.) Skeels, commonly known as "wampee," is an excellent food ingredient of medicinal value. Effects of leaf developmental stages on the composition of phenolics, flavonoids, and antioxidant activity were investigated. Phenolics composition was studied using HPLC-PAD, whereas antioxidant activity was estimated by oxygen radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays. Increase in bound flavonoids, quercetin, and cellular antioxidant activity was observed in bound and free fractions at different stages of leaf development. Predominantly, quercetin and ferulic acid contents were high in free and bound fractions of old leaves. In addition, phenolic components depicted highly significant positive association (p < 0.05) with antioxidant activity. Overall, old leaves of wampee have utility value similar to leaf buds, so they could be a more sustainable and economical source of bioactive compounds for commercial application in nutraceutical and pharmaceutical industries. PMID- 29977916 TI - EGF-Mediated Overexpression of Myc Attenuates miR-26b by Recruiting HDAC3 to Induce Epithelial-Mesenchymal Transition of Lens Epithelial Cells. AB - The previous study has demonstrated that epidermal growth factor (EGF) and EGF receptor (EGFR) signaling plays a critical role in the development of posterior capsule opacification (PCO) through regulating lens epithelial cells (LECs) proliferation. Recent studies have suggested that the residual LECs undergo proliferation and migration, and epithelial-mesenchymal transition (EMT) is the important cause of PCO formation after cataract surgery. EMT of LECs is considered to be playing a central role in the pathogenesis of PCO. In the present study, we investigated whether and how EGF may regulate EMT of LECs. First, we demonstrated that EGF and EGFR signaling induces Myc overexpression in primary human lens epithelial cells (HLECs). In turn, Myc overexpression could inhibit miR-26b by recruitment of HDAC3. Consequently, the downregulated expression of miR-26b increased the expression of EZH2 in primary HLECs. Mechanistically, miR-26b directly controls EZH2 expression by targeting its 3' UTR in HLECs by luciferase reporter assays. Finally, we demonstrated that EGF induces the expression of EMT markers in primary HLECs via a miR-26b-dependent mechanism. In summary, EGF activated Myc and Myc overexpression inhibited miR-26b by recruitment of HDAC3, which in turn induced the expression of EZH2 and promoted the progression of EMT in HLECs. PMID- 29977917 TI - Evaluation of the Accuracy of a System to Align Occlusal Dynamic Data on 3D Digital Casts. AB - In recent years the T-Scan system has introduced the possibility of importing digitization of dental arches to its registrations. This is a remarkable advance, which allows an intuitive display of the location of the gathered dynamic data on the denture. Nevertheless, today's usual method of manually positioning the arch in relation to the T-Scan's force registration gives rise to the possibility of human error. In order to guarantee a good alignment between the dynamic registration and 3D digital casts, a specific method was developed. The aim of this study is to evaluate the accuracy of this alignment method. For this purpose, it was compared with the most common procedure for detecting occlusal contacts, the articulating paper method. The comparison comprised overlapping digital models of both methods. Contacts of casts of 11 adults were registered, both with articulating paper and the T-Scan system. For one method, articulating paper marks were scanned in color; for the second method, the previously mentioned alignment was carried out with the T-Scan registrations. The results of both methods were overlapped in 3D digital casts, quantifying occlusal data matches. Statistical analyses were made to measure the quality of this alignment method. The study revealed a mean matching percentage of 79.02%, confirming the high reliability of the method. PMID- 29977918 TI - Does Adding Silver Nanoparticles to Leukocyte- and Platelet-Rich Fibrin Improve Its Properties? AB - Objectives: Leucocyte- and platelet-rich fibrin (L-PRF) membrane can be used in various regenerative treatments. In the case of classical heterologous membrane exposure, microorganisms can be colonized on it and jeopardize the success of treatment. The aim of this study was to compare the antibacterial, mechanical, and histologic characteristics of the L-PRF membrane before and after the addition of silver nanoparticles (SNP). Materials and Method: This study was performed on 10 volunteer men aged 25-35 years. 20 ml whole bloods were collected from each person and L-PRFs were made by routine and SNP modified method. Mechanical, antibacterial, and histological properties were evaluated. Results: The antibacterial efficacy of L-PRF and nanosilver-modified L-PRF was presented as Klebsiella pneumonia had growth on the L-PRF membrane after 12 hours. After 24 hours, Klebsiella pneumonia and Streptococcus viridans had growth on L-PRF and only Klebsiella pneumonia had growth on SNP-L-PRF. The tensile strength and stiffness were significantly higher in the SNP-L-PRF. Precipitation of the SNPs was patchy in the outer layers and quite homogeneous in the inner core. Conclusion: Modification of L-PRF with SNP improves the mechanical properties and antibacterial activity of the L-PRF. It can play an important role in regenerative procedures. PMID- 29977919 TI - Efficacy of Adjunctive Bioactive Materials in the Treatment of Periodontal Intrabony Defects: A Systematic Review and Meta-Analysis. AB - Objectives: Lots of bioactive materials have been additionally applied for the treatment of periodontal intrabony defect. However, there is dearth of studies to systematically evaluate the supplementary role of them in periodontal regeneration. The goal of this meta-analysis is to evaluate the adjunctive effects of bioactive materials such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF), enamel matrix derivative (EMD), and amnion membrane (AM) on the outcomes of bone grafting treatment for periodontal intrabony defects. Methods: Articles published before December 2017 were searched electronically in three databases (PubMed, Embase, and Cochrane Central), with no date or language limits. Randomized controlled trials (RCTs) on the assessment of effectiveness of the four biomaterials in conjunction with demineralized freeze-dried bone allografts (DFDBA) in the treatment of periodontal intrabony defects were enrolled in this meta-analysis. Data were analyzed with STATA 12. Results: Nine studies were included. PRF and PRP significantly improved pocket depth (PD) reduction and clinical attachment loss (CAL) gain. Only PRF exhibited a positive result in recession reduction (RecRed). Only PRP showed a statistically significant increase in bone fill. AM merely gained more CAL. EMD did not improve any clinical outcome. Conclusion: Our data suggest that PRF/PRP could be taken as a preferred adjunct to facilitate periodontal regeneration of intrabony defects. PMID- 29977920 TI - Awareness of Pleiotropic and Cardioprotective Effect of Statins in Patients with Coronary Artery Disease. AB - Background: Statins are commonly used in the secondary prevention of coronary artery disease. Studies have shown that the rate of statin use is low among patients with coronary artery disease. In this study, we aimed to investigate the reasons for poor patient compliance with statin treatment. Methods: A total of 504 patients diagnosed with coronary heart disease were included in the study. Patients were asked 5 questions to assess their level of knowledge about statin therapy. Results: Among the patients not using statins, 42% stated they did not take the medication because their cholesterol was not high or they did not know they should renew their prescription when they ran out and 35% because they were influenced by news reports in the media suggesting that cholesterol-lowering drugs were harmful. When patients who were aware of the pleiotropic/cardioprotective effects of statins were compared with patients who were not, the more knowledgeable patients had lower noncompliance rate and mean LDL-C level and a higher rate of LDL-C level optimization. Conclusion: We found that patients who are aware of the pleiotropic effects of statins were more compliant with treatment. We believe that spending more time explaining and emphasizing the mechanisms of action, reason for prescribing, and necessary treatment duration of drugs that patients must use will result in greater compliance and improve patient care. In this way, patients may be less influenced by misinformation presented by the media. PMID- 29977921 TI - Differentially Expressed MicroRNAs in Conservatively Treated Nontraumatic Osteonecrosis Compared with Healthy Controls. AB - Deregulation of microRNAs (miRNAs) contributes to nontraumatic osteonecrosis of the femoral head (ONFH-N), but the differentially expressed circulating miRNAs in patients with ONFH-N receiving nonsurgical therapy are unknown. This study aimed to determine the miRNAs expression profile of patients with ONFH-N receiving conservative treatments. This was a case-control prospective study of 43 patients with ONFH-N and 43 participants without ONFH-N, enrolled from 10/2014 to 10/2016 at the Department of Orthopedics of the Linyi People's Hospital (China). The two groups were matched for age, gender, and living area. Microarray analysis and quantitative RT-PCR were used to examine the differentially expressed miRNAs. Bioinformatics was used to predict miRNA target genes and signaling pathways. Microarray and quantitative RT-PCR revealed that nine miRNAs were downregulated and five miRNAs were upregulated in ONFH-N (n = 3) compared with controls (n = 3). Bioinformatics showed that calcium-mediated signaling pathway, regulation of calcium ion transmembrane transporter activity, cytoskeletal protein binding, and caveolae macromolecular signaling complex were probably regulated by the identified differentially expressed miRNAs. In the remaining 80 subjects (n = 40/group), miR-335-5p was downregulated (P = 0.01) and miR-100-5p was upregulated (P = 0.02) in ONFH-N compared with controls. In conclusion, some miRNAs are differentially expressed in conservatively treated ONFH-N compared with controls. Those miRNAs could contribute to the pathogenesis of ONFH-N. PMID- 29977922 TI - Sexuality after Male-to-Female Gender Affirmation Surgery. AB - Male-to-Female (MtF) gender affirmation surgery (GAS) comprises the creation of a functional and aesthetic perineogenital complex. This study aimed to evaluate the effect of GAS on sexuality. We retrospectively surveyed all 254 MtF transsexual patients who had undergone GAS with penile inversion vaginoplasty at the Department of Urology, University Hospital Essen, Germany, between 2004 and 2010. In total, we received 119 completed questionnaires after a median of 5.05 years since surgery. Of the study participants, 33.7% reported a heterosexual, 37.6% a lesbian, and 22.8% a bisexual orientation related to the self-perceived gender. Of those who had sexual intercourse, 55.8% rated their orgasms to be more intensive than before, with 20.8% who felt no difference. Most patients were satisfied with the sensitivity of the neoclitoris (73.9%) and with the depth of the neovaginal canal (67.1%). The self-estimated pleasure of sexual activity correlated significantly with neoclitoral sensitivity but not with neovaginal depth. There was a significant correlation between the ease with which patients were able to become sexually aroused and their ability to achieve orgasms. In conclusion, orgasms after surgery were experienced more intensely than before in the majority of women in our cohort and neoclitoral sensitivity seems to contribute to enjoyment of sexual activity to a greater extent than neovaginal depth. PMID- 29977924 TI - Extraskeletal Myxoid Chondrosarcoma: A Comparative Study of Imaging and Pathology. AB - The purpose of this study was to achieve better understanding of extraskeletal myxoid chondrosarcoma (EMC). 13 cases of EMC confirmed by surgery biopsy were retrospectively studied. All patients underwent preoperative CT or/and MRI examinations. Among six patients who underwent preoperative CT examinations, six cases of lesions exhibited hypodensity on unenhanced image, three cases of tumor showed funicular spots or patchy calcification, and four cases of tumor did not show any obvious enhancement after enhanced CT scan. Among ten patients who underwent preoperative MRI examination, 8 cases of tumor revealed uniform or slight hyposignal intensity on T1WI, 10 cases of tumor demonstrated lobulated hypersignal intensity with multiple low signal intensity of interval septa on T2WI, and 5 cases of lesions indicated characteristic appearance: septa enhancement with tumor stroma between interval septa being unenhanced. EMC usually occurred at older men and at certain location such as limbs, trunk, and subcutaneous tissues. EMC usually exhibited low density mass (mostly 20-40HU) with calcification and in a portion of the cases showed light or no enhancement on CT. On MRI, EMC showed lobulated hypersignal intensity on T2WI with characteristic arc, septa, or interval septa enhancement. PMID- 29977923 TI - Noninvasive Prenatal Testing: Comparison of Two Mappers and Influence in the Diagnostic Yield. AB - Objective: The aim of this study was to determine if the use of different mappers for NIPT may vary the results considerably. Methods: Peripheral blood was collected from 217 pregnant women, 58 pathological (34 pregnancies with trisomy 21, 18 with trisomy 18, and 6 with trisomy 13) and 159 euploid. MPS was performed following a manufacturer's modified protocol of semiconductor sequencing. Obtained reads were mapped with two different software programs: TMAP and HPG Aligner, comparing the results. Results: Using TMAP, 57 pathological samples were correctly detected (sensitivity 98.28%, specificity 93.08%): 33 samples as trisomy 21 (sensitivity 97.06%, specificity 99.45%), 16 as trisomy 18 (sensibility 88.89%, specificity 93.97%), and 6 as trisomy 13 (sensibility 100%, specificity 100%). 11 false positives, 1 false negative, and 2 samples incorrectly identified were obtained. Using HPG-Aligner, all the 58 pathological samples were correctly identified (sensibility 100%, specificity 96.86%): 34 as trisomy 21 (sensibility 100%, specificity 98.91%), 18 as trisomy 18 (sensibility 100%, specificity 98.99%), and 6 as trisomy 13 (sensibility 100%, specificity 99.53%). 5 false positives were obtained. Conclusion: Different mappers use slightly different algorithms, so the use of one mapper or another with the same batch file can provide different results. PMID- 29977925 TI - Risk Factors of Vulvovaginal Candidiasis among Women of Reproductive Age in Xi'an: A Cross-Sectional Study. AB - Purpose. To explore risk factors of vulvovaginal candidiasis (VVC) among women of reproductive age in Xi'an district and then to offer reference for clinical prevention and treatment of VVC. Methods. Patients from the outpatient department of gynecology and obstetrics in the First Affiliated Hospital of Xi'an Jiaotong University from June 2016 to May 2017 were recruited strictly according to the inclusion and exclusion criteria. Participants diagnosed as simple VVC were assigned to the case group, while women who underwent routine gynecological examination and had normal vaginal microflora were assigned to the control group. Then we conducted a questionnaire survey of the two groups and used the logistic regression model to explore the related risk factors of VVC. Results. In the present study, ninety-seven cases were sample VVC patients and eighty-seven cases were healthy women. This cross-sectional study showed that occasionally or never drinking sweet drinks (odds ratio [OR] =0.161, 95% confidence interval [CI] =0.056-0.462, P=0.001), occasionally or never eating sweet foods (OR=0.158, 95%CI=0.054-0.460, P=0.001), and the use of condom (OR=0.265, 95%CI=0.243-0.526, P=0.001) were regarded as protective factors for VVC. In addition, sedentary life style (OR=7.876, 95%CI=1.818-34.109, P=0.006), frequently wearing tights (OR=6.613, 95%CI=1.369-27.751, P=0.018), frequent intravaginal douching (OR=3.493, 95%CI=1.379-8.847, P=0.008), having the first sexual encounter when under 20 years old (OR=2.364, 95%CI=1.181-7.758, P=0.006), the number of sexual partners being over two (OR=3.222, 95%CI=1.042-9.960, P=0.042), history of curettage (OR=3.471, 95%CI=1.317-9.148, P=0.012), history of vaginitis (OR=8.999, 95%CI=2.816-28.760, P<0.001), and not cleaning the vulva before or after sexual encounters (OR=13.684, 95%CI=2.843-65.874, P=0.001) were considered to be risk factors of VVC. Conclusion. In conclusion, risk factors of VVC are various, involving ages, hygienic habits, disease history, and other aspects. PMID- 29977926 TI - Microsurgical Reconstruction of the Jaws Using Vascularised Free Flap Technique in Patients with Medication-Related Osteonecrosis: A Systematic Review. AB - Background: Osteonecrosis of the jaw (ONJ) has been reported to be associated with patients receiving primarily bisphosphonate (BP) therapies. However, lately it has been documented that other medications, such as RANK ligand inhibitor (denosumab) and antiangiogenic drug, can cause ONJ. Micro-osseous-vascular reconstruction of the jaws in patients affected by medication-related osteonecrosis of the jaw represents a viable option of treatment for patients affected by stage III of the disease. However, there are still considerable doubts about the success of this procedure in the short, medium, and long term. Material and Methods: A multidatabase (PubMed/MEDLINE, EMBASE, and CENTRAL) systematic search was performed. Any type of studies considering human patients treated with antiresorptive and antiangiogenic drugs was considered. The aim of the research is to primarily understand the success rate of micro-osseous vascular reconstruction in the short, medium, and long period of time. This review has also the goal of better understanding any perioperative and postoperative complications resulting from the use of the reconstruction techniques. Results: Eighteen studies resulted eligible for the study. Fibula free flap is the most commonly utilised vascularised free flap reconstruction technique (80.76%). Ten out of eighteen studies reported no complications. Recurrence of osteonecrosis was registered in five cases (6.41%) after free flap reconstruction. The overall free flap success rate was 96.16%. Conclusions: Based on the limited data available in literature (Level 4 of the Oxford Evidence-based medicine scale), micro-osseous-vascular reconstruction of the jaws represents a valid treatment in patients with bisphosphonate-related osteonecrosis at stage III of the disease. However, additional data based on a larger cohort of patients are necessary to justify this type of intervention in patient affected by MRONJ. PMID- 29977927 TI - Intravitreal Bevacizumab Injection Attenuates Diabetic Retinopathy in Adult Rats with Experimentally Induced Diabetes in the Early Stage. AB - Diabetic retinopathy is the leading cause of blindness, yet its treatment is very limited. Anti-VEGF drug has been widely applied in ocular disease, but its effects on diabetic retinopathy and the underlying mechanism have remained to be fully explored. To elucidate the role of anti-VEGF treatment, we sought to determine the effects of bevacizumab on diabetic neurovascular changes extending from the 3rd to 9th week with induced diabetes in adult rats. The retinal neurovascular changes included increased expression of VEGF, nNOS, iNOS, eNOS, and NO in the course of diabetes progression. In diabetic rats given bevacizumab injection, the ganglion cell loss and alterations of retinal thickness were ameliorated. In this connection, the immunofluorescence labeling of the above biomarkers was noticeably decreased. Along with this, Western blotting confirmed that bevacizumab treatment was associated with a decrease of VEGF, Flk-1, and cAMP response element binding and protein kinase C protein expression. The present results suggest that bevacizumab treatment in the early stage of the retinopathy may ameliorate the lesions of retinopathy, in which VEGF/Flk-1 signaling has been shown here to play an important role. PMID- 29977928 TI - B Cell Activating Factor, Renal Allograft Antibody-Mediated Rejection, and Long Term Outcome. AB - Antibody-mediated rejection (ABMR) of renal allograft lacks typical phenotypes and clinical manifestations, always resulting in delayed diagnosis and treatment. It has been considered to be an elemental factor influencing the improvement of the long-term outcome of renal allograft. The B cell activating factor (BAFF) signal plays a fundamental function in the process of antibody-mediated immune response. Data from recipients and the nonhuman primate ABMR model suggest that the BAFF signal participates in the ABMR of renal allograft, while there are objections. The challenges in the diagnosis of ABMR, different study population, and details of research may explain the discrepancy. Large quantities of dynamic, credible data of BAFF ligands and their association with renal allograft pathological characteristics would constitute a direct proof of the role of BAFF in the progression of renal allograft ABMR. PMID- 29977929 TI - Autoimmune Diseases and Their Manifestations on Oral Cavity: Diagnosis and Clinical Management. AB - Oral signs are frequently the first manifestation of autoimmune diseases. For this reason, dentists play an important role in the detection of emerging autoimmune pathologies. Indeed, an early diagnosis can play a decisive role in improving the quality of treatment strategies as well as quality of life. This can be obtained thanks to specific knowledge of oral manifestations of autoimmune diseases. This review is aimed at describing oral presentations, diagnosis, and treatment strategies for systemic lupus erythematosus, Sjogren syndrome, pemphigus vulgaris, mucous membrane pemphigoid, and Behcet disease. PMID- 29977930 TI - TRIF Regulates BIC/miR-155 via the ERK Signaling Pathway to Control the ox-LDL Induced Macrophage Inflammatory Response. AB - Toll/IL-1R-domain-containing adaptor-inducing IFN-beta (TRIF) is an important adaptor for TLR3- and TLR4-mediated inflammatory signaling pathways. Recent studies have shown that TRIF plays a key role in vessel inflammation and atherosclerosis; however, the precise mechanisms are unclear. We investigated the mechanisms of the TRIF-regulated inflammatory response in RAW264.7 macrophages under oxidized low-density lipoprotein (ox-LDL) stimulation. Our data show that ox-LDL induces TRIF, miR-155, and BIC expression, activates the ERK1/2 and SOCS1 STAT3-NF-kappaB signaling pathways, and elevates the levels of IL-6 and TNF-alpha in RAW264.7 cells. Knockdown of TRIF using TRIF siRNA suppressed BIC, miR-155, IL 6, and TNF-alpha expression and inhibited the ERK1/2 and SOCS1-STAT3-NF-kappaB signaling pathways. Inhibition of ERK1/2 signaling also suppressed BIC and miR 155 expression. These findings suggest that TRIF plays an important role in regulating the ox-LDL-induced macrophage inflammatory response and that TRIF modulates the expression of BIC/miR-155 and the downstream SOCS1-STAT3-NF-kappaB signaling pathway via ERK1/2. Therefore, TRIF might be a novel therapeutic target for atherosclerosis. PMID- 29977931 TI - LCK as a Potential Therapeutic Target for Acute Rejection after Kidney Transplantation: A Bioinformatics Clue. AB - Objectives: We aim to identify the key biomarker of acute rejection (AR) after kidney transplantation via bioinformatics methods. Methods: The gene expression data GSE75693 of 30 samples with stable kidney transplantation recipients and 15 AR samples were downloaded and analyzed by the limma package to identify differentially expressed genes (DEGs). Then, Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were done to explore the biological functions and potential important pathways of DEGs. Finally, protein-protein interactions (PPIs) and literature mining were applied to construct the cocitation network and to select the hub protein. Results: A total of 437 upregulated genes and 353 downregulated genes were selected according to P < 0.01 and |log2(fold change)| > 1.0. DEGs of AR are mainly located on membranes and impact the activation of receptors in immune responses. In the PPI network, Src kinase, lymphocyte kinase (LCK), CD3G, B2M, interferon-gamma, CD3D, tumor necrosis factor, VAV1, and CD3E in the T cell receptor signaling pathway were selected as important factors, and LCK was identified as the hub protein. Conclusion: LCK, via acting on T-cell receptor, might be a potential therapeutic target for AR after kidney transplantation. PMID- 29977932 TI - MicroRNA in Sjogren's Syndrome: Their Potential Roles in Pathogenesis and Diagnosis. AB - Sjogren's syndrome (SS) or sicca syndrome was described by Swedish ophthalmologist Sjogren in the year 1933 for the first time. The etiology of the SS is multifunctional and includes a combination of genetic predisposition and environmental as well as epigenetic factors. It is an autoimmune disease characterized by features of systemic autoimmunity, dysfunction, and inflammation in the exocrine glands (mainly salivary and lacrimal glands) and lymphocytic infiltration of exocrine glands. In fact, the involvement of lacrimal and salivary glands results in the typical features of dry eye and salivary dysfunction (xerostomia). Only in one-third of the patients also present systemic extraglandular manifestations. T cells were originally considered to play the initiating role in the autoimmune process, while B cells were restricted to autoantibody production. In recent years, it is understood that the roles of B cells are multiple. Moreover, autoantibodies and blood B cell analysis are major contributors to a clinical diagnosis of Sjogren's syndrome. Recently, there has been rising interest in microRNA implication in autoimmunity. Unfortunately, to date, there are only a few studies that have investigated their participation in SS etiopathogenesis. The purpose of this work is to gather the data present in the literature to clarify this complex topic. PMID- 29977934 TI - Endoscopic Retrograde Cholangiopancreatography-Induced Splenic Injury in a Patient With Sleeve Gastrectomy. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive procedure with significant complications. Splenic hematoma is an extremely rare but known complication following ERCP that has been increasingly reported in the past several years. We report the case of a 44-year-old patient with a history of sleeve gastrectomy who underwent an ERCP that was complicated by both acute pancreatitis and splenic hematoma. She was managed conservatively under close monitoring in the intensive care unit. Clinicians should be aware of this potentially life-threatening complication to make a prompt diagnosis and begin early appropriate management. PMID- 29977933 TI - Expression of Galphaq Is Decreased in Lymphocytes from Primary Sjogren's Syndrome Patients and Related to Increased IL-17A Expression. AB - Primary Sjogren's syndrome (pSS) is a rheumatic disease characterized by the destruction of salivary and lacrimal glands, and its pathogenesis mechanism remains unclear. Galphaq is the alpha-subunit of the heterotrimeric Gq protein. Researches demonstrated that Galphaq was involved in the pathogenesis regulation of several rheumatic diseases. This study explored the role of Galphaq in pSS. Galphaq mRNA levels in peripheral blood mononuclear cells (PBMCs) from 39 patients and 26 healthy controls (HCs) were investigated using real-time PCR. IL 17A serum concentrations in 22 pSS patients and 23 HCs were tested by ELISA, and the clinical significance of Galphaq was analyzed. The association of Galphaq with interleukin-17A (IL-17A) expression was also analyzed in patients with pSS. We showed that Galphaq expression in PBMCs from patients with pSS was significantly lower than that in PBMCs from HCs. Galphaq expression level was closely associated with pSS disease activity. Furthermore, a negative association was also found in IL-17A and Galphaq expression level. These data suggest that Galphaq is involved in pSS pathogenesis regulation, possibly due to its regulation of Th17. These results provide new insights into the pSS pathogenesis mechanism involving abnormal Th17 regulation. PMID- 29977935 TI - An Unusual Cause of Failure to Ventilate. AB - We report an unusual case of endotracheal tube failure. It was due to a manufacturing defect in the internal white plastic piece that is normally depressed by the luer-lock syringe within the blue pilot balloon. Prior to use, the endotracheal tube was tested and functioned normally. A 64-year-old patient in the intensive care unit with a history of hypertension was being mechanically ventilated after uneventful abdominal surgery. After several hours in the intensive care unit, he was noted to be suddenly no longer receiving adequate tidal volumes from the ventilator. It was found that the cuff on the endotracheal tube was not retaining air when it was filled with air from a syringe. This lead to a large "leak" around the endotracheal tube such that the intended tidal volumes set on the ventilator were not delivered to the patient. The patient was uneventfully reintubated and did well. Subsequent investigation revealed the cause to be a manufacturing defect in the internal white plastic piece that is normally depressed by the luer-lock syringe within the blue pilot balloon. Other mechanisms of cuff failure are reviewed in this case report. This case is an unusual reason for cuff failure. Illustrations supplied alert the reader how to identify the appearance of this manufacturing defect in a pilot balloon. This case illustrates the potential device malfunctions that can develop during a procedure, even when the equipment has been tested and previously functioned well. Even small defects developing in well-engineered products can lead to critical patient care emergencies. PMID- 29977936 TI - Correlation Between Quality of Evidence and Number of Citations in Top 50 Cited Articles in Rotator Cuff Repair Surgery. AB - Background: The number of article citations has been used as a measure for the impact of an article in the medical literature, with little emphasis on quality. Purpose: To (1) identify the top 50 most cited articles related to rotator cuff repair surgery, (2) determine whether there was a correlation between the top cited articles and level of evidence, and (3) determine whether there was a correlation between the top cited articles and study quality. Study Design: Cross sectional study. Methods: The Web of Science and Scopus online databases were searched to identify the top 50 cited articles in rotator cuff repair surgery. Methodological quality was analyzed for each article using the Modified Coleman Methodology Score (MCMS), Jadad scale, and Methodological Index for Non Randomized Studies (MINORS). Correlation coefficients were calculated to determine the degree of correlation between the top cited articles and level of evidence and study quality using each quality score. Results: The mean number of citations for each article in each of the 2 databases was 319 +/- 187 (range, 177.5-1033.5). Twenty-nine articles (58%) were from the United States. The most common level of evidence was level 4 (54%), with 3 (6%) articles being level 1. There was no significant correlation between the mean number of citations and level of evidence (rs = -0.28), the MCMS (rs = -0.29), and the MINORS score (rs = -0.25). There was a weak negative correlation between the mean number of citations and the Jadad score (rs = -0.36). Conclusion: The top 50 cited articles in rotator cuff repair surgery comprise a variety of years, journals, countries of origin, and study types. Despite being the 50 most cited articles, the most common type of article was the level 4 case series with a poor mean quality assessment score. There was no significant correlation between the mean number of citations and level of evidence or methodological quality using a variety of scores. PMID- 29977937 TI - Biomechanical Comparison of Epiphyseal Anterior Cruciate Ligament Fixation Using a Cortical Button Construct Versus an Interference Screw and Sheath Construct in Skeletally Immature Cadaveric Specimens. AB - Background: Anterior cruciate ligament (ACL) ruptures have become increasingly common in pediatric and adolescent athletes. While multiple methods exist, all epiphyseal ACL reconstruction is a popular technique in the skeletally immature patient. Given the high rate of reruptures in this population and the increasing number of commercially available fixation devices, biomechanical testing is crucial to understand the performance of these devices in pediatric epiphyseal bone. To our knowledge, there has not been a biomechanical analysis of ACL fixation devices in skeletally immature bone. Purpose: To compare cortically based button fixation with interference screw and sheath fixation in skeletally immature femoral epiphyseal cadaveric bone. Our hypothesis was that there would be no difference in peak load to failure, stiffness, or cyclic displacement between these 2 fixation constructs. Study Design: Controlled laboratory study. Methods: Fresh-frozen matched-pair knees from 3 pediatric cadaveric specimens were obtained. A synthetic graft was fixed in an all-epiphyseal femoral tunnel. Both the lateral and medial condyles were utilized to increase the sample size. Specimens were randomized and assigned to receive either an interference screw and sheath construct designed for pediatric patients or an adjustable loop cortical button. Biomechanical testing was performed to obtain ultimate load to failure, stiffness, total displacement after 500 cycles, and the failure mode for each condyle. Results: Each medial and lateral condyle in 3 pairs of skeletally immature cadaveric knees (ages 7, 9, and 11 years) was utilized for testing. One specimen was excluded after it failed by having a transphyseal fracture. The median peak load to failure was 769.80 N (interquartile range [IQR], 628.50 930.41 N) for the screw and sheath group and 862.80 N (IQR, 692.34-872.65 N) for the button group (P = .893). The median displacement after 500 cycles for the screw and sheath group was 0.65 mm (IQR, 0.47-1.03 mm) and 1.13 mm (IQR, 0.96 1.25 mm) for the button group (P = .08). The median stiffness of the screw and sheath group was significantly higher than that of the button group (31.47 N/mm [IQR, 26.40-43.00 N/mm] vs 25.22 N/mm [IQR, 21.18-27.07 N/mm], respectively) (P = .043). Conclusion: When comparing femoral fixation with a screw and sheath construct developed for pediatric patients to an adjustable loop cortical button in skeletally immature bone, our results showed that fixation did not significantly differ with respect to cyclic displacement or peak load to failure. While the screw and sheath construct was significantly stiffer, its effect on clinical outcomes is not yet known. Clinical Relevance: With regard to femoral fixation, there is no significant biomechanical difference between the use of cortically based button fixation or interference screw and sheath fixation in pediatric epiphyseal cadaveric bone. PMID- 29977938 TI - Epidemiology of Recurrent Anterior Cruciate Ligament Injuries in National Collegiate Athletic Association Sports: The Injury Surveillance Program, 2004 2014. AB - Background: An anterior cruciate ligament (ACL) rupture is a serious injury that can be career-ending in collegiate athletics. A rerupture after primary ACL reconstruction occurs in 1% to 11% of all athletes. Purpose: To describe the epidemiology of recurrent ACL ruptures in the 25 National Collegiate Athletic Association (NCAA) sports in the NCAA Injury Surveillance Program (ISP) and to identify and compare sport-specific risk factors for a recurrent ACL rupture. Study Design: Descriptive epidemiology study. Methods: Athletes who experienced a primary or recurrent ACL rupture between 2004 and 2014 were identified using data from the NCAA ISP. ACL ruptures occurred in 12 of 25 sports during the study period. We assessed the rates and patterns of primary and recurrent ACL ruptures and reported them as events per 10,000 athlete-exposures (AEs). Sex-comparable sports were compared using rate ratios. Rupture rates were compared using odds ratios, with P values <.05 indicating significance. Regular-season and postseason data were combined because of low counts of postseason events. Results: Of 350,416 AEs, there were 1105 ACL ruptures, 126 of which were recurrent. The highest rates of recurrent ACL ruptures (per 10,000 AEs) were among male football players (15), female gymnasts (8.2), and female soccer players (5.2). Of sports played by athletes of both sexes, women's soccer had a significantly higher rate of recurrent ACL ruptures than men's soccer (rate ratio, 3.8 [95% CI, 1.3-15]). Among all sports, men had a significantly higher rate of recurrent ACL ruptures (4.3) than women (3.0) (P = .04). Overall, the ratio of recurrent to primary ACL ruptures decreased over the 10-year study period. Both women and men had a decreasing trend of recurrent to primary ACL ruptures, although women had a steeper decrease. Conclusion: These data can help identify athletes who are most at risk of recurrent ACL ruptures after ACL reconstruction and who may benefit from injury prevention programs. PMID- 29977939 TI - Evaluation of Endothelial and Vascular-Derived Progenitor Cell Populations in the Proximal and Distal UCL of the Elbow: A Comparative Study. AB - Background: Vascular-derived progenitor and endothelial cell populations (CD31, CD34, CD146) are capable of multipotent differentiation at the site of injured ligamentous tissue to aid in the intrinsic healing response. Proximal ulnar collateral ligament (UCL) tears have been reported to have better healing capability when compared with distal UCL tears. Purpose: To compare the vascular composition of the proximal and distal insertions of the anterior bundle of the UCL of the elbow via known markers of endothelial and vascular-derived progenitor cells (CD31, CD34, CD146). Study Design: Descriptive laboratory study. Methods: UCLs were harvested from 10 nonpaired fresh-frozen human cadaveric elbows and transected into proximal and distal portions. Endothelial and vascular-derived progenitor cell densities were assessed with 4 staining groups: CD31 (immunohistochemistry) and CD31/alpha-smooth muscle actin (alpha-SMA), CD34/alpha SMA, and CD146/alpha-SMA (immunofluorescence). CD31 immunohistochemistry identified endothelial progenitor cells in the UCL. Later staining of the same slides with alpha-SMA demonstrated the relationship of progenitor cells to the surrounding vasculature. Fluorescent staining was quantified by calculating the proportion of positively stained nuclei versus the total number of nuclei in the proximal and distal UCL. Results: CD31+ cells were present in the proximal and distal sections of all 10 UCLs. Fluorescent staining revealed no significant differences in the ratio of CD31 to total nuclei between the distal (median, 36% [range, 23%-53%]) and proximal UCL (39% [22%-56%]) (P = .432, Wilcoxon signed rank test). Similarly, no differences were seen between CD34 distal (39% [24% 64%]) and proximal regions (46% [28%-63%]) (P = .846, Wilcoxon signed-rank test) or CD146 distal (40% [12%-65%]) and proximal regions (40% [22%-51%]) (P >= .999, Wilcoxon signed-rank test). Conclusion: Analysis of UCL tissues demonstrated equal distributions of vascular endothelial and vascular-derived progenitor cell markers throughout the proximal and distal UCL. Unlike that of the medial collateral ligament of the knee, the microvascular composition of the proximal and distal UCL insertions was not different, suggesting a well-vascularized ligament throughout its course. Clinical Relevance: These findings investigate one of the possible contributors to UCL healing after injury, which may provide insight into operative and nonoperative management of UCL injuries in the future. This study also indicates that reasons other than differences in progenitor cell density alone may explain the clinical healing differences seen between proximal and distal UCL tears. A better understanding of the microvascular environment and associated blood supply is warranted to understand the healing capability of the UCL. PMID- 29977941 TI - Passive Knee Stability After Anterior Cruciate Ligament Reconstruction Using the Endobutton or ToggleLoc With ZipLoop as a Femoral Fixation Device: A Comparison of 1654 Patients From the Danish Knee Ligament Reconstruction Registry. AB - Background: Biomechanical studies show varying results regarding the elongation of adjustable fixation devices. This has led to growing concern over the stability of the ToggleLoc with ZipLoop used in anterior cruciate ligament (ACL) reconstruction (ACLR) in vivo. Purpose/Hypothesis: The purpose of this study was to compare passive knee stability 1 year after ACLR in patients in whom the Endobutton or ToggleLoc with ZipLoop was used for femoral graft fixation. The hypothesis was that the ToggleLoc with ZipLoop would be inferior in knee stability to the Endobutton 1 year after primary ACLR. Study Design: Cohort study; Level of evidence, 2. Methods: Data from 3175 patients (Endobutton: n = 2807; ToggleLoc with ZipLoop: n = 368) were included from the Danish Knee Ligament Reconstruction Registry (DKRR) between June 2010 and September 2013. Data were retrieved from standardized ACL forms filled out by the operating surgeon preoperatively, during surgery, and at a clinical examination 1 year after surgery. Passive knee stability was evaluated using 1 of 2 arthrometers (Rolimeter or KT-1000 arthrometer) and the pivot-shift test. Using the same database, the number of reoperations performed up to 4 years after primary surgery was examined. Results: Full data were available for 1654 patients (Endobutton: n = 1538; ToggleLoc with ZipLoop: n = 116). ACLR with both devices resulted in increased passive knee stability (P < .001). Patients who received the ToggleLoc with ZipLoop were found to have a better preoperative (P = .005 ) and postoperative (P < .001) pivot-shift test result. No statistically significant difference regarding the number of reoperations (P = .086) or the time to reoperation (P = .295) was found. Conclusion: Patients who underwent fixation with the ToggleLoc with ZipLoop had improved passive knee stability 1 year after surgery, measured by anterior tibial translation and pivot-shift test results, similar to patients who underwent fixation with the Endobutton. No difference was seen in knee stability or reoperation rates between the 2 devices. PMID- 29977940 TI - Biomechanical Comparison of Screw Fixation Versus a Cortical Button and Self tensioning Suture for the Latarjet Procedure. AB - Background: Metal screws are traditionally used to fix the coracoid process to the glenoid. Despite stable fixation, metal screws have been associated with hardware complications. Therefore, some studies have advocated for suture button fixation during the Latarjet procedure to reduce the complications associated with screw fixation. Purpose: To biomechanically evaluate the ultimate failure load of a cortical button and self-tensioning suture versus metal screws for coracoid graft fixation during the Latarjet procedure. Study Design: Controlled laboratory study. Methods: Eight matched pairs of fresh-frozen, male cadaveric shoulders (N = 16) underwent the Latarjet procedure. The shoulders of each pair were randomly assigned to 1 of 2 groups: fixation using two 3.75-mm cannulated, fully threaded metal screws or fixation using a double suture button construct. Specimens were secured in a dynamic testing machine and cyclically preconditioned from 2 to 10 N at 0.1 Hz for 10 cycles. After preconditioning, specimens were pulled to failure at a normalized displacement rate of 400% of the measured gauge length per minute. The ultimate failure load and mechanism of failure were recorded for each specimen. Results: The mean ultimate load to failure for screw fixation (226 +/- 114 N; 95% CI, 147-305 N) was not significantly different from that for suture button fixation (266 +/- 73 N; 95% CI, 216-317 N) (P = .257). The mean strain at failure for screw fixation (63% +/- 21%; 95% CI, 48%-77%) was not significantly different from that for suture button fixation (86% +/- 26%; 95% CI, 69%-104%) (P = .060). The most common mechanism of failure for the screw fixation method was at the bone block drill holes, while an intramuscular rupture at the clamp-muscle interface occurred for the suture button construct. Conclusion: The screw and suture button fixation techniques exhibited comparable biomechanical strength for coracoid bone block fixation of the Latarjet procedure. Clinical Relevance: Metal screws have been reported to be a large contributor to intraoperative and postoperative complications. Therefore, given the results of the current study, a suture button construct may be an alternative to metal screw fixation during the Latarjet procedure. However, further clinical studies are warranted. PMID- 29977942 TI - Correlation of Patient Symptoms With Labral and Articular Cartilage Damage in Femoroacetabular Impingement. AB - Background: Femoroacetabular impingement (FAI) can lead to labral and articular cartilage injuries as well as early osteoarthritis of the hip. Currently, the association of patient symptoms with the progression of labral and articular cartilage injuries due to FAI is poorly understood. Purpose: To evaluate the correlation between patient-reported outcome (PRO) scores and cartilage compositional changes seen on quantitative magnetic resonance imaging (MRI) as well as cartilage and labral damage seen during arthroscopic surgery in patients with FAI. Study Design: Cohort study; Level of evidence, 3. Methods: Patients were prospectively enrolled before hip arthroscopic surgery for symptomatic FAI. Patients were included if they had cam-type FAI without radiographic arthritis. All patients completed PRO scores, including the Hip disability and Osteoarthritis Outcome Score (HOOS) and a visual analog scale for pain. MRI with mapping sequences (T1rho and T2) on both the acetabular and femoral regions was performed before surgery to quantitatively assess the cartilage composition. During arthroscopic surgery, cartilage and labral injury grades were recorded using the Beck classification. Pearson and Spearman correlation coefficients were then obtained to evaluate the association between chondrolabral changes and PRO scores. Results: A total of 46 patients (46 hips) were included for analysis (mean age, 35.5 years; mean body mass index [BMI], 23.9 kg/m2; 59% male). Increasing BMI was correlated with a more severe acetabular cartilage grade (rho = 0.37; 95% CI, 0.08-0.65). A greater alpha angle was correlated with an increased labral tear grade (rho = 0.59; 95% CI, 0.37-0.82) and acetabular cartilage injuries (rho = 0.61; 95% CI, 0.42-0.80). With respect to PRO scores, increasing femoral cartilage damage in the anterosuperior femoral head region, as measured on quantitative MRI using T1rho and T2 mapping, correlated with lower (worse) scores on the HOOS Activities of Daily Living (r = 0.35; 95% CI, 0.06 0.64), Symptoms (r = 0.32; 95% CI, 0.06-0.57), and Pain (r = 0.31; 95% CI, 0.06 0.55) subscales. There was no correlation between PRO scores and acetabular cartilage damage or labral tearing found on quantitative MRI or during arthroscopic surgery. Conclusion: Femoral cartilage damage, as measured on T1rho and T2 mapping, appears to have a greater correlation with clinical symptoms than acetabular cartilage damage or labral tears in patients with symptomatic FAI. PMID- 29977944 TI - Return to Play After Anterior Cervical Discectomy and Fusion in Professional Athletes. AB - Background: Data are limited on return to play after anterior cervical discectomy fusion (ACDF) in professional athletes. Purpose: To determine the rate and time of return to play among professional athletes after ACDF. Study Design: Case series; Level of evidence, 4. Methods: This study involved the prospective and retrospective review of patient charts and diagnostic studies as well as an internet search to collect data on a consecutive series of professional athletes who underwent cervical fusion by 1 of the 2 senior authors between 1982 and 2016. Demographic data included sport, preoperative symptoms and radiologic findings, date of surgery, level of surgery, postoperative symptoms and radiologic findings, and confounding factors (eg, other orthopaedic injuries). An internet search engine was used to determine date of return to play and length of career after surgery. Results: A total of 27 ACDFs were performed on 26 professional athletes: 12 National Football League athletes, 5 National Hockey League athletes, 5 Major League Baseball athletes, 3 National Basketball Association athletes, and 1 Major League Soccer athlete. Twenty-six procedures (96.3%) showed clinical and radiographic evidence of fusion, and 20 of 25 eligible players returned to play (80%). At the conclusion of this study, 2 players were still in the rehabilitation phase and expected to return at the start of the next National Football League season. The mean time to return to play in a professional game was 9.5 months (range, 5.0-20.2 months). Of 15 players who returned to play but had retired by the time of this study, the mean career length after fusion was 3.2 years (range, 0.1-8.0 years). Clinical follow-up ranged from 1 to 96 months, with a mean of 22.1 months and mode of 11 months. Conclusion: After single-level ACDF, 80% of professional athletes were able to return to sport at approximately 9 months. The study findings will help athletes, physicians, and teams better predict outcome after ACDF surgery. PMID- 29977943 TI - Comparative Outcomes of All-Inside Versus Inside-Out Repair of Bucket-Handle Meniscal Tears: A Propensity-Matched Analysis. AB - Background: There are limited data comparing the outcomes of all-inside versus inside-out meniscal repair techniques. Purpose: To assess failure rates and clinical outcomes after the surgical repair of bucket-handle meniscal tears utilizing either an all-inside or inside-out technique. Study Design: Cohort study; Level of evidence, 3. Methods: Patients with bucket-handle meniscal tears undergoing all-inside or inside-out repair at a single institution between 2003 and 2013 were analyzed. A total of 28 mensici repaired utilizing second generation all-inside suturing devices and 42 menisci repaired using an inside out technique were eligible for inclusion. Rigorous propensity matching was performed on the basis of age, sex, tear laterality, rim width, and concomitant anterior cruciate ligament reconstruction (ACLR), resulting in a total of 40 patients equally distributed between the 2 repair techniques for comparison. Retear-free survival as well as preoperative and postoperative International Knee Documentation Committee (IKDC) and Tegner scores and physical examination findings were subsequently analyzed. Results: Twenty patients who underwent all inside repair (14 male; mean age, 23.7 +/- 6.7 years) were successfully propensity matched to 20 patients who underwent inside-out meniscal repair (15 male; mean age, 22.5 +/- 7.6 years), with a mean retear-free follow-up of 4.4 years (range, 2.5-7.4 years). Four (20%) all-inside repairs and 4 (20%) inside out repairs failed over the course of follow-up (P > .999), with a mean time to failure of 2.7 years (range, 1.3-4.4 years) and 5.0 years (range, 0.8-7.5 years), respectively (P = .25). Increasing patient age trended toward a decreased clinical retear rate, independent of the repair technique (hazard ratio, 0.86; P = .056). There were no significant differences in the Tegner scores, IKDC scores, or range of motion between the groups as a whole or when subcategorizing by age, sex, body mass index, tear complexity, rim width, isolated versus concomitant ACLR, or medial- versus lateral-sided repair. There were no complications in the all-inside group, while there was a 10% rate of minor complications in the inside out group (P = .49). Conclusion: Overall, satisfactory clinical outcomes are achievable at short-term to midterm follow-up with both inside-out and all-inside repair techniques of bucket-handle meniscal tears in rigorously matched patients with similar meniscal tear patterns. PMID- 29977945 TI - Hamstring Autograft in ACL Reconstruction: A 13-Year Predictive Analysis of Anthropometric Factors and Surgeon Trends Relating to Graft Size. AB - Background: Small-diameter autograft hamstring grafts have been linked to graft failure after anterior cruciate ligament (ACL) reconstruction. The frequency of hamstring autografts that actually meet ideal size criteria remains unknown. Purpose: To examine a large cohort of patients to (1) evaluate sizing variability among a large cohort of surgeons and (2) identify patient factors most predictive of hamstring autograft size. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 1681 ACL reconstructions with hamstring autograft were analyzed as completed by 11 surgeons over a 13-year period. Patient demographics (age, height, weight, body mass index, sex) and intraoperative details (including graft diameter and strands) were extracted. Univariate and multivariate regression analyses were performed to correlate patient demographics with graft size and to develop a predictive model for hamstring graft size. Results: The mean height and weight of patients included in this study were 172.7 cm and 80.1 kg, respectively; 59% of patients were male. The mean diameters of hamstring autografts were 8.4 mm and 8.2 mm for the tibial and femoral ends of the graft, respectively. A total of 55.1% of grafts were <=8 mm. Mixed-effects linear modeling revealed that height, weight, sex, and use of >=5 strands correlated with graft size (P < .001), while age did not. The predictive multivariate model based on the statistically relevant factors demonstrated a moderate correlation (r = 0.39, R2 = 0.150), illustrated a predictive equation, and proved height to be the greatest determinant of graft size. Conclusion: Marked variability in graft size distribution was found among surgeons, and more than half of all grafts did not reach the ideal size for hamstring autograft ACL reconstruction. A predictive equation including anthropometric factors may be able to provide the expected graft size. The risk of early graft failure may be mitigated with preoperative consideration of anthropometric factors-most importantly, height-in preparation for possible augmentation, additional strands, or alternative graft sources. PMID- 29977946 TI - Hurt on the Hill: A Longitudinal Analysis of Obstacle Course Racing Injuries. AB - Background: Obstacle course racing (OCR) has become a popular sport in recent years as it challenges participants' mental and physical endurance through a combination of trail running and obstacles. There is currently only a limited amount of published work reporting injury types or rates at these events. Purpose: This study aims to build on the current literature, analyzing injury rates and patterns at OCR events. Methods: A secondary data analysis of deidentified medical charts from 33 OCR events in Canada from 2015 to 2017 was conducted. The scope of on-site care was first aid. Study Design: Descriptive epidemiology study. Results: A total of 1782 injuries occurred over 3 seasons from 73,366 participants, with an overall average injury rate of 2.4%; 1.0% (n = 17) of injuries required emergency medical services transport to a local emergency department, and the majority of these injuries were musculoskeletal in nature. The most common injuries treated were lacerations and musculoskeletal related injuries; 93.9% of the injuries were able to be treated on site. These findings, in conjunction with the published literature, suggest that OCR medical teams should anticipate injury rates of up to 5.0% and a transportation rate of approximately 4.5% of those injuries to local emergency departments. Conclusion: The injury and transportation rates found in this study are congruent with the current literature and, most notably, they demonstrated a stable trend across a variety of course lengths (5-42 km ) and numbers of obstacles (>=20). While the majority of injuries may be treated on site, there is still a serious potential for life-threatening emergencies to occur. PMID- 29977947 TI - Knee Joint Kinematics and Kinetics During Walking and Running After Surgical Achilles Tendon Repair. AB - Background: Despite the increasing incidence of Achilles tendon (AT) ruptures, there is a lack of information on the possible risks associated with regular running and walking for exercise after an injury. There are some known kinematic gait changes after an AT rupture, especially at the knee. However, it is not clear whether runners with AT ruptures may be at risk for secondary knee injuries during shod or barefoot running/walking. Purpose/Hypothesis: The purpose of this study was to compare the kinematics and kinetics of barefoot walking and barefoot and shod running between athletes with a history of AT ruptures and a healthy control group. We hypothesized that there would be increased knee joint loads in the affected limb of the AT rupture group, especially during shod running. Study Design: Controlled laboratory study. Methods: Ten patients who had undergone surgical treatment of a unilateral acute AT rupture (6.1 +/- 3.7 years postoperatively ) and 10 control participants were matched according to age, sex, physical activity, weight, height, and footfall type. The kinematics and kinetics of barefoot walking and barefoot and shod running were recorded using a high speed motion capture system synchronized with force platforms. Results: The main outcome measures were lower extremity joint angles and moments during the stance phase of walking and running. After AT repair, athletes had increased internal knee abduction moments during shod and barefoot running compared with the healthy control group (P < .05, eta2 > 0.14). There were no significant differences in kinematics and kinetics during walking between the AT rupture and healthy control groups (P >= .05). Conclusion: After an AT rupture, athletes had increased internal knee abduction moments during running compared with the healthy control group. Clinical Relevance: The increased abduction loads on the knee in patients with an AT rupture could lead to further running-related injuries. However, barefoot walking may be used as a proprioceptive exercise without an increased risk of overuse injuries in these patients. PMID- 29977948 TI - Risk Factors for Deep Vein Thrombosis or Pulmonary Embolus Following Anterior Cruciate Ligament Reconstruction. AB - Background: Nearly 350,000 Americans develop a deep venous thromboembolism (DVT) or pulmonary embolism (PE) annually, and nearly 100,000 Americans die from these events. To date, little research has investigated patient-specific risk factors that increase the rate of DVT/PE following anterior cruciate ligament reconstruction (ACLR). Purpose: To determine relevant patient risk factors for the development of DVT/PE following ACLR. Study Design: Case-control study; Level of evidence, 3. Methods: All instances of ACLR from 2005 to 2014 within the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) prospective database were analyzed. Both univariate analysis and binary logistic regression were performed to determine which patient demographics and surgical factors were associated with DVT or PE following surgery. Results: Of the 9146 patients who underwent ACLR, 46 (0.5%) developed postoperative DVT, 8 (0.1%) developed PE, and 5 (0.05%) developed both. The following variables were associated with the development of DVT or PE on univariate analysis: increased age, a high tibial osteotomy (HTO) performed at the time of ACLR, microfracture performed, the presence of hypertension requiring medical therapy, and the presence of an active wound infection. Independent predictors of DVT or PE on multivariate analysis included HTO (odds ratio [OR], 22.7), the presence of an active wound infection (OR, 11.0), or hypertension requiring medication (OR, 2.2). Meniscal repair was not a risk factor for DVT or PE on univariate or multivariate analysis. Conclusion: In a review of 9146 patients undergoing ACLR, 46 (0.5%) developed DVT in the 30-day postoperative period. Increasing age over 30 years, concomitant HTO or microfracture, hypertension requiring medication, and presence of wound infection were all associated with an increased risk of DVT. The annual incidence of DVT/PE following ACLR reconstruction is low (<1%) and has not changed over time. PMID- 29977949 TI - Optical coherence tomography angiography at the acute phase of optic disc edema. AB - Background: The differential diagnosis of optic disc edema at the acute phase can be challenging. OCT angiography (OCTA) is a new technology allowing the visualization of the peripapillary vascular network and optic disc capillaries. The peripapillary network alterations of glaucoma and chronic non-arteritic anterior ischemic optic neuropathy (NAION) were reported. However, no OCTA studies on acute optic disc edema from various causes. The aim of this project was to use OCTA to demonstrate the vascular changes the optic nerve head of various types of optic disc edema at the acute phase. Methods: In this retrospective study, patients with non-arteritic anterior ischemic optic neuropathy (NAION), papillitis or papilledema were recruited. Each patient was imaged using the AngioPlexTM CIRRUSTM HD-OCT device(model 5000, Carl Zeiss Meditec, Inc., Dublin, USA) with a scanning area of 6 * 6 mm2 centered on the optic disc. A morphological analysis of the peripapillary network was performed. For some patients with unilateral optic disc edema, a quantitative analysis was performed using a swept-source OCT-A system (PLEX(r) Elite 9000, Carl Zeiss Meditec, Inc., Dublin, USA). Vessel perfusion density and flux index of the peripapillary area were calculated. Results: Eight eyes with NAION (4 patients), 12 eyes with papillitis (6 patients) and 25 eyes with papilledema (13 patients) were imaged. The apparent disappearance or moderate pattern alteration of the peripapillary capillary vessels were observed in patients with NAION or papillitis, respectively. For papilledema, the capillaries at the surface of the optic disc were dilated and tortuous, but no peripapillary network pattern changes were observed. The quantitative analysis did not show any difference of peripapillary network between NAION and healthy eyes. For papillitis, the flux index was higher in inflammatory eyes compared to the healthy eyes in average (p = 0.03). Conclusion: At the acute phase, the morphological analysis of OCT-A appeared to be more useful than the quantification analysis, facilitating the differentiation between the three kinds of ONH edema: ischemic, inflammatory and papilledema. PMID- 29977950 TI - Word segmentation from noise-band vocoded speech. AB - Spectral degradation reduces access to the acoustics of spoken language and compromises how learners break into its structure. We hypothesised that spectral degradation disrupts word segmentation, but that listeners can exploit other cues to restore detection of words. Normal-hearing adults were familiarised to artificial speech that was unprocessed or spectrally degraded by noise-band vocoding into 16 or 8 spectral channels. The monotonic speech stream was pause free (Experiment 1), interspersed with isolated words (Experiment 2), or slowed by 33% (Experiment 3). Participants were tested on segmentation of familiar vs. novel syllable sequences and on recognition of individual syllables. As expected, vocoding hindered both word segmentation and syllable recognition. The addition of isolated words, but not slowed speech, improved segmentation. We conclude that syllable recognition is necessary but not sufficient for successful word segmentation, and that isolated words can facilitate listeners' access to the structure of acoustically degraded speech. PMID- 29977951 TI - Chronic Meningitis and Hydrocephalus due to Sporothrix brasiliensis in Immunocompetent Adults: A Challenging Entity. AB - Chronic meningitis caused by Sporothrix sp. is occasionally described in immunosuppressed patients. We report the challenges in diagnosing and managing 2 nonimmunocompromised patients with hydrocephalus and chronic meningitis caused by Sporothrix brasiliensis. This more virulent species appears to contribute more atypical and severe cases than other related species. PMID- 29977952 TI - The Effect of Monitoring Viral Load and Tracing Patients Lost to Follow-up on the Course of the HIV Epidemic in Malawi: A Mathematical Model. AB - Background: Antiretroviral therapy (ART) reduces HIV transmission, but treated patients may again become infectious. We used a mathematical model to determine whether ART as prevention is more effective if viral load (VL) is routinely monitored and patients lost to follow-up (LTFU) traced. Methods: We simulated ART cohorts to parameterize a deterministic transmission model calibrated to Malawi. We investigated the following strategies for improving treatment and retention: monitoring VL every 12 or 24 months, tracing patients LTFU, or a generic strategy leading to uninterrupted treatment. We tested 3 scenarios, where ART scale-up continues at current (Universal ART), reduced (Failed scale-up), or accelerated speed (Test&Treat). Results: In the Universal ART scenario, between 2017 and 2020 (2050), monitoring VL every 24 months prevented 0.5% (0.9%), monitoring every 12 months prevented 0.8% (1.4%), tracing prevented 0.3% (0.5%), and uninterrupted treatment prevented 5.5% (9.9%) of HIV infections. Failed scale-up resulted in 25% more infections than the Universal ART scenarios, whereas Test&Treat resulted in 7%-8% less. Conclusions: Test&Treat reduces transmission of HIV, despite individual cases of treatment failure and ART interruption. Whereas viral load monitoring and tracing have only a minor impact on transmission, interventions that aim to minimize treatment interruptions can further increase the preventive effect of ART. PMID- 29977953 TI - Obesity, Diabetes, and the Risk of Invasive Group B Streptococcal Disease in Nonpregnant Adults in the United States. AB - Background: Rates of invasive group B Streptococcus (GBS) disease, obesity, and diabetes have increased in US adults. We hypothesized that obesity would be independently associated with an increased risk of invasive GBS disease. Methods: We identified adults with invasive GBS disease within Active Bacterial Core surveillance during 2010-2012 and used population estimates from the Behavioral Risk Factor Surveillance System to calculate invasive GBS incidence rates. We estimated relative risks (RRs) of invasive GBS using Poisson analysis with offset denominators, with obesity categorized as class I/II (body mass index [BMI] = 30 39.9 kg/m2) and class III (BMI >= 40.0 kg/m2). Results: In multivariable analysis of 4281 cases, the adjusted RRs of invasive GBS disease were increased for obesity (class I/II: RR, 1.52; 95% confidence interval [CI], 1.14-2.02; and class III: RR, 4.87; 95% CI, 3.50-6.77; reference overweight) and diabetes (RR, 6.04; 95% CI, 4.77-7.65). The adjusted RR associated with class III obesity was 3-fold among persons with diabetes (95% CI, 1.38-6.61) and nearly 9-fold among persons without diabetes (95% CI, 6.41-12.46), compared with overweight. The adjusted RRs associated with diabetes varied by age and BMI, with the highest RR in young populations without obesity. Population attributable risks of invasive GBS disease were 27.2% for obesity and 40.1% for diabetes. Conclusions: Obesity and diabetes were associated with substantially increased risk of infection from invasive GBS. Given the population attributable risks of obesity and diabetes, interventions that reduce the prevalence of these conditions would likely reduce the burden of invasive GBS infection. PMID- 29977954 TI - A Real-world Patient Registry for Oritavancin Demonstrates Efficacy and Safety Consistent With the Phase 3 SOLO Program. AB - Background: Oritavancin is a lipoglycopeptide used in the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. To characterize its use in patients in the postapproval setting, a patient registry was developed. Methods: Data collected in an ongoing retrospective observational registry are used to evaluate the utilization, outcomes, and adverse events (AEs) associated with oritavancin for the treatment of infections presumed or confirmed to be caused by gram-positive (GP) bacteria in clinical practice. Results: Data for 112 patients from 8 sites were collected. All patients received a single 1200 mg dose of oritavancin mostly in an infusion center. Infection type included cellulitis (67.0%), cutaneous abscess (21.4%), and wound (4.5%). Most patients (72.3%) received 1 or more antimicrobial agents for the index GP infection within 28 days prior to oritavancin treatment. Of positive cultures obtained prior to oritavancin administration, methicillin-resistant Staphylococcus aureus was the predominant pathogen (78.4%). A positive clinical response was observed in 92.8% of patients, and microbial eradication was observed in 90.0% of patients with post-therapy cultures. Within 28 days following oritavancin administration, 4 (3.6%) patients were hospitalized for failure of treatment of the index infection. Five (4.5%) patients experienced 1 or more possible drug-related AEs, which were consistent with types previously reported. There were no drug-related serious AEs reported. Conclusions: Clinical and microbiologic outcomes and safety of single-dose oritavancin 1200 mg were similar in this older patient population with multiple comorbid conditions to those observed in the phase 3 SOLO trials. PMID- 29977955 TI - Absolute Insurer Denial of Direct-Acting Antiviral Therapy for Hepatitis C: A National Specialty Pharmacy Cohort Study. AB - Background: Despite the availability of new direct-acting antiviral (DAA) regimens, changes in DAA reimbursement criteria, and a public health focus on hepatitis C virus (HCV) elimination, it remains unclear if public and private insurers have increased access to these therapies over time. We evaluated changes in the incidence of absolute denial of DAA therapy over time and by insurance type. Methods: We conducted a prospective cohort study among patients who had a DAA prescription submitted from January 2016 to April 2017 to Diplomat Pharmacy, Inc., which provides HCV pharmacy services across the United States. The main outcome was absolute denial of DAA prescription, defined as lack of fill approval by the insurer. We calculated the incidence of absolute denial, overall and by insurance type (Medicaid, Medicare, commercial), for the 16-month study period and each quarter. Results: Among 9025 patients from 45 states prescribed a DAA regimen (4702 covered by Medicaid, 1821 Medicare, 2502 commercial insurance), 3200 (35.5%; 95% confidence interval, 34.5%-36.5%) were absolutely denied treatment. Absolute denial was more common among patients covered by commercial insurance (52.4%) than Medicaid (34.5%, P < .001) or Medicare (14.7%, P < .001). The incidence of absolute denial increased across each quarter of the study period, overall (27.7% in first quarter to 43.8% in last quarter; test for trend, P < .001) and for each insurance type (test for trend, P < .001 for each type). Conclusions: Despite the availability of new DAA regimens and changes in restrictions of these therapies, absolute denials of DAA regimens by insurers have remained high and increased over time, regardless of insurance type. PMID- 29977956 TI - Repeat Syphilis Is More Likely to Be Asymptomatic in HIV-Infected Individuals: A Retrospective Cohort Analysis With Important Implications for Screening. AB - There is conflicting evidence as to whether repeat syphilis is more likely to present asymptomatically than initial syphilis. If it is, then this would motivate more frequent and long-term syphilis screening in persons with a history of multiple episodes of syphilis. We conducted detailed folder reviews of all individuals with 4 or more diagnoses of syphilis between 2000 and 2017 at the Institute of Tropical Medicine, Antwerp, and assessed if there was a difference in the proportion presenting with symptomatic (primary and secondary) vs asymptomatic (latent) syphilis in initial vs repeat syphilis. Forty-five clients with 4 or more episodes of syphilis were included in the study. All were HIV infected. Repeat episodes of syphilis were less likely to be symptomatic than initial episodes (35/160 [21.9%] vs 28/45 [62.2%]; P < .001). Frequent screening in those with HIV infection may be the only way to diagnose repeat episodes of syphilis. Care providers can use this information to motivate persons with multiple episodes of syphilis to be screened every 3 to 6 months. PMID- 29977957 TI - Redefining Prevention and Care: A Status-Neutral Approach to HIV. AB - Recent biomedical advances inspire hope that an end to the epidemic of HIV is in sight. Adopting new approaches and paradigms for treatment and prevention in terms of both messaging and programming is a priority to accelerate progress. Defining the key sequential steps that comprise engagement in HIV care has provided a useful framework for clinical programs and motivated quality improvement initiatives. Recently, the same approach has been applied to use of pre-exposure prophylaxis for HIV prevention. Building on the various prevention and care continua previously proposed, we present a novel schematic that incorporates both people living with HIV and people at risk, making it effectively "status-neutral" in that it proposes the same approach for engagement, regardless of one's HIV status. This multidirectional continuum begins with an HIV test and offers 2 divergent paths depending on the results; these paths end at a common final state. To illustrate how this continuum can be utilized for program planning as well as for monitoring, we provide an example using data for New York City men who have sex with men, a population with high HIV incidence and prevalence. PMID- 29977958 TI - The Hospital Antimicrobial Use Process: From Beginning to End. AB - Hospital antimicrobial stewardship (AMS) programs are responsible for ensuring that all antimicrobials are utilized in the most appropriate and safe manner to improve patient outcomes, prevent adverse drug reactions, and prevent the development of antimicrobial resistance. This Perspectives article outlines the hospital antimicrobial use process (AUP), the foundational system that ensures that all antimicrobials are utilized in the most appropriate and safe manner. The AUP consists of the following steps: antimicrobial ordering, order verification, preparation and delivery, administration, monitoring, and discharge prescribing. AMS programs should determine how each step contributes to how an antimicrobial is used appropriately or inappropriately at their institution. Through this understanding, AMS programs can integrate stewardship activities at each step to ensure that every opportunity is taken to optimize antimicrobial use during a patient's treatment course. Hence, approaching AMS through the framework of a hospital's AUP is essential to improving appropriate antimicrobial use. PMID- 29977959 TI - Provider Adherence to Pre-exposure Prophylaxis Monitoring Guidelines in a Large Primary Care Network. AB - Insufficient pre-exposure prophylaxis (PrEP) laboratory monitoring could increase HIV resistance and sexually transmitted infections. We examined test-ordering in a primary care network. Providers did not order HIV testing before almost one quarter of PrEP initiations; panel management was associated with higher testing. Effective monitoring is needed to maximize PrEP's preventive impact. PMID- 29977960 TI - Pneumococcal Conjugate Vaccine Safety in Elderly Adults. AB - Background: The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23 valent pneumococcal polysaccharide vaccine (PPSV23) were both recommended to adults aged >=65 years. The study examines adults >=65 years for risk of adverse events (AEs) requiring medical attention following vaccination with PCV13 as compared with vaccination with PPSV23, a long-standing vaccine with a satisfactory safety profile. Methods: The cohort study included 6 Vaccine Safety Datalink sites. The exposed person-time included follow-up time of the first PCV13 received by subjects age >=65 years from January 1 to August 15, 2015. The comparator person-time included follow-up time after the first PPSV23 received by subjects of the same age during Janaury 1 to August 15 of each year of 2011-2015. The prespecified AEs included cardiovascular events, Bell's palsy, Guillain-Barre syndrome, syncope, erythema multiforme, thrombocytopenia, cellulitis and infection, allergic reaction, and anaphylaxis. Inverse probability of treatment weighting-adjusted Poisson regression models was used to estimate the relative risk (RR) of each AE. Results: A total of 313 136 doses of PCV13 and 232 591 doses of PPSV23 were included. The adjusted RRs comparing the incidence of AEs following PCV13 vs PPSV23 were all <1, except for anaphylaxis, which was insignificant with an RR of 1.32 (95% confidence interval, 0.30-5.79). Only 1 patient who received PCV13 and 4 other vaccines concomitantly was confirmed by medical chart review as having experienced anaphylaxis after vaccination. Conclusions: These data do not support an increased rate of adverse events following PCV13 administration in elders compared with PPSV23 and should provide reassurance regarding continued use of PCV13. PMID- 29977961 TI - Leveraging Antimicrobial Stewardship in the Emergency Department to Improve the Quality of Urinary Tract Infection Management and Outcomes. AB - Background: The complex and fast-paced emergency department (ED) practice setting presents unique challenges that demand a tailored approach to antimicrobial stewardship. In this article, we describe the strategies applied by 1 institution's antimicrobial stewardship program (ASP) that were successful in improving prescribing practices and outcomes for urinary tract infection (UTI) in the ED. Methods: Core strategies included pre-implementation research characterizing the patient population, antimicrobial resistance patterns, prescribing behavior, and morbidity related to infection; collaboration across multiple disciplines; development and implementation of a UTI treatment algorithm; education to increase awareness of the algorithm and the background and rationale supporting it; audit and feedback; and early evaluation of post implementation outcomes. Results: We observed a rapid change in prescribing post implementation with increased empiric nitrofurantoin use and reduced cephalosporin use (P < .05). Our elevation of nitrofurantoin to firstline status was supported by our post-implementation analysis showing that its use was independently associated with reduced 30-day return visits (adjusted odds ratio, 0.547; 95% confidence interval, 0.312-0.960). Furthermore, despite a shift to a higher risk population and a corresponding decrease in antimicrobial susceptibility rates post-implementation, the preferential use of nitrofurantoin did not result in higher bug-drug mismatches while 30-day return visits to the ED remained stable. Conclusions: We demonstrate that an outcomes-based ASP can impart meaningful change to knowledge and attitudes affecting prescribing practices in the ED. The success of our program may be used by other institutions as support for ASP expansion to the ED. PMID- 29977962 TI - Similar Low Rates of HCV Recurrence in HCV/HIV- and HCV-Infected Participants who Achieved SVR After DAA Treatment: Interim Results From the ACTG A5320 Viral Hepatitis C Infection Long-term Cohort Study (V-HICS). AB - Hepatitis C virus (HCV) recurrence rates were similar between those with HCV/HIV co-infection (0.35/100 person-years) and HCV infection (0.42/100 person-years). Low rates of recurrence likely represent enrollment of an HIV population at low risk for recurrence. Care should be taken not to label all HCV/HIV co-infected patients as being at high risk for HCV recurrence. PMID- 29977963 TI - Improving Aztreonam Stewardship and Cost Through a Penicillin Allergy Testing Clinical Guideline. AB - Background: Patients reporting penicillin allergy often receive unnecessary and costly broad-spectrum alternatives such as aztreonam with negative consequences. Penicillin allergy testing improves antimicrobial therapy but is not broadly used in hospitals due to insufficient testing resources and short-term expenses. We describe a clinical decision support (CDS) tool promoting pharmacist-administered penicillin allergy testing in patients receiving aztreonam and its benefits toward antimicrobial stewardship and costs. Methods: A CDS tool was incorporated into the electronic medical record, directing providers to order penicillin allergy testing for patients receiving aztreonam. An allergy-trained pharmacist reviewed orders placed through this new guideline and performed skin testing and oral challenges to determine whether these patients could safely take penicillin. Data on tests performed, antibiotic utilization, and cost-savings were compared with patients tested outside the new guideline as part of our institution's standard stewardship program. Results: The guideline significantly increased penicillin allergy testing among patients receiving aztreonam from 24% to 85% (P < .001) while reducing the median delay between admission and testing completion from 3.31 to 1.05 days (P = 0.008). Patients tested under the guideline saw a 58% increase in penicillin exposure (P = .046). Institutional aztreonam administration declined from 2.54 to 1.47 administrations per 1000 patient-days (P = .016). Average antibiotic costs per patient tested before and after CDS decreased from $1265.81 to $592.08 USD, a 53% savings. Conclusions: Targeting penicillin allergy testing to patients on aztreonam yields therapeutic and economic benefits during a single admission. This provides a cost-effective model for inpatient testing. PMID- 29977964 TI - Clinical and Genomic Characterization of Recurrent Enterococcal Bloodstream Infection in Patients With Acute Leukemia. AB - Background: Rates and risk factors for recurrent enterococcal bloodstream infection (R-EBSI) and whether the same genetic lineage causes index EBSI and R EBSI are unknown in patients with acute leukemia (AL) receiving chemotherapy. Methods: Ninety-two AL patients with EBSI from 2010 to 2015 were included. Enterococcal bloodstream infection was defined by 31 positive blood cultures for Enterococcus faecium or Enterococcus faecalis and fever, hypotension, or chills. Clearance was defined by 31 negative cultures 324 hours after last positive culture and defervescence. Recurrent enterococcal bloodstream infection was defined by a positive blood culture for Enterococcus 324 hours after clearance. Categorical variables were reported as proportions and compared by the chi2 test. Continuous variables were summarized by median and interquartile range (IQR) and compared by the Wilcoxon-Mann-Whitney Test. P values <.05 were considered significant. Whole-genome sequencing was performed on available paired BSI isolates from 7 patients. Results: Twenty-four patients (26%) had 31 episodes of R-EBSI. Median time to R-EBSI (IQR) was 26 (13-50) days. Patients with R-EBSI had significantly longer durations of fever and metronidazole exposure during their index EBSI. Thirty-nine percent of E. faecium R-EBSI isolates became daptomycin nonsusceptible Enterococcus (DNSE) following daptomycin therapy for index EBSI. Whole-genome sequencing analysis confirmed high probability of genetic relatedness of index EBSI and R-EBSI isolates for 4/7 patients. Conclusions: Recurrent enterococcal bloodstream infection and DNSE are common in patients with AL and tend to occur within the first 30 days of index EBSI. Duration of fever and metronidazole exposure may be useful in determining risk for R-EBSI. Whole genome sequencing analysis demonstrates that the same strain causes both EBSI and R-EBSI in some patients. PMID- 29977965 TI - Evaluating Antimicrobial Use and Spectrum of Activity in Ontario Hospitals: Feasibility of a Multicentered Point Prevalence Study. AB - Background: Antimicrobial stewardship, a key component of an overall strategy to address antimicrobial resistance, has been recognized as a global priority. The ability to track and benchmark antimicrobial use (AMU) is critical to advancing stewardship from an organizational and provincial perspective. As there are few comprehensive systems in Canada that allow for benchmarking, Public Health Ontario conducted a pilot in 2016/2017 to assess the feasibility of using a point prevalence methodology as the basis of a province-wide AMU surveillance program. Methods: Three acute care hospitals of differing sizes in Ontario, Canada, participated. Adults admitted to inpatient acute care beds on the survey date were eligible for inclusion; a sample size of 170 per hospital was targeted, and data were collected for the 24-hour period before and including the survey date. Debrief sessions at each site were used to gather feedback about the process. Prevalence of AMU and the Antimicrobial Spectrum Index (ASI) was reported for each hospital and by indication per patient case. Results: Participants identified required improvements for scalability including streamlining ethics, data sharing processes, and enhancing the ability to compare with peer organizations at a provincial level. Of 457 patients, 172 (38%) were receiving at least 1 antimicrobial agent. Beta-lactam/beta-lactamase inhibitors were the most common (18%). The overall mean ASI per patient was 6.59; most cases were for treatment of infection (84%). Conclusions: This pilot identified factors and features required for a scalable provincial AMU surveillance program; future efforts should harmonize administrative processes and enable interfacility benchmarking. PMID- 29977966 TI - JC Virus Granule Cell Neuronopathy and Lymphoma. AB - Neurological opportunistic infections are going to increase. Clinicians should be aware of the neurological spectrum of JC virus manifestations, including granule cell neuronopathy. Detection of JC virus DNA by polymerase chain reaction in cerebrospinal fluid should be realized in the assessment of a progressive cerebellar ataxia in an immunocompromised patient. PMID- 29977968 TI - Real-time Utilization of Metagenomic Sequencing in the Diagnosis and Treatment Monitoring of an Invasive Adenovirus B55 Infection and Subsequent Herpes Simplex Virus Encephalitis in an Immunocompetent Young Adult. AB - Background: Metagenomic sequencing has shown tremendous promise in solving difficult infectious diseases cases. In this study, we utilized this technology to help guide the care of a critically ill patient with severe pneumonia, fever of unknown origin, and subsequent encephalitis in the intensive care unit (ICU). Methods: Shotgun metagenomic sequencing was performed on the patient's blood, bronchoalveolar lavage (BAL), and cerebral spinal fluid by using an Illumina MiniSeq sequencer. Results : A high load of human adenovirus B55 (HAdV-B55), a highly pathogenic adenovirus associated with numerous recently reported outbreaks and deaths in China, was detected in both blood and BAL, which explained the severity of the condition. The patient was treated with intravenous ribavirin, which cleared the virus after 26 days. Metagenomic sequencing also helped diagnose an unexpected herpes simplex virus-1 encephalitis during hospitalization, which led to timely treatment. Conclusions : This was the first successful case utilizing metagenomic sequencing to guide diagnosis and treatment in the ICU setting in China. We have proven the concept that metagenomic sequencing can play an important role in determining clinical approaches and ultimately in improving patient outcomes. We also hope to share our successful treatment protocol for the severe pneumonia and viremia caused by HAdV-B55. PMID- 29977969 TI - Performance of TEM-PCR vs Culture for Bacterial Identification in Pediatric Musculoskeletal Infections. AB - Improved diagnostics are needed for children with musculoskeletal infections (MSKIs). We assessed the performance of target-enriched multiplex polymerase chain reaction (TEM-PCR) in children with MSKI. TEM-PCR was concordant with culture in pathogen identification and antibiotic susceptibility testing, while increasing the overall yield of pathogen detection. This technology has the potential to inform judicious antimicrobial use early in the disease course. PMID- 29977967 TI - Impact of the M184V Resistance Mutation on Virological Efficacy and Durability of Lamivudine-Based Dual Antiretroviral Regimens as Maintenance Therapy in Individuals With Suppressed HIV-1 RNA: A Cohort Study. AB - Background: Dual therapy (DT) with boosted protease inhibitors (bPIs) plus lamivudine has been shown to be superior to bPI monotherapy in virologically suppressed patients despite previous selection of the lamivudine resistance M184V mutation. We compared the virological efficacy of lamivudine-based DT in patients with and without a history of M184V detection. Methods: We retrospectively analyzed patients with HIV-RNA <=50 copies/mL switching to DT with at least 1 previous resistance genotype in the ARCA database. Time to virological failure (VF; HIV-RNA >=200 copies/mL or 2 consecutive HIV-RNA >50 copies/mL) and to treatment discontinuation (TD) was analyzed by survival analysis. Results: Four hundred thirty-six patients switching to lamivudine plus bPIs (70%) or integrase inhibitors (30%) were included. Patients with M184V (n = 87) were older, had lower nadir CD4+ cell count, longer duration of antiretroviral therapy and of virologic suppression, and higher rate of hepatitis C virus infection compared with patients without M184V. The 3-year probability of remaining free from VF was 91.9% (95% confidence interval [CI], 86.6-97.2) without M184V and 87.8% (95% CI, 78.4-97.2) with M184V (P = .323). The time to TD did not differ between groups. Multivariate analysis adjusting for baseline variables differing between groups also did not detect M184V as being associated with VF or TD; however, the 3-year probability of remaining free of viral blips (isolated HIV-RNA 51-199 copies/mL) was 79.8% (95% CI, 67.8%-91.8%) with M184V vs 90.1% (95% CI, 84.0%-96.2%) without M184V (P = .016). Conclusions: Previous selection of M184V did not increase the risk of VF or TD with lamivudine-based DT but was associated with a higher probability of viral blips. PMID- 29977971 TI - Effect of a Patient-Centered Phone Call by a Clinical Officer at Time of HIV Testing on Linkage to Care in Rural Kenya. AB - In a randomized controlled trial, we tested whether a structured, patient centered phone call from a clinical officer after HIV testing improved linkage to/re-engagement in HIV care. Among 130 HIV-positive persons, those randomized to the phone call were significantly more likely to link to care by 7 and 30 days (P = .04). PMID- 29977970 TI - The Cefazolin Inoculum Effect Is Associated With Increased Mortality in Methicillin-Susceptible Staphylococcus aureus Bacteremia. AB - Background: Recent studies have favored the use of cefazolin over nafcillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. The clinical influence of the cefazolin inoculum effect (CzIE) in the effectiveness of cephalosporins for severe MSSA infections has not been evaluated. Methods: We prospectively included patients from 3 Argentinian hospitals with S. aureus bacteremia. Cefazolin minimum inhibitory concentrations (MICs) were determined at standard (105 colony-forming units [CFU]/mL) and high (107 CFU/mL) inoculum. The CzIE was defined as an increase of MIC to >=16 ug/mL when tested at high inoculum. Whole-genome sequencing was performed in all isolates. Results: A total of 77 patients, contributing 89 MSSA isolates, were included in the study; 42 patients (54.5%) had isolates with the CzIE. In univariate analysis, patients with MSSA exhibiting the CzIE had increased 30-day mortality (P = .034) and were more likely to have catheter-associated or unknown source of bacteremia (P = .033) compared with patients infected with MSSA isolates without the CzIE. No statistically significant difference between the groups was observed in age, clinical illness severity, place of acquisition (community vs hospital), or presence of endocarditis. The CzIE remained associated with increased 30-day mortality in multivariate analysis (risk ratio, 2.65; 95% confidence interval, 1.10-6.42; P = .03). MSSA genomes displayed a high degree of heterogeneity, and the CzIE was not associated with a specific lineage. Conclusions: In patients with MSSA bacteremia where cephalosporins are used as firstline therapy, the CzIE was associated with increased 30-day mortality. Clinicians should be cautious when using cefazolin as firstline therapy for these infections. PMID- 29977972 TI - Cerebral Abscess by Fonsecaea monophora-The First Case Reported in Germany. AB - We report the first case of cerebral Fonsecaea monophora infection in a German woman without immunodeficiency or travel history. F. monophora infection is a rare differential diagnosis of cerebral tumors; it was previously considered a tropical fungus. This case adds to the scarce reports in nontropical regions. PMID- 29977973 TI - Immunization Mandates, Vaccination Coverage, and Exemption Rates in the United States. AB - Background: Vaccination coverage among children entering kindergarten in the United States is high, but interstate variations exist. The relationship between state immunization laws and vaccination coverage has not been fully assessed. We evaluated associations of state laws on both measles, mumps, and rubella (MMR) and diphtheria, tetanus, and pertussis (DTaP) vaccination coverage and exemptions to school immunization requirements. Methods: We conducted a retrospective, longitudinal analysis of the effect of state immunization laws on vaccination coverage and exemptions among US kindergarteners from SY 2008 to SY 2014. The primary outcome measures were state-level kindergarten entry vaccination coverage rates for 2-dose MMR and 4-dose DTaP vaccines. Secondary outcome measures included rates of state-level exemptions (ie, medical, religious, philosophical) to school immunization requirements. Results: We found that state policies that refer to Advisory Committee on Immunization Practices recommendations were associated with 3.5% and 2.8% increases in MMR and DTaP vaccination rates. Health Department-led parental education was associated with 5.1% and 4.5% increases in vaccination rates. Permission of religious and philosophical exemptions was associated with 2.3% and 1.9% decreases in MMR and DTaP coverage, respectively, and a 1.5% increase in both total exemptions and nonmedical exemptions, respectively. Conclusions: We found higher vaccination coverage and lower nonmedical exemption rates for MMR and DTaP vaccines in states adopting Advisory Committee on Immunization Practices guidelines for school entry. Adherence to these best practices was a successful strategy to increase vaccination coverage and reduce vaccination exemptions. PMID- 29977974 TI - Infectious Scleritis: What the ID Clinician Should Know. AB - Scleritis is an inflammatory process involving the outer coating of the globe which is characterized by focal or diffuse hyperemia, moderate to severe pain, and frequent impairment of vision. Most cases of scleritis are autoimmune in nature and are managed with topical and/or systemic corticosteroids. Infectious scleritis is a less common entity, occurring in 5%-10% of cases, and requiring directed antimicrobial therapy. We present a case of Nocardia farcinica anterior nodular scleritis diagnosed via positive culture of an excisional biopsy of a scleral nodule. The patient improved after combined surgical and medical therapy with amoxicillin-clavulanate and moxifloxacin for 12 months. Based on a literature review, a summary of reported cases of infectious scleritis is provided, and guidelines pertaining to diagnosis and management are offered. PMID- 29977976 TI - Incidence and Risk Factors of Perioperative Mortality in Pediatric ICU Patients. AB - Background: There is a limited data of pediatric patients who presented to the intensive care unit (ICU) and undergo procedures under general anesthesia. The primary objective of this study was to evaluate the mortality of this population and assess the risk factors associated with mortality. Methods: Retrospective study of electronic medical records of pediatric patients who admitted to medical/surgical ICU and underwent produces under general anesthesia during the same ICU admission was performed. Incidence of mortality was obtained and risk factors associated with these mortalities were examined using Univariable logistic regression analysis. Results: The mortality of pediatric patients who were admitted to the ICU and underwent procedures under general anesthesia was 12.6%, while the mortalities of patients without procedures under general anesthesia and patients who admitted to ICU for postoperative management were 3.5% and 0.4%, respectively. Higher ASA class, emergency cases, higher ventilator support, more inotrope requirement, positive microbe in blood stream, blood transfusion requirement, and general surgery or hematological procedures were highly associated with mortalities. Among them, positive blood stream infection was highest odds ratio (102.00, 95% confidence interval 9.78-1064.09). The profile of patients with positive blood stream infection showed that most of them had underlying immunological/hematological disorders. Conclusion: In our institution, pediatric patients who admitted to the ICU and underwent procedures under general anesthesia demonstrated the highest mortality among other patients who admitted to ICU. Risk factor analysis demonstrated that patients with positive blood stream infection had highest odds ratio, and were highly associated with immunological/ hematological disorders. PMID- 29977975 TI - Vibration-Assisted Home Training Program for Children With Spinal Muscular Atrophy. AB - The aim of this study was to determine the effect of a new method of vibration assisted neuromuscular rehabilitation in patients with spinal muscular atrophy types II and III. In this retrospective observational study, 38 children (mean age: 4.64 +/- 1.95 years) were analyzed. The physiotherapy program, Auf die Beine, combines 6 months of home-based side-alternating whole-body vibration with interval blocks of intensive, goal-directed rehabilitation: 13 days at the start and 6 days after 3 months. Assessments were applied at the beginning (M0), after 6 months of home-based training (M6), and after 6 months of follow-up (M12). Motor abilities were assessed by the Gross Motor Function Measure 66 and Hammersmith Functional Mobility Scale. The Gross Motor Function Measure showed an increase of 1.69 (3.73) points (P = .124) and the Hammersmith Functional Mobility Scale a significant increase of 2.73 +/- 1.79 points (P = .007) after 12 months; however, whether this leads to a long-term clinical benefit requires further investigation. PMID- 29977977 TI - Volatile Anesthetic Isoflurane Attenuates Liver Injury in Experimental Polymicrobial Sepsis Model. AB - Volatile anesthetics are often administered to patients with sepsis for procedural anesthesia or sedation in intensive care units. Sepsis still carries significant morbidities and mortalities, and organ injuries pose major complications. Early liver dysfunction is associated with poor outcome mainly as a result of overwhelming neutrophil recruitment. Leukocyte function-associated antigen-1 (LFA-1) and macrophage-1 antigen (Mac-1) are major adhesion molecules on neutrophils and involved in neutrophil recruitment. We have previously showed that volatile anesthetic isoflurane inhibited LFA-1 and Mac-1. Here we studied the role of isoflurane, LFA-1 and Mac-1 on neutrophil recruitment to the liver and liver injury using experimental polymicrobial abdominal sepsis induced by cecal ligation and puncture (CLP) surgery. We used wild type (WT), LFA-1, Mac-1 and intercellular adhesion molecule-1 (ICAM-1) knockout (KO) mice. Following the induction of sepsis by CLP surgery, a group of mice were exposed to isoflurane for 2 hours. We found that Mac-1 and ICAM-1, but not LFA-1 were involved in neutrophil recruitment to liver. Isoflurane attenuated neutrophil recruitment and liver injury in WT and LFA-1 KO mice. Mac-1 KO mice had limited neutrophil recruitment and liver injury, both of which were not attenuated by isoflurane further, suggesting that isoflurane mitigated liver injury via Mac-1. Mac-1 colocalized with ICAM-1 and fibrinogen on liver tissues. In the presence of fibrinogen Mac-1 bound ICAM-1 significantly more, while LFA-1 bound less to ICAM 1, suggesting that Mac-1 used fibrinogen as a bridging molecule to bind ICAM-1. In conclusion, isoflurane exposure attenuated neutrophil recruitment and liver injury via Mac-1. PMID- 29977978 TI - Factors Associated With Physical Performance Measures in a Multiethnic Cohort of Older Adults. AB - Objective: To explore the association between ethnicity, sociodemographic, health, and lifestyle factors, and physical performance (PP) in ethnically diverse community-dwelling older adults from one geographic area. Method: We used multivariable linear regression to identify factors associated with upper (grip strength [GS], arm curls [AC]) and lower (chair stands [CS]) body strength and mobility (gait speed [GSp]) in 577 older adults (mean age 74 +/- 8; 104 African American, 142 Afro-Caribbean, 123 Hispanic, and 208 European American) from South Florida. Results: Worse mental health was negatively associated with CS in African Americans and AC in Hispanics. Older age and higher body mass index (BMI) was associated with slower GSp in all except in Hispanics. Higher physical activity was associated with higher upper body strength in Hispanics and better mobility in African Americans and Afro-Caribbeans, but not in European Americans. Conclusion: Studies with large multiethnic cohorts are needed to further our understanding of ethnic differences in PP, which will help in tailoring interventions and recognizing unmet needs for health and social services. PMID- 29977979 TI - Accuracy of Objective Physical Activity Monitors in Measuring Steps in Older Adults. AB - Objective: The aim of this study is to evaluate accuracy of research activity monitors in measuring steps in older adults with a range of walking abilities. Method: Participants completed an initial assessment of gait speed. The accuracy of each monitor to record 100 steps was assessed across two walking trials. Results: In all, 43 older adults (age 87 +/- 5.7 years, 81.4% female) participated. Overall, the StepWatch had the highest accuracy (99.0% +/- 1.5%), followed by the ActivPAL (93.7% +/- 11.1%) and the Actigraph (51.4% +/- 35.7%). The accuracy of the Actigraph and ActivPAL varied according to assistive device use, and the accuracy of all three monitors differed by gait speed category (all p < .05). StepWatch was highly accurate (?97.7) across all conditions. Discussion: The StepWatch and ActivPAL monitor were reasonably accurate in measuring steps in older adults who walk slowly and use an assistive device. The Actigraph significantly undercounted steps in those who walk slow or use an assistive device. Researchers should consider gait speed and the use of assistive devices when selecting an activity monitor. PMID- 29977980 TI - Marijuana Use Among Adults 50 Years or Older in the 21st Century. AB - Background: Marijuana is the most commonly used illicit drug among older adults. As an older population grows in the United States that has a tolerant attitude toward marijuana use, the dynamics of marijuana use and the effects of marijuana on personal, social, and health outcomes among older adults require attention. Objectives: This review summarizes epidemiological literature on marijuana use among older adults. Method: A literature search was conducted using PubMed, AgeLine, and an online search engine from January 2000 to December 2017, resulting in 18 articles. Results: The greatest increase in marijuana use was observed among those in the older adult population 50 years or older, and those 65 years or older had the greatest increase in marijuana use in the older adult population. Common correlates of marijuana use among those in the older population included being male, being unmarried, having multiple chronic diseases, having psychological stress, and using other substances such as alcohol, tobacco, other illicit drugs, and prescription drugs. Conclusion: The increased use of marijuana in older populations requires surveillance and additional research to understand the use and effects of marijuana in older populations to avoid negative health outcomes. PMID- 29977981 TI - Actual Conditions of Leisure Activity Among Older Community-Dwelling Japanese Adults. AB - For healthy longevity, according to the theoretical framework of "successful aging," it is not only essential to avoid disease and disability, and to keep high levels of mental and physical functioning, but also to engage with life. Thus, satisfactory leisure activity is important for the aged. We examined actual conditions of leisure activity among older adults in Japan, which can contribute to the development of a standardized leisure activity scale. Participants were 843 community-dwellers (390 men and 453 women, 70.5 +/- 6.9 years old) who completed 58 draft leisure activity items. Three procedures (including item selection, factor analyses, and correlation analyses) were conducted to finalize the leisure activity list and evaluate its psychometric properties. Through item selection procedures, 15 items were regarded as inappropriate and were omitted from the analysis. The factor analyses resulted in an 11-factor solution with 43 items. Correlation analysis revealed that Factors 2 (social-public), 5 (social private), 7 (technology use), 8 (travel), and 10 (developmental activity) had relationships with health outcomes (including functional capacity, social network, subjective well-being, and health literacy). A standardized leisure activity list among modern middle-aged and elderly people was developed, and was associated in part with health outcomes. PMID- 29977982 TI - An Individualized Music-Based Intervention for Acute Neuropsychiatric Symptoms in Hospitalized Older Adults With Cognitive Impairment: A Prospective, Controlled, Nonrandomized Trial. AB - Background: Neuropsychiatric symptoms are common features of dementia, and these occur in three fourths of patients on psychogeriatric inpatient units. These symptoms have traditionally been treated with pharmacological agents, but many medications are as likely to harm patients with dementia as to help them. As a result, nonpharmacological interventions are increasingly being investigated as ways to reduce these symptoms. Objective: The current study evaluated the impact of an individualized music-based intervention on agitation, negative mood, positive mood, compliance with care, need for one-on-one nursing staff intervention, and need for PRN medication. Method: Participants in this study were older adults who were admitted to a geriatric behavioral inpatient unit for acute agitation or behavioral disturbance. Twenty patients were in a treatment as usual group and 21 were in the individualized music group. Results: Agitation, negative mood, and positive mood all benefited from the music-based intervention, with resulting large effect sizes. Resisting care level also significantly benefited from the intervention, with a resulting medium effect size. Conclusion: These findings indicate that an easily implemented and reproducible music-based intervention, which is well tolerated and without adverse side effects, can be an effective way to reduce neuropsychiatric symptoms associated with dementia on a hospital unit. PMID- 29977983 TI - A Pediatric Patient With Recurrent Abdominal Pain and Enamel Hypoplasia. PMID- 29977984 TI - Sex Differences in the Developmental Neuroscience of Adolescent Substance Use Risk. AB - Adolescence is a period associated with the initiation and escalation of substance use and is also a time during which substantial changes take place in neural development, personality and behavior. Although rates of substance use between adolescent girls and boys do not differ substantially, there is evidence for sex differences in underlying vulnerability pathways associated with the development of substance use disorder. Here we review sex differences in adolescent brain development and how these differences may contribute to different risk pathways between females and males that emerge during this developmental period. We also discuss methodological considerations in the study of sex differences in brain and behavior and their implications for interpretation. We close by highlighting promising areas for future work. PMID- 29977986 TI - Linear accelerator-based radiosurgery and hypofractionated stereotactic radiotherapy for brain metastasis secondary to gynecologic malignancies: A single institution series examining outcomes of a rare entity. AB - Objective: The use of SRS and fSRT to determine overall survival, tumor control, and local-disease free progression in patient diagnosed with gynecologic brain metastasis. Methods: In this retrospective review, 11 patients aged 50 to 85 (median age of 71) were treated with linear accelerator-based SRS and hypofractionated SRT for brain metastasis secondary to gynecologic malignancies. In total, 16 tumors were treated from 2007 to 2017. Patients were treated to a median dose of 24 Gy (range 15 to 30 Gy) in 3 Fx (range 1 to 5). Median follow-up from SRS or SRT was 4 months (range 3-38 months). Results: The actuarial 1-year overall survival rate was 26% with a median overall survival of 8 months. In addition, 1-year actuarial local control rate was 83.3% and the 1-year distant brain control rate was 31%. One patient experienced toxicity that presented as seizures after 7 months (due to minimal edema) that required anticonvulsants. There was no other acute or late treatment-related toxicity.Conclusion: Linear accelerator based SRS or fSRT is safe and effective for control of local tumor growth in brain metastases secondary to gynecologic malignancies. The course of disease remains aggressive as seen by poor overall survival and distant failure rate. PMID- 29977985 TI - Adjuvant therapy after radical trachelectomy for stage I cervical cancer. AB - *Radical trachelectomy is a fertility sparing option for select stage I cervical patients.*Indications for adjuvant treatment following trachelectomy are based on standard recommendations following hysterectomy.*Case report outlining specifics of imaged-guided brachytherapy as part of the adjuvant treatment after trachelectomy. PMID- 29977987 TI - Uterine preservation in a young patient with adenosarcoma of the uterus - Case report and review of literature. AB - *A young lady with uterine sarcoma had a successful delivery 3 years after diagnosis.*Local recurrence occurred after 8 years.*Ultrasound and endometrial biopsy can be used in the follow-up of these patients.*Patients should be counselled on risk of late recurrence. PMID- 29977989 TI - Sacituzumab Govitecan (IMMU-132) in treatment-resistant uterine serous carcinoma: A case report. AB - Background: Uterine serous carcinoma (USC) is a biologically aggressive variant of uterine cancer. Effective treatment options for recurrent, chemotherapy resistant USC are extremely limited. Case: We describe a 74-year-old woman with recurrent and widespread treatment-resistant disease, who experienced a dramatic response to sacituzumab govitecan, a novel antibody-drug conjugate (ADC) targeting human trophoblast-cell-surface antigen (TROP-2), after failing multiple chemotherapy and immunotherapy. The impressive clinical response (66% reduction of target lesions by RECIST 1.1 with a duration response of over 10 months) was confirmed with serial CT scans in the absence of significant adverse events. Conclusion: Sacituzumab govitecan may present a new treatment option for recurrent USC patients harboring Trop-2+ tumors resistant to chemotherapy. Clinical trials with sacituzumab govitecan are warranted. PMID- 29977990 TI - Prior prescription opioid misuse in a cohort of heroin users in a treatment study. AB - This study investigates prior prescription opioid misuse in a cohort of heroin users whose progress was tracked in a treatment study conducted in the US from 2006 to 2010. Half of the sample misused prescription opioids ("other opiates/analgesics") prior to their onset of heroin misuse (POBs). We found that POBs were demographically younger and more likely to be white than other heroin users (OHUs). There were differences between the two groups with respect to the reporting of at least one year of regular use of substances and age of onset of substance use. POBs were more likely to report regular use, and earlier onset of use of several substances, mostly of the type potentially obtained via prescription. POBs were more persistent in their opioid use and more likely to suffer near-term elevated depressive symptoms compared with OHUs. These findings suggest that heroin addiction treatment may need to be tailored according to opioid misuse history. PMID- 29977988 TI - Endometrial cancer in an increasingly obese population: Exploring alternative options when surgery may not cut it. AB - Objectives: The study objectives were to describe outcomes of obese patients with early endometrial cancer following primary non-surgical treatment, assess predictors of response, and estimate the increased surgical risk for these women. Methods: Retrospective chart review identified women with early stage endometrial cancer at a single institution with BMI >= 30 kg/m2 who did not undergo surgery as primary treatment modality due to obesity and medical co-morbidities. Clinicopathologic factors were abstracted, characteristics of responders vs. non responders compared and the National Surgical Quality Improvement Program (NSQIP) surgical risk calculator utilized to quantify surgical risks. Results: Fifty-one patients were identified, with a mean BMI of 49.0 kg/m2. The NSQIP calculator predicted a significantly higher complication rate for our cohort compared to the expected average risk for hysterectomy (18.8% vs 7.2%, p < .0001). The majority of patients were treated with radiation alone (49%), followed by hormone therapy (45.1%). Response rates were 38.1% for women treated with hormones and 63.6% in the radiation group (p = .063). No significant differences were identified between responders and non-responders with regard to NSQIP scores, BMI, co morbidities or age. Among those with persistent or progressive disease, 87.5% responded to secondary treatment. Only one death was from cancer progression. Two individuals died following treatment complications (one surgical, one chemotherapy); the remaining twelve deaths were due to pre-existing co morbidities. Conclusions: Hormone and radiation therapy are both viable options for obese patients deemed to have too significant risk of surgical complications. Pursuing surgical intervention in this population may do more harm than good. PMID- 29977991 TI - Parental belief and adolescent smoking and drinking behaviors: A propensity score matching study. AB - This research examines the effects of parental belief on adolescent later smoking and drinking behaviors. Previous studies show that parental belief may have detrimental or beneficial influences on adolescents' behaviors. Analysis is based on Wave 1 and 2 data from the National Longitudinal Study of Adolescent Health (Add Health), N = 3232, and is conducted using an OLS regression estimation and propensity score matching (PSM; nearest-neighbor and kernel matching). Results show that, of adolescents who used cigarettes and alcohol at Wave 1, they are more likely to continue the activity if their parents were aware of it. Adolescents are also more likely to use cigarettes if their parents believed they smoked when in fact they did not. Of adolescents who did not use alcohol, no significant association is found between parental belief and their later alcohol use. Self-fulfilling prophecy is proposed to explain the effects of parental belief. Results obtained from PSM show weaker effects of parental belief, suggesting that part of the effects is explained by shared factors which are responsible for the belief and adolescent substance use. Adolescent concealment is proposed as an important unobserved confounder that influences the association between parental belief and adolescent substance use. The study suggests that research on parent-adolescent communication affected by the self-fulfilling prophecy needs to consider adolescents' intentional concealment, which may help avoid conflicts elicited by discussing topics that adolescents feel uncomfortable confiding in. PMID- 29977992 TI - Psychometric evaluation of a lifetime version of the marijuana problems scale. AB - Introduction: The Marijuana Problems Scale (MPS) is a widely-used self-report measure of cannabis-related negative consequences that has a past three-month reporting window. This report describes the psychometric characteristics of a lifetime version (MPS-L). Methods: As part of a larger study, 119 individuals who had recovered from cannabis use disorder completed the MPS-L on two occasions 2 weeks apart and 91 participant-nominated family and friends also completed a collateral version of the scale. Results: Item analyses and principal component analysis (PCA) revealed that three of the 19 items were relatively weaker. Omitting these items, the MPS-L showed good internal reliability (alpha = 0.88, for summed severity total, alpha = 0.85 for number of consequences identified) and test-retest reliability (r = 0.81 and 0.73). As expected, correlations with collateral reports were moderate (r = 0.33 and 0.29), and collaterals reported significantly fewer negative consequences than participants. MPS total scores also correlated as expected with external validity measures (e.g., number of cannabis use disorder symptoms reported, motives for use, lifetime depression, treatment history). PCA supported the use of a total score summed score, but also revealed two secondary factors, measuring internal consequences (e.g., low self esteem) and external consequences (e.g., financial difficulties). Conclusions: These analyses provide good preliminary support for a lifetime version of the MPS, with the summed severity total score performing slightly better than the total number of consequences endorsed. PMID- 29977993 TI - Excluded, then inebriated: A preliminary investigation into the role of ostracism on alcohol consumption. AB - Introduction: Ostracism has only recently been investigated as a relevant social stressor that might precede college student alcohol use. The present study continues initial efforts to examine the effects of ostracism on subsequent alcohol consumption in the laboratory. A 2 (sex: male, female) * 2 (condition: ostracism, control) between-subjects experimental design was conducted to examine the effects of these variables on alcohol consumption in the laboratory. Methods: Social drinking college students (N = 40; 43% female) were randomly assigned to one of two social interaction tasks: either an in-person conversation from which the participant was excluded by two confederates, or independently rating neutrally valenced photographs alongside confederates. Participants then consumed a priming drink (targeted dose = 0.03 BrAC) before completing a mock taste test of up to 710 ml of light beer. Amount consumed (in ml) during the mock taste test served as the primary dependent variable. Results: The ostracism condition was effective at decreasing mood and psychological need variables (i.e., control, belonging) compared to the control condition. After removing from analyses those who identified the confederates as part of the study (n = 7; 3 control, 4 ostracism), results indicated that males consumed more beer than females, and that ostracized participants trended toward consuming more beer than control participants. Conclusions: Findings contribute important methodological additions to a burgeoning literature on the effects of ostracism on drinking, and suggest that ostracism may be a valuable addition to studies examining drinking to cope behaviors. PMID- 29977994 TI - Plastic stents are more cost-effective than lumen-apposing metal stents in management of pancreatic pseudocysts. AB - Background and study aims: Endoscopic ultrasound-guided drainage is an effective and accepted primary modality for management of pancreatic pseudocyst (PP). A lumen-apposing metal stent (LAMS) has recently been developed specifically for drainage of pancreatic fluid collections which may be superior to using traditional plastic stents (PS) but is more expensive. Because use of a stent involves a risk of unplanned endoscopy, percutaneous drainage (PCD) and surgery, their costs should also be included in the comparison and a cost-effectiveness analysis of LAMS and PS should therefore be performed. Patients and methods: A decision tree was developed assessing both endoscopic drainage strategies for patients with PP: LAMS and PS over a 6-month time horizon. For each strategy, inpatients received a stent and were followed for subsequent need for direct further interventions or adverse events leading to unplanned endoscopy, PCD, surgery, or successful endoscopic drainage using probabilities obtained from the literature. The unit of effectiveness was successful endoscopic drainage without need for PCD or surgery. Sensitivity analyses were performed. Results : Success rates were 93.9 % for LAMS and 96.96 % for PS. Respective costs per successful drainage were US $ 18,129 (LAMS) and US $ 10,403 (PS). The LAMS strategy was thus characterized as dominated by the PS approach because it was costlier and less effective than PS. Both deterministic and probabilistic sensitivity analyses confirmed the robustness of these findings. Conclusion: Use of LAMS is not less effective and more costly than PS in management of patients with PP. As such, PS should be preferred over LAMS as initial management of these patients. PMID- 29977995 TI - Use of over-the-scope-clip (OTSC) improves outcomes of high-risk adverse outcome (HR-AO) non-variceal upper gastrointestinal bleeding (NVUGIB). AB - Background and study aims : Endoscopic treatment of non-variceal upper gastrointestinal bleeding (NVUGIB) with high-risk adverse outcome (HR-AO) features has a high risk of failure. We studied the safety and efficacy of over the-scope clips (OTSC) to treat these lesions. Patients and methods : We included patients who were treated using OTSC for NVUGIB from January 2015 to October 2017. We studied rebleeding and mortality rates and used the Rockall data and our institution's prior data for comparison. We used descriptive and chi-square statistics. Results : We studied 18 patients with 19 bleeding lesions: 9 (47 %) duodenal ulcers, 4 (21 %) Dieulafoy's lesion, 3 (16 %) gastric ulcer, and 3 (16 %) bleeding after gastric biopsy, gastric polypectomy and endoscopic ultrasound guided fine-needle aspiration of peri-gastric mass. We applied OTSC as the first line treatment in 10 (53 %) and as the second-line treatment in 9 (47 %) bleeding lesions. Continued bleeding after OTSC occurred in six patients, but we treated it successfully and achieved complete hemostasis in all patients. We found OTSC use significantly decreased (0 % vs. 53 %, P < 0.01) and reduced (0 % vs. 24 %, P = 0.08) the rebleeding rate in our high-risk (RS >= 8) and intermediate-risk (RS = 4 - 7) Rockall score patients as compared to the rates reported by the Rockall study, respectively. When compared to our institution's prior study, we found a decrease in the rebleeding rate with OTSC (0 % vs. 21 %, P = 0.06) in our intermediate-to-high risk Rockall score patients (RS >= 4). There was no difference in mortality rates as compared to both control studies. Conclusion : Use of OTSC is safe, efficacious and appears superior to standard treatment for HR-AO NVUGIB. OTSC should be considered as first-line treatment for HR-AO bleeding. PMID- 29977996 TI - Endoscopic management of difficult benign biliary and pancreatic strictures using a wire-guided cystotome: experience with 25 cases. AB - Background and study aims : Endoscopic management using standard accessories is the preferred modality for treatment of benign biliary strictures. However, with difficult strictures, there is frequently failure of endoscopic therapy. We are reporting our experience regarding use of a standard diathermic dilator (cystotome) to aid in stricture dilatation and stent placement in patients with difficult strictures. Patients and methods : Data were analyzed from January 2014 to January 2017 at a single tertiary care center in North India. Total 25 patients were included. Results : The mean age was 45 years (varying from 38 - 55 years). Of the 25 patients with difficult strictures, 14 (56 %) were male and 11 (44 %) were female. Further, of these, 19 had biliary and 6 had pancreatic strictures. The average time of diathermic current application was 3.5 seconds (ranging 3 - 5 seconds). Technical and clinical success were achieved in 100 % of cases. None of the patients had any procedure-related (early or delayed) major complications. Conclusion : The cystotome is an extremely safe and useful accessory in benign biliary and pancreatic strictures, whereas conventional methods to negotiate stricture have failed. PMID- 29977997 TI - Heads or tails: confusion about "proximal" and "distal" terminology for pancreaticobiliary anatomy. AB - Background and study aims : The anatomical meaning of the terms "proximal" and "distal" in relation to the pancreaticobiliary anatomy can be confusing. We aimed to investigate practice patterns of use of the terms "proximal" and "distal" for pancreaticobiliary anatomy amongst various medical specialties. Materials and methods : An online survey link to a normal pancreaticobiliary diagram was emailed to a multispecialty physician pool. Respondents were asked to label various parts of the common bile duct (CBD) and pancreatic duct (PD) using the terms "proximal," "distal," "not sure," or "other." Variability in use of these terms between specialties was assessed. Results : We received 370 completed surveys from 182 gastroenterologists (49.2 %), 97 surgeons (26.2 %), 68 radiologists (18.4 %), and 23 other physicians (6.2 %). There was overall consensus in describing the upper/sub-hepatic CBD as "proximal CBD" (73.8 %, P = 0.1499) and the lower/pre-ampullary portion as "distal CBD" (84.6 %, P = 0.1821). Conclusions : Although use of the terms "proximal" and "distal" is still very common to describe pancreaticobiliary anatomy, there is a discordance about its meaning, particularly for the PD. Use of descriptive terminology may be a more accurate alternative to prior ambiguous terminologies such as "proximal" or "distal" and can serve to improve communication and decrease the possibility of medical errors. PMID- 29977998 TI - Enteral stent placement for malignant afferent loop obstruction by the through the-scope technique using a short-type single-balloon enteroscope. AB - Background and study aims A short-type single-balloon enteroscope with a 3.2-mm working channel makes it possible to insert an enteral stent by the through-the scope technique in patients with malignant afferent loop obstruction. Here, we report five cases of malignant afferent loop obstruction treated with endoscopic enteral stenting. We also propose a new classification for three types of malignant afferent loop obstruction. Type 1: The obstruction site is located distal to the papilla or the bilioenteric anastomosis. Type 2: The obstruction site is located at the papilla or the bilioenteric anastomosis. Type 3: The obstruction site is located between the bilioenteric and pancreaticoenteric anastomosis. The patients with type 1 and 3 were simply treated by inserting an enteral stent endoscopically. The patient with type 2 was treated with an endoscopic enteral stent for malignant afferent loop obstruction and with percutaneous transhepatic biliary stenting for malignant biliary obstruction. Although double stenting for type 2 remains a difficult endoscopic procedure, the endoscopic approach has become the standard approach for malignant afferent loop obstruction. PMID- 29977999 TI - Polypectomy techniques among gastroenterologists in Norway - a nationwide survey. AB - Background and study aims: Incomplete polyp removal has been estimated to cause 27 % of all colorectal cancers detected soon after colonoscopy. There is limited information regarding polypectomy techniques among endoscopists. The article is a nationwide survey of polypectomy techniques among Norwegian endoscopists. Materials and methods: We invited all board-certified gastroenterologists in Norway to complete a web-based questionnaire about their polypectomy technique. Inadequate polypectomy techniques were defined as using biopsy forceps for polyps larger than 3 mm in diameter, using hot biopsy forceps for polypectomy, and using the same electrocautery output irrespective of polyp size and morphology. Results : Twenty-six of 30 Norwegian gastroenterology departments participated in the study. A total of 119 endoscopists received the survey, and 70 (59 %) responded. Mean duration of endoscopy practice was 11.5 years, and 95 % had performed more than 1,000 colonoscopies during their career. Twenty-eight endoscopists (40 %) used one or more inadequate polypectomy techniques: 10 (14.3 %) used biopsy forceps for removal of polyps larger than 3 mm in diameter, five (7.1 %) used hot biopsy for polypectomy, and 17 (24 %) used the same electrocautery output for all polypectomies. Five (7 %) endoscopists reported that they did not remove polyps smaller than 4 mm. Conclusion: A substantial number of Norwegian endoscopists use inadequate polypectomy techniques. Improved training and certification of endoscopists is warranted. PMID- 29978000 TI - Endoscopic ultrasound-guided coil and glue for treatment of splenic artery pseudo aneurysm: new kid on the block! AB - Background and study aims: Pseudoaneurysm most commonly involves the splenic artery and is conventionally treated with angioembolization or surgery. Herein we describe six patients with splenic artery pseudoaneurysm who were treated using a new technique of endoscopic ultrasound (EUS)-guided glue and coil injection. Patients and methods: Six patients (median age 36.7, range: 19 - 60, M: F = 5:1) with splenic artery pseudoaneurysm who had failed angiographic embolization underwent EUS-guided transgastric injection of coil and glue injection between July 2016 and September 2017. Results : The diameter of the splenic artery pseudoaneurysms varied from 2.5 cm to 6.5 cm . The size (8, 14 and 16 mm) and number (1 to 5) of coils and amount of glue (1 - 2 mL) injected all were greater in larger aneurysm. All six patients had complete occlusion of the pseudoaneurysm as determined by using computed tomography at 4 weeks and EUS at 12 weeks. No complication was encountered. Conclusion : EUS-guided coil and glue injection for obliteration of splenic artery pseudoaneurysm is a feasible, highly effective and safe technique. PMID- 29978001 TI - Mirizzi's syndrome in Roux-en-Y bypass patient successfully treated with cholangioscopically-guided laser lithotripsy via percutaneous gastrostomy. AB - Obesity and bariatric surgery are major risk factors in gallstone disease. In patients with a past history of Roux-en-Y gastric bypass, Mirizzi's syndrome is a challenging endoscopic situation because of the modified anatomy. Here we report the first case of a patient with a Roux-en-Y gastric bypass treated by intracorporeal lithotripsy with a digital single-operator cholangioscope following an endoscopic retrograde cholangiopancreatography (ERCP) using a percutaneous gastrostomy access. PMID- 29978002 TI - White opaque substance visualized by magnifying narrow-band imaging is associated with intragastric acid conditions. AB - Background and study aims: The presence of white opaque substance (WOS) is an endoscopic marker of intestinal metaplasia. Considering that the nature of WOS is absorbed lipid droplets, lipase plays an important role in the lipid absorption process and is inactivated at strong acidity. WOS may only be present in a hypochlorhydria state following Helicobacter pylori infection, and, thus, may not be highly sensitive marker, especially in H. pylori- eradicated patients. We investigated the relationship between WOS and gastric acid conditions. Patients and methods: A total of 501 patients were retrospectively evaluated for the presence of WOS at 2 regions of interest using magnifying narrow-band imaging. The pH level of collected gastric juice was also measured. Study end points were (1) prevalence of WOS and its relationship with gastric juice pH in 3 groups: H. pylori- uninfected , H. pylori- infected, and H. pylori -eradicated; (2) the relationship between prevalence of WOS and gastric juice pH before and after proton pump inhibitor (PPI) administration in 29 H. pylori -eradicated cases. Results: Prevalence of WOS was 0 % (0 /206), 28.4 % (31/109), and 3.2 % (6/186) in the H. pylori -uninfected, H. pylori -infected, and H. pylori -eradicated groups, respectively. Mean gastric juice pH was significantly higher in WOS positive cases than in WOS-negative cases in the H. pylori -infected and H. pylori -eradicated groups ( P < 0.0001). Mean gastric juice pH increased from 1.1 to 6.9 after PPI administration and WOS prevalence increased from 0 % (0/29) to 45 % (13/29) of cases. Conclusion: The prevalence of WOS is closely associated with the neutralization of intragastric pH. PMID- 29978004 TI - Development of a computed cleansing score to assess quality of bowel preparation in colon capsule endoscopy. AB - Background and study aims : Colon capsule endoscopy (CCE) does not possess an objective and reliable scoring system to assess the quality of visualization of the colon mucosa. The aim of this study was to establish a colonic computed assessment of cleansing (CAC) score able to discriminate "adequately cleansed" from "inadequately cleansed" CCE still frames. Patients and methods : Twelve normal and complete CCEs, using the Pillcam Colon 2 system (Medtronic, Minnesota, United States), were prospectively selected amongst a database. A CAC score, defined as the ratio of color intensities red over green (R/G ratio), and red over brown (R/(R + G) ratio) was calculated for each extracted colonic frame. After sorting and random selection, two sets of still frames representative of the range of these ratios were obtained. These images were analyzed twice in random order by two experienced CCE readers who were blinded to the CAC scores. A receiver operating characteristic (ROC) curve was forged for both types of ratios and a threshold established, yielding the highest diagnostic performance in terms of adequate cleansing assessment. Results : Four-hundred-and-eight frames were extracted. Regarding the R/G ratio, a threshold value of 1.55 was calculated, with a sensitivity of 86.5 % and a specificity of 77.7 %. Regarding the R/(R + G) ratio, a threshold value of 0.58 was calculated with a sensitivity of 95.5 % and a specificity of 62.9 %. Conclusion: The two proposed CAC scores based on the ratio of color intensities come with high sensitivities for discriminating between "adequately cleansed" and "inadequately cleansed" CCE still frames, but they lack specificity. Further refinement, with implementation of additional image parameters, is warranted. PMID- 29978003 TI - Length of stay overestimates severity of post-ERCP pancreatitis: Is it time to revise the consensus definition? AB - Introduction: Length of stay (LOS) is an important determinant of the severity of post-ERCP pancreatitis (PEP) in the consensus definition. The aim of our study was to evaluate and compare severity of PEP based on the revised Atlanta classification (RAC) and the consensus definition. Patients and methods: Between 1/2000 and 12/2011, all adult patients admitted with suspicion of PEP after outpatient ERCP were evaluated. PEP was defined using the RAC, but the severity of PEP was defined using both revised Atlanta and consensus definitions. Results: A total of 341 patients (mean age 49 years and 75 % females) were diagnosed with PEP. The consensus definition classified 57 %, 37 %, and 8 % of patients with mild, moderate, and severe PEP, respectively. The RAC diagnosed 94 %, 6 %, and 0 % with mild, moderate, and severe acute pancreatitis, respectively. Of the patients diagnosed with moderate-severe PEP by consensus definition, only 12.5 % had clinical parameters of pancreatitis severity, such as acute fluid collection(s), pancreatic necrosis, transient organ failure and/or required percutaneous or surgical drainage, while 87.5 % were classified only based on a LOS >= 4 days. The most common reason for increased LOS was persistent post procedural abdominal pain in 47 % of patients, followed by other reasons not related to pancreatitis in 17 %. Conclusion: The consensus definition overestimates the rates of severe PEP when compared to the RAC. The majority of PEP patients classified as moderate-severe PEP have extended LOS, due to post procedural abdominal pain rather than complications of PEP. PMID- 29978005 TI - Randomized study of digital single-operator cholangioscope compared to fiberoptic single-operator cholangioscope in a novel cholangioscopy bench model. AB - Background and study aims: Cholangiopancreatoscopy is utilized for diagnosis and therapy of pancreaticobiliary disorders. a fully-disposable, digital, single operator cholangioscope (DSOC) was developed with high image resolution and wide field-of-view. This bench study compared the new DSOC to the previous semi disposable, fiber-optic cholangioscope (FSOC) prior to the clinical availability of the DSOC system. Methods : Five experts performed one practice run followed by randomized runs comparing DSOC to FSOC in a biliary tract model consisting of three fixed left-intrahepatic tracts (LIHD), and variable common bile duct (CBD) and right-intrahepatic tracts (RIHD) with seven total lesions in multiple configurations. Timed runs aimed to visualize and target each lesion using miniature biopsy forceps. Definitions: visual success, visualizing targets; targeting success, touching target with forceps; complete run, touching seven targets within 20 minutes. Image quality, ease-of-use, and time to completion were recorded. Results : Thirty-seven evaluable runs (20 DSOC, 17 FSOC) were completed. DSOC was superior to FSOC in Visual (99 % vs. 67 %, P < 0.001) and targeting success (6.6 vs. 4.5, P = 0.009), proportion of complete runs (13 /20 vs. 0 /17, P < 0.001) and time of run (10.1 min vs. 15.4 min, P < 0.001). For fixed LIHD, DSOC achieved higher targeting success compared to FSOC (2.6 vs. 1.1, P < 0.001) with no difference in RIHD and CBD targets (4.0 vs. 3.4, P = 0.39). Investigators reported superior image quality and ease-of-use with DSOC. Conclusions : In this model, DSOC performed superiorly to FSOC in image quality, visualization, and maneuverability. The model could potentially be utilized for training endoscopists less experienced with cholangiopancreatoscopy. PMID- 29978006 TI - Use of anticoagulants increases risk of bleeding after colorectal endoscopic submucosal dissection. AB - Background and study aims : Japanese guidelines for gastroenterological endoscopy have recommended temporary withdrawal of anticoagulants (warfarin, direct oral anticoagulants [DOAC], or heparin) to prevent hemorrhagic complications during endoscopic submucosal dissection (ESD) for colorectal neoplasias (CRNs). However, serious thrombosis might occur during temporary withdrawal of anticoagulants. The current study aimed to evaluate outcomes with anticoagulants in patients undergoing ESD for CRNs. Patients and methods: This study was a single institution retrospective cohort study based on clinical records. We assessed 650 consecutive patients with 698 CRNs who underwent ESD at Hiroshima University Hospital between December 2010 and June 2016. The patients were divided into three groups: the warfarin group (19 patients with 19 CRNs), DOAC group (7 patients with 9 CRNs), and no-antithrombotics group (624 patients with 670 CRNs). We replaced warfarin with heparin 3 to 5 days before endoscopy. Although DOAC was suspended on the morning of endoscopy, we did not replace heparin. Results: Bleeding after the procedure occurred in 26.3 % (5/19), 22.0 % (2/9), and 2.7 % (18/670) of patients in the warfarin, DOAC, and no-antithrombotics groups, respectively. In the warfarin group, four patients who bled after the procedure took not only warfarin but also other antiplatelets. En bloc resection rates were 94.7 % (18/19), 100 % (9/9), and 96.6 % (647/670) in the warfarin, DOAC, and no antithrombotics groups, respectively. No patients experienced ischemic events in the perioperative period. Conclusions : Among patients undergoing ESD for CRNs, risk of bleeding was higher among patients who took anticoagulants than among those who did not. In particular, careful attention to patients who took antiplatelets in addition to warfarin before ESD for CRNs is warranted. PMID- 29978007 TI - Open-pore film drainage (OFD): a new multipurpose tool for endoscopic negative pressure therapy (ENPT). AB - Background and study aims: Endoscopic negative pressure therapy (ENPT) has been developed to treat gastrointestinal leakages. Up to now, ENPT has usually been performed with open-pore polyurethane foam drains (OPD). A big disadvantage of the OPDs is their large diameter. We have developed a new, small-bore open-pore film drainage (OFD). Herein we report our first experience in a case series of 16 patients. Patients and methods: OFD is constructed with a drainage tube and a very thin double-layered open-pore drainage film (Suprasorb CNP, Drainage Film, Lohmann & Rauscher International, Germany). The distal end of the tube is wrapped with only one layer of film. OFD is placed into the gastrointestinal leakage site with common endoscopic techniques. The tube is connected to an electronic vacuum device and continuous negative pressure of -125 mmHg applied. Results: From 2013 to 2016, 16 patients were treated with the new OFD device. In 10 patients, transmural intestinal defects (4 esophageal, 4 rectum/colon, 1 duodenal, 1 pancreatic cyst) were closed with ENPT in median time of 12 days (range 3 - 34 days). Five of the 10 patients were treated solely with OFD devices. In five patients ENPT started with ODP and changed to OFD when the cavity was shrunken to a channel with a small opening. In four patients postoperative gastric reflux was eliminated for 5 to 16 days. Conclusions: Small-bore OFD opens up promising new treatment options within ENPT. OFD can be used in endoscopic closure management of intestinal leakages in the upper and lower gastrointestinal tract. Gastric reflux can be eliminated in an active manner. OFD can be inserted nasally. OFD may be an adequate substitute for OPD, especially when placement of the larger OPD is difficult. PMID- 29978008 TI - The B-ADENOMA Study: Bowelscope - Accuracy of Detection using Endocuff Optimisation of Mucosal Abnormalities: Study Protocol for randomised controlled trial. AB - Background and study aims: UK Bowel Cancer Screening flexible sigmoidoscopy (BowelScope) currently offers patients aged 55 a one-off flexible sigmoidoscopy for adenoma clearance to decrease colorectal cancer incidence by interrupting the adenoma-carcinoma sequence. Recent evidence has shown maximum benefit in increasing adenoma detection rate (ADR) using the Endocuff Vision device in the left side of the colon and in screening patients. Currently, ADR is low and shows unacceptable variation in BowelScope. ADR is a quality indicator in screening sigmoidoscopy and higher rates have been shown to reduce colorectal cancer incidence. Patients and methods: This will be a prospective, multicenter, UK based randomized controlled trial (RCT) comparing ADR in Endocuff-assisted versus standard bowel cancer screening flexible sigmoidoscopy (BowelScope). All patients aged 55 to 61 years invited to BowelScope screening and able to give informed consent will be eligible for recruitment. Exclusion criteria include absolute contraindications to flexible sigmoidoscopy, known or suspected large bowel obstruction or pseudo-obstruction, colonic strictures or polyposis syndromes, known severe diverticular segment, active colitis, inability to give informed consent, anticoagulation precluding polypectomy and pregnancy. Patients will be randomized on the day of procedure to Endocuff-assisted flexible sigmoidoscopy or standard flexible sigmoidoscopy, stratified by age group and sex. Baseline, endoscopy and polyp data were collected as well as nurse and patient assessment of comfort. Polyp histology was collected when available. Patients will be asked to return a comfort questionnaire the following day and were followed up for 14 days for complications. Results: The ADENOMA trial will be designed to demonstrate a significant improvement in ADR with maximal effect in the left colon and in fecal occult blood test-positive screening patients. This trial will be the first RCT to look at Endocuff Vision in bowel cancer screening flexible sigmoidoscopy. We will aim to establish whether Endocuff vision improves ADR in this population. PMID- 29978009 TI - Number of polyps detected is a useful indicator of quality of clinical colonoscopy. AB - Background and study aims: Adenoma detection rate (ADR) is a well-known quality indicator (QI) for colonoscopy. It is, however, difficult to evaluate ADR during practice. The aim of this study was to investigate the number of endoscopically detected polyps as a QI for colonoscopy. Patients and methods: This was a retrospective single-center cohort study of 5,190 consecutive patients who underwent colonoscopy from January 2015 to May 2016. Among these patients, we ultimately enrolled 1,937 patients for initial colonoscopy. We evaluated QIs including bowel preparation, cecum intubation time, withdrawal time, number of endoscopically detected polyps, ADR and advanced neoplasia detection rate (ANDR). Results : The mean number of endoscopically detected polyps, ADR and ANDR were 1.5 +/- 2.3 (95 % confidence interval (CI)1.4 - 1.6), 38.6 % (95 % CI 36.5-40.8), and 18.3 % (95 % CI 16.6 - 20.1), respectively. ADR and ANDR increased with the number of endoscopically detected polyps, but the correlation reached a plateau at five or more polyps. We divided the patients into three groups based on the number of polyps (1 to 2, 3 to 4, and 5 or more). Logistic regression analysis adjusted by age and sex revealed that presence of a large number of polyps was a strong predictor of advanced neoplasia (odds ratio: 3.1 [95 % CI 2.2 - 4.3] for 3 to 4 polyps and 7.9 [95 % CI 5.4 - 11.8] for 5 or more polyps when using the presence of 1 or 2 polyps as a reference). Conclusion : The number of endoscopically detected polyps can predict risk of advanced neoplasia and may thus be a new QI for colonoscopy. PMID- 29978010 TI - Double balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography in Roux-en-Y gastric bypass anatomy: expert vs. novice experience. AB - Background and study aims: Double-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (DBE-ERCP) in post-Roux-en-Y gastric bypass (RYGB) patients is a technically challenging procedure. We aimed to determine the success rate of DBE-ERCP performed by a novice to the procedure in post-RYGB after training with an expert. Patients and methods: Medical records for 103 consecutive post-RYGB patients who underwent DBE-ERCP in a tertiary center were retrospectively reviewed. The procedures were performed by Operator A (18 years of high-volume ERCP practice before acquiring DBE skill in 2004), and operator B ( < 2 years' experience in DBE and ERCP). ERCP success rate and time in patients with an intact papilla were compared between Operator A's first and last sets of cases in equal number to the cases performed by Operator B. Results: A total of 129 DBE-ERCPs were performed (Operator A: 109; Operator B: 20) over an 80-month time span. Among patients with an intact papilla, DBE-ERCP success rates for Operator A's first (87.5 %) and last (92.9 %) 20 cases were similar to that of Operator B (92.9 %) ( P = 1.00 for both). Mean of DBE-ERCP time for the last 20 cases of Operator A was (100 minutes; 95 % confidence interval: 81,123) less than that for operator B (176 minutes; 95 % confidence interval: 138,224) ( P = 0.01). Overall adverse events rates were 11 % and 5 % for Operators A and B, respectively ( P = 0.69): pancreatitis (n = 10), cholangitis (n = 1), and perforation (n = 2); all were mild and treated conservatively. Conclusions: Despite the intrinsic technical difficulty, DBE-ERCP can be successfully and safely performed in post-RYGB patients by an endoscopist proficient in both conventional DBE and ERCP. Ideally, this endoscopist should observe several cases of DBE-ERCP performed by an expert to learn the techniques. PMID- 29978011 TI - EUS-guided sampling with 25G biopsy needle as a rescue strategy for diagnosis of small subepithelial lesions of the upper gastrointestinal tract. AB - Background and study aims: This study was designed to evaluate the impact of additional tissue obtained with endoscopic ultrasound (EUS)-guided 25-gauge core biopsy needle (25G-PC) following an unsuccessful fine-needle biopsy (FNB) performed with larger-bore needles for the characterization of gastrointestinal subepithelial lesions (GI-SELs). Patients and methods: We prospectively collected and retrospectively analyzed information in our database from January 2013 to June 2017 for all patients with GI-SELs who received a EUS-guided FNB (EUS-FNB) with 25G-PC during the same procedure after failure of biopsy performed with larger-bore needle. Diagnostic yield, diagnostic accuracy and procedural complications were evaluated. Results : Sixteen patients were included in this study, 10 men and 6 women, median age 67.8 (range 43 to 76 years). Five patients were found to have a SEL localized in the distal duodenum, five in the gastric antrum, two in the gastric fundus and four in the gastric body. The mean size of the lesions was 20.5 mm (range 18 - 24 mm). EUS-FNB with 25G-PC enabled final diagnosis in nine patients (56.2 %). Regarding the subgroup of duodenal lesions, the procedure was successful in four of five (80 %). Final diagnoses with EUS guided sampling were GIST (n = 6), leiomyoma (n = 2) and metastatic ovarian carcinoma (n = 1). No procedure-related complications were recorded. Conclusion: In patients with small GI-SELs, additional tissue obtained with 25G-PC could represents a "rescue" strategy after an unsuccessful procedure with larger-bore needles, especially when lesions are localized in the distal duodenum. PMID- 29978012 TI - When to abandon the search for an elusive gastrointestinal bleeding source. AB - Background and study aims: In some patients with gastrointestinal bleeding, even multiple consecutive endoscopic procedures fail to achieve lasting hemostasis. The current decision analysis was designed to answer the question of when to continue or abandon a sequence of endoscopic attempts of endoscopic hemostasis. Materials and methods: A decision tree with a threshold analysis was used to model the decision between continued endoscopy or expectant management. A low threshold probability was indicative of a preferred management option. Results : For continued endoscopy to be the favored decision, its probability of success in achieving hemostasis needed to exceed the success probability of expectant management by a greater amount than its costs exceeded those of expectant management. Endoscopic attempts at hemostasis should be discontinued if the costs of endoscopy are high compared with those of expectant management. The endoscopic attempt should be continued, if its probability for achieving lasting hemostasis is high. Conclusions : Such principles are applicable as rule of thumb in managing patients with ongoing chronic gastrointestinal bleeding. PMID- 29978013 TI - Endosonography-guided drainage of loculated malignant ascites using double pigtail plastic stents. AB - Background and study aims Endoscopic ultrasound (EUS)-guided drainage is a well established procedure for peripancreatic fluid collections (PFC) that develop in the context of acute pancreatitis or following pancreatic surgery. Malignant ascites can occur in a loculated form resembling PFC causing a variety of symptoms, with limited treatment options. There is a paucity of data about application of EUS-guided drainage for these kinds of fluid collections. So far, only one report exists describing clinical success in three cases, using fully covered self-expanding metal stents (FCSEMS). FCSEMS, however, have possible drawbacks, particularly if they have to remain in place for an indeterminate period of time. Herein, we describe EUS-guided drainage of loculated malignant ascites using double-pigtail plastic stents in two patients severely symptomatic from esophagogastric obstruction symptoms. Technical and clinical success was achieved in both cases without clinically significant complications including one case, where ongoing symptom control could be observed after 6 months of follow up. PMID- 29978014 TI - Validation of a simple screening tool for early diagnosis of advanced Parkinson's disease in daily practice: the CDEPA questionnaire. AB - Early clinical diagnosis of advanced Parkinson's disease (APD) may be difficult. This study aimed to validate a simple screening tool, the CDEPA questionnaire ("Cuestionario De Enfermedad de Parkinson Avanzada" [Questionnaire for Advanced Parkinson's Disease]), for the identification of APD in daily practice. The study included 173 consecutively selected patients with PD (40% were women, mean age was 68.4 +/- 10.5 years), stratified according to the Hoehn and Yahr (HY) scale. The CDEPA questionnaire defined APD as the presence of severe disability requiring help for activities of daily living (ADL), motor fluctuations with limitation or inability to perform ADL, severe dysphagia, recurrent falls, or dementia. The diagnostic performance of the questionnaire was assessed against the gold standard criterion based on clinical judgment. PD was categorized as advanced in 65 (38%) patients when using the gold standard and in 109 (63%) patients when the CDEPA questionnaire was used. The CDEPA questionnaire and the gold standard agreed moderately (kappa statistic of 0.48, P < 0.001). The CDEPA classified APD with a sensitivity of 97%; specificity of 57%; total accuracy of 72.3%; and area under the curve (for a binary classifier) of 77.2%. Significant differences were found between the groups created by the CDEPA in several usual PD evaluations (HY Scale, SCOPA Motor Scale, Non-motor Symptoms Scale for PD, Clinical Impression of Severity Index for PD, Clinical Global Impression-Severity Scale, and Patient Global Impression-Severity Scale). CDEPA showed satisfactory inter-rater agreement (kappa = 0.88) and test-retest concordance (kappa 0.83). In conclusion, the CDEPA questionnaire is a valid, reliable, and useful instrument for easily screening APD. PMID- 29978015 TI - Educational Case: Medullary Thyroid Carcinoma. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 29978016 TI - Educational Case: Cervical Neoplasia: HPV and Its Link to Cancer. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 29978017 TI - Educational Case: Head and Neck Neoplasia: Salivary Gland Tumors. AB - The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. PMID- 29978018 TI - Educational Case: Endocrine Neoplasm: Medullary Thyroid Carcinoma. AB - Medullary thyroid cancer is a rare neuroendocrine tumor that arises the neural crest-derived parafollicular C cells and accounts for approximately 5% to 10% of thyroid cancers worldwide. These tumor can occur sporadically or as part of hereditary tumor syndromes, such as multiple endocrine neoplasia 2 and familial medullary thyroid cancer. The most common clinical presentation is a solitary thyroid nodule. The genetic defect in these disorders involves the RET proto oncogene which is important for diagnosis of medullary thyroid cancer (including screening for hereditary medullary thyroid cancer) and for treatment guidance. This review summarizes the molecular basis and clinicopathologic features of medullary thyroid carcinoma. PMID- 29978020 TI - Editor's Letter. PMID- 29978019 TI - The Evolution of Earned, Transparent, and Quantifiable Faculty Salary Compensation: The Johns Hopkins Pathology Experience. AB - Faculty value equitable and transparent policies for determining salaries and expect their compensation to compare favorably to the marketplace. Academic institutions use compensation to recruit and retain talented faculty as well as to reward accomplishment. Institutions are therefore working to decrease salary disparities that appear arbitrary or reflect long-standing biases and to identify metrics for merit-based remuneration. Ours is a large academic pathology department with 97 tenure-track faculty. Faculty salaries are comprised of 3 parts (A + B + C). Part A is determined by the type of appointment and years at rank; part B recognizes defined administrative, educational, or clinical roles; and part C is a bonus to reward and incentivize activities that forward the missions of the department and medical school. A policy for part C allocations was first codified and approved by department faculty in 1993. It rewarded performance using a semiquantitative scale, based on subjective evaluations of the department director (chair) in consultation with deputy directors (vice chairs) and division directors. Faculty could not directly calculate their part C, and distributions data were not widely disclosed. Over the last 2 years (2015 2017), we have implemented a more objective formula for quantifying an earned part C, which is primarily designed to recognize scholarship in the form of research productivity, educational excellence, and clinical quality improvement. Here, we share our experience with this approach, reviewing part C calculations as made for individual faculty members, providing a global view of the resulting allocations, and considering how the process and outcomes reflect our values. PMID- 29978021 TI - Treatment Collaboration When the Stakes Are High: Ethnographically Studying Family-Centered Care in an Outpatient Pediatric Specialty Clinic. AB - Family-centered care (FCC) is vital for children with special health-care needs and serious chronic illnesses. Family-clinician collaboration and partnership formation are key FCC elements associated with improved health outcomes. However, FCC implementation barriers persist. Although some ethnographic research examines how FCC principles align with practice in inpatient settings, more studies are needed in outpatient specialty clinics. Using an FCC-oriented research team (clinicians, social science researchers, and families) blended multidisciplinary clinical knowledge and family/patient expertise with chronic illness. Our ethnographic study in a high-risk asthma outpatient clinic examined how FCC principles align with clinical practice, identified factors affecting partnership, and compared our findings to a large ethnographic study in an inpatient setting. Qualitative data from direct observation of 14 families with lengthy clinic visits were analyzed. Codes were applied to themes using FCC principles. Clinic visits had interactional and contextual elements that both aligned and misaligned with key FCC principles: information sharing, respect, participation, and collaboration. Recommendations for advancing FCC are outlined, and the importance of this step in light of ongoing health disparities is addressed. PMID- 29978022 TI - Towards a More Patient-Centered Approach to Medication Safety. PMID- 29978023 TI - Collaboration and Outside-the-Box Thinking to Overcome Training-Related Challenges for Including Patient Stakeholders as Data Collectors in a Patient Engaged Research Project. AB - Including patient stakeholders as active members of the research team is essential to a patient-engaged research design. To hire community-based research staff for a study comparing the effectiveness of diabetes self-management programs for Latinos, we had to provide phlebotomy training which was not allowed under the fiscal guidelines of our funders. By collaborating with partners at the Clinical and Translational Science Center, we were not only able to find a creative solution and provide phlebotomy training to our research staff but the process of creating the training also contributed to improved infrastructure for patient-engaged research at our institution. PMID- 29978024 TI - A Lifesaving View of Vascularized Composite Allotransplantation: Patient Experience of Social Death Before and After Face, Hand, and Larynx Transplant. AB - Introduction: Most solid organ transplantation is viewed as lifesaving, whereas vascularized composite allotransplantation (VCA) has been viewed as life enhancing. This article challenges the latter and argues that "social death" evident in severe face, hand, and larynx disfigurement can be potentially treated via VCA. Social death (from a social science perspective) consists of a combination of 7 components: social isolation, loneliness, ostracism, loss of personhood, change of role and identity, harm, and disfigurement. Methods: In February 2016, PubMed and Google were searched for case reports of human face, hand, and larynx transplantation. Patient and team narratives were then coded for components of social death using social science and medical model criteria. Results: Eleven narratives were identified among 9 articles. The social science model (but not the medical model) described pretransplant social death and the resolution of social death by receiving VCA. Notably, the medical model of social death was deemed unsuitable for application to VCA. This is because case narratives consistently contradict elements of the medical model. Conclusions: By including social death as a patient inclusion criterion for face, hand, and larynx VCA, these transplants can be considered lifesaving. Additionally, because VCA requires lifelong immunosuppressant medication, considering VCA as a lifesaving intervention improves the technology's risk-benefit analysis. Guidance for assessing social death is provided. PMID- 29978025 TI - Emergency Department Patient Experience: A Systematic Review of the Literature. AB - Introduction: Patient experience with emergency department (ED) care is an expanding area of focus, and recent literature has demonstrated strong correlation between patient experience and meeting several ED and hospital goals. The objective of this study was to perform a systematic review of existing literature to identify specific factors most commonly identified as influencing ED patient experience. Methods: A literature search was performed, and articles were included if published in peer-reviewed journals, primarily focused on ED patient experience, employed observational or interventional methodology, and were available in English. After a structured screening process, 107 publications were included for data extraction. Result: Of the 107 included publications, 51 were published before 2011, 57% were conducted by American investigators, and 12% were published in nursing journals. The most commonly identified themes included staff-patient communication, ED wait times, and staff empathy and compassion. Conclusion: The most commonly identified drivers of ED patient experience include communication, wait times, and staff empathy; however, existing literature is limited. Additional investigation is necessary to further characterize ED patient experience themes and identify interventions that effectively improve these domains. PMID- 29978027 TI - The Influence of National Health Insurance on Medication Adherence Among Outpatient Type 2 Diabetics in Southwest Nigeria. AB - Purpose: Medication adherence (MA) is a challenge among patients with chronic diseases worldwide. Little has been reported on the influence of National Health Insurance Scheme (NHIS) on MA among diabetic patients in Nigeria. Objective: To assess the influence of NHIS on MA among outpatient type 2 diabetics in 2 public secondary health facilities in Southwest Nigeria. Method: A cross-sectional study involving 110 consecutively selected outpatient type 2 diabetics (insured, n = 42; uninsured, n = 68) was carried out. The patients' perceptions of care and the influence of drug cost on MA between the insured and uninsured were compared. The patients' perceptions of care were assessed using a 25-item pretested questionnaire. The MA was measured using the Morisky MA-8 scale. The use of oral antidiabetic drugs (OADs) was evaluated using a medical chart review. Information about patients' sociodemographics, year of diagnosis, comorbidities, and types of OADs prescribed was retrieved from the medical records. Descriptive statistics were used for data presentation. A Pearson chi2 was used for test of associations. P values < .05 were considered significant. Results: Majority of the respondents (68 [61.8%]) were uninsured. The insured and the uninsured patients differed in their perceptions of the adequacy of time used by pharmacists for medication counseling (P < .0005). The MA between the groups also differs (P = .0002). The monthly drug cost for OADs was significantly associated with MA (P = .037). Conclusion: The study concluded that the NHIS may positively influence MA among diabetic patients. The drug cost may have contributed significantly to the difference in MA between the groups. More time should be devoted to the counseling of the uninsured patients. PMID- 29978026 TI - Veteran Patient Perspectives and Experiences During Implementation of a Patient Centered Medical Home Model. AB - Background: The Veterans Health Administration (VA) has implemented the largest shift to a patient-centered medical home (PCMH) model of care in the United States to date. Objective: We interviewed veterans about their experiences of primary care to understand whether they observed changes in care during this period as well as to learn which characteristics of care mattered most to their experiences. Method: Qualitative interviews were conducted with 32 veterans receiving primary care at 1 of 8 VA clinics in the northwest United States. Interviews were analyzed using an inductive-deductive hybrid approach by an interdisciplinary team that included a veteran patient. Result: Participants noticed recent positive changes, including improved communications and shorter waits in clinic, but rarely were aware of VA's PCMH initiative; a strong relationship with the primary care provider and feeling cared for/respected by everyone involved in care delivery were key components of quality care. The needs of the veteran community as a whole also shaped discussion of care expectations. Conclusion: The PCMH model may provide benefits even when invisible to patients. Veteran awareness of population needs suggests a promising role for veteran involvement in further PCMH transformation efforts. PMID- 29978028 TI - Motivations and Experiences of Canadians Seeking Treatment for Lyme Disease Outside of the Conventional Canadian Health-Care System. AB - Objective: We aimed to describe the experiences of Canadians who seek diagnosis and treatment for Lyme disease outside of the conventional Canadian health-care system. Methods: Forty-five individuals who had sought treatment for Lyme disease outside of the conventional Canadian health-care system were recruited from Lyme support and advocacy groups across Canada to answer open-ended questions about their experiences. Results: Respondents sought treatment outside of the conventional medical system due to extensive diagnostic procedures and treatments that did not resolve symptoms. Escalating health concerns, lack of effective treatment, and stigma produced a sense of abandonment and desperation. Respondents accessed alternative forms of care based on the recommendations of peers, yet considerable financial and emotional stress was experienced. Conclusions: Many individuals with Lyme or Lyme-like diseases are deeply dissatisfied with the care received within the conventional Canadian health-care system and therefore felt both pushed and pulled to seek treatments either from international physicians using different treatment protocols or from alternative medicine providers in Canada. PMID- 29978029 TI - Exploring Decisions to Undertake a Marathon and Adherence Challenges in a Novice Runner With Parkinson. AB - : Evidence endorses the benefits of more vigorous exercise for people with Parkinson's, particularly following diagnosis, yet is not clear which style is optimal. The authors share perspectives and decisions made as a physiotherapist (assisted by a sports and exercise science student) and a novice runner with Parkinson's in his late 50s, respectively. The exercise goal chosen by the runner (the case report participant) to minimize the degenerative effects of the progressive condition was to complete a marathon. Methods: This coauthored report evaluates the participant's progress utilizing physical fitness assessment data plus reflections on his training regime and notes from training diaries for the year before and after the marathon. Results: The participant received nutritional advice for weight management as exercise increased and physiotherapy for injuries from mounting activity level on Parkinsonian muscle tone. Fitness and function improved or were maintained (leg power, flexibility, timed functional walking, and balance). Most, however, returned to baseline within 6 months following the marathon as training intensity dropped. Conclusions: Physical function can be improved or maintained in individuals with neurodegenerative conditions with correct exercise and nutritional advice. The participant's choice of running was based on recommendations for condition maintenance and not enjoyment, so adherence and completion of the marathon goal required professional, family, and technological support. PMID- 29978030 TI - Twin-Twin Transfusion Syndrome and Maternal Symptomatology-An Exploratory Analysis of Patient Experiences When Reporting Complaints. AB - Objective: The aim of this study was to assess patient experiences when reporting symptoms of twin-twin transfusion syndrome (TTTS) to their health-care providers. Methodology: The study utilized an online, retrospective survey of women, over the age of 18, who were living in the United States at the time of their pregnancy and had completed a TTTS pregnancy. Results: Three hundred sixty-seven cases were included for analysis. Nearly half of the respondents (45.2%) reported experiencing maternal symptoms prior to TTTS diagnosis. The average number of symptoms experienced was 2.85. The average gestational week of symptom onset was 18.2. A total of 76.2% of respondents experiencing symptoms shared these concerns with their health-care provider; however, slightly more than half (51.2%) believed that the provider dismissed their complaints. Conclusions: Results suggest a disconnect between patients' reporting TTTS symptoms and health-care providers responding attentively, as perceived by the patient. It would be advantageous for health-care providers to inform women pregnant with a monochorionic-diamniotic pregnancy to immediately report the presence of any symptom described in the present research, which may be associated with any number of twin pregnancy-related complications. PMID- 29978031 TI - Subjective Experience of Illness Among Adolescents and Young Adults With Diabetes: A Qualitative Research Study. AB - Diabetes mellitus type 1 is a chronic illness that has its onset in childhood or adolescence. It is determined by the insufficient production of insulin. The main therapies consist of replacement of the lacking insulin, diet, exercise, and glycemic control. If treatment is managed by parents in childhood, adherence seems to be a difficult issue during adolescence. In order to understand the subjective experience of the illness and treatment, the present study aims to investigate the patients' subjective perspective by addressing a group of adolescents and young adults in pediatric care. A qualitative research design was adopted with semi-structured interviews, and later software thematic analysis was performed. Six core issues were deepened: family and health-care professional's mediation support for self-management, adherence to treatments as a boring responsibility, disclosure problems in peer relationships, difficulty in becoming autonomous in a period of socioeconomic crisis, illness as concern for the future, and seeking a normal life in daily activities. The knowledge can be useful for designing more appropriate interventions that favor the active engagement of patients. PMID- 29978032 TI - Patient Experiences in Selecting a Medicare Part D Prescription Drug Plan. AB - Introduction: Medicare beneficiaries often report that the process of choosing a prescription drug plan is frustrating and confusing and many do not enroll in the plan that covers their drugs at the lowest cost. Methods: We conducted 4 focus groups to understand beneficiaries' experiences in selecting a drug plan to identify what resources and factors were most important to them. Participants were patients served by a multispecialty delivery system and were primarily affluent and Caucasian. Results: While low cost was essential to many, other characteristics like having the same plan as a partner, company reputation, convenience, and anticipation of possible future health problems were sometimes more important. Although some used resources including insurance brokers, counselors, and websites beyond Medicare.gov, many expressed a desire for greater assistance with and greater simplicity in the choice process. Conclusion: Although older adults would likely benefit from greater assistance in choosing Medicare Part D prescription drug plans, more research is necessary to understand how to help with decision-making in this context. PMID- 29978033 TI - Splenic Syndrome in a Young Man at High Altitude with Undetected Sickle Cell Trait. AB - Introduction: Splenic syndrome is a rare presentation of sickle cell disease. It is important to rule out this possibility when an ethnically vulnerable patient presents with an acute abdominal symptoms in a background of precipitating events. Case Report: A 26-year-old man who developed a severe abdominal pain at high altitude, found to have a tender splenomegaly. However, further inquiry revealed he is from an area where sickle cell disease is prevalent. Screening for sickle cell disease was positive. Radiological investigations confirmed a massive splenic infarction keeping with a diagnosis of splenic syndrome. Patient was managed conservatively. Conclusion: Sickle cell trait is considered a benign carrier state. However, rarely they can present with life-threatening conditions. Therefore, a high degree of clinical suspicion is required for early diagnosis of these specific entities to avoid increased morbidity and mortality of these patients. PMID- 29978034 TI - Change in longitudinal trends in sleep quality and duration following breast cancer diagnosis: results from the Women's Health Initiative. AB - Breast cancer survivors frequently report sleep problems, but little research has studied sleep patterns longitudinally. We examined trends in sleep quality and duration up to 15 years before and 20 years after a diagnosis of breast cancer, over time among postmenopausal women participating in the Women's Health Initiative (WHI). We included 12,098 participants who developed invasive breast cancer after study enrollment. A linear mixed-effects model was used to determine whether the time trend in sleep quality, as measured by the WHI Insomnia Rating Scale (WHIIRS), a measure of perceived insomnia symptoms from the past 4 weeks, changed following a cancer diagnosis. To examine sleep duration, we fit a logistic regression model with random effects for both short (<6 h) and long (>=9 h) sleep. In addition, we studied the association between depressive symptoms and changes in WHIIRS and sleep duration. There was a significantly slower increase in the trend of WHIIRS after diagnosis (beta = 0.06; p = 0.03), but there were non-significant increases in the trend of the probability of short or long sleep after diagnosis. The probability of depressive symptoms significantly decreased, though the decrease was more pronounced after diagnosis (p < 0.01). Trends in WHIIRS worsened at a relatively slower rate following diagnosis and lower depression rates may explain the slower worsening in WHIIRS. Our findings suggest that over a long period of time, breast cancer diagnosis does not adversely affect sleep quality and duration in postmenopausal women compared to sleep pre diagnosis, yet both sleep quality and duration continue to worsen over time. PMID- 29978035 TI - Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer. AB - The first genomic scar-based homologous recombination deficiency (HRD) measures were produced using SNP arrays. As array-based technology has been largely replaced by next generation sequencing approaches, it has become important to develop algorithms that derive the same type of genomic scar scores from next generation sequencing (whole exome "WXS", whole genome "WGS") data. In order to perform this analysis, we introduce here the scarHRD R package and show that using this method the SNP array-based and next generation sequencing-based derivation of HRD scores show good correlation (Pearson correlation between 0.73 and 0.87 depending on the actual HRD measure) and that the NGS-based HRD scores distinguish similarly well between BRCA mutant and BRCA wild-type cases in a cohort of triple-negative breast cancer patients of the TCGA data set. PMID- 29978036 TI - Alternative cereals can improve water use and nutrient supply in India. AB - Humanity faces the grand challenge of feeding a growing, more affluent population in the coming decades while reducing the environmental burden of agriculture. Approaches that integrate food security and environmental goals offer promise for achieving a more sustainable global food system, yet little work has been done to link potential solutions with agricultural policies. Taking the case of cereal production in India, we use a process-based crop water model and government data on food production and nutrient content to assess the implications of various crop-shifting scenarios on consumptive water demand and nutrient production. We find that historical growth in wheat production during the rabi (non-monsoon) season has been the main driver of the country's increased consumptive irrigation water demand and that rice is the least water-efficient cereal for the production of key nutrients, especially for iron, zinc, and fiber. By replacing rice areas in each district with the alternative cereal (maize, finger millet, pearl millet, or sorghum) with the lowest irrigation (blue) water footprint (WFP), we show that it is possible to reduce irrigation water demand by 33% and improve the production of protein (+1%), iron (+27%), and zinc (+13%) with only a modest reduction in calories. Replacing rice areas with the lowest total (rainfall + irrigation) WFP alternative cereal or the cereal with the highest nutritional yield (metric tons of protein per hectare or kilograms of iron per hectare) yielded similar benefits. By adopting a similar multidimensional framework, India and other nations can identify food security solutions that can achieve multiple sustainability goals simultaneously. PMID- 29978037 TI - Long-term viability of carbon sequestration in deep-sea sediments. AB - Sequestration of carbon dioxide in deep-sea sediments has been proposed for the long-term storage of anthropogenic CO2 that can take advantage of the current offshore infrastructure. It benefits from the negative buoyancy effect and hydrate formation under conditions of high pressure and low temperature. However, the multiphysics process of injection and postinjection fate of CO2 and the feasibility of subseabed disposal of CO2 under different geological and operational conditions have not been well studied. With a detailed study of the coupled processes, we investigate whether storing CO2 into deep-sea sediments is viable, efficient, and secure over the long term. We also study the evolution of multiphase and multicomponent flow and the impact of hydrate formation on storage efficiency. The results show that low buoyancy and high viscosity slow down the ascending plume and the forming of the hydrate cap effectively reduces permeability and finally becomes an impermeable seal, thus limiting the movement of CO2 toward the seafloor. We identify different flow patterns at varied time scales by analyzing the mass distribution of CO2 in different phases over time. We observe the formation of a fluid inclusion, which mainly consists of liquid CO2 and is encapsulated by an impermeable hydrate film in the diffusion-dominated stage. The trapped liquid CO2 and CO2 hydrate finally dissolve into the pore water through diffusion of the CO2 component, resulting in permanent storage. We perform sensitivity analyses on storage efficiency under variable geological and operational conditions. We find that under a deep-sea setting, CO2 sequestration in intact marine sediments is generally safe and permanent. PMID- 29978038 TI - Capacity to support predators scales with habitat size. AB - Habitat reduction could drive biodiversity loss if the capacity of food webs to support predators is undermined by habitat-size constraints on predator body size. Assuming that (i) available space restricts predator body size, (ii) mass specific energy needs of predators scale with their body size, and (iii) energy availability scales with prey biomass, we predicted that predator biomass per unit area would scale with habitat size (quarter-power exponent) and prey biomass (three-quarter-power exponent). We found that total predator biomass scaled with habitat size and prey resources as expected across 29 New Zealand rivers, such that a unit of habitat in a small ecosystem supported less predator biomass than an equivalent unit in a large ecosystem. The lower energetic costs of large body size likely mean that a unit of prey resource supports more biomass of large bodied predators compared to small-bodied predators. Thus, contracting habitat size reduces the predator mass that can be supported because of constraints on predator body size, and this may be a powerful mechanism exacerbating reductions in biodiversity due to habitat loss. PMID- 29978039 TI - Flavivirus serocomplex cross-reactive immunity is protective by activating heterologous memory CD4 T cells. AB - How previous immunity influences immune memory recall and protection against related flaviviruses is largely unknown, yet encounter with multiple flaviviruses in a lifetime is increasingly likely. Using sequential challenges with dengue virus (DENV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), we induced cross-reactive cellular and humoral immunity among flaviviruses from differing serocomplexes. Antibodies against JEV enhanced DENV replication; however, JEV immunity was protective in vivo during secondary DENV1 infection, promoting rapid gains in antibody avidity. Mechanistically, JEV immunity activated dendritic cells and effector memory T cells, which developed a T follicular helper cell phenotype in draining lymph nodes upon secondary DENV1 infection. We identified cross-reactive epitopes that promote recall from a pool of flavivirus serocomplex cross-reactive memory CD4 T cells and confirmed that a similar serocomplex cross-reactive immunity occurs in humans. These results show that sequential immunizations for flaviviruses sharing CD4 epitopes should promote protection during a subsequent heterologous infection. PMID- 29978040 TI - A strategy for the conservation of biodiversity on mid-ocean ridges from deep-sea mining. AB - Mineral exploitation has spread from land to shallow coastal waters and is now planned for the offshore, deep seabed. Large seafloor areas are being approved for exploration for seafloor mineral deposits, creating an urgent need for regional environmental management plans. Networks of areas where mining and mining impacts are prohibited are key elements of these plans. We adapt marine reserve design principles to the distinctive biophysical environment of mid-ocean ridges, offer a framework for design and evaluation of these networks to support conservation of benthic ecosystems on mid-ocean ridges, and introduce projected climate-induced changes in the deep sea to the evaluation of reserve design. We enumerate a suite of metrics to measure network performance against conservation targets and network design criteria promulgated by the Convention on Biological Diversity. We apply these metrics to network scenarios on the northern and equatorial Mid-Atlantic Ridge, where contractors are exploring for seafloor massive sulfide (SMS) deposits. A latitudinally distributed network of areas performs well at (i) capturing ecologically important areas and 30 to 50% of the spreading ridge areas, (ii) replicating representative areas, (iii) maintaining along-ridge population connectivity, and (iv) protecting areas potentially less affected by climate-related changes. Critically, the network design is adaptive, allowing for refinement based on new knowledge and the location of mining sites, provided that design principles and conservation targets are maintained. This framework can be applied along the global mid-ocean ridge system as a precautionary measure to protect biodiversity and ecosystem function from impacts of SMS mining. PMID- 29978041 TI - Krypton isotopes and noble gas abundances in the coma of comet 67P/Churyumov Gerasimenko. AB - The Rosetta Orbiter Spectrometer for Ion and Neutral Analysis mass spectrometer Double Focusing Mass Spectrometer on board the European Space Agency's Rosetta spacecraft detected the major isotopes of the noble gases argon, krypton, and xenon in the coma of comet 67P/Churyumov-Gerasimenko. Earlier, it was found that xenon exhibits an isotopic composition distinct from anywhere else in the solar system. However, argon isotopes, within error, were shown to be consistent with solar isotope abundances. This discrepancy suggested an additional exotic component of xenon in comet 67P/Churyumov-Gerasimenko. We show that krypton also exhibits an isotopic composition close to solar. Furthermore, we found the argon to krypton and the krypton to xenon ratios in the comet to be lower than solar, which is a necessity to postulate an addition of exotic xenon in the comet. PMID- 29978043 TI - A nearly complete foot from Dikika, Ethiopia and its implications for the ontogeny and function of Australopithecus afarensis. AB - The functional and evolutionary implications of primitive retentions in early hominin feet have been under debate since the discovery of Australopithecus afarensis. Ontogeny can provide insight into adult phenotypes, but juvenile early hominin foot fossils are exceptionally rare. We analyze a nearly complete, 3.32 million-year-old juvenile foot of A. afarensis (DIK-1-1f). We show that juvenile A. afarensis individuals already had many of the bipedal features found in adult specimens. However, they also had medial cuneiform traits associated with increased hallucal mobility and a more gracile calcaneal tuber, which is unexpected on the basis of known adult morphologies. Selection for traits functionally associated with juvenile pedal grasping may provide a new perspective on their retention in the more terrestrial adult A. afarensis. PMID- 29978042 TI - The evolution of anti-bat sensory illusions in moths. AB - Prey transmit sensory illusions to redirect predatory strikes, creating a discrepancy between what a predator perceives and reality. We use the acoustic arms race between bats and moths to investigate the evolution and function of a sensory illusion. The spinning hindwing tails of silk moths (Saturniidae) divert bat attack by reflecting sonar to create a misleading echoic target. We characterized geometric morphometrics of moth hindwings across silk moths, mapped these traits onto a new, robust phylogeny, and found that elaborated hindwing structures have converged on four adaptive shape peaks. To test the mechanism underlying these anti-bat traits, we pit bats against three species of silk moths with experimentally altered hindwings that created a representative gradient of ancestral and extant hindwing shapes. High-speed videography of battles reveals that moths with longer hindwings and tails more successfully divert bat attack. We postulate that sensory illusions are widespread and are underappreciated drivers of diversity across systems. PMID- 29978044 TI - CH4 mitigation potentials from China landfills and related environmental co benefits. AB - China's CH4 emissions from 1955 existing (old) and 495 planned (new) landfills are estimated and projected by adopting a bottom-up method, targeting a 2012 baseline year and a 2030 projected target year. Nine key CH4 mitigation measures are proposed for the CH4 mitigation assessment from landfills. Approximately 0.66 million metric tons (Mt) of CH4 and 1.14 Mt of CH4 will be released, respectively, from new and existing landfills under a 2030 business-as-usual (BAU) scenario, which is 23.5% lower than a U.S. Environmental Protection Agency estimation. It is estimated that 0.60 and 0.97 Mt of CH4 can be reduced under new policies (NP) and low-carbon (LC) policy scenarios, respectively. The combined biocover and landfill gas collection and flaring system is the most promising mitigation measure, while mechanical biological treatment and mineral landfill also contribute substantially to CH4 reduction. The odor-affected population under NP and LC scenarios will decrease by 39.5 and 64.2%, respectively, when compared to the 2030 BAU scenario. The LC scenario is a recommended policy for meeting China's nationally determined contribution targets and reducing the not in-my-backyard impact due to this policy's significant reduction of CH4 emissions. PMID- 29978045 TI - A BK channel-mediated feedback pathway links single-synapse activity with action potential sharpening in repetitive firing. AB - Action potential shape is a major determinant of synaptic transmission, and mechanisms of spike tuning are therefore of key functional significance. We demonstrate that synaptic activity itself modulates future spikes in the same neuron via a rapid feedback pathway. Using Ca2+ imaging and targeted uncaging approaches in layer 5 neocortical pyramidal neurons, we show that the single spike-evoked Ca2+ rise occurring in one proximal bouton or first node of Ranvier drives a significant sharpening of subsequent action potentials recorded at the soma. This form of intrinsic modulation, mediated by the activation of large conductance Ca2+/voltage-dependent K+ channels (BK channels), acts to maintain high-frequency firing and limit runaway spike broadening during repetitive firing, preventing an otherwise significant escalation of synaptic transmission. Our findings identify a novel short-term presynaptic plasticity mechanism that uses the activity history of a bouton or adjacent axonal site to dynamically tune ongoing signaling properties. PMID- 29978047 TI - Impactful science as the guiding principle. PMID- 29978046 TI - Biogeography of soil bacteria and archaea across France. AB - Over the last two decades, a considerable effort has been made to decipher the biogeography of soil microbial communities as a whole, from small to broad scales. In contrast, few studies have focused on the taxonomic groups constituting these communities; thus, our knowledge of their ecological attributes and the drivers determining their composition and distribution is limited. We applied a pyrosequencing approach targeting 16S ribosomal RNA (rRNA) genes in soil DNA to a set of 2173 soil samples from France to reach a comprehensive understanding of the spatial distribution of bacteria and archaea and to identify the ecological processes and environmental drivers involved. Taxonomic assignment of the soil 16S rRNA sequences indicated the presence of 32 bacterial phyla or subphyla and 3 archaeal phyla. Twenty of these 35 phyla were cosmopolitan and abundant, with heterogeneous spatial distributions structured in patches ranging from a 43- to 260-km radius. The hierarchy of the main environmental drivers of phyla distribution was soil pH > land management > soil texture > soil nutrients > climate. At a lower taxonomic level, 47 dominant genera belonging to 12 phyla aggregated 62.1% of the sequences. We also showed that the phylum-level distribution can be determined largely by the distribution of the dominant genus or, alternatively, reflect the combined distribution of all of the phylum members. Together, our study demonstrated that soil bacteria and archaea present highly diverse biogeographical patterns on a nationwide scale and that studies based on intensive and systematic sampling on a wide spatial scale provide a promising contribution for elucidating soil biodiversity determinism. PMID- 29978048 TI - An Update on Unloading Knee Braces in the Treatment of Unicompartmental Knee Osteoarthritis from the Last 10 Years: A Literature Review. AB - Background The incidence of osteoarthritis is increasing and it is one of the most common causes of chronic conditions. Total knee replacement is the mainstay of treatment for end-stage knee osteoarthritis; however, with long waiting lists and high levels of dissatisfaction, a treatment like knee braces could potentially delay surgery. Unicompartmental knee osteoarthritis is associated with misalignment of the knee, and unloader bracing has been recommended by various guidelines to correct this misalignment. The aim of this report was to provide an update of evidence from the past 10 years on knee braces. Methods MEDLINE/EMBASE search was performed from the past 10 years. Results We reviewed the evidence from 14 published articles. Almost all articles supported knee brace use and showed it to decrease pain, improve function, and improve the quality of life of patients. One study in 2017 followed patients for long term and found knee bracing to be more cost effective than total knee replacement, and could replace the need for surgery. Several minor complications were reported with bracing, like soft tissue irritation, which could be due to poor fitting. A management strategy for this could be regular follow-up at a nurse-led clinic. Conclusions Unloader braces are an economical and effective treatment for unicompartmental knee osteoarthritis. They can significantly improve a patient's quality of life and potentially delay the need for surgery. Patients should be managed with a multidisciplinary approach with conservative management and knee bracing, before surgery is considered. PMID- 29978049 TI - Characterisation of Newly Emerged Isolates of Classical Swine Fever Virus in China, 2014-2015. AB - Introduction: In 2014-2015, the epidemic of classical swine fever (CSF) occurred in many large-scale pig farms in different provinces of China, and a subgenotype 2.1d of CSF virus (CSFV) was newly identified. Material and Methods: The phylogenetic relationship, genetic diversity, and epidemic status of the 2014 2015 CSFV isolates, 18 new CSFV isolates collected in 2015, and 43 other strains isolated in 2014-2015 were fully analysed, together with 163 CSFV reference isolates. Results: Fifty-two 2014-2015 isolates belonged to subgenotype 2.1d and nine other isolates belonged to subgenotype 2.1b. The two subgenotype isolates showed unique molecular characteristics. Furthermore, the 2.1d isolates were found to possibly diverge from 2.1b isolates. Conclusion: This study suggests that the Chinese CSFVs will remain pandemic. PMID- 29978051 TI - Evaluation of Susceptibility to Antimycobacterial Drugs in Mycobacterium Tuberculosis Complex Strains Isolated from Cattle in Poland. AB - Introduction: Tuberculosis is a highly infectious disease affecting humans and animals. It is caused by the Mycobacterium tuberculosis complex (MTBC) - Mycobacterium bovis and Mycobacterium caprae, which are aetiological factors of bovine tuberculosis (bTB). In Poland, the bTB eradication programme exists. Animals diagnosed with tuberculosis are in the majority of cases not treated, but removed from their herd and then sanitary slaughtered. Material and Methods: In total, 134 MTBC strains isolated from cattle in Poland were subjected to microbiological analysis. The resistance phenotype was tested for first-line antimycobacterial drugs used in tuberculosis treatment in humans: streptomycin, isoniazid, rifampicin, ethambutol, and pyrazinamide. The strains were isolated from tissues collected post mortem, so the test for drug resistance fulfilled only epidemiological criterion. Results: The analysis of drug-resistance of MTBC strains revealed that strains classified as M. bovis were susceptible to 4 antimycobacterial drugs: isoniazid, rifampicin, streptomycin, and ethambutol, and resistant to pyrazynamide. The strains classified as M. caprae were sensitive to all tested drugs. Conclusion: The results indicate that despite enormously dynamic changes in mycobacterial phenotype, Polish strains of MTBC isolated from cattle have not acquired environmental resistance. The strains classified as M. bovis are characterised by natural resistance to pyrazinamide, which is typical for this species. PMID- 29978050 TI - Exploration of the Main Sites for the Transformation of Normal Prion Protein (PrPC) into Pathogenic Prion Protein (PrPsc). AB - Introduction: The functions and mechanisms of prion proteins (PrPC) are currently unknown, but most experts believe that deformed or pathogenic prion proteins (PrPSc) originate from PrPC, and that there may be plural main sites for the conversion of normal PrPC into PrPSc. In order to better understand the mechanism of PrPC transformation to PrPSc, the most important step is to determine the replacement or substitution site. Material and Methods: BALB/c mice were challenged with prion RML strain and from 90 days post-challenge (dpc) mice were sacrificed weekly until all of them had been at 160 dpc. The ultra-structure and pathological changes of the brain of experimental mice were observed and recorded by transmission electron microscopy. Results: There were a large number of pathogen-like particles aggregated in the myelin sheath of the brain nerves, followed by delamination, hyperplasia, swelling, disintegration, phagocytic vacuolation, and other pathological lesions in the myelin sheath. The aggregated particles did not overflow from the myelin in unstained samples. The phenomenon of particle aggregation persisted all through the disease course, and was the earliest observed pathological change. Conclusion: It was deduced that the myelin sheath and lipid rafts in brain nerves, including axons and dendrites, were the main sites for the conversion of PrPC to PrPSc, and the PrPSc should be formed directly by the conversion of protein conformation without the involvement of nucleic acids. PMID- 29978052 TI - Microbiome and Antimicrobial Resistance Genes in Microbiota of Cloacal Samples from European Herring Gulls (Larus Argentatus). AB - Introduction: The aim of the study was to determine microbiota in the cloacal samples of European herring gulls (Larus argentatus) and to compare a variety of genes encoding antimicrobial resistance in cultivable and non-cultivable bacteria. Material and Methods: Cloacal samples from European herring gulls were collected from a Kaunas city dump. Cultivable microbiota were isolated, their microbial susceptibility was tested, and genes encoding antimicrobial resistance were detected. Additionally, a metagenomic study was performed using Next Generation Sequencing (NGS). Results: In total, 697 different operational taxonomic units at genus level were detected; however, only 63 taxonomic units were detected at the amount of >=0.1% of the total number of DNA copies. Catellicoccus marimammalium was found to have the highest prevalence. The bacterial amount of other genera was up to 5% with the most highly prevalent being Psychrobacter (4.7%), Helicobacter(4.5%), unclassified Enterococcaceae (3.2%), Pseudomonas (2.9%), and Brachyspira (2.6%). Conclusions: C. marimammalium are predominant microbiota in the cloacal samples of Larus argentatus. This species of gulls is a reservoir of bacteria carrying a wide-spectrum of genes encoding antimicrobial resistance. The same genes were detected in both cultivable microbiota and in the total DNA of the samples. PMID- 29978053 TI - Withdrawal of Amoxicillin and Penicillin G Procaine from Milk after Intramammary Administration in Dairy Cows with Mastitis. AB - Introduction: There are many veterinary products containing beta-lactam antibiotics which are used for mastitis treatment in cows. The aim of the study was to determine whether mastitis could have any effect on amoxicillin (AMX) or penicillin G procaine (PEN) withdrawal period from milk, in the context of current maximum residue limits established by the European Commission. Material and Methods: The study was conducted on 17 dairy Black and White cows with clinical mastitis during the lactation period. The first group (n = 8) received 200 mg of amoxicillin (AMX), whereas the second group (n = 9) received 200,000 IU/mg of penicillin G procaine (PEN) by intramammary administration. For the measurement of AMX and PEN concentrations in milk, the liquid chromatography tandem mass spectrometry method was applied. Pharmacokinetic calculations were performed using Phoenix WinNonlin 6.4 software. Results: The determined AMX and PEN half-life values in the mammary gland suggest that the drug withdrawal is at a level of 99.9% within 81 h (~3.5 days) and 116 h (~5 days) after administration of AMX and PEN, respectively. The present research indicates that, at 60 h after administration, the average PEN concentration in the milk from cows with clinical signs of mastitis may still reach 4.96 g/kg and that of AMX can even be 6.92 g/kg. Conclusion: The results obtained confirm that, in mastitis cases, a 72-h withdrawal period is sufficient for elimination of AMX to a lower level than the established maximum residue limit (MRL) values. However, in the case of PEN, at 69 h after administration, the drug concentration may be close to that of the determined MRL. PMID- 29978054 TI - Modelling the Growth Rate of Listeria Monocytogenes in Cooked Ham Stored at Different Temperatures. AB - Introduction: The purpose of the study was to determine and model the growth rates of L. monocytogenes in cooked cured ham stored at various temperatures. Material and Methods: Samples of cured ham were artificially contaminated with a mixture of three L. monocytogenes strains and stored at 3, 6, 9, 12, or 15oC for 16 days. The number of listeriae was determined after 0, 1, 2, 3, 5, 7, 9, 12, 14, and 16 days. A series of decimal dilutions were prepared from each sample and plated onto ALOA agar, after which the plates were incubated at 37oC for 48 h under aerobic conditions. The bacterial counts were logarithmised and analysed statistically. Five repetitions of the experiment were performed. Results: Both storage temperature and time were found to significantly influence the growth rate of listeriae (P > 0.01). The test bacteria growth curves were fitted to three primary models: the Gompertz, Baranyi, and logistic. The mean square error (MSE) and Akaike's information criterion (AIC) were calculated to evaluate the goodness of fit. It transpired that the logistic model fit the experimental data best. The natural logarithms of L. monocytogenes' mean growth rates from this model were fitted to two secondary models: the square root and polynomial. Conclusion: Modelling in both secondary types can predict the growth rates of L. monocytogenes in cooked cured ham stored at each studied temperature, but mathematical validation showed the polynomial model to be more accurate. PMID- 29978056 TI - Beef Tenderness Improvement by Dietary Vitamin D3 Supplementation in the Last Stage of Fattening of Cattle. AB - Tenderness is the most important characteristic of meat, determining consumer approval. There are numerous methods of its improvement, although of diverse effectiveness. addition of vitamin D3 to the feed for a short period before slaughter (7-10 days) is one of the natural ways to enhance the tenderness. Vitamin D3 is responsible for Ca2+ mobilisation in serum and increase in activity of proteolytic enzymes belonging to calpains, which results in significant improvement of beef tenderness and reduction of ageing time. The use of vitamin D3 is an application tool determining tenderness improvement of beef with substantial reduction in processing costs. Moreover, shorter post mortem ageing process will exceed the retail display time, which will consequently reduce losses due to unsold meat being returned from shops to the manufacturers. Based on the results of studies conducted over the last 15 years, this paper presents the possibility and the effects of the use of vitamin D3 to improve beef tenderness. PMID- 29978055 TI - Toxinotyping and Antimicrobial Resistance of Clostridium Perfringens Isolated from Processed Chicken Meat Products. AB - Introduction: The toxinotyping and antimicrobial susceptibility of Clostridium perfringens strains isolated from processed chicken meat were determined. Material and Methods: Two hundred processed chicken meat samples from luncheon meats, nuggets, burgers, and sausages were screened for Clostridium perfringens by multiplex PCR assay for the presence of alpha (cpa), beta (cpb), epsilon (etx), iota (ia), and enterotoxin toxin (cpe) genes. The C. perfringens isolates were examined in vitro against eight antibiotics (streptomycin, amoxicillin, ampicillin, ciprofloxacin, lincomycin, cefotaxime, rifampicin, and trimethoprim sulfamethoxazole). Results: An overall of 32 C. perfringens strains (16%) were isolated from 200 processed chicken meat samples tested. The prevalence of C. perfringens was significantly dependent on the type of toxin genes detected (P = 0.0), being the highest in sausages (32%), followed by luncheon meats (24%), burgers (6%), and nuggets (2%). C. perfringens type A was the most frequently present toxinotype (24/32; 75%), followed by type D (21.9 %) and type E (3.1%). Of the 32 C. perfringens strains tested, only 9 (28%) were enterotoxin gene carriers, with most representing type A (n = 6). C. perfringens strains differed in their resistance/susceptibility to commonly used antibiotics. Most of the strains tested were sensitive to ampicillin (97%) and amoxicillin (94%), with 100% of the strains being resistant to streptomycin and lincomycin. It is noteworthy that the nine isolates with enterotoxigenic potential had a higher resistance than the non-enterotoxigenic ones. Conclusion: The considerably high C. perfringens isolation rates from processed chicken meat samples and resistance to some of the commonly used antibiotics indicate a potential public health risk. Recent information about the isolation of enterotoxigenic C. perfringens type E from chicken sausage has been reported. PMID- 29978057 TI - Control of Anabolic Hormone Residues in Tissues of Slaughter Animals in Poland During the Period of 2011-2015. AB - Introduction: Studies of anabolic hormone residues in the tissues of slaughter animals have been carried out in Poland for more than 25 years. During the period of 2011 to 2015, a total of 35 387 samples from different animal species were tested in the National Residue Control Programme for the presence of residues of compounds that cause hormonal effects, as listed in Annex 1 of Directive 96/23/EC. Material and Methods: The research was conducted in the National Reference Laboratory and eight regional laboratories in departments of veterinary hygiene located throughout the country. Urine, muscle tissue, serum, kidney fat, and drinking water were the targeted matrices. Test methods based on instrumental techniques such as gas and liquid chromatography coupled with mass spectrometry were applied, as well as enzyme-linked immunosorbent assays (ELISA). Results: The concentration of detected hormones exceeded the decision limits in 30 samples, the consequence of which was 41 non-compliances with current applicable criteria. The hormones found present pseudo-endogenous (nortestosterone and boldenone) only, while synthetic hormones were not identified. Conclusion: The non-compliant findings constitute a small percentage (0.085%) of the five-year analysis compilation. On this basis the related food produced in Poland can be accepted as safe for human consumption with regard to the hormone residues tested. PMID- 29978058 TI - Development of LC-MS/MS Confirmatory Method for the Determination of Testosterone in Bovine Serum. AB - Introduction: In the European Union the use of steroid growth promoters is prohibited under Council Directive 96/22/EC. For effective control of illegal use of natural steroids, highly sensitive analytical methods are required, because sex hormones can be present in very low concentrations in biological samples. The aim of the study was to develop a confirmatory method for the detection of testosterone in bovine serum at ppt level. Material and Methods: 17beta testosterone and internal standards of 17%-testosterone-d2 were extracted from serum samples with a mixture of tert-butyl methyl ether/petroleum ether and were directly analysed by an LC/MS/MS on QTRAP 5500 instrument with a TurboIon-Spray source operating in a positive ionisation mode. Chromatographic separation was achieved on the analytical column Inertsil(r) ODS-3 with an isocratic elution using mobile phase consisting of acetonitrile, methanol, and water. Method validation has been carried out in accordance with the Commission Decision 2002/657/EC. Results: The method was characterised by good recovery (82%) and precision (R.S.D 17 %). Decision limit (CCalpha) and detection capability (CCbeta) was 0.05 MUg L-1 and 0.09 MUg L-1 respectively. The method met the criteria set out in Commission Decision 2002/657/EC for the purpose of confirmation in terms of retention time and ion ratio in the whole range of its application. Conclusions: The developed method is specific and sensitive, suitable for measuring the natural level of testosterone in blood of cattle and for use in routine control programme for the detection of this hormone in bovine serum. PMID- 29978059 TI - Predictive Value of Plasma Parameters in the Risk of Postpartum Ketosis in Dairy Cows. AB - Introduction: The predictive value of selected parameters in the risk of ketosis and fatty liver in dairy cows was determined. Material and Methods: In total, 21 control and 17 ketotic Holstein Friesian cows with a beta-hydroxybutyrate (BHBA) concentration of 1.20 mmol/L as a cut-off point were selected. The risk prediction thresholds for ketosis were determined by receiver operating characteristic (ROC) curve analysis. Results: In the ketosis group, paraoxonase-1 (PON-1) activity and concentration of PON-1 and glucose (GLU) were decreased, and aminotransferase (AST) activity as well as BHBA and non-esterified fatty acid (NEFA) contents were increased. The plasma activity and concentration of PON-1 were significantly positively correlated with the level of plasma GLU. The plasma activity and concentration of PON-1 were significantly negatively correlated with the levels of AST and BHBA. According to ROC curve analysis, warning indexes of ketosis were: plasma PON-1 concentration of 46.79 nmol/L, GLU concentration of 3.04 mmol/L, AST concentration of 100 U/L, and NEFA concentration of 0.82 mmol/L. Conclusion: This study showed that the levels of PON-1, GLU, AST, and NEFA could be used as indicators to predict the risk of ketosis in dairy cows. PMID- 29978060 TI - Serum Paraoxonase as an Indicator for Fatty Liver in Sheep. AB - Introduction: A model of fatty liver in postpartum sheep was established to measure blood paraoxonase 1 (PON1) and other biochemical indicators, which were used to predict fatty liver in sheep. Material and Methods: Sheep were assigned into two experimental groups: a fatty liver group (T, n = 10) and a healthy control group (C, n = 5). PON1 enzyme activity towards paraoxon as a substrate was quantified spectrophotometrically. The results were analysed by t-test and pearson correlation coefficient. Disease was predicted by binary logistic analysis, and diagnostic thresholds were determined by receiver operatingcharacteristic (ROC) analysis. Results: The activity of serum PON1 in group T was significantly decreased (P < 0.05) when compared with C group, and liver lipid content and the levels of serum BHBA, NEFA, and TG were significantly increased (P < 0.05). Thresholds were lower than 74.0 U/mL for PON1, higher than 0.97 mmol/L for beta-hydroxybutyrate, higher than 1.29 mmol/L for non-esterified fatty acids, higher than 0.24 mmol/L for triglycerides, and lower than 71.35 g/L for total protein. Conclusion: This study verified that PON1, BHBA, NEFA, TG, and TP could be used to predict the risk of fatty liver in sheep. PMID- 29978061 TI - Prevalence of Arrhythmias in Dogs Examined between 2008 and 2014. AB - Introduction: The prevalence of arrhythmias in dogs and the influence of sex, breed, age, and body weight were analysed over a seven-year span. Material and Methods: In total, 1189 referrals for cardiological examination by electrocardiography were received at one academic centre in Poland between 2008 and 2014. The largest proportion of the examined dogs were cross-breeds with body weight below 25 kg (n = 153, 12.87%), followed by German Shepherds (n = 122, 10.26%), Labrador Retrievers (n = 68, 5.72%), Yorkshire Terriers (n = 63, 5.3%), and Boxers (n = 60, 5.05%). Retrospective analysis was made of 1201 standing or right recumbent electrocardiograms without pharmacological sedation. The prevalence of arrhythmias was examined in terms of sex, age, body weight, and breed of the dogs. Results: A total of 630 (52.46%) electrocardiograms showed no signs of arrhythmia, but 96 (7.99%) and 475 (39.55%) pointed to physiological and pathological arrhythmias respectively. The most commonly diagnosed type was atrial fibrillation with 33.68% incidence, followed by ventricular arrhythmias (28%), sinus pauses (27.58%), supraventricular arrhythmias (24%), and atrioventricular blocks (22.95%). Pathological arrhythmias were most commonly found in male dogs and in German Shepherds. Conclusions: Atrial fibrillation predominated, followed by premature ventricular complexes. Male dogs were generally more prone to heart rhythm disturbances. PMID- 29978062 TI - Regional Differences of Densitometric and Geometric Parameters of the Third Metacarpal Bone in Coldblood Horses - pQCT Study. AB - Introduction: The aim of the study was to analyse selected densitometric and geometric parameters in the third metacarpal bone along the long axis in horses. The densitometric parameters included the cortical and trabecular bone mineral density, while the geometric parameters included the cortical, trabecular, and total areas, strength strain index X, strength strain index Y, and the polar strength strain index. Material and Methods: The parameters were analysed using eight sections from 10% to 80% of the length of the bone. Peripheral quantitative computed tomography was used in the study. Statistical analysis was carried out using the Friedman analysis of variance and post-hoc tests. Results: The proximal metaphyseal region showed the highest predicted resistance to bone fractures in the transverse (back-front) plane, the distal metaphyseal region had the highest predicted resistance to transverse and torsional fractures in the transverse (side-side) plane. The cross-sectional area and the shape of the cross-section of the cortical bone of the MCIII had the highest coefficient of variation. The density of the cortical bone was least variable. Conclusions: The cortical area and cortical bone mineral density assumed the highest values in the diaphyseal region, while the highest total area, trabecular area and trabecular bone mineral density values were obtained in the metaphyseal proximal and distal region. PMID- 29978063 TI - Ejaculate Traits and Sperm Morphology Depending on Ejaculate Volume in Duroc Boars. AB - Introduction: The aim of this study was to evaluate the dependence between ejaculate traits, sperm morphology, and ejaculate volume in Duroc boars. Material and Methods: The analysis involved 121 ejaculates collected from 12 Duroc boars kept in three artificial insemination centres located in central Poland. Ejaculates were collected manually at one-month intervals, over a period of 10 months. At least 10 ejaculates were collected from each boar. The material was divided by ejaculate volume and each ejaculate was assigned to one of three volume groups: 160 mL and lower, 161-200 mL, and 201 mL and higher. The ejaculates were assessed to identify the basic physical traits and determine the incidence of morphological abnormalities in the spermatozoa, specifying major and minor abnormalities. Furthermore, the morphological structure indices for the spermatozoa were also calculated. Results: In large-volume ejaculates, spermatozoa were more elongated in shape, their heads were more elongated and had the largest flagella. With an increase in the ejaculate volume, sperm concentration in the ejaculate decreased. Moreover, while the total number of sperm in the ejaculate increased, the number of insemination doses obtained from a single ejaculate were higher. Conclusion: The volume of ejaculate has little impact on the occurrence of morphological abnormalities and the size of sperm cells. Ejaculate volume is important for the shape of the sperm cells. PMID- 29978064 TI - Metabolic Activity of Boar Semen Stored in Different Extenders Supplemented with Ostrich Egg Yolk Lipoproteins. AB - Introduction: The aim of this study was to evaluate the effect of lipoprotein fraction isolated from ostrich egg yolk (LPFo) on the metabolic activity of boar spermatozoa following liquid semen storage in different extenders and temperatures. Material and Methods: Boar ejaculates were extended in Androhep, Beltsville thawing solution (BTS), and Martin-Rillo and Alias (MR-A) without (control) or with the addition of LPFo and stored for three days at either 5 degrees C or 16 degrees C. The analysed sperm parameters included total motility (TMOT), plasma membrane integrity (PMI), mitochondrial membrane potential (MMP), oxygen consumption, and adenosine triphosphate (ATP) production. Results: The sperm metabolic activity seemed to be higher in the LPFo-based extenders following storage for three days, irrespective of the storage temperature. Compared with the LPFo-free extenders, significantly higher (P < 0.05) sperm PMI and MMP were observed in BTS and MR-A extenders supplemented with LPFo during storage for three days at 5 degrees C. Spermatozoa stored in the BTS-LPFo extender exhibited higher (P < 0.05) TMOT and oxygen consumption, whereas higher (P < 0.05) PMI was observed in spermatozoa stored in Androhep-LPFo and MR-A-LPFo for three days at 16 degrees C. No significant differences (P > 0.05) in ATP content were observed between the LPFo-free and LPFo-based extenders during storage. Conclusions: Supplementation of LPFo to semen extenders had varying effects on the metabolic activity of boar spermatozoa stored at different temperatures. It can be suggested that the interactions of various components of the extenders and seminal plasma with LPFo exert beneficial effects on the sperm metabolic activity during liquid storage of boar semen. PMID- 29978066 TI - Identification of Infectious Bursal Disease Virus with Atypical VP2 Amino Acid Profile in Latvia. AB - Introduction: Infectious bursal disease virus (IBDV) is a causative agent of immunosuppressive disorder resulting in significant losses to the world poultry industry. This study describes the molecular characterisation of an atypical IBDV from a field outbreak that occurred in vaccinated chicken flocks in Latvia in 2011. Material and Methods: Ten bursae of Fabricius from each flock were collected for laboratory examination. Virus isolation was performed in embryonated eggs and CEF culture. The RT-PCR aimed at hypervariable domain of VP2 gene combined with sequencing was performed for detection and identification of IBDV. Results: The molecular examinations confirmed the IBDV infection. The analysis of the amino acid sequence revealed that the strain possessed four amino acids at VP2 protein (222A, 256I, 294I, and 299S), indicating a genetic relatedness to a very virulent IBDV. However, some unique or rare amino acid substitutions (219L, 220F, 254D, 279N, and 280T) were also detected. Conclusion: The obtained results demonstrate the occurrence of IBDV with a high mutation rate within the hypervariable domain of VP2 peptide, and highlight the necessity of implementation of IBDV surveillance in Eastern European poultry industry to determine whether this strain is an exception or a new wave of IBDV with new genetic features emerged in the field. PMID- 29978067 TI - Were Polish Wild Boars Exposed to Schmallenberg Virus? AB - Introduction: A novel to Europe Schmallenberg virus (SBV) causes clinical disease manifested by reproduction disorders in farm ruminants. In free-living ruminants, SBV antibodies as well as the virus were detected. Recent studies also revealed SBV antibodies in wild boars. The study investigates SBV antibodies occurring in wild boars in Poland at the peak of recent virus epidemics in the country. Material and Methods: Samples collected from 203 wild boars culled during the 2012/2013 and 2013/2014 hunting season were serologically tested using multi species cELISA. Attempted neutralisation tests failed due to poor serum quality. RT-PCR was implemented in seropositive and doubtful animals. Results: Two samples collected from wild boar in the winter of 2013 gave a positive result in ELISA, while another two from the 2012/2013 hunting season were doubtful. No SBV RNA was detected in spleen and liver tissues. Conclusion: Low SBV seroprevalence in wild boars, despite high incidence of SBV infections occurring simultaneously in wild ruminants, suggests that boars are unlikely to be a significant reservoir of the virus in the sylvatic environment in Poland. PMID- 29978065 TI - Roles of African Swine Fever Virus Structural Proteins in Viral Infection. AB - African swine fever virus (ASFV) is a large, double-stranded DNA virus and the sole member of the Asfarviridae family. ASFV infects domestic pigs, wild boars, warthogs, and bush pigs, as well as soft ticks (Ornithodoros erraticus), which likely act as a vector. The major target is swine monocyte-macrophage cells. The virus can cause high fever, haemorrhagic lesions, cyanosis, anorexia, and even fatalities in domestic pigs. Currently, there is no vaccine and effective disease control strategies against its spread are culling infected pigs and maintaining high biosecurity standards. African swine fever (ASF) spread to Europe from Africa in the middle of the 20th century, and later also to South America and the Caribbean. Since then, ASF has spread more widely and thus is still a great challenge for swine breeding. The genome of ASFV ranges in length from about 170 to 193 kbp depending on the isolate and contains between 150 and 167 open reading frames (ORFs). The ASFV genome encodes 150 to 200 proteins, around 50 of them structural. The roles of virus structural proteins in viral infection have been described. These proteins, such as pp220, pp62, p72, p54, p30, and CD2v, serve as the major component of virus particles and have roles in attachment, entry, and replication. All studies on ASFV proteins lay a good foundation upon which to clarify the infection mechanism and develop vaccines and diagnosis methods. In this paper, the roles of ASFV structural proteins in viral infection are reviewed. PMID- 29978068 TI - Serological Survey of the Influenza a Virus in Polish Farrow-to-finish Pig Herds in 2011-2015. AB - Introduction: The aim of this study was to assess the seroprevalence of swine influenza A virus (SIV) in Polish farrow-to-finish pig herds. Material and Methods: Serum samples collected from 5,952 pigs, from 145 farrow-to-finish herds were tested for the presence of antibodies against H1N1, H1N1pdm09, H1N2, and H3N2 SIV subtypes using haemagglutination inhibition (HI) test. Samples with HI titres equal or higher than 20 were considered positive. Results: HI antibodies to at least one of the analysed SIV subtypes were detected in 129 (89%) herds and in 2,263 (38%) serum samples. Antibodies to multiple SIV subtypes were detected in 104 (71.7%) herds and in 996 (16.7%) serum samples. Concerning the seroprevalence rate, according to age category, the highest prevalence of the antibodies was detected in weaners, with regard to the H1N1, H1N2, and H3N2, and in sows, with regard to the H1N1pdm09. The lowest seroprevalence for all evaluated SIV subtypes was detected in finishers. Conclusion: The study indicates that antibodies against single and multiple SIV subtypes are circulating in Polish farrow-to-finish herds and highlights the importance of conducting a molecular surveillance programme in future studies. PMID- 29978069 TI - Detection of Actinobacillus Pleuropneumoniae ApxIV Toxin Antibody in Serum and Oral Fluid Specimens from Pigs Inoculated Under Experimental Conditions. AB - Introduction: The prevention and control of Actinobacillus pleuropneumoniae in commercial production settings is based on serological monitoring. Enzyme-linked immunosorbent assays (ELISAs) have been developed to detect specific antibodies against a variety of A. pleuropneumoniae antigens, including long-chain lipopolysaccharides (LPS) and the ApxIV toxin, a repeats-in-toxin (RTX) exotoxin unique to A. pleuropneumoniae and produced by all serovars. The objective of this study was to describe ApxIV antibody responses in serum and oral fluid of pigs. Material and Methods: Four groups of pigs (six pigs per group) were inoculated with A. pleuropneumoniae serovars 1, 5, 7, or 12. Weekly serum samples and daily oral fluid samples were collected from individual pigs for 56 days post inoculation (DPI) and tested by LPS and ApxIV ELISAs. The ApxIV ELISA was run in three formats to detect immunlgobulins M, G, and A (IgM, IgG and IgA) while the LPS ELISA detected only IgG. Results: All pigs inoculated with A. pleuropneumoniae serovars 1 and 7 were LPS ELISA serum antibody positive from DPI 14 to 56. A transient and weak LPS ELISA antibody response was observed in pigs inoculated with serovar 5 and a single antibody positive pig was observed in serovar 12 at >=35 DPI. Notably, ApxIV serum and oral fluid antibody responses in pig inoculated with serovars 1 and 7 reflected the patterns observed for LPS antibody, albeit with a 14 to 21 day delay. Conclusion: This work suggests that ELISAs based on ApxIV antibody detection in oral fluid samples could be effective in population monitoring for A. pleuropneumoniae. PMID- 29978070 TI - Distribution of Salmonella Serovars along the Food Chain in Poland, 2010-2015. AB - Introduction: Data collection on the Salmonella occurrence is crucial in effective implementation of different actions or control programmes aiming to protect consumers' health and to reduce the level of Salmonella prevalence in farm animals. The goal was to describe Salmonella serovar distribution along the food chain in Poland during 2010-2015 and to identify their epidemiological importance. Material and Methods: Slide agglutination according to White Kauffmann-Le Minor scheme was used to identify Salmonella serovars of 6,928 isolates originating from animals, food, feeds, and fertilisers. Results: In total, 160 Salmonella serovars were identified. Differences in serovar distribution were observed depending on animal species. Among isolates from hens, S. Enteritidis and S. Infantis were the most prevalent. Serovar pattern in turkeys differed from those in hens, with S. Kentucky, S. Newport, S. Saintpaul being the most prevalent. Monophasic S. Typhimurium was predominant in pigs. Serovars found in food reflected those observed among livestock animals. Nine out of the ten most prevalent serovars in animals and humans were also found in organic fertilisers. Conclusion: Serotyping of large number of isolates from different sources is essential for insight on emerging serovars and trends of Salmonella occurrence. This may increase the value of epidemiological data and result in updating of Salmonella control programmes to target further epidemiologically important serovars in animals and better protection of consumers' health. PMID- 29978071 TI - Epizootic and Epidemiological Situation of Trichinella sp. Infection in Poland in 2006-2015 in View of Wild Boar Population Dynamics. AB - Introduction: The objective was to evaluate the epizootic and epidemiological situation of Trichinella sp. infection in Poland between 2006 and 2015 against the dynamics of the wild boar population and its primary reservoir host. Material and Methods: Boar and porcine trichinosis epizootic analysis was based on General Veterinary Inspectorate data from RRW-6 bulletins. The epidemiological situation was evaluated on the basis of the data supplied by the Department of Epidemiology of the National Institute of Hygiene - National Institute of Public Health. The wild boar hunting harvest and population dynamics were estimated, as these animals remain the basic infection source for humans. Population size and harvest data were obtained from hunting statistics. Results: The study timeframe showed an almost 2.5-fold increase in Trichinella infection cases in wild boars but a significant decline in human cases. In the domestic pig, the incidence rate did not exceed 0.00037%. The highest infection risk exists in West Pomerania, Greater Poland, and Kuyavian-Pomeranian Provinces. Over the study period, the wild boar population increased more than 1.5-fold, while the hunting harvest more than tripled. During the last two seasons the total hunt surpassed 100% of the spring population. Conclusion: Wild boar management by increasing the hunting take of the annual population growth should limit that growth and decrease the take in the future. Thereby, over some years intra-species trichinosis spread should reduce, for a substantial safety gain for wild boar meat. PMID- 29978073 TI - Evaluation of Oxidative Stress in Sheep Infected with Psoroptes Ovis using Total Antioxidant Capacity, Total Oxidant Status, and Malondialdehyde Level. AB - Introduction: The study aimed at evaluating oxidative stress using malondialdehyde (MDA), total antioxidant capacity (TAC), total oxidant status (TOS), and oxidative stress index (OSI) markers in sheep naturally infected with Psoroptes ovis(Acari). Material and Methods: The study was performed on 40 sheep divided into two equal groups: a healthy group (group I) and a group naturally infected with Psoroptes ovis (group II). The sera were obtained by centrifuging blood samples collected from the vena jugularis and serum MDA level changes in the samples were measured spectrophotometrically. Commercially available test kits were used for the measurement of TAC and TOS levels. The percentage ratio of TOS level to TAC level was accepted as OSI. Results: The serum malondialdehyde, total oxidant status levels, and oxidative stress index increased significantly (P < 0.01) in group II, while the serum total antioxidant capacity levels decreased significantly (P < 0.01) in this group. Negative correlations between total antioxidant capacity and total oxidant status and total antioxidant capacity and malondialdehyde, and a positive correlation between total oxidant status and malondialdehyde were found in infected sheep. Conclusion: The obtained results indicated the relationship between oxidant/antioxidant imbalance and Psoroptes ovis infection in sheep. Their MDA, TAC, TOS, and OSI markers may be used to determine the oxidative stress in natural infections with Psoroptes ovis. PMID- 29978072 TI - Dogs' Gastrointestinal Parasites and their Association with Public Health in Iran. AB - Introduction: Dogs harbour zoonotic parasites that cause serious infections in humans, such as visceral larva migrans, ocular larva migrans, cystic echinococcosis, and alveolar echinococcosis. Studies on dogs' gastrointestinal parasites in different geographical locations are required to increase knowledge of the risk of canine zoonoses in human populations. Material and Methods: The presence of parasites was examined in 450 faecal samples collected from eight zones of Zanjan province, northwest Iran from June to November 2015. The samples were examined using the sedimentation concentration method and modified Ziehl Neelsen staining. Results: Gastrointestinal parasites were found in 86 (19.1%) faecal samples. Sarcocystis spp. (7.3%), Taenia/Echinococcus spp. (5.6%), Toxocara spp. (1.8%), and Cystoisospora spp. (1.6%) were the most common parasites observed. The other detected parasites consisted of Dicrocoelium dendriticum (0.7%), Eimeria spp. (0.7%), Cryptosporidium spp. (0.4%), Physaloptera spp. (0.4%), Giardia spp. (1.3%), and Spirocerca lupi (1.3%). The lowest parasite infection rates belonged to Trichuris vulpis and Acanthocephalans (0.2% each). Conclusion: This study provides current information on the infection rates in dog populations in Zanjan Province. Furthermore, the study shows a high prevalence of gastrointestinal parasitic infections, including zoonotic ones and particularly Taenia/Echinococcus spp., potentially transmissible to humans and thus relevant to public health. PMID- 29978074 TI - Expression of Vascular Cell Adhesion Molecule 1 (VCAM-1) in the Mammary Lymph Nodes of Cows with Subclinical Mastitis. AB - Introduction: Vascular cell adhesion molecule 1 (VCAM-1) is a member of Ig superfamily. The aim of this study was to prepare highly specific polyclonal antibodies against bovine VCAM-1 and to evaluate the expression of VCAM-1 in the mammary lymph nodes of cows with subclinical mastitis. Material and Methods: The VCAM-1 gene was cloned from bovine Peyer's patches and inserted into the pGEX-4T 1 and pET-28a vectors. The recombinant plasmids pGEX-4T-1/VCAM-1 and pET-28a/VCAM 1 were transferred into Escherichia coli BL21 and the recombinant strains were induced by isopropyl-D-thiogalactoside to produce fusion proteins tagged with polyhistidine (His) and glutathione S-transferase (GST), respectively. The expressed fusion proteins His-VCAM-1 and GST-VCAM-1 were identified by SDS-PAGE and Western blot. His-VCAM-1 protein was used as an antigen to immunise Wistar rats and polyclonal antibody serum against VCAM-1 was obtained. Results: The serum titre tested by indirect ELISA was 128,000 using GST-VCAM-1 as the well coating antigen. Western blots indicated that the antibody recognised recombinant VCAM-1 protein as well as endogenous VCAM-1. In addition, using qPCR and Western blot, VCAM-1 mRNA and protein expression levels were measured in dairy cows with subclinical mastitis. It was demonstrated that VCAM-1 levels in the mammary lymph nodes of the cows were significantly higher than those from healthy controls (P < 0.05). Conclusion: These results are to our knowledge the first report that VCAM 1 expression in the mammary lymph nodes is elevated in dairy cows with subclinical mastitis. PMID- 29978075 TI - Effect of Pregnancy and Stage of Lactation on Energy Processes in Isolated Blood Cells of Dairy Cows. AB - Introduction: The transition period is the most challenging time for dairy cattle, which is characterised not only by negative energy balance but also by fatty tissue mobilisation. Material and Methods: The efficiency of energy pathways, beta-oxidation in WBC and glycolysis in RBC (based on deoxyglucose transmembrane transport) were estimated. Insulin in blood plasma was determined using ELISA. Results: After calving and up to one month after delivery, a significant drop in blood plasma level was noticed, simultaneously with a rise in beta-oxidation from 18.93 +/-3.64 to 30.32 +/-5.28 pmol/min/mg protein in WBC. A strong negative correlation between these two indices (r = -0.68) was found. During the period of transition to lactation an increase in glucose cross membrane transportation from 41.44 +/-4.92 to 50.49 +/-6.41 MUmol/h/g Hb was observed. A strong positive correlation between glucose transportation in RBC and beta-oxidation in WBC (r = 0.71) was noticed. These data are in agreement with results of studies on dairy cows using liver slices from dairy cows in late pregnancy and different stages of lactation, in which changes in gene expression were analysed. Conclusion: It seems that measuring fatty acids oxidation and glycolysis using isolated blood cells may be an adequate and relatively simple method for energy state analysis to estimate the state of dairy cow metabolism and animal health. PMID- 29978076 TI - Changes in Blood Lymphocyte Subpopulations and Expression of MHC-II Molecules in Wild Mares Before and After Parturition. AB - Introduction: Pregnancy is a physiological state in which the immune system undergoes certain changes. On the one hand, by depleting cell defence mechanisms, it favours development and maintenance of the pregnancy. At the same time cells of the immune system ensure resistance to many risk factors, including infectious agents. Material and Methods: The study was carried out on 24 Polish Konik breed mares which were divided into two equal groups. The first group (group I) included mares living in the reserve. The second group (group II) comprised mares maintained under conventional conditions in the stables. The blood samples were collected for the first time in the perinatal period, i.e. 2 weeks before parturition (trial 0), then within the first 24 h after delivery, and then on 7th and 21st day after foaling. Flow cytometric analysis of lymphocyte expressing TCD4+, TCD8+, CD2+, and MHC class II antigens was performed. Results: Before the delivery, in group I there was a significantly higher CD4:CD8 ratio compared to group II (P <= 0.05). Similarly, significantly increased CD4:CD8 ratio in group I was noted within 24 h after parturition (P <= 0.001) and it was also observed on 7th day (P <= 0.03) and 21st day after foaling (P <= 0.02). In the first 24 h after parturition, a significant decline of lymphocytes CD8+ (P <= 0.02) was noted. No significant differences in terms of lymphocytes CD2+ and CD3+ were observed. Expression of MHC-II molecules before and after the parturition was higher in group I compared to group II; however, the difference between the groups was not significant. Conclusion: The results obtained indicate that mares living in the reserve display higher activity of cell defence mechanisms. PMID- 29978077 TI - Macro-microscopic Research in Reideer (Rangifer Tarandus) Hoof Suitable for Efficient Locomotion on Complex Grounds. AB - Introduction: Reindeer are adapted to long distance migration. This species can cope with variations in substrate, especially in ice and snow environment. However, few detailed studies about reindeer hoof are available. Thus this article describes the results of studies on macro- and micro-structures of reindeer hoof. Material and Methods: The gross anatomy of the reindeer hooves was examined. Stereo microscope (SM) and a scanning electron microscope (SEM) were used to observe four key selected positions of reindeer hooves. Moreover, element contents of the three selected positions of reindeer hooves were analysed using the SEM equipped with energy dispersive spectroscope. Results: Hoof bone structures were similar to other artiodactyl animals. In the microscopic analysis, the surfaces of the ungula sphere and ungula sole presented irregular laminated structure. Ungula edge surfaces were smooth and ungula cusp surfaces had unique features. Aside from C, O, and N, reindeer hooves contained such elements as S, Si, Fe, Al, and Ca. The content of the elements in different parts varied. Ti was the particular element in the ungula sole, and ungula edge lacked Mg and S which other parts contained. Conclusion: The macro- and micro-structures of the reindeer hooves showed high performance of skid and abrasion resistance. It is most probably essential to the long distance migration for the animals. PMID- 29978078 TI - Comparison of Clinical, Biomechanical, and Histopathological Effects of Various Suture Techniques on Repair of Tendon Rupture by using Autograft. AB - Introduction: The purpose of this study was to compare the effectiveness of four different suture techniques in the treatment of experimentally modelled tendon injuries with tissue loss with autograft and grafting applications in rabbits. Material and Methods: The study was performed on 30 male mature (2-year-old) New Zealand rabbits with mean body weight of 3.1 kg, divided into three equal groups. A graft measuring 1 cm in length was collected from the m. tibialis cranialis of each rabbit under general anaesthesia. The graft collected from the right tendon was transplanted into the left tendon, and the graft from the left tendon was transplanted into the right tendon. In all groups, a simple interrupted suture was placed on the left tendon as control, a Bunnell-Mayer suture was placed on the right tendon in group I, a Locking-Loop suture in group II, and a Horizontal U suture in group III. Both hindlimbs were bandaged for four weeks. The tendons were assessed biomechanically and histopathologically. Results: According to the results of the tensile testing, the maximum durability of the techniques ranked as follows: Bunnell-Mayer, Horizontal U, Locking-Loop, and control groups. Conclusion: The use of autografts was a good alternative for the treatment of tendon ruptures with tissue loss. Furthermore, even though there were no clinical or histopathological differences, the suture technique can be chosen based on the results of the tensile test. PMID- 29978079 TI - Detection of Avian Reoviruses in Wild Birds in Poland. AB - Introduction: The purpose of this study was to determine the occurrence of avian reovirus (ARV) infections in wild birds in Poland and attempt to propagate the selected ARV strains in chicken embryo kidney (CEK) cells or chicken SPF embryos. Material and Methods: The study included 192 wild birds representing 32 species, collected between 2014 and 2016. A part of the S4 segment encoding the sigmaNS protein of avian reoviruses (ARVs) isolated from different species of wild birds from that period was amplified. Results: The presence of ARV was demonstrated in 58 (30.2%) wild birds belonging to nine orders. The isolated strains were propagated in chicken embryos by yolk sac inoculation, and CPE was induced in the infected CEK monolayer. Agar gel precipitation showed that two ARV isolates from rock pigeon and mute swan shared a common group-specific antigen with chicken reovirus S1133. Specific products of predicted size were found in two ARV isolates from the chicken embryo passage and 13 ARVs isolated from CEK cells. Conclusion: The study indicates the high prevalence of ARV among wild birds in Poland and its possible transmission to farmed birds. PMID- 29978080 TI - Development of a Recombinant Protein-based ELISA for Detection of Antibodies Against Bovine Foamy Virus. AB - Introduction: Infections with bovine foamy virus (BFV) were found in many countries but there is a lack of large-scale surveys on the prevalence of BFV among dairy cattle. The aim of this study was to develop and validate the recombinant Gag protein-based ELISA and to estimate the prevalence of antibodies against BFV. Material and Methods: Gag coding region from BFV was cloned into expression vector pT7Arg-STOP, which expressed a high level of recombinant Gag protein from E.coli. The ELISA was standardised, and the cut-off value and sensitivity and specificity of the test were calculated using a receiver operating characteristic and Bayesian estimation. Results: A total of 3,051 serum samples were tested by ELISA and 939 (30.8%) sera were recognised as positive. When Bayesian approach was used, the overall true BFV prevalence was 29.7% (95% CI: 25.9-33.4%). Conclusion: Expressed Gag protein of BFV has been used successfully as an antigen for ELISA. Eventually, this study provides basic information about the epidemiological status of infection with BFV in dairy cattle in Poland, which can be used for further studies on dissemination and transmission of BFV infection. PMID- 29978081 TI - Pathological Alterations in Respiratory System During Co-infection with Low Pathogenic Avian Influenza Virus (H9N2) and Escherichia Coli in Broiler Chickens. AB - Introduction: Despite the advancements in the field, there is a lack of data when it comes to co-infections in poultry. Therefore, this study was designed to address this issue. Material and Methods: Broiler birds were experimentally infected with E. coli (O78) and low pathogenic avian influenza (LPAI) strain, alone or in combination. The experimental groups were negative control. Results: The infected birds showed most severe clinical signs in E. coli+LPAI group along with a significant decrease in weight and enhanced macroscopic and microscopic pathological lesions. The survival rate was 60%, 84%, and 100% in birds inoculated with E. coli+LPAI, E. coli, and LPAI virus alone, respectively. The results showed that experimental co-infection with E. coli and H9N2 strain of LPAI virus increased the severity of clinical signs, mortality rate, and gross lesions. The HI titre against LPAI virus infection in the co-infected group was significantly higher than the HI titre of LPAI group, which may indicate that E. coli may promote propagation of H9N2 LPAI virus by alteration of immune response. Conclusion: The present study revealed that co-infection with E. coli and H9N2 LPAI virus caused more serious synergistic pathogenic effects and indicates the role of both pathogens as complicating factors in poultry infections. PMID- 29978082 TI - Pig Lung Immune Cytokine Response to the Swine Influenza Virus and the Actinobacillus Pleuropneumoniae Infection. AB - Introduction: The aim of this study was to evaluate and compare the local innate immune response to the swine influenza virus (SIV) and Actinobacillus pleuropneumoniae (App) infection in pigs. Material and Methods: The study was performed on 37 seven-week-old pigs, divided into four groups: App-infected (n=11), App+SIV-infected (n=11), SIV-infected (n=11), and control (n=4). Lung samples were collected, following euthanasia, on the 2nd and 4th dpi (three piglets per inoculated group) and on the 10th dpi (remaining inoculated and control pigs). Lung concentrations of IL-1beta, IL-6, IL-8, TNF-alpha, IL-10, IFN alpha, and IFN-gamma were analysed with the use of commercial porcine cytokine ELISA kits. Results: Lung concentrations of IL-1beta, IL-6, IL-8, TNF-alpha, IFN alpha, and IFN-gamma were induced in SIV-infected and App+SIV-infected pigs. In the lung tissue of App-infected pigs, only concentrations of IL-1beta, IL-6, IL 8, and IFN-gamma were elevated. Additionally, in App+SIV-infected pigs, significantly greater concentrations of IL-1beta, IL-8, and IFN-alpha were found when compared with pigs infected with either SIV or App alone. In each tested group, the lung concentration of IL-10 remained unchanged during the entire study. Conclusion: The results of the study indicate that the experimental infection of pigs with SIV or App alone and co-infection with both pathogens induced a local lung inflammatory response. However, the local cytokine response was considerably higher in co-infected pigs compared to single-infected pigs. PMID- 29978083 TI - Presence of Methicillin-resistant Staphylococcus Aureus in Slaughterhouse Environment, Pigs, Carcasses, and Workers. AB - Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a highly resistant and difficult to cure zoonotic microorganism, which makes up a large part of food toxic infections and has shown high prevalence among pig population all over the world. The aim of the study was to establish the occurrence of MRSA in slaughterhouses, evaluate its antimicrobial resistance, and verify whether there are any differences or similarities with reference to other European countries. Material and Methods: A total of 100 pigs, 105 carcasses, 19 workers, and 24 samples from the environment of several slaughterhouses were examined by conventional microbial and molecular methods. Results: In total, 78 MRSA isolates were found. MRSA prevalence in slaughtered pigs varied from 8.0% to 88.6% depending on the slaughterhouse, reaching higher prevalence in slaughterhouses with higher slaughter capacity. In total, 21.1% of all workers were carriers of MRSA and 6.7% of carcasses were contaminated with MRSA. The 98.2% of MRSA isolates were resistant to penicillin, 89.1% to tetracycline, 60.1% to erythromycin, 65.5% to gentamycin, and 15 different spa types were found, among which spa type t01333 was most widespread. Conclusion: The study indicated that MRSA prevalence and spa types differed according to slaughterhouse slaughter capacity and good hygiene practices. Quite high MRSA occurrence among slaughterhouse workers is one of the main factors which increase pork contamination risk. PMID- 29978084 TI - Effects of Packaging Methods on Shelf Life of Ratite Meats. AB - Over the last years a growing demand for ratite meat, including ostrich, emu, and rhea has been observed in the world. Ratite meat is recognised as a dietetic product because of low level of fat, high share of PUFA, favourable n6/n3 ratio, and higher amounts of iron content in comparison with beef and chicken meat. The abundance of bioactive compounds, e.g. PUFA, makes ratite meat highly susceptible to oxidation processes. Moreover, pH over 6 creates favourable environment for fast microbial growth during storage conditions affecting its shelf life. However, availability of information on ratite meat shelf life among consumers and industry is still limited. Thus, the aim of the present review is to provide current information about the effect of ratite meat packaging type, i.e. air packaging, vacuum packaging with skin pack, modified atmosphere packaging (MAP), on its shelf life quality during storage, including technological and nutritional properties. PMID- 29978085 TI - Prevalence of C. Botulinum and C. Perfringens Spores in Food Products Available on Polish Market. AB - Introduction: The aim of this study was to evaluate the prevalence of Clostridium botulinum and Clostridium perfringens in food samples purchased from Polish producers. Material and Methods: The analyses were performed on 260 food samples collected in Lublin and Subcarpathian regions: 56 of smoked meat, 21 of pork meat, 20 of dairy products, 26 of vegetable and fruit preserves, 40 of ready-to eat meals, 27 of fish preserves, and 70 of honey collected directly from apiaries. Results: C. botulinum strains were isolated from 2.3% (6/260) of samples and the isolates were classified as toxin types A (4/260) and B (2/260). C. perfringens strains were isolated from 14% (37/260) of samples. All the isolates were classified as toxin type A, 28 of them were able also to produce alpha toxin and 9 - beta2 toxin. Conclusion: On the basis of the obtained results it could be suggested that risk assessment, especially regarding the entire honey harvesting process, should be provided in order to ensure the microbiological safety of the products to be consumed by infants and people with a weakened immune system. PMID- 29978086 TI - Selenium, Copper, and Zinc Concentrations in the Raw and Processed Meat of Edible Land Snails Harvested in Poland. AB - Introduction: The objective of the present research was to carry out a comparative assessment of copper, zinc, and selenium concentrations in the meat of edible land snails collected in Poland (Helix pomatia, Cornu aspersum maxima, and Cornu aspersum aspersum), as well as to determine the effect of preliminary processing of Roman snails (Helix pomatia) on the content of the aforementioned elements. Material and Methods: In the first stage, determinations were made on unprocessed snail meat. In the second stage, the study focused on Roman snails and consisted in an additional evaluation of frozen meat after full processing. Zinc and copper contents were determined by flame atomic absorption spectrometry and the selenium content was established by graphite furnace atomic absorption spectrometry. Results: The selenium content differed significantly among all three species. The copper content in Roman snails differed significantly from that in farmed snails. No significant difference in the zinc level was noted among the three snail species. The selenium content in raw and processed meat of Roman snails did not show any significant difference while the copper and zinc level was significantly higher in processed meat samples. Conclusion: The present research on the meat of edible snails showed different levels of selenium, copper, and zinc, depending on the species, collection site, and subjection to processing. PMID- 29978087 TI - Simultaneous Determination of Ten Illegal Azo Dyes in Feed by Ultra-high Performance Liquid Chromatography Tandem Mass Spectrometry. AB - Introduction: The paper presents the method of simultaneous determination of 10 illegal azo dyes in feed by ultra-high performance liquid chromatography coupled with tandem mass spectrometry technique. Material and Methods: The dyes were extracted with hexane, evaporated to dryness, and analysed. Separation was achieved in 7 min in a gradient elution using acetonitrile (A) and 0.1% formic acid (B) as a mobile phase. Results: The validation results showed the repeatability of the method, which was evaluated at three levels (50, 500, and 5,000 ug/kg). All the matrix calibration curves for the working ranges were linear (R2 0.9904 to 1.0), the repeatability was between 2.1% and 24%, and recoveries ranged from 77.9% to 120%. The LOD and LOQ were at 1-2 and 5-10 ug/kg for different dyes, respectively. Furthermore, the method was applied in the homogeneity tests of the in-house prepared feed containing Sudan I at the levels of 0.5, 5, and 50 mg/kg. Conclusions: A sensitive, selective, and fast multiresidue method was successfully developed and validated. Its robustness was confirmed by the analysis of an experimental feed containing Sudan I. PMID- 29978088 TI - Metaldehyde Poisoning of Companion Animals: A Three-year Retrospective Study. AB - Introduction: Intentional and accidental poisoning of animals is often caused by readily available commercial pesticides, such as the molluscicide metaldehyde. A retrospective analysis of suspected metaldehyde poisonings between 2014 and 2016 in Italy was conducted. Material and Methods: Biological matrices were collected for toxicological analyses in the course of routine Institute activity. A total of 183 organs from dogs and cats and 49 pieces of bait, here specifically poisoned food used to lure animals, were analysed and the presence of metaldehyde was confirmed by gas chromatography coupled to mass spectrometry (GC/MS). Results: A high content of metaldehyde was demonstrated in the analysed samples from dogs and cats: 50 (27.3%) animals were found positive for metaldehyde intoxication together with 17 pieces of bait. Conclusion: The study emphasised the need for the control of metaldehyde use by the veterinary service. PMID- 29978089 TI - Comparison of Albendazole Cytotoxicity in Terms of Metabolite Formation in Four Model Systems. AB - Introduction: Albendazole is used to treat endoparasitic diseases in animals and humans. After oral administration, it is quickly oxidised into its pharmacologically active metabolite albendazole sulfoxide and then to sulfone. However, it is not clear which compound is responsible for toxic effects towards mammalian cells. Material and Methods: The model systems comprised cultures of isolated rat hepatocytes, two hepatoma cell lines (FaO, HepG2), and non-hepatic Balb/c 3T3 line. Cells were exposed for 24, 48, and 72 h to eight concentrations of albendazole ranging from 0.05 to 100 ug/mL. At all three time points cytotoxic effects were assessed by MTT assay and metabolites in the culture media were determined by LC-MS/MS analysis. Results: The effective concentrations EC50-72h showed that Balb/c 3T3 cells were the most sensitive to albendazole (0.2 +/-0.1 ug/mL) followed by FaO (1.0 +/-0.4 ug/mL), and HepG2 (6.4 +/-0.1 ug/mL). In the case of isolated hepatocytes this value could not be attained up to the highest concentration used. Chemical analysis revealed that the concentrations of albendazole in hepatocytes and HepG2 and FaO culture media gradually decreased with incubation time, while the concentrations of its metabolites increased. The metabolism in isolated hepatocytes was dozens of times greater than in HepG2 and FaO cells. Two metabolites (albendazole sulfoxide, albendazole sulfone) were detected in isolated hepatocytes and HepG2 culture medium, one (albendazole sulfoxide) in FaO culture medium and none in Balb/c 3T3. Conclusion: The obtained data indicate that metabolism of albendazole leads to its detoxification. The lower cytotoxic potential of metabolites was confirmed in the independent experiments in this study. PMID- 29978090 TI - Analytical Strategy for Determination of Chloramphenicol in Different Biological Matrices by Liquid Chromatography - Mass Spectrometry. AB - Introduction: The main problem in determination of chloramphenicol in food of animal origin is a large number of matrices. The main target of this study was to create a method for determination and confirmation of chloramphenicol in products and food of animal origin. Material and Methods: Each 5 g matrix sample was mixed with 5 mL of water and 10 mL of acetonitrile/ethyl acetate, homogenised, and centrifuged. The organic layer was evaporated and redissolved in 6 mL of 4% NaCl. The extract was cleaned up by SPE technique. Chloramphenicol was analysed by LC MS/MS in electrospray mode. Results: The procedure was validated according to the Commission Decision No. 2002/657/EC. The apparent recoveries were in the range of 92.1% to 107.1% with a repeatability less than 11.0% (4.4%-11.0%) and within laboratory reproducibility below 13.6% (4.7%-13.6%). Conclusion: The method was successfully validated and proved to be efficient, precise, and useful for quantification of chloramphenicol in more than 20 different matrices. PMID- 29978091 TI - OvSynch Protocol and its Modifications in the Reproduction Management of Dairy Cattle Herds - an Update. AB - Current knowledge about the function of the reproductive tract and appropriate use of hormonal drugs affords control of the oestrus cycle of cows. One of the hormonal protocols is OvSynch, which enables artificial insemination (AI) to be performed at the precise optimum time without control of the ovaries and uterus. Use of such protocols in reproductive management allows oestrus cycles to be synchronised and cows to be effectively inseminated without oestrous detection, which is time-consuming and difficult in farms with numerous cows. Therefore, OvSynch has become the first management tool for AI and is an alternative method to heat detection. Over the 20 years since its first implementation, OvSynch has been modified many times to improve its reproduction outcomes and widen its use. Besides its original use for heat synchronisation, it is also used in many ovarian disorders as a therapeutic method. This review article describes the possibilities which OvSynch provides, its current modifications, various applications, and the advantages and disadvantages of its use in practice. PMID- 29978092 TI - Prevalence of The Main Infectious Causes of Abortion in Dairy Cattle in Algeria. AB - Introduction: Abortion in cattle is a major source of economic losses for the agriculture sector. It can be due to infectious or non-infectious factors. Among infectious factors, parasites, bacteria, viruses, and fungi can be involved. The present work investigated the prevalence of the main infectious agents of abortion in Algerian cattle. Material and Methods: Altogether 278 non-aborting and 82 aborting cows were analysed. Results: The prevalence ranged from 0% for Tritrichomonas foetus to 15% for Neospora caninum. Additionally, a case-control study was performed to find the association between the presence of the pathogens and the occurrence of abortion in cows. The odds ratios were significant for Neospora caninum, bovine herpes virus 4, BVD virus, Brucella abortus, Salmonella Dublin, Leptospira interrogans serovar Hardjo, and Coxiella burnetii. Conclusions: The pathogens enumerated here could be major causes of abortion among Algerian cattle. PMID- 29978093 TI - Application of Two Staining Methods for Sperm Morphometric Evaluation in Domestic Pigs. AB - Introduction: The effect of two smear staining methods on the dimensions and shape of sperm cells in the semen of domestic pigs was evaluated. Material and Methods: The studies were carried out on 30 ejaculates collected from 15 boars, which included five Duroc boars, five Pietrain boars, and five hybrid Duroc * Pietrain boars. Each ejaculate was next sampled to make two microscopic slides, of which one was stained with eosin-nigrosin and the other with eosin-gentian dye. In total, 600 measurements of sperm cells were made. Each sperm was measured for the following morphometric parameters: head length, head width, head area, head perimeter, tail length, and the total sperm length. Results: Sperms measured on slides stained with eosin-nigrosin showed lower dimensions as compared with those stained with the eosin-gentian dye method. Sperm stained with eosin nigrosin had shorter and narrower heads than sperm stained with eosin-gentian dye. The method of staining, therefore, affected not only the dimensions of the sperm, but also the proportions of the dimensions defining the shape of the sperm. Conclusions: The size and shape parameters in porcine sperm may take on different values depending on the method of semen staining. Sperm cells stained with eosin-nigrosin are smaller than the sperm stained with eosin-gentian dye. The sensitivity of the sperm to the type of dye used for the fixation may be associated with genetic factors. PMID- 29978095 TI - DON-induced Changes in Bone Homeostasis in Mink Dams. AB - Introduction: The aim of the study was to investigate the mechanical and geometric properties as well as bone tissue and mineral density of long bones in mink dams exposed to deoxynivalenol (DON) since one day after mating, throughout gestation (ca. 46 d) and lactation to pelt harvesting. Material and Methods: Thirty clinically healthy multiparous minks (Neovison vison) of the standard dark brown type were used. After the mating, the minks were randomly assigned into two equal groups: non-treated control group and DON group fed wheat contaminated naturally with DON at a concentration of 1.1 mg.kg-1 of feed. Results: The final body weight and weight and length of the femur did not differ between the groups. However, DON contamination decreased mechanical endurance of the femur. Furthermore, DON reduced the mean relative wall thickness and vertical wall thickness of the femur, while vertical cortical index, midshaft volume, and cross sectional moment of inertia increased. Finally, DON contamination did not alter bone tissue density, bone mineral density, or bone mineral content, but decreased the values of all investigated structural and material properties. Conclusion: DON at applied concentration probably intensified the process of endosteal resorption, which was the main reason for bone wall thinning and the weakening of the whole bone. PMID- 29978094 TI - Correlation between Endoscopic and Histopathological Findings in Dogs with Chronic Gastritis. AB - Introduction: Chronic gastritis is a common diagnosis in dogs with signs of chronic vomiting. However, there is no data concerning endoscopic and histopathological agreement in dogs with chronic gastritis. Thus, a question should be raised whether taking gastroduodenal biopsies in dogs with chronic gastritis is necessary or not. Consequently, the purpose of the study was to compare the endoscopic and histopathological agreement in dogs with chronic gastritis. Material and Methods: A total of 22 non-pregnant client-owned dogs with the signs of chronic gastritis were enrolled in this prospective study. Procedures including clinical examination, blood analysis, and diagnostic imaging were performed before anaesthesia. Biopsies obtained from gastroduodenal sites were histopathologically evaluated. A total of 110 gastroduodenal samples were examined. Results: Sixty-eight samples had abnormal histopathology and endoscopy while 11 showed normal histopathological and endoscopic evidence. Conclusion: The obtained data demonstrated that it is not necessary to take extra gastroduodenal biopsies in dogs with evidence of endoscopic gastroduodenitis. We also believe that further prospective studies, including cost and time effectiveness and more specific comparison between endoscopic appearance and histopathology, are necessary to make final recommendations regarding the need of using both procedures for definitive diagnosis. PMID- 29978096 TI - Mitral Regurgitation in Dachshund Dogs without Heart Murmurs. AB - Introduction: Older small breed dogs are considered at risk for heart failure secondary to chronic mitral valve disease. However, few data are available on the onset of this disease in such dogs. This study was performed to determine if auscultation alone can be used to eliminate clinically relevant mitral valve regurgitation seen in echocardiography in Dachshund dogs. Material and Methods: Clinical and echocardiographic data were obtained from 107 dogs without heart murmurs. Results: The study revealed that 63.6% of the dogs had mitral regurgitation. Numbers increased with age and a larger percentage of male Dachshunds were affected than female Dachshunds. Mitral valve prolapse and thickening were mild, and the regurgitant area inextensive in most dogs. Conclusions: The study shows that mitral valve regurgitation is prevalent (63.6%) in Dachshunds without heart murmurs. Typical lesions often become apparent during echocardiographic examinations in dogs under 5 years of age. PMID- 29978097 TI - Hoof Quality of Anglo-Arabian and Haflinger Horses. AB - Introduction: Foot quality is essential to the horse's movement. The barefoot approach favours the animal's welfare. Environment and selection determine hoof characteristics. Material and Methods: Hoof characteristics of eight Anglo Arabian (AA) and nine Haflinger (HA) horses were studied. After a preliminary visual analysis of feet, nail samples were collected after trimming for physico chemical analysis. The parameters were submitted to analysis of variance. A principal component analysis and a Pearson correlation were used to compare mineral contents. Results: The hooves of both breeds were healthy and solid. The hooves of HA horses were longer than those of AA horses (14.90 +/-0.30 cm vs 13.10 +/-0.60 cm), while the AA hoof was harder than the HA hoof both in the wall (74.55 +/-2.95 H vs 60.18 +/-2.67 H) and sole (67.00 +/-5.87 H vs 43.0 +/-4.76 H). In comparison with the sole, the AA hoof wall also had a lower moisture percentage (12.56 +/-0.67% vs 20.64 +/-0.76%), while crude protein and ash contents were similar in both regions. The AA hoof showed a higher Se content, while the HA hoof had a higher level of macroelements. The negative correlations of K with Cu, Fe, Ni, Pb, and Zn in the AA hoof may indicate osmoregulation activity. Conclusion: The hoof morphology of AA and HA horses met the literature parameters for mesomorphic horses. Both breeds had healthy and well-conformed hooves, useful for sport and recreation activities. PMID- 29978098 TI - African Swine Fever (ASF) and Ticks. No Risk of Tick-mediated ASF Spread in Poland and Baltic States. AB - Infectious diseases of swine, particularly zoonoses, have had a significant influence on nutritional safety and availability of pig meat as high-energy protein product since the time that pigs were domesticated back in the 7th century BC. The main sources of swine infectious diseases include the so-called primary sources (direct infection, i.e. through contact with infected and sick animals) and secondary sources (contaminated meat products, slaughter products, and vectors, including ticks). At present, the most serious epidemiological and economic threat to swine breeding in Europe is African swine fever (ASF). This disease, originally coming from Africa, is incurable and causes death of infected pigs and wild boars during 7-10 days after infection. Among the various factors that influence the spread of ASF, important role is played by ticks from the genus Ornithodoros, mainly from the species Ornithodoros moubata. Research on the ASF indicates that other species of ticks can also transmit the virus to healthy pigs in laboratory conditions. Sylvatic and domestic cycles of ASF virus transmission, which have been described so far, require further studies and updating in order to point the potential new vectors in the Caucasus and Eastern Europe affected by the ASF. Effective methods of control and biosecurity may significantly slow down the spread of ASF, which undoubtedly is a major threat to world pig production and international swine trade. PMID- 29978099 TI - Phylogenetic Study of H5 Low Pathogenic Avian Influenza Viruses Detected in Wild Birds in Poland in 2010-2015. AB - Introduction: The genomes of nine H5 subtypes of low pathogenic avian influenza virus (LPAIV) strains identified in wild birds in Poland between 2010 and 2015 were sequenced, and their phylogenetic relationship was determined. Material and Methods: AIV genome segments were amplified by RT-PCR and the PCR products were sequenced using Sanger method. Phylogenetic trees were generated in MEGA6 software and digital genotyping approach was used to visualise the relationship between analysed strains and other AIVs. Results: High genetic diversity was found in the analysed strains as multiple subgroups were identified in phylogenetic trees. In the HA tree, Polish strains clustered in two distinct subclades. High diversity was found for PB2, PB1, PA and NP, since 5-8 sublineages could be distinguished. Each strain had a different gene constellation, although relationship of as much as six out of eight gene segments was observed between two isolates. A relationship with poultry isolates was found for at least one segment of each Polish strain. Conclusion: The genome configuration of tested strains indicates extensive reassortment, although the preference for specific gene constellation could be noticed. A significant relationship with isolates of poultry origin underlines the need for constant monitoring of the AIV gene pool circulating in the natural reservoir. PMID- 29978100 TI - Diagnostic Reliability of Different RT-PCR Protocols for the Detection of Bluetongue Virus Serotype 14 (BTV-14). AB - Introduction: The reverse transcription polymerase chain reaction (RT-PCR) is one of the most extensively used methods for identification of animals infected with bluetongue virus (BTV). There are several RT-PCR protocols published and several real-time RT-PCR (rtRT-PCR) commercial kits available on the market. Because Poland faced BTV-14 infection in 2012, different protocols were implemented in the country to confirm the RT-PCR results positive for this virus. The article presents a comparative study of several RT-PCR protocols and discusses their diagnostic reliability and applicability. Material and Methods: Six rtRT-PCR/RT PCR protocols were compared for the laboratory diagnostic of fourteen BTV-14 isolates circulating in Poland in 2012-2014. Results: All 14 isolates were positive in the protocols of Shaw et al. (18), a commercial LSI NS3 kit, and Eschbaumer et al. (5). Four out of fourteen BTV-14 isolates gave positive results in Hoffmann's 2 and 6 protocols and none of the 14 isolates yielded positive results in Maan et al. (8) method. Phylogenetic study of a short fragment of 450 nt of BTV segment 2 (258-696 positions) revealed 100% identity within Polish variants and with Russian and Spanish isolates. Conclusion: The paper points to the possible false negative results in the diagnosis of BTV infections depending on the protocol used. PMID- 29978101 TI - Prevalence of Antibodies to Aujeszky's Disease Virus in Wild Boar in Poland, Between 2011 and 2014: A Retrospective Study. AB - Introduction: Aujeszky's disease virus (ADV) infects a wide range of animals, including members of the Suidae family, i.e. domestic and wild pigs, as well as wild boar. Since wild boar are a potential ADV reservoir and a source of infection for domestic pigs, the aim of the study was to evaluate ADV antibody prevalence in the Polish wild boar population, during the years 2011 to 2014. Material and Methods: Wild boar blood samples were collected during three consecutive hunting seasons; i.e. 2011/2012, 2012/2013, and 2013/2014, and tested for ADV antibodies by ELISA. Results: ADV antibodies were detected in samples from all tested voivodships. The average seroprevalence reached 32.2%. Seroprevalence, over the examined hunting seasons, was 27.4% in 2011/2012, 32.4% in 2012/2013, and 35.5% in 2013/2014. The highest percentage of seroreagents was detected in four voivodships, situated along the western border of Poland, i.e. Zachodnio-Pomorskie (ZP), Lubuskie (LB), Dolnoslaskie (DS), and Opolskie (OP). This area is positively correlated with the highest density of the wild boar population and the highest wild boar hunting bag. Conclusion: The results of this study confirm that the wild boar population may still pose a threat to domestic pigs, which is of special importance at the final stage of Aujeszky's disease eradication programme in Poland. PMID- 29978102 TI - Antiviral and Immunoregulatory Role Against PCV2 in Vivo of Chinese Herbal Medicinal Ingredients. AB - Introduction: The aim of the research was to investigate the antiviral and immunoregulatory effects of saikosaponin A, saikosaponin D, Panax notoginseng saponins, notoginsenoside R1, and anemoside B4 saponins commonly found in Chinese herbal medicines. Material and Methods: control mice were challenged intramuscularly (im) with 0.2 mL of porcine circovirus 2 (PCV2) solution containing 107 TCID50 of the virus/mL. Mice of high-, middle-, and low-dose saponin groups were initially challenged im with 0.2 mL of PCV2 solution and three days later treated intraperitoneally (ip) with one of five saponins at one of three doses (10, 5, or 1 mg/kg b.w.). In the drug control group, mice were dosed ip with 10 mg/kg b.w. of a given saponin, and mice in a blank control group were administered the same volume of normal saline. Results: The results revealed that the saponins could reduce the incidence and severity of PCV2-induced immunopathological damage, e.g. body temperature elevation, weight loss, anaemia, and internal organ swelling. In addition, it was seen that the saponins could affect the immunoglobulin levels and protein absorption. Conclusion: The data suggested that the saponins might effectively regulate immune responses. PMID- 29978103 TI - Poultry in Poland as Chlamydiaceae Carrier. AB - Introduction: The study was conducted to investigate the prevalence and genetic diversity of Chlamydia spp. in poultry in Poland and estimate possible transmission to humans. Material and Methods: Molecular diagnostic methods followed by sequencing and strain isolation were used on cloacal/faecal swabs collected from 182 apparently healthy poultry flocks including chickens, turkeys, ducks, and geese. Serum samples obtained from people exposed (study group) and non-exposed (control group) to birds were tested by complement fixation test to acquire data on Chlamydia spp. antibody level. Results: Overall, 15.9% of the tested flocks were Chlamydiaceae-positive and three Chlamydia spp. were identified. Predominant chlamydial agent found was C. gallinacea occurring in 65.5% of all positive poultry flocks and in 73.0% of positive chicken flocks. The sequences from four chicken flocks were assigned to C. abortus, whereas C. psittaci was confirmed in one duck and one goose flock. The analysis of ompA variable domains revealed at least nine genetic variants of C. gallinacea. Chlamydial antibodies were detected in 19.2% of human serum samples in the study group in comparison with 10.8% in the controls. Conclusion: The obtained results confirm that chlamydiae are common among chicken flocks in Poland with C. gallinacea as a dominant species. Moreover, the presence of C. abortus in chickens is reported here for the first time. Further investigation should focus on possible zoonotic transmission of C. gallinacea and C. abortus as well as potential pathogenic effects on birds' health and poultry production. PMID- 29978104 TI - In silico Analysis of Virulence Associated Genes in Genomes of Escherichia Coli Strains Causing Colibacillosis in Poultry. AB - Introduction: Colibacillosis - the most common disease of poultry, is caused mainly by avian pathogenic Escherichia coli (APEC). However, thus far, no pattern to the molecular basis of the pathogenicity of these bacteria has been established beyond dispute. In this study, genomes of APEC were investigated to ascribe importance and explore the distribution of 16 genes recognised as their virulence factors. Material and Methods: A total of 14 pathogenic for poultry E. coli strains were isolated, and their DNA was sequenced, assembled de novo, and annotated. Amino acid sequences from these bacteria and an additional 16 freely available APEC amino acid sequences were analysed with the DIFFIND tool to define their virulence factors. Results: The DIFFIND tool enabled quick, reliable, and convenient assessment of the differences between compared amino acid sequences from bacterial genomes. The presence of 16 protein sequences indicated as pathogenicity factors in poultry resulted in the generation of a heatmap which categorises genomes in terms of the existence and similarity of the analysed protein sequences. Conclusion: The proposed method of detection of virulence factors using the capabilities of the DIFFIND tool may be useful in the analysis of similarities of E. coli and other sequences deriving from bacteria. Phylogenetic analysis resulted in reliable segregation of 30 APEC strains into five main clusters containing various virulence associated genes (VAGs). PMID- 29978106 TI - T- and B-cell Response Analysis Following Calf Immunisation with Experimental Mycoplasma Bovis Vaccine Containing Saponin and Lysozyme Dimer. AB - Introduction: Mycoplasma bovis is a well-known cause of various disorders in cattle, such as pneumonia, arthritis, mastitis kerato-conjunctivitis, pharyngitis, laryngitis, otitis media, meningitis, and reproductive disorders. There are no commercial vaccines against M. bovis in Europe, therefore, experimental ones are still under investigation. The aim of this study was to evaluate the effect of experimental M. bovis vaccine, containing the Polish field M. bovis strain as well as saponin and lysozyme dimer adjuvants, on the T- and B cell response in calves. Material and Methods: The study was carried out on 12 calves divided into two equal groups: experimental and control. The experimental group was subcutaneously injected with the vaccine composed of the field M. bovis strain as well as saponin and lysozyme dimer as adjuvants, whereas the control one received phosphate buffered saline (PBS). The blood samples were collected prior to the study (day 0), then in 24 h intervals up to day 7 and then each 7 days until day 84 post immunisation. The T- and B-cell response as CD2+ (T cells), CD4+ (T-helper cells), CD8+ (T-cytotoxic cells), and WC4+ (B-cells) markers was analysed using flow cytometry. Results: In response to the immunisation, the general stimulation of T-cell was observed, the most seen in an increase in CD8+ subpopulation. Similarly, a visible rise in the percentage of WC4+ cells was registered in the vaccinated calves when compared to the control animals. Conclusion: This study demonstrated that the novel experimental M. bovis vaccine containing saponin and lysozyme dimer effectively stimulated the cell mediated immunity in the calves. PMID- 29978105 TI - Detection of Listeria Spp. and Listeria Monocytogenes in Biological Samples by SYBR Green I and TaqMan Probe-based Real-time PCRs. AB - Introduction: The aim of the study was the application and comparison of real time PCR methods based on the fluorescence of SYBR Green I intercalating dye and TaqMan probes for the detection of the 23S rDNA gene of Listeria spp. and the hlyA gene of Listeria monocytogenes in biological samples of the liver, brain, and blood. Material and Methods: Five strains of L. monocytogenes and single strains of each species L. ivanovii, L. innocua,L. grayi, L. welshimeri, and L. seeligeri were used for the experiments. Additionally, five strains of other species of bacteria were used for evaluation of the specificity of tests. In the first stage of the study SYBR Green I real-time PCRs, one allowing detection of the 23S rDNA gene and two based on the amplification the hlyA gene, were performed. In the next part, three TaqMan probe-based real-time PCRs allowing confirmation of belonging to Listeria spp. and L. monocytogenes were conducted. Results: The observation of amplification curves in real-time PCRs enabled the detection of both genes. A high regression coefficient of 0.99 was found for all reactions. Specific amplification products were obtained for the 23S rDNA and hlyA genes which confirm their belonging to Listeria spp. and L. monocytogenes, respectively. Other microbial species did not reveal real-time PCR products. Conclusion: Both real-time PCR methods for the detection of Listeria spp. and L. monocytogenes in biological samples demonstrated a significant sensitivity and high specificity. PMID- 29978108 TI - Bacterial Flora Associated with Diseased Freshwater Ornamental Fish. AB - Introduction: Ornamental fish can suffer from different bacterial diseases. Among them the most prevalent are infections caused by Aeromonas, Shewanella, Citrobacter, Plesiomonas, Edwardsiella, and Pseudomonas. But there is a broad spectrum of rarely identified bacteria which may be causative agents of diseases. The aim of the study was to determine the species of bacteria pathogenic for fish which are prevalent in aquariums. Material and Methods: Bacteria were isolated from infected ornamental fish from pet shops and private aquariums in the Lublin region in 2015 and classified to species using MALDI-TOF MS. Results: A total of 182 isolates from ornamental fish were identified. The most frequent bacteria found in diseased fish were Aeromonas veronii (30.8% of total number of strains), A. hydrophila (18.7%), Shewanella putrefaciens (7.1%), Citrobacter freundii (7.1%), Pseudomonas spp. (7.1%), Shewanella baltica (4.9%), and Plesiomonas shigelloides (3.3%). Conclusion: Isolated bacterial species are facultative pathogens for fish and humans and may be isolated from fish without apparent symptoms of the disease. PMID- 29978107 TI - Real-time Loop-mediated Isothermal Amplification (LAMP) of mgc2 Gene of Mycoplasma Gallisepticum. AB - Introduction: Mycoplasma gallisepticum is considered the most pathogenic and economically significant avian Mycoplasma spp. for the worldwide poultry industry. The aim of this study was to develop a novel and sensitive real-time loop-mediated isothermal amplification (LAMP) assay based on the amplification of its mgc2 gene sequence for its rapid molecular detection in poultry. Material and Methods: Blood samples from 300 broiler and layer chickens were screened using a rapid serum agglutination (RSA) test. A real-time LAMP reaction was conducted with seropositive swab samples at 60oC for 90 min in an ESEQuant tube scanner using 6-carboxyfluorescein as the reporting dye. Results: The sensitivity of the developed assay was 10 fg/uL of DNA. The assay was found 100% specific, showing no cross-reactivity with other avian Mycoplasma species. The proportion found of the positive samples by the real-time LAMP was 58%. In comparison, the RSA was found to detect 52% of positive cases. Conclusion: The mgc2 real-time LAMP emerged as a more sensitive and accurate method for molecular detection of M. gallisepticum than RSA. Robustness and precision give it applicability as a potential field diagnostic tool for M. gallisepticum control. The study will be beneficial in reducing economic losses that M. gallisepticum inflicts on the poultry industry. This is the first reported development of a real-time LAMP assay based on the amplification of the mgc2 gene sequence using an ESEQuant tube scanner for galline M. gallisepticum detection. PMID- 29978109 TI - In Ovo Administration of CpG ODN Induces Expression of Immune Response Genes in Neonatal Chicken Spleen. AB - Introduction: Due to their immunostimulatory properties TLR ligands are used prophylactically to protect against a variety of viral and bacterial pathogens in mammals. Knowledge of the molecular and functional aspects of TLRs is essential for a better understanding of the immune system and resistance to diseases in birds. For that reason, this study attempted to determine the impact of TLR21 stimulation by its synthetic ligand (CpG ODN, class B) on the chicken immune system. Material and Methods: Sixty embryonated chicken eggs were randomly allocated into three groups (control and two experimental groups). On day 18 of embryonic development, chickens in one experimental group were administered in ovo a low dose of CpG ODN and the birds of the second experimental group were given a high dose of the ligand. Spleens were collected at 1, 2, 5, and 10 days post-hatching (dph) for analysis of IFN-alpha, IFN-beta, IFN-gamma, IL-6, and IL 10 expression using qRT-PCR. Results: Significant differences were observed in mRNA expression levels of all the measured cytokines associated with the modulation and regulation of the immune response at different time points. Conclusion: The obtained data clearly demonstrate that immune response induction takes place after in ovo administration of class B CpG ODN, and that the ligand has the ability to induce cytokine responses in neonatal chicken spleen. PMID- 29978110 TI - Occurrence of Intestinal Parasites in Pigs in Poland - the Influence of Factors Related to the Production System. AB - Introduction: The aim of study was to estimate the prevalence and intensity of intestinal parasite infections in pigs in Poland and evaluate the influence of factors related to the production system on the infection intensity. Material and Methods: A total of 70 pig farms of all Polish provinces, differing in the herd size and production system, were selected for the study. Fresh faecal samples were collected from all age groups: suckling piglets, weaners, fatteners, and lactating sows. Moreover, data were obtained regarding the size of the herd, the use of paddock and all-in/all-out system, the presence of diarrhoea, and the type of flooring. Results: Parasite eggs or oocysts were detected in 57 of the 70 examined pig farms. Oesphagostomum spp. eggs were found in the largest number of farms (68.6%). Moreover, coccidia (42.9%), Ascaris suum(28.6%), Trichuris suis (21.4%), and Strongyloides spp. (11.4%) were detected. The highest prevalence of coccidia and Strongyloides spp. was found in suckling piglets, A. suum and T. suis in fatteners, and Oesphagostomum spp. in sows. Higher prevalence of parasites was detected in small farms than in medium and large farms, except the prevalence of coccidia, which was the highest in medium farms. Simultaneous infection with several parasites was more often detected than with one parasite. Odds ratio of parasites occurrence was higher in farms with paddock and litter floor and in farms which do not use all-in/all-out system. Conclusion: Relatively high prevalence of intestinal parasites was found in pigs in Poland. Moreover, specific distribution of parasites in different age groups and farms of different size was observed. Influence of breeding factors on parasite prevalence was identified. PMID- 29978111 TI - Detection of Fluoroquinolone Residues in Milk using Yersinia Spp. Strains: Towards Better Sensitivity for Flumequine Determination. AB - Introduction: Plate diffusion methods play an important role in the monitoring system for antimicrobial agents in raw materials and foodstuffs of animal origin. The aim of this work was to select a Yersinia spp. strain for the plate diffusion method based on sensitivity to a fluoroquinolone, namely flumequine. Another aim was to determine the optimal conditions of the method with the selected strain of Yersinia ruckeri CCM 8467 and to determine the detection capability (CCbeta) of this method for residues of selected fluoroquinolones in milk. Material and Methods: Optimum method conditions were set: cell concentration in the test agar at the level of 9.105-106 CFU/mL, discs with a diameter of 12.7 mm, Antimicrobial Inhibitor Test Agar with a pH of 6.0, and incubation at 30 degrees C for at least 18 h and up to 24 h. Results: With respect to the maximum residue limit (MRL), the Y. ruckeri plate method demonstrated the lowest sensitivity to flumequine. The CCbeta of the method for flumequine was in the concentration of 100 MUg/L-1 (twice the MRL). The study also confirmed that the method exhibits very good sensitivity to the other tested fluoroquinolones, which were marbofloxacin (30 MUg/L, 0.4 MRL), ciprofloxacin (10 MUg/L, 0.1 MRL), and enrofloxacin (20 MUg/L, 0.2 MRL), but lower sensitivity to danofloxacin (42 MUg/L, 1.4 MRL). Conclusion: The method with the CCM 8467 strain of Y. ruckeri showed a higher sensitivity to flumequine than the method with the ATCC 11303 strain of E. coli. PMID- 29978113 TI - Occurrence of Ochratoxin a in Animal Tissues and Feeds in Poland in 2014-2016. AB - Introduction: Ochratoxin A (OTA) is a toxic metabolite mainly produced by Aspergillus spp. and Penicillum spp. fungi. Research on the contamination of cereals, complete feeds, and tissues with this mycotoxin has indicated that it can be a toxicological problem impacting animal health and food safety in temperate climes. OTA contamination mainly besets the global pig industry, necessitating the monitoring of feeds and animal tissues. The aim of the study was to present the results of the official monitoring of OTA in animal tissues and feeds in Poland in 2014-2016 and determine the possible correlation between the presence of OTA in different types of samples. Material and Methods: The presence of ochratoxin A was determined using accepted procedures based on liquid chromatography with fluorescence detection after immunoaffinity column clean-up. Determination of OTA was afforded in the range of 0.3 ug/kg to 300 ug/kg in complete feeds and from 0.2 ug/kg to 150 ug/kg in the kidneys, liver, and muscles. Results: Over the three year span, about 23.5% of the animal tissues samples were contaminated by ochratoxin A. In the 2014 survey, 10% of the sample tissues contained 5-10 ug/kg (only one sample above 10 MUg/kg), and in 2015 and 2016, 24% of samples showed levels above the limit of quantification 0.2 MUg/kg, while none of the samples exceeded the established provisional action level of 5 MUg/kg for animal tissues. The animal feed analysis showed that 9% was contaminated with ochratoxin A above the limit of quantification of 0.3MUg/kg. In 2% of feed samples the OTA concentration was greater than 50 MUg/kg. Conclusion: The results confirm the appropriacy of OTA contamination monitoring and help to increase food safety. PMID- 29978112 TI - Application of the AhR Reporter Gene Assay for the Determination of PCDD/Fs and DL-PCBs in Feed Samples. AB - Introduction: Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) belong to a well known group of pollutants. Present in feedstuffs, they bioaccumulate in tissues of food-producing animals. Food is the source of over 90% of human PCDD/Fs and DL PCBs intake. Thus, feed control is one of the pillars of the EU strategy and a mean of reducing human exposure. The article presents AhR based reporter gene bioassay method for PCDD/Fs and DL-PCBs analysis in feed and its validation results. Material and Methods: Analytes were extracted from samples with fat. Subsequently, fat and other interferences were removed from extract using sulphuric acid modified silica. Extract was further cleaned and PCDD/Fs separated from DL-PCBs using carbon column. Contaminants detection was performed using H1L6.1c3 cell line, which produces luciferase in response to AhR ligands present in extract. Results: Performance characteristics (repeatability, reproducibility, and apparent recovery) fulfil the requirements of Regulation 2017/771/EU. The positive correlation between bioassay and reference HRGC-HRMS method was confirmed. Moreover, the role of screening method used in connection with the confirmatory HRGC-HRMS method in providing feed and food safety has been discussed. Conclusion: Bioassay is a useful method for dioxin and DL-PCBs analysis, allowing cost reduction of monitoring programmes with minimal risk of false negative results. PMID- 29978114 TI - Effect of Intrauterine Infusion of Momordica Charantia L. on Oxidative Stress and Pregnancy Rate in Infertile Cows. AB - Introduction: The effect of intrauterine administration of Momordica charantia L. (MC) extract on oxidative changes and pregnancy rate in infertile cows was investigated. Material and Methods: Endometrial smear specimens were taken from 40 cows with fertility problems for cytological examination, and the cows were randomly divided into two groups: group I (n = 20) was subjected to intrauterine administration of 40 mL (0.25 g/mL) of MC extract, group II (n = 20) was subjected to intrauterine administration of 40 mL of pure olive oil. Blood samples were taken starting from the day of administration of MC extract or olive oil (day 0) and then for three weeks at weekly intervals (days 7, 14, 21). Blood serum samples were evaluated for total antioxidant capacity (TAS), total oxidant level (TOS), oxidative stress index (OSI), lipid hydroperoxide (LOOH), and nitric oxide (NO) levels. In addition, on the 14th day following treatment, two doses of PGF2alpha were administrated to all cows at 14-day intervals. Following the second PGF2alpha administration, insemination and GnRH administration was performed at the 60th h after PGF2alpha treatment. Smear samples were stained with Giemsa and immunohistochemically to determine cytological changes and inflammatory status. Results: According to cytological findings, subclinical endometritis was a prevalent disorder in cows with infertility problem (82.5%; 33/40). Additionally, 60.6% (20/33) of the cows with subclinical endometritis had acute inflammation, whereas remaining 13 cows had chronic endometritis. Of the cows with subclinical endometritis, 50% (8/16) and 35% (6/17) became pregnant in group I and II, respectively (P > 0.05). Although the oxidative stress parameters showed similarities between both groups (P > 0.05), there was a significant difference (P < 0.001) between the groups in terms of mean NO and LOOH levels (NO - 31.20 +/- 11.38 vs 44.53 +/- 11.50 MUmol/L and LOOH - 1.22 +/- 0.37 vs 1.89 +/- 0.36 MUmol/L). Conclusion: The obtained results indicated that MC administration, especially in the presence of active inflammation, may improve the pregnancy rate by positive reduction of oxidative changes. PMID- 29978115 TI - MDA and GSH-Px Activity in Transition Dairy Cows Under Seasonal Variations and their Relationship with Reproductive Performance. AB - Introduction: The purpose of the current study was to evaluate the blood glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels under seasonal variations in dairy cows during transition period, and to assess the relationship between chosen reproductive parameters, GSH-Px, and MDA. Material and Methods: Holstein cows calving in January were assigned into winter group (n = 42), while cows calving in August were assigned into summer group (n = 42). Blood samples were collected from the jugular vein 21, 14, and 7 days before calving, at calving (0 day), and 7, 14, and 21 days after calving. Reproductive parameters obtained from farm records were evaluated. Results: In both groups of cows, GSH Px activity decreased from 21 days before calving to day 0, and it gradually continued to increase until 21 days after calving. GSH-Px activity was higher in winter group compared to summer group during the transition period (P < 0.05). MDA levels in both groups increased over time starting from 21 days before calving to 0 day, but it gradually decreased thereafter. MDA levels were higher in summer group compared to winter group during the transition periods (P < 0.05). Summer group of cows showed higher intervals of calving-to-oestrus, calving-to-conception, and higher insemination index (P < 0.01). Negative correlation was recorded between GSH-Px and MDA during all examination days (P < 0.01). MDA levels correlated with calving to conception interval on day 21 before calving and day 0 (P < 0.01) and insemination index on day 0 and 21 days after calving (P < 0.01). GSH-Px activity was negatively correlated with calving to conception interval on day 21 before calving, day 0, and 21 days (P < 0.01) after calving. Negative correlation on day 21 before calving and day 0 was also determined between GSH-Px and insemination index (P < 0.01). Conclusion: This study showed that blood oxidant and antioxidant levels have affected the fertility parameters in cows under seasonal variations. PMID- 29978116 TI - Changes in Synovial Fluid Biomarkers after Experimental Equine Osteoarthritis. AB - Introduction: The study aimed to clarify the changes in the concentration of inflammatory mediators, proteases, and cartilage degradation biomarkers in the synovial fluid of joints in an equine osteoarthritis model. Material and Methods: Osteoarthritis was induced in eight Mongolian horses by a sterile intra-articular injection of amphotericin B, which was injected into the left carpal joint in a dose of 2 mL (25 mg/mL). The control group comprised five horses which were injected with an equal dose of sterile physiological saline into the left carpal joint. Synovial fluid was obtained at baseline and every week after injection. Test methods were based on ELISA. Results: In the course of the osteoarthritis, the concentration of biomarkers in joint synovial fluid showed an increasing trend. IL-1, IL-6, MMP-9, MMP-13, ADAMTS-5, CS846, GAG, HA, CTX-II, and COMP concentrations sharply increased before the onset of significant symptoms of lameness, whereas TNF-alpha, MMP-2, and MMP-3 concentrations rose sharply after the occurrence of such symptoms. Conclusion: The results obtained confirm that the concentrations of IL-1, IL-6, MMP-9, MMP-13, ADAMTS-5, CS846, GAG, HA, CTX-II and COMP increase substantially in equine osteoarthritis, which provides a theoretical basis for the rapid diagnosis of the disease. PMID- 29978117 TI - Effect of Amifostine on Sperm DNA Fragmentation and Testes after Radioiodine Treatment. AB - Introduction: Radioactive iodine (RAI) is commonly used for the treatment of hyperthyroidism caused by Graves' disease or thyroid nodules. However, information available on the impact of RAI therapy on male gonadal function is scarce. This study aimed to determine any possible damage to testicular tissue and sperm quality caused by RAI therapy, and the radioprotective effect of amifostine against such damage. Material and Methods: In total, 36 rats were randomly allocated to three groups, including a control group, RAI group (111 MBq Iodine-131), and RAI + amifostine group (111 MBq Iodine-131 and a single dose of 200 mg/kg amifostine). Blood and epididymal sperm samples were taken for hormone analyses and the evaluation of spermatological parameters. The TUNEL assay and haematoxylin-eosin were used to stain testicular tissue samples to detect histological changes and apoptosis. Results: The groups differed insignificantly for the testicular mass index and spermatozoa concentration. However, spermatozoa motility and percentage of viable spermatozoa were higher in the RAI + amifostine group, compared to the RAI group. Sperm DNA fragmentation and the index of apoptotic germ cells significantly decreased in the amifostine group, in comparison to the radioiodine group. While the testosterone levels showed no significant change, the follicle stimulating hormone (FSH) levels significantly decreased in the RAI + amifostine group. Conclusion: All histopathological parameters and some spermatological parameters showed that RAI therapy caused statistically significant damage of testicular tissue and this damage was reduced by amifostine. PMID- 29978118 TI - Influence of alpha-lipoic Acid on Morphology of Organs of Rabbits Fed a High Fat Diet with the Addition of Oxidised Rapeseed Oil. AB - Introduction: The aim of the study was to assess the influence of alpha-lipoic acid (ALA) on the morphology of the aorta and liver of rabbits fed high fat diet with addition of oxidised (ORO) and non-oxidised rapeseed oil (N-ORO). Material and Methods: The study was conducted on male chinchilla rabbits divided into six groups. The control group (C) was fed a breeding standard diet (BSD), group I received BSD with the addition of ALA in the dose of 10 mg/kg b.w., groups II and III received BSD enriched with 10% addition of N-ORO or ORO, whereas rabbits from groups IV and V received BSD with 10% addition of N-ORO or ORO and ALA. Results: Addition of ORO caused necrosis and steatosis of hepatocytes, as well as atherosclerotic plaques of various intensification in the aorta. In the liver of rabbits from group II (N-ORO) infiltrations of mononuclear cells was observed in the area of liver triads and between liver lobules. The beneficial influence of ALA was demonstrated in rabbits fed a diet containing N-ORO or ORO. In case of ORO, the activity of ALA was not fully effective. Conclusion: Diet supplementation with ALA counteracts the changes generated in the liver and aorta under increased exposure to higher fat content in diet, in particular thermally treated fats. PMID- 29978119 TI - Therapeutic Effect of Hydrogen Injected Subcutaneously on Onion Poisoned Dogs. AB - Introduction: The purpose of this study was to investigate the therapeutic effect of hydrogen on the therapy of onion poisoned dogs. Material and Methods: A total of 16 adult beagle dogs were divided into two groups (control and hydrogen) and all were fed dehydrated onion powder at the dose of 10 g/kg for three days. The dogs of the experimental group were given subcutaneous injection of 0.2 mL/kg of hydrogen for 12 days after making the poisoned model successful. Blood samples were collected before feeding onions, one day before injecting hydrogen, and 2 h after the injection of hydrogen on days 1, 3, 5, 7, 9, and 12. Control dogs were not treated with hydrogen. Results: The levels of leukocyte production, anaemia, red blood cell degeneration which was reflected by the values of Heinz body count, haemolytic ratio, and oxidative products in hydrogen treated group were lower than in control dogs on some days. The capacity of medullary haematopoiesis that was based on reticulocyte counts, and the antioxidation in hydrogen group were higher compared with control group. However, the differences in renal function were not obvious in both groups. Conclusion: Accordingly, it was concluded that subcutaneous injection of hydrogen could alleviate the symptoms in onion poisoned dogs. PMID- 29978120 TI - Microsatellite based Genetic Variation among the Buffalo Breed Populations in Pakistan. AB - Introduction: Eight microsatellite loci were used to define genetic diversity among five native water buffalo breeds in Pakistan. Material and Methods: Blood samples (10 mL) from 25 buffaloes of each of the Nili, Ravi, Nili-Ravi, Kundhi, and Azi-Kheli breeds were collected aseptically from the jugular vein into 50 ml Falcon tubes containing 200 ul of 0.5 M EDTA. The phenol-chloroform method was used to extract DNA and the regions were amplified for microsatellite analysis. The eight microsatellite markers ETH10, INRA005, ILSTS029, ILSTS033, ILSTS049, ILSTS052, ETH225, and CSSM66 were analysed. Results: The effective number of alleles across all loci was as usual lower than the observed values with a mean value of 2.52 alleles per locus. The overall allele frequency varied from 0.0041 for alleles B, I, and J over respective loci ILSTS052, INRA005, and ILSTS029 to 0.80 for allele H over locus ILSTS029. The average observed and expected heterozygosity values across all polymorphic loci in all studied buffalo breeds were 0.43 and 0.53, respectively. The overall value for polymorphic information content of considered microsatellite markers was 0.53, suggesting their appropriateness for genetic diversity analysis in buffalo. The mean Fis value was 0.13 and all loci except ILSTS049 were found significantly deviated from HWE, most likely due to non-random breeding. The five buffalo populations were genetically less diverse as indicated by a small mean Fst value (0.07). The average gene flow (Nm) indicative for population migration was calculated as 3.31. Nei's original measures of genetic distance (Ds) revealed ancient divergence of the Nili and Azi-Kheli breeds (Ds = 0.1747) and recent divergence of the Nili and Ravi breeds (Ds = 0.0374). Conclusion: These estimates of genetic diversity were seen to coincide with phenotypic differentiation among the studied buffalo breeds. The present study reports the first microsatellite marker-based genetic diversity analysis in Pakistani buffalo breeds, and might facilitate similar studies in other livestock breeds of Pakistan. PMID- 29978121 TI - Salmonid Alphavirus (SAV). AB - Salmonid alphavirus (SAV), genus Alphavirus, family Togaviridae, is a single stranded RNA virus affecting Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). It is known to be responsible for pancreas disease (PD) and sleeping disease (SD) which are increasing problems, causing high fish mortality and economic losses in the European aquaculture industry. Pancreas disease was first described in Atlantic salmon in Scotland in 1976 and a similar disease caused by the closely related sleeping disease virus was first described in rainbow trout in France. There have also been reports of salmonid alphavirus infections from other European countries, including Ireland, England, Norway, Germany, Italy, and Spain. Salmonid alphaviruses have been classified into six subtypes (SAV1-6). SAV1 and SAV4-6 cause pancreas disease in Atlantic salmon in Ireland or Scotland, SAV2 is the causative agent of sleeping disease in rainbow trout, and SAV3 has been detected in Atlantic salmon in Norway. The aim of this paper was to summarise current knowledge of infections caused by salmonid alphavirus and diagnostic methods including the newest techniques, and to briefly describe prevention from SAV infections by vaccination. PMID- 29978122 TI - Complete Genome Sequences of Three Sub-genotype 2.1b Isolates of Classical Swine Fever Virus in China. AB - Introduction: Classical swine fever (CSF) has caused severe economic losses in pig production in many countries. Recent CSF outbreaks in China are mainly associated with sub-genotype 2.1 of CSF virus (CSFV). Although there is abundant information regarding 2.1 isolates, few data are available on whole-genome analysis. Material and Methods: The biological and genome characteristics of three recently emerged Chinese CSFV isolates, i.e. SD2014-1, SD2014-2, and SD2014 3, were fully analysed. Results: Sequence analysis showed that the isolates shared 83.4%-95.0% nucleotide identity with eight other CSFV isolates. In addition, the 5' untranslated region (5'UTR) and the non-structural (NS) proteins NS3, NS4A, and NS4B were more conserved than other regions of the genome. Phylogenetic analysis based on the complete genome sequences or full-length structural protein E2 gene sequences revealed that the three isolates belonged to sub-genotype 2.1b. In addition, several unique molecular characteristics of the 5'UTR, 3'UTR, and E2 were identified. Conclusion: The genomic variations of the three isolates will support further analysis of virulence determinants and the evolutionary trend of CSFV. PMID- 29978123 TI - Cloning and Expression of NS3 Gene of Pakistani Isolate Type 2 Dengue Virus. AB - Introduction: Dengue is one of the major emerging viral diseases in the world, with dramatic increases in reported cases in the last few decades and annual worldwide occurrence of approximately 390 million infections. It is a highly important mosquito-vectored disease and is a problem in tropical and subtropical areas of the world. The major aim of this study was to clone and express the dengue NS3 gene, in service to its therapeutic importance for the development of stable cell lines. Material and Methods: Blood samples from dengue fever (DF) patients were collected and subjected to PCR amplification of the NS3 gene of dengue virus serotype-2 (DENV-2). The NS3 gene was amplified using gene specific primers and cloned in the TA cloning vectors. Results: The gene was successfully expressed in mammalian expression vector pcDNA3.1. The current finding was different from a previously reported DENV-2 strain replicon constructed in different cells, in which the whole genetic material of the virus was used instead of an active protease gene, and which gave a low yield of replicon expressing cells. Conclusion: Recombinant NS3 could be used to produce an antibody that is possibly helpful for developing a single step diagnostic assay to detect the dengue virus NS3 antigen in sera of dengue patients. PMID- 29978124 TI - Identification and Control of Sources of Taenia Solium Infection - the Attempts To Eradicate the Parasite. AB - Taenia solium is a parasite causing porcine cysticercosis and human taeniosis and cysticercosis, parasitic zoonoses with a serious public health and economic influence. It has been globally ranked as the top foodborne parasite by the Food and Agriculture Organisation of the United Nations (FAO) and the World Health Organisation (WHO). This parasite is transmitted mainly in countryside regions where animals are free roaming, having access to human faeces, and infected pork is widely available. More developed countries eliminated cysticercosis; nonetheless, there are insufficient data about the current endemicity status of T. solium, due to increased human migration from endemic areas. Formally submitted statistics on cysticercosis in pigs are extremely inadequate. This is the result of not reporting all cases of the disease by some countries and lack of molecular verification during identification of the parasite. There is a need to develop diagnostic tests with increased sensitivity and specificity. The purpose of the present review is to summarise current knowledge about diagnostic and control methods concerning T. solium infection. The article does not address the diagnostics of human cysticercosis, since there is a distinct medical field which should be discussed separately. The paper focuses mainly on identifying the sources of T. solium infection, presenting the methods to detect and control porcine cysticercosis and taeniosis in humans. PMID- 29978125 TI - Histopathological, Immunohistochemical, and Parasitological Studies on Pathogenesis of Coenurus Cerebralis in Sheep. AB - Introduction: This study consisted in histopathological and immunohistochemical examinations of the central nervous system of 15 sheep suspected of infection with Coenurus cerebralis. The sheep displayed compulsive circling and were submitted for necropsy in 2012-2016. Material and Methods: Species identification was made on the basis of the PCR analysis and parasitological examination of the cysts. Results: Coenurus cerebralis cysts were detected only in the cerebral tissue of 13 sheep and in the cerebral and cerebellar tissues of 2 animals. Out of the 33 parasite cysts, most (21.21%) were located in the right and left frontal lobes of the cerebrum. The largest cyst measured 6 * 5 cm and the smallest cyst was 2 * 2 cm in size. The highest and lowest numbers of scolices were 55 and 21, and the number of rostellar hooks ranged between 22 and 30. Histopathological examination revealed the presence of typical parasitic granulomatous inflammatory foci. Immunohistochemical staining showed that most common in the periphery of the parasite cysts were, in descending order by cell number, GFAP, CD163, CD3, and CD79alpha-positive cells. Conclusion: The study confirms the role of cellular defence mechanisms in the pathogenesis of Coenurus cerebralis infection in sheep. PMID- 29978126 TI - Phagocytic Activity and Oxygen Metabolism of Peripheral Blood Granulocytes from Rabbits Experimentally Infected with Trichophyton Mentagrophytes. AB - Introduction: Phagocytic activity and oxygen metabolism of peripheral blood granulocytes from rabbits with experimental trichophytosis were assessed by flow cytometry. Material and Methods: Virulent species of T. mentagrophytes var. granulosum (Tm-K) isolated from rabbits with natural trichophytosis was used for experimental infection. The phagocytic activity of granulocytes was measured in whole blood by flow cytometry using the commercial Phagotest kit. Oxidative burst was measured in whole blood by flow cytometry using the commercial Bursttest kit. Results: It was found that rabbits were susceptible to infection with Trichophyton mentagrophytes under experimental conditions. The analysis of the phagocytic activity indices and oxygen metabolism of granulocytes in peripheral blood of infected rabbits showed that changes of the indices were connected with the progression and regression of the disease. A significant decrease in phagocytic activity and oxygen metabolism was observed during development of fungal lesions and it remained similar throughout the progress of the disease. The highest means of the percentage of activated and ingesting phagocytes and a significant increase in the mean fluorescence intensity (representing the number of ingested bacteria) were observed during spontaneous recovery. Therefore, the decrease or increase in the indices of phagocytic activity and oxygen metabolism of granulocytes from rabbits experimentally infected with T. mentagrophytes is somehow related to the progress of infection and suppressive activity of the fungus, whose elimination during recovery caused significant increases in investigated indices of non-specific cellular immunity. Conclusion: The results of the present investigation confirm that the mechanism of oxygen-dependent killing is crucial in infections caused by T. mentagrophytes. PMID- 29978127 TI - Ready-to-eat Meat Products As a Source of Listeria Monocytogenes. AB - In 2015 in the European Union member states listeriosis caused 270 deaths. Food is the route of transmission in 99% of all human infection cases. Several studies from different countries have shown that the presence of Listeria monocytogenes in food can be as high as 58.3%. One of the most important ways to protect food from these microorganisms is to prevent the spread of the bacteria at processing plants at different stages of food production chain. The ability of L. monocytogenes to survive in extreme conditions and to form biofilms on various surfaces is a significant challenge for food safety. Removal of these bacteria from niches in processing plants is difficult and requires the use of sanitisers and precise equipment cleaning. The presence of L. monocytogenes in processing environment at slaughterhouses, deli meat factories or in retail may be a reason of cross-contamination. Proper hygienic systems applied by workers in food preparing places and knowledge about different routes of spreading of these bacteria may effectively decrease the risk of food contamination. Standardised legal regulations and control of meat product manufacture should be a fundamental way to protect food from L. monocytogenes contamination. PMID- 29978128 TI - Efficacy and Safety Assessment of Microbiological Feed Additive for Chicken Broilers in Tolerance Studies. AB - Introduction: One aim of the study was to evaluate the impact when added to feed of the two potentially probiotic strains of lactic acid bacteria (LAB) Lactobacillus plantarum K KKP 593/p and Lactobacillus rhamnosus KKP 825 on production performance, health, and the composition of gut microbiota. The complementary aim was to assess the safety of these strains in broiler rearing. Material and Methods: A total of 500 one-day-old Ross 308 chicks were divided into four groups. The experimental factor was the admixture of bacterial preparation to the feed at different doses: the recommended maximum dose, a dose ten times higher, the recommended minimum dose, and a zero dose for the control group not receiving bacteria. Results: Addition of bacteria to the diets did not have a significant effect on the final body weight, final body weight gain, nor total feed intake or feed conversion. However, lactic acid bacteria had a positive effect on chicken health. Mortality among chickens fed with LAB was reduced. Moreover, LAB feeding inhibited the growth of Salmonella spp. and Clostridium perfringens in the intestines. There were no significant differences in chicken performance by dose of bacteria in the feed. The group dosed with LAB ten times higher than the recommended maximum did not demonstrate changes in biochemical or haematological parameters of blood compared to the remaining groups. Conclusion: Feeding chicken broilers with two potentially probiotic LAB strains is safe and impacts animal health positively. PMID- 29978129 TI - Histamine Content in Rennet Ripening Cheeses During Storage at Different Temperatures and Times. AB - Introduction: In recent years, there has been a great interest in biogenic amines such histamine, as they are associated with the quality and safety of some kinds of fermented foods. The aim of this study was to evaluate the effect of temperature and storage time on the content of histamine in cheeses. Material and Methods: Samples of mould and hard cheeses were examined with RP-HPLC with an organic-aqueous mobile phase containing acidic buffer and chaotropic salt. The samples were stored either at 22 +/- 2 degrees C for 42 days (mould and hard cheeses) or at 4 +/- 2 degrees C for 112 days (mould cheeses) and 133 days (hard cheeses). Results: The mean total histamine content in cheeses stored at 22 degrees C was higher than the content in those stored at 4 degrees C, with the highest concentrations found in Gorgonzola Piccante cheese (730.47 mg/kg). Histamine concentration in some types of cheeses exceeded the toxic threshold dose, indicating that after long or inadequately cool storage they may not be safe for consumers. Conclusion: To protect cheeses from contamination with histamine-producing bacteria and to safeguard consumers from poisoning, factors conducive to this amine's formation should be minimised during cheese processing. Suitable temperature and time during storage of cheeses are recommended to avoid the intoxication. Monitoring of this toxin in food is necessary to ensure safety of consumers. PMID- 29978130 TI - Relationship Between the Content of Chlorinated Hydrocarbons and Fatty Acid Composition of Milk Fat. AB - Introduction: Reports that the presence of persistent organic pollutants in fat may affect fatty acid metabolism prompted this research aiming to study the relationship between the contents of gamma-HCH and DDT, DDE, DDD, and SigmaDDT, and fatty acid composition of milk fat. Material and Methods: The material consisted of 50 samples of cow and mare milk, collected in 2015. Ludwicki's and the Rose-Gottlieb and IDF Standard methods were used to prepare the samples. Statistical analyses were conducted using Statistica 12.0. Results: There was a negative correlation between the content of gamma-HCH and C16:1, C17:1, C18:1c9, C18:1c9c12, and SigmaMUFA in cow milk fat and C13:0, C14:0, and C10:1 in mare milk fat. A positive correlation was observed between gamma-HCH and C6:0 to C12:0, C14:0, C18:1t16, and SigmaSFA in cow milk fat, and between this compound and C14:0iso, C16:1, C17:1, C18:1c9,11, and SigmaMUFA in mare milk fat. A negative correlation between the contents of SigmaDDT and C16:1, C17:1, C18:1c9,11,13 and SigmaMUFA in cow milk fat and C16:0iso, C17:0, and C18:3 in mare milk fat was noted. A positive correlation was found between the contents of SigmaDDT and saturated and polyunsaturated fatty acids and SigmaSFA and SigmaPUFA in cow milk fat, and C18:2c9c12 in mare milk fat. Conclusion: The correlation between the content of selected organochlorine compounds and the composition of fatty acids in cow and mare milk fat indicates the strong influence of these environmental pollutants on the nutritional value of milk fat. PMID- 29978131 TI - Effects of Polymyxin B on Clinical Signs, Serum TNF-alpha, Haptoglobin and Plasma Lactate Concentrations in Experimental Endotoxaemia in Sheep. AB - Introduction: The experiment evaluated the effects of intravenous administration of polymyxin B on experimental endotoxaemia in sheep. Material and Methods: Twenty clinically healthy fat-tailed sheep were randomly divided into: a group treated with 6,000 U/kg of polymyxin B, a group at 12,000 U/kg, and positive and negative controls. Endotoxaemia was induced by intravenous administration of lipopolysaccharide (LPS) from E. coli serotype O55:B5 at 0.5 MUg/kg. polymyxin was infused intravenously along with 2.5 L of isotonic intravenous fluids at 20 mL/kg/h. The positive control group received LPS and 2.5 L of isotonic fluids, the negatives receiving just 2.5 L of isotonic fluids. Clinical signs were evaluated before and at 1.5, 3, 4.5, 6, 24, and 48 h after LPS administration. Blood was also sampled at the denoted hours and serum haptoglobin, tumour necrosis factor-alpha (TNF-alpha), and plasma lactate concentrations were assayed. Results: The serum concentration of TNF-alpha in the positive control group increased significantly up to 48 h after LPS administration. The concentration of TNF-alpha was significantly different from those of the polymyxin B and positive control groups from 3 to 48 h; also, the concentrations of haptoglobin at different times in the polymyxin groups were lower than those of the positive control group and were significant at hours 3 to 48 (P < 0.05). Following the LPS administration, haptoglobin and TNF-alpha concentrations changed without significant difference between the two polymyxin B groups. Conclusion: Polymyxin B (6,000 U/kg) restrained blood lactate concentrations. Furthermore, it significantly improved the clinical signs in endotoxaemic animals, including rectal temperature and heart and respiratory rates. Polymyxin B may be an antiendotoxic in fat-tailed sheep. PMID- 29978132 TI - Toxicological Evaluation of Flumequine in Pubertal Male Rats After Oral Administration for Six Weeks. AB - Introduction: Veterinarians use flumequine (FLU) widely but its toxicological effects are still unclear. Material and Methods: FLU doses of 53, 200, or 750 mg/kg were administered orally for six weeks to pubertal male rats for evaluation of their toxicity. Results: Weight gain was poorer after seven days of exposure to FLU 750, but relative weights of the brain, adrenal and thyroid glands, and testes were notably higher. Haematological and lipid profile parameters, cardiac markers, and inorganic phosphate significantly increased in the FLU 750 group. Blood glucose, oestradiol and serum concentrations of immunoglobulins G (IgG) and E (IgE) significantly decreased after treatment. The levels of interleukins 10 (IL-10) and 6 (IL-6) fell significantly in the FLU 200 and FLU 750 groups. Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and cyclooxygenase 2 (Cox-2) expression amplified after treatment. Serum levels of free triiodothyronine (fT3) and free thyroxine (fT4) reduced in the FLU 200 and FLU 750 groups without changes in total T3 or T4 level. All doses of FLU significantly depressed concentrations of thyroid-stimulating hormone (TSH) and testosterone. Histopathology of thyroid glands from rats treated with FLU 750 showed degeneration and depletion of thyroid follicular epithelial cells. Expression of 8-hydroxydeoxyguanosine (8-OHdG) was increased in a dose-dependent manner in the brain, but decreased in the testes. Expression of CYP1A1 increased in the adrenal and pituitary glands. Conclusion: The results of this study suggest that the toxicity of FLU in rats is an effect of its disruptive influence on the pituitary-thyroid hormonal system and on the dysfunction of the immune system. PMID- 29978133 TI - Study of Troponin, Creatine Kinase Biomarkers, and Histopathological Lesions in Experimental Nerium Oleander Toxicity in Rats and Mice. AB - Introduction: Nerium oleander is a plant of the Apocynaceae family toxic to humans, animals, and insects. This study was performed to determine the cardiac and neurotoxicity of the plant extract by oral administration in Wistar rats and Balb/c mice and to compare the susceptibility of these animal models to oleander toxicity. Material and Methods: Four groups of eight mice and eight rats received N. oleander extract orally while a fifth group was the control. Serum concentrations of the biochemical toxicity indicators, namely troponin and creatine kinase (CK), were determined and histopathological evaluation of the heart and brain was performed. Results: In mice, CK and troponin concentrations were respectively 1.5 and 7 times higher than in the control group (P < 0.05), while in rats, they were 6-7 and 11 times higher. Hyperaemia, haemorrhage, and myofibrolysis, without infiltration of inflammatory cells, were observed in the heart. In the brain the authors observed hyperaemia associated with perivascular and perineuronal oedema, and in higher-dosed rats multifocal haemorrhagic and liquefactive necrotic lesions. Conclusion: Oleander can affect serum levels of CK and troponin due to nervous and cardiac injuries. Rats showed more severe changes in the biochemical indicators and histopathological lesions than mice. Therefore, biochemical and pathological findings indicate that Wistar rats are more susceptible to the cardiac toxicity and neurotoxicity effects of N. oleander poisoning than Balb/c mice. PMID- 29978134 TI - Effects of Natural Antioxidants on The Stability of Omega-3 Fatty Acids in Dog Food. AB - Introduction: The efficiency of five natural antioxidants (curcumin, cranberry, pomegranate, grape seed extract (GSE), and acai berry) in reducing lipid oxidation in dog food was compared to that of the synthetic antioxidant butylated hydroxyanisole (BHA). Material and Methods: In two different experiments content parameters were measured after 12 days of storage at 55 degrees C. In experiment one, the natural antioxidants were added at 0.2% and BHA at 0.02% of the food (DM basis), and samples were analysed for thiobarbituric acid-reactive substances (TBARS). In experiment two, the effects of GSE and curcumin at two admixture proportions (0.1% and 0.2% of food DM) on omega-3 fatty acid (FA) content were evaluated. Results: TBARS values were lower than the control (P < 0.01) for curcumin, cranberry, pomegranate, and GSE but not for the acai berry (P > 0.05). By day 12, although there were no significant differences (P > 0.05) between the two curcumin treatments, they preserved higher concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (P < 0.05) than the BHA and control treatments. The addition of GSE or BHA to dog food held (P < 0.05) the concentrations of EPA higher than the control. The concentrations of EPA and DHA for the 0.2% GSE treatment were greater (P < 0.05) than the 0.1% GSE treatment. Grape seed extract at 0.2% lost less (P < 0.05) EPA concentration than BHA. Conclusion: The present results showed that, except for acai berry, the tested natural antioxidants could be used as a substitute for BHA in dog food. PMID- 29978135 TI - Analysis of Haematological and Biochemical Blood Parameters After Electrical Cardioversion of Atrial Fibrillation in Dogs. AB - Introduction: Electrical cardioversion is a therapeutic procedure used to convert various types of arrhythmias back to sinus rhythm. It is used to restore the sinus rhythm in dogs with atrial fibrillation. The effect of the electrical energy used during cardioversion on red blood cells (RBC) is not fully understood. Studies on humans reported lysis of RBC following electrical cardioversion. Similar studies have not been carried out on dogs. The aim of the study was to assess the effect of electrical cardioversion on chosen RBC parameters. Material and Methods: The study was carried out on 14 large and giant breed dogs weighing from 30 to 84 kg with lone atrial fibrillation (lone AF). Electrical cardioversion was carried out under general anaesthesia by biphasic shock with 70-360 J of energy. Blood was collected at T0 - during atrial fibrillation, prior to cardioversion, and at T1 - 30 min after electrical cardioversion. Complete blood counts as well as total and direct bilirubin concentrations were evaluated. A maximum output of 360 J was used. Results: In all cases, electrical cardioversion was effective, and no significant changes in the number of RBC and RBC indices were noted. Similarly, there were no statistically significant differences in the levels of total and direct bilirubin. Conclusion: Electrical cardioversion in dogs led neither to statistically nor clinically significant RBC lysis. PMID- 29978136 TI - Cloning and Differential Expression Analyses of Cdc42 from Sheep. AB - Introduction: Serological diagnosis of brucellosis is still a great challenge due to the infeasibility of discriminating infected animals from vaccinated ones, so it is necessary to search for diagnostic biomarkers for differential diagnosis of brucellosis. Material and Methods: Cell division cycle 42 (Cdc42) from sheep (Ovis aries) (OaCdc42) was cloned by rapid amplification of cDNA ends (RACE), and then tissue distribution and differential expression levels of OaCdc42 mRNA between infected and vaccinated sheep were analysed by RT-qPCR. Results: The full length cDNA of OaCdc42 was 1,609 bp containing an open reading frame (ORF) of 576 bp. OaCdc42 mRNAs were detected in the heart, liver, spleen, lung, kidneys, rumen, small intestine, skeletal muscles, and buffy coat, and the highest expression was detected in the small intestine. Compared to the control, the levels of OaCdc42 mRNA from sheep infected with Brucella melitensis or sheep vaccinated with Brucella suis S2 was significantly different (P < 0.01) after 40 and 30 days post-inoculation, respectively. However, the expression of OaCdc42 mRNA was significantly different between vaccinated and infected sheep (P < 0.05 or P < 0.01) on days: 14, 30, and 60 post-inoculation, whereas no significant difference (P > 0.05) was noted 40 days post-inoculation. Moreover, the expression of OaCdc42 from both infected and vaccinated sheep showed irregularity. Conclusion: OaCdc42 is not a good potential diagnostic biomarker for differential diagnosis of brucellosis in sheep. PMID- 29978137 TI - Xylazine Regulates the Release of Glycine and Aspartic Acid in Rat Brain. AB - Introduction: Xylazine, a type of alpha2-adrenoceptors, is a commonly used drug in veterinary medicine. Xylazine-induced changes in the content of amino acid neurotransmitters - glycine (Gly) and aspartic acid (Asp), in different brain regions and neurons were studied. Material and Methods: Wistar rats were administered 50 mg/kg or 70 mg/kg of xylazine by intraperitoneal injection. In addition, in vitro experiments were conducted, in which neurons were treated with 15 MUg/mL, 25 MUg/mL, 35MUg/mL, and 45 MUg/mL of xylazine. Test methods were based on the enzyme-linked immunosorbent assays (ELISA). Results: During anaesthesia, Asp levels in each brain area were significantly lower compared to the control group. Except for the cerebrum, levels of Gly in other brain areas were significantly increased during the anaesthesia period. In vitro, xylazine related neuron secretion of Gly increased significantly compared to the control group at 60 min and 90 min. Moreover, xylazine caused a significant decrease in the levels of Asp secreted by neurons at 20 min, but gradually returned to the level of the control group. Conclusion: The data showed that during anaesthesia the overall levels of Asp decreased and overall levels of Gly increased. In addition, the inhibitory effect of xylazine on Asp and the promotion of Gly were dose-dependent. Our data showed that different effects of xylazine on excitatory and inhibitory neurotransmitters provided a theoretical basis for the mechanism of xylazine activity in clinical anaesthesia. PMID- 29978138 TI - A case of primary extranodal natural killer/T-cell lymphoma in the orbit and intraocular tissues with cerebrospinal fluid involvement. AB - Purpose: To report a rare case of primary orbital natural killer (NK)/T-cell lymphoma without nasal lesions but with cerebrospinal fluid involvement. Observations: A 73-year-old woman was referred to the uveitis clinic with suspected unilateral acute uveitis in her right eye and a right orbital tumor. Epstein-Barr virus DNA was detected in the aqueous humor in her right eye, and orbital biopsy revealed the presence of extranodal NK/T-cell lymphoma (ENKTL), nasal type. Positron emission tomography showed significant 18F fluorodeoxyglucose uptake in the right orbit, with no other signs of systemic involvement. Cerebrospinal fluid analysis demonstrated lymphoma cell infiltration. She was diagnosed with stage IV ENKTL and treated with orbital radiotherapy and systemic chemotherapy, with subsequent remission. However, the lymphoma relapsed in her left vitreous at 10 months after therapy, suggesting metastasis of lymphoma cells to the contralateral eye via the vitreous and cerebrospinal fluid. Conclusions and importance: A few cases of ocular-tissue ENKTL have been reported, mostly involving invasion or dissemination of primary nasal lesions; in contrast, primary orbital and intraocular ENKTL has rarely been reported. To the best of our knowledge, this is the first report of a primary orbital ENKTL metastasizing to the vitreous of the contralateral eye. Although ENKTL is rare in the orbit and intraocular tissues, it should be considered as a possible differential diagnosis in patients with orbital tumors or intraocular inflammation resistant to steroid therapy because ENKTL has a very poor prognosis in the advanced stage. PMID- 29978139 TI - Orbital, eyelid, and nasopharyngeal silicone oil granuloma presenting as ptosis & pseudo-xanthelasma. AB - Purpose: To highlight the presentation and management of a patient with eyelid, orbital and nasopharyngeal silicone oil migration through a glaucoma drainage implant presenting as pseudo-xanthelasma and ptosis. Observations: A 68-year male presented with unilateral ptosis and presumed xanthelasma. He had a history of glaucoma drainage implant surgery, pseudophakia, and multiple retinal detachment repairs with silicone oil. During ptosis repair it was discovered that his presumed xanthelasma was in fact an eyelid silicone granuloma. Additional work up revealed silicone infiltration of the eyelids, orbits, and nasopharynx, resulting from emulsified silicone oil leakage through his glaucoma valve implant. Conclusions and Importance: Silicone oil may emulsify with time, with potential egress via a glaucoma filtration device. Clinicians should be alert for eyelid, orbital and sinonasal findings that may indicate occult migration. PMID- 29978140 TI - Treatment of juxtapapillary hemangioblastoma by intra-arterial (ophthalmic artery) chemotherapy with bevacizumab. AB - Purpose: To report on two cases of treatment-refractory juxtapapillary hemagioblastomas that were managed with intra-arterial bevacizumab delivered via the ophthalmic artery. Observations: Case 1 is a 35 year-old man with juxtapapillary hemangioblastoma who continued to have progressive tractional retinal detachment, optic nerve neovascaularization and cystoid macula edema (CME) despite heavy prior treatment with intravitreal anti-vascular endothelial growth factor (VEGF) and steroid intravitreal injections and laser. Case 2 is a 41 year-old woman with juxtapapillary hemangioblastoma who had progressive tractional retinal detachment, CME and visually-threatening intraocular pressure elevation despite treatment with anti-VEGF injection and laser. Both cases were treated with three infusions of intra-arterial bevacizumab delivered via the ophthalmic artery. Both tumors demonstrated measurable decrease in height, stability of their secondary retinal changes and minimal requirement for additional treatment at 30 mos and 26 mos follow-up, respectively for cases 1 and 2. Conclusions and importance: These cases suggest that higher-dose, targeted delivery of anti-VEGF to hemangioblastomas via ophthalmic artery injection may be useful in stabilizing the disease and abating the typical progression of secondary retinal pathology, at least in the first two years after treatment. PMID- 29978141 TI - Kinetic models for activation and modulation of NMDA receptor subtypes. AB - NMDA receptors are a diverse family of excitatory channels with critical roles in central synaptic transmission, development, and plasticity. Controlled expression of seven subunits and their combinatorial assembly into tetrameric receptors produces a range of molecularly distinct receptor subtypes. Despite relatively similar atomic structures, each subtype has input-output functions with unique biophysical and pharmacologic profiles. Here, we briefly summarize recent advances in understanding how gating and allosteric modulation are similar or distinct across NMDA receptor isoforms and identify open questions that will focus research in this area going forward. PMID- 29978142 TI - MR-Guided Kernel EM Reconstruction for Reduced Dose PET Imaging. AB - PET image reconstruction is highly susceptible to the impact of Poisson noise, and if shorter acquisition times or reduced injected doses are used, the noisy PET data become even more limiting. The recent development of kernel expectation maximisation (KEM) is a simple way to reduce noise in PET images, and we show in this work that impressive dose reduction can be achieved when the kernel method is used with MR-derived kernels. The kernel method is shown to surpass maximum likelihood expectation maximisation (MLEM) for the reconstruction of low-count datasets (corresponding to those obtained at reduced injected doses) producing visibly clearer reconstructions for unsmoothed and smoothed images, at all count levels. The kernel EM reconstruction of 10% of the data had comparable whole brain voxel-level error measures to the MLEM reconstruction of 100% of the data (for simulated data, at 100 iterations). For regional metrics, the kernel method at reduced dose levels attained a reduced coefficient of variation and more accurate mean values compared to MLEM. However, the advances provided by the kernel method are at the expense of possible over-smoothing of features unique to the PET data. Further assessment on clinical data is required to determine the level of dose reduction that can be routinely achieved using the kernel method, whilst maintaining the diagnostic utility of the scan. PMID- 29978143 TI - Insights into Membrane Translocation of Protegrin Antimicrobial Peptides by Multistep Molecular Dynamics Simulations. AB - Protegrin-1 (PG-1) is a cationic arginine-rich antimicrobial peptide. It is widely accepted that PG-1 induces membrane disruption by forming pores that lead to cell death. However, the insertion mechanism for these highly cationic peptides into the hydrophobic membrane environment is still poorly understood at the molecular scale. It has previously been determined that the association of arginine guanidinium and lipid phosphate groups results in strong bidentate bonds that stabilize peptide-lipid complexes. It has also been suggested that arginine residues are able to drag phosphate groups as they insert inside the membrane to form a toroidal pore. However, whether bidentate bonds play a significant role in inducing a pore formation remains unclear. To investigate the role of bidentate complexes in PG-1 translocation, we conducted molecular dynamics simulations. Two computational electroporation methods were implemented to examine the translocation process. We found that PG-1 could insert into the membrane, provided the external electric potential is large enough to first induce a water column or a pore within the lipid bilayer membrane. We also found that the highly charged PG-1 is capable in itself of inducing molecular electroporation. Substitution of arginines with charge-equivalent lysines showed a markedly reduced tendency for insertion. This indicates that the guanidinium group likely facilitates PG-1 translocation. Potential of mean force calculations suggests that peptide insertion inside the hydrophobic environment of the membrane core is not favored. We found that formation of a water column or a pore might be a prerequisite for PG-1 translocation. We also found that PG-1 can stabilize the pore after insertion. We suggest that PG-1 could be a pore inducer and stabilizer. This work sheds some light on PG-1 translocation mechanisms at the molecular level. Methods presented in this study may be extended to other arginine-rich antimicrobial and cell-penetrating peptides. PMID- 29978144 TI - Dandelion-Like Microspherical MCM-22 Zeolite Using BP 2000 as a Hard Template. AB - The chemistry between layered MWW zeolite and carbon black pearls (BP 2000) as an inexpensive hard template was investigated to develop a rational one-pot synthesis of MCM-22 microspheres. The characterization results showed that the insertion of BP 2000 in the gel synthesis did not substantially compromise the crystallinity and microporosity, and the microscopic analyses showed that BP 2000 played a key role in controlling the final morphology of the MCM-22 zeolite, creating beautiful dandelion-like microspherical particles. The morphology obtained is due to the tortuous shape of the hard template, the particular MWW particle crystals, the interaction with the external surface of the MWW zeolitic precursor, and the synthesis conditions. The stacking of MWW crystals with edge to-face orientations generates meso-/macrovoids, allowing access to the interiors of the microspheres. The microspheres were homogeneous with sizes ranging from 6 to 8 MUm with an increase of the external surface and a macroporous size distribution centered at 200 nm, which is two times that of the traditional MCM 22 zeolite. PMID- 29978145 TI - Exposure to Bisphenol A, Bisphenol F, and Bisphenol S in U.S. Adults and Children: The National Health and Nutrition Examination Survey 2013-2014. AB - Bisphenol F (BPF) and bisphenol S (BPS) are replacing bisphenol A (BPA) in the manufacturing of products containing polycarbonates and epoxy resins. Data on current human exposure levels of these substitutes are needed to aid in the assessment of their human health risks. This study analyzed urinary bisphenol levels in adults (N = 1808) and children (N = 868) participating in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 and investigated demographic and lifestyle factors associated with urinary levels of bisphenols. BPA, BPS, and BPF were detected in 95.7, 89.4, and 66.5% of randomly selected urine samples analyzed as part of NHANES 2013-2014, respectively. Median levels of BPA in U.S. adult were higher (1.24 MUg/L) than BPF and BPS levels (0.35 and 0.37 MUg/L, respectively). For children, median BPA levels were also higher (1.25 MUg/L) than BPF and BPS levels (0.32 and 0.29 MUg/L, respectively). The limits of detection for BPA, BPF, and BPS were 0.2, 0.2, and 0.1 MUg/L, respectively. Urinary levels showed associations with gender, race/ethnicity, family income, physical activity, smoking, and/or alcohol intake that depended on the specific bisphenol. The results of this study indicate that exposure of the general U.S. population to BPA substitutes is almost ubiquitous. Because exposures differ across the U.S. population, further studies of environmental, consumer, and lifestyle factors affecting BPF and BPS exposures are warranted. PMID- 29978146 TI - Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation. AB - Hyperpolarized forms of 1-13C-acetates and 1-13C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1-13C isotopically enriched and pure from solvent acetates and pyruvates derivatized with unsaturated ester moiety. The reported unsaturated precursors can be employed for NMR hyperpolarization of 1 13C-acetates and 1-13C-pyruvates via parahydrogen-induced polarization (PHIP). In this PHIP variant, Side arm hydrogenation (SAH) of unsaturated ester moiety is followed by the polarization transfer from nascent parahydrogen protons to 13C nucleus via magnetic field cycling procedure to achieve hyperpolarization of 13C nuclear spins. This work reports the synthesis of PHIP-SAH precursors: vinyl 1 13C-acetate (55% yield), allyl 1-13C-acetate (70% yield), propargyl 1-13C-acetate (45% yield), allyl 1-13C-pyruvate (60% yield), and propargyl 1-13C-pyruvate (35% yield). Feasibility of PHIP-SAH 13C hyperpolarization was verified by 13C NMR spectroscopy: hyperpolarized allyl 1-13C-pyruvate was produced from propargyl 1 13C-pyruvate with 13C polarization of ~3.2% in CD3OD and ~0.7% in D2O. 13C magnetic resonance imaging is demonstrated with hyperpolarized 1-13C-pyruvate in aqueous medium. PMID- 29978147 TI - Analysis of Carbonyl Compounds in Ambient Air by a Microreactor Approach. AB - Aldehydes including formaldehyde, acetaldehyde, and acrolein are toxic organic components of air pollution that cause lung cancer and cardiovascular disease with chronic exposure. The commonly used method for determining the levels of carbonyl compounds based on the derivatizing agent 2,4-dinitrophenylhydrazine is of limited use for ketones and unsaturated aldehydes because of issues such as low capture efficiencies, unstable derivatives, and long sample collection times. This work details the analysis of carbonyls in ambient air by a microreactor approach. The microreactor is fabricated on a silicon wafer and has thousands of micropillars in a microfluidic channel for uniformly distributing the air flow through the channel. The surfaces of the micropillars are coated with a quaternary ammonium aminooxy reagent, 2-(aminooxy)ethyl-N,N,N-trimethylammonium iodide (ATM), for chemoselective capture of carbonyl compounds by means of oximation reactions. ATM-carbonyl adducts are eluted from the microreactor and directly analyzed by Fourier transform ion cyclotron resonance mass spectrometry and ultrahigh-performance liquid chromatography-mass spectrometry. More than 20 carbonyls were detected in ambient air samples. Acetone, 2-butanone, acetaldehyde, and formaldehyde were the most abundant carbonyls in ambient air of the studied urban areas. PMID- 29978148 TI - Nonprotecting Group Synthesis of a Phospholipase C Activatable Probe with an Azo Free Quencher. AB - The near-infrared fluorescent activatable smart probe Pyro phosphatidylethanolamine (PtdEtn)-QSY was synthesized and observed to selectively fluoresce in the presence of phosphatidylcholine-specific phospholipase C (PC PLC). PC-PLC is an important biological target as it is known to be upregulated in a variety of cancers, including triple negative breast cancer. Pyro-PtdEtn-QSY features a QSY21 quenching moiety instead of the Black Hole Quencher-3 (BHQ-3) used previously because the latter contains an azo bond, which could lead to biological instability. PMID- 29978149 TI - Synthesis, Affinity for Complementary RNA and DNA, and Enzymatic Stability of Triazole-Linked Locked Nucleic Acids (t-LNAs). AB - Dinucleoside phosphoramidites containing a triazole internucleotide linkage flanked by locked nucleic acid (LNA) were synthesized and incorporated into oligonucleotides (ONs). ONs bearing both LNA and triazole at multiple sites were obtained and their biophysical properties including enzymatic stability and binding affinity for RNA and DNA targets were studied. t-LNAs with four incorporations of a dinucleoside monomer having LNA on either side of the triazole linkage bind to their RNA target with significantly higher affinity and greater specificity than unmodified oligonucleotides, and are remarkably stable to nuclease degradation. A similar but reduced effect on enzymatic stability and binding affinity was noted for LNA only on the 3'-side of the triazole linkage. Thus, by combining unnatural triazole linkages and LNA in one unit (t-LNA), we produced a promising class of ONs with reduced anionic charge and potential for antisense applications. PMID- 29978150 TI - Transcriptomic Profiling of Obesity-Related Nonalcoholic Steatohepatitis Reveals a Core Set of Fibrosis-Specific Genes. AB - Nonalcoholic steatohepatitis (NASH) is strongly associated with obesity and type 2 diabetes. The molecular factors underlying the development of inflammation and severe fibrosis in NASH remain largely unknown. The purpose of this study was to identify gene expression patterns related to obesity-related NASH inflammation and fibrosis. We performed sequencing-based mRNA profiling analysis of liver samples from individuals with normal histology (n = 24), lobular inflammation (n = 53), or bridging fibrosis, incomplete cirrhosis, or cirrhosis (n = 65). Hepatic expression of a subset of mRNAs was validated using an orthogonal method, analyzed in a hepatic stellate cell line, and used to identify transcriptional patterns shared by other forms of cirrhosis. We observed evidence for differential levels of 3820 and 2980 transcripts in lobular inflammation and advanced fibrosis, respectively, compared with normal histology (false discovery rate <=0.05), including 176 genes specific to fibrosis. Functional enrichment analysis of these genes revealed participation in pathways involving cytokine cytokine receptor interaction, PI3K-Akt signaling pathway, focal adhesion, and extracellular matrix-receptor interaction. We identified 34 differentially expressed transcripts in comparisons of lobular inflammation and fibrosis, a proportion of which were also upregulated during activation of hepatic stellate cells. A set of 16 genes from a previous independent study of NASH bridging fibrosis/cirrhosis were replicated, several of which have also been associated with advanced fibrosis/cirrhosis due to hepatitis viruses or alcohol in human patients. Dysregulated mRNA expression is associated with inflammation and fibrosis in NASH. Advanced NASH fibrosis is characterized by distinct set of molecular changes that are shared with other causes of cirrhosis. PMID- 29978152 TI - Increase in Adiponectin Level Prevents the Development of Type 2 Diabetes in Japanese Men With Low Adiponectin Levels. AB - Context: Low serum adiponectin (Ad) level is an important risk factor for the development of type 2 diabetes mellitus (T2DM). Objective: To determine whether the changes in Ad in subjects with low baseline serum Ad levels can reduce the rate of development of T2DM. Design/Setting/Participants: We performed a large scale longitudinal study of 7052 healthy Japanese men who underwent general health checkups more than twice between April 2007 and May 2015 at the Physical Check up Center, Sumitomo Hospital. The participants were divided into quartile groups according to baseline Ad level. Subjects of the lowest baseline Ad group (<=5.2 MUg/mL) were subdivided into quartile subgroups according to the percent change in Ad (%DeltaAd) and into two subgroups according to endpoint Ad (>5.2 and <=5.2 MUg/mL). Main Outcome Measures: The cumulative incidence rate of T2DM. Results: The cumulative incidence rate of T2DM of the lowest baseline Ad group (<=5.2 MUg/mL) was significantly higher than the other quartile groups. The cumulative incidence rates of T2DM were significantly lower in the largest (>=21.5%) and the second largest (9.3% to 21.4%) %DeltaAd-increased subgroups compared with the %DeltaAd-decreased subgroup (P < 0.001 and P = 0.005, respectively). The cumulative incidence rates of T2DM were significantly lower in the endpoint Ad >5.2 MUg/mL subgroup than in the <=5.2 MUg/mL subgroup (P < 0.001). Conclusions: Increases in serum Ad levels of at least ~10% or >5.2 MUg/mL can potentially reduce the risk of development of T2DM in Japanese men with low baseline Ad levels who are at a high risk of developing T2DM. PMID- 29978151 TI - Unveiling "Musica Universalis" of the Cell: A Brief History of Biological 12-Hour Rhythms. AB - "Musica universalis" is an ancient philosophical concept claiming the movements of celestial bodies follow mathematical equations and resonate to produce an inaudible harmony of music, and the harmonious sounds that humans make were an approximation of this larger harmony of the universe. Besides music, electromagnetic waves such as light and electric signals also are presented as harmonic resonances. Despite the seemingly universal theme of harmonic resonance in various disciplines, it was not until recently that the same harmonic resonance was discovered also to exist in biological systems. Contrary to traditional belief that a biological system is either at stead-state or cycles with a single frequency, it is now appreciated that most biological systems have no homeostatic "set point," but rather oscillate as composite rhythms consisting of superimposed oscillations. These oscillations often cycle at different harmonics of the circadian rhythm, and among these, the ~12-hour oscillation is most prevalent. In this review, we focus on these 12-hour oscillations, with special attention to their evolutionary origin, regulation, and functions in mammals, as well as their relationship to the circadian rhythm. We further discuss the potential roles of the 12-hour clock in regulating hepatic steatosis, aging, and the possibility of 12-hour clock-based chronotherapy. Finally, we posit that biological rhythms are also musica universalis: whereas the circadian rhythm is synchronized to the 24-hour light/dark cycle coinciding with the Earth's rotation, the mammalian 12-hour clock may have evolved from the circatidal clock, which is entrained by the 12-hour tidal cues orchestrated by the moon. PMID- 29978153 TI - Differential Effects of Estradiol and Progesterone on Cardiovascular Risk Factors in Postmenopausal Women. AB - Context: Controlled, blinded studies of sex-hormone replacement in postmenopausal women using natural estradiol (E2) and native progesterone (P) are few. Objective: To delineate the effect of E2 alone or with P on lipids and inflammatory markers. Design: A placebo-controlled, double-masked, prospectively randomized study of 40 healthy, postmenopausal volunteers assigned to four treatment groups: placebo, intramuscular E2, and/or micronized oral P for 23 (+/ 2) days. Results: Treatment with E2 alone compared with placebo lowered total cholesterol (TC; P = 0.006), non-high-density lipoprotein cholesterol (nonHDL-C; P = 0.004), low-density lipoprotein cholesterol (LDL-C; P = 0.012), and apolipoprotein B (Apo B; P = 0.02) levels, and raised HDL-C levels (P = 0.03 vs the 3 other groups). Conversely, addition of P to E2 reduced HDL-C levels (P = 0.015). Triglyceride concentrations manifested no effect on E2 or P. High sensitivity C-reactive protein (hsCRP) level was highest in women with E2 and P replacement (P = 0.018 vs placebo). Leptin and IL-6 concentrations did not vary. P treatment decreased adiponectin levels (P = 0.019). Serum E2 levels correlated linearly with TC, LDL-C, nonHDL-C, Apo B (all negatively), and SHBG (positively) concentrations. P level correlated negatively with TC (P = 0.029), HDL-C (P = 0.002), and adiponectin (P = 0.002) levels. Conclusion: In this study, there were individual and interactive effects of E2 and P on key lipids in postmenopausal individuals. PMID- 29978154 TI - Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL). AB - Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives. However, such approaches rely on accurate estimates of variant pathogenicity and disease penetrance, which may have been subject to ascertainment and reporting biases, although the recent provision of large population-based DNA sequence data sets may provide a potentially unbiased resource to aid variant interpretation. Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals. In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases. Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively. Although the pathogenicity of several SDHA alleles was supported by significant enrichment in PPGL cases relative to GnomAD controls, calculations of disease penetrance based on allele frequencies in the respective cohorts resulted in much lower estimates than previously reported, ranging from 0.1% to 4.9%. Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening. PMID- 29978155 TI - Cx43 overexpression in osteocytes prevents osteocyte apoptosis and preserves cortical bone quality in aging mice. AB - Young, skeletally mature mice lacking Cx43 in osteocytes exhibit increased osteocyte apoptosis and decreased bone strength, resembling the phenotype of old mice. Further, the expression of Cx43 in bone decreases with age, suggesting a contribution of reduced Cx43 levels to the age-related changes in the skeleton. We report herein that Cx43 overexpression in osteocytes achieved by using the DMP1-8kb promoter (Cx43OT mice) attenuates the skeletal cortical, but not trabecular bone phenotype of aged, 14-month-old mice. The percentage of Cx43 expressing osteocytes was higher in Cx43OT mice, whereas the percentage of Cx43 positive osteoblasts remained similar to wild type (WT) littermate control mice. The percentage of apoptotic osteocytes and osteoblasts was increased in aged WT mice compared to skeletally mature, 6-month-old WT mice, and the percentage of apoptotic osteocytes, but not osteoblasts, was decreased in age-matched Cx43OT mice. Aged WT mice exhibited decreased bone formation and increased bone resorption as quantified by histomorphometric analysis and circulating markers, compared to skeletally mature mice. Further, aged WT mice exhibited the expected decrease in bone biomechanical structural and material properties compared to young mice. Cx43 overexpression prevented the increase in osteoclasts and decrease in bone formation on the endocortical surfaces, and the changes in circulating markers in the aged mice. Moreover, the ability of bone to resist damage was preserved in aged Cx43OT mice both at the structural and material level. All together, these findings suggest that increased Cx43 expression in osteocytes ameliorates age-induced cortical bone changes by preserving osteocyte viability and maintaining bone formation, leading to improved bone strength. PMID- 29978157 TI - Capacity fading mechanism of tin phosphide anodes in sodium-ion batteries. AB - Tin phosphide (Sn4P3) is here investigated as an anode material in half-cell, symmetrical, and full-cell sodium-ion batteries. Results from the half-cells using two different electrolyte salts of sodium bis(fluorosulfonyl)imide (NaFSI) or sodium hexafluorophosphate (NaPF6) show that NaFSI provides improved capacity retention but results from symmetrical cells disclose no advantage for either salt. The impact of high and low desodiation cut-off potentials is studied and the results show a drastic increase in capacity retention when using the desodiation cut-off potential of 1.2 V as compared to 2.5 V. This effect is clear for both NaFSI and NaPF6 salts in a 1 : 1 binary mixture of ethylene carbonate and diethylene carbonate with 10 vol% fluoroethylene carbonate. Hard X-ray photoelectron spectroscopy (HAXPES) results revealed that the thickness of the solid electrolyte interphase (SEI) changed during cycling and that SEI was stripped from tin particles when tin phosphide was charged to 2.5 V with NaPF6 based electrolyte. PMID- 29978156 TI - Canagliflozin-associated diabetic ketoacidosis: a case report. AB - Canagliflozin is a novel sodium-glucose cotransporter-2 (SGLT-2) inhibitor approved for the management of diabetes. We report the presentation and management of two cases of canagliflozin associated diabetic ketoacidosis (DKA) and discuss the mechanism of canagliflozin associated DKA. Patient 1, a 55 year old woman maintained on canagliflozin for diabetes mellitus II presented to the emergency department (ED) with 24 hours of nausea and vomiting. She was diagnosed with DKA featuring hypotension, hyperglycemia, ketosis and acidosis. A second 54 year old man also maintained on canagliflozin for diabetes mellitus I presented to the ED with 24 hours of nausea and vomiting. He was diagnosed with DKA with similar manifestations as patient 1. Both patients underwent massive volume resuscitation and intravenous insulin therapy with resolution of ketosis and acidosis. By inhibiting SGLT-2, canagliflozin promotes glucosuria, which in turn can produce up to a 10% decrease in total plasma volume rendering patients maintained on canagliflozin susceptible to dehydration. Inhibition of SGLT-2 also leads to glucagon secretion, which in the volume deplete individual, can exacerbate DKA. Physicians should be aware of the rapid onset of DKA in patients maintained on canagliflozin after just minor additional fluid losses. PMID- 29978158 TI - Hysteretic spin crossover in isomeric iron(ii) complexes. AB - Two mononuclear iron(ii) complexes with isomeric N,N,N-tridentate pyrimidine based ligands were synthesized. Both complexes show reproducible hysteretic spin crossover. Low spin state to high spin state switching is cooperative due to autocatalysis. PMID- 29978159 TI - Full elucidation of the transmembrane anion transport mechanism of squaramides using in silico investigations. AB - A comprehensive experimental and theoretical investigation of the transmembrane chloride transport promoted by four series of squaramide derivatives, with different degrees of fluorination, number of convergent N-H binding units and conformational shapes, is reported. The experimental chloride binding and transport abilities of these small synthetic molecules in liposomes were rationalised with quantum descriptors and molecular dynamics simulations in POPC bilayers. The tripodal tren-based compounds, with three squaramide binding motifs, have high chloride affinity, isolating the anion from water molecules within the membrane model and preventing its release to the aqueous phase, in agreement with the absence of experimental transport activity. In contrast, the symmetrical mono-squaramides, with moderate chloride binding affinity, are able to bind and release chloride either in the aqueous phase or at the membrane interface level, in line with experimentally observed high transport activity. The PMF profiles associated with the diffusion of these free transporters and their chloride complexes across phospholipid bilayers show that the assisted chloride translocation is thermodynamically favoured. PMID- 29978160 TI - A simple and versatile strategy for realizing bright multicolor mechanoluminescence. AB - Multicolor mechanoluminescence (ML) was first realized by using the stable organic blue ML emitter N-phenylcarbazole as the host matrix. It is claimed that a good ML host should have a moderate melting point and be able to dissolve or disperse organic dyes but maintain high ML activity and crystallinity. This strategy is versatile and can avoid difficult molecular design and troublesome chemical synthesis. PMID- 29978161 TI - Rare-earth metal bis(aminobenzyl) complexes supported by pyrrolyl-functionalized arylamide ligands: synthesis, characterization and styrene polymerization performance. AB - An acid-base reaction between the rare-earth tris(o-dimethylaminobenzyl) complexes Ln(CH2C6H4NMe2-o)3 and the pyrrolyl-functionalized arylamide ligands 2,5-Me2C4H2NCH2SiMe2NHC6H4R (R = H, (HL1); R = Cl-p, (HL2)) was investigated. Treatment of HL1 and HL2 with 1 equiv. of Ln(CH2C6H4NMe2-o)3 in toluene at room temperature gave (2,5-Me2C4H2CH2NSiMe2NC6H5)Ln(CH2C6H4NMe2-o)2 (Ln = Sc (1), La (2), Lu (3)) and (2,5-Me2C4H2NCH2SiMe2NC6H4Cl-p)Ln(CH2C6H4NMe2-o)2 (Ln = Sc (4), La (5), Lu (6)) in good isolated yields. These complexes were characterized by elemental analysis and NMR spectroscopy. 2, 4 and 5 were structurally authenticated by single crystal X-ray diffraction. NMR and X-ray diffraction show that there are no interactions between the central metal and the pyrrolyl moiety in small sized metal complexes, while in large lanthanum complexes, besides the coordination of the arylamide moiety to La3+ in eta1-bonding mode through a N atom, the pyrrolyl ring also has close contact with La3+ in 2 and 5. The binary systems of 1-6/[Ph3C][B(C6F5)4] were employed as catalysts for syndio-specific polymerization of styrene, and the pyrrolyl-ligated lanthanum complexes showed much higher activity than the complexes in which the pyrrolyl moiety had no coordination with the central metal. PMID- 29978162 TI - Monitoring surface transformations of metal carbodiimide water oxidation catalysts by operando XAS and Raman spectroscopy. AB - Transition metal carbodiimides MNCN (M = Co, Ni, Co0.9Ni0.1, Mn and Cu), were studied by simultaneous operando Raman and X-ray absorption spectroscopy (XAS) with focus on surface oxide detection during electrocatalytic water oxidation. As a proof of concept, easily modifiable screen-printed electrodes were used in this unified operando synchrotron setup for a trade-off between convenience of electrochemical anodization and spectroscopic data acquisition. Monitoring of chemical and structural transformations at the electrode surface during initial anodic electrode polarization shows stability for MNCN with M = Co, Ni, Co0.9Ni0.1 and Mn. While MnNCN is inactive, CoNCN emerges as the most active representative of the series. CuNCN displays pronounced side reactions and the formation of a surface copper oxide layer leading to lower current density attributed to water oxidation, as evident from an irreversible variation of the CuNCN redox behaviour in rotating ring-disc voltammetry. Furthermore, the accompanying structural and vibrational spectroscopy properties of the different MNCN compounds were explored with complementary ex situ analytical methods. PMID- 29978163 TI - Deciphering the origin of invariance in magnetic anisotropy in {FeIIS4} complexes: a theoretical perspective. AB - For q-bit applications based on coordination complexes, invariance in zero-field splitting parameters upon structural distortions is desired. Here, by employing ab initio calculations, we have probed the origin of such resistance observed in four coordinate [FeII(C3S5)2]2- complexes. While unaltered D parameters are noted for a short range of structural distortions such as dihedral angle, if a wider range is chosen, larger variations are prominent in both D and E/D values. PMID- 29978165 TI - New monolayer ternary In-containing sesquichalcogenides BiInSe3, SbInSe3, BiInTe3, and SbInTe3 with high stability and extraordinary piezoelectric properties. AB - Looking for the high-performance alternatives to conventional lead-containing piezoelectric materials such as lead zirconate titanate (PZT) is absolutely vital for the development of low-dimensional innovative piezoelectric devices. Herein, we present our first-principles calculations on several new monolayers consisting of ternary In-containing sesquichalcogenides, which exhibit high stability and extraordinary piezoelectric properties. Our calculations predict that the in plane (d11) and out-of-plane (d31) piezoelectric coefficients of BiInSe3, SbInSe3, BiInTe3, and SbInTe3 monolayers are much larger than those of most previously reported two-dimensional (2D) materials and widely studied wurtzite type bulk piezoelectrics. Very strikingly, BiInTe3 monolayer possesses a d11 as high as 362 pm V-1 due to its mechanical flexibility, which is the highest among those reported in 2D materials and for the first time reaches those (~360 pm V-1) in bulk lead-containing piezoelectric materials such as PZT. The theoretical predictions of the giant piezoelectricity in these 2D materials suggest that they have great potentials for the applications in atomically thin lead-free piezoelectric devices such as sensors and energy harvesters. PMID- 29978164 TI - Electrocatalytic studies on imidazolium based ionic liquids: defining experimental conditions. AB - The number of publications devoted to studying electrochemical reactions in room temperature ionic liquids (RTILs) is constantly growing, but very few of them have been devoted to defining proper experimental conditions to obtain reproducible electrochemical results. In this work, we demonstrate that the combination of a proper RTIL purification treatment and a filtered Ar gas stream allow us to obtain featureless voltammograms in [C4mim][BF4], [C4mim][NTf2], and [C4m2im][NTf2], which otherwise present signals associated with different types of impurities such as water and some minor electroactive impurities acquired during the RTIL synthesis process. Moreover, we demonstrate that bubbling Ar, or another inert gas, through the electrolyte in order to purge O2 dissolved in RTILs is one of the major sources of water and O2 impurities incorporated in RTILs within the electrochemical cell. To overcome this source of water uptake, we have incorporated a gas stream purification filter before the gas reaches the RTIL in the electrochemical cell. To illustrate the effect of these impurities in relevant electrocatalytic studies, we study the electrocatalytic reduction of CO2 on Pt nanoparticles and the key role of an appropiate filter when the CO2 gas stream is bubbled within imidazolium based RTILs. Our cyclic voltammetric studies point out that CO2 electroreduction on Pt nanoparticles only presents activity in [C4mim][NTf2] and [C4m2im][NTf2], thus suggesting that the C-2 position on the imidazolium ring is not the key position in CO2 electrochemical reduction. In contrast, the same Pt nanoparticles are inactive towards CO2 electroreduction in [C4mim][BF4], which is a more hydrophilic RTIL. PMID- 29978166 TI - Electro-analytical investigation of potential induced degradation in mc-silicon solar cells: case of sodium ion induced inductive loop. AB - Potential induced degradation of the shunt type (PID-s) in multi-crystalline silicon (mc-Si) solar cells is becoming critical for performance reduction of solar panels in large scale photovoltaic (PV) power plants. In this article PID-s has been investigated by applying high voltage stress on mc-Si solar cells for their degradation and recovery and results have been explained on the basis of DC and AC characterization. The efficiency decreases drastically from 15.7% to 2.9% due to a high voltage stress of -800 V at 85 degrees C for 48 hours, which is attributed to a reduction in shunt resistance and an increase in depletion and diffusion capacitances. The reduction in electrical performance due to PID-s has been further explained by morphological, structural and elemental analysis. Observed negative capacitance behaviour in impedance spectra of mc-Si solar cells after PID-s has been attributed to structural deformation caused by potential induced migration of sodium ions (Na+) into mc-Si. The structural deformation induced by potential induced migration of Na+ ions has been confirmed by using non-destructive and lattice strain sensitive micro-Raman spectroscopy. The obtained experimental results have been correlated with existing theoretical understanding of p-n junction solar cells to explain the consequences of PID-s. PMID- 29978167 TI - Label-free tracking of nanosized graphene oxide cellular uptake by confocal Raman microscopy. AB - Graphene oxide (GO), a partially oxidized two-dimensional allotrope of carbon, is an attractive nanocarrier for cancer diagnostics and therapy. The nanometer-sized GO is known to permeate cell membranes. Herein we studied the cellular uptake pathways of GO nanoflakes by cancer and non-cancerous cell lines. By employing confocal Raman imaging, we were able to track the GO cellular uptake in living cells (C33 and MDCK) without any additional fluorescent or plasmonic labels. This specific progress in label-free Raman imaging of GO facilitates the monitoring of nanoflakes at the cellular level. PMID- 29978168 TI - Fabrication of a novel few-layer WS2/Bi2MoO6 plate-on-plate heterojunction structure with enhanced visible-light photocatalytic activity. AB - In this study, a novel few-layer WS2/Bi2MoO6 heterojunction with greatly enhanced visible light photocatalytic performance was synthesized via a facile hydrothermal method. The results indicated that Bi2MoO6 nanosheets were directly grown on the surface of few-layer WS2 and form plate-on-plate heterojunctions. The synthesized nanocomposites exhibited excellent photocatalytic activity under visible-light irradiation. The optimal composite with 5 wt% WS2 showed the highest photocatalytic activity, whose degradation efficiencies and TOC removal were 99.5% and 91.7% for rhodamine B (RhB), 98.9% and 89.8% for ciprofloxacin (CIP), 76.0% and 67.8% for methylene blue (MB), and 69.3% and 58.6% for methimazole (MMI), respectively. Their excellent photocatalytic performance was predominantly ascribed to the construction of a plate-on-plate heterojunction structure between WS2 and Bi2MoO6, which could promote charge separation efficiency and enhance light harvesting efficiency. The present work provides a new understanding for extending the application of transition-metal dichalcogenides in the field of photocatalysis. PMID- 29978169 TI - Incorporation of Sb5+ into CeO2: local structural distortion of the fluorite structure from a pentavalent substituent. AB - Hydrothermal crystallisation of CeO2 from aqueous sodium hydroxide solution at 240 degrees C using CeCl3.7H2O in the presence of hydrogen peroxide with addition of either SbCl3 or SbCl5 yields polycrystalline samples of antimony containing ceria directly from solution. Powder X-ray diffraction shows a contraction of the cubic lattice parameter with increasing Sb content, and also a broadening of Bragg peaks, from which Scherrer analysis yields crystallite domain sizes of 5-20 nm. Scanning transmission electron microscopy provides consistent results with observation of highly crystalline particles of a few nm in diameter. X-ray absorption near edge structure spectroscopy at the Ce LIII- and Sb K-edges reveals the presence of Ce4+ and Sb5+ in the solids. To balance charge the presence of co-included Na is proposed, corroborated by elemental analysis. The general chemical formula of the materials can thus be written as (Ce1-xSbx)1 yNayO2-delta (where x < 0.4 and y >= x/3). Sb K-edge extended X-ray absorption fine structure spectroscopy of the substituted ceria samples shows that the local structure of Sb resembles that in NaSbO3, where six-coordinate metal sites are found, but with evidence of a longer interatomic correlation due to surrounding Ce/Sb atoms in the fluorite structure; this implies that the Sb is displaced from the ideal eight-coordinate site of the fluorite structure. This structural distortion gives materials that are unstable under reducing conditions, coupled by the ease of reduction to elemental antimony, which is extruded leading to phase separation. PMID- 29978170 TI - Direct evidence for surface long-lived superoxide radicals photo-generated in TiO2 and other metal oxide suspensions. AB - Heterogeneous catalytic reactions usually proceed at the surfaces of materials, where many intermediates, such as free radicals, usually were believed to be short-lived. Herein, surface long-lived superoxide radicals (O2-) were identified in UV-irradiated aqueous suspensions of TiO2 and other metal oxide nanoparticles using an online chemiluminescence system. From the decay dynamics process of O2-, a long-lived O2- radical was observed on anatase TiO2 at pH = 12. After separation of the photo-excited suspension via filtration, CL was detected from the particles but not the filtrate, thus confirming O2- surface adsorption. The unusual stability of O2- was also verified using density functional theory (DFT) calculations. The lifetimes of the radicals were estimated on the different kinds of semiconductor surface according to the decay dynamics curves, and followed the order: TiO2 > ZnO > SnO2 > CeO2 > Fe2O3. Furthermore, the function of surface long-lived O2- in TiO2 suspensions with regards to photochemical conversion was investigated using NBT as a chemical model; it was found that half of the molecules were reduced by the surface-adsorbed O2-. The finding of surface stabilized, long-lived superoxide radicals may have important implications in relation to the chemistry, biology and toxicology of these radicals. PMID- 29978172 TI - Hydrogel electrodeposition based on bipolar electrochemistry. AB - Bipolar electrochemistry has attracted great interest for applications based on sensing, electrografting, and electrodeposition, because the technique enables electrochemical reactions to be induced at multiple bipolar electrodes (BPEs) with only a single power supply. However, there are only a few reports on the biofabrication of hydrogels using BPEs. In this study, we applied bipolar electrochemistry to achieve the electrodeposition of calcium-alginate hydrogels at specified target areas, which is possible because of the use of water electrolysis to obtain acidification at the anodic pole. This scheme was used to successfully fabricate an array of hydrogel deposits at a BPE array. In addition, hydrogels were successfully fabricated either at only the target BPEs or only the target areas of BPEs by repositioning the driving electrodes. Furthermore, a hydrogel was drawn on a large BPE as a canvas by using small driving electrodes. As a demonstration of the electrodeposited hydrogels for bioapplications, mammal cells were cultured in the hydrogels. Because the amount and shape of the hydrogel deposits can be controlled by using the bipolar system, the system we developed can be used for biosensors and cell culture platforms. PMID- 29978171 TI - Preclinical safety evaluation of the ethanolic extract from Campomanesia pubescens (Mart. ex DC.) O.BERG (guavira) fruits: analysis of genotoxicity and clastogenic effects. AB - Genotoxicity studies of plants with medicinal and nutritional properties are recommended by international regulatory agencies as part of the risk assessment. Due to their consumption as food, nutraceutical use and ethnopharmacological relevance, Campomanesia pubescens represents one of these plants to be studied. The aim of the present study was to evaluate the genotoxic, cytotoxic potential and clathogenic effects of the ethanolic extract obtained from the pulp of C. pubescens (EEFCP) fruits on rats submitted to experimental genotoxicity models and through the SMART test performed in Drosophila melanogaster. The comet assay and the micronucleus test were performed on peripheral and bone marrow blood, respectively, of Wistar rats orally treated with EEFCP at doses of 125, 250, 500 and 1000 mg per kg per bw for 28 days. In the SMART test, the standard cross between three mutant D. melanogaster strains was used. Larvae were treated with EEFCP at different concentrations and the wings of adult flies were evaluated for the presence/frequency of mutant spots and compared to the negative control group. Phytochemical analysis of EEFCP indicated high levels of flavonoids. The tests performed in rats showed that EEFCP did not present significant genotoxic or clastogenic effects. The biotransformation metabolites of EEFCP did not present genotoxic activity, as demonstrated by the SMART test. Together, all results indicate that, under the experimental conditions used, EEFCP did not reveal any preclinical genetic toxicity. Therefore, the safe consumption can be fomented increasing, consequently, the economic liquidity in the industrial market from the fruits of guavira. PMID- 29978173 TI - Sour cherry extract inhibits human salivary alpha-amylase and growth of Streptococcus mutans (a pilot clinical study). AB - The purpose of this study was to determine whether cherry extract has any effect on salivary alpha-amylase activity (sAA) or on the level of Streptococcus mutans in human saliva. 70 patients (45 females and 25 males) in three age groups (22 children, 25 young adults, and 23 adults) were examined. All participants completed a questionnaire to obtain information on their oral health behaviour and life style. Clinical examination was performed to record the number of decayed, missing and filled teeth (DMF-T). Saliva samples were collected for the measurement of sAA and the salivary S. mutans level before and after chewing a gum with or without cherry extract. Statistical evaluation of data was performed. S. mutans and the sAA level of unstimulated saliva samples did not depend on either age or gender. The basal sAA value of adult patients was in linear correlation with the dental caries status. Habitual chewing-gum use decreased the resting sAA and the mean of DMF-T. The number of S. mutans cells was significantly lower in the resting saliva of allergic patients. The applied mechanical and gustatory stimuli by chewing gum resulted in higher sAA and S. mutans levels and a slow decrease of values was observed in the control group for the next 30 min. Thereafter, sAA and S. mutans levels decreased earlier in the presence of sour cherry extract than those of control cases. Chewing gum with sour cherry extract may be useful for the prevention of dental caries. PMID- 29978175 TI - Solar UV radiation and microbial life in the atmosphere. AB - Many microorganisms are alive while suspended in the atmosphere, and some seem to be metabolically active during their time there. One of the most important factors threatening their life and activity is solar ultraviolet (UV) radiation. Quantitative understanding of the spatial and temporal survival patterns in the atmosphere, and of the ultimate deposition of microbes to the surface, is limited by a number factors some of which are discussed here. These include consideration of appropriate spectral sensitivity functions for biological damage (e.g. inactivation), and the estimation of UV radiation impingent on a microorganism suspended in the atmosphere. We show that for several bacteria (E. coli, S. typhimurium, and P. acnes) the inactivation rates correlate well with irradiances weighted by the DNA damage spectrum in the UV-B spectral range, but when these organisms show significant UV-A (or visible) sensitivities, the correlations become clearly non-linear. The existence of these correlations enables the use of a single spectrum (here DNA damage) as a proxy for sensitivity spectra of other biological effects, but with some caution when the correlations are strongly non linear. The radiative quantity relevant to the UV exposure of a suspended particle is the fluence rate at an altitude above ground, while down-welling irradiance at ground-level is the quantity most commonly measured or estimated in satellite-derived climatologies. Using a radiative transfer model that computes both quantities, we developed a simple parameterization to exploit the much larger irradiance data bases to estimate fluence rates, and present the first fluence-rate based climatology of DNA-damaging UV radiation in the atmosphere. The estimation of fluence rates in the presence of clouds remains a particularly challenging problem. Here we note that both reductions and enhancements in the UV radiation field are possible, depending mainly on cloud optical geometry and prevailing solar zenith angles. These complex effects need to be included in model simulations of the atmospheric life cycle of the organisms. PMID- 29978174 TI - Correction: Crystal-defect-induced facet-dependent electrocatalytic activity of 3D gold nanoflowers for the selective nanomolar detection of ascorbic acid. AB - Correction for 'Crystal-defect-induced facet-dependent electrocatalytic activity of 3D gold nanoflowers for the selective nanomolar detection of ascorbic acid' by Sandip Kumar De, et al., Nanoscale, 2018, 10, 11091-11102. PMID- 29978176 TI - Electrochemical properties and C-H bond oxidation activity of [Ru(tpy)(pyalk)Cl]+ and [Ru(tpy)(pyalk)(OH)]. AB - [Ru(tpy)(pyalk)Cl]Cl (pyalk = 2-(2'-pyridyl)-2-propanol) was synthesized and characterized crystallographically and electrochemically. Upon dissolution in water and acetonitrile, [Ru(tpy)(pyalk)Cl]Cl was found to form [Ru(tpy)(pyalk)Cl]+ and [Ru(tpy)(pyalk)(OH)]+, respectively. The Ru(ii/iii) couple of [Ru(tpy)(pyalk)Cl]+ was found to be relatively low compared to that of other Ru complexes in acetonitrile, but the Ru(iii/iv) couple was not significantly different than other Ru complexes bearing anionic ligands. Pourbaix diagrams were generated for [Ru(tpy)(phpy)(OH2)]+ (phpy = 2-phenylpyridine) and [Ru(tpy)(pyalk)(OH)]+ in water, and it was found that [Ru(tpy)(pyalk)(OH)]+ has a lower Ru(ii/iii) potential than [Ru(tpy)(phpy)(OH2)]+ under neutral to alkaline pH. [Ru(tpy)(pyalk)(OH)]+ was found to catalyze C-H bond hydroxylation of secondary alkanes and epoxidation of alkenes using cerium(iv) ammonium nitrate as the primary oxidant. PMID- 29978177 TI - Triazole vs. triazolium carbene ligands in the site-selective cyclometallation of o-carboranes by M(iii) (M = Ir, Rh) complexes. AB - Ir(iii) and Rh(iii)-mediated site-selective cage B-H and C-H bond activation in o carboranylmethyl derivatives has been achieved. The selectivity of the reaction is related to the electron donating properties of the ligand. 1,2,3-Triazole derivatives use the N2 position of the triazole ring to direct the selective o carborane B-H bond activation, whereas the corresponding triazolylidene derivatives lead to the cage C-H bond activation with complete site-selectivity. PMID- 29978178 TI - Abnormal Ophthalmic Examination Results and Elevated Intracranial Pressure. PMID- 29978179 TI - Improving the Diagnostic Criteria for Vogt-Koyanagi-Harada Disease. PMID- 29978180 TI - Close Margins and Adjuvant Radiotherapy in Acinic Cell Carcinoma of the Parotid Gland. AB - Importance: The precise indications and oncologic effects of adjuvant radiotherapy in acinic cell carcinoma of the parotid gland are not well known, particularly in patients with negative, but close (<=1 mm), margins without other high-risk histopathologic factors. Objective: To evaluate the oncologic outcomes of patients with acinic cell carcinoma of the parotid gland and the results of adjuvant therapy for those with close (<=1-mm) margins. Design, Setting, and Participants: In a retrospective case series with medical record review at a single academic tertiary referral center, patients treated surgically from January 2000 to December 2014 for acinic cell carcinoma of the parotid gland were identified from an institutional database. All data analysis was performed in September 2017. Exposures: All patients underwent parotidectomy with or without adjuvant radiotherapy or chemoradiotherapy. Main Outcomes and Measures: The primary end point was locoregional control. Secondary end points included recurrence patterns and survival. Results: Forty-five patients were identified in this case series (23 [51%] female), with a mean (SD) age of 47.1 (19.5) years. The median follow-up in surviving patients was 56.7 months (range, 18.5-204 months). Four patients (9%) experienced recurrence (1 local and 3 distant) at a median of 67.3 months (range, 12.7-136 months) after surgery. Thirteen patients (29%) had at least one high-risk histopathologic factor (advanced T category, nodal disease, lymphovascular or perineural invasion, high-grade, or positive margins). The remaining 32 patients (71%) without these high-risk factors had significantly improved disease-free survival (hazard ratio, 0.08; 95% CI, 0.01 0.71). Of patients without high-risk factors, those with close (<=1-mm) margins were significantly more likely to receive adjuvant radiotherapy (10 [56%] vs 1 [7%]; difference, 49%; 95% CI, 16%-82%), although this was not associated with disease control. At a median follow-up of 64.3 months (range, 33-204 months) in the 18 patients with close (<=1-mm) margins without other high-risk factors (10 with adjuvant radiotherapy and 8 without adjuvant therapy), only 1 patient (who had received adjuvant radiotherapy) experienced a recurrence, at 136 months after surgery. Conclusions and Relevance: Patients with acinic cell carcinoma of the parotid gland whose only histopathologic risk factor is a close (<=1 mm) but negative margin do not appear to benefit from adjuvant radiotherapy. Recurrent disease is rare but may occur many years after initial treatment, and patients with acinic cell carcinoma could benefit from lifelong clinical surveillance. PMID- 29978181 TI - Paclitaxel and Pazopanib in Ovarian Cancer. PMID- 29978182 TI - Health Barriers and Patterns of Gastric Cancer Care in Rural Central American Resource-Limited Settings. PMID- 29978183 TI - Paclitaxel and Pazopanib in Ovarian Cancer-Reply. PMID- 29978184 TI - Investigating Methods to Prevent Blindness From Facial Fat Injections. PMID- 29978185 TI - Incidence of and Factors Associated With Myopia and High Myopia in Chinese Children, Based on Refraction Without Cycloplegia. AB - Importance: Myopia has reached epidemic levels among children in regions of East and Southeast Asia. High myopia is associated with myopic macular degeneration, glaucoma, and retinal detachment. Objective: To determine the incidence of myopia and high myopia based on refraction without cycloplegia among children in primary and junior high schools in China. Design, Setting, and Participants: This observational cohort study was completed in Guangzhou, China. It consisted of a cohort from 19 primary schools, who were followed up from 2010 to 2015, and a cohort from 22 junior high schools, who were followed up from 2010 to 2012. All schools were randomly chosen at rates proportional to the number of schools in each of the city's 11 districts. Students with or without myopia in grade 1 (primary school) or grade 7 (junior high school) were eligible for inclusion. Data analysis occurred from February 2017 to October 2017. Main Outcomes and Measures: Myopia was defined as a spherical equivalent refraction (SER) of -0.50 diopters (D) or less, as measured by subjective refraction without cycloplegia; high myopia was defined as a SER of -6.0 D or less. Annual incidences were defined as the proportion of participants each year found to have myopia or high myopia who did not previously have the condition. Height, weight, axial length (AL), corneal radius of curvature (CRC), and AL/CRC ratio were examined to assess if these measures were associated with future myopia or high myopia. Results: A total of 4741 students with or without myopia in either grade 1 for the primary school cohort (mean [SD] age 7.2 [0.4] years; 932 of 1975 [47.2%] female) or grade 7 for the junior high school cohort (mean [SD] age 13.2 [0.5] years; 1254 of 2670 [47.0%] female) were included. Baseline mean (SD) SER was 0.31 (0.86) D among 1975 students in grade 1 vs -1.60 (2.00) D among 2670 students in grade 7. Baseline prevalence of myopia was 12.0% in grade 1 students (n = 237 of 1969) and 67.4% in grade 7 students (n = 1795 of 2663). The incidence of myopia was 20% to 30% each year throughout both cohorts. The incidence of high myopia was initially less than 1% in the primary school cohort (grade 1: n = 2 of 1825; 0.1% [95% CI, 0.0%-0.3%]), but incidence exceeded 2% in the junior high school cohort (in grade 9: n = 48 of 2044; 2.3% [95% CI, 1.0%-3.7%]). Conclusions and Relevance: The incidence of myopia among Chinese students based on refraction without cycloplegia is among the highest of any cultural or ethnic group. If confirmed with cycloplegic refraction, interventions to prevent myopia onset in Chinese populations should be initiated in primary schools. PMID- 29978186 TI - Association Between the Cilioretinal Artery and Choroidal Neovascularization in Age-Related Macular Degeneration: A Secondary Analysis From the Age-Related Eye Disease Study. AB - Importance: A hemodynamic role in the pathogenesis of age-related macular degeneration (AMD) has been proposed, but to our knowledge, an association between retinal vasculature and late AMD has not been investigated. Objective: To determine whether the presence and location of a cilioretinal artery may be associated with the risk of late AMD in the Age-Related Eye Disease Study (AREDS). Design, Setting, and Participants: Retrospective analysis of prospective, randomized clinical trial data from 3647 AREDS participants. Fundus photographs of AREDS participants were reviewed by 2 masked graders for the presence or absence of a cilioretinal artery and whether any branch extended within 500 MUm of the central macula. Multivariate regressions were used to determine the association of the cilioretinal artery and vessel location, adjusted for age, sex, and smoking status, with the prevalence of choroidal neovascularization (CNV) or central geographic atrophy (CGA) and AMD severity score for eyes at randomization and progression at 5 years. Main Outcomes and Measures: Association of cilioretinal artery with prevalence and 5-year incidence of CNV or CGA. Results: Among AREDS participants analyzed, mean (SD) age was 69.0 (5.0) years, with 56.3% female, 46.6% former smokers, and 6.9% current smokers. A total of 26.9% of patients had a cilioretinal artery in 1 eye, and 8.4% had the vessel bilaterally. At randomization, eyes with a cilioretinal artery had a lower prevalence of CNV (5.0% vs 7.6%; OR, 0.66; 95% CI, 0.51-0.85; P = .001) but no difference in CGA (1.1% vs 0.8%; OR, 1.33; 95% CI, 0.76-2.32; P = .31). In eyes without late AMD, those with a cilioretinal artery also had a lower mean (SD) AMD severity score (3.00 [2.35] vs 3.19 [2.40]; P = .02). At 5 years, eyes at risk with a cilioretinal artery had lower rates of progression to CNV (4.1% vs 5.5%; OR, 0.75; 95% CI, 0.56-1.00; P = .05) but no difference in developing CGA (2.2% vs 2.7%; OR, 0.83; 95% CI, 0.56-1.23; P = .35) or change in AMD severity score (0.65 [1.55] vs 0.73 [1.70]; P = .11). In patients with a unilateral cilioretinal artery, eyes with the vessel showed a lower prevalence of CNV than fellow eyes (4.7% vs 7.2%; P = .01). Conclusions and Relevance: The presence of a cilioretinal artery is associated with a lower risk of developing CNV, but not CGA, suggesting a possible retinal hemodynamic contribution to the pathogenesis of neovascular AMD. Trial Registration: ClinicalTrials.gov Identifier: NCT00000145. PMID- 29978188 TI - Multiple-Flap Reconstruction of Head and Neck Defects. PMID- 29978187 TI - Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma. AB - Importance: Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives: To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants: In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures: Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results: Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non-clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance: Of patients with non-clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach. PMID- 29978189 TI - Cost-effectiveness and Benefit-to-Harm Ratio of Risk-Stratified Screening for Breast Cancer: A Life-Table Model. AB - Importance: The age-based or "one-size-fits-all" breast screening approach does not take into account the individual variation in risk. Mammography screening reduces death from breast cancer at the cost of overdiagnosis. Identifying risk stratified screening strategies with a more favorable ratio of overdiagnoses to breast cancer deaths prevented would improve the quality of life of women and save resources. Objective: To assess the benefit-to-harm ratio and the cost effectiveness of risk-stratified breast screening programs compared with a standard age-based screening program and no screening. Design, Setting, and Population: A life-table model was created of a hypothetical cohort of 364 500 women in the United Kingdom, aged 50 years, with follow-up to age 85 years, using (1) findings of the Independent UK Panel on Breast Cancer Screening and (2) risk distribution based on polygenic risk profile. The analysis was undertaken from the National Health Service perspective. Interventions: The modeled interventions were (1) no screening, (2) age-based screening (mammography screening every 3 years from age 50 to 69 years), and (3) risk-stratified screening (a proportion of women aged 50 years with a risk score greater than a threshold risk were offered screening every 3 years until age 69 years) considering each percentile of the risk distribution. All analyses took place between July 2016 and September 2017. Main Outcomes and Measures: Overdiagnoses, breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, costs in British pounds, and net monetary benefit (NMB). Probabilistic sensitivity analyses were used to assess uncertainty around parameter estimates. Future costs and benefits were discounted at 3.5% per year. Results: The risk-stratified analysis of this life-table model included a hypothetical cohort of 364 500 women followed up from age 50 to 85 years. As the risk threshold was lowered, the incremental cost of the program increased linearly, compared with no screening, with no additional QALYs gained below 35th percentile risk threshold. Of the 3 screening scenarios, the risk stratified scenario with risk threshold at the 70th percentile had the highest NMB, at a willingness to pay of L20 000 (US $26 800) per QALY gained, with a 72% probability of being cost-effective. Compared with age-based screening, risk stratified screening at the 32nd percentile vs 70th percentile risk threshold would cost L20 066 (US $26 888) vs L537 985 (US $720 900) less, would have 26.7% vs 71.4% fewer overdiagnoses, and would avert 2.9% vs 9.6% fewer breast cancer deaths, respectively. Conclusions and Relevance: Not offering breast cancer screening to women at lower risk could improve the cost-effectiveness of the screening program, reduce overdiagnosis, and maintain the benefits of screening. PMID- 29978191 TI - Implementation Challenges for Risk-Stratified Screening in the Era of Precision Medicine. PMID- 29978190 TI - Development and Evaluation of Diagnostic Criteria for Vogt-Koyanagi-Harada Disease. AB - Importance: To our knowledge, a set of well-defined diagnostic criteria is not yet developed for the diagnosis of Vogt-Koyanagi-Harada (VKH) disease. Objective: To develop and evaluate a set of diagnostic criteria for VKH disease using data from Chinese patients. Design, Setting, and Participants: This case-control study reviewed medical records of patients from a tertiary referral center between October 2011 and October 2016. Data from 634 patients with VKH disease and 623 patients with non-VKH uveitis from southern China were used to develop the Diagnostic Criteria for VKH Disease (DCV). Data from an additional group of 537 patients with a definite VKH disease diagnosis and 525 patients with non-VKH uveitis from northern China were used to evaluate the diagnostic criteria. Main Outcomes and Measures: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic. Results: Of the 1257 patients used to construct the DCV, 665 (52.9%) were male, and the mean (SD) age at disease onset was 38.6 (13.6) years. The 3-class model and 21 clinical findings were selected by latent class analysis. Variables with a high positive rate in the early-phase or late-phase VKH group or high specificity constituted essential parameters. Constellations of these essential parameters constructed the DCV. The sensitivity and NPV of the DCV were higher than those of the Revised Diagnostic Criteria for VKH Disease (RDC) (sensitivity: 94.6% vs 71.9%; difference, 22.7%; 95% CI, 18.5-27.0; NPV: 94.3% vs 76.6%; difference, 17.7%; 95% CI, 13.9-21.5). The specificity and PPV of the DCV were not different from that of the RDC (specificity: 92.2% vs 93.9%; difference, 1.7%; 95% CI, -1.4 to 4.8; PPV: 89.3% vs 92.3%; difference, 3.0%; 95% CI, -1.4 to 4.8). The area under the receiver operating characteristic curve of the DCV and the RDC were 0.934 (95% CI, 0.917-0.951) and 0.829 (95% CI, 0.803-0.855), respectively. Conclusions and Relevance: The DCV were developed and evaluated using data from Chinese patients with VKH disease and showed a high sensitivity, NPV, and area under the receiver operating characteristic curve in comparison with the RDC. However, they were developed using a retrospective analysis and should be evaluated in prospective studies in other racial/ethnic populations. PMID- 29978192 TI - Appraising the Quality of Systematic Reviews for Age-Related Macular Degeneration Interventions: A Systematic Review. AB - Importance: Age-related macular degeneration (AMD) is a leading cause of vision impairment. It is imperative that AMD care is timely, appropriate, and evidence based. It is thus essential that AMD systematic reviews are robust; however, little is known about the quality of this literature. Objectives: To investigate the methodological quality of systematic reviews of AMD intervention studies, and to evaluate their use for guiding evidence-based care. Evidence Review: This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. All studies that self-identified as a systematic review in their title or abstract or were categorized as a systematic review from a medical subject heading and investigated the safety, efficacy and/or effectiveness of an AMD intervention were included. Comprehensive electronic searches were performed in Ovid MEDLINE, Embase, and the Cochrane Library from inception to March 2017. Two reviewers independently assessed titles and abstracts, then full-texts for eligibility. Quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool. Study characteristics (publication year, type of intervention, journal, citation rate, and funding source) were extracted. Findings: Of 983 citations retrieved, 71 studies (7.6%) were deemed eligible. The first systematic review relating to an AMD intervention was published in 2003. More than half were published since 2014. Methodological quality was highly variable. The mean (SD) AMSTAR score was 5.8 (3.2) of 11.0, with no significant improvement over time (r = -0.03; 95% CI, 0.26 to 0.21; P = .83). Cochrane systematic reviews were overall of higher quality than reviews in other journals (mean [SD] AMSTAR score, 9.9 [1.2], n = 15 vs 4.7 [2.2], n = 56; P < .001). Overall, there was poor adherence to referring to an a priori design (22 articles [31%]) and reporting conflicts of interest in both the review and included studies (16 articles [23%]). Reviews funded by government grants and/or institutions were generally of higher quality than industry-sponsored reviews or where the funding source was not reported. Conclusions and Relevance: There are gaps in the conduct of systematic reviews in the field of AMD. Enhanced endorsement of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement by refereed journals may improve review quality and improve the dissemination of reliable evidence relating to AMD interventions to clinicians. PMID- 29978193 TI - The Cilioretinal Artery-A Friend to Age-Related Macular Degeneration? PMID- 29978194 TI - Posterior Embryotoxon, Corectopia, and Cerebellar Dysgenesis. PMID- 29978195 TI - Choroideremia in a Woman With Turner Syndrome. PMID- 29978196 TI - Outcomes in Head and Neck Resections That Require Multiple-Flap Reconstructions: A Systematic Review. AB - Importance: Complex head and neck cancer defects that require multiflap reconstructions are technically feasible, but the morbidity and patient outcomes of such large-scale head and neck operations have yet to be systematically reviewed. Objective: To systematically review existing literature to characterize the outcomes of large-scale head and neck resections that require multiple-flap reconstructions (defined as defects that require >1 flap [free, pedicled, or combinations thereof]). Evidence Review: Two authors independently searched PubMed, Embase, and the Cochrane Review databases for English-only texts published on any date. Included studies examined patients who underwent complex head and neck surgical resections that required multiple simultaneous flaps for reconstruction. Included studies reported results on at least one of the following outcomes: functional and aesthetic, patient survival, or cost (estimated by operating room time, length of stay, and/or complications). Methodological Index for Non-Randomized Studies (MINORS) criteria for bias and modified Oxford Centre for Evidence-Based Medicine recommendations were used to assess study quality. Findings: Twenty-four studies published from November 1, 1992, through September 1, 2016, met the final inclusion criteria, with a total of 487 patients (370 male [79.4%]; mean [SD] weighted age, 55.1 [4.1] years). Sixty-two of 250 patients (24.8%) were partially or fully dependent on feeding tubes at follow-up. Twenty-two of 75 patients (29.3%) had poor postoperative oral competence, causing moderate to severe drooling. Nineteen of 108 patients (17.6%) had unintelligible speech. Nine of 64 patients (14.1%) were unsatisfied with their aesthetic outcome. The mean (SD) reported survival was 2.36 (1.39) years. The mean (SD) length of stay was 24.5 (12.2) days in 219 patients. Eighty-eight minor complications (eg, partial flap necrosis, donor site complications) and 185 major complications (eg, surgical reexplorations, flap loss, or cardiopulmonary complications) were reported in 380 patients. Mean (SD) MINORS scores were 16.0 (3.2) for comparison studies and 11.4 (1.8) for noncomparison studies. Conclusions and Relevance: Because of limited patient life expectancies, modest functional and aesthetic outcomes, and significant associated costs, surgeons should weigh the curative potential and palliative benefits for individual patients with a comprehensive view of the overall outcomes of extensive head and neck resections and reconstructions. Realistic expectations should be emphasized during preoperative discussions with patients. PMID- 29978197 TI - Clarification of the FDA Accelerated Agnostic Approval of Pembrolizumab and the Opportunities Arising From the Required Confirmatory Studies-Reply. PMID- 29978198 TI - Clarification of the FDA Accelerated Agnostic Approval of Pembrolizumab and the Opportunities Arising From the Required Confirmatory Studies. PMID- 29978199 TI - Broadening the View of Germline Mutations in Kidney Cancer. PMID- 29978200 TI - Content Omitted From Abstract. PMID- 29978201 TI - Young Children's Structure Production: A Revision of the Index of Productive Syntax. AB - Purpose: The Index of Productive Syntax (IPSyn; Scarborough, 1990) is widely used to measure syntax production in young children. The goal of this article is to promote greater clarity and consistency in machine and hand scoring by presenting a revised version of the IPSyn (IPSyn-R) and comparing it with the original IPSyn (IPSyn-O). Method: Longitudinal syntax production in 10 30- and 42-month-old typically developing children drawn from the Child Language Data Exchange System (MacWhinney, 2000) Weismer corpus was examined, using both the IPSyn-O and the IPSyn-R. Results: The IPSyn-R provided nearly identical scores to the IPSyn-O with the exception of scores affected primarily by 1 modified noun phrase structure. Structures ranked as more advanced were produced less frequently. The results also reveal which of the IPSyn-R's 59 structures were most and least likely to be produced by this sample at these ages. Conclusions: The qualitative and quantitative differences between the IPSyn-O and the IPSyn-R are relatively minor. The IPSyn-R can make it easier to score the IPSyn, both by clinicians and researchers, and facilitate the IPSyn's move to machine scoring of language samples. PMID- 29978202 TI - Trend Toward the Use of Transcutaneous Osseointegrated Hearing Devices in Pediatric Patients. PMID- 29978203 TI - Association of Autologous Fat Injection in Facial Artery With Ophthalmological Complications: An Experimental Animal Study. AB - Importance: Complications caused by autologous fat filling have been reported. Comprehensive knowledge of the possible adverse effects of autologous fat filling is needed. Objective: To determine the association of autologous fat filling with ophthalmic function complications. Design, Setting, and Participants: Four adult New Zealand white rabbits were killed for a facial anatomy study. Sixty-four adult New Zealand white rabbits underwent fat harvest using the Coleman technique. Autologous fat was minced or digested with collagenase 1 and centrifuged to separate fat lipid and fat granules. Either 0.2 mL or 0.4 mL of minced fat, fat granules, fat lipid, or saline (control) was retrogradely injected into the facial artery of rabbit models. Electroretinography and ophthalmic fundoscopy were performed to measure the retina and fundus artery occlusions 2 weeks after surgery. Main Outcomes and Measures: Visual impairment, blindness, and death. Results: Injection of 0.2 mL of fat granules, fat lipid, and saline resulted in 100% (8 of 8), 62.5% (5 of 8), and 0 ophthalmic complications, respectively; and 0.4 mL resulted in 87.5% (7 of 8), 12.5% (1 of 8), and 0 ophthalmic complications, respectively. Injection of 0.2 mL and 0.4 mL minced fat led to 100% (8 of 8) ophthalmic complications and death, respectively. The mortality rates were 37.5% (3 of 8), 12.5% (1 of 8), and 0 for 0.2 mL emboli injection, and 100% (8 of 8), 50% (4 of 8), and 0 for 0.4 mL, respectively. Conclusions and Relevance: In this study, minced fat injection was associated with more ophthalmic complications than injection of fat granules and fat lipid. Increasing the injection volume of fat tissues could raise the incidence of morbidity and mortality. Level of Evidence: NA. PMID- 29978204 TI - Introduction to the Clinical Forum: Working Memory in School-Age Children. AB - Purpose: The purpose of this article is to introduce the LSHSS Clinical Forum: Working Memory in School-Age Children. All the articles in this clinical forum concern the nature of working memory and its relationship to language and academic skills. Method: The introduction provides a basic overview of working memory and its importance for explicit and implicit learning and highlights the topics of the 8 articles that comprise the clinical forum. Conclusion: The articles in this clinical forum provide readers with important information about the current state of our understanding of working memory and its importance for understanding the language and academic skills of school-age children developing typically and those with language and learning difficulties. Articles in this forum also address the practical implications of this knowledge for assessment and intervention. PMID- 29978205 TI - Theories of Working Memory: Differences in Definition, Degree of Modularity, Role of Attention, and Purpose. AB - Purpose: The purpose of this article is to review and discuss theories of working memory with special attention to their relevance to language processing. Method: We begin with an overview of the concept of working memory itself and review some of the major theories. Then, we show how theories of working memory can be organized according to their stances on 3 major issues that distinguish them: modularity (on a continuum from domain-general to very modular), attention (on a continuum from automatic to completely attention demanding), and purpose (on a continuum from idiographic, or concerned with individual differences, to nomothetic, or concerned with group norms). We examine recent research that has a bearing on these distinctions. Results: Our review shows important differences between working memory theories that can be described according to positions on the 3 continua just noted. Conclusion: Once properly understood, working memory theories, methods, and data can serve as quite useful tools for language research. PMID- 29978207 TI - Math Difficulties and Working Memory Growth in English Language Learner Children: Does Bilingual Proficiency Play a Significant Role? AB - Purpose: The purpose of this study was to determine those components of working memory (WM) that play a significant role in predicting math growth in children who are English language learners (N = 157) with serious math difficulties (MD). Method: A battery of tests was administered in English and Spanish that assessed computation, reading, vocabulary, inhibition, and components of WM in Grade 1 children with follow-up testing in Grades 2 and 3. Results: The results indicated that growth in the executive component of WM was related to growth in math performance. Proficient bilingual children (proficient in both Spanish and English vocabulary) with MD outperformed less proficient bilingual children with MD on measures of math calculation, fluid intelligence, reading, and Spanish WM at Grade 3. Conclusion: Growth in the executive component of WM is significantly related to growth in math computation, and increased bilingual proficiency across testing waves yielded positive gains in both math and cognitive performance in children with MD. PMID- 29978206 TI - Do Bilingual Children Have an Executive Function Advantage? Results From Inhibition, Shifting, and Updating Tasks. AB - Purpose: The purpose of this study was to examine differences in performance between monolingual and Spanish-English bilingual second graders (aged 7-9 years old) on executive function tasks assessing inhibition, shifting, and updating to contribute more evidence to the ongoing debate about a potential bilingual executive function advantage. Method: One hundred sixty-seven monolingual English speaking children and 80 Spanish-English bilingual children were administered 7 tasks on a touchscreen computer in the context of a pirate game. Bayesian statistics were used to determine if there were differences between the monolingual and bilingual groups. Additional analyses involving covariates of maternal level of education and nonverbal intelligence, and matching on these same variables, were also completed. Results: Scaled-information Bayes factor scores more strongly favored the null hypothesis that there were no differences between the bilingual and monolingual groups on any of the executive function tasks. For 2 of the tasks, we found an advantage in favor of the monolingual group. Conclusions: If there is a bilingual advantage in school-aged children, it is not robust across circumstances. We discuss potential factors that might counteract an actual advantage, including task reliability and environmental influences. PMID- 29978208 TI - Decoding: It's Not All About the Letters. AB - Purpose: Reading requires the ability to decode and comprehend. Impairments in working memory (WM) are often implicated in students who are poor decoders. It is unclear whether this is a domain-specific issue or a task-specific issue. Therefore, this study examined how auditory-verbal (AV) WM, visual-spatial (VS) WM, and cognitive load affected the decoding skills of students identified as poor readers. Method: Twenty-five 2nd-grade and 23 fifth-grade students completed 3 different measures requiring various levels of cognitive demand for each domain of WM, and their decoding skills were assessed with word identification and word attack measures. Results: AV WM measures with moderate and high cognitive demands were correlated with 2nd-grade students' abilities to decode words. AV WM measures also predicted their performance on decoding tasks. For 5th-grade students, the AV WM measure with simple cognitive load was correlated with ability to decode words. The VS WM measures were not correlated with word identification or word attack at either level. Conclusions: This study has implications for training instruction in reading. Because the AV WM measures and not the VS WM measures predicted decoding performance in second graders, a greater emphasis on language-rich reading programs could be beneficial in scaffolding early academic achievement and reading performance. PMID- 29978209 TI - Working Memory and Auditory Processing in School-Age Children. AB - Purpose: Our goal is to present the relationships between working memory (WM) and auditory processing abilities in school-age children. Review and Discussion: We begin with an overview of auditory processing, the conceptualization of auditory processing disorder, and the assessment of auditory processing abilities in children. Next, we describe a model of WM and a model of auditory processing followed by their comparison. Evidence for the relationships between WM and auditory processing abilities in school-age children follows. Specifically, we present evidence for the association (or lack thereof) between WM/attention and auditory processing test performance. Clinical Implications: In conclusion, we describe a new framework for understanding auditory processing abilities in children based on integrated evidence from cognitive science, hearing science, and language science. We also discuss clinical implications in children that could inform future research. PMID- 29978210 TI - The Reciprocal Influences of Working Memory and Linguistic Knowledge on Language Performance: Considerations for the Assessment of Children With Developmental Language Disorder. AB - Purpose: This article considers how the language performance of school-age children with language impairments, such as developmental language disorder, is influenced by the reciprocal relationship of existing linguistic knowledge and working memory resources and the resultant implications for assessment. Method: A viewpoint is provided by reviewing working memory theory, empirical evidence of the reciprocal relationship between working memory and existing language knowledge, and critically evaluating available standardized and nonstandardized tools designed to assess working memory or linguistic skills. Conclusions: Speech language pathologists with an excellent understanding of the reciprocal relationship between working memory and linguistic knowledge will need to examine performance across tasks and contexts varying in these demands in order to achieve an accurate clinical profile of relevant strengths and weaknesses for individual children. PMID- 29978212 TI - Wait...What??? Guiding Intervention Principles for Students With Verbal Working Memory Limitations. AB - Purpose: The purpose of this clinical focus article is to present 5 guiding principles for the development of interventions for children with limited verbal working memory abilities. Method: Summarizing and synthesizing previously reported theories and empirical data, we present a framework intended to guide working memory interventions. Results: Existing research and theory support a comprehensive, multidimensional treatment model that considers the knowledge and abilities of the student and the language-learning demands they face in the various contexts of a school day. Conclusion: The clinical framework for which we are advocating is one that embodies the characteristics of complex interventions those made up of many individual components that work synchronously in conjunction with each other. PMID- 29978211 TI - Pull the Andon Rope on Working Memory Capacity Interventions Until We Know More. AB - Purpose: The purpose of this article is to discuss the current state of interventions for improving working memory (WM) capacity language and academic skills and to provide suggestions for speech-language pathologists working with students who have WM capacity limitations. Method: Meta-analyses, systematic reviews, randomized controlled trials, and nonrandomized comparison studies investigating the role of WM interventions for improving WM capacity language and academic skills are reviewed. Strategies for improving WM are discussed. Results: The use of interventions designed to improve WM capacity and other cognitive skills is currently not supported by the research. Direct WM interventions should be considered to be experimental at this time. Such interventions require further investigation before they are used regularly for children with developmental language disorders. Discussion: Clinicians and practitioners should look to already established interventions for improving how students with developmental language disorders utilize organizational strategies and other well-researched methods for improving their cognitive and academic functioning in functional contexts. PMID- 29978214 TI - Transcutaneous Osseointegrated Implants for Pediatric Patients With Aural Atresia. AB - Importance: Patients with aural atresia typically have maximal conductive hearing loss, which can have negative academic and social consequences. Transcutaneous osseointegrated implants (TOIs) can potentially restore hearing on the affected side. Objectives: To review the demographic, audiological, and surgical outcomes of TOI placement in pediatric patients with aural atresia and to describe a modification in incision technique in anticipation of later auricular reconstruction. Design, Setting, and Participants: This retrospective case series reviewed 41 cases of TOI placement in pediatric patients between January 1, 2014, and September 30, 2016, at Lurie Children's Microtia and Aural Atresia Clinic. Patients, all younger than 18 years and with atresia or microtia, received at least 6 months of follow-up and underwent testing before and after surgery. Main Outcomes and Measures: Patient age, indication for procedure, ear sidedness, case length, incision type, complications, and other postoperative events. Audiological outcomes before and after implantation were measured using pure-tone averages and the Hearing In Noise Test for Children, presented in variable signal to noise ratios. Results: In total, 46 TOIs were performed in 38 pediatric patients, but only 41 implantations in 34 patients were included in this study. Of the 34 patients, 13 (38%) were males and 21 (62%) were females, with a mean age of 8.9 (range, 5-17) years at the time of TOI placement. Microtia on the implanted side was present in 39 cases (95%). A modified posterior-superior scalp incision technique was used in 30 (73%) of 41 ears, all in cases of microtia. One perioperative surgical complication occurred: a seroma requiring drainage. Two patients developed minor skin irritation and erythema at the magnet site related to the overnight use of the processor, which resolved when removed while sleeping. The mean (SD; range) score for the Speech In Noise test at 5 dB signal to noise ratio improved from 75.3% (14.4%; range, 50%-92%) correct in unaided/preoperative condition to 93.6% (6.95%; range, 80%-100%) correct in the aided/postoperative condition. The mean improvement in score was 18.3% (95% CI, 10.8%-25.9%), with an effect size of 1.62 (95% CI, 0.95-2.29). The mean pure-tone averages (SD; range) similarly improved from 63.7 (13.2; range, 25-11) dB to 9.6 (4.9; range, 5-15) dB. Conclusions and Relevance: Transcutaneous osseointegrated implantation has a low complication rate among pediatric patients with atresia or microtia and can provide excellent audiological results. It should be included as a treatment option for this population of patients who meet audiological criteria. PMID- 29978215 TI - Association of Space Flight With Problems of the Brain and Eyes. PMID- 29978217 TI - Expert Review of Breast Pathology in Borderline Lesions: A Chance to Reduce Overdiagnosis and Overtreatment? PMID- 29978216 TI - Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Clinical Trial. AB - Importance: Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring. Objective: To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration resistant prostate cancer (mCRPC). Design, Setting, and Participants: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016. Intervention: Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred. Main Outcomes and Measures: The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (>=50% reduction from baseline) and changes in CTC number (from >=5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences). Results: Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]). Conclusions and Relevance: These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated. Trial Registration: ClinicalTrials.gov Identifier: NCT01812746. PMID- 29978218 TI - Introduction to Special Issue on Point-of-Care Ultrasound. PMID- 29978219 TI - Point-of-Care Ultrasound: At the Crossroads of General Medicine. PMID- 29978220 TI - Point-of-Care Ultrasound in Established Settings. AB - The original and most widely accepted applications for point-of-care ultrasound (POCUS) are in the settings of trauma, shock, and bedside procedures. Trauma was the original setting for the introduction of POCUS and has been standardized under the four-plus view examination called the Focused Assessment with Sonography in Trauma (FAST). This examination was found to be especially practice changing for achieving rapid diagnoses in critically ill patients who are too unstable for the delays and transportation inherent in more advanced imaging with computed tomography. This application was broadened from the critically ill trauma patient to any critically ill patient, particularly the patient in undifferentiated shock. Although the Focused Assessment with Sonography in Trauma examination originally focused on sources of hemorrhage causing hypovolemic shock, POCUS also can quickly differentiate cardiogenic, obstructive, and distributive shock and help identify the more specific etiology such as massive pulmonary emboli, pericardial tamponade, and pneumothoraces. By expediting diagnosis, POCUS facilitates faster definitive treatment of life-threatening conditions. In pursuing treatment, US continues to serve a role in the form of visually guiding many procedures that were previously done blindly. US guidance of procedures has improved the safety of central line insertion, thoracentesis, and paracentesis, and has an emerging role in lumbar puncture. Experience in bedside US is becoming a vital tool in the clinician's bedside assessment and management, filling a void between the stethoscope and the more advanced studies and interventions available through radiology. Understanding the strengths and limitations of US enables clinicians to identify the appropriate situations in which they can apply this tool confidently. PMID- 29978221 TI - Point-of-Care Ultrasound in the Inpatient Setting: A Tale of Four Patients. AB - Point of-care ultrasound (POCUS) has become a mainstream bedside tool for clinicians in several specialties and is gaining recognition in hospital medicine. There are many clinical applications in which the inpatient practitioner can use POCUS to improve his or her diagnosis, monitoring, and treatment of patients. POCUS is valuable in many clinical scenarios, including acute renal failure, increasing lower extremity edema, change in inpatient clinical status, and acute dyspnea. The medical literature has demonstrated the ability of nonradiologists to accurately detect conditions, including hydronephrosis; extremes of central venous pressure; deep venous thrombosis; pericardial effusion with tamponade; and several pulmonary pathologic states, including pulmonary edema, pleural effusion, consolidation, and pneumothorax. Further development of POCUS in hospital medicine is highly likely given increased awareness and exposure among medical trainees, a developing literature base, and growing engagement from specialty societies. PMID- 29978222 TI - PEARLS for an Ultrasound Physical and Its Routine Use as Part of the Clinical Examination. AB - At present, there is no consensus on what a routine examination that uses ultrasound (US) should look like. Point-of-care US (POCUS) is poised to be as important a clinical skill as palpation and auscultation; however, the expansive list of potential applications can be intimidating to the beginner. In this article we propose using a PEARLS (Parasternal, Epigastric, Anterior Lung [and/or Apical], Right upper quadrant, Left upper quadrant, and Suprapubic) mnemonic as an approach to a core physical examination augmented with POCUS for routine use. Numerous US protocols for trauma, shock, and respiratory failure have been published, and it is no coincidence that many have evolved overlapping views. These views have numerous uses and applications and should not be confined to only critically ill patients. The PEARLS examination is for both primary care and inpatient settings and is scalable for POCUS beginners and advanced users. From the generalist's perspective, we describe our philosophy on the initial foundation and provide a framework to grow one's POCUS skills. PMID- 29978223 TI - Point-of-Care Ultrasound Improves Shared Diagnostic Understanding Between Patients and Providers. AB - OBJECTIVES: Point-of-care ultrasound (POCUS) has become an integral part of the physical examination. The effect on shared understanding of adding POCUS to the traditional examination is unknown, yet this is an often-described benefit of POCUS. The primary aim of this study was to determine whether the use of POCUS improves shared understanding between providers and patients about patients' diagnoses. METHODS: This was a prospective controlled trial involving a convenience sample of hospitalized adults. Providers in the control arm performed usual care without POCUS, whereas providers in the study arm had the option to add POCUS. Surveys were administered to the subjects and their providers with questions on patient understanding of symptoms, diagnosis, and main contributors to their health problem. Two independent physicians rated the degree of shared understanding between patient and provider surveys. RESULTS: Of the 64 patients enrolled in the study, 60 had complete data. There was increased shared understanding between providers and patients with respect to their diagnosis (POCUS 9.56 +/- 0.63, non-POCUS 7.62 +/- 1.63, P < 0.005) and main contributors (POCUS 9.65 +/- 0.77, non-POCUS 8.30 +/- 1.13, P < 0.005) in the POCUS arm compared with the non-POCUS arm. Patients also increased the self-rating of their understanding of their health problem in the POCUS arm. CONCLUSIONS: These findings suggest that using POCUS improves patients' understanding of the diagnostic process. POCUS may be uniquely poised to enhance patients' understanding of and engagement in that process. PMID- 29978224 TI - A Patient's Perspective: Pairing the Stethoscope with POCUS to Evaluate Acute Dyspnea in the Clinic. AB - Supplemental digital content is available in the text. PMID- 29978225 TI - Point-of-Care Ultrasound Applications in the Outpatient Clinic. AB - Although the use of point-of-care ultrasound (POCUS) is well established in the emergency department (ED) and intensive care unit, the use of POCUS in the outpatient clinic setting is still emerging. General practitioners and specialists alike have increasing access to smaller and less expensive US devices that can assist in making timely diagnoses, guiding procedures, and monitoring patients. In this case-based review, we highlight some of the literature on simple-to-apply POCUS applications relevant to ambulatory medicine. The topics discussed include detecting left ventricular systolic dysfunction, ascites, gallstones, and Achilles tendon tears, as well as distinguishing abscess from cellulitis. Although a robust literature surrounds POCUS use in EDs, literature is limited regarding POCUS in the ambulatory setting; however, the literature supports general practitioners learning this skill set to the benefit of their patients. As POCUS moves out of hospital EDs and into the clinics, high-quality research demonstrating comparable accuracy and utility will be needed. PMID- 29978226 TI - Point-of-Care Sinus Ultrasound: Impact Within a Large Internal Medicine Clinic and Review of Technique. AB - Outpatient diagnosis of acute bacterial sinusitis, using only traditional physical examination and clinical criteria, results in the overuse of antibiotics in patients with upper respiratory complaints. Point-of-care maxillary sinus ultrasound is easy to learn and quick to perform in a primary care clinic. The technique can reduce antibiotic prescribing by reassuring both patients and providers of the absence of fluid in the sinus, the hallmark of maxillary sinusitis. A review of the literature, description of technique, and results of sinus ultrasound implementation in a large internal medicine clinic are included. PMID- 29978227 TI - A Late-Career Internist and Point-of-Care-Ultrasound in a Primary Care Clinic. AB - Supplemental digital content is available in the text. PMID- 29978228 TI - "Old Dogs" Can Learn Ultrasound. PMID- 29978229 TI - Point-of-Care Ultrasound in Resource-Limited Settings: Common Applications. AB - Point-of-care ultrasound (POCUS) is used increasingly in resource-limited settings (RLSs), particularly as inexpensive ultrasound machines and evidence based protocols become more available. POCUS often is the only imaging modality available in such settings, and it has the potential to significantly affect patient care. This article discusses four case-based reviews of POCUS in RLSs for several common diseases: pediatric pneumonia; extrapulmonary tuberculosis; ectopic pregnancy; and tropical parasitic diseases, including echinococcus, schistosomiasis, and amebiasis. It concludes with a discussion of the logistical considerations specific to implementing POCUS in RLSs, particularly equipment and training. The literature reviewed suggests that POCUS has the potential to improve the diagnosis and management of multiple conditions in RLSs, although further research is needed. PMID- 29978230 TI - Point-of-Care Ultrasound as Part of a Short-Term Medical Mission to Rural Nicaragua. AB - OBJECTIVES: The lack of access to diagnostic imaging in resource-limited settings (RLSs) poses a worldwide problem. Advances in ultrasound (US) imaging technology bridge this gap, particularly when examinations are performed by physicians and integrated into the patient encounter, termed point-of-care ultrasound (POCUS). Because the number of physicians participating in short-term medical missions (STMMs) is increasing, the authors sought to characterize how the use of POCUS would affect care delivered as part of a 1-week outreach trip in rural Nicaragua. METHODS: In February 2017, as part of an ongoing collaboration among the University of South Carolina, the Medical University of South Carolina, and OneWorld Health, the authors conducted an observational prospective study of all of the patients who received a POCUS examination as part of standard clinical practice during an STMM to Sebaco, Nicaragua. The goal was to determine how often POCUS changed medical management. In addition, the number and types of scans performed were recorded to assess the most common reasons for POCUS use. RESULTS: More than 1100 patients were seen, and a total of 79 POCUS examinations were performed on 59 patients by 2 physicians with extensive POCUS training. Eighty percent of the patients were women, with an average age of 40.5 years (range 1.6 87 years). The use of US changed management for 35.6% of total patients examined (N = 21), divided among changes in diagnosis, pharmacotherapy, new referral, or referral not needed. The average time to perform a POCUS examination was 6.0 minutes. A wide range of POCUS examinations were performed, with lung, gallbladder, obstetric/gynecologic, and cardiac examinations performed most often. CONCLUSIONS: Incorporating POCUS by trained physicians in an RLS as part of an STMM was successful and often changed management. As interest in nonemergency and noncritical care POCUS increases and proliferation of low-cost, accurate, handheld US devices continues, it is probable that more physicians traveling to RLSs will use POCUS as part of STMMs, positively affecting patient care. PMID- 29978231 TI - Point-of-Care Ultrasound for Internal Medicine: An International Perspective. PMID- 29978232 TI - Point-of-Care Ultrasound Needs Assessment, Curriculum Design, and Curriculum Assessment in a Large Academic Internal Medicine Residency Program. AB - OBJECTIVES: Internal medicine (IM) residency point-of-care ultrasound (POCUS) curricula are being developed but often are limited in scope or components. In this article, we discuss the demonstration of a need for POCUS training in our large academic IM residency program; the development of a longitudinal curriculum; and the impact of the curriculum on POCUS knowledge, use, and confidence. METHODS: In 2014, we designed a cross-sectional POCUS survey and knowledge test for all IM residents at the University of California, San Francisco. The results of this assessment drove the design of a longitudinal POCUS curriculum that included a 2-hour workshop for all IM interns and a 1-month elective offered to all IM residents. Residents were tested on their POCUS knowledge and image interpretation before the elective and were given the same test 6 months after the elective. The posttest included a survey of self-reported POCUS use and confidence. RESULTS: In the needs assessment, residents scored a mean of 27% on the knowledge test, and across all applications the percentage of residents reporting confidence in their POCUS skills was lower than the percentage reporting use of the application in clinical practice. Residents scored a mean of 37% on the elective pretest and 74% on the posttest, an increase of 37% (95% confidence interval 31.6-42.8, P < 0.001), with improvements seen across all applications. After the elective, self-reported use of POCUS and confidence in POCUS skills were increased for the applications, using the needs assessment as an approximate baseline. For core cardiac and pulmonary applications, 76% to 95% of residents, depending on application, reported "high" or "very high" use and 79% to 100% reported "high" or "very high" confidence in their POCUS skills. CONCLUSIONS: We used a needs assessment to guide the development of a longitudinal, multidisciplinary POCUS curriculum. Residents who completed all components showed substantial long-term gains in knowledge in all major applications and high use of and confidence in cardiac and pulmonary applications. PMID- 29978233 TI - Shaping the Future of Point-of-Care-Ultrasound in Medical Education. PMID- 29978234 TI - [Health effects of breastfeeding on the mother]. AB - We evaluated the effect of breastfeeding on maternal health outcomes. We distinguished between long-term effects (breast carcinoma, ovarian carcinoma, endometrial carcinoma, osteoporosis, and type 2 diabetes mellitus) and short-term effects (lactational amenorrhea, postpartum depression, and postpartum weight change).Predominant breastfeeding increases the duration of lactational amenorrhea, which has a short-term effect on the reduction of fertility. There are many studies that show that breastfeeding is protective against breast, ovarian carcinoma, and endometrial carcinoma. The effects depend on the duration of breastfeeding. There is evidence that breastfeeding reduces the risk of type 2 diabetes and metabolic syndrome and cardiac diseases. However, an association between breastfeeding and bone mineral density or maternal depression or postpartum weight change was not clearly evident. PMID- 29978235 TI - Osteophyte piercing of the dura. PMID- 29978236 TI - [Risks in healthcare: recognize, avoid, assess]. PMID- 29978244 TI - MRI findings for unilateral sternoclavicular arthritis: differentiation between infectious arthritis and spondyloarthritis. AB - OBJECTIVES: To analyze and identify magnetic resonance imaging (MRI) and clinical findings for the differentiation between infectious arthritis and spondyloarthritis in patients with unilateral sternoclavicular arthritis. MATERIALS AND METHODS: We retrospectively collected and evaluated the magnetic resonance (MR) images of 21 patients diagnosed with unilateral sternoclavicular arthritis, including 12 with infection and nine with spondyloarthritis, between 2004 and 2017. Capsular distension, extracapsular fluid collection, periarticular muscle edema, the prevalence and distribution of bone marrow edema, and the prevalence and size of bone erosions were assessed on the MR images. Clinical data were also reviewed. RESULTS: Capsular distension was more prominent in patients with infectious arthritis than those with spondyloarthritis (p = 0.002); extracapsular fluid collection and periarticular muscle edema were also more common in infectious arthritis than spondyloarthritis (p < 0.001, respectively); moreover, bone erosions were larger in infectious arthritis than spondyloarthritis (p = 0.023). Other findings significantly associated with infectious arthritis included advanced age (p = 0.007), an elevated C-reactive protein (CRP) level (p = 0.001), and erythrocyte sedimentation rate (ESR) (p < 0.001). The prevalence and distribution of bone marrow edema and the prevalence of bone erosions on MRI, the white blood cell count, and sex showed no significant differences between the two groups. CONCLUSIONS: Capsular distension, extracapsular fluid collection, periarticular muscle edema, and the size of bone erosions on MRI, as well as the age, CRP level, and ESR of patients, could be helpful for differentiating infectious arthritis from spondyloarthritis involving the sternoclavicular joint. PMID- 29978243 TI - Graft use in the treatment of large and massive rotator cuff tears: an overview of techniques and modes of failure with MRI correlation. AB - Despite technical advances, repair of large or massive rotator cuff tears continues to demonstrate a relatively high rate of failure. Rotator cuff repair or superior capsular reconstruction (SCR) using a variety of commercially available grafts provides a promising option in patients with tears that may be at high risk for failure or otherwise considered irreparable. There are three major graft constructs that exist when utilizing graft in rotator cuff repair or reconstruction: augmentation at the rotator cuff footprint, bridging, and SCR. Each construct has a unique appearance when evaluated using postoperative magnetic resonance imaging (MRI), and each construct has unique sites that are predisposed to failure. Understanding the basic principles of these constructs can help the radiologist better evaluate the postoperative MRI appearance of these increasingly utilized procedures. PMID- 29978245 TI - 18F-NaF and 18F-FDG as molecular probes in the evaluation of atherosclerosis. AB - The early detection of atherosclerotic disease is vital to the effective prevention and management of life-threatening cardiovascular events such as myocardial infarctions and cerebrovascular accidents. Given the potential for positron emission tomography (PET) to visualize atherosclerosis earlier in the disease process than anatomic imaging modalities such as computed tomography (CT), this application of PET imaging has been the focus of intense scientific inquiry. Although 18F-FDG has historically been the most widely studied PET radiotracer in this domain, there is a growing body of evidence that 18F-NaF holds significant diagnostic and prognostic value as well. In this article, we review the existing literature on the application of 18F-FDG and 18F-NaF as PET probes in atherosclerosis and present the findings of original animal and human studies that have examined how well 18F-NaF uptake correlates with vascular calcification and cardiovascular risk. PMID- 29978246 TI - Noise in the Operating Room Distracts Members of the Surgical Team. An Observational Study. AB - BACKGROUND: Noise pollution in operation rooms may distract the surgical team members. In particular during phases of high task complexity, noise can jeopardize concentration. Phases of high complexity are related to task specificities and may thus be different for different members of the surgical team. STUDY DESIGN: Noise exposure was measured during 110 open abdominal surgeries. Distinguishing three phases (opening, main phase, and closing), noise was related to self-report of distraction levels by main and secondary surgeons, scrub nurses and anesthetists. RESULTS: Noise pollution was higher than recommended levels for concentrated work. Adjusted for duration, surgical type, and difficulty of the surgery, results showed that second surgeons are more likely distracted when noise pollution was high in the main phase; and anesthetists are more likely distracted when noise pollution was high during the closing phase. Main surgeons' and scrub nurses' concentration was not impaired by measured noise levels. CONCLUSIONS: In phases with higher concentration demands, noise pollution was particularly distracting for second surgeons and anesthetist, corresponding to their specific task demands (anesthetists) and experience (second surgeons). Reducing noise levels particularly in the main and closing phase of the surgery may reduce concentration impairments. PMID- 29978248 TI - Therapeutic cancer vaccine: building the future from lessons of the past. AB - Anti-cancer vaccines have raised many hopes from the start of immunotherapy but have not yet been clinically successful. The few positive results of anti-cancer vaccines have been observed in clinical situations of low tumor burden or preneoplastic lesions. Several new concepts and new results reposition this therapeutic approach in the field of immunotherapy. Indeed, cancers that respond to anti-PD-1/PD-L1 (20-30%) are those that are infiltrated by anti-tumor T cells with an inflammatory infiltrate. However, 70% of cancers do not appear to have an anti-tumor immune reaction in the tumor microenvironment. To induce this anti tumor immunity, therapeutic combinations between vaccines and anti-PD-1/PD-L1 are being evaluated. In addition, the identification of neoepitopes against which the immune system is less tolerated is giving rise to a new enthusiasm by the first clinical results of the vaccine including these neoepitopes in humans. The ability of anti-cancer vaccines to induce a population of anti-tumor T cells called memory resident T cells that play an important role in immunosurveillance is also a new criterion to consider in the design of therapeutic vaccines. PMID- 29978247 TI - Associations of Hospital Length of Stay with Surgical Site Infections. AB - BACKGROUND: Surgical site infections (SSI) are a major cause of morbidity and mortality in surgical patients. Postoperative and total hospital length of stay (LOS) are known to be prolonged by the occurrence of SSI. Preoperative LOS may increase the risk of SSI. This study aims at identifying the associations of pre- and postoperative LOS in hospital and intensive care with the occurrence of SSI. METHODS: This observational cohort study includes general, orthopedic trauma and vascular surgery patients at two tertiary referral centers in Switzerland between February 2013 and August 2015. The outcome of interest was the 30-day SSI rate. RESULTS: We included 4596 patients, 234 of whom (5.1%) experienced SSI. Being admitted at least 1 day before surgery compared to same-day surgery was associated with a significant increase in the odds of SSI in univariate analysis (OR 1.65, 95% CI 1.25-2.21, p < 0.001). More than 1 day compared to 1 day of preoperative hospital stay did not further increase the odds of SSI (OR 1.08, 95% CI 0.77-1.50, p = 0.658). Preoperative admission to an intensive care unit (ICU) increased the odds of SSI as compared to hospital admission outside of an ICU (OR 2.19, 95% CI 0.89-4.59, p = 0.057). Adjusting for potential confounders in multivariable analysis weakened the effects of both preoperative admission to hospital (OR 1.38, 95% CI 0.99-1.93, p = 0.061) and to the ICU (OR 1.89, 95% CI 0.73-4.24, p = 0.149). CONCLUSION: There was no significant independent association between preoperative length of stay and risk of SSI while SSI and postoperative LOS were significantly associated. PMID- 29978249 TI - Reference database design for the automated analysis of microplastic samples based on Fourier transform infrared (FTIR) spectroscopy. AB - The identification of microplastics becomes increasingly challenging with decreasing particle size and increasing sample heterogeneity. The analysis of microplastic samples by Fourier transform infrared (FTIR) spectroscopy is a versatile, bias-free tool to succeed at this task. In this study, we provide an adaptable reference database, which can be applied to single-particle identification as well as methods like chemical imaging based on FTIR microscopy. The large datasets generated by chemical imaging can be further investigated by automated analysis, which does, however, require a carefully designed database. The novel database design is based on the hierarchical cluster analysis of reference spectra in the spectral range from 3600 to 1250 cm-1. The hereby generated database entries were optimized for the automated analysis software with defined reference datasets. The design was further tested for its customizability with additional entries. The final reference database was extensively tested on reference datasets and environmental samples. Data quality by means of correct particle identification and depiction significantly increased compared to that of previous databases, proving the applicability of the concept and highlighting the importance of this work. Our novel database provides a reference point for data comparison with future and previous microplastic studies that are based on different databases. Graphical abstract ?. PMID- 29978250 TI - Interactions between elastin-like peptides and an insulating poly(ortho aminophenol) membrane investigated by AFM and XPS. AB - This investigation was undertaken to explore the mutual recognition of the pentapeptide (ValGlyGlyValGly)n, a hydrophobic elastin-like peptide (ELP), suspended in deionized water in monomer (n = 1) and trimer (n = 3) forms and the outer surface of a very thin, insulating polymer, poly(ortho-aminophenol) (PoAP), electrochemically grown on a platinum foil by cyclic voltammetry in a neutral medium (phosphate-buffered saline, I = 0.1M) immersed in the suspension. As a prior task, the proved propensity of the ValGlyGlyValGly sequence, at the given minimal length (three or more repeats), to self-assemble into amyloid-like fibrils when solubilized in an aqueous environment was considered within the framework of testing PoAP surfaces for the specific detection of amyloid precursors. From our knowledge of the chemical structure and physical properties of both biomacromolecule families obtained in previous studies, we focused on the efficacy of the binding sites offered to ELP fibrils by PoAP in its as-prepared form or properly modified either by postsynthesis oxidation or by adsorption/entrapping of ELP monomer(s) with or without protecting terminal groups. Consistent with all methods of preparation, the best surfaces, recognizable by the trimer fibrils, are those modified to carry a larger number of carbonyls, particularly by entrapment of ELP monomer(s) during PoAP electrosynthesis using an imprinting-inspired method. The degree of attachment of fibrillar aggregates, detected by atomic force microscopy and X-ray photoelectron spectroscopy, provides unequivocal evidence of the cooperative forces involving PoAP-ELP interactions. The results obtained suggest the prospect of using the proposed Pt/PoAP/ELP systems as biodetectors in Alzheimer disease. Graphical abstract Synthesis steps of Pt/PoAP/ELP electrodes for amyloid detection. AFM = Atomic Force Microscopy, CV = Cyclic Voltammetry, ELPs = Elastin like Peptides, PoAP = Poly ortho-Aminophenol, Pt = Platinum, XPS = X-ray Photoelectron Spectroscopy. PMID- 29978251 TI - Lack of relationship between cord blood erythropoietin and intraventricular hemorrhage in premature neonates: a controversial result. AB - PURPOSE: The aim of this study was to assess the incidence and risk factors of intraventricular hemorrhage (IVH) as well as the role of cord blood erythropoietin (EPO) level in predicting the possibility of IVH in premature neonates. MATERIALS AND METHODS: This prospective study included 140 preterm neonates born at hospitals affiliated to Shiraz University of Medical Sciences from May 2014 to April 2015. Complete blood count and cord blood EPO level was measured after birth. Brain ultrasonography was performed at 3 and 7-10 days after birth in these newborns. RESULTS: Brain ultrasonography showed IVH in 8.57% (12/140) until the third day and 20% (28/140) at 7-10 days of life in premature neonates. Early gestational age, low birth weight, low Apgar score, and failure to give prenatal steroid were significant risk factors for developing IVH. The mean level of cord blood EPO was 20.95 +/- 21.09 mIU/mL in premature newborns without IVH and 15.82 +/- 17.11 mIU/mL with IVH. There was no correlation between the cord blood EPO and IVH in premature newborns. CONCLUSION: Antenatal steroids therapy should be encouraged among women at risk of premature delivery. Our results showed that the cord blood EPO was not correlated with IVH in preterm neonates and further research is required to assess this relationship. PMID- 29978252 TI - Tuberculosis of the central nervous system in children. AB - BACKGROUND: Central nervous system tuberculosis (CNS TB) in children is still a socioeconomic problem in developing countries. It has varied manifestations, symptoms are nonspecific, diagnosis can be challenging, and treatment may be difficult. It is often missed or overlooked. Among the various pathological entities, tuberculous meningitis is the most common and devastating manifestation. The resultant vasculitis, infarction, and hydrocephalus can be life-threatening. It can have grave cognitive, intellectual, and endocrine sequelae if not treated in time resulting in handicap, especially in resource constraint countries. Early diagnosis and treatment of tuberculous meningitis is the single most important factor determining outcome. Tuberculous hydrocephalus needs to be recognized early, and cerebrospinal fluid diversion procedure needs to be performed in adequate time to prevent morbidity or mortality in some cases. Tuberculous pachymeningitis and arachnoiditis are rare in children. Tuberculous abscess can mimic pyogenic abscess and requires high index of suspicion. Calvarial tuberculosis is seen in children and responds well to antituberculous chemotherapy. Drug-resistant tuberculosis is a formidable problem, and alternate chemotherapy should be promptly instituted. AIM: The pathogenesis, clinical features, diagnosis, and management of central nervous system tuberculosis in children are summarized. CONCLUSION: Heightened clinical suspicion, early diagnosis, appropriate antituberculous treatment, and surgery in relevant situation are essential for a gratifying outcome and preventing complications. PMID- 29978253 TI - Shunt infections: a review and analysis of a personal series. AB - INTRODUCTION AND PURPOSE: CSF diversion shunts are notoriously prone to complications. The most difficult to manage among them is shunt infection, which warrants a prolonged hospital stay. The aim of this paper is to review the pattern of infections, the pathology, and management of shunt infections with special reference to a tertiary pediatric center in a developing country. MATERIALS AND METHODS: This is a review of shunt infections in general and a retrospective study of all cases operated in the hospital from 2000 to 2015. RESULTS: The authors analyze the data and try to discern patterns, which may enable newer interventions to treat as well as decrease the burden of shunt infections in the future. CONCLUSION: It is difficult to determine the true incidence of shunt infections as there is no definition of what constitutes a shunt infection. There are no standardized international guidelines as to how to deal with an infected shunt. Though the ability to treat shunt infection has improved and the incidence of shunt infection has decreased over time, there is still no consensus on the best way to manage it. The prevention is predominantly based on common sense and has helped but a more scientific algorithm is the need of the hour. PMID- 29978254 TI - The Forteo Patient Registry linkage to multiple state cancer registries: study design and results from the first 8 years. AB - : The Forteo Patient Registry (FPR) aims to estimate the incidence of osteosarcoma in US patients treated with teriparatide. Enrollment began in 2009 and will continue through 2019, with linkage planned through 2024. To date, no incident cases of osteosarcoma have been identified among patients registered in the FPR. INTRODUCTION: The Forteo Patient Registry (FPR) was established in 2009 to estimate the incidence of osteosarcoma in US patients treated with teriparatide. The objective of this paper is to describe study methods, challenges encountered, and progress to date. METHODS: The FPR is a prospective US registry designed to link data from participants annually with state cancer registries. Patient enrollment is planned for 10 years (2009-2019) and annual linkage with US state cancer registries for 15 years (2010-2024). All US state cancer registries and DC were invited to participate. Patients are recruited using pre-enrollment materials included in teriparatide device packaging, kits, and brochures distributed by health-care providers; a toll-free number; and a study website. A linkage algorithm is used to match data from enrolled participants with cancer registry data. RESULTS: For the eighth annual linkage in 2017, information necessary for linkage with 63,270 patients in the FPR was submitted to each of the 42 participating registries. These patients contributed approximately 242,782 person-years of follow-up. A total of 5268 adult osteosarcoma cases diagnosed since January 1, 2009, were available for linkage from participating state cancer registries. To date, no incident cases of osteosarcoma have been identified among patients registered in the FPR. CONCLUSIONS: Based on the estimated 242,782 person-years of observation as of the eighth annual linkage and projecting current enrollment rate to study end in 2024, it is anticipated that the completed study will be able to detect a fourfold increase in the risk of osteosarcoma if one exists. PMID- 29978255 TI - Comments on Bergman et al.: Bisphosphonate use after clinical fracture and risk of new fracture. PMID- 29978256 TI - Genetic variation in Wnt/beta-catenin and ER signalling pathways in female and male elite dancers and its associations with low bone mineral density: a cross section and longitudinal study. AB - : The association of genetic polymorphisms with low bone mineral density in elite athletes have not been considered previously. The present study found that bone mass phenotypes in elite and pre-elite dancers are related to genetic variants at the Wnt/beta-catenin and ER pathways. INTRODUCTION: Some athletes (e.g. gymnasts, dancers, swimmers) are at increased risk for low bone mineral density (BMD) which, if untreated, can lead to osteoporosis. To investigate the association of genetic polymorphisms in the oestrogen receptor (ER) and the Wnt/beta-catenin signalling pathways with low BMD in elite and pre-elite dancers (impact sport athletes). METHODS: The study included three phases: (1) 151 elite and pre-elite dancers were screened for the presence of low BMD and traditional osteoporosis risk factors (low body weight, menstrual disturbances, low energy availability); (2) a genetic association study was conducted in 151 elite and pre-elite dancers and age- and sex- controls; (3) serum sclerostin was measured in 101 pre-elite dancers and age- and sex-matched controls within a 3-year period. RESULTS: Eighty dancers revealed low BMD: 56.3% had at least one traditional osteoporosis risk factor, whereas 28.6% did not display any risk factor (37.2% revealed traditional osteoporosis risk factors, but had normal BMD). Body weight, menstrual disturbances and energy availability did not fully predict bone mass acquisition. Instead, genetic polymorphisms in the ER and Wnt/beta-catenin pathways were found to be risk factors for low BMD in elite dancers. Sclerostin was significantly increased in dancers compared to controls during the 3-year follow-up (p < 0.05). CONCLUSIONS: Elite and pre-elite dancers demonstrate high prevalence of low BMD, which is likely related to genetic variants at the Wnt/beta-catenin and ER pathways and not to factors usually associated with BMD in athletes (body weight, menstrual disturbances, energy deficiency). PMID- 29978257 TI - Maximal strength training improves musculoskeletal health in amphetamine users in clinical treatment. AB - : Amphetamine use leads to impaired skeletal health and elevated risk of osteoporosis. In the current study, we document that maximal strength training (MST), as a part of clinical treatment, works as a countermeasure, improving muscle force generating capacity, body composition, and skeletal health at sites particularly prone to osteoporotic fractures. INTRODUCTION: Amphetamine users have attenuated musculoskeletal health. MST with heavy loads, few repetitions, and emphasis on maximal mobilization in the concentric phase may increase muscle force generating capacity and skeletal health. This study investigated if MST induced improvements in force generating capacity improved bone mineral density (BMD), trabecular bone score, and body composition in amphetamine users participating in 3-months clinical treatment. METHODS: Of 40 randomized patients, 23 completed the study: 11 in the supervised training group (TG; 8 men, 3 women, 34 +/- 10 years) and 12 in the control group (CG; 9 men, 3 women, 32 +/- 8 years). The TG performed hack-squat MST three times a week for 12 weeks with an intensity of ~90% of one repetition maximum (1RM). Both groups attended conventional clinical treatment. Pre-training and post-training, we assessed hack squat 1RM and rate of force development (RFD), BMD, body composition and trabecular bone score by dual X-ray absorptiometry, and serum bone metabolism markers. RESULTS: MST induced increases in 1RM (70%) and RFD (86%), and resulted in BMD improvements at lumbar spine (3.6%) and total hip (2.4%); all improvements were different from CG (p < 0.05). Both the 1RM and RFD increases were associated with BMD improvements (lumbar spine: r = 0.73 (1RM), r = 0.60 (RFD); total hip: r = 0.61 (1RM); all p < 0.05). No differences were observed in trabecular bone score or bone metabolism markers. CONCLUSIONS: MST improved force generating capacity and skeletal health at sites prone to bone loss in amphetamine users, and advocate that MST should be implemented as a clinical strategy to restore the patients' musculoskeletal health. PMID- 29978258 TI - A survey of medicine use in children and adolescents in Austria. AB - : Aims of this survey were to evaluate prescription patterns for children and adolescents in primary and hospital care settings in Austria and to identify the medicines used most frequently in this population. Prescription data were assessed for the year 2014: for primary care, reimbursement data were obtained from Austrian health insurances; for hospital care, information on medicines dispensed to pediatric wards from hospital pharmacies. Frequencies of medicine use were analyzed by Anatomical Therapeutic Chemical classification system, age groups, and care setting. In primary care, anti-infectives (25%) and medicines for the respiratory system (14%) and for the nervous system (13%); in hospitals, anti-infectives (23%) and medicines for the nervous system (13%) and alimentary tract (12%) were prescribed most frequently. Amoxicillin/beta-lactamase inhibitor, ibuprofen, and paracetamol were the most frequent substances in both primary and hospital care settings. Based on the top 80% prescribed substances, a hit list of 150 pediatric medicines was defined for Austria. CONCLUSION: This is the first representative and comprehensive survey of medicine use in children and adolescents in Austria, allowing comparison of prescription patterns to other European countries and assessing temporal trends in the future. Moreover, it serves as basis for planned measures to improve rational use of pediatric medicines. What is Known: * Large knowledge gaps exist for medicine use in children and adolescents concerning appropriate dosing, efficacy, and safety aspects. * Off-label medicine use is common in the treatment of children and adolescents. What is New: * We present a comprehensive survey of current prescription patterns for children and adolescents in Austria and define a hit list of pediatric medicines, as basis for developing an evidence-based information platform for health care professionals. * Anti-infectives, medicines for respiratory tract system, and pain medication are most frequently prescribed. PMID- 29978259 TI - Analysis of dysphagia in advanced-stage head-and-neck cancer patients: impact on quality of life and development of a preventive swallowing treatment. AB - OBJECTIVES: Swallowing and voice dysfunctions are common side effects following head-and-neck squamous-cell carcinoma (HNSCC) treatment. Our aim was to analyze the relationships between quality of life, swallowing, and phonatory problems in patients with an advanced-stage HNSCC and to prospectively evaluate the effects of a prophylactic swallowing program. METHODS: First, we retrospectively studied 60 advanced HNSCC patients treated with exclusive or adjuvant radiotherapy/chemoradiotherapy (RT/CRT). Subjects were classified according to general and clinical-therapeutic features. Outcome measures included EORTC QLQ C30, EORTC QLQ-H&N35, Dysphagia Handicap Index (DHI), M.D.Anderson Dysphagia Inventory (MDADI), and Voice Handicap Index (VHI). Then, we conducted a prospective evaluation of a prophylactic swallowing counselling in 12 consecutive advanced-stage HNSCC patients by a two-arm case-control analysis. These patients were treated with exclusive or adjuvant RT/CRT. RESULTS: 71% of the retrospective population studied reported swallowing dysfunction as a major side effect. No differences were detected in the severity of dysphagia or dysphonia according to type of treatment or staging of the primary tumour, while hypopharyngeal and laryngeal cancer patients showed significantly better swallowing ability and better QoL compared to oral cavity and oropharyngeal localisation (p < 0.05). In addition, a relevant correlation between swallowing and voice problems emerged (p < 0.05). In the prospective part, while no statistical correlation was evident before the start of RT/CRT in the experimental group compared to the control one, the former showed better performances at MDADI (p = 0.006) and DHI (p = 0.002) test 3 months after its end. CONCLUSION: Dysphagia is both an acute-and-long-term side effect which greatly affects QoL of HNSCC patients undergoing multimodality treatment. Our data show that a prophylactic swallowing program could actually produce a beneficial effect on patients' outcomes. LEVEL OF EVIDENCE: 1b and 2b. PMID- 29978260 TI - Acetaminophen reduces the protein levels of high affinity amino acid permeases and causes tryptophan depletion. AB - In yeast, toxicity of acetaminophen (APAP), a frequently used analgesic and antipyretic drug, depends on ubiquitin-controlled processes. Previously, we showed a remarkable overlap in toxicity profiles between APAP and tyrosine, and a similarity with drugs like rapamycin and quinine, which induce degradation of the amino acid permease Tat2. Therefore, we investigated in yeast whether APAP reduced the expression levels of amino acid permeases. The protein levels of Tat2, Tat1, Mup1 and Hip1 were reduced, while the expression of the general permease Gap1 was increased, consistent with a nutrient starvation response. Overexpression of Tat1 and Tat2, but not Mup1, Hip1 and Gap1 conferred resistance to APAP. A tryptophan auxotrophic strain trp1Delta was more sensitive to APAP than wild-type and addition of tryptophan completely restored the growth restriction of trp1? upon APAP exposure, while tyrosine had an additive effect on APAP toxicity. Furthermore, intracellular aromatic amino acid concentrations were reduced upon APAP exposure. This effect was less prominent in ubiquitin-deficient yeast strains that were APAP resistant and showed a reduced degradation of high affinity amino acid permeases. APAP-induced changes in intracellular amino acid concentrations were also detected in hepatoma HepG2 cells indicating significance for humans. PMID- 29978262 TI - First complete genome sequence of a European non-pathogenic rabbit calicivirus (lagovirus GI.3). AB - We report the full genome sequence of the non-pathogenic rabbit lagovirus Lagovirus europaeus/GI.3/O cun/FR/2006/06-11 (GI.3/06-11), collected from a healthy French domestic rabbit in 2006, and initially described as 06-11 strain. The sequence reveals a genomic organization similar to lagoviruses. It was 7,436 bases long and contained two open reading frames (ORF). A dipeptide variation at the potential p23/2C-like helicase cleavage site (EE instead of ED) was observed, a feature only shared with non-recombinant pathogenic lagoviruses in GI.2 and with two European brown hare syndrome viruses (EBHSV) collected in 1982 in Sweden. GI.3/06-11 has only one initiation codon at the beginning of the ORF2 like the avirulent Italian rabbit calicivirus (RCV) and EBHSV. Previous genetic analyses based on the capsid gene sequences showed that GI.3/06-11 was closer to the RCV and pathogenic lagoviruses GI.1 strains than other lagoviruses. This study, by revealing that GI.3/06-11 genome sequence significantly clustered with pathogenic GI.2 strains, gives prominence of new genetic relationship among lagoviruses and should contribute to understand the emergence of pathogenic strains. PMID- 29978261 TI - Immediate effects of transcutaneous electrical nerve stimulation (TENS) administered during resistance exercise on pain intensity and physical performance of healthy subjects: a randomized clinical trial. AB - PURPOSE: Exercise-induced muscle pain is a self-limiting condition which impacts physical activity habits. Transcutaneous electrical nerve stimulation (TENS) promotes pain reduction and functional improvement in different pain conditions. We propose that applying TENS during exercise might reduce pain and improve physical performance. Thus, we aimed to investigate immediate effects of TENS applied during resistance exercise. METHODS: Healthy subjects of both sexes, irregularly active or sedentary were assigned into two groups: active (n = 24) or placebo (n = 22) TENS. The study was conducted over five moments: on day 0, subjects were recruited, on day 1 subjects performed the one-repetition maximum test (1RM); 72 h later, on day 2, 1RM was retested; 48 h later, on day 3, TENS was applied during a functional-resisted exercise protocol for upper limbs (bench press and rowing), with an intensity of 80% of 1RM; and 24 h after, on day 4, subjects were reevaluated. Assessment included pain intensity at rest and with movement, pressure pain thresholds, and muscle fatigue. RESULTS: TENS did not reduce pain intensity when compared to placebo (p > 0.05). TENS reduce PPT in the latissmus dorsi: p = 0.02 and anterior tibialis: p = 0.04 in immediate reassessment. Immediate effects of TENS were significant for fatigue perception at rest (p = 0.01) and number of maximum repetitions during exercise sets, starting from the 5th set of rowing exercise (p = 0.002). CONCLUSION: Our results show that TENS did not reduce pain perception in healthy individuals, but its use induced increased muscle action, contributing to a greater fatigue perception. PMID- 29978263 TI - Enhancement of epsilon-poly-L-lysine production by overexpressing the ammonium transporter gene in Streptomyces albulus PD-1. AB - The antibacterial polymer E-poly-L-lysine (epsilon-PL) has been widely used as a safe food preservative. As the synthesis of epsilon-PL requires a rich supply of nitrogen, the efficiency of nitrogen translocation and utilization is extremely important. The objective of this study was to improve the production of epsilon PL by overexpressing the ammonium transporter gene amtB in Streptomyces albulus PD-1. Using the recombinant bacteria, the optimum carbon-to-nitrogen ratio in the synthesis stage of fermentation increased from 3 to 4.71, compared with that obtained using the wild-type strain, and the utilization efficiency of ammonium was improved too. Ultimately, the production of epsilon-PL increased from 22.7 to 35.7 g/L upon fed-batch cultivation in a 5 L bioreactor. Determination of the expression of the genes and enzymes associated with ammonium metabolism and epsilon-PL synthesis revealed that the overexpression of amtB in S. albulus PD-1 enhanced epsilon-PL biosynthesis by increasing the activity of the corresponding metabolic pathways. To the best of our knowledge, this is the first report on enhancing epsilon-PL production by overexpression of the amtB gene in an epsilon PL-producing strain. PMID- 29978264 TI - Genetic differentiation in the timing of budburst in Fagus crenata in relation to temperature and photoperiod. AB - Climate change is expected to influence plant productivity particularly through changes in the timing of budburst. Nonetheless, knowledge about the intraspecific variation of the timing of budburst and its relationship with climate is insufficient for most tree species. Based on the common garden experiments of Fagus crenata, we investigated the interrelationships between the day of budburst, cumulative degree-days (temperature sum), chilling duration, and photoperiod at the timing of budburst for the trees of different combinations of 11 sites of seed origin and seven experimental sites in Japan. We found that the relationship between the latitude of experimental sites and the timing of budburst differed for the trees of different latitudes of origins. The timing of budburst was earlier for the trees of more northern populations throughout the latitudes of experimental sites. Variation in the timing of budburst among the trees of different seed origins was smaller for more northern experimental sites. Such patterns were caused by directional changes in the relationships between temperature sum, chilling duration, and photoperiod among the trees of different origins: the asymptotes of the curvilinear relationship between chilling duration and temperature sum, chilling duration and photoperiod, and temperature sum and photoperiod, decreased for more northern populations. With the northward expansion of species distribution, the responses of budburst to climate probably changed genetically in such ways in this species. Our results suggest that intraspecific variations in the relationships between the timing of budburst and associated meteorological factors inevitably influence the overall pattern of the timing of budburst at the geographic scale, and the timing of budburst might deviate from predictions when intraspecific variations are not considered. PMID- 29978265 TI - Colorimetric immunoassay for Listeria monocytogenes by using core gold nanoparticles, silver nanoclusters as oxidase mimetics, and aptamer-conjugated magnetic nanoparticles. AB - The authors describe a rapid colorimetric assay for Listeria monocytogenes (L. monocytogenes) based on the o-phenylenediamine-mediated deaggregation of gold nanoparticles. Silver nanoclusters are used as an artificial enzyme that can oxidize o-phenylenediamine to form o-benzoquinone diamine. Aptamer and IgY antibodies were chosen to conjugate with magnetic beads and silver nanoclusters, respectively, which can recognize and bind L. monocytogenes at different specific binding sites. This results in the disassembly of colloidal gold nanoparticles which is accompanied by a color change from blue to red, with peaks at 730 and 525 nm, respectively. The method allows L. monocytogenes to be colorimetrically determined in the 10 to 106 cfu.mL-1 concentration range without pre-enrichment, and the limit of detection is as low as 10 cfu.mL-1. Recoveries ranging from 97.4 to 101.3% are found when analyzing spiked food samples. The assay is rapid, sensitive and specific. Graphical abstract Schematic illustration of a colorimetric method for detection of L. monocytogenes based on silver nanoclusters-catalyzed oxidation of OPD and de-aggregation of GNPs. A color change from blue to red can be observed and correlated to the concentration of L. monocytogenes. PMID- 29978266 TI - Electronic Properties of Vanadium Atoms Adsorption on Clean and Graphene-Covered Cu(111) Surface. AB - The electronic properties of vanadium atoms adsorbed on clean and graphene covered Cu(111) surface have been systematically studied using ab initio theoretical method. Two coverages (1/9 ML and 1 ML) of vanadium adsorption are considered in this work. Our calculations indicate that V staying underneath the Cu surface is found to be the most stable adsorption site at the aforementioned two coverages for V/Cu(111). However, such adsorption may lead to undesired properties. Therefore, we introduce graphene as a buffer layer to effectively alleviate the direct interaction between V and Cu surface. The calculations show that electronic properties of the original graphene layer are significantly affected by the interactions of C atoms with the V adatoms; the Dirac point of graphene is "destroyed" as a consequence at both coverages. In the V/Gra/Cu(111) system, the interaction between graphene layer and the substrate Cu atoms remains weak as in the Gra/Cu(111) system. Moreover, a relatively low coverage of 1/9 ML gives rise to a spin-polarized system while a non-spin-polarized system is observed at the coverage of 1 ML. This finding offers a new way for the application of vanadium-based materials in reality. PMID- 29978267 TI - Electrical Properties of Midwave and Longwave InAs/GaSb Superlattices Grown on GaAs Substrates by Molecular Beam Epitaxy. AB - In the present work, we report on the in-plane electrical transport properties of midwave (MWIR) and longwave infrared (LWIR) InAs/GaSb type-II superlattices (T2SLs) grown by molecular beam epitaxy (MBE) system on GaAs (001) substrate. The huge lattice mismatch between the T2SL and GaAs substrate is reduced by the growth of GaSb buffer layer based on interfacial misfit array (IMF) technique. In order to compensate the strain in the InAs/GaSb T2SL, we utilized a special shutters sequence to get InSb-like and GaAs-like interfaces. It is found that the MWIR InAs/GaSb T2SL exhibits a p- and n-type conduction at low and high temperatures, respectively. Interestingly, the conduction change temperature is observed to be dependent on the growth temperature. On the other hand, LWIR T2SL conduction is dominated only by electrons. It is important to note that the dominant scattering mechanism in LWIR T2SL at low temperatures is the interface roughness scattering mechanism. PMID- 29978269 TI - Religiosity/Spirituality and Physiological Markers of Health. AB - The long-standing interest in the effects of religiosity and spirituality (R/S) on health outcomes has given rise to a large and diverse literature. We conducted a meta-analysis on research involving R/S and physiological markers of health to elucidate both the scope and mechanism(s) of this phenomenon. A combined analysis found a significant, but small, beneficial effect. Subgroup analyses found that some measures of both extrinsic and intrinsic religiosity were significantly associated with health. Several outcome measures, including blood pressure, C reactive protein, and cardiovascular health markers, were significantly associated with R/S. Our findings suggest that R/S benefits health, perhaps through minimizing the disruptive effects of stress/depression on inflammation. We hope that researchers can use these results to guide efforts aimed at elucidating the true mechanism(s) linking religious/spiritual beliefs and physical health. PMID- 29978270 TI - Implications of the Red Beet Ripening on the Colour and Betalain Composition Relationships. AB - The evolution during ripening of Beta vulgaris (var. Pablo) on colour and betalain composition, not previously conducted in conjunction in red beets, has been examined. According to the results, it could be asserted that the ripening stage significantly (p < 0.05) influenced on all the studied parameters. On the basis of the betalain content, the optimum ripening stage corresponded to a medium weigh-to-calibre ratio, in the light of the significantly (p < 0.05) higher content of betalains, especially betanin and vulgaxanthin I. Moreover, colour attributes also differed during ripening, having the medium-ripened beetroots a significantly (p < 0.05) more reddish hue (hab) and lower lightness (L*), probably due to the higher content of betaxanthins in this stage. The colour differences among red beets in the stage II and the rest of stages were visually appreciable (DeltaE*ab > 3) and mainly qualitative. A new range of opportunities for diversification of colorant market, from a nutritional and colorimetric point of view, could be possible by employing red beets with different stages of ripening. PMID- 29978268 TI - Evaluating the effect of photobiomodulation with a 940-nm diode laser on post operative pain in periodontal flap surgery. AB - The aim of this study was to evaluate the efficacy of low-power of 940-nm diode laser on post-operative pain after undisplaced flap surgery. This randomized clinical trial study was conducted using a split-mouth design. The study participants comprised 30 patients who needed periodontal flap surgery for periodontal pockets on the same tooth on both sides of the mandible. One side of the mandible was subjected to undisplaced flap surgery plus treatment with a 940 nm diode laser, and on the contralateral side, the surgery was conducted without applying the laser. Patients received anti-inflammatory medication and analgesics after surgery. The patients were asked to report the number of analgesics they took and the pain they experienced each night for 1 week using a visual analogue scale. An independent-sample t test was used to compare the results between the two groups. Patients reported less pain on days 2, 3, 4, 5, 6, and 7 after surgery in the laser-treated group (p < 0.05). Furthermore, fewer analgesics were used in this group on days 3, 4, 5, 6, and 7 following the surgery (p < 0.05). The 940-nm diode laser with the settings used in this study could significantly reduce pain and the number of analgesics taken by patients after undisplaced flap surgery. PMID- 29978271 TI - The efficacy of intracerebroventricular idursulfase-beta enzyme replacement therapy in mucopolysaccharidosis II murine model: heparan sulfate in cerebrospinal fluid as a clinical biomarker of neuropathology. AB - Mucopolysaccharidosis II (MPS II) is caused by a deficiency of iduronate-2 sulfatase that results in accumulation of glycosaminoglycans (GAG), including heparan sulfate (HS), which is considered to contribute to neuropathology. We examined the efficacy of intracerebroventricular (ICV) enzyme replacement therapy (ERT) of idursulfase-beta (IDS-beta) and evaluated the usefulness of HS as a biomarker for neuropathology in MPS II mice. We first examined the efficacy of three different doses (3, 10, and 30 MUg) of single ICV injections of IDS-beta in MPS II mice. After the single-injection study, its long-term efficacy was elucidated with 30 MUg of IDS-beta ICV injections repeated every 4 weeks for 24 weeks. The efficacy was assessed by the HS content in the cerebrospinal fluid (CSF) and the brain of the animals along with histologic examinations and behavioral tests. In the single-injection study, the 30 MUg of IDS-beta ICV injection showed significant reductions of HS content in brain and CSF that were maintained for 28 days. Furthermore, HS content in CSF was significantly correlated with HS content in brain. In the long-term repeated-injection study, the HS content in the brain and CSF was also significantly reduced and correlated. The histologic examinations showed a reduction in lysosomal storage. A significant improvement in memory/learning function was observed in open-field and fear-conditioning tests. ICV ERT with 30 MUg of IDS-beta produced significant improvements in biochemical, histological, and functional parameters in MPS II mice. Furthermore, we demonstrate for the first time that the HS in the CSF had significant positive correlation with brain tissue HS and GAG levels, suggesting HS in CSF as a useful clinical biomarker for neuropathology. PMID- 29978272 TI - Renal Disease in Chronic Granulomatous Disease: Data from the USIDNET Registry. PMID- 29978274 TI - Social Media: The Unnamed Plaintiff. PMID- 29978275 TI - Testing for center effects on survival and competing risks outcomes using pseudo value regression. AB - In multi-center studies, the presence of a cluster effect leads to correlation among outcomes within a center and requires different techniques to handle such correlation. Testing for a cluster effect can serve as a pre-screening step to help guide the researcher towards the appropriate analysis. With time to event data, score tests have been proposed which test for the presence of a center effect on the hazard function. However, sometimes researchers are interested in directly modeling other quantities such as survival probabilities or cumulative incidence at a fixed time. We propose a test for the presence of a center effect acting directly on the quantity of interest using pseudo-value regression, and derive the asymptotic properties of our proposed test statistic. We examine the performance of our proposed test through simulation studies in both survival and competing risks settings. The proposed test may be more powerful than tests based on the hazard function in settings where the center effect is time-varying. We illustrate the test using a multicenter registry study of survival and competing risks outcomes after hematopoietic cell transplantation. PMID- 29978273 TI - Human peripheral blood-derived mesenchymal stem cells with NTRK1 over-expression enhance repairing capability in a rat model of Parkinson's disease. AB - The potency of mesenchymal stem cells (MSCs) for tissue repair and regeneration is mainly based on their ability to secret beneficial molecules. Administration of MSCs has been proposed as an innovative approach and is proved by a number of clinical trials to a certain degree for the therapy of many diseases including Parkinson's disease (PD). However, the efficacy of MSCs alone is not significant. We investigated the effect of neurotrophic tyrosine receptor kinase 1 (NTRK1) overexpressed peripheral blood MSCs (PB-MSCs) on PD rat model. NTRK1 was overexpressed in PB-MSCs, which were then injected into PD rat model, Dopaminergic (DA) neuron regeneration and rotational performance was assessed. We found that DA neuron repair was increased in lesion site, rotational performance was also improved in MSC transplanted PD rat, with most potent effect in NTRK1 overexpressed PB-MSC transplanted PD rat. Our results indicate that overexpression of NTRK1 in MSCs could be an optimized therapeutic way via MSCs for PD treatment. PMID- 29978276 TI - The effects of different injection techniques of botulinum toxin a in post-stroke patients with plantar flexor spasticity. AB - The purpose of this study was to compare the effects of different injection technique guidance with electrical stimulation (ES) vs ultrasonography (USG) of botulinum toxin A injection (BoNT A) in post-stroke patients with plantar flexor spasticity. Forty chronic post-stroke patients with plantar flexor spasticity and who were able to walk were included in the study. They were randomized into two groups: in 20 patients the BoNT A injection was applied with the guidance of ES and in 20 patients with the guidance of USG by the same physician. Gastrocnemius, soleus, and tibialis posterior were injected. Spasticity was evaluated by ashworth scale; the functional status was evaluated by ankle goniometry for range of motion, Brunnstrom stages, Barthel Index, and 10-m walk test before the treatment, 2nd week, and 3rd month after the treatment. Statistical significance was defined as p < 0.05. Two groups were similar in respect to demographical and clinical features. In both groups, walking speed and range of motion increased significantly after the treatment. When the two groups were compared at 3rd month after the treatment; range of motion of the ankle joint plantar flexion and dorsiflexion when knee in extension showed a significant difference between the two groups. Ashworth scale, Brunnstrom stages, Barthel index, walking speed tests, and other ankle goniometry for range of motion showed no statistically significant difference between two groups. We can conclude that USG and ES guidence are both effective injection techniques when applying BoNT A to ankle plantar flexor muscles. PMID- 29978278 TI - Awake craniotomy using dexmedetomidine and scalp blocks: a retrospective cohort study. AB - PURPOSE: Anesthetic and surgical considerations for awake craniotomy (AC) include airway patency, patient comfort, and optimization of real-time brain mapping. The purpose of this study is to report our experience of using dexmedetomidine and scalp blocks, without airway intervention, as a means to facilitate and optimize intraoperative brain mapping and brain tumour resection during AC. METHODS: We conducted a retrospective cohort study of 55 patients who underwent AC from March 2012 to September 2016. The incidence of critical airway outcomes, perioperative complications, and successful intraoperative mapping was determined. The primary outcome was the incidence of a failed AC anesthetic technique as defined by the need to convert to general anesthesia with a secured airway prior to (or during) brain mapping and brain tumour resection. Secondary outcomes were the intraoperative incidence of: 1) altered surgical management due to information acquired through real-time brain mapping, 2) interventions to restore airway patency or rescue the airway, 3) hemodynamic instability (> 20% from baseline), 4) nausea and vomiting, 5) new onset neurologic deficits, and 6) seizure activity. RESULTS: There were no anesthesia-related critical events and no patients required airway manipulation or conversion to a general anesthetic. Multimodal language, motor, and sensory assessment with direct cortical electrical stimulation was successfully performed in 100% of cases. In 24% (13/55) of patients, data acquired during intraoperative brain mapping influenced surgical decision-making regarding the extent of tumour resection. Nine (16%) patients had intraoperative seizures. CONCLUSIONS: Dexmedetomidine-based anesthesia and scalp block facilitated AC surgery without any requirement for urgent airway intervention or unplanned conversion to a full general anesthetic. This approach can enable physiologic testing before and during tumour resection facilitating real-time surgical decision-making based on intraoperative brain mapping with patients awake thereby minimizing the risk of neurologic deficit and increasing the opportunity for optimal surgical resection. PMID- 29978277 TI - Transcriptome analysis reveals candidate genes involved in splay leg syndrome in piglets. AB - Splay leg is frequently observed in newborn piglets and leads to economic loss as well as welfare concerns. However, the etiology and pathogenesis of splay leg syndrome in piglets are still poorly understood. The aims of this paper were to characterize changes in the transcriptome of splay leg piglets and identify candidate genes responsible for this disease. We chose three splay leg piglets and their healthy full sibs, and constructed six RNA libraries using skeletal muscle samples from both groups and identified the differentially expressed genes between the two groups using RNA-seq. A total of 555 differentially expressed genes were identified, of which 216 were up-regulated and 339 genes were down regulated in the splay leg group relative to the healthy group. In addition, 321 significantly enriched GO terms and 12 significantly enriched KEGG pathways were identified. FBXO32 is one of the ten most differentially expressed genes in our experiment, and it is regulated by the significantly enriched pathway (PI3K-Akt). The overexpression of FBXO32 which leads to the process of muscle atrophy might be responsible for congenital splay leg in piglets. The result of this study could help improve understanding of the molecular mechanism of congenital splay leg syndrome. PMID- 29978279 TI - Challenges and Perspectives to the Rise in General Psychiatry Residency Applications. PMID- 29978280 TI - Processing order in dual-task situations: The "first-come, first-served" principle and the impact of task order instructions. AB - When two overlapping tasks are processed, they hit a bottleneck at a central processing stage that prevents simultaneous processing of the two tasks. Thus far, however, the factors determining the processing order of the tasks at the bottleneck are unknown. The present study was designed to (re)investigate whether the arrival times of the two tasks at the central bottleneck are a key determinant of the processing order (cf. Sigman & Dehaene, 2006). To this end, we implemented a visual-auditory dual task with a random stimulus order, in which we manipulated arrival time by prolonging the initial, perceptual processing stage (stimulus analysis) of the visual task and compared the effects of this manipulation with those of one impacting the central bottleneck stage of the visual task. Additionally, we implemented two instruction conditions: Participants were told to respond either in the order of stimulus presentation or in the order they preferred. The manipulation of the visual perception stage led to an increase in task response reversals (i.e., the response order was different from the order of stimulus presentation), whereas there was no such increase when the bottleneck stage was manipulated. This pattern provides conclusive evidence that the processing order at the bottleneck is (at least in part) determined by the arrival times of the tasks at that point. Reaction time differences between the two instruction conditions indicated that additional control processes are engaged in determining task processing order when the participants are expressly told to respond in the order of stimulus presentation. PMID- 29978281 TI - Improved accuracy of mandible geometry reconstruction at the stage of data processing and modeling. AB - The article presents a comparative study of influence of the Lanczos resampling filter on improving the accuracy of reconstruction of mandible geometries. The research was performed on eight different patients. Digital Imaging and Communications in Medicine data were obtained on the Siemens Somatom Sensation Open 40 scanner. At the stage of reconstruction, the same parameters were utilized, while only slice thickness was changed. Modeling with voxel dimensions of 0.4 mm * 0.4 mm * 1.5 mm was chosen as the gold standard over the modeling approach comprising voxel dimensions of 0.4 mm * 0.4 mm * 3.0 mm and improved using the Lanczos resampling filter. The influence of the Lanczos resampling filter on the accuracy of reconstruction of mandible geometry is very similar for the eight presented patients. The average results show a distribution with a positive skew and kurtosis. The value of skewness is 0.713 and kurtosis is 4.221 for the model without Lanczos filtering applied. When the Lanczos filtering is applied the value of skewness is 0.542 and kurtosis is 4.313. Based on 95% confidence, changes in layer thickness from 1.5 mm to 3 mm generated errors reconstructing the geometry of the mandible at the value of 0.153 mm +/- 1.209 mm. In models improved using the Lanczos resampling filter, the errors generated in reconstructing the geometry of the mandible were minimized at the value of 0.160 mm +/- 1.007 mm. The presented research highlights new opportunities to improve the accuracy of reconstruction geometry of the mandible at the stage of data processing. PMID- 29978282 TI - Sensitive determination of Hg(II) based on a hybridization chain recycling amplification reaction and surface-enhanced Raman scattering on gold nanoparticles. AB - A method was developed for the determination of mercuric ion Hg(II). It is based on hybridization chain reaction (HCR) and surface-enhanced Raman scattering (SERS). Raman signal DNA and streptavidin were self-assembled on gold nanoparticles as a novel signal nanoprobe (AuNP-sDNA). A thymine-mercury(II) thymine structure was immobilized on magnetic beads (MBs). The HCR makes use of two hairpin probes that are initiated by the trigger DNA to form a stable nicked dsDNA structure (MB-TS-hDNAs). A large number of the binding sites is provided to connect the signal nanoprobe. The stable sandwich structure (MB-TS-hDNA/AuNP sDNA) was isolated by applying a magnetic field and used in the amplification step. In this way, Hg(II) can be determined sensitively after multiple signal amplification. The SERS signal, measured at 1499 cm-1, increases linearly in the 0.1 pM to 10 nM Hg(II) concentration range, and the limit of detection is 0.08 pM (at an S/N ratio of 3). The method was applied to the detection of Hg(II) in spiked environment water samples, with recoveries ranging from 96 to 119%. Graphical abstract Schematic of a method based on the use of a stable T-Hg(II)-T structure and a self-assembled nanoprobe. It was applied to the trace Hg(II) detection based on hybridization chain reaction (HCR) and surface-enhanced Raman scattering (SERS). PMID- 29978283 TI - Effects of sulfuric and vinyl sulfonic acid etchants on bond strength of resin composite to polyetherketoneketone. AB - This study aims to evaluate the effects of etching with sulfuric acid (SA) and vinyl sulfonic acid (VSA) on the bond strength between a light-curing indirect resin composite and polyetherketoneketones (PEKK). PEKK specimens were ground with 600 silicon carbide papers, etched with 90% SA for 5 s (90-5 SA) or 95% VSA for 30 s (95-30 VSA), and then modified with a phosphate primer; afterward, a light-curing resin composite was veneered on the specimens. Two control groups were also prepared without etching (unetched/unprimed and unetched/primed). After 20,000 thermocycles in water at 4 and 60 degrees C, the shear bond strengths of the specimens were determined and subjected to a nonparametric (Steel-Dwass) test (alpha = 0.05, n = 8). The etched surfaces were observed by scanning electron microscopy (SEM) at 2000* magnification. Higher bond strengths were obtained when the PEKK surface was etched with 90-5 SA or 95-30 VSA (90-5 SA/unprimed 24.3 +/- 4.3 MPa, 90-5 SA/primed 26.2 +/- 3.2 MPa, 95-30 VSA/unprimed 23.7 +/- 2.5 MPa, 95 30 VSA/primed 24.3 +/- 4.1 MPa), and these values were not statistically different, whereas the two control groups exhibited significantly lower bond strengths (unetched/unprimed 12.2 +/- 1.7 MPa, unetched/primed 9.5 +/- 2.7 MPa). SEM observations revealed that 95-30 VSA led to a microporous (felt-like) surface, which was different from the surface structure etched with 90-5 SA. Etching the PEKK surface with SA or VSA significantly improved the bond strength between resin composite and PEKK in contrast with the application of the phosphate primer. Appropriate chemical etching could be a useful option when fabricating prostheses using PEKK-based materials and indirect resin composites. PMID- 29978285 TI - Cytotoxic T-lymphocyte-associated antigen 4-positive aggressive adult T cell leukemia/lymphoma. PMID- 29978284 TI - Rabbit antithymocyte globulin dose does not affect response or survival as first line therapy for acquired aplastic anemia: a multicenter retrospective study. AB - In a prospective randomized study, treatment for aplastic anemia (AA) with rabbit antithymocyte globulin (r-ATG) and cyclosporine showed inferior hematological response and survival in comparison to horse antithymocyte globulin (h-ATG) and cyclosporine. However, h-ATG was discontinued in most Asian, South American, and European countries, where r-ATG became the only ATG formulation available. We retrospectively evaluated consecutive patients with acquired AA who received either rabbit (n = 170) or horse (n = 85) ATG and cyclosporine for first-line treatment from 1992 to 2014 in seven referral centers in Brazil and Argentina. Overall response at 3 months was 17% (95%CI, 11-23%) for r-ATG and 44% (95%CI, 33 55%) for h-ATG (p < 0.001). At 6 months, it was 31% (95%CI, 34-39%) for r-ATG and 59% (95%CI, 48-69%) for h-ATG (p < 0.001). Overall survival at 5 years was 57% (95%CI, 47-65%) for r-ATG and 80% (95%CI, 69-87%) for h-ATG (log-rank = 0.001). Relapse was significantly higher in patients receiving h-ATG (28%; 95%CI, 17-43%) as compared to r-ATG (9.4%; 95%CI, 4-21%; log-rank, p = 0.01). The type of ATG was the only factor associated with both response and survival. The r-ATG dose varied from 1 to 5 mg/kg/day, but it did not correlate with outcomes. In summary, this is the largest multicenter study comparing the two ATG formulations in AA. Our results indicate that the dose of r-ATG does not influence hematologic response or survival in first-line therapy for acquired AA. Considering the toxicity and costs of r-ATG, our findings challenge its aggregate benefit to cyclosporine therapy and further strengthen that h-ATG should remain standard therapy in AA. PMID- 29978287 TI - Alternative Low-Cost Additives to Improve the Saccharification of Lignocellulosic Biomass. AB - A potential strategy to mitigate problems related to unproductive adsorption of enzymes onto lignin during the saccharification of lignocellulosic biomass is the addition of lignin-blocking agents to the hydrolysis reaction medium. However, there is a clear need to find more cost-effective additives for use in large scale processes. Here, selected alternative low-cost additives were evaluated in the saccharification of steam-exploded sugarcane bagasse using a commercial enzymatic cocktail. The addition of soybean protein, tryptone, peptone, and maize zein had positive effects on glucose release during the hydrolysis, with gains of up to 36% when 8% (w/w) soybean protein was used. These improvements were superior to those obtained using bovine serum albumin (BSA), a much more expensive protein that has been widely reported for such an application. Moreover, addition of soybean protein led to a saving of 48 h in the hydrolysis, corresponding to a 66% decrease in the reactor operation time required. In order to achieve the same hydrolysis yield without the soybean additive, the enzyme loading would need to be increased by 50%. FTIR spectroscopy and nitrogen elemental analysis revealed that the additives probably acted to reduce unproductive binding of cellulolytic enzymes onto the lignin portion of the sugarcane bagasse. PMID- 29978286 TI - Allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia with 11q23 abnormality: a retrospective study of the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). AB - An 11q23 abnormality presents in approximately 5% of adults with acute myeloid leukemia (AML) and is associated with adverse outcomes even after allogeneic hematopoietic cell transplantation (allo-HCT). To evaluate the outcomes and prognostic factors following allo-HCT for adult AML with 11q23 abnormality, we retrospectively analyzed the Japanese registration data of 322 adult AML patients with 11q23 abnormality who had received allo-HCT between 1990 and 2014. In total, the disease status at HCT was first complete remission (CR1) in 159 (49%) patients. The probability of overall survival and the cumulative incidence of relapse at 3 years were 44 and 44%, respectively. In the multivariate analysis, disease status beyond CR1 at the time of HCT was significantly associated with a higher overall mortality and relapse. The 11q23 fusion partner did not have a significant impact on survival. We also evaluated the prognostic value of minimal residual disease (MRD) status at HCT on transplant outcomes among hematological CR patients. MRD status at HCT was the significant prognostic indicator for hematological relapse and survival. These data suggested that allo-HCT offered a curative option for adult AML with 11q23 abnormality. Pretransplant MRD status was the significant prognostic indicator for relapse and survival in CR patients. PMID- 29978288 TI - Removal of Fat Components in High TDS Leather Wastewater by Saline-Tolerant Lipase-Assisted Nanoporous-Activated Carbon. AB - The present investigation was carried out for the degradation of fatty components in high TDS containing wastewater (soak liquor) discharged from leather industry, and the degradation was achieved by saline-tolerant lipase-immobilized functionalized nanoporous-activated carbon (STLNPAC). The lipase was extracted from the halophilic organism, Bacillus cereus. The optimum conditions for lipase production such as time, 60 h; temperature, 50 degrees C; pH, 10; and substrate concentration, 2.5% (w/v) were determined through response surface methodology (RSM). The functionalization of NPAC was done by ethylenediamine/glutaraldehyde covalent interaction technique followed by the immobilization of saline-tolerant lipase onto FNPAC. The functional properties of STLNPAC were analyzed through instrumentation techniques such as TGA-DSC, FT-IR, XRD, and SEM images. The lipid content of soak liquor was removed by > 99% at HRT of 60 min using STLNPAC-packed bed reactor. The efficiency was evaluated by using UV-visible and FT-IR spectroscopic analyses. The degradation of lipids was best obeyed by pseudo first order rate kinetics, and the rate constant was found to be 1.6 * 10-3 min-1. The biodegradability index of soak liquor was increased from 0.322 to 0.426, highly favorable for the complete removal of organic components in subsequent operations. PMID- 29978289 TI - A terbium-based metal-organic framework@gold nanoparticle system as a fluorometric probe for aptamer based determination of adenosine triphosphate. AB - This study reports on a method for fluorometric aptasensing of adenosine triphosphate (ATP). It is based on the interaction of dispersed (red) and agglomerated (blue) gold nanoparticles (AuNPs) with a water-dispered terbium(III) based metal-organic framework (Tb-MOF). The dispersed AuNPs quench the emissions of the Tb-MOF, while the aggregated AuNPs have little effect. Under the condition of high salt concentration, the free aptamer against ATP does not stabilize the AuNPs against aggregation. This causes a color change from red to blue and weak quenching of the fluorescence of the Tb-MOF (with peaks at 489 nm and 544 nm after excitation at 290 nm). On addition of ATP, it will be bound by its aptamer to form a complex that is adsorbed on the AuNPs. This protects the AuNPs from salt-induced aggregation and the color (with a peak at 525 nm) remains red. The two fluorescence bands of the Tb-MOF are therefore suppressed by fluorescence resonance energy transfer (FRET) between Tb-MOF and the dispersed AuNPs. Fluorescence drops linearly in the 50 nM to 10 MUM ATP concentration range, and the detection limit is 23 nM. ATP analogs such as guanosine triphosphate, uridine triphosphate, cytidine triphosphate, adenosine monophosphate and cyclic adenosine monophosphate have no obvious interference. The method was successfully applied to the determination of ATP in (spiked) human plasma samples and gave satisfactory recoveries. Graphical abstract Schematic of a terbium-based metal organic framework@gold nanoparticle system as a fluorometric probe for aptamer based determination of adenosine triphosphate. The dispersed gold nanoparticles (AuNPs) quench the fluorescence of the terbium-based metal-organic framework (Tb MOF), while the aggregated AuNPs have little effect. In the presence of adenosine triphosphate (ATP), the aptamer-ATP complexes provide greater protection towards AuNPs than aptamer alone under high salt condition. Based on this, a novel Tb MOF@AuNP platform is established for ATP detection. PMID- 29978290 TI - Pluronic-Based Mixed Polymeric Micelles Enhance the Therapeutic Potential of Curcumin. AB - Curcumin is a naturally occurring constituent of turmeric that is a good substitute for synthetic medicines for the treatment of different diseases, due to its comparatively safer profile. However, there are certain shortcomings that limit its use as an ideal therapeutic agent. In order to overcome these drawbacks, we prepared novel curcumin-loaded mixed polymeric micelles using different biocompatible polymers by the thin-film hydration method. We investigated the critical micelle concentration and temperature, drug loading and encapsulation efficiency, and minimum inhibitory concentration by spectrophotometry. Surface morphology, stability, particle size, drug-polymer interaction, and physical state of the prepared formulations were investigated using scanning electron microscopy, zeta potential, particle size analyzer, Fourier-transform infrared spectroscopy, and X-ray diffraction, respectively. The drug loading and entrapment efficiency were significantly increased (P < 0.01) when curcumin was encapsulated with pluronic-based mixed polymeric micelles as compared to that of pluronic-based micelles alone. In vitro studies exhibited that pluronic-based mixed polymeric micelles significantly increased anticancer (P < 0.01), antimicrobial (P < 0.001), antioxidant (P < 0.001), and alpha-amylase inhibitory (P < 0.001) activities when compared to pure curcumin and/or pluronic based micelles alone. These findings suggest that the formation of mixed polymeric micelles increases the stability and solubility of curcumin. PMID- 29978291 TI - The Effects of Curing and Casting Methods on the Physicochemical Properties of Polymer Films. AB - Most film coatings in the pharmaceutical industry are prepared using organic solvents or aqueous solvents. Due to different film-formation mechanisms, their properties are significantly different from each other. Curing can alter the microstructure of films by improving the coalescence of polymer particles for aqueous dispersion-based films or accelerating macromolecule relaxation for organic solvent-based films. The aim of this study was to investigate the effects of preparation methods and curing on the physicochemical properties of Kollicoat(r) SR30D and Kollicoat(r) MAE100P films. The film's properties, including water diffusion coefficient, mechanical properties, plasticizer loss, swelling behavior, and contact angle, were measured for uncured or cured aqueous dispersion-based or organic solvent-based films. The results indicated that curing decreased water diffusivities in films and increased film's tensile strength. Curing resulted in plasticizer loss from SR30D films but not from MAE100P films due to strong interaction between plasticizer and MAE100P. The surface of organic solvent-based films was more hydrophobic than that of aqueous dispersion-based films. The contact angle of organic solvent-based films was increased after curing possibly because curing decreased roughness of the film surface. Organic solvent-based SR30D films had better mechanical properties than the corresponding aqueous dispersion-based films because of higher degree of polymer-polymer entanglement in the organic solvent-based films. However, contradictory phenomena were observed in MAE100P films possibly due to a "core shell" structure reserved in the aqueous dispersion-based MAE100P films. In summary, casting methods and curing have significant impact on the film properties due to different film structures, coalescence, or film relaxation, and other concurrent effects including evaporation of residue solvent and plasticizers. PMID- 29978292 TI - Hydroxypropyl-beta-Cyclodextrin and beta-Cyclodextrin as Tablet Fillers for Direct Compression. AB - Cyclodextrins are cyclic carbohydrates widely used as complexing and non complexing excipients in drug delivery systems. The purpose of this work was to study the ability of hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin to act as tablet fillers for direct compression. In this way, several parameters of the cyclodextrins were evaluated, namely: (i) the flow properties such as angle of repose, flow time, Carr index, and Hausner ratio; (ii) the compaction behavior, specifically the energies and forces exerted during tableting, the plasticity index, the lubrication efficiency, and compression profiles (force/time and work/displacement of the upper punch); and (iii) the influence on carbamazepine release characteristics from uncoated tablets, i.e., dissolution rate and disintegration time. In addition, these properties of the cyclodextrins were compared with those from other commonly used direct compression fillers (lactose monohydrate, mannitol, calcium hydrogen phosphate dihydrate, and microcrystalline cellulose) and co-processed excipients (microcrystalline cellulose/mannitol and lactose monohydrate/cellulose). Three main conclusions can be drawn: (i) the studied cyclodextrins can be used as tablet fillers for direct compression; (ii) hydroxypropyl-beta-cyclodextrin showed better properties than beta-cyclodextrin mainly at the level of the physics of compression (higher values of plasticity index and lubrication efficiency) and of the drug release characteristics (faster and greater dissolution rate and a shorter disintegration time); and (iii) lactose monohydrate and hydroxypropyl-beta-cyclodextrin displayed the best results. As there are people intolerant to lactose, hydroxypropyl-beta cyclodextrin, although its cost is higher, can be considered a good substitute for lactose. PMID- 29978294 TI - Preoperative sonographic evaluation of the defect size and the diaphragm rim in congenital diaphragmatic hernia - preliminary experience. AB - BACKGROUND: Sonographic assessment before congenital diaphragmatic hernia repair has rarely been studied. OBJECTIVE: To evaluate the accuracy of preoperative ultrasound in measuring the defect size and in anticipating the presence of a rim and thereby to determine ultrasound's usefulness in informing the surgical approach for definitive repair of congenital diaphragmatic hernia. MATERIALS AND METHODS: We performed a retrospective review of the medical records of seven children with left congenital diaphragmatic hernia who had undergone ultrasound and definitive repair between 2014 and 2017 at our institution. RESULTS: The estimated defect size by ultrasound to the actual defect size measured intraoperatively for each case were as follows: 23 * 25 mm to 20 * 26 mm (case 1); 23 * 30 mm to 20 * 30 mm (case 2); 43 * 25 mm to 30 * 30 mm (case 3); 21 * 23 mm to 20 * 25 mm (case 4); 19 * 24 mm to 10 * 30 mm (case 5); 32 * 33 mm to 30 * 50 mm (case 6); and almost total absence to 40 * 50 mm (case 7). Presence or absence of each part of the diaphragm rim evaluated by ultrasound was almost identical with the actual intraoperative findings. According to the ultrasound findings, we performed a successful thoracoscopic repair in cases 1-5 with relatively small defects and presence of all parts of the rim or absence of only posterolateral rim. CONCLUSION: There was good concordance between ultrasound findings and operative findings regarding the size of the defect and presence or absence of the diaphragm rim. PMID- 29978293 TI - Utility of physiologically based pharmacokinetic (PBPK) modeling in oncology drug development and its accuracy: a systematic review. AB - PURPOSE: Physiologically based pharmacokinetic (PBPK) modeling, a mathematical modeling approach which uses a pharmacokinetic model to mimick human physiology to predict drug concentration-time profiles, has been used for the discover and development of drugs in various fields, including oncology, since 2000. There have been a few general review articles on the utilization of PBPK in the development of oncology drugs, but these do not include an evaluation of model prediction accuracy. We therefore conducted a systematic review to define the accuracy of PBPK model prediction and its utility throughout all the developmental phases of oncology drugs. METHODS: A systematic search was performed in the PubMed, PubMed Central and Cochrane Library databases from 1980 to February 2017 for articles (1) written in English, (2) focused on oncology or antineoplastic or anticancer drugs, tumor or cancer or anticancer drugs listed in the U.S. National Institutes of Health and (3) involving a PBPK model. The absolute-average-folding-errors (AAFEs) of the area under the curve (AUC) between predicted and observed values in each article were calculated to assess model prediction accuracy. RESULTS: Of the 2341 articles initially identified by our search of the databases, 40 were included in the review analysis. These articles reported on six types of studies, i.e. in vivo (n = 4), first-in-human (n = 5), phase II/III clinical trials (n = 9), organ impairment (n = 3), pediatrics (n = 4) and drug-drug interactions (n = 15). AAFEs of the predicted AUC for all groups of studies were within 1.3-fold of each other despite variations in experimental methodologies. CONCLUSION: PBPK modeling is a potential tool which can be effectively applied throughout all phases of oncology drug development. The number of experimental animals and human participants enrolled in the studies can be reduced using PBPK modeling and PBPK-population-PK modeling. The limited number of publications of unsuccessful model application to date may contribute to bias toward the usefulness of modeling. PMID- 29978295 TI - Modified Friedman technique: a new proposed method of measuring glenoid version in the setting of glenohumeral dysplasia. AB - BACKGROUND: Glenoid version angles are measured to objectively follow changes related to glenohumeral dysplasia in the setting of brachial plexus birth palsy. Measuring glenoid version on cross-sectional imaging was initially described by Friedman et al. in 1992. Recent literature for non-dysplastic shoulders advocates time-consuming reconstructions and reformations for an accurate assessment of glenoid version. OBJECTIVE: To compare Friedman's original method for measuring glenoid version to a novel technique we developed ("modified Friedman") with the reference standard of true axial reformations. MATERIALS AND METHODS: With institutional review board approval, we retrospectively examined 30 normal and dysplastic shoulders obtained from magnetic resonance imaging examinations of 30 patients with an established diagnosis of brachial plexus birth palsy between January 2012 and September 2017. Four pediatric radiologists performed glenoid version measurements using Friedman's method, the modified Friedman method and a previously described true axial reformation method. The modified Friedman technique better accounts for scapular positioning by selecting a reference point related to the acromion-scapular body interface. Inter-rater reliability and inter-method agreement were assessed using intraclass correlation, paired t-tests and mixed linear model analysis. Equivalence tests between methods were performed per reader. RESULTS: Glenoid version measurements were significantly different when comparing Friedman's method to true axial reformations in normal (-10.8+/ 5.7 degrees [mean+/-standard deviation] vs. -8.8+/-5.3 degrees ; P<=0.001) and dysplastic shoulders (-34.6+/-17.7 degrees vs. -28.1+/-17.5 degrees ; P<=0.001). Glenoid version measurements were not significantly different when comparing the modified Friedman's method to true axial reformations in normal (-6.3+/-5.8 degrees vs. -8.8+/-5.3 degrees ; P=0.06) and dysplastic shoulders (-29.0+/-18.3 degrees vs. -28.1+/-17.5 degrees ; P=0.06). Friedman's method was not equivalent to true axial reformations for measurements in dysplastic shoulders for all readers (P=0.68, 0.81, 0.86, 0.99); the modified Friedman method was equivalent to of true axial reformations for measurements in dysplastic shoulders for 3 of 4 readers (P<=0.001, P<=0.001, P<=0.001, P=0.10). CONCLUSION: In glenohumeral dysplasia, the modified Friedman method and post-processed true axial reformations provide statistically similar and reproducible values. We propose that our modified Friedman technique can be performed in lieu of post-processed true axial reformations to generate glenoid version measurements. PMID- 29978296 TI - Severe ketoacidosis in a patient with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a genetic neuromuscular disease characterized by progressive muscle weakness and atrophy. We report a case of a 36-year-old man with SMA type 3 who presented to our emergency department with epigastric pain and vomiting. He was found to have severe ketoacidosis on laboratory evaluation. The patient's symptoms and ketoacidosis resolved after dextrose infusion and a relatively small amount of sodium bicarbonate infusion. Given the severity of the ketosis that seemed inconsistent with moderate starvation alone, we postulate that there must have been other contributing factors besides moderate starvation that might explain the severity of acidosis in this particular patient. These factors include low muscle mass, disturbed fatty acid metabolism, hormonal imbalances and defective glucose metabolism. Ketoacidosis is an under-recognized entity in patients with neuromuscular diseases and requires a high index of suspicion for prompt diagnosis and management. PMID- 29978297 TI - Rare skeletal muscle metastasis from renal cell carcinoma: case report and review of the literature. AB - Renal cell carcinoma (RCC) is a tumor that usually metastasizes to lung, liver, bone and brain, but rarely to skeletal muscles. We report a case of an elderly man with a history of bilateral metachronous RCC for which he underwent curative bilateral nephrectomies and renal transplantation, was in remission, and presented with a large solitary skeletal muscle metastasis from the initial RCC, 3 years later. PMID- 29978298 TI - Ultrasound-guided left lateral transversus abdominis plane block combined with rectus sheath block in peritoneal dialysis catheter placement. AB - This study assessed the utility of ultrasound-guided lateral transversus abdominis plane (TAP) block combined with rectus sheath (RS) block for peritoneal dialysis catheter placement surgery. Thirty consecutive patients with end-stage renal disease scheduled to have peritoneal dialysis catheter placement received a left lateral TAP block combined with RS block performed under ultrasound guidance. The TAP and RS blocks were, respectively, conducted with 15 ml of 0.5% ropivacaine and 10 ml of 0.5% ropivacaine. Pain intensity was evaluated by verbal rating scale during operation, and the degree of patient and surgeon satisfaction was qualified by a categorical scale. Twenty-nine patients received successful blocks without any other adjuvant anesthetic drugs. One patient required rescue analgesia with lidocaine infiltration. No complications related to regional anesthesia were noted. Ultrasound-guided left lateral TAP block combined with RS block can serve as the primary anesthetic modality for peritoneal dialysis catheter placement surgery. PMID- 29978300 TI - Reversible cerebral vasoconstriction complicating cerebral atherosclerotic vascular disease in Schimke immuno-osseous dysplasia. PMID- 29978299 TI - Maize opaque mutants are no longer so opaque. AB - The endosperm of angiosperms is a zygotic seed organ that stores nutrient reserves to support embryogenesis and seed germination. Cereal endosperm is also a major source of human calories and an industrial feedstock. Maize opaque endosperm mutants commonly exhibit opaque, floury kernels, along with other abnormal seed and/or non-seed phenotypes. The opaque endosperm phenotype is sometimes accompanied by a soft kernel texture and increased nutritional quality, including a higher lysine content, which are valuable agronomic traits that have drawn attention of maize breeders. Recently, an increasing number of genes that underlie opaque mutants have been cloned, and their characterization has begun to shed light on the molecular basis of the opaque endosperm phenotype. These mutants are categorized by disruption of genes encoding zein or non-zein proteins localized to protein bodies, enzymes involved in endosperm metabolic processes, or transcriptional regulatory proteins associated with endosperm storage programs. PMID- 29978301 TI - [An essay on health services research-contributions from urology]. PMID- 29978302 TI - [Prediction of unplanned discontinuation of treatment in patients with castration resistant prostate cancer-results from the IBuTu study]. PMID- 29978305 TI - Anterior cruciate ligament reconstruction performed within 12 months of the index injury is associated with a lower rate of medial meniscus tears. AB - PURPOSE: To verify the correlation of time to surgery with the prevalence of concomitant intra-articular injuries detected on arthroscopy during anterior cruciate ligament (ACL) reconstruction. METHODS: The medical records of 653 patients who underwent ACL reconstruction surgery were retrospectively analyzed. Univariate and multivariate logistic regression analysis was performed to identify factors that were associated with the presence of at least one intra articular injury, medial meniscus tears, lateral meniscus tears and chondral injuries at the time of surgery. Further univariate analysis was conducted to determine the earliest time-point for surgery, after which the rate of concomitant injuries was significantly higher. RESULTS: Longer time to surgery (OR 1.019 95% CI 1.010, 1.028, p = 0.000), male sex (OR 1.695 95% CI 1.074, 2.675 p = 0.023), and higher BMI (OR 1.050 95% CI 1.006, 1.097 p = 0.025) were correlated with a higher prevalence of medial meniscus tears. There was an increased prevalence of medial meniscus tears when surgery was carried out more than 12 months after the index injury (OR 2.274 95% CI 1.469, 3.522, p = 0.000). The correlation between longer time to surgery and chondral injuries approached statistical significance (OR 1.006 95% CI 0.999, 1.012, p = 0.073). However, a longer time to surgery was not associated with an increased prevalence of lateral meniscus tears (OR 1.003 95% CI 0.998, 1.009, p = n.s.). CONCLUSIONS: Longer time to surgery is associated with an increased prevalence of medial meniscus tears in ACL reconstruction. Surgery performed within 12 months of the index injury reduces the prevalence of medial meniscus tears. Prioritizing males and overweight patients for counselling and early intervention can be considered. LEVEL OF EVIDENCE: Therapeutic level III retrospective cohort study. PMID- 29978304 TI - Characterisation of VIM-2-producing Pseudomonas aeruginosa isolates from lower tract respiratory infections in a Spanish hospital. AB - To analyse the antimicrobial phenotype, carbapenem mechanisms, integrons, virulence factors and molecular typing of 164 Pseudomonas aeruginosa isolates recovered from lower tract respiratory samples in a Spanish hospital (1 year) as well as the patients' clinical data. Susceptibility testing to 12 antipseudomonal agents was determined by microdilution and metallo-beta-lactamase (MBL) phenotype by double disc method. The oprD gene was studied by PCR, sequencing and comparison with P. aeruginosa PAO1 sequence. Detection and characterisation of MBLs, class 1, 2 and 3 integrons, and virulence genes were studied by PCR and sequencing. The prevalence of carbapenem-resistant P. aeruginosa (CRPA) was 26.8%. MBL phenotype was detected in 52.3% CRPA, and all of them were disseminated throughout the intensive care unit. Most of the MBL-carrying patients presented respiratory disease, mechanical ventilation, tracheostomy, bacteraemia, >= 30 hospitalisation days and previous treatment with carbapenems and/or >= 3 different antimicrobial families. The blaVIM-2 gene was the unique MBL encoding gene and was detected inside class 1 integrons. The class 1 integrons detected in 39 strains (23.8%) were associated with aminoglycosides (aadB, aadA1, aadA6, aacA4, aac(3)-I) and carbapenems resistance genes (blaVIM 2). The aac(3)-I + aadA1 and blaVIM-2 arrangements were the most prevalent ones. Thirty-one different PFGE patterns and 4 STs (ST175, ST235, ST253, ST973) were detected among the 39 intI1-positive isolates, being ST235 the most frequent. CRPA showed a great variety of alterations in oprD gene. The exoU+/exoS- genotype was detected in 82.6% of blaVIM-2-producing strains (ST235) and the exoU-/exoS+ in the remaining 17.4% (ST973). PMID- 29978303 TI - Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation. AB - Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course. PMID- 29978306 TI - Awareness of perception and sensory-motor integration: ERPs from the anterior insula. AB - The present work follows recent evidences of studies showing that visual stimuli evoke two early prefrontal event-related potentials (ERP) concomitant to the canonical occipital activities, but originating within the anterior insula (the pN1 and the pP1 components). To clarify the exogenous/endogenous nature of these components, we performed two experiments in which stimulus physical features (Experiment 1) and motor demands of the task (Experiment 2) were considered. In a simple response task (SRT), low-visibility stimuli evoked larger pN1 over the prefrontal areas (Experiment 1) with respect to high-visibility stimuli; in contrast, the occipital P1 component (concomitant to the pN1) had reduced amplitude in the low-visibility condition as expected. Furthermore, the latency of the P1, pN1 and pP1 was slower in the low-visibility condition (from 8 to 18 ms), and the motor response was slowed down as well (on average 14 ms). Pre stimulus analysis showed that low-visibility stimuli were preceded by greater motor readiness. On the other hand, Experiment 2 showed that, compared with the SRT, the request to passively view the same stimuli was associated with smaller pP1. ERP source analysis confirmed the anterior insula source of the prefrontal ERPs; we interpreted these activities as the correlate of two top-down perceptual processing: the sensory awareness (the pN1) and the awareness of the sensory motor integration (the pP1), associated with the subjective experience of the visual perception and the conscious experience of the sensory-motor coupling, respectively. PMID- 29978308 TI - Modeling Cell Dynamics in Colon and Intestinal Crypts: The Significance of Central Stem Cells in Tumorigenesis. AB - Colon and intestinal crypts have been widely chosen to study cell dynamics because of their fairly simple structures. In the colon and intestinal crypts, stem cells (SCs) are located at very bottom of the crypt, fully differentiated cells (FDs) are located in the top of the crypt, and transit-amplifying cells (TAs) are in the middle of the crypt between FDs and SCs. Recently, it has been discovered that there are two types of stem cells in the intestinal crypts: central stem cells (CeSCs) and border stem cells. To investigate dynamics of mutants in colon and intestinal crypts, we develop a four-compartmental stochastic model, which includes two SC compartments, and TAs and FDs compartments. We calculate the probability of the progeny of marked or mutant cells located at each of these compartments taking over the entire crypt or being washed out from the crypt. We found that the progeny of CeSCs will take over the entire crypt with a probability close to one. Interestingly, the progeny of advantageous mutant TAs and FDs will be washed out faster than disadvantageous mutants. Saliently, the model predicts that the time that the progeny of wild type central stem cells will take over the mouse intestinal crypt is around 60 days, which is in perfect agreement with an experimental observation. PMID- 29978307 TI - Radiation-induced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial) : First results of a randomized controlled trial. AB - PURPOSE: Radiation therapy (RT) provides an important treatment approach in the palliative care of vertebral metastases, but radiation-induced toxicities in patients with advanced disease and low performance status can have substantial implications for quality of life. Herein, we prospectively compared toxicity profiles of intensity-modulated radiotherapy (IMRT) vs. conventional three dimensional conformal radiotherapy (3DCRT). METHODS: This was a prospective randomized monocentric explorative pilot trial to compare radiation-induced toxicity between IMRT and 3DCRT for patients with spinal metastases. A total of 60 patients were randomized between November 2016 and May 2017. In both cohorts, RT was delivered in 10 fractions of 3 Gy each. The primary endpoint was radiation induced toxicity at 3 months. RESULTS: Median follow-up was 4.3 months. Two patients suffered from grade 3 acute toxicities in the IMRT arm, along with 1 patient in the 3DCRT group. At 12 weeks after treatment (t2), 1 patient reported grade 3 toxicity in the IMRT arm vs. 4 patients in the 3DCRT group. No grade 4 or 5 adverse events occurred in either group. In the IMRT arm, the most common side effects by the end of irradiation (t1) were grade 1-2 xerostomia and nausea in 8 patients each (29.6%), and dyspnea in 7 patients (25.9%). In the 3DCRT group, the most frequent adverse events (t1) were similar: grade 1-2 xerostomia (n = 10, 35.7%), esophagitis (n = 10, 35.8%), nausea (n = 10, 35.8%), and dyspnea (n = 5, 17.9%). CONCLUSION: This is the first randomized trial to evaluate radiation induced toxicities after IMRT versus 3DCRT in patients with vertebral metastases. This trial demonstrated an additional improvement for IMRT in terms of acute side effects, although longer follow-up is required to further ascertain other endpoints. PMID- 29978309 TI - "Trying to Figure Out If You're Doing Things Right, and Where to Get the Info": Parents Recall Information and Support Needed During the First 6 weeks Postpartum. AB - Objectives The first 6 weeks postpartum represent a time of significant adjustment and learning for parents. Healthcare providers accurately understanding parents' needs and preferences regarding support, education, and services during this critical time is essential for optimizing maternal and infant health. The first objective of this study was to explore parents' experiences adjusting to the parenting role during the first 6 weeks postpartum. The second objective was to elicit from parents where and how they sought support and information during the early postpartum period, and what hindered this process. Methods Five focus groups were conducted with 33 mothers and fathers of young children, stratified by ethnicity, education, and income. An interdisciplinary team thematically coded verbatim transcripts and identified emergent themes. Results Main themes included low confidence in parenting and sifting through parenting information. Additional themes included communicating with partner about changing roles, breastfeeding, maternal mental health, and maternal postpartum recovery. Low parenting confidence was closely linked with information seeking, yet participants expressed being overwhelmed by the task of managing conflicting parenting information. Women reported that providers focused on infant needs, leaving them feeling unprepared for their own mental and physical health needs. Conclusions for Practice Parents report extensive needs for education and support in the early postpartum period, yet also report feeling overwhelmed by the quantity of parenting information available. These findings suggest parents need and desire reliable healthcare education after discharge that includes parent health and adjustment. PMID- 29978310 TI - Occurrence and recovery of small-sized plastic debris from a Brazilian beach: characterization, recycling, and mechanical analysis. AB - Small-sized plastic debris are an increasing global concern, particularly in environmental protected areas. Consequently, tourism-based economy of poor coastal regions is also impaired. Nevertheless, little interest has been shown about recycling approaches of such materials, mostly because of the natural degradation of polymers on these conditions. This research presents the report of the occurrence of plastic debris nearby Lencois Maranhenses National Park, on the northeast Brazilian coast, aiming to provide a feasible method for recycling. We collected more than 80 samples from the sediment and classified them via FT-IR. Degraded polypropylene samples were selected for blending with virgin material using different concentration rates, and were mechanically tested. Tensile testing results suggest that 5% recycled material concentration mixture has suitable mechanical properties on the elastic regime for applications on new parts. Our findings show that particular interest should be addressed on the recovery of commodity plastic debris from environmental protected areas. PMID- 29978311 TI - Assessment of vulnerability and control measures to protect the Salbarua ecosystem from hypothetical spill sites. AB - Population pressure, urbanization, and industrial developments, among other factors, have resulted in severe degradation of environmental resources such as wetlands. Thus, a groundwater model (MODFLOW) was integrated with a particle tracking MODPATH model to simulate the hydrodynamic flow head field and to analyze the vulnerability of the Salburua ecosystem and propose control measures to protect the riparian area. The simulations show that pathways of particle tracking originating at potential contaminant sources will tend to migrate downwards towards the sensitive ecosystem, which suggests that the quality of the hydrological ecosystem is likely to deteriorate in the future. Variation in exit points of particles indicates that the time-related capture areas are affected by changes of the hydraulic gradients. Two control measures of potential sources of pollutants in the vicinity of the Salbarua ecosystem were analyzed. The study results suggest that the travel time-related capture zone with a funnel-and-gate system is much smaller than without the control alternative, which indicates that the gate configuration has an effect on capture zone size and shape and on the residence time with a better attenuation performance. It is also shown that a leakage-proof barrier is less effective for point-source containment, assuming that hydraulic control performance and cost-efficiency are the criteria for pollution control effectiveness. Instead, a program of monitoring wells would effectively characterize water quality in the aquifer and provide a decision support system. This approach may be used in helping water managers to develop more physically based and quantitative protection strategies. PMID- 29978312 TI - Harvesting of Chlorella vulgaris using Fe3O4 coated with modified plant polyphenol. AB - The Chlorella vulgaris harvesting was explored by magnetic separation using Fe3O4 particles coated with the plant polyphenol chemically modified by a Mannich reaction followed by quaternization (Fe3O4@Q-PP). The -N(R)4+ and Cl-N+-C perssad of the Q-PP were linked to the Fe3O4 particles by N-O bonds, as suggested by the X-ray photoelectron spectroscopy spectra. The thermogravimetric analysis displayed the mass percentage of the Q-PP coated on the Fe3O4 surface was close to ~ 5%. Compared with the naked Fe3O4 particles, zeta potentials of the Fe3O4@Q PP particles were improved from the range of - 17.5~- 25.6 mV to 1.9~36.3 mV at pH 2.1~13.1. A 70.2 G coercive force was obtained for the Fe3O4@Q-PP composite, which demonstrated its ferromagnetic behavior. The use of Fe3O4@Q-PP resulted in a harvesting efficiency of 90.9% of C. vulgaris cells (3.06 g/L). The Fe3O4 particles could be detached from the cell flocs by ultrasonication leading to a recovery efficiency of 96.1% after 10 cycles. The recovered Fe3O4 could be re coated with Q-PP and led to a harvesting efficiency of 80.2% after 10 cycles. The magnetic separation using Fe3O4@Q-PP included charge neutralization followed by bridging and then colloid entrapment. PMID- 29978313 TI - Comparative study of the physicochemical and photocatalytic properties of water soluble polymer-capped TiO2 nanoparticles. AB - TiO2 shows great potential as ideal and powerful photocatalyst to degrade and eliminate harmful organic pollutants from waste water. It is desirable to prepare anatase TiO2 with good aqueous solubility and photocatalytic activity for water decontamination. In this paper, water-soluble TiO2 nanoparticles were successfully prepared using polytetramethylene ether glycol (PTMG), poly(ethylene glycol) (PEG), and poly(propylene glycol) (PPG) as stabilizers. The anatase phase of TiO2 was well controlled by introduction of HCl in the reaction system. The results showed that all the polymer-capped TiO2 were well dissolved in water and their aqueous solutions could maintain stable for more than 2 months. The photocatalytic activities of polymer-capped TiO2 were evaluated by monitoring the degradation of Rhodamine B (RhB) with Degussa P25 as a control. The results showed that all the polymer-capped TiO2 presented better photocatalytic activity than that of Degussa P25. PTMG capped TiO2 exhibited the longest average lifetime of charge carriers, indicating the lowest charge recombination rate. Thus, PTMG capped TiO2 presented the best photocatalytic activity. In summary, PTMG, PEG, and PPG can be used as stabilizers to prepare water-soluble TiO2. PTMG is an ideal stabilizer for the synthesis of water-soluble TiO2 with good photocatalytic activity. PMID- 29978314 TI - Contribution of Eisenia andrei earthworms in pathogen reduction during vermicomposting. AB - Vermicomposting is a process of degradation of biowaste which involves complex interactions between earthworms and microorganisms. This process lacks a thermophilic stage and thus, the possible presence of pathogens poses a potential health hazard. To assess the contribution of earthworms during the selective reduction of various pathogens, apple pomace substrate was artificially inoculated with Escherichia coli, Salmonella spp., thermotolerant coliform bacteria, and Enterococci. The artificial bacterial load did not influence the weight, reproduction, or intestinal enzymatic activity of the earthworms, but it caused reversible histological changes to the epithelial layer and chloragogen tissue of their intestines. The reduction of pathogenic Enterococci and E. coli from the substrate was accelerated by earthworms (63-fold, 77-fold, and 840-fold for Enterococci and 6-fold, 36-fold, and 7-fold for E. coli inoculated substrates after 2, 4, and 6 weeks, respectively). Moreover, the rapid elimination of Salmonella spp. was supported by the upregulated expression of two pattern recognition receptors which bind lipopolysaccharide, coelomic cytolytic factor, and lipopolysaccharide-binding protein. Further, the microbiomes of the intestine and the composting substrate differed significantly. Graphical abstract. PMID- 29978315 TI - Stable carbon and nitrogen isotopic composition of PM10 over Indo-Gangetic Plains (IGP), adjoining regions and Indo-Himalayan Range (IHR) during a winter 2014 campaign. AB - For source identification, a field campaign involving simultaneous sampling of particulate matter (PM10) was conducted at eight sampling sites in the Indian mainland during winter 2014. The sampling sites include Delhi (upper IGP), Lucknow (middle IGP), and Kolkata (lower IGP) in the Indo-Gangetic Plains (IGP); Mohal-Kullu and Darjeeling in the Indo-Himalayan Range (IHR). In addition, Ajmer, located upwind of the IGP in NW-India and Giridih and Bhubaneswar, in the downwind to the IGP has also been chosen. To characterize the sources of the ambient PM10, stable isotope ratios of carbon (delta13CTC) and nitrogen (delta15NTN) for the total carbon (TC) and total nitrogen (TN) fractions have been considered. Ancillary chemical parameters, such as organic carbon (OC), elemental carbon (EC), and water-soluble ionic components (WSIC) mass concentrations are also presented in this paper. There was very small variation in the daily average delta13CTC ratios (- 24.8 to - 25.90/00) among the sites. Comparison with end-member stable C isotopic signatures of major typical sources suggests that the PM10 at the sites was mainly from fossil fuel and biofuel and biomass combustion. Daily average delta15NTN ratios were not observed to vary much between sites either (8.3 to 11.00/00), and the low delta15NTN levels also indicate substantial contributions from biofuel and biomass burning of primarily C3 andC4 plant matter. Graphical abstract Scatter plot of the average (+/- 1 standard deviation (SD)) delta13CTC (0/00) compared to delta15NTN (0/00) at the sampling sites. PMID- 29978316 TI - Novel magnetic ion-imprinted polymer: an efficient polymeric nanocomposite for selective separation and determination of Pb ions in aqueous media. AB - A novel ion-imprinted polymer (IIP) toward Pb(II) recognition was synthesized on the surface of magnetic multi-walled carbon nanotubes (magnetic MWCNTs). In order to prepare magnetic functionalized-MWCNT/IIP (magnetic f-MWCNT/IIP), copolymerization of methylenebisacrylamide (MBAm) and acrylamide (AM) in the presence of dithizone-Pb(II) complex was carried out on the surface of the magnetic f-MWCNTs. Selectivity of the new synthesized sorbent toward Pb(II) and the influence of a variety of foreign ions on the recognition, preconcentration, and removal of Pb(II) were evaluated using adsorption experiments in aqueous solution. The synthesized sorbent exhibited a good affinity with high adsorption capacity (Q = 80.81 mg/g) and an excellent selectivity toward Pb(II) in comparison with other common cations including alkaline, alkaline earth, and transition metals such as Na+, K+, Mg2+, Ca2+, Cd2+, and Ni2+. The parameters such as adsorption and desorption time, adsorption capacity, effect of the sorbent mass, eluent type, concentration and volume, and also pH of the solutions were investigated. The result demonstrated that the proposed sorbent provided a fast removal and higher maximum binding capacity compared to other reported synthesized sorbents. The characteristics of the magnetic f-MWCNT/IIP were analyzed using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), vibrating sample magnetometer (VSM), and elemental analysis (EA). Graphical abstract ?. PMID- 29978317 TI - Internal dose of particles in the elderly-modeling based on aerosol measurements. AB - The paper presents an integrated methodology that combines experimental and modeling techniques and links exposure to airborne particulate matter (PM) with internal dose in the respiratory system and burden in adjacent tissues over a period of time. The methodology is used to estimate doses in the respiratory systems of elders that reside in 10 elderly care centers (ECCs) in the metropolitan area of Lisbon. Measurements of PM were performed in the ECCs and combined with a time-budget survey for the occupants. This information served as input to the first model that estimated particle doses in the different regions of the respiratory tract of the elderly, and then a second model was used to calculate particle build-up in the alveolar region, the interstitium and the hilar lymph nodes of the elders over a 5-year exposure period. It was found that in 5 years of continuous exposure to the average particle concentration measured over all ECCs, 258 mg of all particles are deposited on the surface of the alveoli of which 79.6% are cleared, 18.8% are retained in the alveolar region, 1.5% translocate to the hilar lymph nodes, and 0.1% are transferred to the interstitium. PMID- 29978318 TI - Alternative scenarios for ecological urbanizations using ENVI-met model. AB - Natural areas are quickly degraded by opening new settlement and industrial areas in order to meet the increasing demand of the growing population. Concreting, modification of land surfaces, complex urban structures, and depressed urban environments contribute to the formation of an Urban Heat Island (UHI). In this study, the outdoor measurements, meteorological parameters related to the thermal indices such as humidity, temperature, wind velocity, and direction for 24 h measurements, were evaluated. The ENVI-met micro-scale model was performed for evaluating alternative scenarios for winter and summer on thermal comfort for better urban environments. Meteorological parameters together with vegetation characteristics were analyzed for making possible scenarios in botanical garden, auto industrial area, city center, and rural open area. The average of the vegetated simulations of the botanical garden was about 2.2 degrees C cooler than this of the mean of current situation in the city center. Based upon the average of all stations, it was determined that the temperature increased 1.4 degrees C with the simulation of both wooded areas in winter. However, the mean temperature of all stations with coniferous plants was 1.2 degrees C cooler, in summer. It was concluded that deciduous plants in city center produced more positive results than coniferous plants in winter. In general, it can be said that afforestation in cold climatic regions provides great advantages for both summer and winter and positively affects outdoor thermal comfort. However, it needs further measurement and further research in this regard. PMID- 29978319 TI - Transcriptomics and metabonomics analyses of maternal DEHP exposure on male offspring. AB - The objectives of this study were to evaluate the effect of maternal Di-2 ethylhexyl phthalate (DEHP) exposure on male offspring and to explore the mechanism of changes with the metabolic alterations and differential genes. Pregnant female Sprague-Dawley (SD) rats were intragastrically administered with 600 mg/kg body weight of DEHP or corn oil (CON) throughout pregnancy and lactation. The growth of male offspring was investigated until 14 weeks old, the indices of blood were detected, and mechanism was studied using metabonomics and transcriptomics. Compared with the CON group, body weight, body length, food intake, body fat weight, Lee's index, organ coefficient, blood lipids, and oral glucose tolerance test (OGTT) of male offspring were not significantly changed in maternal DEHP group. However, serum biochemical indexes such as alanine transaminase (ALT), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), and creatinine (CREA) were markedly reduced in maternal DEHP group (p < 0.05). In addition, insulin level was elevated and catalase (CAT) level was decreased notably in maternal DEHP group compared with the CON group (p < 0.05). Furthermore, thyroxine (T4) level was lower and thyroid stimulating hormone (TSH) level was higher in maternal DEHP group (p < 0.05). Metabonomics revealed seven principal metabolites were identified, including increased L-allothreonine, creatine, uric acid, retinyl ester, L-palmitoylcarnitine, and decreased glycocholic acid and LysoPC (18:3). Transcriptomics displayed 35 differential genes were involved in the mechanism of maternal DEHP exposure. Therefore, this research confirms the effect of a certain dose of maternal DEHP exposure on male offspring and understands exactly the mechanism of these changes with metabonomics and transcriptomics. PMID- 29978320 TI - IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis. AB - Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD. PMID- 29978322 TI - Coagulant Effect and Tolerability of Yeast-Produced Recombinant Batroxobin in Healthy Adult Subjects. AB - BACKGROUND AND OBJECTIVE: Batroxobin, a snake venom thrombin-like enzyme, converts fibrinogen into fibrin by cleaving fibrinopeptide A. It is used for hemostasis; however, the supply of native batroxobin is limited. Therefore, we developed a recombinant batroxobin (r-batroxobin) from Pichia pastoris and evaluated its pharmacodynamics and safety in humans. METHODS: A randomized, double-blind, placebo-controlled, single ascending-dose study was performed. Eight healthy subjects were enrolled in each r-batroxobin dose group (2.5, 5.0, or 10.0 BU/2.0 mL administered intravenously), and randomized to receive r batroxobin (n = 6) or matching placebo (n = 2). Safety was evaluated during the study, and pharmacodynamics was assessed using prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen level. RESULTS: All subjects in each cohort completed the study. No significant changes in PT or aPTT occurred after intravenous r-batroxobin administration. Compared with the placebo group, the fibrinogen level in all r-batroxobin dose groups decreased significantly to 8.68-33.57% from the baseline within 12 h (p <= 0.05). The TT in the 5.0 and 10.0 BU/2.0 mL groups significantly increased to 7.53 18.48% from baseline within 12 h compared with that of the placebo group (p <= 0.05), whereas that of the 2.5 BU/2.0 mL group exhibited non-significant changes compared with the placebo group. No serious adverse events occurred. CONCLUSIONS: A single intravenous injection of r-batroxobin within a dose range of 2.5-10.0 BU/2.0 mL was well tolerated and resulted in a significant decrease in fibrinogen and prolongation of TT. REGISTRATION: This study is registered at the Clinical Research Information Service (CRIS, http://cris.nih.go.kr ), number KCT0002518. PMID- 29978321 TI - The regulation of junctional actin dynamics by cell adhesion receptors. AB - The formation of cell-cell junctions and the development of stable cell-cell adhesion require the association of actin filaments with the sites of cell-cell adhesion. From the initial formation of cell-cell junctions, which appear as punctate, spot-like junctions, to the formation of a stable actin belt that runs adjacent to cell-cell junctions, the actin cytoskeleton is closely associated with the adhesion apparatus. Importantly, the junctional actin is highly dynamic, even after the maturation of intercellular junctions and the development of apico basal polarity. Regulators of both branched actin networks and of linear actin cables have been identified at cell-cell junctions, in particular at adherens junctions but also at tight junctions. These regulators of actin dynamics are often directly or indirectly associated with cell adhesion receptors, suggesting a critical role for cell adhesion molecules for the recruitment of regulators of actin dynamics to cell-cell junctions. Here, we review the recent developments on the role of cell adhesion molecules at epithelial and endothelial cell-cell junctions in the regulation of junctional actin dynamics. PMID- 29978323 TI - Deposition Process and Properties of Electroless Ni-P-Al2O3 Composite Coatings on Magnesium Alloy. AB - To improve the corrosion resistance and wear resistance of electroless nickel phosphorus (Ni-P) coating on magnesium (Mg) alloy. Ni-P-Al2O3 coatings were produced on Mg alloy from a composite plating bath. The optimum Al2O3 concentration was determined by the properties of plating bath and coatings. Morphology growth evolution of Ni-P-Al2O3 composite coatings at different times was observed by using a scanning electronic microscope (SEM). The results show that nano-Al2O3 particles may slow down the replacement reaction of Mg and Ni2+ in the early stage of the deposition process, but it has almost no effect on the rate of Ni-P auto-catalytic reduction process. The anti-corrosion and micro hardness tests of coatings reveal that the Ni-P-Al2O3 composite coatings exhibit better performance compared with Ni-P coating owing to more appropriate crystal plane spacing and grain size of Ni-P-Al2O3 coatings. Thermal shock test indicates that the Al2O3 particles have no effect on the adhesion of coatings. In addition, the service life of composite plating bath is 4.2 metal turnover, suggesting it has potential application in the field of magnesium alloy. PMID- 29978324 TI - Health professional perceptions of communicating with adolescents and young adults about bone cancer clinical trial participation. AB - PURPOSE: Low recruitment of adolescents and young adults in cancer clinical trials is widely reported and may be linked to limited improvements in survival. Research to date does not adequately explain all underlying reasons for poor trial accrual. This paper reports health professional perceptions of communicating with adolescents and young adults with bone sarcoma about clinical trial participation. METHODS: This study used narrative inquiry. Findings are reported from thematic analysis of in-depth interviews with 18 multidisciplinary health professionals working in a supra-regional bone and soft tissue sarcoma centre. RESULTS: Participants described professional expertise, the development of specialist knowledge and skills and strategies used to develop trusting relationships with adolescents and young adults with bone sarcoma. These factors were perceived to facilitate communication about clinical trial participation. Emergent themes were having credibility through expertise of the team, developing specialist communication skills through reflection on practice, having inclusive approaches to education and training about clinical trials, individual communication styles used to form trusting relationships, using a patient-centred approach to connect with adolescents and young adults, creating time needed to form trusting relationships and effective team working. CONCLUSIONS: We aligned findings of this study with characteristics of patient-physician trust and provide a basis for transferable recommendations. Our findings can be used to inform the development of age-specific, specialist communication skills and highlight health professional education needs about clinical trials. Additional research is needed to explore which elements of team working optimise improved clinical trial participation, in what contexts and why. PMID- 29978326 TI - [Role of visceral surgery in oligometastization]. PMID- 29978325 TI - Early platelet variation during concomitant chemo-radiotherapy predicts adjuvant temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma patients. AB - PURPOSE: Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma. METHODS: A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia <= 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set. RESULTS: Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 >= 35% (?W6 >= 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ?W6 >= 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5-107.5)) corresponding to sensitivity of 77% (66-87%), specificity of 73% (62-84%), a positive predictive value of 42% (29-54%), and a negative predictive value of 92% (86-99%). CONCLUSION: Platelet decrease at W6 >= 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance. PMID- 29978327 TI - Doing It for the Money: The Relationship Between Gambling and Money Attitudes Among College Students. AB - Today's college students have grown up with legalized gambling and access to a variety of gambling venues. Compared to the general adult population, rates of disordered gambling among college students are nearly double. Previous research suggests that the desire to win money is a strong motivator to gamble (Neighbors et al. in J Gambl Stud 18:361-370, 2002a); however, there is a dearth of literature on attitudes towards money in relation to gambling behavior. The current study evaluated the association between the four subscales of the Money Attitude Scale (Yamauchi and Templer in J Pers Assess 46:522-528, 1982) and four gambling outcomes (frequency, quantity, consequences and problem severity) in a sample of college students (ages 18-25; N = 2534) using hurdle negative binomial regression model analyses. Results suggest that college students who hold high Power-Prestige or Anxiety attitudes toward money were more likely to gamble and experience greater consequences related to their gambling. Distrust attitudes were negatively associated with gambling behaviors. Retention-Time attitudes were not significantly associated with gambling behaviors and may not be directly relevant to college students, given their often limited fiscal circumstances. These findings suggest that money attitudes may be potential targets for prevention programs in this population. PMID- 29978328 TI - Trapezius perforator flaps: anatomical basis using 58 dissections. AB - INTRODUCTION: The trapezius muscle is a good option for soft tissue defects in the cervical and thoracic regions. However, pedicled flaps raised from perforators in the trapezius are rare. Through a series of cadaver dissections, the authors aim to map the perforating arteries in the trapezius muscle. MATERIALS AND METHODS: Dissection of 58 anatomical regions in 32 cadavers was carried out. The perforating arteries of the trapezius were inventoried based on their location, dimensions and frequency using the scapular spine and spinous process line as landmarks. RESULTS: In 78% of cases, the main perforators of the trapezius were located along two vertical lines parallel to the spinous process line, 5-6 cm on either side of it, between the scapular spine laterally, the tip of the scapula caudally and the superior margin of the trapezius cranially. On each side of the spinous process line, we found an average of 16 perforators (range 5-27) with an average diameter of 0.6 mm (range 0.1-2.6 mm). CONCLUSION: Our study shows that surgeons can use fixed landmarks when developing trapezius perforator flaps. PMID- 29978329 TI - Safe zone for irrigation and debridement of psoas abscess through a dorsal spinal approach. AB - PURPOSE: This cadaver study was initiated to identify safe zones for psoas abscess debridement using a dorsal spinal approach. METHODS: Twenty total specimens were dissected and lumbar transverse process (TP) and psoas muscles were identified. The distance from the lateral psoas muscle to the transverse process tip was measured. The lumbar plexus was dissected from the psoas and the distance from the TP to the lateral border of the lumbar plexus was measured. The area between the lateral edge of the psoas and lumbar plexus at each lumbar level was considered a safe zone of approach for entry into the psoas muscle for abscess debridement. RESULTS: The most lateral portion of the lumbar plexus was 9.3 mm medial to the superior tip of the L1 TP and 9.2 mm medial to the inferior tip at L1, it was 11.8 and 11.7 mm medial at L2, 10.5 and 9.8 mm medial at L3, 6.6 and 6.2 mm medial at L4, and 1.0 and 0.9 mm medial at L5. The distances from the TP tip to the lateral edge of the psoas muscle were 5.7 and 5.5 mm medial to the superior and inferior tip of the TP at L1, 5.1 and 4.7 mm medial at L2, 2.5 and 1.8 mm medial at L3, 0.4 and 0 mm medial at L4 and 3.7 and 3.8 mm lateral at L5. CONCLUSIONS: This study provides landmarks to avoid the critical structures in the lumbar spine. PMID- 29978330 TI - Olive leaf extract counteracts epithelial to mesenchymal transition process induced by peritoneal dialysis, through the inhibition of TGFbeta1 signaling. AB - The mesothelial cells (MCs) play an important role in the morpho-functional alterations of the peritoneal membrane (PM) undergoing peritoneal dialysis (PD). MCs, through the epithelial-mesenchymal transition process (EMT), progressively acquire a myofibroblast-like phenotype, promoting peritoneal fibrosis (PF) and failure of peritoneal membrane function. Transforming growth factor beta1 (TGFbeta1), through canonical and non-canonical pathways, promotes the epithelial mesenchymal transition (EMT) process leading to PF. To investigate the therapeutic potential of an olive leaf extract (OLE) on preserving peritoneal membrane function, we evaluated the effect of OLE on the TGFbeta1-induced EMT in mesothelial cells, Met5A, and elucidated the underlying molecular mechanisms. As assessed by changes in the expression of epithelial, mesenchymal, and fibrotic cell markers (such as E-cadherin, N-cadherin, alpha-SMA, fibronectin, vimentin), levels of matrix metalloproteinases (MMP2 and MMP9), and cell migration, OLE inhibited the TGFbeta1-induced EMT. Importantly, the beneficial effect of OLE was mediated by reduction of the TGFbeta1-induced activation of Smad2/3 signaling and the mitigation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Smad/non-Smad signaling pathways, activated by TGFbeta1, both reduce expression of epithelial marker E-cadherin which has a crucial role in EMT initiation. Interestingly, we observed that in presence of OLE activity of the E-cadherin, promoter was increased and concomitantly OLE reduced the nuclear content of its co-repressor SNAIL. Our results suggest the potential therapeutic of OLE to counteract fibrotic process in peritoneal dialysis patients. PMID- 29978331 TI - FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma. AB - Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately one third of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1-TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group. PMID- 29978333 TI - Process engineering and pharmaceutical manufacturing technologies. PMID- 29978335 TI - Successful treatment of liver metastases arising from early gastric cancer achieved clinical complete response by nivolumab. AB - BACKGROUND: Although a recent randomized clinical trial has demonstrated that the objective response rate to nivolumab for metastatic gastric cancer was 11.2%, there was no patients confirmed complete response. Herein, we report on a case of liver metastasis arising from early gastric cancer in which a complete clinical response was achieved to nivolumab as third-line therapy. CASE PRESENTATION: A 77 year-old man was referred to Kochi Medical School Hospital for the treatment of liver metastases from gastric cancer. The patient had undergone laparoscopic total gastrectomy with regional lymph node dissection 30 months prior for early gastric cancer, with a final diagnosis of T1N0M0, stage IA. The patient developed solitary splenic metastasis measuring 42 mm 28 months later and underwent splenectomy because there was no evidence of further metastatic lesions in any other organ. The patient was treated with S-1 plus oxaliplatin based on negative immunohistochemical staining of the resected specimens for human epidermal growth factor receptor 2 (HER2). Four months after the splenectomy, the patient developed multiple liver metastases and was treated with ramucirumab plus paclitaxel. Because of disease progression, the patient was administered 3 mg/kg, i.v., nivolumab every 2 weeks. After 4 cycles of systemic treatment using nivolumab, abdominal computed tomography revealed marked shrinkage of the liver metastases. After 12 cycles of nivolumab, the liver metastases had disappeared completely. The patient did not develop any adverse reactions, including immune reactive adverse events, during treatment. The patient continues to receive nivolumab, and there is no evidence of disease recurrence in the 8-month period since starting nivolumab. CONCLUSIONS: To the best of our knowledge, this is the first case report in the English literature of a gastric cancer patient achieving a complete clinical response to nivolumab, and highlights the potential for successful treatment of metastatic gastric cancer using nivolumab. PMID- 29978334 TI - Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNgamma production by human NK cells in the presence of antibody-bound tumor cells. AB - Several clinically successful tumor-targeting mAbs induce NK cell effector functions. Human NK cells exclusively recognize tumor-bound IgG by the FcR CD16A (FcgammaRIIIA). Unlike other NK cell activating receptors, the cell surface density of CD16A can be rapidly downregulated in a cis manner by the metalloproteinase ADAM17 following NK cell stimulation in various manners. CD16A downregulation takes place in cancer patients and this may affect the efficacy of tumor-targeting mAbs. We examined the effects of MEDI3622, a human mAb and potent ADAM17 inhibitor, on NK cell activation by antibody-bound tumor cells. MEDI3622 effectively blocked ADAM17 function in NK cells and caused a marked increase in their production of IFNgamma. This was observed for NK cells exposed to different tumor cell lines and therapeutic antibodies, and over a range of effector/target ratios. The augmented release of IFNgamma by NK cells was reversed by a function blocking CD16A mAb. In addition, NK92 cells, a human NK cell line that lacks endogenous FcgammaRs, expressing a recombinant non-cleavable version of CD16A released significantly higher levels of IFNgamma than NK92 cells expressing equivalent levels of wildtype CD16A. Taken together, our data show that MEDI3622 enhances the release of IFNgamma by NK cells engaging antibody-bound tumor cells by blocking the shedding of CD16A. These findings support ADAM17 as a dynamic inhibitory checkpoint of the potent activating receptor CD16A, which can be targeted by MEDI3622 to potentially increase the efficacy of anti-tumor therapeutic antibodies. PMID- 29978336 TI - Floral colour change in Byrsonima variabilis (Malpighiaceae) as a visual cue for pollen but not oil foraging by oil-collecting bees. AB - Pollinators search for multiple flora resources throughout their life cycle. Most studies, however, only assess how bees discriminate floral cues in the context of nectar foraging. In the present study, we sought to elucidate whether oil collecting bees discriminate flowers of Byrsonima variabilis (Malpighiaceae) with petals of different colours when foraging for pollen or oil. As the colour of the standard petal changes during anthesis, we characterised the spectral reflectance patterns of flowers throughout anthesis and modelled chromatic perceptual space to determine how these colour patterns are perceived by bees. Through the quantification of flower pollen in the different phases, we found that the colour of the standard petal is an honest cue of the presence of pollen. Centridine bees preferentially visited flowers with a yellow (bee's green) colour when searching for pollen, but indiscriminately visited flowers with different petal colours when searching for floral oil. We suggest that standard petals, in the species studied and others of the genus, like nectar guides, act as pollen guides, which oil-collecting females use to detect pollen-rich flowers. Moreover, they use different floral clues during foraging for different resources in the same host plant. PMID- 29978332 TI - Metastatic and triple-negative breast cancer: challenges and treatment options. AB - The major current conventional types of metastatic breast cancer (MBC) treatments include surgery, radiation, hormonal therapy, chemotherapy, or immunotherapy. Introducing biological drugs, targeted treatment and gene therapy can potentially reduce the mortality and improve the quality of life in patients with MBC. However, combination of several types of treatment is usually recommended. Triple negative breast cancer (TNBC) accounts for 10-20% of all cases of breast carcinoma and is characterized by the low expression of progesterone receptor (PR), estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2). Consequently, convenient treatments used for MBC that target these receptors are not effective for TNBC which therefore requires special treatment approaches. This review discusses the occurrence of MBC, the prognosis and predictive biomarkers of MBC, and focuses on the novel advanced tactics for treatment of MBC and TNBC. Nanotechnology-based combinatorial approach for the suppression of EGFR by siRNA and gifitinib is described. PMID- 29978337 TI - Electromagnetic Energy Redistribution in Coupled Chiral Particle Chain-Film System. AB - Metal nanoparticle-film system has been proved that it has the ability of focusing light in the gap between particle and film, which is useful for surface enhanced Raman scattering and plasmon catalysis. The rapid developed plasmonic chirality can also be realized in such system. Here, we investigated an electromagnetic energy focusing effect and chiral near-field enhancement in a coupled chiral particle chain on gold film. It shows large electric field enhancement in the gap between particle and film, as well as chiral near field. The enhancement properties at resonant peaks for the system excited by left circularly polarized light and right circularly polarized light are obviously different. This difference resulted from the interaction of circularly polarized light and the chiral particle-film system is analyzed with plasmon hybridization. The enhanced optical activity can provide promising applications for the enhancement of chiral molecule sensor for this chiral particle chain-film system. PMID- 29978339 TI - Bayesian Estimation of Age-Specific Mortality and Life Expectancy for Small Areas With Defective Vital Records. AB - High sampling variability complicates estimation of demographic rates in small areas. In addition, many countries have imperfect vital registration systems, with coverage quality that varies significantly between regions. We develop a Bayesian regression model for small-area mortality schedules that simultaneously addresses the problems of small local samples and underreporting of deaths. We combine a relational model for mortality schedules with probabilistic prior information on death registration coverage derived from demographic estimation techniques, such as Death Distribution Methods, and from field audits by public health experts. We test the model on small-area data from Brazil. Incorporating external estimates of vital registration coverage though priors improves small area mortality estimates by accounting for underregistration and automatically producing measures of uncertainty. Bayesian estimates show that when mortality levels in small areas are compared, noise often dominates signal. Differences in local point estimates of life expectancy are often small relative to uncertainty, even for relatively large areas in a populous country like Brazil. PMID- 29978338 TI - Father Absence and Accelerated Reproductive Development in Non-Hispanic White Women in the United States. AB - Girls who experience father absence in childhood also experience accelerated reproductive development in comparison with peers with present fathers. One hypothesis advanced to explain this empirical pattern is genetic confounding, wherein gene-environment correlation (rGE) causes a spurious relationship between father absence and reproductive timing. We test this hypothesis by constructing polygenic scores for age at menarche and first birth using recently available genome-wide association study results and molecular genetic data on a sample of non-Hispanic white females from the National Longitudinal Study of Adolescent to Adult Health. We find that young women's accelerated menarche polygenic scores are unrelated to their exposure to father absence. In contrast, polygenic scores for earlier age at first birth tend to be higher in young women raised in homes with absent fathers. Nevertheless, father absence and the polygenic scores independently and additively predict reproductive timing. We find no evidence in support of the rGE hypothesis for accelerated menarche and only limited evidence in support of the rGE hypothesis for earlier age at first birth. PMID- 29978340 TI - Influence of attachment design and material on the retention of resin-bonded attachments. AB - OBJECTIVES: The purpose of this laboratory study was to evaluate the influence of the attachment design and material on the retention of resin-bonded attachments (RBAs) before and after dynamic loading. MATERIALS AND METHODS: Forty-eight caries-free human premolars were prepared for RBAs fabricated either from a CoCr alloy or from zirconia ceramic. Specimens were divided into three groups (n = 16 each). Two groups had a standard attachment design for alloys (group M made from a CoCr alloy and group Z1 made from zirconia ceramic). The third group had an attachment design optimized for zirconia ceramic (group Z2 made from zirconia ceramic). Attachments were bonded to the acid-etched enamel of the premolars using a phosphate monomer containing adhesive resin. Subgroups of eight specimens each were either debonded using a tensile force in a universal testing machine at a cross-head speed of 2 mm/min (S) or were exposed to dynamic loading with 50 N over 1200,000 loading cycles in a chewing simulator prior to debonding (D). RESULTS: There were no significant differences in the initial failure loads of groups. With the exception of subgroup Z1-D, all specimens survived the dynamic loading. Statistical analysis showed that dynamic loading caused a significant decrease of failure loads in group Z1. In contrast, subgroup Z2-D exhibited significantly higher failure loads compared to the subgroup Z1-D. CONCLUSIONS: The results suggest that zirconia RBAs fabricated with an optimized attachment design may be a valid clinical alternative to metal RBAs. CLINICAL RELEVANCE: Clinical data on the long-term potential of zirconia RBAs is required before these restorations can be recommended for general use. PMID- 29978342 TI - Platelet lysate promotes re-epithelialization of persistent epithelial defects: a pilot study. AB - PURPOSE: To study the use of autologous platelet lysate prepared in a standardized method for the healing of persistent corneal epithelial defects (PED). STUDY DESIGN: Clinical and experimental investigation. METHODS: In this prospective pilot study (ClinicalTrials.gov identifier NCT02979912), ten patients with a PED duration of a minimum 14 days were included. Autologous platelet lysate was prepared in a standardized methodology. Repeated freeze-thaw cycles were used to lyse the platelets. Patients were advised to apply the eye drops four times a day and were evaluated at baseline and on days 7, 14, 21, 28. RESULTS: No adverse events were reported due to the use of undiluted autologous platelet lysate. A total of 70% of patients had complete re-epithelialization within 28 days. Of these, 40% healed within 14 days (effective group) and 30% within 28 days (partially effective group). CONCLUSIONS: Undiluted autologous platelet lysate, prepared according to a standardized methodology, is a safe and effective adjunct therapy for the treatment of PED. PMID- 29978341 TI - Computational modelling approaches as a potential platform to understand the molecular genetics association between Parkinson's and Gaucher diseases. AB - Gaucher's disease (GD) is a genetic disorder in which glucocerebroside accumulates in cells and specific organs. It is broadly classified into type I, type II and type III. Patients with GD are at high risk of Parkinson's disease (PD), and the clinical and pathological presentation of GD patients with PD is almost identical to idiopathic PD. Several experimental models like cell culture, animal models, and transgenic mice models were used to understand the molecular mechanism behind GD and PD association; however, such mechanism remains unclear. In this context, based on literature reports, we identified the most common mutations K198T, E326K, T369M, N370S, V394L, D409H, L444P, and R496H, in the Glucosylceramidase (GBA) protein that are known to cause GD1, and represent a risk of developing PD. However, to date, no computational analyses have designed to elucidate the potential functional role of GD mutations with increased risk of PD. The present computational pipeline allows us to understand the structural and functional significance of these GBA mutations with PD. Based on the published data, the most common and severe mutations were E326K, N370S, and L444P, which further selected for our computational analysis. PredictSNP and iStable servers predicted L444P mutant to be the most deleterious and responsible for the protein destabilization, followed by the N370S mutation. Further, we used the structural analysis and molecular dynamics approach to compare the most frequent deleterious mutations (N370S and L444P) with the mild mutation E326K. The structural analysis demonstrated that the location of E326K and N370S in the alpha helix region of the protein whereas the mutant L444P was in the starting region of the beta sheet, which might explain the predicted pathogenicity level and destabilization effect of the L444P mutant. Finally, Molecular Dynamics (MD) at 50 ns showed the highest deviation and fluctuation pattern in the L444P mutant compared to the two mutants E326K and N370S and the native protein. This was consistent with more loss of intramolecular hydrogen bonds and less compaction of the radius of gyration in the L444P mutant. The proposed study is anticipated to serve as a potential platform to understand the mechanism of the association between GD and PD, and might facilitate the process of drug discovery against both GD and PD. PMID- 29978343 TI - Fluency misattribution and auditory hindsight bias. AB - We conducted three experiments to test the fluency-misattribution account of auditory hindsight bias. According to this account, prior exposure to a clearly presented auditory stimulus produces fluent (improved) processing of a distorted version of that stimulus, which results in participants mistakenly rating that item as easy to identify. In all experiments, participants in an exposure phase heard clearly spoken words zero, one, three, or six times. In the test phase, we examined auditory hindsight bias by manipulating whether participants heard a clear version of a target word just prior to hearing the distorted version of that word. Participants then estimated the ability of naive peers to identify the distorted word. Auditory hindsight bias and the number of priming presentations during the exposure phase interacted underadditively in their prediction of participants' estimates: When no clear version of the target word appeared prior to the distorted version of that word in the test phase, participants identified target words more often the more frequently they heard the clear word in the exposure phase. Conversely, hearing a clear version of the target word at test produced similar estimates, regardless of the number of times participants heard clear versions of those words during the exposure phase. As per Roberts and Sternberg's (Attention and Performance XIV, pp. 611-653, 1993) additive factors logic, this finding suggests that both auditory hindsight bias and repetition priming contribute to a common process, which we propose involves a misattribution of processing fluency. We conclude that misattribution of fluency accounts for auditory hindsight bias. PMID- 29978344 TI - Finger Length Ratios of Identical Twins with Discordant Sexual Orientations. AB - A proposed marker of prenatal androgen exposure is the ratio of the index finger to ring finger (2D:4D). Within each sex, this ratio may be lower for those who were exposed to higher levels of androgens and become attracted to women, as compared to those who were exposed to lower levels of androgens and become attracted to men. We examined these patterns in identical twins with discordant sexual orientations. Because these twins are genetically identical, differences in prenatal androgen exposure, as reflected in their different finger length ratios, might contribute to their discordance. For 18 female twin pairs, non straight (bisexual or lesbian) twins had significantly lower, or more masculinized, 2D:4D ratios than their straight co-twins, but only in the left hand. For 14 male pairs, non-straight twins had, contrary to our prediction, more masculinized finger length ratios than straight co-twins, but this difference was not significant. A reanalysis of present and previous data (Hall & Love, 2003; Hiraishi, Sasaki, Shikishima, & Ando, 2012) suggested that these patterns were robust. Furthermore, males had more masculinized 2D:4D ratios than females. This sex difference did not vary by sexual orientation. PMID- 29978345 TI - Routine MRCP in the management of patients with gallbladder stones awaiting cholecystectomy: a single-centre experience. AB - OBJECTIVES: To assess the frequency of choledocolithiasis and the role of preoperative laboratory findings, ultrasound (US) and magnetic resonance cholangio-pancreatography (MRCP) in the detection of choledocolithiasis in patients with gallbladder stones awaiting cholecystectomy. METHODS: A consecutive sample of 104 patients underwent MRCP prior to cholecystectomy. The patients were classified into different groups on the basis of the risk of choledocolithiasis. A specialised doctor with more 10 years of experience performed the US interpretation and a radiologist performed the MRCP interpretation blinded to US or aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/alkaline phosphatase (ALP) results. A chi-square (chi2) test was performed to assess the statistical significance of differences in the frequency of choledocolithiasis based on laboratory findings, choledocal diameter on US and group risk. RESULTS: MRCP showed calculi in 7 out of 104 patients (6.7%), with no statistically significant differences between the high/moderate risk and low/no risk groups and between the patients with normal and altered laboratory findings or choledocal diameter on preoperative US. The sensitivity and specificity of AST/ALT [positive predictive value (PPV): 12%; negative predictive value (NPV): 94%], ALP (PPV: 7%; NPV: 94%), total serum bilirubin (PPV: 6%; NPV: 93%) and choledocal diameter (PPV: 20%; NPV: 94%) were, respectively, 28.6 and 94.8%, 85.7 and 17.5%, 14.3 and 93.8%, and 14.3 and 95.9%. CONCLUSIONS: MRCP is a reliable evaluation for the detection of common bile duct (CBD) stones, reducing the misdiagnosis of retained choledocholithiasis with normal biochemical predictors and US examination. MAIN MESSAGES: * MRCP is a non-invasive method for the detection of CBD stones. * Preoperative MRCP reduces the misdiagnosis of retained choledocholithiasis. * Detection of choledocholithiasis is mandatory prior to cholecystectomy to avoid surgical morbidity. PMID- 29978347 TI - Aberrant Wnt Signaling Pathway in the Hematopoietic Stem/Progenitor Compartment in Experimental Leukemic Animal. AB - The evolutionarily conserved Wnt signaling pathway regulates physiological hematopoiesis, a process of formation of blood cells and has been shown to play crucial role in the development of both myeloid and lymphoid malignancies. The Wnt signaling pathway can be broadly divided into canonical and non-canonical pathways. In the present study, we investigated the pathobiology of leukemia by studying the expression profile of Wnt proteins, receptors, key signaling intermediates and endogenous Wnt antagonist involved in canonical and non canonical pathways in the bone marrow (BM) hematopoietic stem/progenitor cell (HSPC) compartment of experimental leukemic mice. Cell adhesion molecule N Cadherin and leukemic BM microenvironment with reference to Wnt were also studied. We used ENU, a potent carcinogen, to induce leukemia in wild type Swiss albino mice and malignant transformation was cofirmed by peripheral blood and BM studies. Flow cytometric expression analysis revealed profound up-regulation of canonical Wnt3a/beta-catenin/CyclinD1 signaling axis along with N-Cadherin whereas down-regulation of non-canonical Wnt5a/Ca2+/CaMKII signaling axis in the leukemic HSPC compartment. Subsequent use of anti-Wnt3a antibody in the in vitro clonogenicity assay uncovered that anti-Wnt3a antibody preferentially inhibited the growth and number of the primitive leukemic hematopoietic CFU-GEMM and BFU-E colonies. Stromal cells derived from the leukemic BM also exhibited aberrant Wnt3a and Wnt5a protein expression. Taken together, alteration of canonical and non-canonical Wnt signaling pathways in the HSPC compartment along with classical Wnt protein expression pattern in the leukemic stromal microenvironment resulted in progression of leukemia. PMID- 29978346 TI - Psychometric properties of the EQ-5D-5L in patients with hip or knee osteoarthritis: reliability, validity and responsiveness. AB - PURPOSE: To study the psychometric properties, including reliability, validity and responsiveness, of the Spanish EQ-5D-5L questionnaire for patients with hip or knee osteoarthritis (OA). METHODS: We included 758 patients with hip or knee OA who completed the EQ-5D-5L and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline, of whom 644 also did 6 months later. The EQ-5D-5L contains five questions from which a utility index is derived. The WOMAC covers three dimensions: pain, stiffness and physical function. Floor and ceiling effects were calculated. Reliability was assessed using Cronbach's alpha. Convergent validity was tested using the Spearman correlation coefficient between EQ-5D-5L and WOMAC. We examined known-groups validity by comparing the EQ-5D-5L between subgroups defined by WOMAC scores using ANOVA or the Kruskal-Wallis test. Effect sizes were calculated to assess responsiveness, and minimal clinically important difference (MCID) was estimated. RESULTS: The EQ-5D-5L showed minimal floor and ceiling effects (< 3%). Cronbach's alpha was 0.86. The EQ-5D-5L index was strongly correlated with WOMAC pain and function scores (- 0.688 and - 0.782). Patients with higher WOMAC scores had significantly (p < 0.0001) lower EQ 5D-5L index. The 20.19% had hip or knee replacement during the follow-up. Effect sizes were small among non-surgical patients, but > 0.80 among "improved" surgical patients, being the MCID for improvement 0.32 points. CONCLUSIONS: The results support the reliability, validity and responsiveness of the EQ-5D-5L, overcoming the limitations of the EQ-5D-3L in these patients. Therefore, the EQ 5D-5L could be very useful as an outcome measure, at least in patients with hip or knee OA. PMID- 29978348 TI - Immunohistochemistry analysis of Pygo2 expression in central nervous system tumors. AB - Pygo2 as a Wnt signaling pathway component has been detected in multiple cancer types. In this study, we identified Pygo2 expression features by immunohistochemistry in 73 central nervous system tumor specimens, in comparison with 14 normal brain tissues and surrounding non-tumorous tissues of tumor. Our study indicated that 59% of the patient tumor specimens exhibited positive Pygo2 staining and increases intensity with the grade of malignancy, especially for WHO grade III and IV gliomas, was observed high level expression, compared with normal brain tissues. Five out of nine WHO grade III anaplastic astrocytomas and seven out of nine WHO grade IV glioblastomas showed Pygo2-positive staining. The analysis of Pygo2 gene expression by quantitative real-time PCR of additional ten fresh patient samples yielded similar results. Further studies performed with stable cell lines in vitro demonstrated that Pygo2 render cells higher proliferation rate, migration and anchorage-independent colony-forming ability in soft agar. Taken together, our studies suggest an important role of Pygo2 in brain tumor progression. PMID- 29978349 TI - Nonionic surfactants and their effects on asymmetric reduction of 2-octanone with Saccharomyces cerevisiae. AB - In an aqueous buffer system, serious reverse and side reactions were found in the asymmetric reduction of 2-octanone with Saccharomyces cerevisiae. However, some nonionic surfactants added to the aqueous buffer system improved the bioreduction process by decreasing the reverse and side reaction rates in addition to effectively increasing the average positive reaction rate. Further, a shorter carbon chain length of hydrophilic or hydrophobic moieties in surfactants resulted in a higher yield of (S)-2-octanol. The alkylphenol ethoxylate surfactants had a less influence than polyoxyethylenesorbitan trialiphatic surfactants on the product e.e. It suggested that the product e.e. resulting from the change of carbon chain length of the hydrophobic moieties varied markedly compared with the change of carbon chain length of the hydrophilic moiety. Emulsifier OP-10 and Tween 20 markedly enhanced the yield and product e.e. at the concentration of 0.4 mmol L-1 with a yield of 73.3 and 93.2%, and the product e.e. of 99.2 and 99.3%, respectively, at the reaction time of 96 h. PMID- 29978350 TI - [Patent foramen ovale-intervention or pharmaceutical treatment]. AB - BACKGROUND: Approximately 40-50% of patients with cryptogenic stroke have a patent foramen ovale (PFO). A concomitant atrial septal aneurysm aggravates the risk of recurrent stroke. OBJECTIVE: The most important changes regarding the evidence for interventional closure of a PFO in patients with cryptogenic stroke are described. This includes the prerequisites for making a diagnosis and the indications for interventional treatment. The article also provides an overview about platelet aggregation inhibitor treatment with and without oral anticoagulation. CURRENT DATA: The balance between benefits and risks of interventional versus pharmaceutical treatment in patients with cryptogenic stroke and PFO has so far not been sufficiently proven. In 2017 two prospective randomized trials (CLOSE and REDUCE) and the long-term follow-up results of the RESPECT study were published, followed by the results of the DEFENSE-PFO study in 2018. A better assessment of the weighing up of the treatment options can now be made. All four studies showed that the interventional treatment of PFO is superior to pharmaceutical treatment alone for patients with cryptogenic stroke under 60 years of age. CONCLUSION: There was a significant reduction in the incidence of recurrent stroke in patients with interventional PFO closure compared with pharmaceutical treatment. The complication rate of PFO closure is very low and younger patients (<60 years) in particular benefit from PFO closure. PMID- 29978351 TI - Oxidative stress mediated the inhibition of cerebral creatine kinase activity in silver catfish fed with aflatoxin B1-contaminated diet. AB - Aflatoxin B1 (AFB1) is an environmental toxicant and neurotoxic compound that induces the production of free radicals, causing oxidative stress. Creatine kinase (CK) is a central controller of energy metabolism in tissues with a large and fluctuating energy demand, and it is highly susceptible to inactivation by free radicals and oxidative damage. Thus, the aim of this study was to evaluate whether a diet for freshwater silver catfish (Rhamdia quelen) containing AFB1 inhibits cerebral CK activity, as well as the involvement of the oxidative stress on this inhibition. Brain CK activity was lower on days 14 and 21 post-feeding in animals that received AFB1-contaminated diet compared to the control group (basal diet), similarly to the brain sodium-potassium pump (Na+, K+-ATPase) activity. On the other hand, lipid peroxidation and protein carbonylation levels were higher on days 14 and 21 post-feeding in animals fed with AFB1-contaminated feed compared to the control group, while the antioxidant capacity against peroxyl radicals and thiol content was lower. Based on these evidences, the data demonstrated that diet containing AFB1 severely affects CK activity, an essential enzyme that plays an important role in brain energy homeostasis. Also, the impairment of energetic homeostasis linked with the use and generation of ATP via inhibition of CK activity elicited an inhibition of enzymes ATP-dependent, such as Na+, K+-ATPase. Moreover, the inhibition of brain CK activity appears to be mediated by the oxidation of lipids, proteins, and thiol group, as well as by a reduction in the antioxidant capacity. PMID- 29978352 TI - Telmisartan prevents diet-induced obesity and preserves leptin transport across the blood-brain barrier in high-fat diet-fed mice. AB - Obesity is a global health problem and treatment options are still insufficient. When chronically treated with the angiotensin II receptor blocker telmisartan (TEL), rodents do not develop diet-induced obesity (DIO). However, the underlying mechanism for this is still unclear. Here we investigated whether TEL prevents leptin resistance by enhancing leptin uptake across the blood-brain barrier (BBB). To address this question, we fed C57BL/6 mice a high-fat diet (HFD) and treated them daily with TEL by oral gavage. In addition to broadly characterizing the metabolism of leptin, we determined leptin uptake into the brain by measuring BBB transport of radioactively labeled leptin after long-term and short-term TEL treatment. Additionally, we assessed BBB integrity in response to angiotensin II in vitro and in vivo. We found that HFD markedly increased body weight, energy intake, and leptin concentration but that this effect was abolished under TEL treatment. Furthermore, glucose control and, most importantly, leptin uptake across the BBB were impaired in mice on HFD, but, again, both were preserved under TEL treatment. BBB integrity was not impaired due to angiotensin II or blocking of angiotensin II receptors. However, TEL did not exhibit an acute effect on leptin uptake across the BBB. Our results confirm that TEL prevents DIO and show that TEL preserves leptin transport and thereby prevents leptin resistance. We conclude that the preservation of leptin sensitivity is, however, more a consequence than the cause of TEL preventing body weight gain. PMID- 29978353 TI - Complex PCI procedures: challenges for the interventional cardiologist. AB - In recent years, the percentage of patients with multivessel disease and multiple complex stenoses have significantly increased. One factor contributing to this increase is the proportion of elderly and very elderly patients who have been turned down by the Heart Team for surgical revascularization (Landes et al. in Catheter Cardiovasc Interv, https://doi.org/10.1002/ccd.27375 , 2017; Waldo et al. in Circulation 130:2295-2301, https://doi.org/10.1161/CIRCULATIONAHA.114.011541 , 2014). In addition, the marked increase in patients with significant comorbidities further contributes to the increase in patients referred to the interventional cardiologist for stenting procedures. Mostly, the complexity of these patients is characterized not only by their comorbidities but also by multivessel disease, bifurcation disease, left main disease, or stenoses of calcified or tortuous vessels, degenerated saphenous vein graft lesions, and thrombotic lesions (Kirtane et al. in Circulation 134:422 431, 2016; Gennaro Giustino et al. in JACC 86:1851-1864, 2016) These specific lesion types are typically associated with lower rates of procedural success and higher rates of recurrence or major adverse cardiac events (Kirtane et al. 2016) Coming along with this problem, virtually no study exists evaluating revascularization strategies, i.e. percutaneous coronary intervention (PCI), coronary artery bypass graft surgery, or medical therapy alone in complex patients with complex coronary anatomy. Therefore, we are confronted with an increasing patient population that is understudied and potentially underserved. In the absence of robust, accurate, objective, and consistent evidence which could help us in decision-making (e.g. best revascularization strategy, complication prevention, post-interventional medical therapy), we have to stick to personal experience and patients' preferences. In this article, we provide an overview about common definition of complex PCI, general strategies to help decision-making in these patients, and give an overview about post-interventional medical treatment. PMID- 29978354 TI - PAI-1 but Not PAI-2 Gene Deficiency Attenuates Ischemic Brain Injury After Experimental Stroke. AB - After stroke, secondary brain damage is influenced by the extent of fibrin clot formation. This is counteracted by the endogenous fibrinolysis. Of major interest are the key players of the fibrinolytic plasminogen activator system including the urokinase plasminogen activator (uPA), the tissue-type plasminogen activator (tPA), and their endogenous inhibitors plasminogen activator inhibitor 1 (PAI-1) and PAI-2. The role of PAI-1 in brain injury is well established, whereas the importance of PAI-2 is unknown at present. The objectives of the present were twofold: first, to characterize the time-dependent cerebral mRNA expression of the plasminogen activator system (PAS) after brain ischemia and second, to investigate the impact of PAI-1 and PAI-2 on brain infarct volume using gene deficient mice. Adult C57Bl/6J mice were subjected to unilateral transient middle cerebral artery occlusion (MCAO) followed by reperfusion for 3, 24, 72, or 120 h. Quantitative PCR revealed that brain mRNA expression levels of the PAS components, and particularly of PAI-1 (237-fold) and PAI-2 (19-fold), peaked at 24 h after stroke. Accordingly, PAI-1 plasma activity was strongly increased. Brain infarct volume in TTC (2,3,5-triphenyltetrazolium chloride)-stained brain sections was significantly smaller 24 h after MCAO in PAI-1-deficient mice (- 31%), but not in PAI-2-deficient mice (- 6%). Thus, endogenous upregulation of PAI-1, but not of PAI-2, might contribute to increased brain damage after acute ischemic stroke. The present study therefore shows that PAI-2 is induced by brain ischemia, but does not play an important or relevant role for secondary brain damage after brain injury. PMID- 29978355 TI - The endotoxin-induced pulmonary inflammatory response is enhanced during the acute phase of influenza infection. AB - BACKGROUND: Influenza infections are often complicated by secondary infections, which are associated with high morbidity and mortality, suggesting that influenza profoundly influences the immune response towards a subsequent pathogenic challenge. However, data on the immunological interplay between influenza and secondary infections are equivocal, with some studies reporting influenza-induced augmentation of the immune response, whereas others demonstrate that influenza suppresses the immune response towards a subsequent challenge. These contrasting results may be due to the use of various types of live bacteria as secondary challenges, which impedes clear interpretation of causal relations, and to differences in timing of the secondary challenge relative to influenza infection. Herein, we investigated whether influenza infection results in an enhanced or suppressed innate immune response upon a secondary challenge with bacterial lipopolysaccharide (LPS) in either the acute or the recovery phase of infection. METHODS: Male C57BL/6J mice were intranasally inoculated with 5 * 103 PFU influenza virus (pH1N1, strain A/Netherlands/602/2009) or mock treated. After 4 (acute phase) or 10 (recovery phase) days, 5 mg/kg LPS or saline was administered intravenously, and mice were sacrificed 90 min later. Cytokine levels in plasma and lung tissue, and lung myeloperoxidase (MPO) content were determined. RESULTS: LPS administration 4 days after influenza infection resulted in a synergistic increase in TNF-alpha, IL-1beta, and IL-6 concentrations in lung tissue, but not in plasma. This effect was also observed 10 days after influenza infection, albeit to a lesser extent. LPS-induced plasma levels of the anti-inflammatory cytokine IL-10 were enhanced 4 days after influenza infection, whereas a trend towards increased pulmonary IL-10 concentrations was found. LPS-induced increases in pulmonary MPO content tended to be enhanced as well, but only at 4 days post infection. CONCLUSIONS: An LPS challenge in the acute phase of influenza infection results in an enhanced pulmonary pro-inflammatory innate immune response. These data increase our insight on influenza-bacterial interplay. Combing data of the present study with previous findings, it appears that this enhanced response is not beneficial in terms of protection against secondary infections, but rather damaging by increasing immunopathology. PMID- 29978356 TI - An Uncharacterized Member of the Gls24 Protein Superfamily Is a Putative Sensor of Essential Amino Acid Availability in Streptococcus pneumoniae. AB - Proteins belonging to the Gls24 superfamily are involved in survival of pathogenic Gram-positive cocci under oligotrophic conditions and other types of stress, by a still unknown molecular mechanism. In Firmicutes, this superfamily includes three different valine-rich orthologal families (Gls24A, B, C) with different potential interactive partners. Whereas the Streptococcus pneumoniae Deltagls24A deletion mutant experienced a general long growth delay, the Deltagls24B mutant grew as the parental strain in the semisynthetic AGCH medium but failed to grow in the complex Todd-Hewitt medium. Bovine seroalbumin (BSA) was the component responsible for this phenotype. The effect of BSA on growth was concentration-dependent and was maintained when the protein was proteolyzed but not when heat-denatured, suggesting that BSA dependence was related to oligopeptide supplementation. Global transcriptional analyses of the knockout mutant revealed catabolic derepression and induction of chaperone and oligopeptide transport genes. This mutant also showed increased sensibility to cadmium and high temperature. The Deltagls24B mutant behaved as a poor colonizer in the nasopharynx of mice and showed 20-fold competence impairment. Experimental data suggest that Gls24B plays a central role as a sensor of amino acid availability and its connection to sugar catabolism. This metabolic rewiring can be compensated in vitro, at the expenses of external oligopeptide supplementation, but reduce important bacteria skills prior to efficiently address systemic virulence traits. This is an example of how metabolic factors conserved in enterococci, streptococci, and staphylococci can be essential for survival in poor oligopeptide environments prior to infection progression. PMID- 29978357 TI - Nutrient Enrichment Alters Salt Marsh Fungal Communities and Promotes Putative Fungal Denitrifiers. AB - Enrichment of ecosystems with excess nutrients is occurring at an alarming rate and has fundamentally altered ecosystems worldwide. Salt marshes, which lie at the land-sea interface, are highly effective at removing anthropogenic nutrients through the action of macrophytes and through microbial processes in coastal sediments. The response of salt marsh bacteria to excess nitrogen has been documented; however, the role of fungi and their response to excess nitrogen in salt marsh sediments is not fully understood. Here, we document the response of salt marsh fungal communities to long-term excess nitrate in four distinct marsh habitats within a northern temperate marsh complex. We show that salt marsh fungal communities varied as a function of salt marsh habitat, with both fungal abundance and diversity increasing with carbon quantity. Nutrient enrichment altered fungal communities in all habitats through an increase in fungal abundance and the proliferation of putative fungal denitrifiers. Nutrient enrichment also altered marsh carbon quality in low marsh surface sediments where fungal response to nutrient enrichment was most dramatic, suggesting nutrient enrichment can alter organic matter quality in coastal sediments. Our results indicate that fungi, in addition to bacteria, likely play an important role in anaerobic decomposition of salt marsh sediment organic matter. PMID- 29978358 TI - Neoadjuvant Short-Course Radiation Therapy for Rectal Cancer: Trends and Controversies. AB - PURPOSE OF REVIEW: For patients with locally advanced rectal cancer, neoadjuvant hypofractionated short-course radiation remains an underutilized regimen in the USA. We review the current clinical literature highlighting the relative merits of short-course radiation, along with modern neoadjuvant strategies that incorporate its use. RECENT FINDINGS: As compared to long-course chemoradiation with delayed surgery, short-course radiation with early surgery offers similar oncologic efficacy for locally advanced rectal cancer patients. Delaying surgery after short-course radiation decreases post-operative complications as compared to early surgery and improves tumor downstaging. Delaying surgery also offers the opportunity to administer neoadjuvant systemic therapy, which may help increase local-regional tumor response and potentially decrease distant relapse rates, the latter a persisting problem in rectal cancer treatment. Short-course radiation, either with immediate or with delayed surgery, represents an appealing treatment alternative to long-course chemoradiation for patients with locally advanced rectal cancer. PMID- 29978360 TI - Nutrition Education Services Described on National Cancer Institute (NCI) Designated Cancer Center Websites. AB - For women diagnosed with breast cancer, healthy weight and enhanced nutrition may improve outcomes. The goal of this study is to examine the nutrition education services available on National Cancer Institute (NCI)-Designated Cancer Centers' websites. In 2017, websites of all 61 NCI-Designated Cancer Centers that provide adult clinical care were reviewed at least twice. Websites were analyzed for the existence and type of expert-directed nutrition education services for breast cancer survivors. Of the 61 websites analyzed, 49 (80%) provided information about nutrition education. Twenty (33%) included only nutrition counseling, three (5%) only nutrition classes, and 26 (42%) both counseling and classes. Forty-six websites included information about nutrition counseling; of these, 39 had an easily identifiable description. Thirty-seven class options were offered, 22% were specific to breast cancer, 16% to subgroups such as young women, 41% were nutrition-only classes, and 24% included skills education. Nutrition services are an important part of breast cancer treatment. This study demonstrated that most NCI-designated cancer centers offered counseling. However, the type of information that was offered varied and services were not always specific to patients with breast cancer. Further research is needed to confirm the presence of services, assess patient access, and demonstrate their efficacy in promoting optimal survivor outcomes. PMID- 29978361 TI - Faster Insulin Aspart: A New Bolus Option for Diabetes Mellitus. AB - Since the approval of bolus insulin, it has been used frequently in clinical practice for the management of type 1 and 2 diabetes mellitus for postprandial control. Another new product is faster insulin aspart (Fiasp, Novo Nordisk), a fast-acting insulin with 100 units/mL. Several studies have been conducted evaluating the pharmacokinetics and pharmacodynamics of faster insulin aspart, compared with insulin aspart. This new bolus insulin provides greater glucose lowering effect at 20 min, following subcutaneous administration. Faster insulin aspart had a greater reduction in hemoglobin A1c concentrations from baseline in patients with type 1 diabetes mellitus when compared with insulin aspart, whereas the two bolus insulins were similar in this outcome in patients with type 2 diabetes mellitus. Depending on the trial, the safety profile may differ between these two insulins with severe or confirmed hypoglycemia. Based on the clinical evidence for efficacy and safety, faster insulin aspart can be considered a viable option for those patients with type 1 and 2 diabetes mellitus who desire to inject immediately prior to a meal or within 20 min following a meal. However, additional studies should be completed to determine the role of faster insulin aspart in pregnant and pediatric patients, along with patients prescribed insulin pumps. This article evaluates and summarizes the pharmacokinetics and pharmacodynamics of faster insulin aspart for patients with type 1 or 2 diabetes mellitus, and summarizes its application to clinical practice. PMID- 29978359 TI - Testosterone, myocardial function, and mortality. AB - The cardiovascular system is particularly sensitive to androgens, but some controversies exist regarding the effect of testosterone on the heart. While among anabolic abusers, cases of sudden cardiac death have been described, recently it was reported that low serum level of testosterone was correlated with increased risk of cardiovascular diseases (CVD) and mortality rate. This review aims to evaluate the effect of testosterone on myocardial tissue function, coronary artery disease (CAD), and death. Low testosterone level is associated with increased incidence of CAD and mortality. Testosterone administration in hypogonadal elderly men and women has a positive effect on cardiovascular function and improved clinical outcomes and survival time. Although at supraphysiologic doses, androgen may have a toxic effect, and at physiological levels, testosterone is safe and exerts a beneficial effect on myocardial function including mechanisms at cellular and mitochondrial level. The interaction with free testosterone and estradiol should be considered. Further studies are necessary to better understand the interaction mechanisms for an optimal androgen therapy in CVD. PMID- 29978362 TI - Management of iatrogenic perforation during colonoscopy in ulcerative colitis patients: a survey of gastroenterologists and colorectal surgeons. AB - PURPOSE: Patients with ulcerative colitis, a high-risk group for the development of colon cancer, undergo colonoscopy more frequently than the general population. This increase in endoscopic evaluation also exposes these patients to an increased risk of complications, including iatrogenic perforation. Our survey study aims to determine factors that affect the management choices for iatrogenic perforations for ulcerative colitis patients in remission and identify areas of consensus among general gastroenterologists, inflammatory bowel disease specialists, and colorectal surgeons. METHODS: An anonymous, cross-sectional survey was performed using an online platform. A matrix questionnaire posed five clinical scenarios with six management options for an iatrogenic perforation in ulcerative colitis patients with varying disease distribution, disease activity, and maintenance regimens. RESULTS: One hundred thirty-eight general gastroenterologists, 35 inflammatory bowel disease specialists, and 174 colorectal surgeons responded to the survey; 47, 41, and 23%, respectively, answered they did not feel comfortable managing perforations in ulcerative colitis patients in remission. We found the greatest concordance among gastroenterologists and colorectal surgeons in cases of perforation in ulcerative colitis with a history of dysplasia; the majority of respondents chose staged total proctocolectomy with ileal pouch anal anastomosis. We found discordance in decision making for ulcerative colitis in remission without dysplasia, with perforation occurring in colitis involved and uninvolved areas. CONCLUSION: Our survey revealed that a significant fraction of gastroenterologists and colorectal surgeons are uncomfortable managing iatrogenic colonic perforations in ulcerative colitis patients. We have identified knowledge and practice gaps in defining the optimal management of iatrogenic perforations in ulcerative colitis patients. PMID- 29978363 TI - 'Watch and wait' in rectal cancer: summary of the current evidence. AB - BACKGROUND: The management of rectal cancer has evolved considerably over the last few decades with increasing use of neoadjuvant chemoradiotherapy (nCRT). Complete clinical response (cCR) and even complete pathological response (pCR) have been noted in a proportion of patients who had surgery after nCRT. This raises the concern that we may have been 'over-treating' some of these patients and lead to an increasing interest in 'watch and wait' (W&W) approach for patients who had cCR to avoid the morbidity associated with rectal surgery. METHODS: A review of the literature in English pertaining to rectal cancer in the context of W&W, organ preservation and active surveillance. RESULTS: Evidence available to support W&W approach comes from non-randomised controlled trials (RCTs) with no current consensus on patients' selection criteria, lack of viable predictors of both cCR and pCR and lack of universal definitions of cCR and pCR. Also, there is no agreed protocol for disease surveillance. CONCLUSION: Even though there has been increasing reports on the outcomes of W&W in rectal cancer, the current evidence cannot support its routine use in clinical practice. This approach should be used in clinical trials settings or after thorough counselling with the patient on the outcomes of various treatment options. PMID- 29978364 TI - Effect of a patient-support program on once-daily teriparatide adherence and persistence in the Japan Fracture Observational Study (JFOS). AB - : Japanese patients with osteoporosis prescribed once-daily teriparatide for 24 months could enroll in a patient-support program designed to aid adherence and persistence. Patients enrolled in the program had higher adherence and persistence rates than those who did not enroll, highlighting the value of patient-support programs for improving adherence and persistence. OBJECTIVE: To assess the effect of a patient-support program on once-daily teriparatide adherence and persistence of patients who did and did not enroll. METHODS: In the 24-month Japan Fracture Observational Study, patients with osteoporosis prescribed teriparatide 20 MUg/day (N = 1996) could freely enroll in a patient support program (call center support, monthly calendar, certificates of recognition). Outcome measures were medication adherence (investigator assessed) and persistence (first date of teriparatide use to last date of use or study end). Multivariate logistic models were applied for adherence, and Kaplan-Meier survival curve for persistence. RESULTS: Overall, mean +/- standard deviation (SD) age was 76.9 +/- 7.9 years, and the proportion of female patients was 90.1%. Program enrollment status was 39.6% yes (n = 790), 22.9% no (n = 458), and 37.5% unknown (n = 748). In the analysis sample (1248 patients), adherence (> 75%) to teriparatide was more likely for patients enrolled in the support program (54.2 vs. 48.3%; adjusted odds ratio 1.44 [95% confidence intervals 1.04-2.00], p = 0.030). Good to very good (> 75%) adherence was also associated with smoking (negative association) and previous osteoporosis therapy (marginal positive association). Persistence rates were greater for patients enrolled in the support program than not enrolled (12 months 77.2 vs. 69.6%; 24 months 63.2 vs. 54.8%). CONCLUSIONS: Once-daily teriparatide adherence and persistence rates were higher among patients who enrolled in a patient-support program than among those who did not, highlighting the value of patient-support programs for improving adherence and persistence. PMID- 29978365 TI - The Association of Extent of Axillary Surgery and Survival in Women with N2-3 Invasive Breast Cancer. AB - BACKGROUND: Although surgical management of the axilla for breast cancer continues to evolve, axillary lymphadenectomy remains the standard of care for women with advanced nodal disease. We sought to evaluate national patterns of care in axillary surgery, and its association with overall survival (OS) among women with N2-3 invasive breast cancer. METHODS: Women (18-90 years) with clinical N2-3 invasive breast cancer who underwent axillary surgery were identified from the National Cancer Data Base (NCDB) from 2004 to 2013. Axillary surgery was categorized as sentinel lymph node biopsy (SLNB, 1-5 nodes) or axillary lymph node dissection (ALND, >= 10 nodes). Patient and treatment characteristics, trends over time, and overall survival (OS) were compared by surgical treatment. RESULTS: Overall, 22,156 patients were identified. At diagnosis, 68.5% had cN2 and 31.5% had cN3 disease. Treatment included: lumpectomy (27%), mastectomy (73%), adjuvant chemotherapy (53.4%), neoadjuvant chemotherapy (NAC) (39.7%), radiation (74%), and endocrine therapy (54.4%). In total, 9.9% (n = 2190) underwent SLNB and 90.1% (n = 19,966) underwent ALND. Receipt of SLNB was associated with private insurance, grade 3 disease, invasive ductal cancer, NAC, and lumpectomy (all p < 0.001). After adjustment for known covariates, including chemotherapy use, ALND was associated with improved survival [hazard ratio (HR) 0.68, p < 0.001] and this effect was similar for N2 and N3 patients (axillary surgery * cN-stage interaction p = 0.29). CONCLUSIONS: Axillary lymphadenectomy was associated with improved survival in patients presenting with clinical N2-3 invasive breast cancer. Further studies, particularly in the neoadjuvant setting, are needed to identify breast cancer patients with advanced nodal disease who may safely avoid a lesser extent of axillary surgery. PMID- 29978367 TI - Impact of Postmastectomy Radiation Therapy in Prepectoral Versus Subpectoral Implant-Based Breast Reconstruction. AB - BACKGROUND: This study aimed to compare the impact of postmastectomy radiation therapy (PMRT) on outcomes after prepectoral versus subpectoral implant-based breast reconstruction with local deepithelialized dermal flap and acellular dermal matrix (ADM). METHODS: From 2010 to 2017, 274 patients (426 breasts) underwent prepectoral reconstruction. In this group, 241 patients (370 breasts) were not exposed to PMRT, whereas 45 patients (56 breasts) were exposed to PMRT. Of 100 patients (163 breasts) who underwent partial subpectoral reconstruction, 87 (140 breasts) were not exposed to PMRT, whereas 21 patients (23 breasts) were exposed. The outcomes were assessed by comparing complication rates between the pre- and subpectoral groups. RESULTS: A higher rate of capsular contracture was found for the prepectoral patients with PMRT than for those without PMRT (16.1 vs 3.5%; p = 0.0008) and for the subpectoral patients with PMRT than for those without PMRT (52.2 vs 2.9%; p = 0.0001). The contracture rate was three times higher for the subpectoral patients with PMRT than for the prepectoral patients with PMRT (52.2 vs 16.1%; p = 0.0018). In addition, 10 (83.3%) of 12 cases with capsular contracture in the subpectoral cohort that received PMRT were Baker grades 3 or 4 compared with only 2 (22.2%) of 9 cases of the prepectoral group with PMRT (p = 0.0092). CONCLUSIONS: The patients undergoing subpectoral breast reconstruction who received PMRT had a capsular contracture rate three times greater with more severe contractures (Baker grade 3 or 4) than the patients receiving PMRT who underwent prepectoral breast reconstruction. PMID- 29978368 TI - Predicting Post Neoadjuvant Axillary Response Using a Novel Convolutional Neural Network Algorithm. AB - OBJECTIVES: In the postneoadjuvant chemotherapy (NAC) setting, conventional radiographic complete response (rCR) is a poor predictor of pathologic complete response (pCR) of the axilla. We developed a convolutional neural network (CNN) algorithm to better predict post-NAC axillary response using a breast MRI dataset. METHODS: An institutional review board-approved retrospective study from January 2009 to June 2016 identified 127 breast cancer patients who: (1) underwent breast MRI before the initiation of NAC; (2) successfully completed Adriamycin/Taxane-based NAC; and (3) underwent surgery, including sentinel lymph node evaluation/axillary lymph node dissection with final surgical pathology data. Patients were classified into pathologic complete response (pCR) of the axilla group and non-pCR group based on surgical pathology. Breast MRI performed before NAC was used. Tumor was identified on first T1 postcontrast images underwent 3D segmentation. A total of 2811 volumetric slices of 127 tumors were evaluated. CNN consisted of 10 convolutional layers, 4 max-pooling layers. Dropout, augmentation and L2 regularization were implemented to prevent overfitting of data. RESULTS: On final surgical pathology, 38.6% (49/127) of the patients achieved pCR of the axilla (group 1), and 61.4% (78/127) of the patients did not with residual metastasis detected (group 2). For predicting axillary pCR, our CNN algorithm achieved an overall accuracy of 83% (95% confidence interval [CI] +/- 5) with sensitivity of 93% (95% CI +/- 6) and specificity of 77% (95% CI +/- 4). Area under the ROC curve (0.93, 95% CI +/- 0.04). CONCLUSIONS: It is feasible to use CNN architecture to predict post NAC axillary pCR. Larger data set will likely improve our prediction model. PMID- 29978369 TI - Decreasing Use of Axillary Dissection in Node-Positive Breast Cancer Patients Treated with Neoadjuvant Chemotherapy. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) may downstage axillary disease in node positive breast cancer. Several clinical trials have shown that sentinel lymph node (SLN) surgery after NAC is feasible for these patients. We sought to evaluate the use of SLN surgery and ALND in cN1 patients undergoing NAC. METHODS: We identified all patients with biopsy-proven cN1 breast cancer treated with NAC at our institution between January 2009 and December 2017. Approximated biologic subtype was determined by estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status. Cochran-Armitage trend and Chi square tests were used for statistical analysis. RESULTS: Of 430 cN1 patients treated with NAC, 93 (22%) underwent SLN surgery only, 100 (23%) underwent SLN and ALND, and 237 (55%) underwent ALND only. The use of SLN surgery (+/- ALND) increased from 28% in 2009 to 86% in 2017 (p < 0.001), while the performance of ALND decreased from 100% in 2009 to 38% in 2017 (p < 0.001). Among SLN+ patients who underwent ALND, disease was limited to the SLNs in 25/73 (34%) patients. The nodal pathologic complete response rate was 46% and varied by tumor subtype (p < 0.001). Among patients undergoing SLN surgery, ALND was avoided in 48% of patients overall and varied by biologic subtype: 55% ER-/HER2+, 61% ER+/HER2+, 62% ER-/HER2-, and 31% ER+/HER2- (p = 0.001). With short-term follow-up, no nodal recurrences have occurred in patients without ALND. CONCLUSIONS: We observed a significant shift in axillary surgery for cN1 breast cancer patients treated with NAC, with increasing use of SLN surgery to assess nodal treatment response, and decreasing use of ALND. PMID- 29978366 TI - Impact of Combination Chemotherapy in Peritoneal Mesothelioma Hyperthermic Intraperitoneal Chemotherapy (HIPEC): The RENAPE Study. AB - BACKGROUND: The introduction of cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) improved the prognosis of selected patients with peritoneal mesothelioma (PM). OBJECTIVE: The objective of our study was to evaluate whether different HIPEC agents were associated with different outcomes in patients with PM. METHODS: From the RENAPE database, we selected all patients with histology-proven PM who underwent CRS + HIPEC from 1989 to 2014. Inclusion criteria were age <= 80 years, performance status <= 2, and no extraperitoneal metastases. RESULTS: Overall, 249 patients underwent CRS + HIPEC for PM. The HIPEC regimen included five chemotherapeutic agents (CAs), consisting of cisplatin, doxorubicin, mitomycin-C, oxaliplatin, and irinotecan. When considering all CAs (alone or in combination), there was no significant statistical difference in regard to postoperative overall survival (OS). However, OS was better when using two CAs (group 2 drugs) versus one CA (group 1 drug) (p = 0.03). The different CA regimens were equally distributed between the two groups. This association between OS and HIPEC agent, as well as a trend for better progression-free survival, were both observed in the two-drug group versus the one-drug group (p = 0.009) for patients undergoing complete cytoreductive surgery (CC-0) with an epithelioid subtype. CONCLUSIONS: This large study seems to show improved OS when combined CAs, especially with platinum-based regimens, are used for HIPEC in patients with PM, but needs to be confirmed by a randomized controlled trial. PMID- 29978370 TI - Ethical Considerations of Medical Photography in the Management of Breast Disease. AB - BACKGROUND: Medical photography has become an important component of the evaluation and management of patients across many specialties. It is increasingly utilized in contemporary practice with modern smartphones and enhanced digital media. Photography can enhance and improve treatment plans and communication between providers and patients. Additionally, photography supplements education, research, and marketing in both print and social media. Ethical and medicolegal standards for medical photography, specifically for patients with breast disease, have not been formally developed to guide medical providers. PURPOSE: To provide guidelines for breast care physicians using medical photography, the Ethics Committee of the American Society of Breast Surgeons presents an updated review of the literature and recommendations for ethical and practical use of photography in patient care. METHODS: An extensive PubMed review of articles in English was performed to identify studies and articles published prior to 2018 investigating the use of medical photography in patient care and the ethics of medical photography. After review of the literature, members of the Ethics Committee convened a panel discussion to identify best practices for the use of medical photography in the breast care setting. Results of the literature and panel discussion were then incorporated to provide the content of this article. CONCLUSION: The Ethics Committee of the American Society of Breast Surgeons acknowledges that photography of the breast has become an invaluable tool in the delivery of state-of-the-art care to our patients with breast disease, and we encourage the use of this important medium. Physicians must be well informed regarding the concerns associated with medical photography of the breast to optimize its safe and ethical use in clinical practice. PMID- 29978371 TI - Improved False-Negative Rates with Intraoperative Identification of Clipped Nodes in Patients Undergoing Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy. AB - BACKGROUND: Identification and resection of a clipped node was shown to decrease the false-negative rate (FNR) of sentinel lymph node biopsy (SLNB) after neoadjuvant chemotherapy (NAC) for patients presenting with initially node positive breast cancer. METHODS: Between March 2014 and March 2016, a prospective trial analyzed 98 patients with axilla-positive locally advanced breast cancer (T1-4, N1-3) to assess the feasibility and efficacy of placing clips into most suspicious biopsy-proven node. The study considered blue, radioisotope active, and suspiciously palpable nodes as sentinel lymph nodes (SLNs). RESULTS: The SLN identification rate was 87.8%. The median age of the patients with an SLNB (n = 86) was 44 years (range 28-66 years). Of these patients, 77 (88.4%) had cT1-3 disease, and 10 (11.6%) had cT4 disease. The majority of the patients (n = 66, 76.7%) had cN1, whereas 21 patients (23.3%) had cN2 and cN3. A combined method was used for 37 patients (43%), whereas blue dye alone was used for the remaining patients (57%). The clipped node was the SLN in 70 patients (81.4%). For the patients with cN1 before NAC, the FNR was found to be 4.2% (1/24) when the clipped node was identified as an SLN. However, the FNR was estimated to be as high as 16.7% (1/6) for the patients with cN1 before NAC when the clipped node was found to be a non-SLN. CONCLUSIONS: The study results also suggest that axillary dissection could be omitted for patients presenting initially with N1 disease and with a negative clipped node as the SLN after NAC due to the low FNR. PMID- 29978373 TI - Genomic and transcriptomic comparison of Aspergillus oryzae strains: a case study in soy sauce koji fermentation. AB - The filamentous fungus Aspergillus oryzae is used in soy sauce koji making due to its high productivity of hydrolytic enzymes. In this study, we compared the genomes and transcriptomes of an industrial strain RD2 and a strain with decreased fermentation performance TS2, aiming to explain their phenotypic differences at the molecular level. Under the regulation of conidiation and fermentation conditions, the enhanced hydrolytic enzyme production and flavor precursor formation in RD2 described a complete expression profile necessary to maintain desirable fermentation performance. By contrast, central carbon metabolism was up-regulated in TS2 for fast growth, suggesting a conflicting relationship between mycelium growth and fermentation performance. Accumulation of mutations also lowered the fermentation performance of TS2. Our study has deepened the understanding of the metabolism and related regulatory mechanisms in desirable koji fermentation. A list of potential molecular markers identified here could facilitate targeted strain maintenance and improvement for better koji fermentation. PMID- 29978372 TI - Intraoperative Nomograms, Based on One-Step Nucleic Acid Amplification, for Prediction of Non-sentinel Node Metastasis and Four or More Axillary Node Metastases in Breast Cancer Patients with Sentinel Node Metastasis. AB - BACKGROUND: One-step nucleic acid amplification (OSNA) for cytokeratin 19 messenger RNA is an intraoperative diagnostic procedure for the detection of lymph node metastasis. OBJECTIVE: This study aimed to construct intraoperative nomograms using OSNA for the prediction of non-sentinel lymph node (NSLN) metastasis and four or more axillary lymph node (ALN) metastases. METHODS: Of the 4736 breast cancer patients (T1-3, N0) who underwent sentinel lymph node (SLN) biopsy and had SLNs examined intraoperatively with OSNA, 623 with SLN metastasis treated with completion ALN dissection (cALND) were retrospectively analyzed, and were randomly divided into training (n = 312) and validation (n = 311) sets. RESULTS: Of the clinicopathological parameters available preoperatively and intraoperatively, the multivariate analysis of the training set revealed that clinical tumor size and total tumor load (TTL) determined by OSNA were significantly associated with NSLN metastasis, and that clinical tumor size, number of macrometastatic SLNs, and TTL were significantly associated with four or more ALN metastases. Nomograms for NSLN metastasis and four or more ALN metastases were constructed using these parameters, and their area under the receiver operating characteristic curve (AUC) of the validation set were both 0.70, with a diagnostic accuracy similar to that of previously reported postoperative nomograms. CONCLUSIONS: We constructed intraoperative nomograms using OSNA for the prediction of NSLN metastasis and four or more ALN metastases. These nomograms are as accurate as the conventional postoperative nomograms and might be helpful for decision making regarding the indication for cALND or the choice of adjuvant chemotherapeutic regimens and radiation field. PMID- 29978374 TI - Reclassification as NIFTP: a Retrospective Review in a Single Institution with an Emphasis on Workload. AB - The aim of this study was to determine the number of cases of papillary thyroid carcinoma (PTC) which could be reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in our institute over a 10 year period, document their clinical status and assess the number of slides that had to be reviewed per case to exclude NIFTP. The histopathology reports for thyroid resections for all papillary carcinoma over a 10-year period (2007-2016) were reviewed. Five hundred forty-five histopathology reports were reviewed, and 71 cases were identified as potential cases of NIFTP. Forty-nine (69%) cases had been referred from external departments and the slides were not available for review. Of the remaining 22 (31% of 71) cases, 5 were reclassified as NIFTP. The 17 cases that were not reclassified as NIFTP required review of 114 of 356 slides (median 5.5 slides per case) was required to exclude NIFTP. For the 5 NIFTP cases, 58 slides were reviewed (median 12 slides per case). We found that review of the histology reports alone was adequate for exclusion in most cases, e.g. classic PTC or EVPTC cases with documented lymphovascular invasion or capsular invasion. As a single exclusion criterion is required for exclusion from reclassification as NIFTP, this can be achieved efficiently. Two of the five patients received radioactive iodine [RAI] as per standard treatment at time of diagnosis, on the basis of tumour size. None have recurrent or metastatic disease with mean follow-up of 5.8 years. PMID- 29978375 TI - Effect of Vitamin D supplementation on body composition and cardiorespiratory fitness in overweight men-a randomized controlled trial. AB - PURPOSE: Several observational studies have shown an association between vitamin D deficiency and non-skeletal major health issues including impaired cardiorespiratory fitness and adiposity. Only a few studies have examined the impact of vitamin D supplementation on these conditions and the results are ambiguous. The aim of this study was to examine the effect of vitamin D supplementation on body composition and cardiorespiratory fitness in overweight/obese men with vitamin D deficiency. METHODS: This study was a prospective, placebo controlled, double blinded, randomized trial with a study period of 6 months. Forty overweight/obese men (BMI > 25 kg/m2) with vitamin D deficiency (25(OH)D <= 55 nmol/L) were randomized to receive either 2000 IU Cholecalciferol drops or the equivalent amount of drops of placebo. At baseline and follow up body composition and cardiorespiratory fitness were measured and blood samples were obtained. Body composition was measured using bioelectrical impedance analysis (BIA) and cardiorespiratory fitness using cardiopulmonary exercise test (CPET). The primary outcomes were changes in percentage body fat and in maximum oxygen uptake (VO2max). RESULTS: No statistically significant difference between the placebo and the intervention group regarding changes in percentage body fat (p = 0.54) and VO2max (p = 0.90) was observed. Moreover, there was no statistically significant difference between the groups concerning changes in BMI (p = 0.26), maximum load (p = 0.89) and oxygen uptake at anaerobic threshold (AT) (p = 0.14). CONCLUSIONS: We conclude that treatment with 2000 IU/d vitamin D for 6 months does not impact body composition or maximum oxygen uptake in overweight/obese men with vitamin D deficiency. PMID- 29978376 TI - [Expert systems-urgently needed for early diagnosis of sepsis : Results of retrospective clinical validation of the expert system FLORIDA]. AB - The expert system FLORIDA (Fuzzy Logic Orientated Rule Interpreter for Diagnostic Applications) is equipped with a knowledge base applying linguistic rules of clinical experts according to the pathophysiologic conception of the sepsis-3 definition and the mathematics of fuzzy logic. It works independently of any subjective factors. FLORIDA detects sepsis by an increase of a second incoming value >= 25% compared with the reference value. It requires dynamics of the parameters used in knowledge base; thus, if the dynamics are absent, the system is unable to detect sepsis. In a retrospective clinical validation study, FLORIDA was used to scan 498 consecutive patients in a medical intensive care unit, which corresponded to 1700 patient-days. During the study period, the prevalence of sepsis was 10%. In all, 423 patients were identified as not having sepsis, which was confirmed by clinical experts. Among the 48 patients identified as having sepsis, 26 were confirmed (true positive). In 22 patients, sepsis could not be confirmed by the clinician (false positive). FLORIDA did not detect sepsis in 4 patients, but was diagnosed by the clinician (false negative). In the 22 false positive patients, a life-threatening disease existed requiring intensive care. Because of the system philosophy, FLORIDA is unable to recognize patients with full blown sepsis at admission. With this in mind, the sensitivity was 1.0 and specificity was 0.95. Thus, FLORIDA is qualified for the early detection of a developing sepsis. Sepsis is detected on average 12.5 +/- 8.6 h after the start of sepsis has been determined by a clinical expert. FLORIDA should be used on normal wards and should contribute to early detection of sepsis and potentially earlier therapeutic intervention in order to decrease hospital mortality. However, prospective validation is needed. PMID- 29978377 TI - Food groups and risk of age-related macular degeneration: a systematic review with meta-analysis. AB - OBJECTIVE: To systematically review all the available evidence from prospective cohort studies that investigated the association between consumption of food groups and the occurrence of age-related macular degeneration (AMD). METHODS: We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, and bibliographies of retrieved articles up to January, 2018. Studies were included if they analysed prospectively the association between consumption of food groups and AMD. RESULTS: At the end of the selection process, 26 articles were included in the meta-analysis, for a total of 211,676 subjects and 7154 cases of AMD. By comparing the highest vs. the lowest consumption, pooled analyses showed no significant association with AMD for vegetables, fruit, nuts, grains, dairy products, as well as dietary fats such as oils, butter and margarine. Fish determined a significant (p < 0.05) reduction of risk for total AMD (RR 0.82 95% CI 0.75-0.90), as well as for both early (RR 0.84 95% CI 0.73-0.97), and late (RR 0.79 95% CI 0.70-0.90) AMD. On the other hand, high meat consumption was associated with a significant increased risk of early (RR 1.17 95% CI 1.02-1.34), but not late AMD. Finally, a significant increased risk of AMD for the highest consumption of alcohol (RR 1.20 95% CI 1.04-1.39) was reported. CONCLUSIONS: The results of the present meta-analysis show a significant 18% reduced risk for fish and a 20% increased risk for alcohol consumption. In addition, an increased risk was observed for meat, but only in the subgroup of early AMD. PMID- 29978378 TI - Pharmacokinetics of vitamin E, gamma-oryzanol, and ferulic acid in healthy humans after the ingestion of a rice bran-enriched porridge prepared with water or with milk. AB - PURPOSE: In this study, we investigated the absorption and excretion kinetics of antioxidant dietary phytochemicals (vitamin E, gamma-oryzanol, and ferulic acid) in healthy humans after the ingestion of an oatmeal porridge supplemented with rice bran extract (RBE) prepared with water or with whole milk, and we compared it with the intake of an equivalent dose of the rice bran content, in the form of RBE oil. METHODS: Twelve healthy volunteers (6 men and 6 women) orally ingested RBE oil (2 g) or RBE-enriched porridge (35 g, including 2-g RBE) with water or with milk, in a three-armed, crossover trial. Blood and urine samples were collected at baseline and up to 24 h after intake. Vitamin E (alpha-, beta-, gamma-, and delta-tocopherols and tocotrienols), ferulic acid (FA), and gamma oryzanol (ORY) were quantified by HPLC. RESULTS: The ingestion of RBE-fortified oatmeal porridge and RBE oil significantly increased FA concentrations in plasma, showing faster absorption and higher maximum plasma concentrations after the intake of the porridges, irrespective of the addition of water or milk. At least part of the FA could have been hydrolyzed from ORY. However, plasma vitamin E concentrations did not increase from baseline, and no intact FA esters (cycloartenyl ferulate, 24-methylenecycloartanyl ferulate, campesteryl ferulate, and beta-sitosteryl ferulate) were detected in plasma or urine with any of the meal treatments. CONCLUSIONS: Rice bran extract-enriched porridge and, to a lesser extent, RBE oil, provide relevant sources of bioaccessible and bioavailable ferulic acid, and could be further developed into functional foods with health potential. PMID- 29978379 TI - Correction to: Challenges in the assessment of total fluid intake in children and adolescents: a discussion paper. AB - In the original publication of the article, a mistake was introduced in affiliation of Dr. Michael Nelson. PMID- 29978380 TI - Molecular insight into the metabolic activities of a protein-rich micro alga, Arthrospira platensis by de novo transcriptome analysis. AB - To gain genetic insights into the protein-rich microalga, the transcriptome of Arthrospira platensis was sequenced using Illumina technology and de novo assembly was carried out. A total of 6023 transcripts were present in the transcriptome among which 4616 transcripts were annotated with specific functions. Gene ontology analysis revealed that the genes are mainly involved in three major functions such as biological (16.19%), cellular (41.47%) and molecular (42.34%) processes. Pathway analysis indicated that majority of genes are involved in amino acid biosynthesis and metabolism which is depicting the protein-rich nature of spirulina. Other major pathways involved are carbohydrate metabolism, lipid metabolism, metabolism of co-factors and vitamins, antioxidant mechanism and metabolism of terpenoids and polyketides. qRT-PCR analysis was performed to confirm the potential antioxidant role of five candidate genes of spirulina in protecting the cells from oxidative stress induced by hydrogen peroxide. Moreover, these results indicated that spirulina is rich in biological resources which could be efficiently used for multiple applications such as carbon dioxide utilization, nitrogen fixation and biofuel production. PMID- 29978382 TI - Development and characterization of 22 polymorphic microsatellites of the Andean frog Telmatobius chusmisensis (Anura, Telmatobius) and cross amplification in seven Chilean species of the genus. AB - The genus Telmatobius Wiegmann, 1834 is composed of a wide variety of species and is one of the most diverse native components of the high-altitude Andean environments. The species of the genus present in Chile are considered as endangered, critically endangered or data deficient. We isolated and evaluated 44 microsatellites in 80 individuals of 8 species of Telmatobius present in Chile, obtaining 22 polymorphic microsatellite loci for Telmatobius chusmisensis. The cross-amplification test was successful in all other species tested. For the first time, microsatellite markers are described for Telmatobius. The description of these primers will be useful for further genetic studies for T. chusmisensis and other species of the same genus; allowing further analyses of population structuring, dispersal patterns, recent demographic history and population effective size. This information is also significant to undertake conservation actions for the species of the genus Telmatobius, since most species have conservation issues. PMID- 29978381 TI - Cyclin-dependent kinase inhibitors, roscovitine and purvalanol, induce apoptosis and autophagy related to unfolded protein response in HeLa cervical cancer cells. AB - Roscovitine (Rosc) and purvalanol (Pur) are competitive inhibitors of cyclin dependent kinases (CDKs) by targeting their ATP-binding pockets. Both drugs are shown to be effective to decrease cell viability and dysregulate the ratio of pro and anti-apoptotic Bcl-2 family members, which finally led to apoptotic cell death in different cancer cell lines in vitro. It was well established that Bcl-2 family members have distinct roles in the regulation of other cellular processes such as endoplasmic reticulum (ER) stress. The induction of ER stress has been shown to play critical role in cell death/survival decision via autophagy or apoptosis. In this study, our aim was to investigate the molecular targets of CDK inhibitors on ER stress mechanism related to distinct cell death types in time dependent manner in HeLa cervical cancer cells. Our results showed that Rosc and Pur decreased the cell viability, cell growth and colony formation, induced ER stress-mediated autophagy or apoptosis in time-dependent manner. Thus, we conclude that exposure of cells to CDK inhibitors induces unfolded protein response and ER stress leading to autophagy and apoptosis processes in HeLa cervical cancer cells. PMID- 29978383 TI - Assessment of tumor necrosis factor alpha polymorphism TNF-alpha-238 (rs 361525) as a risk factor for development of acute kidney injury in critically ill patients. AB - : Critically ill patients revealed significant adverse outcomes (sepsis, septic shock, organ dysfunction/failure, and mortality) despite variable effort. AIM: this study evaluated the association of TNF-a-238 (rs 361525) with adverse outcomes in critically ill patients. TNF-alpha-238 (rs 361525) SNP was performed by RT-PCR on 200 critically-ill patients (112 had severe sepsis and septic shock and 88 were septic), 127 of them had AKI. Urinary N-acetyl-beta-(D) glucosaminidase and serum creatinine were assessed by modified Jaffe and ELISA respectively. These results revealed that heterozygous genotype GA of TNF-alpha 238 (rs 361525) SNP significantly increased the risk of adverse-outcome (mortality rate) (P = 0.0001; OR 8.9), regardless of organ dysfunction (P = 0.09) or severity of sepsis (P = 0.6). Moreover, heterozygous genotype GA of TNF-alpha 238 (rs 361525) SNP was significantly associated with inflammatory marker (sTNF alpha) (P = 0.014) and tubular injury marker (uNAG) (P = 0.001) that displayed a significant association with severity of sepsis (0.001, 0.035) and organ dysfunction (0.012, 0.0001) respectively. In critically ill patients with sepsis induced AKI, serum TNF-alpha and uNAG measured at admission can predict severity of sepsis and AKI (defined by REFILE) occurrence along with pre-existing CKD and DM. However, TNF-238 yielded additional prognostic information on ICU mortality irrelevant to AKI in septic patients. PMID- 29978384 TI - Polymorphic analysis of CYP2C9 gene in Vietnamese population. AB - Genetic variations in CYP2C9 are associated to inter-individual variability of drugs metabolism and response. The only report has been done previously mainly focusing on the common variant alleles of CYP2C9 in Vietnamese Kinh subjects. However, little is known about the complete spectrum of this gene polymorphism in different ethnic groups of Vietnam. We sequenced the promoter region and all exons of CYP2C9 in 100 healthy unrelated Vietnamese Kinh subjects. Additionally, common CYP2C9 variants, *2 and *3, were also analyzed by RFLP-PCR in extra 194 Kinh subjects and 279 of other four ethnic groups in Vietnam. The results of these common variants observed from five ethnic groups were compared with other populations in the world. Seven previously reported alleles and two genotypes were determined in Kinh subjects. The percentage of CYP2C9*1 and CYP2C9*3 alleles are 96.5 and 3.5%, respectively. We found one novel non-synonymous variant in exon 7 leading to amino acid change at 363 position from proline to histidine. Functional analysis by SIFT and Polyphen-2 indicated that this mutation is intolerant and probably damaging. Prevalence of CYP2C9*2 observed in Vietnamese population was significantly lower compared with that of other populations in the South and West of Asia as well as in Europe. This study provides information of genetic distribution pattern of CYP2C9 in Vietnamese, which would be useful for optimizing drug therapies in Vietnam. PMID- 29978385 TI - A case-oriented approach for analyzing the uncertainty of a reconstructed result based on the evidence theory. AB - Uncertainty analysis is an effective methodology to improve the reliability of an accident reconstruction result. Many existing methods can be employed in this field, which can confuse a practicing engineer who does not know these methods well. To make the selection easier, a case-oriented approach was proposed based on the evidence theory. Users only need to input uncertain traces and a selected accident reconstruction model to calculate the uncertainty of reconstructed results using the proposed approach. Three basic steps of the case-oriented approach are as follows: first, all types of input traces should be transformed into their evidence form; then, focal elements of the reconstructed result and their corresponding basic probability assignment (BPA) need to be calculated; finally, the belief function (Bel) and plausibility function (Pl) of the reconstructed results are calculated. Three common conditions, which are accidents with all interval traces, accidents with all probabilistic traces, and accidents with interval and probabilistic traces, were discussed based on the basic steps of the case-oriented approach. Furthermore, methods for how to transform different traces to their evidence form, how to calculate the interval of the response efficiently, and how to fuse high conflict evidence were presented. Numerical cases showed that the approach worked well in all conditions. Finally, a vehicle collisions accident case was presented to demonstrate the application of the proposed approach in practice. PMID- 29978386 TI - The Progress of Anti-HBV Constituents from Medicinal Plants in China. AB - Hepatitis B virus (HBV) infection causing acute and chronic hepatitis is a serious problem worldwide, whereas the current treatment methods are unsatisfactory. Traditional Chinese herbs that have long been used for medicinal purposes are fascinating sources for novel anti-HBV candidates. This paper summarizes the progress of anti-HBV constituents from diverse medicinal plants in China to provide information for searching new anti-HBV drugs from natural sources. PMID- 29978387 TI - Raman Spectroscopy of Multi-Layer Graphene epitaxially Grown on 4H-SiC by Joule Heat Decomposition. AB - We developed a Joule heating decomposition (JHD) method, which applied direct current on the SiC for the epitaxial growth of multi-layer graphene (MLG) films on Si-terminated (0001) face of the high doping 4H-SiC substrate. By this JHD method, the growth time for preparing MLG was only several minutes. Raman spectroscopy was employed to study the influence of the temperature caused by the Joule heating on the quality and the uniformity of the sample. Then, other properties, such as the strain, the layer's number, and the electric characteristics, of the MLG were studied in details. It was found that the quality of the MLG was substantially dependent on the growth temperature (operation current) and the growth time, while the layer's number was only dependent on the growth temperature but not the growth time. Finally, less-defect and homogeneous MLG (~ 45 layers) with an area of ~ 12 * 5 mm2 could be obtained at a heating temperature of ~ 1470 degrees C with duration time of 5 min. By using the linear transmission line method, the specific contact resistance of Au and MLG was 5.03 * 10-5 Omega cm2, and the sheet resistance was 52.36 Omega/sq, respectively. PMID- 29978388 TI - Intracranial pressure thresholds in severe traumatic brain injury: Con : The injured brain is not aware of ICP thresholds! PMID- 29978389 TI - Intracranial pressure thresholds in severe traumatic brain injury: Pro. PMID- 29978390 TI - Intracranial pressure thresholds in severe traumatic brain injury: we are not sure : Prudent clinical practice despite dogma or nihilism. PMID- 29978391 TI - Critical care research in the World Health Organization Eastern Mediterranean Region over two decades: where do we stand? PMID- 29978393 TI - Survey of Tools for Measuring In Vivo Photosynthesis. AB - Measurements of in vivo photosynthesis are powerful tools that probe the largest fluxes of carbon and energy in an illuminated leaf, but often the specific techniques used are so varied and specialized that it is difficult for researchers outside the field to select and perform the most useful assays for their research questions. The goal of this chapter is to provide a broad overview of the current tools available for the study of in vivo photosynthesis so as to provide a foundation for selecting appropriate techniques, many of which are presented in detail in subsequent chapters. This chapter also organizes current methods into a comparative framework and provides examples of how they have been applied to research questions of broad agronomical, ecological, or biological importance. The chapter closes with an argument that the future of in vivo measurements of photosynthesis lies in the ability to use multiple methods simultaneously and discusses the benefits of this approach to currently open physiological questions. This chapter, combined with the relevant methods chapters, could serve as a laboratory course in methods in photosynthesis research or as part of a more comprehensive laboratory course in general plant physiology methods. PMID- 29978392 TI - May the Best Joint-Actions Win: Physiological Linkage During Competition. AB - Previous work showed that, when we interact with other people, an alignment of psychophysiological measures occur as a clue about the intensity of the social interaction. Available evidence highlighted increase autonomic synchrony, known as physiological linkage, during intense dyadic situations, like conflictual conversations within romantic couples, friends, or therapeutic settings. Starting from the idea that higher physiological linkage could support better performance and be correlated with approach attitudes (Behavioral Activation System, BAS), in the present study a conflictual situation was proposed by making subjects compete during an attentional task and stressing the importance to win as a measure of future professional success. Autonomic activity (electrodermal: skin conductance level and response: SCL, SCR; and cardiovascular indices: heart rate: HR) was recorded during the task, where subjects received trial-related feedbacks on their performance, and an average score halfway which (fictitiously) assessed their position in terms of accuracy and reaction times with respect to the opponent. In parallel, behavioral inhibition and activation have been assessed by means of the Behavioral Inhibition/Activation System Questionnaire (BIS/BAS). 32 subjects coupled in 16 dyads were recruited. Intra-subject analyses revealed that, after the general evaluation assessing a winning condition, the behavioral performance improved and the electrodermal response increased. Also, correlational analyses showed a relation between BAS, and specifically BAS reward, with SCR. Inter-subject analyses showed higher synchrony in SCR and HR after the feedback. Such results confirm the increased synchronic effect after a highly conflictual condition, and the presence of a relation between subjective performance, approach-related motivations, and physiological linkage. PMID- 29978394 TI - Photosynthetic Gas Exchange in Land Plants at the Leaf Level. AB - Leaf-level gas exchange enables insights into the physiology and in vivo biochemical processes of plants. Advances in infrared gas analysis have resulted in user-friendly off-the-shelf gas exchange systems that allow researchers to collect physiological measurements with the push of a few buttons. Here, I describe how to set up the gas exchange equipment and what to pay attention to while making measurements, and provide some guidelines on how to analyze and interpret the data obtained. PMID- 29978395 TI - Design and Use of a Digitally Controlled Device for Accurate, Multiplexed Gas Exchange Measurements of the Complete Foliar Parts of Plants. AB - Performing accurate measurements of photosynthetic and respiration rates is vital to a large proportion of plant-based studies. While several commercial systems exist to perform such measurements, few are ideal for whole-plant measurements of small herbaceous plants such as Arabidopsis and none offer the capacity for simultaneous analysis of multiple plants. We, therefore, designed a multi chamber, computer-controlled, infrared gas analyzer-coupled system for the continuous measurement of gas exchange in whole-plant shoots or rosettes. This system was called ETH Gas Exchange System-1 (EGES-1). We have subsequently expanded the device to accommodate a wider variety of species while providing precise control over environmental parameters. Critically, we have (1) increased the flow rates through each of the eight chambers, (2) introduced a computer controlled feedback loop for the precise introduction of CO2, and (3) added an additional feedback loop for the introduction and control of humidity. The advantages of this new system (EGES-2) are illustrated here in the context of a variety of physiological experiments. PMID- 29978397 TI - Light-Response Curves in Land Plants. AB - Light-response curves reveal the photosynthetic properties of plants. Depending upon the methodology selected they can be used to characterize CO2 assimilation, photochemistry, photoacclimation, photoinhibition, and kinetics of photoprotective mechanisms in response to changing light conditions. They are widely used to describe the ontogeny and range in physiological plasticity of plants. Here we describe methods for acquiring light-response curves using CO2 gas exchange and chlorophyll a fluorescence measurements that are applicable to a wide range of land plants. PMID- 29978396 TI - Measuring Canopy Gas Exchange Using CAnopy Photosynthesis and Transpiration Systems (CAPTS). AB - Canopy photosynthesis (Ac), rather than leaf photosynthesis, is critical to gaining higher biomass production in the field because the daily or seasonal integrals of Ac correlate with the daily or seasonal integrals of biomass production. The canopy photosynthesis and transpiration measurement system (CAPTS) was developed to enable measurement of canopy photosynthetic CO2 uptake, transpiration, and respiration rates. CAPTS continuously records the CO2 concentration, water vapor concentration, air temperature, air pressure, air relative humidity, and photosynthetic photon flux density (PPFD) inside the chamber, which can be used to derive CO2 and H2O fluxes of a canopy covered by the chamber. Here we describe the protocol of using CAPTS to perform experiments on rice (Oryza sativa L.) in paddy field, wheat (Triticum aestivum L.) in upland field, and tobacco (Nicotiana tabacum L.) in pots. PMID- 29978398 TI - Chlorophyll Fluorescence on the Fast Timescale. AB - Chlorophyll fluorescence is a rapid and non-invasive tool used for probing the activity of photosynthesis that can be used in vivo and in the field. It is highly relevant to the demands of high-throughput crop phenotyping and can be automated or manually applied. Here we describe protocols and advice for making fast timescale fluorescence measurements using handheld equipment in the laboratory or in the field. While interpretation of some measured parameters requires caution, we demonstrate that this technique is appropriate for some applications where convenience, rapidity, and sensitivity are required. PMID- 29978399 TI - Sub-saturating Multiphase Flash Irradiances to Estimate Maximum Fluorescence Yield. AB - Many intricacies of leaf-level photosynthesis can be probed by combining infrared gas analysis with pulse-amplitude-modulation chlorophyll a fluorometry. A key fluorescence yield (PhiF) parameter required for estimating many of the phenomena associated with the light reactions of photosynthesis is referred to as the maximum PhiF, which is termed Fm' when measured on a light-adapted leaf. While ubiquitously used to assess many aspects of photosynthesis, Fm' is problematic because it is prone to being underestimated. This error can be propagated to parameters and phenomena that are based on estimation of Fm'. Theoretical and experimental observations have shown that PhiF increases hyperbolically in response to increasing irradiance, asymptotically approaching the maximum PhiF, or Fm', at extreme irradiances. Importantly, depending upon the convexity of the hyperbolic response, PhiF exhibits a linear and inverse relationship with the reciprocal of irradiance, a relationship previously referred to as a reciprocal plot. Given the negative slope of the reciprocal plot, estimates of PhiF at infinite irradiance can be obtained, even over sub-saturating irradiances, by linear regression and extrapolation of the resultant reciprocal plot to the y intercept. Here, we show how to obtain data from a dynamic multiphase flash of sub-saturating irradiance, occurring within the time span of ~1 s, to generate a reciprocal plot that subsequently provides an accurate estimate of PhiF at infinite irradiance, or Fm'. PMID- 29978400 TI - Chlorophyll Fluorescence Imaging. AB - Chlorophyll fluorescence imaging provides a noninvasive rapid screen to assess the physiological status of a number of leaves or plants simultaneously. Although there are no standard protocols for chlorophyll fluorescence imaging, here we provide an example of routines for some of the typical measurements. PMID- 29978401 TI - Measurement of O2 Uptake and Evolution in Leaves In Vivo Using Stable Isotopes and Membrane Inlet Mass Spectrometry. AB - Oxygen is both product and substrate of photosynthesis and metabolism in plants, by oxygen evolution through water splitting and uptake by photorespiration and respiration. It is important to investigate these processes simultaneously in leaves, especially in response to environmental variables, such as light and temperature. To distinguish between processes that evolve or take up O2 in leaves in the light, in vivo gas exchange of stable isotopes of oxygen and membrane inlet mass spectrometry is used. A closed-cuvette system for gas exchange of leaf disks is described, using the stable isotopes 16O2 and 18O2, with a semipermeable membrane gas inlet and isotope mass separation and detection by mass spectrometry. Measurement of evolution and uptake, as well as CO2 uptake, at a range of light levels allows composition of a light-response curve, here described for French bean and maize leaf disks. PMID- 29978402 TI - Using Stable Carbon Isotopes to Study C3 and C4 Photosynthesis: Models and Calculations. AB - Stable carbon isotopes are a powerful tool to study photosynthesis. Initial applications consisted of determining isotope ratios of plant biomass using mass spectrometry. Subsequently, theoretical models relating C-isotope values to gas exchange characteristics were introduced and tested against instantaneous online measurements of 13C photosynthetic discrimination. Beginning in the twenty-first century, tunable diode laser spectroscopes with sufficient precision for determining isotope mixing ratios became commercially available. This has allowed collection of large data sets, at low cost and with unprecedented temporal resolution. With more data and accompanying knowledge, it has become apparent that there is a need for increased complexity in models and calculations. This chapter describes instantaneous online measurements of 13C photosynthetic discrimination, provides recommendations for experimental setup, and presents a thorough compilation of equations needed for different applications. PMID- 29978403 TI - Liquid-Phase Measurements of Photosynthetic Oxygen Evolution. AB - This chapter compares two different techniques for monitoring photosynthetic O2 production: the widespread Clark-type O2 electrode and the more sophisticated membrane inlet mass spectrometry (MIMS) technique. We describe how a simple membrane inlet for MIMS can be made out of a commercial Clark-type cell, and outline the advantages and drawbacks of the two techniques to guide researchers in deciding which method to use. Protocols and examples are given for measuring O2 evolution rates and for determining the number of chlorophyll molecules per active photosystem II reaction center. PMID- 29978404 TI - Quantification of Photosynthetic Enzymes in Leaf Extracts by Immunoblotting. AB - In this chapter, we describe a method to extract and quantify photosynthetic enzymes using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) and immunoblotting. The method is particularly suitable for characterizing altered protein amounts in leaves of plants produced from genetic engineering or gene-editing approaches. We focus on RuBisCO and RuBisCO activase, a molecular chaperone required to sustain the activity of RuBisCO and CO2 fixation, yet the method can be easily adapted to investigate other leaf proteins of interest. PMID- 29978405 TI - Extraction of RuBisCO to Determine Catalytic Constants. AB - RuBisCO enables net carbon fixation through the carboxylation of RuBP during photosynthesis. Its complex biochemistry and catalytic diversity found among different plants make characterization of RuBisCO properties useful for investigations aimed at improving photosynthetic performance. This chapter reports methods for rapid extraction of soluble proteins to examine RuBisCO catalytic properties, and for large-scale purification of RuBisCO from leaves to measure the specificity of the enzyme toward its gaseous substrates. PMID- 29978406 TI - Spectrophotometric Determination of RuBisCO Activity and Activation State in Leaf Extracts. AB - RuBisCO plays a central role in photosynthesis and, due to its catalytic inefficiencies, frequently limits CO2 assimilation in fully illuminated leaves at the top of unstressed crop canopies. The CO2-fixing enzyme is heavily regulated and not all the enzyme present in the leaf is active at any given moment. In this chapter, a spectrophotometric assay is described for measuring RuBisCO activity and activation state in leaf extracts. Most of the assay components are available commercially and others can be produced by established protocols, making adoption of the assay achievable by most plant biochemistry laboratories. Its relative high-throughput capacity enables large-scale experiments aimed at screening germplasm for improved RuBisCO function. PMID- 29978407 TI - Creating Leaf Cell Suspensions for Characterization of Mesophyll and Bundle Sheath Cellular Features. AB - Imaging of mesophyll cell suspensions prepared from Arabidopsis has been pivotal for forming our current understanding of the molecular control of chloroplast division over the past 25 years. In this chapter, we provide a method for the preparation of leaf cell suspensions that improves upon a previous method by optimizing cellular preservation and cell separation. This technique is accessible to all researchers and amenable for use with all plant species. The leaf suspensions can be used for imaging chloroplast features within a cell that are important for photosynthesis such as size, number, and distribution. However, we also provide examples to illustrate how the cells in the suspensions can be easily stained to image other features, for example pit fields where plasmodesmata are located and organelles such as mitochondria, to improve our understanding of traits that are important for photosynthetic physiology. PMID- 29978408 TI - Determining the Subcellular Localization of Fluorescently Tagged Proteins Using Protoplasts Extracted from Transiently Transformed Nicotiana benthamiana Leaves. AB - In plants, stable expression is arguably the method of choice to test transgene function but it is a slow and labor-intensive process. This bottleneck generally limits the number of transgenes that can be tested, and as such hinders construct optimization. In the face of this challenge, transient expression in Nicotiana benthamiana leaves has emerged as a powerful screening platform to test gene expression, as well as subcellular distribution and function of many proteins within a week. This system relies on the infiltration of Agrobacterium tumefaciens (Agrobacterium) carrying DNA of interest into the leaf air spaces of N. benthamiana plants. Agrobacterium rapidly transforms the plant cells and the leaves can be analyzed within a few days. Investigating the subcellular localization of a protein of interest often relies on its fusion to a fluorescent tag. While the amount of accumulation of such fusion proteins can often be gauged by observing the fluorescence of the tag at the whole-leaf level, subcellular protein distribution is best determined in protoplasts extracted from transformed leaves. Here I present a simple and effective method to transform N. benthamiana leaves with Agrobacterium and to prepare protoplasts from these leaves to characterize the subcellular localization of proteins of interest. PMID- 29978409 TI - 3D Clearing and Molecular Labeling in Plant Tissues. AB - Plant histology and imaging traditionally involve the transformation of tissues into thin sections to minimize light scatter in opaque material, allowing optical clarity and high-resolution microscopy. Recently, new techniques in 3D tissue clearing, including PEA-CLARITY, have been developed to minimize light scatter within intact, whole samples. These techniques can achieve equivalent microscopic resolution to that of thin section imaging with the added benefit of maintaining the original 3D structure and position of biomolecules of interest. Furthermore, PEA-CLARITY is compatible with standard stains and immunohistochemistry, allowing molecular interrogation of intact, 3D tissues. This chapter outlines the current methods available for 3D histology in plants and details the materials, equipment, reagents, and procedure for the PEA-CLARITY technique. PMID- 29978410 TI - Evaluation of Lipids for the Study of Photosynthetic Membranes. AB - The biological role of lipids goes far beyond the formation of a structural membrane bilayer platform for membrane proteins and controlling fluxes across the membranes. For example, in photosynthetic thylakoid membranes, lipids occupy well defined binding niches within protein complexes and determine the structural organization of membrane proteins and their function by controlling generic physicochemical membrane properties. In this chapter, two-dimensional thin-layer chromatography (2D TLC) and gas chromatography (GC) techniques are presented for quantitative analysis of lipid classes and fatty acids in thylakoid membranes. In addition, lipid extraction methods from isolated thylakoid membranes and leaves are described together with a procedure for derivatization of fatty acids to fatty acid methyl esters (FAME) that is required for GC analysis. PMID- 29978411 TI - "Click" Methodology for the Functionalization of Water Oxidation Catalyst Iridium Oxide Nanoparticles with Hydrophobic Dyes for Artificial Photosynthetic Constructs. AB - The unusually high tolerance toward chemical functional groups of the copper(I) catalyzed Huisgen-Sharpless-Meldal 1,3-dipolar cycloaddition of azides and alkynes protocol (the CuAAC or "click" reaction) associated with its mild conditions and high yields has been explored in the present methodology to successfully prepare water oxidation catalyst iridium oxide nanoparticles decorated with organic dyes. The "click reaction" has proven to be an excellent synthetic tool to overcome the incompatible solubility of the hydrophilic iridium oxide nanoparticles and the hydrophobic dyes. A complex artificial photosynthetic model designed to mimic the photoinduced redox processes occurring in photosystem II is used as a hydrophobic dye to highlight the efficiency and selectiveness of the method. PMID- 29978412 TI - Biophotovoltaics: Design and Study of Bioelectrochemical Systems for Biotechnological Applications and Metabolic Investigation. AB - Biophotovoltaic methods rely on the fact that photosynthetic microorganisms, like many others, can export small amounts of electric current. For photosynthetic organisms, this current usually increases on illumination. This "exoelectrogenic" property may be of biotechnological interest, and may also provide useful experimental insights into the physiological status of the cell. We describe how to construct biophotovoltaic devices, and the kinds of measurements that are typically made. PMID- 29978413 TI - Neonatal outcome in gestational-diabetic mothers treated with antenatal corticosteroids delivering at the late preterm and term. AB - OBJECTIVE: To determine the association between antenatal corticosteroid treatment and neonatal complications in diabetic mothers delivering after 34 weeks of gestation. METHODS: A retrospective cohort study of women with singleton pregnancies diagnosed with gestational diabetes who delivered after 34 weeks of gestation in a university-affiliated medical center (2012-2016). Mothers treated with corticosteroids prior to 34 + 0 weeks of gestation were divided according to gestational age at delivery: late-preterm (34 + 0 to 36 + 6) and term (37 + 0 to 41 + 6). Each group was compared to women delivering at the same gestational age who were not treated with corticosteroids. Primary outcome was defined as a neonatal adverse composite outcome. Birth weight was amongst secondary outcomes measured. Logistic regression analysis was utilized to adjust results to potential confounders. RESULTS: During the study period, 161 diabetic mothers delivered at late-preterm. Amongst them, 47 (30%) were treated with corticosteroids. 2101 diabetic mothers delivered at term, amongst them 82 (4%) were treated with corticosteroids. Primary outcome did not differ between groups. Multivariate analysis demonstrated that corticosteroid treatment was not associated with neonatal adverse composite outcome when delivery occurred at the late preterm, nor at term (adjusted odds ratio (aOR) = 0.708, 95% CI 0.2-2.3, p = 0.572, and aOR = 1.6, 95% CI 0.2-12.7, p = 0.635, respectively). Birth weight was significantly lower in women treated with corticosteroids (2486 vs. 2675 g, p = 0.02 at late-preterm, and 3160 vs. 3319 g, p < 0.001 at term). CONCLUSION: Corticosteroid treatment for diabetic mothers was not associated with neonatal adverse outcomes, but was found associated with a lower birth weight, when delivery occurs after 34 weeks of gestation. PMID- 29978415 TI - Ring and Gellhorn pessaries used in patients with pelvic organ prolapse: a retrospective study of 8 years. AB - AIM: The aim of this study was to identify factors associated with pessary fitting, continued use of pessary and satisfaction of patients with pelvic organ prolapse. METHODS: A retrospective study was conducted in patients who received an initial pessary fitting. The clinical characteristics of these patients were recorded. The Pelvic Floor Disability Index PFDI-20 and PFIQ-7 were used to assess pelvic floor dysfunction and quality of life. Complications, satisfaction degree, and reasons for abandonment were recorded during the follow-up. T test and Chi square test in SPSS version 20 were used to analyze the data. RESULTS: Three hundred women with symptomatic prolapse were selected for pessary fitting, whose average age was 67.8 +/- 10.7 years. For two hundred and forty-nine (83%) women, the fitting was successful, of whom 162 used ring pessaries and 87 used Gellhorn pessaries. Forty-seven patients abandoned using a pessary at the end of our study. Most clinical characteristics were not significantly different between the successful and unsuccessful fitting groups (P > 0.05). The average score of CRADI-8 was lower in successful fitting group (11.9 +/- 15.9) than that in unsuccessful fitting group (18.8 +/- 19.9) (P < 0.05). 162 patients with successful pessary fitting completed the satisfaction survey, 79% of whom were satisfied or very satisfied. Erosions (24.4%) were the most common complication. Difficulty in inserting or removing (30.4%) and erosions (22.8%) were the main factors, which affected the satisfaction degree. CONCLUSIONS: Patients with obvious symptoms of posterior pelvic prolapse are more likely to fit failure. Difficulty in inserting or removing and erosions are the main factors, which lead to the discontinuation of pessary use and decrease in the satisfaction degree. PMID- 29978414 TI - Supplementation of folic acid in pregnancy and the risk of preeclampsia and gestational hypertension: a meta-analysis. AB - OBJECTIVES: We aimed to systematically assess the relationship between folic acid supplementation in pregnancy and risk of preeclampsia and gestational hypertension. METHODS: The relevant studies were included by retrieving the Embase, PubMed and Cochrane library databases. Data extraction was conducted by two investigators independently. The risk ratio (RR) and 95% confidence interval (CI) were used as effect indexes to evaluate the relationship between folic acid supplementation and risk of gestational hypertension or preeclampsia. A subgroup analysis was performed according to the supplementation patterns of folic acid. The homogeneity of the effect size was tested across the studies, and publication biases were examined. RESULTS: In total, 13 cohort studies and 1 randomized controlled trial study was included, containing 160,562 and 149,320 women with and without folic acid supplementation during pregnancy. Pooled results showed that risk of gestational hypertension was not associated with the supplementation of folic acid. However, folic acid supplementation during pregnancy could significantly reduce the risk of preeclampsia. Moreover, the results of subgroup analysis showed that the decreased preeclampsia risk was associated with supplementation of multivitamins containing folic acid rather than folic acid alone. CONCLUSIONS: Our findings indicate that the supplementation of multivitamins containing folic acid during pregnancy could significantly lower preeclampsia risk. PMID- 29978416 TI - Effect of Zinc Acetate Concentration on Optimization of Photocatalytic Activity of p-Co3O4/n-ZnO Heterostructures. AB - In this work, p-Co3O4/n-ZnO heterostructures were fabricated on Ni substrate by hydrothermal-decomposition method using cobaltous nitrate hexahydrate (Co(NO3)2.6H2O) and zinc acetate dihydrate (Zn(CH3COO)2.2H2O) as precursors with zinc acetate concentration varying from 5.0 to 55.0 mM. Structure and morphology of the developed samples were characterized by X-ray diffraction (XRD), Raman spectroscopy, and scanning electron microscopy (SEM). Effect of zinc acetate concentration on the photocatalytic activity of p-Co3O4/n-ZnO heterostructures was investigated by degradation of methyl orange (MO) under the UV light irradiation. The fabricated p-Co3O4/n-ZnO heterostructures exhibited higher photocatalytic activity than pure Co3O4 particles. In order to obtain the maximum photocatalytic activity, zinc acetate concentration was optimized. Specifically, at 35 mM of zinc acetate, the p-Co3O4/n-ZnO showed the highest photocatalytic activity with the degradation efficiency of MO reaching 89.38% after 72 h irradiation. The improvement of photocatalytic performance of p-Co3O4/n-ZnO heterostructures is due to the increased concentration of photo-generated holes on Co3O4 surface and the higher surface-to-volume ratio in the hierarchical structure formed by nano-lamellas. PMID- 29978417 TI - Extremely brief mindfulness interventions for women undergoing breast biopsies: a randomized controlled trial. AB - PURPOSE: Mindfulness-based programs can reduce stress and help practitioners to have positive attitudes in their daily lives. This randomized controlled trial evaluated the impact of brief Mindfulness interventions on quantitative and qualitative stress parameters in patients undergoing imaging-guided breast biopsies. METHODS: Eighty-two women undergoing percutaneous imaging-guided breast biopsy were randomized into two groups: MBI group or standard care group. One week before the biopsy procedure, on the waiting room and during the biopsy procedure, the MBI group was exposed to mindfulness techniques and the standard care group received supportive dialogue from the biopsy team. Participants completed questionnaires measuring depression, anxiety and stress, demographics, and medical history, besides evaluating their pain experience through a visual analogue scale for pain and had their systolic and diastolic blood pressure, initial and final temperate, heart rate, oxygen saturation, and salivary cortisol measured. RESULTS: Participation in the mindfulness intervention group was associated with reduced levels of perceived stress, blood pressure, heart rate, and oxygen saturation compared to participation in the standard care group (P values < 0.05). No difference was observed regarding salivary cortisol levels, peripheral temperature, and pain perception between the two studied groups. CONCLUSION: Results indicate that an extremely brief mindfulness intervention is a feasible intervention, suggesting that Mindfulness-based programs may be beneficial to reduce discomfort in acutely stressful settings. PMID- 29978418 TI - Dosimetric study to assess the feasibility of intraoperative radiotherapy with electrons (ELIOT) as partial breast irradiation for patients with cardiac implantable electronic device (CIED). AB - PURPOSE: To report in-vivo dosimetry in the infraclavicular region, a potential site of a cardiac implantable electronic device (CIED) and to evaluate the absorbed dose from intraoperative radiotherapy with electrons (ELIOT). METHODS: 27 non-cardiopathic breast cancer (BC) patients without CIED received quadrantectomy and ELIOT as partial breast irradiation. Before delivering ELIOT, two catheters, each containing eight thermoluminescent dosimeters (TLDs), were positioned in the infraclavicular region. TLDs internal catheter was located deep in the tumor bed while the external catheter was placed on patient's skin. RESULTS: Data were available for 24/27 patients. The absorbed doses were referred to the dose of 21 Gy. Values measured by the external catheter were low, although statistically significant higher doses were found close to the applicator (mean values 0.26-0.49 Gy). External TLD doses in proximity of the applicator were lower than those detected by their internal counterparts. Values measured by the internal catheter TLDs varied according to the distance from the applicator while no correlation with tumor site and beam energy was found. The distance from the applicator to deliver < 2 Gy to a CIED was 2 cm, while from 2.5 cm the dose measured in all the patients became negligible. CONCLUSIONS: This dosimetric study provided data to support the clinical use of ELIOT in BC patients having CIEDs as long as the suggested minimum safe distance of 2.5 cm is taken from the RT field in case of ELIOT single dose of 21 Gy, in the energy range of 6-10 MeV. PMID- 29978419 TI - Typical Brazilian genotype of Toxoplasma gondii isolated from a horse destined for human consumption in Europe from a slaughterhouse. AB - Toxoplasmosis is a zoonotic disease caused by the protozoan Toxoplasma gondii. Infections occur via the ingestion of oocysts, consumption of cysts containing bradyzoites, and transplacental transmission of tachyzoites. Diversity in T. gondii strains may affect the outcome of clinical toxoplasmosis. The consumption of horse meat is a common practice in some parts of the world. The objectives of the present study were to isolate and genotype T. gondii from horses from an abattoir in the state of Rio Grande do Sul in southern Brazil that exports horse meat to Europe. Antibodies to T. gondii were found in 32.5% (13/40) of the horses using the modified agglutination test (MAT) with a cut-off of 1:25. Tissues from the 13 seropositive horses were bioassayed in mice, and one isolate, designated TgHorseBrRS1, was obtained. PCR-RFLP of the isolate revealed the ToxoDB-RFLP #228 genotype, a typical non-archetypal Brazilian genotype, and microsatellite analysis showed a unique non-archetypal genotype. This study showed that horses from Brazil can harbor viable T. gondii in their tissues, suggesting that recommendations to consumers should be made, especially in European countries where consumption of raw horse meat is common. PMID- 29978420 TI - Leishmania tropica: suggestive evidences for the effect of infectious dose on pathogenicity and immunogenicity in an experimental model. AB - Leishmania (L.) tropica is a causative agent of cutaneous and occasionally visceral or viscerotropic leishmaniasis in humans. The dose of parasites influences the course and outcome of disease in some Leishmania species. The effect of parasite dose on L. tropica infection in an experimental model was studied in the current paper. High and low doses of L. tropica were used for ear infection of BALB/c mice and lesion development, parasite load, and cytokine responses were assessed. L. major infection was used for comparison. Pre-infected mice were challenged in the footpad by a fixed high dose of L. tropica, and immune response and protection level were evaluated. High dose L. tropica infection in comparison to low dose results in higher lesion diameters, higher load of parasite in draining lymph node, higher levels of interferon-gamma and interleukin-10, dissemination of parasite to spleen, and induction of protection against further L. tropica challenge. Comparison of L. tropica with L. major showed that L. tropica results in lower lesion diameters, more potential for growth in lymph nodes at early phases of infection, parasite dissemination to spleen, lower levels of IL-10, and a permanent lower cytokine response against low parasite dose in comparison to high dose. Our findings suggest that for L. tropica infection, only the high dose results in visceralization of the parasite and protection against further challenge of L. tropica. Therefore, the parasite dose may be an important factor in pathogenesis and immunity in L. tropica infection. PMID- 29978421 TI - Strongyloides stercoralis: detection of parasite-derived DNA in serum samples obtained from immunosuppressed patients. AB - Strongyloidiasis is an important neglected disease, which is life threatening in immunocompromised patients. This study aimed to evaluate the frequency of Strongyloides stercoralis infection among immunosuppressed subjects living in endemic communities by conventional PCR of the 18S rRNA and Cox1 genes to detect cell-free DNA in the patients' serum samples. Fresh stool and serum samples were obtained from participants. The stool samples were examined using parasitological methods. Total DNA was extracted from the serum samples and S. stercoralis larvae isolated from patient fecal samples. Conventional PCR to amplify a 101 bp fragment of the 18S rRNA gene was carried out for all extracted DNA, and then positive samples were further evaluated for a 121 bp fragment of the Cox1 gene. The PCR products of selected samples were sequenced and BLAST analysis was performed. Out of 120 patients, 57 and 63 cases had autoimmune disorders and cancer, respectively. The 101 bp fragments of the 18S rRNA were successfully amplified in 36 out of 120 (30%) serum samples. The PCR products of five samples were sequenced and compared with reference sequences in GenBank, which showed 97% identity and 90% coverage. In conclusion, to the best of our knowledge, this is the first molecular study for the detection of S. stercoralis cell-free DNA in human serum samples. These results provide useful insights for future studies and show that serum is an alternative specimen and may be useful in molecular diagnosis of diseases, particularly in immunosuppressive patients. PMID- 29978422 TI - DNA extraction from amoebal isolates and genotype determination of Acanthamoeba from tap water in Latvia. AB - Acanthamoeba are free-living amoebae found in various ecological environments, and they are major microbial predators. Some Acanthamoeba species can cause keratitis, granulomatous amoebic encephalitis, and infections of the organs. This is the first study in Latvia describing Acanthamoeba detection by molecular techniques and genotyping using tap water from different sources. An 18S rRNA gene investigation of the 20 Acanthamoeba isolates suggested that 19 belonged to the hazardous T4 genotype and one sample was T12. The results indicate that tap water in Latvia may be a source of Acanthamoeba that is potentially pathogenic to humans. All obtained sequences were submitted to the GenBank database under the following accession numbers: MG386295-MG386314. PMID- 29978423 TI - Viral Triggers and Inflammatory Mechanisms in Pediatric Epilepsy. AB - Experimental and clinical findings suggest a crucial role for inflammation in the onset of pediatric seizures; this mechanism is not targeted by conventional antiepileptic drugs and may contribute to refractory epilepsy. Several triggers, including infection with neurotropic viruses such as human herpesvirus 6 (HHV-6), other herpesviruses, and picornaviruses, appear to induce activation of the innate and adaptive immune systems, which results in several neuroinflammatory responses, leading to enhanced neuronal excitability, and ultimately contributing to epileptogenesis. This review discusses the proposed mechanisms by which infection with herpesviruses, and particularly with HHV-6, and ensuing inflammation may lead to seizure generation, and later development of epilepsy. We also examine the evidence that links herpesvirus and picornavirus infections with acute seizures and chronic forms of epilepsy. Understanding the mechanisms by which specific viruses may trigger a cascade of alterations in the CNS ultimately leading to epilepsy appears critical for the development of therapeutic agents that may target the virus or inflammatory mechanisms early and prevent progression of epileptogenesis. PMID- 29978424 TI - Klotho at the Edge of Alzheimer's Disease and Senile Depression. AB - Klotho, encoded by the KL gene, is a single-pass transmembrane protein and a circulating factor that plays a key role in cellular metabolism and body homeostasis and has been associated with age-related diseases. Alterations of this protein seem to influence the development of serotonergic neurons and could play a role in major depression in the elderly. Pretreatment of neurons with Klotho protein can avoid neuronal injury related to the toxic amyloid-beta and glutamate, centrally related to the pathogenesis of Alzheimer's disease (AD), in order that Klotho protein could play a neuroprotective role in AD patients. Late life depression, mild cognitive impairment, and dementia are different nosological entities but share common neurobiological facets and could represent a clinical continuum. Enhancement of Klotho levels in the early stages of the disease could represent a therapeutic strategy to prevent further deterioration and to ameliorate the outcome of elderly AD patients with or without major depression. PMID- 29978425 TI - Alcohol and Cocaine Exposure Modulates ABCB1 and ABCG2 Transporters in Male Alcohol-Preferring Rats. AB - Two efflux transporters, ATP-binding cassettes B1 (ABCB1) and G2 (ABCG2), are highly expressed in the endothelial cells of the brain, where they regulate the bioavailability and distribution of several endogenous and xenobiotic compounds. However, whether ABCB1 or ABCG2 has any link with drug dependence, drug withdrawal effects, or the incidence of adverse effects in drug abuser is not known. In this study, we determined the effects of voluntary ethanol consumption following repeated exposure to cocaine or vehicle on the relative mRNA and protein expression of Abcg2/ABCG2 and Abcb1/ABCB1 in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) of male alcohol-preferring (P) rats. Male P rats were allowed free choice access to ethanol (15 and 30% v/v) and water for 5 weeks to establish baseline drinking behavior. The following week, rats were either injected with 20 mg/kg i.p. of cocaine or saline, once a day, for 7 days. The relative mRNA and protein expression of Abcb1/ABCB1 and Abcg2/ABCG2 in the NAc and mPFC were significantly decreased in ethanol-saline- and ethanol-cocaine exposed rats compared to control rats that received neither ethanol nor cocaine. Thus, prolonged exposure to commonly abused drugs, ethanol and cocaine, alters the expression of Abcb1/ABCB1 and Abcg2/ABCG2 mRNA and protein levels in brain areas that play a role in drug dependence. PMID- 29978426 TI - Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement. AB - Purinergic signaling is the main synaptic and non-synaptic signaling system in brain. ATP acts as a fast excitatory transmitter, while adenosine sets a global inhibitory tone within hippocampal neuronal networks. ATP and adenosine are interconnected by ectonucleotidase enzymes, which convert ATP to adenosine. Existing data point to the converging roles of ovarian steroids and purinergic signaling in synapse formation and refinement and synapse activity in the hippocampus. Therefore, in the present study, we have used enzyme histochemistry and expression analysis to obtain data on spatial distribution and expression of ecto-enzymes NTPDase1, NTPDase2, and ecto-5'-nucleotidase (eN) after removal of ovaries (OVX) and estradiol replacement (E2) in female rat hippocampus. The results show that target ectonucleotidases are predominantly localized in synapse rich hippocampal layers. The most represented NTPDase in the hippocampal tissue is NTPDase2, being at the same time the mostly affected ectonucleotidase by OVX and E2. Specifically, OVX decreases the expression of NTPDase2 and eN, whereas E2 restores their expression to control level. Impact of OVX and E2 on ectonucleotidase expression was also examined in purified synaptosome (SYN) and gliosome (GLIO) fractions. Data reveal that SYN expresses NTPDase1 and NTPDase2, both of which are reduced following OVX and restored with E2. GLIO exhibits NTPDase2-mediated ATP hydrolysis, which falls in OVX, and recovers by E2. These changes in the activity occur without parallel changes in NTPDase2-protein abundance. The same holds for eN. The lack of correlation between NTPDase2 and eN activities and their respective protein abundances suggest a non-genomic mode of E2 action, which is studied further in primary astrocyte culture. Since ovarian steroids shape hippocampal synaptic networks and regulate ectonucleotidase activities, it is possible that cognitive deficits seen after ovary removal may arise from the loss of E2 modulatory actions on ectonucleotidase expression in the hippocampus. PMID- 29978427 TI - Role of silibinin in the management of diabetes mellitus and its complications. AB - Diabetes mellitus is globally approaching epidemic proportions and acts as a major cause of a number of serious health problems diagnosed as diabetic complications. The current oral drugs in the treatment of diabetes and its complications could meet some but not all of the patients' needs, and the development of novel drugs with a hypoglycemic effect is urgently required. Silibinin, a flavonolignan traditionally used for the treatment of gallbladder and hepatic diseases, was reported to improve glycemic homeostasis by improving the activity of pancreatic beta-cells, increasing insulin sensitivity of liver and muscle cells, and decreasing lipid deposition in adipocytes. Researches also indicated the effectiveness of silibinin in controlling several diabetic complications including neuropathy, retinopathy, impaired healing, hepatopathy, cardiomyopathy, nephropathy, and osteoporosis. In this review, we summarize the recent anti-diabetes findings of silibinin and clarify the underlying pharmacological mechanisms, and update the knowledge in understanding the role of silibinin in control of diabetic complications. PMID- 29978428 TI - Lifespan-extending property of 6-shogaol from Zingiber officinale Roscoe in Caenorhabditis elegans. AB - Aging is a key risk factor for many diseases, understanding the mechanism of which is becoming more important for drug development given the fast-growing aging population. In the course of our continued efforts to discover anti-aging natural products, the active constituent 6-shogaol was isolated from Zingiber officinale Roscoe. The chemical structure of 6-shogaol was identified by comparison of its NMR data with literature values. The lifespan-extending effect of 6-shogaol was observed in a dose-dependent manner in Caenorhabditis elegans that has been widely used as a model organism for human aging studies. Mechanism of such action was investigated using C. elegans models, suggesting that 6 shogaol is capable of increasing stress tolerances via enzyme induction. The proposed mechanism was further supported by observation of the increase in SOD and HSP expressions upon treatment with 6-shogaol in transgenic strains of C. elegans which contain GFP-based reporters. In addition, the mechanism was elaborated by confirming that the effect observed for 6-shogaol is independent from other aging-related factors that are known to affect the aging process of C. elegans. PMID- 29978429 TI - Evidence of an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients: a study comparing 18FDG-PET and visual evoked potentials. AB - BACKGROUND: Migraine attacks might be triggered by a disruption of cerebral homeostasis. During the interictal period migraine patients are characterized by abnormal sensory information processing, but this functional abnormality may not be sufficient to disrupt the physiological equilibrium of the cortex unless it is accompanied by additional pathological mechanisms, like a reduction in energetic reserves. The aim of this study was to compare resting cerebral glucose uptake (using positron emission tomography (18fluorodeoxyglucose-PET)), and visual cortex activation (using visual evoked potentials (VEP)), between episodic migraine without aura patients in the interictal period and healthy volunteers. METHODS: Twenty episodic migraine without aura patients and twenty healthy volunteers were studied. 18FDG-PET and VEP recordings were performed on separate days. The overall glucose uptake in the visual cortex-to-VEP response ratio was calculated and compared between the groups. Additionally, PET scan comparisons adding area under the VEP curve as a covariate were performed. For case-wise analysis, eigenvalues from a specific region exhibiting significantly different FDG-PET signal in the visual cortex were extracted. Standardized glucose uptake values from this region and VEP values from each subject were then coupled and compared between the groups. RESULTS: The mean area under the curve of VEP was greater in migraine patients compared to healthy controls. In the same line, patients had an increased neuronal activation-to-resting glucose uptake ratio in the visual cortex. Statistical parametric mapping analysis revealed that cortical FDG-PET signal in relation to VEP area under the curve was significantly reduced in migraineurs in a cluster extending throughout the left visual cortex, from Brodmann's areas 19 and 18 to area 7. Within this region, case-wise analyses showed that a visual neuronal activation exceeding glucose uptake was present in 90% of migraine patients, but in only 15% of healthy volunteers. CONCLUSION: This study identifies an area of increased neuronal activation-to-resting glucose uptake ratio in the visual cortex of migraine patients between attacks. Such observation supports the concept that an activity-induced rupture of cerebral metabolic homeostasis may be a cornerstone of migraine pathophysiology. This article has been selected as the winner of the 2018 Enrico Greppi Award. The Enrico Greppi Award is made to an unpublished paper dealing with clinical, epidemiological, genetic, pathophysiological or therapeutic aspects of headache. Italian Society for the Study of Headaches (SISC) sponsors this award, and the award is supported through an educational grant from Teva Neuroscience. This article did not undergo the standard peer review process for The Journal of Headache and Pain. The members of the 2018 Enrico Greppi Award Selection Committee were: Francesco Pierelli, Paolo Martelletti, Lyn Griffiths, Simona Sacco, Andreas Straube and Cenk Ayata. PMID- 29978430 TI - The Use of Metabolomics to Elucidate Resistance Markers against Damson-Hop Aphid. AB - Phorodon humuli (Damson-hop aphid) is one of the major pests of hops in the northern hemisphere. It causes significant yield losses and reduces hop quality and economic value. Damson-hop aphid is currently controlled with insecticides, but the number of approved pesticides is steadily decreasing. In addition, the use of insecticides almost inevitably results in the development of resistant aphid genotypes. An integrated approach to pest management in hop cultivation is therefore badly needed in order to break this cycle and to prevent the selection of strains resistant to the few remaining registered insecticides. The backbone of such an integrated strategy is the breeding of hop cultivars that are resistant to Damson-hop aphid. However, up to date mechanisms of hops resistance towards Damson-hop aphids have not yet been unraveled. In the experiments presented here, we used metabolite profiling followed by multivariate analysis and show that metabolites responsible for hop aroma and flavor (sesquiterpenes) in the cones can also be found in the leaves, long before the hop cones develop, and may play a role in resistance against aphids. In addition, aphid feeding induced a change in the metabolome of all hop genotypes particularly an increase in a number of oxidized compounds, which suggests this may be part of a resistance mechanism. PMID- 29978431 TI - How to Make a Mimic? Brood Parasitic Striped Cuckoo Eggs Match Host Shell Color but Not Pigment Concentrations. AB - Hosts of avian brood parasites often use visual cues to reject foreign eggs, and several lineages of brood parasites have evolved mimetic eggshell coloration and patterning to circumvent host recognition. What is the mechanism of parasitic egg color mimicry at the chemical level? Mimetic egg coloration by Common Cuckoos Cuculus canorus is achieved by depositing similar concentrations of colorful pigments into their shells as their hosts. The mechanism of parasitic egg color mimicry at the chemical level in other lineages of brood parasites remains unexplored. Here we report on the chemical basis of egg color mimicry in an evolutionarily independent, and poorly studied, host-parasite system: the Neotropical Striped Cuckoo Tapera naevia and one of its hosts, the Rufous-and white Wren Thryophilus rufalbus. In most of South America, Striped Cuckoos lay white eggs that are identical to those of local host species. In Central America, however, Striped Cuckoos lay blue eggs that match those of the Rufous-and-white Wren, suggesting that blue egg color in these cuckoo populations is an adaptation to mimic host egg appearance. Here we confirm that Striped Cuckoo eggs are spectrally similar to those of their hosts and consistently contain the same major eggshell pigment, biliverdin. However, wren eggshells lacked protoporphyrin, which was present in the parasitic cuckoo eggshells. Furthermore, biliverdin concentrations were significantly lower in cuckoo eggshells than in host eggshells. Similarity of host-parasite eggshell appearance, therefore, need not always be paralleled by a quantitative chemical match to generate effective visual mimicry in birds. PMID- 29978432 TI - Quantification of bone-marrow plasma cell levels using various International Myeloma Working Group response criteria in patients with multiple myeloma. AB - We examined the association of residual bone-marrow plasma cells (PCs) and International Myeloma Working Group (IMWG) response assessment in light-chain only multiple myeloma (LCMM) and intact immunoglobulin multiple myeloma (IIMM) using multicolour flow cytometry (MFC). We identify considerable differences in bone-marrow neoplastic PC levels between IIMM and LCMM for the same IMWG response categories. Furthermore, even in the same IMWG response category, residual neoplastic PC levels differed considerably over a logarithmic scale range However, normalization of the free light-chain ratio is associated with deeper response (< 10-4) in LCMM, but not in IIMM. Our observations highlight the importance of quantifying BM PC by MFC for response assessment, especially for relapsed disease when there is suspected discrepancy in paraprotein levels and disease progression. PMID- 29978434 TI - Staurosporine-induced apoptotic water loss is cell- and attachment-specific. AB - Apoptotic volume decrease (AVD) is a characteristic cell shrinkage observed during apoptosis. There are at least two known processes that may result in the AVD: exit of intracellular water and splitting of cells into smaller fragments. Although AVD has traditionally been attributed to water loss, direct evidence for that is often lacking. In this study, we quantified intracellular water in staurosporine-treated cells using a previously described optical microscopic technique that combines volume measurements with quantitative phase analysis. Water loss was observed in detached HeLa and in adherent MDCK but not in adherent HeLa cells. At the same time, adherent HeLa and adherent MDCK cells exhibited visually similar apoptotic morphology, including fragmentation and activation of caspase-3. Morphological changes and caspase activation were prevented by chloride channel blockers DIDS and NPPB in both adherent and suspended HeLa cells, while potassium channel blocker TEA was ineffective. We conclude that staurosporine-induced dehydration is not a universal cell response but depends on the cell type and substrate attachment and can only be judged by direct water measurements. The effects of potassium or chloride channel blockers do not always correlate with the AVD. PMID- 29978433 TI - Immuno-suppressive function of nucleus-transducible BAF57-DeltaPH in T cell activation via degradation of endogenous BAF57. AB - The BAF57 subunit, an indispensable member of the BAF complex, is functionally implicated in apoptosis, cell cycle, and T cell development through chromosomal remodeling. However, the precise roles of BAF57 in the T cell receptor (TcR) mediated signaling pathway have not been elucidated. In this study, a nucleus transducible form of BAF57, absent the proline-rich and HMG domains (ntBAF57 DeltaPH), was generated to interfere with the interaction between BAF57 and its binding protein, BAF155. ntBAF57-DeltaPH was effectively delivered into mouse CD4+ T cells in a dose- and time-dependent manner, without cellular toxicity. Inhibition of T cell activation by ntBAF57-DeltaPH was mediated by its disruption of the interaction between BAF155 and BAF57, leading to the degradation of endogenous BAF57 and BAF155. This phenomenon led to alterations in gene expression similar to those associated with Ciclosporin A treatment. In vivo administration of ntBAF57-DeltaPH enhanced survival rate of sepsis-induced mice and reduced the LPS-induced secretion of pro-inflammatory cytokines and the expression of endogenous BAF57. These results reveal a novel function of BAF57 as an essential regulator of T cell activation. ntBAF57-DeltaPH represents a novel immune-suppressive drug candidate with potential uses in the treatment of autoimmunity and graft rejection. PMID- 29978436 TI - Systematic review and meta-analysis of magnetic resonance imaging features for diagnosis of adhesive capsulitis of the shoulder. AB - OBJECTIVES: To perform a systematic review and meta-analysis to identify magnetic resonance imaging (MRI) features that will aid in the diagnosis of adhesive capsulitis of the shoulder (ACS) and provide a summary of the diagnostic accuracy of the identified features METHODS: The MEDLINE and EMBASE databases were searched for studies assessing the diagnostic accuracy of MRI features of ACS. Overlapping descriptors used to denote the same imaging finding in different studies were subsumed under a single feature. The pooled accuracy including the diagnostic odd ratios (DORs) with 95% confidence intervals (CIs) of the identified features was calculated using a bivariate random-effects model. RESULTS: In total, 15 studies were included, and 74 overlapping descriptors were subsumed under six features. All six features were found to be informative for ACS diagnosis [coracohumeral ligament thickening: DOR, 13; 95% CI, 6-29; fat obliteration of the rotator interval (RI): DOR, 8; 95% CI, 3-24; RI enhancement: DOR, 44; 95% CI, 14-141; axillary joint capsule enhancement: DOR, 52; 95% CI, 27 98; inferior glenohumeral ligament (IGHL) hyperintensity: DOR, 31; 95% CI, 8-115; IGHL thickening: DOR, 28; 95% CI, 11-70]. The sensitivity and specificity of enhancement of the RI and axillary joint capsule and IGHL hyperintensity were > 80%. CONCLUSIONS: Six informative MRI features for ACS diagnosis were identified in this study with RI and axillary joint capsule enhancement and IGHL hyperintensity showing the highest diagnostic accuracy. Informative features observed on non-arthrogram MRI can be as helpful as features observed on direct magnetic resonance arthrography for ACS diagnosis. KEY POINTS: * Six informative MRI features for ACS diagnosis were identified (diagnostic odds ratio > 1). * RI and axillary joint capsule enhancement and IGHL hyperintensity showed high sensitivities/specificities (> 80%). * The use of non-arthrogram MRI is recommended for ACS diagnosis. PMID- 29978435 TI - Tetz's theory and law of longevity. AB - Here, we present new theory and law of longevity intended to evaluate fundamental factors that control lifespan. This theory is based on the fact that genes affecting host organism longevity are represented by subpopulations: genes of host eukaryotic cells, commensal microbiota, and non-living genetic elements. Based on Tetz's theory of longevity, we propose that lifespan and aging are defined by the accumulation of alterations over all genes of macroorganism and microbiome and the non-living genetic elements associated with them. Tetz's law of longevity states that longevity is limited by the accumulation of alterations to the limiting value that is not compatible with life. Based on theory and law, we also propose a novel model to calculate several parameters, including the rate of aging and the remaining lifespan of individuals. We suggest that this theory and model have explanatory and predictive potential to eukaryotic organisms, allowing the influence of diseases, medication, and medical procedures to be re examined in relation to longevity. Such estimates also provide a framework to evaluate new fundamental aspects that control aging and lifespan. PMID- 29978437 TI - Tunable composites prepared from graphene oxide and zeolitic imidazolate framework-8 for improved selective isolation of hemoglobin. AB - The authors report on the preparation of composites made from graphene oxide (GO) and zeolitic imidazolate framework-8 (ZIF-GO), with various fractions of GO. GO acts as the template and as a modulator for the surface properties of the composites. It also improves the selective adsorption of specific proteins, i.e. hemoglobin (Hb) in this case. The adsorption capacity for Hb is as high as 436 mg g-1 when using a composite containing 20% of GO as sorbent, and 95% of specific activity is maintained for the Hb recovered. The sorbent is applied to selectively isolate Hb from human whole blood. Graphical abstract Graphene oxide zeolitic imidazolate framework-8 composites (ZIF-GO) with varying mass ratios of GO were prepared in order to tune surface properties and to improve the adsorption selectivity toward hemoglobin. PMID- 29978438 TI - Skull base versus non-skull base meningioma surgery in the elderly. AB - To compare outcomes after surgery for skull base meningiomas (SBMs) with non skull base meningiomas (NSBMs) in the elderly. Overall, 128 consecutive patients >= 70 years of age with intracranial SBMs operated between 1990 and 2010 were compared to 193 consecutive patients >= 70 years of age with NSBMs operated within the same time period. Median age at surgery was 75.0 years (mean 75.7, range 70.0-92.4). Follow-up was complete with median 4.7 years (mean 5.5, range 0 19). The female-to-male ratio was 2.8 for SBMs and 1.3 for NSBMs (p < 0.005). The groups had similar preoperative KPS (median 80, range 20-100), but SBMs presented significantly more frequently with raised ICP (RR = 2.2, p < 0.005) and less frequently with seizures (RR = 0.6, p < 0.05). WHO I was significantly more frequent in SBMs (p < 0.005). Gross-total resection (GTR) was less frequent in SBMs (63 vs 82%) (RR = 2.1, p < 0.0001). SBMs were similar to NSBMs with respect to neurological outcome at 6-12 months, reoperations for hematomas, postoperative infections, and 30-day mortality. Retreatment rates and time to retreatments were also similar. There were no differences between the two groups with respect to risk of retreatment and overall survival (OS) at 5, 10, 15, and 20 years. In elderly patients with SBMs selected to surgical treatment, the risks of surgery, risk of retreatment, and OS were similar to NBSMs. Therefore, surgery for SBMs may be considered as safe as NSBMs in the elderly population. PMID- 29978439 TI - Letter to the Editor: Mean Platelet Volume May Not Be Increased After Laparoscopic Sleeve Gastrectomy. PMID- 29978441 TI - Response to Letter to the Editor: Effect of Sleeve Gastrectomy on Platelet Counts and Mean Platelet Volumes. PMID- 29978440 TI - Destiny of Failed Adjustable Gastric Bandings: Do All the Patients Need Further Bariatric Surgery? AB - PURPOSE: The number of laparoscopic adjustable gastric banding (LAGB) removal has increased throughout the years. The aim of the study was to evaluate the outcomes in patients undergoing LAGB removal with or without further bariatric surgery. MATERIALS AND METHODS: Data prospectively collected from consecutive patients undergoing LAGB removal from 2008 to 2016 at our institution were retrospectively analyzed. Obesity-related comorbidities, complications, and body mass index (BMI) before removal and at 1-year follow-up were evaluated. RESULTS: A total of 156 patients were included in the study. Seventy-six patients had further surgery (SURG group): 55 underwent laparoscopic sleeve gastrectomy (LSG) and 21 laparoscopic Roux-en-Y gastric bypass (LRYGB). Eighty patients underwent only LAGB removal (No-SURG group). The mean BMI was lower in the No-SURG group (33.9 vs 36.3 kg/m2, p = 0.0055). Reasons for removal were different in the two groups: dysphagia, frequent vomiting, and LAGB-related complications requiring urgent treatment occurred more commonly in the No-SURG group (p < 0.05): 71.3 vs 51.3%, 67.5% vs. 38.2%, 28.8% vs. 6.6%, respectively. At 1-year follow-up, 96.3% of No SURG patients regained weight after LAGB removal; two (2.5%) patients showed new onset comorbidities, four (5%) needed adjustments in pharmacological therapy, and four (5%) complained from persistence of GERD symptoms. Additional surgery provided significant weight loss: the mean %TWL was 23.7% after LSGs and 27.2% after LRYGBs. CONCLUSIONS: LAGB is associated with a high rate of reoperation. Further bariatric surgery after LAGB removal should be considered due to weight regain, persistence of GERD symptoms, and new-onset comorbidities. PMID- 29978442 TI - [DOG recommendations for planning clinical trials commissioned by third parties : March 2018]. PMID- 29978443 TI - Fluorometric determination of sulfide ions via its inhibitory effect on the oxidation of thiamine by Cu(II) ions. AB - A fluorometric assay is described for sulfide ions determination. It is based on the finding that the oxidation of the non-fluorescent substrate thiamine (TH) by Cu(II) in basic solution to form fluorescent thiochrome is inhibited by sulfide ions. This results in a decrease in fluorescence intensity which is proportional to the concentration of sulfide ions. Under the optimized conditions, the decrease in fluorescence, best measured at excitation/emission wavelengths of 370/440 nm, decreases linearly in the 0.03 to 2.5 MUM sulfide ions concentration range. The detection limit is 20 nM. The method shows excellent selectivity over many potentially interfering ions and has been successfully applied to the determination of sulfide ions in spiked tap water, lake water and the synthetic wastewater samples. The method is time-saving and environmentally friendly, and in our perception shows a great potential in water quality inspection and environmental monitoring. Graphical abstract A fluorescent assay for sulfide ions detection is proposed based on its inhibitory effect on the oxidation of thiamine by Cu(II) ions. PMID- 29978444 TI - The association of potentially inappropriate medication use on health outcomes and hospital costs in community-dwelling older persons: a longitudinal 12-year study. AB - AIMS: To determine (1) whether potentially inappropriate medication (PIM) use defined by the Meds75 + database is associated with fracture-specific hospitalisations and all-cause mortality, and (2) the association between PIM use and all-cause hospitalisation costs in a 12-year follow-up of a nationwide sample of people aged >= 65 years in Finland. METHODS: This is a longitudinal study of 20,666 community-dwelling older persons with no prior purchases of PIMs within a 2-year period preceding the index date (1 Jan 2002), who were followed until the end of 2013. Data were obtained from the Finnish Prescription Register, and it was accompanied by information on inpatient care, causes of deaths and socioeconomic status from other national registers. Propensity score matching (PSM) analysis was used to account for potential selection effect in PIM use. Cox proportional hazards regression was used to identify the time to the first fracture or death by comparing PIM-users (n = 10,333) with non-users (n = 10,333). The association between PIM use and hospital costs was analysed with a fixed effects linear model. RESULTS: PIM use was weakly associated with an increased risk of fractures and death. The association was stronger in the first PIM-use periods. Hospitalised PIM-users had 15% higher hospital costs compared to non-users during the 12-year follow-up. CONCLUSION: PIM initiation was associated with an increased risk of fracture-specific hospitalisation and mortality and PIM users had higher hospital costs than non-users. Health care providers should carefully consider these issues when prescribing PIM for older persons. PMID- 29978445 TI - Surgical reconstruction of the acromioclavicular joint: Can we identify the optimal approach? AB - Injuries to the acromioclavicular (AC) joint are common, tending to occur secondary to traumatic injuries. Rockwood grade IV, V and VI injuries involve complete dislocation of the joint and require surgical reconstruction, with inconclusive literature on whether grade III injuries should be surgically or conservatively managed. There are over one hundred reported surgical techniques which reconstruct the AC joint, with little indication of which methods achieve the best results. Techniques can generally be considered as: anatomical reduction; CC ligament reconstruction; and anatomical reconstruction. Techniques which implant hardware to reduce the AC joint, such as the hook plate, are commonly implemented, but have been shown to alter the mechanics of the joint significantly, resulting in poor short-term and long-term outcomes. Methods which reconstruct both the acromioclavicular and coracoclavicular ligaments are comparatively new, and early reports suggest that they achieve biomechanical properties similar to the native joint. More focus should be placed on such techniques in the future to determine whether they offer a more suitable approach to improve patient outcomes following AC joint reconstruction. PMID- 29978446 TI - Sodium removal by peritoneal dialysis: a systematic review and meta-analysis. AB - Achievement of sodium and fluid balance is considered a major determinant of dialysis adequacy in peritoneal dialysis (PD). However, the contribution of different PD modalities to dialytic sodium removal (DSR) remains ill-defined. We performed a systematic review and meta-analysis to compare DSR by manual (continuous ambulatory PD, CAPD) versus automated PD (APD). Alternative PD strategies to remove sodium were also analyzed. Seven cohort studies, including 683 patients, 406 in CAPD and 277 in APD, were meta-analyzed out of the 30 studies selected based on DSR data availability. Overall, the unstandardized mean difference between CAPD and APD was significant [- 56 mmol/day (95% CI - 106, - 6), p = 0.027]. Heterogeneity was high (I2 87.2%; p < 0.001). Meta-regression showed a strict correlation of DSR difference with creatinine dialysate/plasma ratio (D/P) (p = 0.04). DSR was significantly lower in APD than CAPD [86.2 (57.3 115.1) vs. 141.3 (107.6-174.9) mmol/day, p = 0.015]. Conversely, ultrafiltration (UF) did not differ [1122.6 (891.2-1354.0) in CAPD and 893.6 (823.0-964.2) ml/day in APD, p = 0.064]. A very strong correlation between DSR and achieved UF was found in CAPD (R = 0.94; p < 0001) while no relationship was detected in APD (R = - 0.07; p = 0.85). CAPD allows a higher DSR than APD, even though UF is not different. APD removes more water than sodium; therefore, DSR should be measured rather than estimated from the achieved UF. The difference in DSR between the two modalities decreases in high transporters. Novel strategies proposed to increase DSR, e.g. lower sodium dialysate or adapted-APD, are promising, but ad hoc studies are necessary. PMID- 29978447 TI - Erratum to: Effects of Pulse Shape and Polarity on Sensitivity to Cochlear Implant Stimulation: A Chronic Study in Guinea Pigs. AB - In the original version of the chapter, the labels on the x-axis of Figure 2, panels A and B were wrong. This incorrect figure has been replaced with the below figure. PMID- 29978448 TI - Overexpression of lncRNA LINC01793 acts as a potential predictor for progression and poor prognosis of gastric cancer. AB - OBJECTIVE: Accumulating evidence has shown that differentially expressed long non coding RNA (lncRNA) is closely related to the development of gastric cancer. This study aims to explore the role of potential lncRNAs in the development of gastric cancer. METHODS: TCGA database of gastric cancer were analyzed by bioinformatics. LINC01793 was overexpressed in gastric cancer. Furthermore, LINC01793 level in 21 pairs of gastric cancer and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). Prognostic analysis was performed to investigate the predictive effect of LINC01793 on the prognosis of patients with gastric cancer. GSEA analysis was performed to investigate the possible biological processes of LINC01793 involved in the development of gastric cancer. RESULTS: LINC01793 was overexpressed in gastric cancer tissues compared to paracancerous tissues. Moreover, LINC01793 overexpression in gastric cancer was closely related to patients with poor prognosis. GSEA analysis found that LINC01793 was closely related to apoptosis, cell cycle, invasion and metastasis of gastric cancer cells. CONCLUSIONS: Our study showed that overexpression of LINC01793 indicates the poor prognosis of gastric cancer patients. Therefore, LINC01793 may serve as a target for the diagnosis and treatment of gastric cancer. PMID- 29978449 TI - Microenvironment in breast tumorigenesis: Friend or foe? AB - It is now widely accepted that the tumor microenvironment is a pathologically active niche that shapes tumor nature, evolution and response to treatment. Close interactions between cancer cells and stroma are known to regulate several cancer pathways and thus the determination of different tumor-stromal interactions could be an important step in invasiveness. The breast cancer microenvironment is a complex combination of several different cell types and molecules and a key contributor to tumor development and progression. The microenvironment includes fibroblasts, macrophages, immune cells, tumor-infiltrating lymphocytes, endothelial cells and angiogenic vascular cells, whereas stromal cells surround and interact with tumor cells. Recent data demonstrate significant gene expression alterations in microenvironment cells during disease progression and several stromal cell types are implicated in promoting the "hallmarks of cancer", which can be explored as targets for cancer therapy. Besides identifying new therapeutic targets, the microenvironment has also been implicated in chemotherapy resistance, suggesting that the crosstalk between cancer and its microenvironment is a promising strategy to target breast cancer. PMID- 29978451 TI - Obstetric emergencies as antecedents to neonatal hypoxic ischemic encephalopathy, does parity matter? AB - INTRODUCTION: Our aim was to investigate the risk of moderate to severe hypoxic ischemic encephalopathy (HIE) by obstetric emergencies, with focus on the distribution of obstetric emergencies by parity, taking the history of a previous cesarean into account. MATERIAL AND METHODS: Population-based cohort study of 692 428 live births at >= 36 weeks of gestation in Sweden, 2009-2015. Data were retrieved by linking the Swedish Medical Birth Register with the Swedish Neonatal Quality Register. Therapeutic hypothermia served as surrogate for moderate to severe HIE. Logistic regression analysis was used to estimate associations between HIE and placental abruption, eclampsia, cord prolapse, uterine rupture, and shoulder dystocia, presented as adjusted odds ratios (aORs) with 95% CI. RESULTS: An obstetric emergency occurred in 133/464 (29%) of all HIE cases, more commonly in the parous (overall 37%; 48% with and 31% without a previous cesarean) than in the nulliparous (21%). Among nulliparas, shoulder dystocia was the most common obstetric emergency with the strongest association with HIE (aOR 48.2; 95% CI 28.2-82.6). In parous women without a previous cesarean, shoulder dystocia was most common, but placental abruption had the strongest association with HIE. Among parous women with a previous cesarean, uterine rupture was the most prevalent obstetric emergency with the strongest association with HIE (aOR 45.6; 95% CI 24.5-84.6). CONCLUSIONS: Obstetric emergencies are common among cases of moderate to severe HIE. The strong association with shoulder dystocia in nullipara, and with uterine rupture in women with previous cesarean deliveries, implies an opportunity for reducing the incidence of HIE. PMID- 29978452 TI - Stage I Non-Hodgkin Lymphoma: difference in survival outcome by primary extranodal site of involvement. PMID- 29978454 TI - Perioperative goal-directed therapy: A systematic review without meta-analysis. AB - BACKGROUND: Perioperative goal-directed therapy aims to optimise haemodynamics by titrating fluids, vasopressors and/or inotropes to predefined haemodynamic targets. Perioperative goal-directed therapy is a complex intervention composed of several independent component interventions. Trials on perioperative goal directed therapy show conflicting results. We aimed to conduct a systematic review and meta-analysis to investigate the benefits and harms of perioperative goal-directed therapy. METHODS: PubMED, EMBASE, Web of Science and Cochrane Library were searched. Trials were included if they had a perioperative goal directed therapy protocol. The primary outcome was all-cause mortality. The first secondary outcome was serious adverse events excluding mortality. Risk of bias was assessed, and GRADE was used to evaluate quality of evidence. RESULTS: One hundred and twelve randomised trials were included of which one trial (1%) had low risk of bias. Included trials varied in patients: types of surgery which was expected due to inclusion criteria; in intervention and comparison: timing of intervention, monitoring devices, haemodynamic variables, target values, use of fluids, vasopressors and/or inotropes as well as combinations of these within protocols; and in outcome: mortality was reported in 87 trials (78%). Due to substantial clinical heterogeneity also within the various types of surgery a meta-analysis of data, including subgroup analyses, as defined in our protocol was considered inappropriate. CONCLUSION: Clinical heterogeneity in patients, interventions and outcomes in perioperative goal-directed therapy trials is too large to perform meta-analysis on all trials. Future trials and meta-analyses highly depend on universally agreed definitions on aspects beyond type of surgery of the complex intervention and its evaluation. PMID- 29978455 TI - Reconsidering the indication of haematopoietic stem cell transplantation for dyskeratosis congenita. PMID- 29978453 TI - Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm. AB - The Grupo Espanol de Linfomas y Trasplantes de Medula Osea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0.005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype. PMID- 29978456 TI - Paediatric patients with acute leukaemia and KMT2A (MLL) rearrangement show a distinctive expression pattern of histone deacetylases. AB - Histone deacetylase inhibitors (HDACi) had emerged as promising drugs in leukaemia, but their toxicity due to lack of specificity limited their use. Therefore, there is a need to elucidate the role of HDACs in specific settings. The study of HDAC expression in childhood leukaemia could help to choose more specific HDACi for selected candidates in a personalized approach. We analysed HDAC1-11, SIRT1, SIRT7, MEF2C and MEF2D mRNA expression in 211 paediatric patients diagnosed with acute leukaemia. There was a global overexpression of HDACs, while specific HDACs correlated with clinical and biological features, and some even predicted outcome. Thus, some HDAC and MEF2C profiles probably reflected the lineage and the maturation of the blasts and some profiles identified specific oncogenic pathways active in the leukaemic cells. Specifically, we identified a distinctive signature for patients with KMT2A (MLL) rearrangement, with high HDAC9 and MEF2D expression, regardless of age, KMT2A partner and lineage. Moreover, we observed an adverse prognostic value of HDAC9 overexpression, regardless of KMT2A rearrangement. Our results provide useful knowledge on the complex picture of HDAC expression in childhood leukaemia and support the directed use of specific HDACi to selected paediatric patients with acute leukaemia. PMID- 29978457 TI - Lower uterine segment placental thickness in women with abnormally invasive placenta. AB - INTRODUCTION: Ultrasound signs of abnormal placental invasion are subjective in nature. We tested the hypothesis that placental thickness in the lower uterine segment is increased when there is abnormally invasive placenta (AIP) in women with a low-lying placenta. MATERIAL AND METHODS: Retrospective analysis of data of placental thickness in women with ultrasound evidence of major placenta previa or a low-lying anterior placenta was done. The diagnosis of AIP was confirmed both intraoperatively and on histopathology for those managed by partial myometrial excision with uterine conservation or by hysterectomy. RESULTS: In all, 131 records were available for analysis after exclusion of 33 cases due to unsuitable images and eight cases without pregnancy outcomes. The diagnosis of AIP was confirmed in 28 (21.4%) of the 131 cases. The lower segment placental thickness was significantly higher in women with AIP (median = 50.3 mm, IQR: 42.7 64.3) than in those with normal placentation (median = 30.9 mm, IQR: 22.9-42.2, P < 0.001). Logistic regression analysis showed that previous cesarean section and placental thickness on ultrasound were independent predictors for AIP. CONCLUSIONS: Lower uterine segment placental thickness is increased in women with AIP compared with those with noninvasive placentation. This association constitutes a pragmatic objective sign and may be of clinical value in improving prenatal detection of AIP in women with placental implantation in the lower uterine segment. Prospective studies are necessary to ascertain lower segment placental thickness as a predictor for AIP. PMID- 29978458 TI - Clinical outcomes and survival of patients with myeloma and lymphoma enrolled into phase I clinical trials. PMID- 29978459 TI - The dual inhibitor of the phosphoinositol-3 and PIM kinases, IBL-202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment. AB - Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-delta respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance. PMID- 29978461 TI - Response to 'Considering the chemopreventive potential of nicotinamide in Gilmore's Bayesian analysis'. PMID- 29978462 TI - Predicting outcome in the seriously ill-A new approach. PMID- 29978460 TI - Spared CA1 pyramidal neuron function and hippocampal performance following antisense knockdown of microRNA-134. AB - OBJECTIVE: Inhibition of microRNA-134 by an oligonucleotide antagomir (ant-134) has been shown to produce powerful antiseizure effects in multiple models of epilepsy. However, to successfully translate the treatment to the clinic, it is important to assess what potential adverse effects it may have on naive brain tissue. METHODS: To investigate this, adult male Sprague-Dawley rats were treated with either ant-134 or a scrambled control sequence. Animals were later assessed for spatial navigation, before ex vivo slices were taken to assess the effects of microRNA-134 knockdown on well-defined measures of intrinsic and synaptic properties. RESULTS: Hippocampal field potential recordings determined that silencing of microRNA-134 by ant-134 injection was associated with a reduction in epileptiform activity following application of 9 mmol/L K+ . Nevertheless, rats performed normally in the novel object location test. Action potential waveforms and miniature excitatory synaptic currents recorded in CA1 pyramidal neurons were unaffected by ant-134. SIGNIFICANCE: These results demonstrate that ant-134 confers a seizure-protective effect without obvious interference with hippocampal neuronal properties or network function. These findings support further development of this novel approach to epilepsy treatment. PMID- 29978463 TI - The prognostic value of tumor-stroma ratio in tumor-positive axillary lymph nodes of breast cancer patients. AB - The tumor-stroma ratio (TSR) has previously been found to be a strong prognostic parameter in primary breast cancer tumors. Since the presence of tumor cells in lymph nodes is important for clinical decision making, the influence of TSR in the primary breast tumor combined with the TSR in tumor-positive lymph nodes on prognosis was evaluated. Women with invasive breast cancer without distant metastasis who underwent an axillary lymph node dissection between 1985 and 1994 at the Leiden University Medical Center were retrospectively analyzed. TSR assessment was performed on hematoxylin and eosin stained tissue slides. In total, 87 (45.5%) primary tumors were scored as stroma-low and 104 (54.5%) as stroma-high. Patients with a high stromal percentage in the primary tumors had a statistically significant worse relapse free period (RFP) compared to stroma-low tumors (HR 1.97, 95% CI 1.37-2.82, p < 0.001). A total number of 915 lymph nodes were assessed for TSR. In 101 (52.9%) patients, heterogeneity was observed between stroma percentage category in primary tumor and lymph nodes. The combination of TSR of the primary tumor combined with TSR of tumor-positive lymph nodes strengthened each other as independent prognostic parameter for RFP (p = 0.019). Patients with primary tumor stroma-low/lymph nodes stroma-low tumors showed strongly improved RFP rates compared to patients with primary tumor stroma high/lymph node stroma-high tumors with 10-year percentages of 58 versus 8%, respectively. Assessing the TSR on tumor-positive lymph nodes can provide additional prognostic information. Stromal activation strongly differs between primary tumors and lymph node metastasis. PMID- 29978464 TI - DNA methylation accumulation in gastric mucosa adjacent to cancer after Helicobacter pylori eradication. AB - Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication. PMID- 29978465 TI - Genetic variant of IRAK2 in the toll-like receptor signaling pathway and survival of non-small cell lung cancer. AB - The toll-like receptor (TLR) signaling pathway plays an important role in the innate immune responses and antigen-specific acquired immunity. Aberrant activation of the TLR pathway has a significant impact on carcinogenesis or tumor progression. Therefore, we hypothesize that genetic variants in the TLR signaling pathway genes are associated with overall survival (OS) of patients with non small cell lung cancer (NSCLC). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate associations between genetic variants of 165 TLR signaling pathway genes and NSCLC OS using the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). The results were further validated by the Harvard Lung Cancer Susceptibility GWAS dataset. Specifically, we identified IRAK2 rs779901 C > T as a predictor of NSCLC OS, with a variant-allele (T) attributed hazards ratio (HR) of 0.78 [95% confidence interval (CI) = 0.67-0.91, P = 0.001] in the PLCO dataset, 0.84 (0.72-0.98, 0.031) in the Harvard dataset, and 0.81 (0.73-0.90, 1.08x10-4 ) in the meta-analysis of these two GWAS datasets. In addition, the T allele was significantly associated with an increased mRNA expression level of IRAK2. Our findings suggest that IRAK2 rs779901 C > T may be a promising prognostic biomarker for NSCLC OS. PMID- 29978466 TI - Rotating night shift work and colorectal cancer risk in the nurses' health studies. AB - Animal and human data have suggested that shift work involving circadian disruption may be carcinogenic for humans, but epidemiological evidence for colorectal cancer remains limited. We investigated the association of rotating night shift work and colorectal cancer risk in two prospective female cohorts, the Nurses' Health Study (NHS) and NHS2, with 24 years of follow-up. In total, 190,810 women (NHS = 77,439; NHS2 = 113,371) were included in this analysis, and 1,965 incident colorectal cancer cases (NHS = 1,527; NHS2 = 438) were reported during followup (NHS: 1988-2012, NHS2: 1989-2013). We used Cox proportional hazards models adjusted for a wide range of potential confounders. We did not observe an association between rotating night work duration and colorectal cancer risk in these cohorts (NHS: 1-14 years: Hazard Ratio (HR) 1.04, 95% CI: 0.94, 1.16; 15+ years: HR 1.15, 95% CI: 0.95, 1.39; Ptrend = 0.14 and NHS2: 1-14 years: HR 0.81, 95% CI: 0.66, 0.99; 15+ years: HR 0.96, 95% CI: 0.56, 1.64 and Ptrend = 0.88). In subsite analysis in NHS, rectal cancer risk increased after long-term (15+ years) rotating night shift work (proximal colon cancer: HR 1.00, 95% CI: 0.75, 1.34, Ptrend = 0.90; distal colon cancer: HR 1.27, 95% CI: 0.87, 1.85, Ptrend = 0.32; rectal cancer: HR 1.60, 95% CI: 1.09, 2.34, Ptrend = 0.02). We found no overall evidence of an association between rotating night shift work and colorectal cancer risk in these two large cohorts of nurses. Risk for rectal cancer significantly increased with shift work duration, suggesting that long term circadian disruption may play a role in rectal cancer development. PMID- 29978468 TI - DNA concentration from self samples for HPV testing. PMID- 29978467 TI - A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2 positive metastatic breast cancer who had received at least two prior HER2 directed regimens: results of the NOV120101-203 trial. AB - Although the introduction of human epidermal growth factor receptor (HER)2 directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T-DM1) in the treatment of HER2-positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2 positive mBC will eventually progress. Poziotinib is an oral pan-HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2-positive mBC who had progressed from more than two HER2-directed therapies. Patients received 12 mg poziotinib once daily on a 14-day on/7-day off schedule. Progression-free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30-76) and had received a median of four prior therapies including two HER2-directed therapies for advanced or metastatic cancers. The median follow-up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94-4.40 months), and median overall survival has not been reached. The most common treatment-related adverse events were (total/grade >=3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2-positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases. PMID- 29978469 TI - Activation of WNT/beta-catenin signaling results in resistance to a dual PI3K/mTOR inhibitor in colorectal cancer cells harboring PIK3CA mutations. AB - PIK3CA is a frequently mutated gene in cancer, including about ~15 to 20% of colorectal cancers (CRC). PIK3CA mutations lead to activation of the PI3K/AKT/mTOR signaling pathway, which plays pivotal roles in tumorigenesis. Here, we investigated the mechanism of resistance of PIK3CA-mutant CRC cell lines to gedatolisib, a dual PI3K/mTOR inhibitor. Out of a panel of 29 CRC cell lines, we identified 7 harboring one or more PIK3CA mutations; of these, 5 and 2 were found to be sensitive and resistant to gedatolisib, respectively. Both of the gedatolisib-resistant cell lines expressed high levels of active glycogen synthase kinase 3-beta (GSK3beta) and harbored the same frameshift mutation (c.465_466insC; H155fs*) in TCF7, which encodes a positive transcriptional regulator of the WNT/beta-catenin signaling pathway. Inhibition of GSK3beta activity in gedatolisib-resistant cells by siRNA-mediated knockdown or treatment with a GSK3beta-specific inhibitor effectively reduced the activity of molecules downstream of mTOR and also decreased signaling through the WNT/beta-catenin pathway. Notably, GSK3beta inhibition rendered the resistant cell lines sensitive to gedatolisib cytotoxicity, both in vitro and in a mouse xenograft model. Taken together, these data demonstrate that aberrant regulation of WNT/beta-catenin signaling and active GSK3beta induced by the TCF7 frameshift mutation cause resistance to the dual PI3K/mTOR inhibitor gedatolisib. Cotreatment with GSK3beta inhibitors may be a strategy to overcome the resistance of PIK3CA- and TCF7 mutant CRC to PI3K/mTOR-targeted therapies. PMID- 29978470 TI - Temporal changes in characteristics and outcomes among pregnant women with pre gestational diabetes. AB - OBJECTIVE: To evaluate pregnancy outcomes among women with pre-gestational diabetes. METHODS: Retrospective analysis of pregnant women with type 1 or type 2 diabetes attending a university hospital in Brazil. Maternal characteristics and pregnancy outcomes were compared among deliveries between May 1, 2005, and December 31, 2010, and between January 1, 2011, and December 31, 2015. Risks were calculated by Poisson regression. RESULTS: In total 220 women were included. Type 1 diabetes was more frequent in 2005-2010 than in 2011-2015, and type 2 diabetes was more frequent in 2011-2015 (P=0.005). History of macrosomia (P=0.011), hypertensive disorders of pregnancy (P=0.015), and pre-gestational excess weight (body mass index >25 kg/m2 ; P=0.003) was more frequent in 2011-2015. For women with type 1 diabetes, pre-gestational weight (P=0.007) and glycated hemoglobin (P=0.026) were higher in 2011-2015. For women with type 2 diabetes, previous hypertensive disorders of pregnancy (P=0.032) were more prevalent and family history of diabetes (P<0.001) less prevalent in 2011-2015. Adverse pregnancy outcomes were similar for type 1 and type 2, and across both periods. CONCLUSION: Type 2 diabetes became more common over the two time periods and women with type 1 diabetes had higher pre-gestational weight. Perinatal outcomes were similar. PMID- 29978471 TI - Oral contraceptive use and cutaneous melanoma risk: a French prospective cohort study. AB - Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between oral contraceptive (OC) use and melanoma risk. However, findings were conflicting and data from large prospective studies are lacking. E3N is a prospective cohort of 98,995 French women aged 40-65 years at inclusion in 1990. Exposure to lifetime OC use was assessed in 1992 and through biennial questionnaire updates. To assess the association between OC use and melanoma risk, we used Cox models adjusted for age, pigmentary traits, residential ultraviolet (UV) exposure in county of birth and at inclusion and family history of skin cancer. Over 1992-2008, 539 melanoma cases were ascertained among 79,365 women. In age-adjusted models, we found a modest positive association between ever use of OCs and melanoma risk (hazard ratio (HR) = 1.18, 95% confidence intervals (CIs) = 0.98-1.42), which was reduced after adjustment (HR = 1.14, 95% CI = 0.95-1.38). The association was stronger in long-term users (duration >=10 years: HR = 1.33, 95% CI = 1.00-1.75) and in women who used high-estrogen OCs (HR = 1.27, 95% CI = 1.04-1.56). Among users, there was an inverse association with age at first use (ptrend < 0.01), but no evidence of an association with age at last use or time since last use. OC use was positively associated with tanning bed use (OR = 1.14, CI = 1.01-1.29), sunburns (ptrend = 0.5) and sunscreen use (OR = 1.13, CI = 1.00-1.28) since age 25. Overall, our findings do not support a strong association between OC use and melanoma risk and suggest intentional UV exposure in OC users, which supports a potential confusion by UV exposure in this relationship. PMID- 29978472 TI - Long non-coding RNA lnc-PCTST predicts prognosis through inhibiting progression of pancreatic cancer by downregulation of TACC-3. AB - Pancreatic cancer (PC), which is one of the most lethal of malignancies and a major health burden, is associated with a dismal prognosis despite current therapeutic advances. Numerous long noncoding RNAs (lncRNA) have shown to be essential for PC tumorigenesis and progression. Nevertheless, the exact expression pattern of lnc-PCTST and its clinical significance still remain unclear. This study investigates the expression pattern of lnc-PCTST and its associated mRNA in three paired PC tissues and adjacent non-tumor tissues by Microarray-coarray approach. Briefly, our data demonstrated that lnc-PCTST expression is down-regulated in PC tissues. Also, lnc-PCTST has shown to be negatively correlated with transforming acidic coiled-coil 3 (TACC-3) expression. This expression pattern was further confirmed following qRT-PCR validation of 34 out of 48 paired cancer tissues. Furthermore, lnc-PCTST overexpression in PC cell lines inhibited cell proliferation and invasion in vitro, and tumorigenesis in vivo (using nude mice as animal model), but did not altered cell migration. Moreover, lnc-PCTST overexpression increased E-cadherin and repressed vimentin expression in vitro. Additionally, TACC-3 knockdown simulated the inhibiting effect of lnc-PCTST overexpression on PC cell lines, and the impaired proliferation, invasion effect and E-cadherin, vimentin expression on lnc-PCTST over-expressed cell lines can be rescued by overexpressed TACC-3. Significantly, the expression of lnc-PCTST was closely associated with its genomic neighboring gene TACC-3 and inhibited its promoter activity. In conclusion, lnc-PCTST is a potential tumor suppressor in PC, which inhibits cell proliferation, invasion, tumorigenesis and EMT by modulating TACC-3. PMID- 29978473 TI - Misidentification of istiophorid billfishes by fisheries observers raises uncertainty over stock status. AB - We investigated whether commercially landed black marlin Istiompax indica were being misidentified by fisheries observers operating throughout the Pacific Ocean. Of 83 samples reported by observers as I. indica, 77% were genetically identified to be blue marlin Makaira nigricans and 2% to be striped marlin Kajikia audax. The high rate of misidentification by observers places considerable uncertainty over historic catch ratios of Indo-Pacific marlin and stock assessments relying on the validity of these data. PMID- 29978474 TI - Global cancer incidence in older adults, 2012 and 2035: A population-based study. AB - Population ageing has substantially contributed to the rising number of new cancer cases worldwide. We document cancer incidence patterns in 2012 among older adults globally, and examine the changing magnitude of cancer in this age group over the next decades. Using GLOBOCAN 2012 data, we presented the number and proportion of new cancer cases, and the truncated age-standardised incidence rates among adults aged 65 years and older for all cancer sites combined and for the five most common cancer sites by world region. We calculated the incidence in 2035 by applying population projections, assuming no changes in rates. In 2012, 6.7 million new cancer cases (47.5% of all cancers) were diagnosed among older adults worldwide, with marked regional disparities. Nearly 48% of these cases occurred in less developed regions. Lung, colorectal, prostate, stomach and breast cancers represented 55% of the global incidence, yet distinct regional patterns were observed. We predict 14 million new cancer cases by 2035, representing almost 60% of the global cancer incidence. The largest relative increase in incidence is predicted in the Middle East and Northern Africa (+157%), and in China (+155%). Less developed regions will see an increase of new cases by 144%, compared to 54% in more developed regions. The expected increase in cancer incidence at older ages will have substantial economic and social impacts globally, posing considerable and unique challenge to healthcare systems in every world region, especially in those with limited resources and weaker health systems. PMID- 29978475 TI - Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs - a PEARRL review. AB - OBJECTIVES: Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water-soluble drugs. KEY FINDINGS: An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid-based delivery, solid dispersions and nano- or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. SUMMARY: In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early-stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour-intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations. PMID- 29978476 TI - Plant galactolipid dLGG suppresses lung metastasis of melanoma through deregulating TNF-alpha-mediated pulmonary vascular permeability and circulating oxylipin dynamics in mice. AB - This study demonstrates the bioefficacy and gives mechanistic insights into a plant galactolipid 1,2-di-O-linolenoyl-3-O-beta-galactopyranosyl-sn-glycerol (dLGG) against metastatic melanoma using a syngeneic mouse model implanted with B16COX-2/Luc melanoma. dLGG-20 (p.o. dLGG 20 mg/kg) and anti-cancer drug CP-2 (i.p. cisplatin 2 mg/kg) treatment significantly inhibited lung metastasis of melanoma in mice 91 and 57%, respectively, as determined by bioluminescence intensity. Moreover, dLGG-20 and CP-2 treatment prolonged mouse mean survival time. dLGG-20 treatment significantly inhibited the expression levels of several molecular markers, that is, PCNA, MMP2, COX-2, VEGF, vimentin, snail, TGF-beta, beta-catenin, TNF-alpha, PD-1 and PD-L1 in mouse lung tissues compared to tumor control mice. Significant inhibition of macrophage and neutrophil infiltration and promotion of CD8 + Tc cell recruitment in the lung microenvironment was observed in dLGG-20-treated mice. A LC/MS-based comparative oxylipin metabolomics study showed that dLGG-20 treatment significantly induced (5.0- to 12.8-fold) the 12/15-LOX catalyzed oxylipin products in mouse serum including 17-HDHA from DHA, 15-HEPE from EPA, 8- and 12-HETEs from AA, and CYP450-derived 20-HETE from AA. CP 2 treatment increased 12/15-LOX derived 8-, 11- and 12-HETEs from AA, and CYP450 derived 11,12-EET from AA ad 9,10-DHOME from LA by 5.3- to 8.1-fold. Of note, dLGG and 17-HDHA were more effective than CP in preventing B16 melanoma cell induced pulmonary vascular permeability in mice through inhibition of TNF-alpha production, up-regulation of tight junction proteins claudin1 and ZO-2 and deregulation of Src activation. In conclusion, this study shows the novel therapeutic effect of phytoagent dLGG and suggests its potential as a therapeutic agent for metastatic melanoma. PMID- 29978477 TI - MiR-29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive gastrointestinal tumors, with an overall 5-year survival rate less than 8%. The dismal prognosis is mainly due to aggressive potential for metastasis. Hence, there is an urgent need for a better understanding of the molecular mechanisms underlying pancreatic cancer invasion and metastasis to improve the unfavorable overall survival (OS) of PDAC patients. In this study, we identified microRNA-29a (miR-29a) as an important tumor suppressor, which was downregulated in PDAC tissues. Moreover, miR-29a counteracted MUC16-mediated migration and invasion. In the pancreatic cancer cells, MUC16 upregulated c-Myc expression, which enhanced c Myc binding to E-box in the miR-29a promoter and inhibited miR-29a transcription. Thus, miR-29a was negatively correlated with both MUC16 expression and serum CA125 levels. Furthermore, caveolin 2 (CAV2) was demonstrated to be the target of miR-29a by bioinformatics and luciferase reporter assays, and high CAV2 expression was responsible for a poor prognosis, especially in the subgroup with normal CA125 levels. Thus, the present study explains why high levels of serum CA125 are correlated with PDAC metastasis, highlighting the predictive value of this marker in PDAC patients. PMID- 29978478 TI - How long does it take until the effects of endoscopic screening on colorectal cancer mortality are fully disclosed?: a Markov model study. AB - A recent randomized trial has suggested persisting protection from colorectal cancer (CRC) incidence and mortality of a single flexible sigmoidoscopy for up to 17 years and possibly beyond. We performed a simulation study to explore the time course and magnitude of protection provided by screening colonoscopy against CRC death over 25 years. Using data from the German national screening colonoscopy registry, a multistate Markov model was set up based on the adenoma-carcinoma pathway to estimate cumulative CRC mortality when different proportions of the population have a single screening colonoscopy at age 55, or two screening colonoscopies at ages 55 and 65. Cumulative CRC mortality continuously increased with age and reached 2.6 and 1.7% at age 80 in the absence of screening for men and women, respectively. A single colonoscopy at age 55, even with limited uptake, would lead to much lower cumulative mortality (0.7% for men and 0.5% for women at age 80 under 100% uptake). Relative mortality reduction continued to increase over more than 10 years and reached the maximum around 12-13 years after screening. Absolute risk reduction steadily increased throughout follow-up and more than half of the total risk reduction would occur between 15-25 years. A repeat colonoscopy 10 years later further enhanced the effects and cumulative mortality remained at 0.1-0.2% under 100% uptake. Even a single (once-only) screening colonoscopy has the potential to prevent most of CRC mortalities. Protective effects are expected to be long-lasting and to become fully manifest after more than two decades from screening. PMID- 29978479 TI - Fruit and vegetable consumption and breast cancer incidence: Repeated measures over 30 years of follow-up. AB - We evaluated the relation of fruit and vegetable consumption, including specific fruits and vegetables, with incident breast cancer characterized by menopausal status, hormone receptor status, and molecular subtypes. Fruit and vegetable consumption, cumulatively averaged across repeated, validated questionnaires, was examined in relation to risk of invasive breast cancer among 182,145 women initially aged 27-59y in the Nurses' Health Study (NHS, 1980-2012) and NHSII (1991-2013). Cox proportional hazards regression, adjusted for known risk factors, was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and assessed tumors by hormone receptor status and molecular subtypes. We prospectively documented 10,911 invasive breast cancer cases. Greater intake of total fruits and vegetables, especially cruciferous and yellow/orange vegetables, was associated with significantly lower breast cancer risk (>5.5 versus <=2.5 servings/day HR=0.89, 95%CI=0.83-0.96; Ptrend =0.005). Intake of total vegetables was especially associated with lower risk of estrogen receptor negative tumors (HR per 2 additional servings/day as a continuous variable=0.85, 95%CI=0.77-0.93; Pheterogeneity =0.02). Among molecular subtypes, higher intake of total fruits and vegetables (HR per 2 additional servings/day as a continuous variable) was most strongly associated with lower risk of human epidermal growth factor receptor 2 (HER2)-enriched (HR=0.78, 95%CI=0.66-0.92), basal-like (HR=0.85, 95%CI=0.73-0.99), and luminal A (HR=0.94, 95%CI=0.89-0.99), but not with luminal B tumors (Pheterogeneity =0.03). In conclusion, our findings support that higher intake of fruits and vegetables, and specifically cruciferous and yellow/orange vegetables, may reduce the risk of breast cancer, especially those that are more likely to be aggressive tumors. This article is protected by copyright. All rights reserved. PMID- 29978480 TI - A bacterial genotoxin causes virus reactivation and genomic instability in Epstein-Barr virus infected epithelial cells pointing to a role of co-infection in viral oncogenesis. AB - We have addressed the role of bacterial co-infection in viral oncogenesis using as model Epstein-Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram-negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV-negative epithelial cells to the virus in the presence of sub-lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV-induced malignant transformation of epithelial cells. PMID- 29978481 TI - Medical Group Characteristics and the Cost and Quality of Care for Medicare Beneficiaries. AB - OBJECTIVE: To estimate the relationship between outcomes of care and medical practices' structure and use of organized care improvement processes. DATA SOURCES/STUDY SETTING: We linked Medicare claims data to our national survey of physician practices (2012-2013). Fifty percent response rate; 1,040 responding practices; 31,888 physicians; 868,213 attributed Medicare beneficiaries. STUDY DESIGN: Cross-sectional observational analysis of the relationship between practice characteristics and total spending, readmissions, and ambulatory care sensitive admissions (ACSAs), for all beneficiaries and five categories of beneficiary defined by predicted need for care. PRINCIPAL FINDINGS: Practices with 100+ physicians and 50-99 physicians had, respectively, annual spending per high-need beneficiary that was $1,870 (12.5 percent) and $1,824 higher than practices with 1-2 physicians, and readmission rates 1.64 and 1.71 higher. ACSA rates did not vary significantly by practice size. Outcomes did not vary significantly by ownership or by practices' use of organized processes to improve care. CONCLUSIONS: Large practices had higher spending and readmission rates than the smallest practices, especially for high-need beneficiaries. There were no significant performance differences between physician-owned and hospital-owned practices. Policy makers should consider the effects of specific policies on provider organization, pending further research to learn which types of practice provide better care. PMID- 29978482 TI - Validation of the Mental Health Continuum-Short Form and the dual continua model of well-being and psychopathology in an adult mental health setting. AB - OBJECTIVE: The growing evidence for the dual continua model of psychopathology and well-being has important implications for measuring outcomes in mental health care. The aim of the current study is to validate a measure of well-being as well as the dual continua model in adults with mood, anxiety, personality, and developmental disorders. METHODS: 472 adult psychiatric outpatients filled out the Mental Health Continuum-Short Form (MHC-SF) and the Outcome Questionnaire before start of treatment. RESULTS: Confirmatory factor analyses (CFA) confirmed the three-factor structure of emotional, psychological, and social well-being of the MHC-SF. The dual continua model had the best fit in the complete sample and the different diagnostic groups. CONCLUSION: The MHC-SF is a reliable and valid instrument to measure well-being in the psychiatric population. Although relatively high correlations between psychopathology and well-being exist, the results underline the importance to measure well-being in addition to psychopathology in mental health care. PMID- 29978483 TI - Leaf rehydration capacity: Associations with other indices of drought tolerance and environment. AB - Clarifying the mechanisms of leaf and whole plant drought responses is critical to predict the impacts of ongoing climate change. The loss of rehydration capacity has been used for decades as a metric of leaf dehydration tolerance but has not been compared with other aspects of drought tolerance. We refined methods for quantifying the percent loss of rehydration capacity (PLRC), and for 18 Southern California woody species, we determined the relative water content and leaf water potential at PLRC of 10%, 25%, and 50%, and, additionally, the PLRC at important stages of dehydration including stomatal closure and turgor loss. On average, PLRC of 10% occurred below turgor loss point and at similar water status to 80% decline of stomatal conductance. As hypothesized, the sensitivity to loss of leaf rehydration capacity varied across species, leaf habits, and ecosystems and correlated with other drought tolerance traits, including the turgor loss point and structural traits including leaf mass per area. A new database of PLRC for 89 species from the global literature indicated greater leaf rehydration capacity in ecosystems with lower growing season moisture availability, indicating an adaptive role of leaf cell dehydration tolerance within the complex of drought tolerance traits. PMID- 29978484 TI - A novel mutation +5904 C>T of RUNX1 site in the erythroid cell-specific regulatory element decreases the ABO antigen expression in Chinese population. AB - BACKGROUND: An erythroid cell-specific regulatory element (+5.8-kb) in the first intron of ABO is responsible for the antigen differential expression and the regulatory activity of the element was affected by the nucleotide mutation in the +5.8-kb region. Currently, many individuals with ABO subgroups were found in the Chinese population, but there was little information about the function of +5.8 kb region in these individuals. Here, we studied the mechanism of the mutation in the +5.8-kb region responsible for reducing of antigen expression in 30 ABO subtype Chinese individuals without mutation in the coding region or splicing site. MATERIALS AND METHODS: The nucleotide sequence of the partial intron 1 covering the +5.8-kb site was amplified and directly sequenced. The haplotype with the novel mutation was obtained by the TOPO TA cloning. Both of the ABO promoter and the +5.8 kb regulatory element were subcloned into the basic luciferase reporter plasmid using the double endonuclease digestion. The promoter activity was examined by the dual-luciferase report vector with K562 cells. RESULTS: A novel nucleotide substitution +5904 C>T located at RUNX1-binding site in the +5.8 kb site was identified from three individuals with B subtypes. +5890 T>G were found in three Bel and one Ael phenotypes. Cotransfection and luciferase assays demonstrated that the +5904 C>T could obviously reduce activity of the +5.8 kb site. CONCLUSION: The study suggested that the transcriptional activity of the +5.8 kb site could be downregulated by the single point mutation of RUNX1 motif, leading to reduction in A or B antigen expression. PMID- 29978485 TI - Mucin 1 deficiency mediates corticosteroid insensitivity in asthma. AB - BACKGROUND: The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. METHODS: Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL-8, MMP9, and GM-CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines. RESULTS: Mucin 1-CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P < 0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (rho = -0.71; P < 0.0001). Dexamethasone showed lower anti-inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)-alpha phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1-CT/GRalpha complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti inflammatory effects of dexamethasone. CONCLUSION: Mucin 1-CT modulates corticosteroid efficacy in vitro and in vivo asthma models. PMID- 29978486 TI - Immune sensitization during 1 year in the Antarctic high-altitude Concordia Environment. AB - BACKGROUND: Antarctica is a challenging environment for humans. It serves as a spaceflight ground analog, reflecting some conditions of long-duration exploration class space missions. The French-Italian Concordia station in interior Antarctica is a high-fidelity analog, located 1000 km from the coast, at an altitude of 3232 m. The aim of this field study was to characterize the extent, dynamics, and key mechanisms of the immune adaptation in humans overwintering at Concordia for 1 year. METHODS: This study assessed immune functions in fourteen crewmembers. Quantitative and phenotypic analyses from human blood were performed using onsite flow cytometry together with specific tests on receptor-dependent and receptor-independent functional innate and adaptive immune responses. Transcriptome analyses and quantitative identification of key response genes were assessed. RESULTS: Dynamic immune activation and a two step escalation/activation pattern were observed. The early phase was characterized by moderately sensitized global immune responses, while after 3-4 months, immune responses were highly upregulated. The cytokine responses to an ex vivo stimulation were markedly raised above baseline levels. These functional observations were reflected at the gene transcriptional level in particular through the modulation of hypoxia-driven pathways. CONCLUSIONS: This study revealed unique insights into the extent, dynamics, and genetics of immune dysfunctions in humans exposed for 1 year to the Antarctic environment at the Concordia station. The scale of immune function was imbalanced toward a sensitizing of inflammatory pathways. PMID- 29978487 TI - Breaking down CO2 : bicarbonate the other side of central chemosensitivity in retrotrapezoid nucleus neurons. PMID- 29978488 TI - Transport mechanism of ursodeoxycholic acid in human placental BeWo cells. AB - Ursodeoxycholic acid (UDCA) is a first-line drug to treat intrahepatic cholestasis of pregnancy (ICP). However, its effects on the fetus are not clearly known. To better guide its clinical use, we aimed to study the mechanism underlying the placental transport of UDCA. The uptake and efflux of UDCA across placental apical membranes were studied using BeWo cells; effects of different exposure durations, UDCA concentrations, temperatures, and inhibitors of transporters were studied. A transwell assay was performed, and UDCA concentration in both fetal and maternal sides was measured using LC-MS/MS. Higher unidirectional transport of UDCA was observed in the basolateral-to-apical direction than in the apical-to-basolateral direction. Ko143 and verapamil, which are typical inhibitors of efflux transporters, significantly increased UDCA transport from different directions. UDCA uptake from the apical membrane of BeWo cells was time-dependent, but sodium-independent. It was inhibited by inhibitors of energy metabolism and of organic anion transporters, indicating an active transport mechanism. UDCA uptake from the apical membranes of BeWo cells could be mediated by organic anion-transporting polypeptides, whereas its efflux could be mediated by breast cancer resistance protein and multidrug resistant protein 3. The results of the present study may provide a basis for UDCA use in pregnancy. PMID- 29978489 TI - A reliable LC-MS/MS method for the quantification of N-acetyl-p benzoquinoneimine, acetaminophen glutathione and acetaminophen glucuronide in mouse plasma, liver and kidney: Method validation and application to a pharmacokinetic study. AB - A rapid, specific, and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated to simultaneously quantify N acetyl-p-benzoquinoneimine (NAPQI), acetaminophen-glutathione (acetaminophen glut) and acetaminophen-glucuronide (acetaminophen-gluc) in mouse plasma, liver and kidney homogenates. Analytes were eluted by a binary gradient mobile phase composed of water (phase A) and methanol containing 0.1% formic acid (phase B) at a flow rate of 0.3 mL/min, which was performed on a CAPCELL PAK C18 MG II column. It took 3.2 min to detect three analytes in a single run. Quantification was carried out in positive mode combined with multiple reaction monitoring. The validation of the LC-MS/MS method consisted of specificity, linearity, precision, accuracy, protein precipitation recovery, matrix effect, dilution integrity and stability. The plasma and tissue homogenate calibration curves were linear over concentration ranges of 0.050-5.00, 0.050-5.00 and 0.100-40.0 MUg/mL, with a lower limit of quantification of 0.050, 0.050, and 0.100 MUg/mL for NAPQI, acetaminophen-glut and acetaminophen-gluc, respectively. The intra- and inter-run precision values were within 12.47% for NAPQI, 12.11% for acetaminophen-glut and 11.86% for acetaminophen-gluc at their lower limit of quantitation levels. The samples were stable under all tested conditions. This method was successfully applied to study the pharmacokinetics of NAPQI, acetaminophen-glut and acetaminophen-gluc in ICR mice following oral administration of 200 mg/kg of acetaminophen suspension. PMID- 29978490 TI - Photochemical and Photodynamical Properties of Sulfur-Substituted Nucleic Acid Bases. AB - Sulfur-substituted nucleobases (a.k.a., thiobases) are among the world's leading prescriptions for chemotherapy and immunosuppression. Long-term treatment with azathioprine, 6-mercaptopurine and 6-thioguanine has been correlated with the photoinduced formation of carcinomas. Establishing an in-depth understanding of the photochemical properties of these prodrugs may provide a route to overcoming these carcinogenic side effects, or, alternatively, a basis for developing effective compounds for targeted phototherapy. In this review, a broad examination is undertaken, surveying the basic photochemical properties and excited-state dynamics of sulfur-substituted analogs of the canonical DNA and RNA nucleobases. A molecular-level understanding of how sulfur substitution so remarkably perturbs the photochemical properties of the nucleobases is presented by combining experimental results with quantum-chemical calculations. Structure property relationships demonstrate the impact of site-specific sulfur substitution on the photochemical properties, particularly on the population of the reactive triplet state. The value of fundamental photochemical investigations for driving the development of ultraviolet-A chemotherapeutics is showcased. The most promising photodynamic agents identified thus far have been investigated in various carcinoma cell lines and shown to decrease cell proliferation upon exposure to ultraviolet-A radiation. Overarching principles have been elucidated for the impact that sulfur substitution of the carbonyl oxygen has on the photochemical properties of the nucleobases. PMID- 29978491 TI - Photodynamic Therapy in HeLa Cells Incubated with Riboflavin and Pectin-coated Silver Nanoparticles. AB - Riboflavin (Rf) is an endogenous photosensitizer, which can participate in Type I and Type II processes. We have recently shown that the yield of the triplet excited states of Rf is enhanced in the presence of pectin-coated silver nanoparticles (Pec@AgNP) due to formation of a complex between Rf and Pec@AgNP (Rf-Pec@AgNP). Consequently, under aerobic conditions, the amounts of singlet molecular oxygen and superoxide radical anion generated are also larger in the presence of the nanoparticles. This result made us suspect that the nanoparticles could have a beneficial effect in Rf-based PDT. To prove this hypothesis, we here compared the photodamage in HeLa cells incubated with Rf in the presence and in the absence of Pec@AgNP applying several optical assays. We used fluorescence imaging of irradiated HeLa cells incubated with Annexin V and propidium iodide to evaluate the occurrence of apoptosis/necrosis, the reduction of the tetrazolium dye MTT to formazan and neutral red uptake to prove cell viability, as well as synchrotron infrared microscopy of single cells to evaluate possible structural changes of DNA and nuclear proteins. The enhanced photodamage observed in the presence of Pec@AgNP seems to indicate that Rf enters into the cells complexed with the nanoparticles. PMID- 29978492 TI - A promising, novel index in the diagnosis and follow-up of patent ductus arteriosus: Red cell distribution width-to-platelet ratio. AB - BACKGROUND: The role of red cell distribution width-to-platelet ratio (RPR) has not previously been mentioned in reports on patent ductus arteriosus (PDA). Our objective was to evaluate whether RPR would have a role in the diagnosis and/or prediction of pharmacological closure of PDA. METHODS: Preterm infants' gestational age <=30 weeks and <=1500 g who were given first ibuprofen treatment in the first week of life for hemodynamically significant PDA (hsPDA) were included in the study. The patients were matched for gestational age, birthweight, and sex. Patients were subdivided into two groups based on the response to medical treatment (open and closed PDA). Hemogram parameters were recorded before and after medical therapy. Groups were compared with regard to demographic and clinical characteristics and for three sequential hematological parameters. RPR was calculated. Patients with sepsis, anemia, perinatal asphyxia, and congenital/chromosomal anomaly were not included in the study. RESULTS: A total of 112 infants had medically treated hsPDA. Of those, ductus closed in 70 neonates (closed PDA). A total of 96 infants constituted the control group. Mean gestational age and birthweight of the patients were 28.9 +/- 2.4 weeks and 1207 +/- 372 g. While RPR was significantly increased, PCT was lower in both hsPDA and open PDA groups (P < 0.05 and P < 0.05, respectively). In multivariate analysis, high RPR (OR 3.3, 95% CI 1.438-5.872, P < 0.05) and RDS (OR 2.9, 95% CI 1.903 4.811, P < 0.01) were detected as independent risk factors for hsPDA. CONCLUSION: Red cell distribution width-to-platelet ratio and PCT may be promising supportive tools for the diagnosis and prediction of pharmacotherapy success. PMID- 29978493 TI - Rhizosphere interactions between copper oxide nanoparticles and wheat root exudates in a sand matrix: Influences on copper bioavailability and uptake. AB - The impact of copper oxide nanoparticles (CuONPs) on crop production is dependent on the biogeochemistry of Cu in the rooting zone of the plant. The present study addressed the metabolites in wheat root exudates that increased dissolution of CuONPs and whether solubility correlated with Cu uptake into the plant. Bread wheat (Triticum aestivum cv. Dolores) was grown for 10 d with 0 to 300 mg Cu/kg as CuONPs in sand, a matrix deficient in Fe, Zn, Mn, and Cu for optimum plant growth. Increased NP doses enhanced root exudation, including the Cu-complexing phytosiderophore, 2'-deoxymugineic acid (DMA), and corresponded to greater dissolution of the CuONPs. Toxicity, observed as reduced root elongation, was attributable to a combination of CuONPs and dissolved Cu complexes. Geochemical modeling predicted that the majority of the solution phase Cu was complexed with citrate at low dosing or DMA at higher dosing. Altered biogeochemistry within the rhizosphere correlated with bio-responses via exudate type, quantity, and metal uptake. Exposure of wheat to CuONPs led to dose-dependent decreases in Fe, Ca, Mg, Mn, and K in roots and shoots. The present study is relevant to growth of a commercially important crop, wheat, in the presence of CuONPs as a fertilizer, fungicide, or pollutant. Environ Toxicol Chem 2018;37:2619-2632. (c) 2018 SETAC. PMID- 29978494 TI - Levels of polybrominated diphenyl ethers in the Korean metropolitan population are declining: A trend from 2001 to 2013. AB - Polybrominated diphenyl ethers (PBDEs) have been banned or voluntarily withdrawn from commerce worldwide. Declining levels of PBDEs in humans have been reported elsewhere, but not in Korea. We monitored 7 individual PBDE congeners (BDE-28, BDE-47, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183) in 103 human serum samples collected in 2006. The arithmetic mean and median values for the sum of the 7 PBDEs (?PBDEs) were 7.13 and 6.70 ng/g lipid, respectively. In addition, 6 pooled human serum samples collected in 2006, 2007, 2009, 2011, 2012, and 2013 were analyzed. A decrease in PBDE levels was observed, as reflected by the median value of ?PBDEs from 5.98 in 2006 to 2.98 ng/g lipid in 2013 as well as in the pooled samples. The levels of individual congeners also decreased but at different declining rates. Based on these results and previously reported data, a definite decline in PBDE levels in the Korean metropolitan population could be observed from 2001 to 2013, providing the first evidence in Korea of the same decline observed elsewhere in the world. Environ Toxicol Chem 2018;37:2323-2330. (c) 2018 SETAC. PMID- 29978495 TI - Effects of hydrodynamic conditions and temperature on polar organic chemical integrative sampling rates. AB - The effects of changing hydrodynamic conditions and changing temperatures on polar organic chemical integrative sampler (POCIS) sampling rates (Rs ) were investigated for 12 crop protection chemicals. Exposure concentration was held constant in each laboratory experiment, and flow velocities were calculated from measured mass transfer coefficients of the water boundary layer near the surface of POCIS devices. At a given temperature Rs generally increased by a factor of 2 to 5 between a stagnant condition and higher flow velocities (6-21 cm/s), but Rs for most compounds was essentially constant between the higher flow velocities. When temperature was varied between 8 and 39 degrees C for a given flow condition, Rs increased linearly. In general, Rs increased by a factor of 2 to 4 and 2 to 8 over this temperature range under flow and stagnant conditions, respectively. An Arrhenius model was used to describe the dependence of POCIS sampling rates on temperature. Adjustments of Rs for temperature did not fully explain observed differences between time-weighted average concentrations of atrazine determined from POCIS and from composite water sampling in a field setting, suggesting that the effects of other competing factors still need to be evaluated. Environ Toxicol Chem 2018;37:2331-2339. (c) 2018 SETAC. PMID- 29978496 TI - Differences in health outcomes associated with initial adherence to oral antidiabetes medications among veterans with uncomplicated Type 2 diabetes: a 5 year survival analysis. AB - AIM: To determine the association of adherence to oral antidiabetes medication with macrovascular and microvascular complications, time to insulin therapy, revascularization, admissions, and death among veterans with uncomplicated diabetes. METHODS: This was a retrospective cohort study using the Veterans Affairs Corporate Data Warehouse to examine 159 032 veterans diagnosed with uncomplicated diabetes during 2002-2014 and starting oral antidiabetes therapy for the first time. The first uncomplicated diabetes diagnosis was identified and confirmed by subsequent oral antidiabetes therapy initiation. Adherence was calculated from outpatient pharmacy records using the proportion of days covered over the first year of therapy. Health outcomes were observed up to 5 years beyond the first oral antidiabetes agent fill, and compared according to adherence status using Cox proportional hazards models adjusted for baseline demographic and clinical characteristics. RESULTS: During the first 5 years of oral antidiabetes treatment, people initially non-adherent to oral antidiabetes therapy were more likely to experience myocardial infarction (hazard ratio 1.14, 95% CI 1.03-1.27) and ischaemic stroke (hazard ratio 1.22, 95% CI 1.05-0.1.42), or to die (hazard ratio 1.21; 95% CI 1.15-1.28). Veterans with <20% adherence to oral antidiabetes therapy in the first year had particularly high hazards for ischaemic stroke (hazard ratio 1.78, 95% CI 1.27-2.49) and all-cause death (hazard ratio 1.33, 95% CI 1.17-151). Adherent people were more likely to be diagnosed with a microvascular complication or chronic kidney disease. CONCLUSIONS: People who are non-adherent to treatment were more likely to experience detrimental health outcomes within the first 5 years of antidiabetes therapy. Adherence is paramount to disease management and this should be stressed from the time at which treatment is initiated. PMID- 29978497 TI - Coupling toxicokinetic-toxicodynamic and population models for assessing aquatic ecological risks to time-varying pesticide exposures. AB - Population modeling evaluations of pesticide exposure time series were compared with aspects of a currently used risk assessment process. The US Environmental Protection Agency's Office of Pesticide Programs models daily aquatic 30-yr pesticide exposure distributions in its risk assessments, but does not routinely make full use of the information in such time series. We used mysid shrimp Americamysis bahia toxicity and demographic data to demonstrate the value of a toxicokinetic-toxicodynamic model coupled with a series of matrix population models in risk assessment refinements. This species is a small epibenthic marine crustacean routinely used in regulatory toxicity tests. We demonstrate how the model coupling can refine current risk assessments using only existing standard regulatory toxicity test results. Several exposure scenarios (each with the same initial risk characterization as determined by a more traditional organism-based approach) were created within which population modeling documented risks different from those of assessments based on the traditional approach. We also present different acute and chronic toxicity data scenarios by which toxicokinetic-toxicodynamic coupled with population modeling can distinguish responses that traditional risk evaluations are not designed to detect. Our results reinforce the benefits of this type of modeling in risk evaluations, especially related to time-varying exposure concentrations. Environ Toxicol Chem 2018;37:2633-2644. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29978498 TI - Outcomes of patients with simultaneous diagnosis of chronic lymphocytic leukaemia/small lymphocytic lymphoma and multiple myeloma. PMID- 29978499 TI - Determinants of 20-year non-progression to Type 2 diabetes in women at very high risk: the E3N cohort study. AB - AIMS: To identify the most important determinants associated with not developing Type 2 diabetes in women considered to be at very high risk. METHODS: Between 1995 and 2014, we followed 402 women from the E3N cohort study who were considered to be at very high risk of Type 2 diabetes based on the D.E.S.I.R. score. We then computed a classification and regression tree model to identify, among a large set of risk factors, the top risk factors associated with not having Type 2 diabetes at the end of the follow-up. RESULTS: During follow-up, 117 women (29%) were diagnosed with Type 2 diabetes, while 285 (71%) were still free of the disease in 2014. A low Western dietary pattern score was the top characteristic associated with not developing Type 2 diabetes, as only 20% of the women at very high risk in the E3N study with that characteristic developed Type 2 diabetes (compared with 29% overall). In women with a moderate or high Western dietary pattern score, the most important characteristic associated with not developing Type 2 diabetes was a high total dietary antioxidant capacity, as only 26% of these women ultimately developed Type 2 diabetes. CONCLUSIONS: We showed that the top characteristic associated with not developing Type 2 diabetes, despite being at very high risk, was a healthy diet, characterized by limiting Western dietary habits, but with a high intake of antioxidant-rich foods. This underscores the importance of diet in the prevention of Type 2 diabetes in people at high risk. PMID- 29978500 TI - Effects of urban stormwater and iron-enhanced sand filtration on Daphnia magna and Pimephales promelas. AB - Urban stormwater is an important but incompletely characterized contributor to surface-water toxicity. The present study used 5 bioassays of 2 model organisms (Daphnia magna and fathead minnow, Pimephales promelas) to investigate stormwater toxicity and mitigation by full-scale iron-enhanced sand filters (IESFs). Stormwater samples were collected from major stormwater conveyances and full scale IESFs during 4 seasonal events (winter snowmelt and spring, early summer, and late summer rainfalls) and analyzed for a diverse range of contaminants of emerging concern including pharmaceuticals, personal care products, industrial chemicals, and pesticides. Concurrently, stormwater samples were collected for toxicity testing. Seasonality appeared more influential and consistent than site type for most bioassays. Typically, biological consequences were least in early summer and greatest in late summer and winter. In contrast with the unimproved and occasionally reduced biological outcomes in IESF-treated and late summer samples, water chemistry indicated that numbers and total concentrations of detected organic chemicals, metals, and nutrients were reduced in late summer and in IESF-treated stormwater samples. Some potent toxicants showed more specific seasonality (e.g., high concentrations of polycyclic aromatic hydrocarbons and industrial compounds in winter, pesticides in early summer and spring, flame retardants in late summer), which may have influenced outcomes. Potential explanations for insignificant or unexpected stormwater treatment outcomes include confounding effects of complex stormwater matrices, IESF nutrient removal, and, less likely, unmonitored toxicants. Environ Toxicol Chem 2018;37:2645-2659. (c) 2018 SETAC. PMID- 29978501 TI - Survey of 23 Nordic university hospitals showed that 77% lacked written procedures for measuring and interpreting blood pressure in infants. AB - AIM: This study determined the use of standardised procedures for infant noninvasive blood pressure (NIBP) measurements in the Nordic countries and aimed to identify factors included in the standardisation and interpretation of NIBP measurements in infants. METHODS: A cross-sectional electronic questionnaire survey was sent to 84 physicians in all 23 university hospitals in Sweden, Norway, Denmark, Finland and Iceland and was completed from February to March 2017. The survey contained respondent characteristics, the presence and description of standardised procedures for NIBP measurements, daily practice of NIBP measurements and methodological considerations and interpretation of NIBP measurements in a healthy six-month-old child. RESULTS: We received responses from 55 of 84 physicians working in all 23 Nordic university hospitals, in paediatric cardiology (n = 22), general paediatrics (n = 16), paediatric nephrology (n = 14) and other fields (n = 3). Less than a quarter (23%) said their hospital issued specific NIBP procedures relating to infants and they referred to 19 different sources of information. The factors that were most commonly assessed for interpretation were age (100%), arousal state (78%) and cuff size (76%). CONCLUSION: Most of the university hospital units treating children lacked age-specific written procedures for measuring and interpreting infant NIBP, and there is a strong need for common Nordic guidelines. PMID- 29978502 TI - Association of single nucleotide polymorphisms in resistin gene with rheumatoid arthritis in a Chinese population. AB - BACKGROUND: Recent evidences have revealed that resistin is associated with the development of rheumatoid arthritis (RA). The aim of this study was to analyze the association of resistin gene single nucleotide polymorphisms (SNPs) with RA susceptibility. METHODS: In this study, we finally analyzed three resistin SNPs (rs1862513, rs3745368, and rs3745367) in 278 RA patients and 276 normal controls recruited from Chinese population using TaqMan SNP genotyping assays. RESULTS: There were no significant differences for the distribution of allele and genotype frequencies of these three SNPs between RA patients and normal controls (all P > .05). The genotype effects of dominant, recessive models were also analyzed, and no significant association was detected (all P > .05). Haplotype analysis suggested that the frequency of haplotype GAA was notably lower in RA patients in comparison with normal controls (OR = 0.317, 95% CI: 0.125-0.807, P = .011). CONCLUSION: In a ward, our results indicated that resistin gene polymorphisms might affect the genetic predisposition of RA in Chinese population. PMID- 29978504 TI - Suicide Notes: Assessing Their Impact on the Bereaved. AB - OBJECTIVE: Although suicidologists have devoted great interest toward the importance of suicide notes, scant attention has been paid to their impact upon the suicide bereaved. METHOD: To address this issue we conducted on an online survey querying 146 mostly American suicide bereaved adults who indicated severe emotional distress after their losses, 80% of whom had lost first degree relatives. RESULTS: We found no significant differences in mental health outcomes between those who received suicide notes and those who had not; nor were differences noted between those whose notes contained helpful or unhelpful information and those who had not received such information. CONCLUSION: We also observed poorer mental health outcomes among the suicide bereaved who expected to receive a suicide note after their loved one died-and did not receive any communication- indicating needs for clinical support among this vulnerable subgroup. PMID- 29978503 TI - Aluminum toxicity related to SOD and expression of presenilin and CREB in Bombyx mori. AB - Aluminum (Al) is an important environmental metal factor that can be potentially associated with pathological changes leading to neurotoxicity. The silkworm, Bombyx mori, is an important economic insect and has also been used as a model organism in various research areas. However, the toxicity of Al on silkworm physiology has not been reported. Here, we comprehensively investigate the toxic effects of Al on the silkworm, focusing on its effects on viability and development, superoxide dismutase (SOD) activity, and the expression of presenilin and cAMP response element-binding protein (CREB) in BmE cells and silkworm larvae. BmE cell viability decreased after treatment with aluminum chloride (AlCl3 ) in both dose- and time-dependent manners. When AlCl3 solution was injected into newly hatched fifth instar larvae, both larval weight gain and survival rate were significantly decreased in a manner correlating with AlCl3 dose and developmental stage. Furthermore, when BmE cells and silkworm larvae were exposed to AlCl3 , SOD activity decreased significantly relative to the control group, whereas presenilin expression increased more than twofold. Additionally, CREB and phosphorylated CREB (p-CREB) expression in the heads of fifth instar larvae decreased by 28.0% and 50.0%, respectively. These results indicate that Al inhibits the growth and development of silkworms in vitro and in vivo, altering SOD activity and the expressions of presenilin, CREB, and p-CREB. Our data suggest that B. mori can serve as a model animal for studying Al-induced neurotoxicity or neurodegeneration. PMID- 29978505 TI - Internal chirality descriptors iR and iS and ire and isi. A proposed notation to extend the usefulness of the R/S system by retaining the sense of stereochemistry in cases of ligand ranking changes. AB - The R/S system, universally applied for indicating the absolute configuration of a structure, is extremely adept for conveying the absolute configuration unequivocally. However, it suffers from one limitation, viz that due to CIP priority rules the rankings of the ligands attached to an asymmetric center can be altered upon a change in a ligand leading to a change in the designated configuration even if bonds to the asymmetric center were not actually formed or broken. This means that the sense of stereochemistry in situations such as within a set of compounds where family relationships are of focus or where the sense of the stereochemical course of a reaction is of interest can be lost or confusion may occur. This shortcoming is easily remedied though by defining a fixed ranking for a particular ligand in the system under study, eg, the ligand at which the change has occurred. The configurations are then expressed as iR or iS, akin to the R and S descriptors, for sp3 -hybridized tetrahedral chiral structures and similarly, as ire and isi faces, akin to the re and si descriptors, for sp2 hybridized trigonal prochiral structures. All in all, the notation can be considered as an auxiliary to extend the usefulness of the R/S system. Thus, the proposed iR/iS notation could find profitable use in comparative studies where there is a need to avoid confusion arising from changing assignments due to priority rules or to expedite the ease of comprehension. Moreover, in the current digital age, the facile retrieval of stereochemically clear data by machines is highly desirable-something that the iR/iS notation is readily amenable to. PMID- 29978506 TI - Lipid droplets in clusters negatively affect Bos indicus embryos during cryopreservation. AB - Embryo transfer using cryopreserved B. indicus embryos results in low pregnancy rates. The low viability of B. indicus embryos is likely a result of their low freezability relative to embryos from other species, notably B. taurus. Freezability is probably related to the quantity of lipid droplets in the embryonic cells. However, the mechanism underlying this association is unknown. Using multiphoton and transmission electron microscopy, the proportion, volume, morphology and composition of lipid droplets in fresh and cryopreserved B. indicus and B. taurus embryos were studied. B. indicus embryos have more droplets than B. taurus and a greater percentage of lipid droplets in clusters (34% vs. 24%; p < 0.05). Also, B. indicus individual droplets are of greater volume than those of B. taurus (47 MUm3 vs. 34 MUm3 ; p < 0.05). After freezing, the percentage of clusters decreased in B. indicus (11% vs. 5%; p < 0.05), while in B. taurus they increased (2% vs. 7%; p < 0.05). Freezing influenced the lipid droplet morphology, increasing the number of cracked droplets in B. indicus embryos (33% fresh vs. 62% frozen; p < 0.05), but not in B. taurus embryos (35% fresh vs. 34% frozen; ns). Regarding composition, saturated lipid droplets prevail in B. indicus embryos, contrary to B. taurus embryos. We observed differences in lipid droplet organization, proportion, volume, morphology and composition between B. indicus and B. taurus embryos which are altered in opposite directions following freezing. PMID- 29978508 TI - Chronic obstructive pulmonary disease-induced autonomic dysfunction may be associated with cerebral blood flow regulation and brain function. PMID- 29978507 TI - Smoothed quantile regression analysis of competing risks. AB - Censored quantile regression models, which offer great flexibility in assessing covariate effects on event times, have attracted considerable research interest. In this study, we consider flexible estimation and inference procedures for competing risks quantile regression, which not only provides meaningful interpretations by using cumulative incidence quantiles but also extends the conventional accelerated failure time model by relaxing some of the stringent model assumptions, such as global linearity and unconditional independence. Current method for censored quantile regressions often involves the minimization of the L1 -type convex function or solving the nonsmoothed estimating equations. This approach could lead to multiple roots in practical settings, particularly with multiple covariates. Moreover, variance estimation involves an unknown error distribution and most methods rely on computationally intensive resampling techniques such as bootstrapping. We consider the induced smoothing procedure for censored quantile regressions to the competing risks setting. The proposed procedure permits the fast and accurate computation of quantile regression parameter estimates and standard variances by using conventional numerical methods such as the Newton-Raphson algorithm. Numerical studies show that the proposed estimators perform well and the resulting inference is reliable in practical settings. The method is finally applied to data from a soft tissue sarcoma study. PMID- 29978509 TI - Aerobic Oxidation/Annulation Cascades through Synergistic Catalysis of RuCl3 and N-Heterocyclic Carbenes. AB - Cooperative catalysis combining a transition metal with an N-heterocyclic carbene is challenging due to strong binding of NHCs towards late transition metals. We report the first example of synergistic catalysis by a chiral NHC and a coordinatively unsaturated ruthenium compound. RuCl3 was found to mediate efficient aerobic oxidation of homoenolates generated from enals and the N heterocyclic carbene. The resulting alpha,beta-unsaturated acylazolium intermediate reacts selectively with 1,3-dicarbonyl compounds or ketones at either the beta- or gamma-carbon, yielding polysubstituted chiral lactones in high yield and with excellent enantioselectivity (up to 98 % yield, 94 % ee). This protocol can be applied to structurally sophisticated substrates. PMID- 29978510 TI - Anti-inflammatory effects of the GAG-binding CXCL9(74-103) peptide in dinitrofluorobenzene-induced contact hypersensitivity in mice. AB - BACKGROUND: To recruit leucocytes to an inflammatory site, chemokine binding to glycosaminoglycans (GAGs) is critical. Therefore, strategies to interfere with this interaction, aiming at the production of anti-inflammatory agents, were developed. These include production of modified chemokines without affinity for G protein-coupled receptors but with enhanced affinity for GAGs. Such modified chemokines compete with functional chemokines for GAG binding, prevent chemokine immobilization and presentation, and inhibit leucocyte migration. In addition to modified chemokines, a GAG-binding peptide consisting of the 30 COOH-terminal residues of CXCL9, that is CXCL9(74-103), inhibited CXCL8- and monosodium urate crystal-induced neutrophil migration. OBJECTIVE: We wanted to explore whether interference with chemokine-GAG interactions by CXCL9(74-103) reduces inflammation in neutrophil-dependent dinitrofluorobenzene-induced contact hypersensitivity. METHODS: For this study, we evaluated several inflammatory parameters, including ear swelling and the levels of chemokines, cytokines, proteases and neutrophils in the ears of dinitrofluorobenzene-induced mice treated with CXCL9(74-103) or buffer. RESULTS: One intravenous injection of CXCL9(74-103), just before painting with dinitrofluorobenzene on the ear, did not affect protein levels of the major murine neutrophil attractant, that is CXCL6, in this contact hypersensitivity model. However, IL-6, CXCL1, CCL2 and matrix metalloproteinase-9 (MMP-9) protein concentrations and peroxidase activity in challenged ears were reduced. In addition, intravenous injection of the CXCL9 derived peptide led to a reduced ear swelling response, indicating that the locally produced chemokines were hindered to attract leucocytes. The inhibiting potential of CXCL9(74-103) was explained by its competition for GAG binding with CXCL1, CXCL6 and CCL3 and inhibition of transendothelial migration of neutrophils to CXCL6. CONCLUSIONS AND CLINICAL RELEVANCE: The CXCL9(74-103) peptide inhibited dinitrofluorobenzene-induced infiltration of neutrophils and neutrophil-dependent inflammation in ears. Therefore, CXCL9(74-103) may be a lead molecule for the development of therapeutic peptides or peptide derivatives that compete with functional chemokines for GAG binding. PMID- 29978511 TI - Newly characterized motile sperm domain-containing protein 2 promotes human breast cancer metastasis. AB - Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among women worldwide. Breast cancer metastasis results in poor prognosis and increased mortality, but the mechanisms of breast cancer metastasis are yet to be fully resolved. Identifying distinctive proteins that regulate metastasis might be targeted to improve therapy in breast cancer. We previously described MOSPD2 as a surface membrane protein that regulates monocyte migration in vitro. In this study, we demonstrate for the first time that MOSPD2 has a major role in breast cancer cell migration and metastasis. MOSPD2 expression was highly elevated in invasive and metastatic breast cancer while it was absent or residual in normal tissue and in primary in situ tumors. In vitro experiments showed that silencing MOSPD2 in different breast cancer cell lines significantly inhibited cancer cell chemotaxis migration. Mechanistically, we found that silencing MOSPD2 profoundly abated phosphorylation events that are involved in breast tumor cell chemotaxis. In vivo, MOSPD2-silenced breast cancer cells exhibited marked impaired metastasis to the lungs. These results indicate that MOSPD2 plays a key role in the migration and metastasis of breast cancer cells and may be used to prevent the spreading of breast cancer cells and to mediate their death. PMID- 29978513 TI - Oxygen therapy improves cerebral oxygen delivery and neurovascular function in hypoxaemic chronic obstructive pulmonary disease patients. AB - NEW FINDINGS: What is the central question of this study? How does oxygen therapy influence cerebral blood flow, cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients? What is the main finding and its importance? Oxygen therapy improves cerebral oxygen delivery and neurovascular function in chronic obstructive pulmonary disease patients. This improvement in cerebral oxygen delivery and neurovascular function might provide a physiological link between oxygen therapy and a reduced risk of cerebrovascular disease (e.g. stroke, mild cognitive impairment and dementia) in chronic obstructive pulmonary disease. ABSTRACT: We investigated the role of hypoxaemia in cerebral blood flow (CBF), oxygen delivery (CDO2 ) and neurovascular coupling (coupling of CBF to neural activity; NVC) in hypoxaemic chronic obstructive pulmonary disease (COPD) patients (n = 14). Resting CBF (duplex ultrasound), peripheral oxyhaemoglobin saturation (SpO2; pulse-oximetry) and NVC (transcranial Doppler) were assessed before and after a 20 min wash-in of supplemental oxygen (~3 l min-1 ). The peripheral oxyhaemoglobin saturation increased from 91.0 +/- 3.3 to 97.4 +/- 3.0% (P < 0.01), whereas CBF was unaltered (593.0 +/- 162.8 versus 590.1 +/- 138.5 ml min-1 ; P = 0.91) with supplemental O2 . In contrast, both CDO2 (98.1 +/- 25.7 versus 108.7 +/- 28.4 ml dl-1 ; P = 0.02) and NVC were improved. Specifically, the posterior cerebral artery cerebrovascular conductance was increased to a greater extent after O2 normalization (+40%, from 20.4 +/- 9.9 to 28.0 +/- 10.4% increase in conductance; P = 0.04), whereas the posterior cerebral artery cerebrovascular resistance decreased to a greater extent during O2 normalization (+22%, from -16.7 +/- 7.3 to -21.4 +/- 6.6% decrease in resistance; P = 0.04). The cerebral vasculature of COPD patients appears insensitive to oxygen, because CBF was unaltered in response to O2 supplementation leading to improved CDO2 . In patients, the improvements in CDO2 and neurovascular function with supplemental O2 may underlie the cognitive benefits associated with O2 therapy. PMID- 29978512 TI - An Elastic Autonomous Self-Healing Capacitive Sensor Based on a Dynamic Dual Crosslinked Chemical System. AB - Adopting self-healing, robust, and stretchable materials is a promising method to enable next-generation wearable electronic devices, touch screens, and soft robotics. Both elasticity and self-healing are important qualities for substrate materials as they comprise the majority of device components. However, most autonomous self-healing materials reported to date have poor elastic properties, i.e., they possess only modest mechanical strength and recoverability. Here, a substrate material designed is reported based on a combination of dynamic metal coordinated bonds (beta-diketone-europium interaction) and hydrogen bonds together in a multiphase separated network. Importantly, this material is able to undergo self-healing and exhibits excellent elasticity. The polymer network forms a microphase-separated structure and exhibits a high stress at break (~1.8 MPa) and high fracture strain (~900%). Additionally, it is observed that the substrate can achieve up to 98% self-healing efficiency after 48 h at 25 degrees C, without the need of any external stimuli. A stretchable and self-healable dielectric layer is fabricated with a dual-dynamic bonding polymer system and self-healable conductive layers are created using polymer as a matrix for a silver composite. These materials are employed to prepare capacitive sensors to demonstrate a stretchable and self-healable touch pad. PMID- 29978514 TI - Overcoming the Ambient Manufacturability-Scalability-Performance Bottleneck in Colloidal Quantum Dot Photovoltaics. AB - Colloidal quantum dot (CQD) solar cells have risen rapidly in performance; however, their low-cost fabrication under realistic ambient conditions remains elusive. This study uncovers that humid environments curtail the power conversion efficiency (PCE) of solar cells by preventing the needed oxygen doping of the hole transporter during ambient fabrication. A simple oxygen-doping step enabling ambient manufacturing irrespective of seasonal humidity variations is devised. Solar cells with PCE > 10% are printed under high humidity at industrially viable speeds. The devices use a tiny fraction of the ink typically needed and are air stable over a year. The humidity-resilient fabrication of efficient CQD solar cells breaks a long-standing compromise, which should accelerate commercialization. PMID- 29978515 TI - Hidden Structure Ordering Along Backbone of Fused-Ring Electron Acceptors Enhanced by Ternary Bulk Heterojunction. AB - Fused-ring electron acceptors (FREAs), as a family of non-fullerene (NF) acceptors, have achieved tremendous success in pushing the power conversion efficiency of organic solar cells. Here, the detailed molecular packing motifs of two extensively studied FREAs-ITIC and ITIC-Th are reported. It is revealed for the first time the long-range structure ordering along the backbone direction originated from favored end group pi-pi stacking. The backbone ordering could be significantly enhanced in the ternary film by the mutual mixing of ITIC and ITIC Th, which gives rise to an improved in-plane electron mobility and better ternary device performance. The backbone ordering might be a common morphological feature of FREAs, providing explanations to previously observed small open circuit voltage loss and superior performance of FREA-based devices and guiding the future molecular design of high-performance NF acceptors. PMID- 29978516 TI - Doping and Switchable Photovoltaic Effect in Lead-Free Perovskites Enabled by Metal Cation Transmutation. AB - Creating defect tolerant lead-free halide perovskites is the major challenge for development of high-performance photovoltaics with nontoxic absorbers. Few compounds of Sn, Sb, or Bi possess ns2 electronic configuration similar to lead, but their poor photovoltaic performances inspire us to evaluate other factors influencing defect tolerance properties. The effect of heavy metal cation (Bi) transmutation and ionic migration on the defects and carrier properties in a 2D layered perovskite (NH4 )3 (Sb(1-x) Bix )2 I9 system is investigated. It is shown, for the first time, the possibility of engineering the carriers in halide perovskites via metal cation transmutation to successfully form intrinsic p- and n-type materials. It is also shown that this material possesses a direct-indirect bandgap enabling high absorption coefficient, extended carrier lifetimes >100 ns, and low trap densities similar to lead halide perovskites. This study also demonstrates the possibility of electrical poling to induce switchable photovoltaic effect without additional electron and hole transport layers. PMID- 29978517 TI - Synergistic antinociception between ZC88, an N-type voltage-dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain. AB - BACKGROUND: A combination of analgesic agents with different mechanisms can induce additive or synergistic analgesia. The N-type voltage-dependent calcium channel (N-VDCC) is a novel therapeutic target for pain control. In addition to providing effective pain relief when used alone, N-VDCC blockers produce synergistic analgesia when used in combination with opiates. However, the interaction between N-VDCC blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) remains unclear. METHODS: Using isobolographic analysis and composite additive curve analysis, the antinociceptive interaction between ZC88, a selective N-VDCC blocker and ibuprofen, a classical NSAID, was investigated in two mouse models of visceral and somatic inflammatory pain. RESULTS: In the acetic acid writhing test, both ZC88 (10.5-42 mg/kg, intraperitoneally) and ibuprofen (50-200 mg/kg, orally) produced dose-dependent antinociception, with ED50 values of 27.2 and 100.5 mg/kg, respectively. ZC88 in combination with ibuprofen (ZC88 + ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimental ED50 (ED50 mix ) of this combination (34.5 mg/kg) was significantly lower than the theoretical ED50 (ED50 add ; 63.8 mg/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test, ZC88 or ibuprofen alone significantly reduced late-phase rather than early-phase pain, with ED50 values of 31.3 and 123.9 mg/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception of ZC88 + ibuprofen (40.6 mg/kg of ED50 mix vs. 77.6 mg/kg of ED50 add ). CONCLUSION: ZC88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain. SIGNIFICANCE: Because ZC88 + ibuprofen achieves the same antinociceptive effect at lower doses, the use of this combination could result in fewer dose-related untoward effects. The potentiation of ZC88 on ibuprofen-induced antinociception indicates that N-VDCC blocker has potential benefit to treat severe inflammatory pain. PMID- 29978518 TI - Combination of 5-aminolevulinic acid and iron prevents skin fibrosis in murine sclerodermatous graft-versus-host disease. AB - Scleroderma or systemic sclerosis (SSc) is a clinically heterogeneous rheumatological autoimmune disease affecting the skin, internal organs and blood vessels. There is at present no effective treatment for this condition. Our study investigated the effects of 5-aminolevulinic acid (5-ALA), which is a precursor of haem synthesis, on graft-vs-host disease (GvHD)-induced SSc murine model. Lymphocytes were intravenously injected from donor mice (B10.D2) into recipient BALB/c mice (recombination-activating gene 2 (Rag-2)-null mice) deficient in mature T and B cells to induce sclerodermatous GvHD (scl-GvHD). To investigate the effect of 5-ALA on scl-GvHD, combination of 5-ALA and sodium ferrous citrate (SFC) was orally administered to the recipient mice for 9 weeks. 5-ALA/SFC treatment significantly reduced progressive inflammation and fibrosis in the skin and ears. Furthermore, 5-ALA/SFC suppressed mRNA expression of transforming growth factor-beta, type I collagen and inflammatory cytokines. These results indicate that the 5-ALA/SFC combination treatment has a protective effect against tissue fibrosis and inflammation in a murine scl-GvHD-induced skin and ear inflammation and fibrosis. Furthermore, the efficacy of 5-ALA/SFC suggests important implications of HO-1 protective activity in autoimmune diseases, and therefore, 5-ALA/SFC may have promising clinical applications. These findings suggested that the 5-ALA/SFC treatment may be the potential strategies for SSc. PMID- 29978519 TI - A novel SCN9A splicing mutation in a compound heterozygous girl with congenital insensitivity to pain, hyposmia and hypogeusia. AB - Congenital insensitivity to pain (CIP) is a rare autosomal recessive disorder presenting with a spectrum of clinical features caused by mutations in different genes. A 10-year-old girl with CIP, hyposmia and hypogeusia, and her unaffected twin and parents underwent next generation sequencing of SCN9A exons and flanking splice sites. Transcript analysis from whole blood successfully assayed the effect of the mutation on the mRNA splicing by polymerase chain reaction amplification on cDNA and Sanger sequencing. We identified the novel splicing variant c.1108-2A>G compound with the p.Arg896Gln (c.2687G>A) missense mutation previously described in a homozygous patient. The new intronic variant was predicted to induce exon 10 skipping. Conversely, SCN9A mRNA assay demonstrated its partial deletion with a loss of 46 nucleotides causing a premature stop codon in position p.Gln369 (NP_002968). Genetic analysis showed that the two variants were biallelic, being the mother and brother heterozygous carriers of the missense mutation, and the father heterozygous for the splicing mutation. Skin biopsy showed lack of Meissner's corpuscles, loss of epidermal nociceptors and normal autonomic organ innervation. We report a novel splicing mutation and provide clues on its pathogenic effect, broadening the spectrum of genotypes and phenotypes associated to CIP. PMID- 29978520 TI - Gender role strain, core schemas, and psychotic experiences in ethnically diverse women: A role for sex- and gender-based analysis in psychosis research? AB - Negative -self and -others core schemas have been implicated in the development and maintenance of psychotic experiences. One component of the self-system is gender-role strain (GRS; perceived discrepancy between actual self and gender role norms). Although the role of gender in the formation of core schemas has been underscored in social and developmental psychology literatures, GRS has not been investigated in relation to psychosis. We examined whether it might be associated with negative schemas and psychotic experiences in women consistent with the trend toward sex- and gender-based analysis (SGBA) in health research. Forty-four women with a schizophrenia spectrum disorder diagnosis and 48 female nonclinical participants completed a series of questionnaires measuring GRS, femininity ideology, core schemas, childhood trauma, and implicit femininity stereotypes (The Gender Stereotype Implicit Association Test). Half the total sample comprised women with minority-ethnic status. Women in the psychosis group reported higher levels of GRS than comparison participants. Differences in endorsement of femininity ideology between the two groups narrowly missed significance with a trend toward greater femininity ideology in the psychosis group and significantly greater endorsement of the sexual purity domain for minority-ethnic women. There was no difference in implicit femininity stereotypes. Analyses suggested that the relationship between GRS and symptoms was mediated by negative -self and -others schemas. Childhood sexual trauma, though higher for women with psychosis, was associated with gender-role strain in the nonclinical sample only. Findings warrant further investigation with larger samples. SGBA has the potential to fill gaps in our current knowledge with regard to psychosis theory, research, and practice. PMID- 29978521 TI - Scary clowns: adaptive function of anemonefish coloration. AB - Clownfishes, with their showy coloration, are well known for their symbiosis with sea anemones and for their hierarchical reproductive system, but the function of their coloration is unclear. We used a phylogeny of 27 clownfish species to test whether fish coloration (i) serves a protective function that involves their anemone hosts, or (ii) signals species identity in species with overlapping host ranges that can potentially share the same host. We tested for an association between fish colour pattern traits, host morphology and host toxicity and examined coloration in relation to host sharing and geographic proximity. Fish with fewer stripes occupied fewer anemone species, and hosts with shorter tentacles, than fish with multiple stripes. There was a negative relationship between anemone toxicity and tentacle length and these protective traits together were correlated with the evolution of stripes. Host sharing or range overlap was not associated with coloration divergence. We propose that ancestral anemonefishes had multiple stripes that served for hiding/camouflage among the hosts' long tentacles, whereas increased specialization towards fewer and more toxic hosts (with shorter tentacles) led to the use of coloration as an aposematic signal. The intriguing notion that an aposematic signal could advertise the defence of another species may reflect the unique symbiotic relationship between anemonefishes and their hosts. PMID- 29978522 TI - The use of systematic reviews to justify anaesthesiology trials: A meta epidemiological study. AB - AIMS: New randomized clinical trials (RCTs) should be initiated if previous systematic reviews (SRs) indicate that new trials are needed. We analysed whether RCTs published in anaesthesiology journals mentioned previous SRs as a rationale for conducting trial and for discussing results. METHODS: This was a meta epidemiological, descriptive cross-sectional study. We analysed RCTs published in the seven first-quartile anaesthesiology journals between 2014 and 2016. We studied text and bibliography of the RCTs to assess whether the authors made a reference to previous SRs when justifying the need for their own clinical trial and discussing the results. RESULTS: In the 622 studied RCTs 126 (20%) mentioned verbatim or cited one or more SRs as justification for conducting a trial, most commonly in introduction of a manuscript. Almost half of the included RCTs (44%) did not cite a single systematic review. There was no significant difference between the years in the number of explicitly mentioned SRs as justification for conducting a trial (F = 0.540, p = 0.583). Trials citing, mentioning or explicitly using SRs as a justification were published in journals with significantly higher impact factor and included significantly higher number of participants, while there was no difference in using SRs in trials in terms of funding type, type of intervention or positive versus negative results. CONCLUSIONS: Trialists should use evidence from existing SRs for planning a trial, while ethics committees, peer-reviewers and editors should require authors to provide evidence that a new trial is indeed necessary. SIGNIFICANCE: Since less than a fifth of trials published in high-impact journals in the field of anaesthesiology explicitly mention previous systematic review as a justification for conducting the trial, authors, ethics committees, editors and peer-reviewers need to increase their awareness of the need for proper justification regarding the necessity for a new trial. PMID- 29978523 TI - Pain location and widespread pain in youth with orthopaedic conditions: Exploration of the reliability and validity of a body map. AB - BACKGROUND: Pain location and widespread pain are important but underexamined dimensions of paediatric pain. Body map tools to assess pain location in youth have been used for several decades, but few studies have established reliability and validity of these measures. The purpose of this study was to explore the reliability and validity of a pain body map among youth with orthopaedic conditions before surgery. METHOD: Youth ages 10-17 years completed the body map and other self-reported outcomes at their preoperative clinic visit and at their day of surgery. RESULTS: Most (91.7%) youth had small discrepancy between body map scores at preoperative clinic visit (baseline) and day of surgery (second assessment), and site-to-site agreement ranged from 78% to 98%. Those with back and lower extremity diagnoses had high correspondence between body map sites and diagnostic sites. Body map scores and widespread pain were associated with other dimensions of pain, as well as other patient-reported outcomes. Higher pain intensity and widespread pain predicted greater discrepancy between body map scores. CONCLUSIONS: These results support the use of body map tools in further research examining widespread pain among youth by demonstrating adequate reliability, descriptive validity and associative validity. SIGNIFICANCE: These results contribute to the limited information regarding psychometric properties of paediatric pain body maps, provide novel information about widespread pain among youth undergoing orthopaedic surgeries, and pave the way for improved assessment and treatment of paediatric pain. PMID- 29978524 TI - Low serum vitamin D level is associated with intrahepatic cholestasis of pregnancy. AB - AIM: Intrahepatic cholestasis of pregnancy (ICP) is a unique hepatic disorder of pregnancy and is related to adverse maternal and perinatal outcomes. The pathogenesis of the disease is not clear and appears to be multifactorial. There is increasing evidence that vitamin D (Vit D) plays a role in hepatobiliary homeostasis and in various liver diseases. We aimed to investigate the association between serum Vit D level and ICP. METHODS: A total of 40 pregnant women with ICP and 40 healthy pregnant women were included in this controlled cross-sectional study. Their demographic characteristics, including age, body mass index (BMI), gestational week, gravidity and parity, and laboratory parameters, including 25(OH) Vit D3 levels, liver function tests, fasting and postprandial bile acid concentrations, were recorded. Gestational age at delivery, birth weight (BW), neonatal intensive care unit (NICU) admission, meconium staining of amniotic fluid and appearance pulse grimace activity respiration (APGAR) score at 5 min were obtained from medical records for assessment of perinatal outcomes. RESULTS: There was no significant difference between groups in terms of demographic characteristics. The mean serum 25(OH) Vit D3 level was significantly lower in pregnant women with ICP compared to control pregnant women (8.6 +/- 4.9, 11.3 +/- 6.1; P =0.033), and it was significantly lower in severe disease than mild disease (6.9 +/- 2.1, 10.3 +/- 6.2, respectively; P =0.029). We also found that lower serum 25(OH) Vit D3 levels were significantly and inversely correlated with fasting and postprandial bile acid levels. However, in subgroup analyses in ICP pregnant women, there was no difference in mean 25(OH) Vit D3 levels for women with or without perinatal complications. CONCLUSION: Our study suggests that low levels of 25(OH) Vit D3 were associated with ICP disease and its severity. However, further larger studies are needed to evaluate the effect of Vit D in the pathogenesis and outcome of the disease. PMID- 29978525 TI - Environmental stress does not increase the mean strength of selection. AB - A common intuition among evolutionary biologists and ecologists is that environmental stress will increase the strength of selection against deleterious alleles and among alternate genotypes. However, the strength of selection is determined by the relative fitness differences among genotypes, and there is no theoretical reason why these differences should be exaggerated as mean fitness decreases. We update a recent review of the empirical results pertaining to environmental stress and the strength of selection and find that there is no overall trend towards increased selection under stress, in agreement with other recent analyses of existing data. The majority of past studies measure the strength of selection by quantifying the decrease in fitness imposed by single or multiple mutations in different environments. However, selection rarely acts on one locus independently, and the strength of selection will be determined by variation across the whole genome. We used 20 inbred lines of Drosophila melanogaster to make repeated fitness measurements of the same genotypes in four different environments. This framework allowed us to determine the variation in fitness attributable to genotype across stressful environments and to calculate the opportunity for selection among these genotypes in each stress. Although we found significant decreases in mean fitness in our stressful environments, we did not find any significant differences in the strength of selection among any of the four measured environments. Therefore, in agreement with our updated review, we find no evidence for the oft-cited verbal model that stress increases the strength of selection. PMID- 29978526 TI - Nondental orofacial pain in dental practices - diagnosis, therapy and self assessment of German dentists and dental students. AB - BACKGROUND: Patients with non-dental orofacial pain syndromes will often primarily consult general dentists and other dental specialists. Early and correct diagnosis and therapy is crucial to prevent chronification. METHODS: We assessed the experience of dentists (general dentists and dental specialists; n = 533) and knowledge level of dental students (n = 130) on the diagnosis and treatment of non-dental orofacial pain. We used an anonymized survey containing 14 items with the four main themes (1) prescription patterns, (2) treatment strategies in non-dental orofacial pain, (3) interdisciplinary cooperation, and (4) self-assessment of knowledge as well as post-graduate education. RESULTS: Ninety-two percent of dental students stated that they feel either 'not at all' (56%) or only 'somewhat' (36%) prepared for the diagnosis or treatment of non dental orofacial pain. Only 23% of the dentists reported 'good' or 'very good' confidence for the diagnosis of non-dental orofacial pain. NSAID were the analgesics of choice when the pain is unspecific (25%) or even neuralgic (10%). Dentists referred patients with non-dental orofacial pain mostly to ENT physicians (59%), oral and maxillofacial surgeons (54%) or TMD specialists (51%). CONCLUSION: Interdisciplinary pain treatment seems to be well acknowledged, however, with a focus on referral within the community of dental specialists. Dental curricula and post-graduate trainings need to implement the diagnosis and treatment options of non-dental orofacial pain. PMID- 29978527 TI - Peritoneal carcinomatosis from ovarian paraganglioma: Report of a rare case and systematic review of the literature. AB - Paraganglioma is one of the rarest neoplasms involving the ovary, with only 10 previous reports. We present a case of peritoneal carcinomatosis from primary ovarian paraganglioma and a systematic review of the literature. Clinical information was retrieved from medical records, and a systematic review of the literature was performed according to meta-analysis of observational studies in epidemiology guidelines. A 33-year-old woman presented with a 12-month history of hypertension and weight loss. She was diagnosed with ovarian paraganglioma and was treated with extensive debulking surgery to no residual disease after three cycles of neoadjuvant chemotherapy. She recurred after 6 months and was started on somatostatin-analogue. Following further disease progression with bone metastasis (treated with palliative radiotherapy), a trial with Sunitinib was started. The patient died 30 months after initial diagnosis. Of the cases reported to date, only one had peritoneal metastasis at presentation but none of them had such an ominous prognosis. Ovarian paraganglioma is an extremely rare condition. We report the first case of primary malignant ovarian paraganglioma with an exceptionally aggressive behavior. Clinicopathological correlation with immunohistochemistry is essential to avoid misdiagnosis. A standard treatment is not recommended yet but cytoreductive surgery seems to be a favorable approach to prolong survival. PMID- 29978528 TI - 3.0 Tesla magnetic resonance imaging anatomy of the central nervous system, eye, and inner ear in birds of prey. AB - Despite the increasing interest in the clinical neurology of birds, little is known about the magnetic resonance imaging (MRI) appearance of the avian central nervous system, eye, and inner ear. The objective of this cadaveric study was to document the MRI anatomic features of the aforementioned structures using a high resolution 3.0 Tesla MRI system. The final study group consisted of 13 cadavers of the diurnal birds of prey belonging to six species. Images were acquired in sagittal, dorsal, and transverse planes using T1-weighted and T2-weighted turbo spin echo sequences. A necropsy with macroscopic analysis of the brain and spinal cord was performed on all cadavers. Microscopic examination of the brain was performed on one cadaver of each species; the spinal cord was examined in three subjects. Anatomic structures were identified on the magnetic resonance images based on histologic slices and available literature. Very good resolution of anatomic detail was obtained. The olfactory bulbs; cerebral hemispheres; diencephalon; optic lobe; cerebellum; pons; ventricular system; optic, trigeminal, and facial nerves; pineal and pituitary glands; as well as the semicircular canals of the inner ear were identified. Exquisite detail was achieved on the ocular structures. In the spinal cord, the gray and white matter differentiation and the glycogen body were identified. This study establishes normal MRI anatomy of the central nervous system, eye, and inner ear of the birds of prey; and may be used as a reference in the assessment of neurologic disorders or visual impairment in this group of birds. PMID- 29978529 TI - Ga-68-PSMA PET/CT in treatment-naive patients with prostate cancer: Which clinical parameters and risk stratification systems best predict PSMA-positive metastases? AB - PURPOSE: To evaluate the accuracy of clinical parameters and established pre treatment risk stratification systems for prostate cancer (PCa) in predicting PSMA-positive metastases in men undergoing Ga-68-PSMA PET/CT as initial staging examination. MATERIALS AND METHODS: A retrospective analysis in 108 consecutive treatment-naive patients with biopsy-proven PCa undergoing Ga-68-PSMA PET/CT (median age, 72 years [range, 49-82 years]) was performed. Prediction of PSMA positive metastases by serum PSA, clinical T stage (cT), ISUP group, percentage of positive biopsy cores, and derived risk scores (D'Amico risk classification system, Roach [RF], Yale formula [YF], and Briganti nomogram [BN]) was examined with ROC analysis. RESULTS: Any PSMA-positive metastases were found in 36 of 108 patients, including LN metastases in 28 patients, extrapelvic LN metastases in 15 patients, and organ metastases in 19 patients (bone, 19; lung, 1). AUCs for PSA, cT, ISUP, and percentage of positive biopsy cores regarding PSMA-positive metastases did not differ significantly (range, 0.6-0.8; each P > 0.05). D'Amico (AUC, 0.61-0.64) was inferior to RF (0.76-0.83), YF (0.81-0.86), and BN (0.73 to 0.88; each P < 0.05). Among the 89 high-risk patients (D'Amico), decision for or against PET imaging based on RF (cut-off, >18.0), YF (>10.8), or BN (>8.0) would have prevented PSMA PET/CT in 4 (5%), 15 (17%), or 18 patients (20%), respectively, while preserving a sensitivity >=95% for PSMA-positive metastases. CONCLUSIONS: Clinical parameters and established risk stratification systems for PCa can predict Ga-68-PSMA PET-positive metastases in treatment-naive patients. Especially YF and BN may improve identification of patients with the highest probability of metastatic disease detected by Ga-68-PSMA PET/CT. PMID- 29978531 TI - Right aortic arch with bilateral arterial duct and nonconfluent pulmonary arteries without associated cardiac defects: Prenatal diagnosis and successful postnatal treatment. AB - We describe a rare case of right aortic arch with bilateral arterial duct and disconnected left pulmonary artery. Prenatal diagnosis allowed to plan delivery at the referral center and to maintain perfusion of the disconnected pulmonary artery through prostaglandin E1 infusion until surgical reconnection was performed. Early postnatal treatment avoided functional loss of the left lung that would have happened if malformation had not been identified before birth. PMID- 29978530 TI - The effect of sex work regulation on health and well-being of sex workers: Evidence from Senegal. AB - Senegal is the only African country where sex work is legal and regulated by a health policy. Senegalese female sex workers (FSWs) are required to register with a health facility and to attend monthly routine health checks aimed at testing and treating sexually transmitted infections (STIs). Compliance to those routine visits is recorded on a registration card that must be carried by FSWs in order to avoid sanctions in case of police arrests. Although this policy was first introduced in 1969 to limit the spread of STIs, there is no evidence so far of its impact on FSWs' health and well-being. The paper aims to fill this gap by exploiting a unique data set of registered and unregistered Senegalese FSWs. Using propensity score matching, we find that registration has a positive effect on FSWs' health. However, we find that registration reduces FSWs' subjective well being. This finding is explained by the fact that registered FSWs are found to engage in more sex acts, in riskier sex acts, have less social support from their peers, and are more likely to experience violence from clients and police officers. We prove that those results are robust to the violation of the conditional independence assumption, to misspecification of the propensity score model, and that covariate balance is achieved. The results suggest that more efforts should be deployed to reduce the stigma associated with registration and to address the poor well-being of FSWs, which is counterproductive to HIV prevention efforts. PMID- 29978532 TI - Solid-Phase Thiol-Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist. AB - We report a new method herein coined SP-CLipPA (solid-phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono-S-lipidated peptides. This technique utilizes thiol-ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin-bound peptide. Advantages of SP-CLipPA include: ease of handling, conversions of up to 91 %, by-product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP-HPLC purification. To showcase the utility of SP-CLipPA, we synthesized a potent calcitonin gene-related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP8-37 and CGRP7-37 , has potential for the treatment of migraine. PMID- 29978533 TI - Preventive effects of N-acetyl-l-cysteine against imidacloprid intoxication on Bombyx mori larvae. AB - Imidacloprid, a widely used neonicotinoid insecticide, is toxic to silkworm (Bombyx mori). To explore whether N-acetyl-l-cysteine (NAC) has an effect on preventing silkworm (B. mori) from toxification caused by imidacloprid, we fed the fifth-instar larvae with mulberry leaves dipped in 200 mg/L NAC solution before exposing in imidacloprid, and investigated the silkworm growth, survival rate, feed efficiency, cocoon quality, and the activities of antioxidant enzymes in midgut. The results showed that addition of NAC could significantly increase body weight, survival rate, and feed efficiency of imidacloprid poisoned silkworm larvae (P < 0.05), as well as cocoon mass, cocoon shell mass, and the ratio of cocoon shell (P < 0.05). Furthermore, it could significantly promote the activities of the antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxide in the midgut of fifth-instar larvae under imidacloprid exposure at the late stage of treatment. In addition, it also could downregulate the malondialdehyde content. The results of our findings proved that the added NAC may have some beneficial effects on protection or restoration of antioxidant balance in imidacloprid exposed larvae. PMID- 29978534 TI - Single-Particle Reconstruction of Biological Molecules-Story in a Sample (Nobel Lecture). AB - Pictures tell a thousand words: The development of single-particle cryo-electron microscopy set the stage for high-resolution structure determination of biological molecules. In his Nobel lecture, J. Frank describes the ground breaking discoveries that have enabled the development of cryo-EM. The method has taken biochemistry into a new era. PMID- 29978535 TI - Nutritional psychiatry for depression. PMID- 29978536 TI - COPII gets in shape: Lessons derived from morphological aspects of early secretion. AB - Our view of the secretory pathway has evolved from a morphological one to one that includes molecular mechanistic understanding of basic traffic components. These components include coat complexes involved in cargo sorting and budding and proteins that mediate targeting, tethering and fusion. The expanding repertoire of regulators that control basic traffic activities begins to paint a unified morphological-molecular view of secretion. The emerging picture provides key insights into the coupling of secretion with physiology. This review examines aspects of morphological-molecular relations that are derived from studies on traffic from the endoplasmic reticulum carried by the coat protein complex II. PMID- 29978537 TI - Prevention of potentially inappropriate medication in internal medicine patients: A prospective study using the electronic application PIM-Check. AB - WHAT IS KNOWN: Potentially inappropriate medication (PIM) is a risk factor for drug-related problems (DRPs) and an important inpatient safety issue. PIM-Check is a screening tool designed to detect PIM in internal medicine patients. OBJECTIVE: This study aimed to determine whether PIM-Check could help to identify and reduce DRPs. METHOD: Prospective interventional study conducted on patients admitted to internal medicine wards in a university hospital between 1 September 2015 and 30 October 2015. Adult patients were included if they were hospitalized for more than 48 hours. Patients received either usual care (period 1 = control) or usual care plus medication screening by the wards' chief residents using PIM Check (period 2 = intervention). An expert panel, composed of a clinical pharmacist, a clinical pharmacologist and two attending physicians in internal medicine, blinded to patient groups, identified DRPs. RESULTS: A total of 297 patients were included (intervention: 109). The groups' demographic parameters were similar. The expert panel identified 909 DRPs (598: control; 311: intervention). The mean number of DRPs per patient was similar in the control (3.2; 95% CI: 2.9-3.5) and intervention groups (2.9; 95% CI: 2.4-3.3) (P = .12). PIM-Check displayed 33.4% of the 311 DRPs identified in the intervention group. WHAT IS NEW AND CONCLUSION: In this study, PIM-Check had limited value, as the average number of DRPs per person was similar in both groups. Although one-third of DRPs counted in intervention group had been identified by PIM-Check, this did not lead to a reduction in DRPs. This lack of impact of PIM-Check on drug prescription may be explained by the number of alerts displayed by the application and hospital physicians' reluctance to modify the treatments for chronic conditions previously prescribed by general practitioners. PMID- 29978539 TI - Endometrial cancer follow up; finding the confidence to let go? PMID- 29978538 TI - A covert field-intervention experiment to determine how heating controls that conserve energy affect thermal comfort. AB - A field-intervention study was carried out in 106 households in Sweden. Without informing the householders, a retrofitted heat pump controller was twice disabled for 1 week at a time over a 4-week period during the heating season, using a single-blind cross-over design with two pseudorandomly selected groups of householders, each experiencing different conditions at any given time. Thermal comfort was assessed by observing the total number of times that householders made adjustments to their set point temperature under each condition. A within household, repeated-measures analysis was performed to determine whether this indicator was positively or negatively affected when the secondary controller was disabled so the heat pump system operated as designed. While over 80% of households showed no effect, among those that did respond to the imposed changes, a Wilcoxon matched-pairs signed-ranks test indicates that disabling the retrofitted controller had a negative effect on thermal comfort (P < 0.05 for a 2 tail test), in that it resulted in significantly more thermostat adjustments. A concurrent increase in the variance of indoor temperature about the household mean was significant (P < 0.001) but small: The range within which indoor temperatures were maintained for 95% of the time (2.5 K) was increased by only 0.3 K (16%), indicating the sensitivity of the approach. PMID- 29978540 TI - Pain in labor assessed from two discomfort aspects: Physical pain intensity and psychological stress state. AB - AIM: To assess two discomfort aspects of pain in labor, physical pain intensity and psychological stress state, we analyzed the association between the two parameters. METHODS: Twenty-nine pregnant Japanese women with a singleton in 37 40 weeks of gestation were analyzed. Physical pain intensity was examined by the Numeric Rating Scale (NRS). Psychological stress state was measured by chromogranin A (CgA) in saliva. Data were collected thrice during labor (at 4-6 cm and 10 cm of cervical dilatation and immediately after delivery) and were accumulated from 4-6 cm and 10 cm of cervical dilatation. The study was approved by the Ethics Committees of Osaka University and Tokyo Women's Medical University. RESULTS: The median NRS score (10, IQR = 10-18) and the median CgA in saliva (8.0, IQR = 4.3-12.0) pmol/mg at 10 cm of cervical dilatation were significantly higher than those at the other two time points (P < 0.05). Although there were no correlations between NRS scores and concentrations of CgA in saliva at the three time points, there was a significant correlation between accumulated NRS and accumulated CgA in saliva (r = 0.68, P = 0.000). There was a significant difference in the accumulated NRS scores (P = 0.005) but not in the accumulated concentrations of CgA between primiparae and multiparae. CONCLUSION: Women in labor perceived severe pain and psychological stress with similar patterns during labor. However, these parameters were independent and need to be measured to evaluate these two discomfort aspects. PMID- 29978541 TI - Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome with septic shock: A case report. AB - Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome is a rare complex of structural abnormalities of the female urogenital tract. A nulliparous 37-year-old woman was referred to our department for an acute abdomen. Multiple uterine myomas and painful right vaginal bulge were found on gynecological examination. Transvaginal ultrasonography revealed a cystic mass and a right-side cervix that was hidden behind the longitudinal vaginal septum. For these findings, pyocolpos arising from OHVIRA syndrome was suspected. Her general condition gradually worsened within an hour, and she developed septic shock and was hospitalized in the intensive care unit (ICU). Laboratory data revealed disseminated intravascular coagulation (DIC) and multiple organ failure. Her general condition gradually improved as a result of intensive care and transvaginal puncture drainage of the abscess. Hysterectomy, performed 2 months after the acute septic episode, confirmed the diagnosis of septate uterus with obstructed hemivagina. To date, there is no documented case of OHVIRA syndrome with an eventual septic shock. PMID- 29978542 TI - Pain management of surgical abortion using transcutaneous acupoint electrical stimulation: An orthogonal prospective study. AB - AIM: This study aimed to evaluate the optimal combination of parameters for the management of pain during surgical abortion using transcutaneous acupoint electrical stimulation (TEAS). METHODS: This study recruited patients scheduled for surgical abortion between October 2014 and August 2015. The treatment protocol was created using three levels for each factor (stimulating time, acupoints, age, and parity). The primary outcomes were intraoperative visual analog scale (VAS), postoperative VAS, cervical relaxation degree and intraoperative blood loss. The secondary outcomes were the vital signs. RESULTS: Stimulation time was associated with intraoperative VAS scores (P < 0.001), acupoints were associated with postoperative VAS scores (P = 0.037), and age was associated with postoperative VAS scores (P < 0.043). Parity (P = 0.025) was associated with heart rate. A comprehensive analysis of the parameters revealed the best levels for each (stimulation time: from 15 min before operation to immediate postoperative; acupoints: SP 6 and LR 3; patient age 25.1-30.0 years; and parity: G>=2 P0 A>=1 ). Seven patients did not complete follow-up. The remaining 135 subjects did not show continuous vaginal bleeding, abdominal pain, fever or any other adverse effect. CONCLUSION: During surgical abortion, TEAS stimulation from 15 min before operation to immediate postoperative, SP 6 and LR 3, age 25.1-30.0 years and G>=2 P0 A>=1 were associated with the best analgesic effect. PMID- 29978543 TI - The importance of using 24-hour and nighttime blood pressure for the identification of white coat hypertension: Data from the Jackson Heart Study. AB - We calculated the prevalence of white coat hypertension (WCH) using out-of-clinic blood pressure (BP) in the daytime period; daytime and 24-hour periods; and daytime, 24-hour, and nighttime periods among 199 African Americans with clinic measured systolic/diastolic BP >=140/90 mm Hg in the Jackson Heart Study. Left ventricular mass index (LVMI) was measured among participants with WCH and 374 participants with sustained normotension (ie, non-hypertensive clinic, daytime, 24-hour, and nighttime BP). The prevalence of WCH was 29.6%, 21.1%, and 10.6% using daytime BP; daytime and 24-hour BP; and daytime, 24-hour, and nighttime BP, respectively. Compared with sustained normotension, LVMI was higher when WCH was defined using daytime BP (adjusted mean difference [95% CI] 5.0 [-0.2, 10.1] g/m2 ), but not when defined using daytime and 24-hour BP or daytime, 24-hour, and nighttime BP (adjusted mean difference [95% CI] 3.9 [-1.9, 9.7] and 0.4 [ 7.3,8.2] g/m2 , respectively). Using only daytime BP overestimates the prevalence of WCH among African Americans. PMID- 29978545 TI - Near-Infrared Light Responsive Imaging-Guided Photothermal and Photodynamic Synergistic Therapy Nanoplatform Based on Carbon Nanohorns for Efficient Cancer Treatment. AB - Indocyanine green (ICG) is an effective light absorber for laser-mediated photodynamic therapy. However, applications of ICG are limited due to its rapid degradation and poor photostability in water. Herein, we report the development of a multifunctional nanoplatform by coating ICG on the surface of single-walled carbon nanohorns (SWNHs) through pi-pi stacking, obtaining SWNH-ICGs with high solubility and stability under physiological conditions. The SWNH-ICGs could be used as a single nanoplatform to simultaneously produce satisfactory hyperthermia and reactive oxygen species under near-infrared (NIR) laser irradiation. In addition, the SWNH-ICGs not only improved the photostability of ICG in different media, but also protected it from light degradation. The SWNH-ICGs exhibited highly efficient thermal/photoacoustic (PA) imaging-guided photothermal therapy (PTT) and photodynamic therapy (PDT) effects, even under low-power laser irradiation (0.3 W cm-2 ) in vitro. Combined PTT and PDT effectively killed triple-negative breast cancer 4T1 cells, demonstrating a markedly improved and synergistic therapeutic effect compared to PTT or PDT alone. Furthermore, significant tumor growth inhibition as well as tumor cell death were observed following PTT/PDT at 808 nm laser irradiation, confirming the synergistic effects of SWNH-ICGs over free ICG in vivo. This facile and simple methodology for thermal/PA imaging-guided PTT/PDT suggests that SWNH-ICGs may serve as an effective nanoplatform for cancer therapy. PMID- 29978544 TI - Risk factors for bleeding, including platelet count threshold, in newly diagnosed immune thrombocytopenia adults. AB - : Essentials Risk factors of bleeding in adult immune thrombocytopenia are not known. This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset. Platelet count thresholds associated with bleeding were < 20 * 109 L-1 and < 10 * 109 L-1 . Exposure to anticoagulants was a major risk factor of severe bleeding. SUMMARY: Background The aim of this cross-sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds. Methods We selected all newly diagnosed ITP adults included in the Cytopenies Auto-immunes Registre Midi-PyreneEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models. Results Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 * 109 L-1 . In multivariate analysis, factors associated with any bleeding were platelet count (< 10 * 109 L-1 versus >= 20 * 109 L-1 , odds ratio [OR] 48.2, 95% confidence interval [CI] 20.0-116.3; between 10 * 109 L-1 and 19 * 109 L-1 versus >= 20 * 109 L-1 , OR 5.2, 95% CI 2.3-11.6), female sex (OR 2.6, 95% CI 1.3-5.0), and exposure to non-steroidal anti-inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1-20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3-14.1). Conclusions Platelet counts of < 20 * 109 L-1 and < 10 * 109 L-1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding. PMID- 29978546 TI - Early detection of potential errors during patient treatment planning. AB - PURPOSE: Data errors caught late in treatment planning require time to correct, resulting in delays up to 1 week. In this work, we identify causes of data errors in treatment planning and develop a software tool that detects them early in the planning workflow. METHODS: Two categories of errors were studied: data transfer errors and TPS errors. Using root cause analysis, the causes of these errors were determined. This information was incorporated into a software tool which uses ODBC-SQL service to access TPS's Postgres and Mosaiq MSSQL databases for our clinic. The tool then uses a read-only FTP service to scan the TPS unix file system for errors. Detected errors are reviewed by a physicist. Once confirmed, clinicians are notified to correct the error and educated to prevent errors in the future. Time-cost analysis was performed to estimate the time savings of implementing this software clinically. RESULTS: The main errors identified were incorrect patient entry, missing image slice, and incorrect DICOM tag for data transfer errors and incorrect CT-density table application, incorrect image as reference CT, and secondary image imported to incorrect patient for TPS errors. The software has been running automatically since 2015. In 2016, 84 errors were detected with the most frequent errors being incorrect patient entry (35), incorrect CT-density table (17), and missing image slice (16). After clinical interventions to our planning workflow, the number of errors in 2017 decreased to 44. Time savings in 2016 with the software is estimated to be 795 h. This is attributed to catching errors early and eliminating the need to replan cases. CONCLUSIONS: New QA software detects errors during planning, improving the accuracy and efficiency of the planning process. This important QA tool focused our efforts on the data communication processes in our planning workflow that need the most improvement. PMID- 29978547 TI - Smart Bandage for Monitoring and Treatment of Chronic Wounds. AB - Chronic wounds are a major health concern and they affect the lives of more than 25 million people in the United States. They are susceptible to infection and are the leading cause of nontraumatic limb amputations worldwide. The wound environment is dynamic, but their healing rate can be enhanced by administration of therapies at the right time. This approach requires real-time monitoring of the wound environment with on-demand drug delivery in a closed-loop manner. In this paper, a smart and automated flexible wound dressing with temperature and pH sensors integrated onto flexible bandages that monitor wound status in real-time to address this unmet medical need is presented. Moreover, a stimuli-responsive drug releasing system comprising of a hydrogel loaded with thermo-responsive drug carriers and an electronically controlled flexible heater is also integrated into the wound dressing to release the drugs on-demand. The dressing is equipped with a microcontroller to process the data measured by the sensors and to program the drug release protocol for individualized treatment. This flexible smart wound dressing has the potential to significantly impact the treatment of chronic wounds. PMID- 29978548 TI - Dosimetric effects of anatomical deformations and positioning errors in VMAT breast radiotherapy. AB - AIM: Traditional radiotherapy treatment techniques of the breast are insensitive for deformations and swelling of the soft tissue. The purpose of this study was to evaluate the dose changes seen with tissue deformations using different image matching methods when VMAT technique was used, and compare these with tangential technique. METHODS: The study included 24 patients with breast or chest wall irradiations, nine of whom were bilateral. In addition to planar kV setup imaging, patients underwent weekly cone-beam computed tomography (CBCT) imaging to evaluate soft tissue deformations. The effect of the deformations was evaluated on VMAT plans optimized with 5-mm virtual bolus to create skin flash, and compared to standard tangential plans with 2.5 cm skin flash. Isocenter positioning using 2D imaging and CBCT were compared. RESULTS: With postural changes and soft tissue deformations, the target coverage decreased more in the VMAT plans than in the tangential plans. The planned V90% coverage was 98.3% and 99.0% in the tangential and VMAT plans, respectively. When tattoo-based setup and online 2D match were used, the coverage decreased to 97.9% in tangential and 96.5% in VMAT plans (P < 0.001). With automatic CBCT-based image match the respective coverages were 98.3% and 98.8%. In the cases of large soft tissue deformations, the replanning was needed for the VMAT plan, whereas the tangential plan still covered the whole target volume. CONCLUSIONS: The skin flash created using an optimization bolus for VMAT plans was in most cases enough to take into account the soft tissue deformations seen in breast VMAT treatments. However, in some cases larger skin flash or replanning were needed. The use of 2D match decreased the target coverage for VMAT plans but not for FinF plans when compared to 3D match. The use of CBCT match is recommended when treating breast/chest wall patients with VMAT technique. PMID- 29978549 TI - Associations between dietary behaviours and perceived physical and mental health status among Korean adolescents. AB - AIM: To investigate the associations between a wide range of dietary behaviours and self-reported physical and mental health status in a representative sample of Korean adolescents. METHODS: Data from the 2016 Korea Youth Risk Behaviour Web based Survey were used. Participants were middle- and high-school students (n = 65 528) in grades 7-12. Participants' dietary behaviours were assessed using questionnaires on three encouraged dietary behaviours (consumption of fruits, vegetables, and milk) and three discouraged behaviours (skipping breakfast and consumption of fast food and soft drinks). Participants were also asked to rate their perceived general and oral health, happiness, sleep satisfaction, stress, depressed mood, and suicidal ideation. RESULTS: After adjusting for sex, school grade, residential area, socioeconomic status, and other dietary behaviours, a high intake of fast food and soft drink and frequent skipping of breakfast were all associated with worse physical and mental health status. Moreover, a high intake of fruits, vegetables, and milk were associated with better perceived general health, oral health, happiness, and sleep satisfaction. CONCLUSIONS: Our data suggest that existing encouraged dietary habits mostly have beneficial effects on perceived physical and mental health in Korean adolescents. However, the cross-sectional study design prevents our ability to assess causal relationships. PMID- 29978550 TI - Differences between PARTICIPANTS AND NON PARTICIPANTS in a randomised controlled trial - LESSONS LEARNT FROM the ENGAGE study of referral for an exercise program in survivors of prostate cancer. PMID- 29978551 TI - Endoscopic smartphone adaptors in Otolaryngology: How do they compare? PMID- 29978552 TI - McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome. AB - Background The McMaster RARE-Bestpractices project group selected the catastrophic antiphospholipid syndrome (CAPS) for a pilot exercise in guideline development for a rare disease. Objectives The objectives of this exercise were to provide a proof of principle that guidelines can be developed for rare diseases and assist in clinical decision making for CAPS. Patients/Methods The GIN-McMaster Guideline Development checklist and GRADE methodology were followed throughout the guideline process. The CAPS guideline was coordinated by a steering committee, and the guideline panel was formed with representation from all relevant stakeholder groups. Systematic reviews were performed for the key questions. To supplement the published evidence, we piloted novel methods, including use of an expert-based evidence elicitation process and ad hoc analysis of registry data. Results This paper describes the CAPS guideline recommendations, including evidence appraisal and discussion of special circumstances and implementation barriers identified by the panel. Many of these recommendations are conditional, because of subgroup considerations in this heterogeneous disease, as well as variability in patient values and preferences. Conclusions The CAPS clinical practice guideline initiative met the objective of the successful development of a clinical practice guideline in a rare disease using GRADE methodology. We expect that clinicians caring for patients with suspected CAPS will find the guideline useful in assisting with diagnosis and management of this rare disease. PMID- 29978553 TI - Recurrence of pre-eclampsia and the risk of future hypertension and cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND: Women with a history of hypertensive disorders, including pre eclampsia, during pregnancy have a two- to-five-fold increased risk of cardiovascular disease (CVD). In 15% of women, pre-eclampsia recurs in the following pregnancy. OBJECTIVES: To evaluate all evidence on the future risk of developing hypertension and CVD after multiple pregnancies complicated by pre eclampsia compared with pre-eclampsia in a single pregnancy followed by normal subsequent pregnancy. SEARCH STRATEGY: Embase and Medline were searched until June 2017. SELECTION CRITERIA: All relevant studies on the risk of developing hypertension, atherosclerosis, ischaemic heart disease, cerebrovascular accident (CVA), thromboembolism, heart failure or overall hospitalisation and mortality due to CVD after having had recurrent pre-eclampsia. DATA COLLECTION AND ANALYSIS: Twenty-two studies were included in the review. When possible, we calculated pooled risk ratios (RR) with 95% CI through random-effect analysis. MAIN RESULTS: Recurrent pre-eclampsia was consistently associated with an increased pooled risk ratio of hypertension (RR 2.3; 95% CI 1.9-2.9), ischaemic heart disease (RR 2.4; 95% CI 2.2-2.7), heart failure (RR 2.9; 95% CI 2.3-3.7), CVA (RR 1.7; 95% CI 1.2-2.6) and hospitalisation due to CVD (RR 1.6; 95% CI 1.3 1.9) when compared with women with subsequent uncomplicated pregnancies. Other studies on thromboembolism, atherosclerosis and cardiovascular mortality found a positive effect, but data could not be pooled. CONCLUSIONS: This systematic review and meta-analysis support consistent higher risk for future development of hypertension and CVD in women with recurring pre-eclampsia as opposed to women with a single episode of pre-eclampsia. TWEETABLE ABSTRACT: The risk of future cardiovascular disease increases when women have recurrence of pre-eclampsia compared with a single episode. PMID- 29978554 TI - MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Abeta25-35 -induced anxiety and cognitive deficits in a mouse model. AB - AIMS: Recently, histone deacetylase (HDAC) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease (AD). However, HDACi treatments exhibit diverse functions with unfavorable effects in AD. Thus, the development of selective HDACi without side effects is urgently needed. METHODS: HDACi, namely, BML210, MGCD0103, PXD101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Abeta25-35 (50 MUmol/L). MGCD0103 was chosen for in vivo tests and was intraperitoneally injected into C57BL/6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA1 injection of oligomeric Abeta25-35 . Brain samples were collected for pathological analyses after the behavioral analyses including open- field test (OFT), elevated plus maze (EPM), Y-maze, and Morris water maze (MWM). RESULTS: Among the HDACi, MGCD0103 exhibited significant neuroprotection against the Abeta toxicity in primary cultures. MGCD0103 coattenuated cognitive deficits and anxiety against Abeta damage in mice. MGCD0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and alpha-tubulin, synaptophysin, Abeta, tau protein phosphorylation, and serotonergic neuron loss against Abeta toxicity. Furthermore, chronic MGCD0103 treatment did not show liver or kidney toxicity in mice. CONCLUSIONS: These results reveal MGCD0103 could be a potential therapeutic agent against AD. PMID- 29978555 TI - Antenatal staging of congenital lower urinary tract obstruction. AB - AIM: to propose a staging system for congenital Lower Urinary Tract Obstructions (LUTO) capable of predicting the severity of the condition and its prognosis. METHODS: This was a national retrospective study carried out at the eight Academic Hospitals in the Netherlands. We collected prenatal and postnatal data of fetuses at high-risk of isolated LUTO and managed conservatively. Postnatal renal function was assessed by the estimated glomerular filtration rate (eGFR), calculated with the Schwartz formula, considering the length of the infant and the creatinine nadir in the first year of age. Receiver operating characteristic (ROC) curve, univariate analysis and multivariate logistic regression analysis with stepwise backward elimination were performed in order to identify the best antenatal predictors of perinatal mortality and postnatal renal function. RESULTS: In total 261 fetuses suspected for LUTO and managed conservatively were included in the study. The pregnancy was terminated in 110 cases and perinatal death occurred in 35 cases. GA at the appearance of oligohydramnios showed an excellent accuracy in predicting the risk of perinatal mortality with an area under the curve of 0.95 (p < 0.001) and an optimal cut-off at 26 weeks' gestation. Fetuses with still normal AF at 26 weeks' gestation presented with low risk of poor outcome and were therefore defined as cases with mild LUTO. In fetuses referred before the 26th week of gestation, the urinary bladder volume (BV) was the best unique predictor of perinatal mortality. ROC analysis identified a BV of 5.4 cm3 at 20 weeks as the best threshold for predicting an adverse outcome. Therefore, LUTO cases with a BV >= 5.4 cm3 or abnormal AF before 20 weeks' gestation were defined as severe and those with BV < 5.4 cm3 and still normal AF at the 20 weeks' scan were defined as moderate. Risk of perinatal mortality significantly increased according to the stage of severity from mild to moderate and severe stage, from 8%, to 26% and to 55%, respectively. Similarly, risk of severely impaired renal function increased from 11%, to 31% and to 44%, respectively. CONCLUSIONS: Gestational age at first appearance of oligo- or anhydramnios and bladder volume at diagnosis can accurately predict mortality and morbidity in fetuses with LUTO. This article is protected by copyright. All rights reserved. PMID- 29978556 TI - COLLECT, a collaborative database for pregnancy and placental research studies worldwide. PMID- 29978557 TI - Skin closure in arthroplasty surgery: Current practice. AB - The study by Smith et al. (2010) concluded that clips are associated with 3 times the infection rate compared with subcuticular sutures in orthopaedic surgery (P = .01).For hip surgery, there was a 4-fold increase. We aimed to determine the trends and influences in skin closure and wound care for hip and knee arthroplasty in the northwest region as well as what would change surgeons' current practice. A short online survey was emailed to consultants in the northwest of England enquiring about their current practice in superficial skin closure, what has influenced this, and finally what would change their practice. Returned surveys were then analysed. A total of 45 consultants responded (response rate of 40.2%). In both hip and knee arthroplasty, clips were the most commonly used superficial skin closure material (53% and 63%, respectively). Personal experience was the greatest influence on the choice of closure material in both hip and knees (84% and 93% respectively). A total of 66% of hip and 76% of knee surgeons would change their closure material if there was evidence to support this. Hip and knee arthroplasty surgeons are influenced by their personal experience, and most use clips as their skin closure method. Most would change their practice with evidence of one material over another. We conclude that there is need for a prospective, well-powered, multi-centre randomised control trial to determine the skin closure material that has the lowest return-to-theatre rate in arthroplasty surgery. PMID- 29978558 TI - The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour positive to -negative. AB - OBJECTIVES: To assess the impact of conversion from histologically positive to negative soft tissue margins at the apex and bladder neck on biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) after radical prostatectomy (RP) for prostate cancer. MATERIALS AND METHODS: The records of 2 013 patients who underwent RP and intra-operative frozen section (IFS) analysis between July 2007 and June 2016 were reviewed. IFS analysis of the urethra and bladder neck was performed, and if malignant or atypical cells remained, further resection with the aim of achieving histological negativity was carried out. Patients were divided into three groups according to the findings: those with a negative surgical margin (NSM), a positive surgical margin converted to negative (NCSM) and a persistent positive surgical margin (PSM). RESULTS: Among the 2 013 patients, rates of NSMs, NCSMs and PSMs were 75.1%, 4.9%, and 20.0%, respectively. The 5-year BCRFS rates of patients with NSMs, NCSMs and PSMs were 89.6%, 85.1% and 57.1%, respectively (P < 0.001). In both pathological (p)T2 and pT3 cancers, the 5-year BCRFS rate for patients with NCSMs was similar to that for patients with NSMs, and higher than for patients with PSMs. The 7-year DMFS rates of patients with NSMs, NCSMs and PSMs were 97.8%, 99.1% and 89.4%, respectively (P < 0.001). Among patients with pT3 cancers, the 7-year DMFS rate was significantly higher in the NCSM group than in the PSM group (98.0% vs 86.7%; P = 0.023), but not among those with pT2 cancers (100% vs 96.9%; P = 0.616). The 5-year BCRFS rate for the NCSM group was not significantly different from that of the NSM group among the patients with low- (96.3% vs 95.8%) and intermediate-risk disease (91.1% vs 82.8%), but was lower than that of the NSM group among patients in the high-risk group (73.2% vs 54.7%). CONCLUSIONS: Conversion of the soft tissue margin at the prostate apex and bladder neck from histologically positive to negative improved the BCRFS and DMFS after RP for prostate cancer; however, the benefit of conversion was not apparent in patients in the high-risk group. PMID- 29978559 TI - Sex-specific associations between smoking habits and reaching longevity: Netherlands Cohort Study. AB - AIM: Tobacco smoking has been found to be significantly associated with a decreased chance of reaching longevity in men, but not in women. Furthermore, it is still unclear how the association of smoking status with longevity varies under the influence of underlying smoking characteristics. Therefore, we aimed to quantify the association between several smoking characteristics and the chance of reaching the age of 90 years in men and women separately. METHODS: We carried out a prospective cohort study among the oldest birth cohorts (1916-1917) of the Netherlands Cohort Study, who completed a baseline questionnaire in 1986 (at ages 68-70), and had complete vital status information until 90 years-of-age (2006 2007, n = 7807). Multivariable-adjusted analyses were based on 6642 men and women, of which 16.0% and 34.3% reached longevity, respectively. RESULTS: The relationship of smoking status with longevity was stronger in men than in women (current vs never smokers; risk ratio 0.44, 95% CI 0.34-0.56 in men, and risk ratio 0.67, 95% CI 0.57-0.79 in women). Furthermore, significantly inverse associations were found between longevity and increasing cigarette smoking quantity, duration, and tar and nicotine exposure, which partially explain the observed difference between both sexes. Quitting smoking significantly increased the chance of reaching longevity compared with current smokers. CONCLUSIONS: The effect of smoking status on reaching longevity seemed stronger in men compared with women, which can be partially explained by differences in smoking habits. Never smokers had the highest chance of reaching 90 years-of-age in both sexes. Geriatr Gerontol Int 2018; 18: 1249-1258. PMID- 29978561 TI - Expression of Francisella pathogenicity island protein intracellular growth locus E (IglE) in mammalian cells is involved in intracellular trafficking, possibly through microtubule organizing center. AB - Francisella tularensis is the causative agent of the infectious disease tularemia and is designated a category A bioterrorism agent. The type VI secretion system encoded by the Francisella pathogenicity island (FPI) is necessary for intracellular growth; however, the functions of FPI proteins are largely unknown. In this study, we found that the FPI protein intracellular growth locus E (IglE) showed a unique localization pattern compared to other FPI proteins. Deleting iglE from Francisella tularensis subsp. novicida (F. novicida) decreased intracellular growth. Immunoprecipitation and pull-down assays revealed that IglE was associated with beta-tubulin. Additionally, GFP-fused IglE colocalized with microtubule organizing centers (MTOCs) in 293T cells. The iglE deletion mutant was transferred with dynein toward MTOCs and packed into lysosome-localizing areas. Conversely, the wild-type F. novicida exhibited intracellular growth distant from MTOCs. In addition, IglE expressed in 293T cells colocalized with dynein. These results suggest that IglE helps to prevent dynein- and MTOC mediated intracellular trafficking in host cells to inhibit the transport of F. novicida toward lysosomes. PMID- 29978560 TI - Titin-based mechanosensing modulates muscle hypertrophy. AB - BACKGROUND: Titin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing. METHODS: We used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs. RESULTS: In wildtype mice, the denervated hemidiaphragm mass increased 48 +/- 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20DeltaRRM and TtnDeltaIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20DeltaRRM mice (reduced stiffness) showed a 20 +/- 6% attenuated hypertrophy response, whereas the TtnDeltaIAjxn mice (increased stiffness) showed an 18 +/- 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin-binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1. CONCLUSIONS: Titin functions as a mechanosensor that regulates muscle trophicity. PMID- 29978563 TI - Health care policy at a crossroads? A discursive study of patient agency in national health quality strategies between 1993 and 2015. AB - The Danish health care sector currently undergoes changes that imply a gradual transition from an evidence-based activity model to a value-based quality model centered on patient involvement and value-based governance. The patient naturally occupies a central position in health care, and the transition therefore raises important questions about health care quality and how successive national health quality strategies value quality and ascribe roles and agency to patients. To explore the complexity of these quality strategies, we analyze and discuss how political discourse moments influence the contents of the national health quality strategies and how variation in the construal of patient roles and agency indicates discursive struggle in Danish national health care policy. Underlying theoretical concepts are informed by New Public Management, the welfare state, health communication, and discourse theory. Our analytical approach is inspired by Critical Discourse Analysis and combines content analysis with linguistic analysis. PMID- 29978562 TI - Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer. AB - BACKGROUND: By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. METHODS: We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. RESULTS: Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. CONCLUSIONS: Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia. PMID- 29978564 TI - 4D Biofabrication: Materials, Methods, and Applications. AB - The mission of regenerative medicine is the development of methods to regrow, repair, or replace damaged or diseased cells, organs, or tissues. 3D bioprinting techniques are one of the most promising approaches for engineering the design of artificial tissues. Current 3D bioprinting technologies possess, however, several intrinsic limitations. 4D biofabrication, a recently developed technology with the embedded ability of shape transformation upon response to intrinsic and/or external stimuli, may solve challenges of 3D bioprinting as well as more accurately mimic the dynamics of the native tissues. This article covers recent advances in 4D biofabrication. It gives a detailed picture of used materials and technologies, provides critical comparisons of methods, discusses possibilities and limitations of different 4D biofabrication technologies, and gives examples of applications. PMID- 29978565 TI - Delivery Strategies for Immune Checkpoint Blockade. AB - Immune checkpoint blockade, which blocks the regulatory pathways that express on immune cells to improve antitumor immunological responses, is becoming one of the most promising approaches for antitumor therapy. This therapy has achieved important clinical advancement and provided a new opportunity against a variety of cancers. However, limitations of checkpoint inhibitors application, including the risk of autoimmune disease, low objective response rates, and high cost, still largely affect their broad applications in patients. Therefore, it is desirable to seek effective delivery methods to further enhance the therapeutic efficacy and reduce drawbacks of immune checkpoint blockade. This brief review summarizes strategies to increase the antitumor immunity, including the local and targeted delivery of checkpoint inhibitors, and a combination of different checkpoint inhibitors or with other therapeutic treatments. PMID- 29978566 TI - Quantitative in vivo detection of adipose tissue browning using diffuse reflectance spectroscopy in near-infrared II window. AB - White adipose tissue (WAT) and brown adipose tissue (BAT) biologically function in an opposite way in energy metabolism. BAT induces energy consumption by heat production while WAT mainly stores energy in the form of triglycerides. Recent progress in the conversion of WAT cells to "beige" or "brown-like" adipocytes in animals, having functional similarity to BAT, spurred a great interest in developing the next-generation therapeutics in the field of metabolic disorders. Though magnetic resonance imaging and positron emission tomography could detect classical BAT and WAT in animals and humans, it is of a great challenge in detecting the "browning" process in vivo. Here, to the best of our knowledge, for the first time, we present a simple, cost-effective, label-free fiber optic-based diffuse reflectance spectroscopy measurement in the near infrared II window (~1050-1400 nm) for the quantitative detection of browning in a mouse model in vivo. We could successfully quantify the browning of WAT in a mouse model by estimating the lipid fraction, which serves as an endogenous marker. Lipid fraction exhibited a gradual decrease from WAT to BAT with beige exhibiting an intermediate value. in vivo browning process was also confirmed with standard molecular and biochemical assays. PMID- 29978568 TI - Bariatric and metabolic surgery in Asia: Where are we, and where are we going? PMID- 29978567 TI - Imaging in gynecological disease (14): clinical and ultrasound characteristics of ovarian clear cell carcinoma. AB - OBJECTIVE: To describe the clinical and ultrasound characteristics of ovarian pure clear cell carcinoma. METHODS: This was a retrospective study involving data from 11 ultrasound centers. From the International Ovarian Tumor Analysis (IOTA) database, 105 patients who had undergone preoperative ultrasound examination by an experienced ultrasound examiner between 1999 and 2016 were identified with a histologically confirmed pure clear cell carcinoma of the ovary. An additional 47 patients diagnosed with pure clear cell carcinoma between 1999 and 2016 and with available complete preoperative ultrasound reports were identified retrospectively from the databases of the departments of gynecological oncology in the participating centers. The ultrasound images of all tumors were described using IOTA terminology. Clinical and ultrasound characteristics were analyzed for the whole group, and separately, for patients with and those without histologically confirmed endometriosis, and for patients with evidence of tumor developing from endometriosis. RESULTS: Median age of the 152 patients was 53.5 (range, 28-92) years and 92/152 (60.5%) tumors were FIGO Stage I. Most tumors (128/152, 84.2%) were unilateral. On ultrasound examination, all tumors contained solid components and 36/152 (23.7%) were completely solid masses. The median largest diameter of the lesion was 117 (range, 25-310) mm. Papillary projections were present in 58/152 (38.2%) masses and, in most of these (51/56, 91.1%), vascularized papillary projections were seen. Information regarding the presence, site and type of pelvic endometriosis at histology was available for 130/152 patients. Endometriosis was noted in 54 (41.5%) of these. In 24/130 (18.6%) patients, the tumor was judged to have developed from endometriosis. Patients with, compared to those without, evidence of tumor developing from endometriosis were younger (median 47.5 vs 55.0 years, respectively), and ground-glass echogenicity of cyst fluid was more common in pure clear cell cancers developing from endometriosis (10/20 vs 13/79 (50.0% vs 16.5%), respectively). CONCLUSIONS: Ovarian pure clear cell carcinoma is usually diagnosed at an early stage and typically appears as a large unilateral mass with solid components. Patients with clear cell carcinoma developing from endometriosis are younger than other patients with clear cell carcinoma, and clear cell cancers developing from endometriosis more often manifest ground-glass echogenicity of cyst fluid. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29978569 TI - One- and three-year outcomes in patients treated with intermittent hemodialysis for acute kidney injury: prospective observational multicenter post-hoc FINNAKI study. AB - BACKGROUND: Studies reporting renal and overall survival after acute kidney injury (AKI) treated exclusively with intermittent modalities of renal replacement therapy (IRRT) are rare. This study focused on outcomes of AKI patients treated with IRRT both in intensive care units (ICUs) and non-ICU dialysis units. METHODS: This prospective observational study was carried on during a 5-month period in 17 ICUs and 17 non-ICUs. ICU and non-ICU patients (total n = 138; 65 ICU, 73 non-ICU) requiring RRT for AKI and chosen to receive IRRT were included. Patient and RRT characteristics as well as outcomes at 90 days, 1 year, and 3 years were registered. RESULTS: Characteristics of ICU and non-ICU patients differed markedly. Pre-existing chronic kidney disease (CKD) and chronic heart failure were significantly more common among non-ICU patients. At 1 year, RRT dependence was significantly more common in the non-ICU group. At 3 years, there was no significant difference between the groups either in RRT dependence or mortality. CONCLUSION: Outcome of AKI patients treated with IRRT is dismal with regard to 3-year kidney function and mortality. Although pre-existing CKD emerged as a major risk factor for end-stage renal disease after AKI, the poor kidney survival was also seen in patients without prior CKD. PMID- 29978570 TI - Brown rice-specific gamma-oryzanol as a promising prophylactic avenue to protect against diabetes mellitus and obesity in humans. AB - Chronic overconsumption of animal fats causes a variety of health problems, including diabetes mellitus and obesity. Underlying molecular mechanisms encompass leptin resistance, a decrease in rewarding effects of physical activities, xanthine oxidase-induced oxidative stress in vasculature and peripheral tissue, impaired activation of incretin signaling, deviation in food preference, and dysbiosis of gut microbiota. Based on our clinical observation that daily intake of brown rice effectively ameliorates bodyweight gain, impaired glucose tolerance/insulin resistance and dependence on fatty foods in obese, prediabetes men, a line of research on brown rice (rice bran)-derived gamma oryzanol in mice experiments, cultured cells and human clinical trials is underway in our laboratory. Our works in mice showed that gamma-oryzanol, an ester mixture of ferulic acid and several kinds of phytosterols, acts as a molecular chaperone, thereby attenuating the strong preference for animal fats through suppression of endoplasmic reticulum stress in the hypothalamus. In pancreatic islets from both high-fat diet-induced and streptozotocin-induced diabetic mice, gamma-oryzanol ameliorates endoplasmic reticulum stress and protects beta-cells against apoptosis. Noticeably, gamma-oryzanol also acts as a potent inhibitor against deoxyribonucleic acid methyltransferases in the brain reward system (striatum) in mice, thereby attenuating, at least partly, the preference for a high-fat diet through the epigenetic modulation of striatal dopamine D2 receptor. Because dopamine D2 receptor signaling in the brain reward system is considerably attenuated in obese humans and rodents, gamma-oryzanol might represent a unique property to ameliorate both hedonic and metabolic dysregulation of feeding behavior, highlighting a promising prophylactic avenue to protect against metabolic derangement. PMID- 29978571 TI - Impacts of the 2016 Kumamoto Earthquake on glycemic control in patients with diabetes. AB - AIMS/INTRODUCTION: On April 14 and 16 2016, the Kumamoto area was severely damaged by several massive magnitude 7 class earthquakes. MATERIALS AND METHODS: To examine the effects of these earthquakes on glycemic control and stress factors, glycated hemoglobin, glycated albumin, other biochemical parameters, a self-administered lifestyle-associated questionnaire and disaster-associated stress scores were analyzed. A total of 557 patients with diabetes were enrolled, and data were collected at 13 months before to 13 months after the earthquakes. RESULTS: In patients with type 1 diabetes and specific types of diabetes due to other causes, glycemic control was not altered during the observational period. This glycemic stability in type 1 diabetes might result from self-management of insulin doses. In patients with type 2 diabetes, glycated hemoglobin decreased by 0.11% (from 7.33 to 7.22%) at 1-2 months after the earthquakes, and increased thereafter. The reduction of glycated hemoglobin after 1-2 months in type 2 diabetes was associated with 'early restoration of lifelines' and 'sufficient sleep.' The glycemic deterioration at a later stage was related to 'shortage of antidiabetic agents,' 'insufficient amount of food,' 'largely destroyed houses' and 'changes in working environments.' Disaster-associated stress levels were positively correlated with 'age,' 'delayed restoration of lifelines,' 'self management of antidiabetic agents' and 'increased amount of physical activity/exercise,' and negatively associated with 'early restoration of lifelines' and 'sufficient sleep.' CONCLUSIONS: Glycemic control, associated factors and stress levels are altered in chronological order. Post-disaster diabetic medical care must consider these corresponding points in accordance with the time-period. PMID- 29978572 TI - Computer simulation analysis of source-detector position for percutaneously measured O2 -gas signal in a three-dimensional preterm infant lung. AB - Further improvements in the clinical care of our most vulnerable patients-preterm infants-are needed. Novel diagnostic and surveillance tools facilitate such advances. The GASMAS technique has shown potential to become a tool to, noninvasively, monitor gas in the lungs of preterm infants, by placing a laser source and a detector on the chest wall skin. It is believed that this technology will become a valuable clinical diagnostic tool for monitoring the lung function of these patients. Today, the technology is, for this application, in an early stage and further investigations are needed. In the present study, a three dimensional computer model of the thorax of an infant is constructed, from a set of CT images. Light transport simulations are performed to provide information about the position dependence of the laser- and detector probe on the thorax of the infant. The result of the simulations, based on the study method and the specified model used in this work, indicates that measurement geometries in front and on the side of the lung are favorable in order to obtain a good gas absorption signal. PMID- 29978574 TI - Soluble galectin 9 potently enhanced regulatory T-cell formation, a pathway impaired in patients with intracranial aneurysm. AB - Patients with intracranial aneurysm (IA) present a dysregulated immune system with lower frequency of regulatory T (Treg) cells. Here, we examined whether galectin 9 (Gal-9), the natural ligand of Tim-3, could promote Treg cells in IA patients. We first discovered that the intracellular and extracellular Gal-9 was primarily expressed by CD4+ CD25- T conventional (Tconv) cells, and also by monocytes at lower levels, but rarely by CD4+ CD25+ Treg cells. In IA patients, the Gal-9 expression was significantly lower than in healthy controls. CD4+ CD25- Tconv cells could be induced into Foxp3-expressing induced Treg (iTreg) cells using a TGF-beta-containing milieu. We found that soluble Gal-9 significantly enhanced this process by potently upregulating the expression of Foxp3, IL-10 and TGF-beta in a concentration-dependent manner. In addition, in the absence of additional Gal-9, the level of Foxp3 upregulation was directly correlated with the level of intrinsic Gal-9 expression. Notably, the strength of external Gal-9 mediated effects was significantly lower in IA patients than in healthy controls. Using a Tim-3 blocking antibody, we found that the promotion of iTreg development by soluble Gal-9 was dependent on the Tim-3 signalling pathway. Overall, our investigations demonstrated that Gal-9 presented a critical role in the development of iTreg cells. However, this mechanism was impaired in IA patients due to lower expression of both Gal-9 and Tim-3. PMID- 29978573 TI - Toremifene, rather than tamoxifen, might be a better option for the adjuvant endocrine therapy in CYP2D6*10T/T genotype breast cancer patients in China. AB - Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. A total of 230 breast cancer patients who received adjuvant TAM (n = 115) or TOR (n = 115) at the National Cancer Center were analyzed. The CYP2D6 *10 genotype was not significantly associated with DFS in patients who received TOR (p = 0.737). Patients treated with TOR had a higher 5-year disease-free survival (DFS) rate than those treated with TAM (89.6% vs. 80.9%, p = 0.009). TOR treatment remained an independent prognostic marker of DFS in multivariate analysis compared with TAM (hazard ratio = 0.51; p = 0.014). For all of the 50 CYP2D6 *10 T/T genotype patients, TOR treatment group had a significantly higher 5-year DFS rate than TAM group (90.9% vs. 67.9%, p = 0.031). For the remaining 170 CYP2D6 *10 C/C or C/T genotype patients, there was no significant difference between the 5-year DFS rates of the TOR and TAM groups (89.2% vs. 85.1%, p = 0.188). The advantage of adjuvant TOR over TAM in Chinese breast cancer patients might be caused by the significant benefit obtained by the CYP2D6 *10 T/T patients, who accounted for one-fifth of the overall population. TOR might be a good option for adjuvant endocrine therapy in this subgroup of patients in China. PMID- 29978575 TI - Women's perspectives on home-based care for family members with chronic illness: An Interpretive phenomenology study. AB - The number of people with chronic illness who need home-based care is increasing globally. Home-based care is socially constructed to be work carried out by women. However, little attention has been paid to the opinions of middle-aged women caring for family members with chronic illness at home. In this study, Thai women's perspectives on home-based care for family members with chronic illness using interpretive phenomenology were identified. Fifteen middle-aged women were interviewed twice, and the data were analyzed using thematic analysis. Four major themes emerged: (i) role obligation; (ii) social life change; (iii) doing good things; and (iv) lack of support. Important findings were that care was considered a woman's duty owing to cultural beliefs. Most participants sacrificed their own needs to care for others, as doing good things is considered an important Buddhist belief. Caring for others decreased women's social networks, but they cared more for their own health. Support with finances, information, workplaces, and care recipients should be provided to women with care responsibilities. These results can help nurses to better understand women's caring roles and the consequences of home-based care that influence woman's health. PMID- 29978576 TI - Difficulties of fathers whose families evacuated voluntarily after the Fukushima nuclear disaster. AB - The Fukushima nuclear disaster in 2011 resulted in radiation exposure, and many evacuees felt anxious of its health risks. However, little is known about the difficulties faced by fathers whose families evacuated voluntarily. Therefore, the aim of the present case study was to clarify the difficulties and concerns of fathers whose families evacuated voluntarily after the Fukushima nuclear disaster. Eleven fathers in Fukushima were interviewed between 14 December 2014 and 25 February 2015. Four themes emerged: (i) seeking a safe place away from radiation exposure; (ii) burdens of a double life; (iii) feelings of isolation and perceived deterioration of health; and (iv) deciding on whether to continue voluntary evacuation. Fathers were anxious about radiation exposure, similar to mothers, and faced work-family conflicts from the voluntary evacuation of their families, including financial, physical, and mental sacrifice. Half of the fathers did not express their difficulties to others. Our findings identified a new type of conflict between people of a community who did/did not choose voluntary evacuation. Occupational health nurses should understand fathers' feelings of isolation and monitor their health to prevent the development of stress-related diseases. PMID- 29978577 TI - Relative potency of the thrombopoietin receptor agonists eltrombopag, avatrombopag and romiplostim in a patient with chronic immune thrombocytopenia. PMID- 29978579 TI - Rhodium(III)-Catalyzed C-H Alkynylation of N-Methylsulfoximines. AB - A rhodium(III)-catalyzed direct C-H alkynylation of a wide range of N methylsulfoximines with (bromoethynyl)triisopropylsilane has been developed. This protocol is compatible with both (S,S)-diaryl sulfoximines and (S,S)-alkyl aryl sulfoximines, and shows mild conditions, and good functional group tolerance. The synthetic utility of this method has been demonstrated by subsequent various transformations of the products. PMID- 29978578 TI - Practical inter-sectoral linking: Tool to rabies One Health coordination to the grass-roots level. AB - Rabies is an endemic disease in the Philippines. Addressing the disease at source, massive efforts towards dog vaccination and public awareness on rabies have been pursued by various Local Government Units (LGUs) in the country. While marked improvements have been seen, rabies continues to persist where it exists, largely owing to poor surveillance of the disease in animals and weak coordination between the human and animal health sectors. To bridge these critical gaps, the BAI-OIE STANDZ Rabies Project in the Philippines, together with the key rabies stakeholders in Bicol Region, developed the "Practical Inter sectoral Linking"-an operational protocol and practical network of local key players (human health, animal health and LGUs) involved in rabies detection, reporting and implementation of appropriate interventions. It is initiated by recognized triggers such as detection of confirmed or probable rabies cases and is closely linked with early detection in animals, case investigation, quarantine, diagnosis, reporting and post-exposure prophylaxis. People down to the village level are informed about the routine, protocol and contact details of relevant people in responding to bite victims with the flowchart provided by the tool. This tool was initially rolled out in pilot provinces in the Bicol Region and to date has already documented success in initiating timely actions to 31 laboratory confirmed rabies cases being investigated, which actually saved 46 human lives upon further investigation. With this established at the LGU level, the goal to timely detect suspect or probable rabies cases and promptly implement appropriate interventions are expected to improve, while local officials are empowered with their roles as frontline workers in the prevention and control of rabies. PMID- 29978580 TI - Functional variant of MTOR rs2536 and survival of Chinese gastric cancer patients. AB - We previously reported that some single nucleotide polymorphisms (SNPs) of candidate genes involved in the MTOR complex1 (MTORC1) were associated with risk of gastric cancer (GCa). In the present study, we further evaluated associations of eight potentially functional SNPs of MTOR, MLST8 and RPTOR with survival of 1002 GCa patients and also investigated molecular mechanisms underlying such associations. Specifically, we found that the MTOR rs2536 C allele at the microRNA binding site was independently associated with a 26% reduction of death risk (HR = 0.74, 95% CI = 0.57-0.96, p = 0.022). The results remained noteworthy with a prior false positive probability of 0.1. Genotype-phenotype correlation analysis in 144 patients' adjacent normal gastric tissue samples revealed that the MTOR expression levels were lower in rs2536 TC/CC carriers than that in wild type TT carriers (p = 0.043). Dual luciferase assays revealed that the rs2536 C allele had a higher binding affinity to microRNA-150, leading to a decreased transcriptional activity of MTOR, compared to the rs2536 T allele. Further functional analysis revealed that MTOR knockdown by small interference RNA impaired proliferation, migration, and invasion ability in GCa cell lines. In conclusion, The MTOR rs2536 T > C change may be a biomarker for survival of Chinese GCa patients, likely by modulating microRNA-induced gene expression silencing. Additional studies are needed to validate our findings. PMID- 29978581 TI - Fetal optic chiasm: 3 steps for visualization and measure in routine transabdominal ultrasound. AB - The optic chiasm (OC) is an X-shaped structure formed by the crossing of the optic nerves in an axial view of the fetal brain. It is located in the chiasmatic cistern and it is surrounded by the Willis circle. The anterior cerebral arteries lay anteriorly, the posterior communicant arteries lay laterally and the posterior cerebral arteries are identified posteriorly. The decussation or centre of the OC corresponds to the origin of the middle cerebral arteries laterally arising from internal carotids. This article is protected by copyright. All rights reserved. PMID- 29978582 TI - ECE-1 overexpression in head and neck cancer is associated with poor tumor differentiation and patient outcome. AB - BACKGROUND: Endothelin-converting enzyme-1 (ECE-1) primarily converts big endothelins (ETs) into active endothelin-1 (ET-1). However, the expression pattern and prognostication status of ECE-1 in head and neck cancer (HNC) are enigmatic. In this study, we investigated ECE-1 expression and assessed the roles of ECE-1 as a predictor for HNC differentiation and prognosis. MATERIALS AND METHODS: ECE-1 expressions were evaluated by immunohistochemical analysis using a tissue microarray (TMA) composed of 100 cases of head and neck squamous cell carcinoma. The correlation of ECE-1 expression with clinicopathologic variables and patient outcomes was analyzed. RESULTS: ECE-1 may be overexpressed in HNC carcinoma cells. Higher ECE-1 level was detected more frequently in moderately to poorly differentiated tumors and showed a lower differentiation category compared to the G1 cases (p = 0.015); this finding was further confirmed by an adjusted odds ratio (OR) of 4.071 (p = 0.042). Moreover, Kaplan-Meier survival analyses showed that a higher ECE-1 expression was associated with a poorer survival in patients with HNC (p < 0.0001). On multivariate Cox proportional hazards models analysis, ECE-1 of high expression proved to be an independent prognostic factor with a hazard ratio (HR) of 3.985 (p < 0.001). CONCLUSION: Our data provide the first evidence that overexpression of ECE-1 in HNC is a predictor of poor tumor differentiation and prognosis. PMID- 29978583 TI - Clinical, dermoscopic and histopathological features of a rare cutaneous neural tumour. PMID- 29978584 TI - Are long nursing shifts on hospital wards associated with sickness absence? A longitudinal retrospective observational study. AB - OBJECTIVE: To investigate whether working 12 hr shifts is associated with increased sickness absence among registered nurses and health care assistants. BACKGROUND: Previous studies reported negative impacts on nurses' 12 hr shifts; however, these studies used cross-sectional techniques and subjective nurse reported data. METHODS: A retrospective longitudinal study using routinely collected data across 32 general inpatient wards at an acute hospital in England. We used generalized linear mixed models to explore the association between shift patterns and the subsequent occurrence of short (<7 days) or long-term (>=7 days) sickness absence. RESULTS: We analysed 601,282 shifts and 8,090 distinct episodes of sickness absence. When more than 75% of shifts worked in the past 7 days were 12 hr in length, the odds of both a short-term (adjusted odds ratio = 1.28; 95% confidence index: 1.18-1.39) and long-term sickness episode (adjusted odds ratio = 1.22; 95% confidence index: 1.08-1.37) were increased compared with working none. CONCLUSION: Working long shifts on hospital wards is associated with a higher risk of sickness absence for registered nurses and health care assistants. IMPLICATIONS FOR NURSING MANAGEMENT: The higher sickness absence rates associated with long shifts could result in additional costs or loss of productivity for hospitals. The routine implementation of long shifts should be avoided. PMID- 29978585 TI - Evaluation of passive sampling polymers and nonequilibrium adjustment methods in a multiyear surveillance of sediment porewater PCBs. AB - Polymeric passive sampling devices are increasingly used to measure low-level, freely dissolved concentrations of hydrophobic organic contaminants in environmental waters. A range of polymers have been used for this purpose, and several different methods of accounting for nonequilibrium using performance reference compounds (PRCs) have been proposed. The present study explores the practical impacts of these decisions in an applied context using results from a multiyear passive sampling surveillance of polychlorinated biphenyl concentrations in sediment porewater at a contaminated marsh amended with activated carbon (AC) sorbent materials. In a series of 5 sampling events spanning almost 2 yr, we deployed polyoxymethylene and polyethylene samplers and calculated porewater concentrations with 5 different PRC adjustment methods. The results provide a basis for evaluating amendment performance by showing reductions of 34 to 97% in amended sediment porewater concentrations. They also provide a quantitative underpinning for discussions of the differences between sampling polymers, selection of PRCs, generation of high-resolution vertical profiles of porewater concentrations, and a comparison of PRC adjustment methods. For unamended sediment, older methods based on first-order kinetics agreed well with a recently developed method based on diffusion into and out of sediment beds. However, the sediment diffusion method did not work well for the sediments amended with AC. Environ Toxicol Chem 2018;37:2487-2495. (c) 2018 SETAC. PMID- 29978586 TI - Retrospective analysis of the usefulness of a protocol with high-dose methotrexate in polymyalgia rheumatica: Results of a single-center cohort of 100 patients. AB - AIM: The aim of the present study was to define subsets of patients suffering from polymyalgia rheumatica, where methotrexate (MTX) up to 20 mg/week might be more effective. METHODS: A total of 100 patients with polymyalgia rheumatica treated with MTX were studied. The criteria for MTX introduction were: (i) relapse during the first month of therapy, when tapering glucocorticoids (GC); (ii) requiring long-term GC (i.e. >24 consecutive months); (iii) requiring >=5 mg/day of prednisone equivalents after 4 months of GC therapy; (iv) GC-related side-effects; and (v) a high risk of GC-related side-effects. All the patients were followed for at least 12 months. A group of patients treated with GC alone in the same center was also compared with the whole MTX group. RESULTS: Follow up varied from 12 to 185 months (median 46.5 months). Remission with current prednisone dose <=2.5 mg/day at month +12 was observed in 59 out of 100 patients; remission with GC suspension at month +12 was observed in 38 out of 100, without significant difference among groups. Approximately half of the patients showed at least one relapse (54/100) during the follow-up period. The cumulative dose of GC was 1.5 g (range 0.1-15.2 g) . New GC-related side-effects were recorded in 16 out of 100 patients at last follow up. Compared with the GC alone group, the MTX group showed younger age, higher prevalence of female sex and higher level of inflammation. CONCLUSIONS: MTX up to 20 mg/day was useful in defined subsets of polymyalgia rheumatica, also in the long term. No significant differences were noticed among the five subgroups. Geriatr Gerontol Int 2018; 18: 1410-1414. PMID- 29978587 TI - Role of CA125/CEA ratio and ultrasound parameters in identifying metastases to the ovaries in patients with multilocular and multilocular-solid ovarian masses. AB - OBJECTIVES: To investigate ultrasound features and the best cut-off value of CA125/CEA ratio to discriminate benign and primary malignant ovarian neoplasms from ovarian metastases in selected groups of morphological ovarian masses: multilocular masses with 5 or more locules and multilocular-solid masses. METHODS: Patients with multilocular (>=5 locules) or multilocular-solid ovarian masses, operated on within three months from ultrasound, and tumor markers (CEA and CA125) available at diagnosis were retrospectively identified from three ultrasound centers. The masses were described using the International Ovarian Tumor Analysis terminology. RESULTS: 350 (88.4%) patients with an ovarian neoplasm (including 99 benign, 43 borderline, 197 primary epithelial ovarian carcinomas, 7 malignant rare tumors and 4 other types of invasive ovarian tumor) and 46 (11.6%) patients with an ovarian metastasis were analyzed. At ultrasound, ovarian neoplasms were smaller than ovarian metastases (median of the largest diameter: 97, range 20-387 mm, versus 146, range 43-259 mm) (p<0.0001) and presented with a lower number of cysts with >10 locules (18.9% versus 54.3%) (< 0.0001). Receiver operating characteristic curve (ROC) analysis showed that the best cut-off value of CEA for predicting ovarian neoplasms versus ovarian metastases was 2.33 ng/mL. The predictive performance of the CEA cut-off value was: AUC 0.791 (95%CI 0.711-0870), accuracy 73.7%, sensitivity 73.1%, specificity 78.3%, PPV 96.2% and NPV 27.7%. The best cut-off value of CA125/CEA ratio for predicting ovarian neoplasms versus ovarian metastases was 11.92. The predictive performance of the CA125/CEA cut-off value was: AUC of 0.758 (95%CI 0.683-0.833), accuracy 79.8%, sensitivity 82.3%, specificity 60.9% PPV 94.1% and NPV 31.1% CONCLUSIONS: CA125/CEA ratio and CEA alone did not show any significant difference in distinguishing ovarian neoplasms (including benign and malignant) from ovarian metastases in masses with multilocular and multilocular-solid morphology. Therefore, in this morphological subgroup of ovarian masses, CEA alone is enough to use for differentiating between the ovarian neoplasms and ovarian metastases. This article is protected by copyright. All rights reserved. PMID- 29978588 TI - Epsilon waves: Milestones in the discovery and progress. AB - The Epsilon wave was first identified in 1977. Four decades of progress help people to better understand its pathological electrogenesis and diagnostic value. Currently, the Epsilon wave is on the list of the 2010 Task Force recommendations for the diagnosis of arrhythmogenic right ventricular dysplasia (ARVD). In this review, we provide the history of the first recording of the Epsilon wave in coronary artery disease and Uhl's anomaly, subsequently leading to the signal averaging technique to record late potentials. Based on our experience, we discuss some existing controversies. When we look back at the decades of progress of the Epsilon wave, we conclude that the Epsilon wave is only the tip of the iceberg of ECG abnormalities in ARVD. PMID- 29978589 TI - Epigenetic status of subtelomere of peripheral leukocytes corresponds to cardiographic parameters with a sex association. AB - AIM: The telomere length of somatic cells is associated with systemic aging. The attrition of somatic telomere length is accelerated in pathological conditions, such as cardiovascular diseases. However, clinical parameters of cardiac function have not been well studied in this regard. The present study examined how cardiac function was affected by telomere length and the subtelomeric methylation of peripheral leukocytes. METHODS: Telomere length was assessed by Southern blotting analysis of genomic DNA extracted from peripheral leukocytes. Subtelomeric methylation was assessed by comparison between the Southern blotting results with a restriction enzyme Msp I and those with Hpa II, a methylation-sensitive isoschizomer of Msp I. RESULTS: The following parameters were associated with telomere length and/or the subtelomeric methylation status in a sex-associated manner: PR interval, the voltage of QRS complex, QRS interval, QT interval and T wave voltage in electrocardiogram; and ejection fraction, the diameter of the left ventricle at the end diastolic phase, aortic root diameter and inferior vena cava diameter in echocardiogram. CONCLUSIONS: Cardiac function correlates not only with telomere length, but also with the distribution of the telomere length and subtelomeric DNA methylation status. These imply that the loss of young cells, the accumulation of old cells and the acceleration of such changes in the cell population relate to phenotypes of cardiac aging with relative sex specificity. Furthermore, the PR interval showed a very close association with telomeric parameters in both sexes. Hence, PR is the most reliable candidate as an indicator of biological aging in both sexes. Geriatr Gerontol Int 2018; 18: 1415-1419. PMID- 29978590 TI - Longtime driving induced cerebral hemodynamic elevation and behavior degradation as assessed by functional near-infrared spectroscopy and a voluntary attention test. AB - Drowsy driving contributes to ~20% of all traffic accidents worldwide. Onsite monitoring the mental condition of a driver and forewarning may be a preventive solution to reduce occurrence of drowsiness and potential accidents. Functional near-infrared spectroscopy (fNIRS) has been successfully utilized in hemodynamics interpreted functional activity in preliminary voluntary attention experiments. Here, we monitored hemodynamic alternations using fNIRS upon the prefrontal cortex over 13 volunteers in the course of a 7-hour driving simulation and evaluated their reaction capability with a voluntary attention test based on Go/NoGo paradigm. A degradation in attention test score (Accuracy/RT) as well as the elevations in oxy-hemoglobin (Delta[HbO2 ]) and total hemoglobin (Delta[tHb]) were found significantly correlated with driving duration (Accuracy/RT: r = 0.964, P < 0.001; Delta[HbO2 ]: r = 0.950, P < 0.001; Delta[tHb]: r = 0.852, P = 0.007). The hemodynamic parameters are in significant inverse correlations with Accuracy/RT (Delta[HbO2 ]: r = -0.896, p = 0.003; Delta[tHb]: r = -0.844, P = 0.008), indicating the potential to forewarn drivers the attention degradation with onsite fNIRS measurements. PMID- 29978591 TI - easySLM-STED: Stimulated emission depletion microscopy with aberration correction, extended field of view and multiple beam scanning. AB - We demonstrate a simplified set-up for STED microscopy with a straightforward alignment procedure that uses a single spatial light modulator (SLM) with collinear incident excitation and depletion beams to provide phase modulation of the beam profiles and correction of optical aberrations. We show that this approach can be used to extend the field of view for STED microscopy by correcting chromatic aberration that otherwise leads to walk-off between the focused excitation and depletion beams. We further show how this arrangement can be adapted to increase the imaging speed through multibeam excitation and depletion. Fine adjustments to the alignment can be accomplished using the SLM only, conferring the potential for automation. PMID- 29978592 TI - Maximum gait speed is associated with a wide range of cognitive functions in Japanese older adults with a Clinical Dementia Rating of 0.5. AB - AIM: Physical and cognitive functions are mutually associated. However, it is unknown which markers of physical functions or body composition are most strongly associated with cognition. Here, we explored the association between body composition/physical performance and comprehensive neuropsychological assessments in an effort to identify reliable markers of cognition among factors in body composition/physical performance, including both usual and maximum gait speeds. METHODS: We examined a total of 161 Japanese individuals (71 men, 90 women; aged 76.3 +/- 7.2 years) with a Clinical Dementia Rating of 0.5 and a Mini-Mental State Examination score >24. A battery of neuropsychological assessments, physical functional assessments and measurements of body composition was carried out. We conducted a multiple regression analysis to investigate the associations between cognitive performance and the factors in body composition and physical performance with adjustments for age, sex, and number of school years. RESULTS: Maximum gait speed was the factor most widely associated with cognitive performance among the factors of body composition and physical performance. CONCLUSION: Maximum gait speed might be the best marker for cognition in this population of older individuals. Geriatr Gerontol Int 2018; 18: 1323-1329. PMID- 29978593 TI - Patient-initiated follow up affects fear of recurrence and healthcare use: a randomised trial in early-stage endometrial cancer. AB - OBJECTIVE: To test the hypothesis that patient-initiated follow up reduces the fear of cancer recurrence (FCR) and healthcare use when compared with traditional hospital-based follow up. DESIGN: Pragmatic, multicentre randomised trial. SETTING: Four Danish departments of gynaecology between May 2013 and May 2016. POPULATION: One hundred and fifty-six women diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I low-intermediate risk endometrial carcinoma. METHODS: Women allocated to the control group attended hospital-based follow up consisting of regular outpatient visits for 3 years after primary treatment. Women in the intervention group were instructed in patient-initiated follow up, which included careful instruction in alarm symptoms and options for self-referral rather than a schedule of examinations. MAIN OUTCOME MEASURES: The primary end point was FCR as measured by the Fear of Cancer Recurrence Inventory (FCRI) after 10 months of follow up. Secondary end points included cancer-related use of primary and secondary health care during the first 10 months after treatment. RESULTS: In the primary analysis, FCR decreased significantly more in the control group from baseline to 10 months of follow up (difference -5.9, 95% CI -10.9 to -0.9). The majority of this improvement happened after only 3 months of follow up. Women receiving the intervention had fewer examinations at the department compared with the control group (0 versus 2 median visits, P < 0.01) and 58% of these examinations were scheduled because of vaginal bleeding. CONCLUSIONS: Hospital-based follow up alleviates FCR significantly more than patient-initiated follow up, though the estimated difference was small. Patient-initiated follow up is a feasible, potentially cost reducing follow-up approach in a population of endometrial cancer survivors with low risk of recurrence. The decision to use patient-initiated follow up should balance these benefits and harms. TWEETABLE ABSTRACT: Patient-initiated follow up reduces healthcare use but maintains fear of recurrence in endometrial cancer. PLAIN LANGUAGE SUMMARY: Why and how was the study carried out? Follow up of women with endometrial cancer is resource consuming and previous research suggests that it is not effective. Even though the women benefit from reassurance at follow up, routine examinations may also remind the women of the disease and induce fear of cancer recurrence. Furthermore, routine follow up may delay recurrence diagnosis, because the women do not report their symptoms until the next scheduled visit. In the research explained in this article, patient-initiated follow up was evaluated as an alternative to traditional follow up. The women were randomly assigned to one of two follow-up programmes: regular gynaecological examinations at the department of gynaecology or self-referral with careful instruction in alarm symptoms, that is, patient-initiated follow up. The level of fear of cancer recurrence in the two groups was obtained by questionnaires. Information on healthcare use was obtained by questionnaires and a chart review. What were the main findings? Regular examinations at the department of gynaecology reduced the fear of cancer recurrence significantly more than patient-initiated follow up, though the difference was small. Women who were instructed in alarm symptoms, under self-referral, were able to monitor their symptoms, and this approach significantly reduced the number of examinations at the department of gynaecology. What are the limitations of the work? Participants in the self referral group knew that they were examined less than other women, and this may have induced fear of cancer recurrence. Similarly, the regular completion of questionnaires regarding fear of cancer recurrence may have reminded the women of the disease and diminished the difference between the two groups. What are the implications for patients Patient-initiated follow up reduced healthcare use but maintained fear of cancer recurrence in women who had survived early-stage endometrial cancer. Future analyses on quality of life and cost-effectiveness are needed to balance the benefits and harms of patient-initiated follow up. PMID- 29978594 TI - Characteristics of microbial communities and intestinal pathogenic bacteria for migrated Larus ridibundus in southwest China. AB - Larus ridibundus, a migratory wild bird, has become one of the most popular gull species in southwest China in recent years. There has been no information on the gut microbiota and intestinal pathogenic bacteria configuration in wild L. ridibundus, even though the public are in close contact with this bird. In this study, 16S rRNA amplicon-sequencing methods were used to describe the microbial community structure and intestinal pathogenic bacteria were isolated to identify their characteristics. The taxonomic results revealed that Firmicutes (86%), Proteobacteria (10%), and Tenericutes (3%) were the three most abundant phyla in the gut of L. ridibundus. Enterococcaceae, Enterobacteriaceae, and Mycoplasmataceae were the most predominant families, respectively. The number of operational taxonomic units (OTUs), the richness estimates and diversity indices of microbiota, was statistically different (p < 0.05). However, beta diversity showed that no statistical significance (p > 0.05) between all the fecal samples. The most frequently isolated intestinal pathogenic bacteria from L. ridibundus were enteropathogenic Escherichia coli (32%) and Salmonella (21%). Pulsed-field gel electrophoresis (PFGE) results of Salmonella species revealed a high degree of similarity between isolates, which was not observed for other species. None of the potentially pathogenic isolates were identical to human-isolated counterparts suggesting that there was little cross-infection between humans and gulls, despite close proximity. In brief, this study provided a baseline for future L. ridibundus microbiology analysis, and made an understanding of the intestinal bacterial community structure and diversity. PMID- 29978595 TI - Pigment epithelium-derived factor: a key mediator in bone homeostasis and potential for bone regenerative therapy. AB - OBJECTIVES: Pigment epithelium-derived factor (PEDF), a multifunctional endogenous glycoprotein, has a very wide range of biological actions, notably in bone homeostasis. The question has been raised regarding the place of PEDF in the treatment of bone disorders and osteosarcoma, and its potential for tumour growth suppression. METHODS: The PubMed database was used to compile this review. KEY FINDINGS: Pigment epithelium-derived factor's actions in osteoid tissues include promoting mesenchymal stem cell commitment to osteoblasts, increasing matrix mineralisation, and promoting osteoblast proliferation. It shows potential to improve therapeutic outcomes in treatment of multiple cancer types and regrowth of bone after trauma or resection in animal studies. PEDF may possibly have a reduced adverse effect profile compared with current osteo-regenerative treatments; however, there is currently very limited evidence regarding the safety or efficacy in human models. SUMMARY: Pigment epithelium-derived factor is very active within the body, particularly in osseous tissue, and its physiological actions give it potential for treatment of both bone disorders and multiple tumour types. Further research is needed to ascertain the adverse effects and safety profile of PEDF as a therapeutic agent. PMID- 29978596 TI - Curcumin and fisetin internalization into Saccharomyces cerevisiae cells via osmoporation: impact of multiple osmotic treatments on the process efficiency. AB - : Cell osmoporation is a simple and straightforward procedure of creating food grade biocapsules. This study proposes a new protocol of sequential cell osmoporation stages and evaluates its impact on the efficiency of curcumin and fisetin internalization into Saccharomyces cerevisiae cells. To the best of our knowledge, this is the first report in the literature regarding the subject. To assess how multiple osmoporation stages influence the encapsulation efficiency (% EE), encapsulated amount of curcumin (IC) and fisetin (IF) into S. cerevisiae cells and cell viability, the residual supernatant was used for the subsequent encapsulation stages and viability was assessed by the CFU method. Quantification was carried through direct extraction, using an ultrasonic bath and UV-Vis spectrophotometry. Experimental data demonstrated that the addition of a second osmoporation stage increases both the EE (% EE) and the amount of encapsulated curcumin and fisetin (IC and IF). As a result, the EE was considerably improved and the obtained microcapsules contained a higher amount of the targeted bioactive compounds in its internal structure. However, adding a third osmoporation stage proved to less beneficial to the process efficiency due to its lower yield and the significant negative impact to cell viability. SIGNIFICANCE AND IMPACT OF THE STUDY: For the first time in the literature, a protocol of serial osmoporation stages to enhance the encapsulation efficiency of hydrophobic low molecular weight molecules (curcumin and fisetin) into Saccharomyces cerevisiae cells was determined. By increasing overall efficiency, this protocol empowers the encapsulation process and creates a rational way to reduce waste for future industrial osmoporation applications. PMID- 29978598 TI - Tumor suppression effect of targeting periostin with siRNA in a nude mouse model of human laryngeal squamous cell carcinoma. AB - BACKGROUND: The incidence of laryngeal carcinoma is increasing, however, the mechanism is not fully understood. We aimed to investigate the efficacy of periostin gene silencing by siRNA on tumor inhibition, in a novel nude mouse model of human laryngeal squamous cell carcinoma, and to explore possible inhibitory mechanisms. METHODS: Tumors were established in nude mice by transplantation of LSCC AMC-HN-8 cell line. Forty-eight nude mice were randomly divided into groups of eight each, and treated with high (1.0 OD) or low (0.5 OD) doses of periostin-siRNA or appropriate control solutions. Tumor growth was observed and used to calculate an inhibition rate (%). Routine pathological and electron microscopic examination were used to determine tumor apoptosis and proliferation. Changes in periostin mRNA and protein levels were analyzed. RESULTS: Tumor growth was significantly inhibited in mice treated by high dose periostin-siRNA compared to untreated and those treated with low dose periostin siRNA (P < 0.05). Pathological examination showed increased tumor necrosis and apoptotic changes in treated mice, which was confirmed by electron microscopy. Periostin mRNA and protein expression were significantly reduced in tumors from mice treated with high dose periostin-siRNA, compared to controls and low-dose periostin-siRNA treatment groups (P < 0.05). CONCLUSION: Periostin silencing was associated with growth inhibition of tumor cells in a nude mouse model of LSCC. The underlying mechanism may be due to receptor-mediated induction of relevant signal transduction pathways that modulate the microenvironment needed for cancer cell survival. Periostin is expected to become a new target for cancer therapy. PMID- 29978597 TI - Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition. AB - BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526. PMID- 29978599 TI - Prediction of the efficacy of dinoprostone slow release vaginal insert (Propess) for cervical ripening: A prospective cohort study. AB - AIM: To evaluate factors predictive of the success of dinoprostone slow release vaginal insert for cervical ripening. METHODS: A total of 169 women who underwent cervical ripening with dinoprostone slow release vaginal insert were included in the study cohort. The correlation between parameters present before cervical ripening with dinoprostone slow release and its success, as well as complications and adverse outcomes were analyzed. RESULTS: Dinoprostone slow release vaginal insert was successful in achieving vaginal delivery in 148 of 169 (87.6%), while sufficient ripening was achieved in 140 (83%) cases. Factors associated with successful vaginal delivery were multiparity and younger gestational age at delivery. Factors predictive of the success of cervical ripening with dinoprostone slow release vaginal insert were lower body mass index (BMI), higher parity and perceived contractions prior to insertion. Intrauterine growth restriction was associated with a significant risk for dinoprostone insert removal. Neonatal outcomes were similar in cases of successful or failed ripening. CONCLUSION: The success of cervical ripening with dinoprostone slow release vaginal insert can be predicted by factors that can be recognized at admission. PMID- 29978600 TI - A Bioinspired Synthesis of Polyfunctional Indoles. AB - Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C-H, N-H, and O-H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well-defined indole heterocycles. PMID- 29978602 TI - Introduction to unresolved issues in the care of dialysis patients. PMID- 29978601 TI - The effect of the algal microbiome on industrial production of microalgae. AB - Microbes are ubiquitously distributed, and they are also present in algae production systems. The algal microbiome is a pivotal part of the alga holobiont and has a key role in modulating algal populations in nature. However, there is a lack of knowledge on the role of bacteria in artificial systems ranging from laboratory flasks to industrial ponds. Coexisting microorganisms, and predominantly bacteria, are often regarded as contaminants in algal research, but recent studies manifested that many algal symbionts not only promote algal growth but also offer advantages in downstream processing. Because of the high expectations for microalgae in a bio-based economy, better understanding of benefits and risks of algal-microbial associations is important for the algae industry. Reducing production cost may be through applying specific bacteria to enhance algae growth at large scale as well as through preventing the growth of a broad spectrum of algal pathogens. In this review, we highlight the latest studies of algae-microbial interactions and their underlying mechanisms, discuss advantages of large-scale algal-bacterial cocultivation and extend such knowledge to a broad range of biotechnological applications. PMID- 29978604 TI - The proanthocyanidin-specific transcription factor MdMYBPA1 initiates anthocyanin synthesis under low-temperature conditions in red-fleshed apples. AB - In plants, flavonoids play critical roles in resistance to biotic and abiotic stresses, and contribute substantially to the quality, flavor, and nutritional quality of many fruit crops. In apple (Malus * domestica), inbreeding has resulted in severe decreases in the genetic diversity and flavonoid content. Over the last decade, we have focused on the genetic improvement of apple using wild red-fleshed apple resources (Malus sieversii f. niedzwetzkyana). Here, we found that the MYB transcription factors (TFs) involved in the synthesis of proanthocyanidins can be classified into TT2 and PA1 types. We characterized a PA1-type MYB transcription factor, MdMYBPA1, from red-fleshed apple and identified its role in flavonoid biosynthesis using overexpression and knockdown expression transgenes in apple calli. We explored the relationship between TT2- and PA1-type MYB TFs, and found that MdMYB9/11/12 bind the MdMYBPA1 promoter. In addition, MdMYBPA1 responded to low temperature by redirecting the flavonoid biosynthetic pathway from proanthocyanidin to anthocyanin production. In binding analyses, MdbHLH33 directly bound to the low-temperature-responsive (LTR) cis element of the MdMYBPA1 promoter and promotes its activity. In addition, the calli expressing both MdMYBPA1 and MdbHLH33, which together form a complex, produced more anthocyanin under low temperature. Our findings shed light on the essential roles of PA1-type TFs in the metabolic network of proanthocyanidin and anthocyanin synthesis in plants. Studies on red-fleshed wild apple are beneficial for breeding new apple varieties with high flavonoid contents. PMID- 29978605 TI - Global Change Biology Introduction - FACEing the future conference. AB - The adoption of the Paris climate change agreement by the majority of the countries on this Earth shows that most world leaders are taking human-induced climate change seriously and acknowledge that countermeasures are urgently needed to restrict global warming below a threshold of 2 degrees C if we are to avoid damaging consequences for biodiversity, ecosystems function and food production. Elevated atmospheric CO2 and rising temperature, alone and in combination, affect ecosystem processes, plant growth and physiology, and abiotic systems such as the water cycle. Understanding these impacts, and the complex feedback processes that occur in plant-soil interactions under climate change, requires a combination of experimental approaches. This article is protected by copyright. All rights reserved. PMID- 29978606 TI - Testing clustering strategies for metabarcoding-based investigation of community environment interactions. AB - The degradation of freshwater ecosystems has become a common ecological and environmental problem globally. Owing to the complexity of biological communities, there remain tremendous technical challenges for investigating influence of environmental stressors (e.g., chemical pollution) on biological communities. High-throughput sequencing-based metabarcoding provides a powerful tool to reveal complex interactions between environments and biological communities. Among many technical issues, the clustering strategies for operational taxonomic units (OTUs) which are crucial for assessing biodiversity of communities, may affect final conclusions. Here, we used zooplankton communities along an environmental pollution gradient in the Chaobai River in Northern China to test different clustering strategies, including nonclustering and clustering with varied thresholds. Our results showed that though the number of OTUs estimated by nonclustering strategies and clustering strategies with divergence thresholds of 99%-97% largely varied, they were able to identify the same set of significant environmental and spatial variables responsible for geographical distributions of zooplankton communities. In addition, the ecological conclusions obtained by clustering thresholds of 99%-97% were consistent with nonclustering strategies, where for all eight clustering scenarios we detected that species sorting predicted by environmental variables overrode dispersal as the dominant factor in structuring zooplankton communities. However, clustering with the divergence thresholds of <95% affected the environmental and spatial variables identified. We conclude that both newly developed nonclustering methods and traditional clustering methods with divergence thresholds >=97% were reliable to reveal mechanisms of complex community-environment interactions, although different clustering strategies could lead to largely varied biodiversity estimates such as those for alpha diversity. PMID- 29978608 TI - Ataxia-Telangiectasia-Mutated Protein Expression as a Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands. AB - PURPOSE: Adenoid cystic carcinoma (ACC) is a high-grade malignant tumor of the salivary glands, clinically characterized by multiple recurrences and late distant metastasis. Biological markers for assessing the prognosis of ACC have remained elusive. The purpose of this study was to investigate whether the protein expressions of ataxia telangiectasia mutated (ATM), p53, and ATM-mediated phosphorylated p53 are related to patient survival in ACC. MATERIALS AND METHODS: In this study, 48 surgical samples were used to assess the expressions of ATM and its downstream target p53. Fisher's exact test and Kaplan-Meier analysis were conducted to evaluate the role of ATM, p53, and phospho-p53 (S15) protein expressions in predicting patient survival and distant metastasis. RESULTS: Myb expression was positive in 85.4% of ACCs, but did not reflect patient survival rate. In contrast, low expression of ATM in cancer cells was significantly correlated with poor survival rate (p=0.037). Moreover, under positive p53 expression, low expression of ATM was highly predictive of poor survival in ACC (p=0.017). CONCLUSION: These data indicate that combined assessment of ATM and p53 expression can serve as a useful prognostic marker for assessing survival rate in patients with ACC of the salivary glands. PMID- 29978607 TI - Critical and Challenging Issues in the Surgical Management of Low-Lying Rectal Cancer. AB - Despite innovative advancements, the management of distally located rectal cancer (RC) remains a formidable endeavor. The critical location of the tumor predisposes it to a circumferential resection margin that tends to involve the sphincters and surrounding organs, pelvic lymph node metastasis, and anastomotic complications. In this regard, colorectal surgeons should be aware of issues beyond the performance of total mesorectal excision (TME). For decades, abdominoperineal resection had been the standard of care for low-lying RC; however, its association with high rates of tumor recurrence, tumor perforation, and poorer survival has stimulated the development of novel surgical techniques and modifications, such as extralevator abdominoperineal excision. Similarly, difficult dissections and poor visualization, especially in obese patients with low-lying tumors, have led to the development of transanal TME or the "bottom-to up" approach. Additionally, while neoadjuvant chemoradiotherapy has allowed for the execution of more sphincter-saving procedures without oncologic compromise, functional outcomes remain an issue. Nevertheless, neoadjuvant treatment can lead to significant tumor regression and complete pathological response, permitting the utilization of organ-preserving strategies. At present, an East and West dualism pervades the management of lateral lymph node metastasis, thereby calling for a more global and united approach. Moreover, with the increasing importance of quality of life, a tailored, individualized treatment approach is of utmost importance when taking into account oncologic and anticipated functional outcomes. PMID- 29978609 TI - Synergistic Anti-Cancer Effects of AKT and SRC Inhibition in Human Pancreatic Cancer Cells. AB - PURPOSE: To investigate the effect of combined inhibition of protein kinase B (AKT) and SRC on the growth and metastatic potential of human pancreatic cancer cells. MATERIALS AND METHODS: AKT and SRC were inhibited using 10-DEBC and PP2, respectively. The expression of their messenger RNAs were down-regulated by specific small interfering RNA (siRNA). Changes in pancreatic cancer cell growth and metastatic potential were determined using a cell viability assay and a xenotransplant model of pancreatic cancer, as well as cell migration and invasion assays. Signal proteins were analyzed by Western blot. RESULTS: The inhibitors 10 DEBC and PP2 suppressed cell proliferation in a dose-dependent fashion in pancreatic cancer cell lines MIA PaCa-2 and PANC-1. The simultaneous inhibition of AKT and SRC at low concentrations resulted in a significant suppression of cell proliferation. Knockdown of AKT2 and SRC using siRNAs also significantly decreased cell proliferation. In a pancreatic cancer model, combined treatment with 10-DEBC and PP2 also significantly suppressed the growth of pancreatic cancer. Application of 10-DEBC with PP2 significantly reduced the metastatic potential of pancreatic cancer cells by inhibiting migration and invasion. The combined inhibition suppressed the phosphorylation of mTOR and ERK in pancreatic cancer cells. CONCLUSION: Combined targeting of AKT and SRC resulted in a synergistic efficacy against human pancreatic cancer growth and metastasis. PMID- 29978610 TI - Extracellular Vesicles Derived from Hypoxic Human Mesenchymal Stem Cells Attenuate GSK3beta Expression via miRNA-26a in an Ischemia-Reperfusion Injury Model. AB - PURPOSE: Bioactive molecules critical to intracellular signaling are contained in extracellular vesicles (EVs) and have cardioprotective effects in ischemia/reperfusion (IR) injured hearts. This study investigated the mechanism of the cardioprotective effects of EVs derived from hypoxia-preconditioned human mesenchymal stem cells (MSCs). MATERIALS AND METHODS: EV solutions (0.4 MUg/MUL) derived from normoxia-preconditioned MSCs (EV(NM)) and hypoxia-preconditioned MSCs (EV(HM)) were delivered in a rat IR injury model. Successful EV delivery was confirmed by the detection of PKH26 staining in hearts from EV-treated rats. RESULTS: EV(HM) significantly reduced infarct size (24+/-2% vs. 8+/-1%, p<0.001), and diminished arrhythmias by recovering electrical conduction, I(Na) current, and Cx43 expression. EV(HM) also reversed reductions in Wnt1 and beta-catenin levels and increases in GSK3beta induced after IR injury. miRNA-26a was significantly increased in EV(HM), compared with EV(NM), in real-time PCR. Finally, in in vitro experiments, hypoxia-induced increases in GSK3beta expression were significantly reduced by the overexpression of miRNA-26a. CONCLUSION: EV(HM) reduced IR injury by suppressing GSK3beta expression via miRNA 26a and increased Cx43 expression. These findings suggest that the beneficial effect of EVHM is related with Wnt signaling pathway. PMID- 29978611 TI - mRNA Expression of SLC5A5 and SLC2A Family Genes in Papillary Thyroid Cancer: An Analysis of The Cancer Genome Atlas. AB - PURPOSE: The present study investigated the dynamics and prognostic role of messenger RNA (mRNA) expression responsible for 18F-fluorodeoxyglucose (FDG) uptake in FDG positron emission tomography (PET) and radioactive iodine (131I) uptake in whole-body radioactive iodine scans (WBS) in papillary thyroid cancer (PTC) patients. MATERIALS AND METHODS: The primary and processed data were downloaded from the Genomic Data Commons Data Portal. Expression data for sodium/iodide symporter (solute carrier family 5 member 5, SLC5A5), hexokinase (HK1-3), glucose-6-phosphate dehydrogenase (G6PD), and glucose transporter (solute carrier family 2, SLC2A1-4) mRNA were collected. RESULTS: Expression of SLC5A5 mRNA were negatively correlated with SLC2A1 mRNA and positively correlated with SLC2A4 mRNA. In PTC with BRAF mutations, expressions of SLC2A1, SLC2A3, HK2, and HK3 mRNA were higher than those in PTC without BRAF mutations. Expression of SLC5A5, SLC2A4, HK1, and G6PD mRNA was lower in PTC without BRAF mutation. PTCs with higher expression of SLC5A5 mRNA had more favorable disease-free survival, but no association with overall survival. CONCLUSION: Expression of SLC5A5 mRNA was negatively correlated with SLC2A1 mRNA. This finding provides a molecular basis for the management of PTC with negative WBS using 18F-FDG PET scans. In addition, higher expression of SLC5A5 mRNA was associated with less PTC recurrence, but not with deaths. PMID- 29978612 TI - Increased Thrombogenicity in Chronic Renal Failure in a Rat Model Induced by 5/6 Ablation/Infarction. AB - PURPOSE: Abnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function. MATERIALS AND METHODS: CRF was induced by 5/6 ablation/infarction of the kidneys in Sprague Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeCl3) induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry. RESULTS: FeCl3-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2+/-1.1 sec vs. 17.8+/-1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2+/-201.1 MUm vs. 114.0+/ 145.1 MUm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0+/-7.3 sec vs. 72.8+/-5.0 sec, p=0.032) and increased clot growth kinetics (alpha angle, 84.8+/-0.2 degrees vs. 82.0+/-0.6 degrees , p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2+/-0.2% vs. 44.6+/-1.2%, p=0.006). CONCLUSION: Our study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF. PMID- 29978613 TI - Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling. AB - PURPOSE: To compare differentially expressed genes (DEGs) mediating osteoarthritis (OA) in knee cartilage and in normal knee cartilage in a rat model of OA and to identify their impact on molecular pathways associated with OA. MATERIALS AND METHODS: A gene expression profile was downloaded from the Gene Expression Omnibus database. Analysis of DEGs was carried out using GEO2R. Enrichment analyses were performed on the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway using the Search Tool for the Retrieval of Interacting Genes database (http://www.string-db.org/). Subsequently, the regulatory interaction network of OA-associated genes was visualized using Cytoscape software (version 3.4.0; www.cytoscape.org). RESULTS: In the gene expression profile GSE103416, a total of 99 DEGs were identified. Among them, 76 DEGs (76.77%) were overexpressed, and the remaining 23 DEGs (23.23%) were underexpressed. GO and pathway enrichment analyses of target genes were performed. Using gene-gene interaction network analysis, relevant core genes, including MET, UBB, GNAI3, and GNA13, were shown to hold a potential relationship with the development of OA in cartilage. Using quantitative real-time PCR, the Gna13/cGMP-PKG signaling pathway was identified as a potential research target for therapy and for further understanding the development of OA. CONCLUSION: The results of the present study provide a comprehensive understanding of the roles of DEGs in knee cartilage in relation to the development of OA. PMID- 29978614 TI - CT-based Navigation System Using a Patient-Specific Instrument for Femoral Component Positioning: An Experimental in vitro Study with a Sawbone Model. AB - PURPOSE: The intraoperative version of the femoral component is usually determined by visual appraisal of the stem position relative to the distal femoral condylar axis. However, several studies have suggested that a surgeon's visual assessment of the stem position has a high probability of misinterpretation. We developed a computed tomography (CT)-based navigation system with a patient-specific instrument (PSI) capable of three-dimensional (3D) printing and investigated its accuracy and consistency in comparison to the conventional technique of visual assessment of the stem position. MATERIALS AND METHODS: A CT scan of a femur sawbone model was performed, and pre-experimental planning was completed. We conducted 30 femoral neck osteotomies using the conventional technique and another 30 femoral neck osteotomies using the proposed technique. The femoral medullary canals were identified in both groups using a box chisel. RESULTS: For the absolute deviation between the measured and planned values, the mean two-dimensional anteversions of the proposed and conventional techniques were 1.41 degrees and 4.78 degrees , while their mean 3D anteversions were 1.15 degrees and 3.31 degrees . The mean theta1, theta2, theta3, and d, all of which are parameters for evaluating femoral neck osteotomy, were 2.93 degrees , 1.96 degrees , 5.29 degrees , and 0.48 mm for the proposed technique and 4.26 degrees , 3.17 degrees , 4.43 degrees , and 3.15 mm for the conventional technique, respectively. CONCLUSION: The CT-based navigation system with PSI was more accurate and consistent than the conventional technique for assessment of stem position. Therefore, it can be used to reduce the frequency of incorrect assessments of the stem position among surgeons and to help with accurate determination of stem anteversion. PMID- 29978615 TI - Incidence of Cerebral Palsy in Korea and the Effect of Socioeconomic Status: A Population-Based Nationwide Study. AB - PURPOSE: Cerebral palsy (CP) is a neurodevelopmental disorder that causes serious disability. Prematurity and low birth weight (LBW) are known to be the strongest risk factors of CP. While socioeconomic status (SES) has been found to influence the occurrence of CP, prematurity, and LBW, no studies have investigated this effect in Korea. The aim of this study was to evaluate the incidence of CP, prematurity, and LBW in Korea, as well as the effect of SES thereon. MATERIALS AND METHODS: Data were obtained from the National Health Information Database from 2007 to 2013; persons with a history of CP, prematurity, and LBW were investigated by year. SES was defined in accordance with income quintiles, birth regions, and coverage classification. RESULTS: The incidence of CP decreased over the last five years, despite increased rates of prematurity and LBW. CP incidence was significantly lower in affluent groups than in the most deprived group, although this difference disappeared after controlling for confounders. The incidence of CP was significantly higher in medical aid beneficiaries, even after controlling for confounders. CONCLUSION: CP incidence in Korea has decreased over the last five years, despite an increase in high-risk deliveries. Income level had no effect in CP incidence. These results may aid CP management and prevention policies. PMID- 29978616 TI - Effect of rs3910105 in the Synuclein Gene on Dopamine Transporter Availability in Healthy Subjects. AB - PURPOSE: The present study investigated associations between dopamine transporter (DAT) availability and alpha-synuclein levels in cerebrospinal fluid, as well as synuclein gene (SNCA) transcripts, and the effect of single nucleotide polymorphism of SNCA on DAT availability in healthy subjects. MATERIALS AND METHODS: The study population comprised healthy controls who underwent 123I-FP CIT single-photon emission computed tomography screening. Five SNCA probes were used to target the boundaries of exon 3 and exon 4 (SNCA-E3E4), transcripts with a long 3'UTR region (SNCA-3UTR-1, SNCA-3UTR-2), transcripts that skip exon 5 (SNCA-E4E6), and the rare short transcript isoforms that comprise exons 1-4 (SNCA 007). RESULTS: In total, 123 healthy subjects (male 75, female 48) were included in this study. DAT availability in the caudate nucleus (p=0.0661) and putamen (p=0.0739) tended to differ according to rs3910105 genotype. In post-hoc analysis, DAT availability in the putamen was lower in subjects of TT genotype than those of CC/CT (p=0.0317). DAT availability in the caudate nucleus also showed a trend similar to that in the putamen (p=0.0597). Subjects of CT genotype with rs3910105 showed negative correlations with DAT availability in the putamen with SNCA-E3E4 (p=0.037, rho=-0.277), and SNCA-E4E6 (p=0.042, rho=-0.270), but not those of CC/TT genotypes. CONCLUSION: This is the first study to investigate the association of rs3910105 in SNCA with DAT availability. rs3910105 had an effect on DAT availability, and the correlation between DAT availability and SNCA transcripts were significant in CT genotypes of rs3910105. PMID- 29978617 TI - Correction of Eyes and Lip Canting after Bimaxillary Orthognathic Surgery. AB - Patients who have a lower facial asymmetry with compensatory head posture (developmental facial asymmetry) may have minor temporomandibular (T-M) joint problems and tend to mask their asymmetry by tilting the head for camouflage of their chin deviation. However, this compensatory head posture can give the impression of orbital dystopia and c spine deviation. When these patients undergo bimaxillary orthognathic surgery, orbital canting and head tilting improves gradually without the need for camouflage, and bleary eyes become clearer. We evaluated 13 patients who underwent LeFort I osteotomy combined with bilateral sagittal split osteotomy of the mandible for developmental facial asymmetry to quantitatively observe whole facial postural changes after surgery. Pre-operative and post-operative 1:1 full-face photographs of the patients were analyzed to compare the degrees of head tilting and orbital canting and the sizes of the eye opening. After bimaxillary orthognathic surgery, eye canting decreased from 2.6 degrees to 1.5 degrees , eye and lip lines came closer to parallel, and the degree of head tilting decreased from 3.4 degrees to 1.3 degrees . The eyes also appeared to open wider. Correction of lower facial skeletal asymmetry through bimaxillary orthognathic surgery improved head tilting and orbital canting gradually by eliminating the need of compensatory head posture. Facial expressions also changed as the size of the eyes increased due to the reduction of facial muscle tension caused by T-M joint dysfunction. PMID- 29978618 TI - First Molecular Diagnosis of a Patient with Unverricht-Lundborg Disease in Korea. AB - Unverricht-Lundborg disease (ULD) is a form of progressive myoclonus epilepsy characterized by stimulation-induced myoclonus and seizures. This disease is an autosomal recessive disorder, and the gene CSTB, which encodes cystatin B, a cysteine protease inhibitor, is the only gene known to be associated with ULD. Although the prevalence of ULD is higher in the Baltic region of Europe and the Mediterranean, sporadic cases have occasionally been diagnosed worldwide. The patient described in the current report showed only abnormally enlarged restriction fragments of 62 dodecamer repeats, confirming ULD, that were transmitted from both her father and mother who carried the abnormally enlarged restriction fragment as heterozygotes with normal-sized fragments. We report the first case of a genetically confirmed patient with ULD in Korea. PMID- 29978620 TI - Futility of Treatment for Dying Children: Lessons from the Charlie Gard Case. AB - Decision-making about seriously ill and dying children is fraught and distressing for all concerned. The United Kingdom saga involving Charlie Gard and the ruling by four courts hat in his best interests he should not receive experimental therapy overseas provides many lessons for how such controversies should and should not be handled. This editorial places the case in historical and legal context and traces the evolution of the disputation about the treatment to be provided to Charlie, including through the courts and in the media. It argues that it is important for all concerned, including for confidence in clinical guidance and decision-making, that systems be generated which minimise the risk of cases such as that involving Charlie Gard being handled so publicly and in so adversarial a way. PMID- 29978619 TI - Pathologically Confirmed Cerebral Amyloid Angiopathy with No Radiological Sign in a Patient with Early Onset Alzheimer's Disease. AB - Cerebral amyloid angiopathy (CAA) is associated with perivascular disruption, which is caused by progressive amyloid-beta (Abeta) deposition in vessels. Previous autopsy studies have shown that the prevalence of CAA in Alzheimer's disease (AD) is 70% to 90%. CAA is principally characterized by restricted lobar microbleeds (MBs), which can be detected by gradient-echo T2* (GRE) and susceptibility-weighted imaging (SWI). We herein report on a 62-year-old man who presented with 8 years of memory impairment. The apolipoprotein E (APOE) genotype was epsilon4/epsilon4, and a brain GRE performed 28 months before death revealed mild atrophy and no MBs. At autopsy, the patient scored "A3, B3, C3" according to the National Institute on Aging-Alzheimer's Association guidelines; the patient thus exhibited a high level of AD neuropathological changes. Furthermore, immunohistochemical staining for Abeta showed antibody accumulation and severe cerebral amyloid angiopathic changes in numerous vessels with amyloid deposits. Our case suggests that radiological CAA markers, such as cerebral microbleed (CMB) or cerebral superficial siderosis, may not suffice to detect amyloid angiopathy in cerebral vessels. CAA should therefore be considered as a combined pathology in APOE epsilon4 homozygotes with AD, even if such patients do not exhibit CMB on MRI. PMID- 29978621 TI - Voluntary Assisted Dying Legislation in Victoria: What Can We Learn from the Netherlands Experience? AB - The Voluntary Assisted Dying Bill 2017 Vic (VAD Bill) was passed by the Legislative Assembly of the Victorian Parliament on 20 October 2017. The Bill is partly based on the Majority Report provided by the Legal and Social Issues Committee of the Victorian Legislative Council following its Inquiry into End of Life Choices (June 2016). The Majority Report recommended introduction of euthanasia and assisted suicide legislation. The Bill is modelled on the Ministerial Advisory Panel on Voluntary Assisted Dying Final Report, which drafted 66 recommendations on legalising administration and supply of substances for the purpose of causing the person's death. The Victorian government accepted the 66 recommendations, which the Chair of the Ministerial Advisory Panel, Professor Brian Owler, described as detailing safe and compassionate framework for voluntary assisted dying in Victoria. This analysis will focus on matters of major concern relating to the VAD Bill, namely criteria for accessing voluntary assisted dying and in particular, the age threshold and decision-making capacity. The proposed legislation resembles the Dutch Termination of Life on Request and Assisted Suicide (Review Procedures) Act of April 2002 (the Netherlands); consequently, the discussion will draw on the Dutch experience over the past 15 years. PMID- 29978622 TI - Prioritising Patients' Preferences: Victoria's New Advance Planning and Medical Consent Legislation. AB - The introduction of the Medical Treatment Planning and Decisions Act 2016 Vic signals a profound alteration in focus from best interests substitute decision making, and will result in increased opportunities for patients to control their treatment choices. This will apply for advance care directives, and will also more effectively guide decisions made by a proxy. There will be an increased ability for patients to refuse treatment, and an expansion of the treatment choices covered by legislation. This column explores the impact of the legislation and reflects on its extension, and clinical challenges which may arise from the legislation. PMID- 29978623 TI - High Court of Australia and HIV/AIDS Disease Criminalisation: Aubrey v The Queen and Zaburoni v The Queen. AB - In 2017, the High Court of Australia in Aubrey v The Queen (2017) 91 ALJR 601; [2017] HCA 18 considered the term inflict grievous bodily harm, under common law, and expanded its interpretation to incorporate nonviolent and non-immediate infection of a disease, overturning a 120 year authority in R v Clarence (1888) 22 QBD 23. In the previous case of Zaburoni v The Queen (2016) 256 CLR 482; [2016] HCA 12, the High Court allowed an appeal from the Qld Supreme Court finding that repeated acts of unprotected sexual intercourse by a man who knew he was infected with HIV/AIDS, though callous and reckless, did not constitute intention to infect his female partner; consequently, he could be found guilty of a lesser offence of inflicting grievous bodily harm which carried a maximum 14 year prison sentence rather than life imprisonment. These decisions illustrate a court intersecting with an emerging trend to use legislation creating criminal offences to deter those who intentionally or recklessly infect others with life shortening diseases. PMID- 29978624 TI - Doctors with Conditions - Rehabilitation or Risk. AB - This article reports and updates a study that analysed protective orders in medical disciplinary tribunals over a three-year period. It argues that the concept of the protection of the public has been undermined by protective orders that focus on the rehabilitation of problem and impaired doctors in the management of risk. The article posits a medical or psychiatric model of misconduct in which misconduct is seen in terms of illness, rather than attracting negative moral judgment and severe disciplinary sanctions. The findings in the study and cases since indicate that the most common form of risk management in medical tribunals is the imposition of conditions upon a doctor's registration, such as supervision or psychiatric treatment. The article concludes that, given the paucity of research on the rationale and utility of such protective orders, the faith of tribunals in their effectiveness is misplaced. PMID- 29978625 TI - Commentary on Undue Influence Provisions under Oregon Death with Dignity Act and California's End of Life Option Act. AB - This article considers the requirements to assess for elements of undue influence under the Oregon Death with Dignity Act (2013) and California's recently assented to End of Life Option Act (2015). Acting voluntarily, that is free from undue influence, is critical to the operation of these statutes. Indeed, assisted dying largely draws its legitimacy from the requirement that voluntariness is well protected. However, this article argues that the requirements under these statutes fall short of adequately protecting a voluntary decision. This article discusses the provisions concerning voluntariness and undue influence under these two statutes, highlighting ostensible limitations therein. Basic recommendations for improvement are proffered. This article concludes by arguing that Australia should not draw inspiration from these statutory provisions because they fail to protect freedom of choice in a meaningful way. PMID- 29978626 TI - Private Health Care in New Zealand: Five Policy Prescriptions. AB - New Zealand's private healthcare sector has recently drawn political attention as policymakers consider how best to shift the load from the public health system. This article explains and evaluates five policy prescriptions, drawn from experience in the United Kingdom and Australia, as candidates for achieving that broad aim: in brief, they are (1) financial incentives to purchase health insurance, (2) adoption of a lifetime community rating system of health insurance, (3) restrictions on selective contracting, (4) imposing information sharing requirements on providers, and (5) restricting industry incentive schemes. It is concluded that several of these proposals are worthy of further research and analysis. PMID- 29978627 TI - Jurors' and Judges' Evaluation of Defendants with Autism and the Impact on Sentencing: A Systematic Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Review of Autism Spectrum Disorder in the Courtroom. AB - Concern has been highlighted in the literature regarding how juries and judges handle cases which involve a defendant with autism spectrum disorder (ASD). The relatively little research on judicial perceptions or decision-making regarding individuals with ASD indicates that judges have limited understanding and familiarity with high-functioning ASD (hfASD) and ASD. The present systematic review will identify studies which investigate jurors' (eg using mock jurors) and/or judges' evaluations of defendants with ASD and studies which investigate whether the defendant diagnosis of ASD impacts on sentencing. Only four studies were identified which investigated jurors' and/or judges' evaluations of a defendant with an ASD or investigated whether the defendant diagnosis of ASD impacts on sentencing. Further research is recommended which should include an evaluation of cases involving a defendant with an hfASD or ASD diagnosis comparing charges, pleas entered, procedural adjustments at court, evidence adduced about the defendant's condition, directions to juries, judicial remarks on the evidence (eg summing-up for the jury), verdicts and sentencing. This would enable the assessment of the specific offending behaviour and disorder of the defendant, and how these may be relevant to their mental capacity and culpability. PMID- 29978628 TI - Let's Starve Down to the Bone: Pro-anorexia Websites and the Law. AB - Pro-anorexia websites promote anorexia as a positive lifestyle choice. They provide tips to become anorexic and maintain anorexia and diets that people who are anorexic can follow. France became the first country in the world to pass legislation that criminalises the publication of pro-anorexia websites. This article considers the ways that the civil and criminal law in Western Australia can deal with the publishers of pro-anorexia websites. It argues that the law in Western Australia would be unlikely to apply to publishers of pro-anorexia websites, except in the most extreme cases, and it generally cautions against legislative intervention in this area. PMID- 29978629 TI - Legal and Ethical Issues Surrounding Advance Care Directives in Australia: Implications for the Advance Care Planning Document in the Australian My Health Record. AB - This article reviews legal and scientific literature relating to Advance Care Planning (ACP) and Advance Care Directives (ACDs) in Australia, for information about (a) opportunities or benefits of ACP and ACDs and (b) risks, barriers or difficulties in relation to ACP and ACDs. These are discussed in relation to PMID- 29978630 TI - Criticising Current Causation Principles: Views from Victorian Lawyers on Medical Negligence Legislation. AB - Following medical negligence, plaintiffs can be left with devastating permanent injuries that warrant compensation. These plaintiffs might satisfy a breach of duty of care, yet the statutory test of causation presents a hurdle to successful recovery in meritorious negligence claims. In 2015 reforms, the Victorian government reduced injury thresholds and increased compensation caps but did not address the contentious issue of causation. In this article, drawing on interviews with 24 senior tort lawyers, the issue of causation is examined. The majority of participants in this study expressed the view that causation was one of the most significant issues for litigants in medical negligence proceedings. Analysis of the data shows that the participants believed that causation requirements unfairly prevent plaintiffs from succeeding in meritorious claims. The author argues that the recent legislative changes should have addressed causation and failure to do so represents a lost opportunity to provide litigants with just compensation. PMID- 29978631 TI - The Murder Trial of Gerard Baden-Clay: Admissibility of Expert Opinion Evidence of Injuries and Cause of Death. AB - On 20 April 2012, Brisbane real estate agent Gerard Baden-Clay reported that his wife Allison was missing. Ten days later, her body was found under a bridge more than 10 kilometres from the family home. Although the body was badly decomposed, there was no evidence that she had died of a natural cause. Before his trial on the charge of murder, Baden-Clay made application to the Supreme Court to exclude considerable expert opinion evidence relating to the injuries and the possible causes of death of his wife and what had appeared to have been recent scratches on his face. During the subsequent trial, the jury heard extensive evidence from a number of expert witnesses including a forensic pathologist, three forensic medical specialists, a forensic scientist, a botanist, an entomologist, a pharmacologist, a toxicologist and a general psychiatrist. On 15 July 2014, a jury convicted Baden-Clay of murder. On 8 December 2015, after considering the expert evidence and the trial judge's summing up to the jury, the Queensland Court of Appeal set aside the verdict as unreasonable and substituted a verdict of manslaughter. On 31 August 2016, the High Court overturned the decision of the Court of Appeal. The case commentary considers the application of the principles of law relating to the admissibility of expert opinion evidence and the directions a trial judge may give to a jury. PMID- 29978632 TI - Use of Coronial Post-mortem Tissue for Research in New Zealand. AB - Forensic pathology is remarkably under-represented in research: considering the obstacles a researcher must overcome to obtain post-mortem tissue for research, it is perhaps not surprising. We are investigating whether there is any role for altered drug metabolism in potentially fatal clozapine-associated myocarditis and/or cardiomyopathy. As part of this research, the use of post-mortem tissue taken during a coronial autopsy from individuals who have died from, or with, these clozapine-associated cardiotoxicities was considered fundamental. Currently, there is no clear pathway for using coronial post-mortem tissue for research in New Zealand. We have worked through the Coroners Act 2006 NZ, the Human Tissue Act 2008 NZ and the medico-legal death investigation process in New Zealand to use coronial post-mortem tissue for research. The process to obtaining tissue(s) in New Zealand is probably representative of pathways in other coronial systems. PMID- 29978633 TI - Choosing Wisely: Law's Contribution as a Cause of and a Cure for Unwise Health Care Choices. AB - The provision of unnecessary health care is a serious problem in Australia and involves two key legal issues. First, doctors' fear of litigation drives defensive practices - ordering tests and procedures, making referrals, and prescribing drugs to reduce perceived legal risks, rather than to advance patient care. Second, suboptimal communication and decision-making processes undermine a patient's right to make informed health care choices. This article critically analyses these problems and proposes solutions. An extensive body of medico-legal literature is synthesised to highlight the gaps between legal requirements and what happens in practice. Negligence case law is discussed to clarify legal principles and shows that courts discourage defensive practice. Finally, the article presents practical strategies to enhance communication and shared decisionmaking in the clinical encounter. PMID- 29978634 TI - Legal and Medical Aspects of Diverse Gender Identity in Childhood. AB - Diagnosis of gender identity dysphoria among children and young people appears to be increasing around the developed world. For a small proportion of children, the mismatch between their natal physical characteristics and desired gender causes significant distress. Though there are now accepted medical interventions that can assist in these cases, there is a lack of congruence between clinical practice and legal regimes governing the treatment of children and young people in this area. This article seeks to demonstrate the difficulties that may arise by providing a detailed explanation of medical interventions, juxtaposed with a discussion of the legalities of children's consent in some overseas common law jurisdictions. PMID- 29978635 TI - Obesity Prevention Laws and the Australian Constitution. AB - The idea of using law and regulation to prevent obesity in Australia is complicated by federalism. This article analyses in detail the powers of Commonwealth and State governments to determine which level(s) of government would be able to pass laws of the types recommended by the National Preventative Health Taskforce, namely marketing regulation, labelling regulation, content regulation, fiscal measures, built environment regulation and school regulation. The article considers the types of law that the Commonwealth could pass under the trade and commerce, taxation, communications and corporations powers, along with the power to make tied grants to the States. It then considers how the States could pass such laws but avoid levying any duty of excise, restricting freedom of interstate trade and passing any law that would be inconsistent with a Commonwealth law. PMID- 29978636 TI - Capacity and Vulnerability: How Lawyers Assess the Legal Capacity of Older Clients. AB - This article presents the findings of a research project that examined the Capacity Complaints investigated at the New South Wales Office of the Legal Services Commissioner between 2011 and 2013. The article outlines a tripartite theory of vulnerability to demonstrate the potential for lawyers' capacity assessments to increase the vulnerability of older clients with a cognitive impairment. The Capacity Complaints are then analysed, highlighting where reported practice falls short of the prescribed guidelines. The article concludes with recommendations for more consistent and rigorous guidelines and improved legal education to protect the human rights of older people. PMID- 29978637 TI - Vaccination Litigation: The Need for Rethinking Compensation for Victims of Vaccination Injury. AB - Opposition to vaccination has a lengthy history dating back to shortly after the discoveries by Jenner in relation to smallpox. In recent years though governments have sought to counter the concerns of anti-vaccinationists in a variety of ways, including legislatively in Australia, in an effort to protect against childhood diseases and to maintain herd immunity. However, cases continue to make their way through the courts where parents oppose the vaccination of their children, often inspired by the views of both registered and unregistered health practitioners, including homeopaths and chiropractors. This article catalogues recent decisions by the courts in Australia, New Zealand, the United Kingdom and Canada, most of which are in favour of vaccination and have dismissed the arguments of those opposed to vaccination as unscientific. It argues that Australia should give serious consideration to emulating the model existing in multiple countries, including the United States, and should create a no-fault vaccination injury compensation scheme. PMID- 29978638 TI - International Human Rights and Mental Health: Challenges For Law and Practice. AB - The World Health Organization and several United Nations bodies and personnel have called for a human rights perspective to be integrated into mental health and community services. While there are ongoing debates about what this means for law reform and practice, the World Health Organization QualityRights program provides a starting point for educational training in human rights that may be of benefit for mental health practitioners. This column explores some of the challenges for integrating a human rights perspective into mental health treatment and care and outlines the QualityRights program. PMID- 29978639 TI - Policy Development and Regulation of Aged Care. AB - Data from both medical and legal investigation can provide significant opportunities for legal and regulatory policy development that in some sectors are often ignored or missed. The provision of safe and high-quality care for the vulnerable, frail older people who live in residential aged care services (often termed nursing homes) in Australia continues to come under enormous scrutiny. The year 2017 saw a plethora of inquiries, some concluded and others ongoing, investigating the safety and care provided to residents. These inquiries have ramifications for the collection and use of data in the development of policy and regulation aimed at improving care within the aged care sector. PMID- 29978640 TI - Senate inquiry into price regulation on the prostheses list. AB - A recent Senate Inquiry investigated the Prostheses List (PL) which has been an integral part of the private health care system since its introduction in 1985. The PL sets the price of various prostheses products available for private health insurance patients. In recent years however, the PL has come under scrutiny due to the inflated prices of prostheses, lack of transparency from the list's creators and regulators, and increased premiums. This column critically analyses the recent Senate report, particularly as to whether it appropriately addressed the various concerns and issues raised in submissions and terms of reference of the inquiry and what ongoing role the PL should have in the Australian Healthcare System. PMID- 29978641 TI - Hartnett, Epstein, Van der Hope: Regulating Unconventional Doctors. AB - Doctors Francis Timothy Hartnett, Zygmunt Epstein and Izso Hartmayer Van der Hope were the first medical practitioners to appeal against decisions of the Medical Board of Victoria (Board) to cancel doctors' registration to practise medicine after finding that they had engaged in infamous conduct in a professional respect. This article analyses the Board's decisions in the 1940s regarding these three doctors and their appeals. The article argues that the doctors were unconventional and the Board's members, whose own career successes were built on their adherence to custom, allowed their aversion to the doctors' nonconformity to compromise their impartial assessment of their behaviour. The Board had only the finding of infamous conduct and the sanction of deregistration with which to respond to doctors; conduct that fell below professional standards, but in these three cases, cancellation of the doctors' registration to practise medicine was unduly severe and disproportionate to the gravity of their behaviour. This investigation illustrates the importance of the passage of legislation - after these cases were heard - empowering the Board to impose more lenient sanctions than deregistration for doctors' unprofessional conduct. It also highlights that regulators of the medical profession must still ensure that any antipathy they may feel towards doctors for their unconventionality does not influence their assessment of a fitting response to their conduct. PMID- 29978642 TI - Survey of Quasi-Judicial Decision-Makers in NSW and The National Registration Scheme for Health Practitioners. AB - This study is part of a larger, Australian Research Council-funded project studying comparative analyses of complaints and notification handling between the NSW system and National Registration and Accreditation Scheme (2010). This article explores the assessments and decisions made by Tribunal and other quasi judicial decision-makers involved in the two schemes, including the key decision management stages during a disciplinary process. Respondents recruited from both systems completed an online questionnaire comprising a series of closed and open ended questions to case vignettes. While we found no significant difference between jurisdictions in relation to their decision-making processes in this case, the article provides insights into the rationales for their decisions and the outcomes or sanctions selected by decision-makers as being appropriate to the circumstances presented. PMID- 29978643 TI - The Use of Students as Surrogates: The Ethical, Legal and Professional Issues of Student-Student Practical Learning in Dental Education. AB - For generations, dental students have been introduced to, and practised, clinical skills through the use of their fellow classmates as surrogate patients. These skills include verbal and communication skills such as the taking of medical and social histories, and practical skills such as the administration of local anaesthetic by injection. Largely such practices within dental education have been accepted through convention. This article aims to consider the use of students in dental education as surrogate patients and questions whether such practices may create issues relating to consent, coercion and confidentiality. Also examined within this article is whether practical surrogacy may lead to the introduction and development of unprofessional behaviours. PMID- 29978644 TI - The Agony and the Ecstasy: Sacrifice and Pain for Financial Gain: Have Indian Surrogate Mothers Been Exploited by Their Intended Parents in Commercial Surrogacy Arrangements? AB - This article investigates whether a sample of Indian women involved in commercial surrogacy arrangements were exploited by their intended parents. This issue is topical as the Indian parliament is currently considering a ban on commercial surrogacy. This is due to a range of concerns, including that such arrangements are unethical and exploitative of illiterate women from low socio-economic backgrounds. We define the term exploitation and identify from the literature the three key elements that we argue provide a conceptual framework through which to analyse whether exploitation has occurred. We conclude that there are indications that many of the women were exploited. However, we contend that the practice should not be banned as this would mean that the commercial surrogacy industry in India would no longer be regulated and women who become surrogate mothers may be exposed to greater risk. PMID- 29978645 TI - The Patient's Voice: Australian Health Care Quality and Safety Regulation from the Perspective of the Public. AB - The quality and safety of health care is a topic of permanent debate in the field of health services policy and regulation. Often absent from this debate, however, are the views and values of the public. These are excluded by a dominant narrative of health care regulation which understands the regulation of quality and safety in health care as principally a technical and instrumental undertaking. This approach constrains the application of law and legal regulation, devaluing their normative and expressive function in this field. In part as a form of corrective, we offer an analysis based on recent survey data, of the attitudes and perceptions held by the Australian public towards stakeholder responsibility for, and the regulation of, health care quality and safety. PMID- 29978646 TI - Never Mind the Science, Here's the Convention on Biological Diversity: Viral Sovereignty in the Smallpox Destruction Debate. AB - Since the eradication of smallpox was declared in 1980, debate has ensued over what to do with the remaining stocks of the causative agent, variola virus. For more than three decades the World Health Organization has resolved to destroy the virus isolates, now maintained in high-security laboratories in the Russian Federation and the United States, and each time the deadline has been deferred. The legal facets of this debate have been largely overlooked. As genetic resources, all viruses fall within the scope of the United Nations' Convention on Biological Diversity (CBD) that provides for the fair and equitable sharing of the benefits arising out of the utilisation of genetic resources. This article examines the possible ownership scenarios for variola viruses and concludes that the conservation principles of the CBD and the ambiguous sovereign status of individual isolates may preclude the destruction of the world's remaining variola stocks. PMID- 29978647 TI - Women's Rights in the Health Care System: Caesarean Delivery on Maternal Request. AB - This article explores a systems-theoretical question on the resonance capacity of medicine and law that has enabled a recent obstetric change. Insights from autopoietic theory guide my analysis of these subsystems' preconditions or self referencing processes supporting obstetrics to take up pregnant women's requests for caesarean sections for social reasons. Previously, obstetricians performed caesarean sections on medical grounds only. That change became possible: it resonated with obstetrics, despite limitations imposed on obstetrics and law by these subsystems' unique codes and programs, and in light of law's self determining individual. This article argues that although the change represents a victory for women's human rights in challenging paternalistic medical decision making, paradoxically it extended medical control over childbirth by further displacing midwifery. However, obstetricians, midwives and pregnant women have been less empowered by the change. The article interprets how structural limitations or preconditions affect the capacity of communications to resonate and contribute to society's evolution. PMID- 29978648 TI - Sharing the Air: The Need for Strata Law Reform to Reduce Second-hand Smoke Exposure in Multiunit Housing in Australia. AB - There is an immediate need to reform Australian State and Territory strata laws to minimise exposure to second-hand smoke (SHS) in multiunit housing (MUH), particularly in light of the trend towards higher density living. SHS is a cause of lung cancer and other health problems in nonsmokers and no safe level of exposure has been established. Despite being a common cause of dispute in MUH, currently no strata regime in any State or Territory includes a model by-law that specifically addresses smoking, as is the case with other contentious issues like pets. Smoking disputes can currently be dealt with under general strata provisions on nuisances or hazards, but the case law in this area demonstrates that these provisions can be ineffective in dealing with the serious health issue posed by SHS. With enough votes, owners' corporations can introduce a smoking by law. However, without legal advice it may be difficult for owners' corporations to develop a by-law they can be confident falls within their by-law making powers. With several jurisdictions currently reviewing their strata laws, there is a valuable opportunity to sensibly reform the law in the interests of public health. In this article, we survey the legal landscape and consider options for a model by-law on smoking. PMID- 29978649 TI - Eroding Public Health through Liquor Licensing Decisions. AB - This article uses the public record to demonstrate the inadequacy of the current liquor licensing decision-making system in New South Wales (NSW) with regard to reducing alcohol-related harm. It describes and compares planning and liquor licensing decision-making systems and examines all decisions regarding applications for new liquor licences published by the NSW Independent Liquor and Gaming Authority in 2016. These decisions are reviewed with regard to the Authority's duty to consider social impacts. The review identifies processes and patterns of decision-making that favour the applicant, demonstrate inconsistencies, fail to use health statistics, misinterpret other statistics, make inconsistent use of reputable health research findings and treat legal obligations as mitigations. The cumulative effect is a low refusal rate. Of 168 applications, 15 were refused. Review and appeal for objectors have been severely restricted in NSW. PMID- 29978650 TI - The Implementation of Coronial Recommendations in Tasmania: Two Case Studies on Child Deaths. AB - Recommendations are an increasingly important aspect of the coronial jurisdiction. This article offers one of the first critical analyses of the impact of coronial recommendations in Tasmania. In doing so, it provides a fresh perspective on coronial law from a jurisdiction that is sometimes overlooked. The article presents research (based on documentary evidence and interviews with key stakeholders) on the implementation of recommendations made by Tasmanian Chief Coroner McTaggart. The recommendations concerned unexpected infant death and youth suicide. They prompted significant reform in both areas. In view of this evidence of the power of coronial recommendations, the article argues that Tasmania should consider adopting a mandatory response framework. PMID- 29978651 TI - Birth: Why Do Not We Just Tell the Truth? AB - Information regarding childbirth is currently inadequate to allow truly informed decisions regarding mode of delivery. The concept of patient autonomy is complex. How doctors transmit information to allow for patient self-determination should be seen within the different models of patient-doctor relationship. There are a number of specific dilemmas for obstetricians in providing balanced information to women. The profession needs to establish some specific standards of information for women preparing for childbirth. Legal decisions in childbirth related medical litigation have focused on the concept of self-determination but are doctors enabling true informed consent when only information regarding the medical interventions is given and not information regarding the entire process of childbirth? PMID- 29978652 TI - Breaking Bad News about Cancer to Adolescents and Young Adults: The French Experience. AB - The announcement of a serious illness, like cancer, can be very stressful for adolescents and young adults, as well as for their parents. In view of this difficulty, the protection of patients' dignity and autonomy is a central concern of medical ethics. It was with this goal in mind that a French Announcement protocol was developed following the First French Convention for Cancer Patients (1998) and reaffirmed, in 2010, by the First French Convention for Child Cancer Patients and Their Families. Because the ethics literature on this subject is underdeveloped, an empirical study was conducted from 2012 to 2016 to explore patients' and parents' experience. This study concerns adolescents, young adults, their parents and their health care professionals. The objective of this article is to present the outcomes of the study, summarising the experience of patients, parents and professionals and outlining current practices in France. PMID- 29978653 TI - The South Australian Advance Care Directives Act 2013: How Has the Decision Making Paradigm Changed? AB - This article analyses how the Advance Care Directives Act 2013 SA is changing the decision-making paradigm in health care and guardianship in South Australia. It examines the background to the legislation, the main areas that have been transformed by the Act and the amendments to associated legislation. The significant changes include an increased respect for autonomy and a presumption of decision-making capacity, a new paradigm of substitute decision-making, clarification of the decision-making hierarchy, and protections for medical practitioners who decline to give treatment that would have no benefit to a dying patient. Despite some difficulties implementing the new scheme, this article argues that the Act has introduced important changes and clarifications in the law that other States would do well to follow. When it is fully implemented, the Act will ensure that the wishes of patients are respected and that doctors can follow these wishes without fear of prosecution. PMID- 29978654 TI - Mind the Information Gap: Quantifying the Courts' Role in Responding to Patient Harm, 1989 to 2013. AB - An empirical critique of Australia's medical indemnity crisis challenges assumptions about the role of the courts through determination of civil liability for medical negligence, occupational discipline and criminal liability. Courts were identified as a cause of a crisis in the 2000s that triggered extensive legislative reform of medical negligence law, absent adequate empirical data substantiating either criticisms of the courts or supporting the reforms. Changes to the occupational discipline framework for health practitioners were less controversial but have resulted in increasingly legalistic responses. Using a detailed longitudinal analysis across all jurisdictions this article examines the role of the courts in responding to patient harm across the relevant 25-year period encompassing these reforms, to determine whether the courts did cause the medical indemnity crisis, what effect the reforms had and what other roles the courts play in responding to patient harm. PMID- 29978655 TI - Medical Evidence of Capacity in a Legal Setting: To What Extent Do Courts and Tribunals Make Their Own Decisions? AB - The extent to which legal determinations of capacity are genuinely separate from medical opinion on capacity presented to the court as evidence, is an open and important question. In order to explore this question, an empirical study was done on the use of medical and non-medical evidence to establish capacity in three different capacity contexts: personal/financial capacity, testamentary capacity and legal matters capacity. The study showed that the use of medical evidence to establish capacity was by far the heaviest in personal/financial capacity matters, often to the point of effective exclusion of other forms of evidence. Concerns with the weight given to medical evidence in personal/financial capacity matters were identified. The concerns have implications for the specific jurisdiction considered, and for the wider question of how capacity is and should be determined in a legal setting. PMID- 29978656 TI - Regulation of Substandard Medical Practice: Lessons from the Bawa-Garba Case. AB - The regulation of substandard or dangerous clinical work by medical practitioners is one of the most challenging areas of medical regulation. There is an important conceptual distinction between poor or suboptimal clinical conduct and the outcome of such conduct. It is also important that harsh sanctions are not imposed by reason of a tragic result for a patient or a perception that no other regulatory response will be acceptable to the community. The line needs to be straddled between maintaining public confidence with stern and robust action being taken to protect the public and maintain standards, on the one hand, and, on the other hand, informed and realistic evaluation of conduct, taking into account the pressures that exist in the real world of clinical practice and the reality that all practitioners are fallible. Debate has been reignited by the decision of the High Court in General Medical Council v Bawa-Garba [2018] WLR (D) 52; [2018] EWHC 76 (Admin) about whether and when gross negligence manslaughter charges constitute a constructive way of rendering doctors accountable and how draconian the regulatory sanctions should be that are imposed when clinical conduct has been found to be truly exceptionally bad. Such evaluations need to be conducted in humane recognition of systemic and colleagues' deficiencies but principally by reference to what needs to be done to ensure responsible, caring and competent medical practice. PMID- 29978657 TI - Q: Can a Court or Patient Demand Treatment? A: Yeah But No. AB - The principle from Re J [1993] 3 WLR 507 has stood since 1993: a mentally competent patient cannot demand a specific treatment, nor can a court make an order which would force a doctor to administer a treatment, which, in either case, the responsible doctor considers is contrary to his/her best interests. This column considers the extent to which this principle remains good law 25 years later, concluding that it retains most current relevance in respect of mentally competent patients. In respect of mentally incapacitated patients, however, once a court's jurisdiction has been invoked, the principle appears to be observed in form only, rather than in substance. We have moved a long way from doctors having the ultimate power and responsibility for making treatment decisions to courts becoming heavily involved in making them. PMID- 29978658 TI - Medicinal Cannabis in Pregnancy - Panacea or Noxious Weed? AB - The use of medicinal cannabis has been the subject of enabling legislation in Australia since 2016. At present the medical profession has not supported its use for anything but a few indications which include paediatric treatment-resistant epilepsy (especially Dravet's syndrome), pain syndromes associated with multiple sclerosis, Parkinson's disease and chemotherapy-induced nausea. However, in the United States where medicinal cannabis has been legalised in 29 States and Washington DC, nausea is an approved indication in many jurisdictions and this has been followed by widespread use for pregnancy-induced nausea and vomiting. This may prove to be ill advised as serious concerns have been expressed about its safety in pregnancy particularly its proven potential to restrict fetal and postnatal growth as well as to impair childhood cognitive functions such as memory, verbal skills and emotional development. These reported effects on neuropsychiatric behavioural and executive functions may influence future adult productivity and lifetime outcomes. Twenty-one States of the United States approve the use of legal cannabis for nausea and vomiting including its use in pregnancy. This is likely to encourage complacency regarding its fetal risks in pregnancy. In Australia the federal and State legislation restricts use of legal cannabis by placing the pharmaceutical under Sch 8 of the Poisons Act 1971 Tas which requires specific application for each individual patient use. It is to be hoped that this will prevent the excesses of use in pregnancy witnessed in the United States. PMID- 29978659 TI - Analysis of Australia's New Biosecurity Legislation. AB - On 16 June 2016 the Biosecurity Act 2015 Cth came into force. This legislation replaced the Quarantine Act 1908 Cth which had regulated biosecurity in Australia for over a century. Impetus for the change arose from a number of reviews (the Nairn Report and later Beale Review) into Australia's biosecurity system. These identified systemic flaws that were causing the country to be vulnerable to incursions of foreign pests and diseases through the administration of an archaic regulatory regime. The Biosecurity Act 2015 Cth includes new terminology, increased powers for the regulator and additional requirements for industry. The responsible agency, the Department of Agriculture and Water Resources, has stated that the new biosecurity laws are designed to be user-friendly, to be flexible and responsive to changes in technology and future challenges, to remove cluttered and confusing sections of the Quarantine Act 1908 Cth and to achieve the difficult balance of making biosecurity regulation risk-based and equipping the regulator with strong enforcement powers while also being economically prudent and supportive of increasing Australian trade and market access. This column analyses such claims, including the short, and long-term implications of providing biosecurity officers with two sets of authorising legislative powers and sharing the responsibility of biosecurity emergencies with the Department of Health. PMID- 29978660 TI - Beakers and Borders: Export Controls and the Life-sciences under the Defence Trade Controls Act 2012. AB - Aware of the risk to human development from public health emergencies, governments and international organisations have adopted regulatory measures designed to prepare for and mitigate the risk of global pandemics. However, as the development of the Australian Defence Trade Controls Act 2012 Cth reveals, choices in regulatory measures can have profound effects on the delivery of public health and the practice of medical research. Introducing a new regulatory regime for researchers engaged in dual-use research, the Defence Trade Controls Act 2012 Cth (DTCA) seeks to control a variety of research and teaching activities. This article uses the DTCA as a case study of the securitization of infectious diseases, the mechanisms by which biosecurity rules are becoming globalised and the clash of principles that can arise for public health researchers. With the DTCA scheduled for a legislated review in 2018, an awareness of the wider constellation of international and domestic rules restricting dissemination of research findings with national security implications is imperative for public health researchers. PMID- 29978661 TI - Less Is More: Regulating the Weaponisation of Disease under the National Health Security Act 2007 (Cth). AB - This article evaluates whether the National Health Security Act 2007 Cth can effectively accommodate public health and national security policy objectives under one Act to meet the biosecurity challenges of the 21st century. The formation of the Act, its substantive parts, and its subsequent amendments are described before the Act is assessed under the Rule of Law analysis proposed by Professor David Fidler and Professor Lawrence Gostin. This article finds that whereas the public health objective of the Act was to simplify the reporting process surrounding public health incidents under the International Health Regulations, the amendments made to the Act in response to national security needs have had the contrary effect of complicating public health reporting with marginal gains for national security. This article concludes that the concurrent pursuit of national security policy and public health policy is fraught with difficulty and suggests that the Act should be reviewed. PMID- 29978662 TI - Revisiting Breen v Williams: Breathing Life into a Doctor-Patient Fiduciary Relationship. AB - This article considers whether the doctor-patient relationship should be classed as a fiduciary relationship. It considers the general principles surrounding fiduciary obligations, and establishes criteria around which the question of a doctor-patient fiduciary relationship is discussed, namely workability and necessity. In particular, this article discusses the types of conflicts of interest that arise in medical practice as well as the Australian regulatory framework in respect of the medical profession. PMID- 29978663 TI - Who Are Indigenous and Local Communities and What Is Traditional Knowledge for Virus Access and Benefit-sharing? A Textual Analysis of the Convention on Biological Diversity and Its Nagoya Protocol. AB - The United Nations' Convention on Biological Diversity (1992) (CBD) has become the focal point for the regulation of traditional knowledge (TK) held by indigenous and local communities (ILCs). The legally binding CBD is bolstered by a supplementary, non-binding agreement, The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization (2010) (Nagoya Protocol). Both instruments create the conditions for the access and benefit-sharing (ABS) of genetic resources, and for TK associated with those resources. There has been no consideration as to how TK might factor into virus ABS arrangements. Most of the literature on these issues relates to how the TK provisions of the CBD and Nagoya Protocol should be implemented; there is little guidance as to how to interpret the text itself. This article provides a textual analysis of all provisions of the CBD and Nagoya Protocol that relate to TK and the interests of ILCs. The analysis clarifies the differences in scope between the two instruments and will provide some insights as to how to interpret key terms, particularly indigenous and local communities, traditional knowledge and traditional knowledge associated with genetic resources. This is critical to understanding the obligations that apply to accessing virus samples that are regulated as genetic resources under the CBD. PMID- 29978664 TI - Nga Whenu Raranga/Weaving Strands in the Alcohol and Other Drug Treatment Court of Aotearoa/New Zealand. AB - This article reports findings from an ethnographic study that explored the meaning of therapeutic in the Alcohol and Other Drug Treatment (AODT) Court in New Zealand. Descriptions are provided of the therapeutic framework called nga whenu raranga/weaving strands that resulted from interviews with court team members (n = 25), courtroom observations (200 hours), and document analysis. This includes the details of four strands; Law, United States Best Practice, Recovery and Lore that compose the framework. We argue that the therapeutic framework is simultaneously a philosophical and practical accomplishment and we provide brief examples of how the four strands are woven together, with each strand shaping the other, as the court team, participants and wider community interact together. The article concludes by considering the implications of the study's findings, focusing on challenges that come with the widening of therapeutic discourse in the AODT Court. PMID- 29978665 TI - Patenting Nucleic Acid Sequences: More Ambiguity from the High Court? AB - The High Court in D'Arcy v Myriad Genetics Inc (2015) 258 CLR 334; [2015] HCA 35 addressed patent claims under the Patents Act 1990 Cth to deoxyribonucleic acid (DNA) sequences set out in tables listing nucleotides as As, Ts, Gs and Cs finding they are unpatentable. This was a significant development given DNA sequences have been patentable for decades. This article reviews the High Court's judgments in D'Arcy v Myriad Genetics Inc highlighting the introduction of ambiguities to the current subject matter standards and providing a critique of the High Court majority's assessment of DNA sequence as information. The article concludes that the High Court majority has introduced an unhelpful conception of information as a standard for patentability. While this will limit claims to DNA and other nucleic acid sequences, the broader effect of the decision is uncertain because the High Court majority's conception of information could be applied to any matter (including all molecules) and eviscerate the patent system. PMID- 29978666 TI - The Regulatory Evolution of Paramedic Practice in Australia. AB - Australian paramedics have always been regulated as an occupation despite a significant regulatory evolution occurring in their discipline. Paramedics have progressed from stretcher-bearers, ambulance drivers, ambulance officers and finally to paramedics. However, as the paramedic discipline evolved, paramedicine's regulatory framework remained self-regulatory through employer governance which does not reflect the professionalised role of paramedics in society. The final step in securing professional regulation for paramedics is co regulation under the Health Practitioner Regulation National Law Act 2009. Due to recent legislative amendments, paramedics will become a registered health profession in 2018. This article details the regulatory evolution of paramedic practice in Australia and how paramedicine has evolved beyond the current employer-based regulation to professional health practitioner regulation warranting a statutory framework of governance. PMID- 29978667 TI - The Ethical, Legal and Regulatory Issues Associated with Pharmacogenomics: Systematically Quantifying the Literature. AB - Since the human genome was successfully mapped much academic attention has been given to ethical, legal and regulatory issues associated with the integration and application of genomics in health care. In line with the recent political commitment to promoting precision medicine that relies heavily on omic knowledge, it is timely to review the issues that this body of literature has addressed. Focusing on pharmacogenomics, this review quantifies the issues identified in this body of academic work. It reveals that, after nearly two decades, interest in the regulatory and legal issues associated with pharmacogenomics continues to generate significant attention. The ethical issues, while not as predominant, also persist. The analyses highlights that there is a dearth of empirical research exploring the impact that these issues have had. PMID- 29978668 TI - Looking Gift-horses in the Mouth: Gift-giving, Incentives and Conflict of Interest in the Dental Profession. AB - Within medicine, there has been a protracted conversation relating to the appropriateness of accepting gifts and incentives from industry, professional colleagues and from patients. The general principle and anxiety in this debate relates to answering the question of whether accepting gifts or incentives compromises a health professional's duty to provide quality care. Within the dental profession, there is noticeably less discussion as to the effects of gifts and incentives upon the practice of dentistry. Given that dentistry is, like medicine, part of health care this status quo is not one that should persist. The authors hope that this article will stimulate discussion around dentistry's relationship with those who might seek to make commercial benefit out of our practice and how dental professionals should respond to patients bearing gifts - letters to the editor are explicitly invited; personal communication to the authors to compile a follow-up publication is welcome. PMID- 29978669 TI - Outcomes of Notifications against Psychologists in the New Zealand Health Regulation Context 2004-2015. AB - Research focusing on disciplined health practitioners is growing though exploring lower level decisions is also important. This study examines the outcomes and characteristics of psychologists subject to formal notifications between 2004 and 2015. Data were extracted from archived notification files (N = 396) held by the New Zealand Psychologists Board alongside publically available decisions of the Health Practitioners Disciplinary Tribunal (N = 13). Annually, <2% of practising psychologists were subject of a notification. Outcomes varied by type of notification but the vast majority resulted in no further action either at initial triage or after further investigation. Notifications involving psychologist scope practitioners and those with overseas qualifications prior to New Zealand registration were significantly more likely to result in further investigation. All 13 prosecutions resulted in a finding of guilt. Further research is needed to explore risk factors and why female practitioners may be over-represented in cases of sexual boundary transgressions. PMID- 29978670 TI - Pure Psychiatric Injury Pursuant to the Civil Liability Legislation: An(other) Economic Perspective. AB - Despite the enactment of civil liability legislation affecting claims for pure mental harm in many jurisdictions in Australia, the High Court decision in Wicks v State Rail Authority (NSW) (2010) 241 CLR 60; [2010] HCA 22 has caused some concern that the economic goals underpinning the civil liability legislation will be threatened. In this article, the economic sustainability of the law of negligence with respect to pure mental harm is considered in light of three particular issues. The first is the High Court's 2015 decision in King v Philcox (2015) 255 CLR 304; [2015] HCA 19 in which the South Australian civil liability legislation was considered. The second is the threat to healthy insurance markets posed by the civil liability legislation itself as a result of inconsistencies between jurisdictions. The third relates to the threat posed by the civil liability legislation to the ability of the law of negligence to achieve economically efficient levels of accident and accident-prevention costs. It is argued that the civil liability legislation is not only not well-suited to achieve its primary goal of reducing the social costs of accidents, but may well be a greater threat to that goal than the common law. PMID- 29978671 TI - A Phronetic Inquiry into the Australian Euthanasia Experience: Challenging Paternalistic Medical Culture and Unrepresentative Health Policy. AB - Australia's intermittent attempts to legalise euthanasia are typically fraught with brief, polarised, and often sensationalised, public debate. Yet beyond the sensitive arguments in favour and in opposition of reform, the practical antecedents of change that may determine Australia's genuine aptitude to enact reforms have been largely neglected. Phronetic legal inquiry thus offers insights into the euthanasia law reform experience, using Australian and international case comparisons to examine covert power dynamics, cultural discourses, and social and institutional structures that affect the practices of the legislature. On this basis, it is argued that Australia's medical profession, and particularly its dominant providers of palliative care, are hampered by an entrenched culture of medicalisation and paternalism, within which patient autonomy provides only a veneer of self-determination. This can be strikingly contrasted with the Dutch approach of patient-centred care, which seeks to produce collaborative, respectful dialogue between physician and patient and to integrate the principles of autonomy and beneficence. Furthermore, these contrasting medical cultures represent issues in the broader policymaking context, as Australia's health policy remains unduly subject to the pressure of unrepresentative yet influential conservative interest groups, most prominently including the Australian Medical Association. This pressure serves to suppress public opinion on the issue of euthanasia in a parliamentary climate that remains stifled by bipartisan alliances and political inertia. It is therefore argued that Australia's prospects for successful voluntary euthanasia law reform rest on the dual pillars of developing a more patient-centred medical culture and challenging the prevailing paternalistic approach to health policymaking in Australia's currently unrepresentative political landscape. PMID- 29978672 TI - Health Law: The Past and the Future. AB - In the first 25 years of the Journal of Law and Medicine issues relating to abortion, euthanasia, turning off of life support, pandemics, cloning, surrogacy, technological change, patenting of DNA, regulation of health practitioners, health services in the Information and Genomic eras, mental health law, elder law, and medical negligence have figured prominently in the published scholarly contributions. This editorial reflects on the evolution of health law in its many aspects, contrasting issues that were contentious in 1993 with those that are in 2018 and reflecting on what is likely to continue to attract interdisciplinary analysis and the need for critical evaluation in the decades ahead. PMID- 29978673 TI - Computational Modelling, Social Media and Health-Related Datasets: Consent and Privacy Issues. AB - Computational modelling is now being used to analyse posts on social media to predict the emergence of mental health conditions. While the aim is to develop tools for early detection and treatment of such conditions, computational modelling raises issues of user consent and privacy. The European Union has moved to regulate automated profiling of large databases and Australia has introduced a data breach notification scheme for cases where personal information held by an organisation is lost or subjected to unauthorised access or disclosure. There remains the question, however, of whether such regulation will be enough to prevent third-party access to social media and health-related datasets by those with less than benign motives. Opting out of using social media and schemes such as My Health Records may be one option to preserve privacy and avoid the use of personal data being used without consent, but that may be unattainable in a digital age. PMID- 29978674 TI - Responding Better to Desperate Parents: Warnings from the Alfie Evans Saga. AB - The end-of-life litigation involving Alfie Evans (9 May 2016 - 28 April 2018) from Liverpool, England, who suffered from an incurable and degenerative neurological condition was extraordinary. It emerged in the shadow of comparable but not as extensive litigation enabled by crowdfunding in relation to Ashya King and Charlie Gard. Although Alfie's parents lost repeatedly in the High Court, the Court of Appeal and the Supreme Court of England, as well as before the European Court of Human Rights, they persisted in bringing more legal challenges. The public relations campaign on their behalf at times was threatening and accusatory of the clinicians and of Alder Hey Hospital. Both persons employed at the Christian Legal Centre, which represented the parents at times, and medical practitioners from Europe who participated in forensic assessments behaved unethically. There are many lessons to be learned from the Alfie Evans saga. If we are to maintain morale and commitment among those who provide paediatric clinical services to the very ill and the dying, they must be protected from the public relations and litigation campaigns deployed by those purporting to represent the Alfie Evans family, and better non-adversarial methods need to be constructed as a matter of urgency to resolve matters involving disagreements about the treatment of terminally ill children. PMID- 29978675 TI - A New Ethical Model of Commercial Surrogacy Arrangements for Australia. AB - The current regulation of altruistic surrogacy arrangements in Australia has resulted in a dearth of willing participants and is driving intending parents overseas to unregulated countries. This section contends that the current altruistic surrogacy arrangements in Australia violate a number of ethical principles and fail to protect the interests of all parties. This section then proposes a new ethical model for commercial surrogacy arrangements that includes: fair and just compensation; enforceability of surrogacy agreements; amended parentage presumptions and the ability to obtain pre-birth parenting orders; regulation of surrogacy agencies and brokers; recognition of approved international surrogacy arrangements; and review by a Patient Review Panel with legislative safeguards. Altruistic surrogacy arrangements would remain available to those parties who object to commercial surrogacy. This new ethical model better satisfies the four principles of respect for autonomy, beneficence, non maleficence and justice than the current altruistic surrogacy model. PMID- 29978676 TI - Codes of Conduct - A New Era for Nursing and Midwifery in Australia. AB - The Nursing and Midwifery Board of Australia has developed and approved the new Code of Conduct for Nurses and Code of Conduct for Midwives which applies from 1 March 2018. The primary role of the Nursing and Midwifery Board of Australia (NMBA), is to protect the public by ensuring only those who are suitably qualified and trained to practise in a competent and ethical manner are registered. One mechanism by which this objective is achieved is the registration of practitioners who are required not only to meet the mandatory registration standards but also conduct their practice in accordance with the NMBA's standards, codes and guidelines. The language of these new codes clearly articulates the mandatory obligations imposed on nurses and midwives to establish and maintain specified standards of conduct that ensure safe practice. It is therefore important for nurses and midwives not only to read the codes, but incorporate the terms contained therein meaningfully into their practice. PMID- 29978677 TI - Australian Senate Committee Report on Transvaginal Mesh Devices. AB - On 28 March 2018 the Australian Senate Community Affairs References Committee issued its final report on transvaginal mesh devices. It found these devices have caused unnecessary physical and emotional pain and suffering to thousands of women who were not told by their doctors of the objective material risks associated with their use. The Senate Committee concurred with the description by the Public Health Association of Australia of the complications resulting from transvaginal mesh implants as constituting a serious public health issue requiring a response at both an individual and at a population level, including counselling, public education, clinical interventions and long-lasting protective mechanisms. The committee's inquiry highlighted significant shortcomings in Australia's reporting systems for medical devices, with flow-on consequences for the health system's ability to respond in a timely and effective way. Among other recommendations, the Senate Committee backed the establishment on a cost recovery basis of a national registry of high-risk implantable devices linked to a system of mandatory reporting of adverse events. PMID- 29978678 TI - When Is It in a Child's Best Interests to Withhold or Withdraw Life-sustaining Treatment? An Evolving Australian Jurisprudence. AB - Decisions about whether to withdraw or withhold life-sustaining medical treatment from children give rise to complex and value-laden judgments. While recourse to the courts is uncommon, judicial decisions provide an important source of guidance for the children (where they can participate), families and health and medical professionals involved in these decisions. Yet, there has been remarkably little consideration of the Australian jurisprudence on this issue. This article addresses that gap by undertaking the first comprehensive analysis of all publicly available Australian cases that consider whether or not it is in a child's best interests to receive life-sustaining treatment. A total of 25 cases were located and the judicial consideration of best interests was thematically analysed. Key considerations (to varying degrees) when assessing best interests included the likelihood of treatment curing or improving the child's health, medical views about diagnosis, prognosis and treatment and the child's and parents' views and wishes. The article concludes that the law requires greater certainty and transparency in decision-making. Given the significance of these cases, judgments should describe the factors that the court considers relevant and important, and those that are less influential, as well as the weight ascribed to those various factors and the reasoning that underpins an assessment that treatment is or is not in a child's best interests. PMID- 29978679 TI - Biosimilars: The Challenges of Novelty, Inventive Step and Sufficiency. AB - In order to understand the relationship between patents and biosimilars in Australia better, this article examines whether, and in what circumstances, biosimilars can be patented under the Patents Act 1990 (Cth). Part II provides the necessary background in discussing the structure and function of biosimilars as well as the regulation of, and key arguments for, biosimilars in Australia. Part III explores the key challenges faced in patenting biosimilars in Australia, particularly the requirements of novelty, inventive step and sufficiency of description. In so doing, the recent case of Pfizer Ireland Pharmaceuticals v Samsung Bioepis AU Pty Ltd [2017] FCA 285 provides some guidance and is discussed. The article concludes in Part IV with consideration of the implications of biosimilar patents for manufacturers, as well as access and affordability of treatment to the community and the interaction between government subsidy through the Pharmaceutical Benefits Scheme, and biosimilars. PMID- 29978680 TI - The Legal Doctrine of Informed Consent and Renal Dialysis - Do Patients Really Consent? AB - A doctor has a legal duty to secure the informed consent of a patient prior to performing a medical or surgical procedure. The elements of the legal doctrine of informed consent include capacity, voluntariness and the provision and understanding of relevant information. This article examines the doctrine in the context of renal dialysis. Dialysis is a complex therapy that impacts upon quality of life and has limited survival advantage in some patients. It is likely that informed consent is often not fully integrated into the care of patients commencing dialysis. The article analyses the common law doctrine of informed consent as it relates to dialysis and presents the findings of a retrospective study of the adequacy of the consent process based on interviews with dialysis patients who commenced dialysis in the previous 12 months. It concludes with recommendations for improvement in practice. PMID- 29978681 TI - Building Public Confidence in Medical Registration Revalidation: Reform of Medical Registration Law in Australia, a New Risk-based Approach. AB - This article examines the reform of the Health Practitioner National Law to introduce a form of medical registration revalidation. Revalidation is a regulatory performance management practice designed to confirm the competence of medical practitioners regularly and proactively. Its implementation will shift the law's current contribution to constraining dangerous practice from a largely reactive stance onto a more proactive footing. In aid of advancing the case for registration revalidation, we describe the recent history of the National Law, provide analysis of the proposed revalidation reforms and then apply a novel empirical method of a discrete choice experiment to determine the Australian general public's acceptance of and preferred approach to medical registration revalidation regulation. We argue that the reform represents a potentially effective and, importantly, acceptable reform to existing regulatory performance management and disciplinary systems. PMID- 29978682 TI - Holding Out and Protected Titles - Issues for Non-registrant Complementary and Alternative Health Practitioners. AB - The regulation of registered health practitioners in Australia focuses upon holding out provisions rather than statutory scope of practice provisions. One concern for non-registrant complementary and alternative medicine practitioners and other non-registrants is whether these holding out provisions are breached by simply providing a modality which may also be applied by a registered health practitioner (such as the use of Chinese Massage) and when does a breach of the holding out occur when they use particular words that might in the context of when they are used may be deemed to constitute a holding out. This article will analyse the relevant provisions of the National Law and case law to determine some guidelines for practitioners to avoid liability. PMID- 29978683 TI - Legal and Ethical Issues Surrounding the Use of Older Children's Electronic Personal Health Records. AB - This article explores the legal and ethical issues surrounding the production, storage, retrieval and use of electronic personal health records of children aged 14 years and over. Specifically, we explore: (1) the capacity, consent and competence issues; (2) privacy and confidentiality concerns; (3) the tension between a child's right to autonomy and his or her parent's or guardian's rights and responsibilities; and (4) outline implications of this for the implementation of Australia's My Health Record system, particularly for children with communication disability who are high users of health systems and have high health information exchange needs. PMID- 29978684 TI - Changing Law Students' Ideas about Dis/ability: Can We? Should We? How Would We? AB - Access to the law, and effective justice for people with disability is a growing area of concern for lawyers and law teachers. In clinical legal education, where students work with real clients, working effectively and sensitively with people with disability is crucial. The founding principle in any design process of clinical legal education programs with people with disability is nothing about us without us. Students must also be taught specific skills when working with clients with disability, including the appropriate language to use, communication skills, and the connections between sexism, racism and stigma attached to people with disability. Reflection skills and the ability to analyse and critique the law are all essential elements of a program working with people with disability. This article explores key elements drawing on the experience of clinics in Mexico and Australia to recommend the essential elements of a clinic which works with clients with disability. PMID- 29978685 TI - Best Interests and Non-consensual Research. AB - The issue of clinical research on adults who are unable to provide consent (non consensual research - NCR) is a challenging area of law, which has gained prominence in New Zealand and elsewhere. In New Zealand, the legality of such research depends on a best interests test. It has been claimed, however, that a best interests test cannot be satisfied in NCR, and that a new legal standard is required to allow valuable research to appropriately proceed. This article argues that a best interests test can be satisfied in NCR and should be reconsidered as a suitable benefit-harm standard. Furthermore, there is a possibility of maintaining a best interests test as well as adopting a new, more specific standard and other recommendations for reform. These two components could be seen as consistent, or even synergistic, and this dual approach should be considered in current discussion. PMID- 29978686 TI - How Do Coroners' Findings in Australian Jurisdictions Apply to Health Care Practitioners within Safety-I and Safety-II Paradigms? AB - The modern-day coroner sits uniquely at the interface between health care provision, patient safety and the law, playing an important role in informing health care practices to improve patient safety. In the 21st century, the health care system has rapidly developed in the field of patient safety. First came the Safety-I approach of looking at what went wrong, then the Safety-II approach of understanding why things go right. The advent of Safety-II has flipped the way some health care organisations view their systems and it is now time for the coronial jurisdiction to do the same. By applying the Safety-I/Safety-II Model for coronial investigations into health care-related deaths, coroners can address both the positive and negative factors in each case and refine the lessons in their findings. A Safety-II approach allows their role to evolve even further, firmly entrenching their preventive ethos as they become architects of resilience for the health care system. PMID- 29978687 TI - An Analysis of Medico-legal Claims against Dermatologists in Australia from a Single Medical Indemnity Insurer. AB - Risk mitigation practices are essential to protecting patients from harm and reducing medical practitioner exposure to unnecessary reputational damage and economic loss. Despite traditionally being perceived as a low-risk specialty, published data on medico-legal claims against dermatologists in Australia are currently lacking. This article reviews the sources of medico-legal claims against dermatologists in Australia from a single medical indemnity insurer over the most recent three years. The failure to meet patient expectations was the largest source of claims against dermatologists, followed by adverse outcomes. Improved communication from practitioner to patient remains the most effective step to preventing medico-legal claims. Medico-legal claims, when they occur, are more successfully defended when thorough documentation processes are in place. PMID- 29978688 TI - Reproductive Autonomy and Social Sex Selection: A Chance of a Choice? AB - Through preimplantation genetic diagnosis (PGD), individuals can now reliably choose the sex of their baby. However, PGD is largely prohibited for individuals seeking to sex select for non-medical reasons. This article argues that to protect reproductive autonomy, individuals should be allowed to make reproductive choices, regardless of their motivations, unless those choices would cause serious harms to others. It follows that social sex selection should not be prohibited on the basis of moral objections, only when it will cause serious harm. This article considers the opposing ethical framework of parental virtues. A reproductive autonomy framework is preferred, given the challenges of determining and applying parental virtues to social sex selection. This article examines three potential harms identified by opponents to sex selection, and argues that while these remain speculative they do not justify the curtailing of reproductive autonomy. PMID- 29978689 TI - Freedom of Expression, Belief and Assembly: The Banning of Protests Outside of Abortion Clinics in Australia. AB - This article considers the phenomenon of safe access zone laws in Australia that seek to prohibit certain activities that occur outside abortion facilities during protests. While they are characterised as a reasonable reaction to concerns that certain activities may harm women and infringe their rights to privacy and security, such laws do so at the expense of the protesters' right to freedom of political communication and cover activities such as sidewalk counselling and praying. This article critically examines the content and scope of these laws in each jurisdiction, identifies recent cases involving prosecutions for violations of safe access zone laws and considers the impact of the implied freedom of political communication on their constitutional validity in light of recent High Court decisions. PMID- 29978690 TI - Two Problems of Unburied Bodies. AB - No aspect of the law should be neglected, yet it is probably not often within the practice of lawyers or medical doctors that they become involved in litigation over human remains. Yet, within a short period of time, the courts in Britain have been required to adjudicate on such sensitive issues. In two cases public anxiety about the disposal of remains led to litigation and judicial decisions which are likely to remain illustrative of the unique facts and circumstances surrounding such problems. PMID- 29978691 TI - A Whiter Shade of Grey: Comparisons of the Legal and Professional Status of Tooth Whitening in Three Jurisdictions. AB - This article seeks to examine and compare the legal and professional positions of tooth whitening of three jurisdictions: the United Kingdom, Australia and New Zealand. Within each jurisdiction, a differing formula of legislation, case law and professional guidance dictates how tooth whitening is regulated and practised. Tooth whitening still holds curiosity as a procedure with regards to whether it does indeed warrant status as a professional activity and whether its practice should be limited to dental professionals. Through exploration of the differing positions of three different jurisdictions, it is possible to demonstrate that this issue is far greater than the common view within the profession that for reasons of public protection, access to tooth whitening should be controlled by the dental profession. The monopoly upon tooth whitening procedures that the dental profession often celebrates, where it exists, should be viewed to be fragile and not taken as an unending status quo. PMID- 29978692 TI - Infection Control Standards in Private Dental Practice - The Role of Accreditation. AB - There are established standards for the management of infection control in private dental practices, but there is currently no proactive legislation to oversee correct adherence to those standards. The Australian Health Service Safety and Quality Accreditation Scheme (Scheme) promotes a quality and safety management program that includes attention to the prevention of healthcare acquired infections, but adoption of the Scheme is not compulsory for all. A recent case brought before the NSW Civil and Administrative Tribunal demonstrated the seriousness of breaches of infection control standards and the considerable costs of managing the consequences. This article discusses the role of quality and safety assurance programs in the context of private dental practice regulation; compares the different quality and safety assurance schemes operating in Australia, Canada, and the United Kingdom; and argues that the compulsory adoption of an appropriate scheme which focuses on infection control would be in the public interest. PMID- 29978693 TI - Preparation and Characterization of Sugar-Assisted Cross-Linked Enzyme Aggregates (CLEAs) of Recombinant Cellobiose 2-epimerase from Caldicellulosiruptor saccharolyticus ( CsCE). AB - High-efficiency lactulose-producing enzyme of Caldicellulosiruptor saccharolyticus cellobiose 2-epimerase (WT- CsCE) was immobilized in the form of cross-linked enzyme aggregates (CLEAs). Conditions for enzyme aggregation and cross-linking were optimized, and a sugar-assisted strategy with less damage to enzyme secondary structures was developed to improve the activity yield of CLEAs up to approximately 65%. The resulting CLEAs with multiple-layer network structures exhibited an enlarged optimal temperature range (70-80 degrees C) and maintained higher activity at 50-90 degrees C. Besides, CLEAs retained more than 95% of their initial activity after 10 successive batches at 60 degrees C, demonstrating superior reusability. Moreover, CLEAs displayed an equivalent or higher catalytic ability to free WT- CsCE in lactulose biosynthesis, and the final sugar ratios were similar, lactulose 58.8-61.7%, epilactose 9.3-10.2%, and lactose 27.8-30%, with a constant isomerization selectivity of 0.84-0.87 regardless of enzymes used and temperature applied. The proposed strategy is the first trial for enzymatic synthesis of lactulose catalyzed by CLEAs of WT- CsCE. PMID- 29978694 TI - "Dark Deposition" of Ag Nanoparticles on TiO2: Improvement of Electron Storage Capacity To Boost "Memory Catalysis" Activity. AB - "Memory catalysis" (MC) studies have received appreciable attention recently because of the unique talent to retain the catalytic performance in the dark condition. However, the MC activity is still low owing to the relatively limited electron storage capacity of the present materials. Here, a TiO2@Ag composite was synthesized by a "dark-deposition (DD)" method, which is based on the electron trap effect of TiO2. Unlike traditional photodeposition (PD), an exploration of the morphology and chemical compositions of as-prepared samples shows that DD can inhibit the growth of Ag nanoparticles and the formation of Ag2O, which greatly improve the electron storage capacity. We further demonstrated that the maximum electronic capacity was in the order of TiO2@Ag-DD (1 MUmol/mg) > TiO2@Ag-PD (0.35 MUmol/mg) > TiO2 (0.11 MUmol/mg). Moreover, the enhanced MC activity was confirmed by various degradation experiments. Especially, the use of TiO2@Ag-DD as a round-the-clock catalyst for the degradation of multicomponent pollutants has also been achieved. This strategy opens a door for enhancing the MC activity and reveals that the coupling of photocatalysis and MC may provide a new opportunity for the continuous removal of pollutants in day and night. It also may be extended to other fields, such as energy storage and continuous disinfection. PMID- 29978695 TI - Ultrasensitive Au Nanooctahedron Micropinball Sensor for Mercury Ions. AB - Mercury ion (Hg2+) is one of the most toxic heavy metals that has severe adverse effects on the environment and human organs even at very low concentrations. Therefore, highly sensitive and selective detection of Hg2+ is desirable. Here, we introduce plasmonic micropinball constructed from Au nanooctahedron as a three dimensional surface-enhanced Raman spectroscopy (SERS) platform, enabling ultrasensitive detection of trace Hg2+ ions. Typically, strong SERS signals could be obtained when the single-stranded DNA structure converts to the hairpin structure in the presence of Hg2+ ions, due to the formation of thymine (T)-Hg2+ T. As a result, the detection limit of Hg2+ ions is as low as 1 * 10-16 M, which is far below compared to that reported for conventional analytical strategies. Moreover, to achieve rapid multiple detection, we combine the micropinball sensors with microflow tube online detection. Our platform prevents cross-talk and tube contamination, allowing multiassay analysis, rapid identification, and quantification of different analytes and concentrations across separate phases. PMID- 29978696 TI - Atom Efficient Synthesis of Selectively Difluorinated Carbocycles through a Gold(I)-Catalyzed Cyclization. AB - The intramolecular carbocyclization of difluorinated enol acetals has been achieved for the first time using gold(I) catalysis. Difluorinated enol acetals bearing a pendant alkene group can be cyclized and reduced in one pot to form fluorinated diol motifs. Alternatively, the cyclization of terminal alkynes allows for the synthesis of fluorinated pyran scaffolds. Both cyclization processes can be performed under mild conditions allowing access to complex products rich in functionality. The cyclic systems are synthesized concisely (maximum four steps) from trifluoroethanol, an inexpensive fluorinated feedstock. PMID- 29978697 TI - Electrothermal Local Annealing via Graphite Joule Heating on Two-Dimensional Layered Transistors. AB - A simple but powerful device platform for electrothermal local annealing (ELA) via graphite Joule heating on the surface of transition-metal dichalcogenide, is suggested here to sustainably restore intrinsic electrical properties of atomically thin layered materials. Such two-dimensional materials are easily deteriorated by undesirable surface/interface adsorbates and are screened by a high metal-to-semiconductor contact resistance. The proposed ELA allows one to expect a better electrical performance such as an excess electron doping, an enhanced carrier mobility, and a reduced surface traps in a monolayer molybdenum disulfide (MoS2)/graphite heterostructure. The thermal distribution of local heating measured by an infrared thermal microscope and estimated by a finite element calculation shows that the annealing temperature reaches up to >400 K at ambient condition and the high efficiency of site-specific annealing is demonstrated unlike the case of conventional global thermal annealing. This ELA platform can be further promoted as a practical gas sensor application. From an O2 cycling test and a low-frequency noise spectroscopy, the graphite on top of the MoS2 continuously recovers its initial condition from surface adsorbates. This ELA technique significantly improves the stability and reliability of its gas sensing capability, which can be expanded in various nanoscale device applications. PMID- 29978698 TI - Near Zero Area Compressibility in a Perovskite-Like Metal-Organic Frameworks [C(NH2)3][Cd(HCOO)3]. AB - Materials with zero area compressibility (ZAC) can keep their crystal uncompressed in two specific directions upon uniform compression. High-pressure angle-dispersive X-ray powder diffraction (ADXRD) experiments reveal a ZAC phenomenon in the ab-plane in crystal of a formate-based perovskite, [C(NH2)3][Cd(HCOO)3]. The ZAC behavior is ascribed to the unique rhombohedral [Cd(HCOO)3]- frameworks and confirmed by density functional theory (DFT) calculations. For the first time, a near ZAC single material is explicitly reported. This study opens up an exciting research field on pressure-resistant materials. We anticipate more ZAC materials to be discovered in the following explorations under the inspiration of this work. PMID- 29978699 TI - Hacking CD/DVD/Blu-ray for Biosensing. AB - The optical pickup unit (OPU) within a CD/DVD/Blu-ray drive integrates 780, 650, and 405 nm wavelength lasers, diffraction-limited optics, a high-bandwidth optoelectronic transducer up to 400 MHz, and a nanoresolution x-, z-axis, and tilt actuator in a compact size. In addition, the OPU is a remarkable piece of engineering and could enable different scientific applications such as sub angstrom displacement sensing, micro- and nanoimaging, and nanolithography. Although off-the-shelf OPUs can be easily obtained, manufacturers protect their datasheets under nondisclosure agreements to impede their availability to the public. Thus, OPUs are black boxes that few people can use for research, and only experienced researchers can access all their functions. This review details the OPU mechanism and components. In addition, we explain how to utilize three commercially available triple-wavelength OPUs from scratch and optimize sensing quality. Then, we discuss scientific research using OPUs, from standard optical drive-based turnkey-biomarker array reading and OPU direct bioapplications (cytometry, optical tweezing, bioimaging) to modified OPU-based biosensing (DNA chip fluorescence scanning, biomolecular diagnostics). We conclude by presenting future trends on optical storage devices and potential applications. Hacking low cost and high-performance OPUs may spread micro- and nanoscale biosensing research from research laboratories to citizen scientists around the globe. PMID- 29978700 TI - Lewis Acids Catalyzed Annulations of Ynamides with Acyl Chlorides for Constructing 4-Amino-2-naphthol Derivatives and 3-Aminocyclobutenones. AB - Two complementary synthetic manifestations leading to highly substituted 1 naphthol and 2-naphthol derivatives via Lewis acids catalyzed annulations of ynamides with acyl chlorides are described here. A one-pot synthesis of 4-amino-2 naphthol derivatives is accomplished via a ZnI2-catalyzed tandem Friedel-Crafts reaction sequence. While in the presence of Pd(0) catalyst, a [2 + 2] cycloaddition reaction of ynamides with monosubstituted ketenes that were generated from the dehydrohalogenation of suitable acyl chlorides leads to efficient formation of 3-aminocyclobutenones, which were subsequently modified to generate 3-amino-1-naphthols in excellent yields. PMID- 29978701 TI - Hydrogenation of Furfural with Nickel Nanoparticles Stabilized on Nitrogen-Rich Carbon Core-Shell and Its Transformations for the Synthesis of gamma Valerolactone in Aqueous Conditions. AB - In this article, we report the synthesis of nitrogen-rich carbon layer encapsulated Ni(0) nanoparticles as a core-shell structure (Ni@N/C-g-800) for the catalytic hydrogenation of furfural to furfuryl alcohol. The nickel nanoparticles were stabilized by the nitrogen-rich graphitic framework, which formed during the agitation of nickel acetate-impregnated cucurbit[6]uril surface in a reducing atmosphere. Furthermore, the catalyst was characterized using various physicochemical methods such as powder X-ray diffraction, Raman, field emission scanning electron microscopy, high-resolution transmission electron microscopy, X ray photoelectron spectroscopy, Brunauer-Emmett-Teller surface area, CO2 temperature-programmed desorption, inductive coupled plasma, and CHN analyses. The nitrogen-rich environment of the solid support with metallic Ni nanoparticles was found to be active and selective for the catalytic hydrogenation of furfural with molecular H2 in an aqueous medium at 100 degrees C. To understand the reaction mechanism, the diffuse reflectance infrared Fourier transform study was performed, which revealed that the C?O bond is activated in the presence of a catalyst. In addition, we have extended our methodology toward the synthesis of "levulinic acid" and "gamma-valerolactone", by successive hydrolysis and hydrogenation of furfuryl alcohol and levulinic acid, respectively, in an aqueous medium. Moreover, the heterogeneous catalysts used in all of the three consecutive steps help in recovery and recycling of the catalyst and easy separation of products. PMID- 29978702 TI - rawDiag: An R Package Supporting Rational LC-MS Method Optimization for Bottom-up Proteomics. AB - Optimizing methods for liquid chromatography coupled to mass spectrometry (LC-MS) is a nontrivial task. Here we present rawDiag, a software tool supporting rational method optimization by providing MS operator-tailored diagnostic plots of scan-level metadata. rawDiag is implemented as an R package and can be executed on the R command line or through a graphical user interface (GUI) for less experienced users. The code runs platform-independent and can process 100 raw files in <3 min on current consumer hardware, as we show in our benchmark. As a demonstration of the functionality of our package we include a real-world example taken from our daily core facility business. PMID- 29978703 TI - Total Synthesis of (+/-)-Exotine B. AB - The heterodimeric indole/coumarin natural product exotine B was synthesized for the first time. The carbon skeleton of the natural product was formed rapidly by a palladium-catalyzed Suzuki cross-coupling reaction and a gallium-catalyzed three-component [4 + 3] cycloaddition reaction. An alternative biosynthesis of exotine B is proposed based on the total synthesis. Improved syntheses of coumarin natural products gleinadiene and coumurrayin are also reported. PMID- 29978704 TI - Voltage-Controlled Bistable Thermal Conductivity in Suspended Ferroelectric Thin Film Membranes. AB - Ferroelastic domain walls in ferroelectric materials possess two properties that are known to affect phonon transport: a change in crystallographic orientation and a lattice strain. Changing populations and spacing of nanoscale-spaced ferroelastic domain walls lead to the manipulation of phonon-scattering rates, enabling the control of thermal conduction at ambient temperatures. In the present work, lead zirconate titanate (PZT) thin-film membrane structures were fabricated to reduce mechanical clamping to the substrate and enable a subsequent increase in the ferroelastic domain wall mobility. Under application of an electric field, the thermal conductivity of PZT increases abruptly at ~100 kV/cm by ~13% owing to a reduction in the number of phonon-scattering domain walls in the thermal conduction path. The thermal conductivity modulation is rapid, repeatable, and discrete, resulting in a bistable state or a "digital" modulation scheme. The modulation of thermal conductivity due to changes in domain wall configuration is supported by polarization-field, mechanical stiffness, and in situ microdiffraction experiments. This work opens a path toward a new means to control phonons and phonon-mediated energy in a digital manner at room temperature using only an electric field. PMID- 29978705 TI - Metal-Free One-Pot Four-Component Cascade Annulation in Ionic Liquids at Room Temperature: Convergent Access to Thiazoloquinolinone Derivatives. AB - An efficient, eco-friendly, and highly convergent one-pot route to privileged thiazoloquinolinone derivatives has been developed via four-component cascade coupling (4CCC) of alpha-enolic dithioesters, cysteamine/2-aminothiophenols, aldehydes, and cyclic 1,3-diketones in recyclable [EMIM][EtSO4] ionic liquid at room temperature for the first time. The reaction proceeds via a N,S-acetal formation, Knoevenagel condensation, aza-ene reaction, imine-enamine/keto-enol tautomerization, and intramolecular N-cyclization cascade sequence. The merit of the protocol is highlighted by its efficacy of forming consecutive five new bonds (two C-C, two C-N, and one C-S) and two rings with all reactants being efficiently utilized. The operational simplicity, sustainability, mild conditions, excellent yields, tolerance of wide functional groups, and avoidance of expensive/toxic reagents are additional attributes to this domino four component protocol. Notably, the products were easily separated from the ionic liquid, and thus the ionic liquid obtained was reused four times without considerable loss of any activity. PMID- 29978706 TI - Bismuth(III) Triflate Catalyzed Three-Component Reactions of Indoles, Ketones, and alpha-Bromoacetaldehyde Acetals Enable Indole-to-Carbazole Transformation. AB - A three-component reaction of indoles, alpha-bromoacetaldehyde acetals, and ketones was developed by using bismuth(III) triflate as the catalyst to realize a straightforward approach for synthesizing carbazole derivatives. The reaction was established mechanistically through the autotandem catalysis of Bi(OTf)3 in the following two steps: (i) Friedel-Crafts-type alkylation of indole with alpha bromoacetaldehyde acetal, which produced a tryptaldehyde-type intermediate and (ii) [4 + 2] annulation of this intermediate with the ketone component. PMID- 29978707 TI - Synthesis of Triarylmethanes via Palladium-Catalyzed Suzuki Coupling of Trimethylammonium Salts and Arylboronic Acids. AB - An efficient palladium-catalyzed Suzuki coupling of 1,1-diarylmethyl trimethylammonium triflates with arylboronic acids is reported. This reaction offers a novel approach to triarylmethane derivatives in good to excellent yields with the palladium-catalyzed C-N bond cleavage as the key feature. Broad substrate scope regarding both reaction partners are observed. Moreover, reactive functional groups such as vinyl and formyl groups are conserved in this transformation. PMID- 29978708 TI - Polyamino Acid Layer-by-Layer (LbL) Constructed Silica-Supported Mesoporous Titania Nanocarriers for Stimuli-Responsive Delivery of microRNA 708 and Paclitaxel for Combined Chemotherapy. AB - Cellular Fas-associated protein with death domain-like interleukin-1beta converting enzyme-inhibitory protein (c-FLIP), often strongly expressed in numerous cancers, plays a pivotal role in thwarting apoptosis and inducing chemotherapy resistance in cancer. An integrated approach combining chemotherapy with suppression of c-FLIP levels could prove paramount in the treatment of cancers with c-FLIP overexpression. In this study, we utilized a polymeric layer by-layer (LbL) assembly of silica-supported mesoporous titania nanoparticles (MTNst) to co-deliver paclitaxel (PTX) and microRNA 708 (miR708) for simultaneous chemotherapy and c-FLIP suppression in colorectal carcinoma. The resulting LbL miR708/PTX-MTNst showed dose-dependent cytotoxicity in HCT-116 and DLD-1 colorectal carcinoma cell lines, which was remarkably superior to that of free PTX or LbL PTX-MTNst. LbL miR708/PTX-MTNst strongly inhibited c-FLIP expression and resulted in increased expression of proapoptotic proteins. In DLD-1 xenograft tumor-bearing mice, the nanoparticles accumulated in the tumor, resulting in remarkable tumor regression, with the PTX and miR708-loaded nanoparticles showing significantly greater inhibitory effects than the free PTX or PTX-loaded nanoparticles. Immunohistochemical analyses of the tumors further confirmed the remarkable apoptotic and antiproliferative effects of the nanoparticles, whereas organ histology reinforced the biocompatibility of the system. Therefore, the LbL miR708/PTX-MTNst system, owing to its ability to deliver both chemotherapeutic drug and inhibitory miRNA to the tumor site, shows great potential to treat colorectal carcinoma in clinical settings. PMID- 29978709 TI - Real-Time Sensing of TET2-Mediated DNA Demethylation In Vitro by Metal-Organic Framework-Based Oxygen Sensor for Mechanism Analysis and Stem-Cell Behavior Prediction. AB - Active DNA demethylation, mediated by O2-dependent ten-eleven translocation (TET) enzymes, has essential roles in regulating gene expression. TET kinetics assay is vital for revealing mechanisms of demethylation process. Here, by a metal-organic framework (MOF)-based optical O2 sensor, we present the first demonstration on real-time TET2 kinetics assay in vitro. A series of luminescent Cu(I) dialkyl 1,2,4-triazolate MOFs were synthesized, which were noble-metal-free and able to intuitively response to dissolved O2 in a wide range from cellular hypoxia (<=15 MUM) to ambient condition (~257 MUM). By further immobilization of the MOFs onto transparent silicon rubber (MOF@SR) to construct O2 film sensors, and real-time monitoring of O2 consumption on MOF@SR over the reaction time, the complete TET2 mediated 5-methylcytosine (5mC) oxidation process were achieved. The method overcomes the limitations of the current off-line methods by considerably shortening the analytical time from 0.5-18 h to 10 min, and remarkably reducing the relative standard deviation from 10%-68% to 0.68%-4.2%. As a result, the Michaelis-Menten constant ( Km) values of TET2 for 5mC and O2 in ascorbic acid free (AA-) condition were precisely evaluated to be 24 +/- 1 and 43.8 +/- 0.3 MUM, respectively. By comparative study on AA-containing (AA+) conditions, and further establishing kinetics models, the stem-cell behavior of TETs was successfully predicted, and the effects of key factors (AA, O2, Fe2+) on TETs were revealed, which were fully verified in mouse embryonic stem (mES) cells. The method is promising in wide application in kinetics analysis and cell behavior prediction of other important O2-related enzymes. PMID- 29978710 TI - "Stoneless" or Negative Ureteroscopy: A Reality in the Endourologic Routine or Avoidable Source of Frustration? Estimating the Risk Factors for a Negative Ureteroscopy. AB - INTRODUCTION: A "Negative" ureteroscopy (URS) is defined as a URS in which no stone is found during the procedure. It may occur when the stone has already been passed spontaneously or when it is located outside the collecting system. The aim of the study was to outline risk factors for Negative-URS. MATERIALS AND METHODS: We retrospectively analyzed the possible risk factors for Negative-URS from a database of 341 URS cases. In every case where presumptive ureteral stone was not found, a formal nephroscopy as well as a whole collecting system revision was completed. The Negative-URS group was compared with the non-Negative-URS group, in terms of patient and stone characteristics. RESULTS: The database of 341 URS cases included 448 different stone instances, of which 17 (3.8%) were negative and 431 (96.2%) were therapeutic. There was no statistical significant difference between the two groups concerning age, body mass index, stone location in the ureter, stone laterality, and whether the patient was prestented. The stepwise multiple logistic regression revealed three important risk factors, namely CT stone surface area (p < 0.0001), radiopacity of the stone at kidney, ureter, and bladder radiograph (KUB; p = 0.0004), and gender (p = 0.0011) with an area under the curve of 0.91. Women were found to have more possibilities to have a negative procedure by four- to sevenfold than men depending on the model. A nonradio opaque stone at KUB is more likely to be correlated with a Negative-URS by 9.5- to 11-fold more than a radiopaque stone at KUB. For each increase of 1 U in CT stone surface area, there is an increase of 10%-12% to be non-negative. CONCLUSIONS: Female gender, a nonradio-opaque stone at KUB, and a smaller stone surface were statistically significantly different in the Negative-URS population. PMID- 29978711 TI - Expression of Human Endogenous Retroviruses in Peripheral Leukocytes During the Menstrual Cycle Suggests Coordinated Hormonal Regulation. PMID- 29978712 TI - A Question Mark on Emerging Zinc-Related Nutritional Deficiencies in Pakistani Population. PMID- 29978713 TI - Pretreatment Diagnosis of the Small Renal Mass: Status of Renal Biopsy in the United States of America. AB - INTRODUCTION: We surveyed United States of America-based urologists to characterize practice patterns and indications to perform a renal mass biopsy for small renal masses. MATERIALS AND METHODS: Members of the American Urological Association who practice in the United States were invited to participate in a 11 question web-based survey that was distributed via SurveyMonkey(r) from December 2016 to January 2017. RESULTS: There were 1131 respondents. The respondents equally represented all regions of the United States; the majority were in private practice. Overall, 32% of American urologists would "never" perform a biopsy of a renal mass <=4 cm. Those who saw fewer than five small renal masses per year were more likely to "never" perform a renal biopsy on either a renal mass <=4 cm or a renal mass 2-3 cm compared with those who saw more than five small renal masses per year (p < 0.001). Urologists who practiced at an academic hospital were more likely to perform a renal biopsy on both a renal mass <=4 cm and a renal mass 2-3 cm compared with private practice and government-based urologists (p < 0.001 and p = 0.008 respectively). The primary reason for not performing a biopsy, cited by 68% of responding urologists, was that the results of a biopsy "would not change their management of the renal mass." Respondents independently performed only 2% of biopsies; however, almost half stated that they would be interested in learning office-based ultrasound-guided biopsy of a small renal mass. CONCLUSIONS: Among members of the American Urological Association, biopsy of a small renal mass remains an underutilized diagnostic procedure, especially in light of 6000 unnecessary surgeries annually; nonuniversity-based urologists and those who see <5 renal mass cases each year infrequently perform a biopsy. Currently, interventional radiologists perform almost all small renal mass biopsies. PMID- 29978715 TI - ? PMID- 29978714 TI - Bespoke versus off the shelf ankle-foot orthosis for people with stroke: randomized controlled trial. PMID- 29978716 TI - ? PMID- 29978717 TI - ? PMID- 29978718 TI - The Therapeutic Effects of Adipose-Derived Stem Cells and Recombinant Peptide Pieces on Mouse Model of DSS Colitis. AB - Cell therapies using adipose-derived stem cells (ADSCs) have been used to treat inflammatory bowel disease (IBD) in human and dog. We previously reported the CellSaic technique, which uses a recombinant scaffold to enhance the efficacy of cell therapy. To examine whether this technique can be applied to cell therapy for colitis, we evaluated the efficacy of CellSaic in colitis mouse models. Colitis mouse models were developed by administering dextran sulfate sodium (DSS) to C57BL/6 mice for 7 days. Then CellSaic comprising human/canine ADSCs (1.2 * 106 cells) or human/canine ADSCs only (1.2 * 106 cells) were administered to the mice. The body weights were measured, and the colon length measurements and histological evaluations were conducted at 7 days after administration. After in vitro culture of human ADSC (hADSC) CellSaic and hADSC spheroids in medium containing TNFalpha, the levels of the anti-inflammatory protein TSG-6 in each supernatant were measured. Furthermore, we conducted tumorigenicity and general toxicity tests of canine ADSC (cADSC) CellSaic in NOG mice for 8 weeks. In the colitis mouse models, the ADSC CellSaic group presented recovery of body weight and colon length compared with the ADSC-only group. Histological analysis showed that ADSC CellSaic decreased the number of inflammatory cells and repaired ulceration. In vitro, hADSC CellSaic secreted 3.1-fold more TSG-6 than the hADSCs. In addition, tumorigenicity and general toxicity of cADSC CellSaic were not observed. This study suggests that human and canine ADSC CellSaic has a therapeutic effect of colitis in human and dogs. PMID- 29978719 TI - Improvement by Human Oligodendrocyte Progenitor Cells of Neurobehavioral Disorders in an Experimental Model of Neonatal Periventricular Leukomalacia. AB - The effects of human oligodendrocyte progenitor (F3.olig2) cells on improving neurobehavioral deficits were investigated in an experimental model of periventricular leukomalacia (PVL). Seven-day-old male rats were subjected to hypoxia-ischemia-lipopolysaccharide injection (HIL), and intracerebroventricularly transplanted with F3.olig2 (4 * 105 cells/rat) once at post-natal day (PND) 10 or repeatedly at PND10, 17, 27, and 37. Neurobehavioral disorders were evaluated at PND14, 20, 30, and 40 via cylinder test, locomotor activity, and rotarod performance, and cognitive function was evaluated at PND41 45 through passive avoidance and Morris water-maze performances. F3.olig2 cells recovered the rate of use of the forelimb contralateral to the injured brain, improved locomotor activity, and restored rotarod performance of PVL animals; in addition, marked improvement of learning and memory function was seen. It was confirmed that transplanted F3.olig2 cells migrated to injured areas, matured to oligodendrocytes expressing myelin basic protein (MBP), and markedly attenuated the loss of host MBP in the corpus callosum. The results indicate that the transplanted F3.olig2 cells restored neurobehavioral functions by preventing axonal demyelination, and that human oligodendrocyte progenitor cells could be a candidate for cell therapy of perinatal hypoxic-ischemic and infectious brain injuries including PVL and cerebral palsy. PMID- 29978721 TI - Proceedings of SRR. PMID- 29978720 TI - HIV-Infected Pregnant Women: A Microbial Translocation and Inflammatory Status Discussion. PMID- 29978722 TI - Children and E-Cigarettes: A New Threat to Health. AB - The widespread availability and use of E-Cigarettes in many countries has established the need for an assessment of their effect on children. By the end of 2017 the number published annually on E-Cigarettes had increased to 2976 and included 171 papers on E-Cigarettes and children. The objective of this commentary is to provide a review and public health perspective on the effects of E-cigarettes on children. There are four public health questions to be answered: 1. Are E-Cigarettes and replenishing fluids toxic on accidental ingestion? 2. If children smoke E-Cigarettes is this harmful? 3. Does exposure to second hand vapour from E-Cigarettes cause harm to children? 4. Are children (adolescents) who use E Cigarettes more likely to begin smoking conventional cigarettes? There were 2229 reported exposures to e-cigarette fluids and liquid nicotine in the USA in 2017 causing cardiovascular symptoms of varying severity. No deaths were reported although the potential is always there. Exposure to E-Cigarette vapor is less dangerous than cigarette smoke. However it does damage pulmonary endothelium in experimental models. No long term studies are yet available on chronic diseases although vapor does contain carcinogens. Adolescents who use E Cigarettes are more likely to become tobacco smokers. Because of the accumulating evidence of harm to children great caution should be exercised in widening the public promotion and usage of E-Cigarettes. Children should avoid any contact with E-cigarettes or their vapour. PMID- 29978724 TI - 'Not a film about my slackness': Making sense of medically unexplained illness in youth using collaborative visual methods. AB - Persistent medically unexplained symptoms have debilitating consequences for adolescents, dramatically altering their social world and future aspirations. Few studies have focused on social and moral aspects of illness experience relevant to adolescents. In this study, the aim is to explore these aspects in depth by focusing on a single case and to address how young people attempt to create social accountability in a search for meaning when facing illness and adversity. The study is based on a view of meaning as dialogically constituted during the research process, which calls for the use of collaborative film methodology and life-mode interviewing. With a dialogic-performative approach to a narrative emplotment of medically unexplained symptoms, we present Peter as intentional and purposive, and as a person who in a reflective process of meaning making claimed his own voice and developed his own strategies of coping with his illness. The analysis brings forward a narrative of suffering, hope and intentionality that is configured by the immediate limited possibilities of agency due to Peter's medical condition. It is, however, configured to an even greater degree by aspirations, that is, to become an accountable person through social experiences and to meet sociocultural and moral expectations of being an adolescent. The study provides insight into relational and existential aspects of meaning making in dealing with contested illness in youth and points to the potential of visual and other experience-near methods for supporting adolescents in their coping attempts and in overcoming communication barriers in everyday life and clinical encounters. PMID- 29978723 TI - Conducting dyadic, relational research about endometriosis: A reflexive account of methods, ethics and data analysis. AB - Despite a growing literature on the value of relational data in studies of social phenomena, individuals still commonly constitute the basic unit of analysis in qualitative research. Methodological aspects of interviewing couples, particularly interviewing partners separately, and of conducting dyadic analysis have received scant attention. This article describes the experience of conducting separate interviews with both partners in 22 heterosexual couples (n = 44) in a study of the impact of the gynaecological condition endometriosis. In order to advance current methodological thinking regarding interviewing couples, we describe the dyadic, relational approach employed in designing the study and our specific method of dyadic analysis. We argue that utilising separate interviews with dyadic analysis rather than conducting joint interviews, while not without its ethical, practical and analytical challenges, offers considerable methodological benefits. Such an approach allows a unique relational insight into the impact of chronic illness on couples and how they navigate chronic illness by illuminating both shared and individual interpretations, experiences, understandings and meanings. PMID- 29978725 TI - Patient selection for anti-PD-1/PD-L1 therapy in advanced non-small-cell lung cancer: implications for clinical practice. AB - Immune checkpoint inhibitors targeting PD-1 or PD-L1 represent a standard treatment option for patients with advanced non-small-cell lung cancer. However, a substantial proportion of patients will not benefit from these treatments, and robust biomarkers are required to help clinicians select patients who are most likely to benefit. Here, we discuss the available evidence on the utility of clinical characteristics in the selection of patients with advanced non-small cell lung cancer as potential candidates for single-agent anti-PD-1/PD-L1 therapy, and provide practical guidance to clinicians on identifying those patients who are most likely to benefit. Recommendations on the use of immune checkpoint inhibitor in clinically challenging populations are also provided. PMID- 29978726 TI - Double Conjunction Fallacies in Physicians' Probability Judgment. AB - We report the first empirical data showing a significant amount of double conjunction fallacies in physicians' probability judgments concerning prognosis and diagnosis. Our results support the hypothesis that physicians' probability judgments are guided by assessments of evidential impact between diagnostic conditions and clinical signs. Moreover, we show that, contrary to some influential views, double conjunction fallacies represent an experimentally replicable reasoning bias. We discuss how the phenomenon eludes major current accounts of uncertain reasoning in medicine and beyond and how it relates to clinical practice. PMID- 29978727 TI - How Does Stronger Protection of Intellectual Property Rights Affect National Pharmaceutical Expenditure? An Analysis of OECD Countries. AB - Intellectual property rights (IPR) protection for pharmaceuticals has been comprehensive and strict since the establishment of the World Trade Organization in 1995 and the subsequent implementation of the TRIPS Agreement. This study investigated the relationship between the level of IPR and national pharmaceutical expenditure using panel data of 22 OECD countries from 1970 to 2009. The patent index was used to measure the level of national protection for IPR along with other covariates: GDP per capita, the percentage of population aged over 65, number of doctors, proportion of public financing among total pharmaceutical expenditure, under-5 mortality, price index, and period indicators. The regression analysis results showed that the level of IPR protection was significantly correlated with pharmaceutical spending even after controlling for various factors that affect pharmaceutical expenditure. The results were consistent in OLS regression and GLS regression. However, the effect of IPR was stronger and more significant in countries with a relatively small sized pharmaceutical market than in those with big market. Many developed countries incur a financial burden due to rapidly growing pharmaceutical expenditure; therefore, the results of this study present the possibility that stronger IPR would produce welfare loss in developed countries. PMID- 29978729 TI - Impact of the assembly-activating protein (AAP) on molecular evolution of synthetic Adeno-associated virus (AAV) capsids. AB - Over the last decade, others and we have started to dissect the role of the assembly-activating protein AAP for the formation of Adeno-associated virus (AAV) capsids based on different viral serotypes. Recently, our group has specifically studied AAP's relevance during production of AAV gene therapy vectors in mammalian or insect cells, and found AAP to be essential for capsid protein stabilization and generation of functional vector particles. Here, we additionally addressed the lingering question whether molecular AAV evolution via DNA family shuffling of viral capsid genes would perturb AAP functionality due to concurrent and inadvertent recombination of the AAP open reading frame. To this end, we conducted a battery of complementary experiments in which we (i) tested the ability of chimeric AAP from AAVDJ, a hybrid of serotypes 2, 8 and 9, to rescue AAP knock-outs in the three parental serotypes; (ii) measured the functionality of 60 chimeric AAPs extracted from five shuffled, unselected capsid libraries; (iii) assessed whether production of different shuffled libraries, ten wild-type serotypes or 25 individual chimeric capsids can be enhanced by over expression of AAP cocktails; and (iv) studied the activity of 12 chimeric AAPs isolated from a shuffled library that was iteratively selected in vivo in mouse livers. Collectively, our data demonstrate a remarkable tolerance of AAP for recombination via DNA family shuffling, evidenced by our findings that (i) all chimeric AAPs studied here retained at least partial activity, even in cases where the cognate hybrid capsid may be non-functional, and that (ii) ectopic AAP over-expression did not enhance production of shuffled AAV chimeras or libraries, implying that the inherently encoded hybrid AAP variants are sufficiently active. Together, our work provides compelling evidence that AAP is not rate-limiting during AAV capsid shuffling and thereby relieves a major concern in the field of AAV vector evolution. PMID- 29978730 TI - Immunosuppression of Human Adipose-Derived Stem Cells on T Cell Subsets via the Reduction of NF-kappaB Activation Mediated by PD-L1/PD-1 and Gal-9/TIM-3 Pathways. AB - Adipose-derived stem cells (ADSCs) are a type of multipotent mesenchymal stem cells with immunosuppressive capacities. However, the underlying mechanisms involved in the inhibitory effects of ADSCs on T cells are not completely elucidated. In this study, human peripheral blood mononuclear cells (PBMCs) stimulated with anti-CD3/CD28 antibody-coated beads were cultured with or without allogeneic ADSCs (ADSC-to-PBMC ratio, 1:5). Surface marker levels, violet-labeled cell proliferation, apoptosis, interferon-gamma (IFN-gamma) production, and nuclear factor-kappaB (NF-kappaB) phosphorylation of CD4+ and CD8+ T cells were detected using flow cytometry. It was observed that ADSCs significantly suppressed the proliferation and IFN-gamma production but enhanced apoptosis of both CD4+ and CD8+ T cells in T cell receptor (TCR)-stimulated PBMCs. The expressions of programmed death-ligand 1 (PD-L1) and galectin 9 (Gal-9) on ADSCs were significantly upregulated and induced during coculture with PBMCs. TCR stimulated CD4+ and CD8+ T cells cultured with ADSCs had higher expression levels of programmed death-1 (PD-1) and T cell immunoglobulin and mucin-containing protein-3 (TIM-3) than those in cells cultured without ADSCs. Moreover, the suppressive effects of ADSCs on T cells in terms of proliferation and IFN-gamma production were significantly reversed in the presence of anti-PD-L1 and anti-Gal 9 antibodies. Importantly, the phosphorylation of NF-kappaB in CD4+ and CD8+ T cells cocultured with ADSCs was significantly inhibited, and this inhibition was significantly attenuated via the PD-L1 and Gal-9 blockades. In conclusion, human ADSCs perform immunoregulatory functions partially through the inhibition of NF kappaB activation in T cells via the PD-L1/PD-1 and Gal-9/TIM-3 pathways, which provide new insights into the mechanism of human ADSC-mediated immunomodulation. PMID- 29978728 TI - Cerebral imaging in paediatric mitochondrial disorders. AB - OBJECTIVES: Because the central nervous system (CNS) is the second most frequently affected organ in mitochondrial disorders (MIDs) and since paediatric MIDs are increasingly recognised, it is important to know about the morphological CNS abnormalities on imaging in these patients. This review aims at summarising and discussing current knowledge and recent advances concerning CNS imaging abnormalities in paediatric MIDs. METHODS: A systematic literature review was conducted. RESULTS: The most relevant CNS abnormalities in paediatric MIDs on imaging include white and grey matter lesions, stroke-like lesions as the morphological equivalent of stroke-like episodes, cerebral atrophy, calcifications, optic atrophy, and lactacidosis. Because these CNS lesions may be seen with or without clinical manifestations, it is important to screen all MID patients for cerebral involvement. Some of these lesions may remain unchanged for years whereas others may be dynamic, either in the sense of progression or regression. Typical dynamic lesions are stroke-like lesions and grey matter lesions. Clinically relevant imaging techniques for visualisation of CNS abnormalities in paediatric MIDs are computed tomography, magnetic resonance (MR) imaging, MR spectroscopy, single-photon emission computed tomography, positron emission tomography, and angiography. CONCLUSIONS: CNS imaging in paediatric MIDs is important for diagnosing and monitoring CNS involvement. It also contributes to the understanding of the underlying pathomechanisms that lead to CNS involvement in MIDs. PMID- 29978731 TI - Familial inheritance and screening of first-degree relatives in common variable immunodeficiency and immunoglobulin A deficiency patients. AB - Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs. PMID- 29978732 TI - Quality of life, performance status, and work capacity after post-endoscopic retrograde cholangiopancreatography pancreatitis. AB - OBJECTIVES: This study evaluated the long-term consequences of post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) on health related quality of life (HRQOL), performance status, and work capacity. MATERIALS AND METHODS: A follow-up study with prospective outcome measurements on patients with previous PEP and matched controls from a Danish cohort of 772 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). HRQOL was evaluated by the short form 36 health surveys, performance status by the Zubrod score, and work capacity by employment status. Multivariable models were applied to adjust for potential confounders. RESULTS: Twenty-nine cases and 49 controls were included. Twelve (41%), eight (28%), and nine (31%) patients had mild, moderate, and severe PEP, respectively. Mean follow-up time was 4.8 +/- 1.7 years. PEP was associated with long-term reduced mental HRQOL (-13.0 role-emotional score points, 95% CI: 25.4; -0.52). An increased Zubrod score representing reduced performance status was present in 12 of the 29 cases (41.4%) and in nine of the 49 controls (18.4%), p = .002. Reduced work capacity was present in 14 of the 29 cases (48.2%) and in 12 of the 49 controls (24.4%), p = .023. CONCLUSIONS: This study indicates that PEP has a detrimental effect on long-term HRQOL, performance score, and work capacity. PMID- 29978733 TI - Longitudinal analysis of statistical and clinically significant psychosocial change following mental health rehabilitation. AB - PURPOSE: With appropriate mental health rehabilitation, schizophrenia is increasingly associated with reports of recovery and stability. However, there is little empirical evidence evaluating the efficacy of services delivering this care. This study evaluated the effectiveness of rehabilitation for improving psychosocial function in consumers with schizophrenia. METHODS: An electronic database of standardized assessment instruments mandated and maintained by the health service was retrospectively reviewed to extract ratings of psychosocial function, daily living skills, and mood state from consecutive admissions to an inpatient rehabilitation service. Outcomes were compared at admission, discharge, and one-year follow-up to identify statistically significant change. Individual reliable and clinically significant change was also assessed by comparison with a normative group of clients functioning independently in the community. RESULTS: From admission to discharge the rehabilitation group made statistically significant gains in psychosocial function and daily living skills. Improvements were reliable and clinically significant in one-quarter to one-third of individual consumers. Approximately half sustained their improvements at follow up, although this represented only a small fraction of the overall cohort. Consumers not demonstrating gains exhibited psychometric floor effects at admission. CONCLUSIONS: Rehabilitation can produce statistically and clinically significant immediate improvement in psychosocial function for a sub-set of consumers with elevated scores at admission. The durability of any gains is less clear, and strategies promoting longer-term maintenance are encouraged. Furthermore, currently mandated outcome measures are confounded by issues of sensitivity and reporting compliance, and exploration of alternative instruments for assessing recovery is recommended. Implications for Rehabilitation Routinely collected standardized outcome measures can be used to investigate the effectiveness of mental health rehabilitation In addition to statistical significance, the clinical significance of outcomes should be evaluated to identify change that is individually meaningful Currently mandated outcomes instruments do not adequately evaluate many individuals' recovery journey Mental health service evaluation and quality improvement processes would likely benefit from adoption of recovery-oriented measures. PMID- 29978734 TI - "Caregrieving" in palliative care: Opportunities to improve bereavement services. PMID- 29978735 TI - Measuring State Medicaid Home Care Participation and Intensity Using Latent Variables. AB - Population aging and policies to redirect long-term care toward home- and community-based services have led to increases in Medicaid home care spending in most states. Changes in state Medicaid home care policy generosity may result from changes in the number of persons served (i.e., Participation) and/or changes in quantities of services covered (i.e., Intensity). This study measures state Medicaid home care Participation and Intensity comprehensively using latent variables, and uses those latent variables to describe changes in Medicaid home care policy generosity over time and across states. Yearly state-level data from the Medicaid Statistical Information System (1999-2012) are analyzed using exploratory and confirmatory factor analyses. Between 1999 and 2012, 29 states expanded both Participation and Intensity, whereas six states reduced both. In the remaining states, a trade-off occurred. Distinguishing between Medicaid home care Participation and Intensity deserves attention, as expansions along these two dimensions represent potentially different implications for beneficiaries. PMID- 29978736 TI - Allogeneic Adipose-Derived Mesenchymal Stem Cells (Horse Allo 20) for the Treatment of Osteoarthritis-Associated Lameness in Horses: Characterization, Safety, and Efficacy of Intra-Articular Treatment. AB - Osteoarthritis commonly causes lameness in the horse and has a great impact in performance animals. Due to the limitations of current medical therapies, allogenic mesenchymal stem cells (MSCs) may become an alternative method to control inflammation, reduce tissue damage and pain, and therefore improve lameness. We present the results of a regulatory clinical trial testing adipose derived MSCs (Horse Allo 20) in veterinary (Agencia Espanola del Medicamento y Productos Sanitarios, Spanish Medicines Agency, Reference number 325/ECV) involving a total number of 80 participants and with 90 days of follow-up period. The manufacturing process of Horse Allo 20 was robust with no influence of the adipose tissue donor (gender, age, or breed), sample origin (intraperitoneal or subcutaneous), or storage conditions (fresh vs. frozen product presentations) on the quality, safety, and efficacy of the drug product. An in vivo safety study showed that local and systemic tolerance was safe even after repeated intra articular administration (three injections). An in vivo efficacy study demonstrated the efficacy of the treatment after one or two injections by a reduction in lameness (P < 0.05) for an extended period of time (90 days), decreasing the need for prolonged local and/or systemic anti-inflammatory therapies and their well-known deleterious effects and toxicities. PMID- 29978737 TI - The Power of Storytelling: The Experiences of Incarcerated Women Sharing Their Stories. AB - Women are the fastest growing prison population in the United States. Women who are incarcerated are characterized by significant mental health needs and intense societal stigma. Despite such vulnerabilities, little is known about their experiences or the pathways that lead them toward recovery and rehabilitation. This qualitative research explores the lived experiences of incarcerated women sharing their stories with high school students and their teachers as part of a community outreach project entitled "Stories of Change." Six women were interviewed about what it was like to participate in the project. The data were coded and analyzed using phenomenological techniques, and the results were interpreted through a social constructionist framework. Five themes were revealed through an analysis of the interviews: (a) making a contribution, (b) connecting with others, (c) difficulty of telling their story, (d) identifying personal growth, and (e) moving forward. Storytelling is a powerful experience with lasting effects on the teller. This research explores the phenomenon of storytelling within a context of incarceration and stigma. These findings point toward the importance of providing programming to women within the criminal justice system that allows for meaningful interaction with normative individuals and opportunities for storytelling. PMID- 29978738 TI - Interactive Effect of Traumatic Brain Injury and Psychiatric Symptoms on Cognition among Late Middle-Aged Men: Findings from the Vietnam Era Twin Study of Aging. AB - Traumatic brain injury (TBI), post-traumatic stress disorder (PTSD), and depressive symptoms each increase the risk for cognitive impairment in older adults. We investigated whether TBI has long-term associations with cognition in late middle-aged men, and examined the role of current PTSD/depressive symptoms. Participants were 953 men (ages 56-66) from the Vietnam Era Twin Study of Aging (VETSA), who were classified by presence or absence of (1) history of TBI and (2) current elevated psychiatric symptoms (defined as PTSD or depressive symptoms above cutoffs). TBIs had occurred an average of 35 years prior to assessment. Participants completed cognitive testing examining nine domains. In mixed-effects models, we tested the effect of TBI on cognition including for interactions between TBI and elevated psychiatric symptoms. Models adjusted for age, pre morbid cognitive ability assessed at average age 20 years, apolipoprotein E genotype, and substance abuse; 33% (n = 310) of participants had TBI, mostly mild and remote; and 23% (n = 72) of those with TBI and 18% (n = 117) without TBI had current elevated psychiatric symptoms. TBI and psychiatric symptoms had interactive effects on cognition, particularly executive functioning. Group comparison analyses showed that men with both TBI and psychiatric symptoms demonstrated deficits primarily in executive functioning. Cognition was largely unaffected in men with either risk factor in isolation. Among late middle-aged men, the combination of even mild and very remote TBI with current elevated psychiatric symptoms is associated with deficits in executive function and related abilities. Future longitudinal studies should investigate how TBI and psychiatric factors interact to impact brain aging. PMID- 29978739 TI - Antitumor Efficacy of Huqizhengxiao (HQZX) Decoction Based on Inhibition of Telomerase Activity in Nude Mice of Hepatocarcinoma Xenograft. AB - OBJECTIVE: Huqizhengxiao (HQZX) decoction is a mixture of traditional Chinese medicines comprising 10 herbs, with inhibitory effects on hepatocarcinoma. The aim of the study is to observe the antitumor efficacy and mechanism of HQZX decoction in nude mice with hepatocellular carcinoma xenografts. METHODS: HepG2 luc subcutaneous hepatocarcinoma was established in nude mice. The mice were divided into 5 groups: control, cinobufagin, HQZXS, HQZXM, and HQZXH with doses 13.52, 27.03, and 54.06 g/kg, respectively. HQZX decoction was prepared for intraperitoneal intragastric administration for 3 weeks. Tumor growth was measured with Vernier calipers and in vivo imaging system. alpha-Fetoprotein (AFP) was determined by radioimmunoassay. Tumor necrosis factor-alpha (TNF-alpha) was measured with enzyme-linked immunosorbent assay (ELISA) assay. Telomerase activity was measured with polymerase chain reaction-ELISA. Nuclear mitosis and necrosis were observed with hematoxylin-eosin stain. Apoptotic proteins of caspase-3, Bcl-2, and Bax were examined by Western blot. Signaling molecules of ERK, mTOR, and STAT3 were measured with Luminex assay. RESULTS: HQZX decoction showed good inhibition of HepG2-luc xenografts. Compared with control group, the relative tumor proliferation rate was less than 60% in the HQZXH and HQZXS. The tumor inhibition rate of HQZXH group reached 52% +/- 15%. Relative average optical density values of the HQZXS and HQZXH groups decreased significantly. The mitotic index in HQZXS, HQZXM, and HQZXH groups decreased greatly. Telomerase activity of HQZXS was clearly reduced, and, the caspase-3 expression upregulated in HQZXH group. Bcl-2 expression was downregulated in HQZXS and HQZXH. The ratios of p-ERK/ERK and p-STAT3/STAT3 in HQZXS group were significantly downregulated. CONCLUSION: HQZX decoction can clearly inhibit the growth of hepatocellular carcinoma and induce tumor apoptosis. Its antitumor mechanism may be related to reducing telomerase activity and regulating the STAT3 and ERK signal pathway. PMID- 29978740 TI - Establishment of the reference interval for serum pro-gastrin-releasing peptide in healthy adults of Chinese Han ethnicity. AB - OBJECTIVE:: The aim of this study is to establish the reference interval for serum pro-gastrin-releasing peptide (proGRP) determined by electrochemiluminescence immunoassay (ECLIA) in healthy Chinese Han ethnic adults. METHODS:: After screening, 9932 healthy Chinese Han adults (age range 18 95 years) were enrolled in this study, including 6220 men and 3712 women. Serum proGRP levels were measured by ECLIA. The reference interval was defined by non parametric 95th percentile interval. RESULTS:: Serum proGRP levels conformed to a non-Gussian distribution. The reference interval for healthy Chinese Han adults calculated by the non-parametric method was 0-73.90 ng/mL in this study. Since serum proGRP levels were significantly correlated with age (r=0.226, P<0.001), the participants were divided into six age groups: 18-39, 40-49, 50-59, 60-69, 70 79, and ?80 years. No significant difference for serum proGRP levels was found between the sexes at each of six age groups. The reference intervals were gradually increased with age (65.35 ng/mL, 68.65 ng/mL, 74.10 ng/mL, 77.65 ng/mL, 84.57 ng/mL, and 98.03 ng/mL in 18-39, 40-49, 50-59, 60-69, 70-79, and ?80 years, respectively). CONCLUSIONS:: We established the reference interval for serum proGRP, which was determined by ECLIA in the healthy Chinese Han population. Furthermore, our study suggests that it is necessary to establish the age specific reference intervals for serum proGRP. PMID- 29978742 TI - A National Examination of Caregiver Use of and Preferences for Support Services: Does Rurality Matter? AB - OBJECTIVE: The objective of this study was to assess rural-urban differences in caregiver use of and preferences for support services. METHOD: Using the 2015 Caregiving in the U.S. survey data ( n = 1,389), we analyzed rural-urban differences by caregiver residence in use of and preferences for support services. We analyzed bivariate differences in service use and preferences, as well as in sociodemographic and caregiving relationship characteristics. We also assessed the correlates of service use using stratified ordered logistic regression models. RESULTS: Approximately one third of all caregivers had used no supportive services, with few differences in service use and preference by location. For caregivers in both locations, having more financial strain was associated with greater use of services. DISCUSSION: This article identifies broad needs for caregiver support across all geographic locations. Targeted efforts should be made to ensure access to supportive services accounting for unique barriers by geography. PMID- 29978743 TI - The cost of diabetes and obesity in Australia. AB - AIMS: To assess and compare the direct healthcare and non-healthcare costs and government subsidies by body weight and diabetes status. METHODS: The Australian Diabetes, Obesity and Lifestyle study collected health service utilization and health-related expenditure data at the 2011-2012 follow-up surveys. Costing data were available for 4,409 participants. Unit costs for 2016-2017 were used where available or were otherwise inflated to 2016-2017 dollars. Age- and sex-adjusted costs per person were estimated using generalized linear models. RESULTS: The annual total direct cost ranged from $1,998 per person with normal weight to $2,501 per person with obesity in participants without diabetes. For those with diabetes, total direct costs were $2,353 per person with normal weight, $3,263 per person with overweight, and $3,131 per person with obesity. Additional expenditure as government subsidies ranged from $5,649 per person with normal weight and no diabetes to $8,085 per person with overweight and diabetes. In general, direct costs and government subsidies were higher for overweight and obesity compared to normal weight, regardless of diabetes status, but were more noticeable in the diabetes sub-group. The annual total excess cost compared with normal weight people without diabetes was 26% for obesity alone and 46% for those with obesity and diabetes. LIMITATIONS: Participants included in this study represented a healthier cohort than the Australian population. The relatively small sample of people with both obesity and diabetes prevented a more detailed analysis by obesity class. CONCLUSION: Overweight and obesity are associated with increased costs, which are further increased in individuals who also have diabetes. Interventions to prevent overweight and obesity or reduce weight in people who are overweight or obese, and prevent diabetes, should reduce the financial burden. PMID- 29978744 TI - Validation of Pressure Reactivity and Pulse Amplitude Indices against the Lower Limit of Autoregulation, Part I: Experimental Intracranial Hypertension. AB - The purpose of this study was to provide validation of intracranial pressure (ICP) derived continuous indices of cerebrovascular reactivity against the lower limit of autoregulation (LLA). Utilizing an intracranial hypertension model within white New Zealand rabbits, ICP, transcranial Doppler (TCD), laser Doppler flowmetry (LDF), and arterial blood pressure were recorded. Data were retrospectively analyzed in a cohort of 12 rabbits with adequate signals for interrogating the LLA. We derived continuous indices of cerebrovascular reactivity: PRx (correlation between ICP and mean arterial pressure [MAP]), PAx (correlation between pulse amplitude of ICP [AMP] and MAP), and Lx (correlation between LDF-based cerebral blood flow [CBF] and cerebral perfusion pressure [CPP]). LLA was derived via piecewise linear regression of CPP versus LDF or CPP versus systolic flow velocity (FVs) plots. We then produced error bar plots for PRx, PAx, and Lx against 2.5 mm Hg bins of CPP, to display the relationship between these indices and the LLA. We compared the CPP values at clinically relevant thresholds of PRx and PAx, to the CPP defined at the LLA. Receiver operating curve (ROC) analysis was performed for each index across the LLA using 2.5 mm Hg bins for CPP. The mean LLA was 51.5 +/- 8.2 mm Hg. PRx and PAx error bar plots demonstrate that each index correlates with the LLA, becoming progressively more positive below the LLA. Similarly, CPP values at clinically relevant thresholds of PRx and PAx were not statistically different from the CPP derived at the LLA. Finally, ROC analysis indicated that PRx and PAx predicted the LAA, with areas under the curve (AUCs) of 0.795 (95% confidence interval [CI]: 0.731-0.857, p < 0.0001) and 0.703 (95% CI: 0.631-0.775, p < 0.0001), respectively. Both PRx and PAx generally agree with LLA within this experimental model of intracranial hypertension. Further analysis of clinically used indices of autoregulation across the LLA within pure arterial hypotension models is required. PMID- 29978745 TI - Seven-day access to primary care in the UK. PMID- 29978741 TI - Understanding Tendons: Lessons from Transgenic Mouse Models. AB - Tendons and ligaments are connective tissues that have been comparatively less studied than muscle and cartilage/bone, even though they are crucial for proper function of the musculoskeletal system. In tendon biology, considerable progress has been made in identifying tendon-specific genes (Scleraxis, Mohawk, and Tenomodulin) in the past decade. However, besides tendon function and the knowledge of a small number of important players in tendon biology, neither the ontogeny of the tenogenic lineage nor signaling cascades have been fully understood. This results in major drawbacks in treatment and repair options following tendon degeneration. In this review, we have systematically evaluated publications describing tendon-related genes, which were studied in depth and characterized by using knockout technologies and the subsequently generated transgenic mouse models (Tg) (knockout mice, KO). We report in a tabular manner, that from a total of 24 tendon-related genes, in 22 of the respective knockout mouse models, phenotypic changes were detected. Additionally, in some of the models it was described at which developmental stages these changes appeared and progressed. To summarize, only loss of Scleraxis and TGFbeta signaling led to severe tendon developmental phenotypes, while mice deficient for various proteoglycans, Mohawk, EGR1 and 2, and Tenomodulin presented mild phenotypes. These data suggest that the tendon developmental system is well organized, orchestrated, and backed up; this is even more evident among the members of the proteoglycan family, where the compensatory effects are much clearer. In future, it will be of great importance to discover additional master tendon transcription factors and the genes that play crucial roles in tendon development. This would improve our understanding of the genetic makeup of tendons, and will increase the chances of generating tendon-specific drugs to advance overall treatment strategies. PMID- 29978749 TI - Edward Jenner's 1798 report of challenge experiments demonstrating the protective effects of cowpox against smallpox. PMID- 29978747 TI - Time to rebalance and reconsider: are we pathologising informal, family carers? PMID- 29978750 TI - Therapeutic empathy: what it is and what it isn't. PMID- 29978751 TI - The NHS at 70: reasons to be cheerful and fearful. PMID- 29978753 TI - Computerized testing in Parkinson's disease: Performance deficits in relation to standard clinical measures. AB - OBJECTIVE: This study assessed deficits associated with Parkinson's disease (PD) at two time points separated by 1 year using a computerized neuropsychological battery, and determined interrelationships with conventional clinical measures of cognitive functioning (Montreal Cognitive Assessment; MoCA) and motor impairment (Part III of the Unified PD Rating Scale; UPDRS), as well as other factors known to influence cognitive dysfunction in PD. METHOD: Participants included 37 with PD and 47 controls. Linear mixed-effects models were developed for each computerized task. RESULTS: Results showed that the PD group performed worse than controls on all of the computerized tasks at both time points. In contrast, MoCA scores differed between PD and controls only at follow-up. However, the MoCA detected decline over the year in the PD group, whereas only one of the computerized tasks did. In both groups, higher MoCA scores predicted better performance on some but not all of the computerized tasks. Surprisingly, UPDRS rated motor impairment did not predict performance on any of the computerized tasks, and aside from older age, which predicted poorer performance on all but one task, the other factors-education, affective and impulsivecompulsive symptoms, sleep quality, dopaminergic medication-generally had no relationship with performance on the computerized tasks. CONCLUSIONS: The presence of performance deficits for all of the computerized tasks in the PD group compared to controls, but not for the MoCA at initial testing, indicates that the computerized battery was better able to detect deficits. However, in contrast to the MoCA, the current results call into question the suitability of the computerized battery as measured here for tracking decline. PMID- 29978754 TI - Richter transformation to Hodgkin lymphoma on Bruton's tyrosine kinase inhibitor therapy. PMID- 29978756 TI - Not talking about illness at meeting places in Norwegian community mental health care: A discourse analysis of silence concerning illness-talk. AB - Research on the topic of not talking about psychosocial hardships describes the presence of 'house rules' against illness-talk in common areas in 'meeting places' ('day centres') in community mental health care. The aim of this article was to explore the complexity of not talking about psychosocial hardships ('silence') in meeting places in Norwegian community mental health care. The research team consisted of first-hand and academic knowers of community mental health care (participatory research team). We performed two series of focus group discussions with service users and staff of meeting places. The focus group interviews were analysed within a discourse analytic framework, and five discursive constructions were identified: (1) biomedical colonization of illness talk, (2) restricted access for biomedical psychiatry and problem-talk in the common spaces of meeting places, (3) censorship of service users' civil and human rights to freedom of speech, (4) protection from exploitation and burdens and (5) silent knowledge of the peer community. Based on the analysis, we suggest that not talking about illness (silence) entails a complexity ranging from under privileging implications to promoting the interests of people who 'use' meeting places. For instance, restricting biomedical psychiatry may imply the unintended implication of further silencing service users, while silently shared understandings of hardships among peers may imply resistance against demands to speak to legitimize one's situation. The discussion illuminates dilemmas related to silence that require critical reflexive discussions and continuous negotiations among service users, staff and policymakers in community mental health care. PMID- 29978755 TI - Incidence of nonmedical use of OxyContin and other prescription opioid pain relievers before and after the introduction of OxyContin with abuse deterrent properties. AB - OBJECTIVES: There is an epidemic of nonmedical and extra-medical use opioid abuse, addiction, and overdose. Extended-release oxycodone (OxyContin(r)), a prescription opioid pain reliever, was reformulated in 2010 to deter its abuse. The aim of this study was to assess changes in the onset of abuse of OxyContin and other opioids among young people and adults after reformulation of OxyContin with abuse-deterrent properties. METHODS: The study population was U.S. residents >= 12 years sampled in National Surveys on Drug Use and Health (NSDUH), 2004 to 2015, with subsample of 12-21-year-olds. Nonmedical and extra-medical use is the NSDUH proxy for abuse. Confidential audio-computer-assisted self-interviews were assessed. Age-specific incidence of nonmedical and extra-medical use of OxyContin and other prescription opioids were estimated year by year. Interrupted-time series and age-period-cohort analyses were analyzed. RESULTS: Interrupted-time series analysis showed a lower incidence of OxyContin nonmedical and extra medical use after 2010 reformulation compared to the counterfactual predicted by the trend before 2010. No such difference was seen for other prescription opioids for all ages, although a lower incidence was also observed for other prescription opioids among 12-21-year-olds. Among 12-21-year-olds, a robustly lower incidence was found in 2012 compared to 2010 for OxyContin after holding constant age and cohort effects, whereas no robust difference was observed for other prescription opioids. The results showed 137,500 fewer newly incident cases of OxyContin nonmedical and extra-medical use per year. CONCLUSIONS: This study provides evidence supporting the role of OxyContin reformulation in the reduction of onset of OxyContin nonmedical and extra-medical use. PMID- 29978757 TI - Performance evaluation and substrate removal kinetics in an up-flow anaerobic hybrid membrane bioreactor treating simulated high-strength wastewater. AB - The prime objective of the present study is to evaluate the performance of novel up-flow anaerobic hybrid membrane bioreactor (An-HMBR) treating high-strength wastewater (synthetic) using polyurethane foam as filter media. Treatment efficiency of the entire An-HMBR varied from 88-97% corresponding to 0.67-3.90 d of hydraulic retention time (HRT) with organic loading rate of 6.4-1.06 kg COD m 3 d-1. The modified Stover-Kincannon model was the most appropriate model for An HMBR and anaerobic hybrid bioreactor (excluding membrane). The suspended growth system in An-HMBR could be described by both modified Stover-Kincannon and Grau second order model. The attached growth system in An-HMBR followed conventional Monod's kinetics. A novel combination of suspended, attached and membrane in single reactor increased the solid retention time to as high as 756 d at 3.9 d HRT which not only improved the COD removal efficiency but also enhanced the performance of the membrane. PMID- 29978758 TI - Quantifying performance of a diagnostic test as the expected information for discrimination: Relation to the C-statistic. AB - Although the C-statistic is widely used for evaluating the performance of diagnostic tests, its limitations for evaluating the predictive performance of biomarker panels have been widely discussed. The increment in C obtained by adding a new biomarker to a predictive model has no direct interpretation, and the relevance of the C-statistic to risk stratification is not obvious. This paper proposes that the C-statistic should be replaced by the expected information for discriminating between cases and non-cases (expected weight of evidence, denoted as Lambda), and that the strength of evidence favouring one model over another should be evaluated by cross-validation as the difference in test log-likelihoods. Contributions of independent variables to predictive performance are additive on the scale of Lambda. Where the effective number of independent predictors is large, the value of Lambda is sufficient to characterize fully how the predictor will stratify risk in a population with given prior probability of disease, and the C-statistic can be interpreted as a mapping of Lambda to the interval from 0.5 to 1. Even where this asymptotic relationship does not hold, there is a one-to-one mapping between the distributions in cases and non-cases of the weight of evidence favouring case over non-case status, and the quantiles of these distributions can be used to calculate how the predictor will stratify risk. This proposed approach to reporting predictive performance is demonstrated by analysis of a dataset on the contribution of microbiome profile to diagnosis of colorectal cancer. PMID- 29978759 TI - Stem Cell Culture in Microgravity and Its Application in Cell-Based Therapy. AB - Recent years have witnessed a rapid increase in space experiments. Initially, scientists focused on understanding the phenomenon of microgravity to discover countermeasures for preventing the adverse effects of microgravity on the astronauts' bodies. Lately, the application of microgravity environment has been gradually increasing with diverse objectives. Protein crystallization and three dimensional cell culture are typical examples of microgravity application. Our recent studies suggested that microgravity is a useful tool for cell culture in cell-based therapy. In this review, we discussed microgravity-induced changes at cellular and molecular levels observed in experiments conducted during space flight or using simulated microgravity device. In addition, we summarized the utility of microgravity environment in cell-based therapy for central nervous system diseases. PMID- 29978760 TI - La promotion de la sante est-elle culturellement competente pour travailler avec les migrants ? PMID- 29978761 TI - Is health promotion culturally competent to work with migrants? PMID- 29978763 TI - Resumes. PMID- 29978762 TI - La promocion de la salud ?es competente desde el punto de vista cultural para trabajar con migrantes? PMID- 29978764 TI - Resumenes. PMID- 29978766 TI - Carbon quantum dots functionalized agarose gel matrix for in solution detection of nonylphenol. AB - Nonylphenol, an endocrine disrupter, is widely released to the aquatic environment, which is accumulative and extremely toxic to aquatic organisms. Here, we report a simple and cost-effective large-scale green synthesis of water soluble highly fluorescent carbon quantum dots (CQDs) from marine biowaste (offshore washed algae) which gets quenched strongly in the presence of nonylphenol. These CQDs were around 20-40 nm in size and exhibit fluorescence constantly at 360 nm. The XRD profile depicted the interlayer spacing in the particle as 0.284 nm with a humped peak around 14 degrees showing the amorphous nature of the CQDs. FTIR spectra showed the stretching vibration of the hydroxyl groups (OH), asymmetric and symmetric stretching vibrations of the carboxylate anions (COO-). The fluorescence quantum yield of the CQDs is up to 68% and nonyl phenol detection limit is less than 0.1 uM. Furthermore, the CQDs were found to be stable at a wide pH range which makes it a suitable nonylphenol sensor for a variety of environmental samples. We functionalized these CQDs on an agarose gel matrix to develop a convenient sensor for the rapid detection of nonylphenol. PMID- 29978767 TI - Subclinical Hypothyroidism and the Risk of Cardiovascular Disease and All-Cause Mortality: A Meta-Analysis of Prospective Cohort Studies. AB - OBJECTIVES: To determine the impact of subclinical hypothyroidism (SCH) on the risk of cardiovascular disease (CVD) and all-cause mortality, a comprehensive meta-analysis was performed according to the age or coexisting CVD risk status of the participants. METHODS: Studies regarding the association of SCH with all cause mortality from PubMed and Embase databases were included. The pooled relative risk (RR) of CVD and all-cause mortality was calculated using the Mantel Haenszel method. A subgroup analysis of participants with high CVD risk was conducted, including history of coronary, cerebral, or peripheral artery disease; dilated cardiomyopathy; heart failure; atrial fibrillation; venous thromboembolism; diabetes mellitus; or chronic kidney disease. RESULTS: In total, 35 eligible articles incorporating 555,530 participants were included. SCH was modestly associated with CVD and all-cause mortality (RR for CVD = 1.33 [confidence interval (CI) 1.14-1.54]; RR for all-cause mortality = 1.20 [CI 1.07 1.34]). However, the association was not observed in participants aged >=65 years. Subgroup analysis showed that participants with SCH and high CVD risk showed a significantly higher risk of all-cause mortality (RR for CVD = 2.20 [CI 1.28-3.77]; RR for all-cause mortality = 1.66 [CI 1.41-1.94]), whereas those with SCH and low CVD risk did not. Additional subgroup analysis of six studies with a mean participant age of >=65 years and high CVD risk showed a significant high risk of all-cause mortality in the SCH group (RR = 1.41 [CI 1.08-1.85]; I2 = 0%). CONCLUSIONS: SCH is associated with an increased CVD risk and all-cause mortality, particularly in participants with high CVD risk. PMID- 29978769 TI - DIFFERENTIALS IN SEXUAL AND REPRODUCTIVE HEALTH KNOWLEDGE AMONG EAST MALAYSIAN ADOLESCENTS. AB - SummaryThe aim of this study was to assess the knowledge of East Malaysian adolescents on sexual and reproductive health issues. Data were collected in March-July 2015 from 2858 adolescents aged 13-18 years from selected East Malaysian secondary schools using a self-administered questionnaire. Twelve items relating to sexual and reproductive health were used to measure respondents' knowledge based on their responses 'True', 'False' or 'Don't know', with the proportion of correct answers being the variable of interest. Cronbach's alpha for the twelve items was 0.761 and the mean knowledge score was 6.8. While the majority of the respondents knew that a woman can get pregnant if she has sex with a man and that HIV and AIDS can be transmitted through sexual intercourse, knowledge about Malaysia's abortion laws, that a woman can get pregnant if she has sex only once and that people with sexually transmitted infections may look healthy was poor. Older respondents and those from urban schools reported significantly higher knowledge than younger respondents and those from rural schools, respectively. More emphasis should be given in schools to the specific topics for which low levels of sexual and reproductive health knowledge were found, with greater attention being given to younger adolescents and those in rural areas. PMID- 29978768 TI - Magnetic Resonance Imaging of Shear Stress and Wall Thickness in Tissue Engineered Vascular Grafts. AB - OBJECTIVES: Tissue-engineered vascular grafts (TEVGs) have demonstrated potential for treating congenital heart disease (CHD); however, quantitative imaging for tracking functional and structural remodeling of TEVGs has not been applied. Therefore, we evaluated the potential of magnetic resonance (MR) imaging for assessing TEVG wall shear stress (WSS) and wall thickness in a large animal model. METHODS: Cell-seeded (n = 3) or unseeded (n = 3) TEVGs were implanted as inferior vena cava interposition grafts in juvenile lambs. Six months following implantation, two-dimensional phase-contrast MR imaging was performed at 3 slice locations (proximal, middle, and distal) to assess normalized WSS (i.e., WSS-to cross sectional area). T2-weighted MR imaging was performed to assess TEVG wall thickness. Histology was qualitatively assessed, whereas immunohistochemistry was semiquantitatively assessed for smooth muscle cells (alphaSMA), macrophage lineage cells (CD11b), and matrix metalloproteinase activity (MMP-2 and MMP-9). Picrosirius Red staining was performed to quantify collagen content. RESULTS: TEVG wall thickness was significantly higher for proximal, middle, and distal slices in unseeded versus cell-seeded grafts. Significantly higher WSS values existed for proximal versus distal slice locations for cell-seeded TEVGs, whereas no differences in WSS existed between slices for unseeded TEVGs. Additionally, no differences in WSS existed between cell-seeded and unseeded groups. Both groups demonstrated elastin formation, without vascular calcification. Unseeded TEVGs possessed greater content of smooth muscle cells when compared with cell-seeded TEVGs. No differences in macrophage, MMP activity, or collagen content existed between groups. CONCLUSION: MR imaging allows for in vivo assessment of functional and anatomical characteristics of TEVGs and may provide a nonionizing approach that is clinically translatable to children undergoing treatment for CHD. PMID- 29978770 TI - Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family. AB - BACKGROUND: We previously reported four heterozygous missense mutations of MYH7, KCNQ1, MYLK2, and TMEM70 in a single three-generation Chinese family with dual Long QT and hypertrophic cardiomyopathy phenotypes for the first time. However, the clinical course among the family members was various, and the potential myocardial dysfunction has not been investigated. OBJECTIVES: The objective of this study was to investigate the echocardiographic and electrocardiographic characteristics in a genetic positive Chinese family with hypertrophic cardiomyopathy and further to explore the association between myocardial dysfunction and electric activity, and the identified mutations. METHODS: A comprehensive echocardiogram - standard two-dimensional Doppler echocardiography and three-dimensional speckle tracking echocardiography - and electrocardiogram were obtained for members in this family. RESULTS: As previously reported, four missense mutations - MYH7-H1717Q, KCNQ1-R190W, MYLK2-K324E, and TMEM70-I147T - were identified in this family. The MYH7-H1717Q mutation carriers had significantly increased left ventricular mass indices, elevated E/e' ratio, deteriorated global longitudinal stain, but enhanced global circumferential and radial strain compared with those in non-mutation patients (all p<0.05). The KCNQ1-R190W carriers showed significantly prolonged QTc intervals, and the MYLK2 K324E mutation carriers showed inverted T-waves (both p<0.05). However, the TMEM70-I147T mutation carriers had similar echocardiography and electrocardiographic data as non-mutation patients. CONCLUSIONS: Three of the identified four mutations had potential pathogenic effects in this family: MYH7 H1717Q was associated with increased left ventricular thickness, elevated left ventricular filling pressure, and altered myocardial deformation; KCNQ1-R190W and MYLK2-K324E mutations were correlated with electrocardiographic abnormalities reflected in long QT phenotype and inverted T-waves, respectively. PMID- 29978771 TI - Review of children with Takayasu's arteritis at a Southern African tertiary care centre. AB - : IntroductionTakayasu's arteritis is a rare idiopathic arteritis causing stenosis or aneurysms of the aorta, pulmonary arteries, and their branches. It usually occurs in women, but has been described in children. OBJECTIVE: The objective of this study was to determine the clinical presentation, demographic profile, vascular involvement, origins, management, and outcome of children diagnosed with Takayasu's arteritis at a Southern African tertiary care centre between 1993 and 2015. METHODS: This is a retrospective analysis of all children with Takayasu's arteritis captured on a computerised electronic database during the study period. RESULTS: A total of 55 children were identified. The female:male ratio was 3.2:1, and the mean age was 9.7+/-3.04 years. Most originated outside the provincial borders of the study centre. The majority presented with hypertension and heart failure. In all, 37 (67%) patients had a cardiomyopathy with a mean fractional shortening of 15+/-5%. A positive purified protein derivative test was documented in 73%. Abdominal aorta and renal artery stenosis were the predominant angiographic lesions. A total of 23 patients underwent 30 percutaneous interventions of the aorta, pulmonary, and renal arteries: eight stents, 22 balloon angioplasties, and seven had nephrectomies. All patients received empiric tuberculosis treatment, immunosuppressive therapy, and anti-hypertensive agents as required. Overall, there was a significant reduction in systolic blood pressure and improvement in fractional shortening (p<0.05) with all treatments. CONCLUSION: Takayasu's arteritis is more common in girls and frequently manifests with hypertension and heart failure. The abdominal aorta and renal arteries are mostly affected. Immunosuppressive, anti hypertensive, and vascular intervention therapies improve blood pressure control and cardiac function. PMID- 29978772 TI - Detection of potentially human infectious assemblages of Giardia duodenalis in fecal samples from beef and dairy cattle in Scotland. AB - This study aimed to determine the prevalence and assemblages of Giardia duodenalis present in Scottish beef and dairy cattle at different ages, to try to ascertain if cattle could play a role in the spread of zoonotic assemblages of Giardia. A total of 388 fecal samples (128 beef and 253 dairy, seven of unknown breed) were collected from 19 farms in Scotland. Samples were sub-divided by host age, 1, 2, 3, 4, 5 and 6, 7-24 and ?25 weeks. DNA was extracted and tested by PCR to detect G. duodenalis DNA. Of the 388 samples, 126 tested positive, giving an overall prevalence of 32.5%, with positive samples being observed in all age groups tested. The prevalence in dairy cattle was 44.7% (113/235), which was significantly higher (P < 0.001) than the prevalence in beef cattle 10.1% (13/128). Sequence analysis demonstrated the presence of assemblage E (77.2%, sequence types E-S1-E-S5), assemblage B (18.2%) and assemblage A (sub-assemblages AI-AII) (4.6%). These data demonstrate that G. duodenalis is found routinely in both dairy and beef cattle throughout Scotland; the presence of assemblages A and B also indicates that cattle may play a role in the spread of potentially zoonotic assemblages of Giardia. PMID- 29978773 TI - Pressure injury prevention for paediatric cardiac surgical patients using a nurse driven standardized clinical assessment and management plan. AB - BACKGROUND: The description of pressure injury development is limited in children with CHD. Children who develop pressure injuries experience pain and suffering and are at risk for additional morbidity. OBJECTIVES: The objective of this study was to develop a standardized clinical assessment and management plan to describe the development of pressure injury in paediatric cardiac surgical patients and evaluate prevention strategies. METHODS: Using a novel quality improvement initiative, postoperative paediatric cardiac surgical patients were started on a nurse-driven pressure injury prevention standardized clinical assessment and management plan on admission. Data were recorded relevant to nursing assessments and management based on pre-defined targeted data statements and algorithm. Nursing feedback regarding diversions was recorded and analysed. RESULTS: Data on 674 congenital paediatric cardiac surgical patients who met criteria were collected between May, 2011 and June, 2012. In 5918 patient days, a total of 4603 skin assessments were completed by nurses from the cardiac ICU and the cardiac inpatient unit, representing 77% of the expected assessments. The majority (70%, 21/30) of the 30 pressure injuries were medical-device-related and 30% (9/30) were immobility-related. The overall incidence of pressure injury was 4.4%: device-related was 3.1% and immobility-related was 1.3%. Most pressure injuries were Stage 1 (40%), followed by Stage 2 (26.7%), mucosal membrane injury (26.7%), and suspected deep tissue injuries (6.7%). CONCLUSION: A nurse-driven pressure injury prevention standardized clinical assessment and management plan supported a programme-based evaluation of nursing practice and patient outcomes. Review of practices highlighted opportunities to standardise and focus prevention practices and ensure communication of patient vulnerabilities. PMID- 29978774 TI - Sugar-sweetened beverages: still cause for concern in New Zealand and Australia. PMID- 29978775 TI - Diurnal variation in egg excretion by Heterakis gallinarum. AB - Periodicity in nematode egg excretion may be of evolutionary origin as it can favour dispersal of the eggs in the environment. We investigated whether egg excretion by Heterakis gallinarum shows a repeatable pattern of periodicity. The faecal egg concentration and total number of eggs excreted within 4-h intervals were significantly affected by the sampling time within 1 day, but remained unaffected by the sampling day or interaction effects. By contrast, the total number of eggs excreted within 24 h did not differ among the 4 days of the study, collectively indicating repeatable egg excretion patterns. Both host feces and parasite egg excretion increased from night to late afternoon, followed by a decrease in the evening, resulting in higher egg excretion during daytime than the dark period. Feces excretion and worm fecundity showed overlapping diurnal rhythms with similarly timed phases, suggesting the existence of synchronicity between the host feces and nematode egg excretion patterns. We conclude that egg excretion by H. gallinarum is synchronized with host feces excretion and is higher during the daytime than during the dark period. This overlaps with the maximum activity of the day-active host and allows a maximal dispersal of the eggs in the environment. PMID- 29978776 TI - Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals: collateral vessel disease burden and unifocalisation strategies. AB - : IntroductionThe optimal approach to unifocalisation in pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries (pulmonary artery/ventricular septal defect/major aortopulmonary collaterals) remains controversial. Moreover, the impact of collateral vessel disease burden on surgical decision-making and late outcomes remains poorly defined. We investigated our centre's experience in the surgical management of pulmonary artery/ventricular septal defect/major aortopulmonary collaterals.Materials and methodsBetween 1996 and 2015, 84 consecutive patients with pulmonary artery/ventricular septal defect/major aortopulmonary collaterals underwent unifocalisation. In all, 41 patients received single-stage unifocalisation (Group 1) and 43 patients underwent multi-stage repair (Group 2). Preoperative collateral vessel anatomy, branch pulmonary artery reinterventions, ventricular septal defect status, and late right ventricle/left ventricle pressure ratio were evaluated. RESULTS: Median follow-up was 4.8 compared with 5.7 years for Groups 1 and 2, respectively, p = 0.65. Median number of major aortopulmonary collaterals/patient was 3, ranging from 1 to 8, in Group 1 compared with 4, ranging from 1 to 8, in Group 2, p = 0.09. Group 2 had a higher number of lobar/segmental stenoses within collateral vessels (p = 0.02). Group 1 had fewer catheter-based branch pulmonary artery reinterventions, with 5 (inter-quartile range from 1 to 7) per patient, compared with 9 (inter-quartile range from 4 to 14) in Group 2, p = 0.009. Among patients who achieved ventricular septal defect closure, median right ventricle/left ventricle pressure was 0.48 in Group 1 compared with 0.78 in Group 2, p = 0.03. Overall mortality was 6 (17%) in Group 1 compared with 9 (21%) in Group 2.DiscussionSingle-stage unifocalisation is a promising repair strategy in select patients, achieving low rates of reintervention for branch pulmonary artery restenosis and excellent mid-term haemodynamic outcomes. However, specific anatomic substrates of pulmonary artery/ventricular septal defect/major aortopulmonary collaterals may be better suited to multi-stage repair. Preoperative evaluation of collateral vessel calibre and function may help inform more patient-specific surgical management. PMID- 29978777 TI - The Abernethy malformation with inferior caval vein hypoplasia: a tailored technique for transcatheter closure and an insight into embryological perspective. AB - Abernethy malformations manifest as hepatopulmonary syndrome, pulmonary vasculopathy, or encephalopathy. A novel intervention in a child with portosystemic shunt and inferior caval vein hypoplasia led to complete normalisation of hypoxia and relief of obstruction in the inferior caval vein. Embryological explanations of venous anomalies may indicate that inferior caval vein anomalies are frequent but under-recognised in patients with Abernethy malformation. PMID- 29978778 TI - Eyes Wide Open, Blinders Attached. PMID- 29978779 TI - On the Move in Cattle Country: Tracking Nomadic Pastoralists in Southwest Ethiopia. PMID- 29978780 TI - Measles in Returning Adult Travelers. PMID- 29978781 TI - An Unusual Case of a Young Woman with a Postnasal Space Mass. PMID- 29978782 TI - Chikungunya in U.S. Travelers: A Double Challenge. PMID- 29978783 TI - [Dynamical Analysis of the Inhibitory Effect of Aspirin and Clopidogrel on Platelet Adhesion and Aggregation for Healthy People under Physiological Flow Condition by Microfluidic Chip Technology]. AB - Objective To explore the inhibitory effect of aspirin and clopidogrel on platelet adhesion and aggregation behaviors under the physiological flow condition using microfluidic chip technology for health volunteers. Methods Peripheral venous blood samples collected from twelve randomly recruited health volunteers were treated with 20 MUmol/L acetylsalicylic acid,50 MUmol/L 2-methlthioadenosine-5' monophosphate triethylammonium salt,and their combination,respectively,with untreated blood samples being control group. The blood samples were flowed through a microchannel modified with type I collagen protein at a physiological relevant shear rate of 1000 s-1 for 300 s,while the fluorescent images of platelet aggregations were dynamic captured using a microscope. Based on the images,the platelet coverage rates were calculated and used as quantitative parameters for evaluating platelet adhesion and aggregation behaviors. Results Under a flow condition of 1000 s-1 shear rate,an expected in vivo-like platelet adhesion and aggregation behaviors were observed at the surfaces of collagen proteins for control blood samples. Aspirin alone or clopidogrel alone suppressed platelet adhesion and aggregation at the later period of flow(200-300 s),while the combination of aspirin and clopidogrel reduced the adhesion numbers of platelets at the earlier stage of flow(<=150 s) and compromised the stability of platelet aggregation at the later period of flow(200-300 s). The combination showed synergistic effect in inhibiting platelet aggregation. Furthermore,such inhibitory effect was heterogeneous among 12 volunteers. Conclusion This simple microfluidic technology can offer a new technical platform for analyzing the inhibitory effect of antiplatelet drugs. PMID- 29978784 TI - [Methyltransferase-like 3 Promotes the Proliferation of Acute Myeloid Leukemia Cells by Regulating N6-methyladenosine Levels of MYC]. AB - Objective To investigate the role of methyltransferase-like 3(METTL3) in the proliferation of acute myeloid leukemia (AML) cells and its mechanism. Methods METTL3 expression in AML patients was analyzed in Gene Expression Omnibus data files. METTL3 expression was inhibited by lentivirus-mediated gene transduction in MOLM13 cells,after which cell proliferation was analyzed by cell counting kit 8,N6-methyladenosine (m6A) levels of total mRNA was analyzed by ELISA,specific m6A on MYC was analyzed by gene-specific m6A RNA immunoprecipitation,and MYC expression was analyzed by RT-qPCR and Western blot analysis. Results METTL3 level was slightly increased in AML-M5 patients,and its expression was significantly higher in immature cells than in mature monocytes (t=4.504,P=0.0098). METTL3 knock-down significantly suppressed cell proliferation (P<0.001),reduced m6A level of total mRNA (t=3.606,P=0.042) and specific m6A level on MYC mRNA (P<0.01),and suppressed MYC expression (P<0.01). Conclusion METTL3 acts as an oncogene in MOLM13 cells by upregulating MYC expression. PMID- 29978785 TI - [Effects of Gui Zhi Fu Ling Jiao Nang on Hemorheology and Expression of Phenotypic Proteins in Uterine Smooth Muscle Cells in Rats with An Intrauterine Device]. AB - Objective To observe the effect of Gui Zhi Fu Ling Jiao Nang (GZFLJN) on the expressions of alpha smooth muscle actin (alpha-SMA) and proliferating cell nuclear antigen (PCNA) in uterine vascular smooth muscle cells (VSMC) of rat models with an intrauterine device (IUD) and to determine the thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels in peripheral blood. Methods Female Wistar rats were randomly divided into four groups:normal group (n=16,with normal breed without treatment),model group (n=18,drenching 0.9% normal saline after modeling of IUD),GZFLJN group (n=18),and aminocaproic acid tablets group (n=17). Immunohistochemical SP method was used to detect the expressions of alpha-SMA and PCNA in uterine VSMC.ELISA was served to detect the levels of TXB2 and 6-keto-PGF1alpha in peripheral blood. Results The positive rate of alpha-SMA were (50.89+/-9.41)%,(26.93+/-6.80)%,(48.92+/-6.80)%,and (34.63+/-7.26)%,respectively,in normal group,model group,GZFLJN group,and aminocaproic acid tablets group;obviously,it was significantly higher in normal group (t=14.43,P=0.00) and GZFLJN group (t=11.37,P=0.00) than that in model group and it was significantly lower in aminocaproic acid tablets group than in normal group (t=9.96,P=0.00) and GZFLJN group (t=8.23,P=0.00). The positive rate of PCNA were (25.66+/-7.24)%,(61.26+/-9.98)%,(28.36+/-9.17)%,and (50.23+/ 8.71)%,respectively,in these four groups;obviously,it was significantly lower in the normal group (t=20.86,P=0.00) and GZFLJN group (t=19.12,P=0.00) than in model group and it was significantly higher in aminocaproic acid tablets group than in normal group (t=17.82,P=0.00) and GZFLJN group (t=16.05,P=0.00). Serum TXB2 level in these four groups were (445.86+/-24.43),(508.78+/-12.42),(448.11+/-9.63),and (498.11+/-13.63)ng/L;obviously,it was significantly higher in model group than in normal group (t=16.55,P=0.00) and aminocaproic acid tablets group (t= 4.12,P=0.00) and it was significantly lower in GZFLJN group than in model group (t=-15.23,P=0.00) and aminocaproic acid tablets group (t=-12.08,P=0.00). Serum 6 keto-PGF1alpha level in these four groups were (23.17+/-1.93),(18.09+/ 0.93),(22.70+/-1.61),and (20.70+/-1.41)ng/L,respectively;obviously,it was significantly lower in model group than in normal group (t=-13.98,P=0.00) and aminocaproic acid tablets group (t=5.26,P=0.00) and it was significantly higher in GZFLJN group than in model group (t=11.43,P=0.00) and aminocaproic acid tablets group (t=8.76,P=0.00). Conclusion GZFLJN can regulate the expressions of alpha-SMA and PCNA of VSMC in the endometrium of IUD rats and the concentrations of TXB2 and 6-keto-PGF1alpha in the serum. PMID- 29978786 TI - [Analysis of Related Factors in Elderly Patients with Strangulated Small Bowel Obstruction]. AB - Objective To investigate the surgery-related factors of strangulated small bowel obstruction in the elderly patients. Methods The clinical data of 261 elderly patients with acute small bowel obstruction treated between July 2010 and September 2016 were analyzed retrospectively. Differences of clinical data,laboratory Results ,and CT findings were compared between the elderly strangulation group(ESt group,n=139)and the elderly simple group (ESi group,n=122). The surgery-related factors of strangulated small bowel obstruction in the elderly were analyzed by univariate and multivariate Logistic regression analysis. Results The ESt group and the ESi group showed significant differences in factors including muscle guarding (chi2=102.331,P=0.000),American Society of Anesthesiologists(ASA) score>=3 (chi2=69.748,P=0.000),leukocyte count (t=7.453,P=0.000),C-reactive protein (t=2.128,P=0.034),segmental mesenteric fluid (chi2=78.655,P=0.000),thick-walled small bowel (chi2=100.806,P=0.000),intestinal wall of hyperattenuation (chi2=69.068,P=0.000),ascites (chi2=89.299,P=0.000),mesenteric fat stranding (chi2=80.255,P=0.000),bird's beak sign (chi2=84.451,P=0.000),and stranding sign (chi2=98.635,P=0.000). Univariate regression analysis indicated the above 11 factors were the surgery-related factors in elderly patients with strangulated small bowel obstruction. Multivariate Logistic regression analysis showed that the surgery-related factors included segmental mesenteric fluid (OR=3.576,95%CI:1.043-12.261,P=0.043),ASA score>=3 (OR=3.463,95%CI:1.149-10.441,P=0.027),muscle guarding (OR=3.288,95%CI:1.010-10.707,P=0.048),thick-walled small bowel (OR=3.046,95%CI:1.074-8.638,P=0.036),and increased leukocyte count (OR=1.307,95%CI:1.170-1.458,P=0.000). Conclusion Muscle guarding,ASA score>=3,segmental mesenteric fluid,thick-walled small bowel,and increased leukocyte count are the surgery-related factors of strangulated small bowel obstruction in the elderly patients. PMID- 29978787 TI - [Clinical Features and Outcomes of Paraduodenal Pancreatitis]. AB - Objective To summarize the clinical features and outcomes of paraduodenal pancreatitis (PP). Methods Five clinically or pathologically diagnosed PP patients in Peking Union Medical College Hospital and 31 other PP cases reported in Chinese literature since 1988 were retrospectively analysed. Results Most PP patients were young or middle-aged males with a history of alcohol abuse. The clinical symptoms included upper abdominal pain,vomiting,weight loss,and fluctuating jaundice. Serum pancreatic enzymes were normal or elevated. Radiological features in most cases included thickening of the duodenal wall and duodenal stenosis (88.9%,32/36),cysts in the duodenal wall and groove area (47.2%,17/36),dilated bile duct (36.1%,13/36),and dilated pancreatic duct (16.7%,6/36). The main pathological finding was chronic pancreatitis,which could be accompanied by local acute inflammation,which was limited in the groove duodenal area in most cases. The disease can be well controlled by conservative treatment,although surgery was needed in a small number of cases. Conclusion sPP typically occurs in young or middle-aged males. Radiological examination is valuable for diagnosis. Conservative treatment is the mainstream treatment in most patients. PMID- 29978788 TI - [Association between Severity of Scrub Typhus and Serum Procalcitonin Level]. AB - Objective To explore the association between the severity of scrub typhus (ST) and the serum procalcitonin (PCT) level. Methods The clinical data of 58 ST patients who were treated in the First Affiliated Hospital of Xiamen University and confirmed by Xiamen Municipal Center for Disease Prevention and Control (CDC) from January 2016 to October 2017,were retrospectively analyzed. According to clinical manifestations and related laboratory tests,these patients were divided into four grades:I,II,III,and IV. These four grade groups were compared in terms of age,interval from symptom onset to hospital presentation,hospitalization days,and serum PCT level. Results These 58 patients were divided into four grade groups:grade I group (n=17),grade II group (n=17),grade III group (n=11),and grade IV group (n=13). No significant difference was found among these four groups in terms of age (F=0.618,P=0.606),interval from symptom onset to hospital presentation (F=1.744,P=0.169),and hospitalization days (F=0.398,P=0.755).However,the median serum PCT level in the grade IV patients[2.60(1.33,61.08)ng/ml] was significantly higher than those in grade I[0.24(0.10,0.33)ng/ml;Z=-4.63,P=0.000], grade II[0.29(0.21,0.51)ng/ml;Z= 4.63,P=0.000], and grade III[1.33(0.89,2.41)ng/ml;Z=-2.09,P=0.040].The median serum PCT level in the grade III patients was also significantly higher than grade I (Z=-4.16,P=0.000)and grade II(Z=-3.83,P=0.000).There was no significant difference between the grade I patients and grade II patients(Z= 1.37,P=0.170).There was significantly positive correlation between PCT level and the severity of ST (r=0.804,P=0.000).Conclusion There is positive correlation between serum PCT level and the severity of ST,and serum PCT level may be a biomarker in assessing the severity of ST. PMID- 29978789 TI - [Association of Serum Uric Acid Level with Coronary Heart Disease in Men and Women]. AB - Objective To explore the relationship between serum uric acid (SUA) level and coronary heart disease(CHD) in male and female patients. Methods A total of 760 hospitalized patients undergoing coronary angiography in our department from June 2013 to June 2017 were enrolled. Gensini score was calculated according to the result of coronary angiography,and SUA was tested.Patients were divided according to SUA quartiles. The relationship between SUA level and the prevalence of CHD in male and female patients was analyzed. Results Among females,there was significant difference in SUA level between patients with and without CHD (t=4.415,P=0.000). Univariate logistic regression analysis showed that SUA level was independently associated with CHD (OR=1.32,95%CI:1.12-1.58,P=0.002). The prevalence of CHD was 31.2%,52.6%,47.4%,and 59.7%,respectively,in four quartile groups (chi2=13.652,P=0.003);in addition,female patients displayed significantly higher prevalence of CHD in the quartile 2 (P=0.007),3(P=0.038),and 4(P=0.000) groups than in quartile 1 group. Among female patients with CHD,there were significant differences in number of target vessels (Z=4.627,P=0.008),number of lesion vessels (chi2=18.522,P=0.005),and Gensini score (Z=3.683,P=0.029) in four groups. The Gensini scores of coronary artery were significantly higher in the quartile 4 group than in quartile 1 (P=0.012) and 2 (P=0.014) groups. Multiple linear regression analysis showed that there was a dose-response relationship between SUA level and Gensini score (B=1.105,SE=0.365,P=0.003). Among males,however,there was no significant difference in SUA level between patients with and without CHD(t=1.271,P=0.205). The prevalence of CHD in four quartile groups was 77.9%,69.0%,61.7%,and 79.6%,respectively,showing no significant difference(chi2=4.514,P=0.211). Conclusion sSUA is an independent risk fact for female CHD patients. High SUA level is correlated with severity of CHD only in women. PMID- 29978790 TI - [Effectiveness of Extracorporeal Shockwave Therapy in Treating Superior Lateral Brachial Cutaneous Nerve Compression Syndrome]. AB - Objective To evaluate the effectiveness of radial extracorporeal shockwave therapy(rESWT) for the treatment of superior lateral brachial cutaneous nerve(SLBCN) compression syndrome.Methods A total of 40 patients with SLBCN compression syndrome who were treated in our department from March 2013 to October 2015 were equally randomized into two groups according to random number table:rESWT group(treated with rESWT for 1 cycle) and control group(treated with local hormone injection for 1 cycle). Visual analogue scale(VAS) and Constant Murley scale(CMS) were applied to evaluate the shoulder joint function before treatment and 1 month and 1 year after treatment. Results The average CMS scores were(66.7+/-0.9) and(65.7+/-1.1)scores in rESWT group and control group,respectively,before treatment(t=0.67,P=0.510) and were(86.9+/-1.0) and(86.4+/-1.1)scores one month after treatment(t=0.35,P=0.730);it increased to(89.7+/-0.7) scores in rESWT group one year later,which was significantly higher than that in control group[(85.3+/-0.8)scores](t=3.56,P=0.002). The improvement rate was 95% in rESWT group and only 75% in control group. Before treatment,the median VAS score in rESWT group and control group were 5.00(5.00,6.00) and 5.00(4.00,5.75)scores(u=1.13,P=0.29);one month after treatment,the median VAS score in these two groups were 2(1.00,2.75) and 2.00(1.00,2.00)scores(u=0.04,P=0.85);one year later,it was 1.00(0.00,1.00) scores in rESWT group,significantly lower than that in [2.00(1.00,2.00)scores] control group(u=5.09,P=0.02). Conclusion Compared with local hormone injection,rESWT can remarkably alleviate pain and restore shoulder joint function in patients with SLBCN compression syndrome after one year of treatment. PMID- 29978791 TI - [Efficacy of Lactated Ringer's versus Normal Saline in Treating Patients with Septic Shock]. AB - Objective To compare the clinical efficacy of lactated Ringer's (LR) and normal saline (NS) in treating patients with septic shock. Methods The clinical data of 198 patients with septic shock who received fluid resuscitation in the Intensive Care Unit of Quzhou People's Hospital from January 2014 to January 2016 were retrospectively analyzed. These patients were divided into NS group (n=100) and LR group (n=98) according to fluids used. The amounts of trial fluid,other liquids,and blood products and the average total fluid volume were recorded. The oxygenation index (PO2/FiO2),mean artery pressure (MAP),central venous pressure (CVP),and B-type natriuretic peptide (BNP) before and after treatment as well as the early goal-directed therapy (EGDT) 8 h (EGDT8),EGDT 24 h recovery rate,EGDT recovery time,28-day mortality rate were compared. Other secondary outcomes including bleeding,allergic reaction,acute kidney injury (AKI),venous blood filtration (RRT) rate,hyperkalemia,and ICU stay were also recorded. The 28-day survival rate was calculated using the Kaplan-Maier method,and the difference in survival rate was compared by log-rank test. Results The two groups showed no significant difference in gender,age,body weight,source of admission to ICU,procalcitonin level,source of sepsis,Acute Physiology and Chronic Health Evaluation II score,number of AKI patients,amount of white blood cells,and C reactive protein level (all P>0.05). The amount of blood products on the first day [(782+/-357)ml vs.(606+/-273)ml;t=2.044,P=0.046] and the average total amount of liquid on the first three days [(5470+/-1078)ml vs.(5092+/-929) ml;t=2.640,P=0.009] were significantly higher in NS group than in LR group. The amount of trial fluid and the volumes of other fluids were not significantly different (both P>0.05). The PO2/FiO2,MAP,CVP,and BNP levels significantly increased after treatment in both groups (all P<0.05);however,they were not significantly different between LR group and NS group at different time points before and after treatment (all P>0.05). The incidences of hyperlactacidemia (86.0% vs.71.4%,OR:2.457,95%CI:1.202-5.023,P=0.012) and hyperchloremia (25.0% vs.13.2%,OR:2.179,95%CI:1.041-4.562,P=0.036) were significantly higher in NS group than in LR group. These two groups showed no significant difference in EGDT8,24 h recovery rate,EGDT recovery time,28-day mortality rate,AKI,RRT rate,hyperkalemia,and ICU stay (all P>0.05). Kaplan-Meier survival analysis showed that the 28-day survival rate was not significantly different (chi2 log rank=0.012,P=0.911). Conclusion When liquid resuscitation is applied in patients with septic shock,the use of LR can lower blood transfusion requirement on the first day and total liquid dosage on the first three days (compared with NR), along with lower incidences of hyperlactacidemia and hyperchloremia,although there was no significant difference in the 28-day mortality rate. PMID- 29978792 TI - [Influence of Nasal Disinfection on Nasal Bacterial Colonization through the Transsphenoidal Approach]. AB - Objective To explore the influence of the iodine disinfection on nasal bacterial colonization through the transsphenoidal approach. Methods Totally 133 pituitary adenoma patients who underwent transsphenoidal surgery in our department from January to August 2017 were enrolled in this study. Before disinfection,pharyngeal swabs of inferior turbinate root secretions were taken for bacterial culture. After iodine disinfection,pharyngeal swabs were taken again at the same site. Changes in the nasal bacterial spectrum before and after disinfection were compared. Patients were followed up for three months after the surgery,during which any intracranial infection/bacteraemia was recorded,and its correlation with nasal bacteria colonization was analyzed. Results Nasal bacterial colonization was detected in 45 (33.8%) of 133 patients before iodine disinfection and in only 6 cases (4.5%) after iodine disinfection (chi2=34.5,P=0.000). Thus,iodine disinfection eliminated 86.7%(39/45) of the colonized bacteria. The most common nasal bacterium was Staphylococcus aureus (24.4%,11/45),followed by Klebsiella pneumoniae (24.4%,11/45),and Staphylococcus epidermidis (13.3%,6/45). One patient had high fever and chills 2 days after surgery,but blood culture and cerebrospinal fluid culture showed negative Results . After the administration of third-generation cephalosporins,the symptoms disappeared after two days. Conclusion sThere are colonized bacteria in nasal cavity. Iodine disinfection of nasal cavity can effectively clear most of the nasal bacteria. The possibility of intracranial infection/bacteremia after transsphenoidal approach is low. PMID- 29978793 TI - [Application of Combined Special Staining in the Observation of Vascular Pathology]. AB - Objective To evaluate the value of combined special staining technique in observing pathological changes in blood vessels. Methods Totally 999 vascular specimen were harvested from patients with complete medical records,clear diagnosis,and age>=18 years in the Pathology Department of Beijing Anzhen Hospital from January 2014 to September 2017.All specimen were stained with HE,Verhoef-Van Gieson,AB/PAS,and Masson. Then,the result of HE staining was compared with that of the combined special staining (Verhoef-Van Gieson,AB/PAS,and Masson).Results HE staining only showed a small amount of elastic fiber fracture. In contrast,the combined special staining clearly showed the pathological changes including fractures,decreased elastic fibers,and aggregation of extracellular mucous matrix. Diseases in these 999 patients included aneurysm of sinus of valsalva (SVA) (n=3),aortic root aneurysm (ARA) (n=177),thoracic aortic aneurysm (TAA) (n=78),abdominal aortic aneurysm (AAA) (n=17),total thoracoabdominal aortic aneurysm (tTAAA) (n=32),and aortic dissection (AD) (n=692). The median scores of combined special staining of SVA (Z=3.857,P=0.040),ARA (Z=14.307,P=0.000),TAA (Z=26.939,P=0.000),AAA (Z=22.412,P=0.000),tTAAA (Z=15.926,P=0.000),and AD (Z=39.213,P=0.000) were significantly higher than that of HE staining. Conclusion The combined Verhoeff Van Gieson,AB/PAS,and Masson special staining is an effective technique for observing pathological changes of elastic fibers and mucus in blood vessels. PMID- 29978794 TI - [Difference in Perioperative Management for Patients with and without Autism Spectrum Disorders undergoing General Anesthesia]. AB - Objective To compare the difference in perioperative management for patients with or without autism spectrum disorders(ASD) undergoing general anesthesia. Methods We retrospectively analyzed the clinical data of 10 ASD patients(case group) and 10 non-ASD patients(control group) undergoing general anesthesia from January 2013 to February 2018. Both groups were matched by age,gender,and surgical procedures. The induction mode,premedication patterns,narcotic drugs,time to wake up,post-anesthesia care unit(PACU) stay,and perioperative vital signs were compared. Results The main induction mode was combined intravenous and inhaled anesthesia(CIIA) in case group(6/10) and total intravenous anesthesia(TIVA) in control group(10/10)(chi2=8.571,P=0.003). The wake-up time are significantly longer in case group[(36.0+/-10.7) min] than in control group [(22.7+/-6.6)min] (t=18.000,P=0.005). Case group [(12.7+/-6.7)min] needed more time to obtain first vital sign than control group[(6.7+/-3.3)min](t=23.000,P=0.038). There were also significant differences in first systolic blood pressure (SBP)(t=15.500,P=0.007),preinductive SBP(t=24.000,P=0.048),and heart rate(t=22.000,P=0.033) between two groups. Conclusion Compared with non-ASD patients,ASD patients tend to use CIIA as the induction mode,have longer wake up time and later vital sign record,and are more likely to have peri-inductive vital signs. PMID- 29978795 TI - [Adding Ondansetron in Morphine Intravenous Analgesia Pump for Prevention of Postoperative Nausea and Vomiting in Women]. AB - Objective To evaluate the application of adding ondansetron in morphine intravenous analgesia pump for prevention of postoperative nausea and vomiting(PONV)in women. Methods Data of surgical female inpatients who received general anesthesia and postoperative intravenous analgesia with morphine in our center from January 1st,2013 to December 31st,2014 were retrospectively analyzed. Based on whether ondansetron was added,patients were divided into the observation group(n=834) and the control group(n=856). Outcome variables including morphine consumption,visual analogue scale(VAS) score,nausea score,and total times of vomiting within 48 hours after surgery were collected and compared. Results Age(t=0.432,P=0.665),morphine consumption during the first post-operative day(t=0.599,P=0.548) and during the second post-operative day(t=0.236,P=0.813),maximum VAS score of postoperative pain during movement during the first post-operative day [3(2,4) vs. 3(2,5);Z=1.850,P=0.064] and at rest during the second post-operative day [0(0,1) vs. 0(0,1);Z=1.511,P=0.131] were not significantly different between two groups. While the maximum VAS score of postoperative pain at rest during the first post-operative day [0(0,2) vs.0(0,2);Z=2.435,P=0.015] and during movement during the second post-operative day [3(1,3)vs.3(2,4);Z=3.445,P=0.001] were significantly different between two groups. The maximum score of postoperative nausea(chi2=9.810,P=0.020) and cumulative frequency of postoperative vomiting(Z=3.726,P=0.002)in the observation group were significantly lower than those in the control group during the first post-operative day;however,there was no significant difference during the second post-operative day(chi2=5.017,P=0.170;Z=0.000,P=1.000). Logistic regression analysis showed that adding ondansetron in morphine intravenous analgesia pump was an independent influencing factor of reduced postoperative nausea. The probability of nausea during the first post-operative day was 0.781 time(P=0.015)of that in the control group and 0.736 time(P=0.030)during the second post-operative day. Conclusion Adding ondansetron in morphine intravenous analgesia pump may reduce PONV in women. PMID- 29978796 TI - [Characteristics of High-resolution Ultrasound in the Assessment of Microcalcification of Papillary Thyroid Carcinoma]. AB - Objective To investigate the role of 17-MHz high-frequency linear array probe in detecting the microcalcification of papillary thyroid carcinoma (PTC) and its pathological basis. Methods The clinical data of 75 patients with PTC diagnosed by ultrasonography and pathology in China-Japan Friendship Hospital from January 2016 to January 2017 were analyzed. The detection rate of microcalcification was compared between 17-MHz high-frequency ultrasound and conventional ultrasound,and the imaging findings and pathological Results were analyzed. Results Among 93 thyroid nodules,the detection rate of PTC microcalcification by 17-MHz ultrasound was 74.2% (69/93),which was significantly higher than that of conventional ultrasound (59.1%,55/93) (chi2=4.742,P=0.029). The diagnostic sensitivity,specificity,accuracy,positive predictive value,and negative predictive value of the conventional ultrasound and the 17-MHz ultrasound were 73.6% and 98.1%,60.0% and 57.5%,67.7% and 80.6%,70.9% and 75.4%,and 63.1% and 95.8%,respectively. Pathology confirmed the presence of microcalcification at 53 nodules,among which psammoma bodies were found in 10 nodules;in addition,all the psammoma bodies were located in the cell mass,whereas irregular calcium deposits were mainly in proliferated fibrous tissues. Conclusion sThe 17-MHz high frequency ultrasound can increase the detection rate of microcalcification in thyroid nodules. The ultrasonic manifestations of microcalcification do not completely correspond to the psammoma bodies found in pathology;rather,they may represent the irregular calcium deposits on fibrous tissues. PMID- 29978797 TI - [Palliative Care in Undergraduate Medical Education:Experiences in Developed Countries and Regions]. AB - Palliative care focuses on improving the quality of life for patients and families facing life-threatening illness. Since its introduction in China,palliative care has developed rapidly with greater numbers of elderly adults and increasing chronic disease. However,palliative care education lags behind somehow,especially for undergraduate medical students. This article summarizes the history and status quo of palliative care education for undergraduate medical students in countries and regions including the United Kindom,the United States,Japan,and Taiwan Province,with an attempt to further promote the palliative care education for medical students in mainland China. PMID- 29978798 TI - [Needs of Continuing Education on Hospice and Palliative Care in China:A Questionnaire-based Survey]. AB - Objective To analyzed the current situations and needs of the continuing education on hospice and palliative care (HPC) in China based on the response from trainees in the 2016 National Hospice and Palliative Medicine Training Program. Methods A questionnaire-based survey was performed among 141 trainees who attended the program held by Peking Union Medical College Hospital in 2016. The questionnaire items included the awareness and knowledge of HPC,learning Objective s,learning gains,and future plans. Results The trainees came from 19 provinces and municipalities. Their professions included doctors (66.0%),nurses (17.0%),physical therapists (1.4%),psychologists (5.0%),social workers (2.1%),volunteers (6.4%) and hospital managers (2.1%). Doctors'disciplines included geriatrics (56.0%),medical oncology (11.8%),and others (32.2%). Among these 141 participants,111 (78.7%) had not attended any HPC course before,134 (95.0%) were aware of HPC,and 131 (92.9%) needed help from others when providing care for terminally-ill patients. The median score for symptom control and communication skills among 141 trainees were 3.0(2.0,4.0) points and 1.0(0.0,2.0) points,respectively. The average score of the final examination involving case analysis and medical knowledge of symptom control was (59.1+/-18.0)scores (centesimal system). Finally,136 trainees (96.5%) were willing to receive further training on HPC. Conclusion It is important to do more HPC education and training among medical staff,so as to strengthen their knowledge and capability in symptom control,communication,and evaluation of death quality. PMID- 29978799 TI - [Survey on the Accompanying Experience of Palliative Hospice Volunteers in Peking Union Medical College Hospital]. AB - Objective To investigate the experience of accompanying dying patients among hospice and palliative care (HPC) volunteers. Methods By applying the methodologies of phenomenological research and participatory observation,the experiences,awareness,and expectations of accompanying dying patients of 10 volunteers in our center were investigated. Results The experiences of 10 volunteers in HPC could be summarized into three subjects:volunteer personal cognition,volunteer demand and family support,and volunteers' expectations of hospital and society. These could be further divided into 6 sub-themes regarding the personal cognition and feelings of the volunteers:unknown,hostile,suspicious,helpless,role positioning,and passing the message of illness. Three sub-themes associated with individual needs and family support were:self motivation,family ties,and family support. Five sub-themes concerning volunteers' expectations for hospitals and society were:confusion of concept,lack of palliative idea,reach-out service,humanistic care,and adoption of palliative concept. Conclusion sHPC team should widely promote the concept of HPC,seeking supports from individuals,families,and the whole society. A strong volunteer team with robust volunteer service mode and standardized admittance,training,and supervision systems are needed. In particular,strengthened supervision and training of HPC volunteers and standard volunteer system are conducive to the improvement of HPC services in hospitals. PMID- 29978800 TI - [Practice of Palliative Care:Experience of a Patient with Advanced Retroperitoneal Sarcoma at the End of Life]. AB - According to the World Health Organization,palliative care is an approach that prevents and alleviates the pain of patients with life-threatening illness and improves the quality of life of patients and their families through early identification,assessment and treatment of pain and other physical,psychosocial and spiritual problems. It is the active holistic care accomplished by multidisciplinary team. This article describes the practice of the palliative care in a patient with advanced retroperitoneal sarcoma. PMID- 29978801 TI - [Application of Internet-based Interventions in Weight Management]. AB - Overweight and obesity are associated with a range of chronic diseases and have become a major global health concern. With the progress of Internet technology,electronic health care has emerged,providing new tools and Methods for weight management. Internet-based technology has shown certain effectiveness in facilitating interventions on overweight,obesity,and their associated diseases. This article reviews the recent advances in these interventions and evaluates their effectiveness,efficiency,and feasibility. PMID- 29978802 TI - [Research Advances in CIMAvax-EGF for Non-small-cell Lung Cancer]. AB - The past few years have witnessed rapid advances in the immunotherapies for non small-cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic vaccine against lung cancer independently developed by Cuba. It can exert its anti-tumor effect by forming epidermal growth factor (EGF) antibodies to block the binding of EGF to EGF receptor. So far stage both phases II and III trials have proved its effectiveness and long-term safety,and phases III and IV trials are underway. A deeper understanding of the role of CIMAvax-EGF in NSCLC will accelerate the application of immunotherapy. This article summarizes the recent advances of CIMAvax-EGF R&D and its application in treating NSCLC. PMID- 29978803 TI - [Biomechanics and Clinical Applications of Crosslinks]. AB - Crosslinks belong to the pedicle screw internal fixation system. However,whether they can provide stable internal fixation remains controversial. In this article we review the origin/development,design/types,and clinical applications of crosslinks and evaluate the biomechanical function of crosslinks in the whole internal fixation system. PMID- 29978804 TI - [Role of Paradoxical Hypersecretion of Glucagon in the Pathogenesis of Type 2 Diabetes Mellitus]. AB - Insulin resistance and insulin deficiency have long been believed to be the two main causes of type 2 diabetes mellitus (T2DM). However,recent studies have shown that paradoxical hypersecretion of glucagon may also contribute the pathogenesis of T2DM. This article reviews the role of paradoxical hypersecretion of glucagon in the pathogenesis of T2DM and the recent advances in relevant treatment options. PMID- 29978806 TI - [Lynch Syndrome:Report of One Case and Literature Review]. AB - This article reports a female type II Lynch syndrome patient who suffered from colon cancer and endometrium carcinoma consecutively. We also briefly elucidate the pathogenesis,clinicopathological features,screening,and management of Lynch syndrome. Regular screening and early diagnosis and treatment may help to reduce the incidences and mortality rates of tumors associated with Lynch syndrome. PMID- 29978805 TI - [Unusual Isolated Sellar Spindle Cell Carcinoma:Report of One Case]. AB - Sellar malignant tumors are uncommon and usually reported as metastatic diseases from breast or lung cancers. Spindle cell carcinoma (SCC) is a rare malignancy and has been found in breast,oral cavity,lungs,kidneys,and hepatobiliary pancreatic system but not in sellar region. We report here the first case of isolated sellar SCC with aggressive features in Peking Union Medical College Hospital. This patient was referred to our hospital on September 9,2015 and discharged on October 16,2015. We described the clinical manifestations,imaging findings,and pathological features of this rare disease. PMID- 29978807 TI - [Epidermoid Cyst in the Fourth Ventricle:Report of One Case]. AB - We reported a case with epidermoid cyst (EC) in the fourth ventricle. The insinuation and scalloping growth pattern were the distinctive imaging characteristics of EC in the fourth ventricle on magnetic resonance imaging. The accurate identification of the punctate enhancement of vessels around the lesion may be helpful for its differential diagnosis from hemangioblastoma. PMID- 29978808 TI - Impact of extracorporeal cardiopulmonary resuscitation on outcomes of elderly patients who had out-of-hospital cardiac arrests: a single-centre retrospective analysis. AB - OBJECTIVES: Little is known about the effectiveness of extracorporeal cardiopulmonary resuscitation (ECPR) for elderly patients who had out-of-hospital cardiac arrest (OHCA). The aim of this study was to examine the impact of age on outcomes among patients who had OHCA treated with ECPR. DESIGN: Single-centre retrospective cohort study. SETTING: A critical care centre that covers a population of approximately 1 million residents. PARTICIPANTS: Patients who had consecutive OHCA aged >=18 years who underwent ECPR from 2005 to 2013. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were 1 month neurologically favourable outcomes and survival. To determine the association between advanced age and each outcome, we fitted multivariable logistic regression models using: (1) age as a continuous variable and (2) age as a categorical variable (<50 years, 50-59 years, 60-69 years and >=70 years). RESULTS: Overall, 144 patients who had OHCA who underwent ECPR were eligible for our analyses. The proportion of neurologically favourable outcomes was 7%, while survival was 19% in patients who had OHCA. After the adjustment for potential confounders, while advanced age was non-significantly associated with neurologically favourable outcomes (adjusted OR 0.96 (95% CI 0.91 to 1.01), p=0.08), the association between advanced age and the poor survival rate was significant (adjusted OR 0.96 (95% CI 0.93 to 0.99), p=0.04). Additionally, compared with age <50 years, age >=70 years was non significantly associated with poor neurological outcomes (adjusted OR 0.08 (95% CI 0.01 to 1.00), p=0.051), whereas age >=70 years was significantly associated with worse survival in the adjusted model (adjusted OR 0.14 (95% CI 0.03 to 0.80), p=0.03). CONCLUSIONS: In our analysis of consecutive OHCA data from a critical care hospital in an urban area of Japan, we found that advanced age was associated with the lower rate of 1-month survival in patients who had OHCA who underwent ECPR. Although larger studies are required to confirm these results, our findings suggest that ECPR may not be beneficial for patients who had OHCA aged >=70 years. PMID- 29978809 TI - Doctors on Strike -The Nuclear Button. PMID- 29978810 TI - Genetics of Acute Myeloid Leukemia - A Paradigm Shift. PMID- 29978811 TI - Childhood Lupus Nephritis: Achieving and Maintaining Remission Seems Critical for Renal Survival. PMID- 29978812 TI - Cytogenetic Profiles of 472 Indian Children with Acute Myeloid Leukemia. AB - OBJECTIVE: To analyze the cytogenetic abnormalities of a large cohort of consecutive pediatric Acute Myeloid Leukemia (AML) patients, treated on a uniform protocol. DESIGN: Review of case records. SETTING: Pediatric Cancer Center of tertiary care hospital between June 2003 and June 2016. PARTICIPANTS: 617 consecutive de novo pediatric AML patients were screened and 472 patients were found eligible. Eligibility criteria included non M3 patients, successful cytogenetic profile and availability of complete records. MAIN OUTCOME MEASURE: Cytogenetic profile. RESULTS: Gum-hypertropy, chloromas and rate of complete remission were significantly different between European Leukemia Network classification (ELN) cytogenetic risk groups (P<0.01). t (8;21) (141, 29.8%), loss of Y chromosome (61,12.9%) and trisomy 8 (39, 8.3%) were the most common abnormalities. Among the chromosomal gains, trisomy 8 and trisomy 21 (both P<0.01) were significantly different among the three ELN risk groups. Among the chromosome losses, monosomy 5, 7 (both P<0.01) and 9 (P=0.03), loss of X and loss of Y (both P<0.01) were statistically different amongst three cytogenetic risk groups. Event-free survival (P<0.01) and overall survival (P<0.01) were found to be significantly different among the three risk groups. CONCLUSIONS: The higher frequency of t (8; 21) and its association with chloroma in Indian pediatric patients is different from other studies around the world. PMID- 29978813 TI - Lupus Nephritis in Indian Children: Flares and Refractory Illness. AB - OBJECTIVE: To evaluate the incidence of flares and treatment resistance in children with lupus nephritis and their association with renal outcomes. METHODS: We retrospectively reviewed the case records of 34 children treated for lupus nephritis (Class II-IV) at a single center. Patients were followed for a minimum of five years to evaluate treatment response, onset of flares, and renal survival. Regression analyses were performed to identify the factors associated with treatment refractoriness, incidence of flares and renal survival. RESULTS: The incidence of flares was 0.16 episodes/person/year. Eight patients (23.5%) were refractory to treatment. The five-year renal survival was 79%. Multiple episodes of flares (P=0.028) and therapy refractoriness (P=0.003) were associated with poor renal survival. CONCLUSIONS: Prevention and aggressive management of renal flares is expected to prevent progression to end stage renal disease in lupus nephritis. PMID- 29978814 TI - Non-compliance With Neonatal Hearing Screening Follow-up in Rural Western India. AB - OBJECTIVE: The reasons of failure to follow-up for the Universal Neonatal Hearing Screening (UNHS) program were delineated. METHODS: Review of case records for data related to follow-up of neonates who underwent the UNHS between February 2012 - January 2015. RESULTS: 2534 neonates underwent primary screening with Distortion Product Oto-acoustic Emission (DPOAE). 14 (26.9%) were lost to follow up between the first and second DPOAE screenings. 275 neonates (including high risk cases) were to undergo confirmatory Brain Evoked Response Audiometry testing out of which 201 (73.4%) came for follow-up. Out of 74 who failed to follow-up (including those lost between first and second DOPAE screenings), unwillingness and non-compliance was the commonest reason. CONCLUSION: Increasing awareness and counseling of the caretaker are important interventions for ensuring good follow up in hearing screening programs. PMID- 29978815 TI - Diagnostic Accuracy of International Epidemiology Network (INCLEN) Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) in Comparison with Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5). AB - OBJECTIVE: To compare the diagnostic accuracy of INCLEN Diagnostic Tool for Autism Spectrum Disorder (INDT-ASD) against Diagnostic and Statistical Manual of Mental Disorders - 5 (DSM-5) for the diagnosis of Autism Spectrum Disorder (ASD). METHODS: 118 children aged 2-9 years with symptoms suggestive of ASD were assessed by INDT-ASD and DSM-V by trained personnel. ASD diagnosis by INDT-ASD was compared against the expert's DSM-5 diagnosis. RESULTS: INDT-ASD had a sensitivity and specificity of 100% and 75%, respectively against DSM-5 for the diagnosis of ASD; specificity for Autistic Disorder was 87%. CONCLUSION: The INDT ASD has a good sensitivity and specificity against DSM-5, and can continue to be used for the diagnosis of ASD even after the adoption of DSM-5 criteria. PMID- 29978817 TI - 'Ayushman Bharat' Program and Universal Health Coverage in India. AB - India's National Health Policy 2017 (NHP-2017) has its goal fully aligned with the concept of Universal health coverage. The Ayushman Bharat Program announced in the Union budget 2018-19 of the Government of India, aims to carry NHP-2017 proposals forward. The Ayushman Bharat Program has two initiatives/components - Health and Wellness Centers, and National Health Protection Scheme - aiming for increased accessibility, availability and affordability of primary-, secondary- and tertiary-care health services in India. Afterwards, the second component has been renamed as Pradhan Mantri Rashtriya Swasthya Suraksha Mission. The new program has received an unprecedented public, political and media attention; and is being attributed to have placed health higher on political agenda. This review article analyzes and provides critical reflections, suggestions and way forward for rapid and effective implementation of Ayushman Bharat Program. To be effective and impactful in achieving the desired health outcomes, there is a need for getting both design and implementation of Ayushman Bharat Program right, from the very beginning. If implemented fully and supplemented with additional interventions, the program can prove a potential platform to reform Indian healthcare system and to accelerate India's journey towards universal health coverage. PMID- 29978816 TI - Umbilical Cord Blood Banking: Consensus Statement of the Indian Academy of Pediatrics. AB - JUSTIFICATION: Practitioners and people need information about the therapeutic potential of umbilical cord blood stem cells and pros and cons of storing cord blood in public versus private banks. PROCESS: Indian Academy of Pediatrics conducted a consultative meeting on umbilical cord blood banking on 25th June 2016 in Pune, attended by experts in the field of hematopoietic stem cell transplantation working across India. Review of scientific literature was also performed. All expert committee members reviewed the final manuscript. OBJECTIVE: To bring out consensus guidelines for umbilical cord banking in India. RECOMMENDATIONS: Umbilical cord blood stem cell transplantation has been used to cure many malignant disorders, hematological conditions, immune deficiency disorders and inherited metabolic disorders, even when it's partially HLA mismatched. Collection procedure is safe for mother and baby in an otherwise uncomplicated delivery. Public cord blood banking should be promoted over private banking. Private cord blood banking is highly recommended when an existing family member (sibling or biological parent) is suffering from diseases approved to be cured by allogenic stem cell transplantation. Otherwise, private cord blood banking is not a 'biological insurance', and should be discouraged. At present, autologous cord stem cells cannot be used for treating diseases of genetic origin, metabolic disorders and hematological cancers. Advertisements for private banking are often misleading. Legislative measures are required to regularize the marketing strategies of cord blood banking. PMID- 29978818 TI - Flipped Classroom: A Concept for Engaging Medical Students in Learning. AB - Technological advances have created immense pressure on our younger generation to keep themselves abreast with the newer developments in medical sciences. Educators have to evolve innovative pedagogy to help prepare this generation for future challenges as the training periods are getting relatively shorter. Flipped classroom or Inverted classroom is one such innovation that can empower a learner to develop critical thinking skills and master ways to imbibe vast information by engaging students in active learning process. Reading and understanding are carried at home, and the class-time is utilized for higher levels of learning like analyzing, evaluating, and application of the basic information. This review article is aimed to guide the educators in applying the concept of flipped classroom in their teaching learning armamentarium. PMID- 29978819 TI - Clinical Scales for Assessment of Dehydration in Children with Diarrhea: Evidence based Medicine Viewpoint. PMID- 29978820 TI - Clinical Scales for Assessment of Dehydration in Children with Diarrhea: Pediatric Gastroenterologist's Viewpoint. PMID- 29978821 TI - Clinical Scales for Assessment of Dehydration in Children with Diarrhea: Pediatrician's Viewpoint. PMID- 29978822 TI - Transbronchial Lung Cryobiopsy for Diagnosis of Pediatric Interstitial Lung Disease. AB - BACKGROUND: Tissue diagnosis of Childhood interstitial lung diseases is of paramount importance to outline management. CASE CHARACTERISTICS: A 10-year-old boy with prolonged cough, and computed tomography of thorax with features suggestive of primary Langerhans's cell histiocytosis. INTERVENTION: Transbronchial cryobiopsy of lung using flexible cryoprobe, revealed a final diagnosis of Surfactant protein C/ABCA3 deficiency. MESSAGE: Transbronchial cryobiopsy of the lung can provide adequate lung tissue for a categorical diagnosis of interstitial lung diseases in children. PMID- 29978823 TI - Safety-pin Induced Hemopericardium and Cardiac Tamponade in an Infant. AB - BACKGROUND: Safety-pin ingestion causing cardiovascular complications are very rare with high risk for mortality. CASE CHARACTERISTICS: A 10-month-old child who presented with persistent irritability and intermittent fever of 1 month duration. The child had tachypnea and mild subcostal retractions. OBSERVATION: Investigations revealed open safety-pin in lower esophagus, and pericardial effusion that later progressed to cardiac tamponade during handling of the safety pin by endoscope. MESSAGE: It may be safer to drain pericardial collection before handling sharp foreign bodies in lower end of esophagus as it can worsen cardiac complications. PMID- 29978824 TI - Asymmetric Presentation of Retinopathy of Prematurity. AB - Retinopathy of prematurity (ROP) usually has symmetric presentation and progression between fellow eyes. In this retrospective review of records, asymmetric presentation was noted in 16 (3.9%) out of 410 babies over a period of one year. Management and final outcome differed in 10 and 11 infants respectively. ROP need not always be symmetric and may require variable management. PMID- 29978825 TI - Free Style Libre Pro (FSLP) Flash Glucose Monitor (FGM) - A Novel Monitoring Tool for Children with Type 1 Diabetes Mellitus. AB - Flash glucose monitoring using Free Style Libre Pro (FSLP) was undertaken among fifteen diabetic children. Data revealed high glycaemic variability, Time in Target Range (TIR) to be 27% and 12% of time in hypoglycaemia. Sensor insertion and retention were problematic in 33%. Though user friendly, sensors may need an additional adhesive plaster for retention. PMID- 29978826 TI - Seizures and Cerebellar Calcification in a Child with Autoimmune Polyendocrine Syndrome 3A. PMID- 29978827 TI - Two Novel Heterozygous MCCC1 Mutations in a Neonate with Asymptomatic 3 methylcrotonyl-coenzyme A Carboxylase Deficiency. PMID- 29978828 TI - Pseudothrombocytopenia in Type 1 Diabetes. PMID- 29978829 TI - Novel Heterozygous PCCA Mutations with Fatal Outcome in Propionic Acidemia. PMID- 29978830 TI - Assembly of colloidal particles in solution. AB - Advances in both top-down and bottom-up syntheses of a wide variety of complex colloidal building blocks and also in methods of controlling their assembly in solution have led to new and interesting forms of highly controlled soft matter. In particular, top-down lithographic methods of producing monodisperse colloids now provide precise human-designed control over their sub-particle features, opening up a wide range of new possibilities for assembly structures that had been previously limited by the range of shapes available through bottom-up methods. Moreover, an increasing level of control over anisotropic interactions between these colloidal building blocks, which can be tailored through local geometries of sub-particle features as well as site-specific surface modifications, is giving rise to new demonstrations of massively parallel off chip self-assembly of specific target structures with low defect rates. In particular, new experimental realizations of hierarchical self-assembly and control over the chiral purity of resulting assembly structures have been achieved. Increasingly, shape-dependent, shape-complementary, and roughness controlled depletion attractions between non-spherical colloids are being used in novel ways to create assemblies that go far beyond early examples, such as fractal clusters formed by diffusion-limited and reaction-limited aggregation of spheres. As self-assembly methods have progressed, a wide variety of advanced directed assembly methods have also been developed; approaches based on microfluidic control and applying structured electromagnetic fields are particularly promising. PMID- 29978831 TI - Piezoelectric effects on the resonance frequencies of boron nitride nanosheets. AB - By using molecular dynamics (MD) simulations, we find in this work that due to the piezoelectric characteristic of boron nitride (BN) nanosheets their resonance frequencies can be efficiently tuned by applying an external electric field. This finding suggests that BN nanosheet can be treated as a good building block for designing novel piezoelectrically tunable two-dimensional nanoresonators. As BN nanosheets possess an inversely stacked structure, the applied electric field has different effects on the resonance frequency of BN nanosheets with odd and even layers. The influence of piezoelectric effect on the vibration behaviours observed in MD simulations is found to significantly deviate from the prediction of the conventional Euler-Bernoulli beam model (EBM), since the EBM cannot account for the weak van der Waals interaction between neighbouring layers in BN nanosheets. To take into account the interlayer interaction in the mathematical modelling of the piezoelectric effect on the vibration of BN nanosheets, we propose here a novel multiple beam model (MBM), which can account for both interlayer stretching and shearing deformations. The MBM result is found to be in a good agreement with the MD result without any additional parameters fitting, which indicates that the present MBM can be treated as a more precise theoretical model in the future study of the vibration properties of BN nanosheets. PMID- 29978832 TI - Toward adaptive radiotherapy for lung patients: feasibility study on deforming planning CT to CBCT to assess the impact of anatomical changes on dosimetry. AB - Changes in lung architecture during a course of radiotherapy can alter the planned dose distribution to the extent that it becomes clinically unacceptable. This study aims to validate a quantitative method of determining whether a replan is required during the course of conformal radiotherapy. The proposed method uses deformable image registration (DIR) to flexibly map planning CT (pCT) data to the anatomy of online CBCT images. The resulting deformed CT (dCT) images are used as a basis for assessing the effect of anatomical change on dose distributions. The study used retrospective data from a sample of seven replanned lung patients. The settings of an in-house, open-source DIR algorithm were first optimised for CT-to CBCT registrations of the anatomy of the thorax. Using these optimised parameters, each patient's pCT was deformed to the CBCT acquired immediately before the replan. Registration accuracy was rigorously validated both geometrically and dosimetrically to confirm that the dCTs could reliably be used to inform replan decisions. A retrospective evaluation of the changes in dose delivered over time was then carried out for a single patient to demonstrate the clinical application of the proposed method. The geometric analysis showed good agreement between deformed structures and those same structures manually outlined on the CBCT images. Results were consistently better than those achieved with rigid-only registration. In the dosimetric analysis, dose distributions derived from the dCTs were found to match closely to the 'gold standard' replan CT (rCT) distributions across dose volume histogram and absolute dose difference measures. The retrospective analysis of serial CBCTs of a single patient produced reliable quantitative assessment of the dose delivery. Had the proposed method been available at the time of treatment, it would have enabled a more objective replan decision. DIR is a valuable clinical tool for dose recalculation in adaptive radiotherapy protocols for lung cancer patients. PMID- 29978833 TI - Independent application of an analytical model for secondary neutron equivalent dose produced in a passive-scattering proton therapy treatment unit. AB - The purpose of this study was to independently apply an analytical model for equivalent dose from neutrons produced in a passive-scattering proton therapy treatment unit, H. To accomplish this objective, we applied the previously published model to treatment plans of two pediatric patients. Their model accounted for neutrons generated by mono-energetic proton beams stopping in a closed aperture. To implement their model to a clinical setting, we adjusted it to account for the area of a collimating aperture, energy modulation, air gap between the treatment unit and patient, and radiation weighting factor. We used the adjusted model to estimate H per prescribed proton absorbed dose, D Rx , for the passive-scattering proton therapy beams of two children, a 9-year-old girl and 10-year-old boy, who each received intracranial boost fields as part of their treatment. In organs and tissues at risk for radiation-induced subsequent malignant neoplasms, T, we calculated the mass-averaged H, H T , per D Rx . Finally, we compared H T /D Rx values to those of previously-published Monte Carlo (MC) simulations of these patients' fields. H T /D Rx values of the adjusted model deviated from the MC result for each organ on average by 20.8 +/- 10.0% and 44.2 +/- 17.6% for the girl and boy, respectively. The adjusted model underestimated the MC result in all T of each patient, with the exception of the girl's bladder, for which the adjusted model overestimated H T /D Rx by 3.1%. The adjusted model provided a better estimate of H T /D Rx than the unadjusted model. That is, between the two models, the adjusted model reduced the deviation from the MC result by approximately 37.0% and 46.7% for the girl and boy, respectively. We found that the previously-published analytical model, combined with adjustment factors to enhance its clinical applicability, predicted H T /D Rx in out-of-field organs and tissues at risk for subsequent malignant neoplasms with acceptable accuracy. This independent application demonstrated that the analytical model may be useful broadly for clinicians and researchers to calculate equivalent dose from neutrons produced externally to the patient in passive-scattering proton therapy. PMID- 29978834 TI - Burst and continuous high frequency irreversible electroporation protocols evaluated in a 3D tumor model. AB - High frequency irreversible electroporation (H-FIRE) is an emerging cancer therapy which uses bursts of alternating polarity pulses to target and destroy the membranes of cells within a predictable volume. Typically, 2 us pulses are rapidly repeated 24-50 times to create a 48-100 us long energy burst. Bursts are repeated 100* at 1 Hz, resulting in an integrated energized time of 0.01 s per treatment. A 3D in vitro tumor model was used to investigate H-FIRE parameters in search of optimal energy timing protocols. Monopolar IRE treatments (100 * 100 us positive polarity pulses) resulted in a lethal electric field threshold of 423 V cm-1. Baseline H-FIRE treatments (100 * 100 us bursts of 2 us pulses) resulted in a lethal threshold of 818 V cm-1. Increasing the number of H-FIRE bursts from 100* to 1000* reduced the lethal threshold to 535 V cm-1. An alternative diffuse H-FIRE protocol, which delivers 4 us pulse cycles (one positive and one negative 2 us pulse) continuously at 100 Hz, resulted in the lowest H-FIRE lethal threshold of 476 V cm-1. Finite element simulations using 5 kV pulses predict an IRE ablation volume of 3.9 cm3 (1.7 cm diameter) and a maximum H-FIRE ablation volume of 5.3 cm3 (2.4 cm diameter) when a clinical electrode and grounding pad configuration is used. Ablations as large as 15.7 cm3 (3.3 cm diameter) are predicted for H-FIRE treatments with 10 kV pulses. These results combine to demonstrate the importance of electrode geometry, pulse timing, and clinical delivery protocols for the creation of large clinically meaningful ablations. PMID- 29978835 TI - Interplay between membrane tension and the actin cytoskeleton determines shape changes. AB - The ability of mammalian cells to deform their membrane relies on the action of the cytoskeleton. In particular, the dynamics of the actin cytoskeleton, assembling at the plasma membrane, plays a crucial role in controlling cell shape. Many proteins are involved to ensure proper growth of the actin network at the cell membrane. The detailed structure of this network regulates the force that is necessary for membrane deformation. We address here how the presence of capping proteins, which limit the length of actin filaments and thus affects network topology, influences membrane shape. We use a system of liposomes, activated to polymerize actin at their surface, and placed in a mixture of purified proteins that reconstitutes actin dynamics. Our system also allows the variation of membrane tension by deflating the liposomes. We show that membrane deformations are clearly favored in the presence of capping proteins in the actin network. Moreover, in the absence of capping proteins, membrane deformations appear only when the liposomes are deflated. Our results unveil that the interplay between membrane tension and actin network structure and dynamics governs cell shape. PMID- 29978836 TI - Decellularized corneal lenticule embedded compressed collagen: toward a suturable collagenous construct for limbal reconstruction. AB - Recently, compressed collagen has attracted much attention as a potential alternative for a limbal epithelial stem cell (LESC) carrier to treat limbal stem cell deficiency (LSCD), in that it can provide mechanically improved collagen fibrillar structures compared to conventional collagen hydrogel. However, its clinical efficacy as an LESC carrier has not yet been studied through in vivo transplantation due to limited mechanical strength that cannot withstand a force induced by surgical suturing and low resistance to enzymatic degradation. This study firstly presents a suturable LESC carrier based on compressed collagen in the form of a biocomposite. The biocomposite was achieved by integrating a decellularized corneal lenticule, which is a decellularized stromal tissue obtained from corneal refractive surgery, inside a compressed collagen to form a sandwich structure. A suture retention test verified that the biocomposite has a much higher suture retention strength (0.56 +/- 0.12 N) compared to the compressed collagen (0.02 +/- 0.01 N). The biocomposite also exhibited more than 3 times higher resistance to enzymatic degradation, indicating long-term stability after transplantation. In vitro cell culture results revealed that the biocomposite effectively supported the expansion and stratification of the LESCs with expressions of putative stem cell and differentiated corneal epithelial cell markers. Finally, the biocomposite verified its clinical efficacy by stably delivering the LESCs onto an eye of a rabbit model of LSCD and effectively reconstructing the ocular surface. PMID- 29978837 TI - Temporal evolution on SiO2 surface under low energy Ar+-ion bombardment: roles of sputtering, mass redistribution, and shadowing. AB - Self-organized pattern evolution on SiO2 surface under low energy Ar-ion irradiation has been investigated extensively at varied ion energies, angles of ion incidence, and ion flux. Our investigations reveal an instability on SiO2 surface in an angular window of 40 degrees 70 degrees and for a comprehensive range of Ar-ion energies (200-1000 eV). Different topographical features, viz. ripples, mounds, and elongated nanostructures evolve on the surface, depending upon the angle of incidence and ion fluence. The results are compiled in the form of a parametric phase diagram (ion energy versus angle of incidence) which summarizes the pattern formation on SiO2 surface. To understand the evolution of observed patterns, we have carried out theoretical estimation, taking into account the synergetic roles of ion induced curvature-dependent sputter erosion and prompt atomic redistribution. It is shown that irradiation-induced mass redistribution of target atoms plays a crucial role in determining the critical angle of ion incidence for pattern formation on SiO2 under the present experimental conditions, whereas the contribution of curvature-dependent sputtering needs to be considered to understand the existence of the angular window of pattern formation. In addition, ion-beam shadowing by surface features are shown to play a dominant role in the formation of mounds and elongated structures at higher ion fluences. PMID- 29978838 TI - Polymer gel dosimetry by nuclear Overhauser enhancement (NOE) magnetic resonance imaging. AB - The response to radiation of polymer gel dosimeters has previously been measured by magnetic resonance imaging (MRI) in terms of changes in the water transverse relaxation rate (R 2w) or magnetization transfer (MT) parameters. Here we report a new MRI approach, based on detecting nuclear Overhauser enhancement (NOE) mediated saturation transfer effects, which can also be used to detect radiation and measure dose distributions in MAGIC-f (Methacrylic and Ascorbic Acid and Gelatin Initiated by Copper Solution with formaldehyde) polymer gels. Results show that the NOE effects produced by low powered radiofrequency (RF) irradiation at specific frequencies offset from water may be quantified by appropriate measurements and over a useful range depend linearly on the radiation dose. The NOE effect likely arises from the polymerization of methacrylic acid monomers which become less mobile, facilitating dipolar through-space cross-relaxation and/or relayed magnetization exchange between polymer and water protons. Our study suggests a potential new MRI method for polymer gel dosimetry. PMID- 29978839 TI - Dynamic 18F-FLT PET imaging of spatiotemporal changes in tumor cell proliferation and vasculature reveals the mechanistic actions of anti-angiogenic therapy. AB - Anti-angiogenic therapies target tumor vasculature and tumor cells, thus a concurrent assessment of these targets would lead to a greater understanding of therapeutic resistance and facilitate development of improved therapeutic strategies. We utilize dynamic 3'-deoxy-3'-18F-fluorothymidine positron emission tomography (18F-FLT PET) scanning to concurrently assess changes in tumor cell proliferation and vasculature during anti-angiogenic therapy, providing insight into how these therapies may be used effectively with combination chemotherapy. Thirty-three patients with advanced solid malignancies underwent treatment with vascular endothelial growth factor receptor inhibitor (VEGFR-TKI) axitinib on an intermittent schedule (two-weeks-on/one-week-off). Patients had up to three dynamic 18F-FLT PET/CT scans: at baseline, after two weeks of continuous VEGFR TKI treatment, and following a one week treatment break. 18F-FLT kinetics were analyzed using a two-tissue compartment kinetic model. Kinetic parameters V b and K 1 were extracted to quantify changes in tumor vasculature and the 18F-FLT flux constant K i was calculated to quantify changes in tumor cell proliferation. Two weeks of continuous axitinib exposure led to decreases in V b (median -21%, P = 0.07), K 1 (median -39%, P < 0.01), and K i (median -37%, P < 0.01), corresponding to diminished tumor vasculature and cell proliferation that may antagonize treatment with concurrent chemotherapy. Axitinib treatment breaks led to significant increases in V b (median +42%, P < 0.01), K 1 (median +46%, P < 0.01), and K i (median +39%, P < 0.01) that is suggestive of an optimal time to schedule synergistic chemotherapy. Significant negative correlations (rho ? -0.70, P < 0.01) were found between changes in tumor vasculature during axitinib exposure weeks and changes in tumor vasculature during treatment breaks. Imaging with dynamic 18F-FLT PET revealed new insights relating to the interplay of vascular and proliferative pharmacodynamics of axitinib therapy, facilitating a greater understanding of the mechanistic actions of VEGFR-TKIs. Increases in tumor vasculature and cell proliferation during VEGFR-TKI treatment breaks, suggests this period is an optimal time to schedule synergistic chemotherapy and warrants further investigation. PMID- 29978840 TI - A symmetry roadmap to new perovskite multiferroics. PMID- 29978841 TI - Precise implications for real-space pair distribution function modeling of effects intrinsic to modern time-of-flight neutron diffractometers. AB - Total scattering and pair distribution function (PDF) methods allow for detailed study of local atomic order and disorder, including materials for which Rietveld refinements are not traditionally possible (amorphous materials, liquids, glasses and nanoparticles). With the advent of modern neutron time-of-flight (TOF) instrumentation, total scattering studies are capable of producing PDFs with ranges upwards of 100-200 A, covering the correlation length scales of interest for many materials under study. Despite this, the refinement and subsequent analysis of data are often limited by confounding factors that are not rigorously accounted for in conventional analysis programs. While many of these artifacts are known and recognized by experts in the field, their effects and any associated mitigation strategies largely exist as passed-down 'tribal' knowledge in the community, and have not been concisely demonstrated and compared in a unified presentation. This article aims to explicitly demonstrate, through reviews of previous literature, simulated analysis and real-world case studies, the effects of resolution, binning, bounds, peak shape, peak asymmetry, inconsistent conversion of TOF to d spacing and merging of multiple banks in neutron TOF data as they directly relate to real-space PDF analysis. Suggestions for best practice in analysis of data from modern neutron TOF total scattering instruments when using conventional analysis programs are made, as well as recommendations for improved analysis methods and future instrument design. PMID- 29978842 TI - A group-theoretical approach to enumerating magnetoelectric and multiferroic couplings in perovskites. AB - A group-theoretical approach is used to enumerate the possible couplings between magnetism and ferroelectric polarization in the parent Pm{?overline 3}m perovskite structure. It is shown that third-order magnetoelectric coupling terms must always involve magnetic ordering at the A and B sites which either transforms both as R-point or both as X-point time-odd irreducible representations (irreps). For fourth-order couplings it is demonstrated that this criterion may be relaxed allowing couplings involving irreps at X-, M- and R points which collectively conserve crystal momentum, producing a magnetoelectric effect arising from only B-site magnetic order. In this case, exactly two of the three irreps entering the order parameter must be time-odd irreps and either one or all must be odd with respect to inversion symmetry. It is possible to show that the time-even irreps in this triad must transform as one of: X1+, M3,5- or R5+, corresponding to A-site cation order, A-site antipolar displacements or anion rocksalt ordering, respectively. This greatly reduces the search space for type-II multiferroic perovskites. Similar arguments are used to demonstrate how weak ferromagnetism may be engineered and a variety of schemes are proposed for coupling this to ferroelectric polarization. The approach is illustrated with density functional theory calculations on magnetoelectric couplings and, by considering the literature, suggestions are given of which avenues of research are likely to be most promising in the design of novel magnetoelectric materials. PMID- 29978843 TI - A numerical method for deriving shape functions of nanoparticles for pair distribution function refinements. AB - In the structural refinement of nanoparticles, discrete atomistic modeling can be used for small nanocrystals (< 15 nm), but becomes computationally unfeasible at larger sizes, where instead unit-cell-based small-box modeling is usually employed. However, the effect of the nanocrystal's shape is often ignored or accounted for with a spherical model regardless of the actual shape due to the complexities of solving and implementing accurate shape effects. Recent advancements have provided a way to determine the shape function directly from a pair distribution function calculated from a discrete atomistic model of any given shape, including both regular polyhedra (e.g. cubes, spheres, octahedra) and anisotropic shapes (e.g. rods, discs, ellipsoids) [Olds et al. (2015). J. Appl. Cryst. 48, 1651-1659], although this approach is still limited to small size regimes due to computational demands. In order to accurately account for the effects of nanoparticle size and shape in small-box refinements, a numerical or analytical description is needed. This article presents a methodology to derive numerical approximations of nanoparticle shape functions by fitting to a training set of known shape functions; the numerical approximations can then be employed on larger sizes yielding a more accurate and physically meaningful refined nanoparticle size. The method is demonstrated on a series of simulated and real data sets, and a table of pre-calculated shape function expressions for a selection of common shapes is provided. PMID- 29978844 TI - Plesiotwins versus diperiodic twins. AB - Plesiotwins and diperiodic twins have in common the fact of being characterized by a low degree of lattice restoration. Plesiotwins differ from twins by the fact that the relative orientation of the individuals is obtained by a non crystallographic rotation about the normal to the composition plane, whereas for twins this rotation is crystallographic, apart from possible small deviations coming from metric pseudosymmetries. In the case of plesiotwins, the low degree of lattice restoration comes from a large coincidence site lattice (CSL) in the composition plane. Diperiodic twins, instead, have a small CSL in the composition plane but the second plane of the same family contributing to the overall lattice restoration is too far away from the composition plane to be considered significant. It is shown that plesiotwins can occur as reflection twins if the composition plane is not parallel to the twin plane, and as rotation twins in the case of parallel hemitropy. Diperiodic twins can in principle occur in any category, but either the metric conditions to obtain a diperiodic twin are actually in contrast with the metric pseudosymmetry required for twinning or the result is actually a hybrid twin. This justifies why no confirmed examples of diperiodic twins are known to date. PMID- 29978845 TI - X-ray molecular orbital analysis. I. Quantum mechanical and crystallographic framework. AB - Molecular orbitals were obtained by X-ray molecular orbital analysis (XMO). The initial molecular orbitals (MOs) of the refinement were calculated by the ab initio self-consistent field (SCF) MO method. Well tempered basis functions were selected since they do not produce cusps at the atomic positions on the residual density maps. X-ray structure factors calculated from the MOs were fitted to observed structure factors by the least-squares method, keeping the orthonormal relationship between MOs. However, the MO coefficients correlate severely with each other, since basis functions are composed of similar Gaussian-type orbitals. Therefore, a method of selecting variables which do not correlate severely with each other in the least-squares refinement was devised. MOs were refined together with the other crystallographic parameters, although the refinement with the atomic positional parameters requires a lot of calculation time. The XMO method was applied to diformohydrazide, (NHCHO)2, without using polarization functions, and the electron-density distributions, including the maxima on the covalent bonds, were represented well. Therefore, from the viewpoint of X-ray diffraction, it is concluded that the MOs averaged by thermal vibrations of the atoms were obtained successfully by XMO analysis. The method of XMO analysis, combined with X-ray atomic orbital (AO) analysis, in principle enables one to obtain MOs or AOs without phase factors from X-ray diffraction experiments on most compounds from organic to rare earth compounds. PMID- 29978846 TI - A Markov theoretic description of stacking-disordered aperiodic crystals including ice and opaline silica. AB - This article reviews the Markov theoretic description of one-dimensional aperiodic crystals, describing the stacking-faulted crystal polytype as a special case of an aperiodic crystal. Under this description the centrosymmetric unit cell underlying a topologically centrosymmetric crystal is generalized to a reversible Markov chain underlying a reversible aperiodic crystal. It is shown that for the close-packed structure almost all stackings are irreversible when the interaction reichweite s > 4. Moreover, the article presents an analytic expression of the scattering cross section of a large class of stacking disordered aperiodic crystals, lacking translational symmetry of their layers, including ice and opaline silica (opal CT). The observed stackings and their underlying reichweite are then related to the physics of various nucleation and growth processes of disordered ice. The article discusses how the derived expressions of scattering cross sections could significantly improve implementations of Rietveld's refinement scheme and compares this Q-space approach with the pair-distribution function analysis of stacking-disordered materials. PMID- 29978847 TI - Indexing of grazing-incidence X-ray diffraction patterns: the case of fibre textured thin films. AB - Crystal structure solutions from thin films are often performed by grazing incidence X-ray diffraction (GIXD) experiments. In particular, on isotropic substrates the thin film crystallites grow in a fibre texture showing a well defined crystallographic plane oriented parallel to the substrate surface with random in-plane order of the microcrystallites forming the film. In the present work, analytical mathematical expressions are derived for indexing experimental diffraction patterns, a highly challenging task which hitherto mainly relied on trial-and-error approaches. The six lattice constants a, b, c, alpha, beta and gamma of the crystallographic unit cell are thereby determined, as well as the rotation parameters due to the unknown preferred orientation of the crystals with respect to the substrate surface. The mathematical analysis exploits a combination of GIXD data and information acquired by the specular X-ray diffraction. The presence of a sole specular diffraction peak series reveals fibre-textured growth with a crystallographic plane parallel to the substrate, which allows establishment of the Miller indices u, v and w as the rotation parameters. Mathematical expressions are derived which reduce the system of unknown parameters from the three- to the two-dimensional space. Thus, in the first part of the indexing routine, the integers u and v as well as the Laue indices h and k of the experimentally observed diffraction peaks are assigned by systematically varying the integer variables, and by calculating the three lattice parameters a, b and gamma. Because of the symmetry of the derived equations, determining the missing parameters then becomes feasible: (i) w of the surface parallel plane, (ii) the Laue indices l of the diffraction peak and (iii) analogously the lattice constants c, alpha and beta. In a subsequent step, the reduced unit-cell geometry can be identified. Finally, the methodology is demonstrated by application to an example, indexing the diffraction pattern of a thin film of the organic semiconductor pentacenequinone grown on the (0001) surface of highly oriented pyrolytic graphite. The preferred orientation of the crystallites, the lattice constants of the triclinic unit cell and finally, by molecular modelling, the full crystal structure solution of the as-yet-unknown polymorph of pentacenequinone are determined. PMID- 29978848 TI - Primitive substitution tilings with rotational symmetries. AB - This work introduces the idea of symmetry order, which describes the rotational symmetry types of tilings in the hull of a given substitution. Definitions are given of the substitutions sigma6 and sigma7 which give rise to aperiodic primitive substitution tilings with dense tile orientations and which are invariant under six- and sevenfold rotations, respectively; the derivation of the symmetry orders of their hulls is also presented. PMID- 29978849 TI - Spatio-temporal symmetry - crystallographic point groups with time translations and time inversion. AB - The crystallographic symmetry of time-periodic phenomena has been extended to include time inversion. The properties of such spatio-temporal crystallographic point groups with time translations and time inversion are derived and one representative group from each of the 343 types has been tabulated. In addition, stereographic symmetry and general-position diagrams are given for each representative group. These groups are also given a notation consisting of a short Hermann-Mauguin magnetic point-group symbol with each spatial operation coupled with its associated time translation. PMID- 29978852 TI - Clinical Efficacy and Safety of Uterine Artery Embolization (UAE) versus Laparoscopic Cesarean Scar Pregnancy Debridement Surgery (LCSPDS) in Treatment of Cesarean Scar Pregnancy. AB - BACKGROUND The present study aimed to compare the clinical efficacy and safety of uterine artery embolization (UAE) vs. laparoscopic cesarean scar pregnancy debridement surgery (LCSPDS) in the treatment of patients with cesarean scar pregnancy (CSP). MATERIAL AND METHODS A retrospective analysis was performed on 87 CSP patients from March 2012 to February 2017. For the included 87 cases, 51 were treated with UAE and 36 were treated with LCSPDS. The operation success rate, intraoperative blood loss, operation time, length of hospital stay, perioperative complications, and beta-HCG level were compared. RESULTS For the UAE group, 41 patients underwent successful surgeries (80.4% success rate), and 36 cases in the LCSPDS group were successfully treated, with no case of perioperative death. In the UAE group, the operation time, intraoperative blood loss, and length of hospital stay were 82.23+/-45.21 min, 112.58+/-68.54 mL, and 12.56+/-3.03 days, respectively. In the LCSPDS group, the operation time, intraoperative blood loss, and length of hospital stay were 85.45+/-30.02 min, 108.56+/-54.12 mL and 7.65+/-2.48 days, respectively. The length of hospital stay for the UAE group was significantly longer than in the LCSPDS group (P<0.05). CONCLUSIONS UAE and LCSPDS each have their own advantages and disadvantages in treating CSP. Thus, appropriate individualized surgical programs based on specific patient circumstances are needed to avoid indiscriminately performing complete uterine cavity curettage. PMID- 29978853 TI - [Cardiovascular risk factors in young adults of a penitentiary center]. AB - OBJECTIVE: The quantification of the cardiovascular risk factors (CVRF) in a population of young adults, allows to identify their vulnerabilities and contributes to focus on prevention strategies in a group more susceptible of changing their behavior and establishing healthier daily habits. The objectives of this work were to describe the main CVRF and estimate the risk through different models. METHODS: Observational, descriptive, analytical and crosssectional study. All of the population of the centre of both genders, who were admitted and their age span from 18 to 35 as of the 15 September 2017, are included. Sociodemographic, anthropometric and clinical variables were gathered. A descriptive and a gender comparative analysis took place using classical statistical techniques and binary logistic regression analysis. It was determined that cardiovascular risk using Framingham's equation, REGICOR, SCORE, DORICA, and Q-RISK 2017 version. All of the patients who participated gave their authorizations and consent. The project was approved by a Committee of Ethics in Clinical Research. RESULTS: The targeted population were 211 young adults, 6 members could not be contacted so the study held had a population of 205: 170 men (82.9%) and 35 women (17.1%). The average age is 29.9 (IC 95%: 29.3-30.5). The mean stay is 13.3 months. CVRF underlines: genetics 46.3%, sedentariness 38.0%; familiar backgrounds 17.6%; Triglyceridemic 16.6%; obesity 13.2%. Others: psychological 79.5%, eating disorders 72.2%, cocaine consumption 58.0%. Cardiovascular risk by Framingham: low 85.9%, light 12.9%, moderate 1.2%. DORICA: low 87.6%, light 11.8%, moderate 0.6%. REGICOR: low 98.8%, light 1.2%. CONCLUSIONS: The identified risk factors were high toxic consumption, influence of sedentary lifestyle and psychological and alimentary factors. PMID- 29978854 TI - [Design, construction and assessment of a scale to measure the attitude towards the self-medication in adolescents]. AB - OBJECTIVE: An increase in the self-medication in youth has been observed in last decades. Although there are several instruments to measure the behavior of self medication, none of them work is aimed to measure the underlying attitude. The goal of this study was to design and evaluate an attitude towards self-medication measurement scale in youth and adolescence and the assessment of its psychometric characteristics. METHODS: Development and validation of the Attitude towards self medication Scale based on the data obtained in February 2012 of 665 adolescents with an average age of 15.5 years (D.T = 1.1) in educational centers of the Community of Madrid. An Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA) were computed. RESULTS: EFA revealed a 3 factors solution: Self medication and regulation of negative emotions (9 items), Peer-based self medication and advertising (5 items) and Self-medication by own decision (3 items), with adequate reliability indexes. A CFA comparing 2 alternative models revealed that the 3 factor model yielded more satisfactory fit indexes. Results from a CFA for this model was also performed with a random sample, comprising half of the participants, also showed adequate fit indexes. CONCLUSIONS: The developed scale showed acceptable psychometric properties, and even with different latent factors it shows unidimensionality. Inner consistency of the overall scale and of each of the three factors is acceptable. Goodness of fit indexes is adequate. PMID- 29978855 TI - Using the CES-D with custodial grandmothers: cross-validation and convergent validity. AB - Objective: This study is the first to analyze the factor structure of the Center for Epistemological Studies Depression (CES-D) Scale with custodial grandmothers involving both cross validation and convergent validity analyses. Method: Cross validation was accomplished with two different samples of custodial grandmothers (GCM) to calibrate (n=733; Average Age=52) and then validate (n=343; Average Age=52.5) the model. Results: Radloff's originally proposed four factor model (Depressed Affect, Well-Being, Somatic Symptoms, and Interpersonal Problems) was found to best fit the data for both calibration (RMSEA=0.049) and validation samples (RMSEA=0.050). The construct validity of the four CES-D factors was supported by the correlations observed between these factors and conceptually related psychosocial measures. Conclusion: four CES-D factors as proposed are psychometrically sound when applied to custodial grandmothers and that each factor contributes unique and meaningful information in its own right. PMID- 29978856 TI - Treating nosocomial pneumonia: what's new. AB - A detailed and comprehensive summary of the ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia, published in ERJ Open Research, will assist clinicians in their tasks http://ow.ly/XC7N30k8Jhu. PMID- 29978857 TI - SteeringWheel: A Locality-Preserving Magnification Interface for Low Vision Web Browsing. AB - Low-vision users struggle to browse the web with screen magnifiers. Firstly, magnifiers occlude significant portions of the webpage, thereby making it cumbersome to get the webpage overview and quickly locate the desired content. Further, magnification causes loss of spatial locality and visual cues that commonly define semantic relationships in the page; reconstructing semantic relationships exclusively from narrow views dramatically increases the cognitive burden on the users. Secondly, low-vision users have widely varying needs requiring a range of interface customizations for different page sections; dynamic customization in extant magnifiers is disruptive to users' browsing. We present SteeringWheel, a magnification interface that leverages content semantics to preserve local context. In combination with a physical dial, supporting simple rotate and press gestures, users can quickly navigate different webpage sections, easily locate desired content, get a quick overview, and seamlessly customize the interface. A user study with 15 low-vision participants showed that their web browsing efficiency improved by at least 20 percent with SteeringWheel compared to extant screen magnifiers. PMID- 29978858 TI - Design of Interactive Cancer Education Technology for Latina Farmworkers. AB - Latinas in the United States experience higher levels of cervical cancer (CC) incidence and mortality rates than the general population, and many lack access to healthcare or face communication, literacy, and knowledge barriers preventing proper CC screening. Interactive technological interventions, like embodied conversational agents (ECA)/virtual agents, are currently used in other populations, settings, and for other health topics, however, no known initiative has used culturally- and literacy-appropriate technological interventions to deliver Spanish-language CC education. This study aims to create a culturally tailored Spanish-language Virtual Patient Educator (VPE) application to augment a patient navigator (PN) intervention for increasing CC screening rates among Hispanic women in a rural agricultural community. The VPE is a computer character that can simulate face-to-face conversation with an actual person and will embody the characteristics of a PN. Through iterative interviews with the target population, key cultural design factors were identified to inform the design and implementation of a prototype VPE. This paper discusses design and usability issues associated with development of the VPE for low-literacy users in addition to a framework methodology for development of similar tools and a cultural matrix of design factors. A VPE might help close the knowledge gap between Hispanic women and the general population regarding cervical cancer screening. Incorporation of culturally tailored features in technology aids in increasing overall understanding and trust of health information presented. An iterative approach that engages the patient population in design of technology is important to identify population-specific patient preferences. PMID- 29978859 TI - An integrated strategy for highly sensitive phosphoproteome analysis from low micrograms of protein samples. AB - Phosphoproteomics has become a popular proteomic technology for exploring cellular signaling networks. However, current approaches often require milligrams of protein samples which hamper their applications for translational studies with limited starting materials. In this study, we aimed to challenge the lowest starting material limit for phosphoproteome profiling. By carefully optimizing the well-established high-pH reversed-phase (RP) fractionation plus Ti4+-IMAC enrichment strategy, we achieved the identification of 15 260 and 8936 unique phosphopeptides from only 500 MUg and 250 MUg predigested peptides, respectively. To further improve the sensitivity of phosphoproteome analysis for low micrograms of protein samples, we developed an integrated strategy, termed Phospho-SISPROT. This technology integrates three tips in tandem for protein digestion by the simple and integrated spintip-based proteomics technology (SISPROT), phosphopeptide enrichment by the Ti4+-IMAC tip, and desalting by the StageTip, respectively, which could dramatically reduce the phosphoproteome analysis time from a couple of days to only 6 hours and improve the system sensitivity. The flow through of Phospho-SISPROT could be reused for the global protein identification, which is very helpful for accurate phosphoproteome analysis with limited starting materials. More than 5500 and 600 unique phosphopeptides were respectively identified from 20 MUg and 1 MUg pervanadate treated HEK 293T cell lysates processed by the Phospho-SISPROT. To the best of our knowledge, this performance is the highest reported to date by using the standard LC-MS/MS setup. We expect that the Phospho-SISPROT and the optimized high-pH RP fractionation plus Ti4+-IMAC enrichment strategy will be well suited for highly sensitive phosphoproteome analysis of rare biological samples. PMID- 29978860 TI - Contagious degradation of a chemically active surface on the cathodes of lithium ion batteries. AB - Durability is critically important in energy storage applications. Based on the model of the contagious degradation of a chemically active surface (CDCAS), a general model for durability has been systematically built. In practical lithium ion batteries (LIBs), gassing swelling, limited by slow electrochemical processes, occurs over years of use and causes the LIB cell to rupture at an unpredictable moment. As an example of an application, the proposed CDCAS model was used to quantitatively study the gassing behaviors of different LIB systems, resulting in important information that can be used to predict swelling and avoid an accident. Interestingly, what could be deduced from the high nickel system (NCM811) model is that the active reaction area directly degrades to an inactive area without passing through an intermediate active area. The new degradation mechanism of the NCM811 cathode is further supported by the constant activation energy of the charge-transfer (Ea = 0.65 eV) across the whole high temperature storage test. This information shows that it was only partially correct, and even sometimes wrong, to use the increased thickness of the reconstructed rock-salt layer on the surface of some high-Ni cathode particles as an indicator of an increase in the impedance. The in-depth understanding on cathode degradation using the CDCAS model presented in this work will be beneficial for the development of high-safety and high-performance LIBs. PMID- 29978861 TI - Self-assembled phosphate-polyamine networks as biocompatible supramolecular platforms to modulate cell adhesion. AB - The modulation of cell adhesion via biologically inspired materials plays a key role in the development of realistic platforms to envisage not only mechanistic descriptions of many physiological and pathological processes but also new biointerfacial designs compatible with the requirements of biomedical devices. In this work, we show that the cell adhesion and proliferation of three different cell lines can be easily manipulated by using a novel biologically inspired supramolecular coating generated via dip coating of the working substrates in an aqueous solution of polyallylamine in the presence of phosphate anions-a simple one-step modification procedure. Our results reveal that selective cell adhesion can be controlled by varying the deposition time of the coating. Cell proliferation experiments showed a cell type-dependent quasi-exponential growth demonstrating the nontoxic properties of the supramolecular platform. After reaching a certain surface coverage, the supramolecular films based on phosphate polyamine networks displayed antiadhesive activity towards cells, irrespective of the cell type. However and most interestingly, these antiadherent substrates developed strong adhesive properties after thermal annealing at 37 degrees C for 3 days. These results were interpreted based on the changes in the coating hydrophilicity, topography and stiffness, with the latter being assessed by atomic force microscopy imaging and indentation experiments. The reported approach is simple, robust and flexible, and would offer opportunities for the development of tunable, biocompatible interfacial architectures to control cell attachment for various biomedical applications. PMID- 29978862 TI - Secondary nucleation in amyloid formation. AB - Nucleation of new peptide and protein aggregates on the surfaces of amyloid fibrils of the same peptide or protein has emerged in the past two decades as a major pathway for both the generation of molecular species responsible for cellular toxicity and for the autocatalytic proliferation of peptide and protein aggregates. A key question in current research is the molecular mechanism and driving forces governing such processes, known as secondary nucleation. In this context, the analogies with other self-assembling systems for which monomer dependent secondary nucleation has been studied for more than a century provide a valuable source of inspiration. Here, we present a short overview of this background and then review recent results regarding secondary nucleation of amyloid-forming peptides and proteins, focusing in particular on the amyloid beta peptide (Abeta) from Alzheimer's disease, with some examples regarding alpha synuclein from Parkinson's disease. Monomer-dependent secondary nucleation of Abeta was discovered using a combination of kinetic experiments, global analysis, seeding experiments and selective isotope-enrichment, which pinpoint the monomer as the origin of new aggregates in a fibril-catalyzed reaction. Insights into driving forces are gained from variations of solution conditions, temperature and peptide sequence. Selective inhibition of secondary nucleation is explored as an effective means to limit oligomer production and toxicity. We also review experiments aimed at finding interaction partners of oligomers generated by secondary nucleation in an ongoing aggregation process. At the end of this feature article we bring forward outstanding questions and testable mechanistic hypotheses regarding monomer-dependent secondary nucleation in amyloid formation. PMID- 29978863 TI - Cleavage of BN triple bonds by main group reagents. AB - We report two rare instances of an insertion into the strong (ca. 170 kcal mol-1) BN triple bond of iminoboranes. In the first, a silylene inserts into di-tert butyliminoborane to form an iminosilane. In the second, the highly crowded iminoborane Ter-NB-TMP (TMP = 2,2,6,6-tetramethylpiperidyl, Ter = 2,6 (diphenylmethyl)-4-tert-butylphenyl) can be forced to react with Pip-CC-Pip (Pip = piperidyl) at 60 degrees C. The reaction product is the apparent result of Pip CC insertion into the iminoborane BN bond. PMID- 29978864 TI - Electrochemistry at a single nanoparticle: from bipolar regime to tunnelling. AB - This paper is concerned with long-distance interactions between an unbiased metal nanoparticle (NP) and a nanoelectrode employed as a tip in the scanning electrochemical microscope (SECM). A NP immobilized on the inert substrate acts as a bipolar electrode, producing positive SECM feedback. The tip current magnitude depends strongly on the ratio of the particle and tip radii and the heterogeneous charge-transfer kinetics. The onset of electron tunneling was observed at very short separation distances (<2-3 nm) at which the NP behaves as a part of the tip electrode. The rate constant of the electron-transfer (ET) or electrocatalytic reaction at the NP can be extracted from either feedback or tunneling current. The tunneling mode of SECM can be used to investigate heterogeneous reactions occurring at a single NP without making an ohmic contact with it. This technique can also help elucidate nanoparticle/electrode interactions in various electrochemical systems ranging from NPs immobilized on the electrode surface to nanoimpact collision events. PMID- 29978865 TI - The verticillenes. Pivotal intermediates in the biosynthesis of the taxanes and the phomactins. AB - Covering: up to May 2018The verticillene family of 6,12-membered ring-fused diterpenes are found in plants, liverworts, corals and insects. Carbocations derived from verticillene hydrocarbons are central intermediates in the biosynthesis of the taxane and the phomactin families of polycyclic natural products. This perspective delineates these unique biosynthetic interrelationships, which are reinforced by recent biomimetic synthesis investigations, alongside quantum chemical calculations and targeted engineering studies of the taxadiene synthase (TXS) cascade. PMID- 29978866 TI - Droplet microarray: miniaturized platform for rapid formation and high-throughput screening of embryoid bodies. AB - Stem cells are influenced by various factors present in their in vivo microenvironment, such as interactions with neighboring cells, the extracellular matrix or soluble molecules. This demonstrates the high complexity of the in vivo microenvironment. Hence, many advances have been made in developing 3D screening models mimicking this complexity and the in vivo-like state in order to ensure more biomedically relevant investigations in drug discovery. In the field of stem cell research embryoid bodies are often used as relevant 3D systems. Embryoid bodies are embryonic stem cell aggregates that recapitulate the early embryonic development and that can differentiate into derivatives of the three germ layers. Embryoid bodies enable the investigation of processes underlying embryonic development, tissue generation and identification of drugs with developmental toxicity. The ability to perform high-throughput screenings using embryoid bodies could be extremely important to accelerate the progress in the field of stem cell research and embryonic development. To date, there are no simple methods to create high-density microarrays of embryoid bodies that further enable their high throughput screening important for biomedical research. Here we demonstrate a new method that enables formation and high-throughput screening of embryoid bodies in arrays of defined, separated microdroplets. Using the superhydrophobic hydrophilic micropattern of the droplet microarray, we demonstrate rapid and facile one-step formation of a dense array of multiple droplets containing homogeneous, single embryoid bodies. Thorough characterization of the influence of the initial cell number on embryoid body size, roundness and distribution was performed. We applied the embryoid body microarray to screen 774 FDA-approved compounds, identifying compounds with developmental toxicity such as mycophenolate mofetil or embryonic lethality such as eptifibatide. This work demonstrates the potential of the droplet microarray for the rapid formation of high-density microarrays of single embryoid bodies and their high-throughput drug screenings. PMID- 29978867 TI - Ultra-stretchable and highly sensitive strain sensor based on gradient structure carbon nanotubes. AB - High stretchability and sensitivity of strain sensors are two properties that are very difficult to combine together into one material, due to the intrinsic dilemma of the opposite requirements of robustness of the conductive network. Therefore, the improvement of one property is always achieved at the expense of decreasing the other property, and preventing its practical application. Inspired by the micro-structure of the copolymer, which consists of stretchable amorphous and strong crystal domains, we developed a highly stretchable and sensitive strain sensor, based on innovative gradient carbon nanotubes (CNTs). By integrating randomly oriented and well aligned CNTs, acting as sensitive and stretchable conductive elements, respectively, into a continuous changing structure, our strain sensors successfully combine both a high sensitivity (gauge factor (GF) = 13.5) and ultra-stretchability (>550%). With a fast response speed (<33 ms) and recovery speed (<60 ms), lossless detection of a 8 Hz mechanical signal has been easily realized. In addition, the gradient CNTs strain sensors also showed great durability in a dynamic test of 12 000 cycles, as well as extraordinary linearity and ultra-low working voltage (10 mV). These outstanding features mean our sensors have enormous potential for applications in health monitoring, sports performance monitoring and soft robotics. PMID- 29978868 TI - Chiral Cu(ii), Co(ii) and Ni(ii) complexes based on 2,2'-bipyridine modified peptoids. AB - Helical peptoids bearing 2,2'-bipyridine, varied in their chiral bulky side chains and their N-terminus form complexes with Cu(ii), Co(ii) and Ni(ii) via intramolecular binding. Chiral induction from the peptoid to each metal center could be only observed in some cases and is dependent on the identity of the N terminus and on its position relative to the metal center. PMID- 29978869 TI - Understanding quantum emitters in plasmonic nanocavities with conformal transformation: Purcell enhancement and forces. AB - Nanogaps supporting cavity plasmonic modes with unprecedented small mode volume are attractive platforms for tailoring the properties of light-matter interactions at the nanoscale and revealing new physics. Hitherto, there is a concerning lack of analytical solutions to divide the complex interactions into their different underlying mechanisms to gain a better understanding that can foster enhanced designs. Bowtie apertures are viewed as an effective and appealing nanocavity and are studied here within the analytical frame of conformal transformation. We show how the non-radiative Purcell enhancement of a quantum emitter within the bowtie nanocavity depends strongly not only on the geometry of the nanocavity, but also on the position and orientation of the emitter. For a 20 nm diameter (? 20 nm) bowtie nanocavity, we report a change of up to two orders of magnitude in the maximum non-radiative Purcell enhancement and a shift in its peak wavelength from green to infra-red. The changes are tracked down to the overlap between the emitter field and the gap plasmon mode field distribution. This analysis also enables us to understand the self-induced trapping potential of a colloidal quantum dot inside the nanocavity. Since transformations can be cascaded, the technique introduced in this work can also be applied to a wide range of nanocavities found in the literature. PMID- 29978870 TI - Why develop photoactivated chemotherapy? AB - Photoactivated chemotherapy is an approach where a biologically active compound is protected against interaction with the cell environment by a light-cleavable protecting group, and unprotected by light irradiation. As such, PACT represents a major scientific opportunity for developing new bioactive inorganic compounds. However, the societal impact of this approach will only take off if the PACT field is used to address real societal challenges, i.e., therapeutic questions that make sense in a clinical context, rather than purely chemical questions. In particular, I advocate here that the field has become mature enough to switch from a compound-based approach, where a particular cancer model is chosen only to demonstrate the utility of a compound, to a disease-based approach, where the question of which disease to cure comes first: which PACT compound should I make to solve that particular clinical problem? The advantages and disadvantages of PACT vs. other phototherapeutic techniques are discussed, and a roadmap towards real clinical applications of PACT is drawn. PMID- 29978871 TI - Enhancing the health potential of processed meat: the effect of chitosan or carboxymethyl cellulose enrichment on inherent microstructure, water mobility and oxidation in a meat-based food matrix. AB - The addition of dietary fibers can alleviate the deteriorated textural properties and water binding capacity (WBC) that may occur when the fat content is lowered directly in the formulas of comminuted meat products. This study investigated the effects of the addition of chitosan or carboxymethyl cellulose (CMC) (2% w/w) to a model meat product. Both dietary fibers improved the water-binding capacity (WBC), while chitosan addition resulted in a firmer texture, CMC lowered the hardness. Chitosan addition resulted in a 2-fold reduction of lipid oxidation products, whereas CMC had no significant effect on oxidation. The effect of chitosan addition on lipid oxidation was evident both in the meat system and after simulated in vitro gastrointestinal digestion. Low-field nuclear magnetic resonance (NMR) relaxometry revealed that the fibers impacted the intrinsic water differently; the addition of chitosan resulted in a faster T2 relaxation time corresponding to water entrapped in a more dense pore network. Coherent anti Stokes Raman scattering (CARS) microscopy was for the first time applied in a meat product to study the microstructure, which revealed that the two fibers exerted different effects on the size and entrapment of fat droplets in the protein network, which probably explain the mechanisms by which chitosan reduced lipid oxidation in the system. PMID- 29978872 TI - One-step synthesis of red/green dual-emissive carbon dots for ratiometric sensitive ONOO- probing and cell imaging. AB - The synthesis of dual-emissive carbon dots (CDs) with a longer emission wavelength by using a facile strategy is of great importance for the fabrication of ratiometric fluorescent nanoprobes. Herein, red/green dual-emissive carbon dots (RGDE CDs) were synthesized in one step using 2,5-diaminotoluene sulfate (DATS) as a carbon source. The as-prepared RGDE CDs not only exhibited dual emission fluorescence peaks (525 nm, 603 nm) at the single excitation wavelength of 370 nm, but also possessed good water solubility and excellent fluorescence stability. Moreover, the as-prepared RGDE CDs could be directly utilized as a ratiometric fluorescent probe for the determination of trace ONOO- due to the electron transfer process from ONOO- to the excited RGDE CDs. Under optimal conditions, the linear range was 0.03-60 MUM with the limit of detection of 11.6 nM. Importantly, this RGDE CD probe could be applied for the detection of intracellular ONOO- with excellent biocompatibility and cellular imaging capability, indicating great promise in biomedical applications. PMID- 29978873 TI - Correction: Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: a randomized controlled trial. AB - Correction for 'Hibiscus and lemon verbena polyphenols modulate appetite-related biomarkers in overweight subjects: a randomized controlled trial' by Marina Boix Castejon et al., Food Funct., 2018, 9, 3173-3184. PMID- 29978874 TI - Dietary methionine restriction regulated energy and protein homeostasis by improving thyroid function in high fat diet mice. AB - Methionine-restricted diets (MRD) show an integrated series of beneficial health effects, including improving insulin sensitivity, limiting fat deposition, and decreasing oxidative stress, and inflammation responses. We aimed to explore the systemic responses to a MRD in mice fed with a high fat (HFD) and clarify the possible mechanism. Mice were fed with a control diet (0.86% methionine + 4% fat, CON), HFD (0.86% methionine + 20% fat), or MRD (0.17% methionine + 20% fat) for 22 consecutive weeks. HFD-fed mice showed widespread systemic metabolic disorders and thyroid dysfunction. A MRD significantly increased energy expenditure (e.g. fatty acid oxidation, glycolysis, and tricarboxylic acid cycle metabolism), regulated protein homeostasis, improved gut microbiota functions, prevented thyroid dysfunction, increased plasma thyroxine and triiodothyronine levels, decreased plasma thyroid stimulating hormone levels, increased type 2 deiodinase (DIO2) activity, and up-regulated mRNA and protein expression levels of DIO2 and thyroid hormone receptor alpha1 in the skeletal muscle. These results suggest that a MRD can improve the metabolic disorders induced by a HFD, and especially regulate energy and protein homeostasis likely through improved thyroid function. Thus, reducing methionine intake (e.g. through a vegan diet) may improve metabolic health in animals and humans. PMID- 29978875 TI - Lipids as integral components in mussel adhesion. AB - Lipids are fundamental components of cells in organisms. Recent studies reveal that lipids are also present in cell-free bioadhesives. Examples include barnacle cement, sea star footprints, hairy and smooth pads of insects and gecko setae. Whether reliance on lipids is universal in bioadhesion is not known. In the present study, we demonstrated, for the first time, the involvement of lipids in mussel adhesion. We extracted, identified and localized lipids in the byssal threads. The lipids were confirmed as fatty acids by gas chromatograpy mass spectrometry. delta13C measurements of the fatty acids in the byssus were also conducted. Results show that byssal fatty acids, with concentrations ranging from 1.10-2.51 mg g-1 by thread dry weight depending on the mussel species, are localized both on the surface of and inside the byssal thread and plaque. Over half of the fatty acids were loosely attached to the surface while a small portion were tightly bound to the byssus. Most of the surface fatty acids disappear within a week of thread deposition. delta13C values of byssal fatty acids show isotope fractionation suggesting that thread fatty acids are derived from the foot. It is possible that fatty acids are key players in expelling water and preparing the substrate surface for adhesion. Using lipids in the adhesion process might be a common strategy for organisms in need of temporary or permanent attachment. The process of lipid participation may be as important as adhesive components for developing more efficient man-made glues. PMID- 29978876 TI - The stability, electronic structure, and optical absorption of boron-nitride diamondoids predicted with first-principles calculations. AB - Although diamondoids are broadly studied for their fundamental properties and applications, boron-nitride-based diamondoids are scarcely explored. Here we predict the stability, electronic structure, and optical absorption spectra of six boron-nitride (BN) diamondoids with first-principles methods based on pseudopotential density functional theory and many-body perturbation methods implemented with a real-space formalism. We find that four of them are thermodynamically stable at room temperature, while B10N8H24 and B6N4H16 show thermodynamic instability in molecular dynamics simulations. With the GW approximation, we predicted the ionization energies and electron affinities of BN diamondoids and find that the evolution of the electronic structure with size does not follow the same trend as diamondoids, owing to the unbalanced numbers of boron and nitrogen atoms. We show strong photoabsorption of BN-triamantane and BN adamantane in the infrared and visible ranges and analyze the features of low energy absorption by examining the characteristics of related orbitals. PMID- 29978877 TI - Tuning the micro-structure of germanosilicate glass to control Bi0/Bi+ and promote efficient Ho3+ fluorescence. AB - Bi can exist in a variety of chemical states (with varying ionic charges) and the microstructure of the glass surrounding the ions can be engineered to manipulate the chemical state. In this work, efficient enhancement of Ho3+ emission is observed with the change in local glass environment around Bi by adding Al2O3 to multi-component germanosilicate glass. In this multi-component glass, Al3+ can form tetrahedral AlO4 by accepting the non-bridging oxygen (NBO) and then, the addition of the AlO4-tetrahedron to the glass network facilitates the diffusion of alkali metals. Hence, Al2O3 decreases the Ba2+-rich domain and is conducive to the existence of Bi ions that are at low valence state. Moreover, the emission spectra indicate high efficiency energy transfer (ET) derived from NIR emission centers (Bi0/Bi+) located in close proximity to the Ho3+ ions. These results indicate that the optimized fluorescence of Ho3+ for optical fiber laser can be achieved by adjusting the local structure of the host glass. PMID- 29978879 TI - Evaluation of the intrinsic catalytic activity of nanoparticles without prior knowledge of the mass loading. AB - The quantitative characterisation of electrocatalytic properties of nanoparticle catalyst materials is so far only performed for layers typically comprising additionally conducting additives and binders. We propose a method enabling the evaluation of intrinsic catalytic activity of nanoparticles based on the diffusion-limited steady-state current. In a step-after-step process, the influence of coverage on kinetic and diffusion limited current is evaluated to highlight the challenges of sub-monolayer electroanalysis. Conclusions are used to point out strategies and their limitations for qualitative and quantitative comparison of intrinsic catalytic properties. Particularly, the impact of coverage, electrode geometry, altered diffusion profile for nanoparticles and the catalyst activity and selectivity are discussed. Fundamental information about electrochemical sub-monolayer nanoparticle analysis is provided. PMID- 29978878 TI - Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites. AB - The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4]-, [AuCl2(dmso)2]+, [AuCl2(bipy)]+) and Pt(ii) ([PtCl2(dmso)2]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4]- and [PtCl2(dmso)2] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition. PMID- 29978880 TI - Coordination-induced reversible electrical conductivity variation in the MOF-74 analogue Fe2(DSBDC). AB - Inner-sphere changes at the open Fe centers in Fe2(DSBDC) (DSBDC4- = 2,5 disulfidobenzene-1,4-dicarboxylate), as caused by coordination and release of solvent molecules, lead to reversible structural and electrical conductivity changes. Specifically, coordination of N,N-dimethylformamide (DMF) to the open Fe sites improves the room-temperature electrical conductivity by three orders of magnitude. Supported by additional density functional theory calculations, we attribute the electrical conductivity enhancement to partial electron transfer from Fe to DMF, which generates hole carriers and improves the charge carrier density in Fe2(DSBDC). PMID- 29978881 TI - Charge transport at a molecular GaAs nanoscale junction. AB - In recent years, the use of non-metallic electrodes for the fabrication of single molecule junctions has developed into an elegant way to impart new properties to nanodevices. Integration of molecular junctions in a semiconducting platform would also speed technological deployment, as it would take advantage of established industrial infrastructures. In a previous proof-of-concept paper, we used simple alpha,omega-dithiol self-assembled monolayers on a gallium arsenide (GaAs) substrate to fabricate molecular Schottky diodes with a STM. In the devices, we were also able to detect the contribution of a single-molecule to the overall charge transport. The prepared devices can also be used as photodiodes, as GaAs is a III-V direct bandgap (1.42 eV at room temperature) semiconductor, and it efficiently absorbs visible light to generate a photocurrent. In this contribution, we demonstrate that fine control can be exerted on the electrical behaviour of a metal-molecule-GaAs junction by systematically altering the nature of the molecular bridge, the type and doping density of the semiconductor and the light intensity and wavelength. Molecular orbital energy alignment dominates the charge transport properties, resulting in strongly rectifying junctions prepared with saturated bridges (e.g. alkanedithiols), with increasingly ohmic characteristics as the degree of saturation is reduced through the introduction of conjugated moieties. The effects we observed are local, and may be observed with electrodes of only a few tens of nanometres in size, hence paving the way to the use of semiconducting nanoelectrodes to probe molecular properties. Perspectives of these new developments for single molecule semiconductor electrochemistry are also discussed. PMID- 29978882 TI - Change in collective motion of colloidal particles driven by an optical vortex with driving force and spatial confinement. AB - We studied the change in collective behavior of optically driven colloidal particles on a circular path. The particles are simultaneously driven by the orbital angular momentum of an optical vortex beam generated by holographic optical tweezers. The driving force is controlled by the topological charge l of the vortex. By varying the driving force and spatial confinement, four characteristic collective motions were observed. The collective behavior results from the interplay between the optical interaction, hydrodynamic interaction and spatial confinement. Varying the topological charge of an optical vortex not only induces changes in driving force but also alters the stability of three dimensional optical trapping. The switch between dynamic clustering and stable clustering was observed in this manner. Decreasing the cell thickness diminishes the velocity of the respective particles and increases the spatial confinement. A jamming-like characteristic collective motion appears when the thickness is small and the topological charge is large. In this regime, a ring of equally-spaced doublets was spontaneously formed in systems composed of an even number of particles. PMID- 29978883 TI - Diffusiophoretically induced interactions between chemically active and inert particles. AB - In the presence of a chemically active particle, a nearby chemically inert particle can respond to a concentration gradient and move by diffusiophoresis. The nature of the motion is studied for two cases: first, a fixed reactive sphere and a moving inert sphere, and second, freely moving reactive and inert spheres. The continuum reaction-diffusion and Stokes equations are solved analytically for these systems and microscopic simulations of the dynamics are carried out. Although the relative velocities of the spheres are very similar in the two systems, the local and global structures of streamlines and the flow velocity fields are found to be quite different. For freely moving spheres, when the two spheres approach each other the flow generated by the inert sphere through diffusiophoresis drags the reactive sphere towards it. This leads to a self assembled dimer motor that is able to propel itself in solution. The fluid flow field at the moment of dimer formation changes direction. The ratio of sphere sizes in the dimer influences the characteristics of the flow fields, and this feature suggests that active self-assembly of spherical colloidal particles may be manipulated by sphere-size changes in such reactive systems. PMID- 29978884 TI - Cd(ii)-nucleobase supramolecular metallo-hydrogels for in situ growth of color tunable CdS quantum dots. AB - The integration of nanoscale materials into unconventional environments such as gels is a magnificent strategy towards development of engineered hybrid functional systems. Herein, the in situ formation of CdS quantum dots integrated into a metallogel formed through the coordination of Cd2+ with two pyrimidine nucleobases is reported. Thymine and uracil formed spontaneous hydrogels with nanofibrous morphology through coordinative interaction with Cd2+ ions at alkaline pH. Introduction of Na2S resulted in generation of CdS quantum dots within the hydrogels with tunable emission properties from blue to white to yellow. The quenching of emission of white light system was exploited for the sensing of Fe3+ and Cu2+ ions. Such a color tunable quantum dot incorporated metallogel system will find applications in energy harvesting and sensing. PMID- 29978885 TI - Iron promoted C3-H nitration of 2H-indazole: direct access to 3-nitro-2H indazoles. AB - An efficient C3-H functionalization of indazole has been demonstrated. Notably, this method involves chelation-free radical C-H nitration on 2H-indazole. The radical mechanism was confirmed by control experiments and quantum chemical calculations. The synthetic utility has been proven by the synthesis of bio relevant benzimidazoindazoles via reductive cyclization. PMID- 29978886 TI - A Case of Subcutaneous Infection with Mycobacterium mageritense Identified by Matrix-assisted Laser Desorption/Ionization-time of Flight Mass Spectrometry. PMID- 29978887 TI - Changes in Androgen Receptor Expression as a Molecular Marker of Progression from Normal Epithelium to Invasive Cancer in Elderly Patients with Penile Squamous Cell Carcinoma. PMID- 29978888 TI - Efficacy of Oral Ruxolitinib in a Patient with Refractory Chronic Spontaneous Urticaria. PMID- 29978889 TI - Effective permeation of 2.5 and 5% lidocaine hydrochloride in human skin using iontophoresis technique. AB - BACKGROUND: Lidocaine Hydrochloride (HCL) is one of the commonest topical local anesthetic drugs. The permeation of the lidocaine can be enhanced by iontophoresis (IOP). The purpose of this study was to evaluate the permeability of 2.5 and 5% lidocaine permeation in ex vivo human skin using different IOP waveform. METHODS: Continuous and modulated IOP at the current density of 0.5 mA/cm2 were applied across human skin (n = 3) in donor chamber of vertical diffusion cell at 2.5 and 5% lidocaine concentration. High Performance Liquid Chromatography was used to determine lidocaine concentration. RESULTS: Findings revealed that lidocaine concentration increased effectively in a time-dependent manner in both modulated and continuous IOP at 2.5 and 5% lidocaine concentration. Compared to the passive group, the flux of lidocaine with modulated and continuous IOP were higher of about six and ten-fold, respectively. However, no significant difference was observed between continuous and modulated IOP groups at both lidocaine concentrations. At 2.5% lidocaine concentration, the permeation time taken by modulated and continuous IOP to attain therapeutic levels of 142 and 164 MUg/cm2 , respectively, was approximately 10 minutes. At 5% lidocaine, the therapeutic permeation of 129 and 147 MUg/cm2 , respectively, was achieved at approximately 5 minutes after applying iontophoresis waveform. CONCLUSION: Study shows that modulated IOP can be a promising alternative method in clinical settings aside from continuous IOP. Based on the clinical requirements, IOP can be used at 2.5 and 5% lidocaine concentration depending on need of relatively short or very short onset action. PMID- 29978890 TI - Intestinal Nucleoside Transporters: Function, Expression, and Regulation. AB - The gastrointestinal tract is the absorptive organ for nutrients found in foods after digestion. Nucleosides and, to a lesser extent nucleobases, are the late products of nucleoprotein digestion. These metabolites are absorbed by nucleoside (and nucleobase) transporter (NT) proteins. NTs are differentially distributed along the gastrointestinal tract showing also polarized expression in epithelial cells. Concentrative nucleoside transporters (CNTs) are mainly located at the apical side of enterocytes, whereas equilibrative nucleoside transporters (ENTs) facilitate the basolateral efflux of nucleosides and nucleobases to the bloodstream. Moreover, selected nucleotides and the bioactive nucleoside adenosine act directly on intestinal cells modulating purinergic signaling. NT polarized insertion is tightly regulated. However, not much is known about the modulation of intestinal NT function in humans, probably due to the lack of appropriate cell models retaining CNT functional expression. Thus, the possibility of nutritional regulation of intestinal NTs has been addressed using animal models. Besides the nutrition-related role of NT proteins, orally administered drugs also need to cross the intestinal barrier, this event being a major determinant of drug bioavailability. In this regard, NT proteins might also play a role in pharmacology, thereby allowing the absorption of nucleoside- and nucleobase-derived drugs. The relative broad selectivity of these membrane transporters also suggests clinically relevant drug-drug interactions when using combined therapies. This review focuses on all these physiological and pharmacological aspects of NT protein biology. (c) 2017 American Physiological Society. Compr Physiol 8:1003-1017, 2018. PMID- 29978891 TI - Neural Mechanisms of High-Level Vision. AB - The last three decades have seen major strides in our understanding of neural mechanisms of high-level vision, or visual cognition of the world around us. Vision has also served as a model system for the study of brain function. Several broad insights, as yet incomplete, have recently emerged. First, visual perception is best understood not as an end unto itself, but as a sensory process that subserves the animal's behavioral goal at hand. Visual perception is likely to be simply a side effect that reflects the readout of visual information processing that leads to behavior. Second, the brain is essentially a probabilistic computational system that produces behaviors by collectively evaluating, not necessarily consciously or always optimally, the available information about the outside world received from the senses, the behavioral goals, prior knowledge about the world, and possible risks and benefits of a given behavior. Vision plays a prominent role in the overall functioning of the brain providing the lion's share of information about the outside world. Third, the visual system does not function in isolation, but rather interacts actively and reciprocally with other brain systems, including other sensory faculties. Finally, various regions of the visual system process information not in a strict hierarchical manner, but as parts of various dynamic brain-wide networks, collectively referred to as the "connectome." Thus, a full understanding of vision will ultimately entail understanding, in granular, quantitative detail, various aspects of dynamic brain networks that use visual sensory information to produce behavior under real-world conditions. (c) 2017 American Physiological Society. Compr Physiol 8:903-953, 2018. PMID- 29978892 TI - Natriuretic Peptides and Normal Body Fluid Regulation. AB - Natriuretic peptides are structurally related, functionally diverse hormones. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are delivered predominantly by the heart. Two C-type natriuretic peptides (CNPs) are paracrine messengers, notably in bone, brain, and vessels. Natriuretic peptides act by binding to the extracellular domains of three receptors, NPR-A, NPR-B, and NPR-C of which the first two are guanylate cyclases. NPR-C is coupled to inhibitory proteins. Atrial wall stress is the major regulator of ANP secretion; however, atrial pressure changes plasma ANP only modestly and transiently, and the relation between plasma ANP and atrial wall tension (or extracellular volume or sodium intake) is weak. Absence and overexpression of ANP related genes are associated with modest blood pressure changes. ANP augments vascular permeability and reduces vascular contractility, renin and aldosterone secretion, sympathetic nerve activity, and renal tubular sodium transport. Within the physiological range of plasma ANP, the responses to step-up changes are unimpressive; in man, the systemic physiological effects include diminution of renin secretion, aldosterone secretion, and cardiac preload. For BNP, the available evidence does not show that cardiac release to the blood is related to sodium homeostasis or body fluid control. CNPs are not circulating hormones, but primarily paracrine messengers important to ossification, nervous system development, and endothelial function. Normally, natriuretic peptides are not powerful natriuretic/diuretic hormones; common conclusions are not consistently supported by hard data. ANP may provide fine-tuning of reno-cardiovascular relationships, but seems, together with BNP, primarily involved in the regulation of cardiac performance and remodeling. (c) 2017 American Physiological Society. Compr Physiol 8:1211-1249, 2018. PMID- 29978893 TI - Corrigendum. PMID- 29978894 TI - Glucagon-like Peptide-2 and the Regulation of Intestinal Growth and Function. AB - Glucagon-like peptide-2 (GLP-2) is an intestinally derived hormone that enhances intestinal growth, digestion, absorption, barrier function, and blood flow in healthy animals as well as preventing damage and improving repair in preclinical models of enteritis and colitis and following massive small bowel resection. These beneficial effects of GLP-2 on the intestinal tract are largely recapitulated in humans with intestinal failure. The high-specificity of this peptide for the intestinal tract and the development of degradation-resistant, long-acting GLP-2 receptor agonists have rapidly led to clinical implementation of GLP-2-based therapy for the treatment of patients with short bowel syndrome, with few reported side effects. This comprehensive review covers the biology of GLP-2, from the control of proglucagon gene expression and the posttranslational processing of proglucagon to liberate GLP-2 to the regulation of GLP-2 secretion from the intestinal L cell, and from the mechanism of action of GLP-2 through its highly localized receptor to the biological activities of GLP-2 in the intestine and other restricted locations in the body, under physiological conditions as well as in animal models of intestinal disease and in patients with short bowel syndrome. Collectively, the history of GLP-2 serves as a remarkable bench-to bedside story of translational medicine. (c) 2017 American Physiological Society. Compr Physiol 8:1185-1210, 2018. PMID- 29978896 TI - Adiponectin Regulation and Function. AB - Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen activated protein kinase (p38 MAPK), and increased peroxisome proliferator activated receptor alpha (PPARalpha) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. (c) 2017 American Physiological Society. Compr Physiol 8:1031 1063, 2018. PMID- 29978897 TI - Mechanisms and Regulation of Intestinal Phosphate Absorption. AB - States of hypo- and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH)2 vitamin D3 , and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well-characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium-dependent phosphate cotransporter NaPi-IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. (c) 2017 American Physiological Society. Compr Physiol 8:1065-1090, 2018. PMID- 29978898 TI - Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators. AB - The vascular endothelial growth factor (VEGF) family of proteins are key regulators of physiological systems. Originally linked with endothelial function, they have since become understood to be principal regulators of multiple tissues, both through their actions on vascular cells, but also through direct actions on other tissue types, including epithelial cells, neurons, and the immune system. The complexity of the five members of the gene family in terms of their different splice isoforms, differential translation, and specific localizations have enabled tissues to use these potent signaling molecules to control how they function to maintain their environment. This homeostatic function of VEGFs has been less intensely studied than their involvement in disease processes, development, and reproduction, but they still play a substantial and significant role in healthy control of blood volume and pressure, interstitial volume and drainage, renal and lung function, immunity, and signal processing in the peripheral and central nervous system. The widespread expression of VEGFs in healthy adult tissues, and the disturbances seen when VEGF signaling is inhibited support this view of the proteins as endogenous regulators of normal physiological function. This review summarizes the evidence and recent breakthroughs in understanding of the physiology that is regulated by VEGF, with emphasis on the role they play in maintaining homeostasis. (c) 2017 American Physiological Society. Compr Physiol 8:955-979, 2018. PMID- 29978899 TI - Kinesthetic Senses. AB - The kinesthetic senses are the senses of position and movement of the body, senses we are aware of only on introspection. A method used to study kinesthesia is muscle vibration, which engages afferents of muscle spindles to trigger illusions of movement and changed position. When vibrating elbow flexors, it generates sensations of forearm extension, when vibrating extensors, sensations of forearm flexion. Vibrating the elbow joint produces no illusion. Vibrating flexors and extensors together at the same frequency also produces no illusion, because what is perceived is the signal difference between antagonist muscles of each arm and between arms. The size of the illusion depends on how the muscle has been conditioned beforehand, due to a property of muscle called thixotropy. When measuring the illusion, blindfolded subjects may carry out a matching or pointing task. In pointing, signals from muscle spindles are less important than in matching. Afferent signals from kinesthetic receptors project to areas of somatosensory cortex to generate sensations of detection and location. This is referred to the body model, which provides information about size and shape of body parts. Kinesthesia, together with vision and touch, is associated with the sense of body ownership. All three can combine or each, on its own, can generate ownership. Related is the sense of agency, the sense of being responsible for one's own actions. In recent times, much progress has been made using neuroimaging techniques to identify the various areas of the brain likely to be responsible for generating these sensations. (c) 2017 American Physiological Society. Compr Physiol 8:1157-1183, 2018. PMID- 29978900 TI - Platelet-Activation Mechanisms and Vascular Remodeling. AB - This overview article for the Comprehensive Physiology collection is focused on detailing platelets, how platelets respond to various stimuli, how platelets interact with their external biochemical environment, and the role of platelets in physiological and pathological processes. Specifically, we will discuss the four major functions of platelets: activation, adhesion, aggregation, and inflammation. We will extend this discussion to include various mechanisms that can induce these functional changes and a discussion of some of the salient receptors that are responsible for platelets interacting with their external environment. We will finish with a discussion of how platelets interact with their vascular environment, with a special focus on interactions with the extracellular matrix and endothelial cells, and finally how platelets can aid and possibly initiate the progression of various vascular diseases. Throughout this overview, we will highlight both the historical investigations into the role of platelets in health and disease as well as some of the more current work. Overall, the authors aim for the readers to gain an appreciation for the complexity of platelet functions and the multifaceted role of platelets in the vascular system. (c) 2017 American Physiological Society. Compr Physiol 8:1117 1156, 2018. PMID- 29978901 TI - Store-Operated Calcium Entry Mediated by ORAI and STIM. AB - The calcium release-activated calcium (CRAC) channel, composed of ORAI and stromal interaction molecules (STIM), represents a prototypical example of store operated calcium entry in mammals. The ORAI-STIM signaling occurs at membrane contact sites formed by close appositions between the endoplasmic reticulum (ER) and the plasma membrane. ORAI1 is a four-pass transmembrane protein that forms a highly calcium-selective ion channel in the plasma membrane. STIM1 is an ER resident, a single-pass transmembrane protein that serves as a calcium sensor within the ER lumen and a potent activator of ORAI1 calcium channels. The intricate interplay between ORAI and STIM controls calcium entry into cells to regulate a myriad of physiological processes. We highlight herein the current knowledge on the structure-function relationship of CRAC channel, with a focus on key structural elements that mediate STIM1 conformational switch and the dynamic coupling between STIM1 and ORAI1. Furthermore, we discuss the physiological roles of STIM-ORAI signaling in various tissues and organs, as well as major pathological conditions arising from loss- or gain-of-function mutations in human ORAI1 and STIM1. (c) 2017 American Physiological Society. Compr Physiol 8:981 1002, 2018. PMID- 29978895 TI - Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology. AB - Nutrient sensing is a mechanism for organisms to sense their environment. In larger animals, including humans, the intestinal tract is a major site of nutrient sensing for the body, not surprisingly, as this is the central location where nutrients are absorbed. In the gut, bacterial fermentation results in generation of short chain fatty acids (SCFAs), a class of nutrients, which are sensed by specific membrane bound receptors, FFA2, FFA3, GPR109a, and Olfr78. These receptors are expressed uniquely throughout the gut and signal through distinct mechanisms. To date, the emerging data suggests a role of these receptors in normal and pathological conditions. The overall function of these receptors is to regulate aspects of intestinal motility, hormone secretion, maintenance of the epithelial barrier, and immune cell function. Besides in intestinal health, a prominent role of these receptors has emerged in modulation of inflammatory and immune responses during pathological conditions. Moreover, these receptors are being revealed to interact with the gut microbiota. This review article updates the current body of knowledge on SCFA sensing receptors in the gut and their roles in intestinal health and disease as well as in whole body energy homeostasis. (c) 2017 American Physiological Society. Compr Physiol 8:1091 1115, 2018. PMID- 29978902 TI - Interactions of Gut Endocrine Cells with Epithelium and Neurons. AB - Even the simplest animals possess sophisticated systems for sensing and securing nutrients. After all, ensuring adequate nutrition is essential for sustaining life. Once multicellular animals grew too large to be nourished by simple diffusion of nutrients from their environment, they required a digestive system for the absorption and digestion of food. The majority of cells in the digestive tract are enterocytes that are designed to absorb nutrients. However, the digestive tracts of animals ranging from worms to humans contain specialized cells that discriminate between nutrients and nondigestible ingestants. These cells "sense" both the environment within the gut lumen and nutrients as they cross the gut epithelium. This dual sensing is then translated into local signals that regulate the gut epithelium or distant signals through hormones or nerves. This review will discuss how sensors of the gut interact with cells of the epithelium and neurons to regulate epithelial integrity and initiate neural transmission from the gut lumen. (c) 2017 American Physiological Society. Compr Physiol 8:1019-1030, 2018. PMID- 29978903 TI - Psoriasis in Israel: demographic, epidemiology, and healthcare services utilization. AB - BACKGROUND: Updated data regarding the epidemiology of psoriasis and related healthcare utilization are lacking. OBJECTIVE: To investigate the epidemiology, comorbidities, healthcare services utilization, and drug use in a large group of patients with psoriasis from Clalit Health Services (CHS) database. METHODS: A controlled cross-sectional study was performed. Case patients were defined when there was at least one documented diagnosis of psoriasis registered by a CHS dermatologist between the years 1998-2016. The extracted data included metabolic, cardiovascular and psychiatric comorbidities; community clinic visits; in- and outpatient services utilization profiles and drug use data, which included pharmacy claims of topical and systemic treatments, including phototherapy and climatotherapy. Comparative analysis was performed by a univariate and multivariate analysis, adjusting for age, gender, obesity, and smoking. RESULTS: The study included 118,680 patients with psoriasis (prevalence of 2.69%) and 118,680 age- and gender-matched controls. Patients with psoriasis had increased prevalence of metabolic, cardiovascular, and psychiatric illnesses. Psoriasis was significantly associated with an increased healthcare utilization. The mean (SD) number of annual dermatologist clinic visits and emergency room visits was 7.2 +/ 12.4 and 2.9 +/- 7.7 in psoriasis patients as compared to 2.9 +/- 7.9 and 2.7 +/ 7.4 in the control group (P < 0.001). Topical steroids were the most applied treatment in psoriasis patients (15.5%), and topical vitamin D analogs were second in use (14.6%). Traditional systemic treatment for psoriasis was used in 3.8% of the patients, and biologic treatments were used in 1.6% of the patients. CONCLUSIONS: Our study quantifies healthcare services utilization and drug use in patients with psoriasis. PMID- 29978904 TI - Reduced reward responsiveness moderates the effect of maternal depression on depressive symptoms in offspring: evidence across levels of analysis. AB - BACKGROUND: Reduced reward responsiveness (RR) may contribute to depression vulnerability. At the neurophysiological level, RR is reliably and validly assessed using the reward positivity (RewP) event-related potential component. We previously identified a blunted RewP in 9-year-old children at high risk for depression due to maternal depression, but the role of RR in pathways from parental history to the development of depressive symptoms has not been examined. METHODS: At age 9, never-depressed children (N = 369) completed a task in which RewP was measured in response to monetary reward and loss feedback. Parental history of depression was assessed using semistructured interviews, and children reported on their depressive symptoms. At age 12, youth depressive symptoms were reassessed, along with a self-report measure of RR. We tested RR as a moderator of the effects of parental depression on depressive symptoms at age 12, using both neurophysiological and self-report measures and controlling for age 9 symptoms. RESULTS: Main effects of RR and interactions with maternal depression were significant. Maternal depression predicted greater depressive symptoms in youth with blunted and average RewP but was not a significant predictor in youth with an enhanced RewP. A similar pattern was observed for self-reported RR. The two measures of RR were not correlated with each other and accounted for unique variance in symptoms. Interactions between RR and paternal depression were not significant. CONCLUSIONS: Reduced RR, as measured by neurophysiology and self report, moderates the effects of maternal depression on depressive symptoms in offspring. Assessment of RR along with risk factors such as parental depression may aid in identifying children at greatest risk and enhancing RR could be a potential target for prevention. Results highlight the utility of multimethod approaches for advancing understanding of depression risk. PMID- 29978905 TI - Stereoselective uptake and degradation of (+/-)-o,p-DDD pesticide stereomers in water-sediment system. AB - The environmental stereoselective uptake and degradation of (+/-)-o,p-DDD pesticide stereomers in water-sediment system are described. The results were analyzed by artificial neural network model. The optimized experimental parameters were concentration of o,p-DDD streamers (7.0 MUg L-1 ), experimental time (60 min), pH (6), dose (5.0 g L-1 ), and temperature (25 degrees C). The maximum uptake and degradation were 87% and 85% and 33.0% and 30.5% for (-)- and (+)-stereomers of o,p-DDD in 15-day time. Both uptake and degraded phenomenon showed first-order rate reaction. Thermodynamic variables indicated exothermic nature of uptake and degradation processes. The uptake and degradation were slightly higher for (-)-stereomer than (+)-stereomer of o,p-DDD. It was assumed that both uptake and degradation processes are accountable for the removal of the streomers of o,p-DDD from earth's ecosystem, but the uptake is responsible for major contribution. The magnitudes of relative errors obtained by artificial neural network model were in the range of +/-0.2 to 3.5, indicating good applicability of the experimental data. The results are very useful to control the environmental contamination due to the chiral o,p-DDD pesticide as its two enantiomers have different ecological toxicities. PMID- 29978906 TI - Mechanical behavior of metastatic vertebrae are influenced by tissue architecture, mineral content, and organic feature alterations. AB - Diminished vertebral mechanical behavior with metastatic involvement is typically attributed to modified architecture and trabecular bone content. Previous work has identified organic and mineral phase bone quality changes in the presence of metastases, yet limited work exists on the potential influence of such tissue level modifications on vertebral mechanical characteristics. This work seeks to determine correlations between features of bone (structural and tissue level) and mechanical behavior in metastatically involved vertebral bone. It is hypothesized that tissue level properties (mineral and organic) will improve these correlations beyond architectural properties and BMD alone. Twenty-four female athymic rats were inoculated with HeLa or Ace-1 cancer cells lines producing osteolytic (N = 8) or mixed (osteolytic/osteoblastic, N = 7) metastases, respectively. Twenty-one days post-inoculation L1-L3 pathologic vertebral motion segments were excised and MUCT imaged. 3D morphometric parameters and axial rigidity of the L2 vertebrae were quantified. Sequential loading and MUCT imaging measured progression of failure, stiffness and peak force. Relationships between mechanical testing (whole bone and tissue-level) and tissue-level material property modifications with metastatic involvement were evaluated utilizing linear regression models. Osteolytic involvement reduced vertebral trabecular bone volume, structure, CT-derived axial rigidity, stiffness and failure force compared to healthy controls (N = 9). Mixed metastases demonstrated similar trends. Previously assessed collagen cross-linking and proline-based residues were correlated to mechanical behavior and improved the predictive ability of the regression models. Similarly, collagen organization improved predictive regression models for metastatic bone hardness. This work highlights the importance of both bone content/architecture and organic tissue-level features in characterizing metastatic vertebral mechanics. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29978907 TI - The mode of action of remorin1 in regulating fruit ripening at transcriptional and post-transcriptional levels. AB - Remorins are plant-specific and plasma membrane-associated proteins that display a variety of functions in plant growth, development, biotic and abiotic stresses, and signal transduction. However, little information is available for understanding their role in fruit ripening. Here, remorin 1 (SlREM1) is cloned from tomato and its localization is examined by co-localization analysis and immunoblotting. Functions of SlREM1 in fruit ripening are characterized based on gene expression, co-immunoprecipitation coupled with mass spectroscopy and split luciferase complementation imaging assays in SlREM1 overexpression and RNA interference (RNAi) lines. The results indicate that SlREM1 is localized at the plasma membrane. Overexpression of SlREM1 in tomato stimulates fruit ripening with an increase in ethylene production and lycopene accumulation as compared to the wild-type. Consistently, these genes involved in ethylene and lycopene biosynthesis and ripening regulators also are upregulated in SlREM1 overexpression lines. SlREM1 can interact with ethylene biosynthesis proteins SAM1, ACO1 and ACS2 and is degraded by ubiquitin-mediated proteolysis. Our findings reveal that SlREM1 serves as a positive regulator of fruit ripening and provide novel cues for understanding of the molecular regulation network of fruit ripening. PMID- 29978908 TI - Role of corrosion in taper failure and head disassociation in total hip arthroplasty of a single design. AB - Modular junctions have been associated with corrosion in total hip arthroplasty. In a small number of cases, disassociation of the femoral head from the stem following gross wear of the taper has been reported. The purpose of this study was to investigate the role of corrosion in the development of mechanical changes leading to disassociation. Twenty-one retrieved stems and heads of one design previously reported with head disassociation were identified in an IRB-approved database. Components were scored for corrosion and measured for material loss. Stem alloy hardness was measured. Parametric and non-parametric statistics were performed (alpha < 0.05). Seven of twenty-one stems demonstrated gross material loss of the stem taper and head disassociation. The maximum linear depth (MLD) of material loss on stem tapers without dissociation and all head bores was 7.63 +/- 6.04 and 63.76 +/- 60.83 MUm, respectively. Hardness of the stem material was statistically distinct, but similar to other stem materials. Results suggest material loss via corrosion at the head bore loosens the taper lock, allowing relative motion leading to abrasive wear of the stem taper. All cases of disassociation occurred at greater than 65 months with a minimum of 50 MUm of loss at on the head bore. It may be warranted to survey patients with systems reporting head disassociation; for this system, including recalled heads, risk appears to begin after 6 years in vivo. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29978909 TI - Methanogenic Archaea dominate mature heartwood habitats of Eastern Cottonwood (Populus deltoides). AB - While recent reports demonstrate that the direct emission of methane from living tree trunks may be a significant terrestrial emission source, there has been debate whether tree emissions are due to transport from soils or produced in the wood environment itself. Reports of methanogens from wood of trees were prominent in the literature 40 years ago but have not been revisited with molecular ecology approaches. We examined communities associated with Populus deltoides using rRNA gene sequence analyses and how these vary with tree and wood properties. Our data indicate that wood environments are dominated by anaerobic microbiomes. Methanogens are prominent in heartwood (mean 34% relative abundance) compared to sapwood environments (13%), and dominant operational taxonomic units (OTUs) were classified as the Methanobacterium sp. Members of the Firmicutes phylum comprised 39% of total sequences and were in 42% greater abundance in sapwood over heartwood niches. Tree diameter was the strongest predictor of methanogen abundance, but wood moisture content and pH were also significant predictors of taxon abundance and overall community composition. Unlike microbiomes of the soil, rhizosphere and phyllosphere, wood associated communities are shaped by unique environmental conditions and may be prominent and overlooked sources of methane emissions in temperate forest systems. PMID- 29978910 TI - Linkage disequilibrium pattern and genome-wide association mapping for meat traits in multiple porcine F2 crosses. AB - In the present study, data from four F2 crosses were analysed and used to study the linkage disequilibrium (LD) structure within and across the crosses. Genome wide association analyses (GWASes) for conductivity and dressing out meat traits were conducted using single-marker and Bayesian multi-marker models using the pooled data from all F2 crosses. Porcine F2 crosses generated from the distantly related founder breeds Wild Boar, Pietrain and Meishan, as well as from a porcine F2 cross from the closely related founder breed Pietrain and an F1 Large White * Landrace cross were pooled. A total of 2572 F2 animals were genotyped using a 62K SNP chip. The positions of the SNPs were based on genome assembly Sscrofa11.1. After post-alignment and genotype filtering, approximately 50K SNPs were usable for LD studies and GWASes. The main findings of the present study are that the breakdown of LD was faster in crosses from closely related founder breeds compared to crosses from distantly related founders. The fastest breakdown of LD was observed by pooling the data. Based on the single-marker results and LD structure, clusters and windows were built for 1-Mb intervals. For conductivity and dressing out, 183 and 191 nominal significant associations respectively and six and five clusters respectively were found. Dominance was important for conductivity, and considering dominance in GWASes improved the mapping signals. Most clear signals were found for conductivity on SSC6, 8 and 15 and for dressing out on SSC2 and 7. Considering dominance might contribute to the accuracy of genomic selection and serve as a guide for choosing mating pairs with good combining abilities. However, further research is needed to investigate if dominance is also important in crossbreed pig breeding schemes. PMID- 29978911 TI - 131 -Oxophorbine protopheophorbide A from Ziziphus lotus as a novel mesenchymal epithelial transition factor receptor inhibitory lead for the control of breast tumor growth in vitro and in vivo. AB - The failure of chemotherapy especially in triple negative breast cancer (TNBC) patients has been correlated with the overexpression of the mesenchymal epithelial transition factor (c-Met) receptor. Thus, the hepatocyte growth factor (HGF)/c-Met signaling axis has gained considerable attention as a valid molecular target for breast cancer therapy. This study reports for the first time the discovery of the 131 -oxophorbines pheophorbide A and protopheophorbide A along with chlorophyllide A from Ziziphus lotus, an edible typical Tunisian plant, as the potent antiproliferative compounds against the human breast cancer cells MDA MB-231 and MCF-7. Compared to other compounds, protopheophorbide A exerted the highest light-independent antiproliferative effect against the metastatic TNBC MDA-MB-231 cells (IC50 = 6.5 MUM). In silico, this compound targeted the kinase domain of multiple c-Met crystal structures. It potently inhibited the kinase domain phosphorylation of wild and mutant c-Met in Z-LYTE kinase assay. Protopheophorbide A inhibited HGF-induced downstream c-Met-dependent cell proliferation, survival, adhesion and migration through RAF/MEK/ERK and PI3K/PTEN/AKT signaling pathways modulation, ROS generation and activation of JNK and p38 pathways. Interestingly, this compound impaired the ability of the MDA-MB 231 cells to adhere at different extracellular matrix proteins by reducing the HGF-induced expression of integrins alphav, beta3, alpha2, and beta1. Moreover, protopheophorbide A exhibited anti-migratory properties (IC50 = 2.2 MUM) through impacting the expression levels of E-cadherin, vimentin, beta-catenin, FAK, Brk, Rac, and Src proteins. Importantly, treatment with protopheophorbide A significantly inhibited the MDA-MB-231 tumor growth in vivo. Our results suggest that protopheophorbide A could be a novel c-Met inhibitory lead with promise to control c-Met/HGF-dependent breast malignancies. PMID- 29978912 TI - A sensitive and validated HPLC-UV method for the quantitative determination of the new antifungal drug isavuconazole in human plasma. AB - Isavuconazole is a broad-spectrum triazole antifungal drug recently approved for the therapy of both invasive aspergillosis and mucormycosis. To support a widespread therapeutic drug monitoring of isavuconazole, a simple, sensitive, and precise high-performance liquid chromatography method with UV detection was developed and fully validated for the quantification of this drug in human plasma. The method involved a combined protein precipitation-solid-phase extraction and a chromatographic separation on a Waters XTerra RP18 (150 * 4.6 mm, 3.5 MUm) column using an isocratic mobile phase of ammonium acetate buffer (pH 8.0, 10 mm) and acetonitrile (45:55, v/v). The UV detection was performed at 285 nm. This method was linear (correlation coefficients >=0.998), specific (no interference with plasma components or various potentially co-administrated drugs), sensitive (lower limit of quantification of 0.025 MUg/mL), reproducible (coefficients of variation were <=7.9%) and accurate (deviations ranged from -5.0 to 8.0%) over the range of 0.025-10 MUg/mL. The method fulfilled all of the US Food and Drug Administration guidelines validation criteria and performed well in an international proficiency testing program. The assay was also successfully applied to routine therapeutic drug monitoring of patients and to drug stability investigations under various conditions. PMID- 29978913 TI - Designing 'free' spaces for children with disabilities. PMID- 29978914 TI - Variation in health care for children and young people with a disability. PMID- 29978916 TI - The moral self and moral identity: Developmental questions and conceptual challenges. AB - Research into moral identity has provided much support for its role in mature moral functioning, yet the developmental course of this construct remains poorly understood. In this review, we examine the dominant developmental model of moral identity, which emphasizes its key relation with the moral self of early childhood. In reviewing evidence for the model, the assumption of correspondence between the moral self of early childhood and moral identity in adolescence is challenged, in terms of both the moral component and the sense-of-self entailed in both constructs. We argue that progress in mapping the developmental course of moral identity stands to be informed by a focus on middle childhood, which to date has been largely neglected in this literature, despite evidence implicating this period from related fields of inquiry. A number of specific directions for future developmental research into moral identity are outlined based on this perspective. Statement of contribution What is already known on this subject? Moral identity is central to adolescent moral functioning. Early childhood 'moral self' becomes adolescent moral identity. What does this study add? The current dominant developmental model is examined. The model is found to have questionable validity. Middle childhood may be of unique importance to the emergence of moral identity. PMID- 29978915 TI - Mechanism of cytokinesis failure in ovarian cystadenomas with defective BRCA1 and P53 pathways. AB - We previously described an in vitro model in which serous ovarian cystadenomas were transfected with SV40 large T antigen, resulting in loss of RB and P53 functions and thus mimicking genetic defects present in early high-grade serous extra-uterine Mullerian (traditionally called high-grade serous ovarian) carcinomas including those associated with the BRCA1 mutation carrier state. We showed that replicative aging in this cell culture model leads to a mitotic arrest at the spindle assembly checkpoint. Here we show that this arrest is due to a reduction in microtubule anchoring that coincides with decreased expression of the BUB1 kinase and of the phosphorylated form of its substrate, BUB3. The ensuing prolonged mitotic arrest leads to cohesion fatigue resulting in cell death or, in cells that recover from this arrest, in cytokinesis failure and polyploidy. Down-regulation of BRCA1 to levels similar to those present in BRCA1 mutation carriers leads to increased and uncontrolled microtubule anchoring to the kinetochore resulting in overcoming the spindle assembly checkpoint. Progression to anaphase under those conditions is associated with formation of chromatin bridges between chromosomal plates due to abnormal attachments to the kinetochore, significantly increasing the risk of cytokinesis failure. The dependence of this scenario on accelerated replicative aging can, at least in part, account for the site specificity of the cancers associated with the BRCA1 mutation carrier state, as epithelia of the mammary gland and of the reproductive tract are targets of cell-nonautonomous consequences of this carrier state on cellular proliferation associated with menstrual cycle progressions. PMID- 29978917 TI - Nursing care of overweight children: A concept analysis. AB - AIM: To report an analysis of the concept nursing care of overweight children. BACKGROUND: Patient care is the essence of nursing practice. Nursing professionals must define how to serve specific population groups, including overweight children, presenting real solutions to their problem. A clear conceptual analysis is necessary to unify nursing language and to contribute to nursing practice. DESIGN: Concept analysis. DATA SOURCES: The following databases were searched: COCHRANE, SCOPUS, LILACS, CINAHL, MEDLINE/PubMed, and CAPES Theses Library of Brazil. REVIEW METHODS: Walker and Avant's concept analysis methodology was adopted in this study. Twenty-two articles were analyzed, and the uses, attributes, antecedents, and outcomes of the concept were identified. The nursing care assumptions proposed by Virginia Henderson comprised the theoretical referential. RESULTS: The attributes of nursing care for overweight children included investigation, guidance, and monitoring of dietary, clinical, academic, and social aspects, along with evaluation of lifestyle and anthropometric data related to the affected children and their families. CONCLUSION: This study enabled the construction of a defined concept for nursing care of overweight children that may be useful in the construction of a medium-range theory. Further research is recommended to verify the usefulness of the nursing approach. PMID- 29978918 TI - Effect of counterface on cartilage boundary lubricating ability by proteoglycan 4 and hyaluronan: Cartilage-glass versus cartilage-cartilage. AB - The objective of this study was to determine the effect of different sliding interface materials (counterface) on the cartilage lubricating ability of proteoglycan 4 (PRG4) and hyaluronan (HA) by measuring the kinetic coefficient of friction on cartilage-glass and cartilage-cartilage interfaces over a wide range of sliding velocities. The lubrication properties of PRG4 and HA were assessed at cartilage-glass and cartilage-cartilage interfaces using a previously described test setup with a stationary area of contact. Samples were articulated at varying effective sliding velocities of 10, 3, 1, 0.3, 0.1, and 0.01 mm/s. The response of PRG4 and HA as effective friction-reducing cartilage boundary lubricants was varied and was dependent primarily on the test counterface. At a physiological cartilage-cartilage interface both HA and PRG4 effectively reduced friction compared to PBS at slower speeds while at higher speeds PRG4 was similar to PBS, and HA similar to SF. Conversely, at a cartilage-glass interface HA demonstrated no friction reducing ability compared to PBS, and PRG4 appeared just as effective as SF. Cartilage-glass friction coefficients were also significantly greater than cartilage-cartilage friction coefficients. These results indicate the in vitro friction coefficient of putative cartilage boundary lubricants can be affected by the test counterface and suggest that use of synthetic surfaces in studying cartilage boundary lubrication may not always be appropriate for all molecules of interest. As such, care should be taken when interpreting such data, specifically when comparing to in vitro data obtained at a cartilage-cartilage interface, and especially when extrapolating to in vivo situations. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 29978920 TI - Triplet Excited States and Singlet Oxygen Production by Analogs of Red Wine Pyranoanthocyanins. AB - During the maturation of red wines, the anthocyanins of grapes are transformed into pyranoanthocyanins, which possess a pyranoflavylium cation as their basic chromophore. Photophysical properties of the singlet and triplet excited states of a series of synthetic pyranoflavylium cations were determined at room temperature in acetonitrile solution acidified with 0.10 mol dm-3 trifluoroacetic acid (TFA, to inhibit competitive excited state proton transfer) and at 77 K in a rigid TFA-acidified isopropanol glass. In solution, the triplet states of these pyranoflavylium cations are efficiently quenched by molecular oxygen, resulting in sensitized formation of singlet oxygen, as confirmed by direct detection of the triplet-state decay by laser flash photolysis and of singlet oxygen monomol emission in the near infrared. The strong visible light absorption, the relatively small singlet-triplet energy differences, the excited state redox potentials and the reasonably long lifetimes of pyranoflavylium triplet states in the absence of molecular oxygen suggest that they might be useful as triplet sensitizers and/or as cationic redox initiators in polar aprotic solvents like acetonitrile. PMID- 29978919 TI - Pharmacokinetics and metabolic elimination of tolbutamide in female rats: Comparison with male rats. AB - As there are to be known gender differences in the expression profiles of rat hepatic CYP2C, we examined the pharmacokinetic behavior of tolbutamide (TB), a typical probe for CYP2C, and hepatic enzyme activities for metabolizing TB in female rats to compare with male rats. On the pharmacokinetic analysis of TB after intravenous administration to female rats, the elimination rate constant at the terminal phase (ke ), total clearance (CLtot ) and the apparent volume of distribution at steady-state (Vdss ) were significantly lower than in male rats. The binding rates of TB to serum protein were similar in male and female rats, indicating that the change in unbound TB concentration in serum is not associated with the difference in the pharmacokinetic disposition of TB. On metabolic examination using hepatic microsomes, the maximum reaction velocity (Vmax ) of the metabolic conversion from TB to 4-hydroxytolbutamide (4-OH-TB) in female rats was lower than that in male rats, although there was no significant difference in the Michaelis constant (Km ) between genders. Consistent with this, the Vmax -to Km ratio (Vmax /Km ) was significantly lower in female rats than in male rats. Therefore, the low in vitro CYP2C-dependent activity for hepatic TB removal in female rats provided a clear explanation for the lower in vivo elimination clearance of TB. Our findings strongly suggest that there is a gender difference in the metabolic capacity to eliminate drugs that serve as substrates of hepatic CYP2C enzymes in rats. PMID- 29978921 TI - Shear fatigue strength of resin composite bonded to dentin at physiological frequency. AB - The purpose of this study was to examine the shear fatigue strengths of a resin composite bonded to dentin. Three adhesive systems - a two-step self-etch adhesive (OptiBond XTR; Kerr) and two universal adhesives [Scotchbond Universal (3M ESPE) and G-Premio Bond (GC)] - were used in self-etch mode to bond a resin composite to dentin at a physiologic frequency of 2 Hz over 50,000, 100,000, and 1,000,000 cycles. A staircase method of fatigue testing was used. Twenty specimens were used for each test condition. There was no significant difference in shear fatigue strength across the cycling periods for the three individual adhesives. Differences in shear fatigue strength were found among the three adhesives within each cycling period. Regardless of the adhesive used in self etch mode for bonding a resin composite to dentin, shear fatigue strength was not influenced by the number of cycles used for testing. PMID- 29978922 TI - Gas and short-chain fatty acid production from feeds commonly fed to red deer (Cervus elaphus L.) and incubated with rumen inoculum from red deer and sheep. AB - Efficient red deer supplementary feeding depends on estimations of the nutritive value of offered feeds, frequently estimated with the use of equations derived from domestic ruminants. The aim of this study was to compare the 24-hour in vitro true dry matter degradability (ivTD24 ), in vitro gas production (GP) kinetic parameters, GP in 24 hr of incubation (GAS24 ) and short-chain fatty acid (SCFA) and microbial biomass (MBS) produced after 24-hour incubation of feeds in inoculum prepared from sheep and red deer rumen fluid. Eleven feeds, frequently consumed by red deer in Slovenia, which occur either naturally (two fresh grasses, chestnut fruits and common and sessile oak acorns) or are fed as winter supplemental feeds (two grass hays, two grass silages, apple pomace, fresh sugar beetroot), were investigated. The in vitro GP kinetic parameters, GAS24 and ivTD24 , did not differ between animal species. Amounts of SCFAs were greater (p < 0.05) when feeds were incubated in sheep inoculum, while molar proportions of acetic and propionic acids did not differ. Molar proportions of butyric acid produced during incubation of high fibre feeds did not differ between animal species, but were higher (p < 0.05) when feeds high in starch or sugar were incubated in red deer inoculum. Greater production of SCFA by sheep rumen microbes suggests better coverage of host animal with energy precursors, while greater production of MBS by red deer rumen microbes suggests better coverage of host animal with protein. Results also suggest that rumens of sheep and red deer are inhabited by different microbial communities, which did not affect the extent of in vitro GP and degradation of feeds used in the present experiment. However, the possibility exists that the divergent nutrient use could be a consequence of different priming by different feeds of the donor animal diets. PMID- 29978923 TI - Template-Directed Synthesis of an Inverted Spiro Architecture. AB - The regular bicyclic spiro motif is highly abundant given its synthetic accessibility while the diastereomer-virtually obtained through inversion at the central atom-is almost unknown. We have developed methodology to access the elusive inverted spiro architecture by employing a covalent template-directed approach. Comparison with the regular spiro bicycle analog unequivocally established the diastereomeric relationship, providing insight into the fascinating stereochemical and structural properties. PMID- 29978924 TI - Photochemistry of OPN: Formation of Cyclic PON and Reversible Combination with Carbon Monoxide. AB - Cyclic PON, a first 16-electron triatomic ring consisting of two first-row elements, has been generated through 193 nm laser photolysis of OPN in cryogenic matrices. When the photolysis (365 nm) was performed in the presence of CO, OPN combines CO and furnishes an exotic acyclic molecule OPNCO. Upon the 193 nm laser irradiation, OPNCO dissociates mainly to OPN and CO with traces of PN and CO2 . The identification of cyclic PON and OPNCO with IR spectroscopy is supported by 15 N-labeling experiments and quantum chemical calculations. PMID- 29978926 TI - Rural health club program focused on strengthening medical students' intention towards a rural medicine career. AB - OBJECTIVE: The aim of this study was to investigate the Towards Rural and Outback Health Professionals in Queensland rural health club's impact in strengthening the University of Queensland medical students' interest in a rural career. It is hypothesised that the Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship program contributed to participants' intention to practice medicine outside a metropolitan location upon graduation. DESIGN: A retrospective cohort study using a mixed-methods approach. A self-administered online survey was conducted to investigate participants' Year 1 elective rural placement experience and career plans combined with the University of Queensland School of Medicine administrative data. PARTICIPANTS: Sixty Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship participants from 2012-2015. MAIN OUTCOME MEASURE: Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship respondents' strengthened their desire to work outside metropolitan locations. RESULTS: Of the 60 Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship participants from 2012-2015, 40 (66.7%) responded. Overall, the Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship program strengthened 38 (95.0%) respondents' desire to work outside metropolitan locations. Seven respondents have graduated and five (71.4%) of these have chosen to work as an intern in a non-metropolitan location. Qualitative data identified some key themes, including reaffirming of rural practice commitment, the many opportunities for hands-on experience, patient interaction and community engagement. CONCLUSION: Towards Rural and Outback Health Professionals in Queensland rural health club played a role in promoting interest in rural careers among University of Queensland medical students through the Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship program. These early findings show involvement in Towards Rural and Outback Health Professionals in Queensland Rural Elective Experience Scholarship has contributed to participants either intending to, or choosing, a rural medicine career. PMID- 29978925 TI - Mutations of Histidine 13 to Arginine and Arginine 5 to Glycine Are Responsible for Different Coordination Sites of Zinc(II) to Human and Murine Peptides. AB - Because mice and rats do not naturally develop Alzheimer's disease, genetically modified animals are required to study this pathology. This striking difference in terms of disease onset could be due to three alterations in the murine sequence (R5G, Y10F and H13R) of the amyloid-beta peptide with respect to the human counterpart. Whether the metal-ion binding properties of the murine peptide are at the origin of such different amyloidogenicity of the two peptides is still an open question. Herein, the main zinc binding site to the murine amyloid-beta at physiological pH has been determined through the combination of several spectroscopic and analytical methods applied to a series of six peptides with one or two of the key mutations. These results have been compared with the zinc binding site encountered in the human peptide. A coordination mechanism that demonstrates the importance of the H13R and R5G mutations in the different zinc environments present in the murine and human peptides is proposed. The nature of the minor zinc species present at physiological pH is also suggested for both peptides. Finally, the biological relevance and fallouts of the differences determined in zinc binding to human versus murine amyloid-beta are also discussed. PMID- 29978927 TI - Norbornadiene-Based Photoswitches with Exceptional Combination of Solar Spectrum Match and Long-Term Energy Storage. AB - Norbornadiene-quadricyclane (NBD-QC) photoswitches are candidates for applications in solar thermal energy storage. Functionally, they rely on an intramolecular [2+2] cycloaddition reaction, which couples the S0 landscape on the NBD side to the S1 landscape on the QC side of the reaction and vice-versa. This commonly results in an unfavourable correlation between the first absorption maximum and the barrier for thermal back-conversion. This work demonstrates that this correlation can be counteracted by using steric repulsion to hamper the rotational motion of the side groups along the back-conversion path. It is shown that this modification reduces the correlation between the effective back conversion barrier and the first absorption maximum and also increases the back conversion entropy. The resulting molecules exhibit exceptionally long half-lives for their metastable forms without significantly affecting other properties, most notably solar spectrum match and storage density. PMID- 29978928 TI - Optically Functionalized Grid-Type Complexes by a Post-Assembly Strategy. AB - Bisterpyridine-based grid complexes can serve as supramolecular three-dimensional scaffolds for the construction of larger molecular assemblies. Through functionalization of the ligand with azide groups, followed by self-assembly and metal-free Huisgen reactions, eight pyrene molecules can be attached to the grid structure in a single reaction step. The orientation and proximity provided by the scaffold allows for tuning the fluorescence properties of the dye molecules. PMID- 29978930 TI - Headline: IPOS Website - Check Us Out! PMID- 29978929 TI - Physical and psychological health among breast cancer survivors: interactions with sedentary behavior and physical activity. AB - BACKGROUND: Reducing sedentary behavior (SED) may be one promising strategy to reduce treatment-related side effects in breast cancer given the unique health benefits distinct from the beneficial effects of moderate-to-vigorous intensity physical activity (MVPA). OBJECTIVES: To examine the associations between SED and the late-effects symptoms of pain, fatigue, and depression among breast cancer survivors (BCS), and the interactive associations between SED, light PA, and MVPA on these symptoms. METHODS: One hundred and ninety-five BCS provided baseline data 3 to 4 months post-systemic treatment, as part of the Life After Breast Cancer: Moving On longitudinal study. Pain, fatigue, and depression symptoms were assessed using validated self-report questionnaires. Objective measures of MVPA, light PA, and SED (i.e. sitting time) were assessed by accelerometers over the same period. Self-reported demographic and medical variables were collected. RESULTS: In hierarchical multiple regression analyses, the interaction effect of MVPA by SED was significantly associated with pain (p = .02), fatigue (p = .01), and depression (p = .006). Follow-up simple slope analyses demonstrated that among BCS with lower levels of MVPA, higher levels of SED significantly predicted higher levels of fatigue (p < .001), higher levels of pain (p = .06), and higher levels of depression (p = .08). CONCLUSIONS: SED was associated with higher levels of fatigue, pain, and depression in BCS, and was more pronounced among those with lower levels of MVPA. However, SED was not associated with these symptoms among BCS with higher levels of MVPA. Pairing health promotion messages to reduce SED and increase MVPA are likely to result in better symptom management. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 29978931 TI - Reinforcing the role of psycho-social oncology in global cancer prevention: applying psycho-oncology research in programmes and practice. AB - Over the past decade, global action to address the emerging crisis in non communicable diseases (NCDs) has escalated. Central to these efforts has been the support and influence of the World Health Organisation and the United Nations with the 2000 civil societies represented by the Non-Communicable Disease Alliance. In particular this reached expression in the world's first High Level Meeting on NCDs by the United Nations leading to the 2011 Political Declaration urging a coordinated global response to NCDs. Where then does psycho-oncology sit in this global context? Psycho-oncology practitioners and their collective, the International Psycho-Oncology Society (IPOS), have traditionally been situated within a patient focus and context. However, through linkages with community based and non-government cancer organisations' agencies, psycho-oncology research and practice has played a key role in reducing cancer risk, improving cancer survivorship, and influencing social and cultural change to eliminate disease related stigma. As a discipline, psycho-oncology has contributed to widespread recognition of patient-centred care in cancer and along with a broad acceptance and endorsement of the IPOS International Standard. However psycho-oncology is less well accepted in nation-state cancer plans and herein lies opportunity. This special issue includes research across the illness continuum from cancer prevention to screening and early detection, and then to tertiary prevention with lifestyle considerations for cancer survivors. Importantly this demonstrates the capacity within psycho-oncology to develop new understandings of cancer as not only a disease but also a context linked to individual, community, and society health and well-being. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 29978932 TI - Effectiveness of high rate and delayed detection ICD programming by race: A MADIT RIT substudy. AB - INTRODUCTION: Data on inappropriate and appropriate ICD therapy, and efficacy of ICD programing strategies by race are limited. METHODS: In MADIT-RIT, we evaluated the risk of ICD therapy by race, and the efficacy of high rate cut-off ventricular tachycardia (VT) zone >=200 beats per minute (bpm) (Arm B), or 60 seconds delay in VT zone 170-199 bpm (Arm C), compared to 2.5 seconds delay at 170 bpm (Arm A) among black and white patients. RESULTS: MADIT-RIT enrolled 272 (20%) black and 1119 (80%) white patients. The risk of inappropriate therapy was similar among blacks and whites, HR 1.25, 95% CI (0.82-1.93), P = 0.30. High rate cut-off or delayed VT therapy was associated with significant reductions in inappropriate therapy among whites, Arm B versus Arm A, HR 0.15, 95% CI (0.08 0.29), P < 0.0001, Arm C versus Arm A, HR 0.19, 95% CI (0.11-0.33), P < 0.001, and black individuals Arm B versus Arm A, HR 0.24, 95% CI (0.01-0.56), P = 0.0001, Arm C versus Arm A, HR 0.30, 95% CI (0.13-0.68), P = 0.004, P interaction > 0.10). However, delayed VT therapy was associated with a trend toward greater reduction in appropriate therapy in black individuals, HR 0.08, 95% CI (0.03-0.27), P < 0.0001 relative to white individuals, HR 0.27, 95% CI (0.16-0.43), P < 0.0001, P interaction = 0.077. CONCLUSION: In MADIT-RIT, high rate and delayed detection ICD programming provided similar benefit with reductions in both inappropriate therapy and unnecessary appropriate therapy among black and white individuals. CLINICALTRIALS. GOV IDENTIFIER: NCT00947310. PMID- 29978934 TI - Anatomical relevance of ablation to the pulmonary artery root: Clinical implications for characterizing the pulmonary sinus of Valsalva and coronary artery. AB - BACKGROUND: Ablation within the pulmonary sinus of Valsalva (PSV) becomes increasingly common in certain ventricular outflow arrhythmia. Understanding the regional anatomy is intensively concerned to avoid procedure complications. PURPOSE: To describe the anatomic relationships of PSV to its adjacent structures using computed tomographic coronary angiograms (CTCA). METHODS: We studied 145 patients (77 males, age 47 +/- 18 years) investigated for chest pain with CTCA. The relationships between the PSV and adjacent structures were described by analysis of 2-dimensional images and 3-dimensional reconstructions. RESULTS: The left adjacent sinus (LAS) was located within 5 mm of the left main coronary artery (LMCA) in 67% cases (19% within 2 mm) and within 5 mm of the left anterior descending coronary artery (LAD) in 87% (36% within 2 mm). The anterior sinus was within 5 mm of the LAD in 1% and out of 5 mm from LMCA in all cases. Note that 93% LAS was within 5 mm of the left aortic sinus of Valsalva (LASV) (within 2 mm in 27%), remaining 80% right adjacent sinus (RAS) within 5 mm from ascending aorta. The right coronary artery (RCA) was within 5 mm of the RAS/right ventricular outflow tract in 82% cases. CONCLUSIONS: Both the left and RASs are intimately related to the aortic root. The LAS is more often close to LMCA, LAD, and the LASV. The anterior sinus is more frequently related to LAD than LMCA. This information may help heighten operator awareness of safety for increasingly performed complex procedures in this area. PMID- 29978933 TI - Diffusion tensor imaging reveals microstructural alterations in corpus callosum and associated transcallosal fiber tracts in adult macaques with neonatal hippocampal lesions. AB - To investigate the effects of neonatal hippocampal lesions on the microstructural integrity of the corpus callosum (CC) in adulthood, macaque monkeys (n = 5) with neonatal bilateral neurotoxic hippocampal lesion (Neo-Hibo) and sham-operated controls (Neo-C, n = 5) were scanned using magnetic resonance diffusion tensor imaging (DTI) technique at 8-10 years old. CC was segmented into seven regionsgrouped into anterior CC (rostrum, genu, rostral body and anterior midbody) and posterior CC (posterior midbody, isthmus and splenium) for data analysis. Associated transcallosal fiber tracts were delineated using probabilistic tractography and evaluated with tract-based spatial statistics (TBSS). Neo-Hibo lesions resulted in significant increased diffusivity indices (mean, axial and radial diffusivity) in CC posterior segments. Also, significant decreased fractional anisotropy (FA) and increased diffusivity indices were seen in the associated transcallosal fiber tracts proximal to motor, posterior parietal and retrosplenial cortices. In Neo-Hibo animals, increased mean diffusivity (MD) in posterior midbody negatively correlated with reduction of CC surface areaand the magnitude of their memory impairments was significantly correlated with FA in transcallosal fiber tracts across splenium. Although no microstructural changes were observed in CC anterior segments, changes in FA values and diffusivity indices were observed in the white matter fibers of the ventromedial prefrontal cortex. Thus, Neo-H lesions resulted in enduring degradation in transcallosal fibers proximal to parietal and retrosplenial cortices, and hemispheric connections through posterior CC. The findings may provide complementary information for understanding the neural substrate of behavioral and cognitive deficits observed in patients with early insult to the hippocampus. PMID- 29978936 TI - Screening of bacterial endophytes as potential biocontrol agents against soybean diseases. AB - AIMS: This research was aimed at identifying and characterizing endophytic micro organisms associated with soybean that have antimicrobial activity towards soybean pathogens. METHODS AND RESULTS: Soybean plants were collected from field trials in four locations of southern Brazil that were cultivated with conventional (C) and transgenic glyphosate-resistant (GR) soybeans. Endophytic bacteria isolated from roots, stems and leaves of soybeans were evaluated for their capacity to inhibit fungal and bacterial plant pathogens and 13 micro organisms were identified with antagonistic activity. Approximately 230 bacteria were isolated and identified based on the 16S rRNA and rpoN gene sequences. Bacteria isolated from conventional and transgenic soybeans were significantly different not only in population diversity but also in their antagonistic capacity. Thirteen isolates showed in vitro antagonism against Sclerotinia sclerotiorum, Phomopsis sojae and Rhizoctonia solani. Bacillus sp. and Burkholderia sp. were the most effective isolates in controlling bacterial and fungal pathogens in vitro. Extracts and precipitates from culture supernatants of isolates showed different patterns of inhibitory activity on growth of fungal and bacterial pathogens. CONCLUSIONS: Bacillus sp. and Burkholderia sp. were the most effective isolates in controlling fungal pathogens in vitro, and the activity is mainly due to peptides. However, most of the studied bacteria showed the presence of antimicrobial compounds in the culture supernatant, either peptides, bacteriocins or secondary metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: These results could be significant to develop tools for the biological control of soybean diseases. The work brought to the identification of micro-organisms such as Bacillus sp. and Burkholderia sp. that have the potential to protect crops in order to enhance a sustainable management system of crops. Furthermore, the study provides the first evidences of the influence of management as well as the genetics of glyphosate-resistant soybean on the diversity of bacterial endophytes of soybean phytobiome. PMID- 29978937 TI - Integrating the Neurobiology of Minority Stress with an Intersectionality Framework for LGBTQ-Latinx Populations. AB - The comprehensive lived experiences of lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals of color remain invisible in neurobiological studies of LGBTQ populations. Models of minority stress posit that LGBTQ and Latinx individuals experience and internalize sexual, ethnic, racial, and gender discrimination, which may adversely impact mental and physical health. However, the current minority stress models predominantly focus on single categorical social identities and do not account for interlocking systems and processes of oppression based on features of sexuality, race, ethnicity, sex, and gender, as explained by an intersectionality framework in feminist theory. Thus, it remains unclear how LGBTQ people of color internalize and navigate multiple cultural, institutional, and societal stressors, and, furthermore, how these sources of stress may affect health and well-being. A potential mechanism for this adverse internalization process is through the effects of stress on neurobiological regulation. This review will apply an intersectionality framework to the examination of how heterosexism, racism, and cissexism, as systems of oppression, create LGBTQ and Latinx lived experiences, and the differential impacts of these inequalities on neurobiological stress regulation. The overarching goal of this manuscript is to advocate for the application of intersectionality theory to advance the ecological validity of biopsychosocial models of multiple-minority stress. PMID- 29978935 TI - Contributions of mothers' and fathers' parenting to children's self-regulation: Evidence from an adoption study. AB - The origins of top-down self-regulation are attributed to genetic and socialization factors as evidenced by high heritability estimates from twin studies and the influential role of parenting. However, recent evidence suggests that parenting behavior itself is affected by parents' own top-down self regulation. Because children's top-down self-regulation is influenced by genetic factors and parenting is influenced by top-down self-regulation, the effects of parenting on children's top-down self-regulation identified in prior studies may partially reflect passive gene-environment correlation. The goal of this study was to examine parenting influences on children's top-down self-regulation using a longitudinal, adoption-at-birth design, a method of identifying parenting influences that are independent of the role of shared genetic influences on children's characteristics because adoptive parents are genetically unrelated to their adopted child. Participants (N = 361) included adoptive families and biological mothers of adopted children. Adoptive mothers' and fathers' harsh/negative parenting were assessed when children were 27 months of age and biological mothers' top-down self-regulation was assessed when children were 54 months of age. Adopted children's top-down self-regulation was assessed when they were 54 and 72 months of age. Results, accounting for child gender, biological mother top-down self-regulation, and the potential evocative effects of adopted child anger, provide evidence that inherited influences and socialization processes uniquely contribute to children's top-down self-regulation. Furthermore, findings demonstrate the importance of both mother's and father's parenting behavior as an influence on young children's top-down self-regulation. The implications of these findings for understanding the complex mechanisms that influence children's top-down self-regulation are discussed. PMID- 29978938 TI - Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor. AB - Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1 b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1 a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors. PMID- 29978940 TI - Double Z plasty advancement flaps for closure of large defects on the forearm. PMID- 29978939 TI - Targeted resequencing of coding DNA sequences for SNP discovery in nonmodel species. AB - Targeted capture coupled with high-throughput sequencing can be used to gain information about nuclear sequence variation at hundreds to thousands of loci. Divergent reference capture makes use of molecular data of one species to enrich target loci in other (related) species. This is particularly valuable for nonmodel organisms, for which often no a priori knowledge exists regarding these loci. Here, we have used targeted capture to obtain data for 809 nuclear coding DNA sequences (CDS) in a nonmodel organism, the Eurasian lynx Lynx lynx, using baits designed with the help of the published genome of a related model organism (the domestic cat Felis catus). Using this approach, we were able to survey intraspecific variation at hundreds of nuclear loci in L. lynx across the species' European range. A large set of biallelic candidate SNPs was then evaluated using a high-throughput SNP genotyping platform (Fluidigm), which we then reduced to a final 96 SNP-panel based on assay performance and reliability; validation was carried out with 100 additional Eurasian lynx samples not included in the SNP discovery phase. The 96 SNP-panel developed from CDS performed very successfully in the identification of individuals and in population genetic structure inference (including the assignment of individuals to their source population). In keeping with recent studies, our results show that genic SNPs can be valuable for genetic monitoring of wildlife species. PMID- 29978941 TI - Worth the wait: Children trade off delay and reward in self- and other-benefiting decisions. AB - Human prosocial behaviors are supported by early-emerging psychological processes that detect and fulfill the needs of others. However, little is known about the mechanisms that enable children to deliver benefits to others at costs to the self, which requires weighing other-regarding and self-serving preferences. We used an intertemporal choice paradigm to systematically study and compare these behaviors in 5-year-old children. Our results show that other-benefiting and self benefiting behavior share a common decision-making process that integrates delay and reward. Specifically, we found that children sought to minimize delay and maximize reward, and traded off delays against rewards, regardless of whether these rewards were for the children themselves or another child. However, we found that children were more willing to invest their time to benefit themselves than someone else. Together, these findings show that from childhood, other- and self-serving decisions are supported by a general mechanism that flexibly integrates information about the magnitude of rewards, and the opportunity costs of pursuing them. A video abstract of this article can be viewed at: https://youtu.be/r8S0DGe7f8Q. PMID- 29978942 TI - Ordered Porous Nitrogen-Doped Carbon Matrix with Atomically Dispersed Cobalt Sites as an Efficient Catalyst for Dehydrogenation and Transfer Hydrogenation of N-Heterocycles. AB - Single-atom catalysts (SACs) have been explored widely as potential substitutes for homogeneous catalysts. Isolated cobalt single-atom sites were stabilized on an ordered porous nitrogen-doped carbon matrix (ISAS-Co/OPNC). ISAS-Co/OPNC is a highly efficient catalyst for acceptorless dehydrogenation of N-heterocycles to release H2 . ISAS-Co/OPNC also exhibits excellent catalytic activity for the reverse transfer hydrogenation (or hydrogenation) of N-heterocycles to store H2 , using formic acid or external hydrogen as a hydrogen source. The catalytic performance of ISAS-Co/OPNC in both reactions surpasses previously reported homogeneous and heterogeneous precious-metal catalysts. The reaction mechanisms are systematically investigated using first-principles calculations and it is suggested that the Eley-Rideal mechanism is dominant. PMID- 29978943 TI - Kinetics of Reversible Protonation of Transient Neutral Guanine Radical in Neutral Aqueous Solution. AB - Time-resolved chemically induced dynamic nuclear polarization (TR-CIDNP) is applied to follow transformation of the short-lived neutral guanine radical into a secondary guanine radical by its protonation, presumably at position N7. In the initial step the photoreaction of guanosine-5'-monophosphate (GMP) with triplet excited 3,3',4,4'-tetracarboxy benzophenone (TCBP) leads to formation of the neutral radical G(-H). . The evidence of the radical conversion is based on the inversion of CIDNP sign for TCBP and GMP protons on the microsecond timescale as a result of the change in magnetic resonance parameters in the pairs of TCBP and GMP radicals due to structural changes of the GMP radical. Acceleration of the CIDNP sign change upon addition of phosphate (proton donor) confirms that the radical transformation responsible for the observed CIDNP kinetics is protonation of the neutral guanine radical with formation of the newly characterized cation radical, (G.+ )'. From the full analysis of the pH-dependent CIDNP kinetics, the protonation and deprotonation behaviour is quantitatively characterized, giving pKa =8.0+/-0.2 of the cation radical (G.+ )'. PMID- 29978944 TI - Effect of heteroscedasticity between treatment groups on mixed-effects models for repeated measures. AB - Mixed-effects models for repeated measures (MMRM) analyses using the Kenward Roger method for adjusting standard errors and degrees of freedom in an "unstructured" (UN) covariance structure are increasingly becoming common in primary analyses for group comparisons in longitudinal clinical trials. We evaluate the performance of an MMRM-UN analysis using the Kenward-Roger method when the variance of outcome between treatment groups is unequal. In addition, we provide alternative approaches for valid inferences in the MMRM analysis framework. Two simulations are conducted in cases with (1) unequal variance but equal correlation between the treatment groups and (2) unequal variance and unequal correlation between the groups. Our results in the first simulation indicate that MMRM-UN analysis using the Kenward-Roger method based on a common covariance matrix for the groups yields notably poor coverage probability (CP) with confidence intervals for the treatment effect when both the variance and the sample size between the groups are disparate. In addition, even when the randomization ratio is 1:1, the CP will fall seriously below the nominal confidence level if a treatment group with a large dropout proportion has a larger variance. Mixed-effects models for repeated measures analysis with the Mancl and DeRouen covariance estimator shows relatively better performance than the traditional MMRM-UN analysis method. In the second simulation, the traditional MMRM-UN analysis leads to bias of the treatment effect and yields notably poor CP. Mixed-effects models for repeated measures analysis fitting separate UN covariance structures for each group provides an unbiased estimate of the treatment effect and an acceptable CP. We do not recommend MMRM-UN analysis using the Kenward-Roger method based on a common covariance matrix for treatment groups, although it is frequently seen in applications, when heteroscedasticity between the groups is apparent in incomplete longitudinal data. PMID- 29978946 TI - Cucurbit[8]uril (CB[8])-Based Supramolecular Switches. AB - The use of cucurbit[8]uril as a molecular host has emerged in the chemical literature as a reliable strategy for the creation of dynamic chemical systems, owing to its ability to form homo- and heteroternary complexes in aqueous media with appropriate molecular switches as guests. In this manner, CB[8]-based supramolecular switches can be designed in a predictable and modular fashion, through the selection of appropriate guests able to condition the redox, photochemical, or pH-triggered behavior of tailored multicomponent systems. Furthermore, CB[8] allows the implementation of dual/triple and linear/orthogonal stimuli-dependent properties into these molecular devices by a careful selection of the guests. This versatility in their design gives these supramolecular switches great potential for the rational development of new materials, in which their function is not only determined by the custom-made stimuli-responsiveness, but also by the transient aggregation/disaggregation of homo- or heteromeric building blocks. PMID- 29978945 TI - Developments in the Chemistry of alpha-Carbonyl Alkyl Bromides. AB - alpha-Carbonyl alkyl bromides are powerful reactive species for the formation of carbon-carbon bonds. Strategies relying on intermolecular C-H functionalization and cross-coupling reactions, also referred to as intramolecular cyclization, have been employed for the construction of alkenes, alkanes, ketones, and other natural-product-like ring compounds from simple alkynes, alkenes, and 1,n-enynes. In view of the importance of these alpha-carbonyl alkyl bromides, especially the difluoro carbonyl alkyl bromides, many researchers have focused their efforts to develop facile and mild synthetic methods for compounds with important biological activities. This review aims to briefly discuss the latest developments in the transformation of alpha-carbonyl alkyl bromides with emphasis on the related reaction mechanisms. PMID- 29978947 TI - Inaccuracy in meta-analysis on safety of eleven drugs for the treatment of Parkinson's disease. PMID- 29978948 TI - Enantioselective Nazarov Cyclizations Catalyzed by an Axial Chiral C6 F5 Substituted Boron Lewis Acid. AB - A chiral variant of B(C6 F5 )3 with a 3,3'-disubstituted binaphthyl backbone is shown to catalyze Nazarov cyclizations with high levels of enantio- and diastereocontrol. The parent B(C6 F5 )3 also promotes these ring closures efficiently. This electrocyclization is another example of the still small family of C-C bond formations mediated by B(C6 F5 )3 as the catalyst. PMID- 29978949 TI - Well-controlled pleural effusion indicated pseudoprogression after immunotherapy in lung cancer: A case report. AB - Squamous cancer (SqCC) of the lung has a poor prognosis. With the advent of immunotherapy, prognosis has tended to improve; however, pseudoprogression poses a challenge to the management of immunotherapy. Herein, we discuss the case of a 47-year-old heavy smoker with advanced SqCC. The patient had recurrent disease after initial successful control of the tumor by concurrent radiochemotherapy, together with ample pleural effusion. Pleural effusion was well controlled with systematic nivolumab and intra-thoracic recombinant endostatin; however with simultaneous deterioration of performance and tumor progression. Nivolumab was maintained with the addition of nab-paclitaxel. The combination soon led to a partial response and rapid improvement of the patient's performance. During treatment of this case, we advocated the early control of pleural effusion as an indicator for pseudoprogression. Our experience might be helpful to identify pseudoprogression for the clinical management of immunotherapy. PMID- 29978950 TI - Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer. AB - BACKGROUND: ALK-tyrosine kinase inhibitors (TKIs) have been proven effective for treating ALK-positive non-small cell lung cancer (NSCLC), although patients present with variable responses and disease progression courses. The detailed underlying molecular mechanisms require further investigation to yield a better prognosis. METHODS: Targeted next-generation sequencing (NGS) mutation profiling was performed on samples from 42 NSCLC patients confirmed positive for ALK rearrangements by fluorescence in situ hybridization or immunohistochemistry who experienced disease progression after crizotinib treatment. RESULTS: ALK rearrangements were not confirmed in six patients (14%) with other potential oncogenic drivers identified by NGS, who therefore did not respond to crizotinib and had significantly shorter overall survival (OS) compared to NGS ALK -positive patients. Fifteen ALK activating mutations were detected in 8 out of 26 post treatment samples (31%), among which ALK L1196M and G1269A were the most common acquired mutations detected in half of the patients with ALK activating mutations. Dynamic monitoring of the genetic evolution in one patient revealed both spatial and temporal heterogeneity of resistant mechanisms during different ALK-TKI treatment courses. Activation of ALK downstream or bypass pathways was detected in patients without ALK activating mutations, such as genetic alterations in PIK3CA, MET, and KRAS. Interestingly, we identified two patients with acquired mutations in the DNA mismatch repair gene POLE, which resulted in a dramatically increased tumor mutation burden, and might contribute to the poor response to crizotinib. CONCLUSIONS: Heterogeneous resistant mechanisms have been identified and correlate to diverse responses to crizotinib. Comprehensive and dynamic mutation profiling is required to better predict clinical outcomes. PMID- 29978951 TI - A global view of the pathophysiology of varicocele. AB - Varicocele is the most common abnormality identified in men being evaluated for subfertility. In this comprehensive review of the pathophysiology of varicocele, we will shed light on novel pathophysiological findings and their clinical implications that may direct future researches; we will shed light on the impact of transient scrotal hyperthermia and the roles of inflammation and differential protein expression and androgen expression in spermatozoa on inducing pathophysiological findings. Furthermore, we will clarify the linked processes contributing to the pathophysiology of varicocele and the impact of genetics on the induction of these processes. Spermatogenesis is a temperature-sensitive process, and heat stress of varicocele is considered the most plausible cause of impaired spermatogenesis. The three processes associated with the presence of varicocele - heat stress, excess reactive oxygen species, and increased apoptosis - appear to be linked; heat stress is associated with increased levels of reactive oxygen species and oxidative stress, which can induce apoptosis. The genetic role should not be overlooked as a contributing factor in the induction of heat stress, excess reactive oxygen species/oxidative stress, and apoptosis; this is evidenced by the association of varicocele with decreased expression of heat-shock proteins, higher polymorphism of glutathione S transferase and nitric oxide synthase genes, and increased BAX and decreased BCL2 genes and proteins. In this article, we will highlight the need of application of novel diagnostic techniques that can provide a precise pathophysiological diagnosis to guide potential specific innovative therapies. Innovative therapies can counteract the varicocele-induced stasis, suppress the degenerative effects of testicular hyperthermia, reduce the varicocele-induced apoptosis, and target the elevated neutrophil products aiming at abrogating the testicular damage caused by the induced varicocele in rats/mice. In conclusion, on the basis of the novel scientific research, it may be possible to formulate new treatments and achieve the appropriate selection of patients who can benefit from these treatments. PMID- 29978952 TI - Ryanodine- and CaMKII-dependent release of endogenous CGRP induces an increase in acetylcholine quantal size in neuromuscular junctions of mice. AB - OBJECTIVE: The aim of this study was to identify the mechanism responsible for an increase in miniature endplate potentials (MEPPs) amplitude, induced by ryanodine as an agonist of ryanodine receptors in mouse motor nerve terminals. METHODS: Using intracellular microelectrode recordings of MEPPs and evoked endplate potentials (EPPs), the changes in spontaneous and evoked acetylcholine release in motor synapses of mouse diaphragm neuromuscular preparations were studied. RESULTS: Ryanodine (0.1 MUM) increased both the amplitudes of MEPPs and EPPs to a similar extent (up to 130% compared to control). The ryanodine effect was prevented by blockage of receptors of calcitonin gene-related peptide (CGRP) by a truncated peptide CGRP8-37 . Endogenous CGRP is stored in large dense-core vesicles in motor nerve terminals and may be released as a co-transmitter. The ryanodine-induced increase in MEPPs amplitude may be fully prevented by inhibition of vesicular acetylcholine transporter by vesamicol or by blocking the activity of protein kinase A with H-89, suggesting that endogenous CGRP is released in response to the activation of ryanodine receptors. Activation of CGRP receptors can, in turn, upregulate the loading of acetylcholine into synaptic vesicles, which will increase the quantal size. This new feature of endogenous CGRP activity looks similar to recently described action of exogenous CGRP in motor synapses of mice. The ryanodine effect was prevented by inhibitors of Ca/Calmodulin-dependent kinase II (CaMKII) KN-62 or KN-93. Inhibition of CaMKII did not prevent the increase in MEPPs amplitude, which was caused by exogenous CGRP. CONCLUSIONS: We propose that the activity of presynaptic CaMKII is necessary for the ryanodine-stimulated release of endogenous CGRP from motor nerve terminals, but CaMKII does not participate in signaling downstream the activation of CGRP-receptors followed by quantal size increase. PMID- 29978953 TI - Immobilization of a Full Photosystem in the Large-Pore MIL-101 Metal-Organic Framework for CO2 reduction. AB - A molecular catalyst [Cp*Rh(4,4'-bpydc)]2+ and a molecular photosensitizer [Ru(bpy)2 (4,4'-bpydc)]2+ (bpydc=bipyridinedicarboxylic acid) were co-immobilized into the highly porous metal-organic framework MIL-101-NH2 (Al) upon easy postsynthetic impregnation. The Rh-Ru@MIL-101-NH2 composite allows the reduction of CO2 under visible light, while exhibiting remarkable selectivity with the exclusive production of formate. This Rh-Ru@MIL-101-NH2 solid represents the first example of MOFs functionalized with both a catalyst and a photosensitizer in a noncovalent fashion. Thanks to the coconfinement of the catalyst and photosensitizer into the cavity's nanospace, the MOF pores are used as nanoreactors and enable molecular catalysis in a heterogeneous manner. PMID- 29978955 TI - [Neuroblastoma]. PMID- 29978954 TI - The deletion of M4 muscarinic receptors increases motor activity in females in the dark phase. AB - OBJECTIVES: M4 muscarinic receptors (MR) presumably play a role in motor coordination. Previous studies have shown different results depending on genetic background and number of backcrosses. However, no attention has been given to biorhythms. MATERIAL AND METHODS: We therefore analyzed biorhythms under a light/dark cycle obtained telemetrically in intact animals (activity, body temperature) in M4 KO mice growth on the C57Bl6 background using ChronosFit software. Studying pure effects of gene knockout in daily rhythms is especially important knowledge for pharmacological/behavioral studies in which drugs are usually tested in the morning. RESULTS: We show that M4 KO mice motor activity does not differ substantially from wild-type mice during light period while in the dark phase (mice active part of the day), the M4 KO mice reveal biorhythm changes in many parameters. Moreover, these differences are sex-dependent and are evident in females only. Mesor, night-day difference, and night value were doubled or tripled when comparing female KO versus male KO. Our in vitro autoradiography demonstrates that M4 MR proportion represents 24% in the motor cortex (MOCx), 30% in the somatosensory cortex, 50% in the striatum, 69% in the thalamus, and 48% in the intergeniculate leaflet (IGL). The M4 MR densities were negligible in the subparaventricular zone, the posterior hypothalamic area, and in the suprachiasmatic nuclei. CONCLUSIONS: We conclude that cholinergic signaling at M4 MR in brain structures such as striatum, MOCx, and probably with the important participation of IGL significantly control motor activity biorhythm. Animal activity differs in the light and dark phases, which should be taken into consideration when interpreting the results. PMID- 29978956 TI - [Multidisciplinary approach on subglottic pathology: a 5-year review]. AB - INTRODUCTION: Pediatric subglottic pathology still represents a challenge when it comes to choosing the right treatment. We present the management of patients followed in our center for this reason during the last 5 years. MATERIAL AND METHODS: Retrospective study of patients followed by glotosubglottic pathology (stenosis, cysts or granulomas) between 2011 and 2016 in a third level hospital. RESULTS: Twenty-seven patients were included in the review. Treatment options varied according to the nature, location and severity of the subglottic stenosis. Two patients with congenital subglottic stenosis were treated by laryngotracheoplasty. Seventeen patients with acquired subglottic stenosis were included: in one (5.9%) laryngotracheoplasty was performed, one (5.9%) received cricotracheal split, two of them (11.8%) underwent partial cricotracheal resection (PCTR) , seven patients (41.2%) underwent microsurgery, three (17.6%) received tracheal dilatation, and the last three (17.6%) were submitted to observation without needing further treatment. Five patients with post-intubation subglottic cysts received microsurgery. Of three patients diagnosed with post intubation subglottic granuloma, two (66%) resolved spontaneously and one (33%) required microsurgery. CONCLUSIONS: Management of pediatric subglottic pathology remains a major challenge. Since the creation of the Airway Committee in our center, the improvement in the management of these patients has led to a multidisciplinary management, with the consequent impact on the clinical results. PMID- 29978957 TI - [Pulmonary lobectomy in children: the sooner the better?] AB - AIM OF THE STUDY: Recommendation of early pulmonary resection in asymptomatic congenital pulmonary airway malformations (CPAMs) is based on the presumed compensatory lung growth during the first months of life. Our aim is to analyze the long-term pulmonary function after lobectomy before and after one year of age using spirometry. METHODS: We performed a retrospective review of children who underwent pulmonary lobectomy for CPAM between 2001 and 2016. Patients who were old enough (>5 years) to carry out a spirometry were included in the study and were divided into 2 groups (surgery before or after 12 months of age). Pulmonary function testing values were considered normal if they were >80% of predicted. MAIN RESULTS: Forty-seven patients underwent pulmonary lobectomy for CPAM, 23 of them met the inclusion criteria and prospectively performed a spirometry. Among them, 7 had surgery before and 16 after one year of age (0.1 vs. 2); being both groups comparable in terms of sex, type of CPAM and surgical approach. Time from surgery until pulmonary function testing was longer in patients who had surgery before one year of age (9.1 vs. 4.6 years, p = 0.003). After correcting results by time from surgery until spirometry, a better FEV1/FVC was found in patients who had surgery after one year of age (90% vs. 77%, p = 0.043). CONCLUSION: Although spirometry may be influenced by many other variables, these preliminary results do not support the current recommendation of performing early lobectomy in CPAMs. Further studies are required in order to resolve the best age to perform pulmonary lobectomy. PMID- 29978958 TI - [Study of pulmonary hypertension and long-term respiratory clinic in children with congenital diaphragmatic hernia]. AB - INTRODUCTION AND OBJECTIVES: The aim of this study is to identify respiratory clinic and pulmonary arterial hypertension (PAH) in congenital diaphragmatic hernia (CDH) and whether these could be predicted by prenatal measures. MATERIAL AND METHODS: We studied fetal ultrasound: Observed/expected Lung to Head Ratio (O/E LHR) and classified patients according to their outcome (group 1: O/E LHR <25%, group 2: 26-35%, group 3: 36-45%, group 4: >55%) as well as the severity of PAH (group 0: non-PAH, group 1: mild, group 2: moderate, group 3: severe) in echocardiograms at birth, 1st, 6th, 12th and 24 months of life. We also evaluated gestational age, weight, bronchodilator treatment and number of hospital admissions. RESULTS: 58 patients with CDH, 13 without prenatal diagnosis. 36 patients out of 45 had O/E LHR calculated at 22.4 +/- 5.8 weeks. O/E LHR had significant association with the severity of PAH at birth and in the 1st, 6th, 12th and 24th months (p <0.05). At 6 months, only 30.4% had PAH without any association with a higher risk of hospital admission [OR 1.07 (0.11-10.1)] and only three patients (5.1%) required bronchodilator treatment. CONCLUSION: In CDH, PAH and the respiratory clinic improve over time, being uncommon the need for treatment as of the 6th month. O/E LHR predicts the presence and severity of PAH in short and long term. PMID- 29978959 TI - [Management of suspected foreign body aspiration in children. 10-year experience in a single center]. AB - INTRODUCTION: Foreign body aspiration (FBA) is a potentially life-threatening event, and is the leading cause of death in children after road traffic injuries. If suspected, a prompt exploration of the airway should be performed. We present our experience in FBA treatment in the last 10 years. MATERIAL AND METHODS: A retrospective study of patients admitted in our center with suspected FBA between 2005 and 2015 was performed. Clinical history, physical findings, radiologic imaging, treatment and evolution were assessed. RESULTS: A total of 115 children (70 M/45 F) with a median age of 2 years old (8 months-13 years), presented with a clinical history of FBA. All of them suffered a choking event and the most frequent symptoms were persistent cough (88.3%) and respiratory distress (46.8%). Pathologic physical examination was registered in 75% and an abnormal chest X-ray was seen in 72%. Rigid bronchoscopy (RB) was performed in 100% based on compatible history, regardless of physical and radiologic exams. A foreign body was found during RB in 78 patients (68.1%) and the most frequent were seeds and nuts (63.4%), located mainly in the right bronchus (46.8%). If the criteria for RB had been based on a compatible history along with clinical findings and abnormal chest X-ray, 21 foreign bodies (26.9%) would have been missed, with the subsequent risk of sudden death. All the foreign bodies were removed with success, without any immediate complication during the procedure. CONCLUSION: FBA is a frequent accident among children. The history, clinical findings and imaging cannot always concur. In case of a positive history of FBA an examination of the tracheobronchial tree must be done. PMID- 29978960 TI - [Retrospective analysis of morbidity and mortality of intestinal atresias in newborns]. AB - OBJECTIVE: Intestinal atresia (IA) is the most common obstructive congenital malformation in the gastrointestinal tract. The aim is to describe the morbidity and mortality of AI in our series. METHODS: Retrospective study in infants with AI who underwent surgery in our hospital in the past 15 years. Descriptive analysis was performed by collecting clinical and epidemiological variables. Qualitative and quantitative statistical analysis were performed. RESULTS: A total of 32 patients, 40.6% (13) women and 59.4% (19) males, maternal age 31 +/- 5 years. Prenatal care in 96.8% (30) and prenatal diagnosis in 68.8% (22). Gestational age 35 +/- 3 (SG 25-41), birth weight 2,506 +/- 516 g (920-3,470 g). 53% (17/32) were localized in duodenum (65% extrinsic, 35% type I); 37.5% (12/32) jejunoileal (16.6% type I, 25% type II, 16.6% type IIIa, 16.6% type IIIb and 25% type IV); 6.5% (2/32) were colonic and 3% (1/32) pyloric. In 65.6% (21/32) it was associated with other congenital malformation. 81.3% (26) were operated within the first 48 hours of life. 15.6% (5/32) required enterostomy. 21.8% (7/32) had complications requiring reoperation in 71% (5/7) with 1 case of short bowel syndrome. Median time to enteral nutrition onset was 10 days (IQR 7-15), higher in patients with ileal atresia. Hospital stay was 33 days (interquartile range 23 66 days) and overall mortality of 9.3%. CONCLUSION: In our series the congenital malformations associated with intestinal atresia were determinant in the prognosis and mortality of these patients. PMID- 29978961 TI - [Perinatal factors for necrotizing enterocolitis (NEC). A case-control study]. AB - AIM OF THE STUDY: The aim of this study is to identify potential perinatal risk or protective factors associated with NEC. MATERIALS AND METHODS: Single-center, retrospective case-control study of newborns admitted to the neonatal intensive care unit with NEC from 2014 to 2015. Clinical charts were reviewed recording maternal factors (fever, positive recto-vaginal swab and signs of corioamnionitis or fetal distress), and neonatal factors analyzed were: birth-weight and weeks gestation, umbilical vessel catheterization, time of enteral feedings and the use of probiotics, antibiotics and antifungal agents. Cases and controls were matched for all of these factors. Parametric tests were used for statistical analysis and p < 0.05 deemed significant. RESULTS: We analyzed 500 newborns of which 44 developed NEC (cases) and 456 controls. Univariate analysis did not identify any maternal risk factors for NEC. We did not found statistical differences between patients either time of enteral feedings or probiotics. Nevertheless, patients with signs of fetal distress and early sepsis had a higher risk of NEC (p < 0.0001). CONCLUSIONS: Infants with history of fetal distress and signs of early sepsis are at a higher risk of NEC. The use of prophylactic catheter infection or orotracheal intubation with antifungal treatment seemed to elevate the incidence of NEC. However, antibiotic treatment couldn't be demonstrated to increase the risk of NEC. PMID- 29978962 TI - [Management and description of neonatal tumours in a surgical oncology unit]. AB - AIM: Neonatal tumours represents less than 2% of all childhood cancers. The biological behaviour of this tumours will differ in older children. The tumours's biological differences and the immature physiological characteristics of newborns represent a great therapeutically challenge making newborns vulnerable. The aim of this study is to describe the clinical characteristics, associated malformations, diagnostic methods, treatment and the outcomes of neonatal tumours. METHODS: Retrospective review of patients <= 28 days-old with diagnosis of neonatal tumour between 2000-2016. Statistical analysis of clinical characteristics, histology, diagnostic methods, treatment and morbimortality. RESULTS: A total of 26 tumours were diagnosed in newborns with a mean age of 4.85 +/- 8.9 days and 69.2% of boys. Prenatal diagnosis was achieved in 38.5% (n = 10) and 38.5% (n = 10) in the first week of age. Associated malformations were found in 30.6% (n = 8). The most frequent tumours were hepatic hemangioma 23.1% (n = 6), neuroblastoma 15.4% (n = 4) and sacrococcygeal teratoma 11.5% (n = 3). Medical treatment was indicated in 7.7% (n = 5), surgical 57.7% (n = 15) and observation 30.8% (n = 7). Global mortality was 19.23% (n = 5) of which 42.9% (n = 3/7) were perioperatively. CONCLUSIONS: The management of neonatal tumours require a multidisciplinary approach to minimize the consequences and assure the best outcome. Global mortality is low and depends primarily of the physiologic and association of other malformations of the newborn. PMID- 29978963 TI - [Is there a difference in the postoperative follow up of ureteropelvic junction obstruction according to age?] AB - OBJECTIVE: To compare postoperative follow up in patients older and younger than 12 months who underwent surgical treatment of ureteropelvic junction obstruction (UJO). MATERIAL AND METHODS: Retrospective study of 77 patients, 78 kidney units, intervened from UJO (2007-2014). We analyzed epidemiological, clinical, echographic, and pre and postoperative renogram variables, outcomes and complications. We divided the patients into 2 groups according to age: group A <= 12 months and group B > 12 months, comparing the results by statistical analysis, considering p < 0.05 statistically significant. RESULTS: Group A: 38 patients, 26 males (68.4%), one bilateral UJO and 22 rights (57.9%), 36 prenatal diagnoses (92.3%) and mean age of intervention 5.28 months [range 0.24 -11,28]. We performed 9 minilumbotomies, 29 assisted by retroperitoneoscopy (ARP) and 1 pneumatic dilation (PD). Group B: 39 patients, 26 males (66.7%), 10 rights (25.64%), 19 prenatal diagnoses (48.7%) and mean age 6.13 years [range 1.13 14.52]. 15 minilumbotomies, 20 ARP, 3 laparoscopic and 1 PD. Preoperative mean renal function (MRF) of group A: 35.9 +/- 13.4 [range 8-57] vs. 39.74 +/- 13.91 [range 9-57] in group B (p = 0.347). Postoperative MRF 43.29 +/- 18.2 [range 12 100] group A and 39.41 +/- 12.89 [range 11-54] group B (p = 0.464). Group A and B: 11 and 8 complications, respectively (p = 0.429). We did not find statistically significant differences in the mean preoperative anteroposterior diameter (DAP) between both groups (p = 0.313). We compared DAP at 3, 6, 12, 24 and 48 postoperative months, observing a greater reduction of DAP from group A compared to B; however, we found only statistically significant differences in DAP at 3 months postoperatively (p = 0.047). CONCLUSION: Renal DAP is reduced postoperatively more in patients younger than 1 year. Moreover, an improvement of the DRF after pieloplasty can be observed despite not being statistically significant. PMID- 29978966 TI - Targeted communication training raises hospital safety culture scores. PMID- 29978968 TI - Expand your hybrid OR horizons at conference town halls. PMID- 29978969 TI - Help decode ICD-10 for prompt reimbursement. PMID- 29978970 TI - 2016 IAHCSMM Conference: A comprehensive CS learning experience. PMID- 29978971 TI - Higher staff turnover correlates with volume increase at ASCs. PMID- 29978972 TI - High competency levels promote ASC staff and patient satisfaction. PMID- 29978973 TI - Creativity holds keys to competency assessment. PMID- 29978974 TI - Salary remains flat as volume increases for OR leaders. PMID- 29978976 TI - Preventing a cyber attack takes commitment-and money. PMID- 29978975 TI - Bundled payments: Part and parcel of value-based care. PMID- 29978977 TI - Three steps forward: Designing a superior sterile processing system. PMID- 29978978 TI - Survey finds little change in ASC leader compensation, satisfaction. PMID- 29978979 TI - Dirty scopes persist despite cleaning protocol compliance. PMID- 29978980 TI - OR business conference brings big ideas to the Big Easy in 2017. PMID- 29978981 TI - Anesthesia patient satisfaction hinges on safety, comfort, and communication. PMID- 29978982 TI - Performance improvement teams can move the needle from 'good' to 'great'. PMID- 29978983 TI - Seroprevalence of Toxoplasma gondii infection in pregnant women attending antenatal care in southern Ethiopia. AB - OBJECTIVE: The aim of the study was to assess the prevalence and possible risk factors of Toxoplasma gondii (toxoplasmosis) infection in pregnant women attending antenatal care at Gambo General Rural Hospital, southern Ethiopia. METHODS: Hospital-based, prospective cross-sectional study. We collected 401 serum samples from September 1 to October 30, 2015, along with sociodemographic data and data on potential risk factors, using a simple random sampling technique. RESULTS: The overall seroprevalence of T. gondii in pregnant women (mean age 23.1 years) was 23.9% (95% confidence interval [CI] 20.0, 28.3). We did not find any significant risk factors associated with seropositivity in relation with participants' level of education; occupation; contact with cats; consumption of raw or uncooked meat, vegetables, or milk; or type of flooring (soil versus cement) at home. The women who were aware of the risk of toxoplasma infection on the fetus had fewer T. gondii antibodies. Drinking unsafe water was as-sociated with a higher risk of toxoplasmosis (p = 0.08). CONCLUSIONS: The seroprevalence of toxoplasmosis among pregnant women was relatively lower. PMID- 29978984 TI - [Post-vaccine exanthema in a patient with the IgG4 related disease]. PMID- 29978985 TI - Action steps for safe use of reprocessed single-use medical devices. PMID- 29978986 TI - Medicare reimbursement rates set to rise 1.2% in 2017. PMID- 29978987 TI - Smart marketing helps ASCs attract patients and surgeons -- Part 1. PMID- 29978988 TI - Joint Commission survey standards tighten for 2017. PMID- 29978989 TI - New data show enhanced surgical patient care lessens pain, length of stay. PMID- 29978991 TI - ASC quality scores added to Hospital Compare. PMID- 29978990 TI - Cleaning verification tests boost confidence in instrument decontamination. PMID- 29978992 TI - Smart marketing helps ASCs attract patients and surgeons-Part 2. PMID- 29978993 TI - Colorectal SSIs plummet with evidence-based care bundles. PMID- 29978994 TI - Military leadership principles point way to better patient care. PMID- 29978995 TI - SSIs fall sharply with team-based protocol changes. PMID- 29978996 TI - Surgical receipt raises quality standards, lowers costs. PMID- 29978997 TI - Huddles help hospitals move toward the goal. PMID- 29978998 TI - Is pain treatment a risk or reward for ASCs? PMID- 29978999 TI - Total joint PSH helps meet patient satisfaction goals. PMID- 29979000 TI - Building a business case for new technology. PMID- 29979001 TI - Reimbursement denials diminish with more precise precertification. PMID- 29979002 TI - Plan B: Managing surgical equipment failure. PMID- 29979003 TI - IUSS drops to 5% with team intervention. PMID- 29979004 TI - Top 10 health technology hazards for 2017 named. PMID- 29979005 TI - Adding new business to the ASC, one procedure at a time - Part 1. PMID- 29979006 TI - Bedside blood glucose testing in critically ill patients Addressing discrepancies and confusion in the use of handheld meters. PMID- 29979007 TI - Understanding diabetes testing: Where are we, and where are we going? PMID- 29979008 TI - Using strategic marketing approaches in lab outreac. PMID- 29979009 TI - A practical checklist for creating lab value with your physicians. PMID- 29979010 TI - Assessing the suitability of NGS panels for clinical sequencing. PMID- 29979012 TI - LDTs and the FDA: The saga continues. PMID- 29979011 TI - Long-read sequencing An alternative to Sanger-based instruments. PMID- 29979013 TI - Metrics of assay accuracy. PMID- 29979014 TI - Summer's coming! What's new with Zika? PMID- 29979015 TI - A system-wide movement to improve patient care and reduce unnecessary laboratory testing. PMID- 29979016 TI - Engineering Two-Dimensional Mass-Transport Channels of the MoS2 Nanocatalyst toward Improved Hydrogen Evolution Performance. AB - In addition to the intrinsic catalytic activity, the mass transport should be taken into adequate account in order to realize the superior performance of electrocatalysts. Here, we engineer the interstitial space between MoS2 nanosheets via the introduction of "spacers" to construct two-dimensional (2D) channels for favorable mass transport. The nano-sized spacers effectively separate MoS2 nanosheets, generating open and connective channels to fulfill timely reactant supply and rapid gas release. Besides, the spacer served as the physical support can prevent the collapse of 2D channels. Because of the engineering of nanostructured channels, a reduction in overpotential by approximately 100 and 360 mV at -10 and -100 mA cm-2, respectively, a decrease in the Tafel slope from 66.7 to 39.4 mV dec-1, and a more stable operation can be achieved. After being integrated by carbon paper, a further improved performance of 198 mV at -200 mA cm-2 and 36 mV dec-1 can be obtained. This work emphasizes the importance of mass-transport channels and paves a way to enhance the hydrogen evolution reaction performance. PMID- 29979017 TI - Poly(dimethylsiloxane) Stamp Coated with a Low-Surface-Energy, Diffusion Blocking, Covalently Bonded Perfluoropolyether Layer and Its Application to the Fabrication of Organic Electronic Devices by Layer Transfer. AB - It is demonstrated that a stamp composed of a poly(dimethylsiloxane) (PDMS) bulk and perfluoropolyether (PFPE) coating fabricated by a simple dip-coating method has the following properties that are ideal for the transfer patterning of various materials. Deposited by a condensation reaction between PDMS and PFPE molecules as well as the adjacent PFPE molecules, the PFPE coating has a strong adhesion to the PDMS surface and strong internal cohesion, while providing a low energy surface. Furthermore, it is found to function as a bidirectional diffusion barrier: it effectively prevents organic small molecules deposited on the stamp from being absorbed into free volumes of PDMS; it also prevents PDMS oligomers from migrating onto the layer to be transferred, thereby avoiding the contamination of that layer. Morphological and elemental characterization of the surfaces of the transferred organic semiconductor and graphene layers confirms a successful transfer with a high degree of surface cleanliness. The quality of interfaces mechanically bonded using the PFPE-coated stamps and the cleanliness of the transferred layers are remarkably high that the electronic functions of a transfer-bonded organic heterojunction are comparable to those of the same interface formed by vacuum deposition, and that the charge transport across the transfer-bonded graphene-graphene and graphene-MoO3 interfaces is efficient. Our results demonstrate that the PFPE-coated stamp enables patterned depositions of materials with high quality interfaces while avoiding a high temperature or wet process. PMID- 29979018 TI - Self-Cleaning, Chemically Stable, Reshapeable, Highly Conductive Nanocomposites for Electrical Circuits and Flexible Electronic Devices. AB - Materials with multiple functions are highly desirable in practical applications. Developing multifunctional nanocomposites by a straightforward process is still a challenge. Here, a versatile nanocomposite has been developed by simple blending and pressing of multiwalled carbon nanotubes (MWCNTs) and modified polydimethylsiloxane (MPDMS). Because of the synergistic effect of MWCNTs and MPDMS, this nanocomposite exhibits outstanding hydrophobic property, striking self-cleaning capability, and excellent chemical stability against strong acid and strong base, which makes it possible to work under wet and even extreme chemical conditions. Besides, because of its flexibility, this nanocomposite can be reshaped, bended, twisted, and molded into on-demand patterns for special applications. Owing to the good distribution of MWCNTs, the nanocomposite shows high conductivity (with a sheet resistance of 86.33 Omega sq-1) and high healing efficiency (above 96.53%) in an electrical field, and it also exhibits outstanding performance in various electrical circuits and flexible electroluminescent devices. Furthermore, the inherent portability, recyclability, and reusability of this nanocomposite make it more convenient and environmentally friendly for practical applications. Thus, our work provides a new strategy to develop a multifunctional nanocomposite, and it shows tremendous potential in flexible electronics. PMID- 29979019 TI - General and Scalable Approach to Bright, Stable, and Functional AIE Fluorogen Colloidal Nanocrystals for in Vivo Imaging. AB - Fluorescent nanoparticles built from aggregation-induced emission-active organic molecules (AIE-FONs) have emerged as powerful tools in life science research for in vivo bioimaging of organs, biosensing, and therapy. However, the practical use of such biotracers has been hindered owing to the difficulty of designing bright nanoparticles with controlled dimensions (typically below 200 nm), narrow size dispersity and long shelf stability. In this article, we present a very simple yet effective approach to produce monodisperse sub-200 nm AIE fluorescent organic solid dispersions with excellent redispersibility and colloidal stability in aqueous medium by combination of nanoprecipitation and freeze-drying procedures. By selecting polymer additives that simultaneously act as stabilizers, promoters of amorphous-crystalline transition, and functionalization/cross-linking platforms, we demonstrate a straightforward access to stable nanocrystalline FONs that exhibit significantly higher brightness than their amorphous precursors and constitute efficient probes for in vivo imaging of the normal and tumor vasculature. FONs design principles reported here are universal, applicable to a range of fluorophores with different chemical structures and crystallization abilities, and are suitable for high-throughput production and manufacturing of functional imaging probes. PMID- 29979020 TI - Improving the Efficiency of Mustard Gas Simulant Detoxification by Tuning the Singlet Oxygen Quantum Yield in Metal-Organic Frameworks and Their Corresponding Thin Films. AB - The photocatalytically driven partial oxidation of a mustard gas simulant, 2 chloroethyl ethyl sulfide (CEES), was studied using the perylene-based metal organic framework (MOF) UMCM-313 and compared to the activities of the Zr-based MOFs: PCN-222/MOF-545 and NU-1000. The rates of CEES oxidation positively correlated with the singlet oxygen quantum yield of the MOF linkers, porphyrin (PCN-222/MOF-545) < pyrene (NU-1000) < perylene (UMCM-313). Subsequently, thin films of UMCM-313 and NU-1000 were solvothermally grown on a conductive glass substrate to minimize catalyst loading and prevent light scattering by suspended MOF particles. Using a conductive glass support, the initial turnover frequencies of the MOFs in the photocatalytic reaction improved by 10-fold. PMID- 29979021 TI - Confining Mn2+-Doped Lead Halide Perovskite in Zeolite-Y as Ultrastable Orange Red Phosphor Composites for White Light-Emitting Diodes. AB - CsPbX3 (X = Cl, Br, I) perovskite quantum dots (QDs) have emerged as competitive candidate luminescent materials in the photoelectric fields due to their superior luminescence properties. However, the major drawback such as poor resistance to temperature, moisture, and irradiation of light, especially for the red QDs with I-, hinders their practical applications. Herein, we synthesized Mn2+-doped CsPbCl3 embedded in the cage of zeolite-Y as a new orange-red phosphor for the white light-emitting diode (WLED). The composites have significantly improved resistance to both elevated temperature and water over the bare Mn2+-doped QDs. The former exhibits little degradation whereas the latter shows apparent decline upon the irradiation of lights in the orange LED devices, which are fabricated by employing each material as a color-conversion phosphor coated on a 365 nm UV chip. A WLED is also achieved with a 365 nm UV chip coated with a CsPb(Cl0.5,Br0.5)3-Y blue phosphor and a CsPb0.75Mn0.25Cl3-Y orange phosphor. The device possesses a Commission Internationale de l'Eclairage coordinate of (0.34, 0.36), a correlated color temperature of 5336 K and a color rendering index of 81. PMID- 29979022 TI - Self-Quenched Metal-Organic Particles as Dual-Mode Therapeutic Agents for Photoacoustic Imaging-Guided Second Near-Infrared Window Photochemotherapy. AB - The nanosized metal-organic particles (NMOPs) recently have attracted tremendous attentions in biomedical applications. However, few studies have developed metal organic nanoparticles (NMOPs) as near-infrared (NIR) II phototherapeutic agents and as Fenton-like agents for cancer theranostics. Herein, directly using organic dye and Cu(II)-ion complexes to construct NMOPs, as dual-mode therapeutic agent for PA imaging-guided photochemotherapy in NIR II window, is reported. The NMOPs are simply an assembly of Cu(II) ion and tetrahydroxyanthraquinone (THQ) complexes [Cu(II)-THQ] n through the coordination effect, van der Waals force, and pi-pi interactions. After modification of polyethylene glycol (PEG-(NH2)2), the obtained Cu-THQNPs endow excellent biocompatibility and stability in physiological conditions. Because of the strong absorption at NIR II window and photoinduced electrontransfer (PET) mechanism, the Cu-THQNPs not only acted as an excellent photothermal agent with extremely high light-to-heat conversion ability (51.34%) at 1064 nm for phototherapy but also explored as the PA contrast agent for precisely tracking and guiding the therapy in vivo. Most strikingly, our Cu THQNPs can be degraded by tumor-specific acidic-cleaving of the coordination bonds and follow by the slow release of Cu(II) into tumors, which can act as Fenton-like agents to generate *OH from H2O2 for enhancing the antitumor efficacy in vivo. With almost 100% prevention of the tumor growth for ca. 14 days and no obvious toxicity based on blood biochemical/histological analysis, this work highlights the Cu-THQNPs as an efficient NIR II therapeutic agent for precise cancer theranostics. PMID- 29979023 TI - Chemically Engineered Au-Ag Plasmonic Nanostructures to Realize Large Area and Flexible Metamaterials. AB - We developed a simple and systematic method to fabricate optically tunable and thermally and chemically stable Au-Ag nanocrystal-based plasmonic metamaterials. An Ag nanocrystal-based metamaterial with desirable optical properties was fabricated via nanoimprinting and ligand-exchange process. Its optical properties were controlled by selectively substituting Ag atoms with Au atoms through a spontaneous galvanic replacement reaction. The developed Au-Ag-based metamaterials provide excellent tunable plasmonic properties required for various applications in the visible and near-infrared regions by controlling the Au-Ag composition according to the conditions of the galvanic displacement. Furthermore, their thermal and chemical stabilities significantly improved because of the protective Au thin layer on the surface. Using this developed process, chemically and thermally stable and flexible plasmonic metamaterials were successfully fabricated on a flexible polyester terephthalate substrate. PMID- 29979024 TI - Enhanced Power Output of a Triboelectric Nanogenerator using Poly(dimethylsiloxane) Modified with Graphene Oxide and Sodium Dodecyl Sulfate. AB - In this work, a new approach to modifying poly(dimethylsiloxane) (PDMS) as a negative triboelectric material using graphene oxide (GO) and a sodium dodecyl sulfate (SDS) surfactant was reported. A porous PDMS@GO@SDS composite triboelectric nanogenerator (TENG) could deliver an output voltage and current of up to 438 V and 11 MUA/cm2, respectively. These values were 3-fold higher than those of the flat PDMS. The superior performance is attributed to the intensified negative charges on PDMS from the oxygen functional groups of GO and anionic head groups of the SDS molecules. The outstanding performance and straightforward, low cost fabrication process of the PDMS@GO@SDS TENG would be beneficial for the further development of powerful NGs integrated into wearable electronics and self charging power cells. PMID- 29979025 TI - Electrostatic Association of Ammonium-Functionalized Layered-Transition-Metal Dichalcogenides with an Anionic Porphyrin. AB - Ammonium-modified MoS2 and WS2 were prepared and characterized by complementary spectroscopic, thermal, and microscopic means. The positive charges on functionalized MoS2 and WS2, due to the presence of ammonium units, were exploited to electrostatically bring in contact an anionic porphyrin bearing a carboxylate moiety, yielding porphyrin/MoS2 and porphyrin/WS2 ensembles, 5a and 5b, respectively. Efficient photoluminescence quenching of porphyrin's emission by MoS2 and WS2 within nanoensembles 5a and 5b, in combination with time-resolved photoluminescence assays, revealed transduction of energy from the photoexcited porphyrin to MoS2 or WS2. PMID- 29979026 TI - Highly Efficient Target Recycling-Based Netlike Y-DNA for Regulation of Electrocatalysis toward Methylene Blue for Sensitive DNA Detection. AB - In this work, the highly efficient target recycling-based netlike Y-shaped DNA (Y DNA), which regulated the electrocatalysis of Fe3O4@CeO2-Pt nanoparticles (Fe3O4@CeO2-PtNPs) toward methylene blue (MB) for signal amplification, was developed to prepare a sensitive DNA biosensor for detecting the DNA associated with oral cancer. Specifically, with the help of highly efficient enzyme-assisted target recycling (EATR) amplification strategy, one target DNA input was converted to corresponding plenty of DNA strands S1-Fe3O4@CeO2-Pt and S2-MB output, which could be employed to interact with HP2 immobilized on the electrode surface to form stable netlike Y-DNA without any waste of recycling products. Meanwhile, the formation of netlike Y-DNA could regulate electrocatalytic efficiency of Fe3O4@CeO2-PtNPs, inducing the proximity of Fe3O4@CeO2-PtNPs to MB and significantly enhancing electrochemical signal. Further, the signal could also be amplified by Fe3O4@CeO2-PtNPs modified on the electrode surface. By virtue of this ingenious design, a novel netlike Y-DNA structure based on highly efficient EATR was simply constructed and successfully applied to an electrochemical DNA biosensor along with electrocatalysis of Fe3O4@CeO2-PtNPs, achieving the sensitive detection of target DNA ranging from 10 fM to 50 nM with a detection limit of 3.5 fM. Impressively, the biosensor here demonstrates an admirable method for regulating the electrocatalysis of NPs toward substrates to enhance signal, and we believe that this biosensor is a potential candidate for the sensitive detection of target DNA or other disease-related nucleic acids. PMID- 29979027 TI - Thiazole Orange-Modified Carbon Dots for Ratiometric Fluorescence Detection of G Quadruplex and Double-Stranded DNA. AB - A new carbon dot (CD)-based nanoprobe for the ratiometric fluorescence detection of DNA was constructed in this work. Thiazole orange (TO), a specific organic small molecular probe toward DNA, is covalently linked to the surface of CDs, acting as the recognition element and the fluorescence response unit. In the absence of DNA, the nanoprobe only emitted the blue fluorescence of CDs, whereas TO was almost nonfluorescent. Upon addition of DNA, a turn-on emission at 530 nm appeared and gradually enhanced along with the increasing of the target DNA, whereas the fluorescence of CDs was unchanged, which realized the ratiometric detection of the target DNA. The CD-TO nanoprobe showed good selectivity to parallel G-quadruplex (G4) and double-stranded (ds) DNA over antiparallel G4 and single-stranded DNA. Moreover, the ratiometric fluorescence nanoprobe exhibited high sensitivity for ssab (a dsDNA) and c-myc (a parallel G4) with a low detection limit of 0.90 and 3.31 nM, respectively. Additionally, the G4/hemin peroxidase activity inhibition experiment demonstrated that CD-TO bound to the G4s through the end-stacking mode. PMID- 29979028 TI - Peptide-Induced DNA Condensation into Virus-Mimicking Nanostructures. AB - A series of surfactant-like peptides have been designed for inducing DNA condensation, which are all comprised of the same set of amino acids in different sequences. Results from experiments and molecular dynamics simulations show that the peptide's self-assembly and DNA-interaction behaviors can be well manipulated through sequence variation. With optimized pairing modes between the beta-sheets, the peptide of I3V3A3G3K3 can induce efficient DNA condensation into virus mimicking structures. The condensation involves two steps; the peptide molecules first bind onto the DNA chain through electrostatic interactions and then self associate into beta-sheets under hydrophobic interactions and hydrogen bonding. In such condensates, the peptide beta-sheets act as scaffolds to assist the ordered arrangement of DNA, mimicking the very nature of the virus capsid in helping DNA packaging. Such a hierarchy affords an extremely stable structure to attain the highly condensed state and protect DNA against enzymatic degradation. Moreover, the condensate size can be well tuned by the DNA length. The condensates with smaller sizes and narrow size distribution can deliver DNA efficiently into cells. The study helps not only for probing into the DNA packaging mechanism in virus but also delineating the role of peptide self assembly in DNA condensation, which may lead to development of peptide-based gene vectors for therapeutic applications. PMID- 29979029 TI - Understanding the Enhanced Open-Circuit Voltage of Polymer Solar Cells Based on a Diketopyrrolopyrrole Small Molecular Acceptor. AB - In this study, polymer solar cells employing poly(3-hexylthiophene) (P3HT) as a donor and fullerene derivative PC61BM (phenyl-C61-butyric acid methyl ester) or nonfullerene diketopyrrolopyrrole (DPP)-based small molecule (SF-DPPEH) as an acceptor are investigated. Device based on SF-DPPEH shows a remarkably high VOC of 1.20 V, whereas analogous device based on PC61BM only delivers a VOC of 0.64 V. Employing transient photovoltage/photocurrent techniques, we measure charge carrier lifetime and density and nongeminate recombination rate in the photoactive layer and correlate material energetics and charge recombination dynamics with the change of VOC in the devices; thus, the extent to which two factors limit VOC can be quantified. PMID- 29979030 TI - Ultrasensitive Simultaneous Detection of Multiplex Disease-Related Nucleic Acids Using Double-Enhanced Surface-Enhanced Raman Scattering Nanosensors. AB - Developing ultrasensitive probes holds great significance for simultaneous detection of multiplexed cancer-associated nucleic acids. Bimetallic nanoparticles containing silver may be exploited as nanoprobes for disease detection, which can produce stable and strong surface-enhanced Raman scattering (SERS) signals. However, it remains extremely challenging that such SERS nanoprobes are directly synthesized. Herein gold-silver nanosnowmen, grown via a DNA-mediated approach and attached to thiol-containing Raman dyes, are successfully synthesized. Stable SERS-enhanced gold substrates are also prepared and used as the enriching containers, where the capture DNAs are tethered to sense the target genes jointly enhanced by the SERS nanoprobes in a sandwich hybridization assay. This means detection of the target gene can obtain a limit of detection close to 0.839 fM. Such double-enhanced SERS nanosensors are further employed to simultaneously detect the three types of prostate carcinoma-related genes with high sensitivity and specificity, which meanwhile exhibit robust capacity of resisting disturbance in practical samples. Simultaneous and multiplexed detection of cancer-related genes may provide further biomedical applications with new opportunity. PMID- 29979031 TI - Green and Rapid Synthesis of Durable and Super-Oil (under Water) and Water (in Air) Repellent Interfaces. AB - In this letter, a single polymer is rapidly and covalently transformed into a chemically reactive and functional bulk polymeric coatings through a catalyst free mutual chemical reaction between acrylates and amine groups at ambient condition-in the absence of any external reaction solvent, which is unprecedented in the literature. This facile and green chemical approach provided a common basis for achieving two distinct biomimicked wettabilities-that are superhydrophobicity (lotus-leaf mimicked) in air and superoleophobicity (fish scale inspired) under water. The essential chemistry that conferred bioinspired wettability was optimized in the hierarchically featured polymeric material by postcovalent modulation of chemically reactive polymeric material with primary amine-containing small moleculess, glucamine and octadecylamine. The inherently sticky and "chemically reactive" polymeric material having appropriate hierarchical topography is highly capable of providing substrate-independent (irrespective of chemical compositions and mechanical strength of the substrates) stable coatings with robust bioinspired (i.e., lotus leaf and fish scale) wettability. PMID- 29979032 TI - Comparison of Copper(II)-Ligand Complexes as Mediators for Preparing Electrochemically Modulated Nitric Oxide-Releasing Catheters. AB - Further studies aimed at examining the activity of different Cu(II)-ligand complexes to serve as electron-transfer mediators to prepare novel antimicrobial/thromboresistant nitric oxide (NO)-releasing intravenous catheters are reported. In these devices, the NO release can be modulated by applying different potentials or currents to reduce the Cu(II)-complexes to Cu(I) species which then reduce nitrite ions into NO(g) within a lumen of the catheter. Four different ligands are compared with respect to NO generation efficiency and stability over time using both single- and dual-lumen silicone rubber catheters: N-propanoate- N, N-bis(2-pyridylethyl)amine (BEPA-Pr), N-propanoate- N, N-bis(2 pyridylmethyl)amine (BMPA-Pr), 1,4,7-trimethyl-1,4,7-triazacyclononane (Me3TACN), and tris(2-pyridylmethyl)amine (TPMA). Of these, the Cu(II)BEPA-Pr and Cu(II)Me3TACN complexes provide biomedically useful NO fluxes from the surface of the catheters, >2 * 10-10 mol.min-1.cm-2, under conditions mimicking the bloodstream environment. Cu(II)Me3TACN exhibits the best stability over time with a steady and continuous NO release observed for 8 d under a nitrogen atmosphere. Antimicrobial experiments conducted over 5 d with NO-releasing catheters turned "on" electrochemically for only 3 or 6 h each day revealed >2 logarithmic units in reduction of bacterial biofilm attached to the catheter surfaces. The use of optimal Cu(II)-ligand complexes within a lumen reservoir along with high levels of nitrite ions can potentially provide an effective method of preventing/decreasing the rate of infections caused by intravascular catheters. PMID- 29979033 TI - A Library Approach to Cationic Amphiphilic Polyproline Helices that Target Intracellular Pathogenic Bacteria. AB - A number of pathogenic bacteria reproduce inside mammalian cells and are thus inaccessible to many antimicrobial drugs. Herein, we present a facile method to a focused library of antibacterial agents known as cationic amphiphilic polyproline helices (CAPHs). We identified three CAPHs from the library with superior cell penetration within macrophages and excellent antibacterial action against both Gram-positive and Gram-negative bacteria. These cell-penetrating antibacterial CAPHs have specific subcellular localizations that allow for targeting of pathogenic bacteria at their intracellular niches, a unique feature that promotes the successful clearance of intracellular pathogens ( Salmonella, Shigella, and Listeria) residing within macrophages. Furthermore, the selected CAPHs also significantly reduced bacterial infections in an in vivo model of Caenorhabditis elegans, with minimal in vivo toxicity. PMID- 29979034 TI - Ultrafast Synthesis and Thermoelectric Properties of Mn1+ xTe Compounds. AB - MnTe compounds show great potential for thermoelectric applications in the intermediate temperature range (500-800 K) because of their large Seebeck coefficient and intrinsically low thermal conductivity. So far, the existing methods for the synthesis of MnTe compounds remain constrained to multistep processes that are time- and energy-intensive. Herein, we demonstrate ultrafast synthesis of high-density bulk MnTe compounds using a combination of self propagating high-temperature synthesis (SHS) and plasma activated sintering. The entire synthesis and processing procedure takes less than 1 h. The thermodynamic consideration suggests that the SHS process includes two steps: (1) Mn + 2Te -> MnTe2 + Q1 and (2) MnTe2 -> MnTe + Te. With the heat released by step (1), the process moved in cycle and finished in a rather short time. The effect of extra Mn content on the structure and thermoelectric properties was investigated. There is some solubility limit of extra Mn in the Mn1+ xTe compound. The extra Mn occupy interstitial sites, leading to a decrease of carrier concentration while enhancing Seebeck coefficient and decreasing thermal conductivity. Low temperature heat capacity data indicates that the Mn1.06Te compound has a high effective mass of 8.34 m0 and a low Debye temperature of 186 K, which are beneficial for the large Seebeck coefficient and low thermal conductivity. Therefore, the maximum ZT value reaches 0.57 at 850 K for the Mn1.06Te compound. PMID- 29979035 TI - d-Amino Acid-Mediated Translation Arrest Is Modulated by the Identity of the Incoming Aminoacyl-tRNA. AB - A complete understanding of the determinants that restrict d-amino acid incorporation by the ribosome, which is of interest to both basic biologists and the protein engineering community, remains elusive. Previously, we demonstrated that d-amino acids are successfully incorporated into the C-terminus of the nascent polypeptide chain. Ribosomes carrying the resulting peptidyl-d-aminoacyl tRNA (peptidyl-d-aa-tRNA) donor substrate, however, partition into subpopulations that either undergo translation arrest through inactivation of the ribosomal peptidyl-transferase center (PTC) or remain translationally competent. The proportion of each subpopulation is determined by the identity of the d-amino acid side chain. Here, we demonstrate that the identity of the aminoacyl-tRNA (aa tRNA) acceptor substrate that is delivered to ribosomes carrying a peptidyl-d-aa tRNA donor further modulates this partitioning. Our discovery demonstrates that it is the pairing of the peptidyl-d-aa-tRNA donor and the aa-tRNA acceptor that determines the activity of the PTC. Moreover, we provide evidence that both the amino acid and tRNA components of the aa-tRNA acceptor contribute synergistically to the extent of arrest. The results of this work deepen our understanding of the mechanism of d-amino acid-mediated translation arrest and how cells avoid this precarious obstacle, reveal similarities to other translation arrest mechanisms involving the PTC, and provide a new route for improving the yields of engineered proteins containing d-amino acids. PMID- 29979036 TI - Effect of Charcoal in Cigarette Filters on Free Radicals in Mainstream Smoke. AB - The addition of charcoal in cigarette filters may be an effective means of reducing many toxicants from tobacco smoke. Free radicals are a highly reactive class of oxidants abundant in cigarette smoke, and here we evaluated the effectiveness of charcoal to reduce free radical delivery by comparing radical yields from commercially available cigarettes with charcoal-infused filters to those without and by examining the effects of incorporating charcoal into conventional cigarette filters on radical production. Commercial cigarettes containing charcoal filters produced 40% fewer gas-phase radicals than did regular cellulose acetate filter cigarettes when smoked using the International Organization of Standardization (ISO, p = 0.07) and Canadian Intense (CI, p < 0.01) smoking protocols. While mean-particulate-phase radicals were 25-27% lower in charcoal cigarettes, differences from noncharcoal products were not significant ( p = 0.06-0.22). When cellulose acetate cigarette filters were modified to incorporate different types and amounts of activated charcoal, reductions in gas-phase (>70%), but not particulate-phase, radicals were observed. The reductions in gas-phase radicals were similar for the three types of charcoal. Decreases in radical production were dose-responsive with increasing amounts of charcoal (25-300 mg) with as little as 25 mg of activated charcoal reducing gas-phase radicals by 41%. In all studies, charcoal had less of an effect on nicotine delivery, which was decreased 33% at the maximal amount of charcoal tested (300 mg). Overall, these results support the potential consideration of charcoal in cigarette filters as a means to reduce exposure to toxic free radicals from cigarettes and other combustible tobacco products. PMID- 29979037 TI - Kernel-Based Microfluidic Constriction Assay for Tumor Sample Identification. AB - A high-throughput multiconstriction microfluidic channels device can distinguish human breast cancer cell lines (MDA-MB-231, HCC-1806, MCF-7) from immortalized breast cells (MCF-10A) with a confidence level of ~81-85% at a rate of 50-70 cells/min based on velocity increment differences through multiconstriction channels aligned in series. The results are likely related to the deformability differences between nonmalignant and malignant breast cells. The data were analyzed by the methods/algorithms of Ridge, nonnegative garrote on kernel machine (NGK), and Lasso using high-dimensional variables, including the cell sizes, velocities, and velocity increments. In kernel learning based methods, the prediction values of 10-fold cross-validations are used to represent the difference between two groups of data, where a value of 100% indicates the two groups are completely distinct and identifiable. The prediction value is used to represent the difference between two groups using the established algorithm classifier from high-dimensional variables. These methods were applied to heterogeneous cell populations prepared using primary tumor and adjacent normal tissue obtained from two patients. Primary breast cancer cells were distinguished from patient-matched adjacent normal cells with a prediction ratio of 70.07% 75.96% by the NGK method. Thus, this high-throughput multiconstriction microfluidic device together with the kernel learning method can be used to perturb and analyze the biomechanical status of cells obtained from small primary tumor biopsy samples. The resultant biomechanical velocity signatures identify malignancy and provide a new marker for evaluation in risk assessment. PMID- 29979038 TI - Genetically Encoded Forster Resonance Energy Transfer-Based Biosensors Studied on the Single-Molecule Level. AB - Genetically encoded Forster resonance energy transfer (FRET)-based biosensors for the quantification of ligand molecules change the magnitude of FRET between two fluorescent proteins upon binding a target metabolite. When highly sensitive sensors are being designed, extensive sensor optimization is essential. However, it is often difficult to verify the ideas of modifications made to a sensor during the sensor optimization process because of the limited information content of ensemble FRET measurements. In contrast, single-molecule detection provides detailed information and higher accuracy. Here, we investigated a set of glucose and crowding sensors on the single-molecule level. We report the first comprehensive single-molecule study of FRET-based biosensors with reasonable counting statistics and identify characteristics in the single-molecule FRET histograms that constitute fingerprints of sensor performance. Hence, our single molecule approach extends the toolbox of methods aiming to understand and optimize the design of FRET-based biosensors. PMID- 29979039 TI - Pd-Catalyzed Direct C-H Functionalization/Annulation of BODIPYs with Alkynes to Access Unsymmetrical Benzo[ b]-Fused BODIPYs: Discovery of Lysosome-Targeted Turn On Fluorescent Probes. AB - A highly efficient palladium-catalyzed direct C-H functionalization/annulation of BODIPYs with alkynes has been developed for the first time to construct a series of unsymmetrical benzo[ b]-fused BODIPYs from readily available starting materials. These unsymmetrical benzo[ b]-fused BODIPYs exhibit remarkably red shifted emissions and larger Stokes shifts than classical BODIPY dyes. Cell imaging experiments and cytotoxicity assays demonstrate that BODIPYs 4c and 4d have specific lysosome-labeling capacities, turn-on fluorescence emissions in cells, and low cytotoxicity. PMID- 29979040 TI - Functional Evaluation of the pi-Helix in the NAD(P)H:FMN Reductase of the Alkanesulfonate Monooxygenase System. AB - A subgroup of enzymes in the NAD(P)H:FMN reductase family is comprised of flavin reductases from two-component monooxygenase systems. The diverging structural feature in these FMN reductases is a pi-helix centrally located at the tetramer interface that is generated by the insertion of an amino acid in a conserved alpha4 helix. The Tyr insertional residue of SsuE makes specific contacts across the dimer interface that may assist in the altered mechanistic properties of this enzyme. The Y118F SsuE variant maintained the pi-pi stacking interactions at the tetramer interface and had kinetic parameters similar to those of wild-type SsuE. Substitution of the pi-helical residue (Tyr118) to Ala or Ser transformed the enzymes into flavin-bound SsuE variants that could no longer support flavin reductase and desulfonation activities. These variants existed as dimers and could form protein-protein interactions with SsuD even though flavin transfer was not sustained. The DeltaY118 SsuE variant was flavin-free as purified and did not undergo the tetramer to dimer oligomeric shift with the addition of flavin. The absence of desulfonation activity can be attributed to the inability of DeltaY118 SsuE to promote flavin transfer and undergo the requisite oligomeric changes to support desulfonation. Results from these studies provide insights into the role of the SsuE pi-helix in promoting flavin transfer and oligomeric changes that support protein-protein interactions with SsuD. PMID- 29979041 TI - Oxidative Release of Copper from Pharmacologic Copper Bis(thiosemicarbazonato) Compounds. AB - Intracellular delivery of therapeutic or analytic copper from copper bis thiosemicabazonato complexes is generally described in terms of mechanisms involving one-electron reduction to the Cu(I) analogue by endogenous reductants, thereby rendering the metal ion labile and less strongly coordinating to the bis thiosemicarbazone (btsc) ligand. However, electrochemical and spectroscopic studies described herein indicate that one-electron oxidation of CuII(btsc) and ZnIIATSM (btsc = diacetyl-bis(4-methylthiosemicarbazonato)) complexes occurs within the range of physiological oxidants, leading to the likelihood that unrecognized oxidative pathways for copper release also exist. Oxidations of CuII(btsc) by H2O2 catalyzed by either myeloperoxidase or horseradish peroxidase, by HOCl and taurine chloramine (which are chlorinating agents generated primarily in activated neutrophils from MPO-catalyzed reactions), and by peroxynitrite species (ONOOH, ONOOCO2-) that can form under certain conditions of oxidative stress are demonstrated. Unlike reduction, the oxidative reactions proceed by irreversible ligand oxidation, culminating in release of Cu(II). 2 Pyridylazoresorcinol complexation was used to demonstrate that Cu(II) release by reaction with peroxynitrite species involved rate-limiting homolysis of the peroxy O-O bond to generate secondary oxidizing radicals (NO2*, *OH, and CO3*-). Because the potentials for CuII(btsc) oxidation and reduction are ligand dependent, varying by as much as 200 mV, it is clearly advantageous in designing therapeutic methodologies for specific treatments to identify the operative Cu release pathway. PMID- 29979042 TI - Glycal Metallanitrenes for 2-Amino Sugar Synthesis: Amidoglycosylation of Gulal-, Allal-, Glucal-, and Galactal 3-Carbamates. AB - The rhodium(II)-catalyzed oxidative cyclization of glycal 3-carbamates with in situ incorporation of an alcohol nucleophile at the anomeric position provides access to a range of 2-amino sugars having 1,2-trans-2,3-cis stereochemistry, a structural motif present in compounds of medicinal and biological significance such as the streptothricin group of antibiotics and the Chitinase inhibitor allosamidin. All of the diastereomeric d-glycal 3-carbamates have been investigated, revealing significant differences in anomeric stereoselectivity depending on substrate stereochemistry and protecting groups. In addition, some substrates were prone to forming C3-oxidized dihydropyranone byproducts under the reaction conditions. Allal- and gulal 3-carbamates provided uniformly high stereo and chemoselectivity, while for glucal substrates, acyclic, electron-withdrawing protecting groups at the 4 O and 6 O positions were required. Galactal 3 carbamates have been the most challenging substrates; formation of their amidoglycosylation products is most effective with an electron-withdrawing 6 O-Ts substituent and a sterically demanding 4 O-TBS group. These results suggest a mechanism whereby conformational and electronic factors determine the partitioning of an intermediate acyl nitrenoid between alkene addition, leading to amidoglycosylation, and C3-H insertion, providing the dihydropyranone byproduct. Along the amidoglycosylation pathway, high anomeric selectivity results when a glycosyl aziridine intermediate is favored over an aziridine opened oxocarbenium donor. PMID- 29979043 TI - Solid-State Associative Reactions and the Coordination Compression Mechanism. AB - Coordination polymers and metal-organic frameworks can be modified by high pressure, according to its effects on the radii of central and ligand atoms. The pressure reduces the ligands' radii, and the coordination number is usually increased. Such transformations of the coordination quite generally conform to the inverse rule of pressure and temperature effects, although the temperature induced transformations are much less frequently observed. The two-dimensional coordination polymer Cd(APP)2NO3.NO3 [APP = 1,4-bis(3-aminopropyl)piperazine] undergoes a pressure-induced isostructural phase transition triggered by a topochemical reaction, yielding Cd(APP)2(NO3)2. The transition retains the symmetry of both phases, and their structures have been determined by X-ray diffraction for the single crystals compressed in a diamond-anvil cell. The reaction increases the Cd coordination, from 6-fold in phase I to 7-fold in phase II, where the new Cd-O bond involves an additional nitrate anion in the Cd coordination sphere. PMID- 29979044 TI - Visible-Light-Driven Epoxyacylation and Hydroacylation of Olefins Using Methylene Blue/Persulfate System in Water. AB - A visible-light-driven strategy for hydroacylation and epoxyacylation of olefins in water using methylene blue as photoredox catalyst and persulfate as oxidant is reported. In this unprecedented unified approach, two different transformations are accomplished using only one set of reagents. The method has a broad scope spanning a range of aromatic and aliphatic aldehydes as well as conjugated and nonconjugated olefins to deliver ketones and epoxyketones from abundant and inexpensive chemical feedstocks. PMID- 29979045 TI - Tunable Polaron Distortions Control the Extent of Halide Demixing in Lead Halide Perovskites. AB - Photoinduced phase separation in mixed halide perovskites emerges from their electro-mechanical properties and high ionic conductivities, resulting in photoinduced I--rich charge carrier traps that diminish photovoltaic performance. Whether photoinduced phase separation stems from the polycrystalline microstructure or is an intrinsic material property has been an open question. We investigate the nanoscale photoinduced behavior of single-crystal mixed Br-/I- methylammonium (MA+) lead halide perovskite (MAPb(Br xI1- x)3) nanoplates, eliminating effects from extended structural defects. Even in these nanoplates, we find that phase separation occurs, resulting in I--rich clusters that are nucleated stochastically and stabilized by polarons. Upon lowering the electron phonon coupling strength by partially exchanging MA+ for Cs+, a phase-separated steady state is not reached, nevertheless transient I- clustering still occurs. Our results, supported by multiscale modeling, demonstrate that photoinduced phase separation is an intrinsic property of mixed halide perovskites, the extent and dynamics of which depends on the electron-phonon coupling strength. PMID- 29979046 TI - Protein-Water-Ice Contact Angle. AB - The protein-water-ice contact angle is a controlling parameter in diverse fields. Here we show that data from three different experiments, at three different length scales, with three different proteins, in three different laboratories yield a consistent value for the protein-water-ice contact angle (88.0 +/- 1.3 degrees ) when analyzed using the Gibbs-Thomson equation. The measurements reinforce the validity of each other, and the fact that similar values are obtained across diverse length scales, experiments, and proteins yields insight into protein-water interactions and the applicability of thermodynamics at the nanoscale. PMID- 29979047 TI - Cu-Catalyzed Aminoacyloxylation of Unactivated Alkenes of Unsaturated Hydrazones with Manifold Carboxylic Acids toward Ester-Functionalized Pyrazolines. AB - A copper-catalyzed aminoacyloxylation of unactivated alkenes of unsaturated hydrazones is achieved by using various commercially available carboxylic acids as the acyloxylating reagents and di- tert-butyl peroxide (DTBP) as the oxidant. By using this method, a sequence of structurally diversiform acyloxyl-substituted pyrazolines are efficiently synthesized. Significantly, many carboxyl-containing drugs and bioactive molecules with unprotected functional groups are compatible in this reaction. PMID- 29979048 TI - Real and Imaginary Excitons: Making Sense of Resonance Wave Functions by Using Reduced State and Transition Density Matrices. AB - Within non-Hermitian quantum mechanics, metastable electronic states can be represented by isolated L2-integrable complex-valued wave functions with complex energies. An analysis scheme of the real and imaginary parts of resonance wave functions by using reduced transition density matrices and natural transition orbitals is presented. While the real parts of excitons describe changes in the electron density corresponding to the bound part of the resonance, the imaginary excitons can be interpreted as virtual states facilitating one-electron decay into the continuum. The different nature of real and imaginary excitons is revealed by exciton descriptors, in particular hole-particle separation and their correlation. Singular values and respective participation ratios quantify the extent of collectivity of the excitation and a number of distinct decay channels. The utility of the new tool is illustrated by the analysis of bound and metastable excited states of cyanopolyyne anions. PMID- 29979049 TI - Spin Fluctuations Drive the Inverse Magnetocaloric Effect in Mn_{5}Si_{3}. AB - Inelastic neutron scattering measurements are performed on single crystals of the antiferromagnetic compound Mn_{5}Si_{3} in order to investigate the relation between the spin dynamics and the magnetothermodynamics properties. It is shown that, among the two stable antiferromagnetic phases of this compound, the high temperature one has an unusual magnetic excitation spectrum where propagative spin waves and diffuse spin fluctuations coexist. Moreover, it is evidenced that the inverse magnetocaloric effect of Mn_{5}Si_{3}, the cooling by adiabatic magnetization, is associated with field induced spin fluctuations. PMID- 29979050 TI - Direct Observation of Composite Fermions and Their Fully-Spin-Polarized Fermi Sea near nu=5/2. AB - The enigmatic even-denominator fractional quantum Hall state at Landau level filling factor nu=5/2 is arguably the most promising candidate for harboring Majorana quasiparticles with non-Abelian statistics and, thus, of potential use for topological quantum computing. The theoretical description of the nu=5/2 state is generally believed to involve a topological p-wave pairing of fully-spin polarized composite fermions through their condensation into a non-Abelian Moore Read Pfaffian state. There is, however, no direct and conclusive experimental evidence for the existence of composite fermions near nu=5/2 or for an underlying fully-spin-polarized Fermi sea. Here, we report the observation of composite fermions very near nu=5/2 through geometric resonance measurements and find that the measured Fermi wave vector provides direct demonstration of a Fermi sea with full spin polarization. This lends crucial credence to the model of 5/2 fractional quantum Hall effect as a topological p-wave paired state of composite fermions. PMID- 29979051 TI - Shape Control for Experimental Continuation. AB - An experimental method has been developed to locate unstable equilibria of nonlinear structures quasistatically. The technique involves loading a structure by the application of either a force or a displacement at a main actuation point while simultaneously controlling the overall shape using additional bidirectional probe points. The method is applied to a shallow arch, and unstable segments of its equilibrium path are identified experimentally for the first time. Shape control is a fundamental building block for the experimental-as opposed to numerical-continuation of nonlinear structures, which will significantly expand our ability to measure their mechanical response. PMID- 29979052 TI - Direct Frequency-Comb-Driven Raman Transitions in the Terahertz Range. AB - We demonstrate the use of a femtosecond frequency comb to coherently drive stimulated Raman transitions between terahertz-spaced atomic energy levels. More specifically, we address the 3d ^{2}D_{3/2} and 3d ^{2}D_{5/2} fine structure levels of a single trapped ^{40}Ca^{+} ion and spectroscopically resolve the transition frequency to be nu_{D}=1,819,599,021,534+/-8 Hz. The achieved accuracy is nearly a factor of five better than the previous best Raman spectroscopy, and is currently limited by the stability of our atomic clock reference. Furthermore, the population dynamics of frequency-comb-driven Raman transitions can be fully predicted from the spectral properties of the frequency comb, and Rabi oscillations with a contrast of 99.3(6)% and millisecond coherence time have been achieved. Importantly, the technique can be easily generalized to transitions in the sub-kHz to tens of THz range and should be applicable for driving, e.g., spin-resolved rovibrational transitions in molecules and hyperfine transitions in highly charged ions. PMID- 29979053 TI - Publisher's Note: Biological Magnetometry: Torque on Superparamagnetic Beads in Magnetic Fields [Phys. Rev. Lett. 114, 218301 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.218301. PMID- 29979054 TI - Evolution of Magneto-Orbital order Upon B-Site Electron Doping in Na_{1 x}Ca_{x}Mn_{7}O_{12} Quadruple Perovskite Manganites. AB - We present the discovery and refinement by neutron powder diffraction of a new magnetic phase in the Na_{1-x}Ca_{x}Mn_{7}O_{12} quadruple perovskite phase diagram, which is the incommensurate analogue of the well-known pseudo-CE phase of the simple perovskite manganites. We demonstrate that incommensurate magnetic order arises in quadruple perovskites due to the exchange interactions between A and B sites. Furthermore, by constructing a simple mean field Heisenberg exchange model that generically describes both simple and quadruple perovskite systems, we show that this new magnetic phase unifies a picture of the interplay between charge, magnetic, and orbital ordering across a wide range of compounds. PMID- 29979055 TI - Characterization of Topological States via Dual Multipartite Entanglement. AB - We demonstrate that multipartite entanglement is able to characterize one dimensional symmetry-protected topological order, which is witnessed by the scaling behavior of the quantum Fisher information of the ground state with respect to the spin operators defined in the dual lattice. We investigate an extended Kitaev chain with a Z symmetry identified equivalently by winding numbers and paired Majorana zero modes at each end. The topological phases with high winding numbers are detected by the scaling coefficient of the quantum Fisher information density with respect to generators in different dual lattices. Containing richer properties and more complex structures than bipartite entanglement, the dual multipartite entanglement of the topological state has promising applications in robust quantum computation and quantum metrology, and can be generalized to identify topological order in the Kitaev honeycomb model. PMID- 29979056 TI - Role of the Transition Dipole Amplitude and Phase on the Generation of Odd and Even High-Order Harmonics in Crystals. AB - Since the first observation of odd and even high-order harmonics generated from ZnO crystals in 2011, the dependence of the harmonic yields on the orientation of the laser polarization with respect to the crystal axis has never been properly interpreted. This failure has been traced to the lack of a correct account of the phase of the transition dipole moment between the valence band and the conduction band. Using a simple one-dimensional two-band model, here we demonstrate that the observed odd harmonics is directly related to the orientation dependence of the magnitude of the transition dipole, while even harmonics is directly related to the phase of the transition dipole. Our result points out the essential role of the complex transition dipole moment in understanding harmonic generation from solids that has long been overlooked so far. PMID- 29979057 TI - Comment on "Long-Range Repulsion Between Spatially Confined van der Waals Dimers". PMID- 29979058 TI - Detecting Cosmic Reionization Using the Bispectrum Phase. AB - Detecting neutral hydrogen (H i) via the 21 cm line emission from the intergalactic medium at z?6 has been identified as one of the most promising probes of the epoch of cosmic reionization-a major phase transition of the Universe. However, these studies face severe challenges imposed by the bright foreground emission from cosmic objects. Current techniques require precise instrumental calibration to separate the weak H i line signal from the foreground continuum emission. We propose to mitigate this calibration requirement by using measurements of the interferometric bispectrum phase. The bispectrum phase is unaffected by antenna-based direction-independent calibration errors and hence for a compact array it depends on the sky brightness distribution only (subject to the usual thermal-like noise). We show that the bispectrum phase of the foreground synchrotron continuum has a characteristically smooth spectrum relative to the cosmological line signal. The two can be separated effectively by exploiting this spectral difference using Fourier techniques, while eliminating the need for precise antenna-based calibration of phases introduced by the instrument, and the ionosphere, inherent in existing approaches. Using fiducial models for continuum foregrounds, and for the cosmological H i signal, we show the latter should be detectable in bispectrum phase spectra, with reasonable significance at |k_{?}|?0.5h Mpc^{-1}, using existing instruments. Our approach will also benefit other H i intensity mapping experiments that face similar challenges, such as those measuring baryon acoustic oscillations (BAO). PMID- 29979059 TI - Maximum Willis Coupling in Acoustic Scatterers. AB - Willis coupling in acoustic materials defines the cross-coupling between strain and velocity, analogous to bianisotropic phenomena in electromagnetics. While these phenomena have been garnering significant attention in recent years, to date their effects have been considered mostly perturbative. Here, we derive general bounds on the Willis response of acoustic scatterers, show that these bounds can be reached in suitably designed scatterers, and outline a systematic venue for the realistic implementation of maximally bianisotropic acoustic inclusions. We then employ these inclusions to realize acoustic metasurfaces for bending and steering of sound with unitary efficiency. PMID- 29979060 TI - Accessing Quark Helicity through Dihadron Studies. AB - We present a new proposal to study the helicity-dependent dihadron fragmentation functions (DiFF), which describe the correlations of the longitudinal polarization of a fragmenting quark with the transverse momenta of the produced hadron pair. Recent experimental searches for this DiFF via azimuthal asymmetries in back-to-back hadron pair production in e^{+}e^{-} annihilation by the BELLE Collaboration did not yield a signal. Here we propose a new way to access this DiFF in e^{+}e^{-} annihilation, motivated by the recently recalculated cross section of this reaction, which explains why there was in fact no signal for the BELLE Collaboration to see. In this new approach the azimuthal asymmetry is weighted by the virtual photon's transverse momentum square multiplying sine and cosine functions of difference of azimuthal angles of relative and total momentum for each pair. The integration over the virtual photon's transverse momentum has the effect of separating the convolution between the helicity-dependent DiFFs in the quark and antiquark jets and results in a nonzero collinear expression containing Fourier moments of helicity-dependent DiFFs. A second new measurement is also proposed for two-hadron production in semi-inclusive deep inelastic scattering, where the asymmetry is weighted in a similar way for a single pair. This results in a collinear factorized form of the asymmetry, which includes the quark helicity parton distribution function and the same helicity-dependent DiFF, as in e^{+}e^{-} production and will allow us to check the universality of this DiFF. PMID- 29979061 TI - Emergent Failures and Cascades in Power Grids: A Statistical Physics Perspective. AB - We model power grids transporting electricity generated by intermittent renewable sources as complex networks, where line failures can emerge indirectly by noisy power input at the nodes. By combining concepts from statistical physics and the physics of power flows and taking weather correlations into account, we rank line failures according to their likelihood and establish the most likely way such failures occur and propagate. Our insights are mathematically rigorous in a small noise limit and are validated with data from the German transmission grid. PMID- 29979062 TI - Suppressed Solitonic Cascade in Spin-Imbalanced Superfluid Fermi Gas. AB - Cold atoms experiments offer invaluable information on superfluid dynamics, including decay cascades of topological defects. While the cascade properties are well established for Bose systems, our understanding of their behavior in Fermi counterparts is very limited, in particular in spin-imbalanced systems, where superfluid (paired) and normal (unpaired) particles naturally coexist giving rise to complex spatial structure of the atomic cloud. Here we show, based on a newly developed microscopic approach, that the decay cascades of topological defects are dramatically modified by the spin polarization. We demonstrate that decay cascades end up at different stages: "dark soliton," "vortex ring," or "vortex line," depending on the polarization. We reveal that it is caused by sucking of unpaired particles into the soliton's internal structure. As a consequence vortex reconnections are hindered and we anticipate that quantum turbulence phenomenon can be significantly affected, indicating new physics induced by polarization effects. PMID- 29979063 TI - Magnetic-Field-Induced Kondo Metal Realized in YbB_{12}. AB - The specific heat of the Kondo insulator YbB_{12} has been measured up to 60 T. The Sommerfeld coefficient gamma significantly increases at around 50 T, where the insulator metal transition occurs with a steep increase of the magnetization. gamma reaches 67 mJ/(mol K^{2}) at high fields, which directly indicates that the quasiparticles gain a heavy thermodynamic effective mass and transform into a Kondo metal under magnetic fields. The field-induced Kondo metal has a rather high Kondo temperature around 200 K. The strong Kondo coupling proves that the energy gap collapse does not correspond to the breakdown of the Kondo bound state. The steep increase of the magnetization at the transition manifests the sharp density of states at the Fermi energy formed via the Kondo resonance. PMID- 29979064 TI - Visualizing Mie Resonances in Low-Index Dielectric Nanoparticles. AB - Resonant light scattering by metallic and high-index dielectric nanoparticles has received enormous attention and found many great applications. However, low-index dielectric nanoparticles typically do not show resonant scattering behaviors due to poor light confinement caused by small index contrast. This Letter describes a simple and effective approach to drastically enhance the resonance effect of the low-index particles by partial metal dressing. Mie resonances of low-index nanoparticles can now be easily visualized by scattered light. This scattering peak depends on sphere size and has a reasonable linewidth. A size difference as small as 8 nm was resolved by a peak shift or even by color change. The scattering peak is attributed to the enhanced TE_{11} Mie resonance of the low index nanospheres. The metal dress not only provides a high-reflection boundary, but also functions as an antenna to couple the confined light power to the far field, leading to scattering maxima in the spectra. Additionally, the enhanced TE_{11} Mie resonance in low-index nanoparticles features a considerable magnetic response due to the strong circulating displacement currents induced by the intensified E field despite of a low permittivity (hence low index) of the particles. The enhanced Mie resonances could be used to sense minute changes in size or refractive index of low-index nanoparticles and benefit a wide range of applications. PMID- 29979065 TI - Retrieving the Size of Deep-Subwavelength Objects via Tunable Optical Spin-Orbit Coupling. AB - We propose a scheme to retrieve the size parameters of a nanoparticle on a glass substrate at a scale much smaller than the wavelength. This is achieved by illuminating the particle using two plane waves to create rich and nontrivial local polarization distributions, and observing the far-field scattering pattern into the substrate. By using this illumination to control the induced complex dipole moment, the exponential decay of power radiated into the supercritical region, as well as directional scattering due to spin-orbit coupling can be exploited to retrieve the particle's shape, size, and position directly from the far-field scattering with high sensitivity and without the need for a complicated and time-consuming optimization algorithm. Our method brings about a far-field superresolution nanometrology scheme based on the interaction of vectorial light with nanoparticles. PMID- 29979066 TI - Evidence for Ferromagnetic Clusters in the Colossal-Magnetoresistance Material EuB_{6}. AB - We combined scanning tunneling microscopy and locally resolved magnetic stray field measurements on the ferromagnetic semimetal EuB_{6}, which exhibits a complex ferromagnetic order and a colossal magnetoresistance effect. In a zero magnetic field, scanning tunneling spectroscopy visualizes the existence of local inhomogeneities in the electronic density of states, which we interpret as the localization of charge carriers due to the formation of magnetic polarons. Micro Hall magnetometry measurements of the total stray field emanating from the end of a rectangular-shaped platelike sample reveals evidence for magnetic clusters also in finite magnetic fields. In contrast, the signal detected below the faces of the magnetized sample measures a local stray field indicating the formation of pronounced magnetic inhomogeneities consistent with large clusters of percolated magnetic polarons. PMID- 29979067 TI - Sadhukhan and Tkatchenko Reply. PMID- 29979068 TI - Rich Ground-State Chemical Ordering in Nanoparticles: Exact Solution of a Model for Ag-Au Clusters. AB - We show that nanoparticles can have very rich ground-state chemical order. This is illustrated by determining the chemical ordering of Ag-Au 309-atom Mackay icosahedral nanoparticles. The energy of the nanoparticles is described using a cluster expansion model, and a mixed integer programming approach is used to find the exact ground-state configurations for all stoichiometries. The chemical ordering varies widely between the different stoichiometries and displays a rich zoo of structures with nontrivial ordering. PMID- 29979069 TI - Vortical Amplification of the Magnetic Field at an Inward Shock of Supernova Remnant Cassiopeia A. AB - We present an interpretation of the time variability of the x-ray flux recently reported from a multiepoch campaign of 15 years of observations of the supernova remnant Cassiopeia A by Chandra. We show for the first time quantitatively that the [4.2-6] keV nonthermal flux increase up to 50% traces the growth of the magnetic field due to a vortical amplification mechanism at a reflection inward shock colliding with inner overdensities. The fast synchrotron cooling as compared with shock-acceleration time scale qualitatively supports the flux decrease. PMID- 29979070 TI - Work Storage in States of Apparent Negative Thermodynamic Temperature. AB - Inverted quantum states provide a challenge to classical thermodynamics, since they appear to contradict the classical formulation of the second law of thermodynamics. Ramsey interpreted these states as stable equilibrium states of negative thermodynamic temperature, and added a provision to allow these states to the Kelvin-Planck statement of the second law [N. F. Ramsey, Phys. Rev. 103, 20 (1956)PHRVAO0031-899X10.1103/PhysRev.103.20]. Since then, Ramsey's interpretation has prevailed in the literature. Here, we present an alternative option to accommodate inverted states within thermodynamics, which strictly enforces the original Kelvin-Planck statement of the second law, and reconciles inverted states and the second law by interpreting the former as unstable states, for which no temperature-positive or negative-can be defined. Specifically, we recognize inverted quantum states as temperature-unstable states, for which all processes are in agreement with the original Kelvin-Planck statement of the second law, and positive thermodynamic temperatures in stable equilibrium states. These temperature-unstable states can only be created by work done to the system, which is stored as energy in the unstable states, and can be released as work again, just as in a battery or a spring. PMID- 29979071 TI - Active Growth and Pattern Formation in Membrane-Protein Systems. AB - Inspired by recent experimental observations of patterning at the membrane of a living cell, we propose a generic model for the dynamics of a fluctuating interface driven by particlelike inclusions which stimulate its growth. We find that the coupling between interfacial and inclusions dynamics yields microphase separation and the self-organization of traveling waves. These patterns are strikingly similar to those detected in experiments on biological membranes. Our results further show that the active growth kinetics do not fall into the Kardar Parisi-Zhang universality class for growing interfaces, displaying instead a novel superposition of scaling and sustained oscillations. PMID- 29979072 TI - Electronic Structure of Ce-Doped and -Undoped Nd_{2}CuO_{4} Superconducting Thin Films Studied by Hard X-Ray Photoemission and Soft X-Ray Absorption Spectroscopy. AB - In order to realize superconductivity in cuprates with the T^{'}-type structure, not only chemical substitution (Ce doping) but also postgrowth reduction annealing is necessary. In the case of thin films, however, well-designed reduction annealing alone without Ce doping can induce superconductivity in the T^{'}-type cuprates. In order to unveil the origin of superconductivity in the Ce undoped T^{'}-type cuprates, we have performed bulk-sensitive hard x-ray photoemission and soft x-ray absorption spectroscopy on superconducting and nonsuperconducting Nd_{2-x}Ce_{x}CuO_{4} (x=0, 0.15, and 0.19) thin films. By postgrowth annealing, core-level spectra exhibited dramatic changes, which we attributed to the enhancement of core-hole screening in the CuO_{2} plane and the shift of chemical potential along with changes in the band filling. The result suggests that the superconducting Nd_{2}CuO_{4} film is doped with electrons despite the absence of the Ce substitution. PMID- 29979073 TI - Long-Term Monitoring of the Internal Energy Distribution of Isolated Cluster Systems. AB - A method is presented to monitor the internal energy distribution of cluster anions via delayed electron detachment by pulsed photoexcitation and demonstrated on Co_{4}^{-} in an electrostatic ion beam trap. In a cryogenic operation, we calibrate the detachment delay to internal energy. By laser frequency scans, at room temperature, we reconstruct the time-dependent internal energy distribution of the clusters. The mean energies of ensembles from a cold and a hot ion source both approach thermal equilibrium. Our data yield a radiative emission law and the absorptivity of the cluster for thermal radiation. PMID- 29979074 TI - Nonclassical Light from Large Ensembles of Trapped Ions. AB - The vast majority of physical objects we are dealing with are almost exclusively made of atoms. Because of their discrete level structure, single atoms have proved to be emitters of light, which is incompatible with the classical description of electromagnetic waves. We demonstrate this incompatibility for atomic fluorescence when scaling up the size of the source ensemble, which consists of trapped atomic ions, by several orders of magnitude. The presented measurements of nonclassical statistics on light unconditionally emitted from ensembles containing up to more than a thousand ions promise further scalability to much larger emitter numbers. The methodology can be applied to a broad range of experimental platforms focusing on the bare nonclassical character of single isolated emitters. PMID- 29979075 TI - Self-Propelled Particles with Velocity Reversals and Ferromagnetic Alignment: Active Matter Class with Second-Order Transition to Quasi-Long-Range Polar Order. AB - We introduce and study in two dimensions a new class of dry, aligning active matter that exhibits a direct transition to orientational order, without the phase-separation phenomenology usually observed in this context. Characterized by self-propelled particles with velocity reversals and a ferromagnetic alignment of polarities, systems in this class display quasi-long-range polar order with continuously varying scaling exponents, yet a numerical study of the transition leads to conclude that it does not belong to the Berezinskii-Kosterlitz-Thouless universality class but is best described as a standard critical point with an algebraic divergence of correlations. We rationalize these findings by showing that the interplay between order and density changes the role of defects. PMID- 29979076 TI - Interacting Cracks Obey a Multiscale Attractive to Repulsive Transition. AB - The observed repulsive behavior of two initially collinear cracks growing towards each other and leading to a hook-shaped path questioned recently the validity of the principle of local symmetry within linear elastic fracture mechanics theory. Our theoretical and numerical work solves this dilemma, providing the precise geometric conditions for the existence of this repulsive phase. We moreover reveal a multiscale behavior of the repulsive-attractive transition, explaining its ubiquitous occurrence, but also the difficulty to predict the final cracks' paths. PMID- 29979077 TI - Phonon Decoherence of Quantum Dots in Photonic Structures: Broadening of the Zero Phonon Line and the Role of Dimensionality. AB - We develop a general microscopic theory describing the phonon decoherence of quantum dots and indistinguishability of the emitted photons in photonic structures. The coherence is found to depend fundamentally on the dimensionality of the structure resulting in vastly different performance for quantum dots embedded in a nanocavity (0D), waveguide (1D), slab (2D), or bulk medium (3D). In bulk, we find a striking temperature dependence of the dephasing rate scaling as T^{11} implying that phonons are effectively "frozen out" for T?4 K. The phonon density of states is strongly modified in 1D and 2D structures leading to a linear temperature scaling for the dephasing strength. The resulting impact on the photon indistinguishability can be important even at sub-Kelvin temperatures. Our findings provide a comprehensive understanding of the fundamental limits to photon indistinguishability in photonic structures. PMID- 29979078 TI - Machine Learning Out-of-Equilibrium Phases of Matter. AB - Neural-network-based machine learning is emerging as a powerful tool for obtaining phase diagrams when traditional regression schemes using local equilibrium order parameters are not available, as in many-body localized (MBL) or topological phases. Nevertheless, instances of machine learning offering new insights have been rare up to now. Here we show that a single feed-forward neural network can decode the defining structures of two distinct MBL phases and a thermalizing phase, using entanglement spectra obtained from individual eigenstates. For this, we introduce a simplicial geometry-based method for extracting multipartite phase boundaries. We find that this method outperforms conventional metrics for identifying MBL phase transitions, revealing a sharper phase boundary and shedding new insight on the topology of the phase diagram. Furthermore, the phase diagram we acquire from a single disorder configuration confirms that the machine-learning-based approach we establish here can enable speedy exploration of large phase spaces that can assist with the discovery of new MBL phases. To our knowledge, this Letter represents the first example of a standard machine learning approach revealing new information on phase transitions. PMID- 29979079 TI - Rotational Spectroscopy of a Triatomic Molecular Anion. AB - Rotational transitions of the nonlinear triatomic molecular anion NH_{2}^{-} have been observed by terahertz spectroscopy in a cryogenic radio frequency ion trap. Absorption of terahertz photons has been probed by rotational state-dependent photodetachment of the trapped negative ions near the detachment threshold. Using this two-photon scheme, the two lowest rotational transitions for the asymmetric top rotor NH_{2}^{-} have been found. For the para nuclear spin configuration, the 1_{0}<-0_{0} transition frequency was determined to be 933 954(2) MHz, and for the ortho configuration the 1_{+1}<-1_{-1} transition frequency was determined to be 447 375(3) MHz. This result appears to preclude the recent tentative assignment of an interstellar absorption feature to NH_{2}^{-}. PMID- 29979080 TI - Erratum: Anomalous Processes with General Waiting Times: Functionals and Multipoint Structure [Phys. Rev. Lett. 115, 110601 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.115.110601. PMID- 29979082 TI - Nested Transition Path Sampling. AB - We introduce a novel transition path (TPS) sampling scheme employing nested sampling. Analogous to how nested sampling explores the entire configurational phase space for atomistic systems, nested TPS samples the entire available trajectory space in one simulation. Thermodynamic and path observables can be constructed a posteriori for all temperatures simultaneously. We exploit this to compute the rate of rare processes at arbitrarily low temperature through the coupling to easily accessible rates at high temperature. We illustrate the method on several model systems. PMID- 29979081 TI - Observation of Laser Power Amplification in a Self-Injecting Laser Wakefield Accelerator. AB - We report on the depletion and power amplification of the driving laser pulse in a strongly driven laser wakefield accelerator. Simultaneous measurement of the transmitted pulse energy and temporal shape indicate an increase in peak power from 187+/-11 TW to a maximum of 318+/-12 TW after 13 mm of propagation in a plasma density of 0.9*10^{18} cm^{-3}. The power amplification is correlated with the injection and acceleration of electrons in the nonlinear wakefield. This process is modeled by including a localized redshift and subsequent group delay dispersion at the laser pulse front. PMID- 29979083 TI - High-Brilliance Betatron gamma-Ray Source Powered by Laser-Accelerated Electrons. AB - Recent progress in laser-driven plasma acceleration now enables the acceleration of electrons to several gigaelectronvolts. Taking advantage of these novel accelerators, ultrashort, compact, and spatially coherent x-ray sources called betatron radiation have been developed and applied to high-resolution imaging. However, the scope of the betatron sources is limited by a low energy efficiency and a photon energy in the 10 s of kiloelectronvolt range, which for example prohibits the use of these sources for probing dense matter. Here, based on three dimensional particle-in-cell simulations, we propose an original hybrid scheme that combines a low-density laser-driven plasma accelerator with a high-density beam-driven plasma radiator, thereby considerably increasing the photon energy and the radiated energy of the betatron source. The energy efficiency is also greatly improved, with about 1% of the laser energy transferred to the radiation, and the gamma-ray photon energy exceeds the megaelectronvolt range when using a 15 J laser pulse. This high-brilliance hybrid betatron source opens the way to a wide range of applications requiring MeV photons, such as the production of medical isotopes with photonuclear reactions, radiography of dense objects in the defense or industrial domains, and imaging in nuclear physics. PMID- 29979084 TI - Magnon Straintronics: Reconfigurable Spin-Wave Routing in Strain-Controlled Bilateral Magnetic Stripes. AB - We observe and explain theoretically strain-induced spin-wave routing in the bilateral composite multilayer. By means of Brillouin light scattering and microwave spectroscopy, we study the spin-wave transport across three adjacent magnonic stripes, which are strain coupled to a piezoelectric layer. The strain may effectively induce voltage-controlled dipolar spin-wave interactions. We experimentally demonstrate the basic features of the voltage-controlled spin-wave switching. We show that the spin-wave characteristics can be tuned with an electrical field due to piezoelectricity and magnetostriction of the piezolayer and layered composite and mechanical coupling between them. Our experimental observations agree with numerical calculations. PMID- 29979085 TI - Fano Interference between Bulk and Surface States of a Dirac Semimetal Cd_{3}As_{2} Nanowire. AB - Dirac semimetals possess Fermi-arc surface states, which will be a set of discrete surface subbands in a nanowire due to the quantum confinement effect. Here, we report a tunable Fano effect induced by the interference between the discrete surface states and continuous bulk states of a Dirac semimetal Cd_{3}As_{2} nanowire. The discrete surface bands lead to a zero bias peak in conductance as the Femi level is tuned to across the surface subbands. The Fano resonance results in an asymmetric line shape in the differential conductance dI/dV spectrum. Furthermore, the Fano interference would introduce an additional phase into the Weyl orbits and lead to a modification of the oscillation frequency. The results are valuable for further understanding the exotic quantum transport properties of topological semimetals. PMID- 29979086 TI - Structure and Metallicity of Phase V of Hydrogen. AB - A new phase V of hydrogen was recently claimed in experiments above 325 GPa and 300 K. Because of the extremely small sample size at such record pressures the measurements were limited to Raman spectroscopy. The experimental data on increase of pressure show decreasing Raman activity and darkening of the sample, which suggests band gap closure and impending molecular dissociation, but no definite conclusions could be reached. Furthermore, the available data are insufficient to determine the structure of phase V, which remains unknown. Introducing saddle-point ab initio random structure searching, we find several new structural candidates of hydrogen which could describe the observed properties of phase V. We investigate hydrogen metallization in the proposed candidate structures, and demonstrate that smaller band gaps are associated with longer bond lengths. We conclude that phase V is a stepping stone towards metallization. PMID- 29979087 TI - Gauge Fixing the Standard Model Effective Field Theory. AB - We gauge-fix the standard model effective field theory in a manner invariant under background-field gauge transformations using a geometric description of the field connections. PMID- 29979088 TI - Predictors for choledocholithiasis in patients undergoing endoscopic ultrasound. PMID- 29979089 TI - Clinical trials targeting hypoxia. AB - The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials. PMID- 29979090 TI - Highly active antiretroviral therapy adherence among perinatally infected HIV adolescents at a teaching hospital in Ghana. AB - Increased accessibility to Antiretroviral Therapy (ART) has resulted in the decline of deaths among children with Perinatally Infected Human Immunodeficiency Virus (PIHIV). Their adherence to Highly Active ART (HAART) is vital for their survival and quality of life. This study aimed at determining HAART medication adherence among adolescents with PIHIV. The study was cross-sectional conducted from September 2015 to January 2016 at a teaching hospital in Ghana. It involved 106 adolescents aged 10-20 years. Morisky's eight-item medication adherence scale was adapted and used to determine the adherence level. Factors influencing adherence were also determined by interviewing the adolescents. EpiData 3.1 and Stata version 12 were used for data entry and analysis respectively. There was low adherence in 76.4% of the adolescents, and the HAART regimen associated with high medication adherence was tenofovir, lamivudine and efavirenz combinations (p = .011). Forgetfulness (p = .001) and inability to come for refill (p = .013) were the main factors associated with low adherence. However adherence was not significantly associated with a lack of medication supply or stigmatization. Addressing the modifiable factors found in this study to be associated with low adherence are essential interventions for their long-term quality of life. PMID- 29979091 TI - Is there a role for routine colonoscopy in the follow-up after acute appendicitis? AB - BACKGROUND: Mechanical obstruction of the appendiceal lumen is proposed as a possible factor in the pathogenesis of acute appendicitis. Hence, patients over the age of 40 are often referred to a follow-up colonoscopy after admission for acute appendicitis. The use of CT scans question whether routine colonoscopy still has a place in follow-up for these patients. METHODS: All patients aged over 40 years with confirmed acute appendicitis admitted to St. Olav's Hospital in the period from 2010 to 2015 were included in this retrospective study. Findings and distribution of significant colorectal neoplasms (cancer and advanced adenomas) within three years after the admission were evaluated. RESULTS: Fifty-four (7.4%) of the 731 patients were found to have colonic neoplasms; 9 patients (1.2%) were found to have colorectal cancer of which 7 were located on the right side, 22 patients (3.0%) were found to have advanced adenomas and 23 patients (3.1%) were found to have non-advanced adenomas. The sensitivity and specificity for CT to discover cancer was 0.25 and 0.97, respectively. A total of 316 patients (43.2%) had colonoscopy within three years after admission. CONCLUSION: There may be an increased risk of colorectal neoplasms in patients over the age of 40 admitted with acute appendicitis. There seems to be an increased proportion of right-sided cancer relatively to other colonic locations. The sensitivity for CT scans to discover colorectal cancer in this group is low. Further studies are needed to decide whether routine colonoscopy is indicated after acute appendicitis in patients over 40 years. PMID- 29979092 TI - Use of objective evidence of myocardial ischemia to facilitate the diagnostic and prognostic distinction between type 2 myocardial infarction and myocardial injury. AB - AIMS: First, describe how acute myocardial infarction criteria are used to diagnose type 1 (T1MI) and 2 (T2MI) myocardial infarction. Second, determine whether subjective or objective criteria are used for T2MI. Third, examine outcomes for T2MI based on the presence or absence of objective evidence of myocardial ischemia compared with myocardial injury. METHODS AND RESULTS: Post hoc analysis of UTROPIA (NCT02060760), a prospective, observational, cohort study involving 1640 consecutive emergency department patients with serial high sensitivity cardiac troponin I among whom 74 (4.5%) had T1MI, 103 (6.3%) T2MI, and 245 (15%) myocardial injury. Compared with T1MI, patients with T2MI were less likely to have ischemic symptoms (97% vs. 83%), Q waves (24% vs. 1%), new ST-T wave changes (74% vs. 51%), new regional wall motion abnormality (64% vs. 11%), and a culprit lesion on coronary angiography (59% vs. 0%) (all p <0.05). T2MIs were more likely to be diagnosed using subjective criteria (symptoms alone) than T1MI (42% vs. 12%, p <0.0001). Patients with objective T2MI, but not subjective T2MI, had a two-fold increase in early mortality compared with myocardial injury, with 30- and 60-day hazard ratios (95% confidence interval) of 2.3 (0.9, 6.2) and 2.0 (0.9, 4.7) respectively. CONCLUSIONS: Among patients with T2MI, many cases are diagnosed using subjective criteria. The presence of objective evidence of myocardial ischemia may identify a higher-risk group of T2MI patients in whom early outcomes are worse than myocardial injury. Emphasis on using objective evidence of myocardial ischemia to diagnose T2MI may result in a more precise and specific disease definition. PMID- 29979093 TI - Five years before multiple sclerosis onset: Phenotyping the prodrome. AB - BACKGROUND: The multiple sclerosis (MS) prodrome is poorly characterized. OBJECTIVE: To phenotype the MS prodrome via health care encounters. METHODS: Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated. RESULTS: The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05-5.10 to 4.75; 95% CI: 3.11-7.25), sensory (RR (range) = 1.40; 95% CI: 1.34-1.46 to 2.28; 95% CI: 1.72 3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07-1.33 to 1.70; 95% CI: 1.57-1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05-1.30 to 1.59; 95% CI: 1.48-1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36-1.62 to 1.80; 95% CI: 1.61-2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1-1.5 times higher, all p < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71-0.86 to 0.88; 95% CI: 0.84 0.92). CONCLUSION: Phenotyping the prodrome 5 years before clinical recognition of MS is feasible. PMID- 29979095 TI - Mutations in ORP1 Conferring Oxathiapiprolin Resistance Confirmed by Genome Editing using CRISPR/Cas9 in Phytophthora capsici and P. sojae. AB - Oxathiapiprolin is a novel fungicide that was recently registered in a number of countries to control plant-pathogenic oomycetes such as Phytophthora capsici. In our previous study, point mutations G770V and G839W in oxysterol binding protein related protein 1 (ORP1) were detected in oxathiapiprolin-resistant P. capsici isolates (PcORP1). Here, we used the CRISPR/Cas9 system to verify the effects of these two point mutations on P. capsici phenotypes. Transformants containing heterozygous G770V and G839W mutations in PcORP1 showed high levels of oxathiapiprolin resistance. The G770V transformants showed otherwise similar phenotypes compared with the wild-type isolate BYA5, including sporangia and zoospore production, cyst germination, and pathogenicity. However, two independent transformants with heterozygous G839W mutations in PcORP1 could not produce sporangia. Three transformants with an unexpected point mutation in PcORP1 (DeltaN837) showed high oxathiapiprolin resistance, and either similar or significantly reduced fitness compared with BYA5. The same deletion (DeltaN837) was confirmed to confer oxathiapiprolin resistance in P. sojae by using CRISPR/Cas9. These homozygous P. sojae mutants also showed either similar or strongly reduced fitness compared with the wild-type parent isolate P6497. These results improve our understanding of oxathiapiprolin resistance in Phytophthora spp., and will be useful for the development of novel oxysterol-binding protein homolog inhibitor fungicides. PMID- 29979094 TI - Effects of Community Sanitation Program on the Awareness of Environmental Sustainability in Assam, India. AB - Community sanitation is now an essential issue of environmental sustainability. In recently, community-led total sanitation program is going in Bangladesh, India, Indonesia, Pakistan, Ethiopia, and Kenya with the help of government and nongovernmental organizations. In this context, a community sanitation program was organized in Silchar, India, in which the students, local community members, and university professors directly and indirectly participated and gave their valuable feedback. The study aimed to evaluate the effects of community sanitation program on the awareness of environmental sustainability. In this empirical research design, 20 university students, 6 university professors, and 14 local people participated in the community sanitation and hands-on activity program organized on the roadside of Silchar Medical College & Hospital and Irongmara Market nearer to the Assam University, Silchar. The participants' responses towards the feedback cum questionnaire was analyzed by Kruskal -Wallis H test resulted significant effects of community sanitation program on the awareness of environmental sustainability. PMID- 29979096 TI - Serum IL18 is associated with hemophagocytosis and poor survival in extranodal natural killer/T-cell lymphoma. AB - Extranodal natural killer/T-cell lymphoma (ENKTL) is associated with Epstein-Barr virus (EBV) infection, a common cause of hemophagocytosis. As interleukin-18 (IL18) is related with hemophagocytosis, we measured serum IL18 and IL18-related cytokines of newly diagnosed patients with ENKTL (N = 114) to investigate the role as a biomarker for hemophagocytosis and determine the prognosis of ENKTL. The median value of serum IL18 was 20.5 pg/mL (1.23-2021.81 pg/mL). The high IL18 group (>=20.5 pg/mL) was associated with stage III/IV, the presence of hemophagocytosis and poor treatment outcome. Serum IL18 showed significant positive correlations with TNFalpha, IFNgamma, and IP10. Overall survival was significantly different between the high and low IL18 groups (p < .001), and high serum IL18 was independently prognostic for survival in the multivariate analysis. In conclusion, serum IL18 levels may be associated with the hemophagocytosis and poor survival outcomes in patients with ENKTL. PMID- 29979098 TI - LeukeMYC prognostication. PMID- 29979097 TI - Hodgkin lymphoma of the elderly patients: a retrospective multicenter analysis from the Polish Lymphoma Research Group. AB - We retrospectively analyzed long-term disease outcome of 350 elderly Hodgkin Lymphoma (eHL) patients treated with ABVD/ABVD-like regimen enrolled in the PLRG R9 study between 2001 and 2013 in Poland. Complete remission was reported for 73% of early (ES) and 61% advanced stage (AS) patients. Nine (10%) ES and 56 (20%) AS patients have died. With the median follow-up of 36 (1-190) months, 3-year EFS and OS was 0.74 (95%CI: 0.63-0.85) and 0.90 (95%CI: 0.82-0.98) for ES; 0.51 (95%CI: 0.44-0.57), and 0.81 (95%CI: 0.75-0.86) for AS patients, respectively. For ES patients, Cox regression revealed ECOG <2 and age >70 as predictive for inferior OS and EFS. For AS patients, the most predictive for OS was the presence of cardiovascular disorders (CVD) (p = .00044), while for EFS four factors were significantly associated with a poor outcome: ECOG< 2, age >70 years, CVD and extranodal disease. In conclusion, CVD significantly impacts outcomes of ABVD treated advanced eHL patients. PMID- 29979099 TI - The potential of adipose-derived stem cell subpopulations in regenerative medicine. PMID- 29979100 TI - Ultrasonographic findings in cats with acute kidney injury: a retrospective study. AB - Objectives The aims of the study were to identify the ultrasonographic findings in cats with acute kidney injury (AKI) and to assess whether they had prognostic value. Methods This was a descriptive case series. A search of the computerised records of the Queen Mother Hospital for Animals (Hatfield, UK) was performed for cats presenting with AKI between 2007 and 2016. Patients were excluded if they had historical data consistent with chronic kidney disease. Ultrasound images were reviewed for the presence of six renal ultrasonographic abnormalities: nephromegaly, cortical and medullary echogenicity, pyelectasia, retroperitoneal and peritoneal fluid. Ultrasonographic findings were assessed individually and cumulatively to give an ultrasound score out of 6. Ultrasonographic findings were assessed for association with oligouria/anuria and survival. Results Forty-five cats with AKI fulfilled the inclusion criteria. In total, 6.7% (3/45) of cats had normal renal size and architecture. The most common renal ultrasonographic findings were nephromegaly, pyelectasia and increased renal echogenicity. The presence of retroperitoneal fluid was associated with oligouria/anuria. Total ultrasound score (out of 6) was significantly associated with oligouria/anuria and 6 month survival. Conclusions and relevance Ultrasonographic findings are common in cats presenting with AKI. The increasing number of renal ultrasonographic abnormalities and the presence of retroperitoneal fluid alone is associated with oligouria/anuria and a higher ultrasound score may suggest a poorer long-term prognosis. PMID- 29979101 TI - Twelve autologous blood transfusions in eight cats with haemoperitoneum. AB - Objectives The objectives of this study were to describe the clinical use and outcome of autologous transfusions in cats with intracavitary haemorrhage. Methods A retrospective descriptive study was performed. Computerised medical records of a single referral centre were searched for cats receiving an autotransfusion. Medical records were evaluated for underlying disease process, autotransfusion technique, autotransfusion volume, time period over which the autotransfusion was given, packed cell volume (PCV) pre- and post autotransfusion, percentage rise in PCV, use of other blood products and any complications of the procedure. Survival to discharge and survival at 2 months was documented. Results Between July 2012 and March 2018 a total of 12 autotransfusions were performed in eight cats. All patients were diagnosed with haemoperitoneum. Four of the eight cats were diagnosed with abdominal neoplasia, three had postoperative haemorrhage and one had a traumatic haemoperitoneum. Three cats received more than one autotransfusion. Blood was collected using a 23 G butterfly catheter and 20 ml syringe in 7/12 collections, a 23 G needle and 20 ml syringe in 2/12 collections and directly into syringes from the open abdomen at the time of surgery in 3/12 collections. A median volume of 50 ml (range 25-80 ml) was collected and administered, meaning a median volume of 16.5 ml/kg (range 9-26 ml/kg) was administered. The autologous transfusions were given over a median of 3 h (0.25-6 h). Five cats were given another blood product alongside the autotransfusion. Median percentage PCV increase was 5% (range 1-7%). Anticoagulant was used in 5/12 autotransfusions. No clinically relevant adverse effects were reported. Six of the eight cats survived to discharge. Two month survival was 60% (3/5). Conclusions and relevance Autologous transfusion appears to be a safe and effective technique for stabilising cats with haemoperitoneum. This technique allows rapid and cheap provision of blood and avoids the need for an allogenic blood donor. PMID- 29979102 TI - The use of motivational interviewing in improving medication adherence for individuals with asthma: a systematic review. AB - OBJECTIVE:: This review was conducted to examine current literature on the use of motivational interviewing (MI) as a strategy to promote individuals with asthma to make behavioral changes and improve health outcomes. This article systematically reviews empirical MI studies which were used to promote asthma medication adherence in children, adolescents, and adults. METHODS:: Studies were obtained from several databases. We searched CINAHL, MEDLINE, PyscINFO, PubMed, and Cochrane database for articles on the use of MI to improve asthma medication adherence in individuals diagnosed with moderate to severe asthma. Various combinations of the following search terms were used: motivational interviewing, asthma, medication adherence, medication non-adherence, and MI. RESULTS:: MI intervention showed evidence of improved self-efficacy, asthma, self-management, and positive behavior change for individuals diagnosed with asthma. The results suggest that MI is a feasible and promising approach to improve attitudes toward asthma medication adherence. CONCLUSION:: The generally favorable results indicate MI merged with other interventions and support is effective in improving medication adherence and is also more sustainable than MI as a stand-alone intervention. Additional research is necessary to assess the effectiveness of MI in ensuring individuals fill their prescriptions and use their medications as recommended. PMID- 29979103 TI - Attachment Avoidance and Anxiety in Adolescence: Turkish Adaptation of the Experiences in Close Relationships-Relationship Structures Scale. AB - The aim of the present study is to test the factor structure and reliability of the Experience of Close Relationships-Relationship Structures Scale (ECR-RS) mother, father, romantic partner, close friend forms among Turkish adolescents. In order to test the structure validity of the ECR-RS, exploratory factor analysis is performed on a sample of 214 participants in Study 1, and to further investigate the structure validity, confirmatory factor analysis is performed on a second sample of 286 participants in Study 2. Within the scope of the reliability studies of the ECR-RS, internal reliability and test-retest reliability of the Turkish ECR-RS are also tested. The results of the explanatory and confirmatory factor analysis, Cronbach's alpha coefficients, and test-retest reliability scores supported the original two-factor structure (attachment avoidance and attachment anxiety) for all forms of the ECR-RS among Turkish adolescents. PMID- 29979104 TI - The role of the subchondral layer in osteonecrosis of the femoral head: analysis based on HR-QCT in comparison to MRI findings. AB - Background Non-traumatic avascular osteonecrosis of the femoral head (ONFH) is a severe disease causing destruction of the hip joint, often necessitating total hip arthroplasty (THA) even in young patients. Magnetic resonance imaging (MRI) is commonly used for diagnosis of ONFH, but provides limited insight into the subchondral bone microstructure. Purpose To analyze routine MRI findings in comparison to high-resolution quantitative computed tomography (HR-QCT) with a special focus on the subchondral layer and to estimate the importance of differences determining the indication for THA. Material and Methods Twelve patients with ONFH were included before THA. Preoperative MRI and HR-QCT of the retrieved femoral heads were aligned using a registration algorithm. Pathological findings and trabecular bone parameters in matched areas were analyzed by two readers. McNemar, marginal homogeneity test, and Pearson's correlation coefficient were used for comparison. Results Subchondral delamination was found in nine cases on HR-QCT, but missed or underestimated in all but one case on MRI ( P = 0.016). Chondral discontinuity was found in all cases on HR-QCT and in two cases on MRI ( P = 0.016). Areas of complete bone resorption on HR-QCT were linked to high signal intensity on 3D gradient-echo MRI sequences with water selective excitation, while there was no correlation between trabecular bone parameters and MRI signal intensities in other areas ( P = 0.304). Conclusion Subchondral delamination, subchondral resorption, and chondral discontinuity are found frequently in advanced stages of ONFH. These lesions tend to be underestimated on conventional MRI. Our results support the importance of CT imaging in the evaluation of ONFH. PMID- 29979105 TI - Diffusion tensor imaging findings of the median nerve before and after carpal tunnel corticosteroid injection in patients with carpal tunnel syndrome: a preliminary study. AB - Background Corticosteroid injections are a popular technique for carpal tunnel syndrome (CTS) treatment and are believed to provide rapid symptom relief. Purpose To use magnetic resonance diffusion tensor imaging (MR-DTI) to determine the association between diffusion values of the median nerve (MN) at several anatomic locations and symptom relief in patients with CTS following corticosteroid injection. Material and Methods MR-DTI was performed on 15 wrists of 12 patients with CTS before and two weeks after ultrasound-guided corticosteroid injections. We recorded the patients' clinical data including sex, age, side of injection, satisfaction, and symptom relief. Satisfaction and symptom relief were rated using a Likert scale and the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ) scale. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the MN at the levels of the distal radioulnar joint (DRUJ), pisiform bone, and hamate bone were determined. Results All patients had >=50% satisfaction on the injection side. In comparison with baseline values, post-injection ADC was significantly lower ( P = 0.001) but FA was not significantly higher ( P = 0.11) at the pisiform bone level on the injected wrists. At the DRUJ and hamate bone levels, no obvious inter-scan change in FA and ADC ( P > 0.05) was observed. The decrease in ADC at the pisiform bone level strongly correlated with the decrease in BCTQ scores (r = 0.628; P = 0.012). Conclusion Symptom relief in patients with CTS receiving corticosteroid injection is related to the change in ADC of the median nerve at the level of the pisiform bone, as determined using MR-DTI. PMID- 29979106 TI - Application of spectral CT imaging in evaluating lymph node metastasis in patients with gastric cancers: initial findings. AB - Background Traditional computed tomography (CT) can predict the lymph node metastasis of gastric cancers with moderate accuracy; however, investigation of spectral CT imaging in this field is still limited. Purpose To explore the application of spectral CT imaging in evaluating lymph node metastasis in patients with gastric cancers. Material and Methods Twenty-four patients with gastric cancers prospectively underwent spectral CT imaging in the arterial phase. The short and long diameters, material concentrations, and CT values were measured and compared between lymph nodes with and without metastasis. The diagnostic performance of the CT index in identifying metastatic lymph nodes was analyzed with receiver operating characteristic (ROC) analysis. Results A total of 102 lymph nodes (77 metastatic, 25 non-metastatic) were detected on spectral CT imaging with the reference of postoperative pathologic exanimation. The short and long diameters, water/fat concentrations, CT value, and ratio between lymph nodes vs. tumors of metastatic lymph nodes were significantly higher than those of non-metastatic ones (all P < 0.05). With a cut-off of 0.785, the CT ratio of lymph node/tumor on 70-keV monochromatic images yielded an accuracy of 81.4% in differentiating lymph nodes with and without metastasis. Conclusion Spectral CT imaging detects lymph nodes more clearly, and the CT ratio of lymph node/tumor on 70-keV monochromatic images holds great potential in differentiating lymph nodes with and without metastasis, which is more accurate than size measurement. PMID- 29979107 TI - Limited efficacy of somatic cell lysis buffer to purify laboratory mouse sperm. AB - AIM: Epigenetic analyses of sperm require pure samples devoid of diploid cell contamination. We sought to determine the efficacy of somatic cell lysis buffer (SCLB) treatment to purify mouse epididymis sperm samples. MATERIALS & METHODS: Sperm cell concentration, sperm purity, small RNA contents and sperm and somatic marker gene expression was compared in SCLB-treated sperm samples and two different control conditions. RESULTS: The SCLB condition as well as the control condition mimicking the additional pelleting and re-suspension steps resulted in substantial cell loss without evidence of enhanced purification of sperm cells as compared with epididymis-derived sperm samples that were not manipulated further. CONCLUSION: Molecular analyses focused on sperm cells require high levels of purity in order to avoid high-confounding RNA and cytosolic contributions of nonsperm cells. Our findings advocate gradient or cell sorting-based purification approaches where pure samples are required for sensitive molecular assays. PMID- 29979108 TI - An epigenetic pacemaker is detected via a fast conditional expectation maximization algorithm. AB - AIM: DNA methylation has proven to be a remarkably accurate biomarker for human age, allowing the prediction of chronological age to within a couple of years. Recently, we proposed that the Universal PaceMaker (UPM), a flexible paradigm for modeling evolution, could be applied to epigenetic aging. Nevertheless, application to real data was restricted to small datasets for technical limitations. MATERIALS & METHODS: We partition the set of variables into to two subsets and optimize the likelihood function on each set separately. This yields an extremely efficient Conditional Expectation Maximization algorithm, alternating between the two sets while increasing the overall likelihood. RESULTS: Using the technique, we could reanalyze datasets of larger magnitude and show significant advantage to the UPM approach. CONCLUSION: The UPM more faithfully models epigenetic aging than the time linear approach while methylated sites accelerate and decelerate jointly. PMID- 29979109 TI - Comprehensive analysis of hippocampal miRNAomes in humans and mice. AB - AIM: This study aims to explore the similarity and difference of hippocampal miRNAomes between humans and mice. MATERIALS & METHODS: A systematic comparison of the miRNAomes between healthy human and mouse hippocampi was performed using high-throughput sequencing followed by bioinformatic analyses. RESULTS: A novel miRNA termed novel-21-5p and a human-specific miR-656-3p were identified in human hippocampi, which were expressed ubiquitously and predicted to be associated with neural activities. Compared with mouse, abundantly expressed miRNAs in human hippocampus were notably enriched in pathways pertaining to neural activities, such as neurotrophin TRK receptor signaling pathway, axon guidance and synaptic transmission. Expression pattern of orthologous miRNAs between human and mouse hippocampi was conserved. Meanwhile, the expression conservation was positively correlated with the sequence conservation. CONCLUSION: Hippocampal miRNAomes between humans and mice were overall comparable; the differences in expression or function across species should be considered when constructing mouse models. PMID- 29979111 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1 January -28 February 28 2018. PMID- 29979112 TI - Health-Support Needs of Widows in South Africa: A Phenomenological Inquiry. AB - Community health care should facilitate effective adaptation to widowhood. In South Africa, the primary health-care nurses, who are the first-line health-care services, seem to miss opportunities for identifying and effectively managing widows experiencing health risks. This study explored the health-support needs of widows. We purposively selected 12 participants, who were widows between 25 and 65 years old residing in an urban area of South Africa. Data were gathered during unstructured individual phenomenological interviews and analyzed using a descriptive phenomenological method. Widowhood is an embodied and intense emotional experience with a cognitive impact. Related to these experiences are widows' health-support needs. Widows have a need to be listened to and to be understood and cared for; attitudes and skills which require time and availability from primary health-care nurses. Widows expressed a need to engage in support groups, receive home visits, and receive health education from primary health-care nurses. PMID- 29979110 TI - Levosimendan in pulmonary hypertension and right heart failure. AB - Pulmonary hypertension is a multifactorial disease with a high morbidity and mortality. Right ventricular function is the most important predictor of morbidity and mortality in patients suffering from pulmonary hypertension, but currently there are no approved treatments directly supporting the failing right ventricle. Levosimendan is a calcium sensitizing agent with inotropic, pulmonary vasodilatory, and cardioprotective properties. Given its pharmacodynamic profile, levosimendan could be a potential novel agent for the treatment of right ventricular failure caused by pulmonary hypertension. The aim of this review is to provide an overview of the current knowledge on the effects of levosimendan in pulmonary hypertension and right heart failure. PMID- 29979113 TI - Medico-legal dinner speeches: A toast to Medicine. PMID- 29979114 TI - Endoscopic clipping of intraventricular aneurysms using the "wet-field" technique. AB - Intraventricular hemorrhage and intracerebral aneurysms are relatively frequent complications associated with moyamoya disease. Prevention of aneurysm rerupture is important because it significantly decreases the morbidity and mortality rates. Aneurysms arising distal to collateral flow are sometimes observed in patients with intraventricular hemorrhage; however, the treatment of these aneurysms remains challenging because of their deep-seated location in the brain and accompanying narrow surgical corridor. The authors describe a neuroendoscopic aneurysm clipping technique performed in 2 cases using a small-diameter tubular retractor for intraventricular aneurysms of the distal lateral posterior choroidal artery. In this technique, the surgical field was continuously irrigated with artificial CSF to keep the ventricle size intact, and aneurysm clipping was performed through a tubular retractor that was introduced with neuronavigational guidance. The patients' postoperative courses were uneventful, and CT angiography revealed complete clipping of the aneurysms and patent parent arteries. Endoscopic clipping using a tubular retractor is an effective and less invasive alternative for treating intraventricular aneurysms. The wet-field endoscopic technique is performed in an aqueous field and maintains an intact ventricle size, allowing for a clear surgical view and a wider, enhanced surgical field. PMID- 29979115 TI - Risk of de novo aneurysm formation in patients with a prior diagnosis of ruptured or unruptured aneurysm: systematic review and meta-analysis. AB - OBJECTIVE De novo aneurysms are rare entities periodically discovered during follow-up imaging. Little is known regarding the frequency with which these lesions form or the time course. This systematic review and meta-analysis was undertaken to estimate the incidence of de novo aneurysms and to determine risk factors for aneurysm formation. METHODS The authors searched multiple databases for studies of patients with unruptured and ruptured aneurysms describing the rate of de novo aneurysm formation. The primary outcome was incidence of de novo aneurysm formation. A meta-analysis was performed using a random-effects model. The authors examined the associations of multiple aneurysms, prior subarachnoid hemorrhage, smoking, sex, age at presentation, and hypertension with de novo aneurysm formation. RESULTS The meta-analysis included 14,968 aneurysm patients who received imaging follow-up from 35 studies. The overall incidence of de novo aneurysm formation was 2% (95% CI 2%-3%) over a mean follow-up time of 8.3 years. The estimated incidence density was 0.3%/patient-year. There was no statistically significant difference in rates of de novo aneurysm formation between patients who had ruptured aneurysms and those with unruptured aneurysms. In 8 studies, 11.2% of de novo aneurysms were found in patients with <= 5 years of follow-up and 88.8% were found at > 5 years. The mean time to rupture for de novo aneurysms was 10 years. CONCLUSIONS This systematic review demonstrates that formation of de novo aneurysms is rare. Overall, routine screening for de novo aneurysms is likely to be of low yield and could be performed at time intervals of at least 5 to 10 years. PMID- 29979116 TI - Hemodynamic features of offending vessels at neurovascular contact in patients with trigeminal neuralgia and hemifacial spasm. AB - OBJECTIVE Offending vessels at the site of neurovascular contact (NVC) in patients with trigeminal neuralgia (TN) and hemifacial spasm (HFS) may have specific hemodynamic features. The purpose of this study was to investigate the wall shear stress (WSS) of offending vessels at NVCs by conducting a computational fluid dynamics (CFD) analysis. METHODS The authors retrospectively analyzed the cases of 20 patients (10 with TN and 10 with HFS) evaluated by 3D CT angiography and used the imaging findings for analysis of the hemodynamic parameters. The 3D CFD images were directly compared with the NVCs determined by simulated multifusion images of CT angiogram and MR cisternogram, and operative photos. The magnitudes of the WSS (WSSm) at the proximal (WSSm-p), just-beginning (WSSm-j), contact site (WSSm-s), and distal (WSSm-d) areas of each NVC were analyzed. The ratios of the WSSm-j, WSSm-s, and WSSm-d areas to the WSSm-p area were calculated individually. The direction of the WSS (WSSv) and its temporal variation (WSSvV) were depicted and morphologically compared with the NVC confirmed by simulated images and operative findings. RESULTS The ratios of WSSm at the just-beginning and the contact site to the proximal area of the NVCs (WSSm j/WSSm-p and WSSm-s/WSSm-p) were both significantly higher than that at the distal area (WSSm-d/WSSm-p) (p < 0.05). The WSSv and WSSvV at the NVCs showed small variation in a single cardiac cycle, especially along the areas that were in contact with the affected nerve. CONCLUSIONS Areas of relatively high WSSm and temporal variation of WSSm (WSSmV) were observed at the NVCs. Less mobility of the WSSv and WSSvV was detected along the side of the vessels in contact with the nerves. These findings may be consistent with the actual area of the NVC. Hemodynamic features of the site of NVC can be added to the preoperative simulation for MVD surgery, which may be useful for the diagnosis and treatment planning of TN and HFS. PMID- 29979117 TI - Thirty-day readmission rate as a surrogate marker for quality of care in neurosurgical patients: a single-center Canadian experience. AB - OBJECTIVE Readmission to the hospital within 30 days of discharge is used as a surrogate marker for quality and value of care in the United States (US) healthcare system. Concern exists regarding the value of 30-day readmission as a quality of care metric in neurosurgical patients. Few studies have assessed 30 day readmission rates in neurosurgical patients outside the US. The authors performed a retrospective review of all adult neurosurgical patients admitted to a single Canadian neurosurgical academic center and who were discharged to home to assess for the all-cause 30-day readmission rate, unplanned 30-day readmission rate, and avoidable 30-day readmission rate. METHODS A retrospective review was performed assessing 30-day readmission rates after discharge to home in all neurosurgical patients admitted to a single academic neurosurgical center from January 1, 2011, to December 31, 2011. The primary outcomes included rates of all cause, unplanned, and avoidable readmissions within 30 days of discharge. Secondary outcomes included factors associated with unplanned and avoidable 30 day readmissions. RESULTS A total of 184 of 950 patients (19.4%) were readmitted to the hospital within 30 days of discharge. One-hundred three patients (10.8%) were readmitted for an unplanned reason and 81 (8.5%) were readmitted for a planned or rescheduled operation. Only 19 readmissions (10%) were for a potentially avoidable reason. Univariate analysis identified factors associated with readmission for a complication or persistent/worsening symptom, including age (p = 0.009), length of stay (p = 0.007), general neurosurgery diagnosis (p < 0.001), cranial pathology (p < 0.001), intensive care unit (ICU) admission (p < 0.001), number of initial admission operations (p = 0.01), and shunt procedures (p < 0.001). Multivariate analysis identified predictive factors of readmission, including diagnosis (p = 0.002, OR 2.4, 95% CI 1.4-5.3), cranial pathology (p = 0.002, OR 2.7, 95% CI 1.4-5.3), ICU admission (p = 0.004, OR 2.4, 95% CI 1.3 4.2), and number of first admission operations (p = 0.01, OR 0.51, 95% CI 0.3 0.87). Univariate analysis performed to identify factors associated with potentially avoidable readmissions included length of stay (p = 0.03), diagnosis (p < 0.001), cranial pathology (p = 0.02), and shunt procedures (p < 0.001). Multivariate analysis identified only shunt procedures as a predictive factor for avoidable readmission (p = 0.02, OR 5.6, 95% CI 1.4-22.8). CONCLUSIONS Almost one fifth of neurosurgical patients were readmitted within 30 days of discharge. However, only about half of these patients were admitted for an unplanned reason, and only 10% of all readmissions were potentially avoidable. This study demonstrates unique challenges encountered in a publicly funded healthcare setting and supports the growing literature suggesting 30-day readmission rates may serve as an inappropriate quality of care metric in neurosurgical patients. Potentially avoidable readmissions can be predicted, and further research assessing predictors of avoidable readmissions is warranted. PMID- 29979118 TI - Multifocal cavernous hemangioma of the jugular foramen: a rare skull base vascular malformation. AB - Jugular foramen cavernous hemangiomas are extremely rare vascular malformations, and, to the best of the authors' knowledge, their occurrence as multifocal lesions involving both intra- and extracranial compartments has never been reported before. Here, the authors describe the case of a 60-year-old woman with a complex multifocal jugular foramen cavernous hemangioma. The patient presented with signs and symptoms concerning for jugular foramen syndrome, as well as a right neck mass. Surgical extirpation of the lesion was achieved by a multidisciplinary team via a right infratemporal fossa approach (Fisch type A) with concurrent high neck dissection and a closure buttressed with an autologous fat graft and a temporoparietal fascial flap. Although rare, cavernous hemangiomas should be included in the differential diagnosis of jugular foramen masses. PMID- 29979119 TI - Laser ablation for mesial temporal epilepsy: a multi-site, single institutional series. AB - OBJECTIVE Although it is still early in its application, laser interstitial thermal therapy (LiTT) has increasingly been employed as a surgical option for patients with mesial temporal lobe epilepsy. This study aimed to describe mesial temporal lobe ablation volumes and seizure outcomes following LiTT across the Mayo Clinic's 3 epilepsy surgery centers. METHODS This was a multi-site, single institution, retrospective review of seizure outcomes and ablation volumes following LiTT for medically intractable mesial temporal lobe epilepsy between October 2011 and October 2015. Pre-ablation and post-ablation follow-up volumes of the hippocampus were measured using FreeSurfer, and the volume of ablated tissue was also measured on intraoperative MRI using a supervised spline-based edge detection algorithm. To determine seizure outcomes, results were compared between those patients who were seizure free and those who continued to experience seizures. RESULTS There were 23 patients who underwent mesial temporal LiTT within the study period. Fifteen patients (65%) had left-sided procedures. The median follow-up was 34 months (range 12-70 months). The mean ablation volume was 6888 mm3. Median hippocampal ablation was 65%, with a median amygdala ablation of 43%. At last follow-up, 11 (48%) of these patients were seizure free. There was no correlation between ablation volume and seizure freedom (p = 0.69). There was also no correlation between percent ablation of the amygdala (p = 0.28) or hippocampus (p = 0.82) and seizure outcomes. Twelve patients underwent formal testing with computational visual fields. Visual field changes were seen in 67% of patients who underwent testing. Comparing the 5 patients with clinically noticeable visual field deficits to the rest of the cohort showed no significant difference in ablation volume between those patients with visual field deficits and those without (p = 0.94). There were 11 patients with follow-up neuropsychological testing. Within this group, verbal learning retention was 76% in the patients with left-sided procedures and 89% in those with right-sided procedures. CONCLUSIONS In this study, there was no significant correlation between the ablation volume after LiTT and seizure outcomes. Visual field deficits were common in formally tested patients, much as in patients treated with open temporal lobectomy. Further studies are required to determine the role of amygdalohippocampal ablation. PMID- 29979120 TI - Long-term and delayed functional recovery in patients with severe cerebrovascular and traumatic brain injury requiring tracheostomy. AB - OBJECTIVE Data on long-term functional recovery (LFR) following severe brain injury are essential for counseling of surrogates and for appropriate timing of outcome assessment in clinical trials. Delayed functional recovery (DFR) beyond 3 6 months is well documented following severe traumatic brain injury (sTBI), but there are limited data on DFR following severe cerebrovascular brain injury. The objective of this study was to assess LFR and DFR in patients with sTBI and severe stroke dependent on tracheostomy and tube feeding at the time of discharge from the intensive care unit (ICU). METHODS The authors identified patients entered into their tracheostomy database 2008-2013 with sTBI and severe stroke, encompassing SAH, intracerebral hemorrhage (ICH), and acute ischemic stroke (AIS). Eligibility criteria included disease-specific indicators of severity, Glasgow Coma Scale score < 9 at time of tracheostomy, and need for tracheostomy and tube feeding at ICU discharge. Assessment was at 1-3 months, 6-12 months, 12 24 months, and 24-36 months after initial injury for presence of tracheostomy, ability to walk, and ability to perform basic activities of daily living (B ADLs). Long-term functional recovery (LFR) was defined as recovery of the ability to walk or perform B-ADLs by the 24- to 36-month follow-up. Delayed functional recovery (DFR) was defined as progression in functional milestones between any 2 time points beyond the 1- to 3-month follow-up. RESULTS A total of 129 patients met the eligibility criteria. Functional outcomes were available for 129 (100%), 97 (75%), 83 (64%), and 80 (62%) patients, respectively, from assessments at 1-3, 6-12, 12-24 and 24-36 months; 33 (26%) died by 24-36 months. Fifty-nine (46%) regained the ability to walk and 48 (37%) performed B-ADLs at some point during their recovery. Among survivors who had not achieved the respective milestone at 1-3 months, 29/58 (50%) were able to walk and 28/74 (38%) performed B-ADLs at 6 12 months. Among survivors who had not achieved the respective milestone at 6-12 months, 5/16 (31%) were able to walk and 13/30 (43%) performed B-ADLs at 12-24 months. There was no significant difference in rates of LFR or DFR between patients with sTBI and those with severe stroke. CONCLUSIONS Among patients with severe brain injury requiring tracheostomy and tube feeding at ICU discharge, 46% regained the ability to walk and 37% performed B-ADLs 2-3 years after injury. DFR beyond 1-3 and 6-12 months was seen in over 30% of survivors, with no significant difference between sTBI and severe stroke. PMID- 29979121 TI - Clinicoradiological features and surgical outcomes of primary intracranial medulloepitheliomas: a single-center experience and pooled analysis of individual patient data. AB - OBJECTIVE Medulloepithelioma (MEPL) is a rare, malignant primitive neuroectodermal tumor with dismal survival rates. The authors aimed to define independent risk factors for progression-free survival (PFS) and overall survival (OS) and to propose an optimal treatment protocol for MEPL. METHODS The authors reviewed the clinicoradiological data obtained in 12 patients with MEPL who underwent surgical treatment at their institution between January 2008 and June 2016. In addition, they reviewed 55 cases of MEPL published in the literature from January 1957 to July 2017. A pooled analysis of individual patient data of these 67 patients was performed to evaluate risk factors. RESULTS The authors' cohort included 5 males and 7 females with a mean age of 15.7 years. Gross-total resection (GTR) was achieved in 10 (83.3%) patients. Radiotherapy (mean total dose 42.8 Gy) and chemotherapy were administered to 7 and 4 patients, respectively. After a median follow-up of 21.7 months, 6 (50%) patients suffered recurrence and subsequently died, with median PFS and OS times of 5.5 and 13.9 months, respectively. Among the 55 patients in the literature, 13 (23.6%) patients received GTR, and 25 (49.0%) and 15 (29.4%) received radiotherapy (median total dose 53.2 Gy) and chemotherapy, respectively. After a median follow up of 10.0 months, the recurrence and mortality rates were 69.7% (23/33) and 70.8% (34/48), respectively, and the median PFS was 6.0 months. Of the pooled cohort, the actuarial 5-year PFS and OS were 36.3% and 29.2%, respectively, and the estimated median survival time for PFS and OS were 12.8 and 15.2 months, respectively. A multivariate Cox model verified non-GTR (HR 5.537, p < 0.001) and no radiotherapy (HR 3.553, p = 0.008) as independent adverse factors for PFS. The 5-year PFS in patients with or without GTR was 63.8% and 6.3%, respectively, and in patients with or without radiotherapy was 42.7% and 23.1%, respectively. A multivariate model demonstrated non-GTR (HR 9.089, p < 0.001), no radiotherapy (HR 3.126, p = 0.004), and no chemotherapy (HR 3.621, p = 0.004) as independent adverse factors for poor OS. The 5-year OS in patients with GTR, radiotherapy, or chemotherapy was 72.1%, 44.0%, and 58.0%, respectively. In contrast, in patients without GTR, radiotherapy, or chemotherapy, the 5-year OS was 5.8%, 14.3%, and 15.8%, respectively. Overall, in patients receiving GTR plus chemoradiotherapy, the actuarial 5-year PFS and OS were both 87.5%. CONCLUSIONS MEPL is a rare neoplastic entity with a poor prognosis. There are no distinguishing radiological features apart from cystic degeneration. Via the pooled analysis, the authors identified independent adjustable factors associated with PFS and OS, from which they advocate for GTR plus chemoradiotherapy with a sufficient dose if tolerable as an optimal treatment to improve outcomes. Future studies with large cohorts will be necessary to verify our findings. PMID- 29979122 TI - Neurosurgery and the rise of academic social media: what neurosurgeons should know. PMID- 29979123 TI - Association between metal hypersensitivity and implant failure in patients who underwent titanium cranioplasty. AB - OBJECTIVE Digitally designed titanium plates are commonly used for the reconstruction of craniofacial defects, although implant exposure (referred to as failure) is one of the major complications. Metal hypersensitivities have been suggested as possible causes of implant failure of orthopedic, intravascular, gynecological, and dental devices, yet there has been no consensus on the requirement for allergy screening before cranioplasty. METHODS In this study, the authors prospectively investigated the prevalence of metal hypersensitivity in patients for whom cranioplasty is planned and assess its relationship with titanium implant failure (exposure). RESULTS Based on records from 207 included patients, 39.61% of patients showed hypersensitivity to at least one kind of metal. Approximately one-quarter (25.12%) of patients had multiple metal allergies. Co, Cd, and Zn were the 3 most frequently identified metal hypersensitivities. No allergy to titanium was detected in this study. The overall incidence of cranioplasty implant failure was 5.31% (11 of 207). Patients showing hypersensitivities to more than 3 kinds of metal had higher risks of titanium plate exposure. CONCLUSIONS Based on their findings, the authors suggest that routine allergy screening be performed before titanium plate cranioplasty. For patients with hypersensitivities to more than 3 metals, alternative materials, such as polyetheretherketone, should be considered for cranioplasty. PMID- 29979124 TI - Letter to the Editor. Imaging predictor for rebleeding after surgery in intracerebral hemorrhage. PMID- 29979125 TI - Prediction of cavernous sinus invasion in patients with Cushing's disease by magnetic resonance imaging. AB - OBJECTIVE Cavernous sinus invasion (CSI) in Cushing's disease (CD) negatively affects the probability of complete resection, biochemical cure, and need for adjuvant therapy. However, the prediction of CSI based on MRI findings has been inconsistent and variable. Among macroadenomas, the Knosp classification is the most widely utilized radiographic predictor of CSI, but its accuracy in predicting CSI and the probability of gross-total resection is limited in the setting of microadenomas or Knosp grade 0-2 macroadenomas. The authors noticed that the presence of a triangular shape of adenomas adjacent to the cavernous sinus on coronal MR images is frequently associated with CSI. The authors aimed to determine the correlation of this radiographic finding ("sail sign" [SS]) with CSI. METHODS The authors performed a retrospective review of all patients with a pituitary lesion < 20 mm and a biochemical diagnosis of CD treated with endoscopic or microscopic transsphenoidal resection from November 2007 to May 2017. Overall 185 patients with CD were identified: 27 were excluded for negative preoperative imaging, 32 for lacking tumors adjacent to the sinus, 7 for Knosp grade 3 or higher, and 4 for inadequate intraoperative assessment of the CSI. Following application of inclusion and exclusion criteria, 115 cases were available for statistical analysis. Intraoperative CSI was prospectively evaluated at the time of surgery by one of two neurosurgical attending surgeons, and MRI data were evaluated retrospectively by a neurosurgical resident and attending neuroradiologist blinded to the intraoperative results. RESULTS A positive SS was identified in 23 patients (20%). Among patients with positive SS, 91% demonstrated CSI compared to 10% without an SS (p < 0.001). Using the SS as a predictor of CSI provided a sensitivity of 0.7 and a specificity of 0.98, with a positive predictive value (PPV) of 0.91 and a negative predictive value of 0.9. Among patients with positive SS, 30% did not achieve immediate postoperative remission, compared to 3.3% of patients without an SS (p < 0.001). CONCLUSIONS The presence of a positive SS among Cushing's adenomas adjacent to the CS provides strong PPV, specificity, and positive likelihood ratio for the prediction of CSI. This can be a useful tool for preoperative planning and for predicting the likelihood of long-term biochemical remission and the need for adjuvant radiosurgery. PMID- 29979126 TI - How Does Phytophthora infestans Evade Control Efforts? Modern Insight Into the Late Blight Disease. AB - The infamous oomycete Phytophthora infestans has been a persistent threat to potato and tomato production worldwide, causing the diseases known as late blight. This pathogen has proved to be remarkably adept at overcoming control strategies including host-based resistance and fungicides. This review describes the features of P. infestans that make it such a daunting challenge to agriculture. These include a stealthy lifestyle that helps P. infestans evade plant defenses, effectors that suppress host defenses and promote susceptibility, profuse sporulation with a short latent period that enables rapid dissemination, and a genome structure that promotes the adaptive evolution of P. infestans by fostering genetic diversity. Nevertheless, there is reason to be optimistic that accumulated knowledge about the biology of P. infestans and its hosts will lead to improved management of late blight. PMID- 29979127 TI - Penetrating spinal injury in childhood: the influence of mechanism on outcome. An epidemiological study. AB - OBJECTIVE: Penetrating injury of the spine in childhood commonly causes profound and life-long disability, but it has been the object of very little study. The goal of the current report is to document temporal trends in the nationwide incidence of this condition and to highlight the differences between penetrating injuries and closed injuries. METHODS: The Kids' Inpatient Database was queried for spinal injuries in 1997, 2000, 2003, 2006, 2009, and 2012. Penetrating mechanism was determined by diagnostic coding for open injuries and by mechanistic codes for projectiles and knives. Nationwide annual incidences were calculated using weights provided for this purpose. Unweighted data were used as a cross-sectional sample to compare closed and penetrating injuries with respect to demographic and clinical factors. The effect of penetrating mechanism was analyzed in statistical models of death, adverse discharge, and length of stay (LOS). RESULTS: The nationwide incidence of penetrating spinal injury in patients less than 18 years of age trended downward over the study period. Patients with penetrating injury were older and much more predominantly male than patients with closed injuries. They resided predominantly in zip codes with lower median household incomes, and they were much more likely to have public health insurance or none at all. They were predominantly black or Hispanic. The risk of hospital death was no different, but penetrating injuries were associated with much higher rates of adverse discharge after LOS, averaging twice as long as closed injuries. Brain, visceral, and vascular injuries were powerful predictors of hospital death, as was upper cervical level of injury. The most powerful predictor of adverse discharge and LOS was spinal cord injury, followed by brain, visceral, and vascular injury and penetrating mechanism. CONCLUSIONS: Because its pathophysiology requires no elucidation, because the consequences for quality of life are dire, and because the population at risk is well defined, penetrating spinal injury in childhood ought to be an attractive target for public health interventions. PMID- 29979128 TI - Endoscopic surgery for nonsyndromic craniosynostosis: a 16-year single-center experience. AB - OBJECTIVE: In this paper the authors review their 16-year single-institution consecutive patient experience in the endoscopic treatment of nonsyndromic craniosynostosis with an emphasis on careful review of any associated treatment related complications and methods of complication avoidance, including preoperative planning, intraoperative management, and postoperative care and follow-up. METHODS: A retrospective chart review was conducted on all patients undergoing endoscopic, minimally invasive surgery for nonsyndromic craniosynostosis at Rady Children's Hospital from 2000 to 2015. All patients were operated on by a single neurosurgeon in collaboration with two plastic and reconstructive surgeons as part of the institution's craniofacial team. RESULTS: Two hundred thirty-five patients underwent minimally invasive endoscopic surgery for nonsyndromic craniosynostosis from 2000 to 2015. The median age at surgery was 3.8 months. The median operative and anesthesia times were 55 and 105 minutes, respectively. The median estimated blood loss (EBL) was 25 ml (median percentage EBL 4.2%). There were no identified episodes of air embolism or operative deaths. One patient suffered an intraoperative sagittal sinus injury, 2 patients underwent intraoperative conversion of planned endoscopic to open procedures, 1 patient experienced a dural tear, and 1 patient had an immediate reexploration for a developing subgaleal hematoma. Two hundred twenty-five patients (96%) were admitted directly to the standard surgical ward where the median length of stay was 1 day. Eight patients were admitted to the intensive care unit (ICU) postoperatively, 7 of whom had preexisting medical conditions that the team had identified preoperatively as necessitating a planned ICU admission. The 30-day readmission rate was 1.7% (4 patients), only 1 of whom had a diagnosis (surgical site infection) related to their initial admission. Average length of follow-up was 2.8 years (range < 1 year to 13.4 years). Six children (< 3%) had subsequent open procedures for perceived suboptimal aesthetic results, 4 of whom (> 66%) had either coronal or metopic craniosynostosis. No patient in this series either presented with or subsequently developed signs or symptoms of intracranial hypertension. CONCLUSIONS: In this large single-center consecutive patient series in the endoscopic treatment of nonsyndromic craniosynostosis, significant complications were avoided, allowing for postoperative care for the vast majority of infants on a standard surgical ward. No deaths, catastrophic postoperative morbidity, or evidence of the development of symptomatic intracranial hypertension was observed. PMID- 29979129 TI - Severe cranial deformity following cerebrospinal fluid diversion in an adolescent with osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is an inherited connective tissue disorder that causes bone fragility and deformity. Neurological manifestations, including macrocephaly and hydrocephalus, have been reported. Increased vascular fragility or bleeding diathesis also predisposes OI patients to intracranial hemorrhage. The development of chronic subdural fluid collections or hydrocephalus may require CSF diversion. The authors report a previously unrecognized complication of CSF diversion in a patient with OI, that is, a delayed severe cranial deformity, presumably due to over-shunting. In addition to the cosmetic concern, the deformity caused severe headaches and tenderness. The patient underwent craniectomy and titanium mesh cranioplasty, which resulted in the complete resolution of symptoms. This report raises the possibility that over-shunting in patients with OI could predispose to the formation of cranial deformity requiring surgical intervention. PMID- 29979132 TI - A systematic review of endoscopic versus open treatment of craniosynostosis. Part 2: the nonsagittal single sutures. AB - OBJECTIVE: Despite increasing adoption of endoscopic techniques for repair of nonsagittal single-suture craniosynostosis, the efficacy and safety of the procedure relative to established open approaches are unknown. In this systematic review the authors aimed to directly compare open surgical and endoscope-assisted techniques for the treatment of metopic, unilateral coronal, and lambdoid craniosynostosis, with an emphasis on quantitative reported outcomes. METHODS: A literature search was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant articles were identified from 3 electronic databases (MEDLINE, EMBASE, and CENTRAL [Cochrane Central Register of Controlled Trials]) from their inception to August 2017. The quality of methodology and bias risk were assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies. RESULTS: Of 316 screened records, 7 studies were included in a qualitative synthesis of the evidence, of which none were eligible for meta analysis. These reported on 111 unique patients with metopic, 65 with unilateral coronal, and 12 with lambdoid craniosynostosis. For all suture types, 100 (53%) children underwent endoscope-assisted craniosynostosis surgery and 32 (47%) patients underwent open repair. These studies all suggest that blood loss, transfusion rate, operating time, and length of hospital stay were superior for endoscopically treated children. Although potentially comparable or better cosmetic outcomes are reported, the paucity of evidence and considerable variability in outcomes preclude meaningful conclusions. CONCLUSIONS: Limited data comparing open and endoscopic treatments for metopic, unilateral coronal, and lambdoid synostosis suggest a benefit for endoscopic techniques with respect to blood loss, transfusion, length of stay, and operating time. This report highlights shortcomings in evidence and gaps in knowledge regarding endoscopic repair of nonsagittal single-suture craniosynostosis, emphasizing the need for further matched-control studies. PMID- 29979130 TI - Novel suprasellar location of desmoplastic infantile astrocytoma and ganglioglioma: a single institution's experience. AB - OBJECTIVE: The aim of this study was to describe the clinical presentation, imaging appearance, and differential outcomes based on tumor location in 7 patients with desmoplastic infantile astrocytoma and desmoplastic infantile gangliogliomas (DIA/DIG). METHODS: Data of 7 patients with histopathology-proven DIA/DIGs and preoperative imaging were retrospectively reviewed, and age, sex, clinical presentation, imaging characteristics, tumor location, surgical procedure, postoperative morbidity, and overall mortality were recorded. RESULTS: Two subgroups of patients with DIA/DIGs were found to exist based on whether their tumor was located in the cerebral hemispheres or suprasellar region. Nearly all patients presented with rapidly enlarging head circumference regardless of tumor location. However, ocular abnormalities, including nystagmus and preference for downward gaze, were specific for patients with suprasellar disease. These patients experienced significant postoperative complications and had poor long term outcomes. In contrast, patients with hemispheric tumors underwent more extensive resection than patients with suprasellar tumors, had uneventful postoperative courses, and had no documented long-term comorbidities. CONCLUSIONS: Postoperative course and long-term outcome for patients with DIA/DIGs were correlated to the anatomical location and radiographic appearance of their tumor at presentation, despite having histologically and molecularly indistinguishable, WHO grade I tumors. PMID- 29979131 TI - Extensive spinal epidural immature teratoma in an infant: case report. AB - Here, the authors present an extremely rare case of an extensive spinal epidural teratoma (SET) in an infant and provide a review of the cases in the literature. In this report, the authors focused on the clinical manifestation and management of extensive SET. A 64-day-old girl presented with severe dyspnea and paraparesis caused by a large thoracic mass. Imaging studies revealed that the mass originated from the epidural space of the thoracic spine and extended from C7 to L1. The tumor extended bilaterally through the intervertebral foramina and formed a large posterior mediastinal mass. The tumor was partially resected via laminotomy after an emergency thoracotomy. The remnant grade I immature teratoma grew rapidly. After a re-laminotomy and bilateral thoracotomy, the residual tumor stopped growing. However, the patient's paraparesis improved very little, and her scoliosis progressed gradually. Therefore, SET should be included in the differential diagnosis when an infant patient with paraparesis of the lower extremities is encountered. Timely diagnosis, aggressive treatment, and close monitoring are of critical importance to successful recovery in such patients. PMID- 29979133 TI - Letter to the Editor. Hindsight vision and admission after spinal growing implants. PMID- 29979134 TI - Editorial. Endoscopic synostosis surgery: case closed. Or open? Or in between? PMID- 29979135 TI - A systematic review and meta-analysis of endoscopic versus open treatment of craniosynostosis. Part 1: the sagittal suture. AB - OBJECTIVE: In this systematic review and meta-analysis the authors aimed to directly compare open surgical and endoscope-assisted techniques for the treatment of sagittal craniosynostosis, focusing on the outcomes of blood loss, transfusion rate, length of stay, operating time, complication rate, cost, and cosmetic outcome. METHODS: A literature search was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Relevant articles were identified from 3 electronic databases (MEDLINE, EMBASE, and CENTRAL [Cochrane Central Register of Controlled Trials]) from their inception to August 2017. The quality of methodology and bias risk were assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Effect estimates between groups were calculated as standardized mean differences with 95% CIs. Random and fixed effects models were used to estimate the overall effect. RESULTS: Of 316 screened records, 10 met the inclusion criteria, of which 3 were included in the meta analysis. These studies reported on 303 patients treated endoscopically and 385 patients treated with open surgery. Endoscopic surgery was associated with lower estimated blood loss (p < 0.001), shorter length of stay (p < 0.001), and shorter operating time (p < 0.001). From the literature review of the 10 studies, transfusion rates for endoscopic procedures were consistently lower, with significant differences in 4 of 6 studies; the cost was lower, with differences ranging from $11,603 to $31,744 in 3 of 3 studies; and the cosmetic outcomes were equivocal (p > 0.05) in 3 of 3 studies. Finally, endoscopic techniques demonstrated complication rates similar to or lower than those of open surgery in 8 of 8 studies. CONCLUSIONS: Endoscopic procedures are associated with lower estimated blood loss, operating time, and days in hospital. Future long-term prospective registries may establish advantages with respect to complications and cost, with equivalent cosmetic outcomes. Larger studies evaluating patient- or parent-reported satisfaction and optimal timing of intervention as well as heterogeneity in outcomes are indicated. PMID- 29979136 TI - The value of sitting radiographs: analysis of spine flexibility and its utility in preoperative planning for adult spinal deformity surgery. AB - Sitting radiographs are a valuable tool to consider the thoracic compensatory mechanism in patients who are candidates for thoracolumbar correction surgery. PMID- 29979137 TI - Simple presurgical method of predicting C5 palsy after cervical laminoplasty using C5 nerve root ultrasonography. AB - OBJECTIVE: The incidence of C5 palsy after cervical laminoplasty is approximately 5%. Because C5 palsy is related to cervical foraminal stenosis at the C4-5 level, the authors hypothesized that cervical foraminal stenosis can be diagnosed by examining the C5 nerve root (NR) using ultrasonography. The purpose of this study was to investigate whether postoperative C5 palsy could be predicted using ultrasonography. METHODS: This study used a prospective diagnosis design. In total, 140 patients undergoing cervical laminoplasty were examined with ultrasound. The cross-sectional area (CSA) of the C5 NR was measured on both sides before surgery, and the incidence of postoperative C5 palsy was examined. The difference between the CSA of the patients with and without C5 palsy and the lateral differences in the C5 palsy group were determined. RESULTS: The incidence of C5 palsy was 5% (7 cases). Symptoms manifested at a median of 5 days after surgery (range 1-29 days). The CSA of the C5 NR on the affected side was significantly enlarged in the C5 palsy group compared with that in the no-C5 palsy group (p = 0.001). In addition, in the patients who had C5 palsy, the CSA of the C5 NR was significantly enlarged on the affected side compared with that on the unaffected side (p = 0.02). Receiver operating characteristic analysis indicated that the best threshold value for the CSA of the C5 NR was 10.4 mm2, which provided 91% sensitivity and 71% specificity. CONCLUSIONS: C5 palsy may be predicted preoperatively using ultrasound. The authors recommend the ultrasonographic measurement of the CSA of the C5 NR prior to cervical laminoplasty. PMID- 29979138 TI - Correlation of 2-year SRS-22r and ODI patient-reported outcomes with 5-year patient-reported outcomes after complex spinal fusion: a 5-year single institution study of 118 patients. AB - OBJECTIVE: Patient-reported outcomes (PROs) are often measured up to 2 years after surgery; however, prospective collection of longitudinal outcomes for 5 years postoperatively can be challenging due to lack of patient follow-up. The aim of this study was to determine whether PROs collected at 2-year follow-up accurately predict long-term PROs 5 years after complex spinal fusion (>= 5 levels). METHODS: This was an ambispective study of 118 adult patients (>= 18 years old) undergoing >= 5-level spinal arthrodesis to the sacrum with iliac fixation from January 2002 to December 2011. Patient demographics and radiographic parameters as well as intraoperative variables were collected. PRO instruments (Scoliosis Research Society [SRS]-22r function, self-image, mental health, pain, and Oswestry Disability Index [ODI]) were completed before surgery then at 2 and 5 years after surgery. Primary outcome investigated in this study was the correlation between SRS-22r domains and ODI collected at 2- and 5-year follow-up. RESULTS: Of the 118 patients, 111 patients had baseline PROs, 105 patients had 2-year follow-up data, and 91 patients had 5-year follow-up PRO data with 72% undergoing revision surgery. The average pre- and postoperative major coronal curve Cobb angles for the cohort were 32.1 degrees +/- 23.7 degrees and 19.8 degrees +/- 19.3 degrees , respectively. There was a strong correlation between 2- and 5-year ODI (r2 = 0.80, p < 0.001) and between 2- and 5-year SRS 22r domains, including function (r2 = 0.79, p < 0.001), self-image (r2 = 0.82, p < 0.001), mental health (r2 = 0.77, p < 0.001), and pain (r2 = 0.79, p < 0.001). Of the PROs, ODI showed the greatest absolute change from baseline to 2- and 5 year follow-up (2-year Delta 17.6 +/- 15.9; 5-year Delta 16.5 +/- 19.9) followed by SRS-22r self-image (2-year Delta 1.4 +/- 0.96; 5-year Delta 1.3 +/- 1.0), pain (2-year Delta 0.94 +/- 0.97; 5-year Delta 0.80 +/- 1.0), function (2-year Delta 0.60 +/- 0.62; 5-year Delta 0.49 +/- 0.79), and mental health (2-year Delta 0.49 +/- 0.77; 5-year Delta 0.38 +/- 0.84). CONCLUSIONS: Patient-reported outcomes collected at 2-year follow-up may accurately predict long-term PROs (5-year follow-up). PMID- 29979139 TI - Posterior approach for anteriorly located cervical spinal cord hemangioblastomas: technical note. AB - The surgical management of anteriorly located spinal cord hemangioblastomas remains a challenge. Different approaches have been published, of which the anterior approach seems to be the most obvious and commonly used. A posterior approach might be more suitable in certain patients, especially in cases of cystic hemangioblastomas. The authors present 3 cases of anterior spinal hemangioblastomas, which were all resected via a posterior approach. The authors discuss the rationale for choosing this approach and explain the technique in detail. PMID- 29979140 TI - Association between preoperative activity level and functional outcome at 12 months following surgical decompression for lumbar spinal stenosis. AB - OBJECTIVE: This study defines the association of preoperative physical activity level with functional outcomes at 3 and 12 months following surgical decompression for lumbar spinal stenosis. METHODS: Data were collected as a prospective observational registry at a single institution from 2012 through 2015, and then analyzed with a retrospective cohort design. Patients who were able to participate in activities outside the home preoperatively were compared to patients who did not participate in such activities, with respect to 3-month and 12-month functional outcomes postintervention, adjusted for relevant confounders. RESULTS: Ninety-nine patients were included. At baseline, sedentary/inactive patients (n = 55) reported greater back pain, lower quality of life, and higher disability than similarly treated patients who were active preoperatively. Both cohorts experienced significant improvement from baseline in back pain, leg pain, disability, and quality of life at both 3 and 12 months after lumbar decompression surgery. At 3 months postintervention, sedentary/inactive patients reported more leg pain and worse disability than patients who performed activities outside the home preoperatively. However, at 12 months postintervention, there were no statistically significant differences between the two cohorts in back pain, leg pain, quality of life, or disability. Multivariate analysis revealed that sedentary/inactive patients had improved disability and higher quality of life after surgery compared to baseline. Active patients experienced greater overall improvement in disability compared to inactive patients. CONCLUSIONS: Sedentary/inactive patients have a more protracted recovery after lumbar decompression surgery for spinal stenosis, but at 12 months postintervention can expect to reach similar long-term outcomes as patients who are active/perform activities outside the home preoperatively. PMID- 29979141 TI - Use of the Airo mobile intraoperative CT system versus the O-arm for transpedicular screw fixation in the thoracic and lumbar spine: a retrospective cohort study of 263 patients. AB - OBJECTIVE: Navigation-enabling technology such as 3D-platform (O-arm) or intraoperative mobile CT (iCT-Airo) systems for use in spinal surgery has considerably improved accuracy over that of traditional fluoroscopy-guided techniques during pedicular screw positioning. In this study, the authors compared 2 intraoperative imaging systems with navigation, available in their neurosurgical unit, in terms of the accuracy they provided for transpedicular screw fixation in the thoracic and lumbar spine. METHODS: The authors performed a retrospective analysis of clinical and surgical data of 263 consecutive patients who underwent thoracic and lumbar spine screw placement in the same center. Data on 97 patients who underwent surgery with iCT-Airo navigation (iCT-Airo group) and 166 with O-arm navigation (O-arm group) were analyzed. Most patients underwent surgery for a degenerative or traumatic condition that involved thoracic and lumbar pedicle screw fixation using an open or percutaneous technique. The primary endpoint was the proportion of patients with at least 1 screw not correctly positioned according to the last intraoperative image. Secondary endpoints were the proportion of screws that were repositioned during surgery, the proportion of patients with a postoperative complication related to screw malposition, surgical time, and radiation exposure. A blinded radiologist graded screw positions in the last intraoperative image according to the Heary classification (grade 1-3 screws were considered correctly placed). RESULTS: A total of 1361 screws placed in 97 patients in the iCT-Airo group (503 screws) and in 166 in the O-arm group (858 screws) were graded. Of those screws, 3 (0.6%) in the iCT-Airo group and 4 (0.5%) in the O-arm group were misplaced. No statistically significant difference in final accuracy between these 2 groups or in the subpopulation of patients who underwent percutaneous surgery was found. Three patients in the iCT-Airo group (3.1%, 95% CI 0%-6.9%) and 3 in the O-arm group (1.8%, 95% CI 0%-4.0%) had a misplaced screw (Heary grade 4 or 5). Seven (1.4%) screws in the iCT-Airo group and 37 (4.3%) in the O-arm group were repositioned intraoperatively (p = 0.003). One patient in the iCT-Airo group and 2 in the O-arm group experienced postoperative neurological deficits related to hardware malposition. The mean surgical times in both groups were similar (276 [iCT-Airo] and 279 [O-arm] minutes). The mean exposure to radiation in the iCT Airo group was significantly lower than that in the O-arm group (15.82 vs 19.12 mSv, respectively; p = 0.02). CONCLUSIONS: Introduction of a mobile CT scanner reduced the rate of screw repositioning, which enhanced patient safety and diminished radiation exposure for patients, but it did not improve overall accuracy compared to that of a mobile 3D platform. PMID- 29979142 TI - Recovery of respiratory function and autonomic diaphragm movement following unilateral recurrent laryngeal nerve to phrenic nerve anastomosis in rabbits. AB - The authors studied restoration of respiratory function in rabbits, using the recurrent laryngeal nerve to restore function after the phrenic nerve had been severed. The results of this animal study are encouraging and suggest that a similar technique could possibly be used to help patients with severe cervical spinal cord injuries. PMID- 29979143 TI - Proportion and predictors of loss to follow-up in a longitudinal cohort study of female entertainment and sex workers in Cambodia. AB - We examined the proportion and correlates of loss to follow-up (LTFU) among female entertainment and sex workers (FESWs) in a longitudinal HIV prevention intervention trial in Cambodia. The Cambodia Integrated HIV and Drug Prevention Intervention trial tested a comprehensive package of interventions aimed at reducing amphetamine-type stimulant use and HIV risk among FESWs in ten provinces. The present study estimated the proportion of women LTFU and assessed factors associated with LTFU. Logistic regression analyses were used. Of a total 596 women enrolled, the cumulative proportion of LTFU was 29.5% (n = 176) between zero- and 12-month follow-up. In multivariate analyses, women with no living children (adjusted odds ratio [AOR] 1.6; 95% confidence interval [CI]: 1.1, 2.3) and those who experienced recent food insecurity (AOR 1.7; 95%CI: 1.1, 2.7) were more likely to be LTFU. Women who were members of the SMARTgirl HIV prevention programme for >= 6 months compared to non-members were less likely to be LTFU (AOR 0.3; 95%CI: 0.2, 0.6). LTFU was moderately high in this study and similar to other studies, indicating a need for strategies to retain this population in HIV prevention programmes and research. Interventions aimed at stabilizing women's lives, including reducing food insecurity and creating communities of engagement for FESWs, should be considered. PMID- 29979144 TI - HIV testing in patients presenting with indicator conditions in outpatient settings: offer and uptake rates, and educational and active interventions. AB - Approximately 13% of people living with HIV in the UK are undiagnosed which has significant implications in terms of onward transmission and late diagnosis. HIV testing guidelines recommend routine screening in anyone presenting to healthcare with an HIV indicator condition (IC); however, this does not occur routinely. This study aimed to assess the feasibility and effectiveness of using case note prompts highlighting the presence of an IC to increase HIV testing. Clinicians in three outpatient departments received case note prompts either before or after a period of clinician-led identification. Test offer and uptake rates were assessed. A parallel anonymous seroprevalence study estimated the prevalence of undiagnosed HIV. A total of 4191 patients had an appointment during the study period; 608 (14.5%) had an IC. HIV test offer was significantly higher when a prompt was inserted into notes (34.3% versus 3.2%, p < 0.001). The prevalence of diagnosed HIV in the cohort was 4.1%. No cases of undiagnosed HIV infection were identified. Despite guidelines, offer of HIV testing is low. Strategies to increase routine screening of patients presenting with an IC are needed. Individual case note prompts significantly increase HIV test offer; however, the effect is lost if the strategy is withdrawn. PMID- 29979146 TI - Midwest Nursing Research Society News. PMID- 29979145 TI - Fulminant hepatitis in a patient with secondary syphilis. AB - Despite the increasing incidence of syphilis and due to its wide variety of clinical manifestations, syphilis remains an under-diagnosed condition. We report an unusual case of secondary syphilis presenting with acute hepatitis and skin lesions, confirmed based on positive treponemal and non-treponemal assays. Despite adequate diagnosis and treatment, the patient developed fulminant hepatitis and brain death. This atypical presentation emphasizes the importance of high clinical suspicion in recognizing syphilis as an etiology for unexplained acute hepatitis, allowing early diagnosis and treatment and possibly avoiding severe complications such as fulminant hepatic failure. PMID- 29979147 TI - Sacubitril/Valsartan: potential treatment for paediatric heart failure. AB - The Prospective comparison of angiotensin receptor antagonist Valsartan and neprilysin inhibitor Sacubitril with angiotensin-converting enzyme inhibitor (enalapril) to determine impact on Global Mortality and Morbidity in Heart Failure trial has demonstrated that Sacubitril/Valsartan is superior to Enalapril in reducing the risks of both sudden cardiac death and death from worsening heart failure. This novel combination, Sacubitril/Valsartan, is also shown to reduce the risk of hospitalisation and progression of heart failure in adults. However, the benefit of Sacubitril/Valsartan in paediatric heart failure patients is unknown. In this review, we discuss the similarities and differences in pathophysiology of heart failure in children versus adults, and the potential role of Sacubitril/Valsartan in paediatric heart failure patients. PMID- 29979148 TI - Nurse practitioner consultations in primary health care: an observational interaction analysis of social interactions and consultation outcomes. AB - OBJECTIVE: To determine the discrete nature of social interactions occurring in nurse practitioner consultations and investigate the relationship between consultation social interaction styles (biomedical and patient-centred) and the outcomes of patient satisfaction, patient enablement, and consultation time lengths. METHODS: A case study-based observational interaction analysis of verbal social interactions, arising from 30 primary health care nurse practitioner consultations, linked with questionnaire measures of patient satisfaction and enablement. RESULTS: A significant majority of observed social interactions used patient-centred communication styles (P=0.005), with neither nurse practitioners nor patients or carers being significantly more verbally dominant. Nurse practitioners guided the sequence of consultation interaction sequences, but patients actively participated through interactions such as asking questions. Usage of either patient-centred or biomedical interaction styles were not significantly associated with increased levels of patient satisfaction or patient enablement. The median consultation time length of 10.1 min (quartiles 8.2, 13.7) was not significantly extended by high levels of patient-centred interactions being used in the observed consultations. CONCLUSION: High usage levels of patient-centred interaction styles are not necessarily contingent upon having longer consultation times available, and clinicians can encourage patients to use participatory interactions, whilst still then retaining overall guidance of the phased sequences of consultations, and not concurrently extending consultation time lengths. This study adds to the body of nurse practitioner consultation communication research by providing a more detailed understanding of the nature of social interactions occurring in nurse practitioner consultations, linked to the outcomes of patient satisfaction and enablement. PMID- 29979150 TI - Growth kinetics of Ga x In(1-x)P nanowires using triethylgallium as Ga precursor. AB - Ga x In(1-x)P nanowire arrays are promising for various optoelectronic applications with a tunable band-gap over a wide range. In particular, they are well suited as the top cell in tandem junction solar cell devices. So far, most Ga x In(1-x)P nanowires have been synthesized by the use of trimethylgallium (TMGa). However, particle assisted nanowire growth in metal organic vapor phase epitaxy is typically carried out at relatively low temperatures, where TMGa is not fully pyrolysed. In this work, we developed the growth of Ga x In(1-x)P nanowires using triethylgallium (TEGa) as the Ga precursor, which reduced Ga precursor consumption by about five times compared to TMGa due to the lower homogeneous pyrolysis temperature of TEGa. The versatility of TEGa is shown by synthesis of high yield Ga x In(1-x)P nanowire arrays, with a material composition tunable by the group III input flows, as verified by x-ray diffraction measurements and photoluminescence characterization. The growth dynamics of Ga x In(1-x)P nanowires was assessed by varying the input growth precursor molar fractions and growth temperature, using hydrogen-chloride as in situ etchant. We observed a complex interplay between the precursors. First, trimethylindium (TMIn) inhibits Ga incorporation into the nanowires, resulting in higher In composition in the grown nanowires than in the vapor. Second, the growth rate increases with temperature, indicating a kinetically limited growth, which from nanowire effective binary volume growth rates of InP and GaP can be attributed to the synthesis of GaP in Ga x In(1-x)P. We observed that phosphine has a strong effect on the nanowire growth rate with behavior expected for a unimolecular Langmuir-Hinshelwood mechanism of pyrolysis on a catalytic surface. However, growth rates increase strongly with both TEGa and TMIn precursors as well, indicating the complexity of vapor-liquid-solid growth for ternary materials. One precursor can affect the decomposition of another, and each precursor can affect the wetting properties and catalytic activity of the metal particle. PMID- 29979149 TI - An automated high-resolution in vivo screen in zebrafish to identify chemical regulators of myelination. AB - Myelinating oligodendrocytes are essential for central nervous system (CNS) formation and function. Their disruption is implicated in numerous neurodevelopmental, neuropsychiatric and neurodegenerative disorders. However, recent studies have indicated that oligodendrocytes may be tractable for treatment of disease. In recent years, zebrafish have become well established for the study of myelinating oligodendrocyte biology and drug discovery in vivo. Here, by automating the delivery of zebrafish larvae to a spinning disk confocal microscope, we were able to automate high-resolution imaging of myelinating oligodendrocytes in vivo. From there, we developed an image analysis pipeline that facilitated a screen of compounds with epigenetic and post-translational targets for their effects on regulating myelinating oligodendrocyte number. This screen identified novel compounds that strongly promote myelinating oligodendrocyte formation in vivo. Our imaging platform and analysis pipeline is flexible and can be employed for high-resolution imaging-based screens of broad interest using zebrafish. PMID- 29979151 TI - Third International Workshop on Improving Data Quality in XAFS Spectroscopy, Q2XAFS2017. AB - This issue of the Journal of Synchrotron Radiation is a special issue including papers from the Q2XAFS2017 workshop. Here, a brief introduction is given. PMID- 29979152 TI - Propagation of uncertainty in experiment: structures of Ni (II) coordination complexes. AB - Accurate experimental XAFS (X-ray absorption fine-structure) data including uncertainties are required during analysis for valid comparison of results and conclusions of hypothesis testing on structural determinations. Here an approach is developed to investigate data without standard interpolation of experimental data and with minimal loss of information content in the raw data. Nickel coordination complexes bis(i-n-propylsalicylaldiminato)nickel(II) (i-pr) and bis(N-n-propylsalicylaldiminato)nickel(II) (n-pr) are investigated. The additional physical insight afforded by the correct propagation of experimental uncertainty is used to determine newly refined structures for the innermost co ordination shell. Two sets of data are investigated for each complex; one optimized for high point accuracy and one optimized for high point density. Clearly both are important and in this investigation the quality of the physical insight from each is directly provided by measured and propagated uncertainties to fairly represent the relevant accuracies. The results provide evidence for an approximate tetrahedral geometry for the i-pr Ni complex that is more symmetric than previously concluded, with our high point accuracy data yielding ligand lengths of 2.017 +/- 0.006 A and 2.022 ? 0.006 A for Ni-N and Ni-O bonds, respectively, and an even more skewed square-planar (i.e. rhombohedral) arrangement for the n-pr complex with corresponding bond lengths of 2.133 +/- 0.004 A and 1.960 ? 0.003 A. The ability to distinguish using hypothesis testing between the subtle differences in XAFS spectra arising from the approximate local tetrahedral and square-planar geometries of the complexes is also highlighted. The effect of standard interpolation on experimental XAFS spectra prior to fitting with theoretical model structures is investigated. While often performed as a necessary step for Fourier transformation into position space, this will nonetheless skew the fit away from actual data taken, and fails to preserve the information content within the data uncertainty. The artificial effects that interpolation imposes on chir2 are demonstrated. Finally, a method for interpolation is introduced which locally preserves the chir2 and thus information content, when a regular grid is required, e.g for further analysis in r-space. PMID- 29979153 TI - A call for a round robin study of XAFS stability and platform dependence at synchrotron beamlines on well defined samples. AB - Round robin studies have been used across fields of science for quality control testing and to investigate laboratory dependencies and cross-platform inconsistencies as well as to drive forward the improvement of understanding of experimental systems, systematic effects and theoretical limitations. Here, following the Q2XAFS Workshop and Satellite to IUCr Congress 2017 on 'Data Acquisition, Treatment, Storage - quality assurance in XAFS spectroscopy', a mechanism is suggested for a suitable study across XAFS (X-ray absorption fine structure) beamlines and facilities, to enable each beamline to cross-calibrate, provide representative test data, and to enable collaborative cross-facility activities to be more productive. PMID- 29979154 TI - A biological perspective towards a standard for information exchange and reporting in XAS. AB - The complex structural landscape of biological samples and their sensitivity to X ray exposure leads to specific challenges in biological X-ray absorption spectroscopy (bio-XAS) research, which in turn has necessitated standardization of various aspects of bio-XAS data measurement, analysis and interpretation. The bio-XAS community is therefore well suited for the development of a data reporting standard with the specific aim of creating a feedback loop for improving/standardizing data analysis protocols and optionally to make published data available to collaborators/researchers in a meaningful and quantitative format. The XIF (XAFS information file) reporting format presented here contains key experimental and analysis parameters, useful in developing a consistent platform for bio-XAS research worldwide. Such a reporting standard, enforced by the user community and publishing groups alike, can be an important step towards the standardization of data measurement and analysis techniques in bio-XAS. PMID- 29979155 TI - Steps towards XAFS beamline automation and remote access. AB - Although remote access to beamline synchrotron facilities is now a common operation mode at macromolecular crystallography beamlines thanks to substantial efforts in automated processes for sample preparation and handling, experiment planning and analysis, this is still not the case for XAFS beamlines. Here the experience and developments undertaken at LNLS and Diamond in automation are described, in an attempt to tackle the specific challenges posed by the high variability in experimental conditions and configurations that XAFS measurements require. PMID- 29979156 TI - Fully automated beamline control system for XAS beamlines. AB - Owing to the growing demand for complex in situ experiments, the handling of synchrotron experiments has become increasingly complicated. The control system at the XAS beamline of the Karlsruhe Institute of Technology synchrotron was automated based on a user-driven development cycle. By combining intelligent remote-controlled hardware and highly integrated software layers it is now possible to record data with a high level of reproducibility, eliminating human malperformance. The additional advantage of automation is the possibility of real 24/7 operation without tiring. This paper focuses on the options of optimization and enhancement in the data acquisition. PMID- 29979157 TI - The challenge of constructing an international XAFS database. AB - The present state of XAFS databases, particularly in Japan, and proposals for future directions are presented. International collaboration is important for enlarging the database for further development of XAFS spectroscopy. PMID- 29979158 TI - Improving the quality of XAFS data. AB - Following the Q2XAFS Workshop and Satellite to IUCr Congress 2017 on 'Data Acquisition, Treatment, Storage - quality assurance in XAFS spectroscopy', a summary is given of the discussion on different aspects of a XAFS experiment that affect data quality. Some pertinent problems ranging from sources and minimization of noise to harmonic contamination and uncompensated monochromator glitches were addressed. Also, an overview is given of the major limitations and pitfalls of a selection of related methods, such as photon-out spectroscopies and energy-dispersive XAFS, and of increasingly common applications, namely studies at high pressure, and time-resolved investigations of catalysts in operando. Advice on how to avoid or deal with these problems and a few good practice recommendations are reported, including how to correctly report results. PMID- 29979159 TI - Using EXAFS data to improve atomistic structural models of glasses. AB - Quantitative characterization of the atomic structure of multi-component glasses is a long-standing scientific challenge. This is because in most cases no single experimental technique is capable of completely resolving all aspects of a disordered system's structure. In this situation, the most practical solution for the materials scientist is to apply multiple experimental probes offering differing degrees of insight into a material's properties. This powerful and widely adopted approach does, however, transfer the characterization challenge to the task of developing a coherent data analysis framework that can appropriately combine the diverse experimental insight into a single, data-consistent, structural model. Here, taking a terbium metaphosphate glass as an example system, it is illustrated how this can be achieved for X-ray diffraction and extended X-ray absorption fine-structure (EXAFS) spectroscopy data, using an empirical potential structure refinement approach. This methodology is based on performing a Monte Carlo simulation of the structure of a disordered material that is guided to a solution consistent with the provided experimental data, by a series of pairwise perturbation potentials operating on a classical reference potential foundation. For multi-component glasses the incorporation of EXAFS data into the resulting bulk structural models is shown to make a critical contribution that is required to properly account for the increase in local structural order that can develop in the melt-quench process of glass formation. PMID- 29979160 TI - Fluorescence-detected XAS with sub-second time resolution reveals new details about the redox activity of Pt/CeO2 catalyst. AB - A setup for fluorescence-detected X-ray absorption spectroscopy (XAS) with sub second time resolution has been developed. This technique allows chemical speciation of low-concentrated materials embedded in highly absorbing matrices, which cannot be studied using transmission XAS. Using this setup, the reactivity of 1.5 wt% Pt/CeO2 catalyst was studied with 100 ms resolution during periodic cycling in CO- and oxygen-containing atmospheres in a plug-flow reactor. Measurements were performed at the Pt L3- and Ce L3-edges. The reactivity of platinum and cerium demonstrated a strong correlation. The oxidation of the catalyst starts on the ceria support helping the oxidation of platinum nanoparticles. The new time-resolved XAS setup can be applied to various systems, capable of reproducible cycling between different states triggered by gas atmosphere, light, temperature, etc. It opens up new perspectives for mechanistic studies on automotive catalysts, selective oxidation catalysts and photocatalysts. PMID- 29979162 TI - Single-particle XFEL 3D reconstruction of ribosome-size particles based on Fourier slice matching: requirements to reach subnanometer resolution. AB - Three-dimensional (3D) structures of biomolecules provide insight into their functions. Using X-ray free-electron laser (XFEL) scattering experiments, it was possible to observe biomolecules that are difficult to crystallize, under conditions that are similar to their natural environment. However, resolving 3D structure from XFEL data is not without its challenges. For example, strong beam intensity is required to obtain sufficient diffraction signal and the beam incidence angles to the molecule need to be estimated for diffraction patterns with significant noise. Therefore, it is important to quantitatively assess how the experimental conditions such as the amount of data and their quality affect the expected resolution of the resulting 3D models. In this study, as an example, the restoration of 3D structure of ribosome from two-dimensional diffraction patterns created by simulation is shown. Tests are performed using the diffraction patterns simulated for different beam intensities and using different numbers of these patterns. Guidelines for selecting parameters for slice-matching 3D reconstruction procedures are established. Also, the minimum requirements for XFEL experimental conditions to obtain diffraction patterns for reconstructing molecular structures to a high-resolution of a few nanometers are discussed. PMID- 29979161 TI - The Spectroscopy Village at Diamond Light Source. AB - This manuscript presents the current status and technical details of the Spectroscopy Village at Diamond Light Source. The Village is formed of four beamlines: I18, B18, I20-Scanning and I20-EDE. The village provides the UK community with local access to a hard X-ray microprobe, a quick-scanning multi purpose XAS beamline, a high-intensity beamline for X-ray absorption spectroscopy of dilute samples and X-ray emission spectroscopy, and an energy-dispersive extended X-ray absorption fine-structure beamline. The optics of B18, I20 scanning and I20-EDE are detailed; moreover, recent developments on the four beamlines, including new detector hardware and changes in acquisition software, are described. PMID- 29979163 TI - High Bragg reflectivity of diamond crystals exposed to multi-kW mm-2 X-ray beams. AB - X-ray free-electron lasers in the oscillator configuration (XFELO) are future fully coherent hard X-rays sources with ultrahigh spectral purity. X-ray beams circulate in an XFELO optical cavity comprising diamond single crystals. They function as high-reflectance (close to 100%), narrowband (~10 meV) Bragg backscattering mirrors. The average power density of the X-ray beams in the XFELO cavity is predicted to be as high as ~10 kW mm-2. Therefore, XFELO feasibility relies on the ability of diamond crystals to withstand such a high radiation load and preserve their high reflectivity. Here the endurance of diamond crystals to irradiation with multi-kW mm-2 power density X-ray beams is studied. It is shown that the high Bragg reflectivity of the diamond crystals is preserved after the irradiation, provided it is performed at ~1 * 10-8 Torr high-vacuum conditions. Irradiation under 4 * 10-6 Torr results in a ~1 meV shift of the Bragg peak, which corresponds to a relative lattice distortion of 4 * 10-8, while the high Bragg reflectivity stays intact. PMID- 29979165 TI - Characterization of the X-ray coherence properties of an undulator beamline at the Advanced Photon Source. AB - In anticipation of the increased use of coherent X-ray methods and the need to upgrade beamlines to match improved source quality, here the coherence properties of the X-rays delivered by beamline 12ID-D at the Advanced Photon Source have been characterized. The measured X-ray divergence, beam size, brightness and coherent flux at energies up to 26 keV are compared with the calculated values from the undulator source, and the effects of beamline optics such as a mirror, monochromator and compound refractive lenses are evaluated. Diffraction patterns from slits as a function of slit width are analyzed using wave propagation theory to obtain the beam divergence and thus coherence length. Imaging of the source using a compound refractive lens was found to be the most accurate method for determining the vertical divergence. While the brightness and coherent flux obtained without a monochromator ('pink beam') agree well with those calculated for the source, those measured with the monochromator were a factor of three to six lower than the source, primarily because of vertical divergence introduced by the monochromator. The methods described herein should be widely applicable for measuring the X-ray coherence properties of synchrotron beamlines. PMID- 29979164 TI - Performance of quartz- and sapphire-based double-crystal high-resolution (~10 meV) RIXS monochromators under varying power loads. AB - In the context of a novel, high-resolution resonant inelastic X-ray scattering spectrometer, a flat-crystal-based quartz analyzer system has recently been demonstrated to provide an unprecedented intrinsic-energy resolution of 3.9 meV at the Ir L3 absorption edge (11.215 keV) [Kim et al. (2018) Sci. Rep. 8, 1958]. However, the overall instrument resolution was limited to 9.7 meV because of an 8.9 meV incident band pass, generated by the available high-resolution four bounce Si(844) monochromator. In order to better match the potent resolving power of the novel analyzer with the energy band pass of the incident beam, a quartz(309)-based double-bounce, high-resolution monochromator was designed and implemented, expected to yield an overall instrument resolution of 6.0 meV. The choice of lower-symmetry quartz is very attractive because of its wealth of suitable near-backscattering reflections. However, it was found that during room temperature operation typical levels of incident power, barely affecting the Si monochromator, caused substantial thermal distortions in the first crystal of the quartz monochromator, rendering it practically unusable. Finite-element analyses and heat-flow analyses corroborate this finding. As a high-flux, lower resolution (15.8 meV) alternative, a two-bounce sapphire(078) version was also tested and found to be less affected than quartz, but notably more than silicon. PMID- 29979166 TI - More are better, but the details matter: combinations of multiple Fresnel zone plates for improved resolution and efficiency in X-ray microscopy. AB - Fresnel zone plates used for X-ray nanofocusing face high-aspect-ratio nanofabrication challenges in combining narrow transverse features (for high spatial resolution) along with extended optical modulation along the X-ray beam direction (to improve efficiency). The stacking of multiple Fresnel zone plates along the beam direction has already been shown to offer improved characteristics of resolution and efficiency when compared with thin single zone plates. Using multislice wave propagation simulation methods, here a number of new schemes for the stacking of multiple Fresnel zone plates are considered. These include consideration of optimal thickness and spacing in the axial direction, and methods to capture a fraction of the light otherwise diffracted into unwanted orders, and instead bring it into the desired first-order focus. The alignment tolerances for stacking multiple Fresnel zone plates are also considered. PMID- 29979168 TI - Large-area single-photon-counting CdTe detector for synchrotron radiation computed tomography: a dedicated pre-processing procedure. AB - Large-area CdTe single-photon-counting detectors are becoming more and more attractive in view of low-dose imaging applications due to their high efficiency, low intrinsic noise and absence of a scintillating screen which affects spatial resolution. At present, however, since the dimensions of a single sensor are small (typically a few cm2), multi-module architectures are needed to obtain a large field of view. This requires coping with inter-module gaps and with close to-edge pixels, which generally show a non-optimal behavior. Moreover, high-Z detectors often show gain variations in time due to charge trapping: this effect is detrimental especially in computed tomography (CT) applications where a single tomographic image requires hundreds of projections continuously acquired in several seconds. This work has been carried out at the SYRMEP beamline of the Elettra synchrotron radiation facility (Trieste, Italy), in the framework of the SYRMA-3D project, which aims to perform the world's first breast-CT clinical study with synchrotron radiation. An ad hoc data pre-processing procedure has been developed for the PIXIRAD-8 CdTe single-photon-counting detector, comprising an array of eight 30.7 mm * 24.8 mm modules tiling a 246 mm * 25 mm sensitive area, which covers the full synchrotron radiation beam. The procedure consists of five building blocks, namely dynamic flat-fielding, gap seaming, dynamic ring removal, projection despeckling and around-gap equalization. Each block is discussed and compared, when existing, with conventional approaches. The effectiveness of the pre-processing is demonstrated for phase-contrast CT images of a human breast specimen. The dynamic nature of the proposed procedure, which provides corrections dependent upon the projection index, allows the effective removal of time-dependent artifacts, preserving the main image features including phase effects. PMID- 29979167 TI - An all-diamond X-ray position and flux monitor using nitrogen-incorporated ultra nanocrystalline diamond contacts. AB - Diamond X-ray detectors with conducting nitrogen-incorporated ultra nanocrystalline diamond (N-UNCD) films as electrodes were fabricated to measure X ray beam flux and position. Structural characterization and functionality tests were performed for these devices. The N-UNCD films grown on unseeded diamond substrates were compared with N-UNCD films grown on a seeded silicon substrate. The feasibility of the N-UNCD films acting as electrodes for X-ray detectors was confirmed by the stable performance in a monochromatic X-ray beam. The fabrication process is able to change the surface status which may influence the signal uniformity under low bias, but this effect can be neglected under full collection bias. PMID- 29979169 TI - Dual-polarity pulse processing and analysis for charge-loss correction in cadmium zinc-telluride pixel detectors. AB - Charge losses at the inter-pixel gap are typical drawbacks in cadmium-zinc telluride (CZT) pixel detectors. In this work, an original technique able to correct charge losses occurring after the application of charge-sharing addition (CSA) is presented. The method, exploiting the strong relation between the energy after CSA and the beam position at the inter-pixel gap, allows the recovery of charge losses and improvements in energy resolution. Sub-millimetre CZT pixel detectors were investigated with both uncollimated radiation sources and collimated synchrotron X-rays, at energies below and above the K-shell absorption energy of the CZT material. The detectors are DC coupled to fast and low-noise charge-sensitive preamplifiers (PIXIE ASIC) and followed by a 16-channel digital readout electronics, performing multi-parameter analysis (event arrival time, pulse shape, pulse height). Induced-charge pulses with negative polarity were also observed in the waveforms from the charge-sensitive preamplifiers (CSPs) at energies >60 keV. The shape and the height of these pulses were analysed, and their role in the mitigation of charge losses in CZT pixel detectors. These activities are in the framework of an international collaboration on the development of energy-resolved photon-counting systems for spectroscopic X-ray imaging (5-140 keV). PMID- 29979170 TI - Improving the detection efficiency and modulation transfer function of lens coupled indirect X-ray imaging detectors based on point spread functions simulated according to lens performance parameters. AB - Lens-coupled indirect X-ray imaging detectors have the advantage of high resolution and the disadvantage of low detection efficiency. Using thicker single crystalline films (SCFs) can improve the detection efficiency. However, the image quality will become worse due to the degradation of the point spread function (PSF) and modulation transfer function (MTF). This disadvantage can be improved by deconvolution with the PSF, which is unknown. In this article, a method was established to acquire the PSF based on a simulation of the imaging process for a lens-coupled indirect X-ray imaging detector. Because the structural parameters of commercial lenses cannot usually be obtained, the PSFs were calculated from lens performance parameters. PSFs were calculated using the conditions of 12 keV X-ray energy, 10* and 40* magnification objectives and 4.6 um- and 20 um-thick GGG:Tb scintillators. These were then used to deconvolve images of an Xradia resolution test pattern taken under the same conditions. The results show that after deconvolution the MTF had been clearly improved for both the 4.6 um- and 20 um-thick SCFs, indicating that the image has better quality than before deconvolution. Furthermore, a PSF deconvolution was performed on mouse brain tissue projection images, and the original and deconvolution projection images were used to perform computed-tomography reconstruction; the result proved that the method was effective for improving the image quality of low-contrast samples. Therefore, this method shows promise in allowing the use of thick SCFs to improve the detection efficiency while maintaining good image quality. PMID- 29979171 TI - Elemental fingerprinting of mineral species in iron-fortified milk: anomalous small-angle X-ray scattering and resonant soft X-ray scattering studies. AB - Anomalous small-angle X-ray scattering (ASAXS) and resonant soft X-ray scattering (RSoXS) are two related techniques that can enable element-specific structural information to be obtained. The development of iron-fortified milk products can greatly benefit from such techniques, allowing the structure of iron and other minerals (such as native calcium) within the casein micelle to be determined. Each method has advantages and disadvantages: for ASAXS, the sample preparation is straightforward, but the signal is relatively low and information about the structure of Ca is difficult to access. RSoXS can be used to study both Ca and Fe, and the element-specific signals observed are proportionally much higher; however, the measurements are challenging due to the difficulty of precise control of the solution thickness using currently available vacuum-compatible liquid cells. Nevertheless, complementary results from both techniques indicate Fe is co-located with Ca, i.e. within the colloidal calcium phosphate nanoclusters that are present within native casein micelles in milk. PMID- 29979172 TI - Smaller capillaries improve the small-angle X-ray scattering signal and sample consumption for biomacromolecular solutions. AB - Radiation damage by intense X-ray beams at modern synchrotron facilities is one of the major complications for biological small-angle X-ray scattering (SAXS) investigations of macromolecules in solution. To limit the damage, samples are typically measured under a laminar flow through a cell (typically a capillary) such that fresh solution is continuously exposed to the beam during measurement. The diameter of the capillary that optimizes the scattering-to-absorption ratio at a given X-ray wavelength can be calculated a priori based on fundamental physical properties. However, these well established scattering and absorption principles do not take into account the radiation susceptibility of the sample or the often very limited amounts of precious biological material available for an experiment. Here it is shown that, for biological solution SAXS, capillaries with smaller diameters than those calculated from simple scattering/absorption criteria allow for a better utilization of the available volumes of radiation sensitive samples. This is demonstrated by comparing two capillary diameters di (di = 1.7 mm, close to optimal for 10 keV; and di = 0.9 mm, which is nominally sub-optimal) applied to study different protein solutions at various flow rates. The use of the smaller capillaries ultimately allows one to collect higher quality SAXS data from the limited amounts of purified biological macromolecules. PMID- 29979173 TI - Enhanced insulating behavior in the Ir-vacant Sr2Ir1-xO4 system dominated by the local structure distortion. AB - Sr2IrO4, known as the Jeff = 1/2 Mott insulator, was predicted to be an unconventional superconductor upon doping since it highly resembles the high temperature cuprates. However, recent work pointed out an enhanced insulating behavior in the Ir-vacant Sr2Ir1-xO4 system. In this contribution, to investigate the microscopic mechanism of its enhanced insulating behavior, X-ray absorption spectroscopy was applied to study the electronic structure and local structure distortion of Sr2Ir1-xO4. Due to the presence of Ir5+ ions, the preconceived holes are barely doped in the Ir-vacant system. Nevertheless, Ir vacancies finely modulate the local atomic structure, i.e. the topology of IrO6 octahedra and the in-plane Ir-O1-Ir bond angle. Combined with theoretical calculations, it is demonstrated that both the more distorted IrO6 octahedra and decreased Ir-O1-Ir angle contribute to the increment of the band gap, and then result in the enhanced insulating state for Sr2Ir1-xO4. PMID- 29979174 TI - Rutile- and anatase-type temperature-dependent pre-edge peak intensities in K edge XANES spectra for AO (A = Mn), A2O3 (A = Sc, Cr and Mn) and AO2 (A = Ti and V). AB - Pre-edge peaks in 3d transition-metal element (Sc, Ti, V, Cr and Mn) K-edge XANES (X-ray absorption near-edge structure) spectra in AO2 (A = Ti and V), A2O3 (A = Sc, Cr and Mn) and AO (A = Mn) are measured at various temperatures. Quantitative comparisons for the XANES spectra were investigated by using absorption intensity invariant point normalization. The energy position of the difference peak (D peak) is obtained from the difference between the low- and high-temperature XANES spectra. There are two kinds of temperature dependence for pre-edge peak intensity: rutile- and anatase-type. The true temperature dependence of a transition to each orbital is obtained from the difference spectrum. In both anatase and rutile, the pre-edge peak positions of A2 and A3 are clearly different from the D1- and D2-peak positions. The A1 peak-top energies in both phases of VO2 differ from the D1 peak-top energies. The D-peak energy position determined by the difference spectrum should represent one of the true energies for the transition to an independent orbital. The peak-top positions for pre-edge peaks in XANES do not always represent the true energy for independent transitions to orbitals because several orbital transitions overlap with similar energies. This work suggests that deformation vibration (bending mode) is effective in determining the temperature dependence for the D-peak intensity. PMID- 29979175 TI - Distributed X-ray photon correlation spectroscopy data reduction using Hadoop MapReduce. AB - Multi-speckle X-ray photon correlation spectroscopy (XPCS) is a powerful technique for characterizing the dynamic nature of complex materials over a range of time scales. XPCS has been successfully applied to study a wide range of systems. Recent developments in higher-frame-rate detectors, while aiding in the study of faster dynamical processes, creates large amounts of data that require parallel computational techniques to process in near real-time. Here, an implementation of the multi-tau and two-time autocorrelation algorithms using the Hadoop MapReduce framework for distributed computing is presented. The system scales well with regard to the increase in the data size, and has been serving the users of beamline 8-ID-I at the Advanced Photon Source for near real-time autocorrelations for the past five years. PMID- 29979176 TI - 3D reconstruction of magnetization from dichroic soft X-ray transmission tomography. AB - The development of magnetic nanostructures for applications in spintronics requires methods capable of visualizing their magnetization. Soft X-ray magnetic imaging combined with circular magnetic dichroism allows nanostructures up to 100 300 nm in thickness to be probed with resolutions of 20-40 nm. Here a new iterative tomographic reconstruction method to extract the three-dimensional magnetization configuration from tomographic projections is presented. The vector field is reconstructed by using a modified algebraic reconstruction approach based on solving a set of linear equations in an iterative manner. The application of this method is illustrated with two examples (magnetic nano-disc and micro-square heterostructure) along with comparison of error in reconstructions, and convergence of the algorithm. PMID- 29979178 TI - In situ coherent X-ray diffraction imaging of radiation-induced mass loss in metal-polymer composite spheres. AB - A major limitation to the use of coherent X-ray diffraction imaging (CXDI) for imaging soft materials like polymers and biological tissue is that the radiation can cause extensive damage to the sample under investigation. In this study, CXDI has been used to monitor radiation-induced structural changes in metal-coated poly(methyl methacrylate) microspheres. Using a coherent undulator X-ray beam with 8.10 keV photon energy, 14 tomograms at a resolution of ~30 nm were measured consecutively, which resulted in an accumulated dose of 30 GGy. The three dimensional images confirmed that the polymer core was strongly affected by the absorbed dose, giving pronounced mass loss. Specifically, as the metal-polymer composite was exposed to the X-ray beam, a bubble-like region of reduced density grew within the composite, almost filling the entire volume within the thin metallic shell in the last tomogram. The bubble seemed to have its initiation point at a hole in the metal coating, emphasizing that the free polymer surface plays an important role in the degradation process. The irradiation of an uncoated polystyrene microsphere gave further evidence for mass loss at the free surface as the radius decreased with increased dose. The CXDI study was complemented by X-ray photon correlation spectroscopy, which proved efficient in establishing exposure dose limits. Our results demonstrate that radiation-induced structural changes at the tens of nanometer scale in soft materials can be followed as a function of dose, which is important for the further development of soft-matter technology. PMID- 29979177 TI - Synchrotron inline phase contrast uCT enables detailed virtual histology of embedded soft-tissue samples with and without staining. AB - Synchrotron radiation micro-computed tomography (SRuCT) based virtual histology, in combination with dedicated ex vivo staining protocols and/or phase contrast, is an emerging technology that makes use of three-dimensional images to provide novel insights into the structure of tissue samples at microscopic resolution with short acquisition times of the order of minutes or seconds. However, the high radiation dose creates special demands on sample preparation and staining. As a result of the lack of specific staining in virtual histology, it can supplement but not replace classical histology. Therefore, the aim of this study was to establish and compare optimized ex vivo staining and acquisition protocols for SRuCT-based virtual histology of soft-tissue samples, which could be integrated into the standard workflow of classical histology. The high grade of coherence of synchrotron radiation allows the application of propagation-based phase contrast imaging (PBI). In this study, PBI yielded a strong increase in image quality even at lower radiation doses and consequently prevented any damage to the tissue samples or the embedding material. This work has demonstrated that the improvement in contrast-to-noise ratio by PBI enabled label-free virtual histology of soft-tissue specimens embedded in paraffin to a level of detail that exceeds that achieved with staining protocols. PMID- 29979179 TI - A compact and flexible induction furnace for in situ X-ray microradiograhy and computed microtomography at Elettra: design, characterization and first tests. AB - A compact and versatile induction furnace for in situ high-resolution synchrotron and laboratory hard X-ray microradiography and computed microtomography is described. The furnace can operate from 773 to 1723 K. Its programmable controller enables the user to specify multiple heating and cooling ramp rates as well as variable dwell times at fixed temperatures allowing precise control of heating and cooling rates to within 5 K. The instrument can work under a controlled atmosphere. Thanks to the circular geometry of the induction coils, the heat is homogeneously distributed in the internal volume of the graphite cell (ca. 150 mm3) where the sample holder is located. The thermal gradient within the furnace is less than 5 K over a height of ca. 5 mm. This new furnace design is well suited to the study of melting and solidification processes in geomaterials, ceramics and several metallic alloys, allowing fast heating (tested up to 6.5 K s 1) and quenching (up to 21 K s-1) in order to freeze the sample microstructure and chemistry under high-temperature conditions. The sample can be held at high temperatures for several hours, which is essential to follow phenomena with relatively slow dynamics, such as crystallization processes in geomaterials. The utility of the furnace is demonstrated through a few examples of experimental applications performed at the Elettra synchrotron laboratory (Trieste, Italy). PMID- 29979180 TI - X-ray phase-contrast imaging with engineered porous materials over 50 keV. AB - X-ray phase-contrast imaging can substantially enhance image contrast for weakly absorbing samples. The fabrication of dedicated optics remains a major barrier, especially in high-energy regions (i.e. over 50 keV). Here, the authors perform X ray phase-contrast imaging by using engineered porous materials as random absorption masks, which provides an alternative solution to extend X-ray phase contrast imaging into previously challenging higher energy regions. The authors have measured various samples to demonstrate the feasibility of the proposed engineering materials. This technique could potentially be useful for studying samples across a wide range of applications and disciplines. PMID- 29979181 TI - Characterization of a submicro-X-ray fluorescence setup on the B16 beamline at Diamond Light Source. AB - An X-ray fluorescence setup has been tested on the B16 beamline at the Diamond Light Source synchrotron with two different excitation energies (12.7 and 17 keV). This setup allows the scanning of thin samples (thicknesses up to several micrometers) with a sub-micrometer resolution (beam size of 500 nm * 600 nm determined with a 50 um Au wire). Sensitivities and detection limits reaching values of 249 counts s-1 fg-1 and 4 ag in 1000 s, respectively (for As Kalpha excited with 17 keV), are presented in order to demonstrate the capabilities of this setup. Sample measurements of a human bone and a single cell performed at B16 are presented in order to illustrate the suitability of the setup in biological applications. PMID- 29979182 TI - The optical stretcher as a tool for single-particle X-ray imaging and diffraction. AB - For almost half a century, optical tweezers have successfully been used to micromanipulate micrometre and sub-micrometre-sized particles. However, in recent years it has been shown experimentally that, compared with single-beam traps, the use of two opposing and divergent laser beams can be more suitable in studying the elastic properties of biological cells and vesicles. Such a configuration is termed an optical stretcher due to its capability of applying high deforming forces on biological objects such as cells. In this article the experimental capabilities of an optical stretcher as a potential sample delivery system for X ray diffraction and imaging studies at synchrotrons and X-ray free-electron laser (FEL) facilites are demonstrated. To highlight the potential of the optical stretcher its micromanipulation capabilities have been used to image polymer beads and label biological cells. Even in a non-optimized configuration based on a commercially available optical stretcher system, X-ray holograms could be recorded from different views on a biological cell and the three-dimensional phase of the cell could be reconstructed. The capability of the setup to deform cells at higher laser intensities in combination with, for example, X-ray diffraction studies could furthermore lead to interesting studies that couple structural parameters to elastic properties. By means of high-throughput screening, the optical stretcher could become a useful tool in X-ray studies employing synchrotron radiation, and, at a later stage, femtosecond X-ray pulses delivered by X-ray free-electron lasers. PMID- 29979183 TI - Absorption, refraction and scattering retrieval in X-ray analyzer-based imaging. AB - A three-image algorithm is proposed in order to retrieve the absorption, refraction and ultra-small-angle X-ray scattering (USAXS) properties of the object in X-ray analyzer-based imaging. Based on the Gaussian fitting to the rocking curve, the novel algorithm is theoretically derived and presented, and validated by synchrotron radiation experiments. Compared with multiple-image radiography, this algorithm only requires a minimum of three intensity measurements, and is therefore advantageous in terms of simplified acquisition procedure and reduced data collection times, which are especially important for specific applications such as in vivo imaging and phase tomography. Moreover, the retrieval algorithm can be specialized to particular cases where some degree of a priori knowledge on the object is available, potentially reducing the minimum number of intensity measurements to two. Furthermore, the effect of angular mis alignment on the accuracy of the retrieved images was theoretically investigated, which can be of use in image interpretation and optimization of the data acquisition procedure. PMID- 29979184 TI - Multiscale X-ray imaging using ptychography. AB - The success of ptychography and other imaging experiments at third-generation X ray sources is apparent from their increasingly widespread application and the improving quality of the images they produce both for resolution and contrast and in terms of relaxation of experimental constraints. The wider availability of highly coherent X-rays stimulates the development of several complementary techniques which have seen limited mutual integration in recent years. This paper presents a framework in which some of the established imaging techniques - with particular regard for ptychography - are flexibly applied to tackle the variable requirements occurring at typical synchrotron experiments. In such a framework one can obtain low-resolution images of whole samples and smoothly zoom in on specific regions of interest as they are revealed by switching to a higher resolution imaging mode. The techniques involved range from full-field microscopy, to reach the widest fields of view (>mm), to ptychography, to achieve the highest resolution (<100 nm), and have been implemented at the I13 Coherence Branchline at Diamond Light Source. PMID- 29979185 TI - Direct information retrieval after 3D reconstruction in grating-based X-ray phase contrast computed tomography. AB - Grating-based X-ray differential phase-contrast imaging has attracted a great amount of attention and has been considered as a potential imaging method in clinical medicine because of its compatibility with the traditional X-ray tube source and the possibility of a large field of view. Moreover, phase-contrast computed tomography provides three-dimensional phase-contrast visualization. Generally, two-dimensional information retrieval performed on every projection is required prior to three-dimensional reconstruction in phase-contrast computed tomography. In this paper, a three-dimensional information retrieval method to separate absorption and phase information directly from two reconstructed images is derived. Theoretical derivations together with numerical simulations have been performed to confirm the feasibility and veracity of the proposed method. The advantages and limitations compared with the reverse projection method are also discussed. Owing to the reduced data size and the absence of a logarithm operation, the computational time for information retrieval is shortened by the proposed method. In addition, the hybrid three-dimensional images of absorption and phase information were reconstructed using an absorption reconstruction algorithm, hence the existing data pre-processing methods and iterative reconstruction algorithms in absorption reconstruction may be utilized in phase reconstruction immediately. PMID- 29979186 TI - Atmospheric coherent X-ray diffraction imaging for in situ structural analysis at SPring-8 Hyogo beamline BL24XU. AB - Coherent X-ray diffraction imaging (CXDI) is a promising technique for non destructive structural analysis of micrometre-sized non-crystalline samples at nanometre resolutions. This article describes an atmospheric CXDI system developed at SPring-8 Hyogo beamline BL24XU for in situ structural analysis and designed for experiments at a photon energy of 8 keV. This relatively high X-ray energy enables experiments to be conducted under ambient atmospheric conditions, which is advantageous for the visualization of samples in native states. The illumination condition with pinhole-slit optics is optimized according to wave propagation calculations based on the Fresnel-Kirchhoff diffraction formula so that the sample is irradiated by X-rays with a plane wavefront and high photon flux of ~1 * 1010 photons/16 umo(FWHM)/s. This work demonstrates the imaging performance of the atmospheric CXDI system by visualizing internal voids of sub micrometre-sized colloidal gold particles at a resolution of 29.1 nm. A CXDI experiment with a single macroporous silica particle under controlled humidity was also performed by installing a home-made humidity control device in the system. The in situ observation of changes in diffraction patterns according to humidity variation and reconstruction of projected electron-density maps at 5.2% RH (relative humidity) and 82.6% RH at resolutions of 133 and 217 nm, respectively, were accomplished. PMID- 29979187 TI - SwissFEL Aramis beamline photon diagnostics. AB - The SwissFEL Aramis beamline, covering the photon energies between 1.77 keV and 12.7 keV, features a suite of online photon diagnostics tools to help both users and FEL operators in analysing data and optimizing experimental and beamline performance. Scientists will be able to obtain information about the flux, spectrum, position, pulse length, and arrival time jitter versus the experimental laser for every photon pulse, with further information about beam shape and size available through the use of destructive screens. This manuscript is an overview of the diagnostics tools available at SwissFEL and presents their design, working principles and capabilities. It also features new developments like the first implementation of a THz-streaking based temporal diagnostics for a hard X-ray FEL, capable of measuring pulse lengths to 5 fs r.m.s. or better. PMID- 29979190 TI - The simple physics of the bending magnet spectrum. AB - A new elementary model of the bending magnet synchrotron radiation is presented, with minimal mathematical formalism. The model explains features not justified by other simplified approaches; in particular, it brings to light the key role of the directional Doppler effect. PMID- 29979188 TI - ID30B - a versatile beamline for macromolecular crystallography experiments at the ESRF. AB - ID30B is an undulator-based high-intensity, energy-tuneable (6.0-20 keV) and variable-focus (20-200 um in diameter) macromolecular crystallography (MX) beamline at the ESRF. It was the last of the ESRF Structural Biology Group's beamlines to be constructed and commissioned as part of the ESRF's Phase I Upgrade Program and has been in user operation since June 2015. Both a modified microdiffractometer (MD2S) incorporating an in situ plate screening capability and a new flexible sample changer (the FlexHCD) were specifically developed for ID30B. Here, the authors provide the current beamline characteristics and detail how different types of MX experiments can be performed on ID30B (http://www.esrf.eu/id30b). PMID- 29979189 TI - Xi-cam: a versatile interface for data visualization and analysis. AB - Xi-cam is an extensible platform for data management, analysis and visualization. Xi-cam aims to provide a flexible and extensible approach to synchrotron data treatment as a solution to rising demands for high-volume/high-throughput processing pipelines. The core of Xi-cam is an extensible plugin-based graphical user interface platform which provides users with an interactive interface to processing algorithms. Plugins are available for SAXS/WAXS/GISAXS/GIWAXS, tomography and NEXAFS data. With Xi-cam's 'advanced' mode, data processing steps are designed as a graph-based workflow, which can be executed live, locally or remotely. Remote execution utilizes high-performance computing or de-localized resources, allowing for the effective reduction of high-throughput data. Xi-cam's plugin-based architecture targets cross-facility and cross-technique collaborative development, in support of multi-modal analysis. Xi-cam is open source and cross-platform, and available for download on GitHub. PMID- 29979191 TI - Syndecan-2-positive, Bone Marrow-derived Human Mesenchymal Stromal Cells Attenuate Bacterial-induced Acute Lung Injury and Enhance Resolution of Ventilator-induced Lung Injury in Rats. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Human mesenchymal stromal cells demonstrate promise for acute respiratory distress syndrome, but current studies use highly heterogenous cell populations. We hypothesized that a syndecan 2 (CD362)-expressing human mesenchymal stromal cell subpopulation would attenuate Escherichia coli-induced lung injury and enhance resolution after ventilator-induced lung injury. METHODS: In vitro studies determined whether CD362 human mesenchymal stromal cells could modulate pulmonary epithelial inflammation, wound healing, and macrophage phagocytosis. Two in vivo rodent studies determined whether CD362 human mesenchymal stromal cells attenuated Escherichia coli-induced lung injury (n = 10/group) and enhanced resolution of ventilation-induced injury (n = 10/group). RESULTS: CD362 human mesenchymal stromal cells attenuated cytokine-induced epithelial nuclear factor kappa B activation, increased epithelial wound closure, and increased macrophage phagocytosis in vitro. CD362 human mesenchymal stromal cells attenuated Escherichia coli-induced injury in rodents, improving arterial oxygenation (mean +/- SD, 83 +/- 9 vs. 60 +/- 8 mmHg, P < 0.05), improving lung compliance (mean +/- SD: 0.66 +/- 0.08 vs. 0.53 +/- 0.09 ml . cm H2O, P < 0.05), reducing bacterial load (median [interquartile range], 1,895 [100-3,300] vs. 8,195 [4,260-8,690] colony-forming units, P < 0.05), and decreasing structural injury compared with vehicle. CD362 human mesenchymal stromal cells were more effective than CD362 human mesenchymal stromal cells and comparable to heterogenous human mesenchymal stromal cells. CD362 human mesenchymal stromal cells enhanced resolution after ventilator-induced lung injury in rodents, restoring arterial oxygenation (mean +/- SD: 113 +/- 11 vs. 89 +/- 11 mmHg, P < 0.05) and lung static compliance (mean +/- SD: 0.74 +/- 0.07 vs. 0.45 +/- 0.07 ml . cm H2O, P < 0.05), resolving lung inflammation, and restoring histologic structure compared with vehicle. CD362 human mesenchymal stromal cells efficacy was at least comparable to heterogenous human mesenchymal stromal cells. CONCLUSIONS: A CD362 human mesenchymal stromal cell population decreased Escherichia coli-induced pneumonia severity and enhanced recovery after ventilator-induced lung injury. PMID- 29979192 TI - Fluoxetine-Induced Sleep Bruxism Rapidly Treated With Once-Nightly Dosing of Buspirone in a 6-Year-Old Girl. AB - Fluoxetine is a selective serotonin reuptake inhibitor that is commonly used in children and adolescents. Several reports exist regarding the relationship of fluoxetine use and sleep bruxism. We report the case of a 6-year-old girl who was successfully treated with once-nightly dosing of buspirone for fluoxetine-induced sleep bruxism, which was confirmed with clear on-off-on treatment sequence. PMID- 29979193 TI - MiR-199a mediated the dissemination of human mantle cell lymphoma by interacting with the CCR7/CCL21 pair. AB - Mantle cell lymphoma (MCL) is a rare but deadly subtype of non-Hodgkin's lymphomas because of it can progress rapidly and has a poor prognosis. MicroRNA 199a (miR-199a) is a potential diagnostic marker and therapeutic target for MCL patients. However, the function and molecular mechanisms of miRNA-199a in MCL cells are still unclear. In this study, we first analyzed the levels of miR-199a and C-C chemokine receptor 7 (CCR7) in the tumor tissues and tumor-adjacent tissues, and found that the level of miRNA-199a was lower, whereas the level of CCR7 was higher in tumor tissues. Moreover, overexpression of miR-199a in MCL cells downregulated the level of CCR7. Then, it was found that chemokine (C-C motif) ligand 21 (CCL21), a ligand of CCR7, promoted Granta-519 and Mino cell growth and migration in a concentration-dependent and time-dependent manner. Otherwise, the CCL21/CCR7 pair elevated the level of phosphorylation of protein kinase B and extracellular regulated protein kinases 1/2, upregulated the level of matrix metalloproteinases-2, matrix metalloproteinases-9, and the markers of the mesenchymal phenotype (N-cadherin and vimentin), as well as decreased the level of E-cadherin. However, the functions of CCL21/CCR7 in the growth, migration, and dissemination of MCL cells were decreased by overexpression of miR 199a. Thus, miR-199a inhibited the dissemination of MCL cells by reversing the function of CCL21/CCR7, providing a theoretical basis for miRNA-199a as a potential novel diagnostic marker and therapeutic target for MCL patients. PMID- 29979194 TI - Histopathological Findings and Increased D-Dimer Are Predictive Factors of Systemic Thromboses in Eosinophilic Granulomatosis With Polyangiitis. AB - Eosinophilic granulomatosis with polyangiitis (EGPA; ie, Churg-Strauss syndrome) is one of the antineutrophil cytoplasmic antibody-associated vasculitis syndromes. Although extravascular granulomatoses are a well-known histopathological feature, the diverse histopathologic spectrum of cutaneous lesions has not been described in detail. Thus, this study sought to investigate the possible correlation between the clinical features and histopathology of cutaneous lesions in EGPA cases, focusing on systemic thrombogenic conditions, such as visceral infarction and deep vein thrombosis. Fourteen cases of EGPA diagnosed at the Department of Dermatology in Asahikawa Medical University from 1977 to 2017 were clinically and histopathologically reviewed. In 6 (43%) cases, skin lesions were the initial manifestation of EGPA. Among the cutaneous lesions, purpura and erythema were the most common. Persistent proteinuria and macrohematuria were observed in only 2 myeloperoxidase-antineutrophil cytoplasmic antibody-positive cases. Systemic thrombotic symptoms, such as cerebral infarction and deep vein thrombosis, were detected in 5 (36%) cases, and, in 3 of those cases, thromboses in dermal or subcutaneous vessels were observed histopathologically. Elevation of plasma D-dimer level (>2.5 MUg/mL) was significantly correlated with concomitant systemic thrombotic symptoms (P = 0.0152, Fischer exact test). The histopathological finding of thrombotic features and increased plasma D-dimer were predictive factors of EGPA accompanied with systemic thromboses, such as deep vein thromboses and cerebral infarction. PMID- 29979195 TI - Late-Onset Facial Papular Elastorrhexis. AB - Papular elastorrhexis, a rare defect of dermal elastic fibers of unknown origin, usually involves the trunk and extremities of children or young adults. We report the case of a 62-year-old woman with multiple soft, skin-colored facial papules with histological findings characteristic of papular elastorrhexis. Awareness of this entity may allow for its proper identification outside the usual clinical setting. PMID- 29979196 TI - Squamoid Eccrine Ductal Carcinoma: An Aggressive Mimicker of Squamous Cell Carcinoma. AB - Squamoid eccrine ductal carcinoma (SEDC) is an uncommon cutaneous adnexal malignancy that has the potential for an aggressive clinical course. The authors present a case of SEDC that resulted in widespread metastases and death. The clinical, histological, and immunohistochemical features of SEDC and several entities on the differential diagnosis are reviewed. PMID- 29979197 TI - Making the Case for Case Reports. PMID- 29979198 TI - Informed Consent for Sugammadex and Oral Contraceptives: Through the Looking Glass. PMID- 29979199 TI - Use of Hydroxocobalamin (Vitamin B12a) in Patients With Vasopressor Refractory Hypotension After Cardiopulmonary Bypass: A Case Series. AB - Hydroxocobalamin (vitamin B12a) is an emerging treatment for vasoplegic syndrome (VS) associated with cardiopulmonary bypass (CPB). Given its cost and scarcity, an institutional guideline for its use as a rescue treatment in cases of suspected VS was developed. Hemodynamic variables and vasopressor requirements were reviewed for a series of 24 post-CPB patients who received B12a. Favorable changes in hemodynamic parameters and vasopressor requirements were seen after B12a administration although guideline criteria for VS were inconsistently met. These findings support the continued study of B12a in patients with CPB associated VS. PMID- 29979200 TI - Comprehensive Proteomic Profiling-derived Immunohistochemistry-based Prediction Models for BRCA1 and BRCA2 Germline Mutation-related Breast Carcinomas. AB - Heredity, mostly due to BRCA germline mutations, is involved in 5% to 10% of all breast cancer cases. Potential BRCA germline mutation carriers may be missed following the current eligibility criteria for BRCA genetic testing. The purpose of this study was to, therefore, develop an immunohistochemistry-based model to predict likelihood of underlying BRCA1 and BRCA2 germline mutations in unselected female breast cancer patients. The study group consisted of 100 BRCA1-related, 46 BRCA2-related, and 94 sporadic breast carcinomas. Tumor expression of 44 proteins involved in (BRCA-related) breast carcinogenesis was assessed by immunohistochemistry. A prediction model for BRCA-related versus non-BRCA-related breast cancer was developed using Lasso logistic regression analysis with cross validation. The model was assessed for its discriminative value and clinical usefulness. The optimal prediction model included 14 predictors (age, cyclinD1, ERalpha, ERbeta, FGFR2, FGFR3, FGFR4, GLUT1, IGFR, Ki67, mitotic activity index, MLH1, p120, and TOP2A), showed excellent discriminative performance (area under the receiving operating characteristic curve=0.943; 95% confidence interval=0.909 0.978), and reasonable calibration. To enhance possible implementation, we developed an alternative model only considering more widely available immunostains. This model included 15 predictors (age, BCL2, CK5/6, CK8/18, cyclinD1, E-cadherin, ERalpha, HER2, Ki67, mitotic activity index , MLH1, p16, PMS2, PR, and vimentin), and still showed very good discriminative performance (area under the receiving operating characteristic curve=0.853; 95% confidence interval=0.795-0.911). We present a well-applicable and accurate tool to predict which breast cancer patients may have an underlying BRCA germline mutation, largely consisting of immunohistochemical markers independent of clinical characteristics. This may improve identification of potential BRCA germline mutation carriers and optimize referral for germline mutation testing. PMID- 29979201 TI - Genetic stratification for primary prevention of coronary artery disease. AB - PURPOSE OF REVIEW: To review the literature showing genetic risk variants is a reliable means of stratifying for risk of CAD for primary prevention. RECENT FINDINGS: Over 90 genetic risk variants have been discovered that predispose to CAD. Results of several studies show that these risk variants effectively stratify for risk of CAD in asymptomatic individuals. SUMMARY: The total individual genetic risk can be summarized into a single number referred to as the genetic risk score (GRS). The GRS unlike the Framingham Risk Score is not dependent on age and independent of conventional risk factors. As DNA does not change during one's lifetime the GRS can be calculated at birth or any time thereafter. Furthermore, the GRS has been shown to provide superior discriminatory power in selecting individuals who will benefit most from lifestyle changes or statin therapy. A prospective study showed individuals with high GRS and a favorable lifestyle was associated with significant reduction of cardiac events compared with an unfavorable lifestyle. Furthermore, the study shows inherited risk can be reduced analogous to reduction of risk form acquired and environmental factors. The use of GRS to stratify for risk of CAD in asymptomatic individuals could transform primary prevention worldwide. PMID- 29979202 TI - Ultrasound Imaging for Dorsal Radio-Luno-Triquetral Ligament Possibly Causing Wrist Impingement. PMID- 29979203 TI - Imaging of Progressive Neuropathic Arthropathy of The Shoulder. PMID- 29979204 TI - The Dodo Bird is not Extinct: Ultrasound Imaging for Supraspinatus Tendinosis. PMID- 29979205 TI - The Effect of Stabilization Exercises on Pain, Disability, and Pelvic Floor Muscle Function in Postpartum Lumbopelvic Pain: A Randomized Controlled Trial. AB - OBJECTIVE: The effect of stabilization exercises on pain, disability, and pelvic floor muscle function in postpartum lumbopelvic pain. DESIGN: This is a single blind, randomized controlled trial. SETTING: This study was performed at the physiotherapy clinic, Zahedan University of Medical Science, from January to November 2017. PARTICIPANTS: Thirty-six multiparous women with persistent postpartum lumbopelvic pain were recruited at least 3 mos after delivery. INTERVENTIONS: Subjects in the training group (n = 18) received electrotherapy modalities and specific stabilizing exercises. The control group (n = 18) received only electrotherapy modalities. MAIN OUTCOME MEASURES: Pain, disability, and bladder base displacement (at rest and pelvic floor muscles contraction) were measured through visual analog scale, Oswestry Disability Index questionnaires, and transabdominal ultrasound imaging respectively at baseline and after 6 wks of intervention. RESULTS: Between-groups comparison showed significant improvement in pain, disability, and bladder base displacement in the training group (P < 0.05). In within-group comparison, training group had significant difference for all variables (P < 0.05). In the control group, pain and disability had significant difference (P < 0.05), whereas bladder base displacement had no significant change (P < 0.05). CONCLUSIONS: The stabilizing exercises can remarkably improve pain, disability, and pelvic floor muscles function in postpartum lumbopelvic pain (Clinical Trial Registry: NCT03030846). PMID- 29979207 TI - Rationale and Models for Career Advancement Sponsorship in Academic Medicine: The Time Is Here; the Time Is Now. AB - The business community has honed the concept of sponsorship and promulgated its utility for harnessing the talent of high-performing women and minorities whose contributions often go unrecognized within organizations. In recent years, academic medicine has begun to do the same. Whereas mentorship often centers on personal and professional development (e.g., skill building and goal setting), sponsorship focuses on enhancing the visibility, credibility, and professional networks of talented individuals. For upward career mobility, mentorship is limited in scope. Sponsorship, on the other hand, directly targets career advancement and is anchored in the sponsor's awareness of organizational structures and critical professional opportunities for junior faculty. Men are more likely to garner sponsors informally, and these sponsors tend to be male. Existing disparities between male and female medical faculty in achievement of academic rank and leadership roles, compensation, and research support suggest that high-performing women have a visibility gap. Such systemic inequity reflects a suboptimal business model that limits organizational potential. Formal sponsorship programs that match women with senior leaders facilitate access to beneficial relationships and institutionalize the value of equal opportunity. In this Perspective, the authors describe two successful sponsorship models that exist within academic medicine, the Society of General Internal Medicine's Career Advising Program and MD Anderson Cancer Center's Leaders' Sponsorship Program. They issue a call to action for much broader implementation of sponsorship programming to cultivate the advancement of all talented medical faculty and provide recommendations for such endeavors. PMID- 29979206 TI - Creating GridlockED: A Serious Game for Teaching About Multipatient Environments. AB - PROBLEM: As patient volumes increase, it is becoming increasingly important to find novel ways to teach junior medical learners about the intricacies of managing multiple patients simultaneously, as well as about working in a resource limited environment. APPROACH: Serious games (i.e., games not intended purely for fun) are a teaching modality that have been gaining momentum as teaching tools in medical education. From May 2016 to August 2017, the authors designed and tested a serious game, called "GridlockED," to provide a focused educational experience for medical trainees to learn about multipatient care and patient flow. The game is collaborative, allowing as many as six people may play it at once. Gameplay relies on the players working collaboratively (as simulated members of a medical team) to triage, treat, and disposition "patients" in a manner that simulates true emergency department operations. After researching serious games, the authors developed the game through an iterative design process. Next, the game underwent preliminary peer review by experienced gamers and practicing clinicians, whose feedback the authors used to adjust the game. Attending physicians, nurses, and residents have tested GridlockED for usability, fidelity, acceptability, and applicability. OUTCOMES: Based on initial testing, clinicians suggest that this game will be useful and has fidelity for teaching patient-flow concepts. NEXT STEPS: Further playtesting will be needed to fully examine learning opportunities for various populations of trainees and for various media. GridlockED may also serve as a model for developing other games to teach about processes in other environments or specialties. PMID- 29979208 TI - The Contextual Curriculum: Learning in the Matrix, Learning From the Matrix. AB - Changes in the health care landscape over the last 25 years have led to an expansion of training sites beyond the traditional academic health sciences center. The resulting contextual diversity in contemporary medical education affords new opportunities to consider the influence of contextual variation on learning. The authors describe how different contextual patterns in clinical learning environments-patients, clinical and educational practices, physical geography, health care systems, and culture-form a contextual learning matrix. Learners' participation in this contextual matrix shapes what and how they learn, and who they might become as physicians.Although competent performance is critically dependent on context, this dependence may not be actively considered or shaped by medical educators. Moreover, learners' inability to recognize the educational affordances of different contexts may mean that they miss critical learning opportunities, which in turn may affect patient care, particularly in the unavoidable times of transition that characterize a professional career. Learners therefore need support in recognizing the variability of learning opportunities afforded by different training contexts. The authors set out the concept of the contextual curriculum in medical education as that which is learned both intentionally and unintentionally from the settings in which learning takes place. Further, the authors consider strategies for medical educators through which the contextual curriculum can be made apparent and tangible to learners as they navigate a professional trajectory where their environments are not fixed but fluid and where change is a constant. PMID- 29979210 TI - Tenure Appointments for Faculty of Clinical Departments at U.S. Medical Schools: Does Specialty Designation Make a Difference? AB - PURPOSE: To describe differences and trends among clinical specialty departments in number and percentage of tenure-related appointments for full-time faculty. METHOD: Association of American Medical Colleges Faculty Roster annual snapshot reports were used to calculate percentages of full-time faculty holding tenure related appointments in each of the database's 17 groupings of clinical specialty departments. Faculty numbers and percentages by track were compared to investigate trends for 2006 to 2016. RESULTS: In the decade 2006-2016, the number of individuals on tenure-related tracks in clinical departments declined by 0.8% (276/33,610), but those on nontenure appointments increased by 60.5% (36,444/60,195). The number reporting "tenure not available" rose by 58.9% (4,467/7,574). Currently, 62% to 82% of full-time faculty in clinical departments are on nontenure tracks. Specialties differ significantly in current percentage and in rate of change in both numbers and percentage of tenure-related appointments. In 2016, faculty on tenure-related tracks ranged from 34.5% (295/855) in public health and preventive medicine to 13.5% (654/5,654) in family medicine. The most significant drops in percentage of tenure-related appointments in 2006-2016 were in surgery, pediatrics, and internal medicine. CONCLUSIONS: Dramatic changes in size and track distribution of faculty are occurring at significantly different rates across clinical specialty departments. The number of individuals on tenure-related tracks remains relatively stable, but the percentage of such faculty in clinical specialty departments continues to drop dramatically in almost all specialties. The growing dominance of nontenure appointments has important implications for career development and academic promotion policies and practices in all specialties. PMID- 29979209 TI - Open Access: What It Means for Your Article. PMID- 29979211 TI - Exploring the Role of Self-Motives in Postgraduate Trainees' Feedback-Seeking Behavior in the Clinical Workplace: A Multicenter Study of Workplace-Based Assessments From the United Kingdom. AB - PURPOSE: To explore trainees' feedback-seeking behavior in the postgraduate surgical workplace using a self-motives framework. Self-motives include self assessment "to obtain accurate information about the self," self-improvement "to improve one's traits, abilities, and skills," self-enhancement "to enhance the favorability of self views," and self-verification "to maintain consistency between one's central self-view and new self-relevant information." METHOD: This project constituted a further framework analysis of previously obtained qualitative focus group data that originally explored trainees' perceptions and use of workplace-based assessment (WBA). Data were collected from multiple centers in the United Kingdom from 2012 to 2013. Content was analyzed to identify references in the data that reflected the above self-motives and in relation to contextual themes identified from within the data. RESULTS: Trainees' motivations for seeking feedback broadly fit within a self-motives framework. Trainees' feedback seeking using WBA related to self-enhancement and self-verification, whereas outside WBA trainees reported self-improvement and self-assessment motives. Where trainees perceived WBA represented an opportunity to learn, they described a self-improvement motive toward seeking feedback, whereas when WBA represented an assessment of learning, trainees described tensions between self enhancement and self-improvement motives. CONCLUSIONS: Surgical trainees' motivations for seeking feedback can be explained using a conceptual self-motives framework. Trainees need to be motivated to seek accurate informational feedback so they can improve their performance within the clinical workplace. To achieve this, trainees need training; current assessment systems must change to allow trainees to seek such feedback without fear and concern about this information being used as an assessment of learning. PMID- 29979213 TI - Introducing...the pancreas! PMID- 29979212 TI - Obesity and sarcoidosis: consequence or contributor? AB - PURPOSE OF REVIEW: Sarcoidosis is a multisystem disease of unknown cause. Obesity can affect many physiological factors. The relationship between obesity and sarcoidosis is unclear, and can been described as posing a 'chicken and egg' scenario for the patient as it is not always clear whether it is a consequence of, or a risk factor for any disease. The purpose of this review is to examine the dual roles of obesity on sarcoidosis morbidity and the incidence. RECENT FINDINGS: Obesity magnifies the symptoms of sarcoidosis and corticosteroid therapy increases BMI. Prospective epidemiologic studies started to explore the role of obesity as a potential risk factor for sarcoidosis. Three studies in the United States, and one study in Denmark, have demonstrated significantly increased risks of sarcoidosis among obese compared with nonobese patients; risk estimates ranged from 1.42 [95% confidence interval (CI), 1.07-1.89] to 3.59 (95% CI, 2.31-5.57). SUMMARY: Obesity can be both a consequence of sarcoidosis treatment, and a contributor to disease risk likely through the pro-inflammatory environment of obesity. Prospective epidemiologic cohort studies are needed to explore the cause of sarcoidosis and insight into possible avenues of treatment development and prevention. PMID- 29979214 TI - Evolution of surgery to endoscopy. PMID- 29979215 TI - A Novel Posterior Trench Approach Involving Percutaneous Endoscopic Cervical Discectomy for Central Cervical Intervertebral Disc Herniation. AB - OBJECTIVE: This report describes a novel posterior trench approach involving percutaneous endoscopic cervical discectomy (PECD) for central cervical intervertebral disc herniation (CIVDH) and an evaluation of the feasibility, safety, and short-term clinical effect of this approach. BACKGROUND CONTEXT: Central CIVDH is considered the contraindication for posterior PECD. MATERIALS AND METHODS: A single-center retrospective observational study was performed with 30 patients managed with posterior PECD using the trench approach for symptomatic single-level central CIVDH. Primary outcomes included the measures of bodily pain and physical function based on the SF-36 and modified MacNab criteria. Radiographical follow-up included the static and dynamic cervical plain radiographs, computed tomographic scans, and magnetic resonance images. RESULTS: A positive clinical response for symptom relief was achieved in all patients. The postoperative MRI showed total removal of the herniated disc. CONCLUSIONS: As a supplement to the described surgical techniques of PECD, this trench approach provides novel access for the treatment of CIVDH, especially for the central type. The advantages of this technique include the provision of access to decompress the ventral region of the thecal sac and the ability to avoid damage to the facet joint. The steep learning curve might be a major disadvantage, and the sample volume is a limitation of the study; the effectiveness and reliability of the trench approach should be further verified in a comparative cohort study with a large volume of patients. PMID- 29979216 TI - How to Write Effective Discussion and Conclusion Sections. AB - With the exponential increase in research in the field of spine surgery, publishing peer-reviewed articles has become both more desirable and competitive in the past decade. Constructing an impactful manuscript has many important factors, one of which is a well-written Discussion section. A research study can ask a pressing question, have a meticulous methodology and report compelling results; however, without a thoughtful and well-informed analysis of the meaning of the study's findings and their potential influence on the field, the paper will be uninteresting and weak. Thus, formulating an effective Discussion section is crucial to improving the likelihood of the study's publication and its impact. PMID- 29979217 TI - Blood Loss Trends and Financial Implications in Adolescent Idiopathic Scoliosis. AB - STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: The primary goal was to evaluate risk factors related to increased blood loss in adolescent idiopathic surgery (AIS) surgery with the secondary goal being to evaluate the financial implications around the use of intraoperative cell salvage (ICS) and the routine preallocation of autogenous blood products. SUMMARY OF BACKGROUND DATA: Deformity correction for AIS is a complex procedure and can be associated with significant blood loss. METHODS: A retrospective cohort study was conducted on consecutive patients between the ages of 10 and 18 years who underwent posterior spinal fusion of 7-12 levels over a 3-year period between January 2013 and December 2015. Demographic information and surgical characteristics were recorded. All patients had a preoperative type and cross of 2 units and ICS was used in all cases. Charges for preoperative type and cross and ICS were also measured. Univariate and multivariable analyses were performed to identify pertinent variables affecting blood loss. RESULTS: In total, 134 patients met inclusion criteria. ICS was used in all cases. In total, 51 patients were transfused cell saver blood intraoperatively/postoperatively at the discretion of the surgeon. On average 133 mL were returned to the patient. No complications related to ICS were observed. Multivariable analysis identified male sex, lower body mass index and higher surgical time to be associated with increased blood loss (P<0.05). All 134 patients had a preoperative type and cross, with an average charge to patient of $311. Patients were charged $1037 for intraoperative use of ICS and $242 for centrifugation. Patients who had allogeneic transfusion were charged $1047. CONCLUSIONS: Several blood conservation strategies, including use of ICS, exist to minimize the consequences of blood loss. Routine use of preoperative type and cross may be avoided except in cases where significant blood loss is anticipated-that is adolescent male individuals, those with a lower body mass index and in whom a longer surgical time is anticipated. PMID- 29979218 TI - Disease activity, steroid use and extraintestinal manifestation are associated with increased disability in patients with inflammatory bowel disease using the inflammatory bowel disease disability index: a cross-sectional multicentre cohort study. AB - BACKGROUND: The inflammatory bowel disease disability index (IBD-DI) was developed recently. The aim was to translate the IBD-DI into Danish and validate it for future clinical studies and practice, and to assess the level of disability among IBD patients. PATIENTS AND METHODS: The IBD-DI was translated using a transcultural adaptation method. Between January and December 2017, patients from three outpatient clinics in three different regions in Denmark were given the final version of the IBD-DI for self-completion. Validation was carried out according to guidelines. Disability level was assessed among the entire cohort and in various subgroups. RESULTS: A total of 200 patients were included in the study, including 112 Crohn's disease (CD) and 88 ulcerative colitis (UC) patients. The response rate was 90%. The IBD-DI showed excellent reliability and validity. CD patients showed worse disability levels than UC patients [mean (SD): CD: 37.3 (20.2) vs. UC: 21.7 (16.4); P=0.04]. In both CD and UC, significantly increased disability levels were found between patients with active disease, use of steroid and extraintestinal manifestation (P<0.05). CONCLUSION: A valid and reliable version of the IBD-DI is now available in Danish for future studies. Several clinical factors are shown to affect the levels of disability among patients with CD and UC. The disability levels are significantly increased in patients with active disease, treated with systemic steroids, and extraintestinal manifestations are present in both CD and UC. Further testing of the Danish IBD DI is needed to assess its responsiveness and interpretability. PMID- 29979219 TI - Molecular Regulation of Acute Tie2 Suppression in Sepsis. AB - OBJECTIVES: Tie2 is a tyrosine kinase receptor expressed by endothelial cells that maintains vascular barrier function. We recently reported that diverse critical illnesses acutely decrease Tie2 expression and that experimental Tie2 reduction suffices to recapitulate cardinal features of the septic vasculature. Here we investigated molecular mechanisms driving Tie2 suppression in settings of critical illness. DESIGN: Laboratory and animal research, postmortem kidney biopsies from acute kidney injury patients and serum from septic shock patients. SETTING: Research laboratories and ICU of Hannover Medical School, Harvard Medical School, and University of Groningen. PATIENTS: Deceased septic acute kidney injury patients (n = 16) and controls (n = 12) and septic shock patients (n = 57) and controls (n = 22). INTERVENTIONS: Molecular biology assays (Western blot, quantitative polymerase chain reaction) + in vitro models of flow and transendothelial electrical resistance experiments in human umbilical vein endothelial cells; murine cecal ligation and puncture and lipopolysaccharide administration. MEASUREMENTS AND MAIN RESULTS: We observed rapid reduction of both Tie2 messenger RNA and protein in mice following cecal ligation and puncture. In cultured endothelial cells exposed to tumor necrosis factor-alpha, suppression of Tie2 protein was more severe than Tie2 messenger RNA, suggesting distinct regulatory mechanisms. Evidence of protein-level regulation was found in tumor necrosis factor-alpha-treated endothelial cells, septic mice, and septic humans, all three of which displayed elevation of the soluble N-terminal fragment of Tie2. The matrix metalloprotease 14 was both necessary and sufficient for N terminal Tie2 shedding. Since clinical settings of Tie2 suppression are often characterized by shock, we next investigated the effects of laminar flow on Tie2 expression. Compared with absence of flow, laminar flow induced both Tie2 messenger RNA and the expression of GATA binding protein 3. Conversely, septic lungs exhibited reduced GATA binding protein 3, and knockdown of GATA binding protein 3 in flow-exposed endothelial cells reduced Tie2 messenger RNA. Postmortem tissue from septic patients showed a trend toward reduced GATA binding protein 3 expression that was associated with Tie2 messenger RNA levels (p < 0.005). CONCLUSIONS: Tie2 suppression is a pivotal event in sepsis that may be regulated both by matrix metalloprotease 14-driven Tie2 protein cleavage and GATA binding protein 3-driven flow regulation of Tie2 transcript. PMID- 29979220 TI - Early Differentiation of Shiga Toxin-Associated Hemolytic Uremic Syndrome in Critically Ill Adults With Thrombotic Microangiopathy Syndromes. AB - OBJECTIVES: Thrombotic microangiopathy syndromes are a heterogeneous group of severe diseases that often require ICU admission. Prompt initiation of targeted therapies is required for atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, whereas there is no specific consensus therapy for Shiga toxin-associated hemolytic uremic syndrome. We sought to compare the characteristics of Shiga toxin-associated hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura patients at admission in the ICU to allow early differentiation of Shiga toxin-associated hemolytic uremic syndrome from other thrombotic microangiopathy syndromes and help to tailor initial treatment. DESIGN: Retrospective cohort study. SETTING: Two ICUs part of the French reference center for thrombotic microangiopathy syndromes. PATIENTS: Adult patients presenting with features of thrombotic microangiopathy syndromes. Other causes than Shiga toxin-associated hemolytic uremic syndrome, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: From September 2003 to January 2017, 236 thrombotic microangiopathy syndrome patients were admitted, including 12 Shiga toxin-associated hemolytic uremic syndrome, 21 atypical hemolytic uremic syndrome, and 91 thrombotic thrombocytopenic purpura. Shiga toxin-associated hemolytic uremic syndrome patients were older than other thrombotic microangiopathy syndromes patients (64 yr [interquartile range, 50-72 yr] vs 42 yr [31-54 yr]; p = 0.007) and presented with more frequent digestive symptoms (92% vs 42%; p < 0.001), especially nonbloody diarrhea and vomiting. Biologically, Shiga toxin-associated hemolytic uremic syndrome patients displayed higher fibrinogen (490 mg/dL [460-540 mg/dL] vs 320 mg/dL [240-410 mg/dL]; p = 0.003) and creatinine levels (2.59 mg/dL [2.12 3.42 mg/dL] vs 1.26 mg/dL [0.61-1.90 mg/dL]; p < 0.001), and less marked anemia (hemoglobin level, 9.7 g/dL [8.7-11.9 g/dL] vs 7.7 g/dL [6.3-9.1 g/dL]; p < 0.001). Forty-two percent (n = 5) required renal replacement therapy, and 83% (n = 10) were treated with plasma exchange before the distinction from other thrombotic microangiopathy syndromes could be made. CONCLUSIONS: Adult Shiga toxin-associated hemolytic uremic syndrome patients are older, present more frequently with digestive symptoms and display higher hemoglobin and fibrinogen levels than other thrombotic microangiopathy syndromes. However, overlap across the three thrombotic microangiopathy syndromes remains substantial, putting forward the need to implement early plasma therapy until thrombotic thrombocytopenic purpura and atypical hemolytic uremic syndrome can be ruled out. PMID- 29979221 TI - Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis. AB - OBJECTIVE: This systematic review and meta-analysis addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. DATA SOURCES: We updated a comprehensive search of MEDLINE, EMBASE, CENTRAL, and LILACS, and unpublished sources for randomized controlled trials that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. STUDY SELECTION: Reviewers conducted duplicate screening of citations, data abstraction, and, using a modified Cochrane risk of bias tool, individual study risk of bias assessment. DATA EXTRACTION: A parallel guideline committee provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. We assessed overall certainty in evidence using Grading of Recommendations Assessment, Development and Evaluation methodology and performed all analyses using random effect models. For subgroup analyses, we performed metaregression and considered p value less than 0.05 as significant. DATA SYNTHESIS: Forty-two randomized controlled trials including 10,194 patients proved eligible. Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28-31 d) (relative risk, 0.93; 95% CI, 0.84-1.03; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase), and possibly achieve a small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, 0.89-1.00; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Corticosteroids probably result in small reductions in length of stay in ICU (mean difference, 0.73 d; 95% CI, -1.78 to 0.31) and hospital (mean difference, -0.73 d; 95% CI, 2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, 1.12-1.42) and lower Sequential Organ Failure Assessment scores at day 7 (mean difference, -1.39; 95% CI, -1.88 to -0.89) (high certainty). Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, 1.32-2.03) and hyperglycemia (relative risk, 1.16; 95% CI, 1.08-1.24) (moderate certainty), may increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, 1.01-1.52) (low certainty), and appear to have no other adverse effects (low or very low certainty). Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). CONCLUSIONS: In critically ill patients with sepsis, corticosteroids possibly result in a small reduction in mortality while also possibly increasing the risk of neuromuscular weakness. PMID- 29979222 TI - Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism. AB - OBJECTIVES: Recent evidence suggests that half-dose thrombolysis for pulmonary embolism may provide similar efficacy with reduced bleeding risk compared with full-dose therapy, but comparative studies are lacking. We aimed to evaluate the effectiveness and safety of half-dose versus full-dose alteplase for treatment of pulmonary embolism. DESIGN: A retrospective cohort study comparing outcomes in patients receiving half-dose (50 mg) versus full-dose (100 mg) alteplase for pulmonary embolism. We used propensity score matching and sensitivity analyses to address confounding and hospital-level clustering. SETTING: Data from 420 hospitals obtained from the Premier Healthcare Database between January 2010 and December 2014. SUBJECTS: Adult critically ill patients with acute pulmonary embolism treated with IV alteplase therapy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: This study included 3,768 patients: 699 (18.6%) in the half-dose and 3,069 (81.4%) in the full-dose group. At baseline, patients receiving half dose alteplase required vasopressor therapy (23.3% vs 39.4%; p < 0.01) and invasive ventilation (14.3% vs 28.5%; p < 0.01) less often, compared with full dose. After propensity matching (n = 548 per group), half-dose alteplase was associated with increased treatment escalation (53.8% vs 41.4%; p < 0.01), driven mostly by secondary thrombolysis (25.9% vs 7.3%; p < 0.01) and catheter thrombus fragmentation (14.2% vs 3.8%; p < 0.01). Hospital mortality was similar (13% vs 15%; p = 0.3). There was no difference in cerebral hemorrhage (0.5% vs 0.4%; p = 0.67), gastrointestinal bleeding (1.6% vs 1.6%; p = 0.99), acute blood loss anemia (6.9% vs 4.6%; p = 0.11), use of blood products (p > 0.05 for all), or documented fibrinolytic adverse events (2.6% vs 2.8%; p = 0.82). CONCLUSIONS: Compared with full-dose alteplase, half-dose was associated with similar mortality and rates of major bleeding. Treatment escalation occurred more often in half-dose-treated patients. These results question whether half-dose alteplase provides similar efficacy with improved safety, and highlights the need for further study before use of half-dose alteplase therapy can be routinely recommended in patients with pulmonary embolism. PMID- 29979223 TI - Distinctive Roles and Mechanisms of Human Neutrophil Peptides in Experimental Sepsis and Acute Respiratory Distress Syndrome. AB - OBJECTIVES: To examine the effects and mechanisms of human neutrophil peptides in systemic infection and noninfectious inflammatory lung injury. DESIGN: Prospective experimental study. SETTING: University hospital-based research laboratory. SUBJECTS: In vitro human cells and in vivo mouse models. INTERVENTIONS: Wild-type (Friend virus B-type) and conditional leukocyte human neutrophil peptides transgenic mice were subjected to either sepsis induced by cecal ligation and puncture or acute lung injury by intratracheal instillation of hydrochloric acid followed by mechanical ventilation. Using human neutrophil peptides as bait, the basal cell adhesion molecule (CD239) and the purinergic P2Y purinoceptor 6 receptor were identified as the putative human neutrophil peptides receptor complex in human lung epithelial cells. MEASUREMENTS AND MAIN RESULTS: In the cecal ligation and puncture sepsis model, Friend virus B-type mice exhibited higher systemic bacterial load, cytokine production, and lung injury than human neutrophil peptides transgenic mice. Conversely, an increased lung cytokine production was seen in Friend virus B-type mice, which was further enhanced in human neutrophil peptides transgenic mice in response to two-hit lung injury induced by hydrochloric acid and mechanical ventilation. The human neutrophil peptides-mediated inflammatory response was mediated through the basal cell adhesion molecule-P2Y purinoceptor 6 receptor signal pathway in human lung epithelial cells. CONCLUSIONS: Human neutrophil peptides are critical in host defense against infectious sepsis by their cationic antimicrobial properties but may exacerbate tissue injury when neutrophil-mediated inflammatory responses are excessive in noninfectious lung injury. Targeting the basal cell adhesion molecule/P2Y purinoceptor 6 signaling pathway may serve as a novel approach to attenuate the neutrophil-mediated inflammatory responses and injury while maintaining the antimicrobial function of human neutrophil peptides in critical illness. PMID- 29979224 TI - MicroRNA-155 Amplifies Nitric Oxide/cGMP Signaling and Impairs Vascular Angiotensin II Reactivity in Septic Shock. AB - OBJECTIVES: Septic shock is a life-threatening clinical situation associated with acute myocardial and vascular dysfunction, whose pathophysiology is still poorly understood. Herein, we investigated microRNA-155-dependent mechanisms of myocardial and vascular dysfunction in septic shock. DESIGN: Prospective, randomized controlled experimental murine study and clinical cohort analysis. SETTING: University research laboratory and ICU at a tertiary-care center. PATIENTS: Septic patients, ICU controls, and healthy controls. Postmortem myocardial samples from septic and nonseptic patients. Ex vivo evaluation of arterial rings from patients undergoing coronary artery bypass grafting. SUBJECTS: C57Bl/6J and genetic background-matched microRNA-155 knockout mice. INTERVENTIONS: Two mouse models of septic shock were used. Genetic deletion and pharmacologic inhibition of microRNA-155 were performed. Ex vivo myographic studies were performed using mouse and human arterial rings. MEASUREMENTS AND MAIN RESULTS: We identified microRNA-155 as a highly up-regulated multifunctional mediator of sepsis-associated cardiovascular dysfunction. In humans, plasma and myocardial microRNA-155 levels correlate with sepsis-related mortality and cardiac injury, respectively, whereas in murine models, microRNA-155 deletion and pharmacologic inhibition attenuate sepsis-associated cardiovascular dysfunction and mortality. MicroRNA-155 up-regulation in septic myocardium was found to be mostly supported by microvascular endothelial cells. This promoted myocardial microvascular permeability and edema, bioenergetic deterioration, contractile dysfunction, proinflammatory, and nitric oxide-cGMP-protein kinase G signaling overactivation. In isolate cardiac microvascular endothelial cells, microRNA-155 up-regulation significantly contributes to LPS-induced proinflammatory cytokine up-regulation, leukocyte adhesion, and nitric oxide overproduction. Furthermore, we identified direct targeting of CD47 by microRNA-155 as a novel mechanism of myocardial and vascular contractile depression in sepsis, promoting microvascular endothelial cell and vascular insensitivity to thrombospondin-1-mediated inhibition of nitric oxide production and nitric oxide-mediated vasorelaxation, respectively. Additionally, microRNA-155 directly targets angiotensin type 1 receptor, decreasing vascular angiotensin II reactivity. Deletion of microRNA-155 restored angiotensin II and thrombospondin-1 vascular reactivity in LPS-exposed arterial rings. CONCLUSIONS: Our study demonstrates multiple new microRNA-155 mediated mechanisms of sepsis-associated cardiovascular dysfunction, supporting the translational potential of microRNA-155 inhibition in human septic shock. PMID- 29979225 TI - Variation in Sedation and Neuromuscular Blockade Regimens on Outcome After Cardiac Arrest. AB - OBJECTIVES: Sedation and neuromuscular blockade protocols in patients undergoing targeted temperature management after cardiac arrest address patient discomfort and manage shivering. These protocols vary widely between centers and may affect outcomes. DESIGN: Consecutive patients admitted to 20 centers after resuscitation from cardiac arrest were prospectively entered into the International Cardiac Arrest Registry between 2006 and 2016. Additional data about each center's sedation and shivering management practice were obtained via survey. Sedation and shivering practices were categorized as escalating doses of sedation and minimal or no neuromuscular blockade (sedation and shivering practice 1), sedation with continuous or scheduled neuromuscular blockade (sedation and shivering practice 2), or sedation with as-needed neuromuscular blockade (sedation and shivering practice 3). Good outcome was defined as Cerebral Performance Category score of 1 or 2. A logistic regression hierarchical model was created with two levels (patient-level data with standard confounders at level 1 and hospitals at level 2) and sedation and shivering practices as a fixed effect at the hospital level. The primary outcome was dichotomized Cerebral Performance Category at 6 months. SETTING: Cardiac arrest receiving centers in Europe and the United states from 2006 to 2016 PATIENTS:: Four-thousand two-hundred sixty-seven cardiac arrest patients 18 years old or older enrolled in the International Cardiac Arrest Registry. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean age was 62 +/- 15 years, 36% were female, 77% out-of-hospital arrests, and mean ischemic time was 24 (+/- 18) minutes. Adjusted odds ratio (for age, return of spontaneous circulation, location of arrest, witnessed, initial rhythm, bystander cardiopulmonary resuscitation, defibrillation, medical history, country, and size of hospital) was 1.13 (0.74-1.73; p = 0.56) and 1.45 (1.00-2.13; p = 0.046) for sedation and shivering practice 2 and sedation and shivering practice 3, respectively, referenced to sedation and shivering practice 1. CONCLUSION: Cardiac arrest patients treated at centers using as-needed neuromuscular blockade had increased odds of good outcomes compared with centers using escalating sedation doses and avoidance of neuromuscular blockade, after adjusting for potential confounders. These findings should be further investigated in prospective studies. PMID- 29979226 TI - Reporting of blood pressure monitor validation studies. PMID- 29979227 TI - Response to discussion about blood pressure monitor validation studies. PMID- 29979228 TI - Invited commentary. PMID- 29979229 TI - Reporting of blood pressure monitor validation studies. PMID- 29979230 TI - Development of the Modified Lenticule Edge Dissection Technique for Small Incision Lenticule Extraction. AB - PURPOSE: To identify and develop an efficient technique to separate the lenticule edge in small incision lenticule extraction (SMILE). METHODS: Four hundred eyes of 400 consecutive patients with myopia assigned to receive SMILE were included in the study. Eyes with poor-quality laser treatment were excluded, and the second eye of the same patient was included. Two skilled surgeons performed SMILE in the Zhongshan Ophthalmic Center. Each surgeon was allotted 200 patients. One surgeon used the modified technique, whereas the other surgeon used the conventional technique to identify and separate the lenticule edge. All intraoperative complications associated with lenticule edge dissection and the duration of lenticule dissection were recorded. RESULTS: There were 200 eyes each in the modified technique group (group A) and the conventional technique group (group B). The mean lenticule dissection time was 49 +/- 10 seconds in group A and 59 +/- 43 seconds in group B (P = 0.002). Within 70 seconds, lenticule dissection was completely finished in 96.5% of eyes in group A and 86.0% in group B. Difficult lenticule dissection was experienced in 3.5% (7/200) of cases in group A and in 14.0% (28/200) of cases in group B. CONCLUSIONS: The modified lenticule edge dissection technique of SMILE is simpler and faster in identifying the correct dissection plane. It is efficient in reducing surgical manipulation, shortening the learning curve required for lenticule dissection, and allows surgeons to perform SMILE more safely and efficiently. PMID- 29979231 TI - Refractive Stability After Deep Anterior Lamellar Keratoplasty for Keratoconus. AB - PURPOSE: To evaluate the long-term stability of subjective refraction after deep anterior lamellar keratoplasty (DALK) performed in keratoconus-affected eyes. METHODS: This retrospective, comparative interventional case series analyzed the data of 73 eyes in 69 patients with keratoconus who underwent DALK. Only patients with clear grafts who had all sutures removed for at least 12 months were enrolled. The corrected distance visual acuity (CDVA) and manifest refraction were measured several months after all sutures were removed. The CDVA, spherical equivalent refraction, refractive astigmatism, and vector components of refractive astigmatism (J0 and J45) were recorded and compared at different time points. RESULTS: Mean age of patients was 28.3 +/- 8.3 years at the time of keratoplasty. No significant changes in the CDVA were observed during the follow up period. Spherical equivalent refraction measured at 1 month (-3.18 +/- 3.41 D) and 3 months (-4.29 +/- 4.26 D) after complete suture removal differed significantly from that measured at the last examination (-4.70 +/- 3.75 D; P = 0.001 and 0.03, respectively). This measurement stabilized from 6 months after complete suture removal onward. Refractive astigmatism and its vector components (J0 and J45) did not change over time after complete suture removal. CONCLUSIONS: Refraction stabilized 6 months after complete DALK suture removal. Therefore, postponing refractive surgery until this time is advisable to manage post-DALK refractive errors. PMID- 29979232 TI - Biologic Therapies as Adjunctive Treatments in Rotator Cuff Repair. PMID- 29979233 TI - Current Uses of the Transtrochanteric Approach to the Hip: A Systematic Review. AB - BACKGROUND: The indications and technique for the transtrochanteric approach to the hip have evolved greatly since its initial popularization in the 1960s. The purpose of this systematic review was to assess current uses of this approach on the basis of indications, osteotomy technique, trochanteric fixation method, complications, and functional outcome. METHODS: A comprehensive search of MEDLINE and Embase databases from January 2000 to July 2017 was performed in accordance with the PRISMA guidelines. Articles were divided into 3 major categories on the basis of the type of hip surgery performed: (1) primary arthroplasty, (2) revision arthroplasty, and (3) joint-preserving procedures. Patient data were then analyzed according to these 3 categories. RESULTS: Seventy-six studies (5,028 hips), mainly of Level-IV evidence, were included. Four types of osteotomy were reported for a variety of indications. Rates of nonunion were 6.0% (303 of 5,028) across all studies, 4.2% (39 of 921) for primary arthroplasty, 6.7% (114 of 1,690) for revision arthroplasty, and 4.4% (56 of 1,278) for joint-preserving procedures. Rates of dislocation were 1.5% (14 of 921) for primary arthroplasty and 4.6% (77 of 1,690) for revision arthroplasty. The rate of osteonecrosis after joint-preserving procedures was 1.1% (14 of 1,278). Rates of deep infection were 1.1% (55 of 5,028) across all studies, 0.1% (1 of 921) for primary arthroplasty, 2.1% (36 of 1,690) for revision arthroplasty, and 0.6% (8 of 1,278) for joint preserving procedures. CONCLUSIONS: The transtrochanteric approach remains useful in cases requiring extensile exposure of the acetabulum or femoral medullary canal. However, trochanteric complications continue to pose a clinical challenge. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29979234 TI - Management of a Lower Eyelid Defect. PMID- 29979235 TI - Indications, evolving technique, and early outcomes with robotic retroperitoneal lymph node dissection. AB - PURPOSE OF REVIEW: Examine and discuss indications, technique, and outcomes for robotic retroperitoneal lymph node dissection (RPLND) for testicular cancer. RECENT FINDINGS: Open RPLND has been the longstanding standard of care for both primary and post chemotherapy RPLND. Recently, robotic RPLND has been an attractive option with the intent of reducing the morbidity associated with open surgery while providing identical oncologic efficacy. Naysayers of robotic RPLND suggest it is often inappropriately used as a staging procedure and consequently can compromise oncologic efficacy. SUMMARY: Robotic RPLND is being evaluated as a therapeutic equivalent to open RPLND. On the basis of limited published data with modest follow-up from experienced centers, robotic RPLND appears to provide effective staging and therapeutic data mirroring that of open surgery. PMID- 29979236 TI - Current medical management of patients with poor-risk metastatic germ-cell tumors. AB - PURPOSE OF REVIEW: Despite the high cure rate of germ-cell tumors (GCTs), the 5 year survival rate for those patients with metastatic poor-risk GCT rarely exceeds 50%. The purpose of this review is to highlight past and recent discoveries in the treatment of patients with poor-risk GCT. RECENT FINDINGS: Multiple clinical trials to optimize the management of poor-risk germ-cell cancer are ongoing. First-line phase II clinical trials of dose-dense multidrug and paclitaxel-based regimens such as accelerated bleomycin, etoposide, and cisplatin (BEP), dose-dense chemotherapy and paclitaxel, ifosfamide, and cisplatin (TIP) reported promising results. Positive phase III data are still lacking. SUMMARY: Four cycles of BEP or Etoposide (VP16), ifosfamide, cisplatin (VIP) continue to be the standard of care in patients with poor-risk GCT. A significant disparity in patient outcome exists between high-volume and low-volume centers. Referral for centers of excellence should be considered in the management of poor-risk GCT. PMID- 29979238 TI - Advances in pediatric cardiology 2018. PMID- 29979237 TI - Prognostic markers in clinical stage I seminoma and nonseminomatous germ cell tumours. AB - PURPOSE OF REVIEW: Testicular germ cell tumour (TGCT) is a common malignancy among young men. There is controversy regarding the best approach for patients with clinical stage I disease due to rates of relapse with active surveillance in contrast to overtreatment with adjuvant therapy. The aim of this review is to describe the role of prognostic factors in this setting. RECENT FINDINGS: Molecular prognostic factors have been described as a possible future aid to clinical and histologic features in the approach of patients with clinical stage I germ cell tumours. SUMMARY: Prognostic factors currently available are not accurate enough and may lead to overtreatment. However, though active surveillance has shown long-term survival near to 100% in the management of clinical stage I germ cell tumours, there is a significant percentage of patients with occult metastatic disease, who benefit from adjuvant therapy. In light of these data, future research is needed to better define high-risk patients for relapse, taking into account molecular markers recently reported. PMID- 29979239 TI - Imaging of Thoracoabdominal Aortic Aneurysms. AB - Untreated thoracoabdominal aortic aneurysms are associated with an exceedingly high mortality rate, and surgery carries a high complication rate. Crawford's classification system of thoracoabdominal aortic aneurysms describes aneurysm morphology and stratifies patients on the basis of risk of major postoperative complications including mortality, spinal cord injury, and renal failure. Computed tomography and magnetic resonance angiography are essential for classifying thoracoabdominal aortic aneurysms and identifying other important features that impact prognosis and surgical management. Four-dimensional flow sensitive magnetic resonance imaging is an emerging technique that may help predict complications and further impact timing of intervention. PMID- 29979240 TI - Congenital Coronary Artery Anomalies and Implications. AB - This pictorial essay presents cases of congenital coronary artery anomalies, including congenital anomalies of origin, course, and termination. Familiarity with atypical coronary anatomy and clinical presentation may facilitate appropriate diagnosis and management, particularly as cardiac and thoracic computed tomographic utilization increases. PMID- 29979241 TI - Single-phase Split-bolus Dual Energy Computed Tomography Angiography for Evaluation of Hemoptysis: A Novel Application. AB - PURPOSE: The purpose of this study was to assess feasibility and overall utility of single-phase split-bolus dual energy computed tomography (DECT) angiography (DECTA) for evaluation of hemoptysis, and to establish an injection protocol for evaluation of hemoptysis, by comparing 2 contrast injection protocols. MATERIALS AND METHODS: Using dual-source (80 and 140 kV), 2*128-slice equipment, DECTA was performed using 400 mg iodine/mL, 50 to 80 mL iodinated contrast in 257 patients (189 male individuals, 68 female individuals, age range: 15 to 76 y) presenting with hemoptysis. Initially, 50 patients were randomized into 2 groups for 2 different injection protocols (A and B). Images were assessed quantitative and qualitatively. Later, 207 patients were randomized using protocol B, which was technically simpler, and single-CT acquisition, for simultaneous opacification of systemic and pulmonary vessels. RESULTS: Injection protocol A resulted in higher vessel attenuation, both in the aorta and in the pulmonary artery and its segmental branches; however, the difference was not statistically significant. No significant difference was noted in signal-to-noise ratio, contrast-to-noise ratio, as well as subjective image quality parameters. Overall optimal opacification of both systemic and pulmonary arteries was achieved in 247/257 patients. A total of 308 abnormal bronchial arteries were noted. A total of 392 nonbronchial systemic arteries were noted, the majority arising from posterior intercostals and subclavian artery branches. The pulmonary source of hemoptysis was identified in 9 patients (3 pulmonary thromboembolisms, 5 pulmonary artery pseudoaneurysms, and 1 pulmonary venous ectasia). CONCLUSION: Combined DECTA is a novel technique that enables simultaneous evaluation of both systemic and pulmonary vascular cause of hemoptysis in a single acquisition with small contrast dose. Both injection protocols "A" and "B" were equally efficacious in simultaneous opacification of both the aorta and pulmonary arteries. To the best of our knowledge, such a protocol has never been described for hemoptysis evaluation. PMID- 29979242 TI - Long-term nutritional follow-up post bariatric surgery. AB - PURPOSE OF REVIEW: Bariatric surgery is an effective treatment for classes II and III obesity and its associated diseases. However, many important long-term outcomes of bariatric surgery are still poorly understood, such as neurological and psychological complications, bone health, and so on. This review summarizes the current evidence and expert opinions on nutritional care in the long-term postoperative period. RECENT FINDINGS: In the first section, we will provide an update of the main long-term complications: risk of anaemia, risk of bone fracture, neurological and psychological complications, and risk of developing Barrett's oesophagus after sleeve gastrectomy. We will also examine the current strategies used to increase weight loss or reduce weight regain. As adherence to long-term follow-up has been shown to decrease over time, the second section aims to identify all measures that improve follow-up rates, to get the maximum benefit from bariatric surgery, while minimizing long-term adverse effects and complications. SUMMARY: There is still a significant level of uncertainty regarding the best clinical practices for maintaining the health benefits provided by bariatric surgery. The role of family physician in postsurgery care needs to be clearly defined. More effort is needed to improve psychological care, behaviour management, and therapeutic patient education after bariatric surgery. A more patient-centred approach should probably be considered. PMID- 29979243 TI - Epidural Analgesia in Patients Undergoing Elective Ventral Hernia Repair? PMID- 29979244 TI - Letter to Editor: A Proposal to Mitigate the Consequences of Type 2 Error in Surgical Science. PMID- 29979245 TI - Post Hoc Power Calculation: Observing the Expected. PMID- 29979247 TI - Post Hoc Power: A Surgeon's First Assistant in Interpreting "Negative" Studies. PMID- 29979246 TI - Downregulated Pancreatic Beta Cell Genes Indicate Poor Prognosis in Patients With Pancreatic Neuroendocrine Neoplasms. AB - OBJECTIVE: To predict metachronous liver metastasis after pancreatectomy for pancreatic neuroendocrine neoplasms (Pan-NENs). SUMMARY OF BACKGROUND DATA: Liver metastasis determines the prognosis of patients with Pan-NENs, but no index exists in the WHO 2017 classification for this prediction. METHODS: Between April 2014 and March 2018, resected primary tumors from 20 patients with or without simultaneous liver metastasis were examined using genome-wide gene expression analysis. For validation analysis, resected primary tumors from 62 patients without simultaneous liver metastasis were examined for PAX6 expression. RESULTS: Gene expression profiling revealed pancreatic beta cell genes (NES, -2.0; P < 0.001) as the most downregulated set in patients with simultaneous liver metastasis. In the test study, PAX6 was the most valuable index for liver metastasis (log FC, -3.683; P = 0.0096). Multivariate analysis identified PAX6 expression (hazard ratio, 0.2; P = 0.03) as an independent risk factor for metachronous liver metastasis-free survival (mLM-FS). The 5-year mLM-FS of patients with high versus low PAX6 expression was significantly better (95% vs 66%, respectively; P < 0.0001). The 5-year overall survival rate of was also better than in those with high versus low PAX6 expression (100% vs 87%, respectively). Patients with low PAX 6 expression were significantly younger and leaner, had a higher Ki-67 index (P = 0.01, 0.007, 0.008, respectively), and showed a higher mitotic rate than patients with high PAX6 expression. CONCLUSIONS: Downregulated pancreatic beta cell genes involving PAX6 in primary tumors may predict mLM and poor overall survival after primary tumor resection in Pan-NEN patients. PMID- 29979248 TI - Reply to Comments to "Higher Recurrence Rate After Endoscopic Totally Extraperitoneal (TEP) Inguinal Hernia Repair with Ultrapro Lightweight Mesh: 5 Year Results of a Randomized Controlled Trial (TULP-trial)". PMID- 29979249 TI - A Structured Compensation Plan Improves But Does Not Erase the Sex Pay Gap in Surgery. AB - OBJECTIVE: The aim of this study is to examine the relationship between the sex pay gap in a large academic department of surgery and a recently instituted structured compensation plan. SUMMARY OF BACKGROUND DATA: A recent large study found that after controlling for measures of academic and clinical productivity, male physicians earned nearly $20,000 more annually than female physicians. Increased salary transparency has been proposed as a method to reduce this disparity. METHODS: A new structured compensation plan was developed to improve transparency of compensation and financial viability of each division. The total compensations of each faculty member before and after the new compensation plan were calculated. Salaries were compared with the Association of Academic Medical Colleges (AAMC) median value based on specialty, region, academic rank, stratified by sex and compared. Work relative value units (wRVUs) were calculated for each faculty member during the entire study period, stratified by sex and compared. RESULTS: Among 44 eligible surgeons (33 men and 11 women), a sex pay gap existed with male surgeon salaries significantly higher than female surgeon salaries [56% (8 to 213) vs 26% (1 to 64); P < 0.00001] despite similar RVU production (men 8725 +/- 831 vs women 7818 +/- 911, P = 0.454). The new compensation plan did not significantly change male surgeon salaries [56% (8 to 213) vs 58% (26 to 159); P = 0.552] but did significantly increase the salaries of female surgeons [26% (1 to 64) vs 42% (10 to 80); P = 0.026]. CONCLUSION: A structured compensation plan can improve the sex pay gap in a short period of time. More transparency in surgical compensation plans is essential to understand the most equitable way to compensate all surgeons. PMID- 29979250 TI - Accelerated Magnetic Seizure Therapy for Treatment of Major Depressive Disorder: A Report of 3 Cases. AB - INTRODUCTION: Major depressive disorder is a prevalent and debilitating condition that afflicts millions of people worldwide. Magnetic seizure therapy (MST) is a promising convulsive neurostimulation treatment for depression with fewer cognitive adverse effects than electroconvulsive therapy. METHODS: A small case series of patients recruited as part of an open-label clinical trial is presented. Patients with depression underwent an accelerated MST protocol (aMST) consisting of 1 treatment per day for 6 consecutive weekdays. The primary outcome was severity on the HDRS17 (Hamilton Depression Rating Scale 17-item). In addition, patients underwent neuropsychological assessment with the Repeatable Battery for the Assessment of Neuropsychological Status and Stroop test. RESULTS: After completing aMST, all patients experienced improvement. Two patients met response criterion, and the third experienced a 27% decrease on the HDRS17. All 3 patients experienced improvement in cognitive performance with a global 20% mean improvement and strongest improvement in immediate and delayed verbal memory indices (mean improvement of 40% and 27%, respectively). There were no cases of prolonged confusion or delirium after MST treatments. There were no severe adverse effects in any of the 3 patients. CONCLUSIONS: Accelerated MST protocol was well tolerated and associated with positive outcomes in this small case series. Accelerated MST protocol was not associated with prolonged confusion or delirium and was associated with improvement in memory indices. Our results merit further research in large RCT to test whether accelerated MST protocol might be an efficacious treatment for major depressive disorder. PMID- 29979251 TI - PERIPHERAL RETINAL DRUSEN-LIKE DEPOSITS IN GUCY2C CONGENITAL SECRETORY DIARRHEA SYNDROME. AB - PURPOSE: To report the presence of drusen in infancy, in a patient with Type 1 retinopathy of prematurity and a rare congenital sodium diarrhea secondary to a sporadic GUCY2C mutation. METHODS: A case report generated by review of clinical course, with imaging of 1 patient and literature review. RESULTS: A 1.075-kg infant born at gestation age 27 weeks was admitted to our institution with respiratory distress and secretory diarrhea. During screening for retinopathy of prematurity, peripheral drusen-like subretinal deposits were identified. There were no similar findings in either parent or family history of ocular pathologies. Their distribution is atypical for that seen in other causes of early onset drusen such as autosomal dominant drusen or Sorsby fundus dystrophy. Retinopathy of prematurity was identified, which progressed to Type 1, and was treated with bilateral indirect peripheral retinal photocoagulation at gestational age of 40 weeks. Fluorescein angiography was performed and was consistent with peripheral drusen. Optical coherence tomography of the central macula and an awake electroretinogram at 6 months were normal. Serial examinations confirmed no progression in the drusen-like deposits or in retinopathy of prematurity, with clinically appropriate visual development observed during close follow-up. CONCLUSION: We identify a unique ocular phenotype of retinal drusen-like deposits in an infant with a rare, sporadic GUCY2C mutation. PMID- 29979252 TI - TREATMENT OF REFRACTORY TUBERCULAR SERPIGINOUS-LIKE CHOROIDITIS WITH INTRAVITREAL METHOTREXATE. AB - PURPOSE: To describe a case of tubercular serpiginous-like choroiditis that progressed, despite antitubercular medication, corticosteroids, and immunomodulatory treatment, which ultimately quieted after two intravitreal methotrexate injections. METHODS: Case report. RESULTS: A 35-year-old woman reported a shadow in the left eye for 2 weeks. She presented with tubercular serpiginous-like choroiditis in the right eye 2 years prior. At that time, she was started on antituberculosis therapy but was noncompliant and lost to follow up. On re-presentation, there was a new active left-eye serpiginous lesion, with repeat positive QuantiFERON gold testing. Four antituberculosis drugs were started, followed by corticosteroids and azathioprine, with continued progression despite aggressive treatment. She was finally given 2 intravitreal methotrexate injections (400 MUg/0.1 cc) 1 month apart, with final arrest of lesion extension. The uveitis remained quiet for over 24 months, and the patient was able to discontinue all systemic therapy. CONCLUSION: Intravitreal methotrexate injections halted progression of treatment-refractory tubercular serpiginous-like choroiditis. PMID- 29979253 TI - COMBINED INTERNAL LIMITING MEMBRANE FLAP AND AUTOLOGOUS PLASMA CONCENTRATE TO CLOSE A LARGE TRAUMATIC MACULAR HOLE IN A PEDIATRIC PATIENT. AB - PURPOSE: To describe a case of a large, traumatic macular hole in a pediatric patient closed using an internal limiting membrane flap in combination with autologous plasma concentrate (APC). METHODS: Description of a surgical technique as performed in one patient. RESULTS: Successful macular hole closure and improvement in postoperative visual acuity were achieved in the patient in whom the technique was performed. CONCLUSION: The combined use of APC with the internal limiting membrane flap is advantageous because the APC acts to hold the internal limiting membrane in proper position and promotes the proliferation of glial cells through the presence of growth factors. This technique may be particularly advantageous in chronic or recalcitrant holes particularly in the setting of trauma. PMID- 29979255 TI - Five years of Coronary Artery Disease. PMID- 29979256 TI - Prehospital delay in patients with ST-segment elevation myocardial infarction: time for change. PMID- 29979254 TI - Development and Preliminary Findings of the Dizziness Symptom Profile. AB - OBJECTIVES: Dizziness, vertigo, and unsteadiness are common complaints of patients who present to primary care providers. These patients often are referred to otology for assessment and management. Unfortunately, there are a small number of specialists to manage these patients. However, there are several dizziness disorders that can be successfully managed by primary care providers if the disorder is properly identified. To assist in the identification of several of the most common dizziness disorders, we developed the dizziness symptom profile (DSP). The DSP is a self-report questionnaire designed to generate one or more differential diagnoses that can be combined with the patient's case history and physical examination. DESIGN: This report describes three investigations. Investigations 1 and 2 (i.e., exploratory and confirmatory investigations, N = 514) describe the development of the DSP. Investigation 3 (N = 195) is a validation study that describes the level of agreement between the DSP completed by the patient, and, the differential diagnosis of the otologist. RESULTS: The final version of the DSP consists of 31 items. Preliminary findings suggest that the DSP is in agreement with the differential diagnoses of ear specialists for Meniere's disease (100% agreement), vestibular migraine (95% agreement), and benign paroxysmal positional vertigo (82% agreement). CONCLUSIONS: Early results suggest that DSP may be useful in the creation of differential diagnoses for dizzy patients that can be evaluated and managed locally. This has the potential to reduce the burden on primary care providers and reduce delays in the diagnosis of common dizziness and vertigo disorders. PMID- 29979257 TI - Impact of obesity following coronary artery bypass grafting. PMID- 29979258 TI - Autoimmune haemolytic anaemia and autoimmune thrombocytopenia in childhood-onset systemic lupus erythematosus: updates on pathogenesis and treatment. AB - PURPOSE OF REVIEW: Autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia are common complications of childhood-onset lupus, which may be life-threatening. A greater understanding of the pathogenesis of these haematologic manifestations will enhance our understanding of the biology of systemic lupus erythematosus (SLE) and inform the identification of novel treatments. RECENT FINDINGS: The mechanisms underlying AIHA and autoimmune thrombocytopenia are incompletely understood and likely multifactorial. Although the development of auto-antibodies is central to the disease process, recent studies have demonstrated the importance of cytokines in the underlying pathologic process. In-vitro and in-vivo evidence points to a role for IL17 in the pathogenesis of AIHA, which involves loss of tolerance to red cell auto antigens and the development of autoantibodies. Sirolimus, an mTor inhibitor, has benefited patients with primary autoimmune cytopenias, possibly by stimulating T regulatory cells, and may also have efficacy for SLE-associated cytopenias. Similarly, low-dose recombinant human IL-2 therapy has shown promising results for improving platelet counts in patients with autoimmune thrombocytopenia, possibly by restoring the balance between T regulatory, T helper and Th17 cells. SUMMARY: The emergence of new agents directed at restoring immune dysregulation hold promise for the treatment of AIHA and autoimmune thrombocytopenia and should provide better tolerated alternatives to high-dose corticosteroids. PMID- 29979259 TI - Hsa-mir-127 impairs survival of patients with glioma and promotes proliferation, migration and invasion of cancerous cells by modulating replication initiator 1. AB - This work aimed to investigate the inter-regulatory functions of hsa-mir-127 and replication initiator 1 (REPIN1) on the proliferation and metastasis of glioma cells. The in-silico data on the implication of hsa-mir-127 and REPIN1 in glioma were retrieved from The Cancer Genome Atlas (TCGA). The expression levels of hsa mir-127 and REPIN1 mRNA were determined by qRT-PCR, whereas Western blot was used to detect REPIN1 protein expression in glioma cell lines. The proliferation of glioma cells was determined by means of the MTT assay, whereas the transwell assay was employed for assessing the extent of cell migration and invasion. The interaction among REPIN1 and hsa-mir-127 was checked using the luciferase reporter assay. The expression of hsa-mir-127 was markedly increased in clinical data obtained from TCGA and in glioma cells compared with normal tissues and control cells, respectively. Increased expression of hsa-mir-127 and decreased expression of REPIN1 were both associated with poor overall survival. Moreover, hsa-mir-127 overexpression noticeably promoted proliferation, inhibited apoptosis and increased the invasive and migratory capacities of glioma cells. Inverse effects were found with hsa-mir-127 antisense inhibitor. Interestingly, overexpression of hsa-mir-127 downregulated REPIN1 expression, and luciferase reporter assay showed that the tumorigenesis effect of hsa-mir-127 requires, in part, its direct targeting of REPIN1. In conclusion, the hsa-mir-127/REPIN1 pathway is involved in gliomas and could be a potential therapeutic target. PMID- 29979260 TI - Identification of the biological affection of long noncoding RNA BC200 in Alzheimer's disease. AB - BC200 is a long noncoding RNA expressed at high levels in the Alzheimer's disease (AD), and blocking of BC200 by siRNA is assumed to be an effective method for various disease therapy. We have established an AD cell model overexpressing amyloid beta-peptide (Abeta)1-42 to observe the effects of BC200 on the cell viability and apoptosis, and to investigate the associated underlying mechanisms. Efficient knockdown and overexpression of BC200 were established using BC200 siRNA and BC200 mimics, respectively. Cell viability following BC200 knockdown and overexpression was assessed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5 diphenyltetrazolium bromide assay, and cell apoptosis was monitored by flow cytometry. We successfully established an AD cell model overexpressing Abeta1-42 gene, and reported the results of change of BC200 on Abeta1-42 levels. Knockdown of BC200 significantly suppressed b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) expression, and overexpression of BC200 increased BACE1 expression. Besides, inhibition of BC200 significantly increased cell viability and reduced cell apoptosis in the AD model via directly targeting BACE1, which can be increased by overexpression of BC200. BC200 regulated AD cell viability and apoptosis via targeting BACE1, and it may be one of the putative target in AD development and provides potential new insights into genetic therapy against AD. PMID- 29979262 TI - Smart steps for labs and hospital outreach as CMS prepares to cut Medicare fees. PMID- 29979263 TI - VAD infection during bridge-to-transplant, unique aspects of treatment and prevention. AB - PURPOSE OF REVIEW: VAD infections remain a frequent complication of VAD care and can markedly affect patient management before and after transplantation. This review highlights the standard-of-care approaches offered by recent guidelines as well as published data that may improve the care for patients with these challenging and often persistent infections. RECENT FINDINGS: Prevention and management of VAD infections has become more standardized with updated consensus guidelines published in 2017. Unfortunately, advanced devices have not markedly affected the incidence of VAD infection. Efforts to improve, yet streamline, the prevention of VAD-specific infections are ongoing. However, the data provided in the best of recent publications are rarely effectively comparative. Granular data on management strategies are limited to a few studies. Nevertheless, several publications provide more detailed posttransplant outcomes for patients with pretransplant VAD infections and demonstrate overall excellent posttransplant survival. SUMMARY: Prevention and management of VAD-specific and VAD-related infections are the ongoing work of all VAD programs. Consensus guidelines are a marker of progress for this field. Despite very good posttransplant outcomes for these patients, more granular data are required to understand how such patients arrive successfully to transplantation and how their posttransplant course is affected. PMID- 29979264 TI - Outcomes after pancreas retransplantation: is the juice worth the squeeze? AB - PURPOSE OF REVIEW: Pancreas retransplantations are rarely carried out, and their outcomes are still debatable because of a lack of studies and clinical series on this issue. RECENT FINDINGS: In general, pancreas retransplantations achieve similar or even higher patient survival than primary transplantations; however, it should be noted that this finding may be biased, as only healthier patients are selected for retransplantation. Graft survival in retransplantations is usually lower than that in primary transplantation, but this comparison may also be biased, as most retransplantations are solitary pancreas transplantations (which are known to have lower graft survival), whereas primary transplantations are mostly simultaneous kidney-pancreas transplantations. Technical loss is similar between primary pancreas transplantations and pancreas retransplantations, but the occurrence of surgical complications is greater in the latter. SUMMARY: This review summarizes the literature on pancreas retransplantations, comparing them with primary transplantations, and demonstrates that in selected patients in experienced centres, retransplantation can be a valid and effective option for returning the patient to an insulin-free state. PMID- 29979265 TI - Robotic pancreas transplantation: the state of the art. AB - PURPOSE OF REVIEW: Robotic pancreas transplantation is a novel procedure that aims to reduce surgical invasiveness, and thereby limit complications related to the surgical access. Given that few centers are providing robotic transplantation, this review serves as a state of the science article to outline early experiences and highlight areas for future research. RECENT FINDINGS: Pancreas transplantation results in relatively high rates of wound and other surgical complications that are known to deleteriously impact outcomes. The minimally invasive, robotic-assisted approach decreases wound complications. Because of the obesity epidemic, overweight and obese status is encountered in an increasing number of transplant candidates. These candidates are subject to increased wound-related complications and most benefit from a robotic approach. The first clinical reports on laparoscopic, robotic-assisted kidney and pancreas transplantation indicate a significant decrease in wound complications and excellent outcomes in obese patients otherwise denied access to transplantation. SUMMARY: With excellent results achieved in surgically challenging patients and further accumulation of experience, laparoscopic, robotic-assisted pancreas and kidney transplantation may evolve to a new standard approach. PMID- 29979266 TI - The road less traveled: how to grow a pancreas transplant program. AB - PURPOSE OF REVIEW: The volume of pancreas transplants performed annually in the United States (US) has steadily declined for more than a decade. In the face of this negative trend, efforts at several centers are underway to expand their pancreas transplant volumes through alterations in the structure and function of their pancreas transplant programs. We highlight these programmatic changes and emphasize the culture and characteristics of these high volume centers to serve as models for other centers to emulate. As the results of modern-day pancreas transplantation are excellent and continue to improve, pancreas transplant remains an outstanding option for selected patients suffering from diabetes mellitus and end stage renal disease (ESRD) or symptomatic hypoglycemic events (SHEs). Through strong leadership commitment and programmatic restructuring, the transformation of low-volume pancreas transplant centers into high-volume programs is achievable without the need for cost-prohibitive investment. RECENT FINDINGS: Multiple examples may be cited of transplant centers reinvigorating their pancreas transplant programs, increasing their pancreas transplant evaluations and transplant rates, through personnel reorganization and operational restructuring. As a means of providing a roadmap to encourage other transplant centers to re-energize their pancreas transplant programs, we will outline strategies that can be readily instituted to transform a pancreas transplant program, and delineate the basic steps that any transplant center can take to achieve high-volume success. SUMMARY: The negative trends in access to pancreas transplantation in the US may ultimately be addressed by low-volume pancreas transplant programs re-committing themselves through easily achievable institutional changes without substantial added capital investment, thereby maximizing access to pancreas transplantation for their diabetic patients and maintaining excellent outcomes. PMID- 29979268 TI - Lateral Canthotomy and Cantholysis in Operations Iraqi Freedom and Enduring Freedom: 2001-2011. AB - PURPOSE: To describe outcomes and associated ocular injuries of lateral canthotomy and cantholysis (LCC) as performed in combat ocular trauma. METHODS: Data from the Walter Reed Ocular Trauma Database of patients requiring LCC during Operations Iraqi Freedom and Enduring Freedom was reviewed as a retrospective cohort. Primary outcome measures included final visual acuity (VA) and Ocular Trauma Score. Secondary outcome measures were associated injuries and timing of surgery. RESULTS: Thirty-six LCCs were recorded on a total of 890 eyes (4.04 %) in the Walter Reed Ocular Trauma Database. Eighteen out of 36 eyes (50.00%) had a final VA of the affected eye of 20/200 or worse vision. From the initial available VA measured either at the time of injury or at Walter Reed Army Medical Center, 13 eyes (40.63%) had no change in VA, 15 eyes (46.88%) had improvement, and 4 (12.5%) had a decrease in VA (n = 32, data unavailable for 4 eyes). Ocular Trauma score 0-65 was noted in 14 (38.9%) and 66-100 (61.1%). Retinal detachment (6, 16.67%), optic nerve injuries (7, 19.44%), orbital fractures (20, 55.56%), and retrobulbar hematoma (25, 69.44%) were commonly associated injuries. Of the 36 LCC, 18 (50.00%) were performed as the first surgery performed at the combat support hospital, 13 (36.11%) as the second, 4 (11.11%) as the third, and 1 (2.78%) as the fourth. CONCLUSIONS: The largest subgroup of patients had an improvement in VA associated with performance of LCC; however, half of patients remained with a final VA of equal to or worse than 20/200 due to severe ocular trauma. PMID- 29979269 TI - Carboplatin and Pembrolizumab Chemoimmunotherapy Achieves Remission in Recurrent, Metastatic Sebaceous Carcinoma. AB - A 72-year-old Caucasian woman who had recurrent sebaceous carcinoma of the right orbit with bilateral cervical lymph node involvement 24 months after orbital exenteration was treated with carboplatin (area under the curve of 5) and pembrolizumab (2 mg/kg) for 6 cycles, followed by maintenance pembrolizumab. She obtained a complete pathological remission and remains free of local, regional, and systemic disease at 15 months. PMID- 29979271 TI - Felt leadership: When perception is reality. PMID- 29979270 TI - Orbital Extension of Conjunctival Pseudoadenomatous Hyperplasia. AB - A 41-year-old woman developed persistent unilateral conjunctivitis following an upper respiratory infection. A white cystic lesion of the inferior fornix was noted on computed tomography scan to extend behind the orbital septum into the anterior portion of the orbit. Following subtotal excision, histopathology showed benign pseudoadenomatous (pseudoglandular) hyperplasia. The case represents the 5th report of this lesion occurring in the conjunctiva and the only instance of its extension into the orbit. PMID- 29979272 TI - Communicating with empathy in a world of polarity conflict. PMID- 29979273 TI - Comparison of Isolated Lumbar Extension Strength in Competitive and Noncompetitive Powerlifters, and Recreationally Trained Men. AB - Androulakis-Korakakis, P, Gentil, P, Fisher, JP, and Steele, J. Comparison of isolated lumbar extension strength in competitive and noncompetitive powerlifters, and recreationally trained men. J Strength Cond Res XX(X): 000-000, 2018-Low-back strength has been shown to significantly impact performance in a plethora of sports. Aside from its effect on sport performance, low-back strength is strongly associated with low-back pain. A sport that heavily involves the lower-back musculature is powerlifting. This study looked to compare isolated lumbar extension (ILEX) strength in competitive and noncompetitive powerlifters, and recreationally trained men. Thirteen competitive powerlifters (CPL group; 31.9 +/- 7.6 years; 173.4 +/- 5.5 cm; 91.75 +/- 18.7 kg), 10 noncompetitive powerlifters (NCPL group; 24 +/- 3.5 years; 179 +/- 4.8 cm; 92.39 +/- 15.73 kg), and 36 recreationally trained men (RECT group; 24.9 +/- 6.5 years; 178.5 +/- 5.2 cm; 81.6 +/- 10.0 kg) were tested for ILEX. Isolated lumbar extension strength was measured at every 12 degrees throughout participant's full range of motion (ROM) and expressed as the following: "strength index (SI)" calculated as the area under a torque curve from multiple angle testing, average torque produced across each joint angle (AVG), and maximum torque produced at a single angle (MAX). Deadlift and squat strength were measured using 1 repetition maximum for the competitive and noncompetitive powerlifters. The following powerlifting characteristics were recorded for the competitive and noncompetitive powerlifters: primary deadlift stance, primary squat bar position, use of belt, use of performance-enhancing drugs, and use of exercises to target the lower-back musculature. Significant between-group effects were found for participant characteristics (age, stature, body mass, and ROM). However, analysis of covariance with participant characteristics as covariates found no significant between-group effects for SI (p = 0.824), AVG (p = 0.757), or MAX (p = 0.572). In conclusion, this study suggests that powerlifting training likely has little impact on conditioning of the lumbar extensors. PMID- 29979274 TI - Validity of Wearable Electromyographical Compression Shorts to Predict Lactate Threshold During Incremental Exercise in Healthy Participants. AB - Snarr, RL, Tolusso, DV, Hallmark, AV, and Esco, MR. Validity of wearable electromyographical compression shorts to predict lactate threshold during incremental exercise in healthy participants. J Strength Cond Res XX(X): 000-000, 2018-Determination of lactate threshold (LT) is an important variable in improving cardiovascular endurance and performance. Unfortunately, monitoring LT during exercise uses a costly, invasive blood analysis. Recently, electromyography (EMG) has been deemed a potential method of monitoring exercise intensity and may provide a noninvasive technique to monitor lactate during exercise. The purpose of this investigation was to determine if wearable surface EMG technology, acquired from specialized compression shorts, could estimate the LT work rate during incremental cycling. Thirteen men (n = 9) and women (n = 4) completed a maximal exercise test on a cycle ergometer. Blood lactate was measured every minute, whereas EMG was recorded throughout at the site of the vastus lateralis. Lactate and EMG thresholds were calculated using the Dmax method and compared using a Wilcoxon matched-pairs signed-rank test. Results demonstrated no significant differences between lactate and EMG thresholds in regards to work output (p = 0.83), percent maximal heart rate (p = 0.13; Cohen's d = 0.43), or percent peak oxygen consumption (p = 0.64; Cohen's d = 0.09). This confirms that both lactate and EMG exhibit similar properties (i.e., increasing exponential values) during incremental exercise. A possible mechanism includes the rise in blood lactate concentration, which increases motor unit recruitment in an attempt to maintain proper cadence and force output during incremental exercise. Thus, a coincidental, exponential increase in EMG amplitude may occur. Therefore, wearable EMG compression gear may provide a viable field tool for monitoring training intensity and predicting LT work rates. PMID- 29979275 TI - Potentiating Response to Drop-Jump Protocols on Sprint Acceleration: Drop-Jump Volume and Intrarepetition Recovery Duration. AB - Byrne, PJ, Moody, JA, Cooper, SM, Callanan, D, and Kinsella, S. Potentiating response to drop-jump protocols on sprint acceleration: drop-jump volume and intrarepetition recovery duration. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to investigate the postactivation potentiation response first to bounce drop jump (BDJ) volume; second, BDJ intrarepetition recovery duration and recovery duration between BDJs and 20-meter (including 5- and 10-m split times) sprint performance. The study was undertaken in 2 parts, the first part compared different volumes of BDJs and the second part compared different BDJ intrarepetition recovery periods. The effect of recovery periods between the BDJs and the subsequent 20-m sprints was examined in both parts 1 and 2 (15 seconds, 4, 8, and 12 minutes). Fourteen (mean +/- SD: age = 20.83 +/- 1.26 years; height = 1.77 +/- 0.04 m; and mass = 74.89 +/- 6.07 kg) (part 1) and 15 (mean +/- SD: age = 20.64 +/- 1.00 years; height = 1.78 +/- 0.06 m; and mass = 75.67 +/- 6.28 kg) (part 2) male collegiate and club hurling players volunteered to participate. A randomized cross-over design was used to compare BDJ volumes (1, 2, and 3 sets of 3 repetitions) and BDJ intrarepetition recovery time (15 vs. 60 seconds) after a warm-up followed by 2 baseline 20-m sprints. The results in part 1 reported a significant improvement in 5- and 10-m sprint time for 1 set of 3 BDJs between baseline and 4 minutes (5 m: -2.34%, p = 0.04, effect size [ES] = 0.043; 10 m: -1.42%, p = 0.03, ES = -0.35), and baseline and 12 minutes (5 m: 3.33%, p = 0.03, ES = -0.57; 10 m: -2.13%, p = 0.01, ES = -0.52). Part 2 reported a significant improvement in 5-m sprint time between baseline and 15 seconds (5 m: -3.38%, p = 0.01, ES = -0.83; 10 m: -2.07%, p = 0.02, ES = -0.58) after the BDJs. The findings support the use of 1 set of 3 BDJs using a 15-second intrarepetition recovery period to maximize 5-, 10-, and 20-m sprint performance after 15 seconds of recovery after the final BDJ in hurling players. The acute response to this BDJ protocol proves to be time efficient and effective in acutely improving sprint acceleration. PMID- 29979276 TI - Footwear and Sex Differences in Performance and Joint Kinetics During Maximal Vertical Jumping. AB - Smith, RE, Paquette, MR, Harry, JR, Powell, DW, and Weiss, LW. Footwear and sex differences in performance and joint kinetics during maximal vertical jumping. J Strength Cond Res XX(X): 000-000, 2018-This investigation examined the effects of footwear and sex on vertical jump displacement and joint power contributions. Twenty-three young adults with basketball experience performed 3 maximal countermovement vertical jumps in minimal and standard footwear. Ground reaction force and 3D kinematic data were collected during jumping. Footwear by sex analysis of variance for all dependent variables and effect sizes (d) was computed. An interaction effect showed that men produced greater lower-limb positive work than women in standard footwear. Men jumped higher than women (d = 2.53) and produced greater peak ankle, knee and hip joint moments (d > 0.99), positive joint powers (d > 1.07) and, positive knee and hip joint work (d > 1.04) with no sex differences for negative joint powers and work (p > 0.05). Minimal footwear produced less peak-positive knee power (d = 0.27) and less positive ankle (d = 0.34) and knee (d = 0.21) joint work than standard footwear. Because negative joint power and work were similar between sexes, men may be better able to use the stretch-shortening cycle compared with women. Higher joint mechanical demands may provide a better vertical jumping training stimulus in standard compared with minimal footwear. Future studies should investigate footwear training effects on performance and joint mechanics during jumping. PMID- 29979277 TI - Match Demands of National Collegiate Athletic Association Division I Men's Soccer. AB - Curtis, RM, Huggins, RA, Looney, DP, West, CA, Fortunati, A, Fontaine, GJ, and Casa, DJ. Match demands of National Collegiate Athletic Association Division I men's soccer. J Strength Cond Res 32(10): 2907-2917, 2018-This study aimed to profile positional movement characteristics of National Collegiate Athletic Association (NCAA) Division I male soccer players. Eighteen Division I male soccer players were monitored using global positioning systems, inertial movement, and heart rate (HR) technology during 24 matches over a full competitive season (N = 235 observations). Positional groups were classified as either a forward (F), center midfielder (CM), wide midfielder (WM), or defender (D). Movement was profiled by locomotor (walking [0-7.19 km.h], jogging [7.20 14.39 km.h], running [14.40-21.59 km.h], and sprinting [>21.6 km.h]), and acceleration/deceleration characteristics (low intensity [0-1.99 m.s], moderate intensity [2-3.99 m.s], and high intensity [>4 m.s]). Players averaged distances of 9,367 +/- 2,149 m per match at speeds of 91 +/- 20 m.min and physiological intensities of 78 +/- 8 %HRmax. Center midfielder demonstrated the highest average speeds (97 +/- 20 m.min) and covered the most distance (9,941 +/- 2,140 m). Wide midfielder accumulated the most sprint distance (391 +/- 145 m) and high intensity accelerations (129 +/- 30 n)/decelerations (96 +/- 24 n). Several practically meaningful differences exist between positions for internal and external load metrics. Match loads seen in NCAA Division I soccer vary from reports of professional soccer; however, the effects of match regulation, structure, and congestion, which are unique to NCAA soccer, require further investigation. Physical and physiological load monitoring of NCAA soccer may aid coaches and practitioners in the periodization of training programs leading up to and during a competitive soccer season. These data speak to the necessity for examining both internal and external loads by position. PMID- 29979278 TI - Superior Training-Specific Adaptations With an 8-Week Yoak Push-up Training Program. AB - Lima, C, Li, Y, Low, JL, Herat, N, and Behm, DG. Superior training-specific adaptations with an 8-week yoak push-up training program. J Strength Cond Res 32(9): 2409-2418, 2018-There are few progressive metastability training programs in the literature. The purpose of this study was to investigate changes in strength, endurance, muscle activation, and neuromuscular efficiency after an 8 week progressive, push-up training program under stable and unstable conditions. Nineteen male and female recreationally trained participants performed twice per week, an 8-week push-up training program, using either a relatively unstable suspension system (Yoak) or under stable conditions. Participants were tested in 2 separate sessions before and after training for chest press maximal voluntary isometric contraction (MVIC) forces, and unstable and stable push-up endurance. Participants were tested during all testing measures for anterior deltoid, biceps brachii (BB), triceps brachii (TB), and serratus anterior (SA) electromyography (EMG) activity. The training progression consisted of altering the suspension configurations, push-up height, and increasing the number of sets (1-3 sets). The stable group performed 153.3 and 33.8% less repetitions than the Yoak group when performing push-ups on the Yoak device or stable floor, respectively (p = 0.03). Training-induced MVIC forces were 9.2% (p = 0.03) greater for the Yoak vs. the stable group. Regarding neuromuscular efficiency, the Yoak group decreased (30.4%; p = 0.01) and stable group increased (97.8%; p = 0.02) antagonist BB EMG activity from pre- to post-training. Both groups decreased the TB fatigue index from pre- to post-training. Nevertheless, Yoak group demonstrated 12.5% (p = 0.09) and 8.9% (p = 0.02) lower fatigue indexes with TB and SA, respectively, than the stable group. These findings suggest that Yoak training demonstrates superior improvements over stable training for push-up endurance, neuromuscular efficiency, MVIC, and fatigue index. PMID- 29979279 TI - Identifying Contextual Influences on Training Load: An Example in Professional Rugby Union. AB - Dalton-Barron, NE, McLaren, SJ, Black, CJ, Gray, M, Jones, B, and Roe, G. Identifying contextual influences on training load: an example in professional rugby union. J Strength Cond Res XX(X): 000-000, 2018-We aimed to investigate the contextual factors influencing training load (TL), as determined by session rating of perceived exertion (sRPE-TL), accumulated within a match-to-match microcycle in rugby union players. Session rating of perceived exertion-TL data were collected daily from 35 professional rugby union players from the same team in the English Championship over the course of an in-season period. Players were split by positional groups (backs and forwards) and sRPE-TL data were categorized as: field-based on-feet sRPE-TL (sRPEField-TL), gym-based sRPE-TL (sRPEGym-TL), and the total summation of both (sRPETotal-TL). Three 2-level linear mixed models were built for each dependent variable in each positional group, with magnitude based inferences applied. Long between-match recovery cycles (>=7 days) resulted in very likely to almost certainly small to moderate increases in sRPE-TL for all modalities and positions (fixed effect [mean range] = 28.5%-42.0%), apart from sRPEField-TL for forwards. For backs, there was a very likely small decrease in sRPEField-TL as the season progressed (-16.7% per trimester). Losing the last league match was associated with very likely and almost certainly small decreases in sRPETotal-TL and sRPEGym-TL for backs (-20.7% and -36.4%, respectively). Losing the last match in any competition resulted in a very likely small increase in sRPEField-TL (21.2%) and a possibly small decrease sRPEGym-TL (-18.5%) for backs-with a likely smaller sRPEGym-TL for forwards (-33.4%). The strength of the upcoming opposition had no effect on sRPE-TL. Our findings highlight some of the multifactorial contextual factors that must be considered when planning and evaluating training microcycles. PMID- 29979280 TI - Influence of Muscle Quality on the Differences in Strength From Slow to Fast Velocities in Career Firefighters. AB - Gerstner, GR, Giuliani, HK, Mota, JA, and Ryan, ED. Influence of muscle quality on the differences in strength from slow to fast velocities in career firefighters. J Strength Cond Res 32(10): 2982-2986, 2018-The purpose of this study was to examine the relationship between ultrasound-derived muscle quality and the %decrease in peak torque (PT) from slow to fast velocities in career firefighters. Thirty-nine male career firefighters (mean +/- SD: age = 36.90 +/- 6.87 years; stature = 180.93 +/- 6.98 cm; mass = 109.30 +/- 20.57 kg; and body mass index [BMI] = 33.24 +/- 4.95 kg.m) performed 3 maximal concentric isokinetic contractions at a slow (1.05 rad.s) and fast (4.19 rad.s) velocity in random order. The velocity-related decrease in PT was calculated as the %decrease from 1.05 to 4.19 rad.s. Ultrasonography was used to determine subcutaneous fat corrected echo intensity (EI) to represent muscle quality before strength testing. The results indicated that there was a significant relationship between EI and %decrease in PT while adjusting for age (rpartial = 0.331, p = 0.042), and age and BMI (rpartial = 0.325, p = 0.050). These findings suggest that velocity impaired isokinetic strength may be influenced by alterations in skeletal muscle tissue composition. Future studies are needed to determine whether the %decrease in PT is related to performance during critical firefighter tasks. PMID- 29979281 TI - Efficacy of Hot Yoga as a Heat Stress Technique for Enhancing Plasma Volume and Cardiovascular Performance in Elite Female Field Hockey Players. AB - Perrotta, AS, White, MD, Koehle, MS, Taunton, JE, and Warburton, DER. Efficacy of hot yoga as a heat stress technique for enhancing plasma volume and cardiovascular performance in elite female field hockey players. J Strength Cond Res 32(10): 2878-2887, 2018-This investigation examined the efficacy of hot yoga as an alternative heat stress technique for enhancing plasma volume percentage (PV%) and cardiovascular performance. Ten international caliber female field hockey players completed six 60-minute hot yoga sessions using permissive dehydration over 6 days, followed by a 6-day national team camp. Changes in PV% were examined throughout the intervention and postintervention period. A graded maximal exercise test was performed in a thermoneutral environment (23.2 +/- 1.0 degrees C) 24 hours before and 24 hours after intervention. Six days of hot yoga initiated a moderate state of hypovolemia (PV% = -3.5%, 90% confidence limit [CL] [-6.9 to -0.13]), trivial improvements in maximal aerobic power (V[Combining Dot Above]O2max) (effect size [ES] = 0.06, 90% CL [-0.16 to 0.28]), and run time to exhaustion (ES = 0.11, 90% CL [-0.07 to 0.29]). Small meaningful improvements were observed in running speed (km.h) at ventilatory threshold (VT1) (ES = 0.34, 90% CL [-0.08 to 0.76]), VT2 (ES = 0.53, 90% CL [-0.05 to 1.1]), along with adaptations in the respiratory exchange ratio during high-intensity exercise (ES = -0.25, 90% CL [-0.62 to 0.12]). A large plasma volume expansion transpired 72 hours after intervention (PV% = 5.0%, 90% CL [1.3-8.7]) that contracted to a small expansion after 6 days (PV% = 1.6%, 90% CL [-1.0 to 4.2]). This investigation provides practitioners an alternative heat stress technique conducive for team sport, involving minimal exercise stress that can preserve maximal cardiovascular performance over periodized rest weeks within the yearly training plan. Furthermore, improvements in submaximal performance and a delayed hypervolemic response may provide a performance-enhancing effect when entering a 6-day competition period. PMID- 29979282 TI - The Golf Movement Screen Is Related to Spine Control and X-Factor of the Golf Swing in Low Handicap Golfers. AB - Gould, ZI, Oliver, JL, Lloyd, RS, Neil, R, and Bull, M. The golf movement screen is related to spine control and x-factor of the golf swing in low handicap golfers. J Strength Cond Res XX(X): 000-000, 2018-The aim of the study was to investigate the association between the golf movement screen (GMS), x-factor, which is the separation between the upper torso and pelvis rotation, and biomechanical movements of the pelvis, thorax, and spine during the backswing and impact of a golf shot in low handicap golfers. In total, 62 golfers were involved in this study (n = 40 male, n = 22 female); the mean age of the sample was 15.4 +/- 2.4 years. For the GMS, all participants were assessed on their movement ability over a total of 10 different exercises. After a thorough warm-up routine of practice swings, each golfer then performed a single trial for biomechanical analysis. Biomechanical data were collected using an electromagnetic tracking system. Four of the 10 exercises had a significant correlation with x-factor (r = 0.25-0.33; p < 0.05). Four exercises had moderate correlations with spine rotation at the top of backswing. Spine side bend had a significant correlation with 9 of the 10 exercises and total GMS score (r = 0.26-0.53, p < 0.05). Movements of the pelvis and thorax at the top of backswing had minimal associations with the GMS. At impact, trunk inclination, thoracic rotation, and squat had small to moderate significant relationships with biomechanical movements (p < 0.05). Movement competency, as measured by the GMS, is associated with important aspects of swing mechanics. In particular, golfers who achieve better scores in the GMS have better spine control and can create a greater x factor during the golf swing. PMID- 29979283 TI - Acute Hormone Responses Subsequent to Agonist-Antagonist Paired Set vs. Traditional Straight Set Resistance Training. AB - de Souza, JAAA, Scudese, E, Paz, GA, Salerno, VP, Vigario, PdS, Miranda, H, and Willardson, JM. Acute hormone responses subsequent to agonist-antagonist paired set vs. traditional straight set resistance training. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to compare acute hormone responses and rating of perceived exertion (OMNI-Res) subsequent to the agonist-antagonist paired set (PS) vs. the traditional straight set (TS) resistance training method. Twelve recreationally trained men (25.7 +/- 4.7 years, 173 +/- 6.3 cm and 71.5 +/ 6.6 kg) participated in the current study. After 10 repetition maximum (RM) load determination, each subject performed the following 2 experimental sessions in random order: TS session-3 sets of 10 repetitions at 85% of 10RM for the machine seated row and barbell bench press with 2-minute rest intervals between sets; and PS-3 sets of 10 repetitions with 85% of 10RM alternating machine seated row and barbell bench press for the total of 6 PSs with 2-minute rest intervals between sets. Total testosterone (TT), free testosterone (FT), cortisol, TT/cortisol ratio, growth hormone (GH), and blood lactate concentrations were measured before workout and immediately after workout and 15 and 30 minutes after workout. The OMNI-RES was recorded at the end of each set for both exercises within each session. Under the TS session, TT significantly increased immediately post workout vs. the pre-workout time point. For the PS session, TT significantly decreased at 30-minute post-workout vs. the immediate post-workout time point, whereas, FT significantly increased immediately post-workout and 15-minute post workout vs. the pre-workout time point. For the TS session, GH significantly increased immediately post-workout, and at the 15- and 30-minute post-workout time points vs. the pre-workout time point, respectively. For the PS session, GH was significantly increased immediately post-workout vs. the pre-workout time point. Blood lactate significantly increased at all post-workout time points vs. the pre-workout time point under both sessions. The cortisol and TT/cortisol ratio showed no differences between sessions. In conclusion, from an acute standpoint, the TS approach showed a tendency to cause greater disruption in hormone levels, despite the lack of significant differences vs. the PS approach at all time points. However, both strategies may promote similar acute hormone responses. PMID- 29979284 TI - Introduction to Periodic Discharges Volume II. PMID- 29979285 TI - Ictal-Interictal Continuum. AB - The term "ictal-interictal" continuum has seen wide adoption in the critical care EEG domain, referring to the presence of abnormal periodic activity on the scalp EEG variably associated with seizures. The historical origin of the ictal interictal continuum concept is discussed with a review of known and surmised physiological mechanisms for their origin and relationship to seizures. Therapeutic approaches to patients exhibiting ictal-interictal continuum EEG patterns are reviewed, and some open scientific questions highlighted. Further understanding of the ictal-interictal continuum is likely to significantly improve the care of the critically ill neurological patient. PMID- 29979286 TI - Neuroimaging Correlates of Periodic Discharges. AB - Despite being first described over 50 years ago, periodic discharges continue to generate controversy as to whether they are always, sometimes, or never "ictal." Investigators and clinicians have proposed adjunctive markers to help clarify this distinction-in particular measures of perfusion and metabolism. Here, we review the growing number of neuroimaging studies using Fluorodeoxyglucose-PET, MRI diffusion, Magnetic resonance perfusion, Single Photon Emission Computed Tomography, and Magnetoencepgalography to gain further insight into the physiology and clinical significance of periodic discharges. To date, however, no definitive consensus exists regarding the features of periodic discharges that warrant treatment intensification. However, an emerging consilience among neuroimaging modalities suggests that periodic discharges can induce a hyperexcitatory state with associated hypermetabolism and hyperperfusion, which may result in local metabolic failure. PMID- 29979287 TI - The Spectral Footprints of Periodic and Rhythmic Patterns. AB - Visual displays of quantitative EEG, consisting of mathematical processing of EEG signals for graphical display, are powerful tools to enhance review of raw EEG. Quantitative EEG is widely used for seizure detection and for delayed cerebral ischemia detection, and it improves efficiency of long-term monitoring review. Here, we review the signature "footprints" of periodic and rhythmic patterns on quantitative EEG. While changes in the frequency and rhythmicity shown on quantitative EEG can highlight these patterns, review of raw EEG to evaluate and confirm the pattern is vital. PMID- 29979288 TI - Prognosis of Periodic and Rhythmic Patterns in Adult and Pediatric Populations. AB - Although electrographic seizures are known to have an outcome on clinical prognosis, the implications of periodic and rhythmic patterns are less clear. The outcomes of adults with these patterns have been reported and are often poor; however, the outcomes in pediatric populations are less well characterized and may be different than in the adult population, as the etiologies of periodic and rhythmic patterns may differ in children and adults. In adults, generalized periodic discharges are highly associated with toxic-metabolic disturbances, infection, and anoxic injury; 30% to 64% of patients have poor outcomes. By contrast, in pediatric patients, generalized periodic discharges are more commonly associated with refractory status epilepticus, with good outcomes in 50% to 77%. The underlying etiology of the periodic or rhythmic pattern has a large influence on overall morbidity and mortality. PMID- 29979289 TI - Approach to Managing Periodic Discharges. AB - Use of continuous EEG monitoring in the intensive care unit setting has increased detection of not only subclinical seizures, but also patterns of discharges that have epileptiform features and periodicity yet do not meet the criteria for seizures. These periodic discharges present a clinical challenge: some patterns may reflect brain injury that has already occurred, although there is evidence that some periodic discharges represent an ongoing process causing additional brain injury and necessitate treatment. Herein, we review the available data regarding the clinical significance of different categories of periodic discharges, specifically those that have features physiologically similar to seizures. We propose a stepwise approach to assessment and management of periodic discharges and lay out the general paradigm of (1) clinical assessment including benzodiazepine trial, (2) EEG assessment, with a focus on discharge frequency, and (3) integration of adjunctive data such as neuroimaging and metabolic data when available. A flowchart is provided to simplify and summarize this approach. The goal of this approach is to treat patterns associated with increased risk of seizures and/or additional brain injury, while avoiding unnecessary interventions. PMID- 29979290 TI - Multimodal Approach to Decision to Treat Critically Ill Patients With Periodic or Rhythmic Patterns Using an Ictal-Interictal Continuum Spectral Severity Score. AB - We propose a comprehensive review of the subject of epileptiform and potentially harmful EEG patterns that lie on the interictal continuum (IIC) to help with therapeutic decision-making and target future research. This approach to "electro physiological SE" encompasses five dimensions of the IIC: it characterizes a periodic or rhythmic pattern, not only regarding its ictal morphology and potential harm with secondary neuronal injury, but also addresses the "metabolic footprint," clinical repercussion, and epileptogenic potential. Recent studies have attempted to determine and qualify the ictal nature and the epileptogenic potential (i.e., risk of subsequent acute seizures) of particular IIC patterns and their intrinsic EEG characteristics. Others have correlated non-convulsive seizures with cognitive outcomes beyond mortality; non-convulsive seizures and sporadic, periodic, or rhythmic discharges to encephalopathy severity; and the spectrum of periodic or rhythmic patterns to measurable secondary brain injury. Equivocal periodic or rhythmic patterns on the IIC are frequently encountered in critical care neurology where clinicians often incorporate advanced neuroimaging, metabolic neuromonitoring, and anti-seizure drug short trials, in an effort to gauge these patterns. We propose portraying the IIC with a multiaxial graph to disambiguate each of these risks. Quantification along each axis may help calibrate therapeutic urgency. An adaptable scoring system assesses which quasi ictal EEG patterns in this spectrum might reach the tipping point toward anti seizure drug escalation, in neurocritically ill patients. PMID- 29979291 TI - Advancing education and advancing science. PMID- 29979293 TI - When to consider a genetic test. PMID- 29979292 TI - Stewarding the nurse practitioner role in interdisciplinary education. PMID- 29979294 TI - Importance of a team approach to recommending the human papillomavirus vaccination. AB - BACKGROUND AND PURPOSE: Few studies have examined human papillomavirus (HPV) vaccine communication in the context of the health care team. METHODS: In 2016, the investigators conducted a national, online survey of U.S. parents who reported having discussed HPV vaccination with their adolescent's health care team. Multivariable logistic regression assessed associations between HPV vaccine initiation (>=1 dose) and having: 1) discussed HPV vaccination with multiple team members and 2) received congruent recommendations about HPV vaccination. CONCLUSIONS: Of the 795 parents in the sample, about half (52%) reported discussing HPV vaccination with multiple team members, including nurse practitioners, nurses, and physicians. Most reported receiving congruent recommendations for (76%) or against (12%) HPV vaccination; few (12%) received mixed recommendations. Parents who discussed HPV vaccination with multiple team members had greater odds of series initiation (odds ratio [OR] = 2.34, 95% CI: 1.61-3.40), whereas those who received mixed versus congruent recommendations for HPV vaccination had lower odds of vaccination (OR = 0.56, 95% CI: 0.33-0.95). IMPLICATIONS FOR PRACTICE: Findings suggest that a coordinated team approach to recommendations may encourage HPV vaccination. Nurse practitioners are well positioned to facilitate coordination efforts within their clinical practices. PMID- 29979296 TI - Ultra-long-acting insulins: A review of efficacy, safety, and implications for practice. PMID- 29979295 TI - Ultra-long-acting insulins: A review of efficacy, safety, and implications for practice. AB - BACKGROUND AND PURPOSE: In the past decade, there has been much advancement in oral antidiabetic agents, but few changes in insulin therapy. With the addition of the ultra-long-acting insulins, insulin glargine U300 (IGlar 300) and insulin degludec (IDeg 100 and IDeg 200), it is important to understand key aspects in the agents' clinical properties, efficacy, safety, dosing, packaging, and place in therapy. METHODS: A literature review was conducted using PubMed database and was limited to English, full-text articles published from January 2000 to January 2018. The following search terms were used: insulin glargine 300, insulin degludec, Toujeo, Tresiba, and ultra-long-acting insulin. CONCLUSIONS: These agents are longer acting with sustained insulin coverage as compared with other basal insulins while having a low potential for hypoglycemia. Efficacy and safety profiles are quite good, and potential for weight gain was similar to IGlar 100. IMPLICATIONS FOR PRACTICE: Depending on the patient's needs, these newer agents may offer some advantages. Insulin glargine U300 and IDeg 200 are concentrated, allowing for administration of large doses by less volume, thereby theoretically improving absorption. For patients needing flexible dosing, IDeg may be beneficial. The ultra-long-acting agents may also be useful if it is suspected that the basal insulin is not lasting the entire day. PMID- 29979297 TI - Implementing a patient-centered walking program for residents in long-term care: A quality improvement project. AB - BACKGROUND AND PURPOSE: This quality improvement (QI) project was designed to increase walking activity for eligible residents in long-term care (LTC). Walking programs have positive benefits; however, they are underused in LTC. METHODS: The Model for Improvement and Plan-Do-Study-Act cycles were used to implement the key components including building a guiding coalition, environment and policy assessment, development of a patient-centered walking program protocol, staff education, mobility huddle to motivate and mentor staff, and ongoing evaluation and feedback. RESULTS: Of the 78 residents screened for walking activity, 13 (17%) were eligible. Data were collected weekly. After 20 weeks, 69% (n = 9) of the enrolled residents were still in the program. The majority of residents were provided walking activity between 60% and 90% of the time. None of the residents experienced a fall during the activity. Average adherence to documenting the activity was 79%. CONCLUSIONS: The QI project provided the implementation and evaluation of a consistent walking program in a LTC setting. IMPLICATIONS FOR PRACTICE: The project findings may assist nurse practitioners in implementing QI initiatives in LTC to increase walking activity of eligible residents and aid in evaluating those programs. However, leadership commitment and ongoing support are essential to sustain the effectiveness of a program. PMID- 29979299 TI - Current treatment paradigm and landscape for the management of chronic idiopathic constipation in adults: Focus on plecanatide. AB - BACKGROUND AND PURPOSE: Chronic idiopathic constipation (CIC) is a prevalent disorder affecting productivity, quality of life, and health care resource utilization. Nurse practitioners (NPs) play a critical function in managing patients presenting with CIC, with roles including evaluation, diagnosis, treatment decisions, and patient education. For adults with inadequate response or tolerability issues using over-the-counter treatments, three prescription agents (plecanatide, linaclotide, and lubiprostone) are available in the United States to treat CIC, of which plecanatide was mostly recently approved. This review provides NPs with a current overview and summary of plecanatide in the current treatment landscape for CIC. METHODS: PubMed was searched for the literature regarding clinical practice guidelines and published trial data for lubiprostone, linaclotide, and plecanatide in CIC. CONCLUSIONS: Efficacy and safety comparisons between prescription agents are limited beacause of the differences in trial duration and primary end points (all different). Generally, plecanatide and linaclotide demonstrated similar efficacy, with plecanatide demonstrating lower rates of adverse events. IMPLICATIONS FOR PRACTICE: The success of CIC treatment can be affected by patient adherence to the regimen, which is dependent on the efficacy and tolerability of treatment. Plecanatide is a promising option for patients whose CIC symptoms are not adequately controlled using their current treatment approach. PMID- 29979298 TI - Takotsubo cardiomyopathy: A discussion and case study. AB - BACKGROUND AND PURPOSE: Takotsubo cardiomyopathy (TCM), first reported by Japanese doctors, has gained an overall acknowledgment as an independent malady of international attention. It resembles the presentation of an acute myocardial infarction but lacks ischemic myocardial tissue. The objective of this article is to review the physiology, diagnostics, treatment, and complications of TCM and report a case study of a patient who developed TCM. METHODS: Observation through direct patient care allowed for data collection of this unique medical phenomenon. Supporting information was obtained via investigation of scholarly articles on TCM over the past 10 years. CONCLUSIONS: Although TCM is usually transient, it is important to quickly differentiate TCM from other more serious medical conditions, such as myocardial infarction, pulmonary embolism, and pheochromocytoma. Typical diagnostic workup includes electrocardiography, cardiac biomarkers, and echocardiography or coronary angiography. Complications include cardiogenic shock, left ventricular wall rupture, and life-threatening arrhythmias. IMPLICATIONS FOR PRACTICE: The advanced practice nurse (APN) is instrumental in differentiating between TCM versus acute myocardial infarction, heart failure, pulmonary edema, dynamic outflow obstruction, and cardiogenic shock. Because of these possible acute and critical presentations, prompt recognition and intervention for patients with TCM are priorities for nurse practitioners. PMID- 29979300 TI - Mrs. Chase. PMID- 29979302 TI - Osteoporosis: A Clinical Update for Home Healthcare Clinicians. AB - Home healthcare clinicians are in a unique position to assess patients for risk of osteoporosis and fragility fractures. They are also key members of the interdisciplinary care team in the recovery of patients with fragility fractures. Home healthcare clinicians care for an aging patient population with diverse conditions and multiple medications that can increase their risk of osteoporosis. Bone mineral density in addition to an evaluation of clinical risk factors are necessary to diagnose osteoporosis; DEXA and FRAX are the tools available. Undertreatment of osteoporosis is common among community dwelling elderly adults. Lack of patient adherence and insufficient physician prescription of medications are common. There are a wide array of osteoporosis medications and patients need education about their use. With the growing number of older adults in the population, increasing numbers will be vulnerable to osteoporosis and fragility fracture. Home healthcare clinicians need to be proactive to assess the aging population and assist in their treatment of this common disorder. PMID- 29979304 TI - Decreasing Urinary Incontinence in Home Healthcare. AB - Urinary incontinence (UI) in older adult patients poses a risk for complications and hospitalization. The aim of this quality improvement project was to develop and implement a protocol to promote continence in older adults with UI. Data were collected from a convenience sample of 26 participants, 80 years of age or older, in a midsize suburban home care agency. All participants were diagnosed with UI as documented in the Outcomes and Assessment Information Set (OASIS). OASIS question M1610 was used to identify patients with UI status, and M1650 was used, to identify UI frequency. The outcomes for these questions were assessed to examine change over time in UI status and frequency. Eligible patients completed a 3-day bladder diary, then patient education was conducted on UI, risk factors, bladder training, pelvic floor exercises, and hydration/nutrition parameters. Patients then completed 3-day bladder diaries postintervention. At pretest, 100% of the participants were incontinent. At posttest, 24 participants (92.3%) were incontinent. The results suggest that the median frequency of UI declined overtime from 2 (range: 1-4) at pretest to 1 (range: 0-4) at posttest. This decline was statistically significant (z = -3.83; p < .001). Future studies should examine changes in the UI complications and hospitalization rates. PMID- 29979303 TI - Preparing Clinicians for Transitioning Patients Across Care Settings and Into the Home Through Simulation. AB - Assuring home care staff competencies through simulation has the potential to improve care transitions and clinical outcomes. Recreating a home environment can be used for orientation of home care staff and to meet other learning needs. Lessons learned from the use of simulation in a geriatric nursing course in a prelicensure program can be used to prepare clinicians for transitioning patients across care settings. With simulation, learners can identify challenges in patient safety, pain management, and management of patients' cognitive decline as well as learn how to communicate with patients, family members, and the healthcare team. Simulation, as an interactive pedagogy, provides opportunities for learners to practice assessment, monitoring, and patient care in a controlled, safe, risk-free environment. Following participation in a simulation, learners are given the opportunity to reflect on ways to improve patient care when transitioning from acute to home care settings. Simulations described in this article can be used for orientation of staff to a home healthcare agency because they allow clinicians to hone the skills necessary for patient care in the home. Staff educators can also use simulation to validate staff competencies in caring for patients at home. PMID- 29979306 TI - Comparing Functional Status Oasis Ratings Between Occupational Therapists, Physical Therapists, and Registered Nurses in Home Healthcare. AB - The Outcome and Assessment Information Set (OASIS) is mandated for use in home healthcare. The purpose of this descriptive study was to compare occupational therapy (OT) OASIS rating of functional status items compared with registered nurse (RN) and physical therapy (PT) ratings. Functional status data were collected on 80 patients: 40 patients comparing RN with OT and 40 patients comparing PT with OT. RN and PT visits were made first and the OT visit followed. There were no items with perfect agreement. The highest agreement was for feeding (76.3%) and the lowest items were for toileting hygiene and ambulation (37.5%). The largest discrepancy scores were for grooming and dressing lower body. Discipline-specific discrepancy scores were mixed. Krippendorff's alpha scores were almost all above the required minimum of 0.80. There are substantial differences in the functional status items that may reflect differences in the disciplinary training and approaches to patient care. These findings also raise some concerns about OASIS reliability and consistency of measurement. PMID- 29979305 TI - Medication Management in Municipality-Based Healthcare: A Time and Motion Study of Nurses. AB - The objective of this observational time and motion study was to increase our understanding of how nurses in home healthcare currently distribute their work time with a focus on the medication management process. The research was conducted in four municipalities in the southern part of Sweden. Participants were nurses working in home healthcare. The study measured proportion of time, comparison of proportions of time, proportion of time spent multitasking, and rate of interruptions per hour. Of total observed time, 20.4% was spent on medication management and of these tasks the highest proportion of time was spent on communications and dispensing medications. Nurses in nursing homes spent more time (23.0% vs. 17.4%, p = 0.001) on medication management than nurses in private homes. Nurses spent 47.9% of their time completing tasks with someone else, including patients, but had minimal interaction with prescribers. We observed a rate of 1.2 (95% CI 1.1-1.4) interruptions per hour on average and 30% of all interruptions occurred during medication management tasks. Nurses spent 3.7% of their time multitasking. Interruptions while performing medication-related tasks were common, as well as multitasking. Causes and consequences of the results need to be addressed in order to improve the safety of medication management for patients receiving municipality-based home care. PMID- 29979307 TI - Home Healthcare and Hospice: A Pacific Islands Perspective. AB - The Pacific Islands Geriatric Education Center of the University of Hawaii conducted situational assessments of caregivers, older adults, and healthcare professionals in the Republic of Palau. The findings revealed an urgent need for a solution to the identified crisis of an aging population, increasing chronic diseases and their corresponding impact on caregivers and society. In 2010, the National Healthcare Financing Act was signed into law, becoming Palau's first step in helping residents and workers in Palau pay for medical expenses. This program is referred to as the Health Care Fund and consists of two parts: National Health Insurance and Medical Savings Account. Advocacy and promotion of home healthcare services in Palau was facilitated by the Pacific Islands Geriatric Education Center. Because of these efforts, systems changed to establish home healthcare services and expand the Health Care Fund with a proposed Home Health Insurance Benefit from the National Health Insurance. This is a huge leap forward to improve access to care for older adults and homebound in Palau. PMID- 29979308 TI - Vision Care and Diabetes. PMID- 29979309 TI - The Value of Interdisciplinary Teamwork for Total Joint Replacement Rehabilitation. PMID- 29979310 TI - Correct Use of Inhalers: Help Patients Breathe Easier. PMID- 29979311 TI - Beware the Batch Signature. PMID- 29979312 TI - A Day in the Life of a New Orleans Home Care Nurse. PMID- 29979313 TI - What Is an LCD and Why Do I Need to Know? PMID- 29979314 TI - Let's Figure Out a Way to Welcome New Grads Into Home Healthcare. PMID- 29979315 TI - Back to the Future for Home-Based Healthcare. PMID- 29979316 TI - Osteoporosis: A Clinical Update for Home Healthcare Clinicians. PMID- 29979317 TI - Measurement of physical activity in clinical practice and research: advances in cancer and chronic respiratory disease. AB - PURPOSE OF REVIEW: Physical activity has emerged as an important health outcome and its assessment, in particular with objective monitors, has proliferated in recent years. This review considers recent advances in physical activity measurement and clinical trials in cancer and chronic respiratory diseases where physical activity was a primary or key secondary outcome focusing on methodological learning points. RECENT FINDINGS: There is growing data on (i) the validity of commercial 'consumer' physical activity monitors, e.g. FitBit, and (ii) the role of hybrid physical activity assessments; combining objective and subjective measures to understand physical activity quantity and quality. In both cases, adherence is challenging and can be optimized using short monitoring protocols, e.g., 3-4 days, and by providing clear instructions and support materials to participants. Studies in cancer and chronic respiratory disease have found mixed effects from physical activity interventions based on pedometers, behavior change techniques, online resources, and/or therapeutic nutrition. The most responsive physical activity outcomes and minimum clinically important differences are still to be understood. SUMMARY: Physical activity measures provide an opportunity to detect changes in health behavior. However, measuring physical activity as a trial endpoint is challenging and focusing effort to ensure optimal participant compliance is important. PMID- 29979318 TI - Peer support for people with advanced cancer: a systematically constructed scoping review of quantitative and qualitative evidence. AB - PURPOSE OF REVIEW: The number of people living with advanced cancer is increasing, and appropriate support to this population is essential. Peer support is increasingly advocated as a component of care, but little is known about how to provide this in the context of advanced cancer. This review describes the experience and impact of different forms of peer support for people with advanced cancer. RECENT FINDINGS: Data from 22 articles were reviewed, primarily descriptive studies. They describe three forms of peer support (one-to-one, group, and online), reaching primarily those who are women, middle-aged, and well educated. Only two studies focused on support to people with advanced cancer, but those with advanced cancer were frequent users of all forms of peer support. Benefits of peer support were described, but no data were presented to allow a determination of the best form of support for people with advanced cancer. SUMMARY: Practitioners can be assured that peer support is likely to be beneficial and provide care that complements that of clinicians. However, there is a need for a comprehensive programme of high-quality evaluative research of peer support for people with advanced cancer. PMID- 29979319 TI - Relevance of poly (ADP-ribose) polymerase inhibitors in prostate cancer. AB - PURPOSE OF REVIEW: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved drugs for the treatment of ovarian and breast cancer and currently under investigation for the treatment of prostate cancer and other malignancies with aberrations in homologous recombination DNA repair.This review summarizes literature published during 2017 concerning the relevance of PARPi in prostate cancer and presents new evidence on mechanisms of resistance and biomarkers of response. RECENT FINDINGS: The approval of several PARPi (olaparib, rucaparib, and niraparib) has driven the focus of anticancer treatment on synthetic lethality in prostate cancer too. Despite anecdotal reports of long-term responders, most cancers become resistant to these therapies.Different mechanisms of primary and acquired resistance to PARPi have been recently investigated including loss of PARP1 expression, BRCA mutations with partial function, and acquisition of reversion restoration of function mutations. SUMMARY: Here, we discuss the importance of PARPi in metastatic castration-resistant prostate cancer and discuss the possible mechanisms of resistance. PMID- 29979320 TI - Local ablative stereotactic body radiotherapy for oligometastatic prostate cancer. AB - PURPOSE OF REVIEW: The oligometastases is considered an intermediate state of the disease between localized and wide spread metastases. Local ablative therapy to oligometastatic prostate cancer is gaining significant traction and stereotactic body radiotherapy (SBRT) is an emerging treatment modality for this patient population. In this review, we report our literature review of SBRT to prostate oligometastases. Current evidence on the role of SBRT in oligometastatic prostate cancer reported in the last 10 years was summarized. Criteria for inclusion included studies with prostate cancer only as the primary site. RECENT FINDINGS: The unique properties of the oligometastatic prostate cancer appear to carry a better prognosis than wide spread metastatic disease, especially if these metastases are amenable to local ablative therapies. Our literature review revealed that local ablative therapy, using SBRT to prostate oligometastases, is associated with significant 2-years local control and acceptable toxicity profile. SUMMARY: SBRT to oligometastatic prostate cancer patients is feasible and carries an acceptable toxicity profile. The randomized phase II and III trials, currently underway, should clearly define the real benefit of this approach on progression-free and overall survival outcomes. PMID- 29979321 TI - Practical approach for endoscopic resection of colorectal lesions: when West meets East. PMID- 29979322 TI - Treatment of portal vein thrombosis in cirrhosis: is it really needed? PMID- 29979324 TI - Homocysteine: a new diagnostic marker for spontaneous bacterial peritonitis? PMID- 29979326 TI - Impact of Artificial Intelligence in the Brave New Medical World: No Time to Go Back. PMID- 29979323 TI - Folate-dependent constructive effect of cirrhosis on hyperhomocysteinemia. PMID- 29979327 TI - Refinement and Evaluation of Modified Minimally Invasive Harvest Technique for Subepithelial Connective Tissue. AB - INTRODUCTION: The aim of this paper was to refine the modified minimally invasive single-incision technique (MSIT) into 6 steps that are easy to execute. The advantage of this modification was evaluated and compared with the traditional trap-door incision technique (TDIT). Several other harvesting techniques, suturing techniques, indications, contraindications, and limitations were also summarized. MATERIALS AND METHODS: A total of 40 patients presenting with multiple areas of gingival recession were recruited for this study. All patients were randomly assigned to either the MSIT or TDIT group. Standard periodontal instruments and crossed horizontal suspension sutures were used for both procedures. Harvesting and suturing time, verbal rating scale (VRS), and an early wound-healing index (EHI) were recorded. RESULTS: The total operating time, and particularly the suturing time, was shorter in the MSIT group (267.70 +/- 20.24 seconds) than the TDIT group (298.20 +/- 21.07 seconds), and the difference was statistically significant (P < 0.05). However, there was no significant difference in pain level between the 2 groups according to the VRS evaluation (P = 0.3658). One week postsurgery, the EHI of the MSIT group (2.00 +/- 0.95) was significantly lower than the TDIT group (2.85 +/- 1.15) (P < 0.05). DISCUSSION: The 6-step MSIT is more predictable and easy to execute, which decreases the challenge for both dentists and patients. Favorable outcomes occurred because of the streamlined minimally invasive procedure and favorable postoperative recovery. PMID- 29979329 TI - Alopecia due to high androgen index contraceptives. AB - Adverse reactions to hormonal contraceptives are a common patient concern. Alopecia, an adverse reaction to androgen activity caused by the progestin component of hormonal contraceptives, can cause considerable psychosocial distress for women. This article discusses how to identify the level of androgen activity in certain progestins, how increased androgen activity can lead to hair loss, and alternatives for patients experiencing androgenic alopecia due to high androgen index contraceptives. PMID- 29979330 TI - Understanding osteosarcomas. AB - This article reviews the cause, clinical presentation, diagnostic methods, and management of osteosarcoma, the most common primary bone tumor and third most common cancer among children and adolescents. In the 1970s, the introduction of adjuvant chemotherapy following tumor resection improved overall 10-year survival from 30% to about 50% of patients. However, since that change in management strategy, the survival rate has since plateaued, with no improvement in overall 10-year survival since the 1990s. A better understanding of this disease is the first step to help improve these numbers. PMID- 29979331 TI - Risk Factors for Mortality in Children Admitted for Suspected Malaria to a Pediatric Emergency Ward in a Low-Resource Setting: A Case-Control Study. AB - OBJECTIVES: To identify the risk factors for mortality after admission for suspected malaria in a pediatric emergency ward in Sierra Leone. DESIGN: Retrospective case-control. SETTING: Pujehun Hospital Pediatric Ward in Pujehun, Sierra Leone. PATIENTS: All cases were pediatric deaths after admission for suspected malaria at the Pujehun Hospital Pediatric Ward between January 1, 2015, and May 31, 2016. The case-control ratio was 1:1. The controls were infants admitted at Pujehun Hospital Pediatric Ward for malaria and discharged alive during the same period. Controls were selected as the next noncase infant admitted for malaria and discharged alive, as recorded in local medical records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Children characteristics, vital variables on hospital access, comorbidity status at admission, antibiotic and antimalarial therapy at admission; presence of hematemesis, respiratory arrest or bradypnea, abrupt worsening, and emergency interventions during hospital stay; final diagnosis before discharge or death. In total, 320 subjects (160 cases and 160 controls) were included in the study. Multivariable analysis identified being referred from peripheral health units (odds ratio, 4.00; 95% CI, 1.98-8.43), cerebral malaria (odds ratio, 6.28; 95% CI, 2.19-21.47), malnutrition (odds ratio, 3.14; 95% CI, 1.45-7.15), dehydration (odds ratio, 3.94; 95% CI, 1.50-11.35), being unresponsive or responsive to pain (odds ratio, 2.17; 95% CI, 1.15-4.13), and hepatosplenomegaly (odds ratio, 3.20; 95% CI, 1.74-6.03) as independent risk factors for mortality. CONCLUSIONS: Risk factors for mortality in children with suspected malaria include cerebral malaria and severe clinical conditions at admission. Being referred from peripheral health units, as proxy of logistics issue, was also associated with increased risk of mortality. These findings suggest that appropriate interventions should focus on training and resources, including the increase of dedicated personnel and available equipment. PMID- 29979328 TI - Feasibility of Diffusion Tensor and Morphologic Imaging of Peripheral Nerves at Ultra-High Field Strength. AB - OBJECTIVES: The aim of this study was to describe the development of morphologic and diffusion tensor imaging sequences of peripheral nerves at 7 T, using carpal tunnel syndrome (CTS) as a model system of focal nerve injury. MATERIALS AND METHODS: Morphologic images were acquired at 7 T using a balanced steady-state free precession sequence. Diffusion tensor imaging was performed using single shot echo-planar imaging and readout-segmented echo-planar imaging sequences. Different acquisition and postprocessing methods were compared to describe the optimal analysis pipeline. Magnetic resonance imaging parameters including cross sectional areas, signal intensity, fractional anisotropy (FA), as well as mean, axial, and radial diffusivity were compared between patients with CTS (n = 8) and healthy controls (n = 6) using analyses of covariance corrected for age (significance set at P < 0.05). Pearson correlations with Bonferroni correction were used to determine association of magnetic resonance imaging parameters with clinical measures (significance set at P < 0.01). RESULTS: The 7 T acquisitions with high in-plane resolution (0.2 * 0.2mm) afforded detailed morphologic resolution of peripheral nerve fascicles. For diffusion tensor imaging, single shot echo-planar imaging was more efficient than readout-segmented echo-planar imaging in terms of signal-to-noise ratio per unit scan time. Distortion artifacts were pronounced, but could be corrected during postprocessing. Registration of FA maps to the morphologic images was successful. The developed imaging and analysis pipeline identified lower median nerve FA (pisiform bone, 0.37 [SD 0.10]) and higher radial diffusivity (1.08 [0.20]) in patients with CTS compared with healthy controls (0.53 [0.06] and 0.78 [0.11], respectively, P < 0.047). Fractional anisotropy and radial diffusivity strongly correlated with patients' symptoms (r = -0.866 and 0.866, respectively, P = 0.005). CONCLUSIONS: Our data demonstrate the feasibility of morphologic and diffusion peripheral nerve imaging at 7 T. Fractional anisotropy and radial diffusivity were found to be correlates of symptom severity. PMID- 29979332 TI - The Fragility of Statistically Significant Results in Pediatric Orthopaedic Randomized Controlled Trials as Quantified by the Fragility Index: A Systematic Review. AB - BACKGROUND: The randomized controlled trial (RCT) is the gold standard study design allowing critical comparison of clinical outcomes while minimizing bias. Traditionally clinical trials are evaluated through statistical significance, expressed by P-values and confidence intervals. However, until recently, the robustness of a study's conclusions has been given little attention. A new metric, the fragility index, quantifies the number of patients theoretically required to switch outcomes in order to reverse the study conclusions. The primary aim of our work was to determine the fragility index of RCTs in the pediatric orthopaedic literature. The secondary aim was to determine study factors associated with lower fragility index. METHODS: Pubmed and Embase were systematically searched for pediatric orthopaedic RCTs published September 1, 2006 to September 1, 2016. Two independent reviewers screened titles, abstracts, and manuscripts to identify studies published in English involving 2 treatment arms. Trials without dichotomous primary or secondary outcomes or with patients >18 years were excluded. Data were extracted from each eligible article in duplicate and the fragility index was determined using Fisher exact test, with previously published methods. Univariate analysis was used to determine factors associated with lower fragility index. RESULTS: Seventeen trials were eligible for inclusion. The median treatment arm size was 58 and overall sample size was 116 patients. The median fragility index was 3 (range, 0 to 18). A fragility index of 3 means that just 3 patients would need to switch treatment outcomes in order for the trial results to become statistically nonsignificant. In 1 study, the number of patients lost to follow-up exceeded the fragility index, such that the study conclusions could be completely reversed purely depending on the outcomes of the patients lost to follow-up. Lower fragility index was associated with smaller patient sample sizes and greater P-values. CONCLUSIONS: The fragility index is a useful adjunct metric to the P-value and confidence intervals, allowing analysis of the robustness of study conclusions. RCTs in pediatric orthopaedics often have small sample sizes, many with low fragility indices. Future efforts could focus on encouraging institutional collaboration and patient recruitment with the ultimate goal of improving RCT sample sizes, and potentially improving the robustness of RCT results. LEVEL OF EVIDENCE: Level I. PMID- 29979333 TI - A Common mdr1 Gene Polymorphism is Associated With Changes in Linezolid Clearance. AB - BACKGROUND: Several factors contribute to the high variability of linezolid plasma exposure in patients. Very recently, it has been suggested that linezolid could be an ABCB1 substrate. Therefore, the present clinical study was aimed at investigating whether ABCB1 polymorphisms could predict linezolid pharmacokinetics in 27 critically ill patients. METHODS: Genotypes were assessed through a real-time polymerase chain reaction allelic discrimination system, and linezolid plasma concentrations, considering trough concentration (Ctrough) and area under the time-concentration curve (AUC), were analyzed through a nonlinear mixed-effects modeling approach. RESULTS: A significant effect of abcb1 c.3435C>T polymorphism on linezolid clearance was found, whose values accounted for 13.19 L/h in wild-type homozygotes and 7.82 L/h in the remaining individuals. That difference was statistically significant despite the large interindividual variability (60.8%). Terminal half-life and volume of distribution values significantly differed between c.3435CC and c.3435CT/TT patients (2.78 versus 5.45 hours and 37.43 versus 46.71 L, respectively). On the contrary, a modest trend was observed for the difference in AUC and Ctrough based on c.3435C>T genotypes. Simulation according to the final model revealed that the cumulative response fraction for the AUC/MIC parameter was better for .3435CC individuals compared with individuals carrying at least one c.3435T allele with respect to methicillin-sensitive S. aureus, methicillin-resistant S. aureus, and Streptococcus pneumoniae species. CONCLUSIONS: The obtained results suggest the possible influence of ABCB1 in linezolid pharmacokinetics, bringing new interest for pharmacogenetic analyses in antimicrobial chemotherapy. These analyses could be incorporated in therapeutic protocols for precision medicine, including a combined use of genetic evaluation (for starting dose) and follow-up therapeutic drug monitoring. PMID- 29979334 TI - Retinal Neuronal Loss in Visually Asymptomatic Patients With Myoclonic Epilepsy With Ragged-Red Fibers. AB - BACKGROUND: Myoclonic epilepsy with ragged-red fibers (MERRF, OMIM, #545000) is a rare neurological condition mostly caused by the m.8344A>G mitochondrial DNA pathogenic variant, which can variably affect multiple tissues, including the retina and optic nerve. We report detection of visually asymptomatic neuroretinal loss in 3 patients with genetically confirmed MERRF, using spectral domain optical coherence tomography (SD-OCT). METHODS: All patients underwent a complete ophthalmic examination including assessments of visual acuity, color vision, pupillary reactions, extraocular movements, applanation tonometry, slit-lamp, and dilated fundus examinations. Standard automated perimetry or Goldmann kinetic perimetry was performed, as well as fundus photographs and SD-OCT of the optic nerve head and macula. RESULTS: Despite the absence of visual symptoms in all patients, and normal visual acuity and visual fields in 1 patient, the 3 genetically confirmed patients (point mutations m.8344A>G; age range: 18-62 years) with MERRF-related neurological manifestations, displayed thinning of the retinal nerve fiber layer and variable alterations of the macular ganglion cell complex. CONCLUSIONS: Visually asymptomatic patients with genetically confirmed MERRF can display features of structural neuroretinal loss, quantifiable with SD OCT. Further investigations are needed to establish whether OCT can assess early neurodegeneration in MERRF. PMID- 29979335 TI - Seneca and the First Description of Anton Syndrome. AB - Seneca was a Roman philosopher, politician, and mentor to the young Nero. He later fell in disgrace and was sentenced to death by the Emperor. Seneca left many texts, one of the most influential being his Moral Letters to Lucilius (63 CE). In Letter 50, he describes the case of Harpaste, his wife's foolish slave who acutely became blind. She denied her illness and argued irrationally about room darkness, constantly asking attendants to change her quarters. Harpaste's case, consisting of acutely acquired blindness and anosognosia in the presence of relatively well-preserved cognition, fulfills the clinical criteria for the diagnosis of Anton syndrome, and probably constitutes its first description. PMID- 29979336 TI - Mycoplasma genitalium Infections with Macrolide and Fluoroquinolone Resistance Associated Mutations in Heterosexual African American Couples in Alabama. AB - BACKGROUND: Mycoplasma genitalium (MG) is a sexually transmitted pathogen associated with inflammatory syndromes in men and women. Macrolides and fluoroquinolones are recommended MG treatments. The frequency of MG strains with macrolide resistance-associated mutations (MRMs) and quinolone resistance associated mutations (QRMs) is increasing worldwide, however these data are sparse in populations in the US. METHODS: We investigated the prevalence of MG infections with MRMs and QRMs and MG infection concordance within African American couples in Birmingham, Alabama. We used a real-time PCR to detect MG and identify MRMs. QRMs were detected using traditional PCRs amplifying regions in gyrA, gyrB, parC and parE. MG concordance in couples was evaluated by MG positivity and MG genotypes. RESULTS: Oral, anal, urine, and/or vaginal specimens were tested from 116 couples. Twenty-eight (12.1%) participants comprising 22 couples tested MG positive (11.2% in men and 12.9% in women). MRMs were detected in 17 (60.7%) MG positive participants, with gender-specific resistance rates of 69.2% for men and 53.3% for women. QRMs were detected in 3 (11.1%) MG positive participants, all of whom also had MRMs. By MG positivity status, 27.3% of couples were concordant. If MG strain genotypes are also considered, then concordance was 20.0%. CONCLUSIONS: Among heterosexual African Americans with MG infection, about 60% had strains with MRMs and 11% had strains with both MRMs and QRMs, highlighting the potential for MG treatment failure to not only macrolides, but also quinolones. These findings may help to guide clinicians in MG testing and treatment decisions in the US. PMID- 29979337 TI - Goniotomy Using the Kahook Dual Blade in Severe and Refractory Glaucoma: 6-Month Outcomes. AB - PURPOSE: The purpose of the study is to describe short-term efficacy and safety of goniotomy with trabecular meshwork excision using the Kahook Dual Blade (KDB, New World Medical Inc., Rancho Cucamonga, CA) in patients with severe or refractory glaucoma. METHOD: Retrospective multicentric case series of 53 eyes with severe or refractory glaucoma as defined by ICD-10 conducted in the United States, Mexico, and Switzerland. Primary efficacy outcome was a >=20% decrease in intraocular pressure (IOP) from baseline at 6 months. Secondary efficacy outcome measures were probability of achieving an IOP<=14 or 18 mm Hg at 6 months and the mean IOP change from baseline at 6 months. Medication use required to obtain target IOP at last follow up and adverse effects were analyzed. RESULTS: The proportion of eyes achieving an IOP reduction of >20% from preoperative baseline at 6 months was 57.7% (n=30). The mean IOP decreased from 18.4+/-6.1 mm Hg at baseline to 13.9+/-3.5 mm Hg at month 6 (23.9% reduction; P<0.001). At 6 months, 63.5% and 92.3% achieved an IOP<=14 and <=18 mm Hg, respectively, and the mean number of glaucoma medications was reduced by 1.2+/-1.3 (36.6%) compared with baseline (P<0.001). The most common adverse event was hyphema (n=29, 34.9%) with spontaneous resolution in all cases. No severe complications were reported. One case presented with uncontrolled IOP and required glaucoma drainage device surgery at 1 month. CONCLUSIONS: Goniotomy with trabecular meshwork excision using the KDB could be an alternative surgery for severe or refractory glaucoma, significantly reducing IOP and medication use at 6 months, with a low rate of complications. PMID- 29979338 TI - The Translaminar Pressure Gradient: Papilledema After Trabeculectomy Treated With Optic Nerve Sheath Fenestration. AB - INTRODUCTION: Trans-lamina cribrosa pressure has been postulated to be a contributor in the development of a glaucomatous optic nerve versus optic nerve edema, depending on the pressure gradient. Uncertainty remains in the therapeutic outcome of adjusting this gradient. CASE REPORT: We discuss a unique case of idiopathic intracranial hypertension presenting as asymmetric optic disc edema following trabeculectomy. It was treated via optic nerve fenestration due to the patient remaining symptomatic on maximum tolerated acetazolamide. Intraocular pressure stabilized into target range and the optic nerve edema resolved. CONCLUSIONS: Rarely, intraocular pressure reduction can unmask elevated intracranial pressure, leading to optic nerve edema. Optic nerve sheath fenestration is a practical therapeutic modality to consider when treating this occurrence. PMID- 29979339 TI - Patient Outcomes Following Micropulse Transscleral Cyclophotocoagulation: Intermediate-term Results. AB - PURPOSE: To report the safety and efficacy outcomes following micropulse transscleral cyclophotocoagulation (MPTSCPC) procedure in patients with uncontrolled glaucoma. MATERIALS AND METHODS: Longitudinal retrospective cohort, multicenter study. Patients with different types of glaucoma who underwent MPTSCPC with P3 probe between July 2015 and May 2017. Patients were treated by different glaucoma specialists from 5 different locations (Tulane Study Group). Data on preoperative characteristics, surgical procedure(s) performed, and postoperative outcomes were collected and analyzed. Statistical analysis using logistic regression and Kaplan-Meier analysis was performed with Stata software. Intraoperative and postoperative complications, intraocular pressure, visual acuity, need for incisional glaucoma surgery, need for repeat micropulse, and number of topical medications were studied. RESULTS: One hundred ninety-seven eyes from 161 patients were included. Median follow-up was 12 months [interquartile range (IQR), 6 to 14]. Glaucoma diagnosis included 141 primary open-angle glaucoma (POAG), 8 neovascular glaucoma, and 12 others. The total success rate was 71%. Two percent (4 patients) developed postoperative cystoid macular edema. Preoperative mean intraocular pressure (SD) was 22+/-9 and 16+/-6 mm Hg at last follow-up (P<0.001). Median preoperative logMAR visual acuity (IQR) was 0.4 (0.2 to 1.0) and 0.3 (0.2 to 1.0) at last follow-up (P=0.65, Wilcoxon signed-rank test). Median number (IQR) of topical medications was 3 (1 to 4) preoperative and 2 (1 to 3) at last follow-up (P<0.001). Kaplan-Meier analysis indicated 90% of patients free from repeat MPTSCPC at 12 months. Multivariable logistic regression identified 3 significant independent predictors of total success: diagnosis (P=0.011) (POAG), previous glaucoma surgery (P=0.003), and other concurrent procedures (P=0.013). CONCLUSIONS: Our large longitudinal cohort study has provided evidence that MPTSCPC is a safe and generally effective option in the treatment of POAG up to 12 months. PMID- 29979340 TI - Xen Gel Stent to Resolve Late Hypotony After Glaucoma Drainage Implant Surgery: A Novel Technique. AB - PURPOSE: To describe a new surgical method for treating late profound hypotony in 2 patients with glaucoma drainage implant (GDI). PATIENTS AND METHODS: Two patients, an 85-year-old woman and a 44-year-old woman, presented with choroidal effusions secondary related to chronic hypotony after GDI surgery. A novel technique was performed in both cases to narrow the lumen size of the GDI tube. The GDI tube was exposed and ligated temporarily with a polyglactin suture in both cases. The anterior part of the capsule wall was opened. The Xen stent was removed from its injector and pushed through the posterior orifice of the GDI tube. The whole Xen stent was inserted inside the tube to narrow the lumen size of the GDI tube. Once the Xen had been placed inside the tube lumen, a silk suture was tied around the GDI tube to secure the Xen in position. The ligation suture of the GDI tube was removed and suturing of the conjunctiva was performed. RESULTS: Before restriction of aqueous flow through the GDI, both patients had an intraocular pressure (IOP) of 2 mm Hg and blurry vison of 20/40 to 20/200. Following the Xen implant insertion, IOP ranged between 8 and 20 mm Hg and choroidal effusions resolved, and visual acuity improved. In both cases, IOP remained stable through 1 year of follow-up and no choroidal effusions or macular folds were noticed. CONCLUSIONS: A Xen implant placed inside the GDI tube offers an option for the treatment of chronic hypotony in eyes with GDI. PMID- 29979341 TI - Cypass Supraciliary Stent in Eye With Chronic Angle Closure and Postvitrectomy With Silicone Oil. AB - PURPOSE: To report a case of successful intraocular pressure (IOP) reduction following Cypass supraciliary stent implantation in a postvitrectomized eye filled with silicone oil and chronic angle-closure glaucoma. MATERIALS AND METHODS: This is a case report. RESULTS: A 19-year-old female with chronic angle closure glaucoma underwent combined cataract extraction, goniosynechiolysis and Cypass supraciliary shunt implantation. Patient had a history of proliferative diabetic retinopathy and a tractional retinal detachment, which required pars plana vitretomy and silicone oil implantation, and was subsequently complicated by neovascular glaucoma requiring implantation of an inferior glaucoma drainage device. Approximately 6 months later, the patient's IOP increased to 36 mm Hg on maximum tolerable medical therapy. The patient underwent combined cataract extraction and Cypass implantation and is now controlled with an IOP of 16 mm Hg on 3 classes of medications 6 months postoperatively. CONCLUSIONS: Implantation of a Cypass supraciliary shunt can be an effective means for controlling IOP in patients with chronic angle-closure glaucoma in a postvitrectomized eye with silicone oil implantation and failed glaucoma drainage device. PMID- 29979342 TI - South Carolina SOARS: Save Money, Improve Outcomes, Increase Access, and Remove Barriers. PMID- 29979343 TI - Incidence, Risk Factors and Outcomes of Early Acute Kidney Injury After Heart Transplantation: An 18-year Experience. AB - BACKGROUND: Little is known about the incidence of acute kidney injury (AKI), as defined using the Kidney Disease Improving Global Outcome classification, after heart transplantation (HT). Our objective was to evaluate the impact of AKI in a cohort of HT recipients. (Setting: University Hospital.) METHODS: We studied 310 consecutive HT recipients from 1999 to 2017, with AKI being defined according to the Kidney Disease Improving Global Outcome criteria. Risk factors were analyzed by multivariable analyses, and survival by Kaplan-Meier curves and a risk adjusted Cox proportional hazards regression model. RESULTS: One hundred twenty five (40.3%) patients developed AKI, with 73 (23.5%), 18 (5.8%), and 34 (11%) patients having AKI stages 1, 2, and 3, respectively. Cardiac tamponade (odds ratio [OR], 16.82; 95% confidence interval [CI], 1.06-138), acute right ventricular failure (OR, 3.54; 95% CI, 1.82-6.88), and major bleeding (OR, 2.46; 95% CI, 1.18-5.1) were the principal risk factors for AKI. Patients with AKI had a greater hospital mortality (3.8% vs 16%, P < 0.05), especially those requiring renal replacement therapy (46.9% vs 5.4%, P = 0.006). Acute kidney injury requiring renal replacement therapy was independently associated with hospital mortality (OR, 11.03; 95% CI, 4.08-29.8). With a median follow-up after hospital discharge of 6.7 years (interquartile range, 2.4-11.6), overall survival at 1, 5, and 10 years was 95.4%, 85.1%, and 75.4% versus 85.2%, 69.8% and 63.5% among patients without AKI and with AKI stages 2 to 3, respectively (P = 0.08). CONCLUSIONS: The onset of AKI after HT is mainly associated with postoperative complications. Only severe AKI stage predicts worse short-term outcome, with this impact appearing to be lost at long-term follow-up. PMID- 29979344 TI - Intensive Care to Facilitate Organ Donation: A Report on the Experience of 2 Spanish Centers with A Common Protocol?. AB - BACKGROUND: The aim of this study is to report the experience with a program of Intensive Care to facilitate Organ Donation (ICOD) in 2 Spanish centers based on a common protocol. METHODS: Retrospective review of clinical charts of patients with a devastating brain injury whose families were approached to discuss the possibility of ICOD once further treatment was deemed futile by the treating team. STUDY PERIOD: 1/1/2011-12/31/2015. RESULTS: ICOD was discussed with families of 131 patients. Mean age of possible donors was 75 (SD=11) years. The main cause of brain injury was an intracranial hemorrhage (72%).Interviews with families were held after the decision had been made not to intubate/ventilate in 50% of cases, and after the decision not to continue with invasive ventilation in the remaining cases. Most interviews (66%) took place in the emergency department. The majority of families (95%) consented to ICOD.Of the 125 consented cases, 101 (81%) developed brain death (BD), most in <=72 hours. Ninety-nine patients (98%) transitioned to actual donation after BD, with 1.2 organs transplanted per donor. Of patients who did not evolve to BD, 4 died following an unexpected cardiac arrest and 18 after the withdrawal of life-sustaining measures.ICOD contributed to 33% of actual donors registered at both centers. CONCLUSIONS: ICOD is well accepted by families. Most patients evolve to BD within a short period of time. The practice substantially contributes to increasing organ donation and offers more patients the chance of donating their organs after death. PMID- 29979345 TI - Donor-derived Viral Infections in Liver Transplantation. AB - Donor-derived infections are defined as any infection present in the donor that is transmitted to 1 or more recipients. Donor-derived infections can be categorized into 2 groups: "expected" and "unexpected" infections. Expected transmissions occur when the donor is known to have an infection, such as positive serology for cytomegalovirus, Epstein Barr virus, or hepatitis B core antibody, at the time of donation. Unexpected transmissions occur when a donor has no known infection before donation, but 1 or more transplant recipients develop an infection derived from the common donor. Unexpected infections are estimated to occur in far less than 1% of solid organ transplant recipients. We will review the epidemiology, risk factors, and approaches to prevention and management of donor-derived viral infectious disease transmission in liver transplantation. PMID- 29979346 TI - The First Kidney Transplant in Ireland. PMID- 29979347 TI - Minimally Invasive Transplantation of Primary Human Hepatocyte Inserts that Facilitate Vascularization. PMID- 29979348 TI - Tacrolimus-Induced Cholestatic Hepatitis in a Patient With Liver Transplant. PMID- 29979349 TI - iChoose Kidney for Treatment Options: Updated Models for Shared Decision Aid. PMID- 29979350 TI - Irisin Protects Heart Against Ischemia-Reperfusion Injury Through a SOD2 Dependent Mitochondria Mechanism. AB - Irisin, a muscle-origin protein derived from the extracellular domain of the fibronectin domain-containing 5 protein (FNDC5), has been shown to modulate mitochondria welfare through paracrine action. Here, we test the hypothesis that irisin contributes to cardioprotection after myocardial infarction by preserving mitochondrial function in cardiomyocytes. Animal model studies show that intravenous administration of exogenous irisin produces dose-dependent protection against ischemia/reperfusion (I/R)-induced injury to the heart as reflected by the improvement of left ventricular ejection fraction and the reduction in serum level of cTnI (n = 15, P < 0.05). I/R-induced apoptosis of cardiomyocytes is reduced after irisin treatment. The irisin-mediated protection has, at least in part, an effect on mitochondrial function because administration of irisin increases irisin staining in the mitochondria of the infarct area. Irisin also reduces I/R-induced oxidative stress as determined by mitochondrial membrane potential evaluation and superoxide FLASH event recording (n = 4, P < 0.05). The interaction between irisin and superoxide dismutase2 (SOD2) plays a key role in the protective process because irisin treatment increases SOD activity (n = 10, P < 0.05) and restores the mitochondria localization of SOD2 in cardiomyocytes (n = 5, P < 0.05). These results demonstrate that irisin plays a protective role against I/R injury to the heart. Targeting the action of irisin in mitochondria presents a novel therapeutic intervention for myocardial infarction. PMID- 29979351 TI - C1q/TNF-Related Protein 9 Inhibits THP-1 Macrophage Foam Cell Formation by Enhancing Autophagy. AB - During the pathogenesis of early atherosclerosis, lipid-loaded macrophages are involved in plaque development and progression. As a novel adipokine, C1q/tumor necrosis factor-related protein-9 (CTRP9) has beneficial effects in cardiovascular disease. However, previous reports have not studied whether the formation of macrophage foam cell induced by oxidized low-density lipoprotein (ox LDL) is affected by CTRP9. According to our study, in ox-LDL-induced THP-1 macrophages, CTRP9 could reduce the quantity of lipid droplets, lower the level of cholesteryl ester (CE), promote cholesterol efflux, as well as increase the expression level of the cholesterol transport receptors ATP-binding membrane cassette transporter A1 (ABCA1) and G1 (ABCG1). In addition, the protein of LC3 II is elevated and that of p62 is decreased in CTRP9-treated foam cells by enhancing autophagy. However, using 3-methyladenine (3-MA) abolished the role of CTRP9 by inhibiting autophagy. Mechanistically, the autophagy-promoting effects of CTRP9 on foam cells was reversed by an AMPK inhibitor, Compound C, which inhibited the signaling pathway of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR). These results show that CTRP9 protects against atherosclerosis by promoting cholesterol efflux to reduce the formation of foam cell in virtue of inducing autophagy in an AMPK/mTOR signaling pathway-dependent manner. PMID- 29979352 TI - Predictors of Improvement in Physical Function in Older Adults in an Evidence Based Physical Activity Program (EnhanceFitness). AB - BACKGROUND AND PURPOSE: Declines in strength, flexibility, and balance in older adults can lead to injuries and loss of independence and are particularly common in those of greater age and in worse health. EnhanceFitness (EF) is a nationally disseminated, evidence-based group exercise program for older adults that has been shown to improve function through cardiovascular, strength, flexibility, and balance exercises. This article examines changes in, and predictors of, participant physical function from baseline through 2 program cycles of EF as measured by 3 physical function tests: arm curls, chair stands, and 8-foot up-and go. METHODS: We analyzed data on participants who attended at least 2 consecutive 16-week program cycles between January 2005 and June 2016. We ran 3 random effects linear regression models, 1 for each physical function test, and accounted for missing data and clustering by class site. Independent variables included attendance, demographics, and health status. RESULTS AND DISCUSSION: A total of 7483 participants completed baseline and 2 sets of follow-up physical function tests. For all 3 physical function tests, participants showed some degree of improved physical function at each follow-up, and greater program attendance predicted clinically significant improvements. Some participants had less improvement: females, those less active at baseline, older than 75 years, not married or partnered, or in fair or poor health, those who had experienced at least 1 fall, and those with a disability. CONCLUSION: EnhanceFitness program providers may need to implement additional measures to support the participants who could benefit most from EF, such as targeting messaging, coordinating with referring providers to emphasize attendance and general activity in specific participants, and offering additional support to groups who show less improvement during classes. The evidence presented here may inform clinical decision making for older adult patients and increase health care provider confidence in EF and similar exercise programs, thereby providing a mechanism to maintain and continue functional gains made in clinical or rehabilitation settings. PMID- 29979353 TI - Objectively Assessed Physical Activity in the Oldest Old Persons With Coronary Artery Disease. AB - BACKGROUND AND PURPOSE: Accelerometer threshold values to detect physical activity intensity in the oldest old persons with coronary artery disease (CAD) are lacking as well as knowledge about their free-living physical activity behavior. The purpose of this study was 2-fold. (1) To assess the sensitivity and specificity of 3 existing intensity threshold values for ActiGraph accelerometers for the oldest old persons with CAD. (2) To assess free-living physical activity, applying the threshold values with the highest sensitivity and specificity for assessing at least moderate intensity, among these persons. METHODS: In a cross sectional design, a total of 24 persons with CAD, mean age 87.5 (3.7) years, participated in the study at a university hospital in Sweden. To assess the sensitivity and specificity of the existing threshold values, the participants walked at different speeds wearing the accelerometer at a pace corresponding to individualized perceived exertion at light, moderate, and high intensity according to the Borg Rating of Perceived Exertion Scale. For the free-living physical activity assessment, the persons wore the accelerometer for 7 consecutive days. The percentage agreement for light-, moderate-, and high intensity threshold values, as well as receiver operating characteristic curves, was used to identify the sensitivity and specificity of the existing threshold values for moderate intensity. RESULTS AND DISCUSSION: The threshold values for at least moderate intensity at 1041 counts per minute according to Copeland had the highest sensitivity (0.739) and specificity (0.609) to identify at least moderate intensity for the ActiGraph GT3X+ accelerometer. In a free-living setting, the oldest old persons with CAD spent 11 of 13.5 (81%) waking hours in a sedentary position and, of the 2.5 hours of being active, 19 minutes (2%) were at least at moderate intensity. Nine of 24 persons (38%) reached 20 minutes of moderate- to vigorous-intensity physical activity 3 days a week, according to guidelines for exercise-based cardiac rehabilitation. CONCLUSIONS: The existing threshold values according to Copeland had the highest sensitivity and specificity to identify at least moderate intensity and are valid for use in the oldest old persons with CAD. Using accelerometry as an objective measurement for physical activity can help further improve our understanding of free-living physical activity behavior and to assess relationships between free-living physical activity and health outcomes among the oldest old persons with CAD. PMID- 29979354 TI - Validity and Reliability of Jump Height Measurements Obtained From Nonathletic Populations With the VERT Device. AB - BACKGROUND AND PURPOSE: Vertical jump (VJ) is commonly used to assess lower extremity power in athletic populations. A portable device called the VERT has been validated for this population, but not in nonathletic populations. We sought in this study to assess the clinimetric properties of VJ height measurements obtained with the VERT from older and younger nonathletes. METHODS: Twenty-eight participants (14 older, 14 younger, evenly split between male and female) completed 2 submaximal and 3 maximal VJ trials wearing the VERT during 2 sessions separated by 5 to 9 days. During the first session, their VJ heights were also monitored using motion capture video. RESULTS: Analysis revealed concurrent validity of the VERT against motion capture (intraclass correlation coefficient [ICC3,1] = 0.826-0.950) and known-groups validity of the VERT based on age and gender (P < .001). Strong parallel reliability against a second VERT device (ICC = 0.992) was demonstrated as was strong test-retest reliability (ICC = 0.968). CONCLUSIONS: The VERT device provides valid and reliable measures of VJ height in nonathletic populations, including older adults. However, the VERT may not be suitable for recording the low jump heights of some older adults. PMID- 29979355 TI - Comparison of Patient Impact and Clinical Characteristics Between Urgency and Passive Fecal Incontinence Phenotypes. AB - OBJECTIVE: To determine if categorizing fecal incontinence (FI) as urgency or passive FI is clinically meaningful, we compared clinical severity, quality of life, physical examination findings, and functional and anatomic deficits between women with urgency and passive FI. METHODS: This study is a prospective cross sectional study of women with at least monthly FI. All women completed the St Mark's Vaizey and the Fecal Incontinence Quality of Life questionnaires and underwent anorectal manometry and endoanal ultrasound. We compared women with urgency FI to women with passive FI. RESULTS: Forty-six women were enrolled, 21 (46%) with urgency FI and 25 (54%) with passive FI. Clinical severity by Vaizey score did not differ between groups (urgency 11.7 +/- 1.6 vs passive 11.0 +/- 1.0, P = 0.51). Women with urgency FI had worse median (range) lifestyle and coping scores than passive FI (Fecal Incontinence Quality of Life: lifestyle domain 2.5 [1, 4] vs 3.8 [1, 4], P = 0.04; coping domain 1.7 [1, 3] vs 2.4 [0.9, 4], P < 0.01). Women with urgency FI had higher anal resting and squeeze pressure than passive FI (60 +/- 4 mm Hg vs 49 +/- 3 mm Hg, P = 0.03; 78 [48, 150] mm Hg vs 60 [40, 103], P = 0.05). Internal anal sphincter defects were more common in women with passive FI (41.7% vs 30.0%, P = 0.53) and external anal sphincter defects more common in women with urgency FI (25% vs 16.7%, P = 0.71), but this did not reach statistical significance. CONCLUSIONS: We identified functional and anatomic differences between women with urgency FI and passive FI. Pheonotyping women with FI into these subtypes is clinically meaningful. PMID- 29979356 TI - Broken Sacral Neuromodulation Lead Migration Into the Sigmoid Colon: A Case Report. AB - Sacral neuromodulation is an effective treatment of urinary incontinence, fecal incontinence, and idiopathic urinary retention. The procedure is considered low risk with overall low complication rates. This report describes a 40-year-old woman who underwent sacral neuromodulation explant and full-system implant for weaning efficacy of her device. During device removal, the tined lead broke and was left in situ. Four months later, she was diagnosed as having a wound infection at the site of the retained lead. Imaging revealed lead fragment migration into the sigmoid colon. A colocutaneous fistula was noted soon thereafter. The retained lead was removed during a colonoscopy and the fistula healed. A retained lead can result in migration through the peritoneum and into the colon. This can be managed with assistance from colorectal or gastroenterology consultants. PMID- 29979357 TI - Clinical Utility of Routine Preoperative Laboratory Assessment in a Urogynecologic Population. AB - OBJECTIVE: The objective of this study was to determine the incidence of newly diagnosed, clinically meaningful laboratory abnormalities on routine preoperative laboratory testing in women undergoing urogynecologic surgery. METHODS: All urogynecologic cases performed at a single institution over a 3-year period were reviewed. Women undergoing major surgery routinely had a basic metabolic panel, complete blood count (CBC), and type and screen, whereas women undergoing minor surgery had testing at the surgeon's discretion. Demographics, surgical details, preoperative laboratory values, and instances of postoperative transfusion were abstracted. If testing revealed a clinically meaningful abnormality, physician notes were reviewed to determine whether the abnormality was previously known or led to surgical postponement. RESULTS: A total of 836 cases were identified: 411 major (49%) and 425 minor (51%). Patients had a mean +/- SD age of 57 +/- 13 years and body mass index of 27 +/- 6 kg/m. Medical comorbidities were hypertension, 38%; diabetes, 24%; chronic kidney disease, 3%; and congestive heart failure, 4%; 89% had an American Society of Anesthesiologists class of less than or equal to 2. A total of 453 (54%) had preoperative CBC, and 367 (44%) had preoperative basic metabolic panel. Six (1.3%) new abnormalities (hemoglobin between 8.0 and 10.0) were identified on CBC. Thirty-one women had elevated creatinine level (>1.0), and 28 (90%) of these had a history of hypertension. No surgeries were postponed or changed owing to anemia, thrombocytopenia, or renal dysfunction. No clinically significant electrolyte abnormalities were identified. Type and screen were collected on 394 patients; none were transfused intraoperatively. CONCLUSIONS: Routine preoperative laboratory testing does not identify clinically meaningful abnormalities or alter surgical management in women undergoing urogynecologic surgery. PMID- 29979358 TI - Should Genital Hiatus/Perineal Body Be Measured at Rest or on Valsalva? AB - OBJECTIVE: Genital hiatus (Gh) and perineal body (Pb) are part of the Pelvic Organ Prolapse Quantification assessment system, but it is unclear whether measurements should be taken at rest or on Valsalva. This study was designed to assess the predictive value of Gh and Pb measurements obtained at rest and on Valsalva for signs and symptoms of pelvic organ prolapse (POP). METHODS: This is a retrospective study involving 416 women who presented to a tertiary urogynecology unit with symptoms of pelvic floor dysfunction. Genital hiatus and Pb were measured at rest and on maximal Valsalva. The strength of association between binary markers of POP and measurements of Gh/Pb was estimated using logistic regression analysis. Receiver operator characteristic statistics were used to compare predictive values of Gh and Pb measurements obtained at rest and on Valsalva. RESULTS: A total of 451 women were seen during the study period. Thirty-five were excluded owing to missing data, leaving 416. Fifty-four percent (n = 223) complained of POP symptoms. On examination, 80% (n = 332) had significant POP (stage 2+ in anterior or posterior compartments or stage 1+ in the central compartment). On imaging, significant POP was diagnosed in 66% (n = 275). Mean hiatal area was 22 cm (SD, 7; range, 5-49 cm) at rest and 30 cm (SD, 10; range, 11-69 cm) on Valsalva. Genital hiatus and Pb measured on Valsalva were consistently stronger predictors of prolapse symptoms and objective prolapse (by clinician examination and by ultrasound) than at Gh and Pb measured at rest. The corresponding area under the curve values were significantly larger for Gh/Pb measures on Valsalva after adjusting for multiple confounders. CONCLUSIONS: Genital hiatus/Pb measured on maximal Valsalva is a superior predictor of symptoms and signs of POP compared with Gh/Pb at rest. PMID- 29979359 TI - Post Dengue Fever Epidural abscess with or without Spondylodiscitis-a Case series of 8 patients in a single season in a single Centre: Do the dengue has a predilection for the Neural tissue? AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the immunosuppression and secondary bacterial infection after dengue viral infection and the predilection of these infection in the spine. This can trigger further research in to this fact. The possibility of change in the sero type of Dengue virus which are neurotropic may be looked into. SUMMARY OF BACKGROUND DATA: This is the largest case series of epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection. METHODS: We performed a retrospective review of all the 8 cases treated for epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection in our centre during the period of 3 months from June 2017 to Aug 2017 RESULTS.: Of the 8 cases 3 of them were infected with MRSA and all of them grew the bug in the blood culture. Three of them had MSSA, one with MSSA septcemia and one had associated Elizabeth Kingia meningoseptica infection and one patient had positive AFB stained in smears. Two patients were infected with pseudomonas. Some patients had multiple site abscess and epidural abscess without spondylodiscitis. 5 of them had neurological deficit which recovered with abscess drainage and antibiotic treatment. The ESR, CRP and serum ferritin were elevated in these patients. CONCLUSION: This is a large case series of epidural abscess with or without spondylodiscitis within 6 weeks following dengue virus infection. The predilection of dengue virus for the neural tissue should be further investigated. Post dengue immunosuppression also need further study. LEVEL OF EVIDENCE: 4. PMID- 29979360 TI - Cross-Cultural Adaptation, Validity and Reliability Study of the Turkish Version of Back Performance Scale. AB - STUDY DESIGN: Validation of a performance scale. OBJECTIVE: The purpose of this study is to investigate adaptation, validity, and reliability of the Turkish version of the Back Performance Scale (BPS). SUMMARY OF BACKGROUND DATA: Low back pain affects people of all ages and causes pain, disability, and psychosocial problems. BPS is a condition-specific performance measure of activity limitation in patients with low back pain. The purpose of this study is to investigate the cross-cultural adaptation, validity, and reliability of the Turkish version of the BPS. METHODS: The study included 180 patients with low back pain. For the reliability assessment of the scale, test-retest and internal consistency analyses were performed. The results of the test-retest analysis were analyzed by Intraclass Correlation Coefficient method. For the internal consistency, Cronbach Alpha value was calculated and to construct validity, total points of the BPS were compared with the total points of Roland Morris Disability Questionnaire (RMDQ) and Oswestry Disability Index (ODI) using Pearson's correlation coefficient analysis. RESULTS: BPS was found to have high internal consistency (Cronbach alpha value 0.827). Test-retest results were found highly correlated (range from 0.723-0.899). Factor analysis indicated that the scale had one factor. BPS is well correlated with RMDQ and ODI (Pearson correlation coefficient with RMDQ 0.576 and with ODI 0.603). CONCLUSION: The Turkish version of BPS is valid and reliable. LEVEL OF EVIDENCE: 3. PMID- 29979361 TI - The Association of Variations in Hip and Pelvic Geometry with Pregnancy-Related Sacroiliac Joint Pain Based on a Longitudinal Analysis. AB - STUDY DESIGN: cross-sectional study using radiological measurements and longitudinal data analysis. OBJECTIVE: We aim to explore hip/pelvic geometry on anteroposterior radiographs and examine if such parameters are associated with clinical symptoms. SUMMARY OF BACKGROUND DATA: Pregnancy-related sacroiliac joint pain is a common disease and is responsible to the disability of daily activities. The etiology is likely to be correlated with the biomechanical factors which are determined by trunk load and hip/pelvic geometry. Previous studies have already found the association between symptoms and weight increase during pregnancy. However, the relationship between bony anatomy and pregnancy related sacroiliac joint pain remains unknown. METHODS: In total, 72 women were included in the final analysis. In pregnant women with self-reported sacroiliac joint pain, pain scores at 12, 24, 30, and 36 weeks of pregnancy were recorded and included in a mixed-effect linear regression model as dependent variables. The radiological measurements were included as independent variables. Furthermore, to investigate the relationship between hip/pelvic geometry and the activity-specific nociceptive phenomenon, the radiological measurements between patients with and without activity-induced pain were compared using a binominal logistic regression model. RESULTS: The relative bilateral ischial tuberosity distance (betta coefficient: 0.078; P = 0.015) and the relative bilateral femoral head length (betta coefficient: 0.011; P = 0.028) showed significant interactions with the slope of pain scores. Moreover, women whose pain exacerbate during prolonged walking had a higher odds in hip/pelvic geometry of the bilateral ischial tuberosity distance (OR: 1.12; P = 0.050) and the bilateral femoral head length (OR: 1.16; P = 0.076) with approximately significant P-value. CONCLUSIONS: These data indicate hip/pelvic anatomical variations are associated with the degree of pain increasing and the activity-specific pain during pregnancy, which may help to have further understanding on the biomechanical factor in developing pregnancy-related sacroiliac joint pain. LEVEL OF EVIDENCE: 3. PMID- 29979362 TI - In Search of an Ideal Closure Method: A Randomized, Controlled Trial of Octyl-2 Cyanoacrylate and Adhesive Mesh versus Subcuticular Suture in Reduction Mammaplasty. AB - BACKGROUND: An ideal wound closure system is one that is effective, consistent, and efficient. Recent studies have demonstrated the efficacy of octyl-2 cyanoacrylate and mesh (Dermabond Prineo) in the closure of surgical wounds. This study compared the use of Prineo to use of subcuticular suture closure in reduction mammaplasty. METHODS: A prospective, randomized, controlled, single blind study of patients undergoing bilateral reduction mammaplasty was performed. Each breast per patient was randomized to layered closure with Prineo or subcuticular sutures. Incisions were assessed at 2 weeks, 6 weeks, 6 months, and 1 year. Subjects completed the Patient and Observer Scar Assessment Scale for each breast, and two blinded plastic surgeons evaluated scar quality using the Vancouver Scar Scale at each time point. RESULTS: Twenty-one patients participated in the study. On average, Prineo closure took 58.38 seconds (2.50 seconds/cm) and subcuticular closure took 444.76 seconds (18.94 seconds/cm). Prineo closure was approximately 6.8 times faster (p < 0.001) than subcuticular closure, saving an average of 6.4 minutes per incision. Vancouver Scar Scale scores were significantly better in patients with Prineo closure at 2 weeks (p = 0.026), although there was no difference in Patient and Observer Scar Assessment Scale and Vancouver Scar Scale scores at all other time points. CONCLUSIONS: In reduction mammaplasty, Prineo closure results in similar scar quality and lower operative cost without increased complications when compared to subcuticular closure. Prineo is faster than subcuticular closure and represents an effective, consistent, and efficient alternative to subcuticular suture techniques. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29979363 TI - Accuracy of Three Software Applications for Breast Volume Calculations from Three Dimensional Surface Images. AB - BACKGROUND: Knowing breast volumes before certain surgeries helps the surgeon to obtain breast symmetry. Calculating breast volumes from three-dimensional surface images is possible with specialized software applications. However, limited data exist concerning the accuracy of such volume calculations. The purpose of this study was to investigate the accuracy of breast volume calculations performed with the 3D BreAST, 3dMD Vultus, and VECTRA software applications. METHODS: Twenty-six subjects who underwent 44 mastectomies were enrolled. Preoperative three-dimensional surface images were acquired with a VECTRA-XT stereophotogrammetry device. Breast volumes were calculated from these images with the three software applications. The mastectomy specimens were weighed to derive their actual volume and compared with the software calculations. RESULTS: For all three methods, a positive correlation between the breast volume and absolute calculation error was found (p < 0.001), but not for the errors as a percentage of the breast volume (p = 0.17, p = 0.80, and p = 0.42). The 3D BreAST, 3dMD Vultus, and VECTRA applications provided mean volume calculation errors of 21, 186, and -32 ml (p = 0.27, p < 0.001, and p = 0.14) or 2 +/- 25, 48 +/- 26, and -6 +/- 27 percent of the breast volume (p = 0.67, p < 0.001, and p = 0.16), respectively. CONCLUSIONS: Despite that two applications calculated accurate mean breast volumes, all applications showed a high standard deviation in terms of the percentage of the breast volume. Therefore, the usefulness of absolute breast volume calculations from three-dimensional surface images seems limited. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 29979364 TI - The Orbital Oval Balance Principle: A Morphometric Clinical Analysis. AB - BACKGROUND: The aim of this study was to test the validity of the "orbital oval balance principle," a system of analysis and guideline that is used among aestheticians, artists, and makeup artists to create and design aesthetically pleasing eyebrows for optimal upper facial appearance. According to this principle, a face is optimally attractive when the eye is centered in an "oval" defined by the lid-cheek junction and the eyebrow. METHODS: One hundred participants were asked to rank digital morphed images of four female models with four different periorbital proportions: higher or lower lid-cheek junction versus higher or lower eyebrow position. In addition, the participants were asked to quantify seven emotions on these morphed images. RESULTS: A higher lid-cheek junction was rated as significantly more attractive with a lower eyebrow position, and a lower lid-cheek junction was regarded far more attractive in combination with a higher eyebrow position. Moreover, a higher lid-cheek junction was rated as more attractive than a lower lid-cheek junction, and elevation of the lid-cheek junction improved the perception of emotions such as tiredness and sadness. CONCLUSIONS: This study lends support to the orbital oval balance principle that can provide important insight into facial attractiveness to surgeons undertaking procedures intended to improve and rejuvenate facial appearance. Moreover, this study has also shown not only that a high(er) lid cheek junction is regarded as more youthful and attractive, but that it also may reduce the appearance of tiredness and sadness. PMID- 29979365 TI - Preoperative Multimodal Analgesia Decreases Postanesthesia Care Unit Narcotic Use and Pain Scores in Outpatient Breast Surgery. AB - BACKGROUND: The opioid epidemic demands changes in perioperative pain management. Of the 33,000 deaths attributable to opioid overdose in 2015, half received prescription opioids. Multimodal analgesia is a practice-altering evolution that reduces reliance on opioid medications. Ambulatory breast surgery is an ideal opportunity to implement these strategies. METHODS: A retrospective review of 560 patients undergoing outpatient breast procedures was conducted. Patients received (1) no preoperative analgesia (n = 333); (2) intraoperative intravenous acetaminophen (n = 78); (3) preoperative oral acetaminophen and gabapentin (n = 95); or (4) preoperative oral acetaminophen, gabapentin and celecoxib (n = 54). Outcomes included postanesthesia care unit narcotic use, pain scores, postanesthesia care unit length of stay, rescue antiemetic use, and 30-day complications. RESULTS: Both oral multimodal analgesia regimens significantly reduced postanesthesia care unit narcotic use (oral acetaminophen and gabapentin, 14.3 +/- 1.7; oral gabapentin, acetaminophen, and celecoxib, 11.9 +/- 2.2; versus no drug, 19.2 +/- 1.1 mg oral morphine equivalents; p = 0.0006), initial pain scores (oral acetaminophen and gabapentin, 3.9 +/- 0.4; oral gabapentin, acetaminophen, and celecoxib, 3.4 +/- 0.7; versus no drug, 5.3 +/- 0.3 on a 1 to 10 scale, p = 0.0002) and maximum pain scores (oral acetaminophen and gabapentin, 4.3 +/- 0.4; oral gabapentin, acetaminophen, and celecoxib, 3.6 +/- 0.7; versus no drug, 5.9 +/- 0.3 on a 1 to 10 scale; p < 0.0001). Both oral regimens were better than no medications or intravenous acetaminophen alone in multivariate models after controlling for age, body mass index, American Society of Anesthesiologists class, length of surgery, prior narcotic prescription availability, and intraoperative local anesthetic. Postanesthesia care unit length of stay, antiemetic use, and 30-day complications were not different. CONCLUSIONS: Preoperative oral multimodal analgesia reduces narcotic use and pain scores in outpatient breast plastic surgery. These regimens are inexpensive, improve pain control, and contribute to narcotic-sparing clinical practice in the setting of a national opioid epidemic. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29979366 TI - The Influence of Physician Payments on the Method of Breast Reconstruction: A National Claims Analysis. AB - BACKGROUND: Flap-based breast reconstruction demands greater operative labor and offers superior patient-reported outcomes compared with implants. However, use of implants continues to outpace flaps, with some suggesting inadequate remuneration as one barrier. This study aims to characterize market variation in the ratio of implants to flaps and assess correlation with physician payments. METHODS: Using the Blue Health Intelligence database from 2009 to 2013, patients were identified who underwent tissue expander (i.e., implant) or free-flap breast reconstruction. The implant-to-flap ratio and physician payments were assessed using quadratic modeling. Matched bootstrapped samples from the early and late periods generated probability distributions, approximating the odds of surgeons switching reconstructive method. RESULTS: A total of 21,259 episodes of breast reconstruction occurred in 122 U.S. markets. The distribution of implant-to-flap ratio varied by market, ranging from the fifth percentile at 1.63 to the ninety fifth percentile at 43.7 (median, 6.19). Modeling the implant-to-flap ratio versus implant payment showed a more elastic quadratic equation compared with the function for flap-to-implant ratio versus flap payment. Probability modeling demonstrated that switching the reconstructive method from implants to flaps with a 0.75 probability required a $1610 payment increase, whereas switching from flaps to implants at the same certainty occurred at a loss of $960. CONCLUSIONS: There was a correlation between the ratio of flaps to implants and physician reimbursement by market. Switching from implants to flaps required large surgeon payment increases. Despite a relative value unit schedule over twice as high for flaps, current flap reimbursements do not appear commensurate with physician effort. PMID- 29979367 TI - Use of Composite Arterial and Venous Grafts in Microsurgical Breast Reconstruction: Technical Challenges and Lessons Learned. AB - The success of microvascular reconstruction depends on many factors. Although many factors cannot be dictated by a surgeon, the success of anastomosis can be maximized by honing skill with performing anastomoses. However, size discrepancy of vessels remains a common challenge, given the lack of an ideal technique. In this study, the authors introduce their experience in using composite deep inferior epigastric arterial and venous grafts to overcome the vessel size and pedicle length discrepancy in lateral thigh and superficial inferior epigastric artery (SIEA) flaps. Of the 1095 flaps performed, the authors identified a total of 12 flaps (one lateral thigh flap and 11 SIEA flaps) on nine patients for breast reconstruction. The authors used deep inferior epigastric vessels to act as interposition grafts between the internal mammary artery and flap pedicle. For the SIEA flaps, the authors anastomosed the SIEA system to the deep inferior epigastric arterial system, checked the viability of the flap, and then transferred the flap to the internal mammary artery and flap pedicle. For the SIEA flaps, the authors anastomosed the SIEA system to the deep inferior epigastric arterial system, checked the viability of the flap, and then transferred the flap to the internal mammary artery system in three patients. In the last five patients, the authors anastomosed the deep inferior epigastric vessels to the internal mammary artery system first, and then transferred the SIEA flap. For the lateral thigh flap, the authors anastomosed grafts to the internal mammary artery system first as well. There were no flap losses or fat necrosis. Although the authors' outcomes are limited to only breast reconstruction, they believe this method could be expanded to different types of reconstruction, especially reconstruction of the head and neck. PMID- 29979368 TI - Abdominoplasty with Circumferential Liposuction: A Review of 1000 Consecutive Cases. AB - BACKGROUND: The authors present the technique called "abdominoplasty with concurrent circumferential liposuction," where the whole trunk is addressed as a single aesthetic unit. METHODS: Between January of 2008 and June of 2016, abdominoplasty with circumferential liposuction was performed in 1000 patients (984 women and 16 men) by the senior author. Patients had a mean body mass index of 27.5 kg/m (range, 18.1 to 34.5 5 kg/m). Liposuction was performed circumferentially and the abdominal flap was detached up to the costal margins. Simultaneous fat grafting was also performed if required. Outcomes and complications were documented. RESULTS: Traditional abdominoplasty incisions were used in 359 patients, whereas extended incisions were used in 641 patients. The mean duration of follow-up was 27 months (range, 12 days to 61 months), and the mean duration of surgery was 154 minutes (range, 109 to 260 minutes). The mean amount of simultaneously aspired supernatant lipoaspirate was 1940 cc (range, 1700 to 4580 cc). Simultaneous gluteal fat grafting was performed in 34 percent. None of the patients had any skin necrosis. The most common complication was seroma (19 percent). CONCLUSIONS: In abdominoplasty, the entire central body should be considered as a single unit. Circumferential widespread liposuction with standard undermining of the abdominal flap up to the costal margins is safe and yields superior aesthetic outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29979369 TI - Insulin Promotes Adipose-Derived Stem Cell Differentiation after Fat Grafting. AB - BACKGROUND: Adipose-derived stem cells are used to enhance fat graft survival. However, their mechanism of action when grafted is controversial. The grafted cells can be replaced by connective tissue or survive at the recipient site and differentiate. Insulin is a powerful agent used to induce their differentiation to adipocytes. The purpose of this study was to elucidate the fate of grafted adipose-derived stem cells in nonvascularized fat grafts with or without insulin. METHODS: Fat was harvested from a female human donor who had undergone reduction mammaplasty. The authors also isolated and cultured adipose-derived stem cells expressing green fluorescent protein from transgenic Sprague-Dawley rats. Injection of free fat graft, the adipose-derived stem cells, phosphate-buffered saline, and insulin was performed on the four paravertebral points of the back of each mouse (n = 30) as follows: group A (control group) received adipose tissue and phosphate-buffered saline; group B received adipose tissue and adipose derived stem cells; group C received adipose tissue, adipose-derived stem cells, and phosphate-buffered saline; and group D received adipose tissue, adipose derived stem cells, and insulin. Green fluorescent protein expression was evaluated using an in vivo imaging system. The volume of transplanted fat was evaluated at 8 weeks after graft with six histologic parameters. The fat graft was immunostained with green fluorescent protein, 4',6-diamidino-2-phenylindole, and perilipin. Statistical analysis was performed using a one-way analysis of variance test. RESULTS: The fat graft volume was significantly higher in group D (p < 0.05). Histologic examination revealed reduced fibrosis and increased cysts, vacuoles, integrity, and vascularity in group D. The green fluorescent protein and perilipin co-positive area was more apparent in group D compared with groups B and C. CONCLUSION: Insulin could enhance the survival and differentiation of adipose-derived stem cells in nonvascularized fat grafts. PMID- 29979370 TI - Augmentation Gluteoplasty: A Brazilian Perspective. AB - : According to recent data, augmentation gluteoplasty continues to gain popularity in the United States and globally, especially in procedures involving fat grafts. However, serious concerns about its safety have been raised over the past 2 years. Will this trend continue or has it already reached its peak? The answer depends on how the technique is going to be performed hereafter. In this article, the following seven learning objectives for performing gluteal augmentation safely and effectively are covered: (1) the concept of what is a beautiful buttock and how to select the patients who will have better outcomes; (2) diagram each patient's needs for liposuction and graft; (3) use maneuvers for contouring and projection; (4) compare specific indications for fat graft and gluteal implants; (5) evaluate ptosis grade to indicate whether volume repositioning is sufficient; (6) formulate care protocols for risk management; and (7) develop lasting and high-satisfaction-rate results. It is pivotal to recognize each patient's body characteristics and ability to achieve a good result, and to work on her expectations preoperatively and accordingly to perform the procedure in the safest manner possible. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 29979371 TI - Fate of Free Fat Grafts with or without Adipogenic Adjuncts to Enhance Graft Outcomes. AB - BACKGROUND: Free fat grafting is popular, but it is still unclear how it works. Although focusing on graft survival seems an obvious direction for improving clinical results, the authors' research suggests that long-term volume retention is in part attributable to new fat regeneration. Measures to facilitate adipogenesis may therefore be equally important. METHODS: To investigate the relative roles of survival and regeneration of fat grafts, the authors measured the fate of human lipoaspirate implanted into the scalps of immunodeficient mice, with and without stromal vascular fraction and a porcine extracellular matrix (Adipogel). Specifically, the authors were interested in volume retention, and the composition of implanted or regenerated tissue at 6 and 12 weeks. RESULTS: Free fat grafts exhibited poor volume retention and survival. Almost all of the injected human adipocytes died, but new mouse fat formed peripheral to the encapsulated fat graft. Adipogel and stromal vascular fraction improved proliferation of murine fat and human vasculature. Human CD34 stromal cells were present but only in the periphery, and there was no evidence that these cells differentiated into adipocytes. CONCLUSIONS: In the authors' model, most of the implanted tissue died, but unresorbed dead fat accounted substantially for the long-term, reduced volume. A layer of host-derived, regenerated adipose tissue was present at the periphery. This regeneration may be driven by the presence of dying fat, and it was enhanced by addition of the authors' adipogenic adjuncts. Future research should perhaps focus not only on improving graft survival but also on enhancing the adipogenic environment conducive to fat regeneration. PMID- 29979372 TI - Micro-RNA-Regulated Proangiogenic Signaling in Arteriovenous Loops in Patients with Combined Vascular and Soft-Tissue Reconstructions: Revisiting the Nutrient Flap Concept. AB - BACKGROUND: The placement of arteriovenous loops can enable microvascular anastomoses of free flaps when recipient vessels are scarce. In animal models, elevated fluid shear stress in arteriovenous loops promotes neoangiogenesis. Anecdotal reports in patients indicate that vein grafts used in free flap reconstructions of ischemic lower extremities are able to induce capillary formation. However, flow-stimulated angiogenesis has never been systematically investigated in humans, and it is unclear whether shear stress alters proangiogenic signaling pathways within the vascular wall of human arteriovenous loops. METHODS: Eight patients with lower extremity soft-tissue defects underwent two-stage reconstruction with arteriovenous loop placement, and free flap anastomoses to the loops 10 to 14 days later. Micro-RNA (miRNA) and gene expression profiles were determined in tissue samples harvested from vein grafts of arteriovenous loops by microarray analysis and quantitative real-time polymerase chain reaction. Samples from untreated veins served as controls. RESULTS: A strong deregulation of miRNA and gene expression was detected in arteriovenous loops, showing an overexpression of angiopoietic cytokines, oxygenation-associated genes, vascular growth factors, and connexin-43. The authors discovered inverse correlations along with validated and bioinformatically predicted interactions between angiogenesis-regulating genes and miRNAs in arteriovenous loops. CONCLUSIONS: The authors' findings demonstrate that elevated shear stress triggers proangiogenic signaling pathways in human venous tissue, indicating that arteriovenous loops may have the ability to induce neoangiogenesis in humans. The authors' data corroborate the nutrient flap hypothesis and provide a molecular background for arteriovenous loop-based tissue engineering with potential clinical applications for soft-tissue defect reconstruction. PMID- 29979373 TI - Abdominal Panniculectomy: Determining the Impact of Diabetes on Complications and Risk Factors for Adverse Events. AB - BACKGROUND: The prevalence of obesity along with bariatric surgery and massive weight loss requiring panniculectomy is increasing in the United States. The effect of diabetes mellitus on outcomes following panniculectomy remains poorly defined despite its prevalence. This study aims to evaluate the impact of diabetes mellitus on complications following panniculectomy and determine risk factors for adverse events. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify patients undergoing panniculectomy between 2010 and 2015. Patients were stratified based on diabetes status. RESULTS: Review of the database identified 7035 eligible patients who underwent panniculectomy, of which 770 (10.9 percent) were diabetic. Multivariate regression showed that diabetes mellitus was a significant risk factor for wound dehiscence (OR, 1.92; 95 percent CI, 1.41 to 3.15; p = 0.02). Obesity was a significant risk factor for superficial (OR, 2.78; 95 percent CI, 1.53 to 3.69; p < 0.001) and deep (OR, 1.52; 95 percent CI, 1.38 to 3.97; p = 0.01) incisional surgical-site infection. Smokers were also at an increased risk for superficial (OR, 1.42; 95 percent CI, 1.19 to 1.75; p = 0.03) and deep (OR, 1.63; 95 percent CI, 1.31 to 2.22; p = 0.02) incisional surgical-site infection. CONCLUSIONS: Diabetes mellitus is an independent risk factor for wound dehiscence following panniculectomy. Obesity and smoking were significant risk factors for superficial and deep incisional surgical-site infection. These results underscore the importance of preoperative risk factor evaluation in patients undergoing panniculectomy for safe outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 29979374 TI - Effect of pre-transplantation serum ferritin on outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation: A meta-analysis. AB - BACKGROUND: Pre-transplantation serum ferritin (SF) has been considered to be a potential prognostic biomarker in patients undergoing allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), but this conclusion remains controversial. Thus, we performed a meta-analysis to investigate the prognostic significance of pre-transplantation SF in patients undergoing allogeneic HSCT. METHODS: We systematically searched PubMed, Embase, and Web of Science up to September 2017, and finally identified a total of 25 eligible studies with 4545 patients. RESULTS: The pooled results of our meta-analysis showed that high pre transplantation SF was markedly related to worse overall survival (OS) [hazard ratio (HR) = 1.82; 95% confidence interval (95% CI): 1.47-2.26; P < .001], nonrelapse mortality (NRM) (HR = 2.28; 95% CI: 1.79-2.89; P < .001), and progression-free survival (PFS) (HR = 1.72; 95% CI: 1.27-2.33; P < .001). In addition, high pre-transplantation SF was closely associated with a lower incidence of chronic graft versus host disease (cGVHD) (OR = 0.74, 95% CI: 0.58 0.96; P < .05), and a higher incidence of blood stream infections (BSIs) (OR = 1.67, 95% CI: 0.93-3.01; P = .09). However, no significance relationship was found between elevated pre-transplantation SF and acute graft versus host disease (aGVHD) (OR = 1.08, 95% CI:.72-1.62; P = .70). CONCLUSION: In patients undergoing allogeneic HSCT for hematological malignancies, elevated pre-transplantation SF was significantly associated with worse OS and PFS, higher incidence of NRM and BSI, and lower incidence of cGVHD, but it had no effect on aGVHD. Considering the limitations in our meta-analysis, more prospective and homogeneous clinical studies are needed to further confirm our findings. PMID- 29979375 TI - The long-term prognostic significance of high-sensitive C-reactive protein to in stent restenosis. AB - BACKGROUND: In the current meta-analysis, we aim to assess the effect of high sensitive C-reactive protein (hs-CRP) on in-stent restenosis (ISR) outcome in patients receiving stent implantation. METHODS: Embase, PubMed, and Cochrane databases were searched through October 2016 using the keywords "high-sensitive C reactive protein," "in-stent restenosis." An odds ratio (OR) of on ISR endpoints among patients receiving stent implantation was calculated using random-effects models. RESULTS: In the meta-analysis of 6 prospective observational studies, there are 1156 coronary heart disease (CHD) patients, a total of 885 stents were implanted and 194 ISR events had been followed up for 6 to 12 months; high sensitive C-reactive protein levels are associated with the prediction of in stent restenosis among patients receiving stent implantation. The OR of hs-CRP for ISR was 1.16 [95% confidence interval (CI), 1.01-1.30, P < .05]. CONCLUSIONS: This meta-analysis shows that higher levels of hs-CRP are associated with an increased risk of ISR and indicate a poorer prognosis in CHD patients after stent implantation. PMID- 29979376 TI - Use of apatinib combined with pemetrexed for advanced ovarian cancer: A case report. AB - INTRODUCTION: Ovarian cancer is the most deadly gynecologic cancer, and the therapy is very difficult. Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. At present, there are few studies or case reports on apatinib treatment for patients with ovarian cancer. CASE PRESENTATION: A 75-year-old Chinese woman had a medical history of ovarian high-grade serous papillary adenocarcinoma, who got many lines of chemotherapy and apatinib-an antiangiogenesis drug therapy. Either alone or in combination, apatinib may extend the survival time of patients with advanced ovarian cancer. CONCLUSION: Apatinib may be an option for advanced ovarian cancer after failure of chemotherapy or other targeted therapy. The role of apatinib in the treatment of advanced ovarian cancer needs further study. PMID- 29979377 TI - Electroacupuncture for primary insomnia: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Insomnia is a highly widespread sleep disorder in the general population. Electroacupuncture (EA) has been widely received attention as a potential treatment for primary insomnia. However, few previous studies are available to report that EA is a beneficial therapeutic approach to primary insomnia. In addition, there is no critical systematic review or meta-analysis published regarding the effectiveness of this treatment. Here, we provide a protocol to systematically evaluate the efficacy and safety of EA for primary insomnia. METHODS: The reference lists of included studies for relevant randomized controlled trials and 8 electronic databases will be systematically searched by 2 review authors in January 2018, including 4 English databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Cumulative Index to Nursing and Allied Health Literature) and 4 Chinese databases (Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, VIP Database, and Wanfang Database). The primary outcomes will be assessed according to the Pittsburgh Sleep Quality Index. Data synthesis will be computed with the use of RevManV5.3 software when a data-analysis is allowed. Methodological quality will be evaluated with the risk of bias according to Cochrane Handbook. RESULTS: This study will provide a high-quality synthesis of current evidence of EA for primary insomnia. CONCLUSION: The conclusion of this systematic review will provide evidence to judge whether EA is an effective therapeutic intervention for patient with primary insomnia. PMID- 29979378 TI - Elevated heat shock proteins in bipolar disorder patients with hypothalamic pituitary adrenal axis dysfunction. AB - BACKGROUND: Heat shock proteins (HSP) might be useful as biomarkers for bipolar disorder (BD) which would be clinically valuable since no reliable biomarker for BD has so far been identified. The purpose of this study was to assess the heat shock proteins CPN10, CPN60, and CPN70 as potential biomarkers of BD. METHODS: The study included 100 BD patients recruited from a hospital during 2012 and 2013. The study also included 94 healthy controls. Among the BD patients, 33 had abnormal hypothalamic-pituitary-adrenal (HPA) axis activity. Blood samples were obtained from the patients and controls. The chemiluminescence method, mass spectrometry, and flow cytometry were used for analysis. RESULTS: The BD patients compared with the controls had a significantly lower level of CPN10 and significantly higher levels of CPN60 and CPN70. The BD patients with abnormal HPA axis activity had a significantly lower level of CPN60 compared with the normal HPA axis activity group of BD patients. The CPN60 level significantly inversely correlated with adrenocorticotropic hormone (ACTH) level in patients with bipolar depression and in patients with bipolar hypomania, and CPN70 significantly correlated with ACTH level in patients with bipolar depression and hypomania. CONCLUSIONS: Our findings suggest that the heat shock proteins CPN10, CPN60, and CPN70 might have potential as biomarkers for BD and CPN60 blood level might distinguish patients with abnormal HPA axis activity from those with normal HPA axis activity. PMID- 29979379 TI - Staphylococcus aureus colonization and risk of surgical site infection in children undergoing clean elective surgery: A cohort study. AB - Staphylococcus aureus persistently colonizes the skin and nasopharynx of approximately 20% to 30% of individuals, with the highest rates in younger children. To avoid clinical problems for carriers and the spread of S aureus to other hospitalized patients, screening and decolonization of carriers undergoing surgery has been recommended. However, the best approach to patients undergoing clean surgery is not precisely defined. To evaluate whether children carrying S aureus admitted to the hospital for clean elective surgery have an increased risk of postoperative surgical infections, 393 infants and children (77.1% males; mean age +/- standard deviation, 7.6 +/- 4.5 years) who were scheduled for clean elective surgery procedures were evaluated for S aureus carriage on the day of intervention and 5 days after it. Both anterior nares and pharyngeal swabs were collected. S aureus was identified using the RIDAGENE methicillin-resistant S aureus (MRSA) system (R-Biopharm AG, Darmstadt, Germany), according to the manufacturer's instructions. At admission, 138 (35.1%) children screened positive for S aureus. MRSA was identified in 40 (29.0% of S aureus positive subjects) cases. The carriage rates of S aureus and MRSA varied considerably with age, and in children <2 years old the rate was significantly lower than in any other age group (P < .05). Surgical site infection was demonstrated in 4 out of 109 (3.7%) children who were initially colonized by S aureus and in 5 out of 201 (2.5%) children with a negative screening, without any statistically significant difference between groups (P = .72). None of these children had MRSA. These results seem to suggest that children undergoing clean elective surgery do not need to be screened for S aureus colonization because, although positive, they have no increased risk of surgical site infection. Following this statement, preoperative procedures should be simplified with relevant advantages from a clinical, social, and economic point of view. PMID- 29979380 TI - Biomechanical effect of bone resorption of the spinous process after single segment interspinous dynamic stabilization device implantation: A finite element analysis. AB - This study aims to explore the influence of bone resorption of the spinous process after single-segment interspinous process device (IPD) implantation on the biomechanics of the lumbar spine.The 3D finite element model of the lumbar spine (L3-L5) was modified, and 2 models that simulated the presence and absence of bone resorption of the spinous process were developed using an IPD (Wallis). Its biomechanical effects, such as change in range of motion (ROM) and intervertebral disc and facet stress, were introduced at operative (L4/5) and adjacent (L3/4) levels.Compared with the INT model, the Wallis model and Wallis BR model had similar ROMs in lateral flexion and rotation. However, the Wallis model had a lower L3-5 ROM in flexion (20.4% lower) and extension (26.4% lower), and L4-L5 ROM in flexion (74.1% lower) and extension (70.8% lower), while the overall ROM of the Wallis-BR model was greater than that of the Wallis model. The stress on the L3/L4 intervertebral disc and facets was similar for all 3 models. Compared with the INT model and Wallis-BR model, the stress on the L4/L5 intervertebral disc and facets under all movements significantly decreased in the Wallis model. The stress on the L5 process was greater than that on the L4 process in both the Wallis model and Wallis-BR model, and the load on the processes that underwent bone resorption was lower than that of the Wallis model.The function of the IPD slowly decreased with the occurrence of bone resorption of the interspinous process. This bone remodeling may be associated with high stress after IPD implantation. PMID- 29979381 TI - Ogilvie's syndrome: management and outcomes. AB - Ogilvie's syndrome, also known as acute colonic pseudo-obstruction, refers to pathologic dilation of the colon without underlying mechanical obstruction, occurring primarily in patients with serious comorbidities. Diagnosis of Ogilvie's syndrome is based on clinical and radiologic grounds, and can be treated conservatively or with interventions such as acetylcholinesterase inhibitors (such as neostigmine), decompressive procedures including colonoscopy, and even surgery. Based on our clinical experience we hypothesized that conservative management yields similar, if not superior, results to interventional management. Therefore, we retrospectively examined all patients over the age of 18 with Ogilvie's syndrome who presented to the Medical University of South Carolina (MUSC). The diagnosis of Ogilvie's syndrome was confirmed by clinical criteria, including imaging evidence of colonic dilation >=9 cm. Patients were divided and analyzed in 2 groups based on management: conservative (observation, rectal tube, nasogastric tube, fluid resuscitation, and correction of electrolytes) and interventional (neostigmine, colonoscopy, and surgery). Use of narcotics in relation to maximal bowel size was also analyzed. Over the 11-year study period (2005-2015), 37 patients with Ogilvie's syndrome were identified. The average age was 67 years and the average maximal bowel diameter was 12.5 cm. Overall, 19 patients (51%) were managed conservatively and 18 (49%) underwent interventional management. There was no significant difference in bowel dilation (12.0 cm vs 13.0 cm; P = .21), comorbidities (based on the Charlson Comorbidity Index (CCI), 3.2 vs 3.4; P = .74), or narcotic use (P = .79) between the conservative and interventional management groups, respectively. Of the 18 patients undergoing interventional management, 11 (61%) had Ogilvie's syndrome-related complications compared to 4 (21%) of the 19 patients in the conservative management group (P < .01). There was no difference in overall length of stay in the 2 groups. Two patients, one in each group, died from complications unrelated to their Ogilvie's syndrome. We conclude that Ogilvie's syndrome, although uncommon, and typically associated with severe underlying disease, is currently associated with a low inpatient mortality. While interventional management is often alluded to in the literature, we found no evidence that aggressive measures lead to improved outcomes. PMID- 29979382 TI - Analysis and discussion of the rare complication of autoimmune encephalitis: Two case reports. AB - RATIONALE: Autoimmune encephalitis related to many antibodies against neuronal cell surface or synaptic proteins, it is increasingly recognized as the cause of a variety of neuropsychiatric syndromes. PATIENT CONCERNS: The two pediatric cases were about autoimmune encephalitis with rare complication. One patient was a 11-year-old girl and was diagnosed with Voltage-Gated Potassium Channel complex (VGKC) antibody-mediated encephalitis with rhabdomyolysis; the other was also a 11-year-old girl and was diagnosed with anti- N-methyl-D-aspartate receptor (NMDAR) encephalitis. DIAGNOSES: Both patients were diagnosed as autoimmune encephalitis with rare complication. INTERVENTIONS: Intravenous methylprednisolone, oral prednisone and intravenous immunoglobulin was administered to both patients. OUTCOMES: One patient was discharged after a half month's hospitalization; the other was finally with intestinal function failure, gradually developed multiple organ failure, and eventually died. LESSONS: The pathogenic mechanism of autoimmune encephalitis associated with autoimmune disease is not fully understood, but may be related to a common immune pathological mechanism with variance in susceptibility caused by genetic or environmental factors. PMID- 29979383 TI - Myoepithelioma of the lateral abdominal wall: A case report. AB - RATIONALE: Soft-tissue myoepithelioma is a rare neoplasm. It usually occurs in the distal or proximal extremities, but seldomly arises in the abdominal wall. PRESENTING CONCERNS OF THE PATIENT: The patient is a 40-year-old woman who presented with a painless mass at the lateral abdominal wall for 6 months. Computed tomography scan revealed a lobulated and well-defined iso-density mass showing heterogeneously moderate enhancement. The mass exhibited intermediate T1 signal and obvious high T2 signal on magnetic resonance imaging. INTERVENTIONS: The tumor was excised. Hematoxylin-eosin stain and immunohistochemical stain showed that the tumor was myoepithelioma. OUTCOMES: The patient did not undergo chemotherapy and radiotherapy. No recurrence or metastasis was noted during the 1 year follow-up. LESSONS: Radiologists should consider myoepithelioma in the differential diagnosis when finding a tumor in the abdominal wall. PMID- 29979384 TI - Pediatric paraganglioma of the posterior mediastinum: A case report and review of literature. AB - RATIONALE: Paraganglioma is rare in children and most pheochromocytomas originate in the adrenal gland. PATIENT CONCERNS: The clinical characteristics, diagnosis, and managements in a 9-year-old boy who presented with vomiting and occasional headache with a blood pressure of 210/170 mm Hg was retrospectively reviewed. CT scan of the chest revealed a 7 * 5-cm-sized soft tissue mass in the left paraspinal area. Biochemical reports revealed elevated levels of serum norepinephrine, urine norepinephrine, urine dopamine, and serum neuron specific enolase. DIAGNOSES: The immunohistochemical studies suggested that the tumor was a paraganglioma of the posterior mediastinum. INTERVENTIONS: The patient underwent mass resection with thoracotomy. Before operation, the patient was prepared by orally administering captopril, propranolol hydrochloride, and phenoxybenzamine. Body fluid volume was also prepared by vein and mouth in 3 days. OUTCOMES: The patient was followed up postoperatively for 1 year without recurrence. LESSONS: We should be highly vigilant the pediatric tumor of the posterior mediastinum with vomiting and headache as the first clinical manifestation. PMID- 29979385 TI - Low-dose computed tomography (LDCT) versus other cancer screenings in early diagnosis of lung cancer: A meta-analysis. AB - BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide. It is often diagnosed at an advanced stage when treatment is no longer possible. Early population-based screening may provide an opportunity for early diagnosis and reduce mortality rates. METHODS: Study characteristics were collected and outcome data (lung cancer diagnosis and mortality) were extracted and used for meta analysis. Statistical analyses were performed using OpenMetaAnalyst-0.1503 software. The odds ratio (OR) and 95% confidence interval (CI) were used to assess LDCT compared to other screening methods under the random-effects model. The I2 statistic was used to assess heterogeneity. RESULTS: Pooling data from 4 studies (64,129 patients) showed a higher incidence of diagnosed lung cancer with LDCT screening (OR = 1.86, 95% CI: 1.02-3.37), compared to other screening tools. However, no significant difference (OR = 1.13, 95% CI: 0.78-1.64) was found in lung cancer mortality between both groups. CONCLUSIONS: Although no significant difference was found between LDCT and other control groups in terms of lung cancer mortality, this meta-analysis suggests an increased diagnosis of lung cancer with LDCT as compared with other screening modalities. This meta-analysis displays the potential but also the limitations of LDCT for early lung cancer detection. PMID- 29979386 TI - Clinical study of repetitive transcranial magnetic stimulation of the motor cortex for thalamic pain. AB - Thalamic pain is a severe pain that is often unresponsive to medical therapy. Repetitive transcranial magnetic stimulation (rTMS) entirely non-invasively modulates neuronal plasticity to produce therapeutic benefit. Since the rTMS stimulation parameters varied, it is difficult to determine which specific parameters are best for clinical use. The aim of this study was to evaluate the analgesic lasting effect of 10-Hz rTMS over the motor cortex (M1) for 10 consecutive days to treat thalamic pain.Patients were treated with daily 10-Hz rTMS sessions for 1000 pulses applied over the M1 for 10 consecutive days. Pain severity and mood were assessed at baseline, immediately after, 2 weeks, 4 weeks, 6 weeks, 8 weeks after rTMS. Pain severity was measured by the visual analogue scale (VAS) and the percentage of pain relief on VAS score was calculated between baseline and final examination. Mood was monitored using the Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD).Seven patients with thalamic pain were enrolled. VAS score was significantly decreased after rTMS. Mean VAS scores were 7 at baseline and decreased to 5.6 at 2 weeks after rTMS and then decreased to 3.9 at 8 weeks after rTMS. The analgesic effect of rTMS can last up to 8 weeks. The percentage of pain relief ranges from 25.0% to 66.7% at the 8th week. Four patients (3 moderate pain and 1 severe pain) achieved satisfactory relief (pain relief >=40-69%).Although this was an open-label study without a control group, our findings show that 10 Hz rTMS over the M1 for 10 consecutive days can produce satisfactory or partial antalgic effect on patients with thalamic pain. PMID- 29979387 TI - ENPP1 K121Q (rs1044498 C > A) genetic polymorphism confers a high risk of susceptibility to coronary heart disease: A PRISMA-compliant article. AB - BACKGROUND: Previous studies suggested an association between K121Q (rs1044498 C > A) in ecto-nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) gene and the risk of coronary heart disease (CHD), but the results have been inconsistent. In this study, we performed a meta-analysis of several trials to systematically summarize their potential association. METHODS: Relevant articles were identified by searching electronic databases for studies published prior to March 2018. We carefully reviewed published studies on ENPP1 genetic polymorphism in relation to CHD susceptibility. The data extracted from selected high-quality studies were analyzed using STATA statistical software (StataCorp LP, College Station, TX, USA). RESULTS: Nine eligible studies which contained a combined total of 1547 CHD cases and 2213 healthy controls were chosen in the present meta-analysis. Our results indicated that K121Q strongly correlated with increased risk of CHD. The subgroup analysis on race, sample source, disease type, sex, age, and genotype showed that in Caucasians, K121Q strongly correlated with increased risk of CHD, but no difference was found in Chinese. Both single factor and multiple factor regression showed that race, sample origin, disease type, sex, age, and genotype were not the source of heterogeneity. CONCLUSIONS: Our meta-analysis revealed that the K121Q (rs1044498 C > A) in the ENPP1 gene is a risk factor for CHD. PMID- 29979388 TI - Superior blood-saving effect and postoperative recovery of comprehensive blood saving strategy in infants undergoing open heart surgery under cardiopulmonary bypass. AB - BACKGROUND: Optimization of blood-saving strategies during open heart surgery in infants is still required. This study aimed to study a comprehensive blood-saving strategy during cardiopulmonary bypass (CPB) on postoperative recovery in low weight infants undergoing open heart surgery. METHODS: This was a prospective study of 86 consecutive infants (weighing <5 kg) with acyanotic congenital heart disease treated at the Tianjin Chest Hospital between March and December 2016, and randomized to the control (traditional routine CPB) and comprehensive blood saving strategy groups. The primary endpoints were blood saving and clinical prognosis. The secondary endpoints were safety and laboratory indicators, prior to CPB (T1), after 30 minutes of CPB (T2), after modified ultrafiltration (T3), and postoperative 12 (T4), 24 (T5), 48 (T6), and 72 h (T7). RESULTS: The total priming volume and banked red blood cells in the comprehensive strategy group were significantly lower than in the control group (P = .009 and P = .04, respectively). In the comprehensive strategy group, immediately after CPB, the amount of salvaged red blood cells exceeded the priming red blood cells by 40 +/- 11 mL. Postoperatively, the comprehensive strategy group showed a significant decrease in the inotrope score (P = .03), ventilation time (P = .03), intensive care unit stay (P = .04), and hospital stay (P = .03) in comparison with the control group. CONCLUSION: The comprehensive blood-saving strategies for CPB were associated with less blood use and favorable postoperative recovery in low-weight infants with congenital heart disease undergoing open heart surgery. PMID- 29979389 TI - Differences in carotid atherosclerosis between patients with ankylosing spondylitis treated with tumor necrosis factor-alpha antagonists and healthy matched controls. AB - An increased vascular risk is present in patients with ankylosing spondylitis (AS). In this report, we evaluate the presence and grade of atherosclerosis in patients with AS, uninterruptedly treated with tumor necrosis factor-alpha (TNF alpha) antagonists for 2 years, in comparison to that in a nontreated group of healthy controls.Fourteen patients with AS and 14 healthy controls underwent carotid sonography to measure intima-media thickness (IMT) and to evaluate the presence of plaque. Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index scores, erythrocyte sedimentation rate, C-reactive protein, glycemia, total cholesterol, and triglyceride levels were also recorded.Patients with AS showed significantly lower values of mean and maximum IMT at the level of the common carotid (P = .02 and .04, respectively) and the carotid bulb (P = .0006 and .0005, respectively) compared to those of healthy controls. They also had a number of carotid plaques significantly lower than that of healthy controls (P = .02). No differences were found in IMT values at the level of internal carotid between the 2 populations.The significantly lower carotid atherosclerosis found in patients with AS treated with TNF antagonists than in healthy controls shows the important complementary role of this treatment in reducing vascular disease progression probably by decreasing inflammation. PMID- 29979390 TI - High-dose fotemustine in temozolomide-pretreated glioblastoma multiforme patients: A phase I/II trial. AB - BACKGROUND: Glioblastoma multiforme (GBM) is a rare and deadly disease, with a reported average incidence rate of 3.19 cases per 100,000 inhabitants. Fotemustine, a third-generation nitrosourea with an alanine phosphor carrier that facilitates cellular penetration, has been extensively investigated in the setting of recurrent/progressive disease after initial treatment. Fotemustine is usually administered following a schedule consisting of 3 doses every week, followed by maintenance doses administered every 3 weeks. METHODS: In this phase I/II trial, we aimed to assess whether the use of a biweekly regimen allowed administration of higher dose than the standard 100 mg/m dose approved per label indication in a population of patients with recurrent GBM. In this phase I/II trial, fotemustine was administered intravenously over 1 hour every 2 weeks at either 120 or 140 mg/m doses for up to 1 year, until disease progression, unacceptable toxicity, or patient's request to withdraw from the study. The phase I part of the trial was conducted following the classic 3+3 study design. The phase II part of the trial was a single-arm study. The primary efficacy endpoint was the percentage of patients who had not progressed after 24 weeks (PFS-24). RESULTS: Thirty-seven patients were enrolled in this phase I/II trial from August 2006 to November 2011. Treatment was well tolerated in the overall population. Main severe toxicity was grades 3 and 4 thrombocytopenia, which occurred in 4 of 6 patients treated at the 140 mg/m dose level and in 3 of 31 patients treated at 120 mg/m. Median PFS and overall survival were 12.1 (1-40.2) weeks and 19.7 (1 102) weeks, respectively. CONCLUSION: We conclude that fotemustine can be safely administered at 120 mg/m biweekly. The efficacy of such modified schedule and doses should be compared to the biweekly schedule at 80 mg and the standard weekly schedule at 80 to 100 mg/m. PMID- 29979391 TI - Viridans streptococcal infective endocarditis associated with fixed orthodontic appliance managed surgically by mitral valve plasty: A case report. AB - RATIONALE: Streptococcus viridans, a heterogeneous group of alpha-hemolytic streptococci, is part of the normal flora of the mouth, usually responsible for dental caries (Streptococcus mutans, Streptococcus sanguinis), and pericoronitis, as well as for subacute infective endocarditis. They are responsible for 40-60% of the endocarditis cases occurring on the normal valves, especially in male patients and over 45 years of age. A change in the bacterial flora of the oral cavity is taking part after orthodontic fixed appliances are introduced into the oral cavity, change that is associated with an increased concentration of the acidogenic bacteria. Bacteraemia is the consequence of oral cavity infections, the association of infective endocarditis with fixed orthodontic appliance, as it has been described by us for the first time, caused by Abiotrophia defectiva. PATIENT CONCERNS: We present the case of a female Caucasian patient, aged 22 years, who developed infective endocarditis with Streptococcus viridans associated with fixed orthodontic appliance, located on the mitral valve, without previous cardiac pathology, and the therapeutic difficulties associated with allergic reactions (to vancomycin, and spironolactone). DIAGNOSES: Repetitive haemocultures were positive with Streptococcus viridans, while transthoracic echography revealed a severe mitral failure through anteromedial segment of the anterior mitral valve leaf prolapse with eccentric jet to the posterior wall. INTERVENTIONS: During hospitalization, the decision to undergo surgical intervention was taken after obtaining negative haemocultures. The patient underwent surgically intervention, and a mitral valve plasty with insertion of neochords was performed. OUTCOMES: Intraoperative and subsequently post-discharge transesophageal echography, highlighted normofunctional mitral plasty with a remaining regurgitation grade I-II of IV, with good openness, minor tricuspid regurgitation, and mild pulmonary hypertension. LESSONS: Endocarditis with oral streptococci associated with fixed orthodontic appliance seems to be not so unlikely even in young or without previous cardiac pathology patients, requiring attention in identifying possible pre-existing cardiac conditions like mitral valve prolapse with clinical and echographic monitoring of such cases. Educating and motivating the patient to observe the oral hygiene represent key steps for an optimal oral health during orthodontic treatment. Mechanical tooth cleaning helps maintaining a good oral hygiene during fixed orthodontics and decreasing the oral health risks. PMID- 29979392 TI - A retrospective study of transcutaneous electrical nerve stimulation for chronic pain following ankylosing spondylitis. AB - This study investigated the effect of transcutaneous electrical nerve stimulation (TENS) for the treatment of patients with chronic pain after ankylosing spondylitis (AS).A total of 72 eligible patients with chronic pain following AS were included. All included patients received exercise and were assigned to a treatment group and a control group equally. In addition, patients in the treatment group also underwent TENS therapy. All patients were treated for a total of 6 weeks. The primary outcome of pain intensity was measured by visual analog scale (VAS). The secondary outcomes included degree of functional limitation, as assessed by Bath Ankylosing Spondylitis Functional Index (BASFI); and quality of life, as evaluated by Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. All outcomes were assessed before and after 6 weeks treatment. Furthermore, adverse events were also recorded.After 6-week treatment, patients in the treatment group did not show more promising outcomes in pain reduction, as measured by VAS (P = .08); functional evaluation, as evaluated by BASFI (P = .19); as well as quality of life, as assessed by ASQoL (P = .18), compared with patients in the control group. No adverse events occurred in both groups.This study did not exert encouraging outcomes in patients with chronic pain following AS after 6-week treatment. PMID- 29979393 TI - Prognostic value of von Willebrand factor in patients with atrial fibrillation: A meta-analysis. AB - BACKGROUND: Studies on the prognostic role of von Willebrand factor (vWF) in patients with atrial fibrillation (AF) are conflicting. This meta-analysis aimed to evaluate the association of elevated circulating vWF level with adverse outcomes in patients with AF. METHODS: PubMed and Embase were used to search literature through August 2017. Prospective observational studies that evaluated the association of elevated vWF level with major adverse cardiac events (MACEs) and all-cause mortality in patients with AF were deemed eligible. The MACEs included death, stroke/transient ischemic attack, heart failure, myocardial infarction, and systemic/peripheral embolism. RESULTS: A total of 6 studies were included this meta-analysis. Patients with AF with the highest vWF level were independently associated with greater risk of MACEs (risk ratio [RR] 2.20; 95% confidence intervals [CI] 1.61-3.01) and all-cause mortality (RR 1.63; 95% CI 1.39-1.91). Subgroup analysis showed that the prognostic role of higher vWF level was consistently observed in each defined subgroups. CONCLUSION: Patients with AF with elevated vWF level are independently associated with a higher risk of MACEs and all-cause mortality. However, more well-designed prospective studies are needed to confirm these findings. PMID- 29979394 TI - Sellar chondrosarcoma presenting with amenorrhea: A case report. AB - RATIONALE: Intracranial chondrosarcomas are rare entities and most of which arise off the midline. Chondrosarcomas that occur in the sellar region are extremely rare, and to the best of our knowledge, there is no reporting about sellar chondrosarcoma with amenorrhea as the onset symptom. PATIENT CONCERNS: A 45-year old woman presented with a 7-month history of amenorrhea and a 3-month history of progressive visual loss in the left eye. DIAGNOSIS: The patient was diagnosed with recurrent sellar chondrosarcoma arising from intrasellar with extensive tumor invasion into bilateral sphenoid sinuses. INTERVENTIONS: Twice endonasal transsphenoidal tumorectomies were performed followed with a stereotactic radiotherapy and hormone replacement therapy. OUTCOMES: The patient's condition was stable and her visual symptoms improved, the hormones returned to normal, and no recurrence was noted on MRI after six months. LESSONS: Sellar chondrosarcomas with the onset of endocrine dysfunctions are extremely rare, which may be misdiagnosed as pituitary adenoma and the definitive diagnosis depends on histopathological and immunohistochemical evidence. The first choice of treatment is surgery with the goal of complete resection, and postoperative adjuvant radiotherapy should be highlighted. PMID- 29979395 TI - A PRISMA-compliant systematic review and network meta-analysis on the efficacy between different regimens based on Tripterygium wilfordii Hook F in patients with primary nephrotic syndrome. AB - BACKGROUND: The present study aims to comprehensively determine the efficacy of different therapy regimens based on Tripterygium wilfordii Hook F (TwHF) for patients with primary nephrotic syndrome (PNS) using network meta-analysis method. METHODS: Seven electronic databases were searched to identify randomized controlled trials (RCTs) that compared the differences between different therapy regimens based on TwHF for patients with PNS. The risk of bias in included RCTs was evaluated according to the Cochrane Handbook version 5.2.0. Network meta analysis was performed to compare different regimens. Primary outcomes were complete remission rate and total remission rate. The secondary outcomes were hr urinary protein excretion, serum albumin, serum creatinine, and urea nitrogen. Data analysis was performed using R software. RESULTS: A total of 40 studies involving 2846 patients with PNS were included. Compared with prednisone, the improvement in total remission rate and complete remission rate was associated with TwHF alone (odds ratio [OR] = 4.80, 95% credible intervals [CrI]: 2.20 10.00; OR = 6.30, 95% CrI: 2.90-13.00, respectively), TwHF+prednisone (OR = 2.10, 95% CrI: 1.30-3.50; OR = 2.40, 95% CrI: 1.50-3.80, respectively), TwHF+CPA (OR = 12.00, 95% CrI: 1.10-150.00; OR = 16.00, 95% CrI: 1.60-170.00, respectively), and TwHF+Cyclosporine A (OR = 28.00, 95% CrI: 3.20-250.00; OR = 35.00, 95% CrI: 4.50 270.00, respectively). Compared with TwHF alone, TwHF+prednisone showed less benefit in improving total remission rate and complete remission rate (OR = 0.44, 95% CrI: 0.21-0.91; OR = 0.38, 95% CrI: 0.19-0.77, respectively). TwHF alone, TwHF+prednisone could significantly reduce hr urinary protein excretion (MD = 0.69, 95% CrI: -1.30 to -0.14; MD = -1.00, 95% CrI: -1.90 to -0.14, respectively) and increase serum albumin (MD = 5.90, 95% CrI: 2.50-9.30; MD = 3.40, 95% CrI: 1.30-5.50, respectively) when compared to prednisone alone. TwHF alone showed significant reduction in serum creatinine when compared to CPA (MD = -19.00, 95% CrI: -37.00 to -0.56). CONCLUSIONS: TwHF alone, the addition TwHF to prednisone showed more benefit in improving total and complete remission rate, hr urinary protein excretion, serum albumin, and serum creatinine. PMID- 29979396 TI - Clinical data and genetic mutation in Kallmann syndrome with CHARGE syndrome: Case report and pedigree analysis. AB - RATIONALE: This study aimed to investigate the genetic mutation characteristics of Kallmann syndrome (KS) with CHARGE syndrome through the clinical features and genetic analysis of a pediatric patient with KS in one pedigree. PATIENT CONCERNS: Developmental disorders with olfactory abnormalities, developmental lag, heart malformations, external genital malformations. DIAGNOSES: KS combined with some clinical characteristics of CHARGE syndrome. Molecular genetic analysis found that mutation occurred in the CHD7 gene. INTERVENTIONS: One pediatric patient's clinical data were collected and genomic DNA extracted from the peripheral blood. Nextgeneration gene sequencing technology was used to detect pathogenic genes, and the Sanger method was applied to perform pedigree verification for the detected suspicious pathogenic mutations. OUTCOMES: Gene detection revealed there to be a heterozygous mutation in the CHD7 gene of the patient, which was a missense mutation c.6571G > A (p.E2191K). The father's genotype was wild type, whereas it was the mutant type for the mother and younger brother. The distribution frequency of this mutation was zero in the dbSNP database, Hapmap, 1000 genomes database, and ExAC. Neither the mother nor the younger brother showed any clinical feature of KS or CHARGE syndrome. LESSONS: This study reports 1 case of KS with some clinical features of CHARGE syndrome as determined via clinical and genetic analysis, and found a new mutation in the CHD7 gene, suggesting that KS has an incomplete penetrance. Meanwhile, data suggested that mutation in the CHD7 gene could be detected in the setting of incomplete clinical manifestations of CHARGE syndrome, or without the usually believed manifestations of combined deafness as well as morphological abnormalities of the ear, providing new evidence for the differential diagnosis of KS with CHARGE syndrome in the future. PMID- 29979398 TI - A case report of pediatric calciphylaxis-a rare and potentially fatal under diagnosed condition. AB - RATIONALE: Though to be rare, calcific uremic arteriolophathy (CUA) is an ectopic calcification entity causing pain and disabilities in patients with chronic renal insufficiency, thus increasing the morbidity and mortality. PATIENT CONCERN: We report a case of four years old boy admitted with acute respiratory failure. Physical examination revealed: irritability, purple subcutaneous hard nodules, tachypnea, dry spasmodic cough, respiratory rate 45/min, heart rate 110/min, blood pressure 100/60 mmHg, with normal heart sounds, no murmurs, hepatomegaly with hepato-jugular reflux. He was diagnosed at 2 years old with stage 5 chronic kidney disease due to untreated posterior urethral valve, and subsequently started peritoneal dialysis. He developed severe renal osteodystrophy, refractory to standard phosphate binders. DIAGNOSES: Pathology examination revealed the presence of diffuse calcifications involving the skin, brain, heart, lung, kidney, stomach and pancreas, consistent with the underlying diagnosis of CUA. INTERVENTION: Apart from standard treatment for end stage renal disease and associated co-morbidities, intensive care procedures have been initiated: oxygen therapy, continuous positive airway pressure, inotropic medication (Dopamine, Dobutamine), anticonvulsants (Diazepam), and antiedematous therapy (Dexamethasone). OUTCOME: His pulmonary function rapidly deteriorated up to the severe hypoxemia, seizures and cardio-respiratory arrest, despite the initiation of intensive care measures. LESSONS: A careful follow up of small children might detect in time an abnormal urinary pattern. The diagnosis of growth failure should also trigger urgent further investigation. PMID- 29979397 TI - Challenges in the early diagnosis of patients with acute liver failure induced by amatoxin poisoning: Two case reports. AB - RATIONALE: Acute liver failure (ALF) induced by amatoxin-containing mushrooms accounts for more than 90% of deaths in patients suffering from mushroom poisoning. However, due to the fact that most hospitals cannot identify the species of mushrooms involved, or detect amatoxins, the early diagnosis of amatoxin intoxication remains a significant challenge in clinical practice. PATIENT CONCERNS: Two patients were had ingested wild mushrooms 15 hours before admission. Six hours prior to admission they experienced nausea, vomiting, weakness, abdominal pain and diarrhea. The species of mushrooms they had consumed could not be identified. DIAGNOSES: According to their delayed gastroenteritis, the two patients were clinically diagnosed with amatoxin poisoning. One week after the patients were discharged, the species of the mushrooms was identified as Amanita fuliginea and the diagnosis was confirmed. INTERVENTIONS: The two patients were treated with silibinin, penicillin G and plasma exchange. OUTCOMES: Although the two patients progressed to ALF they fully recovered and were discharged on day 10 after admission. LESSONS: Our case reports suggested that patients with unidentified wild mushroom intoxication with delayed gastroenteritis could be clinically diagnosed with amatoxin poisoning; in such cases, liver coagulation function should be frequently evaluated. Early diagnosis and treatment are crucial for survival in patients with ALF induced by amatoxin poisoning. PMID- 29979399 TI - Comparison of free-hand fluoroscopic guidance and electromagnetic navigation in distal locking of tibia intramedullary nails. AB - BACKGROUND: It is challenges for surgeon to position the distal locking screw of a tibia intramedullary nail. The traditional free-hand (FH) technique is related to the proficiency of surgeons and has a long learning curve. Furthermore, the radiation dose and the accuracy of screw placement should be taken into account. The new technology, the electromagnetic navigation system (ET), which is a radiation-free way to locate the position of the drill bit. The purpose of our study is to evaluate the results of the ET for distal locking screw of a tibia intramedullary nail and to compare the effects with the FH technique. METHODS: Eighty-nine cases of tibia diaphyseal fracture who needed to treat by intramedullary nails were analyzed retrospectively, and were divided into 2 groups. Patients in navigation group (n = 54) were treated with intramedullary nail using the ET for distal locking, while other 35 patients using FH technique. Intraoperative fluoroscopy exposure times, screw insertion times, and healing times were recorded. The parameter was used for comparison in 2 groups. RESULTS: The mean time of distal locking in the ET technique was significant less than that in the FH group (5.89 +/- 2.02 minutes vs 12.26 +/- 4.40 minutes) and the exposure time was reduced in ET group significantly (2.13 +/- 0.73 seconds vs 19.09 +/- 10.41 seconds). The healing time was proved to be coincident in FH group and ET group (15.34 +/- 2.98w vs 16.06 +/- 3.74w). The one-time success rate of distal locking nail operation was 100% in the navigation group, which was significantly higher than that in FH group (P < .05). CONCLUSION: Compared with the FH technique, the ET for distal locking of tibia intramedullary nail has the advantages of high efficiency and short locking time without radiation. PMID- 29979400 TI - Effectiveness and safety of simeprevir-based regimens for hepatitis C in Italy: The STIly observational study. AB - The combination of the direct-acting antivirals, simeprevir (SMV) and sofosbuvir (SOF), was the first highly efficacious interferon-free combination for treating patients with hepatitis C virus (HCV), and was widely used in Italy as a result.The aim of this study was to evaluate effectiveness and safety of SMV in Italian patients with HCV genotype (GT) 1 and 4 overall, by treatment regimen [SMV/SOF and SMV/SOF+ribavirin (RBV)], cirrhosis status, and GT (GT1a, GT1b, and GT4).An observational multicenter cohort study was conducted in 46 centers across Italy. Adult HCV + GT1 or GT4 patients, naive or treatment-experienced, with or without cirrhosis, who underwent treatment with a SMV-containing regimen from May to September 2015 were included. The primary endpoint was sustained virologic response (SVR), defined as undetectable serum HCV RNA levels 12 weeks after treatment end (SVR12). The secondary endpoints included duration of treatment, safety and tolerability of each treatment regimen, and SVR by treatment and according to response to previous treatment and fibrosis stage. The association between SVR and a subset of the most clinically relevant variables was investigated by a multivariate logistic regression analysis.A total of 349 HCV positive patients treated with an SMV-based regimen were enrolled, of whom 342 received SMV/SOF +/- RBV and were included in this analysis. Most patients (59.4%) were treatment-experienced and had cirrhosis (78.1%). In the group receiving SMV/SOF + RBV, most (63.1%) were treatment-experienced and 82.9% had cirrhosis. Three patients were lost to follow-up; 330 patients receiving SMV/SOF +/- RBV (96.5%) were treated for 12 weeks. Overall, SVR12 was achieved by 324 patients [94.2%, 95% confidence interval (95% CI) 92-97]. When stratified by treatment and clinical and virologic characteristics, SVR12 was achieved by 77 of 79 [97.5% (95% CI 94.0-100.0)] and 247 of 263 [93.9% (95% CI 91.0-96.8)] patients receiving SMV/SOF and SMV/SOF + RBV, respectively; 132 of 139 (95.0%) naive versus 192/203 (94.6%) treatment-experienced patients; 250 of 267 (93.6%) cirrhotic and 56 of 62 (90.3%) HIV coinfected patients. SMV-based regimens were generally well tolerated. Adverse events leading to treatment discontinuations were not observed.A high proportion of patients treated with SMV/SOF-based regimens achieved SVR12 in this study. A high SVR12 rate was also achieved in patients with cirrhosis, treatment experience, and HUV coinfected patients. PMID- 29979401 TI - Quality of life among men who have sex with men in China measured using the 36 item Short-Form Health Survey: A cross-sectional study. AB - The present study was conducted to assess the quality of life (QOL) of Chinese men who have sex with men (MSM) and to explore possible factors associated with QOL among them.A cross-sectional study of 370 MSM in Dalian and Huludao city was conducted to evaluate QOL in MSM using the Chinese version of the 36-item Short Form Health Survey (SF-36). A t test was used to compare the QOL score of our sample with the Chinese norm. ANOVA, t test, and multivariate linear regression analysis were used to assess the association of QOL with basic characteristics.The QOL score of MSM was lower than the Chinese norm (P < .05). Multivariate analysis showed that marital status and monthly income were factors associated with physical component summary (PCS) and mental component summary (MCS) among MSM population (P < .05). Married MSM had poorer QOL, and respondents with higher income levels had better QOL.The government may need to develop more effective prevention strategies to improve the mental component of QOL in the Chinese MSM population, especially the married MSM population. PMID- 29979402 TI - Comparative effectiveness of open surgery versus endovascular repair for hemodynamically stable and unstable ruptured abdominal aortic aneurysm. AB - Several observational studies and randomized trials have compared open surgery (OS) and endovascular aortic repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA). However, none of these studies addressed optimal management of hemodynamically (hd) unstable patients. Our objective was to compare perioperative outcomes in patients undergoing OS vs EVAR for hd-stable and hd unstable rAAAs.This retrospective study was conducted in West China Hospital from January 2005 to December 2015. Unstable patients were defined as those who have at least 1 of the following: preoperative shock, preoperative transfusion >4 units, preoperative intubation, cardiac arrest, or unconsciousness. Univariable and multivariable logistic regression analyses were performed.Of the 102 patients, 70.6% underwent OS and 29.4% EVAR. About 46.1% were unstable, and for these patients, OS was performed in 70.2% and EVAR in 29.8%. The 30-day mortality was 23.6% (OS, 25.6%; EVAR, 18.8%; P = .585) for hd-stable patients and was 42.6% (OS, 45.5%; EVAR, 35.7%; P = .537) for hd-unstable patients. Patients with OS had longer operative time and more transfusion. Amongst hd-stable patients, OS subgroup had a higher rate of pneumonia (33.3% vs 6.3%, P = .045), longer intensive care unit (ICU) stay (43.2 vs 15.2 hours, P = .02), and length of stay (11.6 vs 8.6 days, P = .041). Among hd-unstable patients, OS subgroup had a longer ICU stay (134.3 vs 63.8 hours, P = .047). Hospitalization costs of OS group were significantly lower than those of EVAR group, regardless of hemodynamic stability.Approximately one-third of patients with rAAA were treated by EVAR at our institution. EVAR may be the preferred approach for anatomically suitable rAAAs. However, patients treated by EVAR had a similar mortality compared with those treated by OS. In addition, OS is not an independent factor for a higher 30-day mortality, and the costs of OS were much cheaper than those of EVAR. Therefore, OS is difficult to replace, especially in developing countries. PMID- 29979403 TI - The association between menstrual cycle pattern and hysteroscopic march classification with endometrial thickness among infertile women with Asherman syndrome. AB - Women with Asherman syndrome (AS) have intrauterine adhesions obliterating the uterine cavity. Hysteroscopic March classification describes the adhesions which graded in terms of severity. This study has been designed to assess the prevalence and association between of clinical presentations, potential causes, and hysteroscopic March classification of AS among infertile women with endometrial thickness.A retrospective descriptive study was carried out that included 41 women diagnosed with AS. All of the patients underwent evaluation and detailed history. All cases classified according to March classification of AS were recorded. Patients were divided into 2 groups based on measurement of endometrial thickness. Group A consisted of 26 patients with endometrial thickness <=5 mm, and group B included 15 patients with endometrial thickness >5 mm.The prevalence of AS was 4.6%. Hypomenorrhea was identified in about 46.3%, and secondary infertility 70.7%. History of induced abortion, curettage, and postpartum hemorrhage were reported among 56.1%, 51.2%, and 31.7%, respectively. AS cases were classified as minimal in 34.1%, moderate 41.5%, and severe among 24.4% as per March classification. Amenorrhea was reported by 23.1% of women in group A, compared to 0% in group B (P = .002). Ten of 26 patients (38.5%) from group A had a severe form of March classification, compared with 0 of 15 patients (0%) in group B. This was statistically significant (P < .001).The thin endometrium associated with amenorrhea and severe form of March classification among patients with AS. PMID- 29979404 TI - Etiological aspects of intragastric bezoars and its associations to the gastric function implications: A case report and a literature review. AB - RATIONALE: Intragastric bezoar is a stony mass found trapped in the stomach, though it can occur in other locations of the gastro-intestinal tract. The etiology of intragastric bezoar is multifactorial, includes certain risk factors and predisposing factors such as coexisting medical disorders, anatomic abnormalities, and gastric motility disorders, which contribute to the development of intragastric bezoar. PATIENT CONCERNS: In this report, we present a rare case of intragastric bezoar with epigastric pain after prolonged consumption of jujubes. To our knowledge, this is the first case of intragastric bezoar to be reported after jujubes ingestion. DIAGNOSES: An upper gastrointestinal (GI) endoscopy performed which revealed an 8 * 5-cm intragastric diospyrobezoar with an adjacent necrotic pressure ulcer of size 0.8 * 0.5-cm without signs of bleeding. INTERVENTIONS: For therapeutic intervention, Coca-Cola ingestion and lithotripsy were applied. OUTCOMES: The therapeutic course was uneventful. There was no recurrence during 1-year follow-up. LESSONS: In our literature, jujube emerged as a new player. A bezoar composed of unripened fruit content in the stomach, could be the cause of chronic abdominal pain, dyspepsia, gastric reflux or heartburn. Moreover, this study provides a detailed overview of recently published literature regarding intragastric manifestations of bezoar, etiological factors, diagnostic and therapeutic approaches. PMID- 29979405 TI - Displacement of occluder as a rare complication of transcatheter closure of ventricular septal defect: A case report. AB - RATIONALE: Ventricular septal defects are the most common congenital heart defect in children. As this method avoids sternotomy, the post-procedural morbidity is lower. However, transcatheter closure of perimembranous ventricular septal defects are still associated with complications such as arrhythmia (particularly, Atrioventricular Block), device embolization, atrioventricularvalve and/or aortic valves regurgitation, residual shunts. Some complications can be life threatening and require urgent surgical intervention. PATIENT CONCERNS: An 32-months-old boy was admitted for a significant precordial systolic murmur. The patient underwent transcatheter perimembranous ventricular septal defects closure. 12 months later, Transthoracic echocardiography revealed the device displaced, 4 mm shunt acrocss the ventricular septum and moderate tricuspid regurgitation detected. DIAGNOSIS: According to the echocardiography result, the patient was diagnosed with displacement of the ventricular septal defect occluder and tricuspid regurgitation. INTERVENTIONS: After the diagnosis, the patient underwent removal of the ventricular septal defect occluder and closure of the perimembranous ventricular septal defect. OUTCOMES: The post-operative recovery was uneventful. One year post-procedural follow-up transthoracic echocardiography showed there was no residual shunt and no tricuspid regurgitation. LESSONS: Transcatheter closure of Ventricular septal defects is an attractive alternative to surgery in simple perimembranous ventricular septal defects. Proper follow-up should be emphasized to the patient. PMID- 29979406 TI - Synchronous occurrence of primary right ovarian endometrioid adenocarcinoma and primary left ovarian clear cell adenocarcinoma: A case report. AB - RATIONALE: Ovarian malignancy is associated with one of the highest rates of death among gynecological reproductive system malignancies. While progress has been made in surgical and postoperative adjuvant treatment approaches, the early atypical clinical manifestations, quick progression, and lack of the effective early screening means imply that the prognosis remains poor. Bilateral ovarian cancers are common, but different types of primary bilateral ovarian carcinomas are extremely rare. PATIENT CONCERNS: According to clinical pathologic, immunohistochemistry, and medical imaging data, a 51-year-old Chinese woman with abdominal pain was diagnosed as having right ovarian well-differentiated endometrioid adenocarcinoma with mucinous adenocarcinoma and left ovarian clear cell adenocarcinoma. DIAGNOSES: Immunohistochemistry confirmed the diagnosis of primary bilateral ovarian cancers. INTERVENTIONS: She received multimodal treatment including surgery and chemotherapy. OUTCOMES: The patient's recovery was uneventful, and she responded well to the chemotherapy. LESSONS: We speculate that the different types of primary bilateral ovarian carcinomas presented in this case may be due to different malignant transformations of the endometriotic lesions. Therefore, clinicians should pay special attention to the possible malignant transformation of endometriosis. PMID- 29979407 TI - Essential thrombocythemia during treatment of acute myeloid leukemia with JAK2 V617F mutation: A case report of a CARE-compliant article. AB - RATIONALE: The JAK2 V617F mutation is frequently found in ET, while it is rare in de novo AML. ET has a low frequency of leukemic transformation. Both secondary AML (sAML) from ET and AML with JAK2 V617F mutation have poor prognoses. Because of the low incidence of JAK2 mutation in acute myeloid leukemia (AML), the clinical features of AML with JAK2 mutation are rarely reported so far, either transformed from essential thrombocythemia (ET) or de novo AML. PATIENT CONCERNS: In this article, we present a pediatric AML patient with the JAK2 V617F mutation. DIAGNOSES: A diagnosis of acute megakaryoblastic leukemia was made and sAML was ruled out. INTERVENTIONS: The patient underwent chemotherapy. OUTCOMES: In the first two complete remission periods, we found significantly increased numbers of platelets and bone marrow megakaryocytes, which are characteristic of ET. After the third chemotherapy phase, the disease relapsed; the platelet count was reduced and continued to decrease. When disease relapsed, her family abandoned treatment. LESSONS: These observations of our case raise two possibilities: either transient posttreatment thrombocythemia is a feature of AML with JAK2 V617F mutation, or this was a case of secondary AML. Additional information is required to reach better conclusions on the connection between AML and JAK2 mutations. PMID- 29979408 TI - Concurrent benign metastasizing leiomyoma in the lung and lumbar spine with elevated standardized uptake value level in positron-emission tomography computed tomography: A case report and literature review. AB - RATIONALE: Benign metastasizing leiomyoma (BML) is rare condition involving distant metastases secondary to benign uterine leiomyoma, and it is most commonly found in the lungs. It rarely metastasizes to the spine to cause osteolytic damage and spinal canal compression. PATIENT CONCERNS: A 51-year-old woman with low back and bilateral leg pain and paresthesia was admitted to our ward. She has a previous medical history of uterine leiomyomas. Magnetic resonance imaging of the lumbar spine revealed vertebral body osteolytic destruction and soft tissue mass in the L4/5 with a secondary lumbar spinal stenosis. Positron emission tomography computed tomography showed moderately intense accumulation of 18F fluorodeoxyglucose in the L4/5 mass, as well as multiple nodules with increased metabolic activity in both lungs. DIAGNOSES: Pulmonary and spinal BML. INTERVENTIONS: The patient underwent a computed tomography-guided percutaneous needle biopsy of the lung nodule and lumbar corpectomy, tumor excision, and vertebroplasty in the L4/5. OUTCOMES: Pathologically, both pulmonary nodule and vertebral mass were diagnosed as leiomyomas without any malignant evidence. Estrogen and progesterone receptors were both positive in the metastatic tumors. The patient's symptoms completely disappeared after the surgery. The patient is currently receiving outpatient anti-estrogen tamoxifen treatment for a BML. LESSONS: Through this case, we suggest that BML should be regarded as part of differential diagnosis in female patients with a previous medical history of uterine leiomyomas presenting with multiple nodules in any parts of the body. PMID- 29979409 TI - Pericecal herniation of sigmoid colon diagnosed by computed tomography: Two case reports. AB - INTRODUCTION: Computed tomography (CT) plays an important role in diagnosing specific types of internal hernias and their complications. In particular, pericecal hernia of the sigmoid colon has never been reported in the English literature. CASE PRESENTATION: The first patient was a 46-year-old female presented to our institution due to acute abdominal pain. The second patient was a 55-year-old male presented to our institution with continuous diarrhea. The patient underwent colonoscopy for further evaluation. However, even with sufficient air insufflation and repetitive maneuvers, the colonoscope could not proceed beyond the narrowed level of the sigmoid colon. In both cases, contrast enhanced abdominal CT was done and a herniated loop of sigmoid colon was noted in the posterolateral aspect of the cecum and ascending colon. Thus, a diagnosis of pericecal herniation of the sigmoid colon was established. CONCLUSION: This case study indicates that radiologic examination can be helpful in detecting pericecal herniation of the sigmoid colon. PMID- 29979410 TI - Clinical efficacy and safety of nuanxin capsule for chronic heart failure: A systematic review and meta-analysis. AB - BACKGROUND: Chronic heart failure (CHF), the final phase of various heart diseases, is a serious public health problem resulting in high hospitalization rates, mortality, and increasing health care costs. Nuanxin capsule (NXC), a Chinese herbal formula, has been widely used in the treatment of CHF. However, the safety and efficacy of NXC used in patients with CHF has been uncertain and there has been no standard clinical trial published to confirm this. Thus, we conduct a study to evaluate the safety and efficacy of NXC for CHF. METHODS: The reference lists of randomized controlled trials and 8 electronic databases will be independently and systematically searched by 2 review authors in May 2018. Four English databases (EMBASE, PubMed, Cumulative Index to Nursing and Allied Health Literature [CINAHL], and Cochrane Central Register of Controlled Trials [CENTRAL]) and 4 Chinese databases (Chinese Biomedical Literature Database [CBM], Chinese National Knowledge Infrastructure [CNKI], Wanfang Database, and VIP Database) will be included. The primary outcomes will be assessed according to the function classification of New York Heart Association (NYHA). Data synthesis will be precisely computed using the RevManV5.3 software when a data-analysis is allowed. Methodological quality will be assessed according to Cochrane Handbook. RESULTS: This study will provide a high-quality synthesis of current evidence of NXC for CHF from different aspects including the mortality, the function classification of NYHA. CONCLUSION: The conclusion of this systematic review will provide evidence to prove whether NXC is an effective therapeutic intervention for patient with CHF.PROSPERO registration number: PROSPERO CRD42018090003. PMID- 29979411 TI - Association between serum leptin levels and breast cancer risk: An updated systematic review and meta-analysis. AB - BACKGROUND: Many studies have indicated that leptin is correlated with breast cancer occurrence and tumor behavior. However, this issue remains controversial. Therefore, we conducted an updated meta-analysis to investigate the role of leptin in breast cancer. METHODS: We performed a systematic literature search and identified relevant papers up to 1 September 2017. Standardized mean differences (SMDs) with 95% confidence intervals (CIs) were used to evaluate effect sizes. RESULTS: Thirty-five eligible studies were included in the current meta-analysis. Serum leptin levels were related to breast cancer risk as demonstrated by calculations of the overall SMD = 0.46 (95% CI = 0.31-0.60, I = 93.5%). A subgroup analysis of BMI identified an association between breast cancer and serum leptin levels in patients who are overweight and obese (overweight: SMD = 0.35, 95% CI = 0.13-0.57, I = 88.1%; obesity: SMD = 1.38, 95% CI = 0.64-2.12, I = 89.6%). Additionally, menopausal status subgroup analysis revealed a significant association in postmenopausal women (SMD = 0.26, 95% CI = 0.12-0.40, I = 77.9%). Furthermore, we identified a significant association between breast cancer and serum leptin levels in Chinese women (SMD = 0.61, 95% CI = 0.44-0.79, I = 40.6%). CONCLUSION: The results of this meta-analysis suggested that leptin could be a potential biomarker for breast cancer risk in women, especially overweight/obese or postmenopausal women. Therefore, it may be useful for identifying subjects with a high risk for breast cancer who may benefit from preventive treatments. PMID- 29979412 TI - Prevalence and mortality of congenital heart disease in Korean adults. AB - The aim of this study was to assess the age-standardized prevalence (prevalence) and age-standardized mortality (mortality) of congenital heart disease (CHD) by sex in Korean adults. Data were collected from the National Health Insurance Service in Korea from 2006 through 2016. The data consisted of main and secondary diagnoses related to CHD. We calculated the prevalence and mortality of CHD in adults with the direct method using the estimated Korean population in 2015 as the reference. The prevalence of CHD in Korean adults increased from 35.8 cases per 100,000 persons in 2006 to 65.6 cases in 2015. In 2015, the prevalence in the 20- to 44-year-old group, 45- to 64-year-old group, and the older than 65 years group was 54.6, 69.6, and 95.1 cases, respectively. Among women, the prevalence was 34.3 and 31.3 cases in men. The mortality of CHD in adults decreased from 3.061 persons per 100,000 persons in 2007 to 0.551 persons in 2015. The 5-year survival rate (SR) for people with CHD was 0.92 (95% confidence interval [CI] 0.91-0.93). The 5-year SR for the 20- to 44- and 45- to 64-year-old groups was more than 0.95; however, the 5-year SR of the older than 65 years group was only 0.73 (95% CI 0.72-0.74). The prevalence of CHD in Korean adults increased and the related mortality decreased during a decade. The 5-year SR of CHD for those over 65 years was lower than that for younger age groups. PMID- 29979413 TI - Genetic polymorphisms of organic cation transporter 1 (OCT1) and responses to metformin therapy in individuals with type 2 diabetes: A systematic review. AB - BACKGROUND: Metformin is one of the most commonly used drugs for the treatment of type 2 diabetes mellitus (T2DM). Despite its widespread use, there are considerable interindividual variations in metformin response, with about 35% of patients failing to achieve initial glycemic control. These variabilities that reflect phenotypic differences in drug disposition and action may indeed be due to polymorphisms in genes that regulate pharmacokinetics and pharmacodynamics of metformin. Moreover, interethnic differences in drug responses in some cases correspond to substantial differences in the frequencies of the associated pharmacogenomics risk allele. AIM: This study aims to highlight and summarize the overall effects of organic cation transporter 1(OCT1) polymorphisms on therapeutic responses to metformin and to evaluate the potential role of such polymorphisms in interethnic differences in metformin therapy. METHODS: We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. We searched for PubMed/MEDLINE, Embase, and CINAHL, relevant studies reporting the effects of OCT1 polymorphisms on metformin therapy in T2DM individuals. Data were extracted on study design, population characteristics, relevant polymorphisms, measure of genetic association, and outcomes. The presence of gastrointestinal side effects, glycated hemoglobin A1 (HbA1c) levels, fasting plasma glucose (FPG), and postprandial plasma glucose (PPG) concentrations after treatment with metformin were chosen as measures of the metformin responses. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO). RESULTS: According to the data extracted, a total of 34 OCT1 polymorphisms were identified in 10 ethnic groups. Significant differences in the frequencies of common alleles were observed among these groups. Met408Val (rs628031) variant was the most extensively explored with metformin responses. Although some genotypes and alleles have been associated with deleterious effects on metformin response, others indeed, exhibited positive effects. CONCLUSION: Genetic effects of OCT1 polymorphisms on metformin responses were population specific. Further investigations in other populations are required to set ethnicity-specific reference for metformin responses and to obtain a solid basis to design personalized therapeutic approaches for T2DM treatment. PMID- 29979414 TI - Complex treatment of vascular prostheses infections. AB - Infections after vascular reconstructions are very rare; however, when they occur, they are associated with a high risk of morbidity. In order to obtain the best results possible, the treatment needs to be initiated as early as possible, from the very first signs of infection, and it needs to be carried out in centers specializing in vascular surgery. The aim of the present study was to assess the incidence of infections in a single university center.This retrospective analysis over a 2-year period is based on the medical reports of hospitalized patients who were diagnosed with infection following revascularization.From 2013 to 2014, a number of 151 open reconstructive surgical procedures were performed. 15 patients suffered from infection (10%) of the vascular reconstruction. Of these patients, 40% have had an aorto-bifemoral bypass, 53%-a femoro-popliteal bypass, and 7% (n = 1)-an axillo-femoral bypass. According to the Samson classification, the patients were categorized as follows: group 2: 6 cases, group 3: 2 cases, group 4: 4 cases, and group 5: 3 cases. The most frequent bacteria found were methicillin-resistant Staphylococcus aureus (MRSA) (n = 6, 40%), followed by S aureus (n = 5, 33%). The treatment options were: application of antibiotics alone without any invasive treatment in 3 patients, local irrigation and debridement in 6 patients, complete explantation of the prosthesis with a new extra-anatomic bypass in 6 cases, and partial excision of the prosthesis, which was replaced and covered with muscle flap, in 3 cases. The amputation rate in our study was 18%, which corresponds to the rates published in the literature.The treatment of infections in vascular surgery needs to be complex and adapted to each individual patient, because infections being in a permanent dynamic state. The treatment needs to be performed in specialized centers that have large experience in vascular surgery, in order for the patient to have the best chances of survival and protection from amputation. PMID- 29979415 TI - Plasma miRNA-223 correlates with risk, inflammatory markers as well as prognosis in sepsis patients. AB - The purpose was to evaluate the role of plasma microRNA-223 (miRNA-223) in risk and prognosis in sepsis patients, and its correlation with inflammatory markers.In this study, 187 sepsis patients from July 2015 to December 2016 were consecutively enrolled. Blood samples from septic patients and healthy controls (HCs) were collected, and plasma was separated for miRNA-223 expression detected by quantitative real-time PCR (qPCR). Enzyme-linked immune sorbent assay (ELISA) was performed to detect inflammatory markers.The results were as follows: miRNA 223 was highly expressed in sepsis patients compared to HCs (P < .001). Receiver operating characteristic (ROC) curve revealed miRNA-223 disclosed a good diagnostic value of sepsis with area under curve (AUC) of 0.754, 95% CI: 0.706 0.803. Sensitivity and specificity were 56.6% and 86.6% at the best cut-off point, respectively. Multivariate logistic analysis indicated that miRNA-223 could predict sepsis risk independently. Spearman's correlation disclosed that miRNA-223 relatively expression positively correlated with APCHE II score (r = 0.459, P < 0.001), CRP (r = 0.326, P < 0.001), TNFalpha (r = 0.325, P < 0.001), IL-1beta (r = 0.165, P = 0.024), IL-6 (r = 0.229, P = 0.002) and IL-8 (r = 0.154, P = 0.035), while it was negatively correlated with IL-10 (r = -0.289, P < 0.001). miRNA-223 expression in non-survivor was higher than that in survivor (P < 0.001). ROC curve revealed miRNA-223 could distinguish sepsis non-survivor form survivor with AUC of 0.600, 95% CI: 0.505-0.695. Sensitivity and specificity were 83.5% and 38.9% respectively at the best cut-off point.In conclusion, plasma miRNA-223 correlates with disease severity and inflammatory markers levels, and it might serve as a novel diagnostic and prognostic biomarker in sepsis patients. PMID- 29979416 TI - Diagnostic value of quantitative coronary flow reserve and myocardial blood flow estimated by dynamic 320 MDCT scanning in patients with obstructive coronary artery disease. AB - We have developed the method for dynamic 320-row multidetector computed tomography (MDCT)-derived quantitative coronary flow reserve (CFRCT) and hyperemic myocardial blood flow (MBFCT). We evaluated diagnostic value of CFRCT and hyperemic MBFCT for detecting obstructive coronary artery disease (CAD) in per-patient and per-vessel analysis, and their relations with the severity of CAD burden.Adenosine stressed and rest dynamic myocardial perfusion MDCT were prospectively performed in patients with known or suspected CAD. Per-patient and per-vessel MBFCT were estimated from dynamic perfusion images in rest and hyperemic phases, and per-patient and per-vessel CFRCT were calculated from the ratio of rest and hyperemic MBFCT. Degree of stenosis was evaluated by coronary CT angiography (CTA) and invasive coronary angiography (ICA). Obstructive stenosis was defined as >=70% stenosis in ICA. CAD burden with MDCT was calculated by logarithm transformed coronary artery calcium (CAC) score and the CTA-adapted Leaman risk score (CT-LeSc). A logistic regression analysis was used to measure the receiver-operating characteristic curve and corresponding area under the curve (AUC) for the detection of obstructive CAD.Twenty-seven patients and 81 vessels were eligible for this study. Sixteen patients had obstructive CAD, and 31 vessels had obstructive stenosis. Using an optimal cutoff, the CFRCT and hyperemic MBFCT had the moderate diagnostic values in per-patient (AUC = 0.89 and 0.86, respectively) and per-vessel (AUC = 0.79 and 0.76, respectively). Per patient CFRCT and hyperemic MBFCT exhibited a moderate inverse correlation with CAC score and the CT-LeSc.Per-patient and per-vessel CFRCT as well as hyperemic MBFCT had moderate diagnostic value for detecting obstructive CAD. These per patient values exhibited a moderate inverse correlation with CAD burden. CFRCT and hyperemic MBFCT might add quantitative functional information for evaluating patients with CAD. PMID- 29979417 TI - Retrospective analysis of the risk of hemorrhage associated with moderate and severe thrombocytopenia of 173 patients with systemic lupus erythematosus. AB - The aim of the study was to observe the risk of hemorrhage from moderate and severe thrombocytopenia in systemic lupus erythematosus (SLE).A retrospective analysis was undertaken of cases admitted to Qilu Hospital, China. Blood platelet counts (BPCs) of <=20 * 10/L represent severe thrombocytopenia, and a BPC of 21 to 50 * 10/L indicates moderate thrombocytopenia. A comparison was made from the perspective of severity with a view to determine the influence of thrombocytopenia on the risk of hemorrhage and the results.Moderate and severe thrombocytopenia occurred in 173 cases, accounting for 15.2% of the total hospitalized patients with SLE with a male to female ratio of 1:23.7. The average age of those patients was 34.8 +/- 14.6 years. In the group of severe thrombocytopenia, patients without visceral involvement had a mean age of onset of 31.4 +/- 14.2 years with a median of 28.0 years compared with 37.8 +/- 14.8 years with a median of 38.5 years for patients with visceral involvement; this difference was statistically significant (P = .034). Seventy-one (76.3%) of 93 patients with severe thrombocytopenia and 20 (25.0%) of 80 patients with moderate thrombocytopenia developed hemorrhagic conditions of various grades, the difference between both were markedly statistically significant. Twenty-three patients with SLE died. Nine deaths were due to a hemorrhage caused by thrombocytopenia, while more were caused by infection.Severe thrombocytopenia is a significant adverse prognostic factor of SLE. SLE with the main manifestation of thrombocytopenia tends to make younger visceral organ owners suffer. PMID- 29979418 TI - The influence of strain due to individual risk factors and social risk factors on depressive symptoms and suicidality-a population-based study in Korean adults: A STROBE-compliant article. AB - Suicide is the outcome of the interaction of biological, personal, and social risk factors. The purpose of this study was to verify the effects of strain due to individual risk factors and social risk factors on suicidality, and the mediating effect of depressive symptoms in relationship between strain related to individual risk factors and social risk factors and suicidality. The data from sociopsychological anxiety survey of Korea society conducted by the Korea Institute for Health and Social Affairs in 2015 were used in verifying the model. We analyzed the data of 7000 adults aged 19 to 79 years using Structural Equation Modeling. Strain due to individual risk factors was positively related to depressive symptoms and suicidality. Interestingly, strain induced by social risk factors was positively associated with depressive symptoms and suicidality. Social support is significantly associated with depressive symptoms and suicidality. Depressive symptoms directly affected suicidality. In addition, strain due to individual risk factors and social risk factors indirectly affected suicidality mediating depressive symptoms. These findings suggest that not only individual efforts such as social interaction and depression prevention but also government efforts such as preparation for aging may be needed to decrease suicide rate. PMID- 29979419 TI - A novel mutation causing type 1 Gaucher disease found in a Japanese patient with gastric cancer: A case report. AB - RATIONALE: Gaucher disease (GD) is an autosomal recessive disorder that leads to multiorgan complications caused by beta-glucocerebrosidase deficiency due to mutations in the beta-glucocerebrosidase-encoding gene (GBA). GD morbidity in Japan is quite rare and clinical phenotype and gene mutation patterns of patients with GD in Japan and Western countries differ considerably. Of Japanese patients with GD, 57% develop types 2 or 3 GD with neurologic manifestations and younger onset, whereas only 6% of patients with GD develop those manifestations in Western countries. Thus, it is relatively difficult to find and diagnose GD in Japan. PATIENT CONCERNS: A 69-year-old Japanese female with mild anemia and thrombocytopenia but without neurologic symptoms was initially referred for gastric cancer. Preoperative F-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed accumulation in the bone marrow and paraabdominal lymph nodes. Following bone marrow aspiration found, abnormal foamy macrophages in the bone marrow and electron microscopy revealed that the macrophages were filled with tubular-form structures. Adding to these signs suggestive of a lysosomal disease, serum beta-glucocerebrosidase activity test found decreased. Sequencing of the patient's GBA gene revealed a RecNciI recombinant mutation and the novel mutation K157R (c.587A>G). DIAGNOSES: On the basis of these findings and clinical manifestations, the final diagnosis of type 1 GD was made. INTERVENTIONS: Enzyme replacement therapy (ERT) with velaglucerase alpha was started after the diagnosis of type 1 GD. OUTCOMES: The patient's beta glucocerebrosidase activity as well as hemoglobin and platelet levels were restored by ERT without any side effects. Bone marrow aspirations 10 months after the start of the treatment with velaglucerase alpha showed reduction of Gaucher cells in bone marrow to 2% from 4% of total cellularity. LESSONS: This is the first report of F-FDG PET/CT application providing a clue for GD diagnosis. A novel mutation in GBA is described, which implies a potential pool of patients with GD with this mutation in Japan. PMID- 29979420 TI - The effect of critical illness insurance in China. AB - Critical illness insurance to reduce the incidence of catastrophic health expenditure was implemented in China in 2012. The aim of this study is to explore the implementation status and medical guarantee effect of critical illness insurance in various cities.We extracted insurance reimbursement data for 2014 from the critical illness insurance information systems of 4 cities. Characteristics of the critical illness insurance system were used to describe the implementation status. The share of medical expenses reimbursed by insurance and the percentage of individuals suffering catastrophic health expenditures were calculated to evaluate the effect of critical illness insurance.The share of medical expenses reimbursed by insurance was 58.93%, 47.29%, 62.05%, and 61.75% in Beijing, Siping, Yichang, and Zhaoqing, respectively; those shares increased by 5.29 percentage points, 7.72 percentage points, 13.30 percentage points, and 22.63 percentage points, respectively, after the introduction of critical illness insurance. The percentage of individuals suffering catastrophic health expenditures was unchanged in Beijing, but decreased by 7.04 percentage points in Siping, 11.22 percentage points in Yichang, and 2.19 percentage points in Zhaoqing.China's critical illness insurance increases the level of medical guarantee to some extent, but its effect on reducing the incidence of catastrophic health expenditure is somewhat limited. PMID- 29979421 TI - Preoperative injection of carbon nanoparticles is beneficial to the patients with thyroid papillary carcinoma: From a prospective study of 102 cases. AB - BACKGROUND: More surgeons had noticed the importance of carbon nanoparticles (CNs) in protection of parathyroid grand in the surgery of thyroidectomy and central lymph lode dissection, but paid less attention to the injection time. The purpose of this study was to investigate whether preoperative injection of CNs can improve the dissection of lymph nodes (LNs) and protect parathyroid grand (PG) for the patients with papillary thyroid carcinoma (TC). METHODS: A total of 102 consecutive patients were enrolled into this study from August 2016 to June 2017. All the patients were divided randomly into preoperative group and intraoperative group by the injecting time of the CNs. We compared the patients who had CNs injected into thyroid gland 1 month before surgery with a control group of patients who had CNs injected during the operation. The primary endpoints were operative time, numbers of total LN and metastatic LN, ratio of PG auto-transplantation, parathyroid hormone (PTH) level, and postoperative complications. RESULTS: We identify 206 PGs and 162 PGs in the preoperative and intraoperative group, respectively, (P = .000) and there was low ratio of auto transplantation in the preoperative group compared with the intraoperative group (39.3% vs 50.62%, P = .003). We also found that the PTH level in the preoperative group was higher than that of preoperative group (2.60 +/- 1.00 vs 2.19 +/- 0.72, P = .021), and the operation time in the preoperative group was less than the intraoperative group (60.17 +/- 6.28 vs 80.94 +/- 7.12, P = .000). Meanwhile pathological results revealed 3 PGs of accidental removal occurred in the preoperative group, whereas 9 PGs of accidental removal occurred in the intraoperative group (P = .039). Also there was no difference in the numbers of total and metastatic LN in the 2 groups (P > .05). CONCLUSION: Preoperative injection of CNs was safe, and can help protect PG and reduce the difficulty of operation. PMID- 29979422 TI - Analysis of the functionally-narrowest portion of the pediatric upper airway in sedated children. AB - The narrowest portions of the pediatric larynx are the glottis and subglottic region. However, the pliable and paralyzed subglottic region, acting like a curtain, is no resistance when passing an endotracheal tube. Therefore, the 'functionally' portion of the pediatric upper airway, which may be the most vulnerable to damage during intubation, is the unyielding portion below the cricoid cartilage. We investigated the functionally-narrowest portion below the cricoid cartilage.Computed tomography (CT) was performed under deep sedation. CT images were used for measurement of dimensions and cross-sectional area (CSA) of the larynx at the level of the cricoid, subcricoid, and trachea. We analyzed the anteriorposterior (AP) diameter, transverse diameter, and CSA below the cricoid cartilage (at the cricoid, subcricoid, and tracheal levels).CT images of 46 children from 8 months to 96 months were reviewed from electric medical record (EMR). The mean +/- SD of AP diameter was the shortest at the subcricoid level (cricoid, 105.7 +/- 15.8 mm; subcricoid, 94.6 +/- 15.3 mm; and trachea, 101.5 +/- 15.7 mm; P < .001). The mean +/- SD of transverse diameter was the shortest at the trachea level (cricoid, 99.8 +/- 12.2 mm; subcricoid, 102.5 +/- 13.7 mm; and trachea, 98.8 +/- 10.7 mm; P = .01). The mean +/- SD of CSA was the smallest at the subcricoid level (cricoid, 8781.5 +/- 1963.3 mm; subcricoid, 8425.0 +/- 2025.7 mm; and trachea, 8523.7 +/- 1791.1 mm; P = .02). The AP diameter at the subcricoid level was narrower than the transverse diameter at trachea level (mean difference: 4.2 mm, 95% confidence interval [CI]: 0.7-7.7, P = .02).Since the most susceptible portion for airway damage is unyielding portion, our findings suggest that, functionally, the narrowest portion of the pediatric larynx is located in the subcricoid region. PMID- 29979423 TI - Is abdominal hollowing exercise using real-time ultrasound imaging feedback helpful for selective strengthening of the transversus abdominis muscle?: A prospective, randomized, parallel-group, comparative study. AB - Despite the importance of strengthening of the transversus abdominis (TrA) muscle in individuals with low back pain, the effect of real-time ultrasound imaging on maintenance in selective strengthening of abdominal hallowing exercise (AHE) performance has not been investigated. So, the aim of this study was to investigate the effects of AHE with real-time ultrasound imaging feedback on selective reinforcing the TrA muscle.Twenty healthy subjects were enrolled prospectively and randomized to train AHE for 2 weeks either by conventional feedback (group A) or by visual feedback from real-time ultrasound imaging additional to conventional feedback (group B). The changes in thickness of TrA, internal oblique abdominal muscle (IO), and external oblique abdominal muscle (EO) were measured using the ultrasonography. The changes in muscle activities of TrA-IO and EO were measured using surface electromyography.The thickness of TrA, IO, and EO muscles in resting was not significantly changed in both groups A and B. However, the ratio of root mean square (RMS) values of TrA-IO/EO muscles, which mirrors selective contraction of TRA-IO muscles against EO muscle, was significantly higher in group B than in group A.In healthy subjects, training with AHE using real-time ultrasound imaging feedback may be a useful additional method to conventional feedback for strengthening the TrA muscles selectively. PMID- 29979424 TI - A case report of unusual cavity presentation of pulmonary extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. AB - RATIONALE: The common CT scan findings of pulmonary MZBL of MALT type include airspace consolidation, nodules and ground-glass opacity. But, to our knowledge, the present case is the first report of a cavity presentation of pulmonary MZBL of MALT type. PATIENT CONCERNS: The patient gives his consent and authorizes the photographs featuring his likeness to be published. DIAGNOSES: This patient was diagnosed as pulmonary MZBL of MALT type by pathology, immunohistochemistry, and gene rearrangement. INTERVENTIONS: The patient was treated with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) chemotherapy for twice and antibiotics. OUTCOMES: He is being followed up for one year, with slight progress in pulmonary MZBL of MALT. LESSONS: This case highlights the need to be suspicious of MZBL of MALT type, when a radiographic image shows cavity lesion. We should consider whether the diagnosis is correct, when the patient's treatment is not effective. PMID- 29979425 TI - Technique for single axillary incision robotic assisted quadrantectomy and immediate partial breast reconstruction with robotic latissimus dorsi flap harvest for breast cancer: A case report. AB - RATIONALE: The clinical application of robotic surgery in breast conserving surgery or volume replacement with robotic latissimus dorsi flap harvest (RLDFH) has been rarely reported. In this study, we report the preliminary experience and clinical outcome of robotic assisted quadrantectomy (RAQ) and immediate partial breast reconstruction (IPBR) with RLDFH. PATIENT CONCERN: Decreasing and avoid back scar length after latissimus dorsi flap harvest. DIAGNOSES: One 28 years old female with left breast cancer underwent RAQ and IPBR with RLDFH. Initially, she was diagnosed with left breast infiltrating carcinoma that was clinical stage T3N1M0 and triple negative. INTERVENTIONS: Neoadjuvant chemotherapy consisting of 4 cycles of epirubicin and cyclophosphamide followed by 4 cycles of docetaxel was performed. Breast magnetic resonance imaging showed residual breast cancer about 4.5 cm over the left upper outer quadrant of the breast. Sentinel lymph node biopsy showed no lymph node metastasis. RAQ, which took 82 minutes, was performed first, and the resected breast specimen's weight was 203 gm. She received IPBR with RLDFH, which took 97 minutes. OUTCOMES: The overall blood loss was 40 mL. The final pathology result was ypT2 (4.2 cm)N0 (sn0/3)M0 and stage IIA. The resection margin was free of tumors. The post-operative recovery was smooth except for seroma formation over the back, which was relieved after repeated aspiration at an outpatient clinic. The patient was satisfied with the post operative scar and aesthetic outcome. No local recurrence, distant metastasis or case mortality was found during 5 months of follow-up. LESSONS: RAQ and IPBR with RLDFH is a safe alternative for small-to-medium-breast-size women with breast cancer who desire breast conservation and are indicated for volume replacement with autologous latissimus dorsi flap. PMID- 29979426 TI - Natural history of cardiac function in Duchenne and Becker muscular dystrophies on home mechanical ventilation. AB - Heart impairment is classical in dystrophinopathies and its management relies on medical drugs. Mechanical ventilation is used to treat respiratory failure, but can affect cardiac function. We aimed to investigate the natural history of cardiac function in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies on home mechanical ventilation (HMV).We reviewed the chart of DMD and BMD patients, followed in our institution, to obtain ventilation setting at HMV initiation and echocardiographic data at baseline and end follow up, as well as onset cardiac events and thoracic mechanical complication. We analyzed cumulative incidence of cardiac events as well as echocardiographic parameters evolution and its association with ventilation settings.We included 111 patients (101 DMD and 10 BMD). Median age was 21 years [18-26], median pulmonary vital capacity (VC) 15% of predicted [10-24]. All patients were on HMV and 46% ventilated using tracheostomy. After a median follow up of 6.3 years, we found a slight decrease of the left ventricular ejection fraction (LVEF) (45% at end follow up vs 50% at baseline P = .019) and a stabilization of the LV end diastolic diameter indexed (LVEDD indexed 29.4 mm/m vs 30.7 mm/m at end follow up, P = .17). Tidal volume (VT) level was inversely associated with the annual rate of the LVEF decline (r = -0.29, P = .025). Left atrium (LA) diameter decreased with mechanical ventilation (24 mm vs 20 mm, P = .039) and we found a reduction of systolic pulmonary pressure (35 mm Hg vs 25 mm Hg, P = .011). The cumulative incidence of cardiac events was 12.6%. Pneumothorax occurred in 4% of patients. Hypoxic arrest secondary to the presence of tracheal plugin occurred in 4% of patients with invasive ventilation.HMV is not harmful, decreases pulmonary pressure and may protect heart in dystrophinopathies, in addition with cardioprotective drugs. In patients with DMD and BMD on HMV, cumulative incidence of cardiac events remains moderate and incidence of pneumothorax is rare. PMID- 29979427 TI - Cyclic adenosine monophosphate-regulated transcriptional co-activator 3 polymorphism in Chinese patients with acute coronary syndrome. AB - To investigate the cAMP-regulated transcriptional co-activator 3 (CRTC3) polymorphism and its significance in the acute coronary syndrome patients.In total, 248 patients with acute coronary syndrome admitted to Taizhou People's Hospital between March 2016 and October 2016 were included in this study. Eighty eight age- and gender-matched healthy individuals received physical examination in our hospital served as normal control. Single nucleotide polymorphism (SNP) analysis of CRTC3 (rs3862434 and rs11635252) was evaluated using PCR amplification.For the SNP of CRTC3, significant differences were identified in rs3862434 (AA/AG) and rs11635252 (TT/CT/CC) between the 2 groups (P < .05). Statistical increase was noticed in the high density lipoprotein cholesterol (HDL C) in those with AG phenotype compared with those with AA phenotype in those with rs3862434. Significant decrease was identified in the total cholesterol (TC), triglyceride (TG), and weight in those with CC phenotype compared with those with CT phenotype among the cases with rs11635252 (P < .05).CRTC3 polymorphism was associated with the onset of acute coronary syndrome in Han Chinese patients, which may be related to the imbalance of the lipid metabolism. PMID- 29979428 TI - Severity of chronic periodontitis and risk of gastrointestinal cancers: A population-based follow-up study from Taiwan. AB - The present study aimed to assess the association between the severity of chronic periodontitis and the risk of gastrointestinal (GI) cancers by investigating whether severe chronic periodontitis (CP), rather than mild CP, correlates with an increased risk of total or individual GI cancers.Adults (>=18 years) with mild and severe CP were identified from a random sample of 2 million insured patients in the National Health Insurance Research Database (2001-2010). After propensity score matching, 25,485 individuals, each with mild or severe CP, were included for comparison. The primary endpoint was the incidence of total or individual GI cancers, including cancers of the esophagus, stomach, small intestine, colon/rectum, and pancreas. Cox proportional hazard models with the robust aggregated sandwich estimator were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) after adjusting for known risk factors.GI cancers occurred in 275 individuals with mild CP and 324 individuals with severe CP. After adjusting for known risk factors, severe CP was not associated with an increased risk of total GI cancer relative to mild CP (HR: 0.99, 95% CI: 0.84 1.16) or individual GI cancers, including esophageal (HR: 1.15, 95% CI: 0.62 2.15), gastric (HR: 1.01, 95% CI: 0.68-1.49), small intestinal (HR: 0.70, 95% CI: 0.22-2.22), colorectal (HR: 0.95, 95% CI: 0.78-1.16), and pancreatic cancers (HR: 0.90, 95% CI: 0.47-1.75).Severe CP was not associated with an increased risk of total or individual GI cancers when compared with mild CP. PMID- 29979429 TI - Association between density of tumor-infiltrating lymphocytes and prognoses of patients with gastric cancer. AB - INTRODUCTION: Tumor-infiltrating lymphocytes (TILs) have been shown to be of prognostic significance in patients with gastric cancer. This study aims to investigate the association between density of TILs and prognoses of patients with gastric cancer. METHODS: The relative studies of tumor-infiltrating lymphocytes in tumor tissue from patients with gastric cancer were systematically searched from PubMed and Embase until October 31, 2017. The pooled hazard ratios (HRs) and their 95% confidence intervals (95%CI) for overall survival (OS) were estimated. RESULTS: Twenty-nine studies involving 4,942 patients were included into analyses. Subset of TILs included CD8, CD3, CD4, and FOXP3 T cell density. Results from meta-analyses revealed that high density of intratumoral CD8 T cells (HR = 0.77, 95% CI 0.63-0.95) and CD3 (HR = 0.62, 95% CI 0.49-0.77) were associated with significantly higher OS than those with low density in patients with gastric cancer. Moreover, a larger number of general TILs density also suggested a favorable prognosis (HR 0.75, 95% CI 0.67-0.84). However, patients with high density of intratumoral FOXP3 T or CD4 T cells were not statistically associated with higher or lower OS than those with low density (HR 1.41, 95% CI 0.97-2.05; HR = 0.86, 95% CI 0.47-1.57). Sample size and follow-up period seemed to influence study outcomes. CONCLUSION: The present study revealed that high density of intratumoral CD8 and CD3 T cells were associated with better OS in patients with gastric cancer. PMID- 29979430 TI - Gastrectomy correlates with increased risk of pulmonary tuberculosis: A population-based cohort study in Taiwan. AB - The objective to assess the association between gastrectomy and the risk of pulmonary tuberculosis among patients without gastric cancer in Taiwan.There were 762 subjects with newly performing gastrectomy as the gastrectomy group since 2000 to 2012, and 2963 randomly selected subjects without gastrectomy as the non gastrectomy group. Subjects with history of pulmonary tuberculosis or gastric cancer before the index date were excluded. Both gastrectomy and non-gastrectomy groups were matched with sex, age, and comorbidities. The incidence of pulmonary tuberculosis was assessed in both groups. The multivariable Cox proportional hazards regression model was used to assess the hazard ratio and 95% confidence interval for risk of pulmonary tuberculosis associated with gastrectomy.The overall incidence of pulmonary tuberculosis was 1.97-fold greater in the gastrectomy group than that in the non-gastrectomy group. The multivariable Cox proportional hazards regression analysis demonstrated that the adjusted HR of pulmonary tuberculosis was 1.97 for the gastrectomy group, compared with the non gastrectomy group. Male sex, age (increase per 1 year), chronic obstructive pulmonary disease, and splenectomy were other factors that could be related to pulmonary tuberculosis.Gastrectomy is associated with 1.97-fold increased risk of pulmonary tuberculosis among patients without gastric cancer. PMID- 29979431 TI - Fasudil combined with methylcobalamin or lipoic acid can improve the nerve conduction velocity in patients with diabetic peripheral neuropathy: A meta analysis. AB - BACKGROUND: Fasudil (F) plus methylcobalamin (M) or lipoic acid (L) treatment has been suggested as a therapeutic approach for diabetic peripheral neuropathy (DPN) in numerous studies. However, the effect of the combined use still remains dubious. OBJECTIVE: The aim of this report was to evaluate the efficacy of F plus M or L (F + M or F + L) for the treatment of DPN compared with that of M or L monotherapy, respectively, in order to provide the basis and reference for clinical rational drug use. METHODS: Randomized controlled trials (RCTs) of F for DPN published up to September 2017 were searched. Relative risk (RR), mean difference (MD), and 95% confidence interval (CI) were calculated and heterogeneity was assessed with the I test. Sensitivity analyses were also performed. The outcomes measured were as follows: the clinical efficacy, median motor nerve conduction velocities (NCVs) (MNCVs), median sensory NCV (SNCV), peroneal MNCV, peroneal SNCV, and adverse effects. RESULTS: Thirteen RCTs with 1148 participants were included. Clinical efficacy of F + M combination therapy was significantly better than M monotherapy (8 trials; RR 1.26, 95% CI 1.17-1.35, P < .00001, I = 0%), the efficacy of F + L combination therapy was also obviously better than L monotherapy (4 trials; RR 1.27, 95% CI 1.16-1.39, P < .00001, I = 0%). Compared with monotherapy, the pooled effects of combination therapy on NCV were (MD 6.69, 95% CI 4.74-8.64, P < .00001, I = 92%) for median MNCV, (MD 6.71, 95% CI 1.77-11.65, P = .008, I = 99%) for median SNCV, (MD 4.18, 95% CI 2.37 5.99, P < .00001, I = 94%) for peroneal MNCV, (MD 5.89, 95% CI 3.57-8.20, P < .00001, I = 95%) for peroneal SNCV. Furthermore, there were no serious adverse events associated with drug intervention. CONCLUSION: Combination therapy with F plus M or L was superior to M or L monotherapy for improvement of neuropathic symptoms and NCVs in DPN patients, respectively. Moreover, no serious adverse events occur in combination therapy. PMID- 29979432 TI - Association between physical activity and risk of prevalent psoriasis: A MOOSE compliant meta-analysis. AB - Psoriasis is a common chronic relapsing immune-mediated inflammatory disease, whose prevalence has increased in recent years. Some physicians believe that physical activity is associated with numerous health-related benefits in adults with dermatoses. While numerous studies have suggested an association between psoriasis and physical activity, others have yielded contradictory results. The aim of our study was to evaluate the association between the level of physical activity and prevalence of psoriasis.A comprehensive search of the literature was performed from January 1970 to February 2017 using EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials electronic databases. Studies published in English were reviewed to identify the contribution of intensity of physical activity on the prevalence of psoriasis.The search strategy yielded 1100 relevant studies, among which 13 observational studies were included. We found that patients with psoriasis exercise significantly less vigorously than controls (relative risk [RR]: 0.76; 95% confidence interval [CI]: 0.67-0.85; P < .00001). Predominantly, these patients exercised at moderate intensity (RR: 0.40; 95% CI: 0.18-0.90; P = .03). Some patients had lesser degree of movement, and some exercised strenuously. There were no significant differences observed in the intensity of exercise performed by controls (RR: 0.90; 95% CI: 0.46-1.77; P = .76). The 3 studies found the frequency of regular exercise differed significantly between patients with psoriasis and controls (RR: 0.88; 95% CI: 0.82-0.95; P = .0007).Different severities of psoriasis have different influences on patients' physical activity levels. Patients with a higher proportion of psoriatic lesions and self-awareness were associated with lower-intensity exercises. Our meta-analysis highlights the fact that intense physical activity may lower the prevalence of psoriasis. PMID- 29979433 TI - Flapless boning to increase space by piezosurgery: A novel mini-invasive strategy for teeth extraction. A retrospective study. AB - This study aimed to investigate the application of piezosurgery-associated flapless surgery for increasing bone space during teeth extraction and evaluate its success rate, postoperative outcomes, and incidence of major complications.From January 2014 to December 2016, patients who experienced teeth extraction via piezosurgery-associated flapless surgery were enrolled in this study. The positions, diagnosis, dental medical history, and radiographic examination of teeth were recorded before the treatment. During the surgery, the fracture or displacement of root, injuries of soft tissue, and fractures of the alveolar process were noted.A total of 140 patients fulfilled the eligibility criteria in the present study. All these teeth were classified into 4 groups based on diagnosis: residual roots that underwent root canal therapy (28 cases), teeth with root fracture (37 cases), teeth extraction because of orthodontics needed (31 cases), and the vertically impacted lower third molar (44 cases). The radiographic presentation revealed about 50% ankylosed teeth. No root fracture and root displacement emerged, and all roots were removed intact. Moreover, fracture of the alveolar process did not occur. Two cases with buccal mucosal injury were noted, which were because of heat injuries caused by the basement of the tip while cool water was used out.This study introduced a novel mini-invasive strategy for increasing space during teeth extraction. The advantage of this piezosurgery-associated flapless surgery included maximal preservation of the alveolar bone, minimal injury to soft tissues, and prevention of root fracture during the surgery. Furthermore, the cool water used during the surgery must be carefully checked before the procedure. PMID- 29979434 TI - The clinical outcomes and surgical strategy for cervical spine tuberculosis: A retrospective study in 78 cases. AB - Literature on the treatment of cervical spinal tuberculosis (CSTB) is uncommon, the surgical approaches to cervical spinal tuberculosis were controversial. The aim of the study was to evaluate the clinical outcomes of 3 surgical techniques in CSTB patients, and to determine the most appropriate approach for CSTB patients. Between April 2006 and June 2012, we performed a retrospective review of clinical and radiographic data that were collected from 850 consecutive spinal tubercular patients, including 87 patients who were diagnosed and treated for CSTB in our hospital. Apart from 9 patients being treated conservatively, the remainder (78 cases) underwent surgery by anterior debridement, interbody fusion and instrumentation (A group), posterior instrumentation and anterior debridement, fusion and instrumentation in a single or two-stage operation (AP group), or posterior debridement, fusion and posterior instrumentation (P group). The patients were evaluated preoperatively and postoperatively on the basis of hematologic, radiographic examinations, and neurologic function. The 78 patients were followed up for a mean duration of 41.2 +/- 7.2 months (range, 24-65 months). Postoperatively, the preoperative erythrocyte sedimentation rate (ESR) value returned to normal within 3 to 6 months in all patients, and solid bone fusion was achieved in 3 to 8 months. The patients exhibited significant improvement in deformity and neurological deficit postoperatively, while the visual analog scale for pain showed significant improvement in all patients at the last follow up visit. The follow-up outcomes demonstrated that all 3 surgical methods were viable management options for CSTB. Individualized therapeutic strategies should be selected according to the patient's general condition, focal characteristics, and the surgeon's experience. PMID- 29979435 TI - Preoperative computed tomography and serum alpha-fetoprotein to predict microvascular invasion in hepatocellular carcinoma. AB - To determine the diagnostic value of computed tomography (CT) for prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). Preoperative CTs for 160 patients with 57 MVI-positive and 103 MVI-negative HCCs diagnosed by surgical pathology were reviewed retrospectively. CT parameters and serum alpha fetoprotein (AFP) level were analyzed in SPSS 16.0. Although univariate analysis showed that tumor size (P = .012), grade (Z = -2.114, P = .034), and peritumoral enhancement (chi = 4.464, P = .035) were associated with MVI, multiple logistic regression analysis showed that capsular invasion (odds ratio [OR] = 23.469, P < .001), margins (OR = 6.751, P < .001), and serum AFP level (OR = 1.001, P = .038) were associated with MVI in HCC (P < .05). Radiographic hepatic capsular invasion and nonsmooth tumor margins identified by preoperative CT images, along with AFP levels greater than 232.2 ng/mL, are important predictors of MVI. PMID- 29979436 TI - Familial screening of children with Wilson disease: Necessity of screening in previous generation and screening methods. AB - Wilson disease (WD) is an autosomal recessive genetic disorder associated with copper metabolism. Early diagnosis and therapy can result in good prognosis of WD. Thus, it is highly recommended to perform familial screening. In this study, we aimed to investigate the range of familial screening of children with WD and determine the appropriate screening methods.We enrolled 20 children with WD and 50 family members of each of these patients (40 parents and 10 siblings). All the subjects underwent a physical examination, Kayser-Fleischer (K-F) rings in the cornea, abdominal ultrasonography (Abdl Ur), cranial magnetic resonance imaging (MRI), serum ceruloplasmin, serum copper, 24-hour urine copper, blood alanine transaminase (ALT) and aspartate transaminase (AST), and ATP7B gene.Two new patients with presymptomatic WD (1 mother and 1 brother) in 2 families were found by screening. They had no clinical symptoms and K-F rings in corneal. Biochemical examination indicated decreased serum ceruloplasmin and serum copper in the mother and decreased serum ceruloplasmin in the brother. Gene sequencing revealed compound heterozygous mutations in them. In addition, 48 heterozygous carriers of Wilson disease (WHDzc) were found in this study. The levels of ceruloplasmin and serum copper in patients of WD were significantly less than WHDzc and 24-hour urinary copper were significantly higher than WHDzc (P = .000). The biochemical profiles of WD and WDHzc overlapped in range of 0.8 to 1.5 g/L in ceruloplasmin, above 9 MUmol/L in serum copper and below 100 MUg/24 h in urinary copper. Gene sequencing showed 2 pathological mutations in all patients with WD and 1 pathological mutation in all WDHzc.Not only siblings but also the previous generation of children probands with WD should be screened. Genetic testing should be conducted for the diagnosis of presymptomatic patients with WD. PMID- 29979438 TI - Rare intestinal fistula caused by primary lymphoma of the gastrointestinal tract: Two case reports and literature review. AB - RATIONALE: Primary lymphoma that arises from the intestine is an uncommon malignant tumour, while intestinal fistula caused by primary lymphoma is even rarer. Non-specific clinical performance makes early diagnosis difficult, although imaging modalities might play an essential role in the detection of intestinal fistula. PATIENT CONCERNS: Patient 1: A 60-year-old male hospitalized with diarrhoea and abdominal pain for seven months underwent computed tomography enterography (CTE) that demonstrated ileum internal fistula and ileac-sigmoid colon fistula. Ultrasound (US) showed small intestinal wall thickened and development of a fistula of the sigmoid colon due to malignance. Patient 2: A 43 year-old male presented with abdominal pain and diarrhoea lasting one year. US revealed a fistula between the sigmoid colon and the ileum, and CTE showed that the wall of the partial sigmoid colon was abnormally thickened and enhanced with an ileal-sigmoid fistula that strongly suggested the diagnosis of lymphoma. DIAGNOSES: Both the two patients were diagnosed as intestinal fistula caused by primary non-Hodgkin's intestinal lymphoma. INTERVENTIONS: The patient 1 underwent surgery followed by chemotherapy. The patient 2 accepted chemotherapy. OUTCOMES: Two patients' general conditions remained stable and the imaging revealed no recurrence after follow-up of about 12 months. LESSIONS: Cross-sectional imaging, such as US and CT, plays an essential role in intestinal lymphoma fistula diagnosis. PMID- 29979439 TI - Recurrent ovarian hemorrhage in a patient with aplastic anemia: A case report. AB - RATIONALE: Recurrent ovarian hemorrhage resulting in ovarian infarction may lead to a life-threatening intraperitoneal hemorrhage in women with bleeding disorders such as aplastic anemia (AA). Moreover, it is seen as ovarian tumors in the diagnosis. The authors report a clinical case with the aim of sharing our experiences and exploring the ways to diagnose, treat, and avoid ovarian hemorrhage. PATIENTS CONCERNS: A 48-year-old woman with AA had suffered from a serious abdominal distension for the past 24 hours, which had occurred intermittently for the past 15 years. DIAGNOSES: Pelvic ultrasonography had revealed a large anechoic area of fluid in the abdomen without any sign of primary hemorrhage each time she had experienced an episode over the past 15 years. The volume of pelvic fluid had decreased after anti-inflammatory and hemostatic treatment. At presentation, the abdominal computed tomography suggested an ovarian tumor with a massive hemoperitoneum (a right ovarian mass, 5.7 * 5.0 * 5.0 cm in size, with a large amount of abdominal and pelvic fluid). INTERVENTIONS: Surgery was performed with respect to the bilateral uterine adnexa. On laparotomy, there were blood clots of approximately 6.0 * 6.0 * 5.0 cm surrounding the right ovary and approximately 400 mL bloody fluid in the abdomen. OUTCOMES: The patient recovered without incident and was transferred to a hematology ward 1 week later. Postoperative pathology confirmed hemorrhagic infarction of the right ovary. LESSONS: In conclusion, continuous ovarian bleeding can cause ovarian infarction to women with bleeding disorders and it may be confused with an ovarian tumor. Moreover, an earlier ovariectomy procedure under stable conditions or treatment with gonadotropin-releasing hormone that prevent bleeding via ovulation suppression may be effective for such cases. PMID- 29979437 TI - Different interventional criteria for chronic hepatitis B pregnant women with HBeAg(+) or HBeAg(-): Epidemiological data from Shaanxi, China. AB - The seroprevalence of hepatitis B virus (HBV) and its impact on pregnancy outcomes of women from Shaanxi Province (China) was assessed. Risk factors for mother-to-child transmission (MTCT) were evaluated based on HBV-related seroprevalence data.Viral markers and biochemical parameters were assessed in HBsAg-positive mothers and their infants out of 13,451 cases recruited. A pretested and structured questionnaire was used to test the general HBV knowledge. Descriptive statistics and logistic regression analysis were done to reveal possible risk factors for MTCT.The overall prevalence of HBsAg in pregnant women was 7.07% (951/13,451), and a rate as high as 9.40% was observed. Among the HBsAg-positive pregnant women, 30.49% (290/951) were HBeAg-positive, 22.08% (210/951) had HBV DNA levels >10 IU/mL and only 16.19% with a high risk of MTCT (34/210) had received antiviral treatment. The overall MTCT rate was 5.21%. Noteworthy, the risk ratio and 95% confidence interval (95% CI) of MTCT in HBeAg negative mothers with HBV DNA levels >2 * 10 IU/mL and HBsAg >10 IU/mL was 26.062 (2.633-258.024), which was significantly higher than that of HBeAg-positive mothers with HBV DNA level >10 IU/mL. Moreover, the awareness and knowledge about HBV transmission, risk factors, and intervention for MTCT were generally lacking among HBsAg-positive mothers.As a higher HBsAg seroprevalence and a higher MTCT rate among HBeAg-negative mothers with lower HBV DNA level was observed, our study emphasizes different interventional criteria for HBeAg-positive and HBeAg negative mothers. Extensive health education, routine screening, and immunization against HBV during pregnancy are highly warranted to minimize the possibility of perinatal transmission. PMID- 29979440 TI - The effect of perigastric lipolymphatic tissue grouping by surgeon on the number of pathologic sampled lymph nodes after radical gastrectomy. AB - To analyze the impact of perigastric lipolymphatic tissue grouping by the surgeon on the number of pathologic sampled lymph nodes and to explore the appropriate lymph node delivery process.The authors collected the medical records of gastric cancer patients who were hospitalized in Wuhan Union Hospital during the period January 2016 to January 2018. The authors selected 126 patients and divided them into experimental group and control group, 63 cases in each group. Samples of standard complete gastrectomy or distal gastrectomy +D2 lymph node dissection was performed. In experimental group, the fresh en bloc specimen was treated by the surgeon before the formalin fixation. The perigastric lipolymphatic tissue was divided into the lymph node grouping according to JSGC guideline III. Then the stomach and each group of lipolymphatic tissue were fixed and then transferred to the pathologic department, then the lymph nodes were harvested by the pathological technician. In control group, the whole en bloc specimen was fixed with formalin and then lymph nodes were detected by palpation and thin slice inspection, and then harvested by the pathological technician. The lymph node acquisition was compared in 2 groups.The total number of lymph nodes in experimental group is 2611, the number of negative lymph nodes is 2273; the total number of lymph nodes in control group is 1643, the number of negative lymph nodes is 1351; the comparison difference in 2 groups was statistical sense (P < .01); patients with lymph node which reach 25 pieces/person of experimental group could reach a ratio of 90.1%, and that is 47.6% in the control group, the comparison difference in 2 groups was statistical sense (P < .01), the number of positive lymph nodes did not increase significantly compared with the control group, and there was no statistical significance in the 2 groups.Dissecting the perigastric lipolymphatic tissue into lymph node groups by the surgeon might improve the total number of lymph node harvested by the pathological technician, and increase the rate of cases with >25 lymph nodes. Our results also implicated that, when the routing harvested lymph nodes were more than 20, the increasing number by perigastric lipolymphatic tissue grouping might result from more negative lymph nodes detected and might not result in stage migrating. PMID- 29979441 TI - Extracorporeal shockwave therapy for the treatment of knee osteoarthritis: A retrospective study. AB - This retrospective study investigated the effect and safety of extracorporeal shockwave therapy (ESWT) for treatment of knee osteoarthritis (KOA).In this retrospective study, 105 patients with KOA were included. Of those, 60 patients underwent ESWT, whereas 45 patients received laser therapy. Effect was measured by the Numeric Rating Scale (NRS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In addition, adverse events (AEs) were also recorded in this study. All outcome measurements were evaluated at the end of weeks 1, 6, and 12.Compared with the laser therapy, ESWT showed greater effect in KOA symptoms relief with regard to NRS, WOMAC total, and its subscores at week 6 (P < .05) and week 12 (P < .01) after treatment. No AE, however, occurred in both groups.The results of this retrospective study found that ESWT may be efficacious and safe for the treatment of patients with KOA. It, however, had an intrinsic limitation as a retrospective study. Prospective study with larger sample size is still needed to warrant the result of this study in the future. PMID- 29979442 TI - Laboratory confirmation of the effect of occupational sun exposure on serum 25 hydroxyvitamin D concentration. AB - Vitamin D concentration is known to correlate with various parameters. A major source of vitamin D is synthesis in the skin; thus, the duration of sun exposure is known to correlate with serum vitamin D levels. We compared serum levels of vitamin D between 2 occupational groups in Korea: the fisherman group, the most sun-exposed, and the general occupation group, relatively less sun-exposed. This study was conducted on 140 healthy fishermen and 140 healthy residents with various occupations, all of whom resided in the southernmost region of Korea, from June to August 2016. We compared serum concentrations of 25-hydroxyvitamin D (25(OH)D) in both occupation groups by gender and age and suggested vitamin D reference interval for the region. Mean serum 25(OH)D concentrations in the general occupation and fisherman group were 13.60 +/- 6.43 and 23.74 +/- 8.88 ng/mL, respectively. Mean serum concentration of 25(OH)D was 1.7 times higher in the fisherman group compared with the general occupation group, which was statistically significant (P < .001). Approximately 98% of subjects in the general occupation group and 78% of subjects in the fisherman group demonstrated either vitamin D insufficiency or deficiency. Calculated serum 25(OH)D reference interval for all subjects in our study was 3.8 to 44.4 ng/mL. Despite exposure to a large amount of sunlight, 78% of subjects in the fisherman group presented with either vitamin D deficiency or insufficiency. By taking laboratory measurements of serum 25(OH)D concentrations in fisherman, who were expected to have the highest vitamin D concentrations in Korea, this study could be epidemiologically useful. PMID- 29979443 TI - Computer-assisted, minimally invasive transforaminal lumbar interbody fusion: One surgeon's learning curve A STROBE-compliant article. AB - Minimally invasive (MI) transforaminal lumbar interbody fusion (TLIF) is a challenging technique with a long learning curve. We combined computer-assisted navigation and MI TLIF (CAMISS TLIF) to treat lumbar degenerative disease. This study aimed to evaluate the learning curve associated with computer-assisted navigation MI spine surgery (CAMISS) and TLIF for the surgical treatment of lumbar degenerative disease. Seventy four consecutive patients with lumbar degenerative disease underwent CAMISS TLIF between March 2011 and May 2015; all surgeries were performed by a single surgeon. According to the plateau of the asymptote, the initial 25 patients constituted the early group and the remaining patients comprised the latter group. The clinical evaluation data included operative times, anesthesia times, intraoperative blood losses, days until ambulation, postoperative hospital stays, visual analog scale (VAS) leg and back pain scores, Oswestry disability index (ODI) values, Macnab outcome scale scores, complications, radiological outcomes, and rates of conversion to open surgery. The complexity of the cases increased over the series, but the complication rate decreased (12.00%-6.12%). There were significant differences between the early and late groups with respect to the average surgical times and durations of anesthesia, but no differences in intraoperative blood losses, days until ambulation, postoperative hospital stays, complication rate, VAS, ODI, Macnab outcome scale scores, or solid fusion rates. There was no need for conversion to open procedures in either group. Our study showed that a plateau asymptote for CAMISS TLIF was reached after 25 operations. The later patients experienced shorter operative times and anesthesia durations. PMID- 29979445 TI - Effect of dexmedetomidine on blood coagulation in patients undergoing radical gastrectomy under general anesthesia: A prospective, randomized controlled clinical trial. AB - BACKGROUND: Dexmedetomidine can inhibit the perioperative stress response, which plays an important role in postoperative hypercoagulability. This study aimed to investigate whether dexmedetomidine could attenuate the activation of postoperative coagulation. METHODS: Patients undergoing open radical gastrectomy under total intravenous anesthesia were randomly allocated to the control group (group Con) and the dexmedetomidine group (group Dex). Dexmedetomidine was intravenously infused at 0.5 MUg/kg over 10 minutes before anesthesia induction and then infused at a rate of 0.5 MUg/kg/h until peritoneal closure in group Dex, whereas saline was administered in group Con. Blood samples were collected for thrombelastograph (TEG) analysis [reaction time (R time), clot formation time (K time), and clot formation rate (alpha angle)] and laboratory coagulation testing before dexmedetomidine administration and at the end of surgery. RESULTS: Coagulation was activated after radical gastrectomy, as indicated by TEG analysis and the increased concentrations of plasma fibrin (fibrinogen) degradation product (FDP) and thrombin-antithrombin complex (TAT). The R and K times were significantly prolonged and alpha angle was significantly decreased in group Dex compared with that in group Con at the end of surgery (P < .05). The concentrations of plasma TAT and FDP in group Dex were significantly lower than those in group Con at the end of surgery (P < .05 or .01). CONCLUSION: Adjunctive dexmedetomidine with general anesthesia attenuates the activation of coagulation following radical gastrectomy. PMID- 29979444 TI - Circulating microRNA expression profiling and bioinformatics analysis of dysregulated microRNAs of patients with coronary artery disease. AB - MicroRNs (miRNAs) are small non-coding RNAs that modulate the expression of protein-coding genes at the post-transcription level and their dysregulated expression has been implicated in cardiovascular diseases. Circulating miRNAs have been widely recommended as potential biomarkers for many diseases including coronary artery disease. In this study, the miRNA expression profiles of 6 normal coronary artery (NCA), 12 patients with coronary artery disease including 6 unstable angina (UA) patients and 6 ST-segment elevation myocardial infarction (STEMI) patients were determined by small RNA sequencing. The differential expression of miRNAs was verified via using quantitative reverse transcription polymerase chain reaction (qRT-PCR). We further performed bioinformatics analysis for the differentially expressed miRNAs. The results showed that 60 miRNAs were up-regulated and 26 miRNAs were down-regulated in the UA group and 49 miRNAs were up-regulated and 62 miRNAs were down-regulated in the UA group when compared with the NCA group. Among them, both of UA group and STEMI group shared 38 dysregulated miRNAs (28 up-regulated and 10 down-regulated) versus NCA group. ROC curves analysis showed that miR-142-3p and miR-17-5p might server as potential biomarkers for the detection and diagnosis of UA and STEMI. Bioinformatics functional predictions showed that the differential expressed miRNAs were closely related with the pathological process of coronary artery disease. We comprehensively analyzed profile expression of circulating miRNAs of patients with coronary artery disease. Our study suggested that miR-142-3p and miR-17-5p might be potential targets for follow-up research in evaluating biomarkers of coronary artery disease. PMID- 29979446 TI - Should kidney volume be used as an indicator of surgical occasion for patients with autosomal dominant polycystic kidney disease? AB - To investigate the best surgical occasion of laparoscopic cyst decortications (LCDs) in patients with autosomal dominant polycystic kidney disease (ADPKD), in accordance with the renal volume (RV). We retrospectively analyzed 135 (65 male and 70 female) patients with ADPKD who underwent LCD between June 2011 and October 2015. Patients were divided into 4 groups according to the volume of the operated kidney measured from computed tomography scans: group A (28 patients, RV < 500 mL), group B (63 patients, RV = 500-1000 mL), group C (30 patients, RV = 1000-1500 mL), and group D (14 patients, RV > 1500 mL). We studied postoperative indicators at least 1-year follow-up. For each RV group, therapeutic responses of LCD in these patients with ADPKD were assessed by improvement of clinical parameters and manifestations. A significant glomerular filtration rate (GFR) improvement was found in RV group B (31.8 +/- 11.1 mL/min; final GFR 36.9 +/- 12.7 mL/min; P < 0.01), and RV group C (21.1 +/- 8.7 mL/min; final GFR 27.4 +/- 9.2 mL/min; P < 0.01). RV group C had much higher GFR improvements than did RV group B (P < 0.01). In addition, refractory pain in patients of RV groups B, C, and D was much relieved by LCD treatment. Compared with other RV groups, blood pressures in patients with ADPKD of RV group D were also improved (P < 0.01). Our study indicates that RV could be used to evaluate LCD clinical outcomes in patients with ADPKD. The results of LCD for patients with ADPKD with RV between 500 and 1500 mL were encouraging, especially with regards to renal function improvement and pain relief. Therefore, RV may become a useful marker to predict the timing of LCD surgery in patients with ADPKD. PMID- 29979447 TI - Effects of 4 major brain protection strategies during aortic arch surgery: A protocol for a systematic review and network meta-analysis using Stata. AB - BACKGROUND: Reliable brain protection during aortic arch surgery remains a formidable surgical challenge. Various cerebral protection techniques have been used in the clinic; however, there is no consensus regarding which strategy is best. We will perform a network meta-analysis (NMA) focusing on the permanent neurological deficits (PND) and perioperative mortality associated with 4 major brain protection strategies used during aortic arch surgery. METHODS: We will perform a literature search of MEDLINE, EMBASE, Cochrane Library, and PubMed databases. The primary outcomes of interest in this analysis will be PND and perioperative mortality. Inconsistencies in the NMA will be evaluated with global and local approaches. Network rank and surface under the cumulative ranking curve (SUCRA) analyses will be performed to evaluate and identify the superiority of different brain protection techniques. RESULTS: This study is ongoing and will be submitted to a peer-reviewed journal for consideration of publication. CONCLUSIONS: Our study will increase understanding of 4 major brain protection strategies during aortic arch surgery and be helpful to clinicians using NMA in their studies. PMID- 29979448 TI - Association between PPP2CA polymorphisms and clinical features in southwest Chinese systemic lupus erythematosus patients. AB - Increasing evidence supports the involvement of a catalytic subunit (PP2Ac) of protein phosphatase 2A (PP2A) in the mechanisms of systemic lupus erythematosus (SLE). This study was conducted to explore the association single nucleotide polymorphisms (SNPs) of PPP2CA with SLE susceptibility, serum cytokines levels, and clinical features in a Chinese Han population. A case-control association study was carried out in 1509 Chinese Han subjects (730 SLE patients and 779 healthy individuals). Genotyping for genetic variants of PPP2CA (rs10491322 and rs7704116) was performed using a polymerase chain reaction-high resolution melting (PCR-HRM) assay. In the cohort of SLE patients, we observed that rs10491322 and rs7704116 were positively increased SLE susceptibility (OR = 1.61, 95% CI = 1.13-2.31, P = .009; OR = 1.59, 95% CI = 1.17-2.15, P = .003, respectively). Interestingly, the AG genotype of rs10491322 carriers presented higher IL-6 (P < .001) and IL-17 (P < .001) than those with AA genotype carriers. Specifically, carriage of the rs10491322 G* allele led to a higher prevalence of arthritis in SLE patients (P = .01). This study demonstrated an association of PPP2CA (rs10491322 and rs7704116) with SLE susceptibility in a Chinese Han population. Furthermore, the minor allele of PPP2CA rs10491322 as a risk factor was correlated with immunologic disorders for SLE. PMID- 29979449 TI - The appropriate management algorithm for diabetic foot: A single-center retrospective study over 12 years. AB - BACKGROUND: Diabetic foot management is a challenge for reconstructive surgeons because it combines dramatically decreased circulation and chronic infection. The goal of managing this condition is to maximize viable tissue; however, unsatisfactory results, such as extremity amputation, are unavoidable in some cases. For appropriate management, thorough understanding of diabetic foot and the phased approach to its management is needed. The purpose of this study is to introduce an optimal algorithm for diabetic foot management by analyzing cases >12 years. METHODS: A total of 274 patients with diabetic foot at Hanyang University Guri Hospital from 2005 to 2017 were reviewed. The management process was divided into 5 steps: patient evaluation, wound preparation, improving vascularity, surgery and dressing, and rehabilitation. Patient evaluation included a microbial culture, evaluation of vascularity, and an osteomyelitis assessment. During wound preparation, debridement and negative-pressure wound therapy were performed. Vascularity was improved by radiological intervention or surgical method. Surgery and dressing were performed depending on the indications. Rehabilitation was started after complete wound healing. RESULTS: An infection was confirmed in 213 of 263 patients (81.0%). Of 74 cases in which a vascular study was performed, 83.8% showed arterial occlusion. When surgery was performed with complete eradication of the infection in 155 patients, the rate of revision surgery was 20.6%. The revision rate after surgery with a remnant infection of 66 patients was 40.9% (P = .0003). When surgery was performed after successful revascularization for improving blood flow of 47 patients, the rate of revision surgery was 21.3%. In contrast, the revision rate after surgery with unsuccessful or no revascularization of 174 patients was 28.2% (P = .359). CONCLUSION: Diabetic foot is a debilitating disease arising from multifactorial process. As its management is complex, a comprehensive but accessible treatment algorithm is needed for successful results. For this reason, the appropriate algorithm for diabetic foot management introduced in this study is significant. PMID- 29979451 TI - Continuous radiofrequency thermocoagulation under CT-guidance for glossopharyngeal neuralgia: Two case reports: Erratum. PMID- 29979452 TI - Are ADHD medications under or over prescribed worldwide?: Protocol for a systematic review and meta-analysis: Erratum. AB - BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, characterized by age inappropriate and impairing levels of inattention and/or hyperactivity/impulsivity. Pharmacotherapy is an important part of the ADHD multimodal treatment. The extent to which ADHD is pharmacologically over or under treated worldwide is controversial. We aimed to estimate the pooled worldwide rate of ADHD pharmacological treatment in individuals with and without the disorder. METHODS: We will include published or unpublished studies reporting the rates of ADHD pharmacological treatment in participants with and without ADHD of any age group. Population-based, cohort, or follow-up studies, as well as data from insurance health system and third-party reimbursements will be eligible. Searches will be performed in a large number of electronic databases, including Medline, Embase, CINAHL, Cochrane, PsycINFO, Web of Science, and Scopus. The primary outcome will be the prevalence of ADHD pharmacological treatment in individuals with ADHD and without ADHD. Two independent reviewers will perform the screening, and data extraction process. Study quality/bias will be assessed with the Newcastle-Ottawa scale by 2 independent reviewers. To test the robustness of the findings, we will perform a series of sensitivity and meta-regression analysis. Analyses will be performed with R and STATA software. RESULTS, AND CONCLUSION: No IRB approval will be necessary. The results of this systematic review and meta-analysis will be presented at international conferences and published in peer-reviewed journals. PMID- 29979450 TI - Gastric fundus splenosis with hemangioma masquerading as a gastrointestinal stromal tumor in a patient with schistosomiasis and cirrhosis who underwent splenectomy: A case report and literature review. AB - RATIONALE: Splenosis is the heterotopic auto-transplantation of the splenic tissues. Gastric splenosis in a rare location mimics a gastrointestinal stromal tumor (GIST). Gastric splenosis with hemangioma has not been reported throughout the literature. PATIENT CONCERNS: We report a case of a 74-year-old schistosomiasis cirrhosis splenectomy woman diagnosed with gastric fundus mass. Preoperative computed tomography and endoscopic ultrasonography revealed findings suggestive of a GIST. DIAGNOSES: The mass located in the gastric fundus muscularis propria, measuring 3.9 * 2.8 * 2.4 cm with a dark red color, was removed by surgery. In the mass, a 1 * 1-cm red-purple nodule was also found. On microscopic examination, a well-formed splenic tissue divided into two compartments-white pulp and red pulp-separated by an ill-defined interphase known as the marginal zone. However, a nodule in the heterotopic spleen was mainly composed of larger thin-walled muscular vessels. The final diagnosis was gastric splenosis with hemangioma. INTERVENTIONS: After discussion in a multidisciplinary conference, the patient was considered for a GIST resection under gastroscopy. In the process of peeling, the surface of the mucosal, submucosal, muscle layers and the tumor surface were diffusely oozing. The effect of electrocoagulation and hemostasis was extremely poor. Therefore, endoscopic surgery was arrested. After dealing with the patient's family, a combination of laparoscopic-gastroscope double-mirror surgery was decided in accordance with the principle of minimally invasive surgery to preserve the stomach. Owing to several adhesions and concealed the location of tumor, we stopped the double-mirror combination surgery plan. Considering the great possibility of a malignant GIST, we still decided to continue the traditional surgical resection. The tumor was then removed via surgery OUTCOMES:: The patient was favorable with healing and discharged on postoperative day 10. LESSONS: Gastric splenosis with an associated hemangioma is the first well-documented case. Its pathogenesis may be direct implantation. Appropriate medical history taking and Tc-99 m heat-denatured RBC spleen scintigraphy (Tc-99MHDRS) are valuable for its diagnosis; however, pathology is the gold standard. Surgery is a reasonable treatment for gastric splenosis with hemangioma. PMID- 29979453 TI - Successful replantation of 2 digits in a patient with thrombocytosis after splenectomy: A case report: Erratum. PMID- 29979454 TI - LONG-TERM VISUAL CHANGES IN INITIALLY STRONGER FELLOW EYES IN PATIENTS WITH UNILATERAL TYPE 3 NEOVASCULARIZATION. AB - PURPOSE: To evaluate long-term visual changes in initially stronger fellow eyes in patients with unilateral Type 3 neovascularization. METHODS: This retrospective study included 102 patients who were newly diagnosed with unilateral Type 3 neovascularization and in whom the best-corrected visual acuity (BCVA) of the fellow eye was initially better than that of the involved eye. All patients were treated with intravitreal anti-vascular endothelial growth factor injections. The BCVAs were compared at diagnosis, 12 months, 24 months, and the final visit. In patients who experienced >=3 lines of visual deterioration in the BCVA of the fellow eye, the reason for visual deterioration was also verified. RESULTS: The patients were followed for 45.9 +/- 18.5 months after diagnosis. At diagnosis, the fellow-eye BCVA was better than that of the initially involved eye in all 102 patients. However, the fellow-eye visual acuity was the same or worse than that of the initially involved eye in 13 patients (12.7%) at 12 months, in 20 patients (19.6%) at 24 months, and in 24 patients (23.5%) at the final visit. At the final visit, 53 patients (51.9%) had experienced >=3 lines of deterioration in the BCVA of the fellow eye. Fellow-eye neovascularization occurred in 42 patients, and geographic atrophy involving the fovea was noted in the remaining 11 patients. CONCLUSION: Deterioration of the visual acuity of the fellow eye is frequently noted in unilateral Type 3 neovascularization. As a result of this deterioration, the initially stronger fellow eye did not remain stronger in 23.5% of the patients, suggesting the need for long-term strict treatment of the initially involved eye even when the visual acuity of the fellow eye is good. PMID- 29979455 TI - Intravitreal Phacoemulsification Through Corneal Incision for Management of Posteriorly Dislocated Lens Material After Complicated Cataract Surgery: A New Surgical Technique. PMID- 29979456 TI - Structure and reactivity/selectivity control by oriented-external electric fields. AB - This is a tutorial on use of external-electric-fields (EEFs) as effectors of chemical change. The tutorial instructs readers how to conceptualize and design electric-field effects on bonds, structures, and reactions. Most effects can be comprehended as the field-induced stabilization of ionic structures. Thus, orienting the field along the "bond axis" will facilitate bond breaking. Similarly, orienting the field along the "reaction axis", the direction in which "electron pairs transform" from reactants- to products-like, will catalyse the reaction. Flipping the field's orientation along the reaction-axis will cause inhibition. Orienting the field off-reaction-axis will control stereo-selectivity and remove forbidden-orbital mixing. Two-directional fields may control both reactivity and selectivity. Increasing the field strength for concerted reactions (e.g., Diels-Alder's) will cause mechanistic-switchover to stepwise mechanisms with ionic intermediates. Examples of bond breaking and control of reactivity/selectivity and mechanisms are presented and analysed from the "ionic perspective". The tutorial projects the unity of EEF effects, "giving insight and numbers". PMID- 29979457 TI - Nitrogen-enriched carbon spheres coupled with graphitic carbon nitride nanosheets for high performance supercapacitors. AB - Three-dimensional (3D) nitrogen-doped carbon materials with a hierarchically porous structure are prepared by the introduction of nitrogen-doped carbon spheres (NCS) into the inter-sheet spaces of graphitic carbon nitride nanosheets (g-CN). The as-prepared graphitic carbon nitride/nitrogen-doped carbon sphere (g CN/NCS) composites present a high nitrogen doping level, a unique hierarchically porous structure, and a high specific surface area of 448 m2 g-1. Such particular features make the g-CN/NCS composite an ideal material for supercapacitor electrodes, which could deliver a large specific capacitance of 403.6 F g-1 at 0.1 A g-1, an excellent rate capability of 220 F g-1 at 10 A g-1, and a high cycling stability with almost 100% capacitance retention after 5000 cycles at 20 A g-1. Furthermore, the g-CN/NCS electrode-based symmetric supercapacitors exhibit a decent energy density of 6.75 W h kg-1 at a power density of 1000 W kg 1. The enhanced performances are mainly attributed to the high nitrogen doping level and the hierarchically porous structure of the 3D structured g-CN/NCS composites, which provide an efficient pathway for transporting ions and electrons, and endow more active sites for electrochemical energy storage. PMID- 29979458 TI - Tumor-selective catalytic nanosystem for activatable theranostics. AB - A novel tumor-selective catalytic nanosystem that enables efficient chemodynamic therapy (CDT) and activatable fluorescence imaging in H2O2-rich tumor microenvironments has been developed. PMID- 29979459 TI - Enhancement of radionuclide bio-decontamination by screening highly efficient microalgae for Sr biomineralization. AB - In this study, a new strategy for improving the radionuclide bio-decontamination (RBD) activity of microalgae by screening a better strain with high potential for biomineral production has been proposed. A noninvasive dielectrophoresis (DEP) based microalgae screening microplatform has been used to select the highly capable microalgae in RBD. Microalgae (Chlorella vulgaris KMMCC9) with a high degree of competence in strontium (Sr) removal were successfully segregated against Chlorella vulgaris KCTC AG10002 that has relatively weak Sr removal activity under an AC electric field. C. vulgaris KMMCC9 with higher Sr biomineral competence (HSC) was also successfully segregated against others with lower Sr biomineral competence (LSC). Furthermore, after the screening and large-scale cultivation of C. vulgaris KMMCC9 with HSC, the microalgae showed highly effective Sr bio-decontamination in both non-radioactive and radioactive Sr contaminated water compared to wild-type (WT). PMID- 29979460 TI - Superior stability of a bifunctional oxygen electrode for primary, rechargeable and flexible Zn-air batteries. AB - Central to commercializing metal-air batteries is the development of highly efficient and stable catalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). In this study, a composite catalyst with a unique interpenetrating network (denoted as NiCo2O4@MnO2-CNTs-3) was synthesized and exhibited better bifunctional activity (DeltaE = 0.87 V) and durability than both Pt/C and Ir/C catalysts. The improved performance arises from three factors: (i) MnO2 promotes the ORR while NiCo2O4 facilitates the OER; (ii) carbon nanotubes improve the electronic conductivity; and (iii) the highly porous structure enables the adsorption-desorption of O2 and enhances the structural stability. As a result, the primary and rechargeable Zn-air battery affords a high power density and specific capacity (722 mA h g-1), an outstanding discharge stability (255 mW cm-2 after 1000 cycles) and a high cycling stability (over 2280 cycles). Electron microscopy and electrochemical analysis revealed that the degradation of the rechargeable Zn-air battery performance resulted from the damage of the air electrode and the hydrogen evolution reaction on the zinc electrode. A flexible Zn-air battery employing a solid-state electrolyte showed an exciting stability (540 cycles) and high power density (85.9 mW cm-2), suggesting that the anion exchange membrane effectively prevents the migration of Zn2+ ions and the deposition of carbonates. PMID- 29979461 TI - Facile synthesis of highly monodisperse EuSe nanocubes with size-dependent optical/magnetic properties and their electrochemiluminescence performance. AB - We reported a facile and robust method for the synthesis of highly monodisperse EuSe nanocubes (EuSe NCs) with controllable edge lengths in the range of 8-70 nm. The EuSe NCs were formed through the aggregation of EuSe small particles (cores) and then their surface reconstruction under the influence of 1-dodecanethiol (DDT) that acted as a capping surfactant. DDT was not only found to be critical to the nucleation temperature of preparing EuSe NCs, but also played a decisive role in the formation of structurally well-defined nanocubes. The results indicated that the remarkable monodispersity and high shape consistency of EuSe NCs were highly controlled by the change in the DDT concentration. Furthermore, the size-dependent optical/magnetic properties based on the quantum size effect and the influence of edge lengths of EuSe NCs were also investigated and discussed. More importantly, the electrochemiluminescence (ECL) performance of EuSe NCs was first reported. This will make possible more biomedical applications in future. PMID- 29979462 TI - Cathodic electrochemiluminescence behaviour of MoS2 quantum dots and its biosensing of microRNA-21. AB - The cathodic electrochemiluminescence (ECL) behaviour of nontoxic MoS2 quantum dots (QDs) was studied for the first time using potassium peroxydisulfate as the co-reactant. Ag-PAMAM NCs, serving as difunctional tags for quenching and enhancing ECL of MoS2-reduced graphene oxide composites, were introduced into the ECL detection system for signal amplification. By modulating the interparticle distance between MoS2 QDs and Ag-PAMAM NCs, the ECL quenching from resonance energy transfer and the ECL enhancement from surface plasma resonance were realized. Coupling the good ECL performance of MoS2 QDs with the excellent ECL quenching and enhancement effects of Ag-PAMAM NCs, a novel MoS2 QDs-based ECL biosensing platform for sensitive detection of microRNA-21 was achieved with a detection limit of 0.20 fmol L-1 (S/N = 3). This method was successfully applied to the determination of microRNA-21 in human serum samples with recoveries of 90.0-110.0%, suggesting great potential for its applications in biological and chemical analysis. PMID- 29979463 TI - Antibacterial properties and clinical potential of pleuromutilins. AB - Covering: up to 2018Pleuromutilins are a clinically validated class of antibiotics derived from the fungal diterpene (+)-pleuromutilin (1). Pleuromutilins inhibit bacterial protein synthesis by binding to the peptidyl transferase center (PTC) of the ribosome. In this review we summarize the biosynthesis and recent total syntheses of (+)-pleuromutilin (1). We review the mode of interaction of pleuromutilins with the bacterial ribosome, which involves binding of the C14 extension and the tricyclic core to the P and A sites of the PTC, respectively. We provide an overview of existing clinical agents, and discuss the three primary modes of bacterial resistance (mutations in ribosomal protein L3, Cfr methylation, and efflux). Finally we collect structure-activity relationships from publicly available reports, and close with some forward looking statements regarding future development. PMID- 29979464 TI - Inflammation, Immunity, and amyotrophic lateral sclerosis: I. Etiology and pathology. AB - Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. Charcot first described ALS in 18691 ; however, its pathogenesis remains unknown, and effective treatments remain elusive. It is apparent that new paradigms must be investigated to understand the effectors of ALS, including inflammation, immune responses, and the body's response to stress and injury. Herein we discuss the potential role of the immune system in ALS pathogenesis and critically review evidence from patient and animal studies. Although immune system components may indeed play a role in ALS pathogenesis, studies implicating immune cells, antibodies, and cytokines in early disease pathology are limited. We propose more focused studies that examine the role of the immune system together with characterized pathogenesis to determine when, where, and if immune and inflammatory processes are critical to disease progression, and thus worthy targets of intervention. Muscle Nerve, 2018. PMID- 29979466 TI - More severe deficits in functional status associated with higher mortality among adults awaiting liver transplantation. AB - The impact of functional status on liver transplant (LT) waitlist outcomes is not well studied. Early evidence suggests frailty portends increased mortality. We aim to evaluate the association of functional status with LT waitlist survival and the probability of receiving LT among adults with cirrhosis. Using 2005-2016 United Network for Organ Sharing (UNOS) data, we retrospectively assessed the association of functional status, as determined by Karnofsky Performance Status Score (KPSS) with LT waitlist survival and the probability of receiving LT using Kaplan-Meier and multivariate Cox proportional hazard models. Among 118 954 patients listed for LT, patients with worse Karnofsky scores, indicating poor functional status, were progressively more likely to receive liver transplantation compared to patients with better scores, with the most functionally disabled group having 68% higher probability of receiving LT (HR 1.68; 95% CI 1.61-1.75, P < 0.001). Worse functional status was associated with increased waitlist mortality, with the most functionally disabled group 97% more likely to die on the waitlist (HR 1.97; 95% CI 1.81-2.16, P < 0.001). In conclusion, among patients awaiting LT, worse functional status was associated with significantly higher waitlist mortality. PMID- 29979465 TI - Improving the Antimicrobial Power of Low-Effective Antimicrobial Molecules Through Nanotechnology. AB - : The objective of this work was on the one hand to assess the antibacterial activity of amines anchored to the external surface of mesoporous silica particles against Listeria monocytogenes in comparison with the same dose of free amines as well. It was also our aim to elucidate the mechanism of action of the new antimicrobial device. The suitability of silica nanoparticles to anchor, concentrate and improve the antimicrobial power of polyamines against L. monocytogenes has been demonstrated in a saline solution and in a food matrix. Moreover, through microscope observations it has been possible to determine that the attractive binding forces between the positive amine corona on the surface of nanoparticles and the negatively charged bacteria membrane provoke a disruption of the cell membrane. The surface concentration of amines on the surface of the nanoparticles is so effective that immobilized-amines were 100 times more effective in killing L. monocytogenes bacteria than the same amount of free polyamines. This novel approach for the creation of antimicrobial nanodevices opens the possibility to put in value the antimicrobial power of natural molecules that have been discarded because of its low antimicrobial power. PRACTICAL APPLICATION: Consumers demand for high-quality products, free from chemical preservatives, with an extended shelf-life. In this study, a really powerful antimicrobial agent based on a nanomaterial functionalized with a non antimicrobial organic molecule was developed as a proof of concept. Following this approach it could be possible to develop a new generation of natural and removable antimicrobials based on their anchoring to functional surfaces for food, agricultural or medical purposes. PMID- 29979467 TI - Carbene-Stabilized Exceptional Silicon Halides. AB - The isolation of stable carbenes, such as N-heterocyclic carbenes, cyclic alkyl amino carbenes, and abnormal N-heterocyclic carbenes, has encouraged synthetic chemists to use them as neutral ligands for stabilizing unusual compounds with main group elements. In this Minireview, an overview is provided of the recent developments in the chemistry of carbene-stabilized silicon halides, in which the silicon atoms are in low oxidation state. The structural diversities emanating from the differences in the HOMO-LUMO gaps of various carbenes will also be discussed. PMID- 29979468 TI - Mandatory sex selection and mitochondrial transfer. AB - The Institute of Medicine has recently endorsed arguments put forward by John Appleby calling for mandatory sex selection against female offspring in the initial trials of mitochondrial replacement techniques. In this paper I argue that, despite this endorsement, the reasons offered by Appleby for mandatory sex selection are inadequate. I further argue that plausible revisions to Appleby's arguments still fail to convincingly defend such an intrusive policy. While I remain neutral about whether intending parents making use of mitochondrial replacement techniques ought to have access to sex selection, I conclude that to date the case for mandatory sex selection has not been satisfactorily made. PMID- 29979469 TI - Microporous Nanotubes and Nanospheres with Iron-Catechol Sites: Efficient Lewis Acid Catalyst and Support for Ag Nanoparticles in CO2 Fixation Reaction. AB - FeIII -containing hyper-crosslinked microporous nanotubes (FeNTs) and nanospheres (FeNSs) are synthesized through the reaction of catechol and dimethoxymethane in the presence of FeCl3 or CF3 SO3 H. Both FeNTs and FeNSs demonstrate excellent catalytic activity in Lewis acid catalysis (hydrolysis and regioselective methanolysis of styrene oxide) and tandem catalysis involving a sequential oxidation-cyclization process, which selectively converts benzyl alcohol to 2 phenyl benzimidazole. Apart from Lewis acidity, the FeNTs and FeNSs also showed CO2 uptake capacities of 2.6 and 2.2 mmol g-1 , respectively, at a pressure of 1 atm and temperature of 273 K. Furthermore, Ag nanoparticles are immobilized successfully on the surfaces of FeNTs and FeNSs by the liquid-phase impregnation method to prepare Ag@FeNT and Ag@FeNS nanocomposites, which show high catalytic activity for the selective fixation of CO2 to phenylacetylene to yield phenylpropiolic acid at 60 degrees C and 1 atm CO2 pressure. Hence, FeIII catechol-containing hyper-crosslinked nanotubes and nanospheres have huge potential not only as Lewis acid catalysts, but also as excellent supports for immobilizing Ag nanoparticles in the design of a robust catalyst for the carboxylation of terminal alkynes, which has wide scope in catalysis and environmental research. PMID- 29979470 TI - Photodissociation of Sodium Iodide Clusters Doped with Small Hydrocarbons. AB - Marine aerosols consist of a variety of compounds and play an important role in many atmospheric processes. In the present study, sodium iodide clusters with their simple isotope pattern serve as model systems for laboratory studies to investigate the role of iodide in the photochemical processing of sea-salt aerosols. Salt clusters doped with camphor, formate and pyruvate are studied in a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) coupled to a tunable laser system in both UV and IR range. The analysis is supported by ab initio calculations of absorption spectra and energetics of dissociative channels. We provide quantitative analysis of IRMPD measurements by reconstructing one-photon spectra and comparing them with the calculated ones. While neutral camphor is adsorbed on the cluster surface, the formate and pyruvate ions replace an iodide ion. The photodissociation spectra revealed several wavelength-specific fragmentation pathways, including the carbon dioxide radical anion formed by photolysis of pyruvate. Camphor and pyruvate doped clusters absorb in the spectral region above 290 nm, which is relevant for tropospheric photochemistry, leading to internal conversion followed by intramolecular vibrational redistribution, which leads to decomposition of the cluster. Potential photodissociation products of pyruvate in the actinic region may be formed with a cross section of <2*10-20 cm2 , determined by the experimental noise level. PMID- 29979471 TI - Importance of anaerobic ammonium oxidation as a nitrogen removal pathway in freshwater marsh sediments. AB - AIMS: To explore the role of anaerobic ammonium oxidation (anammox) in nitrogen removal in freshwater marshes. METHODS AND RESULTS: The 16S rRNA gene sequences of Candidatus Kuenenia and Candidatus Brocadia were simultaneously detected in the sediment of freshwater marshes of Green Bay Wetland that is located in Eastern China by using Illumina-based sequencing of the total bacterial 16S rRNA genes, and Candidatus Brocadia comprised more than 80% of the total anammox related sequences. The abundance of anammox bacteria was determined by quantitative PCR on their hydrazine synthase (hzs) genes, which ranged from 3.13 * 104 to 1.58 * 105 copies per g sediment with little temporal variation. The potential anammox rates measured by 15 N-stable isotope pairing technique were 0.78-5.37 nmol N g-1 sediment per h, accounting for 4.3-38.5% of total sediment dinitrogen gas (N2 ) production. Both the anammox activity and its contribution to N2 production were sensitive to temporal variation and correlated well with the sediment NO3 - content. To further examine the nitrogen removal potential via anammox, batch culture was set-up to enrich anammox bacteria from the marsh sediments. Both the activity and abundance of anammox bacteria increased significantly after 6 months of incubation, varying from 61.6 to 95.8 nmol N g-1 sediment per h and 2.86 * 105 to 6.58 * 105 copies per g sediment respectively. CONCLUSIONS: Our results revealed the great potential of anammox in nitrogen removal in freshwater marshes. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to show the anammox activity and its temporal variation in freshwater marsh sediments, which improved our understanding of nitrogen removal mechanisms in freshwater marshes. PMID- 29979472 TI - Photocatalyzed Intermolecular Aminodifluoromethylphosphonation of Alkenes: Facile Synthesis of alpha,alpha-Difluoro-gamma-aminophosphonates. AB - An efficient and practical method for the synthesis of alpha,alpha-difluoro-gamma aminophosphonates through photocatalyzed intermolecular aminodifluoromethylphosphonation of alkenes has been developed. In this reaction, difluoromethylphosphonate is used as an important fluorinated reagent. Furthermore, the mild reaction conditions, simple operation, and broad substrate scope make this protocol very practical and attractive. The derivatization reaction in the synthesis of difluoromethylphosphonated chiral binaphthylamine ligands and alpha,alpha-difluoro-gamma-aminophosphoric acid highlight the applicability of this method. PMID- 29979473 TI - Course of neuropsychiatric symptoms in dementia: 5-year longitudinal study. AB - OBJECTIVE: Neuropsychiatric symptoms (NPS) in dementia are frequent and challenging for patients, carers, and the health care system, but few long-term studies exist. We analyse the longitudinal course of NPS in patients with mild dementia. METHODS: A longitudinal cohort study of 223 patients with mild dementia and annual assessments using the Neuropsychiatric Inventory (NPI) for 5 years. RESULTS: A total 1043 NPI assessments, representing 97% of all possible measurements of living cohort members, were analysed. Neuropsychiatric symptoms were common at baseline, and only a moderate increase in total NPS score from 15 to 17 with no increase in the proportion with high NPI total scores. Ninety seven percent scored >=16, and 49% scored >=36 on NPI total score at least once during follow-up. Individual NPS fluctuated and often reappeared. The most common symptoms ever reported was apathy (83%), depression (63%), appetite (63%), and aberrant motor behavior (60%). Cognitive decline was associated with higher NPI total score and several NPI items, but only the frequency of apathy increased significantly with time. Lewy body dementia was associated with higher NPI total score and psychotic symptoms. Alzheimer's disease was associated with increase in apathy. CONCLUSIONS: Severe NPS are already common at time of dementia diagnosis, and the increase in overall severity over 5 years was moderate. Individual symptoms tend to fluctuate over time within patients and correspond to states rather than traits. These findings highlight the need to focus on, and plan for, NPS as part of dementia pathway, and are relevant for clinical trial design. PMID- 29979474 TI - Understanding Thermal and Photochemical Aryl-Aryl Cross-Coupling by the AuI /AuIII Redox Couple. AB - Systematic mechanistic investigations of the gold(I)/gold(III) redox-controlled aryl-aryl cross-coupling reaction have been performed by using both a thermal and photochemical approach. Electron-deficient and electron-rich arenes were considered as the coupling partners of the reaction. Based on transition-state modeling and distortion/interaction analyses, it is shown that AuI prefers to react with electron-deficient arenes whereas AuIII likes to activate electron rich arenes. This orthogonal reactivity of gold makes it an efficient catalyst for the aryl-aryl cross-coupling reaction. The crucial role of the carboxylate ligand in the reaction has been elucidated through analysis of the transition states. It is shown that due to the presence of two coordination sites, a carboxylate ligand can stabilize the transition state more efficiently than other monodentate ligands such as chloride (Cl- ). Moreover, carbon-boron transmetalation is shown to be favorable over direct C-H metalation, hence reactions initialized by C-B transmetalation are expected to be much faster and selective. Additionally, a dual photoredox/gold catalyst was employed to access the AuI /AuIII catalytic cycle for the cross-coupling reaction. [Ru(bpy)3 ]2+ was used as the photoredox catalyst for the reaction, which, on excitation, transfers an electron to one of the coupling partners, namely a diazonium salt (ArN2+ ), and initializes the cycle. PMID- 29979475 TI - Molecular modeling, biochemical characterization, and pharmacological properties of Cc3 -SPase: A platelet-aggregating thrombin-like enzyme purified from Cerastes cerastes venom. AB - Cc3 -SPase (30 kDa-proteinase; pI 5.98) was isolated from Cerastes cerastes venom. Its sequence of 271 residues yielded from LC-MALDI-TOF showed high degrees of homology when aligned with other proteinases. Cc3 -SPase cleaved natural and synthetic proteins such as casein and fibrinogen leaving fibrin clots unaffected. Cc3 -SPase was fully abolished by ion chelators, whereas aprotinin, antithrombin III (Sigma Aldrich, Saint-Louis, Missouri, USA), and heparin were ineffective. Affinity of Cc3 -SPase to benzamidine indicated the presence of an aspartate residue in the catalytic site as confirmed by three-dimensional structure consisting of 14 beta-strands and four alpha-helices. Molecular mechanisms revealed that Cc3 -SPase is capable of promoting dysfunctional platelet aggregation via two signaling pathways mediated by the G-coupled protein receptors and alphaIIbbeta3 integrin. Cc3 -SPase is involved in both extrinsic/intrinsic coagulation pathways in deficient plasmas by replacing defective/lacking factors FII, FVII, and FVIII but not FX. Cc3 -SPase could substitute missing factors in blood diseases related to plasma factor deficiencies. PMID- 29979476 TI - Involvement of chalcone reductase in the soybean isoflavone metabolon: identification of GmCHR5, which interacts with 2-hydroxyisoflavanone synthase. AB - Soybean (Glycine max) 5-deoxyisoflavonoids (daidzein and its conjugates) are precursors of glyceollin phytoalexins. They are also converted to equol by microbes in the human intestine, resulting in health benefits. 5 Deoxyisoflavonoids accumulate in the roots (93% mol/mol of the total root isoflavonoids) and seeds of unstressed soybean plants. Chalcone reductase (CHR) is a key enzyme mediating 5-deoxyisoflavonoid biosynthesis because it catalyzes the production of 6'-deoxychalcone through its effects on the chalcone synthase (CHS)-catalyzed reaction. The soybean genome encodes at least 11 CHR-related homologs, but it is unclear which ones are functionally important for daidzein accumulation in unstressed plants. Among the CHR homologs, the temporal and spatial expression patterns of GmCHR5 were the most correlated with the distribution patterns of 5-deoxyisoflavonoids. The CHR activity of GmCHR5 was confirmed in vitro and in planta. In the in vitro assays, the ratio of CHR products (6'-deoxychalcone) to total CHS products (R value) was dependent on GmCHR5 and CHS concentrations, with higher concentrations resulting in higher R values (i.e. approaching 90%). Subcellular localization analyses revealed that GmCHR5 was present in the cytoplasm and nucleus. Protein-protein interaction assays indicated that GmCHR5, but not GmCHR1 and GmCHR6, interacted with 2 hydroxyisoflavanone synthase (IFS) isozymes. The CHS isozymes also interacted with IFS isozymes but not with GmCHR5. The proposed micro-compartmentalization of isoflavone biosynthesis through the formation of an IFS-mediated metabolon is probably involved in positioning GmCHR5 close to CHS, resulting in an R value that is high enough for the accumulation of abundant 5-deoxyisoflavonoids in soybean roots. PMID- 29979477 TI - Polymorphic Phase Transitions in Carbamazepine and 10,11-Dihydrocarbamazepine. AB - Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11 dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetry-X-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine form II undergoes a conversion to form I by a localised melt phase. Carbamazepine (CBZ) form IV converts to form I at 182 degrees C, again by a localised intermediate melt phase. CBZ form II converted to form I at 119 degrees C by a pathway that appears to have included some melting, and form III underwent a part melt-recrystallisation and a part sublimation recrystallisation to form I. PMID- 29979478 TI - Inflammation, immunity, and amyotrophic lateral sclerosis: II. immune-modulating therapies. AB - With the emerging popularity of immune-modulatory therapies to treat human diseases there is a need to step back from hypotheses aimed at assessing a condition in a single-system context and instead take into account the disease pathology as a whole. In complex diseases, such as amyotrophic lateral sclerosis (ALS), the use of these therapies to treat patients has been largely unsuccessful and likely premature given our lack of understanding of how the immune system influences disease progression and initiation. In addition, we still have an incomplete understanding of the role of these responses in our model systems and how this may translate clinically to human patients. In this review we discuss preclinical evidence and clinical trial results for a selection of recently conducted studies in ALS. We provide evidence-based reasoning for the failure of these trials and offer suggestions to improve the design of future investigations. Muscle Nerve, 2018. PMID- 29979479 TI - Exercise training in overweight and obese children: Recreational football and high-intensity interval training provide similar benefits to physical fitness. AB - This study compared the effects of recreational football and high-intensity interval training (HIIT) on body composition, muscular fitness, and cardiorespiratory fitness in overweight and obese children. Forty-two overweight/obese males aged 11-13 years [body mass index (BMI) >20.5 kg/m2 ] were randomly assigned to a recreational football training group (n = 14; 157.9 +/- 5.8 cm; 63.7 +/- 12.6 kg), HIIT group (n = 14; 163.8 +/- 9.4 cm; 71.5 +/- 10.5 kg), or nontraining control group (n = 14; 162.7 +/- 9.3 cm; 67.4 +/- 16.1 kg). Physical fitness components were measured at baseline and after 12 weeks of training at the same time of the day and under similar conditions, including body composition, muscular fitness (lower-body power, change-of-direction speed, and flexibility), and cardiovascular fitness (Yo-Yo Intermittent Endurance test distance, resting heart rate, and blood pressure). Lean body mass (4.3%, ES = 0.40; 95% CI: -0.48, 1.29; P = .382) and muscle mass 4.4% (ES = 0.40; 95% CI: 0.48, 1.29; P = .378) very likely increased in the recreational football group, while possible improvements were observed in the HIIT group (lean body mass: 2.5%, ES = 0.22; 95% CI: -0.62, 1.06; P = .607, muscle mass: 2.8%, ES = 0.23; 95% CI: -0.61, 1.07; P = .594). Only trivial increases were observed in the control group for lean body mass (0.5%, ES = 0.05; 95% CI: -0.70, 0.79; P = .906) and muscle mass (1.1%, ES = 0.09; 95% CI: -0.65, 0.83; P = .814). Significant differences were found between the recreational football and control groups in post-training body mass (P = .034) and body mass index (P = .017). Body fat very likely decreased in the recreational football group (-7.7%, ES = -0.41; 95% CI: 1.29, 0.48; P = .376) and possibly decreased in the HIIT group (-5.2%, ES = 0.22; 95% CI: -1.05, 0.62; P = .607), with a trivial reduction in the control group (-1.1%, ES = -0.04; 95% CI: -0.78, 0.70; P = .914). Very likely increases in lower-body power were evident in the recreational football (17.0%, ES = 0.76; 95% CI: -0.15, 1.66; P = .107) and control groups (16.1%, ES = 0.55; 95% CI: 0.20, 1.31; P = .156), while small improvements were observed in the HIIT group (6.0%, ES = 0.24; 95% CI: -0.60, 1.08; P = .580, possible). Likely to most likely improvements in Yo-Yo Intermittent Endurance test performance and change-of direction speed were noted in the recreational football group (Yo-Yo: 79.8%, ES = 1.09; 95% CI: 0.16, 2.03; P = .025, change-of-direction speed: -10.6%, ES = 1.05; 95% CI: -1.98, -0.12; P = .031) and the HIIT group (Yo-Yo: 81.2%, ES = 1.03; 95% CI: 0.15, 1.92; P = .025, change-of-direction speed: -5.4%, ES = -0.91; 95% CI: -1.79, -0.04; P = .045). Diastolic blood pressure likely decreased in the recreational football (-8.6%, ES = -0.74; 95% CI: -1.64, 0.17; P = .116) and HIIT groups (-9.8%, ES = -0.57; 95% CI: -1.40, 0.30; P = .195), with a possible increase in the control group (1.2%, ES = 0.21; 95% CI: -0.53, 0.96; P = .068). Recreational football and HIIT elicited improvements in all muscular and cardiorespiratory fitness measures. In contrast, the control group, which performed only physical education classes, increased body mass, BMI, and fat mass. Therefore, additional activities such as recreational football or HIIT might counter the prevalence of overweight and obesity in children. PMID- 29979480 TI - The 'TranSeq' 3'-end sequencing method for high-throughput transcriptomics and gene space refinement in plant genomes. AB - High-throughput RNA sequencing has proven invaluable not only to explore gene expression but also for both gene prediction and genome annotation. However, RNA sequencing, carried out on tens or even hundreds of samples, requires easy and cost-effective sample preparation methods using minute RNA amounts. Here, we present TranSeq, a high-throughput 3'-end sequencing procedure that requires 10- to 20-fold fewer sequence reads than the current transcriptomics procedures. TranSeq significantly reduces costs and allows a greater increase in size of sample sets analyzed in a single experiment. Moreover, in comparison with other 3'-end sequencing methods reported to date, we demonstrate here the reliability and immediate applicability of TranSeq and show that it not only provides accurate transcriptome profiles but also produces precise expression measurements of specific gene family members possessing high sequence similarity. This is difficult to achieve in standard RNA-seq methods, in which sequence reads cover the entire transcript. Furthermore, mapping TranSeq reads to the reference tomato genome facilitated the annotation of new transcripts improving >45% of the existing gene models. Hence, we anticipate that using TranSeq will boost large scale transcriptome assays and increase the spatial and temporal resolution of gene expression data, in both model and non-model plant species. Moreover, as already performed for tomato (ITAG3.0; www.solgenomics.net), we strongly advocate its integration into current and future genome annotations. PMID- 29979481 TI - Time, memory, and the legacy of Howard Eichenbaum. AB - Over the past 15 years, there has been an explosion of new research on the role of the hippocampus in the representation of information about time in memory. Much of this work was inspired by the ideas and research of Howard Eichenbaum, who made major contributions to our understanding of the neurobiology of episodic memory and the neural representation of time. In this article, I will review evidence regarding the role of time in understanding hippocampal function. This review will cover a broad range of evidence from studies of humans and nonhuman animals with a narrative arc that follows Howard's major discoveries. These studies demonstrate that the hippocampus encodes information in relation to an episodic context, and that time, as well as space, serves to define these contexts. Moreover, the research has shown that the hippocampus can encode temporal, spatial, and situational information in parallel. Building on this work, I present a new framework for understanding temporal structure in human episodic memory. I conclude by outlining current controversies and new questions that must be addressed by the field in the years to come. PMID- 29979482 TI - Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates. AB - A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 degrees C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3 S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr -N bonds. PMID- 29979483 TI - Relationship between clinical severity of "new" bronchopulmonary dysplasia and HRCT abnormalities in VLBW infants. AB - BACKGROUND: To assess the relationship between HRCT abnormalities and the clinical severity of "new" bronchopulmonary dysplasia (BPD) and respiratory assistance in <1500 g preterm infants. METHODS: HRCT was performed at the time of discharge in 109 preterm infants with BPD who were born between 2008 and 2014. BPD severity was defined as mild, moderate, or severe according to the NIH diagnostic criteria. Total HRCT scores for each infant were obtained from the sum of the number of BPD lobes assessed by two radiologists: a hyperaeration score (Hs) composed of decreased attenuation, mosaic attenuation, and bulla/bleb, and a parenchyma score (Ps) composed of linear lesions, consolidation, bronchial wall thickening, and bronchiectasis. We compared HRCT scores based on BPD severity and respiratory modes, such as invasive mechanical ventilation (IMV), non-invasive MV (NIMV), and oxygen therapy. RESULTS: Among the group of included infants (n = 101), mild BPD was found in 46.5%, moderate BPD in 45.5%, and severe BPD in 7.9%. When partial correlation was adjusted by gestational age (GA) and birth weight, the duration of NIMV was correlated with Ps (r = 0.382, P < 0.001), Hs (r = 0.223, P = 0.027), and total score (r = 0.384, P < 0.001). The duration of oxygen therapy was correlated with Ps (r = 0.374, P < 0.001) and Hs (r = 0.227, P = 0.023). Ps showed a correlation with BPD severity (r = 0.381, P = 0.007) in infants born at <=26 weeks (GA) and those born at >27 weeks GA (r = 0.298, P = 0.042). CONCLUSIONS: Parenchymal changes showed a greater correlation with the clinical severity of "new" BPD cases, especially in infants born at <=26 weeks GA. The use of NIMV showed a greater correlation with Ps than Hs. PMID- 29979484 TI - Association between urinary incontinence and physical frailty in Korea. AB - OBJECTIVE: The purpose of this study was to investigate the associations between urinary incontinence (UI) and physical frailty (PF). METHODS: The study participants (n = 404) who visited the geriatric clinic were divided into two groups according to the presence or absence of UI based on questionnaire results. We analysed the relationship between each factor associated with PF and the risk of UI according to the number of factors associated with PF. RESULTS: Urinary incontinence was associated with grip strength and history of falls (P = 0.01, 0.02, respectively). The risk of UI increased as the patients' number of PF related factors increased (P for trend = 0.04). CONCLUSIONS: The risk of UI increased as the severity of PF increased. Strength and the experiences of falls were associated with UI. PMID- 29979485 TI - Effects of plantar sensitivity on balance and mobility in community-dwelling older adults: A Turkish study. AB - OBJECTIVE: The aim of this study was to investigate the association of regional plantar tactile sensitivity with balance and mobility in community-dwelling older people. METHODS: Fifty-five older adults (39 women and 16 men) mean age 73.5 +/- 6.5 years participated in the study. Plantar tactile sensitivity was assessed at nine regions of the foot using Semmes-Weinstein monofilaments. Balance and mobility of the subjects were evaluated with Berg Balance Scale and Rivermead Mobility Index, respectively. RESULTS: Plantar tactile sensitivity was not significantly correlated with balance and mobility scores. No significant differences were obtained when balance and mobility scores were compared between subjects with and without plantar sensitivity. CONCLUSIONS: This study revealed that plantar tactile sensory was not associated with balance and mobility functions in older adults. This result may be related to the protection of other sensory systems supporting the maintenance of balance and mobility functions in physically active community-dwelling older people. PMID- 29979486 TI - Engineering triterpene metabolism in the oilseed of Arabidopsis thaliana. AB - Squalene and botryococcene are linear, hydrocarbon triterpenes that have industrial and medicinal values. While natural sources for these compounds exist, there is a pressing need for robust, renewable production platforms. Oilseeds are an excellent target for heterologous production because of their roles as natural storage repositories and their capacity to produce precursors from photosynthetically-derived carbon. We generated transgenic Arabidopsis thaliana plants using a variety of engineering strategies (subcellular targeting and gene stacking) to assess the potential for oilseeds to produce these two compounds. Constructs used seed-specific promoters and evaluated expression of a triterpene synthase alone and in conjunction with a farnesyl diphosphate synthase (FPS) plus 1-deoxyxylulose 5-phosphate synthase (DXS). Constructs directing biosynthesis to the cytosol to harness isoprenoid precursors from the mevalonic acid (MVA) pathway were compared to those directing biosynthesis to the plastid compartment diverting precursors from the methylerythritol phosphate (MEP) pathway. On average, the highest accumulation for both compounds was achieved by targeting the triterpene synthase, FPS and DXS to the plastid (526.84 MUg/g seed for botryococcene and 227.30 MUg/g seed for squalene). Interestingly, a higher level accumulation of botryococcene (a non-native compound) was observed when the biosynthetic enzymes were targeted to the cytosol (>1000 MUg/g seed in one line), but not squalene (natively produced in the cytosol). Not only do these results indicate the potential of engineering triterpene accumulation in oilseeds, but they also uncover some the unique regulatory mechanisms controlling triterpene metabolism in different cellular compartments of seeds. PMID- 29979487 TI - The Impact of Adrenomedullin Thr22 on Selectivity within the Calcitonin Receptor like Receptor/Receptor Activity-Modifying Protein System. AB - Adrenomedullin (ADM) is a peptide hormone of the calcitonin gene-related peptide (CGRP) family. It is involved in the regulation of cardiovascular processes such as angiogenesis, vasodilation, and the reduction of oxidative stress. ADM mediates its effects by activation of the ADM-1 and -2 receptors (AM1 R/AM2 R), but also activates the CGRP receptor (CGRPR) with reduced potency. It binds to the extracellular domains of the receptors with its C-terminal binding motif (residues 41-52). The activation motif, consisting of a disulfide-bonded ring structure (residues 16-21) and an adjacent helix (residues 22-30), binds to the transmembrane region and stabilizes the receptor conformation in the active state. While it was shown that the binding motif of ADM guides AM1 R selectivity, there is little information on the activation motif itself. Here, we demonstrate that Thr22 of ADM contributes to the selectivity. By using solid-phase peptide synthesis and cAMP-based signal transduction, we studied the effects of analogues in the activation motif of ADM on AM1 R and CGRPR activity. Our results indicate that Thr22 terminates the alpha-helix and orients the ring segment by hydrogen bonding. Using olefin stapling, we showed that the alpha-helical arrangement of the ring segment leads to decreased AM1 R activity, but does not affect CGRPR activation. These results demonstrate that the conformation of the ring segment of ADM has a strong impact on the selectivity within the receptor system. PMID- 29979488 TI - Patient-reported outcomes of blue-light flexible cystoscopy with hexaminolevulinate in the surveillance of bladder cancer: results from a prospective multicentre study. AB - OBJECTIVE: To evaluate blue-light flexible cystoscopy (BLFC) with hexaminolevulinate in the office surveillance of patients with non-muscle invasive bladder cancer with a high risk of recurrence by assessing its impact on pain, anxiety, subjective value of the test and patient willingness to pay. MATERIALS AND METHODS: A prospective, multicentre, phase III study was conducted during which the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, Pain and 'Was It Worth It' questionnaires were administered at baseline, after surveillance with BLFC and after resection for those referred to the operating room. Comparisons of scores were performed between groups. RESULTS: A total of 304 patients were enrolled, of whom 103 were referred for surgical examination. Of these, 63 were found to have histologically confirmed malignancy. Pain levels were low throughout the study. Anxiety levels decreased after BLFC (? = -2.6), with a greater decrease among those with negative pathology results (P = 0.051). No differences in anxiety were noted based on gender, BLFC results, or test performance (true-positive/false-positive). Most patients found BLFC 'worthwhile' (94%), would 'do it again' (94%) and 'would recommend it to others' (91%), with no differences based on BLFC results or test performance. Most patients undergoing BLFC (76%) were willing to pay out of pocket. CONCLUSIONS: Anxiety decreased after BLFC in patients with negative pathology, including patients with false-positive results. Most of the patients undergoing BLFC were willing to pay out of pocket, found the procedure worthwhile and would recommend it to others, irrespective of whether they had a positive BLFC result or whether this was false-positive after surgery. PMID- 29979489 TI - Happiness, self-esteem, and prosociality in children with and without autism spectrum disorder: Evidence from a UK population cohort study. AB - : High levels of childhood happiness, self-esteem, and prosociality are associated with positive social and emotional outcomes. Little is known about whether these constructs co-occur and how levels of co-occurrence are different in children with or without Autism Spectrum Disorder (ASD). Data was obtained from 13,285 11-year olds (408 with ASD) from a UK based prospective cohort study. Latent class analysis revealed five distinct classes: The "very low prosociality class" (with ASD 32% vs. without ASD 7%) was characterized by children who were happy and had high self-esteem but they were not prosocial. The "low happiness class" (with ASD 3% vs. without ASD 3%), included those children who had moderate self-esteem and were prosocial but were the least happy. Children in the "low to moderate positive functioning class" (with ASD 16% vs. without ASD 6%) were moderately happy and had the lowest self-esteem but were prosocial. The "moderate to high positive functioning class" (with ASD 17% vs. without ASD 23%) was characterized by children who were happy, had moderate self-esteem, and were very prosocial. The majority of children were in the "optimum class" (with ASD 31% vs. without ASD 62%), and were very happy, very prosocial with high self-esteem. Our findings demonstrate that for the majority of children in our sample, happiness, self-esteem, and prosociality co-occur. Furthermore, although as a group children with ASD have lower levels of positive functioning, our multivariable latent class approach suggests that nearly half of children with ASD are happy, have good levels self-esteem, and are prosocial. Autism Res 2018, 11: 1011-1023. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: High levels of childhood happiness, self-esteem, and prosociality are associated with positive social and emotional outcomes. In this study, we investigated whether happiness, self-esteem and prosociality co-occur in children, and how possible co-occurrence differs between those with and without Autism Spectrum Disorder. We found that for the majority of children happiness, self-esteem, and prosociality co-occur. Furthermore, although as a group children with ASD have lower levels of positive functioning, our findings suggest that nearly half of children with ASD are happy, have good levels of self-esteem, and are prosocial. PMID- 29979490 TI - Engineering linear, branched-chain triterpene metabolism in monocots. AB - Triterpenes are thirty-carbon compounds derived from the universal five-carbon prenyl precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Normally, triterpenes are synthesized via the mevalonate (MVA) pathway operating in the cytoplasm of eukaryotes where DMAPP is condensed with two IPPs to yield farnesyl diphosphate (FPP), catalyzed by FPP synthase (FPS). Squalene synthase (SQS) condenses two molecules of FPP to generate the symmetrical product squalene, the first committed precursor to sterols and most other triterpenes. In the green algae Botryococcus braunii, two FPP molecules can also be condensed in an asymmetric manner yielding the more highly branched triterpene, botryococcene. Botryococcene is an attractive molecule because of its potential as a biofuel and petrochemical feedstock. Because B. braunii, the only native host for botryococcene biosynthesis, is difficult to grow, there have been efforts to move botryococcene biosynthesis into organisms more amenable to large-scale production. Here, we report the genetic engineering of the model monocot, Brachypodium distachyon, for botryococcene biosynthesis and accumulation. A subcellular targeting strategy was used, directing the enzymes (botryococcene synthase [BS] and FPS) to either the cytosol or the plastid. High titres of botryococcene (>1 mg/g FW in T0 mature plants) were obtained using the cytosolic targeting strategy. Plastid-targeted BS + FPS lines accumulated botryococcene (albeit in lesser amounts than the cytosolic BS + FPS lines), but they showed a detrimental phenotype dependent on plastid-targeted FPS, and could not proliferate and survive to set seed under phototrophic conditions. These results highlight intriguing differences in isoprenoid metabolism between dicots and monocots. PMID- 29979491 TI - Semiconducting Synthetic Melanin-Based Organic/Inorganic Hybrid Photoanodes for Solar Water Oxidation. AB - We report the development of semiconducting melanin-based organic/inorganic hybrid photoanodes for solar water oxidation. Synthetic melanin thin-film incorporating polyoxometalate (POM) water oxidation catalysts (WOCs) are readily deposited on the surface of various n-type inorganic semiconductors (e.g., Fe2 O3 , BiVO4 , and TiO2 ) by electropolymerization. The deposition of melanin and POM hybrid (MP) thin-film results in the remarkably improved performance of an underlying semiconductor photoanode for solar water oxidation with a significantly increased photocurrent density and decreased onset potential for water oxidation through the formation of a melanin-based p-n heterojunction structure. We believe that this study can provide insights into the design and fabrication of various melanin-based optoelectronic devices by utilizing its unique physicochemical properties. PMID- 29979492 TI - Iridium-Catalyzed Reductive Alkylations of Secondary Amides. AB - Reported herein is the first direct, metal-catalyzed reductive functionalization of secondary amides to give functionalized amines and heterocycles. The method is shown to have exceptionally broad scope with respect to suitable nucleophiles, which cover both hard and soft C nucleophiles as well as a P nucleophile. The reaction exhibits good chemoselectivity and tolerates several sensitive functional groups. PMID- 29979494 TI - Emotion regulation in autism spectrum disorder: Where we are and where we need to go. AB - : Emotion dysregulation is a common issue experienced by individuals with autism spectrum disorder (ASD) and has been associated with a wide range of negative mental and physical health outcomes. This commentary highlights the role emotion dysregulation plays in ASD by first considering the literature on emotion regulation (ER) in the general population and then summarizing the ER research in ASD. Based on the evaluation of previous research findings, we conclude that individuals with ASD have more ER difficulties and consistently self-report or demonstrate a less adaptive pattern of ER strategy use. In addition, the higher prevalence of internalizing and externalizing issues seen in ASD are associated with the greater habitual use of some ER strategies and less habitual use of others. Conceptual and methodological limitations are discussed, including the use of coping measures and single-method approaches, and ASD gender distribution. We propose a set of new directions for investigating ER in ASD, incorporating knowledge from other literatures on the role of flexibility in healthy adaptation, overlaps between flexibility and executive function deficits, the adaptive value of up-regulation of positive emotions, and the importance of emotional self-awareness. Increasing our capacity for identifying the mechanisms underlying co-morbid affective disorders can ultimately inform the design of effective interventions to maximize the wellbeing of individuals with ASD. Autism Res 2018, 11: 962-978. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Research has shown that people diagnosed with autism tend to have difficulties with regulating their own emotions. This commentary article summarizes the main information from emotion regulation research conducted both in autism and in other populations. We make suggestions on how we can improve emotion regulation research in autism, with the ultimate goal being to use the learning gained from research to design effective interventions that can improve the wellbeing of people with autism. PMID- 29979493 TI - Azide- and Alkyne-Bearing Metabolic Chemical Reporters of Glycosylation Show Structure-Dependent Feedback Inhibition of the Hexosamine Biosynthetic Pathway. AB - Metabolic chemical reporters (MCRs) of protein glycosylation are analogues of natural monosaccharides that bear reactive groups, like azides and alkynes. When they are added to living cells and organisms, these small molecules are biosynthetically transformed into nucleotide donor sugars and then used by glycosyltransferases to modify proteins. Subsequent installation of tags by bioorthogonal chemistries can then enable the visualization and enrichment of these glycoproteins. Although this two-step procedure is powerful, the use of MCRs has the potential to change the endogenous production of the natural repertoire of donor sugars. A major route for the generation of these glycosyltransferase substrates is the hexosamine biosynthetic pathway (HBP), which results in uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). Interestingly, the rate-determining enzyme of the HBP, glutamine fructose-6 phosphate amidotransferase (GFAT), is feedback inhibited by UDP-GlcNAc. This raises the possibility that a build-up of UDP-MCRs would block the biosynthesis of UDP-GlcNAc, resulting in off target effects. Here, we directly test this possibility with recombinant human GFAT and a small panel of synthetic UDP-MCRs. We find that MCRs with larger substitutions at the N-acetyl position do not inhibit GFAT, whereas those with modifications of the 2- or 6-hydroxy group do. These results further illuminate the considerations that should be applied to the use of MCRs. PMID- 29979495 TI - Reevaluating approaches to cystic fibrosis pulmonary exacerbations. AB - Cystic Fibrosis (CF) lung disease is characterized by intermittent acute episodes of worsening signs, symptoms, and pulmonary function; these so-called pulmonary exacerbations (PEx) appear to be important drivers of long-term declines in lung function, quality of life, and life expectancy. Surveillance for development of PEx and their treatment is a fundamental component of chronic CF management, and the merits of novel CF therapies are often judged based on their ability to reduce the frequency of PEx. Given the central role that they play, it is surprising how poorly PEx are understood, how thin is the evidence base for their treatment and how often they are left unrecognized and untreated in clinical practice. This paper reviews what is known and what is unknown regarding the nature of PEx, and discusses the impact of missed recognition and treatment of these episodes as well as the apparent variation in practice across CF care centers. The arguments supporting a liberal, highly sensitive approach to the diagnosis of PEx are presented, as well as recommendation for how care programs can achieve consistency in their early recognition and treatment. A stepwise approach to personalized treatment supported by close follow-up to ensure the successful resolution of all signs and symptoms will lead to the stabilization of patients' lung function and quality of life. Recommendations are made regarding important priorities for research into evidence-based approaches to improving the care of PEx. PMID- 29979496 TI - Creation of a myosin Va-TAP-tagged mouse and identification of potential myosin Va-interacting proteins in the cerebellum. AB - The actin-based motor myosin Va transports numerous cargos, including the smooth endoplasmic reticulum (SER) in cerebellar Purkinje neurons (PNs) and melanosomes in melanocytes. Identifying proteins that interact with this myosin is key to understanding its cellular functions. Toward that end, we used recombineering to insert via homologous recombination a tandem affinity purification (TAP) tag composed of the immunoglobulin G-binding domain of protein A, a tobacco etch virus cleavage site, and a FLAG tag into the mouse MYO5A locus immediately after the initiation codon. Importantly, we provide evidence that the TAP-tagged version of myosin Va (TAP-MyoVa) functions normally in terms of SER transport in PNs and melanosome positioning in melanocytes. Given this and other evidence that TAP-MyoVa is fully functional, we purified it together with associated proteins directly from juvenile mouse cerebella and subjected the samples to mass spectroscopic analyses. As expected, known myosin Va-binding partners like dynein light chain were identified. Importantly, numerous novel interacting proteins were also tentatively identified, including guanine nucleotide-binding protein G(o) subunit alpha (Gnao1), a biomarker for schizophrenia. Consistently, an antibody to Gnao1 immunoprecipitates myosin Va, and Gnao1's localization to PN dendritic spines depends on myosin Va. The mouse model created here should facilitate the identification of novel myosin Va-binding partners, which in turn should advance our understanding of the roles played by this important myosin in vivo. PMID- 29979497 TI - Overcoming psychosocial challenges in cystic fibrosis: Promoting resilience. AB - Individuals living with cystic fibrosis (CF), and their families, have experienced significant improvements in treatment and related research that have enhanced outcomes and survival. Despite such advancement, the burden of living with CF still exists. Many psychosocial stressors and risk factors are associated with the impact of CF. The identification and treatment of such risk factors are discussed throughout this review, with an emphasis on strategies to address psychosocial risk and the importance of promoting resiliency in those touched by CF. PMID- 29979498 TI - [The progress of novel drug delivery systems]. AB - The development of pharmaceuticals has been providing many kinds of novel drug deliverysystems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics.According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system.Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have tobe absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oraldisintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short bloodhalf life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeuticeffect and requires multiple administration. To solve this problem, sustained drug release system was developed,which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery systemwas developed that can delayed and pulsed release drug for one or several times. This system is especiallyuseful in the management of asthma and heart disease, which are often found in midnight or early morning whenpatients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugsthrough skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult forpharmaceutical development, thus many methods were developed to improve the solubility and bioavailability ofdrugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poorstability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainlyfocused on structure modification and encapsulation by carriers. Considering therapeutic effect requiresinteraction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targetingdelivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand releasedrug delivery systems are also developed with the property of environment-triggered drug release. In conclusion,the novel drug delivery systems were reviewed in this study. PMID- 29979499 TI - [Advances in studies of ileal apical sodium-dependent bile acid transporter]. AB - Bile acids play critical roles in the regulation of metabolism and absorption of lipids. The ilealapical sodium-dependent bile acid transporter (ASBT) located at the enterocyte brush border is responsible forthe reuptake of bile acids and the maintenance of bile acid homeostasis. Recently, a number of investigationshave been made concerning the regulation and control of ASBT and the relationship between ASBT and intestinalinflammation, tumorigenesis, diabetes mellitus and hyperlipemia, which suggests ASBT as a potential therapeutictarget of these diseases. In this review, advances in the study of above-mentioned issues were summarized. PMID- 29979500 TI - [Applications of immobilization techniques in the screening of active constituents from traditional Chinese medicines]. AB - It has been an active approach to screen the active ingredients in traditional Chinese medicines(TCMs) according to the affinity property between small molecule compounds and biomaterials such as cells,bacteria and proteins. On the other hand, the biomaterials can be immobilized on a solid support before thescreening procedure. The immobilization method not only can maintain the biological activities of biomaterials,but also have other advantages such as high efficiency, simple operation, easy to be continuous and automatic, etc.Carrier materials (solid supports) for the immobilization including silica gel, magnetic materials, hollow fiber,and the surface plasma resonance sensor chips have been used to immobilize biomaterials and successfullyapplied in the screening of active ingredients from TCMs. In this paper, applications of immobilizationtechniques in the screening of active components from TCMs were reviewed to provide a scientific referenceto the future applications. PMID- 29979501 TI - [Recent progress of reactive oxygen species-responsive drug delivery systems]. PMID- 29979502 TI - [Interaction between endophytes and host plant and the role of endophytes in genuineness analysis of medicinal plant]. AB - Research of plant development and metabolism has drawn lots of attention with the fast developmentof science of mycorrhizal biology, molecular biology and metabonomics technology. It has become one ofhot fields in the study of endophytes and plant, which would affect plant 's metabolite composition. This wouldprovide opportunity for appraising and modifying traits to medicinal plant, and would also perfect the tranditionalstandpoint on forming reason of medicinal plant genuineness. Here we provide a review of theory andmechanism, research and application of interaction between plant and endophyte. This review may enhanceunderstanding of medicinal plant, and evaluating the quality of herbs in production. PMID- 29979503 TI - [Antidepressant activity of flavonoid ethanol extract of Abelmoschus manihot corolla with BDNF up-regulation in the hippocampus]. AB - Abelmoschus manihot (L.) Medic., a folk herbal medicine in China, is a flowering plant belongingto Abelmoschus L. genus and Malvaceae family, which has been reported with an antidepressant activity. Thestudy was designed to isolate flavonoids from Abelmoschus manihot corolla and explore the action mechanismof antidepressant activities. The flavonoids were isolated and purified by D101 macroporous resin column,polyamide column and Sephadex LH-20 sequentially and identified as myricetin-3-O-beta-D-glucoside (1),gossypetin-8-O-beta-D glucuronide (2, G-8-G), gossypetin-3'-O-beta-D-glucoside (3), quercetin-3' glucoside (4, Q-3-G),isoquercitrin (5, IQT), hyperoside (6, HY), myricetin (7), quercetin (8, QT). Compounds 2, 4, 5, 6 and 8(15, 30 and 60 mg.kg-1) were orally administered to mice and the reaction was observed in tail suspensiontest (TST) and forced swimming test (FST). Western blot analysis was used in determination of the proteinexpressions of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB) and phosphorylationeukaryotic elongation factor 2 (p eEF2). The results revealed that only Q-3-G and G-8-G (15, 30, 60 mg .kg 1)significantly reduced the immobility time in FST and TST. Furthermore, Q-3-G and G-8-G remarkably increasedthe expression of BDNF and TrkB, and decreased the expression of p-eEF2. These results suggest thatQ-3-G and G-8-G had an obvious antidepressant activity via up-regulation of BDNF expression. Thenew observation will provide a new direction in the development of antidepressant in the treatment of major depressivedisorder (MDD). PMID- 29979504 TI - [Prevention of abdominal adhesions in rats by rhynchophylline through inhibition of Smad singnaling pathway]. AB - Postoperative intra-abdominal adhesion is one of the most common complications in the postoperativeperiod. Current remedies are very ineffective to prevent the pathological outcomes except steroidhormones. Rhynchophylline is deemed as a pharmacologically active component from traditional Orientalmedicine Uncaria rhynchophylla (Miq.) Jacks. (Rubiaceae). This study was designed to investigate the preventativeeffect of rhynchophylline on the abdominal adhesions in rats. Rhynchophylline relieved the experimentalabdominal adhesion and decreased the levels of interleukin-1 beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosisfactor-alpha (TNF-alpha) in the blood serum in a dose-dependent manner. The levels of transforming growth factor- beta1(TGF-beta1) and connective tissue growth factor (CTGF) were reduced significantly in the peritoneal fluid. Thepotential mechanism of the activity is related to inhibition of the TGF- beta1/Smad signaling pathway. PMID- 29979505 TI - ? AB - Property and flavor theory of traditional Chinese medicine (TCM) is the core base for clinicaltreatment of diseases. However, few research about its chemical and biological characterization was performed.In this paper, network pharmacology was adopted to review patterns around the theory of TCM. "Xiaoke"prescription database, which combinations of herb medicines for diabetes therapy, was firstly built to exploreprescription regularity and screen core paired-components. The prescription regularity and molecular mechanismof flavor composition were explored through the relationship of "drug-compound-target-pathway-function" byChEMBL, CTD and KEGG datebase. As a result, the tastes of "Gan" (sweetish taste) and "Ku" (bitter taste)were the popular therapeutic flavor to regulate the disorder of glucose and lipid metabolisms. The mechanismof Xiaoke was summarized from representative traditional Chinese medicine partner "Zhimu-Huangbai" and"Huangqi-Gegen". The key components of "Gan", including saponins stimulated insulin secretion, improveinsulin resistance and promote glucose utilization. The components of "Ku", including flavonoids and alkaloidsregulate inflammatory cytokines, promoted the utilization of glucose, improve endocrine and metabolism throughMAPK, PI3K-Akt, PPAR signal pathway. The TCM therapeutic mechanism about "Xiaoke" was preliminarilysummarized to clear "heat" by anti-inflammation and immunoregulation, to regulate glucolipid metabolism forremoving the satiation of digestion, and to improve the utilization of insulin and diabetes complications forendocrine adjusting. The results demonstrate that therapeutic principle of TCM for "Xiaoke" is comprehensivevia multi pathway. This study provides a new research method and strategy for exploring the mechanism ofTCM for diabetes therapy. PMID- 29979506 TI - [Comparative study of the corticosterone and glutamate induced PC12 cells depression model by 1H NMR metabolomics]. AB - This study was designed to analyze the change of metabolites in the PC12 cells and its mediuminduced by corticosterone (CORT) and glutamate (Glu) by proton nuclear magnetic resonance ( 1H NMR)metabolomics. The multivariate statistical analysis was employed to identify the difference between controlgroups and induced groups, respectively. In addition, metabolite pathway analysis was performed to explorethe characteristic of CORT-induced and or Glu-induced PC12 cells depression model, and to provide thereferences for the selection of in vitro depression models as well as the further understanding of the mechanismon depressive disorders. We found 36 differential metabolites in CORT-induced PC12 cells and medium and42 in Glu-induced PC12 cells. Furthermore, correlation analysis results show that serine and 2-oxoisoleucinewere associated with most differential metabolites in CORT-induced PC12 cells. Lactate and glutathionewere significantly correlated to the vast majority of differential metabolites in Glu induced PC12 cells. Wespeculated that CORT-induced PC12 cell models may affect the fatty acid metabolism and cell membranestructure, and Glu-induced PC12 cell models may have a difference in the glycolysis and antioxidants. PMID- 29979507 TI - [Effects of metoprolol or/and pravastatin on the pharmacokinetics of metformin in rats]. AB - This study investigates the effects of metoprolol (METO) or/and pravastatin (PRAV) on thepharmacokinetics of metformin (METF) in rats. Twenty-eight male SD rats were divided into METF group,METF+METO group, METF+PRAV group and METF+METO+PRAV group. Blood samples were collectedat 10, 20, 40, 60, 90, 120, 180, 240, 360, 480 and 600 min after oral administration of metformin, andconcentration of metformin in plasma was determined by HPLC. Compared to the METF group, Cmax ofmetformin was significantly decreased (P < 0.01) and MRT0-t , t1/2 and V were significantly increased inthe METF+METO group; t1/2 was significantly decreased in the METF+PRAV group; Cmax was significantlydecreased and MRT0-t was significantly increased in the METF+METO+PRAV group. Compared to theMETF+METO group, MRT0-t of metformin was significantly decreased in the METF+METO+PRAV group.Compared to the METF+PRAV group, Cmax of metformin was significantly decreased (P < 0.01), andMRT0-t , t1/2 and V were significantly increased in the METF+METO+PRAV group. There exist multipledrug interactions of metformin, metoprolol and pravastatin in rats. PMID- 29979508 TI - Transforming the microbiology laboratory to address the Triple Aim in healthcare. PMID- 29979509 TI - [In process]. PMID- 29979510 TI - Fibromyalgia syndrome: Basic knowledge, diagnosis and treatment. AB - Fibromyalgia syndrome (FMS) is characterized by chronic widespread pain, unrefreshing sleep and mental/physical fatigue. Most patients report additional somatic and psychological symptoms. Fibromyalgia is a heterogeneous condition. The definite aetiology of this syndrome remains unknown. A model of interacting biological and psychosocial variables in the predisposition, triggering, and development of the chronicity of fibromyalgia symptoms has been suggested. Depression, genetics, obesity combined with physical inactivity, physical and sexual abuse in childhood, sleep problems, and smoking predict future development of fibromyalgia. Psychosocial stress (working place and family conflicts) and physical stress (infections, surgery, accidents) might trigger the onset of chronic widespread pain and fatigue. Mental disorders have a negative impact on the clinical outcome. Several factors are associated with the pathophysiology such as alteration of sensory processing in the brain, reduced reactivity of the hypothalamus-pituitary-adrenal axis to stress, increased pro-inflammatory and reduced anti-inflammatory cytokine profiles, disturbances in neurotransmitters such as dopamine and serotonin, and small fiber pathology. Prolonged exposure to stress, as outlined above, may contribute to these functional changes in predisposed individuals. The prevalence in the general German population is about 2 %. The clinical diagnosis is established by the history of the key symptoms and the exclusion of somatic diseases sufficiently explaining chronic widespread pain. For management, the German evidence and consensus based guideline recommends a stepwise approach according to the severity of FMS. All patients should receive adequate education about the disorder and its management. Non pharmacological therapies such as low intensity aerobic exercise and meditative movement therapies such as Qi-Gong and Yoga are highly recommended for long-term self-management. Drug therapy is not mandatory. Recommended drugs are the antidepressants amitriptyline and duloxetine and the anticonvulsant pregabalin which act as pain modulators. PMID- 29979511 TI - L-Arginine and vascular health. AB - Endothelial dysfunction, characterized by a disturbed vascular NO metabolism, represents a key point in atherogenesis. Modern antiatherogenic therapies improve NO availability within the endothelium. As L-arginine acts as the substrate of endothelial nitric oxide synthase (eNOS), arginine supplementation can enhance NO formation. Actually, L-arginine at appropriate dosage (6-8 g/day) improves endothelial function and lowers blood pressure. However, beneficial effects can only be expected in individuals with pronounced endothelial dysfunction and/or individuals with an absolute (patients with hemodialysis) or relative (patients with elevated ADMA levels) arginine deficiency. Whether L-arginine delays progression of atherosclerotic lesions and lowers cardiovascular morbidity and mortality is unknown. PMID- 29979512 TI - [Change of hepatic drug metabolism enzymes in rat depression model with kidney yang deficiency]. AB - This study was designed to explore the impact of depression on kidney-yang deficiency in rats.Rats were repeatedly injected with hydrocortisone for 21 days to establish the depression model with kidneyyangdeficiency. Tolbutamide, chlorzoxazone, theophylline, midazolam, omeprazole and dextromethorphanwere used as substrates of CYP2C6, CYP2E1, CYP1A2, CYP3A2, CYP2D1, and CYP2D2 to test the depressionimpact on drug metabolism. Plasma concentrations of six CYP450 were determined by LC-MS/MS and used aspharmacokinetic parameters. Consequently, metabolism of theophylline, chlorzoxazone and tolbutamide wereaccelerated significantly in the model relative to the control (P < 0.01), but dextromethorphan, omeprazole andmidazolam did not exhibit a significant difference. The present study suggests that depression with kidneyyangdeficiency had a strong induction of CYP2E1 and moderate induction of CYP1A2, CYP2C6 in the ratmodel. PMID- 29979513 TI - Leprosy - an old infectious disease with unsolved matters. AB - Leprosy is a chronic disease with many clinical manifestations, which affect mainly the skin, the peripheral nerves, mucosa of the upper respiratory tract and the eyes. Although global elimination of leprosy was achieved globally in the year 2000 and the disease is actually rare in most parts of the world, a low but constant number of more than 200,000 new cases are still registered each year. Leprosy is caused by two acid-resistant, slow multiplying Gram-positive bacteria, i. e., Mycobacterium leprae and the recently discovered M. lepromatosis. The transmission routes of these pathogens are not completely understood. All forms of leprosy can be treated with long-lasting antibacterial combination therapy using dapsone and rifampicin and - in cases of multibacillar leprosy - clofazimin. Using this multi-drug approach, leprosy has been shown to be curable in most cases. However, immunological sequelae (leprosy reactions), which may appear during therapy or even several years later, are frequently difficult to treat. Although leprosy has been eliminated in most countries, its complete eradication is extremely unlikely. PMID- 29979514 TI - [Design, synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors]. AB - In this study, 1-(3-(4-chlorophenyl)-5-methylthio-1H-1,2,4-triazol-1-yl)-butan-1 one discoveredpreviously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase ( HsDHODH) forstructural optimization. The co crystal of HsDHODH with the hit was obtained and analyzed for guidingthe subsequent structural optimization. As a result, a series of novel triazole derivatives were designed andsynthesized as potent HsDHODH inhibitors. Among them, compound (3-(4-chlorophenyl)-5-ethylthio-1H-1,2,4-triazol-1-yl)-furan-2-yl methanone displayed high potency in the inhibition of HsDHODH with an IC50value of 1.50 MUmol.L-1. Meanwhile, the structure-activity relationships were analyzed based on the biologicaldata and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4-triazole derivatives as HsDHODH inhibitors in the future. PMID- 29979515 TI - [The interaction between BLF and BSA and impact in interaction of RT-BSA-BLF system]. AB - The binding of rhaponticin to bovine serum albumin (BSA)-bovine lactoferrin (BLF) and thefactors that affect BSA-BLF interaction have been studied by fluorescence spectroscopy and Fourier transforminfrared spectroscopy. In the fluorescence experiment, RT quenched the fluorescence intensity of mixedproteome and the maximum emission wavelength of BSA, BLF and BSA-BLF proteins system. RT causedobvious red-shift fluorescence for an interaction between RT and proteome. The interaction between RT andproteome was impacted by single-component protein molecular interactions and the interaction between RT-BSAand RT-BLF, the microenvironment of solutions were the factors impacting the interactions between RT andproteome, which impacted quantitative expression of the general environment micro environmental factors.In the Fourier transform infrared spectroscopy, the secondary conformation of protein molecules of singlecomponent in the protein group were changed, and the difference of the molecules ' structure was responsible forthe differences in the molecular conformation changes. The molecules ' interaction in the single-componentprotein affected secondary conformation of the proteins' molecule. The proteins' concentration ratio and theinteraction were different in degree of molecular conformational change. These data demonstrates an exampleof combination of fluorescence spectrum experiment with Fourier transform infrared spectroscopy in the study ofprotein structura. PMID- 29979516 TI - [In process]. PMID- 29979517 TI - [In process]. PMID- 29979518 TI - [A new cassane diterpene from Caesalpinia bonduc]. AB - Five cassane diterpenes were isolated from the 95% ethanol extract of the seeds of Caesalpiniabonduc (Leguminosea) by a combination of various chromatographic methods, including silica gel, SephadexLH-20, and semi-preparative HPLC. On the basis of spectroscopic techniques, their structures were identifiedas 3beta acetoxy-cassa-12,14(17),15-trien-7beta-ol (1), caesalmin C (2), caesall E (3), caesalpinin MJ (4), and1-deacetylcaesalmin C (5). Among them, compound 1 is a new compound and 2, 4, 5 were isolated from theplant for the first time. PMID- 29979519 TI - [In process]. PMID- 29979520 TI - [Investigation of the potentially effective components of Semen Ziziphi Spinosae based on "in vitro to in vivo" translation approach]. AB - The study aims to investigate the effective components of Semen Ziziphi Spinosae (SZR) innourishing the heart and tranquilizing the mind. A method of ultra high liquid chromatography (UHPLC)coupled with Q Exactive high resolution mass spectrometry (HR-MS) was developed. Based on the UV spectra,retention time and MS spectra, 25 compounds of SZR extract were identified or tentatively characterized,including 12 flavonoids, 8 triterpenoids saponins, 2 fatty acid and 3 alakoids. The study illuminated the majorchemical components. Twenty bioactive components were determined in rat urine after oral administration ofSZR extract by "in vitro to in vivo" translation approach, including 16 prototype compounds and 4 metabolites.Spinosin, swertisin, jujuboside A and B were considered as the effective and active constituents in SZR ofthe sedative and hypnotic effects, which emodies characteristics of multiple components. It was beneficialexploration for searching the effective and active constituents of SZR in nourishing the heart and tranquilizingthe mind. PMID- 29979521 TI - [In process]. PMID- 29979522 TI - [Generation of Human ScFv Antibodies for Antigenic Site III of Rabies Virus Glycoprotein from Antibody-phage Libraries by Chain Shuffling]. AB - To obtain neutralizing high affinity human recombinant antibodies for antigenic site III of rabies virus(RV)glycoprotein, we chose scFv phage display technology to optimize CR4098 with chain shuffling. Using pHAL14-CR4098 as vector, the combinatorial shuffling scFv antibody phage libraries were constructed to replace CR4098 light or heavy chain genes respectively by antibody genes derived from the blood of RV-vaccinated donors. After package by hyperphage, the chain shuffling scFv phage library was panned and selected by ELISA with purified rabies virus aG strain. The specific antibody was converted to full human IgG antibody with the VH/VK Express cassettes. Affinity and neutralizing test were performed to verify the function of the IgG molecules. Fourteen unique human ScFv antibodies specific for the glycoprotein of rabies virus were obtained by ELISA,IFA and DNA sequencing. Further tested showed that RV3A5 has a high affinity of 2.8*10(-9) M and high neutralizing activity to rabies virus both aG strains and CVS strains. Competitive ELISA showed that RV3A5 and CR4098for antigenic Site III competed with each other, indicating that they had overlapping or shared the epitope. Our results provide more candidates eligible for use in a mAb cocktail aimed at replacing RIG for rabies post-exposure prophylaxis. PMID- 29979523 TI - [In vitro metabolism of daphnetin in rat liver S9 fractions]. AB - Daphnetin is quickly eliminated in rats after dosing, but the mechanism remains unclear. Thisstudy was aimed to investigate the in vitro metabolism of daphnetin using rat liver S9 fractions (RLS9). Themetabolites formed in RLS9 were identified and the kinetic parameters for different metabolic pathwayswere determined. HPLC-DAD-MS analysis showed that daphnetin was biotransformed to six metabolites,which were identified as 7 or 8 mono-glucuronide and mono-sulfate, 8 methylate, and 7-suflo-8-methylate.Methylation and glucuronidation of daphnetin exhibited the Michaelis-Menten kinetic characteristics, whereasthe substrate inhibition kinetic and the two-site kinetic were observed for 8-sulfate and 7 sulfate formations. Ofthe 3 conjugation pathways, the intrinsic clearance rate for sulfation was highest, followed by methylation andglucuronidation. By in vitro-in vivo extrapolation of the kinetic data measured in RLS9, the hepatic clearancewere estimated to be 54.9 mL.min-1.kg-1 which is comparable to the system clearance (58.5 mL.min-1.kg-1)observed in rats. In conclusions, the liver might be the main site for daphnetin metabolism in rats. Sulfation,methylation and glucuronidation are important pathways of the hepatic metabolism of daphnetin in rats. PMID- 29979524 TI - [In process]. PMID- 29979525 TI - [In process]. PMID- 29979526 TI - [Simultaneous determination of salidroside and tyrosol in Beagle dog plasma using UHPLC-MS/MS after pre-column dansyl chloride derivatization]. AB - A pre-column derivatization method combined with UHPLC-MS/MS was developed for thesimultaneous determination of salidroside and tyrosol in Beagle dog plasma. After protein precipitation byacetonitrile, the liquid supernatant was treated with dansyl chloride under dark conditions at 60 C for 30 min,and then, the sample solution was extracted using methyl tertiary butyl ether. The multiple reaction monitoringin positive ion mode was used for MS detection of the tested analytes with the specific ion transitions ofm/z 534.2->372.0 for salidroside derivative, m/z 372.0->171.0 for tyrosol derivative and m/z 506.0->171.0 forarbutin derivative. The chromatograph separation was achieved on an ACQUITY UPLC(r) BEH C18 column(100 mm * 2.1 mm, 1.7 MUm) with a gradient mobile phase consisting of acetonitrile (0.1% formic acid)-water(10% acetonitrile, 0.1% formic acid) for 9 min. The assay showed a good linearity over the range of 0.02/0.1 20/10 MUmol.L-1 with a lower limit of quantitation of 0.02 and 0.1 MUmol.L-1 for salidroside and tyrosol in dogplasma, respectively. The intra- and inter-day precisions were all less than 8.68%, and the accuracy was within+/-11.4%. The established method with a high sensitivity, good specificity and reliability was appropriate forsimultaneous determination of salidroside and tyrosol in dog plasma and successfully applied to a pharmacokineticstudy after intragastric administration of salidroside to Beagle dogs. PMID- 29979527 TI - [In process]. PMID- 29979528 TI - [Inhibition of transformation from puerarin monohydrate to puerarin dihydrate by polyvinylpyrrolidones during dissolution]. AB - Puerarin (PUE), an isoflavone with anti-inflammation, anti-oxidation and neuroprotection effects,has been widely applied to the treatment of cardiovascular diseases in clinics in China. In the current study, wereported that the active pharmaceutical ingredient (API) of marketed products was the PUE monohydrate(PUEMH). During its supersaturated dissolution, the PUE concentration quickly reached a plateau, followed bya gradually concentration decrease to another lower plateau. In order to explore the internal mechanism of abovephenomenon, the solid residues after saturated dissolution test were characterized by powder X-ray diffraction(PXRD), thermal gravity analysis (TGA) and Karl Fisher titration (KFT). PXRD suggested that a novel PUEcrystal different from PUEMH formed during its dissolution, the following TGA and KFT confirmed the generationof PUE dihydrate (PUEDH) with much lower solubility. Moreover, polyvinylpyrrolidones (PVPK12, PVPK30and PVPK90) were added in the dissolution medium to investigate their potential inhibition effects on suchcrystal transformation during dissolution process. We observed that polymers could inhibit the transformationfrom PUEMH to PUEDH and result in much higher PUE concentration level than that in pure water. PMID- 29979529 TI - [In process]. PMID- 29979530 TI - [GGI as a gene carrier delivering MDR1 siRNA to A549/DDP cells for reversal of multidrug resistance]. AB - This study was designed to reverse multidrug resistance of lung cancer cells by downregulatingMDR1 genes through RNA interference (RNAi) technology. A novel biodegradable cationic polymer (PEG- b-PLG-g-PEIs, GGI) was synthesized and characterized by 1H NMR. The particle size and zeta potential weremeasured by dynamic light scattering (DLS). The cell viability profile of GGI was tested by MTT method withboth A549 and A549/DDP cell lines. Flow cytometry (FCM) technology was used to investigate the efficiencyand intensity of delivering siRNA to cells by GGI polymer. RT-PCR and Western blot were used to detectthe mRNA and P-gp expression after GGI/MDR1 siRNA transfection assay. The sensitivity of cisplatinadministration after transfecting GGI/MDR1 siRNA polyplexs was performed with MTT and Annexin V-FITC/PImethods. The results suggest that the particle size and zeta potential of GGI/siRNA were 150 -200 nm and16-28 mV. GGI exhibited a lower cell cytotoxity than PEI 25K and higher efficiency of delivering siRNA,which dramatically decreased the expression of MDR1 mRNA and P-gp of A549/DDP cells and increased muchsensitivity to cisplatin in A549/DDP cells. GGI holds a great potential in gene delivery as a novel cationicpolymer for further investigation. PMID- 29979531 TI - [Development of Recombinant Human Monoclonal Antibody Cocktail for Post-exposure Rabies Prophylaxis]. AB - To evaluate the neutralizing potency and spectrum of three recombinant human mAbs CR57(I), RV08(II), RV3A5 (III) and the triple combination cocktail against antigenic site I, II and III on rabies virus glycoprotein, a standard fluorescent antibody virus neutralization test(FAVN)on several RV vaccine strains, fixed strains, and street strains of total 11 trains was performed by incubation of RV with varying concentrations of antibody followed by incubation with BHK-21 cells. To investigate whether the antibodies display neutralizing activity against a lethal RV infection in vivo, we performed a Syrian hamster study by infecting with 50LD(50)/100MUl of CVS-11 strain intramuscularly (i. m.) in the gastrocnemius muscle. Three recombinant human mAbs CR57 (I), RV08 (II), RV3A5 (III) and the compatibility triple cocktail showed broad cross-neutralizing reactivity to all 11 RV strains. The cocktail composed of three mAbs CR57 (I) RV08 (II), RV3A5 (III) by neutralizing titers of 1 : 1 : 1 has no less in neutralizing ability against these strains, indicating that no mutual interference between the three antibodies. The cocktail exhibited neutralizing synergistic activity against individual strains(JX08-45,Flury,SRV9).The treatment with CR57,RV08,RV3A5 or the triple combination cocktail alone respectively provided better protection with a survival range of 100%against the lethal RV infection compared HRIG immunized alone. Combined immunization with the vaccine, recombinant mAbs protected hamsters with a survival rate of 100%equally as well as HRIG after exposure to a lethal RV infection. Our results provide more candidates eligible for use in a mAb cocktail aimed at replacing RIG for rabies post-exposure prophylaxis. PMID- 29979532 TI - [In process]. PMID- 29979534 TI - [Molecular cloning and prokaryotic expression of a type II ribosome inactivating protein from Polyporus umbellatus]. AB - A type II ribosome inactivating protein (RIP) gene was cloned from Polyporus umbellatussclerotia by RT-PCR method. The full open reading frame cDNA sequence of this gene was 873 bp in lengthand encoded a 290-aa protein with a molecular weight of 32.33 kDa and an isoelectric point of 5.58. Multiplesequence alignment revealed that the deduced amino acids possessed conserved domains of RICIN superfamilyprotein. A neighbor joining phylogenetic analysis suggests that PuRIP was closely related to RIP in Marasmiusoreades. Real time PCR results showed that this gene expressed in all tested tissues of P. umbellatus. Meanwhile,the expression of this gene was significantly up-regulated in the part infected by Armillaria mellea. This resultsuggested that this PuRIP might played important role with potential biotic stress tolerance of P. umbellatus.Otherwise, we successfully constructed the pET15b-PuRIP plasmid, produced and purified the His PuRIP fusionprotein, which would provide the basic material for polyclonal antibody preparation and gene function research. PMID- 29979533 TI - [The molecular identification of licorice species and the quality evaluation of licorice slices]. AB - Licorice is one of the most common herbs in traditional Chinese medicine, and classified as topgrade in Shen Nong Ben Cao Jing. There are three different original plants of licorice stipulated in ChinesePharmacopeia, Glycyrrhiza uralensis Fisch., Glycyrrhiza glabra L., and Glycyrrhiza inflata Bat. However,previous investigation showed that the pharmacodynamic effects of the three licorices were quite different. It isvery difficult to identify them by the classical identification methods. In order to establish a fast and effectiveidentification method, we collected 240 licorice plants from 21 populations of 7 provinces, and amplified theirITS and psbA-trnH sequences. ITS sequences with a full length of 616 bp and psbA-trnH sequences with a fulllength of 389 bp were obtained separately. Using DNAMAN to analyze these sequences, 4 variable sites werefound in ITS sequences and 2 ITS haplotypes were determined, and 3 variable sites were found in psbA-trnHsequences and 4 psbA-trnH haplotypes were determined. With the combination analysis of ITS and psbA-trnHsequences, the molecular identification method of original licorice was established. Using this method, 40samples of licorice slices collected from 4 main herbal material markets in China were identified successfully.Furthermore, the contents of 2 triterpenes, 18alpha-glycyrrhizic acid and 18beta-glycyrrhizic acid, and 4 flavonoids,liquiritin, isoliquiritin, liquiritigenin, and isoliquiritigenin in these licorice pieces were examined by HPLC andthe results were analyzed using SPSS 21.0. This study provides a new method in identification of licorice,which may serve as a guideline for quality control of licorice slices. PMID- 29979536 TI - [Codon Bias Analysis in the Coding Genes of Structural and Accessory Proteins of Middle East Respiratory Syndrome Coronavirus]. AB - Middle East respiratory syndrome coronavirus (MERS-Co V) is a RNA virus causing serious harm to people. In order to investigate the codon usage characteristics and influence factors, codon preference and multivariate statistical analysis of MERS-Co V 9 gene sequences were performed by using Codon W, CUSP and SPSS software, getting the content of GC at three positions of codons, ENC (Effective number of codon)and RSCU(Relative synonymous codon usage)of all genes. In addition, the results were compared with Escherichia coli, yeast and human's codon usage frequency. The results showed that GC3 content is significantly lower than GC1 and GC2content,and less than 50%.It indicates that the third position of codons prefers to A or T.ENC value is 50.59,which implies codon usage bias is a little slight in MERS-Co V genome. According to the neutral drawing analysis and ENC-plot analysis, codon bias is mainly affected by selection pressure in the MERS-Co V genome. It is found that codon usage frequency of MERS-Co V is more close to yeast, compared with other three kinds of biological codon usage frequency.Finally,19 codons are defined as the major preference codons in MERS-Co V. The results have a certain significance for MERS-Co V that selecting gene expression host system, contributing further to development of genetically engineered vaccine and therapeutic antibody. PMID- 29979535 TI - Beers-Criteria: Translation of the recent update. AB - The Beers criteria are an important instrument to improve medication safety in geriatrics. In 2015, the American Geriatrics Society (AGS) updated the Beers criteria and extended the list regarding important aspects. Our translation into German aims to simplify the application in German health care and to improve medication safety. The list was adapted to the German health care market to ensure its suitability for daily clinical use. The updated Beers lists is extended regarding clinical relevant drug-drug interactions and advice for dose titration in patients with renal insufficiency. Thereby, we hope that the updated Beers criteria will help to optimize geriatric pharmacotherapy. PMID- 29979538 TI - [Advances and challenges in preclinical evaluation of therapeutic drugs for treating ischemic stroke]. AB - Translating of scientific advances into clinical practice is a major challenge in the stroke researchfield in the past decades. There were many reasons involved: animal models might not accurately capture allaspects of clinical stroke in humans, the blind and randomized design principle was not closely followed, theinclusion and exclusion criteria was not previously established, sample size was inadequate, endpoint was notscientific nor blindly assessed, inadequate reporting of data and statistical flaws. To bridge the gap betweenexperimental and clinical research, international consortia have attempted to establish standardized guidelinesfor study design and data report, which include optimizing animal models as well as experimental design, usinginnovative approaches to assess endpoint, making raw data and negative results available, establishing priorregistration mechanism, conducting multicenter preclinical randomized controlled trials (pRCTs), systematicreviews and meta-analysis of preclinical studies, evolving the original focus on neuroprotection into a broaderconsideration of the role of neurovascular unit and ischemic cascade. PMID- 29979540 TI - [In process]. PMID- 29979539 TI - Hoarseness - causes and treatments. AB - Due to a hoarseness or dysphonia about 1 % of patients consult a doctor. The causes of hoarseness are very diverse and can range from a harmless laryngitis to vocal cord tumors. In addition to acute and chronic laryngitis (42 % and 10 %), functional dysphonia (30 %), benign (15 %) and malignant tumors (3 %), vocal cord paresis (5 %), the physiological aging voice (2 %) and psychogenic factors (2 %) can cause hoarseness. The manifestation of internal diseases is very rare. Treatment options depending on the cause are drugs, voice therapy or surgery. The present article gives an overview of possible causes of hoarseness, diagnosis and treatment options. Hoarseness lasting more than three weeks should always be taken seriously and be examined laryngoscopically. PMID- 29979537 TI - Risk of renal dysfunction in an elderly patient with chronic heart failure. AB - The treatment of elderly multimorbid patients according to clinical guidelines often results in polypharmacy. An individual risk assessment is required to consider the possibility of deprescribing especially potentially inappropriate medication in the elderly. This exemplary case report describes a medication review of a patient with multiple chronic cardiovascular diseases taking into account the impact on renal function. PMID- 29979542 TI - [In process]. PMID- 29979541 TI - [Comparison of Respiratory Syncytial Virus Infection on Different Week-ages BALB/c Mice]. AB - Respiratory syncytial virus(RSV)is a leading cause of lower respiratory tract disease. The major high risk population for RSV infection are<6month infants and elders with age older than 65 years. At present, BALB/c mice were wildly used as animal model for RSV infection, however there has no report about the comparison of different week-ages BALB/c mice after RSV infection. A different week-ages BALB/c mice model was described in this study to compare their susceptibility after RSV infection. Young(10weeks),middle aged(30weeks)and aged(60weeks)mice were intranasally infected with 106 or 107plaque-forming units (PFU) RSV, then clinical symptom, weight, RSV titer in nose/lung, histology and immunohistochemistry was examined. And age-related susceptibility was analyzed. A high-titer virus(107PFU)infection showed significant weight loss at 6-11 day post infection while 106 PFU didn't lead to obvious weight change. In 10(7) PFU infected group, replication of virus in nose and lung was detected, the virus in lung located around pulmonary alveoli, and the hematoxylin eosin stain showed significant infiltration of inflammatory cells and pathological tissue damage. Mice trended to be more susceptible to RSV infection as the growth of age. Older mice experience more weight loss. Lung histology of older mice showed more serious bronchiolitis and increased number of inflammatory cells in alveolar spaced, and 60week-old mice tended to be the most significant. In this study, we have successfully established a different week-ages BALB/c mice model, which will serve as the basis for investigating antibody or vaccine and further infection mechanism research of RSV. PMID- 29979543 TI - [In process]. PMID- 29979544 TI - [In process]. PMID- 29979545 TI - [In Vitro Anti-HIV-1 Activity of Cordyceps sinensis Extracts]. AB - To investigate the in vitro anti-HIV-1effect of the aqueous extracts of Cordyceps sinensis. The aqueous stroma and sclerotium extracts were isolated from the fresh and dry Cordyceps sinensis specimen, respectively. The CCK-8test and the TZM-bl pseudovirus assay were used to examine the in-vitro cytotoxicity and anti-HIV 1activities of extracts. In addition, the reverse-transcriptase enzyme-activity assay and the surface plasma resonance(SPR)technology were taken to study the inhibition on the activity of reverse transcriptase and interaction with Vif protein. All 5aqueous extracts of Cordyceps sinensis exhibited in vitro anti-HIV 1effects,extracts from the fresh fungus showed more potent effect in inhibiting reverse-transcriptase activity than the dry fungus. Furthermore, a strong interaction was observed between the fresh stroma extract and Vif protein.The study clarified that the in vitro anti-HIV-1activity of the aqueous extracts of Cordyceps sinensis, may be mediated through inhibition of reverse-transcriptase activity and interaction with Vif protein. PMID- 29979546 TI - [In process]. PMID- 29979547 TI - [In process]. PMID- 29979548 TI - [In process]. PMID- 29979549 TI - [Construction of AalDV-3 Mediated mirRNA Sponge Delivery System and Its Effect on Cell and Larva of Aedes aegypti]. AB - microRNAs (miRNAs) not only play the key roles in regulation of the growth and development of mosquito, but also has an important function in interaction between the pathogen and vector. So, miRNAs can be used as the molecular target for development of an alternative method for mosquito and mosquito-borne disease control. However, an effective delivery system is still need. Mosquito densovirus have the potential for vector control as transducing agents to express foreign toxins or small interfering RNAs molecules in vitro and in vivo. In this study, we report the development of a recombinant Aedes albopictus densovirus-3(AalDV-3) miRNA sponge expression system, using an intronic miRNA sponge expression strategy. To test the inhibition effect of recombinant virus medicated miRNA sponge on endogenous miR-210, Aedes aegypti Aag2 cell and 1st-2nd larvae were infected, respectively. The splicing of the intronic miRNA sponge expression constructs in vitro and in vivo were tested by RT-PCR with intron span primers, and the relatively expression level of miR-210 was confirmed by qPCR. As results,AalDV-3can be used to decrease endogenous miRNAs by generating an antisense sponge in vitro and in vivo, which represents a tool for the functional analysis of mosquito genes and lays the foundation for the application of densovirus for vector control. PMID- 29979550 TI - [In process]. PMID- 29979551 TI - [Advances in the study of the rat model of aging induced by D-galactose] AB - D-galactose (D-gal)-induced aging model is widely used in the study of the pharmacodynamics ofantiaging drugs. The model has a shorter life-span, disorders in learning and memory, reduced immune functionand other aging characteristics. Regular and quantitative injection of D-gal solution to rats can producesymptoms of natural aging models that are used in screening of antiaging drugs, and their pharmacologicalactivities. This paper provides a summary of the mechanism of rat model induced with D-gal solution. Themethods of building and evaluation of the aging models are provided. The theoretical basis is included tofacilitate the subsequent research and experiment in the mechanism study of aging and antiaging medicines. PMID- 29979552 TI - [In process]. PMID- 29979553 TI - [Current status of ion channels as drug targets for diabetic neuropathic pain]. AB - Diabetic neuropathic pain (DNP) is the most common chronic complication of diabetes mellitus,significantly affecting people's quality of life. Studies have indicated that ion channels play a very important rolein the occurrence of DNP. This review provides a summary in the role of ion channels in diabetic neuropathicpain and treatment strategies for diabetic neuropathy targeting ion channels. PMID- 29979554 TI - [Canine Circovirus Genome Cloning and Sequence Analysis]. AB - Dog circovirus (DogCV) is a newly discovered mammalian circovirus. To investigate the genomic characteristics and genetic diversity of DogCV spreads in China, the first genome sequence of Chinese isolate, designated as JZ98/2014,was obtained by overlap PCR using the DNA extracted from dog serum as template for amplification. The nucleotide content and genome organization were subsequently analyzed. The results showed that the full-length genome of JZ98/2014 is 2063nt,and contains three major open reading frame: ORF V1 (encodes the 303 amino acid Rep protein),ORF C1(encodes the 270 amino acid Cap protein),and ORF C2(encodes 106 amino acids).JZ98/2014 shared 82.1%-89.5% homology with the complete genome sequences of DogCV isolates from America and Europe. The Rep gene and Cap gene of JZ98/2014 shared 82.1%-89.5%and 84.6%-89.1% homology, respectively, with the same genes from other DogCVs. Phylogenetic tree analysis indicated that there were several different genetic clades of DogCV spread in the world, and JZ98/2014 formed a clade by itself. PMID- 29979555 TI - [Advances in the research of inhibitors of enzymes of bacterial peptidoglycan biosynthesis]. AB - In recent years, owing to the abuse of antibiotics, the widespread of resistant bacterial strainsbecame a serious threat to public health. This status demands development of new antibacterial agents withnovel mechanisms of action. The reason for the limited new antibacterials is the small number of effectivetherapeutic targets, which cannot meet the current needs for the multiple drug-resistant treatment. Screening fornew targets is the key step in the development of novel antibacterial agents. Peptidoglycan is the main componentof the cell wall of bacteria, which is essential for survival of pathogenic bacteria. Within the biochemicalpathway for peptidoglycan biosynthes is the Murligases, described in this review as highly potential targets forthe development of new classes of antibacterial agents. This review provides an in depth insight into the recentdevelopments in the field of inhibitors of the Mur enzymes (MurA-F). Moreover, the reasons for the lack ofcandidate inhibitors and the challenges to overcome the hurdles are also discussed. PMID- 29979556 TI - [Population pharmacokinetics and its application in new drug research]. AB - Population pharmacokinetics is an emerging discipline developed from the combination ofclassical pharmacokinetic compartment model and statistics principles, which has been received more and moreattention in recent years. Population pharmacokinetics plays important roles in all stages of new drug research.In the early preclinical phase, population pharmacokinetic analysis can help to achieve the preliminary predictionof parameters from animal to human, optimize clinical trial designs, and shorten the time required for newdrugs from laboratory to clinical trials. In clinical trials and applications stage, population pharmacokineticresearch can help researchers investigate the related covariates that affecting pharmacokinetic behavior ofpatients comprehensively, and find potential drug-drug interactions in clinical. In addition, populationpharmacokinetics has a unique advantage in pediatric drug development due to its strong analysis ability ofsparse data. This paper provides a summary on the history and methods of population pharmacokinetics,and the application in new drug discovery and development. PMID- 29979557 TI - [In process]. PMID- 29979558 TI - [Rotavirus G9-VI Re-emerging and Circulating Predominantly in Children with Diarrhea in Beijing]. AB - The first reported group A rotavirus(RVA)G9 strain T203 in mainland China detected from an infant in Beijing in 1994 clustered within VP7 lineage VI(G9 VI),whereas the common RVA G9 belong to VP7 lineage III(G9-III) worldwide. Interestingly, since it was first reported in 1994 there was no G9-VI circulating in Beijing, until an unexpected G9-VI strain was identified by sequencing in 2010 RVA surveillance. This present study was to develop a convenient and effective dot-blot hybridization method for differentiating G9-III and G9-VI rotaviruses, to investigate the re-emerging circulating distribution of G9-VI RVAs in outpatient children with diarrhea from 2011 to 2012in Beijing. By multiple sequence aligning and analyzing the collected VP7 gene nucleotide sequences of G9 RVAs worldwide from GenBank database using Clustal W software, a region within VP7 gene which is highly divergent between G9-III and G9-VI rotaviruses and conserved within themselves was selected as probe. One pair of common primers at both side of this probe region was designed, and used for synthesizing DIG labeled G9-III and G9-VI probes with PCR, respectively. Subsequently, RVA G and P genotypes were identified as previously described. Then G9-III and G9-VI were further differentiated from G9 RVAs using dot-blot hybridization method established in this study. It was showed that G9 was the most prevalent genotype(43.5%),followed by G3(30.5%),G1(12.2%)and G2(11.5%),and no G4 genotype was detected.Interestingly,G9-VI was the most predominant(96.5%) type, while only 3.5% was G9-III among these G9 rotaviruses.Phylogenetically,G9-VI rotaviruses in this study clustered closely with human G9-VI rotaviruses which were more recently re-emerging in several countries including China around the world as well as porcine G9-VI rotavirus strain F7P4 in Canada, whereas they clustered distantly to worldwide common G9-III strains.G9-VI rotaviruses were re-emerging in the world, whether it gained stronger spreading ability or virulence than ever common G9-III during evolution with porcine G9-VI rotaviruses need further analysis. PMID- 29979559 TI - [Research progress in natural allopyranosides]. AB - The pharmacological activities of natural glycosides are closely related to the polyfunctionalsugar moieties. Modification of active natural products by glycosylation can change the stereochemicalconfiguration, improve the solubility, tune up the activities and change pharmacokinetic properties for higherefficacy and better selectivity. Compared with the common D-glucose, D-allose, a C-3 epimer of D-glucoserarely exists in nature, but it plays an important role in food, health, medicine, and so on. It is not easilymetabolized in the living organisms, but can be used as a safe and low-calorie sweetener. The naturalallopyranosides are absolute conjugation forms which are same as other glucopyranosides and rhamnopyranosideswith a broad array of biological activities. This article summarizes the major progresses made inphytochemistry and biological activity studies of these compounds. Structure-activity relationship analyses ofpartial anti-tumor and anti-diabetic allopyranosides were performed regarding the data reported in the literatures.These insights may provide a theoretical and experimental reference for the discovery of new drug and drugdesign based on allopyranosides. PMID- 29979560 TI - Plaque psoriasis - more than a skin disorder. AB - Plaque psoriasis is one of the most common skin disorders and has been recognized as a systemic disease for a few years. It,s part of the immune-mediated inflammatory diseases. This is why the management of these patients includes the investigation of possible comorbidity like the metabolic syndrome, depression or psoriatic arthritis. PMID- 29979561 TI - What's the appearance of psoriasis. AB - Psoriatic disorders are a visual diagnosis. Aside from several subtypes of skin psoriasis, skin appendages such nails are often affected. The burden of disease is defined by the disease activity (extent of affliction of skin) as well as restriction of quality of life. Validated scores are a good tool for the evaluation. PMID- 29979562 TI - Boosting Oxygen Reduction Catalysis with N-doped Carbon Coated Co9S8 Microtubes. AB - Herein, nitrogen-doped carbon coated hollow Co9S8 microtubes (Co9S8@N-C microtubes) are prepared through a facile solvothermal procedure, followed by dopamine polymerization process together with a post-pyrolysis which present excellent electrocatalytic activity for oxygen reduction reaction (ORR). The Co9S8 within the hollow Co9S8@N-C microtubes presents a well-defined single crystal structure with dominated (022) plane. To obtain desired electrocatalyst, the annealing temperature and the thickness of carbon layer tuned by changing the dopamine concentration are optimized systematically. The electrochemical results demonstrate that the coordination of the N-doped carbon layer, exposed (022) plane, and hollow architecture of Co9S8 microtubes calcined at 700 degrees C affords outstanding ORR performance to Co9S8@N-C microtubes. The moderate thickness of the carbon layer is crucial for improving ORR activity of Co9S8@N-C microtubes, while increasing or decreasing the thickness would result in activity decrease. More importantly, the N-doped carbon layer can protect inner Co9S8 from undergoing aggregation and dissolution effectively during the ORR, resulting in excellent electrocatalytic stability. PMID- 29979563 TI - Targeting Delivery of Lidocaine and Cisplatin by Nanogel Enhances Chemotherapy and Alleviates Metastasis. AB - Tumor growth inhibition and adverse effect reduction together with metastasis alleviation are still the challenges that need to be overcome in cancer chemotherapy. Combinational therapy provides an alternative solution for these challenges. Nanoparticles are the ideal carriers for combinational therapy due to their versatile drug loading capacities and versatile tumor-targeting strategies. In this study, a cRGDfk modified nanogel system has been utilized to coload lidocaine, a voltage-gated Na+ channels inhibitor, and cisplatin, a common anticancer drug to obtain a tumor-targeted dual drugs-loaded nanogel system. The introduction of lidocaine not only promotes the cisplatin-induced apoptosis in vitro and in vivo but also alleviates the metastasis of MDA-MB-231 breast cancer cells in the mouse model. Besides, the body weight loss caused by cisplatin has also been relieved, and higher dose with less body weight loss can be achieved, which indicated the adverse effect caused by cisplatin-mediated chemotherapy has been alleviated. Furthermore, the introduction of peptide segment-cRGDfk, which presents high affinity to alphavbeta3 integrin, further increases the enrichment of drug-loaded nanogel in the tumor site. It favors the primary tumor growth inhibition. The results demonstrate the coloading of lidocaine and cisplatin by ligand-modified nanogels is a promising strategy for alphavbeta3 integrin overexpressing breast cancer combinational therapy. PMID- 29979564 TI - Peptide Nanofiber Substrates for Long-Term Culturing of Primary Neurons. AB - The culturing of primary neurons represents a central pillar of neuroscience research. Primary neurons are derived directly from brain tissue and recapitulate key aspects of neuronal development in an in vitro setting. Unlike neural stem cells, primary neurons do not divide; thus, initial attachment of cells to a suitable substrate is critical. Commonly used polylysine substrates can suffer from batch variability owing to their polymeric nature. Herein, we report the use of chemically well-defined, self-assembling tetrapeptides as substrates for primary neuronal culture. These water-soluble peptides assemble into fibers which facilitate adhesion and development of primary neurons, their long-term survival (>40 days), synaptic maturation, and electrical activity. Furthermore, these substrates are permissive toward neuronal transfection and transduction which, coupled with their uniformity and reproducible nature, make them suitable for a wide variety of applications in neuroscience. PMID- 29979565 TI - Graphene-Boosted, High-Performance Aqueous Zn-Ion Battery. AB - Given their low cost and eco-friendliness, rechargeable Zn-ion batteries (ZIBs) have received increasing attention as a device with great potential for large scale energy storage. However, the development of ZIBs with high capacities and long lifespans is challenging because of the dendritic growth of Zn and the absence of suitable cathode materials. Herein, we report a novel rechargeable aqueous Zn-ion battery (AZIB) that consist of Zn coated with reduced graphene oxide as the anode and V3O7.H2O/rGO composite as the cathode. The new AZIB exhibits excellent cycle stability with a high capacity retention of 79% after 1000 cycles. Moreover, it can deliver a high power density of 8400 W kg-1 at 77 W h kg-1 and a high energy density of 186 W h kg-1 at 216 W kg-1, and the former is higher than those of previously reported AZIBs. Our work provides a new perspective in developing rechargeable ZIBs and would greatly accelerate the practical applications of rechargeable ZIBs. PMID- 29979566 TI - Photoactive Oligo( p-phenylenevinylene) Functionalized with Phospholipid Units for Control and Visualization of Delivery into Living Cells. AB - To take advantage of the excellent optical properties of conjugated polymers (CPs) or conjugated oligomers (COs) for biological applications, there is still a requirement to find new ways to deliver these conjugated molecular materials into cells in a facile, controllable, and noninvasive manner. Herein, a photoactive oligo( p-phenylenevinylene) (OPV) derivative was covalently attached with phospholipid units (OPV-lipid) to enhance its dispersion in water and facilitate its internalization by cells. OPV-lipid could be delivered into either the cell membrane or cytoplasm controllably through the assistance of liposomes with different formulas. It could also act as a fluorescent probe for cell imaging and visualization of the delivery process. This work shows a good potential for delivering functional conjugated molecular materials into cells in a controllable way. PMID- 29979567 TI - Directed Accumulation of Anticancer Depsipeptides by Characterization of Neoantimycins Biosynthetic Pathway and an NADPH-Dependent Reductase. AB - Neoantimycins (NATs) are members of antimycin-types of depsipeptides with outstanding anticancer activities. We isolated NAT-A (1) and -F (2) from the fermentation extract of Streptomyces conglobatus. The NAT biosynthetic gene cluster ( nat BGC) was identified by genome sequencing and bioinformatics analysis. nat BGC includes two nonribosomal peptide synthetase (NRPS) and one polyketide synthase (PKS) gene, and a gene cassette (10 genes), of which the encoded enzymes share high homology to the ones responsible for 3 formamidosalicylate (3-FAS) biosynthesis in the antimycin biosynthetic pathway. Heterologous expression of the partial nat BGC without the 3-FAS gene cassette in the antimycin producer, Streptomyces albus J1074, results in the production of 1 and 2, suggesting that the nat BGC indeed directs NATs biosynthesis. Targeted in frame deletion of the reductase gene ( natE) abolished the production of 1 and 2 but accumulated two NAT derivatives, the known NAT-H (3) and a new NAT-I (4). Biochemical verification demonstrated that the recombinant NatE indeed catalyzes an NADPH-dependent reaction of 3 or 4 to 1 or 2, respectively. Compound 3 presented significantly stronger activities against eight cancer cell lines than the ones using cisplatin, the clinical chemotherapy medicine. In particular, 3 displayed 559- and 57-fold higher activity toward human melanoma and cervix epidermoid carcinoma cells, respectively, compared with cisplatin. The new derivative, 4, was 1.5- to 10.9-fold more active than cisplatin toward five cancer cell lines. The evaluation of NATs biosynthesis depicted here will pave the way to generate new NAT derivatives through rational pathway engineering. PMID- 29979568 TI - Nanocolloidal Hydrogel for Heavy Metal Scavenging. AB - We report a nanocolloidal hydrogel that combines the advantages of molecular hydrogels and nanoparticle-based scavengers of heavy metal ions. The hydrogel was formed by the chemical cross-linking of cellulose nanocrystals and graphene quantum dots. Over a range of hydrogel compositions, its structure was changed from lamellar to nanofibrillar, thus enabling the control of hydrogel permeability. Using a microfluidic approach, we generated nanocolloidal microgels and explored their scavenging capacity for Hg2+, Cu2+, Ni2+, and Ag+ ions. Due to the large surface area and abundance of ion-coordinating sites on the surface of nanoparticle building blocks, the microgels exhibited a high ion-sequestration capacity. The microgels were recyclable and were used in several ion scavenging cycles. These features, in addition to the sustainable nature of the nanoparticles, make this nanocolloidal hydrogel a promising ion-scavenging material. PMID- 29979569 TI - Biocompatible Peptide-Coated Ultrasmall Superparamagnetic Iron Oxide Nanoparticles for In Vivo Contrast-Enhanced Magnetic Resonance Imaging. AB - The biocompatibility and performance of reagents for in vivo contrast-enhanced magnetic resonance imaging (MRI) are essential for their translation to the clinic. The quality of the surface coating of nanoparticle-based MRI contrast agents, such as ultrasmall superparamagnetic iron oxide nanoparticles (USPIONs), is critical to ensure high colloidal stability in biological environments, improved magnetic performance, and dispersion in circulatory fluids and tissues. Herein, we report the design of a library of 21 peptides and ligands and identify highly stable self-assembled monolayers on the USPIONs' surface. A total of 86 different peptide-coated USPIONs are prepared and selected using several stringent criteria, such as stability against electrolyte-induced aggregation in physiological conditions, prevention of nonspecific binding to cells, and absence of cellular toxicity and contrast-enhanced in vivo MRI. The bisphosphorylated peptide 2PG-S*VVVT-PEG4-ol provides the highest biocompatibility and performance for USPIONs, with no detectable toxicity or adhesion to live cells. The 2PG S*VVVT-PEG4-ol-coated USPIONs show enhanced magnetic resonance properties, r1 (2.4 mM-1.s-1) and r2 (217.8 mM-1.s-1) relaxivities, and greater r2/ r1 relaxivity ratios (>90) when compared to those of commercially available MRI contrast agents. Furthermore, we demonstrate the utility of 2PG-S*VVVT-PEG4-ol coated USPIONs as a T2 contrast agent for in vivo MRI applications. High contrast enhancement of the liver is achieved as well as detection of liver tumors, with significant improvement of the contrast-to-noise ratio of tumor-to-liver contrast. It is envisaged that the reported peptide-coated USPIONs have the potential to allow for the specific targeting of tumors and hence early detection of cancer by MRI. PMID- 29979570 TI - Construction of Hierarchical MoSe2 Hollow Structures and Its Effect on Electrochemical Energy Storage and Conversion. AB - Metal selenides have attracted increased attention as promising electrode materials for electrochemical energy storage and conversion systems including metal-ion batteries and water splitting. However, their practical application is greatly hindered by collapse of the microstructure, thus leading to performance fading. Tuning the structure at nanoscale of these materials is an effective strategy to address the issue. Herein, we craft MoSe2 with hierarchical hollow structures via a facile bubble-assisted solvothermal method. The temperature related variations of the hollow interiors are studied, which can be presented as solid, yolk-shell, and hollow spheres, respectively. Under the simultaneous action of the distinctive hollow structures and interconnections among the nanosheets, more intimate contacts between MoSe2 and electrolyte can be achieved, thereby leading to superior electrochemical properties. Consequently, the MoSe2 hollow nanospheres prepared under optimum conditions exhibit optimal electrochemical activities, which hold an initial specific capacity of 1287 mA h g-1 and maintain great capacity even after 100 cycles as anode for Li-ion battery. Moreover, the Tafel slope of 58.9 mV dec-1 for hydrogen evolution reaction is also attained. PMID- 29979571 TI - Switching of Current Rectification Ratios within a Single Nanocrystal by Facet Resolved Electrical Wiring. AB - Here we show that within a single polyhedral metal oxide nanoparticle a nanometer scale lateral or vertical sliding of a small metal top contact ( e. g., <50 nm) leads to a 10-fold change in current rectification ratios. Electron tunneling imaging and constant-force current-potential analysis in atomic force microscopy demonstrate that within an individual p-n rectifier (a Cu2O nanocrystal on silicon) the degree of current asymmetry can be modulated predictably by a set of geometric considerations. We demonstrate the concept of a single nanoscale entity displaying an in-built range of discrete electrical signatures and address fundamental questions in the direction of "landing" contacts in single-particle diodes. This concept is scalable to large 2D arrays, up to millimeters in size, with implications in the design and understanding of nanoparticle circuitry. PMID- 29979572 TI - Murine and Non-Human Primate Dendritic Cell Targeting Nanoparticles for in Vivo Generation of Regulatory T-Cells. AB - Porous silicon nanoparticles (pSiNP), modified to target dendritic cells (DC), provide an alternate strategy for the delivery of immunosuppressive drugs. Here, we aimed to develop a DC-targeting pSiNP displaying c-type lectin, dendritic cell specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and CD11c monoclonal antibodies. The in vivo tracking of these fluorescent DC targeting nanoparticles was assessed in both C57BL/6 mice and common marmosets ( Callithrix jacchus) by intravenous injection (20 mg/kg). Rapamycin and ovalbumin (OVA)323-339 peptide loaded pSiNP were employed to evaluate their ability to generate murine CD4+CD25+FoxP3+ regulatory T-cells in vivo within OVA sensitized mice. In vivo, pSiNP migrated to the liver, kidneys, lungs, and spleen in both mice and marmosets. Flow cytometry confirmed pSiNP uptake by splenic and peripheral blood DC when functionalized with targeting antibodies. C57BL/6 OVA sensitized mice injected with CD11c-pSiNP loaded with rapamycin + OVA323-339 produced a 5-fold higher number of splenic regulatory T-cells compared to control mice, at 40 days post-pSiNP injection. These results demonstrate the importance of the immobilized targeting antibodies to enhance cellular uptake and enable the in vivo generation of splenic regulatory T-cells. PMID- 29979573 TI - Nondestructive Thickness Mapping of Wafer-Scale Hexagonal Boron Nitride Down to a Monolayer. AB - The availability of an accurate, nondestructive method for measuring thickness and continuity of two-dimensional (2D) materials with monolayer sensitivity over large areas is of pivotal importance for the development of new applications based on these materials. While simple optical contrast methods and electrical measurements are sufficient for the case of metallic and semiconducting 2D materials, the low optical contrast and high electrical resistivity of wide band gap dielectric 2D materials such as hexagonal boron nitride (hBN) hamper their characterization. In this work, we demonstrate a nondestructive method to quantitatively map the thickness and continuity of hBN monolayers and bilayers over large areas. The proposed method is based on acquisition and subsequent fitting of ellipsometry spectra of hBN on Si/SiO2 substrates. Once a proper optical model is developed, it becomes possible to identify and map the commonly observed polymer residuals from the transfer process and obtain submonolayer thickness sensitivity for the hBN film. With some assumptions on the optical functions of hBN, the thickness of an as-transferred hBN monolayer on SiO2 is measured as 4.1 A +/- 0.1 A, whereas the thickness of an air-annealed hBN monolayer on SiO2 is measured as 2.5 A +/- 0.1 A. We argue that the difference in the two measured values is due to the presence of a water layer trapped between the SiO2 surface and the hBN layer in the latter case. The procedure can be fully automated to wafer scale and extended to other 2D materials transferred onto any polished substrate, as long as their optical functions are approximately known. PMID- 29979574 TI - Promoting Osseointegration of Ti Implants through Micro/Nanoscaled Hierarchical Ti Phosphate/Ti Oxide Hybrid Coating. AB - In this study, micro/nanoscaled hierarchical hybrid coatings containing titanium (Ti) phosphate and Ti oxide have been fabricated with the aim of promoting osseointegration of Ti-based implants. Three representative surface coatings, namely, micro/nanograss Ti (P-G-Ti), micro/nanoclump Ti, (P-C-Ti), and micro/nanorod Ti (P-R-Ti), have been produced. In-depth investigations into the coating surface morphology, topography, chemical composition, and the surface/cell interaction have been carried out using scanning electron microscopy, transmission electron microscope, X-ray photoelectron spectroscopy, X ray diffraction, contact-angle measurement, and protein adsorption assay. In addition, in vitro performance of the coating (cell proliferation, adhesion, and differentiation) has been evaluated using rat bone marrow stromal cells (BMSCs), and in vivo assessments have been carried out based on a rat tibia implantation model. All the hybrid coating modified implants demonstrated enhanced protein adsorption and BMSC viability, adhesion and differentiation, with P-G-Ti showing the best bioactivity among all samples. Subsequent i n vivo osseointegration tests confirmed that P-G-Ti has induced a much stronger interfacial bonding with the host tissue, indicated by the 2-fold increase in the ultimate shear strength and over 6-fold increase in the maximum push-out force compared to unmodified Ti implants. The state-of-the-art coating technology proposed for Ti-based implants in this study holds great potential in advancing medical devices for next generation healthcare technology. PMID- 29979575 TI - Aggregation-Induced Emission Nanoparticles Encapsulated with PEGylated Nano Graphene Oxide and Their Applications in Two-Photon Fluorescence Bioimaging and Photodynamic Therapy in Vitro and in Vivo. AB - Aggregation-induced emission (AIE) nanoparticles have been shown promise for fluorescence bioimaging and photodynamic therapy due to the good combination of nanoparticles and organic dyes or photosensitizers. Among several kinds of AIE nanoparticles, those that are capsulated with nanographene oxides (NGO) are easy to make, size-tunable, and have proven to be very stable in deionized water. However, the stability in saline solution still needs improvement for further applications in chemical or biomedical fields, and the efficacy of photodynamic therapy using NGO-capsulate AIE photosensitizers has not been evaluated yet. Herein, we modified NGO with polyethylene glycol (PEG) to improve the stability of NGO-capsulated AIE nanoparticles in phosphate buffer saline. Furthermore, by combining this modification method with a dual-functional molecule which has both typical AIE property and photosensitizing ability, we performed both two-photon fluorescence bioimaging and photodynamic therapy in vitro and in vivo. Our work shows that AIE nanoparticles capsulated with PEGylated nanographene oxide can be a powerful tool for future bioimaging and photodynamic therapy applications. PMID- 29979576 TI - Targeted Elimination of Tumorigenic Human Pluripotent Stem Cells Using Suicide Inducing Virus-like Particles. AB - Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs) and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qbeta bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD) and to simultaneously display multiple IgG-binding ZZ domains. After labeling with antibodies against the hPSC-specific surface glycan SSEA-5, EGFP-containing particles were shown to specifically bind undifferentiated cells in culture, and CD-containing particles were able to eliminate undifferentiated hPSCs with virtually no cytotoxicity to differentiated cells upon treatment with the prodrug 5-fluorocytosine. PMID- 29979577 TI - Serine/Threonine Ligation: Origin, Mechanistic Aspects, and Applications. AB - Synthetic proteins are expected to go beyond the boundary of recombinant DNA expression systems by being flexibly installed with site-specific natural or unnatural modification structures during synthesis. To enable protein chemical synthesis, peptide ligations provide effective strategies to assemble short peptide fragments obtained from solid-phase peptide synthesis (SPPS) into long peptides and proteins. In this regard, chemoselective peptide ligation represents a simple but powerful transformation realizing selective amide formation between the C-terminus and N-terminus of two side-chain-unprotected peptide fragments. These reactions are highly chemo- and regioselective to tolerate the side-chain functionalities present on the unprotected peptides, highly reactive to work with millmolar or submillimolar concentrations of the substrates, and operationally simple with mild conditions and accessible building blocks. This Account focuses on our work in the development of serine/threonine ligation (STL), which originates from a chemoselective reaction between an unprotected peptide with a C terminal salicylaldehyde (SAL) ester and another unprotected peptide with an N terminal serine or threonine residue. Mechanistically, STL involves imine capture, 5- endo-trig ring-chain tautomerization, O-to- N [1,5] acyl transfer to afford the N, O-benzylidene acetal-linked peptide, and acidolysis to regenerate the Xaa-Ser/Thr linkage (where Xaa is the amino acid) at the ligation site. The high abundance of serine and threonine residues (12.7%) in naturally occurring proteins and the good compatibility of STL with various C-terminal residues provide multiple choices for ligation sites. The requisite peptide C-terminal SAL esters can be prepared from the peptide fragments obtained from both Fmoc-SPPS and Boc-SPPS through four available methods (a safety-catch strategy based on phenolysis, direct coupling, ozonolysis, and the n + 1 strategy). In the synthesis of proteins (e.g., ACYP enzyme, MUC1 glycopeptide 40-mer to 80-mer, interleukin 25, and HMGA1a with variable post-translational modification patterns), both C-to- N and N-to- C sequential STL strategies have been developed through selection of temporal N-terminal protecting groups and proper design of the switch-on/off C-terminal SAL ester surrogate, respectively. In the synthesis of cyclic peptide natural products (e.g., daptomycin, teixobactin, cyclomontanin B, yunnanin C) and their analogues, intramolecular head-to-tail STL has been implemented on linear peptide SAL ester precursors containing four to 10 amino acid residues with good efficiency and minimized oligomerization. As a thiol independent chemoselective ligation complementary to native chemical ligation, STL provides an alternative tool for the chemical synthesis of homogeneous proteins with site-specific and structure-defined modifications and cyclic peptide natural products, which lays foundation for chemical biology and medicinal studies of those molecules with biological importance and therapeutic potential. PMID- 29979578 TI - Allosteric Inhibitor of KRas Identified Using a Barcoded Assay Microchip Platform. AB - Protein catalyzed capture agents (PCCs) are synthetic antibody surrogates that can target a wide variety of biologically relevant proteins. As a step toward developing a high-throughput PCC pipeline, we report on the preparation of a barcoded rapid assay platform for the analysis of hits from PCC library screens. The platform is constructed by first surface patterning a micrometer scale barcode composed of orthogonal ssDNA strands onto a glass slide. The slide is then partitioned into microwells, each of which contains multiple copies of the full barcode. Biotinylated candidate PCCs from a click screen are assembled onto the barcode stripes using a complementary ssDNA-encoded cysteine-modified streptavidin library. This platform was employed to evaluate candidate PCC ligands identified from an epitope targeted in situ click screen against the two conserved allosteric switch regions of the Kirsten rat sarcoma (KRas) protein. A single microchip was utilized for the simultaneous evaluation of 15 PCC candidate fractions under more than a dozen different assay conditions. The platform also permitted more than a 10-fold savings in time and a more than 100-fold reduction in biological and chemical reagents relative to traditional multiwell plate assays. The best ligand was shown to exhibit an in vitro inhibition constant (IC50) of ~24 MUM. PMID- 29979579 TI - Severing Ties: Different Responses of Larval and Adult Aquatic Insects to Atrazine and Selenium. AB - Aquatic insects link aquatic and terrestrial ecosystems through their metamorphosis and subsequent transition from water to land. Chemical stressors in freshwater, such as agricultural contaminants, can potentially disrupt insect life cycles and reduce the number of insects emerging as terrestrial adults, thereby damaging or severing this linkage. Atrazine and selenium, though frequently detected in waterways and often co-occurring, have not been previously studied together in controlled experiments. We conducted a six-week mesocosm experiment to measure the responses of larval and emerging aquatic insects to treatments of atrazine (15 MUg/L), selenium (10 MUg/L), and a direct combination of the two. Peak adult insect abundance was reduced in all treatments by 35% to 45% relative to the control. Further, cumulative adult emergence in the combined treatment was 33% lower than in the control. However, no reductions in primary production were observed with treatments, and consistent reductions in benthic insect abundance relative to the control were not observed until the end of the experiment, when overall abundance was low. Results suggest that adult insects are more sensitive than larval insects to atrazine and selenium and that the impacts of these contaminants are stronger on the terrestrial than the aquatic ecosystem. PMID- 29979580 TI - An Artificial Yeast Genetic Circuit Enables Deep Mutational Scanning of an Antimicrobial Resistance Protein. AB - Understanding the molecular mechanisms underlying antibiotic resistance requires concerted efforts in enzymology and medicinal chemistry. Here we describe a new synthetic biology approach to antibiotic development, where the presence of tetracycline antibiotics is linked to a life-death selection in Saccharomyces cerevisiae. This artificial genetic circuit allowed the deep mutational scanning of the tetracycline inactivating enzyme TetX, revealing key functional residues. We used both positive and negative selections to confirm the importance of different residues for TetX activity, and profiled activity hotspots for different tetracyclines to reveal substrate-specific activity determinants. We found that precise positioning of FAD and hydrophobic shielding of the tetracycline are critical for enzymatic inactivation of doxycycline. However, positioning of FAD is suboptimal in the case of anhydrotetracycline, potentially explaining its comparatively poor degradation and potential as an inhibitor for this family of enzymes. By combining artificial genetic circuits whose function can be modulated by antimicrobial resistance determinants, we establish a framework to select for the next generation of antibiotics. PMID- 29979582 TI - Downstream Simultaneous Electrochemical Detection of Primary Reactive Oxygen and Nitrogen Species Released by Cell Populations in an Integrated Microfluidic Device. AB - An innovative microfluidic platform was designed to monitor electrochemically four primary reactive oxygen (ROS) and reactive nitrogen species (RNS) released by aerobic cells. Taking advantage of the space confinement and electrode performances under flow conditions, only a few experiments were sufficient to directly provide significant statistical data relative to the average behavior of cells during oxidative-stress bursts. The microfluidic platform comprised an upstream microchamber for cell culture and four parallel microchannels located downstream for separately detecting H2O2, ONOO-, NO., and NO2-. Amperometric measurements were performed at highly sensitive Pt-black electrodes implemented in the microchannels. RAW 264.7 macrophage secretions triggered by a calcium ionophore were used as a way to assess the performance, sensitivity, and specificity of the integrated microfluidic device. In comparison with some previous evaluations achieved from single-cell measurements, reproducible and relevant determinations validated the proof of concept of this microfluidic platform for analyzing statistically significant oxidative-stress responses of various cell types. PMID- 29979581 TI - Potential Source Apportionment and Meteorological Conditions Involved in Airborne 131I Detections in January/February 2017 in Europe. AB - Traces of particulate radioactive iodine (131I) were detected in the European atmosphere in January/February 2017. Concentrations of this nuclear fission product were very low, ranging 0.1 to 10 MUBq m-3 except at one location in western Russia where they reached up to several mBq m-3. Detections have been reported continuously over an 8-week period by about 30 monitoring stations. We examine possible emission source apportionments and rank them considering their expected contribution in terms of orders of magnitude from typical routine releases: radiopharmaceutical production units > sewage sludge incinerators > nuclear power plants > spontaneous fission of uranium in soil. Inverse modeling simulations indicate that the widespread detections of 131I resulted from the combination of multiple source releases. Among them, those from radiopharmaceutical production units remain the most likely. One of them is located in Western Russia and its estimated source term complies with authorized limits. Other existing sources related to 131I use (medical purposes or sewage sludge incineration) can explain detections on a rather local scale. As an enhancing factor, the prevailing wintertime meteorological situations marked by strong temperature inversions led to poor dispersion conditions that resulted in higher concentrations exceeding usual detection limits in use within the informal Ring of Five (Ro5) monitoring network. PMID- 29979583 TI - Synthesis and Reactivity of Low-Valent f-Element Iodide Complexes with Neutral Iminophosphorane Ligands. AB - The coordination and reactivity of simple iodide salts of low-valent f elements [YbI2, SmI2, TmI2, and UI3(THF)4, where THF = tetrahydrofuran] with iminophosphorane (R3P?NR') ligands are reported. The studied chelates were observed to adapt their geometry and effectively bind divalent ytterbium and samarium centers, as well as the trivalent uranium cation. The reactivity of the ytterbium adducts with benzophenone was found to be dependent on the steric demand of the supporting iminophosphorane ligand. In particular, a rare example of a stable charge-separated ketyl radical species is reported with ytterbium. Additionally, divalent thulium was observed to induce a reductive coupling at the ligand's central pyridine ring. PMID- 29979585 TI - Synthesis and Characterization of Tris(trimethylsilyl)siloxide Derivatives of Early Transition Metal Alkoxides That Thermally Convert to Varied Ceramic-Silica Architecture Materials. AB - In an effort to generate single-source precursors for the production of metal siloxide (MSiO x) materials, the tris(trimethylsilyl)silanol (H-SST or H OSi(SiMe3)3 (1) ligand was reacted with a series of group 4 and 5 metal alkoxides. The group 4 products were crystallographically characterized as [Ti(SST)2(OR)2] (OR = OPr i (2), OBu t (3), ONep (4)); [Ti(SST)3(OBu n)] (5); [Zr(SST)2(OBu t)2(py)] (6); [Zr(SST)3(OR)] (OR = OBu t (7), ONep, (8)); [Hf(SST)2(OBu t)2] (9); and [Hf(SST)2(ONep)2(py) n] ( n = 1 (10), n = 2 (10a)) where OPr i = OCH(CH3)2, OBu t = OC(CH3)3, OBu n = O(CH2)3CH3, ONep = OCH2C(CH3)3, py = pyridine. The crystal structures revealed varied SST substitutions for: monomeric Ti species that adopted a tetrahedral ( T-4) geometry; monomeric Zr compounds with coordination that varied from T-4 to trigonal bipyramidal ( TBPY-5); and monomeric Hf complexes isolated in a TBPY-5 geometry. For the group 5 species, the following derivatives were structurally identified as [V(SST)3(py)2] (11), [Nb(SST)3(OEt)2] (12), [Nb(O)(SST)3(py)] (13), 2[H][(Nb(MU-O)2(SST))6(MU6-O)] (14), [Nb8O10(OEt)18(SST)2.1/5Na2O] (15), [Ta(SST)(MU-OEt)(OEt)3]2 (16), and [Ta(SST)3(OEt)2] (17) where OEt = OCH2CH3. The group 5 monomeric complexes were solved in a TBPY-5 arrangement, whereas the Ta of the dinculear 16 was solved in an octahedral coordination environment. Thermal analyses of these precursors revealed a stepwise loss of ligand, which indicated their potential utility for generating the MSiO x materials. The complexes were thermally processed (350-1100 degrees C, 4 h, ambient atmosphere), but instead of the desired MSiO x, transmission electron microscopy analyses revealed that fractions of the group 4 and group 5 precursors had formed unusual metal oxide silica architectures. PMID- 29979584 TI - Arsenic Reduces Gene Expression Response to Changing Salinity in Killifish. AB - Toxicogenomic approaches can detect and classify adverse interactions between environmental toxicants and other environmental stressors but require more complex experimental designs and analytical approaches. Here we use novel toxicogenomic techniques to analyze the effect of arsenic exposure in wild killifish populations acclimating to changing salinity. Fish from three populations were acclimated to full strength seawater and transferred to fresh water for 1 or 24 h. Linear models of gene expression in gill tissue identified 31 genes that responded to osmotic shock at 1 h and 178 genes that responded at 24 h. Arsenic exposure (100 MUg/L) diminished the responses (reaction norms) of these genes by 22% at 1 h ( p = 1.0 * 10-6) and by 10% at 24 h ( p = 3.0 * 10 10). Arsenic also significantly reduced gene coregulation in gene regulatory networks ( p = 0.002, paired Levene's test), and interactions between arsenic and salinity acclimation were uniformly antagonistic at the biological pathway level ( p < 0.05, binomial test). Arsenic's systematic interference with gene expression reaction norms was validated in a mouse multistressor experiment, demonstrating the ability of these toxicogenomic approaches to identify biologically relevant adverse interactions between environmental toxicants and other environmental stressors. PMID- 29979586 TI - Identification and Rationalization of Kinetic Folding Intermediates for a Low Density Lipoprotein Receptor Ligand-Binding Module. AB - Many mutations that cause familial hypercholesterolemia localize to ligand binding domain 5 (LA5) of the low-density lipoprotein receptor, motivating investigation of the folding and misfolding of this small, disulfide-rich, calcium-binding domain. LA5 folding is known to involve non-native disulfide isomers, yet these folding intermediates have not been structurally characterized. To provide insight into these intermediates, we used nuclear magnetic resonance (NMR) to follow LA5 folding in real time. We demonstrate that misfolded or partially folded disulfide intermediates are indistinguishable from the unfolded state when focusing on the backbone NMR signals, which provide information on the formation of only the final, native state. However, 13C labeling of cysteine side chains differentiated transient intermediates from the unfolded and native states and reported on disulfide bond formation in real time. The cysteine pairings in a dominant intermediate were identified using 13C-edited three-dimensional NMR, and coarse-grained molecular dynamics simulations were used to investigate the preference of this disulfide set over other non-native arrangements. The transient population of LA5 species with particular non-native cysteine connectitivies during folding supports the conclusion that cysteine pairing is not random and that there is a bias toward certain structural ensembles during the folding process, even prior to the binding of calcium. PMID- 29979587 TI - Synthetic Strategies for Modified Glycosphingolipids and Their Design as Probes. AB - The plasma membrane of cells contains a diverse array of lipids that provide important structural and biological features. Glycolipids are typically a minor component of the cell membrane and consist primarily of glycosphingolipids (GSLs). GSLs in vertebrates contain a multifarious assortment of glycan headgroups, which can be important to biological functions based on lipid-lipid and lipid-protein interactions. The design of probes to study these complex targets requires advanced synthetic methodologies. In this Review, we will discuss recent advances in chemical and chemoenzymatic synthesis of GSLs in conjunction with the use of these approaches to design new probes. Examples using either chemical or enzymatic semisynthesis methods starting from isolated GSLs will also be reviewed. Focusing primarily on vertebrate glycolipids, we will highlight examples of radionuclide, fluorophore, photoresponsive, and bioorthogonal tagged GSL probes. PMID- 29979589 TI - Excited-State Proton Transfer from the Photoacid 2-Naphthol-8-sulfonate to Acetonitrile/Water Mixtures. AB - Steady-state and time-resolved fluorescence techniques were used to study excited state proton transfer (ESPT) to water of the reversible photoacid 2-naphthol-8 sulfonate (2N8S) in acetonitrile/water mixtures. In acetonitrile-rich mixtures, up to chiwater <= 0.12, we found a slow ESPT process on the order of nanoseconds. At chiwater ~ 0.15, the RO- fluorescence band intensity is at the minimum, whereas at chiwater ~ 0.030, it is at the maximum. The steady-state fluorescence spectra of these mixtures show that the intensity of the RO- fluorescence band at chiwater ~ 0.030 is about 0.24 of that of the ROH band. We explain this unusual phenomenon by the presence of water clusters that exist in the acetonitrile-rich CH3CN/H2O mixtures. We propose that a water bridge forms between the 2-OH and 8 sulfonate by preferential solvation of 2N8S, and this enables the ESPT process between the two sites of the molecular structure of 2N8S. In mixtures of chiwater >= 0.25, the ESPT process takes place to water clusters in the bulk mixture. The higher the chiwater in the mixture, the greater the ESPT rate constant. In neat water, the rate constant is rather small, 4.5 * 109 s-1. TD-DFT calculations show that a single water molecule can bridge between 2-OH and 8-sulfonate in the excited state. The activation energy for the ESPT reaction is about 9 kcal/mol, and the RO-(S1) species is energetically above the ROH(S1) species by about 1.6 kcal/mol. PMID- 29979588 TI - Conjugation of Amphiphilic Proteins to Hydrophobic Ligands in Organic Solvent. AB - Protein-ligand conjugations are usually carried out in aqueous media in order to mimic the environment within which the conjugates will be used. In this work, we focus on the conjugation of amphiphilic variants of elastin-like polypeptide (ELP), short elastin (sEL), to poorly water-soluble compounds like OPPVs ( p phenylenevinylene oligomers), triarylamines, and polypyridine-metal complexes. These conjugations are problematic when carried out in aqueous phase because hydrophobic ligands tend to avoid exposure to water, which in turn causes the ligand to self-aggregate and/or interact noncovalently with hydrophobic regions of the amphiphile. Ultimately, this behavior leads to low conjugation efficiency and contamination with strong noncovalent "conjugates". After exploring the solubility of sEL in various organic solvents, we have established an efficient conjugation methodology for obtaining covalent conjugates virtually free of contaminating noncovalent complexes. When conjugating carboxylated ligands to the amphiphile amines, we demonstrate that even when only one amine (the N-terminus) is present, its derivatization is 98% efficient. When conjugating amine moieties to the amphiphile carboxyls (a problematic configuration), protein multimerization is avoided, 98-100% of the protein is conjugated, and the unreacted ligand is recovered in pure form. Our syntheses occur in "one pot", and our purification procedure is a simple workup utilizing a combination of water and organic solvent extractions. This conjugation methodology might provide a solution to problems arising from solubility mismatch of protein and ligand, and it is likely to be widely applied for modification of recombinant amphiphiles used for drug delivery (PEG-antibodies, polymer-enzymes, food proteins), cell adhesion (collagen, hydrophobins), synthesis of nanostructures (peptides), and engineering of biocompatible optoelectronics (biological polymers), to cite a few. PMID- 29979590 TI - 5-Annulation of Ketoimines: TFA-Catalyzed Construction of Isoindolinone-3 carboxylates and Development of Photophysical Properties. AB - Herein we have demonstrated the first report on 5-annulation of ketoimines to valuable isoindolinone-3-carboxylates. Instead of commonly used aldimine substrates, relatively less reactive ketoimines are employed for developing a TFA catalyzed organoreductive cyclization to furnish a variety of isoindolinones in excellent yield and reaction rate under mild reaction conditions. This is a metal free event, which proceeds through a one pot ketoimine formation, hydride transfer from an organic reductant 2-(naphthalen-2-yl)-2,3-dihydrobenzo[ d]thiazole, and followed by five member cyclization sequences through TFA activation of imine and ester groups. Studies on ESI-MS kinetics, leaving group aptitude, and control experiments led us to propose the mechanistic pathway of the new ketoimine-lactamization reaction. We have shown the synthetic utility of the emerging synthons through easy transformation of isoindolinones to different synthetic analogues. We investigated photophysical properties of the small molecules for their futuristic application as a pharmaceutical and materials, and the heterocycles displayed brilliant fluorescence activity. PMID- 29979591 TI - Macrophilones from the Marine Hydroid Macrorhynchia philippina Can Inhibit ERK Cascade Signaling. AB - Six new macrophilone-type pyrroloiminoquines were isolated and identified from an extract of the marine hydroid Macrorhynchia philippina. The proton-deficient and heteroatom-rich structures of macrophilones B-G (2-7) were elucidated by spectroscopic analysis and comparison of their data with those of the previously reported metabolite macrophilone A (1). Compounds 1-7 are the first pyrroloiminoquines to be reported from a hydroid. The macrophilones were shown to inhibit the enzymatic conjugation of SUMO to peptide substrates, and macrophilones A (1) and C (3) exhibit potent and selective cytotoxic properties in the NCI-60 anticancer screen. Bioinformatic analysis revealed a close association of the cytotoxicity profiles of 1 and 3 with two known B-Raf kinase inhibitory drugs. While compounds 1 and 3 showed no kinase inhibitory activity, they resulted in a dramatic decrease in cellular protein levels of selected components of the ERK signal cascade. As such, the chemical scaffold of the macrophilones could provide small-molecule therapeutic leads that target the ERK signal transduction pathway. PMID- 29979592 TI - Correction to Relationship between the Degree of Polymerization of Chitooligomers and Their Activity Affecting the Growth of Wheat Seedlings under Salt Stress. PMID- 29979593 TI - Chemoenzymatic Synthesis of the Intermediates in the Peppermint Monoterpenoid Biosynthetic Pathway. AB - A chemoenzymatic approach providing access to all four intermediates in the peppermint biosynthetic pathway between limonene and menthone/isomenthone, including noncommercially available intermediates (-)- trans-isopiperitenol (2), (-)-isopiperitenone (3), and (+)- cis-isopulegone (4), is described. Oxidation of (+)-isopulegol (13) followed by enolate selenation and oxidative elimination steps provides (-)-isopiperitenone (3). A chemical reduction and separation route from (3) provides both native (-)- trans-isopiperitenol (2) and isomer (-)- cis isopiperitenol (18), while enzymatic conjugate reduction of (-)-isopiperitenone (3) with IPR [(-)-isopiperitenone reductase)] provides (+)- cis-isopulegone (4). This undergoes facile base-mediated chemical epimerization to (+)-pulegone (5), which is subsequently shown to be a substrate for NtDBR ( Nicotiana tabacum double-bond reductase) to afford (-)-menthone (7) and (+)-isomenthone (8). PMID- 29979595 TI - Low-Temperature and Fast Kinetics for CO2 Sorption Using Li6WO6 Nanowires. AB - In this paper, lithium hexaoxotungstate (Li6WO6) nanowires were synthesized via facile solid-state reaction and were tested for CO2 capture applications at both low (<100 degrees C) and high temperatures (>700 degrees C). Under dry conditions, the nanowire materials were able to capture CO2 with a weight increment of 12% in only 60 s at an operating temperature of 710 degrees C. By contrast, under humidified ambience, Li6WO6 nanowires capture CO2 with weight increment of 7.6% at temperatures as low as 30-40 degrees C within a time-scale of 1 min. It was observed that the CO2 chemisorption in Li6WO6 is favored in the oxygen ambience at higher temperatures and in the presence of water vapor at lower temperatures. Nanowire morphology favors the swift lithium supply to the surface of lithium-rich Li6WO6, thereby enhancing the reaction kinetics and lowering time scales for high capacity adsorption. Overall, high chemisorption capacities, superfast reaction kinetics, wide range of operating temperatures, and reasonably good recyclability make 1-D Li6WO6 materials highly suitable for various CO2 capture applications. PMID- 29979597 TI - Calmidazolium Chloride and Its Complex with Serum Albumin Prevent Huntingtin Exon1 Aggregation. AB - Huntington's disease (HD) is a genetic disorder caused by a CAG expansion mutation in Huntingtin gene leading to polyglutamine (polyQ) expansion in the N terminus side of Huntingtin (Httex1) protein. Neurodegeneration in HD is linked to aggregates formed by Httex1 bearing an expanded polyQ. Initiation and elongation steps of Httex1 aggregation are potential target steps for the discovery of therapeutic molecules for HD, which is currently untreatable. Here we report Httex1 aggregation inhibition by calmidazolium chloride (CLC) by acting on the initial aggregation event. Because it is hydrophobic, CLC was adsorbed to the vial surface and could not sustain an inhibition effect for a longer duration. The use of bovine serum albumin (BSA) prevented CLC adsorption by forming a BSA-CLC complex. This complex showed improved Httex1 aggregation inhibition by interacting with the aggregation initiator, the NT17 part of Httex1. Furthermore, biocompatible CLC-loaded BSA nanoparticles were made which reduced the polyQ aggregates in HD-150Q cells. PMID- 29979594 TI - Building Blocks of the Outer Membrane: Calculating a General Elastic Energy Model for beta-Barrel Membrane Proteins. AB - The outer membranes of Gram negative bacteria are the first points of contact these organisms make with their environment. Understanding how composition determines the mechanical properties of this essential barrier is of paramount importance. Therefore, we developed a new computational method to measure the elasticity of transmembrane proteins found in the outer membrane. Using all-atom molecular dynamics simulations of these proteins, we apply a set of external forces to mechanically stress the transmembrane beta-barrels. Our results from four representative beta-barrels show that outer membrane proteins display elastic properties that are approximately 70 to 190 times stiffer than neat lipid membranes. These findings suggest that outer membrane beta-barrels are a significant source of mechanical stability in bacteria. Our all-atom approach further reveals that resistance to radial stress is encoded by a general mechanism that includes stretching of backbone hydrogen bonds and tilting of beta strands with respect to the bilayer normal. This computational framework facilitates an increased theoretical understanding of how varying lipid and protein amounts affect the mechanical properties of the bacterial outer membrane. PMID- 29979596 TI - Evolution of a Novel Ribbon Phase in Optimally Doped Bi2Sr2CaCu2O8+delta at High Pressure and Its Implication to High- TC Superconductivity. AB - One challenge in studying high-temperature superconductivity (HTSC) stems from a lack of direct experimental evidence linking lattice inhomogeneity and superconductivity. Here, we apply synchrotron hard X-ray nanoimaging and small angle scattering to reveal a novel micron-scaled ribbon phase in optimally doped Bi2Sr2CaCu2O8+delta (Bi-2212, with delta = 0.1). The morphology of the ribbon like phase evolves simultaneously with the dome-shaped TC behavior under pressure. X-ray absorption studies show that the increasing of TC is associated with oxygen-hole redistribution in the CuO2 plan, while TC starts to decrease with pressure when oxygen holes become immobile. Additional X-ray irradiation experiments reveal that nanoscaled short-range ordering of oxygen vacancies could further lower TC, which indicates that the optimal TC is affected not only by an optimal morphology of the ribbon phase, but also an optimal distribution of oxygen vacancies. Our studies thereby provide for the first time compelling experimental evidence correlating the TC with micron to nanoscale inhomogeneity. PMID- 29979598 TI - Regioselective and Chemoselective Reduction of Naphthols Using Hydrosilane in Methanol: Synthesis of the 5,6,7,8-Tetrahydronaphthol Core. AB - A regioselective and chemoselective method for catalytic synthesis of biologically interesting 5,6,7,8-tetrahydronaphthols by reduction of naphthols was described. The side aromatic hydrocarbons in naphthols were site-selectively reduced, using hydrosilanes in methanol, allowing for retaining functional phenol scaffolds intact. It presents a rare example of using low-cost and air-stable hydrosilane for catalytic reduction of unactivated aromatic hydrocarbons under mild conditions. This reaction is scalable and proceeds in high selectivity without the formation of 1,2,3,4-tetrahydronaphthol byproducts with toleration of sensitive functionalities such as bromide, chloride, fluoride, ketone, ester, and amide. PMID- 29979599 TI - Properties of Ternary Biopolymer Nanocomplexes of Zein, Sodium Caseinate, and Propylene Glycol Alginate and Their Functions of Stabilizing High Internal Phase Pickering Emulsions. AB - A pH-cycle method based on preparing an alkaline solution of zein followed by neutralization with an acid can be used to prepare zein nanoparticles. In the present work, partial alkaline hydrolysis of propylene glycol alginate (PGA) to a lower pH was studied to prepare binary zein-PGA nanocomplexes and ternary complexes with additional sodium caseinate (NaCas). 0.5% or more PGA was sufficient to reduce the pH to 7.5 or lower, eliminating the need for titration, and resulted in simultaneous nanocomplex formation. The addition of NaCas into alkaline zein-PGA solution resulted in smaller complexes with all biopolymers, whereas adsorption on binary zein-PGA complexes was observed when NaCas was added into the neutral zein-PGA dispersions. The formation of nanocomplexes involved with hydrophobic and electrostatic attractions and hydrogen bonds and was further affected by the amount of NaCas. The ternary nanocomplexes with equal masses of zein and NaCas had an excellent capacity to prepare gel-like Pickering emulsions with as much as 80% v/v oil with characteristics suitable for texture modification and delivery systems of bioactive compounds in food and consumer products. Therefore, PGA can be used to possibly scale-up the pH-cycle method to produce zein-based nanoparticles with unique functional properties. PMID- 29979600 TI - Transient Kinetic Selectivity in Nanotubes Growth on Solid Co-W Catalyst. AB - Solid Co-W catalysts have been shown to yield single-walled carbon nanotubes (CNT) with high selectivity, simplistically attributed to CNT-catalyst symmetry match for certain chiral indices ( n, m). Here, based on large-scale first principles calculations combined with kinetic Monte Carlo simulations, we show instead that such selectivity arises from a complex kinetics of growth. The solid Co7W6 catalyst strongly favors a restructured, asymmetric CNT edge which entails preferential nucleation of tubes with 2 m < n but much faster growth of chiral tubes with n ? 2 m. We uncover a tendency of interface defects formation that, although rare, drive CNT type change from smaller to larger chiral angles (zigzag to armchair). Being both least prone to defects and fast growing, the (12,6) CNT appears as a transient, kinetics-selected type reaching highest abundance. PMID- 29979601 TI - Structural Analysis of Cellulose-Coated Oil-in-Water Emulsions Fabricated from Molecular Solution. AB - Natural cellulose has been used as a coating to stabilize oil-in-water (o/w) emulsions by exploiting the amphiphilic character of the cellulose chains molecularly dissolved in the ionic liquid 1-ethyl-3-methylimidazolium acetate. Its cellulose coating exhibits a continuous amorphous structure which differs significantly from the cellulose particle stabilization used in Pickering emulsions. The structure of these cellulose-coated o/w emulsion particles, in particular the cellulose coating shell characteristics (thickness, porosity, and composition), is studied by using a combination of direct imaging methods such as cryogenic electron microscopy and fluorescence microscopy with small-angle neutron scattering measurements. This work suggests a unique multicompartment structure of the emulsion particles: an oil core, surrounded by an inner shell composed of a porous cellulose gel, encapsulated by a dense outer cellulose shell, a few nanometers in thickness. The thickness of the inner cellulose shell varies significantly. The nanoscale emulsion droplets exhibit a thickness of 10 +/- 3 nm, whereas the larger micron-sized droplets exhibit a thicker inner cellulose shell of 500-750 nm. It is also inferred that the cellulose shells contain water rather than oil. PMID- 29979602 TI - Transformations of Isonitriles with Bromoalkanes Using Photoredox Gold Catalysis. AB - Isonitriles have excellent electronic compatibility to react with free radicals. Recently, photoredox catalysis has emerged as a powerful tool for the construction of C-C bonds with few protocols for alkylative heterocycle synthesis through isonitrile addition. Herein, we describe the photocatalytic generation of alkyl radicals from unactivated bromoalkanes as part of an efficient cross coupling strategy for the diversification of isonitriles using a dimeric gold(I) photoredox catalyst, [Au2(dppm)2]Cl2. PMID- 29979603 TI - Induction of the Endoplasmic Reticulum Stress Pathway by Highly Cytotoxic Organoruthenium Schiff-Base Complexes. AB - Current anticancer drug discovery efforts focus on the identification of first-in class compounds with a mode-of-action distinct from conventional DNA-targeting agents for chemotherapy. An emerging trend is the identification of endoplasmic reticulum (ER) targeting compounds that induce ER stress in cancer cells, leading to cell death. However, a limited pool of such compounds has been identified to date, and there are limited studies done on such compounds to allow for the rational design of ER stress-inducing agents. In our present study, we present a series of highly cytotoxic, ER stress-inducing Ru(II)-arene Schiff-Base (RAS) complexes, bearing iminoquinoline chelate ligands. We demonstrate that by structural modification to the iminoquinoline ligand, we could tune its pi acidity and influence reactive oxygen species (ROS) induction, switching between a ROS-mediated ER stress pathway activation and one that is not mediated by ROS induction. Our current study adds to the available ER stress inducers and shows how structural tuning could be used as a means to modulate the mode-of-action of such compounds. PMID- 29979605 TI - Intraoperative Ureter Visualization Using a Novel Near-Infrared Fluorescent Dye. AB - Ureters can be accidentally severed during pelvic surgeries, significantly prolonging the times in the operating room to allow for complete repair of damaged ureters and leading to significant morbidities associated with consequent ureter obstruction and possible kidney dysfunction. In an effort to prevent these complications, light-emitting stents and urine-excreted dyes have been introduced to illuminate the ureter during surgery. However, problems with mechanical insertion, ureter spasm, image contrast, and localized injection have limited interest in their clinical applications. We report here the synthesis and characterization of a new near-infrared (NIR) fluorescent dye (UreterGlow) that can be injected systemically but is excreted primarily through the renal system, allowing ureter imaging with an NIR fluorescence camera. Following intravenous injection of 0.1 mg/kg UreterGlow, we have monitored the flow of UreterGlow through the proximal, medial, and distal segments of the ureter. The timing of ureter visualization was calculated from the time of injection of the drug. The null hypothesis was that "Visualization of the ureter in pigs is possible 60 min after administration of UreterGlow using an NIR camera". UreterGlow displayed excitation and emission maxima of lambdaex = 800 nm and lambdaem = 830 nm in phosphate buffered saline, pH 7.4, and could be imaged in the urinary tract in mice. Shortly after injection of UreterGlow into Yorkshire pigs, peristalsis of the ureter could be observed. The distal ureter could be visualized under NIR illumination after 60 min with constant fluorescence in all five pigs for >2 h. The same ureters could not be seen using visible light ( X2, p = 0.0001). Because both excitation and emission of UreterGlow occurs at >30 nm longer wavelength than most tumor-imaging fluorescent dyes, it should be possible to distinguish ureter fluorescence from tumor fluorescence with this dye. PMID- 29979604 TI - Transdermal Cubic Phases of Metformin Hydrochloride: In Silico and in Vitro Studies of Delivery Mechanisms. AB - Transdermal delivery is one of important controlled drug release strategies for drug development. Cubic phases are the assemblies of amphiphilic molecules in water with the hydrophilic-hydrophobic interpenetrating network for transdermal delivery of both hydrophilic and hydrophobic drugs. However, many details about the transdermal delivery of drugs from cubic phases remain unclear. Here, metformin hydrochloride (Met) cubic phases were prepared with glyceryl monooleate (GMO), ethanol, and water. The cubic structure was identified with the polarizing light microscopy and small-angle X-ray scattering method. Dissipative particle dynamics (DPD) was used for building the microstructures of the cubic phases to explore the mechanism of drug release that mainly depended on drug diffusion from the water channels of cubic phases in accordance with the Higuchi equation of in vitro release experiments. The coarse-grained model and molecular docking method showed that GMO could enhance drug permeation through the skin by disturbing the interaction between Met and the skin proteins, and increasing the fluidity of skin lipids, which was confirmed with the Fourier transform infrared spectroscopy, Langmuir monolayer, and immunohistochemistry. Furthermore, in vitro permeation experiments showed the high Met transdermal improvement of cubic phases. Cubic phases are an ideal transdermal delivery system of Met. In silico methods are very useful for analyzing the molecular mechanisms of transdermal formulations. PMID- 29979606 TI - Maternal Smoking Induces Acquired CFTR Dysfunction in Neonatal Rats. PMID- 29979607 TI - Know Your Limitations: Assumptions in the Single-Beat Method for Estimating Right Ventricular-Pulmonary Vascular Coupling. PMID- 29979608 TI - Underdiagnosis and Overdiagnosis of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is regarded as one of the leading causes of morbidity and mortality across the world, yet its proper diagnosis remains a challenge. Community-based population studies conducted in North and South America, Europe, Australia, and Asia have revealed that 10% to 12% of adults aged 40 years or older have evidence of persistent airflow limitation on spirometry, but only 20% to 30% of these subjects have been diagnosed with COPD. These studies collectively suggest that approximately 70% of COPD worldwide may be underdiagnosed. Conversely, other studies have shown that between 30% and 60% of patients with a previous physician diagnosis of COPD do not actually have the disease, and hence they have been overdiagnosed. In this review, we define under- and overdiagnosis and explore the prevalence and the burden of under- and overdiagnosis of COPD on both patients and healthcare systems. We further describe potential solutions to reduce the incidence of under- and overdiagnosis of COPD. PMID- 29979609 TI - Lactation Assessment Tools: A Qualitative Analysis of Registered Nurses' Perceptions of Tool Limitations and Suggested Improvements. AB - Background Several lactation assessment tools are available for in-hospital assessment of breastfeeding dyads, and their components vary widely. To date, no research has evaluated the perceptions of registered nurses (RNs) regarding the limitations and future improvements of these tools. Research Aim The aim was to describe RNs' perceptions of the limitations of currently used lactation assessment tools and how these tools could be enhanced. Methods Focus groups ( n = 7) were conducted with RNs ( N = 28) whose current responsibilities included in hospital breastfeeding assessment. Recruitment occurred from April through July 2015 at regional and international lactation conferences. Focus groups were audiotaped and transcribed verbatim. Two lactation researchers analyzed the transcripts to identify emerging themes and subthemes. Results RNs identified three key limitations of the tools included being too subjective and time consuming, difficulty in assessing audible swallows, and missing the big picture (e.g., overemphasizing numbers, being a snapshot in time). Suggested improvements focused on maternal characteristics (evolving breasts and nipples, holding it together, "got milk?," risk factors, embracing the role), infant characteristics (day of life, latch/suck/swallow, baby's "driving the bus," risk factors for supplemental feeding), their interaction (two to tango, positioning, better qualitative descriptors), and tool organization (formatting and multiple versions). Conclusions RNs suggested novel components for consideration when developing future lactation assessment scales, including removing audible swallowing, adding mother/infant interactions, infant output, and expressible colostrum, and developing criteria specific to infant age. Future research should translate these suggestions into evidence-based indicators and evaluate the resulting proposed tools for reliability and validity. PMID- 29979610 TI - Kinematics of Rugby Tackling: A Pilot Study With 3-dimensional Motion Analysis. AB - BACKGROUND: Although improper tackling technique in rugby can affect the outcome of the tackle and lead to head, neck, and shoulder injuries, the effects of the height of the tackle or the side of the leading leg at the time of impact have not been investigated. Hypothesis/Purpose: The purpose was to characterize the trunk orientation at impact during various tackles. It was hypothesized that 3 dimensional motion analysis would be able to capture the critical kinematic differences in the 4 types of tackles studied. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 66 tackles on a tackle bag were recorded among 13 elite rugby players. Four types of tackles were evaluated: the normal shoulder tackle, in which the tackler's dominant shoulder made impact while the leading foot was on the same side as that shoulder; the low tackle, in which the tackler targeted the lower portion of the tackle bag; the opposite-leg tackle, in which the tackler's leading leg was on the opposite side as the shoulder making impact; and the low and opposite-leg tackle, which was a combination of the previous 2 types of tackles. The orientation of the trunk at impact was calculated, and 2-way repeated-measures analyses of variance were used to compare the characteristics of these tackles. RESULTS: Trunk inclination at impact was lower in the low tackle than in the normal tackle ( P < .01), regardless of the side of the leading leg. Trunk bending to the side of the impacted shoulder was lower in the opposite-leg tackle ( P < .01), and these findings were more significant in the normal-height tackles ( P < .01). Trunk rotation to the side of the impacted shoulder was lower in the opposite-leg tackles ( P < .01) and more significant in the lower-height tackles ( P = .03). CONCLUSION: The 3 dimensional motion capture system was effective in investigating the kinematics of rugby tackling. The kinematics in the low and opposite-leg tackles were significantly different from those in the normal shoulder tackle, which may affect tackle performance and the possible risk of contact injury. CLINICAL RELEVANCE: When a rugby coach provides tackling instructions to players, it is advantageous to have information about the kinematics of different types of tackles. PMID- 29979611 TI - [Process analysis of weekly self- and external assessments of adolescents with substance abuse disorder during long-term psychotherapy]. AB - : Process analysis of weekly self- and external assessments of adolescents with substance abuse disorder during long-term psychotherapy Abstract. OBJECTIVE: Little is known about the course of emotional and motivational states in young patients with substance use disorder (SUD) during long-term treatment. METHOD: We collected weekly self-reports from N = 42 adolescents, resulting in 853 questionnaires. Additionally, 708 observations were obtained from their key carers. Principal component analysis (PCA) was used to explore the dimensional structure of the questionnaires. Multi-level models were applied to test for group differences and time series models to evaluate dependencies on the person level. RESULTS: PCA yielded four factors: negative mental state, appreciation of the setting, motivation, and addiction dynamics. Correlations between self- and (unidimensional) carer-reports were low to moderate, but differential on the individual level. Scores of all four scales decreased during the course of treatment. The level of appreciation during the initial phase was the only significant predictor for drop-outs of treatment later on: in drop-outs, appreciation decreased, whereas it increased in completers. CONCLUSION: Appreciation was the most important predictive factor for a regular therapy ending in SUD, whereas motivation showed fluctuations typical for adolescence. Addiction dynamics were of lesser relevance than commonly expected. Therefore, programs in long-term SUD treatment should focus more on improving appreciation than on issues of addiction itself. PMID- 29979612 TI - The t(1;10)(p22;q24) TGFBR3/MGEA5 Translocation in Pleomorphic Hyalinizing Angiectatic Tumor (PHAT), Myxoinflammatory Fibroblastic Sarcoma (MIFS), and Hemosiderotic Fibrolipomatous Tumor (HFLT). AB - CONTEXT: - Pleomorphic hyalinizing angiectatic tumor (PHAT) of soft parts, hemosiderotic fibrolipomatous tumor (HFLT), and myxoinflammatory fibroblastic sarcoma (MIFS) are 3 distinct entities of low-grade spindle cell mesenchymal neoplasm. These tumors have similar clinical presentations and partially overlapping but distinctive pathologic features. A recurrent translocation, t(1;10)(p22;q24), has been detected in a subset of PHAT, HFLT, MIFS, and HFLT/MIFS hybrid cases. Translocation t(1;10)(p22;q24) involves transforming growth factor beta-receptor 3 ( TGFBR3) and meningioma-expressed antigen 5 ( MGEA5) genes on chromosomes 1p22 and 10q24, respectively. However, the percentage of translocation in PHAT, HFLT, and MIFS varies significantly among different studies. The relationship among these tumors has been a controversial topic among experts. OBJECTIVE: - To discuss the diagnostic and functional significance of translocation t(1;10)(p22;q24) TGFBR3/MGEA5 rearrangement in HFLT, PHAT, and MIFS. DATA SOURCES: - PubMed was used for this study. CONCLUSIONS: - Diagnosis of HFLT, PHAT, and MIFS is challenging because of a lack of unique morphologic, immunophenotypic, molecular, and cytogenetic markers. The recurrent t(1;10)(p22;q24) translocation and/or TGFBR3/MGEA5 rearrangement was reported in 55 patients, with a relatively even distribution among HFLT, PHAT, and MIFS (17 HFLT, 15 MIFS, 13 MIFS/HFLT, and 10 PHAT). This indicates that current morphology based diagnostic criteria do not identify reliably the subset of soft tissue tumor with t(1;10) translocation. Genetic heterogeneity of these tumors is supported by the recent detection of a mutually exclusive, second recurrent genetic change, t(7;17) TOM1L2-BRAF translocation or BRAF amplification, in a subset of MIFS. PMID- 29979613 TI - Molecular Fingerprinting of Anatomically and Temporally Distinct B-Cell Lymphoma Samples by Next-Generation Sequencing to Establish Clonal Relatedness. AB - CONTEXT: - B-cell lymphomas exhibit balanced translocations that involve immunoglobulin loci and result from aberrant V(D)J recombination, class switch recombination, or somatic hypermutation. Although most of the breakpoints in the immunoglobulin loci occur in defined regions, those in the partner genes vary; therefore, it is unlikely that 2 independent clones would share identical breakpoints in both partners. Establishing whether a new lesion in a patient with history of lymphoma represents recurrence or a new process can be relevant. Polymerase chain reaction (PCR)-based clonality assays used in this setting rely only on evaluating the length of a given rearrangement. In contrast, next generation sequencing (NGS) provides the exact translocation breakpoint at single base resolution. OBJECTIVE: - To determine if translocation breakpoint coordinates can serve as a molecular fingerprint unique to a distinct clonal population. DESIGN: - Thirty-eight follicular lymphoma/diffuse large B-cell lymphoma samples collected from different anatomic sites and/or at different time points from 18 patients were analyzed by NGS. For comparison, PCR-based B-cell clonality and fluorescence in situ hybridization studies were performed on a subset of cases. RESULTS: - IGH-BCL2 rearrangements were detected in all samples. The breakpoint coordinates on derivative chromosome(s) were identical in all samples from a given patient, but distinct between samples derived from different patients. Additionally, 5 patients carried a second rearrangement also with conserved breakpoint coordinates in the follow-up sample(s). CONCLUSIONS: - Breakpoint coordinates in the immunoglobulin and partner genes can be used to establish clonal relatedness of anatomically/temporally distinct lesions. Additionally, an NGS-based approach has the potential to detect secondary translocations that may have prognostic and therapeutic significance. PMID- 29979614 TI - Application of Enzyme Digestion and Deconjugation Followed by Quick, Easy, Cheap, Effective, Rugged, Safe Extraction and Liquid Chromatography-Tandem Mass Spectrometry Methodology To Determine Ractopamine Residue in Pork. AB - A new methodology is proposed for ractopamine residue analysis in pork. It consists of enzyme-mediated digestion and deconjugation steps; modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction; and liquid chromatography-tandem mass spectrometry (LC-MS/MS). In brief, the samples were digested with protease and then deconjugated with beta-glucuronidase enzyme; they were then subjected to extraction and cleanup by QuEChERS and underwent sequential analysis by LC-MS/MS. The method performance was evaluated in accordance to the validation guidelines regulated by the Brazilian Ministry of Agriculture and Food Supply. The limit of detection was 0.15 MUg/kg and limit of quantification was 0.5 MUg/kg. When the method was applied to real samples, ractopamine residue was found in concentrations (up to 7.86 MUg/kg) below international recommendation limits up to 10 MUg/kg. The method is sensitive, accurate, quick, simple, and suitable for routine analysis; therefore, it is a monitoring tool that may be adopted by laboratories to achieve compliance levels. PMID- 29979615 TI - A Novel Selective Medium for Simultaneous Enrichment of Shiga Toxin-Producing Escherichia coli and Salmonella in Ground Beef. AB - Microbiological analysis of ground beef for contamination by both Salmonella and Shiga toxin-producing Escherichia coli (STEC) is performed by the U.S. Department of Agriculture, Food Safety Inspection Service (FSIS), as part of its Performance Standards Verification Testing program. FSIS has established a zero tolerance for STEC serotype O157:H7 and serogroups O26, O45, O103, O111, O121, and O145 because they are regarded as adulterants. The detection and isolation of these specific serogroups presents a technical challenge necessitating time-consuming and costly laboratory procedures that often exceed the technical capabilities of many small internal and reference laboratories. We describe here a method using a novel STEC and Salmonella selective (SSS) broth that allows for simultaneous selective enrichment of STEC and Salmonella sp., providing isolation and detection from the same broth. The method only involves direct plating from beef enrichments to detect suspect isolates that can be easily confirmed by using immunoassays or PCR, rendering the isolation simpler and less costly than the current described methods. In a side-by-side comparison with modified tryptic soy broth (mTSB), the use of SSS broth resulted in primarily isolating STEC and Salmonella sp., while substantially suppressing the growth of other gram-negative Enterobacteriacae by 90%. Significantly more (chi2 < 3.84) samples containing E. coli O157:H7 and STEC O26, O111, O121, and O145 and a nondifferent (chi2 > 3.84) number of samples containing STEC O103 and O45 were identified when enriching in SSS broth. Coenrichment using six different Salmonella serovars showed numerically greater but not significant (chi2 < 3.84) positive samples by using SSS broth compared with mTSB for a majority of serotypes. PMID- 29979617 TI - Comparison of Complications and In-Hospital Mortality in Female Patients with Takotsubo Syndrome and ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: Takotsubo syndrome (TTS) is a clinical condition that mimics acute myocardial infarction (MI). More than 90% patients are women, mainly postmenopausal. Research suggests that up to 5% of women evaluated for a MI actually have TTS and that diagnose may be underestimated. Patients with TTS are generally able to fully recover within a period of days to weeks. However, serious, potentially fatal, complications may occur. METHODS: In 117 consecutive female patients hospitalized with TTS and 117 consecutive female patients with ST segment elevation MI, we collected data regarding cardiovascular risk factors, comorbidities, and complications. We compared all in-hospital complications in both groups and analyzed factors influencing the composite endpoint which was cardiogenic shock and death from any cause. RESULTS: In our study patients with TTS had a lower incidence of serious complications compared to the ST-segment elevation MI group. Moreover, in-hospital mortality was also lower in the TTS group. The factors which influenced cardiogenic shock and death from any cause were: heart rate at admission, diastolic blood pressure at admission, C-reactive protein (CRP) concentration at admission, chest pain at admission, ST-segment depression in the electrocardiography at admission, and ejection fraction at admission. Moreover, patients with exacerbation of chronic disease as the cause of TTS also reached the composite endpoint more often. CONCLUSIONS: Female patients with TTS had more favorable in-hospital prognoses than patients with ST segment elevation MI. However, serious complications occurred. The factors which influenced the composite endpoint came from readily available data-within the first hour after admission to the hospital. PMID- 29979619 TI - The current status of homocysteine as a risk factor for cardiovascular disease: a mini review. AB - INTRODUCTION: Hyperhomocysteinemia has been considered as a risk factor for systemic atherosclerosis, cardiovascular disease (CVD) and stroke and many epidemiologic and case-controlled studies have demonstrated its association with these complications. In addition, treatment of hyperhomocysteinemia with folic acid +/- B vitamins prevents the development of atherosclerosis, CVD and strokes. However, subsequent prospective, randomized, placebo-controlled trials have not shown an association of high homocysteine levels or their lowering with treatment with the incidence of atherosclerosis, CVD or strokes, due possibly, to the fortification of flower with folic acid. Therefore, at present, there is a controversy regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. Areas covered: For these reasons, a focused Medline search of the English language literature was conducted between 2010 and 2017 using the terms, homocysteine, risk factor, atherosclerosis, cardiovascular disease, stroke, treatment, and 38 papers with pertinent information were selected. Expert commentary: The review of data disclosed that there is a great controversy regarding the significance of homocysteine as a risk factor for CVD and stroke. The data from these papers together with collateral literature will be discussed in this mini review. PMID- 29979618 TI - Continuous Glucose Monitoring and Insulin Informed Advisory System with Automated Titration and Dosing of Insulin Reduces Glucose Variability in Type 1 Diabetes Mellitus. AB - BACKGROUND: Glucose variability (GV) remains a key limiting factor in the success of diabetes management. While new technologies, for example, accurate continuous glucose monitoring (CGM) and connected insulin delivery devices, are now available, current treatment standards fail to leverage the wealth of information generated. Expert systems, from automated insulin delivery to advisory systems, are a key missing element to richer, more personalized, glucose management in diabetes. METHODS: Twenty four subjects with type 1 diabetes mellitus (T1DM), 15 women, 37 +/- 11 years of age, hemoglobin A1c 7.2% +/- 1%, total daily insulin (TDI) 46.7 +/- 22.3 U, using either an insulin pump or multiple daily injections with carbohydrate counting, completed two randomized crossover 48-h visits at the University of Virginia, wearing Dexcom G4 CGM, and using either usual care or the UVA decision support system (DSS). DSS consisted of a combination of automated insulin titration, bolus calculation, and CHO treatment advice. During each admission, participants were exposed to a variety of meal sizes and contents and two 45-min bouts of exercise. GV and glucose control were assessed using CGM. RESULTS: The use of DSS significantly reduced GV (coefficient of variation: 0.36 +/- 08. vs. 0.33 +/- 0.06, P = 0.045) while maintaining glycemic control (average CGM: 155.2 +/- 27.1 mg/dL vs. 155.2 +/- 23.2 mg/dL), by reducing hypoglycemia exposure (%<70 mg/dL: 3.8% +/- 4.6% vs. 1.8% +/- 2%, P = 0.018), with nonsignificant trends toward reduction of significant hyperglycemia overnight (%>250 mg/dL: 5.3% +/- 9.5% vs. 1.9% +/- 4.6%) and at mealtime (11.3% +/- 14.8% vs. 5.8% +/- 9.1%). CONCLUSIONS: A CGM/insulin informed advisory system proved to be safe and feasible in a cohort of 24 T1DM subjects. Use of the system may result in reduced GV and improved protection against hypoglycemia. PMID- 29979620 TI - Percutaneous Computed Tomography-Guided Radiotracer-Assisted Localization of Difficult Pulmonary Nodules in Uniportal Video-Assisted Thoracic Surgery. AB - OBJECTIVE: To report our institutional experience with radiotracer-assisted localization of lung nodules (RALN) in combination with uniportal video-assisted thoracoscopic surgery (UVATS). METHODS: We retrospectively reviewed electronic medical records and radiology images of 27 consecutive adult patients who underwent planned UVATS lung resections combined with RALN from January 2014 to May 2017. Based on preoperative imaging, 29 nondescript nodules were marked with technetium 99 m macroaggregated albumin under computed tomography guidance before resection. Perioperative outcomes were analyzed. RESULTS: All 29 nodules were successfully marked and resected with negative margins by UVATS; 12 (41.5%) were pure ground-glass opacities. Three patients had prior ipsilateral lung resections. There were no conversions to multiport VATS or thoracotomy. The majority (86.5%) of the nodules were malignant. The median nodule size was 8 mm (range: 3-20 mm) and depth, 56 mm (range: 22-150 mm). The majority (21/27; 77.8%) of patients underwent wedge resections alone, while 6 patients had anatomical resections. Median times were as follows: radiotracer injection to surgery, 219 minutes (range: 139-487 minutes); operative time, 85.5 minutes (32-236 minutes); chest tube removal, 1 day (range: 1-2 days); and length of stay, 2 days (range: 1 4 days). Four patients (14.8%) had a pigtail catheter placed for pneumothorax after radiotracer injection. One patient was readmitted 1 week after discharge for a spontaneous pneumothorax. There were no other morbidities or any 90-day mortality. CONCLUSION: RALN can be combined with UVATS to effectively resect small, deep, or low-density lung lesions that are difficult to visualize or palpate by thoracoscopy. PMID- 29979621 TI - Health Services Utilization in Asthma Exacerbations and PM10 Levels in Rural Colorado. AB - RATIONALE: The San Luis Valley in rural Colorado often has elevated levels of ambient particulate matter. To date little is known about the impact of ambient particulate matter levels and medical care utilization due to asthma exacerbation in rural communities. OBJECTIVES: We investigated the impact of ambient particulate matter concentrations on emergency/urgent visits and hospitalizations for asthma in a rural community. METHODS: Daily ambient particulate matter concentrations from an air quality monitor in the San Luis Valley (2003-2012) were obtained from the state health department. Deidentified data for emergency/urgent visits with a diagnosis code for asthma were collected from the local health care system organization. A generalized linear model using splines and employing generalized estimating equations for correlated measures over time was used to examine the association between daily counts of emergency/urgent visits for asthma and 3- to 5-day averaged ambient particulate matter concentrations. RESULTS: For each 15-MUg/m3 increase in 3-day averaged ambient particulate matter, there was an associated 3.1% increase in hospital counts for all patients with asthma (95% confidence interval, 0.3-5.9%; P = 0.03). When the 3-day average exceeded 50 MUg/m3, asthma hospital visits increased by 16.8% (P = 0.03), and when it exceeded 100 MUg/m3, visits increased by 65.8% (P = 0.002). In children, the odds of one asthma event requiring an emergency/urgent care visit increased 5.0% with each 15-MUg/m3 increase in 3-day averaged ambient particulate matter (P = 0.22). CONCLUSIONS: We observed associations between ambient air levels of particulate matter with a diameter less than 10 MUm and emergency/urgent care visits and hospitalization counts in a rural U.S. community prone to dust storms and Environmental Protection Agency exceedances. PMID- 29979622 TI - Breastfeeding Without Nursing: "If Only I'd Known More about Exclusively Pumping before Giving Birth". AB - BACKGROUND: Human milk is understood to be the optimal nutrition for infants, yet many women struggle to nurse. Although exclusively pumping human milk can provide a solution, women may be unaware of this possibility and, thus, experience unnecessary frustration. Research aim: This study aimed to (a) determine the proportion of respondents who had heard of exclusive pumping prenatally, (b) describe sources that respondents turned to and/or received breastfeeding-related information from prenatally, (c) explore the ways in which respondents learned prenatally about exclusive pumping, (d) describe how useful respondents found various information sources when learning about exclusive pumping, and (e) describe the differences between respondents who first heard the term exclusive pumping prenatally versus postpartum. METHODS: A cross-sectional, self-report, mixed-methods survey was administered online to a convenience sample of current and/or past exclusive pumpers ( N = 1,215). Descriptive statistics were produced (Research Aims 1-4), and chi-square tests (Research Aims 1, 2, and 5) and a Mann Whitney U test (Research Aim 5) were conducted, to identify trends and compare respondents. RESULTS: Seventy-one percent ( n = 864) of respondents had not heard of exclusive pumping until after giving birth. Respondents reported that very few prenatal breastfeeding information sources mentioned or explained exclusive pumping. Women who had heard about exclusive pumping prior to giving birth ( n = 291, 24%) reported feeling more knowledgeable about how to exclusively pump and less frustrated, insecure, depressed, rejected, embarrassed, envious, burdened, guilty, and disappointed while exclusively pumping. CONCLUSION: For postpartum knowledge and affective outcomes to improve, prenatal infant feeding information and education must include information about exclusive pumping. PMID- 29979623 TI - Airflow Obstruction Categorization Methods and Mortality. AB - RATIONALE: Current guidelines recommend using forced expiratory volume in 1 second (FEV1) % predicted to categorize the severity of airflow obstruction. There are limitations to using FEV1 % predicted for this purpose, including bias associated with demographic factors and the inability to correct for "lung size." Other methods for grading the severity of airflow obstruction have been proposed to address these limitations. OBJECTIVES: Our objectives were to categorize airflow obstruction severity using these methods and then determine which method results in a categorization most closely associated with mortality. METHODS: Study subjects were patients aged 40-80 years tested in our pulmonary function test laboratories in the period 2002 to 2013 with airflow obstruction based on an FEV1/forced vital capacity (FVC) less than the lower limit of normal. Categorization of airflow obstruction severity was determined using four methods: FEV1 % predicted; FEV1 % predicted adjusted by FVC % predicted; FEV1/FVC confidence interval approach; and FEV1 z-scores. Receiver operating characteristic curve analysis was used to determine which categorization method best predicts 5-year survival. RESULTS: We identified 2,000 patients with airflow obstruction. Important differences in the categorization of airflow obstruction severity were observed using the different methods. More patients were categorized as having severe obstruction using FEV1 % predicted and FEV1 z-scores compared with FEV1 % predicted adjusted by FVC % predicted and FEV1/FVC confidence interval approach. FEV1 % predicted was the best predictor of 5-year survival among the four methods studied. CONCLUSIONS: In our study, categorizing airflow obstruction severity using FEV1 % predicted best predicted 5-year survival. This validates the current guideline recommendation that FEV1 % predicted be used to categorize the severity of airflow obstruction. PMID- 29979625 TI - Atrial secretion of ANP is suppressed in renovascular hypertension: shifting of ANP secretion from atria to the left ventricle. AB - In the present study, the change in secretion of atrial natriuretic peptide (ANP) from the atria was defined in hypertension accompanied by ventricular hypertrophy and increased synthesis of ANP. To identify the change of the secretion and mechanisms involved, experiments were performed in isolated perfused beating atria from sham-operated normotensive and renovascular hypertensive rats. Expression of ANP, natriuretic peptide receptor (NPR)-C, components of the renin angiotensin system, and muscarinic signaling pathway was measured in cardiac tissues. Basal levels of ANP secretion and acetylcholine (ACh)- and stretch induced activation of ANP secretion were suppressed in the atria from hypertensive compared with normotensive rats. ACh increased ANP secretion via M2 muscarinic ACh receptor-ACh-sensitive K+ channel signaling. In hypertensive rats, ANP concentration increased in the left ventricle but decreased in the right ventricle. The atrial concentration of ANP was not changed in hypertensive compared with normotensive rats. ANP mRNA expression was accentuated in the left ventricle but suppressed in the other cardiac chambers in the hearts of hypertensive rats. NPR-C expression was inversely related to ANP mRNA levels. Angiotensin II type 1 receptor (AT1R) expression was accentuated in the cardiac chambers from hypertensive rats compared with normotensive rats, whereas angiotensin II type 2 receptor, M2 muscarinic receptor, and Kir3.4 channels were suppressed. AT1R blockade with losartan reversed the change observed in hypertensive rats. The present findings indicate that renovascular hypertension shifts the major site of ANP secretion and synthesis from the atria to the left ventricle through modulation of the expression of ANP, NPR-C, AT1R, and the M2 muscarinic signaling pathway. NEW & NOTEWORTHY Renovascular hypertension suppresses the atrial secretion of ANP and shifts the major site of the regulation of ANP secretion and synthesis from atria to the hypertrophied left ventricle possibly via modulation of the expression of ANP, natriuretic peptide receptor-C, angiotensin II subtype 1 receptor, and M2 muscarinic signaling pathway. PMID- 29979624 TI - Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling. AB - Although improvements in timing and approach for early reperfusion with acute coronary syndromes have occurred, myocardial injury culminating in a myocardial infarction (MI) remains a common event. Although a multifactorial process, an imbalance between the induction of proteolytic pathways, such as matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of metalloproteinase (TIMPs), has been shown to contribute to this process. In the present study, a full-length TIMP-3 recombinant protein (rTIMP-3) was encapsulated in a specifically formulated hyaluronic acid (HA)-based hydrogel that contained MMP cleavable peptide cross-links, which influenced the rate of rTIMP-3 release from the HA gel. The effects of localized delivery of this MMP-sensitive HA gel (HAMMPS) alone and containing rTIMP-3 (HAMMPS/rTIMP-3) were examined in terms of the natural history of post-MI remodeling. Pigs were randomized to one of the following three different groups: MI and saline injection (MI/saline group, 100 MUl injection at nine injection sites, n = 7), MI and HAMMPS injection (MI/HAMMPS group; 100-MUl injection at nine injection sites, n = 7), and MI and HAMMPS/rTIMP 3 injection (MI/HAMMPS/rTIMP-3 group; 20-MUg/100-MUl injection at nine injection sites, n = 7). Left ventricular (LV) echocardiography was serially performed up to 28 days post-MI. LV dilation, as measured by end-diastolic volume, and the degree of MI wall thinning were reduced by ~50% in the HAMMPS/rTIMP-3 group ( P < 0.05). Furthermore, indexes of heart failure progression post-MI, such as LV filling pressures and left atrial size, were also attenuated to the greatest degree in the HAMMPS/rTIMP-3 group. At 28 days post-MI, HAMMPS/rTIMP-3 caused a relative reduction in the transcriptional profile for myofibroblasts as well as profibrotic pathways, which was confirmed by subsequent histochemistry. In conclusion, these findings suggest that localized delivery of a MMP-sensitive biomaterial that releases a recombinant TIMP holds promise as a means to interrupt adverse post-MI remodeling. NEW & NOTEWORTHY The present study targeted a myocardial matrix proteolytic system, matrix metalloproteinases (MMPs), through the use of a recombinant tissue inhibitor of MMPs incorporated into a MMP sensitive hydrogel, which was regionally injected using a large animal model of myocardial infarction. Left ventricular geometry and function and indexes of myocardial remodeling were improved with this approach and support the advancement of localized therapeutic strategies that specifically target the myocardial matrix. PMID- 29979628 TI - Early Life Weight Gain and Development of Childhood Asthma in a Prospective Birth Cohort. AB - RATIONALE: The prevalence of childhood asthma has been increasing worldwide in parallel with childhood obesity. OBJECTIVES: We investigated whether there is a temporal relationship between early life weight gain (reflecting growth velocity) and early life body mass index (BMI) attained status (reflecting accumulative weight) with future risk of asthma in the Boston Birth Cohort. METHODS: This report includes 1,928 children from the Boston Birth Cohort with a mean age of 7.8 years (standard deviation, 3.3 yr), enrolled at birth and followed prospectively. Asthma was defined using physician diagnosis code (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.xx) in children 2 years and older. We categorized the children by their weight gain trajectory on the basis of changes in z-scores: slow (less than -0.67), on track (-0.67 to 0.67), rapid (0.67-1.28), and extremely rapid (>1.28); and by their BMI attained status (underweight, normal weight, and overweight) during the first 4, 12, and 24 months. Poisson regression models with robust variance estimation were applied to examine the relationship between early life weight gain/attained BMI and asthma. RESULTS: During the first 4 months of life, 37% had on-track weight grain, 22% had slow weight gain, 15% had rapid weight gain, and 26% had extremely rapid weight gain. At 4 months, 61% were normal weight, 7% were underweight, and 32% were overweight. In adjusted analyses, extremely rapid early life weight gain during the first 4 and 24 months of life were each associated with increased risks of asthma (risk ratio, 1.34 for extremely rapid weight gain at 4 months; 95% confidence interval [CI], 1.06-1.70; risk ratio, 1.32 for extremely rapid weight gain at 24 months; 95% CI, 1.00-1.75) Similarly, overweight at 4, 12, and 24 months were each associated with an increased risk of asthma. Analyses that further adjusted for birthweight or preterm birth showed similar findings. CONCLUSIONS: In this predominantly urban U.S. low-income minority birth cohort, excessive early life weight gain and overweight status were both associated with an increased risk of asthma in childhood. PMID- 29979626 TI - Age-dependent cardiac function during experimental sepsis: effect of pharmacological activation of AMP-activated protein kinase by AICAR. AB - Age represents a major risk factor for multiple organ failure, including cardiac dysfunction, in patients with sepsis. AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis that controls mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor-gamma coactivator-1alpha and disposal of defective organelles by autophagy. We investigated whether AMPK dysregulation contributes to age-dependent cardiac injury in young (2-3 mo) and mature adult (11-13 mo) male mice subjected to sepsis by cecal ligation and puncture and whether AMPK activation by 5-amino-4-imidazole carboxamide riboside affords cardioprotective effects. Plasma proinflammatory cytokines and myokine follistatin were similarly elevated in vehicle-treated young and mature adult mice at 18 h after sepsis. However, despite equivalent troponin I and T levels compared with similarly treated young mice, vehicle-treated mature adult mice exhibited more severe cardiac damage by light and electron microscopy analyses with more marked intercellular edema, inflammatory cell infiltration, and mitochondrial derangement. Echocardiography revealed that vehicle-treated young mice exhibited left ventricular dysfunction after sepsis, whereas mature adult mice exhibited a reduction in stroke volume without apparent changes in load dependent indexes of cardiac function. At molecular analysis, phosphorylation of the catalytic subunits AMPK-alpha1/alpha2 was associated with nuclear translocation of peroxisome proliferator-activated receptor-gamma coactivator 1alpha in vehicle-treated young but not mature adult mice. Treatment with 5-amino 4-imidazole carboxamide riboside ameliorated cardiac architecture derangement in mice of both ages. These cardioprotective effects were associated with attenuation of the systemic inflammatory response and amelioration of cardiac dysfunction in young mice only, not in mature adult animals. NEW & NOTEWORTHY Our data suggest that sepsis-induced cardiac dysfunction manifests with age-dependent characteristics, which are associated with a distinct regulation of AMP-activated protein kinase-dependent metabolic pathways. Consistent with this age-related deterioration, pharmacological activation of AMP-activated protein kinase may afford cardioprotective effects allowing a partial recovery of cardiac function in young but not mature age. PMID- 29979629 TI - Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen. AB - Nonsteroidal antiinflammatory drugs and analgesic drugs, such as N-acetyl- p aminophenol (APAP; acetaminophen, paracetamol), are widely used by pregnant women. Accumulating evidence has indicated that these molecules can favor genital malformations in newborn boys and reproductive disorders in adults. However, the consequences on postnatal testis development and adult reproductive health after exposure during early embryogenesis are still unknown. Using the mouse model, we show that in utero exposure to therapeutic doses of the widely used APAP ibuprofen combination during the sex determination period leads to early differentiation and decreased proliferation of male embryonic germ cells, and early 5-methylcytosine and extracellular matrix protein deposition in 13.5 d postcoitum exposed testes. Consequently, in postnatal testes, Sertoli-cell maturation is delayed, the Leydig-cell compartment is hyperplasic, and the spermatogonia A pool is decreased. This results in a reduced production of testosterone and in epididymal sperm parameter defects. We observed a reduced sperm count (19%) in utero-exposed (F0) adult males and also a reduced sperm motility (40%) in their offspring (F1) when both parents were exposed, which leads to subfertility among the 6 mo old F1 animals. Our study suggests that the use of these drugs during the critical period of sex determination affects the germ-line development and leads to adverse effects that could be passed to the offspring.-Rossitto, M., Marchive, C., Pruvost, A., Sellem, E., Ghettas, A., Badiou, S., Sutra, T., Poulat, F., Philibert, P., Boizet-Bonhoure, B. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen. PMID- 29979630 TI - Down-regulation of acid sphingomyelinase and neutral sphingomyelinase-2 inversely determines the cellular resistance to plasmalemmal injury by pore-forming toxins. AB - Bacterial pore-forming toxins compromise plasmalemmal integrity, leading to Ca2+ influx, leakage of the cytoplasm, and cell death. Such lesions can be repaired by microvesicular shedding or by the endocytic uptake of the injured membrane sites. Cells have at their disposal an entire toolbox of repair proteins for the identification and elimination of membrane lesions. Sphingomyelinases catalyze the breakdown of sphingomyelin into ceramide and phosphocholine. Sphingomyelin is predominantly localized in the outer leaflet, where it is hydrolyzed by acid sphingomyelinase (ASM) after lysosomal fusion with the plasma membrane. The magnesium-dependent neutral sphingomyelinase (NSM)-2 is found at the inner leaflet of the plasmalemma. Because either sphingomyelinase has been ascribed a role in the cellular stress response, we investigated their role in plasma membrane repair and cellular survival after treatment with the pore-forming toxins listeriolysin O (LLO) or pneumolysin (PLY). Jurkat T cells, in which ASM or NSM-2 was down-regulated [ASM knockdown (KD) or NSM-2 KD cells], showed inverse reactions to toxin-induced membrane damage: ASM KD cells displayed reduced toxin resistance, decreased viability, and defects in membrane repair. In contrast, the down-regulation of NSM-2 led to an increase in viability and enhanced plasmalemmal repair. Yet, in addition to the increased plasmalemmal repair, the enhanced toxin resistance of NSM-2 KD cells also appeared to be dependent on the activation of p38/MAPK, which was constitutively activated, whereas in ASM KD cells, the p38/MAPK activation was constitutively blunted. Schoenauer, R., Larpin, Y., Babiychuk, E. B., Drucker, P., Babiychuk, V. S., Avota, E., Schneider-Schaulies, S., Schumacher, F., Kleuser, B., Koffel, R., Draeger, A. Down-regulation of acid sphingomyelinase and neutral sphingomyelinase 2 inversely determines the cellular resistance to plasmalemmal injury by pore forming toxins. PMID- 29979631 TI - Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated protein (Cas) systems are prokaryotic adaptive immune systems against invading nucleic acids. CRISPR locus variability has been exploited in evolutionary and epidemiological studies of Mycobacterium tuberculosis, the causative agent of tuberculosis, for over 20 yr, yet the biological function of this type III-A system is largely unexplored. Here, using cell biology and biochemical, mutagenic, and RNA-seq approaches, we show it is active in invader defense and has features atypical of type III-A systems: mature CRISPR RNA (crRNA) in its crRNA-CRISPR/Cas protein complex are of uniform length (~71 nt) and appear not to be subject to 3'-end processing after Cas6 cleavage of repeat RNA 8 nt from its 3' end. crRNAs generated resemble mature crRNA in type I systems, having both 5' (8 nt) and 3' (28 nt) repeat tags. Cas6 cleavage of repeat RNA is ion dependent, and accurate cleavage depends on the presence of a 3' hairpin in the repeat RNA and the sequence of its stem base nucleotides. This study unveils further diversity among CRISPR/Cas systems and provides insight into the crRNA recognition mechanism in M. tuberculosis, providing a foundation for investigating the potential of a type III-A-based genome editing system.-Wei, W., Zhang, S., Fleming, J., Chen, Y., Li, Z., Fan, S., Liu, Y., Wang, W., Wang, T., Liu, Y., Ren, B., Wang, M., Jiao, J., Chen, Y., Zhou, Yi., Zhou, Ya., Gu, S., Zhang, X., Wan, L., Chen, T., Zhou, L., Chen, Y., Zhang, X.-E., Li, C., Zhang, H., Bi, L. Mycobacterium tuberculosis type III-A CRISPR/Cas system crRNA and its maturation have atypical features. PMID- 29979632 TI - STAU1 binds to IBDV genomic double-stranded RNA and promotes viral replication via attenuation of MDA5-dependent beta interferon induction. AB - Infectious bursal disease virus (IBDV) infection triggers the induction of type I IFN, which is mediated by melanoma differentiation-associated protein 5 recognition of the viral genomic double-stranded RNA (dsRNA). However, the mechanism of IBDV overcoming the type I IFN antiviral response remains poorly characterized. Here, we show that IBDV genomic dsRNA selectively binds to the host cellular RNA binding protein Staufen1 (STAU1) in vitro and in vivo. The viral dsRNA binding region was mapped to the N-terminal moiety of STAU1 (residues 1-468). Down-regulation of STAU1 impaired IBDV replication and enhanced IFN-beta transcription in response to IBDV infection, while having little effect on the viral attachment to the host cells and cellular entry. Conversely, overexpression of STAU1 but not the IBDV dsRNA-binding deficient STAU1 mutant (469-702) led to a suppression of IBDV dsRNA-induced IFN-beta promoter activity. Moreover, we found that the binding of STAU1 to IBDV dsRNA decreased the association of melanoma differentiation-associated protein 5 but not VP3 with the IBDV dsRNA in vitro. Finally, we showed that STAU1 and VP3 suppressed IFN-beta gene transcription in response to IBDV infection in an additive manner. Collectively, these findings provide a novel insight into the evasive strategies used by IBDV to escape the host IFN antiviral response.-Ye, C., Yu, Z., Xiong, Y., Wang, Y., Ruan, Y., Guo, Y., Chen, M., Luan, S., Zhang, E., Liu, H. STAU1 binds to IBDV genomic double stranded RNA and promotes viral replication via attenuation of MDA5-dependent beta interferon induction. PMID- 29979633 TI - SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis. AB - Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT-decidual cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up regulate cell migration. We further showed that secreted frizzled-related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase-transformed human endometrial stromal cells (T HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3-knockdown T-HESC monolayer. Our results suggest that GCM1 up-regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.-Wang, L.-J., Lo, H.-F., Lin, C.-F., Ng, P.-S., Wu, Y.-H., Lee, Y.-S., Cheong, M.-L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1-WNT10B-FZD7 axis. PMID- 29979635 TI - Advancing Oral Health through Science and Technology. PMID- 29979634 TI - alpha-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease. AB - Fabry disease is an X-linked lysosomal storage disease caused by alpha galactosidase A (alpha-Gal A) deficiency. Kidney and heart failure are frequent complications in adulthood and greatly contribute to patient morbidity and mortality. Because alpha-Gal A-deficient mouse models do not recapitulate cardiorenal findings observed in patients, a nonmouse model may be beneficial to our understanding of disease pathogenesis. In this study, we evaluated disease processes in a recently generated Fabry rat model. We found that male Fabry rats weighed significantly less than wild-type (WT) males, whereas female Fabry rats weighed significantly more than WT females. Whereas no difference in female survival was detected, we observed that male Fabry rats had a decreased lifespan. Skin histology revealed that inflammation and lipoatrophy may be chief disease mediators in patients. With respect to the kidney and heart, we found that both organs accumulate alpha-Gal A substrates, including the established biomarkers, globotriaosylceramide and globotriaosylsphingosine. Longitudinal serum and urine chemistry panels demonstrated pronounced renal tubule dysfunction, which was confirmed histologically. Mitral valve thickening was observed in Fabry rats using echocardiography. We conclude that Fabry rats recapitulate important kidney and heart phenotypes experienced by patients and can be further used to study disease mechanisms and test therapies.-Miller, J. J., Aoki, K., Mascari, C. A., Beltrame, A. K., Sokumbi, O., North, P. E., Tiemeyer, M., Kriegel, A. J., Dahms, N. M., alpha-Galactosidase A-deficient rats accumulate glycosphingolipids and develop cardiorenal phenotypes of Fabry disease. PMID- 29979636 TI - Re: "Harmonizing the Nomenclature for Therapeutic Aerosol Particle Size: A Proposal" by Hillyer et al. (J Aerosol Med Pulm Drug Deliv. 2018 [31(2):111-113]; DOI: 10/1089/jamp.2017.1396). PMID- 29979637 TI - Tetrandrine Enhances Radiosensitization in Human Hepatocellular Carcinoma Cell Lines. AB - The goal of this study was to determine whether tetrandrine enhanced radiosensitization in different hepatocellular carcinoma cell lines and to elucidate the potential mechanism. We also tested whether PA28gamma was regulated by tetrandrine. The human hepatocellular carcinoma cell lines HepG2 and LM3 were divided into six groups: control; low-dosage (0.5 or 5 MUg/ml) tetrandrine alone; high-dosage (1.0 or 10 MUg/ml) tetrandrine alone; irradiation alone; irradiation with low-dosage (0.5 MUg/ml or 5 MUg/ml) tetrandrine; and irradiation with high dosage (1.0 MUg/ml or 10 MUg/ml) tetrandrine. Colony-forming assays were performed. Expression of cyclin and apoptosis-related proteins, including cyclin B1, phosphorylated cyclin-dependent kinase 1 [phospho-CDC2 (Tyr15)], Bax and caspase-3, as well as PA28gamma expression, were evaluated using Western blot analysis. Apoptosis rate and cell cycle distribution were examined using flow cytometry analysis. Tetrandrine enhanced radiosensitivity in HepG2 and LM3 cells, as characterized by a narrower shoulder area and steeper linear area, and the enhanced radiosensitization increased with tetrandrine dosage. After tetrandrine treatment, the apoptosis rate significantly increased, whereas the proportion of cells in the G2 phase dramatically decreased in dose- and time-dependent manners after irradiation. However, the effect of reverse G2 arrest was weaker in p53 mutant cells (LM3 cells). Finally, we observed that tetrandrine downregulated PA28gamma expression. Moreover, when PA28gamma was downregulated, apoptosis and cell cycle distribution were also altered; however, the effects were weaker in p53-mutant cells. Therefore, we propose that tetrandrine-mediated apoptosis induction and G2 arrest attenuation are at least partly mediated by PA28gamma. PMID- 29979638 TI - High Prevalence of VIM, KPC, and NDM Expression among Surgical Site Infection Pathogens in Patients Having Emergency Surgery. AB - BACKGROUND: The rate of surgical site infection (SSI) in patients who undergo emergency operations is higher than in other patients. Previous studies showed an increasing role of gram- negative pathogens (GNP) in SSI. We aimed to identify GNP causing SSIs after emergency surgery, to characterize the carbapenemase resistance genes in carbapenem-resistant pathogens (CRPs), and to identify the risk factors for SSI caused by CRP. METHOD: We conducted a one-year prospective study from September 2014 in the Emergency Hospital of Cairo University Hospitals. Surveillance for SSIs was conducted according to the case definitions of the U.S. Centers for Disease Control and Prevention. Clinical specimens from patients suspected of having SSI were collected; pathogens were identified by Bruker matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectometry. Antimicrobial susceptibility was tested by the VITEK-2 and E test. Carbapenem-resistant GNPs were characterized by multiplex polymerase chain reaction for IMP, VIM, SPM, OXA-48, NDM, KPC, BIC, AIM, GIM, SIM, and DIM. Clinical data for patients with SSI infected with CRP were compared with the non infected patients for detection of risk factors. RESULTS: Surgical site infection affected 6.7% of patients who had emergency operations, and GNP represented 85% of these pathogens. Carbapenem-resistant pathogens caused 61% of the SSI, including all those caused by Acinetobacter baumannii, 70% of those caused by Pseudomonas aeruginosa, and 67% of those caused by Klebsiella pneumoniae. The PCR revealed that VIM, KPC, and NDM were the most common resistance genes. Risk factors for SSI were previous hospitalization, longer hospital stay, type of surgical incision, and abundant drainage; whereas previous hospitalization and infection by non-enteric environmental GNP were the risk factors for SSI caused by CRP. CONCLUSION: The rate of SSIs caused by CRP was high after emergency surgery. VIM, KPC, and NDM were the most commonly found genes. Prior hospitalization and infection by non-enteric GNP were risk factors, which can be mitigated by eradication of bacterial populations in environmental reservoirs and control of transmission. PMID- 29979639 TI - Prevalence, Distribution, and Risk Factors Associated With Macracanthorhynchus ingens Infections In Raccoons From Ontario, Canada. AB - Macracanthorhynchus ingens is an acanthocephalan parasite commonly found in raccoons ( Procyon lotor) in the United States. Little is known, however, about the prevalence and distribution of M. ingens in raccoons in Canada. Our objective was to investigate the prevalence, distribution, and risk factors associated with M. ingens infection in raccoons in southern Ontario, Canada. Raccoon carcasses submitted to the Ontario/Nunavut region of the Canadian Wildlife Health Cooperative for post mortem from June 2016 to January 2017 (n = 380) were examined for the presence of gastrointestinal helminths. Macracanthorhynchus ingens was found in raccoons from areas across southern Ontario where carcasses were submitted. The prevalence of M. ingens in our sample was 14.0% (95% CI = 10.6-17.8) with a median of 4 worms per infected host (range 1-46). Univariable logistic regression modeling was conducted to examine the influence of age, sex, season, degree of urbanization (urban/suburban/rural), and Baylisascaris procyonis infection on the presence of M. ingens. Significant associations were found between M. ingens infection and degree of urbanization as well as B. procyonis infection. No associations were found between M. ingens infection and age, sex, or season. To our knowledge, this is the first report describing the prevalence and distribution of M. ingens in raccoons in Canada. PMID- 29979640 TI - Experiences in the Veterans Health Administration and Impact on Healthcare Utilization: Comparisons Between LGBT and Non-LGBT Women Veterans. AB - PURPOSE: This study aimed to compare experiences related to healthcare of LGBT women and non-LGBT women in a sample of routine users of Veterans Health Administration (VHA) primary care services and examine the impact of those experiences on delaying or missing appointments for VHA care. METHODS: Women veterans (N = 1391) who had at least three primary care visits in the previous year at 12 VHA facilities were surveyed by phone in January-March 2015 in a baseline wave of a cluster-randomized quality improvement trial. The majority identified as non-LGBT (1201; 85.6%) with 190 (14.4%) women identified as LGBT, based on items measuring sexual orientation and gender identity. RESULTS: In models controlling for demographics, health status, and positive trauma screens, LGBT identity was predictive of women veterans experiencing harassment from male veterans at VHA in the past 12 months, as well as feeling unwelcome or unsafe at their VHA. Compared with non-LGBT women veterans, LGBT women veterans attributed missing needed care more often in the previous 12 months to concerns about interacting with other veterans. Participant descriptions of harassment indicated that male veterans' comments and actions were distressing and influenced LGBT women's healthcare accessing behavior. CONCLUSIONS: Compared with non-LGBT women, LGBT women were more likely to report harassment and feeling unwelcome at VHA. Some LGBT women reported delaying or missing needed care, primarily due to concerns about interacting with other veterans. Additional work is necessary to help LGBT women veterans feel safe and welcome at VHA facilities and, thereby, reduce barriers to LGBT women veterans accessing needed care. PMID- 29979641 TI - Identifying and Counting Individuals with Differences of Sex Development Conditions in Population Health Research. AB - PURPOSE: The study purpose was to examine opinions about a single-item assessment of differences of sex development (DSD) to be used in research. METHODS: An online survey was conducted with a convenience sample of 111 adults who self identified as intersex or having a DSD diagnosis. Participants read and provided feedback on the proposed single-item assessment. RESULTS: The item received general endorsement to represent a population that is often not identified in research; however, participants provided suggestions for improvement. CONCLUSION: This study represents a first step toward identifying people with DSD conditions in surveys to better understand their needs. PMID- 29979642 TI - Increasing Human Papillomavirus Vaccination Among Young Gay and Bisexual Men: A Randomized Pilot Trial of the Outsmart HPV Intervention. AB - PURPOSE: The study purpose was to pilot test a web-based human papillomavirus (HPV) vaccination intervention among young gay and bisexual men (YGBM). METHODS: In 2016, we recruited 150 unvaccinated YGBM aged 18-25 years from the United States. We randomized participants to the Outsmart HPV intervention or a control group. RESULTS: HPV vaccine initiation was higher among the intervention group than the control group (45% vs. 26%; odds ratio [OR] = 2.34, 95% confidence interval [CI]: 1.18-4.67). We observed a trend toward higher HPV vaccine completion among the intervention group (11% vs. 3%; OR = 4.24, 95% CI: 0.87 20.66). CONCLUSIONS: Outsmart HPV is a promising strategy for increasing HPV vaccination among YGBM. PMID- 29979643 TI - Provision of renal care for patients with end stage kidney disease in persistent vegetative state, in United Arab Emirates: a national survey of renal physicians. AB - : Patients with end stage kidney disease (ESKD) with severely impaired cognitive function have no survival benefit from dialysis. We therefore undertook a survey to explore the renal physicians' practices of withholding and withdrawal of dialysis treatment in vegetative state patients in the United Arab Emirates (UAE). A cross sectional survey of 29 nephrology practices in UAE exploring physicians' practices in making decisions of withholding and withdrawal of dialysis treatment during provision end-of-life care for patients in persistent vegetative state (PVS).The majority of participants practice in governmental non for-profit dialysis units (79%), and think they are well prepared to make decision with patients and family on issues of dialysis withdrawal and withholding (69%). If a chronic dialysis patient became permanently unconscious only few respondents (17%) indicated probability of stopping dialysis. On the other hand, more respondents (48%) reported that dialysis is likely to be withheld in PVS patients who develop kidney failure. In high risk or poor prognosis ESKD patients and given how likely they would consider each option independently, respondents reported they are likely to consider time-limited dialysis in 78% of the time followed by stopping (46%) or forgoing (27%) dialysis. Majority of the participants perceived that their decisions in providing renal care for PVS patients in UAE were influenced by the family sociocultural beliefs (76% of participants), the current hospital policies (72% of participants), and by Islamic beliefs (66% of participants). Only few perceived access to palliative care (30%) and treatment cost (17%) to have an impact on their decision making.Decisions of initiation and continuation of dialysis treatment to ESKD patients in PVS are prevalent among nephrology practices in UAE. Development of local guidelines based on the societal values along with early integration of palliative kidney failure management care would be required to improve the quality of provision of end-of-life renal care in UAE. ABBREVIATIONS: ESKD: stage kidney disease; UAE: United Arab Emirates; PVS: persistent vegetative state; RPA: Renal Physicians Association; ASN: American Society of Nephrology; EMAN: Emirates Medical Association Nephrology Society; CPR: cardiopulmonary resuscitation. PMID- 29979644 TI - beta-Blocker therapy for cirrhotic cardiomyopathy: a randomized-controlled trial. AB - BACKGROUND: Cirrhotic cardiomyopathy is characterized by an attenuated contractile response to stress. Long-term exposure of beta-adrenergic receptors to persistently high levels of catecholamines has been implicated in its pathogenesis. We hypothesized that beta-blockade with metoprolol could reverse the changes in heart function and morphology in cirrhotic cardiomyopathy. PATIENTS AND METHODS: In this prospective randomized trial, we included 78 patients aged between 18 and 60 years with abnormal cardiac output response under dobutamine stress echocardiography, without primary cardiac disease or a history of alcohol intake. Patients were assigned randomly to receive metoprolol or placebo for 6 months. The primary endpoint was the improvement in cardiac output response to stress, measured by an increase in the left ventricle stroke volume more than 30%. RESULTS: Three (7.3%) patients in the metoprolol group and nine (24.3%) patients in the placebo group showed improved stroke volume (P=0.057). Diastolic dysfunction was found in two (4.8%) patients before and in five (15.6%) patients after therapy in the metoprolol group, and in 10 (27%) patients before and nine (31%) patients after therapy in the placebo group (P=0.67). After treatment, no echocardiography parameter of morphology was significantly different between metoprolol or placebo groups. No significant differences were observed in noradrenaline, plasma renin activity, and troponin levels between groups. Cirrhosis-related clinical events, including hospitalizations and mortality, were not significantly different between the two groups. Six months of therapy with beta-blocker did not ameliorate heart function and morphology in patients with cirrhotic cardiomyopathy. PMID- 29979646 TI - Golden Rice is safe to eat, says FDA. PMID- 29979645 TI - Evaluation of Renal Function in Children with Congenital Scoliosis and Congenital Anomalies of the Kidney and Urinary Tract. AB - BACKGROUND The aim of this study was to compare renal function in children with congenital scoliosis and congenital anomalies of the kidney and urinary tract, with healthy children. MATERIAL AND METHODS Biochemical tests were performed before surgery (pre-therapy) and after surgery (post-therapy) in 16 children with congenital scoliosis and congenital anomalies of the kidney and urinary tract. Thirty-two healthy children were matched for age, sex, and weight (healthy controls). General renal function tests included serum electrolytes, creatinine, urea, cystatin C, and estimated glomerular filtration rate (eGFR). Tests for early renal changes included N-acetyl-beta-D-glucosaminidase (NAG), urine microalbumin, serum transferrin, immunoglobulin G (IgG), urinary alpha-1 microglobulin (A1M), and beta-2-microglobulin (B2M). RESULTS Sixteen patients with congenital anomalies of the kidney and urinary tract included eight boys (mean age, 11.38+/-2.00 years) and eight girls (mean age, 11.00+/-2.78 years). There were no significant differences in renal function between the pre-therapy and post-therapy groups (P>0.05), or between the three groups (pre-therapy, post therapy, and healthy controls). In the pre-therapy group, there were significant differences in IgG, A1M, NAG, and serum phosphate levels between boys and girls, urine microalbumin was significantly increased in girls, but not boys (P<0.05). There were no significant differences between the pre-therapy group and post therapy group (P>0.05). CONCLUSIONS Routine tests of renal function were normal in children with congenital scoliosis and congenital anomalies of the kidney and urinary tract, but early changes in renal function occurred before surgical treatment, indicating long-term follow-up of renal function is recommended. PMID- 29979648 TI - First migraine-prevention antibody approved. PMID- 29979647 TI - Erratum: California voters and CIRM-will lightning strike twice? PMID- 29979649 TI - CRISPR gene therapy trial on hold. PMID- 29979651 TI - Wanted: a reward for antibiotic development. PMID- 29979650 TI - Reportage from the gut. PMID- 29979653 TI - Public biotech in 2017-the numbers. PMID- 29979654 TI - Corrigendum: Assisted reproductive technologies to prevent human mitochondrial disease transmission. PMID- 29979657 TI - Gates unveils biotech-within-a-charity. PMID- 29979656 TI - Drug designers embrace cryo-EM. PMID- 29979658 TI - Erratum: Random access in large-scale DNA data storage. PMID- 29979659 TI - A new route to synthetic DNA. PMID- 29979655 TI - KBase: The United States Department of Energy Systems Biology Knowledgebase. PMID- 29979660 TI - As life sciences sector's positive momentum continues, so do executive compensation levels. PMID- 29979661 TI - The 160K Natural Organism Library, a unique resource for natural products research. PMID- 29979662 TI - Merck vaccine heads Ebola countermeasures. PMID- 29979663 TI - Cardiomyocytes remuscularize the heart. PMID- 29979665 TI - Saying aye to the artificial iris. PMID- 29979664 TI - Clinical trials go virtual, big pharma dives in. PMID- 29979666 TI - New money flows to CARB-X for antimicrobials. PMID- 29979667 TI - The European Union Court's Advocate General's Opinion and new plant breeding techniques. PMID- 29979669 TI - Recent patents in organoids and organs-on-chips. PMID- 29979668 TI - Patent mining and landscaping of emerging recombinant factor VIII through network analysis. PMID- 29979671 TI - Corrigendum: Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea. PMID- 29979672 TI - p38alpha blocks brown adipose tissue thermogenesis through p38delta inhibition. AB - Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT like depot called beige/brite tissue. Here, using mice that are deficient in p38alpha specifically in adipose tissue (p38alphaFab-KO), we unexpectedly found that lack of p38alpha protected against high-fat diet (HFD)-induced obesity. We also showed that p38alphaFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38alpha resulted in the activation of the related protein kinase family member p38delta. Our results showed that p38delta is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38delta Fab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38alpha probably blocks BAT thermogenesis through p38delta inhibition. Consistent with the results obtained in animals, p38alpha was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI). Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes. PMID- 29979673 TI - Subgraphs of functional brain networks identify dynamical constraints of cognitive control. AB - Brain anatomy and physiology support the human ability to navigate a complex space of perceptions and actions. To maneuver across an ever-changing landscape of mental states, the brain invokes cognitive control-a set of dynamic processes that engage and disengage different groups of brain regions to modulate attention, switch between tasks, and inhibit prepotent responses. Current theory posits that correlated and anticorrelated brain activity may signify cooperative and competitive interactions between brain areas that subserve adaptive behavior. In this study, we use a quantitative approach to identify distinct topological motifs of functional interactions and examine how their expression relates to cognitive control processes and behavior. In particular, we acquire fMRI BOLD signal in twenty-eight healthy subjects as they perform two cognitive control tasks-a Stroop interference task and a local-global perception switching task using Navon figures-each with low and high cognitive control demand conditions. Based on these data, we construct dynamic functional brain networks and use a parts-based, network decomposition technique called non-negative matrix factorization to identify putative cognitive control subgraphs whose temporal expression captures distributed network structures involved in different phases of cooperative and competitive control processes. Our results demonstrate that temporal expression of the subgraphs fluctuate alongside changes in cognitive demand and are associated with individual differences in task performance. These findings offer insight into how coordinated changes in the cooperative and competitive roles of cognitive systems map trajectories between cognitively demanding brain states. PMID- 29979674 TI - Excitable neuronal assemblies with adaptation as a building block of brain circuits for velocity-controlled signal propagation. AB - The time scale of neuronal network dynamics is determined by synaptic interactions and neuronal signal integration, both of which occur on the time scale of milliseconds. Yet many behaviors like the generation of movements or vocalizations of sounds occur on the much slower time scale of seconds. Here we ask the question of how neuronal networks of the brain can support reliable behavior on this time scale. We argue that excitable neuronal assemblies with spike-frequency adaptation may serve as building blocks that can flexibly adjust the speed of execution of neural circuit function. We show in simulations that a chain of neuronal assemblies can propagate signals reliably, similar to the well known synfire chain, but with the crucial difference that the propagation speed is slower and tunable to the behaviorally relevant range. Moreover we study a grid of excitable neuronal assemblies as a simplified model of the somatosensory barrel cortex of the mouse and demonstrate that various patterns of experimentally observed spatial activity propagation can be explained. PMID- 29979675 TI - A local uPAR-plasmin-TGFbeta1 positive feedback loop in a qualitative computational model of angiogenic sprouting explains the in vitro effect of fibrinogen variants. AB - In experimental assays of angiogenesis in three-dimensional fibrin matrices, a temporary scaffold formed during wound healing, the type and composition of fibrin impacts the level of sprouting. More sprouts form on high molecular weight (HMW) than on low molecular weight (LMW) fibrin. It is unclear what mechanisms regulate the number and the positions of the vascular-like structures in cell cultures. To address this question, we propose a mechanistic simulation model of endothelial cell migration and fibrin proteolysis by the plasmin system. The model is a hybrid, cell-based and continuum, computational model based on the cellular Potts model and sets of partial-differential equations. Based on the model results, we propose that a positive feedback mechanism between uPAR, plasmin and transforming growth factor beta1 (TGFbeta1) selects cells in the monolayer for matrix invasion. Invading cells releases TGFbeta1 from the extracellular matrix through plasmin-mediated fibrin degradation. The activated TGFbeta1 further stimulates fibrin degradation and keeps proteolysis active as the sprout invades the fibrin matrix. The binding capacity for TGFbeta1 of LMW is reduced relative to that of HMW. This leads to reduced activation of proteolysis and, consequently, reduced cell ingrowth in LMW fibrin compared to HMW fibrin. Thus our model predicts that endothelial cells in LMW fibrin matrices compared to HMW matrices show reduced sprouting due to a lower bio-availability of TGFbeta1. PMID- 29979676 TI - Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy. AB - Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele. Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia. A milder phenotype was observed after Nkx2-5 deletion at fetal stages, during trabecular compaction. A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure. Progressive impaired cardiac function correlates with conduction and strain defects independently of the degree of hypertrabeculation. Transcriptomic analysis of molecular pathways reflects myocardial remodeling with a larger number of differentially expressed genes in the severe versus mild phenotype and identifies Six1 as being upregulated in hypertrabeculated hearts. Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia. PMID- 29979677 TI - Characterization of the microtranscriptome of macrophages infected with virulent, attenuated and saprophyte strains of Leptospira spp. AB - Leptospirosis is a bacterial zoonosis, caused by Leptospira spp., that leads to significant morbidity and mortality worldwide. Despite considerable advances, much is yet to be discovered about disease pathogenicity. The influence of epigenetic mechanisms, particularly RNA-mediated post-transcriptional regulation of host immune response has been described following a variety of bacterial infections. The current study examined the microtranscriptome of macrophages J774A.1 following an 8h infection with virulent, attenuated and saprophyte strains of Leptospira. Microarray analysis revealed that 29 miRNAs were misregulated following leptospiral infection compared to control macrophages in a strain and virulence-specific manner. Pathway analysis for targets of these differentially expressed miRNAs suggests that several processes involved in immune response could be regulated by miRNAs. Our data provides the first evidence that host miRNAs are regulated by Leptospira infection in macrophages. A number of the identified miRNA targets participate in key immune response processes. We suggest that post-transcriptional regulation by miRNAs may play a role in host response to infection in leptospirosis. PMID- 29979678 TI - Factors associated with advance directives completion among patients with advance care planning communication in Taipei, Taiwan. AB - BACKGROUND: Although advance directives (AD) have been implemented for years in western countries, the concept of AD is not promoted extensively in eastern countries. In this study we evaluate a program to systematically conduct advance care planning (ACP) communication for hospitalized patients in Taiwan and identify the factors associated with AD completion. METHODS: In this retrospective evaluation of a clinical ACP program, we identified adult patients with chronic life-limiting illness admitted to Taipei City Hospital between April 2015 and January 2016. Trained healthcare providers held an ACP meeting to discuss patients' preference regarding end-of-life care and AD completion. A multiple logistic regression was performed to determine the factors associated with the AD completion. RESULTS: A total of 2878 patients were determined to be eligible for ACP during the study, among which 1798 (62.5%) completed ACP and data was available for 1411 patients (49.1%). Of the 1411 patients who received ACP communication with complete data, the rate of AD completion was 82.6%. The overall mean (SD) age was 78.2 (14.4) years. Adjusting for other variables, AD completion was associated with patients aged >= 85 years [adjusted odds ratio (AOR) = 1.80, 95% CI 1.21-2.67], critical illness (AOR = 1.17, 95% CI 1.06-1.30), and social workers participating in ACP meetings (AOR = 1.74, 95% CI 1.24-2.45). CONCLUSION: The majority of inpatients with chronic life-limiting illness had ACP communication as part of this ACP program and over 80% completed an AD. Our study demonstrates the feasibility of implementing ACP discussion in East Asia and suggests that social workers may be an important component of ACP communication with patients. PMID- 29979679 TI - Discovery of a dual protease mechanism that promotes DNA damage checkpoint recovery. AB - The DNA damage response is a signaling pathway found throughout biology. In many bacteria the DNA damage checkpoint is enforced by inducing expression of a small, membrane bound inhibitor that delays cell division providing time to repair damaged chromosomes. How cells promote checkpoint recovery after sensing successful repair is unknown. By using a high-throughput, forward genetic screen, we identified two unrelated proteases, YlbL and CtpA, that promote DNA damage checkpoint recovery in Bacillus subtilis. Deletion of both proteases leads to accumulation of the checkpoint protein YneA. We show that DNA damage sensitivity and increased cell elongation in protease mutants depends on yneA. Further, expression of YneA in protease mutants was sufficient to inhibit cell proliferation. Finally, we show that both proteases interact with YneA and that one of the two proteases, CtpA, directly cleaves YneA in vitro. With these results, we report the mechanism for DNA damage checkpoint recovery in bacteria that use membrane bound cell division inhibitors. PMID- 29979680 TI - Both living bacteria and eukaryotes in the mosquito gut promote growth of larvae. AB - We recently reported that larval stage Aedes aegypti and several other species of mosquitoes grow when living bacteria are present in the gut but do not grow when living bacteria are absent. We further reported that living bacteria induce a hypoxia signal in the gut, which activates hypoxia-induced transcription factors and other processes larvae require for growth. In this study we assessed whether other types of organisms induce mosquito larvae to grow and asked if the density of non-living microbes or diet larvae are fed obviate the requirement for living organisms prior results indicated are required for growth. Using culture conditions identical to our own prior studies, we determined that inoculation density of living Escherichia coli positively affected growth rates of Ae. aegypti larvae, whereas non-living E. coli had no effect on growth across the same range of inoculation densities. A living yeast, alga, and insect cell line induced axenic Ae. aegypti first instars to grow, and stimulated similar levels of midgut hypoxia, HIF-alpha stabilization, and neutral lipid accumulation in the fat body as E. coli. However, the same organisms had no effect on larval growth if heat-killed. In addition, no axenic larvae molted when fed two other diets, when fed diets supplemented with heat-killed microbes or lysed and heat-killed microbes. Experiments conducted with An. gambiae yielded similar findings. Taken together, our results indicate that organisms from different prokaryotic and eukaryotic groups induce mosquito larvae to grow, whereas no conditions were identified that stimulated larvae to grow in the absence of living organisms. PMID- 29979682 TI - Correction: The state of the antivaccine movement in the United States: A focused examination of nonmedical exemptions in states and counties. AB - [This corrects the article DOI: 10.1371/journal.pmed.1002578.]. PMID- 29979681 TI - Unsupervised clustering of temporal patterns in high-dimensional neuronal ensembles using a novel dissimilarity measure. AB - Temporally ordered multi-neuron patterns likely encode information in the brain. We introduce an unsupervised method, SPOTDisClust (Spike Pattern Optimal Transport Dissimilarity Clustering), for their detection from high-dimensional neural ensembles. SPOTDisClust measures similarity between two ensemble spike patterns by determining the minimum transport cost of transforming their corresponding normalized cross-correlation matrices into each other (SPOTDis). Then, it performs density-based clustering based on the resulting inter-pattern dissimilarity matrix. SPOTDisClust does not require binning and can detect complex patterns (beyond sequential activation) even when high levels of out-of pattern "noise" spiking are present. Our method handles efficiently the additional information from increasingly large neuronal ensembles and can detect a number of patterns that far exceeds the number of recorded neurons. In an application to neural ensemble data from macaque monkey V1 cortex, SPOTDisClust can identify different moving stimulus directions on the sole basis of temporal spiking patterns. PMID- 29979683 TI - Measuring interdisciplinarity in clinical practice with IPC59, a modified and improved version of IPC65. AB - RATIONALE: Interdisciplinarity is considered a key concept in the management of complex cases in healthcare. However, working in interdisciplinary teams requires the integration of many concepts and a large amount of effort. To help healthcare managers and professionals identify the strengths and weaknesses of their interdisciplinary team and to ensure its continuous improvement, we developed a tool called the IPC65. OBJECTIVE: The purpose of this study was to test the reliability and validity of the IPC65. METHODS: Based on a comprehensive review of the literature and qualitative and quantitative assessments, the IPC65 was developed. In this study, the analysis was based on 392 healthcare professionals and managers from short-term care settings who provided valid responses throughout the province of Quebec in Canada. Descriptive statistics, Cronbach's alpha values, and inter-item correlations were measured, and a principal component analysis (PCA) was conducted. Item discrimination was used to provide an improved version of the IPC65. RESULTS: The IPC65 showed good statistical results. The discriminant procedure provided the basis for shortening and improving the IPC65 to form the IPC59. Cronbach's alpha values ranged from 0.857 to 0.967 in IPC59, demonstrating very good reliability for all four dimensions. The PCA showed good validity. CONCLUSION: The IPC59 can be used to assess the degree of integration of key concepts leading to interdisciplinarity. PMID- 29979684 TI - The current epidemiological status of urogenital schistosomiasis among primary school pupils in Katsina State, Nigeria: An imperative for a scale up of water and sanitation initiative and mass administration of medicines with Praziquantel. AB - INTRODUCTION: Human schistosomiasis, a debilitating and chronic disease, is among a set of 17 neglected tropical infectious diseases of poverty that is currently posing a threat to the wellbeing of 2 billion people in the world. The SHAWN/WASH and MAM programmes in the study area require epidemiological data to enhance their effectiveness. We therefore embarked on this cross-sectional study with the aim of investigating the prevalence, intensity and risk factors of urogenital schistosomiasis. METHODOLOGY/ PRINCIPAL FINDINGS: Interviewed 484 respondents produced terminal urine samples (between 10.00h - 14.00h) which were analyzed with Medi ?Test Combi 10 and centrifuged at 400 r.p.m for 4 minutes using C2 series Centurion Scientific Centrifuge. Eggs of S. haematobium were identified with their terminal spines using Motic Binocular Microscope. Data were analyzed with Epi Info 7. In this study, the overall prevalence and arithmetic mean intensity of the infection were 8.68% (6.39? 11.64) and 80.09 (30.92?129.28) eggs per 10ml of urine respectively. Urogenital schistosomiasis was significantly associated with knowledge about the snail host (chi2 = 4.23; P = 0.0398); water contact activities (chi2 = 25.788; P = 0.0001), gender (chi2 = 16.722; P = 0.0001); age (chi2 = 9.589; P = 0.0019); economic status of school attended (chi2 = 4.869; P = 0.0273); residence distance from open water sources (chi2 = 10.546; P = 0.0012); mothers' occupational (chi2 = 6.081; P = 0.0137) and educational status (chi2 = 4.139; P = 0.0419). CONCLUSION/ SIGNIFICANCE: The overall prevalence obtained in this survey shows that the study area was at a low-risk degree of endemicity for urogenital schistosomiasis. Beneath this is a subtle, latent and deadly morbidity-inducing heavy mean intensity of infection, calling for urgent implementation of WHO recommendation that MAM with PZQ be carried out twice for School-Age Children (enrolled or not enrolled) during their primary schooling age (once each at the point of admission and graduation). The criteria for classifying endemic areas for schistosomiasis should also be reviewed to capture the magnitude of mean intensity of infection rather than prevalence only as this may underplay its epidemiological severity. PMID- 29979685 TI - Age-dependent Pavlovian biases influence motor decision-making. AB - Motor decision-making is an essential component of everyday life which requires weighing potential rewards and punishments against the probability of successfully executing an action. To achieve this, humans rely on two key mechanisms; a flexible, instrumental, value-dependent process and a hardwired, Pavlovian, value-independent process. In economic decision-making, age-related decline in risk taking is explained by reduced Pavlovian biases that promote action toward reward. Although healthy ageing has also been associated with decreased risk-taking in motor decision-making, it is currently unknown whether this is a result of changes in Pavlovian biases, instrumental processes or a combination of both. Using a newly established approach-avoidance computational model together with a novel app-based motor decision-making task, we measured sensitivity to reward and punishment when participants (n = 26,532) made a 'go/no go' motor gamble based on their perceived ability to execute a complex action. We show that motor decision-making can be better explained by a model with both instrumental and Pavlovian parameters, and reveal age-related changes across punishment- and reward-based instrumental and Pavlovian processes. However, the most striking effect of ageing was a decrease in Pavlovian attraction towards rewards, which was associated with a reduction in optimality of choice behaviour. In a subset of participants who also played an independent economic decision making task (n = 17,220), we found similar decision-making tendencies for motor and economic domains across a majority of age groups. Pavlovian biases, therefore, play an important role in not only explaining motor decision-making behaviour but also the changes which occur through normal ageing. This provides a deeper understanding of the mechanisms which shape motor decision-making across the lifespan. PMID- 29979686 TI - Is it time to consider the expression of specific-pituitary hormone genes when typifying pituitary tumours? AB - The aim of the present study is to check whether we can replicate, in an independent series, previous results showing that the molecular study of pituitary-specific gene expression complements the inmunohistochemical identification of pituitary neuroendocrine tumours. We selected 112 patients (51 (46.4%) women; mean age 51.4+/-16 years; 102 macroadenomas (91.9%), 9 microadenomas (8.1%)) with complete clinical, radiological, immunohistochemical and molecular data from our data set of pituitary neuroendocrine tumours. Patients were different from those previously studied. We measured the expression of the pituitary-specific hormone genes and type 1 corticotrophin-releasing hormone and arginine vasopressin 1b receptors, by quantitative real-time polymerase chain reaction using TaqMan probes. Afterwards, we identified the different pituitary neuroendocrine tumour subtypes following the 2017 World Health Organization classification of pituitary tumours, calculating the concordance between their molecular and immuhistochemical identification. The concordance between molecular and immunohistochemical identification of functioning pituitary neuroendocrine tumours with the clinical diagnosis was globally similar to the previous series, where the SYBR Green technique was used instead of TaqMan probes. Our results also corroborated the poor correlation between molecular and immunohistochemical detection of the silent pituitary neuroendocrine tumour variants. This discrepancy was more remarkable in lactotroph, null-cell and plurihormonal pituitary neuroendocrine tumours. In conclusion, this study validates the results previously published by our group, highlighting a complementary role for the molecular study of the pituitary specific hormone genes in the typification of pituitary neuroendocrine tumours subtypes. PMID- 29979687 TI - Significance and usefulness of imaging characteristics of gubernaculum tracts for the diagnosis of odontogenic tumors or cysts. AB - We aimed to determine the significance and usefulness of imaging characteristics of gubernaculum tracts (GT) for the diagnosis of odontogenic tumors or cysts. This was a retrospective analysis of relationships between odontogenic or non odontogenic tumors or cysts and the GT that were visualized using multi-detector computed tomography (MDCT). The relationship between the size of a mass and expansion of the GT in all odontogenic tumors or cysts to which GTs were contiguous on MDCT, was statistically analyzed. Intact or expanded GTs were detected in MDCT images on the top of almost all odontogenic tumors or cysts, but not on non-odontogenic tumors or cysts. Characteristic image findings regarding the relationship between the GT and the odontogenic mass were detected for the respective odontogenic tumors or cysts in which the GTs were contiguous to the mass on MDCT. In ameloblastomas, expansion of the GTs significantly and very strongly correlated with tumor size (r = 0.741, p = 0.0001), but this correlation was very weak in dentigerous cysts (r = 0.167, p = 0.028) and there was no correlation between these parameters in odontogenic keratocysts (r = -0.089, p = 0.557). The imaging characteristics of GTs at the top of masses should be very useful for both the differential diagnosis of the pathological diagnosis of odontogenic masses and for differentiation between odontogenic and non odontogenic masses. PMID- 29979688 TI - Dissolved organic carbon in streams within a subarctic catchment analysed using a GIS/remote sensing approach. AB - Climate change projections show that temperature and precipitation increases can alter the exchange of greenhouse gases between the atmosphere and high latitude landscapes, including their freshwaters. Dissolved organic carbon (DOC) plays an important role in greenhouse gas emissions, but the impact of catchment productivity on DOC release to subarctic waters remains poorly known, especially at regional scales. We test the hypothesis that increased terrestrial productivity, as indicated by the normalized difference vegetation index (NDVI), generates higher stream DOC concentrations in the Stordalen catchment in subarctic Sweden. Furthermore, we aimed to determine the degree to which other generic catchment properties (elevation, slope) explain DOC concentration, and whether or not land cover variables representing the local vegetation type (e.g., mire, forest) need to be included to obtain adequate predictive models for DOC delivered into rivers. We show that the land cover type, especially the proportion of mire, played a dominant role in the catchment's release of DOC, while NDVI, slope, and elevation were supporting predictor variables. The NDVI as a single predictor showed weak and inconsistent relationships to DOC concentrations in recipient waters, yet NDVI was a significant positive regulator of DOC in multiple regression models that included land cover variables. Our study illustrates that vegetation type exerts primary control in DOC regulation in Stordalen, while productivity (NDVI) is of secondary importance. Thus, predictive multiple linear regression models for DOC can be utilized combining these different types of explanatory variables. PMID- 29979689 TI - Cost-effectiveness of PCV13 vaccination in Belgian adults aged 65-84 years at elevated risk of pneumococcal infection. AB - BACKGROUND: The Belgian Superior Health Council (SHC) recently added a 13-valent pneumococcal conjugate vaccine (PCV13) to its recommendations for adult pneumococcal vaccination. This study addresses the policy question regarding whether a single dose of PCV13 should be reimbursed among Belgian adults aged 65 84 years with chronic comorbidities ("moderate-risk") or immunosuppression ("high risk"). METHODS: A cohort model was developed to project lifetime risks, consequences, and costs of invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Parameter values were estimated using published literature and available databases, and were reviewed by Belgian experts. PCV13 effectiveness was assumed to be durable during the first 5 years following receipt, and to progressively decline thereafter with 15 years protection. The Belgian National Health Insurance perspective was employed. RESULTS: Use of PCV13 (vs. no vaccine) in moderate/high-risk persons aged 65-84 years (n = 861,467; 58% vaccination coverage) would be expected to prevent 527 cases of IPD, 1,744 cases of pneumococcal CAP and 176 pneumococcal-related deaths, and reduce medical care costs by ?20.1 million. Vaccination costs, however, would increase by ?36.9 million and thus total overall costs would increase by ?16.8 million. Cost per QALY gained was ?17,126. In probabilistic sensitivity analyses, use of PCV13 was cost-effective in 97% of 1,000 simulations. CONCLUSIONS: Reimbursement of PCV13 in moderate/high-risk Belgian adults aged 65-84 years would be cost-effective from the Belgian healthcare perspective. PMID- 29979690 TI - QTL analysis reveals quantitative resistant loci for Phytophthora infestans and Tecia solanivora in tetraploid potato (Solanum tuberosum L.). AB - Late blight and Guatemalan potato tuber moth caused by Phytophthora infestans and Tecia solanivora, respectively, are major phytosanitary problems on potato crops in Colombia and Ecuador. Hence, the development of resistant cultivars is an alternative for their control. However, breeding initiatives for durable resistance using molecular tools are limited due to the genome complexity and high heterozygosity in autotetraploid potatoes. To contribute to a better understanding of the genetic basis underlying the resistance to P. infestans and T. solanivora in potato, the aim of this study was to identify QTLs for resistance to P. infestans and T. solanivora using a F1 tetraploid potato segregant population for both traits. Ninety-four individuals comprised this population. Parent genotypes and their progeny were genotyped using SOLCAP 12K potato array. Forty-five percent of the markers were polymorphic. A genetic linkage map was built with a length of 968.4 cM and 1,287 SNPs showing good distribution across the genome. Severity and incidence were evaluated in two crop cycles for two years. QTL analysis revealed six QTLs linked to P. infestans, four of these related to previous QTLs reported, and two novel QTLs (qrAUDPC-3 and qrAUDPC-8). Fifteen QTLs were linked to T. solanivora, being qIPC-6 and qOPA-6.1, and qIPC-10 and qIPC-10.1 stable in two different trials. This study is one of the first to identify QTLs for T. solanivora. As the population employed is a breeding population, results will contribute significantly to breeding programs to select resistant plant material, especially in countries where P. infestans and T. solanivora limit potato production. PMID- 29979691 TI - Interspinous process devices for treatment of degenerative lumbar spine stenosis: A systematic review and meta-analysis. AB - BACKGROUND: Degenerative lumbar spinal stenosis is a condition related to aging in which structural changes cause narrowing of the central canal and intervertebral foramen. It is currently the leading cause for spinal surgery in patients over 65 years. Interspinous process devices (IPDs) were introduced as a less invasive surgical alternative, but questions regarding safety, efficacy, and cost-effectiveness are still unanswered. OBJECTIVES: The aim of this study was to provide complete and reliable information regarding benefits and harms of IPDs when compared to conservative treatment or decompression surgery and suggest directions for forthcoming RCTs. METHODS: We searched MEDLINE, EMBASE, Cochrane Library, Scopus, and LILACS for randomized and quasi-randomized trials, without language or period restrictions, comparing IPDs to conservative treatment or decompressive surgery in adults with symptomatic degenerative lumbar spine stenosis. Data extraction and analysis were conducted following the Cochrane Handbook. Primary outcomes were pain assessment, functional impairment, Zurich Claudication Questionnaire, and reoperation rates. Secondary outcomes were quality of life, complications, and cost-effectiveness. This systematic review was registered at Prospero (International prospective register of systematic reviews) under number 42015023604. RESULTS: The search strategy resulted in 17 potentially eligible reports. At the end, nine reports were included and eight were excluded. Overall quality of evidence was low. One trial compared IPDs to conservative treatment: IPDs presented better pain, functional status, quality of life outcomes, and higher complication risk. Five trials compared IPDs to decompressive surgery: pain, functional status, and quality of life had similar outcomes. IPD implant presented a significantly higher risk of reoperation. We found low-quality evidence that IPDs resulted in similar outcomes when compared to standard decompression surgery. Primary and secondary outcomes were not measured in all studies and were often published in incomplete form. Subgroup analysis was not feasible. Difficulty in contacting authors may have prevented us of including data in quantitative analysis. CONCLUSIONS: Patients submitted to IPD implants had significantly higher rates of reoperation, with lower cost effectiveness. Future trials should improve in design quality and data reporting, with longer follow-up periods. PMID- 29979692 TI - Predictive performance of six mortality risk scores and the development of a novel model in a prospective cohort of patients undergoing valve surgery secondary to rheumatic fever. AB - BACKGROUND: Mortality prediction after cardiac procedures is an essential tool in clinical decision making. Although rheumatic cardiac disease remains a major cause of heart surgery in the world no previous study validated risk scores in a sample exclusively with this condition. OBJECTIVES: Develop a novel predictive model focused on mortality prediction among patients undergoing cardiac surgery secondary to rheumatic valve conditions. METHODS: We conducted prospective consecutive all-comers patients with rheumatic heart disease (RHD) referred for surgical treatment of valve disease between May 2010 and July of 2015. Risk scores for hospital mortality were calculated using the 2000 Bernstein-Parsonnet, EuroSCORE II, InsCor, AmblerSCORE, GuaragnaSCORE, and the New York SCORE. In addition, we developed the rheumatic heart valve surgery score (RheSCORE). RESULTS: A total of 2,919 RHD patients underwent heart valve surgery. After evaluating 13 different models, the top performing areas under the curve were achieved using Random Forest (0.982) and Neural Network (0.952). Most influential predictors across all models included left atrium size, high creatinine values, a tricuspid procedure, reoperation and pulmonary hypertension. Areas under the curve for previously developed scores were all below the performance for the RheSCORE model: 2000 Bernstein-Parsonnet (0.876), EuroSCORE II (0.857), InsCor (0.835), Ambler (0.831), Guaragna (0.816) and the New York score (0.834). A web application is presented where researchers and providers can calculate predicted mortality based on the RheSCORE. CONCLUSIONS: The RheSCORE model outperformed pre existing scores in a sample of patients with rheumatic cardiac disease. PMID- 29979693 TI - Concordance of tomographic ultrasound and multiplanar ultrasound in detecting levator ani muscle injury in patients with pelvic organ prolapse. AB - AIM: To compare the evaluations of evaluate levator ani muscle injury (LAMI) by tomographic ultrasound imaging (TUI) and multiplanar (MP) ultrasound in patients with pelvic organ prolapse (POP). METHOD: This retrospective analysis studied women who underwent International Continence Society POP quantification examination between October 2015 and June 2016. LAMI was assessed by both TUI and MP ultrasounds. Concordance of these two testing results was analyzed. Their correlations with clinical symptoms were also studied. RESULTS: A total of 135 women were included. All the patients with POP had a minimal LAMI depth >= 7 mm. Two examinations, TUI and MP, had satisfactory concordance (k = 0.71, P < 0.01). Depth of LAMI in the coronal plane demonstrated good agreement with TUI scores (r = 0.84; P < 0.01). After controlling for age, BMI, and parity, to have clinically significant POP and POP symptoms, the odds ratios (ORs) for the depth of LAMI in the coronal plane were 1.31 (95% CI 1.19-1.44) and 1.25 (95% CI 1.14-1.36), and for TUI scores were 1.72 (95% CI 1.37-2.17) and 1.63 (95% CI 1.31-2.03). Receiver operating characteristic curve analyses showed a cutoff depth of 7 mm of LAMI yielded a sensitivity of 62% and specificity of 80% for POP symptoms. CONCLUSIONS: TUI and MP had satisfactory concordance in detecting LAMI and correlated with clinical symptoms of POP. PMID- 29979694 TI - Air pollution during pregnancy and placental adaptation in the levels of global DNA methylation. AB - BACKGROUND: Health in early life is crucial for health later in life. Exposure to air pollution during embryonic and early-life development can result in placental epigenetic modification and foetus reprogramming, which can influence disease susceptibility in later life. Objectives: The aim of this paper was to investigate the placental adaptation in the level of global DNA methylation and differential gene expression in the methylation cycle in new-borns exposed to high fine particulate matter in the foetal stage. STUDY DESIGN: This is a nested case-control study. We enrolled pregnant healthy women attending prenatal care clinics in Tehran, Iran, who were residents of selected polluted and unpolluted regions, before the 14th week of pregnancy. We calculated the regional background levels of particle mass- particles with aerodynamics diameter smaller than 2.5 MUm (PM2.5) and 10 MUm (PM10)-of two regions of interest. At the time of delivery, placental tissue was taken for gene expression and DNA methylation analyses. We also recorded birth outcomes (the new-born's sex, birth date, birth weight and length, head and chest circumference, gestational age, Apgar score, and level of neonatal care required). RESULTS: As regards PM2.5 and PM10 concentrations in different time windows of pregnancy, there were significantly independent positive correlations between PM10 and PM2.5 in the first trimester of all subjects and placental global DNA methylation levels (p-value = 0.01, p value = 0.03, respectively). The gene expression analysis showed there was significant correlation between S-adenosylmethionine expression and PM2.5 (p = 0.003) and PM10 levels in the first trimester (p = 0.03). CONCLUSION: Our data showed prenatal exposures to air pollutants in the first trimester could influence placental adaptation by DNA methylation. PMID- 29979695 TI - A personalized channel recommendation and scheduling system considering both section video clips and full video clips. AB - With the convergence of various broadcasting systems, the amount of content available in mobile terminals including IPTV has significantly increased. In this paper, we propose a system that enables users to schedule programs considering both section video clips and full video clips based on the user detection method with similar preference. And, since the system constituting the contents can be classified according to the program, the proposed method can store a program desired by the user, and thus create and schedule a kind of individual channel. Experimental results show that the proposed method has a higher prediction accuracy; this is accomplished by comparing existing channel recommendation methods with the program recommendation methods proposed in this paper. PMID- 29979696 TI - Relationship between sympathoadrenal and pituitary-adrenal response during colorectal distention in the presence of corticotropin-releasing hormone in patients with irritable bowel syndrome and healthy controls. AB - Corticotropin-releasing hormone (CRH) mediates stress responses in the brain-gut axis. Administration of CRH modulates brain activation, for example by controlling the autonomic nervous system in response to colorectal distention. Here, we investigated the relationship between sympathoadrenal and hypothalamic pituitary-adrenal (HPA) responses to colorectal distention in patients with irritable bowel syndrome (IBS). We enrolled 32 patients with IBS (16 women and 16 men) and 32 healthy subjects (16 women and 16 men), and randomly divided them between CRH and saline injection groups. The patients randomly underwent no (0 mmHg), mild (20 mmHg), or strong (40 mmHg) colorectal distension. CRH (2 MUg/kg) or saline was then administered via injection, and the distention protocol was repeated. The heart rate (HR) and HR variability (HRV; calculated as the low [LF] to high frequency [HF] peak ratio, LF/HF) were analyzed using electrocardiography. Plasma noradrenaline, adrenaline, adrenocorticotropic hormone (ACTH), and cortisol levels were measured at the time of each distention. Plasma adrenaline levels were shown to be associated with plasma ACTH levels in HCs injected with CRH during distention using structural equation modeling analysis. Patients with IBS injected with placebo during distention displayed a closer association between these two parameters than those injected with CRH. Generalized estimating equation analysis revealed a significant distention * group * drug interaction for HF power. Moreover, there was a strong correlation between adrenaline and HRV upon CRH injection in controls, but not patients with IBS. The relationship between HPA-sympathoadrenal responses and CRH levels during colorectal distention differs between patients with IBS and controls. Modulation of adrenal gland activity in response to ACTH stimulation may contribute to the brain-gut pathophysiology characteristic of IBS. PMID- 29979697 TI - Vibrotactile information improves proprioceptive reaching target localization. AB - When pointing to parts of our own body (e.g., the opposite index finger), the position of the target is derived from proprioceptive signals. Consistent with the principles of multisensory integration, it has been found that participants better matched the position of their index finger when they also had visual cues about its location. Unlike vision, touch may not provide an additional information about finger position in space, since fingertip tactile information theoretically remains the same irrespective of the postural configuration of the upper limb. However, since tactile and proprioceptive information are ultimately coded within the same population of posterior parietal neurons within high-level spatial representations, we nevertheless hypothesized that additional tactile information could benefit the processing of proprioceptive signals. To investigate the influence of tactile information on proprioceptive localization, we asked 19 participants to reach with the right hand towards the opposite unseen index finger (proprioceptive target). Vibrotactile stimuli were applied to the target index finger prior to movement execution. We found that participants made smaller errors and more consistent reaches following tactile stimulation. These results demonstrate that transient touch provided at the proprioceptive target improves subsequent reaching precision and accuracy. Such improvement was not observed when tactile stimulation was delivered to a distinct body part (the shoulder). This suggests a specific spatial integration of touch and proprioception at the level of high-level cortical body representations, resulting in touch improving position sense. PMID- 29979698 TI - Uncertainty modulated exploration in the trade-off between sensing and acting. AB - Many sensorimotor activities have a time constraint for successful completion. In this case, any time devoted to sensory processing is at the expense of time available for motor execution. Earlier studies have explored how this competition between sensory processing and motor execution is resolved by using experimental designs that segregate the sensing and acting phase of the task. It was found that participants switch from the sensing to the acting stage such that the overall (sensorimotor) uncertainty in the outcome of the task is minimized. An unexplained observation in these studies is the substantial variability in switching times. We investigated the variability in switching time by correlating it with the underlying sensorimotor uncertainty. To this end, we used a modified version of the virtual ball catching paradigm proposed by Faisal & Wolpert (2009). Subjects were instructed to catch a ball, but as soon as they initiated their movement the ball disappeared. We extended the range of horizontal velocities and used two different start positions of the ball to quantify the dependence of sensory uncertainty on ball velocity. Velocity dependence of sensory uncertainty allowed us to manipulate sensory uncertainty and hence the sensorimotor uncertainty. We found that the variability in switching times is correlated with two factors. Firstly, variability in switching times is greater when variation in switching time has only minimal effects on sensorimotor uncertainty. Secondly, variability in switching times is greater when the sensorimotor uncertainty is larger. Our results suggest that the variability in switching time reflects an uncertainty-driven exploratory process. PMID- 29979699 TI - Effects of a new intervention based on the Health at Every Size approach for the management of obesity: The "Health and Wellness in Obesity" study. AB - Health at Every Size(r) (HAES(r)) is a weight-neutral approach focused on promoting healthy behaviors in people with different body sizes. This study examined multiple physiological, attitudinal, nutritional, and behavioral effects of a newly developed, intensive, interdisciplinary HAES(r)-based intervention in obese women. This was a prospective, seven-month, randomized (2:1), controlled, mixed-method clinical trial. The intervention group (I-HAES(r); n = 39) took part in an intensified HAES(r)-based intervention comprising a physical activity program, nutrition counseling sessions, and philosophical workshops. The control group (CTRL; n = 19) underwent a traditional HAES(r)-based intervention. Before and after the interventions, participants were assessed for physiological, psychological, and behavioral parameters (quantitative data) and took part in focus groups (qualitative data). Body weight, body mass index, and waist and hip circumferences did not significantly differ within or between groups (P > 0.05). I-HAES(r) showed increased peak oxygen uptake and improved performance in the timed-stand test (P = 0.004 and P = 0.004, between-group comparisons). No significant within- or between-group differences were observed for objectively measured physical activity levels, even though the majority of the I-HAES(r) participants indicated that they were engaged in or had plans to include physical activity in their routines. I-HAES(r) resulted in improvements in eating attitudes and practices. The I-HAES(r) group showed significantly improved all Body Attitude Questionnaire subscale and all Figure Rating Scale scores (P <= 0.05 for all parameters, within-group comparisons), whereas the CTRL group showed slight or no changes. Both groups had significant improvements in health-related quality of life parameters, although the I-HAES(r) group had superior gains in the "physical health," "psychological health," and "overall perception of quality of life and health" (P = 0.05, 0.03, and 0.02, respectively, between-group comparisons) domains. Finally, most of the quantitative improvements were explained by qualitative data. Our results show that this new intensified HAES(r) based intervention improved participants' eating attitudes and practices, perception of body image, physical capacity, and health-related quality of life despite the lack of changes in body weight and physical activity levels, showing that our novel approach was superior to a traditional HAES(r)-based program. PMID- 29979700 TI - One-year mortality of patients with ST-Elevation myocardial infarction: Prognostic impact of creatinine-based equations to estimate glomerular filtration rate. AB - BACKGROUND: Renal dysfunction is associated with worse outcomes after primary percutaneous coronary intervention (PCI). However, whether glomerular filtration rate (GFR) estimated with various equations can equally predict outcomes after ST Elevation Myocardial Infarction (STEMI) is still debated. METHODS: We compared the clinical impact of 3 different creatinine-based equations (Cockcroft and Gault (CG), CKD-epidemiology (CKD-EPI) and Full Age Spectrum (FAS)) to predict 1 year mortality in STEMI patients. RESULTS: Among 1755 consecutive STEMI patients who had undergone primary PCI included between 2006 and 2011, median estimated GFR was 79 (61;96) with the CG, 81 (65;95) with CKD-EPI and 75 (60;91) mL/min/1.73 m2 with FAS equation. Reduced GFR values were independently associated with 1-year mortality risk with the 3 equations. Receiver operating curves (ROC) of CG and FAS equations were significantly superior to the CKD-EPI equation, p = 0.03 and p = 0.01, respectively. Better prediction with FAS and CG equations was confirmed by net reclassification index. CONCLUSIONS: Our results suggest that in STEMI patients who have undergone primary PCI, 1-year mortality is better predicted by CG or FAS equations compared to CKD-EPI. PMID- 29979701 TI - [Protection effects of schizandrin B against liver injury induced by clozapine in mice]. AB - This study was conducted to test the effects of schizandrin B (Sch B) on clozapine (CLZ) inducedchronic liver injury in mice and the mechanism of action, and this may provide a new approach for clinicalprevention of CLZ-induced side effects. The CLZ was given to mice for three weeks alone or co-administrationwith Sch B. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase(ALP) and antioxidation indexes superoxide dismutase (SOD), malonic dialdehyde (MDA), glutathione (GSH)and liver histological evaluation were determined. Expression of Nrf2 was assayed in hepatic cells by immunohistochemicalstaining and Western blotting. The changes of relative gene expression of NAD(P)H: quinoneoxidoreductase l (NQO1) and heme oxygenase 1 (HO-1) were assayed by real-time Q-PCR. The results showedthat pretreatment with a lower dosage of Sch B (25, 50 mg.kg-1) prevented CLZ-induced liver injury as indicatedby the reduced levels of ALT, AST and ALP, and the preserved activities of SOD, GSH and inhibiting MDA. Itwas shown that Sch B could up-regulate Nrf2 expression leading to nuclear accumulation of Nrf2 to induceoxidative response genes such as NQO1 and HO-1. These results suggest that Sch B could protect against liverinjury induced by CLZ via the activation of the Nrf2/ARE signal pathway in a dose-dependent manner. PMID- 29979703 TI - Effects of cnidarian biofouling on salmon gill health and development of amoebic gill disease. AB - This study examines the potential implications of biofouling management on the development of an infectious disease in Norwegian farmed salmon. The hydroid Ectopleura larynx frequently colonises cage nets at high densities (thousands of colonies per m2) and is released into the water during regular in-situ net cleaning. Contact with the hydroids' nematocysts has the potential to cause irritation and pathological damage to salmon gills. Amoebic gill disease (AGD), caused by the amoeba Paramoeba perurans, is an increasingly international health challenge in Atlantic salmon farming. AGD often occurs concomitantly with other agents of gill disease. This study used laboratory challenge trials to: (1) characterise the gill pathology resulting from the exposure of salmon to hydroids, and (2) investigate if such exposure can predispose the fish to secondary infections-using P. perurans as an example. Salmon in tanks were exposed either to freshly 'shredded' hydroids resembling waste material from net cleaning, or to authentic concentrations of free-living P. perurans, or first to 'shredded' hydroids and then to P. perurans. Gill health (AGD gill scores, non specific gill scores, lamellar thrombi, epithelial hyperplasia) was monitored over 5 weeks and compared to an untreated control group. Nematocysts of E. larynx contained in cleaning waste remained active following high-pressure cleaning, resulting in higher non-specific gill scores in salmon up to 1 day after exposure to hydroids. Higher average numbers of gill lamellar thrombi occurred in fish up to 7 days after exposure to hydroids. However, gill lesions caused by hydroids did not affect the infection rates of P. perurans or the disease progression of AGD. This study discusses the negative impacts hydroids and current net cleaning practices can have on gill health and welfare of farmed salmon, highlights existing knowledge gaps and reiterates the need for alternative approaches to net cleaning. PMID- 29979702 TI - CHIP E3 ligase mediates proteasomal degradation of the proliferation regulatory protein ALDH1L1 during the transition of NIH3T3 fibroblasts from G0/G1 to S phase. AB - ALDH1L1 is a folate-metabolizing enzyme abundant in liver and several other tissues. In human cancers and cell lines derived from malignant tumors, the ALDH1L1 gene is commonly silenced through the promoter methylation. It was suggested that ALDH1L1 limits proliferation capacity of the cell and thus functions as putative tumor suppressor. In contrast to cancer cells, mouse cell lines NIH3T3 and AML12 do express the ALDH1L1 protein. In the present study, we show that the levels of ALDH1L1 in these cell lines fluctuate throughout the cell cycle. During S-phase, ALDH1L1 is markedly down regulated at the protein level. As the cell cultures become confluent and cells experience increased contact inhibition, ALDH1L1 accumulates in the cells. In agreement with this finding, NIH3T3 cells arrested in G1/S-phase by a thymidine block completely lose the ALDH1L1 protein. Treatment with the proteasome inhibitor MG-132 prevents such loss in proliferating NIH3T3 cells, suggesting the proteasomal degradation of the ALDH1L1 protein. The co-localization of ALDH1L1 with proteasomes, demonstrated by confocal microscopy, supports this mechanism. We further show that ALDH1L1 interacts with the chaperone-dependent E3 ligase CHIP, which plays a key role in the ALDH1L1 ubiquitination and degradation. In NIH3T3 cells, silencing of CHIP by siRNA halts, while transient expression of CHIP promotes, the ALDH1L1 loss. The downregulation of ALDH1L1 is associated with the accumulation of the ALDH1L1 substrate 10-formyltetrahydrofolate, which is required for de novo purine biosynthesis, a key pathway activated in S-phase. Overall, our data indicate that CHIP-mediated proteasomal degradation of ALDH1L1 facilitates cellular proliferation. PMID- 29979704 TI - Costing analysis of an SMS-based intervention to promote HIV self-testing amongst truckers and sex workers in Kenya. AB - OBJECTIVE: HIV testing rates in many sub-Saharan African countries have remained suboptimal, and there is an urgent need to explore strategic yet cost-effective approaches to increase the uptake of HIV testing, especially among high-risk populations. METHODS: A costing analysis was conducted for a randomized controlled trial (RCT) with male truckers and female sex workers (FSWs) registered in the electronic health record system (EHRS) of the North Star Alliance, which offers healthcare services at major transit hubs in Southern and East Africa. The RCT selected a sample of truckers and FSWs who were irregular HIV testers, according to the EHRS, and evaluated the effect of SMSs promoting the availability of HIV self-testing (HIVST) kits in Kenyan clinics (intervention program) versus a general SMS reminding clients to test for HIV (enhanced and standard program) on HIV testing rates. In this paper, we calculated costs from a provider perspective using a mixed-methods approach to identify, measure, and value the resources utilized within the intervention and standard programs. The results of the analysis reflect the cost per client tested. RESULTS: The cost of offering HIVST was calculated to be double that of routine facility-based testing (USD 10.13 versus USD 5.01 per client tested), primarily due to the high price of the self-test kit. In the two study arms that only offered provider-administered HIV testing in the clinic, only 1% of truckers and 6% of FSWs tested during the study period, while in the intervention arm, which also offered HST, approximately 4% of truckers and 11% of FSWs tested. These lower than expected outcomes resulted in relatively high cost per client estimates for all three study arms. Within the intervention arm, 65% of truckers and 72% of FSWs who tested chose the HIVST option. However, within the intervention arm, the cost per additional client tested was lower for FSWs than for truckers, at USD 0.15 per additional client tested versus USD 0.58 per additional client tested, driven primarily by the higher response rates. CONCLUSION: Whilst the availability of HIVST increased HIV testing among both truckers and FSWs, the cost of providing HIVST is higher than that of a routine health facility-based test, driven primarily by the price of the HIV self-test kit. Future research needs to identify strategies which increase demand for HIVST, and determine whether these strategies and the subsequent increased demand for HIVST are cost-effective in relation to the conventional facility based testing currently available. PMID- 29979705 TI - Selective adipogenic differentiation of human periodontal ligament stem cells stimulated with high doses of glucose. AB - Periodontal tissue damage, accompanied by the degradation and destruction of periodontal tissue collagen, is one of the most clinically common complications and difficulty self-repair in patients with diabetes. Human periodontal ligament stem cells (PDLSC) are the undifferentiated mesenchymal cells that persist in the periodontal ligament after development of periodontal tissue and the ability of PDLSC osteogenic differentiation is responsible for repairing periodontal tissue defects. However, the reasons of high glucose environment in diabetic patients inhibiting PDLSC to repair periodontal tissues are unclear. To address these issues, we propose exposing PDLSC to high-sugar mimics the diabetic environment and investigating the activity of osteogenic differentiation and adipogenic differentiation of PDLSC. At the cellular level, high glucose can promote the adipogenic differentiation and inhibit osteogenic differentiation to decrease the self-repair ability of PDLSC in periodontal tissues. Mechanistically at the molecular level, these effects are elicited via regulating the mRNA and protein expression of C/EBPbeta, PPAR-gamma. PMID- 29979706 TI - The diagnostic performance of musculoskeletal ultrasound in gout: A systematic review and meta-analysis. AB - BACKGROUND: Musculoskeletal ultrasound is widely used in diagnosing gout, but its accuracy is debatable. We conducted a systematic review and meta-analysis to quantitatively evaluate the value of ultrasound in the diagnosis of gout. METHODS: We systematically searched for publications using Cochrane Library, PubMed/Medline and Embase and manually screened the references of eligible articles for additional relevant publications. Studies were included in this systematic review if they assessed the diagnostic accuracy of ultrasound in gout compared to that of the gold standard, demonstration of monosodium urate crystals in joint fluid or tophi. We then conducted quantitative analyses by extracting data from each study and calculating the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR). The summary receiver operating characteristic curves (sROCs) were constructed to obtain the Q*-index and the area under the curve (AUC). RESULTS: Thirteen studies were included in this meta-analysis. The diagnostic performances of three distinctive ultrasonographic features of gout, double contour sign (DCS), the presence of tophi and the snowstorm sign, were evaluated. For person-based evaluations, the pooled sensitivity, specificity, DOR, AUC and Q* were as follows: for the DCS, 66% (95% confidence interval (CI) 62%-69%), 92% (95% CI 90%-94%), 25.91 (95% CI 11.80-56.89), 0.8163 and 0.7503, respectively; for the presence of tophi, 56% (95% CI 52%-60%), 94% (95% CI 92%-96%), 21.11 (95% CI 7.84-56.89), 0.8928 and 0.8236, respectively; for the snowstorm sign, 31% (95% CI 27%-36%), 91% (95% CI 88%-93%), 4.54(95% CI 3.13-6.58), 0.5946 and 0.5712, respectively; and for simultaneous consideration of these ultrasonographic features, 80% (95% CI 76%-83%), 83% (95% CI 79%-86%), 19.03 (95% CI 13.97-25.93), 0.889 and 0.8197, respectively. For the joint-/location-based evaluations, the pooled sensitivity, specificity, DOR, AUC and Q* were as follows: for the DCS, 75% (95% CI 68%-80%), 65% (95% CI 59%-70%), 16.90 (95% CI 5.10-56.03), 0.871 and 0.8014, respectively; and for the presence of tophi, 48% (95% CI 40%-57%), 96% (95% CI 91%-99%), 30.20 (95% CI 9.23-98.87), 0.8776 and 0.8081, respectively. CONCLUSIONS: In this meta-analysis, relatively high specificity but modest or low sensitivity were demonstrated in the diagnosis of gout using each of the three ultrasonographic features for person-based evaluations. Simultaneous consideration of these ultrasound findings may improve the diagnostic sensitivity. However, the double contour sign alone is weak in the differentiation of gout and non-gout for joint-/location-based evaluations. Further well-designed studies are still needed to support the current findings. PMID- 29979708 TI - Biodegradability of polyethylene by bacteria and fungi from Dandora dumpsite Nairobi-Kenya. AB - This study aimed at isolating and identifying bacteria and fungi with the capacity to degrade low density polyethylene (LDPE). The level of biodegradation of LDPE sheets with bacterial and fungal inoculums from different sampling points of Dandora dumpsite was evaluated under laboratory conditions. Incubation of the LDPE sheets was done for sixteen weeks at 37 degrees C and 28 degrees C for bacteria and fungi respectively in a shaker incubator. Isolation of effective candidates for biodegradation was done based on the recorded biodegradation outcomes. The extent of biodegradation on the polyethylene sheets was assessed by various techniques including weight loss analysis, Fourier Transform Infrared Spectroscopy (FTIR) and GC-MS. Fourier Transform Infra-Red spectroscopy (FTIR) analysis revealed the appearance of new functional groups attributed to hydrocarbon degradation after incubation with the bacteria and fungi. Analysis of the 16S rDNA and 18S rDNA sequences for bacteria and fungi respectively showed that bacteria belonging to genera Pseudomonas, Bacillus, Brevibacillus, Cellulosimicrobium, Lysinibacillus and fungi of genus Aspergillus were implicated as polyethylene degraders. An overall analysis confirmed that fungi are generally better degraders of polyethylene than bacteria. The highest fungal degradation activity was a mean weight reduction of 36.4+/-5.53% attributed to Aspergillus oryzae strain A5, 1 (MG779508). The highest degradation activity for bacteria was a mean of 35.72+/- 4.01% and 20.28+/- 2.30% attributed to Bacillus cereus strain A5,a (MG645264) and Brevibacillus borstelensis strain B2,2 (MG645267) respectively. Genus Aspergillus, Bacillus and Brevibacillus were confirmed to be good candidates for Low Density Poly Ethene bio-degradation. This was further confirmed by the appearance of the aldehyde, ether and carboxyl functional groups after FTIR analysis of the polythene sheets and the appearance of a ketone which is also an intermediary product in the culture media. To improve this degrading capacity through assessment of optimum conditions for microbial activity and enzyme production will enable these findings to be applied commercially and on a larger scale. PMID- 29979707 TI - A common molecular signature of patients with sickle cell disease revealed by microarray meta-analysis and a genome-wide association study. AB - A chronic inflammatory state to a large extent explains sickle cell disease (SCD) pathophysiology. Nonetheless, the principal dysregulated factors affecting this major pathway and their mechanisms of action still have to be fully identified and elucidated. Integrating gene expression and genome-wide association study (GWAS) data analysis represents a novel approach to refining the identification of key mediators and functions in complex diseases. Here, we performed gene expression meta-analysis of five independent publicly available microarray datasets related to homozygous SS patients with SCD to identify a consensus SCD transcriptomic profile. The meta-analysis conducted using the MetaDE R package based on combining p values (maxP approach) identified 335 differentially expressed genes (DEGs; 224 upregulated and 111 downregulated). Functional gene set enrichment revealed the importance of several metabolic pathways, of innate immune responses, erythrocyte development, and hemostasis pathways. Advanced analyses of GWAS data generated within the framework of this study by means of the atSNP R package and SIFT tool identified 60 regulatory single-nucleotide polymorphisms (rSNPs) occurring in the promoter of 20 DEGs and a deleterious SNP, affecting CAMKK2 protein function. This novel database of candidate genes, transcription factors, and rSNPs associated with SCD provides new markers that may help to identify new therapeutic targets. PMID- 29979709 TI - A funder-imposed data publication requirement seldom inspired data sharing. AB - Growth of the open science movement has drawn significant attention to data sharing and availability across the scientific community. In this study, we tested the ability to recover data collected under a particular funder-imposed requirement of public availability. We assessed overall data recovery success, tested whether characteristics of the data or data creator were indicators of recovery success, and identified hurdles to data recovery. Overall the majority of data were not recovered (26% recovery of 315 data projects), a similar result to journal-driven efforts to recover data. Field of research was the most important indicator of recovery success, but neither home agency sector nor age of data were determinants of recovery. While we did not find a relationship between recovery of data and age of data, age did predict whether we could find contact information for the grantee. The main hurdles to data recovery included those associated with communication with the researcher; loss of contact with the data creator accounted for half (50%) of unrecoverable datasets, and unavailability of contact information accounted for 35% of unrecoverable datasets. Overall, our results suggest that funding agencies and journals face similar challenges to enforcement of data requirements. We advocate that funding agencies could improve the availability of the data they fund by dedicating more resources to enforcing compliance with data requirements, providing data-sharing tools and technical support to awardees, and administering stricter consequences for those who ignore data sharing preconditions. PMID- 29979711 TI - Do weather changes influence physical activity level among older adults? - The Generation 100 study. AB - INTRODUCTION: Understanding how individual and environmental factors impact physical activity (PA) level is important when building strategies to improve PA of older adults. No studies have examined how hour-to-hour weather changes influence PA in older adults or how the association between weather and PA eventually is related to cardiorespiratory fitness (CRF) measured as peak oxygen uptake. The aim of this study was therefore to examine how hour-to-hour changes in weather effects hour-to-hour PA in a cohort of Norwegian older adults across CRF levels, gender and seasons. METHODS: PA was assessed objectively in 1219 older adults (70-77 years, 51% females) using the Actigraph GT3X+ accelerometer, and quantified as counts.min-1 (CPM). Weather (Norwegian meteorological Institute) and CRF (MetaMax II) were measured objectively. Panel data analysis added a longitudinal dimension when 110.888 hours of weather- and PA data were analyzed. RESULTS: Older adults had a higher PA level in warmer (597 CPM) than colder months (556 CPM) (p<0.01). Fixed effects regression-models revealed that increasing temperatures (per hour) influenced PA positively in both colder and warmer months (all, p<0.01), with greater influence in fitter vs. less fit participants (p<0.01). In warmer months, increasing precipitation negatively influenced PA in both unfit females and unfit males (p<0.01). In colder months, increasing precipitation positively influenced PA for moderately fit to fit males (p<0.01), but not for females and unfit males. CONCLUSION: To the best of our knowledge, this is the first study to examine the association between weather conditions and objectively-measured-PA among Norwegian older adults. Our findings demonstrates that unfit older adults will be less likely to participate in PA when the weather is unpleasant, compared to those highly fit. The data suggests that the impact of weather should not be ignored when planning public health strategies for increasing PA among older adults. PMID- 29979710 TI - Surface functionalization of polyurethane scaffolds mimicking the myocardial microenvironment to support cardiac primitive cells. AB - Scaffolds populated with human cardiac progenitor cells (CPCs) represent a therapeutic opportunity for heart regeneration after myocardial infarction. In this work, square-grid scaffolds are prepared by melt-extrusion additive manufacturing from a polyurethane (PU), further subjected to plasma treatment for acrylic acid surface grafting/polymerization and finally grafted with laminin-1 (PU-LN1) or gelatin (PU-G) by carbodiimide chemistry. LN1 is a cardiac niche extracellular matrix component and plays a key role in heart formation during embryogenesis, while G is a low-cost cell-adhesion protein, here used as a control functionalizing molecule. X-ray photoelectron spectroscopy analysis shows nitrogen percentage increase after functionalization. O1s and C1s core-level spectra and static contact angle measurements show changes associated with successful functionalization. ELISA assay confirms LN1 surface grafting. PU-G and PU-LN1 scaffolds both improve CPC adhesion, but LN1 functionalization is superior in promoting proliferation, protection from apoptosis and expression of differentiation markers for cardiomyocytes, endothelial and smooth muscle cells. PU-LN1 and PU scaffolds are biodegraded into non-cytotoxic residues. Scaffolds subcutaneously implanted in mice evoke weak inflammation and integrate with the host tissue, evidencing a significant blood vessel density around the scaffolds. PU-LN1 scaffolds show their superiority in driving CPC behavior, evidencing their promising role in myocardial regenerative medicine. PMID- 29979712 TI - Efficacy and safety data in elderly patients with metastatic renal cell carcinoma included in the nivolumab Expanded Access Program (EAP) in Italy. AB - BACKGROUND: Results from phase III clinical trial CheckMate 025 have established nivolumab as the standard of care for treatment of metastatic renal-cell carcinoma (mRCC) after VEGF inhibitor failure; however, elderly patients are under-represented in the registration trial and little is known about the activity of nivolumab in this subgroup. The purpose of the Expanded Access Program was to provide nivolumab to patients with mRCC who had progressed despite treatment with other agents that were considered standard of care. METHODS: Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months or until progression or unacceptable toxicity. The current analysis included all patients from the EAP Italian cohort who had received >=1 dose of nivolumab. Adverse events (AEs) were monitored using Common Terminology Criteria for Adverse Events v4.0. RESULTS: A total of 389 patients with advanced RCC were enrolled in the Italian cohort of the EAP and treated with nivolumab. Of these patients, 125 (32%) were at least 70 years of age and 70 (18%) were at least 75 years of age. Efficacy with nivolumab in the elderly patients was similar to that observed in the overall EAP population and in the CheckMate 025 trial. Safety was comparable between the elderly patients and the overall EAP population, and was consistent with what previously reported. CONCLUSION: The final results suggest that elderly patients with pretreated metastatic RCC may benefit from therapy with nivolumab. PMID- 29979713 TI - Medical student preferences for the internal medicine residency interview day: A cross-sectional study. AB - BACKGROUND: Applicant recruitment is an essential part of a residency program's activities with valuable resources dedicated to ensuring its success. Most programs design interview days based on a mix of tradition, budget availability and perception of applicant preferences. There is a paucity of available data on preferences of applicants for interview days. OBJECTIVE: We sought to investigate Internal Medicine applicant preferences for a residency recruitment day in aggregate and stratified by medical school background: United States vs. International Medical School Graduate. METHODS: A survey was developed and used in a cross-sectional study of Internal Medicine categorical and preliminary medicine candidates. Applicants ranked different facets of the interview day using a Likert scale. Variables included interview type, start time, length of interview day, number of interviews, length of each interview, background of interviewers, types of questions, interaction time with residents, month of interview, and components of interview day. RESULTS: 265 applicants received the surveys and 215 completed them correctly (81%). Overall, applicants tended to favor an 8-9 am start time (81.9%) and an optimal duration of four hours (82.8%). The interview was the most preferred component of the day (80.0%) with one-on-one (98.1%) and 15-30 min (95.3%) interviews preferred. Several statistically significant differences were found between the United States and International students as well as Categorical and Preliminary applicants. CONCLUSION: Our findings offer insights into various factors of the interview day that may appeal to Internal Medicine candidates. This information will be useful to graduate medical education departments engaged in recruitment. PMID- 29979714 TI - Construction of an integrated database for hERG blocking small molecules. AB - The inhibition of the hERG potassium channel is closely related to the prolonged QT interval, and thus assessing this risk could greatly facilitate the development of therapeutic compounds and the withdrawal of hazardous marketed drugs. The recent increase in SAR information about hERG inhibitors in public databases has led to many successful applications of machine learning techniques to predict hERG inhibition. However, most of these reports constructed their prediction models based on only one SAR database because the differences in the data format and ontology hindered the integration of the databases. In this study, we curated the hERG-related data in ChEMBL, PubChem, GOSTAR, and hERGCentral, and integrated them into the largest database about hERG inhibition by small molecules. Assessment of structural diversity using Murcko frameworks revealed that the integrated database contains more than twice as many chemical scaffolds for hERG inhibitors than any of the individual databases, and covers 18.2% of the Murcko framework-based chemical space occupied by the compounds in ChEMBL. The database provides the most comprehensive information about hERG inhibitors and will be useful to design safer compounds for drug discovery. The database is freely available at http://drugdesign.riken.jp/hERGdb/. PMID- 29979715 TI - Fluoroquinolone resistance in Campylobacter jejuni and Campylobacter coli from poultry and human samples assessed by PCR-restriction fragment length polymorphism assay. AB - The objective of this study was to determine fluoroquinolone resistance in Campylobacter spp from poultry and human isolates. Forty-one Campylobacter jejuni isolates (30 of poultry origin and 11 of human origin) and 11 Campylobacter coli isolates (10 of human origin and 1 of poultry origin) were examined for ciprofloxacin, norfloxacin, and nalidixic acid resistance using the minimal inhibitory concentration (MIC) method. Thereafter, the isolates were analyzed by PCR-Restriction Fragment Length Polymorphism (RFLP) assay for detection of Thr-86 mutation. Finally, DNA sequencing was performed for confirmation of gyrA gene mutation. A complete correlation was observed between MICs, PCR-RFLP assay, and sequencing. The results revealed high quinolone resistance rates for C. jejuni (100%) and C. coli (100%) isolates obtained from poultry and moderate resistance for C. jejuni (9.1%) and C. coli (40%) samples of human origin. A mutation in codon 86 of the gyrA gene with a Thr-to-Ile substitution is reported to be the main cause of high resistance to quinolones. This mutation can be analyzed by PCR RFLP assay, which has been proven to be a simple and fast method for the detection of fluoroquinolone resistance in Campylobacter spp. PMID- 29979716 TI - Detecting cerebrovascular changes in the brain caused by hypertension in atrial fibrillation group using acoustocerebrography. AB - Acoustocerebrography is a novel, non-invasive, transcranial ultrasonic diagnostic method based on the transmission of multispectral ultrasound signals propagating through the brain tissue. Dedicated signal processing enables the estimation of absorption coefficient, frequency-dependent attenuation, speed of sound and tissue elasticity. Hypertension and atrial fibrillation are well known factors correlated with white matter lesions, intracerebral hemorrhage and cryptogenic stroke numbers. The aim of this study was to compare the acoustocerebrography signal in the brains of asymptomatic atrial fibrillation patients with and without hypertension. The study included 97 asymptomatic patients (40 female and 57 male, age 66.26 +/- 6.54 years) who were clinically monitored for atrial fibrillation. The patients were divided into two groups: group I (patients with hypertension) n = 75, and group II (patients without hypertension) n = 22. Phase and amplitude of all spectral components for the received signals from the brain path were extracted and compared to the phase and amplitude of the transmitted pulse. Next, the time of flight and the attenuation of each frequency component were calculated. Additionally, a fast Fourier transformation was performed and its features were extracted. After introducing a machine learning technique, the ROC plot of differentiations between group I and group II with an AUC of 0.958 (sensitivity 0.99 and specificity 0.968) was obtained. It can be assumed that the significant difference in the acoustocerebrography signals in patients with hypertension is due to changes in the brain tissue, and it allows for the differentiating of high-risk patients with asymptomatic atrial fibrillation and hypertension. PMID- 29979717 TI - Ablation dynamics during laser interstitial thermal therapy for mesiotemporal epilepsy. AB - INTRODUCTION: The recent emergence of laser interstitial thermal therapy (LITT) as a frontline surgical tool in the management of brain tumors and epilepsy is a result of advances in MRI thermal imaging. A limitation to further improving LITT is the diversity of brain tissue thermoablative properties, which hinders our ability to predict LITT treatment-related effects. Utilizing the mesiotemporal lobe as a consistent anatomic model system, the goal of this study was to use intraoperative thermal damage estimate (TDE) maps to study short- and long-term effects of LITT and to identify preoperative variables that could be helpful in predicting tissue responses to thermal energy. METHODS: For 30 patients with mesiotemporal epilepsy treated with LITT at a single institution, intraoperative TDE maps and pre-, intra- and post-operative MRIs were co-registered in a common reference space using a deformable atlas. The spatial overlap of TDE maps with manually-traced immediate (post-ablation) and delayed (6-month) ablation zones was measured using the dice similarity coefficient (DSC). Then, motivated by simple heat-transfer models, ablation dynamics were quantified at amygdala and hippocampal head from TDE pixel time series fit by first order linear dynamics, permitting analysis of the thermal time constant (tau). The relationships of these measures to 16 independent variables derived from patient demographics, mesiotemporal anatomy, preoperative imaging characteristics and the surgical procedure were examined. RESULTS: TDE maps closely overlapped immediate ablation borders but were significantly larger than the ablation cavities seen on delayed imaging, particularly at the amygdala and hippocampal head. The TDEs more accurately predicted delayed LITT effects in patients with smaller perihippocampal CSF spaces. Analyses of ablation dynamics from intraoperative TDE videos showed variable patterns of lesion progression after laser activation. Ablations tended to be slower for targets with increased preoperative T2 MRI signal and in close proximity to large, surrounding CSF spaces. In addition, greater laser energy was required to ablate mesial versus lateral mesiotemporal structures, an effect associated with laser trajectory and target contrast enhanced T1 MRI signal. CONCLUSIONS: Patient-specific variations in mesiotemporal anatomy and pathology may influence the thermal coagulation of these tissues. We speculate that by incorporating demographic and imaging data into predictive models we may eventually enhance the accuracy and precision with which LITT is delivered, improving outcomes and accelerating adoption of this novel tool. PMID- 29979718 TI - Herring supports Northeast Pacific predators and fisheries: Insights from ecosystem modelling and management strategy evaluation. AB - This paper analyzes the trophic role of Pacific herring, the potential consequences of its depletion, and the impacts of alternative herring fishing strategies on a Northeast Pacific food web in relation to precautionary, ecosystem-based management. We used an Ecopath with Ecosim ecosystem model parameterized for northern British Columbia (Canada), employing Ecosim to simulate ecosystem effects of herring stock collapse. The ecological impacts of various herring fishing strategies were investigated with a Management Strategy Evaluation algorithm within Ecosim, accounting for variability in climatic drivers and stock assessment errors. Ecosim results suggest that herring stock collapse would have cascading impacts on much of the pelagic food web. Management Strategy Evaluation results indicate that herring and their predators suffer moderate impacts from the existing British Columbia harvest control rule, although more precautionary management strategies could substantially reduce these impacts. The non-capture spawn-on-kelp fishery, traditionally practiced by many British Columbia and Alaska indigenous peoples, apparently has extremely limited ecological impacts. Our simulations also suggest that adopting a maximum sustainable yield management strategy in Northeast Pacific herring fisheries could generate strong, cascading food web effects. Furthermore, climate shifts, especially when combined with herring stock assessment errors, could strongly reduce the biomasses and resilience of herring and its predators. By clarifying the trophic role of Pacific herring, this study aims to facilitate precautionary fisheries management via evaluation of alternative fishing strategies, and thereby to inform policy tradeoffs among multiple ecological and socioeconomic factors. PMID- 29979719 TI - Toward quantitative and reproducible clinical use of OCT-Angiography. AB - Optical coherence tomography angiography (OCT-A) is an ophthalmic imaging technique which has recently been introduced to clinical use. OCT-A provides visualization of the retinal vascularization in three dimensions, without injection of contrast agents. OCT-A could thus replace the current standard of opthalmic imaging, which is 2D only and requires contrast agents. However, quantitative studies remain to be carried out to assess the full potential of OCT A. In this context, the present work proposes a methodology to perform OCT-A in a more reproducible and precise way. We introduce a procedure to automatically extract the area of interest in avascular regions, which we demonstrate on various avascular areas with a focus on the optic nerve extracted in 2 dimensional images for a selected depth. We then study the repeatability of OCT-A with our segmentation technique when implemented on various clinical devices. For illustration, we apply this segmentation to healthy control group and to patients presenting different stages of glaucoma, a disease of clinical interest. The variability observed between these two cohorts compares favorably to the variability due to instrumental limitations or the segmentation algorithm. Our results thus constitute a significant step toward a more quantitative use of OCT A in a clinical context. PMID- 29979720 TI - Healthcare providers' views and perceptions on post-mortem procedures for cause of death determination in Southern Mozambique. AB - BACKGROUND: The minimally invasive autopsy (MIA) is being investigated as an alternative to the complete diagnostic autopsy (CDA), gold standard for CoD determination, in settings where CDA is unfeasible and/or unacceptable. We aimed to explore healthcare providers' views and perceptions on theoretical and factual acceptability of the CDA and the MIA. METHODS: A qualitative study, combining ethnographic and grounded-theory approaches, was conducted within a project aiming to validate the MIA tool against the CDA for CoD investigation. We present data on in-depth and semi-structured interviews of 33 healthcare providers operating within the formal and informal health services in Southern Mozambique. MIA perception was analysed through the theory of diffusion of innovations. RESULTS: All participants considered CDA useful for CoD determination. CDA was perceived reliable, but the unpleasant nature of the procedure and its associated infection risk were the main perceived disadvantages. Participants considered the MIA simple, easy and quick to perform; likely to meet families' expectations to know the CoD, and able to provide evidence-based knowledge for disease management. Concerns were raised on its reliability compared to the CDA. Family's emotional status and accessibility to decision-makers were mentioned as principal barriers for MIA performance. The main jeopardizing factors for MIA implementation were the shortage of required resources and the significant proportion of people dying at home. Key facilitators for MIA acceptance included the need for the support from community and religious leaders, provision of clear information to the community, and accompaniment to bereaved families. CONCLUSIONS: Healthcare providers consider the MIAs potentially more acceptable and feasible than CDAs in places where the latter have shown significant implementation challenges. A clear understanding of healthcare provider's perceived barriers and facilitators for conducting post-mortem procedures in general, and MIAs in particular, will shed light on their future field implementation for more robust mortality surveillance. PMID- 29979721 TI - Informal healthcare sector and marginalized groups: Repeat visits in rural North India. AB - The interrelationship between the public and private sectors, and formal and informal healthcare sectors effects market-level service quality, pricing behaviour and referral networks. However, health utilisation analysis of national survey data from many low and middle income countries is constrained by the lack of disaggregated health provider data. This study is concerned with the pattern of repeat outpatient consultations for a single episode of fever from public and private qualified providers and private unqualified providers. Cross-sectional survey data from 1173 adult respondents sampled from three districts within India's most populous state-Uttar Pradesh is analysed. Data was collected during the monsoon season-September to October-in 2012. Regression analysis focuses on the pattern of repeats visits for a single episode of mild-sever fever as the dependent variable. Results show that Women and Muslims in rural north India are more likely to not access healthcare, and if they do, consult with low quality unqualified outpatient healthcare providers. For fever durations of four or more days, men are more likely to access unqualified providers compared to women. Results of the current study supports the literature that women's utilisation of outpatient healthcare for communicable illnesses in LMICs is often less than men. A relative lack of access to household resources explains why fever duration parameter estimates for women and men differ. PMID- 29979722 TI - Internal quality assurance of HIL indices on Roche Cobas c702. AB - Automatic assessment of hemoglobin (H), lipaemia (L) and icterus (I) in serum or plasma (HIL indices) is the mainstay for evaluating sample quality. We planned this study to verify whether in-house prepared internal quality control (IQC) materials may be suitable for quality assurance of HIL indices. Pools containing different values of each of the three HIL indices were prepared from routine plasma samples, divided in aliquots and frozen at -20 degrees C. Stability of frozen materials was assessed by thawing one aliquot of each pool after different days of freezing (1, 4, 8, 15, 22 and 29), and by measuring HIL indices on baseline fresh samples and frozen-thawed aliquots with Roche Cobas c702. Five fresh liquid IQCs materials were also measured at the same time points. Intra assay and inter-assay imprecision of HIL indices calculated with commercial IQC materials ranged between 1.1-2.0% and 1.6-3.3%, respectively. When target values of HIL indices were calculated using frozen-thawed aliquots, the inter-assay imprecision of in-house prepared materials was optimal, even better than that of commercial liquid IQCs (H-index, 0.8% versus 1.6%; L-index, 2.2% versus 2.5%; I index, 0.8% versus 3.3%). In conclusion, in-house prepared IQC materials are cost effective alternatives to commercial liquid IQCs for HIL quality assurance. PMID- 29979723 TI - Radio Electric Asymmetric Conveyer (REAC) technology to obviate loss of T cell responsiveness under simulated microgravity. AB - Alterations of the gravitational environment are likely to modify cell behavior. Several studies have proven that T cells are sensitive to gravity alterations and that microgravity conditions may induce immunosuppression and weakened T cell immune response in humans during spaceflights. The aim of this work was to elucidate if a specific treatment of Radio Electric Asymmetric Conveyer (REAC) technology could restore, after mitogenic activation (Con A), a correct expression of cytokine IL2 gene and its receptor IL2R alpha, which are inhibited in T cells under microgravity conditions, as demonstrated in several studies. The results of this study, conducted in microgravity simulated with Random Positioning Machine (RPM), confirm the T cell activation recovery and offer the evidence that REAC technology could contribute to the understanding of T cell growth responsiveness in space, reducing the impact of weightlessness on the immune system experienced by humans in long duration space missions. PMID- 29979724 TI - Gene expression analysis of porcine whole blood cells infected with foot-and mouth disease virus using high-throughput sequencing technology. AB - Foot-and-mouth disease virus (FMDV) is a single-stranded positive RNA virus that belongs to the family Picornaviridae. FMDV infects cloven-hoofed animals, such as pigs, sheep, goats, cattle and diverse wildlife species, and remains a major threat to the livestock industry worldwide. In this study, a transcriptome analysis of whole blood from pigs infected with FMDV was performed using the paired-end Illumina sequencing technique to understand the interactions between the pathogen and its host cells. During infection with FMDV, a total of 120 differentially expressed genes (DEGs) were identified, including 110 up-regulated genes and 10 down-regulated genes. To further investigate the DEGs involved in interactions between the virus and its host, gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were conducted. GO annotation indicated that a number of DEGs were enriched in categories involved in host-virus interactions, such as response to stimulus, immune system process and regulation of biological process. KEGG enrichment analysis indicated that the DEGs were primarily involved in the ribosome signaling pathway and immune-related signaling pathways. Ten DEGs, including the immune-related genes BTK1, C1QB, TIMD4 and CXCL10, were selected and validated using quantitative PCR, which showed that the expression patterns of these genes are consistent with the results of the in silico expression analysis. In conclusion, this study presents the first transcriptome analysis of pig whole blood cells infected with FMDV, and the results obtained in this study improve our understanding of the interactions between FMDV and host cells as well as the diagnosis and control of FMD. PMID- 29979725 TI - A new genus and species of Labeonini (Teleostei: Cyprinidae) from the Pearl River in China. AB - Zuojiangia jingxiensis, both a new genus and species, is described from the Pearl River in China. It is distinguished from all other genera and species of Labeonini by the unique combination of modified oromandibular structures and head skeleton: a well-developed, pendulous, and conspicuously arched rostral fold, with an entirely crenulated margin; prominent papillae densely covering the margin of the rostral fold and anterior part of the lower lip; long postlabial grooves, partitioning the lower lip into three parts; transverse branch of dentary longer than half the length of the longitudinal branch; stubby lateral process present at the anterolateral margin of the longitudinal branch of the dentary, close to the corner; in the upper jaw, the premaxilla bears a triangular ascending process tapering to a point; maxilla exhibits a pair of articular heads at the anterodorsal margin, and a distinct fingerlike descending process posterior to the medial articular head embracing the ascending process of the premaxilla. PMID- 29979726 TI - Systematic review and meta-analyses of intensity-modulated radiation therapy versus conventional two-dimensional and/or or three-dimensional radiotherapy in curative-intent management of head and neck squamous cell carcinoma. AB - INTRODUCTION: Technological advancements in treatment planning and delivery have propelled the use of intensity-modulated radiation therapy (IMRT) in head and neck squamous cell carcinoma (HNSCC). This review compares IMRT with conventional two-dimensional (2D) and/or three-dimensional (3D) radiotherapy (RT) in curative intent management of HNSCC. METHODS: Only randomized controlled trials (RCTs) offering curative-intent RT in patients with non-metastatic HNSCC were included. Outcome data was extracted independently by two reviewers, pooled using the Cochrane methodology, and expressed as risk ratio (RR) or hazard ratio (HR) as appropriate with 95% confidence intervals (CIs). Xerostomia was the primary outcome of interest whereas loco-regional control, overall survival and quality of-life (QOL) were secondary endpoints. RESULTS: Seven RCTs involving 1155 patients directly comparing IMRT with 2D/3D-RT in HNSCC were included. The primary objective in five of seven index RCTs was reduction in xerostomia, with only one trial each using loco-regional control and overall survival as primary endpoints for sample size calculation. The use of IMRT was associated with a 36% relative risk reduction in >=grade 2 acute xerostomia (RR = 0.64, 95%CI = 0.49 0.84; p = 0.001) compared to 2D/3D-RT. More importantly, IMRT significantly reduced the risk of >=grade 2 late xerostomia (RR = 0.44, 95%CI = 0.34-0.57; p = 0.00001) compared to non-IMRT techniques at all time-points. Within the limitations of inadequate sample size and low statistical power, IMRT also resulted in 24% relative reduction in the risk of loco-regional relapse (HR = 0.76, 0.57-1.01; p = 0.06) and 30% relative reduction in risk of death (HR = 0.70, 95%CI = 0.57-0.88; p = 0.002) compared to 2D/3D-RT. However, this benefit of IMRT for loco-regional control and overall survival was limited to nasopharyngeal cancer patients alone, with no significant difference in efficacy between the two techniques in patients with cancers of the laryngo-pharynx in this analysis, highlighting the inconsistency in results of subgroup analyses stratified by primary site. Inadequate reporting of data precluded statistically pooling of results for QOL outcomes. CONCLUSIONS: There is consistent moderate quality evidence that IMRT significantly reduces the risk of moderate to severe acute and late xerostomia compared to 2D/3D-RT in curative-intent radiotherapeutic management of HNSCC. However, the quality of evidence regarding the superiority of IMRT over conventional techniques for disease-related endpoints is rather low due to relative lack of power and inconsistency of results precluding robust conclusions. PMID- 29979727 TI - Mooney face stimuli for visual perception research. AB - In 1957, Craig Mooney published a set of human face stimuli to study perceptual closure: the formation of a coherent percept on the basis of minimal visual information. Images of this type, now known as "Mooney faces", are widely used in cognitive psychology and neuroscience because they offer a means of inducing variable perception with constant visuo-spatial characteristics (they are often not perceived as faces if viewed upside down). Mooney's original set of 40 stimuli has been employed in several studies. However, it is often necessary to use a much larger stimulus set. We created a new set of over 500 Mooney faces and tested them on a cohort of human observers. We present the results of our tests here, and make the stimuli freely available via the internet. Our test results can be used to select subsets of the stimuli that are most suited for a given experimental purpose. PMID- 29979728 TI - Rv1460, a SufR homologue, is a repressor of the suf operon in Mycobacterium tuberculosis. AB - Iron-sulphur (Fe-S) clusters are ubiquitous co-factors which require multi protein systems for their synthesis. In Mycobacterium tuberculosis, the Rv1460 Rv1461-Rv1462-Rv1463-csd-Rv1465-Rv1466 operon (suf operon) encodes the primary Fe S cluster biogenesis system. The first gene in this operon, Rv1460, shares homology with the cyanobacterial SufR, which functions as a transcriptional repressor of the sufBCDS operon. Rv1460's function in M. tuberculosis has however not been determined. In this study, we demonstrate that M. tuberculosis mutants lacking a functional Rv1460 protein are impaired for growth under standard culture conditions. Elevated expression of Rv1460 and Rv1461 was observed in the mutant, implicating Rv1460 in the regulation of the suf operon. Binding of an Fe S cluster to purified recombinant Rv1460 was confirmed by UV-visible spectroscopy and circular dichroism. Furthermore, three conserved cysteine residues, C203, C216 and C244, proposed to provide ligands for the coordination of an Fe-S cluster, were shown to be required for the function of Rv1460 in M. tuberculosis. Rv1460 therefore seems to be functionally analogous to cyanobacterial SufR. PMID- 29979729 TI - Entinostat reverses P-glycoprotein activation in snail-overexpressing adenocarcinoma HCC827 cells. AB - Epithelial-to-mesenchymal transition (EMT) in cancer cells facilitates tumor progression by promoting invasion and metastasis. Snail is a transcriptional factor that induces EMT, while P-glycoprotein (P-gp) is an efflux transporter involved in anticancer drug resistance, and P-gp efflux activity is stimulated in Snail-overexpressing lung cancer cells with EMT characteristics. Since the histone deacetylase (HDAC) inhibitor entinostat (Ent) reverses EMT features, our aim in this study was to determine whether Ent also suppresses P-gp activation in Snail-induced cells. First, we confirmed that Ent treatment reduced migration activity, downregulated E-cadherin and upregulated vimentin at the mRNA level in Snail-overexpressing cells, thus inhibiting EMT. Efflux and uptake assays using rhodamine123 (Rho123), a fluorescent P-gp substrate, showed that Ent also inhibited Snail-induced activation of P-gp. Moreover, P-gp activity was more strongly inhibited by Ent in Snail-overexpressing cells than in Mock cells. When we evaluated the uptakes of Rho123 by LLC-PK1 cells and P-gp-overexpressing LLC GA5COL150 cells, Rho123 accumulation in LLC-GA5COL150 cells was significantly decreased compared with that in LLC-PK1 cells. Coincubation with Ent had no effect on Rho123 accumulation in either of the cell lines. Thus, Ent appears to be an inhibitor, but not a substrate, of P-gp at low concentration. Our results suggest that Ent treatment might suppress not only Snail-induced cancer malignant alteration, but also P-gp-mediated multidrug resistance. PMID- 29979730 TI - Can we monitor adaptation of juvenile goats to a new social environment through continuous qualitative behaviour assessment? AB - We aimed to verify whether Continuous Qualitative Behaviour Assessment (10 observers used a list of six qualitative descriptors) paired with Temporal Dominant Behavioural Expression (the same observers were asked to select the dominant descriptor and to score its intensity level) was able to monitor fluctuations of animal behaviour expression over time. We applied these techniques to three groups of juvenile goats either weaned (group C), or un weaned (groups WOM and WM). Each animal was separated from its group, moved to group C and tested for 30 min either while their mothers were at pasture, or while their mothers were in an adjacent pen (group WOM and WM, respectively). Animals from group C were separated from their group and immediately reintroduced to it. TDBE duration and score of each descriptor of behavioural expression were able to detect differences among groups but were unable to describe how the behaviour of the goats changed as the time progressed. TDBE curves described the evolution of each behavioural expression of each animal over time but were unable to detect differences among groups. The chi2 test conducted on peaks of dominance, albeit displaying the variations of the behavioural expression over time and allowing the assessment of differences among groups, focussed on occurrences of higher agreement between observers while neglecting most of the information concerning the descriptors above the level of significance. Conversely, based on mixed analysis of variance with the fixed effects of group, test interval and group x test interval (animal nested into group and observer were considered to be random), most of the descriptors were able to discriminate the three experimental groups while preserving the information on the fluctuations of the behavioural expression of the animals during the test. PMID- 29979731 TI - Gravity and scaling laws of city to city migration. AB - Models of human migration provide powerful tools to forecast the flow of migrants, measure the impact of a policy, determine the cost of physical and political frictions and more. Here, we analyse the migration of individuals from and to cities in the US, finding that city to city migration follows scaling laws, so that the city size is a significant factor in determining whether, or not, an individual decides to migrate and the city size of both the origin and destination play key roles in the selection of the destination. We observe that individuals from small cities tend to migrate more frequently, tending to move to similar-sized cities, whereas individuals from large cities do not migrate so often, but when they do, they tend to move to other large cities. Building upon these findings we develop a scaling model which describes internal migration as a two-step decision process, demonstrating that it can partially explain migration fluxes based solely on city size. We then consider the impact of distance and construct a gravity-scaling model by combining the observed scaling patterns with the gravity law of migration. Results show that the scaling laws are a significant feature of human migration and that the inclusion of scaling can overcome the limits of the gravity and the radiation models of human migration. PMID- 29979732 TI - Association mapping of quantitative resistance to charcoal root rot in mulberry germplasm. AB - Outbreaks of root rot disease in the productive South Indian sericulture belt have threatened the sustainability of the industry. Macrophomina phaseolina (Tassi) Goid. causing charcoal rot is the predominant pathogen to which all productive mulberry cultivars are susceptible. The present study was undertaken to identify molecular markers associated with charcoal rot resistance in mulberry. A mapping panel comprising 214 diverse entries from the Indian germplasm collection was assessed for charcoal rot resistance by artificial inoculation. Resistance to the pathogen was observed in 20 entries, and 51 were found to be moderately resistant. A total of 773 alleles generated across 105 SSR loci and 20,384 AFLP markers generated using 32 EcoRI-NN and MseI-CNN primer combinations were used in genetic analysis. The panel was weakly structured with two subpopulations. However, most entries were found to be admixtures. Survival of cuttings and number of roots per sapling were associated with root rot resistance. Association mapping was performed using different linear mixed models. Five AFLP markers explaining 9.6-12.7% of the total phenotypic variance were found to be significantly (p < 0.05) associated with root rot resistance. Significant associations were also detected in four AFLP markers for survival of cuttings, and these markers explained 10.7-14.2% of the total phenotypic variance. These markers should be validated using mapping populations derived from contrasting biparental combinations by linkage analysis for use in marker assisted gene pyramiding for durable resistance. The resistant genotypes identified in this study will substantially contribute to genetic improvement of mulberry for charcoal rot resistance and can be integrated into conventional breeding programmes. PMID- 29979733 TI - Consolidated mathematical growth model of the primary tumor and secondary distant metastases of breast cancer (CoMPaS). AB - The goal of this research is to improve the accuracy of predicting the breast cancer (BC) process using the original mathematical model referred to as CoMPaS. The CoMPaS is the original mathematical model and the corresponding software built by modelling the natural history of the primary tumor (PT) and secondary distant metastases (MTS), it reflects the relations between the PT and MTS. The CoMPaS is based on an exponential growth model and consists of a system of determinate nonlinear and linear equations and corresponds to the TNM classification. It allows us to calculate the different growth periods of PT and MTS: 1) a non-visible period for PT, 2) a non-visible period for MTS, and 3) a visible period for MTS. The CoMPaS has been validated using 10-year and 15-year survival clinical data considering tumor stage and PT diameter. The following are calculated by CoMPaS: 1) the number of doublings for the non-visible and visible growth periods of MTS and 2) the tumor volume doubling time (days) for the non visible and visible growth periods of MTS. The diameters of the PT and secondary distant MTS increased simultaneously. In other words, the non-visible growth period of the secondary distant MTS shrinks, leading to a decrease of the survival of patients with breast cancer. The CoMPaS correctly describes the growth of the PT for patients at the T1aN0M0, T1bN0M0, T1cN0M0, T2N0M0 and T3N0M0 stages, who does not have MTS in the lymph nodes (N0). Additionally, the CoMPaS helps to consider the appearance and evolution period of secondary distant MTS (M1). The CoMPaS correctly describes the growth period of PT corresponding to BC classification (parameter T), the growth period of secondary distant MTS and the 10-15-year survival of BC patients considering the BC stage (parameter M). PMID- 29979734 TI - Prevalence of work related musculoskeletal disorders (WMSDs) and ergonomic risk assessment among readymade garment workers of Bangladesh: A cross sectional study. AB - BACKGROUND: Work related Musculoskeletal Disorders (WMSDs) are one of the most common occupational diseases which mainly affects the lower back, neck and upper and lower extremities. The aim of this study was to determine prevalence of WMSDs in nine body regions among Ready Made Garment (RMG) workers in Bangladesh and ergonomics assessment of their exposure to risk factors for the development of WMSDs. METHODS: This cross-sectional study was conducted among 232 RMG employees (male: 46; female: 186; age: >18yrs) from nine RMG factories in Dhaka division during October 2015 to February 2016. Data were collected using a structured questionnaire consist of demographic questions, Nordic Musculoskeletal Questionnaire-Extended (NMQ-E) for WMSDs assessment in nine body regions and Quick Exposure Check (QEC) method for ergonomic assessment. Prevalence of WMSDs for each body region was determined. The association between WMSDs and ergonomic assessment of their exposure to risk factors were also analyzed. RESULTS: Respondents' mean age was 31.3 years (SD = 7). Their mean Body Mass Index (BMI) was 23.51 kg/m2 (SD = 3.74). Among 186 female respondents, 46 reported lower back pain (24.7%) and 44 reported neck pain (23.7%). Among 46 male respondents, 10 reported neck pain (21.7%) while 6 reported knee pain (13%). Statistically significant relationship was found between twelve month WMSDs in anatomical region in elbows (p = 0.02), hips (p = 0.01), knees (p = 0.01) and ankle (p = 0.05) with age; upper back (p = 0.001), elbows (p = 0.001), wrists (p = 0.03), hips (p = 0.001) and ankles (p = 0.01) with job experience; hips with BMI (p = 0.03); elbows (p = 0.04) with daily working hour. QEC assessment showed that level of exposure to WMSDs risk was high among 80% of the study population (p<0.003). CONCLUSION: The study found that lower back and neck were the most affected areas among RMG workers. Moreover, QEC findings warned the level of exposure to WMSDs risks is high and ergonomics intervention along with investigation and change to decrease exposure level is essential. Addressing musculoskeletal risk factors through ergonomic interventions in terms of working space, workers sitting/standing posture, seat and hand position during work and work-rest cycle are encouraged in RMG sector and policy makers. PMID- 29979735 TI - Anxiety behavior and hypothalamic-pituitary-adrenal axis altered in a female rat model of vertical sleeve gastrectomy. AB - Surgical weight loss results in a host of metabolic changes that culminate in net positive health benefit to the patients. However, the psychological impact of these surgeries has not been fully studied. On one hand, surgical weight loss has been reported to improve standard quality of life and resolution of symptoms of depression. But on the other hand, reports of self-harm and increased ER visits for self-harm suggest other psychological difficulties. Inability to handle anxiety following surgical weight loss has alarming potential ramifications for these gastric surgery patients. In the present study, we used models of diet induced obesity and vertical sleeve gastrectomy (VSG) to ask whether anxiety behavior and hypothalamic-pituitary-adrenal (HPA) axis gene changes were affected by surgical weight loss under two diet regimens: i.e. low-fat diet (LFD) and high fat diet (HFD). We show reduced exploratory behavior in the open field test but increased time in the open arms of the elevated plus maze. Furthermore, we show increased plasma levels of corticosterone in female VSG recipients in the estrus phase and increased levels of hypothalamic arginine-vasopressin (avp), pro opiomelanocortin (pomc), and tyrosine hydroxylase (th). We report reduced dopamine receptor D1 (drd1) gene in prefrontal cortex (PFC) in VSG animals in comparison to Sham. Further we report diet-driven changes in stress-relevant gene targets in the hypothalamus (oxt, pomc, crhr1) and adrenal (nr3c1, nr3c2, mc2r). Taken together, these data suggest a significant impact of both surgical weight loss and diet on the HPA axis and further impact on behavior. Additional assessment is necessary to determine whether molecular and hormonal changes of surgical weight loss are the source of these findings. PMID- 29979736 TI - Gene expression assay and Watson for Oncology for optimization of treatment in ER positive, HER2-negative breast cancer. AB - BACKGROUND: Personalized treatment for cancer patients is a hot topic of debate, particularly the decision to initiate chemotherapy in patients with Estrogen receptor (ER)-positive, HER2-negative tumors in the early stages of breast cancer (BC). Owing to significant advancements in information technology (IT) and genomics, clinicians are increasingly attaining therapeutic goals rapidly and safely by effectively differentiating patient subsets that require chemotherapy. IBM Watson for Oncology (WFO) is a cognitive computing system employed by clinicians to provide evidence-based treatment options for cancer. WFO aids in clinical diagnosis, with claims that it may be superior in performance to human clinicians. The current study was based on the hypothesis that WFO alone cannot effectively determine whether or not chemotherapy is essential for the subset of ER-positive, HER2-negative BC patients. PATIENTS AND METHODS: From December 2015 to July 2017, 95 patients with ER-positive, HER2- negative BC subjected to treatment were retrospectively examined using WFO, and outputs compared to real clinical practice. Treatment options were suggested by WFO, and WFO recommendations calculated both with and without data from the gene expression assay (GEA). RESULTS: WFO without GEA was unable to determine the groups of patients that did not require chemotherapy. Concordant therapeutic recommendations between real clinical practice and WFO without GEA were obtained for 23.2% of the patient group. On the other hand, the results of WFO with GEA showed good clinical applicability. Sensitivity, specificity, positive predictive and negative predictive values of WFO with GEA were 100%, 80%, 61% and 100%, respectively. CONCLUSIONS: Our collective findings indicate that WFO without the gene expression assay has limited clinical utility. PMID- 29979737 TI - Design of a novel filter paper based construct for rapid analysis of acetone. AB - The present work was focused to design a cheap, rapid, portable and easy to use filter paper based assay for the qualitative and quantitate analysis of acetone. Sodium alginate gel was loaded with the acetone specific optical signal probe, and subsequently coated onto filter paper surface to design portable colorimetric assays for acetone monitoring. The color of the paper sensor strip was observed to change from dark yellow to light yellowish in the presence of varying concentrations of acetone. Three different color analyzing models including RGB, HSV, and LAB were employed to probe the output optical signal, and their performance was compared in terms of better interpretation of the generated signal. The LAB model was found to provide better analytical figures of merit with a linear response for the acetone concentration ranging from 2.5 to 1500 ppm, and a limit of detection of 0.5 ppm. Furthermore, the specificity of the designed filter paper based sensor was demonstrated against different common interfering compounds. The results demonstrated the potential of our proposed filter paper based sensor as a novel tool for the analysis of acetone. PMID- 29979739 TI - New insights into island vegetation composition and species diversity-Consistent and conditional responses across contrasting insular habitats at the plot-scale. AB - Most island-ecology studies focus on the properties of entire island communities, thus neglecting species-environment relationships operating at the habitat-level. Habitat-specific variation in the strength and sign of these relationships will conceal patterns observed on the island scale and may preclude a mechanistic interpretation of patterns and processes. Habitat-specific species-environment relationships may also depend on the descriptor of ecological communities. This paper presents a comprehensive plot-based analysis of local vegetation composition and species diversity (species richness and species evenness) of (i) rocky shore, (ii) semi-natural grassland and (iii) coniferous forest habitats in three Baltic archipelagos in Sweden. To identify differences and consistencies between habitats and descriptors, we assessed the relative contributions of the variable-sets "region", "topography", "soil morphology", "soil fertility", "soil water", "light availability", "distance" and "island configuration" on local vegetation composition, species richness and species evenness. We quantified the impact of "management history" on the descriptors of local grassland communities by a newly introduced grazing history index (GHI). Unlike species diversity, changes in vegetation composition were related to most of the variable-sets. The relative contributions of the variable-sets were mostly habitat-specific and strongly contingent on the descriptor involved. Within each habitat, richness and evenness were only partly affected by the same variable-sets, and if so, their relative contribution varied between diversity proxies. Across all habitats, soil variable-sets showed highly consistent effects on vegetation composition and species diversity and contributed most to the variance explained. GHI was a powerful predictor, explaining high proportions of variation in all three descriptors of grassland species communities. The proportion of unexplained variance was habitat-specific, possibly reflecting a community maturity gradient. Our results reveal that species richness alone is an incomplete representation of local species diversity. Finally, we stress the need of including habitat-based approaches when analyzing complex species-environment relationships on islands. PMID- 29979738 TI - Recurrence of tuberculosis among newly diagnosed sputum positive pulmonary tuberculosis patients treated under the Revised National Tuberculosis Control Programme, India: A multi-centric prospective study. AB - INTRODUCTION: There is lack of information on the proportion of new smear positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome. OBJECTIVE: To estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined. METHODOLOGY: Adult (aged >= 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared "treatment success" at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years (with 95% confidence interval [95%CI]). Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence. RESULTS: Of the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2 21.6] and TB recurrence rate per 100 person-years was 12.7 [95% CI: 0.4-25]. TB recurrence per 100 person-years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence. CONCLUSION: A substantial proportion of new smear positive PTB patients successfully treated with 6 -month thrice-weekly regimen have TB recurrence under program settings. PMID- 29979740 TI - A year in words: The dynamics and consequences of language experiences in an intervention classroom. AB - Children from low SES backgrounds hear, on average, fewer words at home than those from high SES backgrounds. This word gap is associated with widening achievement differences in children's language abilities and school readiness. However relatively little is known about adult and child speech in childcare settings, in which approximately 30% of American children are enrolled. We examined the influence of teacher and peer language input on children's in-class language use and language development in an intervention classroom for low-SES, high-risk 2- to 3-year-olds. Over the course of a year, day-long recordings of the classroom were collected weekly with LENA recorders. Using LENA software algorithms, we found that language input from peers was positively related to children's in-class language use, both in-the-moment and over the course of each day, as were the number of conversational turns in which children and teachers engaged Both peer input and conversational turns with teachers were also positively related to children's language development rates, as indexed by increases in vocabulary size. Together these results indicate the importance of child-specific rates of classroom language input in the language development of high-risk, preschoolers. PMID- 29979741 TI - Caveat emptor, computational social science: Large-scale missing data in a widely published Reddit corpus. AB - As researchers use computational methods to study complex social behaviors at scale, the validity of this computational social science depends on the integrity of the data. On July 2, 2015, Jason Baumgartner published a dataset advertised to include "every publicly available Reddit comment" which was quickly shared on Bittorrent and the Internet Archive. This data quickly became the basis of many academic papers on topics including machine learning, social behavior, politics, breaking news, and hate speech. We have discovered substantial gaps and limitations in this dataset which may contribute to bias in the findings of that research. In this paper, we document the dataset, substantial missing observations in the dataset, and the risks to research validity from those gaps. In summary, we identify strong risks to research that considers user histories or network analysis, moderate risks to research that compares counts of participation, and lesser risk to machine learning research that avoids making representative claims about behavior and participation on Reddit. PMID- 29979742 TI - Cash incentives versus defaults for HIV testing: A randomized clinical trial. AB - BACKGROUND: Tools from behavioral economics have been shown to improve health related behaviors, but the relative efficacy and additive effects of different types of interventions are not well established. We tested the influence of small cash incentives, defaults, and both in combination on increasing patient HIV test acceptance. METHODS AND FINDINGS: We conducted a randomized clinical trial among patients aged 13-64 receiving care in an urban emergency department. Patients were cross-randomized to $0, $1, $5, and $10 incentives, and to opt-in, active choice, and opt-out test defaults. The primary outcome was the proportion of patients who accepted an HIV test. 4,831 of 8,715 patients accepted an HIV test (55.4%). Those offered no monetary incentive accepted 51.6% of test offers. The $1 treatment did not increase test acceptance (increase 1%; 95% confidence interval [CI] -2.0 to 3.9); the $5 and $10 treatments increased test acceptance rates by 10.5 and 15 percentage points, respectively (95% CI 7.5 to 13.4 and 11.8 to 18.1). Compared to opt-in testing, active-choice testing increased test acceptance by 11.5% (95% CI 9.0 to 14.0), and opt-out testing increased acceptance by 23.9 percentage points (95% CI 21.4 to 26.4). CONCLUSIONS: Small incentives and defaults can both increase patient HIV test acceptance, though when used in combination their effects were less than additive. These tools from behavioral economics should be considered by clinicians and policymakers. How patient groups respond to monetary incentives and/or defaults deserves further investigation for this and other health behaviors. PMID- 29979743 TI - Electric multiple unit circulation plan optimization based on the branch-and price algorithm under different maintenance management schemes. AB - For railway operators, one of many important goals is to improve the utilization efficiency of electric multiple units (EMUs). When operators design EMU circulation plans, EMU type restrictions are critical factors when assigning EMUs to the correct depots for maintenance. However, existing studies only consider that EMUs are maintained at their home depots. However, targeting that problem, in this paper, an optimization model for the EMU circulation planning problem that allows depots to be selected for EMU maintenance is proposed. This model aims at optimizing the number of used EMUs and the number of EMU maintenance tasks and simultaneously incorporates other important constraints, including type restrictions, on EMU maintenance and night accommodation capacity at depots. In order to solve the model, a branch-and-price algorithm is also developed. A case study of a real-world high-speed railway was conducted to compare and analyze the effects of different maintenance location constraints. The results show that the number of EMUs used will decrease under the maintenance sharing scheme, the number of EMU maintenance tasks can be reduced, and the time occupied in EMU maintenance will be released. In addition, the scheme of maintenance resources sharing and increases to mileage limits can effectively decrease the number of EMU maintenance tasks significantly. The model and algorithm can be used as an effective quantitative analysis tool for railway operators' decision-making processes in the EMU circulation planning problem. PMID- 29979744 TI - A 10-year observational study on the trends and determinants of smoking status. AB - INTRODUCTION: Most studies on motivation and intention to quit smoking have been conducted among adolescents and young adults but little is known regarding middle aged subjects. We aimed to assess the trends and determinants of smoking status in a population-based cohort. METHOD: Observational, prospective study with a first mean follow-up at 5.6 years and a second at 10.9 years. Data from 3999 participants (49.2% women, aged 35-75 years) living in Lausanne (Switzerland). RESULTS: Baseline prevalence of never, former and current smokers was 41.3, 34.3 and 24.3%, respectively. During the study period, more than 90% of never and former and almost 60% of current smokers at baseline retained their status after 10.9 years. Among 973 current smokers, 216 (22.2%) had quit for at least 5 years. Multivariable analysis showed increasing age to be positively associated with quitting (p-value for trend <0.001). Among 1373 former smokers, 149 (10.9%) had relapsed; increasing age (p-value for trend <0.001) was negatively associated and family history of lung disease was positively associated with relapse [OR and 95% CI: 1.53 (1.06-2.21)]. Among 1653 never smokers, 128 (7.7%) initiated smoking; Male gender [1.46 (1.01-2.12)] and living in coupled relationship [0.66 (0.45 0.97)] were associated with smoking initiation. CONCLUSION: Most middle-aged never and former smokers did not change their status with time, while 22.2% of current smokers sustained quitting. This is encouraging and could be improved with adequate supportive methods. In comparison to available data, this study confirms the difficult task of identifying subjects at risk of a negative behavioral change. PMID- 29979745 TI - Adequacy of care management of patients with polyhandicap in the French health system: A study of 782 patients. AB - BACKGROUND: The aims of this study were 1) to describe the health profiles and care management of polyhandicapped patients according to 2 modalities, specialized rehabilitation centers (SRC) and residential facilities (RF), and 2) to estimate the adequacy of care management of these patients. METHODS: This was an 18-month cross-sectional study including patients with a combination of severe motor deficiency and profound intellectual impairment. The patients were from 4 SRC and 9 RF. The following data were collected: sociodemographics, health status, care management, and adequacy of care management. RESULTS: A total of 782 patients were included: 410 (52%) were cared for in SRC and 372 (48%) in RF. Global objective adequacy (health severity and age category) was higher for patients cared for in SRC compared with patients cared for in RF (57 vs. 44%, p< = 10-3). Global subjective adequacy (self-perception of the referring physician and request of change in structure) was higher for patients cared for in SRC in comparison with patients cared for in RF (98 vs. 92%, p< = 10-3). CONCLUSIONS: This study provides key elements of adequacy of care management modalities for polyhandicapped patients in France. TRIAL REGISTRATION: ClinicalTrials.gov NCT02400528. PMID- 29979746 TI - Utilizing ExAC to assess the hidden contribution of variants of unknown significance to Sanfilippo Type B incidence. AB - Given the large and expanding quantity of publicly available sequencing data, it should be possible to extract incidence information for monogenic diseases from allele frequencies, provided one knows which mutations are causal. We tested this idea on a rare, monogenic, lysosomal storage disorder, Sanfilippo Type B (Mucopolysaccharidosis type IIIB). Sanfilippo Type B is caused by mutations in the gene encoding alpha-N-acetylglucosaminidase (NAGLU). There were 189 NAGLU missense variants found in the ExAC dataset that comprises roughly 60,000 individual exomes. Only 24 of the 189 missense variants were known to be pathogenic; the remaining 165 variants were of unknown significance (VUS), and their potential contribution to disease is unknown. To address this problem, we measured enzymatic activities of 164 NAGLU missense VUS in the ExAC dataset and developed a statistical framework for estimating disease incidence with associated confidence intervals. We found that 25% of VUS decreased the activity of NAGLU to levels consistent with Sanfilippo Type B pathogenic alleles. We found that a substantial fraction of Sanfilippo Type B incidence (67%) could be accounted for by novel mutations not previously identified in patients, illustrating the utility of combining functional activity data for VUS with population-wide allele frequency data in estimating disease incidence. PMID- 29979747 TI - Optimizing location of variable message signs using GPS probe vehicle data. AB - A multi-objective optimization model is proposed to allocate the location of VMSs by maximizing the average traffic guidance utility of VMSs and the number of benefited links, while minimizing information redundancy. The traffic guidance utility is defined to quantitatively measure the value of an installed VMS, which is calculated from passively collected GPS data and the physical topology of road network. The number of benefited links is to measure how many links are covered by upstream VMS to disseminate information. Information redundancy is introduced to quantify the mutual impairing between any two VMSs. A heuristic search algorithm is developed to solve the optimization model, which can calculate the saturated number of VMS for a road network and optimize the project schedule of VMS installation process based on the proposed objectives. A real-world case study is conducted in Beijing to illustrate the validity of the proposed approach, where taxis are used as probe vehicles to provide GPS data. The results show the effectiveness of the proposed multi-objective optimization model and it is promising to use the emerging GPS data to help agencies to allocate the locations of VMSs on both urban roads and highway networks, instead of relying on the subjective judgment from practitioners. PMID- 29979748 TI - Transcription factor induced conversion of human fibroblasts towards the hair cell lineage. AB - Hearing loss is the most common sensorineural disorder, affecting over 5% of the population worldwide. Its most frequent cause is the loss of hair cells (HCs), the mechanosensory receptors of the cochlea. HCs transduce incoming sounds into electrical signals that activate auditory neurons, which in turn send this information to the brain. Although some spontaneous HC regeneration has been observed in neonatal mammals, the very small pool of putative progenitor cells that have been identified in the adult mammalian cochlea is not able to replace the damaged HCs, making any hearing impairment permanent. To date, guided differentiation of human cells to HC-like cells has only been achieved using either embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs). However, use of such cell types suffers from a number of important disadvantages, such as the risk of tumourigenicity if transplanted into the host's tissue. We have obtained cells expressing hair cell markers from cultures of human fibroblasts by overexpression of GFI1, Pou4f3 and ATOH1 (GPA), three genes that are known to play a critical role in the development of HCs. Immunocytochemical, qPCR and RNAseq analyses demonstrate the expression of genes typically expressed by HCs in the transdifferentiated cells. Our protocol represents a much faster approach than the methods applied to ESCs and iPSCs and validates the combination of GPA as a set of genes whose activation leads to the direct conversion of human somatic cells towards the hair cell lineage. Our observations are expected to contribute to the development of future therapies aimed at the regeneration of the auditory organ and the restoration of hearing. PMID- 29979749 TI - Expectations for dog ownership: Perceived physical, mental and psychosocial health consequences among prospective adopters. AB - Dog ownership is popular worldwide, with most human-dog dyads forming successful attachment bonds. However, millions of dogs are surrendered to animal shelters annually, possibly due to mismatches between owner expectations and the realities of dog ownership. The aim of the current study was to explore the benefits and challenges people expect from dog ownership and how these expectations vary with previous ownership history. An Australian-wide sample of 3465 prospective adopters completed a self-administered online questionnaire about the physical, mental and psychosocial health benefits and challenges they associated with dog ownership. Among the potential benefits, respondents expected increased walking (89%), happiness (89%) and companionship (61%) and decreased stress (74%) and loneliness (61%). Among the challenges, they expected increased responsibility (64%) and dog training (62%). Ownership history influenced respondents' expectations, with previous/current dog owners having consistently greater odds of expecting benefits and reduced odds of expecting challenges than non-owners. A possible explanation is that previous/current dog owners' exhibit bias when considering dog ownership by selectively recalling positive experiences from previous ownership. Our findings support the need for education of prospective dog owners to ensure their expectations align with the reality of ownership, based on current scientific evidence. PMID- 29979750 TI - Effects of virtual reality high heights exposure during beam-walking on physiological stress and cognitive loading. AB - Virtual reality has been increasingly used in research on balance rehabilitation because it provides robust and novel sensory experiences in controlled environments. We studied 19 healthy young subjects performing a balance beam walking task in two virtual reality conditions and with unaltered view (15 minutes each) to determine if virtual reality high heights exposure induced stress. We recorded number of steps off the beam, heart rate, electrodermal activity, response time to an auditory cue, and high-density electroencephalography (EEG). We hypothesized that virtual high heights exposure would increase measures of physiological stress compared to unaltered viewing at low heights. We found that the virtual high height condition increased heart rate variability and heart rate frequency power relative to virtual low heights. Virtual reality use resulted in increased number of step-offs, heart rate, electrodermal activity, and response time compared to the unaltered viewing at low heights condition. Our results indicated that virtual reality decreased dynamic balance performance and increased physical and cognitive loading compared to unaltered viewing at low heights. In virtual reality, we found significant decreases in source-localized EEG peak amplitude relative to unaltered viewing in the anterior cingulate, which is considered important in sensing loss of balance. Our findings indicate that virtual reality provides realistic experiences that can induce physiological stress in humans during dynamic balance tasks, but virtual reality use impairs physical and cognitive performance during balance. PMID- 29979751 TI - Newborn infants' hair cortisol levels reflect chronic maternal stress during pregnancy. AB - Cortisol obtained from hair samples represents a retrospective biomarker of chronic stress experienced by the subject in previous months. Although hair cortisol levels have been used to study the relationship between maternal and neonatal stress levels in primates, this has not yet been performed in humans using a longitudinal design and focusing specifically on this association. Therefore, the objective of this study was to determine whether a relationship existed between maternal psychological stress and hair cortisol levels during pregnancy and postpartum, and neonatal hair cortisol levels. The sample consisted of 80 pregnant women and their 80 newborn infants. We conducted a longitudinal assessment of hair cortisol levels, psychological stress, anxiety, and depression in the three trimesters of pregnancy and postpartum. After childbirth, neonatal hair cortisol levels were also measured. We found that maternal hair cortisol levels in the first trimester negatively predicted neonatal hair cortisol levels. Perceived stress in the third trimester of pregnancy also predicted lower neonatal cortisol, whereas pregnancy-specific stress in the same trimester had a positive relation with neonatal cortisol. Cortisol is essential for embryonic and fetal development; consequently, if fetal synthesis of cortisol is affected by high maternal cortisol levels, such development could be impaired. PMID- 29979752 TI - Response of cord blood cells to environmental, hereditary and perinatal factors: A prospective birth cohort study. AB - BACKGROUND: Many studies investigating the impact of individual risk factors on cord blood immune cell counts may be biased given that cord blood composition is influenced by a multitude of factors. The aim of this study was to comprehensively investigate the relative impact of environmental, hereditary and perinatal factors on cord blood cells. METHODS: In 295 neonates from the prospective Basel-Bern Infant Lung Development Cohort, we performed complete blood counts and fluorescence-activated cell sorting scans of umbilical cord blood. The associations between risk factors and cord blood cells were assessed using multivariable linear regressions. RESULTS: The multivariable regression analysis showed that an increase per 10MUg/m3 of the average nitrogen dioxide 14 days before birth was associated with a decrease in leukocyte (6.7%, 95% CI: 12.1,-1.0) and monocyte counts (11.6%, 95% CI:-19.6,-2.8). Maternal smoking during pregnancy was associated with significantly lower cord blood cell counts in multiple cell populations. Moreover, we observed sex differences regarding eosinophilic granulocytes and plasmacytoid dendritic cells. Finally, significantly increased numbers of cord blood cells were observed in infants exposed to perinatal stress. Cesarean section seems to play a significant role in Th1/Th2 balance. CONCLUSIONS: Our results suggest that all three: environmental, hereditary and perinatal factors play a significant role in the composition of cord blood cells at birth, and it is important to adjust for all of these factors in cord blood studies. In particular, perinatal circumstances seem to influence immune balance, which could have far reaching consequences in the development of immune mediated diseases. PMID- 29979753 TI - Dual sensory impairment: The association between glaucomatous vision loss and hearing impairment and function. AB - BACKGROUND: Hearing impairment, vision impairment, and dual impairment (both hearing and vision impairment), have been independently associated with functional and cognitive decline. In prior studies of dual impairment, vision impairment is generally not defined or defined by visual acuity alone. Glaucoma is a leading cause of blindness and does not affect visual acuity until late in the disease; instead, visual field loss is used to measure vision impairment from glaucoma. OBJECTIVE: To examine the effect of glaucomatous visual field loss and hearing impairment on function. DESIGN: Cross-sectional. SETTING: Hospital-based clinic in Baltimore, Maryland. SUBJECTS: 220 adults, >=55 years presenting to the glaucoma clinic. METHODS: Vision impairment was defined as mean deviation on visual field testing worse than -5 decibels in the better eye, and hearing impairment was defined as pure tone average worse than 25 decibels on threshold audiometry testing in the better ear. Standardized questionnaires were used to assess functional status. RESULTS: Five participants were excluded for incomplete testing, leaving 32 with vision impairment only, 63 with hearing impairment only, 42 with dual impairment, and 78 controls with no hearing impairment or vision impairment. Participants with dual impairment were more likely to be older and non-White. Dual impairment was associated with significantly more severe driving limitation and more difficulty with communication compared to those without sensory impairment when adjusted for age, race, gender and number of comorbidities. CONCLUSION: Older individuals with glaucoma and hearing loss seem to have generally poorer functioning than those with single sensory loss. Health professionals should consider visual field loss as a type of vision impairment when managing patients with dual impairment. PMID- 29979754 TI - Yeast lifespan variation correlates with cell growth and SIR2 expression. AB - Isogenic wild type yeast cells raised in controlled environments display a significant range of lifespan variation. Recent microfluidic studies suggest that differential growth or gene expression patterns may explain some of the heterogeneity of aging assays. Herein, we sought to complement this work by similarly examining a large set of replicative lifespan data from traditional plate assays. In so doing, we reproduced the finding that short-lived cells tend to arrest at senescence with a budded morphology. Further, we found that wild type cells born unusually small did not have an extended lifespan. However, large birth size and/or high inter-generational growth rates significantly correlated with a reduced lifespan. Finally, we found that SIR2 expression levels correlated with lifespan and intergenerational growth. SIR2 expression was significantly reduced in large cells and increased in small wild type cells. A moderate increase in SIR2 expression correlated with reduced growth, decreased proliferation and increased lifespan in plate aging assays. We conclude that cellular growth rates and SIR2 expression levels may contribute to lifespan variation in individual cells. PMID- 29979755 TI - Association between blood lead level and blood pressure: An occupational population-based study in Jiangsu province, China. AB - Studies about the association between lead exposure and the elevation of blood pressure and risk of hypertension are varied, while available data on blood lead levels (BLL) in workers with lead-exposure are scarce. This research aimed to evaluate associations between BLL and blood pressure in an occupational population-based study in Jiangsu province, China. We enrolled 21,688 workers in this study. Information on socioeconomic and occupational background was obtained with face-to-face interviews. BLL, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured, and hypertension status was confirmed. We found that workers in mini-factories had the highest average BLL (20.3 MUg/dL; 95% CI, 19.0-21.6 MUg/dL) for overall participants. The employees in private factories had higher BLL (9.6 MUg/dL; 95% CI, 9.5-9.8 MUg/dL). However, BLL was much lower (4.0 MUg/dL; 95%CI, 3.7-4.2 MUg/dL) in state-owned factories. Participants working in the electrical machinery and equipment manufacturing industry had higher BLL (9.1 MUg/dL; 95% CI, 9.0-9.3MUg/dL). Compared to those workers with <= 4.6 MUg/dL BLL, workers with > 17.5 MUg/dL BLL presented 1.34 mmHg and 0.70 mmHg average difference in SBP and DBP, respectively. The adjusted OR for hypertension was 1.11 (95%CI, 1.08-1.15) compared to the workers with > 17.5 MUg/dL BLL and to those with <= 4.6 MUg/dL BLL. In summary, we found that BLL was positively associated with SBP and DBP and with the morbidity of hypertension in occupational populations with a high concentration of lead exposure. It is important to formulate new standards of blood lead levels to screen for elevated lead exposure. In addition, a series of new systems of risk assessment should be established to further reduce and prevent lead exposure. PMID- 29979756 TI - Pesticide residue survey of pollen loads collected by honeybees (Apis mellifera) in daily intervals at three agricultural sites in South Germany. AB - In agricultural landscapes honeybees and other pollinators are exposed to pesticides, often surveyed by residue analysis of bee bread. However, bee bread is a mixture of pollen pellets of different plants collected over a longer time period. Therefore, pesticide content in the hive varies with plant species and time of pollen collection. Hence, the analysis of bee bread is an approximate approach to gain information on detailed pesticide exposure during the agronomic active season. As high-resolution data is missing, we carried out a pesticide residue survey over five years (2012-2016) of daily collected pollen pellets at three agricultural distinct sites in southern Germany. 281 single day pollen samples were selected and subjected to a multi-pesticide residue analysis. Pesticide contaminations of pollen differed between the sites. Intensive pesticide exposure can be seen by high pesticide concentrations as well as a high amount of different pesticides detected. During the five years of observation 73 different pesticides were found, of which 84% are characterized as non-harmful to honeybees. To estimate pesticide risks for honeybees, the pollen hazard quotient (PHQ) was calculated. Even though pesticides were detected in sublethal concentrations, we found substances not supposed to be exposed to honey bees, indicating the necessity for further improvement of seed treatments and increasing awareness of flowering shrubs, field margins and pesticide drift. Additionally, an in-depth analysis of nine pollen samples, divided into sub fractions dominated by single plant species, revealed even higher concentrations in single crops for some pesticides. We give precise residue data of 1,657 single pesticide detections, which should be used for realistic laboratory and field tests. PMID- 29979757 TI - Health-related quality of life, neuropsychiatric symptoms and structural brain changes in clinically isolated syndrome. AB - BACKGROUND: Neuropsychiatric symptoms and reduced health-related quality of life (HRQoL) are frequent in multiple sclerosis, where are associated with structural brain changes, but have been less studied in clinically isolated syndrome (CIS). OBJECTIVE: To characterize HRQoL, neuropsychiatric symptoms (depressive symptoms, anxiety, apathy and fatigue), their interrelations and associations with structural brain changes in CIS. METHODS: Patients with CIS (n = 67) and demographically matched healthy controls (n = 46) underwent neurological and psychological examinations including assessment of HRQoL, neuropsychiatric symptoms and cognitive functioning, and MRI brain scan with global, regional and lesion load volume measurement. RESULTS: The CIS group had more, mostly mild, depressive symptoms and anxiety, and lower HRQoL physical and social subscores (p<=0.037). Neuropsychiatric symptoms were associated with most HRQoL subscores (beta<=-0.34, p<=0.005). Cognitive functioning unlike clinical disability was associated with depressive symptoms and lower HRQoL emotional subscores (beta<= 0.29, p<=0.019). Depressive symptoms and apathy were associated with right temporal, left insular and right occipital lesion load (beta>=0.29, p<=0.032). Anxiety was associated with lower white matter volume (beta = -0.25, p = 0.045). CONCLUSION: Mild depressive symptoms and anxiety with decreased HRQoL are present in patients with CIS. Neuropsychiatric symptoms contributing to decreased HRQoL are the result of structural brain changes and require complex therapeutic approach in patients with CIS. PMID- 29979758 TI - Inflammatory proteins in maternal plasma, cervicovaginal and amniotic fluids as predictors of intra-amniotic infection in preterm premature rupture of membranes. AB - OBJECTIVE: We aimed to assess the correlations among multiple cytokine concentrations in the maternal plasma, cervicovaginal fluid (CVF), and amniotic fluid (AF) compartments in women with preterm premature rupture of membranes (pPROM), and to develop a prediction model based on non-invasive measures, having better sensitivity and specificity for the identification of microbial invasion of amniotic cavity (MIAC). METHOD: This retrospective study included 75 consecutive women with pPROM (20+0-34+0 weeks), who underwent amniocentesis. Both maternal plasma and CVF samples were collected at the time of amniocentesis. Stored AF, plasma and CVF samples were assayed for cytokine levels [interleukin (IL)-6, IL-8, monocyte chemotactic protein-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta] using a multiplex immunoassay kit. RESULTS: Levels of inflammatory proteins measured in the CVF were significantly correlated with AF proteins levels, whereas none of the proteins in plasma correlated significantly with any in the AF or CVF. Proteins levels measured in the AF and CVF were significantly higher in women with MIAC compared to those without, whereas only high levels of IL-6 in plasma were significantly associated with MIAC. By using stepwise regression analysis, a non-invasive model (using clinical factors and CVF cytokine levels) for the prediction of MIAC was developed; the area under curve of this non-invasive model was similar to that of the invasive model (using clinical factors and AF cytokines). CONCLUSIONS: The levels of inflammatory proteins in the CVF correlated with those in the AF, whereas those in the plasma showed no correlation. A non-invasive model using clinical factors and CVF cytokine levels predicted the risk of MIAC in women with pPROM. PMID- 29979760 TI - Tracing anthropogenic inputs in stream foods webs with stable carbon and nitrogen isotope systematics along an agricultural gradient. AB - Stable carbon (13C) and nitrogen isotopes (15N) are useful tools in determining the presence of agricultural influences in freshwater ecosystems. Here we examined delta15N and delta13C signatures in nitrate, fish, and mussel tissues, from rivers in Southern Ontario, Canada, that vary in their catchment proportion of agriculture land use, nutrients and organic matter quality. We found comparatively 15N-enriched delta15N values in animal tissues and dissolved nitrates, relative to expected values characterized by natural sources. We also observed a strong, positive correlation between riparian agriculture percentages and delta15N values in animal tissues and nitrates, indicating a significant influence of agricultural land use and the probable dominance of organic fertilizer and manure inputs in particular. The use of a 15N-based equation for the estimation of fish trophic position confirmed dietary analyses is showing all fish species to be tertiary consumers, with a relatively consistent 15N enrichment in animal tissues between trophic levels. This indicates that variability in 15N-trophic fractionation is minor, and that fish and mussel tissue delta15N values are largely representative of source nitrogen. However, the trophic fractionation value varied from accepted literature values, suggesting strong influences from either local environmental conditions or dietary variation. The delta13C datasets did not correlate with riparian agriculture, and animal delta13C signatures in their tissues are consistent with terrestrial C3 vegetation, suggesting the dominance of allochthonous DOC sources. We found that changes in water chemistry and dissolved organic matter quality brought about by agricultural inputs were clearly expressed in the delta15N signatures of animal tissues from all trophic levels. As such, this study confirmed the source of anthropogenic nitrogen in the studied watersheds, and demonstrated that this agriculturally-derived nitrogen could be traced with delta15N signatures through successive trophic levels in local aquatic food webs. The delta13C data was less diagnostic of local agriculture, due to the more complex interplay of carbon cycling and environmental conditions. PMID- 29979759 TI - Characterization of two related Erwinia myoviruses that are distant relatives of the PhiKZ-like Jumbo phages. AB - Bacteriophages are a major force in the evolution of bacteria due to their sheer abundance as well as their ability to infect and kill their hosts and to transfer genetic material. Bacteriophages that infect the Enterobacteriaceae family are of particular interest because this bacterial family contains dangerous animal and plant pathogens. Herein we report the isolation and characterization of two jumbo myovirus Erwinia phages, RisingSun and Joad, collected from apple trees. These two genomes are nearly identical with Joad harboring two additional putative gene products. Despite mass spectrometry data that support the putative annotation, 43% of their gene products have no significant BLASTP hit. These phages are also more closely related to Pseudomonas and Vibrio phages than to published Enterobacteriaceae phages. Of the 140 gene products with a BLASTP hit, 81% and 63% of the closest hits correspond to gene products from Pseudomonas and Vibrio phages, respectively. This relatedness may reflect their ecological niche, rather than the evolutionary history of their host. Despite the presence of over 800 Enterobacteriaceae phages on NCBI, the uniqueness of these two phages highlights the diversity of Enterobacteriaceae phages still to be discovered. PMID- 29979761 TI - Comparative risk assessment of school food environment policies and childhood diets, childhood obesity, and future cardiometabolic mortality in the United States. AB - BACKGROUND: Promising school policies to improve children's diets include providing fresh fruits and vegetables (F&V) and competitive food restrictions on sugar-sweetened beverages (SSBs), yet the impact of national implementation of these policies in US schools on cardiometabolic disease (CMD) risk factors and outcomes is not known. Our objective was to estimate the impact of national implementation of F&V provision and SSB restriction in US elementary, middle, and high schools on dietary intake and body mass index (BMI) in children and future CMD mortality. METHODS: We used comparative risk assessment (CRA) frameworks to model the impacts of these policies with input parameters from nationally representative surveys, randomized-controlled trials, and systematic reviews and meta-analyses. For children ages 5-18 years, this incorporated national data on current dietary intakes and BMI, impacts of these policies on diet, and estimated effects of dietary changes on BMI. In adults ages 25 and older, we further incorporated the sustainability of dietary changes to adulthood, effects of dietary changes on CMD, and national CMD death statistics, modeling effects if these policies had been in place when current US adults were children. Uncertainty across inputs was incorporated using 1000 Monte Carlo simulations. RESULTS: National F&V provision would increase daily fruit intake in children by as much as 25.0% (95% uncertainty interval (UI): 15.4, 37.7%), and would have small effects on vegetable intake. SSB restriction would decrease daily SSB intake by as much as 26.5% (95% UI: 6.4, 46.4%), and reduce BMI by as much as 0.7% (95% UI: 0.2, 1.2%). If F&V provision and SSB restriction were nationally implemented, an estimated 22,383 CMD deaths/year (95% UI: 18735, 25930) would be averted. CONCLUSION: National school F&V provision and SSB restriction policies implemented in elementary, middle, and high schools could improve diet and BMI in children and reduce CMD mortality later in life. PMID- 29979762 TI - Changes in perceived scientific consensus shift beliefs about climate change and GM food safety. AB - Despite an overwhelming scientific consensus, a sizable minority of people doubt that human activity is causing climate change. Communicating the existence of a scientific consensus has been suggested as a way to correct individuals' misperceptions about human-caused climate change and other scientific issues, though empirical support is mixed. We report an experiment in which psychology students were presented with consensus information about two issues, and subsequently reported their perception of the level of consensus and extent of their endorsement of those issues. We find that messages about scientific consensus on the reality of anthropogenic climate change and the safety of genetically modified food shift perceptions of scientific consensus. Using mediation models we also show that, for both these issues, high consensus messages also increase reported personal agreement with the scientific consensus, mediated by changes in perceptions of a scientific consensus. This confirms the role of perceived consensus in informing personal beliefs about climate change, though results indicate the impact of single, one-off messages may be limited. PMID- 29979763 TI - The dilemma of agricultural pollination in Brazil: Beekeeping growth and insecticide use. AB - Pollination by bees improves agricultural crop yields and improves the financial outlook of beekeepers because it increases honey production and hive rental revenues. However, in Brazil, with a few exceptions, these benefits have been neglected in recent years because beekeepers are more interested in honey production than in agricultural pollination. The excessive and indiscriminate use of insecticides on agricultural fields in Brazil appears to be one of the principal obstacles preventing partnership between farmers and beekeepers. The goal of this study was therefore to evaluate the most recent situation in Brazil in relation to the use of insecticides, agriculture and to honey production in comparison with other countries. Our results show that Brazil is the largest consumer of insecticides in the world and that consumption has increased by > 150% over 15 years. While countries with a high Human Development Index (i.e., a measure that can also be used to question national policy choices) are reducing their levels of insecticide use in agriculture, Brazil is going in the opposite direction. It is highly likely the increase seen in other countries is a result of alternative methods for pest control rather than a result of the amount of area under agricultural cultivation and their capability to shift their economies from agriculture to other sectors. The number of hives (23%) and the volume of honey production (72%) in Brazil have, however, increased over the same period, raising Brazil to the ninth highest honey producer in the world. Although the data on apiculture are promising, the growth in use of insecticides in Brazil is a cause for concern because they leave residuals on bee products, on crops, and in the environment. Civil society and government in Brazil should encourage reductions in insecticide use and better relations between agricultural farmers and beekeepers. PMID- 29979765 TI - Identification of multiple genes encoding SnRK1 subunits in potato tuber. AB - BACKGROUND: Many studies have proven the importance of SnRK1 in the regulation of carbohydrate metabolism and plant development. Compared to Arabidopsis, much less is known about SnRK1 complexes in crop plants, and therefore, more work needs to be done to identify SnRK1 genes and to investigate their function in crop plants. METHODS: In this study we identified five SnRK1-related genes in potato by analyzing the potato genome through BLAST, which encode one alpha-subunit isoform (stKIN), two beta-subunit isoforms (stKINbeta1 and stKINbeta2) and two gamma subunit isoforms (stKINgamma and stKINbetagamma). To investigate the functions of SnRK1 in the tuber development of potato, we further made overexpression and RNAi transgenic plants of these five genes. Based on these overexpression transgenic plants, the Fast protein liquid chromatography (FPLC) were employed to purify SnRK1 complexes, which were tracked by western-blot. RESULTS: Experiments in vivo and in vitro showed that these five proteins in potato are functional SNF1/AMPK/SnRK1-related proteins. The SnRK1 activity decreased by 60% in the RNAi transgenic lines of stKIN; the starch content increased by 25% in the overexpression transgenic lines of stKIN, compared to that in the wild-type lines, whereas there is no significant difference in SnRK1 activity and starch content in the RNAi transgenic or overexpression lines of stKINbeta1, stKINbeta2, stKINgamma and stKINbetagamma. In addition, we found that a few different SnRK1 complexes are present in potato by partially purifying SnRK1 complexes from these overexpression transgenic plants. CONCLUSIONS: Five functional SnRK1-related genes were identified in potato, including three novel genes, which encode one alpha-subunit isoform (stKIN), two beta-subunit isoforms (stKINbeta1 and stKINbeta2) and two gamma-subunit isoforms (stKINgamma and stKINbetagamma). We found that a few SnRK1 related genes are present in potato tuber, which form several different SnRK1 isoenzymes. We found that stKIN is the primary alpha subunit of SnRK1 in potato tuber and plays important roles in the development of potato tubers. PMID- 29979764 TI - Canine seroprevalence to Orientia species in southern Chile: A cross-sectional survey on the Chiloe Island. AB - BACKGROUND: Scrub typhus is a potentially life-threatening vector-borne infection caused by Orientia species. It occurs mainly in the Asian-Pacific region, where it causes significant morbidity and mortality. Recently, an endemic focus of scrub typhus has been described in South America, on Chiloe Island in southern Chile. Dogs have been used as sentinel hosts to determine the presence and spatial distribution of various vector-borne infections. Their suitability to gain insight into human exposure to Orientia tsutsugamushi has been suggested in studies from Asia. METHODOLOGY: In January 2016, we conducted a cross-sectional study, which included the two main cities on Chiloe Island. Canine blood samples were obtained in households, chosen by double stratified random sampling in urban and by convenience in rural locations. Specimens were tested by ELISA for IgG antibodies against whole-cell antigen preparations from three strains of O. tsutsugamushi. Data were further analyzed for factors associated with seropositivity including spatial clustering. RESULTS: Serum samples from 202 dogs (104 urban, 98 rural) were tested for IgG against O. tsutsugamushi, of which 43 (21.3%) were positive. Seroprevalence rates were higher in rural than in urban settings (p<0.01) and in older compared to younger dogs (p<0.01). Spatial analysis by LISA indicated the presence of four localities of highly grouped cases. CONCLUSIONS: The detected seroprevalence supports the endemicity of scrub typhus in southern Chile and suggests a wide exposure of household dogs to the infected, yet unknown vector(s). The spatial data will be used for future research identifying further human cases as well as the local vector(s)/reservoirs for scrub typhus in southern Chile. The study reinforces that dogs are useful sentinels for Orientia spp. in regions of uncertain endemicity and distribution. PMID- 29979766 TI - "I am not promiscuous enough!": Exploring the low uptake of HIV testing by gay men and other men who have sex with men in Metro Manila, Philippines. AB - The Philippines faces a severe HIV epidemic among gay and other men who have sex with men (MSM). HIV testing uptake remains low. A case series of 12 men from Metro Manila were interviewed to explore barriers to uptake of HIV testing services. Most did not see the need to get tested for HIV despite significant risk, based on the misconception they were feeling well or showed no symptoms. Being of a higher socioeconomic class, feeling morally superior to other gay men, distance of the testing facility, fear of what will happen once infected, fear of HIV- and sexual stigma, fear of side effects of antiretroviral drugs and fear of high health care expenses after testing positive for HIV were key reasons why MSM kept postponing their test. Misconceptions about HIV risk, disease, and treatment and care need to be addressed in order to increase uptake of HIV services in this population. PMID- 29979767 TI - Determinants of high mountain plant diversity in the Chilean Andes: From regional to local spatial scales. AB - Mountains are considered excellent natural laboratories for studying the determinants of plant diversity at contrasting spatial scales. To gain insights into how plant diversity is structured at different spatial scales, we surveyed high mountain plant communities in the Chilean Andes where man-driven perturbations are rare. This was done along elevational gradients located at different latitudes taking into account factors that act at fine scales, including abiotic (potential solar radiation and soil quality) and biotic (species interactions) factors, and considering multiple spatial scales. Species richness, inverse of Simpson's concentration (Dequiv), beta-diversity and plant cover were estimated using the percentage of cover per species recorded in 34 sites in the different regions with contrasted climates. Overall, plant species richness, Dequiv and plant cover were lower in sites located at higher latitudes. We found a unimodal relationship between species richness and elevation and this pattern was constant independently of the regional climatic conditions. Soil quality decreased the beta-diversity among the plots in each massif and increased the richness, the Dequiv and cover. Segregated patterns of species co-occurrence were related to increases in richness, Dequiv and plant cover at finer scales. Our results showed that elevation patterns of alpine plant diversity remained constant along the regions although the mechanisms underlying these diversity patterns may differ among climatic regions. They also suggested that the patterns of plant diversity in alpine ecosystems respond to a series of factors (abiotic and biotic) that act jointly at different spatial scale determining the assemblages of local communities, but their importance can only be assessed using a multi-scale spatial approach. PMID- 29979768 TI - HappyTools: A software for high-throughput HPLC data processing and quantitation. AB - High-performance liquid chromatography (HPLC) is widely used for absolute quantitation. The advent of new columns and HPLC technology has enabled higher sample throughput, and hence, larger scale studies that perform quantitation on different sample types (e.g. healthy controls vs. patients with rheumatoid arthritis) using HPLC are becoming feasible. However, there remains a lack of methods that can analyse the increased number of HPLC samples. To address this in part, the modular toolkit HappyTools has been developed for the high-throughput targeted quantitation of HPLC measurements. HappyTools enables the user to create an automated workflow that includes retention time (tr) calibration, data extraction and the calculation of several quality criteria for data curation. HappyTools has been tested on a biopharmaceutical standard and previously published clinical samples. The results show comparable accuracy between HappyTools, Waters Empower and ThermoFisher Chromeleon. However, HappyTools offered superior precision and throughput when compared with Waters Empower and ThermoFisher Chromeleon. HappyTools is released under the Apache 2.0 license, both the source code and a Windows binary can be freely downloaded from https://github.com/Tarskin/HappyTools. PMID- 29979769 TI - A multi-modal recruitment strategy using social media and internet-mediated methods to recruit a multidisciplinary, international sample of clinicians to an online research study. AB - BACKGROUND: Challenges exist in recruiting an international sample of clinicians and researchers to an online survey. Traditional recruitment methods remain relevant but issues such as narrow geographical reach, high cost and time intensity limit what can be achieved when aiming to recruit an international, multi-disciplinary sample. Internet-mediated and social media approaches to recruitment and engagement offer new, untested ways of capitalizing upon existing professional networks. OBJECTIVE: To develop, use and appraise a multi-modal recruitment strategy for an online, international survey regarding the management of shoulder pain. METHODS: Traditional recruitment methods were combined with internet-mediated recruitment methods to form a multi-modal recruitment strategy. An overview of the development of this three-month recruitment strategy is provided and the value and role of each strand of the recruitment strategy discussed. RESULTS: In response to the multi-modal recruitment strategy, data was received from 565 clinicians and researchers from 31 countries (64% UK). Complete data was received from 387 respondents with no demographic differences between respondents who completed, and those who started but did not complete the survey. Over 30% of responses were received within 1 week, 50% within 4 weeks and 81% within 8 weeks. CONCLUSIONS: This study shows the acceptability and international, multidisciplinary reach of a low cost multi-modal recruitment strategy for an online survey of international clinicians and researchers. Incorporating the use of social media proved to be an effective, time and resource-efficient recruitment strategy for this online survey and appeared to enhance clinician engagement. A multimodal recruitment strategy is worthy of consideration for future online surveys of clinicians and researchers. PMID- 29979770 TI - Effects of lobeglitazone on insulin resistance and hepatic steatosis in high-fat diet-fed mice. AB - Lobeglitazone (Lobe) is a novel thiazolidinedione antidiabetic drug that reduces insulin resistance by activating peroxisome proliferator-activated receptor-gamma (PPARgamma). However, the exact mechanisms of antidiabetic effects of Lobe have not been established in an animal model. The aim of this study was to evaluate the hypoglycemic effects of Lobe and investigate possible factors involved in Lobe-enhanced hepatic steatosis in high-fat diet (HFD)-fed mice. Mice were fed an HFD for 15 weeks. Lobe was administrated orally during the last 9 weeks. Lobe treatment significantly reduced insulin resistance and increased expression of hepatic glucose transporter 4 (GLUT4) and PPARs in HFD-fed mice. However, increased body weight and hepatic steatosis were not reduced by Lobe in these mice. Metabolomics fingerprinting showed that several lipogenesis-related hepatic and serum metabolites in HFD-fed mice had positive or negative correlations with Lobe administration. In particular, increased leptin levels during HFD were further increased by Lobe. HFD-induced signaling transducer and activator of transcription 3 (STAT3) phosphorylation in the hypothalamus was increased by Lobe. In addition, immunohistochemical analysis showed more proopiomelanocortin (POMC)-positive neurons in the hypothalamus of HFD-fed mice (with or without Lobe) compared with normal diet-fed mice. Despite improving leptin signaling in the hypothalamus and enhancing insulin sensitivity in HFD-fed mice, Lobe increased body weight and steatosis. Further research is necessary regarding other factors affecting Lobe-enhanced hepatic steatosis and hyperphagia. PMID- 29979771 TI - Innate immune functions of avian intestinal epithelial cells: Response to bacterial stimuli and localization of responding cells in the developing avian digestive tract. AB - Intestinal epithelial cells are multi-tasked cells that participate in digestion and absorption as well as in protection of the digestive tract. While information on the physiology and immune functions of intestinal epithelial cells in mammals is abundant, little is known of their immune function in birds and other species. Our main objectives were to study the development of anti-bacterial innate immune functions in the rapidly developing gut of the pre- and post-hatch chick and to determine the functional diversity of epithelial cells. After establishing primary intestinal epithelial cell cultures, we demonstrated their capacity to uptake and process bacteria. The response to bacterial products, LPS and LTA, induced expression of pro-inflammatory cytokine genes (IL-6, IL-18) as well as the expression of the acute phase proteins avidin, lysozyme and the secretory component derived from the polymeric immunoglobulin receptor. These proteins were then localized in gut sections, and the goblet cell was shown to store avidin, lysozyme as well as secretory component. Lysozyme staining was also located in a novel rod-shaped intestinal cell, situated at different loci along the villus, thus deviating from the classical Paneth cell in the mammal, that is restricted to crypts. Thus, in the chicken, the intestinal epithelium, and particularly goblet cells, are committed to innate immune protection. The unique role of the goblet cell in chicken intestinal immunity, as well as the unique distribution of lysozyme-positive cells highlight alternative solutions of gut protection in the bird. PMID- 29979772 TI - The genome assembly of the fungal pathogen Pyrenochaeta lycopersici from Single Molecule Real-Time sequencing sheds new light on its biological complexity. AB - The first draft genome sequencing of the non-model fungal pathogen Pyrenochaeta lycopersici showed an expansion of gene families associated with heterokaryon incompatibility and lacking of mating-type genes, providing insights into the genetic basis of this "imperfect" fungus which lost the ability to produce the sexual stage. However, due to the Illumina short-read technology, the draft genome was too fragmented to allow a comprehensive characterization of the genome, especially of the repetitive sequence fraction. In this work, the sequencing of another P. lycopersici isolate using long-read Single Molecule Real Time sequencing technology was performed with the aim of obtaining a gapless genome. Indeed, a gapless genome assembly of 62.7 Mb was obtained, with a fraction of repetitive sequences representing 30% of the total bases. The gene content of the two P. lycopersici isolates was very similar, and the large difference in genome size (about 8 Mb) might be attributable to the high fraction of repetitive sequences detected for the new sequenced isolate. The role of repetitive elements, including transposable elements, in modulating virulence effectors is well established in fungal plant pathogens. Moreover, transposable elements are of fundamental importance in creating and re-modelling genes, especially in imperfect fungi. Their abundance in P. lycopersici, together with the large expansion of heterokaryon incompatibility genes in both sequenced isolates, suggest the presence of possible mechanisms alternative to gene re assorting mediated by sexual recombination. A quite large fraction (~9%) of repetitive elements in P. lycopersici, has no homology with known classes, strengthening this hypothesis. The availability of a gapless genome of P. lycopersici allowed the in-depth analysis of its genome content, by annotating functional genes and TEs. This goal will be an important resource for shedding light on the evolution of the reproductive and pathogenic behaviour of this soilborne pathogen and the onset of a possible speciation within this species. PMID- 29979773 TI - Severe persistent hypocholesterolemia after emergency gastrointestinal surgery predicts in-hospital mortality in critically ill patients with diffuse peritonitis. AB - BACKGROUND: Plasma cholesterol acts as a negative acute phase reactant. Total cholesterol decreases after surgery and in various pathological conditions, including trauma, sepsis, burns, and liver dysfunction. This study aimed to determine whether hypocholesterolemia after emergency gastrointestinal (GI) surgery is associated with in-hospital mortality in patients with diffuse peritonitis. METHODS: The medical records of 926 critically ill patients who had undergone emergency GI surgery for diffuse peritonitis, between January 2007 and December 2015, were retrospectively analyzed. The integrated areas under the curve (iAUCs) were calculated to compare the predictive accuracy of total cholesterol values from postoperative days (PODs) 0, 1, 3, and 7. Cox proportional hazard regression modeling was performed for all possible predictors identified in the univariate and multivariable analyses. RESULTS: The total cholesterol level measured on POD 7 had the highest iAUC (0.7292; 95% confidence interval, 0.6696-0.7891) and was significantly better at predicting in-hospital mortality than measurements on other days. The optimal total cholesterol cut-off value for predicting in-hospital mortality was 61 mg/dL and was determined on POD 7. A Cox proportional hazard regression analysis revealed that a POD 7 total cholesterol level < 61 mg/dL was an independent predictor of in-hospital mortality after emergency GI surgery (hazard ratio, 3.961; 95% confidence interval, 1.786-8.784). CONCLUSION: Severe persistent hypocholesterolemia (<61 mg/dL) on POD 7 independently predicted in-hospital mortality, after emergency GI surgery, in critically ill patients with diffuse peritonitis. PMID- 29979774 TI - Testing the link between visual suppression and intelligence. AB - The impairment to discriminate the motion direction of a large high contrast stimulus or to detect a stimulus surrounded by another one is called visual suppression and is the result of the normal function of our visual inhibitory mechanisms. Recently, Melnick et al. (2013), using a motion discrimination task, showed that intelligence strongly correlates with visual suppression (r = 0.71). Cook et al. (2016) also showed a strong link between contrast surround suppression and IQ (r = 0.87), this time using a contrast matching task. Our aim is to test this link using two different visual suppression tasks: a motion discrimination task and a contrast detection task. Fifty volunteers took part in the experiments. Using Bayesian staircases, we measured duration thresholds in the motion experiment and contrast thresholds in the spatial experiment. Although we found a much weaker effect, our results from the motion experiment still replicate previous results supporting the link between motion surround suppression and IQ (r = 0.43). However, our results from the spatial experiment do not support the link between contrast surround suppression and IQ (r = -0.09). Methodological differences between this study and previous studies which could explain these discrepancies are discussed. PMID- 29979775 TI - Soluble amyloid-beta buffering by plaques in Alzheimer disease dementia versus high-pathology controls. AB - An unanswered question regarding Alzheimer disease dementia (ADD) is whether amyloid-beta (Abeta) plaques sequester toxic soluble Abeta species early during pathological progression. We previously reported that the concentration of soluble Abeta aggregates from patients with mild dementia was higher than soluble Abeta aggregates from patients with modest Abeta plaque burden but no dementia. The ratio of soluble Abeta aggregate concentration to Abeta plaque area fully distinguished these groups of patients. We hypothesized that initially plaques may serve as a reservoir or sink for toxic soluble Abeta aggregates, sequestering them from other targets in the extracellular space and thereby preventing their toxicity. To initially test a generalized version of this hypothesis, we have performed binding assessments using biotinylated synthetic Abeta1-42 peptide. Abeta1-42-biotin peptide was incubated on unfixed frozen sections from non demented high plaque pathology controls and patients with ADD. The bound peptide was measured using ELISA and confocal microscopy. We observed no quantitative difference in Abeta binding between the groups using either method. Further testing of the buffering hypothesis using various forms of synthetic and human derived soluble Abeta aggregates will be required to definitively address the role of plaque buffering as it relates to ADD. PMID- 29979776 TI - Stress tolerance in diapausing embryos of Artemia franciscana is dependent on heat shock factor 1 (Hsf1). AB - Embryos of the crustacean, Artemia franciscana, may undergo oviparous development, forming encysted embryos (cysts) that are released from females and enter diapause, a state of suppressed metabolism and greatly enhanced stress tolerance. Diapause-destined embryos of A. franciscana synthesize three small heat shock proteins (sHsps), p26, ArHsp21 and ArHsp22, as well as artemin, a ferritin homologue, all lacking in embryos that develop directly into nauplii. Of these diapause-specific molecular chaperones, p26 and artemin are important contributors to the extraordinary stress tolerance of A. franciscana cysts, but how their synthesis is regulated is unknown. To address this issue, a cDNA for heat shock factor 1 (Hsf1), shown to encode a protein similar to Hsf1 from other organisms, was cloned from A. franciscana. Hsf1 was knocked down by RNA interference (RNAi) in nauplii and cysts of A. franciscana. Nauplii lacking Hsf1 died prematurely upon release from females, showing that this transcription factor is essential to the survival of nauplii. Diapause cysts with diminished amounts of Hsf1 were significantly less stress tolerant than cysts containing normal levels of Hsf1. Moreover, cysts deficient in Hsf1 possessed reduced amounts of p26, ArHsp21, ArHsp22 and artemin, revealing dependence on Hsf1 for expression of their genes and maximum stress tolerance. The results demonstrate an important role for Hsf1, likely in concert with other transcription factors, in the survival and growth of A. franciscana and in the developmentally regulated synthesis of proteins responsible for the stress tolerance of diapausing A. franciscana cysts. PMID- 29979778 TI - Remaining capacity estimation of lithium-ion batteries based on the constant voltage charging profile. AB - Estimation of remaining capacity is essential for ensuring the safety and reliability of lithium-ion batteries. In actual operation, batteries are seldom fully discharged. For a constant current-constant voltage charging mode, the incomplete discharging process affects not only the initial state but also processed variables of the subsequent charging profile, thereby mainly limiting the applications of many feature-based capacity estimation methods which rely on a whole cycling process. Since the charging information of the constant voltage profile can be completely saved whether the battery is fully discharged or not, a geometrical feature of the constant voltage charging profile is extracted to be a new aging feature of lithium-ion batteries under the incomplete discharging situation in this work. By introducing the quantum computing theory into the classical machine learning technique, an integrated quantum particle swarm optimization-based support vector regression estimation framework, as well as its application to characterize the relationship between extracted feature and battery remaining capacity, are presented and illustrated in detail. With the lithium-ion battery data provided by NASA, experiment and comparison results demonstrate the effectiveness, accuracy, and superiority of the proposed battery capacity estimation framework for the not entirely discharged condition. PMID- 29979777 TI - Linagliptin unmasks specific antioxidant pathways protective against albuminuria and kidney hypertrophy in a mouse model of diabetes. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects on diabetic kidney disease (DKD) via specific antioxidant pathways. The DPP-4 inhibitor, linagliptin, was evaluated with the hypothesis that DPP-4 inhibition would ameliorate the development of DKD in a glucose-independent manner by altering specific antioxidant function. METHODS: DBA/2J mice (a well characterized model of DKD) and glucose 6-phosphate dehydrogenase (G6PD) deficient mice (a model of impaired antioxidant function) were evaluated. Diabetes was induced by streptozotocin. Mice were divided into: diabetic (DM), diabetic+linagliptin (DM+Lina), and non-diabetic control and treated for 12 weeks. RESULTS: In DBA/2J mice, there was no difference in body weight and blood glucose between DM and DM+Lina groups. Linagliptin ameliorated albuminuria and kidney hypertrophy in DM DBA/2J mice and specifically increased the mRNA and protein levels for the antioxidants catalase and MnSOD. In G6PD deficient mice, however, increases in these mRNA levels did not occur and linagliptin renoprotection was not observed. Linagliptin also ameliorated histological trends toward mesangial expansion in wild-type mice but not in G6PD deficient mice. CONCLUSIONS: Linagliptin renoprotection involved glucose-independent but antioxidant-enzyme-system-dependent increases in transcription (not just increased protein levels) of antioxidant proteins in wild-type mice. These studies demonstrate that an intact antioxidant system, in particular including transcription of catalase and MnSOD, is required for the renoprotective effects of linagliptin. PMID- 29979779 TI - Prediction of beauty and liking ratings for abstract and representational paintings using subjective and objective measures. AB - Recent research on aesthetics has challenged the adage that "beauty is in the eye of the beholder" by identifying several factors that predict ratings of beauty. However, this research has emerged in a piecemeal fashion. Most studies have examined only a few predictors of beauty, and measured either subjective or objective predictors, but not both. Whether the predictors of ratings of beauty versus liking differ has not been tested, nor has whether predictors differ for major distinctions in art, such as abstract vs. representational paintings. Finally, past studies have either relied on experimenter-generated stimuli-which likely yield pallid aesthetic experiences-or on a curation of high-quality art thereby restricting the range of predictor scores. We report a study (N = 598) that measured 4 subjective and 11 objective predictors of both beauty ratings and liking ratings, for 240 abstract and 240 representational paintings that varied widely in beauty. A crossover pattern occurred in the ratings, such that for abstract paintings liking ratings were higher than beauty ratings, whereas for representational paintings beauty ratings were higher than liking ratings. Prediction was much better for our subjective than objective predictors, and much better for our representational than abstract paintings. For abstract paintings, liking ratings were much more predictable than beauty ratings. Implications and directions for future research are discussed. PMID- 29979780 TI - Temporal dynamics of the lung and plasma viromes in lung transplant recipients. AB - The human virome plays an important role for the clinical outcome of lung transplant recipients (LTRs). While pathogenic viruses may cause severe infections, non-pathogenic viruses may serve as potential markers for the level of immunosuppression. However, neither the complexity of the virome in different compartments nor the dynamics of the virus populations posttransplantation are yet understood. Therefore, in this study the virome was analyzed by metagenomic sequencing in simultaneously withdrawn bronchoalveolar lavage (BAL) and plasma samples of 15 LTRs. In seven patients, also follow-up samples were investigated for abundance and dynamics of virus populations posttransplantation. Five eukaryotic and two prokaryotic virus families were identified in BAL, and nine eukaryotic and two prokaryotic families in plasma. Anelloviruses were the most abundant in both compartments, followed by Herpes- and Coronaviruses. Virus abundance was significantly higher in LTRs than in healthy controls (Kruskal Wallis test, p<0.001). Up to 48 different anellovirus strains were identified within a single LTR. Analyses in the follow-up patients revealed for the first time a highly complex and unique dynamics of individual anellovirus strains in the posttransplantation period. The abundance of anelloviruses in plasma was inversely correlated with that of other eukaryotic viruses (Pearson correlation coefficient r = -0.605; p<0.05). A broad spectrum of virus strains co-exists in BAL and plasma of LTRs. Especially for the anelloviruses, a high degree of co infections and a highly individual and complex dynamics after transplantation was observed. The biological impact of these findings and their relation to clinical variables remain to be elucidated by future analyses. PMID- 29979782 TI - Neuromuscular blockade of atracurium in permissive hypercapnic versus normocapnic swine undergoing laparoscopy. AB - Neuromuscular blocking agents (NMBAs) are commonly used in experimental laparoscopy in swine undergoing carbon dioxide pneumoperitoneum. Hypercapnia may be present and may prolong NMBAs' pharmacologic activity. The aim of this study is to evaluate the effect of permissive hypercapnia on the neuromuscular blockade of atracurium in swine. Six Large White swine weighing 30.5 +/- 1.6 kg were sedated with intramuscular ketamine and medetomidine, after which anaesthesia was induced with propofol and maintained with sevoflurane. Atracurium 0.4 mg/kg was administered intravenously and the neuromuscular block monitored by acceleromyography during normocapnic and hypercapnic conditions (PaCO2 range 35 45 mmHg and 60-70 mmHg, respectively). Onset time and time to reach a train of four ratio (TOFR) of 0.7 and 0.9 were recorded. Cardiorespiratory parameters, electrolytes and acid-base status were measured under both conditions. Onset time was similar between the two conditions. Time to reach a TOFR of 0.7 and 0.9 (duration of the neuromuscular block) was longer in hypercapnic compared to normocapnic animals being 1325 +/- 300 vs 855 +/-111 (p = 0.002) and 1823 +/- 434 vs 1218 +/- 210 seconds (p = 0.005), respectively. Three hypercapnic swine had a TOF count of 2 and 1 instead of a count of 4 with fade. Permissive hypercapnia was associated with a decrease in pH from 7.444 +/- 0.039 to 7.257 +/- 0.025 (p < 0.001). No differences were observed for heart rate, end-tidal concentration of sevoflurane, body temperature and arterial haemoglobin saturation. Nonetheless, hypercapnic swine had a statistically significant increase in mean arterial pressure (p = 0.020) and plasma potassium concentration (p = 0.003). The values of PaCO2 achieved during hypercapnia were well tolerated in swine undergoing CO2 pneumoperitoneum for laparoscopy. Permissive hypercapnia increased the duration of the atracurium effect and caused an increase in the intensity of the neuromuscular block in few swine. PMID- 29979781 TI - A transcriptome study on Macrobrachium nipponense hepatopancreas experimentally challenged with white spot syndrome virus (WSSV). AB - White spot syndrome virus (WSSV) is one of the most devastating pathogens of cultured shrimp, responsible for massive loss of its commercial products worldwide. The oriental river prawn Macrobrachium nipponense is an economically important species that is widely farmed in China and adult prawns can be infected by WSSV. However, the molecular mechanisms of the host pathogen interaction remain unknown. There is an urgent need to learn the host pathogen interaction between M. nipponense and WSSV which will be able to offer a solution in controlling the spread of WSSV. Next Generation Sequencing (NGS) was used in this study to determin the transcriptome differences by the comparison of control and WSSV-challenged moribund samples, control and WSSV-challenged survived samples of hepatopancreas in M. nipponense. A total of 64,049 predicted unigenes were obtained and classified into 63 functional groups. Approximately, 4,311 differential expression genes were identified with 3,308 genes were up-regulated when comparing the survived samples with the control. In the comparison of moribund samples with control, 1,960 differential expression genes were identified with 764 genes were up-regulated. In the contrast of two comparison libraries, 300 mutual DEGs with 95 up-regulated genes and 205 down-regulated genes. All the DEGs were performed GO and KEGG analysis, overall a total of 85 immune-related genes were obtained and these gene were groups into 13 functions and 4 KEGG pathways, such as protease inhibitors, heat shock proteins, oxidative stress, pathogen recognition immune receptors, PI3K/AKT/mTOR pathway, MAPK signaling pathway and Ubiquitin Proteasome Pathway. Ten genes that valuable in immune responses against WSSV were selected from those DEGs to furture discuss the response of host to WSSV. Results from this study contribute to a better understanding of the immune response of M. nipponense to WSSV, provide information for identifying novel genes in the absence of genome of M. nipponense. Furthermore, large number of transcripts obtained from this study could provide a strong basis for future genomic research on M. nipponense. PMID- 29979783 TI - Molecular marker sequences of cattle Cooperia species identify Cooperia spatulata as a morphotype of Cooperia punctata. AB - The genus Cooperia includes important parasites of ruminants and currently contains 34 accepted species. However, even for those species infecting livestock, there is a considerable lack of molecular information and many species are only identifiable using subtle morphological traits. The present study aimed to provide molecular data to allow diagnosis of Cooperia species infecting cattle. Partial sequences of two mitochondrial (cytochrome oxidase 2, 12S rRNA gene) and two nuclear genes (isotype 1 beta tubulin gene including two introns, internal transcribed spacers (ITS) were obtained from morphologically identified specimens of Cooperia pectinata, Cooperia punctata and Cooperia spatulata as well as from larvae of pure Cooperia oncophora and C. punctata laboratory isolates. Pairwise identity of ITS-2 sequences was very high and it was the only region able to identify a specimen as Cooperia sp. However, the ITS-2 was unreliable for diagnosis at the species level. All other marker sequences could not unequivocally be allocated to the genus Cooperia but allowed clear species identification with the exception of the pair C. punctata/C. spatulata for which no significant differences were found for any marker sequence. Maximum-likelihood phylogenetic analyses of individual genes as well as a multi-locus analysis covering all four sequences confirmed that specimen identified as C. spatulata were randomly distributed throughout the C. punctata cluster and formed no group of their own. In contrast, the other Cooperia species formed clearly separated and statistically supported clusters. These data indicate that C. spatulata is most likely only a morphotype of C. punctata and the name should be considered a synonym. Combinations of nuclear and mitochondrial markers should be used to identify morphotypes or cryptic species to benefit from excellent barcoding properties of the latter but allowing proper phylogenetic analyses and controlling for lineage sorting that might occur for mitochondrial genotypes within a species. PMID- 29979784 TI - Salivary creatinine and urea are higher in an experimental model of acute but not chronic renal disease. AB - Plasma creatinine and urea are commonly used markers of kidney function in both acute and chronic renal failure. The needed repeated blood collection is associated with pain, stress and might lead to infections. Saliva has the potential to be a non-invasive alternative diagnostic fluid. The use of saliva in clinical practice is limited, since many factors affect the concentration of salivary biomarkers. The aim of our study was to analyze salivary creatinine and urea in the animal models of acute and chronic renal disease. Bilateral nephrectomy and adenine nephropathy were induced in adult male mice. Both, plasma creatinine and urea were higher in animals with renal failure compared to controls. Salivary creatinine was higher by 81% and salivary urea by 43% in comparison to the control group, but only in animals with bilateral nephrectomy and not in adenine nephropathy. Our results indicate that the increase of salivary creatinine and urea depends on the experimental model of renal failure and its severity. Further studies are needed to monitor the dynamics of salivary markers of renal function and to reveal determinants of their variability. PMID- 29979785 TI - Correction: The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. AB - [This corrects the article DOI: 10.1371/journal.pone.0193798.]. PMID- 29979786 TI - Distinctions and associations between the microbiota of saliva and supragingival plaque of permanent and deciduous teeth. AB - BACKGROUND: Using salivary microbiota as an accurate proxy for monitoring supragingival microbiota remains controversial because their relationship remains unclear. The eruption of permanent teeth and the exfoliation of primary teeth in mixed dentition greatly alter microbial habitats, which may cause compositional shifts of oral microbiota from childhood to adults. OBJECTIVE: This study's purpose was to assess whether saliva represents a suitable sample for monitoring supragingival microbiota in healthy people, and to explore how the replacement process of deciduous teeth with permanent teeth in mixed dentition influences microbiota within the oral cavity. DESIGN: Samples of saliva and of supragingival plaque from permanent and deciduous teeth were collected separately from 20 healthy children with mixed dentition. To characterize their microbial communities, we used the V3-V4 hypervariable region of the bacterial 16S rRNA gene sequence. RESULTS: Saliva harbored a less even and less diverse community than did the plaque. Discriminating genera, namely Rothia and Streptococcus, contributed to the saliva and plaque differentiation. About half of predicted KEGG pathways varied between the plaque and saliva communities. Oral bacteria showed significantly associations between their supragingival and salivary states. We identified 20 supragingival plaque-related genera in saliva, such as Corynebacterium, Capnocytophaga, Fusobacterium, and Neisseria. Additionally, the relative abundance of Actinobacteria peaked in the permanent teeth plaque but subsided in deciduous teeth plaque and saliva. The exfoliation of deciduous teeth and eruption of permanent teeth might be related to the reported fluctuation in the relative abundance of Actinobacteria from primary dentition to permanent dentition within the oral cavity. The variation between PT and DT was due mainly to permanent teeth being enriched in Actinomyces and deciduous teeth in Treponema. CONCLUSION: These results suggested that the supragingival plaque related bacteria could be suitable candidates when sampling saliva for monitoring supragingival microbiota. The replacement process of deciduous teeth with permanent teeth in mixed dentition might be related to the reported age maturation of phylum Actinobacteria in the oral cavity. PMID- 29979788 TI - Unrecognized myocardial infarction assessed by cardiac magnetic resonance imaging is associated with adverse long-term prognosis. AB - BACKGROUND: Unrecognized myocardial infarctions (UMIs) are common. The study is an extension of a previous study, aiming to investigate the long-term (>5 year) prognostic implication of late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) detected UMI in patients with suspected stable coronary artery disease (CAD) without previously diagnosed myocardial infarction (MI). METHODS: In 235 patients with suspected stable CAD without previous MI, LGE-CMR imaging and coronary angiography were performed. LGE with a subendocardial component detectable in more than one imaging plane was required to indicate UMI. The stenosis grade of the coronary arteries was determined, including in the artery supplying an infarcted area. Stenosis >=70% stenosis was considered significant. Patients were followed for 5.4 years in mean regarding a composite endpoint of cardiovascular death, MI, hospitalization due to heart failure, stable or unstable angina. RESULTS: UMI were present in 58 of 235 patients (25%). Thirty-nine of the UMIs were located downstream of a significant coronary stenosis. During the follow-up 40 patients (17.0%) reached the composite endpoint. Of patients with UMI, 34.5% (20/58) reached the primary endpoint compared to 11.3% (20/177) of patients with no UMI (HR 3.7, 95% CI 2.0-6.9, p<0.001). The association between UMI and outcome remained (HR 2.3, 95% CI 1.2 4.4, p = 0.012) after adjustments for age, gender, extent of CAD and all other variables univariate associated with outcome. Sixteen (41%) of the patients with an UMI downstream of a significant stenosis reached the endpoint compared to four (21%) patients with UMI and no relation to a significant stenosis (HR 2.4, 95% CI 0.8-7.2, p = 0.12). CONCLUSION: The presence of UMI was independently associated with an increased risk of cardiovascular events during long-term follow up. PMID- 29979787 TI - A genome-wide screen of Epstein-Barr virus proteins that modulate host SUMOylation identifies a SUMO E3 ligase conserved in herpesviruses. AB - Many cellular processes pertinent for viral infection are regulated by the addition of small ubiquitin-like modifiers (SUMO) to key regulatory proteins, making SUMOylation an important mechanism by which viruses can commandeer cellular pathways. Epstein-Barr virus (EBV) is a master at manipulating of cellular processes, which enables life-long infection but can also lead to the induction of a variety of EBV-associated cancers. To identify new mechanisms by which EBV proteins alter cells, we screened a library of 51 EBV proteins for global effects on cellular SUMO1 and SUMO2 modifications (SUMOylation), identifying several proteins not previously known to manipulate this pathway. One EBV protein (BRLF1) globally induced the loss of SUMOylated proteins, in a proteasome-dependent manner, as well as the loss of promeylocytic leukemia nuclear bodies. However, unlike its homologue (Rta) in Kaposi's sarcoma associated herpesvirus, it did not appear to have ubiquitin ligase activity. In addition we identified the EBV SM protein as globally upregulating SUMOylation and showed that this activity was conserved in its homologues in herpes simplex virus 1 (HSV1 UL54/ICP27) and cytomegalovirus (CMV UL69). All three viral homologues were shown to bind SUMO and Ubc9 and to have E3 SUMO ligase activity in a purified system. These are the first SUMO E3 ligases discovered for EBV, HSV1 and CMV. Interestingly the homologues had different specificities for SUMO1 and SUMO2, with SM and UL69 preferentially binding SUMO1 and inducing SUMO1 modifications, and UL54 preferentially binding SUMO2 and inducing SUMO2 modifications. The results provide new insights into the function of this family of conserved herpesvirus proteins, and the conservation of this SUMO E3 ligase activity across diverse herpesviruses suggests the importance of this activity for herpesvirus infections. PMID- 29979789 TI - BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains. AB - It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of beta-amyloid precursor protein (APP) by beta-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1 null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1 cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4 weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1 proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease. PMID- 29979791 TI - Correction: A novel badnavirus discovered from Betula sp. affected by birch leaf roll disease. AB - [This corrects the article DOI: 10.1371/journal.pone.0193888.]. PMID- 29979792 TI - The quantitative measure and statistical distribution of fame. AB - Fame and celebrity play an ever-increasing role in our culture. However, despite the cultural and economic importance of fame and its gradations, there exists no consensus method for quantifying the fame of an individual, or of comparing that of two individuals. We argue that, even if fame is difficult to measure with precision, one may develop useful metrics for fame that correlate well with intuition and that remain reasonably stable over time. Using datasets of recently deceased individuals who were highly renowned, we have evaluated several internet based methods for quantifying fame. We find that some widely-used internet derived metrics, such as search engine results, correlate poorly with human subject judgments of fame. However other metrics exist that agree well with human judgments and appear to offer workable, easily accessible measures of fame. Using such a metric we perform a preliminary investigation of the statistical distribution of fame, which has some of the power law character seen in other natural and social phenomena such as landslides and market crashes. In order to demonstrate how such findings can generate quantitative insight into celebrity culture, we assess some folk ideas regarding the frequency distribution and apparent clustering of celebrity deaths. PMID- 29979790 TI - PGL I expression in live bacteria allows activation of a CD206/PPARgamma cross talk that may contribute to successful Mycobacterium leprae colonization of peripheral nerves. AB - Mycobacterium leprae, an obligate intracellular bacillus, infects Schwann cells (SCs), leading to peripheral nerve damage, the most severe leprosy symptom. In the present study, we revisited the involvement of phenolic glycolipid I (PGL I), an abundant, private, surface M. leprae molecule, in M. leprae-SC interaction by using a recombinant strain of M. bovis BCG engineered to express this glycolipid. We demonstrate that PGL I is essential for bacterial adhesion and SC internalization. We also show that live mycobacterium-producing PGL I induces the expression of the endocytic mannose receptor (MR/CD206) in infected cells in a peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent manner. Of note, blocking mannose recognition decreased bacterial entry and survival, pointing to a role for this alternative recognition pathway in bacterial pathogenesis in the nerve. Moreover, an active crosstalk between CD206 and the nuclear receptor PPARgamma was detected that led to the induction of lipid droplets (LDs) formation and prostaglandin E2 (PGE2), previously described as fundamental players in bacterial pathogenesis. Finally, this pathway was shown to induce IL-8 secretion. Altogether, our study provides evidence that the entry of live M. leprae through PGL I recognition modulates the SC phenotype, favoring intracellular bacterial persistence with the concomitant secretion of inflammatory mediators that may ultimately be involved in neuroinflammation. PMID- 29979795 TI - Using risk adjustment to improve the interpretation of global inpatient pediatric antibiotic prescribing. AB - OBJECTIVES: Assessment of regional pediatric last-resort antibiotic utilization patterns is hampered by potential confounding from population differences. We developed a risk-adjustment model from readily available, internationally used survey data and a simple patient classification to aid such comparisons. DESIGN: We investigated the association between pediatric conserve antibiotic (pCA) exposure and patient / treatment characteristics derived from global point prevalence surveys of antibiotic prescribing, and developed a risk-adjustment model using multivariable logistic regression. The performance of a simple patient classification of groups with different expected pCA exposure levels was compared to the risk model. SETTING: 226 centers in 41 countries across 5 continents. PARTICIPANTS: Neonatal and pediatric inpatient antibiotic prescriptions for sepsis/bloodstream infection for 1281 patients. RESULTS: Overall pCA exposure was high (35%), strongly associated with each variable (patient age, ward, underlying disease, community acquisition or nosocomial infection and empiric or targeted treatment), and all were included in the final risk-adjustment model. The model demonstrated good discrimination (c-statistic = 0.83) and calibration (p = 0.38). The simple classification model demonstrated similar discrimination and calibration to the risk model. The crude regional pCA exposure rates ranged from 10.3% (Africa) to 67.4% (Latin America). Risk adjustment substantially reduced the regional variation, the adjusted rates ranging from 17.1% (Africa) to 42.8% (Latin America). CONCLUSIONS: Greater comparability of pCA exposure rates can be achieved by using a few easily collected variables to produce risk-adjusted rates. PMID- 29979794 TI - Two-step production of anti-inflammatory soluble factor by Lactobacillus reuteri CRL 1098. AB - We have demonstrated previously that a soluble factor (LrS) produced by Lactobacillus (L.) reuteri CRL 1098 modulates the inflammatory response triggered by lipopolysaccharide. In this study, the production of LrS by L. reuteri CRL 1098 was realized through two steps: i) bacterial biomass production, ii) LrS production, where the bacterial biomass was able to live but did not proliferate. Therefore, the simultaneous evaluation of the effect of different factors on the growth and LrS production was performed. Biomass production was found to be dependent mainly on culture medium, while LrS production with anti-inflammatory activity depended on culture conditions of the biomass such as pH, agitation and growth phase. The L. reuteri CRL 1098 biomass and LrS production in the optimized culture media designed for this work reduced the complete process cost by approximately 95%, respectively to laboratory scale cost. PMID- 29979796 TI - Pregnant women co-infected with HIV and Zika: Outcomes and birth defects in infants according to maternal symptomatology. AB - BACKGROUND: Zika virus (ZIKV) was first isolated in Uganda in 1947. In Brazil, the first reported case of ZIKV infection was in May 2015. Additionally, dengue (DENV) is endemic and there has been a recent outbreak of chikungunya (CHIKV). Since the clinical manifestations of different arboviral infections (AI) can be similar, definitive diagnosis requires laboratory testing. OBJECTIVES: To determine the prevalence of ZIKV, DENV, and CHIKV infections in a Brazilian cohort of HIV-infected pregnant women, to assess clinical/immunological characteristics and pregnancy outcomes of women with evidence of recent AI. STUDY DESIGN: Laboratory diagnosis of ZIKV, DENV and CHIKV infections utilized serological assays, RT-PCR and PRNT. The tests were performed at the first visit, 34-36 weeks of gestation and at any time if a woman had symptoms suggestive of AI. Mann-Whitney tests were used for comparison of medians, Chi-square or Fisher's to compare proportions; p< 0.05 was considered statistically significant. Poisson regression was used to analyze risk factors for central nervous system (CNS) malformations in the infant according to maternal symptomatology. RESULTS: Of 219 HIV-infected pregnant women enrolled, 92% were DENV IgG+; 47(22%) had laboratory evidence of recent AI. Of these, 34 (72%) were ZIKV+, nine (19%) CHIKV+, and two (4%) DENV+. Symptoms consistent with AI were observed in 23 (10%) women, of whom 10 (43%) were ZIKV+, eight (35%) CHIKV+. No CNS abnormalities were observed among infants of DENV+ or CHIKV+ women; four infants with CNS abnormalities were born to ZIKV+ women (three symptomatic). Infants born to ZIKV+ women had a higher risk of CNS malformations if the mother was symptomatic (RR = 7.20), albeit not statistically significant (p = 0.066). CONCLUSIONS: Among HIV-infected pregnant women with laboratory evidence of a recent AI, 72% were ZIKV-infected. In this cohort, CNS malformations occurred among infants born to both symptomatic and asymptomatic pregnant women with Zika infection. PMID- 29979798 TI - Accuracy of Distal Femoral Valgus Deformity Correction: Fixator-Assisted Nailing vs Fixator-Assisted Locked Plating. AB - Fixator-assisted nailing (FAN) and fixator-assisted locked plating (FALP) are 2 techniques that can be used to correct distal femoral valgus deformities. The fixator aids in achieving an accurate adjustable initial reduction, which is then made permanent with either nail or plate insertion. FALP can be performed with the knee held in a neutral extended position, whereas FAN requires 30 degrees to 90 degrees of knee flexion to insert the nail, which may cause some alignment loss. We hypothesized that FAN may yield less accurate correction than FALP. Prospectively collected data of a consecutive cohort of patients who underwent valgus deformity femoral correction with FAN or FALP at a single institution over an 8-year period were retrospectively evaluated. Twenty extremities (18 patients) were treated using FAN (median follow-up, 5 years; range, 1-10 years), and 7 extremities (6 patients) were treated with FALP (median follow-up, 5 years; range, 1-8 years). In the FAN cohort, the mean preoperative and postoperative mechanical lateral distal femoral angles (mLDFAs) were 81 degrees (range, 67 degrees -86 degrees ) and 89 degrees (range, 80 degrees -100 degrees ), respectively (P = .009). In the FALP cohort, the mean preoperative and postoperative mLDFAs were 80 degrees (range, 71 degrees -87 degrees ) and 88 degrees (range, 81 degrees -94 degrees ), respectively (P < .001). Although the average mechanical axis deviation correction for the FALP group was greater than for the FAN group (32 mm and 27 mm, respectively), the difference was not significant (P = .66). Both methods of femoral deformity correction can be considered safe and effective. On the basis of our results, FAN and FALP are comparable in accuracy for deformity correction in the distal femur. PMID- 29979797 TI - Diagnostic accuracy of adding copeptin to cardiac troponin for non-ST-elevation myocardial infarction: A systematic review and meta-analysis. AB - INTRODUCTION: This study aimed to determine the diagnostic accuracy of adding copeptin to cardiac troponin (cTn) on admission to the emergency department (ED) for non-ST elevation myocardial infarction (NSTEMI) compared to cTn alone. MATERIALS AND METHODS: A literature search of MEDLINE, EMBASE, and the Cochrane Library was performed (search date: April 13, 2018). Primary studies were included if they accurately reported on patients with symptoms suggestive of acute myocardial infarction and measured both cTn alone and cTn with copeptin upon admission to the ED. The patients with evidence of ST elevation myocardial infarction were excluded. To assess the risk of bias for the included studies, the QUADAS-2 tool was used. RESULTS: The study participants included a total of 7,998 patients from 14 observational studies. The addition of copeptin to cTn significantly improved the sensitivity (0.81 [0.74 to 0.87] vs. 0.92 [0.89 to 0.95], respectively, p <0.001) and negative predictive value (0.96 [0.95 to 0.98] vs. 0.98 [0.96 to 0.99], respectively, p <0.001) at the expense of lower specificity (0.88 [0.80 to 0.97] vs. 0.57 [0.49 to 0.65], respectively, p <0.001) compared to cTn alone. Furthermore, adding copeptin to cTn showed significantly lower diagnostic accuracy for NSTEMI compared to cTn alone (0.91[0.90 to 0.92] vs. 0.85 [0.83 to 0.86], respectively, p < 0.001). CONCLUSIONS: Adding copeptin to cTn improved the sensitivity and negative predictive value for the diagnosis of NSTEMI compared to cTn alone. Thus, adding copeptin to cTn might help to screen NSTEMI early upon admission to the ED. PMID- 29979799 TI - Continuous Cryotherapy vs Ice Following Total Shoulder Arthroplasty: A Randomized Control Trial. AB - Postoperative pain management is an important component of total shoulder arthroplasty (TSA). Continuous cryotherapy (CC) has been proposed as a means of improving postoperative pain control. However, CC represents an increased cost not typically covered by insurance. The purpose of this study is to compare CC to plain ice (ICE) following TSA. The hypothesis was that CC would lead to lower pain scores and decreased narcotic usage during the first 2 weeks postoperatively. A randomized controlled trial was performed to compare CC to ICE. Forty patients were randomized to receive either CC or ICE following TSA. The rehabilitation and pain control protocols were otherwise standardized. Visual analog scales (VAS) for pain, satisfaction with cold therapy, and quality of sleep were recorded preoperatively and postoperatively at 24 hours, 3 days, 7 days, and 14 days following surgery. Narcotic usage in morphine equivalents was also recorded. No significant differences in preoperative pain (5.9 vs 6.8; P = .121), or postoperative pain at 24 hours (4.2 vs 4.3; P = .989), 3 days (4.8 vs 4.7; P = .944), 7 days (2.9 vs 3.3; P = .593) or 14 days (2.5 vs 2.7; P = .742) were observed between the CC and ICE groups. Similarly, no differences in quality of sleep, satisfaction with the cold therapy, or narcotic usage at any time interval were observed between the 2 groups. No differences in pain control, quality of sleep, patient satisfaction, or narcotic usage were detected between CC and ICE following TSA. CC may offer convenience as an advantage, but the increased cost associated with this type of treatment may not be justified. PMID- 29979800 TI - Free Composite Serratus Anterior-Latissimus-Rib Flaps for Acute One-Stage Reconstruction of Gustilo IIIB Tibia Fractures. AB - Gustilo IIIB injuries of the tibia with segmental bone loss continue to be a difficult reconstructive problem. The serratus anterior-latissimus-rib (SALR) composite flap consists of bone and muscle; this flap can provide soft tissue coverage and vascularized bone in a single surgical procedure. The purpose of this study is to describe the use of the SALR flap for the treatment of a large open tibia fracture with segmental bone loss, with a specific focus on postoperative complications, limb salvage, and time to union. We reviewed the medical records of patients undergoing an SALR flap (n = 5) for the treatment of Gustilo Type IIIB tibia fractures within 1 month of injury. We compared the mechanism of injury, injury severity score, time from injury to free tissue transfer, complications, and time to radiographic and clinical union. All patients were male, with a mean age of 25 years. On average, patients underwent free tissue transfer within 1 week of injury. The average time to radiographic union was 7 months. Two patients underwent reoperation. There were no graft failures. Free SALR flaps can be a useful option for the treatment of high-energy tibia fractures with extensive soft tissue and bone loss. These flaps provide immediate osseous and soft tissue reconstruction with an acceptable complication profile. PMID- 29979793 TI - Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility. AB - Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations. PMID- 29979801 TI - Impact of Sagittal Rotation on Axial Glenoid Width Measurement in the Setting of Glenoid Bone Loss. AB - Standard 2-dimensional (2-D) computed tomography (CT) scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula, which may challenge the ability to accurately measure glenoid width and glenoid bone loss (GBL). The purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial anterior-posterior (AP) glenoid width measurements in the setting of anterior GBL. Forty-three CT scans from consecutive patients with anterior GBL (minimum 10%) were reformatted utilizing open-source DICOM software (OsiriX MD). Patients were grouped according to extent of GBL: I, 10% to 14.9% (N = 12); II, 15% to 19.9% (N = 16); and III, >20% (N = 15). The uncorrected (UNCORR) and corrected (CORR) images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width. For groups I and III, UNCORR scans underestimated axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated). In Group II, axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut; while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts. Uncorrected 2-D CT scans inaccurately estimated glenoid width and the degree of anterior GBL. This data suggests that corrected 2D CT scans or a 3-dimensional (3 D) reconstruction can help in accurately defining the anterior GBL in patients with shoulder instability. PMID- 29979802 TI - Minimum 5-Year Follow-up of Articular Surface Replacement Acetabular Components Used in Total Hip Arthroplasty. AB - The articular surface replacement (ASR) monoblock metal-on-metal acetabular component was recalled due to a higher than expected early failure rate. We evaluated the survivorship of the device and variables that may be predictive of failure at a minimum of 5-year follow-up. A single-center, single-surgeon retrospective review was conducted in patients who received the DePuy Synthes ASRTM XL Acetabular hip system from December 2005 to November 2009. Mean values and percentages were calculated and compared using the Fisher's exact test, simple logistic regression, and Student's t-test. The significance level was P <= .05. This study included 29 patients (24 males, 5 females) with 32 ASRTM XL acetabular hip systems. Mean age and body mass index (BMI) reached 55.2 years and 28.9 kg/m2, respectively. Mean postoperative follow-up was 6.2 years. A total of 2 patients (6.9%) died of an unrelated cause and 1 patient was lost to follow-up (3.4%), leaving 26 patients with 28 hip replacements, all of whom were available for follow-up. The 5-year revision rate was 34.4% (10 patients with 11 hip replacements). Mean time to revision was 3.1 years. Age (P = .76), gender (P = .49), BMI (P = .29), acetabular component abduction angle (P = .12), and acetabulum size (P = .59) were not associated with the increased rate for hip failure. Blood cobalt (7.6 vs 6.8 ug/L, P = .58) and chromium (5.0 vs 2.2 ug/L, P = .31) levels were not significantly higher in the revised group when compared with those of the unrevised group. In the revised group, a 91% decrease in cobalt and 78% decrease in chromium levels were observed at a mean of 6 months following the revision. This study demonstrates a high rate of failure of ASR acetabular components used in total hip arthroplasty at a minimum of 5 years of follow-up. No variable that was predictive of failure could be identified in this series. Close clinical surveillance of these patients is required. PMID- 29979803 TI - Multi-Modal Pain Control in Ambulatory Hand Surgery. AB - We evaluated postoperative pain control and narcotic usage after thumb carpometacarpal (CMC) arthroplasty or open reduction and internal fixation (ORIF) of the distal radius in patients given opiates with or without other non-opiate medication using a specific dosing regimen. A prospective, randomized study of 79 patients undergoing elective CMC arthroplasty or ORIF of the distal radius evaluated postoperative pain in the first 5 postoperative days. Patients were divided into 4 groups: Group 1, oxycodone and acetaminophen PRN; Group 2, oxycodone and acetaminophen with specific dosing; Group 3, oxycodone, acetaminophen, and OxyContin with specific dosing; and Group 4, oxycodone, acetaminophen, and ketorolac with specific dosing. During the first 5 postoperative days, we recorded pain levels according to a numeric pain scale, opioid usage, and complications. Although differences in our data did not reach statistical significance, overall pain scores, opioid usage, and complication rates were less prevalent in the oxycodone, acetaminophen, and ketorolac group. Postoperative pain following ambulatory hand and wrist surgery under regional anesthesia was more effectively controlled with fewer complications using a combination of oxycodone, acetaminophen, and ketorolac with a specific dosing regimen. PMID- 29979804 TI - Open vs Percutaneous vs Arthroscopic Surgical Treatment of Lateral Epicondylitis: An Updated Systematic Review. AB - This study was performed to compare outcomes of open, arthroscopic, and percutaneous surgical techniques for lateral epicondylitis. We searched PubMed (MEDLINE) for literature published between January 1, 2004 and May 23, 2015 using these key words: lateral epicondylitis AND (surgery OR operative OR surgical OR open OR arthroscopic OR percutaneous). Meta-analyses were performed for outcomes reported in 3 studies using 2-sample and 2-proportion Z-tests. Thirty-five studies including 1640 elbows (1055 open, 401 arthroscopic, 184 percutaneous) met the inclusion criteria. There were no differences between groups regarding duration to return to work, complication rate, or patient satisfaction. A greater proportion of patients were pain free in the open group than in the arthroscopic group (70% vs 60%). Despite the absence of a difference among techniques regarding return to work and subjective function, we recommend open debridement as the technique most likely to achieve a pain-free outcome. PMID- 29979805 TI - Outcomes After Peripheral Nerve Block in Hip Arthroscopy. AB - Pain control following hip arthroscopy presents a significant clinical challenge, with postoperative pain requiring considerable opioid use. Peripheral nerve blocks (PNBs) have emerged as one option to improve pain and limit the consequences of opioid use. The purpose of this study is to provide a comprehensive review of outcomes associated with PNB in hip arthroscopy. We hypothesize that the use of PNB in hip arthroscopy leads to improved outcomes and is associated with few complications. A systematic review of PubMed, Medline, Scopus, and Embase databases was conducted through January 2015 for English language articles reporting outcome data, with 2 reviewers independently reviewing studies for inclusion. When available, similar outcomes were combined to generate frequency-weighted means. Six studies met the inclusion criteria for this review, reporting on 710 patients undergoing hip arthroscopy. The mean ages were 37.0 and 37.7 years for the PNB and comparator groups, respectively, with a reported total of 281 (40.5%) male and 412 (59.5%) female patients. Postoperative post-anesthesia care unit (PACU) pain was consistently reduced in the PNB group, with the use of a lower morphine equivalent dose and lower rates of inpatient admission, compared with that in the control groups. Postoperative nausea and/or vomiting as well as PACU discharge time showed mixed results. High satisfaction and few complications were reported. In conclusion, PNB is associated with reductions in postoperative pain, analgesic use, and the rate of inpatient admissions, though similar rates of nausea/vomiting and time to discharge were reported. Current PNB techniques are varied, and future research efforts should focus on examining which of these methods provides the optimal risk-benefit profile in hip arthroscopy. PMID- 29979806 TI - Reoperation Rates After Cartilage Restoration Procedures in the Knee: Analysis of a Large US Commercial Database. AB - The purpose of this study is to describe the rate of return to the operating room (OR) following microfracture (MFX), autologous chondrocyte implantation (ACI), osteochondral autograft transplantation (OATS), and osteochondral allograft (OCA) procedures at 90 days, 1 year, and 2 years. Current Procedural Terminology codes for all patients undergoing MFX, ACI, OATS, and OCA were used to search a prospectively collected, commercially available private payer insurance company database from 2007 to 2011. Within 90 days, 1 year, and 2 years after surgery, the database was searched for the occurrence of these same patients undergoing knee diagnostic arthroscopy with biopsy, lysis of adhesions, synovectomy, arthroscopy for infection or lavage, arthroscopy for removal of loose bodies, chondroplasty, MFX, ACI, OATS, OCA, and/or knee arthroplasty. Descriptive statistical analysis and contingency table analysis were performed. A total of 47,207 cartilage procedures were performed from 2007 to 2011, including 43,576 MFX, 640 ACI, 386 open OATS, 997 arthroscopic OATS, 714 open OCA, and 894 arthroscopic OCA procedures. The weighted average reoperation rates for all procedures were 5.87% at 90 days, 11.94% at 1 year, and 14.90% at 2 years following the index cartilage surgery. At 2 years, patients who underwent MFX, ACI, OATS, OCA had reoperation rates of 14.65%, 29.69%, 8.82%, and 12.22%, respectively. There was a statistically significantly increased risk for ACI return to OR within all intervals (P < .0001); however, MFX had a greater risk factor (P < .0001) for conversion to arthroplasty. There was no difference in failure/revision rates between the restorative treatment options. With a large US commercial insurance database from 2007 to 2011, reparative procedures were favored for chondral injuries, but yielded an increased risk for conversion to arthroplasty. There was no difference in failure/revision rates between the restorative approaches, yet cell-based approaches yielded a significantly increased risk for a return to the OR. PMID- 29979807 TI - Shoulder Arthroplasty in Patients with Rheumatoid Arthritis: A Population-Based Study Examining Utilization, Adverse Events, Length of Stay, and Cost. AB - It has been suggested that the utilization of joint arthroplasty in patients with rheumatoid arthritis (RA) is decreasing; however, this observation is largely based upon evidence pertaining to lower-extremity joint arthroplasty. It remains unknown if these observed trends also hold true for shoulder arthroplasty. The purpose of this study is to utilize a nationally representative population database in the US to identify trends in the utilization of shoulder arthroplasty among patients with RA. Secondarily, we sought to determine the rate of early adverse events, length of stay, and hospitalization costs associated with RA patients undergoing shoulder arthroplasty and to compare these outcomes to those of patients without a diagnosis of RA undergoing shoulder arthroplasty. Using a large population database in the US, we determined the annual rates of shoulder arthroplasty (overall and individual) in RA patients between 2002 and 2011. Early adverse events, length of stay, and hospitalization costs were determined and compared with those of non-RA patients undergoing shoulder arthroplasty. Overall, we identified 332,593 patients who underwent shoulder arthroplasty between 2002 and 2011, of whom 17,883 patients (5.4%) had a diagnosis of RA. Over the study period, there was a significant increase in the utilization of shoulder arthroplasty in RA patients, particularly total shoulder arthroplasty. Over the same period, there was a significant increase in the number of RA patients who underwent shoulder arthroplasty with a diagnosis of rotator cuff disease. There were no significant differences in adverse events or mean hospitalization costs between RA and non-RA patients. Non-RA patients had a significantly shorter length of stay; however, the difference did not appear to be clinically significant. In conclusion, the utilization of shoulder arthroplasty in patients with RA significantly increased from 2002 to 2011, which may partly reflect a trend toward management of rotator cuff disease with arthroplasty rather than repair. PMID- 29979808 TI - When Would a Metal-Backed Component Become Cost-Effective Over an All Polyethylene Tibia in Total Knee Arthroplasty? AB - The importance of cost control in total knee arthroplasty is increasing in the United States secondary to both changing economic realities of healthcare and the increasing prevalence of joint replacement. Surgeons play a critical role in cost containment and may soon be incentivized to make cost-effective decisions under proposed gainsharing programs. The purpose of this study is to examine the cost effectiveness of all-polyethylene tibial (APT) components and determine what difference in revision rate would make modular metal-backed tibial (MBT) implants a more cost-effective intervention. Markov models were constructed using variable implant failure rates and previously published probabilities. Cost data were obtained from both our institution and published United States implant list prices, and modeled with a 3.0% discount rate. The decision tree was continued over a 20-year timeframe. Using our institutional cost data and model assumptions with a 1.0% annual failure rate for MBT components, an annual failure rate of 1.6% for APT components would be required to achieve equivalency in cost. Over a 20-year period, a failure rate of >27% for the APT component would be necessary to achieve equivalent cost compared with the proposed failure rate of 18% with MBT components. A sensitivity analysis was performed with different assumptions for MBT annual failure rates. Given our assumptions, the APT component is cost saving if the excess cumulative revision rate increases by <9% in 20 years compared with that of the MBT implant. Surgeons, payers, and hospitals should consider this approach when evaluating implants. Consideration should also be given to the decreased utility associated with revision surgery. PMID- 29979809 TI - Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. AB - Long-lived plasma cells (PCs) not only provide protective humoral immunity, they are also an essential component of the autoreactive immunologic memory that may drive chronic immune responses in systemic autoimmunity, such as systemic lupus erythematosus (SLE). The therapeutic relevance of their targeting has been demonstrated in preclinical models and severe, treatment-refractory cases of autoimmune diseases using the proteasome inhibitor bortezomib. Herein, we describe in detail the dynamic serologic changes and effects on immune effector cells in eight SLE patients receiving a median two cycles of 1.3 mg/m2 intravenous bortezomib. Upon proteasome inhibition, immunoglobulin levels gradually declined by ~30%, associated with a significant reduction of autoantibodies, and serum complement whereas B-cell activation factor levels increased. While proteasome inhibition was associated with a significant depletion of short- and long-lived PCs in peripheral blood and bone marrow by ~50%, including those with a distinctly mature CD19- phenotype, their precursor B cells and T cells largely remained unaffected, resulting in a rapid repopulation of short-lived PCs after bortezomib withdrawal, accompanied by increasing autoantibody levels. Collectively, these findings identify proteasome inhibitors as a promising treatment option for refractory SLE, but also indicate that PC depletion needs to be combined with targeted B-cell therapies for sustained responses in systemic autoimmunity. PMID- 29979810 TI - Molecular confirmation and anthelmintic efficacy assessment against natural trichurid infections in zoo-housed non-human primates. AB - INTRODUCTION: This study aimed to assess Trichuris species infection and evaluate the anthelmintic efficacy of fenbendazole and ivermectin against natural trichurid infections in non-human primates (NHPs), kept at Mahendra Chaudhury (MC) Zoological Park, Chhatbir, India. MATERIALS AND METHODS: Molecular confirmation of Trichuris infection was carried out using polymerase chain reaction targeting internal transcribed spacer sequences, and anthelmintic efficacy was assessed by fecal egg count reduction test, respectively. RESULTS: A 710 base pair product confirmed Trichuris species infection in NHPs. Fenbendazole, 10 mg/kg body weight orally for 5 consecutive days and ivermectin, 100 MUg/kg body weight orally for 3 alternate days proved effective and showed a maximum fecal egg reduction of 99.20% and 100% (P < .05) at day 7 post-treatment. CONCLUSIONS: This study highlighted the molecular confirmation of Trichuris species in non-human primates and its management using fenbendazole and ivermectin. PMID- 29979811 TI - Factors associated with additional time dental hygienists spent on educating patients with diabetes. AB - AIMS: To investigate what dental hygienists' practice characteristics and oral health topics are associated with additional time dental hygienists spent on educating patients with diabetes. METHODS: A one-page survey was mailed to 2237 registered dental hygienists in South Carolina. Survey questions focused on perceptions of dental hygienists regarding their oral health preventive education for patients with diabetes. After two follow-up mails, we received 995 usable questionnaires. RESULTS: Multivariable logistic regression modeling showed dental hygienist respondents who spent additional time educating patients with diabetes about oral health felt they had adequately covered the topics on effects of periodontal disease related to diabetes, effects of uncontrolled diabetes on periodontal disease, and nutrition and dietary counseling. In addition, a higher number of patients with diabetes treated per week, and a shorter recall interval for patients were also associated with more likelihood of respondents spending additional time educating patients with diabetes. CONCLUSION: Results suggest that the additional time that dental hygienist respondents spent on educating patients with diabetes was related to oral health issues associated with diabetes, not just repetition of routine oral hygiene and plaque control instructions. PMID- 29979812 TI - Development of multiplex real-time reverse-transcriptase polymerase chain reaction assay for simultaneous detection of Zika, dengue, yellow fever, and chikungunya viruses in a single tube. AB - Zika virus (ZIKV), dengue virus (DENV), chikungunya virus (CHIKV) and yellow fever virus (YFV) share the same mosquito vectors and have similar clinical manifestations early stage of infection. Therefore, simultaneously differentiating these viruses from each other is necessary. We developed a multiplex real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay for the differentiation of these four viruses in a single tube. The linear range was established by regression analysis, and the R2 value for each virus was >=0.98, and the 95% lower limit of detection for each virus was as follows (copies/reaction): ZIKV-Asian, 9; ZIKV-Africa, 15; CHIKV, 11; DENV-1, 19; DENV-2, 13; DENV-3, 24; DENV-4, 36; and YFV, 17. Meanwhile, our multiplex real-time RT PCR has a good consistency with the commercial singleplex assay. In summary, the developed assay can be effectively used for the diagnosis of ZIKV, DENV, CHIKV, and YFV infections. PMID- 29979813 TI - Searching for a simpler treatment for paediatric osteoarticular infections. PMID- 29979814 TI - Listeriolysin O Binding Affects Cholesterol and Phospholipid Acyl Chain Dynamics in Fluid Cholesterol-Rich Bilayers. AB - Listeriolysin O (LLO) is a pore-forming toxin that enables survival and cell-to cell spread of foodborne bacterial pathogen Listeria monocytogenes, which is responsible for the life-threatening disease, listeriosis. LLO-membrane interactions are crucial for pathogenicity of Listeria, but remained unexplained in detail at the molecular level. Here we addressed them by means of 2 H, 31 P, 13 C and 19 F solid-state NMR spectroscopy. Different fluid and ordered cholesterol-rich membrane lipid bilayer systems were prepared and checked for the integrity and properties in the presence of LLO. LLO has significantly changed dynamics of phospholipid acyl chains of more fluid cholesterol-rich bilayers, whereas the lipid bilayer organization was not affected. LLO has also affected cholesterol dynamics by increasing the intensity of low frequency motions, indicating direct interactions of LLO with cholesterol. Additionally, the LLO protein was shown to interact differently with lipid membranes, depending on the properties of cholesterol-rich membranes. The presented results, therefore, provide new insights into the interactions of the bacterial toxin LLO with cholesterol-rich membrane systems. PMID- 29979815 TI - A Bifunctional MOF Catalyst Containing Metal-Phosphine and Lewis Acidic Active Sites. AB - Post-synthetic modification of the hafnium metal-organic framework MOF-808(Hf) to include triarylphosphine ligands is reported. Sulfonated phenylphosphines are incorporated without oxidation to give a "MOF ligand" that can complex late transition metals such as Ir and Rh to give a bifunctional catalyst containing both metal-phosphine complexes and the Lewis acidic framework hafnium metal sites. The metallated phosphine-bearing MOFs act as fully heterogeneous bifunctional catalysts for tandem reductive amination and hydroaminomethylation reactions. PMID- 29979816 TI - Molecular epidemiology of noroviruses in children in South Greece, 2013-2015. AB - Noroviruses constitute the leading cause of acute, nonbacterial gastroenteritis that affects both children and adults in healthcare and community settings. The current study attempted to provide insight on the molecular epidemiology of noroviruses in children in South Greece. Genotypic characterization of 69 norovirus strains detected in stool samples from children with gastroenteritis during a period of 30 months (January 2013 to June 2015) was performed on the basis of ORF2 (VP1 capsid) gene sequences. The results revealed the circulation of a diverse variety of norovirus genotypes. GII.4 was the predominant genotype (74%), followed by GII.2 (8.7%), GII.3 (5.8%), GII.6 (2.9%), GI.2 (2.9%), and four strains identified as GII.1, GII.7, GII.8, and GII.13, respectively. Phylogenetic analysis showed that most of the strains were closely associated with norovirus strains that circulated globally either in outbreaks and sporadic cases of gastroenteritis or in the environment during the last 4 years. Omicronf the GII.4 strains, 80.4% were detected between January 2013 and February 2014, indicating a possible ongoing epidemic. The incidence of other genotypes remained constant throughout the study period. Genotypic and phylogenetic analysis showed the predominance of the "Sydney 2012" variant among the GII.4 strains, whereas one GII.4 strain was identified as a "New Orleans 2009" variant. Five GII.4 strains showed significant nucleotide and amino acid sequence divergence from either the "Sydney 2012" or the "New Orleans 2009" variant, and these divergent strains might represent an emerging GII.4 variant. PMID- 29979817 TI - Three branches to rule them all? UPR signalling in response to chemically versus misfolded proteins-induced ER stress. AB - Study of the unfolded protein responses (UPR) is mainly addressed by challenging eukaryotic cells with chemical compounds that impair calcium, redox or glycan homeostasis. These dramatically alter the endoplasmic reticulum (ER) environment and function, but also trigger pleiotropic effects that may result in multi organellar failure and cell death. Recent works showed that UPR induced by the accumulation of unfolded polypeptides in the ER lumen drastically differs from chemically induced UPR. Unfolded proteins are tolerated by cells, which activate a finely tuned UPR without entering apoptotic programs. How cells adapt the UPR to the burden of misfolded proteins, what structural features of the accumulating proteins determine UPR intensity and how these mechanisms translate into disease are crucial questions to be address in the future. PMID- 29979818 TI - Capture Hi-C Library Generation and Analysis to Detect Chromatin Interactions. AB - Chromosome conformation capture (3C), coupled with next-generation sequencing (Hi C), provides a means for deciphering not only the principles underlying genome folding and architecture, but more broadly, the role 3D chromatin structure plays in gene regulation and the replication and repair of DNA. The recently implemented modification, in situ Hi-C, maintains nuclear integrity during digestion and ligation steps, reducing random ligation of Hi-C fragments. Although Hi-C allows for genome-wide characterization of chromatin contacts, it requires high-depth sequencing to discover significant contacts. To address this, Capture Hi-C (CHi-C) enriches standard Hi-C libraries for regions of biological interest, for example by specifically targeting gene promoters, aiding identification of biologically significant chromatin interactions compared to conventional Hi-C, for an equivalent number of sequence reads. Illustrating the application of CHi-C applied to genome-wide analysis of chromatin interactions with promoters, we detail the protocols for in situ Hi-C and CHi-C library generation for sequencing, as well as the bioinformatics tools for data analysis. (c) 2018 by John Wiley & Sons, Inc. PMID- 29979819 TI - Long-Term Genistein Consumption Modifies Gut Microbiota, Improving Glucose Metabolism, Metabolic Endotoxemia, and Cognitive Function in Mice Fed a High-Fat Diet. AB - SCOPE: The aim of this study is to assess whether the long-term addition of genistein to a high-fat diet can ameliorate the metabolic and the cognitive alterations and whether the changes can be associated with modifications to the gut microbiota. METHODS AND RESULTS: C57/BL6 mice were fed either a control (C) diet, a high-fat (HF) diet, or a high-fat diet containing genistein (HFG) for 6 months. During the study, indirect calorimetry, IP glucose tolerance tests, and behavioral analyses were performed. At the end of the study, plasma, liver, brain, and fecal samples were collected. The results showed that mice fed the HFG diet gained less weight, had lower serum triglycerides, and an improvement in glucose tolerance than those fed an HF diet. Mice fed the HFG diet also modified the gut microbiota that was associated with lower circulating levels of lipopolysaccharide (LPS) and reduced expression of pro-inflammatory cytokines in the liver compared to those fed HF diet. The reduction in LPS by the consumption of genistein was accompanied by an improvement of the cognitive function. CONCLUSIONS: Genistein is able to regulate the gut microbiota, reducing metabolic endotoxemia and decreasing the neuroinflammatory response despite the consumption of a HF diet. PMID- 29979820 TI - Functional Effects of the Buckwheat Iminosugar d-Fagomine on Rats with Diet Induced Prediabetes. AB - SCOPE: The goals of this work are to test if d-fagomine, an iminosugar that reduces body weight gain, can delay the appearance of a fat-induced prediabetic state in a rat model and to explore possible mechanisms behind its functional action. METHODS AND RESULTS: Wistar Kyoto rats were fed a high-fat diet supplemented with d-fagomine (or not, for comparison) or a standard diet (controls) for 24 weeks. The variables measured were fasting blood glucose and insulin levels; glucose tolerance; diacylglycerols as intracellular mediators of insulin resistance in adipose tissue (AT), liver, and muscle; inflammation markers (plasma IL-6 and leptin, and liver and AT histology markers); eicosanoids from arachidonic acid as lipid mediators of inflammation; and the populations of Bacteroidetes, Firmicutes, Enterobacteriales, and Bifidobacteriales in feces. It was found that d-fagomine reduces fat-induced impaired glucose tolerance, inflammation markers, and mediators (hepatic microgranulomas and lobular inflammation, plasma IL-6, prostaglandin E2 , and leukotriene B4 ) while attenuating the changes in the populations of Enterobacteriales and Bifidobacteriales. CONCLUSION: d-Fagomine delays the development of a fat-induced prediabetic state in rats by reducing low-grade inflammation. We suggest that the anti-inflammatory effect of d-fagomine may be linked to a reduction in fat induced overpopulation of minor gut bacteria. PMID- 29979821 TI - Advantages, disadvantages and optimization of one-stage and chromogenic factor activity assays in haemophilia A and B. AB - Haemophilia A and B diagnosis and disease severity classification are determined on the basis of results from factor VIII (FVIII) and factor FIX (FIX) activity assays, respectively. These assays are also used for potency labelling, postinfusion monitoring of factor replacement products and testing for FVIII/FIX inhibitors. This review focuses on activated partial thromboplastin time (APTT) based one-stage assays (OSAs) and two-stage chromogenic substrate assays (CSAs). Currently, there is considerable inter-laboratory variability in the results obtained using OSAs, which can be intensified in a reagent-specific manner by the presence of the new modified recombinant factor replacement products that are entering the market. Furthermore, the use of CSAs, which tend to show less variability, especially with the new modified products, is recommended in a number of clinical scenarios. Clinical laboratories may, therefore, need to establish CSAs for routine use. In this review, we aim to improve understanding and help establish best practices by describing the methodology behind OSAs and CSAs and highlighting assay advantages and limitations. We argue that there can be value in offering both assay methodologies in clinical laboratories that contribute to the care of patients with haemophilia A or B. Educating both laboratory scientists and clinicians about the strengths and weaknesses of each type of assay will help to establish the necessary dialogue that is key to ensuring not only that the appropriate assays are used in the right clinical situations, but also that the results are interpreted correctly. PMID- 29979822 TI - Covalent Assembly of Amphiphilic Bola-Amino Acids into Robust and Biodegradable Nanoparticles for In Vitro Photothermal Therapy. AB - Organic photothermal sensitizers, such as indocyanine green (ICG), have been widely explored in photothermal therapy as a good substitute for inorganic materials owing to their advantageous biosafety and strong absorption in the near infrared region. However, their intrinsic low stability and rapid clearance from the body requires further modification for efficient therapeutic application. In this work, we employed a covalent assembly strategy by covalently cross-linking genipin and a functional bola-amino acid to fabricate stable and degradable nanoparticles capable of loading ICG. The covalent assembly introduced strong covalent interactions in the assembly system together with functional linkers, which led to both enhanced stability and extended functionalities. This is distinguished from the conventional supramolecular strategy that relies only on weak noncovalent interactions. The functional building unit, consisting of phenylalanine and the disulfide bond, enables both good assembly and controllable degradation owing to the disulfide bond that responds to glutathione. The assembled nanoparticles show high stability, negligible toxicity, and considerable biodegradability. After loading ICG, the ICG-loaded nanoparticles possessed high photothermal conversion efficiency, and showed an enhanced photothermal effect in the near-infrared region. This covalent assembly strategy could be extended to various biomolecules containing a primary amino group for the fabrication of efficient and multifunctional nanomaterials used in biomedical applications. PMID- 29979823 TI - Role of estrogen and its receptors in HEV associated feto-maternal outcomes. AB - BACKGROUND: Pregnant women infected with HEV develops adverse pregnancy outcomes like, abortions, intrauterine fetal death, still births, neonatal deaths, preterm delivery and maternal mortality. AIM: To correlate estrogen & its receptors ESR1alpha and ESR2beta levels with HEV associated feto-maternal outcomes. MATERIAL & METHODS: A total of 142 pregnant women with HEV infection and 142 pregnant controls were included in study from Department of Obstetrics & Gynaecology and Department of Medicine, Maulana Azad Medical College (MAMC) and associated Lok Nayak Hospital (LNH), New Delhi. Three ml of blood sample was collected in plain for quantification of estrogen, and its receptors ESR1alpha and ESR2beta using commercially available third generation ELISA kits. RESULTS: The levels of estrogen, ESR1alpha and ESR2beta were considerably higher in HEV infected pregnant women(20.11+/-18.19ng/ml, 10.58+/-3.27ng/ml, 10.42+/-4.71ng/ml, respectively) than pregnant controls(11.74+/-6.42ng/ml, 9.11+/-1.63ng/ml, 9.01+/ 1.18ng/ml, respectively)(p<0.0001). It was found that estrogen levels were significantly higher in pregnant women infected with HEV who had preterm delivery, low birth weight babies and fetal loss(19.64+/-17.60ng/ml, 19.71+/ 17.63ng/ml, 33.62+/-23.20ng/ml, respectively) than who had full term delivery, average birth weight babies and live babies (11.71+/-8.77ng/ml, 11.99+/ 9.44ng/ml, 16.58+/-14.98ng/ml, respectively)(p<0.05). A significant negative correlation was observed between baby birth weight and estrogen levels in HEV infected pregnant women. CONCLUSION: The high level of estrogen plays an important role in preterm delivery, low birth weight babies and fetal mortality in pregnant women with HEV infection through placental dysfunction. Moreover, estrogen level is a significant predictor for preterm delivery & maternal mortality and ESR2beta levels is a significant predictor for maternal mortality in pregnant women infected with HEV. This article is protected by copyright. All rights reserved. PMID- 29979824 TI - Efficient Differentiation of Human Pluripotent Stem Cells to Endothelial Cells. AB - Endothelial cells (ECs) line the interior surface of blood and lymphatic vessels, and play a key role in a variety of physiological or pathological processes such as thrombosis, inflammation, or vascular wall remodeling. Human-induced pluripotent stem cell (iPSCs)-derived ECs provide a new opportunity for vascular regeneration and serve as a model to study the mechanism and to screen for novel therapies. We use developmental cues in a monolayer differentiation approach to efficiently generate mesoderm cells from iPSCs via small-molecule activation of WNT signaling in chemically defined medium for 4 days, and subsequent EC specification using vascular endothelial growth factor and fibroblast growth factor for another 4 days. After 8 days of differentiation, mature ECs are further purified using magnetic-activated cell sorting for the EC surface marker CD144. These ECs exhibit molecular and cellular characteristics consistent with native ECs, such as expression of specific surface markers, formation of tube like structures and acetylated low-density lipoprotein uptake. (c) 2018 by John Wiley & Sons, Inc. PMID- 29979825 TI - Dismantling of Vinyl Ethers by Pentanuclear [(iPr3 P)Ni]5 H6 : Facile Cooperative C-O, C-C and C-H Activation Pathways. AB - The [(iPr3 P)Ni]5 H6 cluster (1) and H2 C=CHOtBu react at room temperature to form the new pentanuclear NiH carbide [(iPr3 P)Ni]5 H4 (C)(CO) (3), along with an equivalent of isobutylene. This transformation requires the activation of multiple unreactive bonds, including C-H, C-C, and C(sp3 )-O bond cleavage. Analysis of the reaction mixture by 1 H NMR revealed the production of two additional paramagnetic species, assigned as [(iPr3 P)Ni]4 H4 (C-CH3 )NiOtBu (4 a) and [(iPr3 P)Ni]4 H4 (C-CH2 OtBu)NiOtBu (5 a), which arise from C(sp2 )-O bond cleavage and CH bond rearrangements. The reaction of 1 with H2 C=CHOSiMe2 CH2 Ph produced the isolable 4 a analogue [(iPr3 P)4 Ni5 ]H4 (CCH3 )(OSiMe2 CH2 Ph) (4 c). An isolable analogue of 5 a was obtained from the reaction of 1 with H2 C=CHOAd (Ad=1-admantyl), which produced [(iPr3 P)4 Ni5 ]H4 (CCH2 OAd)(OAd) (5 d). The utilization of both cluster faces and vertices for bonding substrate fragments in these transformations demonstrates the remarkable flexibility of the robust Ni5 H4 core in the cooperative activation of multiple C-O, C-C and C-H bonds. PMID- 29979826 TI - Fast Gas-Solid Reaction Kinetics of Nanoparticles Unveiled by Millisecond In Situ Electron Diffraction at Ambient Pressure. AB - Acquiring the kinetics of gas-nanoparticle fast reactions under ambient pressure is a challenge owing to the lack of appropriate in situ techniques. Now an approach has been developed that integrates time-resolved in situ electron diffraction and an atmospheric gas cell system in transmission electron microscopy, allowing quantitative structural information to be obtained under ambient pressure with millisecond time resolution. The ultrafast oxidation kinetics of Ni nanoparticles in oxygen was vividly obtained. In contrast to the well-accepted Wagner and Mott-Cabrera models (diffusion-dominated), the oxidation of Ni nanoparticles is linear at the initial stage (<0.5 s), and follows the Avrami-Erofeev model (n=1.12) at the following stage, which indicates the oxidation of Ni nanoparticles is a nucleation and growth dominated process. This study gives new insights into Ni oxidation and paves the way to study the fast reaction kinetics of nanoparticles using ultrafast in situ techniques. PMID- 29979827 TI - MCRiceRepGP: a framework for the identification of genes associated with sexual reproduction in rice. AB - Rice is an important cereal crop, being a staple food for over half of the world's population, and sexual reproduction resulting in grain formation underpins global food security. However, despite considerable research efforts, many of the genes, especially long intergenic non-coding RNA (lincRNA) genes, involved in sexual reproduction in rice remain uncharacterized. With an increasing number of public resources becoming available, information from different sources can be combined to perform gene functional annotation. We report the development of MCRiceRepGP, a machine learning framework which integrates heterogeneous evidence and employs multicriteria decision analysis and machine learning to predict coding and lincRNA genes involved in sexual reproduction in rice. The rice genome was reannotated using deep-sequencing transcriptomic data from reproduction-associated tissue/cell types identifying previously unannotated putative protein-coding genes and lincRNAs. MCRiceRepGP was used for genome-wide discovery of sexual reproduction associated coding and lincRNA genes. The protein-coding and lincRNA genes identified have distinct expression profiles, with a large proportion of lincRNAs reaching maximum expression levels in the sperm cells. Some of the genes are potentially linked to male- and female-specific fertility and heat stress tolerance during the reproductive stage. MCRiceRepGP can be used in combination with other genome-wide studies, such as genome-wide association studies, giving greater confidence that the genes identified are associated with the biological process of interest. As more data, especially about mutant plant phenotypes, become available, the power of MCRiceRepGP will grow, providing researchers with a tool to identify candidate genes for future experiments. MCRiceRepGP is available as a web application (http://mcgplannotator.com/MCRiceRepGP/). PMID- 29979828 TI - Reporting of Clinical Genome Sequencing Results. AB - High-throughput sequencing and high-performance computing technologies have become powerful tools in clinical genetic diagnosis of hereditary disorders and genetic screening of healthy individuals to provide information for the diagnosis, treatment, and prevention of diseases or impairment and assessment of health. For patients with undiagnosed disorders, including many rare disorders, the whole-genome sequencing (WGS) test may end the diagnostic odyssey, ultimately guiding clinical care for them and their families. A clinical WGS test relies on high-quality genome-sequencing data as well as sophisticated data-interpretation approaches. Results are returned to the ordering physician in a concise report featuring an overall test result and in-depth phenotype-driven interpretation of the known or plausible genetic explanation of test indications. Patients have the option to decide whether the report should include secondary and incidental findings. Protocols and templates for reporting clinical WGS results and supplementary information are described in this article. (c) 2018 by John Wiley & Sons, Inc. PMID- 29979829 TI - Acid-Hydrolyzed Gliadins Worsen Food Allergies through Early Sensitization. AB - SCOPE: Food allergies result from a complex immune response involving both innate and adaptive immune cells. Major proteins of wheat flour, gliadins, appear to be important allergens, and their characteristics can influence the allergic response. This study investigates the immune reaction when developing a food allergy to gliadins in native, deamidated, or hydrolyzed forms. METHODS: The immune response after one or two intraperitoneal sensitizations and after oral challenge with each gliadin form is analyzed. RESULTS: Results demonstrate that deamidated gliadins induce a stronger allergic reaction compared to native gliadins. Moreover, deamidation induces an earlier increase in intestinal permeability associated with more pronounced Th2 and Th17 polarizations together with an influx of antigen-presenting cells, especially cDC2. CONCLUSION: Altogether, Results indicate that industrial processes such as deamidation or hydrolysis influences food allergenicity through immune modulation and helps us to develop tools to determine how these processes can influence this reaction and encourage or decrease allergic reactions. PMID- 29979830 TI - Management of psoriasis. AB - Therapeutic procedures are dictated by burden and duration of disease, previous therapies and comorbidity. Possible triggers are to be taken into consideration and eliminate whenever possible. PMID- 29979831 TI - Architecture, remodeling, and functions of the septin cytoskeleton. AB - The septin family of proteins has fascinated cell biologists for decades due to the elaborate architecture they adopt in different eukaryotic cells. Whether they exist as rings, collars, or gauzes in different cell types and at different times in the cell cycle illustrates a complex series of regulation in structure. While the organization of different septin structures at the cortex of different cell types during the cell cycle has been described to various degrees, the exact structure and regulation at the filament level are still largely unknown. Recent advances in fluorescent and electron microscopy, as well as work in septin biochemistry, have allowed new insights into the aspects of septin architecture, remodeling, and function in many cell types. This mini-review highlights many of the recent findings with an emphasis on the budding yeast model. PMID- 29979832 TI - Rapidly growing facial nodule in a kidney transplant patient. PMID- 29979833 TI - Outbreaks associated with treated recreational water - United States, 2000-2014. PMID- 29979834 TI - Preventing PTLD? PMID- 29979835 TI - Stem Cell-Derived Pancreatic Progenitor Cells Have Now Been Transplanted into Patients: Report from IPITA 2018. PMID- 29979836 TI - A multi-institutional review of outcomes in biopsy-proven acute invasive fungal sinusitis. AB - BACKGROUND: Acute invasive fungal sinusitis (AIFS) is a rare, aggressive infection occurring in immunocompromised patients. In this study we examined factors that affect survival in AIFS, and whether immune-stimulating therapies (IST) improve survival. METHODS: Pathology records of biopsy-proven AIFS were reviewed from 3 academic institutions from 1995 to 2016. Univariate and multivariate Cox regressions were performed at 1 and 3 months from diagnosis. RESULTS: One hundred fourteen patients were included; 45 received IST. In the univariate analysis, the following factors were associated with worse survival: hematologic malignancy (3-month hazard ratio [HR], 3.7; p = 0.01); recent chemotherapy (within 1 month of AIFS diagnosis) (3-month HR, 2.3; p = 0.02); recent bone marrow transplant (BMT) (3-month HR, 2.5; p = 0.02); and infection with atypical fungi (1-month HR, 3.1; p = 0.04). The following were associated with improved survival in univariate analysis: increasing A1c% (1-month HR, 0.7; p = 0.01) and surgical debridement (1-month HR, 0.1; p = 0.001). One third of patients with a hematologic malignancy had an absolute neutrophil count (ANC) >1000 at the time of diagnosis. ANC was not associated with prognosis in these patients. The following were associated with worse survival in multivariate analyses: hematologic malignancy; recent chemotherapy; atypical organisms; and cavernous sinus extension. In multivariate analyses, IST was associated with a 70% reduction in mortality at 1 month (p = 0.02). CONCLUSION: We presented the largest series of AIFS. Further studies are needed to examine the importance of ANC in diagnosis and prognosis. Patients diagnosed with atypical organisms may be at higher risk of death. IST likely improves short-term survival, but prospective studies are needed. PMID- 29979837 TI - Total intravenous anesthesia improves intraoperative visualization during surgery for high-grade chronic rhinosinusitis: a double-blind randomized controlled trial. AB - BACKGROUND: Total intravenous anesthesia (TIVA) has been proposed as a method to reduce blood loss during endoscopic sinus surgery (ESS). Impaired sinonasal visualization due to mucosal bleeding may be burdensome in cases of chronic rhinosinusitis (CRS) with high-grade inflammatory disease, suggesting a role for TIVA in that disease subgroup. METHODS: A double-blind, randomized controlled trial was conducted of adults undergoing ESS at a tertiary medical center. Patients considered for inclusion had high-grade CRS defined as either sinonasal polyposis or a preoperative Lund-Mackay score of >=12. Subjects were randomized to receive either TIVA or inhaled anesthesia (IA) during ESS. The primary outcome measure was intraoperative visibility as rated by 3 blinded reviewers utilizing the 10-point Wormald Surgical Field Grading Scale. Secondary outcomes included operative blood loss, complications, and change in quality of life evaluated by the 22-item Sino-Nasal Outcome Test (SNOT-22). RESULTS: A total of 72 patients were randomized into TIVA (n = 37) and IA (n = 35) study arms. Aggregate median (interquartile range) Wormald scores across all reviewers demonstrated a more favorable visual field with TIVA compared to IA (3.5 [2.4-3.9] vs IA 4.1[3.0 5.8], p = 0.0089). There was significantly less blood loss in the TIVA group compared to the IA group (200 mL [100-450] vs 300 mL [200-500], p = 0.046). Baseline patient characteristics were comparable between cohorts with no significant postoperative complications. No significant changes were detected between postoperative SNOT-22 scores at 3 months (p = 0.278) and at 6 months (p = 0.396) following ESS. CONCLUSION: TIVA contributes to improved intraoperative visualization and decreased blood loss in patients undergoing ESS for high-grade inflammatory sinus disease. PMID- 29979838 TI - Inflammatory immune response in rabbits with Staphylococcus aureus biofilm associated sinusitis. AB - BACKGROUND: Staphylococcus aureus is the most commonly isolated bacterium from patients with surgically recalcitrant chronic rhinosinusitis (CRS). Understanding the immune responses to S aureus biofilms will provide insights into how the host response may be manipulated by therapeutic agents to improve the chances of successfully preventing and treating these infections. In this study, we investigated the inflammatory immune response in a rabbit model of S aureus biofilm-related sinusitis by analyzing the levels of some major inflammatory cytokines. METHODS: Eighteen New Zealand white rabbits were randomly divided into 3 groups: a blank-control group; a negative-control group; and a model group. Four weeks after the biofilm-associated sinusitis models were established, the sinus mucosa was harvested and examined using hematoxylin-eosin (H&E) staining, scanning electron microscopy (SEM), reverse transcription polymerase chain reaction (RT-PCR), and western blotting. The expression levels of inflammatory cytokines were analyzed statistically. RESULTS: Interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha expression levels were significantly higher in the model group than in the blank-control group (p < 0.05); mRNA levels were increased by 1600%, 230%, and 130%, respectively, and the protein levels were increased by 180%, 100%, and 100%, respectively. In contrast, IL-4 and IL-5 mRNA levels were reduced by 44% and 70%, respectively, compared with the blank-control group (p < 0.05). CONCLUSION: S aureus biofilms in the rabbit maxillary sinus mucosa were associated with increased IL-1beta, IL-8, and TNF-alpha expression, and decreased IL-4 and IL-5 expression. PMID- 29979839 TI - The effect of urban particulate matter on cultured human nasal fibroblasts. AB - BACKGROUND: Exposure to urban particulate matter (UPM) has been linked to aggravation of various health problems. Although the effects of UPM on the lower respiratory tract have been extensively studied, more research is required on the impact of UPM on the upper respiratory tract and the underlying mechanisms. Thus, we investigated the cytotoxic effects of UPM on cultured human nasal fibroblasts, the underlying signaling pathways involved, and changes in cytokine levels. METHODS: Human turbinate tissue specimens were collected during partial turbinectomies performed on 6 patients, and then cultured. The effect of UPM on nasal fibroblast viability was explored. Real-time reverse transcription polymerase chain reaction was used to measure the mRNA levels of genes encoding cytokines and chemokines (interleukin [IL]-4, IL-6, IL-8, and tumor necrosis factor-alpha) before and after 24 hours of UPM treatment. Enzyme-linked immunosorbent assays were employed to measure IL-6 and IL-8 levels. The status of the p38 and nuclear factor (NF)-kappaB signaling pathways was analyzed by Western blotting. RESULTS: UPM reduced cell viability in a dose-dependent manner and increased IL-6 and IL-8 expression at both the mRNA and protein levels. UPM induced the phosphorylation of p38 and NF-kappaB p65; inhibitors of the actions of these proteins repressed phosphorylation and the expression of IL-6 and IL-8. CONCLUSION: UPM induced IL-6 and IL-8 expression by fibroblasts via p38 and NF kappaB classical signaling, suggesting that UPM can induce or aggravate allergic and/or chronic rhinitis. PMID- 29979840 TI - Association between allergic rhinitis and poor sleep parameters in U.S. adults. AB - BACKGROUND: Evidence suggests relationships between allergic rhinitis (AR) and poor sleep parameters, but population-based studies in the United States are lacking. This study investigates the relationship between AR and sleep parameters in a representative sample of U.S. adults. METHODS: Cross-sectional study of 5563 participants >=18 years old from the 2005-2006 National Health and Nutrition Examination Survey who participated in the allergy and sleep questionnaires. The predictor variable was AR (self-reported hay fever and/or nasal symptoms in the past 12 months). The outcome variables were individual sleep parameters (sleep latency, sleep duration, sleep disorders, sleep habits, sleep medication use, daytime dysfunction). Covariates included age, gender, race, and obesity. RESULTS: The population-weighted prevalence of AR was 36.5%. Adjusting for covariates, subjects with AR had higher odds of sleep latency >=30 minutes (OR 1.24; 95% CI, 1.01 to 1.51; p = 0.04), sleep apnea (OR 1.86; 95% CI, 1.22 to 2.82; p < 0.01), insomnia (OR 1.85; 95% CI, 1.04 to 3.32; p = 0.04), trouble falling asleep (OR 1.43; 95% CI, 1.17 to 1.75; p < 0.01), waking up during the night (OR 1.49; 95% CI, 1.11 to 1.99; p = 0.01), waking up too early in the morning (OR 1.46; 95% CI, 1.20 to 1.79; p < 0.01), feeling unrested during the day (OR 1.76, 95% CI, 1.43 to 2.16; p < 0.01), feeling overly sleeping during the day (OR 1.54; 95% CI, 1.25 to 1.90; p < 0.01), not getting enough sleep (OR 1.68; 95% CI, 1.41 to 1.99; p < 0.01), using sleep medication (OR 1.69; 95% CI, 1.23 to 2.33; p < 0.01), difficulty concentrating (OR 1.93; 95% CI, 1.30 to 2.88; p < 0.01), remembering (OR 1.91; 95% CI, 1.22 to 2.97; p < 0.01), managing finances (OR 1.68; 95% CI, 1.09 to 2.56; p = 0.02), working (OR 2.16; 95% CI, 1.45 to 3.22; p < 0.01), and getting things done (OR 2.35; 95% CI, 1.36 to 4.06; p < 0.01) due to daytime sleepiness. CONCLUSION: This analysis of a representative sample of U.S. adults revealed associations between AR and poor sleep parameters including prolonged sleep latency, insomnia, sleep apnea, sleep disturbances, sleep medication use, and daytime dysfunction. These findings reinforce the need to assess sleep quality in patients undergoing evaluation for AR. PMID- 29979841 TI - Incorporation of antibiotics and systemic steroids by sinus surgeons: is there widespread consensus? AB - BACKGROUND: The objective of this work was to evaluate factors associated with antibiotic and oral corticosteroid (OCS) prescription among otolaryngologists regularly performing sinus surgery. METHODS: Fellowship-trained rhinologists, including fellowship directors, were identified via the American Rhinologic Society (ARS) website. Non-fellowship-trained otolaryngologists performing >=25 balloons (frontal/maxillary) or >=25 functional endoscopic sinus surgeries (FESSs) (frontal/maxillary/ethmoids) were also included in "balloon surgeons" and "sinus surgeon" cohorts, respectively. Prescribing data for Medicare Part D beneficiaries was obtained for 2015. RESULTS: Otolaryngologists included in this analysis wrote a median of 54 scripts for antibiotics, with a 15.1% antibiotic prescription rate. The overall script length per antibiotic was 11.1 days. Of fellowship-trained rhinologists, 90.2% wrote fewer than 100 scripts, compared to 25.6% and 32.5% of sinus surgeons and balloon surgeons, respectively. Fellowship trained rhinologists wrote lengthier antibiotic scripts (14.1 vs 10.3 days, p < 0.05). Clinicians who have been in practice longer prescribed antibiotics significantly more frequently. Fellowship-trained rhinologists had a greater OCS rate (8.9%) than balloon and sinus surgeons (7.1%), also writing lengthier courses (15.0 vs 8.1 days). Early-career otolaryngologists wrote lengthier steroid prescriptions than those with 11 to 20 years and >20 years in practice. CONCLUSION: Antibiotic and OCS utilization varies by type of training, as non fellowship-trained sinus surgeons and balloon surgeons tend to utilize antibiotics more aggressively, and fellowship-trained rhinologists utilize OCS more frequently. Otolaryngologists with more years in practice are more likely to incorporate antibiotics in the management of sinus disorders, although these conclusions must be considered in the context of this resource's limitations. Further clarification of guidelines may be helpful for minimizing divergent practices and maintaining a consensus. PMID- 29979842 TI - The lamina push test: an alternative to the globe push test for identifying the medial orbit during endoscopic sinus surgery. AB - BACKGROUND: Aside from endoscopic and image guidance confirmation, the standard method of identifying the lamina involves the surgeon or an assistant applying gentle pressure on the globe externally. This globe push test requires the surgeon to remove one instrument from the endoscopic field or an assistant to press on the globe, and the test is most useful when either the periorbita or periorbital fat is exposed. We propose an alternative, equally accurate, and more efficient technique dubbed the lamina push test. METHODS: A blunt instrument is used to gently apply lateral pressure in the expected location of the medial orbital wall. If the lamina has been adequately skeletonized, the entire lamina will be seen to move as a unit. If residual ethmoid partitions are present, no movement or only localized movement is observed. RESULTS: Using the lamina push test, we have been able to safely identify the lamina papyracea in all patients undergoing endoscopic sinus surgery, without injury to the lamina or orbital contents. The use of direct pressure significantly increases the movement of an intact lamina. CONCLUSION: The lamina push test is a safe and effective technique for identification of the medial orbital wall, confirmation of removal of all lateral ethmoid partitions, and verification of lamina integrity. It enables more consistent identification of an intact lamina, allows the surgeon to keep both instruments in the endonasal surgical field, and does not require an assistant. PMID- 29979843 TI - The psoriasis patient - an exemplification of interdisciplinarity. AB - As quite typical for patients with plaque psoriasis, mainly if they are seriously affected, some of the major problems aside the obvious systemic inflammatory component, are social decline due to loss of work and/or personal problems. With this case presentation we are shedding light on the actual extent of this disease in our society. PMID- 29979844 TI - [Effect of apigenin on dendritic cells maturation and function in murine splenocytes]. AB - This study was designed to explore the effect of apigenin (Api) on dendritic cell (DCs) maturationand function in murine spleen cells. The single spleen cell was isolated, and then cultured with lipopolysaccharide(LPS) in the present and absence of apigenin. After 24 h, the toxicity of Api and the T cell proliferation weredetermined by CCK8 kit. In addition, we collected the cell-free supernatants to measure cytokine productionusing ELISA, collected the cells to determine the DC maturation using flow cytometry. Finally, we purifiedApi and/or LPS-treated CD11c+ DCs which were pulsed with ovalbumin (OVA)323-339 and then were adoptivetransferred into C57BL/6 mice to detect the OVA323-339-specific T cell proliferation and T helper (Th1) and Th2cell secreting IFN-gamma and IL-4 production, respectively. We found that Api did not affect splenocyte viability, butinhibited the production of pro-inflammatory cytokine IL-1beta, IL-6 and TNF alpha, not anti-inflammatory cytokineIL-10. In addition, Api inhibited the expression of co-stimulatory CD80, CD86 and MHCII of CD11c + DCs.Finally, compared to LPS+OVA DCs group, DCs from Api and LPS co-treated splenocytes (Api+LPS+DCs)impaired OVA323-339-specific T cell proliferation and the production of IFN-gamma and IL-4 in CD4+ T cells, whichhad the similar responses with OVA+DCs. These data suggest that Api exhibits anti-inflammatory propertiesvia inhibiting DC activation and function, as a new immune-modulator, which may induce immune-tolerancewith a benefit to those with chronic inflammation. PMID- 29979845 TI - The cancer patient's soul. AB - In general, every cancer patient should have access to psycho-oncological treatment, aiming at helping patients to deal with the difficult situation. The patient's individual need for treatment can be ascertained by measuring the patient's degree of distress. The general and individual treatment goal should be to maintain a certain quality of life and to assess and treat serious psychiatric diseases resulting from the cancer diagnosis such as anxiety disorder or depression. Treatment possibilities include: psycho-oncological psychotherapy as depth psychology, supportive, analytic or behavioral psychology, as well as group therapy in terms of support groups, with relatives or without as a mere patient group. PMID- 29979846 TI - [Transglutaminase-based antibody-drug conjugation: antibody site-specific mutation and identification]. AB - Transglutaminase (TG) posttranslational modification of antibody permits more preciselyconjugating. Based on the amino acid sequence of an anti-CD24 antibody (cG7), this article is aimed togenerate a deglycosylated cG7 mutant (cG7Q). Firstly, we introduced additional glutamines at position 297(N297Q) by site directed mutagenesis, and then transfected the recombinant plasmids into CHO-s cells viaelectroporation method and screened by Dot blot assay. Subsequently, cG7Q was expressed and purifiedthrough Protein A affinity chromatography, further identified by SDS-PAGE electrophoresis and Western blot.Its affinity was detected with surface plasmon resonance and flow cytometry assay, and ADCC effect wasdetermined by lactate dehydrogenase (LDH) release. Eventually, a cG7 mutant, cG7Q was successfullyexpressed with sequence-specific conjugation sites for further study. PMID- 29979847 TI - Curses or blessings? Opioids in non cancer chronic pain. AB - In the last ten years opioid prescription has increased considerably. It is not that cancer patients would receive more analgesics, but it rather can be traced to a rising use of opioids for non cancer chronic pain (NCCP). There is evidence that serious opioid overuse may be present. Why should NCCP patients not benefit from opioid therapy and which side effects would justify to deprive NCCP patients of these strong analgesics? Our article summarizes the current discussion on opioid use in NCCP and outlines current evidence. PMID- 29979848 TI - [Screening of small molecule inhibitors for PLK1 PBD and evaluation of antitumor activities]. AB - With the method of fluorescence polarization (FP), we screened small molecule inhibitors forPLK1 PBD to identify the lead compounds for antitumor drugs. FP led to the identification of a potent hit,F083-0063, whose inhibition rate was (99.7 +/- 0.4) % at 10 MUg.mL-1. The IC50 was calculated to be 1.9 +/- 0.1MUmol.L-1 using Graphpad Prism 5. The effect of the compound on cells' multiplication was measured by MTTassay which showed that F083-0063 inhibited the proliferation of many tumor cell lines. Flow cytometryanalysis indicated that the F083-0063 promoted cell apoptosis and induced cell G2/M arrest. Migration abilitiesof cells, evaluated using scratch test, increased significantly in the presence of F083-0063 with the migration rateas low as (37.6 +/- 0.7) % at 20 MUmol.L-1. Molecular linkage technique found F083-0063 had good affinity withPLK1 PBD. The results of Western blotting showed that the expression of cyclin-dependent proteins wasincreased after treatment with F083-0063. In summary, F083-0063 has an antitumor activity and is expectedto be an antitumor lead compound targeting PLK1 PBD. PMID- 29979849 TI - [In process]. PMID- 29979851 TI - [In process]. PMID- 29979850 TI - [Design, synthesis and evaluation of a novel MEK protein inhibitors]. AB - This study was conducted to design and synthetize highly efficient, specific, non resistantsmall MEK inhibitors. Based on active small molecules which have been reported, we studied the actionmode with MEK protein using Autodock 4.2, generated innovative and feasible design method, designednovel small MEK protein inhibitors with a reference to molecular modeling and docking. The anti tumoractivities of four kinds of cells including MCF-7, PANC-1, SY5Y, A549 were tested with MTT methodin vitro. The structure of 10 new small molecules has been determined with 1H NMR and 13C NMR. Thecompounds 4, 6, 7, 8, 10 had high antitumor activities, the compounds 1, 3, 5 also showed good activity,and the compounds 2, 9 showed cell selectivity in killing tumor. PMID- 29979852 TI - [In process]. PMID- 29979853 TI - [In process]. PMID- 29979854 TI - [A new triterpenic acid from the roots of Rosa laevigata]. AB - This study was designed to investigate triterpenoids from the roots of Rosa laevigata Michx.The silica gel column chromatography was used to separate the chemical constituents from the roots of Rosalaevigata Michx. HPLC was used to analyze its purity and chemical constitution. Spectroscopy methods wereused to determine their structures. Five constituents were isolated and identified as19alpha-OH-3beta-E-feruloyl corosolicacid (1), 23-hydroxy-tormentic acid (2), 2alpha, 3beta, 19alpha, 23- tetrahydroxy-12-en-28-oleanolic acid (3), 2alpha, 3alpha, 20beta-trihydroxyurs-13 (18)-en-28-oic-acid (4), 2alpha, 3beta, 20beta trihydroxyurs-13 (18)-en-28-oic-acid (5). Compound 1 wasassigned as a new compound, compounds 4, 5 were obtained from the genus Rosa for the first time. PMID- 29979855 TI - [In process]. PMID- 29979856 TI - [Quality control of human chorionic gonadotrophin subunit dissociation]. AB - Human chorionic gonadotrophin (hCG), a glycohormone widely used in treatment of infertility,is a heterodimer composed of an alpha- and a beta-subunit. The heterodimer could be dissociated duringproduction and storage with an impact on its bioactivity. A CE-SDS method for quantitative analysis of hCGsubunit dissociation was established in this study by optimization of a variety of method conditions includingsample preparation buffer compositions, incubation temperature, separation voltage, and capillary temperature.This method was validated for good sensitivity, linearity, precision, and accuracy for both alpha and beta-subunit.CE-SDS also showed much better precision and accuracy than SDS PAGE. The method was successfully usedin both recombinant hCG (r-hCG) produced by cell culture and hCG (u-hCG) derived from urine. The CE-SDSmethod was used in the study of hCG development and stability. Therefore, it is an useful tool for the qualitycontrol of hCG. PMID- 29979857 TI - [Activating blood biological potency assay and chemical fingerprint chromatogram applied to quality evaluation of rhubarb]. AB - The biological potency assay and chemical fingerprint chromatogram were applied to qualityevaluation of rhubarb. Using the biological potency as indicators, we evaluated the differences in quality ofmultiple batches of rhubarbs and related products. Using the platelet aggregation analyzer, we determinedplatelet aggregation rate in the different rhubarbs preparations, and calculated the biological potency based on thesimplified probit principle. UPLC was adopted to establish the fingerprint spectra for rhubarbs. The spectralefficiency correlation analysis between chromatograms and biological potencies were conducted using the doublevariables of SPSS 22.0 software. We used three chemical composition to verify the potency. The biologicalpotency results suggest that Rheum palmatum has a more potent activity than Rheum tanguticum, andwine-treated rhubarb had a higher potentcy than charred. We identified 10 elements in the Fingerprint Spectrum.The relevant elements including rhein-8-O-beta-D-glucoside, emodin-8-O-beta-D-glucoside and rhein have thestrongest activity in the inhibition of platelet aggregation. In conclusion, this study provides a analyticalmethod for rhubarb biological potency based on determination of the maximum antagonism rate model. Therhein may be the effective substance. It may serve as a reference in the quality control of wine processedrhubarb products. PMID- 29979858 TI - [Simultaneous determination of donafenib and its N-oxide metabolite in human plasma by liquid chromatography-tandem mass spectrometry]. AB - Donafenib is the deuterium derivative of sorafenib, and is an anti-tumor drug in clinical trials.An accurate and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developedand validated for the simultaneous determination of donafenib and its N-oxide metabolite in human plasma.The analytes and internal standards (sorafenib and sorafenib N-oxide) were extracted from plasma by proteinprecipitation with acetonitrile, and separated on a Gemini C18 (50 mm * 2.0 mm, 5 MUm) column using a gradientelution procedure. The mobile phase consisted of acetonitrile and 5 mmol .L-1 ammonium acetate (0.2% formicacid) at a flow rate of 0.7 mL.min-1. The total run time was 5.0 min. Positive electrospray ionization wasperformed using multiple reaction monitoring (MRM) with transitions of m/z 468.2 -> 273.2 for donafeniband m/z 465.2 -> 270.2 for its internal standard sorafenib, m/z 484.2 -> 289.2 for donafenib N-oxide and m/z481.2 -> 286.2 for its internal standard sorafenib N-oxide. The standard curves were linear in the range of5.00-5 000 ng.mL-1 for donafenib, and 1.00-1 000 ng.mL-1 for donafenib N-oxide. The method was validatedand successfully applied to the pharmacokinetics study of donafenib tosylate tablets in volunteers. PMID- 29979859 TI - [In vivo study of Chuankezhi metabolism in rat]. AB - To study the metabolic products of main compounds of Chuankezhi injection in rat, 12 SpragueDawley rats were classed into 2 groups, a blank control group and an intermuscular administration group,respectively. Rat feces and urine samples were collected from 0-24 h and 24-48 h after administration. Allthe samples were ultrasonically treated with methanol and then analyzed using LC-LTQ Orbitrap MSn. Bycomparison with the total ion chromatogram of samples from the blank control group, the metabolites in thesamples of drug-treated group were screened. These metabolites were further analyzed by multistage production scanning and comparison of retention time with reference substances. As a result, a total of 12 flavonoidmetabolites were tentatively identified from the rat feces and no metabolite was discovered in the rat urine.Epimedin C and icariin were detected in the rat blood samples after 30 min of administration, but theirmetabolites and other original flavones were not detected. Furthermore, no original flavones and theirmetabolites were detected in rat blood samples after 2 and 4 h of administration. The potential metabolismpaths were further characterized and the principal in vivo transformation of flavones from Chuankezhi injectionwere deglycosylation, dehydration, methylation, oxidation and isomerization in rats. PMID- 29979860 TI - [Chromatographic fingerprint analysis of Toosendan Fructus by HPLC-CAD coupled with chemometrics methods]. AB - A new method was developed for the chromatographic fingerprint analysis of Toosendan Fructusby HPLC coupled with the charged aerosol detector (CAD) in the present study. Samples were well separatedon an Agilent ZOBAX SB C18 column (4.6 mm * 250 mm, 5 MUm) by gradient elution using acetonitrile and watercontaining 0.1 % formic acid (v/v) at the flow rate of 1.0 mL.min-1. The column temperature was 30 C and theinjection volume was 5 MUL. The nitrogen inlet pressure of the charged aerosol detector (CAD) was 35 psi, andthe nebulizer chamber temperature was 35 C. In addition, the method of the chromatographic fingerprintscombined with multivariate statistical analysis was effective and reasonable lead to an accurate classification of20 batches of samples from different locations. The results showed that 28 common peaks were observed in thefingerprint and the samples were classified into three clusters. The established method was well validated, andshowed high precision, good repeatability, and satisfactory stability. It may serve in the quality control andevaluation of Toosendan Fructus. PMID- 29979861 TI - [On-line detection of concentration process of Ganmaoling granules by near infrared spectroscopy combined with automatic control system]. AB - Our research was designed for on-line detection of multi-index in the concentration process ofGanmaoling granules by integration of near infrared spectroscopy and automatic control system. First, on-linedetection system was set up in the concentration tank for Ganmaoling granules production. Spectra werescanned and values of chlorogenic acid, linarin, solid content and relative density were measured. Modelsof partial least squares regression were built and imported into near infrared workstation. By connectingthe control system, real time multi-index values were determined automatically in the concentration process.Results showed that correlation coefficients of chlorogenic acid, linarin, solid content and relative density modelswere 0.963, 0.989, 0.993 and 0.918, respectively. Relative standard errors of prediction were 3.71%, 4.28%,4.17% and 0.24%, respectively, indicating a good performance and high accuracy of the models. Real-time datacollection during the whole process was measured by the near infrared detecting system in the control system.In conclusion, the near infrared detection system is able to perform real-time automatic determination of multiindexin the concentration process of Ganmaoling granules with significant advantages. PMID- 29979862 TI - [Endocytosis pathway and intracellular distribution of heparosan]. AB - In this study, the endocytosis pathway of heparosan and its intracellular distribution wereinvestigated in MCF-7 tumor cells and COS7 normal cells. The endocytosis inhibition and cellular probelocation experiments showed that MCF-7 tumor cells took heparosan more efficiently and selectively than COS7cells. The cellular uptake of heparosan was energy-dependent in both MCF-7 tumor cells and COS7 normalcells. Moreover, the major endocytosis pathway of heparosan into MCF-7 tumor cells was caveolin-mediatedendocytosis and macropinocytosis. The internalized heparosan was mainly located in lysosomes of the cells. PMID- 29979863 TI - [Application of magnetic iron oxide nanoparticles in magnetic resonance / photothermal dual-modal imaging]. AB - In this study, water-dispersible magnetic iron oxide (Fe3O4) nanoparticles were synthesized withsolvothermal method. The nanoparticles were characterized with a transmission electron microscopy (TEM)and vibrating sample magnetometer (VSM). The in vitro magnetic resonance response and photothermalconversion characteristics of the nanoparticles were evaluated. In addition, the cellular uptake, cytotoxicityand biodistribution were studied. Finally, magnetic resonance/photothermal dual-modal imaging effect ofthe as-synthesized Fe3O4 nanoparticles was investigated in the tumor-bearing mice. The results showed thatthe obtained magnetic nanoparticles were uniform with a mean diameter of about 125 nm. Moreover, thesuperparamagnetic Fe3O4 nanoparticles showed remarkable magnetic resonance response and photothermalconversion properties. The results of cellular experiments showed that the cell viability was nearly 85% even theconcentration of the nanoparticles was up to 1 000 MUg.mL-1, an indicator of good biocompatibility. In addition,the nanoparticles could be taken up by the tumor cells and then located in the cytoplasm. After intravenousinjection, the nanoparticles were tended to enrich in the tumor over time, which is helpful in achievingdual-modal magnetic resonance/photothermal imaging. In sum, the obtained Fe 3O4 nanoparticles showed greatpotential to be applied for multi-modal bio imaging which may play an important role in the diagnosis of tumors. PMID- 29979864 TI - [Construction of the brain-targeting drug carrier through imprinting of nicotinic acetylcholine receptor alpha7]. AB - In this study, a novel brain-targeting carrier was made via conformational epitope imprinting.Acrylamide and N,N '-methylene bisacrylamide was used as carrier materials and the N-terminal epitope ofnicotinic acetylcholine receptor alpha7 (nAchR alpha7) was tested as a template molecule, and the polymer nanoparticleswere obtained after polymerization and template removal. The nanoparticles were investigated by particle sizeanalyzer and transmission electron microscopy (TEM). Their targeting capabilities were investigated with a celluptake assay in vitro and fluorescence imaging in vivo. The results suggest that the nanoparticles had a smallparticle size (42.1 +/- 4.3 nm) with a homogeneous distribution, and good targeting properties in vitro and in vivo.We have made the molecularly imprinted polymer nanoparticles with brain targeting capability, which representsa new tool in the treatment of brain diseases. PMID- 29979865 TI - [Identification of water buffalo horn and its adulterants using COI barcode]. AB - Bubali cornu (water buffalo horn) has been used as the substitute for Cornu rhinoceri asiatici(rhino horn) in clinical applications, and is the essential ingredient of Angong Niuhuang Wan. In recent years,there are a number of adulterants on the commercial herbal medicine markets. An efficient tool is requiredfor species identification. In this study, 155 Bubali cornu samples have been taken from original animals andcollected from commercial herbal medicine markets. 153 COI sequences have been successfully obtainedfrom 155 samples through DNA extraction, PCR amplification, bidirectional sequencing and assembly. 93COI sequences have been added to the DNA barcoding database of traditional Chinese animal medicine aftervalidation using DNA barcoding GAP and tree-based methods. The species identification of the 62 commercialBubali cornu medicines has been accomplished on the DNA barcoding system for identifying herbal medicineusing the updated animal medicine database (www.tcmbarcode.cn). Except two samples failed to obtain COIsequences, 54.8% of the commercial Bubali cornu medicines were water buffalo horns and 29% were yak horns.Our results showed that yak horn was the major adulterant of Bubali cornu and the DNA barcoding method mayaccurately discriminate Bubali cornu and their adulterants. Therefore, we recommend that supervision on theherbal medicine markets should be strengthened with this new method to warren the effectiveness of herbalmedicines. PMID- 29979866 TI - [The protective effects of curcumin loaded mesoporous silica nanoparticles on rat cardiomyocytes]. AB - Inhibition of apoptosis induced by oxidative stress is an effective way to reduce myocardial injury.In this study, we used H2O2-stimulated rat cardiac myoblast cell line (H9c2) as an oxidative damage model.Curcumin (Cur) was chosen as a model drug and mesoporous silica nanoparticles (MSNs) were chosen as thecarrier to construct a Cur-loaded delivery system (Cur@MSNs) and to examine its protective effects againstoxidative damage. The MSNs guaranteed efficient loading and controlled release of Cur. Besides, thehydrophilicsilanol groups on the surface of MSNs promoted the Cur solubility in water and increased itscellular uptake amount, which improved the bioavailability of Cur. The results suggest that the Cur@MSNswas pharmacologically active in the reduction of the oxidative damage of H9c2 cells. It was verified that agreat decrease of reactive oxygen species was inducted by Cur@MSNs, which led to the protective effectsagainst oxidative damage. PMID- 29979867 TI - Tight Translational Control Using Site-Specific Unnatural Amino Acid Incorporation with Positive Feedback Gene Circuits. AB - Tight regulatory system for gene expression, which is ideally controlled by unnatural and bio-orthogonal substances, is a keystone for successful construction of synthetic gene circuits. Here, we present a widely applicable approach to construct tight protein translational switches using site-specific unnatural amino acid (Uaa) incorporation systems. As a key mechanism to obtain excellent tightness, we installed gene circuits for positive feedback derepression. This mechanism dramatically suppressed leakage translation in the absence of the Uaa. In a translational switch with the feedback circuit in Escherichia coli, a 1.4 * 103 ON/OFF ratio was achieved which was 3 * 102-fold greater than that of the parent system and was comparable to that of the well known tight expression system using the araBAD promoter and the araC regulator. This method offers an avenue for generation of novel tight genetic switches from over a hundred site-specific unnatural amino acid incorporation systems which have already been established. These tight translational switches will facilitate the development of fine gene control systems in synthetic biology, especially for Uaa-auxotrophy-based biological containments and live attenuated vaccines. PMID- 29979868 TI - New Heterogeneous Rh-Containing Catalysts Immobilized on a Hybrid Organic Inorganic Surface for Hydroformylation of Unsaturated Compounds. AB - Anchoring Rh complexes to the surface of a silica polyamine composite, which has a poly(allylamine) covalently grafted to the surface of amorphous silica gel, yielded a material that proved to be an effective and novel heterogeneous catalyst for hydroformylation of unsaturated compounds. Surface amino groups of the material were modified with phosphines by covalent and ionic coupling. The modified materials were then treated with Rh(acac)(CO)2, giving the catalysts K-1 and K-2. Catalysts were characterized by solid-state NMR spectroscopy, IR spectroscopy, XPS, TEM, and elemental analysis. The activity and stability of K-1 and K-2 were then studied for the hydroformylation of selected unsaturated compounds. Hydroformylation of terminal double bonds occurred selectively in the presence of internal double bonds. Characterization of the catalysts and the problems encountered with the supported catalysts are discussed. Catalyst K-1 is reusable and can be applied to the hydroformylation of linear olefins, styrene, 4 vinylcyclohexene, and dienes, as well as representative terpenes and other unsaturated hydrocarbons in a batch reactor. PMID- 29979869 TI - Understanding Fluoroethylene Carbonate and Vinylene Carbonate Based Electrolytes for Si Anodes in Lithium Ion Batteries with NMR Spectroscopy. AB - Fluoroethylene carbonate (FEC) and vinylene carbonate (VC) are widely used as electrolyte additives in lithium ion batteries. Here we analyze the solid electrolyte interphase (SEI) formed on binder-free silicon nanowire (SiNW) electrodes in pure FEC or VC electrolytes containing 1 M LiPF6 by solid-state NMR with and without dynamic nuclear polarization (DNP) enhancement. We find that the polymeric SEIs formed in pure FEC or VC electrolytes consist mainly of cross linked poly(ethylene oxide) (PEO) and aliphatic chain functionalities along with additional carbonate and carboxylate species. The formation of branched fragments is further confirmed by 13C-13C correlation NMR experiments. The presence of cross-linked PEO-type polymers in FEC and VC correlates with good capacity retention and high Coulombic efficiencies of the SiNWs. Using 29Si DNP NMR, we are able to probe the interfacial region between SEI and the Si surface for the first time with NMR spectroscopy. Organosiloxanes form upon cycling, confirming that some of the organic SEI is covalently bonded to the Si surface. We suggest that both the polymeric structure of the SEI and the nature of its adhesion to the redox-active materials are important for electrochemical performance. PMID- 29979870 TI - Modulating the sigma-Accepting Properties of an Antimony Z-type Ligand via Anion Abstraction: Remote-Controlled Reactivity of the Coordinated Platinum Atom. AB - In search of ligand platforms, which can be used to remotely control the catalytic activity of a transition metal, we have investigated the coordination noninnocence of ambiphilic L2/Z-type ligands containing a trifluorostiborane unit as a Lewis acid. The known dichlorostiboranyl platinum complex (( o (Ph2P)C6H4)2SbCl2)PtCl (1) reacts with TlF in the presence of acetonitrile (MeCN) and cyclohexyl isocyanide (CyNC) to afford the trifluorostiborane platinum complexes 2 ((( o-(Ph2P)C6H4)2SbF3)Pt-NCMe) and 3 ((( o-(Ph2P)C6H4)2SbF3)Pt CNCy), respectively. Formation of these complexes, which results from a redistribution of the halide ligands about the dinuclear core, affects the nature of the Pt-Sb bond. The latter switches from covalent in 1 to polar covalent (or dative) in 2 and 3 where the trifluorostiborane moiety engages the platinum center in a Pt -> Sb interaction. The polarity of the Pt-Sb bond can be modulated further by abstraction of an antimony-bound fluoride ligand using B(C6F5)3. These reactions afford the cationic complexes [(( o-(Ph2P)C6H4)2SbF2)Pt-NCMe]+ ([5]+) and [(( o-(Ph2P)C6H4)2SbF2)Pt-CNCy]+ ([6]+) which have been isolated as [BF(C6F5)3]- salts. These complexes possess a highly Lewis acidic difluorostibonium moiety, which exerts an intense draw on the electron density of the platinum center. As a result, the latter becomes significantly more electrophilic. In the case of [5]+, which contains a labile acetonitrile ligand, this increased electrophilicity translates into increased carbophilicity as reflected by the ability of this complex to promote enyne cyclization reactions. These results demonstrate that the coordination noninnocence of antimony Z ligands can be used to adjust the catalytic activity of an adjoining metal center. PMID- 29979871 TI - Quantitative Study of Charge Carrier Dynamics in Well-Defined WO3 Nanowires and Nanosheets: Insight into the Crystal Facet Effect in Photocatalysis. AB - Photocatalysts with different morphologies and specific exposed facets usually exhibit distinguished activities. Previous researches have focused on revealing the essence of the facet effect in photocatalysis; however, quantitative analyses on the differences of carrier dynamic between different facets are scarce. Herein, we successfully synthesized WO3 nanosheets and nanowires with dominant exposed facets of {001} and {110}, respectively. The lower hole effective mass on {110} (0.94 m0) than on {001} (1.28 m0) calculated by density functional theory leads to the higher hole mobility on {110} (4.92 cm2 V-1 s-1) than on {001} (3.14 cm2 V-1 s-1). Combined with the Einstein equation and the lifetime of the hole, the calculated hole diffusion length on {110} (74.8 nm) is larger than on {001} (53.4 nm). Overall, the lower hole effective mass, higher hole mobility, and greater hole diffusion length on {110} collectively result in a photocatalytic activity on benzyl alcohol oxidation 2.46 times as high as that on {001}. PMID- 29979872 TI - Improved Surface-Enhanced Raman Spectroscopy Sensitivity on Metallic Tungsten Oxide by the Synergistic Effect of Surface Plasmon Resonance Coupling and Charge Transfer. AB - Increasing the sensitivity of non-noble metal surface-enhanced Raman spectroscopy (SERS) is an urgent issue that needs to be solved at present. Herein, metallic W18O49 nanowires with a strong localized surface plasmon resonance (LSPR) effect are prepared. Interestingly, the LSPR peaks of these nanowires would undergo a strong blue shift from near-infrared (NIR) to visible light regions as the aggregation degree of the nanowires increases. By narrowing the gap between the LSPR absorption peak and the Raman excitation wavelength (532 nm), the oriented W18O49 bundles with a LSPR peak centered at 561 nm have greatly improved SERS sensitivity compared with that of the dispersed nanowires with a LSPR peak centered at 1025 nm. Enhancement mechanism investigation shows that the high sensitivity can be attributed to the synergistic effect of LSPR coupling among the oriented ultrathin nanowires and oxygen vacancy (Vo)-assisted charge transfer. PMID- 29979873 TI - Nanofibrillar Patches of Commensal Skin Bacteria. AB - We demonstrate entrapment of the commensal skin bacteria Staphylococcus epidermidis in mats composed of soft nanotubes made by membrane-templated layer by-layer (LbL) assembly. When cultured in broth, the resulting nanofibrillar patches efficiently delay the escape of bacteria and their planktonic growth, while displaying high steady-state metabolic activity. Additionally, the material properties and metabolic activity can be further tuned by postprocessing the patches with additional polysaccharide LbL layers. These patches offer a promising methodology for the fabrication of bacterial skin dressings for the treatment of skin dysbiosis while preventing adverse effects due to bacterial proliferation. PMID- 29979874 TI - Designing Microreactors Resembling Cellular Microenvironment via Polyamine Mediated Nanoparticle-Assembly for Tuning Glucose Oxidase Kinetics. AB - Spatial confinement of glucose oxidase (GOx) in the hollow interior of a bioinspired matrix via polyamine mediated silica nanoparticle assembly under environmentally benign conditions is demonstrated herein. In a similarity to the biosilicification processes in diatoms, we use poly(allylamine hydrochloride) (PAH) to direct the assembly of silica nanoparticles on CaCO3 spheres as the removable core. When this assembly process is performed on the CaCO3 spheres, which are preloaded with GOx in a postsynthesis method, microspheres encapsulating GOx are formed. Interestingly, the encapsulated GOx in these microreactors exhibits activity with a Michaelis-Menten constant ( KM) that is 2- to 3-fold less compared with the free enzyme in the solution. While the microenvironment of the organic (PAH)-inorganic (silica) hybrid system can be advantageous for the substrate to interact with enzyme, the effective pH in the vicinity of the entrapped enzyme may also be accountable for the improved activity, resulting in the lower apparent KM and enhanced specificity constant ( kcat/ KM). A 2-fold higher thermal stability of the encapsulated GOx compared with free GOx in solution further demonstrates the efficacy of the integrated architecture. Additionally, the PAH by virtue of its buffering capability allows the microspheres in imparting pH stability to the encapsulated GOx. Therefore, the method is not only a greener process for performing enzyme immobilization but also anticipated to aid in designing microreactors for enhanced enzyme activity. PMID- 29979875 TI - In Situ Active Poling of Nanofiber Networks for Gigantically Enhanced Particulate Filtration. AB - Enhancing the filtration efficiency of air filtering material without increasing its airflow resistance is a major challenge and of great significance. In this work, we report a type of active-poled nanofiber onto which in situ active poling is applied. It results in significantly enhanced filtration efficiency as well as dust holding capacity while keeping the airflow resistance constant. Owing to the in situ applied electric field, the nanofibers as well as the particulates are polarized. As a result, at a poling voltage of 2 kV, the removal efficiency and the quality factor for PM2.5 are enhanced by 17% and 130%, respectively. More importantly, the dust holding capacity represents a 3.5-fold enhancement over normal nanofibers. The approach reported in this work has the potential of being practically utilized in air purification purposes because it can bring about not only promoted filtration performance but also lowered noise and reduced power consumption. PMID- 29979876 TI - Intrinsic Analysis of Radiative and Room-Temperature Nonradiative Processes Based on Triplet State Intramolecular Vibrations of Heavy Atom-Free Conjugated Molecules toward Efficient Persistent Room-Temperature Phosphorescence. AB - The radiative rate ( kp) of the lowest triplet excited state (T1) and the nonradiative rate based on intramolecular vibrations at room temperature [ knr(RT)] from T1 for heavy atom-free conjugated structures are determined by considering the triplet yield and quenching rate from T1. Donor substitution did not strongly influence knr(RT) but greatly enhanced kp. The knr(RT) values were comparable between donor-substituted molecules and nonsubstituted molecules, which we explain by similar vibrational spin-orbit coupling (SOC) related to the transition from T1 to the ground state (S0). We attribute the enhancement of kp induced by donor substitution to the appearance of a large SOC between high-order singlet excited states (Sm) and T1 together with the large transition dipole moments of the Sm-S0 transitions. Knowledge of this mechanism is important for developing future efficient persistent room-temperature phosphorescence from doped aromatic materials and aromatic crystals. PMID- 29979877 TI - Development of Folate-Thioglycolate-Gold Nanoconjugates by Using Citric Acid-PEG Branched Polymer for Inhibition of MCF-7 Cancer Cell Proliferation. AB - Development of folate (FA)-functionalized gold nanoparticles (AuNPs) has greatly increased in recent years due to their potential in cancer treatment. As surface functionalization of polymer-free AuNPs with thiol groups could result in agglomeration and precipitation, AuNPs should be stabilized with an efficient polymer. In this study, citric acid-PEG branched polymer (CPEG) acted as a reducing as well as stabilizing agent in the synthesis of AuNPs. The thiol group of thioglycolic acid (TGA) attached to CPEG-stabilized AuNPs and interacted with the free carboxylic acid group on the surface of TGA-AuNP nanoconjugates. Stable TGA-AuNP nanoconjugates were obtained only with CPEG-stabilized AuNPs and not with citrate-stabilized AuNPs. The carboxylic acid group on the surface of AuNPs was used to attach FA via an EDC/NHS coupling reaction to obtain FA-TGA-AuNP nanoconjugates. In vitro cytotoxicity studies indicated that FA-TGA-AuNPs were not toxic to normal cells up to a concentration of 200 MUg/mL. However, FA-TGA AuNP nanoconjugates effectively inhibited proliferation of MCF-7 cancer cells at a low concentration of 25 MUg/mL after 3 days of incubation. The anticancer activity of FA-TGA-AuNPs was enhanced by incorporating the anticancer drug 5 fluorouracil into the nanoconjugates, which exhibited sustained drug release up to 5 days. Hence, the developed biocompatible FA-TGA-AuNPs could be used for specific killing of breast cancer cells. PMID- 29979878 TI - Enhanced Transmission and Self-Cleaning of Patterned Sapphire Substrates Prepared by Wet Chemical Etching Using Silica Masks. AB - Highly transparent and superhydrophilic sapphire with surface antireflective subwavelength structures were prepared by wet etching using colloidal monolayer silica masks. The film thicknesses of the silica masks were adjusted by the volume concentrations of polystyrene spheres. The evolution of etching morphologies of sapphire was studied, and antireflective concave pyramid nanoarrays on sapphire substrates were designed by calculation and were then prepared. The transmission and wettability of as-obtained patterned sapphire substrates were also investigated. As for sapphire with optimum surface concave micropyramid arrays, average visible transmittance can reach 91.7%, which is apparently higher than that of flat sapphire (85.5%). Moreover, the concave pyramid arrays can significantly increase the surface hydrophilicity of sapphire, exhibiting a water contact angle of 12.6 degrees compared with 62.7 degrees of flat sapphire. The proposed method can be an excellent strategy for preparing antireflective and self-cleaning concave micropyramid subwavelength structures on sapphire without complicated equipment and expensive raw materials. PMID- 29979879 TI - Kinetics Study of OH Uptake onto Deliquesced NaCl Particles by Combining Laser Photolysis and Laser-Induced Fluorescence. AB - Despite the role of hydroxyl radical (OH) uptake onto sea-salt particles as a daytime chlorine source, affecting the chemical processes in the marine boundary layer, its uptake coefficient has not yet been confirmed by direct measurement methods. This study reports the application of a combination technique of laser flash photolysis generation and laser-induced fluorescence detection for the direct kinetic measurement of OH uptake onto deliquesced NaCl particles. The uptake coefficient was not constant and inversely depended on the initial OH concentration, indicating that the first uptake step is Langmuir-type adsorption. The resistance model, including surface processes, well reproduced the observed uptake coefficient. The model predicted an uptake coefficient for the atmospheric relevant OH concentration within the range from 0.77 to 0.95. Such values may lead to emissions of Cl2 higher than those predicted in previous studies based on other values. Hence, the proposed value may provide more reliable estimations of ozone formation, oxidation of volatile organic compounds, secondary organic aerosol formation, and lifetime of methane and elemental mercury in the marine boundary layer. PMID- 29979880 TI - Magnesium Porphine Supermolecules and Two-Dimensional Nanoaggregates Formed Using the Langmuir-Schaefer Technique. AB - Porphyrins are functional elements of important biomolecules, whose assemblies play a central role in fundamental processes such as electron transfer, oxygen transport, enzymatic catalysis, and light harvesting. Here we report an approach to formation of porphyrin supermolecules, a particular type of nanoparticles with unusually strong noncovalent intermolecular interactions. Key differences between the supermolecules and noncovalent nanostructures described earlier are as follows. (1) Supermolecules consist of molecules of the same type without side groups promoting the self-assembly and without any spacers; no surfactant or catalyst to assist the process is needed. (2) They exhibit unusual photophysical properties and remain stable even in organic solvents. Their formation occurs under specially selected conditions at the air-water interface at room temperature. Following this route, we have formed supermolecules of magnesium porphine, a functional element of chlorophyll. The properties of these supermolecules are markedly different from those of the constituent molecules. For example, in contrast to the pink color of the monomer solution, solutions of supermolecules are transparent for visible light and absorb in the ultraviolet and near-infrared regions. We also present atomic force microscopy visualization of the porphyrin two-dimensional nanoaggregates forming at the air-water interface that were predicted in our previous works. This approach offers a guideline for the discovery of new supermolecules, including complex biological ones, and the formation of supermolecular materials with novel properties. PMID- 29979881 TI - Enhanced Thermoelectric Properties in a New Silicon Crystal Si24 with Intrinsic Nanoscale Porous Structure. AB - Thermoelectric device is a promising next-generation energy solution owing to its capability to transform waste heat into useful electric energy, which can be realized in materials with high electric conductivities and low thermal conductivities. A recently synthesized silicon allotrope of Si24 features highly anisotropic crystal structure with nanometer-sized regular pores. Here, based on first-principles study without any empirical parameter we show that the slightly doped Si24 can provide an order-of-magnitude enhanced thermoelectric figure of merit at room temperature, compared with the cubic diamond phase of silicon. We ascribe the enhancement to the intrinsic nanostructure formed by the nanopore array, which effectively hinders heat conduction while electric conductivity is maintained. This can be a viable option to enhance the thermoelectric figure of merit without further forming an extrinsic nanostructure. In addition, we propose a practical strategy to further diminish the thermal conductivity without affecting electric conductivity by confining rattling guest atoms in the pores. PMID- 29979882 TI - Long-Term Effects from a School-Based Trial Comparing Interpersonal Psychotherapy Adolescent Skills Training to Group Counseling. AB - Adolescence represents a vulnerable developmental period for depression and an opportune time for prevention efforts. In this study, 186 adolescents with elevated depressive symptoms (M age = 14.01, SD = 1.22; 66.7% female; 32.2% racial minority) were randomized to receive either Interpersonal Psychotherapy Adolescent Skills Training (IPT-AST; n = 95) delivered by research clinicians or group counseling (GC; n = 91) delivered by school counselors. We previously reported the short-term outcomes of this school-based randomized controlled trial: IPT-AST youth experienced significantly greater improvements in depressive symptoms and overall functioning through 6-month follow-up. Here, we present the long-term outcomes through 24 months postintervention. We examined differences in rates of change in depressive symptoms and overall functioning and differences in rates of depression diagnoses. Youth in both conditions showed significant improvements in depressive symptoms and overall functioning from baseline to 24 month follow-up, demonstrating the efficacy of school-based depression prevention programs. However, the two groups did not differ in overall rates of change or in rates of depression diagnoses from baseline to 24-month follow-up. Although IPT AST demonstrated advantages over GC in the short term, these effects dissipated over long-term follow-up. Specifically, from 6- to 24-month follow-up, GC youth showed continued decreases in depressive symptoms, whereas IPT-AST youth showed a nonsignificant increase in symptoms. GC youth remained relatively stable in overall functioning, whereas IPT-AST youth experienced a small but statistically significant worsening in functioning. This study highlights the potential of school-based depression prevention efforts and the need for further research. PMID- 29979883 TI - Reply to D'Alessandro-Gabazza et al.: Risks of Treating Idiopathic Pulmonary Fibrosis with a TAM Receptor Kinase Inhibitor. PMID- 29979884 TI - Parental Support for HPV Vaccination Mandates Among African Americans: The Impact of Message Framing and Consideration of Future Consequences. AB - Is parents' support for mandating human papillomavirus (HPV) vaccination for their adolescent children influenced by how the policy advocacy message is framed? In this research, we conducted an experiment in which a group of African American parents were exposed to messages advocating HPV vaccination mandates that were framed in either gains or losses. Our results demonstrate the importance of considering the personality trait - consideration of future consequences - when assessing the efficacy of gain- and loss-framed health advocacy. We found that parents responded more positively to gain-frames if they focused on the distant future and to loss-frames if they focused on the immediate future. Thus, it is important to recognize that public support of HPV vaccination policy is not only contingent on the message-based educational strategy employed to parent, but on the degree to which parents consider how present behaviors influence future well-being. PMID- 29979885 TI - Risks of Treating Idiopathic Pulmonary Fibrosis with a TAM Receptor Kinase Inhibitor. PMID- 29979886 TI - Identifying How Patient Portals Impact Communication in Oncology. AB - Patient portals are becoming widespread throughout health-care systems. Initial research has demonstrated that they positively impact patient-provider communication and patients' health knowledge, but little is known about the impact of patient portals in the cancer setting, where highly complex and uncertain medical data are available for patients to view. To better understand communicative behaviors and perceptions of the patient portal and how it is utilized in oncology, in-depth, semi-structured interviews were conducted with 48 participants: 35 patients and 13 oncologists. Thematic analysis identified that portals help to enhance participation during in-person consultations, increase patients' self-advocacy, and build rapport with providers. However, patients' comfort level with reviewing information via the portal depended upon the severity of the test. Oncologists worried about patient anxiety and widening health disparities, but acknowledged that the portal can motivate them to expedite communication about laboratory and scan results. As patient portals become more widely used in all medical settings, oncologists should become more engaged with how patients are viewing their medical information and consider the portal within the framework of patient-centered care by valuing patients' communication preferences. PMID- 29979887 TI - Parent-Child Interaction Therapy Adapted for Preschoolers with Callous Unemotional Traits: An Open Trial Pilot Study. AB - Children with co-occurring conduct problems and callous-unemotional (CU) traits show a distinct pattern of early starting, chronic, and aggressive antisocial behaviors that are resistant to traditional parent-training interventions. The aim of this study was to examine in an open trial the acceptability and initial outcomes of a novel adaptation of Parent-Child Interaction Therapy, called PCIT CU, designed to target 3 distinct deficits of children with CU traits. Twenty three Australian families with a 3- to 6-year-old (M age = 4.5 years, SD = .92) child with clinically significant conduct problems and CU traits participated in the 21-week intervention and 5 assessments measuring child conduct problems, CU traits, and empathy at a university-based research clinic. Treatment retention was high (74%), and parents reported a high level of satisfaction with the program. Results of linear mixed models indicated that the intervention produced decreases in child conduct problems and CU traits, and increases in empathy, with "medium" to "huge" effect sizes (ds = 0.7-2.0) that maintained at a 3-month follow-up. By 3 months posttreatment, 75% of treatment completers no longer showed clinically significant conduct problems relative to 25% of dropouts. Findings provide preliminary support for using the targeted PCIT-CU adaptation to treat young children with conduct problems and co-occurring CU traits. PMID- 29979888 TI - Effect of nutrition education and psychosocial factors on child feeding practices: findings of a field experiment with biofortified foods and different women categories. AB - Despite the efforts to promote good practices in infant and young child feeding (IYCF), the adoption of such practices has been low. Using data from a sample of 665 women, and the theory of planned behavior, we examine the effect of different types of nutrition education and psychosocial factors on the use of recommended IYCF practices. Regression results show that nutrition education and psychosocial factors have strong positive effect on the extent to which IYCF practices are used, with the latter having conflicting individual but overall positive effect. Moreover, coefficients of latter were mostly less than those of the former indicating that pschosocial factors were less important in explaining variability in usage of IYCF than the nutrition education variables. It further finds that different sets of nutrition education and psychosocial factors affect different categories of women, with interactive nutrition education approaches having a greater effect. The findings also suggest need for targeting of beneficiaries with multiple nutrition education approaches. PMID- 29979889 TI - Correlation of Crystallin Expression and RGC Susceptibility in Experimental Glaucoma Rats of Different Ages. AB - PURPOSE: Glaucoma is one of the leading causes of blindness worldwide with age being an important risk factor. However, the pathogenesis remains poorly understood. Aim of this study was to focus on age-dependent molecular changes in an experimental animal model of glaucoma. METHODS: Intraocular pressure was elevated in Sprague-Dawley rats aged 3, 14, and 47 weeks for a period of 7 weeks by episcleral vein cauterization. Ganglion cell loss was monitored by an immunohistochemical staining of the Brain-specific homeobox/POU (Pit-1, Oct-2, Unc-86) domain protein 3A positive cells in retinal flat-mounts and spectral domain optical coherence tomography measuring the retinal nerve fiber layer thickness. Molecular protein alterations were analyzed using a comprehensive mass spectrometric proteomics approach of the retina and vitreous body. RESULTS: While juvenile animals did not show a significant loss of retinal ganglion cells due to intraocular pressure elevation, adolescent animals showed a decrease up to 26% (p < 0.05). A shift of retinal crystallin protein expression levels within all protein-family subclasses (alpha, beta, gamma) could be observed in the youngest animal group (p < 0.05), while the upregulation of crystallin proteins in older animals was less striking. In addition, numerous crystallin proteins were also detected in the vitreous body. CONCLUSION: These results provide insights of a potential correlation of age-related glaucomatous damage and the absence of crystallin proteins in the retina. PMID- 29979890 TI - ERP correlates of cognitive control in children prenatally exposed to methadone or buprenorphine. AB - Much is still unknown about the potential long-term effects of prenatal methadone and buprenorphine exposure. We examined neural correlates of cognitive control in 19 prenatally methadone and buprenorphine exposed and 21 nondrug exposed children, aged 9-11 years. Children performed a modified version of the Eriksen Flanker task, which taps into selective attention, conflict response, and response inhibition mechanisms. We investigated behavioral responses and the ERP components N1, P2, N2, P3, and the late positive component (LPC). Children in the exposed group showed normal cognitive control function. However, an atypical ERP response related to perceptual and attention allocation processes was found in the exposed group. PMID- 29979891 TI - Delivery of progestins via the subdermal versus the intrauterine route: comparison of the pharmacology and clinical outcomes. AB - INTRODUCTION: Subdermal and intrauterine progestin releasing systems are two types of long-acting reversible contraceptive systems (LARC). Their use has transformed current contraceptive practice management. There is not much objective evidence to help decide which method is preferable and in which particular circumstance using objective criteria. Areas covered: MEDLINE, POPLINE, PubMed, and clinicaltrials.gov were searched using the terms "implant" vs "IUS" and then adding the terms "levonorgestrel" and "etonogestrel" to the implant arm and "levonorgestrel" to the IUS arm. This was done using commercial names as well for the terms "pharmacodynamics" and "pharmacokinetics" as well as for the term "therapeutic." Preference was given to comparative studies of the highest degree. Expert opinion: Under normal circumstances, user satisfaction appeared marginally greater for intrauterine rather than subdermal progestin provision. However, after uterine events such as pregnancy or surgical evacuation of the uterus, implants performed better. Intrauterine progestin is preferable for therapeutic purposes. PMID- 29979892 TI - Genetic variant association of PTPN22, CTLA4, IL2RA, as well as HLA frequencies in susceptibility to alopecia areata. AB - Alopecia areata (AA) is characterized by a genetically complex inheritance. HLA frequencies, as well as the single nucleotide polymorphism (SNP) in PTPN22, CTLA4, and IL2RA genes, have been described to be associated with AA susceptibility. So far, no independent replication of these studies has been reported, and no data exist on a possible association between AA disease and these SNPs or influence of HLA frequencies in Iranian population. A possible association between HLA-DRB1*11 alleles as well as a single variation in PTPN22, CTLA4, and IL2RA genes and patchy AA disease have been investigated in a cohort from Iran. Patient and control subjects were genotyped for PTPN22 (rs2476601), CTLA4 (rs3087243), and IL2RA (rs3118470) variations as well as HLA frequencies. Gene expression levels were analyzed by real-time RT-PCR. In contrast to PTPN22 and CTLA4 gene polymorphisms, a significant association was found between IL2RA SNP and susceptibility to AA in Iranian cohort. While gene expression levels of IL2RA and PTPN22 were higher in the patients than that of controls, CTLA4 expression levels found significantly lower in the patients. Despite a significant association between AA and HLA-DRB1*11 frequencies, the presence of DRB1*11 is not associated with PTPN22, CTLA4, or IL2RA gene SNPs. Although the minor allele in IL2RA SNP can be a significant determinant of AA disease development in Iranian population, reported an association between the PTPN22 and CTLA4 variations was not confirmed by our study. Furthermore, these genetic risk factors might act independently from HLA alleles. PMID- 29979893 TI - Comparative effects of various absorbable threads in a rat model. AB - BACKGROUND: Conventional procedures including botulinum toxin and filler injections have their limitations in improving deep wrinkles and decreasing tissue laxity, and possess the propensity for vascular accidents. Absorbable thread is a recently commercialized field, but there is little evidence on comparative superiority. OBJECTIVES: We observed the effects of polydiaxanone (PDO) threads with different number of strands in relation to collagen production and histopathology in a rat model. MATERIALS AND METHODS: Dorsal skin of rat was divided into five different compartments and four different PDO threads and monofilament poly-lactic acid (PLA) thread were inserted. Tissue samples were obtained at week 1, 2, and 12 after the procedure for histopathologic review and real-time PCR for quantification of collagen. RESULTS: Multiple PDO filaments produced more collagen at 2 weeks. Single-stranded PLA thread insertion resulted in more Col1alpha1 levels than the double PDO thread and also showed the most Col1alpha3 production at week 2. The amount of collagen showed a sharp decline at week 12. Histologic evaluation showed retained threads surrounded by fibrous capsule-like structure at week 12. CONCLUSION: We were able to observe more collagen production in multiple stranded PDO threads compared to a single strand and that increasing number of threads leads to more collagen synthesis. PMID- 29979894 TI - Association between HLA class II alleles and hepatitis B virus infection in Transylvania, Romania. AB - Infection with hepatitis B virus (HBV) is a major problem worldwide. The major histocompatibility complex plays an essential role in host immunity and can help eliminate the HBV of infected hepatocytes. Our study aimed to determine the role of certain human leukocyte antigen (HLA) class II molecules (i.e. HLA-DRB1 and HLA-DQB1) in the persistence or removal of HBV. Sixty patients confirmed to be HBV-positive via real-time polymerase chain reaction (PCR), i.e. people with chronic active hepatitis, were included in the study along with a control group of 100 healthy individuals without evidence of HBV infection. The DNA was subsequently used to determine HLA-DRB1 and HLA-DQB1 low-resolution typing genetic profile via PCR amplification. The univariate analysis performed revealed significant association of the HLA-DRB1*03 and HLA-DQB1*05 alleles to the infected persons (study group), while HLA-DRB1*01 was shown to be protective against HBV infection. To our knowledge, this is the first Romanian study associating HLA with HBV, and it can provide valuable insight concerning the relationship between genetic factors and immune response in the sampled population. PMID- 29979895 TI - The efficiency-frontier approach for health economic evaluation versus cost effectiveness thresholds and internal reference pricing: combining the best of both worlds? AB - INTRODUCTION: The efficiency-frontier approach (EFA) to health economic evaluation aims to benchmark the relative efficiency of new drugs with the incremental cost-effectiveness ratios (ICERs) of non-dominated comparators. By explicitly considering any differences in health outcomes and costs, it enhances the internal reference pricing (IRP) policy that was officially endorsed by Germany as the first country worldwide in 1989. However, the EFA has been repeatedly criticized since its official endorsement in 2009. Areas covered: This perspective aims to stimulate the debate by discussing whether the main objections to the EFA are technically valid, irrespective of national contextual factors in Germany with reservations towards using cost-per-quality-adjusted life year (QALY) thresholds. Moreover, we comparatively assessed whether the objections are truly unique to the EFA or apply equally to IRP and cost effectiveness thresholds. Expert commentary: The plethora of objections to the EFA (n = 20) has obscured that many objections are neither technically valid nor unique to the EFA. Compared with cost-effectiveness thresholds, only two objections apply uniquely to the EFA and concern intended key properties: (1) no external thresholds are needed and (2) the EFA is sensitive to price changes of comparators. Combining these policies and developing them further are under utilized research areas. PMID- 29979896 TI - Growth hormone therapy in children with idiopathic short stature - the effect on appetite and appetite-regulating hormones: a pilot study. AB - AIM: To investigate the effect of growth hormone (GH) therapy on appetite regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE). METHODS: Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP 1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months. RESULTS: Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (p < .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (p = .045) and fasting GLP-1 (p = .038), and an increase in fasting insulin (p = .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: r = .667, p = .05; AUC: r = .788, p = .012) and REE (fasting: r = .866, p = .005; AUC: r = .847, p = .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (r = .741, p = .022) and fat-free-mass (r = .890, p = .001) at 12 months of GH treatment. CONCLUSIONS: The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated. ABBREVIATIONS: SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range. PMID- 29979897 TI - Effect of diverse physical rehabilitative interventions on static postural control in diabetic peripheral neuropathy: a systematic review. AB - BACKGROUND AND PURPOSE: There are diverse forms of rehabilitative techniques available to improve postural control in diabetic peripheral neuropathy but little is known about the efficacy of these techniques. The primary focus of this review is to find out the effectiveness of diverse rehabilitative interventions in improving postural control in type 2 induced diabetic peripheral neuropathy. METHODS: Two reviewers independently scrutinized the included studies. The selected studies underwent quality assessment by PEDro scale. Randomized Controlled Trial (RCT) having a score of 4 or more were included in the review. A search was conducted in PUBMED, MEDLINE, CINAHL, EMBASE, PROQUEST, Science Direct, Cochrane Library, Physiotherapy Evidence Database (PEDro) and Google Scholar. The Medical Subject Headings (MeSH) related to the interventions were also taken into account. RESULTS: A total of 563 studies were identified and finally 8 studies were included in the review process. The included studies were 3 in task-specific balance training, 1 in treadmill, 1 in strengthening, 2 in whole body vibration, and 1 study in pilates analyzing posture using static posturography. No RCTs were reportedly found under tai chi and yoga. CONCLUSIONS: Interventions related to task-specific approach in balance training, treadmill, strengthening, WBV showed improvement in static postural control. Intervention with pilates did not show any beneficial effects. However, there still remains a need for quality trials as the results of these studies were ambivalent in interpretation and quality of the studies were limited by small sample size and higher attrition rates. PMID- 29979899 TI - Intensive, functional training leads to optimal outcomes in a young woman post brain stem hemorrhage due to cerebral cavernous malformation. AB - PURPOSE: Cerebral cavernous malformations (CCMs) can cause intracranial hemorrhages and account for 5-15% of all cerebral vascular malformations. The purpose of this retrospective case report is to describe the unusual motor recovery of a young woman following a large hemorrhage of a previously unknown brainstem CCM, otherwise not reported in the literature. CASE DESCRIPTION: The patient was a 29-year-old female who presented with severe hemiparesis on the left 6 weeks after a first-ever hemorrhage. She had demonstrated minimal improvement in her motor recovery to date, was dependent on a walker for ambulation, and had no distal left upper extremity function. An intensive evidence-based plan of care over 6 weeks included progressive task-specific strengthening, treadmill training, and dynamic balance training. OUTCOMES: The patient achieved complete motor recovery, indicated by improvement from 23/66 to 64/66 in the Fugl-Meyer Upper Extremity Subscale score and from 12/30 to 30/30 in the Functional Gait Assessment. She returned to independent ambulation with functional gait speeds and kinematics. DISCUSSION: This case report demonstrates an unusual clinical course of unexpected full recovery in a young woman after a large brainstem CCM after an intensive 6-week course of physical therapy. Other patients with a similar presentation after CCM may benefit from an intensive plan of care. Clinicians should be aware of the possibility of unusual recovery in this population as not to limit expectations for recovery. PMID- 29979898 TI - Serum of Patients with Psoriasis Modulates the Production of MMP-9 and TIMP-1 in Cells of Monocytic Lineage. AB - Psoriasis is triggered by several stimuli that share a systemic production of interferon (IFN)-gamma and other inflammatory mediators, which are key to regulate the production of matrix metalloproteinase (MMP)-9 and its inhibitor (TIMP)-1 by cells of monocytic lineage. This study evaluates the effect of the sera of 55 patients with psoriasis and 41 non-psoriatic individuals on the production of MMP-9 and TIMP-1 in cultured monocytes from a single healthy blood donor and in U937 cells. The effect of IFN-gamma stimulation was also evaluated. Serum and supernatant concentrations of IFN-gamma, MMP-9, and TIMP-1 were measured by enzyme-linked immunoassays, and the MMP-9/TIMP-1 ratios were calculated. In monocytes, incubation with psoriasis' sera increased the production of MMP-9 and TIMP-1 in comparison with both baseline and monocytes incubated with non-psoriatic sera. Although the MMP-9/TIMP-1 ratio was significantly higher compared to the baseline, no differences between groups were observed. In contrast, IFN-gamma stimulation in monocytes previously exposed to psoriasis' sera increased MMP-9 levels and decreased TIMP-1 levels, whereas stimulation in monocytes exposed to non-psoriatic sera did not further modify the levels of MMP-9 or TIMP-1. Consequently, the MMP-9/TIMP-1 ratio in cells exposed to psoriatic serum was significantly higher than in cells exposed to non psoriatic sera (24.5 versus 16.7; P < 0.05). Similar results were observed in U937 cells. Therefore, our results suggest that soluble mediators in psoriatic sera may enhance the proteolytic phenotype of monocytes when stimulated with IFN gamma, which supports the existence of a primed state in the inflammatory cells of patients with psoriasis. PMID- 29979900 TI - Pharmacological resources, diagnostic approach and coordination of care in joint hypermobility-related disorders. AB - INTRODUCTION: Joint hypermobility (JH) is the hallmark of many hereditary soft connective tissue disorders, including Ehlers-Danlos syndromes and related disorders, disorders of the TGFbeta-pathway, lateral meningocele syndrome, arterial tortuosity syndrome, and cutis laxa syndromes. Contemporary practice separates individuals with isolated, non-syndromic JH from patients with Mendelian syndromes and those with hypermobility spectrum disorders. The latter is a new nosologic entity grouping together individuals with JH and related musculoskeletal manifestations, but lacking inclusion criteria for well-defined and/or single-gene disorders. Area covered: Nomenclature of JH and JH-related disorders are summarized on a practically oriented perspective. Critical areas of clinical management comprise pain; cardiovascular and respiratory issues; fatigue and dysautonomia; bone fragility; and capillary, skin and soft tissue fragility. Medical management stands on low-evidence data. Ongoing preclinical and clinical studies are aimed to reach a more personalized pharmacological approach to the management of the cardiovascular risk, musculoskeletal pain, and reduced bone mass. Expert commentary: Correct classification of patients with JH-related disorders needs a systematic approach, in which a wide array of molecular tests should be intermingled with strong clinical competences in highly specialized settings. A multispecialty, hierarchical approach should be encouraged for optimal coordination of care in systemic phenotypes. PMID- 29979901 TI - Retinal involvement in m.3243A>G carriers. PMID- 29979902 TI - Management of a nonathlete with a traumatic groin strain and osteitis pubis using manual therapy and therapeutic exercise: A case report. AB - INTRODUCTION: Without a definitive single pathoanatomical origin for groin pain, management is difficult. The purpose of this case report is to describe the differential diagnosis and management of an individual with a traumatic groin strain. CASE DESCRIPTION: A 47-year-old sedentary male truck driver presented to physical therapy with a 2-month history of right medial groin pain. Pushing the gas pedal and sitting were painful activities. Pain was 3-8/10 on the Numeric Pain Rating Scale (NPRS). The patient reported 46/80 on the Lower Extremity Functional Scale. EXAMINATION: Tenderness was noted along the adductor longus muscle belly, right pubic ramus and hip range of motion was limited. Special tests directed at the hip and pelvic region indicated intraarticular and pelvic dysfunction. Treatment included hip and pubic symphysis joint mobilizations, lumbopelvic manipulation, adductor longus soft-tissue mobilization, and core strengthening. OUTCOME: 12 sessions of physical therapy resulted in LEFS to 80/80, Global Rating of Change (GROC) + 7, and NPRS 0/10 at worst. The patient returned to full work without restriction. DISCUSSION: Groin pain has many pathoanatomical drivers. Management of a traumatic groin injury requires a thorough evaluation and a global treatment approach, in order to improve outcomes and reduce the risk of the pathology becoming chronic. PMID- 29979903 TI - Methylnaltrexone bromide for the treatment of opioid-induced constipation. AB - INTRODUCTION: The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non tolerable gastrointestinal (GI) adverse effects. Opioid-induced constipation (OIC) is the most common adverse effect impairing patient quality of life (QOL). In addition, OIC is one of the treatment limiting consequences of opioid analgesics. Management of OIC is becoming a challenge since traditional laxatives have limited efficiency. Peripherally acting mu-opioid receptor antagonists (PAMORA) have been developed for the treatment of OIC with methylnaltrexone bromide being the first approved to treat OIC in adults with advanced illness undergoing palliative care. Areas covered: The authors systematically review the clinical evidence for methylnaltrexone bromide including a review of the pharmacokinetic and pharmacodynamic data along with clinical effectiveness and cost-effectiveness. Though there is a need for further long-term clinical investigation, there is a large body of evidence for both its efficacy and safety in the treatment of OIC. Expert opinion: Methylnaltrexone has both subcutaneous injection and oral dosage forms available in the market. The lack of more evidence in specific populations such as pregnant women, pediatrics and elderly still remains. The global consumption of methylnaltrexone shows a projection of increased use since its approval worldwide in 2008. PMID- 29979904 TI - Dynamics of cardiorespiratory response during and after the six-minute walk test in patients with heart failure. AB - PURPOSE: The six-minute walk test (6MWT) is a useful measure to evaluate exercise capacity with a simple method. The kinetics of oxygen uptake ([Formula: see text]O2) throughout constant-load exercise on cardiopulmonary exercise testing (CPX) are composed of three phases and the [Formula: see text]O2 kinetics are delayed in patients with heart failure (HF). This study aimed to investigate the kinetics of the cardiorespiratory response during and after the 6MWT according to exercise capacity. METHODS: Forty-nine patients with HF performed CPX and the 6MWT. They were divided into two groups by 6MWT distance: 34 patients walked >=300 m (HF-M), and 15 patients walked <300 m (HF-L). [Formula: see text]O2, minute ventilation ([Formula: see text]E), breathing frequency, tidal volume, and heart rate, both during and after the 6MWT, were recorded. The time courses of each parameter were compared between the two groups. CPX was used to assess functional capacity and physiological responses. RESULTS: In the HF-M group, [Formula: see text]O2 and [Formula: see text]E stabilized from 3 min during the 6MWT and recovered for 3 min, respectively, after the 6MWT ended. In the HF-L group, [Formula: see text]O2 and VE stabilized from 4 min, respectively, during the 6MWT and did not recover within 3 min after the 6MWT ended. On CPX in the HF M group, [Formula: see text]O2 peak, and anaerobic threshold were significantly higher, while the relationship between minute ventilation and carbon dioxide production was lower compared with the HF-L group. CONCLUSION: In lower exercise capacity patients with HF had slower [Formula: see text]O2 and [Formula: see text]E kinetics during and after the 6MWT. PMID- 29979905 TI - Measuring changes in pharmacy and nursing students' perceptions following an interprofessional high-fidelity simulation experience. AB - The purpose of this study was to evaluate the effects of interprofessional high fidelity simulation-based learning (SBL) on third-year pharmacy and senior nursing students' perceptions of interprofessional care. Students participated in an interprofessional high-fidelity SBL experience consisting of two hospital based scenarios followed by a debriefing. The "Student Perceptions of Interprofessional Clinical Education-Revised" (SPICE-R) instrument was administered pre- and post-SBL. The "Student Satisfaction and Self-Confidence in Learning" (SSSCL) instrument, which uses a 5-point Likert scale, was administered post-SBL. A total of 104 (78%) pharmacy and 93 (77%) nursing students completed both the pre- and post-survey instruments. Baseline differences between pharmacy and nursing students included number of clinical hours completed [200 (190-240) vs. 210 (209-210); p < 0.001] and previous/current experiencing working directly with other healthcare professionals [71 (53%) vs. 88 (73%); p < 0.001]. Median score increases were observed for all SPICE-R items (p < 0.01) for pharmacy students and nine of ten SPICE-R items (p < 0.01) for nursing students. All students rated both the experience and their confidence highly on the SSSCL; however, nursing scores were higher than pharmacy scores for 7 of 13 items (p < 0.05). An interprofessional high-fidelity SBL experience increased pharmacy and nursing students' perceptions of interprofessional care. PMID- 29979906 TI - Single dose versus multiple doses of rituximab for preemptive therapy of Epstein Barr virus reactivation after hematopoietic cell transplantation. AB - Epstein-Barr virus (EBV) reactivation is an unresolved medical issue after allogeneic hematopoietic stem cell transplantation (HSCT). Rituximab treatment is recommended for EBV reactivation after HSCT but the number of doses of rituximab to use is unclear. In this study, risk factors and outcomes of patients who needed 1 dose vs >1 doses of preemptive rituximab to clear EBV viremia were compared. A higher viral load was more likely to be associated with higher doses of rituximab. Patients whose EBV viremia cleared with 1 dose of rituximab were more likely to have a preceding reduction of immunosuppression. Overall survival (OS) in these 2 cohorts was not different (18.7 vs 26.6 months, respectively, p = .96). Since rituximab can have side effects and is fairly costly, a predictive model to determine the number of rituximab doses using viral load would be a useful and cost-effective manner to utilize rituximab for this indication. PMID- 29979907 TI - Lymphangioma circumscriptum treated with combination of Bleomycin sclerotherapy and Radiofrequency ablation. AB - Lymphangioma circumscriptum (LC) is a lymphatic malformation presenting with vesiculo-papules or warty lesions, resembling a "frog-spawn". Many treatment modalities have been described but random excision is still often needed. Bleomycin is a safe sclerosant with specific action on the vascular endothelial cells. It has been used extensively in cystic hygromas but its use in LC of the skin has not been documented previously. We present this case with extensive LC of the flank treated with a combination of intralesional bleomycin and radiofrequency ablation in the same sitting. As the lesion was extensive, treatment was done in three sittings, one to each third. Near complete resolution, with no significant recurrence was achieved with a single sitting to each third. PMID- 29979908 TI - PCSK9 inhibitors and LDL reduction: pharmacology, clinical implications, and future perspectives. AB - INTRODUCTION: PCSK9 inhibitors are monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 which significantly reduce LDL cholesterol concentration in vivo by inhibiting degradation of the LDL receptor in hepatocytes. The introduction of PCSK9 inhibitors heralded a new era of intensive LDL-C reduction with LDL-C concentrations lowered below levels ever thought possible with conventional treatments such as statins. With their introduction considerations regarding cost, clinical outcomes and long-term safety are paramount. Areas covered: This review examines the pharmacology of PCSK9 inhibitors and summarizes the current evidence base for use in clinical practice from an efficacy, safety, and cardiovascular outcome perspective including recently presented data on alirocumab. It also examines the potential role of these agents into the future. Potential issues with PCSK9 inhibitors are examined and future pharmacologic targets are examined including siRNA and PCSK9 vaccination. Expert commentary: It is clear that the PCSK9 inhibitors are highly effective in the lowering of LDL cholesterol. However, this reduction comes at a large financial cost, and although early outcome data has been positive, the role of PCSK9 inhibition remains confined to limited patient groups at present. As more long-term data is gathered on clinical outcomes and safety, the role for these agents may expand. PMID- 29979909 TI - Patient perceptions of visual, vestibular, and oculomotor deficits in people with Parkinson's disease. AB - INTRODUCTION: Disturbances in the visual, vestibular, and oculomotor systems have been identified in Parkinson's disease (PD). Patients' perspectives regarding these symptoms remain unexplored and may provide insights on functional implications of these symptoms and guide future interventions. The goal of this study is to elicit perceptions of individuals with PD with respect to visual, vestibular, and oculomotor deficits. METHODS: Twenty-nine individuals with PD participated in focus group discussions. Participants discussed visual, vestibular, and oculomotor deficits they experience and how these deficits affect function. Discussions were recorded, transcribed, and coded. Inductive qualitative data analysis techniques were used to interpret responses. RESULTS: Four themes emerged: 1) participants perceived visual, vestibular, and oculomotor deficits and related these deficits to their PD diagnosis; 2) participants perceive that these deficits affect function; 3) participants suggested these deficits are not recognized by healthcare providers; and 4) participants indicated they receive limited treatment for these deficits. CONCLUSIONS: Visual, vestibular, and oculomotor deficits are under-reported and under-assessed symptoms, which have a significant impact on the lives of people with PD. Healthcare providers should be aware of such deficits. The findings suggest that the healthcare team can better identify these deficits and identify important future areas of research. PMID- 29979911 TI - CO2 laser treatment for pearly penile papules - personal experience. AB - Pearly penile papules (PPP) are physiological lesions in the epithelium of the corona of the glans penis which extend to its neck. These lesions may also appear on both sides of the frenulum. Although they are not pathological, the lesions frequently cause concern or embarrassment/discomfort in patients. They are the most common reason for seeing a dermatologist. There are several methods of treatment for PPP such as cryosurgery, electrocoagulation, treatment with CO2, Er:YAG, or pulsed dye lasers. This paper describes the authors' experience in removing PPP with a CO2 laser. PMID- 29979910 TI - Predictors of Aggressive Behavior While under the Influence of Illicit Drugs among Young Adult Methamphetamine Users. AB - BACKGROUND: Prior research indicates that patterns of combined alcohol and methamphetamine use may be associated with experiencing subjective feelings of aggression or hostility during methamphetamine use episodes. OBJECTIVES: This study examines whether subjective effects of methamphetamine use (i.e., aggression or hostility and paranoia) are associated with aggressive behavior while under the influence of any illicit drugs, controlling for combined alcohol and methamphetamine use and a number of other potential predictors. METHODS: Data from a population-based sample of Australian young adult methamphetamine users (n = 101) collected in 2010 was analyzed. A prediction model of aggressive behavior under the influence of illicit drugs was developed using penalized maximum likelihood logistic regression. RESULTS: Over one-third (34.7%) of methamphetamine users had engaged in verbal and/or physical aggression under the influence of illicit drugs in the last 12 months. In the prediction model, recurrent feelings of aggression or hostility attributed to methamphetamine use (>=3 times in the last 12 months) were associated with aggressive behavior (adjusted odds ratio 4.95, 95% confidence interval 1.67, 14.69). This association was independent of methamphetamine-attributed paranoia, combined alcohol and methamphetamine use, methamphetamine, ecstasy, cocaine, and cannabis use patterns, heavy episodic drinking, gender, and age. No association was found for combined alcohol and methamphetamine use. CONCLUSIONS: These findings indicate a link between methamphetamine-related subjective feelings of aggression or hostility and self-reported aggressive behavior while under the influence of illicit drugs. This suggests that subjective feelings of aggression or hostility may distinguish those who are involved in aggression from other methamphetamine users. PMID- 29979912 TI - Physical therapist decision-making in managing plantar heel pain: cases from a pragmatic randomized clinical trial. AB - INTRODUCTION: Plantar heel pain (PHP) is a common condition managed by physical therapists that can, at times, be difficult to treat. Management of PHP is complicated by a variety of pathoanatomic features associated with PHP in addition to several treatment approaches with varying efficacy. Although clinical guidelines and clinical trial data support a general approach to management, the current literature is limited in case-specific descriptions of PHP management that addresses unique combinations of pathoanatomical, physical, and psychosocial factors that are associated with PHP. PURPOSE: The purpose of this case series is to describe physical therapist decision-making of individualized multimodal treatment for PHP cases presenting with varied clinical presentations. Treatment incorporated clinical guidelines and recent evidence including a combination of manual therapy, patient education, stretching, resistance training, and neurodynamic interventions. A common clinical decision-making framework was used to progress individualized treatment from a focus on symptom modulation initially to increased load tolerance of involved tissues and graded activity. In each case, patients met their individual goals and demonstrated clinically meaningful improvements in pain, function, and global rating of change that were maintained at the 1-2-year follow-up. IMPLICATIONS: This case series provides details of physical therapist management of a variety of PHP clinical presentations that can be used to complement clinical practice guidelines in the management of PHP. PMID- 29979913 TI - Testing the Replication and Extension of Why-Quit and How-To-Quit Antismoking Health Messages. AB - Research on health campaigns and interpersonal communication has seldom examined how campaign message exposure can influence the transmission of campaign-relevant information into interpersonal communication. Specifically, an individual exposed to a campaign message may send the message's core argument (replication) or other campaign-consistent information (extension) to additional campaign targets. Replication and extension may enhance campaign effects because they are expected to extend a campaign's reach and produce more campaign-consistent communication. Using a randomized controlled experiment, this study examined how exposure to why quit and how-to-quit themed antismoking messages influences replication and extension. Study results showed that while both why-quit and how-to-quit messages were successful in increasing replication, only why-quit messages were successful in influencing extension. The study results demonstrate that there is variation in the degree of how messages can successfully be replicated or extended in interpersonal contexts, which can inform campaign development. PMID- 29979915 TI - Treatment of striae distensae using fractional ablative CO2 laser in skin types II-IV: a retrospective case series study. AB - Striae distensae (SD) are atrophic dermal scars often found on abdomen, breasts, thighs, and hips of pregnant women. The strias' self-healing without any intervention is a poor possibility. Till now, several lasers and light sources have been used for treatment of SD. However, there are no integrated therapeutic approaches determined for treatment of SD yet. So, in this study, the therapeutic effect of fractional ablative CO2 laser in women with pregnancy was assessed. Twenty-four ethic Iranian women aged between 20 and 42 years with various severity of pregnancy SD enrolled in retrospective case series study. Participants with skin types II-IV were treated in four sessions with a one-month interval by fractional ablative CO2 laser. The severity of striae was determined by Daveys scoring. Clinical improvement was assessed by comparing pretreatment and posttreatment clinical photographs based on global improvement scoring. The evaluation of clinical results showed that fractional ablative CO2 laser was an effective treatment. Twenty of 24 (83.3%) patients showed improvement. Clinical improvement was affected by striae severity (P = 0.03). Also, there were no statistical differences between clinical improvements with skin types, striae scar severity, number of pregnancy, and striae location. PMID- 29979916 TI - Mindfulness moderates the relation between trauma and anxiety symptoms in college students. AB - OBJECTIVE: To explore the relations between trauma exposure and anxiety and depression among college students, and to determine whether trait mindfulness may moderate these relations. PARTICIPANTS: Self-report survey data from 2,336 college sophomores were drawn from a larger university-wide study ("Spit for Science"). METHODS: We constructed multiple linear regression models using past year trauma exposure, trait mindfulness, and their multiplicative interaction to predict current anxiety and depressive symptom severity, while controlling for covariates. RESULTS: Mindfulness was associated with lower levels of depression and anxiety symptom severity. Trauma was a significant predictor of anxiety, but not depression, and high levels of mindfulness attenuated the association between trauma exposure and higher anxiety symptom severity. CONCLUSIONS: These results have implications for the treatment and prevention of anxiety among trauma exposed college students and provide a basis for further research into the mechanisms through which mindfulness may facilitate positive mental health. PMID- 29979917 TI - Knowledge and perception of female nursing students about human papillomavirus (HPV), cervical cancer, and attitudes toward HPV vaccination. AB - OBJECTIVE: The researchers aimed to evaluate the knowledge and perceptions of first-year female nursing students about human papillomavirus (HPV), cervical cancer (CC), and HPV vaccination. PARTICIPANTS: The sample included 690 female nursing students from sampled universities between April and June 2015. METHODS: Students were surveyed by using a pretested HPV and CC awareness questionnaire. RESULTS: More than half of the students (65.1%) answered questions incorrectly with a mean HPV knowledge score of 6.085 +/- 3.38. The majority of students (82.6%) did not hear HPV vaccine. Only, 2.8% of the students had been vaccinated. A statistically significant relationship was found between HPV knowledge score and hearing about HPV vaccine (U = 28280.500, p = .015), and believing HPV vaccine protectiveness (chi2 = 14.153, p = .001). CONCLUSIONS: This study highlights the lack of knowledge and low level of awareness about HPV, CC, and HPV vaccination among first-year nursing college students. PMID- 29979914 TI - Compromised phagosome maturation underlies RPE pathology in cell culture and whole animal models of Smith-Lemli-Opitz Syndrome. AB - Treatment of rats with the cholesterol pathway inhibitor AY9944 produces an animal model of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disease caused by defective cholesterol synthesis. This SLOS rat model undergoes progressive and irreversible degeneration of the neural retina, with associated pathological features of the retinal pigmented epithelium (RPE). Here, we provide further insights into the mechanism involved in the RPE pathology. In the SLOS rat model, markedly increased RPE apical autofluorescence is observed, compared to untreated animals, which correlates with increased levels of A2E and other bisretinoids. Utilizing cultured human induced pluripotent stem cell (iPSC)- derived SLOS RPE cells, we found significantly elevated steady-state levels of 7 dehydrocholesterol (7DHC) and decreased cholesterol levels (key biochemical hallmarks of SLOS). Western blot analysis revealed altered levels of the macroautophagy/autophagy markers MAP1LC3B-II and SQSTM1/p62, and build-up of ubiquitinated proteins. Accumulation of immature autophagosomes was accompanied by inefficient degradation of phagocytized, exogenously supplied retinal rod outer segments (as evidenced by persistence of the C-terminal 1D4 epitope of RHO [rhodopsin]) in SLOS RPE compared to iPSC-derived normal human control. SLOS RPE cells exhibited lysosomal pH levels and CTSD activity within normal physiological limits, thus discounting the involvement of perturbed lysosomal function. Furthermore, 1D4-positive phagosomes that accumulated in the RPE in both pharmacological and genetic rodent models of SLOS failed to fuse with lysosomes. Taken together, these observations suggest that defective phagosome maturation underlies the observed RPE pathology. The potential relevance of these findings to SLOS and the requirement of cholesterol for phagosome maturation are discussed. PMID- 29979918 TI - Inadequate and Incomplete: Chinese Newspapers' Coverage of the First Licensed Human Papillomavirus (HPV) Vaccine in China. AB - Glaxo Smith Kline's Cervarix was the first human papillomavirus (HPV) vaccine licensed for use in China and officially launched there on 31 July 2017. Since news media content can influence people's vaccine-related knowledge, understanding, and intentions, a content analysis was used to examine Chinese newspapers' coverage of the HPV vaccine. A total of 253 articles published from 2000 to 2016 met the inclusion criteria and were coded. The results show that HPV and the HPV vaccine received very little newspaper coverage in China both before and after vaccine licensure. Most of the coverage came from China Party press newspapers, with the stories predominantly using thematic rather than episodic framing. Application of the Health Belief Model to the content analysis revealed that benefits, self-efficacy, and cues to action were found in most news stories. Overall, given the relative lack of Chinese newspaper coverage, public health officials and health-care providers in China should assume most people, including those for whom HPV vaccination is recommended, have little or no knowledge about HPV, HPV vaccine, and the reasons for the vaccination recommendation. If news media are to be a source of HPV information for the Chinese public, significant efforts will be needed to increase attention. PMID- 29979920 TI - "Okay, We Get It. You Vape": An Analysis of Geocoded Content, Context, and Sentiment regarding E-Cigarettes on Twitter. AB - The current study examined conversations on Twitter related to use and perceptions of e-cigarettes in the United States. We employed the Social Media Analytic and Research Testbed (SMART) dashboard, which was used to identify and download (via a public API) e-cigarette-related geocoded tweets. E-cigarette related tweets were collected continuously using customized geo-targeted Twitter APIs. A total of 193,051 tweets were collected between October 2015 and February 2016. Of these tweets, a random sample of 973 geocoded tweets were selected and manually coded for information regarding source, context, and message characteristics. Our findings reveal that although over half of tweets were positive, a sizeable portion was negative or neutral. We also found that, among those tweets mentioning a stigma of e-cigarettes, most confirmed that a stigma does exist. Conversely, among tweets mentioning the harmfulness of e-cigarettes, most denied that e-cigarettes were a health hazard. These results suggest that current efforts have left the public with ambiguity regarding the potential dangers of e-cigarettes. Consequently, it is critical to communicate the public health stance on this issue to inform the public and provide counterarguments to the positive sentiments presently dominating conversations about e-cigarettes on social media. The lack of awareness and need to voice a public health position on e-cigarettes represents a vital opportunity to continue winning gains for tobacco control and prevention efforts through health communication interventions targeting e-cigarettes. PMID- 29979919 TI - Are eating behaviors related with by body mass index, gender and age? AB - The present study was carried out with parents of 520 healthy children between the ages of 2-12 and their parents who were referred to the diet polyclinic of a hospital in Ankara. The data were collected through personal interviews. The interviews included identifying the characteristics of the child and his/her parents, anthropometric measurements, questions investigating eating status, and the Children's Eating Behavior Questionnaire. According to the body mass index-Z scores, there were differences between subgroups of food responsiveness, emotional overeating, enjoyment of food, food fussiness, and slowness in eating. The gender-based desire to drink score was, on average, higher in boys. No gender based differences were found in other subgroups, whereas the scores in the food fussiness and slowness in eating and emotional undereating were higher in the preschool group when analyzed by age. In conclusion, eating behaviors of overweight and obese children differ from those of normal and underweight children. PMID- 29979921 TI - Applying the Modified Comprehensive Model of Information Seeking to Online Health Information Seeking in the Context of India. AB - This study extends the Comprehensive Model of Information Seeking (CMIS) to online health information seeking in the context of India. This study considers the Internet (i.e., media) use an antecedent factor and the personal relevance factor salience is separated into two dimensions - susceptibility and severity. Structural equation modeling analysis (N = 990) tested the associations between health-related antecedents, information-carrier factors, and their direct effects on online information seeking. The results among online health information seekers in India showed significant relationships between length and frequency of media use and self-efficacy to engage in preventive behavior to the information carrier utility. As predicted, demographics have no significant relationship with utility of the Internet, and direct experience with illness resulted in negative relationship with the Internet utility. Contrary to expectations, susceptibility and severity produced negative relationships with the Internet utility. Result shows that both information-carrier factors - characteristics related to trust and utility related to perceived usefulness and relevance of information - directly affect online health-information-seeking behavior. Unlike the original CMIS that primarily focused on specific illnesses, the current modified CMIS can be adapted and tailored to general online health-information-seeking behavior. PMID- 29979922 TI - A screening tool for detecting eating disorder risk and diagnostic symptoms among college-age women. AB - OBJECTIVE: As eating disorders (EDs) often emerge during college, managing EDs would ideally integrate prevention and treatment. To achieve this goal, an efficient tool is needed that detects clinical symptoms and level of risk. This study evaluated the performance of a screen designed to identify individuals at risk for or with an ED. PARTICIPANTS: Five hundred forty-nine college-age women. METHODS: Participants completed a screen and diagnostic interview. RESULTS: Using parsimonious thresholds for ED diagnoses, screen sensitivity ranged from 0.90 (anorexia nervosa) to 0.55 (purging disorder). Specificity ranged from 0.99 (anorexia nervosa) to 0.78 (subthreshold binge eating disorder) compared to diagnostic interview. Moderate to high area under the curve values were observed. The screen had high sensitivity for detecting high risk. CONCLUSIONS: The screen identifies students at risk and has acceptable sensitivity and specificity for identifying most ED diagnoses. This tool is critical for establishing stepped care models for ED intervention. PMID- 29979923 TI - Acculturation, diet, and psychological health among Asian students. AB - OBJECTIVE: The study examined the association between acculturation level, dietary nutrient intake, and psychological health of Asian students at the University of Delaware. PARTICIPANTS: A total of 172 students completed the study. METHODS: Data were collected, using questionnaires, through Qualtrics(r). Linear regression models were used to examine the association between normally distributed diet and acculturation and demographic data. RESULTS: As length of residence in the United States increased, acculturation level and maintenance of original culture both increased. There was no significant association between acculturation and nutrient intake. Chinese students were more likely than other Asian students to have nonspecific psychological distress. CONCLUSION: There was no significant association between diet and acculturation level. A larger sample population with longer US residence is needed to further investigate this association. In an effort to improve psychological health of Asian students, challenges specific to this population, such as the language barrier, should be addressed. PMID- 29979924 TI - Measuring characteristics of e-cigarette consumption among college students. AB - OBJECTIVE: E-cigarette use among college students has increased drastically in recent years. This study aims to inform development of a comprehensive measure of e-cigarette consumption for this population. PARTICIPANTS AND METHODS: This mixed method study collected both quantitative and qualitative data from a sample of 43 experienced e-cigarette users from two college campuses, using a self-reported questionnaire and a semi-structured interview, in March-September of 2017. RESULTS: College student users found some of the consumption questions in national surveys difficult to answer. Switching nicotine levels, mixing flavors, co-using with alcohol and marijuana, using with others who were vaping or drinking, and vaping in a car or indoor space were all common. The participants defined "regular user" based on ownership of a device rather than on quantity/frequency. CONCLUSIONS: A comprehensive e-cigarette consumption measure should cover the complex characteristics that are potentially associated with negative health consequences such as flavorings, co-use and social contexts. PMID- 29979925 TI - Patterns of alcohol use and marijuana use among students at 2- and 4-year institutions. AB - OBJECTIVE: The objective of this study was to understand substance use patterns of alcohol, marijuana, and simultaneous alcohol and marijuana (SAM) use among 2- and 4-year college students. PARTICIPANTS: Participants were 526 young adults aged 18-23 (n = 355 4-year students; n = 171 2-year students) recruited from February 2015 to January 2016 who were participating in a larger longitudinal study. METHODS: Latent class analysis (LCA) was used to identify past-month classes of alcohol, marijuana, and SAM use. RESULTS: Among both 2- and 4-year students, a four-class solution yielded the best-fitting model, with 2-year classes tending to include greater marijuana use and less alcohol use and 4-year classes tending to include heavy alcohol use. Demographic characteristics were largely similar across classes. CONCLUSIONS: Classes of alcohol, marijuana, and SAM use differed by education status. Screening and prevention efforts for 4-year students may need to be tailored for the needs of 2-year students. PMID- 29979926 TI - Effects of a web-based pre-enrollment alcohol brief motivational intervention on college student retention and alcohol-related violations. AB - OBJECTIVE: To determine whether completing a pre-enrollment Web-based alcohol brief motivational intervention (BMI) increased student retention and reduced student alcohol-related violations. PARTICIPANTS: Fall 2011 (3,364) and Fall 2012 (3,111) entering cohorts of all first-year students at a midwestern state university. METHOD: Students completing the brief intervention (BI) were compared to students not completing the BI. Retention was tracked for four years for the 2011 cohort and three years for the 2012 cohort. Campus and community alcohol violations were tracked for two academic years following enrollment. Kaplan-Meier survival analysis and Cox regression were used to test retention survival. Logistic regression was used to test campus and community violations. RESULTS: Students in both cohorts who completed the BI had significantly higher retention and significantly fewer alcohol-related violations than noncompleters. CONCLUSIONS: Population-level Web-based BIs help prevent student dropout and decrease alcohol-related violations, with impacts extending multiple years. Web based BI is an efficacious population-level prevention tool. PMID- 29979927 TI - RNA Interference Mechanisms and Applications in Plant Pathology. AB - The origin of RNA interference (RNAi), the cell sentinel system widely shared among eukaryotes that recognizes RNAs and specifically degrades or prevents their translation in cells, is suggested to predate the last eukaryote common ancestor ( 138 ). Of particular relevance to plant pathology is that in plants, but also in some fungi, insects, and lower eukaryotes, RNAi is a primary and effective antiviral defense, and recent studies have revealed that small RNAs (sRNAs) involved in RNAi play important roles in other plant diseases, including those caused by cellular plant pathogens. Because of this, and because RNAi can be manipulated to interfere with the expression of endogenous genes in an intra- or interspecific manner, RNAi has been used as a tool in studies of gene function but also for plant protection. Here, we review the discovery of RNAi, canonical mechanisms, experimental and translational applications, and new RNA-based technologies of importance to plant pathology. PMID- 29979928 TI - Network Analysis: A Systems Framework to Address Grand Challenges in Plant Pathology. AB - Plant pathology must address a number of challenges, most of which are characterized by complexity. Network analysis offers useful tools for addressing complex systems and an opportunity for synthesis within plant pathology and between it and relevant disciplines such as in the social sciences. We discuss applications of network analysis, which ultimately may be integrated together into more synthetic analyses of how to optimize plant disease management systems. The analysis of microbiome networks and tripartite phytobiome networks of host vector-pathogen interactions offers promise for identifying biocontrol strategies and anticipating disease emergence. Linking epidemic network analysis with social network analysis will support strategies for sustainable agricultural development and for scaling up solutions for disease management. Statistical tools for evaluating networks, such as Bayesian network analysis and exponential random graph models, have been underused in plant pathology and are promising for informing strategies. We conclude with research priorities for network analysis applications in plant pathology. PMID- 29979929 TI - Assessment of an e-training tool for college students to improve accuracy and reduce effort associated with reading nutrition labels. AB - OBJECTIVE: Nutrition labels are often underutilized due to the time and effort required to read them. We investigated the impact of label-reading training on effort, as well as accuracy and motivation. PARTICIPANTS: Eighty college students (21 men and 59 women). METHODS: The training consisted of a background tutorial on nutrition followed by three blocks of practice reading labels to decide which of two foods was the relatively better choice. Label-reading effort was assessed using an eye tracker and motivation was assessed using a 6-item scale of healthy food-choice empowerment. RESULTS: Students showed increases in label-reading accuracy, decreases in label-reading effort, and increases in empowerment. CONCLUSIONS: The nutrition label e-training tool presented here, whether used alone or as part of other wellness and health programs, may be an effective way to boost students' label-reading skills and healthy food choices, before they settle into grocery shopping habits. PMID- 29979930 TI - The Perspective of HIV Providers in Western Kenya on Provider-Patient Relationships. AB - Enhancing effective adherence dialogue with HIV patients in an environment that promotes good provider-patient relationships, is key to optimizing the benefits of antiretroviral therapy (ART). The study examines the perspectives of HIV providers in western Kenya on provider-patient relationships. Sixty healthcare providers were sampled using convenience sampling methods from three Academic Model for Providing Access to Healthcare (AMPATH) sites (one urban and two rural). In-depth interviews conducted in either Swahili or English were audio recorded, transcribed, and translated into English. Content analysis was performed after thematic coding. Providers perceived that they had good relationships with most patients, and tended to identify negative patient attributes as the source of poor provider-patient relationships. Providers preferred patients who adhered to treatment guidelines. They did not like patients who challenged their authority, and did not see it as their responsibility to find more effective ways of interacting with patients who they found difficult. Structural barriers to collaborative physician-patient relationships included noncontinuity of relationships, lack of specific appointment times, high provider-patient ratio, and management of provider fatigue and job dissatisfaction. There is need for HIV care programs to identify culturally appropriate interventions to enhance better provider-patient relationship. PMID- 29979931 TI - Demographic differences in response rates for PHQ9 in a university student population. AB - OBJECTIVE: To examine differences in complete response rates for depression screening questions based on demographic characteristics. METHODS: Cross sectional study examining associations between demographic characteristics and completely responding depression-screening questions. PARTICIPANTS: "Healthy Minds Study" data, collected in a public University in February 2016, where 7,326 students participated. RESULTS: women (AOR: 0.69; 95% CI =0.57-0.83) and gay/lesbian students (AOR: 0.24; 95% CI =0.10-0.60) had better complete response rates. Non-US (AOR: 1.46; 95% CI =1.03-2.07), black (AOR: 3.32; 95% CI =1.92 5.77), and Middle-Eastern students (AOR: 3.73; 95% CI =1.73-8.02) had lower complete response rates. CONCLUSIONS: Our study shows sex, gender, citizenship, and race categories have significant differences in complete response rates for the outcome. Our findings have several implications; including recognizing interventions for depression based on responders may not target those that tend to be "partial-responders". Efforts in survey design, recruiting and completion of surveys should be maximized. PMID- 29979932 TI - Prevention of shape and weight concerns among college students: An examination of education status variables. AB - OBJECTIVE: The current study examined whether overlooked aspects of the postsecondary student experience predicted individuals' body-related concerns, beyond the influence of demographic factors that have upheld explanatory power in past research. PARTICIPANTS: Undergraduate and graduate students (n = 3,259) took part in the multi-institute Healthy Bodies Study during the 2015 academic year. METHOD: Participants completed an online survey that assessed their undergraduate/graduate statuses, academic majors, extracurricular involvements, and body-related concerns. Hierarchical multiple regression analyses were run to answer primary study questions. RESULTS: Gender, body mass index (BMI), undergraduate/graduate student status, being a male graduate student, major, and extracurricular activities predicted shape concern (SC), weight concern (WC), and whether these concerns increased since students began at their universities. The addition of the student-specific variables uniquely contributed to the variance in body-related concerns. CONCLUSIONS: Further research on the body-related discontent of the identified student groups should be conducted to elucidate potential campus-based treatment targets. PMID- 29979933 TI - Self-blame and stress in undergraduate college students: The mediating role of proactive coping. AB - OBJECTIVE: This study aimed to examine the mediating relationship of proactive coping on self-blame and stress among US undergraduate college students. PARTICIPANTS: The sample of undergraduate college students (n = 261) were recruited through their Introduction to Psychology course and registered for the study through a research-based computer program utilized at the university in the fall 2010 and spring 2011 semesters. METHODS: Participants voluntarily completed a battery of self-report questionnaires that measured self-blame, proactive coping, and stress. Correlation and regression-based mediation analyses were utilized to address the study objectives. Demographic differences were explored using comparative analyses. RESULTS: Proactive coping was identified as a mediator between self-blame and stress. Correlation analyses revealed self-blame, proactive coping, and stress were interrelated with one another. Ethnicity differences were observed on proactive coping. CONCLUSIONS: Proactive coping mediated the relationship between self-blame and stress and was negatively related to the other included behavioral constructs. PMID- 29979934 TI - Genetic counseling students' experiences with mental illness during training: An exploratory study. AB - Mental illness is a substantive issue for graduate students. We investigated experiences of mental illness during training among genetic counseling students, a subgroup of graduate students for which little data exists on this topic. Genetic counseling students and recent graduates (n = 227) completed an online survey, from who 11 were selected to participate in semi-structured telephone interviews. Thematic analysis and member checking were employed to interpret the interviews. An overarching theme of importance to participants' mental health during genetic counseling training was safety, with subthemes of: trust/confidentiality, stigma and fear of labeling, developing a unique professional identity, and ability to engage in self care strategies. Our data could help genetic counseling training programs develop strategies to support students' mental health. PMID- 29979935 TI - Toward total student health: A qualitative pilot study. AB - OBJECTIVE: Colleges should aim to cultivate healthy behaviors among students by addressing alterations in wellness students view as important. The purpose of this study was to determine the self-perceived wellness-related concerns and behaviors of college students. PARTICIPANTS: Thirty-seven undergraduate students participated in this study between January and March 2017. METHODS: Focus groups served as a data collection method. Groups were recorded and transcribed verbatim. Directed and conventional approaches to data analyses were employed. RESULTS: Participants expressed concern regarding four campus wellness topics: nutrition, economics, mental health, and campus safety. Participants offered solutions for improving campus wellness, representing a fifth theme. CONCLUSIONS: Health concerns for college students and realistic solutions to address concerns were identified across focus groups. Overall, students cared about their own health, as well as the well-being of other students. Future directions include conducting a Web-based survey among students to assess prevalence and impact of select health and wellness topics. PMID- 29979936 TI - Inside MSU: Taking risks to improve climate. PMID- 29979937 TI - Body symmetry and reproductive hormone levels in women. AB - Fluctuating asymmetry (FA), a morphological marker of developmental stability, may be related to an individual's biological condition, e.g., health or fertility. The aim of this study was to test if the level of a woman's FA was related to her fertility and reproductive potential as measured by reproductive hormone levels. Fifty-three healthy, non-pregnant, naturally cycling women (mean age = 23.42, SD = 1.85 years), participated in the study, conducted in Wroclaw (Poland) in May 2015. Early-follicular phase serum levels of anti-Mullerian hormone (AMH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were measured. FA was calculated based on anthropometric measures of six bilateral body traits, and the composite FA index was used in statistical analyses. No relationship was observed between FA and the levels of FSH, LH, and AMH (p > .05), controlled for potential confounders. However, the level of E2 was positively correlated with FA (p < .05). Thus, in young women, FA was not related to hormones levels related to ovarian reserve, but more symmetrical women had lower E2 levels. As FA is an index of developmental stability, environmental, and genetic stress, the results of the study confirm previous research suggesting that developmental conditions may be related to women's endogenous estrogen levels. PMID- 29979938 TI - Worry and rumination: Explanatory roles in the relation between pain and anxiety and depressive symptoms among college students with pain. AB - OBJECTIVE: Pain affects a significant proportion of college students in the United States and has been linked to anxiety and depressive symptoms. Rumination and worry, two transdiagnostic factors linked to comorbidity, may explain the relationship between pain and mental health symptoms. Current Study: The current study examined worry and rumination as explanatory factors in the relationship between pain and anxiety and depressive symptoms in a sample of college students with pain (n = 1,577; 79.9% female). RESULTS: Results indicated that both rumination and worry explained the relationship between pain and depressive and social anxiety symptoms, while rumination alone explained the relationship between pain and anxious arousal symptoms. CONCLUSION: The current study provides novel empirical evidence that worry and rumination each help explain the relationship between pain and anxiety and depressive symptoms among college students with current pain, and college students in pain may benefit from targeted psychosocial strategies aimed at decreasing worry and ruminative responses. PMID- 29979939 TI - Perceived consequences of hazing exposure during the first year of college: Associations with childhood victimization. AB - OBJECTIVE: This study investigates the association between histories of childhood victimization and perceived consequences of college hazing. PARTICIPANTS: First year college students at four US universities (N = 120). METHOD: Participants completed Web-based surveys asking about childhood victimization (eg, child maltreatment), peer victimization, and perceived consequences of hazing during college. RESULTS: Results indicated that college students with childhood victimization histories perceived hazing to be negative. In particular, physical dating violence and a greater total number of childhood victimization exposures were related to a higher number of perceived negative consequences. CONCLUSION: Past victimization exposures confer risk on college students who experience hazing, in that these students are more likely to perceive negative consequences of hazing. Hazing-related policies and outreach efforts should consider these potential negative consequences, and counselors should be aware of the link between past victimization and how hazing might be experienced. PMID- 29979940 TI - Postoperative respiratory muscle training in addition to chest physiotherapy after pulmonary resection: A randomized controlled study. AB - PURPOSE: The effects of preoperative respiratory muscle training (RMT) on postoperative complications in patients with pulmonary resection have recently attracted the attention of researchers. More studies are obviously needed to clarify the effects of RMT after pulmonary resection. The aim of this study was to evaluate the effectiveness of intense RMT in addition to chest physiotherapy after pulmonary resection in terms of respiratory muscle strength, exercise capacity, and length of hospital stay rather than postoperative complications. METHODS: Forty subjects undergoing pulmonary resection were included in the study. Subjects were divided into two groups using a simple randomization method. The subjects in the study group (SG; n = 20) received RMT in addition to regular chest physiotherapy in the postoperative period. The subjects in the control group (CG; n = 20) received only regular chest physiotherapy. Respiratory muscle strength (maximal inspiratory and expiratory pressure [PImax and PEmax]) was measured pre-postoperatively and before discharge, and exercise capacity, which was measured by the 6-min walk test (6MWT), was assessed preoperatively and before discharge. The length of hospital stay was also recorded. RESULTS: There were no differences between groups in terms of demographic and surgical characteristics. The nonsignificant change of PImax from the preoperative to the discharge value was 65.1 +/- 15.5 to 68.2 +/- 19.2 cmH2O in SG and 59.2 +/- 13.7 to 44.3 +/- 14.8 cmH2O in CG (p > 0.05, p > 0.05, respectively). The change of PEmax from the preoperative to the discharge value was 80.4 +/- 24.9 to 81.5 +/- 24.9 cmH2O in SG (nonsignificant) and 85.4 +/- 38.2 to 61.3 +/- 25.4 cmH2O in CG (p > 0.05, p = 0.002, respectively). There was a significant difference between SG and CG in terms of RMT effect (PImax: 11.05 [21.84; 0.25] cmH2O p = 0.045; PEmax: 25.23 [42.83; 7.62] cmH2O p = 0.006). A significant difference was found in the 6MWT when the mean differences were compared between the groups (85.72 [166.15; 5.28] m p = 0.037). The length of hospital stay was significantly shorter in the SG (number of days for SG 9.1 +/- 3 and for CG 12.9 +/- 4.2 [p = 0.002]). CONCLUSION: The addition of RMT to chest physiotherapy after pulmonary resection can have positive effects on respiratory muscle strength, exercise capacity, and length of hospital stay. PMID- 29979941 TI - A Standard of Care for the Prevention of Sexual Misconduct by School Employees. AB - This article describes the development of a standard of care for the prevention of adult to student sexual abuse in pre K-12 schools. Standard of care is not a phrase often used in educational practice, and yet, it is a legal concept that may be useful for school administrators. A sample of administrators, child sexual abuse specialists, and attorneys with experience in school employee sexual misconduct responded to 101 items that the literature indicates should be included in a standard of care. There was agreement on 94 of these items by sample participants. Categories of the standard of care were policies, hiring process, hiring screening, hiring interview, training, and reporting. Where there was disagreement by role of respondent, attorneys, child sexual abuse specialists, or both rated the item as more important for inclusion than did administrators. PMID- 29979942 TI - Pilot study of a Web-based acceptance and commitment therapy intervention for university students to reduce academic procrastination. AB - OBJECTIVE: This pilot study pursued two aims. The first was to investigate the feasibility and acceptability of a Web-based acceptance and commitment therapy (ACT) intervention to reduce academic procrastination among university students. The second aim was to test the effectiveness of the intervention on procrastination and committed actions. PARTICIPANTS: The sample was comprised of Canadian university students (n = 36) that participated in the intervention between September 2016 and April 2017. METHODS: The study relied on a prepost research design. RESULTS: The intervention appears feasible, acceptable, and valuable to students. A significant reduction in procrastination and a significant improvement in committed actions were found between pre and postintervention. The effect sizes for these results were medium. CONCLUSIONS: Results provide preliminary support for the feasibility and effectiveness of a Web-based ACT intervention for academic procrastination. Results also highlight some aspects that need to be improved for further development. PMID- 29979944 TI - Family and community support among older Chilean adults: the importance of heterogeneous social support sources for quality of life. AB - Family and community social networks act as social resources that promote well being at advanced ages. In this study, we analyze the association between social support received from personal social networks (social support from various family members and friends) and community social networks (social support from neighbors and the neighborhood, age, ethnic, or religious group peers and formal social support networks) and quality of life (QoL) for a sample of older Chilean persons (n = 777). The results confirm that social support from family (partner, children, and extended family) and friends, integration in the community (neighbors) and social support from informal systems (social groups) are associated with QoL. Moreover, the model including both types of support explains 25.8% of variance in QoL. The results and their possible implications are discussed. PMID- 29979943 TI - Understanding the social and community support networks of American Indian women cancer survivors. AB - Cancer is the leading cause of death among American Indian and Alaska Native (AI/AN) women. Although cancer disparities among AI women are alarming, there is littlle research focused on the topic of social support and cancer treatment and outcomes. A community advisory board was used to develop and administer the project, and a qualitative descriptive study methodology was used. This research was conducted in partnership with two community-based hospitals in the Northern Plains. The sample included 43 AI female cancer survivors who were interviewed with a semi-structured interview guide. The data were analyzed using content analysis. Emergent themes revealed that AI cancer survivors' non-familial support systems included friends (n = 12), support groups (n = 6), churches (n = 10), co workers (n = 5), communities (n = 4), support from health practitioners (n = 3), and additional forms of support. Results indicate that survivors' networks are diverse and support broad prevention programs that reach out to churches, community groups, and online forums. These sources of supports can be enhanced through sustainable community-based infrastructures. PMID- 29979945 TI - Finding the vulnerable among China's elderly: identifying measures for effective policy targeting. AB - Facing a rapidly aging population, China has recently started to formulate and implement policies with the aim to provide old-age care. While well-developed old age care policies commonly include a built-in component that assesses eligibility based on vulnerability, no such process is established in the context of China. Here, based on data from the China Health and Retirement Longitudinal Study collected in both 2011 and 2013, we (a) developed a simple and effective strategy for identifying vulnerable Chinese elderly, which can serve as a basis for policy targeting, and (b) improved the policy relevance and targeting efficiency of this vulnerability measure by including additional health indicators. Our vulnerability measures identify 35% to 46% of Chinese elderly as vulnerable, covering up to 67% of elderly at high risk of death or functional decline. They can serve as an initial screening step for more comprehensive geriatric assessments and enable policy makers to effectively target vulnerable elderly persons in China. PMID- 29979946 TI - The contribution of social-environmental factors to the emotional adjustment of Israeli religious Jewish women coping with infertility. AB - The community is often considered a resource for coping with health-related stress but has potential for negative effects when coping with fertility problems. In this study, we examined the associations between the social environmental variables (seeking the support of the community, perception of pressure from the community, and perception of spouse support as a possible moderator of this pressure) and emotional adjustment to fertility problems among religious Jewish women in Israel, a highly pronatalist society. Data were collected from January to August 2011. Structural equation modeling using data from 186 women indicated that perception of pressure from the community was associated with poorer emotional adjustment. This association was not moderated by perceived spouse support, but spouse support was associated with better adjustment. Seeking the support of the community was found to be composed of two dimensions: Seeking Ties and Belonging to the Community, which was associated with poorer adjustment, and Seeking Approval and Recognition from the Community, which was associated with better adjustment. These results point to the complexity of dealing with health-related stress when it comes to important community values. Understanding this complexity can help professionals conduct culturally sensitive evaluation and treatment that will contribute to women's emotional adjustment to fertility problems. PMID- 29979947 TI - Effects of Integrating Care for Medicare-Medicaid Dually Eligible Seniors in Minnesota. AB - Individuals dually eligible for Medicare and Medicaid often receive fragmented and inefficient care. Using Minnesota fee-for-service claims, managed care encounters, and enrollment data for 2010-2012, we estimated the likely impact of Minnesota Senior Health Option (MSHO)-seen as the first statewide fully integrated Medicare-Medicaid model-on health care and long-term services and supports use, relative to Minnesota Senior Care Plus (MSC+), a Medicaid-only managed care plan with Medicare fee for service. Estimates suggest that MSHO enrollees had significantly higher use of primary care and, potentially, of community-based services, combined with lower use of hospital-based care than similar MSC+ enrollees. Adopting fully integrated care models like MSHO may have merit in other states. PMID- 29979948 TI - Race and income disparities in disaster preparedness in old age. AB - This study investigated to what extent income status and race/ethnicity in old age interplayed with disaster preparedness. Data came from the 2010 Health and Retirement Study, a nationally representative panel survey of older Americans over 51 years old. Our sample was restricted to respondents who participated in a special survey about disaster preparedness (N=1,711). Disaster preparedness was measured as a score, which includes 13 variables. Race/ethnicity was categorized by White, Black, and Hispanic. Low income was defined as below 300% of the federal poverty line. OLS regression was used to examine the main and interaction effects of race/ethnicity and lower income status on disaster preparedness scores. We found that older adults in lower income status had lower preparedness level than those in higher income (Coef. =-0.318, p<.01). Hispanics tend to be less prepared compared to White and Blacks (Coef. =-0.608, p<.001). Preparedness of Black elders was not significantly different from that of Whites. However, interestingly, Black elders in lower income status were significantly less prepared for disaster than other groups (Coef. =- 0.622, p<.05). This study identified vulnerable subgroups of older adults for disaster preparedness and suggests that preparedness programs should target minority and low income elders. PMID- 29979949 TI - Quality of life and sexual function in obese women with pelvic floor dysfunction. AB - This prospective study was conducted in the urogynecology and gynecology outpatient clinics of Istanbul Faculty of Medicine from December 2014 to March 2015. The objective was to identify the association between obesity and sexual function and quality of life in women with pelvic floor dysfunction (PFD). A total of 387 sexually active women diagnosed with urinary incontinence and/or pelvic organ prolapse were included and categorized as obese (n = 200) or nonobese (n = 187). Mean body mass indexes were 25.7 +/- 2.41 kg/m2 for nonobese women and 34.9 +/- 3.92 kg/m2 for obese women. The Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire-12 total score was significantly lower in obese (27.66 +/- 7.12) than in nonobese women (30.18 +/- 6.54) (p < .05). Quality of life mean scores were higher in obese women for both the Incontinence Impact Questionnaire total score (67.24 +/- 26.8 versus 49.12 +/- 27.5) and Urogenital Distress Inventory total score (65.02 +/- 21.4 versus 55.07 +/- 24.7) (p < .001). Obese women with PFD had symptoms for longer durations, had more frequent urinary incontinence, and worse sexual function and quality of life than nonobese women. Health-care professionals caring for obese women should be aware of the coexistence of obesity and PFD. Future studies should evaluate whether obesity associated PFD can be reduced through successful weight reduction interventions. PMID- 29979951 TI - Level of happiness and happiness-determining factors perceived by women aged over 60 years. AB - The aim of this article is to present the level of happiness perceived by women aged over 60 years (N = 100), to indicate the factors that determine the perception of happiness, and to determine the possibilities for strengthening the feeling of happiness. For the purposes of this article and the analysis of the obtained empirical data, the authors of this article assumed the structural theory of happiness, which allows for study participants to be viewed as biological, psychological, social, and spiritual beings. PMID- 29979952 TI - The effects of meal-timing on self-rated hunger and dietary inflammatory potential among a sample of college students. AB - College is an important time for young adults to establish healthy eating habits since students are at risk for gaining weight during the college years. An emerging area of research is examining the effect of meal-timing, which involves the timing of food intake throughout the day, in an effort to improve satiety and bodyweight. The purpose of this study was to examine the use of meal-timing among a sample of college students and to assess what aspects from an intervention could help them to adhere to meal-timing long term. Participants were randomly assigned to either a daytime group (<=30% total kcals after 5 pm) or a nighttime group (>=50% total kcals after 5 pm). After completing the intervention, almost half of participants (49%) reported they could adhere to meal-timing long-term. Having more resources that support meal-timing are needed to help students potentially achieve a healthy weight and prevent chronic diseases. PMID- 29979950 TI - West Nile virus and other mosquito-borne viruses present in Eastern Europe. AB - Eastern Europe (EE) has been severely affected by mosquito-borne viruses (moboviruses). In this review, we summarize the epidemiology of moboviruses, with particular attention to West Nile virus (WNV). The study of WNV human cases in EE between 2010 and 2016, revealed that the epidemiology of WNV in EE is complex with the combination of introduction of different WNV strains from lineages 1 and 2, and the establishment of endemic cycles. We found a positive correlation between the risk of WNV re-emergence in an area and the number of human cases reported in the previous year. We also report the main ecological and biological characteristics of the key mosquito species vectors of moboviruses. Recent expansion of invasive mosquito species in EE, mainly Aedes albopictus but also Aedes aegypti and Culex quinquefasciatus, may result in new scenarios with an increased risk of transmission of moboviruses. Main gaps of knowledge in relation to moboviruses and their vectors in EE are identified. Understanding the epidemiology of moboviruses in EE is essential for the improvement of their surveillance and the control of the diseases they cause. PMID- 29979953 TI - Association between sex, race/ethnicity, season, day of week, and alcohol use and related risks in college student athletes and nonathletes. AB - OBJECTIVE: To examine personal and social constructs (eg, sex, race) and external influences (ie, competition schedules) that are associated with the pattern and amount of alcohol consumption by student athletes compared to nonathletes. PARTICIPANTS: Students (n = 2,984; 57% female, 61% white, 16% athlete) on a single campus were surveyed in Fall 2011 and Spring 2012. METHODS: Anonymous surveys included demographics, alcohol use, and related problems. RESULTS: Student athletes consumed more alcohol than nonathletes, with male and white athletes posing the highest levels of risk for heavy consumption. Expanded examination of in- and out-of-season athletes found out-of-season athletes drink more frequently and more per occasion than their in-season peers. Athletes were more likely than nonathletes to drink on specific days of the week and daily patterns differed between in- and out-of-season athletes. CONCLUSIONS: The risk of athlete status is moderated by sex, race, season, and day of the week. PMID- 29979954 TI - (Unintended) Consequences of initiating an alcohol sales policy at college football stadiums: A case study. AB - University officials are increasingly considering selling alcoholic beverages at campus football stadiums. To inform this decision, we report on offenses occurring at a campus football stadium and surrounding community on game day weekends between 2009 and 2013. Campus police log data for 35 home football weekends were examined, accounting for 1,940 distinct incidents. There was a general upward trend in crime incidents. On average, 330 total crime incidents occurred when alcohol was not sold (2009-2011) compared to 475 annually when alcohol was sold (2012-2013). Liquor law violations and alcohol consumption by a minor were the two most frequently cited offenses. Liquor law violations (317) was highest after alcohol sales initiated. Police incidents were markedly higher when playing a traditional football rival at home. College administrators, health officials, athletic departments, and local law enforcement must work together to weigh the potential benefit of enhanced financial profit against the risk of increased alcohol-related crime. PMID- 29979955 TI - Nonmedical use of prescription drugs during sexual activity as a predictor of condom use among a sample of college students. AB - OBJECTIVE: To examine the impact of nonmedical use of prescription drugs (NMUPD) during sexual activity on the frequency of condom use among a sample of college students. PARTICIPANTS: Students attending a large Midwestern University (N = 4284) during April 2015. METHODS: Retrospective cross-sectional analysis of survey data using logistic regression. RESULTS: Respondents and/or their sexual partners who engaged in NMUPD during sexual activity were significantly less likely to use condoms during 75% or more of past 12-month sexual encounters compared to respondents who had not engaged in lifetime and past 12-month NMUPD. Although not statistically significant, trends suggest that respondents who engaged in NMUPD during sexual activity may be less likely to use condoms than those who engaged in lifetime or past 12-month NMUPD but not during sexual activity. CONCLUSIONS: Findings suggest a need for specific strategies for reducing risk behaviors related to prescription drugs and sexual activity. PMID- 29979956 TI - Health insurance literacy: A mixed methods study of college students. AB - OBJECTIVE: This study examines the health insurance literacy, or the ability to use health insurance effectively, of college students. PARTICIPANTS: A total of 455 students from a large, public university completed an online questionnaire in November 2016. METHODS: A questionnaire examined students' knowledge of commonly encountered health insurance terms and ability to apply that knowledge to determine cost-sharing in a clinical setting. RESULTS: The majority of students were able to correctly identify the most commonly encountered terms, but could not identify terms related to plan types and options. Eighty-eight percent of students could not determine their cost-sharing for two presented scenarios. Approximately half of the students indicated they had been confused about their health insurance plan, with one-quarter of students stopping or delaying medical care due to confusion. CONCLUSIONS: Outreach and education for students should target specific deficits in knowledge such as those identified in this study. PMID- 29979957 TI - Young people's reasoning about exclusion in novel groups. AB - This study examined children's and adolescents' reasoning about the exclusion of others in peer and school contexts. Participants (80 8-year-olds, 85 11-year olds, 74 14-year-olds, and 73 20-year-olds) were asked to judge and reason about the acceptability of exclusion from novel groups by children and school principals. Three contexts for exclusion between two groups were systematically varied: unequal economic status, geographical location, and a control (no reason provided for group differences). Regardless of condition, participants believed that exclusion was less acceptable in peer contexts than in school contexts and when children were excluded rather than principals. Participants also used more moral and less social conventional reasoning for peer contexts than for school contexts. In terms of condition, whereas 8-year-olds rated exclusion based on unequal economic status as less acceptable than exclusion based on geographical location or no reason when enacted by a principal, 14-year-olds rated the unequal economic condition as more acceptable than the other two contexts. The 11- and 20 year-olds did not distinguish economic status differences. The findings suggest that children and adolescents are sensitive to context and take multiple variables into account, including the type of group difference (socioeconomic status or other reasons), authority status of the perpetrator of exclusion, and setting (school or peer group). Patterns may have differed from past research because of the sociocultural context in which exclusion was embedded and the contexts of group differences. PMID- 29979958 TI - Symbolic flexibility during unsupervised word learning in children and adults. AB - Considerable debate in language acquisition concerns whether word learning is driven by domain-general (symbolically flexible) or domain-specific learning mechanisms. Prior work has shown that very young children can map objects to either words or nonlinguistic sounds, but by 20 months of age this ability narrows to only words. This suggests that although symbolically flexible mechanisms are operative early, they become more specified over development. However, such research has been conducted only with young children in ostensive teaching contexts. Thus, we investigated symbolic flexibility at later ages in more referentially ambiguous learning situations. In Experiment 1, 47 6- to 8 year-olds acquired eight symbol-object mappings in a cross-situational word learning paradigm where multiple mappings are learned based only on co occurrence. In the word condition participants learned with novel pseudowords, whereas in the sound condition participants learned with nonlinguistic sounds (e.g., beeps). Children acquired the mappings, but performance did not differ across conditions, suggesting broad symbolic flexibility. In Experiment 2, 41 adults learned 16 mappings in a comparable design. They learned with ease in both conditions but showed a significant advantage for words. Thus, symbolic flexibility decreases with age, potentially due to repeated experiences with linguistic materials. Moreover, trial-by-trial analyses of the microstructure of both children's and adults' performance did not reveal any substantial differences due to condition, consistent with the hypothesis that learning mechanisms are generally employed similarly with both words and nonlinguistic sounds. PMID- 29979959 TI - Induction of the unfolded protein response (UPR) during Marek's disease virus (MDV) infection. AB - Marek's disease (MD) is a pathology of chickens associated with paralysis, immune suppression, and the rapid formation of T-cell lymphomas. MD is caused by the herpesvirus, Marek's disease virus (MDV). We examined endoplasmic reticulum (ER) stress and the activation of unfolded protein response (UPR) pathways during MDV infection of cells in culture and lymphocytes in vivo. MDV strains activate the UPR as measured by increased mRNA expression of GRP78/BiP with concomitant XBP1 splicing and induction of its target gene, EDEM1. Cell culture replication of virulent, but not vaccine MDVs, activated the UPR at late in infection. Pathotype associated UPR activation was induced to a greater level by a vv + MDV. Discrete UPR activation was observed during MDV in vivo infection, with the level of UPR modulation being affected by the MDV oncoprotein Meq. Finally, ATF6 was found to be activated in vv + MDV-induced primary lymphomas, suggesting a possible role in tumor progression. PMID- 29979961 TI - A First Glimpse of Nucleation of Phase Transitions in Living Cells. AB - Prion formation and propagation involve the nucleation and growth of protein based supramolecular assemblies. In this issue of Molecular Cell, Khan et al. (2018) report novel methods that enable quantitative, high-throughput analyses of nucleation of supramolecular assemblies by prion-forming proteins in living cells. Their approaches turn living cells into veritable test tubes for biophysical investigations. PMID- 29979960 TI - Interleukin-6 and type 1 interferons inhibit varicella zoster virus replication in human neurons. AB - Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that, following primary infection (varicella), establishes latency in sensory, autonomic, sympathetic and parasympathetic neurons, where it remains until reactivation (zoster). VZV-specific cell-mediated immune responses maintain VZV latency; thus, immunosuppressed and elderly persons are at risk of reactivation and associated neurological diseases. However, the cytokines produced by the immune system that control VZV in neurons are largely unknown. Therefore, to better understand how the immune system may restrict VZV in neurons, we studied interleukin-6, tumor necrosis factor-alpha and type 1 interferons for their ability to inhibit VZV replication in human neurons in vitro. Our studies revealed that VZV transcription and viral spread were significantly reduced by interleukin-6 and type 1 interferons, and to a lesser extent by tumor necrosis factor-alpha. These findings will help in understanding how the innate immune system limits virus replication in neurons in vivo. PMID- 29979962 TI - A Muscle-Specific Enhancer RNA Mediates Cohesin Recruitment and Regulates Transcription In trans. AB - The enhancer regions of the myogenic master regulator MyoD give rise to at least two enhancer RNAs. Core enhancer eRNA (CEeRNA) regulates transcription of the adjacent MyoD gene, whereas DRReRNA affects expression of Myogenin in trans. We found that DRReRNA is recruited at the Myogenin locus, where it colocalizes with Myogenin nascent transcripts. DRReRNA associates with the cohesin complex, and this association correlates with its transactivating properties. Despite being expressed in undifferentiated cells, cohesin is not loaded on Myogenin until the cells start expressing DRReRNA, which is then required for cohesin chromatin recruitment and maintenance. Functionally, depletion of either cohesin or DRReRNA reduces chromatin accessibility, prevents Myogenin activation, and hinders muscle cell differentiation. Thus, DRReRNA ensures spatially appropriate cohesin loading in trans to regulate gene expression. PMID- 29979964 TI - Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome. AB - Activity-dependent changes in neuronal function require coordinated regulation of the protein synthesis and protein degradation machinery to maintain protein homeostasis, critical for proper neuronal function. However, the biochemical evidence for this balance and coordination is largely lacking. Leveraging our recent discovery of a neuronal-specific 20S membrane proteasome complex (NMP), we began exploring how neuronal activity regulates its function. Here, we found that the NMP degrades exclusively a large fraction of ribosome-associated nascent polypeptides that are being newly synthesized during neuronal stimulation. Using deep-coverage and global mass spectrometry, we identified the nascent protein substrates of the NMP, which included products encoding immediate-early genes, such as c-Fos and Npas4. Intriguingly, we found that turnover of nascent polypeptides and not full-length proteins through the NMP occurred independent of canonical ubiquitylation pathways. We propose that these findings generally define a neuronal activity-induced protein homeostasis program of coordinated protein synthesis and degradation through the NMP. PMID- 29979965 TI - A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. AB - The TP53 gene is frequently mutated in human cancer. Research has focused predominantly on six major "hotspot" codons, which account for only ~30% of cancer-associated p53 mutations. To comprehensively characterize the consequences of the p53 mutation spectrum, we created a synthetically designed library and measured the functional impact of ~10,000 DNA-binding domain (DBD) p53 variants in human cells in culture and in vivo. Our results highlight the differential outcome of distinct p53 mutations in human patients and elucidate the selective pressure driving p53 conservation throughout evolution. Furthermore, while loss of anti-proliferative functionality largely correlates with the occurrence of cancer-associated p53 mutations, we observe that selective gain-of-function may further favor particular mutants in vivo. Finally, when combined with additional acquired p53 mutations, seemingly neutral TP53 SNPs may modulate phenotypic outcome and, presumably, tumor progression. PMID- 29979966 TI - Polycomb Repressive Complex 1 Generates Discrete Compacted Domains that Change during Differentiation. PMID- 29979967 TI - An Enhancer-Derived RNA Muscles In to Regulate Myogenin In trans. AB - Noncoding RNAs (ncRNAs) transcribed from active enhancers are known as enhancer RNAs (eRNAs). eRNAs have generally been shown to contribute to transcriptional activation of target genes in cis. In this issue, Tsai et al. (2018) demonstrate that an eRNA expressed from a distal enhancer of Myogenic differentiation1 (MyoD) (DRReRNA) does not regulate its neighboring MyoD; instead, it promotes myogenic differentiation by activating Myogenin, which is located on a different chromosome. PMID- 29979963 TI - Quantifying Nucleation In Vivo Reveals the Physical Basis of Prion-like Phase Behavior. AB - Protein self-assemblies modulate protein activities over biological timescales that can exceed the lifetimes of the proteins or even the cells that harbor them. We hypothesized that these timescales relate to kinetic barriers inherent to the nucleation of ordered phases. To investigate nucleation barriers in living cells, we developed distributed amphifluoric FRET (DAmFRET). DAmFRET exploits a photoconvertible fluorophore, heterogeneous expression, and large cell numbers to quantify via flow cytometry the extent of a protein's self-assembly as a function of cellular concentration. We show that kinetic barriers limit the nucleation of ordered self-assemblies and that the persistence of the barriers with respect to concentration relates to structure. Supersaturation resulting from sequence encoded nucleation barriers gave rise to prion behavior and enabled a prion forming protein, Sup35 PrD, to partition into dynamic intracellular condensates or to form toxic aggregates. Our results suggest that nucleation barriers govern cytoplasmic inheritance, subcellular organization, and proteotoxicity. PMID- 29979969 TI - UntRIG(er)ing lncRNAs. AB - In a recent Cell paper, Jiang et al. (2018) have shown that lnc-Lsm3b, a long non coding RNA induced by type I IFN late in the infection in mouse macrophages, prevents further activation of RIG-I acting as a decoy for RIG-I. PMID- 29979968 TI - Enhanced Bacterial Immunity and Mammalian Genome Editing via RNA-Polymerase Mediated Dislodging of Cas9 from Double-Strand DNA Breaks. AB - The ability to target the Cas9 nuclease to DNA sequences via Watson-Crick base pairing with a single guide RNA (sgRNA) has provided a dynamic tool for genome editing and an essential component of adaptive immune systems in bacteria. After generating a double-stranded break (DSB), Cas9 remains stably bound to DNA. Here, we show persistent Cas9 binding blocks access to the DSB by repair enzymes, reducing genome editing efficiency. Cas9 can be dislodged by translocating RNA polymerases, but only if the polymerase approaches from one direction toward the Cas9-DSB complex. By exploiting these RNA-polymerase/Cas9 interactions, Cas9 can be conditionally converted into a multi-turnover nuclease, mediating increased mutagenesis frequencies in mammalian cells and enhancing bacterial immunity to bacteriophages. These consequences of a stable Cas9-DSB complex provide insights into the evolution of protospacer adjacent motif (PAM) sequences and a simple method of improving selection of highly active sgRNAs for genome editing. PMID- 29979970 TI - MitoCPR: Meticulous Monitoring of Mitochondrial Proteostasis. AB - Mitochondrial protein import stress compromises functioning of the organelles, due to inadequate supply of inner mitochondrial proteins. Weidberg and Amon (2018) describe a new monitoring pathway in budding yeast, which restores mitochondrial function following the clearing of accumulated unfolded pre transported mitochondrial proteins, by devising a molecular strategy of overexpressing bi-partite-containing mitochondrial proteins. PMID- 29979971 TI - Sequence-Directed Action of RSC Remodeler and General Regulatory Factors Modulates +1 Nucleosome Position to Facilitate Transcription. AB - Accessible chromatin is important for RNA polymerase II recruitment and transcription initiation at eukaryotic promoters. We investigated the mechanistic links between promoter DNA sequence, nucleosome positioning, and transcription. Our results indicate that positioning of the transcription start site-associated +1 nucleosome in yeast is critical for efficient TBP binding and is driven by two key factors, the essential chromatin remodeler RSC and a small set of ubiquitous general regulatory factors (GRFs). Our findings indicate that the strength and directionality of RSC action on promoter nucleosomes depends on the arrangement and proximity of two specific DNA motifs. This, together with the effect on nucleosome position observed in double depletion experiments, suggests that, despite their widespread co-localization, RSC and GRFs predominantly act through independent signals to generate accessible chromatin. Our results provide mechanistic insight into how the promoter DNA sequence instructs trans-acting factors to control nucleosome architecture and stimulate transcription initiation. PMID- 29979972 TI - Generation of a human induced pluripotent stem cell line, KSCBi003-A, from human adipose tissue-derived mesenchymal stem cells using a chromosomal integration free system. AB - We generated a human induced pluripotent stem cell (hiPSC) line, KSCBi003-A, from adipose tissue-derived mesenchymal stem cells (Ad-MSCs) using a Sendai virus based gene delivery system. We confirmed that the KSCBi003-A has a normal karyotype and short tandem repeat (STR)-based identities that match the parent cells. We also confirmed that the cell line expresses pluripotent stem cell markers such as Nanog, OCT4, SSEA-4, TRA-1-60, and TRA-1-81. We also analyzed that the KSCBi003-A has an ability to differentiate three germ layers (ectoderm, mesoderm, endoderm). This cell line is registered and available at the National Stem Cell Bank, Korea National Institute of Health. PMID- 29979973 TI - GSK3 inhibition, but not epigenetic remodeling, mediates efficient derivation of germline embryonic stem cells from nonobese diabetic mice. AB - The nonobese diabetic (NOD) mouse strain is a predominant animal model of type 1 diabetes. However, this mouse strain is considered to be non-permissive for embryonic stem cell (ESC) derivation using conventional methods. We examined small molecule inhibition of glycogen synthase kinase 3 (GSK3) to block spontaneous cell differentiation and promote pluripotency persistence. Here we show a single pharmacological GSK3 inhibitor, 6-bromoindirubin-3'-oxime (BIO), in combination with leukemia inhibition factor (LIF), promoted generation of stable NOD ESC lines at >80% efficiency. Significantly, expansion of the established NOD ESC lines no longer required treatment with BIO. These NOD ESC lines contributed to chimeric mice and transmitted to germline progeny that spontaneously developed diabetes. By contrast, 5-aza-2'-deoxycytidine (AZA), a small molecule inhibitor of DNA methylation, and trichostatin A (TSA) and valproic acid (VPA), small molecule inhibitors of histone deacetylase, could not promote generation of NOD ESCs by epigenetic remodeling. These combined findings provide strategic insights for imposing pluripotency in cells isolated from a non-permissive strain. PMID- 29979975 TI - Inhibitory effects of tea catechin epigallocatechin-3-gallate against biofilms formed from Streptococcus mutans and a probiotic lactobacillus strain. AB - OBJECTIVE: Effects of tea catechin epigallocatechin-3-gallate (EGCG) against biofilm formation by Streptococcus mutans and probiotic Lactobacillus casei in Yakult(r) (LcY) were examined. DESIGN: Biofilms were formed by S. mutans alone (Sm) and co-culture of S. mutans and LcY (Sm + LcY) in the absence or presence of EGCG. The biomass of biofilms, which were sonicated or not, was measured by the crystal violet assay. Biofilm morphology was observed by scanning electron microscopy. Bacterial viability and extracellular polysaccharides were determined by SYTO9/propidium iodide and dextran-conjugated fluorescein staining, respectively, and confocal microscopy. Gene expression of glucosyltransferase was determined by quantitative polymerase chain reaction. RESULTS: While 250 MUg/ml EGCG significantly decreased the biomass and acid production of Sm biofilms, 500 MUg/ml EGCG was required to inhibit Sm + LcY biofilm formation and acid production. EGCG decreased the amount of live bacteria present in both Sm and Sm + LcY biofilms. The level of dead bacteria in Sm + LcY biofilms was higher than in Sm biofilms when formed in the presence of 250 MUg/ml EGCG. EGCG decreased levels of extracellular polysaccharides in Sm and Sm + LcY biofilms. The extent of biofilm removal by sonication was not different between Sm and Sm+LcY biofilms formed in the absence or presence of 62.5 or 125 MUg/ml EGCG. The level of Sm gtfB and gtfD expression in Sm + LcY biofilms was higher than those in the Sm biofilms when formed in the presence of EGCG at 250 MUg/ml. CONCLUSION: The results indicated that LcY might interfere the inhibitory effects of EGCG against biofilm formation by S. mutans. PMID- 29979974 TI - Effects of far infrared radiation by isotropic high-density carbon on the human oral mucosa. AB - OBJECTIVES: Wound healing of the oral mucosal epithelium through the application of far infrared radiation emitted by isotropic high-density carbon was investigated in order to clarify the preventive and therapeutic effects of isotropic high-density carbon on oral mucosal injury. MATERIALS AND METHODS: A carbon massager with an isotropic high-density carbon tip was used. Far infrared radiation was applied to the human buccal mucosal squamous cell carcinoma cell line, HO-1-N-1 using a carbon massager, and cell growth factors and heat shock protein levels were measured using real-time RT-PCR and ELISA. Far infrared radiation was applied to oral mucosal injury in SD rats over time using the carbon massager, and its effects were examined by HE staining and immunostaining. The immunostaining positive rate was measured and analyzed using image analysis software. RESULTS: Far infrared radiation induced stronger mRNA expression and higher HSP27 and HSP70 protein levels on real-time RT-PCR and ELISA than in the control group. The far infrared radiation of oral mucosal injury in rats induced strong positive reactions, and positive rates for Ki67, HSP27, and HSP70 were higher than those in the control group. CONCLUSIONS: The treatment of oral mucosal injury with far infrared radiation emitted by isotropic high-density carbon appears to have promoted heat shock protein production and induced regenerative reactions more strongly than in the control group. PMID- 29979976 TI - Laryngeal anatomical variants and their impact on the diagnosis of mechanical asphyxias by neck pressure. AB - The aims of this investigation were to determine the characteristics and prevalence of anatomical variants of the larynx apparatus and to evaluate the impact of these variants on the accurate diagnosis of laryngeal fractures. A population-based study was carried out, analyzing a series of 207 consecutive autopsied cases in the Institute of Legal Medicine of Galicia (Northwestern Spain). The prevalence of triticeal cartilage was 52.7% and that of agenesis of thyroid horns 10%. Calcification of the stylo-hyoid ligament accounted for 1.4%. We identified three new anatomical variants: the terminal segmentation of the thyroid horns (11.6%), ectopic superior thyroid horns (8%) and lateral thyrohyoid ossification (5.3%). These three names, based on anatomical criteria, are the author's proposal to solve the lack of uniformity in the designation of these variants. Agenesis of thyroid horns were related to the presence of ectopic superior thyroid horns in 93% of cases, either uni or bilateral. The combination of variants was present in 6.8% of the cases, being the terminal segmentation of the thyroid horns in association with triticeal cartilage the most frequent (3.8%). The probability of misdiagnosis due to the presence of anatomical variations in deaths by pressure on the neck was high in this population (71.5%). The prevalence of triticeal cartilage in more than half of the sample, determined an important rate of potential errors (46.4%), followed by the mistaken diagnoses induced by terminal segmentation of thyroid horns (7.3%) and by ectopic superior thyroid horns (6.3%). The likelihood of a misdiagnosed laryngeal fracture was greater if the thyroid cartilage was affected, with a higher proportion of false positives comparing to the hyoid bone (p<0.001). The higher frequency of thyroid fractures in neck pressure together with the prevalence and location of triticeal cartilage on the lower third of the lateral thyrohyoid ligament are the main reasons for these results. Further studies should be done with larger samples to expand epidemiological data and consolidate these results and their influence on the diagnosis of mechanical asphyxias. PMID- 29979977 TI - Fatalities of stowaways traveling in airplane wheel wells. AB - The earliest mention of a stowaway in the wheel well of an airplane dates back to 1947: A 30-year-old man chose this mode of travel for a trip from Lisbon to Brazil and survived (Veronneau et al., 1996). In a retrospective study, we evaluated cases with lethal outcome of stowaways in airplane wheel wells by focusing on forensic autopsy results, in particular, in regard to hypothermia, hypoxia, and injuries. In addition, the flight routes, flight altitudes, and flight durations were analyzed. Using the forensik(r) program, a search of all the autopsies performed between 1994-2017 at the Institute of Legal Medicine in Frankfurt am Main, Germany, was conducted, using the key words "airplane," "flights," and "wheel well." All of the thus retrieved autopsy reports, medicolegal expert reports, and police investigation reports were then evaluated. Five cases were included in our study. The decedents were all men, aged between 14 and 26 years. Four of the decedents had been discovered at the Frankfurt Main airport within airplane wheel wells; the fifth man had been discovered in a woods underlying one of the flight approach paths to the airport. Two stowaways had died of hypoxic asphyxiation, possibly in conjunction with hypothermia as a contributing factor. One stowaway died of the polytrauma he sustained when he was crushed by retracting landing gear. For a further stowaway, the cause of death could not be macroscopically determined at autopsy. In one case, only an external postmortem examination had been performed, without autopsy. Analysis of the flight routes, altitudes, and durations showed that the flights had been international flights, the flight altitudes had varied between 7000m (~23,000ft) und 11,000m (~36,000ft), and the flight duration had been between 4 and 9.5h. At high altitudes, the ambient conditions in wheel wells, which are not pressurized, are rarely survived by stowaways, with hypoxic asphyxiation likely posing greater peril than hypothermia. Further dangers are that of being crushed by retracting landing gear after takeoff, or of falling out of a wheel well, from a great height, when the landing gear is deployed. When it appears conceivable that a stowaway may have fallen from an aircraft wheel well during landing or takeoff, an autopsy and discovery scene investigation are essential to reconstructing the course of events. PMID- 29979978 TI - Male sexual assaults in the Paris, France area: An observational study over 8 years. AB - BACKGROUND: Male sexual assaults were long ignored, possibly because of the myth acceptance that a man can only be the perpetrator of sexual assaults. It is increasingly admitted that all males can be victims of rape. We described the characteristics of a series of male adolescent and adult victims of sexual assault who had a forensic medical examination. METHODS: We conducted an observational study over 8 years. RESULTS: We included 98 male patients aged 15 years and older (range 15-66, median 25) at the time of a reported sexual assault. Assailants were known by the victim in 59 cases (60%). Forty-four patients (45%) had physical or mental vulnerability. Anal penetration was reported in 49 cases (50%). Genital examination showed abnormalities compatible with traumatic injuries in 23 cases (24%). Psychological symptoms were found in 81 victims (83%), including shame (39, 40%) and anxiety (38, 39%). Of 98 victims, sperm could be detected in 6 cases (6%) (anal, 4; oral, 1; skin, 1). Male victims were more frequently disabled or vulnerable than female victims examined in the same centre (45% vs. 13%, p<0.001). At the one-month follow-up consultation, psychological symptoms, including sleep disorders and fear, were observed in most patients and the proportions of physical and psychological complaints were similar among male and female victims. CONCLUSION: Male victims of sexual assault experienced high level of psychological trauma and felt more ashamed than women, which suggests that sexual assaults should be considered as severe among men as among women. PMID- 29979979 TI - Forensic taphonomy: Scavenger-induced scattering patterns in the temperate southwestern Cape, South Africa - A first look. AB - The effect of vertebrate scavenging can drastically alter the rate of decomposition and cause skeletal scatter, which hinders human forensic recovery and identification. Patterns of scavenging, disarticulation and scatter in a forensic context are specific to different environments with no known data for South Africa. A better understanding of these patterns can increase the chances of full body recovery and improve identification of human remains. In this preliminary study, the effect of wild vertebrate scavenging on skeletal scatter was examined using a porcine model in the forensically significant thicketed Cape Flats Dune Strandveld habitat. This area is a densely populated part of Cape Town, which suffers from poor socioeconomic conditions and a high murder rate. Ethics was granted for the use of three small (~20kg) domestic pig (Sus scrofa domesticus) carcasses as proxies for human decomposition. They were deployed in Delft, Cape Town, and observed by motion-activated cameras to record wild scavenger activity. One pig served as a control and was caged to prevent vertebrate but not invertebrate access; the other two served as experimental treatments. Scatter was recorded every second day by marking the location of skeletal elements and measuring the distance and angle from the centre of each deposition site. No scattering was observed in the control, but notable scattering patterns were observed in the experimental pigs due to Cape grey mongoose (Galerella pulverulenta) scavenging, the only vertebrate scavenger species observed. No clear pattern of scatter distance over time was followed. Scatter began in the skeletonisation phase (day 25-30), resulting in a maximum distance of 12.67m and scatter/search area of 504.32m2. Mongoose-induced skeletal scatter followed a distinct pattern of movement into dense undergrowth, a previously unobserved behaviour and a key finding of this study. These results provide baseline data for sub-adult human scatter, or scatter of smaller components of an adult human skeleton, as demonstrated in the forensic case example provided. Knowledge is provided on locally relevant decomposition patterns and informs search methods for improved human skeletal recovery in forensic cases. There is scope for expansion of this study, with an investigation of seasonal effects, the interaction between invertebrate and vertebrate activity, as well as, the effect of clothing on scavenger access. PMID- 29979981 TI - Concern about Justifying the Release of Genomic Data as a Civil Right. PMID- 29979982 TI - Response to Dreyfus and Sobel. PMID- 29979980 TI - Bi-allelic Mutations in Phe-tRNA Synthetase Associated with a Multi-system Pulmonary Disease Support Non-translational Function. AB - The tRNA synthetases catalyze the first step of protein synthesis and have increasingly been studied for their nuclear and extra-cellular ex-translational activities. Human genetic conditions such as Charcot-Marie-Tooth have been attributed to dominant gain-of-function mutations in some tRNA synthetases. Unlike dominantly inherited gain-of-function mutations, recessive loss-of function mutations can potentially elucidate ex-translational activities. We present here five individuals from four families with a multi-system disease associated with bi-allelic mutations in FARSB that encodes the beta chain of the alpha2beta2 phenylalanine-tRNA synthetase (FARS). Collectively, the mutant alleles encompass a 5'-splice junction non-coding variant (SJV) and six missense variants, one of which is shared by unrelated individuals. The clinical condition is characterized by interstitial lung disease, cerebral aneurysms and brain calcifications, and cirrhosis. For the SJV, we confirmed exon skipping leading to a frameshift associated with noncatalytic activity. While the bi-allelic combination of the SJV with a p.Arg305Gln missense mutation in two individuals led to severe disease, cells from neither the asymptomatic heterozygous carriers nor the compound heterozygous affected individual had any defect in protein synthesis. These results support a disease mechanism independent of tRNA synthetase activities in protein translation and suggest that this FARS activity is essential for normal function in multiple organs. PMID- 29979984 TI - Muscling in on the Awesome Proliferative Power of the Terrible Teratoma. AB - In this issue of Cell Stem Cell, Chan et al. (2018) report that in vivo differentiation of pluripotent stem cells in induced teratomas produces functional embryonic-like muscle stem cells. These purified muscle stem cells engraft with high efficiency and regenerate serially injured muscle. PMID- 29979983 TI - Estimating SNP-Based Heritability and Genetic Correlation in Case-Control Studies Directly and with Summary Statistics. AB - Methods that estimate SNP-based heritability and genetic correlations from genome wide association studies have proven to be powerful tools for investigating the genetic architecture of common diseases and exposing unexpected relationships between disorders. Many relevant studies employ a case-control design, yet most methods are primarily geared toward analyzing quantitative traits. Here we investigate the validity of three common methods for estimating SNP-based heritability and genetic correlation between diseases. We find that the phenotype correlation-genotype-correlation (PCGC) approach is the only method that can estimate both quantities accurately in the presence of important non-genetic risk factors, such as age and sex. We extend PCGC to work with arbitrary genetic architectures and with summary statistics that take the case-control sampling into account, and we demonstrate that our new method, PCGC-s, accurately estimates both SNP-based heritability and genetic correlations and can be applied to large datasets without requiring individual-level genotypic or phenotypic information. Finally, we use PCGC-s to estimate the genetic correlation between schizophrenia and bipolar disorder and demonstrate that previous estimates are biased, partially due to incorrect handling of sex as a strong risk factor. PMID- 29979985 TI - The Regenerative Altruism of Hepatocytes and Cholangiocytes. AB - In this issue of Cell Stem Cell and recently in Nature, Deng et al. (2018) and Schaub et al. (2018) (respectively) demonstrate that following acute liver injury, hepatocytes and cholangiocytes restore liver mass and function. When proliferative capacity of either cell type is impaired, the other cell type will transdifferentiate to restore full regeneration and hepatic histology. PMID- 29979986 TI - Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC) derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL 17R) and NFkappaB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD. PMID- 29979987 TI - Recipes for Making Neurons using Combinatorial Forward Genetics. AB - In a recent issue of Nature, Tsunemoto et al. (2018) perform a systematic screening to identify several transcription factor pairs able to generate a variety of different induced neuronal cell populations that share a core neuronal signature, yet differ for specific molecular features. PMID- 29979988 TI - Mapping Active Gene-Regulatory Regions in Human Repopulating Long-Term HSCs. AB - Genes that regulate hematopoietic stem cell (HSC) self-renewal, proliferation, and differentiation are tightly controlled by regulatory regions. However, mapping such regions relies on surface markers and immunophenotypic definition of HSCs. Here, we use gamma-retroviral integration sites (gammaRV ISs) from a gene therapy trial for 10 patients with Wiskott-Aldrich syndrome to mark active enhancers and promoters in functionally defined long-term repopulating HSCs. Integration site clusters showed the highest ATAC-seq signals at HSC-specific peaks and strongly correlated with hematopoietic risk variants. Tagged genes were significantly enriched for HSC gene sets. We were able to map over 3,000 HSC regulatory regions in late-contributing HSCs, and we used these data to identify miR-10a and miR-335 as two miRNAs regulating early hematopoiesis. In this study, we show that viral insertion sites can be used as molecular tags to assess chromatin conformation on functionally defined cell populations, thereby providing a genome-wide resource for regulatory regions in human repopulating long-term HSCs. PMID- 29979989 TI - Secretion of Shh by a Neurovascular Bundle Niche Supports Mesenchymal Stem Cell Homeostasis in the Adult Mouse Incisor. PMID- 29979990 TI - Mitochondrial Shapeshifting Impacts AML Stemness and Differentiation. AB - In this issue of Cell Stem Cell, Pei et al. (2018) demonstrate that leukemic stem cells (LSCs) have enhanced mitochondrial fission, which is positively regulated by FIS1. FIS1 is necessary to maintain LSC function; thus, targeting its expression and mitochondrial fission is a novel approach to decrease stemness and increase differentiation in Acute Myeloid Leukemia. PMID- 29979991 TI - Th17 Cells in Parkinson's Disease: The Bane of the Midbrain. AB - Emerging data implicate potential roles for T cells in Parkinson's disease (PD); however, direct evidence for human T cells in PD-associated neurodegeneration has been lacking. In this issue of Cell Stem Cell, Sommer et al. (2018) demonstrate that IL-17-producing T cells from sporadic PD patients promote cell death of patient iPSC-derived midbrain neurons. PMID- 29979992 TI - Postmitotic Fate Refinement in the Subplate. AB - How is the astonishing diversity of cortical neurons specified? In this issue of Cell Stem Cell, Ozair et al. (2018) leverage hPSC neural differentiation to show that projection neurons undergo prolonged sojourns in the subplate before migrating to deep layers, suggesting that pausing in the subplate may enable integration of intrinsic and extrinsic cues during postmitotic fate refinement. PMID- 29979993 TI - Skeletal Muscle Stem Cells from PSC-Derived Teratomas Have Functional Regenerative Capacity. AB - Derivation of functional skeletal muscle stem cells from pluripotent cells without genetic modification has proven elusive. Here we show that teratomas formed in adult skeletal muscle differentiate in vivo to produce large numbers of alpha7-Integrin+ VCAM-1+ myogenic progenitors. When FACS-purified and transplanted into diseased muscles, mouse teratoma-derived myogenic progenitors demonstrate very high engraftment potential. As few as 40,000 cells can reconstitute ~80% of the tibialis anterior muscle volume. Newly generated fibers are innervated, express adult myosins, and ameliorate dystrophy-related force deficit and fatigability. Teratoma-derived myogenic progenitors also contribute quiescent PAX7+ muscle stem cells, enabling long-term maintenance of regenerated muscle and allowing muscle regeneration in response to subsequent injuries. Transcriptional profiling reveals that teratoma-derived myogenic progenitors undergo embryonic-to-adult maturation when they contribute to the stem cell compartment of regenerated muscle. Thus, teratomas are a rich and accessible source of potent transplantable skeletal muscle stem cells. VIDEO ABSTRACT. PMID- 29979994 TI - Genotoxic Lemons Become Epigenomic Lemonade. AB - Active regulatory elements in hematopoietic stem cells (HSCs) are incompletely characterized, since extant approaches immunophenotypically define and isolate rare HSCs. In the current issue of Cell Stem Cell, Wunsche et al. (2018) use gamma-retroviral insertion sites from a human gene therapy trial to identify the active enhancer landscape of functionally characterized HSCs. PMID- 29979995 TI - Elevated interleukin-17 and reduced testosterone in bipolar disorder. Relation with suicidal behaviour. AB - Hormonal imbalance and inflammation are associated with bipolar disorder and suicidal behavior. The present study was designed to assess the levels of testosterone and interleukin-17 and their association with suicidal behavior in patients with bipolar disorder in remission. 41 bipolar disorder cases in remission and 41 age matched controls were enrolled in the study. Testosterone and interleukin-17 levels were assessed in both the groups. Interleukin-17 was significantly increased and testosterone was significantly reduced in bipolar disorder when compared with controls. IL-17 was negatively correlated with testosterone (r = -0.368, p = 0.018) and positively correlated with duration of disease (r = 0.382, p = 0.014) in bipolar disorder patients. Both didn't show any association with suicidal behavior. We conclude that testosterone is increased and interleukin-17 is reduced in bipolar disorder in remission and these were not associated with suicidal behavior in these patients. PMID- 29979996 TI - Treatment-resistant depression: A plea to mull over! PMID- 29979998 TI - Drop in oxygen supply pressures: Misleading gas cylinder color coding to be blamed for nearing a mishap? PMID- 29979997 TI - Interstitial telomeric loops and implications of the interaction between TRF2 and lamin A/C. AB - The protein-DNA complexes that compose the end of mammalian chromosomes-telomeres serve to stabilize linear genomic DNA and are involved in cellular and organismal aging. One mechanism that protects telomeres from premature degradation is the formation of structures called t-loops, in which the single-stranded 3' overhang present at the terminal end of telomeres loops back and invades medial double stranded telomeric DNA. We identified looped structures formed between terminal chromosome ends and interstitial telomeric sequences (ITSs), which are found throughout the human genome, that we have termed interstitial telomeric loops (ITLs). While they form in a TRF2-dependent manner similar to t-loops, ITLs further require the physical interaction of TRF2 with the nuclear intermediate filament protein lamin A/C. Our findings suggest that interactions between telomeres and the nucleoskeleton broadly impact genomic integrity, including telomere stability, chromosome structure, and chromosome fragility. Here, we review the roles of TRF2 and lamin A/C in telomere biology and consider how their interaction may relate telomere homeostasis to cellular and organismal aging. PMID- 29979999 TI - Analysis of adverse outcomes in the post-anesthesia care unit based on anesthesia liability data. AB - STUDY OBJECTIVE: The aim of this study is to provide a contemporary medicolegal analysis of claims brought against anesthesiologists in the United States for events occurring in the post-anesthesia care unit (PACU). DESIGN: In this retrospective analysis, we analyzed closed claims data from the Controlled Risk Insurance Company (CRICO) Comparative Benchmarking System (CBS) database. SETTING: Claims closed between January 1, 2010 and December 31, 2014 were included for analysis if the alleged damaging event occurred in a PACU and anesthesiology was named as the primary responsible service. PATIENTS: Forty three claims were included for analysis. Data regarding ASA physical status and comorbidities were obtained, whenever available. Ages ranged from 18 to 94. Patients underwent a variety of surgical procedures. Severity of adverse outcomes ranged from temporary minor impairment to death. INTERVENTIONS: Patients receiving care in the PACU. MEASUREMENTS: Information gathered for this study includes patient demographic data, alleged injury type and severity, operating surgical specialty, contributing factors to the alleged damaging event, and case outcome. Some of these data were drawn directly from coded variables in the CRICO CBS database, and some were gathered by the authors from narrative case summaries. RESULTS: Settlement payments were made in 48.8% of claims. A greater proportion of claims involving death resulted in payment compared to cases involving other types of injury (69% vs 37%, p = 0.04). Respiratory injuries (32.6% of cases), nerve injuries (16.3%), and airway injuries (11.6%) were common. Missed or delayed diagnoses in the PACU were cited as contributing factors in 56.3% of cases resulting in the death of a patient. Of all claims in this series, 48.8% involved orthopedic surgery. CONCLUSIONS: The immediate post operative period entails significant risk for serious complications, particularly respiratory injury and complications of airway management. Appropriate monitoring of patients by responsible providers in the PACU is crucial to timely diagnosis of potentially severe complications, as missed and delayed diagnoses were a factor in a number of the cases reviewed. PMID- 29980000 TI - Postoperative pain management for tracheoesophageal fistula repair using transverse, in-plane, ultrasound guided paravertebral technique in a 2 kg neonate. PMID- 29980001 TI - Delayed recovery of limb muscle power after general anesthesia with cisatracurium in a dermatomyositis patient. PMID- 29980002 TI - Anesthetic management of patients with systemic mastocytosis. PMID- 29980003 TI - Opioid sparing effect of Erector Spinae Plane block for pediatric bilateral inguinal hernia surgeries. PMID- 29980004 TI - Corrigendum to "Paradoxical postural cerebrospinal fluid leak-induced headache: Report of two cases" [J Clin Anesth 20 (5) (2008 Aug) 383-5]. PMID- 29980005 TI - Ultrasound guided erector spinae plane block reduces postoperative opioid consumption following breast surgery: A randomized controlled study. AB - STUDY OBJECTIVE: To evaluate the analgesic effect of ultrasound-guided erector spinae plane (ESP) block in breast cancer surgery. DESIGN: Randomized controlled, single-blinded trial. SETTING: Operating room. PATIENTS: Fifty ASA I-II patients aged 25-65 and scheduled for elective breast cancer surgery were included in the study. INTERVENTIONS: Patients were randomized into two groups, ESP and control. Single-shot ultrasound (US)-guided ESP block with 20 ml 0.25% bupivacaine at the T4 vertebral level was performed preoperatively to all patients in the ESP group. The control group received no intervention. Patients in both groups were provided with intravenous patient-controlled analgesia device containing morphine for postoperative analgesia. MEASUREMENTS: Morphine consumption and numeric rating scale (NRS) pain scores were recorded at 1, 6, 12 and 24 h postoperatively. MAIN RESULTS: Morphine consumption at postoperative hours 1, 6, 12 and 24 decreased significantly in the ESP group (p < 0.05 for each time interval). Total morphine consumption decreased by 65% at 24 h compared to the control group (5.76 +/- 3.8 mg vs 16.6 +/- 6.92 mg). There was no statistically significant difference between the groups in terms of NRS scores. CONCLUSIONS: Our study findings show that US-guided ESP block exhibits a significant analgesic effect in patients undergoing breast cancer surgery. Further studies comparing different regional anesthesia techniques are needed to identify the optimal analgesia technique for this group of patients. PMID- 29980006 TI - Thoracic paravertebral nerve block for treating contraction of the latissimus dorsi muscle after breast cancer surgery. PMID- 29980007 TI - Cell fate reprogramming through engineering of native transcription factors. AB - Cellular reprogramming using cocktails of transcription factors (TFs) affirms the epigenetic and developmental plasticity of mammalian cells. It demonstrates the ability of TFs to 'read' genetic information and to rewire regulatory networks in different cellular contexts. Silenced chromatin is not an impediment to the genome engagement by ectopically expressed TFs. Reprogramming TFs have been identified in diverse structural families that lack shared domains or sequence motifs. Interestingly, the reprogramming activity of non-redundant paralogous TFs can be switched with a few point mutations. These findings revealed that the sequence-function relationships influencing reprogramming are tied to subtle features directing genome wide binding. Therefore, endogenous reprogramming TFs are amenable to directed biomolecular engineering that opens up new avenues to optimize cell fate conversions. PMID- 29980009 TI - Menstrual cycle irregularity and menopause status influence cognition in women with schizophrenia. AB - Cognitive impairments are a core feature of schizophrenia and contribute significantly to functional complications. Current pharmacological treatments do not ameliorate cognitive dysfunction and the aetiology of cognitive impairments are poorly understood. Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain and have been suggested to also influence cognition. The aim of the current study was to investigate how HPG axis hormones effect cognition, specifically exploring the influence of menopause status and menstrual cycle irregularity on cognitive performance in women with schizophrenia. The data for the present study represents pooled baseline data from three clinical trials. Two hundred and forty female participants with a diagnosis of schizophrenia or schizoaffective disorder were included in the analysis. Cognition was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status. Hormone assays for serum sex steroids and pituitary hormones (including estradiol, progesterone, luteinising hormone and follicle stimulating hormone) were conducted and women were classified as postmenopausal; perimenopausal; premenopausal/reproductive, further classified into regular and irregular menstrual cycles. To model a comparison of cognitive performance for i) perimenopausal; ii) post-menopausal women and iii) reproductive aged women with irregular cycles to reproductive aged women with regular cycles a semiparametric regression model (generalised additive mode) was fitted. The results revealed that in females with schizophrenia, menstrual cycle irregularity predicted significantly poorer cognitive performance in the areas of psychomotor speed, verbal fluency and verbal memory. Perimenopause was not associated with cognitive changes and the post-menopausal period was associated with poorer visuospatial performance. This study provides evidence to associate reproductive hormones with cognitive dysfunction in schizophrenia. PMID- 29980008 TI - Decreased use of active coping styles contributes to elevated allostatic load index in first-episode psychosis. AB - Accumulating evidence indicates that stress plays an important role in the development of psychotic disorders. Recent studies have revealed that patients with first-episode psychosis (FEP) present systemic biological dysregulations related to stress-exposure in terms of elevated allostatic load (AL) index. However, the mechanisms underlying this observation remain unknown. Therefore, in this study we aimed to investigate the AL index with respect to stress coping strategies in 36 FEP patients and 31 matched controls. We found significantly higher AL index in FEP patients compared to controls after co-varying for potential confounding factors. Patients with FEP were less likely to use active and task-focused coping. Lower odds of using these coping styles, planning as well as positive reinterpretation and growth were related to higher AL index in FEP patients, but not in controls. Depressive symptoms were associated with lower likelihood of using task-focused coping as well as positive reinterpretation and growth. Additionally, depressive symptoms were related to higher AL index. Finally, depressive symptoms mediated the effects of task-focused coping as well as positive reinterpretation and growth on the AL index. Our results confirm systemic biological dysregulation indexed as AL in FEP patients. Lower odds of using active coping styles might contribute to higher AL index via the mediating effect of depressive symptoms in patients with FEP. Longitudinal studies are required to establish causal inferences between coping styles, depressive symptoms and the AL index in early psychosis. PMID- 29980010 TI - In vitro proinflammatory gene expression predicts in vivo telomere shortening: A preliminary study. AB - The chronic psychological stress of caregiving leads to higher risks for many diseases. One of the mechanisms through which caregiving is associated with disease risk is chronic inflammation. Chronic inflammation may accelerate cellular aging via telomere dysfunction and cell senescence, although this has not been examined in human cells from healthy people. We examined peripheral blood mononuclear cells (PBMCs) from 20 healthy mothers of children with autism (caregivers) and 19 mothers of neurotypical children (controls) in an in vitro culture system where PBMCs were stimulated with phytohaemagglutinin (PHA). We measured RNA expression levels of a panel of immune function genes before and after PHA stimulation, as well as telomere length from PBMCs collected from the participants at baseline and 15 months later. Caregivers and controls had similar gene expression profiles in unstimulated PBMCs, but after PHA stimulation, caregivers had increased RNA levels of the master inflammatory regulator NF kappaB and its proinflammatory cytokine targets IL-1beta, IL-6 and its receptor IL-6R as well as inflammatory chemokines IL-8, CXCL1 and CXCL2. Gene expression analysis suggested caregivers have increased Treg and Th17 T cell differentiation. Additionally, key signaling molecules involved in the upregulation of COX-2, a critical enzyme in the synthesis of the inflammatory mediator prostaglandin, were elevated. When both groups were examined together, higher expression levels of proinflammatory genes were associated with shorter telomere length in PBMCs from blood drawn 15 months later, independent of baseline telomere length. Taken together, these results suggest that chronic stress is associated with an exaggerated inflammatory response in PBMCs, which in turn is associated with shorter telomere length measured from PBMCs collected 15 months later. To our knowledge, this is the first human study that shows increased proinflammatory expression predicts future telomere shortening. PMID- 29980011 TI - Trigonelline inhibits intestinal microbial metabolism of choline and its associated cardiovascular risk. AB - Gut microbiota based metabolism of choline produces trimethylamine (TMA) which is further converted to a pro-atherosclerotic metabolite, trimethylamine-N-oxide (TMAO) by flavin monooxygenase (FMO3). Trigonelline from the plant Trigonella foenum-graecum has been reported for the treatment of CVD. Aim of the present study was to check the effect of trigonelline on the gut microbiota based conversion of TMA to TMAO. Trigonelline was isolated from hydroalcoholic extract of seeds of Trigonella foenum-graecum. The isolated trigonelline was characterized through TLC and UPLC-MS. Anaerobic microbe responsible for the metabolism of choline to TMA was isolated by culturing the human gut microbiota in choline enriched medium. The isolated bacteria was identified at molecular level based on PCR amplification of 1500bp of 16S rRNA gene sequence. Isolated FMO3 was used for ex vivo conversion of TMA to TMAO. Further, we investigated the effect of trigonelline in isolated gut microbe based metabolism of choline, lipid profile and TMAO levels in mice with or without suppression of gut microbiota with antibiotics. Liquid-liquid purification and chromatographic analysis confirmed the trigonelline purity (87.26%) and which was also confirmed by mass spectroscopy with m/z 137.4 in positive ionization mode. A total of 30 anaerobic microbes responsible for TMA production were isolated and Citrobacter freundii was the superior among others for the production of TMA. In vitro culture of C. freundii in choline enriched medium supplemented with trigonelline resulted in significantly reduction TMA and followed by TMAO production. In ex vivo, a maximum of 85.3% TMAO production was reduced by trigonelline at concentration of about 300 MUg/mL. Serum level of lipids and TMAO were significantly altered in choline fed animals with or without suppression of gut microbiota and this phenomenon was reversed upon the oral administration of trigonelline in a dose dependent manner. This study demonstrates the effect of trigonelline on gut microbiota responsible for choline metabolism and this can be used as a model for evaluation of herbal drugs and its effect in gut microbiota prompted cardiovascular disorders. PMID- 29980012 TI - Pharmacokinetics and tissue distribution of eupatilin and its metabolite in rats by an HPLC-MS/MS method. AB - Eupatilin, a major pharmacologically active ingredient in StillenTM, has been known to possess anti-peptic, anti-cancer and anti-allergy activities. A rapid, simple, sensitive and specific high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the simultaneous determination of eupatilin and its main metabolite (eupatilin-7beta-O-glucuronide, E-7-G) in rat plasma and tissues was established and validated. The linear range of eupatilin and E-7-G was 0.20~500 ng/mL and 1.00-2500 ng/mL, and the lowest limit of quantification (LLOQ) of eupatilin and E-7-G was 0.20 and 1.00 ng/mL, respectively. The inter day and intra-day precision of this assay was restricted to within 10%, with a highest accuracy of more than 90%. The matrix effect, recovery and stability of both eupatilin and E-7-G were all demonstrated to be within acceptable limits. The validated method was then successfully applied to a pharmacokinetics and tissue distribution study. The absolute bioavailability (F) of eupatilin was estimated to be 2.7%. After intravenous administration, eupatilin was degraded with high clearance (14.82 L/kg/h) and a short half-life t1/2 (0.29 h). Eupatilin was rapidly metabolized to E-7-G with systemic exposure at 1288.8 ng h ml-1, while the levels of the latter declined more slowly, with a longer t1/2 (4.15 h). Moreover, both eupatilin and E-7-G were widely distributed across various tissues, including the liver, kidney and intestine. Taken together, eupatilin showed poor absorption, extensive metabolism into E-7-G and a wide tissue distribution, especially in the intestine. These pharmacokinetic results yield helpful insights into the pharmacological actions of eupatilin. PMID- 29980013 TI - One-pot synthesis of poly (acrylic acid)-stabilized Fe3O4 nanocrystal clusters for the simultaneously qualitative and quantitative detection of biomarkers in lateral flow immunoassay. AB - Lateral flow immunoassay (LFIAs) has found widespread applications in point-of care testing (POCT). However, conventional LFIAs based on gold nanoparticles can only provide limited information (qualitative or semi-quantitative information) and suffer from low sensitivity. To address this issue, we developed a Fe3O4 nanocrystal cluster-based highly sensitive LFIAs for the simultaneously qualitative and quantitative detection of trace-level biomarkers. The synthesis of poly (acrylic acid)-stabilized superparamagnetic nanocrystal clusters (PAA MNCs) is a one-pot, simple and convenient technique, and the polyelectrolyte coating provides enough stability, good dispersity and downstream conjugation sites. Using these PAA-MNCs as a label nanomaterial in LFIAs, a model biomarker (amino-terminal pro-B-type natriuretic peptide (NT-proBNP) antibody) was detected qualitatively and quantitatively. The results show that tests have a qualitative detection limit of 100 pg/mL and a quantitative linear relationship between the magnetic signal and antibody concentration (20-8000 pg/mL) under the optimized experimental conditions. The developed LFIA based on PAA-MNCs for NT-proBNP could be used for the clinical assessment of heart failure, offering tremendous potential for personalized medicine. PMID- 29980014 TI - Liquid chromatographic enantiomer separations applying chiral ion-exchangers based on Cinchona alkaloids. AB - As the understanding of the various biological actions of compounds with different stereochemistry has grown, the necessity to develop methods for the analytical qualification and quantification of chiral products has become particularly important. The last quarter of the century has seen a vast growth of diverse chiral technologies, including stereocontrolled synthesis and enantioselective separation and analysis concepts. By the introduction of covalently bonded silica-based chiral stationary phases (CSPs), the so-called direct liquid chromatographic (LC) methods of enantiomer separation became the state-of-the-art methodology. Although a large number of CSPs is available nowadays, the design and development of new chiral selectors and CSPs are still needed since it is obvious that in practice one needs a good portfolio of different CSPs and focused "chiral columns" to tackle the challenging tasks. This review discusses and summarizes direct enantiomer separations of chiral acids and ampholytes applying anionic and zwitterionic ion-exchangers derived from Cinchona alkaloids with emphasis on literature data published in the last 10 years. Our aim is to provide an overview of practical solutions, while focusing on the integration of molecular recognition and methodological variables. PMID- 29980015 TI - Variability on ethyl glucuronide concentrations in hair depending on sample pretreatment, using a new developed GC-MS/MS method. AB - Quantitative determination of ethyl glucuronide in keratin matrix, particularly in hair samples, provides a significant contribution to the evaluation of the extent of ethanol intake. The first-choice method to carry out this analysis is LC-MS/MS, but other techniques may be used. The aim of this work is: a) to develop and validate a GC-MS/MS method for ethyl glucuronide determination in hair; b) to compare GC-MS/MS and LC-MS/MS in analysis of real samples; c) to compare EtG concentration obtained after hair cutting and pulverization. About 30 mg hair samples were washed, pulverized and soaked in 1 ml deionized water. After incubation, the solution was purified through a SPE anion exchange cartridge; the eluate was dried under nitrogen stream, derivatized with PFPA and reconstituted in n-hexane. Then, the sample was injected in the GC-MS/MS system, operating in negative chemical ionization mode and in selected reaction monitoring. The two most intense transitions were used to monitor ethyl glucuronide and deuterated internal standard. All the validation parameters fulfilled the international acceptance criteria. LOD and LOQ were set at 2.0 and 3.0 pg/mg respectively. This method was applied to 194 hair samples collected from teetotallers and alcohol consumers and represents a suitable alternative to LC-MS/MS for the determination of EtG in hair samples, in particular when scarce quantity of hair is available. This study confirmed that pulverization of hair increases the concentration of EtG, but some variability of EtG levels remains probably due to the presence of non-homogeneous material even though pulverization. PMID- 29980016 TI - Analysis of pharmaceuticals and small molecules in aqueous humor. AB - Aqueous humor (AH) is a transparent fluid found in the anterior chamber of the eye. The circulating AH nourishes the cornea and lens and removes the metabolic waste moving through the ocular chambers and drains from the eye to the venous blood. Analysis of drugs in AH is necessary to evaluate their pharmacokinetics parameters, which may be crucial to avoid potential adverse effects. Analysis of endogenous components of AH may help to understand its physiology as well as changes evoked by pathological situation. This review describes analytical methods used for determination of pharmaceuticals and small endogenous molecules in AH, focusing on sample preparation procedures and analytical techniques. Studies on human and animal samples are included. After inspection and filtering of records found in PubMed about 100 research papers were selected to review. In these articles AH samples of human and rabbit origin were studied most often. Sample evaporation and reconstitution in smaller solvent volume was the most popular method for analyte pre-concentration. Acetonitrile, methanol or mixture of both solvents were used most often for protein precipitation. PMID- 29980017 TI - Iron oxide/silica/polypyrrole nanocomposite sorbent for the comparison study of direct-immersion and headspace solid-phase microextraction of aldehyde biomarkers in human urine. AB - The short chain alkyl aldehydes, especially hexanal and heptanal, in urine are considered as potential biomarkers of several diseases and their determination in biological fluids has gained a great attention in recent years. Magnetic iron oxide core-shell silica (Fe3O4/SiO2) nanoparticles was synthesized and embedded in polypyrrole (PPy) during the in-situ electropolymerization on the surface of a stainless-steel wire. The Fe3O4/SiO2/PPy coated steel wire was used as a novel and effective solid-phase microextraction (SPME) fibre. It was employed for the extraction and preconcentration of hexanal and heptanal through direct-immersion (DI-) and headspace (HS-) SPME sampling strategies, followed by GC-FID quantification. The prepared nanocomposite fiber was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). All influential variables on the extraction efficiency of the DI- and HS-SPME sampling modes were studied and optimized. The calibration curves showed acceptable linearity (R2 > 0.99) over the range of 0.01-10 MUg mL-1 for the DI SPME-GC-FID and 0.01-15 MUgmL-1 for HS-SPME-GC-GID methods. The limit of detections (LODs) corresponding to the analytes amounts for which signal-to-noise ratios were equal to 3, estimated to be 0.1 and 0.5 ng mL-1, for hexanal and heptanal using HS-SPME-GC-FID, respectively. The LODs for DI-SPME-GC-FID method were 0.1 and 1.0 for hexanal and heptanal. For six replicated analyses of 0.5 MUg mL-1 of the analytes, the relative standard deviations (RSDs) were calculated 6.5 6.6% and 5.1-5.3%, for DI-SPME and HS-SPME, respectively. The two developed methods were successfully applied for analysis of hexanal and heptanal in urine samples without derivatization step. The HS-SPME-GC-FID sampling/determination strategy showed better analytical figures of merit and longer lifetime for the prepared nanocomposite fiber. PMID- 29980018 TI - Determination of benzodiazepines in pericardial fluid by gas chromatography-mass spectrometry. AB - In Forensic Toxicology it is sometimes impossible to obtain a valid blood sample to perform toxicological analysis due to several factors like advanced state of decomposition, severe burns, bleed to death.... Pericardial Fluid has already been studied during the last years and has been proposed as a valid specimen for toxicological tests. Over the years, the consumption of benzodiazepines spread among the drug dependent population and became noticeable in drug facilitated assault cases and road accidents. Improvement of the analytical methodology required for detecting the presence of these drugs in biological samples is of great importance for forensic toxicology, in order to correctly diagnose an exposure or a poisoning. In this study, 9 benzodiazepines (diazepam, nordiazepam, midazolam, bromazepam, oxazepam, temazepam, lorazepam, clonazepam and alprazolam) have been determined in pericardial fluid. For this purpose a solid phase extraction (SPE) was carried out using Bond Elut Certify cartridges. After the derivatization of six of the nine benzodiazepines, gas chromatography coupled to a selective mass detector was used as the technique for the separation of the analytes. The method developed was fully validated for the 9 analytes and was applied to real samples of pericardial fluid received at the Forensic Toxicology Service of the University of Santiago de Compostela. Finally, they were compared with blood results looking for the existence of a possible correlation between both biological samples. PMID- 29980019 TI - New supported liquid membrane for electromembrane extraction of polar basic endogenous metabolites. AB - Extraction of polar endogenous compounds remains an important issue in bioanalysis although different techniques have been evaluated. Among them, electromembrane extraction (EME) is a relevant approach but supported liquid membranes (SLMs) dedicated to polar molecules are still lacking. In this study 22 organic solvents were evaluated as SLMs on a set of 45 polar basic metabolites (log P from -5.7 to 1.5) from various biochemical families. To investigate a large variety of organic solvents, a parallel electromembrane extraction device was used and a constant current approach was applied to circumvent the heterogeneous conductivities of the different SLMs. Among the tested organic solvents, 2-nitrophenyl pentyl ether (NPPE) appeared the most efficient SLM with the extraction of a large variety of polar cationic metabolites, high extraction yields, and low extraction variabilities. The applied current and the composition of the acceptor and donor solutions were also evaluated and 300 MUA per well and acetic acid 1% (v/v), both as acceptor and donor compartments, were the most efficient conditions. The new SLM and the optimized experimental parameters were successfully applied to the extraction of precipitated plasma samples. Although the extraction recovery decreased for most compounds in the biological matrix, process efficiency (PE) up to 90% and low extraction variability (RSD between 2 and 18%) were obtained for several very polar compounds such as choline or acetylcholine, emphasizing the potential of EME for polar compounds. PMID- 29980020 TI - Influence of the solvent system on the stability of doxycycline solutions. AB - Concentrated solutions of doxycycline are often added to drinking water of animals for oral antibiotic therapy. However, stability concerns of doxycycline in solution involve an accurate selection of the solvent system to ensure that the active substance will remain within the acceptance range during the product shelf-life and to avoid sub-therapeutic dosage. Different solvent systems have been evaluated in order to determine their influence on the stability of concentrated doxycycline solutions. The results showed differences in the degradation kinetics of doxycycline depending on the co-solvent used and they permitted to select a solvent system for liquid doxycycline hyclate formulations with low rate of degradation even after several months of storage. So, the inclusion of ethanol together with propylene glycol as main excipient was found to be beneficial, while no benefit was observed concerning the addition of citric acid. Once administered to drinking water, the solutions were stable for 24 h with no influence of the solvent system. PMID- 29980021 TI - Development of monoclonal antibody-based immunoassays for quantification and rapid assessment of dihydroartemisinin contents in antimalarial drugs. AB - Dihydroartemisinin (DHA) is one of the artemisinin derivatives widely used in artemisinin-based combination therapies (ACTs) for malaria treatment. The availability of a point-of-care device for estimation of DHA quantity would allow a quick quality assessment of the DHA-containing drugs. In this study, 9-O succinylartemisinin was obtained from microbial fermentation of artemisinin, which was hydrogenated to 9-O-succinyldihydroartemisinin as the hapten for DHA. A monoclonal antibody (mAb), designated as 2G11G4, was identified after screening the hybridoma library, which showed 52.3% cross reactivity to artemisinin, but low or no cross reactivity to artesunate, artemether, and several ACTs partner drugs. Based on this mAb, a highly-sensitive, indirect competitive enzyme-linked immunosorbent assay was designed, which showed 50% inhibition concentration of DHA at 1.16 ng/mL, a working range of 0.26-4.87 ng/mL, and limit of detection of 0.18 ng/mL. In addition, a colloidal gold-based lateral flow immunoassay (dipstick) was developed with an indicator range (indicating sensitivity) of 50 100 ng/mL. This dipstick was evaluated for determination of DHA contents in commercial drugs and the results were highly agreeable with those determined by high-performance liquid chromatography. PMID- 29980022 TI - Practical fluorimetric assay for the detection of anticancer drug SN-38 in human plasma. AB - The implementation of therapeutic drug monitoring in the routine clinical practice in oncology is mainly limited by the lack of therapeutic indexes for the majority of the anticancer drugs, and by the absence of suitable analytical tools, which can accurately quantify in real time the concentration of the administered drugs and their relevant metabolites in biological fluids. In this work, a simple and efficient fluorimetric determination of SN-38, the active metabolite of the anticancer drug irinotecan, was developed and applied to human plasma samples. The intrinsic fluorescence of SN-38 allowed its quantification in the range 10-500 ng mL-1 with a LOQ of 5.0 ng mL-1 and a LOD of 1.5 ng mL-1. Low interferences due to main metabolites of irinotecan and comedications, commonly associated with administration of irinotecan, were observed. A validation study, according to FDA and EMA guidelines for bioanalytical method validation, was carried out and, finally, blind samples were analyzed in parallel with a HPLC-MS method obtaining an excellent agreement between the two techniques. PMID- 29980023 TI - A simple, sensitive, and high-throughput LC-APCI-MS/MS method for simultaneous determination of vitamin K1, vitamin K1 2,3-epoxide in human plasma and its application to a clinical pharmacodynamic study of warfarin. AB - Warfarin exerts its anticoagulation activity by blocking the vitamin K-epoxide cycle. A quantitative understanding of how warfarin and related genes interact with the vitamin K-epoxide cycle and the associated change of coagulation activity in the human body may help study the pharmacodynamics of warfarin. The plasma concentration of vitamin K1 (VK1) and vitamin K1 2,3-epoxide (VK1O) could reflect the status of vitamin K-epoxide cycle. However, their determination is a challenging task due to their extremely low concentrations in human plasma and the severe interferences caused by co-extracted lipids. In this study, we developed an LC-APCI-MS/MS method for the simultaneous determination of VK1 and VK1O in human plasma using stable deuterium-labeled vitamin K1 (vitamin K1-d7) as the internal standard (IS). Plasma samples were prepared through protein denaturation followed by one-step liquid extraction with cyclohexane. Chromatographic separation of analytes from isobaric interferences and endogenous ion suppressor was performed on a Synergi Hydro-RP column (150 mm * 4.6 mm, 4 MUm) under the reversed-phase condition with isocratic elution. The selective reaction monitoring (SRM) transitions were chosen as m/z = 451.5->187.3 for VK1, m/z = 467.5->161.2 for VK1O, and m/z = 458.6->194.3 for IS in APCI positive mode. The assay was linear in the range of 100-10,000 pg/mL for the two analytes and achieved considerable extraction recoveries (87.8-93.3%, 91.0-96.9%, and 92.0% for VK1, VK1O, and IS, respectively), negligible matrix effects (93.6-96.0%, 96.3 100.1%, and 95.5%), and high selectivity with a small sample volume requirement (0.2 mL) and short run time (15 min). The validated method was successfully applied in a clinical pharmacodynamic study of warfarin, and the clotting activity was found to be negatively correlated with the plasma concentration ratio of VK1O to VK1. PMID- 29980024 TI - LC/QTOF/MS/MS characterization, molecular docking and in silico toxicity prediction studies on degradation products of anagliptin. AB - Pharmaceutical drugs are potential molecules with specific biological activity. However, long-term use of these chemical molecules can affect the human physiological system because of their increased levels in the human body. Therefore, identification and structure elucidation of impurities or degradation products should be taken into consideration in order to assure drug safety. The present study assessed the degradation behaviour of dipeptidyl peptidase-4 (DPP 4) inhibitor anagliptin under different stress conditions as per ICH guidelines Q1A (R2) followed by elucidation of the structure of degradation products. All the stress samples were analysed by using UPLC/PDA. The superior separation of drug from its degradation products was attained with time programmed gradient elution on BEH C18 (100 mm * 2.1 mm, 1.7 MUm) column using 10 mM ammonium formate (aqueous) and acetonitrile (organic) as the mobile phase components. All the degradation products of anagliptin were characterized using LC/QTOF/MS/MS. In addition, the activity and toxicity of degradation products were determined through molecular docking and in silico toxicity prediction studies, respectively. The developed UPLC/PDA method was validated as per ICH guidelines in terms of specificity, accuracy, precision, linearity and robustness. PMID- 29980026 TI - HBV infection and extra-hepatic cancers in adolescents and 20s: A retrospective study in China. AB - BACKGROUND: The mean age at cancer diagnosis is younger in hepatitis B virus (HBV) infected than non-infected patients. It remains unknown whether this association reflects an increase in the incidence rates of extra-hepatic cancers in adolescents and younger. METHODS: We examined 10 common extra-hepatic cancers (lung, breast, gastric, prostate, esophageal, rectal, cervical, nasopharyngeal, lymphatic, and urinary bladder) among patients diagnosed at three Chinese hospitals during 2007-2016. We compared the percentage distribution (frequencies at each age point are shown as a percentage of the total frequency) of HBsAg+ with HBsAg- patients, and calculated the standardized incidence ratio for each age group. RESULTS: A total of 60,323 patients were identified. The mean age at cancer diagnosis was 1.5-5.5 years younger in hepatitis B surface antigen (HBsAg) positive patients compared to HBsAg- patients (p <= 0.001). Lymphoma patients had the highest prevalence rate of HBV infection (20.7%). Among the pooled HBsAg+ cancer patients, 14.8% (1138/7666) were aged <=39 years; by contrast, 9.7% (5122/52657) of HBsAg- cancer patients were in the same age range, giving an odds ratio of 1.6 [95%CI1.509-1.733)]. The observations were similar when each cancer was considered individually. The odds ratio was greater in pooled male patients aged <=39 years [1.9(95%CI1.705-2.085)] compared with females [1.6(95%CI1.382 1.83)]. The ratio of the observed to the expected number of HBsAg+ patients aged 15-19, 20-24, and 25-29 years were 3.3, 4.8 and 2.0, respectively, higher than 1.2-1.7 observed for older age-groups. CONCLUSION: HBV infection is a risk factor for diverse extra-hepatic cancers in adolescents and 20s. PMID- 29980025 TI - Molecular regulation of MCU: Implications in physiology and disease. AB - Ca2+ flux across the inner mitochondrial membrane (IMM) regulates cellular bioenergetics, intra-cellular cytoplasmic Ca2+ signals, and various cell death pathways. Ca2+ entry into the mitochondria occurs due to the highly negative membrane potential (DeltaPsim) through a selective inward rectifying MCU channel. In addition to being regulated by various mitochondrial matrix resident proteins such as MICUs, MCUb, MCUR1 and EMRE, the channel is transcriptionally regulated by upstream Ca2+ cascade, post transnational modification and by divalent cations. The mode of regulation either inhibits or enhances MCU channel activity and thus regulates mitochondrial metabolism and cell fate. PMID- 29980027 TI - Benzene exposure at workplace and risk of colorectal cancer in four Nordic countries. AB - OBJECTIVE: The aim of this case-control study was to assess the effect of occupational benzene exposure on the risk of colorectal cancer, including its subtypes. METHODS: The study included 181,709 colon cancer and 109,227 rectal cancer cases diagnosed between 1961 and 2005 in Finland, Iceland, Norway and Sweden. Cases were identified from the Nordic Occupational Cancer Study (NOCCA) cohort. Five controls per case were selected from the same cohort, matched for country, birth year, and sex. Occupational benzene exposure for each study participant was estimated by linking their job titles to country specific job exposure matrices. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by using conditional logistic regression models. The results were adjusted for physical strain at work, formaldehyde, ionizing radiation and wood dust. RESULTS: Increased risk was observed for all colorectal cancer (OR = 1.12, 95% CI 1.05-1.18) for the high decile of cumulative benzene exposure, indicating a statistically significant dose-response relationship. This excess risk was mainly seen in ascending colon (OR = 1.27, 95% CI 1.13-1.43), and transversal colon (OR = 1.21, 95% CI 1.01-1.41). The ORs in the highest exposure category were markedly higher in women than in men in all subsites of colon and rectum. CONCLUSION: This study showed an association between workplace benzene exposure and colorectal cancer. The risk was restricted to ascending and transversal colon, and was the strongest among women. PMID- 29980028 TI - Hormonal contraceptive use and smoking as risk factors for high-grade cervical intraepithelial neoplasia in unvaccinated women aged 30-44 years: A case-control study in New South Wales, Australia. AB - BACKGROUND: Human papillomavirus (HPV) vaccines protect against HPV types 16/18, but do not eliminate the need to detect pre-cancerous lesions. Australian women vaccinated as teenage girls are now entering their mid-thirties. Since other oncogenic HPV types have been shown to be more prevalent in women >=30 years old, understanding high grade cervical lesions in older women is still important. Hormonal contraceptives (HC) and smoking are recognised cofactors for the development of pre-malignant lesions. METHODS: 886 cases with cervical intraepithelial neoplasia (CIN) 2/3 and 3636 controls with normal cytology were recruited from the Pap Test Register of NSW, Australia. All women were aged 30-44 years. Conditional logistic regression was used to quantify the relationship of HC and smoking to CIN 2/3 adjusted for various factors. RESULTS: Current-users of HC were at higher risk for CIN 2/3 than never-users [odds ratio (OR) = 1.50, 95%CI = 1.03-2.17] and risk increased with increasing duration of use [ORs:1.13 (0.73-1.75), 1.51 (1.00-2.72), 1.82 (1.22-2.72) for <10, 10-14, >=15 years of use; p-trend = 0.04]. Ex-users had risks similar to never-users (OR 1.08, 95%CI = 0.75-1.57) regardless of duration of use. Current smoking was significantly associated with CIN 2/3 (OR = 1.43, 95%CI = 1.14-1.80) and risk increased with increasing number of cigarettes/day (p-trend = 0.02). Among ex-smokers, the risk of CIN 2/3 decreased with increasing time since quitting (p-trend = 0.04). CONCLUSIONS: In this benchmark study, current, long term users of HC and current smokers of >=5 cigarettes/day were each at increased risk of developing CIN 2/3. Findings support smoking cessation in relation to decreasing the risk of pre cancerous lesions and reinforce the continuing need for cervical screening for cancer prevention in vaccinated and unvaccinated populations. PMID- 29980029 TI - Bilateral intra-abdominal testicular tumor: Case report. AB - INTRODUCTION: Bilateral intra-abdominal testis is a very rare clinical entity. These testes may develop cancer in an adult patient with empty scrotum. CASE PRESENTATION: A case of a huge intra-abdominal solid mass in a 32-year-old gentleman is presented. Physical examination revealed an empty scrotum. Laboratory investigations, imaging studies, laparotomy and histopathological examination showed that the solid mass was a mixed germ cell tumor of the left testis. The contra-lateral testis also had a tumor. Resection of the solid mass and contra-lateral orchiectomy was performed. Adjuvant chemotherapy was given. Six months after surgery, his follow-up parameters were all within normal limits. DISCUSSION: Since bilateral intra-abdominal testis tumor is a very rare clinical entity, there are no patient management guidelines available. Management strategies differ significantly among groups and they are based mainly on the experience reflected in the context of anecdotal case reports. CONCLUSION: Surgical exploration and adjuvant chemotherapy seems as a reasonable treatment option in the setting of bilateral intra-abdominal testis tumor in an adult patient. PMID- 29980030 TI - A rare case of pelvic pain caused by Herlyn-Werner-Wunderlich Syndrome in an adult: A case report. AB - INTRODUCTION: Herlyn-Werner-Wunderlich Syndrome (HWWs) is a rare congenital anomaly. This abnormality has 5% percentage of the total Mullerian dysgenesis. The symptomatic patients come with varies condition, such as urinary incontinence, urinary retention endometriosis, pelvic infection and acute pelvic pain. Here we present investigation and management of HWWs with pelvic pain in adult woman. PRESENTATION OF CASE: A 23 years old woman came with pelvic pain. We found abnormalities of HWW syndrome i.e. uterus didelphys with obstructed hemivagina and right renal agenesis through ultrasound imaging, CT scan and MRI. After concluding the diagnosis, the patient underwent vaginal septum excision and vaginoplasty procedures to relieve obstruction which was the cause of pelvic pain. The symptom was improved after surgery and she felt no more pain after a year of follow up. DISCUSSION: The main symptom of HWWs is dysmenorrhea associated with obstruction mass or endometriosis. MRI with capability of tissue differentiation is the gold standard for diagnostic. The primary purpose of surgery is to release the obstruction and to prevent further complication. CONCLUSION: Rarely, HWWs causes an acute pelvic pain with secondary cystic mass finding. Surgery aimed to release obstruction will improve this symptom. PMID- 29980031 TI - Posterior reversible encephalopathy syndrome (PRES) in mesenteric leiomyosarcoma: A case report. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a syndrome characterized by headache, confusion, visual loss and seizures. Many factors influence the appearance of this syndrome, predominantly eclampsia, certain medical treatments and malignant hypertension. Diagnosed by typical transient lesions on magnetic resonance imaging. CASE REPORT: We present a case of mesenteric leiomyosarcoma in a 52 year old woman, who had severe headache, abdominal heaviness, and hypertension. Investigations revealed a mesenteric mass and a Posterior Reversible Encephalopathy Syndrome features on brain MRI, suggesting renin secretion by the tumor, causing the patient's symptoms. CONCLUSION: Patient's symptoms disappeared after resection of the tumor, suggesting a renin production cessation. PMID- 29980032 TI - Radiographic analysis of anatomic risk factors for scaphoid fractures; A case control study. AB - AIM: The purpose of this study was to investigate the role of anatomic variations in distal radius radiographic indices in patients with or without scaphoid fractures. MATERIALS AND METHODS: Radial inclination (RI), volar tilt (VT), radial height (RH) and ulnar variance (UV) were measured on wrist radiographs of 320 patients with (Group I, n = 167) or without (Group II, n = 153) scaphoid fracture, fall on outstretched hand (FOOSH). Receiver operating characteristics (ROC) curve analysis was used to assess the diagnostic performance for each variable. Sensitivity (Sn), specificity (Sp), cutoff value, and area under the ROC curve were analyzed. Odds ratio was calculated for defined cutoff values. RESULTS: The mean age of the groups was similar (29.3 +/- 10.2 vs 31.1 +/- 9.9 years, p = 0.060). RI (30.0 +/- 2.9 vs 26.8 +/- 2.3 degrees ) VT (11.4 +/- 2.4 vs 10.5 +/- 2.2 degrees ), RH (14.8 +/- 2.1 vs 13.2 +/- 1.9 mm), UV (-0.46 +/- 1.7 vs 0.00 +/- 1.5 mm) were higher in scaphoid fracture group (Gr I vs Gr II, p = 0.000, p = 0.000, p = 0.001, p = 0.012 respectively). Ulna minus variant was more prevalent in fracture group (p = 0.001). Optimal cutoff points for RI, VT, RH and UV in differentiating fractured and intact scaphoid were 28.6 degrees (Sn = 81.0%, Sp = 26.3%), 12.2 degrees (Sn = 80.4%, Sp = 67.1%), 14.85 mm (Sn = 80.4%, Sp = 52.1%) and 0 mm (Sn = 88.6%, Sp = 75.8%), respectively. Odds ratios for defined cutoff points for RI, VT, RH and UV were 10.4 (95% CI, 6.2-17.4), 1.8 (95% CI, 1.1-3.0), 3.7 (95% CI, 2.3-6.2) and 2.2 (95% CI, 1.3-3.7) respectively. CONCLUSION: Increased RI, VT, RH and negative UV were found to be predisposing anatomical risk factors for scaphoid fracture when FOOSH. PMID- 29980033 TI - The energetic physiology of juvenile mussels, Mytilus chilensis (Hupe): The prevalent role of salinity under current and predicted pCO2 scenarios. AB - As a result of human activities, climate forecasts predict changes in the oceans pCO2 and salinity levels with unknown impacts on marine organisms. As a consequence, an increasing number of studies have begun to address the individual influence of pCO2 and salinity but much remains to be done to understand their combined effects on the physiology and ecology of marine species. Our study addressed this knowledge gap by measuring the influence of current and predicted levels of pCO2 (380 and 1200 ppm, respectively) and salinity (20, 25 and 30 psMU) on the energetic physiology of juvenile mussels (Mytilus chilensis) from the south-eastern Pacific region. Our results indicate that a reduced salinity caused a significant reduction in clearance rate, absorption efficiency and scope for growth of this species. Meanwhile, an increase in pCO2 levels caused a reduction in excretion rates and interacted significantly with salinity in the rate of oxygen uptake measured in the mussel. These results suggest that potential changes in salinity might have a direct role on the physiology of M. chilensis. The effect of pCO2, although less prevalent among the variables measured here, did interact with salinity and is also likely to alter the physiology of this species. Given the ecological and economic importance of M. chilensis, we call for further studies exploring the influence of pCO2 across a wider range of salinities. PMID- 29980034 TI - Hot spots of antibiotic tolerant and resistant bacterial subpopulations in natural freshwater biofilm communities due to inevitable urban drainage system overflows. AB - Antibiotic resistant bacteria are a threat to human life. Recently, sewers have been identified as potential reservoirs. The intermittent injection of sewage into adjacent surface waters is inevitable, due to capacity limitations of the urban drainage system. Information regarding the effect to natural freshwater biofilms (NFB) due to the intermittent contaminations are scarce. Therefore, a fundamental screening is necessary. In April, we placed NFB-attachment constructions in a brook upstream and downstream from urban drainage overflow constructions. In meanwhile two sampling campaigns were conducted. The sewage and the brook water were collected to gather information about antibiotic background exposure of ciprofloxacin (CIP), clarithromycin (CLA) and doxycycline (DOX). Six months later we experimentally determined the oxygen uptake rate (OUR) of the NFB communities after a 24 h lasting exposure with additionally dosed antibiotics. Concentrations of 0.1, 1.0 and 10.0 mg L-1 were selected. CIP, CLA and DOX were individually dosed, and also in mixtures. The mean antibiotic background concentration in sewage was in a range of 575.5-1289.1 ng L-1, which mainly exceeded the concentrations published in literature. The determined mean concentration in the brook was in a range of 4.6-539.0 ng L-1. The first significant inhibition of the OUR with individually dosed antibiotics started mainly at a concentration of 1.0 mg L-1. Antibiotics in a mixture with concentrations of 0.1 and 1.0 mg L-1 were as effective as single dosed antibiotics with a concentration of 10.0 mg L-1. The increased antibiotic tolerance and resistance of NFB-communities downstream of the combined sewer overflow (CSO) structure was a consequence of a severe impact due to urban drainage overflows. Hence, NFB-communities downstream of CSO-constructions are hot spots of antibiotic tolerant and resistant subpopulations and access restrictions should be announced, if an infection risk is present. PMID- 29980035 TI - Toxic effects of boscalid on the growth, photosynthesis, antioxidant system and metabolism of Chlorella vulgaris. AB - Boscalid is one of the most frequently detected pesticides in main coastal estuaries in California, with concentrations as high as 36 MUg/L. However, ecotoxicology information about boscalid to aquatic organisms is scarce. To investigate toxic effects and mechanisms of boscalid on freshwater algae Chlorella vulgaris (C. vulgaris), C. vulgaris were exposed to a range of boscalid concentrations (0, 0.8, 1.6, 2.4 and 3.2 mg/L) for 96 h to study the changes in photosynthetic pigment contents, responses of the antioxidant enzyme system and alterations in endogenous substances. Results indicated that the growth of algae and the content of chlorophyll and carotenoids were significantly inhibited by 1.6 mg/L boscalid. Reactive oxygen species (ROS) and oxidative damage of C. vulgaris could be induced by boscalid, in accordance with significant changes in ROS levels and a series of antioxidant enzyme activities. Moreover, the alterations in endogenous substances showed that boscalid could affect photosynthesis and energy metabolism of C. vulgaris. These results demonstrated that boscalid could induce impacts on C. vulgaris mainly through disturbing the photosynthesis, oxidative damage and energy metabolism. The present study provided a better understanding of the negative effects and mechanisms of bosaclid in microalgae. PMID- 29980036 TI - Short-term transcriptome and microRNAs responses to exposure to different air pollutants in two population studies. AB - Diesel vehicle emissions are the major source of genotoxic compounds in ambient air from urban areas. These pollutants are linked to risks of cardiovascular diseases, lung cancer, respiratory infections and adverse neurological effects. Biological events associated with exposure to some air pollutants are widely unknown but applying omics techniques may help to identify the molecular processes that link exposure to disease risk. Most data on health risks are related to long-term exposure, so the aim of this study is to investigate the impact of short-term exposure (two hours) to air pollutants on the blood transcriptome and microRNA expression levels. We analyzed transcriptomics and microRNA expression using microarray technology on blood samples from volunteers participating in studies in London, the Oxford Street cohort, and, in Barcelona, the TAPAS cohort. Personal exposure levels measurements of particulate matter (PM10, PM2.5), ultrafine particles (UFPC), nitrogen oxides (NO2, NO and NOx), black carbon (BC) and carbon oxides (CO and CO2) were registered for each volunteer. Associations between air pollutant levels and gene/microRNA expression were evaluated using multivariate normal models (MVN). MVN-models identified compound-specific expression of blood cell genes and microRNAs associated with air pollution despite the low exposure levels, the short exposure periods and the relatively small-sized cohorts. Hsa-miR-197-3p, hsa-miR-29a-3p, hsa-miR-15a-5p, hsa-miR-16-5p and hsa-miR-92a-3p are found significantly expressed in association with exposures. These microRNAs target also relevant transcripts, indicating their potential relevance in the research of omics-biomarkers responding to air pollution. Furthermore, these microRNAs are also known to be associated with diseases previously linked to air pollution exposure including several cancers such lung cancer and Alzheimer's disease. In conclusion, we identified in this study promising compound-specific mRNA and microRNA biomarkers after two hours of exposure to low levels of air pollutants during two hours that suggest increased cancer risks. PMID- 29980037 TI - Cytotoxicity induced by iodinated haloacetamides via ROS accumulation and apoptosis in HepG-2 cells. AB - Iodinated haloacetamides (I-HAcAms) are emerging disinfection by-products and have received great concern due to their extremely high health risk. Previous studies have demonstrated the cytotoxicity of I-HAcAms, but the biological mechanism remained unclear. In this study, cytotoxicity mechanisms of 4 I-HAcAms species were preliminarily examined using HepG-2 cells. The results showed that the cytotoxicity could be ranked as follows: diiodoacetamide (DIAcAm)> iodoacetamide (IAcAm)> bromoiodoacetamide (BIAcAm)> chloroiodoacetamide (CIAcAm). Reactive oxygen species (ROS) and apoptosis played an important role in the cytotoxicity for all I-HAcAms species. Moreover, the ROS and cytotoxicity could be completely reversed by the addition of an antioxidant (N-acetylcysteine (NAC)), but the apoptosis could not. Specifically, the apoptosis induced by DIAcAm and IAcAm was partially reversed by NAC, suggesting that in addition to ROS, other pathways were also possible; While For BIAcAm and CIAcAm, the apoptosis was not reversed by NAC at all, which is potentially due to ROS independent pathways. The apoptosis mechanisms were further analyzed via Bax and Bcl-2 gene expression and the corresponding protein expression in HepG-2 cells, that mitochondrial pathway was important in the apoptosis of HepG-2 cells induced by all I-HAcAms species. Overall, the mitochondrial pathway provided a potential explanation for BIAcAm and CIAcAm-induced apoptosis, while both ROS and mitochondrial pathways explained DIAcAm and IAcAm-induced apoptosis. PMID- 29980038 TI - Introducing relative potency quotient approach associated with probabilistic cumulative risk assessment to derive soil standards for pesticide mixtures. AB - Children can be exposed to organophosphate and carbamate mixtures, which pose additive health effects via soil exposure. However, only 23 countries have soil standard values for organophosphate and carbamate pesticides, and most regulatory jurisdictions do not consider the cumulative exposure. This study derived proposed soil standards for organophosphates and carbamates by introducing the relative potency quotient approach (RPQ). The probabilistic cumulative risk assessment was also applied to evaluate current soil standards of pesticide mixtures. The U.S. Environmental Protection Agency (EPA) have soil standards of 19 organophosphates and five carbamates. However, these standards cannot protect population health via chronic exposure in conservative and semi-conservative scenarios based on the probabilistic risk assessment because the U.S.EPA simplified the regulatory process for the cumulative exposure to pesticide mixtures and omitted the soil allocation factor, which should be set for aggregate exposure. The analysis of proposed soil standards developed by the RPQ approach indicates that some human behavior variables, such as soil intake rate and exposure duration, have stronger impacts on the proposed soil standards than human biometric variables like body weight. This study may be helpful to develop regulatory standards and a framework for pesticide mixtures having additive health effects. PMID- 29980039 TI - Distribution and diagenetic fate of synthetic surfactants and their metabolites in sewage-impacted estuarine sediments. AB - : Surfactants are high production volume chemicals used in numerous domestic and industrial applications and, after use, the most abundant organic contaminants in wastewater. Their discharge might jeopardize the receiving aquatic ecosystems, including sediments, where they tend to accumulate. This is the first comprehensive study on their distribution and fate in this environmental compartment as we performed simultaneous analysis of the three main classes of surfactants (anionic: LAS; nonionic: NPEO and AEO; cationic: DTDMAC, DADMAC, BAC, and ATMAC) and some of their transformation products (SPC, NP, NPEC, and PEG). To account for spatial and time trends, surface sediments and dated cores were collected from Jamaica Bay, a heavily sewage-impacted estuary in New York City. The concentrations of surfactants in surface sediments were between 18 and > 200 MUg g-1 and showed slight variation (<10%) over different sampling years (1998, 2003 and 2008). Cationic surfactants were found at the highest concentrations, with DTDMAC accounting for between 52 and 90% of the total sum of target compounds. Vertical concentration profiles in dated cores from the most contaminated station, in the vicinity of the biggest local sewage treatment plant (STP), indicated two sub-surface surfactant peaks in the mid-1960s (469 MUg g-1) and late 1980s (572 MUg g-1) coinciding with known STP upgrades. This trend was observed for most target compounds, except for DADMAC, C22ATMAC, and PEG, which showed a continuous increase towards the top of the cores. In-situ degradation was studied by comparing sediment core samples taken 12 years apart (1996 and 2008) and revealed a net decrease in PEG and specific surfactants (BAC, ATMAC, NPEO, and AEO) accompanied by growing concentrations of metabolites (SPC, NP, and NPEC). DTDMAC, DADMAC, and LAS, however, remained stable over this period, suggesting recalcitrant behavior under the anaerobic conditions in Jamaica Bay sediments. MAIN FINDING: Chronology of major synthetic surfactants are illustrated in the dated sediment cores, as well as their different diagenetic fates. PMID- 29980040 TI - Occurrence of tetrabromobisphenol a (TBBPA) and hexabromocyclododecane (HBCD) in soil and road dust in Chongqing, western China, with emphasis on diastereoisomer profiles, particle size distribution, and human exposure. AB - Currently, the HBCDs were listed in Annex A by the Stockholm Convention, and the knowledge on the contamination of TBBPA and HBCDs in soil and road dust in China is still limited, and it is unclear what role is played by dust particle size distribution. In this study, a total of 81 soil and 43 road dust samples were analyzed with TBBPA and SigmaHBCDs concentrations ranging from < LOQ to 33.8 ng/g dw (dry weight) and 0.43-15.2 ng/g dw in soil, and from < LOQ to 74.1 ng/g dw and 7.25-14.0 ng/g dw in road dust, respectively. TBBPA and HBCDs exhibited different spatial distribution patterns in soil, where relatively high levels of HBCDs were found in industrial area and commercial area, while high levels of TBBPA were detceted in residential area. However, no distinct variation in spatial distribution of these two compounds was observed in road dust. Different diastereoisomer profiles of HBCDs were also found with gamma-HBCD predominating in soil and alpha-HBCD occupying a large proportion in road dust. The alpha /gamma-HBCD values in road dust were significantly greater (T-test, P < 0.05) than those in soil, which suggested that gamma-HBCD in road dust were likely to transform into alpha-HBCD compared with soil. The distribution of dust particle size showed that HBCDs levels were increasing with the decreasing in particle sizes, while the TBBPA showed some "accidental" peak values in specific diameter ranges. The estimated daily intakes (EDIs) of TBBPA and HBCDs were assessed through dust ingestion, dermal absorption and inhalation via road dust, and all the exposure estimates were well below the reference dose (RfD), but the toddlers were more vulnerable to TBBPA and HBCDs intakes, which should be paid more attention. PMID- 29980041 TI - Functional activity and functional gene diversity of a Cu-contaminated soil remediated by aided phytostabilization using compost, dolomitic limestone and a mixed tree stand. AB - Trace elements (TEs) availability, biochemical activity and functional gene diversity was studied in a Cu-contaminated soil, revegetated for six years with a mixed stand of willow, black poplar, and false indigo-bush, and amended or not with compost plus dolomitic limestone (OMDL). The OMDL amendment significantly reduced Cu and As availability and soil toxicity, and increased the biochemical activity and microbial functional diversity assessed with the GEOCHIP technique, as compared to the unamended soil (Unt). The OMDL soil showed significantly higher abundance of 25 functional genes involved in decomposition organic compounds, and 11, 3 and 11 functional genes involved in the N, P and S biogeochemical cycles. Functional gene abundance was positively correlated with nutrient contents but negatively correlated with Cu availability and soil toxicity. The abundance of microbial functional genes encoding for resistance to various TEs also increased, possibly due to the microbial proliferation and lower Cu exposure in the presence of high total soil Cu concentration. Genes encoding for antibiotic resistance due to the co-occurrence of TEs and antibiotic resistant genes on genetic mobile elements. Overall, phytomanagement confirmed its potential to restore the biological fertility and diversity of a severely Cu contaminated soil, but the increase of TEs and antibiotic resistant gene abundances deserve attention in future studies. PMID- 29980042 TI - Cardiovascular function and ozone exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES). AB - BACKGROUND: To date, there have been relatively few studies of acute cardiovascular responses to controlled ozone inhalation, although a number of observational studies have reported significant positive associations between both ambient ozone levels and acute cardiovascular events and long-term ozone exposure and cardiovascular mortality. OBJECTIVES: We hypothesized that short term controlled exposure to low levels of ozone in filtered air would induce autonomic imbalance, repolarization abnormalities, arrhythmia, and vascular dysfunction. METHODS: This randomized crossover study of 87 healthy volunteers 55 70 years of age was conducted at three sites using a common protocol, from June 2012 to April 2015. Subjects were exposed for 3 h in random order to 0 ppb (filtered air), 70 ppb ozone, and 120 ppb ozone, alternating 15 min of moderate exercise with 15 min of rest. A suite of cardiovascular endpoints was measured the day before, the day of, and up to 22 h after each exposure. Mixed effect linear and logit models evaluated the impact of exposure to ozone on pre specified primary and secondary outcomes. Site and time were included in the models. RESULTS: We found no significant effects of ozone exposure on any of the primary or secondary measures of autonomic function, repolarization, ST segment change, arrhythmia, or vascular function (systolic blood pressure and flow mediated dilation). CONCLUSIONS: In this multicenter study of older healthy women and men, there was no convincing evidence for acute effects of 3-h, relatively low-level ozone exposures on cardiovascular function. However, we cannot exclude the possibility of effects with higher ozone concentrations, more prolonged exposure, or in subjects with underlying cardiovascular disease. Further, we cannot exclude the possibility that exposure to ambient ozone and other pollutants in the days before the experimental exposures obscured or blunted cardiovascular biomarker response to the controlled ozone exposures. PMID- 29980043 TI - Environmental phenols and parabens in adipose tissue from hospitalized adults in Southern Spain. AB - Urinary concentrations of non-persistent environmental pollutants (npEPs) are widely assessed in biomonitoring studies under the assumption that they are metabolised and eliminated in urine. However, some of these chemicals are moderately lipophilic, and their presence in other biological matrices should also be evaluated to estimate mid/long-term exposure to npEPs and its impact on human health. The present study aims to explore concentrations and potential determinants of npEPs in adipose tissue from a hospital-based adult cohort (GraMo cohort, Southern Spain). Concentrations of bisphenol-A (BPA), benzophenone-3 (BP 3), triclosan (TCS), three chlorophenols (2,4-DCP, 2,5-DCP and 2,4,5-TCP) and two phenylphenols (2-PP and 4-PP), triclocarban (TCCB) and parabens [methyl- (MeP), ethyl- (EtP), propyl- (n-PrP and i-PrP), butyl- (n-BuP and i-BuP) and benzyl paraben (BzP)] were analysed in adipose tissue samples from a subcohort of 144 participants. Spearman correlation tests were performed, followed by stepwise multivariable linear regression analyses to assess determinants of the exposure. Detection frequencies and median concentrations were: BPA (86.8%, 0.54 ng/g tissue), BP-3 (79.2%, 0.60 ng/g tissue), TCS (45.8%, =23 with an odds ratio (OR) of 0.923 per point increase of MDS (95% confidence interval 0.869-0.979; p = 0.0079). This association remained significant after adjustment for cardiovascular risk factors (OR 0.934, 95% CI 0.877-0.995, p = 0.035). After further adjustment for log (hs-CRP), the association remained no longer significant (OR 0.955 (0.893-1.022, p = 0.19). CONCLUSIONS: In this contemporary data set, we found an independent association of adherence to MD with a less complex CAD. Hs-CRP correlated significantly with adherence to MD and may be a marker of the vasoprotective effects of MD. These results strengthen the evidence for the protective effect of an MD pattern in CVD prevention. PMID- 29980053 TI - Extreme-risk category: High prevalence among stable coronary patients and an emerging widening treatment gap in achieving LDL-cholesterol less than 55 mg/dL. AB - BACKGROUND AND AIMS: The latest guidelines from the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) proposed a new "extreme-risk" category of patients, for whom a low-density lipoprotein cholesterol (LDL-C) level <55 mg/dL (1.4 mmol/L) is advised. We aimed to identify the proportion of patients with stable coronary artery disease (CAD), who are at extreme cardiovascular (CV) risk, and explore how achievable is the new LDL-C goal. METHODS: We enrolled 1629 consecutive patients <=80 years with stable CAD. Fasting lipids were determined and patients having probable or definite heterozygous familial hypercholesterolaemia (HeFH) were identified using the Dutch Lipid Clinic Network algorithm. RESULTS: The prevalence of risk factors/characteristics suggesting an extreme CV risk were as follows: 32% diabetes mellitus, 33% premature CAD and 9.2% HeFH. In total, 895 (55%) patients had at least one of those risk factors/characteristics and formed the extreme CV risk category. Among patients at extreme risk, 87% were on lipid-lowering therapy, of whom 20.3% had LDL-C <70 mg/dL (1.8 mmol/L) and only 5.3% had LDL-C <55 mg/dL. CONCLUSIONS: More than half of all patients with stable CAD are at extreme CV risk and very few (~5%) achieve LDL-C levels <55 mg/dL. Using maximally-tolerated high-intensity statin combined with ezetimibe, if necessary, is imperative to bridge the treatment gap, while in selected cases the addition of PCSK9 inhibitors will be required. PMID- 29980055 TI - Endocytosis of lipoproteins. AB - During their metabolism, all lipoproteins undergo endocytosis, either to be degraded intracellularly, for example in hepatocytes or macrophages, or to be re secreted, for example in the course of transcytosis by endothelial cells. Moreover, there are several examples of internalized lipoproteins sequestered intracellularly, possibly to exert intracellular functions, for example the cytolysis of trypanosoma. Endocytosis and the subsequent intracellular itinerary of lipoproteins hence are key areas for understanding the regulation of plasma lipid levels as well as the biological functions of lipoproteins. Indeed, the identification of the low-density lipoprotein (LDL)-receptor and the unraveling of its transcriptional regulation led to the elucidation of familial hypercholesterolemia as well as to the development of statins, the most successful therapeutics for lowering of cholesterol levels and risk of atherosclerotic cardiovascular diseases. Novel limiting factors of intracellular trafficking of LDL and the LDL receptor continue to be discovered and to provide drug targets such as PCSK9. Surprisingly, the receptors mediating endocytosis of high-density lipoproteins or lipoprotein(a) are still a matter of controversy or even new discovery. Finally, the receptors and mechanisms, which mediate the uptake of lipoproteins into non-degrading intracellular itineraries for re secretion (transcytosis, retroendocytosis), storage, or execution of intracellular functions, are largely unknown. PMID- 29980054 TI - Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an "FCS score". AB - Familial chylomicronaemia syndrome (FCS) is a rare, inherited disorder characterised by impaired clearance of triglyceride (TG)-rich lipoproteins from plasma, leading to severe hypertriglyceridaemia (HTG) and a markedly increased risk of acute pancreatitis. It is due to the lack of lipoprotein lipase (LPL) function, resulting from recessive loss of function mutations in the genes coding LPL or its modulators. A large overlap in the phenotype between FCS and multifactorial chylomicronaemia syndrome (MCS) contributes to the inconsistency in how patients are diagnosed and managed worldwide, whereas the incidence of acute hypertriglyceridaemic pancreatitis is more frequent in FCS. A panel of European experts provided guidance on the diagnostic strategy surrounding FCS and proposed an algorithm-based diagnosis tool for identification of these patients, which can be readily translated into practice. Features included in this FCS score comprise: severe elevation of plasma TGs (fasting TG levels >10 mmol/L [885 mg/dL] on multiple occasions), refractory to standard TG-lowering therapies, a young age at onset, the lack of secondary factors (except for pregnancy and oral oestrogens) and a history of episodes of acute pancreatitis. Considering 53 FCS patients from three cohorts and 52 MCS patients from three cohorts, the overall sensitivity of the FCS score (>=10) was 88% (95% confidence interval [CI]: 0.76, 0.97) with an overall specificity of 85% (95% CI: 0.75, 0.94). Receiver operating characteristic curve area was 0.91. Pragmatic clinical scoring, by standardising diagnosis, may help differentiate FCS from MCS, may alleviate the need for systematic genotyping in patients with severe HTG and may help identify high priority candidates for genotyping. PMID- 29980056 TI - Cirrhosis and risk of stroke: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Several studies have reported that cirrhosis may increase the risk of stroke. However, its association is controversial. We conducted a systematic review and meta-analysis to investigate the relationship between cirrhosis and the risk of stroke. METHODS: Relevant studies published before December 2017 were identified by searching PubMed, EMBASE, and the ISI Web of Science. The relationships between cirrhosis and the risk of stroke were assessed using relative risk (RR) values and the corresponding 95% confidence intervals (CIs). We used the random-effects model proposed by DerSimonian and Laird to quantify the relationship. RESULTS: Nine studies investigating the effect of cirrhosis on the risk of stroke were included, totaling 3,855,226 participants (26,199 ischemic stroke, 61,281 hemorrhagic stroke, 100,442 total stroke). Among those, four studies reported data for total stroke, six studies reported on hemorrhagic stroke, and four studies reported on ischemic stroke. The present study indicated a 24% increase in the risk of total stroke among patients with cirrhosis compared with healthy controls (RR: 1.24; 95% CI: 1.01-1.48). Subgroup analyses showed that cirrhosis was associated with increased risk of hemorrhagic stroke (RR: 1.35; 95% CI: 1.06-1.64) but not ischemic stroke (RR: 0.90; 95% CI: 0.41-1.38). Sensitivity analysis and 'trim and fill' method yielded similar results. No evidence of publication bias was observed. CONCLUSIONS: Cirrhosis was associated with a higher risk of developing stroke, specifically hemorrhage stroke. PMID- 29980057 TI - Apolipoprotein M in patients with chronic kidney disease. AB - BACKGROUND AND AIMS: Plasma apolipoprotein M (APOM) is bound to HDL-particles and has anti-atherogenic effects. The present study explored whether plasma APOM is reduced in patients with chronic kidney disease (CKD), and associated with cardiovascular disease (CVD). In addition, we tested the hypothesis that the excretion of APOM into the urine is increased in patients with kidney disease. METHODS: Plasma samples were collected from a cohort of patients with CKD stages 1 to 5D (N = 409) and controls (N = 35). Urine was collected from 47 subjects. Plasma APOM was measured with sandwich ELISA and urine APOM with competitive ELISA. RESULTS: Plasma APOM levels were reduced in patients with CKD stages 3-5D as compared to patients with CKD stages 1 + 2 and controls (p < 0.01). CKD patients with known CVD displayed even further reduction in plasma APOM levels than CKD patients without known CVD (p < 0.001). Fast-phase liquid chromatography showed that plasma APOM was primarily associated with HDL-cholesterol (HDL-C) across CKD stages. Accordingly, when plasma APOM values were corrected for HDL-C, a significant difference only persisted between patients with CKD stage 3 and stages 1 + 2 (p < 0.05), and the difference between CKD patients with and without known CVD disappeared. Urine APOM/creatinine ratio was not significantly increased in patients with kidney disease. CONCLUSIONS: The results show that the difference in plasma APOM levels observed between patients with mild and advanced CKD may mainly be due to differences in plasma HDL-C. Whether APOM plays a role in human uremic atherogenesis warrants further experimental studies. PMID- 29980059 TI - Selectivity for La3+ ion by synthesized 4-((5-methylfuran-2 yl)methylene)hydrazono)methyl)phenol receptor and its spectral analysis. AB - The functionalized molecules with specific molecular sites appear to be a promising approach for detection of cation in UV-visible and fluorescence spectroscopy. The synthesized receptor 4-((5-methylfuran-2 yl)methylene)hydrazono)methyl)phenol MFMHMP was found selective for La3+ among Ag+, K+, Na+, Be2+, Mg2+, Ca2+, Eu3+, Al3+, La3+, Zr4+, Th4+, UO22+, Fe3+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+ and Hg2+ metal ions used as their nitrates by UV visible spectroscopy and fluorescence spectroscopy. The binding nature of MFMHMP with La3+ ion was analyzed by UV-visible, fluorescence, IR, mass spectroscopy and cyclic voltammetric studies. The stoichiometry was established to be 1:1 by Benesi-Hildebrand, mole-ratio method and method of continuous variation (Job's method) with good association affinity K = 6.245 * 104 M-1. Computational studies and Density functional theory (DFT) calculation gives the proof of electron transfer during excitation and emission. Binding energy of complex through Density Function Theory -62.387 kcal/mol has also indication of strong binding. The electron transfer energy of Higher occupied molecular orbital (HOMO) to Lower unoccupied molecular orbital (LUMO) is about 4.662 eV for MFMHMP+La3+ Complex. Among that all transitions HOMO -> LUMO + 8 and HOMO -> LUMO + 9 play a key role for the blue shift transition during complexation. PMID- 29980058 TI - Association of serum ADAMTS7 levels and genetic variant rs1994016 with acute coronary syndrome in a Chinese population: A case control study. AB - BACKGROUND AND AIMS: Acute coronary syndrome (ACS) is commonly caused by rupture or erosion of coronary atherosclerotic plaques and secondary thrombus formation. Metalloproteinase ADAMTS7 was found to play an important role in atherogenesis. This study aimed to explore the association of serum ADAMTS7 levels and rs1994016 polymorphism at ADAMTS7 locus with ACS in a Chinese population. METHODS: 1881 patients who underwent coronary angiography were consecutively recruited. Among them, 426 patients were matched for case-controlled analysis. Serum ADAMTS7 levels were determined through enzyme-linked immunosorbent assay (ELISA) and rs1994016 polymorphism was detected by polymerase chain reaction (PCR). RESULTS: Serum ADAMTS7 levels in patients with unstable angina pectoris were much higher than in non-atherosclerotic patients, however, no difference was found among non atherosclerotic patients, the coronary atherosclerosis subgroup and stable angina pectoris subgroup. A higher serum ADAMTS7 level was found in the ACS group than in the non-ACS group (0.61 +/- 0.04 vs. 0.47 +/- 0.02 ng/mL, p = 0.002) and serum ADAMTS7 level was found to be an independent risk factor for ACS after adjusting for major confounding factors (OR:2.81, 95% CI:1.33-5.93, p = 0.007). ADAMTS7 rs1994016 CT/TT polymorphism was negatively associated with the risk of ACS (OR:0.40, 95% CI:0.22-0.71, p = 0.002). Meanwhile, crossover analysis revealed that in CT/TT homozygotes, ACS risk was reduced nearly 80% in patients with serum ADAMTS7 levels <0.594 ng/mL (Interaction p = 0.002). CONCLUSIONS: Serum level of ADAMTS7 was positively associated and rs1994016 CT/TT genotype was negatively associated with the risk of ACS. Patients with lower serum ADAMTS7 level and rs1994016 CT/TT genotype are less likely to suffer from ACS in a Chinese population. PMID- 29980060 TI - Coumarin/fluorescein-fused fluorescent dyes for rapidly monitoring mitochondrial pH changes in living cells. AB - On base of the good optical properties of coumarin and fluorescein, we designed and synthesized two coumarin/fluorescein-fused fluorescent dyes (CF dyes), which enlarged the emission wavelength and increased the Stokes shift of fluorescein moiety. The corresponding optical properties of CF dyes were investigated in detail. CF dyes could easily introduce other groups to design different functional molecules. CF dyes also exhibited rapid and sensitive responses to pH values in the range of 4.0-7.4 through the characterization of absorption and fluorescence spectra in buffer solution. More importantly, CF ethyl ester dye (CFE dye) not only showed good cell membrane permeability and low cytotoxicity, but also had the ability to rapidly monitor mitochondrial pH changes in living cells. PMID- 29980061 TI - Five modified classical least squares based models for stability indicating analysis of cyclobenzaprine HCl with its major degradation products: A comparative study. AB - Five modified multivariate calibration models based on classical least squares (CLS) in addition to traditional CLS model are developed and validated for assaying cyclobenzaprine HCl (CZ) with its major degradants; dibenzocycloheptatrienone (DZ) and anthraquinone (AQ), whether in its pure form or in pharmaceutical dosage form. The five models are net analyte processing CLS (NAP-CLS), orthogonal signal correction CLS (OSC-CLS), direct orthogonal signal correction CLS (DOSC-CLS) and hybrid linear analysis following the strategy of Xu and Schechter (HLA-XS) or Goicoechea et al. (HLA-GO). The five modified CLS models in addition to traditional CLS were subjected to a comparative study through manipulation of ultra-violet absorption data in the region of 220-350 nm. Three factor four level experimental design was adopted which results in 16 mixtures calibration set covering various concentrations of CZ, DZ and AQ. An extra validation set, composed of nine mixtures, was prepared for validation of the prediction power of the presented models. Experimental results showed high capability of the proposed modified CLS models for assaying CZ successfully without any interference from the co-existing degradation products (DZ and AQ). A statistical comparison between the results of CZ analysis in its dosage form by the six CLS based models and the reported HPLC method was carried out presenting no significant difference in regards to precision and accuracy. Significance of CLS based models is a consequent of their high quantitative and qualitative power for assaying multi-components mixtures. PMID- 29980062 TI - Photodegradation of phenanthrene catalyzed by rGO sheets and disk like structures synthesized using sugar cane juice as a reducing agent. AB - In the present report, rGO sheets (rG1) and disk (rG2) like structures of reduced graphene oxide (rGO) were synthesized using sugar cane juice as green reducing agent. The samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis.) spectroscopy and photoluminescence (PL) spectroscopy techniques. The transition of electrons localized in different sized sub-domain of the sp2 bonded carbons having different values of highest occupied molecular orbital (HOMO) -lowest unoccupied molecular orbital (LUMO) gap may likely to be responsible for the observed PL emission in rG1 and rG2 at different excitation wavelengths. The rG1 and rG2 were also used as photocatalyst materials for the degradation of phenanthrene (PHE) under the UV irradiation. The rG2 shows better photocatalytic degradation compared to rG1 by degrading the PHE up to 30%. PMID- 29980063 TI - Reverse dichromatism in gem andalusite related to total pleochroism of the Fe2+ Ti4+ IVCT. AB - We document a dichromatism effect in gem andalusite that shifts from light brownish pink at low thickness to medium green at high thickness. This is roughly reverse to that usually observed in other dichromatic materials. We show that this is due to a very strong pleochroism in andalusite, when dichromatism in other materials is due to an alexandrite effect. Here, colors varies from a strongly absorbing orangey-brown in the c direction to much less absorbing medium green in a and b directions. The brown absorption is so strong that it becomes opaque (total absorption) for thickness above about 1.5 mm (this value may vary according to concentration of the chromophore and intensity of the light source), and hence does not contribute to coloration anymore. For such high thicknesses, only the a and b directions remain transparent and hence only the green component contributes to the color: the sample appears green. For lower thicknesses, the green color combines with the orangey-brown color that becomes transparent along the c direction, resulting in a light brownish pink. From trace elements analysis in zoned samples, we also confirm that the dark orangey-brown color is due to Fe2+-Ti4+, and bring evidences that the light green color is mostly due to Fe, either in the form of isolated Fe3+ or Fe2+-Fe3+ IVCT, with possibly some contributions from isolated Mn3+. PMID- 29980064 TI - Daphnetin: A novel blue-green photonic switch for disodium phosphates that allows monitoring of polymerase chain reactions. AB - This paper describes the very simple and robust ratiometric photonic switching properties of daphnetin (DP) toward HPO42- ions selectively in complex biological fluids, without any interference from other relevant anions under physiological conditions. The sensing ability of DP toward HPO42- ions was first demonstrated using UV-Vis and fluorescence spectroscopy, dynamic light scattering (DLS), and one- and two-dimensional NMR spectroscopy. DP can detect HPO42- ions at concentrations up to the sub-micromolar/nanomolar level very effectively, with a ratiometric response resulting from intramolecular charge transfer aided by aggregated-induced emission. The interactions between DP and HPO42- ions resulted in new bands appearing in the UV-Vis (at 385 nm) and emission (at 535 nm) spectra. The noncovalently held HPO42- ions induced pronounced specific aggregation of DP molecules, resulting in the new excimer band at 535 nm while retaining the monomer band centered at 445 nm. In contrast, reciprocal absorptivity changes were observed at 320 and 385 nm, with exponential decrements and increments, respectively. This probe could effectively monitor the consumption of dNTPs during various cycles of the polymerase chain reaction performed with relatively short oligonucleotides as well as genomic DNA from Agrobacterium tumefaciens (AcH5alpha strain). PMID- 29980065 TI - Photophysical and enhanced nonlinear optical response in asymmetric benzothiazole substituted phthalocyanine covalently linked to semiconductor quantum dots. AB - The synthesis of asymmetric benzothiazole substituted phthalocyanines (complexes 3 to 5) and their covalent attachment to glutathione (GSH) functionalized quantum dots (QDs) are reported in this work. Additionally, their photophysical and nonlinear optical properties were investigated. A decrease in the fluorescence quantum yield with corresponding increase in the triplet quantum yield was observed when the complexes were covalently linked to glutathione (GSH) functionalized cadmium telluride (CdTe) quantum dots. Reverse saturable absorption was found to be predominantly dominated by excited state absorption. The observed limiting threshold values range from 0.29-0.75 J/cm2. PMID- 29980066 TI - Evolutionary and functional analysis of Cyclina sinensis c-Jun AP-1 gene in response to LPS stimulation. AB - The transcription factor activator protein-1 (AP-1) plays an essential and critical role in the regulation of numerous downstream genes involved in various physiological and chemical responses. In this study, we identified a full-length cDNA of the c-Jun AP-1 gene (termed Csc-Jun) from the transcriptome library in Cyclina sinensis. The cDNA contains an 825-bp open reading frame that encodes a 274-amino acid protein sequence, including a characteristic Jun transcription factor domain and a highly conserved basic leucine zipper (bZIP) signature that shares 90% identity to that of Ruditapes philippinarum. Furthermore, a phylogenetic analysis using MrBayes and PhyML software (with Bayesian and maximum likelihood approaches, respectively) revealed that the c-Jun AP-1 family genes might be involved in adapting to various environments in different invertebrates. We implemented the PAML software with the maximum likelihood method to further select and verify the positive selection sites (PSSs) in the Mollusca c-Jun AP-1 genes, and we detected four PSSs located in the Jun transcription factor domain. In addition, a spatial expression analysis showed that the Csc-Jun cDNA transcript was ubiquitously expressed in all of the tested tissues and was strongly expressed in the hepatopancreas and weakly expressed in the tissues of the hemocytes, gill filaments, mantle and adductor muscle. Quantitative real-time PCR showed that the expression profiles of Csc-Jun were significantly upregulated at different times in all of the tested tissues when challenged with lipopolysaccharide (LPS). Furthermore, knockdown of Csc-Jun by RNA interference resulted in a higher mortality of C. sinensis following LPS exposure. Finally, we explored the function of the TLR13-MyD88 signaling pathway in the innate immunity of C. sinensis by RNA interference and immune challenges. The results revealed that the mRNA expression levels of Csc-Jun were all decreased (P < 0.01) in normal and stimulated C. sinensis hemocytes. These data collectively indicated that the c-Jun AP-1 gene might play vital roles in innate immunity and provide new evidence for the evolutionary patterns of innate immune genes in Mollusca. PMID- 29980067 TI - Enhancement in biological treatment of pulping wastewater by fly ash. AB - Sequential batch reactor (SBR) is a simple and flexible activated sludge process for industrial wastewater treatment. Also, biomass-based fly ash is a fairly plentiful and low-cost waste available in the pulp and paper industry. For treating wastewater of the pulping industry through a more efficient and economic approach, the integration of fly ash in the SBR process was investigated in this work. In this study, fly ash dosages of 0.2 wt% and 0.6 wt% were maintained in SBR1 and SBR2 systems, respectively, for treating the wastewater of the pulping industry. The findings indicated that adding fly ash to the bioreactors improved the settling and flocculation affinity of activated sludge without having any significant effect on the performance and the stability of the biological process. Lignin and color removals were 90.9% and 95% in SBR1 and 92.9% and 97.5% in SBR2, while the removals in the control reactor were 85.3% and 91.5%, respectively. The alkaline ions, such as Ca2+ and Mg2+, leached out from fly ash, which improved the sludge's properties, and this leaching reduced 22.1% and 40.5% of alkali consumptions in SBR1 and SBR2, respectively. The structure of sludge flocs in the reactors with and without fly ash was also studied. This technology is environmental friendly, cost-effective and suitable for a full-scale implementation in existing aerobic biological processes. PMID- 29980068 TI - Universal and reusable hapten/antibody-mediated portable optofluidic immunosensing platform for rapid on-site detection of pathogens. AB - A universal and reusable hapten-antibody-mediated portable optofluidic immunosensing platform (OIP) was developed for rapid on-site detection of pathogens. By using Escherichia coli O157:H7 (E. coli O157:H7) and bisphenol A Bovine serum albumin (BPA-BSA)/anti-BPA antibody as a model pathogen and a mediated hapten-antibody, respectively, a novel immunoassay mechanism was proposed to detect pathogens. The BPA-BSA-modified immunosensor and E. coli O157:H7 were initially saturated with anti-BPA antibodies (mouse IgG) and anti-E. coli O157:H7 antibodies (mouse IgG), respectively. Then, the fluorescence-labeled secondary antibodies (goat anti-mouse IgG antibody) were incubated with E. coli O157:H7 with their antibodies. Next, the mixture was introduced into the immunosensor surface bound to the anti-BPA antibodies. A high concentration of E. coli O157:H7 in the sample reduced the number of fluorescence-labeled secondary antibodies bound to the immunosensor surface, thus resulting in the detection of low fluorescence signals. Under optimized conditions, the hapten-antibody mediated OIP system exhibited a detection limit of 8 cfu/mL E. coli O157:H7 after concentrating 100 times by using centrifugation, and a test cycle, including prereaction, detection, and regeneration, was less than 1 h. The robustness of the hapten-carrier protein-modified immunosensor surface allowed multiple pathogen immunoassays. The proposed strategy demonstrated good recovery, precision, and accuracy through the evaluation of the spiked water samples. We expect that the new platform can be readily used for the detection of other pathogens in a variety of application fields ranging from environmental monitoring and food safety to medical diagnosis. PMID- 29980070 TI - Resilience over time: Learning from school-attending adolescents living in conditions of structural inequality. AB - INTRODUCTION: Cross-sectional studies offer inadequate understandings of adolescent resilience. Nevertheless, few longitudinal studies account for the resilience of school-attending adolescents challenged by the structural disadvantages associated with South African township residence. This prompts two questions: (i) Do the same (or different) resilience-enabling resources inform township-dwelling, school-attending adolescents' resilience accounts when they self-explain their resilience at two distinct points in time? (ii) Which resilience-enabling resources, if any, become significantly more (or less) salient over time and how do township-dwelling, school-attending adolescents explain the resilience-enabling value of these resources? METHODS: To answer the aforementioned, we conducted a longitudinal qualitative study with 140, township dwelling, school-attending, South African adolescents (62.1% girls; mean age: 13.8 years [Time 1]; 15.8 years [Time 2]). They completed a draw-and-write activity. This generated visual and narrative data that we analysed using multiple methods (content analyses, chi square tests of frequency counts, and thematic analysis). RESULTS: A comparison of school-attending adolescents' accounts of their resilience at two points in time revealed the longevity of nine, generic resilience-enabling resources. A comparison of how frequently adolescents reported these resources at Time 1 and 2 showed significant increases for education, faith-based supports, and peer support. A comparison of adolescents' reasons for identifying these three resources showed that education promises an improved future, while all three facilitate respite from hardship and/or mastery over current challenges. CONCLUSION: The salience of education, faith-based supports, and peer support can be explained using developmental, contextual and cultural perspectives. This explanation prompts pragmatic and cautionary lessons for resilience advocates. PMID- 29980069 TI - Enhanced removal of Microcystis bloom and microcystin-LR using microcosm constructed wetlands with bioaugmentation of degrading bacteria. AB - The prevalence of cyanobacterial bloom (Cyano-bloom) and hepatotoxic microcystin (MC) pollution caused by eutrophication poses serious problems to aquatic ecosystems and public health. However, conventional water treatment technologies are inefficient for removing cyanotoxins. In this study, the performance of microcosm constructed wetlands (CWs) in the removal of Cyano-bloom, microcystin LR (MC-LR), and nutrients was investigated following repeated loading of pollutants. The effects of plant and bioaugmentation of selected MC-LR degrading bacteria on removal efficiency, degrading gene mlrA abundance, and bacterial community structure were examined. More than 90% of the MC-LR and chlorophyll-a was eliminated by CWs after 3 d of hydraulic retention time (HRT) without a lag phase. No significant differences between planted and unplanted CWs were found in the MC-LR and Cyano-bloom removal and mlrA gene abundance. Nevertheless, the plants improved nutrient removal to reduce eutrophication. Bioaugmentation markedly enhanced the degradation of MC-LR from 16.7 MUg L-1 to below the threshold value within 12 h, which could help shorten the HRT of CWs by increasing functional MC-LR degrading bacteria. In the soil of CWs, the following six bacterial genera with MC-LR-degrading potential were found: Sphingopyxis, Methylotenera, Pseudomonas, Methylosinus, Novosphingobium, and Sphingomonas. Among them, the first three also significantly proliferated in CWs with bioaugmentation during MC-LR degradation, indicating their high adaptability and MC-LR removal contribution. These results suggested that CWs could provide suitable conditions for MC-LR degrading microorganism proliferation, and CWs with bioaugmentation could be effective and practical measures for the remediation of eutrophication and MC pollution. PMID- 29980071 TI - Time-generalized multivariate analysis of EEG responses reveals a cascading architecture of semantic mismatch processing. AB - Event-related brain potentials have a strong impact on neurocognitive models, as they inform about the temporal sequence of cognitive processes. Nevertheless, their value for deciding among alternative cognitive architectures is partly limited by component overlap and the possibility of ambiguity regarding component identity. Here, we apply temporally-generalized multivariate pattern analysis - a recently-proposed machine learning method capable of tracking the evolution of neurocognitive processes over time - to constrain possible alternative architectures underlying the processing of semantic incongruency in sentences. In a spoken sentence paradigm, we replicate established N400/P600 correlates of semantic mismatch. Time-generalized decoding indicates that early vs. late mismatch-sensitive processes are (i) distinct in their neural substrate, arguing against recurrent or latency-shifted single process architectures, and (ii) partially overlapping in time, inconsistent with predictions of strictly serial models. These results are in accordance with an incremental-cascading neurocognitive organization of semantic mismatch processing. We propose time generalized multivariate decoding as a valuable tool for neurocognitive language studies. PMID- 29980072 TI - Prosodic and phonetic subtypes of primary progressive apraxia of speech. AB - Primary progressive apraxia of speech (PPAOS) is a clinical syndrome in which apraxia of speech is the initial indication of neurodegenerative disease. Prior studies of PPAOS have identified hypometabolism, grey matter atrophy, and white matter tract degeneration in the frontal gyri, precentral cortex, and supplementary motor area (SMA). Recent clinical observations suggest two distinct subtypes of PPAOS may exist. Phonetic PPAOS is characterized predominantly by distorted sound substitutions. Prosodic PPAOS is characterized predominantly by slow, segmented speech. Demographic, clinical, and neuroimaging data (MRI, DTI, and FDG-PET) were analyzed to validate these subtypes and explore anatomic correlates. The Phonetic subtype demonstrated bilateral involvement of the SMA, precentral gyrus, and cerebellar crus. The Prosodic subtype demonstrated more focal involvement in the SMA and right superior cerebellar peduncle. The findings provide converging evidence that differences in the reliably determined predominant clinical characteristics of AOS are associated with distinct imaging patterns, independent of severity. PMID- 29980073 TI - Enzymatically degradable alginate hydrogel systems to deliver endothelial progenitor cells for potential revasculature applications. AB - The objective of this study was to design an injectable biomaterial system that becomes porous in situ to deliver and control vascular progenitor cell release. Alginate hydrogels were loaded with outgrowth endothelial cells (OECs) and alginate lyase, an enzyme which cleaves alginate polymer chains. We postulated and confirmed that higher alginate lyase concentrations mediated loss of hydrogel mechanical properties. Hydrogels incorporating 5 and 50 mU/mL of alginate lyase experienced approximately 28% and 57% loss of mass as well as 81% and 91% reduction in storage modulus respectively after a week. Additionally, computational methods and mechanical analysis revealed that hydrogels with alginate lyase significantly increased in mesh size over time. Furthermore, alginate lyase was not found to inhibit OEC proliferation, viability or sprouting potential. Finally, alginate hydrogels incorporating OECs and alginate lyase promoted up to nearly a 10 fold increase in OEC migration in vitro than nondegradable hydrogels over the course of a week and increased functional vasculature in vivo via a chick chorioallantoic membrane (CAM) assay. Overall, these findings demonstrate that alginate lyase incorporated hydrogels can provide a simple and robust system to promote controlled outward cell migration into native tissue for potential therapeutic revascularization applications. PMID- 29980074 TI - Fabrication of injectable and superelastic nanofiber rectangle matrices ("peanuts") and their potential applications in hemostasis. AB - Uncontrolled hemorrhage, which typically involves the torso and/or limb junctional zones, remains a great challenge in the prehospital setting. Here, we for the first time report an injectable and superelastic nanofiber rectangle matrix ("peanut") fabricated by a combination of electrospinning, gas foaming, hydrogel coating and crosslinking techniques. The compressed nanofiber peanut is capable of re-expanding to its original shape in atmosphere, water and blood within 10 s. Such nanofiber peanuts exhibit greater capacity of water/blood absorption compared to current commercial products and high efficacy in whole blood clotting assay, in particular for thrombin-immobilized samples. These nanofiber peanuts are capable of being packed into a syringe for injection. Further in vivo tests indicated the effectiveness of nanofiber peanuts for hemostasis in a porcine liver injury model. This new class of nanofiber-based materials may hold great promise for hemostatic applications. PMID- 29980075 TI - Cellular toxicity of silicon carbide nanomaterials as a function of morphology. AB - Silicon carbide has been shown to be biocompatible and is used as a coating material for implanted medical devices to prevent biofilms. Silicon carbide nanomaterials are also promising in cell tracking due to their stable and strong luminescence, but more comprehensive studies of this material on the nanoscale are needed. Here, we studied the toxicity of silicon carbide nanomaterials on human mesenchymal stem cells in terms of metabolism, viability, adhesion, proliferation, migration, oxidative stress, and differentiation ability. We compared two different shapes and found that silicon carbide nanowires are toxic to human mesenchymal stem cells but not to cancer cell lines at the concentration of 0.1 mg/mL. Control silicon carbide nanoparticles were biocompatible to human mesenchymal stem cells at 0.1 mg/mL. We studied the potential mechanistic effect of silicon carbide nanowires on human mesenchymal stem cells' phenotype, cytokine secretion, and gene expression. These findings suggest that the toxic effect of silicon carbide nanomaterials to human mesenchymal stem cells are dependent on morphology. PMID- 29980076 TI - Studying biomineralization pathways in a 3D culture model of breast cancer microcalcifications. AB - Microcalcifications serve as diagnostic markers for breast cancer, yet their formation pathway(s) and role in cancer progression are debated due in part to a lack of relevant 3D culture models that allow studying the extent of cellular regulation over mineralization. Previous studies have suggested processes ranging from dystrophic mineralization associated with cell death to bone-like mineral deposition. Here, we evaluated microcalcification formation in 3D multicellular spheroids, generated from non-malignant, pre-cancer, and invasive cell lines from the MCF10A human breast tumor progression series. The spheroids with greater malignancy potential developed necrotic cores, thus recapitulating spatially distinct viable and non-viable areas known to regulate cellular behavior in tumors in vivo. The spatial distribution of the microcalcifications, as well as their compositions, were characterized using nanoCT, electron-microscopy, and X ray spectroscopy. Apatite microcalcifications were primarily detected within the viable cell regions and their number and size increased with malignancy potential of the spheroids. Levels of alkaline phosphatase decreased with malignancy potential, whereas levels of osteopontin increased. These findings support a mineralization pathway in which cancer cells induce mineralization in a manner that is linked to their malignancy potential, but that is distinct from physiological osteogenic mineralization. PMID- 29980077 TI - Mussel-inspired degradable antibacterial polydopamine/silica nanoparticle for rapid hemostasis. AB - High-performance hemostasis becomes increasingly essential in civilian and military trauma. However, available topical hemostats still exist various drawbacks and side-effects. Herein, a silica nanoparticle coated with polydopamine (PDA/SiNP) with good degradability, antibacterial performance was developed for hemorrhage control. PDA/SiNP formed a porous network via lyophilization and rendered material with phenol hydroxyls, aminos, proper hydrophobicity, promising for further cells aggregation and inducing clotting. The degradation behaviors in vitro indicated that the weight loss of PDA/SiNP could attain approximately 40% just after 24 h. All results demonstrated that clotting time of blood was shortened by nearly 150 s for PDA/SiNP compared with that of commercial Celox in vitro hemostasis. PDA/SiNP could significantly accelerate coagulation by activating the extrinsic pathway of the coagulation cascade, adhering platelets and aggregating erythrocytes. Therefore, not only the PDA/SiNP achieved adequate hemostasis with low exothermic effects, but also blood loss was remarkably reduced in the femoral artery and vein injury, liver injury models. Importantly, PDA/SiNP exhibited long-lasting inhibition of Escherichia coli even after 208 h. Also, the hemolysis of PDA/SiNP with low cytotoxicity was much lower, while erythrocytes maintained regular morphology. Thus, amorphous nanoscale PDA/SiNP provided a new avenue for design of silica hemostats and nonmetallic ion antimicrobial. PMID- 29980079 TI - Peroxidases-assisted removal of environmentally-related hazardous pollutants with reference to the reaction mechanisms of industrial dyes. AB - Environmental protection is one of the most important challenges for the humankind. Increasing number of emerging pollutants resulting from industrial/human-made activities represents a serious menace to the ecological and environmental equilibrium. Industrial dyes, endocrine disrupters, pesticides, phenols and halogenated phenols, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and other xenobiotics are among the top priority environmental pollutants. Some classical remediation approaches including physical, chemical and biological are being employed, but are ineffective in cleaning the environment. Enzyme-catalyzed transformation reactions are gearing accelerating attention in this context as potential alternatives to classical chemical methods. Peroxidases are catalysts able to decontaminate an array of toxic compounds by a free radical mechanism resulting in oxidized or depolymerized products along with a significant toxicity reduction. Admittedly, enzymatic catalysis offers the hallmark of high chemo-, regio-, and enantioselectivity and superior catalytic efficiency under given reaction environment. Moreover, enzymes are considered more benign, socially acceptable and greener production routes since derived from the renewable and sustainable feedstock. Regardless of their versatility and potential use in environmental processes, several limitations, such as heterologous production, catalytic stability, and redox potential should be overcome to implement peroxidases at large-scale transformation and bio-elimination of recalcitrant pollutants. In this article, a critical review of the transformation of different types of hazardous pollutants by peroxidases, with special reference to the proposed reaction mechanisms of several dyes is presented. Following that major challenges for industrial and environmental applications of peroxidases are also discussed. Towards the end, the information is also given on miscellaneous applications of peroxidases, concluding remarks and outlook. PMID- 29980078 TI - 3D organizational mapping of collagen fibers elucidates matrix remodeling in a hormone-sensitive 3D breast tissue model. AB - Hormones play an important role in normal and diseased breast tissue development. However, they can also disrupt cell-matrix interactions and their role in extracellular matrix reorganization during epithelial morphogenesis remains poorly understood, partly due to a lack of sensitive approaches for matrix characterization. Here, we assess the hormonal regulation of matrix reorganization in a three-dimensional (3D) breast tissue culture model using a novel metric, i.e., 3D directional variance, to characterize the 3D organization of collagen fibers visualized via high-resolution, second harmonic generation imaging. This metric enables resolving and quantifying patterns of spatial organization throughout the matrix surrounding epithelial structures treated with 17beta-estradiol (E2) alone, and E2 in combination with either promegestone, a progestogen, or prolactin. Addition of promegestone results in the most disorganized fibers, while the E2 alone treatment leads to the most organized ones. Location-dependent organization mapping indicates that only the prolactin treatment leads to significant heterogeneities in the regional organization of collagen fibers, with higher levels of alignment observed at the end of the elongated epithelial structures. The observed collagen organization patterns for all groups persist for tens of micrometers. In addition, a comparison between 3D directional variance and typical 2D analysis approaches reveals an improved sensitivity of the 3D metric to identify organizational heterogeneities and differences among treatment groups. These results demonstrate that 3D directional variance is sensitive to subtle changes in the extracellular micro-environment and has the potential to elucidate reciprocal cell-matrix interactions in the context of numerous applications involving the study of normal and diseased tissue morphogenesis. PMID- 29980080 TI - Is the serious ambient air pollution associated with increased admissions for schizophrenia? AB - BACKGROUND: Much of the research has shown an increased risk of psychiatric disorders in association with elevated exposure to air pollution, such as NO2, PM10 and SO2. However, few studies investigate the effect of these air pollution on the risk of schizophrenia admissions and the lagged effect among different subgroups. METHODS: A distributed lag non-linear model (DLNM) combined with a Poisson generalized linear regression model was applied to analyzing the relationship between schizophrenia and air pollution. At first, according to the minimum AIC criterion, we discussed the lagged effect of NO2, PM10 and SO2 for 5 days, 4 days and 10 days, respectively. Then, we chose benchmarks as references (25th) to conduct comparisons with different levels of pollutant concentrations (90th and 95th). All patients were retrieved from the Psychiatric Hospital of TongLing (n = 3469) from January 2014 to December 2016. Daily air pollutants and meteorological data were collected from the Chinese national air quality monitoring (NAQM) and Meteorological Bureau. Subgroup analysis was conducted by gender (male and female), age (0-19 ages, 20-39 ages, 40-59 ages and >= 60 ages) and occupation (farmer, worker and unemployed). RESULTS: The effects of the three air pollutants were statistically significant to schizophrenia admissions. We found that NO2 and PM10 have short-term effects of 4 days and 3 days (NO2: lag 0 4 RR, 1.84(95% CI: 1.49-2.27), PM10: lag 0-3 RR, 1.97(95%CI: 1.57-2.36)), respectively. SO2 had longer effects for 10 days (SO2: lag 0-10 RR, 2.93(95%CI: 2.10-4.10)). Additionally, it significantly increased the risk of schizophrenia episode in subjects with male, 20-59 ages, farmer and worker. CONCLUSION: We find adverse effects of ambient air pollutants on schizophrenia admissions in TongLing, China, which may provide valuable information for the policy makers and local health authorities to conduct effective intervention of air pollution on schizophrenia. PMID- 29980081 TI - Emission control priority of PM2.5-bound heavy metals in different seasons: A comprehensive analysis from health risk perspective. AB - Source-specific health risks of PM2.5-bound metals were analyzed for emission control by integrating source apportionment with health risk assessments of residents affected via inhalation pathways. A total of 218 daily PM2.5 samples were collected in 2016 in the central urban district of Beijing, China. Analyses showed that the mean annual concentrations of total heavy metals (THMs) and PM2.5 were 0.39 and 104.37 MUg m-3, respectively. The heating season had significantly higher concentrations of THMs and PM2.5 (0.61, 134 MUg m-3) than the non-heating season (0.27, 88.1 MUg m-3) (p < 0.05). Among all metals, arsenic had the largest incremental cancer risk of 7.04 * 10-6. Six sources were identified by positive matrix factorization combined with conditional probability function and potential source contribution function analyses. The order of contribution to PM2.5-bound metal concentrations was resuspended dust (61.0%), traffic emission (16.3%), Cu related industry (14.1%), coal combustion (3.7%), Cr-related industry (3.4%), and fuel oil combustion (1.6%). During the heating season, the contribution of coal combustion decreased slightly, which may have been due to the countermeasure of substituting coal for gas or electric heat in 2016. However, in terms of cancer risk contribution, coal combustion was the top contributor in both heating (3.5 * 10-6, 51.6%) and non-heating (2.7 * 10-6, 59.6%) seasons due to high attributable contents of the toxic metals, As, Cd and Pb. The Cr-related and Cu-related industries were the next controlled sources in the heating and non-heating seasons, respectively. Thus, these sources should receive priority in the development of control measures. PMID- 29980082 TI - Stress-driven emigration in complex field scenarios of habitat disturbance: The heterogeneous multi-habitat assay system (HeMHAS). AB - Lines of evidence used in ecological risk assessment (ERA) are essentially three: chemistry, biology and ecotoxicology. Until now, the fundamental assumption made when measuring ecological risks is that organisms are forcedly exposed to stressors. However, when organisms can avoid disturbed habitats by escaping to less stressful areas, the assumption that exposure is mandatory to pose risk may not match field disturbance scenarios. A non-forced exposure approach using a linear free-choice multi-compartmented system has been proposed previously as a complementary tool to assess the effects on organisms' spatial avoidance/preference responses. Yet, the linearity of the latter system limits avoidance measurements to one spatial dimension. A novel, heterogeneous multi habitat assay system (HeMHAS) consisting of 18 connected circular compartments (3 compartments on a vertical axis in each one of 6 zones on a longitudinal axis; a 2D system) is put forward here to be used in heterogeneous-habitat selection studies, as it makes it possible to assess the ability of organisms to detect contamination and other stressors and select more favorable habitats. In the present study, the avoidance to copper by zebrafish (Danio rerio) was tested after exposing organisms to a copper gradient in the HeMHAS and compared with that in the linear system. Avoidance occurred for all copper concentrations: 43% in the lowest (21 MUg.L-1) to 72% in the highest (221 MUg.L-1). Results obtained within the HeMHAS (AC50: 60 MUg.L-1) were statistically (p = 0.72) similar to avoidance of copper by D. rerio in the linear non-forced system (AC50: 89 MUg.L 1). In summary, the simulation of a copper gradient in the HeMHAS (2D system) allowed to assess the potential repellency of copper to zebrafish and to corroborate the ability of organisms to detect and avoid potentially toxic concentrations. PMID- 29980083 TI - Predictors of erythrocyte cadmium levels in 454 adults in Florence, Italy. AB - BACKGROUND: Cadmium bioaccumulates in the body and causes several adverse health effects. Understanding the primary sources of exposure is critical in order to implement effective prevention measures. METHODS: We included 454 adults enrolled in the Florence cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) during 1992-98. At enrolment, information was collected on demographics, lifestyle and dietary habits using validated questionnaires; anthropometric measures were taken; and a blood sample was collected from each study participant. Information on the residential and occupational history prior to enrolment was reconstructed by phone interviews. Cadmium levels were measured in erythrocytes using inductively coupled plasma-mass spectrometry. We used multiple linear regression models to investigate the main determinants of cadmium levels. RESULTS: Median erythrocyte cadmium levels were 0.66 MUg/L (inter quartile range 0.43-1.07 MUg/L). Cadmium levels were lowest in never smokers (0.50 MUg/L) and highest in current smokers (1.38 MUg/L). Smoking status and the number of pack-years were the strongest predictors of cadmium levels in multivariable analysis, together with erythrocyte levels of lead, and biking to work, while an inverse association emerged with consumption of red meat and dairy products and physical activity levels. Cadmium levels were higher among women than men (0.66 vs. 0.58 MUg/L), and, among the former, positively associated with late menopause, nulliparity, and use of hormones for menopause. The predictors included in the multivariable model explained >40% of the variability in erythrocyte cadmium levels. CONCLUSIONS: Smoking was the most important determinant of erythrocyte cadmium levels, which were also affected by dietary habits, physical activity levels, biking, and (among women) hormone-related variables. Our results are important to inform public health actions aimed at reducing the impact of potentially modifiable sources of exposure to cadmium. PMID- 29980084 TI - Culture and horticulture: Protecting soil quality in urban gardening. AB - Urban cultivation for food production is of growing importance. The quality of urban soil can be improved by tillage and the incorporation of organic matter, or can be degraded by chemical treatments. Urban gardeners have a role in this process, through the selection of various cultivation techniques. Our study focuses on an allotment area in the town of Pisa (Italy), which since 1995 has been run as a municipal vegetable garden by the residents. We analysed the soil and compared the data with those collected five years previously, to verify the possible changes in soil properties and fertility. We also interviewed the gardeners regarding their backgrounds, motivations and cultivation practices. We looked for possible changes in the soil quality attributable to the cultivation techniques. We found that the allotment holders influenced the soil quality through the cultivation techniques. Organic carbon, electrical conductivity and the content of copper increased unevenly in relation to the gardeners' cultivation practices. At the same time the study highlights that the urban gardeners were not completely aware of how to protect and enhance the fertility and the quality of urban soil. We believe that town councils should be responsible for providing correct information to the allotment holders and thus prevent the possible misuse of urban soil to grow food, as this can affect everyone's health. PMID- 29980085 TI - Keeping global warming within 1.5 degrees C reduces future risk of yield loss in the United States: A probabilistic modeling approach. AB - This study assess the possible outcomes of yield changes in the United States which is responsible for 40% of global maize supply under 1.5 degrees C and 2 degrees C global warming scenarios. Instead of providing deterministic estimates, this study introduces a probability-based approach that allow for examination of the associated probability of each outcome, which has great implications for decision-makings. Results show distinct spatial patterns in future yield loss risk associated with temperature rise at the county scale, with highest probability in central and southeastern US, and lowest risk in western US and high production regions such as Iowa. Comparing the estimates under 1.5 degrees C global warming against that in 2.0 degrees C warming indicates that keeping global warming within 1.5 degrees C has great benefits for reducing future yield loss risk. Based on the ensemble mean of 97 climate model simulations, the risk of yield dropping below historical long-term mean is projected to decrease from 81% to 75% for the country as a whole. Such benefit is more evident when considering the risk of yield reduction by 10% and 20%, which is expected to decrease by 25% and 28%, respectively. This suggests that constraining global temperature rise to 1.5 degrees C has more benefits for reducing extreme yield reductions. Spatially, keeping global warming within 1.5 degrees C would benefit more in Missouri, South Dakota, Eastern Kansas, Southern Texas and southeastern part of the country than other regions, highlighting the spatially variable benefits of climate mitigation efforts. The analysis framework introduced in this study can also be easily extended to other regions and crops. The results of this study highlight the areas where maize yield is most vulnerable to temperature rise, and the spatially variable benefits for reducing yield loss risk by keeping global warming within 1.5 degrees C. PMID- 29980086 TI - Direct and indirect effects of land use on bryophytes in grasslands. AB - Land-use intensification is the major threat for biodiversity in agricultural grasslands, and fertilization has been suggested as the most important driver. A common explanation for the decline of bryophyte diversity with higher land-use intensity is an indirect negative effect via the increase in vascular plant productivity, which reduces light levels for bryophytes. However, direct negative effects of land-use intensification may also be important. Here, we disentangle direct and vascular plant biomass mediated indirect effects of land use on bryophytes. We analyzed two complementary datasets from agricultural grasslands, an observational study across 144 differently managed grasslands in Germany and an experimental fertilization and irrigation study of eleven grasslands in the Swiss Alps. We found that bryophyte richness and cover strongly declined with land-use intensity and in particular with fertilization. However, structural equation modelling revealed that although both direct and indirect effects were important, the direct negative effect of fertilization was even stronger than the indirect effect mediated by increased plant biomass. Thus, our results challenge the widespread view that the negative effects of fertilization are mostly indirect and mediated via increased light competition with vascular plants. Our study shows that land use intensification reduces bryophyte diversity through several different mechanisms. Therefore, only low-intensity management with limited fertilizer inputs will allow the maintenance of bryophyte-rich grasslands. PMID- 29980087 TI - Characterisation of dissolved organic matter using Fourier-transform ion cyclotron resonance mass spectrometry: Type-specific unique signatures and implications for reactivity. AB - This study investigated the chemodiversity and unique signatures for dissolved organic matter (DOM) from different types of water using high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Eight freshwater hydrophobic DOM (HPO) share 10-17% formulas that were mainly lignin-like compounds. Unique signatures were synthesized: unique to the high-humic HPO (Suwannee River and Blavet River) were condensed aromatic and some aliphatic compounds with H/C > 1.5 and O/C < 0.2, which is considered as decisive of these black river water. Medium-humic isolates (Loire River, Seine River, South Platte River, and Ribou Dam) did not show explicit unique signatures. Nonetheless, enhanced chemodiversity was observed for medium-humic isolates extracted from a variety of indigenous environmental conditions. As an example, South Platte River HPO isolated in winter showed signatures similar to low-humic HPO (Colorado River), i.e., predominantly aliphatic CHO (H/C > 1.0). Effluent HPO was mainly aliphatic molecules with 0.2 < O/C < 0.5 and enriched in S-bearing molecules, and molecules unique to glacial DOM (Pony Lake) incorporated N-bearing compounds that were inferiorly oxidized and were considered as microbial-derived. The weight averaged double bond equivalent and elemental ratio derived from FTICR-MS were compared with SUVA254 and the results from elemental analysis. This acts as the first study to synthesize unique chemical compositions that distinguish different types of DOM and determine certain reactivity. It is also a significant reference for future studies using similar types of DOM. PMID- 29980088 TI - Controlling nutritional status score for predicting 3-mo functional outcome in acute ischemic stroke. AB - BACKGROUND: Malnutrition is an independent risk factor for poor outcomes in patients with acute ischemic stroke. However, the indicator of malnutrition has not yet been established. We investigated the relationship between the Controlling Nutritional Status score, a useful prognostic measure of malnutrition in patients with cardiovascular diseases and malignant tumors, and functional outcomes in patients with acute ischemic stroke. METHODS: Patients with acute ischemic stroke (n = 264, 71 +/- 12 y old) were consecutively evaluated within 7 d of stroke onset. The Controlling Nutritional Status score was calculated from the serum albumin, total peripheral lymphocyte count, and total cholesterol; a Controlling Nutritional Status score of 5 to 12 was defined as malnutrition. Poor functional outcome was defined as a modified Rankin Scale score of 3 to 6 at 3 mo. RESULTS: Of the total cohort, 230 patients (87.1%) were assessed. The patients with poor functional outcome (n = 85) were older; had a lower body mass index; had a higher frequency of atrial fibrillation, chronic heart failure, and anemia; and had a lower frequency of dyslipidemia and a current smoking status. In addition, the Controlling Nutritional Status score and National Institutes of Health Stroke Scale score at admission were significantly higher for the patients with poor functional outcome. After multivariate analysis, adjusted for baseline characteristics, a Controlling Nutritional Status score of 5 to 12 was found to be independently associated with poor outcome (odds ratio: 4.15, 95% confidence interval: 1.52-11.67, P = 0.005). CONCLUSIONS: The Controlling Nutritional Status score at admission could be a useful prognostic marker of 3-mo functional outcomes in patients with acute ischemic stroke. PMID- 29980089 TI - Nutritional assessment and associated factors in the elderly: apopulation-based cross-sectional study. AB - OBJECTIVE: The aim of this study was to assess nutritional status and associated factors in elderly individuals. METHODS: This cross-sectional study was conducted in residential homes with a probabilistic cluster sample. Two-hundred eighty seven individuals 65-74 y of age were interviewed and examined in the city of Cruz Alta, state of Rio Grande do Sul, Brazil. A structured questionnaire was used to assess the socioeconomic, behavioral, and general health conditions; the number of present teeth were counted. Nutrition was assessed with a validated instrument-the Mini Nutritional Assessment-which classifies the patient as normal (eutrophic), at nutritional risk, or malnourished. For data analysis, the participants were categorized in eutrophic or at nutritional risk (at risk of malnutrition + malnourished). The associations were assessed by either the chi2 or Mann-Whitney tests. Uni- and multivariate Poisson regression analyses verified the associations. The significance level was set at 5%. RESULTS: The prevalence of nutritional risk was 48.4%. In the multivariate model, edentulous individuals with no complete denture or with only one complete denture (prevalence ratio PR, 1.59; 95% confidence interval [CI], 1.18-2.13) and elderly individuals with no access to the dentist (PR, 1.48; 95% CI, 1.11-1.88) presented higher potential for nutritional risk than their respective controls. CONCLUSIONS: The results showed that approximately half of the participants (48.4%) were at nutritional risk. The lack of complete or partial rehabilitation of edentulous patients and the lack of access to the dentist were associated with higher nutrition risk. PMID- 29980090 TI - Diagnostic accuracy of undernutrition codes in hospital administrative discharge database: improvements needed. AB - OBJECTIVES: Hospital administrative databases are widely used for disease monitoring. Undernutrition is highly prevalent among hospitalized patients but the diagnostic accuracy of undernutrition coding in administrative data is poorly known. This study examined the diagnostic accuracy of undernutrition coding in administrative hospital discharge databases. METHODS: A retrospective cross sectional study was conducted using 2013 and 2014 administrative data of the Internal Medicine Unit of the Lausanne University Hospital (n = 2509). Two reference diagnoses were defined: Confirmed undernutrition (2002 nutrition risk screening [NRS-2002] score >=3 plus body mass index [BMI] < 18.5 kg/m2) and probable undernutrition (NRS-2002 >= 3 plus any prescribed nutritional management plus BMI >=18.5 and <20 kg/m2 if age <70 y [ < 22 kg/m2 if age >=70 y]). Missing BMI values were imputed. RESULTS: Of the 2509 eligible patients, 262 (10.4%) were classified as confirmed and 631 (25.2%) as probable undernutrition. The sensitivity, specificity, and negative and positive predictive values (and corresponding 95% confidence intervals) for undernutrition codes using confirmed undernutrition were 43.0 (37.0-49.3), 87.2 (85.8-88.6), 92.9 (91.7-94.0), and 28.2 (23.8-32.8), respectively. The corresponding values using both confirmed and probable undernutrition were 30.0 (27.2-32.9), 93.4 (92.0-94.6), 66.7 (64.7 68.7), and 75.1 (70.6-79.3), respectively. Similar findings were obtained after stratifying for sex or age groups or restricting the analysis to patients with non-missing BMI data. CONCLUSIONS: The undernutrition codes in hospital discharge data have good specificity but the sensitivity and positive predictive values are low. PMID- 29980091 TI - Dietary diversity and anthropometric status and failure among infants and young children in Sri Lanka. AB - OBJECTIVES: We investigate the association between child dietary diversity and anthropometric status and failure in Sri Lanka while accounting for other child and household factors by employing multivariable logistic and linear regression analyses. METHODS: Using a nationally representative survey of children ages 6 mo to 59 mo, child dietary diversity was based on the 24-h recall of a child's food intake across seven food groups. The minimum dietary diversity was a score of four or above. Anthropometric status (i.e., height for age (HAZ), weight for age, and weight for height z-scores) and failure (i.e., stunting, wasting, and underweight) were calculated. RESULTS: The prevalence of stunting, wasting, and underweight was 15%, 21%, and 26%, respectively. The prevalence of inadequate dietary diversity was 9%. Child dietary diversity was positively associated with HAZ (b = 0.02; standard error = 0.01; P = 0.04) but not with any indicator of anthropometric failure. However, low birth weight, wealth, and location were strong risk factors for anthropometric status and failure. Analyses stratified by child age indicated that dietary diversity was positively associated with anthropometric status for children ages 24 mo to 59 mo (HAZ: b = 0.03; standard error = 0.01; P = 0.02). Mixed associations were found for children ages 6 mo to 12 mo and there were no associations for children ages 12 mo to 24 mo. CONCLUSIONS: Child dietary diversity predicted anthropometric status among children ages >=24 mo. Interventions to address both proximal and distal risk factors for anthropometric status may be necessary in Sri Lanka to reduce anthropometric failure among infants and young children. PMID- 29980092 TI - Tracking of food and nutrient intake from adolescence into early adulthood. AB - OBJECTIVE: According to the dietary patterns identified in adolescence, we assessed the tracking of food and nutrient intake between adolescence and early adulthood. METHODS: Participants were 962 adolescents from the Epidemiologic Health Investigation of Teenagers in Porto (EPITeen) cohort, with dietary patterns assigned at 13 y and valid information on diet at 21 y. In both waves, diet was evaluated by a food frequency questionnaire. Consumption of each food group, energy, and nutrients at 21 y were compared across the four dietary patterns with one-way analysis of variance or Kruskal-Wallis test. Consumption of each food group was standardized separately at 13 and at 21 y to compare food intake at both ages. RESULTS: Participants identified in the "healthier" dietary pattern at 13 y presented at 21 y with the highest consumption of seafood, vegetable soup, vegetables and legumes, fruit, added fats, protein, monounsaturated fat, dietary fiber, calcium, folate, and vitamin C and lower intake of fast food and sodium. Participants from the "fast food and sweets" dietary pattern presented with the highest consumption of fast food and soft drinks and the highest energy intake at 21 y, whereas participants from the "dairy products" pattern presented with the highest consumption of dairy products, calcium, and potassium. When comparing the standardized food consumption, the ranking of food group consumption across the four dietary patterns in general was maintained from 13 to 21 y, although the differences were attenuated. CONCLUSIONS: Despite differences in food and nutrient intake according to patterns that were attenuated at 21y, our results suggest that they are likely to track from adolescence into early adulthood. PMID- 29980093 TI - Sleep duration of 24 h is associated with birth weight in nulli- but not multiparous women. AB - OBJECTIVES: This study aimed to evaluate the association between nightly, napping, and 24-h sleep duration throughout pregnancy and birth weight z-score among nulli- and multiparous women. METHODS: Nightly,napping, and 24-h sleep duration and birth weight z-score (calculated on thebasis of the International Fetal and Newborn Growth Consortium for the 21st century standards) were studied in a cohort of 176 pregnant women from Brazil. Linear mixed-effect analyses were performed to assess the longitudinal evolution of sleep duration and the best unbiased linear predictors of the random coefficients were estimated. The best unbiased linear predictor estimates of sleep duration intercept and slope were included in the linear regression models with birth weight z-score as the outcome. RESULTS: The mean hours of nightly sleep decreased during pregnancy in nulliparous women (beta = -0.55; 95% confidence interval [CI], -0.83 to -0.27) but the decrease was not statistically significant in multiparous women (beta = 0.19; 95% CI, -0.30 to 0.01). Twenty-four hour sleep duration decreased during pregnancy in both multiparous (beta = -0.50; 95% CI, -0.76 to -0.25) and nulliparous women (beta = 0.77; 95% CI, -1.06 to -0.48). Napping sleep duration did not change in either group. Among the nulliparous women, both first-trimester 24-h sleep duration and its change throughout pregnancy were inversely associated with birth weight (beta = -0.44; 95% CI, -0.68 to -0.21; beta = -1.75; 95% CI, 3.17 to -0.30, respectively). No associations were detected in multiparous women for nightly and napping sleep duration. CONCLUSIONS: Nulliparous women with greater decreases in sleep duration throughout their pregnancy gave birth to newborns with lower birth weight z-scores. PMID- 29980094 TI - Ultrasound measurement of intraabdominal fat thickness as a predictor of insulin resistance and low HDL cholesterol in Asians. AB - OBJECTIVES: Insulin resistance (IR) is important in the pathogenesis of diabetes, the prevalence of which has become a major public health threat in Asia. The aim of this study was to use ultrasound measurements of abdominal fat thickness to predict IR and low high-density lipoprotein cholesterol (HDL-C) levels among Singaporean adults. METHODS: A total of 399 healthy Singaporeans (mean age 36.7 +/- 14.3 y; 43.4% men) took part in this study. Preperitoneal fat thickness (PFT) and subcutaneous fat thickness (SFT) were determined by ultrasound. RESULT: We found that both PFT and SFT had significant positive correlations (P < 0.05) with fasting insulin concentration, homeostasis model assessment of insulin resistance, triacylglycerol (TG), and blood pressure, and negatively correlated to serum HDL-C in all participants. Separating men and women, PFT was an independent determinant of IR and low HDL-C only in men. On receiver-operating characteristic curve analysis, PFT >=1.2 cm was the optimal cutoff value to identify IR and low HDL-C in men. On the other hand, SFT was the determinant of IR, elevated TG, and low HDL-C only in women. An SFT of 1.1 cm was the optimal cutoff value to define IR, elevated TG, and low HDL-C in women. CONCLUSIONS: Results of this study suggested that ultrasound measurements of PFT and SFT could provide simple and useful indices of IR and lipid disorders for healthy Singaporean men and women. They might have the diagnostic values for predicting cardiovascular risks in this population. PMID- 29980095 TI - Limitation of mineral supply as tool for the induction of secondary metabolites accumulation in tomato leaves. AB - Agricultural residues are natural sources for secondary metabolites as high value ingredients for industrial uses. The present work aims to exploit the accumulation potential of rutin and solanesol in tomato leaves following nitrogen and general mineral deficiency in a commercial-like greenhouse. Physiological responses of tomato plants were monitored non-destructively with a multiparametric fluorescence sensor, and biochemical parameters were determined by means of HPLC analysis. Nitrogen and general mineral limitation led to an accumulation of rutin in young tomato leaves while solanesol concentration was higher in mature leaves. In young leaves, the fluorescence indices SFR_R and NBI_G showed lower values compared to control plants for both stress treatments. On the contrary, FLAV and ANTH_RG values increased during the experiment, but no differences could be recorded in mature leaves. However, correlation analysis indicates, that the FLAV index is not a reliable tool to estimate the concentration of rutin and solanesol tomato leaves. To monitor fruit yield/quality as primary objective of tomato production, fruits showing symptoms of blossom end rot (BER) were counted before and after stress treatments. BER was determined more frequently for plants grown under a general mineral deficiency, concluding that a practical applicability at the end of fruit production is advisable. Our results indicate that by-products from Solanaceae plants are promising resources for valuable bioactive leaf compounds. To achieve the highest concentrations, the seasonal variation, the optimal environmental conditions, the concentrations in different plant organs and varieties as well as different production systems are of high interest for commercial implementation. PMID- 29980096 TI - Alginate-derived oligosaccharides promote water stress tolerance in cucumber (Cucumis sativus L.). AB - Marine alginate-derived oligosaccharides (ADOs) are prepared from degraded alginate. Our experiments were carried out to determine the mechanism of ADOs to improve resistance to water stress in cucumber (Cucumis sativus L.). We evaluated the effects of ADOs on physiological indices, photosynthesis, reactive oxygen species (ROS) levels, antioxidant enzyme activities, and relative expression levels of drought resistance genes. The growth of drought stressed cucumber decreased markedly. However, treatment with ADOs significantly improved the diameter, fresh weight, photosynthetic rate, transpiration rate, stomatal conductance, maximum quantum yield of photosystem II (Fv/Fm) and chlorophyll degradation; thus, reversing the effects of drought stress. Moreover, the antioxidant levels and ROS scavenging enzyme activities also increased in response to the ADOs. Additionally, the genes involved in abscisic aid (ABA) signaling and the drought stress response, such as superoxide dismutase [Cu-Zn] (CsSOD(Cu-Zn)), the peroxidase superfamily protein (CsPOD3), ABA deficient 2 (CsABA2), responsive to ABA 18 (CsRAB18), abscisic acid insensitive 5 (CsABI5), responsive to dehydration 22 (CsRD22), and responsive to dehydration 29A (CsRD29A) were upregulated by ADOs. The ABA content was also improved by ADOs. Our results suggest that ADOs induced the expression of some antioxidant enzyme synthetic genes involved in the ABA signaling pathway by stimulating ABA synthesis to improve the drought resistance capacity in cucumber. PMID- 29980097 TI - The transfer to and functional annotation of alien alleles in advanced wheat lines derived from synthetic hexaploid wheat. AB - The abundant genetic diversity in synthetic hexaploid wheat (SHW) can achieve breakthroughs in wheat genetic improvement, but little is known of the genetic mechanisms involved. In this study, three populations of advanced lines (totaling 284 individuals), derived from three top-crosses of SHW-L1 with different common wheat cultivars, followed by ten generations of artificial selection, were used to evaluate the transfer of alien alleles with 24872 Diversity Arrays Technology (DArT) markers. Only 1824, 1786 and 1514 DArT markers were needed to distinguish the alleles from SHW-L1 and the other common wheat parent in the populations SCPD, SS7M and SSYZ, respectively. The data clearly showed that all the advanced lines contained alien alleles from SHW-L1. The lowest percentage of alien alleles was 6.97% in an advanced line in population SSYZ, while the biggest was 30.41% in a SCPD advanced lines. The percentages of alien alleles at each locus ranged from 0% to 100% in all three populations. Forty-four alien alleles did not exist in all advanced lines, while two alien alleles were present in all advanced lines. Two of the 100% alien alleles were associated with thousand-grain weight and leaf rust resistance. Thirteen alien alleles were associated with grain yield, grain thickness and width, thousand-grain weight, grain weight/ear, plant height, grain weight, grain number, powdery mildew resistance, spikelet number per spike or yellow rust resistance. The research provided direct evidence of the existence of alien alleles in advanced lines and detected a number of valuable alleles related to wheat yield or disease resistance. More research is needed to analyze the functional mechanisms of these alleles, and to use these materials and alleles in wheat improvement. PMID- 29980098 TI - Apigenin pretreatment enhances growth and salinity tolerance of rice seedlings. AB - Soil salinity is a limiting factor in rice production. Since flavonoids present in most plant tissues play multiple roles in plant-environment interactions, in this study, we focused on the contribution of flavone aglycone (Apigenin) to the adaptation of salinity-sensitive rice cultivar 'Koshihikari,' to salinity stress, for the first time. Rice seeds were soaked in Apigenin solution (10 ppm) for 24 h, then air-dried and grown hydroponically under 50 mM NaCl for 14 days. Apigenin pretreatment improved the growth of rice seedlings by enhancing shoot elongation and dry mass accumulation under both unstressed and NaCl-stress conditions, compared with that in the non-pretreated seedlings. Apigenin pretreatment significantly reduced Na+ accumulation in the salinity-stressed seedlings, and helped to maintain a lower Na+/K+ ratio in all plant organs, compared with that in the non-pretreated seedlings, possibly by regulating the expression of some important Na+ transporter-encoding genes (OsHKT2;1, OsCNGC1, OsSOS1). Higher levels of lipid peroxidation and hydrogen peroxide (H2O2) concentrations were observed in the shoots of the salinity-stressed seedlings; however, lower levels of lipid peroxidation and H2O2 concentration were detected in the Apigenin treated seedlings. Apigenin pretreatment was associated with the induction of the rice antioxidant defense system represented by the induced activities of the antioxidant enzymes Catalase (CAT) and Ascorbate peroxidase (APX) in the roots, as well as by increased accumulation of the non-enzymatic antioxidants carotenoids and flavonoids in the shoots, relative to that in the untreated seedlings, under salinity stress conditions. Together, these results suggest that Apigenin pretreatment can alleviate the damaging effects of salinity on rice seedlings, presumably by regulating selective ion uptake by the roots and translocation to the shoots, thereby maintaining higher K+/Na+ ratios critical for normal plant growth under salinity stress, and by triggering the induction of the antioxidant defense system. PMID- 29980099 TI - Development of a selective and sensitive high-performance liquid chromatography tandem mass spectrometry assay to support pharmacokinetic studies of LY-487,379 in rat and marmoset. AB - Drugs modulating the metabotropic glutamate type 2 receptor (mGluR2) activity may have therapeutic benefits in treating a large spectrum of neuro-psychiatric disorders, from schizophrenia to Parkinson's disease, both as a symptomatic therapy and potential disease-modifying paradigm. LY-487,379 is a highly selective mGluR2 positive allosteric modulator that is widely used to study mGluR2 function using experimental animal models. The common marmoset is a small primate that has long been used in neuroscience. However, given its small size and small circulating blood volume, conducting studies to determine the PK profile of LY-487,379 is challenging. We developed and validated a sensitive and selective analytical method that enables quantification of LY-487,379 using a limited volume of plasma (10 MUL). The analytical method consists of protein precipitation followed by high-performance liquid chromatography with heat assisted electrospray ionization mass spectrometry (HPLC-HESI-MS/MS). The chromatographic separation was achieved using gradient elution with a mobile phase consisting of acetonitrile and 0.01% formic acid in water on a Thermo Scientific Aquasil C18 analytical column (100 * 2.1 mm I.D., 5 MUm) operating at 40 degrees C and at a flow rate of 300 MUL/min. The method displays a linear relationship ranging from 0.2 to 100 ng/mL. Intra- and inter-day relative standard deviations are <1.4% and 7.9%, respectively and the relative error ranged from -6.9 to 9.7%. The method was used to quantify LY-487,379 in both rat and marmoset plasma, and PK parameters were determined after a single subcutaneous dose of 1.0 mg kg-1 in both species and significant differences in Cmax, AUC and T1/2 were observed. PMID- 29980100 TI - A new method for measuring thyroid hormones using nano-LC-MS/MS. AB - This paper describes a novel mass spectrometry based analytical method for analyzing thyroid hormones (THs). Thyroid hormones play a critical role in the regulation of many biological processes such as growth, metabolism and development. Several analytical methods using liquid chromatography-mass spectrometry (LC-MS) and tandem mass spectrometry (LC-MS/MS) have previously been developed to measure THs, especially in humans. For biomedical and toxicological research using small animal models, and in ecophysiological research using wild species where sample volume is limiting, sensitive methods are needed. In this study, we developed a nano-LC-MS/MS method enabling quantification of low concentrations of two key THs, thyroxine (T4) and 3,3',5-triiodothyronine (T3). The method was tested with egg yolk samples. We used a low flow rate (300 nl/min) to obtain maximal sensitivity of the method. The limit of quantitation was 10.6 amol for T4 and 17.9 amol for T3. The method shows good linearity (r > 0.99), repeatability and reproducibility (CVs <10%). We also reanalyzed yolk samples with radioimmunoassay for a comparison of the newly developed and previously used methods. Finally, we applied the methodology to measure hormones in egg yolk extracts in multiple avian species, and report interesting variation in maternal TH deposition. The newly developed nano-LC-MS/MS method is thus suitable for measuring THs in low concentrations and across species. PMID- 29980101 TI - Forced degradation of l-(+)-bornesitol, a bioactive marker of Hancornia speciosa: Development and validation of stability indicating UHPLC-MS method and effect of degraded products on ACE inhibition. AB - The antihypertensive activity of the medicinal plant Hancornia speciosa has been previously demonstrated by us, being the activity ascribed to polyphenols and cyclitols like l-(+)-bornesitol. We herein evaluated the stability of the bioactive marker bornesitol submitted to forced degradation conditions. Bornesitol employed in the study was isolated from H. speciosa leaves. An UHPLC ESI-MS/MS method was developed to investigate bornesitol stability based on MRM (Multiple Reaction Monitoring) acquisition mode and negative ionization mode, employing both specific (m/z 193 -> 161 Da) and confirmatory (m/z 193 -> 175 Da) transitions. A gradient elution of 0.1% formic acid in water and acetonitrile was performed on a HILIC column. The method was validated and showed adequate linearity (r2 > 0.99), selectivity, specificity, accuracy, and precision (RSD < 2.9%). The method was robust for deliberate variations on dessolvation temperature, but not for changes in the flow rate and dessolvation gas. The results from the stability studies allowed us to classify bornesitol as labile for acidic and alkaline hydrolysis, but as very stable for oxidative and neutral hydrolysis exposure. Bornesitol was categorized as practically stable under photolysis degradation, whereas a considerable reduction on its contents was induced by metal ions and thermolysis exposure. Degraded samples from neutral hydrolysis and thermolysis were assayed in vitro for ACE inhibition and showed a substantial decrease in biological activity as compared to intact bornesitol. myo Inositol was identified as the major degradation products in both matrices. This is the first report on bornesitol stability under different stress conditions and the obtained data are relevant for the development and quality control of standardized products from H. speciosa leaves. PMID- 29980102 TI - Determination of 12 commonly found compounds in DUID cases in whole blood using fully automated supported liquid extraction and UHPLC-MS/MS. AB - A high-throughput UHPLC-MS/MS method for the most frequently found compounds; tetrahydrocannabinol (THC), amphetamine, methamphetamine, MDMA, clonazepam, diazepam, nordiazepam, oxazepam, alprazolam, nitrazepam, morphine, and codeine, in driving under the influence of drugs (DUID) cases in whole blood, is presented. Automated sample preparation by 96-well supported liquid extraction (SLE) plates with ethyl acetate + heptane (80 + 20, v/v) as organic solvent was carried out on a Freedom Evo 200 platform from Tecan. An aliquot of 100 MUL whole blood was used. Sample preparation time for 96 samples was 1.5 h. Compounds were separated with gradient elution on a C18 column (50 * 2.1 mm, 1.7 MUm) with a mobile phase consisting of 5 mM pH 10.2 ammonium formate and methanol. The run time was 4.5 min and 1 MUL was injected on an Acquity UPLC I-Class system with a Xevo TQS tandem-quadrupole mass spectrometer in multiple-reaction monitoring mode (MRM) from Waters. Isotope labelled, 13C, internal standards (ISs) were used for all compounds except for alprazolam and morphine, which had deuterated analogs. Quantification was carried out with calibrators without whole blood matrix. Full validation was carried out according to international guidelines, and a new approach for evaluation of process efficiency (PE) has been presented. Linear or quadratic weighted (1/x) calibration curves were used with R2 >= 0.999. The method showed satisfactory deviations +/-16% when compared to the existing methods, and satisfactory agreement with proficiency testing control samples (z score -1.6 to 1.8, n = 16 samples). The precision, estimated as the relative standard deviation (RSD) of the concentration difference between results from two independent analyses of authentic whole blood samples, was <=7.2% in antemortem and <=9.3% in postmortem samples. Recovery was >=85% for all the compounds, except morphine >=62% and THC >= 50%. PE was satisfactory for all the compounds with low variation in IS response, RSD <= 16% (THC 27%) in antemortem samples and <=34% (THC 66%) in postmortem samples. To the best of our knowledge, this is the first automated 96-well SLE UHPLC-MS/MS method developed for the simultaneous determination of these 12 compounds in whole blood covering the concentration ranges found in forensic samples. The method has been used in routine work during the last ten months, analysing about 9900 antemortem and 1000 postmortem whole blood samples, and has proven to be robust and reliable. PMID- 29980103 TI - Low-cost electromyography - Validation against a commercial system using both manual and automated activation timing thresholds. AB - Widespread use of electromyography (EMG) as an assessment and biofeedback method may be limited by costly commercial systems. Low-cost devices are available; however their validity is unknown. This study determined the concurrent validity of a low-cost EMG on a microchip compared with a commercially available system during isometric and dynamic muscle contractions. Inter-tester, intra-session reliability of manual data extraction during data processing compared to a simple, automatic thresholding method using the Teager-Kaiser energy operator (TKEO) was also evaluated. 10 healthy women (age 28.1 +/- 6.8 yrs, height 162.1 +/- 6.8 cm, mass 60.3 +/- 10.2 kg) were assessed simultaneously with a commercially available EMG system (Telemyo DTS) and a custom low-cost EMG system (Myoware Muscle Sensor) during voluntary isometric contractions, knee extension, squatting, stepping and jumping. Two surface electrode sets (connected to the low cost and the commercial system) were placed end to end along the same Vastus Lateralis muscle fibre line. Peak and mean contraction intensity, and contraction duration were analysed. Overall the relative agreement between systems was excellent for peak muscle activation (ICC 0.77-0.96) and modest to excellent for mean muscle activation (ICC 0.68-0.95) and contraction duration (ICC 0.65-0.99). Inter-tester, intra-session reliability was excellent for peak contraction intensity (ICC > 0.99) and modest to excellent for mean contraction intensity, with the TKEO method primarily recording stronger agreement than the manual method. Poor to excellent inter-tester reliability occurred for contraction duration. Our findings indicate that a low-cost EMG system is comparable to a commercial system for assessing muscle activation, and that using the TKEO improved the reliability of timing related variables. PMID- 29980104 TI - Effects of fatigue on ankle biomechanics during jumps: A systematic review. AB - Fatigue is common during physical activity and can have an effect on ankle biomechanics during different actions, such as a jump. Yet current research on the topic is very heterogeneous and hinders clarity on what changes are actually due to fatigue. Therefore, the aim of this review was to summarise and analyse the current literature that investigates the effects of fatigue on ankle biomechanics during a jump. Searches were conducted in five databases and studies with activities eliciting fatigue and comparing outcomes under a fatigue and non fatigue conditions were selected. Twelve studies were included, six analysed double legged jumps and six single legged jump. When comparing ankle biomechanics between a fatigued condition and a non-fatigued condition, findings suggested that at initial contact at landing, dorsiflexion increased in single legged jump and plantarflexion increased in double legged jump; at maximum knee flexion after landing, dorsiflexion decreased in double legged jumps and plantarflexion increased at full foot contact in single legged jumps. Also, ankle power (for double legged jump) and ground reaction force (for double and single legged jump) reduced at initial contact to maximum knee flexion at landing after fatigue and ankle power also reduced at takeoff in single legged jumps. The current review shows that fatigue affect ankle biomechanics by reducing dorsiflexion, from initial contact to maximum knee flexion at landing, and power during the jump takeoff. Such information could have implications for injury prevention. PMID- 29980105 TI - Structure-based immunogen design-leading the way to the new age of precision vaccines. AB - Vaccines have been one of the most successful interventions in global health. However, traditional vaccine development has proven insufficient to deal with pathogens that elude the immune system through highly variable and non-functional epitopes. Emerging B cell technologies have yielded potent monoclonal antibodies targeting conserved epitopes, and their structural characterization has provided templates for rational immunogen design. Here, we review immunogen design strategies that leverage structural information to steer bulk immune responses towards the induction of precise antibody specificities targeting key antigenic sites. Immunogens designed to elicit well-defined antibody responses will become the basis of what we dubbed precision vaccines. Such immunogens have been used to tackle long-standing vaccine problems and have demonstrated their potential to seed the next-generation of vaccines. PMID- 29980106 TI - Metal-chelating non-canonical amino acids in metalloprotein engineering and design. AB - The ability to rationally design metalloproteins with desired functions remains a difficult challenge despite many years of effort. Recently, the potential of using genetically encoded metal-chelating non-canonical amino acids (NCAAs) to circumvent longstanding difficulties in this field has begun to be explored. In this review, we describe the development of this approach and its application to the rational design or directed evolution of NCAA-containing metalloproteins in which the bound metal ions serve in structural roles, as catalysts, or as regulators of the assembly or disassembly of protein complexes. These successes highlight the fact that amino acids not found in nature can recapitulate the functions of their naturally occurring counterparts and suggest the promise of this nascent approach for simplifying the metalloprotein design problem. PMID- 29980107 TI - Pyrrolizidine alkaloids from Liparis nervosa with antitumor activity by modulation of autophagy and apoptosis. AB - Seven pyrrolizidine alkaloids, nervosine X-XV and nervosine VII N-oxide, together with a reaction product, namely chloride-(N-chloromethyl nervosine VII), were isolated from Liparis nervosa. Their structures were elucidated by extensive spectroscopic analyses. Most of these compounds were investigated for their cytotoxicity in vitro against HCT116 human cancer cell line, and the results showed that chloride-(N-chloromethyl nervosine VII) induced tumor cell death in a dose-dependent manner. Furthermore, the mechanisms underlying its cytotoxicity were investigated, including apoptosis and autophagy. Apoptosis in HCT116 cells was associated with up-regulation of caspase-3 and -9 expressions by activation of the mitochondrial pathway. The autophagy inducing effect was associated with the regulation of autophagic markers, including LC3-II, p62, and Beclin 1. Mechanistic studies showed that JNK, ERK1/2, and p38 MAPKs signaling cascades play an important role in chloride-(N-chloromethyl nervosine VII) induced autophagy and apoptosis. PMID- 29980108 TI - Flavonoids isolated from the fresh sweet fruit of Averrhoa carambola, commonly known as star fruit. AB - Thirteen flavonoids were isolated from the fresh sweet fruit of Averrhoa carambola L. (Oxalidaceae), commonly known as star fruit, and their structures were determined by spectroscopic and chemical methods. 8-Carboxymethyl-(+) epicatechin methyl ester, pinobanksin 3-O-beta-d-glucoside, and carambolasides M Q were undescribed structures. (+)-Epicatechin, aromadendrin 3-O-beta-d glucoside, helicioside A, taxifolin 3'-O-beta-d-glucoside, galangin 3-O rutinoside, and isorhamnetin 3-O-rutinoside were reported from this species for the first time. Pinobanksin 3-O-beta-d-glucoside and carambolasides M-Q showed more potent 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical cation scavenging activity (IC50 = 5.3-2.3 MUM) than l-ascorbic acid (10.5 MUM). Further, (+)-epicatechin, pinobanksin 3-O-beta-d-glucoside, isorhamnetin 3-O rutinoside, and carambolasides O-Q exhibited weak porcine pancreatic lipase inhibitory activity. PMID- 29980109 TI - Generation of an induced pluripotent stem cell line from a patient with adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): HIHCNi003-A. AB - An induced pluripotent stem cell line, HIHCNi003-A (iPSC-ALSP), was created from a skin biopsy of a patient with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) caused by a heterozygous c.2512G>C, p.Val838Leu mutation in the CSF1R gene. Skin fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC, and hLIN28. The iPSC-ALSP line exhibits chromosomal stability with conservation of the CSF1R mutation, expresses pluripotency markers and differentiates into endo-, meso-, and ectodermal cells in vitro. PMID- 29980110 TI - Corrigendum to 'Design and optimization of PLGA microparticles for controlled and local delivery of Neuregulin-1 in traumatic spinal cord injury'. [Journal of Controlled Release 261(2017) 147-162]. PMID- 29980111 TI - Trichomonas vaginalis infection-associated risk of cervical cancer: A meta analysis. AB - Trichomoniasis, caused by the extracellular eukaryotic parasite trichomonas vaginalis, is one of the most common non-viral sexually transmitted infections worldwide. The correlation between trichomoniasis and cervical cancer was ambiguous. This meta-analysis was carried out to determine the relevance between trichomoniasis and cervical cancer. Relevant data from 1985 to 2016 were identified through an extensive search of Medline, Cochrane database, Google Scholar, EMBASE, China National Knowledge Infrastructure. Finally 17 eligible articles covered 7715 individuals with cervical lesions and 67,598 controls were included. Meta-analysis of total eligible studies showed that odds ratio of retrospective studies was 2.06, with 95% confidence interval (95% CI) of 1.77 to 2.39, prospective studies with adjusted relative risk of 1.94 (95% CI = 1.19 to 3.15) and 2.84 (95% CI = 1.32 to 6.12) respectively, and the combined relative risk was 2.03 (95% CI = 1.35 to 3.06). Subgroup analysis indicated that there were significant regional and racial differences in the correlation between trichomoniasis and cervical cancer. Odds ratio of Africa and Europe are 2.43 (95% CI = 1.15 to 5.13) and 1.82 (95% CI = 1.67 to 2.62) respectively. Odds ratio of mixed population is 2.87 (95% CI = 2.00 to 4.12), followed by black and white, Asian with the lowest odds ratio of 1.91 (95% CI = 1.32 to 2.77). In conclusion, our data demonstrate that individuals infected with trichomonas vaginalis have a higher risk of cervical cancer, especially co-infected with Human Papilloma Virus. Besides, there is significant regional and racial variation in the correlation between trichomonas vaginalis infection and risk of cervical cancer. PMID- 29980112 TI - Risk factors analysis and a scoring system proposal for the prediction of retained placenta after vaginal delivery. AB - INTRODUCTION: Retained placenta (RP) is an obstetric complication of third stage of labour. We aimed to evaluate risk factors for RP and to propose a scoring system in order to predict this potentially fatal disorder. METHODS: This was a retrospective case-control study, comparing women with RP after vaginal delivery (>= 24 weeks of gestation) and women with regular placental separation. Data were collected from January 2007 to October 2017, in two 2nd level University Hospitals. Eligibility was limited to singleton pregnancies in vertex presentation with no major foetal anomaly. A nomogram was developed to predict RP risk. RESULTS: Among 22,749 women who delivered vaginally, 138 (0.6%) had RP. RP was directly related with previous uterine curettage (OR = 1.92, 95% CI 1.04 3.54, p = 0.04) and labour induction with prostaglandins (OR = 4.29, 95% CI 1.83 10.02, p = 0.001), while vaginal spontaneous delivery (OR = 0.03, 95% CI 0.01 0.15, p = 0.0001) and higher Apgar score at 1 min (OR = 0.5, 95% CI 0.33-0.76, p = 0.001) were inversely related to RP. Our predictive model showed an overall diagnostic accuracy of 0.803. DISCUSSION: RP is associated with several maternal, pregnancy, foetal and placental risk factors. The development of a new scoring system, with a high predictive power, able to identify the risk of RP, could be a useful tool for physicians in order to promptly face this life-threatening condition. PMID- 29980113 TI - Vanishing gastroschisis visualized by antenatal ultrasound: a case report and review of literature. AB - We report a case of vanishing gastroschisis visualized by antenatal ultrasound with a 7-year long term follow-up. Currently, the child is still dependent on daily parenteral nutrition with no signs of hepatotoxicity. To our knowledge, it's the fourth case with a long-term follow-up. Vanishing gastroschisis is a rare complication of gastroschisis. However, physicians should be aware of it because its prognosis is worse than classical gastroschisis. When a vanishing gastroschisis is visualized or suspected by antenatal ultrasound, prenatal counseling is required with explanations about the risk of short bowel syndrome, the need of parenteral nutrition and related complications (inflammatory colitis, sepsis, liver failure and organ transplant). Mortality rate was initially around 93%, and dropped to 27% after the years 2000 (versus 10% for classical gastroschisis). After birth, all children will require surgery, and sometimes autologous gastro-intestinal reconstruction. Most survivors (68%) could be taken off the TPN. Unfortunately, long-term outcomes for children with vanishing gastroschisis are still missing in current literature. PMID- 29980114 TI - Design, synthesis, docking study, alpha-glucosidase inhibition, and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes. AB - A novel series of acridine linked to thioacetamides 9a-o were synthesized and evaluated for their alpha-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent alpha-glucosidase inhibitory activity in the range of IC50 = 80.0 +/- 2.0-383.1 +/- 2.0 uM against yeast alpha glucosidase, when compared to the standard drug acarbose (IC50 = 750.0 +/- 1.5 uM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N (p-tolyl) acetamide 9b displayed the highest alpha-glucosidase inhibitory activity (IC50 = 80.0 +/- 2.0 MUM). The in vitro cytotoxic assay of compounds 9a o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a Ki of 85 MUM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with alpha-glucosidase were evaluated through the molecular docking studies. PMID- 29980115 TI - Structure-based design of free fatty acid receptor 1 agonists bearing non biphenyl scaffold. AB - The free fatty acid receptor 1 (FFA1) enhances the glucose-stimulated insulin secretion without the risk of hypoglycemia. However, most of FFA1 agonists have a common biphenyl moiety, leading to a relative deprivation in structure types. Herein, we describe the exploration of non-biphenyl scaffold based on the co crystal structure of FFA1 to increase additional interactions with the lateral residues, which led to the identification of lead compounds 3 and 9. In induced fit docking study, compound 3 forms an edge-on interaction with Trp150 by slightly rotating the indole ring of Trp150, and compound 9 has additional hydrogen bond and delta-pi interactions with Leu135, which demonstrated the feasibility of our design strategy. Moreover, lead compounds 3 and 9 revealed improved polar surface area compared to GW9508, and have considerable hypoglycemic effects in mice. This structure-based study might inspire us to design more promising FFA1 agonists by increasing additional interactions with the residues outside of binding pocket. PMID- 29980117 TI - How do older people achieve well-being? Validation of the Social Production Function Instrument for the level of well-being-short (SPF-ILs). AB - In a time of aging populations and an enormous increase in frailty within them, examination of these populations' ability to achieve well-being has become increasingly important. This study aims to validate a theory-driven instrument for the measurement of well-being in three community-dwelling older populations: (i) a general population, (ii) a frail population, and (iii) Turkish migrants. The short (15-item) version of the Social Production Function Instrument for the Level of Well-being (SPF-ILs) measures whether a person's needs for stimulation, comfort, behavioral confirmation, affection, and status are met. This instrument has been validated only in adult (aged 18-65 years) populations. Three datasets were used to validate the SPF-ILs in samples of the general older population (945 respondents aged >= 70 years), frail older people (414 respondents aged >= 70 years), and older Turkish migrants (680 respondents aged >= 65 years) residing in Rotterdam, the Netherlands. Psychometric results showed that the SPF-ILs is a valid and reliable instrument for the assessment of well-being and need-related goals to achieve well-being among (frail) native and migrant older populations. Worldwide, countries face the challenge of maintaining community-dwelling older people's well-being. This study clearly showed that older people differ in their realization of well-being which increased our understanding of the ability of community-dwelling older people in various populations to achieve well-being. PMID- 29980116 TI - Testing competing explanations for graphic warning label effects among adult smokers and non-smoking youth. AB - RATIONALE: The United States courts have blocked the implementation of graphic warning labels on cigarette packages (GWLs). This decision was based, in part, on the premise that GWLs are unnecessarily emotional and are meant to scare rather than inform consumers about smoking's health effects. However, research in judgment and decision-making suggests these relationships are more complex. OBJECTIVE: In this article, we draw on several theoretical frameworks that lead to competing hypotheses about the relationships between negative affect, health risk beliefs, and quit intentions (among adult smokers) or susceptibility to start smoking (among non-smoking youth). METHOD: We tested these competing mediation models using data from two experiments with two populations each-adult smokers (Ns = 313 and 238) and primarily non-smoking middle-school youth (Ns = 340 and 237). Using mobile recruitment methods, we focused specifically on individuals from socioeconomically disadvantaged communities in rural and urban areas of the Northeastern United States. RESULTS: The best fitting model across all four datasets was one in which label-induced negative affect (a) directly predicted intentions/susceptibility but also (b) indirectly predicted intentions/susceptibility via risk beliefs. Although mediation analyses did not demonstrate significant serial mediation effects of label exposure on intentions/susceptibility through negative affect then risk beliefs, there was some evidence that label exposure indirectly promoted adults' quit intentions through negative affect. Additionally, negative affect consistently mediated the indirect effect of label exposure on strengthened risk beliefs among adults and youth. CONCLUSIONS: These results speak to the importance of negative affect in directly motivating adult smokers' quit intentions but also serving an informational function, directing adult smokers and non-smoking youth to accept the health risks of smoking. PMID- 29980118 TI - Moral injury in relation to public debates: The role of societal misrecognition in moral conflict-colored trauma among soldiers. AB - The last decade has witnessed fast-growing scholarly interest in the concept of moral injury, which addresses the link between the ethics of military intervention and deployment-related suffering. However, current research on moral injury, predominantly psychological in nature, tends to approach the phenomenon as an internally contained disorder. Consequently, it medicalizes moral injury and de-contextualizes it from the people who send soldiers to conflict zones and 'welcome' them back. This article addresses the ways in which the experience of moral injury is embedded in and shaped by public debates on military intervention, drawing on relevant literature from the fields of psychology, philosophy, and social sciences, and on in-depth qualitative interviews collected in 2016 and 2017 with 80 Dutch veterans. The article examines the explicit public condemnation experienced by Dutch veterans deployed to Bosnia as peacekeepers, and the more subtle public misunderstanding experienced by Dutch veterans deployed to Afghanistan as combat soldiers. It demonstrates that public criticism and admiration may both be experienced as misrecognition, and, in turn, societal misrecognition may directly or indirectly contribute to moral injury. Moreover, not only soldiers and veterans may struggle with the moral significance of military intervention, but society as well. PMID- 29980119 TI - Beyond medical humanitarianism - Politics and humanitarianism in the figure of the Midani physician. AB - This article explores the complex position of local physicians at times of political unrest or conflict, conceptualizing local medical voluntarism as a form of collective action. It analyzes the evolving interpretation of medical neutrality among Egyptian physicians who provided medical assistance to injured protesters in the Egyptian uprising (2011-2013). In-depth interviews with 24 medical and non-medical volunteers on their perception of medical neutrality were matched with their mobilization and participation history, showing the extent towards which political considerations influenced their voluntary medical engagement. The results firstly show that revolutionary political considerations played a central role in the physicians' mobilization into medical networks active in the protests, as well as in their interpretation of their medical and non-medical activities. Secondly, I argue that the interpretation of medical neutrality among Egyptian physicians evolved significantly over time. A special type of medical volunteer took shape, the midani physician. This physician openly expresses his/her political convictions and adheres to (self-defined) humanitarian principles through a conscious reconciliation of the two. The article details the increasing difficulty of this task after the revolutionary movement splintered into competing factions and citizens ended up fighting each other instead of authoritarian rule. PMID- 29980120 TI - Spiritually integrated care for PTSD: A randomized controlled trial of "Building Spiritual Strength". AB - Previous literature documents important cross-sectional and longitudinal relationships between spiritual distress and posttraumatic stress disorder (PTSD) outcomes. This study tests the efficacy of a spiritually integrated intervention "Building Spiritual Strength" (BSS) that can be delivered by trained chaplains. The intervention addresses spiritual concerns expressed by trauma survivors, including concerns in relationship with a Higher Power, difficulty with forgiveness, and theodicy. In a randomized controlled trial with blinded assessment, veterans were randomized to engage in a BSS condition (n = 71) or Present Centered Group Therapy (PCGT; control) condition (n = 67) with assessments at baseline, posttreatment, and a two-month follow up. Both groups showed similar, statistically significant reductions in symptoms of PTSD as measured by the Clinician Administered PTSD Scale (CAPS). BSS was shown to be more effective than PCGT in treating distress in relationship with a Higher Power. This was the second clinical trial of BSS with promising results and highlights the need for further study in psychospiritual interventions. More research is warranted on BSS being offered by non-specialized chaplains and on the application of BSS in suicide prevention. PMID- 29980121 TI - Detecting implicit cues of aggressiveness in male faces in revictimized female PTSD patients and healthy controls. AB - Victimized women are thought to have impairments in identifying risk and to have dysfunctional reactions to threatening situations, which increase the risk for revictimization. To investigate possible deficits in revictimized women, we used a method examining women's perceptions of an implicit facial cue of aggressiveness - the facial Width-to-Height Ratio (fWHR). We tested whether revictimized women show impairments in detecting aggressiveness in male faces by neglecting cues of fWHR and choosing a smaller preferred distance to men. Fifty two revictimized PTSD patients and 52 healthy controls provided ratings of aggressiveness and attractiveness for 65 photographed men and chose their preferred distance towards 11 pictured men. Multiple regression analyses indicated that revictimized women do not show impairments in perceiving and reacting to cues of aggression accurately. Hierarchical linear models, however, indicated that revictimized women rated all men as less aggressive. Revictimized women with histories of intimate partner violence (IPV) rated men with larger fWHRs and higher values of actual aggression to be more attractive than did revictimized women without IPV histories. A reduced appraisal of threat signals as threatening and an attraction to wider-faced and more aggressive men might increase the risk for revictimization. PMID- 29980122 TI - Immigrants and mental disorders in the united states: New evidence on the healthy migrant hypothesis. AB - OBJECTIVES: Despite experiencing migration-related stress and social adversity, immigrants are less likely to experience an array of adverse behavioral and health outcomes. Guided by the healthy migrant hypothesis, which proposes that this paradox can be explained in part by selection effects, we examine the prevalence and comorbidity of mental disorders among immigrants to the United States (US). METHODS: Findings are based on the National Epidemiologic Survey on Alcohol and Related Conditions (2012-2013), a nationally representative survey of 36,309 adults in the US. RESULTS: Immigrants were significantly less likely than US-born individuals to meet criteria for a lifetime disorder (AOR = 0.63, 95% CI = 0.57-0.71) or to report parental history of psychiatric problems. Compared to US-born individuals, the prevalence of mental disorders was not significantly different among individuals who immigrated as children; however, differences were observed for immigrants who arrived as adolescents (ages 12-17) or as adults (age 18+). DISCUSSION: Consistent with the healthy migrant hypothesis, immigrants are less likely to come from families with psychiatric problems, and those who migrate after childhood-when selection effects are most likely to be observed have the lowest levels of psychiatric morbidity. PMID- 29980123 TI - Women with Anorexia Nervosa do not show altered tactile localization compared to healthy controls. AB - Body image disturbance is a key symptom of Anorexia Nervosa (AN). Previous studies found that women with AN overestimate their body size in comparison with healthy controls (HC), at least for unimodal measures involving either only visual input (e.g. distorted photographs technique) or only tactile input (e.g. tactile distance tasks). Distorted body representations are hypothesized to cause this misperception in AN. We here tested whether this overestimation remains present in a novel one-point-localization (OPL) task involving the mapping of a tactile stimulus onto a visual image. Two experiments compared the ability of 27 women with AN and 40 HC to accurately localize a tactile stimulus on a live image of their body. Women with AN and HC did not differ in their performance. Instead, participants in both groups showed systematic distortions in their localization performance. This study suggests that the mapping of a tactile stimulus does not involve a distorted body representation in women with AN compared to HC. PMID- 29980124 TI - Association of suicidal ideation with trajectories of deployment-related PTSD symptoms. AB - This study examined the association between suicidal ideation and posttraumatic stress disorder (PTSD) symptom trajectories in a nationally representative sample of United States Reserve Component soldiers. PTSD symptoms related to a traumatic event during the most recent deployment were assessed in four annual waves in 2010-2013 among 682 Reserve Component soldiers. Latent Growth Mixture Modeling (LGMM) was used to examine the longitudinal trajectories of PTSD symptoms. The association between the PTSD trajectories and suicidal ideation at waves 2 to 4 was examined in logistic regression analyses. Four trajectories were identified: resilience (73.0%), recovery (11.7%), late onset (11.6%) and chronic (3.6%). Pairwise comparisons demonstrated significant differences between trajectories in risk of suicidal ideation. Among the chronic trajectory group, 50.9% reported suicidal ideation (25.8% late onset group; 11.3% recovery group; 4.0% resilience group). After controlling for baseline characteristics, the late onset and chronic trajectory groups were more likely to have suicidal ideation than the resilience and recovery trajectories, respectively. Findings suggest the late onset and chronic trajectories of PTSD symptoms are associated with higher risk of suicidal ideation. They support the importance of follow-up assessment of suicide risk even among individuals with low PTSD symptoms at homecoming. PMID- 29980125 TI - Distance to threat and risk of acute and posttraumatic stress disorder following bank robbery: A longitudinal study. AB - Identifying pathways through which environmental risk factors influence PTSD is important for understanding PTSD etiology. Here, we hypothesized that the physical proximity to threat influences PTSD risk by increasing ASD following trauma. One hundred six bank employees who had experienced a bank robbery participated in the study. A longitudinal design assessing ASD at day 2 and PTSD at day 30 was used to test the hypothesis. Participants also indicated their location in the bank at the time of the robbery. ASD was identified in 40 (38%) and PTSD in 16 (15%) of the robbery victims. Distance to the robber had a strong effect on ASD (OR 3.51, 95% CI 1.94-6.34) and a somewhat lesser effect on PTSD (OR 2.15, 95% CI 1.04-4.46), indicating that the effect of proximity to threat on PTSD 1 month following trauma could be mediated by its effect on ASD 2 days following trauma. Using structural equation modeling, we confirmed that the effect of distance on PTSD was fully mediated by ASD. These findings suggest that proximity to threat may increase PTSD risk by enhancing the acute stress response following trauma. PMID- 29980126 TI - Identity processes and clusters in individuals with and without pathological buying. AB - The present study investigated the association between pathological buying (PB) and identity processes and clusters. Forty-one patients with PB and 41 gender/age matched controls (73% females) filled out the Dimensions of Identity Development Scale (DIDS), the Pathological Buying Screener, and self-report questionnaires to assess comorbid psychopathology, such as depressive symptoms, pathological internet shopping, and hoarding (excluding acquisition). Patients with PB reported significantly higher scores on ruminative exploration and lower scores on identity commitment processes compared to healthy controls. In the total sample, as well as in the PB sample, we identified four identity clusters: troubled diffusion, moratorium, foreclosure, and achievement, similar to Marcia's identity statuses. Patients with PB were overrepresented in the troubled diffusion cluster and less represented in the foreclosure and achievement clusters. Patients with PB in the troubled diffusion cluster scored significantly higher on PB, pathological internet shopping, hoarding, and depressive symptoms as compared to patients with PB in the other clusters. Based on these findings, we can conclude that patients with identity diffusion report more severe PB and related comorbid symptomatology. PB and related symptoms may be considered as coping strategies to deal with identity-related issues. PMID- 29980127 TI - Food addiction, in obese patients seeking bariatric surgery, is associated with higher prevalence of current mood and anxiety disorders and past mood disorders. AB - The current cross-sectional study investigates the prevalence of the food addiction (FA) phenotype and its association with psychiatric disorders in bariatric surgery candidates. It also investigates the eating behavior characteristics associated with FA and the association between FA and loss of control over specific foods high in sugar, salt and/or fat. We included 128 bariatric surgery candidates and we assessed FA (YFAS 2.0), mood and anxiety disorders, suicidality, eating disorders (current bulimia nervosa and current anorexia nervosa), alcohol and tobacco use disorders (MINI 5.0.0, beck depression inventory, AUDIT, Fagerstrom Test for Nicotine Dependence) and eating behavior (DEBQ). Prevalence of FA in our sample was 25%. FA was significantly associated with higher prevalence of current mood and anxiety disorders and past mood disorders, higher current suicidality but not with eating disorders and alcohol use disorder. FA was significantly associated with higher emotional eating, and with loss of control over consumption of foods high in fat, sugar and/or salt, but not of fruits, vegetables or grain products. Our results provide arguments for considering psychiatric disorders and suicidality in FA and for considering FA as an addictive disorder in obese patients, with many risk factors in common with other addictions. PMID- 29980128 TI - Patterns of symptom change in major depression: Classification and clustering of long term courses. AB - To evaluate treatment effects in depression, it is important to monitor change during treatment and also to follow up for a reasonably long time. Describing the variability of symptom change trajectories is useful to better predict long-term status and to improve interventions. Outcome data (N_complete = 518, 4 time points, 1 year of observation time) from a large naturalistic multi-center study on the effects of inpatient and day hospital treatment of unipolar depression were used to identify clusters of symptom trajectories. Common outcome classifications and statistical methods of longitudinal cluster analysis were applied. However, common outcome classifications (in terms of e.g. remission, relapse or recurrence) were not exhaustive, as 49.3% of the trajectories could not be allocated to its classes. Longitudinal cluster analysis reveals 7 clusters (fast response, slow response, retarded response, temporary or persistent relapse, recurrence, and nonresponse). Nonresponse at the end of treatment was a predictor of poor outcome at long term follow up. The classification of patterns of symptom change in depression should be extended. Longitudinal cluster analysis seems a valid option to analyze outcome trajectories over time if a limited number of time points of measurement are available. PMID- 29980129 TI - Emotional labor and depressive mood in service and sales workers: Interactions with gender and job autonomy. AB - Emotional labor is strongly correlated with negative consequences in psychological well-being and mental health status in workers. We investigated the associations of emotional labor with depressive mood and perceived usual stress level according to gender and its interactions with job autonomy in service and sales workers. The data from 2,055 service and sales workers from the Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2007 to 2009 were analyzed. High emotional labor was associated with increased risk for depressive mood in female workers (adjusted odds ratio [aOR] = 2.19, 95%, confidence interval [CI] = 1.56-3.07). Emotional labor and job autonomy showed interactive effects on depressive mood in that high emotional labor was associated with depressive mood only in the presence of low job autonomy in male workers (aOR = 2.85, 95% CI = 1.13-7.17). A significant mediation pathway between high emotional demand and prevalence of depressive mood through higher stress level was observed in female workers. In conclusion, female workers had high vulnerability to depressive symptoms due to emotional labor, and high job autonomy can act as a buffer against the detrimental effect of emotional labor in male workers. PMID- 29980130 TI - Sex-related variation of neurocognitive functioning in bipolar disorder: Focus on visual memory and associative learning. AB - Bipolar disorder (BD) is associated with cognitive deficits in attention, verbal memory and executive functions. However, only few studies have examined sex effects on cognition despite their clinical relevance. Given that visual memory/ learning has been understudied the aim of our study was to investigate sex related variation in cognition (executive functions and visual memory/ learning) in BD. Cognitive performance of 60 bipolar-I patients and 30 healthy controls was evaluated by using CANTAB battery tasks targeting spatial memory (SRM), paired associative learning (PAL) and executive functions. We fitted a multivariate analysis of covariance (MANCOVA), followed by task-specific ANCOVAs. A significant diagnosis by sex interaction effect was detected (MANCOVA); specifically, diagnosis-specific sex effects were found for SRM and PAL, as healthy males outperformed healthy females but this pattern was attenuated in BD patients. Patients' clinicodemographic characteristics, current psychopathology or medication status did not differ across sexes and were, therefore, unlikely to explain detected sex effects. Our study is one of few studies to assess sex related variation in cognition in BD and the first to record a diagnosis-specific sex effect for two tasks of visuo-spatial memory/ learning, indicating that sex related variation in healthy subjects is disrupted in BD. PMID- 29980131 TI - Copper in depressive disorder: A systematic review and meta-analysis of observational studies. AB - Copper (Cu) has been associated with mental disorders such as autism and epilepsy. So far, publications evaluating copper levels in patients with depressive disorder showed conflicted results. To derive a comprehensive estimation of the relationship between body burden of copper and depressive disorder and explore the possible role of copper in mental health, we performed a systematic review and meta-analysis. Relevant published data were obtained by searching PubMed, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Chinese Biomedical Database (CBM) before October 10, 2017. Weighted mean difference (WMD) with a 95% confidence interval (95%CI) was calculated using STATA 12.0. A total of 21 studies with 1487 patients and 943 controls were collected in this meta-analysis. Pooled analysis found that patients with depression had higher blood levels of copper than the controls without depression, while there was no difference of copper content in hair between the two groups. Subgroup analysis suggested that age had influence on the relationship between copper and depression. No evidence of publication bias was observed. This meta-analysis suggests that increased levels of blood copper might be associated with depressive disorder and therefore the possible role of copper as a biomarker of depression. PMID- 29980132 TI - Exploration of illness perception among patients with mental illness in a multi ethnic Asian sample. AB - Illness perceptions are beliefs that patients have about their illness. These beliefs play an important role in influencing their behaviour and outcomes. This study examined the factor structure and correlates of the Illness Perception Questionnaire Mental Health (IPQ-MH) among patients with mental illness in a multi-ethnic Asian sample. 400 participants with schizophrenia and other psychotic disorders, mood or anxiety disorder were recruited from a tertiary psychiatric institution and administered the IPQ-MH. Data on sociodemographic variables were also collected. A multi-factor structure was identified for the Identity, Structure and Cause subscale of the IPQ-MH. Age was consistently associated with a positive perception of illness across all three disorders; women had a more positive perception of schizophrenia and other psychotic disorders as compared to men while those of Indian ethnicity had a more negative perception of their mood disorder as compared to those of Chinese ethnicity. Those with lower education had a poorer understanding of their illness among those with mood disorder, and a poorer understanding of their illness and the effectiveness of treatment among those with anxiety disorder. The study identified specific groups which can be targeted through tailored and culturally relevant psychoeducational interventions to enhance their understanding and perception of mental illness. PMID- 29980133 TI - Metacognition in schizophrenia disorders: Comparisons with community controls and bipolar disorder: Replication with a Spanish language Chilean sample. AB - Metacognition refers to the activities which allow for the availability of a sense of oneself and others in the moment. Research mostly in North America with English-speaking samples has suggested that metacognitive deficits are present in schizophrenia and are closely tied to negative symptoms. Thus, replication is needed in other cultures and groups. The present study accordingly sought to replicate these findings in a Spanish speaking sample from Chile. Metacognition and symptoms were assessed among 26 patients with schizophrenia, 26 with bipolar disorder and 36 community members without serious mental illness. ANCOVA controlling for age and education revealed that the schizophrenia group had greater levels of metacognitive deficits than the bipolar disorder and community control groups. Differences in metacognition between the clinical groups persisted after controlling for symptom levels. Spearman correlations revealed a unique pattern of associations of metacognition with negative and cognitive symptoms. Results largely support previous findings and provide added evidence of the metacognitive deficits present in schizophrenia and the link to outcome cross culturally. Implications for developing metacognitively oriented interventions are discussed. PMID- 29980134 TI - Anger as an underlying dimension of posttraumatic stress disorder. AB - In this study, we examined the underlying role of anger in posttraumatic stress disorder (PTSD). Although anger is currently considered within two symptoms of PTSD (i.e., anger/irritability; and negative emotional state), some research has found that anger is more than just a diagnostic symptom of PTSD. The sample consisted of 375 trauma-exposed individuals that completed the PTSD Checklist-5 and Dimensions of Anger Reactions Scale. Confirmatory factor analysis was used to assess PTSD's factor structure based on the four-factor DSM-5 PTSD model. Subsequently, the model was re-tested, statistically controlling for anger by regressing PTSD's items on an observed anger score. Individual factor loading differences were then compared to determine anger's underlying role. Results indicated that a significant amount of variance in PTSD, at both the item level and factor level, was attributable to an underlying dimension of anger. The largest factor attenuation was for the symptom of irritability/anger and the smallest attenuation was recklessness. The results suggest that anger underlies more of PTSD than the two diagnostic symptom criteria. PMID- 29980135 TI - Assessment of health needs, satisfaction with care, and quality of life in compulsorily admitted patients with severe mental disorders. AB - This cross-sectional study compared the levels of needs, care satisfaction, quality of life, and social support of compulsory admitted patients with severe mental disorders to a comparable group of voluntary admitted patients. One hundred and twenty-five patients with schizophrenia and schizoaffective disorder were admitted to a hospital by district psychiatrist order (DPO), court observation order (COO), or voluntary (VA). Participants were assessed before discharge using questionnaires, and psychiatric rating scales. A linear discriminant analysis revealed eight variables that best differentiated the three groups. COO patients were significantly discriminated from the two other groups (DPO and VA) by severe negative symptoms, better satisfaction with both nursing staff and family support. COO subjects had more non-illness unmet needs, while reported better hedonic capacity for social and interpersonal pleasure - compared to VA patients. DPO patients were significantly indicated by poorer awareness to illness, but better satisfaction with subjective feelings. VA subjects were significantly discriminated from compulsory admitted patients by higher illness severity scores. Assessment of unmet needs, satisfaction with care, quality of life, hedonic capacity, and social support constitute the factors that differentiate compulsory admitted patients and could be targets for interventions aimed to reduce the negative effects of compulsory admissions. PMID- 29980137 TI - Identification of candidate chemosensory receptors in the antennal transcriptome of the large black chafer Holotrichia parallela Motschulsky (Coleoptera: Scarabaeidae). AB - Olfaction and gustation play critical roles in the daily activities of insects by mediating important behaviors, such as locating host plants, mates and oviposition sites. These behaviors are mediated by a series of chemosensory receptor proteins, including odorant receptors (ORs), gustatory receptors (GRs) and ionotropic receptors (IRs). Holotrichia parallela is a worldwide pest on many crops and particularly on peanuts in China. In the present study, we produced Illumina-based transcriptomes from male and female antennae and ultimately identified 47 candidate ORs, 15 GRs and 27 IRs. Based on phylogenetic analyses, the relatedness with other species and possible functions of chemosensory genes were predicted and analyzed, such as the putative OR co-receptor (HparOR40), IR co-receptors (HparIR1 and HparIR27), carbon dioxide receptors (HparGR5 and HparGR14) and sugar receptors (HparGR8, HparGR11 and HparGR13). The differences in expression between genes and between sexes were analyzed using FPKM values and visualized in heat maps. Furthermore, the qRT-PCR results of 26 candidate genes were assessed to validate the differential expression analyses between sexes and between olfactory and non-olfactory tissues. Thirteen genes were more highly expressed in female than in male antennae, whereas four genes had higher expression in male than in female antennae. Twelve genes were predominantly expressed in the antennae as olfactory organs compared with expression in non olfactory tissues. Our study was the first to annotate the chemosensory receptors of H. parallela, and it will provide a strong foundation for future work on physiology and ecology at the molecular level. PMID- 29980136 TI - Objective investigation of activity preference in schizophrenia: A pilot study. AB - Amotivation and reduced goal-directed activity engagement are prominent features of schizophrenia. Previous investigations of patients' activities have relied on accounts of daily living activities, rather than objective measures. This study used wireless motion capture to objectively evaluate activity preference when individuals are provided an explicit choice between an active versus passive engagement option. Twenty outpatients with schizophrenia and twenty matched healthy controls completed the Activity Preference Task, in which participants play a motion-based game (active) or watch a film (passive), and were administered clinical and cognitive assessments. Schizophrenia participants' duration, intensity, and persistence of active engagement were associated with apathy and community functioning. No group differences emerged from comparisons of task measures; however, exploratory cluster analysis identified a distinct subgroup of schizophrenia patients with reduced engagement and increased apathy compared to other patients and controls. The Task provides a means of quantifying activity engagement, which may be particularly valuable given the lack of objective measures for intrinsically motivated behaviours. Our initial findings suggest that schizophrenia patients as a group are equally inclined as healthy individuals towards actively engaging activities when presented an explicit choice, but such provision may be insufficient for initiation and maintenance of functional behaviours among amotivated patients. PMID- 29980138 TI - Peptidomic analysis of the host-defense peptides in skin secretions of the Trinidadian leaf frog Phyllomedusa trinitatis (Phyllomedusidae). AB - Peptidomic analysis (reversed-phase HPLC combined with MALDI-TOF mass spectrometry and automated Edman degradation) of norepinephrine-stimulated skin secretions from the Trinidadian leaf frog Phyllomedusa trinitatis Mertens 1926 led to the identification and structural characterization of 26 host-defense peptides. On the basis of amino acid sequence similarity, the peptides may be divided into the followings groups: dermaseptins with the conserved N-terminal region GLWSKIK (6 peptides), dermaseptins with the N-terminal region ALWKXXLK (5 peptides), dermaseptins with the conserved N-terminal region GLFKTLIKGAGKMLGHVAK (4 peptides), C-terminally alpha-amidated and non-amidated forms of the phylloseptins (9 peptides), phyllocaerulein, a peptide (GLVSGLLNSVTGLLGNLAGGGL) with structural similarity to the plasticins, and a putative antioxidant peptide (LTWKIPTRFCGVT). The primary structures of the peptides support the claim based upon morphological criteria that P. trinitatis and Phyllomedusa tarsius are very closely related phylogenetically but are probably not conspecific. Among the phylloseptins, phylloseptin-1.1TR (FLSLIPKIAGGIASLVKNL.NH2) displayed the most potent antimicrobial activity. PMID- 29980139 TI - The association between pain beliefs and pain intensity and/or disability in people with shoulder pain: A systematic review. AB - BACKGROUND: Pain beliefs might play a role in the development, transition, and perpetuation of shoulder pain. OBJECTIVE: To systematically review and critically appraise the association and the predictive value of pain beliefs on pain intensity and/or disability in shoulder pain. METHODS: An electronic search of PubMed, EBSCOhost, AMED, CINAHL, EMBASE, and PubPsych, and grey literature was searched from inception to July 2017. Study selection was based on observational studies exploring the association and the predictive value of pain beliefs on pain intensity and/or disability in shoulder pain. RESULTS: A total of thirty three articles were included with a total sample of 10,293 participants with shoulder pain. In the cross-sectional analysis, higher levels of pain catastrophizing and kinesiophobia were significantly associated with more pain intensity and disability, whereas higher levels of expectations of recovery and self-efficacy were significantly associated with lower levels of pain intensity and disability. In the longitudinal analysis, higher levels of pain catastrophizing, fear-avoidance and kinesiophobia at baseline predicted greater pain intensity and disability overtime. Higher levels of self-efficacy and expectations of recovery at baseline predicted a reduction in levels of pain intensity and disability overtime. CONCLUSIONS: Evidence suggests that pain beliefs are associated with and predict the course of pain intensity and disability in shoulder pain. However, the overall body of the evidence after applying the GRADE approach was very low across studies. Further research using higher quality longitudinal designs and procedures would be needed to establish firm conclusions. PMID- 29980140 TI - Non-ischemic heart preconditioning. AB - Ischemic heart conditioning has been shown to protect the organ against ischemia/reperfusion injury. Animal studies have revealed that the heart can also be conditioned by non-ischemic procedures, namely physical exercise and tachycardia. Long and short term endurance training, sprint training, resistance or interval training and even one bout of exercise induce cardiac preconditioning, which is manifested by a reduction in post ischemia/reperfusion infarct size, ventricular arrhythmia and improved heart function. Several factors contribute to the exercise-induced heart preconditioning, among which the most important can be: increased activity of the anti-radical defense system, opioids, interleukin-6, nitric oxide, ATP dependent potassium channels, heat shock protein 72 and sphingosine-1-phosphate. A few studies have also shown that one bout of exercise in patients with stable angina increases tolerated workload. According to some data obtained in swine and dogs, stimulated tachycardia before ischemia/reperfusion reduces the infarct size. Future studies are needed to fully clarify the mechanisms responsible for exercise- or tachycardia-induced heart preconditioning against ischemia/reperfusion. It may lead to the development of new treatment modes of the disease. PMID- 29980141 TI - Wnt signaling pathway in development and cancer. AB - Wnt signaling pathway is one of the most important signaling pathways. The complexity of Wnt signals and their functional role is crucial in development and growth. It is the most active during embryogenesis facilitating new organism formation by cell differentiation, polarization and migration. Its activation is also common during development of many tumors and others diseases. In this review we shortly describe a role of Wnt pathway in development in order to better understand its role in cancer progression. We also describe current anti-cancer therapies targeting Wnt pathway. PMID- 29980142 TI - Evaluation of glucose metabolism in children with growth hormone deficiency during long-term growth hormone treatment. AB - Growth hormone (GH) affects carbohydrate metabolism through direct negative effect on insulin sensitivity and indirectly, via insulin-like growth factor-1 (IGF-1), which exerts positive insulin-mimetic action. The aim of this retrospective study was to evaluate the influence of long-term GH treatment on glucose homeostasis in 118 children with isolated idiopathic GH deficiency (GHD). Based on this analysis we wanted to determine the usefulness of glycated haemoglobin (HbA1c) and parameters derived from the oral glucose tolerance test (OGTT) in the monitoring of disturbed glucose metabolism during GH treatment and to assess the value of IGF-1 in prediction of those changes. Mean duration of GH treatment was 2.5 +/- 1.2 years. Data were analysed in the whole group and according to baseline pubertal status. Significant increases in insulin concentrations, both fasting and during the OGTT, accompanied by a significant increase in fasting glucose and unchanged glucose concentrations during the OGTT, were found after the initiation of GH treatment. HbA1c did not change significantly during GH treatment in comparison to baseline values and remained normal, even in patients with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) found during GH treatment. Changes in glucose metabolism observed after the onset of GH treatment were related to increment in IGF-1 SDS and to GH doses. Significant associations between changes in IGF-1 SDS in the first year of GH treatment and some of the glucose metabolism parameters evaluated after the first, the second and the third year of GH treatment were also confirmed in multiple regression analysis after taking the GH dose into consideration. All cases of IFG and/or IGT detected during GH treatment are reversible after dietary intervention, independently of pubertal status, and do not lead to diabetes mellitus. PMID- 29980143 TI - The peroxisome proliferator-activated receptor gamma agonist pioglitazone improves nitric oxide availability, renin-angiotensin system and aberrant redox regulation in the kidney of pre-hypertensive rats. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand dependent nuclear receptor. It plays an important role in kidney physiology, where it might contribute to arterial blood pressure regulation and hypertension development by modulation of several signaling pathways. In our study we focused on the effect of PPARgamma agonist pioglitazone on changes in the nitric oxide synthase (NOS) expression and activity, the renin-angiotensin system (RAS) cascade, and redox homeostasis signaling pathways in the renal cortex of young pre hypertensive rat models. Young (5-weeks old) spontaneously hypertensive (SHR) and borderline hypertensive (BHR) rats were treated by pioglitazone (PIO, 10 mg/kg/day) during 10 days. Blood pressure (BP) was determined by plethysmography method. Changes in lipid profile were detected in plasma with standard kits using biochemical analyser. Gene expression has been detected by qRT-PCR and protein level was determined using Western blot analysis. Superoxide dismutase (SOD) and catalase (CAT) activities were determined spectrophotometrically and the total enzyme activity of NOS was measured using a radioactive assay based on conversion of [3H] L-arginine to [3H] L- citrulline. Administration of pioglitazone decreased BP in BHR and slowed down the development of BP increase in young SHR animals. For NOS, activation by PPARgamma correlated with increase in gene and protein expression of NOS isoforms and in total enzyme activity both in BHR and SHR. In the AT1R/Nox pathway, the treatment did not significantly influence mRNA expression of the p22phox subunit of NADPH oxidase (Nox) and AT1R, but up regulated the 'pro-vasodilatatory' Mas and AT2R receptors in both BHR and SHR groups. Pioglitazone treatment affected redox regulation. Increase in gene expression of nuclear factor E2-related factor 2 (Nrf2) and SOD isoforms correlated with SOD and CAT enzyme activities. The group treatment-to-control ratios, BHR Pioglitazone to BHR control and SHR Pioglitazone to SHR control for gene expression increased by 10% to 230%. The largest effect of PPARgamma has been observed in SOD1, SOD3 and the Mas receptor gene treatment-to-control ratios. The most prominent differences between BHR and SHR were observed in SOD1 and Mas receptor expressions, with large effects of opposite sign in BHR versus SHR. Our data indicate that an increase of NO release activates signaling in the renal cortex of pre-hypertensive rats after pioglitazone treatment. Improvement of NO availability, AT2R, Mas receptors and aberrant redox regulation is thought to be the major correlated mechanisms mediating the BP decrease affected by the PPARgamma agonist treatment. We also observed that the most sensitive tissue responses to PPARgamma-dependent activation of Nrf2 have been primarily found in the kidney of young hypertensive animals. PMID- 29980144 TI - Beneficial effect of combined spironolactone and quinapril treatment on thrombosis and hemostasis in 2K1C hypertensive rats. AB - A strong correlation between raised aldosterone levels and increased risk of thrombotic disorders has been provided. Clinical studies have demonstrated the benefits of the addition of the aldosterone receptor antagonist to the standard therapy with angiotensin-converting enzyme inhibitor in the reduction of cardiovascular events in patients. We suggest that the benefits of this dual renin-angiotensin-aldosterone system (RAAS) blockade may be related to the drug's effects on the hemostatic and oxidative balance. Thus, we investigated the effect of combined spironolactone (SPIRO) and quinapril (QUIN) administration on thrombosis, hemostasis and oxidative stress in hypertensive rats. A two-kidney, one-clip model of renovascular hypertension in Wistar rats was used. QUIN, SPIRO, or QUIN + SPIRO were administered for 10 days. Venous thrombosis was induced by vena cava ligation. Thrombus weight and incidences of thrombosis were assessed. Bleeding time, platelet adhesion, tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thrombin activatable fibrynolysis inhibitor (TAFI), malonyl dialdehyde, and hydrogen peroxide plasma levels were assayed. Aortic expression of NADPH oxidase and superoxidase dismutase were measured. We observed significant RAAS activation associated with hypercoagulability and oxidative stress augmentation in renovascular hypertensive rats. Thrombosis was reduced only in rats treated with QUIN + SPIRO. In all groups, decreases in TF, PAI-1, and TAFI levels were observed, however in the QUIN + SPIRO group those changes were more pronounced. The inhibition of platelet adhesion was also stronger in rats treated with QUIN + SPIRO. The oxidative stress parameters were markedly reduced in rats treated with QUIN or SPIRO, although the most evident changes were observed in the QUIN + SPIRO group. Dual RAAS blockade with aldosterone receptor antagonist and angiotensin-converting enzyme inhibitor provides additional benefits for experimental thrombosis associated with the antiplatelet, anticoagulative, profibrinolytic, and antioxidative effects in renovascular hypertensive rats. PMID- 29980145 TI - Identification of potential small-molecule protein-protein inhibitors of cancer metastasis by 3D epitope-based computational screening. AB - In cancer cells exposed to extracellular pressure or shear stress, AKT1-FAK interaction drives focal adhesion kinase (FAK) phosphorylation, leading to force activated cancer cell adhesion and metastasis. Blocking the AKT1-FAK interaction is therefore an attractive target for cancer therapy, avoiding the side effects of global FAK inhibition. Starting with our previous identification of a short FAK peptide that binds AKT1, we identified a series of small-molecule inhibitor candidates using a novel approach for inhibiting protein-protein interactions. Using a 3D structural fragment of the FAK peptide as the query, millions of drug like, commercially available molecules were screened to identify a subset mimicking the volume and chemistry of the FAK fragment to test for their ability to block pressure-sensitive FAK phosphorylation by AKT1. Two compounds reduced the stimulation of FAK phosphorylation in response to extracellular pressure in human SW620 colon cancer cells without affecting basal FAK phosphorylation. Thus, using a 3D protein interaction epitope as a novel query for ligand-based virtual screening can successfully identify small-molecules that show promise in modulating cancer cell adhesion and metastasis. PMID- 29980146 TI - Individual objective versus subjective fixation disparity as a function of forced vergence. AB - Inaccuracy in the vergence eye position ("fixation disparity") can occur despite a fusion stimulus. When measured with eye trackers, this inaccuracy is referred to as "objective fixation disparity". It is a matter of debate whether objective fixation disparity can be estimated with a technically simple psycho-physical procedure, i.e. the perceived offset of aligned dichoptic nonius targets, referred to as "subjective fixation disparity". To investigate the relation between these two measures, simultaneous tests were made in far vision when placing prisms in front of the eyes (for a few seconds) in order to induce forced vergence, i.e. to vary the absolute disparity (from 1 deg divergent to 3.4 deg convergent). Frequent repeated measurements in 12 observers allowed for individual analyses. Generally, fixation disparity values and the effects of prisms were much smaller in the subjective than in the objective measures. Some observers differed systematically in the characteristics of the two types of prism-induced curves. Individual regressions showed that the subjective vs. objective slope was 8% on the average (with largest individual values of 18%). This suggests that sensory fusion shifts the visual direction of the (peripheral) binocular targets by the full amount of objective fixation disparity (since single vision was achieved); however, for the (central) monocular nonius lines this shift was more or less incomplete so that the dichoptic nonius targets indicated an individual percentage of objective fixation disparity. The subjective-to-objective ratio seems to be an individual characteristic of fixation disparity in terms of the amount and in terms of the effect of prism induced forced vergence. Therefore, on the group level the subjective measures do not allow for a precise prediction of the objective measures. PMID- 29980147 TI - Evaluating the effectiveness of sexual and reproductive health services during humanitarian crises: A systematic review. AB - BACKGROUND: An estimated 32 million women and girls of reproductive age living in emergency situations, all of whom require sexual and reproductive health (SRH) information and services. This systematic review assessed the effect of SRH interventions, including the Minimum Initial Service Package (MISP) on a range of health outcomes from the onset of emergencies. METHODS AND FINDINGS: We searched EMBASE, Global Health, MEDLINE and PsychINFO databases from January 1, 1980 to April 10, 2017. This review was registered with the PROSPERO database with identifier number CRD42017082102. We found 29 studies meet the inclusion criteria. We found high quality evidence to support the effectiveness of specific SRH interventions, such as home visits and peer-led educational and counselling, training of lower-level health care providers, community health workers (CHWs) to promote SRH services, a three-tiered network of health workers providing reproductive and maternal health services, integration of HIV and SRH services, and men's discussion groups for reducing intimate partner violence. We found moderate quality evidence to support transport-based referral systems, community based SRH education, CHW delivery of injectable contraceptives, wider literacy programmes, and birth preparedness interventions. No studies reported interventions related to fistulae, and only one study focused on abortion services. CONCLUSIONS: Despite increased attention to SRH in humanitarian crises, the sector has made little progress in advancing the evidence base for the effectiveness of SRH interventions, including the MISP, in crisis settings. A greater quantity and quality of more timely research is needed to ascertain the effectiveness of delivering SRH interventions in a variety of humanitarian crises. PMID- 29980148 TI - Secondary Bone Defect in Neuromuscular Diseases in Childhood: A Longitudinal "Muscle-Bone Unit" Analysis. AB - To evaluate the potential bone defect in neuromuscular diseases, we conducted a longitudinal study including three groups of patients: 14 Duchenne muscular dystrophies (DMD) and 2 limb-girdle muscular dystrophies (LGMD); 3 Becker muscular dystrophies (BeMD) and 7 spinal muscular atrophies (SMA). Yearly osteodensitometries assessed body composition and bone mineral density (BMD) associated with bone markers and leptin. Along the 7-year study, 107 osteodensitometries showed that bone status evolved to osteopenia in most patients except BeMD. When analyzing the crude values, BMD improved with age in BeMD and SMA but not in DMD/LGMD. The correlation using the Z-scores displayed a decrease in BMD with age in DMD/LGMD for all regions, in SMA at total body less head, whereas BMD increased in BeMD at lumbar spine. As observed in healthy persons, muscular mass and bone tissue were significantly correlated. Glucocorticoids were deleterious on trabecular and cortical bone. Leptin was high in most patients and correlated to fat mass and bone parameters. This study confirms a secondary bone defect in neuromuscular diseases, further confirming the functional relationship between bone and muscle and arguing for regular bone follow-up in patients to prevent fracture risk. Adipose tissue seems to interfere with bone remodeling in neuromuscular diseases. PMID- 29980150 TI - ? PMID- 29980149 TI - Febrile Infection-Related Epilepsy Syndrome (FIRES) with Multifocal Subcortical Infarcts, A New Imaging Phenotype. AB - Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy of unknown etiology which occurs predominantly in school-aged children, following a febrile illness. The term FIRES was first proposed in 2010 by van Baalen et al. The etiology of FIRES remains elusive, although most believed that it is likely related to inappropriate activation of the innate immune system. It is often a diagnosis of exclusion as it lacks specific clinical criteria and/or confirmatory tests. Familiarity with the range of imaging phenotypes associated with FIRES is crucial as this will assist timely recognition and institution of appropriate treatment plan. With this in mind, the author would like to present a rare case of FIRES with extensive subcortical infarcts, predominantly in the temporo-occipital lobes. This has never been reported before and may represent a new imaging phenotype of FIRES. A detailed literature review, focusing on the various pattern of imaging phenotypes, in relation to patients' age and clinical outcome, will also be included. PMID- 29980151 TI - A novel endoscopic ultrasound-guided through-the-needle microbiopsy procedure improves diagnosis of pancreatic cystic lesions. AB - BACKGROUND: Pancreatic cystic lesions represent a diagnostic dilemma as some may harbor malignancy or have potential for malignant transformation. The aim of this study was to present our experience with a novel endoscopic ultrasound (EUS) guided microbiopsy procedure enabling procurement of tissue from the wall of the cystic lesion. METHODS: We collected data from 31 consecutive patients with pancreatic cystic lesions who underwent an EUS-guided microbiopsy procedure at our institution. Records were retrospectively reviewed from a prospectively maintained database. RESULTS: The technical success was 87.1 %. Diagnostic yield of microbiopsies was 71.0 %. Microbiopsies offered sufficient tissue for morphological and immunohistochemical characterization of the lesions, as well as determination of grade of dysplasia. Furthermore, evaluation of microbiopsies changed the clinical management in six patients (19.4 %). Three nonsevere adverse events were observed (9.7 %): two cases of mild infection and one case of mild pancreatitis. All three patients recovered completely. CONCLUSIONS: EUS-guided microbiopsy procedure was technically feasible, with a high diagnostic yield. Further prospective studies are needed to confirm these promising results. PMID- 29980152 TI - Can Preoperative Magnetic Resonance Imaging Predict Intraoperative Autograft Size for Anterior Cruciate Ligament Reconstruction? A Systematic Review. AB - This systematic review explored the utility of preoperative magnetic resonance imaging (MRI) as a tool for predicting intraoperative graft size for anterior cruciate ligament (ACL) reconstruction. Three databases (EMBASE, PubMed, and MEDLINE) were searched in November 2017 for English-language studies of all levels of evidence that aimed to correlate preoperative MRI measurements of common primary ACL autograft sources to intraoperative measurements of the harvested graft. Two reviewers applied predetermined inclusion/exclusion criteria to independently complete title, abstract, and full-text review of eligible studies. Data abstraction, quality assessment, and descriptive statistics are presented. A systematic screen of 930 titles resulted in 14 studies satisfying inclusion/exclusion criteria. These studies examined 762 patients of mean age 28.6 (9-67) years, with 37.3% females. Comparing the correlation of preoperative MRI measurements to intraoperative harvested measures, the strength was very highly positive for quadriceps tendon (QT) (one study, 29 patients, intraclass correlation coefficient [ICC] = 0.96), highly positive for patellar tendon (two studies, 28 patients, ICC: 0.77-0.87), negligible-highly positive for semitendinosus-only tendon (eight studies, 439 patients, r: 0.16-0.81), and negligible-moderately positive for gracilis-only tendon (four studies, 143 patients, r: 0.29-0.59). When combined semitendinosus-gracilis tendon grafts were considered, the correlation ranged from low-very highly positive (10 studies, 517 patients, r: 0.42-0.93). Preoperative MRI assessment of both QT and bone-patellar tendon-bone autografts most highly correlates with intraoperative measurements of autograft diameter. Considerable variability exists when viewing hamstring tendons either individually or together, where most studies indicate at least a moderate correlation. This highlights the advantage of MRI during the preoperative planning process in equipping the surgeon with a better ability to ensure the diameter of the intended autograft will suffice. This is a Level IV study, systematic review of Levels II to IV studies. PMID- 29980153 TI - Posterolateral Rotatory Knee Instability-MRI Evaluation of Anatomic Landmarks for Tibial Drill Tunnel Placement in Open and Arthroscopic Popliteus Tendon Reconstruction. AB - Anatomic reconstruction of the popliteus tendon and arcuate complex results in superior functional and a biomechanically more stable outcome compared with extra anatomic techniques in posterolateral rotatory knee instability. Although specific characteristics of the femoral and fibular footprint of the anatomic posterolateral reconstruction have been described, data for tibial tunnel placement while popliteus tendon reconstruction do not exist. The purpose of this study was to quantify reasonable parameters, which could be used in arthroscopy, fluoroscopy, or open surgery to determine the anatomic tibial drill tunnel position in popliteus tendon reconstruction. Thirty magnetic resonance images of 30 patients with an intact posterolateral corner (PLC) were analyzed to specify the ideal point for tibial fixation of a popliteus tendon graft with respect to 17 bony, cartilaginous, and ligamentous anatomic landmarks. The ideal point for tibial fixation was defined as the musculotendinous junction of the popliteus tendon near to the insertion of the popliteofibular ligament. In the coronal plane, the ideal tibial fixation was located at the crossing of a tangent to the fibular head, parallel to the joint line with a tangent to the medial border of the fibular head, and vertical to the joint line with a deviation of less than 1 mm. It was located 0.26 (+/-1.91) mm superior to the distal edge and 11.75 (+/ 2.66) mm lateral to the lateral edge of the tibial posterior cruciate ligament footprint and only 8.68 (+/-2.81) mm lateral to the lateral edge of the neurovascular bundle. Interrater reliability to detect the correct position of the popliteus tendon graft footprint was almost perfect. The position for tibial drill tunnel placement in anatomic popliteus tendon reconstruction showed low interindividual differences. The present findings of the quantified anatomic landmarks might improve open, fluoroscopy, or arthroscopy guided PLC reconstruction. PMID- 29980154 TI - Normogram of Middle Cerebral Artery Doppler Indexes and Cerebroplacental Ratio at 12 to 14 Weeks in an Unselected Pregnancy Population. AB - OBJECTIVE: The aim of this study is to assess the feasibility of visualizing the middle cerebral artery (MCA), establishing the normogram for MCA pulsatility index (PI) and peak systolic velocity (PSV), and calculating cerebroplacental ratio (CPR) at 12 to 14 weeks. STUDY DESIGN: Prospective cross-sectional study on 186 gravidas presenting for nuchal translucency (NT) assessment. Maternal body mass index (BMI), fetal crown-rump length (CRL), biparietal diameter (BPD), and NT were obtained. Color Doppler was utilized to visualize the MCA and measure PI, PSV, and umbilical artery PI. Normograms for MCA PI and PSV, and for CPR, were constructed. Regression analysis was used for the reference range of MCA PI and CPR according to CRL and BPD. Chi-square and t-test were utilized. p-Value of < 0.05 was considered significant. RESULTS: MCA was successfully visualized in 176/186 (94.6%), PI and PSV measured on 148/186 (79.6%) and 145/186 (78.0%), respectively, and CPR calculated in 133/186 (71.5%). There was no significant effect of BMI, CRL, or BPD on successful assessment of MCA or CPR. Normograms for MCA PI and CPR revealed no significant relation with CRL or BPD. CONCLUSION: MCA and CPR assessment is feasible at 12 to 14 weeks. A reference range for MCA Doppler indexes and CPR at 12 to 14 weeks has been established. This may prove helpful in the early evaluation of fetuses identified as at-risk for adverse neonatal outcome. PMID- 29980155 TI - Hypertensive Disorders of Pregnancy and Preterm Birth Rates among Black Women. AB - OBJECTIVE: The objective of this study was to investigate the role of gestational hypertension (gHTN) and chronic hypertension (cHTN) on rates of preterm birth (PTB) among black women. STUDY DESIGN: Singleton live births between 20 and 44 weeks' gestation among black women in California from 2007 to 2012 were used for analysis. Risk of PTB by subtype and gestational age among women with cHTN or gHTN, including preeclampsia, was calculated via Poisson's logistic regression modeling. Risks were adjusted for maternal factors associated with increased risk of PTB. RESULTS: A total of 154,950 women met inclusion criteria. Of the 5,948 women in the sample with cHTN, 26.2% delivered preterm; for the 11,728 women with gHTN, 21.6% delivered preterm. Women with gHTN or cHTN had a higher risk of medically indicated and spontaneous PTB, both at less than 32 and 32 to 36 weeks, when compared with nonhypertensive women (adjusted relative risks [aRRs]: 3.4-11.6). Women with superimposed preeclampsia had higher risks of spontaneous (aRR: 2.8, 95% confidence interval [CI]: 2.3-3.4) and medically indicated PTB (aRR: 2.8, 95% CI: 2.0-3.8), especially PTB < 32 weeks, when compared with women with preeclampsia. CONCLUSION: Among black women, superimposed preeclampsia increased the risk for spontaneous and medically indicated PTB, especially PTB < 32 weeks. PMID- 29980156 TI - Adverse Maternal Outcomes Differ between Obese and Nonobese Women with Severe Preeclampsia. AB - OBJECTIVE: This article evaluates the differences in adverse maternal outcomes related to severe preeclampsia in obese versus nonobese women. STUDY DESIGN: Retrospective cohort study and planned secondary analysis of women with severe preeclampsia comparing a composite adverse maternal outcome related to preeclampsia among obese (body mass index [BMI] >= 30 kg/m2) and nonobese (BMI < 30 kg/m2) women. The composite outcome was defined as >= 1 of the following prior to discharge: renal failure, liver abnormality, thrombocytopenia, blood transfusion, pulmonary edema, disseminated intravascular coagulation, stroke, or eclampsia. Multivariable logistic regression was used to control for confounders. RESULTS: Of the 152 women included, 37.5% were obese and 62.5% were nonobese. The prevalence of the primary outcome was 15.8% with obese women less likely to have the composite outcome compared with nonobese women (7% vs. 21.1%, p = 0.02). This remained after adjusting for confounders including maternal age, race, and chronic hypertension (adjusted odds ratio, 0.33 [0.12-0.89], p = 0.03). Obese women were, however, more likely to require intravenous antihypertensive medication peripartum compared with nonobese women (49.1% vs. 28.4%, p = 0.01). CONCLUSION: Obese women with severe preeclampsia may have a different phenotype of severe preeclampsia that is more associated with severe hypertension rather than end-organ damage. PMID- 29980157 TI - Calvian Endo-pen: New Coagulation Forceps for Endoscopic Endonasal Transsphenoidal Surgery. AB - OBJECTIVE: Over the past few years bipolar electrocoagulation techniques in neurosurgery have been continually improving. However, limited access during endoscopic endonasal transsphenoidal surgery (EETS) for central skull base pathologies and the requirement of very precise coagulation in that dedicated anatomical area requires further refinement of bipolar coagulation instruments. We describe our experience (effectiveness of coagulation, intraoperative handling, and the use as a dissecting tool) with a new type of coagulation forceps, the Calvian endo-pen (Sutter Medizintechnik, Freiburg, Germany) during EETS. METHOD: From June to August 2015, 12 patients with central skull base lesions (9 with a pituitary adenoma and 1 each with epidermoid, hemangioma, and juvenile angiofibroma) were operated on with the Calvian endo-pen. RESULTS: The application of the Calvian endo-pen was feasible in all cases. The angled thin tips proved to be very effective and precise for soft tissue coagulation to achieve hemostasis. Even very small vessels could be occluded selectively. It was also helpful for outward dissection in separating normal from tumor tissue. CONCLUSION: The use of the Calvian endo-pen is safe and effective during EETS for central skull base pathologies. Its ease in intraoperative handling (maneuverability, cleaning) and precise coagulation makes it a promising instrument for EETS. PMID- 29980158 TI - Premature Ovarian Insufficiency and Bone Health Care: A Concern of the Gynecologist. PMID- 29980159 TI - Score Establishment and Brazilian Portuguese version of the Pregnancy Sexual Response Inventory (PSRI). AB - OBJECTIVE: To establish the Pregnancy Sexual Response Inventory (PSRI) scores for each domain before and during pregnancy, and to publish the Brazilian Portuguese version of the PSRI. METHODS: Pregnant women were recruited during antenatal care; the PSRI was administered to 244 women prenatally at Faculdade de Medicina de Botucatu, at Universidade do Estado de Sao Paulo (UNESP, in the Portuguese acronym). The PSRI scores were estimated based on the Kings Health Questionnaire (KHQ) and the Medical Outcomes Study 36-item short form survey (SF 36). The raw scale type was used to standardize the minimal value and amplitude of each domain. For each domain, the score varied from 0 to 100, and the composite score was obtained as the domain average. The composite score before and during pregnancy was determined by the sum of the scores of all specific domains for each divided by the full domain number. The categorization of the scale into quartiles was established when all PSRI-specific and composite scores were combined. RESULTS: The composite and specific scores for each domain were categorized into quartiles: 0 < 25 as "very bad;" 25 < 50 as "bad;" 50 < 75 as "good" and 75 to 100 as "excellent." The mean scores were lower during pregnancy than before pregnancy in 8 of the 10 domains. The Brazilian Portuguese PSRI version is presented. CONCLUSION: This study allowed the establishment of the PSRI composite and specific scores for each domain, and the categorization of scores into quartiles: very bad, bad, good and excellent. In addition, the Brazilian Portuguese version of the PSRI is presented in full for application in the Brazilian population. PMID- 29980160 TI - Breastfeeding and the Benefits of Lactation for Women's Health. AB - The offer of the maternal breast to the baby is an unquestionable right of mothers and their children, and all efforts should be made to promote, follow and maintain exclusive breastfeeding for up to 6 months and supplement it until the child completes 2 years of age. Many publications are available in the literature about the qualities of breast milk, its benefits and health repercussions, stimulating the practice of breastfeeding and supporting campaigns for its implementation. However, although it is widely known that breastfeeding is an important step in the reproductive process of women and its practice offers benefits to both mother and child, most of the available information highlights the benefits of breast milk for children, while mention of the effects of breastfeeding on the health of the mother is usually neglected. Thus, the objective of the present study is to highlight the multiple benefits of breastfeeding for the physical and emotional health of the nursing mother. The authors consulted articles published in the databases PubMed, Virtual Health Library and Web of Science using the keywords breastfeeding, breast milk, lactation and maternal health. PMID- 29980161 TI - Vulvar Hemangioma: Case Report. AB - Hemangioma is a benign neoplasm that may affect the vulva, and it can cause functional or emotional disability. This article reports the case of a 52-year old female patient with a history of a genital ulcer for the past 3 years and who had undergone various treatments with creams and ointments. The patient was biopsied and diagnosed with vulvar hemangioma and was subsequently submitted to surgical excision of the lesion. We emphasize the importance of following the steps of the differential diagnosis and proceeding with a surgical approach only if necessary. PMID- 29980162 TI - [Adjuvant electrostimulation therapy for chronic rhinosinusitis]. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is one of the most common chronic diseases in Germany and is often accompanied by years of chronic rhinosinusitis. According to the current German guideline "Rhinosinusitis", the nasal application of salt solutions, topical corticosteroids and in individual cases also systemic corticosteroids appear useful for a symptomatic therapy of CRS. The evidence for other therapeutic procedures such as acupuncture, homeopathy and phytotherapeutics is seen as insufficient. The aim of the present study was to investigate whether anti-inflammatory effects of electrostimulation therapy can also be demonstrated in CRS. METHODOLOGY: randomized, prospective single center study, primary setting; 16 patients with moderate chronic rhinosinusitis with polyps (cRScNP), corresponding to a Lund / Mackay score of 6-12; home based electrostimulation therapy (EST) with amplitude modulated current (base frequency of 4000 Hz, frequency band of 100-250 Hz) over 2 weeks adjuvant to a concurrent sinusitis therapy with topical corticosteroids; measurement of nasal nitric oxide concentration and self-assessment of complaints with the questionnaire instrument SNOT-20 GAV; survey points t0 before EST, t1 after EST, t2 6 weeks after t1. RESULTS: Home based EST was performed by 16 patients. The results indicate that the positive effects of electrostimulation therapy in inflammatory processes also exist in CRS. DISCUSSION: Adjuvant transsinuidal electrostimulation could thus enrich the conservative therapy of CRS. Further studies with larger collectives are desirable. PMID- 29980163 TI - A characterization of postzygotic mutations identified in monozygotic twins. AB - Postzygotic mutations are DNA changes acquired from the zygote stage onwards throughout the lifespan. These changes lead to differences in DNA sequence among cells of an individual, potentially contributing to the etiology of complex disorders. Here we compared whole genome DNA sequence data of two monozygotic twin pairs, 40 and 100 years old, to detect somatic mosaicism. DNA samples were sequenced twice on two Illumina platforms (13X and 40X read depth) for increased specificity. Using differences in allelic ratios resulted in sets of 1,720 and 1,739 putative postzygotic mutations in the 40-year-old twin pair and 100-year old twin pair, respectively, for subsequent enrichment analysis. This set of putative mutations was strongly (p < 4.37e-91) enriched in both twin pairs for regulatory elements. The corresponding genes were significantly enriched for genes that are alternatively spliced, and for genes involved in GTPase activity. This research shows that somatic mosaicism can be detected in monozygotic twin pairs by using allelic ratios calculated from DNA sequence data and that the mutations which are found by this approach are not randomly distributed throughout the genome. PMID- 29980164 TI - beta3 -Adrenoceptor stimulation of perivascular adipocytes leads to increased fat cell-derived NO and vascular relaxation in small arteries. AB - BACKGROUND AND PURPOSE: In response to noradrenaline, healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arterial tissue. Organ bath solution transfer experiments have demonstrated the release of PVAT-derived relaxing factors that mediate this function. The present studies were designed to investigate the mechanism responsible for the noradrenaline induced PVAT anticontractile effect. EXPERIMENTAL APPROACH: In vitro rat small arterial contractile function was assessed using wire myography in the presence and absence of PVAT and the effects of sympathomimetic stimulation on the PVAT environment explored using Western blotting and assays of organ bath buffer. KEY RESULTS: PVAT elicited an anticontractile effect in response to noradrenaline but not phenylephrine stimulation. In arteries surrounded by intact PVAT, the beta3 adrenoceptor agonist, CL-316243, reduced the vasoconstrictor effect of phenylephrine but not noradrenaline. Kv 7 channel inhibition using XE 991 reversed the noradrenaline-induced anticontractile effect in exogenously applied PVAT studies. Adrenergic stimulation of PVAT with noradrenaline and CL-316243, but not phenylephrine, was associated with increased adipocyte-derived NO production, and the contractile response to noradrenaline was augmented following incubation of exogenous PVAT with L-NMMA. PVAT from eNOS-/- mice had no anticontractile effect. Assays of adipocyte cAMP demonstrated an increase with noradrenaline stimulation implicating Galphas signalling in this process. CONCLUSIONS AND IMPLICATIONS: We have shown that adipocyte-located beta3 adrenoceptor stimulation leads to activation of Galphas signalling pathways with increased cAMP and the release of adipocyte-derived NO. This process is dependent upon Kv 7 channel function. We conclude that adipocyte-derived NO plays a central role in anticontractile activity when rodent PVAT is stimulated by noradrenaline. PMID- 29980165 TI - From evidence to implementation: The global challenge for psychosocial oncology. AB - The human dimensions of medical care were highlighted by such pioneering figures as Cicely Saunders, Elizabeth Kubler-Ross, and Jimmie Holland and their tireless advocacy helped to build an evidence base for psychosocial and palliative interventions. In that spirit, we studied physical and psychological distress in advanced cancer and modeled pathways to distress in this population. We considered acute stress disorder as the prototype for psychological disturbances following the acute onset of life-threatening disorders, showing that it occurred in one-third of patients after the diagnosis of acute leukemia. To treat and prevent these symptoms, we developed Emotion and Symptom-focused Engagement (EASE), an integrated psychotherapeutic and early palliative intervention. We showed that EASE reduced both traumatic stress and physical suffering in these patients and a large multi-center trial is now underway. We also identified symptoms of depression and hopelessness n one quarter of patients with metastatic and advanced cancer, with worsening toward the end of life. To alleviate this distress, we developed a brief supportive-expressive therapy, referred to as Managing Cancer and Living Meaningfully (CALM). We showed in a large RCT that CALM improves depression, distress related to dying and death, and preparation for the end of life. We have now launched a global initiative involving 20 sites to date across North and South America, Europe, Australia, and Asia to have CALM implemented routinely in cancer care. Such initiatives are needed to move psychosocial care in cancer from evidence to implementation and to fulfill the dream of Jimmie Holland that cancer care be as humanistic as it is effective. PMID- 29980166 TI - DcC4H and DcPER Are Important in Dynamic Changes of Lignin Content in Carrot Roots under Elevated Carbon Dioxide Stress. AB - In our study, isobaric tags for relative and absolute quantification (iTRAQ) was conducted to determine the significantly changed proteins in the fleshy roots of carrots under different carbon dioxide (CO2) treatments. A total of 1523 proteins were identified, of which 257 were differentially expressed proteins (DEPs). On the basis of annotation analysis, the DEPs were identified to be involved in energy metabolism, carbohydrate metabolism, and some other metabolic processes. DcC4H and DcPER, two lignin-related proteins, were identified from the DEPs. Under elevated CO2 stress, both carrot lignin content and the expression profiles of lignin biosynthesis genes changed significantly. The protein-protein interactions among lignin-related enzymes proved the importance of DcC4H and DcPER. The results of our study provided potential new insights into the molecular mechanism of lignin content changes in carrot roots under elevated CO2 stress. PMID- 29980167 TI - A Meta-Analysis of Gender Differences in Subjective Well-Being: Estimating Effect Sizes and Associations With Gender Inequality. AB - Despite global gender inequalities, findings on gender differences in subjective well-being have been inconsistent. We conducted a meta-analysis on gender differences in subjective well-being to account for the type of subjective-well being measure, sampling variability, and levels of national gender inequality from which samples are gathered. Based on 281 effect sizes for life satisfaction ( N = 1,001,802) and 264 for job satisfaction ( N = 341,949), results showed no significant gender differences in both types of subjective well-being. Supplementary meta-analyses found significantly lower job satisfaction, but not life satisfaction, in women for studies that used both life-satisfaction and job satisfaction measures, and studies that relied on measures that previously demonstrated measurement equivalence. Using the Gender Inequality Index, we found that greater national gender inequality significantly predicts greater gender differences in job satisfaction, but not life satisfaction. We discuss the implications of these findings and the use of subjective well-being as a measure of societal progress. PMID- 29980168 TI - mTOR and ROS regulation by anethole on adipogenic differentiation in human mesenchymal stem cells. AB - BACKGROUND: Adipocyte differentiation of human mesenchymal stem cells (hMSCs) is dependent on mitochondrial metabolism and reactive oxygen species (ROS) to initiate adipocyte differentiation. Although anethole has been known as an anti oxidant and lipid peroxidation inhibitor, there is little investigated about its role in adipogenic differentiation. METHODS: The effects on cytotoxicity and proliferation of anethole in hMSCs were measured by the MTT assay. The anti adipogenic effect of anethole on hMSCs was analyzed by Oil Red O staining and western blot analysis. The anti-oxidant activity of anethole on hMSC was assessed by flowcytometry and fluorescence staining using 2',7' -dichlorofluorescin diacetate (DCFDA). The western blotting was used to detect of phospho-Akt, phospho-mTOR, phospho-p70S6K, PPARgamma, and phsopho-AMP-activated kinase (AMPK). RESULTS: Anethole suppressed the adipogenic differentiation of hMSCs through down regulation of Akt-mTOR-p70S6K-PPARgamma and up-regulation of AMPK. Anethole affected oxidative conditions through ROS generation. Anethole also rescued AMPK activity and reduced activation of mTOR-p70S6K-PPARgamma under oxidative conditions in presence of exogenous hydrogen peroxide. CONCLUSION: ROS and mTOR regulation is a crucial factor in adipogenic differentiation, anethole has an important role in regulating activities of mTOR/PPARgamma and ROS control in adipogenic differentiation of hMSCs. PMID- 29980169 TI - Association between periodontitis and peripheral artery disease: a systematic review and meta-analysis. AB - BACKGROUND: Inflammation is a common feature of both peripheral arterial disease (PAD) and periodontitis. Some studies have evaluated the association between PAD and periodontitis. However, there is still no specialized meta-analysis that has quantitatively assessed the strength of the association. Thus, we conducted this meta-analysis to critically assess the strength of the association between PAD and periodontitis. METHODS: PubMed, Embase, and the Cochrane Library were searched for observational studies of the association between periodontitis and PAD in February 2018. Risk ratios (RRs) and their 95% confidence intervals (CIs) from included studies were pooled to evaluate the strength of the association between periodontitis and PAD. Weighted mean differences (WMDs) and their 95% CIs were pooled to compare the difference in periodontal-related parameters between PAD and non-PAD patients. RESULTS: Seven studies including a total of 4307 participants were included in the meta-analysis. The pooled analysis showed that there was a significant difference in the risk of periodontitis between PAD patients and non-PAD participants (RR = 1.70, 95% CI = 1.25-2.29, P = 0.01). There was also a significant difference in number of missing teeth between PAD patients and non-PAD participants (WMD = 3.75, 95% CI = 1.31-6.19, P = 0.003). No significant difference was found in clinical attachment loss between PAD patients and non-PAD participants (WMD = - 0.05, 95% CI = - 0.03-0.19, P = 0.686). CONCLUSION: In conclusion, the results of this meta-analysis revealed a significant relationship between periodontitis and PAD. Moreover, our study indicated that PAD patients had more missing teeth than control subjects did. Further high-quality and well-designed studies with specific inclusion and exclusion criteria are required to strengthen the conclusions of this study. PMID- 29980170 TI - Metabolic syndrome and biochemical changes among non-alcoholic fatty liver disease patients attending a tertiary care hospital of Nepal. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is mutually and bidirectionally linked with metabolic syndrome (MetS) of which it is both the cause and the consequences. Worldwide, 6.3 to 33% of the general populations are estimated to suffer from the disease with even higher prevalence in the group sharing metabolic co-morbidities. Hence, this study aims to recognize various risk factors including metabolic components and blood parameters to predict the possible incidence of the disease. METHODS: Total of 429 (219 NAFLD and 210 control) subjects were conveniently selected for study during the period of 9 months. Diagnosis of non-alcoholic fatty liver disease was done by liver imaging and based on liver enzymes. Assessment of metabolic syndrome was done by International Diabetic Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. All biochemical and hematological parameters and liver enzymes were estimated by using standard guideline. Mean comparison of quantitative data in different groups were performed using analysis of variance (one-way ANOVA). Risk estimation of NAFLD associated with each character was verified by Chi-square test. RESULTS: There was significant high levels of body mass index (BMI), waist circumference (WC) and lipid profiles in NAFLD patients in comparison to control population (p < 0.001). Further, according to the NCEP ATP III criteria, 13.6% of NAFLD were present with MetS where risk estimate was significant (OR = 2.15). Whereas, other criteria (IDF) for MetS showed higher frequency (30.1%) with higher risk (OR = 29.75) for the presence of MetS in NAFLD patients. The change in triglycerides (TG) and HDL-C (high density lipoprotein cholesterol) was also statistically significant in different grades of NAFLD. High risk for NAFLD was associated with existing co-morbid conditions like cardiovascular risk patients (3.18 times) followed by obese patients (1.72 times) and Diabetes Mellitus patients (1.68 times) at a significant level. CONCLUSION: The result of this study suggests that there is an increased prevalence of all the components of MetS and significant changes in biochemical markers in cases of NAFLD. Timely diagnosis would help in delaying its complications and co-morbidities. PMID- 29980171 TI - Remapping of the belted phenotype in cattle on BTA3 identifies a multiplication event as the candidate causal mutation. AB - BACKGROUND: It has been known for almost a century that the belted phenotype in cattle follows a pattern of dominant inheritance. In 2009, the approximate position of the belt locus in Brown Swiss cattle was mapped to a 922-kb interval on bovine chromosome 3 and, subsequently, assigned to a 336-kb haplotype block based on an animal set that included, Brown Swiss, Dutch Belted (Lakenvelder) and Belted Galloway individuals. A possible candidate gene in this region i.e. HES6 was investigated but the causal mutation remains unknown. Thus, to elucidate the causal mutation of this prominent coat color phenotype, we decided to remap the belted phenotype in an independent animal set of several European bovine breeds, i.e. Gurtenvieh (belted Brown Swiss), Dutch Belted and Belted Galloway and to systematically scan the candidate region. We also checked the presence of the detected causal mutation in the genome of belted individuals from a Siberian cattle breed. RESULTS: A combined linkage disequilibrium and linkage analysis based on 110 belted and non-belted animals identified a candidate interval of 2.5 Mb. Manual inspection of the haplotypes in this region identified four candidate haplotypes that consisted of five to eight consecutive SNPs. One of these haplotypes overlapped with the initial 922-kb interval, whereas two were positioned proximal and one was positioned distal to this region. Next-generation sequencing of one heterozygous and two homozygous belted animals identified only one private belted candidate allele, i.e. a multiplication event that is located between 118,608,000 and 118,614,000 bp. Targeted locus amplification and quantitative real-time PCR confirmed an increase in copy number of this region in the genomes of both European (Belted Galloway, Dutch Belted and Gurtenvieh) and Siberian (Yakutian cattle) breeds. Finally, using nanopore sequencing, the exact breakpoints were determined at 118,608,362 and 118,614,132 bp. The closest gene to the candidate causal mutation (16 kb distal) is TWIST2. CONCLUSIONS: Based on our findings and those of a previously published study that identified the same multiplication event, a quadruplication on bovine chromosome 3 between positions 118,608,362 and 118,614,132 bp is the most likely candidate causal mutation for the belted phenotype in cattle. PMID- 29980173 TI - The importance of including aliases in data linkage with vulnerable populations. AB - BACKGROUND: Records pertaining to individuals whose identity cannot be verified with legal documentation may contain errors, or be incorrect by intention of the individual. Probabilistic data linkage, especially in vulnerable populations where the incidence of such records may be higher, must be considerate of the usage of these records. METHODS: A data linkage was conducted between Queensland Youth Justice records and the Australian National Death Index. Links were assessed to determine how often they were made using the unverified (alias) records that would not have been made in their absence (i.e. links that were not also made using solely verified records). Anomalies in the linked records were investigated in order to make evaluations of the sensitivity and specificity of the linkage, compared to the links made using only verified records. RESULTS: From links made using verified records only, 1309 deaths were identified (2.6% of individuals). Using alias records in addition, the number of links increased by 16%. Links made using alias records only were more common in females, and those born after 1985. Different records belonging to the same individual in the justice dataset did not link to different death records, however there were instances of the same death record linking to multiple cohort individuals. CONCLUSIONS: The inclusion of aliases in data linkage in youths involved in the justice system increased mortality ascertainment without any discernible increase in false positive matches. We therefore conclude that alias records should be included in data linkage procedures in order to avoid biased attenuation of ascertainment in vulnerable populations, leading to the concealment of health inequality. PMID- 29980172 TI - Unlocking pandemic potential: prevalence and spatial patterns of key substitutions in avian influenza H5N1 in Egyptian isolates. AB - BACKGROUND: Avian influenza H5N1 has a high human case fatality rate, but is not yet well-adapted to human hosts. Amino acid substitutions currently circulating in avian populations may enhance viral fitness in, and thus viral adaptation to, human hosts. Substitutions which could increase the risk of a human pandemic (through changes to host specificity, virulence, replication ability, transmissibility, or drug susceptibility) are termed key substitutions (KS). Egypt represents the epicenter of human H5N1 infections, with more confirmed cases than any other country. To date, however, there have not been any spatial analyses of KS in Egypt. METHODS: Using 925 viral samples of H5N1 from Egypt, we aligned protein sequences and scanned for KS. We geocoded isolates using dasymetric mapping, then carried out geospatial hot spot analyses to identify spatial clusters of high KS detection rates. KS prevalence and spatial clusters were evaluated for all detected KS, as well as when stratified by phenotypic consequence. RESULTS: A total of 39 distinct KS were detected in the wild, including 17 not previously reported in Egypt. KS were detected in 874 samples (94.5%). Detection rates varied by viral protein with most KS observed in the surface hemagglutinin (HA) and neuraminidase (NA) proteins, as well as the interior non-structural 1 (NS1) protein. The most frequently detected KS were associated with increased viral binding to mammalian cells and virulence. Samples with high overall detection rates of KS exhibited statistically significant spatial clustering in two governorates in the northwestern Nile delta, Alexandria and Beheira. CONCLUSIONS: KS provide a possible mechanism by which avian influenza H5N1 could evolve into a pandemic candidate. With numerous KS circulating in Egypt, and non-random spatial clustering of KS detection rates, these findings suggest the need for increased surveillance in these areas. PMID- 29980174 TI - Knowledge and attitude towards antimicrobial resistance among final year undergraduate paramedical students at University of Gondar, Ethiopia. AB - BACKGROUND: Globally, antimicrobial resistance (AMR) is a complex public problem, which is mainly fuelled by inappropriate use of antimicrobials. Rational use of antimicrobials is the main strategy for the prevention of AMR, which can be achieved by changing the prescribers' behavior and knowledge. Hence, this study aimed to assess knowledge and attitude of paramedical students regarding antimicrobial resistance, which helps to rationalize the use of antimicrobials. METHODS: An institutional based cross-sectional study was performed on 323 graduates paramedical students at the University of Gondar, Ethiopia. Participants were invited to complete a self-reported structured questionnaire on hard copy. The data were summarized using summary statistics such as the median. Furthermore, Kruskal Wallis test, at the level of significance of 0.05, was conducted to compare group difference. RESULTS: Among 360 eligible paramedical students, 323 (90%) of them participated and most of them were males 202 (62.5%). Nearly 96% of the participants perceived that antimicrobial resistance is a catastrophic and preventable public problem but about half of the participants (55%) had a poor level of knowledge. It was also found that there was a statistically significant knowledge and attitude difference across the department (p-value< 0.0001) and (p = 0.002), respectively. Furthermore, those participants who had a good level of knowledge had greater attitude rank as compared to those who had a moderate and poor level of knowledge (p-value< 0.0001). CONCLUSION: Majority of the participants viewed antimicrobial resistance as a preventable public problem if appropriate strategies are formulated. Nonetheless, most of them had a poor knowledge regarding antimicrobial resistance, and their knowledge and attitude significantly vary across their field of study. This result implicates that improving the students' level of knowledge about antimicrobial resistance might be an approach to flourish their attitude and to rationalize their antimicrobial use. PMID- 29980175 TI - Late-onset paradoxical reactions 10 years after treatment for tuberculous meningitis in an HIV-negative patient: a case report. AB - BACKGROUND: Although paradoxical reactions (PRs) to anti-tuberculosis (anti-TB) therapy during treatment are well-established occurrences, PRs presenting as a new lesion after the completion of treatment are extremely rare, and little is known about the management of such cases, particularly of central nervous system (CNS) tuberculosis. CASE PRESENTATION: A 27-year-old female, with a past medical history of tuberculous meningitis 10 years ago and who completed the anti-TB treatment with asymptomatic remnant tuberculomas in the basal cistern, was admitted to our hospital because of a headache and the worsening of pre-existing visual disturbance. Contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI) revealed new tuberculomas in the left sylvian fissure with a diffuse low signal around it. Because repeated polymerase chain reaction and Mycobacterium tuberculosis culture presented negative results and the patient had no laboratory data suggestive of a relapse of tuberculous meningitis, she was diagnosed with late-onset post-treatment PRs and treated with oral corticosteroids, tapered off over 1 year. Eventually, the symptoms were relieved, and the tuberculomas disappeared. CONCLUSIONS: Clinicians should consider the possibility of PRs long after the completion of tuberculous meningitis treatment. Hence, a precise MRI-based examination is imperative for the follow-up of CNS tuberculosis, and the unnecessary administration of anti-TB drugs should be avoided. The use of corticosteroids as a treatment option for post-treatment PRs is seemingly safe when the isolated M. tuberculosis is sensitive to the first line anti-TB therapy. PMID- 29980176 TI - The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients. AB - BACKGROUND: Cisplatin is one of the major drugs that used in the treatment of osteosarcoma. Cisplatin exerts its function by making cisplatin-DNA adducts culminating in cellular death. These adducts found to be repaired by nucleotide excision repair (NER) pathway. This study aimed to evaluate if polymorphisms in two main genes in the NER pathway, excision repair cross-complementing group 1 and 2 (ERCC1 and ERCC2) could affect the histological response to cisplatin based chemotherapy or clinical outcomes, particularly, event free survival (EFS) and overall survival (OS) rates. METHOD: ERCC1 (C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms were analysed in 44 patients with osteosarcoma, who were treated with cisplatin based neoadjuvant chemotherapy. DNA was extracted from patient's formalin-fixed paraffin-embedded (FFPE) samples, patient's genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism PCR-RFLP assay. The distribution of the patients' genotype and the allele frequencies were reported. The association between each of these genotypes and many clinical and patho-histological parameters (e.g. EFS, OS and patho-histological response to treatment) was examined. The associations between gender, tumor location, presence of metastasis at diagnosis, histological subtypes, and type of neoadjuvant chemotherapy and between the histological response, EFS and OS rates were also examined. RESULTS: This study revealed that there was a positive and significant association between ERCC1 C8092 A genotypes and median EFS rate in years; patients who were carriers of C allele (CC & CA) were found to have longer EFS rates than patients with AA genotype (P value = 0.006) and the median EFS rates were respectively as following: 2.04, 0.24 years. As well, both the presence of metastasis and the histological subtype at the time of diagnosis, were able to affect the EFS rate but not the OS. However, there was a positive correlation between OS rate and the patients' primary response to treatment. CONCLUSIONS: Our results suggested that ERCC1 8092 C allele may play a role as a candidate prognostic marker in patients with osteosarcoma. PMID- 29980178 TI - Efficacy of Hydroxy-L-proline (HYP) analogs in the treatment of primary hyperoxaluria in Drosophila Melanogaster. AB - BACKGROUND: Substrate reduction therapy with analogs reduces the accumulation of substrates by inhibiting the metabolic pathways involved in their biosynthesis, providing new treatment options for patients with primary hyperoxalurias (PHs) that often progress to end-stage renal disease (ESRD). This research aims to evaluate the inhibition efficacy of Hydroxy-L-proline (HYP) analogs against calcium oxalate (CaOx) crystal formation in the Drosophila Melanogaster (D. Melanogaster) by comparing them with Pyridoxine (Vitamin B6). METHODS: Three stocks of Drosophila Melanogaster (W118, CG3926 RNAi, and Act5C-GAL4/CyO) were utilized. Two stocks (CG3926 RNAi and Act5C-GAL4 /CyO) were crossed to generate the Act5C > dAGXT RNAi recombinant line (F1 generation) of D. Melanogaster which was used to compare the efficacy of Hydroxy-L-proline (HYP) analogs inhibiting CaOx crystal formation with Vitamin B6 as the traditional therapy for primary hyperoxaluria. RESULTS: Nephrolithiasis model was successfully constructed by downregulating the function of the dAGXT gene in D. Melanogaster (P-Value = 0.0045). Furthermore, the efficacy of Hydroxy-L-proline (HYP) analogs against CaOx crystal formation was demonstrated in vivo using D. Melanogaster model; the results showed that these L-Proline analogs were better in inhibiting stone formation at very low concentrations than Vitamin B6 (IC50 = 0.6 and 1.8% for standard and dietary salt growth medium respectively) compared to N-acetyl-L Hydroxyproline (IC50 = 0.1% for both standard and dietary salt growth medium) and Baclofen (IC50 = 0.06 and 0.1% for standard and dietary salt growth medium respectively). Analysis of variance (ANOVA) also showed that Hydroxy-L-proline (HYP) analogs were better alternatives for CaOx inhibition at very low concentration especially when both genetics and environmental factors are intertwined (p < 0.0008) for the dietary salt growth medium and (P < 0.063) for standard growth medium. CONCLUSION: Addition of Hydroxy-L-Proline analogs to growth medium resulted in the reduction of CaOx crystals formation. These analogs show promise as potential inhibitors for oxalate reduction in Primary Hyperoxaluria. PMID- 29980177 TI - Implementing evidence-based practices in the care of infants with bronchiolitis in Australasian acute care settings: study protocol for a cluster randomised controlled study. AB - BACKGROUND: Bronchiolitis is the most common reason for admission to hospital for infants less than one year of age. Although management is well defined, there is substantial variation in practice, with infants receiving ineffective therapies or management. This study will test the effectiveness of tailored, theory informed knowledge translation (KT) interventions to decrease the use of five clinical therapies or management processes known to be of no benefit, compared to usual dissemination practices in infants with bronchiolitis. The primary objective is to establish whether the KT interventions are effective in increasing compliance to five evidence based recommendations in the first 24 h following presentation to hospital. The five recommendations are that infants do not receive; salbutamol, antibiotics, glucocorticoids, adrenaline, or a chest x ray. METHODS/DESIGN: This study is designed as a cluster randomised controlled trial. We will recruit 24 hospitals in Australia and New Zealand, stratified by country and provision of tertiary or secondary paediatric care. Hospitals will be randomised to either control or intervention groups. Control hospitals will receive a copy of the recent Australasian Bronchiolitis Guideline. Intervention hospitals will receive KT interventions informed by a qualitative analysis of factors influencing clinician care of infants with bronchiolitis. Key interventions include, local stakeholder meetings, identifying medical and nursing clinical leads in both emergency departments and paediatric inpatient areas who will attend a single education train-the-trainer day to then deliver standardised staff education with the training materials provided and coordinate audit and feedback reports locally over the study period. Data will be extracted retrospectively for three years prior to the study intervention year, and for seven months of the study intervention year bronchiolitis season following intervention delivery to determine compliance with the five evidence-based recommendations. Data will be collected to assess fidelity to the implementation strategies and to facilitate an economic evaluation. DISCUSSION: This study will contribute to the body of knowledge to determine the effectiveness of tailored, theory informed interventions in acute care paediatric settings, with the aim of reducing the evidence to practice gaps in the care of infants with bronchiolitis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616001567415 (retrospectively registered on 14 November 2016). PMID- 29980180 TI - Reference effect measures for quantifying, comparing and visualizing variation from random and fixed effects in non-normal multilevel models, with applications to site variation in medical procedure use and outcomes. AB - BACKGROUND: Multilevel models for non-normal outcomes are widely used in medical and health sciences research. While methods for interpreting fixed effects are well-developed, methods to quantify and interpret random cluster variation and compare it with other sources of variation are less established. Random cluster variation, sometimes referred to as general contextual effects (GCE), may be the main focus of a study; therefore, easily interpretable methods are needed to quantify GCE. We propose a Reference Effect Measure (REM) approach to 1) quantify GCE and compare it to individual subject and cluster covariate effects, and 2) quantify relative magnitudes of GCE and variation from sets of measured factors. METHODS: To illustrate REM, we consider a two-level mixed logistic model with patients clustered within hospitals and a random intercept for hospitals. We compare patients at hospitals at given percentiles of the estimated random effect distribution to patients at a median or 'reference' hospital. These estimates are then compared numerically and graphically to individual fixed effects to quantify GCE in the context of effects of other measured variables (aim 1). We then extend this approach by comparing variation from the random effect distribution to variation from sets of fixed effects to understand their magnitudes relative to overall outcome variation (aim 2). RESULTS: Using an example of initiation of rhythm control treatment in atrial fibrillation (AF) patients within the Veterans Affairs (VA), we use REM to demonstrate that random variation across hospitals (GCE) in initiation of treatment is substantially greater than that due to most individual patient factors, and explains at least as much variation in treatment initiation as do all patient factors combined. These results are contrasted with a relatively small GCE compared with patient factors in 1 year mortality following hospitalization for AF patients. CONCLUSIONS: REM provides a means of quantifying random effect variation (GCE) with multilevel data and can be used to explore drivers of outcome variation. This method is easily interpretable and can be presented visually. REM offers a simple, interpretable approach for evaluating questions of growing importance in the study of health care systems. PMID- 29980179 TI - Clinical characteristics and short-term prognosis of LGI1 antibody encephalitis: a retrospective case study. AB - BACKGROUND: Recently, most reports of Leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis are from Europe and the US, while the short term outcome and clinical characteristics of Chinese patients are rarely reported,we study the clinical manifestations, laboratory results and brain magnetic resonance images (MRI) of eight patients who were recently diagnosed with LGI1 antibody encephalitis in our hospital to improve the awareness and knowledge of this disease. METHODS: Eight patients (five males and three females; mean age, 63.4) with LGI1 antibody encephalitis who were diagnosed and treated in the Department of Neurology of Shengjing Hospital of China Medical University from September 2016 to June 2017 were recruited for the current study. Their general information, clinical manifestations, treatment regimens, and short-term prognoses were retrospectively analyzed, as were the results from MRI and laboratory findings. RESULTS: Overall, patient symptoms included cognitive impairment, which manifested primarily as memory deficits (8/8), seizures (including faciobrachial dystonic seizure, (FBDS)) (8/8), psychiatric and behavioral disorders (7/8), sleep disorders (4/8), and autonomic abnormalities (3/8). Five patients also had abnormal findings on brain MRI, mainly involving the hippocampus, basal ganglia and insula. Hyponatremia occurred in six cases. All patients tested positive for LGI1 antibodies in their serum/cerebrospinal fluid (CSF)and patients were negative for tumors. Symptoms rapidly improved after treatment with immunoglobulin and/or steroid therapy. The patients were followed up for 4-13 months after discharge, and two patients relapsed. CONCLUSION: Primary symptoms of LGI1 antibody encephalitis include memory impairments, seizures, FBDS, and mental and behavioral abnormalities. Increased titers of LGI1 antibodies are also present in the serum/CSF of patients. Patients often have hyponatremia, and MRIs show abnormalities in various brain regions. Finally, immunotherapy shows good efficacy and positive benefits, although patients may relapse in the short-term. PMID- 29980181 TI - The "RCT augmentation": a novel simulation method to add patient heterogeneity into phase III trials. AB - BACKGROUND: Phase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug's effects when prescribed to wider populations and under routine care ("effectiveness"). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug's effect. We developed the "RCT augmentation" method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia. METHODS: We applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the "RCT population" subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1-3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different "augmented RCT populations" (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different "augmented RCT populations". RESULTS: Data from the "RCT population", which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8-6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3-6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10-20% of patients with the corresponding real-world characteristic. CONCLUSIONS: Simulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design. PMID- 29980182 TI - Targeting HOX-PBX interactions causes death in oral potentially malignant and squamous carcinoma cells but not normal oral keratinocytes. AB - BACKGROUND: High HOX gene expression has been described in many cancers, including oral squamous cell carcinoma and the functional roles of these genes are gradually being understood. The pattern of overexpression suggests that inhibition may be useful therapeutically. Inhibition of HOX protein binding to PBX cofactors by the use of synthetic peptides, such as HXR9, results in apoptosis in multiple cancers. METHODS: Activity of the HOX-PBX inhibiting peptide HXR9 was tested in immortalised normal oral (NOK), potentially-malignant (PMOL) and squamous cell carcinoma (OSCC) cells, compared to the inactive peptide CXR9. Cytotoxicity was assessed by LDH assay. Expression of PBX1/2 and c-Fos was assessed by qPCR and western blotting. Apoptosis was assessed by Annexin-V assay. RESULTS: PMOL and OSCC cells expressed PBX1/2. HOX-PBX inhibition by HXR9 caused death of PMOL and OSCC cells, but not NOKs. HXR9 treatment resulted in apoptosis and increased expression of c-Fos in some cells, whereas CXR9 did not. A correlation was observed between HOX expression and resistance to HXR9. CONCLUSION: Inhibition of HOX-PBX interactions causes selective apoptosis of OSCC/PMOL, indicating selective toxicity that may be useful clinically. PMID- 29980183 TI - NGAL protects against endotoxin-induced renal tubular cell damage by suppressing apoptosis. AB - BACKGROUND: We sought to confirm that neutrophil gelatinase-associated lipocalin (NGAL) protects against apoptosis during endotoxemia. METHODS: Endotoxemia was induced in rats with lipopolysaccharide (LPS; 3.5 mg/kg) and serum creatinine (SCr), urinary NGAL (uNGAL), renal histopathology confirmed acute kidney injury (AKI). Renal caspase 3 and NGAL were assayed with immunohistochemistry 6 h later. A HK-2 cell model was used in which NGAL and caspase 3 mRNA were evaluated by qRT PCR within 6 h after LPS (50 MUM) treatment, and correlations were studied. NGAL and caspase 3 mRNA expression were measured after delivering NGAL siRNA in HK-2 cells and apoptosis was measured with TUNEL and flow cytometry. RESULTS: SCr and uNGAL were significantly increased after LPS treatment and renal morphology data indicated AKI and renal tubular epithelial cell apoptosis. Caspase 3 and NGAL were predominantly expressed in the tubular epithelial cells and there was a correlation between caspase 3 and NGAL protein (r = 0.663, p = 0.01). In vitro, there was a strong correlation between caspase 3 and NGAL mRNA in LPS-injured HK 2 cells within 24 h (r = 0.448, p < 0.05). Suppressing the NGAL gene in HK-2 cells increased caspase 3 mRNA 4.5-fold and apoptosis increased 1.5-fold after LPS treatment. CONCLUSIONS: NGAL is associated with caspase 3 in renal tubular cells with endotoxin-induced kidney injury, and may regulate its expression and inhibit apoptosis. PMID- 29980184 TI - Perinatal outcomes in intrahepatic cholestasis of pregnancy with monochorionic diamniotic twin pregnancy. AB - BACKGROUND: The primary aim of the study is to investigate the perinatal outcomes in intrahepatic cholestasis of pregnancy (ICP) with monochorionic diamniotic (MCDA) twin pregnancy. METHODS: This study is a retrospective observational study for women with ICP and MCDA twin pregnancy. Included cases were divided into mild ICP group (10-39 mmol/L) and severe ICP group (> = 40 mmol/L), whose perinatal outcomes were compared between this two groups and whose predictors of adverse perinatal outcomes were evaluated. RESULTS: 37 cases and 21 cases are in mild and severe ICP group respectively, of which, the incidence of gestational diabetes mellitus (GDM) and iatrogenic preterm delivery in severe ICP group are higher than those in mild ICP group. Gestational age (GA) at diagnosis of ICP < 32 weeks is an independent risk factor for GA at delivery < 35 weeks and for composite adverse neonatal outcome. Total bile acids (TBA) > 40 mmol/l is an independent risk factor for meconium-stained amniotic fluid. CONCLUSION: For women with ICP and MCDA twin pregnancy, GA at diagnosis of ICP < 32 weeks and TBA > 40umol/L are associated with adverse perinatal outcomes. PMID- 29980185 TI - Comparison of hepatitis B viral loads and viral antigen levels in child-bearing age women with and without pregnancy. AB - BACKGROUND: Pregnancy is a unique physiological condition with the cellular immune functions compromised at some extents to allow the mature of growing fetus. Whether pregnancy may influence the replication of hepatitis B virus (HBV) is less studied. The present study aimed to investigate the influence of pregnancy on the replication of HBV and expression of viral antigens by comparing the levels of HBV DNA and viral antigens in pregnant and non-pregnant women. METHODS: A total of 727 HBsAg-positive serum samples, collected from 214 pregnant women and 513 non-pregnant women of childbearing age, were included. Based on the pregnancy status, subjects were divided into four groups: nulliparous (n = 158), pregnant (n = 214), 7-12 months postpartum (n = 170), and 2-5 years postpartum (n = 185). The levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were quantitatively measured with microparticle enzyme immunoassay. HBV DNA levels were detected by fluorescent real-time PCR. RESULTS: The median ages of four groups were 25.0, 25.3, 26.2 and 29.3 years, respectively (p < 0.01). HBeAg-positive proportions were 34.2, 33.6, 35.3 and 29.2%, respectively (p = 0.624). HBV DNA levels in HBeAg-positive women were higher than those in HBeAg-negative women (7.88 vs 2.62 log IU/ml, p < 0.001). HBV DNA levels in the four groups with positive HBeAg were 7.8, 7.7, 8.0 and 8.0 log IU/ml, respectively (p = 0.057), while HBsAg titers were 4.4, 4.5, 4.6 and 4.8 log IU/ml (p = 0.086) and HBeAg titers were 3.1, 3.0, 3.1 and 3.0 log S/CO (p = 0.198). In the four groups with negative HBeAg, HBV DNA levels were 2.3, 2.6, 2.5 and 2.8 log IU/ml, respectively (p = 0.085), while HBsAg titers were 3.1, 3.3, 3.3 and 3.0 log IU/ml (p = 0.06). CONCLUSIONS: Serum levels of HBV DNA and viral antigens showed no significant changes in nulliparous, pregnant, and postpartum women, regardless of the HBeAg status. The results indicate that pregnancy has little influence on the replication of HBV and the expression of viral antigens. PMID- 29980186 TI - Thoracic injection of low-dose interleukin-2 as an adjuvant therapy improves the control of the malignant pleural effusions: a systematic review and meta-analysis base on Chinese patients. AB - BACKGROUND: Interleukin-2 (IL-2) is an important immunotherapy cytokine for various diseases including cancer. Some studies reported the efficacy and safety on cisplatin combined with IL-2 versus cisplatin alone for treating malignant pleural effusion (MPE) through thoracic injection. METHODS: We searched these studies from medical electronic database. A total of 18 studies that met the inclusion criteria were recruited in this meta-analysis. Pooled odds ratios (OR) with 95% confidence intervals (CI) were determined by the fixed effects model of meta-analysis. RESULTS: The objective response rate (ORR) and disease control rate (DCR) of cisplatin plus IL-2 for controlling MPE was significantly higher than that of cisplatin alone (p < 0.001). In addition, compared with cisplatin alone, the presence of IL-2 improved the quality of life (QOL) of patients with MPE (p < 0.001). Although the use of IL-2 seemed to increase the probability of fever in patients (p = 0.001), it did not lead to extra other side effects (AEs) including myelotoxicity, nausea/vomiting and chest pain (p > 0.05). CONCLUSIONS: The low-dose IL-2 improved the ORR, DCR and QOL of patients in the treatment of MPE. Although it may cause fever in patients, it did not increase other AEs. PMID- 29980188 TI - Folk prescription for treating rhinitis as a rare cause of childhood lead poisoning: a case series. AB - BACKGROUND: Folk prescriptions continue to be important sources of childhood lead poisoning. Nasal spray folk prescriptions for treating rhinitis has only been reported once previously as a cause of lead poisoning. CASE PRESENTATION: We identified three pediatric cases of severe lead poisoning caused by nasal spray folk medicines prescribed for treating rhinitis. The three patients had similar clinical manifestations including: severe abdominal pain, headache, pale appearance and fatigue. Liver function tests were abnormal. Blood lead levels (BLLs) of the three patients were 91 MUg/dL, 91 MUg/dL, and 105 MUg/dL, respectively. After chelation BLLs decreased. The lead content of the three folk remedies as measured by inductively coupled plasma mass spectrometry (ICP-MS) were 14.8, 22.3, and 33.4%. All the symptoms resolved during a course of chelation therapy. There were no severe side effects of treatment. CONCLUSIONS: Nasal spray folk prescriptions for treating rhinitis may contain extremely high bio-accessible lead content and are potential sources of lead poisoning. Clinicians should be alert to this possibility especially in those children presenting with multisystem symptoms. PMID- 29980187 TI - Analysis of pre-operative factors affecting range of optimal vaulting after implantation of 12.6-mm V4c implantable collamer lens in myopic eyes. AB - BACKGROUND: To evaluate clinical factors affecting postoperative vaulting in eyes that had achieved optimal vaulting within the range of 250-750 MUm following implantation of 12.6-mm V4c implantable collamer lenses (ICL). METHODS: A total of 236 eyes of 236 patients that had achieved optimal vaulting following implantation of a 12.6-mm V4c ICL were retrospectively analyzed. Associations between postoperative vaulting and age, preoperative anterior chamber depth (ACD), preoperative axial length (AL), preoperative white-to-white diameter, preoperative pupil size, preoperative sulcus-to-sulcus diameter, and preoperative manifest refraction spherical equivalent were investigated using simple regression, stepwise multiple regression, and multinomial logistic regression analyses. RESULTS: Mean central vaulting at the 6-month follow-up was 519.0 +/- 112.8 MUm. Variables relevant to postoperative vaulting were, in order of influence, preoperative ACD (beta = 0.305, p < 0.001), preoperative pupil size (beta = 0.218, p < 0.001), and preoperative AL (beta = 0.171, p = 0.006). Low preoperative pupil size was associated with low optimal vaulting (250 to 450 MUm), relative to that observed in the mid optimal vaulting group (451 to 550 MUm) (odds ratio = 0.532, P = 0.021). Increasing preoperative ACD was associated with high optimal vaulting (551 and 750 MUm), relative to that observed the mid optimal vaulting group (odds ratio = 6.340, P = 0.034). CONCLUSIONS: Myopic eyes with greater preoperative ACD, larger pupil size, and longer AL are predisposed to higher postoperative vaulting following 12.6-mm V4c ICL implantation. Therefore, the extremes of these parameters should be considered when choosing V4c ICL size. PMID- 29980189 TI - Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) infections in patients with cystic fibrosis (CF) is increasing globally. However, the related epidemiology, comorbidities, and clinical impact of NTM infection remains unclear in the progress of CF lung disease and patient survival. METHODS: We performed a retrospective, case-control, cohort study (10 years), comparing NTM culture positive CF patients (N = 28) to matched controls (N = 26). NTM positive patients were divided in to two groups of slow-growing (N = 17) and rapid- growing NTM (N = 8). Three patients were positive for both slow and rapid NTM. For independent group comparisons, a non-parametric Mann-Whitney test (Kruskal-Wallis test for more than two groups) was used to compare the continuous variables, and a Fisher's exact test was used for the categorical variables. Paired comparisons were performed using a Wilcoxon signed-rank test. RESULTS: The prevalence of NTM isolation was 8%. The age at CF diagnosis was significantly lower in the slow growing NTM group compared to the rapidly growing NTM group (P = 0.04). The median percent predicted forced expiratory flow of 25% - 75% (FEF25-75) was significantly higher before NTM acquisition in slow-growing (P = 0.013) and rapidly growing NTM group (P = 0.028). The slow-growing NTM group received significantly more penicillin/beta lactamase (P = 0.010) and rifampin (P = 0.042) following isolation. Macrolide use was significantly higher after isolation in both the slow-growing NTM (P = 0.018) and rapidly growing NTM groups (P = 0.042). CONCLUSIONS: An earlier CF diagnosis was associated with a higher isolation of slow-growing NTM and greater antimicrobial use after infection. NTM acquisition is associated with a worsening of FEF25-75. Thus, both the early diagnosis and treatment of an NTM infection in patients with CF may positively impact lung function. PMID- 29980190 TI - Diabetes mellitus in HIV-infected patients: fasting glucose, A1c, or oral glucose tolerance test - which method to choose for the diagnosis? AB - BACKGROUND: Antiretroviral therapy dramatically reduced HIV-related morbidity and mortality, prolonging the lifespan of HIV-infected patients. Greater duration of infection and exposure to antiretroviral therapy makes these patients susceptible to traditional cardio-metabolic risk factors and pathologies. The optimal diagnostic protocol for Diabetes Mellitus in these patients is still controversial. Haemoglobin A1c (HbA1c) has been shown to underestimate glycaemia levels and the oral glucose tolerance test (OGTT) has been shown to reveal cases of glucose metabolism disturbances in patients with normal fasting glucose. Thus, this study aimed to determine the prevalence of prediabetes and diabetes in a population of HIV-infected patients undergoing combined antiretroviral therapy, using three different diagnostic methods (fasting glucose, OGTT and HbA1c), to determine the agreement between the different methods and the characteristics associated with each one. METHODS: This study analyzed 220 HIV-infected patients on antiretroviral therapy. Patient characteristics were collected using a standardized protocol. Disturbances of glucose homeostasis were defined by the ADA 2017 criteria. Patients were characterized according to the presence or absence of clinical lipodystrophy, and distributed into four different categories, according to the presence, or absence of either clinical lipoatrophy, or abdominal prominence. Insulin resistance was assessed by HOMA-IR and QUICKI indexes. Agreement between the diagnostic methods was assessed by Cohen's kappa coefficient. RESULTS: There were no patients diagnosed with diabetes with HbA1c. 5.9% prevalence was obtained when OGTT was used, and 3.2% prevalence when fasting glucose was used. Prediabetes had a prevalence of 14.1% when using HbA1c, 24.1% when using OGTT, and 20% when using fasting glucose. In all three methods, glucose homeostasis disturbances were associated with older age and higher resistance to insulin. Regarding other characteristics, associations varied between the three methods. The agreement between them was fair, or slight. CONCLUSIONS: We observed that HbA1c was the method that diagnosed the least amount of cases and that OGTT was the one that diagnosed the most cases. Accordingly, our results indicate that HbA1c underestimated glycaemia levels in this population and that the use of OGTT might allow an earlier diagnosis of glucose homeostasis disturbances, potentially making it possible to avoid severe complications of DM. PMID- 29980191 TI - The association of mitochondrial DNA haplotypes and phenotypic traits in pigs. AB - BACKGROUND: The mitochondrial genome (mtDNA) is an emerging determiner of phenotypic traits and disease. mtDNA is inherited in a strict maternal fashion from the population of mitochondria present in the egg at fertilisation. Individuals are assigned to mtDNA haplotypes and those with sequences that cluster closely have common origins and their migration patterns can be mapped. Previously, we identified five mtDNA haplotypes in the commercial breeding lines of Australian pigs, which defined their common origins, and showed how these mtDNA haplotypes influenced litter size and reproductive function in terms of egg and embryo quality and fertilisation efficiency. RESULTS: We have determined whether mtDNA haplotypes influence other phenotypic traits. These include fat density; muscle depth; fat to leanness ratios; lifetime daily gain; teat quality; muscle score; front and rear leg assessments; percentage offspring weaned; weaning to oestrus intervals; gilt age at selection; and gestational length. In all, we assessed 5687 pigs of which 2762 were females and 2925 were males. We assessed all animals together and then by gender. We further assessed by gender based on whether a sire had joined with females from only one haplotype or from more than one haplotype. We determined that fat density, muscle depth, fat to leanness ratios, lifetime daily gain and teat quality were influenced by mtDNA haplotype and that there were gender specific effects on teat quality. CONCLUSIONS: Our data illustrate that mtDNA haplotypes are associated with a number of important phenotypic traits indicative of economic breeding values in breeding pigs with gender-specific differences. Interestingly, there are 'trade offs' whereby some mtDNA haplotypes perform better for one selection criterion, such as muscle depth, but less so for another, for example teat quality, indicating that pig mtDNA haplotypes are afforded an advantage in one respect but a disadvantage in another. PMID- 29980192 TI - A pharmacist-led medication switch protocol in an academic HIV clinic: patient knowledge and satisfaction. AB - BACKGROUND: Tenofovir alafenamide (TAF) is associated with less renal and bone toxicity compared with tenofovir disoproxil (TDF). TAF's recent FDA approval has spurred HIV providers to consider switching antiretroviral therapy (ART) regimens containing TDF to TAF to minimize long term risks. Patient views on the process of such medication switches have not been explored. METHODS: Patients taking elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) following the Food and Drug Administration's (FDA) approval of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) received medication education from an HIV pharmacist prior to switching to the tenofovir alafenamide (TAF) formulation. Patients were asked to complete a cross-sectional survey assessing satisfaction with the switch process and knowledge about the new medication 4 to 8 weeks post-switch. RESULTS: Sixty five patients completed the switch and 57 (88%) completed a follow-up survey. Most (86%) reported understanding why the switch was made, while 91% correctly identified that TAF is associated with reduced renal toxicity, and 73% correctly identified that TAF is associated with reduced bone toxicity. No statistically significant difference was found in satisfaction with or understanding of why the medication switch was made when assessed by sex, age, race, or education, but there was a trend toward significance in the distribution of answers based on education level with those with a high school diploma, General Educational Development (GED) or less being more likely to be satisfied with the medication switch (p = 0.074). CONCLUSIONS: Education from an ambulatory clinic-based HIV pharmacist resulted in high rates of patient satisfaction and understanding of the switch from TDF to TAF containing ART. PMID- 29980193 TI - LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway. AB - BACKGROUND: LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear. METHOD: Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting. RESULTS: Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide. CONCLUSION: LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment. PMID- 29980194 TI - MAFb protein confers intrinsic resistance to proteasome inhibitors in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) patients with t(14;20) have a poor prognosis and their outcome has not improved following the introduction of bortezomib (Bzb). The mechanism underlying the resistance to proteasome inhibitors (PIs) for this subset of patients is unknown. METHODS: IC50 of Bzb and carfilzomib (CFZ) in human myeloma cell lines (HMCLs) were established by MTT assay. Gene Expression profile (GEP) analysis was used to determine gene expression in primary myeloma cells. Immunoblotting analysis was performed for MAFb and caspase family proteins. Immunofluorescence staining was used to detect the location of MAFb protein in MM cells. Lentiviral infections were used to knock-down MAFb expression in two lines. Apoptosis detection by flow cytometry and western blot analysis was performed to determine the molecular mechanism MAFb confers resistance to proteasome inhibitors. RESULTS: We found high levels of MAFb protein in cell lines with t(14;20), in one line with t(6;20), in one with Iglambda insertion into MAFb locus, and in primary plasma cells from MM patients with t(14;20). High MAFb protein levels correlated with higher IC50s of PIs in MM cells. Inhibition of GSK3beta activity or treatment with Bzb or CFZ prevented MAFb protein degradation without affecting the corresponding mRNA level indicating a role for GSK3 and proteasome inhibitors in regulation of MAFb stability. Silencing MAFb restored sensitivity to Bzb and CFZ, and enhanced PIs induced apoptosis and activation of caspase-3, - 8, - 9, PARP and lamin A/C suggesting that high expression of MAFb protein leads to insensitivity to proteasome inhibitors. CONCLUSION: These results highlight the role of post translational modification of MAFb in maintaining its protein level, and identify a mechanism by which proteasome inhibitors induced stabilization of MAFb confers resistance to proteasome inhibitors, and provide a rationale for the development of targeted therapeutic strategies for this subset of patients. PMID- 29980195 TI - Reproductive outcomes in women with unicornuate uterus undergoing in vitro fertilization: a nested case-control retrospective study. AB - BACKGROUND: Unicornuate uterus, a congenital uterine malformation resulting from unilateral maldevelopment of Mullerian duct, is more prevalent in women with infertility. Owing to relative rarity of the condition, the evidence on the associated reproductive outcomes is derived from small heterogeneous studies that report different clinical endpoints and often do not account for the anatomical variations of unicornuate uterus. The aim of this study was to evaluate the embryological and clinical outcomes following IVF-ICSI treatment in women with unicornuate uterus without rudimentary functional cavity (ESHRE-ESGE class IVb). METHODS: Retrospective nested case-control study comprised 342 women with unicornuate uterus and 1026 matched controls who underwent IVF-ICSI cycles between October 2012 and October 2016. Cumulative live birth rate upon one complete IVF cycle, including transfers of all resulting embryos was considered as a primary outcome measure. RESULTS: Baseline characteristics were comparable between the unicornuate uterus and control groups except for higher rate of primary infertility in unicornuate uterus. Ovarian response to stimulation did not differ between the groups. Transfer of day-3 embryos in fresh cycle resulted in lower clinical pregnancy rate (35.9% vs. 43.9%, p = 0.028) and live-birth rate (26.9% vs. 35.2%, p = 0.017) per transfer, but the difference was not observed when either cleavage frozen-thaw embryos or blastocysts were transferred. Implantation rate was lower and miscarriage rate was higher in women with unicornuate uterus but the difference between the groups did not reach statistical significance. Transfer of cleavage embryos resulted in significantly higher miscarriage rate and lower live-birth rate in fresh versus frozen-thaw cycles in each group, whereas fresh and frozen-thaw blastocyst embryos had comparable outcomes. Upon completion of one IVF-ICSI cycle, the cumulative pregnancy rate (53.1% vs. 65.7, p < 0.001) and cumulative live birth rate (42.4% vs. 54.6%, p < 0.001) were significantly lower in women with unicornuate uterus compared to those in women with normal uterus. Cumulative outcomes were superior when embryos were cultured to blastocyst stage. CONCLUSIONS: Women with unicornuate uterus have lower clinical pregnancy and live birth rate after IVF ICSI treatment compared to women with normal uterus. The treatment outcomes are improved with blastocyst culture, which warrants evaluation in prospective setting. PMID- 29980196 TI - Increased hypothalamic microglial activation after viral-induced pneumococcal lung infection is associated with excess serum amyloid A production. AB - BACKGROUND: It is well established that lung pathology and inflammation are more severe during respiratory infections complicated by the presence of both bacteria and viruses. Whilst co-infection can result in invasive pneumococcal disease and systemic inflammation, the neuroinflammatory consequences of co-infection are poorly characterised. METHODS: In this study, we utilised a mouse co-infection model involving Streptococcus pneumoniae (S. pneumoniae) and influenza A virus (IAV) lung infection, and we also isolated microglia for ex vivo stimulation with pneumococcus or serum amyloid A (SAA). RESULTS: Co-infection but not S. pneumoniae or IAV alone significantly increased the number of amoeboid-shaped microglia and expression of pro-inflammatory cytokines including tumour necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and C-C motif chemokine ligand-2 (CCL-2) in the hypothalamus. Pneumococcus was only detected in the hypothalamus of co-infected mice. In addition, the systemic inflammatory cytokines TNFalpha, IL-1beta and IL-6 were not elevated in co infected mice relative to IAV-infected mice, whereas SAA levels were markedly increased in co-infected mice (p < 0.05). SAA and its functional receptor termed formyl peptide receptor 2 (Fpr2) transcript expression were also increased in the hypothalamus. In mouse primary microglia, recombinant SAA but not S. pneumoniae stimulated TNFalpha, IL-1beta, IL-6 and CCL-2 expression, and this response was completely blocked by the pro-resolving Fpr2 agonist aspirin-triggered resolvin D1 (AT-RvD1). CONCLUSIONS: In summary, lung co-infection increased the number of 'activated' amoeboid-shaped microglia and inflammatory cytokine expression in the hypothalamus. Whilst persistent pneumococcal brain infection was observed, SAA proved to be a much more potent stimulus of microglia than pneumococci, and this response was potently suppressed by the anti-inflammatory AT-RvD1. Targeting Fpr2 with pro-resolving eicosanoids such as AT-RvD1 may restore microglial homeostasis during severe respiratory infections. PMID- 29980197 TI - The 'lived experience' of palliative care patients in one acute hospital setting a qualitative study. AB - BACKGROUND: There is limited understanding of the 'lived experience' of palliative care patient within the acute care setting. Failing to engage with and understand the views of patients and those close to them, has fundamental consequences for future health delivery. Understanding 'patient experience' can enable care providers to ensure services are responsive and adaptive to individual patient need. METHODS: The aim of this study was to explore the 'lived experience' of a group of patients with palliative care needs who had recently been in-patients in one acute hospital trust in the north-west of England. Qualitative research using narrative interviews was undertaken, and data was analysed using thematic analysis. A sample of 20 consecutive patients complying with the inclusion/exclusion criteria were recruited and interviewed. RESULTS: Patient Sample: Of the 20 patients recruited, there was a fairly equal gender split; all had a cancer diagnosis and the majority were white British, with an age range of 43-87 years. Findings from Interviews: Overall inpatient experience was viewed positively. Individual narratives illustrated compassionate and responsive care, with the patient at the centre. Acts of compassion appeared to be expressed through the 'little things' staff could do for patients, i.e., time to talk, time to care, humanity and comfort measures. AHSPCT involvement resulted in perceived improvements in pain control and holistic wellbeing. However, challenges were evident, particularly regarding over-stretched staff and resources, and modes of communication, which seemed to impact on patient experience. CONCLUSIONS: Listening to patients' experiences of care across the organisation provided a unique opportunity to impact upon delivery of care. Further research should focus on exploring issues such as: why some patients within the same organisation have a positive experience of care, while others may not; how do staff attitudes and behaviours impact on the experience of care; transitions of care from hospital to home, and the role of social networks. PMID- 29980199 TI - Comparison of caries lesion detection methods in epidemiological surveys: CAST, ICDAS and DMF. AB - BACKGROUND: Although dental caries is a globally widespread disease, there is no consensus regarding the method that should be used for their detection. In recent decades, a variety of new methods have been proposed for measuring caries in a population. Three caries detection methods, the decayed, missing and filled (DMF) index, the International Caries Detection and Assessment System (ICDAS) and the Caries Assessment Spectrum and Treatment (CAST), were compared to provide information to guide future method choices. METHODS: This was a descriptive, cross-sectional study in which three methods were used to measure caries in students, staff and their dependents at UNEB (State University of Bahia), Salvador, Brazil. We compared the mean application time of each method and the frequencies obtained by each method using the following indicators: the most severe caries lesion per individual; the mean number of missing, filled and decayed teeth; and the disease extent. RESULTS: The mean time taken to apply the DMF was 3.8 min; for ICDAS, it took 8.9 min, and for CAST, 4.7 min. When calculating the indicator the most severe caries lesion per individual, the prevalence rates were as follows: 28.1% for DMF, 84.0% for ICDAS and 75.0% for CAST. The mean numbers of decayed, missing and filled teeth were 6.0 according to the DMF, 6.2 according to ICDAS and 5.9 according to CAST. When the disease extension indicator was used, the following percentages of teeth were affected by caries: DMF 22.12%, ICDAS 49.11% and CAST 33.2%. CONCLUSIONS: The DMF underestimated the occurrence of caries lesions in individuals but was the fastest method to apply. ICDAS obtained detailed information regarding lesion severity, but it was a time-consuming method and difficult to analyse. CAST described disease distributions very well and identified lesion severities and preventive and curative needs in the examined group, and the time required to apply CAST was similar to that of the DMF. PMID- 29980198 TI - Water extract of Clinacanthus nutans leaves exhibits in vitro, ex vivo and in vivo anti-angiogenic activities in endothelial cell via suppression of cell proliferation. AB - BACKGROUND: Clinacanthus nutans (Burm. f.) Lindau. has traditionally been using in South East Asia countries to manage cancer. However, scientific evidence is generally lacking to support this traditional claim. This study aims to investigate the in vitro, ex-vivo and in vivo effects of C. nutans extracts on angiogenesis. METHODS: C. nutans leaves was extracted with 50-100% ethanol or deionised water at 1% (w/v). Human umbilical veins endothelial cell (HUVEC) proliferation was examined using MTT assay. The in vitro anti-angiogenic effects of C. nutans were assessed using wound scratch, tube formation and transwell migration assays. The VEGF levels secreted by human oral squamous cell carcinoma (HSC-4) cell and HUVEC permeability were also measured. Besides, the rat aortic ring and chick embryo chorioallantoic membrane (CAM) assays, representing ex vivo and in vivo models, respectively, were performed. RESULTS: The MTT assay revealed that water extract of C. nutans leaves exhibited the highest activity, compared to the ethanol extracts. Therefore, the water extract was chosen for subsequent experiments. C. nutans leaf extract significantly suppressed endothelial cell proliferation and migration in both absence and presence of VEGF. However, the water extract failed to suppress HUVEC transmigration, differentiation and permeability. C. nutans water extract also did not suppress HSC-4 cell-induced VEGF production. Importantly, C. nutans water extract significantly abolished the sprouting of vessels in aortic rings as well as in chick embryo CAM. CONCLUSION: In conclusion, these findings reveal potential anti-angiogenic effects of C. nutans, providing new evidence for its potential application as an anti angiogenic agent. PMID- 29980201 TI - Recta Ratio Agibilium in a medical context: the role of virtue in the physician patient relationship. AB - Acting for the good of the patient is the most fundamental and universally acknowledged principle of medical ethics. However, given the complexity of modern medicine as well as the moral fragmentation of contemporary society, determining the good is far from simple. In his philosophy of medicine, Edmund Pellegrino develops a conception of the good that is derived from the internal morality of medicine via the physician-patient relationship. It is through this healing relationship that rights, duties, and privileges are defined for both physicians and patients. Moreover, this relationship determines the characteristics or virtues that are necessary to engage in the medical telos. This paper addresses the role of the moral virtues in clinical medicine and the physician-patient relationship. First, it provides a brief background of the Aristotelian foundations of virtue-ethics. Second, it delves into Pellegrino's philosophy of medicine understood as a practice oriented towards a teleological goal. Third, it relates the telos of medicine to the notion of the medical community as a fundamentally moral community. Finally, it concludes with a section that creates a dialogue between virtue ethics and principlism. PMID- 29980200 TI - Effectiveness and safety of glucosamine and chondroitin for the treatment of osteoarthritis: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To assess the symptomatic effectiveness and safety of oral symptomatic slow-acting drugs (SYSADOAs) on the treatment of knee and/or hip osteoarthritis, such as chondroitin, glucosamine, and combination treatment with chondroitin plus glucosamine. METHODS: We searched electronic database including PubMed, Embase, Cochrane Library, and the reference lists of relevant articles published from inception to May 22, 2018. An updated meta-analysis was performed to assess the effectiveness of these slow-acting drugs for osteoarthritis. RESULTS: Twenty-six articles describing 30 trials met our inclusion criteria and were included in the meta-analysis. The estimates between chondroitin and placebo showed that chondroitin could alleviate pain symptoms and improve function. Compared with placebo, glucosamine proved significant effect only on stiffness improvement. However, the combination therapy did not have enough evidence to be superior to placebo. Additionally, there was no significant difference in the incidence of AEs and discontinuations of AEs when compared with placebo. CONCLUSIONS: Given the effectiveness of these symptomatic slow-acting drugs, oral chondroitin is more effective than placebo on relieving pain and improving physical function. Glucosamine showed effect on stiffness outcome. Regarding on the limited number of combination therapy, further studies need to investigate the accurate effectiveness. This information accompanied with the tolerability and economic costs of included treatments would be conducive to making decisions for clinicians. PMID- 29980202 TI - Comparison of intraoperative handling and wound healing between (NEOSORB(r) plus) and coated polyglactin 910 suture (NEOSORB(r)): a prospective, single-blind, randomized controlled trial. AB - BACKGROUND: Coated polyglactin 910 suture with chlorhexidine (NEOSORB(r) Plus) has recently been developed to imbue the parent suture with antibacterial activity against organisms that commonly cause surgical site infections (SSI). This prospective, single-blinded, randomized trial, was performed to compare the intraoperative handling and wound healing characteristics of NEOSORB(r) Plus with those of the traditional polyglactin 910 suture (NEOSORB(r)) in urologic surgery patients. METHODS: Patients (aged 19 to 80 years, n = 100) were randomized in a 1:1 ratio for treatment with either NEOSORB(r) Plus or NEOSORB(r), and stratified into an open surgery or a minimally invasive surgery group. The primary endpoint was the assessment of overall intraoperative handling of the sutures. Secondary endpoints included specific intraoperative handling measures and wound healing characteristics. Wound healing was assessed at one and 11 days after surgery. Cumulative skin infection, seroma, and suture sinus events within 30 days after surgery were also evaluated. RESULTS: A total of 96 patients were included, with 47 patients in the NEOSORB(r) Plus group and 49 patients in the NEOSORB(r) group. Scores for intraoperative handling were favorable and were not significantly different between the two suture groups. Wound healing characteristics were also comparable. The incidence of adverse events was 13.6%, although none were deemed attributable to the suture, and no difference was observed between the two groups. CONCLUSIONS: NEOSORB(r) Plus is not inferior to traditional sutures in terms of intraoperative handling and wound healing, potentially making NEOSORB(r) Plus a beneficial alternative for patients at increased risk of SSI. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02431039 . Trial registration date 14 August 2015. PMID- 29980203 TI - Using data-driven sublanguage pattern mining to induce knowledge models: application in medical image reports knowledge representation. AB - BACKGROUND: The use of knowledge models facilitates information retrieval, knowledge base development, and therefore supports new knowledge discovery that ultimately enables decision support applications. Most existing works have employed machine learning techniques to construct a knowledge base. However, they often suffer from low precision in extracting entity and relationships. In this paper, we described a data-driven sublanguage pattern mining method that can be used to create a knowledge model. We combined natural language processing (NLP) and semantic network analysis in our model generation pipeline. METHODS: As a use case of our pipeline, we utilized data from an open source imaging case repository, Radiopaedia.org , to generate a knowledge model that represents the contents of medical imaging reports. We extracted entities and relationships using the Stanford part-of-speech parser and the "Subject:Relationship:Object" syntactic data schema. The identified noun phrases were tagged with the Unified Medical Language System (UMLS) semantic types. An evaluation was done on a dataset comprised of 83 image notes from four data sources. RESULTS: A semantic type network was built based on the co-occurrence of 135 UMLS semantic types in 23,410 medical image reports. By regrouping the semantic types and generalizing the semantic network, we created a knowledge model that contains 14 semantic categories. Our knowledge model was able to cover 98% of the content in the evaluation corpus and revealed 97% of the relationships. Machine annotation achieved a precision of 87%, recall of 79%, and F-score of 82%. CONCLUSION: The results indicated that our pipeline was able to produce a comprehensive content based knowledge model that could represent context from various sources in the same domain. PMID- 29980204 TI - Multimorbidity and mortality thereof, among non-western refugees and family reunification immigrants in Denmark - a register based cohort study. AB - BACKGROUND: The prevalence of multimorbidity, defined by having two or more chronic diseases, is increasing in many Western countries. Simultaneously, the migrant population in Western countries has increased, making up a growing proportion of European populations. This study aims i) to determine the quantity and quality of multimorbidity patterns among refugees and family reunification immigrants from non-Western countries compared to Danish-born, and ii) to compare the mortality burden among those with multimorbidity in the two groups. METHODS: Through the Danish Immigration Service, we conducted a historically prospective cohort study. We identified a total of 101,894 adult migrants who were sub categorised into refugees and family reunification immigrants, and matched them to a Danish-born comparison group 1:6 on age and sex. Through the Danish National Patient Registry, we obtained information on all in- and outpatient data on hospitalised and ambulatory patients. To assess multimorbidity we used Charlson Comorbidity Index based on ICD-10 codes, together with ICD-10 diagnostic categories for psychiatric disease. We used Cox regression analysis to calculate risk of multimorbidity and risk of mortality in people with multimorbidity. RESULTS: Overall refugees had higher risk of multimorbidity compared to Danish born, while family reunification immigrants had a lower risk. When adjusting for civil status and mean income, the risk was lower for all migrant groups compared to Danish-born. Risk of mortality in people with multimorbidity, was lower for all migrant groups, compared to Danish-born. CONCLUSION: Refugees are an at-risk group for multimorbidity, however, mortality among those with multimorbidity is lower in all migrant groups compared to Danish-born. PMID- 29980205 TI - Genetic characterization and mutation analysis of Qihe547 Aujeszky's disease virus in China. AB - BACKGROUND: Aujeszky's disease virus (ADV) can cause neurologic disease in young pigs, respiratory disease in older pigs and abortion or birth of mummified fetuses or stillborn neonates. The re-emergence of Aujeszky's disease (AD) in pig farms vaccinated with live vaccine (Bartha-K61) caused substantial economic losses to Chinese pig industry since late 2011. A field ADV, named Qihe547, was isolated from pigs that exhibited suspected AD clinical symptoms. To better understand the genetic characteristics and mutations of Qihe547 ADV, the whole genome was sequenced and analyzed. RESULTS: The genomic length of Qihe547 ADV was 143,404 bp, with 73.59% G + C contents. Phylogenetic analysis based on the whole genome of ADV strains revealed that Chinese ADV strains were located to one group with three subgroups. Qihe547 ADV was closely related to these novel ADV strains isolated in China since 2012. Qihe547 presented numerous hypervariable regions compared with oversea ADV strains. In 34 genes of Qihe547 ADV, amino acid (AA) insertion or deletion were observed. In addition, numerous AA mutations were found in the main protective antigen genes (gB, gC and gD genes). The differences of potential antigenic peptides in the main protective antigens between Qihe547 ADV and ADV Bartha were discovered in the dominant antigenic regions of gB (AA59 AA126, AA507-AA734),the extracellular region of gC and gD. CONCLUSION: High diversity was observed between Qihe547 and foreign ADV isolates. The AA variations and the differences of potential antigenic peptides in the important functional regions of the main protective antigen (gB, gC and gD) of ADV Qihe547 may contribute to immune evasion of the virus and may be partial reason that the virus escapes from the vaccination of Bartha-K61 vaccine. In a word, the effect of the variations obviously requires further research. PMID- 29980207 TI - Validity of environmental audits using GigaPan(r) and Google Earth Technology. AB - BACKGROUND: Health behaviors are shaped by the context in which people live. However, documenting environmental context has remained a challenge. More specifically, direct observation techniques require large investments in time and resources and auditing the environment through web-based platforms has limited stability in spatio-temporal imagery. This study examined the validity of a new methodology, using GigaPan(r) imagery, where we took photos locally and, stitched them together using GigaPan(r) technology, and quantified environmental attributes from the resulting panoramic photo. For comparison, we examined validity using Google Earth imagery. METHODS: A total of 464 street segments were assessed using three methods: GigaPan(r) audits, Google Earth audits, and direct observation audits. Thirty-seven different attributes were captured representing three broad constructs: land use, traffic and safety, and amenities. Sensitivity (i.e. the proportion of true positives) and specificity (i.e. the proportion of true negatives) were used to estimate the validity of GigaPan(r) and Google Earth audits using direct observation audits as the gold standard. RESULTS: Using GigaPan(r), sensitivity was 80% or higher for 6 of 37 items and specificity was 80% or higher for 31 of 37 items. Using Google Earth, sensitivity was 80% or higher for 8 of 37 items and specificity was 80% or higher for 30 of 37 items. The validity of GigaPan(r) and Google Earth was similar, with significant differences in sensitivity and specificity for 7 items and 2 items, respectively. CONCLUSION: GigaPan(r) performed well, especially when identifying features absent from the environment. A major strength of the GigaPan(r) technology is its ability to be implemented quickly in the field relative to direct observation. GigaPan(r) is a method to consider as an alternative to direct observation when temporality is prioritized or Google Earth imagery is unavailable. PMID- 29980206 TI - Haemolysis and haem oxygenase-1 induction during persistent "asymptomatic" malaria infection in Burkinabe children. AB - BACKGROUND: The haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO 1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed "asymptomatic" and the consequences of low-grade haemolysis during subclinical malaria infection are unknown. STUDY DESIGN AND RESULTS: As part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration. CONCLUSIONS: This study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities. PMID- 29980208 TI - Non-typhoidal Salmonella serovars in poultry farms in central Ethiopia: prevalence and antimicrobial resistance. AB - BACKGROUND: Poultry is one of the common sources of non-typhoidal Salmonella and poultry products are the major sources of human infection with non-typhoidal Salmonella. In spite of flourishing poultry industry in the country, data on prevalence and antimicrobial susceptibility of non-typhoidal Salmonella serovars at farm level is not available in Ethiopia. This study investigated prevalence, serotype distribution and antimicrobial resistance of non-typhoidal Salmonella in poultry farms in Addis Ababa and its surrounding districts. RESULTS: A total of 549 fresh pool of fecal droppings (n = 3 each) were collected from 48 poultry farms and cultured for Salmonella using standard laboratory technique and serotyped using slide agglutination technique. Susceptibility of Salmonella isolates to18 antimicrobials was tested according to CLSI guideline using Kirby Bauer disk diffusion assay. Salmonella was recovered in 7 (14.6%) of the farms and 26 (4.7%) of the samples. Salmonella was more common in poultry farms with larger flock size than in the smaller ones and in Ada'a district as compared to other districts. All isolates were obtained from farms containing layers. Two out of 6 (33.3%) farms that kept birds in cage were positive for Salmonella while only 5 (11.9%) of the 42 farms who used floor system were positive. Oxytetracycline was used widely in 40 (83.3%) of the farms, followed by amoxicillin 14 (29.2%) and sulfonamides 11 (22.9%). Salmonella Saintpaul was the dominant serotype detected accounting for 20 (76.9%) of all isolates. Other serovars, such as S. Typhimurium3 (11.5%), S. Kentucky 2 (7.7%) and S. Haifa 1 (3.8%) were also detected. Of all the Salmonella isolates tested, 24 (92.3%) were intermediately or fully resistant to sulfisoxazole and streptomycin, 12 (46.2%) to cephalothin, while 11 (42.3%) were resistant to ampicillin, amoxicillin+clavulanic acid, kanamycin and chloramphenicol. Multidrug resistance (MDR) to several drugs was common in S. Kentucky and S. Saintpaul. CONCLUSION: Despite low prevalence of Salmonella in poultry farms in the study area, circulation of MDR strains in some farms warrant special biosecurity measures to hinder dissemination of these pathogens to other farms and the public. Moreover, awareness creation on prudent use of antimicrobials is recommended. PMID- 29980209 TI - Effect of prolonged submaximal exercise on serum oxidative stress biomarkers (d ROMs, MDA, BAP) and oxidative stress index in endurance horses. AB - BACKGROUND: Oxidative stress (OS) associated with an intense exercise may have a negative influence on equine health. The aim of this study was to determine the effects of endurance races on oxidative and antioxidative status of horses by evaluating changes in reactive oxygen metabolites (d-ROMs), malondialdehyde (MDA), biological antioxidant potential (BAP) and oxidative stress index (OSI) values. The study was carried out on 53 race starts (28 individual horses) competing at different endurance races according to distance (40 and 80 km) and difficulty (easy and demanding). Blood samples were taken before and after the race. RESULTS: Compared to levels of OS serum biomarkers before the race, an increase in values of d-ROMs (P < 0.01), MDA (P < 0.01), and BAP (P < 0.001), and a decrease in OSI (P < 0.001) have been noted after the race. Contrary to other measured biomarkers, BAP did not show significant individual effects of horses. Horses competing at shorter races have shown a significant change in d ROMs (P = 0.002), BAP (P < 0.001) and OSI (P = 0.004), whereas those competing at longer races in MDA (P = 0.002), BAP (P < 0.001) and OSI (P < 0.001) post race values. Endurance racing induced changes in values of d-ROMs, BAP and OSI during both easy and demanding races. CONCLUSIONS: Changes in all measured OS biomarkers indicate that prolonged aerobic exercise during endurance race could contribute to the imbalance between oxidants and antioxidants in horses, mainly characterised by a pronounced antioxidant response. Biological antioxidant potential was found to be the most reliable biomarker of OS in endurance horses in the present study. PMID- 29980210 TI - Phenotype-driven gene prioritization for rare diseases using graph convolution on heterogeneous networks. AB - BACKGROUND: One of the major goals of genomic medicine is the identification of causal genomic variants in a patient and their relation to the observed clinical phenotypes. Prioritizing the genomic variants by considering only the genotype information usually identifies a few hundred potential variants. Narrowing it down further to find the causal disease genes and relating them to the observed clinical phenotypes remains a significant challenge, especially for rare diseases. METHODS: We propose a phenotype-driven gene prioritization approach using heterogeneous networks in the context of rare diseases. Towards this, we first built a heterogeneous network consisting of ontological associations as well as curated associations involving genes, diseases, phenotypes and pathways from multiple sources. Motivated by the recent progress in spectral graph convolutions, we developed a graph convolution based technique to infer new phenotype-gene associations from this initial set of associations. We included these inferred associations in the initial network and termed this integrated network HANRD (Heterogeneous Association Network for Rare Diseases). We validated this approach on 230 recently published rare disease clinical cases using the case phenotypes as input. RESULTS: When HANRD was queried with the case phenotypes as input, the causal genes were captured within Top-50 for more than 31% of the cases and within Top-200 for more than 56% of the cases. The results showed improved performance when compared to other state-of-the-art tools. CONCLUSIONS: In this study, we showed that the heterogeneous network HANRD, consisting of curated, ontological and inferred associations, helped improve causal gene identification in rare diseases. HANRD allows future enhancements by supporting incorporation of new entity types and additional information sources. PMID- 29980211 TI - Evaluation of relationship between endodontic access cavity types and secondary mesiobuccal canal detection. AB - BACKGROUND: The aim of this study was to evaluate the relationship between Endodontic Access Cavity (EAC) types with MB2 canal detection ratio in the upper first molars. METHODS: A total of 60 roots of extracted human maxillary first molars were selected. All teeth were prepared with Point EAC (PEAC), Conservative EAC (CEAC) and Traditional EAC (TEAC) respectively. After each group were completed, extra canal was searched. Preoperative and postoperative tooth weigh was calculated using precise scale. McNemar's chi-square test and a paired test significant difference were used for statistical analyses. RESULTS: The EAC types statistically were changed of tooth tissue loss quantity (p = 0.000). MB2 detection rate of CEAC (%53,3) and TEAC (%60) are higher than statistically that of PEAC (%31.6) (p < 0.05). 8 teeth MB2 canal was detected only with the CBCT images. CONCLUSIONS: In upper molars, CEAC seems reasonable in terms of detected the MB2 canal and removed hard tissue. PMID- 29980212 TI - Necroptosis: a regulated inflammatory mode of cell death. AB - Programmed cell death has a vital role in embryonic development and tissue homeostasis. Necroptosis is an alternative mode of regulated cell death mimicking features of apoptosis and necrosis. Necroptosis requires protein RIPK3 (previously well recognized as regulator of inflammation, cell survival, and disease) and its substrate MLKL, the crucial players of this pathway. Necroptosis is induced by toll-like receptor, death receptor, interferon, and some other mediators. Shreds of evidence based on a mouse model reveals that deregulation of necroptosis has been found to be associated with pathological conditions like cancer, neurodegenerative diseases, and inflammatory diseases. In this timeline article, we are discussing the molecular mechanisms of necroptosis and its relevance to diseases. PMID- 29980213 TI - Analysis of induced abortion-related complications in women admitted to the Kinshasa reference general hospital: a tertiary health facility, Democratic Republic of the Congo. AB - BACKGROUND: Due to a lack of relevant data on induced abortions in the Democratic Republic of the Congo (DRC) as well as the persistence of maternal deaths in the country, this study aims to analyse the induced abortion-related complications in women who were admitted to the Kinshasa Reference General Hospital (KRGH). METHODS: This is a cross-sectional study on 368 obstetric and gynecological patients who were admitted, as emergency cases, to the KRGH during 2014. This health facility was selected because it is a tertiary health facility with an obstetric and gynecological emergency unit most used in the city of Kinshasa. Patient data were collected from patient records and analyzed. RESULTS: From the 368 patients admitted to receive obstetric and gynecological emergency care services in 2014 at the KRGH, 12.2% (95% CI: 9.1-16.1%) had complications due to induced abortion that was significantly diagnosed to adolescents (p < 0.001), single or separated or divorced women or widow(p < 0.001), and to patients with history of one or several induced abortions(p < 0.001). The median duration of hospitalization was ten days and this period of time was significantly longer for the patients who underwent surgery for pelvic peritonitis due to uterine perforation(p < 0.001) compared with the group of patients who underwent Caesarean section/hysterectomy. The mortality rate related to them is 37.8% (95% CI: 23.8-53.5%) with an increase of risk of death in the presence of a post abortive pelvic peritonitis-type complication, 56.3% of deaths occurred after two days of hospitalization. CONCLUSION: The complications of induced abortions are a major public health problem due to its frequency among patients admitted to the KRGH, as well as the poor medical management, and mortality percentage related to them. Therefore, there is a need to understand the reason for the poor medical management to fill in and provide an adequate intervention package. PMID- 29980214 TI - Investigating rectal toxicity associated dosimetric features with deformable accumulated rectal surface dose maps for cervical cancer radiotherapy. AB - BACKGROUND: Better knowledge of the dose-toxicity relationship is essential for safe dose escalation to improve local control in cervical cancer radiotherapy. The conventional dose-toxicity model is based on the dose volume histogram, which is the parameter lacking spatial dose information. To overcome this limit, we explore a comprehensive rectal dose-toxicity model based on both dose volume histogram and dose map features for accurate radiation toxicity prediction. METHODS: Forty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively studied, including 12 with Grade >= 2 rectum toxicity and 30 patients with Grade 0-1 toxicity (non-toxicity patients). The cumulative equivalent 2-Gy rectal surface dose was deformably summed using the deformation vector fields obtained through a recent developed local topology preserved non-rigid point matching algorithm. The cumulative three-dimensional (3D) dose was flattened and mapped to a two dimensional (2D) plane to obtain the rectum surface dose map (RSDM). The dose volume parameters (DVPs) were calculated from the 3D rectum surface, while the texture features and the dose geometric parameters (DGPs) were extracted from the 2D RSDM. Representative features further computed from DVPs, textures and DGPs by principle component analysis (PCA) and statistical analysis were respectively fed into a support vector machine equipped with a sequential feature selection procedure. The predictive powers of the representative features were compared with the GEC-ESTRO dosimetric parameters D0.1/1/2cm3. RESULTS: Satisfactory predictive accuracy of sensitivity 74.75 and 84.75%, specificity 72.67 and 79.87%, and area under the receiver operating characteristic curve (AUC) 0.82 and 0.91 were respectively achieved by the PCA features and statistical significant features, which were superior to the D0.1/1/2cm3 (AUC 0.71). The relative area in dose levels of 64Gy, 67Gy, 68Gy, 87Gy, 88Gy and 89Gy, perimeters in dose levels of 89Gy, as well as two texture features were ranked as the important factors that were closely correlated with rectal toxicity. CONCLUSIONS: Our extensive experimental results have demonstrated the feasibility of the proposed scheme. A future large patient cohort study is still needed for model validation. PMID- 29980215 TI - Incorporating a structural approach to reducing the burden of non-communicable diseases. AB - BACKGROUND: Non-communicable diseases (NCDs) account for over two-thirds of deaths worldwide, and global efforts to address NCDs have accelerated. Current prevention and control efforts rely primarily on individual behavior/lifestyle approaches that place the onus of responsibility for health on the individual. These approaches, however, have not stopped the increasing trend of NCDs worldwide. Thus, there is urgent need for exploring alternative approaches in order to attain the aim of reducing global premature NCDs mortality by 25% by 2025, and meeting the NCD reduction objective in the Sustainable Development Goals. DISCUSSION: We suggest the need for a structural approach to addressing the NCDs epidemic that integrates social science and public health theories. We evaluate two overarching principles (empowerment and human rights) and three social determinants of health (labor and employment, trade and industry, and macroeconomics) addressed in the 2013 Global Action Plan for the Prevention and Control of NCDs to demonstrate how a structural approach to NCDs can be incorporated into existing NCD interventions. For each area considered, theoretical considerations for structural thinking are provided and conclude with recommended actions. CONCLUSION: Achieving the global health agenda goals of reducing NCDs mortality will require a shift to a paradigm that embraces concerted efforts to address both behavioral/lifestyle factors and structural dimensions of NCDs. PMID- 29980216 TI - Molecular diagnosis of anti-laminin 332 (epiligrin) mucous membrane pemphigoid. AB - BACKGROUND: Mucous membrane pemphigoid is a group of chronic subepithelial autoimmune blistering diseases that mainly affect mucous membranes. Laminin 332 specific autoantibodies are present in approximately 1/3 of the patients, being associated with an increased risk of malignancy. Because of the severe complications, an early recognition of the disease allowing a timely therapy is essential. The gold standard methods for detection of laminin 332-specific autoantibodies, including the immunoprecipitation and immunoblotting are non quantitative, laborious and restricted to a few specialized laboratories worldwide. In addition, the use of radioimmunoassays, although highly sensitive and specific, are laborious, expensive and tightly regulated. Therefore, there is a stringent need for a quantitative immunoassay for the routine detection of laminin 332-specific autoantibodies more broadly available to diagnostic laboratories. The aim of this study was to compare different antigenic substrates, including native, recombinant laminin 332 and laminin 332-rich keratinocyte extracellular matrix, for development of an ELISA to detect autoantibodies in mucous membrane pemphigoid. RESULTS: Using a relatively large number of sera from MMP patients with well-characterized autoantibody reactivity we show the suitability of ELISA systems using laminin 332 preparations as adjunct diagnostic tools in MMP. While glycosylation of laminin 332 does not appear to influence its recognition by MMP autoantibodies, ELISA systems using both purified, native and recombinant laminin 332 demonstrated a high sensitivity and good correlation with the detection of autoantibodies by immunoblotting. ELISA systems using different laminin 332 preparations represent a feasible and more accessible alternative for a broad range of laboratories. CONCLUSIONS: Our findings qualify the use of immunoassays with the laminin 332-rich preparations as an ancillary diagnostic tool in mucous membrane pemphigoid. PMID- 29980218 TI - Clinical characteristics and prognosis of bacteraemia during postoperative intra abdominal infections. AB - BACKGROUND: Bloodstream infections of abdominal origin are usually associated with poor prognosis. We assessed the clinical and microbiological characteristics of critically ill patients admitted to the intensive care unit (ICU) for postoperative intra-abdominal infection (PIAI) and analysed the influence of bacteraemia on their outcome. METHODS: All consecutive PIAI patients admitted to the ICU between 1999 and 2014 were prospectively analysed. Bacteraemic patients (at least one positive blood culture in the 24 h preceding/following surgery) were compared with non-bacteraemic patients. Demographic characteristics, underlying disease, severity scores at the time of reoperation, microbiological results, therapeutic management, outcome, and survival were recorded. Results are expressed as median (interquartile range (IQR)) or proportions. RESULTS: Overall, 343 patients (54% male, 62 (49-73) years old) with PIAI were analysed, including 64 (19%) bacteraemic patients. Immunosuppression and cancer were more frequent in bacteraemic patients (p < 0.001 in both cases). No difference between groups was observed for the characteristics of initial surgery. Time to reoperation, site, and cause of PIAI were similar in both groups. At the time of reoperation, Sequential Organ Failure Assessment (SOFA) score was higher in bacteraemic patients (8 (6-10) versus 7 (4-10); p < 0.05). A predominance of Gram-positive (34%) and Gram-negative (47%) bacteria were recovered from blood cultures (polymicrobial bacteraemia in 9 (14%) patients and bacteraemia involving multidrug-resistant organisms in 14 (22%) patients). In multivariate analysis, risk factors for bacteraemia were immunosuppression or cancer, high SOFA score, and E. coli in peritoneal samples. Bacteraemia did not impact the management (with similar results for the adequacy of antibiotic therapy, anti-infective agents used, de-escalation or duration of therapy in both groups). Neither hospital mortality nor morbidity criteria differed between groups. Risk factors for mortality in multivariate analysis were urgent initial surgery, high Simplified Acute Physiology Score (SAPS) II score and documented antifungal therapy, but not perioperative bacteraemia. CONCLUSIONS: In this ICU population, bacteraemia did not change the overall management of patients with PIAI. Our data suggest that bacteraemic patients do not require a specific management. PMID- 29980219 TI - PD-1 deficiency promotes TFH cells expansion in ITV-immunized mice by upregulating cytokines secretion. AB - BACKGROUND: T follicular helper (TFH) cells are fundamental for the development of humoral immunity. In our previous study, we found that PD-1 deficiency substantially promoted the expansion of Plasmodium-specific TFH cells and enhanced the humoral immunity of ITV (infection treatment vaccine)-immunized mice. However, the underlying mechanism by which PD-1 signaling modulates TFH cells activation remains unclear. METHODS: Mice were immunized with the ITV following the standard procedures. The activation phenotype of CD11c+CXCR5+ dendritic cells (DCs), the frequency and number of splenic follicular regulatory T cells (TFR cells), Plasmodium-specific TFH cells and germinal center (GC) B cells were analyzed by FACS. The levels of serum cytokines were quantified using the cytometric bead array (CBA) and in vivo cytokine neutralization was carried out according to a previously described protocol and verified by serum cytokine detection. RESULTS: We found that PD-1-/- naive and immunized mice had more TFR cells in the spleen than WT and WT immunized mice. Additionally, CXCR5+ DC, which prime TFH cells, were activated at similar levels in ITV-immunized WT and PD-1-/- mice. However, the serum levels of IL-10, IFN-gamma and MCP-1 were significantly increased in ITV-immunized PD-1-/- mice, and treatment with an anti-IL-10, anti IFN-gamma or anti-MCP-1 neutralizing antibody in vivo markedly impaired the development of TFH cells and GC B cells. CONCLUSIONS: Our findings demonstrate that the modulation of TFH cells by PD-1 signaling is dependent on the cytokines IL-10, IFN-gamma and MCP-1 in ITV-immunized mice. These results could facilitate the design of an effective malaria vaccine with the aim of inducing humoral immune responses. PMID- 29980217 TI - Definitions and pathophysiology of vasoplegic shock. AB - Vasoplegia is the syndrome of pathological low systemic vascular resistance, the dominant clinical feature of which is reduced blood pressure in the presence of a normal or raised cardiac output. The vasoplegic syndrome is encountered in many clinical scenarios, including septic shock, post-cardiac bypass and after surgery, burns and trauma, but despite this, uniform clinical definitions are lacking, which renders translational research in this area challenging. We discuss the role of vasoplegia in these contexts and the criteria that are used to describe it are discussed. Intrinsic processes which may drive vasoplegia, such as nitric oxide, prostanoids, endothelin-1, hydrogen sulphide and reactive oxygen species production, are reviewed and potential for therapeutic intervention explored. Extrinsic drivers, including those mediated by glucocorticoid, catecholamine and vasopressin responsiveness of the blood vessels, are also discussed. The optimum balance between maintaining adequate systemic vascular resistance against the potentially deleterious effects of treatment with catecholamines is as yet unclear, but development of novel vasoactive agents may facilitate greater understanding of the role of the differing pathways in the development of vasoplegia. In turn, this may provide insights into the best way to care for patients with this common, multifactorial condition. PMID- 29980220 TI - Comparison of cold and hot snaring polypectomy for small colorectal polyps: study protocol for a randomized controlled trial. AB - BACKGROUND: Colorectal cancer remains a considerable challenge in healthcare nowadays. Most patients' disease develops via the adenoma-carcinoma sequence; colonoscopy with polypectomy effectively reduces both mortality and incidence by removing precancerous adenomas. Previous studies showed that polypectomy without electrocautery (cold snaring polypectomy) is a safe and time-saving procedure to manage polyps < 10 mm. However, randomized controlled trials have failed to prove the superiority of cold snaring polypectomy for reducing the risk of delayed bleeding in comparison with hot snaring polypectomy, generally because of their low statistical power that was limited by sample sizes. In this study, we aim to compare the risk of delayed bleeding following cold and hot snaring polypectomy based on a large sample size. METHODS: This is a prospective multicentre randomized controlled trial to compare cold and hot snaring polypectomy for the treatment of small colorectal polyps. A total of 4258 patients with small polyps (4-10 mm) will be randomized 1:1 to each group. Colonoscopy and polypectomy will be performed by 17 experienced endoscopists at six study sites. The randomization will be performed via an online website. Pathological examination using image enhanced endoscopy with either narrow-band imaging or chromoendoscopy will be conducted to confirm optically and histologically that complete resections have been achieved, respectively. The primary outcome measurement is the risk of delayed bleeding. The secondary outcome measurements include the number of hemoclip applications, complete eradication confirmed optically and histologically, tissue retrieval rate, procedure time, emergency unit visits, and any adverse events such as immediate bleeding or perforation. DISCUSSION: We hypothesize that cold snaring polypectomy can reduce the risk of delayed bleeding by avoiding thermal injury. In addition, this study will also compare cold and hot snaring polypectomy in terms of the complete eradication rate and procedure time. Based on data collected, we will demonstrate that cold snaring polypectomy is a safe, effective, and economic procedure for small colorectal polyps. The results will also provide additional data on which to develop recommendations for treating small colorectal polyps. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03373136 . Registered on 29 November 2017. PMID- 29980221 TI - Modeling protein folding in vivo. AB - : A half century of studying protein folding in vitro and modeling it in silico has not provided us with a reliable computational method to predict the native conformations of proteins de novo, let alone identify the intermediates on their folding pathways. In this Opinion article, we suggest that the reason for this impasse is the over-reliance on current physical models of protein folding that are based on the assumption that proteins are able to fold spontaneously without assistance. These models arose from studies conducted in vitro on a biased sample of smaller, easier-to-isolate proteins, whose native structures appear to be thermodynamically stable. Meanwhile, the vast empirical data on the majority of larger proteins suggests that once these proteins are completely denatured in vitro, they cannot fold into native conformations without assistance. Moreover, they tend to lose their native conformations spontaneously and irreversibly in vitro, and therefore such conformations must be metastable. We propose a model of protein folding that is based on the notion that the folding of all proteins in the cell is mediated by the actions of the "protein folding machine" that includes the ribosome, various chaperones, and other components involved in co translational or post-translational formation, maintenance and repair of protein native conformations in vivo. The most important and universal component of the protein folding machine consists of the ribosome in complex with the welcoming committee chaperones. The concerted actions of molecular machinery in the ribosome peptidyl transferase center, in the exit tunnel, and at the surface of the ribosome result in the application of mechanical and other forces to the nascent peptide, reducing its conformational entropy and possibly creating strain in the peptide backbone. The resulting high-energy conformation of the nascent peptide allows it to fold very fast and to overcome high kinetic barriers along the folding pathway. The early folding intermediates in vivo are stabilized by interactions with the ribosome and welcoming committee chaperones and would not be able to exist in vitro in the absence of such cellular components. In vitro experiments that unfold proteins by heat or chemical treatment produce denaturation ensembles that are very different from folding intermediates in vivo and therefore have very limited use in reconstructing the in vivo folding pathways. We conclude that computational modeling of protein folding should deemphasize the notion of unassisted thermodynamically controlled folding, and should focus instead on the step-by-step reverse engineering of the folding process as it actually occurs in vivo. REVIEWERS: This article was reviewed by Eugene Koonin and Frank Eisenhaber. PMID- 29980223 TI - Semilobar holoprosencephaly with cebocephaly associated with maternal early onset preeclampsia: a case report. AB - BACKGROUND: The term holoprosencephaly was proposed by DeMyer and Zeman. It is a developmental defect of the embryonic forebrain with heterogeneous etiology including genetic and environmental factors. It is commonly associated with midfacial defects and has a spectrum of presentations. There are four types: alobar, semilobar, lobar, and variant. Holoprosencephaly is relatively rare. The overall prevalence in a multicenter study was 1 in 13,000 to 18,000 live births. However, the presentation of holoprosencephaly with cebocephaly, micropenis, agenesis of middle phalanges of the fifth finger, and postaxial polydactyly in association with early onset preeclampsia is extremely rare. We report a case with a constellation of the above congenital anomalies. CASE PRESENTATION: A 34 year-old gravida II para l woman presented to Felege Hiwot Referral Hospital with the diagnosis of semilobar holoprosencephaly and early onset preeclampsia with severity features. The gestational age at admission was 26 + 3 weeks. She is Amhara by ethnicity. The pregnancy was from a non-consanguineous marriage. She presented with the complaints of severe and persistent headache associated with blurring of vision and generalized body swelling. After she was stabilized, she and her husband were counselled and termination was decided. She gave birth after three doses of 100 microgram misoprostol given vaginally every 3 hours. The outcome was 1.1 kg male neonate; there were associated dysmorphic features of holoprosencephaly such as cebocephaly, micropenis, and postaxial polydactyl with agenesis of middle phalanges of the fifth finger. Only basic care was given and the neonate died after 20 minutes' stay in our neonatal intensive care unit. The mother was counselled to have preconception and antenatal screening in her next pregnancy. She left the hospital relatively well. CONCLUSION: In women with a history of holoprosencephaly or holoprosencephaly in the current pregnancy, antenatal workups should include workup for fetal chromosomal disorders and metabolic workup for maternal preeclampsia. Sonographic diagnoses of holoprosencephaly always need a careful search for other congenital anomalies. In the severe forms, early termination should be counseled for its poor prognosis. Associated severe congenital anomalies and severe morbidities of the survivor can be discussed while counselling. PMID- 29980222 TI - Early application of continuous high-volume haemofiltration can reduce sepsis and improve the prognosis of patients with severe burns. AB - BACKGROUND: In the early stage of severe burn, patients often exhibit a high level of inflammatory mediators in blood and are likely to develop sepsis. High volume haemofiltration (HVHF) can eliminate these inflammatory mediators. We hypothesised that early application of HVHF may be beneficial in reducing sepsis and improving the prognosis of patients with severe burns. METHODS: Adults patients with burns >= 50% total burn surface area (TBSA) and in whom the sum of deep partial and full-thickness burn areas was >= 30% were enrolled in this randomised prospective study, and they were divided into control (41 cases) and HVHF (41 cases) groups. Patients in the control group received standard management for major burns, whereas the HVHF group additionally received HVHF treatment (65 ml/kg/h for 3 consecutive days) within 3 days after burn. The incidence of sepsis and mortality, some laboratory data, levels of inflammatory cytokines in the blood, HLA-DR expression on CD14+ peripheral blood monocytes, the proportion of CD25+Foxp3+ in CD4+ T lymphocytes, and the counts of CD3+, CD4+ and CD8+ T lymphocytes were recorded within 28 days post-burn. RESULTS: The incidence of sepsis, septic shock and duration of vasopressor treatment were decreased significantly in the HVHF group. In addition, in the subgroup of patients with burns >= 80% TBSA, the 90-day mortality showed significant decreases in the HVHF group. The ratio of arterial oxygen partial pressure to the fraction of inspiration oxygen was improved after HVHF treatment. In the patients who received HVHF treatment, the blood levels of inflammatory cytokines, including tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and IL-8, as well as the blood level of procalcitonin were found to be lower than in the control group. Moreover, higher HLA-DR expression on CD14+ monocytes and a lower proportion of CD25+Foxp3+ in CD4+ T lymphocytes were observed in the patients in the HVHF group. CONCLUSIONS: Early application of HVHF benefits patients with severe burns, especially for those with a greater burn area (>= 80% TBSA), decreasing the incidence of sepsis and mortality. This effect may be attributed to its early clearance of inflammatory mediators and the recovery of the patient's immune status. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR-TRC-12002616 . Registered on 24 October 2012. PMID- 29980224 TI - Effect of low-normal and high-normal IGF-1 levels on memory and wellbeing during growth hormone replacement therapy: a randomized clinical trial in adult growth hormone deficiency. AB - BACKGROUND: The aim of the present study was to investigate the effect of low normal and high-normal levels of IGF-1 in growth hormone (GH) deficient adults on cognition and wellbeing during GH treatment. METHODS: A randomized, open-label, clinical trial including 32 subjects receiving GH therapy for at least 1 year. Subjects were randomized to receive either a decrease (IGF-1 target level of - 2 to - 1 SDS) or an increase of their daily GH dose (IGF-1 target level of 1 to 2 SDS) for a period of 24 weeks. Memory was measured by the Cambridge Neuropsychological Test Automated Battery, selecting the Pattern Recognition Memory task and the Spatial Working Memory. Wellbeing was measured as mood by the Profile of Moods States questionnaire, and quality of life by the Nottingham Health Profile and QoL Assessment in GH Deficiency in Adults questionnaires. RESULTS: Data from 30 subjects (65.6% male, mean age 46.6 (9.9 SD) years), who fulfilled the target levels, were analyzed. Females in the low dose treatment arm were found to have a better working memory and a better strategic memory control after 24 weeks as opposed to the females in the high treatment arm. With respect to mood, the decrease in IGF-1 levels in females within the low treatment arm was associated with more fatigue and less vigor. CONCLUSIONS: The adjustment of GH dose in female patients seems to have a narrow window. A dose too high may impair prefrontal cognitive functioning, while a dose too low may result in decreased vigor. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT01877512. PMID- 29980225 TI - Electroacupuncture ameliorate learning and memory by improving N-acetylaspartate and glutamate metabolism in APP/PS1 mice. AB - OBJECTIVE: To explore the precise mechanism of electroacupuncture (EA) to delay cognitive impairment in Alzheimer disease. METHODS: N-Acetylaspartate (NAA), glutamate (Glu) and myoinositol (mI) metabolism were measured by magnetic resonance spectroscopy, learning and memory of APP/PS1 mouse was evaluated by the Morris water maze test and the step-down avoidance test, neuron survival number and neuronal structure in the hippocampus were observed by Nissl staining, and BDNF and phosphorylated TrkB detected by Western blot. RESULTS: EA at DU20 acupuncture significantly improve learning and memory in behavioral tests, up regulate NAA, Glu and mI metabolism, increase the surviving neurons in hippocampus, and promote the expression of BDNF and TrkB in the APP/PS1 transgenic mice. CONCLUSION: These findings suggested that EA is a potential therapeutic for ameliorate cognitive dysfunction, and it might be due to EA could improve NAA and Glu metabolism by upregulation of BDNF in APP/PS1 mice. PMID- 29980226 TI - Immunohistochemical staining patterns of alpha-keratins in normal tissues from two reptile species: implications for characterization of squamous cell carcinomas. AB - BACKGROUND: Cytokeratins with epitopes in common with those of alpha (acidic and basic) mammalian keratins have been immunohistochemically demonstrated in the epidermis of reptiles. However, there are no reports of immunohistochemical staining patterns of alpha-keratins in other tissues from reptiles. Because the epithelial tumours usually retain the keratin patterns of their normal epithelial origin, it is necessary to know in advance these patterns in the major normal epithelia and organs. We used anti-alpha human keratin AE1 and AE3 monoclonal antibodies to study the staining patterns of alpha-keratins in the major normal epithelia and organs from two reptile species [the bearded dragon (Pogona vitticeps) and the loggerhead sea turtle (Caretta caretta)]. We also studied the immunolocalization of alpha-keratins in squamous cell carcinomas (SCCs) in a bearded dragon and two loggerhead turtles. RESULTS: Acidic alpha-keratin (AE1 positive) was detected in many of the epithelial tissues of the bearded dragons; however, the detection of basic alpha-keratin (AE3 positive) was much more limited. Alpha-keratins were detected in a greater number of tissues of loggerhead turtles compared with those observed in bearded dragons. In the bearded dragon SCC, all layers of the nests of neoplastic cells, including the cornified layer of the keratin pearls, were strongly reactive with the AE1 antibody. However, a weak reactivity using the AE3 antibody was detected in the basal and intermediate layers of these nests. In the cutaneous SCCs of both sea turtles, acidic alpha-keratin was detected in the basal and suprabasal layers, and in all of the invasive neoplastic cords, while basic alpha-keratin was mainly detected in the invasive neoplastic cords. The pattern observed in the metastases in both turtles consisted of immunohistological detection of acidic alpha-keratin in all metastatic foci, and limited or lack of detection of basic alpha-keratin. CONCLUSIONS: This study provides, for the first time, information about the immunohistochemical staining patterns of alpha-keratins in normal tissues from bearded dragons and loggerhead sea turtles, and confirms the usefulness of AE1 and AE3 monoclonal antibodies in these reptile species. The use of these antibodies also contributed to a better characterization of SCCs in these species. PMID- 29980227 TI - The goldilocks effect: the rhythms and pace of hospital life. AB - BACKGROUND: While we have made gains in understanding cultures in hospitals and their effects on outcomes of care, little work has investigated how the pace of work in hospitals is associated with staff satisfaction and patient outcomes. In an era of efficiency, as speed accelerates, this requires examination. DISCUSSION: Older studies of pace in cities found that faster lifestyles were linked to increased coronary heart disease and smoking rates, yet better subjective well-being. In this debate we propose the Goldilocks hypothesis: acute care workplaces operating at slow speeds are associated with factors such as increased wait lists, poor performance and costly care; those that are too fast risk staff exhaustion, burnout, missed care and patient dissatisfaction. We hypothesise that hospitals are best positioned by being in the Goldilocks zone, the sweet spot of optimal pace. CONCLUSION: Testing this hypothesis requires a careful study of hospitals, comparing their pace in wards and departments with measures of performance and patient outcomes. PMID- 29980228 TI - The EMIF-AD Multimodal Biomarker Discovery study: design, methods and cohort characteristics. AB - BACKGROUND: There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer's disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants. METHODS: Participants were selected from existing prospective multicenter and single-center European studies. Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (Abeta) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF). Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF. Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA. Visual rating and volumetric measures were assessed on MRI. Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling. RESULTS: We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 67.9 (SD 8.3) years. The percentage Abeta+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups. Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects. For 759 (62%) individuals, clinical follow-up data were available. In each diagnostic group, the APOE epsilon4 allele was more frequent amongst Abeta+ individuals (p < 0.001). Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p < 0.001). Abeta+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0.001) and MCI (p < 0.001) groups. CONCLUSIONS: The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of Abeta and APOE epsilon4 in AD pathogenesis. The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers. All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog. PMID- 29980229 TI - Aedes aegypti in the Black Sea: recent introduction or ancient remnant? AB - BACKGROUND: The yellow fever mosquito Aedes aegypti transmits viral diseases that have plagued humans for centuries. Its ancestral home are forests of Africa and ~400-600 years ago it invaded the New World and later Europe and Asia, causing some of the largest epidemics in human history. The species was rarely detected in countries surrounding the Mediterranean Sea after the 1950s, but during the last 16 years it re-appeared in Madeira, Russia and in the eastern coast of the Black Sea. We genotyped Ae. aegypti populations from the Black Sea region to investigate whether this is a recent invasion (and if so, where it came from) or a remnant of pre-eradication populations that extended across the Mediterranean. We also use the Black Sea populations together with a world reference panel of populations to shed more light into the phylogeographical history of this species. RESULTS: Microsatellites and ~19,000 genome-wide single nucleotide polymorphisms (SNPs) support the monophyletic origin of all populations outside Africa, with the New World as the site of first colonization. Considering the phylogenetic relationships, the Black Sea populations are basal to all Asian populations sampled. Bayesian analyses combined with multivariate analyses on both types of markers suggest that the Black Sea population is a remnant of an older population. Approximate Bayesian Computation Analysis indicates with equal probability, that the origin of Black Sea populations was Asia or New World and assignment tests favor the New World. CONCLUSIONS: Our results confirmed that Ae. aegypti left Africa and arrived in New World ~500 years ago. The lineage that returned to the Old World and gave rise to present day Asia and the Black Sea populations split from the New World approximately 100-150 years ago. Globally, the Black Sea population is genetically closer to Asia, but still highly differentiated from both New World and Asian populations. This evidence, combined with bottleneck signatures and divergence time estimates, support the hypothesis of present day Black Sea populations being remnants of older populations, likely the now extinct Mediterranean populations that, consistent with the historic epidemiological record, likely represent the original return of Ae. aegypti to the Old World. PMID- 29980231 TI - Correlates of metabolic syndrome among young Brazilian adolescents population. AB - BACKGROUND: Findings available in literature indicate that metabolic syndrome (MetS) diagnosed in young ages tends to remain in adulthood. The aim of the study was to identify demographic, nutritional, anthropometric and behavioral correlates of MetS in a sample of adolescents from Dourados, Mato Grosso do Sul, Brazil. METHODOLOGY: This is a cross-sectional school-based study involving 274 participants aged 12-18 years (186 girls and 88 boys). Anthropometric measurements were performed and a questionnaire with structured questions was applied for data collection. MetS was identified according to criteria proposed by the International Diabetes Federation. Data were statistically treated using bivariate analysis and hierarchical multiple regression. RESULTS: The proportion of adolescents identified with MetS was equivalent to 4.7% [95% CI (3.6-6.0)]. Multivariate analysis showed that older age (OR = 1.22 [1.04-1.73]) and higher economic class (OR = 1.25 [1.07-1.96]) were significantly associated with MetS. Among behavioral factors, longer recreational screen time (OR = 1.26 [1.05-1.94]) and low fruits/vegetables intake (OR = 1.49 [1.23-2.41]) were independently associated with MetS. Likewise, excess body weight (OR = 1.52 [1.24-2.41]) was significantly associated with the outcome. CONCLUSION: The high proportion of adolescents with MetS and the identification of their correlates reinforce the need for early life style intervention and awareness programs in this population group. PMID- 29980230 TI - Gendered health systems: evidence from low- and middle-income countries. AB - BACKGROUND: Gender is often neglected in health systems, yet health systems are not gender neutral. Within health systems research, gender analysis seeks to understand how gender power relations create inequities in access to resources, the distribution of labour and roles, social norms and values, and decision making. This paper synthesises findings from nine studies focusing on four health systems domains, namely human resources, service delivery, governance and financing. It provides examples of how a gendered and/or intersectional gender approach can be applied by researchers in a range of low- and middle-income settings (Cambodia, Zimbabwe, Uganda, India, China, Nigeria and Tanzania) to issues across the health system and demonstrates that these types of analysis can uncover new and novel ways of viewing seemingly intractable problems. METHODS: The research used a combination of mixed, quantitative, qualitative and participatory methods, demonstrating the applicability of diverse research methods for gender and intersectional analysis. Within each study, the researchers adapted and applied a variety of gender and intersectional tools to assist with data collection and analysis, including different gender frameworks. Some researchers used participatory tools, such as photovoice and life histories, to prompt deeper and more personal reflections on gender norms from respondents, whereas others used conventional qualitative methods (in-depth interviews, focus group discussion). Findings from across the studies were reviewed and key themes were extracted and summarised. RESULTS: Five core themes that cut across the different projects were identified and are reported in this paper as follows: the intersection of gender with other social stratifiers; the importance of male involvement; the influence of gendered social norms on health system structures and processes; reliance on (often female) unpaid carers within the health system; and the role of gender within policy and practice. These themes indicate the relevance of and need for gender analysis within health systems research. CONCLUSION: The implications of the diverse examples of gender and health systems research highlighted indicate that policy-makers, health practitioners and others interested in enhancing health system research and delivery have solid grounds to advance their enquiry and that one-size-fits-all heath interventions that ignore gender and intersectionality dimensions require caution. It is essential that we build upon these insights in our efforts and commitment to move towards greater equity both locally and globally. PMID- 29980232 TI - Shisha microbiota: the good, the bad and the not so ugly. AB - OBJECTIVE: Over the last decade, there has been a rapid expansion of the trendy water pipe smoking around the world especially among younger adults. The initial objective of this study was to identify the microbiota of the shisha, which may either be of no harm for the smoker or enhance the threat on his well-being. The total DNA for the metagenomics study was conducted on three different shishas from three different delivery shops in Jounieh, Lebanon. The microbiota in two solid parts of the shisha, shaft and hose, were analysed including the fresh tobacco and the water in the bowl. All samples were analysed using high throughput sequencing of 16S rRNA gene amplicons. RESULTS: Overall, more than 40 bacterial genera were found in the three investigated shishas, some are commensal others are pathogenic. All three shishas showed similar microbial content regarding the bacteria inhabiting in water, shaft, or hose. From the results of this study it appears that a very large quantity of bacteria was found in the water pipes, some are harmful and others beneficial. We assume that the presence of gut dependent microbiota is related to the loose hygienic conditions in which the shisha is prepared. PMID- 29980234 TI - Deep neck infection and descending mediastinitis as lethal complications of dentoalveolar infection: two rare case reports. AB - BACKGROUND: We report two cases of innocuous dentoalveolar infections which rapidly progressed to deep neck abscesses complicated by descending mediastinitis in a resource-constrained rural mission hospital in the Cameroon. CASE PRESENTATION: The clinical presentations of a 35-year-old man and a 32-year-old woman both of Fulani origin in the Northern region of Cameroon were similar with submandibular fluctuant and tender swelling and differential warmth to palpation. The patients had tachycardia, high grade pyrexia, and normal blood pressure. Further physical and neurological examinations were unremarkable. An ultrasound scan of the neck swellings showed submandibular turbid collections. Plain chest radiographs confirmed empyema thoraces. Our patients had serial drainage of the neck abscesses as well as closed thoracostomy tube drainage which were connected to pleurovac and suctioning machines, with significant amount of pus drainage. Both patients were admitted to our intensive care unit for close monitoring. The first patient continued to make satisfactory clinical progress and was discharged by the fourth week of admission. The patient who had human immunodeficiency viral infection died on the fifth postoperative day. CONCLUSIONS: The possibility of lethal complications and the associated morbidity and mortality portray this clinical entity as an important public health concern. Clinicians taking care of patients with dentoalveolar and oropharyngeal infections need to be sensitized to these potentially fatal complications. Alternatively, strategies to improve oral health and reduce the incidence of dental caries, the main cause of dental abscess, would maximize use of resources; especially in resources-constrained centers like ours in Banso Baptist Hospital. PMID- 29980233 TI - Effects of hemodynamic monitoring using a single-use transesophageal echocardiography probe in critically ill patients - study protocol for a randomized controlled trial. AB - BACKGROUND: Hemodynamic instability is one of the leading causes of intensive care unit (ICU) admission. Early stabilization of hemodynamics is associated with improved outcome. The monitoring used to guide hemodynamic support may influence the time needed to achieve stable hemodynamics. Visualization of the heart using echocardiography offers the advantage of direct measurement of cardiac volumes and ventricular function. A miniaturized monoplane transesophageal echocardiography (TEE) probe was developed, allowing for almost continuous qualitative hemodynamic TEE assessment (hTEE) after brief bedside training. The primary objective of the study is to assess whether hemodynamic monitoring using the hTEE technology shortens time to resolution of shock in ICU patients in comparison to standard monitoring using a central venous catheter, pulmonary artery catheter, or conventional echocardiography. METHODS: Five hundred consecutive subjects with circulatory shock (low mean arterial blood pressure (MAP) and signs of organ hypoperfusion) at the time of ICU admission are included in the study. The subjects are randomly assigned to one of four groups using a 2 * 2 factorial design stratified by method of hemodynamic monitoring (hTEE vs standard hemodynamic monitoring) and frequency of hemodynamic assessments (minimum every 4 h vs standard of care). The primary study outcome is the time from study inclusion to resolution of circulatory shock, defined as MAP > 60 mmHg for >= 4 h after discontinuation of vasopressors and inotropes. The hTEE monitoring consists of the acquisition of three defined echocardiography views: Transgastric mid-esophageal short axis with measurement of fractional area change of left ventricle, mid-esophageal four-chamber view with measurement of the ratio of right to left ventricular area, and mid-esophageal ascending aortic short-axis view with measurement of the superior vena cava collapsibility index. In the control groups, monitoring modalities, including conventional TTE and TEE but not hTEE, are at the discretion of the treating physician. The interpretation of hemodynamic monitoring and the subsequent changes in patient management are recorded after each hemodynamic assessment. Differences in the primary and further secondary time-to-event outcomes will be assessed using a competing risk model accounting for the competing risk of death. DISCUSSION: The effect of using echocardiography as a monitoring modality on relevant patient outcomes has not been established so far. The study at hand may be one of the first trials to provide detailed data on effectiveness and safety of echocardiography to guide treatment in patients with circulatory shock. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02048566. Registered on January 29, 2014. PMID- 29980235 TI - Study protocol of the quasi-experimental evaluation of "KEIGAAF": a context-based physical activity and nutrition intervention for primary school children. AB - BACKGROUND: The environment affects children's energy balance-related behaviors to a considerable extent. A context-based physical activity and nutrition school- and family-based intervention, named KEIGAAF, is being implemented in low socio economic neighborhoods in Eindhoven, The Netherlands. The aim of this study was to investigate: 1) the effectiveness of the KEIGAAF intervention on BMI z-score, waist circumference, physical activity, sedentary behavior, nutrition behavior, and physical fitness of primary school children, and 2) the process related to the implementation of the intervention. METHODS: A quasi-experimental, controlled study with eight intervention schools and three control schools was conducted. The KEIGAAF intervention consists of a combined top-down and bottom-up school intervention: a steering committee developed the general KEIGAAF principles (top down), and in accordance with these principles, KEIGAAF working groups subsequently develop and implement the intervention in their local context (bottom-up). Parents are also invited to participate in a family-based parenting program, i.e., Triple P Lifestyle. Children aged 7 to 10 years old (grades 4 to 6 in the Netherlands) are included in the study. Effect evaluation data is collected at baseline, after one year, and after two years by using a child questionnaire, accelerometers, anthropometry, a physical fitness test, and a parent questionnaire. A mixed methods approach is applied for the process evaluation: quantitative (checklists, questionnaires) and qualitative methods (observations, interviews) are used. To analyze intervention effectiveness, multilevel regression analyses will be conducted. Content analyses will be conducted on the qualitative process data. DISCUSSION: Two important environmental settings, the school environment and the family environment, are simultaneously targeted in the KEIGAAF intervention. The combined top-down and bottom-up approach is expected to make the intervention an effective and sustainable version of the Health Promoting Schools framework. An elaborate process evaluation will be conducted alongside an effect evaluation in which multiple data collection sources (both qualitative and quantitative) are used. TRIAL REGISTRATION: Dutch Trial Register NTR6716 (registration date 27/06/2017, retrospectively registered), METC163027, NL58554.068.16, Fonds NutsOhra project number 101.253. PMID- 29980236 TI - Implications of standardization of serum 25-hydroxyvitamin D data for the evaluation of vitamin D status in Germany, including a temporal analysis. AB - BACKGROUND: Comparability of 25-hydroxyvitamin D (25(OH)D) measurements is hampered by method-related differences in measurement values. International standardization of laboratory assays has been suggested to solve this problem. METHODS: As part of the European Commission-funded project 'Food-based solutions for optimal vitamin D nutrition and health through the life cycle' (ODIN), original measurements of serum 25(OH)D of three German national health surveys conducted between 1998 and 2011 have been standardized retrospectively. In these representative population-based samples including persons aged between 1 and 79 years, the original 25(OH)D values were compared with those after standardization. Mean values and prevalences of vitamin D deficiency, insufficiency, and sufficiency (25(OH)D levels < 30, 30- < 50, and > =50 nmol/l, respectively) were calculated by sex and age groups based on original and standardized 25(OH)D data. RESULTS: In comparison to the original 25(OH)D levels, the standardized levels showed higher means overall and in age- and sex-specific analyses. After standardization, the prevalence of vitamin D deficiency was lower in all surveys while the prevalence of vitamin D sufficiency was higher. Nevertheless, even after standardization ~ 15% of adults and 12.5% of children had serum 25(OH)D levels < 30 nmol/l. Thus, the proportion of deficient vitamin D levels in the German population is still considerable. CONCLUSIONS: The use of standardization of 25(OH)D levels has a substantial impact on estimates of the vitamin D status in Germany. Since clinical diagnostic, therapeutic and public health decision-making require valid and comparable data, standardization and calibration of commercial, clinical and research laboratory assays for 25(OH)D measurement should become common practice. Until then, researchers, health practitioners and policy makers should be aware of the peculiarities of the measurement methods when comparing and interpreting 25(OH)D levels. PMID- 29980237 TI - Online assessment of suicide stigma, literacy and effect in Australia's rural farming community. AB - BACKGROUND: In Australia, farming populations have been identified as having higher rates of suicide, in comparison to metropolitan, rural and regional communities. The reasons for this are unclear although stigma is considered a risk factor. This study was designed to understand the role of suicide stigma and suicide literacy and the relationship between these. METHODS: A mixed-methods online intervention was developed. This paper reports on baseline quantitative data (suicide stigma, suicide literacy and suicide effect) collected from male and female rural Australian participants (N = 536) with an experience of suicide. RESULTS: When compared with previous Australian community samples, our sample demonstrated higher levels of stigma and higher levels of suicide literacy. Males were more likely to have considered suicide than females. Females were more likely than males to report a devastating and ongoing effect of suicide bereavement, but less likely than a previous Australian community sample. CONCLUSION: Results of this study reiterate the need for improved understanding of the risk factors and experience of suicide within the context of life and work in rural Australian farming communities and how 'best practice' can be adapted to improve stigma reduction and suicide prevention efforts. TRIAL REGISTRATION: This research project was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) ( ACTRN12616000289415 ) on 7th March, 2016. PMID- 29980238 TI - Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China. AB - BACKGROUND: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. METHODS: We firstly performed next generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. RESULTS: Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112*) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Deltapsim), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. CONCLUSIONS: Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP. PMID- 29980239 TI - Control of triple-negative breast cancer using ex vivo self-enriched, costimulated NKG2D CAR T cells. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease that currently lacks effective targeted therapy. NKG2D ligands (NKG2DLs) are expressed on various tumor types and immunosuppressive cells within tumor microenvironments, providing suitable targets for cancer therapy. METHODS: We applied a chimeric antigen receptor (CAR) approach for the targeting of NKG2DLs expressed on human TNBCs. Lentiviral vectors were used to express the extracellular domain of human NKG2D that binds various NKG2DLs, fused to signaling domains derived from T cell receptor CD3 zeta alone or with CD27 or 4 1BB (CD137) costimulatory domain. RESULTS: Interleukin-2 (IL-2) promoted the expansion and self-enrichment of NKG2D-redirected CAR T cells in vitro. High CD25 expression on first-generation NKG2D CAR T cells was essential for the self enrichment effect in the presence of IL-2, but not for CARs containing CD27 or 4 1BB domains. Importantly, self-enriched NKG2D CAR T cells effectively recognized and eliminated TNBC cell lines in vitro, and adoptive transfer of T cells expressing NKG2D CARs with CD27 or 4-1BB specifically enhanced NKG2D CAR surface expression, T cell persistence, and the regression of established MDA-MB-231 TNBC in vivo. NKG2D-z CAR T cells lacking costimulatory domains were less effective, highlighting the need for costimulatory signals. CONCLUSIONS: These results demonstrate that CD27 or 4-1BB costimulated, self-enriched NKG2D CAR-redirected T cells mediate anti-tumor activity against TNBC tumor, which represent a promising immunotherapeutic approach to TNBC treatment. PMID- 29980240 TI - Endometrial cancer prognosis correlates with the expression of L1CAM and miR34a biomarkers. AB - BACKGROUND: Patients with endometrial cancer (EC) and presumably with good prognosis may develop a recurrence indicating that the classification of this tumor is still not definitive and that new markers are needed to identify a subgroup at risk of relapse. The cell adhesion molecule L1CAM is highly expressed in several human carcinomas and has recently been described as a new marker for endometrial and ovarian carcinomas. The aim of this study was to determine the relevance of L1CAM in recurrent EC. METHODS: In this work we have analyzed, by immunohistochemical and RT-qPCR analysis, the expression of L1CAM in a cohort of 113 endometrial cancers at different stages, which 50% have relapsed. As a predictor of good outcome, the tumors were also analyzed for the expression of miR-34a, a post-transcriptional regulator of L1CAM. RESULTS: Among metastatic EC, the highest levels (60%) and the median level (24%) of L1CAM in tumors correlate with the progression, suggesting that the expression of this molecule is linked to the tumor component most involved in metastatic processes. We also found an inverse correlation between miR-34a and L1CAM protein expression, suggesting that miR-34a is a positive prognostic marker of EC. CONCLUSIONS: Our results demonstrate the expression of L1CAM and miR-34a in EC as prognostic factors that identify subgroup of patients at high risk of recurrence suggesting for them more aggressive schedules of treatment. PMID- 29980241 TI - Characterization of temperature-sensitive leak K+ currents and expression of TRAAK, TREK-1, and TREK2 channels in dorsal root ganglion neurons of rats. AB - Leak K+ currents are mediated by two-pore domain K+ (K2P) channels and are involved in controlling neuronal excitability. Of 15 members of K2P channels cloned so far, TRAAK, TREK-1, and TREK-2 are temperature sensitive. In the present study, we show that strong immunoreactivity of TRAAK, TREK-1 and TREK-2 channels was present mainly in small-sized dorsal root ganglion (DRG) neurons of rats. The percentages of neurons with strong immunoreactivity of TRAAK, TREK-1 and TREK-2 channels were 27, 23, and 20%, respectively. Patch-clamp recordings were performed to examine isolated leak K+ currents on acutely dissociated small sized rat DRG neurons at room temperature of 22 degrees C, cool temperature of 14 degrees C and warm temperature of 30 degrees C. In majority of small-sized DRG neurons recorded (76%), large leak K+ currents were observed at 22 degrees C and were inhibited at 14 degrees C and potentiated at 30 degrees C, suggesting the presence of temperature-sensitive K2P channels in these neurons. In a small population (18%) of small-sized DRG neurons, cool temperature of 14 degrees C evoked a conductance which was consistent with TRPM8 channel activation in cold sensing DRG neurons. In these DRG neurons, leak K+ currents were very small at 22 degrees C and were not potentiated at 30 degrees C, suggesting that few temperature-sensitive K2P channels was present in cold-sensing DRG neurons. For DRG neurons with temperature-sensitive leak K+ currents, riluzole, norfluoxetine and prostaglandin F2alpha (PGE2alpha) inhibited the leak K+ currents at both 30 degrees C and 22 degrees C degree, and did not have inhibitory effects at 14 degrees C. Collectively, the observed temperature-sensitive leak K+ currents are consistent with the expression of temperature-sensitive K2P channels in small sized DRG neurons. PMID- 29980242 TI - Exposure to second-hand tobacco smoke and respiratory symptoms in non-smoking adults: cross-sectional data from the general population of Telemark, Norway. AB - BACKGROUND: In Norway, data on the association between second-hand tobacco smoke (SHS) exposure at home and respiratory symptoms in adults are limited. METHODS: We assessed the association between self-reported exposure to SHS and the prevalence of respiratory symptoms among never-smokers aged 16 to 50 years from the general population who were included in a cross-sectional population-based study in Telemark County, Norway. Logistic regression analysis was used to estimate the odds ratios of symptoms among 8850 never-smokers who provided an affirmative response to questions regarding SHS; 504 (5.7%) of these reported that they lived in a home with daily or occasional indoor smoking. RESULTS: Productive cough and nocturnal dyspnoea were statistically associated with daily SHS exposure (ORs 1.5 [95% CI 1.04-2.0] and 1.8 [1.2-2.7], respectively). In analyses stratified by gender, nocturnal dyspnoea was associated with SHS among women (OR 1.8 [1.1-3.1]), but not among men (OR 0.93 [0.49-1.8]). Symptoms were not associated with occasional SHS exposure in the entire group, but infrequent exposure among men only was associated with increased prevalence of chronic cough; (OR 1.6; [1.04-2.6]) and was negatively associated with wheeze; (OR 0.44 [0.21-0.92)]. CONCLUSIONS: Daily SHS exposure in private homes was associated with productive cough and nocturnal dyspnoea. Our results suggest that preventive measures may be needed to reduce the respiratory effects of SHS at home. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02073708 Registered February 27. 2014. PMID- 29980243 TI - Egg introduction during complementary feeding according to allergic risk: not just for peanuts! AB - The relationship between the timing of introduction of complementary foods and later allergy is a topic of current discussion. Although the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) has recently recommended that potentially allergenic foods may be introduced when complementary feeding is commenced, any time after 4 months, recommendations about egg introduction would be needed mainly for infants with high risk of developing food allergy. Before the first administration in these infants an adequate topical therapy and an evaluation of whole egg-specific IgE serum antibody levels or skin prick tests for egg should be recommended. PMID- 29980244 TI - Comparison of ELISA and DNA Lateral Flow Assays for Detection of Pork, Horse, Beef, Chicken, Turkey, and Goat Contamination in Meat Products. AB - Background: Concerns about the contamination of meat products with undeclared meats and new regulations for the declaration of meat adulterants have established the need for a sensitive test to detect meat adulteration. To address this need, Microbiologique, Inc. has developed ELISA assays that can detect the presence of pork, horse, beef, chicken, turkey, and goat meat adulterants to 0.1% (w/w) and a deoxyribonucleic acid (DNA) lateral flow assay for pork, horse, beef, chicken, turkey, goat, and lamb adulterants to 0.1% (w/w). Objective: We compared the results of the DNA lateral flow assay to the ELISA assays. Methods: ELISA and DNA lateral flow assays were performed on the same spiked meat samples, prepared meats, and pet foods. Results: Both the DNA lateral flow and the ELISA assays were sensitive to 0.1% meat adulterant, and the agreement between the DNA lateral flow and ELISA assays for spiked samples, prepared meat, and pet foods was 100%. Conclusions: Based on the 100% concordance between the two assay formats, the choice between the two is dependent on whether quantitation is desired, which assay is more familiar to the particular laboratory, availability of the required equipment, and time restrictions. Highlights: The ELISA assays are less time consuming, taking about 1.5 h, compared with about 2.5 h for the DNA lateral flow assay. Because the DNA lateral flow test detects seven species in one test, it can be more cost effective when the potential adulterant is not known, while the ELISA may be better for quantification. PMID- 29980245 TI - Assessing the validity of existing dental sealant quality measures. AB - BACKGROUND: Although sealants are highly effective in preventing caries in children, placement rates continue to be low. The authors' goals were to implement and assess the performance of 2 existing sealant quality measures against a manual audit of charts at 4 dental institutions and to identify measurement gaps that may be filled by using data from electronic health records. METHODS: The authors evaluated the performance of 2 quality measures designed for claims-based data: the Dental Quality Alliance (DQA) sealant measure, which includes patients at risk of developing elevated caries, and the Oregon Health Authority (OHA) sealant measure (irrespective of caries risk). The authors adapted and validated these measures at 4 sites: 3 dental schools and 1 large dental accountable care organization. RESULTS: The overall modified DQA and modified OHA measure scores in the 6- through 9-year-old age group were 37.0% and 31.6% and in the 10- through 14-year-old age group were 15.8% and 6.6%, respectively. Results from the manual review of charts showed that 67.6% of children who did not receive sealants did not have any teeth to seal because their molars had not yet erupted, had been extracted, had been sealed previously, or had existing caries or restorations. CONCLUSIONS: Both the DQA and OHA measures, which rely mainly on Current Dental Terminology procedure codes, led to underestimation of the care delivered from a practice perspective. Future sealant quality measures should exclude patients whose teeth cannot be sealed. PRACTICAL IMPLICATIONS: This study's results support the suitability of using electronic health record data for assessing the quality of oral health care, particularly for measuring sealant placement in children. PMID- 29980246 TI - Uncertainty about the effects of dexamethasone in minimizing pain after endodontic treatment owing to limitations in the systematic review. PMID- 29980247 TI - Evidence suggests a small association between malocclusions and caries in adolescents. PMID- 29980249 TI - Cylindrical and tapered implants may result in low marginal bone loss after 1 year, but there is insufficient evidence to judge how they compare. PMID- 29980248 TI - Local anesthesia reversal agent reduces the time to recovery of sensation and function, but there is uncertainty about whether this reduction would be important to patients in clinical settings. PMID- 29980250 TI - Driving with the headlights on: Measuring adequate urinary sodium excretion on the road to precision diuresis. PMID- 29980251 TI - The Reply. PMID- 29980253 TI - Development of assisted reproductive medicine in Europe. AB - The mediocre outcome of microsurgery results in patients with extensive tubal disease was the original driving force behind the search for new methods to assist these infertile patients. Many unsuccessful attempts were carried out before the birth of the first in vitro fertilization baby in Europe 40 years ago. Many pioneers worked tirelessly to develop the tools, procedures, and research necessary. Thanks to the efforts of many, the field of reproductive medicine has grown, advanced, and progressed in ways that seemed nearly impossible just a few decades ago. PMID- 29980254 TI - Abnormal activation of the sonic hedgehog signaling pathway in endometriosis and its diagnostic potency. AB - OBJECTIVE: To investigate the abnormal expression of sonic hedgehog (SHH) signaling molecules in 52 eutopic endometrial tissues and its diagnostic potency in endometriosis. DESIGN: Retrospective study. SETTING: University hospital. PATIENT(S): Twenty-six women with histologically confirmed endometriosis and 26 women with histologically normal endometria who were undergoing curettage or hysterectomy were selected. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The mRNA and protein levels of molecules in the SHH signaling pathway. RESULT(S): The levels of SHH, smoothened, GLI family zinc finger 3, and its downstream signaling transcription factor (GLI1) not only were upregulated in the eutopic endometrium of endometriosis compared with the control endometrium, but also independently predicted the onset and severity of the disease. CONCLUSION(S): This study is the first to reveal differences in the activation of the SHH signaling pathway between women with and without endometriosis and suggests that the SHH signaling pathway has potential in the diagnosis of endometriosis. PMID- 29980255 TI - Development of in vitro fertilization in the United States: a conversation between Zev Rosenwaks and Jairo E. Garcia. AB - In commemoration of 40 years of in vitro fertilization (IVF), herein we describe the early evolution of the first IVF program at the Eastern Virginia Medical School in Norfolk, Virginia. The birth of the first American IVF baby was the result of the work of many investigators, both in experimental animal models and in humans, heavily relying on the experience of Robert Edwards and Patrick Steptoe in Great Britain. Although their first IVF baby was the result of the retrieval of a single oocyte in the natural cycle, duplicating their methods was not successful in Norfolk. It turns out that the achievement of the first pregnancy in the United States was associated with introducing ovarian stimulation with gonadotropins, establishing the appropriate timing for egg retrieval after hCG administration, retrieving multiple mature oocytes, determining the ideal time for in vitro insemination, and optimizing embryo culture media. PMID- 29980257 TI - Uterus transplantation: organ procurement in a deceased donor model. AB - OBJECTIVE: To demonstrate our technique of uterine procurement from a deceased donor. DESIGN: This video uses live action footage from surgery and detailed illustrations to review the steps and techniques involved in deceased donor procurement surgery. SETTING: Academic medical center. PATIENT(S): A deceased multiorgan donor. INTERVENTION(S): Trial organ procurement of a viable uterus from a deceased donor. MAIN OUTCOME MEASURE(S): Procurement time and associated features of suitability of dissected specimen. RESULT(S): This video article describes the advantages of a deceased donor model over a live donor model, including eliminating the risk of surgical complications to a living donor, avoidance of ethical issues inherent in live donation, easier access to generous vascular pedicles for anastomosis, and faster procurement time. This video also outlines the key steps to a successful uterine procurement using illustrations and live action footage from a trial organ procurement. CONCLUSION(S): Uterine transplantation is an emerging surgical treatment for patients with absolute uterine factor infertility. Continued practice is essential in preparing for a deceased donor uterine procurement. The process continues to be refined and adapted as new information becomes available toward the goal of safe, efficient, ethical, and effective surgical treatment of absolute uterine factor infertility. PMID- 29980256 TI - Endometrial regeneration using cell sheet transplantation techniques in rats facilitates successful fertilization and pregnancy. AB - OBJECTIVE: To regenerate functional endometrium tissue using "cell sheet" techniques as a regenerative medicine approach to address endometrial disorders causing female factor infertility. DESIGN: In vivo experimental study. SETTING: Preclinical surgical and biomedical research laboratories. ANIMAL(S): Green fluorescent protein (GFP) transgenic rats [SD-Tg (CAG-EGFP) rats] and nude rats (F344/NJcl-rnu/rnu). INTERVENTION(S): GFP-positive rat uterine-derived cells as cell sheets were transplanted into resected rat uterine endometrial sites. Transplanted cell sheet areas were then analyzed using macroscopic observations and histological analysis including immunohistochemistry. Subsequently, crossbreeding was performed to establish fertility and confirm pregnancy in the rat-regenerated uterus. MAIN OUTCOME MEASURE(S): Morphologic and biochemical markers of regenerated endometrium and establishment of pregnancy in otherwise sterile animals. RESULT(S): After cell sheet transplantation, regenerated endometrium was confirmed as GFP-positive tissue engraftment both visually and under histological analysis. After crossbreeding, GFP-positive tissue areas and living fetuses were observed in the transplantation group. CONCLUSION(S): Cell sheet transplantation can regenerate endometrial tissue with histological structure and physiological function supporting pregnancy similar to normal endometrial tissue. Translation of this endometrial cell sheet transplantation method to human patients with endometrial disorders could yield a novel therapy for uterine infertility. PMID- 29980258 TI - Development of in vitro fertilization in Australia. AB - In vitro fertilization (IVF) began in Melbourne in 1970 when Carl Wood founded a research group at the Queen Victoria Hospital. The group reported the first biochemical pregnancy from a transferred IVF embryo in 1973. The group included the Royal Women's Hospital Melbourne, and they were the first to report confirmation of the British group's pregnancies with the use of IVF in natural cycles in 1980. The group then split, and the Monash group pursued fertility drug induced multiple follicle growth in controlled ovulatory cycles and demonstrated for the first time that they could achieve multiple pregnancies in 1980-1981. This became the basis of a sustainable procedure for treating infertile patients. Successful embryo freezing and thawing methods resulted in pregnancies for the first time and were adopted to cryopreserve excess embryos produced after superovulation. Embryo donation methods were devised for anovulatory patients and were the first reported use of oocyte in vitro maturation techniques (IVM) for polycystic ovarian syndrome patients. Sperm microinjection techniques were pioneered for enabling fertilization for severely infertile men, and micromanipulative techniques were published for embryo biopsy for potential use in preimplantation genetic diagnosis (PGD) for patients with inheritable genetic diseases. The latter research programs were hampered by creation of restrictive embryo research laws in the State of Victoria, handicapping their timely clinical applications. Work on cryopreservation of ovarian tissue for cancer patients enabled clinical application of this for patients at risk of loss of fertility. Vitrification was developed as an alternative to freezing for oocytes and embryos, and this has now replaced the original slow cooling methods. Blastocyst culture systems were devised and optimized to improve IVF success and PGD. PMID- 29980259 TI - Impact factor 2.0: a name can be everything. PMID- 29980260 TI - Introduction: IVF's 40th world birthday. AB - Forty years ago this month the first baby was born as a result of in vitro fertilization (IVF). The arrival of Louise Brown brought with her a new hope and possibility for the many men and women across the global struggling with infertility who previously had very few options for treatment or family building. In this month's Views and Reviews, we turn to the pioneers of IVF in the United States, Europe, and Australia as they share their experiences on the front lines of the development of IVF around the globe. They recount the struggles and trials that led to the first IVF birth in their part of the world and look back on how far we have come in the past forty years. Thanks to their pioneering spirit family building has become an option for men and women across the globe that had few options a mere forty years ago. PMID- 29980261 TI - Semen parameter decline with advancing age: a cause for concern? PMID- 29980262 TI - How might centralization of male factor infertility care impact patients and residents? PMID- 29980263 TI - Leave the intrauterine device! PMID- 29980264 TI - Success rates and pregnancy outcomes in thawed embryos transferred after extended culture: cryopreserved embryos versus cleavage stage cryopreserved embryos. PMID- 29980265 TI - Obesity: a health crisis of enormous proportion. PMID- 29980266 TI - Impact of age, clinical conditions, and lifestyle on routine semen parameters and sperm kinematics. AB - OBJECTIVE: To assess the impact of aging on routine semen and computer-assisted sperm analysis (CASA) motility parameters according to the current World Health Organization guidelines; and to evaluate the effect of obesity and lifestyle (alcohol consumption, cigarette smoking) in older men's semen. DESIGN: Blind cross-sectional study. SETTING: Research laboratory and andrology and reproduction laboratory. PATIENT(S): A population of 11,706 men. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen analysis: routine (semen volume, sperm concentration and count, motility, vitality, morphology, hypo-osmotic swelling test, round and peroxidase-positive cell concentration) and CASA (straight-line velocity, curvilinear velocity, average path velocity, linearity, straightness, beat cross frequency, wobble, amplitude of lateral head displacement, and mean angular displacement) parameters; and body mass index. RESULT(S): A negative correlation was found between age and routine semen parameters: volume, sperm count, motility, vitality, total motile spermatozoa and normal-motile spermatozoa, round cell concentration, and hypo-osmotic swelling test values. Several CASA variables (straight-line velocity, curvilinear velocity, average path velocity, beat cross frequency, amplitude of lateral head displacement, and mean angular displacement) were also negatively affected. Using 40 years as a cut off value, significant differences in most parameters correlated to age. In a selected subpopulation of men unexposed to known fertility-compromising factors, the same evaluations were performed, finding some parameters still decreased. Although obesity exerted a significant deleterious effect on older patients' semen quality, alcohol consumption and cigarette smoking mildly affected it. CONCLUSION(S): Male aging, with the contribution of unhealthy conditions, are paramount effectors of sperm quality deterioration. PMID- 29980267 TI - Changes in practice patterns in male infertility cases in the United States: the trend toward subspecialization. AB - OBJECTIVE: To assess changes in the practice patterns of urologists performing male infertility procedures (vasal reconstruction, sperm retrieval, varicocelectomy) from 2004 to 2015 in the United States. DESIGN: Examination of self-reported procedural volumes from urologists undergoing certification and recertification using case log data provided by the American Board of Urology. The study period was stratified into early (2004-2007) and recent (2012-2015) time periods. SETTING: Not applicable. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOMES MEASURE(S): Temporal variations in male infertility practice patterns among different urologic subspecialties between the early and recent time periods. RESULT(S): The overall proportion of total male infertility procedures performed by andrologists significantly increased between the early and recent groups (23% to 26%). This growth was driven by a significant increase in the proportion of varicocele repairs being performed by andrologists between the early and recent periods (19% to 25%). Most notably, an assessment of total number of male infertility procedures performed by newly certifying urologists showed that there was a significant increase in the overall proportion of all male infertility procedures being performed by recently trained andrologists (24% to 35%). This significant increase was seen individually among all three types of male infertility procedures. CONCLUSION(S): With the increased trend in urologists obtaining fellowship training, male infertility surgical volume is beginning to shift from general urologists to subspecialized andrologists. PMID- 29980268 TI - Effect of cyclic bend loading on a cobalt-chromium clasp fabricated by direct metal laser sintering. AB - STATEMENT OF PROBLEM: Limited information is available regarding the mechanical properties of a partial removable dental prosthesis clasp fabricated by direct metal laser sintering (DMLS). PURPOSE: The purpose of this in vitro study was to measure the mechanical properties of cast clasps, DMLS clasps, and annealed DMLS clasps and to determine the correlation between cyclic bend loading, annealing, and mechanical properties. MATERIAL AND METHODS: Sixty half round clasp specimens were fabricated, with a length of 20 mm and a diameter of 1.5 mm at 10 mm from the tip. The specimens were divided into 6 groups (n=10). Twenty specimens were fabricated by casting (CS, CSAC), and 40 specimens were fabricated by DMLS (DS, DSAC, ADS, ADSAC). Of the DMLS specimens, 20 underwent annealing (ADS, ADSAC). Equivalent to 5 years of clinical use, 0.25 mm of bending was applied to group CSAC, DSAC, and ADSAC 14 600 times. After cyclic bending loads, a cantilever bend test was conducted on all groups, and the loads were measured. To compare the load values, 1-way ANOVA and the Tukey HSD test were performed and statistical significance among the groups was evaluated (alpha=.05). Scanning electron microscopy and energy-dispersive spectroscopy analyses were also used for surface morphology evaluation and element analysis. RESULTS: Bending loads of the DMLS specimens were significantly lower than those of the cast specimens (P<.05). The influence of cyclic bending loads was significant for cast specimens (P<.05), but not for DMLS specimens (P>.05), in terms of variation of loads. Annealed DMLS specimens had significantly higher bending loads than DMLS specimens (P<.05). CONCLUSIONS: The DMLS specimens had lower load values at 0.25 mm bending than cast specimens. The DMLS specimens were less influenced by cyclic bending loads than the cast specimens. Annealing increased load values of the DMLS specimens at 0.25 mm bending. PMID- 29980269 TI - Effect of two heat treatments on mechanical properties of selective-laser-melted Co-Cr metal-ceramic alloys for application in thin removable partial dentures. AB - STATEMENT OF PROBLEM: Heat treatment has been used to reduce the residual stress of alloys fabricated by selective laser melting (SLM) to avoid deformation. Co-Cr metal-ceramic alloys are used to fabricate metal-ceramic restorations and removable partial dentures (RPDs) on the same substrate by SLM. A heat treatment that enables the fabrication of metal-ceramic restorations and RPDs with excellent mechanical properties should be evaluated. PURPOSE: The purpose of this in vitro study was to determine the effects of 2 heat treatments on the mechanical properties of SLM Co-Cr metal-ceramic alloys intended for the fabrication of thin RPDs. MATERIAL AND METHODS: Tensile bars were manufactured using cast metal-ceramics (C-MC group), RPD alloys (C-RPD group), and SLM Co-Cr metal-ceramic alloys. The SLM specimens were subjected to 2 different heat treatments, L1 at 880 degrees C and L2 at 1100 degrees C, and were further divided into subgroups (L1-MC, L1-RPD, L2-MC, and L2-RPD). Thirty-six tensile specimens were prepared in C-RPD, L1-RPD, and L2-RPD (simulated partial denture alloys for clinical use) and in C-MC, L1-MC, and L2-MC (simulated metal-ceramic alloys); 18 metal-ceramic bond strength specimens were prepared in C-MC, L1-MC, and L2-MC groups (n=6). The tensile test and 3-point bend test were conducted using a universal testing machine. The fracture surfaces of the L2-RPD tensile bar were examined using a scanning electron microscope. The Student t test (alpha=.05) was used for statistical analysis. RESULTS: No significant differences were observed between the bond strengths of L1-MC and C-MC (P=.74) or between those of L2-MC and C-MC (P=.124). The 0.2% yield strength (sigma0.2) and elongation of all SLM specimens exceeded the minimum requirements required for the fabrication of thin RPDs as prescribed in ISO 22674:2016. The sigma0.2 value of L1-MC and L2-MC was significantly higher than that of C-MC. Significant differences in sigma0.2 values were found among the 3 RPD groups, L1-RPD>L2-RPD>C RPD. For the elongation, significant differences were found among the 3 groups, L2-RPD>C-RPD>L1-RPD. The fracture surface of L2-RPD showed clear submicroscale dimples with fusion defects. CONCLUSIONS: When Co-Cr metal copings and RPD frameworks were fabricated on the same substrate simultaneously using SLM, heat treatment at 1100 degrees C was found more suitable than at 880 degrees C to release residual stress, considering the toughness required for dental prostheses. PMID- 29980270 TI - Evaluation of shear bond strength between maxillofacial silicone and fiber reinforced composite resin after various surface treatments. AB - STATEMENT OF PROBLEM: The most common reason for remaking a facial prosthesis is the debonding of maxillofacial silicone from the substructure. Improved bonding would help overcome this problem. PURPOSE: The purpose of this in vitro study was to evaluate the shear bond strength between maxillofacial silicone and fiber reinforced composite resin after various surface treatments. MATERIAL AND METHODS: Acrylic resin specimens were prepared with a dimension of 14.4 mm in diameter and 25 mm in height with a depression of 5 mm in depth and 8 mm in diameter, according to International Organization for Standardization technical specification (ISO/TE) 11405:1994. Fiber-reinforced composite resin was dispensed and packed into the depressed part of acrylic resin and allowed to polymerize. A total of 120 specimens were fabricated, and primer was then applied over the specimens. They were washed with acetone and subjected to various surface treatments, including airborne-particle abrasion, silicon carbide paper abrasion, and laser etching. The maxillofacial silicone was mixed according to the manufacturer's instructions and packed into the cylindrical die with dimensions of 3 mm in thickness and 8 mm in diameter. The shear bond strength test on the specimens was carried out in a universal testing machine at a 5-mm/min crosshead speed, at 24 hours after fabrication and 200 hours after accelerated aging. The values were statistically analyzed using 1-way ANOVA and the Tukey honest significant difference (HSD) post hoc test. RESULTS: The mean shear bond strength values of the control group was 24.7 +/-2.1 MPa, 26.9 +/-1.8 MPa for the airborne particle abraded group, 28.4 +/-1.9 MPa for the silicon carbide abraded group SiCp, and 33.4 +/-1.8 MPa for the laser-treated specimens at 24 hours after fabrication and 34.2 MPa at 200 hours after accelerated aging. CONCLUSIONS: The shear bond strength between the maxillofacial silicone and the fiber-reinforced composite resin was increased after laser surface treatment compared with airborne-particle abrasion and silicon carbide paper abrasion 200 hours after accelerated aging. PMID- 29980271 TI - An evolution during a century of leadership, scholarship, mentorship, and fellowship. PMID- 29980272 TI - Meta-analysis of the Impact of Avoiding Balloon Predilation in Transcatheter Aortic Valve Implantation. AB - Balloon predilation (BPD) has been an integral part of transcatheter aortic valve implantation (TAVI) since inception. We sought to investigate the effect of avoiding BPD on outcomes of TAVI across different valve types. Articles were included if outcomes of TAVI without BPD were reported. Pooled meta-analysis used a random effects model and reported odds ratios (ORs). Twenty-one studies with 10,752 patients were pooled for analysis. Age and gender were well matched between NoBPD and BPD groups. There was no difference in mortality, stroke, bleeding, and acute kidney injury. NoBPD showed lower pacemaker rates (OR 0.84, 95% confidence interval [CI] 0.72 to 0.97), vascular complications (OR 0.77, 95% CI 0.62 to 0.95), and early safety at 30 days (OR 0.81, 95% CI 0.66 to 0.99). For balloon-expandable valves, lower rates of aortic regurgitation (OR 0.73, 95% CI 0.53 to 0.99) and early safety (OR 0.68, 95% CI 0.55 to 0.85) were seen. Self expanding valves showed lower pacemaker (OR 0.80, 95% CI 0.66 to 0.97) and vascular complications (OR 0.70, 95% CI 0.50 to 0.99), with a trend toward higher postdilation (OR 1.51, 95% CI 0.85 to 2.67). TAVI without BPD is safe and effective. NoBPD is associated with fewer vascular complications, less aortic regurgitation, and fewer pacemaker requirements and composite early safety end points. PMID- 29980273 TI - Relation of Subclinical Hypothyroidism is Associated With Cardiovascular Events and All-Cause Mortality in Adults With High Cardiovascular Risk. AB - The aim of this study was to determine the association between subclinical hypothyroidism and cardiovascular (CVD) events, and mortality using the atherosclerotic CVD risk score. We carried out an observational study in a prospective cohort that was followed up for 12 years. The study included 3,021 participants aged >= 40 years at baseline from the Ansung cohort, part of the Korean Genome and Epidemiology Study. Cox regression models were constructed to evaluate the hazards ratio (HR) and 95% confidence interval (CI) for all-cause mortality and CVD events in groups classified according to thyroid status. Subgroup analysis was performed with a cut-off age of 65 years or 7.5% of the 10 year atherosclerotic CVD risk score. The subclinical hypothyroidism group in the highest quartile of thyroid-stimulating hormone (>6.57 mIU/L) had a significantly increased risk of all-cause mortality (HR 2.12, 95% CI 1.27 to 3.56) and CVD events (HR 1.92, 95% CI 1.21 to 3.04) compared with euthyroid participants. Subgroup analysis by CVD risk revealed that participants with high CVD risk only had a high risk of all-cause mortality (HR 2.18, 95% CI 1.22 to 3.87) and CVD events (HR 2.42, 95% CI 1.35 to 4.33). Further analysis showed that participants aged <65 years with high CVD risk had the highest risk of all-cause mortality (HR 3.50, 95% CI 1.50 to 8.16) and CVD events (HR 3.37, 95% CI 1.46 to 9.57). Our results demonstrated that high thyroid-stimulating hormone levels were associated with a greater risk of mortality and new CVD risks, particularly among subjects with high CVD risk. PMID- 29980274 TI - Evolution of Procedural and Clinical Outcomes After Balloon-Expanding Transcatheter Aortic Valve Implantation In Canada (from the Early Canadian Experience and SOURCE XT Registries). AB - Transcatheter aortic valve implantation (TAVI) has evolved globally, yet its evolution and performance across the Canadian landscape have yet to be formally assessed. Patients captured within the early Canadian TAVI experience with a balloon-expanding valve (n = 339; 2005 to 2009) and those enrolled in the Canadian SOURCE XT registry (n = 415; 2012 to 2015) were systematically compared with respect to baseline clinical, echocardiographic, and procedural characteristics. Valve-related and clinical outcomes were compared across the 2 time periods according to standardized definitions. Notable baseline between group differences were noted across time, with Society of Thoracic Surgeons Predicted Risk of Mortality score being lower in the SOURCE XT cohort compared with the earlier Canadian cohort (7.4 +/- 6.6% vs 9.8 +/- 6.4%, p <0.001). The SOURCE XT cohort underwent TAVI through the transfemoral approach more frequently than their earlier Canadian counterparts (75% vs 48%), at the expense of transapical access, with major access site vascular complications (2.7% vs 13%), and >=mild residual aortic regurgitation (39% vs 69%) being significantly less frequent (p <0.001 for all). At 30-days, there were no significant differences in rates of stroke (1.9% vs 2.4%) or new pacemakers (5.8% vs 5.0%); however, 30-day and 1-year mortality rates were significantly lower in the SOURCE XT cohort (3.6% vs 10.4%; 13.0% vs 24.2%, respectively, p<0.001 for both). In conclusion, TAVIs evolution in Canada with a balloon-expanding valve coincided with more optimized patient selection and increasing use of transfemoral access, which along with increasing operator experience, contributed to improved procedural and longer term clinical outcomes. PMID- 29980275 TI - Retraction notice to "Overcoming antibiotic resistance: Is siderophore Trojan horse conjugation an answer to evolving resistance in microbial pathogens?" [Journal of Controlled Release, Volume 269, 10 January 2018, Pages 63-87]. PMID- 29980276 TI - Thermo-responsive polypeptides and micromechanical machines for sustained delivery to the posterior eye. PMID- 29980279 TI - Correction. PMID- 29980277 TI - Allergic components of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a disorder of increasing prevalence worldwide, causing clinical symptoms of vomiting, failure to thrive, and dysphagia and complications of esophageal remodeling with strictures and food impactions. Molecular profiling demonstrates EoE to be an eosinophil-predominant disorder with a TH2 cytokine profile reminiscent of other allergic diseases, such as asthma, allergic rhinitis, and atopic dermatitis. Environmental antigens in the form of foods and aeroallergens induce eosinophil, basophil, mast cell, and T cell infiltration. Pathogenesis depends on local epithelial immune activation with production of thymic stromal lymphopoietin and eotaxin-3. Complications mirror asthmatic airway pathogenesis, with increases in subepithelial collagen deposition, angiogenesis, and smooth muscle hypertrophy. The removal of instigating antigens, especially foods, causes disease resolution in more than 50% of adults and children. The prevalence of concurrent atopic disorders in patients with EoE and the need to control antigen-specific TH2 inflammation underscore the importance of testing for allergens and treating the entire atopic subject to control the potential interplay between organ-specific allergic responses. PMID- 29980278 TI - Epithelial origin of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic, allergen-driven inflammatory disease of the esophagus characterized predominantly by eosinophilic inflammation, leading to esophageal dysfunction. Converging data have placed the esophageal epithelium at the center of disease pathogenesis. In particular, the main EoE disease susceptibility loci at 2p23 and 5p22 encode for gene products that are produced by the esophageal epithelium: the intracellular protease calpain 14 and thymic stromal lymphopoietin, respectively. Furthermore, genetic and functional data establish a primary role for impaired epithelial barrier function in disease susceptibility and pathoetiology. Additionally, the EoE transcriptome, a set of genes dysregulated in the esophagi of patients with EoE, is enriched in genes that encode for proteins involved in esophageal epithelial cell differentiation. This transcriptome has a high proportion of esophagus-specific epithelial genes that are notable for the unexpected enrichment in genes encoding for proteases and protease inhibitors, as well as in IL-1 family genes, demonstrating a previously unappreciated role for innate immunity responses in the esophagus under homeostatic conditions. Among these pathways, basal production of the serine protease inhibitor, Kazal-type 7 (SPINK7) has been demonstrated to be part of the normal differentiation program of esophageal epithelium. Profound lost expression of SPINK7 occurs in patients with EoE and is sufficient for unleashing increased proteolytic activity (including urokinase plasminogen activator), impaired barrier function, and production of large quantities of proinflammatory and proallergic cytokines, including thymic stromal lymphopoietin. Collectively, we put forth a model in which the esophagus is normally equipped as an anti inflammatory sensing organ and that defects in this pathway, mediated by epithelial protease/protease inhibitor imbalances, unleash inflammatory responses resulting in disorders, such as EoE. PMID- 29980282 TI - Visual mental imagery: A view from artificial intelligence. AB - This article investigates whether, and how, an artificial intelligence (AI) system can be said to use visual, imagery-based representations in a way that is analogous to the use of visual mental imagery by people. In particular, this article aims to answer two fundamental questions about imagery-based AI systems. First, what might visual imagery look like in an AI system, in terms of the internal representations used by the system to store and reason about knowledge? Second, what kinds of intelligent tasks would an imagery-based AI system be able to accomplish? The first question is answered by providing a working definition of what constitutes an imagery-based knowledge representation, and the second question is answered through a literature survey of imagery-based AI systems that have been developed over the past several decades of AI research, spanning task domains of: 1) template-based visual search; 2) spatial and diagrammatic reasoning; 3) geometric analogies and matrix reasoning; 4) naive physics; and 5) commonsense reasoning for question answering. This article concludes by discussing three important open research questions in the study of visual-imagery based AI systems-on evaluating system performance, learning imagery operators, and representing abstract concepts-and their implications for understanding human visual mental imagery. PMID- 29980281 TI - Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets. AB - BACKGROUND: Vulvar squamous cell carcinoma (VSCC) constitutes over 90% of vulvar cancer. Its pathogenesis can follow two different pathways; high risk human papillomavirus (hrHPV)-dependent and HPV-independent. Due to the rarity of VSCC, molecular mechanisms underlying VSCC development remain largely unknown. The study aimed to identify pathogenic mutations implicated in the two pathways of VSCC development. METHODS: Using next generation sequencing, 81 VSCC tumors, 52 hrHPV(+) and 29 hrHPV(-), were screened for hotspot mutations in 50 genes covered by the Ion AmpliSeq Cancer Hotspot Panel v2 Kit (Thermo Fisher Scientific). RESULTS: Mutations of TP53 (46% and 41%, of hrHPV(+) and hrHPV(-) cases respectively) and CDKN2A (p16) (25% and 21%, of hrHPV(+) and hrHPV(-) cases respectively) were the most common genetic alterations identified in VSCC tumors. Further mutations were identified in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, FLT3, JAK3, GNAQ, and PTEN, albeit at low frequencies. Some of the identified mutations may activate the PI3K/AKT/mTOR pathway. The activation of mTOR was confirmed in the vast majority of VSCC samples by immunohistochemical staining. CONCLUSIONS: Detecting pathogenic mutations in 13/50 genes examined at comparable frequencies in hrHPV(+) and hrHPV(-) tumors suggest that genetic mechanisms of the two routes of VSCC pathogenesis may be similar, despite being initiated from different premalignant lesions. Importantly, our data provide a rationale for new anti-VSCC therapies targeting the PI3K/AKT/mTOR pathway. PMID- 29980283 TI - Value of 123I/99mTc-sestamibi parathyroid scintigraphy with subtraction SPECT/CT in primary hyperparathyroidism for directing minimally invasive parathyroidectomy. AB - BACKGROUND: Primary hyperparathyroidism/(PHPT) is one of the most common endocrinological conditions. Surgery remains the only curative option. We have evaluated the performance of double isotope 123I/99mTc-sestamibi parathyroid scintigraphy/(PS) with subtraction SPECT/CT in PHP for identifying uniglandular disease. METHODS: Ninety PHPT patients undergoing parathyroidectomy (December 2015-August 2016) were included. All patients were evaluated with neck ultrasound/(US), PS and SPECT/CT with a new protocol. Outcomes from imaging modalities were reported as: uniglandular disease/(UGD), multiglandular disease/(MGD), or negative, and were compared to post-operative diagnoses. RESULTS: Post-operatively, 72 and 18 patients had true UGD and MGD, respectively. Sensitivities and specificities of US, pinhole scintigraphy with subtraction, pinhole and SPECT/CT with subtraction, and all modalities combined were 91.7%/38.9%, 88.9%/72.2%, 93%/66.7% and 84.72%/77.78%, respectively: specificity of US + PS superior to US alone, p = 0.074. SPECT/CT enables reclassification of doubtful uptake foci. CONCLUSIONS: Combination of neck US and PS with subtraction SPECT/CT offers a higher specificity for guiding towards minimally invasive parathyroidectomy. PMID- 29980284 TI - A comprehensive review on the utility of capsule endoscopy in coeliac disease: From computational analysis to the bedside. AB - Small bowel capsule endoscopy (SBCE) can identify macroscopic changes of coeliac disease and assess the extent of disease in the small bowel beyond the duodenum. SBCE has a good sensitivity for the detection of coeliac disease in comparison to histology owing to several ideal features such as a high magnification. It also plays a useful role in detecting complications in patients with refractory coeliac disease. Several studies have been carried out on transforming images obtained from small bowel capsule endoscopy to enable the automated detection of features related to coeliac disease. This review discusses the current roles played by small bowel capsule endoscopy in coeliac disease. It identifies future potential roles of this technique and describes in great detail the role of computational analysis in the detection of coeliac disease and how it can be adapted to current available technology. PMID- 29980285 TI - Ischemic Stroke After Plasmapheresis. AB - Plasmapheresis involves the separation of all cellular elements of blood with the help of an extracorporeal semipermeable membrane. Even though plasmapheresis is generally considered safe, there have been anecdotal reports of thrombosis related to this exchange. We present 2 cases of healthy young males developing ischemic strokes within 24 hours of plasmapheresis. Patient A was a 24-year-old man with a family history of Factor V Leiden mutation presented with right-sided weakness 1 hour after donating plasma. A hypercoagulable work-up revealed elevations in Factor II. Patient B was a 42-year-old man who presented with a right facial droop, expressive aphasia and right arm weakness. He had donated plasma 18 hours before his presentation. A hypercoagulable work-up revealed elevated levels of von Willebrand factor antigen and high sensitivity C-reactive protein. A procoagulant state induced by plasmapheresis likely increases the risk for symptomatic thrombosis when an underlying thrombophilic state is present in the donor. PMID- 29980286 TI - Cerebrotendinous xanthomatosis: The diagnostic challenge. PMID- 29980287 TI - Saccharomyces Cerevisiae Infection In An Immunocompetent Host. PMID- 29980288 TI - Purple urine bag syndrome. PMID- 29980290 TI - Association Between Video Laryngoscopy and Adverse Tracheal Intubation-Associated Events in the Neonatal Intensive Care Unit. AB - The effect of video laryngoscopy on adverse events during neonatal tracheal intubation is unknown. In this single site retrospective cohort study, video laryngoscopy was independently associated with decreased risk for adverse events during neonatal intubation. PMID- 29980291 TI - Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. AB - Bone has well documented natural healing capacity that normally is sufficient to repair fractures and other common injuries. However, the properties of bone change throughout life, and aging is accompanied by increased incidence of bone diseases and compromised fracture healing capacity, which necessitate effective therapies capable of enhancing bone regeneration. The therapeutic potential of adult mesenchymal stem cells (MSCs) for bone repair has been long proposed and examined. Actions of MSCs may include direct differentiation to become bone cells, attraction and recruitment of other cells, or creation of a regenerative environment via production of trophic growth factors. With systemic aging, MSCs also undergo functional decline, which has been well investigated in a number of recent studies. In this review, we first describe the changes in MSCs during aging and discuss how these alterations can affect bone regeneration. We next review current research findings on bone tissue engineering, which is considered a promising and viable therapeutic solution for structural and functional restoration of bone. In particular, the importance of MSCs and bioscaffolds is highlighted. Finally, potential approaches for the prevention of MSC aging and the rejuvenation of aged MSC are discussed. PMID- 29980289 TI - T-Cell Receptor Excision Circles in HIV-Exposed, Uninfected Newborns Measured During a National Newborn Screening Program for Severe Combined Immunodeficiency. AB - Severe combined immunodeficiency screening by measuring T-receptor excision circles at birth allows evaluation of the impact of various maternal conditions on newborn immunity. The slight decrease observed in a French cohort of newborns to HIV-infected mothers can be explained by the confounding factors of prematurity and African descent. PMID- 29980292 TI - Acute kidney injury complicating nephrotic syndrome of minimal change disease. AB - Minimal change disease accounts for 70% to 90% of cases of nephrotic syndrome in children. It also causes nephrotic syndrome in adults, including patients older than age 60. Renal function is altered moderately in approximately 20% to 30% of patients because foot-process fusion impairs filtration of water and solutes. The glomerular filtration rate is reduced by approximately 20% to 30% and returns to baseline with remission of proteinuria. Over the past 50 years, a number of publications have reported cases of acute kidney injury occurring in approximately one-fifth to one-third of adult cases in the absence of prior or concomitant renal disease. Clinical attributes point to a male predominance, age >50, massive proteinuria, severe hypoalbuminemia, a background of hypertension and vascular lesions on kidney biopsy, along with ischemic tubular necrosis. Acute kidney injury may require dialysis for weeks or months until remission of proteinuria allows resolution of oliguria. In some cases, renal function does not recover. An effect of endothelin-1-induced vasoconstriction at the onset of proteinuria has been proposed to explain tubular cell ischemic necrosis. The main factors causing acute kidney injury in patients with minimal change disease are diuretic-induced hypovolemia and nephrotoxic agents. Acute kidney injury is uncommon in children in the absence of intercurrent complications. Infection, nephrotoxic medication, and steroid resistance represent the main risk factors. In all patients, the goal of supportive therapy is essentially to buy time until glucocorticoids obtain remission of proteinuria, which allows resolution of renal failure. PMID- 29980294 TI - Quantifying avian avoidance of offshore wind turbines: Current evidence and key knowledge gaps. AB - The risk of collision between birds and turbines is seen as one of the key issues in the planning process for offshore wind farms. In some cases, predictions of collision risk have led to projects either being withdrawn from the planning process, or refused planning consent. Despite this, the evidence base on which collision risk is assessed is extremely limited and assessments rely on models which can be highly sensitive to assumptions, notably about bird collision avoidance behaviour. We present a synthesis of the current state of knowledge about collision risk and avoidance behaviour in seabirds. Evidence suggests species-specific responses to turbines and that in order to avoid collision, most birds adjust their flight paths at some distance from the turbines, rather than making last-second adjustments. We highlight the key gaps in knowledge and make recommendations for future data collection. PMID- 29980293 TI - Molecular Mechanism of Lipid Nanodisk Formation by Styrene-Maleic Acid Copolymers. AB - Experimental characterization of membrane proteins often requires solubilization. A recent approach is to use styrene-maleic acid (SMA) copolymers to isolate membrane proteins in nanometer-sized membrane disks, or so-called SMA lipid particles (SMALPs). The approach has the advantage of allowing direct extraction of proteins, keeping their native lipid environment. Despite the growing popularity of using SMALPs, the molecular mechanism behind the process remains poorly understood. Here, we unravel the molecular details of the nanodisk formation by using coarse-grained molecular dynamics simulations. We show how SMA copolymers bind to the lipid bilayer interface, driven by the hydrophobic effect. Due to the concerted action of multiple adsorbed copolymers, large membrane defects appear, including small, water-filled pores. The copolymers can stabilize the rim of these pores, leading to pore growth and membrane disruption. Although complete solubilization is not seen on the timescale of our simulations, self assembly experiments show that small nanodisks are the thermodynamically preferred end state. Our findings shed light on the mechanism of SMALP formation and on their molecular structure. This can be an important step toward the design of optimized extraction tools for membrane protein research. PMID- 29980295 TI - ? PMID- 29980296 TI - [Ketamine and chronic pain: A narrative review of its efficacy and its adverse events]. AB - Ketamine is frequently used in the management of refractory chronic pain. To date, the level of proof in the literature on ketamine in this type of indication is generally poor and physicians have no consensus or recommendation to support their practice. This narrative review is an update on literature data assessing the efficacy and safety of ketamine in chronic pain. The electronic search of the Medline, PubMed, Google Scholar and Cochrane databases identified a total of 61 articles including randomized and non-randomized trials and 14 international reviews. In view of these data, it is difficult to conclude on the effectiveness of ketamine in this type of indication and on its safety due to the heterogeneity of practice in terms of doses, routes, duration and frequency of administration and especially a lack of clinical trials with a high level of evidence. PMID- 29980297 TI - Corrigendum to 'Embryotoxic and pharmacologic potency ranking of six azoles in the rat whole embryo culture by morphological and transcriptomic analysis' [Toxicol. Appl. Pharmacol., 322 (2017) 15-26]. PMID- 29980298 TI - Dead-space or dead-end: Can prolonged mechanical ventilation be predicted in all children after unifocalization? PMID- 29980300 TI - A real-world experience: Really? PMID- 29980299 TI - Impact of patient-specific morphologies on sinus flow stasis in transcatheter aortic valve replacement: An in vitro study. AB - OBJECTIVE: The goal of this study is to evaluate how sinus flow patterns after transcatheter aortic valve replacement in realistic representative patient roots vary. Sinus flow can affect transcatheter aortic valve operation and likely leaflet thrombosis occurrence due to stasis and poor washout. How the interaction between transcatheter aortic valve and representative patient aortic roots affects sinus hemodynamics is important to establish for future individualization of transcatheter aortic valve replacement therapy. METHODS: Two representative patient aortic roots were selected, segmented and 3-dimensional printed followed by deployment of Medtronic CoreValve (Medtronic Inc, Irvine, Calif) and Edwards SAPIEN (Edwards Lifesciences, Irvine Calif) transcatheter aortic valves. Sinus hemodynamics were assessed in vitro using high spatio-temporal resolution particle-image-velocimetry. Detailed sinus vortex tracking, shear stress probability density functions, and sinus washout were evaluated and assessed as a function of valve type and representative patient morphology as independent case studies. RESULTS: Peak velocity in the sinus with SAPIEN valve was approximately 3 times higher than with CoreValve for both models (0.30 +/- 0.02 m/s and 0.34 +/ 0.041 m/s vs 0.13 +/- 0.01 m/s and 0.10 +/- 0.02 m/s) (P < .01). Between representative patient models, vorticity magnitudes were significantly different (75 +/- 1.1 s-1, 77 +/- 3.2 s-1, 109 +/- 2.3 s-1, and 250 +/- 4.1 s-1) (P < .01) regardless of valve type. Sinus blood washout characteristic as a function of cardiac cycles was strongly both patient related and valve specific. Fluid dynamics favored shear stresses and washout characteristics due to a smaller sinus and sinotubular junction, further amplified by the SAPIEN valve. CONCLUSIONS: Sinus flow dynamics are highly sensitive to aortic root characteristics and transcatheter aortic valve aortic root interaction. Differences in sinus-flow washout and stasis regions between representative patient models may be reflected in different risks of leaflet thrombosis or valve degeneration. PMID- 29980301 TI - Repetitive Transcranial Magnetic Stimulation-Induced Charles Bonnet Syndrome. PMID- 29980302 TI - Letter to the editor regarding "Minimally invasive plate osteosynthesis has equal safety to reamed intramedullary nails in treating Gustilo-Anderson type I, II and III-A open tibial shaft fractures". PMID- 29980303 TI - Obstructive jaundice caused by an adenoma of the common hepatic duct. PMID- 29980304 TI - An integrative review of the literature on in-hospital worsening heart failure. AB - A subset of patients hospitalized for acute exacerbation of chronic heart failure develop in-hospital worsening heart failure. The objective of this paper is to present an integrative review of in-hospital worsening heart failure, including definitions, incidence, prevalence, mechanisms, treatments, outcomes, and early identification by providers. A search of electronic databases was conducted from January 2000-August 2017 using multiple search terms. Papers were reviewed for relevance; retained papers were abstracted and data were reported in a narrative synthesis. Twenty papers were selected. Many papers were observational data from in-hospital events that occurred during research trials. There was great variability in in-hospital worsening heart failure definition, incidence, prevalence, and treatments offered. Despite rescue therapies, in-hospital worsening heart failure was associated with increased risk for longer hospital stays, higher readmission rates, and death. To date, there are no therapies that target the underlying mechanisms or minimize its occurrence. PMID- 29980305 TI - [Dermatopathology histoseminar. Case 5]. PMID- 29980306 TI - [Dermatopathology histoseminar. Case 6]. PMID- 29980307 TI - [Dermatopathology histoseminar. Case 1]. PMID- 29980308 TI - Persistent Isolation of Staphylococcus aureus in Mechanically-ventilated Patients: Impact of Host-Pathogen Factors on Outcome. PMID- 29980309 TI - The Many Radiological Presentations of Pulmonary Nodules in Type IV Ehlers-Danlos Syndrome. PMID- 29980310 TI - Antimicrobial resistance in the Gulf Cooperation Council region: A proposed framework to assess threats, impacts and mitigation measures associated with AMR in the marine and aquatic environment. AB - It is becoming increasingly clear that the genetic diversity and abundance of antimicrobial resistance (AMR) in non-clinical settings has been underestimated and that the environment plays an integral role in enabling the development of AMR. Due to specific demographic and environmental factors the Gulf Cooperation Council (GCC) region may be particularly susceptible to the threat of AMR, with the marine and aquatic environment potentially playing a specific role in its development and propagation. The demographic factors include rapid population growth, significant international population movements, heavy antibiotic use and insufficient antibiotic stewardship. Environmental factors leading to susceptibility include notable inputs of untreated sewage effluent, high ambient water temperatures, elevated concentrations of heavy metals, and poorly regulated use of antimicrobials in veterinary settings. However, to date there is only a limited understanding of the role that this environment plays in enabling the emergence and propagation AMR in this region. This article provides an overview of the risk associated with AMR in the marine and aquatic environment in the GCC region and proposes a framework for understanding how such environments interact with the wider development and propagation of resistance. It identifies priority actions aligned with the World Health Organisation AMR Global Action Plan and associated national action plans to evaluate the role of marine and aquatic systems relative to the wider factors driving AMR emergence and propagation. The proposed framework and actions to evaluate the role of marine and aquatic environments in driving propagation and emergence of AMR are equally applicable at the regional and national level beyond the GCC. PMID- 29980311 TI - Genetic variants of tumor necrosis factor-alpha and its levels: A correlation with dyslipidemia and type 2 diabetes susceptibility. AB - BACKGROUND & AIM: Tumor necrosis factor-alpha (TNF-alpha) and its genetic variants are implicated in the development of type 2 diabetes (T2D) as a result of systemic inflammation, dyslipidemia, and insulin resistance. The aim of the present study was to investigate i) single nucleotide polymorphisms (SNPs) of TNF alpha and its association with altered TNF-alpha transcript levels and plasma concentrations ii) free fatty acid (FFA) concentrations as a marker for dyslipidemia and its association with TNF-alpha and iii) genotype-phenotype correlation analysis in T2D patients. METHODS: Plasma and PBMCs were separated from venous blood of 478 diabetic patients and 502 age-matched non-diabetic individuals. Genomic DNA was isolated from PBMCs and RNA was isolated from PBMCs and adipose tissue samples. PCR-RFLP was used for genotyping and qPCR to estimate TNF-alpha levels. TNF-alpha and FFA concentrations were estimated from plasma samples by ELISA. RESULTS: Our study suggests: i) involvement of TNF-alpha -857 C/T in T2D patients (p < 0.0001), ii) 2.072 and 6.7 fold elevation in TNF-alpha transcript levels in patients' PBMCs and adipose tissues respectively, increased plasma TNF-alpha (p = 0.0122) particularly in obese patients (p = 0.0405), increased plasma FFA (p = 0.0215) and, iii) association of TNF-alpha -238 G/A with body mass index (BMI) (p = 0.0270) and, -857 C/T with fasting blood glucose (FBG) (p = 0.0122) and triglycerides (TG) (p = 0.0015). Correlation analysis suggests that TNF-alpha concentrations are positively correlated with BMI (r = 0.3, p = 0.04) and negatively correlated with HDL (r = -0.39, p = 0.001) while the FFA concentrations are positively correlated with BMI (r = 0.35, p = 0.0004). CONCLUSION: It can be concluded that the genetic variant of TNF-alpha along with elevated TNF-alpha and FFA concentrations play a role in the development of dyslipidemia which could be a potent risk factor towards T2D in Gujarat population. PMID- 29980312 TI - Effects of inositol on glucose homeostasis: Systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND & AIMS: The effect of inositol on glucose homeostasis is not well characterized. The aim of the present meta-analysis is to synthesize the effects of inositol on glucose homeostasis in different clinical conditions. METHODS: We performed a systematic review (CRD42017057927) following PRISMA guidelines. Web of Science and Medline were searched for randomized controlled trials (RCTs) that addressed supplementation with compounds of the inositol family in humans and assessed their effects on glucose homeostasis. RESULTS: We screened 476 abstracts and included 20 RCTs with a total of 1239 subjects. Meta-analysis showed in the treatment arm a reduction in fasting plasma glucose (Mean difference (MD) -0.44 mmol/l, 95% CI -0.65, -0.23), 2 h PG after 75 g OGTT (MD -0.69 mmol/l, 95% CI 1.14, -0.23), abnormal glucose tolerance (Relative risk (RR) 0.28, 95% CI 0.12, 0.66), fasting insulin (MD -38.49 pmol/l, 95% CI -52.63, -24.36), and HOMA-IR (MD -1.96 mmol * mUI/l, 95% CI -2.62, -1.30). No differences were observed in BMI, HbA1c and % of patients requiring insulin treatment. Sensitivity analysis did not change treatment estimates. Mention to adverse events was only present in 13 articles with no sign of seriousness. CONCLUSIONS: Inositol supplementation decreases blood glucose through an improvement in insulin sensitivity that is independent of weight. Assessment of adverse effects is scarce among published trials and should be fully addressed before considering inositol as a therapeutic agent for glucose-related outcomes. The characterization of the subjects achieving benefit from the intervention and the formulations to be used should also be known. PMID- 29980313 TI - Cadmium intake and chronic kidney disease. PMID- 29980314 TI - The compliance coach: A bedside observer, auditor, and educator as part of an infection prevention department's team approach for improving central line care and reducing central line-associated bloodstream infection risk. AB - A compliance coach who audits central line maintenance and provides feedback and education to bedside nurses through timely, nonpunitive conversation is an effective addition to busy infection prevention departments. Staff nurses and nurse managers reported receiving clearly communicated and actionable information from the coach and compliance improved over time in multiple areas of central line maintenance. PMID- 29980315 TI - Disparity of the "screen-and-isolate" policy for multidrug-resistant organisms: A national survey in French adult ICUs. AB - BACKGROUND: The prevalence of multidrug-resistant organisms (MDROs) has dramatically increased. The aim of this survey was to describe and analyze the different screening and isolation policies regarding MDROs in French adult intensive care units (ICUs). MATERIALS AND METHODS: A multicenter online survey was performed among French ICUs, including 63 questions distributed into 4 parts: characteristics of the unit, MDRO screening policy, policy regarding contact precautions, and ecology of the unit. RESULTS: From April 2015 to June 2016, 73 of 301 ICUs (24%) participated in the survey. MDRO screening was performed on admission in 96% of ICUs, for at least 1 MDRO (78%). MDRO screening was performed weekly during ICU stay in 83% of ICUs. Preemptive isolation was initiated on admission in 82% of ICUs, mostly in a targeted way (71%). Imported and acquired MDRO rates >10% were reported in 44% and 27% of ICUs, respectively. An MDRO outbreak had occurred within the past 3 years in 48% of cases. CONCLUSION: French ICUs have variable screening and isolation approaches for MDROs, as up to 10 combinations were met. Discrepancies with the 2009 national guidelines were observed. Very few ICUs practice without some form of screening and isolation of patients upon admission. PMID- 29980316 TI - Barriers and perceptions of environmental cleaning: An environmental services perspective. AB - We examined the barriers and perceptions of using a 1-step daily disinfectant and ultraviolet light for environmental cleaning using an anonymous Likert scale survey. Results indicated that environmental services workers believe that cleaning is important for infection prevention and that ultraviolet light and 1 step daily disinfectant cleaner are effective sporicides. PMID- 29980317 TI - Secondary bladder exstrophy repair with a bilateral gracilis muscle flap in an adult female patient: Case report of an original procedure. AB - Classical bladder exstrophy (CBE), affecting 1 birth out of 30,000, is characterized by an evaginated bladder plate through a defect in the lower abdominal wall, multiple abdominal wall anomalies including a pubic bone arch dehiscence. Numerous approaches from childhood to adulthood are thus required, depending on the severity of the deformity, including the associated genital anomalies. We report the case of a 19-year-old woman with CBE with a history of three-failed primary closure. We performed a secondary neck closure with a concomitant suspension of the bladder neck and reconstruction of the lower abdominal wall using a bilateral gracilis muscle flap transposition. The early postoperative course was uneventful. The patient was discharged at day ten postoperatively. The upper part of the genital sutures (labia minora) secondary healed in three weeks. Assessment at 2, 6 and 16 months postoperatively, respectively noticed a complete healing with successful sexual intercourses, perceived gracilis contraction by the patient, and finally, recent attempts to get pregnant. Neither urinary infection nor urinary leaks occurred. Bilateral crossed gracilis muscles transfer linking both rectus abdominis muscle in front of the reconstructed bladder neck might benefit to bladder exstrophy patients. PMID- 29980318 TI - [The surgical portfolio: A new educational tool for the French plastic surgery residents?] AB - A recent reform of the French government has shortened the plastic surgery residency from 5 to 4 years. Until today, the evaluation and validation of the residency was shared between the local coordinator for practical skills and, after the residency, by the French College of Plastic Surgery for theorical knowledges. The new reform suggests to add a portfolio that will follow the resident during his surgical training. Based on the French reform and syllabus of others medical specialities, we designed a surgical portfolio that will help the resident both with his practical progression and his knowledges acquisition. The aim of the portfolio is to get a national unity of the plastic surgery training. As a first step we will describe the actual plastic surgery residency. Then, we will detail what the reform is going to change. At last, we will introduce the surgical portfolio, its content, its use and its goals. PMID- 29980319 TI - Response to oral ivermectin in three cases of follicular cutaneous larva migrans. PMID- 29980321 TI - Short implants (<=8mm) compared to standard length implants (>8mm) in conjunction with maxillary sinus floor augmentation: a systematic review and meta-analysis. AB - The objective was to test the hypothesis of no difference in the treatment outcome after the installation of short implants (<=8mm) in the posterior part of the maxilla compared to standard length implants (>8mm) in conjunction with maxillary sinus floor augmentation (MSFA) using the lateral window technique, after an observation period of >=3years. A search of the MEDLINE, Embase, and Cochrane Library databases, in combination with a hand-search of relevant journals, was conducted. The search yielded 1102 titles. Finally, three studies that fulfilled the inclusion criteria were included. All were considered to have a low risk of bias. Meta-analyses revealed no significant differences in implant survival or peri-implant marginal bone loss between the two treatment modalities. However, the use of standard length implants in conjunction with MSFA was characterized by a tendency towards more peri-implant marginal bone loss. There was no statistically significant difference between the two treatment modalities with regard to overall patient satisfaction. Short implants seem to be a suitable alternative to standard length implants in conjunction with MSFA. However, further randomized controlled trials with larger patient samples and an observation period of more than 3years are needed before one treatment modality might be considered superior to the other. PMID- 29980320 TI - Predictors for poor cosmetic outcome in patients with early stage breast cancer treated with breast conserving therapy: Results of the Young boost trial. AB - PURPOSE: In the Young Boost trial (YBT), breast cancer patients <=50 years of age, treated with breast conserving therapy (BCT) were randomized between a 26 Gy boost dose and a 16 Gy boost dose, with local recurrence as primary and cosmetic outcome (CO) as secondary endpoint. Data of the YBT was used to investigate which factors are related with worse cosmetic outcome after BCT. METHODS: From 2004 to 2011, 2421 cT1-2N0-2a breast cancer patients were randomized. CO was scored subjectively by the patient and physician, and objectively using BCCT.core: at baseline, one and four years after treatment. Associations between potential risk factors for worse cosmetic outcome, based on the objective BCCT.core, were investigated using a proportional odds model. RESULTS: At four years, CO was significantly better in the standard boost group for all three scoring methods (satisfied CO +/-65% vs 55%). A photon boost, high boost dose, poor cosmesis before radiation therapy, large boost volume and adjuvant chemotherapy significantly deteriorated CO. CONCLUSION: Important risk factors for worse CO were the use of a photon boost instead of an electron boost, a high boost dose, cosmesis at baseline, adjuvant chemotherapy and boost volume. These results can be used to define strategies aimed at improving CO. PMID- 29980322 TI - Evaluation of alternate parasite transport systems for the BD MAXTM enteric parasite panel. AB - Total-Fix, Cary-Blair, and Para-Pak SVT parasite transport systems were compared to 10% formalin with the BD MAX Enteric Parasite Panel, using clinical and contrived samples to determine comparability and limits of detection. The three transport systems have equal or superior limits of detection for all pathogens tested compared to 10% formalin. PMID- 29980323 TI - Litigation claims in relation to radiology: what can we learn? AB - AIM: To analyse data provided by the National Health Service Litigation Authority (NHSLA) to establish common and/or reoccurring themes or trends, and use these established learning points to reduce the possibility of such claims in the future. MATERIALS AND METHODS: Data provided by the NHSLA under the Freedom of Information Act for settled claims against radiology between 1995 and 2014 were analysed for common themes. RESULTS: Seven hundred and ninety-one settled claims were recorded by the NHSLA between 1995 and 2014 where radiology was implicated as the primary specialty at fault. Alleged missed or delayed diagnosis of a tumour accounted for almost a third of claims. Eight percent of claims related to interventional radiology. Almost 10% of claims (n=75) were settled due to an injury whilst in the radiology department, with almost a third of these due to a fall in the department. CONCLUSION: "To err is human", but by analysing NHSLA claims related to radiology, thematic analysis and discussion regarding these cases can be highlighted, and hopefully, to mitigate these risks and thus reduce liability in the future. PMID- 29980324 TI - Identification of pathological complete response after neoadjuvant chemotherapy for breast cancer: comparison of greyscale ultrasound, shear wave elastography, and MRI. AB - AIM: To assess the value of post-treatment shear-wave elastography (SWE) parameters (maximum stiffness [Emax], mean stiffness [Emean], and standard deviation [SD]) compared to greyscale ultrasonography (US) and magnetic resonance imaging (MRI) in identifying pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) in breast cancer. MATERIALS AND METHODS: In a prospective cohort study, 80 patients receiving NACT for breast cancer underwent baseline and post-treatment US, SWE, and MRI examinations. Four SWE images in two orthogonal planes were obtained. Maximum greyscale US diameter and maximum diameter of lesion enhancement on MRI were measured. Percentage reductions between baseline and post-treatment scans were calculated for MRI and greyscale US diameter, and Emean, Emax, and SD. The percentage reduction in Emean and US diameter were also analysed as a combination. Analysis was undertaken using receiver operating characteristic (ROC) curves and the chi-squared test. RESULTS: pCR occurred in 21 of 80 (26%) women. The area under the ROC curve (AUC) for pCR of percentage reductions in Emean, Emax, SD, and greyscale US diameter were 0.89, 0.85, 0.75, and 0.86, respectively. The combination of percentage reductions in Emean and greyscale ultrasound diameter yielded an AUC of 0.92, which is similar to the AUC for MRI of 0.96 (p=0.28). CONCLUSIONS: SWE combined with greyscale US shows promise for end-of-treatment identification of response to NACT in women with breast cancer, with accuracies similar to breast MRI. This technique could be used to inform surgical decision-making after NACT. PMID- 29980325 TI - Small low-risk pulmonary nodules on chest digital radiography: can we predict whether the nodule is benign? AB - AIM: To evaluate digital chest radiography (CR) performance compared to computed tomography (CT) for characterising small low-risk pulmonary nodules detected incidentally in non-oncological patients. A second aim was to assess the prevalence of calcification and possible false-positive findings mimicking nodules. MATERIALS AND METHODS: Two hundred and seven patients who presented with a pulmonary nodule on CR and underwent CT were included prospectively. Nine radiologists blinded to the CT images reviewed the CRs assessing for the presence of nodules. Afterwards, the same radiologists evaluated the corresponding CT for the presence of nodules, dimensions, and calcification. If the nodule was not present on CT, it was considered a false-positive finding, and possible confounding factors on CR were investigated. RESULTS: Among all 213 nodules seen on CR, 32.4% were revealed to be false-positive findings on CT, mostly due to images formed by vessels (53.6%), osseous aetiologies (30.4%), and skin lesions (13%). Most nodules <6 mm detected on radiographies had benign calcification on CT (n=90; 67.7%). Comparatively, only 41.2% of nodules >=6 mm on the CR had benign calcification. Among all nodules <6 mm detected on CR, 95.5% were calcified or not present at CT against 81.2% for those >=6 mm (p<0.001). CONCLUSION: The present study demonstrated that 95.5% of pulmonary nodules smaller than 6 mm on CRs are either calcified (benign) or represent a false positive finding on CT. These results suggest that nodule measures on CR smaller than 6 mm most likely represent a benign finding. PMID- 29980326 TI - Clinical significance of extrathyroidal extension according to size of papillary thyroid carcinoma. PMID- 29980327 TI - Green Therapeutic Biocapsules: Using Plant Cells to Orally Deliver Biopharmaceuticals. AB - The use of innovative platforms to produce biopharmaceuticals cheaply and deliver them through noninvasive routes could expand their social benefits. Coverage should increase as a consequence of lower cost and higher patient compliance due to painless administration. For more than two decades of research, oral therapies that rely on genetically engineered plants for the production of biopharmaceuticals have been explored to treat or prevent high-impact diseases. Recent reports on the successful oral delivery of plant-made biopharmaceuticals raise new hopes for the field. Several candidates have shown protection in animal models, and efforts to establish their production on an industrial scale are ongoing. These advances and perspectives for the field are analyzed. PMID- 29980328 TI - Tracheostomy and mortality in patients with severe burns: A nationwide observational study. AB - BACKGROUND: Tracheostomy is often performed in patients with severe burns who are undergoing prolonged mechanical ventilation. However, the appropriate timing of tracheostomy and its effect on mortality remain unknown. The aim of this study was to determine whether tracheostomy can reduce mortality in patients with severe burns. METHODS: Using the Japanese Diagnosis Procedure Combination database from April 2010 to March 2014, we extracted data on adult patients with severe burns (burn index score of >=15) who started mechanical ventilation within 3days of admission. We estimated the hazard ratio for 28-day in-hospital mortality associated with tracheotomy performed from day 5 to 28. We adjusted for baseline and time-dependent confounders using inverse probability of treatment weighting methods and fitted a marginal structural Cox proportional hazard model. RESULTS: We identified 680 eligible patients (94 in the tracheostomy group, 2289 person-days; 586 in the non-tracheostomy group, 11,197 person-days). Patients who underwent a tracheostomy had worse prognostic factors for mortality. After adjustment for these factors, the hazard ratio for 28-day mortality associated with tracheostomy compared with non-tracheostomy was 0.73 (95% confidence interval, 0.39-1.34). CONCLUSIONS: There was no significant association between 28-day in-hospital mortality and early tracheostomy in adult patients with severe burns. PMID- 29980329 TI - Is it possible for people with severe mental illness to sit less and move more? A systematic review of interventions to increase physical activity or reduce sedentary behaviour. AB - Individuals with severe mental illness (SMI) (schizophrenia-spectrum, bipolar disorder and major depressive disorder) die 10-20 years prematurely due to physical disorders such as cardiovascular disease. Physical activity (PA) is effective in preventing and managing these conditions in the general population, however individuals with SMI engage in substantially less PA and more sedentary behaviour (SB) compared to healthy counterparts. Furthermore, the effectiveness of intervening to increase PA or reduce SB in SMI populations is unknown. Therefore, we systematically reviewed studies measuring changes in PA or SB following behavioural interventions in people with SMI. A systematic search of major databases was conducted from inception until 1/3/2018 for behavioural interventions reporting changes in PA or SB in people with SMI. From 3018 initial hits, 32 articles were eligible, including 16 controlled trials (CT's; Treatment n = 1025, Control n = 1162) and 16 uncontrolled trials (n = 655). Of 16 CTs, seven (47%) reported significant improvements in PA, although only one found changes with an objective measure. Of 16 uncontrolled trials, 3 (20%) found improvements in PA (one with objective measurement). No intervention study had a primary aim of changing SB, nor did any note changes in SB using an objective measure. In conclusion, there is inconsistent and low quality evidence to show that interventions can be effective in changing PA or SB in this population. Future robust randomized controlled trials, using objectively-measured PA/SB as the primary outcome, are required to determine which behavioural interventions are effective in improving the sedentary lifestyles associated with SMI. Systematic review registration- PROSPERO registration number CRD42017069399. PMID- 29980330 TI - Frequent PD-L1 Protein Expression and Molecular Correlates in Urinary Bladder Squamous Cell Carcinoma. PMID- 29980331 TI - Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. AB - BACKGROUND: Long-term androgen deprivation therapy (ADT) combined with radiotherapy (RT) is a standard treatment for patients with localized high-risk prostate cancer (HRPC). However, the optimal duration of ADT is not yet defined. OBJECTIVE: The aim of this superiority randomized trial was to compare outcomes of RT combined with either 36 or 18 mo of ADT. DESIGN, SETTING AND PARTICIPANTS: From October 2000 to January 2008, 630 patients with HRPC were randomized, 310 to pelvic and prostate RT combined with 36 mo (long arm) and 320 to the same RT with 18 mo (short arm) of ADT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and quality of life (QoL) were primary end points. OS rates were compared with Cox Regression model and QoL data were analyzed through mixed linear model. RESULTS AND LIMITATIONS: With a median follow-up of 9.4 yr, 290 patients had died (147 long arm vs 143 short arm). The 5-yr OS rates (95% confidence interval) were 91% for long arm (88-95%) and 86% for short arm (83 90%), p=0.07. QoL analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 mo ADT with two of them presenting a clinically relevant difference in mean scores of >=10 points. CONCLUSIONS: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC. PATIENT SUMMARY: In this study, we report outcomes from high-risk prostate cancer patients treated with radiotherapy and either 36 or 18 mo of androgen deprivation therapy. There was no difference in survival between the two groups, with the 18-mo group experiencing a better quality of life. PMID- 29980332 TI - Case studies of packaging and processing solutions to improve meat quality and safety. AB - A significant amount of the meat is wasted due to spoilage or safety risks. Active packaging systems have a great potential to reduce waste through chemical and microbial control of the product and/or the storage environment. Although commercial products are already available, active packaging is far from being fully developed. In contrast, passive packaging, such as modified atmosphere packaging (MAP) and vacuum packaging, have been fully implemented. Research conducted at the Danish Meat Research Institute (DMRI), demonstrates that it is possible to create new opportunities for the meat industry by modifying MAP or combining microwave treatment with vacuum packaging. Predictive shelf life models can be used to estimate the shelf life in MAP or vacuum under dynamic temperature conditions. Using the tri-gas guidelines, the industry can benefit from the increased eating quality, and the in-package decontamination process using vacuum packaging in combination with 5.8 GHz microwaves eliminates C. botulinum spores, resulting in increased food safety and an extended shelf life. PMID- 29980333 TI - Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Factors Associated with Vision and Edema Outcomes. AB - PURPOSE: To identify baseline factors associated with change in visual acuity or development of vision-impairing central-involved diabetic macular edema (DME) over 2 years when treating proliferative diabetic retinopathy (PDR) with ranibizumab or panretinal photocoagulation (PRP). DESIGN: Post hoc analyses of randomized, multicenter clinical trial data. PARTICIPANTS: Eyes completing the 2 year visit (n = 328) or without vision-impairing central-involved DME at baseline (n = 302) in Diabetic Retinopathy Clinical Research Network Protocol S. METHODS: Intravitreous ranibizumab (0.5 mg/0.05 ml) or PRP. MAIN OUTCOME MEASURES: Change in visual acuity (area under the curve) and development of vision-impairing (20/32 or worse) central-involved DME over 2 years. RESULTS: After multivariable model selection with adjustment for baseline visual acuity and central subfield thickness, no factors were identified as associated with change in visual acuity or development of vision-impairing central-involved DME within the ranibizumab group. In the PRP group, worse change in visual acuity was more likely with higher hemoglobin A1c level (-0.6 letters per 1% increase; 95% confidence interval [CI], -1.2 to -0.1 letters; continuous P = 0.03), more severe diabetic retinopathy (difference between high-risk PDR or worse vs. moderate PDR or better, -2.8 letters [95% CI, -5.5 to -0.2 letters]; continuous P = 0.003), and higher mean arterial pressure (difference between >=100 mmHg vs. <100 mmHg, -2.0 letters [95% CI, -4.6 to 0.5 letters]; continuous P = 0.009). Development of vision-impairing central-involved DME was more likely with higher hemoglobin A1c level (hazard ratio [HR] per 1% increase, 1.31 [95% CI, 1.13-1.52]; continuous P < 0.001), more severe diabetic retinopathy (HR for high-risk PDR or worse vs. moderate PDR or better, 1.46 [95% CI, 0.73-2.92]; continuous P = 0.03), and the presence of cystoid abnormalities within 500 MUm of the macula center (HR, 2.90 [95% CI, 1.35-6.24]; P = 0.006). CONCLUSIONS: For eyes managed with PRP, higher hemoglobin A1c level and more severe diabetic retinopathy were associated with less vision improvement and an increased risk of vision-impairing central involved DME developing. When managing PDR with ranibizumab, eyes gained vision, on average, with no baseline characteristics identified as associated with visual acuity or central-involved DME outcomes. PMID- 29980334 TI - Favorable early vessel healing after everolimus-eluting stent implantation: 3-, 6 , and 12-month follow-up of optical coherence tomography. AB - BACKGROUND: Although a prospective randomized control study revealed that 3-month dual anti-platelet therapy (DAPT) is safe and does not compromise the efficacy of everolimus-eluting stent (EES) in selected patients, detailed vessel healing at early phase after EES implantation has yet to be investigated in Japanese patients. METHODS AND RESULTS: A total of 27 lesions in 19 patients treated with EES were serially evaluated by using optical coherence tomography (OCT) at 3, 6, and 12 months after stent implantation. In addition to standard quantitative OCT parameters, the percentage of stents with peri-strut low-intensity area (PLIA, a region around stent struts homogenously showing lesser intensity than the surrounding tissue, suggesting fibrin deposition or impaired neointima maturation) and that with in-stent thrombi were evaluated. There was a significant, but small increase in neointimal thickness (63+/-17MUm; 83+/-30MUm; and 111+/-44MUm, respectively; p=0.006) and small decrease in average lumen area (6.80+/-2.57mm2, 6.62+/-2.58mm2, 6.33+/-2.58mm2, p=0.038) from the 3- to the 12 month follow-up. The incidences of uncovered and malapposed struts were low at 3 months and did not significantly change at 6 months and 12 months (3.01+/-4.43; 2.45+/-3.75; and 1.47+/-3.16, p=0.143, and 0.75+/-0.65; 0.63+/-0.73; and 0.58+/ 1.42, p=0.162, respectively). Also, frequency of struts with PLIA was already low at three months and significantly decreased during the follow-up (6.4+/-6.5; 4.6+/-5.4; and 2.3+/-3.3, respectively; p=0.001). CONCLUSION: Favorable vessel healing was achieved at 3 months after EES implantation without neointimal hyperplasia which was persistently suppressed up to 12 months. PMID- 29980335 TI - Therapeutic jurisprudence's future in health law: Bringing the patient back into the picture. AB - More than 25 years ago, Professors David Wexler and Bruce Winick envisioned broad application of therapeutic jurisprudence (TJ), an interdisciplinary theory of law suggesting that legislatures, regulators, and judges consider the extent to which their decisions impact the psychological well-being of those upon whom the law acts. TJ most obviously plays a significant role in mental health and criminal law, where it originated, but Wexler and Winick long ago opined that TJ could be useful in a wide variety of other disciplines as well. Indeed, TJ has expanded exponentially in application over the years. Yet, although Wexler and Winick originally suggested that health law was an "obvious" field in which it could expand, application of TJ in that discipline has been less robust than one might have expected. This article will examine the extent to which TJ has been applied in health law other than mental health law, categorize the areas of health law in which it has been applied, and suggest future paths for expansive application in this most obvious of areas. PMID- 29980336 TI - Decision satisfaction among women choosing a method of pregnancy termination in the setting of fetal anomalies and other pregnancy complications: A qualitative study. AB - OBJECTIVE: The decision to undergo a surgical or medical method of second trimester termination for pregnancy complications should be preference-sensitive. Decision satisfaction has not been described in this population; understanding how women describe decision satisfaction in this setting could inform decision support efforts. METHODS: We conducted qualitative interviews with women one to three weeks after termination who chose either a surgical or medical termination for fetal anomalies, pregnancy complications or fetal demise. We analyzed transcripts using modified grounded theory in an iterative manner with a generative thematic approach. RESULTS: We interviewed 36 women (24 surgical and 12 medical). Subjects connected decision satisfaction with counseling experiences and their personal values, including (1) importance of adequate information, (2) autonomous decision making, and (3) choosing the method that facilitates coping. CONCLUSION: Offering women a choice between surgical and medical termination procedures in the setting of pregnancy complications is integral to decision satisfaction. Women in our study reported wanting this decision to be driven by their personal values. PRACTICE IMPLICATIONS: Women should be able to choose between surgical and medical termination based on preference and not availability of services. Decision support from women's health providers should be based on values clarification and providing accurate information. PMID- 29980337 TI - Treatment decision making involving patients with dementia in acute care: A scoping review. AB - OBJECTIVE: To summarize the evidence regarding the factors and processes of treatment decision making involving a person with dementia (PWD) in the acute care setting. METHODS: We conducted a scoping review, searching 4 databases (PubMed, CINAHL, Web of Science, & PsychINfo) for articles that contained primary data from a quantitative or qualitative study involving treatment decision making in the acute care setting for PWD and were published in English. We categorized the factors and processes of decision making identified in each article using inductive content analysis. We also consulted with healthcare practitioners to receive stakeholder input on our findings. RESULTS: Our search initially revealed 12,478 articles, of which 28 were included in the review. We identified 5 categories of factors that influence the decision-making process: knowing the patient, culture and systems, role clarity, appropriateness of palliative care in dementia, and caregiver need for support. CONCLUSION: Our findings highlight the complexities of the decision-making process and the importance of attending to the needs of the caregiver, healthcare practitioners, and the patient. PRACTICE IMPLICATIONS: It is important to address beliefs of involving palliative care for a PWD and the role of each healthcare discipline. PMID- 29980338 TI - Surgical repair of large-to-massive rotator cuff tears seems to be a better option than patch augmentation or debridement and biceps tenotomy: a prospective comparative study. AB - BACKGROUND: This prospective study compared the outcomes after 3 different treatments for large and massive rotator cuff tears. METHODS: Patients with a diagnosis of large-to-massive rotator cuff tears were prospectively included. Patients were allocated in 3 groups: (1) arthroscopic complete repair (repair group), (2) open repair and xenograft patch augmentation (patch group), and (3) arthroscopic debridement and tenotomy of the long head of the biceps (debridement group). Patients were evaluated preoperatively and postoperatively at 3, 6, 12 and 24 months. The primary outcome measure was the Constant-Murley score. RESULTS: The study included 32 consecutive patients. The mean improvement in the Constant-Murley score was +29.1 for the repair group (P < .01), +32.2 for the patch group (P < .01), and +20.1 for the debridement group (P < .01) at the final follow-up examination. No differences were found between the repair and patch groups, but the difference became significant between the debridement group and the patch group (P < .001) and also between the debridement group and the repair group (P < .002) at 12 months and the final follow-up. Moreover, 5 complications occurred in 11 patients in the patch group, whereas there was only 1 complication in the repair group and no complications in the debridement group. CONCLUSION: The use of porcine dermis patches to augment repairs of massive and irreparable rotator cuff tears is not recommended because there is no benefit compared with repair without augmentation and patches result in more complications. PMID- 29980339 TI - What I've learned about open shoulder surgery. PMID- 29980340 TI - Is augmentation with the long head of the biceps tendon helpful in arthroscopic treatment of irreparable rotator cuff tears? AB - BACKGROUND: Although various surgical techniques have been used to treat irreparable rotator cuff tears (RCTs), debate remains regarding which treatment is most effective. The purpose of our study was to compare the outcomes of partial rotator cuff repair versus repair with augmentation of the tenotomized long head of the biceps tendon (LHBT). METHODS: This study included 76 patients with large to massive RCTs. Arthroscopic rotator cuff repair with LHBT augmentation was performed in 39 patients (group I), while partial repair was performed in 37 patients (group II). Clinical and functional outcomes were compared with a visual analog scale for pain and the American Shoulder and Elbow Surgeons score, Constant score, and Korean Shoulder Score. Magnetic resonance imaging was performed 12 months after surgery. RESULTS: The mean follow-up period was 29.6 +/- 7.8 months (range, 24-51 months). Significant improvements in pain and clinical scores were observed in both groups at the last follow-up. However, there were no significant differences in pain, clinical scores, or range of motion between the 2 groups at any time point. Retears were observed in 16 patients in group I (41.0%) and 14 in group II (37.8%, P = .78). Augmented LHBT pathology was observed in 10 patients (25.6%). CONCLUSIONS: Both partial repair and repair with LHBT augmentation were effective in improving clinical and radiologic outcomes. No significant differences in clinical outcomes or repaired cuff integrity were observed between the groups. The investment of operation time and effort in augmenting the LHBT in the treatment of irreparable RCTs is not recommended. PMID- 29980342 TI - 3D graphene-based foam induced by phytic acid: An effective enzyme-mimic catalyst for electrochemical detection of cell-released superoxide anion. AB - Here we present a new method to fabricate enzyme-mimic metal-free catalysts for electrochemical detection of superoxide anion (O2*-) by introducing phosphate groups into graphene-based foam. Through a template-free hydrothermal process, graphene oxide (GO) was treated with different amount of phytic acid (PA) to obtain 3D porous graphene-based foam (PAGF). Characterizations demonstrate that phosphate groups were successfully modified on the surface and inter layer structure of PAGF materials and the defects and disorder degree of PAGF could be controlled by adjusting the addition of PA precursors. Meanwhile, the synthesized PAGF was successfully immobilized on screen printed carbon electrodes (SPCEs) and employed in O2*- detection. With PA treated on graphene structure, the resulted PAGF/SPCEs exhibit distinct characteristic redox peaks, showing enzyme-mimic catalytic activity toward O2*- dismutation. Also, the amount of modified phosphate groups has caused a considerable variety on the performance of PAGF based electrodes. Apart from high sensitivity, wide liner range, low detection limit, good selectivity and long-term stability, our sensors also present satisfying performance in the real-time monitoring of drug-induced O2*- released from Hela cells. The reliability of the biological measurement was further demonstrated via electron paramagnetic resonance (EPR) to characterize the released O2*- from stimulated cells by using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) to trap the transient O2*-. The above results indicate that our established sensors hold potential application in the real-time detection of O2*- in biological samples. PMID- 29980343 TI - Homozygous KLF1 mutation c.901C>T (p.Arg301Cys) resulting in mild thalassemia intermedia in an Indian: A next-generation sequencing diagnosis. PMID- 29980344 TI - Central venous catheter repair is highly successful in children with intestinal failure. AB - PURPOSE: Damaged central venous catheters (CVCs) are commonly repaired to avoid line replacement and preserve vascular access. However, limited data suggest an increased risk for central line-associated bloodstream infections (CLABSIs) associated with the repair procedure. The purpose of this study was to describe outcomes of CVC repairs among parenteral nutrition (PN) dependent children with intestinal failure (IF). METHODS: A 2-year retrospective review was performed on children with IF on home PN > 6 months. Outcomes of interest were repair success and postrepair CLABSI incidence. Descriptive statistics included medians and frequencies. RESULTS: A total of 36 pediatric IF patients underwent 96 CVC repairs during the study period. The median CVC repair count was 1.5 repairs/patient (range, 1 to 16 repairs/patient) with >1 repair in half the patients. Ninety-four broken catheters (98%) were successfully repaired with restoration of function. Of the unsuccessful repairs (2%), the two catheters eventually required surgical removal and replacement. One repair (1%) was followed by a CLABSI with Enterococcus faecalis in an immunocompromised patient. CONCLUSION: CVC repair is a highly successful procedure with a low risk for infection. Catheter repair should be considered whenever possible as it may extend the lifetime of the catheter and decrease the risk for vascular access loss. LEVEL OF EVIDENCE: Treatment study; level IV. PMID- 29980341 TI - Insights from intoxicated Drosophila. AB - Our understanding of alcohol use disorder (AUD), particularly alcohol's effects on the nervous system, has unquestionably benefited from the use of model systems such as Drosophila melanogaster. Here, we briefly introduce the use of flies in alcohol research, and highlight the genetic accessibility and neurobiological contribution that flies have made to our understanding of AUD. Future fly research offers unique opportunities for addressing unresolved questions in the alcohol field, such as the neuromolecular and circuit basis for cravings and alcohol-induced neuroimmune dysfunction. This review strongly advocates for interdisciplinary approaches and translational collaborations with the united goal of confronting the major health problems associated with alcohol abuse and addiction. PMID- 29980346 TI - New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment. AB - BACKGROUND/PURPOSE: Necrotizing enterocolitis (NEC) is a devastating disease of prematurity that develops after feeding, often without warning, and results in diffuse intestinal necrosis leading to sepsis and death in many cases. The lack of improvement in overall survival is influenced by nonspecific diagnostic modalities as well as inexact and nonpersonalized treatment strategies. METHODS/RESULTS: Recently, we and others have shown that NEC develops in response to exaggerated bacterial signaling in the premature intestine, as a consequence of elevated expression and activity of the bacterial receptor toll-like receptor 4 (TLR4), which is important for normal gut development. Breast milk is a powerful TLR4 inhibitor, while mutations in TLR4 genes lead to increased NEC risk in humans, providing proof-of-concept for its role in NEC. Recently, a drug discovery approach has revealed a novel class of TLR4 inhibitors which are being developed for personalized approaches to NEC treatment. CONCLUSION: This review will highlight the current understanding of the role of bacterial signaling in NEC pathogenesis, and will describe advances in diagnosis, prevention and treatment of NEC that may hopefully improve survival for these most fragile patients. SYSTEMATIC REVIEW: Level of Evidence: Level II. PMID- 29980345 TI - Diagnostic accuracy of surgeon performed ultrasound (SPU) for appendicitis in children. AB - AIM: Compare the diagnostic accuracy of surgeon performed ultrasound to radiology performed ultrasound in children presenting with suspected appendicitis to a tertiary care pediatric hospital in Australia. METHODS: Children under 16 presenting to the emergency department of The Children's Hospital at Westmead were considered for the study. Patients with obvious signs of appendicitis not requiring ultrasound and those with established ultrasound diagnosis of appendicitis were excluded. Ultrasound was performed by a Pediatric Surgeon (SPU) after obtaining consent. The treating team was blinded to the results. Patient underwent formal ultrasound in radiology (RPU) and treatment was based on the formal report. SPU result was reviewed by a radiologist blinded to results of RPU. The results were compared. RESULTS: 65 children underwent ultrasound. 35 were male. Median age was 10 (range3-15). Median weight was 36 kg (range 12.6 76.2 kg), z-score median 0.21 (-1.83 to 2.74). Symptom duration ranged from few hours to 2 weeks but majority (45) had symptoms for less than 48 h. Prevalence of appendicitis was 45%. Thirty two underwent surgery. Negative appendicectomy rate was 9.4%. Thirty three did not have surgery. 8 represented but only one proceeded to appendicectomy. SPU was done earlier than RPU (median 12 h vs 14.15 h) p = 0.088. Diagnostic accuracy using ROC did not reveal significant difference. CONCLUSION: SPU can be performed earlier than RPU with reliable accuracy. Training surgical trainees will enable early diagnosis and management of appendicitis. PMID- 29980347 TI - Statistical evaluation of diagnostic tests: A primer for pediatric surgeons. AB - BACKGROUND/PURPOSE: Diagnostic tests are of paramount importance for informing decision making in the surgical setting. Certain statistical methods are necessary to properly analyze data for diagnostic or prognostic tests involving biomarkers and risk factor data. Our goal is to provide a useful primer for the surgical researcher when performing a diagnostic research study in order to best analyze their data. METHODS: We present the key concepts and statistics for diagnostic tests and receiver operating characteristic (ROC) curve analysis, and we illustrate each with hypothetical surgery research examples. We use hypothetical data regarding CT imaging and WBC count in their diagnostic ability in predicting acute appendicitis, an extremely common surgical condition, while reviewing the statistical concepts of sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, relative risk, odds ratio, and ROC curves. Then we will consider a hypothetical a risk factor analysis on 30-day readmission to illustrate how multiple predictors can be combined. CONCLUSIONS: The statistical concepts presented are useful to the pediatric surgeon researcher in assessing the ability of diagnostic tests, which will translate into decision making and patient management implications in the clinical setting. TYPE OF STUDY: Review Article LEVEL OF EVIDENCE: N/A. PMID- 29980349 TI - Choosing wisely in health care. PMID- 29980348 TI - Caval replacement strategy in pediatric retroperitoneal tumors encasing the vena cava: a single-center experience and review of literature. AB - BACKGROUND: Complete encasement of the inferior vena cava by retroperitoneal tumors is rare. Although replacement of the vena cava has been considered for various conditions in adults, it is rarely used in children except for challenging resections and as a last chance approach - often aiming more at debulking than cure. MATERIALS AND METHODS: From January 2009 to February 2017, 4 patients (2 adrenal neuroblastomas, 1 renal cell carcinoma, 1 infantile fibrosarcoma) underwent elective en-bloc resection of tumor and of the infrahepatic portion of the inferior vena cava (IVC), with planned IVC prosthetic replacement. In three cases a portion of the left renal vein had to be resected as well, with the vein reanastomosed onto the prosthesis, and a concomitant auto transplantation of the right kidney was associated in one neuroblastoma patient. RESULTS: All patients had an uncomplicated postoperative course. In one patient, the prosthetic conduit is patent at long-term (43 months), while the middle portion of the prosthesis did eventually thrombose at mid-term after surgery in the three others - with no related symptoms. Interestingly, all renal venous reconstructions remain patent. Three patients (2 neuroblastomas and 1 infantile fibrosarcoma) are alive and disease-free at 43, 74 and 108 months after surgery, respectively. One patient with renal cell carcinoma died of recurrence of the disease 21 months after surgery. CONCLUSION: Resection and reconstruction of the vena cava, including the renal vein portion, can be considered and planned electively in case of tumoral encasement. This strategy is associated with good tolerance of the operation, low morbidity and satisfactory long-term function, even in cases with progressive and/or secondary partial thrombosis. LEVEL OF EVIDENCE: IV. PMID- 29980350 TI - Gender Reporting in Radiology Human Subjects Research. AB - PURPOSE: The aim of this report was to study the presence and extent of gender bias and reporting in radiology human subjects research. METHODS: For this bibliometric analysis, the authors reviewed all articles published between January 1, 2016, and June 30, 2016, in seven of the most cited general radiology journals. From each original research article studying human subjects, the number and gender of participants and whether gender-based results were reported were manually extracted. Articles evaluating gender-specific body parts were excluded. Article-level subject gender matching percentages were calculated and descriptive statistics reported. RESULTS: Of all 1,065 target journal articles during the study window, 522 met the human subjects research inclusion criteria. Of these, 48 (9.2%) made no mention at all of research subjects' gender. Of the 473 articles mentioning gender, 147 (31.1%) had more female and 308 (65.1%) more male subjects. But in aggregate, 105,763 of 254,102 (41.6%) of all subjects were male and 142,069 (55.9%) were female. By quartile distribution, subject gender matching was very variable (12.9% of articles with <25% match, 23.7% with 25% 50%, 29.4% with 50%-75%, and 34.0% with >=75%). Of articles including subjects of both genders, however, only 27.5% (126 of 458) reported any gender-based results. CONCLUSIONS: In human subjects research published in the most cited general radiology journals, the gender of human subjects is a poorly controlled, and frequently neglected, variable. In an emerging era of personalized medicine, initiatives to ensure transparent reporting of gender-specific results may help catalyze otherwise overlooked discoveries to advance the health of all. PMID- 29980351 TI - Contemporary Interventional Radiology Dosimetry: Analysis of 4,784 Discrete Procedures at a Single Institution. AB - PURPOSE: To report dosimetry of commonly performed interventional radiology procedures and compare dose analogues to known reference levels. MATERIALS AND METHODS: Demographic and dosimetry data were collected for gastrostomy, nephrostomy, peripherally inserted central catheter placement, visceral arteriography, hepatic chemoembolization, tunneled catheter placement, inferior vena cava filter placement, vascular embolization, transjugular liver biopsy, adrenal vein sampling, transjugular intrahepatic portosystemic shunt (TIPS) creation, and biliary drainage between June 12, 2014, and April 26, 2018, using integrated dosimetry software. In all, 4,784 procedures were analyzed. The study included 2,691 (56.2%) male subjects and 2,093 (43.8%) female subjects with mean age 55 +/- 21 years (range: 0-104 years) and with mean weight of 76.9 +/- 29.4 kg (range: 0.9-268.1 kg). Fluoroscopy time, dose area product (DAP), and reference dose were evaluated. RESULTS: TIPS had the highest mean fluoroscopy time (49.1 +/ 16.0 min) followed by vascular embolization (25.2 +/- 11.4 min), hepatic chemoembolization (18.8 +/- 12.5 min), and visceral arteriography (17.7 +/- 3.2 min). TIPS had the highest mean DAP (429.2 +/- 244.8 grays per square centimeter [Gy.. cm2]) followed by hepatic chemoembolization (354.6 +/- 78.6 Gy.. cm2), visceral arteriography (309.5 +/- 39.0 Gy.. cm2), and vascular embolization (298.5 +/- 29 Gy.. cm2). TIPS was associated with the highest mean reference dose (2.002 +/- 1.420 Gy) followed by hepatic chemoembolization (1.746 +/- 0.435 Gy), vascular embolization (1.615 +/- 0.381 Gy), and visceral arteriography (1.558 +/- 1.720 Gy). Of the six procedures available for comparison with the reference levels, the mean fluoroscopy time, DAP, and reference dose for each procedure were below the proposed reference levels. CONCLUSION: Advances in image acquisition technology and radiation safety protocols have significantly reduced the radiation exposure for a variety of interventional radiology procedures. PMID- 29980352 TI - Efficacy of buccal infiltration anaesthesia with articaine for extraction of mandibular molars: a clinical trial. AB - It is hard to provide adequate anaesthesia by infiltration of lidocaine into the mandible because of the thick buccal cortex. An inferior alveolar nerve block is often used but has a high failure rate, which has led research workers to look for an anaesthetic agent that will anaesthetise the lower teeth by buccal infiltration alone. We have assessed the efficacy of buccal infiltration anaesthesia with articaine by designing a double-blind controlled clinical trial in 133 patients who required extraction of mandibular molars. They were randomly divided into two groups and given infiltration anaesthesia with either 4% articaine or 2% lidocaine by a single injection deep into the mucobuccal fold at the site of the tooth. After five minutes the mesial, distal, buccal, and lingual sides of the tooth were probed. Pain at this time or later during dissection of soft tissue by periosteal elevator was considered as failure, and an inferior alveolar nerve block was given. The amount of pain, and the number of patients who developed pain, were significantly greater in the group given 2% lidocaine (p<0.001). The two groups did not differ significantly in age or sex. Articaine is more successful in providing adequate depth of anaesthesia, but its efficacy was not sufficient to replace an inferior alveolar nerve block for extraction of mandibular molars (Registration code: IRCT2016062627111N2). PMID- 29980353 TI - Accuracy of two midsagittal planes in three-dimensional analysis and their measurement in patients with skeletal mandibular deviation: a comparative study. AB - Our aim was to evaluate the accuracy of two midsagittal planes (MSP) to provide a better reference plane for studying the 3-dimensional structural symmetry in patients with skeletal mandibular deviation. Thirty adult patients with facial asymmetry were admitted to the Department of Orthodontics, Hospital of Stomatology, between January 2015 and 2017. The DICOM data were collected and reconstructed using ProPlan CMF(r) 2.0 (Materialise). Two sets of reference planes were set up. In the orbital margin plane group, the plane crossing the nasion (N) point and perpendicular to the frontozygomatic (FZ) suture line was used as the MSP. In the skull base plane group, the MSP was established using the sella turcica (S), N, and basion (Ba). The distances from the craniofacial skeletal and soft tissue midline landmarks to the two MSP were separately measured, and the significance of differences between measurements corresponding to two reference planes were assessed using the paired t test. Except for the posterior nasal spine (PNS)-MSP, the distances from other soft and hard tissue landmarks to the MSP in the orbital margin plane group were significantly shorter than those in the skull base plane group. In the 3-dimensional measurement analysis, the skeletal and soft tissue anatomical midline landmarks were closer to the MSP in the orbital margin plane group. The MSP crossing point N, perpendicular to the FZ suture line, was more accurate and suitable. PMID- 29980354 TI - Tear of the sternocleidomastoid muscle: a rare complication of lifting weights that can be managed conservatively. PMID- 29980355 TI - Knowledge of final-year medical students about oral and maxillofacial surgery: a two-centre study. AB - The aim of this study was to assess the exposure of final-year medical students to oral and maxillofacial surgery (OMFS) and to find out how this has influenced them in terms of recruitment or possible future referral patterns. We sent questionnaires to final-year students at Oxford University and St George's University medical schools (n=100 in each) to find out how much experience they had had of the specialty, their knowledge of disease (through clinical situations), and specific knowledge about oral cancer. In both, exposure to, and knowledge about, OMFS were poor, and patients had been referred inappropriately to ear, nose, and throat (ENT) or plastic surgery. Despite targeted teaching in OMFS at both institutions, further engagement is needed, and awareness of the specialty may need to be improved at all medical schools. PMID- 29980356 TI - Lateral sinus floor elevation without grafting materials. Individual- and aggregate-data meta-analysis. AB - PURPOSE: To perform a systematic review and individual- and aggregate-data meta analysis of observational studies to determine the success rate of the lateral sinus floor elevation with simultaneous implant placement and without grafting materials. MATERIAL AND METHODS: We included prospective and retrospective observational studies analyzing survival rate of implants in patients who underwent graftless lateral sinus floor elevation. Secondary outcomes included increase of bone height, marginal bone loss (MBL), implant stability, and adverse events such as sinus membrane perforation and signs of infection in the maxillary sinuses. Survival rate and proportion of adverse outcomes were calculated using the variance-stabilizing Freeman-Tukey double-arcsine transformation. Meta analyses of bone gain and MBL were performed based on changes from baseline and sampling variance. Implant stability was analyzed at follow-up. Individual participant data were modeled using a one-step approach. The survival probability was determined using the Kaplan-Meier method, and the Cox proportional-hazards regression was applied to investigate the association between survival time of implants and covariates. RESULTS: 11 observational studies were included in the study. The meta-analysis based on 660 implants and 17 failures showed a pooled survival rate of 97.5% (CI 95% 95.8 to 98.9). Pooled analysis also showed an increase in mean bone height of 5.7 mm (CI 95% 4.78 to 6.56), MBL of 1.2 mm (CI 95% 0.84 to 1.51), and implant stability quotient of 70.5 (CI 95% 64.2 to 76.9). A pooled rate of 20.0% (CI 95% 10.9 to 30.6) and 3.0% (CI 95% 0.5 to 6.8), respectively, for membrane perforations and sinus infection was found. Individual data meta-analysis showed an overall 5-year survival of 93.1% (SE 2.67%) with a mean survival time of 6.7 years (SE 0.08). Longer implants were associated with a decreased hazard ratio (0.64; CI 95% 0.41 to 0.99). CONCLUSIONS: Current available evidence based on aggregate and individual patient data meta-analysis suggests that lateral maxillary sinus floor elevation without grafting, and simultaneous implant placement, is a safe and effective technique with high survival rates, especially for implants with more than 13 mm in length. PMID- 29980357 TI - Inducing protein-protein interactions with molecular glues. AB - The drugable proteome is limited by the number of functional binding sites that can bind small molecules and respond with a therapeutic effect. Orthosteric and allosteric modulators of enzyme function or receptor signaling are well established mechanisms of drug action. Drugs that perturb protein-protein interactions have only recently been launched. This approach is more difficult due to the extensive contact surfaces that must be perturbed antagonistically. Compounds that promote novel protein-protein interactions promise to dramatically expand opportunities for therapeutic intervention. This approach is precedented with natural products (rapamycin, FK506, sanglifehrin A), synthetic small molecules (thalidomide and IMiD derivatives) and indisulam analogues. PMID- 29980358 TI - Discovery of novel selective GPR120 agonists with potent anti-diabetic activity by hybrid design. AB - GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50 = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure-activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications. PMID- 29980359 TI - Long-term renal outcome in infants with congenital lower urinary tract obstruction. AB - INTRODUCTION: Congenital Lower Urinary Tract Obstructions (LUTO) is a heterogeneous group of diseases in which urine elimination is obstructed at the level of bladder neck or urethra. The aim of the study is to evaluate the long term renal outcome of patients suffering of congenital LUTO. PATIENTS AND METHOD: We retrospectively reviewed patients with congenital LUTO. All patients had at least 1 year follow-up. Data on surgery, renal imaging and Schwartz estimate creatinine clearance were collected. Incidence of Chronic Renal Disease (CRD) is presented with Kaplan-Meier method. RESULTS: 40 patients were included, 23 patients with Posterior Urethral Valve (PUVs) and 17 patients with other aetiologies: anterior urethral valve (2), urethral atresia (2), urethral stenosis (2), cloacal malformations (2), obstructive ureterocele (1), bladder trigone malformation (1) and neonatal bladder-sphincter dysfunction without neurological abnormalities (7). Incidence of CRD at age 10 years was 37% in congenital LUTO, 42% in PUVs and 30% in other aetiologies, and was significantly higher in PUVs (P=0.032). Renal prognosis was significantly worsened by discover of retentional bladder wall changes in initial cystoscopy, and by loss of parenchymal differentiation or cortical microcysts in first ultrasonography. The use of urinary diversion was significantly higher in LUTO of other aetiologies. CONCLUSION: A high incidence of CRD is observed in patients with congenital LUTO, significantly higher in patients with PUV. LUTO of other aetiologies require step by step surgical management and higher use of urinary diversion. Precise initial evaluation in cystoscopy and ultrasonography is required and participate to evaluate future renal outcome. LEVEL OF INCIDENCE: 4. PMID- 29980360 TI - Comparison of the 2017 Taiwan lipid guidelines and the Western lipid guidelines for high risk patients. AB - Dyslipidemia is a major contributor in initiation, development and progression of atherosclerotic cardiovascular disease (ASCVD). Most lipid guidelines are from Europe and America and centered on the reduction of atherogenic lipids levels through lifestyle intervention and pharmacotherapy. Recently, the 2017 Taiwan lipid guidelines for high risk patients was published to facilitate the control of dyslipidemia in patients that are highly susceptible to ASCVD, including patients with preexisting ASCVD, diabetes, chronic kidney disease and familial hypercholesterolemia. Most recommendations outlined in the 2017 Taiwan lipid guidelines for high risk patients are in concordance with those of Western guidelines. However, based on evidence from the studies originating from Asia and local expert opinions, there are some recommendations different from the other guidelines. The purpose of the current review is to compare the similarities and differences between the perspectives of the 2017 Taiwan lipid guidelines for high risk patients and other Western guidelines in individuals at high risk of ASCVD. The definitions of high risk groups and treatment goals defined to achieve ASCVD risk reduction are specifically compared. PMID- 29980361 TI - Comparison of midwife-led and obstetrician-led care in Lithuania: A retrospective cohort study. AB - OBJECTIVE: To compare midwife-led and obstetrician-led care and their relation to caesarean section rates and obstetric and neonatal outcomes in low-risk births. DESIGN: Hospital registry based retrospective cohort study. SETTING: Tertiary care women's hospital in Kaunas, Lithuania. PARTICIPANTS: A total of 1384 and 1283 low-risk delivering women in 2012 and 2014, respectively. METHODS: The women choose either a midwife as their lead carer (midwife-led group), or an obstetrician-gynaecologist (obstetrician-led group). MAIN OUTCOME MEASURES: The primary outcome was caesarean birth. Secondary outcomes included instrumental vaginal births, amniotomy, augmentation of labour, epidural analgesia, episiotomy, perineal trauma, labour duration, birthweight and Apgar score < 7 at 5 min. RESULTS: The proportion of caesarean births was 4.4% in the midwife-led and 10.7% in the obstetrician-led group (p < 0.001) in 2012, and 5.2% and 11.8% (p < 0.001) in 2014, respectively. Younger maternal age (<=34 years) and midwife led care was associated with a significantly decreased odds for caesarean section and nulliparity with a significantly increased odds for caesarean birth. Women in the midwife-led group had fewer amniotomies and labour augmentations compared with the obstetrician-led group. Episiotomy, perineal trauma, duration of labour and neonatal outcomes did not differ between the groups. CONCLUSION: Midwife-led care for women with low-risk birth reduced the caesarean section and several medical interventions with no apparent increase in immediate adverse neonatal outcomes compared with obstetrician-led care. IMPLICATIONS FOR PRACTICE: Midwife led care for low-risk women should be encouraged in countries with health care system where obstetrician-led care births dominates. PMID- 29980362 TI - The Australian Nurse-Family Partnership Program for aboriginal mothers and babies: Describing client complexity and implications for program delivery. AB - CONTEXT: The Australian Nurse-Family Partnership Program is a home visiting program for Aboriginal mothers and infants (pregnancy to child's second birthday) adapted from the US Nurse Family Partnership program. It aims to improve outcomes for Australian Aboriginal mothers and babies, and disrupt intergenerational cycles of poor health and social and economic disadvantage. The aim of this study was to describe the complexity of Program clients in the Central Australian family partnership program, understand how client complexity affects program delivery and the implications for desirable program modification. METHODS: Australian Nurse-Family Partnership Program data collected using standardised data forms by nurses during pregnancy home visits (n = 276 clients from 2009 to 2015) were used to describe client complexity and adversity in relation to demographic and economic characteristics, mental health and personal safety. Semi structured interviews with 11 Australian Nurse-Family Partnership Program staff and key stakeholders explored in more depth the nature of client adversity and how this affected Program delivery. FINDINGS: Most clients were described as "complicated" being exposed to extreme poverty (66% on welfare), living with insecure housing, many experiencing domestic violence (almost one third experiencing 2 + episodes of violence in 12 months). Sixty-six percent of clients had experienced four or more adversities. These adversities were found challenging for Program delivery. For example, housing conditions mean that around half of all 'home visits' could not be conducted in the home (held instead in staff cars or community locations) and together with exposure to violence undermined client capacity to translate program learnings into action. Crises with the basics of living regularly intruded into the delivery of program content, and low client literacy meant written hand-outs were unhelpful for many, requiring the development of pictorial-based program materials. Adversity increased the time needed to deliver program content. CONCLUSIONS: Modifications to the Australian Nurse-Family Partnership Program model to reflect the specific complexities and adversities faced by the client populations is important for effective service delivery and to maximise the chance of meeting program goals of improving the health and well-being of Australian Aboriginal mothers and their infants. PMID- 29980363 TI - What is next? Midwifery education building partnerships for tomorrow's maternal and neonatal health care. PMID- 29980364 TI - Synthesis and biological properties of aryl methyl sulfones. AB - A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile. Molecular modeling assisted the design of compounds and the interpretation of the experimental results. Biological assay results showed that methyl sulfone compounds 2 and 7 were the most potent COX inhibitors of this series and best than the corresponding carboxylic acids (methyl sulfone 2: IC50 COX-1 = 0.04 and COX-2 = 0.10 MUM, and naproxen: IC50 COX-1 = 11.3 and COX-2 = 3.36 MUM). Interestingly, the inhibitory activity of compound 2 represents a significant improvement compared to that of the parent carboxylic compound, naproxen. Further support to the results were gained by the docking studies which suggested the ability of compound 2 and 7 to bind into COX enzyme with low binding free energies. The improvement of the activity of some sulfones compared to the carboxylic analogues would be performed through a change of the binding mode or mechanism compared to the standard binding mode displayed by ibuprofen, as disclosed by molecular modeling studies. So, this study paves the way for further attention in investigating the participation of these new compounds in the pain inhibitory mechanisms. The most promising compounds 2 and 7 possess a therapeutical profile that enables their chemical scaffolds to be utilized for development of new NSAIDs. PMID- 29980365 TI - Fractional flow reserve derived from routine coronary angiography. PMID- 29980366 TI - Prevention of sudden cardiac death in patients with Tetralogy of Fallot: Risk assessment and long term outcome. AB - BACKGROUND: In patients with repaired Tetralogy of Fallot (ToF), implantable cardioverter defibrillators (ICD) are considered reasonable in selected adults with multiple risk factors for sudden cardiac death. PATIENTS AND METHODS: We performed a retrospective cohort study of all 174 patients with repaired ToF who are followed at the University Hospital of Muenster. We analyzed data according to the risk score previously proposed by Khairy and coworkers and patient outcome. We analyzed data separately for patients without previous sustained ventricular tachycardia (VT) (risk stratification group, n = 157) and patients with VT/secondary prevention ICD (n = 17). RESULTS: In the risk stratification group, a mean of 4 +/- 1 risk score parameters were available. All six risk parameters were known in 10%, five in 14%. Risk score increased with availability of parameters. 15 patients with secondary prevention ICD had a mean risk score of 6.3 +/- 2.2 (range 2-10). 11 patients of the risk stratification group with primary prevention ICD had a mean risk score 5.8 +/- 2.4 (range 3-8). During follow-up of up to 14 years, five patients died (3%): at age 58, two at 69 and two at 76 years. CONCLUSION: In the majority of patients risk score variables were incomplete, severely limiting its applicability because the true score cannot be calculated. Risk scores were not different between patients with secondary prevention ICD and patients with ICD for primary prevention based on current guidelines. Standardization of follow-up and prospective evaluation of these standards in large prospective patient cohorts is desirable to improve risk stratification in patients with ToF. PMID- 29980367 TI - Safety and usefulness of acetylcholine provocation test in patients with no culprit lesions on emergency coronary angiography. AB - BACKGROUND: Vasospastic angina (VSA), which often causes acute coronary syndrome (ACS), can be diagnosed by intracoronary acetylcholine (ACh) provocation test. However, the safety and usefulness of ACh provocation test in ACS patients on emergency coronary angiography (CAG) compared to non-emergency settings are unclear. METHODS: A total of 529 patients undergoing ACh provocation test during emergency or non-emergency CAG were included. Patients with resuscitated cardiac arrest were excluded. The primary endpoint was adverse events defined as a composite of death, ventricular fibrillation or sustained ventricular tachycardia, myocardial infarction, cardiogenic shock, cardiac tamponade, and stroke within 24 h after ACh provocation test. RESULTS: There were no significant differences of the clinical characteristics between the groups of emergency (n = 84) and non-emergency (n = 445) ACh provocation test. The rate of positive ACh provocation test was similar between the 2 groups (50% vs. 49%, p = 0.81). Similarly, the incidence of adverse events in patients with emergency and non emergency ACh provocation test did not significantly differ (1.2% vs. 1.3%, p = 1.00). CONCLUSION: ACh provocation test can be safely performed in ACS patients with no obstructive culprit lesions on emergency CAG, and may be useful to diagnose VSA in those patients. PMID- 29980368 TI - Does cardiac pacing reduce syncopal recurrences in cardioinhibitory vasovagal syncope patients selected with head-up tilt test? Analysis of a 5-year follow-up database. AB - PURPOSE: Benefit of cardiac pacing in patients with vasovagal syncope (VVS) and cardioinhibitory response to head-up tilt test (HUTT) is still debated. We aimed at retrospectively assessing the long-term effect of cardiac pacing in a cohort routinely followed in our institutions. METHODS AND RESULTS: From a cohort of 1502 patients who performed HUTT between 2008 and 2014, 181 (12%) patients had VASIS 2A (40) or 2B (141) response (median age 43 [interquartile range, 25-56] years, 59% male). Fifty patients (28%) received a dual-chamber pacemaker and 131 (72%) received training on physical maneuvers and medical therapy. The so-called 'Closed Loop Stimulation' (CLS) function was activated for at least 18 months in the pacing group. The 5-year recurrence rate of syncope of paced patients was compared with non-paced patients and with a subgroup of 18 propensity-score matched patients selected among non-paced patients. The 5-year Kaplan-Meier syncope free-rate was 81% (CI, 67%-90%) in the pacing group, 57% (47%-67%; p = 0.004) in the unmatched control group, 53% (27%-74%; p = 0.005) in the 18 propensity-matched patients. The hazard ratio of pacing versus non-pacing was 0.34 (CI, 0.18-0.70) when comparing with the whole non-pacing control group, and 0.25 (CI, 0.09-0.65) including only the propensity-score matched subgroup. No deaths were observed during the follow-up. CONCLUSIONS: In the selected VVS population with HUTT-induced cardioinhibitory response, pacemaker therapy with CLS function was associated to 66% relative and 24% absolute risk reduction of 5 year syncopal recurrence rate. Benefit was confirmed after controlling variables affecting propensity for pacemaker therapy. PMID- 29980369 TI - Rhythm control better prevents stroke and mortality than rate control strategies in patients with atrial fibrillation - A nationwide cohort study. AB - BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke and mortality. However, rhythm control strategy did not reduce cardiovascular risks in short term studies. We hypothesize that rhythm control better prevents stroke and mortality than rate control in AF patients over a long-term period. METHODS: AF patients aged >=18 years were identified from Taiwan National Insurance Database. Patients using anti-arrhythmia drugs to control rhythm at a >30 defined daily dose (DDD) were defined as the rhythm control group. Patients who used rate control medications for >30 DDDs constituted the rate control group. Multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for major adverse cardiovascular events (MACE), including ischemic/hemorrhagic stroke and mortality. RESULTS: A total of 11,968 AF patients were enrolled, and 2850 of them (654 in rhythm control group; 2196 in rate control group) were analyzed. During a 6.3 +/- 3.7 year's follow-up, a total of 1101 MACE occurred. Compared to rate control group, rhythm control group displayed a lower rate of ischemic stroke (adjusted HR: 0.65, p = 0.002) and mortality (adjusted HR: 0.81, p = 0.009). The rhythm control group showed a lower incidence of MACE than that of the rate control group (adjusted HR: 0.82, p = 0.009). The reduction of stroke (p = 0.004), mortality (p = 0.006), and MACE (p = 0.007) risk was observed particularly in rhythm control patients with a CHA2DS2-VASc score of >=3. CONCLUSIONS: In patients with AF, rhythm control better prevents MACE risk than rate control over a long-term period, particularly in those at high risk (CHA2DS2 VASc score >=3) for stroke. PMID- 29980370 TI - Activation-repolarization mapping to guide VT-ablation without the need to induce the arrhythmia. PMID- 29980371 TI - Asplenia and polysplenia syndromes: time of successful treatment and updated terminology. PMID- 29980372 TI - Predictors of the extended-spectrum-beta lactamases producing Enterobacteriaceae neonatal sepsis at a tertiary hospital, Tanzania. AB - The study was conducted to establish predictors of extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-PE) neonatal sepsis and mortality in a tertiary hospital, Tanzania. Between July and December 2016, blood culture was performed in neonates with clinical features of sepsis and neonates/mothers/guardians were screened for ESBL colonization. Selected isolates underwent whole genome sequencing to investigate relatedness. Logistic regression analysis was performed to determine predictors for ESBL-PE associated neonatal sepsis and mortality. Neonatal ESBL-PE sepsis was detected in 32(10.5%) of the 304 neonates investigated. Neonatal ESBL-PE sepsis was independently predicted by admission at the Intensive care Unit and positive mother and neonate ESBL-PE colonization. Deaths occurred in 55(18.1%) of neonates. Neonates infected with ESBL-PE, admitted at ICU, increased age and those transferred from other centres had significantly high mortality rates. Gram-negative bacteria formed the majority (76%) of the isolates, of which 77% were ESBL-PE. Virulent Klebsiella pneumoniae ST45 carrying blaCTX-M-15 were commonly isolated from neonates. Klebsiella pneumoniae (ST45) were the predominant cause of ESBL-PE neonatal sepsis and mortality. Improved infection control and antibiotic stewardship are crucial in controlling the spread of resistant strains. Rapid diagnostic tests to detect ESBL-PE in low-income countries are needed to guide treatment and reduce ESBL-PE-associated mortality. PMID- 29980373 TI - An examination of the profile and journey of patients with mental illness in the emergency department. AB - OBJECTIVE: To examine the profile and journey of patients with mental illness in the emergency departments (ED) of a Local Health District in Australia. There is limited evidence around the patient profile and journey of people in who present to EDs with mental illness, and the aim of this study was to inform the development of a psychiatric emergency service model. METHODS: The study design was a retrospective descriptive analysis of routinely collected data of two hospital EDs. Retrospective health care data of patients who presented to the EDs between July 2016 and June 2017 was analysed using descriptive and inferential statistics. RESULTS: Mental health presentations (N = 4506) consisted of 3.44% of all presentations to the Emergency Department, mostly for anxiety and stress, comorbid alcohol and drug issues, and suicidality. Females were more likely to present, and significantly more likely to present multiple times (specifically for age groups 12-17 and over 65). Presenting issues were associated with age and gender for most diagnostic groups, but not with number of presentations, except for personality disorder. 24.83% were admitted to a mental health inpatient unit, 54.34% were referred to a mental health community team, 4.63% medically, and the remaining referred to alcohol and drug services, GPs, or NGOs. Length of stay was associated with gender (female), age (>65) and diagnosis (drug related and eating disorder). CONCLUSION: There is limited evidence around the patient profile and journey of people who present to EDs for mental health reasons, and this study contributes to this literature. PMID- 29980374 TI - Selection of Intravenous Fluids. PMID- 29980376 TI - Mass-transfer impact on solute mobility in porous media: A new mobile-immobile model. AB - The theory for modeling non-equilibrium solute transport in porous media is still based on approximations to a model proposed by Lapidus and Amundson in 1952 that has not been updated. This Mobile-Immobile Model (MIM) is based on the definition of a mass-transfer coefficient (alpha), which has been proven subject to some severe limitations. Measurements at both laboratory and field scales have demonstrated the scale-dependency of alpha values. This means that the MIM theory fails in real applications, since alpha is not constant, as defined in the kinetic model theory, but is a time-residence (or distance) dependent coefficient. Multi-rate mass-transfer models have been proposed in recent literature to capture real-world solute transport with a multiple mass transfer. In this study, we propose a novel model, which implements the analytical solution of Fick's second law of diffusion directly in the nonequilibrium advection/dispersion equation of solute transport in porous media. New model solutions properly fitted data collected during tracer tests carried out at the CNR-IRSA Laboratory (Bari, Italy) in a horizontal sandbox, 2 m of length, by using sodium chloride as the conservative tracer. Selected breakthrough curves at specific positions were used to validate the proposed model solution and estimate both conventional and proposed coefficients of mass transfer. Results have shown a decreasing trend of alpha from 0.09 to 0.04 h-1 after about 1.2 m of filtration for the investigated sand, whereas new solutions provide two scale-invariant tracer coefficients of rate of tracer mass-transfer (0.004 +/- 0.005 h-1) and of tracer time delay (1.19 +/- 0.01). The proposed model performs very well, since it provides a readily solved analytical solution with respect to the conventional MIM. Results of the proposed MIM are very similar to those provided by the conventional MIM. The new model solution can be implemented in particle tracking or random walk software in order to solve two-dimensional nonequilibrium solute transport in groundwater. PMID- 29980375 TI - Child and Parental Perspectives on Communication and Decision Making in Pediatric CKD: A Focus Group Study. AB - BACKGROUND & OBJECTIVES: Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. STUDY DESIGN: Qualitative study. SETTING & PARTICIPANTS: Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. ANALYTICAL APPROACH: Transcripts were analyzed thematically. RESULTS: We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden). LIMITATIONS: Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. CONCLUSIONS: Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed. PMID- 29980377 TI - Race, contrast-induced nephropathy and long-term outcomes after coronary and peripheral angiography and intervention. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is a complication of diagnostic angiography and percutaneous coronary and endovascular intervention. We investigated the effect of race on the development of CIN. METHODS: We studied 4070 predominantly male patients undergoing peripheral and coronary angiography and percutaneous coronary and endovascular intervention. We analyzed the incidence of CIN at 72 h, of renal dysfunction at 3 months as well as the long term incidence of hemodialysis and of death. RESULTS: The mean age was 67.2 years. CIN occurred in 92 (7.1%) Caucasian patients and in 42 (6.6%) non Caucasians at 72 h after the procedure (odds ratio [OR] 1.08, 95% confidence interval [CI] 0.74-1.57; P = 0.69). At 3 months, renal dysfunction was seen in 231 (11.24%) Caucasian patients versus 121 (11.52%) of the non-Caucasian group (OR 0.97, CI 0.77-1.23; P = 0.81). After a follow-up of 5 years, of the 4070 patients, 17 patients (0.64%) of the Caucasian group were placed on dialysis versus 27 (1.88%) of the non-Caucasian group (OR 0.34, 0.18-0.62; P = 0.0004) and 535 (20.28%) of the Caucasian patients had died compared to 293 (20.44%) of the non-Caucasian group (OR = 0.99, 95% CI 0.85-1.17; P = 0.94). CONCLUSIONS: In this cohort of patients, race was not associated with the development of CIN at 72 h, or the development of renal dysfunction at 3 months post angiography or intervention. In the long-term, the rate of initiation of dialysis was significantly lower in the Caucasian patients but mortality was not. PMID- 29980378 TI - Serum Vitamin D and Its Upregulated Protein, Thioredoxin Interacting Protein, Are Associated With Beta-Cell Dysfunction in Adult Patients With Type 1 and Type 2 Diabetes. AB - OBJECTIVES: Diabetes mellitus is characterized by either complete deficiency of insulin secretion, as in type 1 diabetes, or decompensation of the pancreatic beta cells in type 2 diabetes. Both vitamin D (vitD) and thioredoxin interacting protein (TXNIP) have been shown to be involved in beta-cell dysfunction. Therefore, this study was designed to examine vitD and TXNIP serum levels in patients with diabetes and to correlate these levels with beta-cell function markers in both types of diabetes. METHODS: The routine biochemical parameters and the serum levels of vitD and TXNIP were measured in 20 patients with type 1 diabetes and 20 patients with type 2 diabetes. The levels were then compared to those of 15 healthy control volunteers. Insulin, C-peptide and proinsulin (PI), vitD and TXNIP were measured by ELISA. Beta-cell dysfunction was assessed by homeostatic model assessment (HOMA-beta), proinsulin-to-C-peptide (PI/C) and proinsulin-to-insulin (PI/I) ratios. Correlations among various parameters were studied. RESULTS: Patients with type 1 diabetes had significantly lower HOMA beta, vitD and TXNIP levels; however, they had higher PI/C levels than the control group. Meanwhile, patients with type 2 diabetes had significantly higher C-peptide, proinsulin, PI/C, HOMA-insulin resistance (HOMA-IR) and lower HOMA beta and vitD levels, with no significant difference in TXNIP levels as compared to the control group. In addition, vitD was significantly correlated positively with HOMA-beta and TXNIP and negatively with PI, PI/C, PI/I and HOMA-IR. TXNIP correlated positively with HOMA-beta and negatively with PI/C. CONCLUSIONS: Our data showed that vitD and TXNIP were associated with different beta-cell dysfunction markers, indicating their potential abilities to predict the beta cell status in people with diabetes. PMID- 29980379 TI - Fitness, knee function and competition performance in professional alpine skiers after ACL injury. AB - OBJECTIVES: To assess the fitness of elite alpine skiers during recovery from anterior cruciate ligament (ACL) reconstruction and changes in performance level after return to competition. DESIGN: Retrospective cohort study. METHODS: The database of a specialized sports clinic was screened for professional alpine skiers with a history of ACL rupture and reconstruction. Strength and further functional tests as well as questionnaire data reflecting the athletes' subjective perception of pain, function in activities of daily living and physical activity levels were extracted. The website of the International Ski Federation (FIS) was used to obtain FIS points reflecting the competition performance level prior to injury, after return to competition as well as one year later. RESULTS: Questionnaire data revealed the highest patient satisfaction. Measurements performed 161.5+/-24.2days after surgery showed persistent muscle strength and power deficits, which primarily affected the knee extensor muscles and were more pronounced following reconstruction using quadriceps as compared to hamstring tendon grafts. FIS points increased immediately after return to competition (364.3+/-142.5days post-reconstruction) but dropped below pre-injury levels within the first year. CONCLUSIONS: ACL injuries sustained by professional skiers entail muscle strength and power deficits that persist for more than five months after surgery. The rate of recovery of knee extensor muscle function may be slower following ACL reconstruction using quadriceps tendon grafts. On average, athletes returned to competition within one year after surgery and succeeded in surpassing their baseline performance level within the first year after return to competition. PMID- 29980380 TI - Electric and acoustic harmonic integration predicts speech-in-noise performance in hybrid cochlear implant users. AB - BACKGROUND: Pitch perception of complex tones relies on place or temporal fine structure-based mechanisms from resolved harmonics and the temporal envelope of unresolved harmonics. Combining this information is essential for speech-in-noise performance, as it allows segregation of a target speaker from background noise. In hybrid cochlear implant (H-CI) users, low frequency acoustic hearing should provide pitch from resolved harmonics while high frequency electric hearing should provide temporal envelope pitch from unresolved harmonics. How the acoustic and electric auditory inputs interact for H-CI users is largely unknown. Harmonicity and inharmonicity are emergent features of sound in which overtones are concordant or discordant with the fundamental frequency. We hypothesized that some H-CI users would be able to integrate acoustic and electric information for complex tone pitch perception, and that this ability would be correlated with speech-in-noise performance. In this study, we used perception of inharmonicity to demonstrate this integration. METHODS: Fifteen H-CI users with only acoustic hearing below 500 Hz, only electric hearing above 2 kHz, and more than 6 months CI experience, along with eighteen normal hearing (NH) controls, were presented with harmonic and inharmonic sounds. The stimulus was created with a low frequency component, corresponding with the H-CI user's acoustic hearing (fundamental frequency between 125 and 174 Hz), and a high frequency component, corresponding with electric hearing. Subjects were asked to identify the more inharmonic sound, which requires the perceptual integration of the low and high components. Speech-in-noise performance was tested in both groups using the California Consonant Test (CCT), and perception of Consonant-Nucleus-Consonant (CNC) words in quiet and AzBio sentences in noise were tested for the H-CI users. RESULTS: Eight of the H-CI subjects (53%), and all of the NH subjects, scored significantly above chance level for at least one subset of the inharmonicity detection task. Inharmonicity detection ability, but not age or pure tone average, predicted speech scores in a linear model. These results were significantly correlated with speech scores in both quiet and noise for H-CI users, but not with speech in noise performance for NH listeners. Musical experience predicted inharmonicity detection ability, but did not predict speech performance. CONCLUSIONS: We demonstrate integration of acoustic and electric information in H-CI users for complex pitch sensation. The correlation with speech scores in H-CI users might be associated with the ability to segregate a target speaker from background noise using the speaker's fundamental frequency. PMID- 29980381 TI - Understanding the Revised Fourth Edition of the World Health Organization Classification of Tumours of the Central Nervous System (2016) for Clinical Decision-making: A Guide for Oncologists Managing Patients with Glioma. AB - The recognition of specific molecular prognostic factors has altered the management of primary brain tumours over the past decade. These factors have allowed stratification of morphologically similar tumours into different prognostic groups and are now also being used to determine clinical trial eligibility. Many of these factors have been included in the revised fourth edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System, released in May 2016. This revised edition places greater emphasis on molecular testing and, for certain tumour types, molecular testing is required for diagnosis. Many pathology departments have also adopted the four tiered report format suggested in the Haarlem guidelines, and provide a final 'integrated diagnosis' incorporating a morphological diagnosis, the WHO grade and molecular findings. Pathologists need to perform and report these molecular tests in a timeframe that is relevant for clinical decision-making. Clinicians need to understand and incorporate these changes into their daily practice, as they have direct effects on both the type and intent of therapeutic interventions. PMID- 29980382 TI - Anterior eye surface changes following miniscleral contact lens wear. AB - PURPOSE: To quantify the effect of short-term miniscleral contact lens wear on the anterior eye surface of healthy eyes, including cornea, corneo-scleral junction and sclero-conjuctival area. METHODS: Twelve healthy subjects (29.9 +/- 5.7 years) wore a highly gas-permeable miniscleral contact lens of 16.5 mm diameter during a 5-hour period. Corneo-scleral height profilometry was captured before, immediately following lens removal and 3 h after lens removal. Topography based corneo-scleral limbal radius estimates were derived from height measurements. In addition, elevation differences in corneal and scleral region were calculated with custom-written software. Sclero-conjuctival flattening within different sectors was analysed. RESULTS: Short-term miniscleral lens wear significantly modifies the anterior eye surface. Significant limbal radius increment (mean +/- standard deviation) of 146 +/- 80 MUm, (p = 0.004) and flattening of -122 +/- 90 MUm in the sclero-conjuctival area, (p << 0.001) were observed immediately following lens removal. These changes did not recede to baseline levels 3 h after lens removal. The greatest anterior eye surface flattening was observed in the superior sector. No statistically significant corneal shape change was observed immediately following lens removal or during the recovery period. CONCLUSIONS: Short-term miniscleral contact lens wear in healthy eyes does not produce significant corneal shape changes measured with profilometry but alters sclero-conjuctival topography. In addition, sclero conjuctival flattening was not uniformly distributed across the anterior eye. PMID- 29980383 TI - Laboratory medicine in Africa since 2008: then, now, and the future. AB - The Maputo Declaration of 2008 advocated for commitment from global stakeholders and national governments to prioritise support and harmonisation of laboratory systems through development of comprehensive national laboratory strategies and policies in sub-Saharan Africa. As a result, HIV laboratory medicine in Africa has undergone a transformation, and substantial improvements have been made in diagnostic services, networks, and institutions, including the development of a competent workforce, introduction of point-of-care diagnostics, and innovative quality improvement programmes that saw more than 1100 laboratories enrolled and 44 accredited to international standards. These improved HIV laboratories can now be used to combat emerging continental and global health threats in the decades to come. For instance, the unprecedented Ebola virus disease outbreak in west Africa exposed the severe weaknesses in the overall national health systems in affected countries. It is now possible to build robust health-care systems in Africa and to combat emerging continental and global health threats in the future. In this Personal View, we aim to describe the remarkable transformation that has occurred in laboratory medicine to combat HIV/AIDS and improve global health in sub-Saharan Africa since 2008. PMID- 29980385 TI - Familial hypercholesterolemia: Experience in the Lipid Clinic of Alava. AB - INTRODUCTION: Familial hypercholesterolaemia (FH) is the autosomal dominant genetic disorder most frequently associated with premature cardiovascular disease (CVD). MATERIAL AND METHODS: A retrospective, observational study was conducted to determine the clinical characteristics, analytical parameters and cardiovascular risk factors of 133 patients with a genetically confirmed diagnosis of FH on follow-up in the Lipid Clinic of Alava. RESULTS: CVD was observed in 8.30% of the patients (ischaemic heart disease in 100% of the cases). The LDL concentration goal was achieved in 40.6% (45.50% in primary prevention and 27.30% in secondary prevention). The large majority (81.80%) of patients with coronary heart disease (CHD) were male. The odds ratio (OR) of males having CHD compared to females is 4.97 (1.03-23.93, P=.03). The OR of developing CHD in patients with a family history of premature CVD is 6.86 (1.32-35.67, P=.02). A statistically significant association was found between smoking and the risk of CVD (P=.005), and also between having diabetes and the risk of CVD (P=0.0001). If the treatment with statins begins at older than 40 years, the OR of suffering CHD is 6.40 (1.53-26.5) (P=.009). The mean time from diagnosis to the cardiovascular event in the group of ex-smokers is 10.80+/-5.80 years, and in the non-smoking group it is 17.50+/-2.50 years (P=.011). CONCLUSIONS: In our reference population with FH, it was found that there was an increased risk of suffering a cardiovascular event in male patients, with a family history of premature CVD, diabetics, and in those in whom lipid lowering treatment was started after 40 years of age. PMID- 29980384 TI - Population and methodology of the SIMETAP study: Prevalence of cardiovascular risk factors, cardiovascular diseases, and related metabolic diseases. AB - The prevention of cardiovascular disease is based on the detection and control of cardiovascular risk factors (CVRF). In Spain there are important geographical differences both in the prevalence and in the level of control of the CVRF. In the last decade there has been an improvement in the control of hypertension and dyslipidaemia, but a worsening of cardio-metabolic risk factors related to obesity and diabetes. The SIMETAP study is a cross-sectional descriptive, observational study being conducted in 64 Primary Care Centres located at the Community of Madrid. The main objective is to determine the prevalence rates of CVRF, cardiovascular diseases, and metabolic diseases related to cardiovascular risk. A report is presented on the baseline characteristics of the population, the study methodology, and the definitions of the parameters and diseases under study. A total of 6,631 study subjects were selected using a population-based random sample. The anthropometric variables, lifestyles, blood pressure, biochemical parameters, and pharmacological treatments were determined. The highest crude prevalences were detected in smoking, physical inactivity, obesity, prediabetes, diabetes, hypertension, dyslipidaemias, and metabolic syndrome. A detailed analysis needs to be performed on the prevalence rates, stratified by age groups, and prevalence rates adjusted for age and sex to assess the true epidemiological dimension of these CVRF and diseases. PMID- 29980386 TI - Thoughts on the American Board of Radiology Examinations and the resident experience in radiation oncology. PMID- 29980387 TI - Feasibility of jet injector use during inactivated poliovirus vaccine house-to house vaccination campaigns. AB - BACKGROUND: To attain high coverage during polio vaccination campaigns, an outreach house-to-house strategy is used to administer oral poliovirus vaccine. Administering an injectable vaccine house-to-house requires a skilled work force and increases risks of needle stick injuries. Needle-free injection devices provide a safer alternative to needles and syringes for administering injectable vaccines. We evaluated the feasibility and acceptability of a needle-free injection device to administer injectable poliovirus vaccine during a house-to house vaccination outreach activity. METHODS: Vaccination teams administered injectable poliovirus vaccine using the Pharmajet(r) needle-free intramuscular jet injector to children ages 6-59 months in 766 homes. Data on the feasibility of using the jet injector in an outreach campaign setting and the acceptability of the jet injector by caregivers and vaccinators were collected. RESULTS: A total of 993 injections were administered. Vaccinators faced challenges during device preparation in 16% (n = 158) of injections; challenges were related to problems loading the injector and not having a flat surface to use for setup of the injector. Among 32 vaccinators interviewed after the vaccination campaign, the main reported advantage of the device was absence of sharps disposal (91%) while the main reported disadvantage was unacceptability by parents (90%) which was related to the vaccine, not the device. CONCLUSIONS: The needle-free jet injector was feasible for use in house-to-house campaigns. Acceptability by vaccinators was low as 81% stated that the jet injector was not easier to use than needle and syringe. Parental refusal related to frequent polio vaccination campaigns was the biggest challenge. In addition, novelty of the device posed a challenge to teams as they needed to reassure parents about safety of the device. To take full advantage of the ability to take injectable vaccines door-to-door during vaccination campaigns using a needle-free jet injector device, tailored social mobilization efforts are needed ahead of campaigns. PMID- 29980388 TI - Parental predictors of HPV vaccine initiation among low-income Hispanic females aged 11-17 years. AB - PURPOSE: Hispanic women experience a disproportionate burden of cervical cancer morbidity and mortality compared to non-Hispanic women. Increasing HPV vaccination among Hispanic adolescents can help alleviate disparities. This study aimed to identify parental psychosocial predictors associated with HPV vaccine initiation and correlates of parental intentions to obtain the vaccine for their Hispanic adolescent daughters aged 11-17 years. METHODS: This study is part of a larger three-arm randomized controlled trial testing the effectiveness of interventions to increase HPV vaccination. Parents of adolescent females were recruited in community clinics where we conducted baseline surveys. We obtained electronic medical records six months after baseline to assess vaccination status. Multilevel logistic regression was used to identify correlates of parental intentions to vaccinate and predictors of HPV vaccine initiation. Analyses with initiation as the outcome also controlled for intervention study arm. The Integrated Behavioral Model guided selection of psychosocial and outcome variables. RESULTS: Our sample (n = 765) consisted mostly of mothers with less than a high school education born outside of the U.S. Forty-one percent had a household income less than $15,000. Most daughters had public or private insurance. Twenty-one percent initiated the HPV vaccine series. Correlates of intention to vaccinate intention included subjective norms related to daughter's doctor (AOR = 1.04; 95% CI 1.01-1.07), belief that the vaccine is safe (AOR = 1.38; 95% CI 1.06-1.78), self-efficacy to obtain the vaccine for their daughter (AOR = 2.39; 95% CI 1.52-3.77), and parental concern about vaccine side effects (AOR = 0.73; 95% CI 0.60-0.89). Intentions predicted initiation (AOR = 2.01; 95% CI 1.10-5.26); concern about sexual disinhibition decreased the odds of having a vaccinated daughter at follow-up (AOR = 0.66; 95% CI 0.47-0.92). DISCUSSION: Parental intention and concerns about sexual disinhibition predict vaccine initiation. Further research is needed to explore the role of intention as a potential mediator between psychosocial variables and vaccination status. PMID- 29980389 TI - A comparison of the test-negative and traditional case-control study designs with respect to the bias of estimates of rotavirus vaccine effectiveness. AB - Estimation of the effectiveness of rotavirus vaccines via the test-negative control study design has gained popularity over the past few years. In this study design, children with severe diarrhea who test positive for rotavirus infection are considered as cases, while children who test negative serve as controls. We use a simple probability model to evaluate and compare the test-negative control and the traditional case-control designs with respect to the bias of resulting estimates of rotavirus vaccine effectiveness (VE). Comparisons are performed under two scenarios, corresponding to studies performed in high-income and low income countries. We consider two potential sources of bias: (a) misclassification bias resulting from imperfect sensitivity and specificity of the test used to diagnose rotavirus infection, and (b) selection bias associated with possible effect of rotavirus vaccination on the probability of contracting severe non-rotavirus diarrhea. Our results suggest that both sources of bias may produce VE estimates with substantial bias. Particularly, lack of perfect specificity is associated with severe negative bias. For example, if the specificity of the diagnostic test is 90% then VE estimates from both types of case-control studies may under-estimate the true VE by more than 20%. If the vaccine protects children against non-rotavirus diarrhea then VE estimates from test-negative control studies may be close to zero even though the true VE is 50%. However, the sensitivity and specificity of the enzyme immunoassay test currently used to diagnose rotavirus infections are both over 99%, and there is no solid evidence that the existing rotavirus vaccines affect the rates of non rotavirus diarrhea. We therefore conclude that the test-negative control study design is a convenient and reliable alternative for estimation of rotavirus VE. PMID- 29980390 TI - Predictors for influenza vaccine acceptance among patients with inflammatory rheumatic diseases. AB - BACKGROUND: Patients with inflammatory rheumatic diseases are at higher risk for influenza and current guidelines recommend vaccination for this group of patients. The aim of this study was to evaluate the vaccination coverage and predictors for influenza vaccination among patients with inflammatory rheumatic diseases. METHODS: This survey was conducted at the outpatient rheumatology clinic at the Medical University of Vienna between July and October 2017. All patients diagnosed with an inflammatory rheumatic disease and receiving immunosuppressive therapy were asked to complete a questionnaire about their influenza vaccination status for 2016/17. RESULTS: 490 patients with rheumatic diseases completed a questionnaire (33% male, mean age 55.3 years). The influenza vaccination rate for the previous season was 25.3% (n = 124/490). Predictors for a positive influenza vaccination status were higher age (Adjusted Odds Ratio 5.0, 95% Confidence Interval 2.4-10.4) and treatment with biological disease-modifying antirheumatic drugs (AOR 2.0, 95% CI 1.3-3.1). Patients who received a recommendation for influenza vaccination by their general practitioner were significantly more likely to be vaccinated than those who did not (57% vs. 15%, AOR 6.6, 95% CI 4.1-10.8); even more so if they received a recommendation by their rheumatologist (62% vs. 19%, AOR 9.0, 95% CI 4.9-16.5). The main reasons for patients to decline influenza vaccination were fear of side effects (36%), concerns that vaccination might not be effective due to their immunosuppressed condition (38%) or that it might worsen the rheumatic disease (20%). CONCLUSIONS: A moderate influenza vaccination rate of 25.3% was detected among patients with inflammatory rheumatic diseases. Recommendation of the influenza vaccine by a physician exerts the most effective impact on a positive vaccination status. PMID- 29980391 TI - Combination treatment for cicatrix after neonatal circumcision: An office-based solution to a challenging problem. AB - Cicatrix formation, which can form after neonatal circumcision to entrap the glans penis, presents a therapeutic challenge. Previous studies in the literature have described either using a topical steroid cream or stretching of the scar tissue with an instrument but not a combination of both modalities. In our experience, monotherapy has resulted in significant recurrence and/or need for further treatment. We present our successful experience that combines cicatrix stretching with a hemostat using local anesthesia in the office followed by several weeks of topical steroids with a minority of patients needing any additional therapy. PMID- 29980392 TI - The influence of bowel management on the frequency of urinary infections in spina bifida patients. AB - OBJECTIVE: To examine the effects of bowel management on the frequency of urinary infections in spina bifida patients. STUDY DESIGN: The research was carried out from 2014 to 2017, with the recruitment process from June 2014 to March 2016. The first group consisted of 35 patients who were administered bowel management combined with anticholinergic medication therapy and clean intermittent catheterization (CIC). The second group consisted of 35 patients who were treated only with anticholinergic medication therapy and CIC. Bowel management included daily enema, laxative application, and a special diet, with a view to treating constipation that was estimated on the basis of Roma III criteria and echosonographically determined transversal rectal diameter. The effects of the administered bowel management on urinary infections were estimated on the basis of the number of urinary infections before and after the administered therapy. The observation period of every patient was 1 year. RESULTS: There were no significant statistical differences regarding age, gender, and baseline clinical features between the two groups. In the group treated with bowel management combined with anticholinergic medication therapy and CIC, the average number of urinary infections was 0.3 +/- 0.5 SD, whereas in the group treated exclusively with anticholinergic medication therapy and CIC the average number of urinary infections was 1.1 +/- 1.0 SD. There was a statistical difference regarding urinary infections, that is the average number of urinary infections between these two groups of patients (p < 0.001). CONCLUSION: Administering bowel management considerably decreases the frequency of urinary infections, and should form an integral part of treatment of spina bifida patients. PMID- 29980393 TI - Cortical Gradients and Laminar Projections in Mammals. AB - A key component of current theories of brain structure and function is the layer specific origin of structural connections of the cerebral cortex. This fundamental connectional feature pertains to different mammalian cortices, and recent neuroimaging advancements have started to pave the way for its function based mapping in humans. Here, we propose a framework that systematically explains the characteristic layer-specific origin of structural connections and its graded variation across the cortical sheet and across mammalian species. The framework unifies seemingly dispersed observations on multiple levels of cortical organization, including the cellular, connectional, and functional level. Moreover, the framework allows the prediction of the layer-specific origin of connections in a spectrum of mammals, from rodents to humans. PMID- 29980394 TI - Use of a 5-Item Modified Frailty Index for Risk Stratification in Patients Undergoing Surgical Management of Distal Radius Fractures. AB - PURPOSE: Compared with cast treatment, surgery may expose patients with distal radius fractures to undue risk. Surgical intervention in this cohort may offer less benefit than previously thought and appropriate patient selection is imperative. The modified Frailty Index (mFI) predicts complications after other orthopedic surgeries. We hypothesized that this index would predict, and might ultimately prevent, complications in patients older than 50 years with distal radius fractures. METHODS: We retrospectively reviewed the American College of Surgeons-National Surgery Quality Improvement Program (ACS-NSQIP) database, including patients older than 50 years who underwent open reduction and internal fixation of a distal radius fracture. A 5-item mFI score was then calculated for each patient. Postoperative complications, readmission and reoperation rates, as well as length of stay (LOS) were recorded. Bivariate and multivariable statistical analysis was then performed. RESULTS: We identified 6,494 patients (mean age, 65 years). Compared with patients with mFI of 0, patients with mFI of 2 or greater were nearly 2.5 times as likely to incur a postoperative complication (1.7% vs 7.4%). Specifically, the rates of Clavien-Dindo IV, wound, cardiac, and renal complications were increased significantly in patients with mFI of 2 or greater. In addition, as mFI increased from 0 to 2 or greater, 30-day reoperation rate increased from 0.8% to 2.4%, 30-day readmission from 0.8% to 4.6%, and LOS from 0.5 days to 1.44 days. Frailty was associated with increased complications as well as rates of readmission and reoperation even when controlling for demographic data, LOS, and operative time. Age alone was not significantly associated with postoperative complications, readmission, reoperation, or LOS. CONCLUSIONS: A state of frailty is highly predictive of postoperative complications, readmission, reoperation, and increased LOS following open reduction and internal fixation of distal radius fractures. Our data suggest that a simple frailty evaluation can help inform surgical decision making in patients older than 50 years with distal radius fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 29980395 TI - Bone Graft Options in Upper-Extremity Surgery. AB - Bone grafting in the upper extremity is an important consideration in patients with injuries or conditions resulting in missing bone stock. A variety of indications can necessitate bone grafting in the upper extremity, including fractures with acute bone loss, nonunions, malunions, bony lesions, and bone loss after osteomyelitis. Selecting the appropriate bone graft option for the specific consideration is important to ensure optimal patient outcomes. Considerations such as donor site morbidity and the amount and characteristics of bone graft needed all weigh in the decision making regarding which type of bone graft to use. This article reviews the options available for bone grafting in the upper extremity. PMID- 29980396 TI - The Impact of the Left Ventricle on Right Ventricular Function and Clinical Outcomes in Infants with Single-Right Ventricle Anomalies up to 14 Months of Age. AB - BACKGROUND: Children with single-right ventricle anomalies such as hypoplastic left heart syndrome (HLHS) have left ventricles of variable size and function. The impact of the left ventricle on the performance of the right ventricle and on survival remains unclear. The aim of this study was to identify whether left ventricular (LV) size and function influence right ventricular (RV) function and clinical outcome after staged palliation for single-right ventricle anomalies. METHODS: In the Single Ventricle Reconstruction trial, echocardiography-derived measures of LV size and function were compared with measures of RV systolic and diastolic function, tricuspid regurgitation, and outcomes (death and/or heart transplantation) at baseline (preoperatively), early after Norwood palliation, before stage 2 palliation, and at 14 months of age. RESULTS: Of the 522 subjects who met the study inclusion criteria, 381 (73%) had measurable left ventricles. The HLHS subtype of aortic atresia/mitral atresia was significantly less likely to have a measurable left ventricle (41%) compared with the other HLHS subtypes: aortic stenosis/mitral stenosis (100%), aortic atresia/mitral stenosis (96%), and those without HLHS (83%). RV end-diastolic and end-systolic volumes were significantly larger, while diastolic indices suggested better diastolic properties in those subjects with no left ventricles compared with those with measurable left ventricles. However, RV ejection fraction was not different on the basis of LV size and function after staged palliation. Moreover, there was no difference in transplantation-free survival to Norwood discharge, through the interstage period, or at 14 months of age between those subjects who had measurable left ventricles compared with those who did not. CONCLUSIONS: LV size varies by anatomic subtype in infants with single-right ventricle anomalies. Although indices of RV size and diastolic function were influenced by the presence of a left ventricle, there was no difference in RV systolic function or transplantation-free survival on the basis of LV measures. PMID- 29980397 TI - Improving the Quality and Reporting of Perioperative Echocardiography. PMID- 29980398 TI - An International Affair. PMID- 29980399 TI - Have Noninvasive Imaging Studies Supplanted the Need for Invasive Hemodynamics: Lessons Learned from Lymphangioleiomyomatosis. PMID- 29980400 TI - Association between environmental exposure and CD4+CD25+ regulatory T cells. AB - BACKGROUND: It is considered that farm areas protect young patients from allergy and asthma due to high exposure to endotoxins. AIM: To compare CD4+/CD25+ T regulatory cells and forkhead transcription factor Foxp3 expression in asthmatic children allergic to house dust mites (HDM) living in rural and farm areas. MATERIALS AND METHODS: This was a prospective analysis of 35 children living in farm areas (n=19) and rural areas (n=16), aged 8-16, with allergic rhinitis (allergic to dust mites) and newly diagnosed asthma. Surface molecule CD4+CD25+Foxp3+ expression on cultured PBMCs was estimated by flow cytometry using fluorophore-conjugated monoclonal antibodies in each patient. RESULTS: Thirty-five children were included into the analysis: 19 children living in farm areas and 16 in rural areas. Within and between-groups (farm area vs. rural area) differences in CD4+/CD25+ and CD4+/CD25+Foxp3+ cell expression did not reach the level of significance. CONCLUSION: The current analysis showed that CD4+/CD25+ and CD4+/CD25+Foxp3+ cell expression was not associated with place of living in asthmatic children sensitive to HDM. PMID- 29980401 TI - Adherence to the Mediterranean diet and inflammatory markers in children with asthma. AB - INTRODUCTION: There is accumulated evidence supporting a beneficial role of Mediterranean diet (MD) in the control of asthma symptoms. The aim of this study was to investigate the relationships between adherence to MD and serum levels of certain cytokines namely, interleukin (IL)-4, and IL-17 known to have a pathogenetic role in the airway changes associated with asthma. METHODS: We measured serum IL-4, IL-33, and IL-17, in 44 asthmatic and 26 healthy children, 5 15 years old. Their adherence to MD was estimated with the Mediterranean Diet Quality Index for children and adolescents (KIDMED) score. RESULTS: KIDMED score did not differ between the two groups (P=0.59) and was not correlated with any of the three measured cytokines. However, when the analysis was restricted only to asthmatic children, the KIDMED score was correlated with IL-4, IL-33, and IL-17 (Beta: -0.56, P=0.007; Beta: 0.57, P=0.010; Beta: -0.62, P=0.017, respectively). CONCLUSION: Our results indicate that MD can modulate the production of some of the main inflammatory mediators of asthma, in asthmatic children. PMID- 29980402 TI - Laboratory and severity evaluation of pediatric atopic dermatitis and moisturizer response in different phenotypes. AB - INTRODUCTION AND OBJECTIVES: Atopic dermatitis (AD) is an eczematous skin disease. Our aim was to evaluate the clinical and laboratory findings of children with AD and identify the higher responsive group to moisturizers. MATERIALS AND METHODS: Total and specific IgE, eosinophil count, prick/patch test results of patients with AD were retrospectively analyzed. The presentation SCORAD was compared between the demographic and clinical subgroups. The SCORAD change (presentation to third month) between the intrinsic and extrinsic groups was compared. The effect of age, sex, disease duration, presentation SCORAD, being intrinsic/extrinsic, exclusive breastfeeding duration, familial atopy, total IgE, eosinophil count, concomitant illness presence, moisturizer use frequency and exacerbation frequency on SCORAD change was examined. RESULTS: The mean age was 3.65+/-3.77 years. Food allergy was found in 5.90% and inhalant allergy was found in 12.67% of patients. 158 (44.5%) were mild, 154 (43.4%) were moderate and 43 (12.1%) were severe AD. 141 (39.7%) were intrinsic AD. The SCORAD at 3rd visit and SCORAD change was different between the intrinsic and extrinsic groups. SCORAD change was positively associated with presentation SCORAD, eosinophil count, moisturizer use frequency and being extrinsic AD. CONCLUSIONS: The clinical and laboratory findings of AD patients in our community were revealed. Higher SCORAD and eosinophils at presentation, frequent daily moisturizer use and being extrinsic increased the moisturizer response. Although the barrier defect was shown to be lesser in intrinsic AD by considering transepidermal water loss, this study is the first to evaluate intrinsic and extrinsic AD patients according to response to moisturizers. PMID- 29980403 TI - Microbiome in the primary prevention of allergic diseases and bronchial asthma. AB - Tremendous progress in the ability to identify and test the function of microorganisms in recent years has led to a much better understanding of the role of environmental and host microbiome in the development of immune function, allergic sensitization and asthma. In this review, the most recent findings on the relationships between environmental microbiota, respiratory, intestinal microbiome, the consequences of early-life microbial exposure type and gut-lung microbial axis and the development of asthma and atopy are summarized. The current perspective on gut and airway microbiome manipulation for the primary prevention of allergic diseases and asthma is also discussed. PMID- 29980404 TI - Endoscopic endonasal transmaxillary ligation of a feeding artery and coblation plasma technology enables en bloc resection of advanced juvenile nasopharyngeal angiofibroma without preoperative embolization. AB - Juvenile nasopharyngeal angiofibroma (JNA) is a hypervascular tumor and uncontrolled hemorrhage makes its removal very difficult. Although preoperative intravascular embolization of a feeding artery is recommended, serious complications such as iatrogenic thrombosis in the brain and insufficient decrease in blood flow to the tumor are concerns. Recently, coblation plasma technology has been reported to be useful for tumor removal with minimum hemorrhage under a clear surgical field. Here we report successful removal of advanced JNA without preoperative embolization, using intraoperative ligation of the maxillary artery and coblation plasma technology. The left nasal cavity of a 23-years-old man was closed by a JNA tumor at Radkowski stage IIC, which was 65mm in size and extended from the nasal cavity to the infratemporal fossa. MRA imaging showed the maxillary artery running along the posterior wall of the maxillary sinus. Therefore, the maxillary artery was first clipped using an endoscopic modified medial maxillectomy (EMMM) approach and endoscopic endonasal en bloc resection of the tumor was then completed using coblation technology with no need for blood transfusion. This case illustrates that preoperative embolization is dispensable in JNA surgery even at Stage IIC if the maxillary artery can be ligated during surgery and a coblation device can be utilized. PMID- 29980405 TI - Introduction of WT-TP53 into pancreatic cancer cells alters sensitivity to chemotherapeutic drugs, targeted therapeutics and nutraceuticals. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10%. Mutations at the TP53 gene are readily detected in pancreatic tumors isolated from PDAC patients. We have investigated the effects of restoration of wild-type (WT) TP53 activity on the sensitivity of pancreatic cancer cells to: chemotherapy, targeted therapy, as well as, nutraceuticals. Upon introduction of the WT-TP53 gene into the MIA-PaCa 2 pancreatic cancer cell line, the sensitivity to drugs used to treat pancreatic cancer cells such as: gemcitabine, fluorouracil (5FU), cisplatin, irinotecan, oxaliplatin, and paclitaxel increased significantly. Likewise, the sensitivity to drugs used to treat other cancers such as: doxorubicin, mitoxantrone, and 4 hydroxy tamoxifen (4HT) also increased upon introduction of WT-TP53 into MIA-PaCa 2 cells. Furthermore, the sensitivity to certain inhibitors which target: PI3K/mTORC1, PDK1, SRC, GSK-3, and biochemical processes such as proteasomal degradation and the nutraceutical berberine as increased upon introduction of WT TP53. Furthermore, in some cases, cells with WT-TP53 were more sensitive to the combination of drugs and suboptimal doses of the MDM2 inhibitor nutlin-3a. However, TP53-independent effects of nutlin-3a were observed upon treatment with either a proteasomal or a PI3K/mTOR inhibitor. These studies indicate the sensitizing effects that WT-TP53 can have in PDAC cells which normally lack WT TP53 to various therapeutic agents and suggest approaches to improve PDAC therapy. PMID- 29980406 TI - Quality of Care and 30-day Mortality of Women and Men With Acute Myocardial Infarction. AB - INTRODUCTION AND OBJECTIVES: Despite increased awareness of sex disparities in care and outcomes of acute myocardial infarction (AMI), there appears to have been no consistent attenuation of these differences over the last decade. We investigated differences by sex in management and 30-day mortality using the European Society of Cardiology Acute Cardiovascular Care Association quality indicators (QIs) for AMI. METHODS: Proportions and standard errors of the 20 Acute Cardiovascular Care Association QIs were calculated for 771 patients with AMI who were admitted to the cardiology departments of 2 tertiary hospitals in Portugal between August 2013 and December 2014. The association between the composite QI and 30-day mortality was derived from logistic regression. RESULTS: Significantly fewer eligible women than men received timely reperfusion, were discharged on dual antiplatelet therapy and high-intensity statins, and were referred to cardiac rehabilitation. Women were less likely to receive recommended interventions (59.6% vs 65.2%; P <.001) and also had higher mean GRACE 2.0 risk score-adjusted 30-day mortality (3.0% vs 1.7%; P <.001). An inverse association between the composite QI and crude 30-day mortality was observed for both sexes (OR, 0.08; 95%CI, 0.01-0.64 for the highest performance tertile vs the lowest). CONCLUSIONS: Performance in AMI management is worse for women than men and is associated with higher 30-day mortality, which is also worse for women. Evidence based QIs have the potential to improve health care delivery and patient prognosis in the overall AMI population and may also bridge the disparity gap between women and men. PMID- 29980407 TI - A 3D Printed Patient-specific Simulator for Percutaneous Coronary Intervention. PMID- 29980408 TI - Perianesthetic Implications and Considerations for Myasthenia Gravis. AB - Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease in which antibodies against the post-nicotinic acetylcholine receptor at the neuromuscular junction develop. Although the exact cause of MG remains unknown, the thymus is a common factor in many cases. Patients with underlying junctional disease, such as MG, have greater anesthesia-related risks because of their known predisposition toward prolonged muscle weakness. Medications given in the perioperative period, such as anesthetic agents, antibiotics, cardiovascular drugs, and corticosteroids, affect neuromuscular transmission that contributes to muscle weakness. Judicious use of neuromuscular blocking agents for patients with MG must be considered. This patient population is at high risk for respiratory failure, and therefore must be carefully assessed throughout the perioperative period to ensure that a regular spontaneous respiratory pattern is sufficient to provide adequate oxygenation. Perianesthesia providers must consider anesthetic, ventilatory, and pharmacologic implications when proposing, providing, and recovering anesthesia for the patient with MG. PMID- 29980410 TI - Primary carcinoma ex-pleomorphic adenoma of anterior commissure of the larynx. PMID- 29980409 TI - Worldwide arthroplasty research productivity and contribution of Turkey. AB - PURPOSE: Bibliometrics is increasingly used to assess the quantity and quality of scientific research output in many research fields worldwide. However, to the best of our knowledge, no studies have documented the main characteristics of arthroplasty publications from different countries. This study aimed to evaluate the worldwide research productivity and status of Turkey in the field of arthroplasty using bibliometric methods and to provide an insight into the arthroplasty research for surgeons and researchers. METHODS: The Web of Science database was searched to identify arthroplasty articles published between 2006 and 2016. The contributions of countries were evaluated based on publication count, citation average, h-index and publication rate in the top 10 ranked journals. Each countries publication output was adjusted according to population size. RESULTS: A total of 26.167 articles were identified. World arthroplasty publications were increased significantly over time (p < .005). The United States was the most productive country with 9007 articles (34,4% of total) followed by England with 2939 articles (11,4 of total) and Germany with 1881 articles (7,1% of total). According to average citations per item, Scotland was in the first place followed by Denmark and Sweden, whereas in the first place according to publication output adjusted by population size was Switzerland followed by Denmark and Scotland. The United States was also in the first place according to h-index and publication rate in the top 10 ranked journals. Founding average was 28,8% (7539 of 26164) for the arthroplasty articles that were analyzed in the study. CONCLUSION: There is a rapid increase in the number of articles in arthroplasty research from 2006 to 2016. The United States was the most productive country as measured by total publications in the arthroplasty field. However, some small European countries with high in-come have higher quality of articles and better productivity when adjusted for population. Gross domestic product (GDP) per capita and research foundation had positive affect on arthroplasty publications, both qualitatively and quantitatively. PMID- 29980411 TI - Hodgkin Lymphoma With Multiple Autoimmune Disorders: Case Report and Review of the Literature. PMID- 29980412 TI - Prevalence of Monoclonal Gammopathy of Undetermined Significance in India-A Hospital-based Study. AB - BACKGROUND: We sought to determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a hospital-based cohort in India. PATIENTS AND METHODS: From March 2015 to May 2015, 3429 patients (age range, 40-88 years) were enrolled in the present study. Of the 3429 enrolled patients, 2354 (68.6%) were men and 1075 (31.4%) were women. Serum samples were collected from all patients and analyzed using serum protein electrophoresis (SPEP). The positive SPEP samples were subjected to immunofixation. The patients with positive results for both SPEP and immunofixation were registered in the oncology department and investigated further for plasma cell dyscrasias. RESULTS: Of the 3429 study patients, 49 (1.43%) were found to have MGUS, and multiple myeloma was diagnosed in another 6 (0.17%). The prevalence rate of MGUS in patients aged 40 to 49, 50 to 59, 60 to 69, and 70 to 80 years was 0.83%, 1%, 2.62%, and 1.75%, respectively. Of the 49 MGUS patients, 5 (10.2%) were in the high-intermediate risk category using the Mayo Clinic criteria for risk stratification. At 30 months of follow-up, 1 patient in the high-intermediate category had developed multiple myeloma. CONCLUSION: To the best of our knowledge, the present study is the first systematic study on the prevalence of MGUS in an Indian population. The overall prevalence of MGUS was 1.43% in the evaluated Indian cohort, lower than that reported for white and black populations. The incidental detection of 6 subjects with multiple myeloma of 3429 screened subjects in our study was high compared with the reported incidence of multiple myeloma in India of only 1.9 per 100,000 persons. This finding indicates the need to create awareness about myeloma-related symptoms and screening studies in appropriate age groups, at least in the hospital-based setting. PMID- 29980413 TI - COL1A1 is a fusionpartner of USP6 in myositis ossificans - FISH analysis of six cases. PMID- 29980414 TI - Combining Perfusion and High B-value Diffusion MRI to Inform Prognosis and Predict Failure Patterns in Glioblastoma. AB - PURPOSE: Advanced imaging modalities such as high b-value diffusion and dynamic contrast enhancement magnetic resonance imaging have the potential to improve the clinical management of glioblastoma by informing prognosis, predicting sites of progression, and guiding dose-escalated radiation to maximize tumor control and minimize toxicity. METHODS AND MATERIALS: Fifty-two patients with de novo glioblastoma underwent magnetic resonance imaging before chemoradiation therapy. Enhanced tumor volumes (TVs), excluding the surgical cavity, hypercellularity (TVHCV) and increased cerebral blood volume (TVCBV) were defined using conventional gadolinium-enhanced T1-weighted images, high b-value (3000 s/mm2) diffusion-weighted images, and cerebral blood volume maps from T1-weighted dynamic contrast enhancement images, respectively. The image-phenotype TVs were analyzed for prediction of progression-free survival (Cox proportional hazard models), and sites of progression (pattern of failure tumor volume). RESULTS: The median progression-free survival (PFS) of the cohort was 13 months. The TVCBV and TVHCV were spatially distinct, with a mean overlap of only 21%. Univariate analysis showed that increasing age, decreasing radiation dose, larger TVHCV, and larger overlap of TVHCV and TVCBV were significantly associated with inferior PFS. Multivariate analysis identified that TVHCV was the most adversely prognostic imaging-defined variable. Enhanced TVs, excluding the surgical cavity, and the union of TVHCV and TVCBV showed a high likelihood of containing the pattern of failure tumor volume, and the volume composed of the intersection of TVHCV and TVCBV had an especially high likelihood of progression. CONCLUSIONS: TVHCV and the overlap of TVHCV and TVCBV are prognostic for PFS. Combinations of gadolinium-enhanced TVs, TVCBV, and TVHCV could predict tumor progression locations better than could individual subvolumes. Radiation dose escalation to these subvolumes could be a promising therapeutic strategy. PMID- 29980415 TI - Results From 10 Years of a Free Oral Cancer Screening Clinic at a Major Academic Health Center. PMID- 29980416 TI - Making Sense of MACRA: A Guide for Diagnostic Radiologists. AB - The Medicare Access and CHIP Reauthorization Act of 2015 was signed into law on April 16, 2015, fundamentally altering the way clinicians are reimbursed for the treatment of Medicare patients starting in 2017. Under this new pay-for performance model, reimbursement will be tied to multiple metrics related to quality and cost of care. A scaled scoring system will require providers to compete for positive reimbursement adjustments, while also penalizing poor performers with negative adjustments. A firm understanding of this new system will be essential for all physicians looking to maximize their reimbursement, particularly diagnostic radiologists and members of other highly focused fields where special considerations lead to alterations in the scoring system. PMID- 29980417 TI - A review of syndromes associated with blue sclera, with inclusion of malformations of the head and neck. AB - Blue sclera is attributed to a diversity of mechanisms, mostly arising in genetic syndromes and, to a lesser extent, in nongenetic disorders and may occur as a side effect of medication intake. A literature search was conducted to establish a database of blue scleral associations. This article represents the most comprehensive assemblage of etiopathologies coincidental with blue sclera, comprising 66 genetic syndromes, 8 disorders, and 4 pharmacologically induced pigmentations. To increase the knowledge regarding the clinical significance of blue sclera, summaries of the systemic and oral maxillofacial comorbidities are provided. Recognition of the presence of blue sclera is important as it could prompt a timelier and more thorough diagnostic evaluation of possible systemic and dental malformations, potentially improving clinical outcomes. PMID- 29980418 TI - Alleles with more than one mutation can complicate genotype/phenotype studies in Mendelian disorders: Lessons from Gaucher disease. AB - Autosomal resessive Mendelian disorders usually result from two inherited disease causing mutations. However, this is not always the case. Focusing on Gaucher disease, which results from mutations in GBA1, we found that more comprehensive genotyping revealed important exceptions. For example, patients with uniparental disomy or new mutations do not inherit a mutation from each parent. Furthermore, we identified patients found to carry more than one GBA1 mutation on the same allele. It is essential to examine the entire GBA1 gene in order to establish an accurate genotype. Missing the second mutation can complicate genotype/phenotype studies and result in improper genetic counseling. PMID- 29980419 TI - Cutaneous Hypesthesia and Kneeling Ability After Total Knee Arthroplasty: A Randomized Controlled Trial Comparing Anterolateral and Anteromedial Skin Incision. AB - BACKGROUND: Anterolateral skin incision can preserve the skin sensory of the anterior aspect of the knee and may improve kneeling ability after total knee arthroplasty (TKA). METHODS: This is a prospective, 2-arm, parallel-group, randomized, controlled trial involving patients scheduled for TKA. A total of 118 patients (162 knees) were randomly assigned to receive anterolateral skin incision or anteromedial skin incision with 1:1 treatment allocation. The surgical techniques other than skin incision were identical in both groups. The area of cutaneous hypesthesia was measured by a nonblinded assessor, and kneeling ability was evaluated by 2 blinded assessors at 12 months after surgery. RESULTS: The area of cutaneous hypesthesia was significantly smaller in the anterolateral skin incision group than the anteromedial skin incision group (3.0 +/- 8.7 cm2 vs 10.6 +/- 18.6 cm2; 95% confidence interval, 2.8-12.3 cm2; P = .0019). The rates of patients judged to be able to kneel were significantly higher in the anterolateral skin incision group by both assessors (81% vs 60%; P = .025 and 81% vs 59%; P = .015, respectively) with almost perfect agreement between the 2 assessors (kappa value = 0.94). There were no significant differences in terms of complication rate, including wound complications, between the 2 groups (P > .05). CONCLUSION: Compared with anteromedial skin incision, anterolateral skin incision may provide less cutaneous hypesthesia and better kneeling ability after TKA without increasing complication rate. PMID- 29980420 TI - Letter to the Editor on "Contemporary Dual Mobility Head Penetration at Five Years: Concern for the Additional Convex Bearing Surface?" PMID- 29980421 TI - Outcomes After Arthroscopic Evaluation of Patients With Painful Medial Unicompartmental Knee Arthroplasty. AB - BACKGROUND: Persistent pain after medial unicompartmental knee arthroplasty (UKA) is a prevailing reason for revision to total knee arthroplasty (TKA). Many of these pathologies can be addressed arthroscopically. The purpose of this study is to examine the outcomes of patients who undergo an arthroscopy for any reason after medial UKA. METHODS: A query of our practice registry revealed 58 patients who had undergone medial UKA between October 2003 and June 2015 with subsequent arthroscopy. Mean interval from medial UKA to arthroscopy was 22 months (range 1 101 months). Indications for arthroscopy were acute anterior cruciate ligament tear (1), arthrofibrosis (7), synovitis (12), recurrent hemarthrosis (2), lateral compartment degeneration including isolated lateral meniscus tears (11), and loose cement fragments (25). RESULTS: Mean follow-up after arthroscopy was 49 months (range 1-143 months). Twelve patients have been revised from UKA to TKA. Relative risk of revision after arthroscopy for lateral compartment degeneration was 4.27 (6 of 11; 55%; P = .002) and for retrieval of loose cement fragments was 0.05 (0 of 25; 0%; P = .03). Relative risk for revision after arthroscopy for anterior cruciate ligament tear, arthrofibrosis, synovitis, or recurrent hemarthrosis did not meet clinical significance secondary to the low number of patients in these categories. CONCLUSION: The results of this study suggest that arthroscopic retrieval of cement fragments does not compromise UKA longevity. However, arthroscopy for lateral compartment degradation after UKA, while not the cause of revision, appears to be an ineffective treatment and predicts a high risk of revision to TKA regardless of its relative radiographic insignificance. PMID- 29980422 TI - Letter to the Editor on "Comparison of Customized Cutting Block and Conventional Cutting Instruments in Total Knee Arthroplasty: A Randomized Controlled Trial". PMID- 29980423 TI - Response to Letter to the Editor on "Contemporary Dual Mobility Head Penetration at Five Years: Concern for the Additional Convex Bearing Surface?" PMID- 29980424 TI - On the effects of tyrosine supplementation on interference control in a randomized, double-blind placebo-control trial. AB - Exerting cognitive control is an effortful endeavor that is strongly modulated by the availability of dopamine (DA) and norepinephrine (NE), which are both synthesized from the amino acid precursor tyrosine. Supplementing tyrosine may increase the synthesis of both catecholamines. This has been suggested to improve executive functioning and potentially even counteract depletion effects in this domain. Yet, it has remained unclear whether tyrosine also improves interference control and whether subliminally and consciously triggered response conflicts are subject to the same modulation. We investigated this question in a double-blind intra-individual study design. N = 26 young healthy subjects performed two consecutive cognitive control tasks that triggered automatic incorrect response tendencies; once with tyrosine supplementation and once with a placebo. The results show that tyrosine decreased the size of consciously perceived conflicts in a Simon Task, but not a Flanker task, thus suggesting that stimulus-response conflicts might be modulated differently from stimulus-stimulus conflicts. At the same time, tyrosine supplementation increased the size of subliminally triggered conflicts whenever a different, consciously perceived conflict was also present. This suggests that control-related DA and NE release may increase visuo-motor priming, especially when no conflict-specific top-down control may be triggered to counteract subliminal priming effects. Also, these subliminal conflicts might be aggravated by concurrent control investments in other kinds of conflict. Taken together, our data suggest that beneficial effects of tyrosine supplementation do not require depletion effects, but may be limited to situations where we consciously perceive a conflict and the associated need for conflict-specific control. PMID- 29980425 TI - Characteristics of patients with confirmed epilepsy and psychogenic nonepileptic seizures in Qatar. AB - OBJECTIVE: The Middle Eastern country of Qatar opened its first epilepsy monitoring unit (EMU) in late 2015. This study compared demographic and clinical characteristics of patients with confirmed epilepsy to those of patients with confirmed psychogenic nonepileptic seizures (PNES). METHODS: Data were collected via retrospective chart review on 113 patients admitted for evaluation to the Qatar national health system EMU between November 2015 and May 2017. RESULTS: Seventy-one patients had a confirmed diagnosis (20 had PNES, 46 had epilepsy, 5 had both PNES and epilepsy). Evaluation in 33 patients was inconclusive, and 9 had other medical conditions. Patients with PNES were significantly more likely to be primary Arabic speakers (p = 0.003), and this difference was not explained by education or employment status. The most common referral request in patients with PNES was for recurrent/refractory seizures (p = 0.011), and there was a trend for patients with PNES to have more frequent seizures compared with patients with epilepsy (daily to several per week versus several times a month or less, p = 0.051). Depression was identified in 47% of patients with epilepsy and 65% of patients with PNES, and patients with PNES had higher mean depression scores on the PHQ-9 than patients with epilepsy (p = 0.014). Patients with PNES experienced significantly more fatigue (p = 0.021). Seventy percent of patients with PNES and 50% of patients with epilepsy reported sleep problems. CONCLUSIONS: The characteristics of patients with epilepsy and PNES at the EMU in Qatar were generally similar to those found worldwide. Patients with PNES more often suffered from frequent depression, sleep problems, and fatigue than those with epilepsy, but these were significant concerns for both groups. PMID- 29980426 TI - Effects of posterior condylar offset and posterior tibial slope on mobile-bearing total knee arthroplasty using computational simulation. AB - BACKGROUND: Postoperative changes of the femoral posterior condylar offset (PCO) and posterior tibial slope (PTS) affect the biomechanics of the knee joint after fixed-bearing total knee arthroplasty (TKA). However, the biomechanics of mobile bearing is not well known. Therefore, the aim of this study was to investigate whether alterations to the PCO and PTS affect the biomechanics for mobile-bearing TKA. METHODS: We used a computational model for a knee joint that was validated using in vivo experiment data to evaluate the effects of the PCO and PTS on the tibiofemoral (TF) joint kinematics, patellofemoral (PF) contact stress, collateral ligament force and quadriceps force, for mobile-bearing TKA. The computational model was developed using +/-1-, +/-2- and +/-3-mm PCO models in the posterior direction and -3 degrees , 0 degrees , +3 degrees , and +6 degrees PTS models based on each of the PCO models. RESULTS: The maximum PF contact stress, collateral ligament force and quadriceps force decreased as the PTS increased. In addition, the maximum PF contact stress and quadriceps force decreased, and the collateral ligament force increased as PCO translated in the posterior direction. This trend is consistent with that observed in any PCO and PTS. CONCLUSIONS: Our findings show the various effects of postoperative alterations in the PCO and PTS on the biomechanical results of mobile-bearing TKA. Based on the computational simulation, we suggest that orthopaedic surgeons intraoperatively conserve the patient's own anatomical PCO and PTS in mobile bearing TKA. PMID- 29980427 TI - Meniscal sizing before allograft: Comparison of three imaging techniques. AB - BACKGROUND: Accuracy of meniscal sizing is an important issue before allograft transplantation. To date, there is no consensus on the best imaging method. The purpose of this study was to compare plain radiographs, magnetic resonance imaging (MRI) and computed tomography (CT) arthrography in the assessment of meniscal size. We hypothesized that MRI and CT arthrography had better correlations than plain radiographs. METHODS: All patients operated on by meniscal allograft between January 2005 and May 2015 were screened. Among them, 32 patients had both preoperative radiographs, MRI and CT arthrography of the affected knee. The meniscal dimensions were evaluated, blindly and randomly, using three imaging methods. A correlation analysis between each technique was made. For radiographic methods, an additional comparison was made between original Pollard's method and the modified method (Yoon). Bone dimensions (tibial metaphysis) were also collected, using radiographs and MRI, in order to build new equations allowing determination of meniscal dimensions from those bone measurements. RESULTS: The radiographic methods offered satisfying evaluations of the meniscal dimensions in the sagittal plane, without significant difference when compared with CT arthrography or MRI. In the frontal plane, the radiograph methods were less effective. With new equations, allowing determination of meniscal dimensions from tibial plateau dimensions, the mean correlation coefficient was 0.39 (0.14-0.71). CONCLUSIONS: The correlation between radiographic methods and MRI depended on which parameter (frontal or sagittal) was measured. Thus, we proposed a new method for sizing of meniscus, easily measurable from bony landmarks, aiming to improve the accuracy of graft selection. PMID- 29980428 TI - Acute Generalized Exanthematous Pustulosis Induced by Docetaxel and Recurrent With Letrozole: A Case Report. PMID- 29980429 TI - A Systematic Review of Heart Dose in Breast Radiotherapy. AB - Radiotherapy (RT) for breast cancer improves survival, but poses risk to the heart, resulting from a linear relationship between RT dose and heart disease. This review presents studies worldwide reporting heart doses from whole breast RT after 2014 to update a previous systematic review (Taylor et al, Int J Radiat Oncol Biol Phys, 2015) in order to determine patterns of current heart dosimetry among varying RT regimens. Studies published between January 2014 and September 2017 were included if they reported whole heart dose based on whole breast RT technique or treatment position and had a sample size of >= 20 patients. Studies reporting brachytherapy, proton RT only, or boost to tumor bed were excluded. Among 99 studies, whole heart dose was reported by 231 regimens. The mean heart dose for left-sided breast cancer, reported by 84 studies (196 regimens), was 3.6 Gy, compared with a review of those previously reported (5.4 Gy). Regimens employing breathing control in any position had a significantly lower mean heart dose (1.7 Gy) compared with regimens without breathing control (4.5 Gy) (P < .0001). The mean heart dose varied significantly between continents (P < .0001), with heterogeneity reported among countries within Europe (P = .04) although not within other continents. On average, the mean heart dose steadily decreased between 2014 (4.6 Gy) and 2017 (2.6 Gy) (P = .003). Other heart dose parameters including the mean dose to the left anterior descending artery were reported by 80 left-sided regimens, and the mean left anterior descending artery dose was 12.4 Gy. PMID- 29980430 TI - Recurrent Ventricular Arrhythmia Caused by Ingestion of Aconitum (Monkshood) Flowers. AB - We report the case of a patient who presented with respiratory failure, recurrent ventricular fibrillation, ventricular arrhythmias, and hypotension after an intentional ingestion of aconite flowers. Significant ingestion of this plant can produce life-threatening cardio- and neurotoxicity that may require evacuation from the wilderness to a medical facility capable of advanced treatment and intensive care monitoring. PMID- 29980431 TI - Elevated N-acetyl-beta-d-glucosaminidase, a urinary tubular damage marker, is a significant predictor of carotid artery atherosclerosis in type 1 diabetes, independent of albuminuria: A cross-sectional study. AB - AIMS: Recent evidence has shown that renal tubulointerstitial injuries play an important role in diabetic nephropathy. In this study, we evaluated the association between urinary N-acetyl-beta-d-glucosaminidase (uNAG), an early renal tubular damage marker, and carotid artery atherosclerosis in patients with type 1 diabetes (T1D). METHODS: This was a cross-sectional study of 88 patients with T1D. Demographic and laboratory data; urinary indices, including urinary NAG to-creatinine ratio (uNCR), and albumin-to-creatinine ratio (uACR); and carotid ultrasonography were investigated. RESULTS: Eighty-eight subjects were divided into three groups based on uNCR tertiles. Subjects belonging to the highest tertile of uNCR had the highest average mean and maximum carotid intima-media thickness (IMT). An elevated uNCR was also significantly correlated with increased average mean and maximum carotid IMT, whereas an elevated uACR was not. Even after adjusting for confounding factors, uNCR continued to be a meaningful predictive marker for increased average mean and maximum IMT. Conversely, the uACR could not predict carotid IMT after adjustment for confounding factors. CONCLUSIONS: Elevated levels of uNAG are significantly associated with carotid artery atherosclerosis in patients with T1D independently of albuminuria, a marker of glomerular damage. PMID- 29980432 TI - Bone mineral content and bone density is lower in adolescents with type 1 diabetes: A brief report from the RESISTANT and EMERALD studies. AB - To understand the effect of type 1 diabetes (T1D) on bone mineral content (BMC) and bone density (BMD), we studied 125 T1D adolescents and 80 pubertal stage matched controls. T1D was associated with lower whole-body BMC and BMD compared to controls, even when adjusted for age, sex and sex hormones. PMID- 29980433 TI - Early predictors of diabetic retinopathy in type 1 diabetes: The Retinopathy Champagne Ardenne Diabete (ReCAD) study. AB - AIMS: To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes. METHODS: A historic cohort study was conducted on 712 patients from the CAReDIAB database. HbA1c and usual metabolic parameters were measured one year after diagnosis of diabetes. First occurrences of severe hypoglycemia and ketoacidosis during follow-up were selected as time-dependent markers of diabetes control. Data were analyzed in a Cox model using SPSS software to predict DR with significance level at p-value <0.05. RESULTS: In multivariate regression, any diabetic retinopathy was predicted by HbA1c (HR = 1.38; CI = 1.25-1.52; p < 0.0001), severe hypoglycemia (HR = 3; CI = 1.99-4.52; p < 0.0001), ketoacidosis (HR = 1.96; CI = 1.17-3.22; p = 0.009), and age at diagnosis (HR = 1.016; CI = 1.002-1.031; p = 0.02). Proliferative DR was predicted by HbA1c (HR = 1.67; CI = 1.51-1.79; p < 0.0001), severe hypoglycemia (HR = 3.67; CI = 2.74-5.25; p < 0.0001), and ketoacidosis (HR = 2.37; CI = 1.56-3.18; p < 0.0001). CONCLUSION: This study shows that the failure to achieve diabetes control after the first year of diagnosis as well as early episodes of acute diabetes complications may contribute to the occurrence of diabetic retinopathy in type 1 diabetes patients. PMID- 29980434 TI - Analysis of torsadogenic and pharmacokinetic profile of E-4031 in dogs bridging the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects. AB - We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects. PMID- 29980435 TI - Joining forces to understand hemostasis and thrombosis: A call to communicate: Comment on "Modeling thrombosis in silico: Frontiers, challenges, unresolved problems and milestones" by A.V. Belyaev et al. PMID- 29980436 TI - Gain-of-Function Mutation of Card14 Leads to Spontaneous Psoriasis-like Skin Inflammation through Enhanced Keratinocyte Response to IL-17A. AB - Genetic mutations of CARD14 (encoding CARMA2) are observed in psoriasis patients. Here we showed that Card14E138A/+ and Card14DeltaQ136/+ mice developed spontaneous psoriasis-like skin inflammation, which resulted from constitutively activated CARMA2 via self-aggregation leading to the enhanced activation of the IL-23-IL-17A cytokine axis. Card14-/- mice displayed attenuated skin inflammation in the imiquimod-induced psoriasis model due to impaired IL-17A signaling in keratinocytes. CARMA2, mainly expressed in keratinocytes, associates with the ACT1-TRAF6 signaling complex and mediates IL-17A-induced NF-kappaB and MAPK signaling pathway activation, which leads to expression of pro-inflammatory factors. Thus, CARMA2 serves as a key mediator of IL-17A signaling and its constitutive activation in keratinocytes leads to the onset of psoriasis, which indicates an important role of NF-kappaB activation in keratinocytes in psoriatic initiation. PMID- 29980442 TI - N degrees 363 - Evaluation et prise en charge de l'anasarque foetoplacentaire non immune. AB - OBJECTIF: Decrire les methodes actuelles d'evaluation et de prise en charge de l'anasarque foetoplacentaire non immune en mettant l'accent sur les etiologies traitables ou recurrentes. ReSULTATS: Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque foetoplacentaire non immune diagnostiquee en periode prenatale. DONNeES: La litterature publiee a ete recuperee au moyen de recherches menees dans PubMed, MEDLINE, CINAHL, et la Bibliotheque Cochrane en 2017 a l'aide de mots-cles (" non-immune hydrops fetalis ", " fetal hydrops ", " fetal therapy ", " fetal metabolism "). Les articles retenus portaient sur des revues systematiques, des essais cliniques controles, randomises ou non, des etudes observationnelles et des etudes de cas importantes. D'autres publications ont ete reperees dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a ete employee. Les recherches ont ete mis a jour regulierement, et les resultats ont ete incorpores a la directive clinique jusqu'en septembre 2017. Nous avons egalement tenu compte de la litterature grise (non publiee) trouvee sur les sites Web d'organismes d'evaluation des technologies de la sante et d'autres organismes lies aux technologies de la sante, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue aupres d'associations nationales et internationales de medecins specialistes. AVANTAGES, INCONVeNIENTS ET COuTS: La presente directive clinique renseigne les lecteurs sur les causes de l'anasarque foetoplacentaire non immune ainsi que sur son evaluation et sa prise en charge. Elle propose egalement une approche standardisee d'evaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en periode prenatale et des etiologies genetiques recurrentes. VALEURS: La qualite des donnees probantes a ete evaluee en fonction des criteres decrits dans le rapport du Groupe d'etude canadien sur les soins de sante preventifs. RECOMMANDATIONS. PMID- 29980437 TI - Critical Role for the Microbiota in CX3CR1+ Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses. AB - The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX3CR1 reduced expansion of intestinal microbe specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX3CR1+ APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis. PMID- 29980443 TI - Current surgical treatment of malignant pleural mesothelioma. PMID- 29980445 TI - Role of Hepatitis C Virus (HCV) core antigen in improving blood transfusion safety in high prevalence, resource limited countries, a step forward. AB - OBJECTIVE: The aim of the present study was to evaluate the efficacy of hepatitis C virus [HCV] core Ag as an alternative affordable test in resource limited countries blood banks. BACKGROUND: Implementing nucleic acid testing in developing countries with low resources is still unaffordable. Egypt has the highest prevalence of hepatitis C in the world and still in need to efficient affordable transfusion program that reduces the window period for the virus before implementing the complex high cost NAT. STUDY DESIGN AND METHODS: HCV core Ag by ELISA in serum, in the presence or absence of anti-HCV antibodies was compared to HCV- RNA by PCR on total number of 1850 first time and repeat donations from Fayoum University Hospital and Badr University Hospital. RESULTS: Among 1850 healthy voluntary donors, 143 donors with anti-HCV antibody positivity, 105 were determined as positive, 38 were negative for HCV core Ag, and 107 were positive for HCV RNA. CONCLUSION: Hepatitis C virus core antigen ELISA can be a useful alternative in the developing nations and Greater consideration should be given to its implementation as an additional serological test for blood donors in Egypt as the most cost-effective measure for further improvement of transfusion safety. PMID- 29980446 TI - Different clinical presentation of intralabyrinthine schwannomas - a systematic review. AB - INTRODUCTION: Intralabyrinthine schwannoma is a rare, benign tumor that affects the most terminal portions of the vestibular and cochlear nerves. This tumor can be classified into 10 subtypes, according to its inner ear location. OBJECTIVE: To carry out a comprehensive review of the most frequent auditory manifestations secondary to the intralabyrinthine schwannoma, describing the possible underlying pathophysiological mechanisms. METHODS: Systematic review of the literature until October 2017 using the PubMed, Web of Science and Scopus databases. The inclusion criteria were clinical manifestations of the intralabyrinthine schwannoma. Three researchers independently assessed the articles and extracted relevant information. The description of a case of an intravestibular subtype intralabyrinthine schwannoma with multiple forms of clinical presentations was used as an example. RESULTS: Twenty-seven studies met our inclusion criteria. The most common intralabyrinthine schwannoma subtype was the intracochlear, followed by the intravestibular type. All the cases demonstrated hearing loss, usually progressive hearing loss. CONCLUSION: The diagnosis of intralabyrinthine schwannomas is based on high-resolution magnetic resonance imaging and should be included in the differential diagnosis of patients with vestibulocochlear complaints. Although there are approximately 600 cases in the literature, we still lack a detailed description of the clinical evolution of the patients, correlating it with MRI findings of temporal bones and tumor subtype. PMID- 29980444 TI - Japanese guideline for the treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology which accounts for a large proportion of cases of idiopathic interstitial pneumonia. It has a very poor prognosis with a 5-year survival rate of 30% or below, and so far there has been no guideline in Japan offering an established effective therapy based on evidence. In addition to the establishment of basic therapies, there is also an urgent need to establish therapies to deal with complications, as death occurs in many cases due to acute exacerbation or comorbid lung cancer. It was therefore decided to formulate a guideline in order to promote evidence-based clinical practice, to further improve the quality of medical treatment in the clinical setting, and to allow the benefits to be enjoyed by the public. PMID- 29980447 TI - Development of a medication synchronization common language for community pharmacies. AB - OBJECTIVES: To develop a common language for the medication synchronization process in community pharmacies. METHODS: A systematic and iterative process was used to create and refine a common language for medication synchronization. First, a review of all available medication synchronization-related documents was completed. Second, a systematic scoping literature review was conducted to determine what core components of medication synchronization have been implemented by community pharmacies. Third, semistructured interviews were conducted with community pharmacists and key stakeholders to identify principles and successful practices. Findings from the document review, systematic scoping review, and semistructured interviews were integrated to develop a medication synchronization common language. Finally, researchers and key stakeholders refined the initial draft by means of a systematic process. RESULTS: This process generated a medication synchronization common language that includes common language for the philosophy and values of medication synchronization. This profile also includes descriptions of core components with activities to be conducted for each of the identified 5 core components. The 5 core components are: 1) identification and enrollment of patients; 2) completion of a medication review and patient assessment; 3) alignment of medication refills; 4) preparation for medication delivery; and 5) delivery of medication and other services. CONCLUSION: The development of a common language for medication synchronization will allow for the promotion of consistency in implementation and operation of these programs across community pharmacies. Consistency in implementation will allow for better interpretation of patient outcomes such as adherence and other clinical measures. PMID- 29980448 TI - Giant Extrarenal Retroperitoneal Angiomyolipoma: A Rare Case of a Large Size Tumor. PMID- 29980449 TI - Prognostic Impact of Preoperative Albumin-Globulin Ratio on Oncologic Outcomes in Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy. AB - PURPOSE: To identify the impact of albumin-globulin ratio (AGR) on pathologic and survival outcomes in patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). PATIENTS AND METHODS: We retrospectively reviewed medical records of 620 patients treated with RNU for UTUC at our institution. Logistic regression analysis was used to evaluate the relation between low AGR (<1.45) and adverse pathologic features. Kaplan-Meier curves were used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) probabilities between 2 groups. Univariable and multivariable Cox regression models were performed to address prognostic factors related to RFS, CSS, and OS. RESULTS: Of the 620 patients, 323 (52.1%) had AGR < 1.45. During a median follow-up of 50.0 months (interquartile range, 28-78 months), 277 (44.7%) experienced disease recurrence and 194 (31.3%) died of disease. The results showed that low AGR was significantly associated with adverse pathologic features (all P < .05). Kaplan-Meier analysis showed that compared to those with high AGR (>=1.45), patients with low AGR had poorer RFS, CSS, and OS (P < .001). After adjusting for the confounding clinicopathologic factors, multivariate analyses showed that AGR < 1.45 independently predicted poor RFS (hazard ratio [HR] = 1.321, P = .029), CSS (HR = 1.503, P = .010) and OS (HR = 1.403, P = .015). CONCLUSION: Low preoperative AGR is an independent predictor of worse pathologic and oncologic outcomes in patients with UTUC after RNU. The application of AGR as an easily assessed blood-based biomarker in predicting the prognosis of patients with UTUC is promising. PMID- 29980450 TI - Postoperative chest ultrasound findings and effectiveness after thoracic surgery: A pilot study. AB - The aim of this study was to analyze the information from post-operative chest ultrasound (CU) to evaluate the possibility to use this method instead of chest X ray (CXR) after thoracic surgery. Patients who underwent thoracic surgery were evaluated with CU blinded to CXR after surgery, deciding if it was useful or CU was exhaustive. Twenty-four patients were enrolled prospectively. The CU allowed a further discrimination of the lung abnormalities, discriminating between atelectasis, infections or hematoma. CXR was required in only 5 cases due to the presence of massive subcutaneous emphysema or absence of lung point. In the remaining 19 cases, CU was considered exhaustive and effective. In particular, CU was considered exhaustive in 67% of cases after open surgery and in 85% of cases after video-assisted thoracic surgery. In conclusion, CU appears to be effective in post-operative management after thoracic surgery and it can increase the diagnostic accuracy reducing any unnecessary X-ray exposure. PMID- 29980451 TI - Application of ARFI-SWV in Stiffness Measurement of the Abdominal Wall Musculature: A Pilot Feasibility Study. AB - The purpose of this study was to assess the feasibility of acoustic radiation force impulse shear wave velocity and textural features for characterizing abdominal wall musculature and to identify subject-related and technique-related factors that can potentially affect measurements. Median shear wave velocity measurements for the right external abdominal oblique were the same (1.89 +/- 0.16 m/s) for both the active group (healthy volunteers with active lifestyles) and the control group (age and body mass index-matched volunteers from an ongoing hernia study). When corrected for thickness, the ratio of right external abdominal oblique shear wave velocity -to-muscle thickness was significantly higher in the control group than in the active volunteers (4.33 s-1 versus 2.88 s 1; p value 0.006). From the textural features studied for right external abdominal oblique, 8 features were found to be statistically different between the active and control groups. In conclusion, shear wave velocity is a feasible and reliable technique to evaluate the stiffness of the abdominal wall musculature. Sonographic texture features add additional characterization of abdominal wall musculature. PMID- 29980452 TI - Usefulness of Left Ventricular Vortex Flow Analysis for Predicting Clinical Outcomes in Patients with Chronic Heart Failure: A Quantitative Vorticity Imaging Study Using Contrast Echocardiography. AB - The goal of the study described here was to evaluate whether left ventricular vortex flow parameters, as assessed by contrast echocardiography, enhance prediction of major adverse cardiac events (MACE) in patients with chronic heart failure and systolic dysfunction. A total of 75 patients with contrast echocardiography and systolic dysfunction (ejection fraction <=45%) were prospectively enrolled and underwent vortex flow analysis with particle image velocimetry using contrast echocardiography. Vortex flow parameters, including kinetic energy fluctuation (KEF), were evaluated. Patients were followed up for a primary endpoint of MACE that comprised hospital admission for cardiovascular causes and cardiac deaths. Across a median 277-d follow-up, 29 patients (38.7%) experienced MACE. Among these, the incidence of diabetes and the E/e' ratio were significantly higher in patients with MACE than in those without, whereas the hemoglobin level and ejection fraction were significantly lower. KEF was significantly lower in patients with MACE. In the multivariate analysis, higher KEF was associated with a lower risk of MACE (hazard ratio = 0.18, 95% confidence interval: 0.04-0.97, p = 0.046). The addition of KEF to a model with conventional parameters (e.g., age, diabetes, ejection fraction and the E/e' ratio) significantly improved the model's discrimination. Elevations in the quantitative left ventricular vortex flow parameter, KEF, as determined by contrast echocardiography, are associated with a lower risk of MACE and improved functional status among patients with chronic heart failure. PMID- 29980453 TI - Adherence to Treatment Guidelines in Heart Failure Patients in the Top End Region of Northern Territory. AB - BACKGROUND: Heart failure (HF) is associated with significant morbidity and mortality and recurrent hospitalisations, particularly in the Indigenous Australians of the Northern Territory. In remote Northern Australia, the epidemiology is less clear but anecdotal evidence suggests it may be worse. In addition, some anecdotal evidence suggests that prognostic pharmacological therapy could also be underutilised. Minimal HF data exists in the remote and Indigenous settings, making this study unique. METHODS: A retrospective cohort review of pharmacological management of 99 patients from 1 January 2014 to 31 December 2014 was performed. RESULTS: Ninety-nine patients were identified. 59.6% were non-Indigenous vs 40.4% Indigenous. The majority was male (69.7%). Indigenous patients were younger; median age was 51.4 (43.4-60.6) vs 70.5 (62.2 77.0), p<0.001. Major causes of HF were coronary artery disease (61%) and dilated cardiomyopathy (27%). Associated comorbidities included hypertension (52%), dyslipidaemia (38%), diabetes mellitus (40%) and atrial fibrillation (25%). The use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) and beta-blocker was 68% and 87%, respectively. Forty-one patients not on an ACEI/ARB and/or beta-blocker were identified. Seventeen of those patients (42%) did not receive an ACEI/ARB because of renal failure. Four patients (10%) did not take a beta-blocker due to hypotension. Fourteen patients (34%) were not prescribed an ACEI/ARB and/or beta-blocker had no identifiable contraindications. CONCLUSIONS: Indigenous patients are over-represented at a younger age demonstrating the alarming rate of disease burden in NT's young Indigenous population. Generally, ACEI/ARBs were underutilised compared to beta-blockers with renal impairment being the primary contraindication. There is a need to develop processes to further improve the use of heart failure medications and setting up a HF database could be the first step in progress. PMID- 29980454 TI - Prevalence and characteristics of metabolic syndrome in gout patients in a hospital setting in sub-Saharan Africa. AB - BACKGROUND: Evidence from epidemiological studies suggests an important association between gout and the metabolic syndrome (MetS). However, to the best of our knowledge, prevalence of metabolic syndrome in gout has not been reported in sub-Saharan African (SSA) settings. OBJECTIVES: The aim of this study was to determine the prevalence and characteristics of MetS in gout in a SSA population. METHOD: After prior ethical clearance, we carried out a cross-sectional study involving gout patients in a referral hospital in Douala-Cameroon. Metabolic syndrome was defined using International Diabetes Foundation criteria. Associations between variables were assessed using logistic regression.p < 0.05 was considered significant. RESULTS: On 174 gout patients (48.3% females) who consented to participate in the study, the median (IQR) age was 55.00 (14.25) years, and the median (IQR) duration of gout was 7.5 (10.0) years. Prevalence of metabolic syndrome was 54.6% (95% CI: 47.9%-62.8%). One hundred and forty-seven (84.5%) participants had central obesity, 62 (35.6%) raised triglycerides, 79 (45.4%) reduced HDL-C, 129 (74.1%) raised blood pressure, and 85 (48.9%) had raised fasting plasma glucose. On logistic regression analyses, gout patients with metabolic syndrome significantly had a higher body mass index (OR: 1.09, 95% CI: 1.02-1.17), and higher levels of serum uric acid (OR: 1.02, 95% CI: 1.01 1.04). CONCLUSIONS: About 1 out of every 2 gout patients in this population have metabolic syndrome. These gout patients with metabolic syndrome significantly have a higher body mass index, and higher levels of serum uric acid. Cohort studies are required to clearly establish the direction of the relationship between gout and metabolic syndrome. PMID- 29980455 TI - Comparative study of phrenic and partial ulnar nerve transfers for elbow flexion after upper brachial plexus avulsion: A retrospective clinical analysis. AB - The widely used nerve transfer sources for elbow flexion in patients with upper brachial plexus avulsion (UBPA) include partial ulnar nerve, phrenic nerve, and intercostal nerves. A retrospective review of 21 patients treated with phrenic and partial ulnar nerve transfers for elbow flexion after UBPA was carried out. In the phrenic nerve transfer group, the phrenic nerve was transferred to the anterolateral bundle of the anterior division of the upper trunk; in the partial ulnar nerve transfer group, one fascicle of the ulnar nerve was transferred to the biceps branch. The British Medical Research Council (MRC) grading system, angle of elbow flexion, electromyography (EMG), and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scoring were used to evaluate the recovery of elbow flexion at least 3 years postoperatively. The efficiency of motor function in phrenic nerve transfer group was 82%, whereas it was 80% in partial ulnar nerve transfer group. The outstanding rates of angle of elbow flexion were 64% and 70% in phrenic and partial ulnar nerve transfer groups, respectively. The DASH scores after surgery were significantly lower than those before surgery in the two groups. There was no statistical difference between the two groups in the changes of DASH scores before and after surgery. Both of phrenic and partial ulnar nerve transfers had good prognosis for elbow flexion in patients with UBPA. PMID- 29980456 TI - Risk factors for developing capsular contracture in women after breast implant surgery: A systematic review of the literature. AB - BACKGROUND: Capsular contracture is the most frequent complication in breast augmentation or reconstruction with breast implants. The exact mechanism for this complication is not completely understood. Yet, it is most likely to be a multifactorial condition. Several patient-, surgery-, and implant-specific risk factors have been related to cause capsular contracture. This review aims to provide a clear overview of all risk factors for capsular contracture. METHODS: A systematic literature review was performed focusing on patient-, surgery-, and/or implant-related factors related to capsular contracture in breast implants. PubMed, Embase, and Wiley/Cochrane Library databases were searched for relevant articles published from inception up to October 20, 2016. The included studies were assessed for the following main variables: study characteristics, patient characteristics, indication for surgery, type of surgery, implant characteristics, and other characteristics. RESULTS: Data on the risk factors for the development of capsular contracture were retrieved from 40 studies. A presumptive increased risk in the development of capsular contracture is shown for the following variables: longer duration of follow-up, breast reconstructive surgery in patients with a history of breast cancer, subglandular implant placement, postoperative hematoma, and a textured implant surface. There is little, weak, or no evidence for the association of other factors with capsular contracture. This review also shows a large heterogeneity between studies and within the definition of capsular contracture. CONCLUSION: This review provides an overview of the relationship between patient-, surgery-, and implant-specific risk factors in the development of capsular contracture. PMID- 29980457 TI - Incidence of heparin-induced thrombocytopenia in lower-extremity free flap reconstruction correlates with the overall surgical population. AB - BACKGROUND: Lower-extremity free flap reconstruction is a growing trend in the management of lower extremity wounds. Heparin-induced thrombocytopenia (HIT) is a significant risk to free flap reconstruction. The purpose of this study was to investigate the incidence of HIT in patients receiving lower-extremity free flap surgery. METHODS: We conducted a retrospective, single center, IRB approved cohort study in which we reviewed all patients who received lower-extremity free flap surgeries between 2011 and 2016. The 4T and HIT Expert Probability (HEP) scores were calculated to assess the likelihood of HIT. RESULTS: One hundred patient charts revealed three patients with HIT. One patient was excluded due to a prior diagnosis of HIT. HIT incidence in patients receiving lower-extremity free flaps was between 1% and 3%, which is consistent with the national average. 4T scores indicated that two of three HIT-positive patients had a high probability of HIT (approximately 64%), and one of three HIT-positive patients had an intermediate probability (approximately 14%). HEP scoring indicated that all the three (100%) patients had HIT. CONCLUSIONS: These data suggest that the incidence of HIT in patients receiving lower-extremity free flaps correlates with the incidence of HIT nationally. The use of available scoring methods and other algorithms, combined with patient history helps to assess the immediate perioperative risks of HIT in the absence of rapid immunologic confirmatory tests. This knowledge can allow for successful free flap salvage or for performance of free flaps in patients with a history of HIT. PMID- 29980458 TI - Letter to the editor: Evaluation of anatomical and round breast implant aesthetics and preferences in Dutch young lay and plastic surgeon cohort. PMID- 29980459 TI - Reference equations for the 6-minute walk distance in healthy Portuguese subjects 18-70 years old. AB - INTRODUCTION: Six-minute walk test (6MWT) is used for evaluating functional exercise capacity. To the best of our knowledge, there are no reference equations to predict six-minute walk distance (6MWD) for the Portuguese population. The aims of the present study were to measure anthropometric data and 6MWD in a sample of healthy Portuguese population, to establish reference equations to predict 6MWD and to compare our equations with those obtained by previously published studies. METHODS: We conducted an observational prospective study. We consecutively recruited 158 healthy 18-70 years old subjects from Porto district, who performed two 6MWTs using a standardized protocol. The best 6MWD was used for further analysis. RESULTS: The mean 6MWD was 627.8m (SD=73.3m). The variables that were significantly associated with the 6MWD were age, sex, BMI and DeltaHR (Heart Rateat the end of the test-HRat rest). We found three explanatory models for 6MWD, the best with an explanatory power of 38%: 6MWD=721.7-1.6*Age 4.0*BMI+0.9*DeltaHR+58.4*Sex. We verified that 6MWD decreased 1.6m per year of age, and 4.0m per unit of BMI and increased 0.892m per beat per minute. Moreover, on average, males walk 58.4m more than females (p<0.001). Applying equations from other studies to our population resulted in an overestimation or underestimation of the 6MWD. CONCLUSION: The present study was the first to describe the 6MWD in healthy Portuguese people aged 18-70 years old and to propose predictive equations. These can contribute to improving the evaluation of Caucasian Mediterranean patients with diseases that affect their functional capacity. PMID- 29980460 TI - Point-of-Care Ultrasound Assessment of Bladder Fullness for Female Patients Awaiting Radiology-Performed Transabdominal Pelvic Ultrasound in a Pediatric Emergency Department: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: Radiology-performed transabdominal pelvic ultrasound, used to evaluate female patients with suspected pelvic pathology in the pediatric emergency department (ED), is often delayed by the need to fill the bladder. We seek to determine whether point-of-care ultrasound assessment of bladder fullness can predict patient readiness for transabdominal pelvic ultrasound more quickly than patient sensation of bladder fullness. METHODS: We performed a randomized controlled trial of female patients aged 8 to 18 years who required transabdominal pelvic ultrasound in a pediatric ED. Patients were randomized to usual care or point-of-care ultrasound and then assessed every 30 minutes for subjective bladder fullness (0 to 4 ordinal scale) and qualitative bladder fullness by point-of-care ultrasound. Patients were sent for pelvic ultrasound when they reported 3 or 4 on the subjective fullness scale (usual care) or a large bladder was visualized (point-of-care ultrasound). Primary outcome was time from enrollment to completion of pelvic ultrasound. Secondary outcome was success rate of pelvic ultrasound on first attempt. RESULTS: One hundred twenty patients were randomized and 117 had complete outcomes (59 usual care, 58 point-of-care ultrasound). Kaplan-Meier curves differed between groups (P<.001). Median time to successful completion of pelvic ultrasound was 139 minutes (usual care) and 87.5 minutes (point-of-care ultrasound), with difference in medians 51.5 minutes (95% confidence interval [CI] 23.4 to 77.2 minutes). All point-of-care ultrasound patients had successful transabdominal pelvic ultrasound on the first attempt compared with 84.7% in the usual care group, with difference -15.3% (95% Bayesian credible interval -5.3% to -25.0%). Weighted kappa for interrater agreement was 0.83 (95% CI 0.79 to 0.87). CONCLUSION: Point-of-care ultrasound assessment of bladder fullness decreases time to transabdominal pelvic ultrasound and improves first-attempt success rate for female patients in the pediatric ED. PMID- 29980462 TI - Emergency Department Urinary Tract Infections Caused by Extended-Spectrum beta Lactamase-Producing Enterobacteriaceae: Many Patients Have No Identifiable Risk Factor and Discordant Empiric Therapy Is Common. AB - STUDY OBJECTIVE: Community-onset urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, which are resistant to ceftriaxone and usually coresistant to fluoroquinolones, are increasing worldwide. We investigate and describe in detail UTIs caused by ESBL producing Enterobacteriaceae in our emergency department (ED), and determine the proportion that occurred in patients without health care-associated risk factors and who received discordant initial antibiotic therapy. METHODS: At an urban public hospital in Northern California, microbiology staff prospectively reviewed ED urine culture results weekly for 1 year and presumptively identified ESBL producing isolates by ceftriaxone plus ceftazidime resistance. For isolates associated with a clinical UTI, patient demographic and case clinical features were abstracted retrospectively. Health care-associated infections were defined by standard risk factors plus aged 65 years or older, bladder catheter, urologic procedure, functional dependence, or antibiotics in the previous 90 days. Community-associated infections were defined by absence of these. A subset of community-associated ESBL-producing Escherichia coli isolates underwent genotyping. Electronic health record query was used to determine the denominator of ED UTI patients who underwent urine culture during the study period. RESULTS: Between August 2016 and July 2017, there were 1,045 unique ED patients diagnosed with a UTI, whose specimens underwent culture. There were 62 ESBL-producing isolates (5.9%; 95% confidence interval [CI] 4.6% to 7.5%). Selected characteristics of the entire ESBL UTI cohort were median age 50 years, 37 (60%) patients were women, 28 (44%) Hispanic, 11 (18%) had been hospitalized in the previous 3 months, 19 (31%) had pyelonephritis, 49 (79%) of isolates were E coli, 44 (71%) were levofloxacin-resistant, and 24 (23%) nitrofurantoin-resistant. Initial antibiotic choice was discordant with isolate susceptibility in 26 of 56 cases (46%; 95% CI 33% to 60%), and the initial oral antibiotic prescred was discordant in 19 of 41 cases (46%; 95% CI 31% to 63%). Twenty-seven infections (44%; 95% CI 31% to 57%) were categorized as community-associated. Eight patients with community-associated infection were women younger than 50 years, with no comorbidities and no more than 1 UTI in the previous year. Of 12 community associated E coli isolates tested, all were confirmed to harbor ESBL genes; the CTX-M1 beta-lactamase gene was found in 8 (67%); 4 belong to genotype ST131. CONCLUSION: At this single Northern California ED, greater than 5% of culture proven UTI were caused by ESBL-producing Enterobacteriaceae, and in nearly half of cases there was no identifiable health care-associated risk factor. Levofloxacin co-resistance and discordant antibiotic therapy were common. PMID- 29980463 TI - Efficacy of video-based education program in improving metabolic surgery perception among patients with obesity and diabetes. AB - BACKGROUND: Metabolic surgery remains underutilized despite its efficacy and safety. Poor perception of surgery has been cited as one of the major reasons. OBJECTIVES: Evaluate current patient perceptions about metabolic surgery and measure the impact a video-based education program has on changing the perceptions of patients diagnosed with obesity and type 2 diabetes. SETTING: A university hospital in the United States. METHODS: A prospective interventional study was performed at an endocrinology clinic. Patients were asked to complete surveys evaluating their perception of metabolic surgery before and after watching a short educational video. RESULTS: A total of 51 patients were recruited; almost all patients (98%) attempted weight loss in the past, and approximately 90.1% voiced dissatisfaction with their current weight. The video based education program was effective in improving the patient's perception of the efficacy and safety with regard to surgery. In addition, the proportion of patients with overall positive impression toward metabolic surgery increased from 22.5% to 53.1% (P < .01) and those willing to undergo surgical consultation increased from 41.7% to 51.0% (P < .01). Among those that remained unwilling, fear of surgery in general was the most commonly voiced reason (31.4%), with safety (27.5%) and cost of metabolic surgery (27.5%) being equally concerning. CONCLUSIONS: Most patients with obesity and type 2 diabetes held negative impressions of metabolic surgery due to its perceived risk profile. A video-based educational intervention may improve patients' perception and increase their willingness for surgical referral. Future trials with a broader sample and longer follow-up could provide answers to its efficacy in increasing metabolic surgery accessibility. PMID- 29980464 TI - Resolution of metabolic syndrome and related metabolic disorders after bariatric surgery: comparison of sleeve gastrectomy and gastric bypass. AB - BACKGROUND: The effects of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) on metabolic syndrome (MS) in morbidly obese patients have not been well studied. OBJECTIVE: To compare the effectiveness of LSG and LRYGB in Chinese morbidly obese patients with MS. SETTING: University Hospital, China. METHODS: Patients who underwent LRYGB or LSG surgery and had completed at least 1 year of follow-up were retrospectively reviewed. Bariatric and metabolic outcomes in the 2 groups were compared. Univariate and multivariate analyses were performed to identify the predictors of MS remission. RESULTS: Of the 176 patients enrolled in this study, 79 underwent LSG and 97 underwent LRYGB. Eighty-three met 3 of the International Diabetes Federation criteria for diagnosis of MS, 69 met 4 of the criteria, and 24 met 5 of the criteria. At 1 year after bariatric surgery, 79% of patients achieved remission of MS. In both LSG and LRYGB groups, the number of MS criteria met by patients decreased significantly after surgery. The MS remission rate was not significantly different between the 2 groups (74.7% in LSG versus 82.5% in LGB; P = .21). In LSG patients, there was no significant decrease in blood pressure or increase in the high-density lipoprotein cholesterol at 1 year. On logistic regression analysis, younger age, lower body mass index, and lower homeostatic model of assessment-insulin resistance were independently associated with MS remission at 1 year after surgery. Both groups showed satisfactory and comparable weight loss (percentage of excess weight loss: 71.7% in LSG versus 74.4% in LRYGB). No surgery-related mortality occurred. CONCLUSIONS: Both LSG and LRYGB are feasible, safe, and effective in Chinese obese patients with MS. LSG seems to be inferior to LRYGB with regard to control of hypertension and high-density lipoprotein cholesterol. PMID- 29980465 TI - Bariatric procedures in adolescents are safe in accredited centers. AB - BACKGROUND: With the rise of obesity in adolescents, there is an exponential increase in bariatric procedures in this patient population. OBJECTIVES: The purpose of our study was to examine perioperative outcomes after bariatric surgery in this cohort. SETTING: University hospital, involving a large database in New York State. METHODS: The Metabolic and Bariatric Surgery Accreditation Quality and Improvement Program public use file was queried to identify all adolescent patients (age <19 years) undergoing primary laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) in 2015. We assessed 30-day postoperative complications. RESULTS: We identified 1072 patients who underwent Roux-en-Y gastric bypass (n = 279) or SG (n = 793). The majority were Caucasian (n = 790) and female (n = 857) with mean body mass index and age of 47.9 +/- 8.1 kg/m2 and 18.2 +/- 1 years, respectively, preoperative hypertension, type 2 diabetes, and obstructive sleep apnea were present in 90 (8.4%), 139 (13%), and 165 (15.4%) of patients, respectively. There was significant difference in preoperative gastroesophageal reflux disease (18.6% versus 13.4%, P = .033), obstructive sleep apnea (19.7% versus 13.9%, P = .02), and body mass index (48.6 +/- 7.9 versus 47.6 +/- 8.2 kg/m2, P = .03) between patients undergoing Roux-en-Y gastric bypass and SG, respectively. Thirty-day reoperation, readmission, and reintervention were reported in 1.5%, 3.3%, and 1.6% of the adolescent cohort, respectively. Four patients (.4%) developed a staple line/anastomotic leak, and 1 patient (.09%) died within 30 days; 93.9% of all adolescent patients experienced an uneventful 30-day recovery. Uneventful recovery was significantly more likely for patients undergoing SG (95.3% versus 90%, P = .001; adjusted odds ratio 2.2, 95% confidence interval 1.31-3.69). CONCLUSION: Perioperative safety of bariatric surgery in adolescents in accredited centers is safer than previously reported with low rate of 30-day events. SG is a safer procedure in this patient population. PMID- 29980466 TI - Treatment of complex Charcot foot by single stage surgery with static circular fixation. Case series report. AB - OBJECTIVE: We present a case series report of patients with Charcot foot treated by single-stage surgery with static circular fixation. MATERIAL AND METHOD: Retrospective review of 10 cases treated with static circular external fixation since 2016, with the following inclusion criteria: 1) Deformity with any of the following: ulcers, osteoporosis, osteomyelitis or instability 2) peripheral neuropathy, 3) failed orthopaedic treatment. EXCLUSION CRITERIA: 1) peripheral vascular obstruction without revascularization, 2) inability to comply with treatment, 3) non-ambulatory patients, 4) medical contraindication for surgery. Of the 10patients, 7men and 3women, 6had involvement of the left foot and 4of the right one. The average age of our patients was 58 years (range 39-71). We also evaluated Eichenholtz and Brodsky classification, presence of ulcers, osteomyelitis and instability. All were treated with circular external fixation with a medium follow up of 17 months (11-24 months). Postoperatively we evaluated limb salvation, ulcer healing, stability and re-ulcerations. RESULTS: In all patients a functional plantigrade foot was achieved, cutaneous ulcer healed without recurrence. Four cases presented superficial pin infection, solved with local wound care. We had wire ruptures in 2 cases, which did not require replacement. We had a traumatic tibial fracture after frame removal, orthopedically solved. All patients were satisfied and would opt for the same technique, if necessary. CONCLUSIONS: of the study In Charcot foot, the objectives are to avoid amputation and achieve a functional plantigrade foot, without ulcer. Single-stage surgery with static circular external fixation is reproducible in our country, and also a valid technique for those cases in which internal fixation may not be the best option. PMID- 29980467 TI - Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area. AB - BACKGROUND: Immune checkpoint inhibitors, including programmed cell death-1, programmed cell death ligand-1 and cytotoxic lymphocyte antigen-4 inhibitors, have emerged as important therapeutic alternatives for advanced malignancies. This drug class upregulates T-cell activity, leading to an immune response against cancer cells. However, the increased activity of T cells can lead to autoimmune reactions. METHODS: We conducted a systematic review of all published articles and grey literature in PubMed, Medline, and Embase on cardiac complications associated with checkpoint inhibitor use from September 1, 1996 to November 10, 2017. RESULTS: The search strategy yielded 908 unique articles. Of these, 835 were excluded on the basis of abstract and full-text review. A total of 73 studies met eligibility criteria and were included. We found a total of 99 cases of cardiotoxicity with the use of checkpoint inhibitors. Myocarditis (45%) was the most common cardiotoxicity. The overall case fatality rate was 35%. This was notably higher in patients with myocarditis, complete heart block, or conduction abnormalities, and ventricular arrhythmias. There was no difference in outcomes for patients treated with or without steroids. Immunosuppressive therapies such as infliximab, mycophenolate, intravenous immunoglobulin, antithymocyte globulin, and/or plasmapheresis were used in 12 patients leading to survival in 9 of these patients (75%). CONCLUSIONS: Immune checkpoint inhibitors are associated with cardiotoxicity. Because of the high case fatality rate, close surveillance and prompt empiric therapy for cardiovascular complications of checkpoint inhibitors should be considered. Aggressive treatment with immunosuppressive agents and/or plasmapheresis might lead to clinical improvement and increased survival. PMID- 29980468 TI - Variability in Non-Vitamin K Antagonist Oral Anticoagulants Dose Adjustment in Atrial Fibrillation Patients With Renal Dysfunction: The Influence of Renal Function Estimation Formulae. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) require renal dose adjustment. The most common estimates of renal function in clinical practice are derived from estimated glomerular filtration rate (eGFR; Modified Diet in Renal Disease [MDRD] or the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). However, the landmark stroke prevention trials and product monographs recommend the use of the Cockcroft-Gault creatinine clearance equation (eCrCl) for drug eligibility and dose adjustment. We sought to evaluate the agreement in NOAC dosing between these 3 equations in a large population of patients with atrial fibrillation and moderate chronic kidney disease. METHODS: We identified 831 patients with non-dialysis-dependent chronic kidney disease and atrial fibrillation (CHA2DS2-VASc 3.9). For each patient, eCrCl, MDRD eGFR, and CKD-EPI eGFR were prospectively calculated. Eligibility criteria for NOAC medications were evaluated by comparing the eGFR as estimated by MDRD or CKD-EPI equation with the eCrCl as estimated by Cockcroft-Gault, with the latter regarded as the "gold standard." RESULTS: The use of eGFR resulted in significant misclassification with respect to NOAC dosing. Compared with eCrCl, the MDRD eGFR and CKD-EPI eGFR misclassified 36.2% and 35.8% of patients, respectively. The misclassification resulted in undertreatment (eg, inappropriate dose reduction; 26.9% MDRD, 28.8% CKD-EPI), and to a lesser extent overtreatment (eg, inappropriate use of standard dose; 9.3% MDRD, 7.0% CKD-EPI). CONCLUSIONS: MDRD and CKD-EPI eGFR fail to correctly identify a significant proportion of patients who require NOAC dose adjustment, limiting their clinical utility. Cockcroft Gault eCrCl should be calculated for all patients in whom a NOAC is being prescribed. PMID- 29980469 TI - Sudden Onset of Platypnea-Orthodeoxia Syndrome Caused by Traumatic Tricuspid Regurgitation With Ruptured Chordae Tendineae After Blunt Chest Trauma. AB - An 86-year-old man was admitted our hospital because of sudden onset of dyspnea after blunt chest trauma. Because his oxygen saturation deteriorated from 92% in the supine position to 86% in the sitting position, platypnea-orthodeoxia syndrome was suspected. Transesophageal echocardiography showed severe tricuspid regurgitation (TR) caused by anterior papillary muscle rupture. Furthermore, right-to-left shunt with TR through a patent foramen ovale (PFO) was observed. The diagnosis was therefore platypnea-orthodeoxia syndrome with right-to-left shunt through PFO with shunting exacerbated by acute severe TR after blunt chest trauma. The patient underwent urgent tricuspid valve repair and PFO closure and has remained asymptomatic postoperatively. PMID- 29980470 TI - Physicians' Attitudes Towards Anticoagulation for Prevention and Treatment of Left Ventricular Thrombus Following Anterior Myocardial Infarction. PMID- 29980471 TI - CD46 activation induces distinct CXCL-10 response in monocytes and monocyte derived dendritic cells. AB - CD46 is an important immune regulatory receptor with dual functions, however, the CD46 isoform distribution and the effect of CD46 activation on the cytokine production in monocytes and monocyte-derived dendritic cells (moDCs) is unclear. Here, we show that CD46 activation of moDCs downregulates LPS-induced CXCL-10 expression, while the expression of CXCL-10 in monocytes is unaffected. Furthermore, the differentiation of moDCs induces a switch towards dominance of CYT-2 isoforms of CD46. These data indicate that CD46 activation exerts different functions in monocytes and moDCs and this correlates with a switch in CD46 isoform expression upon differentiation of moDCs. PMID- 29980461 TI - The Social Media Index as an Indicator of Quality for Emergency Medicine Blogs: A METRIQ Study. AB - STUDY OBJECTIVE: Online educational resources such as blogs are increasingly used for education by emergency medicine clinicians. The Social Media Index was developed to quantify their relative impact. The Medical Education Translational Resources: Indicators of Quality (METRIQ) study was conducted in part to determine the association between the Social Media Index score and quality as measured by gestalt and previously derived quality instruments. METHODS: Ten blogs were randomly selected from a list of emergency medicine and critical care Web sites. The 2 most recent clinically oriented blog posts published on these blogs were evaluated with gestalt, the Academic Life in Emergency Medicine Approved Instructional Resources (ALiEM AIR) score, and the METRIQ-8 score. Volunteer raters (including medical students, emergency medicine residents, and emergency medicine attending physicians) were identified with a multimodal recruitment methodology. The Social Media Index was calculated in February 2016, November 2016, April 2017, and December 2017. Pearson's correlations were calculated between the Social Media Index and the average rater gestalt, ALiEM AIR score, and METRIQ-8 score. RESULTS: A total of 309 of 330 raters completed all ratings (93.6%). The Social Media Index correlated moderately to strongly with the mean rater gestalt ratings (range 0.69 to 0.76) and moderately with the mean rater ALiEM AIR score (range 0.55 to 0.61) and METRIQ-8 score (range 0.53 to 0.57) during the month of the blog post's selection and for 2 years after. CONCLUSION: The Social Media Index's correlation with multiple quality evaluation instruments over time supports the hypothesis that it is associated with overall Web site quality. It can play a role in guiding individuals to high-quality resources that can be reviewed with critical appraisal techniques. PMID- 29980472 TI - Genetic diagnosis of CADASIL in three Hong Kong Chinese patients: A novel mutation within the intracellular domain of NOTCH3. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an adult onset hereditary stroke syndrome characterized by recurrent stroke and progressive cognitive impairment caused by NOTCH3 mutations. We report here the clinical and molecular findings of three unrelated Hong Kong Chinese families with CADASIL syndrome. Sanger sequencing of genomic DNA revealed a novel heterozygous variant NM_000435.2(NOTCH3):c.[5903_5904insATAA];[5903_5904=] NP_000426.2:p.(Asp1969*);(Asp1969=) and two previously reported heterozygous mutations NM_000435.2(NOTCH3):c.[328C>T];[328C=] NP_000426.2:p.[(Arg110Cys)];[(Arg110=)] and NM_000435.2(NOTCH3):c.[580T>A];[580T=] NP_000426.2:p.(Cys194Ser);(Cys194=) in the three families respectively. Molecular basis of CADASIL in these three patients were further established. Genetic analysis provides a reliable method for confirming the diagnosis of CADASIL and enables proper genetic counseling and cascade testing. PMID- 29980473 TI - Novel approach to the treatment of a cerebral abscess using the Apollo vibration/suction device. AB - BACKGROUND AND IMPORTANCE: Intracerebral abscess is a very serious condition associated with significant morbidity and mortality. This article describes a novel treatment for a cerebral abscess, using the Penumbra Apollo suction/vibration aspiration system (Penumbra, Almeda, CA, USA). This article represents the first reported case of the device's use for treatment of an intracerebral abscess. CLINICAL PRESENTATION: The patient discussed presented to the emergency department in critical condition, and was found to be suffering from a right thalamic cerebral abscess. She underwent treatment with both medical management and surgical intervention with the use of the Apollo system. CONCLUSION: This report details a novel technique for surgical abscess drainage with an excellent clinical outcome. The aim is to provide insight into the treatment of intracerebral abscesses, the utility of the Apollo system, and the device's application beyond intracerebral and intraventricular hemorrhage. PMID- 29980474 TI - Direct head injury caused by a tear gas cartridge. Questions on safety: A case report from Iraq and review of the literature. AB - INTRODUCTION AND BACKGROUND: Primary injuries from tear gas weapons include injuries to the visual and respiratory systems and skin. However, few studies have reported direct mechanical brain injuries from tear gas weapons. CASE REPORT: A 27-year-old male presented to the emergency department of a neurosurgery teaching hospital in Baghdad, Iraq, with a penetrating head injury of unknown source. DISCUSSION: Tear gas weapons are considered safe, but tear gas exposure causes severe complications. Traumatic brain injuries as a direct effect of tear gas bombs are rarely reported in the literature. Tear gas cartridge injuries should be managed in the same manner as any penetrating brain injury, with appropriate neuromonitoring. This monitoring is crucial for the detection and prevention of secondary brain insults. CONCLUSION: Emergency medicine specialists and neurosurgeons should be aware that tear gas weapons are not always safe, and they should anticipate chemical, thermal and mechanical side effects of tear gas weapons. The literature and our results suggest that these weapons should not be considered civil and harmless. PMID- 29980475 TI - Impact of resident participation on outcomes following lumbar fusion: An analysis of 5655 patients from the ACS-NSQIP database. AB - The role of resident involvement on patient safety, morbidity, and mortality in lumbar spinal surgery has been poorly defined in the literature. The objective of this study is to investigate the relationship between resident involvement in the operating room and 30-day complication rates in patients undergoing lumbar spinal fusion procedures. We used the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to retrospectively identify all patients who underwent a lumbar spinal fusion from 2006 to 2013. A propensity score matching algorithm was employed to minimize baseline differences. Multivariate logistic regression analysis of unadjusted and propensity-matched groups was performed to examine the effect of resident participation on operative details and 30-day complication rates. A total of 5655 patients met the inclusion criteria and propensity score matching yielded 1965 well-matched pairs. Resident involvement in lumbar fusion procedures was not found to be a significant predictor for mortality or reoperation. It was found to be a significant predictor for increased hospital stay (matched non-resident 4.0 +/- 5.8 days vs. resident 4.6 +/- 4.3 days, p < 0.001), operative time (matched non-resident 198 +/- 102 min vs. resident 243 +/- 118 min, p < 0.001), sepsis (matched OR 4.36, 95% CI 2.10-9.05, p < 0.001), development of DVT/PE (matched OR 2.02, 95% CI 1.10 3.70, p = 0.023), and superficial surgical site infections (matched OR 1.78, 95% CI 1.04-3.06, p = 0.037). In conclusion, this large-scale, population-based study found that resident participation in the operating room was safe but increased the risk of 30-day complications and increased operative duration and length of hospital stay. PMID- 29980476 TI - Metastatic prostate cancer mimicking a subdural hematoma: A case report and literature review. AB - Occurrences of metastatic prostate cancer imitating a subdural hematoma are limited to a small number of case reports, even though prostate cancer spreads to the dura more than other types of cancer. Here, we present the case of a 64 year old male whose prostate carcinoma's metastasis mimicked a subdural hematoma, and he suffered a middle cerebral artery stroke. Prostate cancer's high rate of progression to the dura is disproportionate to its relatively low rate of brain metastasis. Furthermore, we explore the potential molecular implications of prostate cancer's propensity to spread to the dura. PMID- 29980477 TI - Invited Perspective on "Unsolicited Patient Complaints Identify Physicians with Evidence of Neurocognitive Disorders". PMID- 29980478 TI - An overview of Human Papillomavirus (HPV) as an etiological factor of the anal cancer. AB - Human papillomavirus (HPV) is a DNA tumour virus that is the primary cause of sexually transmitted infections (STIs). The direct connection between HPV and cervical cancer was discovered in 1980, however, many physicians and the general public are still oblivious to the association of HPV and anal cancer; most individuals find out about this relationship after a confirmed diagnosis, and therefore, it is important to raise awareness about HPV as an etiological agent in anal cancer. There is a quadrivalent vaccine available, which prevents an individual from being infected with HPV, thus anal cancer is mainly a preventable cancer when caused by HPV, and ultimately, preventing cancer is better than curing cancer, especially when there is no definite cure.This article aims to review the microbiology, pathophysiology, epidemiology, clinical presentation, diagnostic evaluation, prophylaxis and treatment options for HPV as an etiology agent in anal cancers in light of recent literature. PMID- 29980479 TI - Exercise Training as Therapy for Cancer-Induced Cardiac Cachexia. AB - Cancer-induced cardiac cachexia is an insidious syndrome with a dramatic impact on a patient's quality of life and survival. Since exercise training provides several cardiovascular benefits in both physiological and pathological conditions (e.g., athletes and patients with heart failure, respectively), its use as a preventive and/or therapeutic tool for cancer-induced cardiac cachexia has been hypothesized. Existing evidence on the effects of exercise training in this particular setting is limited, but points towards a beneficial outcome. We report the current knowledge on cancer-induced cardiac cachexia and discuss the molecular pathways that may be modulated by exercise training in this setting, providing insights into possible future roads of study, namely in stem cell research and cardiac regeneration. PMID- 29980480 TI - Katalin Susztak. PMID- 29980481 TI - Are the Kihon Checklist and the Kaigo-Yobo Checklist Compatible With the Frailty Index? AB - OBJECTIVES: To explore comparability of Kihon Checklist (KCL) and Kaigo-Yobo Checklist (KYCL) to Frailty Index (FI) in predicting risks of long-term care insurance (LTCI) certification and/or mortality over 3 years. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 1023 Japanese community-dwelling older adults from the Kusatsu Longitudinal Study of Aging and Health. MEASURES: Frailty status was quantified at baseline using KCL, KYCL, and 32-deficit and 68-deficit FI. Relationships of the measures were examined using Spearman rank correlation coefficients. Cox regression models examined the risk of new certification of LTCI or mortality according to KCL, KYCL, and FI. Predictive abilities of KCL and KYCL were compared with FI using area under the receiver operating characteristic curve (AUC), C statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Mean age was 74.7 years and 57.6% were women. KCL and KYCL were significantly correlated to 32-FI (r = 0.60 and 0.36, respectively) and to 68-FI (r = 0.88 and 0.61, respectively). During the follow up period, 92 participants (9%) were newly certified for LTCI or died. Fully adjusted Cox models showed that higher KCL, KYCL, 32-FI, and 68-FI were all significantly associated with elevated risks [hazard ratio (HR) = 1.03, 95% CI = 1.01-1.04, P < .001; HR = 1.04, 95% CI = 1.02-1.05, P < .001; HR = 1.03, 95% CI = 1.01-1.05, P = .001; HR = 1.04, 95% CI = 1.02-1.06, P < .001, respectively, per 1/100 increase of max score]. AUC and C-statistics of KCL and KYCL were not different statistically from those of 32-FI and 68-FI. Predictive abilities of KCL were superior to 32-FI in NRI and IDI but inferior to 68-FI in category-free NRI, and those of KYCL were superior to 32-FI in IDI but inferior to 68-FI in NRI. CONCLUSIONS: Although KCL and KYCL include smaller numbers of items than standard FI, both tools were shown to be highly correlated with FI, significant predictors of LTCI certification and/or mortality, and compatible to FI in the risk prediction. PMID- 29980482 TI - From enforcement to advocacy - Developing a Foucauldian perspective of pharmacists' reflections on interactions with complex patients. AB - BACKGROUND: Pharmacists are extending their engagement in health care beyond the supply and monitoring of medicines. Extended roles for pharmacists propose participation in health promotion, disease monitoring and other health surveillance activities, involving them more closely in the lives of patients. OBJECTIVES: To explore pharmacists' written reflections on patient-centred practice after interactions with people who experience complexity and difficulties to participate in their health care, using a Foucauldian approach. METHODS: For this qualitative study, pharmacists enrolled in a postgraduate program first watched a video introducing them to the concept of complexity and conflicting patient priorities in health care. They then interacted with patients and reflected on these encounters, their understanding and practice of patient centeredness. The reflective texts were thematically analysed, using the constant comparison method. Foucault's method of problematisation was used to construct and interpret themes. RESULTS: Sixty-six pharmacists provided reflective accounts of their patient interaction. Main themes showed how pharmacists emphasised adherence to prescribed medicines, disease monitoring and other desirable health behaviours over tailoring advice to patients' priorities. The Foucauldian analysis elucidated how they prioritised supporting individual patient responsibility over addressing complexity in medication regimens and prescribed health care, risking normalisation of an enforcing role. Pharmacists acknowledged a discrepancy in their patient-centred practice when taking responsibility for patients' medication taking behaviour while encouraging the adoption of certain disciplines to achieve compliance. When pharmacists respected patients' agency and tailored advice and professional support to the needs, wishes and capacities of patients, they developed opportunities for advocacy via increased patient centeredness. CONCLUSION: Pharmacists' discursive practices as described in their reflections raise questions of how they employ their sociological and professional roles in negotiating the relatively best outcomes for patients. Pharmacists increasing their awareness of how they conduct themselves may enhance their patient-centeredness when extending participation in disease monitoring and surveillance. PMID- 29980483 TI - Health care utilization among children with chronic conditions in military families. AB - BACKGROUND: Studies have examined utilization of health care services by civilian children with chronic conditions but not utilization among child dependents of military personnel. OBJECTIVE: To identify children with chronic conditions among military members and retirees and examine their health care utilization and its association with type of condition. METHODS: We derived our sample from child dependents ages birth to 18 years of military personnel with health care enrollment in FY2011. We defined chronic conditions based on diagnoses and repeated specialty care visits. We accrued one year of health care utilization for each child starting with the date of first diagnosis that qualified (i.e., 2 + visits). Health care utilization measures were any inpatient stay; number of outpatient visits (excluding emergency department [ED] visits), ED visits, and number of psychotropic and non-psychotropic prescriptions. RESULTS: Conditions with the highest prevalence were ADHD/conduct disorders (41.2%), other behavioral health (BH) disorders (30.4%), asthma (25.3%) and arthritis (23.8%). Boys and children ages 6-18 were more likely to have BH conditions. Twelve percent had inpatient stays, 63% used the ED, and mean ED visits was 4.6. The mean outpatient visits was 27.9. Utilization was consistently higher for children with both BH and physical health (PH) conditions, children under age 5 (except for number of psychotropic prescriptions), and those enrolled in the military's Extended Health Care Options (ECHO) program. CONCLUSIONS: Prevalence and utilization findings provide data for future service planning and highlight subgroups of children with chronic conditions who may need better access to supportive military programs. PMID- 29980484 TI - FGF21 regulates insulin sensitivity following long-term chronic stress. AB - OBJECTIVE: Post-traumatic stress disorder (PTSD) increases type 2 diabetes risk, yet the underlying mechanisms are unclear. We investigated how early-life exposure to chronic stress affects long-term insulin sensitivity. METHODS: C57Bl/6J mice were exposed to chronic variable stress for 15 days (Cvs) and then recovered for three months without stress (Cvs3m). RESULTS: Cvs mice showed markedly increased plasma corticosterone and hepatic insulin resistance. Cvs3m mice exhibited improved whole-body insulin sensitivity along with enhanced adipose glucose uptake and skeletal muscle mitochondrial function and fatty acid oxidation. Plasma FGF21 levels were substantially increased and associated with expression of genes involved in fatty acid oxidation and formation of brown-like adipocytes. In humans, serum FGF21 levels were associated with stress coping long time after the exposure. CONCLUSIONS: Early-life exposure to chronic stress leads to long term improvements in insulin sensitivity, oxidative metabolism and adipose tissue remodeling. FGF21 contributes to a physiological memory mechanism to maintain metabolic homeostasis. PMID- 29980485 TI - Erector spinae plane block for bilateral lumbar transverse process fracture in emergency department: A new indication. AB - Plane blocks have become very popular in recent years with the introduction of ultrasonography into the regional anesthesia and algology practice. Ultrasound guided erector spinae plane (ESP) block was first described in 2016. ESP block involves injection of local anesthetics between erector spinae muscles and transverse process of thoracic or lumbar vertebrae and can block the dorsal and ventral rami of thoracolumbar spinal nerves. ESP block has been successfully reported to relieve the pain of multiple rib fracture in the emergency department (ED). Here we first report a novel indication for ESP block in ED; transverse process fracture of lumbar vertebra. PMID- 29980486 TI - Spontaneous pneumocephalus and subdural hemorrhage after sneezing. AB - Spontaneous pneumocephalus is defined as the presence of air in the absence of intracranial factors. The management of spontaneous pneumocephalus can be conservative or surgical, and surgical intervention could be urgently required if clinical deterioration is rapid. Here, we report a case of pneumocephalus and subdural hemorrhage after sneezing. A 24-year-old male reported to our emergency department with a chief complaint of headache and dizziness. The patient gave a history of onset of headache and dizziness after 2 episodes of heavy sneezing. There was neither a history of recent traumatic episode or previous surgery, nor any signs and symptoms of recent fever or upper respiratory tract infections. Physical examination showed no specific findings. Computed tomography was performed, which showed subdural hemorrhage and PNC in the left occipital lobe, left hemomastoid, and maxillary hemosinus. A neurosurgeon was consulted, who suggested admission in the intensive care unit. An otolaryngologist was then consulted for the left ear otorrhea and hearing impairment. Otoscopic examination showed hemotympanum of the left ear, for which pain control and conservative treatment was suggested. The patient was transferred to general ward 4 days later, since the following brain computed tomography showed resolution of the hemorrhage, and discharged 6 days later because of the improved signs and symptoms. Pneumocephalus and intracranial hemorrhage can occur without a history of trauma or surgery. Special attention is required if headache, dizziness, or other neurologic signs and symptoms occur immediately after sneezing. Intracranial hemorrhage and penumocephalus should be considered in the differential diagnosis. PMID- 29980487 TI - Non-surgical management in hemodynamically unstable blunt traumatic pericardial effusion: A feasible option for treatment. AB - INTRODUCTION: Little is known about the outcomes of deliberate non-surgical management for hemodynamically unstable patients with blunt traumatic pericardial effusion. We evaluated the efficacy of management with pericardiocentesis or subxiphoid pericardial window in hemodynamically unstable patients who reach the hospital alive with blunt traumatic pericardial effusion. METHODS: We conducted a review of a consecutive series of patients with pericardial effusion following blunt trauma who arrived at Fukui Prefectural Hospital between January 1, 2009 and December 31, 2017. All patients with traumatic pericardial effusion were included, irrespective of the type of blunt trauma. RESULTS: Eleven patients were identified arrived to the Emergency Department with a pericardial effusion after blunt trauma. Of the eleven patients, five patients had cardiopulmonary arrest on arrival and none survived. Of the other six patients who reached the hospital alive, five were hemodynamically unstable and clinically diagnosed with cardiac tamponade. One patient was hemodynamically stable and managed conservatively without pericardiocentesis or pericardial window. Otherwise, two patients were managed with pericardiocentesis alone. One patient was managed with pericardial window alone. One was managed with both pericardiocentesis and pericardial window. The remaining patient underwent median sternotomy because of unsuccessful pericardial drainage tube insertion. All six patients who reached the hospital alive survived. Five patients did not require surgical repair. CONCLUSION: The results of the present study suggested that non-surgical management of hemodynamically unstable patients who reach hospital alive with blunt pericardial effusion may be a feasible option for treatment. PMID- 29980488 TI - Secure smartphone application-based text messaging in emergency department, a system implementation and review of literature. AB - BACKGROUND: The utilization of smartphone-based technology and applications to streamline patient care provides an exciting opportunity for quality improvement research. As traditional communication methods such as paging have repeatedly been shown to be susceptible to errors and inefficiency that can delay patient care, smartphones continue to be investigated as means of improving inter hospital communication and patient outcomes. METHODS AND MATERIALS: We conducted a systematic literature review in PubMed, MEDLINE using the keywords Health Insurance Portability and Accountability Act (HIPAA) Compliant Group Messaging (HCGM), text paging communication, secure hospital text message, HIPAA text message, and secure hospital communication. The search considered studies published until January 2018. Only English-language studies were included. We reviewed the reference lists of included articles for additional studies, as well. Abstracts, unpublished data, and duplicate articles were excluded. RESULTS: 569 studies were screened and assessed for eligibility with 35 meeting the inclusion criteria. 15 of these studies are data-driven with topics of investigation ranging from facilitation of communication (40%), security (33%), provider/patient satisfaction with communication (26%), diagnostic assistance (20%), demographics of use (13%), time spent in communication (13%), and finances (7%). Sample size per study varied from 30 to 10,000 encounters. CONCLUSIONS: The use of smartphones can positively impact patient care; however, these benefits must be balanced with the responsibility to protect patient privacy and confidentiality. In order to continue to support HCGM's expansion and integration into daily practice, further data-driven studies into HCGM-specific interventions must be pursued. PMID- 29980489 TI - Spain shows that a humane response to migrant health is possible in Europe. PMID- 29980490 TI - AMALTHEA: Prospective, Single-Arm Study of the Hellenic Cooperative Oncology Group (HeCOG) Evaluating Efficacy and Safety of First-Line FOLFIRI + Aflibercept for 6 Months Followed by Aflibercept Maintenance in Patients With Metastatic Colorectal Cancer. AB - BACKGROUND: The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity. RESULTS: Seventy three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of < 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P <= .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]). CONCLUSION: The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology. PMID- 29980491 TI - Stage-based Variation in the Effect of Primary Tumor Side on All Stages of Colorectal Cancer Recurrence and Survival. AB - BACKGROUND: Multiple studies have defined the prognostic and potential predictive significance of the primary tumor side in metastatic colorectal cancer (CRC). However, the currently available data for early-stage disease are limited and inconsistent. MATERIALS AND METHODS: We explored the clinicopathologic, treatment, and outcome data from a multisite Australian CRC registry from 2003 to 2016. Tumors at and distal to the splenic flexure were considered a left primary (LP). RESULTS: For the 6547 patients identified, the median age at diagnosis was 69 years, 55% were men, and most (63%) had a LP. Comparing the outcomes for right primary (RP) versus LP, time-to-recurrence was similar for stage I and III disease, but longer for those with a stage II RP (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52-0.90; P < .01). Adjuvant chemotherapy provided a consistent benefit in stage III disease, regardless of the tumor side. Overall survival (OS) was similar for those with stage I and II disease between LP and RP patients; however, those with stage III RP disease had poorer OS (HR, 1.30; 95% CI, 1.04-1.62; P < .05) and cancer-specific survival (HR, 1.55; 95% CI, 1.19 2.03; P < .01). Patients with stage IV RP, whether de novo metastatic (HR, 1.15; 95% CI, 0.95-1.39) or relapsed post-early-stage disease (HR, 1.35; 95% CI, 1.11 1.65; P < .01), had poorer OS. CONCLUSION: In early-stage CRC, the association of tumor side and effect on the time-to-recurrence and OS varies by stage. In stage III patients with an RP, poorer OS and cancer-specific survival outcomes are, in part, driven by inferior survival after recurrence, and tumor side did not influence adjuvant chemotherapy benefit. PMID- 29980492 TI - Survival in Advanced Esophagogastric Adenocarcinoma Improves With Use of Multiple Lines of Therapy: Results From an Analysis of More Than 500 Patients. AB - BACKGROUND: Although progress has been made in the molecular stratification of esophagogastric adenocarcinoma, the outlook for advanced disease remains poor. The present evaluation of over 500 patients treated at a single European high volume tertiary center during a 6-year period gives important information on current and developing "real-world" treatment patterns and outcomes. RESULTS: The overall survival for the whole cohort was 11.5 months, with a range of treatments used in first-, second-, and third-line settings. Treatment with sequential lines of therapy was associated with better outcomes, although only 39% and 14% of patients subsequently received treatment in the second- and third-line setting, respectively. Treatment within a therapeutic clinical trial was associated with significantly improved survival. CONCLUSION: At present, a substantial proportion of patients with advanced esophagogastric adenocarcinoma will not proceed beyond first-line therapy, and for this group refinement of initial systemic therapies are required to improve outcomes. Although a number of established first- and second-line treatment options are now available, the therapeutic landscape of the disease continues to change, most notably in the application of immunotherapy and increasing interest in establishing evidence-based interventions in the third line setting and beyond. A small but growing proportion of patients will benefit from sequential treatment approaches incorporating multiple lines of therapy, and improved selection of such patients will be a key challenge for clinicians moving forwards. Data such as these provide an overview of current treatment patterns and outcomes which can be used to inform planning of future research effectively within existing treatment frameworks. PMID- 29980493 TI - Angiotensin Regulation of Amygdala Response to Threat in High-Trait-Anxiety Individuals. AB - BACKGROUND: The antihypertensive drug losartan has been shown to improve memory in humans as well as learning and fear extinction in rodent models, highlighting its potential to have similar synergistic effects on exposure-based cognitive behavioral therapy for anxiety disorders. This study investigated the effect of losartan on neural correlates of processing threat versus safety stimuli in highly anxious individuals to identify potential pathways of how the drug might facilitate psychological treatment. METHODS: Thirty healthy volunteers high in trait anxiety were randomly assigned to a single dose of losartan (50 mg) versus placebo before undergoing functional magnetic resonance imaging. We measured brain response to happy and fearful faces presented for 80 seconds to assess emotional processing and habituation over time. RESULTS: The placebo group showed similarly high left amygdala activation early on during presentation of fearful and happy faces, which decreased over time. In contrast, losartan reduced amygdala response to happy faces early on. In response to fearful faces, the drug prevented habituation, caused sustained amygdala activation, and led to increased activation in other brain areas associated with threat processing, such as the insula and putamen. CONCLUSIONS: Our findings suggest two distinct effects of losartan on emotional processing, including an improvement of early discrimination of stimuli as threatening versus safe, and facilitation of threat processing. Both processes are known to be relevant for successful exposure, highlighting two potential pathways by which losartan might exert facilitative effects on psychological treatment. PMID- 29980494 TI - Data-Driven Clustering Reveals a Link Between Symptoms and Functional Brain Connectivity in Depression. AB - BACKGROUND: Depression is a complex disorder with large interindividual variability in symptom profiles that often occur alongside symptoms of other psychiatric domains, such as anxiety. A dimensional and symptom-based approach may help refine the characterization of depressive and anxiety disorders and thus aid in establishing robust biomarkers. We use resting-state functional magnetic resonance imaging to assess the brain functional connectivity correlates of a symptom-based clustering of individuals. METHODS: We assessed symptoms using the Beck Depression and Beck Anxiety Inventories in individuals with or without a history of depression (N = 1084) and high-dimensional data clustering to form subgroups based on symptom profiles. We compared dynamic and static functional connectivity between subgroups in a subset of the total sample (n = 252). RESULTS: We identified five subgroups with distinct symptom profiles, which cut across diagnostic boundaries with different total severity, symptom patterns, and centrality. For instance, inability to relax, fear of the worst, and feelings of guilt were among the most severe symptoms in subgroups 1, 2, and 3, respectively. The distribution of individuals was 32%, 25%, 22%, 10%, and 11% in subgroups 1 to 5, respectively. These subgroups showed evidence of differential static brain connectivity patterns, in particular comprising a frontotemporal network. In contrast, we found no significant associations with clinical sum scores, dynamic functional connectivity, or global connectivity. CONCLUSIONS: Adding to the pursuit of individual-based treatment, subtyping based on a dimensional conceptualization and unique constellations of anxiety and depression symptoms is supported by distinct patterns of static functional connectivity in the brain. PMID- 29980495 TI - Indigenous Adolescents' Perception of an eMental Health Program (SPARX): Exploratory Qualitative Assessment. AB - BACKGROUND: Depression is a major health issue for indigenous adolescents, yet there is little research conducted about the efficacy and development of psychological interventions for these populations. In New Zealand there is little known about taitamariki (Maori adolescent) opinions regarding the development and effectiveness of psychological interventions, let alone computerized cognitive behavioral therapy. SPARX (Smart, Positive, Active, Realistic, X-factor thoughts) is a computerized intervention developed in New Zealand to treat mild-to-moderate depression in young people. Users are engaged in a virtual 3D environment where they must complete missions to progress to the next level. In each level there are challenges and puzzles to completeIt was designed to appeal to all young people in New Zealand and incorporates several images and concepts that are specifically Maori. OBJECTIVE: The aim was to conduct an exploratory qualitative study of Maori adolescents' opinions about the SPARX program. This is a follow-up to an earlier study where taitamariki opinions were gathered to inform the design of a computerized cognitive behavior therapy program. METHODS: Taitamariki were interviewed using a semistructured interview once they had completed work with the SPARX resource. Six participants agreed to complete the interview; the interviews ranged from 10 to 30 minutes. RESULTS: Taitamariki participating in the interviews found SPARX to be helpful. The Maori designs from the SPARX game were appropriate and useful, and the ability to customize the SPARX characters with Maori designs was beneficial and appeared to enhance cultural identity. These helped young people to feel engaged with SPARX which, in turn, assisted with the acquisition of relaxation and cognitive restructuring skills. Overall, using SPARX led to improved mood and increased levels of hope for the participants. In some instances, SPARX was used by wider whanau (Maori word for family) members with reported beneficial effect. CONCLUSIONS: Overall, this small group of Maori adolescents reported that cultural designs made it easier for them to engage with SPARX, which, in turn, led to an improvement in their mood and gave them hope. Further research is needed about how SPARX could be best used to support the families of these young people. PMID- 29980496 TI - Determinants of Successful eHealth Coaching for Consumer Lifestyle Changes: Qualitative Interview Study Among Health Care Professionals. AB - BACKGROUND: Success with lifestyle change, such as weight loss, tobacco cessation, and increased activity level, using electronic health (eHealth) has been demonstrated in numerous studies short term. However, evidence on how to maintain the effect long-term has not been fully explored, even though there is a pressing need for long-term solutions. Recent studies indicate that weight loss can be achieved and maintained over 12 and 20 months in a primary care setting using a collaborative eHealth tool. The effect of collaborative eHealth in promoting lifestyle changes depends on competent and skilled dieticians, nurses, physiotherapists, and occupational therapists acting as eHealth coaches. How such health care professionals perceive delivering asynchronous eHealth coaching and which determinants they find to be essential to achieving successful long-term lifestyle coaching have only been briefly explored and deserve further exploration. OBJECTIVE: The aim of this study is to analyze how health care professionals perceive eHealth coaching and to explore what influences successful long-term lifestyle change for patients undergoing hybrid eHealth coaching using a collaborative eHealth tool. METHODS: A total of 10 health care professionals were recruited by purposive sampling. They were all women aged 36 to 65 years of age with a mean age of 48 years of age. A total of 8/10 (80%) had more than 15 years of experience in their field, and all had more than six months of experience providing eHealth lifestyle coaching using a combination of face-to face meetings and asynchronous eHealth coaching. They worked in 5 municipalities in the Region of Southern Denmark. We performed individual, qualitative, semistructured, in-depth interviews in their workplace about their experiences with health coaching about lifestyle change, both for their patients and for themselves, and mainly how they perceived using a collaborative eHealth solution as a part of their work. RESULTS: The health care professionals all found establishing and maintaining an empathic relationship essential and that asynchronous eHealth lifestyle coaching challenged this compared to face-to-face coaching. The primary reason was that unlike typical in-person encounters in health care, they did not receive immediate feedback from the patients. We identified four central themes relevant to the health care professionals in their asynchronous eHealth coaching: (1) establishing an empathic relationship, (2) reflection in asynchronous eHealth coaching, (3) identifying realistic goals based on personal barriers, and (4) staying connected in asynchronous coaching. CONCLUSIONS: Establishing and maintaining an empathic relationship is probably the most crucial factor for successful subsequent eHealth coaching. It was of paramount importance to get to know the patient first, and the asynchronous interaction aspect presented challenges because of the delay in response times (both ways). It also presented opportunities for reflection before answering. The health care professionals found they had to provide both relational communication and goal-oriented coaching when using eHealth solutions. Going forward, the quality of the health care professional-patient interaction will need attention if patients are to benefit from collaborative eHealth coaching fully. PMID- 29980497 TI - Users' Perspectives, Opportunities, and Barriers of the Strengthen Your Ankle App for Evidence-Based Ankle Sprain Prevention: Mixed-Methods Process Evaluation for a Randomized Controlled Trial. AB - BACKGROUND: The "Strengthen Your Ankle" neuromuscular training program has been thoroughly studied over the past 8 years. This process evaluation is a part of a randomized controlled trial that examined both the short- and long-term effectiveness of this particular program. Although it was shown previously that the program, available both in a printed booklet and as a mobile app, is able to effectively reduce the number of recurrent ankle sprains, participants' compliance with the program is an ongoing challenge. OBJECTIVE: This process evaluation explored participants' opinions regarding both the methods of delivery, using RE-AIM (Reach Effectiveness Adoption Implementation Maintenance) Framework to identify barriers and challenges to program compliance. Although Reach, Effectiveness, and Adaptation were the focus of a previous study, this paper focuses on the implementation and maintenance phases. METHODS: Semistructured interviews and online questionnaires were analyzed using qualitative content analysis. Fisher exact, chi-square, and t tests assessed between-group differences in quantitative survey responses. Interviews were assessed by thematic analysis to identify key themes. RESULTS: While there were no significant differences in the perceived simplicity, usefulness, and liking of the exercise during the 8 weeks of the neuromuscular training program, semistructured interviews showed that 14 of 16 participants agreed that an app would be of additional benefits over a booklet. After the 12-month follow-up, when asked how they evaluated the overall use of the app or the booklet, the users of the app gave a mean score of 7.7 (SD 0.99) versus a mean score 7.1 (SD 1.23) for the users of the booklet. This difference in mean score was significant (P=.006). CONCLUSIONS: Although both the app and booklet showed a high user satisfaction, the users of the app were significantly more satisfied. Semistructured questionnaires allowed users to address issues they would like to improve in future updates. Including a possibility for feedback and postponement of exercises, an explanation of the use of specific exercises and possibly music were identified as features that might further improve the contentment of the program, probably leading to increased compliance. TRIAL REGISTRATION: Netherlands Trial Register NTR4027; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4027 (Archived by Webcite at http://www.webcitation.org/70MTo9dMV). PMID- 29980498 TI - Reaching Those At Risk for Psychiatric Disorders and Suicidal Ideation: Facebook Advertisements to Recruit Military Veterans. AB - BACKGROUND: Younger military veterans are at high risk for psychiatric disorders and suicide. Reaching and engaging veterans in mental health care and research is challenging. Social media platforms may be an effective channel to connect with veterans. OBJECTIVE: This study tested the effectiveness of Facebook advertisements in reaching and recruiting Iraq and Afghanistan-era military veterans in a research study focused on mental health. METHODS: Facebook ads requesting participation in an online health survey ran for six weeks in 2017. Ads varied imagery and headlines. Validated instruments were used to screen for psychiatric disorders and suicidality. Outcomes included impressions, click through rate, survey completion, and cost per survey completed. RESULTS: Advertisements produced 827,918 impressions, 9,527 clicks, and 587 survey completions. Lack of enrollment in Veterans Affairs health care (193/587, 33%) and positive screens for current mental health problems were common, including posttraumatic stress disorder (266/585, 45%), problematic drinking (243/584, 42%), major depression (164/586, 28%), and suicidality (132/585, 23%). Approximately half of the survey participants (285/587, 49%) were recruited with just 2 of the 15 ads, which showed soldiers marching tied to an "incentive" or "sharing" headline. These 2 ads were also the most cost-effective, at US $4.88 and US $5.90 per participant, respectively. Among veterans with current suicidal ideation, the survey-taking image resulted in higher survey completion than the soldiers marching image (P=.007). CONCLUSIONS: Facebook advertisements are effective in rapidly and inexpensively reaching military veterans, including those at risk for mental health problems and suicidality, and those not receiving Veterans Affairs health care. Advertisement image and headlines may help optimize the effectiveness of advertisements for specific subgroups. PMID- 29980499 TI - The Impact of Patient Online Access to Computerized Medical Records and Services on Type 2 Diabetes: Systematic Review. AB - BACKGROUND: Online access to computerized medical records has the potential to improve convenience, satisfaction, and care for patients, and to facilitate more efficient organization and delivery of care. OBJECTIVE: The objective of this review is to explore the use and impact of having online access to computerized medical records and services for patients with type 2 diabetes mellitus in primary care. METHODS: Multiple international databases including Medline, Embase, CINAHL, PsycINFO and the Cochrane Library were searched between 2004 and 2016. No limitations were placed on study design, though we applied detailed inclusion and exclusion criteria to each study. Thematic analysis was used to synthesize the evidence. The Mixed Methods Appraisal Toolkit was used to appraise study quality. RESULTS: A search identified 917 studies, of which 28 were included. Five themes were identified: (1) disparities in uptake by age, gender, ethnicity, educational attainment, and number of comorbidities, with young men in full-time employment using these services most; (2) improved health outcomes: glycemic control was improved, but blood pressure results were mixed; (3) self management support from improved self-care and shared management occurred especially soon after diagnosis and when complications emerged. There was a generally positive effect on physician-patient relationships; (4) accessibility: patients valued more convenient access when online access to computerized medical records and services work; and (5) technical challenges, barriers to use, and system features that impacted patient and physician use. The Mixed Methods Appraisal Toolkit rated 3 studies as 100%, 19 studies as 75%, 4 studies as 50%, and 1 study scored only 25%. CONCLUSIONS: Patients valued online access to computerized medical records and services, although in its current state of development it may increase disparities. Online access to computerized medical records appears to be safe and is associated with improved glycemic control, but there was a lack of rigorous evidence in terms of positive health outcomes for other complications, such as blood pressure. Patients remain concerned about how these systems work, the rules, and timeliness of using these systems. PMID- 29980500 TI - Head-Mounted Virtual Reality and Mental Health: Critical Review of Current Research. AB - BACKGROUND: eHealth interventions are becoming increasingly used in public health, with virtual reality (VR) being one of the most exciting recent developments. VR consists of a three-dimensional, computer-generated environment viewed through a head-mounted display. This medium has provided new possibilities to adapt problematic behaviors that affect mental health. VR is no longer unaffordable for individuals, and with mobile phone technology being able to track movements and project images through mobile head-mounted devices, VR is now a mobile tool that can be used at work, home, or on the move. OBJECTIVE: In line with recent advances in technology, in this review, we aimed to critically assess the current state of research surrounding mental health. METHODS: We compiled a table of 82 studies that made use of head-mounted devices in their interventions. RESULTS: Our review demonstrated that VR is effective in provoking realistic reactions to feared stimuli, particularly for anxiety; moreover, it proved that the immersive nature of VR is an ideal fit for the management of pain. However, the lack of studies surrounding depression and stress highlight the literature gaps that still exist. CONCLUSIONS: Virtual environments that promote positive stimuli combined with health knowledge could prove to be a valuable tool for public health and mental health. The current state of research highlights the importance of the nature and content of VR interventions for improved mental health. While future research should look to incorporate more mobile forms of VR, a more rigorous reporting of VR and computer hardware and software may help us understand the relationship (if any) between increased specifications and the efficacy of treatment. PMID- 29980504 TI - Accountable care organisations: second legal challenge fails in High Court. PMID- 29980503 TI - Outcomes after admission on weekend day compared with weekday. PMID- 29980502 TI - Relative Validity and Reproducibility of a New 44-Item Diet and Food Frequency Questionnaire Among Adults: Online Assessment. AB - BACKGROUND: Dietary questionnaires currently available which can assess the habitual diet are timely, costly, or not adapted well to the modern diet; thus, there is a need for a shorter food frequency e-Questionnaire (FFeQ) adapted to Western diets, in order to properly estimate energy and macronutrient intakes or rank individuals according to food and nutrient intakes. OBJECTIVE: The aim of this study was to evaluate the relative validity and reproducibility of a 30 minute and 44-item FFeQ in a sample of adults obtained from the general population. METHODS: A sample of French adults was recruited through social media and an advertising campaign. A total of 223 volunteers completed the FFeQ twice at one-year intervals and were included in the reproducibility study. During that interval, 92 participants completed three-to-six 24-hour recalls and were included in the validity study. Nutrient and dietary intakes were computed for all validity and reproducibility participants. The level of agreement between the two methods was evaluated for nutrient and food group intakes using classification into quintiles of daily intake, correlation coefficients and Bland Altman plots. RESULTS: For relative validity, correlation coefficients ranged from 0.09 to 0.88 (unadjusted correlation coefficients, median: 0.48) and 0.02 to 0.68 (deattenuated and energy adjusted correlation coefficients, median: 0.50) for food group and nutrient intakes, respectively. The median proportion of subjects classified into the same or adjacent quintile was 73% and 66% for food and nutrient intakes, respectively. Bland-Altman plots showed good agreement across the range of intakes. Regarding reproducibility, intraclass correlation coefficients ranged from 0.33 to 0.72 (median: 0.60) and 0.55 to 0.73 (median: 0.64), for food and nutrient intakes, respectively. CONCLUSIONS: The FFeQ showed acceptable validity and reproducibility in a sample of adults based on their food and nutrient intakes. The FFeQ is a promising and low-cost tool that can be used in large-scale online epidemiological studies or clinical routines and could be integrated into evidence-based smartphone apps for assessing diet components. PMID- 29980505 TI - Poor quality services are harming global drive to improve healthcare, experts warn. PMID- 29980506 TI - New era for health services will focus on systems and creativity-an essay by Nick Black. PMID- 29980501 TI - Automated Real-Time Collection of Pathogen-Specific Diagnostic Data: Syndromic Infectious Disease Epidemiology. AB - BACKGROUND: Health care and public health professionals rely on accurate, real time monitoring of infectious diseases for outbreak preparedness and response. Early detection of outbreaks is improved by systems that are comprehensive and specific with respect to the pathogen but are rapid in reporting the data. It has proven difficult to implement these requirements on a large scale while maintaining patient privacy. OBJECTIVE: The aim of this study was to demonstrate the automated export, aggregation, and analysis of infectious disease diagnostic test results from clinical laboratories across the United States in a manner that protects patient confidentiality. We hypothesized that such a system could aid in monitoring the seasonal occurrence of respiratory pathogens and may have advantages with regard to scope and ease of reporting compared with existing surveillance systems. METHODS: We describe a system, BioFire Syndromic Trends, for rapid disease reporting that is syndrome-based but pathogen-specific. Deidentified patient test results from the BioFire FilmArray multiplex molecular diagnostic system are sent directly to a cloud database. Summaries of these data are displayed in near real time on the Syndromic Trends public website. We studied this dataset for the prevalence, seasonality, and coinfections of the 20 respiratory pathogens detected in over 362,000 patient samples acquired as a standard-of-care testing over the last 4 years from 20 clinical laboratories in the United States. RESULTS: The majority of pathogens show influenza-like seasonality, rhinovirus has fall and spring peaks, and adenovirus and the bacterial pathogens show constant detection over the year. The dataset can also be considered in an ecological framework; the viruses and bacteria detected by this test are parasites of a host (the human patient). Interestingly, the rate of pathogen codetections, on average 7.94% (28,741/362,101), matches predictions based on the relative abundance of organisms present. CONCLUSIONS: Syndromic Trends preserves patient privacy by removing or obfuscating patient identifiers while still collecting much useful information about the bacterial and viral pathogens that they harbor. Test results are uploaded to the database within a few hours of completion compared with delays of up to 10 days for other diagnostic-based reporting systems. This work shows that the barriers to establishing epidemiology systems are no longer scientific and technical but rather administrative, involving questions of patient privacy and data ownership. We have demonstrated here that these barriers can be overcome. This first look at the resulting data stream suggests that Syndromic Trends will be able to provide high-resolution analysis of circulating respiratory pathogens and may aid in the detection of new outbreaks. PMID- 29980507 TI - Positive Results for Tazemetostat in Follicular Lymphoma. AB - A recently reported clinical trial indicates that the EZH2 inhibitor tazemetostat is effective against relapsed or refractory follicular lymphoma. Three of 28 patients with EZH2 mutations had complete responses, and 17 had partial responses. PMID- 29980508 TI - IL23 Produced by MDSCs Promotes Castration-Resistant Prostate Cancer. AB - In patients with CRPC an increase in tumor-infiltrating MDSCs that secrete IL23 upregulates AR. PMID- 29980509 TI - Second-Site IDH2 Mutations Confer Resistance to Enasidenib In Trans. AB - Two patients with IDH2R140Q AML acquired resistance to an IDH2 inhibitor via secondary IDH2 mutations. PMID- 29980510 TI - Paralog Dependency May Be Exploitable in Tumors Lacking Chromosome 1p. AB - Cells with chromosome 1p loss and hemizygous deletion of MAGOH are dependent on its paralog, MAGOHB. PMID- 29980511 TI - CBFbeta-SMMHC Activates MYC Enhancers to Promote Leukemogenesis. AB - CBFbeta-SMMHC inhibition induces RUNX1-mediated repression of MYC to induce apoptosis in inv(16) AML cells. PMID- 29980512 TI - Prejudice persists against black and ethnic minority doctors. PMID- 29980513 TI - CMV encephalitis in an immune-competent patient. AB - After being admitted to hospital with atypical chest pain, a 61-year-old woman was noted to become lethargic and confused. She also developed global dysphasia. MRI was suggestive of encephalitis, and lumbar puncture was positive for cytomegalovirus (CMV) PCR. The patient was treated with intravenous ganciclovir and subsequent oral valganciclovir and she gradually made a reasonable recovery. While this infection is usually closely linked to immunosuppression, the patient was found to be HIV negative, and was not on any immunosuppressive therapy. Going through the patient's medical history revealed two possible risk factors which might have led to the development of CMV encephalitis: immunosuppression secondary to underlying poorly controlled diabetes mellitus; and previous admission to the intensive care unit which might have lead to CMV reactivation. PMID- 29980514 TI - Case of hepatic portal venous gas in an infant with hypertrophic pyloric stenosis. AB - Hepatic portal venous gas is the presence of gas within the portal vein and its branches. A 4-week-old male infant presented with 1-week history of non-bloody, non-bilious projectile emesis. Examination was significant for an olive-shaped mass in the abdomen. Bloodwork showed hypokalaemic metabolic alkalosis. Abdominal ultrasound and radiograph was significant for portal venous gas and did not meet radiographic criteria for pyloric stenosis. He underwent upper endoscopy, which showed a narrowed, hypertrophic pylorus. The child underwent pyloromyotomy with resolution of his emesis. Hepatic portal venous gas (HPVG) is very rare and can be seen in the setting of hypertrophic pyloric stenosis. It is believed that an increase in intraluminal dilation and pressure subsequently moves gas from the intestinal mucosa venous system and lymphatics into the portal veins. The presence of HPVG in a well-appearing patient can be benign and should not prompt further testing nor delay treatment. PMID- 29980515 TI - Surgical management of chronic genital lymphoedema. AB - A 44-year-old man with a spinal cord injury was referred to a specialist urology service with a 7-year history of significant genital swelling. His condition had eluded diagnosis and was refractory to all previous treatments. The considerable swelling both impacted his quality of life and prevented the patient from adequately managing his neurogenic bladder. He was diagnosed with chronic idiopathic genital lymphoedema and underwent total scrotectomy, wide penile skin excision and split skin graft to the penile shaft. The patient made an excellent recovery. We present this unusual case with preoperative, intraoperative and postoperative images. PMID- 29980516 TI - Renal cell carcinoma with level 2 IVC thrombus. PMID- 29980517 TI - The Ashitaba (Angelica keiskei) Chalcones 4-hydroxyderricin and Xanthoangelol Suppress Melanomagenesis By Targeting BRAF and PI3K. AB - Malignant melanoma is an aggressive tumor of the skin and still lacks effective preventive and therapeutic treatments. In melanoma, both the BRAF/MEK/ERK and PI3 K/AKT signaling pathways are constitutively activated through multiple mechanisms, which result in cell-cycle progression and prevention of apoptosis. Therefore, the development of novel strategies for targeting BRAF and PI3K are of utmost importance. In this study, we found that Ashitaba (Angelica keiskei) chalcones, 4-hydroxyderricin (4HD) and xanthoangelol (XAG), suppressed melanoma development by directly targeting both BRAFV600E and PI3K, which blocked the activation of downstream signaling. This led to the induction of G1 phase cell cycle arrest and apoptosis in melanoma cells. Importantly, 4HD or XAG dramatically attenuated tumor incidence and volume in the BRAF-activated Pten deficient melanoma mouse model. Our findings suggest that 4HD and XAG are promising chemopreventive or potential therapeutic agents against melanomagenesis that act by targeting both BRAF and PI3K, providing hope for rapid clinical translation. Cancer Prev Res; 11(10); 607-20. (c)2018 AACR. PMID- 29980518 TI - Grand Sumo Tournaments and Out-of-Hospital Cardiac Arrests in Tokyo. AB - BACKGROUND: Sumo wrestling is a demanding sport. Although watching sumo wrestling may have cardiovascular effects, no studies of this relationship have been performed. Thus, we aimed to evaluate the association between sumo wrestling tournaments and the rate of out-of-hospital cardiac arrests. METHODS AND RESULTS: We counted the daily number of patients aged 18 to 110 years who had an out-of hospital cardiac arrest of presumed-cardiac origin in the Tokyo metropolis between 2005 and 2014. A Poisson regression was used to model out-of-hospital cardiac arrests of presumed-cardiac origin per day. Exposure days were the days on which a sumo tournament was held and broadcast, whereas control days were all other days. Events that occurred on exposure days were compared with those that occurred on control days. Risk ratios for out-of-hospital cardiac arrests on Grand Sumo tournaments days compared with control days were estimated. In total, 71 882 out-of-hospital cardiac arrests met the inclusion criteria. We recorded a 9% increase in the occurrence of out-of-hospital cardiac arrests on the day of a sumo tournament compared with control days. In patients aged 75 to 110 years, we found a 13% increase in the occurrence of out-of-hospital cardiac arrests on the day of a sumo tournament compared with control days. CONCLUSIONS: We found a significant increase in the occurrence of out-of-hospital cardiac arrests on the days of sumo tournaments compared with control days in the Tokyo metropolis between 2005 and 2014. Further studies are needed to verify these initial findings on sumo tournaments and cardiovascular events. PMID- 29980519 TI - Slow Potential at the Entrance of the Slow Conduction Zone in the Reentry Circuit of a Verapamil-Sensitive Atrial Tachycardia Originating From the Atrioventricular Annulus. AB - BACKGROUND: Slow conduction zone in a verapamil-sensitive reentrant atrial tachycardia originating from atrioventricular annulus is composed of calcium channel-dependent tissue. We examined whether there was a slow potential (SP) at the entrance of the slow conduction zone. METHODS AND RESULTS: We first identified the pacing site from where manifest entrainment and orthodromic capture of the earliest atrial activation site were demonstrated in 40 atrioventricular annulus patients with atrioventricular annulus. Radiofrequency energy was then delivered 2 cm proximal to the earliest atrial activation site in the direction of entrainment pacing site and gradually advanced toward the earliest atrial activation site until atrial tachycardia termination to localize the entrance of the slow conduction zone. Electrogram characteristics were analyzed at successful and unsuccessful ablation sites. During sinus rhythm, SP was observed at all 40 successful sites, but was observed at only 12 unsuccessful sites (P<0.0001). During sinus rhythm, there was no significant difference in electrogram amplitude nor width of atrial electrogram between successful and unsuccessful sites (0.407+/-0.281 versus 0.487+/-0.447 mV [P=0.1989] and 37.0+/ 9.2 versus 38.9+/-8.0 ms [P=0.1773]); however, SP amplitude and width at successful sites were significantly greater than those at unsuccessful sites (0.110+/-0.049 versus 0.025+/-0.046 mV [P<0.0001] and 38.8+/-13.4 versus 8.1+/ 13.2 ms [P<0.0001]). During atrial tachycardia, SP amplitude was significantly attenuated (0.088+/-0.042 versus 0.110+/-0.049 mV, P<0.001) and SP width was significantly prolonged (47.8+/-14.1 versus 38.8+/-13.4 ms, P<0.0001) at successful sites. CONCLUSIONS: SP was observed during sinus rhythm at the entrance of the slow conduction zone; however, SP amplitude was attenuated and SP width was prolonged during atrial tachycardia, suggesting that SP reflects the characteristics of calcium channel-dependent tissue involved in atrioventricular annulus reentry circuit. PMID- 29980520 TI - Implantable Ventricular Assist Device Use and Outcomes in People With End-Stage Renal Disease. AB - BACKGROUND: People with end-stage renal disease (ESRD) are at risk for advanced heart failure, but little is known about use and outcomes of durable mechanical circulatory support in this setting. We examined use and outcomes of implantable ventricular assist devices (VADs) in a national ESRD cohort. METHODS AND RESULTS: We performed a retrospective cohort study of Medicare beneficiaries with ESRD who underwent implantable VAD placement from 2006 to 2014. We examined in-hospital and 1-year mortality, all-cause and cause-specific hospitalizations, and heart/kidney transplantation outcomes. We investigated as predictors demographic factors, time-period of VAD implantation, primary or post-cardiotomy implantation, and duration of ESRD before VAD implantation. We identified 96 people with ESRD who underwent implantable VAD placement. At time of VAD implantation, 74 (77.1%) were receiving hemodialysis, 10 (10.4%) were receiving peritoneal dialysis and 12 (12.5%) had renal transplant. Time from incident ESRD to VAD implantation was median 4.0 (interquartile range 1.1, 8.2) years. Mortality during the implantation hospitalization was 40.6%. Within 1 year of implantation 61.5% of people had died. On multivariable analysis, males had half the mortality risk of females. Lower mortality risk was also seen with VAD implantation in a primary setting, and with more recent year of implantation, but these results did not reach statistical significance. CONCLUSIONS: Medicare beneficiaries with ESRD are undergoing durable VAD implantation, often several years after incident ESRD, although in low numbers. Mortality is high among these patients, highlighting the need for investigations to improve treatment selection and management. PMID- 29980521 TI - Association Between Mineralocorticoid Receptor Antagonist Use and Outcome in Myocardial Infarction Patients With Heart Failure. AB - BACKGROUND: There are no studies of mineralocorticoid receptor antagonist (MRA) treatment examining outcome in unselected real-life patients with myocardial infarction (MI) and heart failure (HF). There is uncertainty regarding effects of MRA in relation to left ventricular ejection fraction (LVEF) and chronic kidney disease (CKD). The aim was to assess MRA use and compare outcomes in MI patients with HF in relation to LVEF and CKD. METHODS AND RESULTS: Patients with MI and HF registered in the Swedish myocardial infarction registry, SWEDEHEART, 2005-2014, were included. Associations between MRA use and all-cause mortality up to 3 years were assessed with multivariable Cox regression, stratified by EF groups and presence of CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m2). Of 45 071 patients with MI and HF, 4470 (9.9%) received MRA. Those with HF and LVEF <40% more often had MRA (19.6%) compared with those with LVEF 40% to 49% (9.1%) or LVEF >=50% (4.7%). 8.6% of patients with CKD received MRA. After adjustment, MRA use was associated with lower mortality in those with LVEF <40% (hazard ratio [95% confidence interval] 0.81 [0.75-0.88]) and LVEF 40% to 49% (0.88 [0.75 1.03]) but not in those with LVEF >=50% (1.29 [1.09-1.53]), with significant interaction between MRA and LVEF (P<0.0001). The association between MRA use and mortality was similar in those without (0.96 [0.88-1.05]) and with (0.92 [0.85 0.99]) CKD. CONCLUSIONS: In patients with MI and HF, MRA use was associated with better long-term survival in patients with LVEF <40% but not in those with LVEF >=50%, while the mortality risk was similar in MRA-treated patients with or without CKD. PMID- 29980522 TI - Implementation of a Regional Network for ST-Segment-Elevation Myocardial Infarction (STEMI) Care and 30-Day Mortality in a Low- to Middle-Income City in Brazil: Findings From Salvador's STEMI Registry (RESISST). AB - BACKGROUND: Few data exist on regional systems of care for the treatment of ST segment-elevation myocardial infarction (STEMI) in developing countries. Our objective was to describe temporal trends in 30-day mortality and identify predictors of mortality among STEMI patients enrolled in a prospective registry in Brazil. METHODS AND RESULTS: From January 2011 to June 2013, 520 patients who received initial STEMI care at 23 nonspecialized public health units or hospitals, some of whom were transferred to a public cardiology referral center, were identified through a regional STEMI network supported by telemedicine and the local prehospital emergency medical service. We stratified patients into five 6-month periods based on presentation date. Mean age (+/-SD) of patients was 62.0 (+/-12.2) years, and 55.6% were men. The mean Global Registry of Acute Coronary Events (GRACE) score was 145 (+/-34). Overall mortality at 30 days was 15.0%. Use of dual antiplatelet therapy and statins increased significantly from baseline (January 2011) to period 5 (June 2013): 61.8% to 93.6% (P<0.001) and 60.4% to 79.7% (P<0.001), respectively. Rates of primary reperfusion also increased (29.1% 53.8%; P<0.001), and more patients were transferred to the referral center (44.7% 76.3%; P=0.001). Thirty-day mortality rates decreased from 19.8% to 5.1% (P<0.001). In multivariable analysis, factors independently associated with 30 day mortality were higher GRACE score, history of previous stroke, lack of transfer to the referral center, and lack of use of optimized medical therapy. CONCLUSIONS: Implementation of a regional STEMI system was associated with lower mortality and higher use of evidence-based therapies. PMID- 29980523 TI - Diagnostic Performance of In-Procedure Angiography-Derived Quantitative Flow Reserve Compared to Pressure-Derived Fractional Flow Reserve: The FAVOR II Europe Japan Study. AB - BACKGROUND: Quantitative flow ratio (QFR) is a novel modality for physiological lesion assessment based on 3-dimensional vessel reconstructions and contrast flow velocity estimates. We evaluated the value of online QFR during routine invasive coronary angiography for procedural feasibility, diagnostic performance, and agreement with pressure-wire-derived fractional flow reserve (FFR) as a gold standard in an international multicenter study. METHODS AND RESULTS: FAVOR II E-J (Functional Assessment by Various Flow Reconstructions II Europe-Japan) was a prospective, observational, investigator-initiated study. Patients with stable angina pectoris were enrolled in 11 international centers. FFR and online QFR computation were performed in all eligible lesions. An independent core lab performed 2-dimensional quantitative coronary angiography (2D-QCA) analysis of all lesions assessed with QFR and FFR. The primary comparison was sensitivity and specificity of QFR compared with 2D-QCA using FFR as a reference standard. A total of 329 patients were enrolled. Paired assessment of FFR, QFR, and 2D-QCA was available for 317 lesions. Mean FFR, QFR, and percent diameter stenosis were 0.83+/-0.09, 0.82+/-10, and 45+/-10%, respectively. FFR was <=0.80 in 104 (33%) lesions. Sensitivity and specificity by QFR was significantly higher than by 2D QCA (sensitivity, 86.5% (78.4-92.4) versus 44.2% (34.5-54.3); P<0.001; specificity, 86.9% (81.6-91.1) versus 76.5% (70.3-82.0); P=0.002). Area under the receiver curve was significantly higher for QFR compared with 2D-QCA (area under the receiver curve, 0.92 [0.89-0.96] versus 0.64 [0.57-0.70]; P<0.001). Median time to QFR was significantly lower than median time to FFR (time to QFR, 5.0 minutes [interquartile range, -6.1] versus time to FFR, 7.0 minutes [interquartile range, 5.0-10.0]; P<0.001). CONCLUSIONS: Online computation of QFR in the catheterization laboratory is clinically feasible and is superior to angiographic assessment for evaluation of intermediary coronary artery stenosis using FFR as a reference standard. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02959814. PMID- 29980525 TI - Correction to "Structure-Activity Relationships of the Main Bioactive Constituents of Euodia rutaecarpa on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis". PMID- 29980524 TI - Cancer-associated thrombosis in patients with implanted ports: a prospective multicenter French cohort study (ONCOCIP). AB - The need to accurately identify cancer outpatients at high risk of thrombotic complications is still unmet. In a prospective, multicenter cohort study (ONCOlogie et Chambres ImPlantables [ONCOCIP]), consecutive adult patients with a solid tumor and implanted port underwent 12-month follow-up. Our primary objective was to identify risk factors for (1) catheter-related thrombosis, defined as ipsilateral symptomatic upper-limb deep-vein thrombosis with or without pulmonary embolism, and (2) venous thromboembolism other than catheter related, defined as any symptomatic superficial- or deep-vein thrombosis (other than catheter-related) or pulmonary embolism, and incidental pulmonary embolism. All events were objectively confirmed and centrally adjudicated. Rate assessments integrated competing risk of death. Overall, 3032 patients were included (median age: 63 years; women: 58%). The most frequent cancer locations were breast (33.7%), lung (18.5%), and colorectal (15.6%), cancer being metastatic in 43.2% of patients. Most patients (97.1%) received chemotherapy. By 12 months, 48 (1.6%) patients had been lost to follow-up and 656 (24.6%) had died; 3.8% (n = 111) of patients had experienced catheter-related thrombosis, and 9.6% (n = 276) venous thromboembolism other than catheter-related. By multivariate analysis, use of cephalic vein for catheter insertion predicted catheter-related thrombosis, whereas ongoing antiplatelet therapy was protective; risk factors for venous thromboembolism other than catheter-related were advanced age, previous venous thromboembolism, cancer site, and low hemoglobin level or increased leukocyte count before chemotherapy. In conclusion, this large prospective cohort study showed a high rate of venous thromboembolism in patients with a solid tumor and implanted port. Risk factors for catheter-related thrombosis differed from those for venous thromboembolism not catheter-related. This trial was registered at www.clinicaltrials.gov as #NCT02025894. PMID- 29980526 TI - Targeted breast screening could reduce overdiagnosis and be more cost effective, study finds. PMID- 29980528 TI - Does the addition of mesh improve outcomes in implant based breast reconstruction after mastectomy for breast cancer? PMID- 29980529 TI - Neoantigens in Ovarian Cancer: Embarrassment of Riches or Needles in a Haystack? AB - Comprehensive genomic and transcriptomic analysis demonstrate that tumor infiltrating T lymphocytes that react to mutated neoepitopes could be identified in recurrent ovarian cancer. Two of these T-cell populations reacted against TP53 hotspot missense mutations that are present in a wide variety of malignancies. Clin Cancer Res; 24(22); 5493-5. (c)2018 AACR See related article by Deniger et al., p. 5562. PMID- 29980527 TI - Validation of Plasma Biomarker Candidates for the Prediction of eGFR Decline in Patients With Type 2 Diabetes. AB - OBJECTIVE: The decline of estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes is variable, and early interventions would likely be cost effective. We elucidated the contribution of 17 plasma biomarkers to the prediction of eGFR loss on top of clinical risk factors. RESEARCH DESIGN AND METHODS: We studied participants in PROVALID (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers), a prospective multinational cohort study of patients with type 2 diabetes and a follow-up of more than 24 months (n = 2,560; baseline median eGFR, 84 mL/min/1.73 m2; urine albumin-to-creatinine ratio, 8.1 mg/g). The 17 biomarkers were measured at baseline in 481 samples using Luminex and ELISA. The prediction of eGFR decline was evaluated by linear mixed modeling. RESULTS: In univariable analyses, 9 of the 17 markers showed significant differences in median concentration between stable and fast-progressing patients. A linear mixed model for eGFR obtained by variable selection exhibited an adjusted R2 of 62%. A panel of 12 biomarkers was selected by the procedure and accounted for 34% of the total explained variability, of which 32% was due to 5 markers. The individual contribution of each biomarker to the prediction of eGFR decline on top of clinical predictors was generally low. When included into the model, baseline eGFR exhibited the largest explained variability of eGFR decline (R2 of 79%), and the contribution of each biomarker dropped below 1%. CONCLUSIONS: In this longitudinal study of patients with type 2 diabetes and maintained eGFR at baseline, 12 of the 17 candidate biomarkers were associated with eGFR decline, but their predictive power was low. PMID- 29980530 TI - ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer. AB - PURPOSE: DNA damaging agents comprise the backbone of systemic treatment for many tumor types; however, few reliable predictive biomarkers are available to guide use of these agents. In muscle-invasive bladder cancer (MIBC), cisplatin-based chemotherapy improves survival, yet response varies widely among patients. Here, we sought to define the role of the nucleotide excision repair (NER) gene ERCC2 as a biomarker predictive of response to cisplatin in MIBC. EXPERIMENTAL DESIGN: Somatic missense mutations in ERCC2 are associated with improved response to cisplatin-based chemotherapy; however, clinically identified ERCC2 mutations are distributed throughout the gene and the impact of individual ERCC2 variants on NER capacity and cisplatin sensitivity is unknown. We developed a microscopy based NER assay to profile ERCC2 mutations observed retrospectively in prior studies and prospectively within the context of an institution-wide tumor profiling initiative. In addition, we created the first ERCC2-deficient bladder cancer preclinical model for studying the impact of ERCC2 loss-of-function. RESULTS: We used our functional assay to test the NER capacity of clinically observed ERCC2 mutations and found that most ERCC2 helicase domain mutations cannot support NER. Further, we show that introducing an ERCC2 mutation into a bladder cancer cell line abrogates NER activity and is sufficient to drive cisplatin sensitivity in an orthotopic xenograft model. CONCLUSIONS: Our data support a direct role for ERCC2 mutations in driving cisplatin response, define the functional landscape of ERCC2 mutations in bladder cancer, and provide an opportunity to apply combined genomic and functional approaches to prospectively guide therapy decisions in bladder cancer. PMID- 29980531 TI - Molecular Imaging of Radiolabeled Bispecific T-Cell Engager 89Zr-AMG211 Targeting CEA-Positive Tumors. AB - Purpose: AMG 211, a bispecific T-cell engager (BiTE) antibody construct, targets carcinoembryonic antigen (CEA) and the CD3 epsilon subunit of the human T-cell receptor. AMG 211 was labeled with zirconium-89 (89Zr) or fluorescent dye to evaluate the tumor-targeting properties.Experimental Design: 89Zr-AMG211 was administered to mice bearing CEA-positive xenograft tumors of LS174T colorectal adenocarcinoma or BT474 breast cancer cells, as well as CEA-negative HL-60 promyelocytic leukemia xenografts. Biodistribution studies with 2- to 10-MUg 89Zr AMG211 supplemented with unlabeled AMG 211 up to 500-MUg protein dose were performed. A BiTE that does not bind CEA, 89Zr-Mec14, served as a negative control. 89Zr-AMG211 integrity was determined in tumor lysates ex vivo Intratumoral distribution was studied with IRDye800CW-AMG211. Moreover, 89Zr AMG211 was manufactured according to Good Manufacturing Practice (GMP) guidelines for clinical trial NCT02760199Results: 89Zr-AMG211 demonstrated dose-dependent tumor uptake at 6 hours. The highest tumor uptake was observed with a 2-MUg dose, and the lowest tumor uptake was observed with a 500-MUg dose. After 24 hours, higher uptake of 10-MUg 89Zr-AMG211 occurred in CEA-positive xenografts, compared with CEA-negative xenografts. Although the blood half-life of 89Zr-AMG211 was approximately 1 hour, tumor retention persisted for at least 24 hours. 89Zr-Mec14 showed no tumor accumulation beyond background level. Ex vivo autoradiography revealed time-dependent disintegration of 89Zr-AMG211. 800CW-AMG211 was specifically localized in CEA-expressing viable tumor tissue. GMP-manufactured 89Zr-AMG211 fulfilled release specifications.Conclusions: 89Zr-AMG211 showed dose dependent CEA-specific tumor targeting and localization in viable tumor tissue. Our data enabled its use to clinically evaluate AMG 211 in vivo behavior. Clin Cancer Res; 24(20); 4988-96. (c)2018 AACR. PMID- 29980532 TI - Functions and Mechanisms of Tumor Necrosis Factor-alpha and Noncoding RNAs in Bone-Invasive Pituitary Adenomas. AB - Purpose: To explore the molecular mechanism and prognosis of bone-invasive pituitary adenomas (BIPA).Experimental design: A total of 274 patients with pituitary adenomas were followed up. Transcriptomic microarrays analysis was performed on 10 pituitary adenomas, including five BIPAs and five non-bone invasive pituitary adenomas (NBIPA). The targeted molecular markers were validated by qRT-PCR, IHC, ELISA, and osteoclast differentiation.Results: Clinical variable analyses revealed a significant correlation between bone invasion and female sex, large tumor volume, non-gross total resection (NGTR), and tumor regrowth. BIPAs had worse progression-free survival (PFS) than did NBIPAs in the NGTR and nonfunctional pituitary adenoma (NFPA) groups. Gene ontology functional and KEGG pathway analyses showed that the biological processes and pathways were primarily immune and inflammatory pathways. Pathway act work showed that osteoclast differentiation pathway was significantly implicated in the pathway network. BIPAs had higher expression of TNFalpha than that of NBIPAs on IHC. In vitro, TNFalpha could induce RAW264.7 cells to differentiate into mature osteoclasts, leading to bone destruction. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFalpha expression.Conclusions: BIPAs had worse PFS than did NBIPAs in the NGTR and NFPA groups. Inflammatory and immune factors play an important role in BIPAs. TNFalpha can directly induce osteoclast differentiation in BIPAs. NR_033258, lncRNA SNHG24, miR-181c-5p, and miR-454-3p can regulate TNFalpha expression. TNFalpha and its related lncRNAs and miRNAs represent potential therapeutic targets for bone-invasive pituitary adenomas in the future. Clin Cancer Res; 24(22); 5757-66. (c)2018 AACR. PMID- 29980533 TI - Forestalling BRAF-Inhibitor Resistance in a Shocking Way. AB - Targeting BRAF in BRAF-mutant melanoma is highly effective, but most patients develop resistance. HSP90 has been implicated and identified as a therapeutic target. Ultimately, early-stage clinical investigation will be necessary to provide proof of principle of this approach and if appropriate randomized trials to confirm promising findings. Clin Cancer Res; 24(22); 5496-8. (c)2018 AACR See related article by Eroglu et al., p. 5516. PMID- 29980534 TI - High-Fat Diet Causes Mitochondrial Dysfunction as a Result of Impaired ADP Sensitivity. AB - Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial H2O2 emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA. PMID- 29980536 TI - IL35 Hinders Endogenous Antitumor T-cell Immunity and Responsiveness to Immunotherapy in Pancreatic Cancer. AB - Although successes in cancer immunotherapy have generated considerable excitement, this form of treatment has been largely ineffective in patients with pancreatic ductal adenocarcinoma (PDA). Mechanisms that contribute to the poor antitumor immune response in PDA are not well understood. Here, we demonstrated that cytokine IL35 is a major immunosuppressive driver in PDA and potentiates tumor growth via the suppression of endogenous antitumor T-cell responses. The growth of pancreatic tumors in mice deficient for IL35 was significantly reduced. An analysis of tumor-infiltrating immune cells revealed a role for IL35 in the expansion of regulatory T cells and the suppression of CD4+ effector T cells. We also detected a robust increase in both the infiltration and activation of cytotoxic CD8+ T cells, suggesting that targeting IL35 may be an effective strategy to convert PDA from an immunologically "cold" to "hot" tumor. Although PDA is typically resistant to anti-PD-1 immunotherapy, we demonstrated robust synergistic reduction in tumor growth when IL35 deficiency was combined with anti PD-1 treatment. These findings provide new insight into the function of IL35 in the pathogenesis of pancreatic cancer and underscore the potential significance of IL35 as a therapeutic target for use in combination immunotherapy approaches in this deadly malignancy. Cancer Immunol Res; 6(9); 1014-24. (c)2018 AACR. PMID- 29980535 TI - Regulation of Human Adipose Tissue Activation, Gallbladder Size, and Bile Acid Metabolism by a beta3-Adrenergic Receptor Agonist. AB - beta3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human beta3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the beta3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ? mean standardized uptake value [SUVmean] ? g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human beta3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective beta3-AR agonists to treat obesity-related complications. PMID- 29980537 TI - Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2 Based Immunotherapy in Acute Myeloid Leukemia. AB - Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML. Cancer Immunol Res; 6(9); 1110-9. (c)2018 AACR. PMID- 29980538 TI - Siglec-6 on Chronic Lymphocytic Leukemia Cells Is a Target for Post-Allogeneic Hematopoietic Stem Cell Transplantation Antibodies. AB - Although the 5-year survival rate of chronic lymphocytic leukemia (CLL) patients has risen to >80%, the only potentially curative treatment is allogeneic hematopoietic stem cell transplantation (alloHSCT). To identify possible new monoclonal antibody (mAb) drugs and targets for CLL, we previously developed a phage display-based human mAb platform to mine the antibody repertoire of patients who responded to alloHSCT. We had selected a group of highly homologous post-alloHSCT mAbs that bound to an unknown CLL cell surface antigen. Here, we show through next-generation sequencing of cDNAs encoding variable heavy-chain domains that these mAbs had a relative abundance of ~0.1% in the post-alloHSCT antibody repertoire and were enriched ~1,000-fold after three rounds of selection on primary CLL cells. Based on differential RNA-seq and a cell microarray screening technology for discovering human cell surface antigens, we now identify their antigen as Siglec-6. We verified this finding by flow cytometry, ELISA, siRNA knockdown, and surface plasmon resonance. Siglec-6 was broadly expressed in CLL and could be a potential target for antibody-based therapeutic interventions. Our study reaffirms the utility of post-alloHSCT antibody drug and target discovery. Cancer Immunol Res; 6(9); 1008-13. (c)2018 AACR. PMID- 29980539 TI - Impact of social relationships on income-laughter relationships among older people: the JAGES cross-sectional study. AB - OBJECTIVES: Laughter has a positive and quantifiable effect on certain aspects of health, and previous studies have suggested that income influences the emotion. However, it is unknown whether social relationship-related factors modify the association between equivalised income and laughter among older people. In the present study, we examined the relationship between equivalised income and the frequency of laughter. In addition, we examined the impact of social relationship related factors on the association between equivalised income and frequency of laughter using a cross-sectional study design. DESIGN: Cross-sectional study and binomial regression analysis. SETTING: We sampled from 30 municipalities in Japan. PARTICIPANTS: We examined 20 752 non-disabled Japanese individuals aged >=65 years using data from the Japan Gerontological Evaluation Study. PRIMARY OUTCOME: Frequency of laughter. RESULTS: Laughter increased significantly with an increase in equivalent income (p for trend <0.0001). Prevalence ratios (PR) for laughing almost every day were calculated according to quartile equivalised income after adjusting for age, instrumental activities of daily living, depression, frequency of meeting friends, number of social groups and family structure. The results revealed that PRs in Q4 (men; >=?24 420, women; >=?21 154) were 1.21 (95% CI 1.13 to 1.30) among men and 1.14 (95% CI 1.08 to 1.20) among women, as compared with Q1 (men; =20 years completed the survey. Women reporting at least one of four gynaecological alarm symptoms within the preceding 6 months form the study base (n=2957). RESULTS: The proportion of women reporting GP contact ranged from 21.1% (pain during intercourse) to 32.6% (postmenopausal bleeding). Women aged 60+ years had higher odds of reporting GP contact for at least one of the four gynaecological cancer alarm symptoms compared with those aged 20-39 years (OR 2.56, 95% CI 1.69 to 3.89), and immigrants had higher odds of reporting GP contact for at least one of the symptoms (OR 1.56, 95% CI 1.13 to 2.15) compared with ethnic Danish individuals. Among those reporting postmenopausal bleeding and/or bleeding during intercourse, women in the age group 60+ years had higher odds of reporting GP contact compared with those aged 20-39 years (OR 2.79, 95% CI 1.33 to 5.87). A high educational level (>12 years) was positively associated with reporting GP contact for postmenopausal bleeding and/or bleeding during intercourse compared with a low educational level (<10 years) (OR 2.23, 95% CI 1.19 to 4.19). No associations were found with lifestyle factors. CONCLUSIONS: Few women contacted their GP with recent onset gynaecological cancer alarm symptoms. Higher age, being immigrant and higher educational level increased the odds of GP contact. Future studies should explore the reasons for these findings as this may aid in prompting early diagnosis and thereby improve the prognosis of gynaecological cancer. PMID- 29980547 TI - Integrating culturally informed approaches into physiotherapy assessment and treatment of chronic pain: a pilot randomised controlled trial. AB - OBJECTIVE: To evaluate patient engagement with, and the feasibility of, a novel, culturally adapted physiotherapy pain management approach. DESIGN: A participant blinded and assessor-blinded pilot randomised controlled trial. SETTING: Outpatient physiotherapy departments at two public hospitals and one district pain clinic. PARTICIPANTS: Adults (n=48) with chronic musculoskeletal pain (daily pain >3 months), who self-identified as Mandaean, Assyrian or Vietnamese, were randomised to one of two physiotherapy treatment conditions. INTERVENTIONS: 24 participants underwent combined group and individualised treatment described as 'culturally adapted physiotherapy', while 24 underwent evidence-informed 'usual physiotherapy care'. Both treatment arms consisted of up to 10 sessions over a 3 month period. OUTCOME MEASURES: Patient engagement was measured via participant attendance, adherence and satisfaction data. Secondary outcomes included clinical measures of pain severity, interference and suffering, physical function and negative emotional state. RESULTS: 96% of participants undergoing culturally adapted physiotherapy completed treatment, compared with 58% of the usual physiotherapy group. For the culturally adapted group attendance (87%+/-18%) and adherence (68%+/-32%) were higher relative to usual care (68%+/-32% and 55%+/ 43%). Satisfaction was similar for the culturally adapted (82.7%+/-13.4%) and usual care (79.3+/-17.3) groups. For secondary outcomes, a significant between group effect for pain-related suffering in favour of the culturally adapted group was observed with a medium effect size (partial eta2 0.086, mean 3.56, 95% CI 0.11 to 7), while results for pain severity, interference, physical function and negative emotional state were similar. CONCLUSIONS: Aligning treatment with the beliefs and values of culturally and linguistically diverse communities enhances patient engagement with physiotherapy. These results support the feasibility of a larger, multisite trial to determine if improved engagement with culturally adapted physiotherapy translates to improved clinical outcomes. TRIAL REGISTRATION NUMBER: ACTRN12616000857404; Pre-results. PMID- 29980549 TI - Start-up e-cigarette brand aims to "improve smokers' lives". PMID- 29980548 TI - Exploration and characterisation of the phenotypic and genetic profiles of patients with early onset schizophrenia associated with autism spectrum disorder and their first-degree relatives: a French multicentre case series study protocol (GenAuDiss). AB - INTRODUCTION: Early-onset schizophrenia (EOS) is a rare and severe condition. A higher rate of neurodevelopmental abnormalities, such as intellectual or communication impairments as well as attention deficit hyperactivity disorder, is observed in EOS compared with adult-onset schizophrenia. Early signs of autism spectrum disorders (ASD) are present in about 30% of patients. Genetic abnormalities, including copy number variations, are frequent in neurodevelopmental disorders and have been associated to ASD physiopathology. Implicated genes encode proteins involved in brain development, synapses morphology and plasticity and neurogenesis. In addition, an increasing number of genetic abnormalities are shared by EOS and ASD, underlying the neurodevelopmental hypothesis of EOS.The main objective of our study is to identify disease-causing genetic mutations in a cohort of patients affected by both EOS and ASD. Special attention will be paid to genes involved in neurodevelopmental pathways. METHODS AND ANALYSIS: We describe a multicentric study in a paediatric population. The study started in April 2014. Inclusion criteria are: age 7-22 years, diagnosis of EOS with comorbid ASD and IQ >50; Parents and siblings are also enrolled. We perform psychiatric assessments (Mini International Neuropsychiatric Interview, Kiddie Schedule for Affective Disorders and Schizophrenia -Present and Lifetime Version, Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms) together with neurocognitive evaluations (IQ, Trail Making Test A/B and verbal fluency). Then, we study variants of the coding part of DNA (exome), using next-generation sequencing process on trio (mother, father and child). Bioinformatics tools (RVIS and PolyPhen-2) are used to prioritise disease-causing mutations in candidate genes. The inclusion period will end in November 2019. ETHICS AND DISSEMINATION: The study protocol was approved by the Local Ethic Committee and by the French National Agency for Medicines and Health Products Safety. All patients signed informed consent on enrolment in the study. Results of the present study should help to unravel the molecular pathology of EOS, paving the way for an early therapeutic intervention. TRIAL REGISTRATION NUMBER: NCT0256552; Pre-results. PMID- 29980550 TI - Fengycins, Cyclic Lipopeptides from Marine Bacillus subtilis Strains, Kill the Plant-Pathogenic Fungus Magnaporthe grisea by Inducing Reactive Oxygen Species Production and Chromatin Condensation. AB - Rice blast caused by the phytopathogen Magnaporthe grisea poses a serious threat to global food security and is difficult to control. Bacillus species have been extensively explored for the biological control of many fungal diseases. In the present study, the marine bacterium Bacillus subtilis BS155 showed a strong antifungal activity against M. grisea The active metabolites were isolated and identified as cyclic lipopeptides (CLPs) of the fengycin family, named fengycin BS155, by the combination of high-performance liquid chromatography (HPLC) and electrospray ionization mass spectrometry (ESI-MS) and tandem mass spectrometry (ESI-MS/MS). Analyses using scanning and transmission electron microscopy revealed that fengycin BS155 caused morphological changes in the plasma membrane and cell wall of M. grisea hyphae. Using comparative proteomic and biochemical assays, fengycin BS155 was demonstrated to reduce the mitochondrial membrane potential (MMP), induce bursts of reactive oxygen species (ROS), and downregulate the expression level of ROS-scavenging enzymes. Simultaneously, fengycin BS155 caused chromatin condensation in fungal hyphal cells, which led to the upregulation of DNA repair-related protein expression and the cleavage of poly(ADP-ribose) polymerase (PARP). Altogether, our results indicate that fengycin BS155 acts by inducing membrane damage and dysfunction of organelles, disrupting MMP, oxidative stress, and chromatin condensation, resulting in M. grisea hyphal cell death. Therefore, fengycin BS155 and its parent bacterium are very promising candidates for the biological control of M. grisea and the associated rice blast and should be further investigated as such.IMPORTANCE Rice (Oryza sativa L.) is the most important crop and a primary food source for more than half of the world's population. Notably, scientists in China have developed several types of rice that can be grown in seawater, avoiding the use of precious freshwater resources and potentially creating enough food for 200 million people. The plant-affecting fungus Magnaporthe grisea is the causal agent of rice blast disease, and biological rather than chemical control of this threatening disease is highly desirable. In this work, we discovered fengycin BS155, a cyclic lipopeptide material produced by the marine bacterium Bacillus subtilis BS155, which showed strong activity against M. grisea Our results elucidate the mechanism of fengycin BS155-mediated M. grisea growth inhibition and highlight the potential of B. subtilis BS155 as a biocontrol agent against M. grisea in rice cultivation under both fresh- and saltwater conditions. PMID- 29980551 TI - A Short Protocol for Gene Knockout and Complementation in Xylella fastidiosa Shows that One of the Type IV Pilin Paralogs (PD1926) Is Needed for Twitching while Another (PD1924) Affects Pilus Number and Location. AB - Twitching motility is one of the major virulence factors of the plant-pathogenic bacterium Xylella fastidiosa, and it is mediated by type IV pili (TFP) that are present at one of the cell poles. Genome analysis of X. fastidiosa showed the presence of at least four paralogs of the gene pilA, which encodes the TFP major pilin subunit. However, whether all of these paralogs have a functional role in TFP structure and function is unknown. Here, using a short and reliable protocol based on overlap extension PCR and natural transformation, deletion mutants of two pilA paralogs (pilA1 PD1924 and pilA2 PD1926) were generated in two X. fastidiosa subsp. fastidiosa strains, WM1-1 and TemeculaL, followed by assessment of twitching motility and biofilm formation. Deletion of pilA2 caused loss of twitching motility, whereas deletion of pilA1 did not influence twitching motility but caused hyperpiliation and extended distribution of TFP along the sides of the cell. Loss of twitching motility due to pilA2 deletion was restored when a wild-type copy of the pilA2 gene was added at a neutral site in the genome of mutants in both wild-type backgrounds. This study demonstrates that PCR templates generated by overlap extension PCR can be successfully used to rapidly generate gene knockouts and perform genetic complementation in X. fastidiosa, and that twitching motility in X. fastidiosa is controlled by regulating the transcription of the major pilin subunit, pilA2IMPORTANCE The bacterial plant pathogen Xylella fastidiosa causes incurable diseases in multiple hosts, including grape, citrus, and blueberry. Historically restricted to the Americas, it was recently found to cause epidemics in olives in Italy and to infect other hosts in Europe and Asia. In this study, we report a short protocol to create deletion and complemented mutants using fusion PCR and natural transformation. We also determined the distinct function of two pilin paralogs, the main structural component of TFP involved in twitching motility, which allows this bacterium to move inside the xylem vessels against the flow. One of the paralogs is needed for twitching movement, whereas the other does not have an effect on motility but influences the number and position of TFP. Since twitching motility is fundamental for the virulence of this xylem-limited bacterium, this study contributes to the understanding of the regulation of virulence by this pathogen. PMID- 29980552 TI - Yersinia pseudotuberculosis Prevalence and Diversity in Wild Boars in Northeast Germany. AB - In this study, the prevalence of Yersinia pseudotuberculosis in wild boars in northeast Germany was determined. For that purpose, the tonsils of 503 wild boars were sampled. The presence of Y. pseudotuberculosis was studied by diagnostic PCR. Positive samples were analyzed by cultural detection using a modified cold enrichment protocol. Ten Y. pseudotuberculosis isolates were obtained, which were characterized by biotyping, molecular serotyping, and multilocus sequence typing (MLST). In addition, whole-genome sequences and the antimicrobial susceptibility of the isolates were analyzed. Yersinia pseudotuberculosis was isolated from male and female animals, most of which were younger than 1 year. A prevalence of 2% (10/503) was determined by cultural detection, while 6.4% (32/503) of the animals were positive by PCR. The isolates belonged to the biotypes 1 and 2 and serotypes O:1a (n = 7), O:1b (n = 2), and O:4a (n = 1). MLST analysis revealed three sequence types, ST9, ST23, and ST42. Except one isolate, all isolates revealed a strong resistance to colistin. The relationship of the isolates was studied by whole-genome sequencing demonstrating that they belonged to four clades, exhibiting five different pulsed-field gel electrophoresis (PFGE) restriction patterns and a diverse composition of virulence genes. Six isolates harbored the virulence plasmid pYV. Besides two isolates, all isolates contained ail and inv genes and a complete or incomplete high-pathogenicity island (HPI). None of them possessed a gene for the superantigen YPM. The study shows that various Y. pseudotuberculosis strains exist in wild boars in northeast Germany, which may pose a risk to humans.IMPORTANCEYersinia pseudotuberculosis is a foodborne pathogen whose occurrence is poorly understood. One reason for this situation is the difficulty in isolating the species. The methods developed for the isolation of Yersinia enterocolitica are not well suited for Y. pseudotuberculosis We therefore designed a protocol which enabled the isolation of Y. pseudotuberculosis from a relatively high proportion of PCR-positive wild boar tonsils. The study indicates that wild boars in northeast Germany may carry a variety of Y. pseudotuberculosis strains, which differ in terms of their pathogenic potential and other properties. Since wild boars are widely distributed in German forests and even populate cities such as Berlin, they may transmit yersiniae to other animals and crop plants and may thus cause human infections through the consumption of contaminated food. Therefore, the prevalence of Y. pseudotuberculosis should be determined also in other animals and regions to learn more about the natural reservoir of this species. PMID- 29980553 TI - Linking Uncultivated Microbial Populations and Benthic Carbon Turnover by Using Quantitative Stable Isotope Probing. AB - Benthic environments harbor highly diverse and complex microbial communities that control carbon fluxes, but the role of specific uncultivated microbial groups in organic matter turnover is poorly understood. In this study, quantitative DNA stable isotope probing (DNA-qSIP) was used for the first time to link uncultivated populations of bacteria and archaea to carbon turnover in lacustrine surface sediments. After 1-week incubations in the dark with [13C]bicarbonate, DNA-qSIP showed that ammonia-oxidizing archaea (AOA) were the dominant active chemolithoautotrophs involved in the production of new organic matter. Natural 13C-labeled organic matter was then obtained by incubating sediments in the dark for 2.5 months with [13C]bicarbonate, followed by extraction and concentration of high-molecular-weight (HMW) (>50-kDa) organic matter. qSIP showed that the labeled organic matter was turned over within 1 week by 823 microbial populations (operational taxonomic units [OTUs]) affiliated primarily with heterotrophic Proteobacteria, Chloroflexi, Verrucomicrobia, and Bacteroidetes However, several OTUs affiliated with the candidate microbial taxa Latescibacteria, Omnitrophica, Aminicentantes, Cloacimonates, AC1, Bathyarchaeota, and Woesearchaeota, groups known only from genomic signatures, also contributed to biomass turnover. Of these 823 labeled OTUs, 52% (primarily affiliated with Proteobacteria) also became labeled in 1-week incubations with [13C]bicarbonate, indicating that they turned over carbon faster than OTUs that were labeled only in incubations with 13C-labeled HMW organic matter. These taxa consisted primarily of uncultivated populations within the Firmicutes, Bacteroidetes, Verrucomicrobia, and Chloroflexi, highlighting their ecological importance. Our study helps define the role of several poorly understood, uncultivated microbial groups in the turnover of benthic carbon derived from "dark" primary production.IMPORTANCE Little is known about the ecological role of uncultivated microbial populations in carbon turnover in benthic environments. To better understand this, we used quantitative stable isotope probing (qSIP) to quantify the abundance of diverse, specific groups of uncultivated bacteria and archaea involved in autotrophy and heterotrophy in a benthic lacustrine habitat. Our results provide quantitative evidence for active heterotrophic and autotrophic metabolism of several poorly understood microbial groups, thus demonstrating their relevance for carbon turnover in benthic settings. Archaeal ammonia oxidizers were significant drivers of in situ "dark" primary production supporting the growth of heterotrophic bacteria. These findings expand our understanding of the microbial populations within benthic food webs and the role of uncultivated microbes in benthic carbon turnover. PMID- 29980554 TI - A Lytic Bacteriophage for Controlling Pseudomonas lactis in Raw Cow's Milk. AB - The control of bacterial growth during milk processing is crucial for the quality maintenance of commercial milk and milk products. During a period of cold storage prior to heat treatments, some psychrotrophic bacteria grow and produce extracellular heat-resistant lipases and proteases that cause product defects. The use of lytic bacteriophages (phages) that infect and kill bacteria could be a useful tool for suppressing bacterial growth during this cold storage phase. In this study, we isolated a Pseudomonas lactis strain and a phage from raw cow's milk. Quantitative characterization of the phage was used to elucidate whether this phage was active under low temperatures and neutral pH and whether it was inactivated during pasteurization. Phage titer determination was possible under conditions ranging from pH 4 to 9 and from 3 degrees C to 25 degrees C; the phage was inactivated under pasteurization conditions at 63 degrees C for 30 min. Furthermore, we showed that this phage reduced viable bacterial cell counts in both skim and whole milk. The results of this study represent the potential uses of phages for controlling psychrotrophic bacterial growth in raw cow's milk during cold storage.IMPORTANCE Suppression of bacterial growth in raw milk under cold storage is crucial for the quality control of commercially supplied milk. The use of lytic phages as low-cost microbicides is an attractive prospect. Due to strict host specificities, phages must be isolated from the raw milk where the host bacteria are growing. We first isolated the P. lactis bacterial strain and then the phage infecting that strain. Partial phage genomic analysis showed that this is a newly isolated phage, different from any previously reported. This study reports a lytic phage for P. lactis, and we have presented evidence here that this phage reduced viable bacterial cell counts not only in rich medium but also in skim and whole milk. As a result, we have concluded that the phage reported in this study would be useful in milk processing. PMID- 29980555 TI - Proximity to Other Commercial Turkey Farms Affects Colonization Onset, Genotypes, and Antimicrobial Resistance Profiles of Campylobacter spp. in Turkeys: Suggestive Evidence from a Paired-Farm Model. AB - Campylobacter is a leading foodborne pathogen, and poultry products are major vehicles for human disease. However, determinants impacting Campylobacter colonization in poultry remain poorly understood, especially with turkeys. Here, we used a paired-farm design to concurrently investigate Campylobacter colonization and strain types in two turkey breeds (Hybrid and Nicholas) at two farms in eastern North Carolina. One farm (the Teaching Animal Unit [TAU]) was a university teaching unit at least 40 km from commercial turkey farms, while the other (SIB) was a commercial farm in an area with a high density of turkey farms. Day-old birds were obtained from the same breeder flock and hatchery and placed at TAU and SIB on the same day. Birds were marked to identify turkey breed and then commingled on each farm. TAU birds became colonized 1 week later than SIB and had lower initial Campylobacter levels in the cecum. Interestingly, Campylobacter genotypes and antimicrobial resistance profiles differed markedly between the farms. Most TAU isolates were resistant only to tetracycline, whereas multidrug-resistant isolates predominated at SIB. Multilocus sequence typing revealed that no Campylobacter genotypes were shared between TAU and SIB. A bovine-associated genotype (sequence type 1068 [ST1068]) predominated in Campylobacter coli from TAU, while SIB isolates had genotypes commonly encountered in commercial turkey production in the region. One multidrug resistant Campylobacter jejuni strain (ST1839) showed significant association with one of the two turkey breeds. The findings highlight the need to further characterize the impact of farm-specific factors and host genetics on antimicrobial resistance and genotypes of C. jejuni and C. coli that colonize turkeys.IMPORTANCE Colonization of poultry with Campylobacter at the farm level is complex, poorly understood, and critically linked to contamination of poultry products, which is known to constitute a leading risk factor for human campylobacteriosis. Here, we investigated the use of a paired-farm design under standard production conditions and in the absence of experimental inoculations to assess potential impacts of farm and host genetics on prevalence, antimicrobial resistance and genotypes of Campylobacter in commercial turkeys of two different breeds. Data suggest impacts of farm proximity to other commercial turkey farms on the onset of colonization, genotypes, and antimicrobial resistance profiles of Campylobacter colonizing the birds. Furthermore, the significant association of a specific multidrug-resistant Campylobacter jejuni strain with turkeys of one breed suggests colonization partnerships at the Campylobacter strain-turkey breed level. The study design avoids potential pitfalls associated with experimental inoculations, providing novel insights into the dynamics of turkey colonization with Campylobacter in actual farm ecosystems. PMID- 29980556 TI - A Long-Standing Complex Tropical Dipole Shapes Marine Microbial Biogeography. AB - Microbial population size, production, diversity, and community structure are greatly influenced by the surrounding physicochemical conditions, such as large scale biogeographic provinces and water masses. An oceanic mesoscale dipole consists of a cyclonic eddy and an anticyclonic eddy. Dipoles occur frequently in the ocean and usually last from a few days to several months; they have significant impacts on local and global oceanic biological, ecological, and geochemical processes. To better understand how dipoles shape microbial communities, we examined depth-resolved distributions of microbial communities across a dipole in the South China Sea. Our data demonstrated that the dipole had a substantial influence on microbial distributions, community structure, and functional groups both vertically and horizontally. Large alpha and beta diversity differences were observed between anticyclonic and cyclonic eddies in surface and subsurface layers, consistent with distribution changes of major bacterial groups in the dipole. The dipole created uplift, downward transport, enrichment, depletion, and horizontal transport effects. We also found that the edge of the dipole might induce strong subduction, indicated by the presence of Prochlorococcus and Synechococcus in deep waters. Our findings suggest that dipoles, with their unique characteristics, might act as a driver for microbial community dynamics.IMPORTANCE Oceanic dipoles, which consist of a cyclonic eddy and an anticyclonic eddy together, are among the most contrasted phenomena in the ocean. Dipoles generate strong vertical mixing and horizontal advection, inducing biological responses. This study provides vertical profiles of microbial abundance, diversity, and community structure in a mesoscale dipole. We identify the links between the physical oceanography and microbial oceanography and demonstrate that the dipole, with its unique features, could act as a driver for microbial community dynamics, which may have large impacts on both the local and global marine biogeochemical cycles. PMID- 29980557 TI - Modeling Surface Disinfection Needs To Meet Microbial Risk Reduction Targets. AB - Nosocomial viral infections are an important cause of health care-acquired infections where fomites have a role in transmission. Using stochastic modeling to quantify the effects of surface disinfection practices on nosocomial pathogen exposures and infection risk can inform cleaning practices. The purpose of this study was to predict the effect of surface disinfection on viral infection risks and to determine needed viral reductions to achieve risk targets. Rotavirus, rhinovirus, and influenza A virus infection risks for two cases were modeled. Case 1 utilized a single fomite contact approach, while case 2 assumed 6 h of contact activities. A 94.1% viral reduction on surfaces and hands was measured following a single cleaning round using an Environmental Protection Agency (EPA) registered disinfectant in an urgent care facility. This value was used to model the effect of a surface disinfection intervention on infection risk. Risk reductions for other surface-cleaning efficacies were also simulated. Surface reductions required to achieve risk probability targets were estimated. Under case 1 conditions, a 94.1% reduction in virus surface concentration reduced infection risks by 94.1%. Under case 2 conditions, a 94.1% reduction on surfaces resulted in median viral infection risks being reduced by 92.96 to 94.1% and an influenza A virus infection risk below one in a million. Surface concentration in the equations was highly correlated with dose and infection risk outputs. For rotavirus and rhinovirus, a >99.99% viral surface reduction would be needed to achieve a one-in-a-million risk target. This study quantifies reductions of infection risk relative to surface disinfectant use and demonstrates that risk targets for low-infectious-dose organisms may be more challenging to achieve.IMPORTANCE It is known that the use of EPA-registered surface disinfectant sprays can reduce infection risk if used according to the manufacturer's instructions. However, there are currently no standards for health care environments related to contamination levels on surfaces. The significance of this research is in quantifying needed reductions to meet various risk targets using realistic viral concentrations on surfaces for health care environments. This research informs the design of cleaning protocols by demonstrating that multiple applications may be needed to reduce risk and by highlighting a need for more models exploring the relationship among microbial contamination of surfaces, patient and health care worker behaviors, and infection risks. PMID- 29980558 TI - Transcription Factor NsdD Regulates the Expression of Genes Involved in Plant Biomass-Degrading Enzymes, Conidiation, and Pigment Biosynthesis in Penicillium oxalicum. AB - Soil fungi produce a wide range of chemical compounds and enzymes with potential for applications in medicine and biotechnology. Cellular processes in soil fungi are highly dependent on the regulation under environmentally induced stress, but most of the underlying mechanisms remain unclear. Previous work identified a key GATA-type transcription factor, Penicillium oxalicum NsdD (PoxNsdD; also called POX08415), that regulates the expression of cellulase and xylanase genes in P. oxalicum PoxNsdD shares 57 to 64% identity with the key activator NsdD, involved in asexual development in Aspergillus In the present study, the regulatory roles of PoxNsdD in P. oxalicum were further explored. Comparative transcriptomic profiling revealed that PoxNsdD regulates major genes involved in starch, cellulose, and hemicellulose degradation, as well as conidiation and pigment biosynthesis. Subsequent experiments confirmed that a DeltaPoxNsdD strain lost 43.9 to 78.8% of starch-digesting enzyme activity when grown on soluble corn starch, and it produced 54.9 to 146.0% more conidia than the DeltaPoxKu70 parental strain. During cultivation, DeltaPoxNsdD cultures changed color, from pale orange to brick red, while the DeltaPoxKu70 cultures remained bluish white. Real-time quantitative reverse transcription-PCR showed that PoxNsdD dynamically regulated the expression of a glucoamylase gene (POX01356/Amy15A), an alpha amylase gene (POX09352/Amy13A), and a regulatory gene (POX03890/amyR), as well as a polyketide synthase gene (POX01430/alb1/wA) for yellow pigment biosynthesis and a conidiation-regulated gene (POX06534/brlA). Moreover, in vitro binding experiments showed that PoxNsdD bound the promoter regions of the above-described genes. This work provides novel insights into the regulatory mechanisms of fungal cellular processes and may assist in genetic engineering of Poxalicum for potential industrial and medical applications.IMPORTANCE Most filamentous fungi produce a vast number of extracellular enzymes that are used commercially for biorefineries of plant biomass to produce biofuels and value-added chemicals, which might promote the transition to a more environmentally friendly economy. The expression of these extracellular enzyme genes is tightly controlled at the transcriptional level, which limits their yields. Hitherto our understanding of the regulation of expression of plant biomass-degrading enzyme genes in filamentous fungi has been rather limited. In the present study, regulatory roles of a key regulator, PoxNsdD, were further explored in the soil fungus Penicillium oxalicum, contributing to the understanding of gene regulation in filamentous fungi and revealing the biotechnological potential of Poxalicum via genetic engineering. PMID- 29980559 TI - Legionella pneumophila and Other Legionella Species Isolated from Legionellosis Patients in Japan between 2008 and 2016. AB - The Legionella Reference Center in Japan collected 427 Legionella clinical isolates between 2008 and 2016, including 7 representative isolates from corresponding outbreaks. The collection included 419 Legionella pneumophila isolates, of which 372 belonged to serogroup 1 (SG1) (87%) and the others belonged to SG2 to SG15 except for SG7 and SG11, and 8 isolates of other Legionella species (Legionella bozemanae, Legionella dumoffii, Legionella feeleii, Legionella longbeachae, Legionella londiniensis, and Legionella rubrilucens). L. pneumophila isolates were genotyped by sequence-based typing (SBT) and represented 187 sequence types (STs), of which 126 occurred in a single isolate (index of discrimination of 0.984). These STs were analyzed using minimum spanning tree analysis, resulting in the formation of 18 groups. The pattern of overall ST distribution among L. pneumophila isolates was diverse. In particular, some STs were frequently isolated and were suggested to be related to the infection sources. The major STs were ST23 (35 isolates), ST120 (20 isolates), and ST138 (16 isolates). ST23 was the most prevalent and most causative ST for outbreaks in Japan and Europe. ST138 has been observed only in Japan, where it has caused small-scale outbreaks; 81% of those strains (13 isolates) were suspected or confirmed to infect humans through bath water sources. On the other hand, 11 ST23 strains (31%) and 5 ST120 strains (25%) were suspected or confirmed to infect humans through bath water. These findings suggest that some ST strains frequently cause legionellosis in Japan and are found under different environmental conditions.IMPORTANCELegionella pneumophila serogroup 1 (SG1) is the most frequent cause of legionellosis. Our previous genetic analysis indicated that SG1 environmental isolates represented 8 major clonal complexes, consisting of 3 B groups, 2 C groups, and 3 S groups, which included major environmental isolates derived from bath water, cooling towers, and soil and puddles, respectively. Here, we surveyed clinical isolates collected from patients with legionellosis in Japan between 2008 and 2016. Most strains belonging to the B group were isolated from patients for whom bath water was the suspected or confirmed source of infection. Among the isolates derived from patients whose suspected infection source was soil or dust, most belonged to the S1 group and none belonged to the B or C groups. Additionally, the U group was discovered as a new group, which mainly included clinical isolates with unknown infection sources. PMID- 29980562 TI - Managing blood pressure in older adults. PMID- 29980560 TI - A Colicin M-Type Bacteriocin from Pseudomonas aeruginosa Targeting the HxuC Heme Receptor Requires a Novel Immunity Partner. AB - Pyocins are bacteriocins secreted by Pseudomonas aeruginosa, and they assist in the colonization of different niches. A major subset of these antibacterial proteins adopt a modular organization characteristic of polymorphic toxins. They include a receptor-binding domain, a segment enabling membrane passage, and a toxin module at the carboxy terminus, which eventually kills the target cells. To protect themselves from their own products, bacteriocin-producing strains express an immunity gene concomitantly with the bacteriocin. We show here that a pyocin equipped with a phylogenetically distinct ColM toxin domain, PaeM4, mediates antagonism against a large set of P. aeruginosa isolates. Immunity to PaeM4 is provided by the inner membrane protein PmiC, which is equipped with a transmembrane topology not previously described for the ColM family. Given that strains lacking a pmiC gene are killed by PaeM4, the presence of such an immunity partner likely is a key criterion for escaping cellular death mediated by PaeM4. The presence of a TonB box in PaeM4 and enhanced bacteriocin activity under iron poor conditions strongly suggested the targeting of a TonB-dependent receptor. Evaluation of PaeM4 activities against TonB-dependent receptor knockout mutants in P. aeruginosa PAO1 revealed that the heme receptor HxuC (PA1302) serves as a PaeM4 target at the cellular surface. Because other ColM-type pyocins may target the ferrichrome receptor FiuA, our results illustrate the versatility in target recognition conferred by the polymorphic nature of ColM-type bacteriocins.IMPORTANCE The antimicrobial armamentarium of a bacterium is a major asset for colonizing competitive environments. Bacteriocins comprise a subset of these compounds. Pyocins are an example of such antibacterial proteins produced by Pseudomonas aeruginosa, killing other P. aeruginosa strains. A large group of these molecules show a modular protein architecture that includes a receptor binding domain for initial target cell attachment and a killer domain. In this study, we have shown that a novel modular pyocin (PaeM4) that kills target bacteria via interference with peptidoglycan assembly takes advantage of the HxuC heme receptor. Cells can protect themselves from killing by the presence of a dedicated immunity partner, an integral inner membrane protein that adopts a transmembrane topology distinct from that of proteins currently known to provide immunity against such toxin activity. Understanding the receptors with which pyocins interact and how immunity to pyocins is achieved is a pivotal step toward the rational design of bacteriocin cocktails for the treatment of P. aeruginosa infections. PMID- 29980561 TI - CRISPR-Cpf1-Assisted Multiplex Genome Editing and Transcriptional Repression in Streptomyces. AB - Streptomyces has a strong capability for producing a large number of bioactive natural products and remains invaluable as a source for the discovery of novel drug leads. Although the Streptococcus pyogenes CRISPR-Cas9-assisted genome editing tool has been developed for rapid genetic engineering in Streptomyces, it has a number of limitations, including the toxicity of SpCas9 expression in some important industrial Streptomyces strains and the need for complex expression constructs when targeting multiple genomic loci. To address these problems, in this study, we developed a high-efficiency CRISPR-Cpf1 system (from Francisella novicida) for multiplex genome editing and transcriptional repression in Streptomyces Using an all-in-one editing plasmid with homology-directed repair (HDR), our CRISPR-Cpf1 system precisely deletes single or double genes at efficiencies of 75 to 95% in Streptomyces coelicolor When no templates for HDR are present, random-sized DNA deletions are achieved by FnCpf1-induced double strand break (DSB) repair by a reconstituted nonhomologous end joining (NHEJ) pathway. Furthermore, a DNase-deactivated Cpf1 (ddCpf1)-based integrative CRISPRi system is developed for robust, multiplex gene repression using a single customized crRNA array. Finally, we demonstrate that FnCpf1 and SpCas9 exhibit different suitability in tested industrial Streptomyces species and show that FnCpf1 can efficiently promote HDR-mediated gene deletion in the 5-oxomilbemycin producing strain Streptomyces hygroscopicus SIPI-KF, in which SpCas9 does not work well. Collectively, FnCpf1 is a powerful and indispensable addition to the Streptomyces CRISPR toolbox.IMPORTANCE Rapid, efficient genetic engineering of Streptomyces strains is critical for genome mining of novel natural products (NPs) as well as strain improvement. Here, a novel and high-efficiency Streptomyces genome editing tool is established based on the FnCRISPR-Cpf1 system, which is an attractive and powerful alternative to the S. pyogenes CRISPR Cas9 system due to its unique features. When combined with HDR or NHEJ, FnCpf1 enables the creation of gene(s) deletion with high efficiency. Furthermore, a ddCpf1-based integrative CRISPRi platform is established for simple, multiplex transcriptional repression. Of importance, FnCpf1-based genome editing proves to be a highly efficient tool for genetic modification of some important industrial Streptomyces strains (e.g., S. hygroscopicus SIPI-KF) that cannot utilize the SpCRISPR-Cas9 system. We expect the CRISPR-Cpf1-assisted genome editing tool to accelerate discovery and development of pharmaceutically active NPs in Streptomyces as well as other actinomycetes. PMID- 29980563 TI - Nodal and Hedgehog synergize in gill slit formation during development of the cephalochordate Branchiostoma floridae. AB - The larval pharynx of the cephalochordate Branchiostoma (amphioxus) is asymmetrical. The mouth is on the left, and endostyle and gill slits are on the right. At the neurula, Nodal and Hedgehog (Hh) expression becomes restricted to the left. To dissect their respective roles in gill slit formation, we inhibited each pathway separately for 20 min at intervals during the neurula stage, before gill slits penetrate, and monitored the effects on morphology and expression of pharyngeal markers. The results pinpoint the short interval spanning the gastrula/neurula transition as the critical period for specification and positioning of future gill slits. Thus, reduced Nodal signaling shifts the gill slits ventrally, skews the pharyngeal domains of Hh, Pax1/9, Pax2/5/8, Six1/2 and IrxC towards the left, and reduces Hh and Tbx1/10 expression in endoderm and mesoderm, respectively. Nodal auto-regulates. Decreased Hh signaling does not affect gill slit positions or Hh or Nodal expression, but it does reduce the domain of Gli, the Hh target, in the pharyngeal endoderm. Thus, during the neurula stage, Nodal and Hh cooperate in gill slit development - Hh mediates gill slit formation and Nodal establishes their left-right position. PMID- 29980564 TI - An ancestral role for Semaphorin3F-Neuropilin signaling in patterning neural crest within the new vertebrate head. AB - The origin of the vertebrate head is one of the great unresolved issues in vertebrate evolutionary developmental biology. Although many of the novelties in the vertebrate head and pharynx derive from the neural crest, it is still unknown how early vertebrates patterned the neural crest within the ancestral body plan they inherited from invertebrate chordates. Here, using a basal vertebrate, the sea lamprey, we show that homologs of Semaphorin3F (Sema3F) ligand and its Neuropilin (Nrp) receptors show complementary and dynamic patterns of expression that correlate with key periods of neural crest development (migration and patterning of cranial neural crest-derived structures). Using CRISPR/Cas9 mediated mutagenesis, we demonstrate that lamprey Sema3F is essential for patterning of neural crest-derived melanocytes, cranial ganglia and the head skeleton, but is not required for neural crest migration or patterning of trunk neural crest derivatives. Based on comparisons with jawed vertebrates, our results suggest that the deployment of Nrp-Sema3F signaling, along with other intercellular guidance cues, was pivotal in allowing early vertebrates to organize and pattern cranial neural crest cells into many of the hallmark structures that define the vertebrate head. PMID- 29980565 TI - The Drosophila insulin pathway controls Profilin expression and dynamic actin rich protrusions during collective cell migration. AB - Understanding how different cell types acquire their motile behaviour is central to many normal and pathological processes. Drosophila border cells represent a powerful model for addressing this issue and to specifically decipher the mechanisms controlling collective cell migration. Here, we identify the Drosophila Insulin/Insulin-like growth factor signalling (IIS) pathway as a key regulator in controlling actin dynamics in border cells, independently of its function in growth control. Loss of IIS activity blocks the formation of actin rich long cellular extensions that are important for the delamination and the migration of the invasive cluster. We show that IIS specifically activates the expression of the actin regulator chickadee, the Drosophila homolog of Profilin, which is essential for promoting the formation of actin extensions and migration through the egg chamber. In this process, the transcription factor FoxO acts as a repressor of chickadee expression. Altogether, these results show that local activation of IIS controls collective cell migration through regulation of actin homeostasis and protrusion dynamics. PMID- 29980566 TI - Eyeless/Pax6 initiates eye formation non-autonomously from the peripodial epithelium. AB - The transcription factor Pax6 is considered the master control gene for eye formation because (1) it is present within the genomes and retina/lens of all animals with a visual system; (2) severe retinal defects accompany its loss; (3) Pax6 genes have the ability to substitute for one another across the animal kingdom; and (4) Pax6 genes are capable of inducing ectopic eye/lens in flies and mammals. Many roles of Pax6 were first elucidated in Drosophila through studies of the gene eyeless (ey), which controls both growth of the entire eye-antennal imaginal disc and fate specification of the eye. We show that Ey also plays a surprising role within cells of the peripodial epithelium to control pattern formation. It regulates the expression of decapentaplegic (dpp), which is required for initiation of the morphogenetic furrow in the eye itself. Loss of Ey within the peripodial epithelium leads to the loss of dpp expression within the eye, failure of the furrow to initiate, and abrogation of retinal development. These findings reveal an unexpected mechanism for how Pax6 controls eye development in Drosophila. PMID- 29980567 TI - Dynamic cytoplasmic projections connect mammalian spermatogonia in vivo. AB - Throughout the male reproductive lifespan, spermatogonial stem cells (SSCs) produce committed progenitors that proliferate and then remain physically connected in growing clones via short cylindrical intercellular bridges (ICBs). These ICBs, which enlarge in meiotic spermatocytes, have been demonstrated to provide a conduit for postmeiotic haploid spermatids to share sex chromosome derived gene products. In addition to ICBs, spermatogonia exhibit multiple thin cytoplasmic projections. Here, we have explored the nature of these projections in mice and find that they are dynamic, span considerable distances from their cell body (>=25 MUm), either terminate or physically connect multiple adjacent spermatogonia, and allow for sharing of macromolecules. Our results extend the current model that subsets of spermatogonia exist as isolated cells or clones, and support a model in which spermatogonia of similar developmental fates are functionally connected through a shared dynamic cytoplasm mediated by thin cytoplasmic projections. PMID- 29980570 TI - We must make clear that racism is unacceptable. PMID- 29980568 TI - Binding of Dickkopf-3 to CXCR7 Enhances Vascular Progenitor Cell Migration and Degradable Graft Regeneration. AB - RATIONALE: Vascular progenitor cells play key roles in physiological and pathological vascular remodeling-a process that is crucial for the regeneration of acellular biodegradable scaffolds engineered as vital strategies against the limited availability of healthy autologous vessels for bypass grafting. Therefore, understanding the mechanisms driving vascular progenitor cells recruitment and differentiation could help the development of new strategies to improve tissue-engineered vessel grafts and design drug-targeted therapy for vessel regeneration. OBJECTIVE: In this study, we sought to investigate the role of Dkk3 (dickkopf-3), recently identified as a cytokine promotor of endothelial repair and smooth muscle cell differentiation, on vascular progenitor cells cell migration and vascular regeneration and to identify its functional receptor that remains unknown. METHODS AND RESULTS: Vascular stem/progenitor cells were isolated from murine aortic adventitia and selected for the Sca-1 (stem cell antigen-1) marker. Dkk3 induced the chemotaxis of Sca-1+ cells in vitro in transwell and wound healing assays and ex vivo in the aortic ring assay. Functional studies to identify Dkk3 receptor revealed that overexpression or knockdown of chemokine receptor CXCR7 (C-X-C chemokine receptor type 7) in Sca-1+ cells resulted in alterations in cell migration. Coimmunoprecipitation experiments using Sca-1+ cell extracts treated with Dkk3 showed the physical interaction between DKK3 and CXCR7, and specific saturation binding assays identified a high-affinity Dkk3-CXCR7 binding with a dissociation constant of 14.14 nmol/L. Binding of CXCR7 by Dkk3 triggered the subsequent activation of ERK1/2 (extracellular signal-regulated kinases 1/2)-, PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B)-, Rac1 (Ras-related C3 botulinum toxin substrate 1)-, and RhoA (Ras homolog gene family, member A)-signaling pathways involved in Sca-1+ cell migration. Tissue-engineered vessel grafts were fabricated with or without Dkk3 and implanted to replace the rat abdominal aorta. Dkk3-loaded tissue engineered vessel grafts showed efficient endothelization and recruitment of vascular progenitor cells, which had acquired characteristics of mature smooth muscle cells. CXCR7 blocking using specific antibodies in this vessel graft model hampered stem/progenitor cell recruitment into the vessel wall, thus compromising vascular remodeling. CONCLUSIONS: We provide a novel and solid evidence that CXCR7 serves as Dkk3 receptor, which mediates Dkk3-induced vascular progenitor migration in vitro and in tissue-engineered vessels, hence harnessing patent grafts resembling native blood vessels. PMID- 29980569 TI - Imaging the Vascular Bone Marrow Niche During Inflammatory Stress. AB - RATIONALE: Inflammatory stress induced by exposure to bacterial lipopolysaccharide causes hematopoietic stem cell expansion in the bone marrow niche, generating a cellular immune response. As an integral component of the hematopoietic stem cell niche, the bone marrow vasculature regulates the production and release of blood leukocytes, which protect the host against infection but also fuel inflammatory diseases. OBJECTIVE: We aimed to develop imaging tools to explore vascular changes in the bone marrow niche during acute inflammation. METHODS AND RESULTS: Using the TLR (Toll-like receptor) ligand lipopolysaccharide as a prototypical danger signal, we applied multiparametric, multimodality and multiscale imaging to characterize how the bone marrow vasculature adapts when hematopoiesis boosts leukocyte supply. In response to lipopolysaccharide, ex vivo flow cytometry and histology showed vascular changes to the bone marrow niche. Specifically, proliferating endothelial cells gave rise to new vasculature in the bone marrow during hypoxic conditions. We studied these vascular changes with complementary intravital microscopy and positron emission tomography/magnetic resonance imaging. Fluorescence and positron emission tomography integrin alphaVbeta3 imaging signal increased during lipopolysaccharide-induced vascular remodeling. Vascular leakiness, quantified by albumin-based in vivo microscopy and magnetic resonance imaging, rose when neutrophils departed and hematopoietic stem and progenitor cells proliferated more vigorously. CONCLUSIONS: Introducing a tool set to image bone marrow either with cellular resolution or noninvasively within the entire skeleton, this work sheds light on angiogenic responses that accompany emergency hematopoiesis. Understanding and monitoring bone marrow vasculature may provide a key to unlock therapeutic targets regulating systemic inflammation. PMID- 29980571 TI - Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer. AB - Erbin belongs to the LAP (leucine-rich repeat and PDZ domain) family of scaffolding proteins that plays important roles in orchestrating cell signaling. Here, we show that Erbin functions as a tumor suppressor in colorectal cancer. Analysis of Erbin expression in colorectal cancer patient specimens revealed that Erbin was downregulated at both mRNA and protein levels in tumor tissues. Knockdown of Erbin disrupted epithelial cell polarity and increased cell proliferation in 3D culture. In addition, silencing Erbin resulted in increased amplitude and duration of signaling through Akt and RAS/RAF pathways. Erbin loss induced epithelial-mesenchymal transition, which coincided with a significant increase in cell migration and invasion. Erbin interacted with kinase suppressor of Ras 1 (KSR1) and displaced it from the RAF/MEK/ERK complex to prevent signal propagation. Furthermore, genetic deletion of Erbin in Apc knockout mice promoted tumorigenesis and significantly reduced survival. Tumor organoids derived from Erbin/Apc double knockout mice displayed increased tumor initiation potential and activation of Wnt signaling. Results from gene set enrichment analysis revealed that Erbin expression associated positively with the E-cadherin adherens junction pathway and negatively with Wnt signaling in human colorectal cancer. Taken together, our study identifies Erbin as a negative regulator of tumor initiation and progression by suppressing Akt and RAS/RAF signaling in vivoSignificance: These findings establish the scaffold protein Erbin as a negative regulator of EMT and tumorigenesis in colorectal cancer through direct suppression of Akt and RAS/RAF signaling. Cancer Res; 78(17); 4839-52. (c)2018 AACR. PMID- 29980572 TI - Telomere shortening correlates with leukemic stem cell burden at diagnosis of chronic myeloid leukemia. AB - Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL-, nonleukemic CD34+CD38- hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL+ leukemic stem cell (LSC) counterparts. We observed significantly accelerated telomere shortening in LSC compared with nonleukemic HSC. Interestingly, the degree of LSC telomere shortening was found to correlate significantly with the leukemic clone size. To validate the diagnostic value of nonleukemic cells as internal controls and to rule out effects of tyrosine kinase inhibitor (TKI) treatment on these nontarget cells, we prospectively assessed TL in 134 PB samples collected in deep molecular remission after TKI treatment within the EURO-SKI study (NCT01596114). Here, no significant telomere shortening was observed in granulocytes compared with an age-adjusted control cohort. In conclusion, this study provides proof of principle for accelerated telomere shortening in LSC as opposed to HSC in CML patients at diagnosis. The fact that the degree of telomere shortening correlates with leukemic clone's size supports the use of TL in leukemic cells as a prognostic parameter pending prospective validation. TL in nonleukemic myeloid cells seems unaffected even by long-term TKI treatment arguing against a reduction of telomere-mediated replicative reserve in normal hematopoiesis under TKI treatment. PMID- 29980573 TI - Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells. PMID- 29980574 TI - The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance. AB - Plasma levels of von Willebrand factor (VWF) vary considerably in the general population and this variation has been linked to several genetic and environmental factors. Genetic factors include 2 common single nucleotide variants (SNVs) located in VWF, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), although to date the mechanistic basis for their association with VWF level is unknown. Using genotypic/phenotypic information from a European healthy control population, in vitro analyses of recombinant VWF expressing both SNVs, and in vivo murine models, this study determined the precise nature of their association with VWF level and investigated the mechanism(s) involved. Possession of either SNV corresponded with a significant increase in plasma VWF in healthy controls (P < .0001). In vitro expression confirmed this observation and highlighted an independent effect for each SNV (P < .0001 and P < .01, respectively), despite close proximity and strong linkage disequilibrium between them both. The influence of c.2365A>G on VWF levels was also confirmed in vivo. This increase in VWF protein corresponded to an increase in VWF messenger RNA (mRNA) resulting, in part, from prolonged mRNA half-life. In addition, coinheritance of both SNVs was associated with a lower VWF propeptide-to-VWF antigen ratio in healthy controls (P < .05) and a longer VWF half-life in VWF knockout mice (P < .0001). Both SNVs therefore directly increase VWF plasma levels through a combined influence on VWF biosynthesis and clearance, and may have an impact on disease phenotype in both hemostatic and thrombotic disorders. PMID- 29980575 TI - Biologic refractory disease in rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. AB - OBJECTIVES: Biologic disease-modifying antirheumatic drugs (bDMARDs) have revolutionised treatment and outcomes for rheumatoid arthritis (RA). The expanding repertoire allows the option of switching bDMARD if current treatment is not effective. For some patients, even after switching, disease control remains elusive. This analysis aims to quantify the frequency of, and identify factors associated with, bDMARD refractory disease. METHODS: Patients with RA starting first-line tumour necrosis factor inhibitor in the British Society for Rheumatology Biologics Register for RA from 2001 to 2014 were included. We defined patients as bDMARD refractory on the date they started their third class of bDMARD. Follow-up was censored at last follow-up date, 30 November 2016, or death, whichever came first. Switching patterns and stop reasons of bDMARDs were investigated. Cox regression identified baseline clinical factors associated with refractory disease. Multiple imputation of missing baseline data was used. RESULTS: 867 of 13 502 (6%) patients were bDMARD refractory; median time to third bDMARD class of 8 years. In the multivariable analysis, baseline factors associated with bDMARD refractory disease included patients registered more recently, women, younger age, shorter disease duration, higher patient global assessment, higher Health Assessment Questionnaire score, current smokers, obesity and greater social deprivation. CONCLUSIONS: This first national study has identified the frequency of bDMARD refractory disease to be at least 6% of patients who have ever received bDMARDs. As the choice of bDMARDs increases, patients are cycling through bDMARDs quicker. The aetiopathogenesis of bDMARD refractory disease requires further investigation. Focusing resources, such as nursing support, on these patients may help them achieve more stable, controlled disease. PMID- 29980576 TI - Inequity in access to bDMARD care and how it influences disease outcomes across countries worldwide: results from the METEOR-registry. AB - OBJECTIVE: To establish in a global setting the relationships between countries' socioeconomic status (SES), measured biological disease modifying antirheumatic drug (bDMARD)-usage and disease outcomes. To assess if prescription and reimbursement rules and generic access to medication relates to a countries' bDMARD-usage. METHODS: Data on disease activity and drug use from countries that had contributed at least 100 patients were extracted from the METEOR database. Mean disease outcomes of all available patients at the final visit were calculated on a per-country basis. A questionnaire was sent to at least two rheumatologists per country inquiring about DMARD-prices, access to treatment and valid regulations for prescription and reimbursement. RESULTS: Data from 20 379 patients living in 12 different countries showed that countries' SES was positively associated with measured disease activity (meanDAS28), but not always with physical functioning (HAQ-score). A lower country's SES, stricter rules for prescription and reimbursement of bDMARDs as well as worse affordability of bDMARDs were associated with lower bDMARD-usage. bDMARD-usage was negatively associated with disease activity (although not with physical functioning), but the association was moderate at best. CONCLUSIONS: Disease activity in patients with rheumatoid arthritis as well as bDMARD-usage varies across countries worldwide. The (negative) relationship between countries' bDMARD-usage and level of disease activity is complex and under the influence of many factors, including but not limited to-countries' SES, affordability of bDMARDs and valid prescription and reimbursement rules for bDMARDs. PMID- 29980577 TI - Tetraspanin CD82 affects migration, attachment and invasion of rheumatoid arthritis synovial fibroblasts. AB - : Tetraspanins function as membrane adaptors altering cell-cell fusion, antigen presentation, receptor-mediated signal transduction and cell motility via interaction with membrane proteins including other tetraspanins and adhesion molecules such as integrins. CD82 is expressed in several malignant cells and well described as tumour metastasis suppressor. Rheumatoid arthritis (RA) is based on persistent synovial inflammation and joint destruction driven to a large extent by transformed-appearing activated synovial fibroblasts (SF) with an increased migratory potential. OBJECTIVE: CD82 is upregulated in RA synovial fibroblasts (RASF) compared with osteoarthritis (OA) SF as well as within RA compared with OA synovial lining layer (LL) and the role of CD82 in RASF was evaluated. METHODS: CD82 and integrin immunofluorescence was performed. Lentiviral CD82 overexpression and siRNA-mediated knockdown was confirmed (realtime-PCR, Western blot, immunocytochemistry). RASF migration (Boyden chamber, scrape assay), attachment towards plastic/Matrigel, RASF-binding to endothelial cells (EC) and CD82 expression during long-term invasion in the SCID mouse-model were evaluated. RESULTS: CD82 was induced by proinflammatory stimuli in SF. In RA-synovium, CD82 was expressed in RASF close to blood vessels, LL, sites of cartilage invasion and colocalised with distinct integrins involved in tumour metastasis suppression but also in RA-synovium by RASF. CD82 overexpression led to reduced RASF migration, cell-matrix and RASF-EC adhesion. Reduced CD82 expression (observed in the sublining) increased RASF migration and matrix adhesion whereas RASF-EC-interaction was reduced. In SCID mice, the presence of CD82 on cartilage-invading RASF was confirmed. CONCLUSION: CD82 could contribute to RASF migration to sites of inflammation and tissue damage, where CD82 keeps aggressive RASF on site. PMID- 29980578 TI - Recellularized Native Kidney Scaffolds as a Novel Tool in Nephrotoxicity Screening. AB - Drug-induced kidney injury in medicinal compound development accounts for over 20% of clinical trial failures and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity; neither are such models easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform on the basis of decellularized rat kidney scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1). A 5-day SDS-based decellularization protocol was used to generate DS, of which 100-MUm slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D-tubule formation along with tubular epithelial characteristics, including drug transporter function. Exposure of RS to cisplatin (CDDP), tenofovir (TFV), or cyclosporin A (CsA) as prototypical nephrotoxic drugs revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. This was most probably attributable to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1), and CsA competing for P-glycoprotein-mediated efflux. Compared with 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24-hour exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically relevant 3D nephrotoxicity screening platform that could be a novel tool in drug development. PMID- 29980580 TI - Differences in the In Vivo and In Vitro Metabolism of Imrecoxib in Humans: Formation of the Rate-Limiting Aldehyde Intermediate. AB - Imrecoxib is a typical cyclooxygenase-2 inhibitor and the benzylic carbon motif is its major site of oxidative metabolism, producing a hydroxymethyl metabolite (M1) and a carboxylic acid metabolite (M2). The plasma exposure of M2 is four times higher than those of both M0 and M1 in humans. However, this metabolite is rarely formed in in vitro experiments. Therefore, this study aims to investigate the formation mechanism of M2 and to further elucidate the reason for the discrepancy between in vitro and in vivo metabolic data. By employing human hepatocytes, human liver microsomes (HLMs), human liver cytosols (HLCs), recombinant enzymes, and selective enzyme inhibitors, the metabolic map of imrecoxib was elaborated as follows: the parent drug was initially hydroxylated to form M1 in HLMs, mainly mediated by CYP3A4 and CYP2D6, and to subsequently form aldehyde imrecoxib (M-CHO) in HLMs and HLCs. The latter process is the rate limiting step in generating the end-product M2. In further M-CHO metabolism, two opposite reactions (namely, rapid oxidation catalyzed by CYP3A4, CYP2D6, and cytosolic aldehyde oxidase to form M2 versus reduction to regenerate M1 mediated by NADPH-dependent reductases in HLMs and HLCs, such as cytochrome P450 reductase) led to marked underestimation of the M2 amount in static in vitro incubations. The findings provided a possible explanation for the difference between in vitro and in vivo metabolism of imrecoxib, suggesting that the effect of competitive reduction on the static oxidation metabolism in in vitro metabolic experiments should be considered. PMID- 29980579 TI - Single Nucleotide Polymorphisms (SNPs) Distant from Xenobiotic Response Elements Can Modulate Aryl Hydrocarbon Receptor Function: SNP-Dependent CYP1A1 Induction. AB - CYP1A1 expression can be upregulated by the ligand-activated aryl hydrocarbon receptor (AHR). Based on prior observations with estrogen receptors and estrogen response elements, we tested the hypothesis that single-nucleotide polymorphisms (SNPs) mapping hundreds of base pairs (bp) from xenobiotic response elements (XREs) might influence AHR binding and subsequent gene expression. Specifically, we analyzed DNA sequences 5 kb upstream and downstream of the CYP1A1 gene for putative XREs. SNPs located +/-500 bp of these putative XREs were studied using a genomic data-rich human lymphoblastoid cell line (LCL) model system. CYP1A1 mRNA levels were determined after treatment with varying concentrations of 3 methylcholanthrene (3MC). The rs2470893 (-1694G>A) SNP, located 196 bp from an XRE in the CYP1A1 promoter, was associated with 2-fold variation in AHR-XRE binding in a SNP-dependent fashion. LCLs with the AA genotype displayed significantly higher AHR-XRE binding and CYP1A1 mRNA expression after 3MC treatment than did those with the GG genotype. Electrophoretic mobility shift assay (EMSA) showed that oligonucleotides with the AA genotype displayed higher LCL nuclear extract binding after 3MC treatment than did those with the GG genotype, and mass spectrometric analysis of EMSA protein-DNA complex bands identified three candidate proteins, two of which were co-immunoprecipitated with AHR. In conclusion, we have demonstrated that the rs2470893 SNP, which maps 196 bp from a CYP1A1 promoter XRE, is associated with variations in 3MC-dependent AHR binding and CYP1A1 expression. Similar "distant SNP effects" on AHR binding to an XRE motif and subsequent gene expression might occur for additional AHR-regulated genes. PMID- 29980581 TI - 18F-HX4 Hypoxia PET Holds Promise as a Prognostic and Predictive Imaging Biomarker in a Lung Cancer Xenograft Model Treated with Metformin and Radiotherapy. AB - Metformin may improve tumor oxygenation and thus radiotherapy response, but imaging biomarkers for selection of suitable patients are still under investigation. First, we assessed the effect of acute metformin administration on non-small cell lung cancer (NSCLC) xenograft tumor hypoxia using positron emission tomography (PET) imaging with the hypoxia tracer 18F-flortanidazole (18F HX4). Second, we verified the effect of a single dose of metformin prior to radiotherapy on long-term treatment outcome. Third, we examined the potential of baseline 18F-HX4 as a prognostic and/or predictive biomarker for treatment response. Methods: A549 tumor-bearing mice underwent a 18F-HX4 PET/computed tomography (CT) scan to determine baseline tumor hypoxia. The next day, mice received an intravenous (IV) injection of 100 mg/kg metformin. 18F-HX4 was administered IV 30 min later and a second PET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were divided into three therapy groups: controls (group 1), radiotherapy (group 2), and metformin+radiotherapy (group 3). Animals received saline (groups 1-2) or 100 mg/kg metformin (group 3) IV, followed by a single radiotherapy dose of 10 Gy (groups 2-3) or sham irradiation (group 1) 30 min later. Tumor growth was monitored triweekly by caliper measurement and relative tumor volumes (RTV=Vtime x/Vbaseline) were calculated. The tumor doubling time (TDT), i.e. the time to reach 2* the pre irradiation tumor volume, was defined as the endpoint. Results: Thirty min post metformin treatment, 18F-HX4 demonstrated a significant change in tumor hypoxia with a mean intratumoral reduction in 18F-HX4 tumor-to-background ratio (TBR) from 3.21+/-0.13 to 2.87+/-0.13 (P = 0.0001). Overall, RTV over time differed across treatment groups (p<0.0001). Similarly, the median TDT was 19, 34 and 52 days in controls, the radiotherapy-group and the metformin+radiotherapy-group, respectively (log-rank p<0.0001). Both baseline 18F-HX4 TBR (HR 2.0; P = 0.0004) and change from baseline TBR (HR 0.39; P = 0.04) were prognostic biomarkers for TDT irrespective of treatment, and baseline TBR predicted metformin-specific treatment effects which were dependent on baseline tumor hypoxia. Conclusion: Using 18F-HX4 PET imaging in a NSCLC xenograft model, we showed that metformin may act as radiosensitizer by increasing tumor oxygenation and that baseline 18F HX4 shows promise as an imaging biomarker. PMID- 29980583 TI - Occupational exposure to benzene, toluene, xylene and styrene and risk of prostate cancer in a population-based study. AB - OBJECTIVES: While several monocyclic aromatic hydrocarbons are classified as definite or possible carcinogens to humans, little data exist on their role in prostate cancer (PCa). We examined occupational exposure to benzene, toluene, xylene (BTX) and styrene and PCa risk in a population-based case-control study in Montreal, Canada. METHODS: Cases aged <=75 years diagnosed with PCa in 2005-2009 (n=1920) and population controls frequency-matched on age (n=1989) provided detailed work histories. Experts evaluated the certainty, frequency and concentration of exposure to monocyclic aromatic hydrocarbons in each job lasting >=2 years. Logistic regression estimated OR and 95% CIs for PCa risk, adjusting for potential confounders. RESULTS: Exposures to BTX were highly intercorrelated, except for durations of exposure at substantial levels. Ever exposure to any BTX was associated with overall PCa (OR 1.27, 95% CI 1.05 to 1.53), while the OR for styrene was 1.19. However, increases in risk were largely confined to low-grade tumours, with ORs of 1.33 (95%CI 1.08 to 1.64) and 1.41 (95% CI 0.85 to 2.31) for ever exposure to any BTX and styrene, respectively, and a duration response pattern for any BTX. Risks for low-grade tumours were elevated among men exposed >=25 years at substantial levels of benzene (OR 2.32) and styrene (OR 2.44). Some cumulative exposure categories showed increased risks but without clear trends. CONCLUSION: Exposure to any BTX was associated with higher risks of overall PCa. Prolonged exposures at the substantial level to benzene and styrene increased risks of low-grade tumours. These novel findings were independent from PCa screening. PMID- 29980582 TI - Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I driven CD8+ T cell response. AB - Psoriasis is a complex inflammatory skin disease affecting ~3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell-depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP-IFN-I-driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease. PMID- 29980584 TI - In vitro follicle culture in the context of IVF. AB - The currently available assisted reproduction techniques for fertility preservation (i.e. in vitro maturation (IVM) and in vitro fertilization) are insufficient as stand-alone procedures as only few reproductive cells can be conserved with these techniques. Oocytes in primordial follicles are well suited to survive the cryopreservation procedure and of use as valuable starting material for fertilization, on the condition that these could be grown up to fully matured oocytes. Our understanding of the biological mechanisms directing primordial follicle activation has increased over the last years and this knowledge has paved the way toward clinical applications. New multistep in vitro systems are making use of purified precursor cells and extracellular matrix components and by applying bio-printing technologies, an adequate follicular niche can be built. IVM of human oocytes is clinically applied in patients with polycystic ovary/polycystic ovary syndrome; related knowhow could become useful for fertility preservation and for patients with maturation failure and follicle stimulating hormone resistance. The expectations from the research on human ovarian tissue and immature oocytes cultures, in combination with the improved vitrification methods, are high as these technologies can offer realistic potential for fertility preservation. PMID- 29980585 TI - Research Consent at the Age of Majority: Preferable but not Obligatory. AB - In this issue of Pediatrics, Berkman et al argue that parental permission to obtain samples is sufficient to continue storing them and using them for research after the pediatric participant reaches the age of majority. In this Ethics Rounds, we argue that there are important ethical reasons for obtaining consent from participants when they reach majority. However, these reasons must be balanced with the aim of efficiently and economically conducting research that benefits children. Given current guidance from the relevant regulatory bodies, it remains necessary to obtain consent for the continued use of identified pediatric samples when participants reach the age of majority unless the institutional review board grants a waiver of consent. However, we argue that waivers of consent should more frequently be granted by institutional review boards and used for this purpose. PMID- 29980586 TI - Reconsidering the Need for Reconsent at 18. AB - The prevalence of research with biological specimens has led to a debate over what type of consent is needed to obtain biological specimens from minors and store them for future studies. In most cases, parental permission is needed to obtain samples from minors. In addition, almost all commentators and guidelines maintain that researchers need the consent of the donors if they want to continue to store the samples and make them available for future studies after the donors reach the age of majority. In this Ethics Rounds, we argue that this near consensus view is mistaken on the grounds that the agreement of the parents at the time of obtaining samples provides sufficient permission to store them and use them in research even after the donors turn 18 years old. PMID- 29980587 TI - The Use of Cell-Free Xenopus Extracts to Investigate Cytoplasmic Events. AB - Experiments using cytoplasmic extracts prepared from Xenopus eggs have made important contributions to our understanding of the cell cycle, the cytoskeleton, and cytoplasmic membrane systems. Here we introduce the extract system and describe methods for visualizing and manipulating diverse cytoplasmic processes, and for assaying the functions, dynamics, and stability of individual factors. These in vitro approaches uniquely enable investigation of events at specific cell cycle states, including the assembly of actin- and microtubule-based structures, and the formation of the endoplasmic reticulum. Maternal stockpiles in extracts recapitulate diverse processes in the near absence of gene expression, and this biochemical system combined with microscopy empowers a wide range of mechanistic investigations. PMID- 29980588 TI - Adoptive Transfer of Fluorescently Labeled Immune Cells in Xenopus. AB - Adoptive cell transfer from inbred adult Xenopus to inbred tadpoles is a useful way to study the dissemination of immune cells or pathogen-infected immune cells in tadpoles. For example, Xenopus peritoneal leukocytes (PLs) can be readily infected by pathogens such as Frog virus 3 (FV3) and Mycobacterium marinum (M. marinum). By transferring fluorescently labeled, FV3-infected PLs into tadpoles, we observed infiltration of these cells into the tadpole's brain, which indicates that FV3-infected PLs can cross blood brain barrier. Taking advantage of tadpoles' transparency, fluorescently labeled immune cells can be tracked in real time using fluorescence microscopy. PMID- 29980589 TI - Family integrated care: what's all the fuss about? PMID- 29980590 TI - Regulation of PI4P levels by PI4KIIIalpha during G-protein-coupled PLC signaling in Drosophila photoreceptors. AB - The activation of phospholipase C (PLC) is a conserved mechanism of receptor activated cell signaling at the plasma membrane. PLC hydrolyzes the minor membrane lipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], and continued signaling requires the resynthesis and availability of PI(4,5)P2 at the plasma membrane. PI(4,5)P2 is synthesized by the phosphorylation of phosphatidylinositol 4-phosphate (PI4P). Thus, a continuous supply of PI4P is essential to support ongoing PLC signaling. While the enzyme PI4KA has been identified as performing this function in cultured mammalian cells, its function in the context of an in vivo physiological model has not been established. In this study, we show that, in Drosophila photoreceptors, PI4KIIIalpha activity is required to support signaling during G-protein-coupled PLC activation. Depletion of PI4KIIIalpha results in impaired electrical responses to light, and reduced plasma membrane levels of PI4P and PI(4,5)P2 Depletion of the conserved proteins Efr3 and TTC7 [also known as StmA and L(2)k14710, respectively, in flies], which assemble PI4KIIIalpha at the plasma membrane, also results in an impaired light response and reduced plasma membrane PI4P and PI(4,5)P2 levels. Thus, PI4KIIIalpha activity at the plasma membrane generates PI4P and supports PI(4,5)P2 levels during receptor activated PLC signaling. PMID- 29980591 TI - Co-infection: when whole can be greater than the sum: The complex reaction to co infection of different pathogens can generate variable symptoms. PMID- 29980592 TI - Correction: An update on the management of gout. PMID- 29980593 TI - Salmonella serovar distribution from non-human sources in Italy; results from the IT-Enter-Vet network. AB - The study summarises the results obtained over the period 2002-2013 by the Italian IT-Enter-Vet network, aimed at collecting data on Salmonella isolates from non-human sources. A total of 42,491 Salmonella isolates were reported with a progressive decrease over the years. S. Typhimurium was the most frequent serovar up to 2011, but then, it was overtaken by S. 4,[5],12,:i:-, S. Derby, S. Livingstone and S. Enteritidis alternated as the third most commonly isolated serovars. With regard to the sources of isolation, S. Typhimurium was distributed ubiquitously among the animal species. On the contrary, S. 4,[5],12,:i:- and S. Derby were strictly associated with pigs, whereas S. Livingstone, S. Enteritidis and S. Infantis were clearly related to poultry. Intriguingly, when the frequency of serovar distribution along the food chain was considered, it was evident that S. Typhimurium and S. Derby tended to persist along the chain, as they were isolated even more frequently from foods than from animals. A similar distribution was found for S. Enteritidis and S. Hadar. Despite limitations related to non-mandatory participation of laboratories in the network, the data presented are valuable to obtain a picture of the evolution of Salmonella from non-human sources over time in Italy. PMID- 29980594 TI - Sarcomeric Auto-Oscillations in Single Myofibrils From the Heart of Patients With Dilated Cardiomyopathy. AB - BACKGROUND: Left ventricular wall motion is depressed in patients with dilated cardiomyopathy (DCM). However, whether or not the depressed left ventricular wall motion is caused by impairment of sarcomere dynamics remains to be fully clarified. METHODS AND RESULTS: We analyzed the mechanical properties of single sarcomere dynamics during sarcomeric auto-oscillations (calcium spontaneous oscillatory contractions [Ca-SPOC]) that occurred at partial activation under the isometric condition in myofibrils from donor hearts and from patients with severe DCM (New York Heart Association classification III-IV). Ca-SPOC reproducibly occurred in the presence of 1 MUmol/L free Ca2+ in both nonfailing and DCM myofibrils, and sarcomeres exhibited a saw-tooth waveform along single myofibrils composed of quick lengthening and slow shortening. The period of Ca-SPOC was longer in DCM myofibrils than in nonfailing myofibrils, in association with prolonged shortening time. Lengthening time was similar in both groups. Then, we performed Tn (troponin) exchange in myofibrils with a DCM-causing homozygous mutation (K36Q) in cTnI (cardiac TnI). On exchange with the Tn complex from healthy porcine ventricles, period, shortening time, and shortening velocity in cTnI-K36Q myofibrils became similar to those in Tn-reconstituted nonfailing myofibrils. Protein kinase A abbreviated period in both Tn-reconstituted nonfailing and cTnI-K36Q myofibrils, demonstrating acceleration of cross-bridge kinetics. CONCLUSIONS: Sarcomere dynamics was found to be depressed under loaded conditions in DCM myofibrils because of impairment of thick-thin filament sliding. Thus, microscopic analysis of Ca-SPOC in human cardiac myofibrils is beneficial to systematically unveil the kinetic properties of single sarcomeres in various types of heart disease. PMID- 29980596 TI - Cardiac Shock Revealing Systemic Lupus Erythematosus. PMID- 29980595 TI - Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial. AB - BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7+/-8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had >=1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), beta-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711. PMID- 29980597 TI - The effects of obesity on skeletal muscle contractile function. AB - Obesity can cause a decline in contractile function of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. We reviewed the literature to establish the current state-of-knowledge of how obesity affects skeletal muscle contraction and relaxation. At a cellular level, the dominant effects of obesity are disrupted calcium signalling and 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. As a result, there is a shift from slow to fast muscle fibre types. Decreased AMPK activity promotes the class II histone deacetylase (HDAC)-mediated inhibition of the myocyte enhancer factor 2 (MEF2). MEF2 promotes slow fibre type expression, and its activity is stimulated by the calcium-dependent phosphatase calcineurin. Obesity-induced attenuation of calcium signalling via its effects on calcineurin, as well as on adiponectin and actinin affects excitation-contraction coupling and excitation transcription coupling in the myocyte. These molecular changes affect muscle contractile function and phenotype, and thereby in vivo and in vitro muscle performance. In vivo, obesity can increase the absolute force and power produced by increasing the demand on weight-supporting muscle. However, when normalised to body mass, muscle performance of obese individuals is reduced. Isolated muscle preparations show that obesity often leads to a decrease in force produced per muscle cross-sectional area, and power produced per muscle mass. Obesity and ageing have similar physiological consequences. The synergistic effects of obesity and ageing on muscle function may exacerbate morbidity and mortality. Important future research directions include determining: the relationship between time course of weight gain and changes in muscle function; the relative effects of weight gain and high-fat diet feeding per se; the effects of obesity on muscle function during ageing; and if the effects of obesity on muscle function are reversible. PMID- 29980598 TI - Identification of two distinct peptide-binding pockets in the SH3 domain of human mixed-lineage kinase 3. AB - Mixed-lineage kinase 3 (MLK3; also known as MAP3K11) is a Ser/Thr protein kinase widely expressed in normal and cancerous tissues, including brain, lung, liver, heart, and skeletal muscle tissues. Its Src homology 3 (SH3) domain has been implicated in MLK3 autoinhibition and interactions with other proteins, including those from viruses. The MLK3 SH3 domain contains a six-amino-acid insert corresponding to the n-Src insert, suggesting that MLK3 may bind additional peptides. Here, affinity selection of a phage-displayed combinatorial peptide library for MLK3's SH3 domain yielded a 13-mer peptide, designated "MLK3 SH3 interacting peptide" (MIP). Unlike most SH3 domain peptide ligands, MIP contained a single proline. The 1.2-A crystal structure of the MIP-bound SH3 domain revealed that the peptide adopts a beta-hairpin shape, and comparison with a 1.5 A apo SH3 domain structure disclosed that the n-Src loop in SH3 undergoes an MIP induced conformational change. A 1.5-A structure of the MLK3 SH3 domain bound to a canonical proline-rich peptide from hepatitis C virus nonstructural 5A (NS5A) protein revealed that it and MIP bind the SH3 domain at two distinct sites, but biophysical analyses suggested that the two peptides compete with each other for SH3 binding. Moreover, SH3 domains of MLK1 and MLK4, but not MLK2, also bound MIP, suggesting that the MLK1-4 family may be differentially regulated through their SH3 domains. In summary, we have identified two distinct peptide-binding sites in the SH3 domain of MLK3, providing critical insights into mechanisms of ligand binding by the MLK family of kinases. PMID- 29980599 TI - Substrate-induced domain movement in a bifunctional protein, DcpA, regulates cyclic di-GMP turnover: Functional implications of a highly conserved motif. AB - In eubacteria, cyclic di-GMP (c-di-GMP) signaling is involved in virulence, persistence, motility and generally orchestrates multicellular behavior in bacterial biofilms. Intracellular c-di-GMP levels are maintained by the opposing activities of diguanylate cyclases (DGCs) and cognate phosphodiesterases (PDEs). The c-di-GMP homeostasis in Mycobacterium smegmatis is supported by DcpA, a conserved, bifunctional protein with both DGC and PDE activities. DcpA is a multidomain protein whose GAF-GGDEF-EAL domains are arranged in tandem and are required for these two activities. To gain insight into how interactions among these three domains affect DcpA activity, here we studied its domain dynamics using real-time FRET. We demonstrate that substrate binding in DcpA results in domain movement that prompts a switch from an "open" to a "closed" conformation and alters its catalytic activity. We found that a single point mutation in the conserved EAL motif (E384A) results in complete loss of the PDE activity of the EAL domain and in a significant decrease in the DGC activity of the GGDEF domain. Structural analyses revealed multiple hydrophobic and aromatic residues around Cys579 that are necessary for proper DcpA folding and maintenance of the active conformation. On the basis of these observations and taking into account additional bioinformatics analysis of EAL domain-containing proteins, we identified a critical putatively conserved motif, GCXXXQGF, that plays an important role in c-di-GMP turnover. We conclude that a substrate-induced conformational switch involving movement of a loop containing a conserved motif in the bifunctional diguanylate cyclase-phosphodiesterase DcpA controls c-di-GMP turnover in M. smegmatis. PMID- 29980600 TI - Long-range function of secreted small nucleolar RNAs that direct 2'-O methylation. AB - Small nucleolar RNAs (snoRNAs) are noncoding RNAs that guide chemical modifications of structural RNAs. Whereas snoRNAs primarily localize in the nucleolus, where their canonical function is to target nascent ribosomal RNAs for 2'-O-methylation, recent studies provide evidence that snoRNAs traffic out of the nucleus. Furthermore, RNA-Seq data indicate that extracellular vesicles released from cells contain snoRNAs. However, it is not known whether snoRNA secretion is regulated or whether secreted snoRNAs are functional. Here, we show that inflammation stimulates secretion of Rpl13a snoRNAs U32a (SNORD32a), U33 (SNORD33), U34 (SNORD34), and U35a (SNORD35a) from cultured macrophages, in mice, and in human subjects. Secreted snoRNAs co-fractionate with extracellular vesicles and are taken up by recipient cells. In a murine parabiosis model, we demonstrate that snoRNAs travel through the circulation to function in distant tissues. These findings support a previously unappreciated link between inflammation and snoRNA secretion in mice and humans and uncover a potential role for secreted snoRNAs in cell-cell communication. PMID- 29980601 TI - Mechanism-based inhibition of human persulfide dioxygenase by gamma-glutamyl homocysteinyl-glycine. AB - Hydrogen sulfide (H2S) is a signaling molecule with many beneficial effects. However, its cellular concentration is strictly regulated to avoid toxicity. Persulfide dioxygenase (PDO or ETHE1) is a mononuclear non-heme iron-containing protein in the sulfide oxidation pathway catalyzing the conversion of GSH persulfide (GSSH) to sulfite and GSH. PDO mutations result in the autosomal recessive disorder ethylmalonic encephalopathy (EE). Here, we developed gamma glutamyl-homocysteinyl-glycine (GHcySH), in which the cysteinyl moiety in GSH is substituted with homocysteine, as a mechanism-based PDO inhibitor. Human PDO used GHcySH as an alternative substrate and converted it to GHcy-SO2H, mimicking GS SO2H, the putative oxygenated intermediate formed with the natural substrate. Because GHcy-SO2H contains a C-S bond rather than an S-S bond in GS-SO2H, it failed to undergo the final hydrolysis step in the catalytic cycle, leading to PDO inhibition. We also characterized the biochemical penalties incurred by the L55P, T136A, C161Y, and R163W mutations reported in EE patients. The variants displayed lower iron content (1.4-11-fold) and lower thermal stability (1.2-1.7 fold) than WT PDO. They also exhibited varying degrees of catalytic impairment; the kcat/Km values for R163W, L55P, and C161Y PDOs were 18-, 42-, and 65-fold lower, respectively, and the T136A variant was most affected, with a 200-fold lower kcat/Km Like WT enzyme, these variants were inhibited by GHcySH. This study provides the first characterization of an intermediate in the PDO-catalyzed reaction and reports on deficits associated with EE-linked mutations that are distal from the active site. PMID- 29980603 TI - Probiotic Lactobacillus paracasei HII01 protects rats against obese-insulin resistance-induced kidney injury and impaired renal organic anion transporter 3 function. AB - The relationship between gut dysbiosis and obesity is currently acknowledged to be a health topic which causes low-grade systemic inflammation and insulin resistance and may damage the kidney. Organic anion transporter 3 (Oat3) has been shown as a transporter responsible for renal handling of gut microbiota products which are involved in the progression of metabolic disorder. The present study investigated the effect of probiotic supplementation on kidney function, renal Oat3 function, inflammation, endoplasmic reticulum (ER) stress, and apoptosis in obese, insulin-resistant rats. After 12 weeks of being provided with either a normal or a high-fat diet (HF), rats were divided into normal diet (ND); ND treated with probiotics (NDL); HF; and HF treated with probiotic (HFL). Lactobacillus paracasei HII01 1 * 108 colony forming unit (CFU)/ml was administered to the rats daily by oral gavage for 12 weeks. Obese rats showed significant increases in serum lipopolysaccharide (LPS), plasma lipid profiles, and insulin resistance. Renal Oat 3 function was decreased along with kidney dysfunction in HF-fed rats. Obese rats also demonstrated the increases in inflammation, ER stress, apoptosis, and gluconeogenesis in the kidneys. These alterations were improved by Lactobacillus paracasei HII01 treatment. In conclusion, probiotic supplementation alleviated kidney inflammation, ER stress, and apoptosis, leading to improved kidney function and renal Oat3 function in obese rats. These benefits involve the attenuation of hyperlipidemia, systemic inflammation, and insulin resistance. The present study also suggested the idea of remote sensing and signaling system between gut and kidney by which probiotic might facilitate renal handling of gut microbiota products through the improvement of Oat3 function. PMID- 29980604 TI - Immunoproteasomes as a novel antiviral mechanism in rhinovirus-infected airways. AB - Rhinovirus (RV) infection is involved in acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). RV primarily infects upper and lower airway epithelium. Immunoproteasomes (IP) are proteolytic machineries with multiple functions including the regulation of MHC class I antigen processing during viral infection. However, the role of IP in RV infection has not been explored. We sought to investigate the expression and function of IP during airway RV infection. Primary human tracheobronchial epithelial (HTBE) cells were cultured at air-liquid interface (ALI) and treated with RV16, RV1B, or interferon (IFN)-lambda in the absence or presence of an IP inhibitor (ONX-0914). IP gene (i.e. LMP2) deficient mouse tracheal epithelial cells (mTECs) were cultured for the mechanistic studies. LMP2-deficient mouse model was used to define the in vivo role of IP in RV infection. IP subunits LMP2 and LMP7, antiviral genes MX1 and OAS1 and viral load were measured. Both RV16 and RV1B significantly increased the expression of LMP2 and LMP7 mRNA and proteins, and IFN-lambda mRNA in HTBE cells. ONX-0914 down-regulated MX1 and OAS1, and increased RV16 load in HTBE cells. LMP2-deficient mTECs showed a significant increase in RV1B load compared with the wild-type (WT) cells. LMP2-deficient (compared with WT) mice increased viral load and neutrophils in bronchoalveolar lavage (BAL) fluid after 24 h of RV1B infection. Mechanistically, IFN-lambda induction by RV infection contributed to LMP2 and LMP7 up-regulation in HTBE cells. Our data suggest that IP are induced during airway RV infection, which in turn may serve as an antiviral and anti-inflammatory mechanism. PMID- 29980605 TI - Adrenergically and non-adrenergically mediated human adipose tissue lipolysis during acute exercise and exercise training. AB - Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined alpha-/beta-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) (n=10), obese IS (n=10), and obese insulin resistant (IR) (n=10) men. Obese men participated in a 12-week exercise training intervention to determine the effects on SCAT lipolysis. Abdominal SCAT extracellular glycerol concentration and blood flow (ATBF) were investigated using microdialysis, with/without locally combined alpha-/beta-adrenoceptor blockade at rest, during low-intensity endurance-type exercise and post-exercise recovery. In obese IR men, microdialysis was repeated after exercise intervention. The exercise-induced increase in SCAT extracellular glycerol was more pronounced in obese IS compared with lean IS men, possibly resulting from lower ATBF in obese IS men. The exercise-induced increase in extracellular glycerol was blunted in obese IR compared with obese IS men, despite comparable local ATBF. Abdominal SCAT extracellular glycerol was markedly reduced (remaining ~60% of exercise-induced SCAT extracellular glycerol) following the local alpha-/beta-adrenoceptor blockade in obese IS but not in IR men, suggesting reduced catecholamine-mediated lipolysis during exercise in obese IR men. Exercise training did not affect (non )adrenergically mediated lipolysis in obese IR men. Our findings showed a major contribution of non-adrenergically-mediated lipolysis during exercise in male abdominal SCAT. Furthermore, catecholamine-mediated lipolysis may be blunted during exercise in obese IR men but could not be improved by exercise intervention, despite an improved metabolic profile and body composition. PMID- 29980606 TI - Assessing the efficacy of peripherally acting u-opioid receptor antagonists (PAMORAs) in the treatment of opioid-induced constipation: authors reply. PMID- 29980602 TI - The enigmatic endosome - sorting the ins and outs of endocytic trafficking. AB - The early endosome (EE), also known as the sorting endosome (SE) is a crucial station for the sorting of cargoes, such as receptors and lipids, through the endocytic pathways. The term endosome relates to the receptacle-like nature of this organelle, to which endocytosed cargoes are funneled upon internalization from the plasma membrane. Having been delivered by the fusion of internalized vesicles with the EE or SE, cargo molecules are then sorted to a variety of endocytic pathways, including the endo-lysosomal pathway for degradation, direct or rapid recycling to the plasma membrane, and to a slower recycling pathway that involves a specialized form of endosome known as a recycling endosome (RE), often localized to the perinuclear endocytic recycling compartment (ERC). It is striking that 'the endosome', which plays such essential cellular roles, has managed to avoid a precise description, and its characteristics remain ambiguous and heterogeneous. Moreover, despite the rapid advances in scientific methodologies, including breakthroughs in light microscopy, overall, the endosome remains poorly defined. This Review will attempt to collate key characteristics of the different types of endosomes and provide a platform for discussion of this unique and fascinating collection of organelles. Moreover, under-developed, poorly understood and important open questions will be discussed. PMID- 29980609 TI - Cellular Mechanisms Controlling Surfacing of AICL Glycoproteins, Cognate Ligands of the Activating NK Receptor NKp80. AB - AICL glycoproteins are cognate activation-induced ligands of the C-type lectin like receptor NKp80, which is expressed on virtually all mature human NK cells, and NKp80-AICL interaction stimulates NK cell effector functions such as cytotoxicity and cytokine secretion. Notably, AICL and NKp80 are encoded by adjacent genes in the NK gene complex and are coexpressed by human NK cells. Whereas AICL is intracellularly retained in resting NK cells, exposure of NK cells to proinflammatory cytokines results in AICL surfacing and susceptibility to NKp80-mediated NK fratricide. In this study, we characterize molecular determinants of AICL glycoproteins that cause intracellular retention, thereby controlling AICL surface expression. Cys87 residing within the C-type lectin-like domain not only ensures stable homodimerization of AICL glycoproteins by disulfide bonding, but Cys87 is also required for efficient cell surface expression of AICL homodimers and essential for AICL-NKp80 interaction. In contrast, cytoplasmic lysines act as negative regulators targeting AICL for proteasomal degradation. One atypical and three conventional N-linked glycosylation sites in the AICL C-type lectin-like domain critically impact maturation and surfacing of AICL, which is strictly dependent on glycosylation of at least one conventional glycosylation site. However, although the extent of conventional N-linked glycosylation positively correlates with AICL surface expression, the atypical glycosylation site impairs AICL surfacing. Stringent control of AICL surface expression by glycosylation is reflected by the pronounced interaction of AICL with calnexin and the impaired AICL expression in calnexin-deficient cells. Collectively, our data demonstrate that AICL expression and surfacing are tightly controlled by several independent cellular posttranslational mechanisms. PMID- 29980607 TI - Faecal microbiota transplantation alters gut microbiota in patients with irritable bowel syndrome: results from a randomised, double-blind placebo controlled study. AB - OBJECTIVE: IBS is associated with an intestinal dysbiosis and faecal microbiota transplantation (FMT) has been hypothesised to have a positive effect in patients with IBS. We performed a randomised, double-blind placebo-controlled trial to investigate if FMT resulted in an altered gut microbiota and improvement in clinical outcome in patients with IBS. DESIGN: We performed this study in 52 adult patients with moderate-to-severe IBS. At the screening visit, clinical history and symptoms were assessed and faecal samples were collected. Patients were randomised to FMT or placebo capsules for 12 days and followed for 6 months. Study visits were performed at baseline, 1, 3 and 6 months, where patients were asked to register their symptoms using the IBS-severity scoring system (IBS-SSS) and IBS-specific quality of life (IBS-QoL). Prior to each visit, faecal samples were collected. RESULTS: A significant difference in improvement in IBS-SSS score was observed 3 months after treatment (p=0.012) favouring placebo. This was similar for IBS-QoL data after 3 months (p=0.003) favouring placebo. Patients receiving FMT capsules had an increase in faecal microbial biodiversity while placebos did not. CONCLUSION: In this randomised double-blinded placebo controlled study, we found that FMT changed gut microbiota in patients with IBS. But patients in the placebo group experienced greater symptom relief compared with the FMT group after 3 months. Altering the gut microbiota is not enough to obtain clinical improvement in IBS. However, different study designs and larger studies are required to examine the role of FMT in IBS. TRIAL REGISTRATION NUMBER: NCT02788071. PMID- 29980608 TI - Glucocorticoids Inhibit Group 3 Innate Lymphocyte IL-22 Production. AB - Glucocorticoids (GCs) are commonly prescribed to patients with a variety of inflammatory disorders, including inflammatory bowel disease (IBD). GCs mediate their immunomodulatory effects through many different mechanisms and target multiple signaling pathways. The GC dexamethasone downmodulates innate and adaptive immune cell activation. IBD is the manifestation of a dysregulated immune response involving many different immune cells. Group 3 innate lymphocytes (ILC3s) have critical roles in mucosal inflammation. ILC3s secrete high levels of the cytokine IL-22, promoting epithelial proliferation, antimicrobial peptides, and mucins. In this study, we examined the effects of dexamethasone on IL-22 production by ILC3s. We found that dexamethasone suppressed IL-23-mediated IL-22 production in human and mouse ILC3s. This was mediated in part through dexamethasone modulation of the NF-kappaB pathway. Inhibition of NF-kappaB signaling with a small molecule inhibitor also downmodulated IL-23- and IL-1beta mediated IL-22 production in ILC3s. These findings implicate NF-kappaB as a regulator of IL-22 in ILC3s and likely have repercussions on GC treatment of IBD patients. PMID- 29980610 TI - Mesenchymal Stromal Cells Stimulate the Proliferation and IL-22 Production of Group 3 Innate Lymphoid Cells. AB - Infusion of mesenchymal stromal cells (MSCs) is a promising and increasingly applied therapy for patients who suffer from a variety of inflammatory diseases, including graft-versus-host disease (GvHD), a common and life-threatening complication after allogeneic hematopoietic stem cell transplantation. The therapeutic effect of MSCs is mainly ascribed to their ability to suppress T cells and to support tissue repair. However, clinical response rates in patients with GvHD are limited to 50%, and the determinants for MSC responsiveness are unknown. We recently reported that high frequencies of activated group 3 innate lymphoid cells (ILC3s) before and after allogeneic hematopoietic stem cell transplantation were associated with a lower risk of GvHD. This may be related to IL-22 production by ILC3s, a cytokine important for intestinal epithelial cell homeostasis. In this study, we investigated whether ILC3s may contribute to the therapeutic effect of MSCs by studying the interaction between MSCs and ILC3s in vitro. ILC3s isolated from human tonsils were cocultured with human bone marrow derived MSCs for 5 d in the presence of IL-2. Coculture with MSCs enhanced the proliferation and IL-22 production of ILC3s. Reciprocally, ILC3s promoted ICAM-1 and VCAM-1 expression on MSCs. For both directions, the activation was mainly mediated by cell-cell contact and by MSC-derived IL-7 and likely by aryl hydrocarbon receptor ligands. Thus, in addition to inhibiting the proliferation of alloreactive T cells, MSCs also promote the expansion and IL-22 production of ILC3s, which may contribute to healthy homeostasis and wound repair in the treatment of various inflammatory conditions in the intestine, including GvHD. PMID- 29980611 TI - Temporal Requirement for Pulmonary Resident and Circulating T Cells during Virulent Francisella tularensis Infection. AB - The lung is a complex organ with anatomically distinct pools of T cells that play specific roles in combating infection. Our knowledge regarding the generation and/or maintenance of immunity by parenchymal or circulating T cells has been gathered from either persistent (>60 d) or rapidly cleared (<10 d) infections. However, the roles of these distinct T cell pools in infections that are cleared over the course of several weeks are not understood. Clearance of the highly virulent intracellular bacterium Francisella tularensis subspecies tularensis (Ftt) following pulmonary infection of immune animals is a protracted T cell dependent process requiring ~30-40 d and serves as a model for infections that are not acutely controlled. Using this model, we found that intranasal vaccination increased the number of tissue-resident CD4+ effector T cells, and subsequent challenge of immune mice with Ftt led to a significant expansion of polyfunctional parenchymal CD4+ effector T cells compared with the circulating pool. Despite the dominant in vivo response by parenchymal CD4+ T cells after vaccination and challenge, circulating CD4+ T cells were superior at controlling intracellular Ftt replication in vitro. Further examination in vivo revealed temporal requirements for resident and circulating T cells during Ftt infection. These requirements were in direct contrast to other pulmonary infections that are cleared rapidly in immune animals. The data in this study provide important insights into the role of specific T cell populations that will be essential for the design of novel effective vaccines against tularemia and potentially other agents of pulmonary infection. PMID- 29980612 TI - Isotype-Switched Autoantibodies Are Necessary To Facilitate Central Nervous System Autoimmune Disease in Aicda-/- and Ung-/- Mice. AB - B cell-depleting therapies have been shown to ameliorate symptoms in multiple sclerosis (MS) patients; however, the mechanism of action remains unclear. Following priming with Ag, B cells undergo secondary diversification of their BCR, including BCR class-switch recombination (CSR) and somatic hypermutation (SHM), with both processes requiring the enzyme activation-induced (cytidine) deaminase. We previously reported that activation-induced (cytidine) deaminase is required for full clinical manifestation of disease in an animal model of MS (experimental autoimmune encephalomyelitis; EAE) provoked by immunization with the extracellular domain of recombinant human myelin oligodendrocyte glycoprotein (hMOG). In this study, we investigated the role of CSR versus SHM in the pathogenesis of EAE. We found that passive transfer of class-switched anti-MOG IgG1 Abs into hMOG-primed Aicda-/- mice is sufficient to fully rescue EAE disease. In addition, we found that the nature of the Ag is an important determinant of EAE severity in Aicda-/- mice because the lack of a diversified BCR does not affect the induction of EAE when immunized with the extracellular domain of rat MOG. To discriminate the effect of either CSR or SHM, we induced EAE in uracil DNA glycosylase-deficient mice (Ung-/-) that exhibit a defect primarily in CSR. We observed that Ung-/- mice exhibit milder clinical disease compared with control mice, concomitant with a reduced amount of anti-MOG IgG1 class-switched Abs that preserved normal affinity. Collectively, these results indicate that CSR plays an important role in governing the incidence and severity of EAE induced with hMOG but not rat MOG. PMID- 29980613 TI - Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation. AB - Two million infants die each year from infectious diseases before they reach 12 mo; many of these diseases are vaccine preventable in older populations. Pattern recognition receptors represent the critical front-line defense against pathogens. Evidence suggests that the innate immune system does not fully develop until puberty, contributing to impaired response to infection and impaired vaccine responses in neonates, infants, and children. The activity of the pattern recognition receptor family of cytosolic nucleic acid (CNA) sensors in this pediatric population has not been reported. We show that in direct contrast to weak TLR-induced type I IFN in human cord blood mononuclear cells, cord blood mononuclear cells are capable of initiating a potent response to CNA, inducing both antiviral type I IFN and, unexpectedly, proinflammatory TNF-alpha. A deficiency in Rab11-GTPase endosome formation and consequent lack of IRF3 activation in neonatal monocytes is at least in part responsible for the marked disparity in TLR-induced IFN production between neonatal and adult monocytes. CNA receptors do not rely on endosome formation, and therefore, these responses remain intact in neonates. Heightened neonatal responses to CNA challenge are maintained in children up to 2 y of age and, in marked contrast to TLR4/9 agonists, result in IL-12p70 and IFN-gamma generation. CNA sensors induce robust antiviral and proinflammatory pathways in neonates and children and possess great potential for use as immunostimulants or vaccine adjuvants for targeted neonatal and pediatric populations to promote cell-mediated immunity against invasive infectious disease. PMID- 29980614 TI - Thermal proteome profiling in bacteria: probing protein state in vivo. AB - Increasing antibiotic resistance urges for new technologies for studying microbes and antimicrobial mechanism of action. We adapted thermal proteome profiling (TPP) to probe the thermostability of Escherichia coli proteins in vivoE. coli had a more thermostable proteome than human cells, with protein thermostability depending on subcellular location-forming a high-to-low gradient from the cell surface to the cytoplasm. While subunits of protein complexes residing in one compartment melted similarly, protein complexes spanning compartments often had their subunits melting in a location-wise manner. Monitoring the E. coli meltome and proteome at different growth phases captured changes in metabolism. Cells lacking TolC, a component of multiple efflux pumps, exhibited major physiological changes, including differential thermostability and levels of its interaction partners, signaling cascades, and periplasmic quality control. Finally, we combined in vitro and in vivo TPP to identify targets of known antimicrobial drugs and to map their downstream effects. In conclusion, we demonstrate that TPP can be used in bacteria to probe protein complex architecture, metabolic pathways, and intracellular drug target engagement. PMID- 29980615 TI - Influenza A Virus Induces Autophagosomal Targeting of Ribosomal Proteins. AB - Seasonal epidemics of influenza A virus are a major cause of severe illness and are of high socio-economic relevance. For the design of effective antiviral therapies, a detailed knowledge of pathways perturbed by virus infection is critical. We performed comprehensive expression and organellar proteomics experiments to study the cellular consequences of influenza A virus infection using three human epithelial cell lines derived from human lung carcinomas: A549, Calu-1 and NCI-H1299. As a common response, the type I interferon pathway was up regulated upon infection. Interestingly, influenza A virus infection led to numerous cell line-specific responses affecting both protein abundance as well as subcellular localization. In A549 cells, the vesicular compartment appeared expanded after virus infection. The composition of autophagsomes was altered by targeting of ribosomes, viral mRNA and proteins to these double membrane vesicles. Thus, autophagy may support viral protein translation by promoting the clustering of the respective molecular machinery in autophagosomes in a cell line dependent manner. PMID- 29980616 TI - Decreased NAD Activates STAT3 and Integrin Pathways to Drive Epithelial Mesenchymal Transition. AB - Nicotinamide adenine dinucleotide (NAD) plays an essential role in all aspects of human life. NAD levels decrease as humans age, and supplementation with NAD precursors plays a protective role against aging and associated disease. Less is known about the effects of decreased NAD on cellular processes, which is the basis for understanding the relationship between cellular NAD levels and aging associated disease. In the present study, cellular NAD levels were decreased by overexpression of CD38, a NAD hydrolase, or by treating cells with FK866, an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT). Quantitative proteomics revealed that declining NAD levels downregulated proteins associated with primary metabolism and suppressed cell growth in culture and nude mice. Decreased glutathione synthesis caused a 4-fold increase in cellular reactive oxygen species levels, and more importantly upregulated proteins related to movement and adhesion. In turn, this significantly changed cell morphology and caused cells to undergo epithelial to mesenchymal transition (EMT). Secretomic analysis also showed that decreased NAD triggered interleukin-6 and transforming growth factor beta (TGFbeta) secretion, which activated integrin-beta-catenin, TGFbeta-MAPK, and inflammation signaling pathways to sustain the signaling required for EMT. We further revealed that decreased NAD inactivated sirtuin 1, resulting in increased signal transducer and activator of transcription 3 (STAT3) acetylation and phosphorylation, and STAT3 activation. Repletion of nicotinamide or nicotinic acid inactivated STAT3 and reversed EMT, as did STAT3 inhibition. Taken together, these results indicate that decreased NAD activates multiple signaling pathways to promote EMT and suggests that age-dependent decreases in NAD may contribute to tumor progression. Consequently, repletion of NAD precursors has potential benefits for inhibiting cancer progression. PMID- 29980618 TI - Revisiting IL-2: Biology and therapeutic prospects. AB - Interleukin-2 (IL-2), the first cytokine that was molecularly cloned, was shown to be a T cell growth factor essential for the proliferation of T cells and the generation of effector and memory cells. On the basis of this activity, the earliest therapeutic application of IL-2 was to boost immune responses in cancer patients. Therefore, it was a surprise that genetic deletion of the cytokine or its receptor led not only to the expected immune deficiency but also to systemic autoimmunity and lymphoproliferation. Subsequent studies established that IL-2 is essential for the maintenance of Foxp3+ regulatory T cells (Treg cells), and in its absence, there is a profound deficiency of Treg cells and resulting autoimmunity. We now know that IL-2 promotes the generation, survival, and functional activity of Treg cells and thus has dual and opposing functions: maintaining Treg cells to control immune responses and stimulating conventional T cells to promote immune responses. It is well documented that certain IL-2 conformations result in selective targeting of Treg cells by increasing reliance on CD25 binding while compromising CD122 binding. Recent therapeutic strategies have emerged to use IL-2, monoclonal antibodies to IL-2, or IL-2 variants to boost Treg cell numbers and function to treat autoimmune diseases while dealing with the continuing challenges to minimize the generation of effector and memory cells, natural killer cells, and other innate lymphoid populations. PMID- 29980617 TI - Metabolic signaling directs the reciprocal lineage decisions of alphabeta and gammadelta T cells. AB - The interaction between extrinsic factors and intrinsic signal strength governs thymocyte development, but the mechanisms linking them remain elusive. We report that mechanistic target of rapamycin complex 1 (mTORC1) couples microenvironmental cues with metabolic programs to orchestrate the reciprocal development of two fundamentally distinct T cell lineages, the alphabeta and gammadelta T cells. Developing thymocytes dynamically engage metabolic programs including glycolysis and oxidative phosphorylation, as well as mTORC1 signaling. Loss of RAPTOR-mediated mTORC1 activity impairs the development of alphabeta T cells but promotes gammadelta T cell generation, associated with disrupted metabolic remodeling of oxidative and glycolytic metabolism. Mechanistically, we identify mTORC1-dependent control of reactive oxygen species production as a key metabolic signal in mediating alphabeta and gammadelta T cell development, and perturbation of redox homeostasis impinges upon thymocyte fate decisions and mTORC1-associated phenotypes. Furthermore, single-cell RNA sequencing and genetic dissection reveal that mTORC1 links developmental signals from T cell receptors and NOTCH to coordinate metabolic activity and signal strength. Our results establish mTORC1-driven metabolic signaling as a decisive factor for reciprocal alphabeta and gammadelta T cell development and provide insight into metabolic control of cell signaling and fate decisions. PMID- 29980619 TI - Type 2 immunity: Expanding our view. AB - The classical vision of type 2 immune reactions is that they are characterized by a distinct cellular and cytokine repertoire that is critical for host resistance against helminthic worm infections but, when dysregulated, may cause atopic reactions that result in conditions such as asthma, rhinitis, dermatitis, and anaphylaxis. In this traditional view, the type 2 response is categorized as an adaptive immune response with differentiated T helper cells taking center stage, driving eosinophil recruitment and immunoglobulin production via the secretion of a distinct repertoire of cytokines that include interleukin-4 (IL-4), IL-5, and IL-13. The recent discovery of a group of innate cells that has the capacity to secrete copious amounts of type 2 cytokines, potentially in the absence of adaptive immunity, has reignited interest in type 2 biology. The discovery that these innate lymphoid cells and type 2 cytokines are involved in diverse biological processes-including wound healing, control of metabolic homeostasis, and temperature-has considerably changed our view of type 2 responses and the cytokines, chemokines, and receptors that regulate these responses. PMID- 29980620 TI - If we build it, they will come. AB - Our author-centric approach to publishing your research. PMID- 29980621 TI - Celebrating twoness at Science Immunology. AB - Science Immunology's second anniversary invites a pause for editorial reflections. PMID- 29980622 TI - Macrophages that fix or break the heart. AB - Human myocardium contains different types of macrophages with heterogenous functions and origins. PMID- 29980623 TI - cROSs-presentation in pDCs: An energetic (m)CAT and mouse game. AB - pDC cross-presentation of antigens to CD8+ T cells depends on mitochondrial generation of reactive oxygen species. PMID- 29980626 TI - An actin shell delays oocyte chromosome capture by microtubules. AB - The large nuclei and tiny spindles of oocytes create a challenge for chromosome capture at M-phase entry. A contractile F-actin mesh in starfish oocytes delivers chromosomes to the spindle and Burdyniuk et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201802080) show that F-actin delays the capture of chromosomes until they are within reach of microtubules. PMID- 29980624 TI - Genome-edited human stem cells expressing fluorescently labeled endocytic markers allow quantitative analysis of clathrin-mediated endocytosis during differentiation. AB - We developed a general approach for investigation of how cellular processes become adapted for specific cell types during differentiation. Previous studies reported substantial differences in the morphology and dynamics of clathrin mediated endocytosis (CME) sites. However, associating specific CME properties with distinct differentiated cell types and determining how these properties are developmentally specified during differentiation have been elusive. Using genome edited human embryonic stem cells, and isogenic fibroblasts and neuronal progenitor cells derived from them, we established by live-cell imaging and platinum replica transmission electron microscopy that CME site dynamics and ultrastructure on the plasma membrane are precisely reprogrammed during differentiation. Expression levels for the endocytic adaptor protein AP2MU2 were found to underlie dramatic changes in CME dynamics and structure. Additionally, CME dependency on actin assembly and phosphoinositide-3 kinase activity are distinct for each cell type. Collectively, our results demonstrate that key CME properties are reprogrammed during differentiation at least in part through AP2MU2 expression regulation. PMID- 29980625 TI - Fibronectin rescues estrogen receptor alpha from lysosomal degradation in breast cancer cells. AB - Estrogen receptor alpha (ERalpha) is expressed in tissues as diverse as brains and mammary glands. In breast cancer, ERalpha is a key regulator of tumor progression. Therefore, understanding what activates ERalpha is critical for cancer treatment in particular and cell biology in general. Using biochemical approaches and superresolution microscopy, we show that estrogen drives membrane ERalpha into endosomes in breast cancer cells and that its fate is determined by the presence of fibronectin (FN) in the extracellular matrix; it is trafficked to lysosomes in the absence of FN and avoids the lysosomal compartment in its presence. In this context, FN prolongs ERalpha half-life and strengthens its transcriptional activity. We show that ERalpha is associated with beta1-integrin at the membrane, and this integrin follows the same endocytosis and subcellular trafficking pathway triggered by estrogen. Moreover, ERalpha+ vesicles are present within human breast tissues, and colocalization with beta1-integrin is detected primarily in tumors. Our work unravels a key, clinically relevant mechanism of microenvironmental regulation of ERalpha signaling. PMID- 29980627 TI - Intermediate filaments control collective migration by restricting traction forces and sustaining cell-cell contacts. AB - Mesenchymal cell migration relies on the coordinated regulation of the actin and microtubule networks that participate in polarized cell protrusion, adhesion, and contraction. During collective migration, most of the traction forces are generated by the acto-myosin network linked to focal adhesions at the front of leader cells, which transmit these pulling forces to the followers. Here, using an in vitro wound healing assay to induce polarization and collective directed migration of primary astrocytes, we show that the intermediate filament (IF) network composed of vimentin, glial fibrillary acidic protein, and nestin contributes to directed collective movement by controlling the distribution of forces in the migrating cell monolayer. Together with the cytoskeletal linker plectin, these IFs control the organization and dynamics of the acto-myosin network, promoting the actin-driven treadmilling of adherens junctions, thereby facilitating the polarization of leader cells. Independently of their effect on adherens junctions, IFs influence the dynamics and localization of focal adhesions and limit their mechanical coupling to the acto-myosin network. We thus conclude that IFs promote collective directed migration in astrocytes by restricting the generation of traction forces to the front of leader cells, preventing aberrant tractions in the followers, and by contributing to the maintenance of lateral cell-cell interactions. PMID- 29980629 TI - Natural history of mitochondrial disorders: a systematic review. AB - The natural history of a disease defines the age of onset, presenting features, clinical phenotype, morbidity and mortality outcomes of disease that is unmodified by treatments. A clear understanding of the natural history of mitochondrial disorders is essential for establishing genotype-phenotype prognosis correlations. We performed a systematic review of the reported natural history of mitochondrial disease by searching the literature for all published natural history studies containing at least 20 individuals. We defined a phenotype as 'common' if it was observed in >=30% of cases in a study, thereby highlighting common and uncommon phenotypes for each disorder. Thirty-seven natural history studies were identified encompassing 29 mitochondrial disease entities. Fifty-nine percent of disorders had an onset before 18 months and 81% before 18 years. Most disorders had multisystemic involvement and most often affected were the central nervous system, eyes, gastrointestinal system, skeletal muscle, auditory system and the heart. Less frequent involvement was seen for respiratory, renal, endocrine, hepatic, haematological and genitourinary systems. Elevated lactate was the most frequent biochemical abnormality, seen in 72% of disorders. Age of death was <1 y in 13% of disorders, <5 y in 57% and <10 y in 74%. Disorders with high mortality rates were generally associated with earlier deaths. The most robust indicators of poor prognosis were early presentation of disease and truncating mutations. A thorough knowledge of natural history has helped to redefine diagnostic criteria for classical clinical syndromes and to establish a clinical baseline for comparison in single-arm clinical trials of novel therapies. PMID- 29980631 TI - Biomarkers for mitochondrial energy metabolism diseases. AB - Biomarkers are an indicator of biologic or pathogenic processes, whose function is indicating the presence/absence of disease or monitoring disease course and its response to treatment. Since mitochondrial disorders (MDs) can represent a diagnostic challenge for clinicians, due to their clinical and genetic heterogeneity, the identification of easily measurable biomarkers becomes a high priority. Given the complexity of MD, in particular the primary mitochondrial respiratory chain (MRC) diseases due to oxidative phosphorylation (OXPHOS) dysfunction, a reliable single biomarker, relevant for the whole disease group, could be extremely difficult to find, most of times leading the physicians to better consider a 'biosignature' for the diagnosis, rather than a single biochemical marker. Serum biomarkers like lactate and pyruvate are largely determined in the diagnostic algorithm of MD, but they are not specific to this group of disorders. The concomitant determination of creatine (Cr), plasma amino acids, and urine organic acids might be helpful to reinforce the biosignature in some cases. In recent studies, serum fibroblast growth factor 21 (sFGF21) and serum growth differentiation factor 15 (sGDF15) appear to be promising molecules in identifying MD. Moreover, new different approaches have been developed to discover new MD biomarkers. This work discusses the most important biomarkers currently used in the diagnosis of MRC diseases, and some approaches under evaluation, discussing both their utility and weaknesses. PMID- 29980628 TI - Mitochondrial DNA transcription and translation: clinical syndromes. AB - Diagnosing primary mitochondrial diseases is challenging in clinical practice. Although, defective oxidative phosphorylation (OXPHOS) is the common final pathway, it is unknown why different mtDNA or nuclear mutations result in largely heterogeneous and often tissue -specific clinical presentations. Mitochondrial tRNA (mt-tRNA) mutations are frequent causes of mitochondrial diseases both in children and adults. However numerous nuclear mutations involved in mitochondrial protein synthesis affecting ubiquitously expressed genes have been reported in association with very tissue specific clinical manifestations suggesting that there are so far unknown factors determining the tissue specificity in mitochondrial translation. Most of these gene defects result in histological abnormalities and multiple respiratory chain defects in the affected organs. The clinical phenotypes are usually early-onset, severe, and often fatal, implying the importance of mitochondrial translation from birth. However, some rare, reversible infantile mitochondrial diseases are caused by very specific defects of mitochondrial translation. An unbiased genetic approach (whole exome sequencing, RNA sequencing) combined with proteomics and functional studies revealed novel factors involved in mitochondrial translation which contribute to the clinical manifestation and recovery in these rare reversible mitochondrial conditions. PMID- 29980630 TI - Coenzyme Q10 deficiencies: pathways in yeast and humans. AB - Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1-COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1-COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway. PMID- 29980633 TI - Minimal molecular determinants of isoform-specific differences in efficacy in the HCN channel family. AB - Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels generate rhythmic activity in the heart and brain. Isoform-specific functional differences reflect the specializations required for the various roles that they play. Despite a high sequence and structural similarity, HCN isoforms differ greatly in their response to cyclic nucleotides. Cyclic AMP (cAMP) enhances the activity of HCN2 and HCN4 isoforms by shifting the voltage dependence of activation to more depolarized potentials, whereas HCN1 and HCN3 isoforms are practically insensitive to this ligand. Here, to determine the molecular basis for increased cAMP efficacy in HCN2 channels, we progressively mutate residues in the C-linker and cyclic nucleotide-binding domain (CNBD) of the mouse HCN2 to their equivalents in HCN1. We identify two clusters of mutations that determine the differences in voltage-dependent activation between these two isoforms. One maps to the C-linker region, whereas the other is in proximity to the cAMP-binding site in the CNBD. A mutant channel containing just five mutations (M485I, G497D, S514T, V562A, and S563G) switches cAMP sensitivity of full-length HCN2 to that of HCN1 channels. These findings, combined with a detailed analysis of various allosteric models for voltage- and ligand-dependent gating, indicate that these residues alter the ability of the C-linker to transduce signals from the CNBD to the pore gates of the HCN channel. PMID- 29980632 TI - Emerging therapies for mitochondrial diseases. AB - For the vast majority of patients with mitochondrial diseases, only supportive and symptomatic therapies are available. However, in the last decade, due to extraordinary advances in defining the causes and pathomechanisms of these diverse disorders, new therapies are being developed in the laboratory and are entering human clinical trials. In this review, we highlight the current use of dietary supplement and exercise therapies as well as emerging therapies that may be broadly applicable across multiple mitochondrial diseases or tailored for specific disorders. Examples of non-tailored therapeutic targets include: activation of mitochondrial biogenesis, regulation of mitophagy and mitochondrial dynamics, bypass of biochemical defects, mitochondrial replacement therapy, and hypoxia. In contrast, tailored therapies are: scavenging of toxic compounds, deoxynucleoside and deoxynucleotide treatments, cell replacement therapies, gene therapy, shifting mitochondrial DNA mutation heteroplasmy, and stabilization of mutant mitochondrial transfer RNAs. PMID- 29980635 TI - Heartbeat-enhanced immersive virtual reality to treat complex regional pain syndrome. AB - OBJECTIVES: To develop and test a new immersive digital technology for complex regional pain syndrome (CRPS) that combines principles from mirror therapy and immersive virtual reality and the latest research from multisensory body processing. METHODS: In this crossover double-blind study, 24 patients with CRPS and 24 age- and sex-matched healthy controls were immersed in a virtual environment and shown a virtual depiction of their affected limb that was flashing in synchrony (or in asynchrony in the control condition) with their own online detected heartbeat (heartbeat-enhanced virtual reality [HEVR]). The primary outcome measures for pain reduction were subjective pain ratings, force strength, and heart rate variability (HRV). RESULTS: HEVR reduced pain ratings, improved motor limb function, and modulated a physiologic pain marker (HRV). These significant improvements were reliable and highly selective, absent in control HEVR conditions, not observed in healthy controls, and obtained without the application of tactile stimulation (or movement) of the painful limb, using a readily available biological signal (the heartbeat) that is most often not consciously perceived (thus preventing placebo effects). CONCLUSIONS: Next to these specific and well-controlled analgesic effects, immersive HEVR allows the application of prolonged and repeated doses of digital therapy, enables the automatized integration with existing pain treatments, and avoids application of painful bodily cues while minimizing the active involvement of the patient and therapist. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that HEVR reduces pain and increases force strength in patients with CRPS. PMID- 29980634 TI - The N terminus of alpha-ENaC mediates ENaC cleavage and activation by furin. AB - Epithelial Na+ channels comprise three homologous subunits (alpha, beta, and gamma) that are regulated by alternative splicing and proteolytic cleavage. Here, we determine the basis of the reduced Na+ current (INa) that results from expression of a previously identified, naturally occurring splice variant of the alpha subunit (alpha-ENaC), in which residues 34-82 are deleted (alphaDelta34 82). alphaDelta34-82-ENaC expression with WT beta and gamma subunits in Xenopus oocytes produces reduced basal INa, which can largely be recovered by exogenous trypsin. With this alphaDelta34-82-containing ENaC, both alpha and gamma subunits display decreased cleavage fragments, consistent with reduced processing by furin or furin-like convertases. Data using MTSET modification of a cysteine, introduced into the degenerin locus in beta-ENaC, suggest that the reduced INa of alphaDelta34-82-ENaC arises from an increased population of uncleaved, near silent ENaC, rather than from a reduced open probability spread uniformly across all channels. After treatment with brefeldin A to disrupt anterograde trafficking of channel subunits, INa in oocytes expressing alphaDelta34-82-ENaC is reestablished more slowly than that in oocytes expressing WT ENaC. Overnight or acute incubation of oocytes expressing WT ENaC in the pore blocker amiloride increases basal ENaC proteolytic stimulation, consistent with relief of Na+ feedback inhibition. These responses are reduced in oocytes expressing alphaDelta34-82-ENaC. We conclude that the alpha-ENaC N terminus mediates interactions that govern the delivery of cleaved and uncleaved ENaC populations to the oocyte membrane. PMID- 29980636 TI - Neurology outreach clinic for Huntington disease in Peru: Lessons for neurodegenerative diseases. PMID- 29980638 TI - Isolated gait dysfunction due to intracranial hypotension. PMID- 29980637 TI - Anticonvulsants and the risk of perinatal bleeding complications: A pregnancy cohort study. AB - OBJECTIVE: To examine the risk of postpartum hemorrhage (PPH) and neonatal bleeding complications associated with late-pregnancy exposure to anticonvulsant drugs (ACDs) that induce cytochrome P450 enzymes (ACDi) and alter the metabolism of vitamin K compared to other ACDs. METHODS: We used a population-based cohort study stemming from a nationwide sample of publicly insured pregnant women with a liveborn infant from the 2000 to 2010 Medicaid Analytic eXtract. ACDi (carbamazepine, phenobarbital, phenytoin, oxcarbazepine, topiramate) were compared to other ACDs dispensed during the last month of pregnancy. Relative risks (RRs) and 95% confidence intervals (CIs) of PPH and neonatal bleeding complications were estimated using generalized linear models with fine stratification on the propensity score to control for indication and other potential confounders. RESULTS: Among 11,572 women with an ACD prescription overlapping delivery, 2.6% (135/5,109) in the ACDi group and 3.6% (231/6,463) in the other ACDs group had a diagnosis of PPH: unadjusted RR 0.74 (95% CI 0.60 0.91), adjusted RR 0.77 (95% CI 0.58-1.00). The prevalence of neonatal bleeding complications was 3.1% (157/5,109) in the ACDi group and 3.5% (229/6,463) in the other ACDs group: unadjusted RR 0.87 (95% CI 0.71-1.06), adjusted RR 0.83 (95% CI 0.64-1.08). CONCLUSIONS: Evidence from this large observational study suggests that use of ACDi near delivery does not increase the risk of bleeding complications compared to other ACDs in clinical settings where neonatal intramuscular or oral vitamin K administration is considered standard of care. These findings provide reassurance for clinicians and pregnant women successfully treated with ACDi. PMID- 29980639 TI - Leukoaraiosis is independently associated with naming outcome in poststroke aphasia. AB - OBJECTIVE: To test the hypothesis that severity of leukoaraiosis in the noninfarcted hemisphere at onset is associated with poorer language outcome after poststroke aphasia independently of volume of infarct, damage to 3 critical language areas (left inferior frontal gyrus, superior longitudinal fasciculus, and superior temporal gyrus), comorbid conditions, and time since stroke. METHODS: In this cross-sectional study, we evaluated naming outcome (>3 months after stroke) in 42 individuals who initially had aphasia after stroke. We rated leukoaraiosis in the right hemisphere 1 to 4 weeks from onset of stroke using the Cardiovascular Health Study rating scale. We evaluated associations between severity of leukoaraiosis and each measure of naming using Spearman correlations and evaluated the independent contributions of leukoaraiosis, lesion volume, months since onset, comorbid conditions, and damage to critical nodes of the language network on language outcomes using logistic regression. We also evaluated associations between dichotomously defined leukoaraiosis and language outcomes using chi2 tests. RESULTS: Severity of leukoaraiosis at onset correlated with object naming (rho = -0.56, p = 0.0008) and word fluency (rho = -0.37, p = 0.01) outcomes. Severe leukoaraiosis was associated with failure to achieve the highest quartile of object naming and word fluency. Severity of leukoaraiosis was associated with degree of naming outcome with the use of both measures after controlling for lesion volume, months since stroke, comorbid conditions, and damage to specific locations. CONCLUSION: Naming outcome after poststroke aphasia is influenced by the initial severity of right hemisphere leukoaraiosis independently of other variables. Degree of recovery from aphasia may depend on the integrity of the noninfarcted brain tissue. PMID- 29980642 TI - 65 YEARS OF THE DOUBLE HELIX: It's all in the DNA: understanding and managing endocrine neoplasms. PMID- 29980643 TI - 65 YEARS OF THE DOUBLE HELIX: Could Watson and Crick have envisioned the true impact of their discovery? AB - Landmark scientific findings are applauded. However, at the time of discovery, the future impact that these types of new knowledge might have on patients is not foreseen. This article discusses how unraveling the structure of DNA has advanced medical treatment, particularly for patients with rare diseases. In addition, each new scientific discovery brings with it the emotion of hope for improved diagnosis and treatment, as well as enhanced outcomes and increased longevity for patients facing a life-long disease. PMID- 29980641 TI - Socioeconomic determinants of outcome after childhood arterial ischemic stroke. AB - OBJECTIVE: To determine whether lower socioeconomic status (SES) is associated with worse 1-year neurologic outcomes and reduced access to rehabilitation services in children with arterial ischemic stroke (AIS). METHODS: From 2010 to 2014, the Vascular effects of Infection in Pediatric Stroke (VIPS) observational study prospectively enrolled and confirmed 355 children (age 29 days-18 years) with AIS at 37 international centers. SES markers measured via parental interview included annual household income (US dollars) at the time of enrollment, maternal education level, and rural/suburban/urban residence. Receipt of rehabilitation services was measured by parental report. Pediatric Stroke Outcome Measure scores were categorized as 0 to 1, 1.5 to 3, 3.5 to 6, and 6.5 to 10. Univariate and multivariable ordinal logistic regression models examined potential predictors of outcome. RESULTS: At 12 +/- 3 months after stroke, 320 children had documented outcome measurements, including 15 who had died. In univariate analysis, very low income (10-3 S cm-1) and magnetic ordering in MOFs will afford them new functions for spintronics, which remains relatively unexplored. Here, we demonstrate the synthesis of a two-dimensional MOF by solvothermal methods using perthiolated coronene as a ligand and planar iron-bis(dithiolene) as linkages enabling a full pi-d conjugation. This 2D MOF exhibits a high electrical conductivity of ~10 S cm-1 at 300 K, which decreases upon cooling, suggesting a typical semiconductor nature. Magnetization and 57Fe Mossbauer experiments reveal the evolution of ferromagnetism within nanoscale magnetic clusters below 20 K, thus evidencing exchange interactions between the intermediate spin S = 3/2 iron(III) centers via the delocalized pi electrons. Our results illustrate that conjugated 2D MOFs have potential as ferromagnetic semiconductors for application in spintronics. PMID- 29980688 TI - Highly stretchable and transparent ionic conducting elastomers. AB - Traditional elastomers are mostly dielectrics; existing conductive elastomers are conductive composites with electric conductors. Herein, we introduce a series of ionic conducting elastomers (ICE) by salt in polymer strategy. The ICEs possess good stretchability, transparency and ionic conductivity. Moreover, the ICEs exhibit very high stability in air, under high temperature and voltage, with excellent adhesion properties and no corrosive effects to metal electrodes. Touch sensors are fabricated using these ICEs-impedance spectra and impedance complex plane are tested and analyzed to clarify different stimulus of the touch sensors. These ICEs provide possibilities for flexible electronics and soft machines. PMID- 29980689 TI - Effect of different filling tendencies on the spatial quantum Zeno effect. AB - The quantum Zeno effect is deeply related to the quantum measurement process and thus studies of it may help shed light on the hitherto mysterious measurement process in quantum mechanics. Recently, the spatial quantum Zeno effect is observed in a Bose-Einstein condensate depleted by an electron beam. We theoretically investigate how different intrinsic tendencies of filling affect the quantum Zeno effect in this system by changing the impinging point of the electron beam along the inhomogeneous condensate. Surprisingly, we find no visible effect on the critical dissipation intensity at which the quantum Zeno effect appear. Our finding shows the recent capability of combining the Bose Einstein condensate with an electron beam offers a great opportunity for studying the spatial quantum Zeno effect, and more generally the dynamics of a quantum many-body system out of equilibrium. PMID- 29980690 TI - Co-treatment of TGF-beta3 and BMP7 is superior in stimulating chondrocyte redifferentiation in both hypoxia and normoxia compared to single treatments. AB - Signaling by members of the transforming growth factor-beta (TGF-beta) superfamily, such as TGF-beta3 and BMP7, and oxygen tension play a pivotal role in chondrocyte biology. The objective of this research was to investigate the endogenous BMP7 expression in human osteoarthritis (OA) cartilage and the effect of oxygen tension on the single or combined treatment with TGF-beta3 and BMP7 on OA chondrocyte redifferentiation in three dimensional (3D) pellet cultures. The results showed the expression of BMP7 and its intracellular signaling target SMAD1/5/8 was decreased in early OA, while it was increased in later stages of OA. The combined treatment with TGF-beta3 and BMP7, both in normoxia and hypoxia, was more effective than TGF-beta3 or BMP7 alone in redifferentiating chondrocytes. This was reflected by Alcian blue/Safranin O staining and collagen type II protein expression, as well as by gene expression. Hypoxia elevated TGF beta3 and BMP7-induced matrix formation of OA chondrocytes and alleviated the catabolic gene expression. Interestingly, cells cultured under normoxia displayed mild signs of an inflammatory stress response, which was effectively counteracted by culturing the cells under low oxygen tension. Our data underscores the important modulatory role of oxygen tension on the chondrocyte's responsiveness to TGF-beta3 and/or BMP7. PMID- 29980691 TI - Risk-adjustment of diabetes health outcomes improves the accuracy of performance benchmarking. AB - Benchmarking clinical performance by comparing diabetes health outcomes across healthcare providers drives quality improvement. Non-care related patient risk factors are likely to confound clinical performance, but few studies have tested this. This cross-sectional study is the first Australian investigation to analyse the effect of risk-adjustment for non-care related patient factors on benchmarking. Data from 4,670 patients with type 2 (n = 3,496) or type 1 (n = 1,174) were analysed across 49 diabetes centres. Diabetes health outcomes (HbA1c levels, LDL-cholesterol levels, systolic blood pressure and rates of severe hypoglycaemia) were risk-adjusted for non-care related patient factors using multivariate stepwise linear and logistic regression models. Unadjusted and risk adjusted funnel plots were constructed for each outcome to identify low performing and high-performing outliers. Unadjusted funnel plots identified 27 low-performing outliers and 15 high-performing outliers across all diabetes health outcomes. After risk-adjustment, 22 (81%) low-performing outliers and 13 (87%) high-performing outliers became inliers. Additionally, one inlier became a low-performing outlier. Risk-adjustment of diabetes health outcomes significantly reduced false positives and false negatives for outlier performance, hence providing more accurate information to guide quality improvement activity. PMID- 29980692 TI - GABA promotes gastrin-releasing peptide secretion in NE/NE-like cells: Contribution to prostate cancer progression. AB - In prostate cancer (PCa), neuroendocrine cells (NE) have been associated with the progression of the disease due to the secretion of neuropeptides that are capable of diffusing and influence surrounding cells. The GABAergic system is enriched in NE-like cells, and contributes to PCa progression. Additionally, gamma aminobutyric acid (GABA) stimulates the secretion of gastrin-releasing peptide (GRP) in peripheral organs. For the first time, in this study we show the role of GABA and GABAB receptor 1 (GABBR1) expression in GRP secretion in NE-like prostate cancer cells. We demonstrated an increase in GRP levels in NE-like cell medium treated with GABAB receptor agonist. Moreover, the blocking of this receptor inhibited GABA-induced GRP secretion. The invasive potential of PC3 cells was enhanced by either GRP or conditioned medium of NE-like cells treated with GABA. Additionally, we confirmed a positive correlation between GABA and GRP levels in the serum of PCa patients with NE markers. Finally, using public available data sets, we found a negative correlation between GABBR1 and androgen receptor (AR) expression, as well as a strong positive correlation between GABBR1 and enolase 2. These results suggest that GABA via GABBR1 induces GRP secretion in NE like cells involved in PCa progression. PMID- 29980693 TI - Automaticity of social cues: The influence of limiting cognitive resources on head orientation cueing. AB - Our ability to communicate effectively often relies on being able to shift our focus of attention to align with that of another person. This so-called "social attention" reflects the use of cues such as gaze, pointing and head orientation to infer the attentional focus of others. An important, but unresolved, question is whether these socially relevant cues automatically direct attention in observers, or whether cognitive resources shape this process. An additional issue is that existing work has almost exclusively examined eye gaze cues, thus potentially limiting the generalizability of this work across types of social cues. To examine these issues, the present research investigates the influence of limiting resource availability (using a concurrent memory load) on the ability of an oriented head cue to direct attention. The results indicate that reducing resource availability increases the impact of the head cue on attentional orienting - the opposite pattern to that obtained with gaze cues. This outcome suggests that resource availability does not affect all social cues the same, and that caution is warranted in drawing broad conclusions about mechanisms underlying social cueing of attention without appropriate comparisons across multiple types of social cues. PMID- 29980694 TI - Application of Real-time Elastography Ultrasound in the Diagnosis of Axillary Lymph Node Metastasis in Breast Cancer Patients. AB - The pathological status of axillary lymph nodes (ALN) plays a critical role in the staging and treatment of patients with breast cancer. Therefore, differential diagnosis of metastatic ALN is highly desirable in the clinic. We used real-time elastography (RTE) and gray-scale ultrasound to generate a new scoring system for determining ALN status and estimate their performance of this system. Ninety seven ALNs were examined by both gray-scale ultrasound and RTE. The performance of gray-scale ultrasound was evaluated by the sum of scores according to its features. RTE images were determined by a modulated scoring system based on the percentage and distribution of hypoechoic cortex regions in the ALNs. Strain ratio was also calculated. Diagnostic performance was obtained by receiver operating characteristic curve analysis with pathologic findings used as the reference standard. The sensitivity, specificity and accuracy were 92%, 73% and 83%, respectively, for gray-scale ultrasound; 78%, 93%, 86%, respectively, for RTE; 88%, 96% and 92%, respectively, for the combined evaluation (AUC = 0.963), and 87%, 76% and 81%, respectively, for strain ratio. Gray-scale ultrasonography had a better sensitivity than RTE (92% vs 78%, P = 0.039), while the specificity for RTE was superior to that of gray-scale ultrasonography (93% vs 73%, P = 0.012). In conclusion, RTE showed a high specificity for evaluating the ALN status and may improve the diagnostic accuracy when combined with gray-scale ultrasound. PMID- 29980695 TI - Knee Joint Tissues Effectively Separate Mixed Sized Molecules Delivered in a Single Bolus to the Heart. AB - The role of molecular size selectivity in the onset and progression of osteoarthritis (OA), a degenerative disease of the musculoskeletal system and the most common cause of disability in aging adults, is unknown. Here we delivered a mixture of Texas-red (70 kDa), and Rhodamine-green (10 kDa) tagged, dextrans of neutral charge in a single bolus via heart injection to middle aged (8-10 months) and aged (17-19 months) Dunkin-Hartley Guinea pigs, a natural model for OA. We quantified tracer transport in serial-sectioned, cryofixed block specimens after five minutes' circulation. A remarkable separation of the molecules was observed in serial fluorescent images of whole joint sections. The larger, 70 kDa red tracer was abundant in the marrow cavity albeit less prevalent or absent in the bone, cartilage, meniscus and other tissues of the joint. Tissues of the meniscus, ligament, and tendon exhibited abundant 10 kDa tracer; volumes of tissue containing this molecular tracer were significantly lower in older than in younger animals. Surprisingly, muscle fiber bundles exhibited little fluorescence, while their bounding fasciae fluoresced either red or green. Small caliber channels through the articular cartilage appeared to show a degree of green fluorescence not observed in the surrounding cartilage matrix. This study opens up new avenues for study of musculoskeletal physiology in health and disease as well as new strategies for drug delivery. PMID- 29980696 TI - Antigenic characteristics and genomic analysis of novel EV-A90 enteroviruses isolated in Xinjiang, China. AB - Enterovirus A90 (EV-A90) is a novel serotype of enterovirus A species that is rarely reported. Here, we isolated five enteroviruses from patients with acute flaccid paralysis in Hotan and Kashgar cities in Xinjiang, China that were identified as EV-A90 by molecular typing. The VP1 sequences of these Xinjiang EV A90 strains showed 88.4-89% nucleotide sequence identity to the prototype EV-A90 strain; however, genome analysis indicated complex recombination events in P2 and P3 regions. Next, the seroprevalence of EV-A90 was examined in 49 serum specimens collected in Hotan and Kashgar, and 37.5% were EV-A90 antibody positive (>1:8), with a geometric mean titre (GMT) of 1:10.47. The low positive rate and GMT suggest a low-level EV-A90 epidemic in Xinjiang. Two of the five Xinjiang EV-A90 strains were temperature sensitive, and three were temperature resistant, and a comparative genomics analysis suggested that an amino acid substitution (H1799Y) in the 3Dpol region was related to temperature sensitivity. Although the epidemic strength is low, some EV-A90 strains were temperature resistant, which is suggestive of strong virulence and transmission capacity. This study expanded the number of EV-A90 in GenBank and provided basic data that may be useful for studying the molecular epidemiology of EV-A90. PMID- 29980697 TI - Spinal PKCalpha inhibition and gene-silencing for pain relief: AMPAR trafficking at the synapses between primary afferents and sensory interneurons. AB - Upregulation of Ca2+-permeable AMPA receptors (CP-AMPARs) in dorsal horn (DH) neurons has been causally linked to persistent inflammatory pain. This upregulation, demonstrated for both synaptic and extrasynaptic AMPARs, depends on the protein kinase C alpha (PKCalpha) activation; hence, spinal PKC inhibition has alleviated peripheral nociceptive hypersensitivity. However, whether targeting the spinal PKCalpha would alleviate both pain development and maintenance has not been explored yet (essential to pharmacological translation). Similarly, if it could balance the upregulated postsynaptic CP-AMPARs also remains unknown. Here, we utilized pharmacological and genetic inhibition of spinal PKCalpha in various schemes of pain treatment in an animal model of long lasting peripheral inflammation. Pharmacological inhibition (pre- or post treatment) reduced the peripheral nociceptive hypersensitivity and accompanying locomotive deficit and anxiety in rats with induced inflammation. These effects were dose-dependent and observed for both pain development and maintenance. Gene therapy (knockdown of PKCalpha) was also found to relieve inflammatory pain when applied as pre- or post-treatment. Moreover, the revealed therapeutic effects were accompanied with the declined upregulation of CP-AMPARs at the DH synapses between primary afferents and sensory interneurons. Our results provide a new focus on the mechanism-based pain treatment through interference with molecular mechanisms of AMPAR trafficking in central pain pathways. PMID- 29980698 TI - Plasma-Induced Phase Transformation of SnS2 to SnS. AB - Layered van der Waals materials have recently attracted attention owing to their exceptional electrical and optical properties in thin layer form. One way to extend their utility is to form a heterostructure which combines various properties of layered materials to reveal intriguing behavior. Conventional heterostructure synthesis methods are difficult to develop and the heterostructure formed can be limited to a small area. Here, we investigate the phase transformation of SnS2 to SnS by removing sulfur atoms at the top surface using Ar plasma. By varying the plasma power and exposure time, we observed that SnS is subsequently formed on top of the mogul-like structure of SnS2. Since SnS is a p-type semiconductor and SnS2 is an n-type semiconductor, we naturally formed a vertical p-n junction. By using graphene at the top and bottom as transparent electrodes, a vertical p-n diode device is constructed. The device demonstrates good rectifying behavior and large photocurrent generation under white light. This method can be applied to large-area heterostructure synthesis using plasma via phase transformation of various metal dichalcogenides to metal monochalcogenides. PMID- 29980699 TI - Diversity among blaKPC-containing plasmids in Escherichia coli and other bacterial species isolated from the same patients. AB - Carbapenem resistant Enterobacteriaceae are a significant public health concern, and genes encoding the Klebsiella pneumoniae carbapenemase (KPC) have contributed to the global spread of carbapenem resistance. In the current study, we used whole-genome sequencing to investigate the diversity of blaKPC-containing plasmids and antimicrobial resistance mechanisms among 26 blaKPC-containing Escherichia coli, and 13 blaKPC-containing Enterobacter asburiae, Enterobacter hormaechei, K. pneumoniae, Klebsiella variicola, Klebsiella michiganensis, and Serratia marcescens strains, which were isolated from the same patients as the blaKPC-containing E. coli. A blaKPC-containing IncN and/or IncFIIK plasmid was identified in 77% (30/39) of the E. coli and other bacterial species analyzed. Complete genome sequencing and comparative analysis of a blaKPC-containing IncN plasmid from one of the E. coli strains demonstrated that this plasmid is present in the K. pneumoniae and S. marcescens strains from this patient, and is conserved among 13 of the E. coli and other bacterial species analyzed. Interestingly, while both IncFIIK and IncN plasmids were prevalent among the strains analyzed, the IncN plasmids were more often identified in multiple bacterial species from the same patients, demonstrating a contribution of this IncN plasmid to the inter-genera dissemination of the blaKPC genes between the E. coli and other bacterial species analyzed. PMID- 29980700 TI - Lifespan and functionality of mycorrhizal fungal mycelium are uncoupled from host plant lifespan. AB - Arbuscular mycorrhizal fungi (AMF) are obligate symbionts, living in associations with the roots of most land plants. AMF produce wide networks of extraradical mycelium (ERM) of indeterminate length, spreading from host roots into the surrounding soil and establishing belowground interconnections among plants belonging to the same or to different taxa. Whether their lifespan and functionality are limited by host plant viability or can be extended beyond this limit is unknown. To address this issue, we performed time-course studies to investigate viability and functionality of ERM produced in an in vivo whole-plant system by Funneliformis mosseae and Rhizoglomus irregulare, after shoot detachment. Our data revealed that viability and functionality of F. mosseae and R. irregulare extraradical hyphae were uncoupled from host plant lifespan. Indeed, ERM spreading from roots of intact or shootless plants showed comparable levels of viability, similar structural traits and ability to establish mycorrhizal symbioses with new plants, as long as five months after shoot removal. Our findings expand the current knowledge on AMF biology and life cycle, providing data on ERM long-term survival in the soil of two Glomeracean species, functional to the prompt establishment of mycorrhizal symbioses and to the maintenance of soil biological fertility. PMID- 29980701 TI - Comparative and phylogenetic analysis of a novel family of Enterobacteriaceae associated genomic islands that share a conserved excision/integration module. AB - Genomic Islands (GIs) are DNA regions acquired through horizontal gene transfer that encode advantageous traits for bacteria. Many GIs harbor genes that encode the molecular machinery required for their excision from the bacterial chromosome. Notably, the excision/integration dynamics of GIs may modulate the virulence of some pathogens. Here, we report a novel family of GIs found in plant and animal Enterobacteriaceae pathogens that share genes with those found in ROD21, a pathogenicity island whose excision is involved in the virulence of Salmonella enterica serovar Enteritidis. In these GIs we identified a conserved set of genes that includes an excision/integration module, suggesting that they are excisable. Indeed, we found that GIs within carbapenem-resistant Klebsiella pneumoniae ST258 KP35 and enteropathogenic Escherichia coli O127:H6 E2348/69 are excised from the bacterial genome. In addition to putative virulence factors, these GIs encode conjugative transfer-related proteins and short and full-length homologues of the global transcriptional regulator H-NS. Phylogenetic analyses suggest that the identified GIs likely originated in phytopathogenic bacteria. Taken together, our findings indicate that these GIs are excisable and may play a role in bacterial interactions with their hosts. PMID- 29980702 TI - Assessment of fine-scale parameterizations at low latitudes of the North Pacific. AB - Fine-scale parameterizations based on shear and stratification are widely used to study the intensity and spatial distribution of turbulent diapycnal mixing in the ocean. Two well-known fine-scale parameterizations, Gregg-Henyey-Polzin (GHP) parameterization and MacKinnon-Gregg (MG) parameterization, are assessed with the full-depth microstructure data obtained in the North Pacific. The GHP parameterization commonly used in the open ocean succeeds in reproducing the dissipation rates over smooth topography but fails to predict the turbulence over rough topography. Failure of GHP parameterization over rough topography is attributed to the deviation of internal wave spectrum from the Garrett-Munk (GM) spectrum. The internal wave field over rough topography is characterized by energetic intermediate-scale and small-scale internal waves that are not described well by the GM model. The MG parameterization that is widely used in coastal environments is found to be successful in reproducing the dissipation rates over both smooth and rough topographies. The efficacy of GHP and MG parameterizations in evaluating the dissipation rates has been assessed. The result indicates that MG parameterization predicts the magnitude and variability of the dissipation rates better than the GHP parameterization. PMID- 29980703 TI - Naturally derived Heme-Oxygenase 1 inducers attenuate inflammatory responses in human dendritic cells and T cells: relevance for psoriasis treatment. AB - Psoriasis is a chronic autoimmune disease mediated by dysregulated immune responses in dendritic cells (DC) and T cells. The stress-response enzyme heme oxygenase-1 (HO-1) has been described as protective in animal models of psoriasis, however, implementation of HO-1-based therapies is hindered by the lack of clinically-suitable HO-1 inducers. The plant-derived polyphenols, carnosol and curcumin, have been identified as candidate HO-1 inducers however there has been little investigation into their effects on human immune cells. We demonstrate that treatment of human DC with these polyphenols limits DC maturation, reduces pro-inflammatory cytokine production, and prevents induction of allospecific T cell responses, in a manner partially dependent on carbon monoxide (CO). We also characterised their effects in ex-vivo psoriasis PBMC and report that curcumin, but not carnosol, strongly reduces T cell proliferation and cytokine poly-functionality, with reduced expression of psoriatic cytokines IFNgamma, IL-17, GM-CSF and IL-22. This study therefore supports reports highlighting the therapeutic potential of curcumin in psoriasis by providing insight into its immunological effects on healthy human DC and psoriasis PBMC. We also demonstrate, for the first time, the anti-inflammatory effects of carnosol in human immune cells. PMID- 29980704 TI - Quantitative characterization of high temperature oxidation using electron tomography and energy-dispersive X-ray spectroscopy. AB - We report quantitative characterization of the high temperature oxidation process by using electron tomography and energy-dispersive X-ray spectroscopy. As a proof of principle, we performed 3D imaging of the oxidation layer of a model system (Mo3Si) at nanoscale resolution with elemental specificity and probed the oxidation kinetics as a function of the oxidation time and the elevated temperature. Our tomographic reconstructions provide detailed 3D structural information of the surface oxidation layer of the Mo3Si system, revealing the evolution of oxidation behavior of Mo3Si from early stage to mature stage. Based on the relative rate of oxidation of Mo3Si, the volatilization rate of MoO3 and reactive molecular dynamics simulations, we propose a model to explain the mechanism of the formation of the porous silica structure during the oxidation process of Mo3Si. We expect that this 3D quantitative characterization method can be applied to other material systems to probe their structure-property relationships in different environments. PMID- 29980706 TI - Factors in glucocorticoid regimens associated with treatment response and relapses of IgG4-related disease: a multicentre study. AB - Glucocorticoids (GC) are effective for treating IgG4-related disease (IgG4-RD); however, relapse is often observed. We conducted a retrospective multicentre study to investigate risk factors in GC regimens associated with relapses of IgG4 RD. Data on 166 patients with definitive IgG4-RD diagnosis were collected from 12 institutions. Comprehensive surveillance of clinical backgrounds and GC regimens as well as multivariate analysis of factors associated with treatment responses and relapses was performed. To determine the initial maximal GC dose, the patients were stratified into three groups depending on the initial prednisolone (PSL) dosage: <0.39, 0.4-0.69 and >0.7 mg/kg/day. The multivariate analysis extracted the disease duration and reduction speed of initial GC dose. Patients treated with initial GC <0.39 or >0.7 mg/kg/day of PSL showed higher relapse rates than those treated with 0.4-0.69 mg/kg/day. The relapse rates were significantly higher in patients with fast reduction of the initial dose (>0.4 mg/day) than in patients with slow reduction (<0.4 mg/day). To avoid relapse, 0.4 0.69 mg/kg/day of initial PSL with slow reduction speed (<0.4 mg/day) is needed in the early treatment of IgG4-RD. PMID- 29980705 TI - PID/WAG-mediated phosphorylation of the Arabidopsis PIN3 auxin transporter mediates polarity switches during gravitropism. AB - Intercellular distribution of the plant hormone auxin largely depends on the polar subcellular distribution of the plasma membrane PIN-FORMED (PIN) auxin transporters. PIN polarity switches in response to different developmental and environmental signals have been shown to redirect auxin fluxes mediating certain developmental responses. PIN phosphorylation at different sites and by different kinases is crucial for PIN function. Here we investigate the role of PIN phosphorylation during gravitropic response. Loss- and gain-of-function mutants in PINOID and related kinases but not in D6PK kinase as well as mutations mimicking constitutive dephosphorylated or phosphorylated status of two clusters of predicted phosphorylation sites partially disrupted PIN3 phosphorylation and caused defects in gravitropic bending in roots and hypocotyls. In particular, they impacted PIN3 polarity rearrangements in response to gravity and during feed back regulation by auxin itself. Thus PIN phosphorylation, besides regulating transport activity and apical-basal targeting, is also important for the rapid polarity switches in response to environmental and endogenous signals. PMID- 29980707 TI - Intestinal permeability, digestive stability and oral bioavailability of dietary small RNAs. AB - Impactful dietary RNA delivery requires improving uptake and enhancing digestive stability. In mouse feeding regimes, we have demonstrated that a plant-based ribosomal RNA (rRNA), MIR2911, is more bioavailable than synthetic MIR2911 or canonical microRNAs (miRNAs). Here mutagenesis was used to discern if MIR2911 has a distinctive sequence that aids stability and uptake. Various mutations had modest impacts while one scrambled sequence displayed significantly enhanced digestive stability, serum stability, and bioavailability. To assess if small RNA (sRNA) bioavailability in mice could be improved by increasing gut permeability, various diets, genetic backgrounds and pharmacological methods were surveyed. An intraperitoneal injection of anti-CD3 antibody enhanced gut permeability which correlated with improved uptake of the digestively stable scrambled MIR2911 variant. However, the bioavailability of canonical miRNAs was not enhanced. Similarly, interleukin-10 (IL-10)-deficient mice and mice treated with aspirin displayed enhanced gut permeability that did not enhance uptake of most plant based sRNAs. This work supports a model where dietary RNAs are vulnerable to digestion and altering gut permeability alone will not impact apparent bioavailability. We suggest that some dietary sRNA may be more digestively stable and methods to broadly increase sRNA uptake requires delivery vehicles to optimize gut and serum stability in the consumer. PMID- 29980708 TI - Crossover from Jamming to Clogging Behaviours in Heterogeneous Environments. AB - Jamming describes a transition from a flowing or liquid state to a solid or rigid state in a loose assembly of particles such as grains or bubbles. In contrast, clogging describes the ceasing of the flow of particulate matter through a bottleneck. It is not clear how to distinguish jamming from clogging, nor is it known whether they are distinct phenomena or fundamentally the same. We examine an assembly of disks moving through a random obstacle array and identify a transition from clogging to jamming behavior as the disk density increases. The clogging transition has characteristics of an absorbing phase transition, with the disks evolving into a heterogeneous phase-separated clogged state after a critical diverging transient time. In contrast, jamming is a rapid process in which the disks form a homogeneous motionless packing, with a rigidity length scale that diverges as the jamming density is approached. PMID- 29980709 TI - Iron-Overload triggers ADAM-17 mediated inflammation in Severe Alcoholic Hepatitis. AB - Severe alcoholic hepatitis (SAH) is associated with iron accumulation in hepatocytes/macrophages. This possibly correlates with inflammation and stress but the exact mechanism still remains obscure. To understand the role of iron and the mechanisms of systemic iron-overload, a transcriptomic study of liver and Peripheral Blood -Mononuclear-Cells (PBMCs) was undertaken in SAH patients, with and without hepatic iron-overload. Our results show that iron-overload in hepatocytes/macrophages is due to an increased expression of iron-loading receptors and CD163 signaling cascade. Increase in labile iron pool induces expression of iron-loading, oxidative-stress and inflammatory genes along with expression of CD163 and ADAM17. Increased liver iron correlated with circulatory iron, TNF-alpha, macrophage activation (sCD163) and peroxide-stress in CD163+macrophages in patients who were iron-overloaded and died. Circulatory TNF alpha and sCD163 levels were associated with poor outcome. Temporal iron/Fenton stress induced in healthy monocyte-derived-macrophage (MDM)/Tohoku-Hospital Pediatrics-1(THP1) cells showed higher expression of iron-regulatory, inflammatory and oxidative-stress genes. These genes could be suppressed by iron chelation. These results suggest that iron mediates inflammation through ADAM17 induction, resulting in macrophage activation and increased shedding of TNF-alpha and sCD163. These events could be inhibited with iron chelation or with ADAM17 blockade, postulating a therapeutic strategy for SAH patients with iron overload. PMID- 29980710 TI - Discrimination of three Ephedra species and their geographical origins based on multi-element fingerprinting by inductively coupled plasma mass spectrometry. AB - Discrimination of species and geographical origins of traditional Chinese medicine (TCM) is essential to prevent adulteration and inferior problems. We studied Ephedra sinica Stapf, Ephedra intermedia Schrenk et C.A.Mey. and Ephedra przewalskii Bge. to investigate the relationship between inorganic element content and these three species and their geographical origins. 38 elemental fingerprints from six major Ephedra-producing regions, namely, Inner Mongolia, Ningxia, Gansu, Shanxi, Shaanxi, and Sinkiang, were determined to evaluate the importance of inorganic elements to three species and their geographical origins. The contents of 15 elements, namely, N, P, K, S, Ca, Mg, Fe, Mn, Na, Cl, Sr, Cu, Zn, B, and Mo, of Ephedra samples were measured using inductively coupled plasma mass spectroscopy. Elemental contents were used as chemical indicators to classify species and origins of Ephedra samples using a radar plot and multivariate data analysis, including hierarchical cluster analysis (HCA), principal component analysis (PCA), and discriminant analysis (DA). Ephedra samples from different species and geographical origins could be differentiated. This study showed that inorganic elemental fingerprint combined with multivariate statistical analysis is a promising tool for distinguishing three Ephedra species and their geographical origins, and this strategy might be an effective method for authenticity discrimination of TCM. PMID- 29980711 TI - A comprehensive analysis of the Korean fir (Abies koreana) genes expressed under heat stress using transcriptome analysis. AB - Korean fir (Abies koreana), a rare species endemic to South Korea, is sensitive to climate change. Here, we used next-generation massively parallel sequencing technology and de novo transcriptome assembly to gain a comprehensive overview of the Korean fir transcriptome under heat stress. Sequencing control and heat treated samples of Korean fir, we obtained more than 194,872,650 clean reads from each sample. After de novo assembly and quantitative assessment, 42,056 unigenes were generated with an average length of 908 bp. In total, 6,401 differentially expressed genes were detected, of which 2,958 were up-regulated and 3,443 down regulated, between the heat-treated and control samples. A gene ontology analysis of these unigenes revealed heat-stress-related terms, such as "response to stimulus". Further, in depth analysis revealed 204 transcription factors and 189 Hsps as differentially expressed. Finally, 12 regulated candidate genes associated with heat stress were examined using quantitative real-time PCR (qRT PCR). In this study, we present the first comprehensive characterisation of Korean fir subjected to heat stress using transcriptome analysis. It provides an important resource for future studies of Korean fir with the objective of identifying heat stress tolerant lines. PMID- 29980712 TI - Irradiation-based design of mechanically resistant microstructures tuned via multiscale phase-field modeling. AB - We present a multi-scale phase field modeling of stationary microstructures produced under 1 MeV krypton ion irradiation in a phase separating concentrated solid solution of silver and copper. We show that the mixture reaches ultimately a stationary micro-structural state made of phase domains with composition and size distribution mapped to the values of the incident flux of particles and of the temperature, variables that help defining a non equilibrium phase-diagram for the irradiated alloy. The modeling predicts the formation of diverse microstructures likely connected to spinodal hardening, thus opening the perspective of the on-purpose tuning of mechanically resistant microstructures and the preparation of metastable alloys with mechanical properties improved by comparison to counterparts obtained via classical thermo-mechanical treatments. PMID- 29980713 TI - Microstructure characterization of BaSnO3 thin films on LaAlO3 and PrScO3 substrates from transmission electron microscopy. AB - Detailed microstructure analysis of epitaxial thin films is a vital step towards understanding essential structure-property relationships. Here, a combination of transmission electron microscopy (TEM) techniques is utilized to determine in detail the microstructure of epitaxial La-doped BaSnO3 films grown on two different perovskite substrates: LaAlO3 and PrScO3. These BaSnO3 films are of high current interest due to outstanding electron mobility at ambient. The rotational disorder of low-angle grain boundaries, namely the in-plane twist and out-of-plane tilt, is visualized by conventional TEM under a two-beam condition, and the degree of twists in grains of such films is quantified by selected-area electron diffraction. The investigation of the atomic arrangement near the film substrate interfaces, using high-resolution annular dark-field scanning TEM imaging, reveals that edge dislocations with a Burgers vector along [001] result in the out-of-plane tilt. It is shown that such TEM-based analyses provide detailed information about the microstructure of the films, which, when combined with complimentary high-resolution X-ray diffraction, yields a complete structural characterization of the films. In particular, stark differences in out of-plane tilt on the two substrates are shown to result from differences in misfit dislocation densities at the interface, explaining a puzzling observation from X-ray diffraction. PMID- 29980714 TI - One-time root-zone N fertilization increases maize yield, NUE and reduces soil N losses in lime concretion black soil. AB - Excess N-fertilizer application and inappropriate fertilization methods have led to low N use efficiency (NUE) and high N leaching. A field experiment was performed in a typical lime concretion black soil area to compare N application methods: split surface broadcasting (SSB) and one-time root-zone fertilization (RZF) on grain yield, NUE, the fate of 15N urea and soil N loss during the 2015 and 2016 maize growing seasons. Each application method was tested at N rates of 135 and 180 kg N ha-1, and a control (CK) with no N fertilizer. The RZF treatment remarkably increased grain yield by 7.0% compared with SSB treatment under 180 kg N ha-1, and significantly increased N derived from fertilizer by 28.5%. The residual 15N in the 0-80 cm soil layer was 40.6-47.6% after harvest, 61.8-70.9% of which was retained in 0-20 cm. The RZF remarkably increased the 15N recovery in maize by 28.7%, while significantly decreased the potential N losses by 30.2% compared with SSB in both seasons. In conclusion, one-time RZF of urea is recommended for obtaining high yields, increasing NUE, and minimizing N losses in maize, which deserves more attention for developing and applying in the future. PMID- 29980715 TI - Fingerprint Detection and Differentiation of Gas-phase Amines Using a Fluorescent Sensor Array Assembled from Asymmetric Perylene Diimides. AB - A series of structurally analogous PDIs were fabricated and used as fluorescent sensor arrays. Adjustment of the molecular electron-donating ability and polarity (i.e., chemical structure) was found to greatly influence the fluorescent quenching by different types of amines. Moreover, the sensor array displayed high sensitivity to amine vapors and allowed the fingerprint differentiation of different species. PMID- 29980716 TI - Sound abnormally stimulates the vestibular system in canal dehiscence syndrome by generating pathological fluid-mechanical waves. AB - Individuals suffering from Tullio phenomena experience dizziness, vertigo, and reflexive eye movements (nystagmus) when exposed to seemingly benign acoustic stimuli. The most common cause is a defect in the bone enclosing the vestibular semicircular canals of the inner ear. Surgical repair often corrects the problem, but the precise mechanisms underlying Tullio phenomenon are not known. In the present work we quantified the phenomenon in an animal model of the condition by recording fluid motion in the semicircular canals and neural activity evoked by auditory-frequency stimulation. Results demonstrate short-latency phase-locked afferent neural responses, slowly developing sustained changes in neural discharge rate, and nonlinear fluid pumping in the affected semicircular canal. Experimental data compare favorably to predictions of a nonlinear computational model. Results identify the biophysical origin of Tullio phenomenon in pathological sound-evoked fluid-mechanical waves in the inner ear. Sound energy entering the inner ear at the oval window excites fluid motion at the location of the defect, giving rise to traveling waves that subsequently excite mechano electrical transduction in the vestibular sensory organs by vibration and nonlinear fluid pumping. PMID- 29980717 TI - Spatial-temporal characteristics and the epidemiology of haemorrhagic fever with renal syndrome from 2007 to 2016 in Zhejiang Province, China. AB - Zhejiang Province is one of the six provinces in China that has the highest incidence of haemorrhagic fever with renal syndrome (HFRS). Data on HFRS cases in Zhejiang Province from January 2007 to July 2017 were obtained from the China Information Network System of Disease Prevention and Control. Joinpoint regression analysis was used to observe the trend of the incidence rate of HFRS. The monthly incidence rate was predicted by autoregressive integrated moving average(ARIMA) models. Spatial autocorrelation analysis was performed to detect geographic clusters. A multivariate time series model was employed to analyze heterogeneous transmission of HFRS. There were a total of 4,836 HFRS cases, with 15 fatal cases reported in Zhejiang Province, China in the last decade. Results show that the mean absolute percentage error (MAPE) of the modelling performance and the forecasting performance of the ARIMA model were 27.53% and 16.29%, respectively. Male farmers and middle-aged patients account for the majority of the patient population. There were 54 high-high clusters and 1 high-low cluster identified at the county level. The random effect variance of the autoregressive component is 0.33; the spatio-temporal component is 1.30; and the endemic component is 2.45. According to the results, there was obvious spatial heterogeneity in the endemic component and spatio-temporal component but little spatial heterogeneity in the autoregressive component. A significant decreasing trend in the incidence rate was identified, and obvious clusters were discovered. Spatial heterogeneity in the factors driving HFRS transmission was discovered, which suggested that a targeted preventive effort should be considered in different districts based on their own main factors that contribute to the epidemics. PMID- 29980718 TI - Interaction between parasite-encoded JAB1/CSN5 and macrophage migration inhibitory factor proteins attenuates its proinflammatory function. AB - Multiple protozoans produce homologs of the cytokine MIF which play a role in immune evasion, invasion and pathogenesis. However, how parasite-encoded MIF activity is controlled remains poorly understood. Cytokine activity can be inhibited by intracellular binding partners that are released in the extracellular space during cell death. We investigated the presence of an endogenous parasite protein that was capable of interacting and interfering with MIF activity. A screen for protein-protein interaction was performed using immunoaffinity purification of amebic cell lysate with specific anti-Entamoeba histolytica MIF (EhMIF) antibody followed by mass spectrometry analysis, which revealed an E. histolytica-produced JAB1 protein (EhJAB1) as a potential binding partner. JAB1 was found to be highly conserved in protozoans. Direct interaction between the EhMIF and EhJAB1 was confirmed by several independent approaches with GST pull-down, co-immunoprecipitation, and Biolayer interferometry (BLI) assays. Furthermore, the C-terminal region outside the functional JAMM deneddylase motif was required for EhMIF binding, which was consistent with the top in silico predictions. In addition, EhJAB1 binding blocked EhMIF-induced IL-8 production by human epithelial cells. We report the initial characterization of a parasite encoded JAB1 and uncover a new binding partner for a protozoan-produced MIF protein, acting as a possible negative regulator of EhMIF. PMID- 29980719 TI - Intramuscular infiltration of a local anesthetic, lidocaine, does not result in adverse behavioural side effects in rainbow trout. AB - Fish are a useful animal model for research, but our improvement in some aspects of their welfare has not kept pace with their increased popularity for this use. For example, researchers rarely use analgesics. We evaluated the side effects of lidocaine, a local anesthetic widely used in human and veterinary medicine. We infiltrated lidocaine on each side of the dorsal fin (total 20 mg/kg) of young rainbow trout (15 fish per group) compared with infiltration with an equal volume of saline. We monitored behaviour of individual trout during the 4-hour trial. Food was presented 5 times during the trial (30 min, 1 h, 2 h, 3 h, 4 h after infiltration) and we analyzed behaviour for 1 minute before and after food presentation. Behaviour of Saline-Infiltrated trout compared with trout that received no infiltration showed that infiltration in and of itself had no statistically significant effects on trout behaviour. However, there were many statistically significant effects of Lidocaine-Infiltrated trout compared with Saline-Infiltrated trout; none of the side-effects were adverse. PMID- 29980720 TI - A genealogical assessment of familial clustering of anorectal malformations. AB - Familial recurrence of anorectal malformations (ARMs) has been reported in single institution case series and in two population-based studies. Here, we investigate the familial aggregation of ARMs using well-established, unbiased methods in a population genealogy of Utah. Study subjects included 255 ARM cases identified from among the two largest healthcare providers in Utah with linked genealogy data using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. The genealogical index of familiality (GIF) statistic, which compares the average pair-wise relatedness of cases to sets of matched controls, was used to test excess familial clustering. We also estimated relative risks (RRs) for ARM and associated phenotypes in relatives of cases adjusting for age-, sex-, and birthplace. Significant excess familial clustering was observed for all ARM subjects (GIF p < 1e-3). Significant RR estimates for ARM (RR = 15.6, p = 3.3e-6), and for almost all co-morbid birth defects previously associated with ARM, were observed among first-degree relatives of ARM case subjects. This genealogically-based population survey of familial aggregation of ARMs confirms the presence of a heritable component to ARMs and provides unbiased risk estimates to relatives of cases, which may have clinical utility. PMID- 29980721 TI - Transcription factor profiling identifies Sox9 as regulator of proliferation and differentiation in corneal epithelial stem/progenitor cells. AB - Understanding transcription factor (TF) regulation of limbal epithelial stem/progenitor cells (LEPCs) may aid in using non-ocular cells to regenerate the corneal surface. This study aimed to identify and characterize TF genes expressed specifically in LEPCs isolated from human donor eyes by laser capture microdissection. Using a profiling approach, preferential limbal expression was found for SoxE and SoxF genes, particularly for Sox9, which showed predominantly cytoplasmic localization in basal LEPCs and nuclear localization in suprabasal and corneal epithelial cells, indicating nucleocytoplasmic translocation and activation during LEPC proliferation and differentiation. Increased nuclear localization of Sox9 was also observed in activated LEPCs following clonal expansion and corneal epithelial wound healing. Knockdown of SOX9 expression in cultured LEPCs by RNAi led to reduced expression of progenitor cell markers, e.g. keratin 15, and increased expression of differentiation markers, e.g. keratin 3. Furthermore, SOX9 silencing significantly suppressed the proliferative capacity of LEPCs and reduced levels of glycogen synthase kinase 3 beta (GSK-3beta), a negative regulator of Wnt/beta-catenin signaling. Sox9 expression, in turn, was significantly suppressed by treatment of LEPCs with exogenous GSK-3beta inhibitors and enhanced by small molecule inhibitors of Wnt signaling. Our results suggest that Sox9 and Wnt/beta-catenin signaling cooperate in mutually repressive interactions to achieve a balance between quiescence, proliferation and differentiation of LEPCs in the limbal niche. Future molecular dissection of Sox9-Wnt interaction and mechanisms of nucleocytoplasmic shuttling of Sox9 may aid in improving the regenerative potential of LEPCs and the reprogramming of non ocular cells for corneal surface regeneration. PMID- 29980722 TI - Routine hemodialysis induces a decline in plasma magnesium concentration in most patients: a prospective observational cohort study. AB - In hemodialysis patients, lower plasma magnesium (Mg) concentrations are associated with a higher overall and cardiovascular mortality. The optimal concentration appears to be above the reference range for the healthy population. Plasma Mg is not routinely measured after hemodialysis. Aim of this study was to determine the effect of routine hemodialysis on plasma Mg. Plasma Mg was measured in duplicate before (Mgpre) and after (Mgpost) dialysis in 6 consecutive hemodialysis sessions of 34 patients using a fixed 0.50 mmol/L dialysate Mg concentration. Mean Mgpre was 0.88 mmol/L (+/-0.14) and mean Mgpost was statistically significantly lower: mean intra-dialytic decline 0.10 mmol/L (95% CI 0.06-0.13). A 0.10 mmol/L higher Mgpre was associated with a 0.03 mmol/L higher Mgpost (95%-CI 0.024-0.037). At a Mgpre of 0.74 mmol/L, Mgpost equalled Mgpre. There was an intra-dialytic decline of plasma Mg at higher Mgpre values and an increase at lower Mgpre values. In conclusion, in the majority of the hemodialysis patients, Mgpre concentrations are in the reference range of the healthy population, which may be too low for hemodialysis patients. Routine hemodialysis with the widely used 0.50 mmol/L dialysate Mg concentration, further declines magnesium in the majority of patients. Current dialysate Mg concentrations may be too low. PMID- 29980723 TI - Synchronisation of Arabidopsis flowering time and whole-plant senescence in seasonal environments. AB - Synchronisation of flowering phenology has often been observed between individuals within plant species. We expected that a critical role of flowering time control under natural conditions is a phenological synchronisation. However, no studies have quantified the level of synchronisation of reproductive timing relative to germination timing under natural conditions. In a sequential seeding experiment (SSE) in which we manipulated the germination timing of Arabidopsis thaliana accessions, we developed a quantification index to evaluate reproductive synchrony in annual plants. In the SSE, we identified a novel phenomenon of reproductive synchrony: senescence synchrony. The role of vernalisation in realising flowering synchrony between plants of different ages under natural conditions was demonstrated by synchronisation and de-synchronisation of flowering initiation in vernalisation-sensitive and less-vernalisation-sensitive accessions, respectively. We also observed up-regulation of senescence-related genes at corresponding times. The approach we developed in this study provides a set of concepts and procedures that can be used to study reproductive synchrony experimentally under natural conditions. PMID- 29980724 TI - Undilated versus dilated monoscopic smartphone-based fundus photography for optic nerve head evaluation. AB - Smartphone-based fundus photography (SBFP) allows for a cheap and mobile fundus examination with the potential to revolutionize eye care especially in low income settings. The purpose of this study was to assess the impact of pupil dilation on image quality in optic nerve head (ONH) imaging and vertical cup-to-disc ratio (vCDR) evaluation with SBFP. Eyes with glaucoma or suspected to have glaucoma were imaged with conventional digital fundus photography (CFP) and SBFP undilated and following dilation, all monoscopically. SBFP was possible in 74% of eyes without dilation and in 98% following dilation. Better image quality on SBFP was achieved with dilation and complete visualization of the optic disc rim was possible in 46% of images without dilation and on 94% of images with dilation. VCDR measurements on images obtained following dilation highly correlated with measurements on CFP (coefficient of correlation r = 0.91, p < 0.001), whereas vCDR on images obtained without dilation correlated less well with CFP (r = 0.70, p < 0.001). SBFP for ONH evaluation is promising, however dilation appears mandatory to achieve results comparable to optic disc evaluation on CFP. ONH imaging with smartphones without dilation might bear the risk of underestimating the CDR and hence overlooking patients at risk for glaucoma. PMID- 29980725 TI - Strategy of optical path of daylight signal into tissues in cold-season turfgrasses using small, concave silica bodies. AB - Plants incorporate inorganic materials (biominerals), such as silica, into their various components. Plants belonging to the order Poales, like rice plants and turfgrasses, show comparatively high rates of silicon accumulation, mainly in the form of silica bodies. This work aims to determine the shapes and roles of these silica bodies by microscopic observation and optical simulation. We have previously found convex silica bodies on the leaves of rice plants and hot-season turfgrasses (adapted to hot-seasons). These silica bodies enabled light reflection and ensured reduction of the photonic density of states, which presumably prevented the leaves from overheating, as suggested by theoretical optical analyses. The silica bodies have been considered to have the functions of reinforcement of the plant body. The present work deals with cold-season turfgrasses, which were found to have markedly different silica bodies, cuboids with a concave top surface. They presumably acted as small windows for introducing light into the tissues, including the vascular bundles in the leaves. The area of the silica bodies was calculated to be about 5% of the total surface area of epidermis, which limits the thermal radiation of the silica bodies. We found that the light signal introduced through the silica bodies diffused in the organs even reaching the vascular bundles, the physiological functions of this phenomena remain as future problems. Light signal in this case is not related with energy which heat the plant but sensing outer circumstances to respond to them. PMID- 29980726 TI - Nannochloropsis oceanica, a novel natural source of rumen-protected eicosapentaenoic acid (EPA) for ruminants. AB - We hypothesize that whole microalga biomass is a natural rumen-protected source of eicosapentaenoic acid (EPA, 20:5n-3) for ruminants. To test our hypothesis, we studied the ruminal biohydrogenation of EPA from two microalgae, Nannochloropsis oceanica and Phaeodactylum tricornutum using in vitro incubations with rumen fluid. A total mixed ration was incubated with: no EPA (control), EPA as free fatty acid, N. oceanica spray-dried (SD), N. oceanica freeze-dried (FD), or P. tricornutum FD. The kinetics of EPA disappearance and of products formed during the 24 hours of incubation were evaluated, and complemented by deuterated-EPA incubation. Results showed that EPA metabolism from the N. oceanica was remarkably reduced compared with the P. tricornutum and free-EPA, and this reduction was even more effective with the N. oceanica FD. Our data also indicates that neither feed dry matter disappearance nor rumen microbial markers (branched-chain fatty acids and dimethyl acetals) were affected by EPA-sources. We reported for the first time the kinetics of EPA biohydrogenation class products and the unequivocal formation of 20:0 from EPA. Overall, N. oceanica shows a strong potential to be used as a natural dietary source of EPA to ruminants, nevertheless further studies are needed to verify its protection in vivo. PMID- 29980727 TI - Lupus nephritis pathology prediction with clinical indices. AB - Effective treatment of lupus nephritis and assessment of patient prognosis depend on accurate pathological classification and careful use of acute and chronic pathological indices. Renal biopsy can provide most reliable predicting power. However, clinicians still need auxiliary tools under certain circumstances. Comprehensive statistical analysis of clinical indices may be an effective support and supplementation for biopsy. In this study, 173 patients with lupus nephritis were classified based on histology and scored on acute and chronic indices. These results were compared against machine learning predictions involving multilinear regression and random forest analysis. For three class random forest analysis, total classification accuracy was 51.3% (class II 53.7%, class III&IV 56.2%, class V 40.1%). For two class random forest analysis, class II accuracy reached 56.2%; class III&IV 63.7%; class V 61%. Additionally, machine learning selected out corresponding important variables for each class prediction. Multiple linear regression predicted the index of chronic pathology (CI) (Q2 = 0.746, R2 = 0.771) and the acute index (AI) (Q2 = 0.516, R2 = 0.576), and each variable's importance was calculated in AI and CI models. Evaluation of lupus nephritis by machine learning showed potential for assessment of lupus nephritis. PMID- 29980728 TI - Change in the magnetic configurations of tubular nanostructures by tuning dipolar interactions. AB - We have investigated the equilibrium states of ferromagnetic single wall nanotubes by means of atomistic Monte Carlo simulations of a zig-zag lattice of Heisenberg spins on the surface of a cylinder. The main focus of our study is to determine how the competition between short-range exchange (J) and long-range dipolar (D) interactions influences the low temperature magnetic order of the nanotubes as well as the thermal-driven transitions involved. Apart from the uniform and vortex states occurring for dominant J or D, we find that helical states become stable for a range of intermediate values of gamma = D/J that depends on the radius and length of the nanotube. Introducing a vorticity order parameter to better characterize helical and vortex states, we find the pseudo critical temperatures for the transitions between these states and we establish the magnetic phase diagrams of their stability regions as a function of the nanotube aspect ratio. Comparison of the energy of the states obtained by simulation with those of simpler theoretical structures that interpolate continuously between them, reveals a high degree of metastability of the helical structures that might be relevant for their reversal modes. PMID- 29980729 TI - TLR10 and NFKBIA contributed to the risk of hip osteoarthritis: systematic evaluation based on Han Chinese population. AB - Multiple lines of evidence have confirmed the importance of genetic factors for hip osteoarthritis (HOA). Our study aimed to investigate the associations of TLR10 and NFKBIA with respect to the HOA risk in Han Chinese individuals. A total of 1,043 HOA patients and 2,664 controls were recruited. Then, 23 tag single nucleotide polymorphisms (SNPs) in the TLR10 and NFKBIA genes were selected for genotyping. Genetic association analyses were conducted in both single-marker and haplotype-based ways. Gene by gene, two-way interactions were analysed using a case-only method. Multiple bioinformatics tools were utilised to examine the potential functional significance of the SNPs. Two significant SNPs, rs11096957 (OR = 1.26, P = 1.35 * 10-5) and rs2273650 (OR = 1.2, P = 1.57 * 10-3), were significantly associated with HOA risk. Rs11096957 was also associated with the severity of the HOA. Bioinformatics analysis indicated that the allele T of rs2273650 would create new miRNA/SNP target duplexes, which suggests that rs2273650 could alter the NFKBIA expression by affecting the miRNA/SNP target duplexes. Our study identified significant association signals from NFKBIA with HOA for the first time, and it also confirmed the contribution of TLR10 to the HOA risk. These findings would provide clues for identifying individuals at high risk of HOA. PMID- 29980730 TI - Improving catalytic activity of the Baeyer-Villiger monooxygenase-based Escherichia coli biocatalysts for the overproduction of (Z)-11 (heptanoyloxy)undec-9-enoic acid from ricinoleic acid. AB - Baeyer-Villiger monooxygenases (BVMOs) can be used for the biosynthesis of lactones and esters from ketones. However, the BVMO-based biocatalysts are not so stable under process conditions. Thereby, this study focused on enhancing stability of the BVMO-based biocatalysts. The biotransformation of ricinoleic acid into (Z)-11-(heptanoyloxy)undec-9-enoic acid by the recombinant Escherichia coli expressing the BVMO from Pseudomonas putida and an alcohol dehydrogenase from Micrococcus luteus was used as a model system. After thorough investigation of the key factors to influence stability of the BVMO, Cys302 was identified as an engineering target. The substitution of Cys302 to Leu enabled the engineered enzyme (i.e., E6BVMOC302L) to become more stable toward oxidative and thermal stresses. The catalytic activity of E6BVMOC302L-based E. coli biocatalysts was also greater than the E6BVMO-based biocatalysts. Another factor to influence biocatalytic performance of the BVMO-based whole-cell biocatalysts was availability of carbon and energy source during biotransformations. Glucose feeding into the reaction medium led to a marked increase of final product concentrations. Overall, the bioprocess engineering to improve metabolic stability of host cells in addition to the BVMO engineering allowed us to produce (Z)-11-(heptanoyloxy)undec-9-enoic acid to a concentration of 132 mM (41 g/L) from 150 mM ricinoleic acid within 8 h. PMID- 29980731 TI - Indole-3-acetic-acid-induced phenotypic plasticity in Desmodesmus algae. AB - Phenotypic plasticity is the ability of a single genotype of an organism to exhibit variable phenotypes in response to fluctuating environments. It plays a crucial role in their evolutionary success. In natural environments, the importance of interactions between microalgae and other microorganisms is generally well appreciated, but the effects of these interactions on algal phenotypic plasticity has not been investigated. In this study, it revealed that indole-3-acetic acid (IAA), the most common naturally occurring plant hormone, can exert stimulatory at low concentrations and inhibitory effects at high concentrations on the growth of the green alga Desmodesmus. The morphological characteristics of Desmodesmus changed drastically under exposure to IAA compared with the algae in the control environment. The proportion of Desmodesmus unicells in monocultures increased with the IAA concentration, and these unicells exhibited less possibility of sedimentation than large cells. Furthermore, we discovered that lipid droplets accumulated in algal cells grown at a high IAA concentration. Results also demonstrated that the presence of algal competitor further stimulated inducible morphological changes in Desmodesmus populations. The relative abundance of competitors influenced the proportion of induced morphological changes. The results indicate that phenotypic plasticity in microalgae can be a response to fluctuating environments, in which algae optimize the cost-benefit ratio. PMID- 29980732 TI - Author Correction: Effect of Plant Density, Boron Nutrition and Growth Regulation on Seed Mass, Emergence and Offspring Growth Plasticity in Cotton. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29980733 TI - Competing for enhancers: PVT1 fine-tunes MYC expression. PMID- 29980736 TI - Lab heads should learn to talk about racism. PMID- 29980735 TI - Cape Town's drought: don't blame climate change. PMID- 29980737 TI - COUNTERTRANSFERENCE DREAMING: LIFE IN THE INTERSUBJECTIVE THIRD. AB - In this paper the author asks, "How long is the life of an intersubjective field?" She proposes that it is possible for the field to remain active and instructive even after formal sessions have ended: This occurs in her case of Carla, a young woman who terminates prematurely. Carla enters treatment in a downward spiral of severe trauma symptoms that began subsequent to her rape, a decade earlier. Although Carla's symptoms diminish and the analysis continues to be productive, it suddenly ends in an impasse, leaving the analyst perplexed and feeling professionally insufficient. Months later, she has three dreams pertaining to Carla and her rape. Largely employing Jessica Benjamin's recognition theory and her representation of the intersubjective third, as well as contemporary Bionian thinking, the paper depicts how countertransference dreaming is one example of how the intersubjective field can carry on the psychoanalytic function-even outside of formal treatment. PMID- 29980740 TI - RFX7 keeps killers quiescent. PMID- 29980741 TI - The phase-separation mechanism of a binary mixture in a ring trimer. AB - We show that, depending on the ratio between the inter- and the intra-species interactions, a binary mixture trapped in a three-well potential with periodic boundary conditions exhibits three macroscopic ground-state configurations which differ in the degree of mixing. Accordingly, the corresponding quantum states feature either delocalization or a Schrodinger cat-like structure. The two-step phase separation occurring in the system, which is smoothed by the activation of tunnelling processes, is confirmed by the analysis of the energy spectrum that collapses and rearranges at the two critical points. In such points, we show that also Entanglement Entropy, a quantity borrowed from quantum-information theory, features singularities, thus demonstrating its ability to witness the double mixining-demixing phase transition. The developed analysis, which is of interest to both the experimental and theoretical communities, opens the door to the study of the demixing mechanism in complex lattice geometries. PMID- 29980739 TI - Transcriptional responses of soybean roots to colonization with the root endophytic fungus Piriformospora indica reveals altered phenylpropanoid and secondary metabolism. AB - Piriformospora indica, a root endophytic fungus, has been shown to enhance biomass production and confer tolerance to various abiotic and biotic stresses in many plant hosts. A growth chamber experiment of soybean (Glycine max) colonized by P. indica compared to uninoculated control plants showed that the fungus significantly increased shoot dry weight, nutrient content, and rhizobial biomass. RNA-Seq analyses of root tissue showed upregulation of 61 genes and downregulation of 238 genes in colonized plants. Gene Ontology (GO) enrichment analyses demonstrated that upregulated genes were most significantly enriched in GO categories related to lignin biosynthesis and regulation of iron transport and metabolism but also mapped to categories of nutrient acquisition, hormone signaling, and response to drought stress. Metabolic pathway analysis revealed upregulation of genes within the phenylpropanoid and derivative pathways such as biosynthesis of monolignol subunits, flavonoids and flavonols (luteolin and quercetin), and iron scavenging siderophores. Highly enriched downregulated GO categories included heat shock proteins involved in response to heat, high-light intensity, hydrogen peroxide, and several related to plant defense. Overall, these results suggest that soybean maintains an association with this root endosymbiotic fungus that improves plant growth and nutrient acquisition, modulates abiotic stress, and promotes synergistic interactions with rhizobia. PMID- 29980742 TI - Repurposing matrine for the treatment of hepatosteatosis and associated disorders in glucose homeostasis in mice. AB - The present study investigated the efficacy of the hepatoprotective drug matrine (Mtr) for its new application for hepatosteatosis and associated disorders in glucose homeostasis. The study was performed in two nutritional models of hepatosteatosis in mice with various abnormal glucose homeostasis: (1) high fructose diet (HFru) induced hepatosteatosis and glucose intolerance from hepatic, and (2) hepatosteatosis and hyperglycemia induced by high-fat (HF) diet in combination with low doses of streptozotocin (STZ). Administration of Mtr (100 mg/kg every day in diet for 4 weeks) abolished HFru-induced hepatosteatosis and glucose intolerance. These effects were associated with the inhibition of HFru stimulated de novo lipogenesis (DNL) without altering hepatic fatty acid oxidation. Further investigation revealed that HFru-induced endoplasmic reticulum (ER) stress was inhibited, whereas heat-shock protein 72 (an inducible chaperon protein) was increased by Mtr. In a type 2 diabetic model induced by HF-STZ, Mtr reduced hepatosteatosis and improved attenuated hyperglycemia. The hepatoprotective drug Mtr may be repurposed for the treatment of hepatosteatosis and associated disorders in glucose homeostasis. The inhibition of ER stress associated DNL and fatty acid influx appears to play an important role in these metabolic effects. PMID- 29980744 TI - Sodium thiosulfate halves the risk of cisplatin-induced hearing loss. PMID- 29980743 TI - Self-assembly of multi-stranded perylene dye J-aggregates in columnar liquid crystalline phases. AB - Many discoid dyes self-assemble into columnar liquid-crystalline (LC) phases with packing arrangements that are undesired for photonic applications due to H-type exciton coupling. Here, we report a series of crystalline and LC perylene bisimides (PBIs) self-assembling into single or multi-stranded (two, three, and four strands) aggregates with predominant J-type exciton coupling. These differences in the supramolecular packing and optical properties are achieved by molecular design variations of tetra-bay phenoxy-dendronized PBIs with two N-H groups at the imide positions. The self-assembly is driven by hydrogen bonding, slipped pi-pi stacking, nanosegregation, and steric requirements of the peripheral building blocks. We could determine the impact of the packing motifs on the spectroscopic properties and demonstrate different J- and H-type coupling contributions between the chromophores. Our findings on structure-property relationships and strong J-couplings in bulk LC materials open a new avenue in the molecular engineering of PBI J-aggregates with prospective applications in photonics. PMID- 29980745 TI - Identification of a novel bacteriocin-like protein and structural gene from Rhodococcus erythropolis JCM 2895, using suppression-subtractive hybridization. AB - A novel bacteriocin-like protein and its structural gene (rap) were identified from Rhodococcus erythropolis JCM 2895. The rapA and B genes are located on a 5.4 kb circular plasmid, and were obtained using a modified suppression-subtractive hybridization method. The rapA and B genes were heterologously expressed in Rhodococcus sp. or Escherichia coli, and then characterized. The results indicated that RapA is a small, water-soluble, heat-stable antimicrobial protein, and that RapB is an immunity protein against RapA, estimated to be located on the cell membrane. RapA showed antimicrobial activity particularly against R. erythropolis, and the activity persisted even after SDS-PAGE analysis. For the heterologous expressed RapA protein, N-terminal amino acid sequence was also confirmed. This is the first report of a bacteriocin-like substance obtained from the genus Rhodococcus. PMID- 29980746 TI - Dolyemycins A and B, two novel cyclopeptides isolated from Streptomyces griseus subsp. griseus HYS31. AB - Two novel cyclopeptides with special skeleton, namely, dolyemycins A (1) and B (2) were isolated from Streptomyces griseus subsp. griseus HYS31 by bio-guided isolation. Their structures were elucidated by detailed analysis of spectroscopic data. These two compounds were cyclopeptides containing eleven amino acids including five unusual amino acids (hydroxyglycine, 3-hydroxyleucine, 3 phenylserine, beta-hydroxy-O-methyltyrosine, 2,3-diaminobutyric acid) in both of them and an extra nonprotein amino acids (3-methylaspartic acid) in Dolyemycin B only. Dolyemycins A and B performed antiproliferative activity against human lung cancer A549 cells with IC50 values of 1.0 and 1.2 uM, respectively. PMID- 29980747 TI - Correction: Patient experience and utility of genetic information: a cross sectional study among patients tested for cancer susceptibility and thrombophilia. AB - This article was originally published under an incorrect license. This has now been amended and is available under a CC BY-NC-ND 4.0 license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 29980748 TI - The serrulatane diterpenoid natural products RAD288 and RAD289 stimulate properties of olfactory ensheathing cells useful for neural repair therapies. AB - Olfactory ensheathing cells (OECs) are being trialled for cell transplantation therapies for neural repair as they have unique properties which can enhance neuron regeneration. However, improvements in cell viability, proliferation and migration are needed to enhance therapeutic outcomes. Growth factors can enhance cell activity, but they can also induce side effects as they can act on numerous cell types. An alternative approach is to identify natural products (NPs) that more selectively activate specific cell functions. We have examined two pure NPs, 3-acetoxy-7,8-dihydroxyserrulat-14-en-19-oic acid (RAD288) and 3,7,8 trihydroxyserrulat-14-en-19-oic acid (RAD289) isolated from the Australian plant Eremophila microtheca. We determined that RAD288 and RAD289 stimulated the viability and proliferation of OECs in two-dimensional cultures and increased cell viability in three-dimensional spheroids. Both compounds also enhanced OEC mediated phagocytosis of neural debris. However, only RAD288 stimulated migration of OECs, demonstrating that key structural changes to the compound can dramatically affect the resultant cellular action. In addition, cell-type specific action is highlighted by the result that neither compound stimulated the viability of Schwann cells which are a closely-related glial cell type. Therefore, these small molecules may have high potential for selective activation of specific therapeutically-useful activities of OECs for transplantation therapies to repair the nervous system. PMID- 29980749 TI - Electrical Detection of Charge-to-spin and Spin-to-Charge Conversion in a Topological Insulator Bi2Te3 Using BN/Al2O3 Hybrid Tunnel Barrier. AB - One of the most striking properties of three-dimensional topological insulators (TIs) is spin-momentum locking, where the spin is locked at right angles to momentum and hence an unpolarized charge current creates a net spin polarization. Alternatively, if a net spin is injected into the TI surface state system, it is distinctively associated with a unique carrier momentum and hence should generate a charge accumulation, as in the so-called inverse Edelstein effect. Here using a Fe/Al2O3/BN tunnel barrier, we demonstrate both effects in a single device in Bi2Te3: the electrical detection of the spin accumulation generated by an unpolarized current flowing through the surface states, and that of the charge accumulation generated by spins injected into the surface state system. This work is the first to utilize BN as part of a hybrid tunnel barrier on TI, where we observed a high spin polarization of 93% for the TI surfaces states. The reverse spin-to-charge measurement is an independent confirmation that spin and momentum are locked in the surface states of TI, and offers additional avenues for spin manipulation. It further demonstrates the robustness and versatility of electrical access to the spin system within TI surface states, an important step towards its utilization in TI-based spintronics devices. PMID- 29980751 TI - A compact diffractive sorter for high-resolution demultiplexing of orbital angular momentum beams. AB - The design and fabrication of a compact diffractive optical element is presented for the sorting of beams carrying orbital angular momentum (OAM) of light. The sorter combines a conformal mapping transformation with an optical fan-out, performing demultiplexing with unprecedented levels of miniaturization and OAM resolution. Moreover, an innovative configuration is proposed which simplifies alignment procedures and further improves the compactness of the optical device. Samples have been fabricated in the form of phase-only diffractive optics with high-resolution electron-beam lithography (EBL) over a glass substrate. A soft lithography process has been optimized for fast and cheap replica production of the EBL masters. Optical tests with OAM beams confirm the designed performance, showing excellent efficiency and low cross-talk, with high fidelity even with multiplexed input beams. This work paves the way for practical OAM multiplexing and demultiplexing devices for use in classical and quantum communication. PMID- 29980750 TI - Cognition based bTBI mechanistic criteria; a tool for preventive and therapeutic innovations. AB - Blast-induced traumatic brain injury has been associated with neurodegenerative and neuropsychiatric disorders. To date, although damage due to oxidative stress appears to be important, the specific mechanistic causes of such disorders remain elusive. Here, to determine the mechanical variables governing the tissue damage eventually cascading into cognitive deficits, we performed a study on the mechanics of rat brain under blast conditions. To this end, experiments were carried out to analyse and correlate post-injury oxidative stress distribution with cognitive deficits on a live rat exposed to blast. A computational model of the rat head was developed from imaging data and validated against in vivo brain displacement measurements. The blast event was reconstructed in silico to provide mechanistic thresholds that best correlate with cognitive damage at the regional neuronal tissue level, irrespectively of the shape or size of the brain tissue types. This approach was leveraged on a human head model where the prediction of cognitive deficits was shown to correlate with literature findings. The mechanistic insights from this work were finally used to propose a novel protective device design roadmap and potential avenues for therapeutic innovations against blast traumatic brain injury. PMID- 29980752 TI - Gestational exposure to chlordecone promotes transgenerational changes in the murine reproductive system of males. AB - Environmental factors can affect epigenetic events during germline reprogramming and impose distinctive transgenerational consequences onto the offspring. In this study, we examined the transgenerational effects of chlordecone (CD), an organochlorine insecticide with well-known estrogenic properties. We exposed pregnant mice to CD from embryonic day 6.5 to 15.5 and observed a reduction in spermatogonia (SG) numbers in F3, meiotic defects in spermatocytes and decrease in spermatozoa number in the first and third generation of male progeny. The RNA qRT-PCR expression analysis in F1 and transcriptomics analysis in F3 males using the whole testes revealed changes in the expression of genes associated with chromosome segregation, cell division and DNA repair. The expression of the master regulator of pluripotency, Pou5f1, decreased in foetal and increased in adult F1, but not in F3 adult testes. Analysis of histone H3K4me3 distribution revealed widespread changes in its occupancy in the genome of F1 and F3 generations. We established that 7.1% of altered epigenetic marks were conserved between F1 and F3 generations. The overlapping changes common to F1 and F3 include genes implicated in cell adhesion and transcription factor activities functions. Differential peaks observed in F1 males are significantly enriched in predicted ESR1 binding sites, some of which we confirmed to be functional. Our data demonstrate that CD-mediated impairment of reproductive functions could be transmitted to subsequent generations. PMID- 29980753 TI - Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy. AB - Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors. PMID- 29980754 TI - Attention deficit-hyperactivity disorder is associated with allergic symptoms and low levels of hemoglobin and serotonin. AB - This study investigated whether common comorbidities or biochemical factors, such as allergic disease, anemia, inflammation, and neurotransmitters, are singly or additively associated with an increased risk of attention deficit-hyperactivity disorder (ADHD). We recruited 216 children diagnosed with ADHD and 216 age-, sex , height-, weight-, and class-matched controls from 31 elementary schools in Taipei, Taiwan. The International Study of Asthma and Allergies in Childhood questionnaire was used to measure allergic symptoms. Fasting venous blood was collected and analyzed for complete blood count, white blood cell differential count, immunoglobulin (Ig) E level, and serotonin (5-HT) level. The results showed that symptoms of both rhinitis (OR = 2.08, 95% CI = 1.42-3.05) and eczema (OR = 1.72, 95% CI = 1.02-2.88) were significantly associated with increased risk of ADHD. Children with ADHD showed considerably lower levels of hemoglobin (p = 0.001) and 5-HT (p < 0.001) and higher IgE level (p < 0.001) and eosinophil count (p = 0.001) than did control children. ADHD risk increased with the number of aforementioned biochemical risk factors present (one factor: OR = 1.87, 95% CI = 0.87-4.18; two factors: OR = 2.90, 95% CI = 1.29-6.48; three factors: OR = 4.47, 95% CI = 1.97-10.13; four factors: OR = 6.53, 95% CI = 2.43-17.57). Findings suggest that either ADHD's etiology is multidimensional or the aforementioned conditions have shared etiology with ADHD. PMID- 29980755 TI - Common marmoset (Callithrix jacchus) personality, subjective well-being, hair cortisol level and AVPR1a, OPRM1, and DAT genotypes. AB - We studied personality, subjective well-being, and hair cortisol level, in common marmosets Callithrix jacchus, a small, cooperatively breeding New World monkey, by examining their associations with one another and genotypes. Subjects were 68 males and 9 females that lived in the RIKEN Center for Life Science Technologies. Personality and subjective well-being were assessed by keeper ratings on two questionnaires, hair samples were obtained to assay cortisol level and buccal swabs were used to assess AVPR1a, OPRM1 and DAT genotypes. Three personality domains-Dominance, Sociability, and Neuroticism-were identified. Consistent with findings in other species, Sociability and Neuroticism were related to higher and lower subjective well-being, respectively. Sociability was also associated with higher hair cortisol levels. The personality domains and hair cortisol levels were heritable and associated with genotypes: the short form of AVPR1a was associated with lower Neuroticism and the AA genotype of the A111T SNP of OPRM1 was related to lower Dominance, lower Neuroticism, and higher hair cortisol level. Some genetic associations were not in directions that one would expect given findings in other species. These findings provide insights into the proximate and ultimate bases of personality in common marmosets, other primates and humans. PMID- 29980756 TI - Climate-driven shifts in algal-bacterial interaction of high-mountain lakes in two years spanning a decade. AB - Algal-bacterial interactions include mutualism, commensalism, and predation. However, how multiple environmental conditions that regulate the strength and prevalence of a given interaction remains unclear. Here, we test the hypothesis that the prevailing algal-bacterial interaction shifted in two years (2005 versus 2015), due to increased temperature (T) and Saharan dust depositions in high mountain lakes of Sierra Nevada (S Spain). Our results support the starting hypothesis that the nature of the prevailing algal-bacterial interaction shifted from a bacterivory control exerted by algae to commensalism, coinciding with a higher air and water T as well as the lower ratio sestonic nitrogen (N): phosphorous (P), related to greater aerosol inputs. Projected global change conditions in Mediterranean region could decline the functional diversity and alter the role of mixotrophy as a carbon (C) by-pass in the microbial food web, reducing the biomass-transfer efficiency up the web by increasing the number of trophic links. PMID- 29980757 TI - Multiple liver insults synergize to accelerate experimental hepatocellular carcinoma. AB - The urgent unmet need for hepatocellular carcinoma (HCC) therapies is addressed here by characterising a novel mouse model of HCC in the context of ongoing liver damage and overnutrition. Male C57Bl/6J mice were treated with diethylnitrosamine (DEN) and thioacetamide (TAA), and some were provided with an atherogenic high fat diet (HFD). Inflammation, steatosis, fibrosis, 87 genes, liver lesions and intratumoural leukocyte subsets were quantified up to 24 weeks of age. Adding HFD to DEN/TAA increased fibrosis, steatosis and inflammation, and the incidence of both HCC and non-HCC dysplastic lesions. All lesions contained alpha-SMA positive fibroblasts. Macrophage marker F4/80 was not significantly different between treatment groups, but the macrophage-associated genes Arg-1 and Cd47 were differentially expressed. Fibrosis, cancer and cell death associated genes were upregulated in DEN/TAA/HFD livers. Fewer Kupffer cells and plasmacytoid dendritic cells were in tumours compared to control liver. In conclusion, combining a hepatotoxin with an atherogenic diet produced more intrahepatic tumours, dysplastic lesions and fibrosis compared to hepatotoxin alone. This new HCC model provides a relatively rapid means of examining primary HCC and potential therapies in the context of multiple hepatotoxins including those derived from overnutrition. PMID- 29980758 TI - Anti-survivin effect of the small molecule inhibitor YM155 in RCC cells is mediated by time-dependent inhibition of the NF-kappaB pathway. AB - Constitutive activation of the NF-kappaB signaling cascade is associated with tumourigenesis and poor prognosis in many human cancers including RCC. YM155, a small molecule inhibitor of survivin, was previously shown to potently inhibit the viability of immortalized and patient derived renal cell carcinoma (RCC) cell lines. Here we investigated the role of NF-kappaB signaling to the anti-cancer properties of YM155 in RCC786.0 cells. YM155 diminished nuclear levels of p65 and phosphorylated p65 and attenuated the transcriptional competencies of the p65/p50 heterodimers. Accordingly, we found that YM155 diminished the transcription of NF kappaB target gene survivin. Events that led to the interception of the nuclear translocation of p65/p50 were the activation of the deubiquinating enzyme CYLD by YM155, which led to the inhibition of IKKbeta, stabilization of IkappaBalpha and retention of NF-kappaB heterodimers in the cytosol. Importantly, the suppressive effects of YM155 were time-dependent and observed at the 24 h time point, and not earlier. TNF-alpha, a stimulator of NF-kappaB signaling did not affect its inhibitory properties. The ability of YM155 to intercept a major transcriptional pathway like NF-kappaB, would have important ramifications on the pharmacodynamics effects elicited by this unusual molecule. PMID- 29980759 TI - Understanding the indirect DNA read-out specificity of I-CreI Meganuclease. AB - The high DNA specificity of homing endonucleases makes them a powerful protein scaffold to engineer enzymes for genome manipulation. Understanding their molecular recognition of DNA is an important prerequisite to generate engineered enzymes able to cleave DNA in specific desired genome sites. Protein-DNA recognition studies have been mostly focused on specific direct contacts between amino acid side chains and bases to redesign the binding interface. However, the important role of indirect readout in the central region of the target DNA of the homing endonuclease I-CreI suggested that indirect readout may play a key role in the redesign of protein-DNA interactions. The sequences of the I-CreI central substrate region, 2NN, along with the adjacent 5NNN, are key for substrate cleavage. Here, we analyse the mechanism of target discrimination at the 5NNN region by the I-CreI protein, revealing its critical role in the location and occupancy of the catalytic metal ions, which is crucial for cleavage. Our data highlight the importance of indirect readout for target DNA cleavage, thus aiding I-CreI engineering when targeting new DNA sequences. PMID- 29980760 TI - Trends in overweight, obesity, and waist-to-height ratio among Australian children from linguistically diverse backgrounds, 1997 to 2015. AB - OBJECTIVE: To report the cross-sectional prevalence and 18-year trends in overweight, obesity and abdominal obesity among Australian children from culturally and linguistically diverse (CALD) backgrounds. SUBJECTS/METHODS: Four cross-sectional population health surveys conducted among children (age 4-16 years; n=26, 449) in 1997-2004-2010-2015 in New South Wales, (NSW) Australia. Adiposity outcomes were measured by trained field staff using standard procedures. Binomial regression models with a robust error variance were used to estimate prevalence ratio (PR) and 95% confidence intervals (CI) for overweight and obesity, obesity, and waist-to-height ratio (WHtR) >= 0.5 for children from Asian, European, and Middle Eastern language backgrounds compared with children from English-speaking backgrounds, adjusted for sociodemographic characteristics. RESULTS: Over time, children from Middle Eastern language backgrounds were consistently more likely to be overweight-obese (PR: 1.29-1.42), obese (PR: 1.49 1.65), and have WHtR >= 0.5 (PR: 1.42-1.90), compared with children from English speaking backgrounds. Children from European language backgrounds generally had higher prevalence and children from Asian language backgrounds had lower prevalence, compared with children from English-speaking backgrounds. Between 1997 and 2015, there were significant trends in the prevalence of overweight and obesity combined among children from English-speaking (PR: 1.06, 95%CI: 1.02, 1.09), Middle Eastern (PR: 1.14, 95%CI: 1.05, 1.24), and Asian language backgrounds (PR: 1.14, 95%CI: 1.05, 1.24). The prevalence of WHtr >= 0.5 increased among children from English-speaking (PR: 1.21, 95%CI: 1.13, 1.31) and Middle Eastern (PR: 1.35, 95%CI: 1.16, 1.56) language backgrounds. CONCLUSIONS: Overall, the prevalence of overweight and obesity and abdominal obesity is high among NSW children from CALD backgrounds and has increased over time. This suggests that there is a greater scope in understanding, developing, and implementing interventions across the early life-course of children from CALD backgrounds. PMID- 29980762 TI - Overfed but undernourished: recognizing nutritional inadequacies/deficiencies in patients with overweight or obesity. AB - Overweight and obesity are highly prevalent throughout the world and can adversely affect the nutritional status of individuals. Studies have shown that many people with obesity have inadequate intake of iron, calcium, magnesium, zinc, copper, folate and vitamins A and B12, likely as a result of poor diet quality. Nutritional inadequacies or deficiencies may also occur due to altered pharmacokinetics in the individual with obesity and due to interactions in those with overweight or obesity with various pharmaceuticals. However, it has been demonstrated that the adult population in the United States as a whole is deficient in certain micronutrients as a result of the availability and overconsumption of high-calorie, low-nutrient processed foods. Poor nutrition may contribute to the development of certain chronic conditions, such as type 2 diabetes, which is already more prevalent in those with obesity. Clinicians need to be aware of these gaps, particularly in those individuals with obesity who are undergoing bariatric surgery or taking pharmaceutical products long term to facilitate weight loss. Patients with overweight or obesity likely struggle to achieve a balanced diet and may benefit from consultation with a dietitian. Along with providing recommendations for healthy eating and exercise, supplementation with specific micronutrients or multivitamins should be considered for individuals at the highest risk for or with established deficiencies. Further research is needed to understand the factors underlying nutritional inadequacies in individuals with overweight or obesity, as well as the outcomes of treatment strategies employed to address them. PMID- 29980761 TI - GWAS for BMI: a treasure trove of fundamental insights into the genetic basis of obesity. AB - Muller et al. [1] have provided a strong critique of the Genome-Wide Association Studies (GWAS) of body-mass index (BMI), arguing that the GWAS approach for the study of BMI is flawed, and has provided us with few biological insights. They suggest that what is needed instead is a new start, involving GWAS for more complex energy balance related traits. In this invited counter-point, we highlight the substantial advances that have occurred in the obesity field, directly stimulated by the GWAS of BMI. We agree that GWAS for BMI is not perfect, but consider that the best route forward for additional discoveries will likely be to expand the search for common and rare variants linked to BMI and other easily obtained measures of obesity, rather than attempting to perform new, much smaller GWAS for energy balance traits that are complex and expensive to measure. For GWAS in general, we emphasise that the power from increasing the sample size of a crude but easily measured phenotype outweighs the benefits of better phenotyping. PMID- 29980763 TI - Spatial navigation deficits - overlooked cognitive marker for preclinical Alzheimer disease? AB - Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities. PMID- 29980764 TI - Geometric compensation applied to image analysis of cell populations with morphological variability: a new role for a classical concept. AB - Immunofluorescence is the gold standard technique to determine the level and spatial distribution of fluorescent-tagged molecules. However, quantitative analysis of fluorescence microscopy images faces crucial challenges such as morphologic variability within cells. In this work, we developed an analytical strategy to deal with cell shape and size variability that is based on an elastic geometric alignment algorithm. Firstly, synthetic images mimicking cell populations with morphological variability were used to test and optimize the algorithm, under controlled conditions. We have computed expression profiles specifically assessing cell-cell interactions (IN profiles) and profiles focusing on the distribution of a marker throughout the intracellular space of single cells (RD profiles). To experimentally validate our analytical pipeline, we have used real images of cell cultures stained for E-cadherin, tubulin and a mitochondria dye, selected as prototypes of membrane, cytoplasmic and organelle specific markers. The results demonstrated that our algorithm is able to generate a detailed quantitative report and a faithful representation of a large panel of molecules, distributed in distinct cellular compartments, independently of cell's morphological features. This is a simple end-user method that can be widely explored in research and diagnostic labs to unravel protein regulation mechanisms or identify protein expression patterns associated with disease. PMID- 29980765 TI - Layer-by-layer hybrid chemical doping for high transmittance uniformity in graphene-polymer flexible transparent conductive nanocomposite. AB - A traditional transparent conducting film (TCF) such as indium tin oxide (ITO) exhibits poor mechanical flexibility and inconsistent transmittance throughout the UV-VIS-NIR spectrum. Recent TCFs like graphene films exhibit high sheet resistance (Rs) due to defect induced carrier scattering. Here we show a unique hybrid chemical doping method that results in high transmittance uniformity in a layered graphene-polymer nanocomposite with suppressed defect-induced carrier scattering. This layer-by-layer hybrid chemical doping results in low Rs (15 Omega/sq at >90% transmittance) and 3.6% transmittance uniformity (300-1000 nm) compared with graphene (17%), polymer (8%) and ITO (46%) films. The weak localization effect in our nanocomposite was reduced to 0.5%, compared with pristine (4.25%) and doped graphene films (1.2%). Furthermore, negligible Rs change (1.2 times compared to 12.6 * 103 times in ITO) and nearly unaltered transmittance spectra were observed up to 24 GPa of applied stress highlighting mechanical flexibility of the nanocomposite film. PMID- 29980766 TI - An integrative approach to develop computational pipeline for drug-target interaction network analysis. AB - Understanding the general principles governing the functioning of biological networks is a major challenge of the current era. Functionality of biological networks can be observed from drug and target interaction perspective. All possible modes of operations of biological networks are confined by the interaction analysis. Several of the existing approaches in this direction, however, are data-driven and thus lack potential to be generalized and extrapolated to different species. In this paper, we demonstrate a systems pharmacology pipeline and discuss how the network theory, along with gene ontology (GO) analysis, co-expression analysis, module re-construction, pathway mapping and structure level analysis can be used to decipher important properties of biological networks with the aim to propose lead molecule for the therapeutic interventions of various diseases. PMID- 29980767 TI - Modified scanning electron microscopy reveals pathological crosstalk between endothelial cells and podocytes in a murine model of membranoproliferative glomerulonephritis. AB - This study evaluated endothelial cells and podocytes, both being primary components of the glomerular filtration barrier, in the progression of membranoproliferative glomerulonephritis (MPGN) using modified scanning electron microscopy (mSEM) analysis. BXSB/MpJ-Yaa model mice exhibited autoimmune-mediated MPGN characterised by elevated serum autoantibody levels, albuminuria, renal dysfunctional parameters, and decreased glomerular endothelial fenestrations (EF) and podocyte foot process (PFP) effacement with immune cell infiltration. Similar to transmission electron microscopy, mSEM revealed a series of pathological changes in basement membrane and densities of EF and PFP in BXSB/MpJ-Yaa compared with control BXSB/MpJ at different stages. Further, immunopositive area of endothelial marker (CD34), podocyte functional molecules (Nephrin, Podocin, Synaptopodin, and Wilms' tumour 1 (WT1)), and vascular endothelial growth factor A (VEGF A) significantly decreased in the glomerulus of BXSB/MpJ-Yaa compared with BXSB at final stage. The indices of glomerular endothelial injuries (EF density and immunopositive area of CD34 and VEGF A) and podocyte injuries (PEP density and immunopositive area of podocyte functional molecules) were also significantly correlated with each other and with indices of autoimmune disease and renal dysfunction. Thus, our results elucidated the pathological crosstalk between endothelial cells and podocytes in MPGN progression and the usefulness of mSEM for glomerular pathological analysis. PMID- 29980768 TI - Fundoscopy screening for intraocular candida in patients with positive blood cultures-is it justified? AB - INTRODUCTION: Although the worldwide prevalence of disseminated candidaemia is rising, reported intraocular candidiasis rates are variable, even as low as 1%. The Infectious Diseases Society of America recommends fundoscopy screening for all fungal blood culture positive patients. We wished to evaluate the impact of this recommendation on our department. METHODS: A retrospective observational study was performed in NHS Greater Glasgow and Clyde (population = 1.15 million) for all patients with candida positive blood culture results over a 2-year period. RESULTS: From January 2015 to December 2016, 258 candida positive cultures were obtained from 168 adults (mean age = 62 years, range: 17-94 years; 85 females, 83 males). Candida species were isolated in 161/168 (95.8%) cases (43.5% Candida albicans, 35.7% Candida glabrata). All 168 cases were treated with intravenous antifungals. 84 patients (50%) were formally referred to ophthalmology. Of those not referred, 21 were deceased prior to culture result (12.5%) and 14 patients subsequently deteriorated (8.3%). Six patients reported visual symptoms. In total, 65% had no ocular findings and 32.5% had unrelated ocular signs. Only one patient had signs consistent with Candida chorioretinitis, making the prevalence of intraocular candida in our population 1.3% (1/80). CONCLUSIONS: The prevalence of ocular candidiasis is low, presumably due to potent systemic antifungal agents and good intraocular penetration. Our findings support the view that routine fundoscopy screening may not be indicated in every culture positive patient. This paper provides an evidence base for the Royal College's Eyecare in intensive care unit recommendations regarding targeted screening of non-verbal, symptomatic or high-risk patients. PMID- 29980769 TI - Publisher Correction: A naturally occurring antiviral ribonucleotide encoded by the human genome. AB - Change history: In the HTML version of this Letter, Extended Data Fig. 4 incorrectly corresponded to Fig. 4 (the PDF version of the figure was correct). This has been corrected online. PMID- 29980770 TI - Short-term Dynamics after Single- and Three-piece Acrylic Intraocular Lens Implantation: A Swept-source Anterior Segment Optical Coherence Tomography Study. AB - Accurate alignment of an intraocular lens (IOL) is indispensable for achieving accurate postoperative refractive outcomes. Thus, we evaluated decentration and tilt of single- and three-piece IOLs, as well as anterior chamber depth (ACD), at 3 hours, 24 hours, 2 weeks, and 4 weeks after cataract surgery, using swept source anterior segment optical coherence tomography. There was no significant difference in postoperative visual acuity between eyes with single- or three piece IOLs. Absolute values of IOL decentration at 24 hours and 2 weeks after surgery were significantly larger (P = 0.008 and 0.046, respectively) in eyes with the single-piece IOL than in those with the three-piece IOL. Both single- and three-piece IOLs tended to tilt toward the inferotemporal direction; however, there was no significant difference in the absolute values of IOL tilt at any postoperative time point. ACD at 24 hours after surgery was significantly deeper (P = 0.009) in eyes with the three-piece IOL, compared with eyes with the single piece IOL. Therefore, although both single- and three-piece IOL locations varied transiently after surgery, IOL locations were similar between both IOLs at 4 weeks after surgery and were not associated with any statistical difference in visual function. PMID- 29980771 TI - Role of inter-hemispheric connections in functional brain networks. AB - Today the human brain can be modeled as a graph where nodes represent different regions and links stand for statistical interactions between their activities as recorded by different neuroimaging techniques. Empirical studies have lead to the hypothesis that brain functions rely on the coordination of a scattered mosaic of functionally specialized brain regions (modules or sub-networks), forming a web like structure of coordinated assemblies (a network of networks. NoN). The study of brain dynamics would therefore benefit from an inspection of how functional sub-networks interact between them. In this paper, we model the brain as an interconnected system composed of two specific sub-networks, the left (L) and right (R) hemispheres, which compete with each other for centrality, a topological measure of importance in a networked system. Specifically, we considered functional scalp EEG networks (SEN) derived from high-density electroencephalographic (EEG) recordings and investigated how node centrality is shaped by interhemispheric connections. Our results show that the distribution of centrality strongly depends on the number of functional connections between hemispheres and the way these connections are distributed. Additionally, we investigated the consequences of node failure on hemispherical centrality, and showed how the abundance of inter-hemispheric links favors the functional balance of centrality distribution between the hemispheres. PMID- 29980773 TI - Plastic not so fantastic. PMID- 29980772 TI - Renal denervation: one step backwards, three steps forward. PMID- 29980774 TI - Setting up boundaries. PMID- 29980775 TI - Longer wires conduct better. PMID- 29980776 TI - Low-dimensional perovskites. PMID- 29980777 TI - Listening. PMID- 29980778 TI - Strong bundles based on carbon nanotubes. PMID- 29980779 TI - From an idea to a technology. PMID- 29980780 TI - Factors that make an impact. PMID- 29980782 TI - AAA: to screen or not to screen? PMID- 29980781 TI - Advanced tools for the safety assessment of nanomaterials. AB - Engineered nanomaterials (ENMs) have tremendous potential to produce beneficial technological impact in numerous sectors in society. Safety assessment is, of course, of paramount importance. However, the myriad variations of ENM properties makes the identification of specific features driving toxicity challenging. At the same time, reducing animal tests by introducing alternative and/or predictive in vitro and in silico methods has become a priority. It is important to embrace these new advances in the safety assessment of ENMs. Indeed, remarkable progress has been made in recent years with respect to mechanism-based hazard assessment of ENMs, including systems biology approaches as well as high-throughput screening platforms, and new tools are also emerging in risk assessment and risk management for humans and the environment across the whole life-cycle of nano enabled products. Here, we highlight some of the key advances in the hazard and risk assessment of ENMs. PMID- 29980783 TI - MRI at term equivalent in preterm infants: the wise choice. PMID- 29980784 TI - Moth oviposition shapes the species-specific transcriptional and phytohormonal response of Nicotiana attenuata to larval feeding. AB - Oviposition by lepidopteran herbivores on Nicotiana attenuata primes plant defence responses that are induced by the feeding larvae. While oviposition by both the generalist Spodoptera exigua and the specialist Manduca sexta primes the production of defensive phenylpropanoids, their larvae are differentially affected. We investigate here the impact of prior oviposition on the transcriptome and phytohormone levels of plants that were later attacked by larvae to find regulatory signals of this priming. In a full-factorial design, we evaluated the effects of oviposition and herbivory by both species. Oviposition alone had only subtle effects at the transcriptional level. Laval feeding alone induced species-specific plant responses. Larvae of the generalist regulated phytohormones and gene expression stronger than larvae of the specialist. A day after larvae started to feed, we detected no significant alterations of the plant's response to larval feeding due to prior oviposition by conspecific moths. Yet, oviposition by each of the species profoundly influenced the plant's transcriptional and phytohormonal response to feeding larvae of the other species. Remarkably, the species-specific plant responses to larval feeding shifted towards the response normally elicited by larvae of the ovipositing species. Thus, plants may already recognise an insect's identity upon its oviposition. PMID- 29980785 TI - Seasonal changes in the diversity and composition of the litter fauna in native forests and rubber plantations. AB - The litter layer of tropical forests supports a significant fraction of total arthropod diversity and decomposition of this layer is the main pathway by which nutrients are returned to the soil and CO2 to the atmosphere. Conversion of tropical forests to agriculture is the main threat to biodiversity and ecosystem services, and understanding effects on the litter layer is important for understanding and mitigating these impacts. We used high through-put DNA sequencing of the mitochondrial cytochrome c oxidase subunit I (COI) gene to assess seasonal changes in the diversity and composition of the litter fauna at five matched pairs of native forests and rubber plantations in tropical SW China every month for a year, and measured the environmental factors expected to drive intra-annual variation. Forests and rubber had very different arthropod assemblages throughout the year, with forests more species-rich than rubber in all months except February. Very high rates of intra-annual turnover in species composition in both forests and rubber were associated with seasonality in environmental variables, with the influence of particular variables differing among taxa. Tropical arthropods are very sensitive to seasonality and sampling at only one time of the year captures only a subset of the total community. PMID- 29980786 TI - Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. AB - It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1), driving cancer cells toward a stem-like state. In contrast, in the differentiated non-CSCs, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Furthermore, a methylation panel including the PAX6 gene yielded a sensitivity of 79.1% and specificity of 83.3% for cancer detection using serum DNA from stage IA LUAD. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy and support the clinical utility of PAX6 gene promoter methylation as a biomarker for early lung cancer detection. PMID- 29980787 TI - Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3beta/Snail signaling. AB - The devastating prognosis of pancreatic ductal adenocarcinoma (PDAC) is partially attributed to chemotherapy resistance. Glutathione peroxidase-1 (GPx1) plays various roles in the development and progression of multiple tumors, with the exception of pancreatic cancer. Here, we tentatively explored the role of GPx1 in the malignant biological behavior and gemcitabine (GEM) resistance of PDAC. GPx1 levels were detected using tissue microarrays and were negatively correlated with the overall survival of patients with PDAC. GPx1 silencing induced a mesenchymal transition phenotype and increased GEM resistance in vitro and in vivo. Additionally, the activation of reactive oxygen species (ROS)-mediated Akt/glycogen synthase kinase 3beta (GSK3beta)/Snail signaling was involved in this process, as determined by RNA sequencing. Moreover, low GPx1 expression correlated with a worse survival rate in patients with PDAC who received GEM adjuvant chemotherapy, whereas this correlation was not detected in patients receiving fluoropyrimidine. Based on our results, GPx1 inhibits the epithelial mesenchymal transition (EMT) and chemoresistance by regulating the Akt/GSK3beta/Snail signaling axis in PDAC. Furthermore, GPx1 may be a potential predictive biomarker in GEM-treated PDAC patients. PMID- 29980788 TI - Histone deacetylase 6 regulates the immunosuppressive properties of cancer associated fibroblasts in breast cancer through the STAT3-COX2-dependent pathway. AB - Cancer-associated fibroblasts (CAFs) are important components in breast tumors and essential for tumor progression and metastasis. However, the role of epigenetic modification in driving the function of CAFs within breast tumors is only marginally known. Herein, we reported that histone deacetylase 6 (HDAC6), one of class II histone deacetylases, was frequently upregulated in the CAFs of breast tumor and promotes an immunosuppressive microenvironment. The genetic or pharmacologic disruption of HDAC6 in CAFs delays tumor growth, inhibits the tumor recruitment of myeloid-derived suppressor cells and regulatory T cells, alters the macrophage phenotype switch, and increases the CD8+ and CD4+ T-cell activation in vivo. Mechanistically, we identified prostaglandin E2/cyclooxygenase-2 (COX2) as a major target of HDAC6 in CAFs by regulating STAT3 activation. Overexpressing COX2 in HDAC6-knockdown CAFs can completely restore the immunosuppressive properties of the fibroblasts. Clinically, a positive correlation among the stromal expression levels of HDAC6, p-STAT3, and COX2 in human breast cancer was observed. High-stromal expression of HDAC6 was markedly associated with poor survival outcome. Overall, our findings indicated that fibroblastic HDAC6 was a vital epigenetic mediator involved in programming an immunosuppressive tumor microenvironment that dampens antitumor immunity. Thus, HDAC6 may be a good potential target to improve breast cancer immunotherapy. PMID- 29980790 TI - Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir-bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death. AB - Cancer cells lose homeostatic flexibility because of mutations and dysregulated signaling pathways involved in maintaining homeostasis. Tuberous Sclerosis Complex 1 (TSC1) and TSC2 play a fundamental role in cell homeostasis, where signal transduction through TSC1/TSC2 is often compromised in cancer, leading to aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 hyperactivation increases the basal level of endoplasmic reticulum (ER) stress via an accumulation of unfolded protein, due to heightened de novo protein translation and repression of autophagy. We exploit this intrinsic vulnerability of tumor cells lacking TSC2, by treating with nelvinavir to further enhance ER stress while inhibiting the proteasome with bortezomib to prevent effective protein removal. We show that TSC2-deficient cells are highly dependent on the proteosomal degradation pathway for survival. Combined treatment with nelfinavir and bortezomib at clinically relevant drug concentrations show synergy in selectively killing TSC2-deficient cells with limited toxicity in control cells. This drug combination inhibited tumor formation in xenograft mouse models and patient-derived cell models of TSC and caused tumor spheroid death in 3D culture. Importantly, 3D culture assays differentiated between the cytostatic effects of the mTORC1 inhibitor, rapamycin, and the cytotoxic effects of the nelfinavir/bortezomib combination. Through RNA sequencing, we determined that nelfinavir and bortezomib tip the balance of ER protein homeostasis of the already ER-stressed TSC2-deficient cells in favor of cell death. These findings have clinical relevance in stratified medicine to treat tumors that have compromised signaling through TSC and are inflexible in their capacity to restore ER homeostasis. PMID- 29980789 TI - HMGA1/E2F1 axis and NFkB pathways regulate LPS progression and trabectedin resistance. AB - Although the medical treatments of sarcoma have evolved in the last years, a significant portion of patients develops recurrence after therapies suggesting the need to identify novel targets to improve the treatments. By the use of patient-derived and established cell lines from liposarcoma, as well as specimens from patient biopsies, we found that HMGA1 is involved in the progression of dedifferentiated and myxoid liposarcoma. The immunohistochemical and RT-PCR analyses of 68 liposarcoma specimens revealed a significant high expression of HMGA1, at the protein and RNA levels, both in myxoid and dedifferentiated liposarcoma subtypes compared with differentiated ones. Loss- and gain-of function experiments by HMGA1-specific depletion and overexpression in dedifferentiated and myxoid liposarcoma cells showed the contribution of this oncogenic factor in cell proliferation, motility, invasion, and drug resistance. The in vitro and in vivo treatment of myxoid liposarcoma with trabectedin, a drug with a potent anti-tumor activity, revealed downregulation of HMGA1, E2F1, and its-downstream targets, vimentin and ZEB1, indicating a critical role of trabectedin in inhibiting the mesenchymal markers of these tumors through the HMGA1/E2F1 axis. These data were also confirmed in patients' tumor biopsies being HMGA1, E2F1, and vimentin expression significantly reduced upon trabectedin therapy, administered as neo-adjuvant chemotherapy. Furthermore, trabectedin treatment inhibits in vitro NFkB pathway in mixoyd liposarcoma sensitive but not in resistant counterparts, and the inhibition of NFkB pathway re-sensitizes the resistant cells to trabectedin treatment. These data support the rational for combining NFkB inhibitors with trabectedin in liposarcoma patients, who have become resistant to the drug. PMID- 29980791 TI - ARID1A and CEBPalpha cooperatively inhibit UCA1 transcription in breast cancer. AB - As one of the primary members of SWI/SNF chromatin remodeling complexes, ARID1A contains frequent loss-of-function mutations in many types of cancers. However, the molecular mechanisms underlying ARID1A deficiency in cancer biology remain to be investigated. Using breast cancer as a model, we report that silencing ARID1A significantly increased cellular proliferation and migration. Mechanistically, primarily functioning as a transcriptional repressor, loss of ARID1A profoundly alters histone modifications and the transcriptome. Notably, ARID1A inhibited the expression of a long non-coding RNA, UCA1, by regulating chromatin access of the transcription factor CEBPalpha. Restoration experiments showed that UCA1 mediates the functions of ARID1A that induces loss of cellular proliferation and migration. Together, our findings characterize ARID1A as a key tumor-suppressor gene in breast cancer through cooperation with CEBPalpha, and loss-of-function mutations of ARID1A activates UCA1. PMID- 29980792 TI - Listening to earthworms burrowing and roots growing - acoustic signatures of soil biological activity. AB - We report observations of acoustic emissions (AE) from growing plant roots and burrowing earthworms in soil, as a noninvasive method for monitoring biophysical processes that modify soil structure. AE emanating from earthworm and plants root activity were linked with time-lapse imaging in glass cells. Acoustic waveguides where installed in soil columns to monitor root growth in real time (mimicking field application). The cumulative AE events were in correlation with earthworm burrow lengths and with root growth. The number of AE events recorded from the soil columns with growing maize roots were several orders of magnitude larger than AE emanating from bare soil under similar conditions. The results suggest that AE monitoring may offer a window into largely unobservable dynamics of soil biomechanical processes such as root growth or patterns of earthworm activity - both important soil structure forming processes. PMID- 29980794 TI - Efficiency of genomic prediction across two Eucalyptus nitens seed orchards with different selection histories. AB - Genomic selection is expected to enhance the genetic improvement of forest tree species by providing more accurate estimates of breeding values through marker based relationship matrices compared with pedigree-based methodologies. When adequately robust genomic prediction models are available, an additional increase in genetic gains can be made possible with the shortening of the breeding cycle through elimination of the progeny testing phase and early selection of parental candidates. The potential of genomic selection was investigated in an advanced Eucalyptus nitens breeding population focused on improvement for solid wood production. A high-density SNP chip (EUChip60K) was used to genotype 691 individuals in the breeding population, which represented two seed orchards with different selection histories. Phenotypic records for growth and form traits at age six, and for wood quality traits at age seven were available to build genomic prediction models using GBLUP, which were compared to the traditional pedigree based alternative using BLUP. GBLUP demonstrated that breeding value accuracy would be improved and substantial increases in genetic gains towards solid wood production would be achieved. Cross-validation within and across two different seed orchards indicated that genomic predictions would likely benefit in terms of higher predictive accuracy from increasing the size of the training data sets through higher relatedness and better utilization of LD. PMID- 29980793 TI - Quantitative epigenetics and evolution. AB - Epigenetics refers to chemical modifications of chromatin or transcribed DNA that can influence gene activity and expression without changes in DNA sequence. The last 20 years have yielded breakthroughs in our understanding of epigenetic processes that impact many fields of biology. In this review, we discuss how epigenetics relates to quantitative genetics and evolution. We argue that epigenetics is important for quantitative genetics because: (1) quantitative genetics is increasingly being combined with genomics, and therefore we should expand our thinking to include cellular-level mechanisms that can account for phenotypic variance and heritability besides just those that are hard-coded in the DNA sequence; and (2) epigenetic mechanisms change how phenotypic variance is partitioned, and can thereby change the heritability of traits and how those traits are inherited. To explicate these points, we show that epigenetics can influence all aspects of the phenotypic variance formula: VP (total phenotypic variance) = VG (genetic variance) + VE (environmental variance) + VGxE (genotype by-environment interaction) + 2COVGE (the genotype-environment covariance) + VE (residual variance), requiring new strategies to account for different potential sources of epigenetic effects on phenotypic variance. We also demonstrate how each of the components of phenotypic variance not only can be influenced by epigenetics, but can also have evolutionary consequences. We argue that no sources of epigenetic effects on phenotypic variance can be easily cast aside in a quantitative genetic research program that seeks to understand evolutionary processes. PMID- 29980795 TI - Determining lineage-specific bacterial growth curves with a novel approach based on amplicon reads normalization using internal standard (ARNIS). AB - The growth rate is a fundamental characteristic of bacterial species, determining its contributions to the microbial community and carbon flow. High-throughput sequencing can reveal bacterial diversity, but its quantitative inaccuracy precludes estimation of abundances and growth rates from the read numbers. Here, we overcame this limitation by normalizing Illumina-derived amplicon reads using an internal standard: a constant amount of Escherichia coli cells added to samples just before biomass collection. This approach made it possible to reconstruct growth curves for 319 individual OTUs during the grazer-removal experiment conducted in a freshwater reservoir Rimov. The high resolution data signalize significant functional heterogeneity inside the commonly investigated bacterial groups. For instance, many Actinobacterial phylotypes, a group considered to harbor slow-growing defense specialists, grew rapidly upon grazers' removal, demonstrating their considerable importance in carbon flow through food webs, while most Verrucomicrobial phylotypes were particle associated. Such differences indicate distinct life strategies and roles in food webs of specific bacterial phylotypes and groups. The impact of grazers on the specific growth rate distributions supports the hypothesis that bacterivory reduces competition and allows existence of diverse bacterial communities. It suggests that the community changes were driven mainly by abundant, fast, or moderately growing, and not by rare fast growing, phylotypes. We believe amplicon read normalization using internal standard (ARNIS) can shed new light on in situ growth dynamics of both abundant and rare bacteria. PMID- 29980797 TI - Protective effect of pentoxifylline on oxidative renal cell injury associated with renal crystal formation in a hyperoxaluric rat model. AB - The aim of the study is to investigate the effects of pentoxifylline (PTX) on the renal tubular cell injury and stone formation in a hyperoxaluric rat model induced by ethylene glycol and its possible underlying mechanisms. The study was performed with 30 male Wistar rats and randomized into three groups of teen. The sham-control (group 1) received only drinking water orally. The EG/untreated (group 2) received drinking water containing 0.75% EG for 4 weeks orally. The EG/PTX treated (group 3) received drinking water containing 0.75% EG for 4 weeks orally and PTX. Urine and blood were collected to determine some parameters. The kidneys were also removed for histological examination. Serum and urinary parameters were significantly improved in the EG/PTX treated. In the EG/PTX treated group, the MDA, TOS and MPO activity reduced and the TAS, SOD, CAT and GSH-Px activities were increased markedly compared with the group 2. In urine of the group 2 rats, a large number of CaOx crystals were displayed and most tubules that contained crystals were dilated and showed degeneration, necrosis, and desquamation of the lining epithelium. Only few CaOx crystals were r in EG/PTX treated animal's urine. Mild tissue damage was observed in PTX-treated rats. iNOS expression was significantly elevated in the group 2. In contrast, in the EG/PTX treated group, eNOS expression in renal tubular epithelial cells was increased. Current study indicates that PTX may partially reduce renal tubular injury resulting from hyperoxaluria-induced oxidative and nitrosative stress. PMID- 29980796 TI - Disentangling the drivers of functional complexity at the metagenomic level in Shark Bay microbial mat microbiomes. AB - The functional metagenomic potential of Shark Bay microbial mats was examined for the first time at a millimeter scale, employing shotgun sequencing of communities via the Illumina NextSeq 500 platform in conjunction with defined chemical analyses. A detailed functional metagenomic profile has elucidated key pathways and facilitated inference of critical microbial interactions. In addition, 87 medium-to-high-quality metagenome-assembled genomes (MAG) were assembled, including potentially novel bins under the deep-branching archaeal Asgard group (Thorarchaetoa and Lokiarchaeota). A range of pathways involved in carbon, nitrogen, sulfur, and phosphorus cycles were identified in mat metagenomes, with the Wood-Ljungdahl pathway over-represented and inferred as a major carbon fixation mode. The top five sets of genes were affiliated to sulfate assimilation (cysNC cysNCD, sat), methanogenesis (hdrABC), Wood-Ljungdahl pathways (cooS, coxSML), phosphate transport (pstB), and copper efflux (copA). Polyhydroxyalkanoate (PHA) synthase genes were over-represented at the surface, with PHA serving as a potential storage of fixed carbon. Sulfur metabolism genes were highly represented, in particular complete sets of genes responsible for both assimilatory and dissimilatory sulfate reduction. Pathways of environmental adaptation (UV, hypersalinity, oxidative stress, and heavy metal resistance) were also delineated, as well as putative viral defensive mechanisms (core genes of the CRISPR, BREX, and DISARM systems). This study provides new metagenome-based models of how biogeochemical cycles and adaptive responses may be partitioned in the microbial mats of Shark Bay. PMID- 29980798 TI - High prevalence of pediatric urinary tract stones in Xinjiang Uyghur. AB - The aim of the study was to report the characteristics of urolithiasis in Uyghur patients from Xinjiang, China. The composition of stones collected from 1863 patients in the Uyghur region of Xinjiang was analyzed. The median age of patients was 17 years [25th and 75th percentiles: 2, 36]. The stones were delivered by 1299 males (69.7%) and 564 females (30.3%). Calcium oxalate was the predominant stone component in 42.1% of the patients, followed by ammonium urate in 20.6%. Females had formed more stones of magnesium ammonium phosphate 8.9 vs. 5.6% (p = 0.010) and carbonate apatite 6.2 vs. 3.3% (p = 0.004). In contrast uric acid was more common in males than in females; 21.6 vs. 15.1% (p = 0.001). In this series, pediatric patients (age range 0-18) were more likely to present with a stone (51.5%, p < 0.001). Moreover, the largest number of pediatric stones was recorded in children 1-2 years old (37.9%, p < 0.001). The occurrence of ammonium urate stones was extremely high (52.4%) in children with an age below 1 year. There was a downward trend for ammonium urate with age in both children and adults (p for trend < 0.001, respectively). In contrast the frequency of uric acid declined with age in pediatric patients, but increased in adults (p for trend < 0.001, respectively). This study provides a basis for further considerations on the management of Xinjiang Uyghur patients and emphasize the severity of pediatric stone problems. PMID- 29980800 TI - [Digitalization in medicine]. PMID- 29980799 TI - Dsg2 via Src-mediated transactivation shapes EGFR signaling towards cell adhesion. AB - Rapidly renewing epithelial tissues such as the intestinal epithelium require precise tuning of intercellular adhesion and proliferation to preserve barrier integrity. Here, we provide evidence that desmoglein 2 (Dsg2), an adhesion molecule of desmosomes, controls cell adhesion and proliferation via epidermal growth factor receptor (EGFR) signaling. Dsg2 is required for EGFR localization at intercellular junctions as well as for Src-mediated EGFR activation. Src binds to EGFR and is required for localization of EGFR and Dsg2 to cell-cell contacts. EGFR is critical for cell adhesion and barrier recovery. In line with this, Dsg2 deficient enterocytes display impaired barrier properties and increased cell proliferation. Mechanistically, Dsg2 directly interacts with EGFR and undergoes heterotypic-binding events on the surface of living enterocytes via its extracellular domain as revealed by atomic force microscopy. Thus, our study reveals a new mechanism by which Dsg2 via Src shapes EGFR function towards cell adhesion. PMID- 29980802 TI - Urinary biomarkers of exposure to the mycoestrogen zearalenone and its modified forms in German adults. AB - Zearalenone (ZEN), a mycotoxin with estrogenic activity, can exert adverse endocrine effects in mammals and is thus of concern for humans. ZEN is found in cereal crops and grain-based foods, often along with modified ('masked') forms usually not detected in routine contaminant analysis, e.g., ZEN-O-beta-glucosides and ZEN-14-sulfate. These contribute to mycoestrogen exposure, as they are cleaved in the gastrointestinal tract to ZEN, and further metabolized in animals and humans to alpha- and beta-zearalenol (alpha-ZEL and beta-ZEL). ZEN and its metabolites are mainly excreted as conjugates in urine, allowing to monitor human exposure by a biomarker-based approach. Here, we report on a new study in German adults (n = 60) where ZEN, alpha-ZEL, and beta-ZEL were determined by LC-MS/MS analysis after enzymatic hydrolysis and immunoaffinity column clean-up of the aglycones in urines. Biomarkers were detected in all samples: ZEN ranges 0.04 0.28 (mean 0.10 +/- 0.05; median 0.07) ng/mL; alpha-ZEL ranges 0.06-0.45 (mean 0.16 +/- 0.07; median 0.13) ng/mL, and beta-ZEL ranges 0.01-0.20 (mean 0.05 +/- 0.04; median 0.03) ng/mL. Notably, average urinary levels of alpha-ZEL, the more potent estrogenic metabolite, are higher than those of ZEN, while beta-ZEL (less estrogenic than ZEN) is found at lower levels than the parent mycotoxin. Similar results were found in ten persons who collected multiple urine samples to gain more insight into temporal fluctuations in ZEN biomarker levels; here some urines had higher maximal concentrations of total ZEN (the sum of ZEN, alpha-ZEL, and beta-ZEL) with 1.6 and 1.01 ng/mL, i.e., more than those found in the majority of other urines. A preliminary approach to translate the new urinary biomarker data into dietary mycotoxin intake suggests that exposure of most individuals in our cohort is probably below the tolerable daily intake (TDI) of 0.25 ug/kg b.w. set by EFSA as group value for ZEN and its modified forms while that of some individuals exceed it. In conclusion, biomonitoring can help to assess consumer exposure to the estrogenic mycotoxin ZEN and its modified forms and to identify persons at higher risk. PMID- 29980801 TI - Surgical repair of acute pectoralis major muscle ruptures. AB - OBJECTIVE: Surgical repair of a partial or complete tear of the pectoralis major muscle to restore internal rotation, adduction, and anteversion. INDICATIONS: Acute avulsion, acute tear of the tendinous insertion, acute tear of the musculotendinous region (<6 weeks after trauma). Relative indication: chronic retracted tear (>6 weeks). CONTRAINDICATIONS: Muscular tears, local infection, other general contraindications. SURGICAL TECHNIQUE: Open repair using suture anchors or flip buttons. POSTOPERATIVE MANAGEMENT: Week 1-3: early passive assisted functional physical therapy. Week 3-6: early active-assisted functional physical therapy. Week 7-9: active assisted free range of motion (ROM). From week 9: free ROM. From week 12: exercise with resistance, careful strengthening. RESULTS: Between 2005 and 2017, 20 men with an acute or subacute tear of the pectoralis major muscle underwent surgery. Mean age 36 years (range 28-55 years). No previous antibiotic treatment or steroid abuse/treatment reported. Reasons for rupture were weight lifting (bench-press, n = 10), skiing and snowboard accidents (n = 3), fitness training (n = 3), soccer (n = 1), martial arts (n = 1), a canyoning accident (n = 1), and a simple fall (n = 1). Follow-up examinations were performed 6 weeks and 3 months postoperative. No infections or wound healing disorders; no revisions necessary. Normal muscle function via open refixation of the tendon stump. No re-rupture observed. Free ROM observed 3 months after surgery. PMID- 29980803 TI - Induction of inducible nitric oxide synthase (iNOS) in Porphyromonas gingivalis LPS-treated mouse macrophage cell line (RAW264.7) requires Toll-like receptor 9. AB - OBJECTIVE: The aim of this study is to investigate the involvement of TLR9 in the regulation of iNOS expression and nitric oxide (NO) production in Porphyromonas gingivalis LPS-treated mouse macrophages. METHODS: Mouse macrophage cell line (RAW264.7) was transfected with siRNAs against TLR9 and then stimulated with P. gingivalis LPS. At indicated time points, the activated cells were lysed. Gene and protein expression of iNOS were determined by RT-PCR and immunoblotting, respectively. The level of nitric oxide (NO) production in the supernatant of the activated cells was determined by Griess reaction assay. RESULTS AND CONCLUSION: Depletion of TLR9 in mouse macrophages demonstrated the markedly decreased iNOS gene and protein expression by P. gingivalis LPS compared to those of the wild type or control siRNA transfected cells. In consistent with these results, the level of NO secretion was also significantly diminished in TLR9-depleted cells after challenged with P. gingivalis LPS. These results indicate that TLR9 involves in the regulation of the iNOS expression and the NO secretion in P. gingivalis LPS-treated macrophages. PMID- 29980804 TI - Foot impairments contribute to functional limitation in individuals with ankle sprain and chronic ankle instability. AB - PURPOSE: To investigate the clinical measures of foot posture and morphology, multisegmented joint motion and play, strength, and dynamic balance in recreationally active young adults with and without a history of a lateral ankle sprain (LAS), copers, and chronic ankle instability (CAI). METHODS: Eighty recreationally active individuals (healthy: n = 22, coper: n = 21, LAS: n = 17, CAI: n = 20) were included. Foot posture index (FPI), morphologic measures, joint motion (weight-bearing dorsiflexion (WBDF), rearfoot dorsiflexion, plantar flexion, inversion, eversion; forefoot inversion, eversion; hallux flexion, extension), joint play (proximal and distal tibiofibular; talocrural and subtalar, forefoot; 1st tarsometatarsal and metatarsophalangeal), strength (dorsiflexion, plantar flexion, inversion, eversion, hallux flexion, lesser toe flexion), and Star Excursion Balance Test (SEBT) (anterior, posteromedial, posterolateral) were assessed. RESULTS: There were no group differences in FPI or morphological measures. LAS and CAI groups had decreased ankle dorsiflexion (p = 0.001) and greater frontal plane motion (p < 0.001), first MT plantar flexion, and sagittal excursion (p < 0.001); increased talocrural glide (p = 0.02) and internal rotation (p < 0.001) and decreased forefoot inversion joint play (p < 0.001); and decreased strength in all measures (p < 0.001) except dorsiflexion compared to healthy controls. The LAS group also demonstrated decreased distal tibiofibular (p = 0.04) and forefoot general laxity (p = 0.05) and SEBT performance (anterior: p = 0.02; posteromedial: p < 0.001; posterolateral: p < 0.001). CONCLUSION: Individuals with LAS or CAI have increased pain, impaired physiologic and accessory joint motion, ligamentous tenderness, and strength in the foot and ankle. Clinicians should assess the multiple segments of the ankle foot complex when caring for individuals with an LAS or CAI. LEVEL OF EVIDENCE: II. PMID- 29980806 TI - [Development and challenges to breastfeeding in sub-Saharan Africa]. AB - Since there is no doubt concerning the superiority of breastfeeding compared to other forms of infant feeding, the promotion of exclusive breastfeeding up to six months and continued breastfeeding up to two years and beyond are again embraced at the highest global nutrition agenda. The latest is the United Nations decade of action on nutrition 2016-2025, building on research results and the work by the World Health Organization (WHO) over the last two decades, and extensive societal, clinical, and academic discussions in the field of breastfeeding.While the discussion was about the optimal duration of exclusive breastfeeding around the millennium shift, the focus is on the most effective measures for the promotion and protection of breastfeeding. Contemporary breastfeeding rates are well behind the goals. In sub-Saharan Africa, almost all infants are breastfed, while exclusive breastfeeding is more seldom and not sufficient. Africa, being a vast and diverse continent with a myriad of cultural practices, has had some shared attitudes ranging from the west to east regarding views on motherhood, body fluids, including milk, infant feeding, and responsible others.The region still faces high maternal HIV infection rates and high infant and child mortality rates. However, due to effective antiretroviral therapies, it is now possible and safe for women living with HIV to breastfeed their infants and to ensure them HIV free survival. However, there is need for improvement regarding availability, compliance, and adherence to these drugs. Research gaps include the long-term effects of antiretroviral therapy on the growth, health, and development of the exposed children. PMID- 29980807 TI - Issues with analyzing noble gases using gas chromatography with thermal conductivity detection. AB - The noble gases, namely neon, argon, krypton and xenon, have many uses including in incandescent and gas discharge lighting, in plasma televisions, shielding gas in welding, in lasers for surgery and semiconductors, and in magnetic resonance imaging (MRI) of the lungs. When incorporating these noble gases in industries, especially the medical field, it is important to know accurately the composition of the noble gas mixture. Therefore, there is a need for accurate gas standards that can be used to determine the noble gas amount-of-substance fraction in the appropriate mixture application. A recent comparison of mixtures containing four noble gases in a helium balance showed mixed results among National Metrology Institutes. Significant differences, 0.7 to 3.8% relative, were seen in the analytical amount-of-substance assignments versus the gravimetric value of the noble gases in the comparison mixture when using "binary standards", i.e. neon in helium, argon in helium and krypton in helium, as applied by the National Institute of Standards and Technology. Post-comparison studies showed that when all four noble gases were included in the standards, the agreement between analytical and gravimetric values was within 0.05% relative. Further research revealed that different carrier gases (hydrogen, helium and nitrogen) resulted in varying differences between the analytical and gravimetric values assignments. This paper will discuss the findings of these analytical comparisons. Graphical abstract ?. PMID- 29980805 TI - Return to sport after acute acromioclavicular stabilization: a randomized control of double-suture-button system versus clavicular hook plate compared to uninjured shoulder sport athletes. AB - PURPOSE: Traumatic high-grade acromioclavicular joint (ACJ) separations can be surgically stabilized by numerous anatomic and non-anatomic procedures. The return to sport (Maffe et al. in Am J Sports Med 23:93-98, 1995] and remaining sport-associated impairments after acute ACJ stabilization has not yet been investigated. METHODS: 73 consecutive athletes with acute high-grade ACJ separation were prospectively assigned into two groups (64.4% randomized, 35.6% intention-to-treat): open clavicular hook plate (cHP) implantation (GI) or arthroscopically assisted double double-suture-button (dDSB) implantation (GII). Patients were analyzed using shoulder sport-specific measurement tools for sport ability (ASOSS), sport activity (SSAS), and numerical analog scales: NASpain during sport, NASshoulder function in sport, and NASre-achievement of sport level. Four points of examination were established: preoperative evaluation (FU0) and first postoperative follow-up (FU1) at 6 months; FU2 at 12 months; and FU3 at 24 months after surgery. The control group (GIII) consisted of 140 healthy athletes without anamnesis of prior macro-injury or surgery. RESULTS: After surgical stabilization, 29 of 35 athletes in GI (82.9%; 38.6 +/- 9.9 years) and 32 of 38 in GII (82.9%; 38.6 +/- 9.9 years) were followed up for 24 months (FU3) (loss 17.8%). All operated athletes showed significantly increased scores compared to FU0 (p < 0.05). Compared to GI, GII showed significantly superior outcome data for sporting ability as well as for NASre-achievement of sport level (p < 0.05). While GII re-achieved GIII-comparable SSAS and ASOSS levels, GI remained at a significantly inferior level. Athletes after ACJ injury of Rockwood grade IV/V and overhead athletes benefited significantly from the dDSB procedure. CONCLUSION: The dDSB procedure enabled significantly superior sport-specific outcomes compared to the cHP procedure. Athletes after dDSB surgeries re-achieved the sporting ability and the sport activity levels of healthy athletes, whereas athletes after cHP implantation remained at significantly inferior levels. The more extensive dDSB procedure and the more restrictive rehabilitation are recommended for treatment of acute high-grade ACJ separations of functionally high-demanding athletes. LEVEL OF EVIDENCE: I. PMID- 29980808 TI - Counseling after perineal laceration: does it improve functional outcome? AB - INTRODUCTION AND HYPOTHESIS: Since 2006, the Lausanne University Hospital (CHUV) has offered a 12-week post-partum perineum consultation for patients with third /fourth-degree tears, providing advice for future deliveries. This study consisted of a retrospective follow-up of these patients, focused on subsequent deliveries and current urinary and anorectal incontinence symptoms. METHODS: Patients meeting eligibility criteria were invited to complete a questionnaire on their deliveries, along with validated questionnaires grading urinary (UDI-6 and IIQ-7) and anorectal (Wexner-Vaizey score) incontinence. RESULTS: Sixty-two percent of third-/fourth-degree tears occurred following operative vaginal deliveries. Of 160 participants, 45.6% did not redeliver, 5.6% of whom felt traumatized by their first delivery and reluctant to have another children; 33.2% had a second vaginal delivery, 19.4% had a cesarean section (CS), and 1.2% had both vaginal and CS deliveries; 28% of the CS were not medically indicated. The recurrence rate of third-/fourth-degree tears for subsequent vaginal deliveries was 3.6%. Most patients were mildly or not affected by incontinence symptoms. Symptomatic patients reported urinary incontinence during physical activity and gas leakages; 50-60% saw no change of symptoms since the consultation, 30-40% reported partial or complete recovery. Patients redelivering by CS reported significantly less urinary incontinence (p = 0.046) and less anorectal incontinence (p = 0.069). CONCLUSION: Anal sphincter laceration is associated with urinary and anorectal incontinence, but symptoms improve or disappear in most cases and are globally not invalidating. Perineal physiotherapy seems to contribute to this positive evolution. Fertility rate among these patients is unaffected, but the CS rate is higher than average. Further consideration of sexual and emotional sequelae could improve our current service. PMID- 29980809 TI - Conflicts of interest and the patient-doctor covenant. PMID- 29980810 TI - Genome-wide identification of m6A-associated SNPs as potential functional variants for bone mineral density. AB - : This study investigated the effect of the N6-methyladenosine (m6A)-associated SNPs on bone mineral density (BMD) and found plenty of m6A-SNPs that were associated with BMD. This study increases our understanding on the regulation patterns of SNP and may provide new clues for further detection of functional mechanism underlying the associations between SNPs and osteoporosis. INTRODUCTION: m6A plays critical roles in many fundamental biological processes and a variety of diseases. The m6A-associated SNPs may be potential functional variants for BMD. The aim of this study was to investigate the effect of the genome-wide m6A-SNPs on BMD. METHODS: We examined the association of m6A-SNPs with femoral neck (FN) and lumbar spine (LS) BMD in 32,961 individuals and quantitative heel ultrasounds (eBMD) in 142,487 individuals. Furthermore, we performed expression quantitative trait locus (eQTL) analyses for the m6A-SNPs using whole genome data of about 10.5 million SNPs and 21,323 mRNAs from 43 Chinese individuals, as well as public available data. Differential expression analyses were also performed to support the identified genes. RESULTS: We found 138, 125, and 993 m6A-SNPs which were associated with FN-BMD, LS-BMD, and eBMD (P < 0.05), respectively. The associations of rs11614913 (P = 8.92 * 10-10) in MIR196A2 and rs1110720 (P = 2.05 * 10-10) in ESPL1 with LS-BMD reached the genome wide significance level. In addition, a total of 24 m6A-SNPs were significantly associated with eBMD (P < 5.0 * 10-8). Further eQTL analyses showed that 47 of these BMD-associated m6A-SNPs were associated with expressions of the 46 corresponding local genes. Moreover, the expressions of 26 of these genes were associated with BMD. CONCLUSION: The present study represents the first effort of investigating the associations and the mechanisms underlying the link between m6A SNPs and BMD. The results suggested that m6A-SNP may play important roles in the pathology of osteoporosis. PMID- 29980811 TI - Characterization of Acute and Chronic Toxicity of DBP to Daphnia magna. AB - As a commonly used phthalate compound, di(n-butyl) phthalate (DBP) is an emerging group of polyvinyl chloride plasticizers. The acute toxicity of DBP has been extensively studied using the aquatic indicator organism, Daphnia magna. However, little is known about chronic and transgenerational toxicity of DBP. In this study, acute LC50 values were 3.04 mg/L (24 h) and 2.55 mg/L (48 h). Chronic toxicity tests in the case of maternal exposure to DBP revealed that DBP had negligible effects on growth and reproduction of F3 generation of D. magna, although the growth rate of body length and the intrinsic rate of increase were prominently reduced, to a pretty small extent. At specific concentrations, DBP generated beneficial effects on the parental generation of D. magna and no obvious impacts on the F1 generation. This study showed that maternal exposure to DBP did not cause any transgenerational effects on D. magna. PMID- 29980812 TI - Evaluation of Legiolert for Quantification of Legionella pneumophila from Non potable Water. AB - Legiolert(r) is a new culture method for quantification of Legionella pneumophila, which is the primary species associated with Legionnaires' disease. The test is based on a most probable number approach, and differs significantly from traditional culture methods by providing results at 7 days, rapid sample preparation and analysis, and objective interpretation of test results. In this study, we compared the performance of Legiolert with the U.S. Centers for Disease Control and Prevention (CDC) method for detection of L. pneumophila from non potable samples, primarily comprising cooling tower waters. Our results demonstrated no significant difference between Legiolert and the CDC method for quantification of L. pneumophila. However, Legiolert showed a significant increase in sensitivity when water samples containing higher L. pneumophila concentrations were examined. Cooling tower waters often contain non-Legionella organisms (NLO) that interfere with traditional Legionella test methods, and we observed varying degrees of NLO interference on many CDC method plates. In contrast, Legiolert was resistant to NLO interference and produced a very low rate of false-positive results. Collectively, Legiolert is a sensitive and specific method for quantification of L. pneumophila from non-potable water that provides advantages over the CDC method. PMID- 29980813 TI - Actinomadura hankyongense sp. nov. Isolated From Soil of Ginseng Cultivating Field. AB - A Gram-positive, rod-shaped, non-spore-forming, and aerobic bacterium (Gsoil 556T) was isolated from soil of a ginseng field and subjected to its taxonomic position. Based on 16S rRNA gene sequence similarity, strain Gsoil 556T was shown to belong to the genus Actinomadura of the family Thermomonosporaceae and was closely related to A. montaniterrae CYP1-1BT (99.3%), A. nitritigenes DSM 44137T (98.7%), and A. rudentiformis HMC1T (98.5%), while it showed less than 98.4% sequence similarity to the other species of this genus. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that it is most closely related to A. rudentiformis HMC1T and A. nitritigenes DSM 44137T. The DNA G+C content was 73.1 mol%. The peptidoglycan was meso-diaminopimelic acid and the whole-cell sugar contained fucose, galactose, glucose, mannose, and ribose. The predominant menaquinone (KK) was MK-9(H8) [55%] and MK-9(H6) [45%]. The major cellular fatty acids were C14:0, C16:0, C18:1 omega9c and summed feature 3 (C16:1 omega6c/C16:1 omega7c). All these data supported the affiliation of strain Gsoil 556T to the genus Actinomadura. The DNA-DNA hybridization between strain Gsoil 556T and its phylogenetically closest relatives were less than 40%. Furthermore, the results of physiological and biochemical tests enabled strain Gsoil 556T to be differentiated genotypically and phenotypically from currently known Actinomadura species. Therefore, strain Gsoil 556T represents a novel species of the genus Actinomadura, for which the name Actinomadura hankyongense sp. nov. is proposed. The type strain Gsoil 556T (=KACC 19438T=LMG 30327T). PMID- 29980814 TI - Regulation of IAA Biosynthesis in Azospirillum brasilense Under Environmental Stress Conditions. AB - Indole-3-acetic acid (IAA) is one of the most important molecules produced by Azospirillum sp., given that it affects plant growth and development. Azospirillum brasilense strains Sp245 and Az39 (pFAJ64) were pre-incubated in MMAB medium plus 100 mg/mL L-tryptophan and treated with or exposed to the following (a) abiotic and (b) biotic stress effectors: (a) 100 mM NaCl or Na2SO4, 4.0% (w/v) PEG6000, 0.5 mM H2O2, 0.1 mM abscisic acid, 0.1 mM 1-aminocyclopropane 1-carboxylic acid, 45 degrees C or daylight, and (b) 4.0% (v/v) filtered supernatant of Pseudomonas savastanoi (Ps) or Fusarium oxysporum (Fo), 0.1 mM salicylic acid (SA), 0.1 mM methyl jasmonic acid (MeJA), and 0.01% (w/v) chitosan (CH). After 30 and 120 min of incubation, biomass production, cell viability, IAA concentration (ug/mL), and ipdC gene expression were measured. Our results show that IAA production increases with daylight or in the presence of PEG6000, ABA, SA, CH, and Fo. On the contrary, exposure to 45 degrees C or treatment with H2O2, NaCl, Na2SO4, ACC, MeJA, and Ps decrease IAA biosynthesis. In this report, growth and IAA biosynthesis in A. brasilense under biotic and abiotic stress conditions are discussed from the point of view of their role in bacterial lifestyle and their potential application as bioproducts. PMID- 29980815 TI - [Pharmacotherapy and kidney dysfunction]. AB - Essential for drug dose adjustment is the glomerular filtration rate (GFR) not the serum creatinine level. In acute disease, a loading dose must be given that usually corresponds to the normal dose. The eliminated half-life is used to estimate the administration interval. For anti-infective drugs with a concentration-dependent effect, the target is the high peak such as for daptomycin, linezolide, and colistin. For anti-infective drugs with a time dependent effect, the target is the high trough such as for piperacillin, meropenem and vancomycin. Such drugs with a time-dependent action should best be administered by infusion not by bolus dosing. With continuous renal replacement therapy (CRRT), the total filtration rate corresponds to a GFR of 30-50 ml/min and many antibiotics will not need a dose reduction on CRRT. After intermittent hemodialysis, a new loading dose should be given to ascertain sufficiently high concentrations in the interval until the next dose or next dialysis. PMID- 29980816 TI - Contemporary CBCT diagnostics-discovery of a new artery with possible impact on surgical planning: the anterior superior palatal alveolar artery. AB - PURPOSE: An ongoing clinical trial regarding intra- and post-surgical morbidity in maxillary apicoectomies showed significant higher morbidity for upper canines and palatal roots of upper 1st premolars. Analysis of available presurgical cone beam computed tomography (CBCT)-scans revealed the existence of an unknown bone canal branching off from the bone-canal or groove of the anterior superior alveolar artery (asaa). Aim of the study was the determination of the contents of this newly found bone canal in human cadaver heads, its prevalence as possible standard anatomical structure and its automatized detection with a contemporary high-resolution TRIUM-CBCT-device in vivo. METHODS: 35 human cadaver heads were dissected, the prevalence of the bone-canal determined and its contents analyzed by histology. 835 consecutive routine high-resolution TRIUM-CBCT-scans from routine patients were analyzed by an automatized detection- and tracing-algorithm for in vivo-determination of prevalence of this bone canal. Automatized detection and additional manual tracing were statistically evaluated by SSPS 20.0 software. RESULTS: The bone-canal was found in 96% of the anatomical specimens, its content identified as artery not described until now and named after the first finder "Arteria Kurrekii". Automatized tracing of TRIUM-CBCT-scans with additional manual tracing revealed an in vivo prevalence of this newly found artery of 95% (p <= 0.05). CONCLUSIONS: The newly found anterior superior palatal alveolar artery (aspaa-"Arteria Kurrekii") might have the same clinical impact for surgical procedures in the maxilla as the posterior superior alveolar artery (psaa). Its first detection was enabled by high-resolution TRIUM-CBCT devices and prevalence as standard anatomical structure proven in vivo by automatized CBCT scan analysis. PMID- 29980817 TI - Acute Massive and Submassive Pulmonary Embolism: Preliminary Validation of Aspiration Mechanical Thrombectomy in Patients with Contraindications to Thrombolysis. AB - PURPOSE: The aim of this study is to assess the feasibility of aspiration mechanical thrombectomy in patients with massive and submassive pulmonary embolism (PE) and contraindications to thrombolysis. MATERIALS AND METHODS: Eighteen patients presenting massive (8/18) or submassive (10/18) PE were prospectively enrolled between October 2016 and November 2017. All the patients enrolled had contraindications to thrombolysis (haemorrhagic stroke n = 1, ischaemic stroke in the preceding 6 months n = 7, central nervous system damage or neoplasms n = 1, recent major trauma/surgery/head injury in the preceding 3 weeks n = 5, gastrointestinal bleeding within the last month n = 4). Eight patients out of 18 (44.44%) were women and 10 (55.55%) were men, with an average age of 74.76 years (range 51-87 years). All the patients were stratified according to the PE severity index (PESI) and the simplified PESI score. RESULTS: Technical and procedural success was achieved in 18 patients (100%), as per the Society of Interventional Radiology reporting standards definition, while clinical success was achieved in 14 out of 18 patients (78%), with a significant improvement in the pre- and post-procedural right ventricular/left ventricular (RV/LV) ratio, pulmonary oxygen saturation (SpO2), heart rate, pulmonary artery systolic pressure and the Miller score with a consistent p value of < 0.00001, 0.01, 0.001, < 0.00001 and < 0.00001, respectively. The median days of hospitalization in the intensive care unit was 8.35 days (range 2-12), and during the follow-up, none of the patients developed pulmonary hypertension or PE recurrence. CONCLUSION: The high technical and clinical success of the procedure employed in this study suggests that aspiration mechanical thrombectomy is a promising technique when used alone. More extensive prospective studies are needed to assess the feasibility of this treatment. PMID- 29980818 TI - Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study. AB - PURPOSE: The recent release of a medical cannabis strain has given a new impulse for the study of cannabis in Italy. The National Health Service advises to consume medical cannabis by vaporizing, in decoction or oil form. This is the first study that explores the pharmacokinetics and tolerability of a single oral dose of cannabis as decoction (200 ml) or in olive oil (1 ml), as a first step to improve the prescriptive recommendations. METHODS: This is a single-center, open label, two-period crossover study designed to assess the pharmacokinetics and tolerability of oral cannabis administered to 13 patients with medication overuse headache (MOH). A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was conducted for the quantification of THC, CBD, 11-OH-THC, THC-COOH, THC COOH-glucuronide, THCA-A, and CBDA. Blood pressure, heart rate, and a short list of symptoms by numerical rating scale (NRS) were assessed. RESULTS: Decoctions of cannabis showed high variability in cannabinoids content, compared to cannabis oil. For both preparations, THCA-A and CBDA were the most widely absorbed cannabinoids, while THC and CBD were less absorbed. The most important differences concern the bioavailability of THC, higher in oil (AUC0-24 7.44, 95% CI 5.19, 9.68) than in decoction (AUC0-24 3.34, 95% CI 2.07, 4.60), and the bioavailability of CBDA. No serious adverse events were reported. CONCLUSIONS: Cannabis decoction and cannabis oil showed different pharmacokinetic properties, as well as distinct consequences on patients. This study was performed in a limited number of patients; future studies should be performed to investigate the clinical efficacy in larger populations. PMID- 29980820 TI - Correction to: Appetitive startle modulation in the human laboratory predicts Cannabis craving in the natural environment. AB - The name of Hayley Treloar Padovano was incorrectly tagged in the original version of this article. Instead of Padovano as family name and Hayley Treloar as given name, it should be Hayley as given name and Treloar Padovano as family name. Correct presentation of author name when online should be Treloar Padovano H. PMID- 29980819 TI - [Pancreatic ductal adenocarcinoma]. AB - Pancreatic ductal adenocarcinoma represents the most common malignant tumor of the pancreas. Despite substantial research efforts and gradual diagnostic and therapeutic improvements, its prognosis remains dismal. In accordance with the current German, European, and US guidelines, this CME-article provides a comprehensive review of the disease. In addition, selected up-to-date aspects of epidemiology, etiopathology, genetics, and basic principles of diagnostics and therapy including potential future therapeutic options are discussed. PMID- 29980821 TI - Before and after: craving, mood, and background stress in the hours surrounding drug use and stressful events in patients with opioid-use disorder. AB - RATIONALE: Ecological momentary assessment (EMA) of specific events usually focuses more on antecedents and concomitants than on aftermaths. OBJECTIVES: To examine mental state both before and after discrete episodes of stress and drug use. METHODS: For up to 16 weeks, outpatients on opioid-agonist treatment carried smartphones on which they initiated entries for stressful events (SEs) or lapses to drug use (DUs), and thrice daily when randomly prompted (RPs). Participants rated their stress, opioid craving, cocaine craving, and moods. RP entries within 5 h of an event were analyzed and compared to other RPs. RESULTS: Stress, negative mood, and craving were generally higher before and after DUs and SEs compared to background levels in participants with at least one DU (n = 149) or SE (n = 158). Before DUs, there were increases in negative mood, opioid craving, and cocaine craving, but not background stress. Before SEs, there were increases in background stress, opioid craving, and cocaine craving, but not negative mood. These changes were more variable after events than before. Neither DUs nor SEs were significantly related to positive mood. CONCLUSIONS: Stress increased before stressful-event entries, but was less evident before drug use. Craving increased in the hours before drug use and stressful events-and remained elevated in the hours after either event. These results suggest a stronger link between drug use and craving than between drug use and stress. Lapses to drug use did not improve mood or reduce stress, at least not at our 1-h-bin time resolution, suggesting that if such benefits exist, they are brief. PMID- 29980822 TI - The contribution of agonist and antagonist activities of alpha4beta2* nAChR ligands to smoking cessation efficacy: a quantitative analysis of literature data. AB - RATIONALE AND OBJECTIVE: Two mechanisms underlie smoking cessation efficacies of alpha4beta2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP 601927, and CP-601932, relative to the functional effects of nicotine from smoking. METHODS: Functional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target alpha4beta2 nAChR, as well as at alpha6beta2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist. RESULTS: Comparisons with odds ratios at end of treatment suggest that extensive alpha4beta2 and alpha6beta2* nAChR desensitization combined with alpha6beta2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT 418). Effective competition with inhaled nicotine for alpha4beta2 and alpha6beta2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at alpha4beta2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT 089, CP-601927, CP-601932). CONCLUSION: Three pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of alpha6beta2* nAChRs, desensitization of alpha4beta2 and alpha6beta2* nAChRs (agonist activity), and the reduction of nicotine occupancy at alpha4beta2 and alpha6beta2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of alpha4beta2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline). PMID- 29980823 TI - Small-world indices via network efficiency for brain networks from diffusion MRI. AB - The small-world architecture has gained considerable attention in anatomical brain connectivity studies. However, how to adequately quantify small-worldness in diffusion networks has remained a problem. We addressed the limits of small world measures and defined new metric indices: the small-world efficiency (SWE) and the small-world angle (SWA), both based on the tradeoff between high global and local efficiency. To confirm the validity of the new indices, we examined the behavior of SWE and SWA of networks based on the Watts-Strogatz model as well as the diffusion tensor imaging (DTI) data from 75 healthy old subjects (aged 50 70). We found that SWE could classify the subjects into different age groups, and was correlated with individual performance on the WAIS-IV test. Moreover, to evaluate the sensitivity of the proposed measures to network, two network attack strategies were applied. Our results indicate that the new indices outperform their predecessors in the analysis of DTI data. PMID- 29980825 TI - Echocardiographic Follow-Up of Congenital Aortic Valvular Stenosis II. AB - We evaluated the natural course of congenital aortic valvular stenosis (AVS) and factors affecting AVS progression during long-term follow-up with echocardiography. Medical records of 388 patients with AVS were reviewed; patients with concomitant lesions other than aortic regurgitation (AR) were excluded. Trivial AVS was defined as a transvalvular Doppler peak systolic instantaneous gradient of < 25 mmHg; mild stenosis, 25-49 mmHg; moderate stenosis, 50-75 mmHg; and severe stenosis, > 75 mmHg. Median age of the patients was 3 years (range 0 day to 21 years), and 287 (74%) were male. A total of 355 patients were followed with medical treatment alone for a median of 4.6 years (range 1 month to 20.6 years), and the degree of AVS increased in 75 (21%) patients. The risk of AVS progression was higher when AVS was diagnosed in neonates (OR 4.29, CI 1.81-10.18, p = 0.001) and infants (OR 3.79, CI 2.21-6.49, p = 0.001). After the infancy period, bicuspid valve morphology increased AVS progression risk (OR 2.4, CI 1.2-4.6, p = 0.034). Patients with moderate AVS were more likely to have AVS progression (OR 2.59, CI 1.3-5.1, p = 0.006). Bicuspid valve morphology increased risk of AR development/progression (OR 1.77, CI 1.1 2.7, p = 0.017). The patients with mild and moderate AVS were more likely to have AR development/progression (p = 0.001). The risk of AR development/progression was higher in patients with AVS progression (OR 2.25, CI 1.33-3.81, p = 0.002). Newborn babies and infants should be followed more frequently than older patients according to disease severity. Bicuspid aortic valve morphology and moderate stenosis are risk factors for the progression of AVS and AR. PMID- 29980826 TI - Malignant granular cell tumor of the median nerve: a case report with a literature review of 157 cases. AB - Malignant granular cell tumors are an extremely rare, high-grade sarcoma with a schwannian phenotype and are composed of malignant granular cells with cytoplasmic lysosomal inclusion. To date, 157 cases of malignant granular cell tumors have been reported. We report the first case of a malignant granular cell tumor arising from the digital nerve to the median nerve in the palm, and we review the 157 previously reported cases and summarize the clinical profile, treatment, and outcome of this tumor. The median age, tumor size, and follow-up periods were 51 years, 6 cm, and 24 months respectively. With respect to the oncological result, 53 patients (33.8%) had no evidence for disease, 31 (19.7%) were alive with the disease, and 51 (32.5%) died because of the disease. Our case report indicates that rare malignant tumors can arise from the digital nerve to the median nerve in the palm, an anatomical site that is usually affected by benign lesions. Exhaustive discussions between surgeons and pathologists are necessary for the treatment of this rare malignant tumor. PMID- 29980824 TI - Phenotypic lag and population extinction in the moving-optimum model: insights from a small-jumps limit. AB - Continuous environmental change-such as slowly rising temperatures-may create permanent maladaptation of natural populations: Even if a population adapts evolutionarily, its mean phenotype will usually lag behind the phenotype favored in the current environment, and if the resulting phenotypic lag becomes too large, the population risks extinction. We analyze this scenario using a moving optimum model, in which one or more quantitative traits are under stabilizing selection towards an optimal value that increases at a constant rate. We have recently shown that, in the limit of infinitely small mutations and high mutation rate, the evolution of the phenotypic lag converges to an Ornstein-Uhlenbeck process around a long-term equilibrium value. Both the mean and the variance of this equilibrium lag have simple analytical formulas. Here, we study the properties of this limit and compare it to simulations of an evolving population with finite mutational effects. We find that the "small-jumps limit" provides a reasonable approximation, provided the mean lag is so large that the optimum cannot be reached by a single mutation. This is the case for fast environmental change and/or weak selection. Our analysis also provides insights into population extinction: Even if the mean lag is small enough to allow a positive growth rate, stochastic fluctuations of the lag will eventually cause extinction. We show that the time until this event follows an exponential distribution, whose mean depends strongly on a composite parameter that relates the speed of environmental change to the adaptive potential of the population. PMID- 29980827 TI - Can effusion-synovitis measured on ultrasound or MRI predict response to intra articular steroid injection in hip osteoarthritis? AB - OBJECTIVES: Intra-articular steroid injection (IASI) is an effective therapy for hip osteoarthritis (OA), but carries risks and provides significant pain relief to only two thirds of patients. We attempted to predict response to IASI in hip OA patients using baseline clinical, ultrasound, and MRI data. METHODS: Observational study of 97 subjects with symptomatic hip OA presenting for IASI. At baseline and 8 weeks we obtained hip MRI, grayscale and Doppler ultrasound, clinical range of motion (ROM), timed-up and go test (TUG) scores, and self reported Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, stiffness, and function scores. Bone-capsule distance (BCD) measurements of inflammation on hip ultrasound and MRI were measured at three locations: the proximal-most uncovered portion of the femoral head, the superficial-most (apex) portion of the femoral head, and the largest fluid pocket at the femoral neck. RESULTS: Ultrasound and MRI BCD correlated with each other significantly and strongly at the apex and neck. Power Doppler findings did not correlate significantly with any other imaging indices. Eight weeks post-injection, WOMAC pain, function, and stiffness scores significantly improved and TUG time improved nearly to the level of significance, but there were no significant changes in ultrasound, MRI, or Doppler indices. Baseline variables were not significantly different between responder and nonresponder WOMAC pain or TUG time cohorts. CONCLUSION: Basic measures of inflammation on ultrasound and MRI are highly related to each other, but provide little insight into patient function and pain after IASI. Other mechanisms to explain improvement in patient status after IASI are likely at work. PMID- 29980828 TI - Comparison of image noise and image quality between full-dose abdominal computed tomography scans reconstructed with weighted filtered back projection and half dose scans reconstructed with improved sinogram-affirmed iterative reconstruction (SAFIRE*). AB - PURPOSE: To retrospectively compare the image noise, signal-to-noise ratio (SNR), and subjective image quality between CT images acquired with a dual-source, split dose imaging protocol reconstructed at full and half doses with weighted filtered back projection (wFBP) and an improved sinogram-affirmed iterative reconstruction algorithm (SAFIRE*). METHODS: Fifty-three consecutive patients underwent contrast enhanced CT of the abdomen using a standardized dual-source, single energy CT protocol. Half-dose images were retrospectively generated using data from one detector only. Full-dose datasets were reconstructed with wFBP, while half-dose datasets were reconstructed with wFBP and SAFIRE* strengths 1-5. Region of interest analysis was performed to assess SNR and noise. Diagnostic acceptability, subjective noise, and spatial resolution were graded on a 10-point scale by two readers. Statistical analysis was carried out with repeated measures analysis of variance, Wilcoxon signed rank test, and Cohen's kappa test. RESULTS: With the increasing strengths of SAFIRE*, a progressive reduction in noise and increase in SNR (p < 0.01) was observed. There was a statistically significant decrease in objective noise and increase in SNR in half-dose SAFIRE* strength 4 and 5 reconstructions compared to full-dose reconstructions using wFBP (p < 0.01). Qualitative analysis revealed a progressive increase in diagnostic acceptability, decrease in subjective noise and increase in spatial resolution for half-dose images reconstructed with the increasing strengths of SAFIRE* (p < 0.01). CONCLUSIONS: Half-dose CT images reconstructed with SAFIRE* at strength 4 and 5 have superior image quality compared to full-dose images reconstructed with wFBP. SAFIRE* potentially allows dose reductions in the order of 50% over wFBP. PMID- 29980829 TI - MRI of pancreatic ductal adenocarcinoma: texture analysis of T2-weighted images for predicting long-term outcome. AB - PURPOSE: To assess the association between T2-weighted imaging (T2WI) texture analysis parameters and the pathological aggressiveness or long-term outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS: A total of 66 patients (mean age 65.3 +/- 9.0 years) who underwent preoperative MRI followed by pancreatectomy for PDAC between 2013 and 2015 were included in this study. A radiologist performed a texture analysis twice on one axial image using commercial software. Differences in the tex parameters, according to pathological factors, were analyzed using a Student's t test or an ANOVA with Tukey's test. Univariate and multivariate Cox proportional hazards regression analyses were used to evaluate the association between tex parameters and recurrence-free survival (RFS) or overall survival (OS). RESULTS: The mean follow-up time was 18.5 months, and there were 58 recurrences and 39 deaths. The mean of the positive pixel (MPP)-related factors was significantly lower in poorly differentiated tumors than in well-differentiated tumors as well as in cases with perineural invasion. The univariate Cox proportional hazards analysis showed a significant association between the tex parameters and RFS or OS. However, only tumor size was statistically significant after the multivariate analysis. Only tumor size and entropy with medium texture were significantly associated with OS after the multivariate analysis. CONCLUSIONS: Tumor size was a significant predictive factor for RFS and OS in PDAC patients. Although entropy with medium texture analysis was significantly associated with OS, there were also limitations in the texture analysis; thus, further study is necessary. PMID- 29980830 TI - Renal tumor structured reporting including nephrometry score and beyond: what the urologist and interventional radiologist need to know. AB - The purpose of this paper is to describe cross-sectional imaging anatomic and morphologic parameters of solid renal tumors that urologists and interventional radiologists need for precise management, review the commonly used terms and descriptors of those parameters, and suggest a comprehensive reporting system for detected masses. PMID- 29980831 TI - Amyloid involvement in subcortical regions predicts cognitive decline. AB - PURPOSE: We estimated whether amyloid involvement in subcortical regions may predict cognitive impairment, and established an amyloid staging scheme based on degree of subcortical amyloid involvement. METHODS: Data from 240 cognitively normal older individuals, 393 participants with mild cognitive impairment, and 126 participants with Alzheimer disease were acquired at Alzheimer's Disease Neuroimaging Initiative sites. To assess subcortical involvement, we analyzed amyloid deposition in amygdala, putamen, and caudate nucleus. We staged participants into a 3-stage model based on cortical and subcortical amyloid involvement: 382 with no cortical or subcortical involvement as stage 0, 165 with cortical but no subcortical involvement as stage 1, and 203 with both cortical and subcortical involvement as stage 2. RESULTS: Amyloid accumulation was first observed in cortical regions and spread down to the putamen, caudate nucleus, and amygdala. In longitudinal analysis, changes in MMSE, ADAS-cog 13, FDG PET SUVR, and hippocampal volumes were steepest in stage 2 followed by stage 1 then stage 0 (p value <0.001). Stage 2 showed steeper changes in MMSE score (beta [SE] = -0.02 [0.004], p < 0.001), ADAS-cog 13 (0.05 [0.01], p < 0.001), FDG PET SUVR (-0.0008 [0.0003], p = 0.004), and hippocampal volumes (-4.46 [0.65], p < 0.001) compared to stage 1. CONCLUSIONS: We demonstrated a downward spreading pattern of amyloid, suggesting that amyloid accumulates first in neocortex followed by subcortical structures. Furthermore, our new finding suggested that an amyloid staging scheme based on subcortical involvement might reveal how differential regional accumulation of amyloid affects cognitive decline through functional and structural changes of the brain. PMID- 29980832 TI - Impact of long-term androgen deprivation therapy on PSMA ligand PET/CT in patients with castration-sensitive prostate cancer. AB - PURPOSE: Since the introduction of PSMA PET/CT with 68Ga-PSMA-11, this modality for imaging prostate cancer (PC) has spread worldwide. Preclinical studies have demonstrated that short-term androgen deprivation therapy (ADT) can significantly increase PSMA expression on PC cells. Additionally, retrospective clinical data in large patient cohorts suggest a positive association between ongoing ADT and a pathological PSMA PET/CT scan. The present evaluation was conducted to further analyse the influence of long-term ADT on PSMA PET/CT findings. METHODS: A retrospective analysis was performed of all 1,704 patients who underwent a 68Ga PSMA-11 PET/CT scan at our institution from 2011 to 2017 to detect PC. Of 306 patients scanned at least twice, 10 had started and continued ADT with a continuous clinical response between the two PSMA PET/CT scans. These ten patients were included in the current analysis which compared the tracer uptake intensity and volume of PC lesions on PSMA PET/CT before and during ongoing ADT. RESULTS: Overall, 31 PC lesions were visible in all ten patients before initiation of ADT. However, during ongoing ADT (duration 42-369 days, median 230 days), only 14 lesions were visible in eight of the ten patients. The average tracer uptake values decreased in 71% and increased in 12.9% of the PC lesions. Of all lesions, 33.3% were still visible in six patients with a complete PSA response (<=0.1 ng/ml). CONCLUSION: Continuous long-term ADT significantly reduces the visibility of castration-sensitive PC on PSMA PET/CT. If the objective is visualization of the maximum possible extent of disease, we recommend referring patients for PSMA PET/CT before starting ADT. PMID- 29980833 TI - Prediction of Post-operative Morbidity and Mortality in Patients with Lung Cancer: Methodological Issues. PMID- 29980835 TI - Primary and secondary prevention of stroke and systemic embolism with rivaroxaban in patients with non-valvular atrial fibrillation : Sub-analysis of the EXPAND Study. AB - The EXPAND Study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non valvular atrial fibrillation (NVAF). In this sub-analysis, we compared the differences in efficacy and safety between patients with and those without history of stroke or transient ischemic attack (TIA). This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients aged >= 20 years [mean age 71.6 +/- 9.4 (SD) years] who were being or planned to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for a mean period of 897.1 +/- 206.8 days with a high follow-up rate (99.7%). The primary prevention group comprised patients without history of ischemic stroke or TIA (n = 5546, 77.7%), and the secondary prevention group comprised those with history of ischemic stroke or TIA (n = 1595, 22.3%). In the primary and secondary prevention groups, the incidence rate of stroke or SE (primary efficacy endpoint) was 0.7 and 2.2%/year, respectively (P < 0.001), and the incidence rate of major bleeding (primary safety endpoint) was 1.2 and 1.5%/year, respectively (P = 0.132). For major bleeding events, the incidence rate of intracranial bleeding was 0.4 and 0.8%/year (P = 0.002) in the primary and secondary prevention groups, respectively. This sub-analysis of the EXPAND Study showed that the Japan specific dosages of rivaroxaban were effective and safe in Japanese NVAF patients with and those without ischemic stroke or TIA in routine clinical practice. PMID- 29980834 TI - FRAX tool in type 2 diabetic subjects: the use of HbA1c in estimating fracture risk. AB - AIMS: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures, despite having greater bone mineral density (BMD) than non-diabetic subjects. This has led to the hypothesis that the presence of impaired bone quality among diabetics reduces bone strength. The Fracture Risk Assessment Score (FRAX) algorithm, introduced to facilitate the evaluation of fracture risk, underestimates the risk of fracture in diabetic patients. The purpose of this study is to confirm the relationship between the degree of metabolic compensation and the 10-year probability of a major fracture or a hip osteoporotic fracture observed in our previous study and to ascertain whether glycosylated hemoglobin (HbA1c) can improve the predictive value of FRAX in patients with T2DM. METHODS: Our data derive from a retrospective clinical study conducted at the "Tor Vergata" Polyclinic in Rome on 6355 subjects over 50 years of age evaluated for osteoporosis. All available clinical records were examined. HbA1c was available for 242 of these subjects and all had had a Dual-energy X-ray Absorption (DXA) scan of the lumbar spine and femoral neck. The risk of fracture was estimated using the Italian version of the FRAX algorithm. RESULT: Patients with T2DM had BMD and T-scores higher than those of non-diabetic subjects, while FRAX average values were higher in the non-diabetic group. HbA1c and FRAX are inversely correlated with each other: for each incremental percentage point of HbA1c growth, the FRAX major osteoporotic fracture probability is reduced by 0.915 points and the FRAX hip osteoporotic fracture probability by 1.438 points. The introduction of a correction factor derived from HbA1c, resulted in mean FRAX values of diabetic patients equivalent to those of non-diabetic subjects. CONCLUSIONS: We propose a correction factor derived from HbA1c that could enhance the predictive ability of fracture risk estimated by the FRAX algorithm in subjects with T2DM. PMID- 29980836 TI - Intracranial neurenteric cyst arising at the suprasellar cistern with extension to middle cranial fossa. AB - INTRODUCTION: Intracranial neurenteric cysts are rare and are not often found in the supratentorial space. We present a case of an intracranial neurenteric cyst that arose at the suprasellar cistern with extension to the middle cranial fossa. HISTORY: A 3-year-old girl presented with seizure. Neuroimaging showed a huge extra-axial cyst involving the suprasellar cistern and left middle cranial fossa. Under the impression of an arachnoid cyst, she underwent fenestration of the cyst with basal cisterns and ventricle. The pathologic diagnosis was neurenteric cyst. Four years after the surgery, MRI showed no recurrence but did show poorly developed myelination of the left temporal white matter. Three years after surgery, seizures recurred. We consider epilepsy surgery in case of uncontrolled seizure. DISCUSSION: We discuss the unique case of supratentorially located neurenteric cyst that is just treated by fenestration. A close follow-up is needed for children with intracranial neurenteric cysts to surveil not only recurrence of lesion but also normal brain development. PMID- 29980838 TI - Cost analysis of prostate cancer detection including the prostate health index (phi). AB - OBJECTIVE: To assess the economic impact of introducing the prostate health index (phi) for prostate cancer (PCa) detection. METHODS: A total of 177 patients who presented in an academic institution with a tPSA between 2 and 10 ng/ml and underwent prostate biopsies within the 3 months were enrolled. With phi and tPSA thresholds of 43 and 4 ng/ml, respectively, probability for each branch of a decision tree model for PCa diagnosis and corresponding mean cost were estimated with "Monte Carlo" simulations. A sensitivity analysis was performed. RESULTS: With a similar sensitivity, phi strategy increased positive predictive value by 13.9 points and negative predictive value by 31.6 points in comparison to tPSA strategy. Mean costs per patient with tPSA and phi strategies were ?514 and ?528, respectively, for a phi test price at 50?. One-way sensitivity analysis showed that phi strategy was less expensive (508?/patient) than tPSA strategy with a phi test price below 30?. In multi-criteria sensitivity analysis, PPV and the rates of positive phi and tPSA were the parameters with the largest impact on the final cost as opposed to the cost of the biopsy or imaging which have less influence. With an expected rate of positive phi test < 60%, tPSA strategy was more expensive than phi strategy. CONCLUSIONS: The introduction of phi index in PCa detection would result in a significant clinical benefit compared to tPSA strategy. In our economic model, the phi strategy was equivalent or slightly more expensive than the current tPSA strategy. PMID- 29980837 TI - Providing integrative care in the pre-chemotherapy setting: a pragmatic controlled patient-centered trial with implications for supportive cancer care. AB - CONTEXT AND OBJECTIVES: To examine the impact of a complementary/integrative medicine (CIM) program on quality of life (QoL)-related concerns among patients scheduled for chemotherapy for breast and gynecologic cancer. METHODS: Chemotherapy-naive patients were referred by their oncology healthcare professional to an integrative oncology program, where CIM is provided as part of palliative/supportive care. CIM treatments were tailored to patients' preferences and leading concerns, and for most included acupuncture and mind-body-spirit modalities, which were usually co-administered in the week preceding the first chemotherapy cycle. Patients attending the program were considered part of the treatment group; those who chose to receive only standard supportive care as controls. Assessment of quantitative outcomes was conducted during the week before chemotherapy; at 24 h before and after the treatment; and at 1 week post treatment. For this purpose, the Edmonton Symptom Assessment Scale (ESAS) and Measure Yourself Concerns and Well-being questionnaire (MYCAW) were used. Qualitative assessment was based on short narratives at the end of the follow-up MYCAW questionnaire, which were analyzed with ATLAS.Ti software for systematic coding. RESULTS: Of the 55 patients referred, 31 (56%) underwent CIM treatments, with 24 controls. Both groups had similar baseline demographic and cancer-related characteristics. QOL-related outcomes were significantly less impaired following CIM treatments for ESAS fatigue scores (P = 0.013), depression (P = 0.005), and feeling of well-being (P = 0.027); and MYCAW scores for well-being (P = 0.005) and emotional distress (P = 0.02). Qualitative analysis detected both specific and non-specific effects of the CIM treatment regimen, most describing a reduction in pre-chemotherapy anxiety. CONCLUSION: A patient-tailored CIM program, initiated within a week of the first chemotherapy cycle, may help reduce the severity of fatigue, depression, and impaired well-being among patients with breast and gynecological cancers. PMID- 29980839 TI - Malignant invasion of the central nervous system: the hidden face of a poorly understood outcome of prostate cancer. AB - Malignancies of the central nervous system include primary brain tumors and brain metastases, the latter being the major cause of intracranial neoplasms in adults. Although prostate cancer (PCa) brain metastases are not the most common source, recent data show that the relevance of prostate cancer brain metastases (PCBM) cannot be neglected. In this review, we focus on the molecular repertory as well as on the phenotypical similarities between PCBM and primary PCa, such as the cellular evolution and the maintenance of androgen-receptor expression. Moreover, the simultaneous occurrence of PCBM with other PCa metastatic sites and the significance of the clinical heterogeneity of the disease are also discussed. In addition, a potential relationship between the heterogeneous behavior exhibited by PCBM and the co-occurrence of malignant cell clusters with distinct genetic profiles is also hypothesized, as well as the prominent role of astrocytes in the establishment of PCBM. PMID- 29980840 TI - The role of spatial texture in visual control of bumblebee learning flights. AB - When leaving the nest for the first time, bees and wasps perform elaborate learning flights, during which the location of the nest is memorised. These flights are characterised by a succession of arcs or loops of increasing radius centred around the nest, with an incremental increase in ground speed, which requires precise control of the flight manoeuvres by the insect. Here, we investigated the role of optic flow cues in the control of learning flights by manipulating spatial texture in the ventral and panoramic visual field. We measured height, lateral displacement relative to the nest and ground speed during learning flights in bumblebees when ventral and panoramic optic flow cues were present or minimised, or features of the ground texture varied in size. Our observations show that ventral optic flow cues were required for the smooth execution of learning flights. We also found that bumblebees adjusted their flight height in response to variations of the visual texture on the ground. However, the presence or absence of panoramic optic flow did not have a substantial effect on flight performance. Our findings suggest that bumblebees mainly rely on optic flow information from the ventral visual field to control their learning flights. PMID- 29980841 TI - Genetics of congenital eye malformations: insights from chick experimental embryology. AB - Embryological manipulations in chick embryos have been pivotal in our understanding of many aspects of vertebrate eye formation. This research was particularly important in uncovering the role of tissue interactions as drivers of eye morphogenesis and to dissect the function of critical genes. Here, we have highlighted a few of these past experiments to endorse their value in searching for hitherto unknown causes of rare congenital eye anomalies, such as microphthalmia, anophthalmia and coloboma. We have also highlighted a number of similarities between the chicken and human eye, which might be exploited to address other eye pathologies, including degenerative ocular diseases. PMID- 29980842 TI - A prospective cohort study of biopsychosocial factors associated with childhood urinary incontinence. AB - The objective of the study was to examine the association between biopsychosocial factors and developmental trajectories of childhood urinary incontinence (UI). We used developmental trajectories (latent classes) of childhood UI from 4-9 years including bedwetting alone, daytime wetting alone, delayed (daytime and nighttime) bladder control, and persistent (day and night) wetting (n = 8751, 4507 boys, 4244 girls). We examined whether biopsychosocial factors (developmental level, gestational age, birth weight, parental UI, temperament, behaviour/emotional problems, stressful events, maternal depression, age at initiation of toilet training, constipation) are associated with the trajectories using multinomial logistic regression (reference category = normative development of bladder control). Maternal history of bedwetting was associated with almost a fourfold increase in odds of persistent wetting [odds ratio and 95% confidence interval: 3.60 (1.75-7.40)]. In general, difficult temperament and behaviour/emotional problems were most strongly associated with combined (day and night) wetting, e.g. children with behavioural difficulties had increased odds of delayed (daytime and nighttime) bladder control [1.80 (1.59-2.03)]. Maternal postnatal depression was associated with persistent (day and night) wetting [2.09 (1.48-2.95)] and daytime wetting alone [2.38 (1.46-3.88)]. Developmental delay, stressful events, and later initiation of toilet training were not associated with bedwetting alone, but were associated with the other UI trajectories. Constipation was only associated with delayed bladder control. We find evidence that different trajectories of childhood UI are differentially associated with biopsychosocial factors. Increased understanding of factors associated with different trajectories of childhood UI could help clinicians to identify children at risk of persistent incontinence. PMID- 29980843 TI - Contribution of toxic shock syndrome toxin-1 to systemic inflammation investigated by a mouse model of cervicovaginal infection with Staphylococcus aureus. AB - Toxic shock syndrome toxin-1 (TSST-1), a superantigen produced by Staphylococcus aureus is a causative agent of toxic shock syndrome (TSS) that is frequently associated with tampon use. It has long been suggested that TSS is induced when TSST-1 circulates through the body. However, the systemic distribution of TSST-1 from vagina or uterus has never been demonstrated. In this study, a mouse cervicovaginal infection model was established. Transcervical inoculation with a virulence strain of S. aureus and its derivative TSST-1-deficient mutant demonstrated that TSST-1 distributed to the bloodstream and spleen, and promoted systemic inflammation without bacteremia. Transcervical administration with the wild-type toxin and a superantigen-deficient mutant of TSST-1 (mTSST-1) demonstrated that the superantigenic activity of TSST-1 was essential to stimulate the systemic inflammation. Furthermore, this activity was not promoted by co-transcervical inoculation with lipopolysaccharides. The circulating TSST-1 and systemic inflammation rapidly reduced at 48 h after administration, suggesting that persistence of S. aureus in the uterus may be involved in long term complications of TSS. Transcervical inoculation with mTSST-1-producing S. aureus showed that this toxin promoted bacterial number, uterine tissue damage, and localization of bacterial cells around uterine cavity. The results suggest that TSST-1 enhances S. aureus burden in uterine cavity, the secreted TSST-1 distributes into circulation system, and then systemic inflammation is induced. PMID- 29980844 TI - Intra- and interspecific densities shape life-history traits in a salmonid population. AB - Population dynamics can be regulated through intra- and interspecific density dependence. In species with close ecological requirements, interspecific competition for resources may add to intraspecific density, or even exceed its effect; it may impact single or multiple traits. However, the relative impact of intra- and interspecific densities on demographic parameters has been rarely empirically assessed. We analyzed 18 years of capture-mark-recapture data from brown trout (Salmo trutta) coexisting with Atlantic salmon (Salmo salar) during the juvenile freshwater phase in the Oir River (France) to estimate the relative effects of intra- and interspecific density on trout early life. In trout, a species with optional migration, we estimated the migration probability of young of-the-year trout out of their natal site, survival probability during the first winter, as well as body size, in relation to both intra- and interspecific density. Trout density correlated negatively with body size and with winter survival in resident trout but not with trout migration. Salmon density correlated positively with trout migration, but no impact was detected on trout body size or survival. Our study highlighted contrasting effects of intra- and interspecific density on trout early life, and the need to account for both factors when studying population dynamics in coexisting species. In particular, by affecting trout migration decision, salmon density may drive trout life history. PMID- 29980845 TI - Functional plasticity in vertebrate scavenger assemblages in the presence of introduced competitors. AB - Introduced species may suppress or enhance ecological functions, or they may have neutral effects in ecosystems where they replace or complement native species. Few studies, however, have explicitly tested for these trajectories, and for the effect these might have for native species. In this study, we experimentally test the trajectory and scale of change in the function of 'carrion removal' at different carrion loads along ocean beaches in Eastern Australia that have different numbers of introduced red foxes (Vulpes vulpes) and several species of native raptors. We hypothesized that the 'positive' effect of foxes on carrion removal would be greatest at high carrion loads, because competition for resources between native and introduced species is lower. Scavenger abundance, fox occurrences, and carrion consumption by these species differed widely between locations and times. Despite distinct spatial differences in the structure of vertebrate scavenger assemblages, total carrion consumption was not significantly different between locations at any carrion load. This lack of variation in functional rates indicates potential functional plasticity in the scavenger assemblage and possible functional accommodation of red foxes. Neutral fox effects on ecological functions or the ecosystem more broadly are, however, very unlikely to extend beyond carrion consumption. PMID- 29980847 TI - The "real-world" efficacy and safety of DAAs for the treatment of HCV patients throughout Japan. PMID- 29980846 TI - Post-reperfusion hydrogen gas treatment ameliorates ischemia reperfusion injury in rat livers from donors after cardiac death: a preliminary study. AB - BACKGROUND AND PURPOSE: We reported previously that hydrogen gas (H2) reduced hepatic ischemia and reperfusion injury (IRI) after prolonged cold storage (CS) of livers retrieved from heart-beating donors. The present study was designed to assess whether H2 reduced hepatic IRI during donation of a cardiac death (DCD) graft with subsequent CS. METHODS: Rat livers were harvested after 30-min cardiac arrest and stored for 4 h in University of Wisconsin solution. The graft was reperfused with oxygenated buffer, with or without H2 (H2 or NT groups, respectively), at 37 degrees for 90 min on isolated perfused rat liver apparatus. RESULTS: In the NT group, liver enzyme leakage, apoptosis, necrosis, energy depletion, redox status, impaired microcirculation, and bile production were indicative of severe IRI, whereas in the H2 group these impairments were significantly suppressed. The phosphorylation of cytoplasmic MKK4 and JNK were enhanced in the NT group and suppressed in the H2 group. NFkB-p65 and c-Fos in the nucleus were unexpectedly unchanged by IRI regardless of H2 treatment, indicating the absence of inflammation in this model. CONCLUSION: H2 was observed to ameliorate IRI in the DCD liver by maintaining microcirculation, mitochondrial functions, and redox status, as well as suppressing the cytoplasmic MKK4-JNK mediated cellular death pathway. PMID- 29980849 TI - Protocol biopsies in pediatric renal transplantation: a precious tool for clinical management. AB - BACKGROUND: Kidney transplantation is the best treatment for children with end stage kidney disease. Early results have improved, but late graft loss is still a major problem. Non-invasive, fully reliable early biomarkers of acute rejection are currently missing. METHODS: Our aim was to evaluate the efficacy of protocol biopsies (PBXs) in a pediatric population. During 11 years, 209 renal transplantations were performed in 204 pediatric patients. Biopsies were performed 3-6 months, 1 year, and 5 years after transplantation. Procedure related complications were systematically looked for by means of ultrasound scans. RESULTS: Unexpected findings (mainly subclinical rejections) requiring therapeutic intervention were found in 19.3% biopsies performed at 3-6 months, in 18.4% in 12-month biopsies and in none of those performed after 5 years. The 13.6% patients at 12-month biopsies and 23.6% at 5-year biopsies showed calcineurin inhibitor (CNI) toxicity. Interstitial fibrosis and tubular atrophy (IF/TA) was found in 17.6 and 83.6% of patients at 12-month and 5-year biopsies, respectively. Complications of the PBX were infrequent. Five-year estimated glomerular filtration rate (GFR) was not significantly different in patients who received treatment for any cause and patients with normal histology. CONCLUSIONS: Although we do not have a control group, we may speculate that patients who received treatment returned to a "standard" condition possibly improving final outcome. Protocol biopsies are a powerful diagnostic tool for the management of pediatric renal transplant recipients. In view of the lack of evidence that biopsies taken 5 years after transplantation lead to any therapeutic change, their use should be reconsidered. PMID- 29980848 TI - The state of the art on treatment of Crohn's disease. AB - Crohn's disease (CD) is a chronic, progressive, and destructive disease of the gastrointestinal tract. Although its incidence appears to be stable or decreasing in most countries in the North America and Europe, the incidence is rising rapidly in Asian countries. Immunomodulators and biologics are increasingly used to avoid long-term bowel damage and subsequent disability. Therapeutic drug monitoring facilitates optimizing thiopurines and anti-TNFs use. New biologic agents targeting various pathological pathways of CD are blooming in recent years, and the high cost of biologics and expiration of patents for several biologic agents have driven the utility of biosimilars for CD treatment. Here, the literature regarding the efficacy, safety, and withdrawal of the drugs, as well as the evolution of therapeutic targets will be reviewed. PMID- 29980850 TI - Leptin and ghrelin in chronic kidney disease: their associations with protein energy wasting. AB - BACKGROUND: This study aimed to evaluate plasma concentrations of leptin and total ghrelin in children with chronic kidney disease (CKD) and assess their roles in protein-energy wasting (PEW). METHODS: This study consisted of three different CKD populations [CKD group (20 patients with non-dialysis CKD), dialysis group (39 patients on dialysis), and kidney transplant (KTx) group (35 KTx recipients)] and control group (18 healthy children). Plasma leptin and total ghrelin levels were measured. Multi-frequency bioimpedance analysis was used for the assessment of fat and lean mass. PEW was defined using criteria including body mass, muscle mass, growth, serum albumin level, and protein intake. RESULTS: While plasma leptin levels did not differ among the study groups, total ghrelin levels were significantly higher in the dialysis group (P < 0.001). Seven dialysis patients (18%) and one CKD patient (5%) but none of the KTx recipients met the criteria of PEW. Dialysis patients with PEW had lower plasma leptin levels compared to their counterparts (P = 0.018); however, total ghrelin levels did not differ between the two groups (P = 0.10). Low leptin level in dialysis patients was independently associated with lower fat mass index (P < 0.001) and lower height-specific SD scores of BMI (P = 0.019). CONCLUSIONS: PEW is prevalent in dialysis patients. Low levels of leptin seem to be associated with PEW. Our result suggests that low leptin levels may be a consequence rather than a cause of PEW. Longitudinal studies are required to investigate this complex relationship between leptin and PEW in pediatric dialysis patients. PMID- 29980851 TI - Effects of acute ingestion of whey protein with or without prior aerobic exercise on postprandial glycemia in type 2 diabetics. AB - PURPOSE: Acute protein co-ingestion or a single bout of aerobic exercise can attenuate postprandial glycemia, but their combined effect has not been investigated in type 2 diabetics. METHODS: Using a randomised crossover design, male type 2 diabetics (n = 8) [mean (95% CI); age, 55.0 (45.2, 64.8) year; BMI, 33.7 (25.6, 41.8) kg.m- 2; 2 h glucose 14.0 (12.5, 15.5) mM] completed (1) 75 g oral glucose tolerance test (OGTT) (CON); (2) OGTT supplemented with 0.33 g.kg BM 1 of whey protein concentrate (PRO); or OGTT supplemented with PRO but preceded by a bout of aerobic cycling exercise (PRO + EX). Postprandial venous blood samples were collected for glucose, insulin, C-peptide and glucagon. RESULTS: Despite a fold-increase of 1.90 (1.26, 2.56; p < 0.05) in postprandial insulin compared to CON, PRO failed to attenuate postprandial glycemia measured by 2 h glucose area under the curve. During PRO + EX, plasma glucose was elevated by 1.51 (0.5, 2.5) mM and 1.3 (0.3, 2.3) mM at 15 and 30 min, respectively, compared to CON, but was lower by 1.60 (0.6, 2.6) mM and 1.5 (0.5, 2.5) mM at 90 and 120 min, respectively (all p < 0.01). The additive effect of exercise and protein ingestion resulted in a fold-increase of 1.67 (1.35, 2.00; p < 0.05) in postprandial glucagon compared to CON. CONCLUSION: In type 2 diabetics, prior aerobic exercise altered the humoral response to co-ingestion of whey protein with a carbohydrate load, but neither protein ingestion alone nor when preceded by prior exercise attenuated postprandial glycemia. PMID- 29980852 TI - Genetic characterization of a new astrovirus in goslings suffering from gout. AB - Since early 2016, the Chinese goose industry has experienced severe outbreaks of gout; however, the etiological factor of the disease is still unclear. Here, we investigated the possible involvement of viral infection in the disease. Using sequence-independent PCR amplification, astrovirus sequences were generated from a gout case. Full-length genomic sequencing and sequence analysis of three goose astrovirus (GoAstV) strains revealed that they belong to a new avastrovirus most closely related to viruses classified within species Avastrovirus 3. The GoAstV was detected in 16/16 gout cases collected from two provinces, supporting a pathogenic role for the new avastrovirus. PMID- 29980854 TI - Sneddon syndrome and non-bacterial thrombotic endocarditis: a clinicopathological study. PMID- 29980853 TI - Dysfunctional inhibitory control in Parkinson's disease patients with levodopa induced dyskinesias. AB - INTRODUCTION: Chronic dopamine replacement therapies in Parkinson's disease can induce side effects, such as levodopa-induced dyskinesias and impulse control disorders. A dysfunction of inhibitory brain networks has been related to both disorders; however, there is no clear behavioral evidence supporting this hypothesis. We aimed to determine whether PD patients with levodopa-induced dyskinesias show features of increased impulsivity in parallel with altered motor inhibition. METHODS: Two matched samples of Parkinson's disease patients with (n = 14) or without (n = 14) levodopa-induced dyskinesias and a control group (n = 10) participated in the study. All groups were evaluated by the Barratt Impulsiveness Scale-11 to assess impulsivity traits. Furthermore, participants performed a stop signal task to evaluate reactive-motor inhibition and a Go/NoGo task to evaluate proactive-inhibitory control. PD patients were tested both in OFF and ON levodopa medication. RESULTS: Parkinson's disease patients with levodopa-induced dyskinesias showed higher impulsivity scores than PD patients without levodopa-induced dyskinesias. Dyskinetic patients presented also delayed stop signal reaction times indicating a worse performance in reactive inhibition. The slowness in inhibiting a motor command correlated with the impulsiveness scores. Furthermore, in the dyskinetic group, a positive correlation was found between stop reaction times and the severity of involuntary movements. Under the effect of levodopa, all patients were faster but dyskinetic patients were significantly less accurate in proactive inhibition. CONCLUSION: Inhibitory control is compromised in dyskinetic patients in parallel with increased impulsivity, revealing an impairment of motor and behavioral inhibitory control in Parkinson's disease patients with levodopa-induced dyskinesias. PMID- 29980855 TI - Analysis of QTL-allele system conferring drought tolerance at seedling stage in a nested association mapping population of soybean [Glycine max (L.) Merr.] using a novel GWAS procedure. AB - MAIN CONCLUSION: RTM-GWAS identified 111 DT QTLs, 262 alleles with high proportion of QEI and genetic variation accounting for 88.55-95.92% PV in NAM, from which QTL-allele matrices were established and candidate genes annotated. Drought tolerance (DT) is one of the major challenges for world soybean production. A nested association mapping (NAM) population with 403 lines comprising two recombinant inbred line (RIL) populations: M8206 * TongShan and ZhengYang * M8206 was tested for DT using polyethylene-glycol (PEG) treatment under spring and summer environments. The population was sequenced using restriction-site-associated DNA sequencing (RAD-seq) filtered with minor allele frequency (MAF) >= 0.01, 55,936 single nucleotide polymorphisms (SNPs) were obtained and organized into 6137 SNP linkage disequilibrium blocks (SNPLDBs). The restricted two-stage multi-locus genome-wide association studies (RTM-GWAS) identified 73 and 38 QTLs with 174 and 88 alleles contributed main effect 40.43 and 26.11% to phenotypic variance (PV) and QTL-environment interaction (QEI) effect 24.64 and 10.35% to PV for relative root length (RRL) and relative shoot length (RSL), respectively. The DT traits were characterized with high proportion of QEI variation (37.52-41.65%), plus genetic variation (46.90-58.40%) in a total of 88.55-95.92% PV. The identified QTLs-alleles were organized into main-effect and QEI-effect QTL-allele matrices, showing the genetic and QEI architecture of the three parents/NAM population. From the matrices, the possible best genotype was predicted to have a weighted average value over two indicators (WAV) of 1.873, while the top ten optimal crosses among RILs with 95th percentile WAV 1.098-1.132, transgressive over the parents (0.651-0.773) but much less than 1.873, implying further pyramiding potential. From the matrices, 134 candidate genes were annotated involved in nine biological processes. The present results provide a novel way for molecular breeding in QTL-allele-based genomic selection for optimal cross selection. PMID- 29980856 TI - Response to 'Aberrant expression of TdT in seminomatous germ cell neoplasia'. PMID- 29980857 TI - [Screening and management of retinal diseases using digital medicine]. AB - BACKGROUND: Modern retinal imaging creates gigantic amounts of data (big data) of anatomic information. At the same time patient numbers and interventions are increasing exponentially. OBJECTIVE: Introduction of artificial intelligence (AI) for optimization of personalized therapy and diagnosis. MATERIAL AND METHODS: Deep learning was introduced for automated segmentation and recognition of risk factors and activity levels in retinal diseases. RESULTS: Automated algorithms enable the precise identification and quantification of retinal fluid in all compartments. Early detection of retinopathy in diabetes or glaucoma or risk determination for the development of age-related macular degeneration (AMD) are possible as well as an individual visual prognosis and evaluation of the need for retreatment in intravitreal injection therapy. CONCLUSION: Methods using AI constitute a breakthrough perspective for the introduction of individualized medicine and optimization of diagnosis and therapy, screening and prognosis. PMID- 29980858 TI - [Glaucoma in inpatient care in Germany in 2015]. AB - AIM: Analysis of structural characteristics of inpatient treatment of glaucoma in clinical units run by affiliated physicians and those run by hospital physicians in Germany are described. The frequency and distribution of glaucoma diagnoses as the main and secondary diagnosis at different departments and glaucoma diagnoses, number of cases, surgeries and procedures and patient characteristics of the four glaucoma-specific diagnosis-related groups (DRG) are presented. METHOD: Secondary data analysis using the G-DRG browser from 2015/2016 provided by the German Institute for Remuneration Systems in Hospitals. RESULTS: In 30% of the 156,524 cases glaucoma was classified as the main diagnosis, in 24% as secondary diagnosis in ophthalmological departments and 46% as secondary diagnosis in other departments. Primary open angle glaucoma was reported most frequently (40%), whilst non-ophthalmological departments mainly coded as "other" or "unspecified types of glaucoma". Glaucoma was coded in 20 DRGs as the main diagnosis and in all ophthalmic DRGs as secondary diagnosis. The number of cases and procedures differed among the four glaucoma-specific DRGs (C06Z, C07A, C07B, C64Z), the diagnostic spectrum, however, was similar. Patients were mainly women, older and with few comorbidities or complications. The C64Z was mainly characterized by cases with "suspected glaucoma" and only conservative procedures. Only 6% of the glaucoma patients were treated in clinical units run by affiliated physicians. In contrast to units run by hospital physicians surgical DRGs and operations prevailed but the diagnostic spectrum and patient characteristics were not different. DISCUSSION AND CONCLUSION: With 20% of the main diagnoses, glaucoma was highly relevant for inpatient ophthalmological care. Glaucoma as a secondary diagnosis was also common in other medical specialties, though no diagnostic differentiation was made here. Patients with glaucoma are mainly treated in clinical units run by hospital physicians. Nevertheless, patients of affiliated physicians showed the same characteristics. PMID- 29980859 TI - Current concepts in radiologic assessment of pediatric brain tumors during treatment, part 1. AB - Pediatric brain tumors differ from those in adults by location, phenotype and genotype. In addition, they show dissimilar imaging characteristics before and after treatment. While adult brain tumor treatment effects are primarily assessed on MRI by measuring the contrast-enhancing components in addition to abnormalities on T2-weighted and fluid-attenuated inversion recovery images, these methods cannot be simply extrapolated to pediatric central nervous system tumors. A number of researchers have attempted to solve the problem of tumor assessment during treatment in pediatric neuro-oncology; specifically, the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was recently established to deal with the distinct challenges in evaluating treatment related changes on imaging, but no established criteria are available. In this article we review the current methods to evaluate brain tumor therapy and the numerous challenges that remain. In part 1, we examine the role of T2-weighted imaging and fluid-attenuated inversion recovery sequences, contrast enhancement, volumetrics and diffusion imaging techniques. We pay particular attention to several specific pediatric brain tumors, such as optic pathway glioma, diffuse midline glioma and medulloblastoma. Finally, we review the best means to assess leptomeningeal seeding. PMID- 29980860 TI - Ultrasound-based measurements of testicular volume in 6- to 16-year-old boys - intra- and interobserver agreement and comparison with Prader orchidometry. AB - BACKGROUND: Prader orchidometry has been the standard method for evaluating testicular size. As this technique is subjective and tends to overestimate the testicular volume, ultrasound (US) has been proposed as more reliable. OBJECTIVE: To evaluate the intra- and interobserver agreement of US measurements of testicular volume and to compare US with the Prader orchidometer. MATERIALS AND METHODS: Dimensions of the right testicle were measured using US in 57 boys ages 6.5 to 16.4 years (mean: 12.0 years). The measurements were performed twice by one main observer and once by a second observer. A third observer estimated testicular volume using a Prader orchidometer. Agreement was investigated with Bland-Altman plots, summarized as the mean and standard deviation (SD) of differences, 95% limits of agreement and technical error of measurement. RESULTS: Mean intra-observer difference of testicular volume was 2.2%, SD=9.2% (limits of agreement: -20.3 to 15.9%) and technical error of measurement 6.5%. The mean interobserver difference was 4.8%, SD=20.7% (limits of agreement: -35.7 to 45.3%) and technical error of measurement 14.6%. Comparing US and orchidometer volumes required conversion that was nonlinear and volume dependent, estimated as VolOM = 1.96*VolUS0.71. The mean difference after transformation was 0.7% with an SD of 18.0% (limits of agreement: -34.5 to 35.9%). CONCLUSION: Our results showed a small mean intra- and interobserver difference that indicates the potential of US for measurement of testicular volume at group level. The intra-observer error was limited, which justifies its use in longitudinal follow-up of testicular development in an individual child, but the larger interobserver variability indicates the need for good standardization of methods. Agreement between the two methods requires a power transformation. PMID- 29980861 TI - Multiphase acquisitions in pediatric abdominal-pelvic CT are a common practice and contribute to unnecessary radiation dose. AB - BACKGROUND: Many patients at our pediatric hospital have had a contrast-enhanced CT of the abdomen and pelvis performed by an outside imaging facility before admission. We have noticed that many of these exams are multiphase, which may contribute to unnecessary radiation dose. OBJECTIVE: To determine the frequency of multiphase acquisitions and radiation dose indices in contrast-enhanced CTs of the abdomen and pelvis performed by outside imaging facilities in patients who were subsequently transferred to our pediatric hospital for care, and compare these metrics to contrast-enhanced CTs of the abdomen and pelvis performed internally. MATERIALS AND METHODS: A retrospective analysis was performed of contrast-enhanced CTs of the abdomen and pelvis from outside imaging facilities uploaded to our picture archiving and communication system (PACS) between January 1, 2012, and December 31, 2015. CT images and dose pages were reviewed to determine the number of phases and dose indices (CT dose index-volume [CTDIvol], dose-length product, size-specific dose estimate). Exams for abdominal or pelvic mass, trauma or urinary leak indications were excluded. Data were compared to internally acquired contrast-enhanced CTs of the abdomen and pelvis by querying the American College of Radiology (ACR) Dose Index Registry. This review was institutional review board and HIPAA compliant. RESULTS: There were 754 contrast enhanced CTs of the abdomen and pelvis from 104 outside imaging facilities. Fifty three percent (399/754) had 2 phases, and 2% (14/754) had 3 or more phases. Of the 939 contrast-enhanced CTs of the abdomen and pelvis performed internally, 12% (115) were multiphase exams. Of 88% (664) contrast-enhanced CTs of the abdomen and pelvis from outside imaging facilities with dose data, CTDIvol was 2.7 times higher than our institution contrast-enhanced CTs of the abdomen and pelvis (939) for all age categories as defined by the ACR Dose Index Registry (mean: 9.4 vs. 3.5 mGy, P<0.0001). The majority (74%) of multiphase exams were performed by 9 of 104 outside imaging facilities. CONCLUSION: Multiphase acquisitions in routine contrast-enhanced CT of the abdomen and pelvis exams at outside imaging facilities are more frequent than those at a dedicated pediatric institution and contribute to unnecessary radiation dose. A contrast-enhanced CT of the abdomen and pelvis exam from an outside imaging facility with two passes may have as much as four times to six times the dose as the same exam performed with a single pass at a pediatric imaging center. We advocate for imaging facilities with high multiphase rates to eliminate multiple phases from routine contrast-enhanced CT of the abdomen and pelvis exams in children. PMID- 29980863 TI - Fabrication of chitin/graphene oxide composite sponges with higher bilirubin adsorption capacity. AB - Chitin/graphene oxide (Ch/GO) composite sponges had been synthesized in 11 wt% NaOH/4 wt% urea aqueous solution by a simple method. The structure, thermal stability and mechanical properties of the composite sponges were investigated by scanning electron microscopy, Fourier-transform infrared spectroscopy, wide-angle X-ray diffraction, thermogravimetric analysis, and compressive strength measurements. The results revealed that chitin and GO were mixed homogeneously. Interestingly, the composite sponges showed meso-macroporous structure, which played an important role in improving their adsorption properties. Besides, thermal stability and mechanical properties were significantly improved compared with pure chitin sponges. Taking advantages of these fantastic characteristics, the maximum adsorption capacity of composite sponges for bilirubin was up to 422.9 mg/g under the optimized condition, which was not only significantly higher than the adsorption capacities of pure chitin sponges, but also superior to those of many reported adsorbents for removal of bilirubin. Furthermore, blood compatibility evaluations confirmed that this blended sponges had negligible hemolysis and coagulation. Therefore, this work provided a potential possibility to offer Ch/GO composite sponges for removal of bilirubin. PMID- 29980862 TI - Biodegradation of chlorpropham and its major products by Bacillus licheniformis NKC-1. AB - Chlorpropham [isopropyl N-(3-chlorophenyl) carbamate] (CIPC), an important phenyl carbamate herbicide, has been used as a plant growth regulator and potato sprout suppressant (Solanum tuberosum L) during long-term storage. A bacterium capable of utilizing the residual herbicide CIPC as a sole source of carbon and energy was isolated from herbicide-contaminated soil samples employing selective enrichment method. The isolated bacterial strain was identified as Bacillus licheniformis NKC-1 on the basis of its morphological, cultural, biochemical characteristics and also by phylogenetic analysis based on 16S rRNA gene sequences. The organism degraded CIPC through its initial hydrolysis by CIPC hydrolase enzyme to yield 3-chloroaniline (3-CA) as a major metabolic product. An inducible 3-CA dioxygenase not only catalyzes the incorporation of molecular oxygen but also removes the amino group by the deamination yielding a monochlorinated catechol. Further, degradation of 4-chlorocatechol proceeded via ortho- ring cleavage through the maleylacetate process. 3-Chloroaniline and 4 chlorocatechol are the intermediates in the CIPC degradation which suggested that dechlorination had occurred after the aromatic ring cleavage. The presence of these metabolites has been confirmed by using ultra-violet (UV), high-performance liquid chromatography (HPLC), thin layer chromatography (TLC), Fourier transmission-infrared (FT-IR), proton nuclear magnetic resonance (1H NMR) and gas chromatography-mass (GC-MS) spectral analysis. Enzyme activities of CIPC hydrolase, 3-CA dioxygenase and chlorocatechol 1, 2-dioxygenase were detected in the cell-free-extract of the CIPC culture and are induced by cells of NKC-1 strain. These results demonstrate the biodegradation pathways of herbicide CIPC and promote the potential use of NKC-1 strain to bioremediate CIPC-contaminated environment with subsequent release of ammonia, chloride ions and carbon dioxide. PMID- 29980864 TI - Determination and quantification of asiaticoside in endophytic fungus from Centella asiatica (L.) Urban. AB - Centella asiatica (L.) Urban is a highly considered medicinal plant owing to its secondary metabolites asiaticoside, madecassoside, asiatic acid, and madecassic acid. The asiaticoside, one of the most important constituents of the plant, is a triterpenoid saponin having memory enhancement property. Given its medicinal properties, we isolated and characterized endophytic fungi from this plant with the aim to screen these microorganisms for asiaticoside production. In total, we isolated 13 endophytic fungi from the leaves of the plant, out of which one of the isolates produced asiaticoside. This asiaticoside producing isolate was identified as Colletotrichum gloeosporioides by internal transcribed spacer-based rDNA sequencing. The presence of asiaticoside in ethyl acetate extract of C. gloeosporioides was confirmed by LC-MS. The production of asiaticoside measured in relation to incubation time and subculture generation revealed presence of 62.29 +/- 3.36 ug/100 mL of asiaticoside by C. gloeosporioides on the 15th day in first subculture generation followed by a decrease in subsequent generations. A similar trend was also shown by yield and growth curve of C. gloeosporioides. The asiaticoside production and yield were found to be positively correlated. This paper reported the production of asiaticoside by an endophytic fungus C. gloeosporioides for the first time. The present findings definitely provide an impetus to the production of asiaticoside by utilizing the endophytic source. Chemical compound studied in this article: Asiaticoside (PubChemCID: 108062). PMID- 29980867 TI - Investigation of copper inhibition of nitrifying moving bed biofilm (MBBR) reactors during long term operations. AB - Copper, a prevalent heavy metal in industrial mining wastewaters, has been shown to inhibit nitrification in wastewater treatment systems. Biofilm treatment systems have an inherent potential to reduce inhibition. This study investigated the effects of copper concentration on nitrifying biofilms in moving bed biofilm reactor (MBBR) systems across long term operation using influent ammonia concentrations representative of gold mining wastewater. Conventional isotherm models did not adequately model the attachment of copper to the biofilm. Long term nitritation was shown to be uninhibited at influent copper concentrations between 0.13 and 0.61 mg Cu/L. Nitratation was inhibited with influent copper concentrations of 0.28-0.61 mg Cu/L. There was no statistical difference in biofilm characteristics, including biofilm thickness, mass and density, across all copper concentrations tested, however, changes in biofilm morphology were observed. The demonstrated resistance of the nitrifying biofilm to copper inhibition makes the MBBR system a promising technology for treating ammonia in mining wastewaters. PMID- 29980866 TI - Evaluation and Management of Stage 2 Hypertension in Pediatric Patients. AB - PURPOSE OF REVIEW: To update the definition and clinical practice of stage 2 hypertension (HTN) in pediatrics. RECENT FINDINGS: The 2017 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) for Screening and Management of High Blood Pressure in Children and Adolescent includes new normative blood pressure tables for children and adolescents ages 1 to 17 years and new definitions for stage 2 HTN. This review will highlight these aspects as well as new recommendations in the guideline specific to stage 2 HTN. It will outline how the new guideline differs from the previous 2004 guideline, the implications of these differences, and suggested changes in evaluation and management of stage 2 HTN. Lastly, the review will address topics relevant to daily clinical practice including competitive athletic participation, investigation for secondary HTN and HTN comorbidities, and blood pressure-lowering therapy. With the publication of the new AAP CPG introducing revised normative tables, the prevalence of stage 2 HTN in pediatrics is expected to rise. Based on the new guidelines, there is less emphasis on investigation for secondary HTN and more attention to lifestyle modifications for primary HTN. Future research should address whether there is BP level within the stage 2 HTN range above which the approach to evaluation and management should be altered in this heterogeneous patient population. PMID- 29980865 TI - Future Direction for Using Artificial Intelligence to Predict and Manage Hypertension. AB - PURPOSE OF REVIEW: Evidence that artificial intelligence (AI) is useful for predicting risk factors for hypertension and its management is emerging. However, we are far from harnessing the innovative AI tools to predict these risk factors for hypertension and applying them to personalized management. This review summarizes recent advances in the computer science and medical field, illustrating the innovative AI approach for potential prediction of early stages of hypertension. Additionally, we review ongoing research and future implications of AI in hypertension management and clinical trials, with an eye towards personalized medicine. RECENT FINDINGS: Although recent studies demonstrate that AI in hypertension research is feasible and possibly useful, AI-informed care has yet to transform blood pressure (BP) control. This is due, in part, to lack of data on AI's consistency, accuracy, and reliability in the BP sphere. However, many factors contribute to poorly controlled BP, including biological, environmental, and lifestyle issues. AI allows insight into extrapolating data analytics to inform prescribers and patients about specific factors that may impact their BP control. To date, AI has been mainly used to investigate risk factors for hypertension, but has not yet been utilized for hypertension management due to the limitations of study design and of physician's engagement in computer science literature. The future of AI with more robust architecture using multi-omics approaches and wearable technology will likely be an important tool allowing to incorporate biological, lifestyle, and environmental factors into decision-making of appropriate drug use for BP control. PMID- 29980868 TI - A surgical strategy for lower grade gliomas using intraoperative molecular diagnosis. AB - Lower grade gliomas are both treated and diagnosed via surgical resection. Maximum tumor resection is currently the standard of care; however, this risks the loss of brain function. Glioma can be genetically subdivided into three different types, based on isocitrate dehydrogenase (IDH) mutation status and the presence of 1p/19q codeletion, which have radically different prognoses and responses to adjuvant therapies. Therefore, the means to identify the subtype and evaluate the surrounding tissues during surgery would be advantageous. In this study, we have developed a new surgical strategy for lower grade glioma based on the fourth edition of the World Health Organization Brain Tumor Classification, involving intraoperative molecular diagnosis. High-resolution melting analysis was used to evaluate IDH mutational status, while rapid immunohistochemistry of p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) was used to evaluate the 1p/19q codeletion status, allowing genetic classification during surgery. In addition, intraoperative flow cytometry was used to evaluate the surgical cavity for additional tumor lesions, allowing maximal resection while mitigating the risk of functional losses. This strategy allows the rapid intraoperative diagnosis and mapping of lower grade gliomas, and its clinical use could dramatically improve its prognosis. PMID- 29980869 TI - Change in the quality of life of caregivers of pediatric department patients undergoing kidney transplantation: a single-center prospective study. AB - BACKGROUND: Caregivers of patients with chronic kidney disease experience great burdens. Changes in these caregivers' quality of life (QOL) before and after their children underwent kidney transplantation (KTx) were evaluated in this prospective study. METHODS: The sequential QOL scores of 31 caregivers (median age 38.5 years) whose children (5.8 years) underwent KTx from 2012 to 2014 were studied. The same questionnaires were administered before and 1, 3, and 12 months after KTx. We evaluated whether the following factors were associated with QOL: pre-transplant dialysis, recipient's mental and/or motor disability, and acute rejection or infections after KTx. RESULTS: The average QOL score before KTx (3.40) was higher than that of the general population (3.23). Despite a temporal decrease at 1 month (3.15), the final QOL scores were maintained at 3 months (3.40) and 1 year (3.42) after KTx. The mean QOL scores were significantly higher for caregivers of patients with than without dialysis before KTx [3.46 vs. 3.28 (p = 0.041) at 3 months and 3.53 vs. 3.18 (p = 0.001) at 1 year, respectively]. Conversely, these scores were significantly lower for caregivers of patients with than without disabilities [2.97 vs. 3.20 (p = 0.021) at 1 month, 3.18 vs. 3.46 (p = 0.006) at 3 months, and 3.10 vs. 3.50 (p = 0.001) at 1 year, respectively]. CONCLUSION: Dialysis of children before KTx was a particularly larger burden for caregivers. The child's comorbidities and social adaptation problems might be focused after KTx, we need to evaluate for more long-term QOL of caregivers. PMID- 29980870 TI - Changes in conjunctival-scleral thickness after strabismus surgery measured with anterior segment optical coherence tomography. AB - PURPOSE: To evaluate changes in conjunctival-scleral thickness following strabismus surgery with anterior segment optical coherence tomography (AS-OCT). STUDY DESIGN: Prospective, observational, consecutive case series. METHODS: Distances between the conjunctival epithelium and inner scleral wall were measured with AS-OCT before and 3-5 months after strabismus surgery. The measurements were performed at 1.5 mm (limbus), 7.0 mm (insertion), and 8.0 mm (tendon) posterior to the scleral spur on the lateral rectus muscle (LR); and 1.5 mm (limbus), 4.0 mm (insertion), and 5.5 mm (tendon) posterior to the scleral spur on the medial rectus muscle (MR). Thirty-three extraocular muscles (20 LRs and 13 MRs) from 23 subjects were studied. RESULTS: Thicknesses were significantly less at the insertion (0.95-0.78 mm; p < 0.001) and tendon (0.99 0.78 mm; p < 0.001) after LR recession and at the tendon (1.21-0.92 mm; p = 0.02) after MR recession. Thicknesses were significantly greater at the insertion (0.82 1.07 mm; p = 0.01) and tendon (0.95-1.28 mm; p = 0.01) after MR resection or plication and at the limbus, insertion, and tendon (0.75-0.90 mm, 0.94-1.19 mm, 1.03-1.28 mm, respectively; all p = 0.04) after LR resection or plication. CONCLUSION: Conjunctival-scleral thicknesses showed various changes after recession and resection or plication. These findings may help detect previous surgical operations when conjunctival scarring and ciliary vessel changes are unclear. PMID- 29980871 TI - Classical Hodgkin lymphoma-type and monomorphic-type post-transplant lymphoproliferative disorder following liver transplantation: a case report. AB - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a life threatening complication that can be difficult to treat; moreover, determination of the pathophysiological type is difficult. We report a rare case of a patient who developed two types of Epstein-Barr virus (EBV)-negative PTLD following living donor liver transplantation (LDLT). CASE PRESENTATION: A 64-year-old man underwent LDLT for acute fulminant hepatitis B. Sixty-five months later, he developed EBV-negative monomorphic B cell PTLD. Reduction of immunosuppressive therapy and chemotherapy with rituximab resulted in a partial response. He received radioimmunotherapy with yttrium-90-ibritumomab tiuxetan, which was effective for all lesions, except for the splenic hilar lesion, which enlarged and seemed to penetrate the stomach. Therefore, he underwent resection of the pancreatic tail with splenectomy and partial gastrectomy. The pathological diagnosis was EBV-negative classical Hodgkin lymphoma (cHL)-type PTLD. CONCLUSIONS: This patient showed an unexpected course of PTLD, from both a clinical and pathological perspective. There are no prior reports of an adult case of EBV-negative cHL-type PTLD coexisting with EBV-negative monomorphic B cell PTLD. When a strange and refractory lesion persists despite effective therapy for PTLD, we must consider the possibility of another type of PTLD within the residual lesion. PMID- 29980872 TI - Imaging of acute ischemic stroke. AB - For decades, imaging has been a critical component of the diagnostic evaluation and management of patients suspected of acute ischemic stroke (AIS). With each new advance in the treatment of AIS, the role of imaging has expanded in scope, sophistication, and importance in selecting patients who stand to benefit from potential therapies. Although the field of stroke imaging has been evolving for many years, there have been several major recent changes. Most notably, in late 2017, the window for treatment expanded to 24 h from onset of stroke symptoms in selected patients. Furthermore, for those patients in expanded time windows, guidelines issued in early 2018 now recommend the use of "advanced" imaging techniques in the acute setting, including CT perfusion and MRI, to guide therapeutic decision-making. With these and other changes, the emergency radiologist must be prepared to handle a growing volume and complexity of AIS imaging. This article reviews the various imaging modalities and techniques employed in the imaging of AIS patients, with an emphasis on recommendations from recent randomized controlled trials and national consensus guidelines. PMID- 29980873 TI - A novel compound heterozygous mutation of the L2HGDH gene in a Chinese boy with L 2-hydroxyglutaric aciduria: case report and literature review. AB - OBJECTIVE: L-2-hydroxyglutaric aciduria is a genetic metabolic disorder. Its clinical features include elevated levels of hydroxyglutaric acid in body fluids and abnormal magnetic resonance imaging (MRI) in the subcortical white matter, which are affected by the accumulation of L-2-hydroxyglutaric acid. METHOD: A boy with psychomotor retardation and progressive ataxia accompanied by abnormal brain MRI findings was tested using whole-exome sequencing. RESULTS: Next-generation sequencing (NGS) revealed two novel compound heterozygous frameshift mutations, c.407 del A (p.K136SfsTer3) and c.699_c700 ins A (p.D234RfsTer42), in the L-2 hydroxyglutarate dehydrogenase (L2HGDH) gene, leading to premature termination codons and truncated FAD/NAD(P)-binding domain of L2HGDH protein. Further laboratory testing revealed an increase in the 2-hydroxyglutaric acid level in the urine. CONCLUSION: The results suggested that NGS could provide clues for identifying patients with abnormal neuroradiological findings in the subcortical white matter. PMID- 29980874 TI - Long-term remission of refractory Rosai-Dorfman disease after salvage therapy with clofarabine in an adult patient. PMID- 29980875 TI - Structural modeling of a novel TERC variant in a patient with aplastic anemia and short telomeres. PMID- 29980876 TI - Diagnostic accuracy of miRNAs as potential biomarkers for systemic lupus erythematosus: a meta-analysis. AB - To systematically evaluate the diagnostic accuracy of miRNAs as potential biomarkers for systemic lupus erythematosus (SLE). Studies were searched in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and China Biology Medicine (CBM) disc database, and languages were limited in English and Chinese. QUADAS-2 tool was applied to assess the quality of eligible studies. Random-effect model was applied to calculate pooled effects of miRNAs on diagnosing SLE. Subgroup analysis was used to explore the sources of heterogeneity. All data were calculated and analyzed by Meta-Disc 1.4 and RevMan 5.3 software. Six eligible studies were included in this meta-analysis. The pooled sensitivity, specificity, and diagnostic odds ratio of miRNAs were 0.75(95% CI 0.71-0.79), 0.72(95% CI 0.66-0.78), and 8.79(95% CI 4.91-15.73), respectively. The pooled positive likelihood ratio was 2.71(95% CI 2.20-3.33) and negative likelihood ratio was 0.34(95% CI 0.24-0.48). The area under the curve was 0.787. The subgroup analysis showed that the number of healthy controls might be the sources of heterogeneity. MiRNAs in blood have moderate accuracy and influence on diagnosing SLE, and the exact diagnostic value should be confirmed by further studies. PMID- 29980877 TI - Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in Behcet's disease: which and when to use? AB - Behcet's disease (BD) is an uncommon autoimmune/autoinflammatory disease. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were investigated in many diseases as a marker of inflammation. In this study, we investigated NLR and PLR in patients with BD as a marker of disease activity and its association with different clinical manifestations. The study included 23 BD patients; their mean age was (32.5 +/- 6.76) and M:F ratio was 16:7. Complete blood picture was done for all patients. NLR and PLR were compared in both active and inactive BD patients and its relation with different clinical manifestations was assessed. NLR was higher in active BD patients than in inactive BD patients (P < 0.01). Although both NLR and PLR were correlated with Behcet's Disease Current Activity Form (BDCAF), the correlation of NLR with BDCAF was much stronger than that of PLR. NLR was associated with some mucocutaneous lesions. Both NLR and PLR were associated with articular and GIT manifestations, but also NLR showed more significant results. In our studied patients, both NLR and PLR were not informative about any ongoing ocular activity (P > 0.05). Both ratios were not affected by the presence of neurologic deficits nor previous vascular events (P > 0.05). NLR was superior to PLR as an indicator of disease activity. NLR was closely related to skin manifestations while PLR was not. In our study, both were not considered reliable in representing ocular activity. PMID- 29980879 TI - Thermoelectric Properties of Hot-Pressed Bi-Doped n-Type Polycrystalline SnSe. AB - : ?: We report on the successful preparation of Bi-doped n-type polycrystalline SnSe by hot-press method. We observed anisotropic transport properties due to the (h00) preferred orientation of grains along the pressing direction. The electrical conductivity perpendicular to the pressing direction is higher than that parallel to the pressing direction, 12.85 and 6.46 S cm-1 at 773 K for SnSe:Bi 8% sample, respectively, while thermal conductivity perpendicular to the pressing direction is higher than that parallel to the pressing direction, 0.81 and 0.60 W m-1 K-1 at 773 K for SnSe:Bi 8% sample, respectively. We observed a bipolar conducting mechanism in our samples leading to n- to p-type transition, whose transition temperature increases with Bi concentration. Our work addressed a possibility to dope polycrystalline SnSe by a hot-pressing process, which may be applied to module applications. HIGHLIGHTS: 1. We have successfully achieved Bi-doped n-type polycrystalline SnSe by the hot-press method. 2. We observed anisotropic transport properties due to the [h00] preferred orientation of grains along pressing direction. 3. We observed a bipolar conducting mechanism in our samples leading to n- to p-type transition. PMID- 29980878 TI - Prediction of chronic kidney disease after acute kidney injury in ICU patients: study protocol for the PREDICT multicenter prospective observational study. AB - BACKGROUND: Acute kidney injury (AKI) is frequent and associated with poor outcome in intensive care unit (ICU) patients. Besides the association with short and long-term mortality, the increased risk of chronic kidney disease (CKD) has been recently highlighted in non-ICU patients. This study aims to describe the incidence and determinants of CKD after AKI and to develop a prediction score for CKD in ICU patients. METHODS: Prospective multicenter (n = 17) observational study included 1200 ICU patients who suffered from AKI (defined by an AKIN stage >= 1) during their ICU stay and were discharged alive from ICU. Preexisting end stage renal disease (ESRD) and immunosuppressant treatments are the main exclusion criteria. Patients will be monitored by a nephrologist at day 90 and every year for 3 years. The main outcome is the occurrence of CKD defined by a creatinine-based estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m2 or renal replacement therapy for ESRD in patients whose eGFR will be normalized (>= 60 mL/min/1.73 m2) at day 90. Secondary outcomes include albuminuria changes, eGFR decline slope and ESRD risk in patients with preexisting CKD, cardiovascular and thromboembolic events and health-related quality of life. DISCUSSION: This is the first study prospectively investigating kidney function evolution in ICU patients who suffered from AKI. Albuminuria and eGFR monitoring will allow to identify ICU patients at risk of CKD who may benefit from close surveillance after recovering from AKI. Major patient and AKI related determinants will be tested to develop a prediction score for CKD in this population. Trial registration ClinicalTrials.gov, NCT03282409. Registered on September 14, 2017. PMID- 29980880 TI - Association Between Neighborhood Cohesion and Cancer Screening Utilization in Chinese American Older Adults. AB - This study aims to examine the association between neighborhood cohesion and cancer screening utilization in a community-dwelling Chinese American older population. Data were drawn from the Population Study of Chinese Elderly including 3159 Chinese American older adults aged 60 and above in the greater Chicago area. Cancer screening utilization was assessed by asking whether participants had undergone colon, breast, cervical, or prostate cancer screening. Neighborhood cohesion was measured through six questions. Logistic regression analysis showed that greater neighborhood cohesion was associated with higher likelihood of utilizing a mammogram (OR 1.32, 95% CI 1.14-1.52), a Pap test (OR 1.22, 95% CI 1.06-1.41), but not of a blood stool test (OR 1.10, 95% CI 0.98 1.23), a colonoscopy (OR 1.05, 95% CI 0.94-1.17), and a PSA test (OR 1.13, 95% CI 0.95-1.34). This study suggests positive associations between neighborhood cohesion and breast and cervical cancer screening utilization among a Chinese American older population. PMID- 29980881 TI - CYP2D6 genotype and endoxifen plasma concentration do not predict hot flash severity during tamoxifen therapy. AB - PURPOSE: Tamoxifen is frequently prescribed to prevent breast cancer recurrence. Tamoxifen is a prodrug and requires bioactivation by CYP2D6. Tamoxifen use is often limited by adverse effects including severe hot flashes. There is paucity of prospectively collected data in terms of CYP2D6 genotype and measured tamoxifen, 4-hydroxytamoxifen and endoxifen concentrations in relation to hot flash severity during tamoxifen therapy. METHODS: We conducted a longitudinal prospective study of breast cancer patients on tamoxifen (n = 410). At each visit, blood samples were collected, and patients completed a standardized hot flash survey (n = 1144) that reflected hot flash severity during the 7 days prior to the visit. Plasma concentrations of tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using liquid chromatography-tandem mass spectrometry and genotyping was carried out for CYP2D6. A linear mixed-effects regression analysis assessed the association of covariates in relation to the hot flash severity score (HFSS). RESULTS: Median age at first assessment was 50 years with 61.9% of patients considered peri-menopausal. Most patients (92.2%) experienced hot flash symptoms with 51.0% having low HFSS (0-4) and 7.32% experiencing HFSS > 25. Age was significantly associated with hot flash severity, with patients aged 45-59 more likely to have higher HFSS. Neither duration of tamoxifen therapy nor observed tamoxifen, endoxifen and 4-hydroxy tamoxifen plasma concentration predicted hot flash severity. Genetic variation in CYP2D6 or CYP3A4 was not predictive of hot flash severity. CONCLUSIONS: Hot flash severity during tamoxifen therapy can not be accounted for by CYP2D6 genotype or observed plasma concentration of tamoxifen, 4-hydroxytamoxifen, or endoxifen. PMID- 29980882 TI - The effects of ethoxyquin and Angelica sinensis extracts on lipid oxidation in fish feeds and growth, digestive and absorptive capacities and antioxidant status in juvenile red carp (Cyprinus carpio var. xingguonensis): a comparative study. AB - Firstly, a linoleic and linolenic acid emulsion and fish feeds were incubated with graded levels of ethoxyquin (EQ) and petroleum ether extract, ethyl acetate extract (EAE), ethanol extract and aqueous extract of Angelica sinensis. The results showed that EQ and extracts of Angelica sinensis (EAs) inhibited lipid oxidation in material above. Of all of the examined EAs, EAE showed the strongest protective effects against the lipid oxidation. Moreover, EAE at high concentrations showed a stronger inhibitory effect on lipid oxidation than that of EQ. Next, 7 experimental diets that respectively supplemented 0.0, 0.2, 0.8 and 3.2 g kg-1 of EQ and EAE were fed to 280 juvenile red carp (Cyprinus carpio var. xingguonensis) with seven treatment groups for 30 days. The results indicated that dietary EAE improved growth performance in carp. Moreover, dietary EAE increased the activities of trypsin, lipase, alpha-amylase, alkaline phosphatase, glutamate-oxaloacetate transaminase and glutamate-pyruvate transaminase (GPT) and decreased plasma ammonia content in carp. Meanwhile, dietary EAE reduced the levels of malondialdehyde and raised the activities of anti-superoxide anion, anti-hydroxyl radical, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase and the content of reduced glutathione in the hepatopancreas and intestine of carp. However, with the exception of GPT, dietary EQ got the opposite results to dietary EAE in carp. These results revealed that dietary EAE improved the digestive, absorptive and antioxidant capacities in fish. However, dietary EQ inhibited the digestive, absorptive and antioxidant capacities in fish. So, EAE could be used as a natural antioxidant for replacing EQ in fish feeds. PMID- 29980883 TI - Anti-inflammatory and anticancer effects of p-methoxycinnamic acid, an active phenylpropanoid, against 1,2-dimethylhydrazine-induced rat colon carcinogenesis. AB - p-methoxycinnamic acid (p-MCA) is an active phenolic acid found in rice bran, turmeric, brown rice, Kaempferia galanga, buckwheat inflorescence, etc. Earlier, we have reported that p-methoxycinnamic acid possesses antioxidant and antilipidperoxidative effects on 1,2-dimethylhyrdrazine (DMH)-induced colon carcinogenesis. The purpose of this study is to unravel the anti-inflammatory and anticancer properties of p-MCA against DMH-induced colon carcinogenesis. Male albino Wistar rats were randomly divided into six groups. Group 1 served as control, group 2 rats received 40 mg/kg b.wt. of p-MCA in 0.1% carboxymethylcellulose (CMC) every day, and colon cancer was induced in groups 3 6 using DMH at the dose of (20 mg/kg b.wt. subcutaneously) once a week for 15 weeks. In addition, along with DMH, groups 4 (initiation), 5 (post initiation) and 6 (entire period) rats received p-MCA (40 mg/kg b.wt.) p.o. every day during different time periods for the total experimental period of 30 weeks. Colon of animals treated with DMH showed an increased number of aberrant crypt foci (ACFs), increased nuclear translocation of transcription factor NF-kappaB p65 subunit, increased expression of inflammatory markers (iNOS, COX-2), cytokines (tumour necrosis factor-alpha, interleukin-6), cyclin D1, antiapoptotic protein (Bcl-2), metastasis marker (matrix metalloproteinase-2 (MMP-2)) and angiogenic marker (vascular endothelial growth factor VEGF) and decreased expression of pro apoptotic proteins (Bax, caspases 3 and 9). On supplementing with p-MCA (40 mg/kg b.wt.) throughout the entire experimental period, DMH-induced pathological alterations reversed significantly to normal. PMID- 29980884 TI - Self-Reported Negative Influence of Gambling Advertising in a Swedish Population Based Sample. AB - This study investigated the negative influence of gambling advertising, that is, gambling more often or for more money than intended. We analyzed data from wave four of the Swedish Longitudinal Gambling Study (Swelogs), in which the self perceived negative influence of gambling advertising was measured by responses to three survey questions. Few gamblers reported having been negatively influenced by gambling advertising. Among those who reported such influence, problem gamblers were overrepresented. Those who had set limits for their gambling reported a negative influence from advertising more often than others, which likely was caused by a perception that advertising is detrimental to efforts to cut down on excessive gambling. A multivariate regression analysis showed that negative influence from gambling advertising was positively associated with problem gambling, gambling at least monthly, participation in online gambling, and being in the age group 30-49 years. We conclude that although few gamblers are negatively influenced by gambling advertising, the adverse effects on those that are should not be neglected. For a considerable number of people, gambling advertising substantially contributes to problem gambling. PMID- 29980885 TI - Management of acute uncomplicated diverticulitis without antibiotics: a systematic review, meta-analysis, and meta-regression of predictors of treatment failure. AB - BACKGROUND: Diverticulitis is a common complication of diverticular disease of the colon. While complicated diverticulitis often warrants intervention, acute uncomplicated diverticulitis (AUD) is usually managed conservatively. The aim of the present review was to evaluate the efficacy and safety of conservative treatment of AUD without antibiotics compared to standard antibiotic treatment. METHODS: A systematic literature review in compliance with PRISMA guidelines was conducted. Electronic databases including PubMed/Medline, Scopus, Embase and Cochrane central register of controlled trials were searched. Studies that assessed efficacy and safety of treatment of AUD without antibiotics were included. Outcome parameters were rates of treatment failure, recurrence of diverticulitis, complications and mortality, readmission to hospital, and need for surgery. RESULTS: Nine studies including 2565 patients were included to the review. Of these patients, 65.1% were treated conservatively without antibiotics. Treatment failure was observed in 5.1% of patients not-given-antibiotic treatment versus 3.4% of those given antibiotic treatment. Recurrent diverticulitis occurred in 9.3% of patients in the non-antibiotic group versus 12.1% of patients in the antibiotic group. On meta-analysis of the studies, there were no significant differences between non-antibiotic and antibiotic treatment groups regarding rates of treatment failure (OR = 1.5, p = 0.06), recurrence of diverticulitis (OR = 0.81, p = 0.2), complications (OR = 0.56, p = 0.25), readmission rates (OR = 0.97, p = 0.91), need for surgery (OR = 0.59, p = 0.28), and mortality (OR = 0.64, p = 0.47). The only variable that was significantly associated with treatment failure in the non-antibiotic treatment group was associated comorbidities (standard error (SE) = - 0.07, 95% CI - 0.117 - 0.032; p < 0.001). CONCLUSIONS: Treatment of AUD without antibiotics is feasible, safe, and effective. Adding broad-spectrum antibiotics to the treatment regimen did not serve to decrease treatment failure, recurrence, complications, hospital readmissions, and need for surgery significantly compared to non-antibiotic treatment. PMID- 29980886 TI - Laparoscopic management of sigmoid colon gallstone ileus. AB - Gallstone ileus is an uncommon clinical presentation of complicated biliary lithiasis that mostly occurs in the elderly without specific signs. Various types of surgical management have been proposed: primary enterolithotomy, enterolithotomy, cholecystectomy and fistula closure (one stage), or enterolithotomy with delayed cholecystectomy (two stage). All are associated with a high complication rate. We present a video of a laparoscopic cololithotomy for gallstone ileus caused by a gallstone impacted in the sigmoid colon. As a safe and feasible procedure, enterolithotomy appears to be the treatment of choice based on the scientific literature, especially in frail patients. However, except in case of an impacted gallstone in a colorectal cancer, colon resection is not mandatory. Further surgery (such as cholecystectomy or colectomy in benign disease such as diverticulosis) may be selectively considered. PMID- 29980887 TI - Authors reply: Damage control surgery in patients with generalized peritonitis secondary to perforated diverticulitis-the risk of overtreatment. PMID- 29980888 TI - Molecular survey of Rickettsia spp. in the Neotropical deer tick Haemaphysalis juxtakochi from Brazilian Pampa. AB - Spotted fever (SF) is a tick-borne disease associated with Rickettsia spp.. In the Pampa biome, Southern Brazil, cases of SF seem to be strongly linked with the practice of hunting wild animals. An investigation of rickettsiae in tick species found on wild animals could provide more information regarding the rickettsiosis enzootic cycle. The aim of this study is to describe the results of a molecular survey of Rickettsia spp. in the Neotropical deer tick, Haemaphysalis juxtakochi Cooley, 1946 (Acari: Ixodidae), from the Brazilian Pampa. Ticks were obtained from 14 road-killed gray brocket deer, Mazama gouazoubira (Artiodactyla: Cervidae), found in nine different municipalities of Rio Grande do Sul state, Southern Brazil. Ticks were processed individually to obtain genomic DNA, and then Rickettsia spp. was investigated using a set of PCR reactions that amplified the rickettsial fragments of the gltA, ompA, and htrA genes. Of the 24 tick samples tested, DNA of Rickettsia parkeri sensu stricto (s.s.) was found in 11 H. juxtakochi specimens collected in two different areas of the Brazilian Pampa. This is the first report of R. parkeri s.s. (the main agent associated with SF in the Uruguayan, Argentinian, and Brazilian Pampa) in H. juxtakochi ticks. These findings indicate that R. parkeri s.s. may be much more common and widely distributed in the Pampa biome than previously assumed. Moreover, H. juxtakochi ticks and gray brocket deer could participate in the potential spillover of R. parkeri s.s. from endemic to non-endemic areas in the South American Pampa. PMID- 29980890 TI - Correction to: The impact of parity on life course blood pressure trajectories: the HUNT study in Norway. AB - The article was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 January 2018 without open access. PMID- 29980889 TI - Molecular identification of Physaloptera sp. from wild northern bobwhite (Colinus virginianus) in the Rolling Plains ecoregion of Texas. AB - Physaloptera spp. are common nematodes found in the stomach and muscles of mammals, reptiles, amphibians, and birds. Physaloptera spp. have a complicated life cycle with multiple definitive hosts, arthropod intermediate hosts, aberrant infections, and possible second intermediate hosts or paratenic hosts. For example, Physaloptera sp. larvae have been found within the tissues of wild northern bobwhite quail (Colinus virginianus), and it is suspected that quail may serve as paratenic or secondary hosts of these parasites. However, because it is not known what role quail play in the life cycle of Physaloptera spp. and descriptions of Physaloptera spp. larvae are limited, molecular tools may be beneficial when identifying these helminths. In this study, we generated primers using universal nematode primers and obtained a partial mitochondrial cytochrome oxidase 1 (COX 1) sequence. Morphological identification of Physaloptera sp. in bobwhite was confirmed via polymerase chain reaction (PCR), and a phylogenetic tree was constructed using the maximum likelihood method. BLAST analysis revealed a strong identity to other Physaloptera spp. and the phylogenetic tree placed all Physaloptera spp. in the same cluster. We also documented a marked increase in Physaloptera infections in bobwhite from 2017 to 2018, and the similarity of these parasites to Onchocerca volvulus and Wuchereria bancrofti may give insight into the increased prevalence we observed. This study demonstrates the usefulness of molecular techniques to confirm the identity of species that may lack adequate descriptions and provides new insight for the diagnosis and potentially overlooked significance of Physaloptera sp. infections of bobwhite in the Rolling Plains ecoregion of Texas. PMID- 29980891 TI - Lymphedema surgery: the current state of the art. AB - BACKGROUND/PURPOSE: Lymphedema surgery, when integrated into a comprehensive lymphedema treatment program for patients, can provide effective and long-term improvements that non-surgical management alone cannot achieve. Such a treatment program can provide significant improvement for many issues such as recurring cellulitis infections, inability to wear clothing appropriate for the rest of their body size, loss of function of arm or leg, and desire to decrease the amount of lymphedema therapy and compression garment use. METHODS: The fluid predominant portion of lymphedema may be treated effectively with surgeries that involve transplantation of lymphatic tissue, called vascularized lymph node transfer (VLNT), or involve direct connections from the lymphatic system to the veins, called lymphaticovenous anastomoses (LVA). VLNT and LVA are microsurgical procedures that can improve the patient's own physiologic drainage of the lymphatic fluid, and we have seen the complete elimination for the need of compression garments in some of our patients. These procedures tend to have better results when performed when a patient's lymphatic system has less damage. The stiff, solid-predominant swelling often found in later stages of lymphedema can be treated effectively with a surgery called suction-assisted protein lipectomy (SAPL). SAPL surgeries allow removal of lymphatic solids and fatty deposits that are otherwise poorly treated by conservative lymphedema therapy, VLNT or LVA surgeries. CONCLUSION: Overall, multiple effective surgical options for lymphedema exist. Surgical treatments should not be seen as a "quick fix", and should be pursued in the framework of continuing lymphedema therapy and treatment to optimize each patient's outcome. When performed by an experienced lymphedema surgeon as part of an integrated system with expert lymphedema therapy, safe, consistent and long-term improvements can be achieved. PMID- 29980892 TI - 11th International Symposium on Minimal Residual Cancer (ISMRC): 3-5 May 2018, Montpellier, France. PMID- 29980893 TI - Aflatoxin-induced upregulation of protein arginine methyltransferase 5 is mediated by protein kinase C and extracellular signal-regulated kinase. AB - Aflatoxins are fungal metabolites classified into four major groups such as B1, B2, G1, and G2. These natural aflatoxins are designated as group I carcinogen by the International Agency for Research on Cancer. Among these, the aflatoxin B1 is more potent. Protein arginine methyltransferase 5, an epigenetic modulator, emerged as an oncoprotein, is overexpressed in diverse forms of cancers. The present study aims to explore the AFB1-mediated overexpression of PRMT5. The AFB1 at nanomolar concentrations increased the cell viability, as well as the expression of PRMT5 and its binding partner methylosome protein 50 level significantly in L-132 and HaCaT cells. The knockdown of PRMT5 by its siRNA is attenuated by AFB1, thus substantiating AFB1-mediated PRMT5 overexpression. The PKC isoform-specific inhibitor study revealed direct relation with PKCalpha and an inverse relation with PKCdelta. The analysis of mitogen-activated protein kinase pathway revealed reduced p38 phosphorylation with increased phosphorylation of ERK1/2 upon exposure to AFB1. The combination of MEK and PKC inhibitors with AFB1 treatment revealed that PKCalpha activates downstream kinase ERK which leads to overexpression of PRMT5. In summary, we propose that PKCalpha and extracellular signal-regulated kinases are conjointly involved in the induction of PRMT5 upon AFB1 exposure. PMID- 29980894 TI - A phase 1, first-in-human study of AMG 900, an orally administered pan-Aurora kinase inhibitor, in adult patients with advanced solid tumors. AB - Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade >= 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer. PMID- 29980895 TI - Contraction behaviour reduces embryo competence in high-quality euploid blastocysts. AB - PURPOSE: The aim of the study is to investigate how blastocyst contraction behaviour affects the reproductive competence in high-quality euploid embryos. METHODS: Eight hundred ninety-six high-quality blastocysts derived from 190 patients (mean age 38.05 (SD = 2.9) years) who underwent preimplantation genetic testing for aneuploidies (PGT-A) from January 2016 to October 2017 were included in this study. PGT-A results were reported as euploid or aneuploid. Aneuploid embryos were sub-classified into three categories: monosomy, trisomy and complex aneuploid. Retrospective studies of time-lapse monitoring (TLM) of those embryos were analysed and reproductive outcome of transferred embryos was collected. RESULTS: A total of 234/896 were euploid (26.1%) whilst 662/896 (73.9%) blastocysts were proven to be aneuploid from which 116 (17.6%) presented monosomies, 136 (20.5%) trisomies and 410 (61.9%) were complex aneuploid. The most frequent chromosomal complements were trisomies affecting chromosome 21 and monosomies involving chromosomes 16 and 22. Data analysis showed a statistical difference in the number of contractions being reported greater in aneuploid when compared to euploid embryos (0.6 vs 1.57; p < 0.001). Analysis of the aneuploid embryos showed that monosomies present less number of contractions when compared to embryos affected with trisomies or complex aneuploidies (1.23 vs 1.53 and 1.40; p < 0.05). No difference was observed when comparing the latter two groups. Euploid embryos presenting at least one contraction resulted in lower implantation and clinical pregnancy rates when compared to blastocysts that do not display this event (47.6 vs 78.5% and 40.0 vs 59.0% respectively). CONCLUSIONS: Most aneuploid blastocysts diagnosed by PGT-A have complex aneuploidies, showing that aneuploid embryos can develop after genomic activation and reaching high morphological scores. It becomes clear that embryo contraction, despite being a physiological feature during blastulation, is conditioned by the ploidy status of the embryo. Furthermore, the presence of contractions may compromise implantation rates. PMID- 29980896 TI - Protective effects of circulating microvesicles derived from ischemic preconditioning on myocardial ischemia/reperfusion injury in rats by inhibiting endoplasmic reticulum stress. AB - Microvesicles (MVs) have been shown to be involved in pathophysiology of ischemic heart diseases. However, the underlying mechanisms are still unclear. Here we investigated the effects of MVs derived from ischemic preconditioning (IPC-MVs) on myocardial ischemic/reperfusion (I/R) injury in rats. Myocardial IPC model was elicited by three cycles of ischemia and reperfusion of the left anterior descending (LAD) coronary artery. IPC-MVs from the peripheral blood of the above animal model were isolated by ultracentrifugation and characterized by flow cytometry and transmission electron microscopy. IPC-MVs were administered intravenously (7 mg/kg) at 5 min before reperfusion procedure in I/R injury model which was induced by 30-min ischemia and 120-min reperfusion of LAD in rats. We found that total IPC-MVs and different phenotypes, including platelet-derived MVs (PMVs), endothelial cell-derived MVs (EMVs), leucocyte-derived MVs and erythrocyte-derived MVs (RMVs) were all isolated which were identified membrane vesicles (< 1 um) with corresponding antibody positive. The numbers of PMVs, EMVs and RMVs were significantly increased in circulation of IPC treated rats respectively. Additionally, treatment with IPC-MVs significantly alleviated damage of myocardium, and restored cardiac function of I/R injury rats, as evidenced by increased heart rate, and decreased the elevation of ST-segment. The size of myocardial infarction, lactate dehydrogenase activity, and the number of apoptotic cardiomyocytes were also reduced significantly with IPC-MVs treatment, coincident with the above function amelioration. Moreover, IPC-MVs decreased the activity of caspase 3, and the expression of endoplasmic reticulum stress (ERS) markers, GRP78, CHOP and caspase 12 indicating the involvement of ERS-specific apoptosis in I/R injury, and cardioprotective effects of IPC-MVs. In summary, our study demonstrated a novel mechanism of IPC in which circulating IPC-MVs could protect hearts from I/R injury in rats through attenuation of ERS-induced apoptosis. These findings provide new insight into therapeutic potential of IPC induced MVs in cardioprotection against I/R injury. PMID- 29980897 TI - Efficient processing of MRSA screening specimens by a modified inoculation protocol. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of healthcare associated infections and mortality, and therefore constitutes a serious cost factor in public health. Culture-based MRSA screening is a crucial part of MRSA infection prevention and control strategies in the hospital setting. Manual inoculation of screening swabs onto culture plates still constitutes the major part of the technicians' workload in laboratories. We present a modified inoculation protocol that comprises direct inoculation of specimen onto a chromogenic MRSA-selective agar plate without further streaking for isolation. This study aims to evaluate the impact of this inoculation protocol on technicians' workload and the downstream workflow in our laboratory. Batches of 50 specimens were processed by different technicians and the hands-on time was compared between the standard and modified inoculation protocol. To assess the impact on downstream processing, a retrospective analysis of the rate of subcultures and turnaround time (TAT) of specimens yielding putative MRSA colonies from 9 months before (n = 1548) and after (n = 1267) the protocol change was carried out based on laboratory information system (LIS) data. The implementation of the modified protocol significantly reduced technicians' hands on time needed for inoculation by 26.5% without altering the overall turnaround time of surveillance cultures or causing higher costs for extra plates needed for subcultures. Our modified inoculation protocol offers a cost-effective and easy to implement procedure for MRSA surveillance cultures which significantly decreases technicians' workload and does not impede the downstream workflow. It therefore increases the capacity of laboratory technicians' to execute more demanding tasks. PMID- 29980898 TI - Antifungal drug susceptibility profile of clinically important dermatophytes and determination of point mutations in terbinafine-resistant isolates. AB - With regard to increasing number of antifungal-resistant dermatophytes, antifungal susceptibility testing of dermatophytes serves as a useful tool in managing clinical dermatophytosis. This study aimed to determine antifungal susceptibility profile of clinically important dermatophytes and determination of point mutations in terbinafine-resistant isolates. Based on our results, dermatophytosis was confirmed in 97 cases by direct microscopic examination, culture, and sequencing of ITS region. Antifungal susceptibility of 97 dermatophyte isolates distributed in four species including Trichophyton interdigitale (26 isolates), T. rubrum (19 isolates), T. tonsurans (29 isolates), and Epidermophyton floccosum (21 isolates) was assessed to nine antifungal agents using CLSI M38-A2 guidelines. Minimum inhibitory concentration range (MIC range) for luliconazole and terbinafine was 0.001-0.008 MUg/ml and 0.003-> 32 MUg/ml, compared to 0.03-64 MUg/ml for griseofulvin, 0.01-16 MUg/ml for itraconazole and voriconazole, 0.03-8 MUg/ml for ketoconazole, 0.03-32 MUg/ml for econazole, 0.03 1 MUg/ml for lanoconazole, and 0.01-4 MUg/ml for butenafine. Trichophyton tonsurans was the most susceptible (MIC = 0.006 MUg/ml) and E. floccosum was the most resistant (MIC = 0.02 MUg/ml) species to terbinafine. Terbinafine resistance was reported for two species, i.e., T. rubrum and T. tonsurans at the total rate of 2% which was due to Leu393Phe substitution in both species. Taken together, our results assist clinicians and prompt the current knowledge about the necessity of antifungal susceptibility testing to select effective strategies for management of clinical cases of dermatophytosis. PMID- 29980899 TI - Support Group Value and Design for Parents of Children with Severe or Profound Intellectual and Developmental Disabilities. AB - The purpose of this study was to interview parents of children with severe or profound intellectual and developmental disabilities to determine the perceived value of support groups and identify recommendations for support group design based on their experiences and feedback. Despite varied experiences with support groups, most parents indicated the value of support groups is in providing a place where parents can feel understood and both share and gather information. Parents recommended support groups be targeted for parents of children with similar disabilities and needs, have flexible structures and qualified leaders, and offer a wide variety of content in various formats. Given parental recommendations for support group design varied, summary recommendations addressing a wide range of preferences are provided. PMID- 29980900 TI - Exploratory Study of Executive Function Abilities Across the Adult Lifespan in Individuals Receiving an ASD Diagnosis in Adulthood. AB - Little is known about cognition in autism spectrum disorder (ASD) across adulthood. We examined executive function abilities and autism traits in 134 adults receiving a first diagnosis of ASD. Participants aged 18-75 years with abilities in the normal range were assessed on executive function and self-report autism traits. Results suggest that for some abilities relying on speed and sequencing (Trails A and B; Digit Symbol), late-diagnosed individuals with ASD may demonstrate better performance than typical age-norms. On other executive measures (Digit Span, Hayling and Brixton tests) age-related correlations were similar to typical age-norms. Different domains of executive function may demonstrate different trajectories for ageing with ASD, with patterns of slower, accelerated or equivalent age-related change being observed across different measures. PMID- 29980902 TI - Sex Differences in Attributions to Positive and Negative Sexual Scenarios in Men and Women With and Without Sexual Problems: Reconsidering Stereotypes. AB - People with sexual problems are more likely to attribute negative sexual experiences to themselves, in contrast to sexually functional individuals who attribute negative sexual experiences to external factors such as the circumstance or partner. We investigated attribution patterns in 820 men and 753 women, some of whom reported an orgasmic problem, to assess differences between the sexes and those with and without an orgasmic difficulty. Specifically, using an Internet-based approach, we compared attribution responses to four sexual scenarios, one representing a positive sexual experience and three representing negative sexual experiences. Women were more likely to attribute positive outcomes to their partner than men. Women were also more likely to attribute negative outcomes to themselves than men, but they more readily blamed their partner and circumstances for negative outcomes than men as well. Those with orgasmic problems were less willing to take credit for positive outcomes and more willing to accept blame for negative outcomes. Interaction effects between sex and orgasmic problems further highlighted differences between men's and women's attribution patterns. These results are interpreted in the context of traditional notions that men's attributions tend to be more self-serving and women's attributions more self-derogatory. PMID- 29980901 TI - Three new Leptographium spp. (Ophiostomatales) infecting hardwood trees in Norway and Poland. AB - Species of Leptographium are characterized by mononematous or synnematous conidiophores and are commonly associated with different arthropods. Some of them also produce a sexual state characterised by globose ascomata with elongated necks. Compared to investigations on coniferous trees, the occurrence of Leptographium species on hardwood trees has been poorly studied in Europe. During a survey of ophiostomatoid fungi on various hardwood tree species in Norway and Poland, three unusual species, which fit in the broader morphological description of Leptographium spp., were found in association with Trypodendron domesticum, Trypodendron signatum and Dryocoetes alni, and from wounds on a variety of hardwoods. Phylogenetic analyses of sequence data for six different loci (ITS1 5.8 S-ITS2, ITS2-LSU, ACT, beta-tubulin, CAL, and TEF-1alpha) showed that these Leptographium species are phylogenetically closely related to the species of the Grosmannia olivacea complex. The first species forms a well-supported lineage that includes Ophiostoma brevicolle, while the two other new taxa resided in a separate lineage; possibly affiliated with Grosmannia francke-grosmanniae. All the new species produce perithecia with necks terminating in ostiolar hyphae and orange-section shaped ascospores with cucullate, gelatinous sheaths. These species also produce dark olivaceous mononematous asexual states in culture. In addition, two of the newly described species have a second type of conidiophore with a short and non-pigmented stipe. The new Leptographium species can be easily distinguished from each other by their appearance and growth in culture. Based on novel morphological characters and distinct DNA sequences, these fungi were recognised as new taxa for which the names Leptographium tardum sp. nov., Leptographium vulnerum sp. nov., and Leptographium flavum sp. nov. are provided. PMID- 29980903 TI - Postpartum depressive mood (PDM) among Chinese women: a meta-analysis. AB - Postpartum depression is a common complication of childbearing and up to 12 months postpartum. This study aimed to determine the prevalence of postpartum depressive mood (PDM) in China by performing a meta-analysis of published studies. Studies that reported the prevalence of PDM in China were identified by searching the PubMed, Embase, CNKI, and CQVIP databases. Three thousand, one hundred, and two articles were obtained, and after careful evaluation, 26 studies were finally included in the meta-analysis. The combined studies included a total of 7618 cases with 1621 cases of PDM. The studies were assessed on the basis of heterogeneity testing and the potential for publication bias. Stata software 11.0 was used to perform the meta-analysis. The random-effect model showed that the prevalence of PDM was 21% with a 95% confidence interval (CI) of 17-25%. PDM was the highest 0 to 1.5 months after delivery. PDM levels decreased to 10.4% (95% CI 9.7-11.1%, P < 0.001) after publication bias were corrected. Sensitivity analyses evaluated the stability of our results and showed no significant change when any single study was excluded. Subgroup analyses showed that region, instruments used, cut-off score, and time points for depression assessment were positively associated with PDM prevalence. The prevalence of PDM differed among regions, with South Central China and East China exhibiting the lowest prevalence. The prevalence was higher in regions with poor economic development, suggesting that more attention should be devoted to Southwest and North China and that the prevalence of PDM should be evaluated 0 to 1.5 months after delivery. PMID- 29980904 TI - A combination of follicle stimulating hormone, estradiol and age is associated with the pregnancy outcome for women undergoing assisted reproduction: a retrospective cohort analysis. AB - To investigate the effect of basal hormone levels including follicle stimulating hormone (FSH) and estradiol (E2) and age on the pregnancy outcomes in women undergoing in vitro fertilization and embryo transfer (IVF-ET), we designed a retrospective cohort analysis and collected information of patients undergoing IVF between January 2014 and April 2017. We found that young women had much better pregnancy outcomes than older women regardless of the hormone levels. The pregnancy outcomes declined in young women with high basal E2, even though they had normal FSH. Older women with higher FSH had a worse outcome of pregnancy, especially with increased E2 level. The results suggest that a combination of FSH, E2 and age could effectively predict the pregnancy outcome for women undergoing IVF-ET, and we should encourage infertile women with diminished ovarian reserve, especially young infertile women, to try the assisted reproduction as early as possible. After 40-yearold, the cost-benefit ratio should be considered according to the ovarian function. PMID- 29980905 TI - Side effects of corticosteroids in patients with advanced cancer: a systematic review. AB - PURPOSE: Corticosteroids are commonly used in palliative care settings, but are associated with several side effects. Although adverse events (AEs) are highly distressing for patients, few data are available from prospective studies to look at incidence or predictors of such harms. The aim of this study is to identify AE reporting among studies of patients with advanced cancer receiving corticosteroids for any reason. METHODS: A systematic review was conducted using the following data sources: PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL. Randomized controlled trials (RCTs) with patients with advanced cancer assessing the effect of corticosteroids were included. Consecutive cohort observational studies of corticosteroid toxicities in cancer patients were also included. RESULTS: Twenty-seven RCTs and 12 consecutive cohort observational studies were identified. The most frequently reported primary outcome of RCTs was nausea and vomiting (8/27). Dexamethasone was prescribed in almost half of RCTs (13/27). In consecutive cohort studies, the primary outcomes were a wide variety of symptoms. Dexamethasone was also the most common glucocorticoid used (7/12). In terms of quality of AE reporting, two RCTs and one consecutive cohort study used a validated AE assessment tool in their studies. CONCLUSIONS: Side effects of corticosteroids in advanced cancer patients were poorly reported with few data using validated tools. Researchers should be aware of the guideline of AE reporting to provide the best evidence of risk-benefit balance. Developing specific consensus guidelines about AE reporting in studies of glucocorticoids in studies of people with advanced cancer would be useful. PMID- 29980906 TI - Patients' experience of lung cancer care coordination: a quantitative exploration. AB - PURPOSE: Improving the coordination of care for people with lung cancer is a health priority. This study aimed to tailor an existing care coordination survey for a lung cancer population, investigate coordination experiences for patients who had received hospital-based treatment and identify any factors that may be associated with poor care coordination. METHODS: We conducted a cross-sectional survey of lung patients within two tertiary hospitals in Sydney, Australia. The Cancer Care Coordination Questionnaire for Patients (CCCQ-P) is a psychometrically valid and reliable survey originally developed for colorectal cancer. We pilot tested a survey adaptation with lung cancer patients, support group members and medical specialists (n = 49). A revised survey was mailed to eligible patients via their medical specialist. RESULTS: Fifty-three of 118 eligible participants (45%) completed the CCCQ-P; most had early-stage disease and were about 70 years old. Overall, participants reported positive experiences of care coordination (mean total score 78.1), with high scores on communication and navigation subscales. The most problematic areas related to administrative aspects of care coordination and communication and information provision. Two patient groups (those residing in regional and rural areas, or no experience with the health system prior to diagnosis) reported significantly lower scores on the navigation subscale. CONCLUSIONS: This study found that lung cancer patients' experience of care coordination was positive, but highlighted the need for strategies to assist patients living in rural areas, and those with no experience of the health care system. The CCCQ-P survey instrument can be used in future lung cancer studies. PMID- 29980907 TI - Lymphedema symptoms and limb measurement changes in breast cancer survivors treated with neoadjuvant chemotherapy and axillary dissection: results of American College of Surgeons Oncology Group (ACOSOG) Z1071 (Alliance) substudy. AB - PURPOSE: Lymphedema is a potential complication of breast cancer treatment. This longitudinal substudy aimed to prospectively assess arm measurements and symptoms following neoadjuvant chemotherapy and axillary dissection in the ACOSOG/Alliance Z1071 trial to characterize the optimal approach to define lymphedema. METHODS: Z1071 enrolled patients with cT0-4, N1-2, M0 disease treated with neoadjuvant chemotherapy. All patients underwent axillary dissection. Bilateral limb volumes, circumferences, and related symptoms were assessed pre-surgery, 1-2 weeks post surgery, and semiannually for 36 months. Lymphedema definitions included volume increase >= 10% or limb circumference increase >= 2 cm. Symptoms were assessed by the Lymphedema Breast Cancer Questionnaire. RESULTS: In 488 evaluable patients, lymphedema incidence at 3 years by >= 10%-volume-increase was 60.3% (95% CI 55.0 66.2%) and by >= 2 cm-circumference increase was 75.4% (95% CI 70.8-80.2%). Symptoms of arm swelling and heaviness decreased from post-surgery for the first 18 months and then were relatively stable. The 3-year cumulative incidence of arm swelling and heaviness was 26.0% (95% CI 21.7-31.1%) and 30.9% (95% CI 26.3 36.3%), respectively. There was limited agreement between the two measurements (kappa 0.27) and between symptoms and measurements (kappa coefficients ranging from 0.05-0.09). CONCLUSIONS: Lymphedema incidence by limb volume and circumference gradually increased over 36 months post-surgery, whereas lymphedema symptoms were much lower. These findings underscore the importance of prospective surveillance and evaluation of both limb measurements and symptom assessment. Lymphedema incidence rates varied by definition. We recommend that >= 10% volume change criterion be used for lymphedema evaluation for referral for specialist care. TRIAL REGISTRATION: NCT00881361. PMID- 29980908 TI - IMproved MAnagement (IM-MA study) in cancer-related pain: the value of a joint approach by an integrated team of radiotherapist and anesthetist. AB - PURPOSE: Purpose of this study was to retrospectively review our experience of multidisciplinary clinic providing a joint approach by radiation oncologist and anesthetist for patients with cancer pain to evaluate the adequacy and the IMprovement in MAnagement (IM-MA study) of this symptom. METHODS: A Team for Pain Management (TPM) represented by radiation oncologist and anesthetist weekly provided consultations to patient presenting cancer pain. TPM prospectively reported epidemiologic, symptomatic, and pharmacological data. TPM modified pain therapy and indicated antalgic radiotherapy. Patients were evaluated at baseline and after 4 weeks after intervention. RESULTS: From November 2015 to April 2016, 65 patients were evaluated by TPM. At the baseline, 18 patients (27.7%) were undertreated (i.e., receiving inadequate pain management); furthermore, 27 patients (41.5%) despite receiving strong opioids had uncontrolled pain. After 4 weeks from intervention, undertreated patients were reduced to 1.53%. For those patients undergone to radiotherapy, response at 34 weeks was scored as follows: complete response 28.8%, partial response 46.7%, pain progression 0.95%, indeterminate response 23.8%. CONCLUSIONS: A multidisciplinary Team for Pain Management improved the clinical management, optimizing pain control and increasing adequacy of pharmacological management. The TPM intervention seems particularly worth for patients presenting specific features including BTcP, neuropathic pain, severe pain due to bone metastases, and any potential candidate to radiotherapy. Larger series and QoL questionnaires are required to confirm these results. PMID- 29980909 TI - Robotic resection of lingual thyroglossal duct cyst in an infant. AB - Thyroglossal duct cysts (TDCs) are the most common congenital midline neck masses. Lingual TDC is a rare variant that emerges as an isolated cyst at the tongue base. Unlike conventional procedures aiming removal of cyst, duct, and hyoid bone via open surgical access, a transoral cystectomy is mostly sufficient in cases with lingual TDC. We present a case describing a 3-month-old infant patient with lingual TDC who was successfully treated with transoral robotic surgery. The cyst wall was completely excised with no complications or obvious bleeding occurred. The operating time was 10 min. He had an uneventful postoperative course. Six months postoperatively, he is free of symptoms with no evidence of recurrence. Surgical treatment of lingual TDC in an infant is possible with transoral robotic approach and minimal risk of complication. Further studies are strongly needed to confirm the safety of robotic surgery in pediatric population. PMID- 29980911 TI - Adipogenesis in Primary Cell Culture. AB - Obesity involves a contrasting expansion of the energy-storing white fat and loss of functionally competent brown fat, an energy-consuming thermogenic adipose. Leveraging our understanding of white and brown adipocyte recruitment and investigating factors that regulate these processes might reveal novel targets for counteracting obesity. In vitro differentiation of primary preadipocytes mimics many of the morphological and transcriptional events occurring during adipogenesis in vivo. Moreover, preadipocytes isolated from a specific depot maintain features of their originating niche. This makes in vitro adipogenesis a valuable model for identifying differential regulation patterns between brown and white adipogenesis. In this chapter, we describe step-by-step how to isolate brown and white preadipocytes from human tissue biopsies and how to culture and differentiate them in vitro. We discuss this process, what to consider, and how this in vitro system can be used to model in vivo adipogenesis. PMID- 29980910 TI - Correction to: Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan. AB - In the original publication of this article, Tables 2, 3 and 4 were published incorrectly. The corrected tables 2, 3 and 4 are given in the following pages. PMID- 29980912 TI - Infrared Thermography. AB - Historically, brown adipose tissue has been elusive and not easy to detect, hence its relative obscurity in human physiology until its rediscovery in 2009. At that point, it was proven that the symmetrical artefacts frequently detected on positron emission tomography-computed tomography (PET-CT), which resolved if the environment was kept warm, were brown adipose tissue deposits. PET-CT has remained the stalwart of human brown adipose tissue research and is still considered the gold standard. However, PET-CT exposes the participant to ionising radiation, limiting studies to large, but retrospective, review of clinical imaging or a small-scale, but prospective, design. Within this context, alternative imaging modalities have been sought. Due to the heat-generating properties of brown adipose tissue, infrared thermography is a natural candidate for measuring its activity and the supraclavicular depot is relatively superficial, allowing detection of the heat signature. Infrared thermography is a non-invasive, non-contact technique for measuring temperature remotely. Recent developments in image analysis techniques have facilitated the use of infrared thermography to study brown adipose tissue activation in populations, and in ways, not previously feasible. PMID- 29980913 TI - Pathways of CGRP Release from Primary Sensory Neurons. AB - The benefit reported in a variety of clinical trials by a series of small molecule antagonists for the calcitonin gene-related peptide (CGRP) receptor, or four monoclonal antibodies against the neuropeptide or its receptor, has underscored the release of CGRP from terminals of primary sensory neurons, including trigeminal neurons, as one of the major mechanisms of migraine headaches. A large variety of excitatory ion channels and receptors have been reported to elicit CGRP release, thus proposing these agonists as migraine provoking agents. On the other side, activators of inhibitory channels and receptors may be regarded as potential antimigraine agents. The knowledge of the intracellular pathways underlying the exocytotic process that results in CGRP secretion or its inhibition is, therefore, of importance for understanding how migraine pain originates and how to treat the disease. PMID- 29980914 TI - The Chemistry and Pharmacology of Synthetic Cannabinoid Receptor Agonists as New Psychoactive Substances: Origins. AB - Synthetic cannabinoid receptor agonists (SCRAs) have proliferated as new psychoactive substances (NPS) over the past decade. Relative to other classes of NPS, SCRAs are structurally heterogeneous; however, most SCRAs act as potent, high-efficacy agonists of cannabinoid type 1 and type 2 receptors (CB1 and CB2, respectively). Characterization of the pharmacology and toxicology of these substances is hindered by the dynamic nature of the SCRA marketplace. Beyond basic pharmacological profiling at CB1 and CB2 receptors, very little is known about the acute or chronic effects of SCRAs. Many of the effects of SCRAs are qualitatively similar to those of the Delta9-tetrahydrocannabinol (Delta9-THC) found in cannabis. However, unlike Delta9-THC, SCRAs are frequently associated with serious adverse effects, including cardiotoxicity, nephrotoxicity, and death. This chapter will provide an overview of the structure and function of the primary target for SCRAs, the CB1 receptor, and survey the structure-activity relationships of the historical SCRAs that served as templates for the earliest generations of NPS. PMID- 29980915 TI - Effects of pasireotide treatment on coagulative profile: a prospective study in patients with Cushing's disease. AB - INTRODUCTION: Cushing's disease (CD) is characterized by procoagulative profile. Treatment with cortisol-reducing medications might normalize the coagulation impairment potentially eliminating the risk of thromboembolic complications. AIM: The aim of this prospective study is to evaluate the effectiveness of 6-12 months of treatment with pasireotide (Signifor(r), Novartis) 600 ug twice daily on coagulative factors in 21 patients (16 females, mean age 46 +/- 12.2 years) with CD. Biochemical, hormonal (urinary free cortisol, UFC; late night salivary cortisol, LNSC; ACTH) and coagulative parameters as Protrombin time (PT), aPTT, factors VIII, IX and XI, antithrombin III, protein C, protein S, fibrinogen, were evaluated at baseline and during therapy. RESULTS: UFC showed a significant reduction from baseline (3.2 +/- 1.8 vs. 1.0 +/- 0.8, p < 0.0001) with normalization in 13/21 (61.9%) and in 7/16 (43.8%) at 6 and 12 months, respectively. On the same way LNSC returned to normal in 5/11 at 6 months, showing a trend to reduction (8.6 +/- 5 vs. 4.1 +/- 2.9), even though without statistical significance (p = 0.07). Throughout the treatment period there was an increase in serum glycaemia (5.5 +/- 2.3 vs. 6.8 +/- 2.3 mmol/L, p = 0.09), with a concomitant significant increase in HbA1c after 6 months (40.7 +/- 8.4 vs. 50.7 +/- 12.3 mmol/mol, p = 0.006). Regarding coagulative parameters, no differences were found neither in clotting nor in anticoagulant factors during therapy. No patients developed thrombotic complication during treatment. CONCLUSIONS: Pasireotide resulted an effective treatment in controlling hypercortisolism in more than half of CD patients with partial restoration also of circadian cortisol secretion. No significant improvements were observed on clotting factors; this fact might depend on persistence of typical alteration of CD, such as obesity and hypertension, and reflects also on the worsening in glucide metabolism induced by the drug. Clinical implications of persistent procoagulative impairment while on medical therapy should be considered. PMID- 29980916 TI - Normal liver tissue change after proton beam therapy. AB - PURPOSE: Normal liver tissue changes after proton beam therapy (PBT) were investigated in patients at 1 and 2 years after the therapy. MATERIALS AND METHODS: Changes in normal liver tissue volume were examined. The dose distribution of the normal liver tissue was also simulated on the follow-up CTs. RESULTS: The normal liver tissue volume was 1149 +/- 215 cm3 before treatment, 1089 +/- 188 cm3 at 1 year, and 1080 +/- 236 cm3 at 2 years after treatment. The normal liver tissue volume was increased in 10 and decreased in 20 patients at 2 years and was smaller than that before the treatment in total (P = 0.03). The simulated volume that received more than 30 Gray equivalent [V30 (cm3)] at 1 year was 258 +/- 187 cm3 and that at 2 years (244 +/- 171 cm3) was smaller than that before treatment (297 +/- 140 cm3) (P = 0.03). CONCLUSIONS: The changes in the shape and volume of normal liver tissue are not constant, which cause a large dose distribution discrepancy in the normal liver for 2 years. Therefore, careful consideration of the dose distribution of normal liver tissue is required when planning re-irradiation. PMID- 29980917 TI - Intravitreal bevacizumab treatment reduces ocular blood flow in retinopathy of prematurity: a four-case report. AB - PURPOSE: To evaluate the relationship between ocular blood flow, expressed as mean blur rate (MBR) by laser speckle flowgraphy, and intravitreal bevacizumab (IVB) therapy in neonates with retinopathy of prematurity (ROP). METHODS: This was a case series study of 4 neonates with ROP under sedation before and after IVB and evaluated 8 eyes, in which the circulation could be measured three times consecutively. We performed optic nerve head blood flow measurement and fluorescein angiography (FA) before and 1 week after treatment. Blood flow was analyzed separately for MBR-A (mean of all values), MBR-V (vessel mean), and MBR T (tissue mean). Comparisons between the MBR (-A, -V, -T), body weight, and other systemic and ocular parameters before and after treatment were performed using a paired t test. RESULTS: The MBR values after IVB were lower than the pre treatment values in all cases. All eyes showed leakage at neovascularization on FA before treatment. Although leakage improved 1 week after treatment, the neovascularization did not completely regress. CONCLUSIONS: IVB improves vein dilation and artery tortuosity, while reducing ocular blood flow in neonates with ROP. We suggest that neovascularization might not be involved in reducing ocular blood flow in the early stage of IVB treatment. PMID- 29980918 TI - Superficial and deep retinal foveal avascular zone OCTA findings of non infectious anterior and posterior uveitis. AB - PURPOSE: To compare the superficial (FAZ-S) and deep foveal avascular zones (FAZ D) of non-infectious anterior and posterior uveitis to healthy controls, using optical coherence tomography angiography (OCTA). METHODS: OCTA was performed on 74 eyes: 34 eyes with non-infectious posterior uveitis (with (post+CME) and without macular edema (post-CME)), 11 eyes with non-infectious anterior uveitis (with (ant+CME) and without macular edema (ant-CME)), and the control group which included 29 healthy eyes. RESULTS: Eyes suffering from non-infectious posterior uveitis presented with significantly larger FAZ-D when compared to healthy controls, both in the presence or in the absence of macular edema (p < 0.001). In the presence of macular edema, eyes presenting with anterior uveitis (ant+CME) also showed significantly larger FAZ-S (p = 0.03) and FAZ-D (p < 0.001), when compared to healthy controls. In the absence of macular edema, eyes with anterior uveitis cannot be distinguished from controls (p > 0.6). CONCLUSION: The deep retinal foveal avascular zone seems to be enlarged in eyes presenting with non infectious posterior uveitis, both in the presence or absence of macular edema. PMID- 29980919 TI - Comparative analysis of visual outcomes, reading skills, contrast sensitivity, and patient satisfaction with two models of trifocal diffractive intraocular lenses and an extended range of vision intraocular lens. AB - PURPOSE: To compare visual and contrast sensitivity (CS) outcomes, reading skills, and spectacle independence in patients implanted with two models of trifocal intraocular lenses (IOLs) or an extended range of vision (ERV) IOL. METHODS: This non-randomized prospective series of cases included 120 eyes of 60 patients undergoing cataract surgery with bilateral implantation of three different IOLs: the ERV IOL Tecnis Symfony (40 eyes) (Abbott Medical Optics), the trifocal IOLs PanOptix IQ (40 eyes) (Alcon), and AT LISA tri 839MP (40 eyes) (Carl Zeiss Meditec). Visual results, photopic and mesopic CS, binocular reading skills (MNREAD charts), and patient satisfaction were evaluated 3 months after surgery. RESULTS: There was no statistically significant difference between groups regarding uncorrected and corrected distance visual acuity. The Tecnis Symfony IOL showed better mesopic intermediate visual outcomes than the two trifocal IOLs (p < 0.05 vs AT LISA). Under photopic conditions, AT LISA tri 839MP and PanOptix IQ showed better near visual outcomes compared with the ERV IOL (p < 0.05 to p < 0.001). The Tecnis Symfony IOL provided significantly better photopic and mesopic CS outcomes than the other IOL models (p < 0.001). Reading skills were not significantly different between the three IOL models (p > 0.05). Less patients implanted with the two trifocal IOLs required a near addition than patients with the ERV IOL. CONCLUSIONS: All the tested IOLs provided good visual outcome, reading performance, and spectacle independence after cataract surgery. While trifocal IOLs gave better near visual acuity results, the ERV IOL provided better contrast sensitivity. PMID- 29980920 TI - Medicolegal Complications of Apnoea Testing for Determination of Brain Death. AB - Recently, there have been a number of lawsuits in the United States in which families objected to performance of apnoea testing for determination of brain death. The courts reached conflicting determinations in these cases. We discuss the medicolegal complications associated with apnoea testing that are highlighted by these cases and our position that the decision to perform apnoea testing should be made by clinicians, not families, judges, or juries. PMID- 29980921 TI - Axonal myelin decrease in the splenium in major depressive disorder. AB - The corpus callosum has become a key area of interest for researchers in severe mental illness. Disruptions in fractional anisotropy in the callosum have been reported in schizophrenia and major depressive disorder. No change has been reported in oligodendrocyte density and overall size of the callosum in either illness, suggesting that gross morphology is unchanged, but subtler organisational disruption may exist within this structure. Using high-resolution oil immersion microscopy, we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath; and using standard high-resolution light microscopy, we measured the density of myelinated axons. These measurements were made in the splenium of the corpus callosum. Measures were taken in the sagittal plane in the callosal splenium to contrast with the previous similar examination of the callosal genu. Cases of major depressive disorder had significantly decreased mean myelin cross-sectional area (p = 0.014) per axon in the splenium than in controls or schizophrenia groups. There was no significant change in the density of myelinated axons. The results suggest a clear decrease of myelin in the axons of the callosal splenium in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. In contrast with increased myelin in the callosal genu, this result suggests a longitudinal change in callosal myelination in major depressive disorder not present in normal or schizophrenic brains. PMID- 29980922 TI - Influence of gauche effect on uncharged oxime reactivators for the reactivation of tabun-inhibited AChE: quantum chemical and steered molecular dynamics studies. AB - The neutral oxime reactivator RS194B with a seven-membered ring has shown better efficacy towards the tabun-inhibited AChE than that of RS69N with a six-membered ring and RS41A with a five-membered ring. The difference in the efficacy of these reactivators has remained unexplored. We report here the origin of the difference of efficacy of these reactivators based on the conformational analysis, quantum chemical calculations and steered molecular dynamics (SMD) simulations. The conformational analysis using B3LYP/6-31G(d) level of theory revealed that RS41A and RS194B are more stable in gauche conformation due to the gauche effect (-N-C C-N- bonds) whereas RS69N prefers anti-conformation. The SMD simulations show that RS194B retains in more stable gauche conformation inside the active gorge of AChE during different time intervals that experiences more hydrogen bonding, hydrophobic interactions with the catalytic anionic site (CAS) residues and weaker interactions with the peripheral anionic site (PAS) residues compared to RS41A and RS69N. In an effort to design an even superior reactivator, RS194B-S has been chosen with a subtle change in the geometry of RS194B by replacing the carbonyl oxygen with the sulfur atom. The newly designed reactivator RS194B-S can also be a promising candidate to reactivate tabun-inhibited AChE. PMID- 29980923 TI - Demystifying the pH dependent conformational changes of human heparanase pertaining to structure-function relationships: an in silico approach. AB - Heparanase (HPSE) is an endo-beta-D-glucuronidase that has diverse functions in mammals which includes cell survival, cell adhesion and cell migration. HPSE features both enzymatic and non-enzymatic functionalities in a pH dependent manner. Hence, in this study, an extensive molecular dynamics simulation, molecular docking, protein Angular dispersion analysis were performed for apo form and holo forms to understand its conformational changes at varied pH conditions. On comparative conformational analysis of apo and holo forms, it was inferred that the HSPE has undergone pH dependent structural changes, thereby affecting the binding of Heparan sulfate proteoglycan (HSPG). Moreover, HPSE also showed favourable structural changes for optimal binding of HSPG at pH 5.0 and 6.0, as inferred from functional flap displacements within HPSE. Thus, this study provides significant insights on optimal pH for HPSE to exhibit its enzymatic activity. The outcome of this study shall aid in ideal lead generation for targeting HPSE mediated disease conditions. PMID- 29980924 TI - A novel method for prediction of stone composition: the average and difference of Hounsfield units and their cut-off values. AB - PURPOSE: The purpose of the study was to investigate the predictive value of stone measurements by including a novel method on non-contrast computed tomography (NCCT) images for stone composition. METHODS: We retrospectively evaluated patients who had stone analysis, NCCT images, and underwent percutaneous nephrolithotomy between 2013 and 2016. Patient characteristics, stone measurements on NCCT images, and stone analysis results were evaluated. Hounsfield unit (HU) values (maximum (HUmax), minimum (HUmin), and average (HUave) of HU values) were investigated on NCCT images. HUdiff was calculated as the difference between the HUmax and the HUmin values. Patients were divided into seven stone groups and data were compared. Then patients were separately divided into two groups according to mineral complexity (mono-mineral and multi-mineral groups) and calcium-based (calcium and other stone groups) evaluation. RESULTS: In the study, 115 patients were evaluated. Age, gender, HUmin, HUmax, and HUave were significantly different between the stone groups. HUdiff and HUave were found to be 341.5 HU (AUC = 0.719, p = 0.017) and 1051.5 HU (AUC = 0.701, p = 0.029) as cut-off, respectively. Seventy of 72 > 341.5 HUdiff patients and 64 of 67 > 1051.5 HUave patients had multi-mineral stones (p = 0.001, OR 9.26, and p = 0.028, OR 4.27), respectively. In multivariate analysis, > 341.5 HUdiff rate was significantly higher in multi-mineral and calcium stone groups; HUave was also significantly higher in the calcium stone group. CONCLUSIONS: HUdiff and HUave were significant predictors of mineral complexity. HUdiff of < 341.5 HU showed 81.8% sensitivity and 67.2% specificity for identification of mono-mineral stones. PMID- 29980925 TI - Bitter taste sensitivity, food intake, and risk of malignant cancer in the UK Women's Cohort Study. AB - PURPOSE: There is variability in sensitivity to bitter tastes. Taste 2 Receptor (TAS2R)38 binds to bitter tastants including phenylthiocarbamide (PTC). Many foods with putative cancer preventive activity have bitter tastes. We examined the relationship between PTC sensitivity or TAS2R38 diplotype, food intake, and cancer risk in the UK Women's Cohort Study. METHODS: PTC taste phenotype (n = 5500) and TAS238 diplotype (n = 750) were determined in a subset of the cohort. Food intake was determined using a 217-item food-frequency questionnaire. Cancer incidence was obtained from the National Health Service Central Register. Hazard ratios (HR) were estimated using multivariable Cox proportional hazard models. RESULTS: PTC tasters [HR 1.30, 95% confidence interval (CI) 1.04, 1.62], but not supertasters (HR 0.98, CI 0.76, 1.44), had increased cancer risk compared to nontasters. An interaction was found between phenotype and age for supertasters (p = 0.019) but not tasters (p = 0.54). Among women > 60 years, tasters (HR 1.40, CI 1.03, 1.90) and supertasters (HR 1.58, CI 1.06, 2.36) had increased cancer risk compared to nontasters, but no such association was observed among women <= 60 years (tasters HR 1.16, CI 0.84, 1.62; supertasters HR 0.54, CI 0.31, 0.94). We found no association between TAS2R38 diplotype and cancer risk. We observed no major differences in bitter fruit and vegetable intake. CONCLUSION: These results suggest that the relationship between PTC taster phenotype and cancer risk may be mediated by factors other than fruit and vegetable intake. PMID- 29980926 TI - Benign anastomotic biliary strictures untreatable by ERCP: a novel percutaneous balloon dilatation technique avoiding indwelling catheters. AB - OBJECTIVE: To evaluate long-term patency rates of a novel percutaneous threefold balloon dilatation protocol in benign anastomotic biliary strictures. METHODS: Patients with a benign biliary stricture after hepatobiliary surgery or liver transplantation, untreatable with endoscopy, underwent a percutaneous treatment cycle consisting of a 20-min balloon dilatation session on day one, repeated on days three and five. No catheters were left behind after the last dilatation session. Technical and clinical success as well as complications were analysed. Mean primary and secondary patency times were assessed. Cumulative primary and secondary patency rates at 6 months and 1, 2 and 3 years were determined. RESULTS: Seventy patients underwent 135 dilatation treatment cycles (mean 1.9) with a technical success rate of 99%. Clinical success was achieved in 87% of the patients. Fifty-eight of 135 (43%) patients had minor and 15/135 (11%) had major complications. Mean primary and secondary patency times were 26 months and 46 months, respectively, with a median follow-up of 69 months. Cumulative primary patency rate at 6 months was 67%, at 1 year 56%, at 2 years 41% and at 3 years 36%. The cumulative secondary patency rate at 6 months was 83%, at 1 year 79%, at 2 years 70% and at 3 years 64%. CONCLUSION: In benign anastomotic biliary strictures, a percutaneous threefold balloon dilatation treatment is effective. As long indwelling catheters are avoided, patient comfort improves. KEY POINTS: * Percutaneous threefold balloon dilatation treatment is effective in benign anastomotic biliary strictures. * As indwelling catheters after dilatation are avoided, patient comfort improves. * The dilatation protocol can be repeated efficiently in case of recurrent stricture. PMID- 29980927 TI - FDG-PET/MRI in patients with pelvic recurrence of rectal cancer: first clinical experiences. AB - OBJECTIVES: To determine the value of 18F-FDG-PET/MRI in the diagnosis and management of patients with pelvic recurrence of rectal cancer. METHODS: Forty four patients (16 women, 28 men) with a history of rectal cancer who received FDG PET/MRI between June 2011 and February 2017 at our institution were retrospectively enrolled. Three patients received two FDG-PET/MRIs; thus a total of 47 examinations were included. Pelvic recurrence was confirmed either with histology (n = 27) or imaging follow-up (n = 17) (> 4 months). Two readers (one radiologist, one nuclear medicine physician) interpreted the images in consensus. Pelvic lesions were assessed regarding FDG uptake and morphology. Sensitivity, specificity, positive and negative predictive values as well as accuracy of PET/MRI in detecting recurrence were determined. RESULTS: In 47 FDG-PET/MRIs 30 suspicious pelvic lesions were identified, 29 of which were malignant. Two patients underwent resection and had histologically proven pelvic recurrence without showing suspicious findings on FDG-PET/MRI. Changes in management due to FDG-PET/MRI findings had been implemented in eight patients. Eighty per cent (16/20) of resected patients had histologically negative resection margins (R0), one patient had uncertain resection margins. Sensitivity of FDG-PET/MRI in detecting recurrence was 94%, specificity 94%, positive/negative predictive value and accuracy were 97%, 90% and 94%, respectively. CONCLUSIONS: FDG-PET/MRI is a valuable tool in the diagnosis and staging of pelvic recurrence in patients with rectal cancer. KEY POINTS: * Metabolic information obtained from PET coupled with excellent soft tissue contrast from MRI could facilitate detection of rectal cancer recurrence and assist in treatment planning. * PET/MRI demonstrates high sensitivity and specificity for the diagnosis of local recurrence of rectal cancer * PET/MRI led to alterations in management in 18.2% of patients. PMID- 29980928 TI - Medical students' attitude towards artificial intelligence: a multicentre survey. AB - OBJECTIVES: To assess undergraduate medical students' attitudes towards artificial intelligence (AI) in radiology and medicine. MATERIALS AND METHODS: A web-based questionnaire was designed using SurveyMonkey, and was sent out to students at three major medical schools. It consisted of various sections aiming to evaluate the students' prior knowledge of AI in radiology and beyond, as well as their attitude towards AI in radiology specifically and in medicine in general. Respondents' anonymity was ensured. RESULTS: A total of 263 students (166 female, 94 male, median age 23 years) responded to the questionnaire. Around 52% were aware of the ongoing discussion about AI in radiology and 68% stated that they were unaware of the technologies involved. Respondents agreed that AI could potentially detect pathologies in radiological examinations (83%) but felt that AI would not be able to establish a definite diagnosis (56%). The majority agreed that AI will revolutionise and improve radiology (77% and 86%), while disagreeing with statements that human radiologists will be replaced (83%). Over two-thirds agreed on the need for AI to be included in medical training (71%). In sub-group analyses male and tech-savvy respondents were more confident on the benefits of AI and less fearful of these technologies. CONCLUSION: Contrary to anecdotes published in the media, undergraduate medical students do not worry that AI will replace human radiologists, and are aware of the potential applications and implications of AI on radiology and medicine. Radiology should take the lead in educating students about these emerging technologies. KEY POINTS: * Medical students are aware of the potential applications and implications of AI in radiology and medicine in general. * Medical students do not worry that the human radiologist or physician will be replaced. * Artificial intelligence should be included in medical training. PMID- 29980929 TI - Microvascular perfusion in infarcted and remote myocardium after successful primary PCI: angiographic and CMR findings. AB - OBJECTIVES: The aim of this study was to investigate the association between TIMI myocardial perfusion (TMP) grading acute and cardiac magnetic resonance (CMR) first-pass perfusion early and at 4 months in patients with ST-segment-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention (PCI). MATERIAL AND METHODS: One hundred ninety-eight STEMI patients were recruited from the POSTEMI study. TMP grade was assessed after PCI; CMR was performed at day 2 and after 4 months. Signal intensity was measured on first pass perfusion images, and a maximum contrast enhancement index (MCE) was calculated. RESULTS: Patients with TMP grade 2-3 (n = 108) after PCI had significantly better EF (59 +/- 10 vs. 51 +/- 13, p < 0.001) and smaller infarct volume (12 +/- 8 vs. 19 +/- 12 %, p < 0.001) at 4 months compared with patients with TMP grade 0-1 (n = 81). MCE in the infarcted (MCEi) and remote myocardium (MCEr) improved from early to follow-up CMR, MCEi from 94 +/- 56 to 126 +/- 59, p < 0.001, and MCEr from 112 +/- 51 to 127 +/- 50, p < 0.001. In patients with the lowest CMR perfusion early, perfusion at 4 months remained decreased compared with the other groups, MCEi 108 +/- 75 vs. 133 +/- 51, p = 0.01, and MCEr 115 +/- 41 vs. 131 +/- 52, p = 0.047. CONCLUSION: TMP grade and early CMR first-pass perfusion were associated with CMR outcomes at 4 months. First-pass perfusion improved after 4 months in the infarcted and remote myocardium. However, in patients with the lowest CMR perfusion early, perfusion was still reduced after 4 months. KEY POINTS: * Cardiac magnetic resonance myocardial first-pass perfusion and TMP grading after successful PCI helps to assess risk in patients with ST elevation myocardial infarction. * Cardiac magnetic resonance myocardial first pass perfusion shows that microvascular perfusion after ST elevation myocardial infarction can be impaired in both infarcted and non-infarcted myocardium. * Microvascular perfusion improves over time in patients with ST elevation myocardial infarction treated with primary PCI. PMID- 29980930 TI - Study of pallial neurogenesis in shark embryos and the evolutionary origin of the subventricular zone. AB - The dorsal part of the developing telencephalon is one of the brain areas that has suffered most drastic changes throughout vertebrate evolution. Its evolutionary increase in complexity was thought to be partly achieved by the appearance of a new neurogenic niche in the embryonic subventricular zone (SVZ). Here, a new kind of amplifying progenitors (basal progenitors) expressing Tbr2, undergo a second round of divisions, which is believed to have contributed to the expansion of the neocortex. Accordingly, the existence of a pallial SVZ has been classically considered exclusive of mammals. However, the lack of studies in ancient vertebrates precludes any clear conclusion about the evolutionary origin of the SVZ and the neurogenic mechanisms that rule pallial development. In this work, we explore pallial neurogenesis in a basal vertebrate, the shark Scyliorhinus canicula, through the study of the expression patterns of several neurogenic markers. We found that apical progenitors and radial migration are present in sharks, and therefore, their presence must be highly conserved throughout evolution. Surprisingly, we detected a subventricular band of ScTbr2 expressing cells, some of which also expressed mitotic markers, indicating that the existence of basal progenitors should be considered an ancestral condition rather than a novelty of mammals or amniotes. Finally, we report that the transcriptional program for the specification of glutamatergic pallial cells (Pax6, Tbr2, NeuroD, Tbr1) is also present in sharks. However, the segregation of these markers into different cell types is not clear yet, which may be linked to the lack of layering in anamniotes. PMID- 29980931 TI - Clusters of DCX+ cells "trapped" in the subcortical white matter of early postnatal Cetartiodactyla (Tursiops truncatus, Stenella coeruloalba and Ovis aries). AB - The cytoskeletal protein doublecortin (DCX) is a marker for neuronal cells retaining high potential for structural plasticity, originating from both embryonic and adult neurogenic processes. Some of these cells have been described in the subcortical white matter of neonatal and postnatal mammals. In mice and humans it has been shown they are young neurons migrating through the white matter after birth, reaching the cortex in a sort of protracted neurogenesis. Here we show that DCX+ cells in the white matter of neonatal and young Cetartiodactyla (dolphin and sheep) form large clusters which are not newly generated (in sheep, and likely neither in dolphins) and do not reach the cortical layers, rather appearing "trapped" in the white matter tissue. No direct contact or continuity can be observed between the subventricular zone region and the DCX+ clusters, thus indicating their independence from any neurogenic source (in dolphins further confirmed by the recent demonstration that periventricular neurogenesis is inactive since birth). Cetartiodactyla include two orders of large-brained, relatively long-living mammals (cetaceans and artiodactyls) which were recognized as two separate monophyletic clades until recently, yet, despite the evident morphological distinctions, they are monophyletic in origin. The brain of Cetartiodactyla is characterized by an advanced stage of development at birth, a feature that might explain the occurrence of "static" cell clusters confined within their white matter. These results further confirm the existence of high heterogeneity in the occurrence, distribution and types of structural plasticity among mammals, supporting the emerging view that multiple populations of DCX+, non-newly generated cells can be abundant in large-brained, long-living species. PMID- 29980932 TI - Mini-biography for Mr. Xitao Cai: the pioneer botanist of the plant kingdom. PMID- 29980933 TI - TMEM43-S358L mutation enhances NF-kappaB-TGFbeta signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic cardiac muscle disease that accounts for approximately 30% sudden cardiac death in young adults. The Ser358Leu mutation of transmembrane protein 43 (TMEM43) was commonly identified in the patients of highly lethal and fully penetrant ARVD subtype, ARVD5. Here, we generated TMEM43 S358L mouse to explore the underlying mechanism. This mouse strain showed the classic pathologies of ARVD patients, including structural abnormalities and cardiac fibrofatty. TMEM43 S358L mutation led to hyper-activated nuclear factor kappaB (NF-kappaB) activation in heart tissues and primary cardiomyocyte cells. Importantly, this hyper activation of NF kappaB directly drove the expression of pro-fibrotic gene, transforming growth factor beta (TGFbeta1), and enhanced downstream signal, indicating that TMEM43 S358L mutation up-regulates NF-kappaB-TGFbeta signal cascade during ARVD cardiac fibrosis. Our study partially reveals the regulatory mechanism of ARVD development. PMID- 29980934 TI - Correlation between relative bacterial activity and lactate dehydrogenase gene expression of co-cultures in vitro. AB - OBJECTIVES: The present study aims at correlating the relative bacterial activity with the H+ concentration and the ldh expression of caries-associated bacteria in co-cultures. MATERIALS AND METHODS: Well plates were prepared with BHI medium and cultures of Lactobacillus paracasei and Fusobacterium nucleatum. Bacterial growth at 37 degrees C was measured using a microplate-photometer before and after adding sucrose to the samples. Samples of co-cultures (n = 12) and single-species cultures (n = 3) were taken and pH was assessed. Real-time quantitative PCRs were applied targeting the 16S-gene, the 16S-rRNA, the ldh-gene, and the ldh-mRNA. RESULTS: For L. paracasei with sucrose, an increase in relative bacterial activity (62.8% +/- 23.5% [mean, SE]) was observed, while F. nucleatum showed a clear decrease in relative bacterial activity (- 35.0% +/- 9.6%). Simultaneously, the H+ concentration increased (1.15E-05 mol*l-1 +/- 4.61E-07 mol*l-1). Consequently, a significant positive correlation was found between L. paracasei's relative bacterial activity and H+ concentration (Spearman rank correlation, r = 0.638; p = 0.002), while F. nucleatum exhibited a negative correlation (r = - 0.741; p <= 0.001). Furthermore L. paracasei with sucrose showed a moderate, but significant positive correlation between relative bacterial activity and ldh expression (r = 0.307; p = 0.024). CONCLUSIONS AND CLINICAL RELEVANCE: The relative bacterial activity after sucrose pulse showed a significant correlation not only to the acid production (H+ concentration) but also to ldh expression of L. paracasei. However, further research is required to confirm these findings in a mature biofilm in vivo. PMID- 29980935 TI - Skin Involvement in Psoriatic Arthritis Worsens Overall Disease Activity, Patient Reported Outcomes, and Increases Healthcare Resource Utilization: An Observational, Cross-Sectional Study. AB - INTRODUCTION: Psoriatic arthritis (PsA) is an inflammatory arthropathy that exhibits heterogeneity in clinical presentation and severity of skin and joint symptoms. This heterogeneity results in an incomplete understanding of the relationship between the skin and joint components of PsA, and their relative impact on PsA disease activity and patient-reported outcomes. The objective of the study was to Investigate the clinical presentation of joint and active skin symptom involvement and the associated impact on physician- and patient-reported outcomes [patient global assessment (PtGA), health-related quality of life (HRQoL), and physical function), and healthcare resource burden in patients with PsA. METHODS: This was a retrospective analysis of the Adelphi 2015 PsA Disease Specific Programme, a real-world, cross-sectional survey of rheumatologists and their consulting PsA patients from the USA and Europe (France, Germany, Italy, Spain, and UK). The sample included data collected during the fourth quarter of 2015, on 1201 patients from 410 rheumatologists. Physician-reported joint and active skin symptom involvement were investigated for associations with clinical outcomes, patient/physician-reported outcomes, and healthcare resource utilization (HCRU). RESULTS: The majority of patients with PsA with documented skin involvement had both joint and active skin involvement (80.9%, njoint+skin = 515, njoint only = 122, noverall = 637). Patients with skin involvement possessed a more severe global clinical profile, and the PsA clinical symptom severity profile positively correlated with skin severity. Physician global assessment scores were not significantly different in patients with joint-only involvement vs. joint with active skin involvement. Patients with skin involvement in PsA possessed significantly worse PtGA scores and increased HCRU. CONCLUSION: Patients with PsA involving both joint and active skin symptoms exhibit a more severe overall disease state, worse patient-reported outcomes, and increased HCRU relative to patients with joint-only involvement in PsA. These results indicate that treating skin involvement should be considered along with treating joint involvement in patients with PsA. FUNDING: Eli Lilly and Company. PMID- 29980937 TI - Emergent genital infection by Leptotrichia trevisanii. AB - We report the first case of an association between Leptotrichia trevisanii and an episode of pelvic inflammatory disease (PID) and the second case of the isolation of this infection in the cervical canal. A 45-yr-old woman was admitted to our emergency department with clinical and radiological signs and symptoms compatible with an episode of PID. She was hospitalized for intravenous antibiotic control and treatment and the subsequent surgical drainage of abscesses. Cultures were taken throughout the process, but only cultures from cervical canal exudate were positive, with the growth of L. trevisanii species. It appears important to carry out a complete microbiological screening, not limited to conventional agents, on adequate clinical samples to detect possible infectious agents that may be missed in these cases. PMID- 29980936 TI - Dihydroartemisinin-piperaquine treatment failure in uncomplicated Plasmodium falciparum malaria case imported from Ethiopia. AB - Dihydroartemisinin-piperaquine (DHA-PPQ) is the artemisinin combination therapy that was recently introduced for the treatment of Plasmodium falciparum uncomplicated malaria, but emerging resistance in South-East Asia is threatening its use. This report describes a case of DHA-PPQ treatment failure in uncomplicated malaria occurring in an immigrant living in Italy, after a travel to Ethiopia. Thirty days after malaria recovery following DHA-PPQ therapy, the patient had malaria recrudescence. According to the genotyping analysis, the same P. falciparum was responsible for both episodes. Thus, it seems important to consider possible malaria recrudescence occurring after DHA-PPQ therapy in patients from African countries. PMID- 29980938 TI - Sympathetic Nervous System, Sleep, and Hypertension. AB - PURPOSE OF REVIEW: To evaluate the relation between sleep alterations, with or without breathing disorders, and incidence of hypertension and other cardiovascular diseases RECENT FINDINGS: Several studies have clearly shown the mechanisms linking sleep disorders and cardiovascular diseases. The sympathetic hyperactivity seems to play a fundamental role in favoring and sustaining the increase in blood pressure values. Several other mechanisms also contribute to this effect and to the increase cardiovascular risk. The mechanisms responsible for the increase in blood pressure values in subjects with alteration in sleep quantity and quality, with or without breathing disorders, have been clearly established. The recent findings refer to the result of meta-analysis of cross sectional studies or longitudinal studies showing a significant association between short sleep duration and hypertension. It has also been shown that sleep fragmentation could be considered the main determinant of the sympathetic activation independently of the frequency and severity of oxygen desaturation. PMID- 29980939 TI - Correction to: A best-practice position statement on pregnancy after kidney transplantation: focusing on the unsolved questions. The Kidney and Pregnancy Study Group of the Italian Society of Nephrology. AB - In the original publication of the article, the first name and last name of the authors were interchanged. PMID- 29980940 TI - A new approach to understanding canine social cognition. AB - Domestic dogs have become well known for their socio-cognitive successes, so what does it mean when domestic dogs fail to cooperate? A new study by Marshall Pescini, Schwarz, Kostelnik, Viranyi, and Range (PNAS, 114(44) 11793-11798, 2017) highlights the importance of considering socioecological context, learning, and relationship quality when evaluating the social cognition of dogs and wolves. PMID- 29980941 TI - Would dogs copy irrelevant actions from their human caregiver? AB - Companion dogs learn easily from humans, including human behavior, human communication, and some aspects of the human-made environment. They benefit from having the opportunity to learn from humans and are able to spontaneously synchronize their behavior with that of their caregiver. Here, we tested whether pet dogs would show a special form of observational learning, one that has been considered uniquely human. Indeed, humans show overimitation, the faithful copying of causally irrelevant actions, but great apes do not. Because in humans this peculiar form of imitation is strongly motivated by social factors, such as affiliation or conformity, we hypothesized that domesticated and enculturated dogs are more likely than apes are to copy such actions, especially if shown by their affiliated caregiver. Indeed, half of the dogs replicated a causally irrelevant action that was demonstrated by their caregiver, and about the same number did this whether they saw only this action being demonstrated or being demonstrated before or after a causally relevant, functional action. The demonstration of a causally relevant action, one that is immediately followed by access to food, thus does not inhibit the copying of an action that is spatially separated and functionally opaque. Given that the copying frequency in this study was low overall, these results suggest evidence for overimitation in dogs, which might challenge the human uniqueness of this type of social learning. PMID- 29980942 TI - Interfollicular Epidermal Stem Cells: Boosting and Rescuing from Adult Skin. AB - Epidermal stem cells (EpSCs) isolation struggle remains, mainly due to the yet essential requirement of well-defined approaches and markers. The herein proposed methodology integrates an assemblage of strategies to accomplish the enrichment of the interfollicular EpSCs multipotent fraction and their subsequent separation from the remaining primary human keratinocytes (hKC) culture. Those include rapid adherence of freshly isolated hKC to collagen type IV through the beta1-integrin ligand and Rho-associated protein kinase inhibitor (Rocki) Y-27632 administration to the cultures, followed by an immunomagnetic separation to obtain populations based in the combined CD49fbri/CD71dim expression. Flow cytometry is the supporting method to analyze the effect of the treatments over the expression rate of early epidermal markers keratins19/5/14 and in correlation to CD49fbri/CD71dim sub-populations. The step-by-step methodology herein described indulges the boosting and consecutive purification and separation of interfollicular epidermal stem cells, from human keratinocytes cultures. PMID- 29980943 TI - Research of Panax spp. in Kunming Institute of Botany, CAS. AB - Panax, a genus of the Araliaceae family, is an important herbal group in traditional Chinese medicine (TCM). Nine species and three varieties are included in the genus of Panax, in which nearly all species have been used for medicinal purposes. Among them, Panax notoginseng (Burk) F. H. Chen, Panax ginseng C. A. Meyer and Panax quinquefolius L. are the most representative and valuable herbs world-wide, with a long history of cultivation. As the main bioactive chemical constituents, saponins with different aglycones are the major components in various Panax spp., and their pharmacological activities are mainly reflected in the effects on blood system, cardio- and cerebro-vascular systems, nervous system, metabolism, and immune regulation. Researchers of Kunming Institute of Botany (KIB), Chinese Academy of Sciences (CAS), have put many efforts into conducting the investigations on Panax species. Herein, we reviewed the research progress on Panax spp. in KIB, CAS, over the past few decades, from the aspects of history and origin, phytochemistry and pharmacological activities. PMID- 29980944 TI - Laser treatment contributes to maintain membrane integrity in stem cells from human exfoliated deciduous teeth (shed) under nutritional deficit. AB - This study aimed to analyze the effects of laser irradiation on the membrane integrity and viability of stem cells from human exfoliated deciduous teeth (SHED) that were kept in serum starvation. Nutritional deficit was used to mimic the cellular stress conditions of SHED isolation for regenerative dental approaches, where laser therapy could be beneficial. SHED were cultured under serum starvation (MEMalpha + 1%FBS) for 1 or 24 h pre-irradiation (protocols A and B, respectively). Then, cells received low-level laser therapy (LLLT; 660 nm) at 2.5 J/cm2 (0.10 W; groups I and V), 5.0 J/cm2 (0.20 W; groups II and VI), 7.5 J/cm2 (0.30 W; groups III and VII), or remained non-irradiated (groups IV and VIII). During irradiation, cells were maintained in 1% FBS (groups I-IV) or 10% FBS (normal culture conditions; groups V-VIII). Membrane integrity was evaluated by quantifying lactate dehydrogenase (LDH) release (immediately after irradiation), and cell viability was assessed by the MTT assay (24, 48, and 72 h post-irradiation). Serum starvation did not alter LDH release by non-irradiated SHED, while LDH release decreased significantly in groups irradiated in 1% FBS (I and III), but not in groups irradiated in 10% FBS (V-VII), regardless the pre irradiation conditions (protocols A/B). Cell viability was significantly higher 24 h after irradiation, in most protocol A groups. In contrast, cell viability remained mostly unaltered in protocol B groups. LLLT contributed to maintain membrane integrity in SHED subjected to nutritional deficit before and during irradiation with 0.10 or 0.30 W. Short serum starvation before irradiation improved SHED viability at 24 h post-irradiation. PMID- 29980945 TI - Qualitative evaluation of ferritin in serum samples by Raman spectroscopy and principal component analysis. AB - Iron molecule is of great importance in the synthesis of hemoglobin which is essential for oxygen transport. Iron levels are quantified by accurately high sensitivity tests, such as serum ferritin (SF). However, common studies to quantify SF are long and strenuous (~ 5 h), for example enzyme-linked immunosorbent assay (ELISA). In this paper, blood serum samples were analyzed by Raman spectroscopy (RS), and a computational analysis of spectra is proposed to detect differences in SF as an alternative procedure. Serum samples were obtained from 22 patients, 9 who were clinically diagnosed with anemia and 13 controls. Patients with anemia had low levels of SF (< 30 ng/ml), and a control group had levels between 30 and 500 ng/ml. The spectra obtained were conditioned with a baseline correction and smoothing, then evaluated by principal component analysis (PCA), and a predictive model was estimated by lineal discrimination analysis (LDA). The results showed a clear differentiation of the study groups by PCA, also 99.69% sensitivity and 100% specificity by LDA. This study suggest that Raman spectroscopy is a fast (~ 5 min) and a powerful tool capable to qualitative differentiate ferritin concentrations. PMID- 29980946 TI - Effectiveness of low concentration of sodium hypochlorite activated by Er,Cr:YSGG laser against Enterococcus faecalis biofilm. AB - Bacteria living in biofilms exhibit altered growth phenotypes, while the biofilm provides benefits, the foremost of which is a certain protection against both immune system and killing effect by antimicrobials. Laser-activated irrigation (LAI) and passive ultrasonic irrigation (PUI) have been proposed as alternative methods for cleaning and disinfecting the root canal, as an adjuvant to conventional chemo-mechanical preparation in order to improve debridement and disinfection. Nevertheless, the potential antibacterial effect of LAI using 0.5% of sodium hypochlorite (NaOCl) has received little attention. Glass Pasteur pipettes were used to mimic single-tooth root canal and to build Enterococcus faecalis biofilm. Several irrigants and treatments were assayed for 60 s including (I) Saline, (II) NaOCl 0.5%, (III) NaOCl 5%, (IV) Er,Cr:YSGG, (V) Saline + LAI, (VI) NaOCl 0.5% + LAI, (VII) Saline + PUI, and (VIII) NaOCl 0.5% + PUI. Bacterial reduction was measured by counting the colony-forming units (CFUs). Additionally, AFM visualization and measurement of nano-roughness parameters were used to evaluate LAI effect on bacteria. NaOCl 5% unpowered and NaOCl 0.5% + LAI were capable of eliminating all bacteria, whereas non-activated saline solution and NaOCl 0.5% failed to eliminate E. faecalis. Lower efficiencies were achieved by PUI. Surface analysis by AFM revealed apparent alterations in NaOCl + LAI-treated cells. The Er,Cr:YSGG laser-activated irrigation (LAI) increased the bactericidal efficiency of 0.5% NaOCl against E. faecalis biofilm. PMID- 29980947 TI - Comparative study of the effect of Er:YAG and Er:Cr;YSGG lasers on porcelain: etching for the bonding of orthodontic brackets. AB - This study investigated the effect of Er:YAG (smart 2940 Dplus, DEKA, Italy) and Er:CrYSGG (Waterlase iPlus, Biolase, USA) lasers on the shear bond strength (SBS) between the orthodontic brackets and dental porcelain in comparison with conventional acid etching with 9% hydrofluoric acid (HF, Ultradent, USA). A total of 60 specimens of maxillary incisor crown were prepared and randomly assigned to five groups; each group was subjected to a different porcelain surface conditioning: (1) etching with the 9% HF for 2 min; (2) etching with the 9% HF for 2 min followed by irradiation with the Er:CrYSGG laser (3-W power, 10-Hz frequency for 10 s); (3) etching with the 9% HF for 2 min followed by irradiation with the Er:YAG laser (3-W power, 10-Hz frequency for 10 s); (4) Irradiation with the Er:CrYSGG laser (3-W power, 10-Hz frequency for 10 s without acid etching) and (5) irradiation with the Er:YAG laser (3-W power,10-Hz frequency for 10 s without acid etching). After using Transbond XT primer and Transbond XT adhesive, the metal brackets (Dentaurum, Germany equilibrium 2, optimal design) bonded to the conditioned porcelain surface. Subsequently, the specimens were thermocycled for 5000 cycles and then debonded using the Universal Testing Machine (Zwick). In each group, one specimen was not bonded to brackets to allow further examination with electron microscopy. After debonding, the specimens were examined by stereomicroscope to determine their adhesive remnant index (ARI). The average SBS [Mean (SD)] values in the five groups were as follows: HF (32.58 +/- 9.21 MPa), Er:CrYSGG + HF (27.81 +/- 7.66 MPa), Er:YAG + HF (23.08 +/- 9.55 MPa), Er:CrYSGG (14.11 +/- 9.35 MPa), and Er:YAG (6.30 +/- 3.09 MPa). A statistically significant difference in SBS existed between the first three groups and the two laser groups (df = 4, F = 18.555, p < 0.001). Evaluation of ARI values showed that bond failures in the first three groups were mostly of cohesive and mixed types, but in the laser groups, they were mostly adhesive. Chi-square was not significant between groups (p = 0.219). The Er:YAG laser with the stated specifications is not a suitable alternative to HF etching. In the case of Er:CrYSGG laser, although the conditioning outcome met the bond strength requirement for orthodontic brackets (that is, 6-8 MPa). Therefore, the bond strength must be further improved by fine-tuning the irradiation details. PMID- 29980948 TI - The Resveratrol Alleviates the Hepatic Toxicity of CuSO4 in the Rat. AB - Cu is toxic to humans and other animals. Oxidative stress is an important mechanism involved in Cu toxicity. Resveratrol (RSV) is an antioxidative compound, so could counteract Cu toxicity. The aim of this study was to determine whether RSV protects the liver from the effects of CuSO4. Forty male Sprague Dawley rats (5 weeks old, 110-120 g) were divided into four groups (n = 10 per group), a control group and groups treated with CuSO4 at a dose of 200 mg/kg body weight (BW), RSV at a dose of 15 mg/kg BW, and CuSO4 at a dose of 200 mg/kg BW and RSV at a dose of 15 mg/kg BW. The treatments were orally administered for 30 days. The livers were removed from the rats at the end of the study, and the cytochrome P450, cytochrome b5, Cu, Fe, Zn, glutathione peroxidase, superoxide dismutase, reactive oxygen species, aspartate aminotransferase, and alanine aminotransferase concentrations in the livers were determined. CuSO4 decreased the BW, liver weight, and cytochrome P450, cytochrome b5, Fe, Zn, glutathione peroxidase, and superoxide dismutase concentrations but increased the Cu, aspartate aminotransferase, alanine aminotransferase, and reactive oxygen species concentrations relative to the control group. RSV alleviated the toxic effects of CuSO4 on the liver, indicating that RSV attenuates CuSO4-induced liver injury by decreasing the liver transaminase concentration and oxidative stress, promoting antioxidative activity and cytochrome P450 enzymes, and maintaining balance in the trace element concentrations. The results indicate that RSV could be used to treat CuSO4 toxicity. PMID- 29980949 TI - Suppressive Role of Boron on Adipogenic Differentiation and Fat Deposition in Human Mesenchymal Stem Cells. AB - Over the past years, adipose tissue has become an invaluable source of mesenchymal stem cells (MSCs) due to development of improved isolation methodologies. In a recent work, our group established a primary culture of human adipose-derived stem cells (hADSCs), which were characterized for their stem cell characteristics in detail and studied their myogenic differentiation potential in presence of boron. In the current study, we focused on the effects of a boron containing compound, sodium pentaborate pentahydrate (NaB), on the adipogenic differentiation of hADSCs. Incorporation of boron in various chemical derivates has been a novel interest in drug-discovery attempts due to increasing number of reports on their anticancer, antibacterial, antiviral, and antifungal activities. In this report, a striking suppressive activity of boron on adipogenic differentiation of hADSCs is observed in a dose-dependent manner. Higher concentrations of NaB (20, 50, and 100 MUg/mL (68, 170 and 340 MUM)) resulted in a progressive decrease of lipid deposition, suppressed master regulators of adipogenesis transcriptional programming at the mRNA and protein levels, while having no evident cytotoxicity on the cells. The findings of this study are encouraging to undertake further investigations on potential beneficial effects boron in terms of its impact on normal and dysfunctional adipose biology. In that respect, these results pave the path to evaluate boron-based compounds in prevention and treatment of obesity which is a modern age pandemic that is predominant worldwide and found in strong association with comorbidities, including type 2 diabetes, hypertension, cardiovascular disease, cancers, and others." PMID- 29980950 TI - Valuation of preference-based measures: can existing preference data be used to select a smaller sample of health states? AB - BACKGROUND: Different countries have different preferences regarding health, and there are different value sets for popular preference-based measures across different countries. However, the cost of collecting data to generate country specific value sets can be prohibitive for countries with smaller population size or low- and middle-income countries (LMIC). This paper explores whether existing preference weights could be modelled alongside a small own country valuation study to generate representative estimates. This is explored using a case study modelling UK data alongside smaller US samples to generate US estimates. METHODS: We analyse EQ-5D valuation data derived from representative samples of the US and UK populations using time trade-off to value 42 health states. A nonparametric Bayesian model was applied to estimate a US value set using the full UK dataset and subsets of the US dataset for 10, 15, 20 and 25 health states. Estimates are compared to a US value set estimated using US values alone using mean predictions and root mean square error. RESULTS: The results suggest that using US data elicited for 20 health states alongside the existing UK data produces similar predicted mean valuations and RMSE as the US value set, while 25 health states produce the exact features. CONCLUSIONS: The promising results suggest that existing preference data could be combined with a small valuation study in a new country to generate preference weights, making own country value sets more achievable for LMIC. Further research is encouraged. PMID- 29980952 TI - Positive correlation between the density of macrophages and T-cells in undifferentiated sarcoma. AB - Undifferentiated sarcoma (US) is a frequent soft tissue sarcoma. Although the 10 year survival rate is around 60%, advanced US is highly resistant to chemo/radiotherapy. The tumor microenvironment (TME) is closely associated with tumor progression. However, few studies of infiltrated immune cells in US have been published. In this study, we evaluated tumor-associated macrophages (TAMs) and CD8-positive cytotoxic T lymphocytes (CTLs) in 28 cases of US. Iba1, CD163, and CD204 were used as markers for TAMs. The density of CTLs was positively correlated with the density of TAMs. However, a negative correlation was seen between the density of CTLs and the percentage of CD204-positive TAMs. We found no significant association between the density of Iba1-/CD204-/CD8-positive cells and clinicopathological factors. No significant correlation between immune cell infiltration and clinical outcome was observed. Although we found no significant association between immune cells and clinicopathological factors, these findings may provide new insight into the characterization of immune cells in the TME of US. PMID- 29980951 TI - Potential Role of Antihypertensive Medications in Preventing Excessive Arterial Stiffening. AB - PURPOSE OF REVIEW: Increased arterial stiffness, an abnormal structural and functional change in the vascular wall, is a precursor for hypertension, coronary heart disease, stroke, and associated cardiovascular disease (CVD). The aim of this paper is to review the etiology of arterial stiffening and potential therapeutic approaches to modulate arterial fibrosis and stiffness. RECENT FINDINGS: The Framingham Heart Study demonstrated that arterial stiffness is an independent predictor of CVD and related morbidity and mortality. Dysfunction of endothelial cells, vascular smooth muscle cells, extracellular matrix, and other functional elements of the vessel wall contribute to underlying pathophysiology of increased arterial stiffness. An activated renin-angiotensin-aldosterone system, oxidative stress, abnormal peri-vascular adipose tissue, inflammation, and increased sympathetic nervous system activity are associated with the development and progression of arterial fibrosis, stiffening, and associated CVD. In this review, we will discuss the structural and function changes and mechanisms of the vessel wall in arterial stiffness and provide potential therapeutic strategies. PMID- 29980953 TI - How useful are hemoglobin concentration and its variations to predict significant hemorrhage in the early phase of trauma? A multicentric cohort study. AB - BACKGROUND: The diagnostic value of hemoglobin (Hb) for detecting a significant hemorrhage (SH) in the early phase of trauma remains controversial. The present study aimed to assess the abilities of Hb measurements taken at different times throughout trauma management to identify patients with SH. METHODS: All consecutive adult trauma patients directly admitted to six French level-1 trauma centers with at least one prehospital Hb measurement were analyzed. The abilities of the following variables to identify SH (>= 4 units of red blood cells in the first 6 h and/or death related to uncontrolled bleeding within 24 h) were determined and compared to that of shock index (SI): Hb as measured with a point of-care (POC) device by the prehospital team on scene (POC-Hbprehosp) and upon patient's admission to the hospital (POC-Hbhosp), the difference between POC Hbhosp and POC-Hbprehosp (DeltaPOC-Hb) and Hb as measured by the hospital laboratory on admission (Hb-Labhosp). RESULTS: A total of 6402 patients were included, 755 with SH and 5647 controls (CL). POC-Hbprehosp significantly predicted SH with an area under ROC curve (AUC) of 0.72 and best cutoff values of 12 g/dl for women and 13 g/dl for men. POC-Hbprehosp < 12 g/dl had 90% specificity to predict of SH. POC-Hbhosp and Hb-Labhosp (AUCs of 0.92 and 0.89, respectively) predicted SH better than SI (AUC = 0.77, p < 0.001); best cutoff values of POC-Hbhosp were 10 g/dl for women and 12 g/dl for men. DeltaPOC-Hb also predicted SH with an AUC of 0.77, a best cutoff value of - 2 g/dl irrespective of the gender. For a same prehospital fluid volume infused, DeltaPOC-Hb was significantly larger in patients with significant hemorrhage than in controls. CONCLUSIONS: Challenging the classical idea that early Hb measurement is not meaningful in predicting SH, POC-Hbprehosp was able, albeit modestly, to predict significant hemorrhage. POC-Hbhosp had a greater ability to predict SH when compared to shock index. For a given prehospital fluid volume infused, the magnitude of the Hb drop was significantly higher in patients with significant hemorrhage than in controls. PMID- 29980954 TI - Preliminary evidence of the seroprevalence and risk factors associated with Chlamydia abortus infection in goats on the Canary Islands, Spain. AB - The aims of this cross-sectional study were to estimate the prevalence of IgG antibodies against Chlamydia abortus, the cause of enzootic abortion, in goats and to determine its associated risk factors on the Canary Islands. A total of 325 goats from 11 non-vaccinated herds were sampled and assessed using a commercial ELISA kit. Related data were also obtained for further statistical analysis and associated risk factors to seropositive flocks. For comparison, abortion rates between the vaccinated and non-vaccinated herds were compared. The overall seroprevalence of the unvaccinated herds was 33%, which can be considered as high when compared to other European regions. Associated risk factors such as herd size, management system, diet, and manure removal frequency were found statistically significant. However, no significant differences were found in the abortion rates between vaccinated and non-vaccinated flocks, indicating that other microorganisms could also cause abortions in goats on the region. Despite this, the seroprevalence of C. abortus is relatively high in this limited survey of goat herds and may pose a threat to both human and animals on the Canary Islands. PMID- 29980955 TI - Efficient CO2 removal using extracorporeal lung and renal assist device. AB - We developed a novel system comprising acid infusion, membrane lung, and a continuous renal replacement therapy console for efficient CO2 removal at a low blood flow. To evaluate the new system, we used an ex vivo experimental model using swine blood. A liter of aliquoted blood adjusted to pH 7.25 and pCO2 65 mm Hg was mixed with acid (0, 10, or 20 mL of lactic or hydrochloric acid [1 mol/L]) and was immediately delivered to the system in a single pass. We collected blood samples at each point of the circuit and calculated the amount of CO2 eliminated by the membrane lung. The new system removed 13.2 +/- 0.8, 32.0 +/- 2.1, and 51.6 +/- 3.7 mL/min of CO2 (with 0, 10, and 20 mEq/L of lactic acid) and 21.2 +/- 1.2, 27.3 +/- 0.3, and 42.0 +/- 1.3 mL/min (with 0, 10, and 20 mEq/L of hydrochloric acid), respectively. The levels of lactate and Cl- ions for acid-base equilibrium were restored after continuous hemodiafiltration. Thus, the amount of CO2 eliminated by the membrane lung was 3.9 times higher with lactic acid and 2.0 times higher with hydrochloric acid compared with non-acid controls. In conclusion, this easy-to-setup CO2 removal system was safe, effective, and removed CO2 at a low blood flow. PMID- 29980956 TI - Comparatively salient: examining the influence of preceding performances on assessors' focus and interpretations in written assessment comments. AB - Recent literature places more emphasis on assessment comments rather than relying solely on scores. Both are variable, however, emanating from assessment judgements. One established source of variability is "contrast effects": scores are shifted away from the depicted level of competence in a preceding encounter. The shift could arise from an effect on the range-frequency of assessors' internal scales or the salience of performance aspects within assessment judgments. As these suggest different potential interventions, we investigated assessors' cognition by using the insight provided by "clusters of consensus" to determine whether any change in the salience of performance aspects was induced by contrast effects. A dataset from a previous experiment contained scores and comments for 3 encounters: 2 with significant contrast effects and 1 without. Clusters of consensus were identified using F-sort and latent partition analysis both when contrast effects were significant and non-significant. The proportion of assessors making similar comments only significantly differed when contrast effects were significant with assessors more frequently commenting on aspects that were dissimilar with the standard of competence demonstrated in the preceding performance. Rather than simply influencing range-frequency of assessors' scales, preceding performances may affect salience of performance aspects through comparative distinctiveness: when juxtaposed with the context some aspects are more distinct and selectively draw attention. Research is needed to determine whether changes in salience indicate biased or improved assessment information. The potential should be explored to augment existing benchmarking procedures in assessor training by cueing assessors' attention through observation of reference performances immediately prior to assessment. PMID- 29980958 TI - Predictors of mortality among older patients in the medical wards of a tertiary hospital in Nigeria. AB - BACKGROUND: Older people face the biggest challenges in the overburdened healthcare services in Nigeria especially when hospitalized. There is no reliable data on the predictors of mortality in this population. AIMS: To determine the predictors of mortality among older patients on admission in the medical wards of University College Hospital, Ibadan. METHODS: Using a prospective cohort design, we investigated 450 patients (> 60 years) from the day of admission to death or discharge. Variables assessed included sociodemographic, family dynamics, lifestyle habits, healthcare utilization, quality of life, frailty, anxiety, depression, cognition, functional disability and anthropometric parameters. Kaplan-Meier method and Log-rank test were used to estimate and compare survival functions, respectively. Cox proportional hazard regression analysis was used to determine the predictors of mortality. RESULTS: The mean age of the subjects was 71.5 +/- 8.0 years and 234 (52.0%) were females. Overall, there were 99 (22.0%) in-hospital deaths. The median survival time (MST) was 36.0 +/- 3.0 days [females = 40.0 +/- 3.5 days vs males = 31.0 +/- 4.5 days (p < 0.001)]. There was a significant negative correlation between MST and age (r = - 0.931). Predictors of mortality on Cox's proportional hazard regression analyses were male sex HR = 2.03 (95% CI 1.27-3.24), severe frailty HR = 2.07 (1.02-4.20), cognitive impairment HR = 1.90 (1.14-3.17) and having >= 5 morbidities HR = 1.94 (1.14 3.30). CONCLUSION: There was a high mortality among older patients particularly the frail, male or those with multiple morbidities. Prompt and holistic management of morbidities and targeted interventions for cognitive impairment and frailty are needed to improve survival during hospitalization. PMID- 29980957 TI - Modeling Trajectories of Sensation Seeking and Impulsivity Dimensions from Early to Late Adolescence: Universal Trends or Distinct Sub-groups? AB - Developmental imbalance models attribute the rise in risk-taking during adolescence to a universal imbalance between rising reward sensitivity and lagging cognitive control. This study tested predictions of an alternate Lifespan Wisdom Model that distinguishes between exploratory/adaptive (e.g., sensation seeking) and maladaptive (e.g., acting-without-thinking, delay discounting) risk taking propensities and attributes the latter to a sub-set of youth with weak cognitive control. Latent trajectory modeling of six waves of data from 387 adolescents (52% females; spanning average ages of 11-18 years) revealed distinct sub-groups with heterogeneous trajectory patterns for acting-without-thinking and delay-discounting. Only those trajectory groups with weak cognitive control, characterized as "high-increasing" acting-without thinking and "high-stable" delay discounting were predictive of a maladaptive risk-taking outcome, namely substance use disorder. Sensation seeking demonstrated a universal peak, but high levels of sensation seeking were not associated with weakness in cognitive control and were unrelated to substance use disorder, controlling for impulsivity. The findings suggest that maladaptive risk-taking characterized by weak cognitive control over reward-driven impulses is a phenomenon limited to only a sub-set of youth. PMID- 29980960 TI - A Decision-Support Tool for Renal Mass Classification. AB - We investigate the viability of statistical relational machine learning algorithms for the task of identifying malignancy of renal masses using radiomics based imaging features. Features characterizing the texture, signal intensity, and other relevant metrics of the renal mass were extracted from multiphase contrast-enhanced computed tomography images. The recently developed formalism of relational functional gradient boosting (RFGB) was used to learn human interpretable models for classification. Experimental results demonstrate that RFGB outperforms many standard machine learning approaches as well as the current diagnostic gold standard of visual qualification by radiologists. PMID- 29980959 TI - Herbivore-Induced Defenses in Tomato Plants Enhance the Lethality of the Entomopathogenic Bacterium, Bacillus thuringiensis var. kurstaki. AB - Plants can influence the effectiveness of microbial insecticides through numerous mechanisms. One of these mechanisms is the oxidation of plant phenolics by plant enzymes, such as polyphenol oxidases (PPO) and peroxidases (POD). These reactions generate a variety of products and intermediates that play important roles in resistance against herbivores. Oxidation of the catecholic phenolic compound chlorogenic acid by PPO enhances the lethality of the insect-killing bacterial pathogen, Bacillus thuringiensis var. kurstaki (Bt) to the polyphagous caterpillar, Helicoverpa zea. Since herbivore feeding damage often triggers the induction of higher activities of oxidative enzymes in plant tissues, here we hypothesized that the induction of plant defenses would enhance the lethality of Bt on those plants. We found that the lethality of a commercial formulation of Bt (Dipel(r) PRO DF) on tomato plants was higher if it was applied to plants that were induced by H. zea feeding or induced by the phytohormone jasmonic acid. Higher proportions of H. zea larvae killed by Bt were strongly correlated with higher levels of PPO activity in the leaflet tissue. Higher POD activity was only weakly associated with higher levels of Bt-induced mortality. While plant mediated variation in entomopathogen lethality is well known, our findings demonstrate that plants can induce defensive responses that work in concert with a microbial insecticide/entomopathogen to protect against insect herbivores. PMID- 29980961 TI - Inappropriate shock from myopotentials due to subcutaneous defibrillator (S-ICD) movement confirmed on fluoroscopy with subsequent device pocket revision. PMID- 29980962 TI - Large-volume paracentesis effects plasma disappearance rate of indo-cyanine green in critically ill patients with decompensated liver cirrhosis and intraabdominal hypertension. AB - BACKGROUND: Ascites is a major complication of decompensated liver cirrhosis. Intraabdominal hypertension and structural alterations of parenchyma involve decisive changes in hepatosplanchnic blood flow. Clearance of indo-cyanine green (ICG) is mainly dependent on hepatic perfusion and hepatocellular function. As a consequence, plasma disappearance rate of ICG (ICG-PDR) is rated as a useful dynamic parameter of liver function. This study primarily evaluates the impact of large-volume paracentesis (LVP) on ICG-PDR in critically ill patients with decompensated cirrhosis. Additionally, it describes influences on intraabdominal pressure (IAP), abdominal perfusion pressure (APP), hepatic blood flow, hemodynamic and respiratory function. METHODS: We analyzed LVP in 22 patients with decompensated liver cirrhosis. ICG-PDR was assessed by using noninvasive LiMON technology (Pulsion(r) Medical Systems; Maquet Getinge Group), and hepatic blood flow was analyzed by color-coded duplex sonography. RESULTS: Paracentesis of a median volume of 3450 mL ascites evoked significant increases of ICG-PDR from 3.6 (2.8-4.6) to 5.1 (3.9-6.2)%/min (p < 0.001). Concomitantly, we observed a raise in "ICG-Clearance" from 99 (73.5-124.5) to 104 (91-143.5) mL/min/m2 (p = 0.005), while circulating blood volume index was unchanged [2412 (1983-3025) before paracentesis vs. 2409 (1997-2805) mL/m2, p = 0.734]. Sonography revealed a significant impact of paracentesis on hepatic blood flow: Hepatic artery resistance index dropped from 0.74 (0.68-0.75) to 0.68 (0.65-0.71) (p < 0.001) and maximum flow velocity in hepatic vein increased from 24 (17-30) to 30 (22-36) cm/s (p < 0.001). Consistent with previous studies, paracentesis caused significant decreases in IAP from 19.0 (15.0-20.3) to 11.0 (8.8-12.3) mmHg (p < 0.001) and central venous pressure from 22.5 (17.8-29.0) to 17.5 (12.8-24.0) mmHg (p < 0.001) with inverse increases in APP from 63.0 (56.8-69.5) to 71.0 (65.5 78.5) mmHg (p < 0.001). Changes in ICG-PDR were concomitant with changes in IAP (r = - 0.602) and APP (r = 0.576). Moreover, we found a substantial improvement in respiratory function. By contrast, hemodynamic parameters assessed by transpulmonary thermodilution, serum bilirubin and international normalized ratio did not change after paracentesis. CONCLUSION: Critically ill patients with decompensated cirrhosis and elevated IAP showed dramatically impaired ICG-PDR. Paracentesis evoked an improvement in ICG-PDR in parallel with a decreased IAP and an increased APP, while conventional parameters of liver function did not change. This effect on ICG-PDR is mainly referable to a relief of intraabdominal hypertension and changes in hepatosplanchnic blood flow. PMID- 29980963 TI - Topical application of Mentha piperita essential oil accelerates wound healing in infected mice model. AB - This study was conducted to evaluate the effects of the prepared ointments from Mentha piperita essential oil (M. piperita) on wound healing in the infected mice models. Each circular full-thickness wound was inoculated with 25 * 107 units of Staphylococcus aureus and Pseudomonas aeruginosa bacteria strains. The tissue bacterial count, histological analyses and expression levels of IL-10, TNF-alpha, TGF-beta1, IL-1beta, CCL2, CXCL1, VEGF and FGF-2 were assessed to identify the different doses of M. piperita on wound healing. Total tissue bacterial count, edema and inflammation level were declined, but the migration of fibroblasts, collagen synthesis and re-epithelization were increased in treated animals with M. piperita. The expression levels of CCL2, CXCL1, IL-1beta, TGF-beta1 and IL-10 genes were up-regulated in the M. piperita-treated animals compared to the control group. While the expression of TNF-alpha, VEGF and FGF-2 was down regulated in comparison to the control group. This study indicated that M. piperita can be used for treatment of the infected wound. PMID- 29980964 TI - Correction to: A Tertiary-Care/Primary-Care Partnership Aimed at Improving Care for People with Eating Disorders. AB - The original version of this article unfortunately contained a mistake in EAT-26 values under "Patients Receiving Treatment for an ED in their Sector" section. PMID- 29980965 TI - PET myocardial blood flow is now officially declared ready for prime time (and a little bit about how the US coding/valuation/coverage system works). PMID- 29980967 TI - High Frequency Oscillations in the Ripple Band (80-250 Hz) in Scalp EEG: Higher Density of Electrodes Allows for Better Localization of the Seizure Onset Zone. AB - High frequency oscillations (HFO) are known as markers of epileptic areas in intracranial EEG and possibly scalp EEG. We compared distributions of HFO in the ripple band (80-250 Hz) in intracranial and scalp EEG with either a conventional 10-20-montage (10-20-EEG) or a high density recording using 128 electrodes (HD EEG). HFO were visually identified, in all intracranial EEG channels (80-500 Hz) and all channels of the 10-20-EEG (scalp EEG 80-250 Hz). For the HD-EEG, HFO were analyzed in regions of interest using areas with HFO as seen on the 10-20-EEG as well as areas in the clinically-defined seizure onset zone (SOZ). 13 patients were included in the study, of whom 12 showed HFO in the ripple band. In 8 patients HD-EEG revealed additional regions of ripples compared to the 10-20-EEG. With HD-EEG, areas of highest ripple rates were corresponding between scalp and intracranial EEG in 7 patients (58%) and 8 (67%) patients showed highest ripple rates over the SOZ. In contrast, with 10-20-EEG only 2 patients (17%) had corresponding areas of highest ripple rates and only 3 patients (23%) showed highest ripple rates over the SOZ. HD-EEG proved to be better to identify scalp HFO in the ripple band compared to standard 10-20-EEG. Moreover, ripples in 10-20 EEG seem to lead to false localization of epileptic areas. In contrast ripples detected with HD-EEG were located over the seizure onset zone and maybe a promising tool to localize epileptic tissue in the future. PMID- 29980966 TI - Is vegetative area, photosynthesis, or grape C uploading involved in the climate change-related grape sugar/anthocyanin decoupling in Tempranillo? AB - Foreseen climate change is expected to impact on grape composition, both sugar and pigment content. We tested the hypothesis that interactions between main factors associated with climate change (elevated CO2, elevated temperature, and water deficit) decouple sugars and anthocyanins, and explored the possible involvement of vegetative area, photosynthesis, and grape C uploading on the decoupling. Tempranillo grapevine fruit-bearing cuttings were exposed to CO2 (700 vs. 400 ppm), temperature (ambient vs. + 4 degrees C), and irrigation levels (partial vs. full) in temperature-gradient greenhouses. In a search for mechanistic insights into the underlying processes, experiments 1 and 2 were designed to maximize photosynthesis and enlarge leaf area range among treatments, whereas plant growth was manipulated in order to deliberately down-regulate photosynthesis and control vegetative area in experiments 3 and 4. Towards this aim, treatments were applied either from fruit set to maturity with free vegetation and fully irrigated or at 5-8% of pot capacity (experiments 1 and 2), or from veraison to maturity with controlled vegetation and fully irrigated or at 40% of pot capacity (experiments 3 and 4). Modification of air 13C isotopic composition under elevated CO2 enabled the further characterization of whole C fixation period and C partitioning to grapes. Increases of the grape sugars-to anthocyanins ratio were highly and positively correlated with photosynthesis and grape 13C labeling, but not with vegetative area. Evidence is presented for photosynthesis, from fruit set to veraison, and grape C uploading, from veraison to maturity, as key processes involved in the establishment and development, respectively, of the grape sugars to anthocyanins decoupling. PMID- 29980968 TI - Induced pluripotent stem cells (iPSCs) as model to study inherited defects of neurotransmission in inborn errors of metabolism. AB - The ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human disease. Especially for the modeling of rare human monogenetic diseases with limited numbers of patients available worldwide and limited access to the mostly affected tissues, iPSCs have become an invaluable tool. To study rare diseases affecting neurotransmitter biosynthesis and neurotransmission, stem cell models carrying patient-specific mutations have become highly important as most of the cell types present in the human brain and the central nervous system (CNS), including motoneurons, neurons, oligodendrocytes, astrocytes, and microglia, can be differentiated from iPSCs following distinct developmental programs. Differentiation can be performed using classical 2D differentiation protocols, thereby generating specific subtypes of neurons or glial cells in a dish. On the other side, 3D differentiation into "organoids" opened new ways to study misregulated developmental processes associated with rare neurological and neurometabolic diseases. For the analysis of defects in neurotransmission associated with rare neurometabolic diseases, different types of brain organoids have been made available during the last years including forebrain, midbrain and cerebral organoids. In this review, we illustrate reprogramming of somatic cells to iPSCs, differentiation in 2D and 3D, as well as already available disease-specific iPSC models, and discuss current and future applications of these techniques. PMID- 29980969 TI - Completeness of a Maternal and Perinatal Mortality Enhanced Surveillance System in Pakistan: Evidence from Capture-Recapture Methods. AB - Objectives An enhanced surveillance system that integrated health information systems and extended surveillance to previously uncovered areas to capture all births, perinatal and maternal deaths in a rural district of Pakistan was established in 2015, and this study uses capture-recapture methodology to assess completeness. Methods Births and deaths collected by the survey were matched with the data captured by the enhanced surveillance system. Capture-recapture methodology was used to estimate the total number of births and deaths, measure the degree of underestimation, and adjust mortality rates. Results Of all births, 99% were captured by the enhanced surveillance system. Ninety percent of neonatal deaths and 86% of early neonatal deaths were recorded. The recorded neonatal mortality rate was 40 per 1000 live births (95% CI 35-44), and after adjustment for under-enumeration was 42 per 1000 live births (95% CI 37-46). Recorded rates underestimated neonatal mortality by 5% and perinatal mortality by 7%. Five stillbirths were recorded by the survey and all were matched to recorded stillbirths. The one maternal death recorded by the survey was matched with the maternal death captured by the enhanced surveillance system. The maternal mortality ratio prior to adjustment for under-enumeration was 247 per 100,000 live births (95% CI 147-391), whereas after adjustment it was 246 per 100,000 live births (95% CI 146-389). Conclusion Application of capture-recapture methods to the enhanced surveillance system indicated a high completeness of birth and death recording by the surveillance system. PMID- 29980970 TI - The Art of Living in Transitoriness: Strategies of Families in Repeated Geographical Mobility. AB - In the context of migratory instabilities, an increasing number of professionals engage in repeated moves across countries with their families, living more or less permanently on the move. Yet the international adjustments of these families are usually studied in terms of the adaptation of family members to a single host country. This article uses in-depth interviews conducted with families in repeated geographical mobility and currently living in Switzerland to identify the strategies enabling them to move across countries while adjusting to diverse sociocultural environments. By bringing together studies on psychology with those on migration and mobility, the article introduces the specific challenge of repeated geographical mobility and sets out a theoretical framework for understanding this phenomenon from a sociocultural perspective. It then presents three types of strategies employed by families. The findings show that against the backdrop of constant changes, families recreate the same spheres of experience everywhere, transform their relations to objects, and build a continuum of social relationships by enlarging their social networks while focusing inward on the relationships within the nuclear family. The analyses bring to the fore a new modality of establishing a sense of continuity that involves a complete reconfiguration of investments so to embrace more complex ways to cope with the apparent concurrent requirement of adjusting to a new country while preserving some degree of mobility in view of the next move. The research sheds light on very contemporary dynamics embedded in the broader unfolding context of mobility by taking into account its experiential dimension. PMID- 29980971 TI - Postoperative Pneumonia is Associated with Long-Term Oncologic Outcomes of Definitive Chemoradiotherapy Followed by Salvage Esophagectomy for Esophageal Cancer. AB - BACKGROUND OR PURPOSE: As we previously indicated, postoperative pneumonia has a negative impact on the overall survival after planned esophagectomy. However, the impact of postoperative pneumonia after salvage esophagectomy on long-term oncologic outcomes still remains unclear. This study aimed to indicate the association between postoperative pneumonia and long-term outcomes of definitive chemoradiotherapy followed by salvage esophagectomy. Furthermore, we determined a prediction model for overall survival (OS) and disease-free survival (DFS) using a survival classification and regression tree (CART). METHODS: Ninety-three patients who underwent CRT followed by esophagectomy for thoracic esophageal cancer were identified for this study. Forty-nine patients and 44 patients were included in the salvage and neoadjuvant groups, respectively. We investigated the association between postoperative pneumonia and long-term oncologic outcomes following salvage esophagectomy. RESULTS: Patients from the salvage group tended to have a lower OS compared to neoadjuvant group (median survival: salvage, 24 months vs neoadjuvant, 43 months, p = 0.117). Multivariate analyses revealed that postoperative pneumonia adversely affected both OS (p < 0.001) and DFS (p = 0.044) after salvage esophagectomy. We generated the prediction model for OS and DFS in the salvage group using survival CART. Postoperative pneumonia was the most important parameter for predicting the OS. DISCUSSION: The present study demonstrates the long-term outcomes and risk factors for mortality of salvage esophagectomy. To improve OS after salvage surgery, the development of a means of decreasing pulmonary complications is needed. PMID- 29980972 TI - The Presence of an Advanced Gastrointestinal (GI)/Minimally Invasive Surgery (MIS) Fellowship Program Does Not Impact Short-Term Patient Outcomes Following Fundoplication or Esophagomyotomy. AB - INTRODUCTION: The current surgical landscape reflects a continual trend towards sub-specialization, evidenced by an increasing number of US surgeons who pursue fellowship training after residency. Despite this growing trend, however, the effect of advanced gastrointestinal (GI)/minimally invasive surgery (MIS) fellowship programs on patient outcomes following foregut/esophageal operations remains unclear. This study looks at two representative foregut surgeries (laparoscopic fundoplication and esophagomyotomy) performed in New York State (NYS), comparing hospitals which do and do not possess a GI/MIS fellowship program, to examine the effect of such a program on perioperative outcomes. We also aimed to identify any patient or hospital factors which might influence perioperative outcomes. METHODS: The SPARCS database was examined for all patients who underwent a foregut procedure (specifically, either an esophagomyotomy or a laparoscopic fundoplication) between 2012 and 2014. We compared the following outcomes between institutions with and without a GI/MIS fellowship program: 30-day readmission, hospital length of stay (LOS), and development of any major complication. RESULTS: There were 3175 foregut procedures recorded from 2012 to 2014. Just below one third (n = 1041; 32.8%) were performed in hospitals possessing a GI/MIS fellowship program. Among our entire included study population, 154 patients (4.85%) had a single 30-day readmission, with no observed difference in readmission between hospitals with and without a GI/MIS fellowship program, even after controlling for potential confounding factors (p = 0.6406 and p = 0.2511, respectively). Additionally, when controlling for potential confounders, the presence/absence of a GI/MIS fellowship program was found to have no association with risk of having a major complication (p = 0.1163) or LOS (p = 0.7562). Our study revealed that postoperative outcomes were significantly influenced by patient race and payment method. Asians and Medicare patients had the highest risk of suffering a severe complication (10.00 and 7.44%; p = 0.0311 and p = 0.0036, respectively)-with race retaining significance even after adjusting for potential confounders (p = 0.0276). Asians and uninsured patients demonstrated the highest readmission rates (15.00 and 12.50%; p = 0.0129 and p = 0.0012, respectively)-with both race and payment method retaining significance after adjustment (p = 0.0362 and p = 0.0257, respectively). Lastly, payment method was significantly associated with postoperative LOS (p < 0.0001), with Medicaid patients experiencing the longest LOS (mean 3.99 days) and those with commercial insurance experiencing the shortest (mean 1.66 days), a relationship which retained significance even after adjusting for potential confounders (p < 0.0001). CONCLUSION: The presence of a GI/MIS fellowship program does not impact short-term patient outcomes following laparoscopic fundoplication or esophagomyotomy (two representative foregut procedures). Presence of such a fellowship should not play a role in choosing a surgeon. Additionally, in these foregut procedures, patient race (particularly Asian race) and payment method were found to be independently associated with postoperative outcomes, including postoperative LOS. PMID- 29980973 TI - Effects of Calcitonin Gene-Related Peptide on Colonic Motility and Defecation in Conscious Dogs. AB - BACKGROUND: Although intra-arterial infusion of calcitonin gene-related peptide (CGRP) reportedly stimulates giant migrating contractions (GMCs) of the small intestine in conscious dogs, the effect of intravenous CGRP administration on colonic motility remains unclear. In the present study, we investigated the effects of intravenous CGRP on colonic motility and defecation and determined the underlying mechanism of action in conscious dogs. METHODS: Sixteen Beagle dogs weighing 11-13 kg were included. The effects of intravenous CGRP at doses of 3.33 (with various antagonists), 0.83, and 1.67 MUg/kg on colonic motility and defecation were evaluated in neurally intact dogs (n = 6). For comparison, dogs with transection/re-anastomosis (T/R) between the proximal and middle segments of the colon (n = 5) and dogs with extrinsic denervation of the ileocolonic segments (n = 5) also received intravenous CGRP at 3.33 MUg/kg. All dogs were equipped with strain gauge force transducers on the ileocolon for measurement of the colonic contractile activity. RESULTS: Intravenous CGRP evoked GMCs and defecation in the neurally intact group; these stimulatory effects were inhibited by atropine and hexamethonium. Compared with the neurally intact group, the T/R group exhibited similar proximal colonic motility and decreased distal colonic motility after intravenous CGRP administration, whereas the extrinsic denervation group exhibited increased colonic motility overall. CONCLUSIONS: Intravenous CGRP induces colonic motility and defecation through acetylcholine release in conscious dogs. The continuity of the enteric nerves plays an important role in CGRP-induced colonic contractions and defecation, while the extrinsic nerves suppress CGRP-induced colonic motility. PMID- 29980974 TI - Late Pancreatic Anastomosis Stricture Following Pancreaticoduodenectomy: a Systematic Review. AB - BACKGROUND: With an increasing postoperative survival and prolonged follow-up, late complications following pancreaticoduodenectomy (PD) have yet to be thoroughly described and analyzed. Among those, pancreatic anastomosis stricture may lead to severe consequences. METHODS: A systematic review focusing on pancreaticojejunostomy anastomosis (PJA) stricture. RESULTS: PJA stricture incidence reached 1.4-11.4% with a median time interval of 34 months after PD. No risk factor was identified. PJA stricture repercussions were inconsistent but postprandial abdominal pain and recurrent acute pancreatitis were the most common symptoms, followed by impaired pancreatic function. To confirm diagnosis, secretin-enhanced magnetic resonance cholangiopancreatography (SMRCP) sensitivity reached 56-100%. As impaired pancreatic function is not improved by any procedure, only PJA stricture leading to abdominal pain or acute pancreatitis should be considered for treatment. Endoscopic techniques (mainly ultrasound assisted "rendezvous") should be proposed prior to surgical repair, with a morbidity, an overall technical and clinical success reaching 16.5-33% and 28.6 100% and 33-100%, respectively. Regarding surgical repair, overall morbidity varied between 14.3 and 33%, with a clinical success reaching 26.1-100%. Finally, total pancreatectomy with islet auto-transplantation should be considered only for pain intractable to medical management and recurrent acute pancreatitis which has failed medical, endoscopic, and traditional surgical management strategies. CONCLUSION: PJA stricture following PD is a late, unusual, and potentially serious complication. When there is currently no clear consensus, PJA stricture leading to abdominal pain or acute pancreatitis should be considered treatment. With increasing survival after PD, further studies should focus on late complications. CORE TIP: Stricture of pancraticojejunostomy is a late and potentially serious complication after pancreaticoduodenectomy. Incidence reaches 1.4-11.4% and no risk factor is identified. Symptoms are inconsistent but postprandial abdominal pain, recurrent acute pancreatitis, and impaired pancreatic function are the most frequent. To confirm diagnosis, secretin enhanced magnetic resonance cholangiopancreatography is the best modality. Only PJA stricture leading to abdominal pain or acute pancreatitis should be considered for treatment. Endoscopic techniques (mainly ultrasound-assisted "rendezvous") should be proposed prior to surgical repair. Finally, total pancreatectomy with islet auto-transplantation should be considered only for pain intractable to medical management and recurrent acute pancreatitis which has failed medical, endoscopic, and traditional surgical management strategies. PMID- 29980975 TI - Preoperative Biliary Drainage Is Associated with Increased Complications After Liver Resection for Proximal Cholangiocarcinoma. AB - BACKGROUND: Preoperative biliary drainage (PBD) prior to liver resection for hilar and intrahepatic cholangiocarcinoma (CCA) is common. While PBD for those with distal obstructions has been studied extensively and is associated with increased infectious complications, the impact of PBD among patients undergoing hepatectomy for non-disseminated proximal CCA has yet to be clearly elucidated. METHODS: Patients undergoing liver resection between 2014 and 2016 for non disseminated hilar and intrahepatic CCA were analyzed using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Associations between PBD (percutaneous or endoscopic) and 30-day outcomes were evaluated. RESULTS: There were 905 liver resections performed, with 186 (20.6%) for hilar CCA and 719 (79.4%) for intrahepatic CCA. Of those, 251/897 (28.0%) patients underwent PBD. Independent preoperative predictors of PBD were hilar CCA, major hepatectomy, open surgery, lower BMI, and higher preoperative bilirubin. Adjusting for preoperative variables, extent of resection, and bilirubin, PBD was independently associated with increased wound infection (OR 2.93), organ space infection (OR 3.63), sepsis (OR 3.17), renal insufficiency (OR 4.25), transfusion (OR 2.40), bile leak (OR 3.23), invasive intervention (OR 2.72), liver failure (OR 3.20), readmission (OR 3.01), reoperation (OR 2.32), and mortality (OR 4.24, all p < 0.05). CONCLUSIONS: Among patients undergoing hepatectomy for proximal CCA, PBD is associated with increased postoperative complications. These data suggest that avoidance of routine preoperative biliary drainage may decrease short-term complications. PMID- 29980976 TI - Risk Factors for Post-ERCP Pancreatitis in High-Risk Patients Receiving Post procedure Rectal Indomethacin. AB - BACKGROUND: Post-ERCP pancreatitis (PEP) is the most common adverse event of ERCP. Rectal indomethacin has been widely administered to decrease the incidence of PEP in high-risk patients. However, it cannot completely prevent the occurrence of PEP. The purpose of the study was to evaluate the risk factors for PEP in high-risk patients receiving post-ERCP indomethacin. METHODS: From June 2012 to July 2015, patients undergoing ERCP and at high risk for PEP in three tertiary hospitals in China were enrolled. All patients received indomethacin after the procedure. Patient-related and procedure-related risk factors for PEP were collected. Logistic regression analysis was used to investigate the risk factors. RESULTS: Seven hundred ninety patients at high risk for PEP received post-ERCP indomethacin. The incidence of overall PEP and moderate-to-severe PEP was 8.0 and 1.5%, respectively. In multivariate analysis, suspected sphincter of Oddi dysfunction (SOD) (OR 2.73; 95%CI 1.38-5.43; p = 0.004), the presence of hilar obstruction (OR 4.53; 95%CI 1.60-12.81; p = 0.004), number of cannulation attempts >= 13 (OR 2.00; 95%CI 1.07-3.77; p = 0.030), inadvertent pancreatic duct (PD) cannulation >= 1 (OR 2.26; 95%CI 1.04-4.90; p = 0.040), and pancreatic contrast injections >= 1 (OR 2.30; 95%CI 1.02-5.23; p = 0.046) were high risk factors for overall PEP. For moderate-to-severe PEP, suspected SOD (OR 4.67; 1.19 18.35; p = 0.027), the presence of hilar obstruction (OR 7.95; 1.39-44.97; p = 0.010), and more cannulation attempts (OR 3.71; 1.09-12.65; p = 0.036) were three independent risk factors. CONCLUSIONS: A substantial number of high-risk patients had PEP even receiving post-ERCP rectal indomethacin. The independent risk factors included suspected SOD, hilar stricture, more cannulation attempts, inadvertent PD cannulation, and PD contrast injections. TRIAL REGISTRATION: NCT02709421. PMID- 29980977 TI - The Impact of Extent of Liver Resection Among Patients with Neuroendocrine Liver Metastasis: an International Multi-institutional Study. AB - BACKGROUND: Liver resection in patients with neuroendocrine liver metastasis (NELM) provides a survival benefit, yet the optimal extent of resection remains unknown. We sought to examine outcomes of patients undergoing non-anatomic (NAR) versus anatomic liver resection (AR) for NELM using a large international cohort of patients. METHODS: Two hundred and fifty-eight patients who underwent curative intent liver resection from January 1990 to December 2016 were identified from eight institutions. Patients were excluded if they underwent concurrent ablation, had extrahepatic disease, underwent a debulking operation, or had mixed anatomic and non-anatomic resections. Overall (OS) and recurrence-free (RFS) survival were compared among patients based on the extent of liver resection (AR vs. NAR). RESULTS: Most primary tumors were located in the pancreas (n = 117, 45.4%) or the small intestine (n = 65, 25.2%). Liver resection consisted of NAR (n = 126, 48.8%) or AR (n = 132, 51.2%) resection. The overwhelming majority of patients who underwent NAR had an estimated liver involvement of < 50% (NAR 109, 97.3% vs. AR n = 82, 65.6%; P < 0.001). Patients who underwent NAR also had higher rates of primary tumor lymph node metastasis (NAR n = 79, 71.2% vs. AR n = 37, 33.6%; P < 0.001) and microscopically positive margins (R1) (NAR n = 29, 25.7% vs. AR n = 16, 12.5%; P = 0.009). After a median follow-up of 47.7 months, 48 (18.6%) patients died and 37.0% (n = 95) had evidence of disease recurrence. Patients who underwent AR had both longer median OS (not reached) and RFS (not reached) versus patients who underwent NAR (median OS 138.3 months; median RFS 31.3 months) (both P < 0.01). After controlling for patient and disease-related factors, extent of liver resection was independently associated with an increased risk of recurrence (HR 2.39, 95% CI 1.04-5.48; P = 0.04) but not death (HR 1.92, 95% CI 0.40-9.28; P = 0.42). CONCLUSION: NAR was independently associated with a higher incidence of recurrence versus patients who undergo a formal anatomic hepatectomy among patients with NELM. PMID- 29980978 TI - Effect of Delay to Operation on Outcomes in Patients with Acute Appendicitis: a Systematic Review and Meta-analysis. AB - BACKGROUND: Many studies have investigated the association between time interval and incidence of complicated appendicitis and post-operative surgical site infection (SSI), but the results are controversial. METHODS: A systematic search of the electronic databases identified studies that investigated the association of appendectomy delay with complicated appendicitis and SSI among patients with acute appendicitis. Qualitative and quantitative meta-analysis of the results was conducted. RESULTS: Twenty-one studies were included in the final analysis. Meta analysis showed no significant difference in complicated appendicitis incidence between patients in the 6-12 h, > 12 and < 6 h groups (OR 1.07, 95% CI 0.89-1.30, p = 0.47; OR 1.04, 95% CI 0.88-1.22, p = 0.64). Comparison of the 6-12 h category with the < 6 h category of in-hospital delay revealed significant associations between longer in-hospital delay and increased risk of post-operative SSI (OR 1.40, 95% CI 1.11-1.77, p = 0.004). Patients in the 24-48 h category had 1.99- and 1.84-fold (p < 0.05) higher odds of developing complicated appendicitis compared to patients in the < 24 h category for pre-hospital delay and total delay, respectively (OR 1.99, 95% CI 1.35-2.94, p = 0.0006; OR 1.84, 95% CI 1.05 3.21, p = 0.03). When pre-hospital and total delay time extended to more than 48 h, the odds of risk increased 4.62- and 7.57-fold, respectively (OR 4.62, 95% CI 2.99-7.13, p < 0.00001; OR 7.57, 95% CI 6.14-9.35, p = < 0.00001). CONCLUSION: Complicated appendicitis incidence was associated with overall elapsed time from symptom onset to admission or operation; short appendectomy in-hospital delay did not increase the risk of complicated appendicitis but was associated with a slightly increased risk of SSI. Prompt surgical intervention is warranted to avoid additional morbidity, enabling quicker recovery in this population. PMID- 29980980 TI - Cerebrospinal Fluid C-Reactive Protein in Parkinson's Disease: Associations with Motor and Non-motor Symptoms. AB - Parkinson' disease (PD) is characterized by motor symptoms including bradykinesia, resting tremor, postural instability, and rigidity and non-motor symptoms such as cognitive impairment, sleep disorder, and depression. Neuroinflammation has been recently implicated in pathophysiology of both motor and non-motor symptoms of PD. One of the most notable inflammatory proteins is C reactive protein (CRP), which is elevated in the conditions of systemic inflammation. Using BioFIND database, we scrutinized the possible association between cerebrospinal fluid (CSF) levels of CRP and severity of PD motor and non motor symptoms. Eighty-four healthy controls (HCs) and 109 PD subjects were entered into this study. A significant correlation was observed between CSF CRP levels and Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS part III) score and Montreal Cognitive Assessment (MoCA) score in PD patients. We found significant correlations between MoCA score and CSF CRP levels in female patients and between CSF CRP and MDS-UPDRS part III score and MoCA score in male patients. In linear regression, CSF CRP could predict 6.9 and 10% of changes in MDS-UPDRS part III score in all PD patients male PD patients, respectively. In summary, we confirmed that CSF concentrations of CRP are in correlation with motor and non-motor severity in PD subjects. Our findings suggest that neuroinflammation plays an important role in the initiation and probably progression of PD motor and non-motor symptoms, which may give us a better insight into the underlying pathologic mechanisms in PD. PMID- 29980979 TI - Practical Contribution of Virtual Hepatectomy for Colorectal Liver Metastases: a Propensity-Matched Analysis of Clinical Outcome. AB - BACKGROUND: Recent improvements in imaging technologies have enabled surgeons to perform precise planning using virtual hepatectomy (VH). However, the practical and clinical benefits of VH remain unclear. This study sought to assess how three dimensional analysis using a VH contributed to preoperative planning and postoperative outcome in patients undergoing liver surgery for the treatment of colorectal liver metastases (CRLM). METHODS: From 2007 to 2017, a total of 473 CRLM patients who received curative hepatectomy were retrospectively assessed. A 1:1 matched propensity analysis was performed between patients who did not receive a VH (without 3D group: n = 188) and received a VH (3D(+) group: n = 285). RESULT: The rate of VH increased over the study period (P < 0.001). After propensity score matching (n = 150 for each group), no significant differences were observed in the intraoperative and postoperative outcome, including liver transection time, blood loss, or morbidity between the groups. More patients received a small anatomical resection (plus limited resections) in the 3D(+) group (25 vs 11%, [P = 0.03]). A submillimeter margin was less frequent in the 3D(+) group. No significant differences in the 5-year overall survival and disease-free survival rates were seen between the without 3D group and the 3D(+) group (38.0 vs. 45.9% [P = 0.99], 11.1 vs. 21.7%, respectively [P = 0.109]). CONCLUSION: Although VH did not significantly influenced on the long-term outcome after hepatectomy, a more parenchymal-sparing operative procedure (anatomical resections, plus limited resections) was selected and the risk of a submillimeter surgical margin was reduced after introduction of VH. PMID- 29980982 TI - Effect of Arginine on the Aggregation of Protein in Freeze-Dried Formulations Containing Sugars and Polyol: II. BSA Reconstitution and Aggregation. AB - The current paper continues our study on the ability of L-arginine to prevent/reduce the aggregation of proteins that results from the various stresses during the lyophilisation and/or storage of lyophilized protein-based products. The first part of our study, i.e. formulation development, was devoted to the rational design and optimization of an L-arginine containing lyophilized formulation which can resist the natural tendency of L-arginine to absorb atmosphere moisture. Mannitol and trehalose were chosen among other excipients to be included in the protein-based formulation, as mannitol in a combination with L arginine has been shown to reduce moisture sorption while trehalose provides a degree of lyoprotection. In the present study, a number of formulations, which comprised bovine serum albumin (BSA) with and without L-arginine, and with five different ratios of trehalose-to-mannitol (from 30:70 to 80:20) were lyophilised and assessed. The internal structures and the moisture sorption/retention of the lyophilized formulations were characterised. To study the effect of L-arginine on BSA solid-phase stability, the lyophilized powder was exposed to accelerated storage conditions (high moisture (75% RH) and temperature (22 or 45 degrees C)) for up to 24 h. The lyophilized BSA formulations were then reconstituted and solution-state protein aggregation assessed by turbidimetry at 360 nm and fluorescence spectroscopy using the thioflavin T assay. It was demonstrated that L-arginine can be used in protein-based freeze-dried formulations to significantly reduce the aggregation of protein during the manufacturing, storage and subsequent reconstitution. The results also revealed the importance of a sufficient amount of mannitol in the arginine-containing formulations. PMID- 29980981 TI - Analysis of the Paternally-Imprinted DLK1-MEG3 and IGF2-H19 Tandem Gene Loci in NT2 Embryonal Carcinoma Cells Identifies DLK1 as a Potential Therapeutic Target. AB - The paternally-imprinted genes insulin-like growth factor 2 (IGF2), H19, delta like homologue 1 (DLK1), and maternally-expressed gene 3 (MEG3) are expressed from the tandem gene loci IGF2-H19 and DLK1-MEG3, which play crucial roles in initiating embryogenesis and development. The erasure of imprinting (EOI) at differentially methylated regions (DMRs) which regulate the expression of these genes maintains the developmental quiescence of primordial germ cells (PGCs) migrating through the embryo proper during embryogenesis and prevents them from forming teratomas. To address the potential involvement of the IGF2-H19 and DLK1 MEG3 loci in the pathogenesis of embryonal carcinoma (EC), we investigated their genomic imprinting at DMRs in the human PGC-derived EC cell line NTera-2 (NT2). We observed EOI at the IGF2-H19 locus and, somewhat to our surprise, a loss of imprinting (LOI) at the DLK1-MEG3 locus. As a result, NT2 cells express imprinted gene ratios from these loci such that there are i) low levels of the proliferation-promoting IGF2 relative to ii) high levels of the proliferation inhibiting long noncoding RNA (lncRNA) H19 and iii) high levels of proliferation promoting DLK1 relative to iv) low levels of the proliferation-inhibiting lncRNA MEG3. Consistent with this pattern of expression, the knockdown of DLK1 mRNA by shRNA resulted in decreased in vitro cell proliferation and in vivo tumor growth as well as decreased in vivo organ seeding by NT2 cells. Furthermore, treatment of NT2 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5 azaD) inhibited their proliferation. This inhibition was accompanied by changes in expression of both tandem gene sets: a decrease in the expression of DLK1 and upregulation of the proliferation-inhibiting lncRNA MEG3, and at the same time upregulation of IGF2 and downregulation of the lncRNA H19. These results suggest that the DLK1-MEG3 locus, and not the IGF2-H19 locus, drives the tumorigenicity of NT2 cells. Based on these results, we identified DLK1 as a novel treatment target for EC that could be downregulated by 5-azaD. PMID- 29980983 TI - Risk of gallstones in patients with obstructive sleep apnea: a nationwide observational cohort study. AB - PURPOSE: To assess the association between obstructive sleep apnea (OSA) and gallstones. METHODS: We identified 3827 patients aged >= 20 years with OSA between 2000 and 2010 from the Longitudinal Health Insurance Research Database 2000 (LHID2000) as the study cohort. The beneficiaries without OSA were randomly selected and propensity-matched with the study cohort in a 1:1 ratio according to age; sex; occupation; urbanization; comorbidities of hypothyroidism, hyperlipidemia, diabetes, liver cirrhosis, alcohol-related illness, hypertension, chronic obstructive pulmonary disease (COPD), obesity, inflammatory bowel disease, stroke, coronary artery disease (CAD), hepatitis B virus, and hepatitis C virus; and the index year. All patients were followed until the end of 2011 or withdrawal from the National Health Insurance program to determine the incidence of gallstones. RESULTS: The prevalence of OSA was higher in men (67.3%) and in patients younger than 49 years (57.0%; mean age 47.8 +/- 15.1 years). The cumulative incidence of gallstones was higher in the OSA cohort than in the non OSA cohort (log-rank test, P < 0.001). Compared with patients without OSA, those with OSA had an increased risk of gallstones (adjusted hazard ratio = 1.53, 95% confidence interval = 1.16-2.03) after adjustment for age, sex, hyperlipidemia, diabetes, hypertension, COPD, stroke, and CAD. CONCLUSION: The study shows a strong association between OSA and gallstones. Moreover, our findings suggest the requirement for survey and health education for gallstones in OSA and further studies to verify whether the treatment of OSA can reduce the risk of gallstones. PMID- 29980984 TI - Breast cancer awareness in the sub-Saharan African ABC-DO cohort: African Breast Cancer-Disparities in Outcomes study. AB - A greater understanding of the nature and drivers of poor breast cancer (BC) awareness in sub-Saharan Africa (SSA) will inform much needed awareness programmes. We aimed to assess the level and nature of BC awareness in the multi country African Breast Cancer-Disparities in Outcome (ABC-DO) cohort of women newly diagnosed with BC during 2014-2017. Awareness indicators were assessed during a baseline interview at/near diagnosis. Logistic/ordinal regression was used to estimate odds ratios (OR) for indicators of BC awareness in relation to woman-level characteristics for individual settings and then meta-analyzed. In the 1,451 women included, almost all Namibian non-black women (n = 104) knew of BC and its curability, while in Namibian black and Zambian women, one in 7 (~ 15%) had not previously heard of BC and 25-40% did not know it was curable. In Uganda and Nigeria awareness was lowest: one in four women had no BC awareness, and 2 in 3 had no knowledge of its cure potential. Low educational level, unskilled employment, low socioeconomic position, rural residence, older age, being unmarried, and in some settings HIV-positivity, were associated with lower BC awareness-e.g., having unskilled employment was associated with not having heard of BC (summary OR 3.37; 95% confidence interval (CI) 2.17-5.23), believing that it is incurable (2.43; 1.81-3.26), and not recognizing a breast lump symptom (1.85; 1.41-2.43) but with between-setting variation (I2 > 68% for all). The findings provide evidence of the level and difference in BC awareness and beliefs across different settings, highlighting the urgent need for context-specific education programmes in the SSA region. PMID- 29980986 TI - MBR 35 Editorial. PMID- 29980985 TI - Racial differences in maternal and umbilical cord blood leukocyte telomere length and their correlations. AB - PURPOSE: Telomere length at birth sets the baseline for telomere shortening and may influence adult disease risk like cancer. Telomere length is heritable, but may also be a marker of exposures in utero, including those influencing racial differences in risk. We examined racial differences in telomere length in maternal and umbilical cord blood from male neonates, and maternal-neonate correlations to generate hypotheses. METHODS: Black and white pregnant women were recruited in 2006-2007 and followed to postpartum. Data came from questionnaires and medical records. Relative telomere length was measured by qPCR in leukocyte DNA. We estimated mean telomere length in mothers and neonates (n = 55 pairs) using linear regression and maternal-cord blood Spearman correlations, overall and by race. RESULTS: Black mothers had shorter age- and plate-adjusted telomere length (2.49, 95% CI 2.11-2.86) than whites (2.92, 95% CI 2.63-3.22; p = 0.1) and black neonates had shorter telomere length (2.58, 95% CI 2.16-3.01) than whites (3.13, 95% CI 2.79-3.47; p = 0.1), though not statistically significant. Differences were attenuated after further adjustment for maternal factors. Maternal-cord blood correlations were moderate (r = 0.53, p < 0.0001), and did not differ by race. CONCLUSION: Telomere length may differ by race at birth due to both inherited and racial differences in maternal factors. This study was for hypothesis generation and results should be followed up in larger studies. PMID- 29980987 TI - Indoleamine 2,3-Dioxygenase (IDO) Inhibition as a Strategy to Augment Cancer Immunotherapy. AB - Indoleamine 2,3-dioxygenase (IDO) is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. IDO is upregulated in malignancy and is associated with poor prognosis in multiple cancer types. IDO inhibitors have been developed to target IDO, both directly and indirectly. Pre-clinical data have shown combined IDO and checkpoint inhibition to be an efficacious strategy for tumor control. Clinical trials of IDO inhibitors with chemotherapy or immunotherapy are currently underway. This review describes the function of IDO and its inhibitors and summarizes the efficacy and toxicity data from recent clinical trials with these drugs. PMID- 29980988 TI - Comparative Characteristics of Patients with Type 2 Diabetes Mellitus Treated by Bariatric Surgery Versus Medical Treatment: a Multicentre Analysis of 277,862 Patients from the German/Austrian DPV Database. AB - INTRODUCTION: Bariatric surgery is a well-established treatment option for serious obesity and concomitant type 2 diabetes mellitus (T2DM). In this analysis, we investigated predictors for bariatric surgery in everyday clinical practice. MATERIALS AND METHODS: In the DPV-registry, patients with T2DM from Germany and Austria treated by bariatric surgery were compared to non-surgery controls by descriptive statistics and regression analysis. RESULTS: Among 277,862 patients with T2DM, 0.07% underwent bariatric surgery. Surgery patients were predominantly female [61.20%], younger [median age (Q1;Q3) 54.74(47.40;61.61) vs. 70.04 (60.36;77.58) years] and had a longer diabetes duration [11.21 (7.15;17.93) vs. 8.36 (2.94;14.91) years]. They had a higher BMI [40.02 vs. 30.61 kg/m2, adjusted p < 0.0001] and a slightly lower HbA1c [7.25 vs. 7.56%, adjusted p < 0.05]. There was a trend using more often insulin therapy (52.79 vs.50.08%, n.s.) with no difference in insulin dose/kg * day [0.56 vs. 0.58, n.s.]. Sleeve gastrectomy was performed most frequently, followed by Roux en-Y gastric bypass, gastric banding, gastric balloon and others. A 2-year follow up data in 29 patients demonstrated significant reductions in BMI [45.23 to 38.00 kg/m2, p < 0.005] and HbA1c [7.98 to 6.98%, p < 0.005], and a trend for reduced insulin requirements [62.07 vs. 44.83%, n.s.]. CONCLUSION: Despite favourable 2 year outcomes, bariatric surgery is still used rarely in patients with T2DM and obesity. BMI rather than metabolic control seems to represent the major selector for or against bariatric surgery in T2DM. PMID- 29980990 TI - A Preliminary Study of Health Literacy in an Ethnically Diverse University Sample. AB - There is a considerable body of research on health literacy in adult healthcare settings, mostly among at-risk clinical populations. However, much less is known about health literacy among youth transitioning to adulthood, including college students. Despite the protective effects of higher levels of education, some college students might have other risk factors for low health literacy (i.e., minority status). Hence, the purpose of the present study was to explore health literacy in an ethnically diverse public urban university. Although a majority of the students performed within the adequate range, we observed a subset of Hispanic and foreign students with lower health literacy, particularly in the domain of numeracy. Our preliminary results suggest that, contrary to common belief, there exists a vulnerable subpopulation of college students that have difficulty understanding and using health-related information. Health professionals should be alert to possible low health literacy among college students that may interfere with communication of vital health-related information and decision-making. PMID- 29980989 TI - Laparoscopic-Guided Transversus Abdominis Plane (TAP) Block as Part of Multimodal Analgesia in Laparoscopic Roux-en-Y Gastric Bypass Within an Enhanced Recovery After Surgery (ERAS) Program: a Prospective Randomized Clinical Trial. AB - BACKGROUND: Despite the ultrasound guidance of transversus abdominis plane (TAP) blocks has allowed greater precision of needle placement in the desired tissue plane, visualization of the abdominal wall muscles can be hindered by morbid obesity and could lead to failed regional anesthesia. The aim of this study was to assess the feasibility and effect of laparoscopic-guided TAP block in patients undergoing Roux-en-Y gastric bypass and to compare it with port-site infiltration. PATIENTS AND METHODS: A prospective randomized clinical trial was performed. Patients were randomized into two groups: patients undergoing laparoscopic-guided TAP (TAP-lap) and patients undergoing port-site infiltration (PSI). Pain quantification as measured by visual analogic scale (VAS) and morphine needs during the first 24 h were evaluated. RESULTS: One hundred and forty patients were included, 70 in each group. The mean operation time was 83.3 + 15.6 min in TAP-lap and 80.5 + 14.4 min in PSI (NS). The mean postoperative pain, as measured by VAS, 24 h after surgery was 16.8 + 11.2 mm in PSI and 10 + 8.1 mm in TAP-lap (p = 0.001). Morphine rescues were necessary in 13.2% in PSI and 2.9% in TAP-lap (p = 0.026). The mean hospital stay was 2.1 + 1.2 days in TAP lap and 2.9 + 1.3 days in PSI (p = 0.019). Hospital discharge during the first 48 h after surgery was possible in 52.9% of the patients in PSI and 71% in TAP-lap (OR 4.75; 95% CI 2.1-10.8; p = 0.029). CONCLUSION: Laparoscopic-guided TAP block can reduce postoperative pain, opioid needs, and hospital stay, when compared with port-site infiltration with the same anesthetic drug, without increasing operation time. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03203070. PMID- 29980991 TI - Gender Differences in Predictors of HIV Testing Among African American Young Adults. AB - OBJECTIVE: The primary aim of this study was to examine gender differences in predictors of past HIV test behavior among young African Americans. METHOD: Data from (n = 190) young adults participating in an evidenced-based safer sex behavioral intervention were analyzed. Participants completed measures of previous HIV testing, HIV test attitudes, HIV knowledge, HIV test behavior, and HIV risk behaviors. A series of t tests and chi-square tests were performed to assess gender differences in these variables. Multivariate logistic regressions were performed to examine the influence of HIV test attitudes, knowledge of where to get tested, and HIV risk behaviors on having previously been tested for HIV. RESULTS: Overall, approximately 58% of the sample had been previously tested for HIV. There were significant differences between groups on HIV risk factors (i.e., number of sexual partners), such that men reported a significantly higher number of sexual partners in the past 3 months. Men also reported more negative HIV testing attitudes compared with women. Predictors of past HIV testing differed by gender. Negative attitudes about HIV testing were associated with significantly lower odds of past HIV testing among men, but this was not a significant predictor of testing among women. Older age was significantly associated with greater odds of past HIV testing among women, but not among men. CONCLUSIONS: Understanding gender differences in predictors of HIV testing can provide important information for clinicians, counselors, and others working to increase rates of HIV testing among young Black/African American adults. PMID- 29980992 TI - Psychosocial Functioning in Parents of MPS III Patients. AB - BACKGROUND: Mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) is a lysosomal storage disease resulting in progressive neurocognitive decline during childhood and early demise. Its diagnosis may have a great impact on parents, potentially leading to psychosocial problems such as anxiety, depression, parental distress, and posttraumatic stress. METHODS: Twenty-six mothers and 19 fathers of 34 Dutch MPS III patients completed the "Hospital Anxiety and Depression Scale" (HADS), the "Distress Thermometer for Parents" (DT-P), and the "Self-Rating Scale for Posttraumatic Stress Disorders" (SRS-PTSD). Independent sample T-tests and chi-square tests were used to assess differences between parents of MPS III patients and reference groups regarding anxiety and depression (HADS), distress (DT-P), and posttraumatic stress (SRS-PTSD). RESULTS: Mothers met the criteria for clinically relevant anxiety (50%) and depression (34.6%) more frequently compared to reference mothers (p = 0.001). Fathers more often met the criteria for clinically relevant depression (36.8%) compared to reference fathers (p = 0.022). Clinically relevant distress was highly prevalent in mothers (84.6%) and fathers (68.4%) of MPS III patients compared to reference parents (p < 0.01). Finally, the prevalence of PTSD was strikingly higher in both mothers (26.9%) and fathers (15%) than reported in the general Dutch population (respectively, p < 0.001 and p < 0.05). CONCLUSIONS: We report a clinically relevant impact of parenting an MPS III patient on psychosocial functioning, which is demonstrated by high levels of anxiety, depression, distress, and a remarkably high prevalence of PTSD. Structural monitoring of the psychosocial functioning of MPS III parents is therefore essential and may be beneficial for the whole family. PMID- 29980993 TI - Pre-exposure Prophylaxis Among Men Who have Sex with Men: Dual Motivational Model of Intention to Use Pre-exposure Prophylaxis. AB - Men who have sex with men (MSM) account for most new HIV infections in the United States. Despite representing a fraction of the population, MSM make up an estimated 65% of new infections. To address this epidemic, pre-exposure prophylaxis (PrEP) is recommended to supplement condom use. Despite its effectiveness, PrEP uptake among MSM is low. Few studies have employed theoretical approaches to understand PrEP use intention. Incorporating factors like safe sex fatigue, expectation of better sexual experiences, and perceived risk are proposed in this dual motivational path model of PrEP use intention. This model hypothesized that PrEP use intention is influenced by two key pathways: (1) protection motivation pathway, and (2) sexual expectancy pathway. Data were collected using social networking applications from 402 MSM. The model was tested using structural equation modeling. We elaborate the complex decision making process proposed by this novel theoretical model and discuss its practical implications. PMID- 29980994 TI - The quality of life in Chinese population with chronic non-communicable diseases according to EQ-5D-3L: a systematic review. AB - PURPOSE: Over the past decade, a changing spectrum of disease has turned chronic non-communicable diseases (CNCDs) into the leading cause of death worldwide. During the 2015 in China, there were more than 6.6 million deaths from NCDs, which was the highest rate around the world. In the present study, we performed a systematic review to analyze the health-related quality of life (HRQoL) according to EQ-5D-3L instrument in patients with different kinds of CNCDs in China. METHODS: We searched PubMed, Embase, Web of Science, Cochrane Library, VIP, WanFang Data, and CNKI databases up to April 12, 2018, to identify all relevant studies that reported on HRQoL assessed by EQ-5D-3L instrument in Chinese patients with CNCDs. Expert consultation and hand-searching of reference lists from retrieved studies were employed to identify additional references. The variation of mean utility values, EQ-VAS score ranges, and responses for each EQ 5D dimension described in relevant studies were extracted. RESULTS: A total of 5027 English-language articles and 618 Chinese-language articles were identified, among which 38 articles met full inclusion criteria. These 38 studies involved 18 kinds of CNCDs. In this review, the health utility for diabetes mellitus ranged from 0.79 to 0.94 (EQ-5D VAS scores from 61.5 to 78.6), hypertension from 0.78 to 0.93 (70.1-77.4), coronary heart disease from 0.75 to 0.90 (71.0-77.0), chronic obstructive pulmonary disease from 0.64 to 0.80 (55.0-67.0), epilepsy from 0.83 to 0.87 (78.3-79.6), cerebral infarction from 0.51 to 0.75 (49.7-79.0), while children cerebral palsy was 0.44 (27.3). CONCLUSIONS: EQ-5D-3L is widely used in studies of HRQoL associated with CNCDs in China. Our results suggest that many factors may influence the measurement results of health utilities, including age, gender, sample source, comorbidities, rural/urban, and EQ-5D-3L value sets. PMID- 29980995 TI - Numerical error monitoring. AB - Error monitoring has recently been discovered to have informationally rich foundations in the timing domain. Based on the common properties of magnitude based representations, we hypothesized that judgments on the direction and the magnitude of errors would also reflect their objective counterparts in the numerosity domain. In two experiments, we presented fast sequences of "beeps" with random interstimulus intervals and asked participants to stop the sequence when they thought the target count (7, 11, or 19) had been reached. Participants then judged how close to the target they stopped the sequence, and whether their response undershot or overshot the target. Individual linear regression fits as well as the linear mixed model with a fixed effect of reproduced numerosity on confidence ratings, and participants as independent random effects on the intercept and the slope, revealed significant positive slopes for all the target numerosities. Our results suggest that humans can keep track of the direction and degree of errors in the estimation of discrete quantities, pointing at a numerical-error-monitoring ability. PMID- 29980996 TI - Delay knowledge and trial set count modulate use of proactive versus reactive control: A meta-analytic review. AB - The AX-continuous performance task (AX-CPT) and dot pattern expectancy (DPX) are the predominant cognitive paradigms used to assess the relative utilization of proactive versus reactive cognitive control. Experimental parameters vary widely between studies and systematically between different modalities (i.e., fMRI vs. EEG) with unknown consequences for the implementation of control. This meta analytic review systematically surveyed these bodies of literature (k = 43, 73 data points) to resolve how cue-probe delay knowledge, delay length, and trial set count modulate the preferential use of proactive versus reactive control. In healthy young adults, delay knowledge and increasing trial set count each bias participants toward greater proactive control. Further, the interaction of delay knowledge and trial set count accounts for ~40% of variability in proactive/reactive control performance. As trial count varies reliably between experimental modalities, it is critical to understand how these parameters activate distinct cognitive processes and tap into different neural mechanisms for control. Subgroup analyses revealed important distinctions from our results in healthy young adults. Healthy, slightly older adults (ages 30-45 years) performed more reactively compared to healthy young adults. In addition, participants with schizophrenia showed evidence of more proactive control as trial set count increased. In light of this meta-analytic review, we conclude that delay knowledge and trial set length are important parameters to account for in the assessment of proactive versus reactive control. More broadly, this metaregression provides strong evidence that cognitive control becomes more reactive when timing demands are not known, and that both healthy persons and persons with schizophrenia shift toward proactive control with increasing repetitions of a task set. PMID- 29980997 TI - L1 Orthography in L2 Chinese Morphological Awareness: An Investigation of Alphabetic and Abugida Readers. AB - The current study aimed to explore the effect of first language (L1) orthography on second language (L2) Chinese morphological awareness. One hundred and twenty nine students (61 L1 English readers and 68 L1 Thai readers) who studied Chinese as a second language participated in this study. They completed four tasks of morphological awareness (morpheme segmentation, morpheme discrimination, compound structure discrimination, compound structure analysis) and two control measures (reading vocabulary tasks). Drawing upon MANCOVA analysis, the study revealed that Thai readers outperformed English readers on compound awareness after the effect of L2 reading vocabulary was accounted for. The study suggests that L1 orthographic differences and similarities (e.g. interword boundary) may affect word identification, thus contributing to morphological processing of Chinese compound words. The study provided empirical evidence to support cross-language influence in morphological processing of a non-alphabetic language. PMID- 29980998 TI - The impact of delayed critical care outreach team activation on in-hospital mortality and other patient outcomes: a historical cohort study. AB - PURPOSE: Early warning scores (EWS) and critical care outreach teams (CCOT) have been developed to respond to decompensating patients. Nevertheless, controversy exists around their effectiveness. The primary objective of this study was to determine if a delay of >= 60 min between when a patient was identified as meeting EWS criteria and the CCOT was activated impacted in-hospital mortality. METHODS: This was a historical cohort study evaluating all new CCOT activations over a four-year study period (1 June 2007 to 31 August 2011) for inpatients >= 18 yr of age at two academic tertiary care hospitals in London, Ontario, Canada. Multivariable logistic regression accounting for repeated measures was used to determine the effect of delayed CCOT activation on in-hospital mortality (primary outcome). Differences in outcomes between medical and surgical patients were also examined. RESULTS: There were 3,133 CCOT activations for 1,684 (53.8%) medical patients and 1,449 (46.2%) surgical patients during the study period. The CCOT was activated < 60 min of a patient meeting EWS criteria in 2,160 (68.9%) cases and >= 60 min in 973 (31.1%) cases. Patients with >= 60 min delay were more likely be admitted to the intensive care unit (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.07 to 1.47) and to suffer in-hospital mortality (OR, 1.30; 95% CI, 1.08 to 1.56). Irrespective of delay, surgical patients were less likely to experience in-hospital mortality than medical patients (OR, 0.46; 95% CI, 0.39 to 0.55). CONCLUSION: Including the rates of delay in CCOT activation and the admitting service could be an additional step in exploring the conflicting results seen in the current literature assessing the impact of CCOT on patient outcomes. PMID- 29980999 TI - End-of-life decision-making is difficult (problems with the Consent and Capacity Board). PMID- 29981000 TI - CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage, HIV-Associated Neurocognitive Disorders, and Peripheral HIV DNA: reseeding of CNS reservoirs? AB - HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14+CD16+ monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14+CD16+ monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14+CD16+ monocytes with cognitive status, proton magnetic resonance spectroscopy (1H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14+CD16+ monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14+CD16+ monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r2 = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r2 = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14+CD16+ monocytes also correlated with PBMC HIV DNA copies (rho = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14+CD16+ monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14+CD16+ monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND. PMID- 29981001 TI - When is a Phylogenetic Network Simply an Amalgamation of Two Trees? AB - Phylogenetic networks generalise phylogenetic (evolutionary) trees by allowing for the representation of reticulation (non-treelike) events. The structure of such networks is often viewed by the phylogenetic trees they embed. In this paper, we determine when a phylogenetic network [Formula: see text] has two phylogenetic tree embeddings which collectively contain all of the edges of [Formula: see text]. This determination leads to a polynomial-time algorithm for recognising such networks and an unexpected characterisation of the class of reticulation-visible networks. PMID- 29981002 TI - A Critical Comparison of Rejection-Based Algorithms for Simulation of Large Biochemical Reaction Networks. AB - The rejection-based simulation technique has been applying to improve the computational efficiency of the stochastic simulation algorithm (SSA) in simulating large reaction networks, which are required for a thorough understanding of biological systems. We compare two recently proposed simulation methods, namely the composition-rejection algorithm (SSA-CR) and the rejection based SSA (RSSA), aiming for this purpose. We discuss the right interpretation of the rejection-based technique used in these algorithms in order to make an informed choice when dealing with different aspects of biochemical networks. We provide the theoretical analysis as well as the detailed runtime comparison of these algorithms on concrete biological models. We highlight important factors that are omitted in previous analysis of these algorithms. The numerical comparison shows that for reaction networks where the search cost is expensive then SSA-CR is more efficient, and for reaction networks where the update cost is dominant, often the case in practice, then RSSA should be the choice. PMID- 29981003 TI - Perceptions of tableware size in households of children and adolescents with obesity. AB - PURPOSE: Portion size influences energy intake and is an important factor when developing weight management strategies. The effect of tableware on food intake is less clear, especially in children. To date, the relationship between the body weight of individuals and the tableware used in their households has not been investigated. The aim of this study was to analyze the sizes of tableware in households of children and adolescents with obesity (OBE) in comparison to participants with normal-weight matched for age and gender (NW). METHODS: 60 OBE (32 female, 26 male) and 27 NW (12 female, 15 male) aged between 9 and 17 years participated in a structured interview on the tableware used at home. Responses were standardized based on the selection of different sizes of tableware and everyday objects presented to the children. RESULTS: In households of NW, larger plates and bowls were used during meals and desserts compared to OBE. OBE drank out of larger bottles. Shapes and sizes of drinkware, the number of children drinking out of bottles and the cutlery used during dessert did not differ between the groups. CONCLUSIONS: Drinking out of large bottles may be an unfavourable habit of OBE if they contain sugar-rich liquids. The use of smaller plates and bowls of OBE may result in multiple helpings being consumed and so contribute to an overall increased portion size. LEVEL OF EVIDENCE: Level V, Descriptive study. PMID- 29981004 TI - Economic Evaluation for the UK of Systemic Chemotherapies as First-Line Treatment of Metastatic Pancreatic Cancer. AB - BACKGROUND: Gemcitabine (GEM), oxaliplatin plus GEM (OX + GEM), cisplatin plus GEM (CIS + GEM), capecitabine plus GEM (CAP + GEM), FOLFIRINOX (FFX), and nab paclitaxel plus GEM (NAB-P + GEM) are the most commonly used regimens as first line treatment of metastatic pancreatic cancer (MPC) in the UK. Independent economic evaluation of these regimens simultaneously has not been conducted for the UK. OBJECTIVE: Using data from a network meta-analysis as efficacy measures, we estimated the cost effectiveness and cost utility of these regimens for the UK. METHODS: A three-state Markov model (progression-free, progressed-disease, and death) simulating the total costs and health outcomes (quality-adjusted life years [QALYs] gained and life-years [LYs]) was developed to estimate the incremental cost-utility (ICUR) and incremental cost-effectiveness ratios (ICER) for patients with MPC, from the payer perspective. The model was specified to calculate total costs in 2017 British pounds (GBP, L). All values were discounted at 3.5% per year over a full lifetime horizon. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on the results. RESULTS: FFX was the most effective regimen, NAB-P + GEM was the most costly regimen, and GEM was the least costly and least effective regimen. OX + GEM, CIS + GEM, and NAB-P + GEM were dominated by CAP + GEM and FFX. Compared with GEM, the ICUR for CAP + GEM and FFX was L28,066 and L33,020/QALY gained, respectively; compared with GEM, the ICER for CAP + GEM and FFX was L17,437 and L22,291/LY gained, respectively; and compared with CAP + GEM, the ICUR and ICER for FFX were L34,947/QALY gained and 24,414/LY gained, respectively. CONCLUSIONS: At a threshold value of L30,000/QALY, CAP + GEM was found to be the only cost-effective regimen in the management of MPC in the UK. PMID- 29981005 TI - Attention-deficit hyperactivity disorder in Brazilian patients with phenylketonuria. AB - Recent studies have shown that patients with phenylketonuria (PKU), even with the early diagnosis and continuous treatment, may have symptoms of attention-deficit hyperactivity disorder (ADHD) and that the prevalence of ADHD in this population would be higher than in the general population. This study aims to determine the prevalence of ADHD in a sample of PKU patients from Southern Brazil. Patients were prospectively assessed by clinical interviews, neurological examination, and application of the MTA-SNAP-IV scales for patients aged 5-17 years and the Adult Self-Report Scale for patients over 17 years. Thirty-one patients (mean age = 17.4; early diagnosis = 27) were followed. Patients with ADHD and younger than 17 years had a median Phe in the last 6 months of life higher than those without the diagnosis of ADHD (ADHD patients = 617.1 umol/L, no-ADHD patients 393.2 umol/L, and p = 0.03). There was a predominantly hyperactive/impulsivity clinical presentation of ADHD (n = 4/5 patients), which differs from that reported elsewhere in the literature. Future studies are essential to better define the clinical presentation of ADHD in these patients and further elucidate its pathophysiology. PMID- 29981006 TI - The course of epilepsy and seizure control in pregnant women. AB - To investigate the course of epilepsy and seizure control during pregnancy. 105 pregnant women with epilepsy were studied prospectively during the period from 2013 to 2017. The average age at the onset of epilepsy was 17.4 +/- 0.5 years. Seizures during pregnancy were observed in 76 (72.4 +/- 4.4%) women. Eleven (10.5 +/- 3.0%) women had their first seizure during current pregnancy. Among those 94 women who were diagnosed with epilepsy before pregnancy, 29 (30.9 +/- 4.8%) remained seizure free; seizure frequency increased in 27 (28.7 +/- 4.7%), decreased in 24 (25.5 +/- 4.5%) women, in 14 (14.9 +/- 3.7%) remained unchanged. Among 15 women who were seizure free for the 1 year prior to pregnancy 11 (73.3 +/- 11.4%) women remained seizure free during pregnancy. The worsening in seizure control during pregnancy occurred in 22 (35.5 +/- 6.1%) of 62 women with focal epilepsy and 5 (15.6 +/- 6.4%) of 32 with idiopathic generalized epilepsy (OR 2.97, 95% CI 1.0-8.81). Non-compliance with the antiepileptic drug therapy was observed in 20 (19.0 +/- 3.8%) pregnant women, seizure frequency increased in 18 (90.0 +/- 6.7%) of them compared with 5 (9.8 +/- 4.2%) of 51 of those who followed correct antiepileptic drug regimen (p < 0.001). The risk of seizures during pregnancy was lower in women who were seizure-free for the 1 year prior to pregnancy; focal epilepsy was associated with an increased risk of seizure relapse during pregnancy; non-compliance with the antiepileptic drug therapy and inappropriate treatment may lead to worsening of seizure control and to the status epilepticus during pregnancy. PMID- 29981007 TI - Cerebral microbleeds and intracerebral hemorrhage associated with veno-venous extracorporeal membrane oxygenation. PMID- 29981009 TI - Quantitative assessment and risk factors for nipple-areolar complex malposition after nipple-sparing mastectomy. AB - PURPOSE: Nipple sparing mastectomy (NSM) for breast cancer preserves the nipple areola complex (NAC) and has limited the extent of the scar, giving good cosmetic results. However, NAC malposition may occur. The aim of this study is to evaluate NAC malposition after NSM and to determine factors associated with malposition in two-stage reconstruction. METHODS: The subjects were 46 patients who underwent unilateral NSM, without contralateral mastopexy or reduction surgery, in two stage reconstruction using an expander with implant or flap replacement. Vertical and horizontal NAC malposition and predictors of malposition were evaluated before and more than 1 year after reconstruction surgery. RESULTS: The total amount of saline injected into the expander and aging were significant predictors of increased superior malposition of NAC before and more than 1 year after reconstruction or implant surgery. In contrast, the amount of saline injected into the expander until 2 weeks after expander insertion was a significant predictor of decreased superior NAC malposition. BMI was also a statistically significant predictor of decreased superior NAC malposition, but this result was likely to have been due to the measurement method. Autologous reconstruction was a significant negative predictor of superior malposition at more than 1 year after surgery. Superior NAC malposition resulting from full expansion of the expander improved by a mean vertical angle of 4.5 degrees after autologous reconstruction, but hardly improved after implant use. In autologous reconstruction, NAC tended to move slightly to the lateral side after autologous reconstruction, compared to implant use. CONCLUSIONS: Until 2 weeks after expander insertion, as much saline as possible should be injected to prevent superior NAC malposition. At full expansion, superior malposition of vertical angle > 4.5 degrees may require repositioning surgery. PMID- 29981008 TI - Posttraumatic Stress Disorder and Psychiatric Co-morbidity among Syrian Refugees of Different Ages: the Role of Trauma Centrality. AB - It has been documented that trauma centrality is associated with posttraumatic stress disorder (PTSD) and psychiatric co-morbidity among Syrian refugees. Whether age would influence the levels of the above constructs and the association between trauma centrality and distress outcomes is unclear. This study compared age differences in 1) the levels of trauma centrality, posttraumatic stress disorder and psychiatric co-morbidity, and 2) models depicting the association between trauma centrality and distress outcomes among Syrian refugees. One thousand one hundred and ninety-seven refugees completed the Centrality of Event Scale, Harvard Trauma Questionnaire and General Health Questionnaire-28. Age groups were divided into young, middle-aged adults and adults of 45 or above. No significant group differences were found in the proportion of refugees meeting the diagnostic criteria for PTSD. Controlling for demographic variables, all subscales of trauma centrality and psychiatric co morbidity were significantly different between groups. Young adults reported significantly less trauma centrality and psychiatric co-morbidity than the other groups. Multiple-indicator multiple-cause modelling showed that trauma centrality was significantly correlated with PTSD and psychiatric co-morbidity. Multi-group analysis showed the model for the young adult group to be significantly different from the middle-aged group model. To conclude, age did not seem to influence the severity of PTSD among Syrian refugees. The war had a less severe impact on young adults' sense of self and other psychological problems than those who were older. The way in which young and middle-aged adults responded to distress varied depending on environment and personal characteristics. PMID- 29981010 TI - The U.S. food-energy-water system: A blueprint to fill the mesoscale gap for science and decision-making. AB - Food, energy, and water (FEW) are interdependent and must be examined as a coupled natural-human system. This perspective essay defines FEW systems and outlines key findings about them as a blueprint for future models to satisfy six key objectives. The first three focus on linking the FEW production and consumption to impacts on Earth cycles in a spatially specific manner in order to diagnose problems and identify potential solutions. The second three focus on describing the evolution of FEW systems to identify risks, thus empowering the FEW actors to better achieve the goals of resilience and sustainability. Four key findings about the FEW systems that guide future model development are (1) that they engage ecological, carbon, water, and nutrient cycles most powerfully among all human systems; (2) that they operate primarily at a mesoscale best captured by counties, districts, and cities; (3) that cities are hubs within the FEW system; and (4) that the FEW system forms a complex network. PMID- 29981011 TI - Fixed-target efficient search has logarithmic efficiency with and without eye movements. AB - Stage 1 processing in visual search (e.g., efficient search) has long been thought to be unaffected by factors such as set size or lure-distractor similarity (or at least to be only minimally affected). Recent research from Buetti, Cronin, Madison, Wang, and Lleras (Journal of Experimental Psychology: General, 145, 672-707, 2016) showed that in efficient visual search with a fixed target, reaction times increase logarithmically as a function of set size and, further, that the slope of these logarithmic functions is modulated by target distractor similarity. This has led to the proposal that the cognitive architecture of Stage 1 processing is parallel, of unlimited capacity, and exhaustive in nature. Such an architecture produces reaction time functions that increase logarithmically with set size (as opposed to being unaffected by it). However, in the previous studies, eye movements were not monitored. It is thus possible that the logarithmicity of the reaction time functions emerged simply as an artifact of eye movements rather than as a reflection of the underlying cognitive architecture. Here we ruled out the possibility that eye movements resulted in the observed logarithmic functions, by asking participants to keep their eyes at fixation while completing fixed-target efficient visual search tasks. The logarithmic RT functions still emerged even when participants were not allowed to make eye movements, thus providing further support for our proposal. Additionally, we found that search efficiency is slightly improved when eye movements are restricted and lure-target similarity is relatively high. PMID- 29981012 TI - Quantitative Analysis on Ex Vivo Nonlinear Microscopy Images of Basal Cell Carcinoma Samples in Comparison to Healthy Skin. AB - Basal cell carcinoma (BCC) is the most frequent malignant neoplasm in the Caucasian population. There are several therapeutic options for BCC, but surgical excision is considered gold standard treatment. As BCCs often have poorly defined borders, the clinical assessment of the tumor margins can be challenging. Therefore, there is an increasing demand for efficient in vivo imaging techniques for the evaluation of tumor borders prior to and during surgeries. In the near future, nonlinear microscopy techniques might meet this demand. We measured the two-photon excitation fluorescence (TPEF) signal of nicotinamide adenine dinucleotide hydride (NADH) and elastin and second harmonic generation (SHG) signal of collagen on 10 ex vivo healthy control and BCC skin samples and compared the images by different quantitative image analysis methods. These included integrated optical density (IOD) measurements on TPEF and SHG images and application of fast Fourier transform (FFT), CT-FIRE and CurveAlign algorithms on SHG images to evaluate the collagen structure. In the BCC samples, we found significantly lower IOD of both the TPEF and SHG signals and higher collagen orientation index utilizing FFT. CT-FIRE algorithm revealed increased collagen fiber length and decreased fiber angle while CurveAlign detected higher fiber alignment of collagen fibers in BCC. These results are in line with previous findings which describe pronounced changes in the collagen structure of BCC. In the future, these novel image analysis methods could be integrated in handheld nonlinear microscope systems, for sensitive and specific identification of BCC. PMID- 29981014 TI - Toxicity effects and biomarkers of tebufenozide exposure in Yuukianura szeptyckii (Collembola: Neanuridae). AB - Tebufenozide is an insect growth regulator used to control pest caterpillar populations. As an ecdysone agonist, tebufenozide is equally toxic to several non target arthropod species, binding the receptor sites of the molting hormone 20 hydroxyecdysone and causing premature and lethal molting. In this study, the toxic effects of tebufenozide were assessed, and biomarkers of tebufenozide exposure were identified, in the non-target soil collembolan species Yuukianura szeptyckii. Adult mortality and reproduction in Y. szeptyckii exposed to tebufenozide were evaluated after 28 days of exposure and were used to calculate LC50 and EC50, respectively. The LC50 could not be determined, because the mortality values observed were below 50%, even when exposed to the highest concentration tested (700 mg/kg), but the EC50 was 95.5 mg/kg. Effects on hatching and molting rates were evaluated using compressed soils, to prevent experimental individuals from burrowing; thus, all eggs and exuviae were detectable on the soil surface. Significant negative effects of tebufenozide exposure on the hatching rate and molting frequency were observed only at the highest concentration tested (700 mg/kg). Proteomic analyses were conducted to detect the cryptic effects of toxicity in adult collembolans exposed for 28 days to 43.8 mg/kg of tebufenozide, a concentration at which no toxicity effects were observed. The production rates of two ribosomal proteins, as well as proteins involved in apoptotic cell signaling, were higher in collembolans exposed to tebufenozide than in the control group. However, the production of proteins involved in glycolysis and energy production was downregulated. Therefore, the ecotoxicoproteomic approach is a promising tool for measuring the cryptic effects of tebufenozide exposure in Y. szeptyckii at low concentrations. PMID- 29981013 TI - The ER - Glycogen Particle - Phagophore Triangle: A Hub Connecting Glycogenolysis and Glycophagy? AB - Glycogen particle is an intracellular organelle, which serves as a carbohydrate reserve in various cells. The function of glycogen is not entirely known in several cell types. Glycogen can be mobilized for different purposes, which can be related to cellular metabolic needs, intracellular redox state, metabolic state of the whole organism depending on regulatory aspects and also on cell functions. Essentially there are two different ways of glycogen degradation localized in different cellular organelles: glycogenolysis or lysosomal breakdown by acid alpha-glucosidase. While glycogenolysis occurs in glycogen particles connected to endoplasmic reticulum membrane, glycogen particles can be also combined with phagophores forming autophagosomes. A subdomain of the endoplasmic reticulum membrane - omegasomes - are the sites for phagophore formation. Thus, three organelles, the endoplasmic reticulum, the phagophore and the glycogen particle forms a triangle in which glycogen degradation occurs. The physiological significance, molecular logic and regulation of the two different catabolic paths are summarized and discussed with special aspect on the role of glycogen particles in intracellular organelle homeostasis and on molecular pathology of the cell. Pathological aspects and some diseases connected to the two different degradation pathways of glycogen particles are also detailed. PMID- 29981015 TI - Source patterns and contamination level of polycyclic aromatic hydrocarbons (PAHs) in urban and rural areas of Southern Italian soils. AB - Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic pollutants. They have been identified as a type of carcinogenic substance and are relatively widespread in environment media such as air, water and soils, constituting a significant hazard for human health. In many parts of the world, PAHs are still found in high concentrations despite improved legislation and monitoring, and it is therefore vital defining their profiles, and assessing their potential sources. This study focused on a large region of the south of Italy, where concentration levels, profiles, possible sources and toxicity equivalent quantity (TEQ) level of sixteen PAHs were investigated. The survey included soils from five large regions of the south of Italy: 80 soil samples (0 20 cm top layer) from urban and rural locations were collected and analysed by gas chromatography-mass spectrometry. Total PAHs and individual molecular compounds from the US Environmental Protection Agency priority pollutants list were identified and measured. Results showed that 16 PAHs varied significantly in urban and rural areas, and different regions presented discordant characteristics. Urban areas presented concentrations ranging from 7.62 to 755 ng g-1 (mean = 84.85 ng g-1), whilst rural areas presented ranges from 1.87 to 11,353 ng g-1 (mean = 333 ng g-1). Large urban areas, such as Rome, Naples and Palermo, exhibited high PAHs total concentration, but high values were also found in rural areas of Campania region. Different PAHs molecular ratios were used as diagnostic fingerprinting for source identification: LWMPAHs/HWMPAHs, Fluo/(Fluo + Pyr), BaA/(BaA + Chr), Ant/(Ant + Phe) and IcdP/(IcdP + BghiP). These ratios indicated that PAHs sources in the study area were mainly of pyrogenic origin, i.e. mostly related to biomass combustion and vehicular emission. On the other hand, values in Sicilian soils seemed to indicate a petrogenic origin, possibly linked to emissions from crude oil combustion and refineries present in the region. Finally, results allowed to calculate the toxicity equivalent quantity (TEQBAP) levels for the various locations sampled, highlighting that the highest values were found in the Campania region, with 661 and 54.20 ng g-1, in rural and urban areas, respectively. These findings, which could be linked to the presence of a large solid waste incinerator plant, but also to well-documented illegal waste disposal and burning, suggest that exposure to PAH may be posing an increased risk to human health in some of the studied areas. PMID- 29981016 TI - Intravascular ultrasound-guided drug-eluting stent implantation is associated with improved clinical outcomes in patients with unstable angina and complex coronary artery true bifurcation lesions. AB - Stenting coronary artery bifurcation lesion is associated with suboptimal clinical results. Clinical improvement by intravascular ultrasound (IVUS) guided bifurcation stenting is controversial because small-side-branch (SB), low-risk patients and false bifurcations were included in previous studies that had no exact IVUS criteria for optimal stent expansion. We sought determine whether IVUS guidance is superior to angiography guidance for patients with true and complex bifurcation lesions. Between July 2006 and July 2012, 1465 patients with unstable angina and Medina 1,1,1 or 0,1,1 coronary bifurcation lesions were prospectively studied. 310 patients in the IVUS guidance (defined as stent symmetry index > 0.7, stent expansion index > 0.9, well apposition, and no Type B/C dissection) group were paired with 620 patients in the angiography group by propensity score matching. The primary endpoint was the rate of composite major adverse cardiac events (MACE) (cardiac death, myocardial infarction (MI), or clinically-driven target vessel revascularization) at 1-year and at the end of study after indexed procedure. Use of IVUS guidance was mainly driven by stenting technique selection and identification of lesions' specificities. IVUS criteria for optimal stent expansion were achieved in 82.9% of patients which contribute to IVUS group data assessment and the rest did not meet optimal criteria. MACE occurred in 10.0% of patients at 1-year follow-up and 15.2% at the 7-year follow-up in the IVUS group, significantly different from 15.0% (p = 0.036) and 22.4% (p = 0.01) in the angiography group, respectively. Compared to angiography guidance, IVUS guidance also resulted in a lower 7-year cardiac death rate (6.5 versus 1.3%, p = 0.002) and MI (8.4 versus 2.3%, P < 0.001). Any revascularization was also statistically lower in the IVUS group through whole study period, compared to the angiography group. Lower MACE rates were observed in IVUS guidance group in a 7-year follow up compared with angiography guidance alone. PMID- 29981017 TI - Hippocampal sulcal cavities: prevalence, risk factors and association with cognitive performance. The SMART-Medea study and PREDICT-MR study. AB - Hippocampal sulcal cavities (HSCs) are frequently observed on MRI, but their etiology and relevance is unclear. HSCs may be anatomical variations, or result from pathology. We assessed the presence of HSCs, and their cross-sectional association with demographics, vascular risk factors and cognitive functioning in two study samples. Within a random sample of 92 patients with vascular disease from the SMART-Medea study (mean age = 62, SD = 9 years) and 83 primary care patients from the PREDICT-MR study (mean age = 62, SD = 12 years) one rater manually scored HSCs at 1.5 T 3D T1-weighted coronal images blind to patient information. We estimated relative risks of age, sex and vascular risk factors with presence of HSCs using Poisson regression with log-link function and robust standard errors adjusted for age and sex. Using ANCOVA adjusted for age, sex, and education we estimated the association of the number of HSCs with memory, executive functioning, speed, and working memory. In the SMART-Medea study HSCs were present in 65% and in 52% in the PREDICT-MR study (chi2 = 2.99, df = 1, p = 0.08). In both samples, no significant associations were observed between presence of HSCs and age (SMART-Medea: RR = 1.00; 95%CI 0.98-1.01; PREDICT-MR: RR = 1.01; 95%CI 0.99-1.03), sex, or vascular risk factors. Also, no associations between HSCs and cognitive functioning were found in either sample. HSCs are frequently observed on 1.5 T MRI. Our findings suggest that, in patients with a history of vascular disease and primary care attendees, HSCs are part of normal anatomic variation of the human hippocampus rather than markers of pathology. PMID- 29981018 TI - Language function shows comparable cortical patterns by functional MRI and repetitive nTMS in healthy volunteers. AB - In preoperative planning, fMRI and repetitive navigated transcranial magnetic stimulation (rTMS) repeatedly revealed differences in the detected language sites, which can be attributed to tumor-induced oxygenation changes impairing the accuracy of fMRI. We therefore compared the accordance of those techniques in healthy subjects using exactly the same tasks in both investigations. 19 healthy right-handed subjects performed object naming, pseudoword reading, verb generation, and action naming during fMRI at 3 T and rTMS. For rTMS language mapping, we stimulated 46 cortical spots over the left hemisphere; each site was stimulated for three times. Language positive points during rTMS for one, two, or three errors out the three stimulations per spot (1/3, 2/3, 3/3) were exported via DICOM, and compared to the positive fMRI clusters. As a result of this comparison, the best correlation was observed between 3/3 errors and fMRI for pseudoword reading and verb generation with t-values of pu < 0.001, uncorrected for multiple comparisons, on average across the whole rTMS-spot map. We found a close spatial agreement between several rTMS-spots (2/3 and 3/3 errors) and fMRI clusters accentuated in the frontal lobe, followed by the parietal lobe and less in the temporal lobe. Compared to the fMRI clusters, there was a higher congruence for 2/3 and 3/3 errors than for 1/3 errors. Overall, results of language mapping in healthy subjects by fMRI and rTMS correspond well yet depending on the used language task. PMID- 29981019 TI - Metals in fish of different trophic levels in the area of influence of the AHE Foz do Chapeco reservoir, Brazil. AB - In regions where there is intense polluting activity, a greater availability of metals in water impounded by dams increases the availability and contamination of the fauna and flora. Thus, we assessed the accumulation of metals in muscle and gills of fish of different trophic levels in the area of influence of Foz do Chapeco hydroelectric plant on the Uruguai river. We analyzed the metals Pb, Cd, Cu, Cr, Mn, Zn, and Fe in Hypostomus isbrueckeri (cascudo), Pimelodus maculatus (mandi), and Salminus brasiliensis (dourado). We collected specimens from both upstream and downstream of the reservoir in February and March 2014. We also measured the allometric condition factor of the fish to determine their physiological status. Physical and chemical variables of the water were measured to determine the influence of these abiotic variables on the bioavailability of metals and on the condition factor of the fish. Gills had a higher concentration of metals than muscle. Hypostomus isbrueckeri and Pimelodus maculatus possessed high concentrations of metals, indicating greater bioaccumulation in benthic species. Only chromium in muscle varied significantly between upstream and downstream, with higher concentrations in H. isbrueckeri and P. maculatus upstream. Chromium contamination, however, did not change the condition factor, which did not vary between upstream and downstream for any of the studied species. We found no influence of abiotic variables of the water on the bioavailability of the metals in the environment. Although the data do not indicate trophic magnification, the different species react differently to environmental changes and their trophic plasticity makes it difficult to assign them to specific guilds. PMID- 29981020 TI - Assessment of hepato-renal damage and genotoxicity induced by long-term exposure to five permitted food additives in rats. AB - The present study assessed the long-term daily administration of benzoic acid (BA), potassium sorbate (PS), chlorophyll (CPL), tartrazine (TAZ), and butylated hydroxyanisole (BHA) on hepato-renal changes and DNA damage in rats. Animals were orally administered with the 10 times of the acceptable daily intake (ADI) from each tested substance daily for 60 consecutive days. Blood, liver, and kidney samples were collected to evaluate hematological, biochemical, histopathological, and genotoxic alterations. The extent of liver and kidney damage was evaluated by comet assay and histopathologically. Significant reduction of leukocyte numbers and lymphocytes % in CPL- and TAZ-treated rats. However, significant increases in platelet count in all treated groups after 60 days were detected. The levels of serum transaminases enzymes (ALT, AST), alkaline phosphatase (ALP), and creatinine were significantly increased in all treatments except with BHA group, but no substantial differences were found in urea after 60 days. Aside from BHA, results of DNA damage revealed significant increases in tailed nuclei, tail moment, DNA% in the tail, and tail length in liver and kidney at different degrees. Moreover, the histopathological figures of liver and kidneys affirmed destructive and degenerative changes. The study indicates that most of the tested food additives may provoke genotoxicity and hepato-nephropathy, which could be serious for human health. Therefore, it is necessary to be informed about the hazardous effects of food additives and more attention should be focused towards using natural substitutes. PMID- 29981021 TI - Novel Bacillus cereus strain from electrokinetically remediated saline soil towards the remediation of crude oil. AB - A new strain SWH-15 was successfully isolated after initial electrokinetic remediation experiment using the same saline soil sampled from Shengli Oilfield, China. Four methods (morphological and biochemical characteristics, whole-cell fatty acid methyl esters (FAMEs) analysis, 16S rRNA sequence analysis and DNA G + C content and DNA-DNA hybridization analysis) were used to identify the taxonomic status of SWH-15 and confirmed that SWH-15 was a novel species of the Bacillus (B.) cereus group. Then, we assessed the degrading ability of the novel strain SWH-15 to crude oil through a microcosm experiment with four treatments, including control (CK), bioremediation using SWH-15 (Bio), electrokinetic remediation (EK), and combined bioremediation and electrokinetic remediation (Bio + EK). The results showed that the Bio + EK combined remediation treatment was more effective than the CK, Bio, and EK treatments in degrading crude oil contaminants. Bioaugmentation, by addition of the strain SWH-15 had synergistic effect with EK in Bio + EK treatment. Bacterial community analysis showed that electrokinetic remediation alone significantly altered the bacterial community of the saline soil. The addition of the strain SWH-15 alone had a weak effect on the bacterial community. However, the strain SWH-15 boosted the growth of other bacterial species in the metabolic network and weakened the impact of electrical field on the whole bacterial community structure in the Bio + EK treatment. PMID- 29981022 TI - Status, sources and contamination levels of organochlorine pesticide residues in urban and agricultural areas: a preliminary review in central-southern Italian soils. AB - Organochlorine pesticides (OCPs) are synthetic chemicals commonly used in agricultural activities to kill pests and are persistent organic pollutants (POPs). They can be detected in different environmental media, but soil is considered an important reservoir due to its retention capacity. Many different types of OCPs exist, which can have different origins and pathways in the environment. It is therefore important to study their distribution and behaviour in the environment, starting to build a picture of the potential human health risk in different contexts. This study aimed at investigating the regional distribution, possible sources and contamination levels of 24 OCP compounds in urban and rural soils from central and southern Italy. One hundred and forty eight topsoil samples (0-20 cm top layer) from 78 urban and 70 rural areas in 11 administrative regions were collected and analysed by gas chromatography-electron capture detector (GC-ECD). Total OCP residues in soils ranged from nd (no detected) to 1043 ng/g with a mean of 29.91 ng/g and from nd to 1914 ng/g with a mean of 60.16 ng/g in urban and rural area, respectively. Endosulfan was the prevailing OCP in urban areas, followed by DDTs, Drins, Methoxychlor, HCHs, Chlordane-related compounds and HCB. In rural areas, the order of concentrations was Drins > DDTs > Methoxychlor > Endosulfans > HCHs > Chlordanes > HCB. Diagnostic ratios and robust multivariate analyses revealed that DDT in soils could be related to historical application, whilst (illegal) use of technical DDT or dicofol may still occur in some urban areas. HCH residues could be related to both historical use and recent application, whilst there was evidence that modest (yet significant) application of commercial technical HCH may still be happening in urban areas. Drins and Chlordane compounds appeared to be mostly related to historical application, whilst Endosulfan presented a complex mix of results, indicating mainly historical origin in rural areas as well as potential recent applications on urban areas. Contamination levels were quantified by Soil Quality Index (SoQI), identifying high levels in rural areas of Campania and Apulia, possibly due to the intensive nature of some agricultural practices in those regions (e.g., vineyards and olive plantations). The results from this study (which is in progress in the remaining regions of Italy) will provide an invaluable baseline for OCP distribution in Italy and a powerful argument for follow-up studies in contaminated areas. It is also hoped that similar studies will eventually constitute enough evidence to push towards an institutional response for more adequate regulation as well as a full ratification of the Stockholm Convention. PMID- 29981023 TI - Intraperitoneal sodium metavanadate exposure induced severe clinicopathological alterations, hepato-renal toxicity and cytogenotoxicity in African giant rats (Cricetomys gambianus, Waterhouse, 1840). AB - Pollution of environment due to increased exploitation of minerals has been on the rise, and vanadium, a metal in the first transition series essential for mammalian existence, is a major component of air pollution. This study investigated the clinico-pathological, hepato-renal toxicity, and cytogenotoxicity of intraperitoneal exposure of African giant rats (AGRs), a proposed model for ecotoxicological research to sodium metavanadate. A total of 27 adult male African giant rats weighing 975 +/- 54.10 g were distributed into two major groups: sodium metavanadate (SMV) treated and control. They were observed daily for clinical signs of toxicity. Four rats from each group were randomly collected and sacrificed after 3, 7, and 14 days of SMV treatment. Liver, kidney, and bone marrow were analyzed for histopathology and micronucleated normochromated and polychromated erythrocytes (MNNCE and MNPCE), respectively. Clinical signs in treated AGR include sluggish and weak movements, un-groomed fur, and labored breathing. Histology of the kidney revealed severe glomerular atrophy, tubular ectasia, and vacuolar degeneration of tubular epithelium, while liver histology showed sinusoidal congestion and severe hepatocellular necrosis after 14 days SMV exposure. Also, MNNCE and MNPCE significantly increased with a decrease in PCE/NCE ratio in SMV-treated AGR, suggestive of alternations in bone marrow cell proliferation. Hence, SMV treatment to AGR resulted to severe clinicopathologic alterations, kidney, and liver dysfunction and cytogenotoxicity evident by somatic mutation induction which could be severe with prolonged exposure. This suggests African giant rat as an ecotoxicological model to measure major health risks to animals and human populations in highly polluted environment. PMID- 29981024 TI - Extracellular Vesicle RNA Sequencing Reveals Dramatic Transcriptomic Alterations Between Metastatic and Primary Osteosarcoma in a Liquid Biopsy Approach. AB - BACKGROUND: Osteosarcoma (OS) is a highly metastasizing bone malignancy despite wide surgical resection of the primary lesion. A liquid biopsy approach to detect residual disease and identify therapeutic targets is still lacking. In this report, we aimed to track the metastasis of OS via extracellular vesicle (EV) RNA profiling in a non-invasive manner. METHODS: We applied RNA sequencing for 10 matched metastatic and primary OS EV samples, including two pairs of cell lines and three pairs of plasma, and compared the expressed mutation, gene expression, fusion transcript, and alternative splicing (AS) between metastatic and primary OS at the transcriptome-wide level. Additional paired tissue/EVs were sequenced and public datasets were used to validate the EV-based metastatic biopsy. RESULTS: EVs were characterized through size-profiling, immunolabeling, and morphological examination. A drastic increase of mutation burden was observed in metastatic OS versus the non-metastatic counterpart. Hierarchical clustering of the expression profiles differentiated the metastatic EVs from the non metastatic, with a signature enriched in cell-adhesion signaling and tyrosine kinase pathways. Moreover, 30 cancer-related gene fusions were identified in EV RNA as AS events tend to be more frequently observed in metastatic EVs. Further investigation suggested that over 70% of expressed point mutations from EVs could be validated in paired cell line/EV and tissue/EV analyses, and the expression signature significantly predicted 5-year survivorship of 42 patients from a public dataset. CONCLUSION: We have demonstrated a liquid biopsy-based approach for tracking cancer transcriptomic alterations, which is a promising source of prognostic and therapeutic biomarkers for metastatic OS. CLINICAL TRIAL REGISTRATION: NCT03108677. PMID- 29981025 TI - Impact of Neoadjuvant Chemotherapy on Breast Cancer Subtype: Does Subtype Change and, if so, How? : IHC Profile and Neoadjuvant Chemotherapy. AB - BACKGROUND: Breast cancer subtype, as determined by the expression of estrogen receptor (ER) and progesterone receptor (PR), together defined as hormone receptor (HR) status, and the HER2/neu receptor (HER2), is important in predicting prognosis and guiding therapy. Knowledge regarding how tumors evolve during treatment and whether subtype is influenced by neoadjuvant chemotherapy (nCT) is limited. The purpose of this study was to compare the HR and HER2 status between core needle biopsy and residual tumor after surgery of breast cancer patients treated with nCT and to evaluate the impact of status change on therapeutic management. METHODS: After institutional review board approval, we performed a retrospective review of all patients with a diagnosis of breast cancer who received nCT and had their initial biopsy and post-nCT surgical specimens evaluated for tumor subtype between January 2009 and December 2014 at our institution. Immunohistochemistry (IHC) of ER, PR, HER2, and fluorescence in situ hybridization for HER2 expression, when indicated, was performed using identical technique and measured by a single pathologist who specializes in breast pathology. Pre- and post-nCT subtype was cross-tabulated to assess change. Standard diagnostic metrics were computed. RESULTS: Fifty-two patients with 54 cancers were identified to have their initial biopsy and post-nCT surgical specimens evaluated for tumor subtype in identical fashion. There was a complete pathologic response after nCT in 23 cancers (42.6%). Residual disease was noted in 31 cancers (57.4%). Five of these (16.1%) had a change in tumor subtype, of which four changes were based on IHC. HR status changed from positive to negative in two cases and from negative to positive in one case. HER2 status changed from positive to negative in one case and from negative to positive in one case. Subtype change led to treatment change in all five cases, with either the addition or discontinuation of adjuvant therapies. CONCLUSIONS: Patients with breast cancer may experience alterations in their tumor subtype after nCT. At our institution, this led to a change in adjuvant treatment in 100% of such patients. This implies that retesting receptor status of residual tumors after nCT should be routinely performed to tailor adjuvant therapy after nCT. PMID- 29981026 TI - Resection of a Perirectal Leiomyosarcoma via a Posterior Transcoccygeal Approach. AB - INTRODUCTION: The management of perirectal tumors often requires rectal wall resection, and sometimes a complete proctectomy is required. Access to posterior perirectal masses via a posterior, transcoccygeal approach (Kraske procedure) avoids dissection of the intraperitoneal rectum. PATIENT: The patient was a 63 year-old male who presented to his primary care physician with debilitating perirectal pain of several months' duration. He did not respond to therapy with pain medications and topical agents, and underwent a lateral internal sphincterotomy for what was thought to be an anal fissure, without relief prior to referral. Diagnostic workup showed a low signal intensity mass on magnetic resonance imaging (MRI), and biopsy revealed high-grade leiomyosarcoma with myxoid features. Staging workup included a contrast-enhanced computed tomography chest, abdomen and pelvis, flexible sigmoidoscopy and endoscopic ultrasound. A lytic lesion in his left ilium on MRI was found to be avid on fluorodeoxyglucose positron emission tomography scan and was therefore consistent with oligometastatic disease. He received six cycles of adriamycin, cyclophosphamide and dacarbazine, with good response. The metastatic lesion was treated with 24 Gy of radiotherapy, while the primary tumor was treated with 50 Gy of radiotherapy. The patient underwent the Kraske approach with radical resection of the perirectal mass. The rectal wall was closed with interrupted silk sutures, and layered closure of incision over a drain was performed. An R0 resection was achieved. A laparoscopic diverting loop ileostomy to protect the rectal repair was performed. CONCLUSION: The Kraske approach allows for adequate resection, while avoiding the morbidity of the transabdominal approach, and allowing the patient to maintain a continent rectum. PMID- 29981027 TI - Bullying victimization and illicit drug use among students in Grades 7 to 12 in Manitoba, Canada: a cross-sectional analysis. AB - OBJECTIVES: There is inconsistent evidence examining the relationship between bullying victimization and illicit drug use, with most studies only examining the association between bullying victimization and marijuana use. The current study aims to (1) determine the relationship between bullying victimization and six types of illicit drug use among boys and girls in grades 7 to 12 and (2) examine gender and grade differences in the relationships between bullying victimization and drug use. METHODS: Data were drawn from the Manitoba Youth Health Survey (N = 64,174) collected in the 2012-2013 school year among students in grades 7 to 12 from Manitoba, Canada. Logistic regression models were used to analyze the relationships between nine different types of bullying victimization and marijuana, cocaine, methamphetamines, ecstasy, hallucinogens, and prescription/over-the-counter drugs used to get high. All analyses were stratified by gender and grade. RESULTS: Bullying victimization was associated with increased odds of all types of drug use among boys and girls in grades 7 to 12. A dose-response relationship was noted with more frequent bullying victimization corresponding to greater odds of drug use. Grade and gender differences were found for some drug use types. CONCLUSIONS: There are strong relationships between bullying victimization and illicit drug use among boys and girls in grades 7 to 12, indicating that reductions in bullying victimization may result in reductions in illicit drug use. Grade and gender differences may signify the need for early and gender-specific bullying prevention and intervention strategies. PMID- 29981028 TI - The lows of getting high: sentinel surveillance of injuries associated with cannabis and other substance use. AB - OBJECTIVES: Cannabis is a widely used illicit substance that has been associated with acute injuries. This study seeks to provide near real-time injury estimates related to cannabis and other substance use from the electronic Canadian Hospitals Injury Reporting and Prevention Program (eCHIRPP) database. METHODS: Data from the eCHIRPP database, years 2011 to 2016, were analyzed via data mining, descriptive, logistic regression, and sensitivity analyses. Drug use trends over time for cannabis and/or other substances (alcohol, illicit drugs, and medications) were assessed. Descriptive statistics (intent, external cause, and nature of injury) and proportionate injury ratios (PIR) associated with cannabis use are presented. RESULTS: Cannabis use was observed in 184 cases/100,000 eCHIRPP cases, and related injuries were mostly identified as unintentional (66.8%). Poisoning (68.5%) and intoxication (69.4%) were the external cause and nature of injury most associated with these events, and hospitalization was recorded for 14.3% of cases. Per 100,000 eCHIRPP cases, cannabis was used alone in 72.4 cases, and in combination with alcohol, illicit drugs, or medications in 74.6 cases, 11.3 cases, and 7.9 cases, respectively. Relative to non-use, the PIR of hospitalization was not significant for cannabis only users of either sex (males: PIR 1.0, 95% CI 0.6-1.7, females: PIR 0.9, 95% CI: 0.5-1.7). CONCLUSION: Cannabis use injuries are rare, but can occur when cannabis is used with or without other substances. As Canada considers legislative changes, our finding of cases related to unintentional injury, poisoning, and intoxication suggests areas that might benefit from health literacy efforts. PMID- 29981029 TI - The synthetic opioid epidemic and the need for mental health support for first responders who intervene in overdose cases. PMID- 29981030 TI - Une formation complementaire et appliquee : un besoin pour la releve en recherche interventionnelle en sante des populations. AB - Population Health Intervention Research (PHIR) is an emerging and distinct field that combines scientific research and public health practice. However, traditional academic training in research, which is founded on specific disciplinary orientations, does not sufficiently inform and prepare new PHIR researchers. In this commentary, we advance the idea that PHIR requires a broader range of competencies and knowledge that must be developed through a complementary and applied training program. Drawing on our experience as 4P Strategic Training Program fellows, we identified key elements of the program that have helped prepare us in our careers as future and new PHIR researchers. We believe that complementary and applied training programs such as the 4P Program are a promising strategy in training and supporting the next generation of PHIR researchers in their efforts to improve population health. PMID- 29981032 TI - Climate change, colonialism, and women's well-being in Canada: what is to be done? AB - The impacts of accelerating climate change across Canada are unequally distributed between populations and regions. Emerging evidence shows climate change and resultant policies to be worsening gendered social and economic inequities between women and men, with women's participation largely absent in climate change research and decision-making. These dynamics are resulting in negative impacts for women's well-being, with Indigenous and historically marginalized women at increased risk of experiencing health inequities as a result of climate change. To date, public health discourse has largely failed to incorporate gender as a key determinant of health in discussions of climate change impacts on populations. Paralleling this lack of development, the entangled relationship between climate and colonialism tends to be subsumed under the term "Aboriginality" within health determinants discourse. This commentary on gender and climate change in Canada is framed within a radical intersectional approach as an alternative course of public health analysis and action aimed at addressing resulting health and power inequities. Following an overview of evidence regarding the gendered impacts of climate change on women's work, roles, agency, and well-being, several possible public health action areas on climate change and gender are highlighted as necessary components for resilient communities capable of meeting contemporary challenges. PMID- 29981031 TI - Sexual orientation and alcohol-related harms in Canadian youth. AB - OBJECTIVES: To determine associations between experiencing alcohol-related harm, sex, and sexual orientation among Canadian high school students. METHODS: We used data from the 2012 Atlantic Student Drug Use Survey (ASDUS), including a comprehensive six-category measure of sexual orientation and nine different alcohol-related harms for analyses. Simple logistic regression was used to determine the association between experiencing any of the nine harms and each specific alcohol-related harm and sexual orientation, stratified by sex. Analysis was limited to those who indicated they had consumed alcohol in the year prior to the survey. RESULTS: High rates of having any alcohol-related harm were seen among both males (41.7%) and females (46.0%) attending Atlantic Canadian high schools. Mostly heterosexual males had a lower odds ratio for experiencing any alcohol-related harm compared to heterosexual males. Mostly heterosexual females and bisexual females had higher odds ratios for experiencing any alcohol-related harm than heterosexual females. CONCLUSIONS: High rates of alcohol-related harm in this population suggest that youth may benefit from a harm reduction approach to alcohol use. While we found that mostly heterosexual and bisexual female youth experience higher levels of alcohol-related harm than heterosexual females, further research is required to confirm this association and to determine its relevance to harm reduction strategies. PMID- 29981033 TI - Derivation and application of a composite annoyance reaction construct based on multiple wind turbine features. AB - OBJECTIVES: Noise emissions from wind turbines are one of multiple wind turbine features capable of generating annoyance that ranges in magnitude from not at all annoyed to extremely annoyed. No analysis to date can simultaneously reflect the change in all magnitudes of annoyance toward multiple wind turbine features. The primary objective in this study was to use principal component analysis (PCA) to provide a single construct for overall annoyance to wind turbines based on reactions to noise, blinking lights, shadow flicker, visual impacts, and vibrations evaluated as a function of proximity to wind turbines. METHODS: The analysis was based on data originally collected as part of Health Canada's cross sectional Community Noise & Health Study (CNHS). One adult participant (18-79 years), randomly selected from dwellings in Ontario (ON) (n = 1011) and Prince Edward Island (PEI) (n = 227), completed an in-person questionnaire. Content relevant to the current analysis included the annoyance responses to wind turbines. RESULTS: The first construct tested in the PCA explained 58-69% of the variability in total annoyance. Reduced distance to turbines was associated with elevated aggregate annoyance scores among ON and PEI participants. In the ON sample, aggregate annoyance was effectively absent in areas beyond 5 km (mean 0.12; 95% CI 0.00, 1.19), increasing significantly between (2 and 5] km (mean 2.13; 95% CI 0.92, 3.33), remaining elevated, but with no further increase until (0.550-1] km (mean 3.37; 95% CI 3.02, 3.72). At <= 0.550 km, the average overall annoyance was 3.36 (95% CI 2.03, 4.69). In PEI, aggregate annoyance was essentially absent beyond 1 km; i.e., (1-2] km (mean 0.21; 95% CI 0.00, 0.88); (2 5] km (mean 0.00; 95% CI 0.00, 1.37); > 5 km (mean 0.00; 95% CI 0.00, 1.58). Annoyance significantly increased in areas between (0.550 and 1] km (mean 1.59; 95% CI 1.02, 2.15) and was highest within 550 m (mean 4.25; 95% CI 3.34, 5.16). CONCLUSION: The advantages and disadvantages to an aggregated annoyance analysis, including how it should not yet be considered a substitute for relationships based on changes in high annoyance, are discussed. PMID- 29981034 TI - The association between self-reported and objective measures of health and aggregate annoyance scores toward wind turbine installations. AB - OBJECTIVE: An aggregate annoyance construct has been developed to account for annoyance that ranges from not at all annoyed to extremely annoyed, toward multiple wind turbine features. The practical value associated with aggregate annoyance would be strengthened if it was related to health. The objective of the current paper was to assess the association between aggregate annoyance and multiple measures of health. METHODS: The analysis was based on data originally collected as part of Health Canada's Community Noise and Health Study (CNHS). One adult participant per dwelling (18-79 years), randomly selected from Ontario (ON) (n = 1011) and Prince Edward Island (PEI) (n = 227), completed an in-person questionnaire. RESULTS: The average aggregate annoyance score for participants who indicated they had a health condition (e.g., chronic pain, Pittsburgh Sleep Quality Index (PSQI) > 5, tinnitus, migraines/headaches, dizziness, highly sensitive to noise, and reported a high sleep disturbance) ranged from 2.53 to 3.72; the mean score for those who did not report these same conditions ranged between 0.96 and 1.41. Household complaints about wind turbine noise had the highest average aggregate annoyance (8.02), compared to an average of 1.39 among those who did not complain. CONCLUSION: A mean aggregate annoyance score that could reliably distinguish participants who self-report health effects (or noise complaints) from those who do not could be one of several factors considered by jurisdictions responsible for decisions regarding wind turbine developments. However, the threshold value for acceptable changes and/or levels in aggregate annoyance has not yet been established and could be the focus of future research efforts. PMID- 29981035 TI - Protecting the public from exposure to secondhand cannabis smoke and vapour following legalization. AB - The adverse effects of direct cannabis use are well described in the literature; however, researchers are now beginning to expose the health consequences of secondhand exposure. Given the commitment by the federal government to legalize cannabis in Canada by summer 2018, public health officials must build on the successes of existing smoke-free programs and work with provinces and municipalities to develop policies that protect the public from secondhand exposure to cannabis smoke and vapour. While harmonization with existing tobacco laws may offer the simplest approach, other alternatives may allow stricter control of public consumption by different levels of government. Further research will be needed to assess the health implications of secondhand cannabis exposure, as well as the population impacts of legalization. PMID- 29981036 TI - Community strengths in addressing opioid use in Northeastern Ontario. AB - The number of opioid-related deaths in Ontario is rising, and remote First Nations communities face unique challenges in providing treatment for opioid use disorder. Geographic barriers and resource shortages limit access to opioid agonist therapy, such as buprenorphine or methadone. However, attempts to rapidly expand access have the potential to overlook community consultation. Our experience in Moose Factory, Ontario, offers insight into the ethical questions and challenges that can arise when implementing opioid agonist therapy in Northern Ontario and provides an example of how a community working group can strengthen relationships and create a culturally relevant program. We call on medical regulators and the provincial and federal governments to invest in community-based opioid dependence treatment programs that incorporate cultural and land-based healing strategies and draw on First Nations teachings. PMID- 29981037 TI - The "Lac-Megantic tragedy" seen through the lens of the EnRiCH Community Resilience Framework for High-Risk Populations. AB - SETTING: On July 6, 2013, a train carrying oil derailed in downtown Lac-Megantic (Quebec, Canada), causing major human, environmental, and economic impacts. We aim to describe, and learn from, public health strategies developed to enhance community resilience following the train derailment though the lens of the EnRiCH Community Resilience Framework for High-Risk Populations. INTERVENTION: Annual population-level surveys were conducted in Lac-Megantic and surrounding areas to assess the long-term impacts of the disaster. Findings suggested that a solid upstream investment towards the development of adaptive capacity was needed. A "Day of Reflection" bringing together local stakeholders and citizens was organized, inspiring the elaboration of an innovative action plan. Leaders advocated for funding to support its implementation, leading to a substantial investment from the provincial government. Through a wide range of actions, the plan aims to bring psychosocial services closer to people, stay connected with the community, and foster community engagement. OUTCOMES: Several lessons have been identified. After a disaster, there needs to be a balanced focus between the gaps/needs and strengths/capacities of a community. Moreover, public health actors must collaborate closely, all along the continuum of the upstream downstream paradigm, with local organizations and citizens. IMPLICATIONS: This unique experience, supported by an empirically-based framework, suggests that three vital ingredients are required for success in recovering from a disaster: (1) fostering community strengths and valuing citizen participation, (2) a strong political commitment to support upstream actions, and (3) a public health team able to support these actions. PMID- 29981038 TI - Youth violence victims and perpetrators in Ontario: identifying a high-risk group and a focus for public health prevention. AB - OBJECTIVES: Bullying and violence are common experiences and pose significant lifelong burdens of disease for youth. This study identifies upstream determinants of youth violence and examines the shared characteristics of victims and perpetrators. METHODS: Multivariable multinomial logistic regression modeling analyzed a subsample of 5403 students who participated in the 2015 Ontario Student Drug Use and Health Survey to estimate the likelihood that students with various risk profiles were victims and perpetrators. RESULTS: Risk factors associated with an increased likelihood of being both a victim and a perpetrator, compared to neither, included harmful alcohol use, potential problem drug use, psychological distress, traumatic brain injury, problem video game playing, fighting, and carrying a weapon in the past 12 months. Many risk factors were more strongly associated with both victimization and perpetration relative to reporting either alone. CONCLUSION: This study demonstrates an association between risk factors of interest to public health for students reporting both victimization and perpetration. This group may warrant further targeted public health interventions to prevent violence alongside existing public health programs addressing other health risk behaviours. PMID- 29981039 TI - Expanding supervised injection facilities across Canada: lessons from the Vancouver experience. AB - The opioid crisis has led to an unprecedented rise in the number of overdose deaths across Canada. In response, there has been an expansion of supervised injection facilities (SIFs), with several new SIFs approved or under review across the country. Much of the evidence for the benefits of SIFs in reducing overdose mortality, infectious-related complications, and public disorder comes from Insite in Vancouver, North America's first SIF. While implementing SIFs in other Canadian cities is a major step forward in combating the opioid epidemic, the diversity within our country's socio-demographic and political landscape leaves the application of SIFs in these new settings a matter of uncertainty. This commentary highlights key lessons learned from Vancouver and the potential modifications required to enhance implementation in other cities to ensure the success of new SIFs across Canada. PMID- 29981040 TI - Epidemiologic trends in substance and opioid misuse-related emergency department visits in Alberta: a cross-sectional time-series analysis. AB - OBJECTIVES: Substance and opioid misuse are growing public health concerns. This study's objectives were to evaluate trends in substance and opioid misuse-related emergency department (ED) visits in Alberta, Canada. METHODS: This is a cross sectional time-series analysis utilizing National Ambulatory Care Reporting System ED data from Alberta, Canada. All substance and opioid misuse-related visits made by adults (>= 18 years) from 2010/11 to 2014/15 were analyzed. Acuity was measured by the Canadian Triage and Acuity Scale (CTAS). Relevant visits were identified by ICD-10 diagnostic coding. Substance and opioid visits over 60 months were compared to all ED visits per 100,000 adult population using regression analysis, while controlling for temporal and seasonal variation. Trends among age and sex subgroups were also evaluated. RESULTS: From 2010/11 to 2014/15, substance and opioid misuse-related visits increased by 38.0% and 57.3% to 1119 and 118 visits per 100,000 population, respectively. Annual growth rates for substance and opioid visits were 4.4% higher (95% CI: 2.2, 6.7) and 10.6% higher (95% CI: 6.8, 14.6) than all ED visits. The 18-29 year-old category experienced the highest annual growth rate of all age groups, and the annual opioid visit growth rate was 5.6% higher among males than females. Compared to all visits, substance misuse-related visits arrived more frequently by ambulance, were higher acuity, and were hospitalized more often. CONCLUSION: Substance and opioid misuse-related ED visits increased significantly from 2010 to 2015, especially among younger patients. Future research should elaborate causes and evaluate interventions to curb the growth of this issue. PMID- 29981042 TI - Response from the Editor-in-Chief to Siddiqui and Chambers' letter. PMID- 29981041 TI - Le marche legal du cannabis suite a sa legalisation au Canada : pistes de reflexion pour un encadrement efficace. AB - The upcoming legalization of cannabis in Canada poses several challenges in which each province will have to respond with effective regulation. Studies show that policies alone have little impact on use rates. However, regulatory approaches and modalities seem important to reduce the possible negative consequences that may result from legalization. Although no framework system offers a perfect solution to the issues surrounding the use and sale of cannabis, it seems essential to implement a legalization model based on a public health perspective. The modalities of this model will have to ensure a compromise between restricted access to cannabis and the maintenance of a sufficient supply to counter the illegal market. We recommend controlling the legal cannabis market through the following: a state monopoly, competitive pricing in relation to the illicit market, a sales tax modeled on the THC content, the implementation of a controlled number of points of sale of small surface area and density, a legal age of purchase from the age of majority, and a complete ban on the promotion and advertising of cannabis products, as well as massive funding for prevention and research. PMID- 29981043 TI - Sexual violence: a call for public health research. PMID- 29981044 TI - Apprendre de l'experience : Learning from experience. PMID- 29981045 TI - Clinical and functional characteristics of young adults living in single room occupancy housing: preliminary findings from a 10-year longitudinal study. AB - OBJECTIVE: Young adults living in single room occupancy (SRO) hotels, a form of low-income housing, are known to have complex health and substance problems compared to their peers in the general population. The objective of this study is to comprehensively describe the mental, physical, and social health profile of young adults living in SROs. METHODS: This study reports baseline data from young adults aged 18-29 years, as part of a prospective cohort study of adults living in SROs in Vancouver, British Columbia, Canada. Baseline and follow-up data were collected from 101 young adults (median follow-up period 1.9 years [IQR 1.0 3.1]). The comprehensive assessment included laboratory tests, neuroimaging, and clinician- and patient-reported measures of mental, physical, and social health and functioning. RESULTS: Three youth died during the preliminary follow-up period, translating into a higher than average mortality rate (18.6, 95% CI 6.0, 57.2) compared to age- and sex-matched Canadians. High prevalence of interactions with the health, social, and justice systems was reported. Participants were living with median two co-occurring illnesses, including mental, neurological, and infectious diseases. Greater number of multimorbid illnesses was associated with poorer real-world functioning (rho = - 0.373, p < 0.001). All participants reported lifetime alcohol and cannabis use, with pervasive use of stimulants and opioids. CONCLUSION: This study reports high mortality rates, multimorbid illnesses, poor functioning, poverty, and ongoing unmet mental health needs among young adults living in SROs. Frequent interactions with the health, social, and justice systems suggest important points of intervention to improve health and functional trajectories of this vulnerable population. PMID- 29981046 TI - Syringe sharing among people who inject drugs in London, Canada. AB - OBJECTIVES: London, Ontario, is facing an outbreak of HIV among people who inject drugs (PWID), as well as persistently high levels of hepatitis C virus (HCV). Syringe sharing is the primary driver of HIV and HCV transmission risks among PWID, however, little is known about factors contributing to syringe sharing in this setting. Therefore, we sought to characterize syringe sharing and its correlates among London PWID. METHODS: Between March and April, 2016, PWID participated in a survey administered by peer research associates as part of the Ontario Integrated Supervised Injection Services Feasibility Study. Bivariable and multivariable logistic regression models examined associations with syringe sharing (borrowing or lending previously used syringes) over the previous 6 months. A sub-analysis described patterns of borrowing and lending by self reported HIV and HCV statuses. RESULTS: Of 198 PWID, 44 (22%) reported syringe sharing in the past 6 months. In the multivariable analysis, selling drugs (adjusted odds ratio; AOR = 1.92, 95% CI = 1.20-3.08), daily crystal methamphetamine injection (AOR = 1.66, 95% CI = 1.07-2.59), and identifying as HIV-positive (AOR = 3.11, 95% CI = 1.61-6.01) were independently associated with increased syringe sharing. While not independently associated with syringe sharing, problems accessing syringes were common (13-50%). Self-reported HIV positive respondents were more likely to report syringe borrowing (p < 0.001), but not lending (p = 0.26). CONCLUSION: We observed a high rate of syringe sharing among London PWID, with sharing being associated with high-intensity injection of crystal methamphetamine, as well as with involvement in drug sales. Considering the current HIV outbreak in London, multi-level prevention efforts are urgently needed. PMID- 29981047 TI - Redescription of Sibling Species of Rhinoleucophenga (Diptera: Drosophilidae): R. brasiliensis and R. fluminensis. AB - Rhinoleucophenga Hendel comprises an unusual Drosophilidae (Diptera) genus with predaceous larvae, currently compounded by 29 nominal species with New World distribution. In the present study, Rhinoleucophenga brasiliensis (Costa Lima) and R. fluminensis (Costa Lima) are redescribed. These two species are commonly misidentified in Drosophilidae species inventories, mainly by the few morphological character details presented in the original taxonomic description. Thus, by the morphological review performed here, lectotype and paralectotypes designed to R. brasiliensis and R. fluminensis, as well as new morphological characters, drawings and photos (for the first time) are presented in order to avoid further taxonomic mistakes with those referred sibling species of Rhinoleucophenga. PMID- 29981049 TI - A gaze interactive assembly instruction with pupillometric recording. AB - This paper presents a study of a gaze interactive digital assembly instruction that provides concurrent logging of pupil data in a realistic task setting. The instruction allows hands-free gaze dwells as a substitute for finger clicks, and supports image rotation as well as image zooming by head movements. A user study in two LEGO toy stores with 72 children showed it to be immediately usable by 64 of them. Data logging of view-times and pupil dilations was possible for 59 participants. On average, the children spent half of the time attending to the instruction (S.D. 10.9%). The recorded pupil size showed a decrease throughout the building process, except when the child had to back-step: a regression was found to be followed by a pupil dilation. The main contribution of this study is to demonstrate gaze-tracking technology capable of supporting both robust interaction and concurrent, non-intrusive recording of gaze- and pupil data in the-wild. Previous research has found pupil dilation to be associated with changes in task effort. However, other factors like fatigue, head motion, or ambient light may also have an impact. The final section summarizes our approach to this complexity of real-task pupil data collection and makes suggestions for how future applications may utilize pupil information. PMID- 29981048 TI - Aptamers that bind to the human complement component receptor hC5aR1 interfere with hC5aR1 interaction to its hC5a ligand. AB - The complement system plays an important role in inflammation and immunity. In this system, a potent inflammatory ligand is C5a, which initiates its effects by activating its core receptor C5aR1. Thus, compounds that interfere with the C5a C5aR1 interaction could alleviate some inflammatory conditions. Consequently, several ligands that bind to either C5a or C5aR1 have previously been isolated and evaluated. In the present study, two RNA aptamers, aptamer 1 and aptamer 9, that specifically bind to hC5aR1 with much higher affinity than antibodies were isolated. These two aptamers were tested for their ability to interfere with the cognate ligand of hC5aR1, C5a, using a chemotaxis assay. Both aptamer 1 and 9 interfered with the C5a interaction, suggesting that the aptamers recognized the extracellular domain of hC5aR1 responsible for hC5a ligand binding. Considering the higher affinity of aptamers to the hC5aR1 and their interference with hC5a ligand binding, further study is warranted to explore not only their applications in the diagnosis of inflammatory diseases but also their usefulness in modulating hC5a and hC5aR1 interactions. PMID- 29981050 TI - Introducing rLSM: An integrated metric assessing temporal reciprocity in language style matching. AB - The way that individuals use function words in a conversation-reflecting how they say things, rather than what they say-is called their individual language style. The dyadic coordination of language styles, called language style matching (LSM), is central to the development of social relationships in conversations. Despite a growing body of research on LSM, conceptual and methodological approaches are inconsistent between scholars. After giving a conceptual overview of LSM, we derive the properties desirable for analyses of LSM in interaction (e.g., reciprocity, consistency, and frequency sensitivity). Building on these properties, the existing three methodological approaches to LSM are reviewed. Since none of the existing metrics fulfills all the desired properties, we introduce a new metric to assess LSM in dyadic interaction, capturing reciprocal adaption throughout the dynamic process of a conversation. Hence, the new metric is called reciprocal LSM (rLSM). To empirically establish the conceptual underpinnings of rLSM, the metric is compared to the LSM metric most commonly used in psychological research. Both metrics are applied to a set of N = 77 transcribed real-life dyadic conversations, analyzed with the Linguistic Inquiry and Word Count software. The results indicate that rLSM is a better estimate of LSM than is the old metric and that there is high conceptual similarity between the two metrics. Implications for existing research and directions for future research are discussed. To facilitate the standardization and comparability of research, guidelines are provided for authors on the use of the new and existing metrics. PMID- 29981051 TI - A fast segmentation-free fully automated approach to white matter injury detection in preterm infants. AB - White matter injury (WMI) is the most prevalent brain injury in the preterm neonate leading to developmental deficits. However, detecting WMI in magnetic resonance (MR) images of preterm neonate brains using traditional WM segmentation based methods is difficult mainly due to lack of reliable preterm neonate brain atlases to guide segmentation. Hence, we propose a segmentation-free, fast, unsupervised, atlas-free WMI detection method. We detect the ventricles as blobs using a fast linear maximally stable extremal regions algorithm. A reference contour equidistant from the blobs and the brain-background boundary is used to identify tissue adjacent to the blobs. Assuming normal distribution of the gray value intensity of this tissue, the outlier intensities in the entire brain region are identified as potential WMI candidates. Thereafter, false positives are discriminated using appropriate heuristics. Experiments using an expert annotated dataset show that the proposed method runs 20 times faster than our earlier work which relied on time-consuming segmentation of the WM region, without compromising WMI detection accuracy. Graphical Abstract Key Steps of Segmentation-free WMI Detection. PMID- 29981052 TI - Finite element analysis and design of an interspinous device using topology optimization. AB - Recently, interspinous stabilization with Coflex-F implant has become an alternative to treat lumbar spinal stenosis (LSS). However, little attention focused on modifying the structure of the device to obtain the better clinic application. The purpose of this study was to design a new interspinous implant using topology optimization methods and evaluate its biomechanical performance. The finite element models of healthy lumbar spine and surgical lumbar spine with Coflex-F and Coflex-NEW (the new designed implant) were constructed. Finite element analysis was applied to each of the three models. The interspinous implant structure after topology optimization was remodeled at an 8% reduced volume compared with the Coflex-F device, and they can both provide stability in all motion at the surgical segment. Additionally, the advantage of Coflex-NEW was that it can decrease the von Mises stress of the implant structure in flexion, extension, torsion, and the spinous process in flexion, extension, and bending. The stress in spinous process with Coflex-NEW was well-distributed. Graphical abstract ?. PMID- 29981053 TI - Possible Involvement of PI3-K/Akt-Dependent GSK-3beta Signaling in Proliferation of Neural Progenitor Cells After Hypoxic Exposure. AB - We previously demonstrated that proliferation of endogenous neural progenitor cells is enhanced by cerebral ischemia and that phosphatidylinositol 3-kinase (PI3-K)/Akt-dependent glycogen synthase kinase (GSK)-3beta signaling is involved in ischemia-induced neurogenesis. It is important to learn more about the regulation of proliferation and differentiation of neural progenitor cells under ischemic conditions, as such knowledge that may serve as the basis for the development of new therapeutic approaches for stroke. However, it remains to be addressed whether a change in that signaling pathway is induced in neural progenitor cells. We prepared neural progenitor cells by using the neurosphere method and conducted experiments to determine the relative contributions of the PI3-K/Akt-dependent GSK-3beta signaling pathway to the proliferation and differentiation of neural progenitor cells under the hypoxic condition in vitro. We showed that hypoxic exposure induced the proliferation of neural progenitor cells. This proliferation was accompanied by phosphorylation of Akt and GSK-3beta at its Ser9. Furthermore, treatment with a PI3-K inhibitor decreased the hypoxia induced phosphorylation of GSK-3beta and proliferation of neural progenitor cells. Furthermore, hypoxic exposure enhanced the differentiation of neural progenitor cells, and this increased differentiation was not affected by treatment with the PI3-K inhibitor. Although the expression of NeuroD1 mRNA during cell differentiation was also enhanced by hypoxic exposure, this increased expression was not affected by treatment with the PI3-K inhibitor. Our findings suggest that the PI3K/Akt-dependent GSK-3beta signaling pathway was involved in the proliferation of neural progenitor cells under a pathologic condition, such as hypoxia and/or cerebral ischemia in vivo. PMID- 29981054 TI - Effects of Prion Protein on Abeta42 and Pyroglutamate-Modified AbetapEpsilon3-42 Oligomerization and Toxicity. AB - Soluble Abeta oligomers are widely recognized as the toxic forms responsible for triggering AD, and Abeta receptors are hypothesized to represent the first step in a neuronal cascade leading to dementia. Cellular prion protein (PrP) has been reported as a high-affinity binder of Abeta oligomers. The interactions of PrP with both Abeta42 and the highly toxic N-truncated pyroglutamylated species (AbetapE3-42) are here investigated, at a molecular level, by means of ThT fluorescence, NMR and TEM. We demonstrate that soluble PrP binds both Abeta42 and AbetapE3-42, preferentially interacting with oligomeric species and delaying fibril formation. Residue level analysis of Abeta42 oligomerization process reveals, for the first time, that PrP is able to differently interact with the forming oligomers, depending on the aggregation state of the starting Abeta42 sample. A distinct behavior is observed for Abeta42 1-30 region and C-terminal residues, suggesting that PrP protects Abeta42 N-tail from entangling on the mature NMR-invisible fibril, consistent with the hypothesis that Abeta42 N-tail is the locus of interaction with PrP. PrP/AbetapE3-42 interactions are here reported for the first time. All interaction data are validated and complemented by cellular tests performed on Wt and PrP-silenced neuronal cell lines, clearly showing PrP dependent Abeta oligomer cell internalization and toxicity. The ability of soluble PrP to compete with membrane-anchored PrP for binding to Abeta oligomers bears relevance for studies of druggable pathways. PMID- 29981055 TI - Small Molecule GSK-J1 Affects Differentiation of Specific Neuronal Subtypes in Developing Rat Retina. AB - Histone post-translational modification has been shown to play a pivotal role in regulating gene expression and fate determination during the development of the central nervous system. Application of pharmacological blockers that control histone methylation status has been considered a promising avenue to control abnormal developmental processes and diseases as well. In this study, we focused on the role of potent histone demethylase inhibitor GSK-J1 as a blocker of Jumonji domain-containing protein 3 (Jmjd3) in early postnatal retinal development. Jmjd3 participates in different processes such as cell proliferation, apoptosis, differentiation, senescence, and cell reprogramming via demethylation of histone 3 lysine 27 trimethylation status (H3K27 me3). As a first approach, we determined the localization of Jmjd3 in neonate and adult rat retina. We observed that Jmjd3 accumulation is higher in the adult retina, which is consistent with the localization in the differentiated neurons, including ganglion cells in the retina of neonate rats. At this developmental age, we also observed the presence of Jmjd3 in undifferentiated cells. Also, we confirmed that GSK-J1 caused the increase in the H3k27 me3 levels in the retinas of neonate rats. We next examined the functional consequences of GSK-J1 treatment on retinal development. Interestingly, injection of GSK-J1 simultaneously increased the number of proliferative and apoptotic cells. Furthermore, an increased number of immature cells were detected in the outer plexiform layer, with longer neuronal processes. Finally, the influence of GSK-J1 on postnatal retinal cytogenesis was examined. Interestingly, GSK-J1 specifically caused a significant decrease in the number of PKCalpha-positive cells, which is a reliable marker of rod-on bipolar cells, showing no significant effects on the differentiation of other retinal subtypes. To our knowledge, these data provide the first evidence that in vivo pharmacological blocking of histone demethylase by GSK-J1 affects differentiation of specific neuronal subtypes. In summary, our results indisputably revealed that the application of GSK-J1 could influence cell proliferation, maturation, apoptosis induction, and specific cell determination. With this, we were able to provide evidence that this small molecule can be explored in therapeutic strategies for the abnormal development and diseases of the central nervous system. PMID- 29981056 TI - Fully robotic left hepatectomy for malignant tumor: technique and initial results. AB - Robotic liver surgery has been considered as a unique opportunity to overcome the traditional limitations of laparoscopy; thus, it can potentially extend the indications of minimally invasive liver surgery. From April 2015 to May 2017, 35 patients underwent fully robotic left hepatectomy. The mean operative time was 315 min (200-445 min) and the mean estimated blood loss was 245 ml (125-628 ml). Pringle maneuver was required in six cases. Cancer was the indication for surgery in all patients (14 liver metastases, 18 hepatocellular carcinomas and 3 cholangiocarcinomas). There were one to four lesions in a patient and the mean lesion size was 39.2 mm (15-85 mm). The average length of hospital stay was 6.5 days (5-14 days). Perioperative morbidity rate was 17.2%. Two patients underwent conversion to open surgery. The 90-day mortality rate was nil. The mean surgical resection margin was 12 (1-22) mm, and R0-resection was reached in 33 out of 35 cases. The robotic left hepatectomy provides interesting surgical outcomes and good oncologic adequacy. It can be safely applied for the management of liver malignancies. PMID- 29981057 TI - Linguistic mortality gradients in Quebec and the role of migrant composition. AB - OBJECTIVE: Anglophones and Allophones in Quebec (Canada) have lower mortality than Francophones, despite being linguistic minorities. This study assesses whether (1) language is a risk factor for mortality after accounting for migrant composition and (2) interprovincial migrants differ in mortality with respect to Quebec-born individuals. METHODS: We analyzed death records between 2004 and 2008 from Quebec (all-cause and main causes) and population data from the 2006 census to estimate age-adjusted mortality rates according to language and migrant status. Risk ratios by language and migrant status, adjusted for age, sex, and socioeconomic status, were estimated using Poisson generalized estimating equations. RESULTS: Francophone Quebec-borns had the highest mortality. Among Quebec-borns, Anglophones [RR= 0.85, 95% CI (0.79-0.91)] and Allophones [RR = 0.16, 95 %CI (0.12-0.22)] had lower mortality relative to Francophones. Interprovincial migrants had lower mortality (Anglophones [RR = 0.58, 95% CI (0.53-0.63)], Francophones [RR = 0.55, 95% CI (0.50-0.60)]) relative to Francophone Quebec-borns (Allophones were excluded due to small sample size). Among immigrants, mortality was lower for Francophones [RR = 0.62, 95% CI (0.57 0.67] and Allophones [RR = 0.35, 95% CI (0.31-0.38], but not Anglophones [RR = 0.92, 95% CI (0.84-1.01)], relative to Francophone Quebec-borns. CONCLUSION: In Quebec, linguistic disparities in mortality remained after accounting for migrant status, and both Francophone and Anglophone interprovincial migrants in Quebec had lower mortality than Quebec-born Francophones. Public health initiatives to reduce linguistic disparities in health should account for migrant status. PMID- 29981058 TI - Disability and workplace harassment and discrimination among Canadian federal public service employees. AB - OBJECTIVES: Policy and legislation that prohibits workplace harassment and discrimination, including that which is disability related, has been in place in Canada for many years. The study objective was to examine associations between disability and workplace harassment and discrimination in the current Canadian context, as well as the intersection of disability with age, gender, and ethnicity. METHODS: Cross-sectional data from the 2014 Canadian Public Service Employee Survey was analyzed (n = 175,742) using logistic regression to investigate the relationship between self-reported disability and workplace harassment and discrimination in the last 2 years. Age, gender, and ethnicity were included as potential confounders and effect modifiers. Additive and multiplicative effect modifications were examined using linear binomial and logistic regression, respectively. RESULTS: Overall, 18 and 8% of the sample of Canadian public service employees reported workplace harassment and discrimination, respectively. The prevalence was higher for workers with disability (37 and 26%). Disability was significantly associated with an increased odds of harassment (odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.68-2.92) and discrimination (OR = 4.97; 95% CI, 4.72-5.23) in models adjusted for confounders. Significant positive additive effect modification was observed for (1) age in the harassment and discrimination models and (2) ethnicity in the discrimination model. CONCLUSION: Findings from a 2014 census of the Canadian federal public service suggest that additional efforts are needed to address workplace harassment and discrimination beyond those already in place. Consideration should be given to workers with disability, as well as the intersectional impacts for older workers, visible minorities, and Aboriginal peoples. PMID- 29981060 TI - Quitting the smoke break: a successful partnership with the construction industry. AB - SETTING: The Conference Board of Canada cites that 77% of employees want to receive health information in the workplace. From 2014 to 2016, Ottawa Public Health (OPH) partnered with 25 construction companies, to implement smoking cessation programs on 41 construction sites. INTERVENTION: OPH partnered with local construction companies, unions, and workers to design, deliver, and evaluate a tailored initiative to build smoke-free culture and encourage quit attempts. Workers received group and one on one counseling and nicotine replacement therapy (NRT) from OPH staff. Client satisfaction was assessed and used to inform ongoing quality improvement. OUTCOMES: Since 2014, this project has expanded from one pilot site to 41 sites and has engaged two of the largest construction companies in Canada. A participant's survey (N = 62) found that at 1 month, 40% remained smoke-free and 38% had reduced the amount tobacco smoked. At 6 months, 34% remained smoke-free and 45% had reduced their consumption of tobacco. IMPLICATIONS: Construction workers typically have high smoking rates and low engagement with cessation programs. Public health practitioners working with the construction industry must understand the culture, engage on-site champions, and articulate the added value of tobacco cessation to the business. Using this information on partnering with the construction industry, this innovative program, first of its kind in Canada, could be duplicated in other communities. PMID- 29981059 TI - Limitations of administrative data to identify measles cases in Ontario, Canada: a cautionary tale. AB - OBJECTIVE: To explore the utility of laboratory data and determine the validity of healthcare administrative data for describing the frequency of measles in Ontario. METHODS: We linked Ontario healthcare utilization administrative data to Public Health Ontario (PHO) laboratory data from 01 January 2006 to 30 November 2012. RESULTS: The sensitivity of the administrative data was 54% and the positive predictive value was 1% when compared with 50 cases identified in laboratory data as a gold standard. CONCLUSIONS: As measles is no longer endemic in Ontario, the high number of measles-coded healthcare visits found in Ontario health administration data exceeds the true number of cases. Great caution should be taken in using administrative data to calculate the incidence of measles in areas where it has been eliminated. PMID- 29981061 TI - Health of mothers of young children in Canada: identifying dimensions of inequality based on socio-economic position, partnership status, race, and region. AB - OBJECTIVES: Little is known about the nature of health inequalities present among women who are mothers of young children in Canada. Therefore, the purpose of the study is to identify dimensions of inequalities based on socio-economic position, race, partner status, and region and determine whether each type of inequality is independent of another. METHODS: Data are from the 2014 Canadian Community Health Survey. Women identifying as a parent living with a child <= 5 years, with complete data on the variables of interest, were selected (n = 2656). Poor health was defined as the presence of two or more chronic conditions. Exposures included partner status, education level, race, income, and region (Quebec vs. rest of Canada). Logistic regression was used to estimate the odds of poor health according to each exposure unadjusted and adjusted for all other exposures. All analyses controlled for age and employment status. RESULTS: In the fully adjusted model, among mothers of young children, the odds of poor health were significantly higher among non-white identifying (OR = 1.72; 95% CI = 1.34-2.21) and lone mothers (OR = 1.80; 95% CI = 1.35-2.39), but were significantly lower among those with higher incomes (OR[per decile] = 0.86; 95% CI = 0.82-0.90) and those from Quebec (vs. the rest of Canada; OR = 0.50; 95% CI = 0.38-0.67). CONCLUSIONS: Living in Quebec compared to elsewhere in Canada appears to protect against poor health among mothers of young children. Regardless of region, health inequalities exist by socio-economic position, race, and partnership status. These findings have implications for public health programs and policies, such as universal child care. PMID- 29981062 TI - Examining the association between area level deprivation and vehicle collisions that result in injury. AB - OBJECTIVE: The objective of this study was to examine the association between area level deprivation and vehicle collisions resulting in either property damage or injury. METHODS: A multilevel observational study was conducted using the 2000 to 2010 Saskatchewan Traffic Accident Information System (TAIS) (n = 72,234) and 2006 Census data at the Dissemination Area level (n = 337) for the city of Saskatoon. RESULTS: Total area level deprivation was associated with severity of traffic collisions, but the association varied based on time of day and road repair status. Collisions were more likely to result in injury from the most deprived (Q5) versus the least deprived quintile (Q1) at all times of day; the difference was greatest in the evening (OR 1.7, 95% CI 1.3 to 2.3). However, there was no other evidence of a monotonic increase in risk associated with area level deprivation. When there were faded markings or potholes, the odds of a collision involving injury were 2.6 (95% CI 1.5 to 4.4) times greater for the most deprived quintile compared to the least deprived quintile. There were no significant differences in the risk of injury between area level deprivation quintiles when road conditions were good. CONCLUSION: While the association between area level deprivation and whether vehicle collisions result in injury in Saskatoon varies based on time of day and road repairs, under many circumstances the most deprived areas report more injuries from collisions compared to the least deprived. PMID- 29981063 TI - Preventing alcohol-related cancer: what if everyone drank within the guidelines? AB - OBJECTIVES: The purpose of this study was to estimate the proportion and number of cancer cases diagnosed in Ontario in 2012 that are attributable to alcohol consumption and to compare the impact of drinking within two sets of guidelines on alcohol-attributable cancer incidence. METHODS: We estimated the proportion of cancers in Ontario attributable to alcohol consumption by calculating population attributable fractions (PAFs) for six cancer types using drinking prevalence from the 2000/2001 Canadian Community Health Survey and relative risks from a meta analysis. Each PAF was multiplied by the number of incident cancers in 2012, allowing for a 12-year latency period, to calculate the number of alcohol attributable cases. We also estimated the number of alcohol-attributable cases under two scenarios: (1) assuming consumption had not exceeded the levels recommended by the Low-Risk Alcohol Drinking Guidelines (LRADG) and (2) assuming consumption had not exceeded the recommended levels by the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. RESULTS: One thousand two hundred ninety-five (95% confidence interval 1093-1499) new cases of cancer diagnosed in Ontario during 2012 are estimated to be attributed to alcohol consumption, representing approximately 1.7% (1.4-1.9%) of all new cancer cases. If no Ontario adults had exceeded the LRADG, an estimated 321 fewer cancer cases could have been diagnosed in 2012, whereas an estimated 482 fewer cancer cases could have been diagnosed if no Ontario adults had exceeded the stricter WCRF/AICR guidelines. CONCLUSION: Strategies to limit alcohol consumption to the levels recommended by drinking guidelines could potentially reduce the cancer burden in Ontario. PMID- 29981065 TI - The accuracy of Canadian Nutrient File data for reporting phosphorus, potassium, sodium, and protein in selected meat, poultry, and fish products. PMID- 29981064 TI - The Montreal heat response plan: evaluation of its implementation towards healthcare professionals and vulnerable populations. AB - OBJECTIVES: Since 2004, the Montreal heat response plan (MHRP) has been developed and implemented on the Island of Montreal to reduce heat-related health effects in the general population. In this paper, we aimed to assess the barriers and facilitators to implementation of the MHRP and evaluate the awareness of key elements of the plan by healthcare professionals and individuals from vulnerable populations. METHODS: Data were gathered from monitoring reports and a questionnaire administered to managers of healthcare institutions and healthcare workers in Montreal-area health and social services institutions. Individual interviews and focus groups with healthcare workers and with individuals with schizophrenia or suffering from drug or alcohol dependencies were performed. Data were categorized according to predefined subthemes. Coding matrices were then used to determine the most frequently occurring elements in the subthemes. RESULTS: Our results indicate that actions are progressively implemented each year in the healthcare network. Intensification of surveillance for signs of heat related illness is the most frequently reported measure. Identification and prioritization of clientele and homecare patients are identified as a challenge, as is ensuring the availability of sufficient personnel during a heat wave. Analysis of practice and awareness in healthcare professionals reveals that preventive measures are known and applied by the personnel. Individuals from vulnerable population groups were not uniformly aware of preventive measures, and consequently, variability was observed in their application. CONCLUSION: The framework proposed in this study revealed valuable information that can be useful to improve plans aimed at reducing heat-related health effects in the population. PMID- 29981066 TI - Characterizing the health and information-seeking behaviours of Ontarians in response to the Zika virus outbreak. AB - OBJECTIVES: The purpose of this study is to describe the impact of the 2016 Zika virus (ZIKV) outbreak on the health-seeking and information-seeking behaviours of Ontarians. METHODS: A timeline that included events and announcements from health agencies was constructed to describe the unfolding of the ZIKV outbreak between January 1 and September 30, 2016. In order to gain an understanding of the information and health-seeking behaviours of Ontarians, data from the following sources were collected and analyzed descriptively over time in 1-week intervals: trends in web searches, calls to a provincial telemedicine advice line, test submissions to the provincial laboratory and Zika-related media coverage. RESULTS: The World Health Organization's declaration that the ZIKV outbreak was a public health emergency of international concern (PHEIC) prompted a surge in media coverage peaking at 165 articles in a 1-week period. Concurrently, the frequency of Zika-related web searches was at its highest over the time period of the study, weekly telemedicine calls requesting Zika-related information were at their highest (177 calls/week) and requests for laboratory testing increased (162 patients submitting specimens/week). CONCLUSIONS: Understanding the public response to novel and re-emerging infectious disease outbreaks as they unfold has the potential to facilitate timely public messaging for disease prevention, enable resource planning and inform effective public health action. PMID- 29981067 TI - Rates of concussions and minor head injuries in Quebec, 2003 and 2016, in children under 18 years old, and comparisons with Ontario's rates of mild traumatic brain injuries. AB - OBJECTIVES: Increases of mild traumatic brain injuries in children have been reported in the USA and Ontario over the past decade. The main objective of this study is to calculate the pediatric rates of mild traumatic brain injury in Quebec, and our second objective is to compare them with those in Ontario. METHODS: Analysts from the Regie de l'Assurance Maladie du Quebec (RAMQ, Quebec Health Insurance Board) compiled tables, by age and sex, of all medical services for mild traumatic brain injuries (concussions and minor head injuries) between 2003 and 2016. Quebec's population rates were calculated and yearly graphs were plotted by age and sex. RESULTS: In Quebec, there were statistically significant increases in rates of mild traumatic brain injury (concussion and minor head injury) in older children: a 2.0-fold increase for those aged 13-17 years, and 1.4-fold increase for those aged 9-12 years. When only considering concussions, girls (13-17 years) had more concussions than boys in 2015 and 2016. The increase in the rates of concussion was significantly higher in Ontario than in Quebec: 4.4- vs. 2.2-fold increase. CONCLUSIONS: The recent increase in rates of mild traumatic brain injuries reported in the scientific literature has also been observed in Quebec. The fact that the rate of visits for mild traumatic brain injury, per person, remained the same from 2003 to 2016 suggests that the increase was not the result of parents seeking more medical services, but that more of them consulted when their child injured his/her head. PMID- 29981068 TI - A systematic review of the risk factors and interventions for the prevention of playground injuries. AB - OBJECTIVES: The primary objectives of this work were to (1) identify the risk and/or protective factors associated with playground injuries among children less than 18 years of age and (2) identify interventions/programs/policies aimed at preventing playground-related injuries among children less than 18 years of age. Secondary objectives include a summary of the data that reflect alignment with current playground standards. METHODS: For the primary outcome, 4 databases and 12 online resources were systematically searched to include observational and experimental studies examining risk and/or protective factors or interventions associated with playground injury or outcomes related to playground injury (e.g., risky playground behaviour). Data extraction included study design, participants, outcome, exposure or intervention, data analysis, and effect estimates. The quality of evidence for all studies was assessed using the Downs and Black criteria. RESULTS: This review included studies of moderate quality, revealing a number of risk factors and effective interventions for playground injury. Risk factors included absence of handrails and guardrails on playground equipment, non impact-absorbing surfacing, and critical fall heights. Effective interventions included modifying playground surfacing and reducing equipment height to less than 1.5 m. CONCLUSION: Equipment- and structure-based playgrounds should adhere to and maintain playground standards in order to reduce the risk of serious injury. Organizations responsible for installing and maintaining playgrounds should consider alternative play spaces that allow children to play outdoors, in a natural environment that supports healthy child development and promotes physical activity. PMID- 29981069 TI - Primary care intervention to address cardiovascular disease medication health literacy among Indigenous peoples: Canadian results of a pre-post-design study. AB - CONTEXT: Cardiovascular diseases (CVD) are a leading cause of illness and death for Indigenous people in Canada and globally. Appropriate medication can significantly improve health outcomes for persons diagnosed with CVD or for those at high risk of CVD. Poor health literacy has been identified as a major barrier that interferes with client understanding and taking of CVD medication. Strengthening health literacy within health services is particularly relevant in Indigenous contexts, where there are systemic barriers to accessing literacy skills. OBJECTIVE: The aim of this study is to test the effect of a customized, structured health literacy educational program addressing CVD medications. METHODS: Pre-post-design involves health providers and Indigenous clients at the De dwa da dehs nye>s Aboriginal Health Centre (DAHC) in Ontario, Canada. Forty seven Indigenous clients with or at high risk of CVD received three educational sessions delivered by a trained Indigenous nurse over a 4- to 7-week period. A tablet application, pill card and booklet supported the sessions. Primary outcomes were knowledge of CVD medications and health literacy practices, which were assessed before and after the programe. RESULTS: Following the program compared to before, mean medication knowledge scores were 3.3 to 6.1 times higher for the four included CVD medications. Participants were also more likely to refer to the customized pill card and booklet for information and answer questions from others regarding CVD. CONCLUSIONS: This customized education program was highly effective in increasing medication knowledge and health literacy practice among Indigenous people with CVD or at risk of CVD attending the program at an urban Indigenous health centre. PMID- 29981070 TI - Quelle est l'association entre les caracteristiques residentielles et du quartier et le developpement de l'enfant a la maternelle? AB - OBJECTIVES: Evaluate the association between residential and neighbourhood characteristics of families and children and the latter's development, using data from the Montreal Survey on the Preschool Experiences of Children in Kindergarten (MSPECK). METHOD: A sample of 1101 children was extracted from a survey frame that included Montreal children assessed in the 2012 Quebec Survey of Child Development in Kindergarten (2012 QSCDK). Data collected from the children's parents were used to document the following residential and neighbourhood characteristics (independent variables): material deprivation in the neighbourhood, housing health, residential crowding, housing instability, neighbourhood safety, and access to resources. Linking QSCDK data provided a measure of development for children in kindergarten (dependent variable). Logistic regression was used to predict the probability of kindergarten children being vulnerable in at least one domain of development, or in two or more domains. RESULTS: Children living in neighbourhoods perceived to be dangerous are 1.5 times more likely to be vulnerable in at least one domain of development, compared with their peers living in neighbourhoods perceived to be safe (95% CI: 1.02-2.14). A similar result is observed for vulnerability in two or more domains of development (OR 1.67; 95% CI: 1.07-2.61). Children living in families who lack access to resources are also more likely to be vulnerable in two or more domains of development than their peers in families who have easy access to resources (OR 1.56; 95% CI: 1.003-2.44). CONCLUSION: Parents' feelings of insecurity and lack of access to local resources can limit children's opportunities for socialization and their exposure to enriching experiences. PMID- 29981071 TI - The elusive goal of social integration: A critical examination of the socio economic and psychosocial consequences experienced by homeless young people who obtain housing. AB - OBJECTIVES: The objective of this study was to provide an insider perspective on the experiences of nine formerly homeless young people as they transitioned into independent (market rent) housing and attempted to achieve meaningful social integration. METHODS: The study was conducted in Toronto, Canada, and guided by the conceptual framework developed for the World Health Organization by the Commission on Social Determinants of Health. A critical ethnographic methodology was used. Over the course of 10 months, the lead author met every other week with nine formerly homeless young people who had moved into their own homes within 30 days prior to study recruitment. RESULTS: Unaffordable housing, limited education, inadequate employment opportunities, poverty-level income, and limited social capital made it remarkably challenging for the young people to move forward. As the study progressed, the participants' ability to formulate long range plans was impeded as they were forced to focus on day-to-day existence. Over time, living in a perpetual state of poverty led to feelings of "outsiderness," viewing life as a game of chance, and isolation. CONCLUSION: Rather than a secure, linear path from the streets to the mainstream, study participants were forced to take a precarious path full of structural gaps that left them stuck, spinning, and exhausted by the day-to-day struggle to meet basic needs. Despite their remarkable agency, it was almost impossible for the participants to achieve meaningful social integration given the structural inequities inherent in society. These observations have implications for practice, policy, and research. PMID- 29981072 TI - Dieting predicts engagement in multiple risky behaviours among adolescent Canadian girls: a longitudinal analysis. AB - OBJECTIVES: We investigated associations between dieting and other health compromising behaviours among adolescent girls, both cross-sectionally and longitudinally. The behaviours considered included smoking, binge drinking, and breakfast-skipping, and clusters of these. METHODS: Data for 3386 adolescent Ontario girls were drawn from COMPASS, a school-based study, which collects self reported measures of weight, dieting, and other health-related factors. Multilevel logistic regression models were used to investigate relationships between dieting at baseline and smoking, binge drinking, and breakfast-skipping, as well as clusters of these behaviours at baseline and 2 years later. RESULTS: Baseline dieters were at an elevated risk of smoking and binge drinking (RR = 1.8 and 1.5, respectively) by follow-up compared to non-dieters. Further, dieting was associated with combinations of these behaviours, with the highest risks for smoking/breakfast-skipping (RR = 1.64) and smoking/binge drinking (RR = 1.55). Over one in two (58%) girls reported dieting at baseline and four in five baseline dieters reported dieting 2 years later. Seven in ten girls were dieting at one or both time points. Baseline dieters were more likely to engage in a greater number of risky behaviours, regardless of what the actual behaviours were. CONCLUSION: Dieting is longitudinally associated with engagement in other risky behaviours among adolescent girls. These findings suggest that dieting may be an early risk factor for engagement in other risky behaviours and highlight the need for comprehensive prevention strategies to target shared underlying drivers. In addition, attention is needed to the potential for well-meaning weight-related initiatives to promote dieting. PMID- 29981073 TI - Prevalence of latent tuberculosis infection in Syrian refugees to Canada. AB - OBJECTIVES: Canada has accepted more than 25,000 Syrian refugees fearing persecution in their homeland. Canadian guidelines recommend screening recent refugees from high incidence countries for tuberculosis (TB) and latent TB infection (LTBI). The prevalence of TB in this population is unknown. A refugee clinic in Edmonton presented a unique opportunity to estimate prevalence of TB and LTBI in Syrian refugees arriving in Canada. METHODS: In January 2016, 100 consecutive Syrian refugees were screened for TB with clinical assessment and LTBI using QuantiFERON Gold In-Tube assay (QFT-GIT). Patients with positive QFT GIT were referred to Edmonton Tuberculosis Clinic (ETBC) for evaluation and, if appropriate, offered prophylaxis. RESULTS: No cases of active TB were found. Valid QFT-GIT were measured in 99 of 100 individuals and of these, nine (9%) were positive using a threshold concentration of blood interferon-gamma greater than 0.35 IU/L. Eight of the nine patients attended follow-up appointments; of these, seven began LTBI prophylaxis and all seven (78%) completed same. CONCLUSION: The 9% (95% confidence interval 3-15%) prevalence of LTBI was higher than expected in this population. PMID- 29981074 TI - Change of publisher for the Canadian Journal of Public Health. PMID- 29981075 TI - Determinants of non-vaccination against seasonal influenza in Canadian adults: findings from the 2015-2016 Influenza Immunization Coverage Survey. AB - OBJECTIVES: The study objectives were to (1) identify determinants of non vaccination against seasonal influenza in Canadian adults and (2) examine self reported reasons for non-vaccination. METHODS: The data source was the 2015-2016 Influenza Immunization Coverage Survey, a national telephone survey of Canadian adults. Participants (n = 1950) were divided into three groups: adults aged 18-64 years with (n = 408) and without (n = 1028) chronic medical conditions (CMC) and adults >= 65 years (n = 514). Logistic regression was used to measure associations between sociodemographic factors and non-vaccination for the 2015 2016 influenza season. Weighted proportions were calculated to determine the main self-reported reasons for not receiving the influenza vaccine. RESULTS: Younger age was found to be associated with non-vaccination across all groups. In adults >= 65 years, elementary- or secondary- vs. university-level education (aOR 1.87, 95% CI 1.14-3.06) was also significantly associated with non-vaccination. Significant variation in vaccine uptake was found for several sociodemographic factors in adults aged 18-64 without CMC. Low perceived susceptibility or severity of influenza and lack of belief in the vaccine's effectiveness were the most commonly reported reasons for not receiving the vaccine. CONCLUSION: In general, our results were consistent with findings from other Canadian and American studies on seasonal influenza vaccine uptake. Belief that the influenza vaccine is not needed was common, even among those at increased risk of influenza related complications. Additional research is needed to better understand how sociodemographic factors such as income and education may influence uptake and to raise awareness of potential complications from influenza infection in high-risk adults. PMID- 29981076 TI - Geographic variation in incidence and prevalence rates for rheumatoid arthritis in Saskatchewan, Canada 2001-2014. AB - OBJECTIVES: To estimate and compare incidence/prevalence of rheumatoid arthritis (RA) in different geographic health regions and between urban/rural locations of residence within the province of Saskatchewan. METHODS: Saskatchewan Provincial Administrative Health Databases (2001-2014) were utilized as data sources. Two RA case-definitions were employed: (1) three physician billing diagnoses, at least one of which was submitted by a specialist (rheumatologist, general internist, or orthopedic surgeon) within 2 years; (2) one hospitalization diagnosis (ICD-9-CM code-714 and ICD-10-CA codes-M05, M06). Data from these definitions were combined to estimate annual RA incidence and prevalence. Annual incidence and prevalence rates across geographic regions and between rural and urban residences were examined. RESULTS: An increasing RA prevalence gradient was observed in a south to north direction within the province. In the 2014-2015 Fiscal Year, the southern region of Sun Country had a 0.57% RA prevalence and the Northern Health Regions a prevalence of 1.15%. Incidence rates fluctuated over time in all regions but tended to be higher in Northern Health Regions. A higher RA prevalence trend was observed in rural residents over the study period. CONCLUSIONS: Higher prevalence rates were observed for RA in Northern Health Regions than elsewhere in the province. Rural prevalence rates were higher than for urban residents. Healthcare delivery strategic planning will need to ensure appropriate access for RA patients throughout the province. PMID- 29981077 TI - Beauty and the Banana: it is a commercial promotion, not a public health campaign. AB - This commentary examines the recent Disney-Dole "There's Beauty in Healthy Living" initiative and the implications of using character licensing to market produce to children. While the idea of promoting healthy foods to children is appealing, it is critical to consider the ethics of marketing to children-and whether, in fact, these commercial promotions deliver when it comes to improving public health. PMID- 29981078 TI - The occupational health and safety vulnerability of recent immigrants accessing settlement services. AB - OBJECTIVE: To compare occupational health and safety (OHS) vulnerability of recent Canadian immigrants and workers born in Canada. METHODS: Recent immigrants (n = 195) were recruited at four settlement agencies in Southern Ontario, and non immigrants in Ontario (n = 1030) were contacted by phone and email by a third party survey provider. The questionnaire measured OHS vulnerability using a 27 item measure and collected sociodemographic and workplace information. Responses were used to evaluate one overall and three specific (policy and procedure, awareness, and empowerment) measures of OHS vulnerability. Log-binomial models compared the overall and policy and procedure-, awareness- and empowerment related vulnerability of recent immigrants to non-immigrant workers. Models were adjusted for demographic and workplace characteristics. RESULTS: New immigrants experience statistically elevated levels of overall (adjusted risk ratio [ARR] = 1.60, 95% CI 1.23-2.07) and empowerment-related vulnerability (ARR = 1.54, 95% CI 1.09-2.17). Compared to workers born in Canada, immigrants also report elevated levels of policy and procedure vulnerability (ARR = 1.37, 95% CI 0.98-1.92), although this estimate did not meet traditional criteria for statistical significance. CONCLUSIONS: This study uses a novel multi-dimensional measure to identify how differences in workplace context place recent immigrant workers at increased risk of work-related injury or illness. Recent immigrant workers experience increased risk of OHS vulnerability. In particular, this vulnerability results from exposure to hazards in combination with inadequate levels of empowerment to protect themselves in the workplace. Policy-makers, advocates, and employers should implement strategies that not only build workplaces where occupational hazards are minimized but also ensure immigrant workers are empowered to act on their workplace rights and engaged to improve workplace safety. PMID- 29981079 TI - Innovative public health response to an event on the fringe of regulatory changes. AB - SETTING: During a period of regulatory uncertainty, a local public health unit in Ontario was notified of an exhibition for electronic nicotine delivery systems (ENDS) and novel tobacco delivery products (NTDs), specifically e-cigarettes and waterpipes, which have seen increasing use particularly among youth. Relevant statutes creating regulatory uncertainty included a new provincial Electronic Cigarettes Act (ECA) with certain sections awaiting proclamation, and a local waterpipe bylaw awaiting approval, which would have prohibited the use of these products in public spaces if they entered into force ahead of the exhibition date. Public health staff had concerns the event would normalize use of ENDS/NTDs, particularly among youth, and also planned to enforce already proclaimed ECA sections, as well as the existing Smoke-Free Ontario Act (SFOA) with regulations applicable to use of tobacco shisha in waterpipes. INTERVENTION: Public health staff contacted event organizers and proprietors to communicate obligations under the SFOA and ECA, as well as share hypothetical implications from pending regulatory changes, including risk of charges for regulatory non compliance if regulations came into force ahead of the planned event. OUTCOMES: Following discussion with health unit staff and legal consultation, the exhibition was cancelled. IMPLICATIONS: By directly communicating regulatory uncertainty, a public health unit was able to achieve local health goals. In this situation, public health advised exhibition proprietors of potential event disruption implicated by forthcoming regulatory changes. Subsequent cancellation of the event prevented potential adverse health impacts for at-risk groups. A similar communications approach could be used to achieve public health goals during a period of regulatory uncertainty. PMID- 29981080 TI - Association between sleep and overweight/obesity among women of childbearing age in Canada. AB - OBJECTIVES: Tests of the relationship between sleep and overweight/obesity (OW/OB) among women have been inconsistent. Few studies reporting such associations have focused on women of childbearing age. This paper investigates this association among Canadian women of childbearing age. METHODS: Data were from the Canadian Community Health Survey 2011-2014. The sample consisted of women aged 18-44 years. All variables were self-reported. Sleep duration was dichotomized as insufficient (< 7 h/night) or adequate (>= 7 h/night). A composite score of sleep quality was used and dichotomized as poor none/little of the time or some/most/all of the time. Height and weight were used to calculate body mass index. Associations between sleep and OW/OB were assessed using logistic regression analyses with survey weights. Three models were computed for sleep duration/quality: model without covariates, model adjusted for demographics (age, ethnicity, level of education, household income, marital status, employment, parity, region, and season), and model adjusted for demographics and variables associated with OW/OB (mood disorder, fruit and vegetable intake, physical activity, smoking, and alcohol). RESULTS: Total sample consisted of 9749 women of childbearing age. Thirty-eight percent had insufficient sleep duration. Sleep duration was significantly associated with OW/OB in the model with no covariates and discriminated 52.8% of women of childbearing age, but this association was no longer significant in the models adjusted for covariates. Sleep quality was not significantly linked to OW/OB in any of the models. CONCLUSION: Targeting sleep alone would likely not contribute to lower risk of OW/OB among Canadian women of childbearing age. Additional studies, especially longitudinal ones, are needed to confirm these findings. PMID- 29981081 TI - Comparing Twitter data to routine data sources in public health surveillance for the 2015 Pan/Parapan American Games: an ecological study. AB - OBJECTIVES: This study examined Twitter for public health surveillance during a mass gathering in Canada with two objectives: to explore the feasibility of acquiring, categorizing and using geolocated Twitter data and to compare Twitter data against other data sources used for Pan Parapan American Games (P/PAG) surveillance. METHODS: Syndrome definitions were created using keyword categorization to extract posts from Twitter. Categories were developed iteratively for four relevant syndromes: respiratory, gastrointestinal, heat related illness, and influenza-like illness (ILI). All data sources corresponded to the location of Toronto, Canada. Twitter data were acquired from a publicly available stream representing a 1% random sample of tweets from June 26 to September 10, 2015. Cross-correlation analyses of time series data were conducted between Twitter and comparator surveillance data sources: emergency department visits, telephone helpline calls, laboratory testing positivity rate, reportable disease data, and temperature. RESULTS: The frequency of daily tweets that were classified into syndromes was low, with the highest mean number of daily tweets being for ILI and respiratory syndromes (22.0 and 21.6, respectively) and the lowest, for the heat syndrome (4.1). Cross-correlation analyses of Twitter data demonstrated significant correlations for heat syndrome with two data sources: telephone helpline calls (r = 0.4) and temperature data (r = 0.5). CONCLUSION: Using simple syndromes based on keyword classification of geolocated tweets, we found a correlation between tweets and two routine data sources for heat alerts, the only public health event detected during P/PAG. Further research is needed to understand the role for Twitter in surveillance. PMID- 29981082 TI - Ontario's Healthy Babies Healthy Children Screen tool: identifying postpartum families in need of home visiting services in Ottawa, Canada. AB - INTERVENTION: Across Ontario, the Healthy Babies Healthy Children (HBHC) postpartum screening tool is routinely used to identify families with potential risk of negative development outcomes for children. RESEARCH QUESTION: To identify screening questions associated with subsequent high-risk in-depth assessment (IDA) in order to prioritize services. METHODS: Ottawa families who gave birth (2013-2016) consented to the postpartum HBHC Screen (N = 29,162). Maternal socio-demographics, perinatal indicators, and 36 questions assessing pregnancy/birth, family, parenting, infant development, and health professional observations were analyzed for association with a high-risk IDA using regression analysis. RESULTS: Upon first screen, 51% of families scored two or more risks. Most commonly, labour/delivery complications (27%), previous loss (26%), health professional concerns (22%), and mental illness (17%) were identified. Among IDA completions, 41% were assessed as high risk and this proportion increased when screened with 4+ risks. Characteristics associated with high-risk IDA among families scoring two or three included the following: maternal age <= 19 years (aRR = 2.0, 95% CI 1.50-2.80), 20-29 years (1.3, 1.12-1.53), >= 35 years (1.2, 1.04-1.45); combination breast and formula feeding on discharge (1.2, 1.03-1.37); < 18 years old at birth of first child (1.7, 1.13-2.43); single parent and no partner involved (1.6, 1.07-2.33); high school incomplete (1.8, 1.45-2.35); newcomer support needed (1.8, 1.43-2.17); financial concerns (1.6, 1.27-2.14); history of mental illness (1.2, 1.01-1.33); and parent disability (1.7, 1.09 2.78). CONCLUSION: While offering the IDA when scoring 2+ risks is a provincial requirement, practices of increasing effort toward contacting families screened with 4+ risks are substantiated. An adapted approach to prioritize families screened with two or three risks is described. PMID- 29981083 TI - Rien ne doit se faire pour eux sans eux : renforcer la participation des demandeurs d'asile, refugies et migrants sans statut et des organismes communautaires dans la recherche en sante. AB - The number of vulnerable migrants in Canada is on the rise. While debates on immigration policies have been at the forefront, there has been little dialogue regarding the health and well-being of refugees, asylum-seekers and non-status migrants despite the significant health inequities that these populations face. In this context, health research that aims to understand migrants' realities, develop appropriate health and social services and policies, and empower these populations, is needed more than ever. Participatory action research (PAR) is one approach for conducting relevant and empowering research with migrants, however it remains underutilized due to inadequate funding, infrastructure and support. PAR addresses real-life challenges, emphasizes collaboration with communities, and involves all stakeholders, including community-based organizations, in the co construction and implementation of practical solutions. In this commentary, we call for more research with and for migrants, particularly in the form of PAR, as well as for more targeted funding initiatives and research conditions (University, funding agencies) that foster and support this type of research. PMID- 29981084 TI - Predictors of pertussis outbreak in urban and rural municipalities of Saskatchewan, Canada. AB - OBJECTIVES: Increased numbers of pertussis cases in September 2015 led to the declaration of an outbreak in the Saskatoon Health Region (SHR). SHR (population approximately 350,000) is a geographic area in central Saskatchewan consisting of both urban and rural municipalities. The purpose of this study was to describe the epidemiology and identify possible predictors of the outbreak. METHODS: Confirmed cases of pertussis in SHR from 2010 to 2015 were extracted from the integrated Public Health Information System (iPHIS) database. Univariate and bivariate analyses and a comparison of the two outbreaks were conducted. Poisson regression modelling was used to estimate incidence rate ratios (IRRs) of factors associated with pertussis infection. OUTCOMES: Two outbreaks between 2010 and 2015. Factors associated with the 2015 outbreak were residence in rural areas (IRR = 18.67, 95% CI 11.82-29.49; 11.37, 95% CI 6.40-20.21; and 6.31, 95% CI 3.43 11.62) for Humboldt, Watrous, and Rosthern areas, respectively, compared to the City of Saskatoon, and among children 11-14 years of age (IRR = 3.11, 95% CI 1.67 5.79) compared to children under 5 years of age. Unvaccinated persons had increased risk (IRR = 1.60, 95% CI 1.07-2.38). Multiple interventions, including enhanced contact tracing, supplemental immunization clinics, and cocooning, were employed in the 2015 outbreak. CONCLUSION: Pertussis is a cyclical disease with outbreaks occurring every 3 to 5 years. Teenagers have increased risk of disease compared to younger children, likely due to waning immunity. Rural residents had a higher incidence of disease, possibly due to clusters of conscientious objectors. Control efforts require recognition of waning immunity and unvaccinated susceptibles. PMID- 29981085 TI - Disentangling the effects of primary and secondary international migration on psychological distress: the role of mastery. AB - OBJECTIVES: This study examined the effect of mode of migration-primary immigration (direct migration from origin country) and secondary immigration (migration from a country of residence other than the origin country)-by level of economic development of country of origin on psychological distress of immigrants to Canada. The study focused on the explanatory role of mastery in the relationship between mode of migration/level of economic development of origin country and distress. Mastery is the belief that one can and does master, control, and shape one's own life. METHODS: Data from the Neighbourhood Effects on Health and Well-being study, which contains important measures such as the mode of migration, was used to assess the study objectives. The analytic sample included 1496 Canadian-born and 387 foreign-born (non-refugee) participants. Hierarchical linear modeling was used to address the study objectives. RESULTS: Results point to a "healthy immigrant effect"-lower distress among the foreign born than the native-born-but only among primary immigrants from less-developed countries. Secondary immigrants from less-developed countries report higher distress than the native-born and their primary-immigrant counterparts. The higher distress among secondary immigrants was due in part to lower mastery among this group. Immigrants from developed origin countries did not report different levels of distress than the native-born, irrespective of mode of migration. CONCLUSION: This study fills an important gap in the literature on immigration and mental health and reveals that the healthy immigrant effect is not generalizable to all immigrants; it is contingent on the mode of migration/level of economic development of the country of origin. PMID- 29981087 TI - Domestic/intimate partner violence in the lives of immigrant women: a New Brunswick response. AB - OBJECTIVES: This article highlights barriers in accessing public services for domestic and intimate partner violence (D/IPV) from the perspectives of immigrant women and service providers in the province of New Brunswick. Addressing these barriers can assist in building capacity among immigrant women to talk about D/IPV; increase awareness and facilitate the use of public services by immigrant women experiencing D/IPV; and improve collaboration among D/IPV service providers in different sectors. METHODS: The study is based on social determinants of health and intersectional theoretical frameworks. Semi-structured interviews and focus group discussions were conducted with immigrant women and public service providers, representing the province's linguistic and geographic (rural/urban) diversity. Qualitative data were coded thematically. Common and disparate themes between immigrant women and service providers were identified. RESULTS: Common themes include lack of understanding, the complexity of the intersection of D/IPV and Canada's immigration framework, and issues of trust. Disparate themes include differences in cultural values, the lack of collaboration between different types of service provision, and financial issues. Recommendations are made to mitigate structural barriers and increase collaboration. CONCLUSION: Acknowledgement and better understanding of the cultural differences between service providers and immigrant survivors of D/IPV would go a long way to improve trust and break down barriers in communication. Revision of the New Brunswick Woman Abuse Protocols will highlight the perspectives of immigrant women. Long-term and increased funding for D/IPV and settlement public services will ensure that women-centered programming and professional translation services are available and improved collaboration takes place. PMID- 29981086 TI - Guelph Family Health Study: pilot study of a home-based obesity prevention intervention. AB - OBJECTIVE: To examine the feasibility and preliminary impact of a home-based obesity prevention intervention among Canadian families. METHODS: Families with children 1.5-5 years of age were randomized to one of three groups: (1) four home visits (HV) with a health educator, emails, and mailed incentives (4HV; n = 17); (2) two HV, emails, and mailed incentives (2HV; n = 14); or (3) general health advice through emails (control; n = 13). Parents randomized to the 2HV and 4HV groups completed post-intervention satisfaction surveys. At baseline and post intervention, parents reported frequency of family meals and their children's fruit, vegetable, and sugar-sweetened beverage (SSB) intake. We assessed the children's physical activity, sedentary behaviour, and sleep using accelerometers and their % fat mass using bioelectrical impedance analysis. Differences in outcomes at post-intervention, controlling for baseline, were examined using generalized estimating equations. RESULTS: Of the 44 families enrolled, 42 (96%) had 6-month outcome data. Satisfaction with the intervention was high; 80% were "very satisfied" and 20% were "satisfied." At post-intervention, children randomized to the 4HV and 2HV groups had significantly higher fruit intake and children randomized to the 2HV group had significantly lower percentage of fat mass, as compared to the control. No significant intervention effect was found for frequency of family meals, the children's vegetable or SSB intake, physical activity, sedentary behaviour, or sleep. CONCLUSIONS: Our results suggest that the delivery of a home-based intervention is feasible among Canadian families and may lead to improved diet and weight outcomes among children. A full-scale trial is needed to test the effectiveness of this home-based intervention. CLINICAL TRIALS REGISTRATION NUMBER: NCT02223234. PMID- 29981088 TI - Trends in the awareness, acceptability, and usage of HIV pre-exposure prophylaxis among at-risk men who have sex with men in Toronto. AB - OBJECTIVES: Pre-exposure prophylaxis (PrEP) with daily oral tenofovir/emtricitabine dramatically reduces HIV risk in men who have sex with men (MSM). However, uptake is slow worldwide. METHODS: We administered anonymous cross-sectional questionnaires to MSM presenting for anonymous HIV testing at a Toronto sexual health clinic at four successive time points during the period 2013-2016. We assessed trends in PrEP awareness, acceptability, and use over time using the Cochran-Armitage Trend Test, and identified barriers to using PrEP by constructing "PrEP cascades" using 2016 data. We assumed that to use PrEP, MSM must (a) be at risk for HIV, (b) be at objectively high risk (HIRI-MSM score >= 10), (c) perceive themselves to be at medium-to-high risk, (d) be aware of PrEP, (e) be willing to use PrEP, (f) have a family doctor, (g) be comfortable discussing sexual health with that doctor, and (h) have drug coverage/be willing to pay out of pocket. RESULTS: MSM participants were mostly white (54-59.5%), with median age 31 years (IQR = 26-38). PrEP awareness and use increased significantly over time (both p < 0.0001), reaching 91.3% and 5.0%, respectively, in the most recent wave. Willingness to use PrEP rose to 56.5%, but this increase did not reach statistical significance (p = 0.06). The full cascade, ABCDEFGH, suggested few could readily use PrEP under current conditions (11/400 = 2.8%). The largest barriers, in descending order, were low self-perceived HIV risk, unwillingness to use PrEP, and access to PrEP providers. CONCLUSION: To maximize its potential public health benefits, PrEP scale-up strategies must address self perceived HIV risk and increase access to PrEP providers. PMID- 29981089 TI - Canadian and Dutch doctors' roles in assistance in dying. AB - According to the Canadian law legalizing physicians to provide medical assistance in dying (MAID) under certain circumstances, the patients alone determine if their suffering cannot be relieved under conditions "that they consider acceptable." This contrasts with the laws on MAID in the Netherlands, which require that physicians only grant access to MAID if they concur with the patient that there are no other potential means of alleviating the suffering. In the Netherlands, when a doctor believes that other means to reduce the suffering exist, they must be tried before having access to MAID. This criterion is often applied and is considered an essential precaution to ensure that lives are not ended prematurely when other viable interventions exist. The Canadian emphasis on the patient's right to decide whether to try potential alternatives a physician may suggest, such as palliative care, instead of dying by MAID, gives patients the liberty to make informed decisions, even when they may not seem to be in their best interest. This contrasts with the belief in the Netherlands that the state has an obligation to protect citizens from making decisions that are not in their best interest, such as choosing to die when the "intolerable suffering" can be diminished sufficiently for the person to abandon the desire to end the suffering by dying. The Canadian parliament, when they consider expanding access to MAID, should incorporate the Dutch due care safeguards to ensure that death is not the solution when other ways of reducing suffering exist. PMID- 29981090 TI - What is the effect of ADHD stimulant medication on heart rate and blood pressure in a community sample of children? AB - OBJECTIVE: This study examines the effect of ADHD (attention deficit hyperactivity disorder) diagnosis and stimulant medication for ADHD treatment on child heart rate (HR) and blood pressure (BP) in a community sample compared to children without ADHD. METHODS: Data came from the HBEAT Study. From 49 schools, 2013 participants from southern Ontario in grades 5-8 were included. Linear regression analyses examined the effects of ADHD medications on systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate adjusting for age, sex and body mass index (BMI). RESULTS: Compared to non-ADHD children and adjusting for age, sex and BMI, children with ADHD on stimulant medication had a 12.3-bpm higher HR, and 3.0-mmHg higher SBP and DBP (all statistically significant). Children with ADHD on no stimulant medication had no differences in HR and BP compared to those children without a diagnosis of ADHD. CONCLUSION: Stimulant medications used to treat ADHD are associated with elevated HR and higher BP. While it is unknown whether children on ADHD medications may be at risk for longer-term cardiovascular issues, this study supports the need to examine the long-term consequences of ADHD medication. PMID- 29981091 TI - Comparing individual and area-based income measures: impact on analysis of inequality in smoking, obesity, and diabetes rates in Canadians 2003-2013. AB - OBJECTIVES: The aims of this study were to examine (1) the concordance between income measured at the individual and area-based level and (2) the impact of using each measure of income on inequality estimates for three health indicators the prevalence, respectively, of diabetes, smoking, and obesity. METHODS: Data for the health indicators and individual income among adults came from six cycles of the Canadian Community Health Survey (cycles 2003 through 2013). Area-based income was obtained by linking respondents' residential postal codes to neighbourhood income quintiles derived from the 2006 Canadian census. Relative and absolute inequality between the lowest and highest income quintiles for each measure was assessed using rate ratios and rate differences, respectively. RESULTS: Concordance between the two income measures was poor in the overall sample (weighted Kappa estimates ranged from 0.19 to 0.21 for all years), and for the subset of participants reporting diabetes, smoking, or obesity. Despite the poor concordance, both individual and area-based income measures identified generally comparable levels of relative and absolute inequality in the rates of diabetes, smoking, and obesity over the 10-year study period. CONCLUSION: The results of this study show that individual and area-based income measures categorize Canadians differently according to income quintile, yet both measures reveal striking income-related inequalities in rates of diabetes and smoking, and obesity among women. This suggests that either individual or area-level measures can be used to monitor income-related health inequalities in Canada; however, whenever possible, it is informative to consider both measures since they likely represent distinct social constructs. PMID- 29981092 TI - Are young Canadians supportive of proposed nutrition policies and regulations? An overview of policy support and the impact of socio-demographic factors on public opinion. AB - OBJECTIVES: Many countries, including Canada, are considering nutrition policies that seek to improve dietary behaviour and related health outcomes. The current study examined support for policy measures among youth and young adults in Canada. METHODS: Participants aged 16-30 years were recruited for online surveys using in-person intercept sampling in five Canadian cities as part of the Canada Food Study conducted in October-December, 2016 (n = 2729). Items included support for 21 specific policies in seven key areas: menu labelling, food package symbols and warnings, school policies, taxation and subsidies, zoning restrictions, marketing bans, and food formulation. Linear regression models examined support by age, sex, city, race/ethnicity, parental status, body mass index (BMI), and health literacy. RESULTS: Very high levels of support were observed for menu labelling in restaurants and schools, as well as food package symbols and warnings. Taxation, zoning restrictions (e.g., fast food and convenience stores near schools), and bans on marketing to children received relatively lower levels of support. In general, policy support increased with age for all 21 policies (p < 0.01) and greater health literacy for 4 policies (p < 0.05). Males were less supportive than females for 5 policies (p < 0.01). There were significant differences in support for specific race/ethnicity groups for 4 policies (p < 0.05). Support for menu labelling policies increased with BMI (p < 0.05). CONCLUSION: Overall, youth and young adults in Canada reported high levels of support for menu labelling, food package symbols/warnings, and school policies. Levels of support were generally consistent across socio-demographic subgroups, with some exceptions. PMID- 29981093 TI - HIV and hepatitis C virus infections in Quebec's provincial detention centres: comparing prevalence and related risky behaviours between 2003 and 2014-2015. AB - OBJECTIVES: To compare the prevalence of HIV, hepatitis C virus (HCV) infections, and related risky behaviours among inmates in Quebec's provincial prisons between 2003 and 2014-2015. METHODS: Cross-sectional data were anonymously collected from May 2014 to March 2015 for men (n = 1315) and women (n = 250) and combined with data collected in 2003 to evaluate trends in the last decade. Participants completed a questionnaire and provided saliva samples. The data from the 2003 and 2014-2015 surveys were merged for statistical analysis. RESULTS: HIV prevalence was stable between 2003 and 2014-2015 for men (2.4% vs. 1.8%, p = 0.4), whereas it decreased for women (8.8% vs. 0.8%, p < 0.001). HCV prevalence decreased between 2003 and 2014-2015 for both men (16.6% vs. 11.9%, p < 0.001) and women (29.2% vs. 19.2%, p = 0.02). HIV and HCV prevalence were higher among people who inject drugs (PWID), for both sexes and both studies. PWID-specific prevalence did not change between 2003 and 2014-2015, except for a decrease in HIV prevalence in PWID women. However, the proportion of prisoners reporting a history of injection drug use outside prison was lower in 2014-2015 than in 2003 for men (19.8% vs. 27.7%, p < 0.0001) and women (28.6% vs. 42.6%, p = 0.002). CONCLUSION: The lower proportion of PWID inmates in 2014-2015 compared to 2003 explained in large part the decrease in HIV and HCV prevalence. Despite the decrease in prevalence, HIV and HCV infections among incarcerated individuals still represent a major public health problem due to the sizable increase of individuals in Quebec's correctional system over the same period. PMID- 29981094 TI - Assessing health literacy among older adults living in subsidized housing: a cross-sectional study. AB - OBJECTIVES: This study aimed to assess functional health literacy levels among older adults living in subsidized housing in Hamilton, Ontario, and to assess the relationships between health literacy and other important health indicators, such as education level, age, ethnicity, body mass index (BMI), and self-reported health status. METHODS: Older adults (n = 237) living in subsidized housing buildings in Hamilton, ON, were assessed using the NVS-UK as a measure of functional health literacy in addition to a health indicator questionnaire through structured interview. Health literacy levels were analyzed using descriptive statistics and logistic regression to determine relationships between health literacy levels and other health indicators. RESULTS: Participants' mean age was 73 years, 67% were female, 70% were not educated beyond high school, and 91% were white. Over 82% of participants had below adequate health literacy levels using the NVS-UK. Multivariable logistic regression revealed significant relationships between functional health literacy and BMI, education level, and pain and discomfort levels. No significant relationships were found between health literacy level and age group, anxiety and depression levels, CANRISK (Diabetes risk) score, gender, marital status, mobility issues, self-care issues, self-reported health status, or performance of usual activities. CONCLUSIONS: As the population of older adults continues to grow, the appropriate resources must be available to both improve and support the health literacy level of the population. Future health research should gather information on the health literacy levels of target populations to ensure more equitable health service. This research provides a significant opportunity to better understand populations with health literacy barriers. PMID- 29981095 TI - Child maltreatment and adult multimorbidity: results from the Canadian Community Health Survey. AB - OBJECTIVES: This study investigated associations between three types of child maltreatment (exposure to intimate partner violence, sexual, and physical abuse) and multimorbidity (chronic physical conditions, pain conditions, and mental disorders) in adults. METHODS: Multinomial logistic regression was used to analyze weighted data from the 2012 Canadian Community Health Survey (CCHS - MH 2012), a representative population sample (N = 23,846) of respondents ages 18+. RESULTS: All three subtypes of child maltreatment independently predicted increased odds of experiencing multimorbidity as an adult, while adjusting for covariates (adjusted odds ratios ranged from 1.34 (95% CI = 1.00, 1.80) to 4.87 (95% CI = 2.75, 8.63)). A dose-response relationship between the number of child maltreatment subtypes and risk for multimorbidity was also observed (adjusted odds ratios ranged from 1.38 (95% CI = 1.11, 1.73) to 10.96 (95% CI = 6.12, 19.64)). CONCLUSION: The current results highlight the importance of considering a range of childhood adversities and suggest that public health approaches that aim to decrease the prevalence and severity of child maltreatment have the potential to ameliorate adult multimorbidities. Future research is encouraged to investigate these issues using longitudinal population-level data. PMID- 29981097 TI - Ethnic differences in vascular function and factors contributing to blood pressure. AB - OBJECTIVE: Indigenous populations experience greater proportions of cardiovascular disease, diabetes, and obesity, though lower rates of hypertension. This investigation evaluated blood pressure relationships with vascular measures, anthropometry, cultural identity, and smoking status among Canadian Indigenous and European adults. METHODS: In 2013, in Vancouver, Canada, blood pressure, anthropometry, cultural identity, smoking status, pulse wave velocity (PWV), arterial compliance, baroreceptor sensitivity, and intima-media thickness (IMT) were directly measured among 58 Indigenous (39 +/- 18 years, 31 female) and 58 age- and sex-matched European Canadian (42 +/- 18 years) adults. Systolic (SBP) and diastolic (DBP) blood pressures were related to vascular measures, and hypertension was related to anthropometry, cultural identity, and smoking status. RESULTS: Similar vascular measures were recorded between Indigenous and European adults, respectively (PWV 5.3 +/- 2.4 vs. 6.2 +/- 3.4 m s 1, p = 0.12; IMT 0.59 +/- 0.11 vs. 0.61 +/- 0.11 mm, p = 0.40; and large arterial compliance 16.1 +/- 6.4 vs. 17.5 +/- 6.6 mL mmHg-1 * 10, p = 0.26). Similar relationships between vascular measures with SBP and DBP were identified between Indigenous and European adults (spectral baroreceptor sensitivity and SBP, r = 0.48, p = 0.001 vs. r = - 0.11, p = 0.44; ethnic difference p = 0.38; PWV; and DBP, r = 0.23, p = 0.09 vs. r = 0.06, p = 0.65, ethnic difference p = 0.23). Anthropometry only related to blood pressures among Europeans. Cultural identity only related to blood pressures among Indigenous populations. Smoking was not related to hypertension. CONCLUSION: Similar vascular measures between Indigenous and European Canadians were identified among populations experiencing similar social determinants of health. PMID- 29981096 TI - Red blood cell folate levels in Canadian Inuit women of childbearing years: influence of food security, body mass index, smoking, education, and vitamin use. AB - BACKGROUND: The benefits of folic acid for prevention of congenital anomalies are well known. For the Inuit of Canada, where vitamin use is low and access to folate-rich foods limited, fortification is likely a major source of intake. We sought to determine whether red blood cell folate (RBCF) levels of Inuit women reached accepted target levels. METHODS: The Inuit Health Survey, 2007-2008, included evaluation of RBCF levels among 249 randomly selected non-pregnant women of reproductive age. Using descriptive statistics and linear regression analyses, RBCF levels were assessed and compared across several socio-demographic variables to evaluate the characteristics associated with RBCF status. RESULTS: Mean (SD) RBCF levels of 935.5 nmol/L (+/- 192) reached proposed target levels (> 906 nmol/L); however, 47% of women had lower than target levels. In bivariate analysis, non-smoking, higher education, higher income, food security, increased body mass index, and vitamin use were each significantly associated with higher RBCF. Increased levels of smoking had a negative association with RBCF levels (- 5.8 nmol/L per cigarette smoked per day (p = 0.001)). A total of 6.8% of women reported taking vitamin supplements, resulting in a 226 nmol/L higher RBCF level on average compared to non-users (p < 0.001). CONCLUSION: While mean levels of folate reached target levels, this was largely driven by the small number of women taking vitamin supplements. Our results suggest that folate status is often too low in Inuit women of childbearing years. Initiatives to improve food security, culturally relevant education on folate-rich traditional foods, vitamin supplements, and smoking cessation/reduction programs may benefit Inuit women and improve birth outcomes. PMID- 29981098 TI - Lived experience of a record wildfire season in the Northwest Territories, Canada. AB - OBJECTIVES: During the period of June-September 2014, the Northwest Territories (NWT) experienced its worst wildfire season on record, with prolonged smoke events and poor air quality. In the context of climate change, this study sought to qualitatively explore the lived experience of the 2014 wildfire season among four communities in the NWT. METHODS: Our team conducted 30 semi-structured interviews in four communities (Yellowknife, N'Dilo, Detah, and Kakisa). Interviewees were purposively sampled to include a broad cross-section of backgrounds and experiences. Interviews were video recorded, and the audio portion of each interview was transcribed to facilitate analysis and theme generation. RESULTS: Interviewees reported how their experiences of evacuation and isolation as well as feelings of fear, stress, and uncertainty contributed to acute and long-term negative impacts for their mental and emotional well-being. Prolonged smoke events were linked to extended time indoors and respiratory problems. Livelihood and land-based activities were disrupted for some interviewees, which had negative consequences for mental, emotional, and physical well-being. Individual and community stories of adaptation and resilience prior to and during the summer, including the opening of indoor recreational spaces, were shared; however, there was consensus about the need for improved risk communication and coordination at the community and territorial levels to address similar events in the future. CONCLUSION: Coordinated community-based education, communication, and adaptation initiatives that are inclusive of local knowledge, values, and context are needed to address the expressed needs of community members associated with prolonged smoke events and wildfire seasons. PMID- 29981099 TI - Industry and geographic patterns of use and emission of carcinogens in Ontario, Canada, 2011-2015. AB - OBJECTIVES: The goal of this study was to leverage data from two environmental regulatory initiatives, Ontario's Toxics Reduction Act (TRA) and Canada's National Pollutant Release Inventory (NPRI), to assess their ability to monitor trends in the use and emission of carcinogens by industry sector in Ontario. METHODS: Data reported to the TRA and NPRI by industrial facilities in Ontario were retrieved from 2011 to 2015. Twenty-six known and suspected carcinogens were identified (IARC) and the trends in the use and emission were evaluated by industry sector. The locations of industrial facilities that used and released carcinogens were mapped by Public Health Unit (PHU). RESULTS: Chemical manufacturing and primary metal manufacturing sectors accounted for 84% of all reported industrial use of carcinogens during the period 2011-2015. The largest source of carcinogen emissions came from facilities in the primary metal manufacturing and paper manufacturing sectors. The largest number of industrial facilities that reported the use and release of carcinogens were located in the City of Toronto and Peel Region PHUs. Overall, the use of carcinogens across all sectors appeared to decrease by 8%, while emissions increased by about 2%. CONCLUSION: The results of this study show the need to reduce the use and emission of select carcinogens in priority industry sectors. Environmental reporting programs, such as the TRA and NPRI, can serve as important tools in cancer prevention by tracking potential carcinogen exposures in the environment and in the workplace. PMID- 29981100 TI - Food sources among young people in five major Canadian cities. AB - OBJECTIVE: To examine food sources among young people in five major Canadian cities. METHODS: As part of the 2016 Canada Food Study, respondents aged 16-30 were recruited from five Canadian cities (Toronto, Montreal, Halifax, Edmonton, and Vancouver) using in-person intercept sampling and completed an online survey (n = 2840 retained for analysis). Descriptive statistics were used to summarize food preparation and purchase locations. A linear regression model was fitted to examine correlates of the proportion of meals that were ready-to-eat or prepared outside the home. RESULTS: In total, 80% of meals were prepared at home and 20% were prepared outside the home. More than 25% of meals prepared at home were ready-to-eat/box food. Of all meals consumed, 42% were either ready-to-eat/box food prepared at home or prepared outside the home. Food for meals prepared at home was purchased predominantly at grocery stores/supercentres while meals prepared outside the home were purchased predominantly at fast food/quick service/coffee shop outlets. Respondents who were younger, identified as Aboriginal, had obesity, had no children, lived in residence at school, university, or college, and reported poorer cooking skills reported more meals that were ready-to-eat or prepared outside the home. CONCLUSIONS: The current findings indicate that a substantial proportion of meals consumed by young people consist of meals either prepared outside the home or ready-to-eat/box food prepared at home. Dietary recommendations should highlight basic patterns of food preparation and eating, such as limiting ultra-processed food and food prepared outside the home. PMID- 29981101 TI - Severe obesity in children 17 to 24 months of age: a cross-sectional study of TARGet Kids! and Better Outcomes Registry & Network (BORN) Ontario. AB - OBJECTIVES: International data suggest the prevalence of severe obesity in young children may be increasing, yet no Canadian data are available. The objectives of this study were to examine definitions of severe obesity and to evaluate associated risk factors among young children in Ontario. METHODS: A cross sectional study was conducted in children 17 to 24 months of age using two Ontario data sources: TARGet Kids! (n = 3713) and BORN Ontario (n = 768). Body mass index z score (zBMI) definitions were adapted from the World Health Organization (WHO) (z score > 3) and the US Centers for Disease Control (CDC) (> 120% of the 95th percentile) and applied to define severe obesity in young children. Multinomial logistic regression was used to evaluate associations between demographic and pregnancy risk factors and zBMI categories. RESULTS: A total of 1.1% (95% CI, 0.8-1.4) of children met the adapted WHO definition of severe obesity compared to 0.3% (95% CI, 0.2-0.6) using the CDC definition. Median neighbourhood household income (OR = 0.80, 95% CI, 0.69-0.93) and maternal pre-pregnancy BMI (OR = 1.08, 95% CI, 1.01-1.15) were associated with severe obesity in unadjusted analyses. After adjustment for potential confounders, the OR for the association between maternal pre-pregnancy BMI and severe obesity was 1.04 (95% CI, 0.94-1.15). CONCLUSION: More than 1% of Ontario children met the adapted WHO definition of severe obesity in very early childhood. Modifiable risk factors were identified. Future studies are needed to understand the terminology, prevalence, and risk factors for severe obesity in young children across Canada. PMID- 29981102 TI - Population-level trends in the distribution of body mass index in Canada, 2000 2014. AB - OBJECTIVE: Research studying population-level body mass index (BMI) trends document increases in mean or prevalence of overweight/obese but less consideration has been given to describing the changing distribution of BMI. The objective of this research was to perform a detailed analysis of changes in the BMI distribution in Canada. METHODS: Using data from the CCHS (2000-2014), we analyzed distributional parameters of BMI for 492,886 adults aged 25-64 years. We further stratified these analyses for women and men, education level, and region of residence. RESULTS: Mean BMI has increased for most subgroups of the Canadian population. Mean BMI values were higher for men, while standard deviation (SD) of the BMI distribution was systematically higher in women. Increases in mean BMI were accompanied with increases in SD of BMI across cycles. Across survey cycles, the 95th percentile increased more than 10 times more rapidly compared to the 5th percentile, showing a very unequal change between extreme values in the BMI distribution over time. There was a relationship between SD with BMI, but these relations were generally not different between educational categories and regions. This suggests that the growing inter-individual inequalities (i.e., dispersion) in BMI were not solely attributable to socioeconomic and demographic factors. CONCLUSIONS: This study supports the hypothesis that the simultaneous increases in mean BMI and SD of the BMI distribution are occurring, and suggests the need to move beyond the mean-centric paradigm when studying a complex public health phenomenon such as population change in BMI. PMID- 29981103 TI - Awareness of, interest in, and willingness to pay for HIV pre-exposure prophylaxis among Canadian gay, bisexual, and other men who have sex with men. AB - OBJECTIVES: Pre-exposure prophylaxis (PrEP) is a highly effective, HIV prevention strategy increasingly being accessed by gay, bisexual, and other men who have sex with men (GBMSM). GBMSM face structural and individual-level barriers accessing PrEP, including awareness and cost. This paper assesses socio-demographic factors associated with awareness, interest, and willingness to pay for PrEP in a sample of Canadian GBMSM. METHODS: Data were derived from the 2015 Sex Now survey, a cross-sectional, online survey of GBMSM. Respondents were recruited through social media, sex-seeking "apps," and by word of mouth. We used univariable and multivariable logistic regression models to estimate associations between socio demographic factors and three primary outcomes. RESULTS: Our sample consisted of 7176 HIV-negative Canadian GBMSM. Of respondents, 54.7% were aware of PrEP, 47.4% were interested in PrEP, and 27.9% of PrEP-interested respondents reported they would pay for PrEP out-of-pocket. Awareness and interest varied between provinces, while GBMSM outside urban areas were less likely to be PrEP aware. Bisexual-identified men, and men over 50, were less likely to be aware and interested in PrEP in multivariable models. Only annual income and educational attainment were associated with willingness to pay for PrEP. CONCLUSION: This study identifies important disparities in awareness, interest, and willingness to pay for PrEP. Future interventions and educational efforts should target non-gay identified and older GBMSM, as well as GBMSM outside urban areas. PrEP implementation may risk further perpetuating existing health inequities based on socio-economic status if PrEP continues to be accessed primarily through private insurance or paid for out-of-pocket. PMID- 29981104 TI - Cost-effectiveness of alternative strategies for use of 13-valent pneumococcal conjugate vaccine (PCV13) in Canadian adults. AB - OBJECTIVES: The Canadian National Advisory Committee on Immunization (NACI) recommends use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in a sequential schedule (PCV13 -> PPV23) among adults aged >= 65 years and those aged >= 18 years who are immunocompromised. In light of recent PCV13 efficacy data from the Community Acquired Pneumonia Immunization Trial in Adults (CAPiTA), and new sero epidemiology data on community-acquired pneumonia (CAP), we examined the economic implications of funding an expanded adult pneumococcal immunization program in Canada. METHODS: A microsimulation model depicting expected lifetime risks, consequences, and costs of invasive pneumococcal disease (IPD) and CAP was developed. PPV23 effectiveness was based on published literature, and PCV13 effectiveness was based on CAPiTA; all other model parameters were based on published data or secondary sources. Herd effects from the PCV13 pediatric program were considered. Outcomes and costs were evaluated assuming use of PPV23 alone, and alternatively, use of PCV13 -> PPV23 among (1) all adults aged >= 65 years (n = 5.4 M) and (2) immunocompromised and high-risk adults aged >= 65 years (n = 3.0 M). RESULTS: For population no. 1, PCV13 -> PPV23 reduced IPD cases by 1100, CAP cases by 7000, and disease costs by $135.8M; vaccination costs increased by $254.3M, and cost per QALY gained was $35,484. For population no. 2, PCV13 -> PPV23 reduced IPD cases by 900, CAP cases by 6000, and disease costs by $120.3M; vaccination costs increased by $149.8M, and cost per QALY gained was $10,728. CONCLUSION: Expanding use of PCV13 -> PPV23 by funding PCV13 among Canadian adults aged >= 65 would be a cost-effective use of healthcare resources. PMID- 29981105 TI - Contested roles of Canada's Chief Medical Officers of Health. AB - The roles and responsibilities of Canada's Chief Medical Officers of Health (CMOHs) are contested. On the one hand, they are senior public servants who confidentially advise government on public health matters and manage the implementation of government priorities. On the other hand, CMOHs are perceived as independent communicators and advocates for public health. This article analyzes public health legislation across Canada that governs the CMOH role. Our legal analysis reveals that the presence and degree of advisory, communication, and management roles for the CMOH vary considerably across the country. In many jurisdictions, the power and authority of the CMOH is not clearly defined in legislation. This creates great potential for confusion and conflict, particularly with respect to CMOHs' authority to act as public health advocates. We call on governments to clarify their preferences when it comes to the CMOH role and either amend the relevant statute or otherwise find ways to clarify the mandate of their CMOHs. PMID- 29981106 TI - The effect of body weight on employment among Canadian women: evidence from Canadian data. AB - OBJECTIVES: This paper examines the impact of obesity on labour market participation among Canadian women by using various Canadian population health surveys. METHODS: We estimate the impact of obesity on labour market participation using probit and bivariate probit regression models. To correct for a potential endogenous relationship between obesity and labour market participation, we also use instrumental variables in the bivariate probit regression context. RESULTS: The results suggest that the probability of employment has negative association with the body weight of women. This effect is statistically significant and has substantial impact on employment. The results show that obesity decreases employment probability by about 25 percentage points for women. CONCLUSION: In addition to well-known negative health consequences, obesity also has additional negative effect on employment. This negative impact on employment is comparable to the impacts of mental health or illicit drug use on employment. Public health policies aimed at reducing obesity would generate additional benefits to society. Our results also provide additional evidence for lawmakers to amend the labour laws in Canada in order to acknowledge and prohibit hiring practices that discriminate against individuals with high body weight. PMID- 29981107 TI - Towards equity-focused intersectoral practice (EquIP) in children's environmental health and housing: the transformational story of RentSafe. AB - SETTING: This paper chronicles the transformational process through which a national intersectoral collaboration, the Canadian Partnership for Children's Health and Environment (CPCHE), came to embrace a more upstream, equity-based focus in its mandate to advance children's environmental health. INTERVENTION: After 15 years of working within a conventional, evidence-informed approach to health promotion and policy advocacy, in 2010-2013, CPCHE had the opportunity to collaborate on the development of equity-focused knowledge translation (EqKT). EqKT is a relational approach to knowledge practices that challenges intersectoral actors to work to uncover biases and limitations within their own institutional paradigms and professional practices that constrain their capacity to address population health inequities. OUTCOME: The ensuing transformation towards equity-focused intersectoral practice led CPCHE to create an intersectoral initiative called RentSafe. Conceptually and operationally, RentSafe provides an intersectoral space within which the grounded expertise of people with experience of unhealthy and undignified housing provides a roadmap for public health and other practitioners to critically explore professional and institutional blind spots and barriers. With RentSafe as its watershed moment, CPCHE is shifting from a top-down "for whom" orientation to an authentically engaged "with whom" approach that seeks to work integrally with community partners to expose and challenge systemic roots of health inequity. IMPLICATIONS: The transformational story of CPCHE underscores the competencies needed for public health professionals to acknowledge the sources of our own biases and limitations as a necessary first step in equity-focused intersectoral practice (EquIP). It also affirms the value of working in partnership with those who experience the environmental health inequities that such efforts seek to address. PMID- 29981108 TI - Carbon pricing: a win-win environmental and public health policy. AB - Carbon pricing is an important tool for mitigating climate change. Carbon pricing can have significant health co-benefits. Air pollution from fossil fuels leads to detrimental health effects, including premature mortality, heart attacks, hospitalization from cardiorespiratory conditions, stroke, asthma exacerbations, and absenteeism from school and work, and may also be linked to autism spectrum disorder and Alzheimer's disease. Reduction in fossil fuel combustion through a carbon price can lead to improvements in all these areas of health. It can also improve health by encouraging active transportation choices and improving ecosystems. Furthermore, it can promote health equity in society and improve overall societal health where the revenue from carbon pricing is used as a progressive redistribution mechanism for low-income households. Hence, carbon pricing is a win-win environmental and public health policy and an important step toward achieving Canada's emission target by 2030. However, carbon pricing has several potential pitfalls which need to be considered in the design and implementation of any such policy. As Canada moves ahead with mandatory carbon pricing this fall, it is important to monitor its impact, evaluate it objectively, and modify and complement as necessary with policies and regulations. PMID- 29981109 TI - The effect of socio-demographic factors on mental health and addiction high-cost use: a retrospective, population-based study in Saskatchewan. AB - OBJECTIVE: A small proportion of the population accounts for the majority of healthcare costs. Mental health and addiction (MHA) patients are consistently high-cost. We aimed to delineate factors amenable to public health action that may reduce high-cost use among a cohort of MHA clients in Saskatoon, Saskatchewan. METHODS: We conducted a population-based retrospective cohort study. Administrative health data from fiscal years (FY) 2009-2015, linked at the individual level, were analyzed (n = 129,932). The outcome of interest was >= 90th percentile of costs for each year under study ('persistent high-cost use'). Descriptive analyses were followed by logistic regression modelling; the latter excluded long-term care residents. RESULTS: The average healthcare cost among study cohort members in FY 2009 was ~ $2300; for high-cost users it was ~ $19,000. Individuals with unstable housing and hospitalization(s) had increased risk of persistent high-cost use; both of these effects were more pronounced as comorbidities increased. Patients with schizophrenia, particularly those under 50 years old, had increased probability of persistent high-cost use. The probability of persistent high-cost use decreased with good connection to a primary care provider; this effect was more pronounced as the number of mental health conditions increased. CONCLUSION: Despite constituting only 5% of the study cohort, persistent high-cost MHA clients (n = 6455) accounted for ~ 35% of total costs. Efforts to reduce high-cost use should focus on reduction of multimorbidity, connection to a primary care provider (particularly for those with more than one MHA), young patients with schizophrenia, and adequately addressing housing stability. PMID- 29981110 TI - Cancer incidence among First Nations adults in Canada: follow-up of the 1991 Census Mortality Cohort (1992-2009). AB - OBJECTIVES: Estimate site-specific cancer incidence rates for a wide range of cancers in First Nations adults in Canada, and compare these with rates in non Aboriginal adults. METHODS: Responses from persons aged 25 and older to the 1991 Long Form Census were linked to national mortality and cancer databases. First Nations- and non-Aboriginal-specific incidence rates were age-standardized to the world standard population. The sex- and site-specific relative risks (RR) of cancer in First Nations compared to those in non-Aboriginal adults were estimated with Poisson regression. Results were stratified by residence on-reserve (all cancers combined) and region of Canada (four most common cancer sites). RESULTS: Compared to non-Aboriginal adults, First Nations had higher incidence of colon and rectum, kidney, cervix, and liver cancers and lower incidence of prostate, breast, bladder, uterus, ovary, and brain cancers, as well as non-Hodgkin lymphoma, leukemia, and melanoma. First Nations women additionally had higher incidence of stomach, gallbladder, and laryngeal cancers and lower incidence of thyroid cancers compared to non-Aboriginal women. The higher relative incidence of stomach and gallbladder cancers was observed only among First Nations adults who reported living on-reserve. Incidence of lung cancer was similar for First Nations and non-Aboriginal adults nationally, though variation by region of Canada was observed. CONCLUSION: First Nations people in Canada have disproportionately high rates of certain cancers, providing evidence to support public health policy and programming. More research is needed to identify factors contributing to the significantly lower incidence observed for various cancer types. Novel methods for studying disparities in cancer incidence among First Nations people are required to support ongoing cancer control planning and advocacy. PMID- 29981111 TI - An Introduction to Plant Tissue Culture: Advances and Perspectives. AB - Plant tissue culture techniques are the most frequently used biotechnological tools for basic and applied purposes ranging from investigation on plant developmental processes, functional gene studies, commercial plant micropropagation, generation of transgenic plants with specific industrial and agronomical traits, plant breeding and crop improvement, virus elimination from infected materials to render high-quality healthy plant material, preservation and conservation of germplasm of vegetative propagated plant crops, and rescue of threatened or endangered plant species. Additionally, plant cell and organ cultures are of interest for the production of secondary metabolites of industrial and pharmaceutical interest. New technologies, such as the genome editing ones combined with tissue culture and Agrobacterium tumefaciens infection, are currently promising alternatives for the highly specific genetic manipulation of interesting agronomical or industrial traits in crop plants. Application of omics (genomics, transcriptomics, and proteomics) to plant tissue culture will certainly help to unravel complex developmental processes such as organogenesis and somatic embryogenesis, which will probably enable to improve the efficiency of regeneration protocols for recalcitrant species. Additionally, metabolomics applied to tissue culture will facilitate the extraction and characterization of complex mixtures of natural plant products of industrial interest. General and specific aspects and applications of plant tissue culture and the advances and perspectives are described in this edition. PMID- 29981112 TI - Micropropagation in the Twenty-First Century. AB - Despite more than a century of research on effective biotechnological methods, micropropagation continues to be an important tool for the large-scale production of clonal plantlets of several important plant species that retain genetic fidelity and are pest-free. In some cases, micropropagation is the only technique that supports the maintenance and promotes the economic value of specific agricultural species. The micropropagation of plants solved many phytosanitary problems and allowed both the expansion and access to high-quality plants for growers from different countries and economic backgrounds, thereby effectively contributing to an agricultural expansion in this and the last century. The challenges for micropropagation in the twenty-first century include cost reduction, enhanced efficiency, developing new technologies, and combining micropropagation with other systems/propagation techniques such as microcuttings, hydroponics, and aeroponics. In this chapter, we discuss the actual uses of micropropagation in this century, its importance and limitations, and some possible techniques that can effectively increase its wider application by replacing certain conventional techniques and technologies. PMID- 29981113 TI - Cellular and Morpho-histological Foundations of In Vitro Plant Regeneration. AB - In vitro plant regeneration systems have turned into invaluable tools to plant biotechnology. Despite being poorly understood, the molecular mechanisms underlying the control of both morphogenetic pathways, de novo organogenesis and somatic embryogenesis, have been supported by recent findings involving proteome , metabolome-, and transcriptome-based profiles. Notwithstanding, the integration of molecular data with structural aspects has been an important strategy of study attempting to elucidate the basis of the cell competence acquisition to further follow commitment and determination to specific a particular in vitro regeneration pathway. In that sense, morpho-histological tools have allowed to recognize cellular markers and patterns of gene expression at cellular level and this way have collaborated in the identification of the cell types with high regenerative capacity. This chapter ties together up those fundamental and important microscopy techniques that help to elucidate that regeneration occurs, most of the time, from epidermis or subepidermal cells and from the procambial cells (pericycle and vascular parenchyma). Important findings are discussed toward ultrastructural differences observed in the nuclear organization among pluripotent and totipotent cells, implying that regeneration occurs from two cellular mechanisms based on cellular reprogramming or reactivation. PMID- 29981114 TI - Bacterial Endophytes in Plant Tissue Culture: Mode of Action, Detection, and Control. AB - Endophytic bacteria have been increasingly in the focus of research projects during the last decade. This has changed the view on bacteria in plant tissue culture and led to the differentiation between artificially introduced contaminations and naturally occurring endophytes with neutral, negative, or positive impact on the plant propagation process. This review chapter gives an overview on recent findings about the impact that bacteria have on the plant physiology in general and during micropropagation. Additionally, methods for the detection and identification of bacteria in plant tissue are described and, finally, suggestions of how to deal with bacterial endophytes in in vitro culture are given. PMID- 29981115 TI - Digital Photography as a Tool of Research and Documentation in Plant Tissue Culture. AB - Scientific photography is an important and indispensable tool in plant tissue culture research: photographs should be taken throughout a project for documentation. The aim of photography in plant tissue culture should be to illustrate clearly the differentiation, growth, and developmental stages occurring in vitro. Poor-quality scientific photography in tissue culture research and professional reports results in poor documentation. If visual aspects of the tissue culture are not well documented or not well reproduced in the image, an important part of the research is missed, the resulting report is of limited scientific value, and the research results may not be reproducible. Simple methods for improving the results of photography of materials from plant tissue culture are described and discussed, along with the necessary photographic equipment, suitable backgrounds, the construction of photographic plates, and correct use of electronic files for images. Finally, ethical concerns about image manipulation are discussed. PMID- 29981116 TI - Selection of Molecular Markers for the Estimation of Somaclonal Variation. AB - Tissue culture for plant micropropagation is known to be a source of genetic changes termed "somaclonal variation". This protocol is designed to help in the selection of one or more types of molecular marker systems for the optimal detection and measurement of somaclonal variation. Somaclonal variation is influenced by the reproductive biology of the species, the number of individuals taken as tissue source, and the tissue culture protocol, while its detection and measurement depends upon the molecular marker system selected, which can also vary in the intensity of genome sampling. In turn, the intensity of genome sampling can be regulated varying parameters of the molecular technique. These factors are discussed and illustrated with in silico molecular marker protocols. Software, programed in R, to perform simulation and evaluation of somaclonal variation is made publicly available. PMID- 29981117 TI - Plant Tissue Culture: A Battle Horse in the Genome Editing Using CRISPR/Cas9. AB - Plant tissue culture (PTC) is a set of techniques for culturing cells, tissues, or organs in an aseptic medium with a defined chemical composition, in a controlled environment. Tissue culture, when combined with molecular biology techniques, becomes a powerful tool for the study of metabolic pathways, elucidation of cellular processes, genetic improvement and, through genetic engineering, the generation of cell lines resistant to biotic and abiotic stress, obtaining improved plants of agronomic interest, or studying the complex cellular genome. In this chapter, we analyze in general the use of plant tissue culture, in particular protoplasts and calli, in the implementation of CRISPR/Cas9 technology. PMID- 29981118 TI - Micropropagation of Agave Species. AB - The genus Agave originates from the American continent and grows in arid and semiarid places, being Mexico the center of origin. Many species of the genus are a source of diverse products for human needs, such as food, medicines, fibers, and beverages, and a good source of biomass for the production of biofuels, among many others. These plants are gaining importance as climate change becomes more evident as heat is reaching temperatures above 40 degrees C worldwide and rains are scarce. Many species of the genus grow in places where other plant species do not survive under severe field conditions, due to their CAM pathway for fixing CO2 where gas exchange occurs at night when stomata are open, allowing them to avoid excess loss of water. Most of the important species and varieties are usually propagated by offshoots that develop from rhizomes around the mother plant and by bulbils that develop up in the inflorescence, which are produced by the plant mostly when there is a failure in the production of seeds.Areas for commercial plantations are growing worldwide and therefore in the need of big amounts of healthy and good quality plantlets. Although many Agave species produce seeds, it takes longer for the plants to reach appropriate maturity and size for diverse purposes. Micropropagation techniques for the genus Agave offer the opportunity to produce relatively high amounts of plants year around in relatively small spaces in a laboratory. Here, a protocol for micropropagation that has proven good for several Agave species (including species from both subgenera) is presented in detail with two different kinds of explants to initiate the process: rescued zygotic embryos and small offshoots that grow around a mother plant. PMID- 29981119 TI - Protocol for the Micropropagation of Coconut from Plumule Explants. AB - Coconut is a crop that is economically important in several countries throughout the world. Unfortunately, production is decreasing because palms are affected by very serious phytoplasma diseases, such as lethal yellowing, and also most of coconuts are already very old. On the other hand, markets for coconut products have been rapidly growing in recent years. Hence, replanting of most cultivation surface worldwide, as well as establishing new surface, is urgently needed. This is an immense task, requiring at least a billion coconut palms that cannot be accomplished by traditional propagation through seed. Therefore the biotechnological alternative of micropropagation by somatic embryogenesis is needed. Research has been carried out on this subject in laboratories in several countries studying different approaches, testing different types of explants. The most responsive tissue has been plumule from zygotic embryos. A protocol for micropropagation of coconut based on plumule explants is described here. It involves the use of different media that are based on Y3 medium complemented with activated charcoal, gelling agent, sucrose, and growth regulators. These media allow the formation of embryogenic callus and somatic embryos, growth of shoots, and development of plantlets. PMID- 29981120 TI - Micropropagation of Yucca Species. AB - Yuccas are plants adapted to arid and semiarid regions and have been used as source of food and raw materials and for ornamental purposes. Lately, the interest in this genus has grown due to the presence of potential useful compounds such as saponins and polyphenolics. However, they present very low reproductive rates and virtually all the plants used are wild individuals; as consequence, their natural populations have been depleted. We present an efficient method to establish in vitro cultures of Yucca species starting with seeds and then obtaining shoots from the seedling meristems using cytokinins and auxins. These shoots can be rooted and transferred to soil or can be used as explants for another multiplication cycle. Hence, it is necessary to acquire seeds just once to establish a large-scale micropropagation protocol. PMID- 29981121 TI - Auxin Immunolocalization in Coffea canephora Tissues. AB - Auxins are plant growth regulators that participate in a variety of biological mechanisms during the growth and development of plants. The most abundant natural auxin is indole-3-acetic acid (IAA). The physiological processes regulated by IAA depend on their temporal space accumulation in different tissues of a plant. This accumulation is regulated by its biosynthesis, conjugation, degradation, and transport. Therefore tools that allow us a qualitative and quantitative detection of IAA in plant tissues are very useful to understand the homeostasis of IAA during the life cycle of plants. In this protocol, the complete procedure for localization of IAA in different tissues of Coffea canephora is described using specific anti-IAA monoclonal antibodies. PMID- 29981122 TI - Somatic Embryogenesis in Common BeanPhaseolus vulgaris L. AB - Common bean Phaseolus vulgaris L. has been shown to be a recalcitrant plant to induce somatic embryogenesis (SE) under in vitro conditions. An alternative strategy to yield SE is based upon the use of a cytokinin (benzyladenine) coupled with osmotic stress adaptation instead of the auxin-inducing SE in common bean. Here we described the induction of proembryogenic masses (PEM) derived from the apical meristem and cotyledonary zone of zygotic embryos, from which secondary SE indirect embryogenesis emerged. Maturation of SE was achieved by using osmotic stress medium and converted to plants. Long-term recurrent SE was demonstrated by propagation of PEM at early stages of SE. This protocol is currently being applied for stable genetic transformation by means of Agrobacterium tumefaciens and biobalistics as well as basic biochemical and molecular biology research. PMID- 29981123 TI - Induction of Somatic Embryogenesis in Jatropha curcas. AB - Jatropha curcas has been a promising crop for biofuel production for the last decade. However, the lack of resistant materials to diseases and improved quality of the oil produced by the seeds has restricted the use of this promising crop. The genetic modifications in the fatty acid pathway, as well as the introduction of resistance to different diseases, would change the fate of Jatropha. To achieve these goals, we need to have a very efficient regeneration system. Here, we report a very useful protocol to induce somatic embryogenesis from leaves of Jatropha using cytokinin as the only growth regulator. PMID- 29981124 TI - In Vitro Proliferation of Female Buds for Induction of Somatic Embryogenesis from False Horn Plantain (AAB, cv. Currare). AB - Most cultivated bananas (Musa spp.) are polyploids, and their fruits are seedless and propagated exclusively vegetatively; however, they can also be cloned by micropropagation techniques, viz., direct organogenesis (DO) or somatic embryogenesis (SE). Banana indirect SE (ISE), with an embryogenic callus phase, is possible using young male or female flowers as direct explant depending on the genotype or shoot tips (scalps). For the False Horn Plantain, cv. Currare (AAB, plantain subgroup), which has a degenerating male bud, female flowers are used to regenerate plants through ISE. Here, a protocol for increasing the number of initial explant material from a single mother plant and its embryogenic response is described. For those purposes, hands with young female buds are in vitro proliferated in the presence of 1 MUM indole-3-acetic acid and 2.5 MUM thidiazuron. Friable embryogenic cultures, here called ISE-2, obtained from the new proliferative secondary female bud clusters are initiated on medium containing auxins. Embryogenic suspensions are then established from the ISE-2 cultures. Regeneration of plants is achieved from embryogenic suspensions after plating on semisolid medium free of plant growth regulators; greenhouse acclimatized plantlets are ready for banana farming. This study demonstrates that proliferative female buds are a proper choice for ISE. PMID- 29981125 TI - Somatic Embryogenesis in Theobroma cacao L. AB - Theobroma cacao L. is a tropical tree originating in the Amazon, where it grows naturally in the shade of tropical rainforests. Cacao sub-products, such as butter and powder, are produced as principal components of chocolate and contain important nutritional compounds such as polyphenols and flavonoids. However, bean production is decreasing because plantations are antiquated and unproductive. Cacao propagation has been traditionally performed through classical propagation methods, such as grafting or rooted cuttings, but those methods are not sufficient to obtain large quantities of planting material with the desired genetic quality and optimal plant health. In the search for solutions to this problem, somatic embryogenesis (SE) is a vegetative method used for cacao propagation that has the potential to be explored. SE is a type of clonal propagation by which totipotent cells in the somatic tissue can develop into embryos and subsequently convert into plants.This method offers significant technological advantages because it is possible to obtain a large quantity of disease-free planting material with good agronomic characteristics and genetic stability. In T. cacao, tow techniques of in vitro micropropagation have been reported as direct and indirect SE. Indirect SE requires the additional step of cell dedifferentiation, unlike direct SE, which does not require this step. Here, we report a protocol using direct and indirect SE techniques using two types of culture methodologies-solid and liquid culture media. PMID- 29981126 TI - Somatic Embryogenesis of Quercus suber L. From Immature Zygotic Embryos. AB - Quercus suber L., cork oak, is a forest tree of high social and economic value. The cork is traditionally used in the wine industry to produce bottle stoppers, but it is also a very good material for both thermal and acoustic insulation in construction. Since its harvest does not harm the tree, the use of cork in the industry has a positive impact on the environment.Somatic embryogenesis is considered a feasible system for in vitro regeneration procedures, with many advantages in woody species. Classical genetic breeding programs have important limitations in forest trees, like cork oak, due to their long life span and difficulties of seed conservation and vegetative reproduction. Therefore, somatic embryogenesis has a great potential for large-scale propagation and cryopreservation of elite genotypes, as well as for transformation strategies. In the case of Q. suber, several in vitro propagation systems through somatic embryogenesis have been reported, with different efficiency rates.In the present chapter, updated information is reported about an efficient protocol for induction of somatic embryogenesis of Q. suber from immature zygotic embryos, as well as methods for proliferation and maturation of somatic embryos, germination, plantlet regeneration, and acclimatization. PMID- 29981127 TI - Cryotherapy: A Novel Method for Virus Eradication in Economically Important Plant Species. AB - Virus diseases have been a great threat to production of economically important crops. In practice, the use of virus-free planting material is an effective strategy to control viral diseases. Cryotherapy, developed based on cryopreservation, is a novel plant biotechnology tool for virus eradication. Comparing to the traditional meristem culture for virus elimination, cryotherapy resulted in high efficiency of pathogen eradication. In general, cryotherapy includes seven major steps: (1) introduction of infected plant materials into in vitro cultures, (2) shoot tip excision, (3) tolerance induction of explants to dehydration and subsequent freezing in liquid nitrogen (LN), (4) a short-time treatment of explants in LN, (5) warming and post-culture for regeneration, (6) re-establishment of regenerated plants in greenhouse conditions, and (7) virus indexing. PMID- 29981128 TI - Cryopreservation of Pineapple Shoot Tips by the Droplet Vitrification Technique. AB - Cryopreservation is a technique that allows the conservation of many species for long periods. Among the protocols used for cryopreservation, droplet vitrification has shown efficient results in preserving shoot tips of various wild and cultivated pineapple genotypes. The method consists of extraction of shoot tips from plants grown in vitro, dehydration for a period of 48 h in a preculture medium supplemented with a high concentration of sucrose, treatment in a plant vitrification solution (PVS2), and immersion in liquid nitrogen. The method described in this chapter has produced survival and regeneration indices of around 70%, depending on the genotype and physiological conditions of the initial explants. The objective of this chapter is to describe in detail a droplet vitrification protocol for shoot tips that is easy to perform for cryopreservation of pineapple germplasm. PMID- 29981129 TI - Cryopreservation of Pollen Grains of Pineapple and Other Bromeliads. AB - Cryopreservation of pollen grains is an efficient technique to overcome asynchronous flowering and to support actions for genetic improvement and conservation of important alleles. It can be used both by germplasm curators and plant breeders. In the case of Bromeliaceae, a family with wide diversity but also high vulnerability, the form of conservation can be crucial to prevent the increasing problem of genetic erosion. This chapter describes a method of cryopreservation of pollen grains of different Bromeliaceae species, including pineapple, after dehydration with silica and subsequent immersion in liquid nitrogen. The efficiency of this protocol has been demonstrated by the high pollen viability percentage and production of seeds after in vivo pollination with cryopreserved grains. The protocol can be used for cryopreserving pollen of many species of bromeliads and is easy to perform. PMID- 29981130 TI - Application of in Casa Pollination and Embryo Rescue Techniques for Breeding of Agave Species. AB - Species of the genus Agave are distributed originally in the tropical and subtropical areas of the American continent with about 200 taxa and 136 species, and its center of origin is probably limited to Mexico. These kind of plants usually grow and live in extreme environmental conditions such as heat and drought where their CAM pathway for fixing CO2 allow them to survive in conditions where other plants cannot survive. Although this kind of plants resist harsh environmental conditions, climate change is imposing stronger kinds of stress that diminish their productive potential and in some cases are cause of death. Because of this, genetic improvement becomes a need of fundamental importance in this kind of species. Despite their economic importance, Agave species have received scarce attention with regard to its genetic improvement, probably due to their unique botanical features such as plant architecture, spines, long life span, and monocarpy, among others, which make hybridization a difficult task for the intra- and interspecific gene transfer and creation of genetic variability among many other breeding techniques.The protocol here presented is a combination of a novel hybridization technique and biotechnological tools, and allows the use of several procedures for the genetic improvement of agaves such as pollen selection, clonal selection, and somatic cell selection, among others, since the rescued embryos can be used for micropropagation, for phenotype/genotype selection or the production of cell lineages for diverse genetic improvement purposes. PMID- 29981131 TI - Haploid and Doubled Haploid Plant Production in Carrot Using Induced Parthenogenesis and Ovule Excision In Vitro. AB - Haploid plants have a gametophytic number of chromosomes (n) in the sporophyte. A doubled haploid (DH) plant results from doubling the chromosome set of a haploid plant, as a consequence a homozygosity plant is produced at every locus (true homozygous plant). DH plants are of great significance in breeding programs for the improvement of plants. Here we describe a protocol for the production of doubled haploid plants in carrot (Daucus carota L.) using parthenogenesis induced by wide pollination. PMID- 29981132 TI - Using Flow Cytometry Analysis in Plant Tissue Culture Derived Plants. AB - Somaclonal variation (SC) in plants regenerated from tissue culture, via organogenesis or somatic embryogenesis, is frequently associated with abnormalities in the content of deoxyribonucleic acid (DNA), viz., aneuploidy and polyploidy. Flow cytometry (FCM) using the nucleic acid-specific fluorochrome propidium iodide has proven to be a rapid, simple, and reproducible technique for assessment of DNA content and ploidy variation occurring in plant tissue cultures. Here an outline of the sample preparation of suspension with intact nuclei by the two-step standard method, and FCM analysis of DNA ploidy stability in plants regenerated from embryogenic cell suspension (ECS) of banana Musa acuminata, AAA, cv. Grand Naine (Cavendish subgroup) using an internal standard is described. PMID- 29981133 TI - Procedure for Estimating the Tolerance and Accumulation of Heavy Metals Using Plant Cell Cultures. AB - The tolerance index (TI) and the bioaccumulation factor (BF) for the estimation of accumulation and tolerance of different heavy metals in cell suspension cultures are reviewed. Procedures for measuring these parameters are described for the purposes of phytoremediation research. PMID- 29981134 TI - Proteomics as a Tool to Study Molecular Changes During Plant Morphogenesis In Vitro. AB - Proteome analysis represents a promising approach for plant tissue culture since it is now possible to identify and quantify proteins on a large scale. Biomarker discovery and the study of the molecular events associated with in vitro plant morphogenesis are considered potential targets for application of proteomics technologies. This chapter describes a protocol for application in in vitro plant material using two proteomics approaches: 2-DE coupled to mass spectrometry and liquid chromatography-linked tandem mass spectrometry. PMID- 29981135 TI - Proteomic Analysis of Non-model Plant Tissues Using Phenol Extraction, Two Dimensional Electrophoresis, and MALDI Mass Spectrometry. AB - Separation of plant proteins by means of electrophoretic techniques is quite challenging since different compounds typical for plant cells can interfere and/or reduce the effectiveness of the protein isolation. This is particularly problematic for two-dimensional electrophoresis (2-DE). Therefore, it is important to optimize protein extraction and to establish a robust protocol for 2 DE and downstream processing, primarily mass spectrometry (MS) analysis. Here we give a detailed protocol for protein extraction using phenol method, 2-DE, and MALDI-MS analysis. PMID- 29981136 TI - Chromatin Immunoprecipitation (ChiP) Protocol for the Analysis of Gene Regulation by Histone Modifications in Agave angustifolia Haw. AB - Chromatin is a dynamic entity that regulates different biological processes crucial for the proper functioning of the cell. Chromatin regulation depends largely on the interactions that occur between DNA with histones and nonhistone proteins. The chromatin immunoprecipitation assay (ChiP) is a widely used technique for the study of these DNA-histone and DNA-nonhistone interactions and their biological repercussions. Here we describe a ChiP protocol that allows in vivo analysis of the associations of histone modifications with genomic DNA in Agave angustifolia Haw. Although this protocol is established for A. angustifolia, it can be used in other species to obtain similar results. We also propose a strategy to shorten the times in some steps of the standard protocol. PMID- 29981137 TI - Transcription Factors: Their Role in the Regulation of Somatic Embryogenesis in Theobroma cacao L. and Other Species. AB - Transcription factors are proteins that help with the control and regulation in the transcription of the DNA to mRNA by binding to special DNA sequences. With the aim to understand more about gene transcription regulation in Theobroma cacao L., this review outlines the principal transcription factors that were reported in other plants especially Arabidopsis thaliana and attempts at looking for the homologies with transcription factors in T. cacao. The information cited in this work is about the initiation, development, and maturation of the cacao somatic embryos and other crops. It is important to underline that there are very few publications in T. cacao discussing transcription factors that control the somatic embryogenesis process, but there is some information about transcription factors in other crops that we have used as a guide to try to understand this process. PMID- 29981138 TI - MicroRNA Expression and Regulation During Maize Somatic Embryogenesis. AB - MicroRNAs are tiny molecules that strikingly change their expression patterns and distribution during somatic embryogenesis induction and plant regeneration. It is of great relevance to analyze simultaneously the microRNA and target mRNA fates to understand their role in promoting an adequate embryogenic response to external stimulus in the regenerating tissues. Here we describe a method to evaluate the expression patterns of miRNAs or other sRNAs and their target regulation in distinctive tissues observed during maize plant regeneration. Key features of the method include the classification of regenerating plant material with reproducibly distinctive morphological characteristics and a purification procedure that renders high-quality small and large RNA separation from the same sample for qRT-PCR analysis. PMID- 29981139 TI - Elaboration of Transcriptome During the Induction of Somatic Embryogenesis. AB - Somatic embryogenesis (SE) is one of the most studied developmental processes due to its applications, such as plant micropropagation, transformation, and germplasm conservation. The use of massive techniques of sequencing, as well as the use of subtractive hybridization and macroarrays, has led to the identification of hundreds of genes involved in the SE process. These have been important developments to study the molecular aspects of the progress of SE. With the advent of the new massive techniques for sequencing RNA, it has been possible to see a more complete picture of whole processes. In this chapter we present a technique to handle the elaboration of the transcriptome from the extraction of RNA until the assembly of the complete transcriptome. PMID- 29981140 TI - Induction of Specialized Metabolism in In Vitro Cultures of Capsicum chinense Jacq. AB - A protocol for the elicitation of capsaicinoids, the pungent principle of peppers, as well as for the biosynthetic intermediaries vanillin and ferulic acid was developed for in vitro cell suspension cultures, and immobilized placentas of Capsicum chinense Jacq. in vitro cultures were exposed to different doses of methyl jasmonate and salicylic acid, which were effective in eliciting specialized metabolism in both of these cultures, resulting in an increased accumulation of the analyzed metabolites. PMID- 29981141 TI - Analysis of Terpenoid Indole Alkaloids, Carotenoids, Phytosterols, and NMR-Based Metabolomics for Catharanthus roseus Cell Suspension Cultures. AB - The plant Catharanthus roseus is a rich source of terpenoid indole alkaloids (TIA). Some of the TIA are important as antihypertensive (ajmalicine) and anticancer (vinblastine and vincristine) drugs. However, production of the latter is very low in the plant. Therefore, in vitro plant cell cultures have been considered as a potential supply of these chemicals or their precursors. Some monomeric alkaloids can be produced by plant cell cultures, but not on a level feasible for commercialization, despite extensive studies on this plant that deepened the understanding of the TIA biosynthesis and its regulation. In order to analyze the metabolites in C. roseus cell cultures, this chapter presents the method of TIA, carotenoids, and phytosterols analyses. Furthermore, an NMR-based metabolomics approach to study C. roseus cell culture is described. PMID- 29981142 TI - Transformed Root Culture: From Genetic Transformation to NMR-Based Metabolomics. AB - Hairy root (HR) culture is considered as "green factory" for mass production of bioactive molecules with pharmaceutical relevance. As such, HR culture has an immense potential as a valuable platform to elucidate biosynthetic pathways and physiological processes, generate recombinant therapeutic proteins, assist molecular breeding, and enhance phytoremediation efforts. However, some plant species appear recalcitrant to the classical Agrobacterium rhizogenes transformation techniques. Sonication-assisted Agrobacterium-mediated transformation (SAArT) is a highly effective method to deliver bacteria to target plant tissues that includes exposure of the explants to short periods of ultrasound in the presence of the bacteria.Nuclear magnetic resonance (NMR)-based metabolomics is one of the most powerful and suitable platforms for identifying and obtaining structural information on a wide range of compounds with a high analytical precision. In terms of plant science, NMR metabolomics is used to determine the phytochemical variations of medicinal plants or commercial cultivars in certain environments and conditions, including biotic stress and plant biotic interaction, structural determination of natural products, quality control of herbal drugs or dietary supplements, and comparison of metabolite differences between plants and their respective in vitro cultures.In this chapter, we attempt to summarize our knowledge and expertise in induction of hairy roots from rare and recalcitrant plant species by SAArT technique and further methodology for extraction of secondary metabolites of moderate to high polarity and their identification by using NMR-based metabolomics. PMID- 29981143 TI - Genetic Transformation of Pentalinon andrieuxii Tissue Cultures. AB - Pentalinon andrieuxii is a species used in Mayan traditional medicine due to its biological properties. Recent studies indicate that it produces a pentacyclic triterpene-denominated betulinic acid, which presents various biological activities: antibacterial, antifungal, antiplasmodial, anti-inflammatory, antimalarial, anticancer, leishmanicidal, and antiviral, as well as steroids and sterols with leishmanicidal properties. A recent study also reported the presence of urechitol A and B in the roots; these are secondary metabolites whose biochemical function is as yet unknown. This plant therefore represents a natural source of metabolites with potential application in the pharmaceutical industry. In this chapter, a protocol is described for obtaining transgenic plants, at the reporter gene of the beta-glucuronidase (GUS) via Agrobacterium tumefaciens from hypocotyl and root explants. The protocol established herein could be employed for the manipulation of the genes involved in the biosynthesis of isoprenoids or secondary metabolites of interest. To our knowledge, this is the first report of stable transformation of Pentalinon andrieuxii via Agrobacterium tumefaciens. PMID- 29981144 TI - Seroprevalence of hepatitis C virus among the newcomer students, Kafrelsheikh University, Egypt. AB - BACKGROUND: Hepatitis C virus (HCV) constitutes a global public health problem in Egypt, as it has the highest worldwide prevalence. This study aimed at determining the seroprevalence of HCV among the newcomer students of Kafrelsheikh University, Egypt. METHODS: A cross-sectional serosurvey was conducted including 9049 students. Medical examination, ultrasonography, and laboratory investigations were done. Liver function tests and HCV antibody testing were carried out for all students who gave an informed consent; HCV-RNA polymerase chain reaction was performed for students with positive HCV antibody testing. RESULTS: The mean age of screened students were 18.6 +/- 0.39 years. In total, 4233 (46.8%) were males and 4816 (53.2%) were females. Using HCV antibody testing, only 25 students (0.0028%) had positive antibodies; among them, 24 students (0.0026%) had HCV RNA positive; the study showed none statistically significant higher percentage of HCV infection among males (13 out of 24, 54.2%) than females (11 out of 24, 48.5%), P > 0.05. The results of liver function tests were not significantly different between the HCV-positive and HCV-negative students. However, the liver transaminase enzymes were significantly higher ( P < 0.0001) in HCV positive students compared to the negative ones, despite its mean values did not exceed the upper normal level. HCV infection among young Egyptian generations showed a marked decline. CONCLUSION: Prevalence of HCV infection among young Egyptian generations had markedly decline, indicating the start of successful control of HCV infection. PMID- 29981145 TI - Aneuploidy: Cancer strength or vulnerability? AB - Aneuploidy is a very rare and tissue-specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age-related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell-like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy-tolerating mechanisms as cancer vulnerability. PMID- 29981146 TI - Routine blood tests during pregnancy for predicting future increases in risk of cardiovascular morbidity. AB - OBJECTIVE: To examine the association between routine blood tests during pregnancy and future risk of cardiovascular morbidity. METHODS: The present case control study was conducted among women who delivered at a teaching hospital in Israel between January 1, 2000, and December 31, 2012. The cohort comprised women who were subsequently hospitalized owing to cardiovascular morbidity (case group) and age-matched non-hospitalized women (control group). Blood levels of creatinine, glucose, potassium, urea, and uric acid were measured during pregnancy. Only women with at least one test result available for all five measurements were included. The relationship between upper quartile blood test values and cardiovascular hospitalization was assessed. RESULTS: The study included 4115 women (212 in the case group and 3903 in the control group). Three measures were associated with a future risk of cardiovascular morbidity requiring hospitalization: creatinine (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.37-2.53; P<0.001); potassium (HR 1.48, 95% CI 1.09-2.01; P=0.013), and urea (HR 1.60, 95% CI 1.17-2.19; P=0.003). The number of blood test results in the upper quartile also increased such risk. The HRs for two tests and at least three tests were 1.65 (95% CI 1.06-2.56; P=0.026) and 3.32 (95% CI 2.19-5.04; P<0.001), respectively. CONCLUSIONS: Future cardiovascular morbidity was predicted by routine blood tests during pregnancy. PMID- 29981147 TI - Maize lateral root developmental plasticity induced by mild water stress. I: Genotypic variation across a high-resolution series of water potentials. AB - Lateral root developmental plasticity induced by mild water stress was examined across a high-resolution series of growth media water potentials (Psiw ) in two genotypes of maize. The suitability of several media for imposing near-stable Psiw treatments on transpiring plants over prolonged growth periods was assessed. Genotypic differences specific to responses of lateral root growth from the primary root system occurred between cultivars FR697 and B73 over a narrow series of water stress treatments ranging in Psiw from -0.25 to -0.40 MPa. In FR697, both the average length and number of first-order lateral roots were substantially enhanced at a Psiw of -0.25 MPa compared with well-watered controls. These effects were separated spatially, occurring primarily in the upper and lower regions of the axial root, respectively. Furthermore, first-order lateral roots progressively increased in diameter with increasing water stress, resulting in a maximum 2.3-fold increase in root volume at a Psiw of -0.40 MPa. In B73, in contrast, the length, diameter, nor number of lateral roots was increased in any of the water stress treatments. The genotype-specific responses observed over this narrow range of Psiw demonstrate the necessity of high resolution studies at mild stress levels for characterization of lateral root developmental plasticity. PMID- 29981148 TI - Is Proflavine Exposure Associated with Disease Progression in Women with Cervical Dysplasia? A Brief Report. AB - Proflavine is an acridine dye used with high-resolution microendoscopy for in vivo diagnostic evaluation of cervical epithelial cells. However, there are concerns that even short-term exposure of cervical tissue to dilute proflavine may increase cervical cancer risk. We performed a retrospective analysis of women referred for colposcopy to Barretos Cancer Hospital comparing the risk of cervical disease progression in those whose cervical tissue was (n = 232) or was not exposed (n = 160) to proflavine. Patients in both groups underwent treatment and follow-up based on histopathologic results and per the local standards of care. Progression of disease was evaluated by comparing histopathology from the initial visit to the worst subsequent histopathology result from all follow-up visits. Mean duration of follow-up was 18.7 and 20.1 months for the proflavine exposed and controls groups, respectively. There were no significant differences in disease progression from normal/CIN1 to CIN2/3 or from any initial diagnosis to invasive cancer between the proflavine exposed and control groups overall. Risks of cervical dysplasia progression observed in this study are in agreement with those of the natural history of cervical cancer. Our results suggest that cervical exposure to dilute proflavine does not increase the risk of cervical precancer and cancer. PMID- 29981149 TI - Survival from childhood cancers in Eastern Africa: A population-based registry study. AB - Cancers occurring in children in Africa are often underdiagnosed, or at best diagnosed late. As a result, survival is poor, even for cancers considered 'curable'. With limited population-level data, understanding the actual burden and survival from childhood cancers in Africa is difficult. In this study, we aimed at providing survival estimates for the most common types of cancers affecting children aged 0-14 years, in three population-based Eastern African registries; Harare, Zimbabwe (Kaposi sarcoma, Wilms tumour (WT), non-Hodgkin lymphoma (NHL), retinoblastoma, and acute lymphocytic leukaemia (ALL)), Kampala, Uganda (Burkitt lymphoma, Kaposi sarcoma, WT, and retinoblastoma), and Nairobi, Kenya (ALL, retinoblastoma, WT, Burkitt lymphoma, and Hodgkin lymphoma). We included cases diagnosed within the years 1998-2009 and followed up till the end of 2011. We estimated the observed and relative survival at 1, 3, and 5 years after diagnosis. We studied 627 individual patient records. Median follow-up ranged from 2.2 months for children with Kaposi sarcoma in Harare to 30.2 months for children with ALL in Nairobi. The proportion of children lost to follow-up was highest in the first year after diagnosis. In Harare and Kampala, the 5-year relative survival was <46% for all cancer types. The 5-year relative survival was best for children in Nairobi, though with wider confidence intervals. Survival from childhood cancers in Africa is still poor, even for cancers with good prognosis and potential for cure. Supporting cancer detection, treatment, and registration activities could help improve survival chances for children with cancers in Africa. PMID- 29981150 TI - The Mechanism of CIRP in Regulation of STAT3 Phosphorylation and Bag-1/S Expression Upon UVB Radiation. AB - Cold-inducible RNA binding protein (CIRP) is a stress-inducible protein, which could be activated by various cellular stresses, such as hypothermia, hypoxia and UV irradiation. Our previous study indicated that UVB radiation (3 mJ cm-2 ) induces CIRP expression, which promotes keratinocytes growth, survival and eventually transformation via activation of STAT3-Bag-1/S signaling cascade. However, the mechanism(s) of CIRP in regulating p-STAT3 activation and Bag-1/S expression have not been fully elucidated. In this study, we demonstrate that repeated exposure of UVB radiation (3 mJ cm-2 ) or overexpression of CIRP could lead to an elevation of the phosphorylation of Janus kinase (JAK) family proteins (JAK2 and JAK3) in HaCaT cells. The increased phosphorylation of the JAKs correlates to an increased phosphorylation of STAT3 (p-STAT3) in the cells; inhibiting JAKs using JAK inhibitor I lead to a reduction of STAT3 phosphorylation and Bag-1/S expression in wild type HaCaT and CIRP stably transfected HaCaT cells with or without UVB exposure. Furthermore, our data indicated that inhibiting the downstream factor of CIRP, NF-kappaB, using BAY 11 7085 could also decrease the p-STAT3. These results lead us to propose that CIRP mediates the activation of STAT3-Bag-1/S signaling cascade via activating the JAKs and NF-kappaB signaling pathways. PMID- 29981152 TI - Double Effect Electron Transfer System in the AgBr/ZnO Composite with Enhanced Photocatalytic Degradation Performance against 3-Chlorophenol under Visible Light Irradiation. AB - Visible light-driven novel and highly efficient AgBr/ZnO photocatalysts were synthesized by a facile precipitation and dehydration methods. The synthesized samples were characterized using scanning electron microscope (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), UV-Visible diffuse reflectance spectroscopy (UV-Vis DRS), and photoluminescence (PL) techniques. Within various combinations of AgBr and ZnO components in the composites, 1AgBr/ZnO showed higher photocatalytic activity against 3-chlorophenol (3-CP). UV Vis DRS spectra showed that the absorbance of AgBr/ZnO was higher than pure ZnO in the visible light region. The PL results showed that efficient inhibition of the generated electron/hole pairs has occurred during the degradation process due to the formation of heterojunctions. The forming of metallic Ag0 by photogenerated electrons, which captures Ag+ ions, could act as an interfacial charge transmission bridge in the AgBr/ZnO composite. These results provided an important insight into the plasmonic Ag particles to obtain an efficient visible light-driven photocatalyst. In addition, the possible mechanism of charge transfers and separation of electron/hole pairs were also evaluated in detail. PMID- 29981151 TI - Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective. AB - Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy.Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs; further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches. Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug-drug interactions (DDIs).5,6. PMID- 29981153 TI - Wheat leaves embolized by water stress do not recover function upon rewatering. AB - New techniques now make it possible to precisely and accurately determine the failure threshold of the plant vascular system during water stress. This creates an opportunity to understand the vulnerability of species to drought, but first, it must be determined whether damage to leaf function associated with xylem cavitation is reparable or permanent. This question is particularly relevant in crop plants such as wheat, which may have the capacity to repair xylem embolism with positive root pressure. Using wheat (Triticum aestivum, Heron), we employed non-invasive imaging to find the water potential causing 50% xylem embolism ( 2.87 +/- 0.52 MPa) in leaves. Replicate plants were water-stressed to varying degrees to induce embolism ranging from minimal to substantial. Plants were then rewatered to determine the reversibility of xylem damage and photosynthetic inhibition in glasshouse conditions. Rewatering after drought-induced xylem cavitation did not induce visible refilling of embolized xylem, and embolized leaves showed photosynthetic impairment upon rewatering. This impairment was significant even after only 10-20% of leaf veins were embolized, and leaves accumulating >20% embolism died upon rewatering in 7/10 individuals. Photosynthetic damage and hydraulic decline occurred concurrently as wheat leaves dehydrated, and leaf shrinkage during drying was the best predictor of photosynthetic recovery. PMID- 29981154 TI - Comparative genomics of Vibrio cholerae O1 isolated from cholera patients in Bangladesh. AB - : Whole genome sequencing was utilized to investigate the genomic profile of Vibrio cholerae O1 strains, isolated from symptomatic patients in a low-income urban area of Dhaka, Bangladesh. Comparative genomics using bioinformatics tools were applied to identify major virulence factors, biotype and antimicrobial resistance genes in three V. cholerae O1 strains (VC-1, 2 and 3) isolated from two case patients. A phylogenetic SNP (single nucleotide polymorphism)-based analysis was conducted to infer the relatedness to V. cholerae O1 strains isolated elsewhere. The V. cholerae strains were the El Tor variant carrying ctxB1 (standard classical genotype). SNP-based global phylogeny revealed that the three isolates were strictly clonal and the closest neighbouring genomes were epidemic clones of V. cholerae O1 isolated in 2010 from cholera patients in Pakistan. All strains harboured the integrase gene of the SXT element (intSXT ), antimicrobial resistance genes for aminoglycosides, phenicol, sulphonamide and trimethoprim except VC-1 that lacked sulphonamide resistance genes. The multilocus sequence typing (MLST) revealed that the strains belonged to sequence type, ST69. The study provides knowledge on current genetic traits of clinical V. cholerae O1 circulating in urban household clusters of Bangladesh which may help in predicting emergence of new pandemic strains in Bangladesh. SIGNIFICANCE AND IMPACT OF THE STUDY: Vibrio cholerae has frequently experienced genetic changes with rapid evolution of pandemic clones in the Ganges Delta region. Whole genome sequencing can reveal genetic information of current pathogenic V. cholerae in Bangladesh which includes cefotaxime genotypes, virulence factors, altered antimicrobial resistance pattern as well as mobile genetic element compared to global pandemic strains. This study data could be used in planning future surveillance strategies in Ganges Delta region by informing new epidemiology of current outbreak strains. PMID- 29981155 TI - Dual TGF-beta and PD-1 blockade synergistically enhances MAGE-A3-specific CD8+ T cell response in esophageal squamous cell carcinoma. AB - PD-1 is highly expressed on tumor-infiltrated antigen-specific T cells and limit the antitumor function. Blocking of PD-1/PD-L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE-A3-specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE-A3-specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE-A3-specific CD8+ T cells could lyse HLA-A2+ /MAGE-A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD-1 was highly expressed on dysfunctional antigen-specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid-derived suppressor cells (MDSCs) derived-TGF-beta mediated PD-1high expression on CD8+ T cells, which led to be resistance to PD 1/PD-L1 blockade in TME. Dual PD-1/PD-L1 and TGF-beta signaling pathway blockades synergistically restored the function and antitumor ability of antigen-specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE-A3-specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs-derived TGF-beta increased PD-1 expression on T cells and decreased the sensitivity to PD-1/PD-L1 blockade. Combining T cell-based therapy with dual PD-1/PD-L1 and TGF-beta signaling pathway blockade could be considered a promising strategy for cancer treatment. PMID- 29981156 TI - Trousseau's syndrome triggered by an immune checkpoint blockade in a non-small cell lung cancer patient. AB - PD-1 blockade therapy activates T cells by blocking the interaction between PD-1 and PD-L1 and promotes IFN-gamma and Th1 cytokine production. In turn, IFN-gamma and Th1 cytokines produced by activated T cells promote TF synthesis in monocytes/macrophages, which results in hypercoagulability leading to thrombosis. PMID- 29981157 TI - Exploring drivers of litter decomposition in a greening Arctic: results from a transplant experiment across a treeline. AB - Decomposition of plant litter is a key control over carbon (C) storage in the soil. The biochemistry of the litter being produced, the environment in which the decomposition is taking place, and the community composition and metabolism of the decomposer organisms exert a combined influence over decomposition rates. As deciduous shrubs and trees are expanding into tundra ecosystems as a result of regional climate warming, this change in vegetation represents a change in litter input to tundra soils and a change in the environment in which litter decomposes. To test the importance of litter biochemistry and environment in determining litter mass loss, we reciprocally transplanted litter between heath (Empetrum nigrum), shrub (Betula nana), and forest (Betula pubescens) at a sub-Arctic treeline in Sweden. As expansion of shrubs and trees promotes deeper snow, we also used a snow fence experiment in a tundra heath environment to understand the importance of snow depth, relative to other factors, in the decomposition of litter. Our results show that B. pubescens and B. nana leaf litter decomposed at faster rates than E. nigrum litter across all environments, while all litter species decomposed at faster rates in the forest and shrub environments than in the tundra heath. The effect of increased snow on decomposition was minimal, leading us to conclude that microbial activity over summer in the productive forest and shrub vegetation is driving increased mass loss compared to the heath. Using B. pubescens and E. nigrum litter, we demonstrate that degradation of carbohydrate-C is a significant driver of mass loss in the forest. This pathway was less prominent in the heath, which is consistent with observations that tundra soils typically have high concentrations of "labile" C. This experiment suggests that further expansion of shrubs and trees may stimulate the loss of undecomposed carbohydrate C in the tundra. PMID- 29981158 TI - Electronic Structure and Triplet-Triplet Energy Transfer in Artificial Photosynthetic Antennas. AB - Three Pd(II) phthalocyanine-carotenoid dyads featuring chromophores linked by amide bonds were prepared in order to investigate the rate of triplet-triplet (T T) energy transfer from the tetrapyrrole to the covalently attached carotenoid as a function of the number of conjugated double bonds in the carotenoid. Carotenoids having 9, 10 and 11 conjugated double bonds were studied. Transient absorption measurements show that intersystem crossing in the Pd(II) phthalocyanine takes place in 10 ps in each case and that T-T energy transfer occurs in 126, 81 and 132 ps in the dyads bearing 9, 10 and 11 double bond carotenoids, respectively. To identify the origin of this variation in T-T energy transfer rates, density functional theory (DFT) was used to calculate the T-T electronic coupling in the three dyads. According to the calculations, the primary reason for the observed T-T energy transfer trend is larger T-T electronic coupling between the tetrapyrrole and the 10-double bond carotenoid. A methyl group adjacent to the amide linker that connects the Pd(II) phthalocyanine and the carotenoid in the 9 and 11-double bond carotenoids is absent in the 10 double bond carotenoid, and this difference alters its electronic structure to increase the coupling. PMID- 29981159 TI - Photophysics of Xanthene Dyes at High Concentrations in Solid Environments: Charge Transfer Assisted Triplet Formation. AB - The photophysical behavior of two xanthene dyes, Eosin Y and Phloxine B, included in microcrystalline cellulose particles is studied in a wide concentration range, with emphasis on the effect of dye concentration on fluorescence and triplet quantum yields. Absolute fluorescence quantum yields in the solid-state were determined by means of diffuse reflectance and steady-state fluorescence measurements, whereas absolute triplet quantum yields were obtained by laser induced optoacoustic spectroscopy and their dependence on dye concentration was confirmed by diffuse reflectance laser flash photolysis and time-resolved phosphorescence measurements. When both quantum yields are corrected for reabsorption and reemission of radiation, PhiF values decrease strongly on increasing dye concentration, while a less pronounced decay is observed for PhiT . Fluorescence concentration quenching is attributed to the formation of dye aggregates or virtual traps resulting from molecular crowding. Dimeric traps are however able to generate triplet states. A mechanism based on the intermediacy of charge-transfer states is proposed and discussed. Calculation of parameters for photoinduced electron transfer between dye molecules within the traps evidences the feasibility of the proposed mechanism. Results demonstrate that photoactive energy traps, capable of yielding dye triplet states, can be formed even in highly-concentrated systems with random dye distributions. PMID- 29981160 TI - A prognostic model for the patient-reported outcome of surgical treatment of carpal tunnel syndrome. AB - INTRODUCTION: Many prognostic factors have been studied in carpal tunnel decompression, but most studies consider only a subset of variables. METHODS: Three thousand three hundred thirty-two operations were used to develop prognostic models, and 885 operations were used for validation. Outcome recorded on a Likert scale was dichotomized into success or failure. Modeling was performed with both logistic regression and artificial neural networks using 87 candidate variables. RESULTS: Both approaches produced predictive multivariate models for outcome with areas under a receiver operating characteristic curve of 0.7 in the validation data set. Patients with moderately severe nerve conduction abnormalities, night waking, a family history of carpal tunnel syndrome, a good response to corticosteroid injection, and women have better outcomes. Greater functional impairment, diabetes, hypertension, and surgery on the dominant hand are associated with poorer outcomes. DISCUSSION: A multivariate model partially predicts the outcome of carpal tunnel surgery, aids decision making, and helps to manage patient expectations. Muscle Nerve, 2018. PMID- 29981161 TI - Targeting toll-like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension? AB - The immune system plays a prominent role in the initiation and maintenance of hypertension. The innate immune system, via toll-like receptors (TLRs), identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream signalling cascades, leading to secretion of pro-inflammatory cytokines and shaping the adaptive immune response. Over the past decade, a dysfunctional TLR-mediated response, particularly via TLR4, has been suggested to support a chronic inflammatory state in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression. While the underlying mechanisms triggering TLR4 need further research, evidence suggests that sustained elevations in BP disrupt homeostasis, releasing endogenous TLR4 ligands in hypertension. In this review, we discuss the emerging role of TLR4 in the pathogenesis of hypertension and whether targeting this receptor and its signalling pathways could offer a therapeutic strategy for management of this multifaceted disease. PMID- 29981162 TI - Shared social mechanisms underlying the risk of nine cancers: A life course study. AB - Identifying life periods during which social conditions have the highest impact on risk of common cancers in a population may help to reveal their underlying shared social mechanisms. We used the life course framework to estimate the extent to which life course SEP is associated with risk of nine cancers. In addition, we tested whether these associations conform to a critical period or cumulative life course model. Data were from a population-based case-control study of occupational exposures and cancer conducted in Montreal, Canada. Participants were males aged 35-70 years (n = 2,547) residing in the Montreal metropolitan area with primary, histologically confirmed cancers diagnosed between 1979 and 1985. Population controls (n = 512) were sampled from electoral lists. SEP was measured at three different periods of life based on respondent's report: during childhood, young adulthood and mid-life. We used a structured modeling approach using a series of unconditional logistic regressions to test which models best fit the data. Life course SEP increased the risk of all cancers. SEP in childhood was identified as a critical period for prostate and all gastrointestinal tract cancers except for esophagus cancer. In addition, the accumulation model best explained the data for melanoma and lung squamous cell carcinoma. Our findings suggest that childhood social circumstances are a common risk factor for several cancers among men; our results provide insights into the mechanisms involved in the etiology of nine cancers. PMID- 29981163 TI - A Nationwide Cohort Study on the risk of non-gynecological cancers in women with surgically verified endometriosis. AB - We assessed the association of surgically verified endometriosis and risk of non gynecological cancers according to the type of endometriosis (i.e., ovarian, peritoneal and deep infiltrating endometriosis). All diagnoses of endometriosis combined with relevant procedural codes were identified from the Finnish Hospital Discharge Register 1987-2012. Non-gynecological cancers diagnosed after the endometriosis diagnosis were obtained from the Finnish Cancer Registry. The cohort of 49,933 women with surgically verified endometriosis and the sub-cohorts of ovarian (n = 23,210), peritoneal (n = 20,187), and deep infiltrating (n = 2,372) endometriosis were analyzed separately. The endometriosis cohort contributed 838,685 person-years of follow-up and the Finnish female population served as the reference cohort. The standardized incidence ratio (SIR) and 95% confidence interval (95%CI) was calculated for each cancer separately. The follow up ended at emigration, death or on the 31st of December 2014. The non gynecological cancer risk was not increased among women with endometriosis (SIR 1.03, 95%CI 0.98-1.08). Endometriosis was associated with an increased risk of thyroid cancer in the entire cohort (SIR 1.43, 95%CI 1.23-1.64) and in the sub cohorts of ovarian and peritoneal endometriosis. We found a decreased risk of mouth and pharynx cancer (SIR 0.60, 95%CI 0.41-0.80), and of pancreatic cancer (SIR 0.76, 95%CI 0.58-0.96). The incidence of basal cell carcinoma was elevated in the entire cohort (SIR 1.18, 95%CI 1.10-1.25) and in the sub-cohorts of ovarian and peritoneal endometriosis. In conclusion, women with surgically verified endometriosis have an altered risk of only few non-gynecological cancers. PMID- 29981164 TI - Ketorolac for postoperative pain in children. AB - BACKGROUND: Children who undergo surgical procedures in ambulatory and inpatient settings are at risk of experiencing acute pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce moderate to severe pain without many of the side effects associated with opioids. However, NSAIDs may cause bleeding, renal and gastrointestinal toxicity, and potentially delay wound and bone healing. Intravenous administration of ketorolac for postoperative pain in children has not been approved in many countries, but is routinely administered in clinical practise. OBJECTIVES: To assess the efficacy and safety of ketorolac for postoperative pain in children. SEARCH METHODS: We searched the following databases, without language restrictions, to November 2017: CENTRAL (The Cochrane Library 2017, Issue 10); MEDLINE, Embase, and LILACS. We also checked clinical trials registers and reference lists of reviews, and retrieved articles for additional studies. SELECTION CRITERIA: We included randomised controlled trials that compared the analgesic efficacy of ketorolac (in any dose, administered via any route) with placebo or another active treatment, in treating postoperative pain in participants zero to 18 years of age following any type of surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We analyzed trials in two groups; ketorolac versus placebo, and ketorolac versus opioid. However, we performed limited pooled analyses. We assessed the overall quality of the evidence for each outcome using GRADE, and created a 'Summary of findings' table. MAIN RESULTS: We included 13 studies, involving 920 randomised participants. There was considerable heterogeneity among study designs, including the comparator arms (placebo, opioid, another NSAID, or a different regimen of ketorolac), dosing regimens (routes and timing of administration, single versus multiple dose), outcome assessment methods, and types of surgery. Mean study population ages ranged from 356 days to 13.9 years. The majority of studies chose a dose of either 0.5 mg/kg (as a single or multiple dose regimen) or 1 mg/kg (single dose with 0.5 mg/kg for any subsequent doses). One study administered interventions intraoperatively; the remainder administered interventions postoperatively, often after the participant reported moderate to severe pain.There were insufficient data to perform meta-analysis for either of our primary outcomes: participants with at least 50% pain relief; or mean postoperative pain intensity. Four studies individually reported statistically significant reductions in pain intensity when comparing ketorolac with placebo, but the studies were small and had various risks of bias, primarily due to incomplete outcome data and small sample sizes.We found limited data available for the secondary outcomes of participants requiring rescue medication and opioid consumption. For the former, we saw no clear difference between ketorolac and placebo; 74 of 135 (55%) participants receiving ketorolac required rescue analgesia in the post-anaesthesia care unit (PACU) versus 81 of 127 (64%) receiving placebo (relative risk (RR) 0.85, 95% confidence interval (CI) 0.71 to 1.00, P = 0.05; 4 studies, 262 participants). For opioid consumption in the PACU, we saw no clear difference between ketorolac and placebo (P = 0.61). For the time period zero to four hours after administration of the interventions, participants receiving ketorolac received 1.58 mg less intravenous morphine equivalents than those receiving placebo (95% CI -2.58 mg to -0.57 mg, P = 0.002; 2 studies, 129 participants). However, we are uncertain whether ketorolac has an important effect on opioid consumption, as the data were sparse and the results were inconsistent. Only one study reported data for opioid consumption when comparing ketorolac with an opioid. There were no clear differences between the ketorolac and opioid group at any time point. There were no data assessing this outcome for the comparison of ketorolac with another NSAID.There were insufficient data to allow us to analyze overall adverse event or serious adverse event rates. Although the majority of serious adverse events reported in those receiving ketorolac involved bleeding, the number of events was too low to conclude that bleeding risk was increased in those receiving ketorolac perioperatively. There was not a statistically significant increase in event rates for any specific adverse event, either in pooled analysis or in single studies, when comparing ketorolac and placebo. When comparing ketorolac with opioids or other NSAIDs, there were too few data to make any conclusions regarding event rates. Lastly, withdrawals due to adverse events were vary rare in all groups, reflecting the acute nature of such studies.We assessed the quality of evidence for all outcomes for each comparison (placebo or active) as very low, due to issues with risk of bias in individual studies, imprecision, heterogeneity between studies, and low overall numbers of participants and events. AUTHORS' CONCLUSIONS: Due to the lack of data for our primary outcomes, and the very low-quality evidence for secondary outcomes, the efficacy and safety of ketorolac in treating postoperative pain in children were both uncertain. The evidence was insufficient to support or reject its use. PMID- 29981165 TI - Prevalence of C-C chemokine receptor type 5 tropism among human immunodeficiency virus 1-infected patients in South Korea. AB - OBJECTIVE: The discovery of two main coreceptors for human immunodeficiency virus (HIV), C-C chemokine receptor type 5 (CCR5), and C-X-C chemokine receptor type 4 has led to a better understanding of the interaction between HIV envelope and host cells, and development of new therapeutic approaches. The purpose of this study was to estimate the prevalence of CCR5 tropism among HIV-1-infected Koreans and identify the predictors for CCR5 tropism. METHODS: We enrolled 250 HIV-1 infected subjects from four medical centers of three different cities in South Korea between April 2013 and May 2014. Genotypic assay for identifying coreceptor tropism of HIV-1 was performed with HIV RNA or HIV DNA. Nested polymerase chain reaction and population-based sequencing for the V3 region (HXB2 position 6225 7758) of the envelope were performed with HIV RNA or proviral DNA. Proviral DNA was used if the viral load of the subject was below 2000 copies/mL. Genotypic tropism was determined by a web-based bioinformatics tool (http://coreceptor.bioinf.mpi-inf.mpg.de/). RESULTS: Among 250 individuals enrolled, only 143 subjects could be analyzed for genotypic tropism assay with HIV RNA or proviral DNA. The prevalence of CCR5 tropism was 69.2% (N = 99). We could not identify any significant clinical or epidemiological predictors for CCR5 tropism among enrolled subjects. CONCLUSIONS: The prevalence of CCR5 tropism in HIV-1-infected Korean individuals was 69.2%. Since we cannot predict coreceptor tropism by clinical factors, tropism assay should be performed before treatment with the CCR5 antagonist. PMID- 29981166 TI - The Saudi Arabian 2030 vision and the nursing profession: the way forward. AB - AIM: To examine the outlook of the Saudi Arabian nursing profession in relation to the recently launched Kingdom 2030 Vision. INTRODUCTION: Nursing in Saudi Arabia has advanced noticeably in education and clinical practice, but challenges remain in building and sustaining a Saudi nursing profession and workforce. BACKGROUND: Health care in Saudi Arabia is currently experiencing transformation because of population and economic growth. These transformations have been influenced by the Saudi Arabian 2030 Vision. SOURCES OF EVIDENCE: A literature review here examines the progress in transforming the nursing profession in Saudi Arabia. Relevant studies published between 2001 and 2017 were identified, using databases such as Medline, PubMed and PsychInfo. RESULTS: Nineteen studies reporting challenges and opportunities that the nursing profession faces in Saudi Arabia were included. DISCUSSION: The nursing profession in Saudi Arabia faces challenges from nursing shortages, underdeveloped nursing education and unclear scope of practice. However, the new 2030 Vision offers many opportunities for social and economic transformation. CONCLUSION: Effective strategies must be implemented to accommodate the new outlook the 2030 Saudi Vision in order to advance the nursing profession and to improve healthcare delivery in Saudi Arabia. IMPLICATIONS FOR NURSING AND NURSING POLICY: Nursing policymakers urgently need to improve nursing care in Saudi Arabia by addressing the nursing shortage, generating strategies to improve nursing education and establishing scope of practice guidelines. These critical issues must be addressed with the context of the 2030 Vision. PMID- 29981167 TI - Modification of alpha2,6-sialylation mediates the invasiveness and tumorigenicity of non-small cell lung cancer cells in vitro and in vivo via Notch1/Hes1/MMPs pathway. AB - The alterations of sialylation on cell surface N-glycans due to overexpression of different sialyltransferases play a vital role in tumorigenesis and tumor progression. The beta-galactoside alpha2-6-sialyltransferase 1 (ST6Gal-I) has been reported to be highly expressed in several cancers, including breast cancer, hepatocellular cancer and colon carcinoma. However, the roles and underlying mechanisms of ST6Gal-I in non-small cell lung cancer (NSCLC) still need to be elucidated. In this study, we determined that mRNA levels of ST3GAL1, ST6GALNAC3 and ST8SIA6 were remarkably reduced in lung cancer tissues and cells, whereas ST6GAL1 level significantly increased. The mRNA, protein and glycan levels of ST6Gal-I were higher in lung cancer tissues and cells. Moreover, down-regulation of ST6Gal-I decreased protein levels of Jagged1, DLL-1, Notch1, Hes1, Hey1, matrix-metalloproteinases (MMPs) and VEGF, and suppressed proliferation, migration and invasion capabilities of A549 and H1299 cells in vitro. In vivo, ST6Gal-I silencing suppressed tumorigenicity of NSCLC cells in athymic nude mice via the Notch1/Hes1/MMPs pathway. In addition, overexpression of Notch1 rescued the reduced growth and metastasis of A549 and H1299 cells resulted by ST6Gal-I silencing. Modification of alpha2,6-sialylation positively associates with lung cancer progression, thereby indicating that ST6Gal-I may mediate the invasiveness and tumorigenicity of NSCLC cells via the Notch1/Hes1/MMPs pathway both in vitro and in vivo. Thus, our results provide a novel therapeutic approach for blocking metastasis in lung cancer patients. PMID- 29981169 TI - Molecular epidemiology of coxsackievirus A6 derived from hand, foot, and mouth disease in Fukuoka between 2013 and 2017. AB - Coxsackievirus (CV)-A6 has been the primary causative agent of hand, foot, and mouth disease (HFMD) in Japan since 2011. In Fukuoka, CV-A6-associated HFMD caused epidemics in 2013, 2015, and 2017. This paper reports the genetic characteristics of the CV-A6 entire viral protein 1 (VP1) derived from patients with HFMD in Fukuoka between 2013 and 2017. CV-A6 was detected in 105 of 280 clinical specimens, and the entire VP1 sequences could be analyzed for 90 of the 105 specimens. Phylogenetic analysis revealed that the CV-A6 strains were classified into clade A and subgrouped into subclade A3 or subclade A4. Each subclade strain carried amino acid substitutions in the presumed DE and GH loops of the VP1, and no amino acid substitutions were identified as deleterious to the protein function. No significant difference was found in the clinical symptoms between the genetic subclades using statistical analyses. In conclusion, this study clarified the genetic diversity of CV-A6 in Fukuoka from 2013 to 2017. The emergence of the CV-A6 strains was classified into derived new subclades based on phylogenetic analysis of the VP1 gene that may cause CV-A6-associated HFMD epidemics approximately every 2 years. PMID- 29981168 TI - Potential effect modifiers of the arsenic-bladder cancer risk relationship. AB - Populations exposed to arsenic in drinking water have an increased bladder cancer risk and evidence suggests that several factors may modify arsenic metabolism, influencing disease risk. We evaluated whether the association between cumulative lifetime arsenic exposure from drinking water and bladder cancer risk was modified by factors that may impact arsenic metabolism in a population-based case control study of 1,213 cases and 1,418 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between cumulative arsenic intake and bladder cancer stratified by age, sex, smoking status, body mass index (BMI), alcohol consumption and folate intake. P-values for interaction were computed using a likelihood ratio test. We observed no statistically significant multiplicative interactions although some variations in associations were notable across risk factors, particularly for smoking and BMI. Among former smokers and current smokers, those with the highest cumulative arsenic intake had elevated risks of bladder cancer (OR = 1.4, 95% CI: 0.96-2.0 and OR = 1.6, 95% CI: 0.91-3.0, respectively; while the OR among never smokers was 1.1, 95% CI: 0.6-1.9, p interaction = 0.49). Among those classified as normal or overweight based on usual adult BMI, the highest level of cumulative arsenic intake was associated with elevated risks of bladder cancer (OR = 1.3, 95% CI: 0.89-2.0 and OR = 1.6, 95% CI: 1.1-2.4, respectively), while risk was not elevated among those who were obese (OR = 0.9, 95% CI: 0.4-1.8) (p-interaction = 0.14). Our study provides some limited evidence of modifying roles of age, sex, smoking, BMI, folate and alcohol on arsenic-related bladder cancer risk that requires confirmation in other, larger studies. PMID- 29981170 TI - Nanoparticle-based photothermal and photodynamic immunotherapy for tumor treatment. AB - Nanoparticle-based phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), exhibit strong efficacy, minimal invasion and negligible side effects in tumor treatment. These phototherapies have received considerable attention and been extensively studied in recent years. In addition to directly killing tumor cells through heat and reactive oxygen species, PTT and PDT can also induce various antitumor effects. In particular, the resultant massive tumor cell death after PTT and PDT triggers immune responses, including the redistribution and activation of immune effector cells, the expression and secretion of cytokines and the transformation of memory T lymphocytes. The antitumor effects can be enhanced by immune checkpoint blockage therapy. This article reviewed the recent advances of nanoparticle-based PTT and PDT, summarized the studies on nanoparticle-based photothermal and photodynamic immunotherapies in vitro and in vivo, and discussed challenges and future research directions. PMID- 29981171 TI - Genome-wide association and gene validation studies for early root vigour to improve direct seeding of rice. AB - Elucidation of the genetic control of rice seedling vigour is now paramount with global shifts towards direct seeding of rice and the consequent demand for early vigour traits in breeding programmes. In a genome-wide association study using an indica-predominant diversity panel, we identified quantitative trait loci (QTLs) for root length and root number in rice seedlings. Among the identified QTLs, one QTL for lateral root number on chromosome 11, qTIPS-11, was associated with a 32.4% increase in lateral root number. The locus was validated in independent backgrounds, and a predicted glycosyl hydrolase, TIPS-11-9, was identified as the causal gene for observed phenotypic differences. TIPS-11-9 was differentially expressed in emerging lateral roots of contrasting qTIPS-11 haplotypes, which was likely due to differences in cis-regulatory elements and auxin responsiveness. Abolishment of Tips-11-9 function through T-DNA insertion in a qTIPS-11-positive background resulted in a reduction of lateral root number, which negatively affected biomass accumulation, particularly under phosphorous-limiting conditions. Marker-assisted introgression of qTIPS-11 into modern indica varieties will aid in the generation of varieties adapted to direct seeding and thus facilitate the adoption of direct seeding practices in tropical Asia. PMID- 29981172 TI - Prevalence and distribution of cervical human papillomavirus genotypes in women with cytological results from Sichuan province, China. AB - The epidemiologic characteristics of human papillomavirus (HPV) genotypes vary by age, ethnicity, and geographic location, and the available data on HPV epidemiological characteristics with cytology results in Sichuan province are limited. Our research was conducted from June 2016 to July 2017. A total of 10 953 women getting HPV testing were enrolled. Liquid-based cytological and histological results were collected. The overall HPV infection rate was 24.1% in Sichuan province. The prevalence of high-risk HPV (hrHPV) was 19.9%. For hrHPV genotypes, HPV52 (15.5%) was the most prevalent genotype, followed by HPV16 (13.8%), HPV58 (13.3%), HPV51 (8.6%), HPV39 (8.1%), and HPV68 (7.8%). Among all HPV-positive women with a cytology or histology result, HPV16-positive women have the highest cervical intraepithelial neoplasia 1 (CIN1)+ prevalence (11.1%), followed by HPV18 and HPV33; HPV16-positive women also have the highest CIN2+ prevalence (9.3%), followed by HPV58 and HPV18. To date, this is the largest study done in the Sichuan province for HPV prevalence and subtype distribution with normal and abnormal cytological results. The age-specific prevalence in patients at gynecology clinics and other clinics is different. Besides, patients at the same age also have a different hrHPV prevalence and lrHPV prevalence. Our result revealed that in every 10 HPV16-positive women, there is approximately one women with CIN2, CIN3, or cervical cancer. A higher oncogenic potential of HPV58 than that of HPV52 was observed. PMID- 29981173 TI - How self-generated labelling shapes transfer of learning during early childhood: The role of individual differences. AB - Multiple factors influence imitation during toddlerhood, including task complexity, social contingency, and individual differences. We conducted a secondary data analysis of individual differences in self-generated labelling using data collected from a complex puzzle imitation task with 355 2- to 3-year olds. This analysis indicated that toddlers' ability to label the completed puzzle (fish or boat) was associated with better imitation performance. Labelling occurs during social interactions; therefore, our second analysis tested how labelling differed as a function of the level of social scaffolding in each condition. This analysis revealed that self-generated labelling was lower when the social demonstrator was removed and the task was presented on a touchscreen. This study is one of the first to examine self-generated labelling during a complex imitation task in toddlers and increases our understanding of the complexity of memory processing needed for imitation learning. Statement of contribution What is already known on this subject? Toddlers exhibit a transfer of learning deficit from 2D media, including books, TV, and tablets. Self generated labelling enhances children's learning, through attentional and cognitive mechanisms. Children are sensitive to reduced social cues in screen media contributing to the transfer deficit. What does this study add? Self generated labelling is associated with better goal imitation performance. Self generated labelling occurs more frequently under social conditions. PMID- 29981174 TI - Impact of donor and recipient cytomegalovirus serology on long-term survival of lung transplant recipients. AB - BACKGROUND: Pre-transplant cytomegalovirus (CMV) serostatus has been associated with lung transplant patient survival. We retrospectively analyzed the relationship between pre-transplant donor/recipient CMV serostatus and long-term mortality in a cohort of lung transplant recipients at our center. METHOD: Adult (Age >17 years) lung recipients transplanted between July 1985-December 2015 were analyzed. Variables included age, sex, pre-transplant donor (D)/recipient (R) serostatus [D-/R-, D-/R+, D+/R+, D+/R-], CMV infection within 2 years of transplant and transplant eras divided by changes in CMV prevention strategies: Era 1 (pre-ganciclovir, July 1985-April 1998), Era 2 (oral ganciclovir, May 1998 December 2004), Era 3 (valganciclovir, January 2005-December 2015). Survival analysis and Cox regression were performed at 10 years. RESULTS: A total of 652 lung recipients were analyzed. Twenty percent were CMV mismatched pre-transplant and 45% had CMV infection within 2 years post-transplant. Survival at 10 years appeared worse in D+ transplants (P = 0.027). D-/R- lungs did not have significantly different survival across eras (P = 0.76), but survival of D-/R+, D+/R+, D+/R- lungs improved (P < 0.001). Cox regression revealed that transplantation in the valganciclovir era reduced risk of death in lung transplants by an estimated 52% (P < 0.001) compared to transplantation in the pre-ganciclovir era after controlling for age at transplant, D/R CMV serostatus and CMV infection. Age at transplant and CMV infection were also significant predictors of mortality in lung transplants (P < 0.001 and 0.033 respectively). CONCLUSION: Our review of the impact of CMV managed differently across eras suggests in lung transplantation there is no independent influence of D/R CMV serostatus on 10-year survival. PMID- 29981175 TI - Prediction of particle deposition around the cabin air supply nozzles of commercial airplanes using measured in-cabin particle emission rates. AB - Enhanced soiling on the surfaces around air supply nozzles due to particle deposition is frequently observed in commercial airliners. The problem is worsened by severe outdoor air pollution and flight delays in China. The particles in an aircraft cabin originate from both outdoor and in-cabin sources. This study conducted measurements on multiple commercial flights to obtain particle emission rates from in-cabin sources. Additional experiments on a retired MD-82 airplane provided justification of the in-flight measurements. The in-cabin sources emitted more particles during boarding/deplaning than during meal servicing and sitting. The average PM2.5 emission rates were 7.2, 2.6, 1.9, and 1.8 (MUg/min per person), respectively, during the boarding/deplaning, sitting on the ground, sitting in the air, and meal servicing. The corresponding PM10 emission rates were 15.4, 6.1, 5.3, and 5.4 (MUg/min per person), respectively, for these four periods. The average particle emission rate from in cabin sources varied seasonally and was the highest in winter. With the measured data, this investigation used a CFD model to predict the accumulation of particles deposited around the nozzles of an airplane, taking into account the flight routes and the outdoor particle concentrations at the airports where the airplanes were parked. For the most polluted airplane in China, the dirty spots/areas around the nozzles inside the airplane became visible after 6 months. The method proposed in this study can be used for any commercial airplane to predict the accumulation of particles deposited around the air supply nozzles. PMID- 29981177 TI - Homoleptic Trifluoromethyl Derivatives of AgI and AgIII. AB - The homoleptic silver(I) compound [PPh4 ][CF3 AgCF3 ] (1) provides a convenient entry to the homoleptic silver(III) derivative [PPh4 ][Ag(CF3 )4 ] (2). Once isolated as pure substances, these compounds exhibit marked thermal stabilities. Their structural and spectroscopic properties have been experimentally established. Moreover, their electronic structures have been calculated by theoretical methods. The electronic structure of the oxidized species [Ag(CF3 )4 ]- provides a new case of ligand-field inversion caused by the CF3 ligands. PMID- 29981176 TI - Territory-wide population-based study of chronic hepatitis C infection and implications for hepatitis elimination in Hong Kong. AB - BACKGROUND: To study the epidemiology of chronic hepatitis C virus infection in Hong Kong and to estimate the service gap for achieving the WHO hepatitis elimination targets of attaining a diagnosis rate of 90%, treatment rate of 80% and 65% reduction in mortality rate by 2030. METHODS: From January 2005 to March 2017, patients who were tested positive for anti-HCV were retrospectively retrieved from all public hospitals in Hong Kong. The epidemiological data of 15 participating hospitals were analysed. RESULTS: A total of 11 309 anti-HCV+ patients were identified and the estimated diagnosis rate was 50.9%. Our HCV infected patients were ageing (median age 59). The all-cause mortality rate increased from 26.2 to 54.8 per 1000 person-years over the last decade. Our estimated treatment rate was 12.4%. Among the treated patients, 93.6% had received pegylated interferon/ribavirin (Peg-IFN/RBV) but only 10.8% had received interferon-free direct-acting antivirals (DAAs). In a cohort of 1533 patients, 39% already had advanced liver fibrosis or cirrhosis. The sustained virological response rate for Peg-IFN/RBV and DAAs were 74.8% and 97.2% respectively. However, more than 70% of patients were not subjected to interferon treatment for various reasons. Patients who achieved SVR were associated with a significantly lower risk of HCC (4.7% vs 9.6%, P = 0.005) and death (1.7% vs 23.8%, P < 0.001). CONCLUSION: Our diagnosis rate, treatment rate and mortality rate reduction were still low, particularly the Peg-IFN outcomes, making it difficult to meet the WHO hepatitis elimination targets. A more generalized use of DAAs is urgently needed to improve the situation. PMID- 29981178 TI - Variability in nutrient composition and in vitro crude protein digestibility of 16 microalgae products. AB - The chemical composition of 16 microalgae products of four genera, Arthrospira (n = 2), Chlorella (n = 8), Nannochloropsis (n = 4) and Phaeodactylum (n = 2), was assayed to evaluate the intra- and inter-genera variation of nutrient profiles of commercial microalgae products. Crude protein was the main component in all genera, followed by ether extract and crude ash. Mean crude protein concentrations were 690, 502, 431 and 446 g/kg dry matter, and mean ether extract concentrations were 63, 157, 188 and 113 g/kg dry matter for Arthrospira, Chlorella, Nannochloropsis and Phaeodactylum respectively. However, there was considerable inter- and intra-genera variation. The concentration of alpha-linked glucose was low (0-143 g/kg dry matter). There was high variation between and within genera in the crude ash concentration (22-237 g/kg dry matter), which was also observed for the mineral composition. In contrast to the crude protein concentration, the amino acid composition of the protein (g amino acid/16 g N) was less variable. The investigated samples possessed high concentrations of Glx, Asx and Leu, and low concentrations of Cys and Met. The mean concentration of non protein nitrogen compounds was highest in Phaeodactylum (110 g/kg dry matter) and lowest in Nannochloropsis (47 g/kg dry matter) products, and as with proximate nutrients, high variability between and within genera was observed. In vitro crude protein digestibility varied between 54% (non-cell-disrupted Nannochloropsis) and 84% (cell-disrupted Chlorella). Inositol phosphate isomers were not detectable in any sample (concentration <1 MUmol/g dry matter). The predominant fatty acids were C16:0 in Arthrospira products, C18:2 n-6+ C19:1 t7 and C18:3 n-3 in Chlorella products, and C20:5 n-3 in Nannochloropsis and Phaeodactylum products; however, the relative proportions of fatty acids varied within genera. Commercially available microalgae products appear to be valuable alternative food and feed products. However, because of the high variability in nutrient profiles, attention should be given to the analytical characterization of the products. PMID- 29981179 TI - Transplantation in foreign nationals: Lower rates of waitlist mortality and higher rates of lost to follow-up posttransplant. AB - A controversial issue in the transplant community is whether or not to provide deceased donor liver transplantation (DDLT) to noncitizen/nonresidents (NCNRs) who travel for liver transplantation (LT). The expectation is that transplantation of NCNRs will not compromise access for US citizens/residents (USCRs), and that NCNRs would have similar post-LT follow-up. This has never been formally assessed. The United Network for Organ Sharing (UNOS) data from February 27, 2002 to December 31, 2016 were used to identify NCNRs and compare to USCRs, excluding Status 1 adults. Multivariable logistic regression was used to analyze waitlist outcomes, and competing risk analysis was used to assess rates of lost to follow-up post-LT. From February 27, 2002 to December 31, 2016, 1260 NCNRs were listed for LT (0.86% of listings). Adjusted probability of DDLT was not significantly different for NCNRs and USCRs (P > .5), but NCNRs were significantly less likely to be removed from the waitlist for death or clinical deterioration (aOR: 0.80, 95% CI: 0.69-0.93, P = .003). In multivariable competing risk models, NCNRs had an 11-fold higher risk of being lost to follow up after accounting for the competing risk of death (SHR: 11.44, 95% CI: 8.72 15.01, P < .001), as well as lower rates of posttransplant mortality (SHR: 0.67, 95% CI: 0.49-0.91, P = .012). Our findings speak to the need to standardize practices for NCNRs and set expectations for post-LT care. PMID- 29981180 TI - Three-dimensional speckle tracking echocardiography: Is it the magic wand in the diagnosis of subclinical myocardial dysfunction in children with type 1 diabetes mellitus? AB - OBJECTIVES: To revaluate the role of three-dimensional speckle tracking echocardiography (3D-STE) in the evaluation of subclinical myocardial dysfunction in asymptomatic children with type 1 diabetes mellitus (DM). PATIENTS AND METHODS: Fifty asymptomatic children with type 1 DM were included as a patient group. Fifty healthy children of matched age, sex, and weight served as a control group. Laboratory investigations in the form of complete blood count (CBC), liver function test, renal function test, complete blood lipid profile, glycosylated hemoglobin (HbA1c), fasting and 2 hours postprandial (PP) glucose levels, and cardiac troponin I (cTnT I) were drawn. Complete echocardiographic evaluation of the left ventricular (LV) function was performed in the form of conventional echo, 2D strain, tissue Doppler imaging (TDI), and 3D- STE. RESULTS: cTnT I levels were significantly higher in the patient group than the control group, and this increase was significantly correlated with Hb A1c. Conventional echocardiography showed normal systolic and diastolic function of the LV. Diastolic (by TDI) as well as systolic functions of LV (by 4D LV quantification tool) were found to be significantly lower in patient group than control group. 3D-STE examination showed that there was a significant decrease in all component of strain in patient group than control group and that decrease correlated well with 4D LV EF but did not correlate with the duration of DM. There was a significant negative correlation between longitudinal strain and the control of DM. CONCLUSION: 3D-STE is a good tool for prediction of early cardiac dysfunction in asymptomatic children with type 1 DM. PMID- 29981181 TI - Clinical and echocardiographic predictors of new-onset atrial fibrillation in patients admitted with blunt trauma. AB - BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia after trauma or burn injury; however, its predisposing factors are not well known. Moreover, little is known about its effect on mortality and other short-term clinical outcomes. OBJECTIVES: This study is aimed at identifying risk factors for new-onset AF in patients admitted with blunt trauma or burn injuries at a Level 1 academic trauma center, and to determine its effects on the short-term clinical outcomes. METHODS: This case-control study compared patients with new-onset AF with a cohort of patients without AF during the hospital stay after trauma or burn injury. Patients with prior AF or lack of transthoracic echocardiogram were excluded. Demographic, clinical factors including injury severity score and echocardiographic parameters were compared in both cohorts. Risks of short-term clinical outcomes, namely persistent AF, new stroke, myocardial infarction, or death, were compared. RESULTS: Older age, sepsis, CHADS2-VASC score >1, larger left atrium (LA) size, left ventricular hypertrophy (LVH), and left ventricular diastolic dysfunction imposed a significant risk for new-onset AF on univariate analysis. On multivariate, independent predictors of new-onset AF were LA dilation and LVH. LA enlargement increased odds of new-onset AF by 23-fold (OR 23; CI: 5.7-92, P < 0.0001) and the presence of LVH increased the odds of new onset AF more than 20-fold (OR 20.8; CI: 5-87, P < 0.0001). CONCLUSIONS: Dilated LA and LVH are independent predictors of new-onset AF in the patients with blunt trauma or burn. New-onset AF did not confer increased risk for in-hospital mortality. PMID- 29981182 TI - Multifold Nanostructuring and Atomic-Scale Modulation of Cobalt Phosphide to Significantly Boost Hydrogen Production. AB - Water electrolysis is regarded as a green and highly efficient approach to producing high-purity hydrogen, but commercialization of this technology still requires the development of high-performance and affordable electrocatalysts for the hydrogen evolution reaction (HER). Currently, because of its excellent electrical conductivity and good corrosion resistance in acidic media, cobalt phosphide (CoP) has become a representative non-noble-metal HER catalyst despite its inadequate catalytic activity. Herein, a strategy of multiple catalyst structure engineering, which simultaneously includes doping, nanostructuring, and in situ nanocarbon coating, was employed to significantly improve the HER performance of CoP. CoP with optimized ruthenium doping and covered by ultrathin graphitic carbon shells shows remarkably high HER catalytic behaviour with a low overpotential of only 73 mV at a current density of 10 mA cm-2 and a small Tafel slope of 46 mV dec-1 , close to that of the Pt/C benchmark, while maintaining excellent durability. Moreover, the ultrathin graphene shell has a significant positive effect on catalytic activity. This work demonstrates the necessity and validity of multifold structural control, which can be widely used to design various materials for different catalytic processes. PMID- 29981183 TI - Lung transplant after prolonged ex vivo lung perfusion: predictors of allograft function in swine. AB - Portable normothermic EVLP has been evaluated in clinical trials using standard and extended-criteria donor lungs. We describe a swine model of lung transplant following donation after circulatory death using prolonged normothermic EVLP to assess the relationship between EVLP data and acute lung allograft function. Adult swine were anesthetized and heparinized. In the control group (n = 4), lungs were procured, flushed, and transplanted. Treatment swine underwent either standard procurement (n = 3) or agonal hypoxia followed by 1 (n = 4) or 2 hours (H) (n = 4) of ventilated warm ischemia. Lungs were preserved for 24H using normothermic blood-based EVLP then transplanted. Recipients were monitored for 4 H. After 24H of preservation, mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), and dynamic compliance (Cdyn ) were improved in all EVLP groups. After transplant, EVLP groups showed similar allograft oxygenation. EVLP PVR, mPAP, and lung block weights had significant negative correlations with post-transplant allograft oxygenation. EVLP P:F ratio did not correlate with acute post-transplant allograft function until 24H of preservation. Data measured in the first 8H of EVLP were sufficient for predicting acute post-transplant allograft function. This study provides a benchmark and platform for evaluation of therapies for donor-related allograft injury in injured lungs treated with prolonged normothermic EVLP. PMID- 29981184 TI - Belatacept rescue for delayed kidney allograft function in a patient with previous combined heart-liver transplant. PMID- 29981185 TI - Long-term treatment costs of chronic periodontitis patients in Germany. AB - AIM: We assessed the long-term costs for treating chronic periodontitis (CP) patients. METHODS: A cohort of compliant CP patients was retrospectively evaluated. Costs for active periodontal therapy (APT, including scaling and root planning, open flap debridement, root resections) and supportive periodontal therapy (SPT including periodontal, restorative, endodontic, prosthetic and surgical treatments) were estimated from a mixed payer perspective in Germany. The impact of tooth- and patient-level factors on annual costs was assessed using mixed-modelling. RESULTS: Two hundred and seventy-three patients (mean +/- SD age: 49.6 +/- 8.8 years), with 24.3 +/- 4.5 teeth, were included. Mean follow-up was 18.7 +/- 5.7 years. Total treatment costs per patient and per tooth were 6,146 +/- 2,236 and 222 +/- 98 Euro, respectively. Costs were generated mainly by periodontal therapy and during SPT. Annualized patient- and tooth-level costs were 348 +/- 159 and 12.4 +/- 5.7 Euro, respectively. Annual costs increased significantly in older patients, regular attenders, those with fewer teeth (<24) at baseline and teeth with higher probing pocket depths or mobility 3 at baseline. CONCLUSIONS: Annual costs for treating CP patients were lower than those found for aggressive periodontitis patients. Regular attendance and having more severe periodontitis came with higher costs per year. PMID- 29981187 TI - Comparison of methods to estimate water-equivalent diameter for calculation of patient dose. AB - Modern CT systems seek to evaluate patient-specific dose by converting the CT dose index generated during a procedure to a size-specific dose estimate using conversion factors that are related to patient attenuation properties. The most accurate way to measure patient attenuation is to evaluate a full-field-of-view reconstruction of the whole scan length and calculating the true water-equivalent diameter (Dw ) using CT numbers; however, due to time constraints, less accurate methods to estimate Dw using patient geometry measurements are used more widely. In this study we compared the accuracy of Dw values calculated from three different methods across 35 sample scans and compared them to the true Dw . These three estimation methods were: measurement of patient lateral dimension from a pre-scan localizer radiograph; measurement of the sum of anteroposterior and lateral dimensions from a reconstructed central slice; and using CT numbers from a central slice only. Using the localizer geometry method, 22 out of 35 (62%) samples estimated Dw within 20% of the true value. The middle slice attenuation and geometry methods gave estimations within the 20% margin for all 35 samples. PMID- 29981186 TI - Altitude-induced responses observed in the control group. PMID- 29981188 TI - Ten-year changes in ambulatory blood pressure: The prognostic value of ambulatory pulse pressure. AB - Blood pressure (BP) changes and risk factors associated with pulse pressure (PP) increase in elderly people have rarely been studied using ambulatory blood pressure monitoring (ABPM). The aim is to evaluate 10-year ambulatory blood pressure (ABP) changes in older hypertensives, focusing on PP and its associations with mortality. An observational study was conducted on 119 consecutive older treated hypertensives evaluated at baseline (T0) and after 10 years (T1). Treatment adherence was carefully assessed. The authors considered clinical parameters at T1 only in survivors (n = 87). Patients with controlled ABP both at T0 and T1 were considered as having sustained BP control. Change in 24-hour PP between T0 and T1 (Delta24-hour PP) was considered for the analyses. Mean age at T0: 69.4 +/- 3.7 years. Females: 57.5%. Significant decrease in 24 hour, daytime, and nighttime diastolic BP (all P < .05) coupled with an increase in 24-hour, daytime, and nighttime PP (all P < .05) were observed at T1. Sustained daytime BP control was associated with lower 24-hour PP increase than nonsustained daytime BP control (+2.23 +/- 9.36 vs +7.79 +/- 8.64 mm Hg; P = .037). The association between sustained daytime BP control and Delta24-hour PP remained significant even after adjusting for age, sex, and 24-hour PP at T0 (beta=0.39; P = .035). Both 24-hour systolic BP and 24-hour PP at T0 predicted mortality (adjusted HR 1.07, P = .001; adjusted HR 1.25, P < .001, respectively). After ROC comparison (P = .001), 24-hour PP better predicted mortality than 24 hour systolic BP. The data confirm how ABP control affects vascular aging leading to PP increase. Both ambulatory PP and systolic BP rather than diastolic BP predict mortality in older treated hypertensives. PMID- 29981189 TI - First report of a living liver graft in combined lung and liver transplantation. PMID- 29981190 TI - Impact of pharyngeal endoscopic tip placement and water flushing interval on upper respiratory tract disorders in horses undergoing overground endoscopy. AB - BACKGROUND: Endoscopic tip placement in the pharynx and water flushing interval (FI) may affect exercising upper respiratory tract (URT) endoscopic results. OBJECTIVES: To determine associations between the endoscopic tip position in the pharynx and automated FI with overground endoscopic (OGE) results. STUDY DESIGN: Randomised balanced 2X5 factorial design. METHODS: A total of n = 200 horses undergoing OGE were randomly assigned into 10 groups (n = 20/group) of different automated endoscopic FIs (no flushing, 60, 120, 180, 240 s) with the endoscope tip positioned either rostrally (position A) or caudally (position B) in the pharynx. Endoscopic videos were analysed and all URT abnormalities graded using published scales. Disorders with <=10% prevalence were excluded from the final analysis with only arytenoid asymmetry at exercise (AAex), vocal fold collapse (VFC), palatal dysfunction (PD) and medial deviation of the aryepiglottic folds (MDAF) included. The association of endoscope position and FI with URT disorders was assessed using ordinal regression models with P<=0.05 significant. RESULTS: Endoscope tip positioning was significantly associated with PD grading (P = 0.002), with 63/100 horses diagnosed with PD in position A and 45/100 in position B. No other significant direct associations between URT disease and endoscope tip position were identified, although interactions between exercise velocity and endoscope position affected MDAF grade. FI was not directly associated with alterations in disorder grading, although interactions between exercise velocity and FI appeared to affect MDAF grade. MAIN LIMITATIONS: The same horse was not evaluated under each test condition potentially resulting in sample bias. Interactions between disorders were not evaluated. The sample size was insufficient to conclusively explore relationships between all factors and disorder grading. CONCLUSIONS: Position of the endoscope tip within the pharynx appears to affect grading of PD during OGE examination. Exercise velocity may affect MDAF grade through interactions with endoscope position and FI. PMID- 29981191 TI - Response to Millet and Brocherie. PMID- 29981192 TI - Effects of football simulated fatigue on neuromuscular function and whole-body response to disturbances in balance. AB - The effect of football-specific fatigue on explosive neuromuscular performance and dynamic balance has received little attention in the literature despite the potential consequences for injury risk. This study aimed to investigate the effect of fatigue induced by simulated football match play on maximal and explosive knee flexor (KF) and knee extensor (KE) torque, and thus the maximal and explosive KF/KE ratio, as well as the effect of fatigue induced by simulated football match play on whole-body response to disturbances in balance. Fifteen male team sports players (mean +/- SD: age 24.2 +/- 4.2 years; stature 1.79 +/- 0.09 m; body mass, 77.3 +/- 10.7 kg) underwent ~90 minutes of the modified Loughborough Intermittent Shuttle Test (LIST; fatiguing exercise condition) or seated rest (control condition) on separate days. Maximal and explosive isometric KF and KE voluntary torque (MVT/EVT) were assessed pre- and post-condition. Maximal and explosive KF/KE ratios were calculated. Center of mass (COM) response (displacement) to unexpected anterior and posterior platform perturbations were also assessed pre- and post-condition. Football simulated fatigue resulted in reduced KF (15%) and KE (12%) MVT (P <= 0.002) but was not found to reduce EVT of either muscle group, or explosive KF/KE ratio. Football simulated fatigue resulted in impaired balance response (11% increase in COM displacement) to unexpected perturbation in the posterior (P = 0.002) but not the anterior direction. Impaired response to dynamic disturbances in balance, rather than explosive torque or changes in muscle balance (H/Q ratios), may be a contributory factor toward increased injury risk in the latter portion of football games, and likely highlights the influence of fatigue on sensory/proprioceptive processes. PMID- 29981193 TI - Dearomatization of the PCP Pincer Ligand in a ReV Oxo Complex. AB - A high-valent, rhenium(V) oxo complex (PCP)ReOCl2 (1; PCP=bis(2,6-di-tert butylphosphinomethyl)phenyl) undergoes a deprotonation and "dearomatization" upon treatment with LiN(SiMe3 )2 to give (P*CP)ReOCl (2 a), in which Re is bound to a new dianionic P*CP ligand. Compound 2 a was studied spectroscopically, structurally, and computationally and was determined to have non-negligible Re=C multiple bond character, leading to its formulation as a new pseudo-carbenoid species. Reaction of 2 a or its iodo analogue (P*CP)ReOI (2 b) with CO2 provided access to (PCP)ReOX(CO2 ) (X=Cl or I, 3 a/b), the product of 1,3-cycloaddition and C-C bond formation. PMID- 29981194 TI - The association between paraoxonase 1 activity and the susceptibilities of diabetes mellitus, diabetic macroangiopathy and diabetic microangiopathy. AB - We carried out this meta-analysis to explore the influence of paraoxonase 1 activity on the susceptibility of diabetes mellitus (DM), diabetic macroangiopathy and diabetic microangiopathy. Relevant studies were identified from PubMed, Web of Science and CNKI without language limitation, following the inclusion and exclusion criteria. Statistical analyses were implemented with the STATA 12.0 statistical software. Thirty-six case-control studies were included in the meta-analyses, in which 35 for the association between paraoxonase 1 activity and DM risk, 8 for diabetic macroangiopathy and 7 for diabetic microangiopathy. Paraoxonase 1 activity was significantly associated with the susceptibility of DM in pooled population (SMD = -1.37, 95% CI = -1.79 ~ -0.96, P = .000), and Asians (SMD = -2.00, 95% CI = -2.56 ~ -1.44, P = .000), but not in non-Asians (SMD = 0.44, 95% CI = -0.91 ~ 0.03, P = .069). However, marked heterogeneity was existed (I2 = 98.10%, P = .000) and subgroup analyses failed to investigate the sources of heterogeneity. Then, meta-regression was performed and found that ethnicity could explain the observed between-study heterogeneity (P = .002). Meanwhile, significant associations were found between paraoxonase 1 activity and diabetic macroangiopathy (SMD = -1.06, 95% CI = -1.63 ~ -0.48, P = .000) and diabetic microangiopathy (SMD = -0.72, 95% CI = -1.32 ~ -0.13, P = .018). In conclusion, paraoxonase 1 activity plays important roles in the risk of DM, diabetic macroangiopathy and microangiopathy with ethnicity differences. Further studies with large sample and well design are needed to confirm these results. PMID- 29981195 TI - Proximity to transplant center and outcome among liver transplant patients. AB - In the United States, distance from liver transplant center correlates with worsened outcomes; the effects of geography elsewhere are unassessed. We performed a national registry analysis of United Kingdom listings for liver transplantation (1995-2014) and assessed whether travel time to transplant center correlates with outcome. There were 11 188 listings assessed (8490 transplanted), with a median travel time to center of 60 minutes (range 36-86). Of the national population, 3.38 * 107 (55.1%) reside >=60 minutes from a center, and 7.65 * 106 (12.5%) >119 minutes. After competing risk analysis, increasing travel time was associated with an increased risk of death after listing (subdistribution hazard ratios relative to <60 minutes of 1.33 for 60-119 and 1.27 for >119 minutes; P < 0.001) and reduced likelihood of transplantation or recovery (0.94 and 0.86; P < 0.001). Among those transplanted, travel time was not associated with retransplant-free survival (P = 0.532). We used our model to examine optimal placement of a new center and identify a single site with a total travel time reduction of ~10%. Our findings of disparities in accessibility of liver transplantation showed worse outcomes following listing in those distant from their transplant center, and our description of a method to model a new center complement existing data and support similar analyses of other networks. PMID- 29981196 TI - Neurodevelopmental subtypes of bipolar disorder are related to cortical folding patterns: An international multicenter study. AB - OBJECTIVES: Brain sulcation is an indirect marker of neurodevelopmental processes. Studies of the cortical sulcation in bipolar disorder have yielded mixed results, probably due to high variability in clinical phenotype. We investigated whole-brain cortical sulcation in a large sample of selected patients with high neurodevelopmental load. METHODS: A total of 263 patients with bipolar disorder I and 320 controls were included in a multicentric magnetic resonance imaging (MRI) study. All subjects underwent high-resolution T1-weighted brain MRI. Images were processed with an automatized pipeline to extract the global sulcal index (g-SI) and the local sulcal indices (l-SIs) from 12 a priori determined brain regions covering the whole brain. We compared l-SI and g-SI between patients with and without early-onset bipolar disorder and between patients with and without a positive history of psychosis, adjusting for age, gender and handedness. RESULTS: Patients with early-onset bipolar disorder had a higher l-SI in the right prefrontal dorsolateral region. Patients with psychotic bipolar disorder had a decreased l-SI in the left superior parietal cortex. No group differences in g-SI or l-SI were found between healthy subjects and the whole patient cohort. We could replicate the early-onset finding in an independent cohort. CONCLUSIONS: Our work suggests that bipolar disorder is not associated with generalized abnormalities of sulcation, but rather with localized changes of cortical folding restricted to patients with a heavy neurodevelopmental loading. These findings support the hypothesis that bipolar disorder is heterogeneous but may be disentangled using MRI, and suggest the need for investigations into neurodevelopmental deviations in the disorder. PMID- 29981197 TI - Three-dimensional transesophageal echocardiography vs cardiac magnetic resonance in the assessment of planimetric mitral valve area in rheumatic mitral stenosis. AB - AIM: Rheumatic heart disease is a common cause of valvular disease, especially in developing countries. Echocardiography is the gold standard investigation modality for cardiac valves. In rheumatic mitral stenosis (MS), three-dimensional transesophageal echocardiography (3D TEE) provides better alignment of the image plane at the mitral tips and more accurate and reproducible planimetric measurement of mitral valve area (MVA). Cardiac magnetic resonance (CMR) is a new method that provides evaluation of cardiac anatomy and function noninvasively. Previous studies showed strong correlation between planimetric MVA measured by two-dimensional transthoracic echocardiography and CMR. We aimed to compare the planimetric MVAs assessed by 3D TEE and CMR in rheumatic MS patients. To best of our knowledge, this is the first study that compares 3D TEE and CMR for the assessment of the planimetric MVA in rheumatic MS. METHODS: We retrospectively evaluated 28 rheumatic MS patients who underwent 3D TEE and ECG-gated CMR. 3D TEE planimetric MVAs were measured manually by multiplanar reconstruction (MPR) method and CMR planimetric MVAs were measured manually on short-axis cine images. Then, 3D TEE and CMR measurements were compared. RESULTS: A total of 28 patients' (mean age 44 +/- 12, 82.1% female) planimetric 3D TEE MVAs (1.00 +/- 0.20 cm2 ) and CMR MVAs (1.04 +/- 0.17 cm2 ) were found to be highly correlated (P < 0.0001, r: 0.744) with Pearson correlation analysis. Bland-Altman analysis showed strong agreement between two techniques. CONCLUSION: For the diagnosis and the follow-up of rheumatic MS, planimetric CMR MVA is an alternative noninvasive method which highly correlates with planimetric 3D TEE MVA. PMID- 29981198 TI - Acute administration of interleukin-6 does not increase secretion of glucagon like peptide-1 in mice. AB - Interleukin 6 (IL-6) is a cytokine secreted from skeletal muscle in response to exercise which, based on animal and cell studies, has been suggested to contribute to glucose metabolism by increasing secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and affecting secretion of insulin and glucagon from the pancreatic islets. We investigated the effect of IL-6 on GLP-1 secretion in GLP-1 producing cells (GLUTag) and using the perfused mouse small intestine (harboring GLP-1 producing cells). Furthermore, the direct effect of IL-6 on insulin and glucagon secretion was studied using isolated perfused mouse pancreas. Incubating GLUTag cells with 1000 ng/mL of IL-6 for 2 h did not significantly increase secretion of GLP-1 whereas 10 mmol/L glucose (positive control) did. Similarly, IL-6 (100 ng/mL) had no effect on GLP-1 secretion from perfused mouse small intestine whereas bombesin (positive control) increased secretion. Finally, administering IL-6 (100 ng/mL) to perfused mouse pancreases did not significantly increase insulin or glucagon secretion regardless of perfusate glucose levels (3.5 vs. 12 mmol/L glucose). Acute effects of IL-6 therefore do not seem to include a stimulatory effect on GLP-1 secretion in mice. PMID- 29981199 TI - Application of a novel molecular method to age free-living wild Bechstein's bats. AB - The age profile of populations fundamentally affects their conservation status. Yet, age is frequently difficult to assess in wild animals. Here, we assessed the use of DNA methylation of homologous genes to establish the age structure of a rare and elusive wild mammal: the Bechstein's bat (Myotis bechsteinii). We collected 62 wing punches from individuals whose ages were known as a result of a long-term banding study. DNA methylation was measured at seven CpG sites from three genes, which have previously shown age-associated changes in humans and laboratory mice. All CpG sites from the tested genes showed a significant relationship between DNA methylation and age, both individually and in combination (multiple linear regression R2 = 0.58, p < 0.001). Despite slight approximation around estimates, the approach is sufficiently precise to place animals into practically useful age cohorts. This method is of considerable practical benefit as it can reliably age individual bats. It is also much faster than traditional capture-mark-recapture techniques, with the potential to collect information on the age structure of an entire colony from a single sampling session to better inform conservation actions for Bechstein's bats. By identifying three genes where DNA methylation correlates with age across distantly related species, this study also suggests that the technique can potentially be applied across a wide range of mammals. PMID- 29981200 TI - Sodium and magnesium in the distal convoluted tubule: no longer a couple? PMID- 29981201 TI - Exercise prevents HFD- and OVX-induced type 2 diabetes risk factors by decreasing fat storage and improving fuel utilization. AB - Previous studies suggest that the loss of estrogens increase one's risk for type 2 diabetes (T2D), and combining the loss of estrogens with a high-fat diet (HFD) poses an even greater risk for T2D. The extent to which exercise can ameliorate the deleterious effects of estrogen loss combined with a HFD and the molecular mechanisms accounting for the whole body changes is currently unknown. Therefore, we fed female Wistar rats a standard diet or a HFD for 10 weeks. The rats fed the HFD were either ovariectomized (OVX) or their ovaries remained intact. A subset of the HFD/OVX rats also underwent exercise training on a motor-driven treadmill. Exercise significantly reduced the total body weight gain, periuterine white adipose tissue (WAT) weight, hyperglycemia, and hyperinsulinemia. Additionally, the ability to store fat, as measured by lipoprotein lipase (LPL) in the WAT, was increased in the HFD/OVX group; however, exercise reduced the LPL levels. Furthermore, the combination of the HFD with OVX decreased the WAT citrate synthase protein level, which was increased with exercise. These data suggest that even during the combined HFD/OVX physiological state, exercise can decrease several risk factors associated with T2D, decrease fat storage, and increase fuel utilization. PMID- 29981202 TI - MELD-based organ allocation policy: Time for change. PMID- 29981204 TI - Board certification in transplant pharmacotherapy. PMID- 29981203 TI - Neuropeptide Y1 and alpha-1 adrenergic receptor-mediated decreases in functional vasodilation in gluteus maximus microvascular networks of prediabetic mice. AB - Prediabetes is associated with impaired contraction-evoked dilation of skeletal muscle arterioles, which may be due to increased sympathetic activity accompanying this early stage of diabetes disease. Herein, we sought to determine whether blunted contraction-evoked vasodilation resulted from enhanced sympathetic neuropeptide Y1 receptor (Y1R) and alpha-1 adrenergic receptor (alpha1R) activation. Using intravital video microscopy, second-, third-, and fourth-order (2A, 3A, and 4A) arteriolar diameters were measured before and following electrical field stimulation of the gluteus maximus muscle (GM) in prediabetic (PD, Pound Mouse) and control (CTRL, c57bl6, CTRL) mice. Baseline diameter was similar between groups; however, single tetanic contraction (100 Hz; 400 and 800 msec) and sustained rhythmic contraction (2 and 8 Hz, 30 sec) evoked rapid onset vasodilation and steady-state vasodilatory responses that were blunted by 50% or greater in PD versus CTRL. Following Y1R and alpha1R blockade with sympathetic antagonists BIBP3226 and prazosin, contraction-evoked arteriolar dilation in PD was restored to levels observed in CTRL. Furthermore, arteriolar vasoconstrictor responses to NPY (10-13 -10-8 mol/L) and PE (10-9 -10-5 mol/L) were greater in PD versus CTRL at higher concentrations, especially at 3A and 4A. These findings suggest that contraction-evoked vasodilation in PD is blunted by Y1R and alpha1R receptor activation throughout skeletal muscle arteriolar networks. PMID- 29981205 TI - Comparative evaluation of subgingivally-delivered 1% metformin and Aloe vera gel in the treatment of intrabony defects in chronic periodontitis patients: A randomized, controlled clinical trial. AB - AIM: The aim of the current study was to explore the effectiveness of locally delivered 1% metformin (MtF) and Aloe vera (AV) gel as an adjunct to scaling and root planning (SRP) in the treatment of intrabony defects in chronic periodontitis patients. METHODS: A total of 90 volunteers were randomly assigned to three treatment groups: (a) SRP + placebo gel; (b) SRP + 1% MtF gel; and (c) SRP + AV gel. Clinical parameters, including gingival index (GI), bleeding on probing (BoP), pocket probing depth (PPD), and clinical attachment level (CAL), were recorded at baseline, and 6 and 12 months. The radiological assessment of bone defect fill was done at 6 and 12 months. RESULTS: GI, BoP, PPD, and CAL improved in all the groups; however, the mean PPD reduction, CAL gain, and percentage of bone fill was found to be greater in the MtF and AV groups than the placebo group at all visits. CONCLUSION: Local delivery of 1% MtF and AV gel stimulates a significant PPD reduction, CAL gain, and improved bone fill and regeneration when compared with placebo gel. Results were significantly better with the use of 1% MtF gel than AV gel. PMID- 29981206 TI - Renal transplant from infant and neonatal donors is a feasible option for the treatment of end-stage renal disease but is associated with increased early graft loss. AB - Kidney transplants from young pediatric donors are uncommonly performed in the UK. Published literature of kidney transplant from donors weighing less than 5 kg is sparse. We present our initial experience of en bloc kidney transplantation (EKT) from donors weighing less than 20 kg, including neonatal donors. All recipients undergoing EKT from donors under 20 kg at our center from January 2005 to October 2016 were included. Donor and recipient details were recorded from a prospective database. Electronic patient records were examined for follow-up data. Of 30 EKTs included, 15 were from <=5 kg donors and 15 from >5 kg donors (median weight 3.4 and 12.7 kg, respectively). One-year graft survival for <=5 kg and >5 kg donors for EKT was 86.7% and 93.3% (P = 0.85), respectively. Progressive improvement in estimated GFR (eGFR) was noted in both donor categories through first-year posttransplant but in the <=5 kg donor category significant improvement was seen at 12 months compared to 3 months after transplantation (median eGFR 37.3 vs 70.0 mL/min/1.73 m2 , P = 0.03). Two early graft losses were attributable to early vascular complications and one graft loss due to primary nonfunction. Our data show that kidney transplantation from such donors is a feasible option at centers with experience of EKT, albeit with increased risk of early graft loss. PMID- 29981207 TI - Facilely Synthesized spiro[fluorene-9,9'-phenanthren-10'-one] in Donor-Acceptor Donor Hole-Transporting Materials for Perovskite Solar Cells. AB - We have demonstrated two novel donor-acceptor-donor (D-A-D) hole-transport material (HTM) with spiro[fluorene-9,9'-phenanthren-10'-one] as the core structure, which can be synthesized through a low-cost process in high yield. Compared to the incorporation of the conventional HTM of commonly used 2,2',7,7' tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene (Spiro-OMeTAD), the synthesis process is greatly simplified for the presented D-A-D materials, including a minimum number of purification processes. This results in an increased production yield (>55 %) and suppressed production cost (<30 $ g-1 ), in addition to high power conversion efficiency (PCE) in perovskite solar cells (PSCs). The PCE of a PSC using our D-A-D HTM reaches 16.06 %, similar to that of Spiro-OMeTAD (16.08 %), which is attributed to comparable hole mobility and charge-transfer efficiency. D-A-D HTMs also provide better moisture resistivity to prolong the lifetime of PSCs under ambient conditions relative to their Spiro OMeTAD counterparts. The proposed new type of D-A-D HTM has shown promising performance as an alternative HTM for PSCs and can be synthesized with high production throughput. PMID- 29981208 TI - Loss of slit protein nephrin is associated with reduced antioxidant superoxide dismutase expression in podocytes shed from women with preeclampsia. AB - Recent findings of podocyte shedding/podocyturia highlight the central significance of podocyte injury in preeclampsia, a hypertensive disorder unique to human pregnancy. To test the hypothesis that oxidative stress contributes to kidney podocyte injury in preeclampsia, we specifically examined expression and distribution of antioxidant CuZn-SOD with nephrin and podoplanin in shed podocytes from women with preeclampsia. Human podocyte AB 8/13 cells served as control. We found that CuZn-SOD was localized at the front/outreach region of nephrin at the cell periphery (foot process areas) in control podocytes and expression of CuZn-SOD, nephrin, and podoplanin were all dislocated or lost in shed podocytes from preeclamptic patients. We further tested oxidative stress induced nephrin shedding in podocytes, in which AB 8/13 podocytes were cultured under lowered oxygen condition (2%O2 ) or treated with hypoxic mimicking agent cobalt chloride. Our results showed that reduced nephrin and podoplanin expression were associated with downregulation of CuZn-SOD expression in podocytes when cells were cultured under lowered oxygen or hypoxic conditions. Nephrin shed in urinary specimen from preeclamptic women was also determined by immunoprecipitation/immunoblotting. The molecular sizes of nephrin that corresponded to that were lost when cells were cultured under hypoxic conditions. We concluded that increased oxidative stress plays a significant role in inducing podocyte protein shedding in preeclampsia. PMID- 29981209 TI - Prognostic tools to assess candidacy for and efficacy of antibody-removal therapy. AB - Currently, the ability to predict or monitor the efficacy of HLA antibody-removal therapies is deficient. We previously reported that titration studies are a consistent and accurate means of assessing antibody strength. To test whether titration studies can also predict which patients are better candidates for desensitization, we studied 38 patients from 3 centers (29 receiving plasmapheresis/low-dose intravenous immunoglobulin [IVIg]; 9 patients receiving high-dose IVIg). For patients undergoing plasmapheresis/low-dose IVIg, antibody titer reduction correlated with number of treatment cycles for both class I and II antibodies but only up to approximately 4 cycles. Reduction in titer slowed with additional cycles, suggesting a limit to the efficacy of this approach. Furthermore, initial titer (predesensitization) can guide the selection of candidates for successful antibody-removal treatment. In our experience, patients with antibodies at an initial titer >1:512 could not be reduced to the goal of a negative lymphocyte crossmatch, corresponding to a 1:16 titer, despite a significant increase in the number of treatment cycles. Change in mean fluorescence intensity (MFI) value did not correlate with success of treatment if initial MFI values were >10 000, likely due to single antigen bead saturation. Overall, we present a potential prognostic tool to predict candidacy and a monitoring tool to assess efficacy of desensitization treatment. PMID- 29981210 TI - Efficient and Supplementary Enzyme Cocktail from Actinobacteria and Plant Biomass Induction. AB - Actinobacteria plays a key role in the cycling of organic matter in soils. They secret biomass-degrading enzymes that allow it to produce the unique metabolites that originate in plant biomass. Although past studies have focused on these unique metabolites, a large-scale screening of Actinobacteria is yet to be reported to focus on their biomass-degrading ability. In the present study, a rapid and simple method is constructed for a large-scale screening, and the novel resources that form the plant biomass-degrading enzyme cocktail are identified from 850 isolates of Actinobacteria. As a result, Nonomuraea fastidiosa secretes a biomass degrading enzyme cocktail with the highest enzyme titer, although cellulase activities are lower than a commercially available enzyme. So the rich accessory enzymes are suggested to contribute to the high enzyme titer for a pretreated bagasse with a synergistic effect. Additionally, an optimized cultivation method of biomass induction caused to produce the improved enzyme cocktail indicated strong enzyme titers and a strong synergistic effect. Therefore, the novel enzyme cocktails are selected via the optimized method for large-scale screening, and then the enzyme cocktail can be improved via the optimized production with biomass-induction. PMID- 29981211 TI - Cellular localization of the K+ -dependent Na+ -Ca2+ exchanger NCKX5 and the role of the cytoplasmic loop in its distribution in pigmented cells. AB - NCKX5 is a bidirectional K+ -dependent Na+ -Ca2+ exchanger, which belongs to the SLC24A gene family. In particular, the A111T mutation of NCKX5 has been associated with reduced pigmentation in European populations. In contrast to other NCKX isoforms, which function in the plasma membrane (PM), NCKX5 has been shown to localize either in the trans-Golgi network (TGN) or in melanosomes. Moreover, sequences responsible for retaining its intracellular localization are unknown. This study addresses two major questions: (i) clarification of intracellular location of NCKX5 and (ii) identification of sequences that retain NCKX5 inside the cell. We designed a set of cDNA constructs representing NCKX5 loop deletion mutants and NCKX2-NCKX5 chimeras to address these two questions after expression in pigmented MNT1 cells. Our results show that NCKX5 is not a PM resident and is exclusively located in the TGN. Moreover, the large cytoplasmic loop is the determinant for retaining NCKX5 in the TGN. PMID- 29981212 TI - Association between leukocytospermia and semen interleukin-6 and tumor necrosis factor-alpha in infertile men. AB - Seminal cytokines were previously reported to adversely affect process of spermatogenesis and ultimately induce poor semen quality. However, association between both IL-6 and TNF-alpha and leukocytospermia was not yet settled. The aim of this study was to evaluate the association between leukocytospermia and levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) in semen of infertile men. This cross-sectional study included 100 age-matched (>=18-45 years.) men. Participants were divided into four groups with 25 patients in each group: Group (A) - infertile patients with leukocytospermia and normal other semen parameters; Group (B) - infertile patients with leukocytospermia and abnormal semen parameters; Group (C) - infertile patients with oligospermia and/or asthenospermia and/or teratospermia but with no leukocytospermia; Group (D) - fertile patients with normal semen parameters and without leukocytospermia. All patients were assessed by detailed medical, sexual, fertility history, and complete physical examination. Laboratory assessment included hormonal and semen analysis and assessment of IL-6 and TNF-alpha in semen plasma. There were significant differences among the study groups regarding total sperm count, sperm concentration, and progressive motility (p < 0.05 for each). There was significant increase in semen WBC counts in groups A and B vs. groups C and D (p = 0.003). There were significant associations between increase levels of WBCs >= 5/HPF and decrease levels of total sperm count (p = 0.023), sperm concentration (p = 0.001), and sperm progressive motility (p = 0.02). There were significant upregulations in mean level of IL-6 (p = 0.001) and mean level of TNF-alpha (p = 0.003) in groups A and B vs. groups C and D. Overall, leukocytospermia is associated with reduction in sperm count, progressive motility and further upregulation of seminal IL-6 and TNF-alpha. The effect of treatment of leukocytospermia on the level of seminal cytokines is important point of future research. PMID- 29981213 TI - Suicide Deaths. PMID- 29981214 TI - Echocardiography in transcatheter aortic (Core)Valve implantation: Part 2 Transesophageal echocardiography. AB - Transesophageal echocardiography (TEE) plays a significant role during transcatheter aortic valve implantation (TAVR). 2DTEE allows assessment of anatomy of the aortic valve, aortic root, left ventricular (LV) outflow tract, severity of the aortic valve stenosis (AS), and the presence and severity of other valve stenosis and regurgitation. Left and right ventricular size and global function as well as cardiac hemodynamics pre and post TAVR and LV regional wall motion can be assessed. Three-dimensional (3D) imaging adds significantly via accurate measurement of aortic annulus that helps select the appropriate valve size. Biplane imaging allows simultaneous assessment of target cardiac structure in two orthogonal views and provides a rapid assessment during and immediately post valve deployment by evaluating stent height, leaflet motion, and the presence and severity of paravalvular leak (PVL). 2DTEE and 3DTEE allow evaluation of mechanism of PVL that helps guide the decision regarding need for balloon post dilation of the implanted valve or valve in valve implantation. PMID- 29981215 TI - Hair, encoding a single C2H2 zinc-finger protein, regulates multicellular trichome formation in tomato. AB - Trichomes originate from the epidermal cells of nearly all terrestrial plants, which are specialized unicellular or multicellular structures. Although the molecular mechanism regulating unicellular trichome formation has been extensively characterized, most of the genes essential for multicellular trichome formation remain unknown. In this study, we identified an associated locus on the long arm of chromosome 10 using a genome-wide association study (GWAS) on type-I trichomes of 180 diverse Solanum lycopersicum (tomato) accessions. Using map based cloning we then cloned the key gene controlling the initiation of this type of trichome, named Hair (H), which encodes a single C2H2 zinc-finger protein. Transgenic experiments showed that hair-absent phenotype is caused by the deletion of the entire coding region of H. We identified three alleles of H containing several missense mutations and a nucleotide deletion, which result in amino acid substitutions and a reading frame shift, respectively. In addition, knockdown of H or Woolly (Wo) represses the formation of type-I trichomes, suggesting that both regulators may function as a heterodimer. Direct protein protein interaction between them was further detected through pull-down and yeast two-hybrid assays. In addition, ectopic expression of H in Nicotiana tabacum (tobacco) and expression of its homologs from Capsicum annuum (pepper) and tobacco in tomato can trigger trichome formation. Taken together, these findings suggest that the H gene may be functionally conserved in multicellular trichome formation in Solanaceae species. PMID- 29981216 TI - The interaction between DNA methylation and long non-coding RNA during the onset of puberty in goats. AB - Epigenetics plays an important role in controlling female puberty. Both DNA methylation and long non-coding RNAs (lncRNA) regulate the initiation of puberty by affecting the expression of genes related to puberty. While recent studies have indicated that DNA methylation of lncRNA represses the expression of lncRNA, its role in regulating puberty remains unclear. To explore the mechanism between DNA methylation and lncRNAs during puberty onset, we performed whole-genome bisulphite sequencing (WGBS) and RNA-sequencing (RNA-seq). We found that DNA methylation was inversely correlated to gene expression levels during puberty. Methylation levels gradually decreased near the transcription initiation site and were present at high levels in the exon, intron and 3' untranslated regions. In the promoter, lncRNA expression was negatively related to DNA methylation. We reported hypermethylation in the gene body and downstream of the lncRNA compared with upstream regions. In GO and KEGG analyses, we found enriched target genes of lncRNA, XLOC_960044 and XLOC_767346. During puberty, methylation of these genes increased while expression decreased. Our study indicates that DNA methylation of the promoter is negatively correlated with lncRNA during puberty onset, and methylation regulates the initiation of puberty via lncRNA, which provides new insight into the epigenetic mechanism of puberty onset. PMID- 29981217 TI - No impact of disseminated intravascular coagulation in kidney donors on long-term kidney transplantation outcome: A multicenter propensity-matched study. AB - The diagnosis of disseminated intravascular coagulation (DIC) is often considered to be a contraindication to organ donation. The aim of this study was to evaluate the impact of DIC+ donors on kidney recipient (KR) evolution. We identified 169 KRs with DIC+ donation after brain death donors between January 1996 and December 2012 in 6 French transplant centers. Individuals were matched using propensity scores to 338 recipients with DIC- donors according to donor age and sex, whether expanded criteria for the donor existed, graft year, and transplantation center. After kidney transplantation, delayed graft function was observed in 28.1% of DIC+ KRs and in 22.8% of DIC- KRs (NS). Renal allograft survival at 1, 5, and 10 years was 94.5%, 89.3%, and 73.9% and 96.2%, 90.8%, and 81.3% in DIC+ KRs and DIC KRs, respectively (NS). The median estimated glomerular filtration rate (eGFR) was similar between DIC+ and DIC- KRs at 3 months, 1 year, and 10 years: 45.9 vs 48.1 mL/min, 42.1 vs 43.1 mL/min, and 33.9 vs 38.1 mL/min, respectively. Delayed calcineurin inhibitor introduction or induction had no impact on delayed graft function rate or eGFR evolution at 10 years after transplantation in DIC+ KRs. Donor DIC did not seem to affect initial outcome, long-term graft function, or allograft survival. PMID- 29981219 TI - Quantification of the Leydig cell compartment in testicular biopsies and association with biochemical Leydig cell dysfunction in testicular cancer survivors. AB - A simple histological method to evaluate the Leydig cell compartment is lacking. We aimed to establish such a method and to investigate if Leydig cell hyperplasia of the biopsy contralateral to the tumour-bearing testicle in patients with testicular germ cell cancer is associated with biochemical signs of Leydig cell dysfunction after long-term follow-up. A case group of 50 long-term testicular germ cell cancer survivors without human chorionic gonadotropin elevation, 10 testicular germ cell cancer patients with elevated human chorionic gonadotropin and 10 controls without testicular malignancy were included. For each subject, 2 4 representative sections from their testicular biopsies were selected for analysis. Using the image processing program ImageJ (V.1.48, NIH), an area with a minimum of 50 tubules was selected and delineated (total selected area) and the total Leydig cell area was calculated by adding up every delineated Leydig cell group within the total selected area. Four different methods were tested for the ability to quantify the Leydig cell compartment. In the 50 testicular germ cell cancer survivors, associations between the area of the Leydig cell compartment and serum levels of testosterone and luteinising hormone were investigated using linear regression analysis. The Leydig cell compartment was best quantified by the total Leydig cell area/total selected area index, which was significantly larger in the human chorionic gonadotropin-positive patients than in controls (P = 0.00001). In the 50 human chorionic gonadotropin-negative testicular germ cell cancer survivors, increasing total Leydig cell area/total selected area was significantly associated with decreased levels of total testosterone and decreased total testosterone/luteinising hormone ratio after a median of 9-year follow-up. In conclusion, a new simple method, total Leydig cell area/total selected area, was established to estimate the Leydig cell compartment in testicular biopsies. The index identified Leydig cell hyperplasia in the contralateral biopsy in patients with testicular germ cell cancer, and it was associated with long-term biochemical Leydig cell dysfunction. Although in testicular germ cell cancer survivors, the clinical value is limited because the contralateral biopsies are not commonly available, we propose a closer andrological follow-up in any patient with an increased total Leydig cell area/total selected area index. PMID- 29981218 TI - Impact of aging on diaphragm muscle function in male and female Fischer 344 rats. AB - The diaphragm muscle (DIAm) is the primary inspiratory muscle in mammals and is active during ventilatory behaviors, but it is also involved in higher-force behaviors such as those necessary for clearing the airway. Our laboratory has previously reported DIAm sarcopenia in rats and mice characterized by DIAm atrophy and a reduction in maximum specific force at 24 months of age. In Fischer 344 rats, these studies were limited to male animals, although in other studies, we noted a more rapid increase in body mass from 6 to 24 months of age in females (~140%) compared to males (~110%). This difference in body weight gain suggests a possible sex difference in the manifestation of sarcopenia. In mice, we previously measured transdiaphragmatic pressure (Pdi) to evaluate in vivo DIAm force generation across a range of motor behaviors, but found no evidence of sex related differences. The purpose of this study in Fischer 344 rats was to evaluate if there are sex-related differences in DIAm sarcopenia, and if such differences translate to a functional impact on Pdi generation across motor behaviors and maximal Pdi (Pdimax ) elicited by bilateral phrenic nerve stimulation. In both males and females, DIAm sarcopenia was apparent in 24-month old rats with a ~30% reduction in both maximum specific force and the cross sectional area of type IIx and/or IIb fibers. Importantly, in both males and females, Pdi generated during ventilatory behaviors was unimpaired by sarcopenia, even during more forceful ventilatory efforts induced via airway occlusion. Although ventilatory behaviors were preserved with aging, there was a ~20% reduction in Pdimax , which likely impairs the ability of the DIAm to generate higher-force expulsive airway clearance behaviors necessary to maintain airway patency. PMID- 29981221 TI - A focus on quality. PMID- 29981220 TI - Corrigendum. PMID- 29981222 TI - Miniature ureteroscope distal tip designs for potential use in thulium fiber laser lithotripsy. AB - Thulium fiber laser lithotripsy using smaller optical fibers may enable development of miniature ureteroscopes. Two ureteroscope distal tip prototypes were built and characterized. The first design was 4.5-French (Fr) [1.5-mm outer diameter (OD)], five channel tip, housing 200-MUm inner diameter (ID) dedicated central channel for insertion of 100-MUm core fibers and four surrounding channels, each with 1.5 Fr (510-MUm ID) for instrumentation, irrigation, imaging, and illumination, respectively. The second design was 6.0-Fr (2.0-mm OD), three dimensional printed tip with larger, hemispherical common working channel and separate detection port integrated with ring lighting. Standard instruments, including optical fibers, guidewires, and stone baskets, were inserted through working channels to demonstrate feasibility. Gravitational and manual pump assisted saline irrigation rates were measured. Luminous intensity distribution curves (LIDCs) were modeled for both ring and conventional lighting designs. Imaging was conducted using 3000, 6000, and 10,000 pixel, miniature, flexible endoscopes with 0.4-, 0.6-, and 0.9-mm OD, to differentiate between urinary stones and ureter wall, for potential clinical application. The multichannel ureteroscope tip with 1.5-Fr working channel yielded a gravitational saline flow rate of 3.9 +/- 0.2 mL / min compared to 31.3 +/- 0.6 mL / min for standard (3.6 Fr) ureteroscope channel. Manual, pump-assisted irrigation increased flow rate to 32.5 +/- 3.0 mL / min. The 6000 pixel, 0.6-mm OD, flexible endoscope provided a balance of clear differentiation between stones and ureter wall and sufficiently small OD. A ring lighting configuration provided more uniform illumination than conventional cross-lighting geometry as demonstrated by LIDCs. With further development, these miniature ureteroscope tip designs may be integrated into a fully functional ureteroscope to permit ureteral access with minimal trauma and improved patient safety and comfort. PMID- 29981223 TI - Measurements of the optical coefficients of the protoporphyrin IX endogenously producing yeast-based model in the visible and NIR. AB - Models mimicking the endogenous production of protoporphyrin IX (PpIX), as well as its fluorescence, are of high interest for applied and fundamental studies in the fields of cancer detection by fluorescence imaging, photodynamic therapy (PDT), and photobiomodulation (PBM). Here, we present and describe optical properties of the yeast-based models able to produce PpIX endogenously after the administration of 5-aminolevulinic acid (ALA) and/or 2,2'-bipyridyl. As their optical properties have an important impact on the spatial distribution of the fluence rate in these liquid models, their absorption and reduced scattering coefficients were determined to be between 400 and 808 nm for two yeast solutions previously described by our group. These coefficients were derived from measurements of the total reflectance and light penetration depth using a dedicated Monte Carlo simulation. We observed that absorption and scattering coefficients were smaller than those of soft tissues at all wavelengths. This work will enable the production of a low-cost optical phantom loaded with appropriate amounts of light-absorbing and -scattering particles to mimic tumors containing PpIX, offering a useful tool to optimize the spectral and radiometric design of certain cancer photodetection setups. PMID- 29981224 TI - Fully automated fiber-based optical spectroscopy system for use in a clinical setting. AB - While there are a plethora of in vivo fiber-optic spectroscopic techniques that have demonstrated the ability to detect a number of diseases in research trials with highly trained personnel familiar with the operation of experimental optical technologies, very few techniques show the same level of success in large multicenter trials. To meet the stringent requirements for a viable optical spectroscopy system to be used in a clinical setting, we developed components including an automated calibration tool, optical contact sensor for signal acquisition, and a methodology for real-time in vivo probe calibration correction. The end result is a state-of-the-art medical device that can be realistically used by a physician with spectroscopic fiber-optic probes. We show how the features of this system allow it to have excellent stability measuring two scattering phantoms in a clinical setting by clinical staff with ~0.5 % standard deviation over 25 unique measurements on different days. In addition, we show the systems' ability to overcome many technical obstacles that spectroscopy applications often face such as speckle noise and user variability. While this system has been designed and optimized for our specific application, the system and design concepts are applicable to most in vivo fiber-optic-based spectroscopic techniques. PMID- 29981225 TI - Dual-axis illumination for virtually augmenting the detection view of optical resolution photoacoustic microscopy. AB - Optical-resolution photoacoustic microscopy (OR-PAM) has demonstrated fast, label free volumetric imaging of optical-absorption contrast within the quasiballistic regime of photon scattering. However, the limited numerical aperture of the ultrasonic transducer restricts the detectability of the photoacoustic waves, thus resulting in incomplete reconstructed features. To tackle the limited-view problem, we added an oblique illumination beam to the original coaxial optical acoustic scheme to provide a complementary detection view. The virtual augmentation of the detection view was validated through numerical simulations and tissue-phantom experiments. More importantly, the combination of top and oblique illumination successfully imaged a mouse brain in vivo down to 1 mm in depth, showing detailed brain vasculature. Of special note, it clearly revealed the diving vessels that were long missing in images from original OR-PAM. PMID- 29981226 TI - Electrochemically deposited silver detection substrate for surface-enhanced Raman spectroscopy cancer diagnostics. AB - Surface-enhanced Raman spectroscopy (SERS) of blood plasma on an electrochemically prepared silver surface has been studied as a label-free, noninvasive diagnostic test for colorectal cancer. Indium tin oxide glass substrates were modified with 0.01 mol dm - 3 silver nitrate using the pulsed double-potentiostatic method. The prepared silver substrates were tested with Rhodamine 6G as a model analyte and the surface with the highest signal enhancement was selected. This silver dendritic surface was used as a diagnostic substrate for SERS measurements of human blood plasma. A group of oncological patients with declared colorectal carcinoma (n = 15) and the control group of healthy volunteers (n = 15) were compared. The biomolecular changes in chemical composition in the cancer samples were detected by statistical processing of the resulting SERS spectra. About 94% specificity and 100% sensitivity were achieved for the analysis by the ratio of the SERS peak intensity at 725 cm - 1 for adenine to the peak intensity at 638 cm - 1 for tyrosine and 100% specificity and sensitivity by using principal component analysis. This method of SERS diagnostics of colorectal cancer, which does not require the nanoparticle preparation, mixing, and incubation of plasma with a colloidal solution as in conventional tests, is a rapid, inexpensive method, which could be introduced as a primary diagnostic test. PMID- 29981227 TI - Special Section Guest Editorial: Special Section on Selected Topics in Biophotonics: Optogenetics and Label-Free Optical Spectroscopy. AB - A guest editorial to introduce the Special Section on Selected Topics in Biophotonics: Optogenetics and Label-Free Optical Spectroscopy. PMID- 29981228 TI - Depth-resolved mapping of muscular bundles in myocardium pulmonary junction using optical coherence tomography. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and has high patient morbidity. One of the root causes of AF is initiating triggers from atrial myocardium extending into the pulmonary veins. Visualizing the muscular bundles of myocardial extension is essential to guide the catheter radio frequency ablation and confirm the curative tissue necrosis thereafter. We applied optical coherence tomography (OCT) for direct visualization of cardial muscle extension in myocardium pulmonary junction. Two perspectives (cross sectional and en face images) are presented for imaging myocardial extensions. The results demonstrated that cross-sectional images can quickly locate the myocardium pulmonary junction. And en face images provide depth-resolved arrangement information of muscular bundles in the myocardium pulmonary junction. The results indicated that OCT could potentially be used to guide catheter radio frequency ablation for treatment of AF. PMID- 29981229 TI - Through-focus or volumetric type of optical imaging methods: a review. AB - In recent years, the use of through-focus (TF) or volumetric type of optical imaging has gained momentum in several areas such as biological imaging, microscopy, adaptive optics, material processing, optical data storage, and optical inspection. We provide a review of basic TF optical methods highlighting their design, major unique characteristics, and application space. PMID- 29981230 TI - Nile Red derivatives enable improved ratiometric imaging for nerve-specific contrast. AB - Surgical nerve damage due to difficulty with identification remains a major risk for postsurgical complications and decreased quality of life. Fluorescence-guided surgery offers a means to specifically highlight tissues of interest such as nerves and a number of fluorescence-guided surgical systems are in clinical trial or are approved for clinical use. However, no clinically approved nerve-specific fluorophores exist. In addition, many preclinical nerve-specific fluorophores tend to accumulate in adipose tissue due to the molecular composition similarities between the two tissues, making it challenging to generate a specific nerve signal. To alleviate this difficulty, we have synthesized a library of oxazine fluorophores based on the Nile Red scaffold, with the goal of strong adipose specificity without nerve uptake to facilitate ratiometric imaging. The library was screened for tissue specificity ex vivo and in vivo, enabling quantification of adipose-, nerve- and muscle-specific uptake as well as selection of the best candidate for adipose selectivity without nerve signal. We showed our selected Nile Red fluorophore improved nerve contrast using ratiometric imaging, especially nerve-to-adipose contrast as compared to the parent Nile Red compound or nerve-specific imaging alone. This adipose-specific Nile Red derivative could be used in future fluorescence-guided surgery applications where adipose- or nerve-specific contrast is required. PMID- 29981231 TI - Gender-based violence among Rohingya refugees in Bangladesh: a public health challenge. AB - On August 25, 2017, the military and paramilitary forces of Myanmar launched "clearance operations" against the Rohingya population in Rakhine state of Myanmar. In the resulting humanitarian crisis, a Medecins Sans Frontieres (MSF) report estimated that the number of deaths crossed 9000 within the first 31 days of these "operations". In addition to mass murder, other atrocities including burning down of residences, torture, rape, kidnapping continued to be practised on the Rohingya living in Myanmar. Those who could escape, braved great risks to cross the border between Bangladesh and Myanmar to seek refuge in Cox's Bazar district of Bangladesh. Currently, the number of refugees living in temporary camps has crossed one million, and local and international agencies are attempting to support them with basic living amenities and medical care. Their physical and mental health status is a global concern calling for immediate action. The magnitude of violence has been much higher among the adolescent girls and women of reproductive age. PMID- 29981232 TI - Under-recognised ethical dilemmas of diabetes care in resource-poor settings. AB - Ineffective diabetes management results in suboptimal glycaemic control and adverse health outcomes. In resource-poor settings, a combination of high burden of medication nonadherence in patients and therapeutic inertia amongst clinicians is largely attributed to the failure to achieve glycaemic targets in diabetic populations. The potential health risks from intensification of medical therapy for aggressive lowering of glucose levels in Type 2 diabetes patients represents an ethical dilemma between averting risk from overtreatment and preventing future harm from raised blood glucose levels. However, the ethical dilemmas experienced by clinicians in most of the developing world when contemplating prescription of additional oral hypoglycaemic agents or initiating insulin have received little attention from the medical community. Such ethical dilemmas unique to resource poor settings often emerge from poor availability of drugs, diagnostics and physician consultation time for diabetic patients. Furthermore, existing evidence based guidelines for diabetes management assume a standard of care which is lacking in such settings. This often compels the developing world clinicians when confronted with such diabetes-related ethical dilemmas to rely solely on their clinical judgement which could be ethically unjust and medically prone to error. Newer research needs to generate evidence to develop best practice guidelines for optimal therapeutic outcomes, while acknowledging the reality of limited healthcare services available in resource-poor settings. PMID- 29981233 TI - Ethical gaps in conducting research among adult survivors of child sexual abuse: a review. AB - Although there have been numerous studies, especially in the last few decades, on the impact of child sexual abuse (CSA) on adult survivors, there is a dearth of studies focusing on the ethical aspects of research in this area. Against this background, we reviewed the literature published between January 2000 and December 2016 on the reporting of ethical guidelines followed in research on adult survivors of CSA. We conducted a PubMed (MEDLINE) and Google Scholar search to find published research, using the keywords: "child sexual abuse", "adult survivors", "research", "guidelines" and "ethics". Our findings suggest that no particular assessment method is superior in terms of disclosure of information or reduction of distress. The use of developmentally appropriate educative materials, sensitisation, and debriefing sessions have shown some benefit in reducing distress. There is a lack of legal or social consensus on mandatory legal reporting of information provided by adult survivors of sexual abuse, with most researchers working on the premise that adults have the freedom of choice. Often, a constraint among researchers is the lack of structured training or supervision in sensitive research, which may negatively impact both the participant and the researcher. Institute ethics boards and institutions currently lack the framework to consider protocols and facilitate research, and this poses serious obstacles to fostering research. In this situation, ongoing research needs to focus on ethical aspects. Together with this, we recommend certain ethical practices drawn from various studies that may be employed for participants, researchers, and institutional ethics boards. PMID- 29981234 TI - Global research partnerships in advancing public health: A case study on India. AB - Collaborative research is integral to medicine. Multi-national and multi institutional research partnerships produce advances in medicine and public health that have a significant societal impact. Developing nations can gain from such collaborative partnerships in achieving progress in sustainable development goals. However, it is important that the research agenda is relevant to the region where studies are conducted. Funding of research by the national government and regional organisations will ensure that the research is appropriate for the region, and ethically rigorous. In this study, I investigated the characteristics of research partnerships in India, especially the sources of research funding. PMID- 29981235 TI - Perceived need and attitudes towards communication skill training in recently admitted undergraduate medical students. AB - The Medical Council of India intends to implement an attitude, ethics, and communication training module for medical students. This study investigates undergraduate students' attitudes towards communication skills training (CST). Forms were distributed to 81 recently admitted undergraduates, of whom 76 responded, in an anonymous cross-sectional survey. Single questions assessed knowledge of communication skills (CS), need for formal curriculum, and importance of CST. Attitudes toward CS were measured using a modified Communication Skills Attitude Scale. While 72% participants considered CST to be important and 68.4% reported a need for formal training, 43% felt CST would have a better image if it sounded more like a science subject. Forty percent of the students were ambiguous about willingness to trust information on communication skills given by non-clinical lecturers, whereas 15.8% were not receptive. Fifty five percent felt nobody would fail because of poor communication skills, and 46% felt that the ability to pass exams would get them through medical school. We found a high prevalence of unfavourable attitudes about CS (as a subject). Course implementers should be mindful of and address attitudes towards CST while delivering the content of the course. PMID- 29981236 TI - Glucocorticoid-Induced Transcription Factor 1 (GLCCI1) Variant Impacts the Short Term Response to Intranasal Corticosteroids in Chinese Han Patients with Seasonal Allergic Rhinitis. AB - BACKGROUND Genetic correlations with the response to intranasal corticosteroids (INCS) in seasonal allergic rhinitis (SAR) treatment are unknown. This study aimed to evaluate the role of gene polymorphisms in the response to INCS in Chinese Han patients with moderate to severe SAR. MATERIAL AND METHODS In this study, 286 Chinese Han patients with SAR were genotyped for 4 candidate genes: the glucocorticosteroid receptor (NR3C1) gene, glucocorticoid-induced transcription factor 1 (GLCCI1) gene, T-box 21 gene (TBX21), and ATP binding cassette subfamily B member 1 (ABCB1) gene. Patients were treated with INCS for 4 weeks. The total nasal symptom score (TNSS), total ocular symptom score (TOSS), and visual analogue scale (VAS) score were assessed at baseline and on week 4. The primary endpoint was the effective rate after 4 weeks of INCS therapy. RESULTS In addition to the known contributing factors, one genotype of GLCCI1, namely, rs37973, was significantly associated with the INCS response (OR=0.598, 95% confidence interval: 0.41 to 0.87, P=0.007). The effective rate of the GG group was lower than those of the AA and AG groups (AA vs. GG: 73.7% vs. 51.6%, P=0.007; AG vs. GG: 78.8% vs. 51.6%, P=0.000). In addition, the TNSS, TOSS, and VAS were higher for the patients in the GG group than for those in the AA and AG groups on week 4. CONCLUSIONS The GLCCI1 rs37973 variant is a risk factor for glucocorticoid resistance in Chinese patients with SAR who receive short-term INCS treatment. PMID- 29981237 TI - Metabolic engineering of Bacillus subtilis for l-valine overproduction. AB - Bacillus subtilis has been commonly applied to industrial enzyme production due to its genetic tractability, "generally recognized as safe (GRAS)" status, and robust growth characteristics. In spite of its ideal attributes as a biomanufacturing platform, B. subtilis has seen limited use in the production of other value-added biochemicals. Here, we report the derivation of engineered strains of B. subtilis for l-valine overproduction using our recently developed CRISPR (clustered regularly interspaced palindromic repeats)-Cas9 (CRISPR associated [protein] 9) toolkit. We first manipulate the native l-valine biosynthetic pathway by relieving transcriptional and allosteric regulation, resulting in a >14-fold increase in the l-valine titer, compared to the wild-type strain. We subsequently identify and eliminate factors limiting l-valine overproduction, specifically increasing pyruvate availability and blocking the competing l-leucine and l-isoleucine biosynthetic pathways. By inactivating (a) pdhA, encoding the E1alpha subunit of the pyruvate dehydrogenase complex, to increase the intracellular pyruvate pool, and (b) leuA and ilvA, respectively encoding 2-isopropylmalate synthase and l-threonine dehydratase, to abolish the competing pathways, the l-valine titer reached 4.61 g/L in shake flask cultures. Our engineered l-valine-overproducing strains of B. subtilis are devoid of plasmids and do not sporulate due to the inactivation of sigF, encoding the sporulation-specific transcription factor sigma F , making them attractive for large-scale l-valine production. However, acetate dissimilation was identified as limiting l-valine overproduction in DeltapdhA B. subtilis strains, and improving acetate dissimilation or identifying alternate modes of increasing pyruvate pools to enhance l-valine-overproduction should be explored. PMID- 29981239 TI - Cranial ultrasound and neurophysiological testing to predict neurological outcome in infants born very preterm. AB - AIM: Infants born preterm are at risk of cerebral palsy (CP) and motor or cognitive developmental delay. For clinicians, it is essential to know the relative predictive accuracy of the most commonly used neuroimaging and neurophysiological tests for the early prediction of adverse neurodevelopmental outcome. The aim of this study was to compare the accuracy of these tests in survivors of a population of infants born very preterm. METHOD: A retrospective cohort study was performed in 163 children born before 32 weeks gestational age. We compared the accuracy in predicting adverse neurodevelopmental outcome at the age of 2 years 6 months of early and late cranial ultrasound (CUS), magnetic resonance imaging, somatosensory evoked potentials after stimulation of the posterior tibial nerve, and electroencephalography by calculating positive and negative likelihood ratios. RESULTS: An abnormal early CUS is the best predictor of the presence of CP (positive likelihood ratio 6.09), motor developmental delay (positive likelihood ratio 3.11), and cognitive developmental delay (positive likelihood ratio 5.66). Overall, negative likelihood ratios were poor, ranging between 0.49 and 0.98, meaning that a normal test result had only minimal influence on the probability of adverse neurological outcome. INTERPRETATION: None of the diagnostic tests had a good performance in predicting future neurodevelopmental problems in infants born preterm. A normal test result provided very little clinically useful information. WHAT THIS PAPER ADDS: An abnormal early cranial ultrasound (positive test result) is the best predictor of adverse neurodevelopmental outcome. All negative results have poor predictive value of future neurodevelopmental problems. PMID- 29981238 TI - Angiotensin II, a stress-related neuropeptide in the CNS, facilitates micturition reflex in rats. AB - BACKGROUND AND PURPOSE: We investigated the effects of centrally administered stress-related neuropeptide, angiotensin II, on the micturition reflex and the downstream signalling pathways in rats. EXPERIMENTAL APPROACH: Male Wistar rats were anaesthetized with urethane for cystometry before and after i.c.v. administration of vehicle or angiotensin II (30 pmol). Muscimol (a GABAA receptor agonist) or baclofen (a GABAB receptor agonist) was i.c.v. administered 30 min before or 15 min after central angiotensin II administration. Telmisartan [an angiotensin II type 1 (AT1 ) receptor antagonist], valsartan (an AT1 receptor antagonist), PD123319 (an AT2 receptor antagonist), U-73122 (a PLC inhibitor), chelerythrine chloride (a PKC inhibitor), apocynin (a NADPH oxidase inhibitor) or tempol (an antioxidant) was centrally administered 30 min before central angiotensin II administration. KEY RESULTS: Centrally administered angiotensin II significantly shortened the intercontraction interval and decreased the voided volume and bladder capacity without altering the maximum voiding pressure, post voiding residual urine volume or voiding efficacy. Muscimol, baclofen, telmisartan, valsartan, U-73122, chelerythrine chloride, apocynin or tempol pretreatment significantly suppressed the reduction in intercontraction interval induced by central angiotensin II. Post-treatment with muscimol or baclofen also ameliorated the decrease in intercontraction interval induced by central angiotensin II. CONCLUSIONS AND IMPLICATIONS: Angiotensin II in the CNS facilitates micturition reflex by inhibiting central GABAergic activity and activating the AT1 receptor/PLC/PKC/NADPH oxidase/superoxide anion pathway. PMID- 29981240 TI - Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol dimethylheptyl at the type 1 and type 2 cannabinoid receptors. AB - BACKGROUND AND PURPOSE: We sought to understand why (-)-cannabidiol (CBD) and (-) cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures. EXPERIMENTAL APPROACH: HEK293A cells expressing either human type 1 cannabinoid (CB1 ) receptors or CB2 receptors were treated with CBD or CBD-DMH with or without the CB1 and CB2 receptor agonist CP55,940, CB1 receptor allosteric modulator Org27569 or CB2 receptor inverse agonist SR144528. Ligand binding, cAMP levels and betaarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB1 or CB2 receptors, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist bound (5TGZ) human CB1 receptors. KEY RESULTS: At CB1 receptors, CBD was a negative allosteric modulator (NAM), and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB1 receptors (5TGZ) but shared a binding site with CP55,940 in the agonist-bound model of CB1 receptors (5XRA). The binding site for CBD-DMH in the CB1 receptor models overlapped with CP55,940 and Org27569. At CB2 receptors, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation but a NAM of betaarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB2 receptor models that was separate from CBD-DMH. CONCLUSION AND IMPLICATIONS: The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB1 and CB2 receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1 and CB2 receptors. PMID- 29981241 TI - Neuromuscular ultrasound in electrically non-localizable ulnar neuropathy. AB - INTRODUCTION: The aim of this study was to determine the value of high-resolution ultrasound (HRUS) in patients with ulnar neuropathy whose electrophysiology displayed an axonal, non-localizing pattern. METHODS: A prospective study of patients referred to an electromyography laboratory for ulnar neuropathy was performed. Of the 56 patients with clinical and electrodiagnostic (EDx) evidence of ulnar neuropathy, 12 were identified with non-localizing electrophysiology who subsequently underwent HRUS of the ulnar nerve. RESULTS: HRUS localized the ulnar neuropathy in all patients. In 2 patients, HRUS demonstrated structural lesions not at the elbow. DISCUSSION: HRUS often adds complementary information to standard EDx studies, including ulnar neuropathy. Thus, HRUS should be employed in patients with a non-localizing ulnar neuropathy on EDx studies. Muscle Nerve 58: 655-659, 2018. PMID- 29981242 TI - Muscle morphology of the lower leg in ambulant children with spastic cerebral palsy. AB - INTRODUCTION: In this study we aimed to determine the lower limb morphological characteristics of skeletal muscle of ambulant children with spastic cerebral palsy (CP) and typically developing (TD) children. METHODS: Seventeen children with spastic diplegic CP (10 boys and 7 girls, 5-12 years of age, Gross Motor Function Classification System [GMFCS] level I or II) and 19 TD children (8 boys and 11 girls, 5-11 years of age) underwent lower limb T1-weighted MRI. Morphological characteristics of the triceps surae, including muscle volume, anatomical cross-sectional area, muscle length, and subcutaneous adipose tissue, were digitally quantified, and the proportional distribution calculated. RESULTS: Children with GMFCS II had significantly reduced muscle volume, cross-sectional area, and muscle length, and increased subcutaneous fat compared with TD children. Children classified as GMFCS II consistently exhibited the greatest deficits in all morphology variables. DISCUSSION: Morphological variables were significantly different between the groups. These alterations have the potential to influence the functional capabilities of the triceps surae muscle group. Muscle Nerve, 2018. PMID- 29981243 TI - Use Of Ankle Immobilization In Evaluating Treatments To Promote Longitudinal Muscle Growth In Mice. AB - INTRODUCTION: Difficulty in modeling congenital contractures (deformities of muscle-tendon unit development that include shortened muscles and lengthened tendons) has limited research of new treatments. METHODS: Early immobilization of the ankle in prepuberal mice was used to produce deformities similar to congenital contractures. Stretch treatment, electrostimulation, and local intramuscular injection of a follistatin analog (FST-288) were assessed as therapeutic interventions for these deformities. RESULTS: Ankle immobilization at full plantarflexion and 90 degrees created tendon lengthening and muscle shortening in the tibialis anterior and soleus. Stretch treatment produced minimal evidence for longitudinal muscle growth and electrostimulation provided no additional benefit. Stretch treatment with FST-288 produced greater longitudinal muscle growth and less tendon lengthening, constituting the best treatment response. DISCUSSION: Ankle immobilization recapitulates key morphologic features of congenital contracture, and these features can be mitigated by a combination of stretch and pharmacological approaches that may be useful in patients. Muscle Nerve 58: 718-725, 2018. PMID- 29981244 TI - CoO/Co-Activated Porous Carbon Cloth Cathode for High Performance Li-S Batteries. AB - Li-S batteries are one of the most promising candidates for the next generation of batteries because of their high theoretical specific capacity of 1675 mA h g-1 . However, the dissolution of polysulfide causes severe capacity fading during cycling. Herein, a 3 D CoO/Co-activated free-standing porous carbon fiber cloth (CoO/Co@PCF) is designed to suppress polysulfide diffusion from the cathode. The metallic Co and polar CoO can anchor polysulfide through Co-S ionic bonding and the pores of the carbon cloth can provide abundant active sites for electrochemical reactions. Specifically, sulfur in the cathode is loaded by sulfur vapor deposition, which is scalable for fabrication and adjustable to the sulfur-loading amount. The CoO/Co@PCF cathode with sulfur loading of 3 mg cm-2 displays high discharge capacities of 1214.2 and 684.3 mA h g-1 at 0.1 and 2 C, respectively. When the sulfur loading is increased to 5.4 mg cm-2 , low capacity fading of 0.075 % per cycle over 100 cycles at 0.5 C is still observed. PMID- 29981245 TI - Current and future treatment of hidradenitis suppurativa. AB - This scholarly review on the current and future treatment of hidradenitis suppurativa (HS) focuses on medical and surgical treatment options, while novel pipeline drugs are also discussed. Treatment goals are to limit the incidence and duration of flares, reducing inflammation and suppuration, achieving local cure after surgery and, most importantly, to improve the quality of life of patients with HS. The type of medication and/or surgery should be chosen based on the stage of the disease and the degree of inflammation. However, the lack of a simple scoring system and the lack of clear surgical outcome definitions hamper the interpretation of treatment efficacy and the comparison between different treatment strategies. The therapeutic pipeline for HS is gradually expanding, and will probably lead to a broader panel of more effective therapeutic options. PMID- 29981247 TI - Motor unit number estimation of human abductor hallucis from a compound muscle action potential scan. AB - INTRODUCTION: This study performed motor unit number estimation (MUNE) of the abductor hallucis (AH) muscle from 16 healthy control participants on the basis of the compound muscle action potential (CMAP) scan. METHODS: Muscle responses to electrical stimuli ranging from subthreshold to supramaximal intensity were recorded, and MUNE was determined from a model of the responses (MScanFit program). RESULTS: The average CMAP amplitude and MUNE of the AH for the right and left sides combined were 19.6 +/- 0.75 mV and 127 +/- 5 (mean +/- SE), respectively. DISCUSSION: Findings of the study provide useful information about the motor unit number of the AH. Muscle Nerve 58: 735-737, 2018. PMID- 29981246 TI - High expression of CD44v9 and xCT in chemoresistant hepatocellular carcinoma: Potential targets by sulfasalazine. AB - CD44v9 is expressed in cancer stem cells (CSC) and stabilizes the glutamate cystine transporter xCT on the cytoplasmic membrane, thereby decreasing intracellular levels of reactive oxygen species (ROS). This mechanism confers ROS resistance to CSC and CD44v9-expressing cancer cells. The aims of the present study were to assess: (i) expression status of CD44v9 and xCT in hepatocellular carcinoma (HCC) tissues, including those derived from patients treated with hepatic arterial infusion chemoembolization (HAIC) therapy with cisplatin (CDDP); and (ii) whether combination of CDDP with sulfasalazine (SASP), an inhibitor of xCT, was more effective on tumor cells than CDDP alone by inducing ROS-mediated apoptosis. Twenty non-pretreated HCC tissues and 7 HCC tissues administered HAIC therapy with CDDP before surgical resection were subjected to immunohistochemistry analysis of CD44v9 and xCT expression. Human HCC cell lines HAK-1A and HAK-1B were used in this study; the latter was also used for xenograft experiments in nude mice to assess in vivo efficacy of combination treatment. CD44v9 positivity was significantly higher in HAIC-treated tissues (5/7) than in non-pretreated tissues (2/30), suggesting the involvement of CD44v9 in the resistance to HAIC. xCT was significantly expressed in poorly differentiated HCC tissues. Combination treatment effectively killed the CD44v9-harboring HAK-1B cells through ROS-mediated apoptosis and significantly decreased xenografted tumor growth. In conclusion, the xCT inhibitor SASP augmented ROS-mediated apoptosis in CDDP-treated HCC cells, in which the CD44v9-xCT system functioned. As CD44v9 is typically expressed in HAIC-resistant HCC cells, combination treatment with SASP with CDDP may overcome such drug resistance. PMID- 29981248 TI - Application of microRNA Targeted 3'UTRs to Repress DHFR Selection Marker Expression for Development of Recombinant Antibody Expressing CHO Cell Pools. AB - The dihydrofolate reductase (DHFR) system is used for the selection of recombinant Chinese hamster ovary (CHO) cell lines using the inhibitor methotrexate (MTX). During clonal selection, endogenous DHFR expression, and resistance to MTX allows the selection of cells expressing sufficient DHFR to survive. Here, the authors describe a novel vector platform for the DHFR system, whereby addition of a synthetic 3'UTR destabilizes DHFR expression. miRs ability to negatively regulate gene expression by their near-complementary binding to the 3'UTR region of transcripts are harnessed. From the literature, the authors identified let-7f as a highly abundant, invariant miR in CHO cells. Three 3'UTR targets of the let-7f miR are then cloned in the DHFR host 3'UTR to determine the impact on gene expression (HMGA2 3'UTR sequence 1, 2, and 3). Using luciferase as a reporter, the authors show down-regulation of luciferase activity is mediated by the nature of the 3'UTR and its ability to bind let-7f. The same 3'UTRs downstream of the DHFR gene to show this also results in reduced transcript amounts are then applied. Finally, the authors applied this methodology to generate stable DG44-derived cell pools expressing a model monoclonal antibody (mAb), demonstrating this approach can be used for the selection of antibody producing cells with low MTX concentrations. PMID- 29981250 TI - Impact of expiratory strength training in amyotrophic lateral sclerosis: Results of a randomized, sham-controlled trial. AB - INTRODUCTION: The purpose of this study was to determine the impact of an in-home expiratory muscle strength training (EMST) program on pulmonary, swallow, and cough function in individuals with amyotrophic lateral sclerosis (ALS). METHODS: EMST was tested in a prospective, single-center, double-blind, randomized, controlled trial of 48 ALS individuals who completed 8 weeks of either active EMST (n = 24) or sham EMST (n = 24). The primary outcome to assess treatment efficacy was change in maximum expiratory pressure (MEP). Secondary outcomes included: cough spirometry; swallowing; forced vital capacity; and scoring on the ALS Functional Rating Scale-Revised. RESULTS: Treatment was well tolerated with 96% of patients completing the protocol. Significant differences in group change scores were noted for MEP and Dynamic Imaging Grade of Swallowing Toxicity scores (P < 0.02). No differences were noted for other secondary measures. DISCUSSION: This respiratory training program was well-tolerated and led to improvements in respiratory and bulbar function in ALS. Muscle Nerve, 2018. PMID- 29981249 TI - Updated long-term outcomes after carbon-ion radiotherapy for primary renal cell carcinoma. AB - Long-term oncological outcomes for primary renal cell carcinoma (RCC) treated with carbon-ion radiotherapy (CIRT) are poorly understood. Patients with primary RCC were treated with 12 or 16-fraction CIRT at The Hospital of the National Institute of Radiological Sciences outside of clinical trials. Outcome data were pooled and retrospectively analyzed for toxicity, local control, and disease free, cancer-specific, and overall survival. From 1997 to 2014, 19 RCC patients (11 with T1aN0M0, 4 with T1bN0M0, and 4 with inoperable advanced stage [T4N0M0, T3aN1M0, and T1aN0M1]) were treated with CIRT and followed up for a median of 6.6 (range, 0.7-16.5) years; 9 of these patients were inoperable because of comorbidities or advanced-stage disease. Diagnoses were confirmed by imaging in 11 patients and by biopsy in the remaining 8. In 4 of 5 patients with definitive renal comorbidities, including diabetic nephropathy, sclerotic kidney or solitary kidney pre-CIRT progressed to grade 4 chronic kidney disease (CKD). In contrast, the remaining 14 patients without definitive renal comorbidities did not progress to grade 3 or higher CKD. Furthermore, although 1 case of grade 4 dermatitis was observed, there were no other grade 3 or higher non-renal adverse events. Local control rate, and disease-free, cancer-specific, and overall survival rates at 5 years of all 19 patients were 94.1%, 68.9%, 100%, and 89.2%, respectively. This updated retrospective analysis based on long-term follow-up data suggests that CIRT is a safe treatment for primary RCC patients without definitive renal comorbidities pre-CIRT, and yield favorable treatment outcomes, even in inoperable cases. PMID- 29981252 TI - Protein Engineering of the Progesterone Hydroxylating P450-Monooxygenase CYP17A1 Alters Its Regioselectivity. AB - The CYP171 enzyme is known to catalyse a key step in the steroidogenesis of mammals. The substrates progesterone and pregnenolone are first hydroxylated at the C17 position, and this is followed by cleavage of the C17-C20 bond to yield important precursors for glucosteroids and androgens. In this study, we focused on the reaction of the bovine CYP17A1 enzyme with progesterone as a substrate. On the basis of a created homology model, active-site residues were identified and systematically mutated to alanine. In whole-cell biotransformations, the importance of the N202, R239, G297 and E305 residues for substrate conversion was confirmed. Additionally, mutation of the L206, V366 and V483 residues enhanced the formation of the 16alpha-hydroxyprogesterone side product up to 40 % of the total product formation. Furthermore, residue L105 was found not to be involved in this side activity, which contradicts a previous study with the human enzyme. PMID- 29981251 TI - Branched rolling circle amplification method for measuring serum circulating microRNA levels for early breast cancer detection. AB - Serum circulating microRNAs (c-miRNAs) are serving as useful biomarkers for cancer diagnosis. Here, we describe the development of a one-step branched rolling circle amplification (BRCA) method to measure serum c-miRNAs levels for early diagnosis of breast cancer. Four c-miRNAs, c-miRNA16 (c-miR-16), c-miRNA21 (c-miR-21), c-miRNA155 (c-miR-155), and c-miRNA195 (c-miR-195) were isolated from the serum of 49 breast cancer patients (stages I-IV) and 19 healthy controls, and analyzed using one-step BRCA. The serum levels of c-miR16, c-miR21, c-miR155, and c-miR195 were higher (P < 0.0001) in stage I breast cancer patients than healthy controls. These levels were also higher in several breast cancer molecular subtypes (HER-2 over-expression, Luminal A, Luminal B, and triple negative breast cancer) than in healthy control subjects. The diagnostic accuracy of c-miR16, c miR21, c-miR155, and c-miR195 for early diagnosis of breast cancer was confirmed by receiver operating characteristic (ROC) curve assay. These results show that the BRCA method can be used to measure serum c-miRNAs levels, and that this method has high accuracy, sensitivity, and specificity. Moreover, both BRCA approach and quantitative real-time PCR (qRT-PCR) method show that the serum levels of c-miR16, c-miR21, c-miR155, and c-miR195 could be used as biomarkers to improve the early diagnosis of breast cancer, and distinguish different breast cancer molecular subtypes. PMID- 29981254 TI - TRANSPARENT TESTA 4-mediated flavonoids negatively affect embryonic fatty acid biosynthesis in Arabidopsis. AB - Flavonoids are involved in many physiological processes in plants. TRANSPARENT TESTA 4 (TT4) acts at the first step of flavonoid biosynthesis, and the loss of TT4 function causes a lack of flavonoid. Flavonoid deficiency is reportedly the main cause of increased fatty acid content in pale-coloured oilseeds, but details regarding the relationship between seed flavonoids and fatty acid biosynthesis are elusive. In this work, we applied a genetic strategy combined with biochemical and cytological assays to determine the effect of seed flavonoids on the biosynthesis of fatty acids in Arabidopsis thaliana. We showed that TT4 mediated flavonoids negatively affect embryonic fatty acid biosynthesis. A crossing experiment indicated that seed flavonoid biosynthesis and the impact of this process on fatty acid biosynthesis were controlled in a maternal line dependent manner. Loss of TT4 function activated glycolysis in seed embryos, thereby enhancing fatty acid biosynthesis, but did not improve seed mucilage production. Moreover, loss of TT4 function reduced PIN-FORMED 4 expression and subsequently increased auxin accumulation in embryos. Pharmacologically and genetically elevated auxin levels enhanced seed fatty acid biosynthesis. These results indicated that flavonoids affect fatty acid biosynthesis by carbon source reallocation via regulation of WRINKLE1 and auxin transport. PMID- 29981253 TI - Ultrasonic-Assisted Wet Chemistry Synthesis of Ultrafine SnO2 Nanoparticles for the Electron-Transport Layer in Perovskite Solar Cells. AB - SnO2 was recently employed as an efficient electron-transport layer (ETL) in perovskite solar cells (PSCs) and high power conversion efficiencies (PCEs) have been reported. However, it is still challenging to fabricate SnO2 thin films through facile solution-based synthesis at low temperature (<150 degrees C) to be compatible with the large scale module fabrication, especially for flexible devices. Here, we report a low temperature solution-based method for preparation of SnO2 nanoparticles. Ultrasonic-assisted wet chemistry synthesis of ultrafine SnO2 nanocrystals with particle size ranging from 2 to 5 nm was achieved by employing a SnCl4 ?5 H2 O solution in a mixed ethanol-water solution and with no annealing step. The crystallinity and microstructure of the SnO2 nanoparticles were investigated by X-ray diffraction (XRD) and transmission electron microscopy (TEM), as well as selected area electron diffraction (SAED) analysis. The added water in ethanol and increased pH values were demonstrated as two key factors to successful fabrication of highly crystallized samples with high reproducability. An efficiency of 16.56 % was achieved for PSCs based on SnO2 nanoparticles synthesized by ultrasonic-assisted wet chemistry. PMID- 29981255 TI - Age-associated changes in waking hippocampal sharp-wave ripples. AB - Hippocampal sharp-wave ripples are brief high-frequency (120-250 Hz) oscillatory events that support mnemonic processes during sleep and awake behavior. Although ripples occurring during sleep are believed to facilitate memory consolidation, waking ripples may also be involved in planning and memory retrieval. Recent work from our group determined that normal aging results in a significant reduction in the peak oscillatory frequency and rate-of-occurrence of ripples during sleep that may contribute to age-associated memory decline. It is unknown, however, how aging alters waking ripples. We investigated whether characteristics of waking ripples undergo age-dependent changes. Sharp-wave ripple events were recorded from the CA1 region of the hippocampus in old (n = 5) and young (n = 6) F344 male rats as they performed a place-dependent eyeblink conditioning task. Several novel observations emerged from this analysis. First, although aged rats expressed more waking ripples than young rats during track running and reward consumption, this effect was eliminated, and, in the case of track-running, reversed when time spent in each location was accounted for. Thus, aged rats emit more ripples, but young rats express a higher ripple rate. This likely results from reduced locomotor activity in aged animals. Furthermore, although ripple rates increased as young rats approached rewards, rates did not increase in aged rats, and rates in aged and young animals were not affected by eyeblink conditioning. Finally, although the oscillatory frequency of ripples was lower in aged animals during rest, frequencies in aged rats increased during behavior to levels indistinguishable from young rats. Given the involvement of waking ripples in memory retrieval, a possible consequence of slower movement speeds of aged animals is to provide more opportunity to replay task-relevant information and compensate for age-related declines in ripple rate during task performance. PMID- 29981257 TI - Two-Step Synthesis of Unsymmetrical Diaryl Sulfides by Electrophilic Thiolation of Non-functionalized (Hetero)arenes. AB - This article reports the efficient preparation of a series of unsymmetrically substituted thioethers through a two-step procedure consisting of an initial metal-free C-H sulfenylation of electron-rich (hetero)arenes with newly prepared succinylthioimidazolium salts. Subsequent reaction of the arylthioimidazolium intermediates with Grignard reagents afford the desired thioethers. The synthetic protocol described is modular, scalable, and high yielding, and provides access to sulfides that are not easy to obtain through the existing methodologies. Importantly, no prefunctionalization of the initial (hetero)arene is required. PMID- 29981258 TI - Effects of a Behavioral Economics Intervention on Food Choice and Food Consumption in Middle-School and High-School Cafeterias. AB - INTRODUCTION: Changing food choice architecture in school cafeterias through behavioral economics may increase student selection and consumption of healthy foods. However, most research assesses the effects of short-term interventions. We evaluated a year-long choice architecture intervention implemented by school food service staff. METHODS: Food service staff from 6 secondary schools in one school district received training and support to implement behavioral economics strategies in their cafeterias to promote student selection of fruit, vegetables, and low-fat white milk. We compared student selection and consumption of these foods in the intervention schools to 5 comparison schools in the same district on the basis of visual assessment of plate waste. We applied a difference-in differences approach to estimate intervention effect. RESULTS: Data for 902 students were assessed at baseline, and data for 1,407 were assessed at follow up. In fully adjusted analyses for all students, there were significantly greater absolute increases in the proportions of intervention school students selecting any fruit, including (0.09) and excluding (0.16) juice, and students selected more fruit items including (0.21) and excluding (0.17) juice. The absolute increase in proportion of intervention students consuming fruit excluding juice (0.14) was significantly greater. However, in some analyses, fewer intervention students who selected fruits or vegetables ate them, or they ate fewer of them. There were no intervention effects for vegetables or low-fat white milk. CONCLUSION: Our results indicate that behavioral economics-based choice architecture can promote student selection of healthy foods, but they raise questions about whether it increases their consumption. PMID- 29981256 TI - Novel chemical compound SINCRO with dual function in STING-type I interferon and tumor cell death pathways. AB - Recent years have seen a number of regulatory approvals for immune oncology or immunotherapies based on their ability to enhance antitumor immune responses. Nevertheless, the majority of patients remain refractory to these treatments; hence, new therapies that augment current immunotherapies are required. Innate immune receptors that recognize nucleic acids are potent activators of subsequent T-cell responses and, as a result, can evoke potent antitumor immune responses. Herein, we present a novel compound N-{3-[(1,4'-bipiperidin)-1'-yl]propyl}-6-[4 (4-methylpiperazin-1-yl)phenyl]picolinamide (SINCRO; STING-mediated interferon inducing and cytotoxic reagent, original) as an anticancer drug that activates the cytosolic DNA-sensing STING (stimulator of interferon genes) signaling pathway leading to the induction of type I interferon (IFN) genes. Indeed, IFN beta gene induction by SINCRO is abolished in STING-deficient cells. In addition to its IFN-inducing activity, SINCRO shows STING-independent cytotoxic activity against cancer cells. SINCRO does not evoke DNA double-strand break or caspase-3 cleavage. Thus, SINCRO induces cell death in a method different from conventional apoptosis-inducing pathways. Finally, we provide evidence that giving SINCRO significantly attenuates in vivo tumor growth by both type I IFN-dependent and independent mechanisms. Thus, SINCRO is an attractive anticancer compound with dual function in that it evokes type I IFN response to promote antitumor immunity as well as inducing tumor cell death. SINCRO may provide a new platform for the development of drugs for effective cancer therapy. PMID- 29981259 TI - Using the Infrastructure of State Aging Services to Promote Prevention Behavior. AB - INTRODUCTION: State infrastructure for aging services, such as programs in county senior centers, can help promote prevention of chronic disease and reach large numbers of older adults. The objective of our study was to assess how well such infrastructure can support prevention efforts. METHODS: The University of Pittsburgh CDC Prevention Research Center partnered with the Pennsylvania Department of Aging APPRISE program to deliver the 10 Keys to Healthy Aging program. APPRISE is a Medicare counseling program offered at senior centers; the 10 Keys is a series of behavior-activation workshops for people aged 50 or older that cover recommendations of the US Preventive Services Task Force and other evidence-based recommendations for health promotion. We assessed implementation, increases in prevention knowledge, and maintenance of prevention behavior. RESULTS: From 2013 through 2016, 1,534 adults at 83 sites participated in the program; 1,044 (68.1%) completed at least 8 of 10 Keys workshops. A total of 736 adults (mean [standard deviation] age, 74.9 [8.3] y) voluntarily completed a 14 item pretest and posttest of prevention knowledge; respondents' knowledge score increased from 61.5% to 78.5% correct (P < .001). In a subsample (n = 339) reporting on their own prevention behaviors at baseline, quiz scores and prevention behaviors were correlated (r = 0.30, P < .001). In monthly telephone follow-up with 147 respondents over 6 months, maintenance of prevention behaviors was strong in the areas of physical activity and hypertension management and significantly higher for people completing a greater number of Keys workshops. CONCLUSION: Prevention behavior can be activated in aging services settings and can be incorporated into daily routines. PMID- 29981260 TI - Gut-liver on a chip toward an in vitro model of hepatic steatosis. AB - Hepatic steatosis is a process of abnormal lipid deposition within the liver cells, often caused by excessive alcohol uptake or obesity. A conventional in vitro model for hepatic steatosis uses a liver cell culture, treated with fatty acids and measures accumulation of lipids within the cells. This model does not recapitulate the complex process of absorption and metabolism of digestive lipids. Here, we introduce a gut-liver chip, which mimics the gut absorption and hepatic metabolism in a microfluidic chip. Absorption of fatty acids through gut layer and subsequent deposition within liver cells was demonstrated. Tumor necrosis factor-alpha, butyrate, and alpha-lipoic acid were chosen as model molecules that can affect hepatic steatosis via different mechanisms, and their effects were evaluated. Our results suggest that the gut-liver chip can mimic the absorption and accumulation of fatty acids in the gut and the liver. PMID- 29981262 TI - Suppression of hepatitis B surface antigen production by combination therapy with nucleotide analogues and interferon in children with genotype C hepatitis B virus infection. AB - AIM: Sustained suppression of hepatitis B surface antigen (HBsAg) production after interferon (IFN) treatment has not been reported for children with genotype C chronic hepatitis B virus (HBV) infection, which is prevalent in Asia. Among children with hepatitis B envelope antigen-positive genotype C chronic HBV infection, we compared the efficacy of combination therapy with nucleotide analogues and IFN-alpha in 11 children with 12 historical cases treated with IFN monotherapy. METHODS: The combination of lamivudine and conventional IFN-alpha was introduced for the first three patients; the other eight patients were treated with entecavir and pegylated IFN. RESULTS: Demographic factors as well as baseline HBsAg titers and HBV-DNA levels were similar between the two groups. In the combination therapy group, viral loads were suppressed in 9/11 to below 4.0 log copies/mL both at the end of the therapy (EOT) and at 6 months after EOT. In contrast, in the IFN monotherapy group, suppression of viral loads was observed in 2/12 and 3/12 at EOT and at 6 months after EOT, respectively. In the combination therapy group, HBsAg titers dropped from 4.03 at pretreatment to 2.91 log IU/mL at 6 months after EOT with 4/11 showing a drop to below 1000 IU/mL (one patient achieved HBsAg clearance). In contrast, the amount of HBsAg did not change during the corresponding periods in the IFN monotherapy group. CONCLUSIONS: Our preliminary results suggest that combination therapy might be effective in the suppression of HBsAg production as well as HBV-DNA production for children with genotype C chronic HBV infection. PMID- 29981261 TI - Dynamic microRNA activity identifies therapeutic targets in trastuzumab-resistant HER2+ breast cancer. AB - MicroRNAs (miRNAs) are implicated in numerous physiologic and pathologic processes, such as the development of resistance to chemotherapy. Determining the role of miRNAs in these processes is often accomplished through measuring miRNA abundance by polymerase chain reaction, sequencing, or microarrays. We have developed a system for the large-scale monitoring of dynamic miRNA activity and have applied this system to identify the contribution miRNA activity to the development of trastuzumab resistance in a cell model of HER2+ breast cancer. MiRNA activity measurements identified significantly different activity levels between BT474 cells (HER2 + breast cancer) and BT474R cells (HER2 + breast cancer cells selected for resistance to trastuzumab). We created a library of 32 miRNA reporter constructs, which were delivered by lentiviral transduction into cells, and miRNA activity was quantified by bioluminescence imaging. Upon treatment with the bioimmune therapy, trastuzumab, the activity of 11 miRNAs were significantly altered in parental BT474 cells, and 20 miRNAs had significantly altered activity in the therapy-resistant BT474R cell line. A combination of statistical, network and classification analysis was applied to the dynamic data, which identified miR 21 as a controlling factor in trastuzumab response. Our data suggested downregulation of miR-21 activity was associated with resistance, which was confirmed in an additional HER2 + breast cancer cell line, SKBR3. Collectively, the dynamic miRNA activity measurements and analysis provided a system to identify new potential therapeutic targets in treatment-resistant cancers. PMID- 29981263 TI - Analysis of ethylene-induced gene regulation during carposporogenesis in the red seaweed Grateloupia imbricata (Rhodophyta). AB - Ethylene favors carposporogenesis in the red seaweed Grateloupia imbricata. Analyses of cystocarp development in vitro in thalli treated with ethylene suggest an interconnection between polyamine and ethylene biosynthesis pathways. Yet, little is known about molecular mechanisms underlying carposporogenesis. Here, we used droplet digital PCR to analyze genes encoding enzymes related to polyamine (Spermidine [Spd] synthase) and ethylene (ACC synthase) synthesis; a pivotal compound of both pathways (S-adenosyl methionine synthase, SAMS); the gene that encodes amine oxidase, which is involved in polyamine degradation, and a candidate gene involved in seaweed reproduction (ornithine decarboxylase, ODC). In addition, we analyzed genes encoding proteins related to stress and reactive oxygen species, ascorbate peroxidase (APX), cytochrome P450 and WD 40. We characterized gene expression in fertilized and fertile thalli from G. imbricata that were exposed to ethylene for 15 min at two time points after treatment (1 and 7 d). The differential gene expression of SAMS, Spd synthase, ACC synthase, and cytochrome P450 was related to disclosure and development of cystocarps in fertilized thalli that transitioned from having no visible cystocarps at 1 d to developing cystocarps at 7 d. Likewise, cytochrome P450 was associated with cystocarp disclosure and maturation. In addition, amine oxidase and APX were involved in fine-tuning polyamine and reactive oxygen species during carposporogenesis, respectively, whereas WD 40 did so in relation to ethylene signaling. Expression of the candidate gene ODC was increased when cystocarps were not visible (fertilized thalli, 1d), as previously described. This analysis suggests developmental stage-specific roles for these genes during carposporogenesis. PMID- 29981264 TI - The Structure of the Cobalt Oxide/Au Catalyst Interface in Electrochemical Water Splitting. AB - The catalytic synergy between cobalt oxide and gold leads to strong promotion of the oxygen evolution reaction (OER)-one half-reaction of electrochemical water splitting. However, the mechanism behind the enhancement effect is still not understood, in part due to a missing structural model of the active interface. Using a novel interplay of cyclic voltammetry (CV) for electrochemistry integrated with scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy (XPS) on an atomically defined cobalt oxide/Au(111) system, we reveal here that the supporting gold substrate uniquely favors a flexible cobalt oxyhydroxide/Au interface in the electrochemically active potential window and thus suppresses the formation of less active bulk cobalt oxide morphologies. The findings substantiate why optimum catalytic synergy is obtained for oxide coverages on gold close to or below one monolayer, and provide the first morphological description of the active phase during electrocatalysis. PMID- 29981265 TI - PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway: reply. PMID- 29981266 TI - A comment on the comparative safety of intravenous ferumoxytol versus ferric carboxymaltose in iron deficiency anemia. PMID- 29981267 TI - Predictors of refractoriness to therapy and healthcare resource utilization in 378 patients with primary autoimmune hemolytic anemia from eight Italian reference centers. PMID- 29981268 TI - Techniques for chromosomal integration and expression optimization in Escherichia coli. AB - Due to the inherent expression stability and low metabolic burden to the host cell, the expression of heterologous proteins in the bacterial chromosome in a precise and efficient manner is highly desirable for metabolic engineering and live bacterial applications. However, obtaining suitable chromosome expression levels is particularly challenging. In this minireview, we briefly present the technologies available for the integration of heterologous genes into Escherichia coli chromosomes and strategies to optimize the expression levels of heterologous proteins. PMID- 29981271 TI - The Mackay-Type Cluster [Cu43 Al12 ](Cp*)12 : Open-Shell 67-Electron Superatom with Emerging Metal-Like Electronic Structure. AB - The paramagnetic cluster [Cu43 Al12 ](Cp*)12 was obtained from the reaction of [CuMes]5 and [AlCp*]4 (Cp*=eta5 -C5 Me5 ; Mes=mesityl). This all-hydrocarbon ligand-stabilized M55 magic atom-number cluster features a Mackay-type nested icosahedral structure. Its open-shell 67-electron superatom configuration is unique. Three unpaired electrons occupy weakly antibonding jellium states. The situation prefigures the formation of a conduction band, which is in line with the measured temperature-independent magnetism. Steric protection by twelve Cp* ligands suppresses the intrinsic polyradicalar reactivity of the Cu43 Al12 core. PMID- 29981270 TI - Anti-C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model. AB - : Essentials Inhibitor formation remains a challenging complication of hemophilia A care. The Bethesda assay is the primary method used for determining bleeding risk and management. Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance. Antibodies that increase clearance contribute to antibody pathogenicity. SUMMARY: Background The development of neutralizing anti-factor VIII (FVIII) antibodies remains a challenging complication of modern hemophilia A care. In vitro assays are the primary method used for quantifying inhibitor titers, predicting bleeding risk, and determining bleeding management. However, other mechanisms of inhibition are not accounted for in these assays, which may result in discrepancies between the inhibitor titer and clinical bleeding symptoms. Objectives To evaluate FVIII clearance in vivo as a potential mechanism for antibody pathogenicity and to determine whether increased FVIII dosing regimens correct the associated bleeding phenotype. Methods FVIII-/- or FVIII-/- /von Willebrand factor (VWF)-/- mice were infused with anti-FVIII mAbs directed against the FVIII C1, C2 or A2 domains, followed by infusion of FVIII. Blood loss via the tail snip bleeding model, FVIII activity and FVIII antigen levels were subsequently measured. Results Pathogenic anti-C1 mAbs that compete with VWF for FVIII binding increased the clearance of FVIII-mAb complexes in FVIII-/- mice but not in FVIII-/- /VWF-/- mice. Additionally, pathogenic anti-C2 mAbs that inhibit FVIII binding to VWF increased FVIII clearance in FVIII-/- mice. Anti-C1, anti-C2 and anti-A2 mAbs that do not inhibit VWF binding did not accelerate FVIII clearance. Infusion of increased doses of FVIII in the presence of anti-C1 mAbs partially corrected blood loss in FVIII-/- mice. Conclusions A subset of antibodies that inhibit VWF binding to FVIII increase the clearance of FVIII-mAb complexes, which contributes to antibody pathogenicity. This may explain differences in the bleeding phenotype observed despite factor replacement in some patients with hemophilia A and low-titer inhibitors. PMID- 29981269 TI - Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk. AB - : Essentials Microbe-dependent production of trimethylamine N-oxide (TMAO) contributes to thrombosis risk. The impact of host flavin monooxygenase 3 (FMO3) modulation on platelet function is unknown. Genetic manipulation of FMO3 in mice alters systemic TMAO levels and thrombosis potential. Genetic manipulation of FMO3 is associated with alteration of gut microbial community structure. SUMMARY: Background Gut microbes play a critical role in the production of trimethylamine N-oxide (TMAO), an atherogenic metabolite that impacts platelet responsiveness and thrombosis potential. Involving both microbe and host enzymatic machinery, TMAO generation utilizes a metaorganismal pathway, beginning with ingestion of trimethylamine (TMA)-containing dietary nutrients such as choline, phosphatidylcholine and carnitine, which are abundant in a Western diet. Gut microbial TMA lyases use these nutrients as substrates to produce TMA, which upon delivery to the liver via the portal circulation, is converted into TMAO by host hepatic flavin monooxygenases (FMOs). Gut microbial production of TMA is rate limiting in the metaorganismal TMAO pathway because hepatic FMO activity is typically in excess. Objectives FMO3 is the major FMO responsible for host generation of TMAO; however, a role for FMO3 in altering platelet responsiveness and thrombosis potential in vivo has not yet been explored. Methods The impact of FMO3 suppression (antisense oligonucleotide-targeting) and overexpression (as transgene) on plasma TMAO levels, platelet responsiveness and thrombosis potential was examined using a murine FeCl3 -induced carotid artery injury model. Cecal microbial composition was examined using 16S analyses. Results Modulation of FMO3 directly impacts systemic TMAO levels, platelet responsiveness and rate of thrombus formation in vivo. Microbial composition analyses reveal taxa whose proportions are associated with both plasma TMAO levels and in vivo thrombosis potential. Conclusions The present studies demonstrate that host hepatic FMO3, the terminal step in the metaorganismal TMAO pathway, participates in diet dependent and gut microbiota-dependent changes in both platelet responsiveness and thrombosis potential in vivo. PMID- 29981272 TI - Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation. AB - Patients with acute myeloid leukemia (AML) in morphological first complete remission (CR1) pre-allogeneic hematopoietic cell transplantation (HCT) may have measurable residual disease (MRD) by molecular and immunophenotyping criteria. We assessed interactions of MRD status with HCT conditioning regimen intensity in patients aged <50 years (y) or >=50y. This was a retrospective study by the European Society for Blood and Marrow Transplantation registry. Patients were >18y with AML CR1 MRD NEG/POS and recipients of HCT in 2000-2015. Conditioning regimens were myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA). Outcomes included leukemia free survival (LFS), overall survival (OS), relapse incidence (RI), non-relapse mortality (NRM), chronic graft-vs-host (cGVHD), and GVHD-free and relapse-free survival (GRFS). The 2292 eligible patients were categorized into four paired groups: <50y MRD POS MAC (N = 240) vs RIC/NMA (N = 58); <50y MRD NEG MAC (N = 665) vs RIC/NMA (N = 195); >=50y MRD POS MAC (N = 126) vs RIC/NMA (N = 230), and >=50y MRD NEG MAC (N = 223) vs RIC/NMA (N = 555). In multivariate analysis RIC/NMA was only inferior to MAC for patients in the <50y MRD POS group, with worse RI (HR 1.71) and LFS (HR 1.554). Patients <50Y MRD NEG had less cGVHD after RIC/NMA HCT (HR 0.714). GRFS was not significantly affected by conditioning intensity in any group. Patients aged <50y with AML CR1 MRD POS status should preferentially be offered MAC allo-HCT. Prospective studies are needed to address whether patients with AML CR1 MRD NEG may be spared the toxicity of MAC regimens. New approaches are needed for >=50y AML CR1 MRD POS. PMID- 29981273 TI - Cholesterol: A Key in the Pathogenesis of Alzheimer's Disease. AB - Herein we highlight recent advances in our understanding of the role of cholesterol in Alzheimer's disease (AD). It has been proposed that cholesterol could enhance the risk of AD, and the interaction between cholesterol and amyloid beta peptide 42 (Abeta42) has been studied extensively, yet until recently, the specific interaction mechanisms between them and how this affects Abeta42 aggregation had not yet been fully explored and had remained ambiguous. Vendruscolo and co-workers addressed these issues in their recent article entitled "Cholesterol catalyses Abeta42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes" (Habchi et al., Nat. Chem. 2018, 10, 673). In this article, the authors revealed the mechanism behind cholesterol-catalyzed Abeta42 aggregation, providing the potential to address the molecular origins of AD, thereby opening a new avenue for effective AD therapy. PMID- 29981274 TI - A Chinese herbal medicine preparation (Pei Tu Qing Xin) for children with moderate-to-severe atopic eczema: a pilot randomized controlled trial. PMID- 29981275 TI - Canakinumab treatment in kidney transplant recipients with AA amyloidosis due to familial Mediterranean fever. AB - BACKGROUND: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent serosal inflammation with fever, which can result in amyloid deposition. Anti-interleukin-1 drugs emerge as a therapeutic option for colchicine-resistant patients. In this study, we aimed to document our experience with canakinumab use in kidney transplant recipients who developed AA amyloidosis due to FMF. METHODS: A total of nine patients with FMF amyloidosis treated with canakinumab were enrolled. Laboratory and clinical data were collected from the patient files, electronic database of the hospital and with interviews. RESULTS: Five of the patients were male and four were female (median age: 33, range: 27-62 years). All of the patients had rapid or gradual disappearance of FMF attacks. The following changes in the laboratory parameters were observed before and after the treatment: C-reactive protein: 18.31 +/- 13.58 mg/L vs 9.98 +/- 11.66 mg/L, creatinine clearance: 45.27 +/- 21.5 mL/min vs 50.71 +/- 22.48 mL/min, and 24 hour proteinuria: 2381.8 +/- 3910.4 mg vs 710.0 +/- 1117.5 mg; there were no statistically significant differences on those parameters. One patient developed a reaction to injection while another showed symptoms of Cytomegalovirus pneumonia. CONCLUSION: Canakinumab can be considered as a safe and efficient drug in preventing the FMF attacks in kidney transplant recipients. PMID- 29981276 TI - Validation of the binary designation Symbiodinium thermophilum (Dinophyceae). AB - The binary designation Symbiodinium thermophilum was invalid due to the absence of an illustration as required by Article 44.2 of the ICN. Herein, it is validated. This species is the most common symbiont in reef corals in the southern Persian/Arabian Gulf, the world's hottest body of water sustaining reef coral growth. PMID- 29981277 TI - Improved vasculogenesis and bone matrix formation through coculture of endothelial cells and stem cells in tissue-specific methacryloyl gelatin-based hydrogels. AB - The coculture of osteogenic and angiogenic cells and the resulting paracrine signaling via soluble factors are supposed to be crucial for successfully engineering vascularized bone tissue equivalents. In this study, a coculture system combining primary human adipose-derived stem cells (hASCs) and primary human dermal microvascular endothelial cells (HDMECs) within two types of hydrogels based on methacryloyl-modified gelatin (GM) as three-dimensional scaffolds was examined for its support of tissue specific cell functions. HDMECs, together with hASCs as supporting cells, were encapsulated in soft GM gels and were indirectly cocultured with hASCs encapsulated in stiffer GM hydrogels additionally containing methacrylate-modified hyaluronic acid and hydroxyapatite particles. After 14 days, the hASC in the stiffer gels (constituting the "bone gels") expressed matrix proteins like collagen type I and fibronectin, as well as bone-specific proteins osteopontin and alkaline phosphatase. After 14 days of coculture with HDMEC-laden hydrogels, the viscoelastic properties of the bone gels were significantly higher compared with the gels in monoculture. Within the soft vascularization gels, the formed capillary-like networks were significantly longer after 14 days of coculture than the structures in the control gels. In addition, the stability as well as the complexity of the vascular networks was significantly increased by coculture. We discussed and concluded that osteogenic and angiogenic signals from the culture media as well as from cocultured cell types, and tissue-specific hydrogel composition all contribute to stimulate the interplay between osteogenesis and angiogenesis in vitro and are a basis for engineering vascularized bone. PMID- 29981278 TI - [Molecular Detection and Genomic Characterization of Enterovirus D68 among Children with Severe Acute Respiratory Infection in Beijing and Shanghai]. AB - To understand the prevalence and molecular typing of enterovirus D68 among children with severe acute respiratory infection(SARI)in Beijing and Shanghai,259 respiratory samples were collected from in Beijing during 2008-2010,and 441 respiratory samples were collected in Shanghai city between 2013and2014.All the samples were used for the screening of EV-D68 by nest RT-PCR and sequencing, and then EV-D68-positive samples were used for the complete genome sequencing through overlapping PCR. All available EV-D68full-length genomes collected from GenBank were used for phylogenetic analysis and comparison of EV-D68 types prevalent in China and America. One(0.4%)from 259 respiratory samples in Beijing was positive for EV-D68,and 4(0.9%)among the 441 samples from Shanghai were positive for EV D68.Phylogenetic analysis of full length genome indicated that the EV-D68 prevalent in Beijing belong to Clade A2 and Clade B2,different from the American popular strains(Clade A1,Clade B1,Clade B4 and Clade B5).Partial sequence analysis declared phylogenetic conflict among different gene sequences. We concluded that the prevalence rate of EV-D68 among SARI Children in Beijing and Shanghai currently was lower(5/700;<1%),and the EV-D68 genotype prevalent in China and America belong to different clusters. Partial sequence analysis indicated that intratypic recombinant events may occur in EV-D68 prevalent in China. PMID- 29981279 TI - [Genetic Characteristic Analysis of H Gene among Four Genotypes of MeasIes Viruses Isolated in Mainland China during 2013-2014]. AB - To study the genetic characterization and amino acid mutation of hemagglutinin protein of four genotypes of wild type measles Viruses isolated in 2013 and 2014year,in China, including H1,B3,D8 and D9.Four genotype isolates of H1,D8,D9 and B3measles viruses were selected, and RNA of MV isolates were extracted. The complete sequence of hemagglutinin (1854nt) were amplified by RT-PCR and sequenced and Sequencher5.0was used to splice sequence. Phylogenetic analysis and the diversity of gene and amino acid were done by MEGA version 5.0,compared with 24 representative strains, repectively 4 H a sub-genotype strains,8D8 genotype strains,2D9 genotype strains,8B3 genotype strains and 2Chinese vaccine Strains, which were downloaded from GenBank. The homology of H gene nucleotide sequence and amino acid between the four genotype measles virus strains including H1,B3,D8,D9 and A genotype strains were respectively 94.2%-96.7%and 95.4% 96.7%and there were 20-28 amino acids difference between them; And the homology of H gene nucleotide sequence between Beijing14-1(H1a)and A genotype vaccine strains was 97.7%-98.2%.The N-glycosylation site in 240th was losen because of mutation. The homology of H gene nucleotide sequence and amino acid between the four genotype measles virus strains including H1,B3,D8,D9 and A genotype strains were high, and the Chinese vaccine can effectively prevent infection caused by H1asub-genotype,D8,D9 and B3imported genotypes virus strains. PMID- 29981280 TI - [Complete Genome Characterization of Vaccine-derived Polioviruses Isolated in Yunnan,China]. AB - To explore the genomic characterization of 4vaccine-derived poliovirus(VDPV)strains isolated from 2acute flaccid paralysis(AFP)cases in Yunnan Province in 2010 and 2012,respectively,the complete genome sequences of the 4strains were determined. Sequence analysis revealed that the complete genome length of the type II and type I VDPV was 7439nt and 7441 nt, respectively. Nucleotide and amino acid sequence similarities of type II VDPV were 95.4% and 97.7%,respectively,and type I VDPV were93.9% and 97.9%,respectively as compared with those of Sabin strains. Nucleotide substitutions were found at two important attenuation sites (nt 481 and nt in type II VDPV, and three important attenuation sites(nt480,nt2795 and nt6203)in type I VDPV. Type 2 and type 1VDPV strains had 1.0% and2.3% divergence with Sabin strains, respectively. Similarity plot analysis showed multiple recombination events in the genome of the 4strains,which showed that the recombination was common and complex. Analysis of the characteristics of VDPVs on molecular level could provide valuable information on evolutionary dynamics and lay foundation for developing scientific and feasible strategy to control VDPV. PMID- 29981281 TI - A Spatio-Temporal Model and Inference Tools for Longitudinal Count Data on Multicolor Cell Growth. AB - Multicolor cell spatio-temporal image data have become important to investigate organ development and regeneration, malignant growth or immune responses by tracking different cell types both in vivo and in vitro. Statistical modeling of image data from common longitudinal cell experiments poses significant challenges due to the presence of complex spatio-temporal interactions between different cell types and difficulties related to measurement of single cell trajectories. Current analysis methods focus mainly on univariate cases, often not considering the spatio-temporal effects affecting cell growth between different cell populations. In this paper, we propose a conditional spatial autoregressive model to describe multivariate count cell data on the lattice, and develop inference tools. The proposed methodology is computationally tractable and enables researchers to estimate a complete statistical model of multicolor cell growth. Our methodology is applied on real experimental data where we investigate how interactions between cancer cells and fibroblasts affect their growth, which are normally present in the tumor microenvironment. We also compare the performance of our methodology to the multivariate conditional autoregressive (MCAR) model in both simulations and real data applications. PMID- 29981282 TI - Clinical Associations with ABO Blood Group and Rhesus Blood Group Status in Patients with Breast Cancer: A Nationwide Retrospective Study of 3,944 Breast Cancer Patients in Turkey. AB - BACKGROUND The aim of this study was to investigate the association between A, B, O, Rhesus (Rh)-positive and Rh-negative blood groups and breast cancer in a nationwide cohort of 3,944 patients in Turkey. MATERIAL AND METHODS A retrospective study included 3,944 patients diagnosed with breast cancer between 2004 and 2015 and with known blood type. Clinical and demographic patient data included age, sex, body mass index (BMI), menopausal status. The breast tumor type, size, grade, TNM stage, and the presence of lymph node and distant metastases were noted. Histopathology of the breast tumors had included routine detection of human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER) levels. RESULTS The 3,944 patients with breast cancer were blood group, type A, B, O, and Rh-positive or Rh-negative; the median age was 47.9 years (range, 18.2-89.6 years); 99.5% (3923/3,844) were women, and 0.5% (21/3944) were men. Patients with blood type 0 had a significantly smaller tumor size compared with patients with blood types A or B. There were no significant differences between blood groups and patient age, BMI, menopausal status, tumor histology, ER status, HER2 status, lymph node and distant metastasis. However, there was a significant difference in the prevalence of lobular breast cancer, levels of ER-positive tumor cells, and prevalence of cases with tumor metastases in Rh-positive patients compared with Rh-negative patients. CONCLUSIONS The findings of this retrospective study showed that the type, grade, stage, and hormonal status of breast cancer showed no significant associations with ABO blood grouping. PMID- 29981283 TI - Clustering of end-organ disease and earlier mortality in adults with sickle cell disease: A retrospective-prospective cohort study. AB - Chronic end-organ complications result in morbidity and mortality in adults with sickle cell disease (SCD). In a retrospective-prospective cohort of 150 adults with SCD who received standard care screening for pulmonary function abnormalities, cardiac disease, and renal assessment from January 2003 to 2016, we tested the hypothesis that clustering of end-organ disease is common and multiple organ impairment predicts mortality. Any end-organ disease occurred in 59.3% of individuals, and 24.0% developed multiple organ (>1) end-organ disease. The number of end-organs affected was associated with mortality (P <= .001); 8.2% (5 of 61) of individuals with no affected end-organ, 9.4% (5 of 53) of those with 1 affected organ, 20.7% (6 of 29) of those with 2 affected end-organs, and 85.7% (6 of 7) with 3 affected end-organs died over a median follow up period of 8.7 (interquartile range 3.5-11.4) years. Of the 22 individuals who died, 77.3% had evidence of any SCD-related end-organ impairment, and this was the primary or secondary cause of death in 45.0%. SCD-related chronic impairment in multiple organs, and its association with mortality, highlights the need to understand the common mechanisms underlying chronic end-organ damage in SCD, and the urgent need to develop interventions to prevent irreversible end-organ complications in SCD. PMID- 29981284 TI - Non-transferrin-bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload. PMID- 29981285 TI - Evaluation of the effect of lanthanum carbonate hydrate on the pharmacokinetics of roxadustat in non-elderly healthy adult male subjects. AB - WHAT IS KNOWN AND OBJECTIVE: Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor currently being investigated for the treatment of anemia in chronic kidney disease. Lanthanum carbonate is a phosphate binder that is commonly used to treat hyperphosphatemia in patients with chronic kidney disease. This study investigated the effect of lanthanum carbonate on the pharmacokinetics, safety and tolerability of a single oral dose of roxadustat in healthy non-elderly adult male subjects. METHODS: This was an open-label, randomized, two-period, two-sequence crossover study in non-elderly healthy adult males. Subjects randomized to Group 1 received roxadustat alone during Period 1 and roxadustat concomitantly with lanthanum carbonate during Period 2; subjects randomized to Group 2 received roxadustat concomitantly with lanthanum carbonate during Period 1 and roxadustat alone during Period 2. All subjects received a single oral dose of 100 mg roxadustat on Day 1 in both periods. Subjects receiving concomitant lanthanum carbonate received 750 mg lanthanum carbonate three times daily on Days 1 and 2. Pharmacokinetic assessments were conducted on Days 1-4 in both periods. The primary study outcomes were the area under the concentration-time curve from the time of dosing extrapolated to infinity (AUCinf ), and maximum concentration (Cmax ); the geometric least squares mean ratio (GMR; roxadustat + lanthanum carbonate/roxadustat alone) and corresponding 90% confidence interval (CI) was calculated for AUCinf and Cmax . Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs), laboratory test results, vital signs and standard 12-lead electrocardiogram. RESULTS AND DISCUSSION: A total of 18 subjects were enrolled (Group 1, n = 9; Group 2, n = 9); no subjects discontinued from the study. Roxadustat was rapidly absorbed, reaching maximum plasma concentration between 1 and 4 hours. The GMRs for AUCinf and Cmax were 88.00% (90% CI: 84.01, 92.17) and 98.58% (90% CI: 92.92, 104.58), respectively. The 90% CIs for both parameters were within the no-effect boundaries of 80% and 125%, indicating a lack of effect of lanthanum carbonate on roxadustat absorption. No deaths or serious TEAEs occurred. WHAT IS NEW AND CONCLUSIONS: Concomitant administration of a single oral dose of 100 mg roxadustat and 750 mg lanthanum carbonate three times daily did not impact the AUCinf or Cmax of roxadustat and was considered safe and well tolerated in non elderly healthy adult male Japanese subjects. PMID- 29981287 TI - Early thrombotic events and preemptive systemic anticoagulation following splenectomy for myelofibrosis. PMID- 29981286 TI - Metabolomic profiling of rat urine after oral administration of the prescription antipyretic Hao Jia Xu Re Qing Granules by UPLC/Q-TOF-MS. AB - Hao Jia Xu Re Qing Granules (HJ), is an effective clinically used antipyretic based on traditional Chinese medicine. Although its antipyretic therapeutic effectiveness is obvious, its therapeutic mechanism has not been comprehensively explored yet. In this research, we first identified potential biomarkers which may be relevant for the antipyretic effect of HJ based on urine metabolomics using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A rat model of fever was established using the yeast-induced febrile response. Total-ion-current metabolic profiles of different groups were acquired and the data were processed by multivariate statistical analysis-partial least-squares discriminant analysis. As envisioned, the results revealed changes of urine metabolites related to the antipyretic effect. Fourteen potential biomarkers were selected from the urine samples based on the results of Student's t-test, "shrinkage t", variable importance in projection and partial least-squares discriminant analysis. N-Acetylleucine, kynurenic acid, indole-3 ethanol, nicotinuric acid, pantothenic acid and tryptophan were the most significant biomarkers found in the urine samples, and may be crucially related to the antipyretic effect of HJ. Consequently, we propose the hypothesis that the significant antipyretic effect the HJ may be related to the inhibition of tryptophan metabolism. This research thus provides strong theoretical support and further direction to explain the antipyretic mechanism of HJ, laying the foundation for future studies. PMID- 29981288 TI - The development of autoverification rules applied to urinalysis performed on the AutionMAX-SediMAX platform. AB - BACKGROUND: Fully automated urine analyzers integrated with expert software can help to select samples that need review in routine clinical laboratory. This study aimed to define review rules to be set in the expert software Director for routine urinalysis on the AutionMAX-SediMAX platform. METHODS: A set of 1002 urinalysis data randomly extracted from the daily routine was used. The blind on screen assessment was used as a reference. The data set was used to optimize the standard rules preset in the software to establish review criteria useful to intercept automated microscopy misidentification and particles suggestive of clinically significant profile. The review rate was calculated. The rules-set was also evaluated for the selection of clinically significant samples. RESULTS: The review rules established were cross-checked between AutionMAX and SediMAX parameters, element reporting by SediMAX and strip results. For the complete rules-set the review rate was 47.6% and the efficiency for clinically significant sample selection was 58%. Finally, on the basis of the review rules an algorithm for routine practice was created. CONCLUSIONS: Review rules applied to the algorithm for routine practice enhance workflow efficiency and optimize sample screening. Revision is not necessary for samples not flagged by the rules. PMID- 29981289 TI - LncRNA HOXA-AS2 and its molecular mechanisms in human cancer. AB - Long non-coding RNAs (lncRNAs), a novel class of noncoding RNAs, are commonly defined as RNA molecules more than 200 nucleotides in length. Emerging research indicated that lncRNA played a vital role in human tumorigenesis and progression by serving as tumor oncogenes or suppressors. LncRNA has been shown to get involved in participate various biological processes, such as cell growth, anti apoptosis, migration and invasion. LncRNA HOXA cluster antisense RNA2 (HOXA-AS2) is a novel cancer-related lncRNA. It was recently found to exhibit aberrant expression in a variety of malignancies, including breast cancer, gastric cancer, gallbladder carcinoma, hepatocellular carcinoma and pancreatic cancer. The oncogenicity of lncRNA HOXA-AS2 mainly inhibits or promotes the expression of related genes through direct or indirect pathways, suggesting that HOXA-AS2 likely represents a feasible biomarker or therapeutic target in human cancers. In this review, we summarize current evidences concerning the biological functions and mechanisms of HOXA-AS2 during tumor development. PMID- 29981290 TI - Early BBB breakdown and subacute inflammasome activation and pyroptosis as a result of cerebral venous thrombosis. AB - Cerebral venous thrombosis (CVT) is a rare form of cerebral stroke that causes a variety of symptoms, ranging from mild headache to severe morbidity or death in the more severe forms. The use of anti-coagulant or thrombolytic agents is the classical treatment for CVT. However, the development of new therapies for the treatment of the condition has not been the focus. In this study, we aimed to analyze the pathophysiology of CVT and to identify the pathways associated with its pathology. Moreover, mechanisms that are potential drug targets were identified. Our data showed the intense activation of immune cells, particularly the microglia, along with the increase in macrophage activity and NLRP3 inflammasome activation that is indicated by NLRP3, IL-1beta, and IL-18 gene and caspase-1 upregulation and cleavage as well as pyroptotic cell death. Leukocytes were observed in the brain parenchyma, indicating a role in CVT-induced inflammation. In addition, astrocytes were activated, and they induced glial scar leading to parenchymal contraction during the subacute stage and tissue loss. MMP9 was responsible primarily for the BBB breakdown after CVT and it is mainly produced by pericytes. MMP9 activation was observed before inflammatory changes, indicating that BBB breakdown is the initial driver of the pathology of CVT. These results show an inflammation driven pathophysiology of CVT that follows MMP9-mediated BBB breakdown, and identified several targets that can be targeted by pharmaceutical agents to improve the neuroinflammation that follows CVT, such as MMP9, NLRP3, and IL-1beta. Some of these pharmaceutical agents are already in clinical practice or under clinical trials indicating a good potential for translating this work into patient care. PMID- 29981291 TI - Neural activity to threat in ventromedial prefrontal cortex correlates with individual differences in anxiety and reward processing. AB - Emotion studies show that ventromedial prefrontal cortex (vmPFC) plays a critical role in negative affect evaluation. Here we investigated two questions: Does the neural sensitivity to threat of bodily harm in vmPFC alter as anxiety levels increase? If the neural sensitivity to threat in vmPFC reflects a kind of general emotional processing, does it predict reward processing? To address these questions, we first recorded participants' self-reported anxiety. In an investigation of neural responses in vmPFC (Session 1), we measured brain activity (fMRI) associated with the anticipation of threat, using a sphere based ROI approach. In a behavioral experiment (Session 2), participants' reward processing efficiency was evaluated when they performed a visual discrimination task in which they had the opportunity to earn cash rewards. We found that across participants, there were tightly coupled associations between signal changes in the vmPFC and self-reported state anxiety. Specifically, participants who showed more activation in vmPFC to threat also exhibited greater behavioral efficiency in reward processing. Path analysis revealed a closely interconnected network of vmPFC (cortical) and VS (ventral striatum, subcortical) which predicted reward processing. Therefore, in addition to negative affect evaluation, neural sensitivity in vmPFC correlated with both anxiety and reward-related metrics. These results support an emerging model in which the vmPFC functions to defend the organism from acute stress and facilitate reward processes. PMID- 29981292 TI - The cognitive resource and foreknowledge dependence of auditory perceptual inference. AB - Auditory perceptual inference engages learning of complex statistical information about the environment. Inferences assist us to simplify perception highlighting what can be predicted on the basis of prior learning (through the formation of internal "prediction" models) and what might be new, potentially necessitating an investment of resources to remodel predictions. In the present study, we tested the hypothesis that sound sequences with multiple levels of predictability may rely on cognitive resources and be cognitively penetrable to a greater extent than was previously shown by studies presenting simpler sound sequences. Auditory evoked potentials (AEPs) were recorded from 117 participants. All participants heard the exact same sound sequence but under different conditions: 51 while watching a DVD movie and 66 while performing a cognitively demanding task. Participants were asked to ignore the sounds and focus their attention on the movie/task. However, prior to commencing the experiment we manipulated what participants knew about the sound sequence by providing explicit sequence information to 15 and 34 of the participants in the DVD and cognitive-task conditions, respectively, and no information to the others. The results demonstrated that although local pattern violations elicited distinctive AEP responses (namely, mismatch negativity), the way the amplitude of this response was modulated by sequence learning over time was dependent upon both task and explicit sequence knowledge. The implications are discussed with reference to how the division of available attention resources between the primary task and concurrent sound impacts what is learned. PMID- 29981293 TI - Identification of long noncoding RNAs in Schistosoma mansoni and Schistosoma japonicum. AB - Schistosomiasis is a major parasitic disease caused by 3 principal species of schistosome. Studies of schistosome transcriptomes have focused on protein-coding transcripts and although miRNAs are attracting increased attention, few reports have concerned the long noncoding RNAs (lncRNAs). These have been shown to play key roles in the regulation of gene expression through interactions with mRNAs, proteins and miRNAs. In this study, we first identified lncRNAs from RNA-seq data in Schistosoma mansoni and Schistosoma japonicum: 3247 and 3033 potential lncRNAs were found in these two species respectively. ChIP-seq analysis to determine H3K4me3 profiles along the gene regions corresponding to lncRNAs showed that in 12% of cases this mark was enriched in regions proximal to the transcription start sites, supporting their validity as actively transcribed genes. Besides, the sequence conservation of lncRNAs between schistosome species was much lower than that of mRNAs, but higher than that of the randomly selected genomic sequences, which is consistent with that in mammals. Our results demonstrate that lncRNAs form a significant part of the schistosome transcriptome and suggest that they play an important role in the biology of the parasite. PMID- 29981295 TI - Cholecalciferol counteracts depressive-like behavior and oxidative stress induced by repeated corticosterone treatment in mice. AB - Depression is one of the most frequent neuropsychiatric diseases in the western world and its physiological causes are not yet fully understood. Since the available antidepressants failed to provide a complete illness remission, the diversification of the therapy in the management of depression could be a useful contribution. The present study aimed to investigate the cholecalciferol capability to revert depressive-like behavior induced by chronic corticosterone (CORT) treatment in mice and its implication on the oxidative stress modulation. Sixty minutes after having orally received different doses of cholecalciferol, adult male mice were evaluated in the forced swimming and tail suspension tests, whereas in the seven-day treatment they were only tested in tail suspension. Additionally, for 21 days, the animals received CORT (20 mg/kg, p.o.) and cholecalciferol or fluoxetine, once a day for the last 7-days of the CORT treatment. Moreover, the markers of oxidative stress, lipid peroxidation, protein carbonyl and nitrite levels were assessed in the plasma and brain's mice after the splash and tail suspension tests. It was observed that corticosterone treatment resulted in depressive-like behavior with established oxidative stress in mice, while cholecalciferol ameliorated both, behavioral (immobility time and grooming latency) and biochemical (protein carbonyl and nitrite levels) changes induced by CORT model, suggesting that cholecalciferol has antidepressant-like effect with the involvement of the oxidative stress modulation. PMID- 29981294 TI - Inhibition of peptidylarginine deiminase alleviates LPS-induced pulmonary dysfunction and improves survival in a mouse model of lethal endotoxemia. AB - Immune cell death caused by neutrophil extracellular traps (NETs), referred to as NETosis, can contribute to the pathogenesis of endotoxemia and organ damage. Although the mechanisms by which infection induces NETosis and how that leads to organ dysfunction remain largely unknown, NET formation is often found following citrullination of histone H3 (CitH3) by peptidylarginine deiminase (PAD). We hypothesized that lipopolysaccharide (LPS)-induced activation of PAD and subsequent CitH3-mediated NET formation increases endothelial permeability and pulmonary dysfunction and, therefore, that inhibition of PAD can mitigate damage and improve survival in lethal endotoxemia. Here, we showed that treatment with YW3-56, a PAD2/PAD4 inhibitor, significantly diminished PAD activation, blocked LPS-induced pulmonary vascular leakage, alleviated acute lung injury, and improved survival in a mouse model of lethal LPS-induced endotoxemia. We found CitH3 in the bloodstream 30 min after intraperitoneal injection of LPS (35 mg/kg) into mice. Additionally, CitH3 production was induced in cultured neutrophils exposed to LPS, and NETs derived from these LPS-treated neutrophils increased the permeability of endothelial cells. However, YW3-56 reduced CitH3 production and NET formation by neutrophils following LPS exposure. Moreover, treatment with YW3 56 decreased the levels of circulating CitH3 and abolished neutrophil activation and NET formation in the lungs of mice with endotoxemia. These data suggest a novel mechanism by which PAD-NET-CitH3 can play a pivotal role in pulmonary vascular dysfunction and the pathogenesis of lethal endotoxemia. PMID- 29981296 TI - Identification and genetic characterization of bovine enterovirus by combination of two next generation sequencing platforms. AB - Prompt and accurate diagnosis is warranted for infectious diseases of domestic animals which may have a significant impact on animal production or clinical practice. In this study, the identification and genetic characterization of a bovine enterovirus (BEV) strain isolated from a calf with diarrhea, are described. Two different next generation sequencing platforms were employed. Shotgun metagenomic accomplished by MinION sequencing (Oxford Nanopore Technologies) allowed the identification of BEV RNA from a cell-culture isolate. BEV was then confirmed by a specific real time RT-PCR assay. To achieve the whole genome of this isolate, sequence reads obtained by MinION were coupled with those originating from NextSeq500 (Illumina). Genomic relatedness and phylogeny with extant BEV strains is also reported. Overall, this manuscript highlights the use of the portable MinION sequence technology as a tool for support diagnostics in veterinary practice. PMID- 29981297 TI - Comparison of viral elution-concentration methods for recovering noroviruses from deli meats. AB - This study aimed to assess viral elution-concentration methods for recovering noroviruses from deli meats. Spiking experiments were conducted to evaluate the recovery success rates and recovery efficiencies of human norovirus (NoV) GI and GII and murine norovirus 1 (MNV-1) using polyethylene glycol (PEG 6000) precipitation, skimmed milk flocculation (SMF), TRIzol(r) reagent, and a combination of PEG/TRIzol(r) and SMF/TRIzol(r) methods. Molecular analysis using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) revealed TRIzol(r) as the best method to be used for viral recovery from ham with medium recovery rates of 37.6% for NoV GI and 50.1% for NoV GII. Viral recovery from turkey meat showed medium recovery rates of 14.4% for NoV GI and 8.9% for NoV GII. For MNV-1, the rates varied from 0.5% to 80.8% not only according to the matrix but also with the associated virus and its inoculum (NoV GI or GII). The monitoring of commercial samples obtained in the Great Metropolitan region of Rio de Janeiro in order to demonstrate the occurrence of NoV GI and GII contamination in both matrices was also performed in 60 samples. NoV GI or GII were not detected in any samples, while MNV-1 used as the sample process control viruswas successfully recovered in 100% of samples. PMID- 29981300 TI - Note on "Glass formation in plant anhydrobiotes: Survival in the dry state". AB - We make some crucial remarks about the recent review by Buitink and Leprince (2004) [Cryobiology 48 (2004) 215-228] considering their false definition about the glass transition temperature based on the value of (shear) viscosity: 1014 Pa?s. The correct value is 1012 Pa?s as evidenced from http://goldbook.iupac.org/html/G/G02641.html or http://iupac.org/goldbook/G02641.pdf. PMID- 29981299 TI - The Impact of Microsurgical Repair of Subclinical and Clinical Varicoceles on Total Motile Sperm Count: Is There a Difference? AB - OBJECTIVE: To determine if subclinical varicocele repair produces similar results to palpable varicocele repair. METHODS: Retrospective review was performed on 190 infertile men who underwent a microsurgical varicocele repair by two surgeons from 2009 to 2017. Improvement in total motile sperm count (TMC) that enables men limited to in vitro fertilization (IVF) or intrauterine insemination (IUI) to undergo IUI or natural conception (upgrade) is clinically meaningful. Using TMC, men were grouped into three pre- and postoperative categories: IVF, (TMC < 5 million), IUI (TMC 5-9 million), or natural pregnancy (TMC > 9 million). Changes in category after varicocele repair were assessed. We compared the proportion of men in each category with clinical varicoceles to those with subclinical varicoceles. RESULTS: Men with clinical and subclinical varicoceles had improvements in TMC after surgery (change in TMC of 9.3 +/- 19.5, 7.7 +/- 22.6 million, P < 0.001 for both, respectively). There was no difference in TMC improvement between men with clinical and subclinical varicoceles (P = 0.66). Of men initially limited to IVF, 11% improved to IUI, and 38% to natural pregnancy. Of patients starting in IUI category, 22% transitioned to natural pregnancy category. No difference exists in the proportion of men who "upgraded" between palpable or subclinical varicoceles. CONCLUSION: Men with subclinical varicoceles have similar, clinically meaningful improvement in TMC after varicocele repair compared with men with palpable varicoceles. PMID- 29981298 TI - Gene Expression Signature for Prediction of Golimumab Response in a Phase 2a Open Label Trial of Patients With Ulcerative Colitis. AB - Golimumab, a tumor necrosis factor antagonist, is an effective treatment for patients with moderate-to-severe ulcerative colitis (UC); however, more than 50% of initial responders lose their response to the drug within the first year of therapy. A gene expression signature identified in colon biopsies collected before treatment was associated with response to infliximab, and was subsequently refined to associate with mucosal healing in response to golimumab. We performed a phase 2a open-label study of 103 golimumab-treated patients with moderate-to severe UC to test whether the baseline gene expression signature could be used to predict which patients would achieve mucosal healing, clinical response, and clinical remission at weeks 6 and 30 of treatment. The gene expression signature identified patients who went on to achieve mucosal healing at treatment week 6 with an area under the receiver operating characteristic curve (AUCROC) of 0.688 (P = .002) and at week 30 with an AUCROC of 0.671 (P = .006). The signature identified patients with mucosal healing with 87% sensitivity, but only 34% specificity, limiting its clinical utility. The baseline gene expression signature did not identify patients who went on to achieve clinical remission or clinical response with statistical significance. Further studies are needed to identify biomarkers that can be used to predict which patients with UC will respond to treatment with anti-tumor necrosis factor agents. ClinicalTrials.gov no: NCT01988961. PMID- 29981301 TI - Cat ovarian follicle ultrastructure after cryopreservation with ethylene glycol and dimethyl sulfoxide. AB - Ovarian tissue cryopreservation is a promising technique for fertility maintenance. The aim of this study was to compare the morphology of domestic cat ovarian follicles after tissue cryopreservation with ethylene glycol (EG) and dimethyl sulfoxide (Me2SO). Ovaries from healthy adult cats undergoing elective ovariohysterectomy were used. Eight fragments were obtained from each pair of ovaries: two were used as fresh controls; three were submitted to fresh perfusion toxicity test and perfused with M199, 10% fetal calf serum and 0.4% sucrose containing Me2SO 1.5 M, EG 1.5 M or Me2SO 0.75 M + EG 0.75 M; and the remaining three fragments were perfused as described and submitted to slow freezing. After 45 days of cryopreservation, the samples were thawed, fixed and processed for light and transmission electron microscopy (TEM). The percentages of morphologically normal follicles identified by light microscopy were higher in the control group (94.45%) in comparison to the frozen groups (80.56% with EG, 78.7% with Me2SO and 75.87% with EG + Me2SO). The fresh perfused tissue showed no statistical difference compared to control or frozen samples. The TEM analysis showed less damage in the ultrastructure of follicles from the Me2SO group in comparison with the EG and Me2SO + EG groups. According to the morphological analysis, 1.5 M Me2SO is the best cryoprotectant for cryopreservation of domestic cat ovarian tissue regarding the morphology of preantral follicles after thawing. Further studies regarding the viability of these follicles should be performed. PMID- 29981302 TI - Preoperative EUS-guided FNA: effects on peritoneal recurrence and survival in patients with pancreatic cancer. AB - BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is an accurate and relatively safe tissue confirmation method for pancreatic cancer. However, there is concern that this procedure may spread tumor cells along the needle track or within the peritoneum. We aimed to estimate the effect of preoperative EUS-FNA on the risk of peritoneal recurrence and long-term outcomes in resected pancreatic cancer. METHODS: We retrospectively reviewed records of patients diagnosed with pancreatic cancer who had undergone curative resection between 2009 and 2013 to investigate the overall survival, cancer-free survival, and peritoneal recurrence. Peritoneal recurrence was diagnosed based on image findings or cytology-confirmed ascites. RESULTS: Of 411 patients, 90 underwent preoperative EUS-FNA (EUS-FNA group), whereas 321 did not (non-EUS-FNA group). The median length of follow-up was 16.2 months (range, 2-46). Peritoneal recurrence occurred in 131 patients: 30% (27/90) in the EUS-FNA group versus 32% (104/321) in the non EUS-FNA group (P = .66). Cancer-free survival or overall survival was not significantly different between the 2 groups: median overall survival of 25.3 months in the EUS-FNA group versus 23.7 months in the non-EUS-FNA group (P = .36) and median cancer-free survival of 12.7 months in the EUS-FNA group versus 11.6 months in the non-EUS-FNA group (P = .38). CONCLUSIONS: Preoperative EUS-FNA for pancreatic cancer was not associated with an increased rate of peritoneal recurrence or mortality. Therefore, EUS-FNA is an accurate and safe method to obtain suspicious pancreatic mass tissue. PMID- 29981304 TI - Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats. AB - BACKGROUND: Hypertension promotes cardiac hypertrophy which finally leads to cardiac dysfunction. Although aberrant mitochondrial dynamics is known to be a relevant contributor of pathogenesis in heart disease, little is known about the relationship between mitochondrial dynamics and cardiac hypertrophy. We investigated the pathophysiological roles of Dynamin-related protein1 (Drp1, a mitochondrial fission protein) on the hypertensive cardiac hypertrophy. METHODS & RESULTS: Dahl salt-sensitive rats were fed with a low-salt (0.3% NaCl) or a high salt (8% NaCl) chow to promote hypertension with and without administration of mdivi1 (an inhibitor of Drp1: 1 mg/kg/every alternative day), and then the hypertensive cardiac hypertrophy was assessed. High-salt fed rats exhibited left ventricular hypertrophy (LVH), myocytes hypertrophy, and cardiac fibrosis, and mdivi-1 suppressed them without alteration of the blood pressure. Mdivi1 also reduced ROS production by hypertension, which subsequently suppressed the Ca2+ activated protein phosphatase calcineurin and Ca2+/calmodulin-dependent kinase II (CaMKII). CONCLUSIONS: Our results suggest that Drp1 contributes to the pathogenesis of hypertensive cardiac hypertrophy via ROS production and the Drp1 suppression may be effective to prevent the hypertensive cardiac hypertrophy. PMID- 29981303 TI - Cartilage oligomeric matrix protein is a novel notch ligand driving embryonic stem cell differentiation towards the smooth muscle lineage. AB - Cartilage oligomeric matrix protein (COMP), a protective component of vascular extracellular matrix (ECM), maintains the homeostasis of mature vascular smooth muscle cells (VSMCs). However, whether COMP modulates the differentiation of stem cells towards the smooth muscle lineage is still elusive. Firstly, purified mouse COMP directly induced mouse embryonic stem cell (ESC) differentiation into VSMCs both in vitro and in vivo, while the silencing of endogenous COMP markedly inhibited ESC-VSMC differentiation. RNA-Sequencing revealed that Notch signaling was significantly activated by COMP during ESC-VSMC differentiation, whereas the inhibition of Notch signaling attenuated COMP-directed ESC-VSMC differentiation. Furthermore, COMP deficiency inhibited Notch activation and VSMC differentiation in mice. Through silencing distinct Notch receptors, we identified that Notch1 mainly mediated COMP-initiated ESC-VSMC differentiation. Mechanistically, COMP N terminus directly interacted with the EGF11-12 domain of Notch1 and activated Notch1 signaling, as evidenced by co-immunoprecipitation and mammalian two-hybrid assay. In conclusion, COMP served as a potential ligand of Notch1, thereby driving ESC-VSMC differentiation. PMID- 29981305 TI - In vitro analysis of antigen induced T cell-monocyte conjugates by imaging flow cytometry. AB - There is a lack of suitable correlates of immune protection against Mycobacterium tuberculosis (Mtb) infection. T cells and monocytes play key roles in host immunity against Mtb. Thus, a method that allows assessing their interaction would contribute to the understanding of immune regulation in tuberculosis (TB). We have established imaging flow cytometer (IFC) based in vitro assay for the analysis of early events in T cell-monocyte interaction, upstream of cytokine production and T cell proliferation. This was achieved through short term stimulation of peripheral blood mononuclear cells (PBMC) from healthy Norwegian blood donors with Mycobacterium bovis Bacille Calmette-Guerin (BCG). In our assay, we examined the kinetics of BCG uptake by monocytes using fluorescently labeled BCG and T cell-monocyte interaction based on synapse formation (CD3/TCR polarization). Our results showed that BCG stimulation induced a gradual increase in the proportion of conjugated T cells displaying NF-kappaB translocation to the nucleus in a time dependent manner, with the highest frequency observed at 6 h. We subsequently tested PBMC from a small cohort of active TB patients (n = 7) and observed a similar BCG induced NF-kappaB translocation in T cells conjugated with monocytes. The method allowed for simultaneous evaluation of T cell-monocyte conjugates and T cell activation as measured by NF-kappaB translocation, following short-term challenge of human PBMC with BCG. Whether this novel approach could serve as a diagnostic or prognostic marker needs to be investigated using a wide array of Mtb specific antigens in a larger cohort of patients with different TB infection status. PMID- 29981306 TI - Chicken interferon regulatory factor 1 (IRF1) involved in antiviral innate immunity via regulating IFN-beta production. AB - Interferon regulatory factors (IRFs) is an important family for IFN expression regulating while viral infection. IRF1, IRF3, and IRF7 are the primary regulators that trigger type I IFN response in mammals. However, IRF3, which has been identified as the most critical regulator in mammals, is absent in chickens, and it is unknown whether IRF1 is involved in type I IFN signaling pathways in IRF3 deficient chicken cells. Here, we identified chicken IRF1 (chIRF1) as a critical IFN-beta mediator in response to viral infection. Overexpression of chIRF1 activated IFN-beta intensively and suppressed AIV and NDV viral replication. Moreover, the mRNA levels of IFN-beta and ISGs increased during chIRF1 overexpression. In addition, deletion mutant analysis revealed that the first four domains of chIRF1 are indispensable for IFN-beta induction. Together, our studies demonstrate that chIRF1 is an important regulator of IFN-beta and is involved in chicken antiviral innate immunity. PMID- 29981307 TI - Monoamine system disruption induces functional somatic syndromes associated symptomatology in mice. AB - Functional somatic syndromes (FSS), a clinical condition manifesting a variety of unexplained somatic symptoms, has been proposed as an inclusive nosology encompassing individual syndromes such as fibromyalgia syndrome and irritable bowel syndrome. Accumulating evidence suggests that disturbance of the endogenous monoamine system could be involved in the aetiology of FSS. Therefore, the purpose of present study was to investigate whether the disturbance of the monoamine system would cause FSS-associated symptomatology in mice. The optimal dose of reserpine, an inducer of endogenous monoamines reduction, was first explored in mice. General body condition (body weight, rectal temperature, and ptosis) and FSS-associated symptomatology (paw withdrawal threshold, small intestinal transit, and locomotor activity) were measured. The concentration of monoamines was measured in central and peripheral tissues. Mice dosed with reserpine (0.25 mg/kg s.c., once daily for 3 consecutive days) exhibited a decrease in paw withdrawal threshold, delay in small intestinal transit, and reduction of locomotor activity without deterioration of general body condition on day 5 after the first reserpine injection. The concentration of monoamines was decreased in the central nervous system and skeletal muscle, but not in the small intestine. A reserpine dose of 0.5 mg/kg or more caused deterioration of general body condition. In conclusion, the optimal protocol of reserpine treatment for inducing pain symptom without deterioration of general physical condition is 0.25 mg/kg s.c., once daily for 3 consecutive days in mice. This protocol causes not only pain but also FSS-associated symptomatology which are associated with disruption of the endogenous monoamine system. The reserpine-treated animal may be useful for the research of not only fibromyalgia syndrome but also FSS, especially for the research focusing on the hypothesis that FSS is associated with the disturbance of endogenous monoamine system. PMID- 29981308 TI - Co-expression of CDX2 and CK20 in hepatocellular carcinoma, an exceedingly rare co-incidence with potential diagnostic pitfall-reply. PMID- 29981309 TI - Gliogenesis in lampreys shares gene regulatory interactions with oligodendrocyte development in jawed vertebrates. AB - Glial cells in the nervous system regulate and support many functions related to neuronal activity. Understanding how the vertebrate nervous system has evolved demands a greater understanding of the mechanisms controlling evolution and development of glial cells in basal vertebrates. Among vertebrate glia, oligodendrocytes form an insulating myelin layer surrounding axons of the central nervous system (CNS) in jawed vertebrates. Jawless vertebrates lack myelinated axons but it is unclear when oligodendrocytes or the regulatory mechanisms controlling their development evolved. To begin to investigate the evolution of mechanisms controlling glial development, we identified key genes required for the differentiation of oligodendrocytes in gnathostomes, including Nkx2.2, SoxE genes, and PDGFR, analyzed their expression, and used CRISPR/Cas9 genome editing to perturb their functions in a primitively jawless vertebrate, the sea lamprey. We show in lamprey that orthologs required for oligodendrocyte development in jawed vertebrates are expressed in the lamprey ventral neural tube, in similar locations where gnathostome oligodendrocyte precursor cells (OPC) originate. In addition, they appear to be under the control of conserved mechanisms that regulate OPC development in jawed vertebrates and may also function in gliogenesis. Our results suggest that although oligodendrocytes first emerged in jawed vertebrates, regulatory mechanisms required for their development predate the divergence of jawless and jawed vertebrates. PMID- 29981310 TI - Constitutive activation of hedgehog signaling adversely affects epithelial cell fate during palatal fusion. AB - Cleft palate is one of the most common craniofacial congenital defects in humans. It is associated with multiple genetic and environmental risk factors, including mutations in the genes encoding signaling molecules in the sonic hedgehog (Shh) pathway, which are risk factors for cleft palate in both humans and mice. However, the function of Shh signaling in the palatal epithelium during palatal fusion remains largely unknown. Although components of the Shh pathway are localized in the palatal epithelium, specific inhibition of Shh signaling in palatal epithelium does not affect palatogenesis. We therefore utilized a hedgehog (Hh) signaling gain-of-function mouse model, K14-Cre;R26SmoM2, to uncover the role of Shh signaling in the palatal epithelium during palatal fusion. In this study, we discovered that constitutive activation of Hh signaling in the palatal epithelium results in submucous cleft palate and persistence of the medial edge epithelium (MEE). Further investigation revealed that precise downregulation of Shh signaling is required at a specific time point in the MEE during palatal fusion. Upregulation of Hh signaling in the palatal epithelium maintains the proliferation of MEE cells. This may be due to a dysfunctional p63/Irf6 regulatory loop. The resistance of MEE cells to apoptosis is likely conferred by enhancement of a cell adhesion network through the maintenance of p63 expression. Collectively, our data illustrate that persistent Hh signaling in the palatal epithelium contributes to the etiology and pathogenesis of submucous cleft palate through its interaction with a p63/Irf6-dependent biological regulatory loop and through a p63-induced cell adhesion network. PMID- 29981312 TI - Relationship of Fitness and Wheelchair Mobility With Encounters, Avoidances, and Perception of Environmental Barriers Among Manual Wheelchair Users With Spinal Cord Injury. AB - OBJECTIVE: To assess (1) if fitness and mobility are related to behavior and perception of physical barriers and (2) if behavior and physical barrier perception are related. DESIGN: Cross-sectional case series. SETTING: Academic Medical Laboratory. PARTICIPANTS: Manual wheelchair users (N=50) with chronic spinal cord injury (62% paraplegia). INTERVENTION: None. MAIN OUTCOME MEASURES: Participants completed the following assessments: (1) fitness: graded exercise test (aerobic) and Wingate (anaerobic); (2) mobility: 6-minute push test and 30 second sprint test; (3) physical barrier behavior: Encounters of Environmental Features in the Environmental Aspects of Mobility Questionnaire (EAMQ); (4) physical barrier perception: Craig Hospital Inventory of Environmental Factor (CHIEF) Environmental Barriers domain. RESULTS: Individuals with paraplegia had higher fitness, mobility, and environmental barrier encounter rates and lower avoidance per encounter rates vs tetraplegia (all P<=.05). For individuals with tetraplegia only, as mobility and fitness increased, frequencies of (1) encounters increased; (2) avoidances per encounter decreased, in multiple EAMQ domains (all P<=.05). Perception of barriers did not differ between lesion levels (P=.79). Mobility and fitness were not related to environmental barriers perception in both groups (all P>.17). CONCLUSIONS: Fitness and mobility are associated with barrier behaviors (ie, encounters and avoidances) among individuals with tetraplegia, but not paraplegia. Despite a greater barrier avoidance rate, persons with tetraplegia do not perceive more physical barriers than persons with paraplegia. Surprisingly, fitness and mobility were not related to perception of barriers in either group. More research is required on if barrier perception, behavior, or both influence participation, to enable rehabilitation programs to tailor interventions to enhance participation. PMID- 29981313 TI - Determining Peak Cough Flow Cutoff Values to Predict Aspiration Pneumonia Among Patients With Dysphagia Using the Citric Acid Reflexive Cough Test. AB - OBJECTIVE: To investigate the clinical usefulness of the peak cough flow generated during the citric acid reflexive cough test (0.28 mol/L) by determining the appropriate cutoff values that could accurately predict aspiration pneumonia within the first 6 months after onset. DESIGN: Retrospective analysis of a prospectively maintained database. SETTING: University-affiliated hospital. PARTICIPANTS: Patients (N=163) with first-ever diagnosed dysphagia attributable to cerebrovascular disease, who had undergone the citric acid reflexive cough test on the same day they underwent the instrumental assessment of swallowing, such as videofluoroscopy or the functional endoscopic swallowing test. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Peak cough flow (L/min) from the citric acid reflexive cough test. RESULTS: A final 163 patients had full medical records with 6-month follow-up. Receiver operating curve analysis showed that peak cough flow cutoff values set at 59 L/min were significantly associated with aspiration pneumonia (area under the curve [AUC] 95% confidence interval =0.88 [0.83-0.93]). This cutoff value significantly (P<.001) predicted the risk of aspiration pneumonia with an odds ratio of 21.56 (9.62-48.28). A multivariate regression logistic regression analysis model including initial dysphagia severity, low body mass index, and decreased level of cognition showed that inclusion of the peak cough flow from the citric acid reflexive cough test significantly improved the predictive model of aspiration pneumonia within the first 6 months after onset (AUC=0.91 vs 0.79). CONCLUSIONS: Those with reflexive cough strength less than 59 L/min may be at high risk of respiratory infections within the first 6 months after dysphagia onset. Objective measurement of reflexive cough strength may help to predict those at risk of aspiration pneumonia. PMID- 29981314 TI - The Feasibility and Longitudinal Effects of a Home-Based Sedentary Behavior Change Intervention After Stroke. AB - OBJECTIVE: To evaluate the feasibility and preliminary effects of a sedentary behavior change intervention on sedentary behavior, physical activity, function, and quality of life following inpatient stroke rehabilitation. DESIGN: Single group, longitudinal, intervention study with 1-week baseline, 8-week intervention, and 8-week follow-up. SETTING: Community. PARTICIPANTS: Individuals (N=34) with subacute stroke recruited within 1 month following discharge home from inpatient stroke rehabilitation. INTERVENTION: STand Up Frequently From Stroke (STUFFS) intervention that involved interrupting and replacing sedentary time with upright activities (standing and walking) at home and in the community. A motivational wrist-worn activity monitor was used throughout the intervention. MAIN OUTCOME MEASURES: Primary outcomes were reach (enrolled/eligible), retention (completed/enrolled), satisfaction, and compliance with the intervention. Secondary outcomes were sedentary behavior, physical activity, lower extremity impairment, self-efficacy, cognitive status, mobility, and quality of life outcomes. RESULTS: Forty-four participants were eligible to participate. Of the eligible, 34 (77.3%; time since stroke onset: 3.5+/-1.1 months) were enrolled at baseline and 32 (94.1%) of the enrolled had complete data at follow-up. Satisfaction with the program was 89%. Sedentary time decreased by 54.2+/-13.7 minutes per day (P<.01) at postintervention and 26.8+/-14.0 minutes per day (P=.07) at follow-up, relative to baseline. There were significant improvements in walking speed, cognition, impairment, and self-reported quality of life over time (P<.05). Self-efficacy was high across all time points. The number of steps and time spent stepping were not statistically different across both time periods. CONCLUSIONS: The program was feasible to deliver in the home environment with good retention and satisfaction. Further research is required to test the effectiveness of the STUFFS program compared with usual care. PMID- 29981311 TI - Augmentation of a wound response element accompanies the origin of a Hox regulated Drosophila abdominal pigmentation trait. AB - A challenge for evolutionary research is to uncover how new morphological traits evolve the coordinated spatial and temporal expression patterns of genes that govern their formation during development. Detailed studies are often limited to characterizing how one or a few genes contributed to a trait's emergence, and thus our knowledge of how entire GRNs evolve their coordinated expression of each gene remains unresolved. The melanic color patterns decorating the male abdominal tergites of Drosophila (D.) melanogaster evolved in part by novel expression patterns for genes acting at the terminus of a pigment metabolic pathway, driven by cis-regulatory elements (CREs) with distinct mechanisms of Hox regulation. Here, we examined the expression and evolutionary histories of two important enzymes in this pathway, encoded by the pale and Ddc genes. We found that while both genes exhibit dynamic patterns of expression, a robust pattern of Ddc expression specifically evolved in the lineage of fruit flies with pronounced melanic abdomens. Derived Ddc expression requires the activity of a CRE previously shown to activate expression in response to epidermal wounding. We show that a binding site for the Grainy head transcription factor that promotes the ancestral wound healing function of this CRE is also required for abdominal activity. Together with previous findings in this system, our work shows how the GRN for a novel trait emerged by assembling unique yet similarly functioning CREs from heterogeneous starting points. PMID- 29981315 TI - Factors Associated With Long-Term Improvement of Gait After Selective Dorsal Rhizotomy. AB - OBJECTIVE: To identify factors associated with long-term improvement in gait in children after selective dorsal rhizotomy (SDR). DESIGN: Retrospective cohort study. SETTING: University medical center. PARTICIPANTS: Children (N=36) (age 4 13y) with spastic diplegia of Gross Motor Function Classification System (GMFCS) level I (n=14), II (n=15), and III (n=7) were included retrospectively from the database of our hospital. Children underwent SDR between January 1999 and May 2011. Patients were included if they received clinical gait analysis before and 5 years post-SDR, age >4 years at time of SDR and if brain magnetic resonance imaging (MRI) scan was available. INTERVENTION: Selective dorsal rhizotomy. MAIN OUTCOME MEASURES: Overall gait quality was assessed with Edinburgh visual gait score (EVGS), before and 5 years after SDR. In addition, knee and ankle angles at initial contact and midstance were evaluated. To identify predictors for gait improvement, several factors were evaluated including functional mobility level GMFCS, presence of white matter abnormalities on brain MRI, and selective motor control during gait (synergy analysis). RESULTS: Overall gait quality improved after SDR, with a large variation between patients. Multiple linear regression analysis revealed that worse score on EVGS and better GMFCS were independently related to gait improvement. Gait improved more in children with GMFCS I and II compared to III. No differences were observed between children with or without white matter abnormalities on brain MRI. Selective motor control during gait was predictive for improvement of knee angle at initial contact and midstance, but not for EVGS. CONCLUSION: Functional mobility level and baseline gait quality are both important factors to predict gait outcomes after SDR. If candidates are well selected, SDR can be a successful intervention to improve gait both in children with brain MRI abnormalities as well as other causes of spastic diplegia. PMID- 29981316 TI - Factors Associated With Participation in Life Situations for Adults With Stroke: A Systematic Review. AB - OBJECTIVES: To identify biopsychosocial factors associated with participation outcomes for adults with stroke and to investigate factors associated with participation at different time points poststroke. DATA SOURCES: Medline, CINAHL, AMED, PyschINFO, and Web of Science were systematically searched using keywords stroke, participation, and outcomes and their synonyms on May 15, 2017. STUDY SELECTION: Observational studies reporting on biopsychosocial factors and participation outcomes for community-dwelling adults with stroke were selected. Studies were eligible for inclusion if participation outcomes were measured using indices that mapped to the participation domain of the International Classification of Functioning, Disability and Health (ICF). Intervention studies were excluded. A second reviewer checked all studies against eligibility criteria at each stage. DATA EXTRACTION: Data were extracted on any statistically determined association between biopsychosocial factors and participation outcomes. DATA SYNTHESIS: The proportion of studies reporting significant associations with variables was classified according to the ICF. The exact binomial test was used to determine the probability that the proportion of studies reporting significant associations was due to chance alone. Qualitative descriptive summaries of each study allowed consideration of interactions between variables and changes in participation over time points. CONCLUSIONS: Although depressive symptoms, cognitive functioning, and mobility were found to have the strongest associations with participation, we found that other frequently occurring factors (such as fatigue and environmental factors) were less extensively considered. The diversity of outcome measures encountered within the review highlight the need for a consensus on a core set of outcome measures to evaluate long-term participation in life situations poststroke. PMID- 29981317 TI - Advancements in electrochemical DNA sensor for detection of human papilloma virus - A review. AB - Human papillomavirus (HPV) is one of the most common sexually transmitted disease, transmitted through intimate skin contact or mucosal membrane. The HPV virus consists of a double-stranded circular DNA and the role of HPV virus in cervical cancer has been studied extensively. Thus it is critical to develop rapid identification method for early detection of the virus. A portable biosensing device could give rapid and reliable results for the identification and quantitative determination of the virus. The fabrication of electrochemical biosensors is one of the current techniques utilized to achieve this aim. In such electrochemical biosensors, a single-strand DNA is immobilized onto an electrically conducting surface and the changes in electrical parameters due to the hybridization on the electrode surface are measured. This review covers the recent developments in electrochemical DNA biosensors for the detection of HPV virus. Due to the several advantages of electrochemical DNA biosensors, their applications have witnessed an increased interest and research focus nowadays. PMID- 29981318 TI - Determination of methionine-enkephalin and leucine-enkephalin by LC-MS in human plasma: Study of pre-analytical stability. AB - The aim of this work was to assess the influence of preanalytical variables on the stability of two endogenous opioid peptides (Methionine-Enkephalin and Leucine-Enkephalin) in human plasma. For this purpose, first a sensitive LC-MS/MS analytical method was developed and validated for the simultaneous quantitative analysis of these two peptides. The methodology consisted of a simple protein precipitation step followed by UPLC separation and MRM quantitative analysis using a stable isotope labelled Methionine-Enkephalin as internal standard. The method with a limit of quantitation of 10 pg/mL showed good reproducibility with excellent accuracy and precision, and was linear up to 2000 pg/mL. An extensive evaluation of the pre-analytical stability of these peptides in human blood was carried out to ensure an adequate sample collection procedure to obtain reliable results in the analysis of clinical samples. PMID- 29981319 TI - The steroid hormone dydrogesterone inhibits myometrial contraction independently of the progesterone/progesterone receptor pathway. AB - AIMS: In this study, we aimed to investigate the direct effects of steroid hormones on pregnant myometrial contraction. MAIN METHODS: The effect of steroids on oxytocin-induced contraction was examined in vitro using pregnant rat or human myometrium. Subsequently, we evaluated whether RU486, a potent progesterone antagonist, influenced the effects of progestin on myometrial contraction. Additionally, we evaluated the effects of progestin on high-concentration KCl induced contraction caused by voltage-dependent calcium channels in order to investigate the mechanisms involved in this process. KEY FINDINGS: Of the natural steroids examined, 17beta-estradiol, progesterone, testosterone, cortisol, and aldosterone did not influence oxytocin-induced contraction at concentrations <10 6 M. Of the tested progestins, medroxyprogesterone acetate, norethisterone, chlormadinone acetate, levonorgesterol, 17alpha-hydroxyprogesterone capronate, and dienogest had no effect on contraction at <10-6 M. However, dydrogesterone showed rapid and direct inhibition of contraction at 10-6 M, and this inhibitory effect was dependent on dose and time. RU486 did not block the inhibitory effects of dydrogesterone on contraction. High-concentration KCl-induced contraction was also inhibited by dydrogesterone, and the inhibitory effects of dydrogesterone were observed at concentrations as low as 10-7 M. Additionally, oxytocin-induced contraction in pregnant human myometrium was inhibited by 10-6 M dydrogesterone. SIGNIFICANCE: These results suggested that the rapid and direct effects of dydrogesterone on myometrial contraction were caused by a nongenomic pathway and that the progesterone receptor was not required for dydrogesterone action. Additionally, the mechanism of dydrogesterone action may involve voltage dependent calcium channels. PMID- 29981320 TI - Ergothioneine ameliorates oxaliplatin-induced peripheral neuropathy in rats. AB - AIMS: Oxaliplatin (l-OHP) is a key drug in therapeutic regimens for metastatic or advanced-stage colorectal cancer, but causes peripheral neuropathy as a dose limiting adverse effect. It is reported that this peripheral neuropathy results from l-OHP accumulation in dorsal root ganglion (DRG) neurons, and that one of the transporters responsible for the accumulation in DRG neurons is organic cation transporter novel (OCTN) 1. Here, we examined whether co-administration of ergothioneine, a substrate/inhibitor of OCTN1, with l-OHP could prevent this peripheral neuropathy. MAIN METHODS: l-OHP (4 mg/kg, i.p., twice/week, for 6 weeks) and ergothioneine or l-carnitine (1.5 or 15 mg/kg, i.v., twice per l-OHP administration) were administered to rats, and tissue/cellular platinum concentrations and peripheral neuropathy were determined. Expression of transporters in DRG neuronal cells was evaluated by real-time PCR and immunocytochemistry. KEY FINDINGS: On administration of l-OHP to rats, it accumulated in DRG neurons and their mitochondria, while negligible accumulation was found in Schwann cells. Expression of OCTN1 was observed in DRG neurons, especially in small- and medium-sized ones, which are responsible for the nociceptive response. In rats repeatedly administered l-OHP, co-administration of ergothioneine (15 mg/kg), but not l-carnitine, a substrate/inhibitor of OCTN2, decreased l-OHP accumulation in DRGs and development of the mechanical allodynia. SIGNIFICANCE: These results indicated that l-OHP-induced peripheral neuropathy was ameliorated by co-administration of ergothioneine, at least in part, via a decrease in its accumulation in DRG neurons. Plant diets contain ergothioneine, and thus their consumption might offer relief to patients suffering from l-OHP induced peripheral neuropathy. PMID- 29981321 TI - Atorvastatin, losartan and captopril may upregulate IL-22 in hypertension and coronary artery disease; the role of gene polymorphism. AB - AIMS: Interleukin-22 (IL-22) may be considered as an important cytokine in maintenance and progression of hypertension and coronary artery disease (CAD). The aim of the present study was to investigate the effect of treatment of hypertension and CAD on serum levels of IL-22 and the possible association of IL 22-rs1179251 gene polymorphism with hypertension and CAD. MATERIALS AND METHODS: A total of 286 subjects with suspected CAD were enrolled. Serum levels and gene polymorphism of IL-22 were investigated in hypertensive patients with no CAD (H Tens), hypertensive patients with CAD (CAD + H-Tens); 3), CAD patients with no hypertension (CAD); and non-hypertensive with no CAD subjects as a control group (Ctr). The patients received routine medications for hypertension and CAD. Serum IL-22 levels and IL-22-rs1179251 gene polymorphism were evaluated using ELISA and RFLP-/PCR techniques, respectively. KEY FINDINGS: Findings demonstrated that there were significantly higher levels of IL-22 in case groups (H-Tens, CAD + H Tens, and CAD) compared to the Ctr group (P = 0.001, P = 0.014, and P < 0.001, respectively). Moreover, atorvastatin, losartan and captopril were administered significantly more in patients compared to the Ctr group. The results indicated a decreased risk of CAD + H-Tens of rs1179251 dominant genetic model (OR = 0.324; 95% CI = 0.121-0.873; P = 0.026). SIGNIFICANCE: Atorvastatin, losartan and captopril may be led to upregulation of IL-22 in CAD and hypertensive patients. Meanwhile, higher levels of circulating IL-22 could contribute to alleviating the hypertension and CAD conditions. The G allele of IL-22 rs1179251 may be a protective factor for concomitant hypertension and CAD. PMID- 29981322 TI - Corticotropin-releasing factor suppresses glioma progression by upregulation of long non-coding RNA-p21. AB - Corticotropin-releasing factor (CRF) plays a key role in neuroendocrine regulation of hypothalamo-pituitary-adrenal axis under normal condition and stress by binding to CRF receptor1 (CRFR1). CRF and its receptors have been reported in many types of tumors. Little is known about the role of CRF in the development of glioma. And lincRNA-p21 was reported to act as a role in progression of some cancers. The aim of the present study was to investigate the levels of CRF in glioma, and explore the link between CRF and lincRNA-p21 in this disease. In this study, we found CRF mRNA expression was significantly down regulated in glioma mice. Moreover, CRF could suppress the proliferation of glioma cells and promote the expression of lincRNA-p21. Afterwards, lincRNA-p21 repressed the proliferation and invasion of glioma cells, which was reversed by miR-34c targeted with 3'-UTR. Furthermore, miR-34c decreased the expression of CRFR1 by binding with the 3'-UTR, which interact with CRF to inhibit the proliferation of glioma cells. Together, these results CRF plays as an important role in glioma progression and metastasis through activation of lincRNA-p21, providing a novel insight for the pathogenesis and underlying therapeutic target for glioma. PMID- 29981323 TI - Alternative RNA splicing associated with axon regeneration after rat peripheral nerve injury. AB - The intrinsic axon regeneration capacity is crucial for peripheral nerve regeneration after injury. Identifying key molecules involved in this process makes great contribution to the investigation of peripheral nerve injury repair. Alternative splicing (AS) is an important regulation mode of eukaryotic gene expression, which has been widely studied both in physiological and pathological processes. However, less is known about the role of AS in peripheral nerve regeneration. In this work, to identify the AS events associated with axon regeneration capacity, we analyzed the AS events during sciatic nerve injury repair by RNA sequencing (RNA-Seq) and replicate multivariate analysis of transcript splicing (rMATS). The differential AS events were underwent gene ontology enrichment and pathway analyses. Moreover, we identified a significantly increased AS event of neuronal cell adhesion molecule Nrcam (Nrcam-S), and demonstrated down-regulation of Nrcam-S by specific siRNAs inhibited axon regeneration of Dorsal Root Ganglion (DRG) neurons after sciatic nerve injury in vitro and in vivo. Additionally, we found expression levels of RNA binding proteins (RBPs) CUGBP Elav-like family member 3 (CELF3) and RNA binding protein fox-1 homolog 2 (Rbfox2) were markedly increased after sciatic nerve injury. Our data may serve as a resource useful for further understanding how AS contributes to molecular regulations in DRG during sciatic nerve regeneration. PMID- 29981324 TI - Appetitive and aversive learning of plants odors inside different nest compartments by foraging leaf-cutting ants. AB - Cues inside the nest provide social insect foragers with information about resources currently exploited that may influence their decisions outside. Leaf cutting ants harvest leaf fragments that are either further processed as substrate for their symbiotic fungus, or disposed of if unsuitable. We investigated whether Acromyrmex ambiguus foragers develop learned preferences for olfactory cues they experienced either in the fungus or in the waste chamber of the nest. Foragers' olfactory preferences were quantified as a choice between sugared papers disks scented with a novel odor and with the odor experienced in one of the nest compartments, before and after odor addition. Odors incorporated in the fungus chamber led to preferences towards paper disks smelling of them. Conversely, odors experienced in the waste chambers led to avoidance of similarly scented disks. To investigate context-specificity of responses, we quantified learned preferences towards an odor that occurred first in the fungus chamber, and 14 h later in the waste chamber. Foragers initially developed a preference for the odor added in the fungus chamber that turned into avoidance when the same odor solely occurred later in the waste chamber. Avoidance of plants could also be induced in a more natural context, when fresh leaf disks of novel plants, privet or firethorn, were presented in the waste chamber. We conclude that learned acceptance or rejection of suitable plants by foragers depend on the learning context: smells can lead to appetitive learning when present in the fungus garden, or to avoidance learning when they occur at the dump. PMID- 29981325 TI - Dietary supplementation with purified wheat germ glycoprotein improve immunostimulatory activity in cyclophosphamide induced Balb/c mice. AB - Wheat germ has been reported to possess critical biological activities. However, the molecular mechanisms are not fully illuminated. In this work, the immunostimulating activity of a newly purified wheat germ glycoprotein (WGPII) was investigated in immunosuppressed Balb/c mice. Subsequently, WGPII increased the indices of spleen and thymus. Histopathological analysis indicated the protective function of WGPII against cyclophosphamide (CTX) induced immunosuppression. It also showed that WGPII could strengthen macrophage phagocytosis capacity, and NK cell activity. Following, flow cytometry was used to investigate spleen T lymphocyte subpopulations, real-time polymerase chain reaction (RT-PCR) was used to investigate spleen secreted cytokines, and western blot was used to analysis the receptor protein and protein kinase. These results indicated that WGPII could enhance CD4+ and CD8+ splenic T lymphocytes, inflammatory cytokines (IL-beta, IL-6, IL-12, TNF-alpha mRNA), receptor protein (TLR2, TLR4) and protein kinase (IRAK4, TRAF6, TAK1, p38-MAPK, pho-p38-MAPK, NF kappaB p65, and nucleu-NF-kappaB p65) production. This study suggests that WGPII, used as a dietary supplement, could be considered a good candidate to improve immune functions. PMID- 29981326 TI - Effects of intrinsic metal ions of lentinan with different molecular weights from Lentinus edodes on the antioxidant capacity and activity against proliferation of cancer cells. AB - In this study, effects of intrinsic metal ions in lentinan on its bioactivities were evaluated. Lentinan extracted from Lentinus edodes was separated to four fractions with different molecular weights with Sephadex G-200 gel chromatography, and intrinsic metal ions were removed by EDTA. The ferrous ion chelating capacity of ELWs was measured to estimate EDTA residue after extensive dialysis. Antioxidant and antitumor activities of the isolated lentinans (LWs and ELWs) were investigated in vitro and compared, respectively. The results indicated that all of the isolated lentinan contained a large amount of intrinsic metal ions and the fraction with the lowest Mw had highest metal content. After removing intrinsic metal ions, the polysaccharides showed lower ABTS and DPPH radicals scavenging capacity and the reduced inhibition of the proliferation of BXPC-3 and Hela cells. Our results indicated that the metal ions in lentinan had positive effects on its bioactivities. PMID- 29981327 TI - Antioxidant and antimicrobial evaluation of carboxymethylated and hydroxamated degraded polysaccharides from Sargassum fusiforme. AB - In order to improve the bioactivity of the polysaccharide from Sargassum fusiforme (PSF), the degraded polysaccharide (DPSF) was modified by carboxymethylation, yielding carboxymethylated degraded polysaccharides (CDPSF), which were further modified to generate hydroxamated derivatives (HCDPSF). Both CDPSF and HCDPSF were characterized by Fourier transform infrared spectroscopy. The molecular weight of CDPSF and HCDPSF was found to be 354 kDa and 375 kDa, respectively. The in vitro antioxidant activity of CDPSF and HCDPSF was evaluated by determining the radical scavenging ability and total antioxidant activity. The results indicated that the antioxidant activity of CDPSF and HCDPSF was significantly improved when compared to those of DPSF. Antimicrobial assays indicated that both CDPSF and HCDPSF possessed a marked antimicrobial ability, while DPSF did not exhibit such effects under the same conditions. Such polysaccharide derivatives have potentials in the pharmaceutical and food industries. PMID- 29981328 TI - Arginine suppresses opalescence and liquid-liquid phase separation in IgG solutions. AB - Antibody formulation often necessitates the protein concentration to be increased above 100 mg/ml, because of the large therapeutic doses of antibodies required and the volume limitations of subcutaneous injections. However, high concentrations of antibody lead to opalescent states in solution, resulting in safety and application problems. In this study, we investigated the effect of additives on opalescence in IgG solutions. Arginine (Arg) was observed to most effectively suppress opalescence in IgG solutions among the additives tested, which included guanidine hydrochloride, NaCl, and other amino acids. Moreover, Arg also suppressed liquid-liquid phase separation (LLPS) of highly concentrated IgG solutions during incubation at low temperature. Comparative analysis showed that the effects of Arg on opalescence and LLPS in IgG solutions result from its unique structure, which comprises an amino acid main chain, a guanidinium group, and a counter ion. These results indicate that Arg has high potency as an excipient in antibody drug formulations for the suppression of opalescence and LLPS as well as protein aggregation. PMID- 29981329 TI - The complete mitochondrial genome of Clostera anastomosis (Lepidoptera: Notodontidae) and implication for the phylogenetic relationships of Noctuoidea species. AB - In the present study, the complete mitochondrial genome (mitogenome) of Clostera anastomosis (C. anastomosis) has been determined for the first time. The mitogenome is 15,390 base pairs (bp) in length, comprised of 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and one non coding control region (CR). The gene order shows a typical trnM rearrangement (trnM-trnI-trnQ) compared to ancestral insects (trnI-trnQ-trnM). Almost all the PCGs have the same start codon (ATN) except for cox1 (CGA), and almost all tRNAs have a typical cloverleaf secondary structure except for trnS1. At the beginning of the CR, we found a conserved motif "ATAGA + poly-T" as found in other lepidopteran insects. There are 20 intergenic regions and 11 overlapping regions, ranging from 1 to 53 bp and 1 to 9 bp, respectively. The A + T content is relatively high across the whole mitogenome. The optimal tree topologies of Noctuoidea were given by the dataset consisting of all 13 PCGs from five families (exclude Oenosandridae). Our trees suggested a topology of (Notodontidae + (Erebidae + (Nolidae + (Euteliidae + Noctuidae)))) and identified that C. anastomosis belongs to Notodontidae. PMID- 29981330 TI - Thermal degradation behaviour and crystallization kinetics of poly (lactic acid) and cellulose nanocrystals (CNC) based microcellular composite foams. AB - The current investigation addresses the thermal degradation and non-isothermal crystallization behaviour of the fabricated poly (lactic acid) foam (nPLA) and poly (lactic acid) (PLA)/cellulose nanocrystal (CNC) based foams at three different loadings of CNC (i.e. 1%, 2% and 3%) as PLA/CNC 1, PLA/CNC 2 and PLA/CNC 3 having highly porous, interconnected and microcellular morphology. The formation of various gaseous products at two different conversions (alpha = 0.3 and alpha = 0.7) are investigated by using thermogravimetric analyser hyphenated Fourier transmission infrared spectroscopy (TGA-FTIR) analysis in isothermal condition. Effect of porosity and CNC reinforcement towards thermal degradation and crystallization of the PLA is thoroughly investigated by using mercury intrusion porosimetry (MIP). "Model-free" and "modelistic" approaches like Friedman, Flynn-Wall-Ozawa (FWO), Kissinger-Akahira-Sinouse (KAS), Kissinger and Augis & Bennet have been utilized for non-isothermal degradation kinetics of the fabricated foams. Non-isothermal melt crystallization kinetics of fabricated foams reveals that both primary and secondary crystallization process taking place. The apparent activation energy calculated from FWO are ~175.8 kJ/mol, ~198.6 kJ/mol, ~175.5 kJ/mol and ~174.7 kJ/mol for nPLA, PLA/CNC 1, PLA/CNC 2 and PLA/CNC 3 respectively. It is also observed that at higher conversions, complex three dimensional diffusion mechanism of degradation might be taking place in accordance with Criado plots. PMID- 29981331 TI - Wet electrospun alginate/gelatin hydrogel nanofibers for 3D cell culture. AB - Convergence of biological and biofabrication approaches is necessary to progress new biomaterials promoting three-dimensional (3D) cell growth and maturation towards tissue regeneration and integration. Here, we have developed a novel approach to fabricate 3D macroporous, alginate/gelatin hydrogel nanofibers (Alg/GelF-MA), which provide superior cell adhesion, motility, proliferation and maturation. The electrospinning process greatly depends on the ionic strength and viscoelastic behavior of the solution. The polyelectrolyte nature of alginate favors intramolecular bundles over intermolecular entanglement, which hinders its electrospinnability. Electrospinning of alginate was achieved by the aid of a supporting polymer, polyethylene oxide and a surfactant, Pluronic(r)F127. Furthermore, the Ca2+-mediated coagulation process of alginate was realized in situ during wet electrospinning, where the rapid physical crosslink-ability of alginate was applied in conjunction with the jet entrance into the wet electrospinning collector, a coagulation bath. Consequently, the rapid formation of Ca2+-alginate complex stabilized the nanofiber morphology. The low surface tension of the non-solvent ethanol used in the bath prevented fibers from dense packing, thus allowing the generation of 3D macroporous structure favoring cell motility. The subsequent UV-mediated chemical crosslinking further stabilized the gelatin content in the Alg/GelF-MA hydrogel nanofibers. It is demonstrated that the Alg/GelF-MA nanofibers with low cytotoxicity (below 10%) supported an over 8 fold proliferation of mesenchymal stem cells over 5 weeks and supported the maturation of human iPSC-derived ventricular cardiomyocytes, which significantly outperform the cell encapsulated bulk GelF-MA hydrogel. The work provides an insight for rational design and development of 3D cell culture matrix for advancement of stem cell therapy and tissue regeneration. PMID- 29981332 TI - Distribution of tightly and loosely bound water in biological macromolecules and age-related diseases. AB - This mini-review article is focused on publications devoted to the changes in water binding energy and content of bound water in biological tissues during aging processes, when bound water lost from the hydration layer becomes free water. Bound water is released during cataractogenesis. In skin, water bound to proteins and other biomacromolecules becomes more mobile with increasing skin age. Extracellular to intracellular water ratio increases with age and was associated with muscle cell atrophy. Bound water concentration decreases with age in hydrated human bone and can be correlated with the strength and toughness of the bone. Higher fraction of free water in malignant tissues compared to normal tissues was observed. Hydration water mobility is enhanced around tau amyloid fibers. Water plays a decisive role in amyloid formation as entropic driving force. In the natural aging processes dehydration and glycation may be considered as subsequent steps. PMID- 29981333 TI - Invasion of the assassin bug Agriosphodrus dohrni (Hemiptera: Reduviidae) to Japan: Source estimation inferred from mitochondrial and nuclear gene sequences. AB - A large-sized assassin bug Agriosphodrus dohrni (Signoret), has been recorded from India, Vietnam, China and Japan. It is one of the potential biological control agents against some important agricultural and forest pests. This species is speculated to have invaded Japan from its native range in China about 60 years ago. We used three mitochondrial gene fragments (COI, Cytb, and ND5) and one nuclear gene fragment (EF-1alpha) to clarify the invasion history of A. dohrni and assess the effects of geographic events and associated ecological adaptation on the distribution pattern. The native populations of A. dohrni in China are divided into three distinct groups, which might be molded by the Early Pleistocene glaciation event and diverged during the Calabrian Stage. However, consistent with the hypothesis of a recent invasion, extremely low level of genetic variation was detected in the Japanese populations, with only two haplotypes for the combined mitochondrial genes. Both the splits network and the ML/BI phylogenetic trees revealed that haplotypes of Japan were more closely related to those from eastern China. Therefore, we postulate that there has been only one introduction event, probably from somewhere around the Nanjing (NJ) and Lin'an (LA) populations of eastern China. PMID- 29981334 TI - Thioredoxin-1 downregulation in the nucleus accumbens promotes methamphetamine primed reinstatement in mice. AB - Relapse of drug abuse after abstinence is a major challenge to the treatment of addicts. Thioredoxin-1 (Trx-1) is an important regulator of neuroprotection, and inhibits morphine-induced hyperlocomotion, reward and withdrawal signs, as well as blocks methamphetamine (METH)-induced conditioned place preference (CPP). The nucleus accumbens (NAc) is essential for relapse like behavior in reinstatement animal models. In the present study, we aimed to investigate the role of Trx-1 in the NAc in METH-primed reinstatement by using a reinstatement procedure in mice. Adeno-associated virus vectors expressing shRNA-mTrx-1 (AAV-shRNA-mTrx-1) were bilaterally microinjected into the NAc after METH-CPP extinction. The results showed that Trx-1 downregulation in the NAc promoted the reinstatement of METH CPP. We also examined the expression of N-methyl-D-asparate (NMDA) receptor 2B subunit (GluN2b), the levels of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated cAMP-response element binding protein (p-CREB) in the NAc by western blot analysis, and found that the GluN2b expression, p-ERK and p-CREB levels were increased in the NAc in response to low-dose METH in AAV shRNA-mTrx-1 mice, but were not changed in control and AAV-vehicle mice. These data indicate that the increased GluN2b expression, and p-ERK and p-CREB levels in the NAc of AAV-shRNA-mTrx-1 mice may be responsible for the METH-primed reinstatement. Thus, we suggest that downregulation of Trx-1 in the NAc may make mice more sensitive to METH reinstatement. PMID- 29981335 TI - Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and dose-limiting side effect of cancer treatment that affects millions of cancer survivors throughout the world and current treatment options are extremely limited by their side effects. Cannabinoids are highly effective in suppressing pain symptoms of chemotherapy-induced and other peripheral neuropathies but their widespread use is limited by central nervous system (CNS)-mediated side effects. Here, we tested one compound from a series of recently developed synthetic peripherally restricted cannabinoids (PRCBs) in a rat model of cisplatin-induced peripheral neuropathy. Results show that local or systemic administration of 4-{2-[-(1E) 1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI) dose-dependently suppressed CIPN mechanical and cold allodynia. Orally administered PrNMI also dose-dependently suppressed CIPN allodynia symptoms in both male and female rats without any CNS side effects. Co-administration with selective cannabinoid receptor subtype blockers revealed that PrNMI's anti allodynic effects are mediated by CB1 receptor (CB1R) activation. Expression of CB2Rs was reduced in dorsal root ganglia from CIPN rats, whereas expression of CB1Rs and various endocannabinoid synthesizing and metabolizing enzymes was unaffected. Daily PrNMI treatment of CIPN rats for two weeks showed a lack of appreciable tolerance to PrNMI's anti-allodynic effects. In an operant task which reflects cerebral processing of pain, PrNMI also dose-dependently suppressed CIPN pain behaviors. Our results demonstrate that PRCBs exemplified by PrNMI may represent a viable option for the treatment of CIPN pain symptoms. PMID- 29981336 TI - Use of image texture analysis to find DNA sequence similarities. AB - Sequence similarity analysis is a basic method in computational biological studies. Determining the similarity of biological sequences is a vital step in much research, such as exploring the evolutionary relationship among species, gene function analysis, protein structure prediction, and sequence retrieving. This paper introduces a method that uses the theory of the gray-level co occurrence matrix, which is important in image texture analysis, to define and calculate the features of a DNA sequence. The proposed method can make a quantitative analysis and compute the defined texture features of a DNA sequence. Using these quantified sequence features, a similarity distance matrix can be computed and phylogenetic relationships also can be inferred. From the quantified features, we found that the DNA sequence of humans has the highest entropy and lowest energy. From human to chimpanzee, orangutan, gorilla, and other species, the entropy decreases and energy increases. The advantage of the proposed method is that it can compute multiple features inherent in each sequence. Furthermore, the defined features can be the key values or tags for each sequence for sequence retrieval and similarity analysis. PMID- 29981337 TI - A Network Hierarchy-Based method for functional module detection in protein protein interaction networks. AB - In the post-genomic era, one of the important tasks is to identify protein complexes and functional modules from high-throughput protein-protein interaction data, so that we can systematically analyze and understand the molecular functions and biological processes of cells. Although a lot of functional module detection studies have been proposed, how to design correctly and efficiently functional modules detection algorithms is still a challenging and important scientific problem in computational biology. In this paper, we present a novel Network Hierarchy-Based method to detect functional modules in PPI networks (named NHB-FMD). NHB-FMD first constructs the hierarchy tree corresponding to the PPI network and then encodes the tree such that genetic algorithm is employed to obtain the hierarchy tree with Maximum Likelihood. After that functional module partitioning is performed based on it and the best partitioning is selected as the result. Experimental results in the real PPI networks have shown that the proposed algorithm not only significantly outperforms the state-of-the-art methods but also can detect protein modules more effectively and accurately. PMID- 29981338 TI - The influence of social behaviour on competition between virulent pathogen strains. AB - Infectious disease interventions like contact precautions and vaccination have proven effective in disease control and elimination. The priority given to interventions can depend strongly on how virulent the pathogen is, and interventions may also depend partly for their success on social processes that respond adaptively to disease dynamics. However, mathematical models of competition between pathogen strains with differing natural history profiles typically assume that human behaviour is fixed. Here, our objective is to model the influence of social behaviour on the competition between pathogen strains with differing virulence. We couple a compartmental Susceptible-Infectious Recovered model for a resident pathogen strain and a mutant strain with higher virulence, with a differential equation of a population where individuals learn to adopt protective behaviour from others according to the prevalence of infection of the two strains and the perceived severity of the respective strains in the population. We perform invasion analysis, time series analysis and phase plane analysis to show that perceived severities of pathogen strains and the efficacy of infection control against them can greatly impact the invasion of more virulent strain. We demonstrate that adaptive social behaviour enables invasion of the mutant strain under plausible epidemiological scenarios, even when the mutant strain has a lower basic reproductive number than the resident strain. Surprisingly, in some situations, increasing the perceived severity of the resident strain can facilitate invasion of the more virulent mutant strain. Our results demonstrate that for certain applications, it may be necessary to include adaptive social behaviour in models of the emergence of virulent pathogens, so that the models can better assist public health efforts to control infectious diseases. PMID- 29981339 TI - Hepatitis B virus suppresses the secretion of insulin-like growth factor binding protein 1 to facilitate anti-apoptotic IGF-1 effects in HepG2 cells. AB - Hepatitis B virus (HBV) infection is a major global health burden as chronic hepatitis B (CHB) is associated with the development of liver diseases including hepatocellular carcinoma (HCC). To gain insight into the mechanisms causing HBV related HCC, we investigated the effects of HBV replication on global host cell gene expression using human HepG2 liver cells. By microarray analysis, we identified 54 differentially expressed genes in HBV-replicating HepG2 cells. One of the differentially-expressed genes was insulin-like growth factor binding protein 1 (IGFBP1) which was downregulated in HBV-replicating cells. Consistent with the gene expression data, IGFBP1 was suppressed at both the cellular and secreted protein levels in the presence of HBV replication. Transient transfection experiments with an inducible plasmid encoding the HBV X protein (HBx) revealed that HBx alone was sufficient to modulate IGFBP1 expression. Small interference RNA (siRNA)-mediated loss of function studies revealed that knockdown of IGFBP1 reduced apoptosis induced by either thapsigargin (TG) or staurosporine (STS). Treatment of cells with recombinant insulin-like growth factor 1 (IGF-1) decreased both TG- or STS-induced apoptosis. Interestingly, addition of recombinant IGFBP1 reversed the anti-apoptotic effect of IGF-1 on TG induced, but not STS-induced, apoptosis. In conclusion, our results suggest an anti-apoptotic autocrine function of HBV-mediated downregulation of IGFBP1 in HepG2 cells. Such an effect may contribute to the development of HBV-mediated HCC by increasing pro-survival and anti-apoptotic IGF-1 effects. PMID- 29981340 TI - Upregulated SCUBE2 expression in breast cancer stem cells enhances triple negative breast cancer aggression through modulation of notch signaling and epithelial-to-mesenchymal transition. AB - BACKGROUND: Metastatic and/or recurrent breast carcinomas are leading causes of cancer-related death worldwide. Breast cancer stem cells (BCSCs) have been implicated in cancer metastases and progression, thus, the need for the discovery and development of effective BCSCs-specific therapies against metastatic and triple negative breast cancer (TNBC). The expression of SCUBE2, originally identified in vascular endothelia, then in several non-endothelial cell types, is downregulated in invasive breast carcinomas. However, the role of SCUBE2 in BCSCs remains unknown. This present study investigated the probable involvements of SCUBE2 in BCSCs and TNBC metastasis. METHODS: The mRNA expression of SCUBE2, stemness and EMT markers in MDA-MB-231 and Hs578T tumorspheres or adherent cells were evaluated by qRT-PCR and microarray analyses. Using gene overexpression, in vitro migration and invasion assays, as well as in vivo bioluminescence imaging, we evaluated the role of SCUBE2 in MDA-MB-231 or Hs578T BCSCs. Western blot and cytotoxicity assays helped identify and validate SCUBE2 molecular target(s) and inhibitor(s). RESULTS: Concurrently increased SCUBE2 expression and cell motility were observed in TNBC tumorspheres compared to the parental adherent cells. SCUBE2 overexpression augmented BCSCs motility in vitro, and enhanced TNBC metastasis in vivo. While SCUBE2 overexpression activated Notch signaling its downregulation suppressed Notch signal effectors NICD, Jagged 1, HEY1, and HES1. CONCLUSIONS: We demonstrate that SCUBE2 expression is upregulated in BCSCs, promote EMT and enhance TNBC metastasis by activating Notch signaling. This reveals a potential druggable molecular target and an effective therapeutic strategy against metastatic and aggressive TNBC. PMID- 29981341 TI - Quantitative microinjection using fluorescence calibration of streaming microdroplets on a superhydrophobic surface. AB - A simple and reproducible procedure was developed to measure the volume of liquid microinjected into cells. A calibration curve of droplet fluorescence intensity versus volume was constructed by injecting a fluorescent dextran solution through a 125-150 um diameter micropipette into an oil-filled culture dish to create a spray of varied-sized droplets. The droplets retained a spherical shape because they were in an oil medium and they settled onto a glass surface coated with a superhydrophobic surface. Fluorescent micrographs of the droplets were obtained and analyzed with Image-J software to quantify the fluorescence intensity and radius of each spherical droplet to produce the calibration curve. Subsequently, Dut-145 human prostate carcinoma cells were microinjected with the same fluorescent dextran solution and fluorescent micrographs of the cells were obtained using the identical exposure conditions used to photograph the droplets. The measured fluorescence intensity of the microinjected cells was entered into the formula for the regression line that was fit to the calibration curve allowing determination of the volume of solution injected into each cell. Thus, a mixture consisting of known concentrations of a test material of test material (macromolecules, drugs, etc.) and a fluorescent dextran, volumetric, tracer can be used to quantify the relationship between the amount of a microinjected material and subsequent effects on cells. PMID- 29981342 TI - Exogenous hydrogen sulfide protects from endothelial cell damage, platelet activation, and neutrophils extracellular traps formation in hyperhomocysteinemia rats. AB - Hydrogen sulfide (H2S) prevents endothelial cells damage and P-selectin of platelets promotes neutrophils extracellular traps (NETs) formation. However, how sodium hydrosulfide (NaHS), a donor that produces H2S regulates the activation of platelets and whether H2S inhibits the formation of neutrophils extracellular traps in hyperhomocysteinemia rats have not been previously investigated. The morphological and ultrastructural alterations of endothelial cells (ECs) and platelets were tested by transmission electron microscopy. The expressions of P selectin of platelets were determined by flow cytometry. Additionally, the cellular ROS and the H2S level were detected by DCFH-DA staining and H2S probe, the expressions of Bax and Bcl-2 in arteries and cultured ECs from rat thoracic aortas and the phosphor-p38 mitogen-activated protein kinase (MAPK), CSE and CBS of platelets were measured by western blotting. The NETs formations, the concentration of DNA in serum and supernatant of cultured neutrophils stimulated with platelet-rich plasma (PRP) were tested by Sytox Green and PicoGreen commercial Kits. The vascular ECs damaged, the expression of P-selectin of platelets and NETs formation increased; the concentration of DNA in serum and supernatant of cultured neutrophils stimulated with PRP also increased; the expression of Bax increased while Bcl-2 decreased in arteries, the phosphor-p38 MAPK of platelets increased while CSE and CBS have no statistically significant changes in the HHcy group compared to the control group. In the cultured ECs, the ROS level increased while the H2S level decreased after 48 and 72 h treatment by HHcy; the expression of Bcl-2 decreased while Bax increased after 72 h treatment by HHcy. NaHS significantly inhibited the ECs injured, cellular ROS production, platelet activation and NETs formation, reversed the expressions of Bax, Bcl-2, phosphor-p38 MAPK, P-selectin and the increased concentration of DNA in serum and supernatant of cultured neutrophils which caused by high homocysteine. Our results demonstrate that the donor of H2S inhibits the platelets activation and NETs formation, which concerts the protection of ECs in hyperhomocysteinemia. PMID- 29981343 TI - miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature. AB - We have previously published that miR15a can reduce inflammatory cytokines, which could be key to diabetic retinal pathology. In this work, we wanted to investigate whether miR15a altered NLR pyrin domain 3 (NLRP3) proteins. Whole retinal lysates from both miR15a overexpressing mice and endothelial cell specific miR15a/16 knockout mice were used to investigate protein levels of forkhead box protein O1 (Foxo1), NLRP3, cleaved caspase 1 and interleukin-1 beta (IL-1beta). Primary human retinal endothelial cells (REC) were cultured in normal and high glucose followed by transfection with a miR15a mimic for protein analyses. miR15a expression was verified by quantitative PCR, and a luciferase binding assay was used to examine whether miR15a directly bound Foxo1. In mouse retinal lysates, loss of miR15a increased Foxo1, IL-1beta, NLRP3, and cleaved caspase 1 levels. REC grown in high glucose transfected with the miR15a mimic had decreased levels of Foxo1 and NLRP3. miR15a directly binds to Foxo1. miR15a regulates NLRP3 actions in the retinal vasculature. Work in mice showed that loss of miR15a increased NLRP3 pathway signaling and Foxo1. miR15a mimics decreased levels of Foxo1 and NLRP3. Taken together, miR15a reduced inflammasome proteins and Foxo1 levels in the retinal vasculature. PMID- 29981344 TI - Targeting corneal inflammation by gene therapy: Emerging strategies for keratitis. AB - Inflammation is the underlying process of several diseases within the eye, specifically in the cornea. Current treatment options for corneal inflammation or keratitis, and related neovascularization, are restricted by limited efficacy, adverse effects, and short duration of action. Gene therapy has shown great potential for the treatment of diseases affecting the ocular surface, and major efforts are being targeted to inflammatory mediators and neovascularization, in order to develop potential treatments for corneal inflammation. Gene therapy to treat ocular disorders is still starting, and current therapies are primarily experimental, with most human clinical trials still in research state, although some of them have already shown encouraging results. In this review, we focus on the progress and challenges of gene therapy to treat corneal inflammation. After introducing the inflammation process, we present the main nucleic acid delivery systems, including viral and non-viral vectors, and the most studied strategies to address the therapy: control of neovascularization and regulation of pro- and anti-inflammatory cytokines. PMID- 29981346 TI - Effect of wedelolactone and gallic acid on quinolinic acid-induced neurotoxicity and impaired motor function: significance to sporadic amyotrophic lateral sclerosis. AB - Quinolinic acid (QUIN) is a well-known neuroactive metabolite of tryptophan degradation pathway or kynurenine pathway. The QUIN is involved in the development of several toxic cascades which leads to the neuronal degeneration processes. The QUIN-induced toxicity is also responsible for the impairment of the motor function and motor learning ability. This study seeks to investigate the several mechanisms which are involved in the intrastriatal administration of QUIN-induced neurodegeneration and the neuroprotective effects of wedelolactone (WL) and gallic acid (GA) over QUIN-induced toxicity. The Wistar rats were used for the study and conducted behavioral model to evaluate the effects of WL (100 & 200 mg/kg) and GA (100 & 200 mg/kg) on impaired motor function and motor learning ability. We also assessed the effects of WL and GA on the antioxidant profile, cytotoxicity, apoptosis, excitotoxicity, inflammatory cascades, and on growth factors which helps in neurogenesis. The compounds effectively improved the motor function, motor learning memory in the rats. Similarly, enhanced the activity of Glutathione peroxidase, SOD, catalase, and declined the lipid peroxidation and nitrite production in the brain. The treatment with WL and GA lowered the activities of LDH, m-calpain, and caspase-3. The reports strongly support that both compounds are useful in the prevention of glutamate excitotoxicity induced by QUIN. The NAA, IGF-1, and VEGF levels in the brain were improved after treatment with WL and GA. The neuroprotective effects of WL and GA further proved through the anti-inflammatory effects. The compounds significantly down-regulated the expression of TNF-alpha, IL-6, and IL-beta in the brain. Immunohistochemical analysis shows that the WL and GA reduced the expression of NF-kappaB. The histopathological studies for cerebellum, hippocampus, striatum, and spinal cord confirms the toxic effects of QUIN and neuroprotective effects of WL and GA. The results suggest that WL and GA could ameliorate the toxic events triggered by QUIN and might be effective in the prevention and progression of several cascades which lead to the development of sALS. PMID- 29981345 TI - Narrow-band, long-wavelength lighting promotes hyperopia and retards vision induced myopia in infant rhesus monkeys. AB - The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and form-deprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 +/- 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), -3 D (-3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens- (+3D NL, n = 9; -3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus. PMID- 29981347 TI - Prenatal exposure to environmental insults and enhanced risk of developing Schizophrenia and Autism Spectrum Disorder: focus on biological pathways and epigenetic mechanisms. AB - When considering neurodevelopmental disorders (NDDs), Schizophrenia (SZ) and Autism Spectrum Disorder (ASD) are considered to be among the most severe in term of prevalence, morbidity and impact on the society. Similar features and overlapping symptoms have been observed at multiple levels, suggesting common pathophysiological bases. Indeed, recent genome-wide association studies (GWAS) and epidemiological data report shared vulnerability genes and environmental triggers across the two disorders. In this review, we will discuss the possible biological mechanisms, including glutamatergic and GABAergic neurotransmissions, inflammatory signals and oxidative stress related systems, which are targeted by adverse environmental exposures and that have been associated with the development of SZ and ASD. We will also discuss the emerging role of the gut microbiome as possible interplay between environment, immune system and brain development. Finally, we will describe the involvement of epigenetic mechanisms in the maintenance of long-lasting effects of adverse environments early in life. This will allow us to better understand the pathophysiology of these NDDs, and also to identify novel targets for future treatment strategies. PMID- 29981349 TI - Introduction and Update on Obesity and Cardiovascular Diseases 2018. PMID- 29981350 TI - Obesity and Kidney Disease. AB - Obesity is a systemic disease of the white adipose tissue, which has evolved into a global epidemic. It is associated with a plethora of adipocyte hormonal (adipokine) imbalances, dysregulation of the energy-balance system, imbalances in metabolic homeostasis, a pro-inflammatory state and multiple target organ damages. Clinically, the obesity phenotype is not homogenous and is more likely to represent a spectrum with varying degrees of metabolic un-health; metabolically-unhealthy obesity is often a part of the metabolic syndrome. The links between obesity and chronic kidney disease are numerous, bidirectional, multi-layered and complex; this complexity may be explained by shared pathophysiological pathways (e.g. chronic inflammation, increased oxidative stress, and hyper-insulinemia), shared clusters of risk factors as well as associated diseases (e.g. insulin resistance, hypertension and dyslipidemia). We will review these links and their clinical manifestations, and offer a summary of available non-pharmacological as well as pharmacological therapeutic strategies. PMID- 29981351 TI - Role of Human Brown Fat in Obesity, Metabolism and Cardiovascular Disease: Strategies to Turn Up the Heat. AB - Human brown adipose tissue (BAT) was re-discovered in 2009 by several independent groups, who showed that it is present and active in adults, as judged from the profound uptake of the glucose analogue radiotracer 18F-fluorodeoxyglucose in positron-emission tomography and computed tomography scan analysis after cold exposure. A potential clinical implication of activating BAT relates to its high metabolic activity and its potential role in stimulating energy expenditure (i.e. resting energy expenditure, meal-induced thermogenesis, and cold-induced thermogenesis), which makes it an attractive target to reduce adiposity. Moreover, due to its ability to oxidise glucose and lipids, BAT activation may also potentially exert beneficial metabolic and cardiovascular effects through reducing glucose and lipid levels, respectively. This review describes the potential role of human BAT in the prevention and treatment of obesity, metabolism, and cardiovascular disease focusing on its impact on energy expenditure and management of body fat accumulation as well as on glucose and lipid metabolism. This article also summarises the strategies that are currently being studied to activate human BAT. PMID- 29981352 TI - The Joint Association of Fitness and Fatness on Cardiovascular Disease Mortality: A Meta-Analysis. AB - The joint association of cardiorespiratory fitness (CRF) and body mass index (BMI) on cardiovascular disease (CVD) mortality was determined. PubMed and CINAHL were searched following PRISMA guidelines. Included studies were prospective, had objective assessments of maximal CRF and BMI, and compared the joint impact of CRF and BMI on CVD mortality risk to normal weight, fit referents. Pooled hazard ratios and 95% confidence intervals were calculated from eight articles with nine independent groups using a random effects model. Unfit individuals had two to three times the risk of mortality across all levels of BMI. Overweight and obese fit individuals had 25% and 42% increased mortality risk, respectively, compared to normal weight-fit individuals. However, for the obese-fit group, a one study removed analysis for five studies resulted in non-significant changes in mortality risk. Researchers, clinicians, and public health officials are encouraged to employ CRF interventions to reduce CDV mortality risk. PMID- 29981348 TI - Obesity Paradox in Advanced Kidney Disease: From Bedside to the Bench. AB - While obesity is associated with a variety of complications including diabetes, hypertension, cardiovascular disease and premature death, observational studies have also found that obesity and increasing body mass index (BMI) can be linked with improved survival in certain patient populations, including those with conditions marked by protein-energy wasting and dysmetabolism that ultimately lead to cachexia. The latter observations have been reported in various clinical settings including end-stage renal disease (ESRD) and have been described as the "obesity paradox" or "reverse epidemiology", engendering controversy. While some have attributed the obesity paradox to residual confounding in an effort to "debunk" these observations, recent experimental discoveries provide biologically plausible mechanisms in which higher BMI can be linked to longevity in certain groups of patients. In addition, sophisticated epidemiologic methods that extensively adjusted for confounding have found that the obesity paradox remains robust in ESRD. Furthermore, novel hypotheses suggest that weight loss and cachexia can be linked to adverse outcomes including cardiomyopathy, arrhythmias, sudden death and poor outcomes. Therefore, the survival benefit observed in obese ESRD patients can at least partly be derived from mechanisms that protect against inefficient energy utilization, cachexia and protein-energy wasting. Given that in ESRD patients, treatment of traditional risk factors has failed to alter outcomes, detailed translational studies of the obesity paradox may help identify innovative pathways that can be targeted to improve survival. We have reviewed recent clinical evidence detailing the association of BMI with outcomes in patients with chronic kidney disease, including ESRD, and discuss potential mechanisms underlying the obesity paradox with potential for clinical applicability. PMID- 29981353 TI - The Fluctuating Journal Statistics. PMID- 29981354 TI - Bicoid signal extraction: Another powerful approach. AB - This belief has been widely accepted that Bicoid (Bcd) protein distributes in a concentration gradient that organizes the anterior/posterior axis of the Drosophila embryo. Segment polarity protein provides positional cues for the development of head and thoracic segments. Therefore As a result of its essential role, modeling the Bicoid gradient has been welcomed by many researchers in various scientific fields. In this paper, We present investigation of gene expression profiles by means of Singular Spectrum Decomposition (SSD), an optimizing version of Singular Spectrum Analysis for filtering and extracting the bicoid gene expression signal. The results with strong evidence suggest that the proposed technique is capable of eliminating noise and can be considered as an acceptable method for filtering gene expression. PMID- 29981355 TI - SEDDS: A game changing approach for the oral administration of hydrophilic macromolecular drugs. AB - Since the development of self-emulsifying drug delivery systems (SEDDS) in 1980's, they attract the attention of researchers in order to confront the challenge of poor water-solubility of orally given drugs. Within recent years, SEDDS were also discovered for oral administration of hydrophilic macromolecular drugs such as peptides, proteins, polysaccharides and pDNA. Due to hydrophobic ion pairing (HIP) with oppositely charged lipophilic auxiliary agents the resulting complexes can be incorporated in the lipophilic phase of SEDDS. Depending on the solubility of the complex in the SEDDS pre-concentrate and in the release medium drug release can be adjusted on purpose by choosing more or less lipophilic auxiliary agents in appropriate quantities for HIP. Within the oily droplets formed in the GI-tract drugs are protected towards degradation by proteases and nucleases and thiol-disulfide exchange reactions with dietary proteins. The oily droplets can be made mucoadhesive or highly mucus permeating depending on their target site. Furthermore, even their cellular uptake properties can be tuned by adjusting their zeta potential or decorating them with cell penetrating peptides. The potential of SEDDS for oral administration of hydrophilic macromolecular drugs could meanwhile be demonstrated via various in vivo studies showing a bioavailability at least in the single digit percentage range. Owing to these properties advanced SEDDS turned out to be a game changing approach for the oral administration of hydrophilic macromolecular drugs. PMID- 29981356 TI - Modulation of neural regulators of energy homeostasis, and of inflammation, in the pups of mice exposed to e-cigarettes. AB - BACKGROUND: Maternal smoking can lead to perturbations in central metabolic regulators such as neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) signalling components in offspring. With the growing interest in e-cigarettes as a tobacco replacement, this short report assessed central metabolic regulation in offspring of mouse dams exposed to e-cigarettes. We examined the impact of continuous use of e-cigarettes, and e-cigarette replacement of tobacco cigarettes during pregnancy. Supplementation of an antioxidant l-carnitine was also co-used with tobacco cigarette in the mother to determine whether the impact of maternal tobacco smoking was oxidative stress driven. METHODS: Balb/c mice were exposed to either nicotine-containing (E-cig18) or nicotine-free (E-cig0) e-cigarette aerosols or tobacco smoke (SE) prior to mating and until their pups were weaned. After mating, two SE sub-groups were changed to E-cig18 exposure (Replacement), or supplementation l-carnitine while SE was continued. Male offspring were studied at weaning age. RESULTS: The offspring of E-cig0 dams were the heaviest with the most body fat. Replacing SE with E-cig18 during pregnancy resulted in offspring with significantly less body fat. E-cig0 offspring had significantly increased mRNA expression of brain NPY and iNOS. Maternal SE upregulated mRNA expression of NPY, NPY Y1 receptor, POMC downstream components, and iNOS expression, which were normalised in Replacement offspring, but only partially normalised with maternal L-carnitine supplementation during gestation and lactation. CONCLUSIONS: Maternal exposure to either tobacco and nicotine-free e cigarettes lead to disturbances in the level of central homeostatic control markers in offspring, suggesting that maternal exposure to e-cigarettes is not without risks. PMID- 29981358 TI - Long-term effects of curcumin in the non-human primate brain. AB - Curcumin has recently been shown to be a potential treatment for slowing or ameloriating cognitive decline during aging in our nonhuman primate model of normal aging. In these same monkeys, we studied for the first time the neurological impacts of long-term curcumin treatments using longitudinal magnetic resonance imaging (MRI). Sixteen rhesus monkeys received curcumin or a vehicle control for 14-18 months. We applied a combination of structural and diffusion MRI to determine whether the curcumin resulted in structural or functional changes in focal regions of the brain. The longitudinal imaging revealed decreased microscale diffusivity (mD) measurements mainly in the hippocampus and basal forebrain structures of curcumin treated animals. Changes in generalized fractional anisotropy (GFA) and grey matter density (GMd) measurements indicated an increased grey matter density in cortical ROIs with improved white matter integrity in limbic, cerebellar, and brain stem regions. These findings suggest that noticeable changes in the neuronal environment could be induced from long term curcumin treatments. Results may provide a neurological basis on the recent findings demonstrating improved spatial working memory and motor function in nonhuman primates. PMID- 29981357 TI - Injectable and protease-degradable hydrogel for siRNA sequestration and triggered delivery to the heart. AB - Injectable hydrogels have significant therapeutic potential for treatment of myocardial infarction (MI) through tissue bulking and local drug delivery, including the delivery of small interfering RNAs (siRNAs). As siRNA targets are identified as potential treatments for MI, hydrogels may bolster efficacy through local and sustained release. Here, we designed an injectable hydrogel to respond to local upregulation in proteolytic activity after MI to erode and release siRNA against MMP2 (siMMP2), a target implicated in deleterious remodeling. Specifically, hyaluronic acid (HA) was modified with hydrazides or aldehydes and mixed to form shear-thinning and self-healing hydrogels through dynamic hydrazone bonds and with peptide crosslinkers that degrade in response to protease activity. HA was further modified with beta-cyclodextrin to sequester cholesterol modified siRNA, limiting passive diffusion. Hydrogels eroded in response to proteases and released active siRNA that knocked down MMP2 in primary cardiac fibroblasts. In a rat model of MI, hydrogels delivering siMMP2 attenuated hydrogel erosion by ~46% at 4 weeks when compared to hydrogels delivering control siRNA, ultimately improving myocardial thickness in the infarct. Delivery of the siMMP2 hydrogel led to significant functional improvements, including increased ejection fraction (27%, 66%), stroke volume (32%, 120%), and cardiac output (20%, 128%) when compared to controls (% increase versus hydrogels with control siRNA, % increase versus saline injection alone). This report demonstrates the utility of biomaterial-based RNA delivery systems for cardiac applications. PMID- 29981359 TI - Disruption of endothelial barrier function is linked with hyposecretion and lymphocytic infiltration in salivary glands of Sjogren's syndrome. AB - Sjogren's syndrome (SS) is an inflammatory autoimmune disease that causes hyposecretion in salivary glands. Endothelial tight junctions (TJs) play crucial roles in salivation and barrier function of blood vessels. However, whether the alteration of endothelial TJs were involved in pathogenesis of SS was still unknown. Here, the ultrastructure and function of endothelial TJs in submandibular glands (SMGs) were detected by transmission electron microscopy and in vivo paracellular permeability assay in different aged NOD mouse model for SS. CFSE-labeled lymphocytes were injected into tail vein to trace the infiltration, while claudin-5 expression and distribution were detected by immunofluorescence, qRT-PCR, and western blot. Results showed that the stimulated salivary flow rate was gradually decreased and lymphocytic infiltration was found as age increased in 12- and 21-week-old NOD mice, but not 7-week-old NOD mice. Blood vessels were dilated, while endothelial TJ width and paracellular tracer transport were increased in 12-week-old NOD mice. Moreover, the injected CFSE-labeled lymphocytes were observed in SMGs of 12-week-old NOD mice. Claudin-5 level was increased and relocalized from the apical portion of neighboring endothelial cells to lateral membranes and cytoplasm in 12-week-old NOD mice. Additionally, the alteration of claudin-5 expression and distribution was further confirmed in labial salivary glands and bilateral parotid glands from SS patients. In cultured human microvessel endothelial cell line (HMEC-1), IFN-gamma stimulation significantly increased claudin-5 expression. Taken together, we identified that the endothelial TJ barrier was disrupted and contributed to the development of salivary hyposecretion and lymphocytic infiltration in SS. PMID- 29981360 TI - Avobenzone suppresses proliferative activity of human trophoblast cells and induces apoptosis mediated by mitochondrial disruption. AB - Avobenzone is widely used in various personal care products, is present in swimming pools, and is toxic to aquatic organisms. However, it is unclear how avobenzone affects human trophoblast cells. Results of the present study demonstrated that avobenzone inhibited the proliferation of HTR8/SVneo cells, the immortalized human trophoblast cell line, and inhibited the expression of PCNA. In addition, avobenzone increased the activity of AKT and ERK1/2 in HTR8/SVneo cells. When LY294002 (AKT inhibitor) and U0126 (ERK1/2 inhibitor) were treated with avobenzone, the anti-proliferative effect of avobenzone was alleviated. Moreover, avobenzone promoted Ca2+ overload into the mitochondria and induced depolarization of the mitochondrial membrane. Expression of IFI27, which is located in the mitochondria, was elevated by avobenzone via inhibition of expression through siRNA transfection against IFI27, but did not alter cell properties. This study suggests that avobenzone induces mitochondrial dysfunction mediated apoptosis leading to abnormal placentation during early pregnancy. PMID- 29981362 TI - Metagenomic binning reconstruction coupled with automatic pipeline annotation and giant viruses: A potential source of mistake in annotations. AB - Metagenomic binning reconstructions represent an emergent powerful tool to discover novel microbial genomes and explore the diversity in microbial communities. This method is sometimes coupled with automatic pipeline to perform automatic annotations. Nevertheless, we found a publish Alphaproteobacteria in public database that containing 20 contigs identified as a bacterium that were actually a novel giant viruses close to Aureococcus anophagefferens virus. This virus was completely misidentified by automatic pipeline and missed by control program and finally concern near to 20% of this 2,4 Mb. PMID- 29981361 TI - Using ecological momentary assessment to better understand dietary lapse types. AB - Frequency of lapsing from a diet predicts weight loss failure, however previous studies have only utilized one definition of dietary lapse. No study has examined different types of lapse behaviors among individuals with overweight/obesity. The current study uses ecological momentary assessment (EMA) to examine predictors of three lapse types-eating a larger portion than intended, eating an unintended type of food, and eating at an unplanned time-in adults (N = 189; MBMI = 36.93 +/ 5.83 kg/m2; 82.0% female; Mage = 51.81 +/- 9.76 years) enrolled in a 12-month randomized controlled trial of two behavioral weight loss treatments. Participants completed 14 days of EMA at the start of treatment during which they indicated types of lapses that occurred with time and location of the lapse. Participants also responded to questions assessing current physical (e.g., hunger, tiredness), environmental (e.g., presence of "delicious" foods), and affective (e.g., loneliness, sadness) states at each prompt. Weight change was assessed at post-treatment. Separate generalized estimating equations were used to examine whether states prospectively predicted lapse occurrence at the next survey. Results indicated that lapse types differed significantly across time and location. Momentary increases in deprivation, hunger, and boredom increased likelihood of different lapse types. Lastly, we examined the prospective association between lapse type and weight loss. Eating at an unintended time was the only lapse type that predicted worse weight loss outcomes. Results support the theory that distinct lapse types exist, and that lapse types can be predicted by both momentary conditions and individual tendencies toward certain physical and affective states. However, not all lapse types may impact weight outcomes. Future research on behaviors that constitute dietary lapse is warranted and could inform personalized weight loss treatments. PMID- 29981363 TI - AMPA Receptor Antagonist Perampanel Ameliorates Post-Stroke Functional and Cognitive Impairments. AB - Perampanel (PER), a noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist, clinically used for seizure control, has been reported to exert neuroprotective effects in experimental models of neurodegenerative diseases. However, few studies have investigated the therapeutic effects of PER in brain injury including stroke. Our aim was to investigate the neuroprotective potential of PER using a rat transient middle cerebral artery occlusion (MCAO) model. Sprague-Dawley rats underwent 90-min MCAO followed by intraperitoneal PER administration at a dose of 1.5 mg/kg. Infarct volumes, neurological deficits, and immunological analyses were performed at 7 days after MCAO. PER significantly reduced infarct volumes (p < 0.05) and improved motor function (p < 0.05) compared with vehicle. Immunological analysis showed that PER significantly inhibited microglial activation, pro-inflammatory cytokine expression, and oxidative stress compared with vehicle. Moreover, PER suppressed neurodegeneration in the cortical ischemic boundary zone, via downregulation of Bcl-2-associated x and upregulation of Bcl-extra-large with Akt activation. In addition, post-stroke secondary neuronal damage and cognitive impairments, using the Y-maze test, were assessed 30 days after MCAO. PER significantly improved spatial working memory, which was accompanied by hippocampal CA1 neuronal loss and cortical thinning, compared with vehicle. These results indicate that PER attenuates infarct volumes and motor function deficits possibly through its anti-inflammatory, antioxidant, and anti-apoptotic activities, mediated via activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathways in the acute ischemic phase, and further ameliorates post-stroke cognitive impairments via the suppression of secondary neuronal damage in the chronic ischemic phase. PMID- 29981364 TI - Effect of Mirror Therapy on Recovery of Stroke Survivors: A Systematic Review and Network Meta-analysis. AB - Mirror therapy (MT) as a relatively new rehabilitation technique has been widely applied in stroke patients. A number of randomized controlled trials (RCTs) have investigated the effects of MT for stroke survivors. The main purpose of this network meta-analysis was to investigate the effects of MT on motor function, activities of daily living (ADL), and pain perception in stroke survivors. Several databases were searched to identify RCTs evaluating the effects of MT in stroke patients to perform this network meta-analysis. Thirty-seven RCTs (42 analyses, 1685 subjects) were eligible for inclusion in the meta-analysis. Standard meta-analysis showed that MT significantly improved of motor function according to the increased Fugl-Meyer Assessment (FMA), Functional Independence Measure (FIM), and decreased Modified Ashworth Scale (MAS) score. In addition, ADL was promoted by MT as the elevated Modified Barthel Index (MBI) and Motor Activity Log (MAL) score. Moreover, MT effectively relieved the pain of stroke patients as the Visual Analog Scale (VAS) score was reduced. Subgroup analyses and meta-regressions identified that the sources of heterogeneity might be different intervention arms and duration of interventions. Network meta-analysis showed that MT combined with electrical stimulation (ES) for less than 4 weeks along with conventional rehabilitation therapy (CT), and MT accompanied with CT for less than 4 weeks might be the most suitable interventions for improvement of motor function and ADL, respectively. Overall, MT could effectively improve motor function and ADL, as well as relieve pain for stroke survivors. The study was registered at PROSPERO (CRD42017081742). PMID- 29981365 TI - Protagonist or antagonist? The complex roles of retinoids in the regulation of hematopoietic stem cells and their specification from pluripotent stem cells. AB - Hematopoietic stem cells (HSCs) are multipotent cells responsible for the maintenance of the hematopoietic system throughout life. Dysregulation of the balance in HSC self-renewal, death, and differentiation can have serious consequences such as myelodysplastic syndromes or leukemia. All-trans retinoic acid (ATRA), the biologically active metabolite of vitamin A/RA, has been shown to have pleiotropic effects on hematopoietic cells, enhancing HSC self-renewal while also increasing differentiation of more mature progenitors. Furthermore, ATRA has been shown to have key roles in regulating the specification and formation of hematopoietic cells from pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Here, we summarize the known roles of vitamin A and RA receptors in the regulation of hematopoiesis from HSCs, ES, and iPSCs. PMID- 29981366 TI - Right atrial appendage tachycardia: A rare cause of tachycardia induced cardiomyopathy in a 4-year-old child. AB - We present a rare case of tachycardiomyopathy in a 4-year-old girl. The child had incessant atrial tachycardia (AT) and refractory heart failure. Right atrial appendage (RAA) was localised as the source of the ectopic tachycardia. The child underwent successful radiofrequency ablation (RFA) using 3-D electroanatomical mapping. Fluoroscopy was used sparingly only to rule out underlying anomalies. The left ventricular functions returned to normal by one month after the procedure. RAA AT is rare in very young children and usually necessitates surgical appendectomies. RFA is a challenge in such age groups and there are very few published literature on RAA AT in very young children. PMID- 29981367 TI - Lysosomal N-acetyltransferase interacts with ALIX and is detected in extracellular vesicles. AB - Heparan acetyl CoA: alpha-glucosaminide N-acetyltransferase (HGSNAT) is a lysosomal multi-pass transmembrane protein whose deficiency may lead to an accumulation of heparan sulphate and the neurodegenerative lysosomal storage disorder mucopolysaccharidosis (MPS) IIIC. In this study, HGSNAT activity was detected in extracellular vesicles isolated from both human urine and culture medium conditioned with HEK 293T cells. We also demonstrate that HGSNAT co immunoprecipitates with antibodies to ALIX, which is associated with the endosomal sorting complexes required for transport (ESCRT) proteins, and is implicated in the targeting of proteins to intraluminal vesicles of multivesicular bodies, the origin of exosomes. Furthermore, mutation of a putative LYPXnL-based binding site within HGSNAT for the V-domain of ALIX ablated association of HGSNAT with ALIX, post-translational maturation, and transport through the endo-lysosomal network. Unexpectedly, however, a mutation within the V-domain of ALIX demonstrated enhanced HGSNAT association, perhaps due to the actual involvement of other binding sites in this interaction. Indeed, HGSNAT still co-immunoprecipitates with truncations of ALIX lacking the V-domain. Interestingly, CRISPR/Cas9 mediated knock-down of ALIX did not inhibit HGSNAT trafficking through the endo-lysosomal network, suggesting that there is an alternative pathway for trafficking HGSNAT that does not require ALIX. Nonetheless, the targeting of HGSNAT to extracellular vesicles may provide a mechanism to subsequently transfer this enzyme extracellularly to provide a foundation for a therapy for MPS IIIC patients. PMID- 29981368 TI - Mechanisms of action of vitamin D in colon cancer. AB - Colorectal cancer (CRC) is the neoplasia that is most frequently associated with vitamin D deficiency in epidemiological and observational studies in terms of incidence and mortality. Many mechanistic studies show that the active vitamin D metabolite (1alpha,25-dihydroxyvitamin D3 or calcitriol) inhibits proliferation and promotes epithelial differentiation of human colon carcinoma cell lines that express vitamin D receptor (VDR) via the regulation of a high number of genes. A key action underlining this effect is the multilevel inhibition of the Wnt/beta catenin signaling pathway, whose abnormal activation in colon epithelial cells initiates and promotes CRC. Recently, our group has shown that calcitriol modulates gene expression and inhibits protumoral properties of patient-derived colon cancer-associated fibroblasts (CAFs). Accordingly, high VDR expression in tumor stromal fibroblasts is associated with longer survival of CRC patients. Moreover, many types of immune cells express VDR and are regulated by calcitriol, which probably contributes to its action against CRC. Given the role attributed to the intestinal microbiota in CRC and the finding that it is altered by vitamin D deficiency, an indirect antitumoral effect of calcitriol is also plausible at this level. In summary, calcitriol has an array of potential protective effects against CRC by acting on carcinoma cells, CAFs, immune cells and probably also the gut microbiota. PMID- 29981370 TI - Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration. AB - Numerous chemicals, such as phenolic compounds are strong radical scavengers, capable of alleviating oxidative stress induced neurodegeneration. Dietary antioxidants, especially flavonoids, are being considered as a promising approach to prevent or slow the pathological development of neurological illness and aging. One of the major advantage of natural products is that of their anti amyloid effects over synthetic counterpart, however a healthy diet provides these beneficial natural substances as nutraceuticals. The extracellular-signal regulated kinase (ERK) is one of the main pharmacological target of natural phenolic compounds, participating in several therapeutic effects. Mounting evidence revealed that numerous bioflavonoids, obtained from a variety of dietary fruits or plants as well as medicinal herbal sources, exhibit protective or therapeutic functions versus development of neurodegenerative diseases mainly through modulation of different compartments of ERK signaling pathway. Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism. PMID- 29981369 TI - Usnic acid reactive metabolites formation in human, rat, and mice microsomes. Implication for hepatotoxicity. AB - Usnic acid is a lichen compound which is extensively studied due to its cytotoxic, antiproliferative, antimicrobial, antiviral, antiprotozoal, and anti inflammatory activities. Despite a broad spectrum of biological properties, usnic acid is a hepatotoxic agent, thus its potential use as a drug is limited. Certain hepatotoxic drugs may act by generating reactive metabolites that damage the liver. The aim of the study was to predict the biotransformation of usnic acid enantiomers to reactive products using a trapping assay with glutathione in human, rat, and mice liver microsomes. Our results indicate that each enantiomer forms two reactive metabolites; in turn, these metabolites form adducts with glutathione, which may partially explain the toxicity of usnic acid. In silico analysis indicated structural alerts for the generation of reactive metabolites in usnic acid formula. This study proposes a novel mode of the hepatic toxicity of usnic acid enantiomers; it also provides some useful suggestions for designing safer usnic acid derivatives. PMID- 29981371 TI - Pre-drug Self-assembled Nanoparticles: Recovering activity and overcoming glutathione-associated cell antioxidant resistance against photodynamic therapy. AB - In photodynamic therapy (PDT), the elevated glutathione (GSH) of cancer cells have two sides for treatment efficacy, activation pre-drug by removing activity suppressor part (advantages) and consumption reactive oxygen species (ROS) to confer PDT resistance (disadvantages). Preparation all-in-one system by simple method to make best use of the advantages and bypass the disadvantages still were remains a technical challenge. Herein, we report a robust PDT nanoparticle with above function based on a self-assembled pyridine modified Zinc phthalocyanine (ZnPc-DTP). The activity suppressor and active part of ZnPc-DTP were linked by disulfide bond. After targeting cancer cells, GSH can react with ZnPc-DTP nanoparticles by cutting disulfide bond to release its active part (ZnPc-SH) and oxidize GSH. In vitro and in vivo results indicated that ZnPc-SH can effective suppress tumor growth under the low antioxidant tumor microenvironment (TME). PMID- 29981372 TI - A scar-like lesion is apparent in basement membrane after wound repair in vivo. AB - Basement membrane is a highly conserved sheet-like extracellular matrix in animals, underlying simple and complex epithelia, and wrapping around tissues like muscles and nerves. Like the tissues they support, basement membranes become damaged by environmental insults. Although it is clear that basement membranes are repaired after damage, virtually nothing is known about this process. For example, it is not known how repaired basement membranes compare to undamaged ones, whether basement membrane components are necessary for epithelial wound closure, or whether there is a hierarchy of assembly that repairing basement membranes follow, similar to the hierarchy of assembly of embryonic basement membranes. In this report, we address these questions using the basement membrane of the Drosophila larval epidermis as a model system. By analyzing the four main basement membrane proteins - laminin, collagen IV, perlecan, and nidogen - we find that although basement membranes are repaired within a day after mechanical damage in vivo, thickened and disorganized matrix scars are evident with all four protein components. The new matrix proteins that repair damaged basement membranes are provided by distant adipose and muscle tissues rather than by the local epithelium, the same distant tissues that provide matrix proteins for growth of unwounded epithelial basement membranes. To identify a hierarchy of repair, we tested the dependency of each of the basement membrane proteins on the others for incorporation after damage. For proper incorporation after damage, nidogen requires laminin, and perlecan requires collagen IV, but surprisingly collagen IV does not to depend on laminin. Thus, the rules of basement membrane repair are subtly different than those of de novo assembly. PMID- 29981373 TI - Exosomes and exosomal miRNAs from muscle-derived fibroblasts promote skeletal muscle fibrosis. AB - Exosomes, natural carriers of mRNAs, non-coding RNAs and proteins between donor and recipient cells, actively contribute to cell-cell communication. We investigated the potential pro-fibrotic role of exosomes released by muscle derived fibroblasts of Duchenne muscular dystrophy (DMD) patients, and of miRNAs carried by exosomes. By fibrosis focused array analysis we found that exosomes from DMD fibroblasts, had significantly higher levels of miR-199a-5p, a miRNA up regulated in fibrotic conditions, compared to control exosomes, while levels in myoblast-derived exosomes were not increased. In control fibroblasts, exposure to DMD fibroblast-derived exosomes induced a myofibroblastic phenotype with increase in alpha-smooth actin, collagen and fibronectin transcript and protein expression, soluble collagen production and deposition, cell proliferation, and activation of Akt and ERK signaling, while exposure to control exosomes did not. Transfecting control fibroblasts or loading control exosomes with miR-199a-5p mimic or inhibitor induced opposing effects on fibrosis-related mRNAs and proteins, on collagen production and Akt and ERK pathways. Finally, injection of DMD fibroblast-derived exosomes into mouse tibialis anterior muscle after cardiotoxin-induced necrosis, produced greater fibrosis than control exosomes. Our findings indicate that exosomes produced by local fibroblasts in the DMD muscle are able to induce phenotypic conversion of normal fibroblasts to myofibroblasts thereby increasing the fibrotic response. This conversion is related to transfer of high levels of miR-199a-5p and to reduction of its target caveolin-1; both, therefore, are potential therapeutic targets in muscle fibrosis. PMID- 29981375 TI - Posaconazole inhibits dengue virus replication by targeting oxysterol-binding protein. AB - Dengue virus (DENV) is associated with an estimated 390 million infections per year, occurring across approximately 100 countries in tropical and sub-tropical regions. To date, there are no antiviral drugs or specific therapies to treat DENV infection. Posaconazole and itraconazole are potent antifungal drugs that inhibit ergosterol biosynthesis in fungal cells, but also target a number of human proteins. Here, we show that itraconazole and posaconazole have antiviral activity against DENV. Posaconazole inhibited replication of multiple serotypes of DENV and the related flavivirus Zika virus, and reduced viral RNA replication, but not translation of the viral genome. We used a combination of knockdown and drug sensitization assays to define the molecular target of posaconazole that mediates its antiviral activity. We found that knockdown of oxysterol-binding protein (OSBP) inhibited DENV replication. Moreover, knockdown of OSBP, but not other known targets of posaconazole, enhanced the inhibitory effect of posaconazole. Our findings imply OSBP as a potential target for the development of antiviral compounds against DENV. PMID- 29981374 TI - Repurposing potential of 1st generation H1-specific antihistamines as anti filovirus therapeutics. AB - Ebola and Marburg are filoviruses and biosafety level 4 pathogens responsible for causing severe hemorrhagic fevers in humans with mortality rates up to 90%. The most recent outbreak in West Africa resulted in approximately 11,310 deaths in 28,616 reported cases. Currently there are no FDA-approved vaccines or therapeutics to treat infections of these deadly viruses. Recently we screened an FDA-approved drug library and identified numerous G protein-coupled receptor (GPCR) antagonists including antihistamines possessing anti-filovirus properties. Antihistamines are attractive targets for drug repurposing because of their low cost and ease of access due to wide use. In this report we identify common over the counter antihistamines, such as diphenhydramine (Benadryl) and chlorcyclizine (Ahist) as potential candidates for repurposing as anti-filovirus agents. Furthermore, we demonstrate that this potential is wide-spread through the 1st generation of H1-specific antihistamines but is not present in newer drugs or drugs targeting H2, H3 and H4 receptors. We showed that the filovirus entry inhibition is not dependent on the classical antagonism of cell surface histamine or muscarinic acetylcholine receptors but occurs in the endosome, like the cathepsin inhibitor CA-074. Finally, using extensive docking studies we showed the potential for these drugs to bind directly to the EBOV-GP at the same site as toremifene. These findings suggest that the 1st generation antihistamines are excellent candidates for repurposing as anti-filovirus therapeutics and can be further optimized for removal of unwanted histamine or muscarinic receptor interactions without loss of anti-filovirus efficacy. PMID- 29981376 TI - Acupuncture Resolves Persistent Pain and Neuroinflammation in a Mouse Model of Chronic Overlapping Pain Conditions. AB - Patients with chronic overlapping pain conditions have decreased levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Consistent with clinical syndromes, we previously demonstrated that COMT inhibition in rodents produces persistent pain and heightened immune responses. Here, we sought to determine the efficacy of manual acupuncture in resolving persistent pain and neuroinflammation in the classic inbred C57BL/6 strain and the rapid-wound healing MRL/MpJ strain. Mice received subcutaneous osmotic minipumps to deliver the COMT inhibitor OR486 or vehicle for 13 days. On day 7 after pump implantation, acupuncture was performed at the Zusanli (ST36) point or a non-acupoint for 6 consecutive days. Behavioral responses to mechanical stimuli were measured throughout the experiment. Immunohistochemical analysis of spinal phosphorylated p38 mitogen-activated protein kinase, a marker of inflammation, and glial fibrillary acidic protein, a marker of astrogliosis, was performed on day 13. Results demonstrated that ST36, but not sham, acupuncture resolved mechanical hypersensitivity and reduced OR486-dependent increases in phosphorylated p38 and glial fibrillary acidic protein in both strains. The magnitude of the analgesic response was greater in MRL/MpJ mice. These findings indicate acupuncture as an effective treatment for persistent pain linked to abnormalities in catecholamine signaling and, furthermore, that analgesic efficacy may be influenced by genetic differences. PERSPECTIVE: Chronic overlapping pain conditions remain ineffectively managed by conventional pharmacotherapies. Here, we demonstrate that acupuncture alleviates persistent pain and neuroinflammation linked to heightened catecholaminergic tone. Mice with superior healing capacity exhibit greater analgesic efficacy. Findings indicate acupuncture as an effective treatment for chronic overlapping pain conditions and provide insight into treatment response variability. PMID- 29981377 TI - Predictors of treatment response in rheumatoid arthritis. AB - The expanding array of drugs available for treating rheumatoid arthritis is creating challenges in drug selection for the individual patient. The identification of biomarkers that predict the treatment response prior to drug exposure is therefore a current priority. This new approach, known as theranostics, is a component of personalized medicine, which involves selecting the management strategies that are most effective for a given patient at a given point in time. Antibodies to citrullinated peptides, rheumatoid factor, and the interferon signature are the most robust and best validated biomarkers identified to date. Matrices containing clinical or laboratory parameters of diagnostic or prognostic relevance may help to select the best treatment for the individual patient. Furthermore, the development of large-scale approaches requiring no a priori knowledge, such as functional genomics and metabolomics, hold considerable promise, despite persistent difficulties in replicating findings. The complexity of the treatment response in a given patient and substantial variability across patients suggest that biomarkers may be more helpful in combination than singly. The objectives of this review article are to discuss the approaches used to identify theranostic biomarkers and to present an overview of currently available biomarkers and of their performance in everyday clinical practice. However, the range of biomarkers suitable for use in daily practice remains extremely narrow. PMID- 29981378 TI - Compression of the common peroneal nerve due to peroneal muscle infarction in a patient with diabetes. PMID- 29981380 TI - Disparities in Familiarity With Developmental Disabilities Among Low-Income Parents. AB - OBJECTIVE: Parent knowledge about developmental disabilities (DDs) may facilitate access to DD care; however, parents may vary in their knowledge and familiarity with common DDs. This study aimed to assess racial/ethnic and language differences in low-income families' familiarity, knowledge, and personal experience with DDs. METHODS: We conducted a child development survey among 539 low-income parents of young children attending visits at the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in 6 Oregon counties in 2015. Survey items assessed parent familiarity with early signs of DDs, self reported knowledge about DDs, and personal experience with a friend or family member with a DD. Bivariable and multivariable analyses assessed differences in outcomes among non-Latino white (white), Latino English-proficient (Latino-EP), Latino limited-English-proficient (Latino-LEP), and non-Latino other race English proficient (other race) parents. RESULTS: Overall, parent participants correctly identified 64.7% of early signs of DDs. White parents correctly identified the most early signs, even after adjustment for sociodemographic factors. Compared with white parents, Latino-LEP, Latino-EP, and other race parents were less likely to have heard of prevalent DDs, such as attention-deficit/hyperactivity disorder and autism, and less likely to have a friend or family member with a DD. CONCLUSIONS: Low-income Latino-LEP and other race parents have less familiarity or personal experience with DDs and are less aware of early signs of DDs compared to low-income white parents. Study findings suggest that interventions to reduce disparities in DD diagnosis and treatment should include increasing information transfer to parents in racial/ethnic and language minority communities. PMID- 29981379 TI - Early morphologic changes in trapeziometacarpal joint bones with osteoarthritis. AB - OBJECTIVE: Characterising the morphological differences between healthy and early osteoarthritic (EOA) trapeziometacarpal (TMC) joints is important for understanding osteoarthritis onset, and early detection is important for treatment and disease management. This study has two aims: first, to characterise morphological differences between healthy and EOA TMC bones. The second aim was to determine the efficacy of using a statistical shape model (SSM) to detect early signs of osteoarthritis (OA). METHODS: CT image data of TMC bones from 22 asymptomatic volunteers and 47 patients with EOA were obtained from an ongoing study and used to generate a SSM. A linear discriminant analysis (LDA) classifier was trained on the principal component (PC) weights to characterise features of each group. Multivariable statistical analysis was performed on the PC to investigate morphologic differences. Leave-one-out classification was performed to evaluate the classifiers performance. RESULTS: We found that TMC bones of EOA subjects exhibited a lower aspect ratio (P = 0.042) compared with healthy subjects. The LDA classifier predicted that protrusions (up to 1.5 mm) at the volar beak of the first metacarpal were characteristic of EOA subjects. This was accompanied with widening of the articular surface, deepening of the articular surface, and protruding bone growths along the concave margin. These characteristics resulted in a leave-one-out classification accuracy of 73.9% (95% CI [61.9%, 83.8%]), sensitivity of 89.4%, specificity of 40.9%, and precision of 75.9%. CONCLUSION: Our findings indicate that morphological degeneration is well underway in the EOA TMC joint, and shows promise for a clinical tool that can detect these features automatically. PMID- 29981381 TI - New optical sources for interstitial and metronomic photodynamic therapy. AB - Multiple clinical studies have shown that interstitial photodynamic therapy (iPDT) is a promising modality in the treatment of several cancers. Laser fibers are usually inserted into the target tissue via needles, or placed in catheters. However, they must be removed from the body soon after use. Innovative implantable and biodegradable light sources could offer interesting alternatives since they not need to be removed as they are gradually resorbed by the tissue. Bioabsorbable polymer optical waveguide are relatively easy to manufacture and can deliver substantial light intensities. Near-infrared rechargeable "optical battery" can be easily optimized in size and shape aiming at different nidus sites. Further studies should evaluate the safety of the biodegradation process which will be required in order to approve these light sources on humans. PMID- 29981382 TI - Domain intelligible models. AB - Mining biological information from rich "-omics" datasets is facilitated by organizing features into groups that are related to a biological phenomenon or clinical outcome. For example, microorganisms can be grouped based on a phylogenetic tree that depicts their similarities regarding genetic or physical characteristics. Here, we describe algorithms that incorporate auxiliary information in terms of groups of predictors and the relationships between them into the metagenome learning task to build intelligible models. In particular, our cost function guides the feature selection process using auxiliary information by requiring related groups of predictors to provide similar contributions to the final response. We apply the developed algorithms to a recently published dataset analyzing the effects of fecal microbiota transplantation (FMT) in order to identify factors that are associated with improved peripheral insulin sensitivity, leading to accurate predictions of the response to the FMT. PMID- 29981383 TI - Hydroxychloroquine efficiently suppresses inflammatory responses of human class switched memory B cells via Toll-like receptor 9 inhibition. AB - Hydroxychloroquine is widely used for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Although B cells contribute to the pathogenesis of these diseases, the action of hydroxychloroquine on B cells remains unclear. Here we examined the effects of hydroxychloroquine on functions of B cell subsets. Hydroxychloroquine efficiently inhibited the mammalian target of rapamycin complex 1, differentiation of CD19+IgD-CD27+ class-switched memory B cells to plasmablasts and their IgG production, under stimulation with CpG, a Toll-like receptor (TLR)-9 ligand. Hydroxychloroquine also inhibited CpG-induced production of interleukin-6 and tumor necrosis factor-alpha in B cell subsets. Taken together, hydroxychloroquine markedly suppresses the TLR9-mediated human B cell functions during inflammatory processes. Based on our results, we believe that hydroxychloroquine can be beneficial in the treatment of B cell-mediated autoimmune diseases. PMID- 29981384 TI - A survey-based study on nail examinations at an American Academy of Dermatology free skin cancer screening. PMID- 29981385 TI - Drug utilization patterns and adherence in patients on systemic medications for the treatment of psoriasis: A retrospective, comparative cohort study. AB - BACKGROUND: Nonadherence to systemic treatments for psoriasis leads to treatment failure and increased health care utilization. OBJECTIVE: Examine drug utilization patterns and adherence of new users of systemic medications for psoriasis. METHODS: We conducted a retrospective, comparative cohort study using a large US health insurance claims database including psoriasis patients who were new users of acitretin, adalimumab, etanercept, methotrexate, or ustekinumab. Adherence was measured by using proportion of days covered dichotomized as adherent (>=0.80) or nonadherent (<0.80). Odds ratios (ORs) and 95% confidence intervals (CIs) comparing adherence to each exposure (acitretin, adalimumab, etanercept, or ustekinumab) to the referent (methotrexate) were estimated via logistic regression, with pairwise 1:1 propensity score matching to adjust for potential confounders. RESULTS: In total, 22,742 patients were new users of systemic medications. Among these patients, adherence to adalimumab (OR 2.24, 95% CI 2.05-2.45); etanercept (OR 1.77, 95% CI 1.63-1.92); and ustekinumab (OR 2.54, 95% CI 2.24-2.87) was greater and acitretin (OR 0.57, 95% CI 0.50-0.63) lower compared with methotrexate. LIMITATIONS: Unable to evaluate reasons for discontinuation. CONCLUSION: We report greater adherence to biologics than methotrexate in new users. Further research is needed to understand overall low adherence to systemic medications for psoriasis. PMID- 29981386 TI - Fluorescent tattoos as anatomic markers to track trichologic responses. PMID- 29981387 TI - Comment on "Guidelines of care for the management of basal cell carcinoma". PMID- 29981388 TI - Reply to: "Comment on 'Guidelines of care for the management of basal cell carcinoma'". PMID- 29981389 TI - Skin Confident: A skin health and acne educational intervention to improve the Acne Quality of Life measures in adolescents. PMID- 29981390 TI - Atypical fibroxanthoma: Systematic review and meta-analysis of treatment with Mohs micrographic surgery or excision. AB - BACKGROUND: Atypical fibroxanthoma (AFX) is a fibrohistiocytic tumor with relatively high local recurrence rates but low metastatic potential. Wide local excision (WLE) and Mohs micrographic surgery (MMS) are common treatments, although no consensus exists regarding optimal therapy. OBJECTIVE: To systematically review evidence of AFX recurrence and metastatic rates after different surgical modalities. METHODS: A comprehensive search was performed for articles published from 1946 or database inception to March 20, 2017. Studies selected included those that had 5 or more patients with atypical fibroxanthoma treated surgically. Two reviewers independently abstracted the data. Risk of bias was assessed with the Newcastle-Ottawa scale. Main outcomes and measures included recurrence and metastasis. RESULTS: In total, 23 studies were selected (907 patients and 914 tumors); 175 patients were treated with MMS (recurrence rate 2.0%, 95% confidence interval [CI] 0%-4.1%; metastatic rate 1.9%, 95% CI 0.1% 3.8%), and 732 were treated with WLE (recurrence rate 8.7%, 95% CI 5%-12.3%; metastasis rate 1%, 95% CI 0.2%-1.9%). Among immunocompromised patients, no recurrence or metastases developed in the MMS subgroup, although 4 of 10 recurred and 1 of 10 metastasized in the WLE subgroup. LIMITATIONS: Low quality of the studies published. CONCLUSION: MMS for atypical fibroxanthoma is associated with a lower recurrence rate than WLE. PMID- 29981391 TI - Neuroactive steroids, neurosteroidogenesis and sex. AB - The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice. Here we review the mechanisms of synthesis, metabolism and action of neuroactive steroids, including the role of epigenetic modifications and the mitochondria in their sex specific actions. We examine sex differences in neuroactive steroid levels under physiological conditions and their role in the establishment of sex dimorphic structures in the nervous system and sex differences in its function. In addition, particular attention is paid to neuroactive steroids under pathological conditions, analyzing how pathology alters their levels and their role as neuroprotective factors, considering the influence of sex in both cases. PMID- 29981392 TI - Insights into the pharmaceuticals and mechanisms of neurological orphan diseases: Current Status and future expectations. AB - Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ~6%-10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes. This review debates current progress in chemical genetics, and how a variety of compounds and reaction mechanisms can be used to study and ultimately treat rare genetic diseases. We focus here on a study involving Amyotrophic lateral sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Spinal muscular atrophy (SMA) and Familial Amyloid Polyneuropathy (FAP), approaching different treatment methods and the reaction mechanisms of several compounds, trying to elucidate new routes capable of assisting in the treatment profile. PMID- 29981393 TI - The histology, physiology, neurochemistry and circuitry of the substantia gelatinosa Rolandi (lamina II) in mammalian spinal cord. AB - The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to understand - at least in part - its role in the initial processing of pain and itch. Here, I will first provide a comprehensive picture of the histology, physiology, and neurochemistry of the normal SGR. Then, I will analytically discuss the SGR circuits that have been directly demonstrated or deductively envisaged in the course of the intensive research on this area of the spinal cord, with particular emphasis on the pathways connecting the primary afferent fibers and the intrinsic neurons. The perspective existence of neurochemically defined sets of primary afferent neurons giving rise to these circuits will be also discussed, with the proposition that a cross-talk between different subsets of peptidergic fibers may be the structural and functional substrate of additional gating mechanisms in SGR. Finally, I highlight the role played by slow acting high molecular weight modulators in these gating mechanisms. PMID- 29981394 TI - Thinking about the nerve impulse: A critical analysis of the electricity-centered conception of nerve excitability. AB - Nerve impulse generation and propagation are often thought of as solely electrical events. The prevalence of this view is the result of long and intense study of nerve impulses in electrophysiology culminating in the introduction of the Hodgkin-Huxley model of the action potential in the 1950s. To this day, this model forms the physiological foundation for a broad area of neuroscientific research. However, the Hodgkin-Huxley model cannot account for non-electrical phenomena that accompany nerve impulse propagation, for which there is nevertheless ample evidence. This raises the question whether the Hodgkin-Huxley model is a complete model of the nerve impulse. Several alternative models have been proposed that do take into account non-electrical aspects of the nerve impulse and emphasize their importance in gaining a more complete understanding of the nature of the nerve impulse. In our opinion, these models deserve more attention in neuroscientific research, since, together with the Hodgkin-Huxley model, they will help in addressing and solving a number of questions in basic and applied neuroscience which thus far have remained outside our grasp. Here we provide a historico-scientific overview of the developments that have led to the current conception of the action potential as an electrical phenomenon, discuss some major objections against this conception, and suggest a number of scientific factors which have likely contributed to the enduring success of the Hodgkin Huxley model and should be taken into consideration whilst contemplating the formulation of a more extensive and complete conception of the nerve impulse. PMID- 29981395 TI - Cerrenins A-C, cerapicane and isohirsutane sesquiterpenoids from the endophytic fungus Cerrena sp. AB - One new cerapicane cerrenin A (1), and two new isohirsutane sesquiterpenoids cerrenins B and C (2 and 3), were isolated from the broth extract of Cerrena sp. A593. Cerrenin A featured a rare cage-like bicyclo[3.2.1]octane skeleton, and cerrenin B represented the rearranged triquinane-type sesquiterpenoid. Their structures were extensively elucidated by NMR spectroscopic analysis with the absolute configuration determined by X-ray crystallography and ECD calculations. The anti-cancer activity for all the compounds were evaluated, and their plausible biosynthetic relationships involving fascinating carbon skeleton rearrangements were also suggested. PMID- 29981396 TI - Limonoids from the fruits of Swietenia macrophylla with inhibitory activity against H2O2-induced apoptosis in HUVECs. AB - The fruits of Swietenia macrophylla (skyfruits) are commercially used as healthcare products to improve blood circulation. An investigation of active ingredients of skyfruits led to the isolation of four new limonoids, swietemacrolides A-D (1-4), together with ten known limonoids (5-14) and one proto-limonoid (15). Their structures were elucidated on the basis of MS and NMR data analysis. Swietemacrolide C (3) at the concentration of 10 MUM showed significant protective effect on H2O2-induced apoptosis in human umbilical vascular endothelial cells (HUVECs), while swieteliacate D (5) displayed moderate anti-apoptotic activity. PMID- 29981397 TI - New polyoxypregnane glycosides from Aspidopterys obcordata vines with antitumor activity. AB - Nine new polyoxypregnane glycosides, obcordatas A-I (1-9), were isolated from Aspidopterys obcordata Hemsl vines. Their structures were elucidated by extensive spectroscopic methods. Separated compounds were evaluated for antitumor activities against the human cancer cell lines AGS, SW480, HuH-7 and MCF-7, and compounds 1-6 and 9 showed selective cytotoxicity against HuH-7 cells with IC50 values of 8.7, 10.2, 7.5, 12.1, 16.5, 14.3, and 17.4 MUM, respectively. Flow cytometry experiments showed that the effects of compound 1 on the cell cycle were attributable to cell cycle arrest at G1/S phase. PMID- 29981398 TI - Proteome profiling in the hippocampus, medial prefrontal cortex, and striatum of aging rat. AB - Decrease in multiple functions occurs in the brain with aging, all of which can contribute to age-related cognitive and locomotor impairments. Brain atrophy specifically in hippocampus, medial prefrontal cortex (mPFC), and striatum, can contribute to this age-associated decline in function. Our recent metabolomics analysis showed age-related changes in these brain regions. To further understand the aging processes, analysis using a proteomics approach was carried out. This study was conducted to identify proteome profiles in the hippocampus, mPFC, and striatum of 14-, 18-, 23-, and 27-month-old rats. Proteomics analysis using ultrahigh performance liquid chromatography coupled with Q Exactive HF Orbitrap mass spectrometry identified 1074 proteins in the hippocampus, 871 proteins in the mPFC, and 241 proteins in the striatum. Of these proteins, 97 in the hippocampus, 25 in mPFC, and 5 in striatum were differentially expressed with age. The altered proteins were classified into three ontologies (cellular component, molecular function, and biological process) containing 44, 38, and 35 functional groups in the hippocampus, mPFC, and striatum, respectively. Most of these altered proteins participate in oxidative phosphorylation (e.g. cytochrome c oxidase and ATP synthase), glutathione metabolism (e.g. peroxiredoxins), or calcium signaling pathway (e.g. protein S100B and calmodulin). The most prominent changes were observed in the oldest animals. These results suggest that alterations in oxidative phosphorylation, glutathione metabolism, and calcium signaling pathway are involved in cognitive and locomotor impairments in aging. PMID- 29981399 TI - Learning new gait patterns: Age-related differences in skill acquisition and interlimb transfer. AB - Evidence from upper-extremity literature suggests that the normal ageing process affects an individual's ability to learn and retain a motor skill, but spares their ability to transfer the skill to the untrained, opposite limb. While this phenomenon has been well-studied in the upper-extremity, evidence in the lower extremity is limited. Further, it is unclear to what extent age-related differences in motor learning and transfer are dependent on visual feedback of the motor task. Therefore, the purpose of this study was to examine the effects of ageing on motor learning, retention, and interlimb transfer during walking with and without visual feedback. Forty-four subjects (24 young; 20 older adults) were tested on a treadmill over two consecutive days. On day 1, subjects learned a new gait pattern by performing a foot-trajectory tracking task that necessitated greater hip and knee flexion during the swing phase of the gait. On day 2, subjects repeated the task with their training leg to test retention, then with their untrained leg to test interlimb transfer. Trials without visual feedback were also collected on both days. Results indicated that older adults had reduced ability to learn the task, and also exhibited lower retention and inter-limb transfer. However, these differences were dependent on visual feedback as the groups performed similarly when feedback was removed. The findings provide novel evidence indicating that ageing impairs learning, retention, and transfer of motor skills in the lower-extremity during walking, which may have implications for gait therapy after stroke and other geriatric conditions. PMID- 29981400 TI - Population pharmacokinetics of valproic acid in epileptic children: Effects of clinical and genetic factors. AB - Valproic acid (VPA) is a first-line anti-epileptic drug that is used in the treatment of generalized and partial seizures. Gene variants had been proved to influence the pharmacokinetics (PK) of VPA and contribute to its inter-individual variability (IIV). The aim of this study was to systematically investigate the effects of candidate gene variants (CYPs, UGTs, ABC transporters, and nuclear receptors) on VPA PK in Chinese children with epilepsy. A total of 1065 VPA serum trough concentrations at steady state were collected from 264 epileptic pediatric patients aged 3 months to 16 years. The population pharmacokinetic (PPK) model was developed using a nonlinear mixed effects modelling (NONMEM) approach. For the final PPK model, the oral clearance (CL/F) of VPA was estimated to be 0.259 L/h with IIV of 13.3%. The estimates generated by NONMEM indicated that the VPA CL/F was significantly influenced by patient body weight (increased by an exponent of 0.662), co-administration with carbamazepine (increased CL/F by 22%), and daily dose of VPA (increased by an exponent of 0.22). CL/F in patients with the LEPR rs1137101 variant (668 AG and GG genotypes) was much lower than in patients with the AA genotype (17.8% and 22.6% lower, respectively). However, none of the CYPs or UGTs gene variants was found to influence the PK of VPA in this study. Evaluation by bootstrap and normalized prediction distribution error (NPDE) showed that the final model was stable. The predictive performance was evaluated by goodness-of-fit (GOF) plots and visual predictive checks (VPC), and the results indicated satisfactory precision. Our model suggests a correlation between VPA CL/F and LEPR rs1137101 variants, which might be beneficial in the context of individual dose optimization. PMID- 29981401 TI - Dermal flurbiprofen nanosuspensions: Optimization with design of experiment approach and in vitro evaluation. AB - Flurbiprofen (FB) is the one of the non-steroidal anti-inflammatory drugs (NSAIDs) which has low water solubility and dissolution. Nanosuspensions are promising drug delivery systems consisting pure drug particles to overcome poor water solubility issues. Recently, design of experiment (DoE) approaches have often been used to develop new formulations include nanosuspensions. The main objective of this study was to prepare FB nanosuspensions in existence of Plantacare 2000 (PL) as stabilizer using DoE approach to evaluate the critical formulation attributes (CFAs) and critical process parameters (CPPs). Particle size, particle size distribution and zeta potential values were selected as dependent variables and FB%, FB: PL and homogenization cycles were independent variables. Both 23 and 33 factorial designs were used to achieve optimum nanosuspension formulation. The final nanosuspension was freeze-dried and then crystalline state, morphological and thermal properties were investigated using X ray diffraction, scanning electron microscopy and differential scanning calorimetry, respectively. The saturation solubility studies of nanosuspensions were conducted in comparison with the coarse powder and the physical mixture. The in vitro permeation of nanosuspension and FB solution were determined through dialysis membrane and rat skin. The particle size, polydispersity index and zeta potential values were found to range 665 nm-700 nm, 0.200-0.300 and approximately -30 mV, respectively. Nanosuspensions were obtained with spherical shape and no polymorphic or crystalline state change were observed. The saturation solubility of FB was 5.3 fold increased in nanosuspension formulation. Permeability of FB nanosuspension was higher than FB solution in rat skin. It was concluded that the DoE approach is a useful tool to prepare FB nanosuspensions and nanosuspensions benefit to improve water solubility and dermal permeation of Biopharmaceutical Classification System (BCS) Class II drugs. PMID- 29981402 TI - Dexamethasone-diclofenac loaded polylactide nanoparticles: Preparation, release and anti-inflammatory activity. AB - Inflammation is a nonspecific response of tissues to diverse stimuli and/or insults associated with the release of various mediators that induce pain, fever, and general sense of illness. Such responses can be reduced by the administration of non-steroidal or steroidal anti-inflammatory drugs. These anti-inflammatory drugs are associated with various side effect. However, the combination of non steroidal anti-inflammatory drugs (NSAIDs) with glucocorticoids provides a synergistic anti-inflammatory and pain relief with less side effects. In this study, we aimed to synthesize a novel twin-drug of Dexamethasone-Diclofenac formulated into polylactide (PLA) nanoparticles to improve their solubility and provide a sustained release system. The twin-drug was synthesized through an esterification reaction which was then encapsulated into PLA nanoparticles. The hydrolysis of the synthesized twin-drug and drug release from PLA nanoparticles were studied in vitro with and without esterase enzyme. The anti-inflammatory activity was studied in BALB/c mice. After the successful synthesis of the twin drug, its water solubility was improved by its encapsulation into PLA nanoparticles with a loading capacity of 66%. The in vitro release showed a sustained release profile of the twin-drug up to 52 h. The esterase hydrolysis showed a rapid release with a maximum hydrolysis after 1.5 h. Moreover, the anti inflammatory activity exhibited a synergistic effect with a higher percentage of inhibition for the TNF-alpha level in comparison to the parent drugs after 6 h treatment. In conclusion, the prepared nano twin-drug is a novel therapy that showed a sustained release profile with an excellent anti-inflammatory activity. PMID- 29981403 TI - Melatonin vitamin C-based nanovesicles for treatment of androgenic alopecia: Design, characterization and clinical appraisal. AB - The present study aimed to develop vitamin C based nanovesicles (aspasomes) loaded with the antioxidant melatonin, as a novel cosmeceutical to be used for clinical treatment of androgenic alopecia (AGA). Aspasomes were assessed regarding their particle size, charge, drug entrapment, anti-oxidant potential, physical stability, in vitro release, surface morphology, and ex-vivo skin deposition. Clinically, melatonin aspasomes were tested on AGA patients, and assessed by evaluating the degree of improvement through conduction of hair pull test, histometric analysis and dermoscopic evaluation. Results revealed that melatonin aspasomes showed favorable pharmaceutical properties in addition to clinically promising results compared to melatonin solution, manifested by increased hair thickness, density and decreased hair loss, with photographic improvement in most patients. Therefore, melatonin vitamin C-based aspasomes were clinically auspicious in the treatment of AGA, hence, paving the way for their further exploration in other oxidative-dependent dermatological diseases. PMID- 29981404 TI - Functionalized Graphene Oxide as a nanocarrier of new Copper (II) complexes for targeted therapy on nasopharyngeal carcinoma. AB - Cancer cell targeted therapy using a biocompatible targeted drug delivery system can increase the therapeutic effects of cellular cancer therapy. Here, we report a Folic Acid (FA) and polyethyleneimine (PEI) functionalized Graphene Oxide (GO) nanocarrier, FA-PEI-GO, used to deliver two new Copper complexes into the folate receptor-positive nasopharyngeal carcinoma cell line. GO was prepared by modified Hummers method and then decorated by PEI and FA. Afterwards, the material was characterized by the X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Copper complexes were synthesized by a hydrothermal method and then characterized by single crystal X-ray diffraction analysis. Cytotoxicity assessment of the complexes illustrated that the IC50 values against the nasopharyngeal carcinoma cell lines, HNE-1 and CNE-2, were, respectively, 17.7 +/- 1.2, 13.2 +/- 1.9, 6.7 +/- 0.8, 2.9 +/- 0.7 MUM. Flow cytometry findings suggested that both complexes were capable of decreasing cancer cell viability through causing late-stage cell apoptosis. The obtained targeted drug delivery systems had good biocompatibility and stability. Compared with Cis Dichlorodiamineplatinum (CDDP), the non-specific antitumor drug normally used in chemotherapy, one of the obtained agents had similar therapeutic effect while the other had significantly higher activity, suggesting future possible application of this new targeted therapy against nasopharyngeal carcinoma. PMID- 29981405 TI - UV filter entrapment in mesoporous silica hydrogel for skin protection against UVA with minimization of percutaneous absorption. AB - The UVA absorbers such as avobenzone are widely used for sunlight protection; however, they show a significant skin penetration. The aim of the present study was to formulate UVA absorbers into mesoporous silicas (MSs) for enhanced UVA protection with reduced percutaneous absorption. Two MSs prepared with different structure-directing agents (Pluronic P123 as single MS and combined Pluronic P123 Pluronic F68 as hybrid MS) were synthesized in this study. The hybrid MS exhibited higher specific surface area (853 m2/g) than the single MS (764 m2/g). The particle sizes of single MS and hybrid MS were about 1 and 1.5 MUm, respectively. The adsorbed avobenzone had greatly decreased crystallinity compared with free avobenzone. The in vitro photoprotection determined by UVA/UVB ratio showed that the MS-loaded avobenzone in hydrogel endowed a synergistic effect on UVA protection compared to the free avobenzone. The skin absorption test using Franz diffusion cell indicated that the skin permeation of avobenzone and oxybenzone from MSs in semisolid preparations was one-third to one-half of those from free control. This effect was observed by using both pig skin and UVA damaged nude mouse skin as the penetration barriers. Topical application of hybrid MS on nude mouse skin before UVA irradiation had prevented the increased transepidermal water loss (TEWL), furrow formation, keratinocyte apoptosis, and neutrophil infiltration. Our findings conclude that MSs containing avobenzone or oxybenzone effectively ameliorated UVA-induced skin disruption and reduced the possible toxicity elicited by percutaneous penetration. PMID- 29981406 TI - Bioequivalence of topical generic products. Part 2. Paving the way to a tailored regulatory system. AB - Hitherto, for the approval of a topical generic drug product, the majority of the regulatory agencies require clinical endpoint studies to prove its therapeutic equivalence in relation to a reference product. Pharmacodynamic studies are also available to support bioequivalence, however, these are solely applicable for corticosteroids. The first strategy is considered the "gold standard", since it can be applied to all drug products. Nevertheless, the high variability intrinsic to topical drug delivery makes this analysis relatively insensitive, costly, time consuming, besides requiring a large number of subjects. There are, however, alternative methods capable of providing a more rigorous analysis and requiring a lower cost. Amongst them, in vitro methods have sparked considerable attention, not only in the academic field, but also in the pharmaceutical industry and regulatory agencies. In this context, this review attempts to discuss the main regulatory constraints and the recent advances in the regulatory science of topical generic drugs bioequivalence assessment. Initiatives, such as the Strawman decision tree and the topical drug classification system are specially referred, since these highlight the importance of establishing a broader concept of pharmaceutical equivalence for topical generic drugs, similar to the one already set for orally administered conventional dosage forms, such as tablets and capsules. Finally, the FDA Product-Specific Guidances for Generic Drug Development released for topical products in recent years and particular European Public Assessment Reports are presented and discussed, to illustrate the change of paradigm which is occurring in this regulatory field. PMID- 29981407 TI - Characterization of a smart pH-cleavable PEG polymer towards the development of dual pH-sensitive liposomes. AB - To facilitate the development of PEG-cleavable pH-sensitive liposomes (CL-pPSL), this study aimed to fully characterize a new pH-sensitive polymer, PEGB-Hz-CHEMS. Polyethylene glycol (PEG) functionalised with 4-carboxybenzaldehyde (PEGB) was linked to cholesteryl hemisuccinate (CHEMS) via an acid labile hydrazide hydrazone hybrid bond (CONHNCH) to form PEGB-Hz-CHEMS. The polymer was post inserted into DOPE/CHEMS liposomes to form CL-pPSL. A validated stability indicating HPLC-UV method was developed with the aid of multiple linear regression for the mobile phase. The assay was used to evaluate the pH sensitivity, pathways of cleavage of the polymer and the PEGylation degree of CL pPSL. The pH-sensitivity of CL-pPSL was compared with conventional PEGylated pH sensitive (pPSL) using a calcein leakage assay. At 37 degrees C, PEGB-Hz-CHEMS was relatively stable at pH 7.4 with a half-life of 24 h. In comparison, at pH 5.5 and pH 6.5 PEG detachment within 1 h was determined as 80%, and 50%, respectively. PEG detachment of the polymer was through simultaneous cleavage of the hydrazine (CON) and hydrazone (NC) bonds, depending on pH, thus the polymer is more pH-sensitive than those with a hydrazine bond only. The grafting densities of PEGB-Hz-CHEMS on CL-pPSL were optimised to achieve a PEG density of 1.7% (mol). The unilamellar CL-pPSL (123 nm) were shown to be sable at least for 3 months at 4 degrees C and have enhanced pH-sensitivity compared with pPSL in the calcein leakage assay. Therefore, the smart cleavable PEG polymer is promising in liposome formulation to overcome the PEG dilemma. PMID- 29981408 TI - In-situ forming PLGA implants for intraocular dexamethasone delivery. AB - Different types of in-situ forming implants based on poly(lactic-co-glycolic acid) (PLGA) and N-methyl-pyrrolidone (NMP) were prepared for controlled ocular delivery of dexamethasone. The impact of the volume of the release medium, initial drug content, polymer molecular weight and PLGA concentration on the resulting drug release kinetics were studied and explained based on a thorough physico-chemical characterization of the systems. This included for instance the monitoring of dynamic changes in the implants' wet and dry mass, morphology, PLGA polymer molecular weight, pH of the surrounding bulk fluid and water/NMP contents upon exposure to phosphate buffer pH 7.4. Importantly, the systems can be expected to be rather robust with respect to variations in the vitreous humor volumes encountered in vivo. Interestingly, limited drug solubility effects within the implants as well as in the surrounding aqueous medium play an important role for the control of drug release at a drug loading of only 7.5%. Furthermore, the polymer molecular weight and PLGA concentration in the liquid formulations are decisive for how the polymer precipitates during solvent exchange and for the swelling behavior of the systems. These features determine the resulting inner system structure and the conditions for mass transport. Consequently, they affect the degradation and drug release of the in-situ formed implants. PMID- 29981410 TI - Direct quantification of unencapsulated doxorubicin in liposomal doxorubicin formulations using capillary electrophoresis. AB - To understand the quality, efficacy, and safety of liposomal drugs, it is necessary to develop a robust and accurate method for the separation and the quantification of unencapsulated and liposome-associated drugs (or liposomal encapsulated drugs). Conventional methods involve separation of unencapsulated and liposome-associated drug using solid phase extraction and further drug quantification. This is a lengthy process, and sometimes solid phase extraction induces drug leakage from the liposomes causing erroneous results. In this study, a capillary electrophoresis (CE) with UV-Vis detection method was developed for the simultaneous separation and quantification of unencapsulated drug from liposome-associated drug using a doxorubicin-containing liposome formulation as the model drug. CE separates the unencapsulated drug and liposomal drugs based on their electrophoretic mobility under the electric field. Liposomal drugs were diluted to the appropriate concentrations with running buffer or 5% dextrose before hydrodynamic sample injection. Using a high-sensitivity detection cell, the doxorubicin detection sensitivity was enhanced about 10-fold compared to the conventional on-column UV-Vis detection with a 75 um i.d. capillary column. The optimal separation of unencapsulated doxorubicin from liposome-associated doxorubicin with minimal perturbation of liposomes was accomplished using phosphate buffer (20 mM, pH 6.5) in the presence of 10% sucrose. PMID- 29981409 TI - Implication of linker length on cell cytotoxicity, pharmacokinetic and toxicity profile of gemcitabine-docetaxel combinatorial dual drug conjugate. AB - The present study investigates effect of linkers [zero length (without linker), short length linker (glycine and lysine) and long length linker (PEG1000, PEG2000 and PEG3500)] on pharmacokinetics and toxicity of docetaxel (DTX) and gemcitabine (GEM) bio-conjugates. Conjugates were synthesized via carbodiimide chemistry and characterized by 1H NMR and FTIR. Conjugation of DTX and GEM via linkers showed diverse physiochemical and plasma stability profile. Cellular uptake mechanism in MCF-7 and MDA-MB-231 cell lines revealed clathrin mediated internalization of bio conjugates developed by using long length linkers, leading to higher cytotoxicity compared with free drug congeners. DTX-PEG3500-GEM and DTX-PEG2000-GEM demonstrated 4.21 and 3.81-fold higher AUC(0-infinity) of GEM in comparison with GEM alone. DTX-PEG2000-GEM and DTX-PEG3500-GEM exhibited reduced hepato-, nephro- and haemolytic toxicity as evident via histopathology, biochemical markers and SEM analysis of RBCs. Conclusively, PEG2000 and PEG3500 significantly improved pharmacokinetics without any sign of toxicity and hence can be explored further for the development of dual-drug conjugates for better therapeutic efficacy. PMID- 29981411 TI - Preparation of spray dried submicron particles: Part A - Particle generation by aerosol conditioning. AB - The preparation of submicron-sized particles is relevant in chemical, food and pharmaceutical applications. In pharmaceutics, spray dried submicron-sized particles (0.1-1 um) can increase the dissolution rate as well as the solubility of poorly water-soluble drugs. Since the particle size during spray drying is mainly influenced by the droplet size, the preparation of uniform droplets smaller than 3 um is of particular interest. In this work, a two-fluid nozzle was combined with a cyclone droplet separator. Droplets larger than the cut-off size were separated with a cyclone droplet separator and returned to the liquid feed. The aerosol at the outlet of the droplet separator was subsequently dried. The drop size of the conditioned aerosol was small, d50,3=2 um, and independent of the liquid-to-gas mass flow ratio and the viscosity of the liquid feed. Thus it only depended on the characteristics of the separator. Finally, the dried particles were spherical in shape and in the submicron-sized range. PMID- 29981413 TI - Assessment of hot-processability and performance of ethylcellulose-based materials for injection-molded prolonged-release systems: An investigational approach. AB - The present work focuses on application of an investigational approach to assess the hot-processability of pharmaceutical-grade polymers with a potential for use in the manufacturing of reservoir drug delivery systems via micromolding, and the performance of resulting molded barriers. An inert thermoplastic polymer, ethylcellulose (EC), widely exploited for preparation of prolonged-release systems, was employed as a model component of the release-controlling barriers. Moldability studies were performed with plasticized EC, as such or in admixture with release modifiers, by the use of disk-shaped specimens >= 200 um in thickness. The disks turned out to be a suitable tool for evaluation of the dimensional stability and diffusional barrier performance of the investigated materials after demolding. The effect of the amount of triethyl citrate, used as a plasticizer, on hot-processability of EC was assessed. The rate of a model drug diffusion across the polymeric barriers was shown to be influenced by the extent of porosity from the incorporated additives. The investigational approach proposed, of simple and rapid execution, holds potential for streamlining the development of prolonged-release systems produced by micromolding in the form of drug reservoirs, with no need for molds and molding processes to be set up on a case-by-case basis. PMID- 29981414 TI - Exploring gastric drug absorption in fasted and fed state rats. AB - The small intestine is generally considered the major site of absorption after oral drug administration. Absorption from the stomach is often disregarded, though passive diffusion across the gastric mucosal barrier is theoretically possible. In this study, an in situ gastric bolus administration model was used to study the gastric absorption of pharmaceutical compounds in fasted and fed state rats. Three drugs [paracetamol (neutral), diclofenac (acidic) and posaconazole (basic)] were administered directly into the stomach as solution (paracetamol and diclofenac) or suspension (posaconazole). Transfer to the intestine was blocked by ligating the pylorus; as a reference, non-ligated conditions were used. Blood samples were collected and gastric absorption was assessed by the appearance of compounds in the systemic circulation. Paracetamol and diclofenac were readily absorbed from the fasted and fed state rat stomach. For paracetamol, the relative contribution of gastric absorption was higher in the fed state compared to the fasted state. Posaconazole absorption was negligible. Since the ability of the stomach to absorb pharmaceutical compounds was clearly confirmed, the present study warrants further research to quantify the contribution of gastric absorption to total gastrointestinal drug absorption. PMID- 29981412 TI - Subcutaneous administration of Lyso-phosphatidylserine nanoparticles induces immunological tolerance towards Factor VIII in a Hemophilia A mouse model. AB - A major complication with enzyme replacement therapy of Factor VIII (FVIII) in Hemophilia A (HA) is the development of anti-drug antibodies. Recently, we have shown that FVIII administration in the presence of heterogeneous phosphatidylserine (PS) nanoparticles derived from a natural source induces tolerance to FVIII, suggesting that PS converts an immunogen to a tolerogen. However, the specific structural features responsible for the immune-regulatory properties of PS is unclear. Identifying a specific PS species that is responsible is critical in order to further develop and optimize this nanoparticle. Further, clinical development of this lipid-based strategy requires optimization of the lipid particle that is homogeneous and synthetic. Here, we investigate the ability of mono-acylated Lyso-PS to induce hypo-responsiveness towards FVIII in HA mice. Administration of both PS and Lyso-PS FVIII significantly reduced anti-FVIII antibody responses despite rechallenge with FVIII. Additionally, the Lyso-PS-mediated effect was shown to be antigen-specific as mice responded normally against a rechallenge with an unrelated antigen, ovalbumin. Furthermore, the hypo-responsiveness observed with Lyso-PS may involve interactions with a specific PS receptor, TIM-4, along with increasing regulatory T-cells. These data indicate that using Lyso-PS allows for a more homogenous formulation in order to induce tolerance towards therapeutic proteins. PMID- 29981415 TI - Involvement of insulin signalling pathway in methamphetamine-induced hyperphosphorylation of Tau. AB - Methamphetamine (METH), an amphetamine-like drug, is one of the most commonly used central nervous system psychostimulants worldwide. METH abuse frequently leads to cognitive decline and dementia-like changes, but the mechanisms remain poorly understood. In the present study, the mechanisms of METH-induced changes in Alzheimer's disease-like pathological protein in Neuro2A cells were explored. Our results indicated that METH exposure significantly increased the expression of the pathological protein hyperphosphorylated tau (p-tau). Further analysis revealed that METH exposure obviously disrupted insulin signalling, resulted in brain insulin resistance, which manifested as downregulation of the insulin receptor substrate-1, AKTser 473, and GSK3beta activation. Notably, the linkage between p-tau expression and insulin signalling can be partially verified by treatment with the insulin-sensitizing drug rosiglitazone and GSK3beta inhibitor TWS119 which specifically reversed METH-induced hyperphosphorylation of tau. Our results indicate that insulin signalling can be therapeutically exploited for attenuating METH-induced upregulation of p-tau. PMID- 29981416 TI - Overexpression of long noncoding RNA LINC01296 indicates an unfavorable prognosis and promotes tumorigenesis in breast cancer. AB - Breast cancer (BC) is one of the most common malignancies in female worldwide. Long non-coding RNAs (lncRNAs) play imperative roles in cancer cell initiation and progression. Recently, aberrantly expressed LINC01296 was observed in several malignancies. To the best of our knowledge, its clinical significance and exact effects on BC is still unclear. In this work, the clinical value of LINC01296 was evaluated in patients with BC. Additionally, cell proliferation, apoptosis, migration and invasion capacities were detected after silencing of LINC01296. Furthermore, the xenograft experiment was used to confirm the in vitro results. As a result, LINC01296 is up-regulated in both BC tissue samples and cells. Up regulated LINC01296 is correlated with larger tumor size, positive lymph node metastasis, and advanced TNM stage of patients with BC. Additionally, Cox regression analysis confirmed LINC01296 as an independent prognostic indicator for patients with BC. For the part of functional assays, silencing of LINC01296 inhibited BC cell growth in vitro and in vivo. Also, cell apoptosis was enhanced after LINC01296 silenced. Moreover, cell migration and invasion potential were both abrogated in the si-LINC01296 groups. Collectively, LINC01296 may function as a potential prognostic predictor and therapeutic target for patients with BC. PMID- 29981417 TI - Integrated analysis of long noncoding RNA expression profiles in lymph node metastasis of hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and metastasis of HCC is the leading cause of poor prognosis. Among all the extrahepatic metastases, lymph node metastasis (LNM) is common, second only to lung metastasis. However, the pathogenesis of HCC LNM remains largely unknown. METHODS: Microarray was performed to investigate the long noncoding RNA (lncRNA) and messenger RNA (mRNA) expression profiles in serum samples from HCC LNM patients (N = 4) and HCC non-LNM controls (N = 5). Subsequently, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was applied to validate the expression levels of randomly selected differential lncRNAs and mRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were employed to explore the potential functions of differentially expressed mRNAs. Co-expression networks were further constructed to elucidate the interactions of the differential genes and to speculate on the potential functions of the dominant lncRNAs. In this research, we attempted to illuminate the correlations between lncRNA and HCC LNM. RESULTS: Compared with the non-LNM group, a total of 234 lncRNAs and 58 mRNAs were obtained as significantly dysregulated genes in LNM group (p < 0.05, fold change >= 2). Functional enrichment analyses showed that upregulated mRNAs are mostly enriched for glucose 6-phosphate dehydrogenase activity, biotin binding and AP-3 adaptor complex, while the downregulated mRNAs are enriched for macrophage colony-stimulating factor receptor binding, succinate-CoA ligase activity and palmitoyltransferase activity. In addition, coexpression network revealed that the dominant lncRNAs are potential participants of protein metabolic process, integral component of membrane, RNA binding, Golgi apparatus, as well as focal adhesion pathway. CONCLUSION: This study first revealed the expression profiles and potential functions of dysregulated lncRNAs and mRNAs in HCC LNM, which may provide novel clues for further studies on HCC LNM. PMID- 29981418 TI - Molecular identification of single hormone-encoding proglucagon cDNA isoforms from squamates and their abundant expression. AB - Among ectothermic reptiles, the order Squamata has adapted most successfully to the terrestrial environment. However, the physiological background of this success remains unknown. Since the regulation of energy metabolism provides an important insight into terrestrial adaption by ectothermic animals, we focused on proglucagon-derived peptides (PGDPs). In the process of cloning proglucagon mRNA in geckos, we identified several novel proglucagon (PG) cDNA isoforms. They were tissue-specifically and strongly expressed in the pancreas and small intestine of the geckos, suggesting their biological relevance. Therefore, in order to clarify whether these novel cDNA isoforms are phylogenetically conserved, we performed the additional molecular characterization of proglucagon cDNAs from several representative species of the Squamata and Testudine clade and examined the expression of proglucagon mRNAs in the small intestine and pancreas. In the present study, a total of 7 proglucagon cDNA isoforms were identified and divided into two groups (Classes A and B) based on the 3'-UTR sequence of each isoform. The longest isoform of each group (named PG-A1 and PG-B1, respectively) had the same molecular characteristics as those previously reported from chickens and reptiles, namely, PG-A and PG-B. Other 5 isoforms were novel-type cDNAs, and were the products of exon skipping (named PG-A2, PG-A2s, PG-B2, PG-B2s, and PG-B3). Some of these isoforms coded for only one peptide hormone (GLP-1 or GLP-2). This is the first identification of single hormone-encoding proglucagon cDNAs in vertebrates. Moreover, an expression analysis of these isoforms revealed that single hormone-encoding proglucagon mRNAs were predominantly expressed with tissue and lineage specificities in the reptile clade. Collectively, the present results suggest an independent regulatory system for GLP-1 and GLP-2 secretion and indicate the plasticity of proglucagon genes in expressing different isoforms in different tissues in Squamata. These results also provide insights into the plastic energy metabolic system of Squamata in accordance with various habitats in the terrestrial environment, supporting their successful prosperity. PMID- 29981419 TI - The novel cathelicidin of naked mole rats, Hg-CATH, showed potent antimicrobial activity and low cytotoxicity. AB - We performed the in silico genome-wide identification of antimicrobial peptides against the available genome sequence of the naked mole rat Heterocephalus glaber (H. glaber). Our results showed the presence of Hg-CATH, the single cathelicidin containing the antimicrobial domain in H. glaber. We chemically synthesized a 25 amino-acid peptide (DeltaHg-CATH) corresponding to the predicted antimicrobial active core region of Hg-CATH, and evaluated its antibacterial activity against seven bacterial strains. The DeltaHg-CATH peptide exhibited strong bactericidal activity against gram-negative bacteria, including a multi-drug resistant strain, while showing low toxicity towards mammalian cells, including erythrocytes. Scanning electron microscopy images of bacterial cells treated with DeltaHg-CATH showed disruption of their membranes due to the formation of toroidal pores. Identifying novel antimicrobial peptides, such as Hg-CATH, may be important for identifying candidate peptides for the control of multi-drug resistant bacteria. PMID- 29981420 TI - Genetic variants in long noncoding RNA H19 and MEG3 confer risk of type 2 diabetes in an Iranian population. AB - PURPOSE: Long-noncoding RNAs (lncRNAs) have been reported to regulate glucose homeostasis and insulin synthesis and secretion. However, the association of genetic variants of lncRNAs and type 2 diabetes (T2D) has not been evaluated. Therefore, in the present study we investigated the association between H19 rs217727 and H19 rs3741219 variants and MEG3 rs7158663 polymorphism with T2D susceptibility. MATERIALS AND METHODS: The study population consists of 969 subjects including 496 T2D patients and 473 non-diabetic age and sex-matched controls. The H19 and MEG3 variants genotyping were performed by PCR-RFLP method. RESULTS: Our results revealed that the T allele of rs217727 was more frequent in T2D group compared with controls (P = 0.007, OR = 1.1, 95% CI:1.02-1.18). Moreover, the rs217727-TT genotype was significantly associated with T2D after adjustment for age, BMI and lipid levels (P = 0.041, OR = 1.53, 95% CI: 1.01 2.32). However, no significant difference was detected for allele or genotype frequencies of H19 rs3741219 between T2D and controls (P = 0.71). Furthermore, the findings showed that the AA genotype of MEG3 rs7158663 was associated with significantly increased risks of T2D compared with the GG genotype (P = 0.026, OR = 1.79, 95% CI: 1.07-2.99). The results remained significance after analysis by logistic regression (P = 0.033, Adjusted OR = 1.72, 95% CI: 1.04-2.84). Finally, bioinformatics analysis showed that these SNPs could alter local RNA folding structure and also the miRNA-lncRNA interactions. CONCLUSIONS: Our findings provided the evidence of significant association between H19 rs217727-TT and MEG3 rs7158663-AA genotypes with T2D susceptibility. PMID- 29981421 TI - Functional genetic variants in the SIRT5 gene promoter in acute myocardial infarction. AB - Coronary artery disease (CAD) including acute myocardial infarction (AMI) is a common complex disease. To date, genetic causes for atherosclerosis remain largely unknown. It has recently been proposed that low frequency and rare genetic variants may be the main causes. Mitochondrial sirtuins, SIRT3, SIRT4 and SIRT5, function as critical regulators of mitochondrial metabolism, oxidative stress and cell survival. We speculated that altered SIRT5 level resulting from DNA sequence variants (DSVs) within SIRT5 gene regulatory regions may contribute to the CAD and AMI development. In this study, the SIRT5 gene promoter was genetically and functionally analyzed in large cohorts of AMI patients (n = 381) and healthy controls (n = 391). A total of eleven DSVs and SNPs were found. Two novel heterozygous DSVs (g.13574131C>A and g.13574287G>C) and three heterozygous SNPs [g.13573450A>G (rs573515169), g.13574110G>A (rs2804924) and g.13574259G>C (rs112443954)] were identified only in AMI patients. The DSVs and SNPs significantly decreased the transcriptional activity of the SIRT5 gene promoter in both HEK-293 and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assay indicated that the SNPs significantly affected the binding of transcription factors. In contrast, the DSVs and SNPs found only in controls or in both AMI patients and controls did not significantly change the SIRT5 gene promoter activity (P > 0.05). Therefore, our data suggested that the DSVs and SNPs identified in AMI patients may change SIRT5 level by affecting activity of SIRT5 gene promoter, contributing to the AMI development as a risk factor. PMID- 29981422 TI - Specific enzyme functionalities of Fusarium oxysporum compared to host plants. AB - The genus Fusarium contains some of the most studied and important species of plant pathogens that economically affect world agriculture and horticulture. Fusarium spp. are ubiquitous fungi widely distributed in soil, plants as well as in different organic substrates and are also considered as opportunistic human pathogens. The identification of specific enzymes essential to the metabolism of these fungi is expected to provide molecular targets to control the diseases they induce to their hosts. Through applications of traditional techniques of sequence homology comparison by similarity search and Markov modeling, this report describes the characterization of enzymatic functionalities associated to protein targets that could be considered for the control of root rots induced by Fusarium oxysporum. From the analysis of 318 F. graminearum enzymes, we retrieved 30 enzymes that are specific of F. oxysporum compared to 15 species of host plants. By comparing these 30 specific enzymes of F. oxysporum with the genome of Arabidopsis thaliana, Brassica rapa, Glycine max, Jatropha curcas and Ricinus communis, we found 7 key specific enzymes whose inhibition is expected to affect significantly the development of the fungus and 5 specific enzymes that were considered here to be secondary because they are inserted in pathways with alternative routes. PMID- 29981423 TI - A translational perspective on neural circuits of fear extinction: Current promises and challenges. AB - Fear extinction is the well-known process of fear reduction through repeated re exposure to a feared stimulus without the aversive outcome. The last two decades have witnessed a surge of interest in extinction learning. First, extinction learning is observed across species, and especially research on rodents has made great strides in characterising the physical substrate underlying extinction learning. Second, extinction learning is considered of great clinical significance since it constitutes a crucial component of exposure treatment. While effective in reducing fear responding in the short term, extinction learning can lose its grip, resulting in a return of fear (i.e., laboratory model for relapse of anxiety symptoms in patients). Optimization of extinction learning is, therefore, the subject of intense investigation. It is thought that the success of extinction learning is, at least partly, determined by the mismatch between what is expected and what actually happens (prediction error). However, while much of our knowledge about the neural circuitry of extinction learning and factors that contribute to successful extinction learning comes from animal models, translating these findings to humans has been challenging for a number of reasons. Here, we present an overview of what is known about the animal circuitry underlying extinction of fear, and the role of prediction error. In addition, we conducted a systematic literature search to evaluate the degree to which state-of the-art neuroimaging methods have contributed to translating these findings to humans. Results show substantial overlap between networks in animals and humans at a macroscale, but current imaging techniques preclude comparisons at a smaller scale, especially in sub-cortical areas that are functionally heterogeneous. Moreover, human neuroimaging shows the involvement of numerous areas that are not typically studied in animals. Results obtained in research aimed to map the extinction circuit are largely dependent on the methods employed, not only across species, but also across human neuroimaging studies. Directions for future research are discussed. PMID- 29981424 TI - Theta oscillations underlie retrieval success effects in the nucleus accumbens and anterior thalamus: Evidence from human intracranial recordings. AB - Previous imaging studies independently highlighted the role of the anterior thalamus (ANT) and nucleus accumbens (NAcc) in successful memory retrieval. While these findings accord with theoretical models, the precise temporal, oscillatory and network dynamics as well as the interplay between the NAcc and ANT in successfully retrieving information from long-term memory are largely unknown. We addressed this issue by recording intracranial electroencephalography in human epilepsy patients from the NAcc (n = 5) and ANT (n = 4) during an old/new recognition test. Our findings demonstrate that differences in event-related potentials between correctly classified old (i.e., studied) and new (i.e., unstudied) images emerged in the NAcc and ANT already between 200 and 600 ms after stimulus onset. Moreover, time-frequency analyses revealed theta (4-8 Hz) power decreases for old compared to new items in the NAcc and the opposite effect in the ANT. Importantly, Granger causality analyses revealed a directional communication from ANT to NAcc suggesting that entrainment from ANT drives successful memory retrieval. Together, our findings show evidence for the notion that the NAcc and ANT receive memory signals, and that theta oscillations may serve as a mechanism to bind these distributed neural assemblies. PMID- 29981426 TI - Early-life sickness may predispose Siberian hamsters to behavioral changes following alterations of the gut microbiome in adulthood. AB - Although it is well-established that the immune system plays an important role in the development of physiology and behavior, the gut microbiome has recently become of interest in the study of developmental origins of behavior. Studies suggest that the effects of early-life immune activation may not occur until a secondary stressor is introduced, though the precise nature and timing of the stressor may be critical in the response. Further, recent work suggests that the microbiome and the immune system develop in parallel, and therefore any perturbations to one of these systems early in life will likely affect the other. Here, we sought to determine whether early-life activation of the immune system had long-term consequences on how the gut microbiome responds to antibiotic treatment in adulthood and whether those changes influence adult same-sex social behavior. In order to test the hypothesis that an early-life immune challenge makes individuals more vulnerable to the effects of antibiotics, we mimicked an early-life infection by injecting pups at postnatal day 3 and 5 with lipopolysaccharide (LPS; cell wall component of gram-negative bacteria) or saline, and subsequently exposed the same animals to antibiotic treatment (known to influence microbial community composition and behavior) or water in adulthood. We tracked physiology across development, and paired males and females with a novel individual of the same age and sex in adulthood to score same-sex behavior (e.g., aggression, investigation, grooming) before antibiotic treatment, immediately following treatment, and after recovery from antibiotics. LPS-treated females exhibited impaired reproductive physiology and function in adulthood (e.g., smaller ovaries and abnormal estrous cycles), and female and male gut microbial communities were strongly affected by antibiotic treatment in adulthood, but only slightly affected by postnatal LPS alone. Interestingly, LPS treated males exhibited more robust changes in their behavioral response following adult antibiotic treatment, including decreased investigation and increased grooming, suggestive of changes in anxiety-like behaviors. These data suggest that males may be more vulnerable than females to behavioral abnormalities after being predisposed to an immune challenge early in life. Collectively, these results provide novel evidence that some of the sex-specific behavioral consequences of an early-life immune challenge may not transpire until an individual is faced with a secondary challenge, and the context in which an individual is exposed can greatly influence the response. PMID- 29981425 TI - Ca2+-activated K+ channels modulate microglia affecting motor neuron survival in hSOD1G93A mice. AB - Recent studies described a critical role for microglia in amyotrophic lateral sclerosis (ALS), where these CNS-resident immune cells participate in the establishment of an inflammatory microenvironment that contributes to motor neuron degeneration. Understanding the mechanisms leading to microglia activation in ALS could help to identify specific molecular pathways which could be targeted to reduce or delay motor neuron degeneration and muscle paralysis in patients. The intermediate-conductance calcium-activated potassium channel KCa3.1 has been reported to modulate the "pro-inflammatory" phenotype of microglia in different pathological conditions. We here investigated the effects of blocking KCa3.1 activity in the hSOD1G93AALS mouse model, which recapitulates many features of the human disease. We report that treatment of hSOD1G93A mice with a selective KCa3.1 inhibitor, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), attenuates the "pro-inflammatory" phenotype of microglia in the spinal cord, reduces motor neuron death, delays onset of muscle weakness, and increases survival. Specifically, inhibition of KCa3.1 channels slowed muscle denervation, decreased the expression of the fetal acetylcholine receptor gamma subunit and reduced neuromuscular junction damage. Taken together, these results demonstrate a key role for KCa3.1 in driving a pro-inflammatory microglia phenotype in ALS. PMID- 29981427 TI - The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis. AB - BACKGROUND & AIMS: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. METHODS: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes. Gene expression patterns in response to glucagon and FXR agonists were characterized by quantitative reverse transcription PCR and microarray analysis. FXR phosphorylation by protein kinase A was determined by mass spectrometry. The interaction of FOXA2 with FXR was identified by cistromic approaches and in vitro protein-protein interaction assays. The functional impact of the crosstalk between FXR, the PKA and FOXA2 signaling pathways was assessed by site-directed mutagenesis, transactivation assays and restoration of FXR expression in FXR-deficient hepatocytes in which gene expression and glucose production were assessed. RESULTS: FXR positively regulates hepatic glucose production through two regulatory arms, the first one involving protein kinase A-mediated phosphorylation of FXR, which allowed for the synergistic activation of gluconeogenic genes by glucagon, agonist-activated FXR and CREB. The second arm involves the inhibition of FXR's ability to induce the anti-gluconeogenic nuclear receptor SHP by the glucagon-activated FOXA2 transcription factor, which physically interacts with FXR. Additionally, knockdown of Foxa2 did not alter glucagon-induced and FXR agonist enhanced expression of gluconeogenic genes, suggesting that the PKA and FOXA2 pathways regulate distinct subsets of FXR responsive genes. CONCLUSIONS: Thus, hepatic glucose production is regulated during physiological fasting by FXR, which integrates the glucagon/cAMP signal and the FOXA2 signal, by being post translationally modified, and by engaging in protein-protein interactions, respectively. LAY SUMMARY: Activation of the nuclear bile acid receptor FXR regulates gene expression networks, controlling lipid, cholesterol and glucose metabolism, which are mostly effective after eating. Whether FXR exerts critical functions during fasting is unknown. The results of this study show that FXR transcriptional activity is regulated by the glucagon/protein kinase A and the FOXA2 signaling pathways, which act on FXR through phosphorylation and protein protein interactions, respectively, to increase hepatic glucose synthesis. PMID- 29981428 TI - Urea cycle dysregulation in non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: In non-alcoholic steatohepatitis (NASH), the function of urea cycle enzymes (UCEs) may be affected, resulting in hyperammonemia and the risk of disease progression. We aimed to determine whether the expression and function of UCEs are altered in an animal model of NASH and in patients with non-alcoholic fatty liver disease (NAFLD), and whether this process is reversible. METHODS: Rats were first fed a high-fat, high-cholesterol diet for 10 months to induce NASH, before being switched onto a normal chow diet to recover. In humans, we obtained liver biopsies from 20 patients with steatosis and 15 with NASH. Primary rat hepatocytes were isolated and cultured with free fatty acids. We measured the gene and protein expression of ornithine transcarbamylase (OTC) and carbamoylphosphate synthetase (CPS1), as well as OTC activity, and ammonia concentrations. Moreover, we assessed the promoter methylation status of OTC and CPS1 in rats, humans and steatotic hepatocytes. RESULTS: In NASH animals, gene and protein expression of OTC and CPS1, and the activity of OTC, were reversibly reduced. Hypermethylation of Otc promoter genes was also observed. Additionally, in patients with NAFLD, OTC enzyme concentration and activity were reduced and ammonia concentrations were increased, which was further exacerbated in those with NASH. Furthermore, OTC and CPS1 promoter regions were hypermethylated. In primary hepatocytes, induction of steatosis was associated with Otc promoter hypermethylation, a reduction in the gene expression of Otc and Cps1, and an increase in ammonia concentration in the supernatant. CONCLUSION: NASH is associated with a reduction in the gene and protein expression, and activity, of UCEs. This results in hyperammonemia, possibly through hypermethylation of UCE genes and impairment of urea synthesis. Our investigations are the first to describe a link between NASH, the function of UCEs, and hyperammonemia, providing a novel therapeutic target. LAY SUMMARY: In patients with fatty liver disease, the enzymes that convert nitrogen waste into urea may be affected, leading to the accumulation of ammonia, which is toxic. This accumulation of ammonia can lead to scar tissue development, increasing the risk of disease progression. In this study, we show that fat accumulation in the liver produces a reversible reduction in the function of the enzymes that are involved in detoxification of ammonia. These data provide potential new targets for the treatment of fatty liver disease. PMID- 29981429 TI - Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. AB - Epithelial cell adhesion molecule (EpCAM) is highly expressed in colon cancers, but its role in cancer progression remains to be elucidated. In this work, we found that the extracellular domain of EpCAM (EpEX) activated EGFR and downstream ERK1/2 signaling to promote colon cancer cell migration and proliferation, as well as tumor growth. Mechanistically, we discovered that EpEX-EGFR-ERK1/2 signaling positively regulated intramembrane proteolysis (RIP) of EpCAM and shedding of the intracellular domain (EpICD). Treatment with an EGFR inhibitor ablated the EpEX-induced phosphorylation of ERK1/2 and AKT. Additionally, treatment with inhibitors of either EGFR or MEK decreased EpEX-induced EpICD shedding and further revealed that EpICD is necessary for nuclear accumulation of beta-catenin and the induction of HIF1alpha target gene expression in vitro and in vivo. Moreover, an anti-EpCAM neutralizing monoclonal antibody, EpAb2-6, inhibited the nuclear translocation of EpICD and beta-catenin and induced apoptosis in colon cancer cells. Importantly, analysis of colorectal cancer tissues showed that nuclear accumulation of EpICD was highly correlated with metastasis and poor prognosis, suggesting that it may play an important functional role in cancer progression. Thus, we provide novel insights into the mechanisms and functions of EpEX-mediated signaling, which may be considered as a promising target for the treatment of colon cancer. PMID- 29981430 TI - USP22 promotes resistance to EGFR-TKIs by preventing ubiquitination-mediated EGFR degradation in EGFR-mutant lung adenocarcinoma. AB - As a newly discovered deubiquitinating enzyme, ubiquitin-specific protease 22 (USP22) is predictive of therapeutic outcomes in individual cancer patients. However, its clinical effects on malignancy and its roles in conferring resistance to EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) in lung adenocarcinoma (ADC) remain largely unknown. Here, we showed that USP22 promotes cell proliferation, migration and invasion, and contributes to resistance to EGFR-TKIs in EGFR mutant lung ADC cells. Mechanistically, USP22 deubiquitinates EGFR localized on late endosomes, prevents ubiquitination mediated EGFR degradation and enhances recycling of EGFR after EGF stimulation. Additionally, USP22 sustained the activation of multiple EGFR downstream signaling pathways, including STAT3, AKT/mTOR and MEK/ERK pathways, in lung ADC cell lines H1975 and PC9. Furthermore, USP22 stabilizes EGFR protein expression, which correlates with USP22 expression in EGFR-mutant lung ADC patient samples. We are the first to demonstrate that silencing USP22 counteracts EGFR-TKIs resistance both in vitro and in vivo. We propose USP22 as a potential therapeutic target for EGFR-TKIs-resistant lung ADC. PMID- 29981431 TI - Tumor necrosis factor-alpha promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells. AB - Hepatocellular carcinoma (HCC) is an inflammation-related disease. Tumor necrosis factor alpha (TNF-alpha) is an important inflammatory factor and it has been confirmed to promote tumor growth and poor prognosis of HCC. Hepatic progenitor cells (HPCs) are thought to play an important role in liver injury and repair, as well as tumorigenesis. Chronic inflammation influences HPCs activation as well as differentiation. However, the mechanism is still unclear. In our study, the rat liver cancer model was constructed by DEN treatment, TNFR2-Fc fusion protein variant (TNFR2-FcV) and TNF-alpha-/- rats were used to detect the role of TNF alpha in liver injury and tumorigenesis. And the effect of TNF-alpha on HPCs activation and proliferation was investigated, and the specific molecular mechanism was explored. We found that TNF-alpha inhibition and deletion could reduce tumor incidence but shorten survival time by increasing apoptosis and decreasing proliferation of hepatocytes. Further analysis indicated that TNF alpha knochdown cloud inhibit HPCs activation and proliferation through TNFR2/STAT3 signaling pathway. And clinically TNF-alpha expression was correlated to HPCs activation and HCC recurrences. Our work suggested that TNF-alpha played a key role in liver injury and tumorigenesis. PMID- 29981432 TI - Arbutus unedo L.: From traditional medicine to potential uses in modern pharmacotherapy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Arbutus unedo L., the strawberry tree (Ericaceae family) is of increasing interest because of its common traditional, industrial, chemical and pharmaceutical uses. The plant is a typical evergreen plant of the Mediterranean basin, as well as of other regions with hot summers and mild rainy winters. This review covers the studies relevant to Arbutus unedo L. utilization in the current pharmacological therapy. MATERIALS AND METHODS: The available information on traditional uses, phytochemistry and biological activities of Arbutus unedo L. was collected from scientific databases through a search using the keywords 'Arbutus unedo L.' and/or 'strawberry tree' in 'Google Scholar', 'Pubmed', 'Sciencedirect', 'SpringerLink', 'Web of Science - Clarivate Analytics' and 'Wiley'. Unpublished Ph.D. and M.Sc. dissertations were also consulted for chemical composition, biological activities and traditional uses of Arbutus unedo L. and for manual search of additional references. RESULTS: The fruits of the plant have been traditionally used as antiseptics, diuretics and laxatives in folk medicine, while the leaves have been used due to their diuretic, urinary antiseptic, antidiarrheal, astringent, depurative and antihypertensive properties. According to the scientific literature survey, different extracts obtained from Arbutus unedo L. have demonstrated a high pharmacological potential due to their in vitro and preclinical antibiotic, antifungal, antiparasitic, antiaggregant, antidiabetic, antihypertensive, anti-inflammatory, antitumoral, antioxidant, and spasmolytic properties. CONCLUSION: This review suggests that A. unedo is a promising source of phytopharmaceutical products. The potential advantages of Arbutus unedo are related with the presence of polyphenolic compounds in its composition. However, further studies are needed to ascertain some profitable effects in humans. The beneficial effects associated with this shrub suggest that Arbutus unedo can be used for the development of new drugs to treat diseases such diabetes, hypertension, among others. Nonetheless, the safety of the Arbutus unedo compounds should also be examined. PMID- 29981434 TI - Colonic Mass in a Patient With Coagulopathy. PMID- 29981433 TI - Ilex asprella aqueous extracts exert in vivo anti-inflammatory effects by regulating the NF-kappaB, JAK2/STAT3, and MAPK signaling pathways. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ilex asprella (Hook. et Arn.) Champ. ex Benth. (IA) is a representative medicinal plant from the South of the Five Ridges of China. Its roots (RIA) and stems (SIA) have been traditionally used for the inflammation-related diseases, such as acute and chronic pharyngitis, cough, and sore throats. AIM OF THE STUDY: To evaluate the in vivo anti-inflammatory effects of IA extracts to provide evidence for its traditional use and to enhance the knowledge of the medicinal properties of IA. MATERIALS AND METHODS: Models of xylene-induced ear edema in mice and carrageenan-induced paw edema in rats were used for the pharmacological evaluations. The mice were randomly divided into eight groups (n = 10 per group): a model group, a positive control group [dexamethasone (Dex), 10 mg/kg, intragastrically (i.g.)], RIA aqueous extract groups with three dosages (30, 15, and 7.5 mg/kg, i.g.), and SIA aqueous extract groups with three dosages (60, 30, and 15 mg/kg, i.g.). The rats were randomly divided into eight groups (n = 6 per group): a model group, a positive control group [acetylsalicylic acid (ASA), 300 mg/kg, i.g.], RIA groups with three dosages (80, 40, and 20 mg/kg, i.g.) and SIA aqueous extract groups with three dosages (160, 80, and 40 mg/kg, i.g.). Histological examinations of the ear and paw tissues were observed by hematoxylin-eosin (HE) staining, and neutrophil elastase levels were assessed in ear tissues by immunohistochemical analysis. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta) were measured by ELISAs, and expression levels of TNF-alpha, IL-6, and IL-1beta in rat paw tissues were measured by RT-PCR. The signal transduction proteins p65, IkappaBalpha, Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinases (p38), extracellular regulated protein kinases (ERK1/2), and c Jun N-terminal kinase (JNK) in the rat paw tissues were investigated by western blot analyses. RIA and SIA were characterized by HPLC and LC-MS analyses, and the components were confirmed by comparison with isolated compounds. RESULTS: Intragastric administration with RIA (30 mg/kg) and SIA (60, 30 mg/kg) significantly mitigated ear edema in mice. RIA administration at 80 and 40 mg/kg reduced paw edema in rats 2-3 h after injection. SIA administration with 160 mg/kg inhibited paw edema in rats after the injection of carrageenan for 1-4 h, and SIA administration at 80 mg/kg inhibited paw edema after the injection of carrageenan for 2-4 h. Meanwhile, RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced inflammatory cell infiltration in the ear and paw tissues and infiltration of neutrophil leukocytes in rat paw tissues. RIA (80, 40, and 20 mg/kg) and SIA (160, 80, and 40 mg/kg) notably inhibited the increases of TNF alpha, IL-6 and IL-1beta in the serum and mRNA expression in the rat paw tissues. RIA (80, 40 mg/kg) and SIA (160, 80 mg/kg) reduced the p-p65/p-IkappaBalpha, p JAK2/p-STAT3, and p-p38/p-ERK1/2/p-JNK levels in the pathological tissues of the animals. Phenolic acids and triterpenoids likely contributed to the anti inflammatory activity. CONCLUSIONS: Both RIA and SIA aqueous extracts showed anti inflammatory effects in vivo in a dose-independent manner (20-80 and 40-160 mg/kg, respectively). The underlying mechanisms are mediated by inhibiting the pro-inflammatory cytokines TNF-alpha, IL-6, and IL-1beta via regulation of the NF kappaB, JAK2/STAT3, and MAPK signaling pathways. The present results provided pharmacological evidence that stems are alternative medicinal parts of IA but function at different doses. Additionally, this study supports the use of IA as an anti-inflammatory herbal medicine. PMID- 29981435 TI - Calcifying Fibrous Tumor of Small Bowel Causing Intussusception. PMID- 29981436 TI - Microscopic Colitis: A Rare Cause of Pseudomembranes. PMID- 29981437 TI - Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer. AB - BACKGROUND: Genome-wide association studies are widely used to map genomic regions contributing to lung cancer (LC) susceptibility, but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited genetic variants that cause LC, we performed focused exome-sequencing analyses on genes located in 121 genome-wide association study-identified loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level, and smoking behavior. METHODS: Germline DNA from 260 case patients with LC and 318 controls were sequenced by utilizing VCRome 2.1 exome capture. Filtering was based on enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single-variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1773 case patients and 1123 controls. RESULTS: We identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant, namely, BRCA2, DNA repair associated gene (BRCA2) K3326X (OR = 2.36, 95% confidence interval [CI]: 1.38-3.99), and three newly identified variations, namely, lymphotoxin beta gene (LTB) p.Leu87Phe (OR = 7.52, 95% CI: 1.01-16.56), prolyl 3-hydroxylase 2 gene (P3H2) p.Gln185His (OR = 5.39, 95% CI: 0.75-15.43), and dishevelled associated activator of morphogenesis 2 gene (DAAM2) p.Asp762Gly (OR = 0.25, 95% CI: 0.10-0.79). Burden tests revealed strong associations between zinc finger protein 93 gene (ZNF93), DAAM2, bromodomain containing 9 gene (BRD9), and the gene LTB and LC susceptibility. CONCLUSION: Our results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility. PMID- 29981439 TI - Very early introduction of semisolid foods in preterm infants does not increase food allergies or atopic dermatitis. AB - BACKGROUND: The optimal age for the introduction of solid foods for infants has long been a controversial issue. OBJECTIVE: To determine whether the early introduction of semisolid foods influences the incidence of food allergy or atopic dermatitis among preterm infants. METHODS: Retrospective data from 464 preterm infants born in Oulu University Hospital between 2008 and 2012 were analyzed. Age- and sex-matched full-term control children from the general population were identified. The primary outcome of the study was the difference in timing of the introduction of complementary feeding between preterm and full term infants. The secondary outcomes were the incidences of food allergies and atopic dermatitis by the ages of 1 and 2 years. RESULTS: Semisolid food was introduced at the median corrected age of 1.4 months for all preterm infants, at 1.9 months for late preterm, at 0.9 months for very preterm, and at 0.1 months for extremely preterm infants. The cumulative incidence, either of food allergies or of atopic dermatitis, did not differ significantly between preterm infants and controls by the ages of 1 and 2 years. CONCLUSION: The very early introduction of complementary foods into the diet of preterm babies did not increase the incidence of food allergies or atopic dermatitis even among the most preterm infants. This finding supports the hypothesis that the gut-associated lymphoid tissue of preterm infants is ready to encounter food proteins and to begin the maturation process within 3 to 6 months of birth, regardless of gestational age. PMID- 29981438 TI - Predictors of Physical and Functional Loss in Advanced-Stage Lung Cancer Patients Receiving Platinum Chemotherapy. AB - INTRODUCTION: Muscle wasting has detrimental effects, including increased mortality. Identifying patients at risk can guide treatment efforts. METHODS: POWER 1 and 2 were randomized, double-blind, placebo-controlled, multinational phase III trials that studied 600 patients with lung cancer at the start of chemotherapy; the studies' aim was to assess the efficacy of enobosarm on prevention and treatment of muscle loss. We performed a secondary analysis restricted to the control group, using a cumulative logit model for ordinal outcome to determine which baseline characteristics predicted physical and functional loss during chemotherapy. RESULTS: In all, 53% of patients had loss of lean body mass and 49% had loss of stair climb power (SCP) at day 84 of treatment. Of the 322 patients who received placebo, 232 with observable outcome and baseline covariates were included for lean body mass analysis and 236 for SCP analysis. More advanced disease predicted a higher probability of greater physical loss (OR = 1.96; 95% confidence interval [CI]: 1.14-3.36). Three factors predicted higher probability of SCP loss: taxane chemotherapy (OR = 1.73; 95% CI: 1.06-2.83), tobacco use before chemotherapy (OR = 2.15, 95% CI: 1.10-4.18), and SCP at baseline (OR = 1.01, 95% CI: 1.004-1.015). Higher body mass index was a protective factor for functional loss (OR = 0.85; 95% CI: 0.73-0.98). A higher Eastern Cooperative Oncology Group Performance Status trended toward being predictive of greater probability of both physical loss (0.767) and functional loss (0.070), but the results were not statistically significant. CONCLUSIONS: Approximately 50% of patients with advanced lung cancer who were undergoing chemotherapy had ongoing loss of muscle mass and muscle function. Advanced stage predicted physical loss. Tobacco use and taxane chemotherapy predicted functional loss. Body mass index was a protective factor for functional loss. We identified predictors of physical and functional loss that could be used as therapeutic targets or to guide treatment efforts. PMID- 29981440 TI - The effects of caregiver depression on childhood asthma: Pathways and mechanisms. AB - OBJECTIVE: To review the literature regarding the effects of caregiver depression on childhood asthma and integrate the findings into a multilevel model of pathways by which these effects occur to further the understanding of the complex biopsychosocial nature of childhood asthma and the key role that is played by caregiver depression. DATA SOURCES: PubMed was searched for articles published from 2007 to the present (10-year search), and Google Scholar was searched for articles published in 2017 and 2018 to identify the most recent publications. STUDY SELECTIONS: Studies selected were recent, empirical, or meta-analytic, conducted in humans, and had specific relevance to one or more of the identified pathways. Articles published before 2007 were included if deemed essential because they addressed key pathways, for which there were no more recent articles. RESULTS: Review of the literature substantiates that caregiver depression plays a key role in the socioeconomic, familial, psychological, and biological cascade of effects on childhood asthma. Childhood asthma outcomes are affected indirectly by socioeconomic status and family stress mediated by caregiver depression, which affects disease management, and/or stress and depression in the child, which, in turn, affect asthma through alterations in immune modulation and autonomic regulation. CONCLUSION: Findings indicate that future research should concentrate on mediators and moderators to further clarify the complex interplay of these factors that affect childhood asthma. The findings also have substantial translational implications. Given that child stress and depression contribute to asthma disease activity and that treating caregiver depression improves child stress and depression, there is strong rationale for treating depressed caregivers of children with asthma as a component means of improving childhood asthma control. PMID- 29981441 TI - Seasonal and regional variation of asthma-related hospitalizations and mortality among adults in the United States. PMID- 29981442 TI - Trends in the diagnosis and management of anaphylaxis in a tertiary care pediatric emergency department. AB - BACKGROUND: Underdiagnosis of anaphylaxis is a major concern in the pediatric emergency department (PED), leading to failure to administer and prescribe intramuscular epinephrine treatment. OBJECTIVE: To examine the clinical features, triggers, and management of anaphylaxis in the PED, with a special focus on the rate of cases diagnosed and treated correctly over time, and to compare correctly diagnosed and misdiagnosed cases. METHODS: All records of patients presenting to a tertiary care PED between 2013 and 2016 with a final diagnosis of anaphylaxis or allergic reaction were reviewed. RESULTS: The rate of anaphylaxis increased from 0.1% between 2013 and 2014 and 0.24% between 2015 and 2016. Symptoms such as breathing difficulties and wheezing were found significantly less among misdiagnosed patients compared with patients correctly diagnosed with anaphylaxis. Food was the most common causative agent in both of the study periods (88% in 2013-2014 and 91% in 2015-2016), with milk (20% in 2013-2014 and 28% in 2015-2016) and tree nuts (23.1% in 2013-2014 and 23.7% in 2015-2016 as the most prevalent identified triggers. Intramuscular epinephrine treatment in the prehospital and hospital settings and the automatic epinephrine injector prescription rate did not change significantly throughout the study. Referral to an allergist increased from 68% in 2013 to 2014 to 90% in 2015 to 2016. CONCLUSION: The rate of visits attributable to anaphylaxis in our PED doubled during the study period, with milk allergy as the most common trigger. Most cases of misdiagnosed and undertreated anaphylaxis had no respiratory signs and symptoms. Novel methods to improve recognition of anaphylaxis and adherence to treatment guidelines are needed. PMID- 29981443 TI - The role of nuclear matrix protein HNRNPU in maintaining the architecture of 3D genome. AB - The complexity of higher eukaryote genomes is far from being explained by linear information. There is a need to understand roles of genome regulation at the organism level through defining a comprehensive profile of chromosomal organization. Chromosome conformation capture (3C)-based studies reveal that higher-order of chromatin include not only long-range chromatin loops, but also compartments and topologically associating domains as the basis of genome structure and functions. However, the molecular machinery how the genome is spatially organized is still inadequate. Exciting progress has been made with the development of today's technology, we find that heterogeneous nuclear ribonucleoprotein U, initially identified as a structural nuclear protein, plays important role in three-dimensional (3D) genome organization by high-throughput assays. The disruption of this protein not only results in compartment switching on of the genome, it also reduces of TAD boundary strengths at borders between two types of compartments, and regulates chromatin loop by decrease its intensities. In addition, HNRNPU mainly binds to active chromatin. Most of HNRNPU peaks is consistent with CTCF or RAD21.It also plays an irreplaceable role in the processes of mitosis. This review aims to discuss the role of HNRNPU in maintaining the 3D chromatin architecture, as well as the recent development and human diseases involved in this nuclear matrix (NM)-associated protein. PMID- 29981444 TI - Solubilisation behaviour of poorly water-soluble drugs during digestion of solid SMEDDS. AB - Lipid based-formulations can enhance the bioavailability of poorly water-soluble lipophilic drugs through enhanced solubilisation of drugs in the gastrointestinal (GI) tract during digestion. This study investigates the solubilisation behaviour of poorly water-soluble drugs upon digestion of solid self-microemulsifying drug delivery system (S-SMEDDS). The S-SMEDDS were prepared using two different core lipids, Gelucire(r) 44/14 (GEL) or glyceryl monooleate (GMO), and were loaded with two model drugs, fenofibrate (FEN) and cinnarizine (CINN). S-SMEDDS formulations were characterized using wide-angle X-ray scattering (WAXS) and Raman spectroscopy, and their structural behaviour and drug solubilisation behaviour were monitored using drug-related diffraction peaks during digestion under fasted and fed simulated intestinal conditions using time-resolved small and wide-angle X-ray scattering (SAXS/WAXS). The concentrations of FEN and CINN released into the aqueous phase (AP) during digestion were quantified using high performance liquid chromatography (HPLC). Both model drugs, FEN and CINN, had greater solubility in the GMO-based S-SMEDDS formulations and were partially solubilised into lipid matrix and uniformly distributed in solid formulations. The extent of digestion was greater for the GEL-based systems (92-94%) than GMO based systems (65-75%) as was the rate of digestion. GEL-based S-SMEDDS formulations formed a lamellar phase during digestion in the fasted state and formed mixed micelles in the fed state. In contrast, the GMO-based system formed the mixed micelles in both intestinal conditions. The time-resolved SAXS profiles revealed solubilisation of crystalline drugs into the lipolysis products. Synchrotron SAXS results were in correlation with the HPLC measurements, confirming the ability of the SAXS technique to monitor drug behaviour and showing that the digestion of S-SMEDDS can enhance drug solubilisation. PMID- 29981445 TI - Features of the transglutaminase-activating metalloprotease from Streptomyces mobaraensis DSM 40847 produced in Escherichia coli. AB - Transglutaminase from Streptomyces mobaraensis (MTG) is an important enzyme for numerous industrial applications. Recombinant production requires proteolytic activation of the zymogen. The study provides a convenient procedure for the preparation of the transglutaminase-activating metalloprotease (TAMP) in Escherichia coli. In contrast to wtTAMP, rTAMP exhibited the P domain of convertases as molecular mass of 55.7 kDa suggested. Protein integrity was beneficially influenced by 2-5 mM CaCl2. Study of pH and temperature optima assigned rTAMP to the neutral metalloproteases, more heat-resistant than Dispase but not thermolysin. Zinc had no inhibiting effect but 3.1 MUM EDTA completely reduced activity of 5 nM TAMP. MTG, exceeding concentration of rTAMP by three orders of magnitude, was largely activated within few minutes. The kinetic parameters KM (1.31 +/- 0.05 mM) and kcat (135 +/- 4.3 s-1), monitored by isothermal titration calorimetry (ITC), further highlighted catalytic efficiency (103,053 M-1 s-1) of rTAMP and rapid processing of MTG. ITC even revealed that inhibition of rTAMP by its intrinsic inhibitory protein SSTI was an enthalpy driven process resulting in Kd of 199 +/- 37.9 nM. The production procedure of rTAMP in E. coli closes the gap between production and application of recombinant MTG and may enhance relevance of MTG-mediated reactions in pharmaceutical processes. PMID- 29981447 TI - Enhanced overexpression, purification of a channelrhodopsin and a fluorescent flux assay for its functional characterization. AB - Channelrhodopsins (ChRs) are a group of membrane proteins that allow cation flux across the cellular membrane when stimulated by light. They have been emerged as important tools in optogenetics where light is used to trigger a change in the membrane potential of live cells which induces downstream physiological cascades. There is also increased interest in their applications for generating light responsive biomaterials. Here we have used a two-step screening protocol to develop a Pichia pastoris strain that produces superior yields of an enhance variant of CaChR2 (from Chlamydomonas reinhardtii), called ChIEF. We have also studied the effect of the co-factor, namely all-trans retinal (ATR), on the recombinant overexpression, folding, and function of the protein. We found that both ChIEF-mCitrine and CaChR2 can be overexpressed and properly trafficked to the plasma membrane in yeast regardless of the presence of the ATR. The purified protein was reconstituted into large unilamellar lipid vesicle using the detergent-assisted method. Using 9-amino-6-chloro-2-methoxyacridine (ACMA) as the fluorescent proton indicator, we have developed a flux assay to verify the light activated proton flux in the ChIEF-mCitrine vesicles. Hence such vesicles are effectively light-responsive nano-compartments. The results presented in this work lays foundations for creating bio-mimetic materials with a light-responsive function using channelrhodopsins. PMID- 29981446 TI - Crosslinked enzyme aggregates (CLEA) of phytase with soymilk proteins. AB - Crosslinked Enzyme Aggregates (CLEA) of phytase (E.C. 3.1.3.8) have been successfully prepared using soymilk as protein feeder. Compared to total initial activity of 4428 units used for immobilization, the recovered activity in the CLEA is enhanced to 8000 units. The CLEA retained 100% phytase activity up to 50 degrees C and 70% activity at 70 degrees C after 6 h incubation while soluble enzyme lost 50% activity at 50 degrees C and 80% at 70 degrees C. Soluble phytase has an optimum pH of 2.1 while immobilized enzyme maintains high level of activity in a broad pH range of 1-6. CLEA also retain 80% activity upon proteolytic hydrolysis with pepsin, pancreatin, trypsin and chymotrypsin, while soluble enzyme loses 40% activity under same conditions. Phytase CLEA were recycled for 5 times without loss in activity using a stirred basket reactor. PMID- 29981448 TI - A multifunctional tag with the ability to benefit the expression, purification, thermostability and activity of recombinant proteins. AB - In this study, a novel multifunctional tag, S1v1 (AEAEAHAH)2, was generated from a self-assembling amphipathic peptide in the Zuotin protein sequence by replacing lysine residues with histidine residues. After fusing S1v1 at the N-terminus through a PT-linker, the expressions of polygalacturonate lyase (PGL), lipoxygenase (LOX) and green fluorescent protein (GFP) were enhanced by 3.8, 0.2 and 1.52-fold, respectively,compared to the wild-type proteins. However, the frequently used His-tag with a PT-linker had negligible effects on expression. Moreover, the three S1v1 fusions were purified with high purities and acceptable recovery rates due to their affinity to the nickel column. In contrast, PGL and LOX fused with His-tag were unable to be adsorbed by the nickel column, and His tag fusion only achieved 8.23% of GFP recovery in the same purification process.In addition, S1v1 fusions induced the enhancement of thermostabilties and/or activities of PGL, LOX and GFP. These results indicated that S1v1 was much more effective than the frequently used His-tag during protein expression and purification in these cases, and will be especially suitable for those proteins requiring the simultaneous enhancement of expression, production and catalytic properties. PMID- 29981449 TI - Enzymatic characterization of a soluble aggregate induced by N-terminal extension to a lipolytic enzyme. AB - A self-assembling peptide (27PEP) was isolated from an open reading frame (ORF). The ORF consisted of an unknown functional domain and a catalytic (lipolytic and phospholipolytic) domain (MPlaG) on metagenomic fosmid clone. This extension of 27 amino acids prior to the N-terminus of the catalytic domain (27PEP-MPlaG), starting at Met261, produced an aggregate of high molecular weight (> 700 kDa). Compared with MPlaG, 27PEP-MPlaG showed the same temperature and pH effect for maximum activity but was stable in the presence of inhibitors such as EDTA and PMSF. The 27PEP-MPlaG exhibited lower specific activity than that of MPlaG, but when pre-incubated for 30 min at temperatures between 4 and 100 degrees C, its activity increased at temperatures greater than 40 degrees C under alkaline conditions and eventually reached the specific activity level of MPlaG at 60 degrees C. We experimentally determined that the aggregate caused by 27PEP was dissociated at elevated temperatures resulting in an active catalytic monomer. The 27PEP-indued aggregation may be attractive as application tool for improving or engineering of biocatalysts and biomaterials. PMID- 29981450 TI - Characterization of a new microbial Pictet-Spenglerase NscbB affording the beta carboline skeletons from Nocardiopsis synnemataformans DSM 44143. AB - The enzymatic Pictet-Spengler (PS) reaction, catalyzed by Pictet-Spenglerase (PSase), is the feature of beta-carboline (betaC) alkaloid biosynthesis. NscbB is a rare microbial PSase discovered from a cryptic beta-carboline alkaloid biosynthetic gene cluster (BGC) in the Nocardiopsis synnemataformans DSM 44143 (kidney transplant patient derived) by homologous alignment with its well characterized counterpart McbB. The biochemical analysis showed that NscbB could catalyze l-tryptophan (KM = 89.64 +/- 8.69 MUM) and methylglyoxal (KM = 147.70 +/ 16.38 MUM), without cofactors, to form the two betaC skeletons 1-acetyl-3 carboxy-beta-carboline and 1-acetyl-beta-carboline in vitro. Additionally, the heterologous expression of nscbB in E. coli BL21 (DE3) revealed the efficient bioproductivity of NscbB to bioproduce two betaC skeletons, 1-acetyl-3-carboxy beta-carboline (5.5 mg/L) and 1-acetyl-beta-carboline (3.1 mg/L), within 16 h fermentation. These results demonstrate NscbB is a novel and practical microbial PSase, which is useful for future bioactive betaC alkaloid exploitation and development. PMID- 29981452 TI - Molecular and functional analysis of PmCHST1b in nacre formation of Pinctada fucata martensii. AB - Keratan sulfate possesses considerable amounts of negatively charged sulfonic acid groups and participates in biomineralization. In the present study, we investigated characteristics and functions of a CHST1 gene identified from the pearl oyster Pinctada fucata martensii (PmCHST1b) which participated in the synthesis of keratan sulfate. PmCHST1b amino acid sequence carried a typical sulfotransferase-3 domain (sulfotransfer-3 domain) and belonged to membrane associated sulfotransferases. Homologous analysis of CHST1 from different species showed the conserved motif (5' PSB motif and 3' PB motif) which interacted with 3'-phosphoadenosine-5'-phosphosulfate (PAPS). Structure analysis of sulfotransferase domain indicted that PmCHST1b showed the conserved catalytic structure character and the relationships presented in the phylogenetic tree conformed to that of traditional taxonomy. Expression pattern of PmCHST1b in different tissues and development stages showed that PmCHST1b widely expressed in all the detected tissues and development stages and showed the highest expression level in the central zone of mantle (MC). PmCHST1b expressed highly in the trochophore, D-stage larvae and spat which corresponded to prodissoconch and dissoconch shell formation, respectively. RNA interference (RNAi) successfully inhibited expression level of PmCHST1b in MC (P<0.05), and sulfate polymer content in the extrapallial fluid significantly reduced (P<0.05). Crystallization of shell nacre became irregular. Results above indicated that PmCHST1b may affect nacre formation by participating in synthesis of keratan sulfate in extrapallial fluid. This study provided fundamental materials for further research on the role of sulfotransferases and keratan sulfate in nacre formation. PMID- 29981451 TI - Characterization of transforming growth factor beta regulator 1-like and association between its expression levels and growth of the giant tiger shrimp Penaeus monodon. AB - Molecular markers that allow selection of juveniles and broodstock with improved growth performances are useful for the shrimp industry. Here, the full-length cDNA of transforming growth factor beta regulator 1-like (PmTbrg1-l) in the giant tiger shrimp Penaeus monodon was determined. It was 1184 bp in length and contained an open reading frame (ORF) of 975 bp corresponding to a deduced polypeptide of 324 amino acids. Successful RNA interference (RNAi) carried out using juveniles injected with PmTbrg1-l dsRNA revealed reduced levels of PmTbrg1 l and myostatin (PmMstm) in hemocytes when compared to shrimp injected with saline solution and GFP dsRNA (P < .05). Associations between single-strand conformational polymorphism (SSCP) patterns or single nucleotide polymorphism (SNP) patterns and growth-related parameters (average body weight and total length) were examined. Juveniles with pattern III (corresponding to A/A918; N = 37) showed a trend for greater average body weight and total length than those with patterns II (G/G918; N = 42) and IV (A/G918; N = 75). The expression level of PmTbrg1-l in the hepatopancreas of females was significantly higher than that in males (P < .05) in two sample sets of three-month-old domesticated juveniles (N = 59 and 50; P < .05). Moreover, its expression level in large-size juveniles was significantly higher than that in medium-size and small-size juveniles in both groups of samples (P < .05). Results indicated that PmTbrg1-l is functionally related with growth of P. monodon. PMID- 29981453 TI - Identification and expression of cathepsin B from the freshwater mussel Cristaria plicata. AB - Cathepsin B plays crucial roles in host immune defense against pathogen infection. In present study, a cathepsin B gene from the freshwater mussel, Cristaria plicata (CpCathB) was cloned and characterized. The full-length cDNA of CpCathB was 1825 bp, and contained a 5' untranslated region (UTR) of 36 nucleotides, an open reading frame (ORF) of 1044 bp and a 3' UTR of 745 bp with a poly (A) tail. The deduced CpCathB protein was encoded as a preproenzyme with 347 amino acid residues and predicted molecular weight of 38.55 kDa. Sequence alignment revealed that CpCathB protein shared 56% - 60.7% identity comparison with other species. The predicted tertiary structure of CpCathB protein was highly similar to that of human. The CpCathB mRNA was expressed in hemocytes, hepatopancreas, adductor muscle, gills and mantle tissues of healthy mussels, and the highest expression level was in hepatopancreas. The transcripts of CpCathB were increased in hemocytes and hepatopancreas from mussels after Aeromonas hydrophila challenge. Moreover, the recombinant CpCathB was expressed in the Escherichia coli Rosetta-gami (DE3) strain. The maximum titer of the anti-CpCathB polyclonal antibodies was 1:640,000.The CpCathB protein had a higher expression in hepatopancreas and mantle and a lower level in hemocytes. PMID- 29981455 TI - Prevalence of vancomycin-intermediate Staphylococcus aureus among clinical isolates in Iran: A systematic review and meta-analysis. AB - OBJECTIVES: Vancomycin-intermediate Staphylococcus aureus (VISA) strains have been reported in many countries around the world and their prevalence is increasing. The incidence of these strains in Iran has been reported in some studies, however there is no overall estimation of the VISA incidence in Iran. The objective of this systematic review was to estimate the total prevalence of VISA strains reported from Iran. METHODS: A systematic literature review of relevant articles published on 'S. aureus isolates with intermediate resistance to vancomycin in Iran' was performed in PubMed and Scopus databases in the period 2010-2017. RESULTS: From 335 records found in the electronic search, 40 related studies were included in the current analysis. This systematic review indicated that the overall prevalence rate of VISA was 0.09% [95% confidence interval (CI) 0.00-0.20] in Iran in 2010-2017. In the classification of VISA based on location, the highest frequency was in Mazandaran Province at 8.36% (95% CI 0.00-18.49%). The most prevalent VISA genotypes in Iran were staphylococcal cassette chromosome mec (SCCmec) type III, accessory gene regulator (agr) group II, sequence type 22 (ST22) and staphylococcal protein A (spa) type t790. CONCLUSIONS: Regarding the upward trend in the incidence of VISA strains in Iran and the importance of preventing VISA in public health, it is recommended to control nosocomial infections and to be cautious in the use of vancomycin. PMID- 29981454 TI - Whole-genome sequencing of a CTX-M-11-encoding and quinolone-non-susceptible Klebsiella pneumoniae ST194 isolate from a hospitalised dog in Greece. AB - OBJECTIVES: The emergence and spread of transferable beta-lactamases among Enterobacteriaceae is a major problem both to human and veterinary medicine and is an important contributing factor to the development of multidrug-resistant bacterial isolates. In the present study, whole-genome sequencing of a Klebsiella pneumoniae isolate (LKP817909) resistant to first- and second-generation cephalosporins and non-susceptible to fluoroquinolones, isolated from a urine sample of a hospitalised dog, was performed. METHODS: Genome sequencing was performed on an Illumina MiniSeq Sequencing System. Multilocus sequence typing (MLST) was performed using a BLAST-based approach, whereas antimicrobial resistance genes and plasmid replicons were identified by ResFinder and PlasmidFinder, respectively. The Rapid Annotation using Subsystem Technology (RAST) server v.2.0 was used for genome annotation. RESULTS: Data analyses revealed the complete resistome of isolate LKP817909, which included the cefotaximase-Munchen-11 (CTX-M-11) extended-spectrum beta-lactamase together with 11 other resistance genes. Ten resistance genes were located on plasmids and two on the chromosome. CONCLUSIONS: To the best of our knowledge, this is the first detection of a CTX-M-11-producing K. pneumoniae isolated from a canine. The whole genome sequence of the isolate has been deposited at GenBank to serve as a future reference. PMID- 29981456 TI - Outbreak of hypervirulent Klebsiella pneumoniae harbouring blaVIM-2 among mechanically-ventilated drug-poisoning patients with high mortality rate in Iran. AB - OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae infections are associated with increased rates of treatment failure and death. Several studies have reported isolates with a combined hypervirulent and antimicrobial-resistant phenotype. METHODS: In this study, the molecular characteristics of hypervirulent K. pneumoniae (hvKP) isolated from mechanically-ventilated patients admitted to a toxicological intensive care unit (ICU) in Tehran, Iran, were examined. String test, antimicrobial susceptibility testing, virulence factors analysis and plasmid replicon typing were performed. The clonal relatedness of the isolates was analysed by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). RESULTS: hvKP accounted for 9.4% (5/53) of K. pneumoniae isolated from ventilator-associated pneumonia among patients admitted to the ICU with acute drug poisoning. The mortality rate was 7.5% (4/53) among K. pneumoniae infected patients. All fatal K. pneumoniae were hvKP isolates, were resistant to imipenem and harboured an aacA7, blaVIM-2 and dhfrI cassette arrangement in a class 1 integron. The isolates were shown to be ST23 (Pasteur scheme) and exhibited similar PFGE patterns. Plasmid analysis revealed a class 1 integron harbouring blaVIM-2 located on an ca. 45-kb IncN plasmid. CONCLUSION: Here we describe the emergence of VIM-2-producing hvKP serotype K1/ST23 in an outbreak with high mortality in a hospital toxicological ICU. It appears that we must alert and prepare the hospital's surveillance system for the appearance, expansion and clinical importance of new K. pneumoniae clones associated with high antimicrobial resistance and robust virulence capabilities. PMID- 29981457 TI - Microbial keratitis in Stevens-Johnson syndrome: Clinical and microbiological profile. AB - PURPOSE: To study the clinical and microbiological profile of microbial keratitis in Stevens-Johnson syndrome (SJS). STUDY DESIGN: Case series. PARTICIPANTS: Patients with SJS who developed microbial keratitis. METHODS: Medical records and microbiological data of patients with SJS who developed microbial keratitis from January 1991 to December 2012 were reviewed. We analysed the type of causative organisms and their antibiotic susceptibility along with the clinical pattern and responses to medications in this group of patients. MAIN OUTCOME MEASURE: Clinical and microbiological profile of microbial keratitis. RESULTS: We reviewed 65 eyes of 60 patients seen between January 1991 and December 2012. Positive microbiological culture results were obtained in 45 eyes (69.2%). Isolated bacterial infections were noted in 27 eyes (60%) while isolated fungal growth was seen in 1/45 eyes (2.2%). Polymicrobial infections were noted in 17/45 eyes (37.8%). The most common bacteria isolated were Staphylococcus species (35%). The median duration of SJS before presentation was 5 months (IQR, 2 months to 7 years) with 50% presenting within four months of the onset of SJS. Twenty-eight eyes (43%) needed treatment in addition to antibiotics for resolution of tarsorraphy, epilation, tissue adhesive application, and amniotic membrane grafting or punctal cautery. The average time for resolution was 25 days. CONCLUSION: Microbial keratitis in SJS patients is different from patients without SJS in presentation and the response to medications. It requires a multi disciplinary approach for healing. PMID- 29981458 TI - Hair analysis to monitor adherence to prescribed chronic inhaler drug therapy in patients with asthma or COPD. AB - BACKGROUND: Poor adherence to inhaled drug therapy in individuals with asthma and/or chronic obstructive pulmonary disease (COPD) may be associated with suboptimal therapeutic outcomes. Measurement of drug residues in hair samples has been employed to assess oral medication use over time. Here, we test the feasibility of analyzing hair samples from patients with asthma and/or COPD for assessing adherence to prescribed inhaled medication. METHODS: In total, 200 male and female subjects, >= 18 years of age, with stable asthma and/or COPD who were receiving an acceptable standard of care daily inhaled product consistently, were recruited. Head hair samples were taken during a single visit to the clinical site and grouped by hair color according to the Fischer-Saller scale. Drug residues were extracted from milled hair samples using solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Inhaled drugs were detected in hair for 72% of subjects from whom it was possible to analyze hair samples (n = 157/200). Most hair samples obtained from subjects receiving formoterol or vilanterol had amounts of drug present that allowed determination of a quantifiable concentration, and demonstrated a dose response. Drugs were detected in all hair colors, with higher concentrations of formoterol observed in dark-haired versus light-haired individuals. CONCLUSIONS: This is the first study to demonstrate that inhaled medication can be measured in hair samples from subjects with asthma and/or COPD. The results show that hair drug concentration data could potentially provide a record of historical adherence to inhaled therapeutics. PMID- 29981459 TI - Is aging a "comorbidity" of asthma? AB - The aging population is growing at an unparalleled rate. Asthma is common in the elderly (age over 65 years) and can be more severe with little chance for remission. Asthma in older individuals is often under-diagnosed, misdiagnosed and frequently under-treated. Concomitant medical and psychosocial conditions are more prevalent in the elderly and can obfuscate the presentation of asthma and make it more difficult to assess and manage. While these comorbidities are important in understanding elderly asthma, aging itself can be considered a "comorbidity" since it impacts structural and functional changes in the lung. Structural changes of the aging lung may worsen physiologic function in asthma. The immune system also changes with age, with increased vulnerability to pathogens and differences in airway inflammation, leading to variability in how asthma manifests and responds to treatment. The fact that aging can influence the severity and presentation of asthma along with its diagnosis and management is important for the treating physician to understand. This article will discuss the multitude of factors that justify considering aging as a comorbidity of asthma. PMID- 29981460 TI - Near-infrared light-activated IR780-loaded liposomes for anti-tumor angiogenesis and Photothermal therapy. AB - Tumor angiogenesis is a key step in the process of tumor development, and antitumor angiogenesis has a profound influence on tumor growth. Herein we report a dual-function drug delivery system comprising a Near-infrared (NIR) dye and an anti-angiogenic drug within liposomes (Lip-IR780-Sunitinib) for enhanced antitumor therapy. The hydrophobic NIR dye IR780 was loaded into the liposome phospholipid bilayer, and the bilayer would be disrupted by laser irradiation so that anti-angiogenic drug sunitinib release would be activated remotely at the tumor site. The released hydrophilic sunitinib could potentially target multiple VEGF receptors on the tumor endothelial cell surface to inhibit angiogenesis. Meanwhile, IR780-loaded liposomes kill the cancer cells by photothermal therapy. Lip-IR780-Sunitinib exhibited enhanced anti-tumor and anti-angiogenic effects in vitro and in vivo. This system facilitates easy and controlled release of cargos to achieve anti-tumor angiogenesis and photothermal therapy. PMID- 29981461 TI - 18F-3'-Deoxy-3'-Fluorothymidine Positron Emission Tomography Imaging for the Prediction of Acute Graft-Versus-Host Disease in Mouse Hematopoietic Stem Cell Transplant Models. AB - Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation. In mice, studies have demonstrated that donor conventional T cells traffic into host secondary lymphoid tissues early after transplant, and that this process is critical for the development of disease. As a result, the measurement of cellular proliferation within lymphoid sites early after transplant might be a useful approach for predicting aGVHD in humans. 18F-3'-deoxy-3'-fluorothymidine (FLT) positron emission tomography (PET) imaging has recently emerged as a functional imaging modality in oncology patients. FLT, a thymidine analog, is incorporated into replicating DNA and is thus an indirect marker of cellular proliferation. Here we report that FLT PET imaging can differentiate mice receiving alloreactive T cells and destined to develop lethal aGVHD from control mice. Mice receiving allogeneic T cells demonstrated a stronger FLT signal within the peripheral lymph nodes compared with control mice at all time points after transplant. In addition, allogeneic T cell recipients transiently demonstrated stronger FLT uptake within the spleen. Importantly, these differences were apparent before the development of clinical disease. In contrast, the FLT signal within the host bowel, an important aGVHD target organ, was more variable after transplant and was not consistently different between aGVHD mice and control mice. Collectively, these findings suggest that the imaging of patient lymphoid sites using existing FLT PET technology might be useful for predicting aGVHD in the clinical setting. PMID- 29981462 TI - Lumbar Lordosis Correction with Interbody Fusion: Systematic Literature Review and Analysis. AB - OBJECTIVE: The goal of this study was to conduct an evidence-based quantitative assessment of the correction of lumbar lordosis achieved by each of the 3 principal lumbar interbody fusion techniques: anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (L-LIF), and transforaminal lumbar interbody fusion (TLIF). METHODS: A systematic review of the literature was conducted to identify studies containing degrees of correction of lumbar lordosis achieved by ALIF, L-LIF, and TLIF as shown on standing lumbar radiography at least 6 weeks after surgical intervention. Pooled and Forest plot analyses were performed for the studies that met inclusion criteria. RESULTS: For ALIF, 21 studies were identified with mean correction 4.67 degrees (standard deviation [SD] +/- 4.24) and median correction 5.20 degrees . Fifteen studies were identified that met criteria for Forest plot analysis with mean correction 4.90 degrees (standard error of the mean [SEM] +/- 0.40). For L-LIF, 17 studies were identified with mean correction 4.47 degrees (SD +/- 4.80) and median correction 4.00 degrees . Nine studies were identified that met criteria for Forest plot analysis with mean correction 2.91 degrees (SEM +/- 0.56). For TLIF, 31 studies were identified with mean correction 3.89 degrees (SD +/- 4.33) and median correction 3.50 degrees . Twenty-five studies were identified that met criteria for Forest plot analysis with mean correction 5.33 degrees (SEM +/- 0.27). CONCLUSIONS: We present the current evidence-based mean correction for each of the 3 principal lumbar interbody fusion techniques based on standing radiographic data. PMID- 29981463 TI - Surgical Treatment of the Medullary Cavernous Malformations: 53 Cases. AB - OBJECTIVE: The aim of this study was to investigate patient clinical features, surgical complications and outcomes, and the prognostic risk factors of surgical treatment of cavernous malformations (CMs) involving the medulla oblongata. METHODS: The charts of 53 patients who underwent surgical treatment for CMs involving the medulla oblongata between 2011 and 2017 were reviewed retrospectively. Patient demographics, lesion characteristics, operative documents, and patient outcomes were examined. RESULTS: The study population consisted of 53 patients, with a male/female ratio of 1.4 and a mean age of 32.6 years. Eighteen patients (34.0%) had respiratory dysfunction, and 2 patients (3.8%) had cardiac instabilities, preoperatively. The mean modified Rankin Scale score was 2.7 on admission. Gross total resection was achieved in 52 patients (98.1%). Postoperatively, 23 patients (43.4%) had respiratory dysfunction, and 16 patients (30.2%) had dysphagia or cough. The mean follow-up duration was 35.7 months. At the last follow-up evaluation, the mean modified Rankin Scale score was 1.7, and 42 patients (84%) had favorable outcomes, with mRS scores <=2. The conditions of the patients improved in 34 cases (68%), remained unchanged in 10 cases (20%), and worsened in 6 cases (12%) relative to the preoperative baseline. The independent adverse factors for long-term outcome were age >=50 years and increased time of reservation of tracheal intubation after surgery. CONCLUSIONS: Surgical treatment of CMs involving the medulla oblongata was challenging, notably, perioperative respiratory dysfunction, with which patients tend to have unfavorable long-term outcomes, especially for elder patients. PMID- 29981465 TI - Selection of Surgical Approach for Trigonal Meningiomas in Consideration of Visual Outcome. AB - OBJECTIVES: We report the surgical outcome of trigonal meningiomas through 3 different approaches with attention to visual outcomes. METHODS: Between 1994 and 2017, 23 patients underwent resection of trigonal meningiomas. We performed tumor removal using 3 different surgical approaches through the superior parietal lobule, middle temporal gyrus (MTG), and modified MTG. The patients were retrospectively identified, and surgical results including visual outcome were analyzed. RESULTS: Twenty-three patients with a mean age of 45 years formed the study group. The most common symptom and sign were headache (N = 14, 60.9%) and visual disturbance (N = 6, 26.1%). All patients underwent surgical resection, 6 via a translateral approach through MTG, 8 via a translateral approach through modified MTG, and 9 via a transparietal approach through the superior parietal lobule (SPL). Gross total resection was achieved in all patients. We found that visual preservation rate was 25% (1/4) in the MTG group, 62.5% (5/8) in the modified MTG group, and 100% (7/7) in the SPL group, respectively (P = 0.044). Permanent complication rate was 50% (3/6) in the MTG group, 50% (n = 4/8) in the modified MTG group, and 11.1% (n = 1/9) in the SPL group. CONCLUSIONS: The superior parietal lobule approach is a safe and applicable procedure with a great visual preservation and an acceptable risk of morbidity for trigonal meningiomas when there is a chance of visual recovery or preservation. PMID- 29981464 TI - Protective Effects of Astragaloside IV on Delayed Cerebral Vasospasm in an Experimental Rat Model of Subarachnoid Hemorrhage. AB - BACKGROUND: Delayed cerebral vasospasm is an important cause of morbidity and mortality in patients with subarachnoid hemorrhage (SAH). This study aimed to assess the effects of Astragaloside IV (AS-IV) on delayed cerebral vasospasm after SAH. METHODS: A rat model of SAH was established by puncturing one side of the internal carotid artery. Then, rats received daily intraperitoneal injections of AS-IV (20 mg/kg; SAH-AS-IV group), 0.1% dimethyl sulfoxide (DMSO) (SAH-DMSO group), or saline (SAH group) for 5 days; an additional control group consisted of rats receiving sham surgery and saline injections. Morphologic characteristics of the basilar artery (BA) were measured from histologic sections stained with hematoxylin and eosin and used as indicators of cerebral vasospasm. Immunohistochemistry was used to detect Toll-like receptor-4 (TLR4) and nuclear factor kappa B (NF-kappaB) p65 protein levels in the BA. Enzyme-linked immunosorbent assay was used to measure the plasma concentrations of tumor necrosis factor-alpha and interleukin-6. RESULTS: Compared with controls, the SAH DMSO and SAH groups showed increased wall thickness and reduced luminal cross sectional area (indicative of vasospasm) and increased TLR4 expression and enhanced NF-kappaB activation in the BA, as well as elevated plasma levels of tumor necrosis factor-alpha and interleukin-6. Administration of AS-IV was associated with significant attenuation of all the aforementioned changes induced by SAH (P < 0.05). CONCLUSIONS: AS-IV may attenuate delayed cerebral vasospasm after SAH through inhibition of TLR4/NF-kappaB-mediated inflammatory signaling pathways. PMID- 29981466 TI - Clinical and Pathologic Characteristics Predicted the Postoperative Recurrence and Progression of Pituitary Adenoma: A Retrospective Study with 10 Years Follow Up. AB - OBJECTIVE: Tumor recurrence or residual regrowth are poor prognoses for pituitary adenoma (PA). However, there is no validated and well-accepted prognostic classification of PAs to predict the clinical outcome and guide clinical practice. We analyzed the relevant data of a large cohort of patients with PA and thereafter proposed a new clinicopathologic classification for prognostic prediction. METHODS: Tumor recurrence or residual regrowth identified by magnetic resonance imaging scans and endocrine studies were analyzed along with associated clinical and pathological characteristics for patients who underwent surgery in 2008-2016 at West China Hospital. A new clinicopathologic classification was proposed and applied. RESULTS: After a median follow-up of 44.0 months, tumor recurrence and residual progression were identified in 48 (25.0%) and 29 (37.2%) patients, respectively. Proliferative potential (hazard ratio [HR], 2.188; P = 0.002), invasiveness (HR, 1.698; P = 0.029), larger tumor size (HR, 1.029; P = 0.004), high-risk PA subtype (HR, 2.151; P = 0.004), and postoperative residual (HR, 1.941; P = 0.007) were risk factors for recurrence/progression in the early stage after surgery. With respect to clinicopathologic classification, compared with grade 1a tumors, grade 1b, 2a, and 2b adenomas had poorer prognosis with an increased probability of tumor recurrence/progression of 5.133-fold, 4.467-fold, and 20.1-fold, respectively. CONCLUSIONS: The proposed clinicopathologic classification of PAs showed significant value in predicting prognosis and succeeded in identifying cases with more clinically aggressive lesions with recurrence or residual regrowth. This prognostic classification may be helpful when identifying aggressive PAs and deciding the appropriate therapeutic strategy for patients with PAs. PMID- 29981467 TI - The Subjective Experience of Patients Undergoing Shunt Surgery for Idiopathic Normal Pressure Hydrocephalus. AB - OBJECTIVE: The counseling of patients with idiopathic normal pressure hydrocephalus (iNPH) is difficult; there is variability in the diagnostic criteria, and a definitive diagnosis can be made only postoperatively. A patient's clinical response to shunting is also difficult to predict. This study examines the subjective experience of patients treated for iNPH, to identify the challenges patients face and to improve patient outcomes and satisfaction. METHODS: We reviewed a consecutive series of patients diagnosed with iNPH who underwent ventriculoperitoneal shunt surgery between January 2012 and March 2016 at our institution. Semistructured telephone interviews were conducted with 31 patients. Interviews were analyzed using the principles of grounded theory. RESULTS: Thirty-one patients who underwent shunt surgery for iNPH were interviewed to reach saturation of themes. Seven themes were identified: 1) long preoperative course causes morbidity; 2) the decision to have shunt surgery is easy to make; 3) patients primarily desire to gain independence; 4) patients show variable levels of anxiety; 5) comorbid conditions interfere with postoperative assessment; 6) patients stand by their decision to have shunt surgery; and 7) outside information is used before surgery. CONCLUSIONS: Patients often present to the neurosurgeon frustrated and desperate after a long preoperative course. It is important to acknowledge the uncertainty regarding diagnosis and response to shunting when counseling patients. Comorbid conditions interfere with the ability to assess progression of iNPH and the effectiveness of the shunt. Patient caregivers play a large role in decision making and clinical course and should be included when counseling patients. PMID- 29981468 TI - Masslike Cystic Endosalpingiosis in the Uterine Myometrium. PMID- 29981469 TI - Re: 'A pragmatic approach for mortality prediction after surgery in infective endocarditis' by Ferreira-Gonzalez, et al. PMID- 29981470 TI - Plastome organization, genome-based phylogeny and evolution of plastid genes in Podophylloideae (Berberidaceae). AB - Species of Podophylloideae (Berberidaceae, Ranunculales) are of great pharmacogenetic importance and represent the classic biogeographic disjunction between eastern Asia (EA; 10 ssp.) and eastern North America (ENA; 2 ssp.). However, previous molecular studies of this group suffered from low phylogenetic resolution and/or insufficient marker variability. This study is the first to report whole-plastome sequence data for all 12 species of Podophylloideae (14 individuals) and a close relative, Achlys triphylla. These 15 plastomes proved highly similar in overall size (156,240-157,370 bp), structure, gene order and content, also when compared to other Ranunculales, but also revealed some structural variations caused by the expansion or contraction of the inverted repeats (IRs) into or out of adjacent single-copy regions. Our phylogenomic analysis, based on 63 plastome-derived protein-coding genes (CDS), supported the monophyly of Podophylloideae and its two major genera (EA: Dysosma, EA/ENA: Diphylleia), with Podophyllum peltatum L. (ENA) being more closely related to Diphylleia than to the group's earliest diverging species, Sinopodophyllum hexandrum (EA). Furthermore, within this subfamily/dataset, matK was identified as the fastest evolving gene, which proved to be under positive selection especially in more recently derived, lower-elevation lineages of Dysosma, possibly reflecting an adaptive response to novel environmental (i.e. subtropical compared to higher-elevation/alpine) conditions. Finally, several highly variable noncoding regions were identified in the plastomes of Podophylloideae and Ranunculales. These highly variable loci should be the best choices for future phylogenetic, phylogeographic, and population-level genetic studies. Overall, our results demonstrate the power of plastid phylogenomics to improve phylogenetic resolution, and contribute to a better understanding of plastid gene evolution in Podophylloideae. PMID- 29981471 TI - Membrane attack complex-associated molecules from redlip mullet (Liza haematocheila): Molecular characterization and transcriptional evidence of C6, C7, C8beta, and C9 in innate immunity. AB - The redlip mullet (Liza haematocheila) is one of the most economically important fish in Korea and other East Asian countries; it is susceptible to infections by pathogens such as Lactococcus garvieae, Argulus spp., Trichodina spp., and Vibrio spp. Learning about the mechanisms of the complement system of the innate immunity of redlip mullet is important for efforts towards eradicating pathogens. Here, we report a comprehensive study of the terminal complement complex (TCC) components that form the membrane attack complex (MAC) through in-silico characterization and comparative spatial and temporal expression profiling. Five conserved domains (TSP1, LDLa, MACPF, CCP, and FIMAC) were detected in the TCC components, but the CCP and FIMAC domains were absent in MuC8beta and MuC9. Expression analysis of four TCC genes from healthy redlip mullets showed the highest expression levels in the liver, whereas limited expression was observed in other tissues; immune-induced expression in the head kidney and spleen revealed significant responses against Lactococcus garvieae and poly I:C injection, suggesting their involvement in MAC formation in response to harmful pathogenic infections. Furthermore, the response to poly I:C may suggest the role of TCC components in the breakdown of the membrane of enveloped viruses. These findings may help to elucidate the mechanisms behind the complement system of the teleosts innate immunity. PMID- 29981472 TI - Characterization, expression signatures and microbial binding analysis of cathepsin A in turbot, Scophthalmus maximus L.(SmCTSA). AB - Mucosal immune system is one of the most vital components in the innate immunity and constitutes the first line of host defense against bacterial infections, especially for the teleost, which live in the pathogen-rich aquatic environment. Cathepsins, a superfamily of hydrolytic enzymes produced and enclosed within lysosomes, play multiple roles at physiological and pathological states. In this regard, we sought here to identify Cathepsin A in turbot (SmCTSA), characterize its mucosal expression patterns following Vibrio anguillarum and Streptococcus iniae infections in mucosal tissues, and explore its binding ability with three microbial ligands for the first time. The SmCTSA was 2631 bp long containing a 1422 bp open reading frame (ORF) that encoded 473 amino acids. Phylogenetic analysis revealed that SmCTSA showed the closest relationship to half-smooth tongue sole (Cynoglossus semilaevis). In addition, SmCTSA was ubiquitously expressed in all examined healthy tissues, with high expression levels in head kidney (HK) and intestine, while the lowest expression level in blood. Moreover, SmCTSA was significantly differentially expressed at least two timepoints in each mucosal tissue, suggesting its potential important roles in innate immune responses of turbot. Finally, in vitro assays showed that recombinant SmCTSA bound Lipopolysaccharide (LPS) with high affinity, and lipoteichoic acid (LTA) and peptidoglycan (PGN) with relatively low affinity. This study provides valuable data for understanding the roles of ctsa in the host defense against bacterial infections. PMID- 29981473 TI - Preliminary investigations on the role of Drp-1 dependent mitochondrial fission in attenuating RLR downstream signaling during nervous necrosis virus infection. AB - Member of the dynamin family of large GTPases, dynamin-related protein 1 (Drp1) dependent mitochondrial fission is an intricate process regulating both cellular and organ dynamics. Present study shows that NNV perturbs mitochondrial dynamics by promoting Drp-1 dependent mitochondrial fission, which attenuates MAVS mediated downstream signaling. NNV infected SISS cells revealed induction in Drp1 expression and subsequent translocation into mitochondria. The level of MAVS expression was up-regulated over a period of 24 hpi and declined with the progression of NNV infection at 48 and 72 hpi confirmed by western blot and mRNA transcript analysis. Drp-1 displayed its association with fragmented mitochondria and the transcript abundance was significant post infection along with Mff. Expression levels of IRF-3 IFN-1 and Mx followed a similar pattern with abundant expression at 48 hpi and diminished expression during the further period. Importantly, silencing of Drp1 caused significant elevation in the RLR downstream molecules and reduction in viral RNA expression. These results suggest that NNV induced mitochondrial fission serve to attenuate host RLR signaling. This provides an illustration of host-pathogen interaction in which the virus evades innate immunity by enhancing mitochondrial fission and perturbs MAVS, and the downstream molecules. PMID- 29981474 TI - Synthesis and antiviral activity of a new coumarin derivative against spring viraemia of carp virus. AB - Coumarin as a lead structure have received a considerable attention in the last three decades for the discovery of antiviral agents. Our previous study indicated that imidazole coumarins possessed antiviral activities against SVCV. Based on the structure-activity relationship in that study, a new imidazole coumarin derivative, 7-(4-benzimidazole-butoxy)-coumarin (BBC), was designed, synthesized and its anti-SVCV activity was evaluated. By comparing inhibitory concentration at half-maximal activity (IC50), we found that BBC (IC50 = 0.56 mg/L) possessed a higher antiviral activity than those imidazole coumarins in our previous study. Besides, BBC can significantly inhibit cell death and reduce cellular morphological damage induced by SVCV. Our further data indicated that intraperitoneal injection of BBC increased the survival rate of zebrafish by 17.5%, decreased viral titer in fish body and inhibited SVCV glycoprotein expression in kidney and spleen. In uninfected zebrafish, the expression levels of ifngamma, ifnphi1, ifnphi2 and rig1 genes were up-regulated after BBC treatment, which indicated that BBC could activate interferon response. In addition, data of the antioxidant enzymes activities and results of the antioxidant enzymes-related genes expressions suggested BBC could reduce SVCV induced oxidative damage in infected zebrafish. Altogether, BBC is expected to be a therapeutic agent against SVCV infection in the field of aquaculture. PMID- 29981475 TI - Presumption of pericardial endometriosis using MRI: Case report and review of the literature. AB - Endometriosis is a condition where hormonal-responsive endometrial tissue grows outside the uterus usually within the pelvic cavity. Extra-pelvic endometriosis is rare and may involve the pericardium. We report the first case of pericardial endometriosis suspected using cardiac magnetic resonance imaging. PMID- 29981476 TI - Severe immune thrombocytopenia in pregnancy treated with Eltrombopag - A case report. AB - Immune thrombocytopenia (ITP) during pregnancy is an acquired autoimmune disease present in 1-2 of every 1000 pregnancies. Thrombopoietin (TPO)-mimetic drugs, such as eltrombopag, have been successfully used for treatment of ITP during pregnancy, but studies regarding its safety during gestation are lacking. A 33 year-old nulliparous woman with a history of chronic ITP, presented at the emergency department with petechiae, epistaxis, bruises, conjunctival effusions and a platelet count of 3*109/L at 25 weeks gestation. Her pregnancy had been uneventful until then. She was unresponsive to a therapeutic escalade of corticosteroids, azathioprine and intravenous immunoglobulin (IV Ig) so, at 27 weeks, eltrombopag was initiated, and analytical and clinical improvement was achieved. Labor was induced at 37 weeks due to preeclampsia, culminating in a vacuum-assisted vaginal delivery. A healthy female newborn weighing 2400g was born. After delivery, both had normal platelet counts and remained clinically stable through follow-up. PMID- 29981478 TI - Screening for atrial fibrillation using smartphone-based technology and layperson volunteers: High-tech meets community participatory research for the best of both worlds. PMID- 29981479 TI - Brugada syndrome: Let's talk about sex. PMID- 29981477 TI - Poly(ADP-ribosyl)ation associated changes in CTCF-chromatin binding and gene expression in breast cells. AB - CTCF is an evolutionarily conserved and ubiquitously expressed architectural protein regulating a plethora of cellular functions via different molecular mechanisms. CTCF can undergo a number of post-translational modifications which change its properties and functions. One such modifications linked to cancer is poly(ADP-ribosyl)ation (PARylation). The highly PARylated CTCF form has an apparent molecular mass of 180 kDa (referred to as CTCF180), which can be distinguished from hypo- and non-PARylated CTCF with the apparent molecular mass of 130 kDa (referred to as CTCF130). The existing data accumulated so far have been mainly related to CTCF130. However, the properties of CTCF180 are not well understood despite its abundance in a number of primary tissues. In this study we performed ChIP-seq and RNA-seq analyses in human breast cells 226LDM, which display predominantly CTCF130 when proliferating, but CTCF180 upon cell cycle arrest. We observed that in the arrested cells the majority of sites lost CTCF, whereas fewer sites gained CTCF or remain bound (i.e. common sites). The classical CTCF binding motif was found in the lost and common, but not in the gained sites. The changes in CTCF occupancies in the lost and common sites were associated with increased chromatin densities and altered expression from the neighboring genes. Based on these results we propose a model integrating the CTCF130/180 transition with CTCF-DNA binding and gene expression changes. This study also issues an important cautionary note concerning the design and interpretation of any experiments using cells and tissues where CTCF180 may be present. PMID- 29981481 TI - Fast and accurate Slicewise OutLIer Detection (SOLID) with informed model estimation for diffusion MRI data. AB - The accurate characterization of the diffusion process in tissue using diffusion MRI is greatly challenged by the presence of artefacts. Subject motion causes not only spatial misalignments between diffusion weighted images, but often also slicewise signal intensity errors. Voxelwise robust model estimation is commonly used to exclude intensity errors as outliers. Slicewise outliers, however, become distributed over multiple adjacent slices after image registration and transformation. This challenges outlier detection with voxelwise procedures due to partial volume effects. Detecting the outlier slices before any transformations are applied to diffusion weighted images is therefore required. In this work, we present i) an automated tool coined SOLID for slicewise outlier detection prior to geometrical image transformation, and ii) a framework to naturally interpret data uncertainty information from SOLID and include it as such in model estimators. SOLID uses a straightforward intensity metric, is independent of the choice of the diffusion MRI model, and can handle datasets with a few or irregularly distributed gradient directions. The SOLID-informed estimation framework prevents the need to completely reject diffusion weighted images or individual voxel measurements by downweighting measurements with their degree of uncertainty, thereby supporting convergence and well-conditioning of iterative estimation algorithms. In comprehensive simulation experiments, SOLID detects outliers with a high sensitivity and specificity, and can achieve higher or at least similar sensitivity and specificity compared to other tools that are based on more complex and time-consuming procedures for the scenarios investigated. SOLID was further validated on data from 54 neonatal subjects which were visually inspected for outlier slices with the interactive tool developed as part of this study, showing its potential to quickly highlight problematic volumes and slices in large population studies. The informed model estimation framework was evaluated both in simulations and in vivo human data. PMID- 29981480 TI - Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus. AB - To understand how proper circuit formation and function is established in the mammalian brain, it is necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synapse development. We previously demonstrated that the ligand-receptor pair, Sema4D and Plexin-B1, regulates inhibitory synapse development on an unprecedentedly fast time-scale while having no effect on excitatory synapse development. Here, we report previously undescribed synaptogenic roles for Sema4A and Plexin-B2 and provide new insight into Sema4D and Plexin-B1 regulation of synapse development in rodent hippocampus. First, we show that Sema4a, Sema4d, Plxnb1, and Plxnb2 have distinct and overlapping expression patterns in neurons and glia in the developing hippocampus. Second, we describe a requirement for Plexin-B1 in both the presynaptic axon of inhibitory interneurons as well as the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development. Third, we define a new synaptogenic activity for Sema4A in mediating inhibitory and excitatory synapse development. Specifically, we demonstrate that Sema4A signals through the same pathway as Sema4D, via the postsynaptic Plexin-B1 receptor, to promote inhibitory synapse development. However, Sema4A also signals through the Plexin-B2 receptor to promote excitatory synapse development. Our results shed new light on the molecular cues that promote the development of either inhibitory or excitatory synapses in the mammalian hippocampus. PMID- 29981482 TI - The aging brain and cerebrovascular reactivity. AB - Cerebrovascular reactivity (CVR) is a measure of vascular response to a vasoactive stimulus, and can be used to assess the health of the brain vasculature. In this current study we used different analyses of BOLD fMRI responses to CO2 to provide a number of metrics including ramp and step CVR, speed of response and transfer function analysis (TFA). 51 healthy control volunteers between the ages of 18-85 (26 males) were recruited and scanned at 3T field strength. Atlases reflecting voxel-wise means and standard deviations were compiled to assess possible differences in these metrics between four age cohorts. Testing was carried out using an automated computer-controlled gas blender to induce hypercapnia in a step and ramp paradigm, and monitoring end tidal partial pressures of CO2 (PETCO2) and O2 (PETO2). No significant differences were found for resting PETCO2 values between cohorts. Ramp CVR decreased significantly with age in white matter frontal regions comprising the ACA-MCA watershed area, a finding that may be indicative of age related changes. Similarly, TFA showed that gain was reduced in the left white matter ACA-MCA watershed area as well as the posterior and anterior cingulate cortex, and superior frontal gyrus in the oldest compared to youngest cohort. These findings, detailing changes in cerebrovascular regulation in the healthy aging brain should prove useful in mapping areas of dysregulated blood flow in individuals with vascular risk factors especially those at risk for developing vascular dementia. PMID- 29981484 TI - Pipeline validation for connectivity-based cortex parcellation. AB - Structural connectivity plays a dominant role in brain function and arguably lies at the core of understanding the structure-function relationship in the cerebral cortex. Connectivity-based cortex parcellation (CCP), a framework to process structural connectivity information gained from diffusion MRI and diffusion tractography, identifies cortical subunits that furnish functional inference. The underlying pipeline of algorithms interprets similarity in structural connectivity as a segregation criterion. Validation of the CCP-pipeline is critical to gain scientific reliability of the algorithmic processing steps from dMRI data to voxel grouping. In this paper we provide a proof of concept based upon a novel model validation principle that characterizes the trade-off between informativeness and robustness to assess the validity of the CCP pipeline, including diffusion tractography and clustering. We ultimately identify a pipeline of algorithms and parameter settings that tolerate more noise and extract more information from the data than their alternatives. PMID- 29981483 TI - Age-associated increase in mnemonic strategy use is linked to prefrontal cortex development. AB - Memory functioning undergoes dynamic changes between childhood and adulthood. Spontaneous use of elaborative strategies, which can enhance the recall of information, expands with age and contributes to age-associated improvement in memory functioning. Findings from lesion and neuroimaging studies suggest that the ability to use elaborative strategies is dependent upon intact functioning of the prefrontal cortex (PFC), particularly the dorsolateral PFC region. Because the PFC undergoes protracted maturation, we examined whether age difference in the structure of the PFC is correlated with age-associated increase in strategy use. Here, we investigated the relationship between PFC volume and spontaneous strategy use in a sample of 120 participants aged 5-25 years. We assessed semantic clustering during recall with a standardized word-list recall task (California Verbal Learning Task children's version, CVLT-C) and computed PFC regional volumes from participants' structural brain images. We observed an age associated increase in the use of semantic clustering and an age-associated decrease in volumes of the PFC. Further, we found that smaller PFC volume was linked to increased use of semantic clustering. Importantly, the volume of the right dorsolateral PFC partially explained the relation between age and the use of semantic clustering. These findings suggest that PFC maturation supports the development of strategy use and lends further support for the notion that brain behavior relations change across development. PMID- 29981485 TI - Routine determination of ice thickness for cryo-EM grids. AB - Recent advances in instrumentation and automation have made cryo-EM a popular method for producing near-atomic resolution structures of a variety of proteins and complexes. Sample preparation is still a limiting factor in collecting high quality data. Thickness of the vitreous ice in which the particles are embedded is one of the many variables that need to be optimized for collection of the highest quality data. Here we present two methods, using either an energy filter or scattering outside the objective aperture, to measure ice thickness for potentially every image collected. Unlike geometrical or tomographic methods, these can be implemented directly in the single particle collection workflow without interrupting or significantly slowing down data collection. We describe the methods as implemented into the Leginon/Appion data collection workflow, along with some examples from test cases. Routine monitoring of ice thickness should prove helpful for optimizing sample preparation, data collection, and data processing. PMID- 29981486 TI - Ionic stress induces fusion of mitochondria to 3-D networks: An electron tomography study. AB - Mitochondria are central organelles for energy supply of cells and play an important role in maintenance of ionic balance. Consequently mitochondria are highly sensitive to any kind of stress to which they mainly response by disturbance of respiration, ROS production and release of cytochrome c into the cytoplasm. Many of the physiological and molecular stress reactions of mitochondria are well known, yet there is a lack of information on corresponding stress induced structural changes. 3-D visualization of high-pressure frozen cells by FIB-SEM tomography and TEM tomography as used for the present investigation provide an excellent tool for studying structure related mitochondrial stress reactions. In the present study it is shown that mitochondria in the unicellular fresh-water algal model system Micrasterias as well as in the closely related aquatic higher plant Lemna fuse to local networks as a consequence of exposure to ionic stress induced by addition of KCl, NaCl and CoCl2. In dependence on concentration and duration of the treatment, fusion of mitochondria occurs either by formation of protuberances arising from the outer mitochondrial membrane, or by direct contact of the surface of elongated mitochondria. As our results show that respiration is maintained in both model systems during ionic stress and mitochondrial fusion, as well as formation of protuberances are reversible, we assume that mitochondrial fusion is a ubiquitous process that may help the cells to cope with stress. This may occur by interconnecting the respiratory chains of the individual mitochondria and by enhancing the buffer capacity against stress induced ionic imbalance. PMID- 29981487 TI - Studies on the UV filtering and radical scavenging capacity of the bitter masking flavanone Eriodictyol. AB - A computational analysis of UV filtering and radical scavenging capacity of a flavanone, Eriodictyol has been performed under DFT-B3LYP/6-31+ G (d, p). Eriodictyol is nontoxic and nonirritant bitter masker commonly used in the wine industry. It has been reported that the flavanones were widely acceptable for photoprotection due to its potential UV filtering and radical scavenging capacity. This study provides theoretical evidence that the eriodictyol has an absorbance in the UV-A and UV-B region of the electromagnetic spectrum and therefore can be used as a potential UV filter in sunscreen lotions and other cosmetic products. The major transitions in the UV-Visible spectrum of Eriodictyol are between HOMO and HOMO-1 with LUMO level and are well explained by NBO-NLMO tool in G09 software. In addition to this, Eriodictyol is a potent antioxidant than that of the most commonly studied Quercetin. The most active site in the compound is 3' position and is confirmed by NPA, NBO and pKa value analysis. The lowest energy conformer of Eriodictyol contains a Hydrogen bond between carbonyl oxygen (O2) and H30. This is confirmed by the highest value of interaction energy between lone pairs of O2 and sigma* of O3- H30. Both the two lone pairs of O2 interacts with the sigma* of O3-H30. This decreases the bond order of 5 OH and at the same time it restricts the hydrogen transfer from this position to form a radical. Similarly, the lone pair of O5 (3' position) interacts with H33 resulting in the low bond order value and consequently less favorable for radical formation. These results indicate that the BDE values follow the order 3' < 4' < 7 < 5. Thus the title compound can be used for photo protection due to its potential UV filtering and radical scavenging capacity. PMID- 29981488 TI - Biogenic synthesis of iron oxide nanoparticles using Agrewia optiva and Prunus persica phyto species: Characterization, antibacterial and antioxidant activity. AB - A phytoextract mediated synthesis of iron oxide nanoparticles using Agrewia optiva (Dhaman or Biul) and Prunus persica (Peach) leaf extract as capping and stabilizing agent without using hazardous toxic chemicals via biogenic route has been studied. The biogenic method of synthesis is convenient, rapid, cost effective and ecofriendly. The green synthesized nanoparticles were characterized by Ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, Attenuated total reflectance spectroscopy, X-ray diffraction analysis, scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy and dynamic light scattering measurements. The antibacterial study was determined by agar well diffusion method to measure the efficiency of both phyto species extract and its mediated iron oxide nanoparticles against five gram positive bacterial stains such as Staphylococcus aureus (S. aureus), Streptococcus mutans (S. mutans), Streptococcus pyrogenes (S. pyrogenes), Corynebacterium diphtheriae (C. diphtheriae) and Corynebacterium xerosis (C. xerosis) and three gram negative bacterial stains such as Escherichia coli (E. coli), Klebsiella pneuomoniae (K. pneuomoniae) and Pseudomonas aeruginosa (P. aeruginosa). The antibiotic Ciprofloxacin and Gentamicin have been used as reference standard drugs for gram positive and gram negative bacterial stains, respectively. The antioxidant activity of the phyto extracts and prepared nanoparticles have been performed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical assay employing l-ascorbic acid as a standard. PMID- 29981490 TI - Relevance feedback for enhancing content based image retrieval and automatic prediction of semantic image features: Application to bone tumor radiographs. AB - BACKGROUND: The majority of current medical CBIR systems perform retrieval based only on "imaging signatures" generated by extracting pixel-level quantitative features, and only rarely has a feedback mechanism been incorporated to improve retrieval performance. In addition, current medical CBIR approaches do not routinely incorporate semantic terms that model the user's high-level expectations, and this can limit CBIR performance. METHOD: We propose a retrieval framework that exploits a hybrid feature space (HFS) that is built by integrating low-level image features and high-level semantic terms, through rounds of relevance feedback (RF) and performs similarity-based retrieval to support semi automatic image interpretation. The novelty of the proposed system is that it can impute the semantic features of the query image by reformulating the query vector representation in the HFS via user feedback. We implemented our framework as a prototype that performs the retrieval over a database of 811 radiographic images that contains 69 unique types of bone tumors. RESULTS: We evaluated the system performance by conducting independent reading sessions with two subspecialist musculoskeletal radiologists. For the test set, the proposed retrieval system at fourth RF iteration of the sessions conducted with both the radiologists achieved mean average precision (MAP) value ~0.90 where the initial MAP with baseline CBIR was 0.20. In addition, we also achieved high prediction accuracy (>0.8) for the majority of the semantic features automatically predicted by the system. CONCLUSION: Our proposed framework addresses some limitations of existing CBIR systems by incorporating user feedback and simultaneously predicting the semantic features of the query image. This obviates the need for the user to provide those terms and makes CBIR search more efficient for inexperience users/trainees. Encouraging results achieved in the current study highlight possible new directions in radiological image interpretation employing semantic CBIR combined with relevance feedback of visual similarity. PMID- 29981489 TI - Cystic fibrosis, body composition, and health outcomes: a systematic review. AB - OBJECTIVES: Patients with cystic fibrosis are characterized by an increased risk of nutrient malabsorption and inflammation, which may influence body composition. We examined the differences in body composition between patients with cystic fibrosis and healthy controls and how body composition differences may impact disease risk and mortality. METHODS: Three different electronic databases (PubMed, Web of Science, and Embase) were used to find articles from inception until March 2017. The search strategy excluded articles that reported data on anthropometric measures only such as body weight, height, or waist circumference. Information on the characteristics of the study populations (e.g., age, sex, body mass index), type of study design, body composition methods, body compartments, and health outcomes was extracted. RESULTS: Thirty-nine articles were included in the systematic review. The total number of patients with cystic fibrosis and controls that were included in these studies was 1839 and 2178, respectively. Only one study explored the association between body composition and risk of mortality whereas the majority of the studies examined the association between body composition and respiratory function (33%). Patients with cystic fibrosis had less fat-free mass and bone mineral density compared with the controls and fat-free mass was associated with decreased inspiratory muscle strength. CONCLUSIONS: Patients with cystic fibrosis may be at an increased risk of sarcopenia and osteopenia. The measurement of body composition could improve the assessment of nutritional status and reduce the risk for respiratory and metabolic complications in patients with cystic fibrosis. PMID- 29981492 TI - Elder abuse and its impact on quality of life in nursing homes in China. AB - There are limited available data on elder abuse and its impact on quality of life (QOL) in China. This study investigated the prevalence of elder abuse in nursing homes and its associated demographic, clinical factors and QOL in Macau and Guangzhou, China. A total of 681 subjects (244 in Macau and 437 in Guangzhou) were consecutively recruited. The prevalence of elder abuse was 11.48% and 8.24% in Macau and Guangzhou, respectively. Multivariate analyses revealed that having a religion and depressive symptoms were independently and positively associated with elder abuse. No significant association between elder abuse and any QOL domain was found. Elder abuse is common in nursing homes in both Macau and Guangzhou. Appropriate strategies and educational programs should be developed for health professionals to reduce the risk of elder abuse. PMID- 29981491 TI - From narrative descriptions to MedDRA: automagically encoding adverse drug reactions. AB - CONTEXT: The collection of narrative spontaneous reports is an irreplaceable source for the prompt detection of suspected adverse drug reactions (ADRs). In such task qualified domain experts manually revise a huge amount of narrative descriptions and then encode texts according to MedDRA standard terminology. The manual annotation of narrative documents with medical terminology is a subtle and expensive task, since the number of reports is growing up day-by-day. OBJECTIVES: Natural Language Processing (NLP) applications can support the work of people responsible for pharmacovigilance. Our objective is to develop NLP algorithms and tools for the detection of ADR clinical terminology. Efficient applications can concretely improve the quality of the experts' revisions. NLP software can quickly analyze narrative texts and offer an encoding (i.e., a list of MedDRA terms) that the expert has to revise and validate. METHODS: MagiCoder, an NLP algorithm, is proposed for the automatic encoding of free-text descriptions into MedDRA terms. MagiCoder procedure is efficient in terms of computational complexity. We tested MagiCoder through several experiments. In the first one, we tested it on a large dataset of about 4500 manually revised reports, by performing an automated comparison between human and MagiCoder encoding. Moreover, we tested MagiCoder on a set of about 1800 reports, manually revised ex novo by some experts of the domain, who also compared automatic solutions with the gold reference standard. We also provide two initial experiments with reports written in English, giving a first evidence of the robustness of MagiCoder w.r.t. the change of the language. RESULTS: For the current base version of MagiCoder, we measured an average recall and precision of 86.9% and 91.8%, respectively. CONCLUSIONS: From a practical point of view, MagiCoder reduces the time required for encoding ADR reports. Pharmacologists have only to review and validate the MedDRA terms proposed by the application, instead of choosing the right terms among the 70 K low level terms of MedDRA. Such improvement in the efficiency of pharmacologists' work has a relevant impact also on the quality of the subsequent data analysis. We developed MagiCoder for the Italian pharmacovigilance language. However, our proposal is based on a general approach, not depending on the considered language nor the term dictionary. PMID- 29981493 TI - Physical and cognitive functions affecting road traffic injuries among senior drivers. AB - BACKGROUND: The size of elderly populations is growing in most areas of the world. The Thai Eleventh National Economic and Social Development Plan revealed an increase in the elderly, while numbers of younger, working-age adults decreased. Thailand has become an aging society since 2015, which is significant in that senior adults have a higher risk of involvement in motor vehicle accidents and are more susceptible to injuries and fatalities. This study investigated the role of physical and cognitive function with regard to road traffic injury in senior drivers. METHODS: A community survey was carried out among people aged 60 years and older in the villages representing four regions of Thailand. Face-to-face interviews and anthropometric measurements were used to gather data including individual characteristics, medical history, risk behaviors, cognitive function and traffic injury within the last 12 months. Associations between risk factors and injury were assessed by the chi-square tests, and comparison of the cognitive function score between the injury and non injury groups was identified using the independent t-test. RESULTS: A total of 314 completed questionnaires were used for analysis. Ten percent of respondents had experienced a road traffic injury in the last 12 months. Analysis revealed that level of cognitive function, smoking behavior and been diagnosed with arthritis were associated with road traffic injury incidence in senior drivers (p value < 0.05). CONCLUSION: Results revealed the potential need for strategies to increase road traffic safety in senior drivers. Special protection should be prioritized for the elderly with physical and cognitive impairment. PMID- 29981494 TI - In vivo annular repair using high-density collagen gel seeded with annulus fibrosus cells. AB - OBJECTIVE: The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model. SUMMARY OF BACKGROUND DATA: Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo. METHODS: 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair. RESULTS: Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels. CONCLUSIONS: AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture. STATEMENT OF SIGNIFICANCE: This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential. PMID- 29981495 TI - Injectable degradable PVA microgels prepared by microfluidic technology for controlled osteogenic differentiation of mesenchymal stem cells. AB - : The direct injection of bone marrow mesenchymal stem cells (hMSCs) is a promising strategy for bone tissue engineering applications. Herein, we have developed injectable degradable poly(vinyl alcohol) (PVA) microgels loaded with hMSCs and growth factors and prepared by a high-throughput microfluidic technology. The PVA-based microgels with tunable mechanical and degradable properties were composed of vinyl ether acrylate-functionalized PVA (PVA-VEA) and thiolated PVA-VEA (PVA-VEA-SH) through a Michael-type crosslinking reaction under mild conditions. The hMSCs sustain high viability in PVA microgels, and cell proliferation and migration behaviors can easily be adjusted by varying crosslinking densities of PVA microgels. Additionally, bone morphogenetic protein 2 (BMP-2) co-encapsulated into the microgel environments enhanced osteogenic differentiation of hMSCs as indicated by a significant increase in alkaline phosphatase activity, calcium content, and Runx2 and OPN gene expression levels. These results demonstrate the degradable PVA microgels with tailored stem cell microenvironments and controlled release profile of the growth factor to promote and direct differentiation. These PVA-based microgels have promising potential as ideal cell vehicles for applications in regenerative medicine. STATEMENT OF SIGNIFICANCE: Stem cell transplantation by an injectable, minimally invasive method has great and promising potential for various injuries, diseases, and tissue regeneration. However, its applications are largely limited owing to the low cell retention and engraftment at the lesion location after administration. We have developed an injectable degradable poly(vinyl alcohol) (PVA) microgel prepared by a high-throughput microfluidic technology and co-loaded with bone marrow mesenchymal stem cells (hMSCs) and growth factor to protect the stem cells from harsh environmental stress and realize controlled cell differentiation in well-defined microenvironments for bone regeneration. We demonstrated that these degradable PVA microgels can be used as stem cell scaffolds with tailored cell microenvironments and controlled release profile of growth factor to promote and direct differentiation. We are convinced that these PVA-based microgels have promising potential in the future as cellular scaffolds for applications in regenerative medicine. PMID- 29981496 TI - Strength-size relationships in two porous biological materials. AB - : According to the Weibull theory for brittle materials, the mean experimental strength decreases with test specimen size. For the brittle parts of an organism this would mean that becoming larger in size results automatically in reducing strength. This unfavorable relationship was investigated for two porous, biological materials that are promising concept generators for crack deflective and energy dissipative applications in compressive overloading: the quasi-brittle coconut endocarp and the brittle spines of the sea urchin Heterocentrotus mamillatus. Segments in different volumes were prepared and tested in uniaxial compression experiments. Failure of both materials is Weibull distributed underlining that it is caused by statistically distributed flaws in the structure. However, the coconut endocarp has a much higher Weibull modulus (m = 14.1-16.5) than the spines (m = 5). The more predictable failure of the endocarp is probably attributed to a rather homogeneous microstructural design and water bound in the structure. In terms of the spines it was found that the Weibull modulus is structure dependent: More homogeneous spines feature a higher Weibull modulus than spines with a heterogeneous structure. Whereas the nearly dense endocarp exhibited, although less pronounced, the expected decrease in strength with increase in size, the spines showed a failure independently of size. This remarkable behavior may be explained with their highly porous internal structure. Small and large spines consist of struts of similar size, which constitute the porous internal structure, potentially limiting the flaw size to the size of the strut regardless of the spine size. STATEMENT OF SIGNIFICANCE: Scaling is an important aspect of the biomimetic work process, since biological role models and structures have rarely the same size as their technical implementations. The algorithms of Weibull are a standard tool in material sciences to describe scaling effects in materials whose critical strength depends on statistically distributed flaws. The challenge is to apply this theory (developed for homogeneous, isotropic technical materials) to brittle and quasi-brittle biological materials with hierarchical structuring. This study is a first approach to verify whether the Weibull theory can be applied to the coconut endocarp and to sea urchin spines in order to model their size/volume/property relations. PMID- 29981497 TI - Tolerability of a comprehensive cardiorespiratory monitoring protocol in an epilepsy monitoring unit. AB - BACKGROUND: Recent reports of fatal or near-fatal events in epilepsy monitoring units (EMUs) and an increasing awareness of the effects of seizures on breathing have stimulated interest in cardiorespiratory monitoring for patients undergoing video-electroencephalography (EEG) recording. Patient and provider acceptance of these extra recording devices has not previously been studied and may represent a barrier to widespread adoption. METHODS: We queried EMU subjects regarding their experiences with a monitoring protocol that included the continuous measurement of oral/nasal airflow, respiratory effort (chest and abdominal respiratory inductance plethysmography), oxygen saturation, and transcutaneous CO2. Surveys were returned by 71.4% (100/140) of eligible subjects. RESULTS: Overall, 73% of participants reported being moderately to highly satisfied with the monitoring, and 82% reported moderate to strong agreement that advance knowledge of the monitoring would not have changed their decision to proceed with the video-EEG study. Except for nasal airflow, none of the additional monitoring devices caused more discomfort than EEG electrodes. CONCLUSION: Patient acceptance of an EMU comprehensive cardiorespiratory monitoring protocol is high. The information obtained from "multimodality recording" should help clinicians and investigators understand the effect of seizures on both cardiac and respiratory physiology, may enhance safety in the EMU, and may aid in the identification of biomarkers for sudden unexpected death in epilepsy (SUDEP). PMID- 29981498 TI - Utilization of brain imaging in evaluating patients with psychogenic nonepileptic spells. AB - BACKGROUND: Psychogenic nonepileptic spells (PNES) are paroxysmal movements or sensory events that resemble epileptic seizures but lack corresponding ictal electrographic changes. A confirmed diagnosis of PNES is only accomplished via video electroencephalogram (vEEG) monitoring. Prior to diagnosis, patients are often assessed with neurodiagnostic imaging and their conditions treated with anticonvulsant medications, both of which are of limited clinical value and contribute to the higher cost of care. In this study, we assessed the relationship between the semiological features of PNES, medication regimen, or psychiatric comorbidities and the frequency of referrals for brain imaging tests prior to diagnosis of PNES. METHODS: This is a retrospective chart review of 224 adult patients diagnosed as having PNES at a level 4 epilepsy care center from 2012 to 2017. Patients with coexisting epilepsy were excluded. The 882 segments of vEEG records were reviewed for semiology of spells, and patients were categorized into one of seven distinct phenotypic classes according to the accepted clinical classification. The frequency of neurodiagnostic tests completed for each patient prior to vEEG was correlated with PNES phenotype and other clinical characteristics. RESULTS: There were 68 (30%) males and 156 (70%) females diagnosed as having PNES with a median age of 36 years. Seventy-four percent of patients were receiving one or several anticonvulsant medications, and 67% of patients were treated with psychotropic medications other than benzodiazepines. The most prevalent PNES events were characterized by semirhythmic small amplitude movements in the extremities (class 2; 34%) followed by those resembling tonic-clonic seizures (class 4; 28%). Neurodiagnostic imaging tests including computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were performed at least once in 60% of patients and 4 times or more in 11% prior to vEEG. There was a significant association between the frequency of neurodiagnostic tests and the PNES phenotype (p = 0.02). Specifically, patients with sensory changes (class 6) had more imaging tests than those with primitive gesturing and truncal posturing (classes 1 and 5, respectively). Additionally, patients diagnosed with 3 or more psychiatric disorders underwent significantly more neurodiagnostic tests relative to patients diagnosed with two or fewer psychiatric disorders (p = 0.03). Furthermore, patients whose conditions were treated with anticonvulsant medications tended to undergo more imaging scans prior to vEEG as compared with the patients whose conditions were not being treated with anticonvulsants. CONCLUSIONS: These findings suggest that the frequency of brain imaging obtained prior to the definitive diagnosis of PNES is influenced by semiology of spells and the psychiatric health of patients. Patients who demonstrate minimal paroxysmal movements in the settings of multiple psychiatric comorbidities represent a particularly challenging patient phenotype which is linked to more frequent referrals for brain imaging. These patients should be promptly referred for vEEG to improve diagnostic accuracy and prevent treatment with anticonvulsants as well as referrals for serial neurodiagnostic tests. PMID- 29981499 TI - Snail-overexpressing Cancer Cells Promote M2-Like Polarization of Tumor Associated Macrophages by Delivering MiR-21-Abundant Exosomes. AB - Epithelial-mesenchymal transition (EMT) is a major event during cancer progression and metastasis; however, the definitive role of EMT in remodeling tumor microenvironments (TMEs) is unclear. Tumor-associated macrophages (TAMs) are a major type of host immune cells in TMEs, and they perform a wide range of functions to regulate tumor colonization and progression by regulating tumor invasiveness, local tumor immunity, and angiogenesis. TAMs are considered to have an M2-like, i.e., alternatively activated, phenotype; however, how these EMT undergoing cancer cells promote M2 polarization of TAMs as a crucial tumor-host interplay during cancer progression is unclear. In this study, we investigated the mechanism of EMT-mediated TAM activation. Here, we demonstrate that the EMT transcriptional factor Snail directly activates the transcription of MIR21 to produce miR-21-abundant tumor-derived exosomes (TEXs). The miR-21-containing exosomes were engulfed by CD14+ human monocytes, suppressing the expression of M1 markers and increasing that of M2 markers. Knockdown of miR-21 in Snail expressing human head and neck cancer cells attenuated the Snail-induced M2 polarization, angiogenesis, and tumor growth. In head and neck cancer samples, a high expression of miR-21 was correlated with a higher level of SNAI1 and the M2 marker MRC1. This study elucidates the mechanism of EMT-mediated M2 polarization through delivery of the miR-21-abundant exosomes, which may serve as a candidate biomarker of tumor progression and provide a potential target for intercepting EMT-mediated TME remodeling. PMID- 29981500 TI - A Novel Flavonoid Composition Targets Androgen Receptor Signaling and Inhibits Prostate Cancer Growth in Preclinical Models. AB - The high prevalence and long latency period of prostate cancer (PCa) provide a unique opportunity to control disease progression with dietary and nutraceutical approaches. We developed ProFine, a standardized composition of luteolin, quercetin, and kaempferol, and investigated its potential as a nutraceutical for PCa in preclinical models. The three ingredients of ProFine demonstrated synergistic in vitro cytotoxicity and effectively induced apoptosis in PCa cells. ProFine markedly affected the transcriptome of PCa cells, suppressed the expression of androgen receptor, and inhibited androgen-regulated genes. Oral administration of ProFine did not exhibit obvious toxicities in mice, and the three ingredients retained their individual pharmacokinetic and bioavailability profiles. Importantly, ProFine significantly retarded the growth of PCa xenografts in athymic nude mice and extended the survival of animals. This study provides preclinical evidence supporting the promise of ProFine as a safe, efficacious, and affordable intervention to control PCa progression and improve clinical outcomes. PMID- 29981502 TI - The use of digital badges by undergraduate nursing students: A three-year study. AB - During a three-year study, 32% (n = 67) in 2015, 16% (n = 44) in 2016 and 55% (n = 161) of students in 2017 expressed an interest in using digital badges to enhance their learning. But who are these students? This paper explores the features of students who are interested in using digital badges as a motivational reward to prepare for weekly face-to-face classes through engaging with online activities and resources. This paper uses a first-year undergraduate Bachelor of Nursing bioscience topic at an Australian university to report nursing students' interests around playing games, their digital badge history during the topic, and their self-reported attitudinal interest in using digital badges to enhance and personalise their learning. Overall, the results indicate that some students chose to enhance their learning potential in class by earning digital badges prior to class. The results of this paper are relevant for nursing educators and educational designers seeking to integrate digital badges into motivational teaching practices, by evaluating the role digital badges play as a motivational game-based learning design element. PMID- 29981501 TI - Three Dimensional Mixed-Cell Spheroids Mimic Stroma-Mediated Chemoresistance and Invasive Migration in hepatocellular carcinoma. AB - Interactions between cancer cells and cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) play an important role in promoting the profibrotic microenvironment and epithelial-mesenchymal transition (EMT), resulting in tumor progression and drug resistance in hepatocellular carcinoma (HCC). In the present study, we developed a mixed-cell spheroid model using Huh-7 HCC cells and LX-2 stellate cells to simulate the in vivo tumor environment with respect to tumor-CAF interactions. Spheroids were cultured from cancer cells alone (monospheroids) or as a mixture (mixed-cell spheroids) in ultra-low attachment plates. Compact, well-mixed, and stroma-rich mixed-cell spheroids were successfully established with heterotypic cell-cell contacts shown by the presence of gap junctions and desmosomes. Mixed-cell spheroids showed enhanced expression of collagen type-I (Col-I) and pro-fibrotic factors such as, transforming growth factor beta1 (TGF-beta1), and connective tissue growth factor (CTGF) compared to the levels expressed in mono-spheroids. The EMT phenotype was evident in mixed-cell spheroids as shown by the altered expression of E-cadherin and vimentin. Differential drug sensitivity was observed in mixed-cell spheroids, and only sorafenib and oxaliplatin showed dose-dependent antiproliferative effects. Simultaneous treatment with TGF-beta inhibitors further improved sorafenib efficacy in the mixed-cell spheroids, indicating the involvement of TGF beta in the mechanism of sorafenib resistance. In 3D matrix invasion assay, mixed cell spheroids exhibited fibroblast-led collective cell movement. Overall, our results provide evidence that mixed-cell spheroids formed with Huh-7 and LX-2 cells well represent HCC tumors and their TME in vivo and hence are useful in studying tumor-stroma interactions as mechanisms associated with drug resistance and increased cell motility. PMID- 29981503 TI - 'I didn't expect teaching to be such a huge part of nursing': A follow-up qualitative exploration of new graduates' teaching activities. AB - BACKGROUND: Teaching has long been recognised as an important role for nurses. In addition, much has also been written about new graduates' transitions to professional practice. However, the role of new graduates in teaching is unclear, and at what point they are required to teach others as part of their practice. OBJECTIVES: To explore the teaching activities undertaken by new nursing graduates, and their readiness for this role following a semester-long education subject in their undergraduate degrees. DESIGN: A qualitative descriptive design SETTINGS: All participants were undertaking graduate nurse programs and working in different hospitals across Melbourne, Australia. Five were working in public hospitals, and one in a private hospital. PARTICIPANTS: Six graduate nurses who had completed the education subject at one Australian university and were between four and six months into their graduate year program. METHODS: Semi-structured interviews guided by key questions were conducted by telephone. Transcripts were analysed using thematic analysis. RESULTS: Three themes emerged: expectations and the nature of teaching, nature of learners, and attitudes to teaching role. All participants were engaged in some teaching activity early in their graduate programs. This included students of nursing and other disciplines, and qualified staff, as well as patients and their families. Participants reported feeling more confident and better prepared for their roles having completed the education subject than those of their peers, educated at other universities, who had not covered such content. CONCLUSIONS: New graduates are required to teach others, both formally and informally, early after registration. This requirement of professional practice is assisted by the inclusion of an education subject embedded in the undergraduate nursing degree. PMID- 29981504 TI - Self-rated disability in first treated episode of psychosis: A 1-year follow-up study. AB - OBJECTIVES: Knowledge about self-rated disability over time in psychotic disorders is limited. How self-rated disability relates to clinician-rated global functioning, self-rated life satisfaction and symptomatology was investigated across the first year of treatment in early psychosis. METHODS: Participants with first treated episode of psychosis (n = 115) were investigated at baseline and 1 year follow-up. Self-rated Disability was measured with World Health Organization Disability Assessment Schedule 2.0. Clinician-rated global functioning, self rated life satisfaction, and symptomatology were measured with appropriate scales. RESULTS: Average self-rated disability in first-treated episode of psychosis was high, corresponding with the 10% highest in a general population sample. However, 37% were not disabled at a clinically significant level after one year. Self-rated disability was highest in the two social domains (Getting along with people and Participation in society), but improved significantly from baseline to 1-year. At 1-year follow-up self-rated disability had significant weak to medium correlations with clinician-rated global functioning and positive symptoms, and mainly medium to strong correlations with life satisfaction and depressive symptoms. Yet only baseline depression significantly predicted disability after one year. CONCLUSION: Self-rated disability in first treated episode of psychosis is high, but improves across the first year, indicating signs of early recovery. Moreover, self-rated disability is related, but distinct from clinician-rated global functioning and self-rated life satisfaction, suggesting that self-rated disability should also be assessed in order to more fully describe outcomes in first episode psychosis. The findings highlight the need for specialised treatment of depression and social disability in early psychosis. PMID- 29981505 TI - Impaired neuropsychological profile in homicide offenders with schizophrenia. AB - BACKGROUND: Our ability to predict and prevent homicides committed by individuals with schizophrenia is limited. Cognitive impairments are associated with poorer functional outcome in schizophrenia, possibly also homicide. The aim of the current study was to investigate global and specific cognition among homicide offenders with schizophrenia (HOS). METHODS: Twenty-six HOS were compared to 28 individuals with schizophrenia and no history of violence (non-HOS), and a group of healthy controls (HC, n = 151). HOS and non-HOS participants were recruited from in- and outpatient units across Norway. An extensive neuropsychological test battery was administered. RESULTS: HOS participants performed significantly weaker than HC in all cognitive domains. Further, statistically significant differences between HOS and non-HOS participants were found for IQ (d = 0.52) and verbal learning (d = 0.82), with larger impairments in the HOS compared to the non-HOS group. CONCLUSIONS: Our results indicate that HOS participants show clinically significant impairments in global and specific cognition. PMID- 29981507 TI - Malpractice risk at the physician level: Claim-prone physicians. AB - Professional liability and patient safety are worldwide concerns and efforts to identify claimed physicians' characteristics cross borders. Interventions with "at risk populations" would help to better address the underlying problems that lead to many claims. We analyzed physicians' characteristics of every paid claim between 2005 and 2014 in Catalonia region (Spain). We identified 808 physicians involved in 725 paid claims. A total of 12.38% physicians had at least two paid claims over the study period. Physicians' risk of future paid claims was increased if they had more than one previous paid claim (hazard ratio, 1.87; 95% confidence interval [CI], 1.67-2,1). More than half the claims were accounted for by physicians in four specialty groups: obstetrics and gynecology (20.4%), traumatology and orthopedic Surgery (17.5%), plastic surgery (10%) and general surgery (9.7%). The risk of recurrence was higher among surgery-related specialties than among non-surgery-related specialties. Specialty is a particularly strong determinant of claim incidence, so the risk issue may not be so individually determined, but conditioned by the kind of medicine or procedures we practice. Nevertheless, physicians' risk of future paid-claims increases after the second claim. Management systems should take advantage of this information, in order to prevent patient safety events and malpractice claims. Our results support both specialty-based interventions in high-risk specialties, such us Plastic Surgery, as well as interventions at a physician level in those physicians with more than one paid claim. PMID- 29981506 TI - Male sexual assault: Physical injury and vulnerability in 103 presentations. AB - OBJECTIVES: To i) describe the demographic and assault characteristics of males alleging recent sexual assault, ii) determine the severity and frequency of general body injury and the frequency of anal and genital injury, iii) identify vulnerability factors and assault characteristics associated with injury. DESIGN: Cross-sectional study. SETTING: Sexual Assault Resource Centre (SARC), Western Australia. PARTICIPANTS: Total of 103 post-pubertal males attending SARC from Jan 2009 to Dec-2016. METHODS: Men underwent a standardised medical examination and data collection by forensically trained doctors following consent for general body and/or ano-genital examination. Men were considered vulnerable if at least one of the following factors was present: current mental illness; intellectual or physical disability; alcohol intoxication; previous sexual victimization; living in prison or homeless (no fixed address), aged < 18 years. Statistical analysis was performed by Fisher exact test. An algorithm was used to classify general body injuries as mild, moderate or severe. RESULTS: At least one vulnerability factor was present in 88.3% of the 103 men. More than one factor was present in 54.4%. General body injury was observed in 58.0% (40/69) of men consenting to general body examination; 46.4%, 10.1% and 1.4% were classified as having respectively, mild, moderate and severe injuries. Three assault characteristics were associated with general body injury: the use of blunt force (p = 0.002), multiple assailants (p = 0.049) and deprivation of liberty (p = 0.040). Genital injury and anal injury was observed in, respectively, 6.5% (5/77) and 14.3% (11/77) of men consenting to ano-genital examination. Of the 49 men examined following completed penetrative anal assault, 18.4% (9/49) had anal injuries. In these 49 men, those assaulted by strangers were more likely to have an anal injury compared to non-stranger assaults (p = 0.019). No demographic, clinical or vulnerability characteristics of the sexually assaulted men were associated with general body, genital and/or anal injury. CONCLUSION: Although general body injuries were more frequent than genital and anal injuries, most of the body injuries were mild in severity. While the majority of men in our study presented with one or more vulnerabilities only assault characteristics (not vulnerabilities) were associated with injury. PMID- 29981508 TI - Pre-analytical factors related to the stability of ethanol concentration during storage of ante-mortem blood alcohol specimens. AB - Sterile ante-mortem blood specimens were spiked with ethanol at the South African blood alcohol legal concentration limits of 0.20 g/L and 0.50 g/L and were stored in tubes containing sodium fluoride over a period of twenty-nine weeks under refrigeration (4 degrees C) and at room temperature (22 degrees C) to study the stability of the ethanol concentrations over time. Those stored under refrigeration were found to be stable, while a significant decrease in ethanol concentration at 99% confidence was observed in those stored at room temperature. Additional blood specimens, also spiked with ethanol, were inoculated with the dimorphic fungus Candida albicans at five different levels (1 * 106 cells/mL, 5 * 105 cells/mL, 1 * 104 cells/mL, 5 * 103 cells/mL and 5 * 101 cells/mL) and stored with and without sodium fluoride at 4 degrees C and 22 degrees C. The ethanol concentrations were monitored for nine weeks unless no fungal colonies were detected. Regardless of the presence or absence of NaF in samples - sterile or otherwise - storing specimens at 4 degrees C was sufficient to maintain the integrity of blood alcohol concentrations. The ethanol analyses were performed with an in-house validated isotope dilution gas chromatography-mass spectrometry analytical method on newly opened specimens once a week after which significance testing was performed to draw conclusions regarding changes in ethanol concentrations with measurement uncertainty in mind. PMID- 29981509 TI - Age trajectories of musculoskeletal morbidities in adults with cerebral palsy. AB - BACKGROUND: Individuals with cerebral palsy (CP) are at an increased risk for age related morbidities due to functional impairments, maladapted growth, and altered body composition. While musculoskeletal (MSK) deficits are present in children, little is understood about MSK morbidity throughout the lifespan in those with CP. The purpose of this study was to examine the age-related trajectories of MSK morbidity and multimorbidity throughout adulthood in those with CP. METHODS: A clinic-based sample of adults with CP (n = 1395; >=18 years) was examined to determine prevalence of MSK morbidities at the University of Michigan Medical Center. Logistic regression was used to determine the effects of age on individual MSK morbidities and multimorbidity (i.e., >=2 morbidities) after adjusting for sex, race, weight, and smoking. RESULTS: With the 18-30 year age group as the reference, the adjusted odds of osteopenia was lower in the 41-50 and >50 year age groups, the odds of osteoporosis and rheumatoid arthritis was higher in 41-50 and >50 year age groups, and the odds of osteoarthritis was higher in 31-40, 41-50, and >50 year age groups. The adjusted odds of MSK multimorbidity increased substantially with increasing age for 31-40 year olds (OR: 1.919; 95% CI 1.05-3.52), 41-50 year olds (OR: 4.30; 95% CI 2.40-7.69), and >50 year olds (OR: 6.05; 95% CI 3.56-10.27). CONCLUSIONS: Adults with CP are at high risk for MSK morbidities across all ages. Future studies are needed to examine the global aging trajectories of MSK health among adults with CP. Study findings highlight the importance of maximizing MSK accretion, and developing programs to assist individuals with CP and their caregivers to maintain MSK mass and function throughout the lifespan. PMID- 29981510 TI - Exposure of Brazilian soil and groundwater to pollution by coccidiostats and antimicrobial agents used as growth promoters. AB - The World Health Organization has identified antimicrobial resistance as one of the most important threats to global health. Brazil is one of the world's leading meat producers and the Brazilian use of veterinary antimicrobials as therapeutic agents and prophylactic or growth promoters in animal production remains problematic. Many antimicrobials are not completely metabolized and their excretion represents a significant source of environmental exposure. The aim of this work was to estimate the exposure risk of soil and groundwater to pollution by growth promoters (GPs) and anticoccidial additives (AAs) in Brazil by using a method based on a geographical information system (GIS). The principle adopted is that the greater the amount of animals, the greater the quantity of antimicrobials present, and the greater the soil vulnerability to pollution. Our research showed that GPs and AAs are extensively used in the Brazilian animal production system. An analysis of market data showed that zinc bacitracin, monensin, salinomycin, colistin and tylosin are representative GPs and AAs. This study presents a qualitative approach for risk assessment based on worst-case scenarios. First, the probable environmental concentration was estimated using a correlation between the number of heads of the herds of poultry and cattle, and the amounts of drug released. The leaching risk potential was characterized for each compound, as proposed in ISO 15175. The potential of soil pollution was evaluated for each antimicrobial as a function of its binding and dissipation rates. These rates were calculated using georeferenced data of organic carbon, average temperature, water balance and hydro-geological parameters. The consequences were modeled based on Brazilian soil usage. Finally, the risk was calculated by combining the different maps generated using spatial multi-criteria decision analysis. Higher risk was found for the midwest, southeast and south regions of Brazil. Groundwater was found to be more vulnerable than soil. PMID- 29981511 TI - Temporal variability of short term effects of PM10 on mortality in Seoul, Korea. AB - Health effects of PM10 on mortality have been studies worldwide. However, not many studies have questioned possibility that short-term effects of PM10 can be changed over time. Identifying temporal variability of the effects would be of help to getting more valid PM10 effect estimates which are a major basis for public health policies. In this study, temporal variability of short-term effects of PM10 for mortality was investigated from 2001 to 2015 in Seoul, Korea. A time series analysis was used to estimate the effects of PM10 on all-cause, circulatory, and respiratory mortality. Study period was divided into five years of moving time window, and relative risks and its 95% confidence intervals were estimated using distributed lag model for each time window. The annual average of PM10 in Seoul decreased from 52.6 MUg/m3 in 2001 to 40.5 MUg/m3 in 2015. There were significant temporal trends in PM10 effects regarding each mortality. The effects of PM10 tend to slightly increase in early of the study period and then dropped in recent years. An increase of 2 days of cumulative exposure of PM10 was associated with 0.31% (95% confidence interval: 0.15, 0.46) increase in all-cause mortality for 2001-2005 period, 0.61% (95% confidence interval: 0.34, 0.89) increase in 2005-2009 period, and -0.06% (95% confidence interval: -0.38, 0.25) increase in 2011-2015 period. We found evidence that short-term effects of PM10 on mortality have been changed over time in Seoul, Korea. The observed temporal trend might attributable from two factors which are change of PM10 compositions and population vulnerability. If effects of PM10 vary over time, considering its change would be necessary not only in the estimation of the PM10 effect but also its application for a variety of public health policies. PMID- 29981512 TI - Exposure of an urban population to pesticides assessed by wastewater-based epidemiology in a Caribbean island. AB - Wastewater-based epidemiology is an innovative approach to estimate the consumption of chemicals and their exposure patterns in a population, on the basis of measurements of biomarkers in wastewater. This method can provide objective real-time information on xenobiotics directly or indirectly ingested by a population. This approach was used to examine the exposure of the Martinique population to the three classes of pesticides: triazines, organophosphates and pyrethroids. Martinique island (French West Indies) is a closed market and has been closely monitored since the early 2000's when contamination with chlordecone, an organochlorine insecticide widely applied between 1972 and 1993 in banana plantations, became a critical political issue. The aim of this study was to identify and quantify the patterns of human exposure and compare the results to those from other countries. Wastewater was collected as 24-h composite samples and analysed for selected urinary pesticide metabolites by liquid chromatography-tandem mass spectrometry. Organophosphate and pyrethroid metabolites were found in all the samples up to 330 ng/L, while triazines were found only at trace levels. Mass loads indicated higher exposure to pyrethroids than in some cities in Europe, but lower exposure to triazines and organophosphates. The estimated human intake for pyrethroids was close to the Acceptable Daily Intake, but importation of these pesticides to Martinique was low. This study illustrates the high human exposure with indoor pesticide use in comparison to its use in agriculture. PMID- 29981513 TI - Benthic nutrient cycling at the sediment-water interface in a lagoon fish farming system (northern Adriatic Sea, Italy). AB - Metabolism and carbon, oxygen, and nutrient fluxes (DIC, DOC, DO2, NO2-, NO3-, NH4+, PO43- and SiO44-) were studied during three surveys at two sites (VN1 and VN3) located at a fish farm at the Marano and Grado Lagoon (northern Adriatic Sea), using an in situ benthic chamber. Field experiments were conducted in July and October 2015 and March 2016 at a depth of approximately 2 m along the main channels of the fish farm. Water samples were collected by a scuba diver every 2 h in order to investigate daily fluxes of solutes across the sediment-water interface (SWI). Regarding the solid phase, Corg/Ntot and Corg/Porg molar ratios suggested an autochthonous marine origin of the organic matter and a minor preservation of P in the sediments, respectively; high values of sulphur (Stot) were also encountered (0.8-2%). The conditions at VN3 were mostly anoxic with high NH4+ levels (30-1027 MUM) and the absence of NO3-. Substantial daily patterns of all solutes occurred especially in autumn and winter. On the contrary, fluxes at VN1 were less pronounced. Usually, inverse correlations appeared between dissolved O2 and DIC trends, but in our system this was observed only at VN3 in autumn and accomplished by a parallel increase in NH4+, PO43- and SiO44- during intense nutrient regeneration. These results are significantly different than those reported for open lagoon environments, where nutrient regeneration at the SWI and in surface sediments is the primary source of nutrients available for assimilation processes, especially during the warmer period of the year when the natural nutrient input by fresh water inflows is limited. Due to the importance of this site for aquaculture, biodiversity and ecosystem services, useful suggestions have been provided from this study in order to improve the quality of this unique aquatic system. PMID- 29981514 TI - Comment on: Dysregulation of major functional genes in frontal cortex by maternal exposure to carbon black nanoparticle is not ameliorated by ascorbic acid pretreatment. PMID- 29981515 TI - Chronic lead intoxication decreases intestinal helminth species richness and infection intensity in mallards (Anas platyrhynchos). AB - Lead (Pb) pollution of aquatic habitats is a known threat to vertebrate health. Depending on Pb dosage, resulting symptoms can be chronic (sublethal) or acute (lethal). While acute exposure results in death of the animal, chronic sublethal exposure can also have consequences, reproduction, antioxidant defense and immunity being the most affected traits. While a great deal is known about Pb intoxication on avian health, relatively little is known about how intoxication impacts parasites dependent on their avian hosts. The effect of Pb on intestinal helminth species richness and infection intensity was investigated in mallards (Anas platyrhynchos, n = 100) from German waters. Coracoid bones were used to measure chronic Pb exposure. Intestinal helminths were characterized morphologically. Molecular approaches were also applied to identify poorly morphologically preserved parasites to obtain sequence data (cox1 gene) for species identification and future parasitological studies. Parasite species richness and infection intensity was found to be significantly lower in birds with higher chronic Pb levels suggesting both host and parasites respond to Pb exposure. Altered immune modulation in the avian host may be the underlying mechanisms of Pb triggered decrease of parasites. However, it also likely reflects differences in the susceptibility of different helminths to Pb. Cestode and acanthocephala species richness were particularly impacted by Pb exposure. We conclude that, Pb intoxication may both negatively impact avian host and parasite diversity in aquatic habitats. PMID- 29981516 TI - Ecological risk assessment of pesticide mixtures in the alluvial aquifers of central Italy: Toward more realistic scenarios for risk mitigation. AB - In this study we used the data of an extensive pesticide monitoring survey that took place in 11 alluvial aquifers of central Italy from 2010 to 2015 to explore 4 different scenarios of risk. The Scenarios 1 and 2 were used to depict the risk of failing to meet the good groundwater chemical status as defined by the Water Framework Directive. The Scenarios 3 and 4 were used to assess for the first time the ecological risk in groundwater bodies, defined as the likelihood of hazard to the groundwater communities stably residing in the 11 alluvial aquifers that may be affected by pesticide contamination. The ecological risk was assessed through a new procedure called GERAp (Groundwater Ecological Risk Assessment due to pesticides). The main results of this study highlighted that: 1) the Scenario 1 provided information of little use for risk managers; 2) more realistic information was provided by using the highest concentrations measured in the six year monitoring period and considering the ecological risk in a combined scenario (Scenarios 2 and 4); 3) the achievement of the good chemical status by 2027 in 3 aquifers will be likely much more difficult than in the others because the ecosystem services, such as pesticide biodegradation, are likely less efficient in the 3 groundwater bodies; 4) some pesticides that were banned in Europe in 2009 should be kept monitored in the next surveys because they showed a persistent occurrence in the 11 aquifers; 5) DDT forms, Dieldrin and Heptachlor are expected to damage groundwater communities at concentrations that are lower than the present legal limits. PMID- 29981517 TI - Removal of metals and phosphorus recovery from urban anaerobically digested sludge by electro-Fenton treatment. PMID- 29981518 TI - Succession of toxicity and microbiota in hydraulic fracturing flowback and produced water in the Denver-Julesburg Basin. AB - Hydraulic fracturing flowback and produced water (FPW) samples were analyzed for toxicity and microbiome characterization over 220 days for a horizontally drilled well in the Denver-Julesberg (DJ) Basin in Colorado. Cytotoxicity, mutagenicity, and estrogenicity of FPW were measured via the BioLuminescence Inhibition Assay (BLIA), Ames II mutagenicity assay (AMES), and Yeast Estrogen Screen (YES). Raw FPW stimulated bacteria in BLIA, but were cytotoxic to yeast in YES. Filtered FPW stimulated cell growth in both BLIA and YES. Concentrating 25* by solid phase extraction (SPE) revealed significant toxicity throughout well production by BLIA, toxicity during the first 55 days of flowback by YES, and mutagenicity by AMES. The selective pressures of fracturing conditions (including toxicity) affected bacterial and archaeal communities, which were characterized by 16S rRNA gene V4V5 region sequencing. Conditions selected for thermophilic, anaerobic, halophilic bacteria and methanogenic archaea from the groundwater used for fracturing fluid, and from the native shale community. Trends in toxicity echoed the microbial community, which indicated distinct stages of early flowback water, a transition stage, and produced water. Biota in another sampled DJ Basin horizontal well resembled similarly aged samples from this well. However, microbial signatures were unique compared to samples from DJ Basin vertical wells, and wells from other basins. These data can inform treatability, reuse, and management decisions specific to the DJ Basin to minimize adverse environmental health and well production outcomes. PMID- 29981519 TI - Catchment response to climate and land use changes in the Upper Blue Nile sub basins, Ethiopia. AB - The impacts of climate and land development on streamflow and water balance components were analyzed in the Tana and Beles watersheds by using the Soil and Water Assessment Tool (SWAT). Streamflow response to simultaneous future land-use and land-cover (fLULC) and climate change (fCC) scenarios on the seasonal scale varied among the key water abstraction locations. The General Circulation Models (GCMs) average simulation of short-term climate indicated wetter and warmer climatic condition compared to that in the baseline period (1971/1980-2013). The near-future climate scenario would intensify extreme flow by increasing rainy season flow and reducing dry period flow. However, conversion of cultivation land on steep slope into forest might mitigate these extreme flows. At the outlet of Tana watershed, streamflow response would be amplified under concurrent scenarios of fLULC and fCC; but the streamflow would have an augmenting response at the outlet of the Beles watershed. Compared to response due to fCC alone, the streamflow and surface runoff components under combined fLULC and fCC scenarios would be alleviated in sub-catchments subject to conversion of cultivation in steep slope into forest land. The present results have significances for water resource management and land use planning in the Tana and Beles watersheds, and for other regions encountering identical pressures from climate change and LULC dynamics. In view of ongoing land use and climate dynamics, environmental policies must be carried out to cope with the potential changes of hydrologic regime. Moreover, catchment management should be adapted to changing hydrological regimes at different water abstraction points. PMID- 29981520 TI - Carbon footprint and nutritional quality of different human dietary choices. AB - Apart from industrial activities, our eating habits also have a significant environmental cost associated with crop cultivation, manufacturing processes, packaging, refrigeration, transport cooking and waste management. In a context of growing social awareness of the role of different dietary choices in the environment, the review of different alternatives on the road to a healthy and sustainable diet should integrate relevant information on the nutritional quality of different eating habits. Since dietary choices have an effect on environmental sustainability and human health, a literature review on different dietary choices has been conducted to determine the differences in carbon footprint and nutritional quality identifying the main hotspots trying to give advice towards the identification of sustainable diets. After applying a set of criteria for reference selection, 21 peer-reviewed studies have been analysed in detail, allowing the comparison of 66 dietary scenarios. We identified that the so-called Mediterranean and Atlantic diets present high nutritional scores and low carbon footprints. On the contrary, the dietary choices identified in northern and Western Europe, as well as in the United States, have the highest carbon footprints, highlighting the contribution of dairy products as a basic source of high-quality nutrients and protein. Broadly speaking, dietary choices rich in vegetables (e.g., vegan, vegetarian as well as Indian and Peruvian) have a better environmental profile than those rich in meat (mainly ruminant meat). In line with these findings, the shift in meat consumption habits from beef and veal to chicken, pork and poultry, the introduction of alternative foods to animal protein (e.g. quinoa) and the consumption of olive oil as a major source of vegetable oil may be compatible with a healthier and more environmentally friendly diet. However, the complete elimination of meat and dairy products from the daily diet may not be feasible in case the supply of some micronutrients (e.g., calcium and vitamin D) is not guaranteed. Limitations were identified in the consulted studies related to the consideration of the different system boundaries, as well as underlying uncertainties related to data sources. Therefore, efforts should be made to develop consistent and agreed-upon methods for estimating both the carbon footprint and nutritional quality scores. PMID- 29981521 TI - Spatial variation in determinants of agricultural land abandonment in Europe. AB - Agricultural abandonment is widespread and growing in many regions worldwide, often because of agricultural intensification on productive lands, conservation policies, or the spatial decoupling of agricultural production from consumption. Abandonment has major environmental and social impacts, which differ starkly depending on the geographical context, as does its potential to serve as a land reservoir for recultivation. Understanding determinants of abandonment patterns, and especially how their influence varies across broad geographic extents, is therefore important. Using a pan-European map of agricultural abandonment derived from MODIS NDVI time series between 2001 and 2012, we quantified the importance of farm management, climatic, environmental, and socio-economic variables in explaining abandonment patterns. We chose a machine learning modelling framework that accounts for spatial variation in the relationship between abandonment and its determinants. We predicted abandonment probability as well as determinant coefficients for the entire study area and summarised them for regions under selected EU support schemes. Our results highlight that agricultural abandonment was mainly explained by climate conditions suboptimal for agriculture (i.e., low/high growing degrees days). Determinants related to farm management (smaller field size, lower yields) and socio-economic conditions (high unemployment, negative migration balance) also contributed to describing agricultural abandonment patterns in Europe. Several determinants influenced abandonment in strongly non-linear ways and we found substantial spatial non-stationarity effects, although abandonment patterns were equally well-explained by predictors specified with spatially constant and varying effects. Predicted abandonment probability was similar inside and outside EU support or conservation zones, whereas observed MODIS-based abandonment was generally higher outside these zones, suggesting that schemes such as Natura 2000 or High Nature Value Farmland likely influence abandonment patterns. Our work highlights the potential value of spatial boosting for gaining insights into land-use change processes and their outcomes, which should increase the ability of such models to inform context specific, regionalised decision making. PMID- 29981522 TI - Protein biomarkers and coronary microvascular dilatation assessed by rubidium-82 PET in women with angina pectoris and no obstructive coronary artery disease. AB - BACKGROUND AND AIMS: While a plethora of biomarkers have been shown to be associated with coronary artery disease, studies assessing biomarkers in coronary microvascular dysfunction (CMD) are few. We investigated associations between cardiovascular protein biomarkers and non-endothelium dependent CMD assessed by positron emission tomography (PET). METHODS: In 97 women with angina pectoris and no significant obstructive coronary artery disease (<50% stenosis on invasive coronary angiography), CMD was defined as myocardial blood flow reserve (MBFR) < 2.5 by rubidium-82 PET. Blood samples were analyzed with a cardiovascular disease proteomic panel encompassing 92 biomarkers. The relation between MBFR and biomarkers was evaluated with age-adjusted regression analysis. RESULTS: Median age was 62 years (range 31-79), median MBFR was 2.7 (range 1.2-4.7) and 32% had non-endothelium dependent CMD (MBFR<2.5). Four biomarkers were significantly correlated with MBFR: Galectin-4 (Gal4, p = 0.008), growth differentiation factor 15 (GDF15, p = 0.026), tissue-type plasminogen activator (tPA, p = 0.030) and von Willebrand factor (vWF, p = 0.018), while 12 biomarkers showed a trend for correlation (0.05 <= p < 0.15). Of the 16 identified biomarkers, 10 are involved in pro-inflammatory pathways. CONCLUSIONS: In a panel of 92 cardiovascular protein biomarkers, 4 were significantly associated with non-endothelium dependent CMD in women: Gal4, GDF15, tPA and vWF, suggesting that inflammatory status and coagulation changes are associated with impaired microvascular dilatation. Further confirmatory studies are needed to corroborate these findings. PMID- 29981523 TI - Development of a core outcome set for trials on induction of labour: an international multistakeholder Delphi study. AB - OBJECTIVE: To develop a set of core outcomes to be minimally reported in trials on induction of labour. DESIGN: Two-round Delphi survey and consensus meeting. POPULATION: Four stakeholder groups: midwives, obstetricians, neonatologists, and women's representatives. METHODS: Protocol registered with COMET (Registration Number: 695). Stakeholders rated reported outcomes for importance (1-limited to 9 critical). The median rating of each outcome was calculated. The consensus criteria to include outcomes were as follows: >=70% participants rated outcomes as critical and <15% rated outcomes as limited importance. Outcomes that did not achieve consensus were taken to round two and, if there was still no consensus, to the final consensus meeting. MAIN OUTCOME MEASURES: Outcomes in trials of induction of labour. RESULTS: Of the 159 invited participants, 54% (86/159) completed the first round, and 83% completed the second round (71/86). The core outcome set included 28 core outcomes in four domains: Short-term maternal outcomes (n = 18)-cardiorespiratory arrest, damage to internal organs, death, haemorrhage, hysterectomy, infection, intensive care admission, length of hospital stay, mode of delivery, need for more than one induction agent, oxytocin augmentation, postnatal depression, pulmonary embolus, satisfaction with care, stroke, time from induction to delivery, uterine hyperstimulation, uterine scar dehiscence/rupture; short-term offspring outcomes (n = 8)-admission to the neonatal unit, birth trauma, death, hypoxic ischaemic encephalopathy/need for therapeutic hypothermia, meconium aspiration syndrome, need for respiratory support, infection, and seizures; long-term maternal outcomes (n = 1)-operative pelvic floor repair; long-term offspring outcomes (n = 1)-disability including neurodevelopmental delay. CONCLUSION: Trials on induction of labour should include this core outcome set to standardise reporting. TWEETABLE ABSTRACT: International multistakeholder Delphi study identifies a core outcome set for trials on induction of labour. PMID- 29981524 TI - A retrospective comparative study of venous vs nonringed expanded polytetrafluoroethylene extension grafts for anterior sector outflow reconstruction in right lobe living donor liver transplantation. AB - BACKGROUND: Prosthetic vessel grafts are increasingly being used for anterior sector (AS) outflow reconstruction in right lobe living donor liver transplantation (RL-LDLT) in view of easy availability and proper fit. The aim of the study was to analyze technique and outcomes of AS reconstruction using nonringed expanded polytetrafluoroethylene (ePTFE) grafts and compare outcomes with venous extension grafts. METHODS: This is a retrospective study of 437 consecutive RL-LDLTs from January 2014 to August 2015. Vein (V) and ePTFE (alone or composite) were used alternatively or best fit for particular right lobe graft. RESULT: V graft was used in 200 recipients and ePTFE in 237 recipients with comparable preoperative donor and recipient characteristics. Cold ischemia time was significantly high in the ePTFE group. Postoperative recipient outcomes were comparable between the groups. The graft patency rate was comparable between the groups at different time intervals of follow-up. However, 12-month patency was low in those with multiple venous tributaries than with single outflow reconstruction ([V 90%, ePTFE 86.7%] vs [V 97.4%, ePTFE 95.2%]). No patient was re-explored for graft blockage. There was no significant difference in 30-day (V 92%, ePTFE 94.5%, P = 0.34), 90-day (V 90%, ePTFE 90.7%, P = 0.87) and one-year (V 87.5%, ePTFE 89%, P = 0.66) patient survival between the groups. CONCLUSION: Expanded polytetrafluoroethylene gives equivalent patency and recipient outcomes with the added advantage of proper size match fit, allowing more complex AS reconstruction with ease without increased infection rate or associated complications. PMID- 29981525 TI - A common garden experiment with Porphyra umbilicalis (Rhodophyta) evaluates methods to study spatial differences in the macroalgal microbiome. AB - While macroalgal microbiomes are the focus of many recent studies, there is little information about microbial spatial diversity across the thallus. Reliance on field material makes it difficult to discern whether recovered microbiomes belong to the host or its epiphytes, and technical comparisons of macroalgal samples for microbial studies are needed. Here, we use a common garden approach that avoids the problem of epiphytes, particularly at holdfasts, to examine the microbiome of Porphyra umbilicalis (strain Pum1). We used the V6 hypervariable region of the 16S rDNA with Illumina HiSeq sequencing and developed PNA clamps to block recovery of organelle V6 sequences. The common garden approach allowed us to determine differences in the microbiome at the holdfast versus blade margin. We found a notable increase in the relative abundance of Planctomycetes and Alphaproteobacteria at the holdfast, particularly of the possible symbiont Sulfitobacter sp. Nonadjacent 1.5 cm2 samples of blade margin had microbiomes that were not statistically different. The most abundant phylum in the overall microbiome was Proteobacteria, followed by Bacteroidetes. Because phycologists often work in remote sites, we compared three stabilization and preparation techniques and found silica gel desiccation/bead-beating and flash freezing/lyophilization/bead-beating to be interchangeable. Core taxa (>=0.1% of sequences) across treatments were similar and accounted for >=95% of all sequences. Finally, statistical conclusions for all comparisons were the same, regardless of which microbial community analysis tool was used: mothur or minimum entropy decomposition. PMID- 29981526 TI - A new asymmetric diketopiperazine dimer from the sponge-associated fungus Aspergillus versicolor 16F-11. PMID- 29981527 TI - Impact of hepatocellular carcinoma aetiology and liver function on the benefit of surveillance: A novel approach for the adjustment of lead-time bias. AB - BACKGROUND & AIMS: Surveillance reportedly has benefit on survival in patients with hepatocellular carcinoma (HCC), even after adjustment for lead-time bias. However, previous adjustment for lead-time bias using tumour volume doubling time (TVDT) had inherent problem in accuracy. We evaluated survival benefit of HCC surveillance with newly developed approach for adjusting lead-time bias. In addition, survival benefit was evaluated according to HCC aetiology and liver function. METHODS: A total of 3899 patients were studied. TVDT was calculated in 255 study patients with >=2 tumour size measurements before the diagnosis of HCC. Adjusted survival time was calculated based on TVDT, as the time from when HCC was assumed to be 5 mm to death or last follow-up. Survival rates based on this adjusted survival time were compared between the surveillance and nonsurveillance groups and categorized by HCC aetiology and liver function. RESULTS: Calculated TVDT varied widely by study patients (median 141.9, IQR, 73.1-261.7 days). Survival rates based on adjusted survival time were higher in the surveillance group overall and by patients HCC aetiology. Whereas adjusted survival rates were higher in the surveillance group in Child-Pugh class A patients, the survival benefit was smaller in Child-Pugh class B patients and not statistically significant in Child-Pugh class C patients. CONCLUSIONS: The survival benefit of surveillance for patients with HCC was demonstrated after adjustment for lead time bias with novel, more accurate methodology. However, the benefits differed based on liver function and may vary largely by patients because of wide variation in TVDT. PMID- 29981528 TI - Design, Synthesis, and Antifungal Activities of Novel 1,2,4-Triazole Schiff Base Derivatives. AB - With the aim to find new compounds with high antifungal activity, 21 4-amino-5 substituted-1,2,4-triazole Schiff bases (2a - 2g, 3a - 3g, and 4a - 4g) were designed and synthesized. Their antifungal activities against Pythium solani, Gibberlla nicotiancola, Fusarium oxysporium f. sp. niveum, Gibberlla saubinetii, Alternaria iycopersici, Phytophthora capsici, Physalospora piricola, Cercospora arachidicola hori, and Fusarium oxysporium f. sp. cucumber were tested, parts of the compounds exhibited excellent antifungal activity. This research provides useful information for further study of antifungal agents. PMID- 29981530 TI - Involvement of aquaporin-4 in laminin-enhanced process formation of mouse astrocytes in 2D culture: Roles of dystroglycan and alpha-syntrophin in aquaporin 4 expression. AB - In the central nervous system, astrocytes extend endfoot processes to ensheath synapses and microvessels. However, the mechanisms underlying this astrocytic process extension remain unclear. A limitation of the use of 2D cultured astrocytes for such studies is that they display a flat, epithelioid morphology, with no or very few processes, which is markedly different from the stellate morphology observed in vivo. In this study, we obtained 2D cultured astrocytes with a rich complexity of processes using differentiation of neurospheres in vitro. Using these process-bearing astrocytes, we showed that laminin, an extracellular matrix molecule abundant in perivascular sites, efficiently induced process formation and branching. Specifically, the numbers of the first- and second-order branch processes and the maximal process length of astrocytes were increased when cultured on laminin, compared with when they were cultured on poly L-ornithine or type IV collagen. Knockdown of dystroglycan or alpha-syntrophin, constituent proteins of the dystrophin-glycoprotein complex that provides a link between laminin and the cytoskeleton, using small interference RNAs inhibited astrocyte process formation and branching, and down-regulated expression of the water channel aquaporin-4 (AQP4). Direct knockdown and a specific inhibitor of AQP4 also inhibited, whereas over-expression of AQP4 enhanced astrocyte process formation and branching. Knockdown of AQP4 decreased phosphorylation of focal adhesion kinase (FAK) that is critically implicated in actin remodeling. Collectively, these results indicate that the laminin-dystroglycan-alpha syntrophin-AQP4 axis is important for process formation and branching of 2D cultured astrocytes. OPEN PRACTICES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Read the Editorial Highlight for this article on page 436. PMID- 29981529 TI - Characterizing a pH-switch anti-C5 antibody as a tool for human and mouse complement C5 purification and cross-species inhibition of classical and reactive lysis. AB - C5 plays a major role in complement activation; C5 convertase cleaves C5 into the pro-inflammatory C5a, and C5b, the nidus for the formation of the lytic membrane attack complex. C5 is a major target for anti-complement drugs, necessitating better methods for the study of C5 function. Purification of C5 is complicated; classical methods involve precipitation or pH shifts that result in functional loss and low yield. We here present a method for C5 purification using a novel anti-C5 monoclonal antibody (mAb); RO7112689 (C5i mAb, SKY59), pH-switch engineered to induce antibody-antigen dissociation in the acidic endosome (~ pH 5.5). RO7112689 was bound on an affinity column; applied serum was completely depleted of C5. Elution at pH 5 produced fully active C5 at 98% yield. The mAb also bound C5b in the C5b6 complex, preventing C5b6 binding to target membranes and enabling purification of C5b6 from activated serum. RO7112689 inhibited C5 in mouse serum and efficiently purified mouse C5. Used as capture, RO7112689 produced sensitive and specific assays for human and mouse C5. This novel antibody enables efficient production of intact, fully active, pure human and mouse C5, and quantification of C5 in these species. The demonstration that RO7112689 binds C5b6 adds an additional mechanism of membrane attack complex inhibition by this mAb. PMID- 29981531 TI - Introduction of marine-derived Streptomyces sp. UTMC 1334 as a source of pyrrole derivatives with anti-acetylcholinesterase activity. AB - AIM: Alzheimer's disease (AD) is the most common cause of dementia. The acetylcholinesterase (AChE) inhibitors are the most viable therapeutic target for its symptomatic treatment. The present study was aimed at exploring anti-AChE metabolite producing marine Actinobacteria. METHODS AND RESULTS: Of 220 isolates, 34 Actinobacteria extracts were tested for the presence of AChE inhibitors. The obtained results showed that bacterial strain UTMC 1334, inhibited AChE activity in a dose-dependent manner (IC50 = 0.36 +/- 0.019 mg ml-1 ). Based on anti oxidant and cytotoxicity studies, the most potent extract was able to scavenge DPPH radicals with an IC50 value of 45.67 MUg ml-1 with the least cytotoxicity. The GC-MS analysis demonstrated that the mentioned activities could be related to pyrrole-derived compounds as were found the predominant constituents in the extract. The most active extract belonged to the strain that shows 99.41% similarity with Streptomyces lateritius based on 16S rRNA gene sequencing. CONCLUSIONS: Our results show anti-AChE activity is prevalent in marine Actinobacteria, and even in rather comparable prevalence with the antibiotics. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights that exploring new lead anti-AChE compounds may result in discovering novel adjuvant candidates with potency in the treatment of cognitive diseases such as AD. PMID- 29981532 TI - Risk factors and impact of allergic bronchopulmonary aspergillosis in Pseudomonas aeruginosa-negative CF patients. AB - BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a major complication in cystic fibrosis (CF) patients. Risk factors for ABPA and clinical deterioration in CF patients, negative for Pseudomonas aeruginosa (Pa), were explored. METHODS: We performed a retrospective case-control study in 73 Pa negative patients. Each patient was matched with 2 controls for age, gender, pancreas sufficiency, DeltaF508 mutation (homozygous or heterozygous), and Pa colonization. RESULTS: Median FEV1 at the year of diagnosis (index year) was significantly lower in patients with ABPA. The median of cumulative values of FEV1 and FVC before the index year was not significantly different. After the index year, the median of cumulative data for FEV1 and FVC was significantly lower; there were significantly more hospitalization days and more IV antibiotic days compared to controls. Comparing pre- and post-index year data in patients with ABPA, significantly more hospitalization days and more IV antibiotic days were observed after the index year. During the period preceding the index year, significantly more ABPA patients were treated with rhDNase and inhaled corticosteroids. CONCLUSIONS: Bronchial damage cannot be considered as a facilitating factor for ABPA. ABPA causes a significant increase in bronchial damage. In patients with ABPA, further bronchial damage can be controlled by an increase in hospitalization days and use of IV antibiotics. rhDNase and inhaled corticosteroids were associated with the development of ABPA. PMID- 29981534 TI - Electronically nonadiabatic mechanism of the vibrational relaxation of NO in Ar: Rate coefficients from ab initio potentials and asymptotic coupling. AB - In this paper, the electronically nonadiabatic Landau-Zener (LZ) mechanism for the vibrational relaxation v = 1 -> v = 0 of NO(X2Pi) in collisions with Ar(S01) is discussed. It corresponds to nonadiabatic transitions between two crossing vibronic potential energy surfaces (PESs) originating from vibrational states of the collision complex and supported by two coupled electronic PESs. The LZ rate coefficients k10LZ are calculated within the uniform Airy approach in the reaction coordinate approximation with parameters derived from ab initio PESs and an asymptotic estimation of the Franck-Condon factor in the nonadiabatic coupling region. The rate coefficients are close to the experimental rate coefficients available over the range of 900-2500 K, where the electronically adiabatic Landau Teller (LT) mechanism with the rate coefficients k10LT does not make a noticeable contribution to the total relaxation rate. The ratio k10LZ/k10LT increases with temperature and the LZ and LT mechanisms have comparable rates at about 4000 K. PMID- 29981533 TI - Hydrodynamic coupling and rotational mobilities near planar elastic membranes. AB - We study theoretically and numerically, the coupling and rotational hydrodynamic interactions between spherical particles near a planar elastic membrane that exhibits resistance toward shear and bending. Using a combination of the multipole expansion and Faxen's theorems, we express the frequency-dependent hydrodynamic mobility functions as a power series of the ratio of the particle radius to the distance from the membrane for the self mobilities and as a power series of the ratio of the radius to the interparticle distance for the pair mobilities. In the quasi-steady limit of zero frequency, we find that the shear- and bending-related contributions to the particle mobilities may have additive or suppressive effects depending on the membrane properties in addition to the geometric configuration of the interacting particles relative to the confining membrane. To elucidate the effect and role of the change of sign observed in the particle self mobilities and pair mobilities, we consider an example involving a torque-free doublet of counterrotating particles near an elastic membrane. We find that the induced rotation rate of the doublet around its center of mass may differ in magnitude and direction depending on the membrane shear and bending properties. Near a membrane of only energetic resistance toward shear deformation, such as that of a certain type of elastic capsules, the doublet undergoes rotation of the same sense as observed near a no-slip wall. Near a membrane of only energetic resistance toward bending, such as that of a fluid vesicle, we find a reversed sense of rotation. Our analytical predictions are supplemented and compared with fully resolved boundary integral simulations where very good agreement is obtained over the whole range of applied frequencies. PMID- 29981535 TI - Large-scale relativistic complete active space self-consistent field with robust convergence. AB - We report an efficient algorithm using density fitting for the relativistic complete active space self-consistent field (CASSCF) method, which is significantly more stable than the algorithm previously reported by one of the authors [J. E. Bates and T. Shiozaki, J. Chem. Phys. 142, 044112 (2015)]. Our algorithm is based on the second-order orbital update scheme with an iterative augmented Hessian procedure, in which the density-fitted orbital Hessian is directly contracted to the trial vectors. Using this scheme, each microiteration is made less time consuming than one Dirac-Hartree-Fock iteration, and macroiterations converge quadratically. In addition, we show that the CASSCF calculations with the Gaunt and full Breit interactions can be efficiently performed by means of approximate orbital Hessians computed with the Dirac Coulomb Hamiltonian. It is demonstrated that our algorithm can also be applied to systems under an external magnetic field, for which all of the molecular integrals are computed using gauge-including atomic orbitals. PMID- 29981536 TI - Perspective: Chain dynamics of unfolded and intrinsically disordered proteins from nanosecond fluorescence correlation spectroscopy combined with single molecule FRET. AB - The dynamics of unfolded proteins are important both for the process of protein folding and for the behavior of intrinsically disordered proteins. However, methods for investigating the global chain dynamics of these structurally diverse systems have been limited. A versatile experimental approach is single-molecule spectroscopy in combination with Forster resonance energy transfer and nanosecond fluorescence correlation spectroscopy. The concepts of polymer physics offer a powerful framework both for interpreting the results and for understanding and classifying the properties of unfolded and intrinsically disordered proteins. This information on long-range chain dynamics can be complemented with spectroscopic techniques that probe different length scales and time scales, and integration of these results greatly benefits from recent advances in molecular simulations. This increasing convergence between the experiment, theory, and simulation is thus starting to enable an increasingly detailed view of the dynamics of disordered proteins. PMID- 29981537 TI - Absolute fluorescence and absorption measurements over a dynamic range of 106 with cavity-enhanced laser-induced fluorescence. AB - We present a novel spectroscopic technique that exhibits high sensitivity and a large dynamic range for the measurement of absolute absorption coefficients. We perform a simultaneous and correlated laser-induced fluorescence and cavity ring down measurement of the same sample in a single pulsed laser beam. The combined measurement offers a large dynamic range and a lower limit of detection than either technique on its own. The methodology, dubbed cavity-enhanced laser induced fluorescence, is developed and rigorously tested against the electronic spectroscopy of 1,4-bis(phenylethynyl)benzene in a molecular beam and density measurements in a cell. We outline how the method can be used to determine absolute quantities, such as sample densities, absorption cross sections, and fluorescence quantum yields, particularly in spatially confined samples. PMID- 29981538 TI - Vibrational spectroscopy of hydroxylated alpha-Al2O3(0001) surfaces with and without water: An ab initio molecular dynamics study. AB - Using gradient- and dispersion-corrected density functional theory in connection with ab initio molecular dynamics and efficient, parametrized Velocity-Velocity Autocorrelation Function (VVAF) methodology, we study the vibrational spectra (Vibrational Sum Frequency, VSF, and infrared, IR) of hydroxylated alpha Al2O3(0001) surfaces with and without additional water. Specifically, by considering a naked hydroxylated surface and the same surface with a particularly stable, "ice-like" hexagonal water later allows us to identify and disentangle main spectroscopic bands of OH bonds, their orientation and dynamics, and the role of water adsorption. In particular, we assign spectroscopic signals around 3700 cm-1 as being dominated by perpendicularly oriented non-hydrogen bonded aluminol groups, with and without additional water. Furthermore, the thin water layer gives spectroscopic signals which are already comparable to previous theoretical and experimental findings for the solid/(bulk) liquid interface, showing that water molecules closest to the surface play a decisive role in the vibrational response of these systems. From a methodological point of view, the effects of temperature, anharmonicity, hydrogen-bonding, and structural dynamics are taken into account and analyzed, allowing us to compare the calculated IR and VSF spectra with the ones based on normal mode analysis and vibrational density of states. The VVAF approach employed in this work appears to be a computationally accurate yet feasible method to address the vibrational fingerprints and dynamical properties of water/metal oxide interfaces. PMID- 29981539 TI - Hydration and dehydration of monovalent cations near an electrode surface. AB - The mechanism of hydration and dehydration of monovalent ions, Li+, Na+, K+, and Cs+, in a dilute solution near an electrode surface was studied by molecular dynamics simulations. The potentials of mean force for these ions were calculated as a function of the distance from the electrode surface and the potential barriers for dehydrating the first and the second hydration shell near the electrode surface and were estimated for each ion species. It was found that the mechanism of hydration for Li+ is distinct from those for Na+, K+, and Cs+. Penetration of ions into the first layer of water molecules on the electrode surface is unlikely to occur for the case of Li+, while that would occur with certain probabilities for the case of Na+, K+, or Cs+, whether or not voltage is applied to the electrode. Li+ ions would be adsorbed on the electrode surface in a doubly hydrated form with a significant probability, while Na+, K+, and Cs+ ions would be adsorbed most likely in a singly hydrated form. Furthermore, the theory of ionic radii, which has been successfully used in the analysis of bulk solutions, was applied to the electrode/electrolyte interface. It was found that the theory of ionic radii is also useful in explaining the structural behaviors of ions near an electrode surface. The distance between an ion and the layers of water molecules on the electrode surface showed almost linear dependence on the radius of the ion, as predicted by the theory of ionic radii. Analysis of the deviation from the linearity showed that Li+ ions are most likely adsorbed in the first layer of water molecules on the electrode surface, while Na+, K+, and Cs+ ions are adsorbed on the second layer of water molecules. These analyses indicate that Li+ is a structure maker, while Na+, K+, and Cs+ are structure breakers, which is consistent with the widely accepted idea in explaining the behaviors of the bulk solutions. PMID- 29981540 TI - Collisional excitation of interstellar CCN(X2Pi) induced by He. AB - The CCN radical has been recently detected in the interstellar medium. Accurate modeling of its abundance in such media requires one to model its excitation by both radiation and collisions. Here, we report the first quantum mechanical close coupling study of CCN-He collisions. Calculations of fine-structure resolved excitation cross sections of CCN(X2Pi) induced by collision with He are performed for kinetic energies below 500 cm-1. The calculations are based on new two dimensional potential energy surfaces obtained from coupled cluster approaches. We found that the inelastic cross sections for spin-orbit conserving transitions are larger than those for spin-orbit changing transitions. The new collisional data should significantly help the interpretation of interstellar CCN emission lines observed with current and future telescopes and we expect that they will allow accurate determination of the CCN abundance in the interstellar medium, which is crucial to understand the chemistry of carbon chain species in the interstellar gas. PMID- 29981541 TI - Treating linear molecule HCCH in calculations of rotation-vibration spectra. AB - Special treatment is required for ro-vibrational calculations involving polyatomic molecules of linear geometry in order to avoid singularities in the kinetic energy operator. Here we present a variational approach which allows calculations involving such configurations, with a set of 3N-5 linearized coordinates used to represent the vibrations. This approach has been implemented as part of the variational nuclear motion program TROVE (Theoretical ROVibrational Energies). A symmetry adapted basis set based on the Dnh symmetry point group is used. As an illustration of the 3N-5 model presented, TROVE has been used to compute an ab initio room temperature line list for C212H2 using symmetry-adapted ab initio potential energy (CCSD(T)-F12c/cc-pVQZ-F12) and dipole moment surfaces for the ground electronic state. Line positions and intensities (J <= 58, l < 8, covering the wavenumbers up to 10 000 cm-1) are compared against HITRAN-2016 and ASD-1000. Alternative methods for treating linear molecules and future work are discussed. PMID- 29981542 TI - Density functional theory calculations for magnetic properties of Co3W systems. AB - Cheaper permanent magnetic nanostructures with magnetic properties equivalent to those of noble-metal or rare-earth nanomagnets have been experimentally developed for their potential applications in ultrahigh storage densities in magnetic memory. To date, their intrinsic magnetic properties are not well understood under the micro-level of local atomic arrangements and electronic structures. In this work, we performed theoretical investigations on the Co3W bulk, the clean surface, nanoclusters, and the Co|Co3W bilayers and superlattices for their geometrical structures, magnetic moments, and magnetic anisotropy energies (MAEs). We found that the Co3W nanostructures we constructed are stable and have the local minima in the energetic landscape, whose stabilities increase with increasing proportion of W and cluster size. The Co and W atoms in clusters are antiferromagnetically coupled, and their local magnetic moments decrease with increasing proportion of W. The breakdown of the Hund's third rule in W atoms observed in experiment can be interpreted as the competition between the intra atomic spin-orbit coupling in W atoms and interatomic Co-W hybridizations. The highest MAE of about a few tens of meV is obtained in small cluster sizes, whereas it is an order of magnitude reduction in large cluster sizes. The magnetic systems of Co3W clean surface, Co|Co3W bilayer and superlattice can present large MAEs, and their easy-axes of magnetization are perpendicular to the (001) surface. Our calculated MAEs are of the same order of magnitude as that of the experimental measurements, and the electronic origin is revealed through the second-order perturbation method. PMID- 29981543 TI - A comparison of dynamic mean field theory and grand canonical molecular dynamics for the dynamics of pore filling and capillary condensation of fluids in mesopores. AB - We use results from grand canonical molecular dynamics (GCMD) to test the predictions from dynamic mean field theory (DMFT) for the pore filling and capillary condensation mechanisms of a fluid confined in slit shaped mesopores. The theory predicts that capillary condensation occurs by a nucleation process in which a liquid bridge forms between the two walls, and the pore is filled via the growth of this bridge. For longer pores, multiple bridging is seen. These mechanisms are confirmed by the molecular dynamics simulations. The primary difference between the theory and simulations lies in the role of fluctuations. DMFT predicts a single nucleation time and location, while in GCMD (and in nature) a distribution of nucleation times and locations is seen. PMID- 29981544 TI - Calculations of coherent two-dimensional electronic spectra using forward and backward stochastic wavefunctions. AB - Within the well-established optical response function formalism, a new strategy with the central idea of employing the forward-backward stochastic Schrodinger equations in a segmented way to accurately obtain the two-dimensional (2D) electronic spectrum is presented in this paper. Based on the simple excitonically coupled dimer model system, the validity and efficiency of the proposed schemes are demonstrated in detail, along with the comparison against the deterministic hierarchy equations of motion and perturbative second-order time-convolutionless quantum master equations. In addition, an important insight is provided in this paper that the characteristic frequency of the overdamped environment is an extremely crucial factor to regulate the lifetimes of the oscillating signals in 2D electronic spectra and of quantum coherence features of system dynamics. It is worth noting that the proposed scheme benefiting from its stochastic nature and wavefunction framework and many other advantages of substantially reducing the numerical cost has a great potential to systematically investigate various quantum effects observed in realistic large-scale natural and artificial photosynthetic systems. PMID- 29981545 TI - Properties of the hard-sphere fluid at a planar wall using virial series and molecular-dynamics simulation. AB - We study the hard-sphere fluid in contact with a planar hard wall. By combining the inhomogeneous virial series with simulation results, we achieve a new benchmark of accuracy for the calculation of surface thermodynamics properties such as surface adsorption Gamma and the surface free energy (or surface tension), gamma. We briefly introduce the problem of choosing a position for the dividing surface and avoid it by proposing the use of alternative functions to Gamma and gamma that are independent of the adopted frame of reference. Finally, we present analytic expressions for the dependence of system surface thermodynamic properties on packing fraction, ensuring the high accuracy of the parameterized functions for any frame of reference. The proposed parametric expressions for both, Gamma and gamma, fit the accurate simulation results within the statistical error. PMID- 29981546 TI - Mean-field Matsubara dynamics: Analysis of path-integral curvature effects in rovibrational spectra. AB - It was shown recently that smooth and continuous "Matsubara" phase-space loops follow a quantum-Boltzmann-conserving classical dynamics when decoupled from non smooth distributions, which was suggested as the reason that many dynamical observables appear to involve a mixture of classical dynamics and quantum Boltzmann statistics. Here we derive a mean-field version of this "Matsubara dynamics" which sufficiently mitigates its serious phase problem to permit numerical tests on a two-dimensional "champagne-bottle" model of a rotating OH bond. The Matsubara-dynamics rovibrational spectra are found to converge toward close agreement with the exact quantum results at all temperatures tested (200 800 K), the only significant discrepancies being a temperature-independent 22 cm 1 blue-shift in the position of the vibrational peak and a slight broadening in its line shape. These results are compared with centroid molecular dynamics (CMD) to assess the importance of non-centroid fluctuations. Above 250 K, only the lowest-frequency non-centroid modes are needed to correct small CMD red-shifts in the vibrational peak; below 250 K, more non-centroid modes are needed to correct large CMD red-shifts and broadening. The transition between these "shallow curvature" and "deep curvature" regimes happens when imaginary-time Feynman paths become able to lower their actions by cutting through the curved potential surface, giving rise to artificial instantons in CMD. PMID- 29981547 TI - Theory of nonionic hydrophobic solutes in mixture solvent: Solvent-mediated interaction and solute-induced phase separation. AB - We present a theory of nonionic solutes in a mixture solvent composed of water like and alcohol-like species. First, we show the relationship among the solvation chemical potential, the partial volumes vi, the Kirkwood-Buff integrals, the second osmotic virial coefficient, and the Gibbs transfer free energy. We examine how the solute density n3 is coupled to the solvent densities n1 and n2 in thermodynamics. In the limit of small compressibility, we show that the space-filling condition ?i vini = 1 nearly holds for inhomogeneous densities ni, where the concentration fluctuations of the solvent can give rise to a large solute-solute attractive interaction. We also derive a solute spinodal density n3spi for solute-induced instability. Next, we examine gas-liquid and liquid liquid phase transitions induced by a small amount of a solute using the Mansoori, Carnahan, Starling, and Leland model for hard-sphere mixtures [J. Chem. Phys. 54, 1523-1525 (1971)]. Here, we assume that the solvent is close to its gas liquid coexistence and the solute interacts repulsively with the water-like species but attractively with the alcohol-like one. We calculate the binodal and spinodal curves in the phase diagrams and examine nucleation for these two phase transitions. PMID- 29981548 TI - Structural analysis of sulfuric acid solutions containing Ti and Mn using x-ray diffraction, x-ray absorption fine structure, and molecular dynamics simulation. AB - Structural analyses have been performed for sulfuric acid (H2SO4) aqueous solutions containing Ti and/or Mn. These solutions are used as the positive electrolyte in the Ti-Mn redox flow (RF) battery, in which it had been found that adding Ti4+ in the positive electrolyte is very effective to reduce the MnO2 precipitation at a high state of charge. X-ray diffraction and x-ray absorption fine structure (XAFS) measurements were employed in order to obtain total correlation functions, T(r)'s, and coordination numbers around Mn and Ti in the solutions, respectively. The T(r)'s showed some peculiar peaks that were assigned to correspond to S-O, O-O, Mn-O, and Ti-O pairs in the solutions. The XAFS analysis demonstrated that both Mn and Ti have 6-coordinating oxygen atoms in the solutions. The classical molecular dynamics simulation was also carried out to obtain structural models of the solutions. By tuning the Born-Mayer type potential parameters, the T(r)'s calculated from the models showed good agreement with the experimental ones. Regarding the coordination number, the 6-coordinated Mn-O was reproduced successfully, while we need further investigation to find parameters that can reproduce the 6-coordinated Ti-O in the solutions. The simulation results also indicated the existence of Ti-SO4 bonds, which should promote the H+ dissociation from HSO4- and increase the H+ concentration in the solutions. This may be effective to suppress the MnO2 precipitation at a high state of charge in the RF battery. PMID- 29981549 TI - Stretching our understanding of C3: Experimental and theoretical spectroscopy of highly excited nnu1 + mnu3 states (n <= 7 and m <= 3). AB - We present the high resolution infrared detection of fifteen highly vibrationally excited nnu1 + mnu3 combination bands (n <= 7 and m <= 3) of C3 produced in a supersonically expanding propyne plasma, of which fourteen are reported for the first time. The fully resolved spectrum, around 3 MUm, is recorded using continuous wave cavity ring-down spectroscopy. A detailed analysis of the resulting spectra is provided by ro-vibrational calculations based on an accurate local ab initio potential energy surface for C3 (X1Sigmag+). The experimental results not only offer a significant extension of the available data set, extending the observed number of quanta v1 to 7 and v3 to 3, but also a vital test to the fundamental understanding of this benchmark molecule. The present variational calculations give remarkable agreement compared to experimental values with typical accuracies of ~0.01% for the vibrational frequencies and ~0.001% for the rotational parameters, even for high energy levels around 10 000 cm-1. PMID- 29981550 TI - Formation of H2 on graphene using Eley-Rideal and Langmuir-Hinshelwood processes. AB - A hydrogen atom can either physisorb or chemisorb onto a graphene surface. To describe the interaction of H with graphene, we trained the C-C, H-H, and C-H interactions of the ReaxFF CHO bond order potential to reproduce Density Functional Theory (DFT) generated values of graphene cohesive energy and lattice constant, H2 dissociation energy, H on graphene adsorption potentials, and H2 formation on graphene using the Eley-Rideal (ER) and Langmuir-Hinshelwood (LH) processes. The results, generated from the trained H-graphene potentials, are in close agreement with the corresponding results from DFT. The advantage of using optimized CH potentials is, for example, the inclusion of physisorption interactions and quantum mechanical features of chemical bonding in the functional forms of the potentials. The trained CH potentials are utilized to study the energetics of formation of an H2 molecule on graphene using the Eley Rideal and Langmuir-Hinshelwood processes. Potential energy surfaces for the formation of H2 through ER are generated for the collinear and oblique approach of the second hydrogen atom. Energetics of the formation of H2 through LH is studied for a variety of cases such as when hydrogen atoms are chemisorbed or physisorbed and when hydrogen occupies ortho, meta, or para chemisorption sites. The likelihood of H2 formation through LH for various configurations is discussed. Furthermore, the tunneling probability of an atom through a continuous symmetric/asymmetric barrier is calculated and applied to an adsorbed hydrogen atom on graphene. PMID- 29981552 TI - Free-energy analysis of physisorption on solid-liquid interface with the solution theory in the energy representation. AB - Physisorption of urea on its crystal in contact with water was subject to energetics analysis with all-atom molecular dynamics simulation. The transfer free energy of urea to an adsorption site was treated in the framework of the energy-representation theory of solutions, which allows a fast computation of the free energy in an inhomogeneous environment with solid-liquid interface. The preference of adsorption was then compared between the (001) and (110) faces, and it was found that the physisorption is more favorable on (001) than on (110) in correspondence to the hydrogen bonding between the adsorbed urea and the crystal urea. Among the terrace configurations of adsorption, the attractive interaction governs the preferable site with a minor role of the repulsive interaction. The effect of an edge was also treated by examining the terrace and step and was shown to be strongly operative on the (110) face when the CO group of the adsorbed urea points toward the edge. The present work demonstrates that the solution theory can be a framework for analyzing the energetics of physisorption and addressing the roles of the crystal and liquid at the interface through the systematic decomposition of free energy. PMID- 29981551 TI - Infrared spectra of 3-hydroxy-(1H)-pyridinium cation and 3-hydroxy-(1H)-pyridinyl radical isolated in solid para-hydrogen. AB - As pyridine and its derivatives are regarded as building blocks of nitrogen containing polycyclic aromatic hydrocarbons, spectral identifications of their protonated and hydrogenated species are important. The infrared (IR) absorption spectra of the 3-hydroxy-(1H)-pyridinium cation, 3-C5H4(OH)NH+, and the 3-hydroxy (1H)-pyridinyl radical, 3-C5H4(OH)NH, produced on electron bombardment during deposition of a mixture of 3-hydroxypyridine, 3-C5H4(OH)N, and para-H2 to form a matrix at 3.2 K were recorded. Intense IR absorption lines of trans-3-C5H4(OH)NH+ at 3594.4, 3380.0, 1610.6, 1562.2, 1319.4, 1193.8, 1167.5, and 780.4 cm-1 and eleven weaker ones decreased in intensity after the matrix was maintained in darkness for 20 h, whereas lines of trans-3-C5H4(OH)NH at 3646.2, 3493.4, 3488.7, 1546.7, 1349.6, 1244.1, 1209.1, 1177.3, 979.8, and 685.2 cm-1 and nine weaker ones increased. The intensities of lines of trans-3-C5H4(OH)NH decreased upon irradiation at 520 nm and diminished nearly completely upon irradiation at 450 nm, whereas those of trans-3-C5H4(OH)NH+ remained unchanged upon irradiation at 370, 450, and 520 nm. Observed vibrational wavenumbers and relative intensities of these species agree satisfactorily with the scaled harmonic vibrational wavenumbers and IR intensities predicted with the B3LYP/aug-cc-pVTZ method. The observed 3-C5H4(OH)NH+ cation and 3-C5H4(OH)NH radical are predicted to be the most stable species among all possible isomers by quantum-chemical calculations. PMID- 29981553 TI - The intersystem crossing of a cyclic (alkyl)(amino) carbene gold (i) complex. AB - The intersystem crossing (ISC) mechanism of a cyclic (alkyl)(amino) carbene gold (I) complex (CMA1) is studied using quantum dynamics. A model spin-vibronic Hamiltonian is developed, which includes 10 excited states and two important nuclear degrees of freedom. The quantum dynamics reveals that ISC from S1 -> T1 occurs on the tens of picosecond time scale, consistent with recent experiments. It is driven by motion along the torsional degree of freedom of the carbazole (Cz) ligand, which causes orthogonality between the donor and acceptor groups closing the gap between the initial (S1) and final (T1) states. The role of higher triplet states through spin-vibronic interactions is also discussed. Although previous calculations, evaluated in the Condon approximation, yield large ISC rates, our present dynamical treatment, taking into account the large amplitude torsional motion, increases the calculated rate by an order of magnitude improving the agreement with experiments. The model spin-vibronic Hamiltonian developed can also be used to understand the properties of related linear metal carbene compounds, facilitating molecular design. PMID- 29981554 TI - Addressing hysteresis and slow equilibration issues in cavity-based calculation of chemical potentials. AB - In this paper, we explore the strengths and weaknesses of a cavity-based method to calculate the excess chemical potential of a large molecular solute in a dense liquid solvent. Use of the cavity alleviates some technical problems associated with the appearance of (integrable) divergences in the integrand during alchemical particle growth. The excess chemical potential calculated using the cavity-based method should be independent of the cavity attributes. However, the performance of the method (equilibration time and the robustness) does depend on the cavity attributes. To illustrate the importance of a suitable choice of the cavity attributes, we calculate the partition coefficient of pyrene in toluene and heptane using a coarse-grained model. We find that a poor choice for the functional form of the cavity may lead to hysteresis between growth and shrinkage of the cavity. Somewhat unexpectedly, we find that, by allowing the cavity to move as a pseudo-particle within the simulation box, the decay time of fluctuations in the integrand of the thermodynamic integration can be reduced by an order of magnitude, thereby increasing the statistical accuracy of the calculation. PMID- 29981555 TI - Macroscopic superhydrophobicity achieved by atomic decoration with silicones. AB - Modulating wetting states of water droplets on a solid surface has great potential in numerous applications such as self-cleaning, heat transfer, and water purification. Present strategies to achieve controlled wettability usually employ surface roughness and/or chemical coating at the nanometer-to-micrometer scale. Here we propose that atomic-scale decoration and patterning with silicones can be used to fabricate superhydrophobic surfaces. Atomic decoration, differing from chemical coatings in the characteristic size and partial coverage, controls wetting states with the atomic precision (several angstroms) at low cost and maintains a long lifetime. We attribute the mechanism of atomic decoration to the decrease in effective potential-well depth, inducing weak interactions between the substrate and water droplet. Our work pushes water wetting to the limit of atomic scales, hinting for a paradigm shift from macroscopic to atomically precise engineering of wetting states and providing new insights for fabricating superhydrophobic surfaces. PMID- 29981556 TI - Non-local stresses in highly non-uniformly flowing suspensions: The shear curvature viscosity. AB - For highly non-uniformly flowing fluids, there are contributions to the stress related to spatial variations of the shear rate, which are commonly referred to as non-local stresses. The standard expression for the shear stress, which states that the shear stress is proportional to the shear rate, is based on a formal expansion of the stress tensor with respect to spatial gradients in the flow velocity up to leading order. Such a leading order expansion is not able to describe fluids with very rapid spatial variations of the shear rate, like in micro-fluidics devices and in shear-banding suspensions. Spatial derivatives of the shear rate then significantly contribute to the stress. Such non-local stresses have so far been introduced on a phenomenological level. In particular, a formal gradient expansion of the stress tensor beyond the above mentioned leading order contribution leads to a phenomenological formulation of non-local stresses in terms of the so-called "shear-curvature viscosity". We derive an expression for the shear-curvature viscosity for dilute suspensions of spherical colloids and propose an effective-medium approach to extend this result to concentrated suspensions. The validity of the effective-medium prediction is confirmed by Brownian dynamics simulations on highly non-uniformly flowing fluids. PMID- 29981557 TI - Development of effective stochastic potential method using random matrix theory for efficient conformational sampling of semiconductor nanoparticles at non-zero temperatures. AB - The relationship between structure and property is central to chemistry and enables the understanding of chemical phenomena and processes. Need for an efficient conformational sampling of chemical systems arises from the presence of solvents and the existence of non-zero temperatures. However, conformational sampling of structures to compute molecular quantum mechanical properties is computationally expensive because a large number of electronic structure calculations are required. In this work, the development and implementation of the effective stochastic potential (ESP) method is presented to perform efficient conformational sampling of molecules. The overarching goal of this work is to alleviate the computational bottleneck associated with performing a large number of electronic structure calculations required for conformational sampling. We introduce the concept of a deformation potential and demonstrate its existence by the proof-by-construction approach. A statistical description of the fluctuations in the deformation potential due to non-zero temperature was obtained using infinite-order moment expansion of the distribution. The formal mathematical definition of the ESP was derived using the functional minimization approach to match the infinite-order moment expansion for the deformation potential. Practical implementation of the ESP was obtained using the random-matrix theory method. The developed method was applied to two proof-of-concept calculations of the distribution of HOMO-LUMO gaps in water molecules and solvated CdSe clusters at 300 K. The need for large sample size to obtain statistically meaningful results was demonstrated by performing 105 ESP calculations. The results from these prototype calculations demonstrated the efficacy of the ESP method for performing efficient conformational sampling. We envision that the fundamental nature of this work will not only extend our knowledge of chemical systems at non zero temperatures but also generate new insights for innovative technological applications. PMID- 29981558 TI - Bridging molecular simulation models and elastic theories for amphiphilic membranes. AB - The Single Chain Mean Field theory is used to link coarse-grained models of amphiphilic molecules with analytical models for membrane elasticity, where phenomenological parameters are deduced from explicit molecular models and force fields. We estimate the elastic constants based on the free energy of the amphiphilic bilayer in planar and cylindrical geometries on the example of four amphiphilic molecules that differ in length and stiffness. We study how these variations affect the equilibrium bilayer structure, the equilibrium free energy, and the elastic constants. Bending rigidities are obtained within the typical range of experimental values for phospholipid membranes in a liquid state. PMID- 29981559 TI - Probabilistic characterization of the Widom delta in supercritical region. AB - We present a probabilistic classification algorithm to understand the structural transition of supercritical Lennard-Jones (LJ) fluid. The classification algorithm is designed based on the exploratory data analysis on the nearest Voronoi neighbors of subcritical vapor and liquid. The algorithm is tested and applied to LJ type fluids modeled with the truncated and shifted potential and the Weeks-Chandler-Andersen potential. The algorithm makes it available to locate the Widom delta, which encloses the supercritical gas-liquid boundary and the percolation transition loci in a geometrical manner, and to conjecture the role of attractive interactions on the structural transition of supercritical fluids. Thus, the designed algorithm offers an efficient and comprehensible method to understand the phase behavior of a supercritical mesophase. PMID- 29981560 TI - Announcement: Top reviewers for The Journal of Chemical Physics 2017. PMID- 29981561 TI - Calculations of free energy of surface interactions in crystalline polyethylene. AB - The surface free energy of the crystalline polyethylene (PE) is an important property related with wettability, adhesion, and crystal growth. We investigated the profiles of free energy of surface interactions in the fully thermalized crystalline PE during debonding and shearing with atomistic molecular dynamics simulations using steered molecular dynamics and umbrella sampling techniques. The stress profiles during debonding and shearing processes were also estimated and compared with those obtained from analogous deformation simulations. We estimated the vacuum surface free energies of two different crystallographic surfaces (100) and (010) of the crystalline PE from the free energy changes during the debonding process. The estimated surface free energies were insensitive to the choice of simulation protocols after combining estimates from both forward and backward processes and were in excellent agreement with those obtained from an experiment on PE single crystal aggregates, which underscores the importance of the inclusion of the entropic contribution in the free energy calculated with the fully flexible interface adopted in this study. PMID- 29981563 TI - Cross-reactivity pattern of a rare presentation of generalized delayed-type hypersensitivity to local anaesthetics. AB - A seven-year-old girl developed angioedema and a generalized, erythematous rash several hours after receiving lignocaine with adrenaline reproducible on provocative challenge, confirming the first known case of generalized delayed type hypersensitivity to local anaesthetics with cross-reactivity to bupivacaine but not chloroprocaine. PMID- 29981562 TI - Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation. AB - BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is medically unexplained post-exertional fatigue associated with significant reduction in natural killer cell (NK) cytotoxicity activity. Cytotoxic activity relies on glycolytic flux and mitochondrial respiration to fulfill energetic cellular demands. While mitochondrial dysfunction has been reported in ME/CFS patients, no previous investigation has examined the bioenergetic profile of isolated NK cells from ME/CFS patients. OBJECTIVE: This study was to determine the metabolic function in resting NK cells from ME/CFS patients. METHOD: Six ME/CFS patients (aged 50.33+/-4.95) were age and sex-matched with non-fatigued healthy controls (aged 50.00+/-5.04). Mitochondrial stress tests measured parameters of mitochondrial function in the NK cells including basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and bioenergetic health index. Glycolytic stress tests measured parameters of glycolytic function such as glycolytic reserve, glycolysis and glycolytic capacity in isolated NK cells from ME/CFS patients and healthy controls using an extracellular flux analyzer, Seahorse XFp. RESULT: There was a significant reduction of glycolytic reserve in resting NK cells from ME/CFS patients (0.6+/ 0.07 mpH/ min) compared with healthy control (2.25+/-1.3 mpH/min). Mitochondrial respiration in resting NK cells did not approach statistical significance between ME/CFS patients and healthy controls. CONCLUSION: These findings suggest resting NK cells from ME/CFS patients have reduced ability to increase glycolytic flux to respond to high energetic demands for ATP production. Hence, the reduced glycolytic reserves we have identified in isolated resting isolated NK cells should be further investigated to assist in understanding ME/CFS pathogenesis. PMID- 29981564 TI - Reduced CD4+ terminally differentiated effector memory T cells in moderate-severe house dust mites sensitized allergic rhinitis patients. AB - BACKGROUND: Terminally differentiated effector memory (TEMRA) T cells exert potent effector function after activation. The proportions of CD4+ T cell subsets especially memory cells in allergic rhinitis (AR) patients sensitized to house dust mites (HDMs) have not been extensively studied. OBJECTIVE: This study aimed to compare the mean percentages and absolute counts of CD4+ memory T cell subsets between: (i) non-allergic controls and AR patients; (ii) mild AR patients and moderate-severe AR patients. METHODS: Sensitization to Dermatophagoides farinae and Dermatophagoides pteronyssinus were determined in 33 non -allergic controls, 28 mild AR and 29 moderate-severe AR patients. Flow cytometry was used to determine the percentage of CD4+ na?ve (TN; CD45RA+CCR7+), central memory (TCM; CD45RA-CCR7+), effector memory (TEM; CD45RA-CCR7-) and TEMRA (CD45RA+CCR7-) T cells from the peripheral blood. The absolute counts of CD4+ T cell subsets were obtained by dual platform method from flow cytometer and hematology analyzer. RESULTS: There were no significant differences in the mean percentages and absolute counts of CD4+ T cell subsets between non-allergic controls and AR patients sensitized to HDMs. However, there were significant reduction in the mean percentage (p=0.0307) and absolute count (p=0.0309) of CD4+ TEMRA cells in moderate-severe AR patients compared to mild AR patients sensitized to HDMs and 13/24 (54.2%) moderate-severe AR patients sensitized to HDMs had persistent symptoms. CONCLUSION: Reduction in the mean percentage and absolute count of CD4+CD45RA+CCR7- TEMRA cells were observed in moderate-severe AR patients compared to mild AR patients in our population of AR patients sensitized to HDMs. PMID- 29981565 TI - The prevalence and sex difference of allergen sensitization among adult patients with allergic diseases in Shanghai, China. AB - BACKGROUND: The worldwide prevalence of allergic diseases has increased during the last few decades, but it is not well known about the sensitization profiles of adult patients in Shanghai. OBJECTIVE: This study aimed to identify the prevalence and sex difference of allergen sensitization among adult with allergic diseases in Shanghai. METHODS: The sensitization profiles of 7,996 patients (18 60 yrs old) with allergic diseases at our center were retrospectively analyzed, based on the results of skin prick tests. The prevalence of various allergen, age and sex difference of allergen sensitization were investigated. RESULTS: The most common allergens were Dermatophagoides farinae (73.10%), Dermatophagoides pteronyssinus (72.21%) and Blomia tropicalis (53.10%), followed by Blattella germanica (31.18%), Periplaneta americana (27.75%), dog dander (24.96%), mixed molds (17.56%), and shrimp (17.02%). For the patients aged 18-30 yrs, mites and animal dander were most common allergen, whereas cockroaches and mixed molds for those aged over 40 yrs old. As for sex difference, males were more sensitive to Blomia tropicalis, cockroaches and mixed molds. Females were more sensitive to Dermatophagoides farinae and animal dander. CONCLUSIONS: The most common allergen in Shanghai are mites, cockroaches, and dog dander. There are sex and age difference on profiles of allergen sensitization. PMID- 29981566 TI - Randomized comparison of Caregivers' ability to use Epinephrine Autoinjectors and Prefilled Syringes for anaphylaxis. AB - BACKGROUND: Caregivers often incorrectly use epinephrine autoinjectors. It is unclear whether this is due to insufficient training or a difficult-to-use tool. Furthermore, the high costs of epinephrine autoinjectors may limit their availability; so low-cost prefilled syringes may be the alternative. OBJECTIVES AND METHODS: We performed a prospective randomized trial to compare successful epinephrine administration at four stages: after reading written instructions, and immediately after, 6 weeks, and 3 months following video training. The time required for successful epinephrine administration and failed steps in the administration of epinephrine autoinjectors and prefilled syringe were also investigated. RESULTS: Complete data analysis of 113 participants (prefilled syringe group, n=57; EpiPen, n=56) was performed. Significantly more participants correctly demonstrated the use of prefilled syringes compared to EpiPen after reading instructions, and immediately following 6 weeks, and 3 months after video training. ((adjusted OR 26.17 (95%CI 8.2583.04), adjusted OR 4.07 (95%CI 1.29 12.86), adjusted OR 14.01 (95%CI 3.62-54.22)) and adjusted OR 31.44 (95%CI 5.73172.39), respectively) Four key step errors would likely result in failure of administration and were more common with EpiPen (14.0% vs. 2.3%, p<0.001). There were no statistically significant differences in time of successful administration between the two groups (p>0.05). CONCLUSION: Epinephrine prefilled syringe was significantly easier to use with a higher rate of correct use compared to EpiPen over time. All four key step errors in the administration were more likely with EpiPen. The time required for successful epinephrine administration was not significantly different. PMID- 29981567 TI - Clinical and immunological characteristics of antiphospholipid syndrome in an Asian population: a retrospective study. AB - OBJECTIVES: To describe the characteristics of patients with antiphospholipid syndrome (APS) in an Asian clinical practice setting. METHODS: We conducted a single-center, retrospective study of APS patients attending the rheumatology or hematology clinics, between January 2012 and December 2016. RESULTS: There were 450 patients suspected of having APS referred to our clinics. Seventy-four (16.4%) were diagnosed of APS, 51% of which were definite. Fifty-two (70%) patients were classified as primary APS, 50% of which were definite APS. The most common clinical manifestation was stroke (33%), followed by deep vein thrombosis of the lower extremities (30%) and pulmonary embolism (19%). Hypertension and the presence of at least one established cardiovascular risk factor were independently associated with stroke. Seven (9%) patients had multiorgan thrombosis as their first presentation of APS, 71% of which ultimately suffered from permanent organ damage or died of severe thrombosis, despite not fulfilling the criteria for 'definite' catastrophic APS (CAPS). Late fetal loss was the most prevalent obstetric complication. The majority of patients (79%) tested positive for lupus anticoagulant (LAC), while only 32% tested positive for anti cardiolipin antibodies. Triple positive profile was documented in 14% of the cohort. Overall, recurrent thrombosis and bleeding complications were recorded in 9% and 28%, respectively. CONCLUSION: APS patients in central Thailand demonstrated high prevalence of stroke, late fetal loss, LAC positivity, and multiorgan thrombosis at first presentation, leading to poor outcomes. PMID- 29981568 TI - Formative evaluation and adaptation of pre-and early implementation of diabetes shared medical appointments to maximize sustainability and adoption. AB - BACKGROUND: Understanding the many factors that influence implementation of new programs, in addition to their success or failure, is extraordinarily complex. This qualitative study examines the implementation and adaptation process of two linked clinical programs within Primary Care, diabetes shared medical appointments (SMAs) and a reciprocal Peer-to-Peer (P2P) support program for patients with poorly controlled diabetes, through the lens of the Consolidated Framework for Implementation Research (CFIR). We illustrate the role and importance of pre-implementation interviews for guiding ongoing adaptations to improve implementation of a clinical program, achieve optimal change, and avoid type III errors. METHODS: We conducted 28 semi-structured phone interviews between September of 2013 and May of 2016, four to seven interviewees at each site. The interviewees were physician champions, chiefs of primary care, pharmacists, dieticians, nurses, health psychologists, peer facilitators, and research coordinators. Modifiable barriers and facilitators to implementation were identified and adaptations documented. Data analysis started with immersion in the data to obtain a sense of the whole and then by cataloging principal themes per CFIR constructs. An iterative consensus-building process was used to code. CFIR constructs were then ranked and compared by the researchers. RESULTS: We identified a subset of CFIR constructs that are most likely to play a role in the effectiveness of the diabetes SMAs and P2P program based on our work with the participating sites to date. Through the identification of barriers and facilitators, a subset of CFIR constructs arose, including evidence strength and quality, relative advantage, adaptability, complexity, patient needs and resources, compatibility, leadership engagement, available resources, knowledge and beliefs, and champions. CONCLUSIONS: We described our method for identification of contextual factors that influenced implementation of complex diabetes clinical programs - SMAs and P2P. The qualitative phone interviews aided implementation through the identification of modifiable barriers or conversely, actionable findings. Implementation projects, and certainly clinical programs, do not have unlimited resources and these interviews allowed us to determine which facets to target and act on for each site. As the study progresses, these findings will be compared and correlated to outcome measures. This comprehensive adaptation data collection will also facilitate and enhance understanding of the future success or lack of success of implementation and inform potential for translation and public health impact. The approach of using the CFIR to guide us to actionable findings and help us better understand barriers and facilitators has broad applicability and can be used by other projects to guide, adapt, and improve implementation of research into practice. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02132676 . PMID- 29981569 TI - The DIAMOND trial - DIfferent Approaches to MOderate & late preterm Nutrition: Determinants of feed tolerance, body composition and development: protocol of a randomised trial. AB - BACKGROUND: Babies born at moderate-late preterm gestations account for > 80% of all preterm births. Although survival is excellent, these babies are at increased risk of adverse neurodevelopmental outcomes. They also are at increased risk of adverse long-term health outcomes, such as cardiovascular disease, obesity and diabetes. There is little evidence guiding optimal nutritional practices in these babies; practice, therefore, varies widely. This factorial design clinical trial will address the role of parenteral nutrition, milk supplementation and exposure of the preterm infant to taste and smell with each feed on time to tolerance of full feeds, adiposity, and neurodevelopment at 2 years. METHODS/DESIGN: The DIAMOND trial is a multi-centre, factorial, randomised, controlled clinical trial. A total of 528 babies born between 32+ 0 and 35+ 6 weeks' gestation receiving intravenous fluids and whose mothers intend to breastfeed will be randomised to one of eight treatment conditions that include a combination of each of the three interventions: (i) intravenous amino acid solution vs. intravenous dextrose solution until full milk feeds established; (ii) milk supplement vs. exclusive breastmilk, and (iii) taste/smell given or not given before gastric tube feeds. Babies will be excluded if a particular mode of nutrition is clinically indicated or there is a congenital abnormality. Primary study outcome: For parenteral nutrition and milk supplement interventions, body composition at 4 months' corrected age. For taste/smell intervention, time to full enteral feeds defined as 150 ml.kg- 1.day- 1 or exclusive breastfeeding. SECONDARY OUTCOMES: Days to full sucking feeds; days in hospital; body composition at discharge; growth to 2 years' corrected age; development at 2 years' corrected age; breastfeeding rates. DISCUSSION: This trial will provide the first direct evidence to inform feeding practices in moderate- to late preterm infants that will optimise their growth, metabolic and developmental outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12616001199404 . This trial is endorsed by the IMPACT clinical trials network ( https://impact.psanz.com.au ). PMID- 29981570 TI - Omega-3 polyunsaturated fatty acids favourably modulate cardiometabolic biomarkers in type 2 diabetes: a meta-analysis and meta-regression of randomized controlled trials. AB - BACKGROUND: Randomized controlled trials (RCTs) suggest that supplementation with omega-3 polyunsaturated fatty acids (n-3PUFAs) may favourably modify cardiometabolic biomarkers in type 2 diabetes (T2DM). Previous meta-analyses are limited by insufficient sample sizes and omission of meta-regression techniques, and a large number of RCTs have subsequently been published since the last comprehensive meta-analysis. Updated information regarding the impact of dosage, duration or an interaction between these two factors is therefore warranted. The objective was to comprehensively assess the effect of n-3PUFAs supplementation on cardiometabolic biomarkers including lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control, in people with T2DM, and identify whether treatment dosage, duration or an interaction thereof modify these effects. METHODS: Databases including PubMed and MEDLINE were searched until 13th July 2017 for RCTs investigating the effect of n-3PUFAs supplementation on lipid profiles, inflammatory parameters, blood pressure, and indices of glycaemic control. Data were pooled using random-effects meta-analysis and presented as standardised mean difference (Hedges g) with 95% confidence intervals (95% CI). Meta-regression analysis was performed to investigate the effects of duration of supplementation and total dosage of n-3PUFAs as moderator variables where appropriate. RESULTS: A total of 45 RCTs were identified, involving 2674 people with T2DM. n-3PUFAs supplementation was associated with significant reductions in LDL [ES: - 0.10, (95% CI - 0.17, - 0.03); p = 0.007], VLDL (ES: - 0.26 (- 0.51, - 0.01); p = 0.044], triglycerides (ES: - 0.39 (- 0.55, - 0.24; p <= 0.001] and HbA1c (ES: - 0.27 (- 0.48, - 0.06); p = 0.010]. Moreover, n-3PUFAs supplementation was associated with reduction in plasma levels of TNF alpha [ES: - 0.59 (- 1.17, - 0.01); p = 0.045] and IL-6 (ES: - 1.67 (- 3.14, - 0.20); p = 0.026]. All other lipid markers, indices of glycaemic control, inflammatory parameters, and blood pressure remained unchanged (p > 0.05). CONCLUSIONS: n-3PUFAs supplementation produces favourable hypolipidemic effects, a reduction in pro-inflammatory cytokine levels and improvement in glycaemia. Neither duration nor dosage appear to explain the observed heterogeneity in response to n-3PUFAs. Trial registration This trial was registered at http://www.crd.york.ac.uk as CRD42016050802. PMID- 29981571 TI - Dual inhibition of sodium-glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction. AB - BACKGROUND: Inhibiting both type 1 and 2 sodium-glucose linked cotransporter (SGLT1/2) offers the potential to not only increase glucosuria beyond that seen with selective SGLT2 inhibition alone but to reduce glucose absorption from the gut and to thereby also stimulate glucagon-like peptide 1 secretion. However, beyond the kidney and gut, SGLT1 is expressed in a range of other organs particularly the heart where it potentially assists GLUT-mediated glucose transport. Since cardiac myocytes become more reliant on glucose as a fuel source in the setting of stress, the present study sought to compare the effects of dual SGLT1/2 inhibition with selective SGLT2 inhibition in the normal and diseased heart. METHODS: Fischer F344 rats underwent ligation of the left anterior descending coronary artery or sham ligation before being randomized to receive the dual SGLT1/2 inhibitor, T-1095, the selective SGLT2 inhibitor, dapagliflozin or vehicle. In addition to measuring laboratory parameters, animals also underwent echocardiography and cardiac catheterization to assess systolic and diastolic function in detail. RESULTS: When compared with rats that had received either vehicle or dapagliflozin, T-1095 exacerbated cardiac dysfunction in the post myocardial infarction setting. In addition to higher lung weights, T-1095 treated rats had evidence of worsened systolic function with lower ejection fractions and reduction in the rate of left ventricle pressure rise in early systole (dP/dtmax). Diastolic function was also worse in animals that had received T-1095 with prolongation of the time constant for isovolumic-pressure decline (Tau) and an increase in the end-diastolic pressure volume relationship, indices of the active, energy-dependent and passive phases of cardiac relaxation. CONCLUSIONS: The exacerbation of post myocardial infarction cardiac dysfunction with T-1095 in the experimental setting suggests the need for caution with the use of dual SGLT1/2 inhibitors in humans. PMID- 29981572 TI - Rational modification of tricarboxylic acid cycle for improving L-lysine production in Corynebacterium glutamicum. AB - BACKGROUND: Oxaloacetate (OAA) and L-glutamate are essential precursors for the biosynthesis of L-lysine. Reasonable control of all potentially rate-limiting steps, including the precursors supply rate, is of vital importance to maximize the efficiency of L-lysine fermentation process. RESULTS: In this paper, we have rationally engineered the tricarboxylic acid (TCA) cycle that increased the carbon yield (from 36.18 to 59.65%), final titer (from 14.47 +/- 0.41 to 23.86 +/ 2.16 g L-1) and productivity (from 0.30 to 0.50 g L-1 h-1) of L-lysine by Corynebacterium glutamicum in shake-flask fermentation because of improving the OAA and L-glutamate availability. To do this, the phosphoenolpyruvate-pyruvate oxaloacetate (PEP-pyruvate-OAA) node's genes ppc and pyc were inserted in the genes pck and odx loci, the P1 promoter of the TCA cycle's gene gltA was deleted, and the nature promoter of glutamate dehydrogenase-coding gene gdh was replaced by Ptac-M promoter that resulted in the final engineered strain C. glutamicum JL 69Ptac-M gdh. Furthermore, the suitable addition of biotin accelerates the L lysine production in strain JL-69Ptac-M gdh because it elastically adjusts the carbon flux for cell growth and precursor supply. The final strain JL-69Ptac-M gdh could produce 181.5 +/- 11.74 g L-1 of L-lysine with a productivity of 3.78 g L-1 h-1 and maximal specific production rate (qLys, max.) of 0.73 +/- 0.16 g g-1 h-1 in fed-batch culture during adding 2.4 mg L-1 biotin with four times. CONCLUSIONS: Our results reveal that sufficient biomass, OAA and L-glutamate are equally important in the development of L-lysine high-yielding strain, and it is the first time to verify that fed-batch biotin plays a positive role in improving L-lysine production. PMID- 29981573 TI - A comparison between topical and retrobulbar anesthesia in 27-gauge vitrectomy for vitreous floaters: a randomized controlled trial. AB - BACKGROUND: To compare the safety and efficacy of topical anesthesia versus retrobulbar anesthesia in 27-gauge pars plana vitrectomy (PPV) for vitreous floaters. METHODS: 30 patients with vitreous floaters were randomized into Group T (topical anesthesia, proparacaine eye drop) and Group R (retrobulbar anesthesia), and underwent 27-gauge PPV. A 5-point visual analogue pain scale (VAPS) was used to assess patients' pain experience of anesthesia and surgery procedure (during surgery, 2 h and 1 day after surgery). RESULTS: The VAPS of anesthesia procedure was 1.27 +/- 0.59 for patients in Group R, while it was all 0 for patients in Group T (p < 0.001). There was no significant difference for VAPS during surgery (Group T: 1.13 +/- 0.74, Group R: 0.67 +/- 0.62, p = 0.67), 2 h (Group T: 0.80 +/- 1.01, Group R: 0.67 +/- 0.62, p = 0.67) and 1 day (Group T: 0.20 +/- 0.41, Group R: 0.27 +/- 0.46, p = 0.68) after surgery between these two groups. Only one patient (6.7%) in Group T required additional topical anesthesia during the surgery. Most of the patients reported the pain experience came from initial trocar insertion in both groups. None of the patients required post operative analgesia in both groups. No intraoperative or postoperative complications were noted in both groups. CONCLUSION: This study suggested that topical anesthesia is a safe and effective anesthetic approach for patients with floaters who underwent 27-gauge PPV. TRIAL REGISTRATION: ClinicalTrials.gov NCT03049163 . Registered 8 February 2017. PMID- 29981574 TI - Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection. AB - BACKGROUND: Inflammation-induced endothelial precursor cell recruitment and angiogenesis are thought to be associated with CXCL16-CXCR6 pair activity. This study's main purpose was to determine plasma CXCL16 levels after minimally invasive colorectal resection (MICR) for colorectal cancer (CRC); an adjunct study assessed wound fluid (WF) and plasma CXCL16 levels in a separate group of CRC patients. METHODS: CRC patients who had MICR and for whom plasma was available in a tissue bank were eligible. Plasma samples were collected preoperatively from all patients. Samples were also collected on postoperative days (POD) 1 and 3 and at various late postoperative time points (POD 7-34). In a separate study, blood and intra-abdominal wound fluid (WF) samples were collected from CRC MICR patients (pts). Samples were stored at - 80 degrees C. CXCL16 levels were determined via ELISA. The Wilcoxon signed-rank and Mann and Whitney tests were used for analysis. RESULTS: Main study: 86 CRC pts. were included. The mean preoperative plasma CXCL16 level was 2.36 +/- 0.57 ng/ml. Elevated mean plasma levels (p < 0.0001 * first 4 time points) were noted on POD 1 (2.82 +/- 0.81, n = 86), POD 3 (3.12 +/- 0.77, n = 82), POD 7-13 (3.28 +/- 0.88, n = 64), POD 14-20 (3.03 +/- 0.62, n = 24), POD 21-27 (3.06 +/- 0.67, n = 20, p = 0.0003), and POD 28-34 (3.17 +/- 0.43, n = 11, p = 0.001) vs. preop levels. WF study: In the adjunct study, plasma and WF CXCL16 levels were determined for 23 CRC MICR pts. WF levels at all time points were significantly elevated over plasma levels. CONCLUSION: Plasma CXCL16 levels were elevated for 4 weeks after minimally invasive colorectal resection for cancer. Also, WF CXCL16 levels were 3-10 times greater than the corresponding plasma concentrations. The source of the late plasma elevations may be the healing wound. Increased plasma CXCL16 levels may promote tumor angiogenesis in the first month after MICR. PMID- 29981575 TI - Laparoscopic intersphincteric resection with intraoperative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer. AB - BACKGROUND: In order to overcome the shortcomings of laparoscopic intersphincteric resection (Lap ISR), an alternative method of delivering intraoperative radiotherapy by Intrabeam X-rays radiotherapy system (XRS) is proposed in this paper. Intrabeam XRS is a device that uses low-energy X-rays source generated by a mobile controller unit, which is featured in accurate irradiation, reduced complications, and less exposure. The purpose of this study is to discuss the feasibility of Lap ISR with intra-operative radiotherapy using low-energy X-rays for locally advanced ultra-low rectal cancer in Asian woman. This novel proposed method will greatly increase the anus preserving probability and improved the quality of life. METHODS: A 53-year-old woman diagnosed with rectal adenocarcinoma had a strong desire to preserve the anal function and presented at the Jilin University Second Hospital, Jilin, China. The tumor's size was 4 cm * 3 cm. It was located 2 cm from the anus merge and invaded the levator ani muscle. Preoperative clinical staging was T4N1M0 and could be reached R0 resection. After the consent form was signed by the patient, Lap ISR combined with the applicator put through the anus (natural orifice) to the tumor bed was performed and prophylactic ileostomy synchronized the anastomosis. Patient only received 1-cycle chemotherapy regimen of oxaliplatin with capecitabine postoperatively due to personal reasons. Pre- or postoperative radiotherapy was not given. RESULTS: After clinical follow-up, until now, there is not any sign of local recurrence. Anus function and short-term complications are acceptable. The short-term effect is satisfying and we look forward to further assess the long term effect. CONCLUSION: Laparoscopic intersphincteric resection with IORT using low-energy X-rays for the patients with late-stage ultra-low rectal cancer could provide an opportunity of preserving the anus function, and it is feasible for the selected patients. TRIAL REGISTRATION: Retrospectively registered; Trial registration: NCT03393234 ; Registered time: 05 January 2017. PMID- 29981576 TI - Comparison of the effect of breast pump stimulation and oxytocin administration on the length of the third stage of labor, postpartum hemorrhage, and anemia: a randomized controlled trial. AB - BACKGROUND: This study aimed to compare the effect of breast pump stimulation with that of oxytocin administration regarding the duration of the third stage of labor, postpartum hemorrhage, and anemia after delivery. METHODS: In this study, 108 women were randomly assigned to two groups of breast pump stimulation (n = 54) and oxytocin administration (n = 54). Women in the breast stimulation group received breast pump stimulation (10 min intermittently for each breast with a negative pressure of 250 mmHg), while the women in the oxytocin (control) group received an infusion of 30 IU oxytocin in 1000 mL of Ringer's serum with a maximum rate of 10 mL infusion per min after delivery. The duration of the third stage of labor, blood loss during the third stage of labor and 24 h after delivery, hemoglobin and hematocrit (before and 24 h after delivery), after-birth pain, and the number of breastfeedings during the 24 h after delivery were recorded. The data were analyzed using the chi-square test, independent t-test, and Wilcoxon test. RESULTS: The mean duration of the third stage was 5 +/- 1.97 and 5.4 +/- 2.5 min in the breast stimulation and women that received intravenous oxytocin respectively (p = 0.75). Most participants had mild postpartum hemorrhage (98.1 and 96.2% in the breast stimulation and women that received intravenous oxytocin, respectively, p = 0.99). Although hemoglobin and hematocrit levels significantly decreased in both groups 24 h after delivery, there was no significant difference between both groups regarding both parameters. After-birth pain was significantly lower and the number of breastfeeding during the 24 h after delivery was significantly more in the breast stimulation group compared to the control group. CONCLUSIONS: Our results demonstrated no differences between breast pump stimulation and oxytocin administration regarding the duration of the third stage of labor, postpartum hemorrhage, anaemia, after-birth pain, and the number of breastfeedings during the 24 h after delivery. TRIAL REGISTRATION NUMBER: The study protocol was registered in the Iranian Randomized Controlled Trial Registry (Ref. No.: IRCT2015050722146N1 ; Registration date: 2015-11-04). The study was registered prospectively and the enrollment date was 23/8/2015. PMID- 29981577 TI - Evaluation of the palliative symptom burden score (PSBS) in a specialised palliative care unit of a university medical centre - a longitudinal study. AB - BACKGROUND: The implementation of standardised, valid and reliable measurements in palliative care is subject to practical and methodological challenges. One aspect of ongoing discussion is the value of systematic proxy-based assessment of symptom burden in palliative care. In 2011, an expert-developed proxy-based instrument for the assessment of symptom burden in palliative patients, the Palliative Symptom Burden Score (PSBS), was implemented at the Specialised Palliative Care Unit of the University Medical Centre in Dusseldorf, Germany. The present study investigated its feasibility, acceptance and psychometric properties. METHODS: The PSBS was rated by nursing staff three times a day over 5 years (N = 820 patients). Feasibility and nurses' acceptance of PSBS were analysed. Structural validity was investigated by principal component analysis. Construct validity was examined via cross-validation with the Hospice and Palliative Care Evaluation checklist. Discriminative validity of the PSBS was analysed by means of Kruskal-Wallis test of patients' performance score. Reliability of the PSBS was evaluated by internal consistency analysis, test retest and split-half-reliability. Inter-rater reliability was investigated by observer agreement of nurses' ratings of symptom burden within a day. Sensitivity to change was analysed by Wilcoxon test with repeated measures of the PSBS before and after palliative complex treatment. RESULTS: A high degree of acceptance and the feasibility of a high-frequency proxy-based symptom burden assessment approach were demonstrated. There were low rates of missing values and no indications of the adoption of prior ratings. PSBS in its present form demonstrates good structural and construct validity (rs = .27-.79, p's < .001) and high sensitivity to changes in symptom burden (p's < .01, except sweating), but unsatisfactory reliability (alpha = .41-.67; test-retest: rs = .30-.88; p's < .001; split-half: rs = .69; p < .001; inter-rater: n.s.). CONCLUSIONS: The study presents a framework for the post hoc validation of an already existing documentation tool in palliative care. This study supports the notion that PSBS might not be reflective of an overall construct and will therefore require further development and critical comparison to other already established symptom burden instruments in palliative care. PMID- 29981578 TI - The diversity of uncharacterized antibiotic resistance genes can be predicted from known gene variants-but not always. AB - BACKGROUND: Antibiotic resistance is considered one of the most urgent threats to modern healthcare, and the role of the environment in resistance development is increasingly recognized. It is often assumed that the abundance and diversity of known resistance genes are representative also for the non-characterized fraction of the resistome in a given environment, but this assumption has not been verified. In this study, this hypothesis is tested, using the resistance gene profiles of 1109 metagenomes from various environments. RESULTS: This study shows that the diversity and abundance of known antibiotic resistance genes can generally predict the diversity and abundance of undescribed resistance genes. However, the extent of this predictability is dependent on the type of environment investigated. Furthermore, it is shown that carefully selected small sets of resistance genes can describe total resistance gene diversity remarkably well. CONCLUSIONS: The results of this study suggest that knowledge gained from large-scale quantifications of known resistance genes can be utilized as a proxy for unknown resistance factors. This is important for current and proposed monitoring efforts for environmental antibiotic resistance and has implications for the design of risk ranking strategies and the choices of measures and methods for describing resistance gene abundance and diversity in the environment. PMID- 29981579 TI - FMR1 expression in human granulosa cells increases with exon 1 CGG repeat length depending on ovarian reserve. AB - BACKGROUND: Fragile-X-Mental-Retardation-1- (FMR1)-gene is supposed to be a key gene for ovarian reserve and folliculogenesis. It contains in its 5'-UTR a triplet-base-repeat (CGG), that varies between 26 and 34 in general population. CGG-repeat-lengths with 55-200 repeats (pre-mutation = PM) show instable heredity with a tendency to increase and are associated with premature-ovarian insufficiency or failure (POI/POF) in about 20%. FMR1-mRNA-expression in leucocytes and granulosa cells (GCs) increases with CGG-repeat-length in PM carriers, but variable FMR1-expression profiles were also described in women with POI without PM-FMR1 repeat-length. Additionally, associations between low numbers of retrieved oocytes and elevated FMR1-expression levels have been shown in GCs of females with mid-range PM-CGG-repeats without POI. Effects of FMR1-repeat lengths-deviations (n < 26 or n > 34) below the PM range (n < 55) on ovarian reserve and response to ovarian stimulation remain controversial. METHODS: We enrolled 229 women undergoing controlled ovarian hyperstimulation for IVF/ICSI treatment and devided them in three ovarian-response-subgroups: Poor responder (POR) after Bologna Criteria, polycystic ovary syndrome (PCO) after Rotterdam Criteria, or normal responder (NOR, control group). Subjects were subdivided into six genotypes according to their be-allelic CGG-repeat length. FMR1-CGG-repeat length was determined using ALF-express-DNA-sequencer or ABI 3100/3130 * 1 sequencer. mRNA was extracted from GCs after follicular aspiration and quantitative FMR1-expression was determined using specific TaqMan-Assay and applying the DeltaDeltaCT method. Kruskall-Wallis-Test or ANOVA were used for simple comparison between ovarian reserve (NOR, POR or PCO) and CGG-subgroups or cohort demographic data. All statistical analysis were performed with SPSS and statistical significance was set at p <= 0.05. RESULTS: A statistically significant increase in FMR1-mRNA-expression-levels was detected in GCs of PORs with heterozygous normal/low-CGG-repeat-length compared with other genotypes (p = 0.044). CONCLUSION: Female ovarian response may be negatively affected by low CGG alleles during stimulation. In addition, due to a low-allele-effect, folliculogenesis may be impaired already prior to stimulation leading to diminished ovarian reserve and poor ovarian response. A better understanding of FMR1 expression-regulation in GCs may help to elucidate pathomechanisms of folliculogenesis disorders and to develop risk-adjusted treatments for IVF/ICSI therapy. Herewith FMR1-genotyping potentially provides a better estimatation of treatment outcome and allows the optimal adaptation of stimulation protocols in future. PMID- 29981580 TI - The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study. AB - BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Delta9-tetrahydrocannabinol (Delta9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827. PMID- 29981581 TI - Rare tumor in unusual location - glomus tumor of the finger pulp (clinical and dermoscopic features): a case report. AB - BACKGROUND: Glomus tumors are rare, benign, vascular neoplasms arising from the glomus body. Although they can develop in any part of the body, they commonly do so in the upper extremities, most frequently subungual areas. They can be either solitary or multiple. Most typically they present as a small, round, bluish nodule visible through the nail plate with a classic triad of symptoms: hypersensitivity to cold, heightened pinprick sensitivity, and paroxysmal pain. Several tests can help in diagnosing these tumors with multiple imaging tools such as X-ray, magnetic resonance imaging, and ultrasonography. However, only histology can confirm the diagnosis. Complete surgical excision of the tumor is the only effective treatment to achieve pain relief and low recurrence rate. CASE PRESENTATION: We report here a rare case of a 54-year-old Moroccan Berber woman presenting with a 10-year history of a glomus tumor at an unusual site. Dermoscopy and histology were helpful to confirm the diagnosis. CONCLUSIONS: We aim to discuss clinical, dermoscopical aspects of this tumor and surgical modalities. We also emphasize the importance of keeping this tumor in mind among the possibilities of differential diagnosis of painful digital nodules. PMID- 29981584 TI - Pathologic Findings of the Gallbladder in Patients Undergoing Surgery for BD. PMID- 29981582 TI - Inflammation and blood-brain barrier breach remote from the primary injury following neurotrauma. AB - BACKGROUND: Following injury to the central nervous system, increased microglia, secretion of pro- and anti-inflammatory cytokines, and altered blood-brain barrier permeability, a hallmark of degeneration, are observed at and immediately adjacent to the injury site. However, few studies investigate how regions remote from the primary injury could also suffer from inflammation and secondary degeneration. METHODS: Adult female Piebald-Viral-Glaxo (PVG) rats underwent partial transection of the right optic nerve, with normal, age-matched, unoperated animals as controls. Perfusion-fixed brains and right optic nerves were harvested for immunohistochemical assessment of inflammatory markers and blood-brain barrier integrity; fresh-frozen brains were used for multiplex cytokine analysis. RESULTS: Immediately ventral to the optic nerve injury, immunointensity of both the pro-inflammatory biomarker inducible nitric oxide synthase (iNOS) and the anti-inflammatory biomarker arginase-1 (Arg1) increased at 7 days post-injury, with colocalization of iNOS and Arg1 immunoreactivity within individual cells. CD11b+ and CD45+ cells were increased 7 days post injury, with altered BBB permeability still evident at this time. In the lower and middle optic tract and superior colliculus, IBA1+ resident microglia were first increased at 3 days; ED1+ and CD11b+ cells were first increased in the middle and upper tract and superior colliculus 7 days post-injury. Increased fibrinogen immunoreactivity indicative of altered BBB permeability was first observed in the contralateral upper tract at 3 days and middle tract at 7 days post-injury. Multiplex cytokine analysis of brain homogenates indicated significant increases in the pro-inflammatory cytokines, IL-2 and TNFalpha, and anti-inflammatory cytokine IL-10 1 day post-injury, decreasing to control levels at 3 days for TNFalpha and 7 days for IL-2. IL-10 was significantly elevated at 1 and 7 days post-injury with a dip at 3 days post-injury. CONCLUSIONS: Partial injury to the optic nerve induces a complex remote inflammatory response, characterized by rapidly increased pro- and anti-inflammatory cytokines in brain homogenates, increased numbers of IBA1+ cells throughout the visual pathways, and increased CD11b+ and ED1+ inflammatory cells, particularly towards the synaptic terminals. BBB permeability can increase prior to inflammatory cell infiltration, dependent on the brain region. PMID- 29981596 TI - How Technology Shaped Modern Surgery. AB - The history of endoscopy and minimally invasive surgery is the story of technological advances in illumination, optics, and imaging that allowed operations to be performed within the body. After invention of the incandescent bulb by Joseph Swan and Thomas Edison in 1879, the basic design of early cystoscopes remained unchanged during the first half of the 20th century. Three inventions made endoscopy and laparoscopy possible. Invented in the 1950s, the Hopkins glass rod lens system was so elegant and effective-it gave images 80 times better than traditional Galilean optics-that endoscopes of the same design remain in use today. Also, originating in the same decade, fiber optics had in turn two major contributions: Flexible endoscopy and the transfer of light from a high voltage source into the body to illuminate internal structures and organs. Solid-state camera technology, developed in the late 1970s and 1980s, gave images of exceptional detail from a camera chip at the eyepiece of an endoscope. The panorama of advances created by the same technologies-global telecommunications, cellphone cameras, images from interplanetary space probes-reveals endoscopy and laparoscopic surgery as two more examples of today's technological age. PMID- 29981583 TI - Disruption of maternal gut microbiota during gestation alters offspring microbiota and immunity. AB - BACKGROUND: Early life microbiota is an important determinant of immune and metabolic development and may have lasting consequences. The maternal gut microbiota during pregnancy or breastfeeding is important for defining infant gut microbiota. We hypothesized that maternal gut microbiota during pregnancy and breastfeeding is a critical determinant of infant immunity. To test this, pregnant BALB/c dams were fed vancomycin for 5 days prior to delivery (gestation; Mg), 14 days postpartum during nursing (Mn), or during gestation and nursing (Mgn), or no vancomycin (Mc). We analyzed adaptive immunity and gut microbiota in dams and pups at various times after delivery. RESULTS: In addition to direct alterations to maternal gut microbial composition, pup gut microbiota displayed lower alpha-diversity and distinct community clusters according to timing of maternal vancomycin. Vancomycin was undetectable in maternal and offspring sera, therefore the observed changes in the microbiota of stomach contents (as a proxy for breastmilk) and pup gut signify an indirect mechanism through which maternal intestinal microbiota influences extra-intestinal and neonatal commensal colonization. These effects on microbiota influenced both maternal and offspring immunity. Maternal immunity was altered, as demonstrated by significantly higher levels of both total IgG and IgM in Mgn and Mn breastmilk when compared to Mc. In pups, lymphocyte numbers in the spleens of Pg and Pn were significantly increased compared to Pc. This increase in cellularity was in part attributable to elevated numbers of both CD4+ T cells and B cells, most notable Follicular B cells. CONCLUSION: Our results indicate that perturbations to maternal gut microbiota dictate neonatal adaptive immunity. PMID- 29981597 TI - Algernon Brashear Jackson, M.D.: A Pioneer for Community and Minority Advocacy. AB - A historical vignette regarding Dr. Algernon Brashear Jackson, the first Black male graduate from Jefferson Medical College. It details his early life, medical school years, surgical training, and contributions to his local community and beyond as he paved the way for future doctors of color. PMID- 29981598 TI - The Rise of the Surgeon in the Seventeenth Century Virginia Colony. AB - Life in the early American colonies presented unique challenges to the British colonists. There was an acute need for health-care providers in the early Virginia colony at Jamestown. Many of the medical men who first arrived at Jamestown were surgeons who adapted themselves to fit the medical needs of the community. These men trained in the British system where they sat beneath physicians in a hierarchy that did not consider surgeons to be doctors. Through their service to the colonists, early surgeons earned the reputation traditionally given to physicians in Great Britain. The colonists in Virginia respected the surgeons and viewed them as doctors, which allowed surgeons to stand on equal ground with physicians as the colonies grew to eventually become the United States of America. PMID- 29981599 TI - Antisepsis and Asepsis and How They Shaped Modern Surgery. AB - Surgical antisepsis and asepsis established the standard of using scientific evidence to determine surgical practice. The microbiological discoveries of Louis Pasteur (1822-1895) were the inspiration for Joseph Lister's (1827-1912) use of carbolic acid as an antiseptic on surgical wounds. German and Swiss surgeons invented aseptic surgical practice based on the studies of Robert Koch (1843 1910), a life-saving revolution in medicine as profound as anesthesia. Together they changed human history, sparing millions the horrors of hospital gangrene and making the entire body accessible to surgical intervention. In the United States, surgeons followed the lead of their brethren across the Atlantic. Americans, characteristically pragmatic, naturally resisted what they saw as unnecessary complexity in Listerism. Once they accepted germ theory, the undeniable scientific evidence led to the rapid acceptance of asepsis. Among the wide ranging effects of this transition in practice were the creation of the current model of the academic department of surgery and the modern concept of surgical professionalism. PMID- 29981600 TI - Factors Influencing Time to Decrease in Intraoperative Parathyroid Hormone (ioPTH) Levels in Patients Undergoing Focused Parathyroidectomy (FP). AB - The aim of this study was to evaluate potential factors affecting the time period in which a 50 per cent parathyroid hormone (PTH) drop is observed. Eight-seven patients undergoing focused parathyroidectomy between 2011 and 2015, whose PTH values dropped to within normal range, were grouped according to whether they required > or <=15 minutes after gland excision to achieve a 50 per cent PTH. Groups were compared according to preoperative PTH, calcium, age, glomerular filtration rate, and adenoma weight. Lower preoperative and preincision PTH levels were associated with requiring >15 minutes to achieve a >50 per cent drop in ioPTH. Time to >50 per cent ioPTH drop did not affect cure rates at one year, though a >15 minutes requirement was associated with higher serum calcium levels (P = 0.015). Lower baseline PTH and preincision PTH levels are significantly associated with a >15 minutes postexcision time to achieve a >50 per cent drop in ioPTH. Future analyses are warranted to determine whether a longer postexcision time threshold before proceeding with four-gland exploration is warranted in patients with primary hyperparathyroidism and mildly elevated preoperative PTH. PMID- 29981601 TI - The Impact of Ostomy Creation after Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy in a Newly Established Peritoneal Malignancy Program. AB - Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has improved outcomes for selected patients with peritoneal carcinomatosis and often requires ostomy creation. We examined the impact of ostomy creation in a newly established peritoneal malignancy program. A retrospective review was performed of CRS-HIPEC procedures from 2011 to 2016. Those who did and did not receive an ostomy were compared. Fifty-eight patients underwent CRS-HIPEC and an ostomy was created in 25.9 per cent. Median peritoneal cancer index (14 vs 16, P = 0.63) and multivisceral resection rates (87.9 vs 100.0%, P = 0.17) were similar between groups. Multivariable analysis revealed that bowel resection (OR 210.65, P = 0.02) was significantly associated with ostomy creation. Advanced age was noted to be inversely associated with stoma formation (OR 0.04, P = 0.04). Progression-free survival was significantly lower in the ostomy group (18 vs 23 months, P = 0.03). Those with an ostomy experienced prolonged length of stay (13.3 +/- 7.4 vs 9.5 +/- 3.7, P = 0.01). At follow-up, 6/10 temporary ostomies had undergone reversal and three patients experienced morbidity after reversal. Ostomy creation may occur during CRS-HIPEC and carries potential for morbidity. Ostomy creation may contribute to postoperative length of stay. Patients should be counseled preoperatively on the potential impact of ostomy placement during CRS-HIPEC. PMID- 29981602 TI - Utilizing Surgical Bootcamps to Teach Core Entrustable Professional Activities to Senior Medical Students. AB - To promote residency preparedness, the Association of American Medical Colleges defined 13 core entrustable professional activities for entering residency (CEPAERs), which represent tasks that students should be able to perform on day one of residency. At the authors' institution, a four-week surgery boot camp course is offered to senior medical students, which may provide an effective mechanism for teaching the CEPAERs. Nine senior students participating in a surgery boot camp course were subjected to pre- and post-course surveys. Student expectations were closely aligned with the CEPAERs. Competence was demonstrated in all CEPAERs; however, four students did require remediation with Advanced Cardiovascular Life Support before achieving competence. In the "death on the wards module," we found a significant increase in student confidence (19.78, SD 1.47, P > 0.05 vs 31.56, SD 1.49, P < 0.01) and knowledge (16.11, SD 1.32, P > 0.05 vs 31.33, SD 2.04, P < 0.01). In a one-year follow-up survey, all participants agreed that the boot camp course was useful and positively impacted their intern year. Surgical boot camp courses provide an effective and reproducible means for teaching the CEPAERs and was found useful in preparing medical students for residency. PMID- 29981603 TI - The Use of Standardized Measures to Predict and Assess Quality of Life after Laparoscopic Hiatal Hernia Repair. AB - The literature regarding laparoscopic hiatal hernia repair is difficult to interpret because of inconsistencies in describing hernia characteristics and outcome measures. This study was performed to evaluate risk factors for an unsatisfactory outcome after repair using objective definitions of hernia size and a clinically relevant outcome instrument. A retrospective review of a prospectively maintained database was conducted over a seven-year period. Data collected included patient demographics and hernia-related variables. Outcomes were defined using a validated quality of life (QOL) instrument. Postoperatively, the mean total QOL score decreased from 22.9 to 5.8 (P < 0.001). In all, 13.8 per cent of patients had unsatisfactory QOL scores postoperatively. Multivariate analysis showed that high gastroesophageal (GE) junction position (P = 0.03) and female gender (P = 0.02) were the only significant factors associated with an unsatisfactory postoperative QOL. Laparoscopic hiatal hernia repair significantly improves QOL. With respect to predicting clinically relevant outcomes, hernias are best characterized by the position of the GE junction. Females with high GE junction position are at the highest risk for an unsatisfactory outcome. PMID- 29981604 TI - The Branching Pattern of the Inferior Pancreaticoduodenal Artery in Patients with a Replaced Right Hepatic Artery. AB - Understanding the anatomy of the inferior pancreaticoduodenal artery (IPDA) is important in patients undergoing pancreaticoduodenectomy, especially in an artery first approach, resulting in some studies focusing on IPDA anatomy. However, the studies have covered only cases without variation in hepatic arterial anatomy, a common arterial variant, suggesting the necessity of the investigation of IPDA anatomy in cases with the variant. Using images of multidetector row computed tomography, cases with replaced right hepatic artery (rRHA) were picked out among 714 patients undergoing multidetector row computed tomography for determining arteries of the pancreatic head at our institution. IPDA branching pattern was investigated in the rRHA cases. Three-dimensional reconstruction was performed to visually understand the branching pattern in representative cases. rRHA was identified in 139 cases (19.5%); rRHA originating from the superior mesenteric artery (SMA) (type 1; 74.1%), celiac axis (type 2; 18.0%), and others (type 3; 7.9%). IPDA branching pattern was categorized; IPDA originated from SMA (type A), posterior and anterior IPDA originated from rRHA and SMA, respectively (type B), or IPDA originated from rRHA (type C). Of type 1 cases, 69, 23, and 11 cases showed type A, B, and C pattern, respectively. Of type 2 cases, 16 and 9 cases showed type A and B, respectively. All 11 type 3 cases showed type C. IPDA branching pattern was determined in the rRHA cases. This would help identification of rRHA cases where the artery-first approach is technically less feasible at pancreaticoduodenectomy (type 1-B, 1-C, and 2-B). PMID- 29981605 TI - "Enhanced Recovery" Protocol Compliance Influences Length of Stay: Resolving Barriers to Implementation. AB - Initial implementation and maintenance of an enhanced recovery protocol (ERP) is complex and has not been adequately described. The aim of this study was to investigate the efficacy of an ERP at a tertiary care academic institution. A secondary aim was to identify barriers to implementation and continued protocol compliance (PC) to further decrease length of stay (LOS). Patients undergoing colon resection from February 2, 2011 to December 19, 2014 were compared with patients that followed implementation of an ERP from August 10, 2015 to July 14, 2016. The primary endpoint was LOS. Secondary endpoints were PC, analgesia requirements, time to return of bowel function, and ileus. One hundred and seventy-seven historical controls were compared with 68 ERP patients. LOS was shorter in study patients (4.9 vs 7.1 days for open surgery; 3.3 vs 6.1 for laparoscopic surgery). Intraoperative IVF balance, morphine equivalents, and length of time to return of bowel function were significantly less in the ERP group (1445.89 +/- 845.25 mL vs 3006.08 +/- 1197.97 mL), (64.48 +/- 114.49 vs 232.90 +/- 541.47), (2.41 +/- 1.32 days vs 3.82 +/- 2.00 days). Rate of ileus was less in study patients (4.8 vs 14.7%). The readmission rate and 30-day National Surgical Quality Improvement Program complication rates were not significantly different. PC was negatively associated with LOS (r = -0.35, P = 0.0026). Similar to prior studies, this study demonstrates the efficacy of an ERP. Increased PC is associated with decreased LOS, thus providing further evidence that ERPs should be the standard of care. Scheduled interdisciplinary meetings to discuss patient outcomes and methods to increase PC can help further improve efficacy of ERPs. PMID- 29981606 TI - Mild to Moderate to Severe: What Drives the Severity of ARDS in Trauma Patients? AB - Acute respiratory distress syndrome (ARDS) is a complex inflammatory process with multifactorial etiologies. Risk factors for its development have been extensively studied, but factors associated with worsening severity of disease, as defined by the Berlin criteria, are poorly understood. A retrospective chart and trauma registry review identified trauma patients in our surgical intensive care unit who developed ARDS, defined according to the Berlin definition, between 2010 and 2015. The primary outcome was development of mild, moderate, or severe ARDS. A logistic regression model identified risk factors associated with developing ARDS and with worsening severity of disease. Of 2704 total patients, 432 (16%) developed ARDS. Of those, 100 (23%) were categorized as mild, 176 (41%) as moderate, and 156 (36%) as severe. Two thousand two hundred and seventy-two patients who did not develop ARDS served as controls. Male gender, blunt trauma, severe head and chest injuries, and red blood cell as well as total blood product transfusions are independent risk factors associated with ARDS. Worsening severity of disease is associated with severe chest trauma and volume of plasma transfusion. Novel findings in our study include the association between plasma transfusions and specifically severe chest trauma with worsening severity of ARDS in trauma patients. PMID- 29981607 TI - Temporal Variations in Pediatric Trauma: Rationale for Altered Resource Utilization. AB - Trauma is a major cause of morbidity and mortality in the pediatric population. However, temporal variations of trauma have not been well characterized and may have implications for appropriate allocation of hospital resources. Data from patients evaluated at an ACS-verified Level I pediatric trauma center between 2011 and 2015 were retrospectively analyzed. Date and time of injury, type of injury (blunt vs penetrating), and postemergency department disposition were reviewed. To assess temporal trends, heatmaps were constructed and a mixed poisson regression model was used to assess statistical significance. Pediatric trauma from blunt and penetrating injuries occurred at significantly higher rates between the hours of 1800 and 0100, on weekends compared with weekdays, and from May to August compared with November to February. These data provide useful information for hospital resource utilization. The emergency department, operating room, and intensive care unit should be prepared for increased trauma related volume between May and August, weekends, and evening hours by appropriately increasing staff volume and resource availability. PMID- 29981608 TI - The Strategy of Treatment for Mid to Distal Cholangiocarcinoma after Surgical Resection. AB - The overall survival (OS) rate of extrahepatic cholangiocarcinoma (ECC) remains much lower than that for other gastrointestinal malignancies. A variety of factors have been used to predict prognosis after surgical resection for ECC, but no consensus has been reached. Therefore, this study sought to identify useful prognostic factors for patients with ECC. In our institution, within the study period, 76 patients received surgical resection for mid to distal cholangiocarcinoma. Clinicopathological data were retrospectively collected, along with survival and prognosis. In multivariate analysis for OS, ductal margin status (P = 0.008) and pT category (P < 0.02) presented independent predictors of survival. In the R0 resection group, N stage and adjuvant chemotherapy presented independent predictors of recurrence in the multivariate model. The three- and five-year survival rates were significantly better in patients with negative ductal margins (77.% at three years and 63.6% at five years) than in those with positive ductal margins (33.3% at three years and 25.0% at five years) (P < 0.05). Survival rates were similar between cases of R0 resection without gemcitabine-based chemotherapy and R1 resection with gemcitabine-based chemotherapy (P = 0.6193, Log-rank test). However, survival rates between R0 resection with gemcitabine-based chemotherapy and R1 resection with gemcitabine based chemotherapy were significantly different (P = 0.0086, Log-rank test). For good prognosis, radical resection to ensure adequate margin may be recommended for middle common bile duct cancer. In addition, regardless of margin negativity, gemcitabine-based chemotherapy is recommended for prolongation of relapse-free time and OS time. PMID- 29981609 TI - Moped Crashes Are Just as Dangerous as Motorcycle Crashes. AB - Mopeds' (MP) limited speed gives the impression that they are safer than motorcycles (MCs), but factors other than speed may contribute to crash outcome. Records of patients involved in MC or MP crashes evaluated at the University of Louisville Hospital emergency department between 2010 and 2014 were reviewed. Among patients who required hospital admission, the frequency of rib fractures, hemo- or pneumothorax, abdominal injury, extremity injury, and vertebral body fractures were greater in the MC group, whereas head and facial injuries were more common in the MP group. Positive toxicology screens were equivalent (MC 51.8% vs MP 56.8%, P = 0.25), and fewer MP riders wore helmets (33.8% vs 9.2%, P < 0.01). The injury severity score for MC was higher (15.2 vs 13.9, P = 0.039), but mortality was equivalent between groups (7.5 vs 7.6%, P = 0.98). Among patients discharged from the emergency department with minor injuries, frequency of all injury types were equivalent. Although MC patients had a statistically higher injury severity score, differences were clinically similar with equal mortality rate. Moped riders are just as likely to suffer death or serious injury after a crash compared with MC riders, and injury prevention efforts should be aimed at both groups. PMID- 29981610 TI - Optimizing Nutrition for the Surgical Patient: An Evidenced Based Update to Dispel Five Common Myths in Surgical Nutrition Care. AB - Traditional practices in the delivery of nutrition to the surgical patient include reliance on nonspecific laboratory markers to define malnutrition, prolonged periods of nil per os, early and liberal initiation of parenteral nutrition, withholding enteral feedings based on gastric residual volume measurements, and pursuing feeding tube access for most patients unable to take oral nutrition. However, recent studies call into question all of these practices. This review aims to provide evidenced-based support to abandon these myths regarding nutrition delivery and offer practical up-to-date advice for best practices in patient care. PMID- 29981611 TI - Delayed Healing Associated with Silver Sulfadiazine Use for Partial Thickness Scald Burns in Children. AB - Burns are a leading cause of injury in children. Management principles vary widely, with no consensus about the best treatment. The purpose of this study was to compare outcomes of three different dressings for pediatric partial-thickness scald burns. A retrospective, single-center study was conducted for patients 0-16 years old with a diagnosis of acute partial-thickness scald burn between July 2007 and December 2012. Data regarding prehospital, inpatient, and outpatient course were collected. Cohort was stratified into topical antimicrobial (TA) ointment, silver sulfadiazine (SS), and biosynthetic dressing (BD) groups for analysis. The primary outcome of interest was time to full healing. One hundred and seventy-seven patients met all study criteria. Overall, mean total body surface area burned was 8.3 per cent. TA was used in 24 per cent cases, SS in 32 per cent, and BD in 44 per cent. The groups were comparable in terms of presenting burn characteristics and hospital course with the exception of the BD group being associated with greater extent of injury. Patients treated with SS had a significantly longer time to full healing and increased requirement of compression garments for scar therapy. Based on these data, the authors have amended their practice and presently use BD or TA dressings to improve healing. PMID- 29981612 TI - A Prospective, Comparative Evaluation on Totally Implantable Venous Access Devices by External Jugular Vein versus Cephalic Vein Cutdown. AB - The request for totally implantable venous access devices (TIVADs) has rapidly grown up through the last decades. TIVADs are implanted by direct vein puncture or by surgical approach with vein cutdown. The authors present a comparative prospective study evaluating external jugular vein (EJV) and cephalic vein cutdown techniques. Two hundred and fifteen patients were consecutively submitted to TIVAD implantation to perform chemotherapy. Patients were divided in two groups, depending on the implantation technique. Group A patients (106) underwent implantation via EJV cutdown and group B (109) patients underwent implantation by cephalic vein cutdown. The following variables were investigated: operating time, need for conversion to other approaches, complications, and intraoperative and postoperative pain. In Group A patients, the success rate of the procedure was 100 per cent, whereas in 11 patients (10.1%) of Group B, a modification of the initial approach was needed. Mean operative time was 23.9 +/- 9.2 minutes in Group A and 35.4 +/- 11.9 in Group B, and this was statistically significant (P < 0.05). Complication rates at 30 days were similar. Considering intraoperative pain, a difference was found between the two groups because the mean value of pain in Group A was lower than that in Group B (4.13 +/- 0.3 vs 5.22 +/- 1.24), even if not significant. External jugular vein cutdown approach is quick and safe and allows a very high success rate with very low risk of complications. For these reasons, this approach could be considered as a first choice in TIVAD placement. PMID- 29981613 TI - Bone Autograft Coupled with Locking Plates Repairs Symptomatic Rib Fracture Nonunions. AB - Symptomatic rib nonunions are a rare complication after rib fractures. Methods used to address these nonunions range from pain management, rib resection, and rib fixation with plates and occasional autologous bone grafting. Given potential complications associated with rib resections such as pulmonary hernia, we hypothesized that plate fixation and autologous bone grafting would yield satisfactory long-term outcomes and a high union rate. Patients (aged >=18 years) at a single institution with a symptomatic rib nonunion who underwent surgical rib stabilization of the nonunion coupled with bone autograft were evaluated (2010-2014). Pertinent clinical, operative, radiologic, and follow-up data were abstracted. Univariate analyses to assess the relationship of clinical outcomes were performed. Six patients underwent nonunion repair with autograft and plating. The mean time from injury to surgical repair of nonunion was 15 (+/-6.1) months. A median of 3 [1-3] ribs were repaired with surgery. Postoperative radiographic union was demonstrated on cross-sectional imaging at three months in four patients (57%) and in all patients at five months postoperatively. No patients developed postoperative pulmonary hernia during follow-up. All patients had a significant reduction in median patient-reported pain at follow-up. Surgical rib fixation and bone autograft can provide acceptable outcomes for patients with rib fracture nonunion. This method provides pain relief and promotes healing of the nonunion gap without pulmonary hernia development. Operative fixation and bone autograft should be considered as a viable technical alternative to resection alone for rib nonunion. PMID- 29981614 TI - The Impact of Epidural Analgesia on the Rate of Thromboembolism without Chemical Thromboprophylaxis in Major Oncologic Surgery. AB - Patients with abdominopelvic cancers are at increased risk of venous thromboembolism (VTE) due to their malignancy. We evaluated outcomes and the rate of VTE in patients undergoing abdominopelvic surgery for malignancy with preoperative epidural analgesia without postoperative chemical VTE prophylaxis. A retrospective review between 2009 and 2015 identified 285 patients with malignancy who underwent abdominopelvic surgery by a single surgeon (AWS). Lower extremity venous duplex scans (VDS) were performed preoperatively and before discharge. Demographics, procedures, and VTE outcomes were reviewed. The median age was 66 years. The average operative time was 315 minutes. All patients ambulated on postoperative day (POD) one or two. Epidural catheters (ECs) were removed on postoperative day four or five. No patient received VTE prophylaxis while an epidural catheter was in place. Preoperative lower extremity VDS revealed above-knee deep vein thrombosis (DVT) in seven patients (2.5%). Postoperative lower extremity VDS revealed acute DVT in 24 patients (8.4%): nine (3.2%) above-knee and 15 (5.2%) below-knee. The nine patients with above-knee DVT were anticoagulated after epidural removal. No patient developed a pulmonary embolism. Our data suggest that patients undergoing major open operations with epidural analgesia have low rates of DVT and may obviate the need for chemical prophylaxis. However, larger studies are required to determine the overall effects of epidural analgesia on the development of DVTs postoperatively. PMID- 29981615 TI - Correlation between Ki-67 Expression and Hemodynamics of Contrast-Enhanced Ultrasound in Patients with Breast Infiltrative Ductal Carcinoma. AB - Breast cancer causes great threats to public health worldwide. The aim of this study was to investigate the correlation between Ki-67 expression and the hemodynamics of contrast-enhanced ultrasound (CEUS) in patients with infiltrative ductal carcinoma (IDC). CEUS was performed on 109 masses in 85 IDC cases before resection. Based on the immunohistochemical staining on the antigen Ki-67, the masses were divided into negative group, weakly positive group, positive group, and strong-positive group. Significant statistical differences were noticed in time to peak, arrive intensity, and peak intensity in the positive groups compared with the negative group. Compared with the positive groups, the negative group showed significant statistical differences in arrive intensity and peak intensity. The antigen Ki-67 was positively correlated with arrived intensity, intensity changes, and rising curve's slope. In contrast, it was negatively correlated with arrived time, time to peak, and continuous time. The hemodynamic parameters of CEUS were correlated with the expression of antigen Ki-67. On this basis, Ki-67 is an effective supplement to the diagnosis of IDC. PMID- 29981616 TI - When Minutes Fly by: What Is the True "Golden Hour" for Air Care? AB - Air transport was developed to hasten patient transport based on the "golden hour" belief that delayed care leads to poorer outcome. The primary aim of our study was to identify the critical inflection point of increased nonsurvivors on total prehospital time. This was a multicenter review of adult trauma patients transported by air between November 2014 and August 2015. Primary outcome of interest was all-cause inhospital mortality. Total helicopter emergency medical services times of nonsurvivors were plotted to visualize the distribution of prehospital time. Of 636 patients included, 71 per cent were male and 86 per cent suffered blunt trauma. Among nonsurvivors, mortality doubled once total helicopter emergency medical services time exceeded 30 minutes (P < 0.001). Nonsurvivors presented with significantly lower median [interquartile range (IQR)] Glasgow Coma Score compared with survivors [3 (3-13) vs 15 (12-15), respectively; P < 0.001] as well as a significantly higher median (IQR) Injury Severity Score [26 (19-41) vs 12 (5-22); P < 0.001], increased incidence of penetrating mechanism of injury [21 vs 8%; P = 0.002], and higher median (IQR) shock index [0.84 (0.63-1.06) vs 0.71 (0.6-0.87); P = 0.023]. We identified an inflection point of doubling in mortality after 30 minutes. This suggests a possible threshold effect between time and mortality in severely injured patients. Revised field criteria for determining which injured patients would most benefit from helicopter transport are needed. PMID- 29981617 TI - Correlation of Biliary Colic in the Absence of Cholelithiasis with Pancreaticobiliary Obstruction. AB - A small fraction of patients undergoing cholecystectomy for biliary colic are subsequently diagnosed with an obstructive pancreatic head mass. We review our experience with such patients to provide insight into improving evaluation before cholecystectomy. Retrospective chart review of patients undergoing cholecystectomy from 2004 to 2015 identified six patients who underwent laparoscopic cholecystectomy for biliary colic before being diagnosed with a pancreatic head neoplasm within six months after cholecystectomy. Charts were analyzed for presenting symptoms, evaluation before and after cholecystectomy, and operative findings. Patients ranged from 50 to 72 years of age and included five males and one female. None had evidence of cholelithiasis or acute cholecystitis on initial evaluation. Median time from cholecystectomy to diagnosis of pancreatic head mass was two months (range 1-5 months). Two patients eventually underwent pancreaticoduodenectomy. Patients with symptoms of biliary colic in the absence of evidence of cholecystitis or choledochal abnormality should undergo intraoperative cholangiogram at the time of cholecystectomy as well as close clinical follow-up to ensure resolution of symptoms. Abnormalities of either should prompt radiographic evaluation focused on identification of a pancreatic mass causing extrinsic compression of the bile duct. PMID- 29981618 TI - Delirium in Postoperative Patients Admitted to the Intensive Care Unit. AB - Postoperative delirium (POD) is common among surgical patients admitted to the intensive care unit (ICU) and is associated with increased resource utilization, morbidity, and death. Our primary aim was to compare rates of POD using administrative International Classification of Diseases, Ninth Revision, records and automated interrogation of electronic health records from Confusion Assessment Method for the ICU (CAM-ICU) screening. The secondary aim was to assess POD risk associated with patient and perioperative characteristics. Electronic health records of surgical patients admitted to the ICU during 2011 through 2014 were abstracted for POD assessment by CAM-ICU and by administrative codes, Charlson comorbidity index, surgical characteristics, and Acute Physiology, Age, Chronic Health Evaluation III scores. Of 6338 patients, CAM-ICU identified 606 (9.6%) and administrative records identified 55 (0.9%) POD cases, with agreement on 50 cases. In multivariable logistic regression based on POD identified with CAM-ICU, preexisting dementia had the strongest association with POD (odds ratio [95% confidence interval], 6.47 [3.68-11.37]; P < 0.001). Other associations found were older age, congestive heart failure, chronic pulmonary disease, increased surgical duration, emergency cases, blood transfusions, postoperative ventilation, and higher Acute Physiology, Age, Chronic Health Evaluation III scores (all P <= 0.01). POD cases had lengthier ICU and hospital stays and a higher mortality rate (all P < 0.001). CAM-ICU scores identified higher rates of POD than a search for POD based on administrative codes. Preoperative presence of dementia and major comorbidities were associated with POD. Delirium in surgical patients is associated with worse outcomes. PMID- 29981619 TI - Triple-Negative Breast Cancer: A Comparison of Race and Survival. AB - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a high prevalence in blacks. South Carolina demographically has a high percentage of blacks. This study examines survival and recurrence associated with TNBC in black and white women. A retrospective review of breast cancer patients within the Palmetto Health Cancer Registry was performed from 1999 to 2015. Patient demographics and tumor characteristics were collected and correlated with outcomes. Overall survival (OS), disease-specific survival (DSS), and recurrence free survival (RFS) were analyzed. The total number of breast cancer patients in the registry was 1723 (1085-white and 638-black). The median follow-up was 48.4 months. The majority of cancers diagnosed in both cohorts were early stage (I, IIA, IIB, 93.4% vs 90.4% P = NS). We identified 332 patients with TNBC. Of those 332 patients, 144 (43.4%) were whites and 188 (56.6%) were blacks. Older age (P = 0.01), high-grade (P < 0.001), and black race (P < 0.001) were significantly associated with TNBC on multivariate analysis. Five- and 10-year OS was significantly worse in blacks with TNBC (P < 0.001). There was no difference in DSS or RFS between the two cohorts. TNBC disproportionately affects black women and is an aggressive subtype of breast cancer with limited treatment options compared with receptor-positive breast cancer. Black patients with TNBC in our study had statistically worse OS. These findings are similar to what has been reported in the literature and prompts further research in newer targeted therapies. PMID- 29981620 TI - The Combination of Pancreas Texture and Postoperative Serum Amylase in Predicting Pancreatic Fistula Risk. AB - : Postoperative pancreatic fistula (PF) remains one of the most significant complications after pancreaticoduodenectomy (PD). Recently, studies have suggested that post-PD serum hyperamylasemia (HA) may be a risk factor. In this study, we evaluate the relationship of pancreas texture and post-operative serum amylase levels in determining PF risk. This retrospective cohort study evaluated all patients who underwent PD at Thomas Jefferson University from 2009 to 2014. The highest postoperative serum amylase level from postoperative day (POD) 0 to POD 5 was obtained. Chi-square analyses and odds ratio (OR) evaluated the relationship between pancreas texture, serum amylase level, and the development of PF. Data from 524 consecutive patients were analyzed. Serum amylase threshold value of 165 IU/L yielded greatest accuracy from the receiver operating characteristic curve analysis (Sensitivity, 0.70; specificity, 0.72). Grade B or C PF were more common among HA patients (20 vs 3%; P < 0.001). HA was associated with increased rates of PD-associated complications. On multivariable analysis, early postoperative serum HA was more predictive of PF risk (OR, 4.87; P < 0.001) than either pancreatic duct size <=3 mm (OR, 2.97; P = 0.01) or pancreas texture (OR,1.87; P = 0.05). CONCLUSION: The presence of HA on POD 0 or POD 1 is more predictive than soft pancreas texture or small pancreas duct size alone. PMID- 29981621 TI - Incidence of Surgical Site Infections after Thyroid and Parathyroid Surgery: No Role for Antimicrobial Prophylaxis. AB - To better define the value of antimicrobial prophylaxis (AMP) and antiseptic skin preparation (ASP) in thyroid and parathyroid surgery, we examined the rate of surgical site infections (SSIs) with and without AMP. Retrospective analysis was performed using the National Surgical Quality Improvement Program database at a single institution. Patients undergoing thyroid or parathyroid surgery with data entered into the National Surgical Quality Improvement Program database at our institution between November 2007 and June 2015 were studied, including patient demographics, wound classification, other risk factors for SSI, and wound outcome. Charts were retrospectively reviewed for AMP, ASP, and use of drains. Of the 534 patients who underwent thyroid (n = 358) or parathyroid (n = 176) surgery, 58 (10.9%) were diabetic, 54 (10.1%) used tobacco, and 14 (2.6%) were on steroids. Most wounds were classified as "clean" (99.6%). Betadine was used for ASP in 96 per cent. AMP was given to 141 patients (26%) using cefazolin, vancomycin, or clindamycin. The remaining 393 patients (74%) received no AMP. Zero infections occurred in the group who did not receive AMP. One (0.7%) superficial, nonpurulent SSI occurred in the group that received AMP which was not statistically significantly different (P = 0.319). The rates of SSI after thyroid and parathyroid surgery are extremely low, around two per 1000 cases, and do not decrease with AMP. Therefore, AMP is not necessary in thyroid and parathyroid surgery and should be avoided to reduce costs, adverse reactions, and antibiotic resistance. PMID- 29981622 TI - Outcomes after Robotic Ventral Hernia Repair: A Study of 21,565 Patients in the State of New York. AB - The purpose of our study is to assess outcomes following robotic ventral hernia (RVH) repair. The New York Statewide Planning and Research Cooperative System administrative database was used to identify all patients undergoing laparoscopic ventral hernia (LVH) and RVH between 2010 and 2013. Outcome measures including complications, hospital length of stay (HLOS), 30-day readmissions, and 30-day emergency department (ED) visits were compared. Propensity score (PS) analysis was used to estimate the adjusted marginal differences between patients who underwent robotic-assisted and laparoscopic procedures. There were 20,896 LVH and 679 (3.2%) RVH repairs. Initial univariate analysis demonstrated that patients undergoing RVH had worse outcomes in terms of complications (20.18% vs 10.56%, P < 0.0001), longer HLOS (4.32 vs 2.19 days, P = 0.0023), higher rates in 30-day readmissions (9.28% vs 5.06%, P < 0.0001), and 30-day ED visits (14.43% vs 10.46%, P < 0.0001). Following PS analysis, which accounts for all patient associated variables, there was no difference found in 30-day readmission or 30 day ED visits between RVH and LVH (P = 0.2760 and 0.2043, respectively). Patients undergoing RVH had a significantly shorter HLOS (P < 0.0001) and lower rate of complications (P = 0.0134). Following PS analysis, this study demonstrates that RVH may be associated with shorter HLOS and lower complication rate. Further studies are necessary to compare laparoscopic and robotic approaches for ventral hernia. PMID- 29981623 TI - Primary Pulmonary Thrombus in Combat Casualties: Is Treatment Necessary? AB - The objective of this study was to describe the natural history of primary pulmonary thrombus (PPT) in combat casualties. This was a retrospective study of casualties treated at a major military treatment facility from 2010 to 2012. Patients with a downrange chest CT were included. CTs were reviewed by two independent, blinded radiologists to confirm PPT on initial imaging. Follow-up CTs, if obtained, were also independently reviewed to determine the extent of clot burden. Two hundred and forty-nine casualties with a downrange, acceptable quality chest CT were included. 9 per cent (23/249) of patients sustained PPT. Thirty nine per cent (9/23) were initially treated with therapeutic anticoagulation (AC). Conversely, 61 per cent (14/23) arrived to our military treatment facility without AC. Seven arriving without AC-developed pulmonary symptoms during their hospitalization and had interval chest CTs. Of those, three had no evidence of pulmonary thrombus. The other four had subsegmental filling defects and three were started AC whereas one had an IVC (Inferior Vena Cava) filter inserted. In total, 11/23 (48%) PPT patients were managed without AC and discharged without complications. This is the first study attempting to look at PPT natural history. There were no adverse sequelae from managing PPT without AC. Further studies are warranted to further characterize PPT. PMID- 29981624 TI - The South Carolina Surgical Quality Collaborative: A New Effort to Improve Surgical Outcomes in South Carolina. AB - Regional surgical quality Collaboratives are improving surgical quality and cutting costs by building regional relationships that leverage information sharing to improve outcomes. The South Carolina Surgical Quality Collaborative (SCSQC) is a new regional surgical quality Collaborative focused on improving general surgery outcomes in South Carolina. It is a joint effort which brings together the skills and resources of Health Sciences South Carolina, the South Carolina Hospital Association, and the Blue Cross Blue Shield of SC Foundation to create a web-based data collection system to provide real-time outcomes data to participating surgeons, and establishing a supportive network for sharing best practices and promoting data driven quality improvement. Members of the SCSQC abstracted more than 8000 general surgery cases from eight participating hospitals in its first year. These facilities are spread across the state of South Carolina and range from large academic referral centers to small community hospitals. The resulting data should be representative of much of the surgical care provided in South Carolina. Monthly conference calls and quarterly face-to face meetings occur with site Surgeon Leads, site Surgical Clinical Quality Reviewer, and Collaborative leaders. Each site is pursuing a quality improvement project addressing issues identified from analysis of their initial data. Early results on these efforts are encouraging. The SCSQC is a new regional surgical quality Collaborative, which leverages multiple state resources, builds on the successes of similar Collaboratives in Michigan and Tennessee, with the goal to improve the quality and value of general surgical care for South Carolinians. PMID- 29981625 TI - Predictive Factors of Operative Hemodynamic Instability for Pheochromocytoma. AB - Pheochromocytoma is an uncommon catecholamine-secreting tumor in which resection is often associated with hemodynamic instability (HI). In this study, we aim to clarify the factors affecting surgical HI in patients who underwent surgery with the diagnosis of pheochromocytoma. All patients who underwent surgery with the diagnosis of pheochromocytoma between 2008 and 2015 were analyzed retrospectively. Patients with inconsistent diagnosis or missing outcomes and follow-up data were excluded. A total of 37 patients were included in this study. Patient demographics, operative time, tumor size, period of medical treatment until surgery, catecholamine levels in urine, and HI patterns were analyzed. There were 23 (62%) male and 14 (38%) female patients. Hemodynamic instability occurred in 13 (35%) patients. Overall, HI was higher in patients with tumor size <6 cm (P < 0.02); moreover, urine catecholamine levels were detected significantly higher than a cutoff value of 2000 MUg/24 hours in hemodynamically instable group. In this study, tumor diameter of <6 cm and urine catecholamine levels >2000 MUg/24 hours were associated with HI. Preoperative management is essential for preventing hypertensive crisis and HI before or during surgery. PMID- 29981626 TI - Influence of Insurance Status on Hospital Length of Stay and Discharge Location in Burn Patients. AB - Insurance status affects many aspects of healthcare in America, from access to delivery to outcomes. Our goal in this study was to determine whether different subtypes of insurance status affected hospital lengths of stay (LOS) and/or the location to which patients were discharged. The National Burn Repository was used to examine a total of 119,509 burn patients. Patients with noncommercial insurance (NONCOM) have increased LOS and are more likely to be discharged to a nonhome location, compared with no insurance or other insurance subtypes. Patients with no insurance have similar injury characteristics and comorbidities as patients with NONCOM, but have a shorter LOS and are more likely to be discharged home rather than to a skilled nursing facility or rehabilitation facility. PMID- 29981627 TI - Incisional Hernia in Renal Transplant Recipients: A Systematic Review. AB - Incisional hernia follows midline laparotomy in 8 to 20 per cent of cases, but the rate following lateral incision is not well documented. This systematic review summarizes incisional hernia rate after open renal transplant. We searched EMBASE, MEDLINE, and the Cochrane Library databases from January 2000 to November 2016 inclusive. The outcomes included in our analysis were the posttransplant incisional hernia rate, significant patient risk factors for incisional hernia, the definition of incisional hernia used, the method used to detect incisional hernia, and the incision used for transplantation. Eight retrospective case series were identified, three describing renal transplant recipients and five describing incisional hernia repairs postrenal transplant. All reported the incisional hernia rate postrenal transplant at the host institution. The hernia rate ranged from 1.1 to 7.0 per cent, with a mean of 3.2 per cent. Factors associated with incisional hernia were body mass index >30, age >50, cadaveric graft, and reoperation through the same incision. Despite the significant comorbidity of renal transplant recipients, the incisional hernia rate postrenal transplant is significantly lower than that of post-midline laparotomy. The reasons for this are discussed. This demonstrates the importance of operative technique, local tissue quality and biomechanical factors in the formation of incisional hernia. PMID- 29981628 TI - Early Closure of Infected Laparotomy Wound with Negative-Pressure Wound Therapy: Safety and Efficacy in 42 Consecutive Cases. AB - Postoperative surgical site infections (SSIs) are one of the most common complications. SSIs after laparotomy have a high incidence and are complicated and expensive to heal. The aim of this study was to evaluate the safety and efficacy of a novel therapy of early closure of open abdominal SSIs wound combining wound irrigation with negative pressure wound therapy (NPWT). Open abdominal SSIs wounds were closed with sutures in 42 consecutive patients. Topical NPWT was applied over a closed wound with a deep drain to allow dynamic drainage and wound irrigation. CT scan with contrast medium injected through the deep drain was performed in patients with suspicious tracts detected during debridement surgery three days after surgery to identify a potential fistula. Wound healing and safety of the therapy was evaluated during an average six months follow-up. Closed wounds healed successfully in all the patients without recurrence of wound infection. Fistulas were easily diagnosed in all four fistula patients by using CT scan with contrast medium injection through the wound. Fistula was confirmed in these four patients at re-exploration. All the drain tube wounds healed spontaneously after drain removal. No severe adverse event occurred during therapy in any patients. With the aid of topical NPWT and deep drainage and irrigation, early closure of open SSIs wound can be done safely. We were also able to diagnose gastrointestinal fistulas at an early stage with the use of CT scan imaging after contrast injection into the wound. PMID- 29981629 TI - Elimination of Routine Benzodiazepine Administration for Nonprocedural Sedation in a Trauma Intensive Care Unit Is Feasible. AB - Current guidelines on the management of pain, agitation, and delirium in the intensive care unit (ICU) recommend a non-benzodiazepine (BDZ)-based approach to sedation. Management of agitation can be challenging in multitrauma patients but is imperative to facilitate patient recovery. Given the current guideline recommendations, a protocol to eliminate BDZ administration and maintain light levels of sedation was adopted in our ICU. The purpose of this analysis was to demonstrate that it is feasible to safely eliminate BDZ administration in a trauma ICU. This was a single-center, retrospective, observational analysis at a Level I trauma center. Adult patients (>18 years old) admitted to the Trauma Critical Care service from March 2015 to August 2015 were included. The primary outcome recorded was the use and duration of nonprocedural BDZs which was defined as BDZ not given within one hour of a procedure or test. A total of 64 patients met the inclusion criteria. The average Injury Severity Score was 18.7. A total of 14 patients (21.9%) received BDZ for a nonprocedure-related indication. Of those patients, all (100%) received less than three as-needed doses of BDZs during their ICU stay. In mechanically ventilated patients, continuous sedation or analgesia was not continued for more than 1.3 days. Only five patients (7.8%) received continuous BDZ. Limiting sedation is feasible in critically ill polytrauma patients. Protocols to standardize sedation strategies should be implemented in the ICU to avoid unnecessary sedation. PMID- 29981630 TI - Analysis of Helicopter-Transported Trauma Patients at a Regional Trauma Center. AB - Our medical center's regional helicopter emergency medical service (HEMS) serves southeastern North Carolina. Judicious HEMS use is vital to ensure that the resource is available for critically injured patients and to reduce morbidity and mortality by providing timely access to definitive care. We reviewed HEMS use, clinical outcomes, and overtriage rates. The data included airlifted trauma patients from January 2004 to December 2012. Of 1210 total patients, 733 were flown directly from the scene (FS) and 477 from referring hospitals (FH). The HEMS catchment area was a 100-mile radius of our trauma center. FS patients were younger and sustained more motor vehicle collisions. FH patients were older and sustained more falls. FS patients required more hospital resources including longer ventilator requirements, intensive care unit (ICU) stay, and hospital stay. For all HEMS patients, there was 92.2 per cent blunt injury, 47.5 per cent required Trauma I or II activation, 31 per cent required mechanical ventilation, and 50 per cent required ICU care. 59.5 per cent of HEMS trauma patients were critically injured (defined as requiring either immediate surgical intervention, immediate ICU admission, or immediate death). The overtriage rate was 1.8 per cent. The emergency department mortality rate was 2.3 per cent and the ultimate mortality rate was 7.5 per cent. Most of the airlifted trauma patients were critically injured, and therefore, HEMS transport was appropriate. However, overtriage was low, suggesting high incidence of undertriage. There should be a lower threshold for HEMS use for trauma patients in our region. More research is needed to determine ideal overtriage and undertriage rates. PMID- 29981631 TI - The Impact of Mesh Reinforcement with Components Separation for Abdominal Wall Reconstruction. AB - The goal in abdominal wall reconstruction (AWR) is to minimize morbidity and prevent hernia recurrence. Components separation and mesh reconstruction are two options, however, with advantages and disadvantages. The purpose of this review was to investigate outcomes in patients with abdominal wall hernia undergoing primary closure with component separation (CS) versus CS with acellular dermal matrix (ADM) reinforcement (CS + mesh). Medical records of consecutive patients who underwent abdominal wall reconstruction using CS with or without ADM reinforcement were retrospectively reviewed. Primary fascial closure was achieved in all patients. ADM reinforcement when used was performed using the underlay technique. Reconstructive technique and postoperative complications including delayed healing, skin necrosis, fistula, seroma, hematoma and surgical site infection, recurrence, and reoperation were recorded. Comparisons between the two groups were assessed. One hundred and seven patients were included (mean age, 55.7; 51.4% male; median follow-up 297 days). Twenty-six patients (24%) underwent CS alone; whereas 81 patients (76%) CS + mesh placement. Patient comorbidities, including smoking (26%), diabetes (20%), and hypertension (46%); body mass index (mean 32.3 +/- 7.6); and albumin level on the day of surgery (mean 3.4 +/- 0.5 mg/dL) were not significantly different between groups. Surgical site infection was significantly higher among CS + mesh patients (22.2%) versus CS only patients (3.9%) (P = 0.02). The recurrence rate of abdominal hernia was significantly lower in CS + mesh patients compared with CS only (14.8% vs 34.6%; P = 0.02). No significant differences in other postoperative complications were identified between the two groups. ADM reinforcement at the time of components separation is often selected in more complex, higher risk patients. Although the incidence of infection was higher in these patients, it was usually treated without mesh removal and recurrence rate was significantly lower when compared to CS alone. PMID- 29981632 TI - A Calculated Risk: Performing Laparoscopic Cholecystectomy for Acute Cholecystitis on Patients with End Stage Renal Disease. AB - End-stage renal disease (ESRD) is a multifactorial disease linked to socioeconomic status and associated with worse surgical outcomes. We explore intraoperative and postoperative outcomes in patients with cholecystitis undergoing laparoscopic cholecystectomy (LC). The Nationwide Inpatient Sample from 2005 to 2012 was used to identify patients undergoing LC for cholecystitis using ICD-9 codes. Outcomes of interest were mortality, common bile duct injury, conversion to open, intraoperative complications, postoperative complications, length of stay (LOS), and total charge. Univariate analysis was performed using t test for continuous variables and chi-squared test for categorical variables. Multivariable models were created that adjusted for age, demographics, year of admission, comorbidities, and presence of ESRD. Of 225,058 patients that underwent LC, 2,115 had ESRD. On univariate analysis, the ESRD cohort had a higher incidence of mortality and complications: intraoperative, mechanical wound, respiratory, cardiovascular, and postoperative infections. ESRD patients had higher median LOS and total charge. Multivariate analysis showed ESRD as an independent risk factor for mortality, mechanical wound complications, and intraoperative complications. Negative binomial regression analysis showed that ESRD patients had LOS 50.4 per cent longer than non-ESRD patients. Linear regression analysis showed that, after adjustment, ESRD patients had total charge 6.82 per cent higher than non-ESRD patients. In this large retrospective analysis, we find that after adjusting for clinical, socioeconomic, and demographic variables, ESRD is an independent risk factor for increased mortality, intraoperative complications, mechanical wound complications, increased LOS, and cost for patients undergoing LC. Prospective studies exploring risk optimization strategies for patients with ESRD are warranted. PMID- 29981633 TI - Life over Limb: Lower Extremity Ischemia in the Setting of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). AB - Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a temporizing maneuver used to decrease hemorrhage, and thus perfusion, below the level of aortic occlusion (AO). We sought to investigate lower extremity ischemia in patients who received REBOA. Between February 2013 and September 2016 patients at a tertiary center that received REBOA and survived more than six hours were enrolled. Thirty-one patients were identified, the mean ISS was 40 +/- 14 and inhospital mortality was 39 per cent. Twenty received REBOA in zone 1 (distal thoracic aorta). Three (15%) developed lower extremity compartment syndrome (LECS) after zone 1 REBOA. Injury of iliofemoral arteries and veins was each associated with calf fasciotomies (both P = 0.005). A longer duration of AO at zone 1 was associated with calf and thigh fasciotomy (P = 0.046 and P = 0.048, respectively). Iliofemoral arterial injury was associated with thigh fasciotomy (P = 0.04). Eleven patients received REBOA in zone 3 (distal abdominal aorta). Five (45%) patients underwent fasciotomy; four (36%) due to LECS. Femoral arterial injury was associated with calf fasciotomies (P = 0.02). There was no association with sheath size or laterality and need for fasciotomy. Neither groin access for REBOA or AO solely caused limb loss or LECS. The contribution to distal ischemia by REBOA remains unclear in patients with lower extremity injury. PMID- 29981634 TI - GERD: Presence and Size of Hiatal Hernia Influence Clinical Presentation, Esophageal Function, Reflux Profile, and Degree of Mucosal Injury. AB - A hiatal hernia (HH) is a frequent finding in patients with gastroesophageal reflux disease (GERD). We examined a consecutive series of patients with GERD diagnosed by a 24-hour pH monitoring. Based on the presence and size of HH on barium swallow, patients were divided into the following groups: no HH, HH <3 cm, HH 3-5 cm and HH >5 cm. A total of 175 patients were included: 43 with no HH, 86 with HH <3 cm, 34 with HH 3-5 cm, and 12 with HH >5 cm. Patients with larger HH had more frequent episodes of coughing and wheezing associated with episodes of reflux. High-resolution manometry showed that the increasing size of the HH was associated with decreasing pressure of the lower esophageal sphincter and weaker peristalsis. Ambulatory pH monitoring revealed that patients with larger HH had more acid reflux, in both the distal and proximal esophagus. Endoscopy showed that patients with larger HH had more severe esophagitis. Fifty per cent of patients with HH >5.0 cm had Barrett's esophagus. These findings should guide gastroenterologists and surgeons in choosing the appropriate therapy in patients with GERD and large HH. PMID- 29981635 TI - New Protocol Avoiding Tube Feed Interruptions in Critically Ill Patients Requiring Tracheostomy. AB - Current anesthesia guidelines require tube feed (TF) interruption for at least four hours before tracheostomy. We hypothesized that preprocedural TF interruption is not required before tracheostomy. We developed a protocol allowing continued feeding. Fifty-six patients undergoing tracheostomy with or without percutaneous endoscopic gastrostomy placement were included. Eleven patients underwent tracheostomy without TF interruption (TF group); the remaining 45 patients had TFs held per the existing anesthesia protocol (nil per os group). Data were collected by retrospective chart review. The groups were similar with regard to age, sex, race, risk of mortality, and preoperative albumin levels (3.2 vs 2.9 g/dL). There was no difference in pulmonary complications. No intraoperative aspiration occurred in either group, and there was no increase in mortality in the TF group (9.1 vs 22.2%, P = 0.43). The TF group had feeds held for 9.5 +/- 6.3 vs 25.4 +/- 19.0 hours (P = 0.0018). The TF group had a decreased missed caloric intake [761.5 +/- 566.6 vs 1983.5 +/- 1590.8 kcal (P = 0.0039)]. The TF group had a shorter time from consultation [40.4 vs 50.6 hours (P = 0.54)] and case booking [7.9 vs 12.8 hours (P = 0.40)] to the OR. The average length of stay for the TF group was 26.3 versus 31.1 days (P = 0.45). There was no increase in pulmonary complications or mortality in the fed patients, who experienced less procedural delays. Meanwhile, patients kept nil per os sustained a substantial caloric deficit. Tracheostomy without TF interruption is feasible and reduces malnutrition. PMID- 29981636 TI - Resident Operative Reports before and after Structured Education. AB - The operative note records surgical indication and pertinent events.In addition, it is a central facet in billing, malpractice lawsuits, research, and future medical planning. However, few residencies have structured education concerning dictation and there is little research on effective techniques for dictation training. The purpose of this study was to evaluate the efficacy of an educational intervention on the dictations of operative cases in which the residents were participants. Two hundred and eighty operative reports were reviewed for the presence or absence of criteria listed in Table 1 and given a score equal to the number of items included. One hundred and forty reports were evaluated before and 140 after an educational intervention. The intervention consisted of a lecture provided by a faculty expert while residents received an instructional card similar to Table 1 as a template. Primary endpoint was dictation score before and after the intervention. The pre- and postintervention scores for all residents were 16.28 and 17.37, respectively (P = 0.001). Junior and senior residents' preintervention average differed by 1.18 (P < 0.001), however there was no significant postintervention difference. The four most commonly missed data points were the amount of intravenous fluids given, preoperative indications, intraoperative findings, and whether or not a drain was placed. This study used real operative reports to show the benefit of dictation templates for improving resident dictations. These data support previous studies on dictation templates and depict the benefits within one surgical program after implementing a formal plan for dictation education. PMID- 29981637 TI - Comparison of Treatment Outcomes of Endoscopic Stenting and Laparoscopic Gastrojejunostomy for Malignant Gastric Outlet Obstruction. AB - To compare the clinic outcomes of endoscopic stenting and laparoscopic gastrojejunostomy (LGJ) for patients with malignant gastric outlet obstruction (GOO). We retrospectively reviewed 63 patients with malignant GOO that underwent endoscopic stenting [Stent Group (SG), n = 29] or LGJ [Laparoscopic Group (LG), n = 34]. Then, we evaluated the medical effects, postoperative hospital stay, and hospitalization expenses in both groups. Compared to LG, SG has a shorter operation time [SG: (41.1 +/- 9.3) minutes vs LG: (137.4 +/- 21.7) minutes, P = 0.000], less intraoperative blood loss [(23.7 +/- 9.0) mL vs (121.1 +/- 24.3) mL, P = 0.000], relatively lower hospitalization expenses [(2272.7 +/- 413.9) $ vs (5182.4 +/- 517.3) $, P = 0.000]. Besides, the median intake time was significantly shorter in the SG than that in the LG [(0.9 +/- 0.3) days vs (4.1 +/- 0.6) days, P = 0.000]. However, there were no significant differences between SG with LG in surgical success rate (100 vs 100%, P = 1.000), length of hospital stay [(6.1 +/- 3.3) days vs (10.9 +/- 4.7) days, P = 0.422], recurrent obstructive rate (37.9 vs 26.5%, P = 0.949) and median survivals [(141.4 +/- 81.4) days vs (122.7 +/- 88.8) days, P = 0.879]. Endoscopic stenting and LGJ are both relatively safe and effective treatments for patients with malignant GOO. But we suggest that endoscopic stenting should be considered first in patients with malignant GOO because it has many advantages over LGJ. PMID- 29981638 TI - Neoadjuvant Chemotherapy Is Associated with Lower Lymph Node Counts in Colon Cancer. AB - Adequate lymphadenectomy is associated with improved survival in patients who undergo oncologic resection of colorectal cancer and has been identified as a quality metric. Neoadjuvant chemotherapy has been found to be associated with collection of <12 lymph nodes in patients with rectal cancer. The purpose of this study was to evaluate patient and operative risk factors for inadequate lymph node retrieval during oncologic colectomy. The 2014 American College of Surgeons National Surgical Quality Improvement Program Participant Use File data set for oncologic colectomy (n = 9077) was analyzed. Patient- and operation-related factors were assessed by univariate and multivariate regression analyses to determine factors associated with the number of lymph nodes collected. Adequate lymphadenectomy was defined by collection of >12 lymph nodes. Of 9077 patients with a diagnosis of colon cancer who underwent colectomy, a minimum of 12 lymph nodes was harvested in 7897 (87%). Significant factors independently associated with inadequate lymphadenectomy included preoperative chemotherapy, emergent surgery, and T1 tumors (all P < 0.05). A large majority of patients who undergo colectomy for colon cancer have at least 12 lymph nodes collected. Preoperative chemotherapy is a major risk factor for inadequate lymph node retrieval. Recognition of factors associated with inadequate lymphadenectomy may improve colectomy lymph node yield and survival in patients with colon cancer. PMID- 29981640 TI - Cost Analysis of Direct Oral Anticoagulants Compared with Warfarin in Patients with Blunt Traumatic Intracranial Hemorrhages. AB - Direct oral anticoagulants (DOACs) are rapidly gaining popularity as alternatives to warfarin in the prevention of stroke or systemic embolic events because of the simplicity of their dosing and lack of monitoring requirement. Many physicians feared that these novel agents would be cost-prohibitive not only in their administration but also in their sequelae of bleeding, given the few reversal agents available. Whereas the medication itself is more expensive than traditional warfarin, the total cost of a hospital admission has not been compared between patients on DOACs and warfarin who have sustained a blunt traumatic intracranial hemorrhage (ICH). We conducted a retrospective review of our hospital's trauma database from June 2011 through September 2015 at our Level II trauma center of patients who suffered from an ICH who were anticoagulated at the time of their trauma. Patients who died during their hospital admission or were exclusively on antiplatelet agents were excluded. Of the 136 patients studied, 79 were on warfarin and 57 were on a DOAC at the time of their presentation for a traumatic ICH. The average charged cost for the hospital stay of a patient with an ICH was significantly higher for patients on warfarin compared with DOACs [$70,384.08 vs $49,226.66 (P = 0.02)]. The average reimbursement rate for the hospital was also significantly higher for those patients on warfarin as compared with those on DOACs [$23,922.93 vs $14,705.77 (P = 0.02)]. DOACs are associated with a significant cost benefit in patients admitted for blunt traumatic ICHs when compared with those on warfarin. PMID- 29981639 TI - Early Enteral Nutrition Is Associated with Reduced Morbidity in Critically Ill Soft Tissue Patients. AB - Soft tissue diseases including necrotizing soft tissue infections are associated with high mortality and morbidity with hospital-acquired infection rates up to 76 per cent. Critically ill patients with soft tissue infections have increased metabolic requirements; however, the effect of early nutrition on inhospital morbidity including nosocomial infection rates remains unclear. We hypothesized that enteral nutrition within 48 hours of intensive care unit admission would be associated with fewer hospital-acquired infections. We conducted a retrospective review of patients with soft tissue infection requiring intensive care unit admission for >72 hours from January 2013 through December 2014 to a high-volume, dedicated soft tissue service. Variables were compared using chi-squared, Student's t test, linear regression, and binary logistic regression analysis. Eighty-five patients met inclusion criteria; 80 per cent started enteral nutrition within 48 hours. Twenty-six per cent had a hospital-acquired infection postadmission requiring treatment. Patients started on enteral nutrition within 48 hours had fewer ventilator days (mean 5 vs 12) and shorter hospital length of stay (mean 18 vs 40 days) when adjusted for age, gender, and confounding variables present on admission. Patients receiving early nutrition also had fewer hospital-acquired infections (18 vs 59%) when adjusted for confounding factors (aOR 0.15, P = 0.045). No significant difference in mortality (13.2% early vs 5.9% late, P = 0.4) or for inhospital morbidity when evaluating percentage of goal calories or protein received or time to goal tube feed rate was found. Early enteral feeding is associated with reduced inhospital morbidity in critically ill soft tissue patients, including fewer hospital-acquired infections and ventilator days, and shorter total length of stay. PMID- 29981641 TI - The Role of Noncontrast CT in the Evaluation of Surgical Abdomen Patients. AB - Acute surgical abdomen is commonly encountered in the ED and CT is widely used as an informative diagnostic tool to evaluate potential surgical indications. However, the adverse effects of contrast material used in CT scanning have been documented. We sought to delineate the role of noncontrast CT in the evaluation of patients with acute surgical abdomen. Between August 2015 and December 2015, patients with nontraumatic surgical abdomen who underwent preoperative CT were enrolled in the current study. The patients for whom the CT results permitted surgical decision-making were the focus of this study. The disease entities included acute appendicitis, acute cholecystitis, hollow organ perforation, mechanical bowel obstruction, intra-abdominal abscess that could not be drained percutaneously, and ischemic bowel disease. The results of contrast-enhanced and noncontrast CT were compared and analyzed. The surgical conditions identifiable by noncontrast CT were recorded. In total, 227 patients were enrolled in the study. In 90.7 per cent of patients overall, the findings indicating the need for surgical treatment were visualized on both the noncontrast and contrast-enhanced images (acute appendicitis: 89.3%, acute cholecystitis: 89.7%, hollow organ perforation: 97.4%, bowel obstruction: 100%, intra-abdominal abscess: 100%, and ischemic bowel disease: 55.6%). Noncontrast CT provides benefit for critical decision-making. Body mass index may affect the accuracy of noncontrast imaging in the evaluation of patients with surgical abdomen. In some specific situations, contrast enhancement remains necessary. PMID- 29981642 TI - Heller Myotomy: To Wrap or Not to Wrap? AB - Heller myotomy (HM) is widely recognized as the most effective treatment of achalasia. Although effective in improving dysphagia symptoms, HM is associated with reflux. Over a five-year period, 63 laparoscopic HM were performed. Patients underwent myotomy alone or HM plus reconstitution of the angle of His without any fundoplication, anterior, or posterior partial fundoplication. Two postoperative outcomes were examined: dysphagia and reflux. Twenty-two patients received no fundoplication (34.9%). Forty-one (65.1%) antireflux procedures were performed, including 21 reconstitutions of the angle of His (33.3%), nine (14.3%) anterior fundoplications, and 11 (17.5%) posterior fundoplications. All patients demonstrated preoperative dysphagia. Postoperative dysphagia was present in 23 of 63 (36.5%). Of these, 13 (56.5%) patients had an antireflux procedure, whereas 28 of 40 who had an antireflux procedure (70%) had no postoperative dysphagia (P = 0.28). Thirty-nine of 62 (62.9%) had symptomatic esophageal reflux preoperatively, and postoperative reflux was reported in 22 of 63 (34.9%). Reflux was present in 72.7 per cent of patients who had an antireflux procedure versus 61 per cent of those without the addition of an antireflux procedure (P = 0.415). However, HM independently improved reflux status regardless of whether an antireflux procedure was performed using the exact McNemar's test (P = 0.0014). Although the performance of an antireflux procedure did not appear to alter the reflux status after HM for achalasia, neither was it associated with postoperative dysphagia. More importantly, HM was independently associated with an improvement of reflux symptoms regardless of the type of antireflux procedure performed or whether one was used or not. PMID- 29981643 TI - Wiser with Age? Increased Per-Surgeon Elderly Patient Volume Is Associated with Lower Postinjury Complications. AB - We hypothesize that higher elderly patient volume per trauma surgeon is associated with fewer clinical complications. This is a retrospective cohort study which included elderly patients admitted to trauma surgery service within a five-year period, from 2009 to 2013, at two Level I trauma centers in Florida. Trauma surgeons were stratified into three groups depending on patient volume. Primary outcomes were postinjury complications and in-hospital mortality, and secondary outcomes were hospital length of stay (LOS), intensive care unit LOS, and ventilator days. A total of 2379 elderly patients were included in this study. Elderly patient volume per surgeon did not significantly differ based on years in practice after fellowship (P = 0.88). The higher volume group had lower incidence of complications (15% complication rate, P = 0.02), compared with the average and low-volume group (18.1 and 21%, respectively), and had significantly lower rates of acute respiratory failure (P = 0.04) and acute renal failure (P = 0.004). In-hospital mortality was not affected by volume. Hospital LOS was decreased in the higher volume group (mean LOS 7.4 days, P < 0.001). There appears to be a relationship between elderly patient volume and outcome, independent of surgeon years of experience. PMID- 29981644 TI - Splenic Bed Laparoscopic Splenectomy Approach for Massive Splenomegaly Secondary to Portal Hypertension and Liver Cirrhosis. AB - This study was performed to evaluate the feasibility of the splenic bed laparoscopic splenectomy approach (SBLS) for massive splenomegaly (>=30 cm) in patients with hypersplenism secondary to portal hypertension and liver cirrhosis. Patients who underwent laparoscopic splenectomy (LS) from January 2012 to December 2016 were retrospectively reviewed. We performed LS in 83 patients with massive splenomegaly (>=30 cm) secondary to portal hypertension and liver cirrhosis. Of these patients, 37 underwent the SBLS and 46 underwent anterior LS (ALS). Five patients in the ALS group and none in the SBLS group underwent conversion to open surgery. The operation time, intraoperative blood loss volume, transfusion volume, frequency of transfusion, hemorrhage of short gastric vessels, conversion rate, postoperative hospital stay, and incidence of pancreatic fistula were all significantly lower in the SBLS than ALS group (all P < 0.05). No death or postoperative bleeding occurred in the two groups, and there were no significant differences in age, gender, spleen size, hemoglobin level, platelet count, prothrombin time, Child-Pugh class, hypoproteinemia, or ascites (all P > 0.05). The SBLS is more feasible and effective than ALS in patients with massive splenomegaly (>=30 cm) secondary to portal hypertension and liver cirrhosis. PMID- 29981645 TI - Assessing the Veterans Affairs Surgical Quality Improvement Program Risk Calculator in Cholecystectomy. AB - The Veterans Affairs Surgical Quality Improvement Program (VASQIP) risk calculator has been validated for several operations but has not been assessed specifically for cholecystectomy. Our aim was to externally validate the VASQIP calculator's accuracy in predicting 30-day morbidity and mortality (M&M) for patients undergoing cholecystectomy. A retrospective review of patients undergoing cholecystectomy at the North Texas Veterans Affairs hospital was performed. The VASQIP risk calculator was used to determine predicted 30-day M&M, which was compared with actual M&M. The predictive accuracy of the Veterans Affairs risk calculator was assessed using the C-statistic and a graphical assessment of a locally weighted least squares regression smoother. Overall, 848 patients were included in the study. Actual M&M were 6.3 and 0.94 per cent, respectively, whereas predicted M&M were 6.0 and 0.54 per cent. The C-statistic was 0.75 for morbidity and 0.78 for mortality. In our analysis, the VASQIP risk calculator reasonably predicted 30-day M&M. PMID- 29981646 TI - Ultrasound-Guided Breast-Conservative Surgery Decreases the Rate of Reoperations for Palpable Breast Cancer. AB - The purpose of this study is to verify whether the performance of ultrasound guided quadrantectomy (USGQ) versus palpation-guided quadrantectomy (PGQ) can reduce the incidence of positive margins and if it can change the attitude of the surgeon. A retrospective study was conducted on 842 patients underwent quadrantectomy for breast cancer, 332 of them underwent USGQ, whereas 550 underwent PGQ. The histological type of the tumors and the margin status obtained with the histological examination were compared. The histological examination of the surgical specimen showed involvement of the margins in 24/842 patients (2.85%), 22 (2.61%) of them belonged to the PGQ group, and two to the USGQ group (P = 0.0011). The highest rate of microscopically positive margins was, statistically significant, for carcinoma in situ, when compared with patients with invasive carcinoma (0.0001). USGQ technique showed several advantages compared with PGQ. In fact, the former notes a lower positive margin rate and, consequently, a lower rate of reintervention. In addition, it may change the surgeon's attitude by causing him to remove another slice of margin to ensure more histological negativity. It should be the gold standard technique for breast conservative surgery of palpable tumors. PMID- 29981647 TI - Correlating Geographic Location with Incidence of Motor Vehicle-Induced Pedestrian Injury. AB - To date, no studies have examined the relationship between geographic and socioeconomic factors and the frequency of pedestrians sustaining traumatic injuries from a motor vehicle. The objective of this study was to analyze the impact of location on the frequency of pedestrian injury by motor vehicle. The University of Louisville Trauma Registry was queried for patients who had been struck by a motor vehicle from 2010 to 2015. Demographic and injury information as well as outcome measures were evaluated to identify those impacting risk of pedestrian versus motor vehicle accidents. Number of incidents was correlated with lower median household income. There was also a moderate correlation between the number of incidents and population density. Multivariable analysis demonstrated a significant association between increased median household income and distance from downtown Louisville and decreased risk of death following pedestrian versus motor vehicle accident. Incidence of pedestrian injury by motor vehicles is influenced by regional socioeconomic status. Efforts to decrease the frequency of these events should include further investigation into the mechanisms underpinning this relationship. PMID- 29981648 TI - Comparison of Outcomes for Pediatric Trauma at Different Types of Trauma Centers: The Unresolved Mystery. AB - In Florida, injured children can receive emergent care at one of three types of state-approved trauma centers (TCs). A Level 1 combined adult/pediatric TC (L1, A + P), a Level 2 TC with an associated pediatric hospital (L2 + PH) or a pediatric TC at a pediatric hospital (PTH). This study aims to compare the mortality outcomes between Florida L1, A + Ps, to L2 + PHs, and PTHs. A retrospective review of dataset from the Agency for Health Care Administration compared outcomes from 2013 to 2016 at all three types of TCs. Outcomes were stratified by using the observed over expected mortality (O/E). Significance defined as P < 0.05. A total of 13,428 pediatric trauma patients were treated at all three TCs (L1, A + P, L2 + PHs, or PTH). L1, A + Ps treated 6975 pediatric patients with 104 deaths [crude mortality rate (CMR) 1.49%, O/E = 0.96], L2 + PHs treated 4066 patients with 69 deaths (CMR 1.70%, O/E = 1.21), PTHs treated 2387 patients with 34 deaths (CMR 1.42%, O/E = 1.25). When O/E's at L1, A + Ps and L2 + PHs were compared, results were statistically significant (P = <0.03),but not at L1, A + P versus PTHs. This is the first study to reveal that Level 1 adult/pediatric TCs have lower mortality rates compared with Level 2 TCs with an associated pediatric hospital. Level 1,A + P TCs had similar outcomes to pediatric TCs at stand-alone pediatric hospitals. PMID- 29981649 TI - Importance of Markers of Sepsis in Surgical Patients. AB - Sepsis, severe sepsis, and septic shock represent a serious medicinal and general social problem and still maintain an important position among the present issues in the basic and clinical research. In the prospective analysis of patients satisfying the criteria of septic condition, we determined serum levels of bioparameters in three consecutive days from the first signs of sepsis depending on the stage or advancement of the septic condition. We determined the most significant parameter/parameters which are able to determine the stage of sepsis or to predict patient's death. In the group of 68 patients, all monitored biomarkers showed significant difference in serum concentrations versus the control group (P = 0.001). The strongest positive connection between the seriousness of sepsis and serum level is in case of procalcitonin. Predictor of mortality (r = -0.468; P = 0.001), transferrin (r = -0.506; P = 0.003), and tumor necrosis factor-alpha (r = 0.939; P = 0.001). Our results show that the monitored parameters (procalcitonin, C-reactive protein, tumor necrosis factor-alpha, and interleukin 6) have strong correlations between the serum levels and the stage of disease. Examination of at least one cytokine in normal clinical practice might lead to better interpretation of the patient's condition, determining the risk of death. PMID- 29981650 TI - Adenoma Detection Rate in Colonoscopy: Does the Participation of a Resident Matter? AB - Presently, endoscopic procedures are a requirement for training competency for completion of a general surgery residency. There are no studies to date that have assessed whether having a resident perform a colonoscopy impacts quality indicators such as adenoma detection rate (ADR). To retrospectively review ADR in adult patients, who undergo screening colonoscopy at a single institution with (ColFacR) and without (ColFac) the participation of a general surgery resident. A total of 792 patients were identified in the database screening colonoscopies between the ages of 45 and 80 from July 2013 to June 2015. Of those, 501 were reviewed after exclusion criteria. When comparing the ColFac group (n = 316) to the ColFacR group (n = 185), there were no differences between age, gender, body mass index, American Society of Anesthesiologists score, or quality of bowel preparation. The mean number of total polyps, hyperplastic polyps, and adenomatous polyps retrieved were similar between the two groups. There was no difference in the ADR for the ColFac cases and ColFacR cases (25.95% vs 27.03%, respectively, P = 0.834). ADR is similar in elective colonoscopies that were performed with or without a general surgery resident. The participation of a general surgery resident in routine colonoscopies should not impact reported quality indicators. PMID- 29981651 TI - Association of Treatment for Critical Limb Ischemia with Gender and Hospital Volume. AB - Critical limb ischemia (CLI) is a frequent and major vascular problem and can lead to amputation and death despite surgical revascularization. Women have been shown to have 3 to 4 per cent lower revascularization rates for CLI compared with men as well as inferior outcomes. We hypothesize that this difference is a result of women being more likely admitted to low-volume hospitals, which in turn perform fewer revascularizations. Prospective cohort study. Data from the Nationwide Inpatient Sample 2007 to 2010 were used to identify admissions with primary International Classification of Diseases-9 codes for CLI (International Classification of Diseases-9 codes: 440.22, 440.23, 440.24, 707.1, 707.10-707.15, or 707.19). Hospitals were grouped in quintiles by annual revascularization procedures. Bivariate analyses were performed and multivariable logistic regression was used to analyze the odds of revascularization, amputation, and mortality while controlling for patient and hospital-level factors. Of 113,631 admissions, 54,370 (47.8%) were women, who were more likely admitted to low volume hospitals (very low: 49.6% vs very high: 47.1%; P < 0.001). Revascularization rates were lower in women (31.6% vs 35.1%, P < 0.001) across all volume quintiles, whereas the difference was greatest in the use of open surgical revascularization (12.5% vs 16.0%, P < 0.001). In multivariable analysis, female gender [odds ratio (OR) 0.87, 95% confidence interval (CI) 0.83 0.92, P < 0.001] and very-low hospital volume (OR 0.21, 95% CI 0.17-0.26, P < 0.001) were both significantly associated with lower rates of revascularization. Women had lower odds of major amputation compared with men (OR 0.75, 95% CI 0.69 0.82, P < 0.001), whereas treatment in a very high-volume hospital was associated with increased odds for amputation (OR 1.37, 95% CI 1.09-1.73, P = 0.008). Neither gender nor hospital volume were independently associated with in-hospital mortality in the multivariable regression model. Women are more likely to be admitted to low-volume hospitals for treatment of CLI. Because of this, they are less likely to undergo revascularization, although they also had lower rates of major amputation. PMID- 29981652 TI - Paramedic and Surgeon Views on Trauma Surgical Readiness: Implications for Guideline Implementation. AB - Centers for disease control (CDC) Guidelines for Field Triage are effective when proper implementation by EMS personnel is paired with surgeon willingness to care for trauma victims. We hypothesized that in a state with an immature trauma system, a discrepancy exists between medic and surgeon perception of surgical readiness, coinciding with inconsistent implementation of protocols. Surveys were conducted among medics and general surgeons. Destination protocols, trauma center locations, surgeon readiness, and interest in trauma were assessed. A standard clinical trauma scenario was also used. Surgeon willingness to operate is not affected by working outside of trauma centers or interest in trauma. Medics working far from trauma centers are less confident in local surgeon's willingness to operate and less likely to have destination protocols. Trauma center proximity affects medic perception of surgeon willingness to operate, but mere presence of general surgeons does not. In a trauma scenario, surgeon willingness to operate was related to medic perception but not action. In rural states, most surgeons do not work in trauma centers and most medics do not work near them. Although most responding surgeons indicate willingness to operate, medics are confident of such willingness only half the time. This disparity results in inconsistent use of the CDC guidelines. Although most medics report protocols for destination determination, nearly one-fourth of victims are taken to the geographically closest centers, sometimes with no surgeon at all. Efforts at medic training, enhancing surgeon readiness, and alignment of goals are necessary for the CDC Guidelines to be effective. PMID- 29981654 TI - Use of Computerized Tomography in Abdominal Pain. AB - Annually, approximately 70 million computed tomography (CT) scans are performed in emergency department (ED) settings in the United States of America. From 1995 to 2007, there has been a 5.9-fold increase in the use of CT scans nationally. The radiation risks and high costs associated with CT scans underscore the fact that the imaging modality, although necessary, carries a myriad of long-term risks to both patients and providers. For the workup of abdominal pain, most algorithms include the use of CT scan as an early step. To understand better the use of CT scans in our ED, we performed a retrospective review of patients presenting to the ED with abdominal pain. Two main questions were addressed: 1) what were the reasons for scans and how often did the scans reveal pathology related to the presenting symptoms, 2) how often were incidental findings identified. Our results showed that among patients presenting with abdominal pain to the ED, 50 per cent of the scans were normal, about 20 per cent of the patients had findings correlating with acute abdominal pain, whereas the rest (30%) had incidental findings that may have led to further outpatient studies or long standing abdominal pain. Most patients who presented to the ED had nonspecific abdominal pain i.e. 64.4 per cent. There was a low agreement between the presenting quadrant of pain and final pathological diagnosis (9.5-33.3% concordance), with left flank pain presentation having the highest level of agreement with the final pathologic diagnosis. PMID- 29981653 TI - Predictive Factors for Delayed Gastric Emptying after Distal Gastrectomy with Roux-en-Y Reconstruction. AB - Delayed gastric emptying (DGE) after distal gastrectomy (DG) followed by Roux-en Y (R-Y) reconstruction is one of the most worrisome complications, and the course of DGE has not been completely elucidated. This retrospective study aimed to evaluate the frequency of DGE after DG followed by R-Y reconstruction for gastric cancer and identify the risk factors for its development. This study included 266 patients with gastric cancer who underwent DG followed by R-Y reconstruction between 2005 and 2016. We compared clinicopathological characteristics and surgical procedures between the DGE group and non-DGE group. DGE occurred in 24 of the 266 patients. There were no relationships of gender, age, TNM stage, historical grade, surgical approach, extent of lymphadenectomy, preservation of the vagal nerve, and reconstruction route with DGE development. Body mass index (BMI) was higher in DGE patients than in non-DGE patients (P = 0.053). Univariate analysis revealed that a tumor located in the lower third of the stomach (P = 0.005) and isoperistaltic reconstruction (P = 0.043) were significant factors for DGE. Multivariate analysis showed that a tumor located in the lower third of the stomach (P = 0.007), isoperistaltic reconstruction (P = 0.044), and BMI (P = 0.034) were significant predictors of DGE. Our findings suggest that tumor location, the direction of peristalsis for gastrojejunostomy, and BMI are associated with DGE after R-Y reconstruction. PMID- 29981655 TI - Improving Pharmacologic Prevention of VTE in Trauma: IMPACT-IT QI Project. AB - Enoxaparin regimens commonly used for prophylaxis fail to achieve optimal anti factor Xa levels in up to 70 per cent of trauma patients. Accordingly, trauma services at the study institution endeavored to develop a standardized approach to optimize pharmacologic prevention with enoxaparin. An enoxaparin venous thromboembolism (VTE) prophylaxis protocol implemented in October 2015 provided weight-adjusted initial dosing parameters with subsequent dose titration to achieve targeted anti-factor Xa levels. Symptomatic VTE rate was evaluated 12 months pre- and post-implementation. Data were obtained from the trauma registry and charts were reviewed from electronic medical records. The rate of symptomatic VTE significantly declined post-implementation (2.0% vs 0.9%, P = 0.009). Enoxaparin use was comparable in these two phases validating that the decline in symptomatic VTEs was not due to an increase in enoxaparin use. Symptomatic VTE rate for patients who received enoxaparin in the post-implementation cohort decreased from 3.2 to 1.0 per cent (P = 0.023, 95% confidence interval = 0.124 0.856). There was also a significant decrease in the rate of symptomatic deep vein thrombosis (2.8% vs 0.9%, P = 0.040, 95% confidence interval = 0.117-0.950). This approach to VTE prophylaxis with enoxaparin resulted in a significant reduction in symptomatic VTE rates. Implementation of similar practices may be equally impactful in other institutions that use enoxaparin. PMID- 29981656 TI - Initial Experience with Fibrin Glue Treatment of Anal Fistulae in Children. AB - Pediatric anal fistulae commonly result from recurrent perianal abscesses, of which nearly 50 per cent develop an anal fistula. The purpose of this study was to report the results of using fibrin glue to treat anal fistula in pediatric patients. Infants and children with recurrent perianal abscesses and anal fistulae were treated with either fistulectomy or fibrin glue. Demographic and clinical characteristics and outcomes were compared between the groups. A total of 34 children were included; 27 received fistulectomy (median age eight months) and seven received fibrin glue treatment (median age 14 months). No significant differences in demographic or clinical characteristics were found between the two groups (all, P > 0.05). Median follow-up duration was significantly higher in the fibrin glue group compared with that in the fistulectomy group (five months vs one month, P = 0.003). There was one recurrence in the fistulectomy group, and no recurrences in the fibrin glue group (P = 1.0). No complications occurred in either group. Fibrin glue treatment is a simple and effective treatment alternative in the management of anal fistula in children, offering the advantage of sphincter muscle-sparing and reduced risk of fecal incontinence. PMID- 29981657 TI - Laparoscopic Appendectomy: A Report on 1164 Operations at a Single-Institution, Safety-Net Hospital. AB - Laparoscopic appendectomy (LA) is the standard of care for the treatment of acute appendicitis. There is an ongoing debate regarding the optimal management of appendicitis, which led us to study outcomes after an appendectomy at a large safety-net hospital. We hypothesize that despite a high-risk population, LA remains a safe and effective treatment for acute appendicitis. A retrospective review was performed of all patients who underwent an appendectomy from 2011 to 2013. The primary end point was significant morbidity defined as a score of three or greater on the Clavien-Dindo scale of surgical morbidity. Thousand hundred and sixty-four patients underwent an appendectomy. A total of 1102 (94.7%) patients underwent either an LA or laparoscopic converted to open appendectomy, and 62 (5.3%) patients underwent an open appendectomy (OA). Two hundred and forty six patients (21.1%) had complicated appendicitis. Laparoscopic converted to OA conversion rate was 4.4 per cent and differed between years (P < 0.001). LA had a significantly shorter length of stay, shorter length of postoperative antibiotics, and less postoperative morbidity. When limited to only patients with complicated appendicitis, major morbidity was still greater in the OA group (22.6 vs 52.0%, P = 0.001). Length of stay was significantly longer in the OA group [3.42 (2.01, 5.97) vs 7.04 (5.05, 10.13), P < 0.001]. Odds for complication were 2.6 times greater in the OA group compared with the LA group. In the absence of peritonitis and systemic illness necessitating urgent laparotomy, patients who are laparoscopic surgical candidates should be offered an LA. Our study demonstrates that these patients have better outcomes and shorter hospital stays. PMID- 29981658 TI - Follicular Carcinoma Masquerading as a Hot Nodule in a Pediatric Patient. AB - Autonomous functioning thyroid nodules (AFTNs) are generally considered to be benign entities, with malignancy found in about 1 per cent considered to be rare in the general population. Because of this low rate, fine needle aspiration is generally not recommended, and these lesions are most often treated with radioactive iodine, medication, or surgery. However, AFTNs are exceedingly rare in the pediatric population and the optimal treatment is not defined. We present a 14-year-old female patient with an AFTN treated with surgical resection and found to contain a follicular carcinoma with capsular invasion. PMID- 29981659 TI - An Interdisciplinary Perioperative Management Protocol for Patients with Sickle Cell Anemia: A Single-Surgeon Experience. PMID- 29981660 TI - Managing Infected Pancreatic Necrosis. AB - The management of infected pancreatic necrosis has historically been based on early, open necrosectomy, associated with significant mortality. In recent years, an evidence based transformation has occurred towards the step-up approach consisting of percutaneous catheter drainage, if necessary, followed by minimally invasive necrosectomy. More recently the endoscopic step-up approach has gained popularity. This review evaluates the diagnosis, prevention and treatment of infected necrotizing pancreatitis. Key points in managing infected pancreatic necrosis: - multidisciplinary team approach in tertiary level centres; - no indication for prophylactic antibiotics or probiotics; - nasogastric, enteral nutrition indicated after 72 hours, if oral feeding is insufficient; - only intervene in infected necrosis; - delay intervention until "walled-off necrosis"; - step-up approach of percutaneous or endoscopic catheter drainage, followed by minimally invasive necrosectomy, if required; - endoscopic strategies are preferable where possible. PMID- 29981661 TI - Surgical Treatment of Chronic Pancreatitis: The State of the Art. AB - Chronic pancreatitis is a common disease accompanied with considerable morbidity and mortality. Complications associated with chronic pancreatitis, such as pseudocysts, stenosis of adjacent anatomic structures or pain that cannot be managed conservatively, may be treatable surgically or interventionally by endoscopy. Surgery is superior to endoscopy in regard to long-term pain management. Duodenum preserving pancreatic resection is the surgical procedure of choice in patients with inflamed changes of the head of the pancreas. The best timing of surgery, the ideal standardized perioperative management are the focus of current research. PMID- 29981662 TI - Pancreatic Cancer in the Era of Neoadjuvant Therapy: A Narrative Overview. AB - Pancreatic adenocarcinoma is an aggressive systemic disease with around 30% of patient presenting locally advanced disease at diagnosis and being not candidate to surgical resection. Pioneering experiences with neoadjuvant treatment for locally advanced pancreatic cancer (LAPC) were undertaken more than 25 years ago and this strategy kept on gaining consensus over time. In recent years two main breakthroughs have been done: first, clear definitions of resectable, borderline resectable and locally advanced unresectable disease were released, and, soon after, two different chemotherapy regimens (namely, FOLFIRINOX and Gemcitabine plus Nab-Paclitaxel) were introduced in the clinical practice for LAPC after their effectiveness in metastatic patients was demonstrated. This article reviews papers regarding the administration of neoadjuvant chemotherapy, with or without radiation therapy, published from 2011 through 2017 with particular significance been given to reported results in term of resection rates, complete resection (R0) rates and Overall Survival, and briefly summarizes recommendations provided by the most recent guidelines for the treatment of non-metastatic pancreatic cancer. PMID- 29981663 TI - Pancreatic Cystic Lesions: Diagnostic, Management and Indications for Operation. Part II. PMID- 29981664 TI - What is the Value of Total Mesopancreas Excision in Pancreatic Ductal Adenocarcinoma? Current Evidence of the Literature. AB - Pancreatic ductal adenocarcinoma (PDAC) is a disease with a grim prognosis. Pancreatectomy represents the single hope for long-term survival in a patient with PDAC. Recurrence is a common event after curative-intent surgery for PDAC, mainly related to incomplete removal at the site of resection margins; medial/ superior mesenteric margins are the most often positive. The concept of total mesopancreas excision (TMpE) in PDAC was proposed in analogy to the concept of total mesorectal excision for rectal cancer, to better control loco-regional recurrence. This paper aims to discuss the current evidence for the value of TMpE in PDAC. PMID- 29981665 TI - Is Hepatitis B Virus a Player in Pancreatic Cancer? AB - Pancreatic cancer (i.e., pancreatic ductal adenocarcinoma, PDAC) is an important healthcare issue and a highly lethal disease. Thus, almost 80% of patients with PDAC will die within one year after diagnosis. Several factors including smoking, obesity, advanced age, diabetes mellitus and chronic pancreatitis have been associated with increased risk of PDAC. Hepatitis B virus (HBV) infection is also considered as a risk factor for PDAC development in some studies. However, the role of HBV infection in PDAC is poorly explored. The present paper reviews the current relevant literature exploring the impact of HBV infection in PDAC. Assessment of HBV infection impact in PDAC is challenging because its effects could be easily underestimated. Indeed, the role played by occult B infection (OBI) and intrinsic difficulties to detect HBV antigens or DNA in pancreatic tissue remains major limitations to further progress. To date a significant proportion of available literature suggests the potential oncogenic role of HBV in PDAC but experimental evidences remain scarce. Remarkably, it appears that HBV infection might influence some clinical and pathological features of patients with PDAC. Future researches to better define the role of HBV infection in developing PDAC are urgently needed. PMID- 29981666 TI - Therapeutical Aspects Regarding Pancreatic Pseudocysts. AB - Frequently appearing as a complication of pancreatitis, pancreatic pseudocysts are rare appearances in current medical practice. Multiple therapeutical options are available, from minimum invasive methods to complex open surgical techniques. The indications of drainage include symptomatic pseudocysts, large pseudocysts along with the development of complications such as hemorrhage, secondary infection, and rupture. Choosing the best drainage technique is often a challenge. Multiple factors need to be considered in managing a pseudoocyst, including its location, dimension and the patient's general state and comorbidities. Thus, a therapeutical algorithm may be of great use in choosing the most feasible technique for the diagnosed lesion that is also patient adapted. PMID- 29981667 TI - One Hundred Pancreatectomies with Venous Resection for Pancreatic Adenocarcinoma. AB - Introduction: Invasion of portal vein (PV)/ superior mesenteric vein (SMV) in pancreatic ductal adenocarcinoma (PDAC) is no longer a contraindication for resection when reconstruction is technically feasible. However, the literature data reached conflicting conclusions regarding the early and long-term outcomes of patients with venous resection and pancreatectomies for PDAC. The study aims to present the outcomes in a large series of patients with pancreatectomies and associated PV/ SMV resection for PDAC, in a single center experience. Patients Methods: The data of 100 patients with pancreatectomies and PV and/ or SMV resection performed between 2002 and 2016 (February, 1st) were retrospectively analyzed from a prospectively maintained electronic database, which included 474 pancreatectomies for PDAC. Only patients with a final pathological diagnosis of PDAC were included in the present study. Results: Overall, 21.1% of patients with pancreatectomies for PDAC required a venous resection (100 patients out of 474 patients). Segmental resection was performed in 77 patients (out of 100 patients with pancreatectomies and venous resection - 77%), while 23 patients (23%) have had tangential venous resection. In the group of patients with segmental venous resection, reconstruction was made by end-to-end anastomosis in 53 patients (out of 77 patients - 68.8%), while in 24 patients (out of 77 patients - 31.2%) a graft interposition was necessary. Negative resections margins were obtained in 63 patients (63%). Histological tumor invasion of the resected vein was confirmed in 64 patients (64%). Postoperative complications occurred in 47 patients (47%), with severe complications (i.e., Dindo-Clavien grade III-V) in 19 patients (19%). Postoperative pancreatic fistulae, delayed gastric emptying and post pancreatectomy hemorrhage rates were 9%, 20% and 15%, respectively. PV/ SMV thrombosis occurred in 5 patients (5%). The 90-day mortality rate in the group of patients with venous only resection, without any associated procedures, was 8%. Adjuvant treatment was performed in 63 patients (63%), while only 2 patients (2%) underwent neoadjuvant chemotherapy. Median follow-up time was 105 months (range, 3 - 186 months), with a median overall survival time of 13 months (range, 3 - 186 months). In the group of patients with negative resection margins, the median overall survival time was 16 months (range, 3 - 186 months). Conclusions: PV/ SMV resection during pancreatectomies for PDAC is technically feasible, and grafts are rarely required for venous reconstruction. However, venous resection is associated with high postoperative complications rates, and the mortality rate is not neglectable. The main goal of such complex procedure is to obtain negative resection margins, a situation associated with encouraging survival rates. PMID- 29981668 TI - An Attempt to Build a National Prospective Electronic Database for Pancreaticoduodenectomies in Romania - Preliminary Results of the First Year Enrollment. AB - Introduction: National databases for pancreaticoduodenectomies (PD) have contributed to better postoperative outcomes after such complex surgical procedure because the multicentre collection of data allowed more reliable analyses with quality assessment and further improvement of technical issues and perioperative management. The current practice and outcomes after PD are poorly known in Romania because there was no national database for these patients. Thus, in 2016 a national-intent electronic registry for PD was proposed for all Romanian surgical centers. The study aims to present the preliminary results of this national-intent registry for PD after one-year enrollment. Patients Methods: The database was started on October 1st, 2016. Data were prospectively collected with an electronic online form including 102 items for each patient. The registry was opened to all the Departments of Surgery from Romania performing PD, with no restriction. Results: During the first year of enrollment were collected the data of 181 patients with PD performed by 24 surgeons from four surgical centers. The age of patients was 64 years (28 - 81 years), with slightly male predominance (61.3%). Computed tomography was the main preoperative imaging investigation (84.5%). All the PDs were performed by an open approach. The Whipple technique was used in 53% of patients, and a venous resection was required in 14.3% of cases. A posterior approach PD was considered in 16.6% of patients. The stomach was used to treat the distal remnant pancreas in 50.1% of patients. The operative time was 285 min (110 - 615 min), and the estimated blood loss was 400 ml (80 - 3000 ml). The overall morbidity rate was 55.8%, with severe (i.e., grade III-IV Dindo-Clavien) morbidity rate of 10%, and 3.9% in-hospital mortality rate. The overall pancreatic fistula, delayed gastric emptying and hemorrhage rates were 19.9%, 39.8% and 15.5%. Periampullary malignancies were the main indications for PD (78.9%), with pancreatic cancer on the top (48%). Conclusions: To build a prospective electronic online database for PD in Romania appears to be a feasible project and a useful tool to know the current practice and outcomes after PD in our country. However, improvements are still required to encourage a larger number of surgical centers to introduce the data of patients with PD. PMID- 29981669 TI - Severe Acute Pancreatitis - Determinant Factors and Current Therapeutic Conduct. AB - Considered by Dieulafoy as the "great abdominal drama", acute pancreatitis has always been, and still remains, a real diagnostic and therapeutic challenge because of its etiological, clinical and biological variability, the unpredictable evolution and the difficulty of establishing appropriate treatment for each patient. In this context, various, sometimes diametrically opposed, conceptions about the interpretation of the cases and the adopted therapeutic algorithm have been encountered over time, as evidenced by the great number of papers dedicated to this subject. A more thorough understanding of acute pancreatitis pathophysiology, with increasing interest in severity classification based on determinant factors (local and general) are decisive factors in predicting severity and adopting the modern therapeutic strategy of this complex and heterogeneous disease. PMID- 29981671 TI - Evaluation of P-POSSUM Risk Scoring System in Prediction of Morbidity and Mortality after Pancreaticoduodenectomy. AB - : Background: POSSUM and P-POSSUM are risk scores recommended by ERAS Society for the preoperative evaluation of patients undergoing major surgery. Methods: This study includes 113 consecutive pancreaticoduodenectomy performed in a single centre between July 2013-December 2015. Patients data were prospectively collected using Excel 2009 and retrospectively analysed with R v3.2.4 software. Biological status score, surgical severity score and risk scores for complications and death were calculated using: http://www.riskprediction. org.uk/index-pp.php. Results: Morbidity rate was 61,95%: 19,47% general complications, 14,16% wound infections and 28,32% PD specific complications (11,5% POPF; 8,85% DGE and 6,19% PPH). Comparing the observed and estimated morbidity and mortality, we obtained statistical significant results (p=0,05 and p=0,03, respectivelly). When we considered only specific PD complications and subsequent mortality, there was no longer significant difference between observed and estimated values (p=0,8 and p=0,86).The under ROC curve aria was 0,61 for morbidity and 0,64 for specific PD morbidity, respectively 0,61 for mortality and 0,68 for specific PD complications related mortality. CONCLUSION: P-POSSUM represents a useful tool for appreciating the complication and death risk after PD, but better results could be obtain by considering also specific PD risk factors. PMID- 29981670 TI - Functional Results Following Pylorus-Preserving Pancreatoduodenectomy with Pancreaticogastrostomy. AB - Background: Pylorus preserving (PP) pancreaticoduodenectomy (PD) has several advantages in terms of shorter operation time and improved nutritional status but with an increased risk for delayed gastric emptying. Methods: We performed a retrospective study on all patients in which PD was performed from May 2012 to May 2018. It was analyzed early postoperative outcomes and the incidence of delayed gastric emptying (DGE) syndrome for patients with pylorus PP PD technique and pancreaticogastrostomy (PG). Results: There were 47 PD, in which PP technique was performed in 42 cases. The tumour location was in the pancreatic head (n=21, 44.68%), periampullary (ampulla of Vater) (n=14,29.78%), distal bile duct (n=7,14.89%), duodenum (n=2, 4.25%) and advanced right colon cancer (n=3, 6.38%). There were 10 cases (21.2%) of grade III-V complications, grade A pancreatic fistula (PF)8 cases (17%), grade B in 3 cases (6.4%) and grade C in 1 case (2.12%). DGE was encountered in 17 cases (36.17%), grade A 2 cases (4.25%), grade B in 4 cases (8.5%) and grade C in 2 cases (4.25%). Biliary fistula occurred in 3 cases (6.4%) and in 4 cases relaparotomy was needed. Conclusions: The results of our study are concluding with the previous studies, the addition of PG to PP PD does not increase the risk of DGE. PMID- 29981672 TI - Very Early Onset Pancreatic Adenocarcinoma - Clinical Presentation, Risk Factors and Therapeutic Options. AB - Background: Pancreatic cancer (PC) is usually diagnosed in the 7th decade, but cases diagnosed in younger patients are associated with a greater disease burden, through the potential years of life lost. The aim of our study was to compare the differences in risk factors, clinical presentation and treatment options between patients diagnosed with pancreatic adenocarcinoma below 45 years of age (very early onset pancreatic adenocarcinoma - VEOPC), and those diagnosed over 45 years. Methods: A retrospective study has been conducted by registering in standardized Excel Worksheets all PC cases diagnosed in our tertiary referral center between 01.01.2015 and 31.12.2017. Only patients with a documented diagnosis of pancreatic adenocarcinoma (PDAC) were included in the statistical analysis that has been conducted using the NCSS v9 Statistical Software package. Categorical data have been compared using Chi2 test or Fisher Exact as appropriate, with a statistical significance p value 0.05. Results: There were 296 patients diagnosed with pancreatic solid tumors during the study period, 183 cases with documented histology: 80.87% PDAC, 17.5% neuroendocrine tumors, 2 cases of LMNH and 1 MANEC tumor. In our study group there were 24 patients (16.22%) with VEOPC. Family history of pancreatic neoplasia (33.3% vs 1.03%, p=0.0004) and alcohol consumption (42.86% vs 5.41%, p=0.01) were significantly more prevalent in young patients. Pain, as primary symptom, was reported at higher rates in patients with VEOPC (60% vs 22.94%, p=0.006). Tumors were more frequently located in the head of the pancreas in younger patients (56.52%) and in the body of the pancreas in older patients (52.07%, p=0.02). There was no significant difference in therapy or death rate during follow-up period between the two study groups, although patients diagnosed under 45 years were more frequently subjected to a radical resection (33.3% vs 22.69%). Conclusions: Our study has identified alcohol consumption and family history of pancreatic neoplasia as risk factors for VEOPC. Pain is the primary symptom at diagnosis in young patients with PDAC. In our cohort, therapeutic options do not differ significantly in PDAC patients with age of onset. PMID- 29981673 TI - Laparoscopic Spleen Preserving Distal Pancreatectomy with Splenic Vessels Preservation. AB - Spleen preserving Distal Pancreatectomy (SPDP) is commonly applied in patients with benign or low-grade malignant tumors in the body and tail of the pancreas. Our aim is to present our technique and the early results in performing laparoscopic spleen preserving distal pancreatectomy with splenic vessel preservation (LSPDP-SVP) during 2017-2018 in Ponderas Academic Hospital. PMID- 29981674 TI - Cystic Dystrophy of the Duodenal Wall in Heterotopic Pancreas with Groove Pancreatitis: A Diagnostic and Therapeutic Challenge. AB - : Background: Cystic dystrophy of heterotopic pancreas is a benign, rare disease characterized by development of true cysts into the duodenal wall. Non-specific clinical manifestations and difficult to interpret imaging provide a diagnostic challenge, especially when pancreatic cancer is suspected. Surgical treatment (pancreatoduodenectomy) offer best outcomes. CASE REPORT: A 48 years-old man, chronic alcohol consumer, with a history of recurrent mild acute pancreatitis episodes, was diagnosed in 2010 with segmental chronic pancreatitis complicated by a 4cm pseudocyst in the pancreatic head. He stopped drinking, but acute episodes continued to reoccur, while the pseudocyst disappeared. In 2012 the patient was admitted to our department with painful chronic pancreatitis and a new acute episode. EUS diagnosed a cystic dystrophy of the duodenal wall with groove pancreatitis, and endoscopic opening of the cysts into the duodenum was performed. Laparoscopic cholecystectomy was imposed by small gallbladder stones seen at EUS. After 6 months of silence, pain and acute episodes reappeared, imposing pancreatoduodenectomy. Patient is now well, without symptoms during 5 years of follow-up. Conclusions: Cystic dystrophy of heterotopic pancreas can be thought of in case of recurrent idiopathic acute pancreatitis. EUS is the best diagnosis tool, and can provide opening of the cysts into the duodenum. Surgery - pancreatoduodenectomy - offer best results. PMID- 29981675 TI - A Rare Case of Walled-off Pancreatic Necrosis Complicated by Splenic Artery Rupture Manifested After Surgical Internal Drainage - Diagnostic and Therapeutic Aspects. AB - Large walled-off pancreatic necrosis (WON) is a well-known complication of severe acute pancreatitis, and it is associated with significant morbidity and mortality. This is the case report of a rare and potentially fatal complication of WON - a delayed splenic artery rupture close to its origin after surgical drainage. A 44-year old male patient admitted in our Surgical Department and diagnosed with WON evolving without infection for 6 months, after an episode of acute pancreatitis, underwent a Rouxen- Y WON-jejunostomy. In the 4th postoperative day patient presented melenic stools and a selective celiac trunk angiography was performed with the suspicion of a bleeding from the WON. At the initial injection of contrast a small leakage of contrast was observed but did not reappear despite repeated injection. The procedure was aborted, and the patient put under close observation. The 6th postoperative day bleeding re occurred, and the angiography indicated a breach in the splenic artery. As the patient developed hemodynamic instability in the Radiology Department he was immediately transferred into the operating room and an exploratory laparotomy with suture of the splenic artery was performed. The patient had an uneventful recovery and at one-year follow-up was without any particular problems. PMID- 29981676 TI - Surgical Treatment of a Mucinous Cystic Neoplasm in a Young Female Patient - A Case Report. AB - The major challenge in the evaluation of pancreatic cystic neoplasms is identifying lesions with malignant potential or signs of malignancy. Overall, the risk of malignancy in incidentally detected pancreatic cysts is low. Pancreatic cystic neoplasms with malignant potential are: serous cystic tumors (SCTs), mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs) and solid pseudopapillary neoplasms (SPNs). The risk for developing malignancy is very low for SCTs, moderate to high in MCNs, solid pseudopapillary tumors and some IPMNs (up to 70 percent for main-duct IPMNs). We present a thirty five years old female patient, without risk factors for the occurrence of pancreatic cancer was diagnosed via clinical examination and crosssectional imaging of the abdomen with a 7 cm cystic lesion located in the pancreatic body and tail, in the context of gastric outlet obstruction and upper abdominal pain with no improvement following conservative treatment. A distal pancreatectomy was thus performed, with favorable postoperative outcome. The histopathology examination described a non-invasive mucinous cystic neoplasm with low grade dysplasia. Many pancreatic cysts can be followed with surveillance imaging, through an algorithm which combines CT scan, MRI or endoscopic ultrasound. The decision to recommend surgery should take into account factors such as the patient's age and general health, the malignant risk of the specific lesion, potential complications and the suspicion for malignancy. PMID- 29981677 TI - Flavonoids, bioactive components of propolis, exhibit cytotoxic activity and induce cell cycle arrest and apoptosis in human breast cancer cells MDA-MB-231 and MCF-7 - a comparative study. AB - Breast cancer is one of the most common causes of mortality in women. Flavonoids, among other compounds, are bioactive constituents of propolis. In this comparative study, we investigated the effects of flavonoids apigenin (API), genistein (GEN), hesperidin (HES), naringin (NAR) and quercetin (QUE) on the proliferation, apoptosis, and cell cycle of two different human cancer cells - MDA-MB-231, estrogen-negative, and MCF-7, estrogen-positive receptor breast carcinoma cells. Many cytotoxic reports of flavonoids were performed by MTT assay. However, it's reported that MTT is reduced in metabolically active cells and yields an insoluble purple formazan, which indicates that obtained cytotoxic results of flavonoids could be inconsistent. Cell viability was measured by NR, neutral red assay, while the percentage of apoptotic cells and cell cycle arrest were determined by flow cytometry and Muse cell cycle assay, respectively. The results showed a high dose-dependent effect in cell viability tests. IC50 values were as follows (MCF-7/MDA-MB-231, for 48 h, in uM): 9.39/50.83 for HES, 25.19/88.17 for API, 40.26/333.51 for NAR, 49.49/47.50 for GEN and 95.12/130.10 for QUE. Flavonoid-induced apoptosis was dose- and time-dependent, for both cancer cell lines, though flavonoids were more active on MCF-7 cells. The flavonoids also induced cell cycle arrest in cancer cells. PMID- 29981678 TI - Antiviral activity of Veronica persica Poir. on herpes virus infection. AB - The lack of an effective anti-viral agent and the emergence of drug-resistant strains dictate a real need for discovery of novel therapies able to ameliorate viral infections. In this regards, medicinal plants and natural products offer safe and inexpensive platforms for discovery of efficient and novel anti-viral agents. We have investigated the potential anti-viral activities of Veronica persica Poir. as a medicinal plant against herpes simplex viruses (HSVs). In vitro screening of the ethanol plant extract against HSV-1 and HSV-2 infected Vero cells revealed the extract to show a dose-dependent inhibitory activity against both virus strains. After fractionation of the extract by a stepwise methanol gradient and evaluation of each fraction, the 80% methanol fraction displayed a pronounced inhibitory activity against the herpes viruses. The highest antiviral activity was observed when the Vero cells were treated with the extract both during and after infection by viruses. Moreover, the extract showed a prominent synergistic activity in combination with acyclovir anti-HSV therapy. Our findings revealed the potential of V. persica extract, especially its 80% methanol fraction, in inhibition of herpes simplex viral infections. PMID- 29981679 TI - Pulicaria vulgaris Gaertn. essential oil: an alternative or complementary treatment for Leishmaniasis. AB - Leishmaniasis is a neglected parasitic protozoal disease that affects approximately 12 million people and represents a public health problem in Iran. The objectives of this study were to obtain the essential oil (EO) from Pulicaria vulgaris Gaertn. growing in Iran and to carry out in-vitro antileishmanial screening of the EO against promastigotes of Leishmania major and Leishmania infantum. The EO from the aerial parts of P. vulgaris was extracted by hydrodistillation. Serial dilutions of the EO were screened for in-vitro antileishmanial activity using 96-well microtiter plates. The P. vulgaris EO was active against the promastigote forms of L. major and L. infantum, with IC50 values of 244.70 and 233.65 ug/mL, respectively. Pulicaria vulgaris EO may serve as an alternative or complementary treatment for leishmaniasis. PMID- 29981680 TI - Pullulan gum production from low-quality fig syrup using Aureobasidium pullulans. AB - Pullulan is an important polysaccharide with several potential applications in food science, pharmaceutical and cosmetic industries, but high costs of pullulan production are the main limitation for commercial utilization. Therefore, a cost effective process for pullulan production was developed using fig syrup as an exclusive nutrient source. In particular, the feasibility of using low quality fig syrup as a supplemental substrate for pullulan gum production by Aureobasidium pullulans was investigated. Fermentation was carried out over a range of fig syrup and sucrose degrees Brix (5-15%). Maximum pullulan gum production was observed after 96h using 12.5% fig syrup, yielding approximately14.06 g/L. This value of pullulan production (14.06 g/L) was higher than the amount of pullulan produced using sucrose as substrate (5.01 g/L). In conclusion, fig syrup was an effective substrate for pullulan production by Aureobasidium pullulans, and, therefore, this byproduct deserves attention for the cost-effective and environmentally friendly pullulan production. PMID- 29981682 TI - Susceptibility of Leishmania major to Veronica persica Poir. extracts - In vitro and in vivo assays. AB - Leishmania major is an intracellular parasite generally responsible for cutaneous leishmaniasis (CL), one of the most encountered skin diseases especially in Pakistan, Iran, Iraq, and Saudi Arabia. Current treatment options are not ideal, due to unwanted side effects and increasing resistance and availability is often limited in developing countries. Medicinal plants continue to attract attention because of their beneficial effects in the prevention or/and accelerating the healing process of various diseases. In this study, in vitro and in vivo susceptibility of L. major to Veronica persica Poir. extract, a medicinal plant with many applications, has been evaluated. Antileishmanial activity of plant extract was investigated both on cultured L. major promastigotes and in mice challenged with L. major. Animals were divided into three groups including control (without any treatment), test (treated with plant extract) and glucantime (the reference drug) treated groups. After treatments, skin lesion sizes and body weights of animals were checked during 4 weeks. The potential of the plant extract in decreasing the number of parasites in spleen cells of animals as well as inducing the nitric oxide (NO) production by macrophage cells was also investigated. In vitro tests showed that the plant extract was able to reduce the survival time of promastigotes in a concentration-dependent manner. In vivo experiments also revealed a significant influence of V. persica extracts on accelerating the healing process as well as reducing the overall disease burden in animal model by inducing NO production in macrophage cells. Our findings indicated the promising potential of V. persica extract as an ideal candidate in the treatment of CL caused by L. major. PMID- 29981681 TI - Satyrium nepalense, a high altitude medicinal orchid of Indian Himalayan region: chemical profile and biological activities of tuber extracts. AB - The present study investigated antioxidant and antibacterial activities of 5 different extracts and derived fractions from the S. nepalense tubers. Identification of the most active fractions, their phytochemical characterization, total phenolic and flavonoid contents, and biological activities were also evaluated. Petroleum ether, chloroform, ethyl acetate, methanol, water extracts and methanol fractions were screened for their antibacterial activity at 10, 50 and 100 mg/mL doses against ten Gram-negative and Gram-positive bacterial strains by disc diffusion method. Their total antioxidant activity was measured by DPPH and ABTS assays. Identification of the main compounds was performed by LC-MS/MS. Methanol extract exhibited the highest antioxidant (IC50= 30.79 ug/mL and 24.53 ug/mL for DPPH and ABTS, respectively) and antibacterial (MIC 71.5 to >100 ug/mL) activities in comparison with the other extracts. Levels of phenolics and flavonoids were also the highest in the same extract, i.e. 19.2 mg GAE/g and 11.20 mg QE/g, respectively. Phytochemical investigation of the active fractions of the methanol extract led to the isolation of gallic acid (19.04 mg/g) and quercetin (23.4 mg/g). Therefore, methanol extract showed an interesting potential for both antioxidant and antibacterial activities, thus deserving attention for future applications in the fields of medicinal plants and food supplements. PMID- 29981683 TI - Veronica persica Poir. extract - antibacterial, antifungal and scolicidal activities, and inhibitory potential on acetylcholinesterase, tyrosinase, lipoxygenase and xanthine oxidase. AB - Veronica persica (Persian speedwell) is a flowering plant local to Eurasia. In this study, several analyses were done to discover the antimicrobial and scolicidal activities and acetyl cholinesterase (AChE), tyrosinase (TYR), lipoxygenase (LOX), and xanthine oxidase (XO) inhibitory activities of V. persica extract. The results presented that B. subtilis was the most susceptible to the extract (MIC = 40.3 MUg/mL), while P. aeruginosa was the most resistant strain (MIC = 250.9 MUg/mL) among all bacteria evaluated. The extracts demonstrated significant activity versus E. granulosus (P < 0.5) with dose-dependent inhibitions of the protoscolices. The analyzed plant extract exhibited a high AChE and TYR inhibitory activity 55.3% and 52.7% (at the highest utilized dose - 3 mg/mL), respectively. The extract also showed high anti-inflammatory activities in analyses tested. Our research proposed that extract of this plant could be promising to the human health, markedly in the infectious, neurodegenerative and inflammatory disorders. PMID- 29981684 TI - In vitro and in vivo assessment of free radical scavenging and antioxidant activities of Veronica persica Poir. AB - With the appearance of new disorders along with inability of some conventional therapies for the treatment of diseases without any side effects, the discovery of safe and efficient therapeutic agents is of utmost importance in the medical area. In this context, medicinal plants as promising therapeutic candidates can provide a reliable and efficient profile. Since free radicals are at the center of various disorder pathways, reducing their production or complete removal of these chemical species could be advantageous for prevention and treatment of many diseases. In this experiment, free radical scavenging and antioxidant activities of Veronica persica Poir., a known medicinal plant, were evaluated using in vitro and in vivo assays. Chemical characterization results showed a high phenolic content in the V. persica methanol extract. In addition, in vitro assays including DPPH radical-scavenging assay, nitric oxide-scavenging activity assay, hydrogen peroxide scavenging test and bleomycin-dependent DNA damage test revealed significant antioxidant power and radical scavenging capacity of this plant. In accordance, in vivo experiments showed inhibitory effects of the methanol extract on lipid peroxidation, a main cause of cell damage. Our findings revealed the promising potential of this plant in reducing free radicals through different pathways. Moreover, our data suggested a correlation between the high phenolic content of the V. persica extract and its free radical scavenging and antioxidant activities. PMID- 29981685 TI - Antibacterial potential of Saussurea obvallata petroleum ether extract: A spiritually revered medicinal plant. AB - Uttarakhand Himalayan region holds Asteraceae or Compositae as the largest family of flowering, medicinal and aromatic plants. Species belonging to this family rises from low altitude to the alpine region. Among Asteraceae, Saussurea obvallata (DC.) Edgew. is widely used in several indigenous systems of medicine. Flowers, leaves and rhizomes of S. obvallata are used for several traditional, religious, therapeutic and ornamental purposes. Aim of this study was to determine the chemical composition and antibacterial efficacy of petroleum ether extract (PEE) of S. obvallata. Gas chromatography-mass spectrometry (GC-MS) analysis was used for identifying phytochemicals present in the plant extract. Furthermore, the PEE was assessed for in-vitro antibacterial activity against selected Gram positive and negative strains. Structure of squalene and alpha linolenic acid methyl ester were identified in PEE by GC-MS analysis, by comparing the results obtained with NIST library and literature reports. PEE exhibited significant activity against Staphylococcus aureus, Escherichia coli, Bacillus cereus, Bacillus subtilis with IC50 value of 87.2 +/- 1.6, 98.4 +/- 1.1 and 90.2 +/- 1.8 ug/ml, respectively. These results showed that squalene and alpha-linolenic acid derivative identified in S. obvallata may be responsible for the observed antibacterial activity. To the best of our knowledge, this is the first report focused on the chemical composition and antibacterial activity of S. obvallata. PMID- 29981686 TI - Antibacterial activity of some Lamiaceae species against Staphylococcus aureus in yoghurt-based drink (Doogh). AB - Doogh is a dairy drinkable fermented product, whose shelf-life and quality is mostly affected by bacteria such as Staphylococcus spp.. This study investigated the antibacterial activity of essential oils (EOs) from Thymus vulgaris L., Mentha piperita L. and Ziziphora tenuior L., alone or in combination, against Staphylococcus aureus in industrial doogh. A three-level and three-variable face centered central composite design experiment was used. Results showed that EOs significantly inhibited S. aureus growth after 1 and 7 days of storage. According to the model, the maximum inhibition was obtained in the presence of 0.2% of EO, independently of the type, and no synergistic or additive effects were observed. Slightly lower S. aureus survivals were observed at the maximum concentration of Z. tenuior EO. In spite of the antimicrobial activity of these EOs, further research is needed to assess their performance in food matrix and, in particular, in dairy product. PMID- 29981687 TI - Anti-inflammatory and wound healing effects of an essential oils-based bioadhesive gel after oral mucosa biopsies: preliminary results. AB - Post-operative management of patients receiving oral biopsy includes the control of edema, pain, infection, and re-epithelization at the surgical site. This clinical study investigates the topical use of a bioadhesive gel, containing essential oils, to promote wound healing and prevent post-operative pain and infection, avoiding the need for surgical suture and chlorhexidine applications. Ten patients, who needed to receive oral biopsies (<=6 mm in diameter) for the diagnosis of mucosal oral lesions, were enrolled. The bioadhesive gel successfully controlled the post-surgical pain; at 1-week follow-up visit, no signs of infection nor side effects were reported and the surgical sites were completely healed. The bioadhesive gel resulted in a very promising agent for the post-operative management of oral biopsy site, without the need for surgical suture and chlorhexidine applications. PMID- 29981688 TI - Bioactive compounds and health benefits of edible Rumex species-A review. AB - Medicinal and food plants as well as their bioactive fractions have been used by diverse human cultures since ancient times. These plants provide multiple health benefits because of the presence of a plethora of phytochemicals including phenylpropanoids, isoprenoids, alkaloids, sulphated compounds, peptides and polysaccharides that are responsible for various biological activities such as anticancer, antioxidant, antifungal, antibacterial, anti-dysenteric, anti inflammatory, antiulcer, anti-hypertensive and anticoagulant properties. The genus Rumex includes edible and medicinal herbs belonging to buckwheat (Polygonaceae) family, consisting of about 200 species rich in phenylpropanoids and anthraquinones. Some Rumex species have exhibited health-promoting effects and have been used as traditional foods and herbal remedies, though a limited information has been documented on their specific biological properties. Therefore, this survey aimed at reviewing the Rumex species with documented biological activity, focusing on preclinical evidences on their efficacy and safety. PMID- 29981689 TI - Rice allelopathy in weed management - An integrated approach. AB - The intensive use of pesticides with low biodegradability and high persistence in soil, surface and ground waters, represents a considerable environmental risk, especially under high weed pressure conditions. Furthermore, the number of herbicide-resistant weeds is increasing. Against this background, the investigation of alternative weed control strategies has taken on considerable importance. Among these, allelopathy as a negative effect of one plant on another due to the direct or indirect (including microorganisms) release of chemicals in the environment can be a useful tool for the integrated management of weeds in agroecosystems. In particular, the paddies have been considered in this work by reviewing the data both on rice allelopathy and rice weed agronomic control methods developed to improve the crop yield. PMID- 29981690 TI - Intraperitoneal Chemotherapy: Historic Anomaly or Hope for the Future? PMID- 29981691 TI - Radiation Therapy in Ovarian Cancer: An Overview and Future Directions. AB - Clear cell cancer of the ovary is a rare and aggressive subtype. There is a general paucity of data from randomised trials to inform the most appropriate approach to adjuvant therapy. Retrospective data has highlighted an improvement in disease free survival with the addition of whole abdominal radiotherapy. This approach merits further exploration in a randomised clinical trial. PMID- 29981692 TI - Migration and diversification of the vagal neural crest. AB - Arising within the neural tube between the cranial and trunk regions of the body axis, the vagal neural crest shares interesting similarities in its migratory routes and derivatives with other neural crest populations. However, the vagal neural crest is also unique in its ability to contribute to diverse organs including the heart and enteric nervous system. This review highlights the migratory routes of the vagal neural crest and compares them across multiple vertebrates. We also summarize recent advances in understanding vagal neural crest ontogeny and discuss the contribution of this important neural crest population to the cardiovascular system and endoderm-derived organs, including the thymus, lungs and pancreas. PMID- 29981693 TI - Stem cells and plant regeneration. AB - Multicellular organisms show the ability to replace damage cells, tissues and even whole organs through regeneration mechanisms. Plants show a remarkable regenerative potential. While the basic principles of plant regeneration have been known for a number of decades, the molecular and cellular mechanisms underlying such principles are currently starting to emerge. Some of these mechanisms point to the existence of highly reprogrammable cells. Developmental plasticity is a hallmark for stem cells, and stem cells are responsible for the generation of distinctive cell types forming plants. In the last years, a number of players and molecular mechanism regulating stem cell maintenance have been described, and some of them have also been involved in regenerative processes. These discoveries in plant stem cell regulation and regeneration invite us to rethink several of the classical concepts in plant biology such as cell fate specification and even the actual meaning of what we consider stem cells in plants. In this review we will cover some of these discoveries, focusing on the role of the plant stem cell function and regulation during cell and organ regeneration. PMID- 29981694 TI - Experimental infection of BALB/c mice with a caprine Pestivirus H isolate. AB - To data, small animal Pestivirus H infection models have not been established. In order to develop a new infection model, BALB/c mice were inoculated with Pestivirus H strain HN1507. The virus-inoculated mice displayed nasal discharge and fever clinical signs. Histopathological changes in Pestivirus H-infected mice included alveolar septa thickening and alveolar atrophy in the lungs from 1 to 11 days post-inoculation (PI). Furthermore, we observed tracheal epithelial cell abscission and inflammatory cell infiltration in the tracheas from 1 to 9 days PI, infiltration of eosinophils in the spleens from 1 to 9 days PI, intestinal villi abscission and lysis of epithelial cells in the intestines from 1 to 11 days PI. The results of virus isolation showed that Pestivirus H replicated well in the lungs, tracheas, spleens, and intestines of infected BALB/c mice, and peak viral titers were observed 3 days PI. RT-PCR and immunofluorescence results were in agreement with the virus isolation results; however, the hearts of infected mice from 1 to 3 days PI were positive while virus isolation results were negative. To the best of our knowledge, this is the first study reporting Pestivirus H detection in BALB/c mice. Our findings indicated that Pestivirus H strain HN1507 was pathogenic to BALB/c mice and caused clinical signs and histopathological lesions in Pestivirus H-infected BALB/c mice. PMID- 29981695 TI - Distinct bacterial metacommunities inhabit the upper and lower respiratory tracts of healthy feedlot cattle and those diagnosed with bronchopneumonia. AB - Specific nasopharyngeal bacterial communities can provide colonization resistance against respiratory pathogens in cattle. However, the role of bacterial communities of the lower airways in respiratory health remains largely unknown. Therefore, our objective was to compare nasopharyngeal and tracheal bacterial communities between healthy feedlot cattle and those with bronchopneumonia (BP). Deep nasal swabs and trans-tracheal aspiration samples were collected from steers with (n = 60) and without (n = 60) BP at 4 feedlots in Western Canada. After DNA extraction, 16S rRNA gene (V4) was amplified and sequenced. Alpha-diversity analysis revealed a lower bacterial diversity in the nasopharynx and trachea of steers with BP compared to healthy pen-mates. Bacterial communities present within the airways clustered into 4 distinct metacommunities that were associated with sampling locations and health status. Metacommunity 1, enriched with Mycoplasma bovis, Mannheimia haemolytica and Pasteurella multocida, was dominant in the nasopharynx and trachea of steers with BP. In contrast, metacommunity 3, enriched with Mycoplasma dispar, Lactococcus lactis and Lactobacillus casei, was mostly present in the trachea of healthy steers. Metacommunity 4, enriched with Corynebacterium, Jeotgalicoccus, Psychrobacter and Planomicrobium, was present in the nasopharynx only. Metacommunity 2, enriched with Histophilus somni, Moraxella and L. lactis, was present in both healthy and sick steers, but was primarily detected in one feedlot. We concluded that distinct bacterial metacommunities inhabited the nasopharynx and trachea of healthy feedlot cattle and those with BP. Because L. lactis and L. casei can inhibit M. haemolytica growth in vitro, their presence in healthy steers may have provided colonization resistance against bacterial respiratory pathogens. PMID- 29981696 TI - Novel mutations in avian PA in combination with an adaptive mutation in PR8 NP exacerbate the virulence of PR8-derived recombinant influenza A viruses in mice. AB - The polymerase complex of the low-pathogenic avian influenza virus [A/chicken/Korea/KBNP-0028/2000] (0028) has previously been characterized, and novel amino acid residues present in the polymerase acidic protein (PA) that likely contribute to pathogenicity toward mammals have been identified. In the present study, our aims were to generate A/Puerto Rico/8/34 (PR8)-derived recombinant viruses containing the 0028-PA gene with a single amino acid mutation and to test their pathogenicity and replication ability. We found that the recombinant viruses acquired additional single mutations in the nucleoprotein (NP). Because the additional mutations in NP did not affect viral pathogenicity, but rather attenuated viral replication and polymerase activity, the incompatibility of the avian PA gene within the PR8 backbone may have induced an adaptive mutation in NP. To minimize the differences due to NP mutations, we generated 0028-PA mutants with an E375G mutation, not affecting viral replication and pathogenicity, in the NP gene. The PR8-PA(0028)-E684G mutant showed significantly higher viral replication in mammalian cells as compared to PR8 PA(0028) and led to 100% mortality in mice, with significantly increased interferon beta expression. Thus, the E684G mutation in the PA gene may play an important role in viral pathogenicity in mice by increasing viral replication and the host immune response. PMID- 29981697 TI - Dissemination of the mcr-1 colistin resistance gene among pigs: An experimental study. AB - Colistin resistance in Enterobacteriaceae is a public health problem. The present study was designed to evaluate the dissemination of a colistin-resistant Escherichia coli strain and its resistance gene, mcr-1, between orally inoculated pigs and their contacts. A non-inoculated control group, one low-dose and one high-dose group-both including two pens of two inoculated and three contact pigs were raised in separate rooms. After inoculation of a colistin- and rifampicin resistant E. coli suspension (2.5 * 105 CFU/pig for the low-dose group and 2.5 * 108 CFU/pig for the high-dose group), feces from inoculated and non-inoculated contact pigs were collected and inoculated on colistin- and rifampicin supplemented media directly or after enrichment in rifampicin-supplemented media, then the isolates were characterized. PCR was used to detect the mcr-1 gene in lysates from feces cultivated in colistin-supplemented broth and DNA prepared from feces. Results showed that the low-dose inoculum was probably insufficient to obtain durable colonization, but could lead to the temporary presence of mcr-1 positive E. coli strains. The high-dose inoculum resulted in durable colonization of both inoculated and contact animals. In all groups, the mcr-1 gene was also detected in rifampicin-susceptible strains, suggesting its transfer to several commensal strains. A comparison of detection methods showed that more positive samples were obtained with cultures in rifampicin-supplemented media and suggests that current methods to evaluate the prevalence of colistin resistance in fecal samples suffer from poor sensitivity. PMID- 29981698 TI - Detection of rat hepatitis E virus, but not human pathogenic hepatitis E virus genotype 1-4 infections in wild rats from Lithuania. AB - Rat hepatitis E virus (HEV) is an orthohepevirus which is related to other HEV found in humans and other mammals. It was first identified in Norway rats (Rattus norvegicus) from Germany in 2010, and later it has been detected in Black rats (Rattus rattus) and Norway rats from USA, China, Indonesia, Vietnam and many European countries. In this study, we describe molecular and serological investigations of Black and Norway rats trapped in Lithuania, Eastern Europe, for infections with rat HEV and human HEV genotypes 1-4. Rat HEV-specific real-time reverse transcription-PCR (RT-qPCR) analysis of rat liver samples revealed the presence of rat HEV in 9 of 109 (8.3%) samples. In contrast, a RT-qPCR specific for HEV genotypes 1-4 did not reveal any positive samples. A nested broad spectrum RT-PCR was used for a confirmation of rat HEV infection with a subsequent sequencing of the amplified rat HEV genome fragment. Phylogenetic analysis revealed a clustering of all newly identified rat HEV sequences with Norway rat-derived rat HEV sequences from Germany within the species Orthohepevirus C. An indirect ELISA using a yeast-expressed truncated rat HEV capsid protein variant revealed 31.2% seropositive samples indicating a high rate of rat HEV circulation in the rat population examined. In conclusion, the current investigation confirms rat HEV infections in Norway and Black rats in Lithuania, Eastern Europe, and the non-persistent nature of HEV infection. PMID- 29981699 TI - Porcine epidemic diarrhea virus (PEDV) introduction into a naive Dutch pig population in 2014. AB - Porcine epidemic diarrhea virus (PEDV) is the highly contagious, causative agent of an economically important acute enteric disease in pigs of all ages. The disease is characterized by diarrhea and dehydration causing mortality and growth retardation. In the last few decades, only classical PEDV was reported sporadically in Europe, but in 2014 outbreaks of PEDV were described in Germany. Phylogenetic analysis showed a very high nucleotide similarity with a variant of PEDV that was isolated in the US in January 2014. The epidemiological situation of PEDV infections in the Netherlands in 2014 was unknown and a seroprevalence study in swine was performed. In total, 838 blood samples from sows from 267 farms and 101 samples from wild boars were collected from May till November 2014 and tested for antibodies against PEDV by ELISA. The apparent herd prevalence of 0.75% suggests that PEDV was not circulating on a large scale in the Netherlands at this time. However, in November 2014 a clinical outbreak of PEDV was diagnosed in a fattener farm by PCR testing. This was the first confirmed PEDV outbreak since the early nineties. Sequence analyses showed that the viruses isolated in 2014 and 2015 in the Netherlands cluster with recently found European G1b strains. This suggests a one event introduction of PEDV G1b strains in Europe in 2014, which made the Netherlands and other European countries endemic for this type of strains since then. PMID- 29981700 TI - Chaperone-assisted selective autophagy in healthy and papillomavirus-associated neoplastic urothelium of cattle. AB - Chaperone-assisted selective autophagy (CASA) is a newly-described selective tension-induced macroautophagy pathway mediated by Bag3 that is believed to be essential for mechanotransduction in skeletal muscle and to be an important regulator of the immune system. We investigated CASA machinery both in healthy and in fifteen papillomavirus-associated neoplastic bovine urothelium. The components of CASA complex, that comprises the molecular chaperones HspA8/Hsc70 and Hsp8B/Hsp22 and the cochaperones Bag3 and STUB1/CHIP, were studied by molecular, microscopic and submicroscopic investigations. CASA complex was found to be constitutively expressed in healthy bovine urothelium; its expression increased in urothelial cancers of cattle, namely thirteen papillary carcinomas and two papillary urothelial neoplasm of low malignant potential (PUNLMPs). We suggest that basal levels of CASA are important in the healthy urothelium which interfaces with the community of urinary microbiota thus representing an important epithelial cell-autonomous mechanism of antibacterial defense. Co immunoprecipitation studies using an antibody against bovine papillomavirus E5 protein revealed that the oncoprotein co-localized with CASA complex in urothelial cancer cells. This suggests that infection by BPV E5 could influence cell behaviour by interfering with basal autophagy processes although this study did not conclusively show that this interaction increased the expression of CASA proteins. In neoplastic urothelium, CASA could be involved in regulating fundamental cellular processes such adhesion, migration, and proliferation and so might influence the biological behaviour of urothelial tumors in cattle. PMID- 29981701 TI - Multidrug resistant Mannheimia haemolytica isolated from high-risk beef stocker cattle after antimicrobial metaphylaxis and treatment for bovine respiratory disease. AB - Antimicrobial resistance (AMR) in bacterial respiratory pathogens in high-risk stocker cattle has been poorly characterized. The objective of this study was to describe the prevalence of multidrug resistant (MDR; resistance to > 3 antimicrobial classes) respiratory pathogens in 50 conventionally managed stocker cattle over 21 days after arrival. Cattle received tildipirosin metaphylaxis on day 0 and were eligible to receive up to 3 additional antimicrobials for bovine respiratory disease (BRD): florfenicol, ceftiofur and enrofloxacin. Nasopharyngeal swabs were collected on days 0, 7, 14, and 21 for bacterial culture and antimicrobial susceptibility testing using disc diffusion and broth microdilution. Mannheimia haemolytica was isolated from 5 of 48, 27 of 50, 44 of 50, and 40 of 50 cattle on days 0, 7, 14, and 21, respectively. One of 5, 27 of 27, 43 of 44, and 40 of 40 M. haemolytica were MDR on days 0, 7, 14, and 21, respectively. Pasteurella multocida was isolated from 6 of 48 cattle on day 0 and none were MDR; no other pathogens were isolated. Twenty-four cattle required at least one BRD treatment; M. haemolytica was isolated before treatment from 13 of 24 cattle; all were MDR. One hundred-eighteen M. haemolytica isolates were subjected to pulsed-field gel electrophoresis (PFGE); multiple genotypes were identified. Whole genome sequencing of 33 isolates revealed 14 known AMR genes. Multidrug resistant M. haemolytica can be highly prevalent and genetically diverse in stocker cattle; additional research is necessary to determine factors that influence prevalence and the impact on cattle health. PMID- 29981702 TI - Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) among employees and in the environment of a small animal hospital. AB - The aim of the study was to investigate methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) among employees of a small animal hospital and the hospital environment. In total, 96 swabs from employees and 73 swabs from the clinic environment were investigated. Cation-adjusted-Mueller-Hinton broth (CAMHB) + 6.5% NaCl was used for enrichment before plating on Mueller-Hinton (MH) agar with 2% NaCl and 0.25 mg/L oxacillin. The staphylococcal species was determined using MALDI-TOF MS. The isolates were subjected to mecA-PCR, macrorestriction analysis, and antimicrobial susceptibility testing. MRSA were present in five nasal swabs of the 55 employees tested and in six environmental samples, MRSP in two employees (nasal and hand swabs, each) and in three environmental samples. All isolates harboured mecA. Susceptibility testing revealed that all but one of the isolates were multiresistant. All isolates were resistant to beta-lactams and fluoroquinolones. All but one of the isolates were resistant to macrolides and lincosamides. A single MRSA was resistant to gentamicin. All MRSP were resistant to trimethoprim/sulfamethoxazole and non-susceptible to gentamicin. One isolate was also resistant to tetracycline. Macrorestriction analysis revealed three main SmaI patterns for MRSA and two main SmaI patterns for MRSP. All environmental isolates were found in areas of high people and animal traffic, such as dog ward areas, waiting and triage rooms. The finding of indistinguishable MRSA or MRSP among employees and in the environment of the small animal hospital suggests the possibility of transfer of these bacteria between humans, animals, and the hospital environment. PMID- 29981703 TI - Porcine epidemic diarrhea vaccine evaluation using a newly isolated strain from Korea. AB - Porcine epidemic diarrhea virus (PEDV) infects pigs and causes an enteric disease that is characterized by vomiting and watery diarrhea. PEDV outbreaks have a tremendous financial impact on the worldwide pork industry. In South Korea, the incidence of PEDV has continued despite nationwide use of attenuated and inactivated vaccines, raising questions regarding the current vaccines' efficacy and the need for new vaccine development. In the present study, we isolated a new Korean PEDV epidemic strain, PED-CUP-B2014, in Vero cells. Phylogenetic analysis of the spike gene demonstrated that the PED-CUP-B2014 belongs in genogroup G2b and is close to PEDVs currently circulating in many countries including the United States, and is distinct from many current vaccine strains. Upon serial passages into Vero cells, PED-CUP-B2014 adapted to Vero cells, which was evidenced as higher virus growth in Vero cells and confirmed lower virulence in suckling piglets. The administration of the inactivated 65-passaged PED-CUP-B2014 to sows greatly increased the survival rate of their offspring and significantly reduced diarrhea severity after PEDV challenge. Higher serum/colostrum PEDV specific antibodies and higher neutralizing titers were shown in sows vaccinated with PED-CUP-B2014 compared to unvaccinated sows or sows administered commercial PEDV vaccine. Altogether, our data demonstrated that the newly isolated PEDV strain conferred critical passive immune protection to pigs against epidemic PEDV infection. PMID- 29981704 TI - Molecular characterization and virulence of an alphaherpesvirus isolated from a BoHV1 gB-seropositive and gE-seronegative Italian buffalo. AB - During a serological survey, 157 out of 681 unvaccinated buffaloes resulted seropositive for bovine alphaherpesvirus 1 (BoHV1) glycoprotein B (gB) and seronegative for BoHV1 glycoprotein E (gE). These serological results were generally expected in animals vaccinated with a BoHV1 gE-deleted vaccine but not in unvaccinated animals. Seroneutralization tests on 36 selected sera detected neutralizing antibody titers more than three times higher for BuHV1 than for BoHV1. In order to investigate the virus, one of these buffaloes was injected with dexamethasone, and from nasal and vaginal swabs collected at different time points, a ruminant herpesvirus was isolated, characterized and also detected by PCR. Restriction enzyme analysis, sequencing and phylogenic analysis of gB and gD genes showed that the virus was genetically similar but not identical to BuHV1 strain b6. Intranasal inoculation of the virus in a healthy seronegative buffalo resulted in a mild and transient upper respiratory disease; the virus was isolated from clinical specimens and DNA was detected by PCR in nasal and vaginal swabs up to 9 days after infection. Further investigations should be aimed at sequencing the whole viral genome and at evaluating the host-range of this virus. Specific tests are needed to discriminate infections by different ruminant herpesviruses and to improve eradication programs of infectious bovine rhinotracheitis/infectious pustular vulvovaginitis in cattle. PMID- 29981705 TI - Novel duck hepatitis A virus type 1 isolates from adult ducks showing egg drop syndrome. AB - Generally, duck hepatitis A virus type 1 (DHAV-1) only infects young ducklings. Since December 2016, severe outbreaks of duck viral infection with egg drop, feed consumption decline, and ovary-oviduct disease have occurred in some laying duck flocks in Shandong Province of China. DHAV-1 isolated from the affected ducks was confirmed as the causative pathogen of the egg drop. Compared with other DHAV-1 strains, the novel isolate has three special amino acid mutation points in the most variable regions at the C-terminus of VP1. The experimental infection in laying ducks indicated that successful immunization with DHAV-1 vaccine could protect laying duck from infection. To the best of our knowledge, this is the first reported incidence of a severe duck disease outbreak involving egg drop syndrome caused by DHAV-1. PMID- 29981706 TI - Characterization of the fecal virome in dogs with chronic enteropathy. AB - The fecal virome has been investigated in humans and various animal species using next generation sequencing. However, limited information is available about the fecal virome of dogs with chronic enteropathy (CE). We aimed to characterize the canine fecal virome of dogs with CE and compare it with the virome of previously analyzed healthy dogs.A total of 16 adult dogs; 8 healthy dogs (data from a parallel study) and 8 dogs with CE had fecal samples assessed by viral shotgun sequencing. Fecal samples were subjected to enrichment of viral nucleic acids prior to sequencing and metagenomic analyses. Characterization of the complete genome of a canine kobuvirus was performed by Sanger sequencing. An additional 21 healthy dogs and 14 dogs with CE were further analyzed for the prevalence of canine kobuvirus.Three fecal samples from dogs with CE contained in total 3 eukaryotic viral families. In contrast, 4/8 fecal samples previously identified from healthy dogs, contained 5 eukaryotic viral families with 2 families exclusive to this group. Bacteriophages were identified in all fecal samples from CE and healthy dogs. Canine kobuvirus was identified in one dog with CE, by shotgun sequencing, and the complete genome was then characterized. This kobuvirus was classified within canine kobuvirus group, being similar to strains from Korea and China. The larger prevalence study did not detect additional samples positive for canine kobuvirus. The fecal virome of dogs with CE differs in number and type of viral families from healthy dogs. The first Australian canine kobuvirus sequence was identified and characterized from a dog with CE. PMID- 29981707 TI - Suitability of group-level oral fluid sampling in ruminant populations for lumpy skin disease virus detection. AB - The geographic expansion of Lumpy skin disease (LSD) from the near East into the European Union highlighted again the need for appropriate disease detection tools applicable to animal host populations where access to individual animals is difficult. This is of particular importance considering that the clinical manifestation of LSD is often mild making early disease detection challenging under the above-mentioned conditions. Building on positive experiences of group level oral fluid sampling for pathogen detection as it is known to work for swine herds and wild boar, the concept was transferred to ruminants. Two groups of six cattle were infected experimentally with Lumpy skin disease virus (LSDV) under controlled conditions. Blood as well as oropharyngeal and nasal swab samples were collected at regular intervals. Group samples were obtained by placing cotton gauze around a salt lick block provided commonly as dietary supplement. Pieces of the gauze with visible signs of manipulation were tested in parallel to samples obtained from individual animals. Genome load analysis by qPCR technology revealed LSDV detection window starting from day 2 post infection until day 28 post infection, the end of the animal trial. At the individual level, detection periods varied between animals and type of sample and included intermitted detection. The accumulative character of the alternative sampling method makes it suitable to detect LSDV DNA at group-level even at times of the infection where a selective sampling of individuals from a group - as normally done in LSD surveillance - would have most likely failed in the detection. PMID- 29981708 TI - Susceptibility of porcine IPEC-J2 intestinal epithelial cells to infection with porcine deltacoronavirus (PDCoV) and serum cytokine responses of gnotobiotic pigs to acute infection with IPEC-J2 cell culture-passaged PDCoV. AB - The porcine small intestinal epithelial cell line, IPEC-J2, is useful to characterize the interactions of enterocytes with enteric viruses in vitro. We investigated whether IPEC-J2 cells are susceptible to porcine deltacoronavirus (PDCoV) infection. We conducted quantification of infectious virus or viral RNA, immunofluorescent (IF) staining for the detection of PDCoV antigens, and TUNEL assay in IPEC-J2 cells inoculated with the strain OH-FD22-P8 grown in LLC-PK cells, and supplemented with 10 MUg/ml of trypsin in the cell culture medium. Cytopathic effects (CPE) that consisted of enlarged and rounded cells followed by cell shrinkage and detachment, were identified by the 3rd viral passage in the IPEC-J2 cells. PDCoV antigen was detected in the cells showing CPE. By double IF and TUNEL staining, most PDCoV antigen-positive IPEC-J2 cells failed to show TUNEL-positive signals, indicating that PDCoV-infected IPEC-J2 cells may not undergo apoptosis, but rather necrosis, similar to necrotic cell death of infected enterocytes in vivo. There was increased interleukin-6 in PDCoV-infected IPEC-J2 cell culture supernatants at post-inoculation hour (PIH) 48-96, as evaluated by ELISA, concurrent with increased titers of PDCoV at PIH 24-72. The susceptibility of IPEC-J2 cells to PDCoV infection supports their usefulness to characterize the interactions of enterocytes with PDCoV. We also demonstrated that IPEC-J2 cell culture-passaged PDCoV (OH-FD22-P8-I-P4) was enteropathogenic in 10-day-old gnotobiotic pigs, and induced systemic innate and pro-inflammatory cytokine responses during the acute PDCoV infection. PMID- 29981709 TI - Prevalence and molecular features of ESBL/pAmpC-producing Enterobacteriaceae in healthy and diseased companion animals in Brazil. AB - Extended-spectrum beta-lactamase (ESBL)- and plasmid-mediated AmpC (pAmpC) carrying Enterobacteriaceae have widely disseminated in human, animal and environmental reservoirs. Pets have been recognized as a source of ESBL/pAmpC worldwide, and are possibly also a source of human contamination. The aim of this study was to document to what extent cats and dogs may act as a driving force in the spread of ESBLs and pAmpCs in Brazil. A total of 113 healthy stray cats and dogs and 74 sick pets were sampled, and extended-spectrum cephalosporin-resistant Enterobacteriaceae (ESC-R) were detected in 28/113 (24.8%) and 8/74 (10.8%) tested animals, respectively. Different Enterobacteriaceae isolates (mostly E. coli), a large number of E. coli clones (with ST90, ST457, ST973 and ST2541 being predominant), and several ESBL/pAmpC genes and plasmids were characterized, highlighting the ability of stray and pet cats and dogs to further spread a wide range of ESC-resistance determinants. The ESBL phenotype was due to the blaCTX-M 2 and blaCTX-M-8 genes, as found in human epidemiology in Brazil, but blaCTX-M-9 and blaCTX-M-15 were also identified. The pAmpC phenotype was systematically due to the presence of the blaCMY-2 gene, mostly carried by IncI1 ST12 plasmids. Our results showed that pets can be considered a significant reservoir of multidrug resistant bacteria in Brazil. This is especially true for healthy stray dogs that displayed the highest prevalence (24.8%) of ESBLs/pAmpC resistance determinants, which can then be further spread both to the environment and to other animals or humans by contact. PMID- 29981710 TI - Sequential circulation of canine adenoviruses 1 and 2 in captive wild carnivores, France. AB - Scarce data are currently available about the ecology of canine adenoviruses (CAdVs) in wild carnivores. In this paper, the consecutive circulation of CAdV-1 and CAdV-2 in wild carnivores maintained in a French zoological park is reported. A fatal CAdV-1 infection was observed in a Eurasian wolf (Canis lupus lupus), which displayed gross lesions, histopathological changes and immunohistochemical findings suggestive of CAdV-1 infection. The virus was isolated on cell cultures and its genome was determined through next-generation sequencing, resulting genetically related to a recent Italian CAdV-1 strain detected in an Italian wolf. Subsequently, subclinical circulation of CAdV-2 was demonstrated by molecular methods in wild carnivores maintained in the same zoological park, some of which had been previously vaccinated with a CAdV-2 vaccine. Virus detection at a long distance from vaccination and by unvaccinated animals was suggestive of infection by a CAdV-2 field strain, although no data are available about the extent and duration of shedding of CAdV-2 modified-live virus in wild or domestic carnivores. The present paper provides new insights into the CAdV ecology in wildlife, although future studies are needed to fully understand the pathogenic potential of both CAdVs especially in endangered carnivore species. PMID- 29981711 TI - gga-miR-142-5p attenuates IRF7 signaling and promotes replication of IBDV by directly targeting the chMDA5's 3' untranslated region. AB - Chicken melanoma differentiation-associated gene 5 (chMDA5) is a key pattern recognition receptor (PRR) that recognizes RNA viral infections and initiates an antiviral innate immune response in chickens. MicroRNAs (miRNAs) are involved in the regulation of chMDA5 to sense RNA virus infection, but how it exerts antiviral activity against infectious bursal disease virus (IBDV) infection and regulates chMDA5 in chicken cells is unclear. Thus, we measured the expression of chMDA5 in IBDV-infected DT40 cells and found it significantly increased. Overexpression of chMDA5 activated the IFN-beta and Mx promoters via IRF7 dependent pathways and inhibited replication of IBDV in DT40 cells. The opposite effect occurred after chMDA5 knockdown using siRNA. Also, gga-miR-142-5p regulated chMDA5 according to bioinformatic analysis and data from a dual luciferase reporter system. Overexpression of gga-miR-142-5p reduced the expression of the chMDA5 protein, promoting IBDV replication, and decreased the activity of the IFN-beta and Mx promoters via an IRF7-dependent pathway; however, it had no effect on the NF-kappaB-dependent pathway in DT40 cells. Thus, gga-miR 142-5p is a negative regulator of chMDA5 and promotes IBDV replication in DT40 cells through an IRF7-dependent pathway. PMID- 29981712 TI - Synthetic RNA derived from the foot-and-mouth disease virus genome elicits antiviral responses in bovine and porcine cells through IRF3 activation. AB - Foot-and-mouth disease virus (FMDV) is the causative agent of a highly transmissible disease affecting wild and domestic animals including pigs, cattle and sheep. The ability of synthetic RNA transcripts mimicking distinct domains in the non-coding regions of the FMDV genome (ncRNAs) to induce a potent innate immune response in swine cultured cells and mice has been previously described, as well as their enhancing effect on conventional inactivated FMD vaccines. Here, we provide evidence of the activation of interferon regulatory factor 3 (IRF3), a key transcriptional regulator of type I interferon (IFN)-dependent immune responses after transfection of swine and bovine cells with transcripts corresponding to the FMDV 3' non-coding region (3'NCR). Induction of IFN-beta and Mx1expression, concomitantly with antiviral activity and IRF3 activation was observed in bovine MDBK cells transfected with the 3'NCR. Our results link the stimulation of the innate immune response observed in 3'NCR-transfected cells to the intracellular type I IFN signaling pathway and suggest the potential use of these molecules for antiviral strategies in cattle. PMID- 29981713 TI - Isolation and characterization of Chinese porcine epidemic diarrhea virus with novel mutations and deletions in the S gene. AB - Porcine epidemic diarrhea (PEDV) has raised growing concerns in the pig-breeding industry because it has caused significant economic losses. To better understand the molecular epidemiology and genetic diversity of PEDV field isolates, in this study, the complete spike (S) and ORF3 genes of 17 PEDV variants in Zhejiang, China during 2014 to 2017, were characterized and analyzed. Phylogenetic analysis based on the S gene and ORF3 gene of these 17 novel PEDV strains and PEDV reference strains indicated that all the PEDV strains fell into two groups designated G1 and G2. Notably, the strains identified in 2014-2015 were in G2, while the other five strains identified from 2016 to 2017 were in G1. Sequencing and phylogenetic analyses showed that recently prevalent Chinese PEDV field strains shared higher identities with United States strains than with South Korean strains. Compared with classical vaccine strains, a series of deletions and frequently occurring mutations were observed in the receptor binding domains of our PEDV strains. Besides, we successfully isolated and reported the genetic characterization two novel PEDV strains, PEDV-LA1 and PEDV-LY4-98, found on the Chinese mainland, which had significant variations in the S gene. Meanwhile, the virulence of the new mutants may be changed, the PEDV-LY4-98 strain, which has multiple mutations in the signal peptide-encoding fragment of the S gene showed delayed cytopathic effects and smaller plaque size compared with strain PEDV-LA1, which lacks these mutations. Three unique amino acid substitutions (L7, G8, and V9) were identified in the SP-encoding fragment of the S1 N-terminal domain of the PEDV-LY4-98 S protein compared with the S proteins of all the previous PEDV strains. The animal experiment revealed that these two novel strains were high pathogenic to neonatal pigs. Whether these amino acids substitutions and the N glycosylation site substitutions influence the antigenicity and pathogenicity of PEDV remains to be investigated. Meanwhile, amino acid substitutions in the neutralizing epitopes may have conferred the capacity for immune evasion in these PEDV field strains. This study improves our understanding of ongoing PEDV outbreaks in China, and it will guide further efforts to develop effective measures to control this virus. PMID- 29981714 TI - Lesser housefly (Fannia canicularis) as possible mechanical vector for Aleutian mink disease virus. AB - Flies are known vectors for a variety of infectious diseases in animals. In fur mink farming, one of the most severe diseases is Aleutian disease, which is caused by the Aleutian mink disease virus (AMDV). The presence of large fly populations is a frequent issue in mink farms; however, no studies assessing their role as AMDV carrier vectors have been conducted to-date. In order to determine the presence of AMDV in aerial flies from an infected mink farm, flies (n = 254) and environmental swab samples (n = 4) were collected from two farm barns. Fannia canicularis (L.) (Diptera: Muscidae) represented more than 99% of the fly population. One hundred and fifty specimens of this species were divided into pools of ten flies and analysed by qPCR, and positive samples were further sequenced. All fly pools and environmental samples tested positive for AMDV, and sequence analysis revealed identical genotypes in both types of samples. This is the first report of AMDV contamination in flies from mink farms, suggesting that F. canicularis may act as an AMDV vector. These results may be of interest for epidemiological studies and also for the improvement of control measures against this virus in mink farms. PMID- 29981715 TI - A molecular survey of hemoplasmas in domestic dogs from Turkey. AB - Mycoplasma haemocanis (Mhc) and Candidatus Mycoplasma haematoparvum (CMhp) are cell-wall-deficient bacterial pathogens that localize on the vertebrate erythrocyte surface. Prevalence of infection with these hemoplasmas and associated risks factors were ascertained from archived DNA samples collected from 621 domestic dogs (201 strays, 262 from shelters, 158 domestic pets) by species-specific PCR assay. The overall prevalence of infection was 15.3% (CI 12.5-18.4), with Mhc and CMhp single infection prevalence of 4.5% (CI 3.0-6.4) and 4.3% (CI 2.9-6.3), respectively. Dual infection with Mhc and CMhp was found in 6.4% (I 4.6-8.715). Infection rates for male (15.8%, CI 12.5-18.4) and female (14.5%, CI 10.5-19.4) dogs were not significantly different (P > 0.05), and the frequency of hemoplasmas was higher in adult dogs (18.9%, CI 15.1-23.2) than in young (9.5%, CI 6.1-14.0) (P < 0.05). Shelter and free-roaming stray dogs had higher prevalence of infection compared to domestic pet dogs (P < 0.05), but there was no significant difference in prevalence between free-roaming and shelter dogs (P> 0.05). A significant association between hemoplasma infection and the presence of Rhipicephalus sanguineus sensu lato was observed (P < 0.05). Presence of tick-borne pathogens (Babesia, Hepatozoon, Anaplasma, Ehrlichia) was also significantly associated with canine hemoplasmas (P < 0.05). PMID- 29981716 TI - Diversity of CTX-M-1-producing E. coli from German food samples and genetic diversity of the blaCTX-M-1 region on IncI1 ST3 plasmids. AB - Antimicrobial resistance to cephalosporins is commonly mediated by extended spectrum beta-lactamases (ESBL) or plasmidic AmpC beta-lactamases (pAmpC). In livestock blaCTX-M-1 is the most frequently detected ESBL-encoding gene. As transmission to consumers through contaminated food is often proposed, this study characterized ESBL/pAmpC-producing E. coli collected from food samples. Therefore, samples from food products of animal origin and vegetables were screened for phenotypically resistant E. coli by selective cultivation. The ESBL genotype was confirmed for 404 isolates with the majority of them (n = 212) harboring the blaCTX-M-1 gene. PFGE and MLST analyses as well as plasmid characterization were carried out for 89 isolates, selected under epidemiological aspects. In addition, 44 isolates were investigated by whole genome sequencing and/or sequencing of their plasmids on an Illumina Miseq platform. MLST and PFGE indicated a diverse population of CTX-M-1-producing E. coli in German food samples with no spread of single clonal lineages. The majority of the isolates harbored the blaCTX-M-1 gene on IncI1 plasmids. Frequently, the gene was associated with the ISEcp1 element and located on a ~100 kb IncI1 plasmid depicting the plasmid multilocus sequence type (ST) 3. The blaCTX-M-1 gene and its flanking sequences were located within the shufflon of the type IV pilus region in diverse orientations. In conclusion, dissemination of the CTX-M-1 beta lactamase within food samples of animal origin is driven by the transmission of a ~100 kb large IncI1 ST3 plasmid. Apart from conjugal transfer of IncI1 ST3 plasmids the transmission of the blaCTX-M-1 gene might be further promoted through mobilization due to its location within a recombination hot-spot of IncI1 plasmids. PMID- 29981717 TI - Doing It Better for Less: Incorporating OSA Management Into Alternative Payment Models. AB - As the cost of health care continues to escalate, payers are adapting by moving away from models based on traditional fee-for-service reimbursement to models focused on rewarding care delivery that reduces costs and improves quality. These alternative payment models (APMs) are being introduced by government and commercial payers and will likely become the norm over time. Recent changes in sleep medicine related to advances in technology and approaches by payers for the management of OSA make this an appropriate time to incorporate the delivery of sleep medicine services into APMs. For OSA, the approaches that should lead to success include the appropriate use of home sleep apnea testing and automatic positive airway pressure; lower cost providers to manage less complex patients; evolving technologies including cloud-based positive airway pressure adherence monitoring, telemedicine, and Internet-based coaching to improve adherence with treatments; data analytics to better identify high-risk populations and to more appropriately allocate resources; and appropriate referrals of more complex cases to sleep specialists for management. All of these approaches should improve the value of care for payers, providers, and patients while allowing sleep specialists to more appropriately allocate their efforts to overseeing APM program development and administration and allowing them to focus on the management of more complicated patients. PMID- 29981718 TI - US Patient-Centered Research Priorities and Roadmap for Bronchiectasis. AB - Noncystic fibrosis bronchiectasis (bronchiectasis) is an increasingly common chronic lung disease that is difficult to manage because of a lack of evidence on which to base treatment decision-making. We sought to develop a practical list of US-based patient-centered research priorities and an associated roadmap to guide bronchiectasis research. We designed and administered a web-based patient needs assessment survey to establish broad research priorities, convened three stakeholder webinars to confirm the top priorities, obtained written stakeholder feedback, and completed a final consensus survey of objectives. The stakeholder panel consisted of clinical research experts in bronchiectasis, a seven-member patient advisory panel, and representatives from the two key patient advocacy organizations: COPD Foundation and NTM Info and Research Inc. Based on survey results from 459 patients with bronchiectasis, the stakeholder panel identified 27 patient-centered research priorities for bronchiectasis in the areas of bronchiectasis treatment and prevention of exacerbations, improving treatment of exacerbations and infections, improving health-related quality of life, predictors of poor prognosis, understanding the impact of underlying conditions, and conducting patient-centered clinical trials. These priorities should further inform the development and evaluation of both new and previously unproven therapies, with particular attention to the inclusion of patient-reported outcomes. We anticipate a great deal of progress will be made in the field of bronchiectasis in the next decade. PMID- 29981719 TI - Validation model of a laboratory-developed method for the ISO15189 accreditation: The example of salivary cortisol determination. AB - BACKGROUND: The ISO 15189:2012 describes the requirements for quality and competence, which are specific for all sectors of a medical laboratory. Laboratory-developed methods, standard methods used outside their intended scope and validated methods subsequently modified shall be validated. The main objective of validation of an examination procedure (EP) is to demonstrate its fitness-for-purpose. The aim of the present study is to illustrate a model to validate laboratory-developed methods in agreement with the ISO 15189:2012 requirement, through the example of salivary cortisol (sF) measurement by liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: The proposed validation model for a laboratory developed method includes 6 steps: 1) analysis of available scientific documentation pertinent to specific EP; 2) evaluation of EP intended use; 3) identification of performance characteristics to evaluate; 4) definition of experimental procedure; 5) identification of acceptability criterion for results evaluation; 6) preparation of a validation plan; 7) production of a validation certificate. RESULTS: sF is an EP sampled during the accreditation audit and resulted in compliance with the Standard. A structured procedure to certify that the achieved performance specifications are appropriate for the purpose of the test is therefore necessary. CONCLUSIONS: A high competence is required for laboratory professionals in order to guarantee that the validated quality specifications have a positive impact on patients' management. The ISO 15189 accreditation is an important tool that allows demonstrating the value of a medical laboratory in the clinical context. PMID- 29981720 TI - Developing Faculty in Emerging Areas of Interdisciplinary Research. AB - The availability of new techniques and technologies to answer important medical questions is accelerating at a breathtaking pace. In response to these exciting new opportunities, clinical departments, in general, and departments of medicine, in particular, have broadened their research portfolios. Organization of the traditional structures of clinical departments, research infrastructure, training programs, and rewards for faculty has only begun to catalyze emerging research areas such as artificial intelligence, bioinformatics, bioengineering, cell and tissue engineering, cost effectiveness, health services, implementation science, integrative epidemiology, medical informatics, nanomedicine, and quality improvement. Success in these emerging areas of research requires interdisciplinary collaboration on a much larger scale than in the past. The effectiveness of efforts to recruit, develop, mentor, and promote faculty in these exciting areas will be critical to the success of departmental and institutional research programs. We describe examples of initiatives from our 5 departments of medicine designed to develop and promote faculty conducting research in emerging interdisciplinary areas. We focus on core resources, training, organizational structures, and recognition and promotion. Faculty have a compelling opportunity and obligation to pursue emerging research areas that have the potential to further improve the prevention, diagnosis, and treatment of disease. As departments prepare to meet this exciting opportunity in the future, the lessons learned must inform investments in faculty development. Although many of the strategies outlined herein could and should expand beyond any individual department, departments of medicine have a distinct obligation and opportunity to lead this effort. PMID- 29981721 TI - Global spectroscopic analysis to study the regulation of the photosynthetic proton motive force: A critical reappraisal. AB - In natural variable environments, plants rapidly adjust photosynthesis for optimum balance between photochemistry and photoprotection. These adjustments mainly occur via changes in their proton motive force (pmf). Recent studies based on time resolved analysis of the Electro Chromic Signal (ECS) bandshift of photosynthetic pigments in the model plant Arabidopsis thaliana have suggested an active role of ion fluxes across the thylakoid membranes in the regulation of the pmf. Among the different channels and transporters possibly involved in this phenomenon, we previously identified the TPK3 potassium channel. Plants silenced for TPK3 expression displayed light stress signatures, with reduced Non Photochemical Quenching (NPQ) capacity and sustained anthocyanin accumulation, even at moderate intensities. In this work we re-examined the role of this protein in pmf regulation, starting from the observation that both TPK3 knock down (TPK3 KD) and WT plants display enhanced anthocyanin accumulation in the light under certain growth conditions, especially in old leaves. We thus compared the pmf features of young "green" (without anthocyanins) and old "red" (with anthocyanins) leaves in both genotypes using a global fit analysis of the ECS. We found that the differences in the ECS profile measured between the two genotypes reflect not only differences in TPK3 expression level, but also a modified photosynthetic activity of stressed red leaves, which are present in a larger amounts in the TPK3 KD plants. PMID- 29981722 TI - Dynamics of the mixed exciton and charge-transfer states in light-harvesting complex Lhca4: Hierarchical equation approach. AB - We model the energy transfer dynamics in the Lhca4 peripheral antenna of photosystem I from higher plants. Equilibration between the bulk exciton levels of the antenna and the red-shifted charge-transfer (CT) states is described using the numerically inexpensive Redfield-Forster approach and exact hierarchical equation (HEOM) method. We propose a compartmentalization scheme allowing a quantitatively correct description of the dynamics with the Redfield-Forster theory, including the exciton-type relaxation within strongly coupled compartments and hopping-type migration between them. The Redfield-Forster method gives the kinetics close to the HEOM solution when treating the CT state as dynamically localized. We also demonstrate that the excited states strongly coupled with the CT should be considered as localized as well. PMID- 29981723 TI - Auditory sensory memory and working memory skills: Association between frontal MMN and performance scores. AB - OBJECTIVE: Memory is the faculty responsible for encoding, storing and retrieving information, comprising several sub-systems such as sensory memory (SM) and working memory (WM). Some previous studies exclusively using clinical population revealed associations between these two memory systems. Here we aimed at investigating the relation between modality-general WM performance and auditory SM formation indexed by magnetic mismatch negativity (MMN) responses in a healthy population of young adults. METHODS: Using magnetoencephalography (MEG), we recorded MMN amplitudes to changes related to six acoustic features (pitch, timbre, location, intensity, slide, and rhythm) inserted in a 4-tone sequence in 86 adult participants who were watching a silent movie. After the MEG recordings, participants were administered the WM primary subtests (Spatial Span and Letter Number Sequencing) of Wechsler Memory Scale (WMS). RESULTS: We found significant correlations between frontal MMN amplitudes to intensity and slide deviants and WM performance. In case of intensity, the relation was revealed in all participants, while for slide only in individuals with a musical background. CONCLUSIONS: Automatic neural responses to auditory feature changes are increased in individuals with higher visual WM performance. SIGNIFICANCE: Conscious WM abilities might be linked to pre-attentive sensory-specific neural skills of prediction and short-term storage of environmental regularities. PMID- 29981725 TI - Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway. AB - BACKGROUND: Thymoquinone (TQ), the major active compound isolated from black seed oil (Nigella sativa), has been reported to exhibit anti-inflammatory and anticancer abilities. However, the exact molecular mechanism underlying the anticancer effect of TQ is still poorly understood, especially in regard to TQ's effect on endoplasmic reticulum stress-mediated apoptosis. METHODS: The cytotoxicity of TQ on T24 and 253J bladder cancer cells was analyzed by MTT assay, colony formation assay and Annexin V-FITC/PI staining, while SV-HUC-1, the SV-40 immortalized human uroepithelial cell line, was used as a normal control. The change in mitochondrial membrane potential was assessed by JC-1 staining. mRNA expression and protein expression were detected by qPCR and western blotting. Caspase-3 activity was detected by colorimetric assay. KEY FINDING: TQ has a significant cytotoxicity on bladder cancer cells and can inhibit their proliferation and induce apoptosis. The protein changes of Bcl-2, Bax, cytochrome c and endoplasmic reticulum stress-related proteins (GRP78, CHOP, and caspase-12) revealed that the anticancer effect of TQ was associated with mitochondrial dysfunction and the endoplasmic reticulum stress pathway. Pretreatment with a pan caspase inhibitor, Z-VAD-fmk, or an ER stress inhibitor, 4-PBA, or knockdown of CHOP by shRNA can partly reverse the pro-apoptotic effect of TQ by enhancing the expression of the anti-apoptotic protein Bcl-2, blocking the release of cytochrome c and the translocation of Bax from the cytoplasm to mitochondria. SIGNIFICANCE: Our findings provide the first demonstration of the anticancer effect of TQ on bladder cancer, and the relationship between ER stress and mitochondrial dysfunction was clearly understood when the apoptosis progressed is revealed. PMID- 29981724 TI - Immunohistochemical localization of Nrf2 in the human cochlea. AB - Oxidative stress plays an important role in several inner ear diseases and normal aging. Nuclear (erythroid-derived 2)-like 2, also known as Nrf2, is a transcription factor encoded by the NFE2L2 gene that controls the expression of genes necessary to reduce oxidative stress. There are no studies to the date on the localization of Nrf2 in the human inner ear in normal or pathological conditions. Therefore, we investigated the immunohistochemical localization of Nrf2 in the human cochlea and vestibule using formalin-fixed celloidin-embedded human temporal bone sections. Nrf2 immunoreactivity (IR) was found in the inner and outer hair cells and supporting cells of the organ of Corti throughout the cochlea. Nfr2-IR was also found in hair cells and supporting cells of the maculae and cristae vestibular sensory epithelia. Nrf2-IR was decreased in the organ of Corti of older age individuals. The immunolocalization of Nrf2 in both auditory and vestibular sensory epithelia suggest that this transcription factor may play a relevant role in protecting sensory hair cells from oxidative stress. PMID- 29981726 TI - New chalcone derivative exhibits antiproliferative potential by inducing G2/M cell cycle arrest, mitochondrial-mediated apoptosis and modulation of MAPK signalling pathway. AB - In the present study, we investigated antiproliferative activity of seven newly synthesized chalcone derivatives. Among tested compounds, (2 E)-3-(acridin-9-yl) 1-(2,6-dimethoxyphenyl)prop-2-en-1-one (1C) was the most potent with IC50 = 4.1 MUmol/L in human colorectal HCT116 cells and was selected for further studies. Inhibition of cell proliferation was associated with cell cycle arrest in G2/M phase and dysregulation of alpha, alpha1 and beta5 tubulins. Moreover, 1C caused disruption of the mitochondrial membrane potential and increased number of cells with sub G0/G1 DNA content which is considered as marker of apoptosis. Apoptosis was confirmed by annexin V/PI and AO/PI staining. Furthermore, we found increased concentration of cytochrome c, Smac/Diablo and increased caspase-3 and caspase-9 activity, cleavage of PARP as well as activation of DNA repair mechanisms in 1C treated HCT116 cancer cells. Moreover this chalcone derivative up-regulated proapoptotic Bax expression and down-regulated antiapoptotic Bcl-2 and Bcl-xL expression. Additionally, 1C treatment led to modulation of MAPKs and Akt signalling pathways. In conclusion, our data showed ability of 1C to suppress cancel cell growth and provide the rationale for further in vivo study. PMID- 29981727 TI - Realizing pharmacy's significance. PMID- 29981728 TI - Leading our communities in patient care. PMID- 29981729 TI - Compression therapy in mixed ulcers. PMID- 29981730 TI - Supervised short-stretch compression therapy in mixed leg ulcers. AB - OBJECTIVES: This study was conducted to determine hemodynamic and clinical tolerance under short-stretch compression therapy in elderly patients suffering from mixed-etiology leg ulcers. DESIGN: Transversal observational study conducted in 25 hospitalized patients with a moderate peripheral arterial occlusive disease defined as an ankle-brachial pressure index>0.5, an ankle pressure of>70mmHg and a toe cuff pressure (TP)>50mmHg. MATERIAL AND METHODS: Short-stretch bandages were applied daily with pressures from 20 to 30mmHg. Ankle-brachial pressure, great toe laser Doppler flowmetry (LDF) and transcutaneous oxygen pressure (TcPO2) on dorsum of the foot were measured at baseline and after its removal at 24hours. Great toe LDF was also measured at 10minutes after bandage application. Compression pressure (CP) was measured with a sub-bandage device at baseline, at 10minutes and before bandage removal at 24hours. Clinical tolerance was evaluated taking into account the patient's pain and skin tolerance. RESULTS: Mean age of patients was 80+/-15 years. Median duration of ulcers was 18 months. Hypertension was highly prevalent. One third of patients had diabetes. Toe pressure index and TcPO2 values did not significantly change under compression therapy (P=0.51 and P=0.09, respectively) whereas CP decreased significantly during 24hours. The loss of CP was significant 10minutes after bandage application (P<0.001). Nearly all ulcers were painful prior to placement of compression therapy and required level 1 analgesics. One patient required level 2 analgesic for pain relief. No increase in pain and no ischemic skin damage occurred under compression therapy. CONCLUSIONS: In elderly patients with mixed leg ulcers and with an absolute TP>50mmHg, short-stretch compression of up to 30mmHg does not adversely affect arterial flow and appears clinically well tolerated. Such bandages with appropriate levels of compression may aid ulcer healing by treating the venous part of the disease. PMID- 29981731 TI - Performance analysis of walking of 10,000 regular users of a connected activity tracker. AB - BACKGROUND: According to the World Health Organization, individuals should walk 10,000 per day. Our aim was to determine the factors influencing this objective by using connected activity trackers. METHODS: Anonymized data of 10,000 regular users of the Withings pulse Ox over a 3-month period. RESULTS: Ratio men/women was 2.2, mean age 44.9+/-10.6 years, mean BMI 27.0+/-5.3kg/m2, proportion of individuals living in big towns 21.4%, proportion of physical activity<2 METs 66%. The frequency of achieving 10,000 daily steps was similar for work days, weekends and whole weeks. Mean number of daily steps, mean daily covered distances and slopes were higher during work days (P<0.0001); mean speed was higher during the weekends (P<0.0001). According to a quartile-repartition (percentages of use-days with 10,000 steps), the goal was more often achieved during work days (P<0.0001), if BMI<25kg/m2 (P<0.001), in individuals living in big towns (P<0.001) or having>=2 acquaintances to take up challenges (P<0.001). CONCLUSION: Connected activity trackers represent a valuable tool for evaluating the number of daily steps and for providing feedback to promote walking. PMID- 29981732 TI - [Staff knowledge of radiation protection in endovascular surgery]. AB - INTRODUCTION: Image intensification exposes the endovascular surgery staff to ionizing radiation. The aim of this study was to determine awareness of ionizing radiation risks among personnel working in the endovascular surgery environment and the availability of radiation protection clothes and to propose appropriate corrective measures. METHODS: This descriptive study was performed in the endovascular operating theatre equipped with a mobile image intensifier unit in La Rabta vascular department in September 2017. We visited the endovascular theatre to identify the availability of radiation protection clothes. We used a questionnaire to identify personnel knowledge about ionizing radiation. We established a global score of knowledge to classify our population. RESULTS: We identified 85 professionals exposed to ionizing radiation. Sixty-four of them (75%) responded to our questionnaire; 65% were male; median age was 34 years (range: 25-61). Endovascular theatre personnel were surgeons (35%), nurses (34%), qualified technicians (18%) and other department employees (13%). The mean global score of knowledge was 8.15/20 (2-18). This score increased significantly with grade and seniority (Kruskal-Wallis test). CONCLUSION: In the present study, the results indicate insufficiency knowledge about radiation exposure among the endovascular staff and in radioprotection tools availability. In order to minimize all unnecessary radiation, attempts should be made to increase vascular theatre staff knowledge about radiation protection. Safety culture is a referral method to reduce radiation exposure as low as possible. PMID- 29981733 TI - [Venous thromboembolism and pancreatic cancer]. AB - Pancreatic cancer (PC) is a devastating malignancy with an overall 5-year survival of 8% for all stages combined. Most of the PC patients diagnosed have an advanced disease (40%) or metastatic stage (40%), which eliminates surgery as a potentially curative treatment. The disease course is often complicated by venous thromboembolism (VTE) events, which per se account for significant morbidity and mortality, with significantly worsen survival. PC is associated with the highest risk of VTE among all cancer patients. We review the literature data to address the incidence and clinical outcomes of VTE in PC patients. VTE incidence varies from 5 to 41% according to epidemiological studies and is as high as 57% in postmortem series. Since 2013, international clinical practice guidelines recommend primary thromboprophylaxis with a grade 1B level of evidence as an adjuvant therapy in advanced PC. A recent meta-analysis of randomized controlled trials investigating the benefit and risk of low-molecular-weight heparins (LMWH) in ambulatory advanced PC patients under chemotherapy showed that the incidence of VTE was 2.1% in patients treated with LMWH and 11.2% in controls (risk ratio, 0.18; 95% CI, 0.083-0.39; P<0.0001). In conclusion, improved earlier diagnosis and effective management of VTE, a frequent and life-threatening complication in PC, is warranted to improve PC patient outcomes. PMID- 29981734 TI - [College of the French Vascular Medicine Teachers (CEMV) statement: Arterial Doppler waveforms analysis (simplified Saint-Bonnet classification)]. AB - Lower extremity peripheral artery disease is a frequent disease. Arterial Doppler waveforms analysis is a key element in vascular medicine, especially to diagnose lower peripheral artery disease. Although Doppler waveforms are often used, descriptions are highly heterogeneous. This review presents the simplified Saint Bonnet classification that is tought to vascular medicine residents in order to homogenize arterial flow description. PMID- 29981735 TI - Surgical management of internal carotid artery aneurysm near the skull base. AB - Extracranial carotid artery aneurysms are rare. The most common location is the common carotid artery near the bifurcation. The mid to distal internal carotid artery is the second most common location. We are reporting the case of a 64-year old woman who was admitted to our department for management of an asymptomatic left internal carotid artery aneurysm. Physical examination revealed a pulsatile mass, and imaging confirmed the aneurysm diagnosis. Computed tomography angiography detailed a 28mm*3cm*6cm aneurysm of the left cervical internal carotid artery with tortuous outflow the aneurysm sac. Open repair was undertaken. Exposure with incision anterior to the sternocleidomastoid was performed although extended more superiorly than usual because of the distal aneurysm location. After carotid clamping, the aneurysm was resected and an end to-end anastomosis with prosthesis was performed. After closure, the patient was extubated demonstrating baseline neurologic function. Histologic examination of the arterial wall confirmed the diagnosis of fibromuscular dysplasia. PMID- 29981736 TI - [Aorto-cava fistula complicating abdominal aorta aneurysm]. AB - We report here a case of aorto-cava fistula complicating the rupture of a sub renal aortic aneurysm into the inferior vena cava, which is a rare complication of aortic abdominal aneurysms with often-fatal outcome. Abdominal computed tomography with multi-planar reconstructions remains the firstline-imaging tool allowing positive diagnosis and preoperative planning. Treatment may be surgical or endovascular. PMID- 29981737 TI - [Traumatic dissection of the left renal pedicle in a young adult]. AB - Blunt trauma rarely causes renal pedicle dissection. Clinical signs are minimal and inconsistently reported. The diagnosis is based on computed tomographic angiography; arteriography is still useful when revascularization is considered. We report here a case of traumatic dissection with thrombosis of a juxta-aortic renal pedicle monitored in the intensive care unit. An endovascular procedure could not be proposed because of the juxta-aortic localization. PMID- 29981738 TI - Endophthalmitis Rates after Bilateral Same-Day Intravitreal Anti-Vascular Endothelial Growth Factor Injections. AB - PURPOSE: To evaluate practice patterns for bilateral same-day intravitreal anti vascular endothelial growth factor (VEGF) injections and determine the rate of unilateral and bilateral postinjection endophthalmitis after bilateral same-day intravitreal anti-VEGF injections. DESIGN: Retrospective cohort study. METHODS: The records of a large academic private practice were electronically queried for all office visits, during which bilateral intravitreal anti-VEGF injections were performed between April 1, 2012 and August 21, 2017 for patients with a diagnosis of neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. Demographic information and indication for injection were recorded for each patient and office visit. Charts of patients with endophthalmitis were reviewed, and information was collected on presentation examination, culture data, and visual outcomes. RESULTS: During the study period, 101 932 bilateral same-day intravitreal anti-VEGF injections were performed over 50 966 office visits for 5890 patients. The mean (standard deviation) age of patients in this cohort was 74.2 (14.1) years and 60.6% of patients were female. The 2 most common indications for injection were neovascular age-related macular degeneration (54.3% of patients) and diabetic macular edema (35.4% of patients). Twenty-eight cases of endophthalmitis (0.027% of total injections) occurred during the study period. There were no cases of bilateral endophthalmitis, and no patients had more than 1 occurrence of endophthalmitis. CONCLUSIONS: In this large cohort of patients undergoing bilateral same-day intravitreal anti-VEGF injections, there were no cases of bilateral endophthalmitis. Additionally, the overall rate of unilateral endophthalmitis was low and comparable to prior studies of unilateral injections. These results support the safety of bilateral same-day intravitreal anti-VEGF treatment. PMID- 29981739 TI - Systemic Disease and Long-term Intraocular Pressure Mean, Peak, and Variability in Nonglaucomatous Eyes. AB - PURPOSE: Elevated intraocular pressure (IOP) is a well-known risk factor in glaucoma development and progression. As most glaucoma risk factors are not modifiable, IOP remains the sole focus of medical and surgical therapy. Identifying modifiable factors and their effects on IOP, such as systemic diseases, is therefore of interest. The objective is to assess the long-term, longitudinal relationship between systemic diseases and IOP mean, peak, and variability, including diabetes, hypertension, body mass index (BMI), and smoking status. DESIGN: Secondary analysis of randomized clinical trial data. METHODS: Longitudinal IOP and systemic disease data from the Age-Related Eye Disease Study (AREDS), a randomized clinical trial of high-dose antioxidants, was analyzed. STUDY POPULATION: A total of 3909 older participants without a reported diagnosis of glaucoma or glaucoma treatment during AREDS with up to 12 years of annual IOP and systemic disease data. MAIN OUTCOME MEASURES: Independent systemic disease risk factors associated with IOP. RESULTS: Univariate analysis identified numerous systemic disease factors associated with IOP mean, peak, and variability. Longitudinal adjusted models identified diabetes, obesity, and systolic hypertension as significantly associated with increased IOP, while systemic beta-blocker use was inversely associated. CONCLUSIONS: Results demonstrate a relationship between multiple systemic diseases and IOP; moreover, they demonstrate that systemic diseases influence additional parameters beyond mean IOP, such as IOP peak and variability. Although only to be taken within the context of IOP, these population-level trends reveal potentially modifiable factors in IOP control, and are particularly important in the context of increasing obesity and diabetes prevalence rates in American adults. PMID- 29981740 TI - The Border of Macular Atrophy in Age-Related Macular Degeneration: A Clinicopathologic Correlation. AB - PURPOSE: To correlate in vivo imaging to histology in an eye with macular atrophy owing to age-related macular degeneration (AMD; complete retinal pigment epithelium [RPE] and outer retinal atrophy [cRORA]) to evaluate the utility of new optical coherence tomography (OCT) suggested by previous histology. DESIGN: Case study with clinicopathologic correlation. METHODS: In vivo eye-tracked cross sectional OCT scans at 13 and 8 months before death were compared to postmortem histopathology. On OCT, the atrophy border was identified as either the descent of the external limiting membrane (ELM) toward the Bruch membrane (BrM) (representing gliosis) or the presence of choroidal hypertransmission (representing lack of shadowing by RPE). Thicknesses of RPE, basal laminar deposit (BLamD), and BrM were measured at 500 and 100 MUm on the nonatrophic and atrophic sides of these borders, on in vivo eye-tracked OCT and histology matched to the same location. RESULTS: In all OCT scans, the ELM descent was visible. The RPE-BLamD band significantly thickened toward it (P < .005), over time (P = .015 and P = .043, at 500 and 100 MUm, respectively). On OCT, the ELM descent delineated a smaller atrophic area than did hypertransmission. RPE-BLamD thicknesses manually measured on OCT overestimated histologic thicknesses. BrM visibility varied with RPE status. CONCLUSION: Visible on OCT, the ELM descent is a histopathologic atrophy border supporting new terminology of cRORA, whereas hypertransmission reveals RPE degeneration. RPE-BLamD thickening across the macula, toward the atrophy and over time is confirmed. The presence of gliosis and thick RPE-BLamD suggests that macular atrophy is a late stage in disease progression, encouraging anatomic endpoints at earlier AMD stages than atrophy enlargement. PMID- 29981741 TI - The status of sublingual immunotherapy in the treatment of allergic diseases. PMID- 29981742 TI - Association of Elevated Urinary miR-126, miR-155, and miR-29b with Diabetic Kidney Disease. AB - Effective diabetic kidney disease (DKD) biomarkers remain elusive, and urinary miRNAs represent a potential source of novel noninvasive disease sentinels. We profiled 754 miRNAs in pooled urine samples from DKD patients (n = 20), detecting significantly increased miR-126, miR-155, and miR-29b compared with controls (n = 20). These results were confirmed in an independent cohort of 89 DKD patients, 62 diabetic patients without DKD, and 41 controls: miR-126 (2.8-fold increase; P < 0.0001), miR-155 (1.8-fold increase; P < 0.001), and miR-29b (4.6-fold increase; P = 0.024). Combined receiver operating characteristic curve analysis resulted in an area under the curve of 0.8. A relative quantification threshold equivalent to 80% sensitivity for each miRNA gave a positive signal for 48% of DKD patients compared with 3.6% of diabetic patients without DKD. Laser-capture microdissection of renal biopsy specimens, followed by quantitative RT-PCR, detected miR-155 in glomeruli and proximal and distal tubules, whereas miR-126 and miR-29b were most abundant in glomerular extracts. Subsequent experiments showed miR-126 and miR-29b enrichment in glomerular endothelial cells (GEnCs) compared with podocytes, proximal tubular epithelial cells, and fibroblasts. Significantly increased miR-126 and miR-29b were detected in GEnC conditioned medium in response to tumor necrosis factor-alpha and transforming growth factor beta1, respectively. Our data reveal an altered urinary miRNA profile associated with DKD and link these variations to miRNA release from GEnCs. PMID- 29981744 TI - Imaging Mass Microscopy of Kidneys from Azithromycin-Treated Rats with Phospholipidosis. AB - Drug-induced phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of tissue phospholipids. Although azithromycin can be used to induce phospholipidosis, no experimental studies evaluating the relationship between drug accumulation and phospholipid localization have been performed. In this study, azithromycin was orally administered to rats for 7 days, and the relationship between drug and phospholipid accumulation was performed using imaging mass microscopy. The administration of azithromycin induced tubular epithelial vacuolation in the inner stripe of the outer medulla of the kidney, consistent with the lamellar bodies that are typical manifestations of drug-induced phospholipidosis. Azithromycin and phospholipid tissue levels were extensively elevated in the kidneys of azithromycin-treated rats. Imaging mass microscopy revealed that both azithromycin and its metabolites were found in the kidneys of azithromycin-treated rats but not in control animals. The vacuolated areas of the kidneys were primarily found in the inner stripe of the outer medulla, consistent with the areas of high azithromycin concentration. Azithromycin was colocalized with several phospholipids phosphatidylinositol (18:0/20:4), phosphatidylethanolamine (18:0/20:4 and 16:0/20:4), and possibly didocosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate, a putative biomarker of drug-induced phospholipidosis. In summary, we found correlations between regions of kidney damage and the accumulation of azithromycin, its metabolites, and phospholipids using imaging mass microscopy. Such analyses may help reveal the mechanism and identify putative biomarkers of drug-induced phospholipidosis. PMID- 29981743 TI - Proliferative, Migratory, and Transition Properties Reveal Metastate of Human Amnion Cells. AB - Amnion epithelial cell (AEC) shedding causes microfractures in human placental membranes during gestation. However, microfractures are healed to maintain membrane integrity. To better understand the cellular mechanisms of healing and tissue remodeling, scratch assays were performed using primary AECs derived from normal term not in labor membranes. AECs were grown under different conditions: i) normal cultures (control), ii) oxidative stress (OS) induction by cigarette smoke extract (CSE), iii) co-treatment of CSE and antioxidant N-acetyl-l cysteine, and iv) treatment with amniotic fluid (AF). Cell migration time and distance, changes in intermediate filament (cytokeratin-18 and vimentin) expressions, and cellular senescence were determined. Control AECs in culture exhibited a metastate with the expression of both cytokeratin-18 and vimentin. During healing, AECs proliferated, migrated, and transitioned from epithelial to mesenchymal phenotype with increased vimentin. Wound healing was associated with mesenchymal to epithelial transition (MET). CSE-induced OS and senescence prevented wound healing in which cells sustained mesenchymal state. N-acetyl-l cysteine reversed CSE's effect to aid wound closure through MET. AF accelerated cellular transitions and healing. Our data suggest that AECs undergo epithelial to mesenchymal transition during proliferation and migration and MET at the injury site to promote healing. AF accelerated whereas OS diminished cellular transitions and healing. OS-inducing pregnancy risk factors may diminish remodeling capacity contributing to membrane dysfunction, leading to preterm birth. PMID- 29981745 TI - Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases. AB - Histone lysine demethylases (KDMs) are 2-oxoglutarate-dependent dioxygenases (2 OGDDs) that regulate gene expression by altering chromatin structure. Their dysregulation has been associated with many cancers. We set out to study the catalytic and inhibitory properties of human KDM4A, KDM4B, KDM5B, KDM6A and KDM6B, aiming in particular to reveal which of these enzymes are targeted by cancer-associated 2-oxoglutarate (2-OG) analogues. We used affinity-purified insect cell-produced enzymes and synthetic peptides with trimethylated lysines as substrates for the in vitro enzyme activity assays. In addition, we treated breast cancer cell lines with cell-permeable forms of 2-OG analogues and studied their effects on the global histone methylation state. Our data show that KDMs have substrate specificity. Among the enzymes studied, KDM5B had the highest affinity for the peptide substrate but the lowest affinity for the 2-OG and the Fe2+ cosubstrate/cofactors. R-2-hydroxyglutarate (R-2HG) was the most efficient inhibitor of KDM6A, KDM4A and KDM4B, followed by S-2HG. This finding was supported by accumulations of the histone H3K9me3 and H3K27me3 marks in cells treated with the cell-permeable forms of these compounds. KDM5B was especially resistant to inhibition by R-2HG, while citrate was the most efficient inhibitor of KDM6B. We conclude that KDM catalytic activity is susceptible to inhibition by tumorigenic 2-OG analogues and suggest that the inhibition of KDMs is involved in the disease mechanism of cancers in which these compounds accumulate, such as the isocitrate dehydrogenase mutations. PMID- 29981746 TI - Folding up and Moving on-Nascent Protein Folding on the Ribosome. AB - All cellular proteins are synthesized by the ribosome, an intricate molecular machine that translates the information of protein coding genes into the amino acid alphabet. The linear polypeptides synthesized by the ribosome must generally fold into specific three-dimensional structures to become biologically active. Folding has long been recognized to begin before synthesis is complete. Recently, biochemical and biophysical studies have shed light onto how the ribosome shapes the folding pathways of nascent proteins. Here, we discuss recent progress that is beginning to define the role of the ribosome in the folding of newly synthesized polypeptides. PMID- 29981747 TI - CDK7 activated beta-catenin/TCF signaling in hepatocellular carcinoma. AB - Over-activation of beta-catenin/TCF signaling is very common in the progression of hepatocellular carcinoma (HCC). The molecular mechanisms leading to the aberrant activation of beta-catenin/TCF signaling are not fully understood. In this study, it was found that CDK7 was up-regulated in HCC tissues and its expression inversely correlated with the survival of HCC patients. Functional study showed that CDK7 promoted the growth and migration of HCC cells, and knocking down the expression of CDK7 inhibited the growth of HCC cells in both liquid culture and soft agar. Mechanistically, CDK7 interacted with beta-catenin, enhanced the interaction between beta-catenin and TCF4, and activated beta catenin/TCF signaling. Taken together, this study demonstrated the oncogenic roles of CDK7 in HCC and suggested that CDK7 might be a promising therapeutic target. PMID- 29981748 TI - Mechanism responsible for inhibitory effect of indirubin 3'-oxime on anticancer agent-induced YB-1 nuclear translocation in HepG2 human hepatocellular carcinoma cells. AB - YB-1 nuclear translocation/accumulation caused by anticancer agents leads to malignant transformation. Nuclear import of YB-1 requires a nuclear localization signal (YB-NLS). Previously, we identified five nucleocytoplasmic-shuttling proteins as YB-NLS binding proteins, and showed that they co-accumulate in the nucleus with YB-1 in response to treatment with actinomycin D. In addition, another group reported that transportin-1 is the molecule responsible for YB-1 nuclear translocation, binding to a region (PY-NLS) consistent with the YB-NLS. Recently, we found that indirubin 3'-oxime inhibits the nuclear localization of YB-1 in HepG2 cells and increases their sensitivity to actinomycin D. Here, we found that YB-1 nuclear translocation is dependent on the cellular mRNA level and that indirubin 3'-oxime inhibits the interaction between YB-1 and transportin-1. Interestingly, in cells showing inhibition of actinomycin D-induced YB-1 nuclear translocation by the compound, the YB-NLS-binding proteins as well as transportin 1 and its cargos were imported to the nucleus. Furthermore, the compound inhibited nuclear localization of the GFP-conjugated full-length YB-1 but not that of GFP-conjugated YB-NLS. These results indicate that indirubin 3'-oxime is a specific inhibitor of anticancer agent-induced YB-1 nuclear translocation, interacting with YB-1 itself in a region other than the YB-NLS/PY-NLS. This compound would increase the efficacy of cancer therapy. PMID- 29981749 TI - Escitalopram attenuates fear stress-induced increase in amygdalar dopamine following methamphetamine-induced sensitisation: Implications of fine-tuning action of selective serotonin reuptake inhibitors on emotional processing. AB - Serotonin reuptake inhibitors modulate the serotonergic pathways of the nervous system and are widely used for treating psychiatric conditions such as anxiety and depression. The dopaminergic system is related to the development of these conditions. Previous studies on methamphetamine-sensitised rats (behavioural models of stress vulnerability) have shown increased release of dopamine in response to conditioned stress in the amygdala. This biochemical abnormality was proposed to underlie the pathophysiology of stress vulnerability. However, the effect of serotonin reuptake inhibitors on dopamine levels and its consequent impact on emotional processing is unclear. Here we examined the acute effect of escitalopram, a highly selective serotonin reuptake inhibitor, on fear-related behaviour, baseline dopamine release and dopamine release in response to conditioned fear stress in the amygdala of model rats. Male Sprague-Dawley rats received 2 mg/kg/day, s.c. of methamphetamine for 10 days to sensitise them to the drug, and a fear conditioning paradigm was instituted to model psychological stress. Dopamine changes in the amygdala in response to systemic administration of escitalopram followed by conditioned fear stress were measured using microdialysis and high-performance liquid chromatography. Baseline dopamine release in the amygdala was increased by escitalopram in non-sensitised rats but not in methamphetamine-sensitised rats. Escitalopram attenuated dopamine release in response to the fear-conditioned stimulus in both sensitised and non sensitised rats. The extent of suppression in methamphetamine-sensitised rats (- 90%) was greater than that in non-sensitised rats (- 48%). These findings suggest that serotonin reuptake inhibitors indirectly stabilise the dopaminergic pathway and modulate emotional processing in the amygdala. PMID- 29981750 TI - Notoginsenoside R1, a unique constituent of Panax notoginseng, blinds proinflammatory monocytes to protect against cardiac hypertrophy in ApoE-/- mice. AB - Notoginsenoside R1, a unique constituent from the root of Panax notoginseng, exerts anti-inflammatory, anti-oxidative and anti-apoptotic properties. The purpose of this study was to assess the contribution of the anti-inflammatory effects of R1 to the amelioration of isoproterenol (ISO)-induced hypertrophied hearts of atherosclerosis-prone mice. As a model of in vivo atherosclerosis, ApoE /- C57BL/6 J mice were fed a high-cholesterol diet for 12 weeks. Intraperitoneal injection of R1 (1-50 mg/kg/day) or saline for 7 days was followed by continuous infusion with ISO (25 mg/kg/day) for 14 days to experimentally induce heart hypertrophy. We assessed fibrosis, myocardial function, and protein or mRNA levels of several inflammatory mediators. ISO infusion induced cardiac ventricular contractile and diastolic dysfunction, which was consistent with massive replacement fibrosis and apoptosis in hypertrophied hearts. However, R1 attenuated ISO-induced hypertrophy. R1 suppressed the expression of CC chemokine receptor 2 (CCR2) and prevented Ly6Chigh proinflammatory monocytes and the subsequent myocardial inflammatory responses and expression of various cell derived factors around the cardiac wound. R1-supressed cardiac dysfunction, atherosclerotic lesions, and inflammatory cytokine accumulation in the myocardium can be partially inhibited by CCR2 translation in bone marrow cells. R1 is a novel cardioprotective agent that can attenuate adverse cardiac dysfunction, hypertrophy, and associated disorders, such as fibrosis. The mechanisms are closely correlated with CCR2, which plays a crucial role in the recruitment of proinflammatory monocytes to sites of inflamed hypertrophic heart tissues. PMID- 29981751 TI - Review of environmental effects of oxybenzone and other sunscreen active ingredients. AB - With increasing awareness regarding the risks of sunburn, photoaging, and skin cancer, the use of sunscreens has increased. Organic and inorganic filters are used in sunscreen products worldwide. Concerns have been raised regarding the environmental effects of commonly used organic ultraviolet (UV) filters, including oxybenzone (benzophenone-3), 4-methylbenzylidene camphor, octocrylene, and octinoxate (ethylhexyl methoxycinnamate). Studies have identified UV filters such as oxybenzone, octocrylene, octinoxate, and ethylhexyl salicylate in almost all water sources around the world and have commented that these filters are not easily removed by common wastewater treatment plant techniques. Additionally, in laboratory settings, oxybenzone has been implicated specifically as a possible contributor to coral reef bleaching. Furthermore, UV filters such as 4 methylbenzylidene camphor, oxybenzone, octocrylene, and octinoxate have been identified in various species of fish worldwide, which has possible consequences for the food chain. As dermatologists, it is important for us to continue to emphasize the public health impact of excessive sun exposure and advise our patients about proper photoprotection practice, which consists of seeking shade, wearing photoprotective clothing (including hats and sunglasses), and applying appropriate sunscreens. PMID- 29981752 TI - Gender incongruence and the brain - Behavioral and neural correlates of voice gender perception in transgender people. AB - The phenomenon of gender incongruence is hypothesized to arise from a discrepant sexual development of the brain and the genitals, contingent on genetic and hormonal mechanisms. We aimed at visualizing transgender identity on a neurobiological level, assuming a higher functional similarity to individuals of the aspired rather than assigned sex. Implementing a gender perception paradigm featuring male and female voice stimuli, behavioral and functional imaging data of transmen were compared to men and women, and to transwomen, respectively. Men had decreased activation in response to voices of the other sex in regions across the frontoparietal and insular cortex, while the activation patterns of women and transmen were characterized by little or no differentiation between male and female voices. Further, transmen had a comparatively high discrimination performance for ambiguous male voices, possibly reflecting a high sensitivity for voices of the aspired sex. Comparing transmen and transwomen yielded only few differences in the processing of male compared to female voices. In the insula, we observed a pattern similar to that of men and women, the neural responses of the transgender group being in accordance with their gender identity rather than assigned sex. Notwithstanding the similarities found dependent on biological sex, the findings support the hypothesis of gender incongruence being a condition in which neural processing modes are partly incongruent with one's assigned sex. PMID- 29981753 TI - Water exchange colonoscopy increases adenoma detection rate: a systematic review with network meta-analysis of randomized controlled studies. AB - BACKGROUND AND AIMS: Water-aided colonoscopy techniques, such as water immersion (WI) and water exchange (WE), have shown different results regarding adenoma detection rate (ADR). We determined the impact of WI and WE on ADR and other procedural outcomes versus gas (air, AI; CO2) insufflation colonoscopy. METHODS: A systematic search of multiple databases for randomized controlled trials comparing WI and/or WE with AI and/or CO2 and reporting ADR was conducted. A network meta-analysis with mixed comparisons was performed. Primary outcome was ADR (overall, in the right side of the colon and by colonoscopy indication). RESULTS: Seventeen randomized controlled trials (10,350 patients) were included. WE showed a significantly higher overall ADR versus WI (odds ratio [OR], 1.31; 95% credible interval [CrI], 1.12-1.55) versus AI (OR, 1.40; CrI, 1.22-1.62) versus CO2 (OR, 1.48; 95% CrI, 1.15-1.86). WE achieved the highest ADR also in the right side of the colon and in colorectal cancer screening cases (both significant vs AI and WI) as well as in patients taking a split-dose preparation (significant vs all the other techniques). The Boston Bowel Preparation Scale cleanliness score (vs AI and WI) was significantly higher for WE. Both WI and WE showed increased proportion of unsedated examinations and decreased real-time insertion pain, with WE being the least-painful insertion technique. Withdrawal time was comparable across techniques, but WE showed the longest insertion time (3-5 additional minutes). CONCLUSIONS: WE significantly increases overall ADR, ADR in screening cases, and in the right side of the colon; it also improves colon cleanliness but requires a longer insertion time. PMID- 29981755 TI - An Integrated Data Resource for Genomic Analysis of Cutaneous T-Cell Lymphoma. PMID- 29981754 TI - Renal matrix Gla protein expression increases progressively with CKD and predicts renal outcome. AB - BACKGROUND: Matrix Gla Protein (MGP) is a potent inhibitor of ectopic calcification and modulates bone morphogenesis. Little is known about MGP expression or function in kidney. METHODS: We investigated renal MGP expression in Sprague-Dawley rats after 5/6 nephrectomy (5/6 Nx) and in human kidney biopsies in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We analyzed associations between glomerular (n = 182) and tubulointerstitial (TI) (n = 219) MGP mRNA levels and the disease activity/histologic features in NEPTUNE patients. Additionally, uncarboxylated and carboxylated MGP (ucMGP and cMGP, respectively) were localized by immunohistochemistry and quantitated in kidney tissues of patients at different stages of CKD (n = 18). RESULTS: Renal MGP expression was increased in rats after 5/6 Nx. In NEPTUNE data, baseline estimated glomerular filtration rate (eGFR) negatively correlated with glomerular and TI MGP expression (p <0.001). TI MGP expression strongly correlated with interstitial fibrosis, tubular atrophy, acute tubular injury, and interstitial inflammation, independent of eGFR. Kaplan-Meier analysis and multivariable Cox regression showed that higher levels of TI MGP expression were associated with an increased risk for the composite of 40% decline in eGFR and end-stage renal disease (ESRD) (HR, 3.31; 95% CI, 1.31 to 6.32; p =0.02). Glomerular and tubulointerstitial cells demonstrated nuclear and cytoplasmic cMGP and ucMGP staining, and eGFR inversely correlated with quantified glomerular cMGP staining (p <0.05). CONCLUSIONS: Our data demonstrate that renal MGP expression is increased in human and experimental CKD, and is associated with renal outcome. Additional studies are needed to determine its mechanism of action. PMID- 29981756 TI - Impacts of infection avoidance for populations affected by sexually transmitted infections. AB - Sexually transmitted infections are ubiquitous in nature and affect many populations. The key process for their transmission is mating, usually preceded by mate choice. Susceptible individuals may avoid mating with infected individuals to prevent infection provided it is recognizable. We show that accounting for infection avoidance significantly alters host population dynamics. We observe bistability between the disease-free and endemic or disease-induced extinction equilibria, significant abrupt reduction in the host population size and disease-induced host extinction. From the population persistence perspective, the best strategy is either not to avoid mating with the infected individuals, to prevent disease-induced host extinction, or to completely avoid mating with the infected individuals, to prevent pathogen invasion. Increasing sterilization efficiency of the infection leads to lower population sizes and reduced effect of mating avoidance. We also find that the disease-free state is more often attained by populations with strong polyandry, whereas a high-density endemic state is more often observed for populations with strong polygyny, suggesting that polygamy rather than monogamy may be promoted in denser host populations. PMID- 29981757 TI - An agent-based model of nest-site selection in a mass-recruiting ant. AB - Complex systems are modular entities which can collectively generate sophisticated emergent solutions through interactions based on simple, local rules. In this study, I use an agent-based model to elucidate how numerous individual-level components contribute to the collective decision process during house-hunting in a mass-recruiting ant species. Myrmecina nipponica combines the use of pheromone trails with a quorum decision rule in collective decisions among nest sites when searching for a new home. The model employed only individual level rules but accurately emulated group-level properties observed in empirical studies. Simulations suggest that in this system i) both social and private information are necessary for effective decision making, ii) decision making was effective even with very low numbers of 'discriminating' individuals, iii) individual acceptance thresholds were more influential than quorum thresholds in tuning decisions to emphasise speed or accuracy, and iv) acceptance thresholds could also help tune decisions to suit environmental complexity. Similar findings in species using one-to-one recruitment suggest that some individual parameters, such as acceptance thresholds, may hold key functions in collective decision making regardless of the form of recruitment. PMID- 29981758 TI - Melanin-concentrating hormone and orexin systems in rat nucleus incertus: Dual innervation, bidirectional effects on neuron activity, and differential influences on arousal and feeding. AB - The rat nucleus incertus (NI) contains GABA/peptide-projection neurons responsive to orexin (hypocretin)/orexin receptor-2 (OX2) signalling. Melanin-concentrating hormone (MCH) and orexin neurons often innervate and influence common target areas. Therefore, we assessed the relationship between these hypothalamic peptidergic systems and rat NI, by investigating the presence of an MCH innervation and MCH receptor-1 (MCH1) expression, and neurophysiological and behavioural effects of MCH c.f. orexin-A (OXA), within the NI. We identified lateral hypothalamus (LH), perifornical and sub-zona incerta MCH neurons that innervate NI, and characterised the rostrocaudal distribution of MCH-containing fibres in NI. Single-cell RT-PCR detected MCH1 and OX2 mRNA in NI, and multiplex, fluorescent in situ hybridisation revealed distinct co-expression patterns of MCH1 and OX2 mRNA in NI neurons expressing vesicular GABA transporter (vGAT) mRNA. Patch-clamp recordings revealed 34% of NI neurons tested were hyperpolarised by MCH (1 MUM), representing a distinct population from OXA sensitive NI neurons (35%). Intra-NI OXA infusion (600 pmol) in satiated rats during the light/inactive phase produced increased locomotor activity and food (standard chow) intake, whereas intra-NI MCH infusion (600 pmol) produced only a trend for decreased locomotor activity and no effect on food intake. Furthermore, in satiated or pre-fasted rats tested during the dark/active phase, intra-NI infusion of MCH did not alter the elevated locomotor activity or higher food intake observed. However, quantification of neuropeptide-immunostaining revealed differential diurnal fluctuations in orexin and MCH trafficking to NI. Our findings identify MCH and orexin inputs onto divergent NI populations which may differentially influence arousal and motivated behaviours. PMID- 29981759 TI - Optimization of relative parameters in transfer entropy estimation and application to corticomuscular coupling in humans. AB - BACKGROUND: As a non-modeled information theoretical measure, the transfer entropy (TE) could be applied to quantitatively analyze the linear and nonlinear coupling characteristics between two observations. However, the parameters selection of TE (the parameters used in state space reconstruction and estimating Shannon entropy) has a serious influence on the accuracy of its results. NEW METHOD: In this study, the hybrid particle swarm optimization (HPSO) was applied to improve the accuracy of TE by optimizing its parameters. In HPSO, the TE calculation and significant analysis were integrated into the fitness function, and the optimal parameters group within the parameter space could be automatically found through an iteration process. RESULTS: The TE results computed under the parameters optimized by HPSO (HPSO-TE), was assessed with a numerical non-linear model, the neural mass model and the recorded electroencephalogram (EEG) and electromyogram (EMG) signals. Compared with TE, HPSO-TE could reduce the 'false positive' in non-linear model, and 'spurious coupling', i.e. two nonzero TEs for unidirectionally coupled systems, especially when coupling strength was weak. The robustness against noise and long time-delay was improved. Moreover, the experimental data analysis showed HPSO-TE revealed the dominant direction (EEG -> EMG) in corticomuscular coupling, and had higher values than TE which showed the same dominant direction. COMPARISON WITH EXISTING METHOD: The implication of HPSO improved the accuracy of TE in estimating the coupling strength and direction. CONCLUSIONS: The efficiency of TE could be improved by HPSO for estimating coupling relationships, especially for weakly coupled, strong noisy and long time-delay series. PMID- 29981760 TI - IDF School of Diabetes - Paving the way for improved health professional education. PMID- 29981761 TI - Evidence of macro- and micro-angiopathy in scleroderma: An integrated approach combining 22-MHz power Doppler ultrasonography and video-capillaroscopy. AB - OBJECTIVE: We aimed to study in SSc patients macrovascular involvement by using power Doppler ultrasound (PDUS) and microvascular one by PDUS and nailfold video capillaroscopy (NVC) and to examine the association between history of digital ulcers (HDU) and imaging (PDUS and NVC) parameters. METHODS: NVC and PDUS were systematically performed in 106 consecutive SSc patients at the 3rd and 4th finger of the dominant hand after exclusion of ulnar artery occlusion (UAO). 22 MHz PDUS measurements included nailbed and fingertip qualitatively graded, and resistivity index (RI) of ulnar and radial proper digital arteries. Capillary number/mm was calculated by NVC on the same digits examined by PDUS. RESULTS: Vascularization at fingertip and nailbed showed a good correlation between them and to capillary number. RI, representative of macrovascular involvement, did not correlate to microvascular involvement as assessed by PDUS and NVC. RI and capillary number at NVC showed significant correlation to HDU while fingertip and nailbed vascularization as assessed by PDUS did not. As such, PDUS and NVC provide different and potentially complementary information on SSc-related peripheral macro- and micro-vascular involvement. CONCLUSION: Macro- and micro vascular involvement in SSc patients are different processes and are not present at the same time in every patient. Thus, both these aspects should be carefully evaluated in SSc patients. PMID- 29981762 TI - Genetic variability and lineage phylogeny of human papillomavirus type 45 based on E6 and E7 genes in Southwest China. AB - The current study investigated nucleotide variability and phylogeny in high-risk HPV45 collected from Chinese women. Fifty-one samples positive for single infections of HPV45 were collected for DNA extraction and HPV typing. The E6 and E7 genes of HPV45 were sequenced, and then the phylogenetic tree was reconstructed by the maximum likelihood method implemented in IQ-TREE under the HKY nucleotide substitution model. The selection pressures of the E6 and E7 genes were estimated using PAML software. Eleven nucleotide polymorphism sites were observed in the HPV45 E6 sequences, with 6 synonymous (C134T, T163C, A284C, T341C, T482C, A497G) and 5 non-synonymous (A124C, C157T, T162A, G259T, G487A) mutations. Six nucleotide polymorphism sites were observed in the E7 sequences, with 5 non-synonymous (G600A, A603C, A769C, G808T, G832T) and 1 synonymous (A718C) mutation. Our investigation suggests that B2 was the most frequent HPV45 sublineage in Southwest China, followed by A2; no A1 or A3 variants were detected. Selective pressure analysis showed that these mutations could reflect positive selection in HPV45 E6 and E7 genes. PMID- 29981763 TI - Monitoring collegiate soccer players during a congested match schedule: Heart rate variability versus subjective wellness measures. AB - The aims of this study were a) to examine within-group changes of wellness and heart rate variability measures and b) to compare their sensitivity to a congested match schedule in collegiate soccer players (n = 8). Wellness (Hooper index and its subsets) and heart rate variability (Ln rMSSD, SDNN) measures were assessed after selected low-load (training sessions) and high-load (a congested match schedule) phases. Session rating of perceived exertion (sRPE) was computed for training and match sessions. A very likely large difference in accumulated sRPE was observed between low-load and high-load phases (+148.4%, 90% confidence interval CI [87.3; 229.5%]); effect size, ES, 2.16 [1.49; 2.82]. While the Hooper index showed an almost certainly moderate increase (+49.8%, [33.9; 67.5%]), ES, 1.05 [0.76; 1.34], heart rate variability measures (i.e., Ln rMSSD and SDNN) only changed with a possible trivial effect (range -2.1; 8.2%, [-7.1; 16.7%]), ES, 0.15; 0.15 [-0.50; 0.44]. The Hooper index showed a moderately higher sensitivity than Ln rMSSD to a congested match schedule (34.7%, [26.9; 41.6%], ES, 0.81 [0.60; 1.03]). Relationships between changes in the Hooper index and some of its subsets (?Hooper index, ?sleep, and ?fatigue), with changes in mean sRPE (?sRPE) were very large (range r = 0.72; 0.89). However, small associations were observed between changes in heart rate variability (?Ln rMSSD, and ?SDNN) and ?sRPE (range r = -0.21; 0.10). This study suggests the use of subjective wellness indices, instead of heart rate variability measures, to monitor collegiate soccer players during congested match schedules. PMID- 29981764 TI - Comparative tactile sensitivity of the fingertip and apical tongue using complex and pure tactile tasks. AB - Both the tongue and fingertip are highly tactile tissues relevant in texture perception, but work comparing relative sensitivity to elucidate potential differences in stimulus processing is limited. Presently, the acuity of the tongue and fingertip were compared using a series of tactile acuity tasks. We hypothesized the tongue would show superior acuity regardless of stimuli due to an absent epidermal barrier and its involvement in many high-sensitivity behaviors (e.g. eating, speaking). Acuity was determined using three different tests, two "purely-tactile" just noticeable difference (JND) tasks (punctate pressure and roughness sensitivity) and a more-complex, stereognostic letter recognition task to evaluate point-and-edge sensitivity. JNDs were determined using the forced-choice staircase method for the punctate deformation force of a monofilament (F;0.0044-0.010 g) and the surface roughness of stainless steel coupons (Ra; 0.177-0.465 MUm) in populations of 30 and 31 individuals, respectively. Point-and-edge sensitivity was assessed by determining the letter recognition threshold (RT) based on height (h;1.5-8.0 mm) in an additional 28 individuals using a modified staircase method. While subjects had significantly lower JNDs with their tongues for both "purely-tactile" tasks (punctate: 0.0017 +/- 0.0001 g vs. 0.0023 +/- 0.0002 g (fingertip), p = .018; roughness: 0.039 +/- 0.004 MUm vs. 0.112 +/- 0.020 MUm (fingertip), p < .001), subjects had significantly higher RTs with their tongues for the letter identification task (3.98 +/- 0.84 mm vs. 4.54 +/- 1.41 mm (fingertip), p = .0417). The latter difference is likely attributable to the more complex nature of the RT task and the finger's frequent involvement in object recognition. Binomial statistics (p = 1/2, alpha = 0.05) showed a significant number of subjects were better at the roughness task with their tongues (p = .021); however, a significant majority were better at the letter identification task with their fingers (p = .049); no significant difference was found for the punctate pressure task. While data appear to suggest the tongue is more sensitive to exclusively tactile stimuli, further study of other "pure-tactile" sensations should help clarify the contradictory results of the RT task. PMID- 29981766 TI - Identifying the relationship between oscillatory dynamics and event-related responses. AB - Event related potentials (ERPs) and time frequency analysis of the EEG can identify the temporally distinct coordination of groups of neurons across brain regions during sentence processing. Although there are strong arguments that ERP components and neural oscillations are driven by the same changes in the neural signal, others argue that the lack of clear associations between the two suggests oscillatory dynamics are more than just time frequency representations of ERP components, making it unclear how the two are related. The current study seeks to examine the neural activity underlying auditory sentence processing of both semantic and syntactic errors to clarify if ERP and time frequency analyses identify the same or unique neural responses. Thirty-nine adults completed an auditory semantic judgment task and a grammaticality judgment task. As expected, the semantic judgment task elicited a larger N400 and greater increase in theta power for semantic errors compared to correct sentences and the syntactic judgment task elicited a greater P600 and beta power decrease for both grammatical error types compared to syntactically correct sentences. Importantly, we identified a significant relationship between the N400 and P600 ERPs and theta and beta oscillatory dynamics during semantic and syntactic processing. These findings suggest that ERPs and neural oscillations measure similar neural processes; however, unaccounted for variance may indicate that neural oscillations provide additional information regarding fluctuations in power within a given frequency band. Future studies that vary semantic and syntactic complexity are necessary to understand the cognitive processes that are indexed by these oscillations. PMID- 29981765 TI - Latent consequences of early-life lead (Pb) exposure and the future: Addressing the Pb crisis. AB - BACKGROUND: The lead (Pb) exposure crisis in Flint, Michigan has passed from well publicized event to a footnote, while its biological and social impact will linger for lifetimes. Interest in the "water crisis" has dropped to pre-event levels, which is neither appropriate nor safe. Flint's exposure was severe, but it was not unique. Problematic Pb levels have also been found in schools and daycares in 42 states in the USA. The enormity of Pb exposure via municipal water systems requires multiple responses. Herein, we focus on addressing a possible answer to long-term sequelae of Pb exposure. We propose "4R's" (remediation, renovation, reallocation, and research) against the Pb crisis that goes beyond a short-term fix. Remediation for affected individuals must continue to provide clean water and deal with both short and long-term effects of Pb exposure. Renovation of current water delivery systems, at both system-wide and individual site levels, is necessary. Reallocation of resources is needed to ensure these two responses occur and to get communities ready for potential sequelae of Pb exposure. Finally, properly focused research can track exposed individuals and illuminate latent (presumably epigenetic) results of Pb exposure and inform further resource reallocation. CONCLUSION: Motivation to act by not only the general public but also by scientific and medical leaders must be maintained beyond initial news cycle spikes and an annual follow-up story. Environmental impact of Pb contamination of drinking water goes beyond one exposure incident in an impoverished and forgotten Michigan city. Population effects must be addressed long-term and nationwide. PMID- 29981767 TI - Controlling for caffeine in cardiovascular research: A critical review. AB - Caffeine, the most widely consumed drug in the world, exerts numerous effects on cardiovascular activity. Thus, it is important and advisable to control for caffeine consumption in studies examining caffeine and/or cardiovascular activity and reactivity. This paper 1) reviews the literature concerning caffeine's effects on cardiovascular parameters; 2) summarizes the widely varying protocols used to control for the drug in extant cardiovascular literature, and 3) provide guidelines for caffeine control procedures to minimize potentially confounding acute and withdrawal effects of the drug. An abstention period equal to the average half-life of the drug is recommended for creation of methodological controls for caffeine. Additional methodological recommendations are described concerning factors that moderate the half-life of caffeine. When feasible, researchers should consider and aim to control for caffeine's acute and extended psychophysiological effects. This understudied issue has fundamental implications for caffeine-related investigations and research in psychophysiology and behavioral medicine. PMID- 29981768 TI - Telocytes as possible precursors of PDGFRA-mutant gastrointestinal mesenchymal tumors-reply. PMID- 29981769 TI - Telocytes as possible precursors of PDGFRA-mutant gastrointestinal mesenchymal tumors. PMID- 29981770 TI - Diagnostic criterion of noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP): absence of papillae. PMID- 29981771 TI - An Overview and Update on Obesity and the Obesity Paradox in Cardiovascular Diseases. AB - Obesity increases a number of cardiovascular disease (CVD) risk factors, but patients with many types of CVD may have a better prognosis if classified as overweight or obese, a phenomenon known as the "obesity paradox". This paradoxical benefit of a medically unfavorable phenotype is particularly strong in the overweight and class I obesity, and less pronounced in the more severe or morbidly obese populations (class II-III and greater). Rather than an obesity paradox, it is possible that this phenomenon may represent a "lean paradox", in which individuals classified as normal weight or underweight may have a poorer prognosis with respect to CVD, as a result of a progressive catabolic state and lean mass loss. Cardiorespiratory fitness (CRF) is a fundamental part of this discussion. A greater CRF is associated with lower CVD risk, regardless of body mass index (BMI). Also, the assessment of body composition compartments (i.e., fat mass, fat-free mass, lean mass) and the presence of metabolic derangements may be better indicators of CVD risk than BMI alone. The focus of this review is to summarize the current evidence of the obesity paradox. Moreover, we discuss the utility and limitations of BMI for cardiometabolic risk stratification, in addition to concepts such as "metabolically healthy obesity" (MHO) and the "fat but fit" phenomenon, which describe patients who are diagnosed with obesity using BMI, but without major metabolic derangements and with greater CRF, respectively. Finally, we propose that obese patients presenting with an excess body fat, yet without metabolic abnormalities, should still be viewed as an "at risk" population, and as such should receive advice to change their lifestyle to improve their CRF and to prevent the development of impaired fasting glucose, diabetes mellitus and other CVD risk factors as a form of primary prevention. PMID- 29981772 TI - Structural bases of the assembly, recognition and disassembly of linear ubiquitin chain. AB - Linear ubiquitin chain is a latest discovered type of poly-ubiquitin chain that is broadly involved in innate immune and inflammatory pathways. Dysfunctions in its assembly, recognition or disassembly are intimately related with numerous immunodeficiency or autoimmune diseases. Our understanding of the molecular mechanism for linear ubiquitin chain formation, recognition and disassembly has being significantly evolved in recent years, with particular contribution from the biochemical and structural characterizations of related proteins. Here, we focus on the relevant proteins for the synthesis, recognition and digestion of linear ubiquitin chain, and review recent findings to summarize currently known molecular mechanism from a perspective of structural biology. PMID- 29981773 TI - Global access to antibiotics without prescription in community pharmacies: A systematic review and meta-analysis. AB - OBJECTIVE: To estimate the proportion of over-the-counter antibiotic requests or consultations that resulted in non-prescription supply of antibiotics in community pharmacies globally. METHODS: We systematically searched EMBASE, Medline and CINAHL databases for studies published from January 2000 to September 2017 reporting the frequency of non-prescription sale and supply of antibiotics in community pharmacies across the world. Additional articles were identified by checking reference lists and a Google Scholar search. A random effects meta analysis was conducted to calculate pooled estimates of non-prescription supply of antibiotics. RESULTS: Of the 3302 articles identified, 38 studies from 24 countries met the inclusion criteria and were included in the review. All the included countries with the exception of one, classified antibiotics as prescription-only medicines. The overall pooled proportion of non-prescription supply of antibiotics was 62% (95% CI 53-72). The pooled proportion of non prescription supply of antibiotics following a patient request was 78% (95% CI 59 97) and based on community pharmacy staff recommendation was 58% (95% CI 48-68). The regional supply of non-prescription antibiotics was highest in South America, 78% (95% CI 72-84). Antibiotics were commonly supplied without a prescription to patients with symptoms of urinary tract infections (68%, 95% CI 42-93) and upper respiratory tract infections (67%, 95% CI 55-79). Fluoroquinolones and Penicillins respectively were the most commonly supplied antibiotic classes for these indications. CONCLUSION: Antibiotics are frequently supplied without prescription in many countries. This overuse of antibiotics could facilitate the development and spread of antibiotic resistance. PMID- 29981774 TI - Impact of influenza on outpatient visits and hospitalizations among pregnant women in Catalonia, Spain. AB - OBJECTIVE: To estimate outpatient visits and hospitalization rates due to cardiopulmonary illness attributable to influenza from 2008-09 to 2012-13 in a large cohort of pregnant women from Catalonia, Spain. METHODS: We estimated the event rates occurring during influenza epidemic, influenza non-epidemic and non influenza seasons, and by pregnancy status (one year before pregnancy, first, second and third trimester). We fitted quasi-Poisson models in order to identify the variables associated to higher event rates. RESULTS: During influenza epidemic seasons, pregnant women in their second trimester had the highest rates of outpatient visits (153 per 10,000 women-months). An increased risk of outpatient visits was associated to first or second trimester (adjusted rate ratio (aRR) = 1.17; 95% CI, 1.10-1.23 and aRR, 1.36; 95% CI, 1.28-1.43, respectively) and having any comorbidity (aRR = 1.28; 95% CI, 1.21-1.36). Women during third trimester had the highest rates of hospitalizations (1.60 per 10,000 women-months), and an increased risk of hospitalization was significantly associated to third trimester (aRR, 1.85; 95% CI, 1.01-3.39), having any comorbidity (aRR, 1.93; 95% CI, 1.10-3.41) and the pandemic influenza season (aRR, 2.90 (1.81; 95% CI, 1.81-4.64). CONCLUSION: Our findings provide significant information regarding influenza burden of disease among pregnant women. PMID- 29981775 TI - Mania-like elevated mood in rats: Enhanced 50-kHz ultrasonic vocalizations after sleep deprivation. AB - Mania is characterized by elevated drive and mood but animal models of mania have often neglected elevated mood. Ultrasonic vocalizations (USV) of 50-kHz emitted by rats are thought to index the subject's positive affective state. Fifty-kHz USV emission is increased by amphetamine, an effect blocked by lithium administration. Sleep deprivation (SD) is an environmental model of mania and the present study evaluated SD effects on behavioral activity and USV emission, together with the impact of lithium treatment. Adult rats were submitted to 24h or 72h SD, and locomotor activity and USV emission were assessed. To test their sensitivity to a standard antimanic drug, these behavioral parameters were also evaluated after acute administration of lithium carbonate (25, 50 or 100 mg/kg, i.p.). Striatal monoamine content was measured post-mortem. SD (24h and 72h) led to increased locomotor activity, rearing behavior and 50-kHz USV emission, together with a change in the call profile characterized by an increase in the percentage of frequency-modulated 50-kHz USV, which may indicate the mania-like consequences of SD. Importantly, all SD effects were reverted by lithium administration. SD also led to a decrease in dopamine content in the ventral striatum, while increasing dopamine turnover. In conclusion, SD increased 50-kHz USV emission, an effect prevented by acute lithium administration. This suggests 50-kHz USV as a new marker for mania-like elevated mood, which shows construct validity (associated with increased dopaminergic tone), face validity (reflecting increased positive affect) and predictive validity (high sensitivity to lithium treatment). PMID- 29981776 TI - Protective roles of melatonin against the amyloid-dependent development of Alzheimer's disease: A critical review. AB - Since its discovery almost 60 years ago by Lerner and colleagues, melatonin (N acetyl-5-metoxytryptamine), a hormone mainly produced in the pineal gland, has been the subject of numerous investigations aimed at establishing its physiological functions. The subsequent seminal observation that melatonin levels decrease during normal aging, combined with the facts that AD patients show melatonin deficits when compared to age-matched controls and that the extent of melatonin loss in the cerebrospinal fluid parallels the progression of the disease, was the starting point of a series of studies, conducted during the past 20 years, aimed at determining whether this non-peptide hormone could reasonably be considered as a possible promising anti-AD compound and at establishing through which mechanisms it can control the time course of the disease. In this context, particular attention has been paid to the amyloid peptide (Abeta), which, according to the now well accepted "amyloid cascade" hypothesis, is a key element of the pathology. Indeed, works performed in vitro and in vivo, thanks to the development of reliable mouse models of the pathology, consistently proved melatonin as an efficient anti-amyloid remedy when considering all the steps of Abeta biology (production, conformational changes, oligomerization, fibrillation and ultimately senile plaque formation). This review proposes to draw up a detailed inventory of our current knowledge on the subject with a particular focus on the recent advances in the field. Given the fact that melatonin conveys very few secondary effects, it is nowadays possible to seriously envision melatonin as an effective preventive anti-AD molecule. PMID- 29981777 TI - Sternal surgical site infection in Egypt following coronary artery bypass graft surgery: incidence and risk factors. PMID- 29981778 TI - Assessment of tubule occlusion properties of an experimental stannous fluoride toothpaste: A randomised clinical in situ study. AB - OBJECTIVES: To evaluate the ability of a modified in situ model to differentiate dentinal tubule occlusion properties of toothpaste formulations over 10 days of treatment. METHODS: This was a single-centre, three-treatment period, crossover, randomised, single-blind study with healthy participants wearing two lower oral appliances, each retaining four dentine samples, for 10 treatment days during each period of the study. Samples were power-brushed ex vivo twice on each treatment day with a Test toothpaste containing 0.454% stannous fluoride, a Control fluoride toothpaste containing 0.76% sodium monofluorophosphate, or mineral water. Dentine samples were subjected to in situ acid challenge (orange juice) on Days 9 and 10. Scanning electron microscopy images obtained at baseline and after 1, 4, 8 and 10 days of treatment were graded for degree of surface coverage by four calibrated examiners; the primary study endpoint was Day 8. RESULTS: After 4, but not 8, days' treatment, the degree of tubule occlusion increased in the dentine samples treated with the Test or Control toothpastes compared with the water-treated samples (p < 0.01 and p < 0.05, respectively). Following the acid challenge (Day 10), there was a statistically significantly greater degree of occlusion in the Test toothpaste-treated dentine samples compared with those treated with water (p < 0.01). No other comparisons were statistically significant. All study treatments were generally well-tolerated. CONCLUSIONS: This modified in situ model was unable to demonstrate statistically significant between-treatment differences in dentinal tubule occlusion after 8 days. Conversely, there are recognised developments that could be made to better identify product differences. Clinicaltrials.gov: NCT02768194. CLINICAL SIGNIFICANCE: Dentine hypersensitivity can be managed through brushing with stannous fluoride toothpastes, which occlude patent dentine tubules. Clinical studies measure pain but in situ models are needed to demonstrate occlusion intra orally. However, this study did not demonstrate superior occlusion with stannous toothpaste; further methodological development is required to investigate its mode of action. PMID- 29981782 TI - Bone marrow eosinophils in plasma cell disorders. AB - In experimental studies, eosinophils have been shown to promote the survival, proliferation, and retention of plasma cells in the bone marrow (BM). The clinical significance of eosinophils in plasma cell disorders (PCDs) in humans is largely unknown. This study focuses on the frequency and phenotype of eosinophils in the BM and peripheral blood (PB) in patients with untreated PCD compared with healthy controls. The number of eosinophils per se did not correlate with the number of BM plasma cells or disease stage. The expression of chemokine receptor 4, which is important in the homing capacity to bone marrow stromal cells, was significantly higher in patient eosinophils and increased with disease stage. BM eosinophils from patients, especially from those with manifest disease, were more activated. Another finding in this study was that eosinophils in PB and BM from both patients and healthy controls expressed CD80 (B7-1). We discuss probable immunomodulatory consequences of surface expression of CD80 by eosinophils in conditions with marked T-cell exhaustion (e.g., multiple myeloma). Finally, we found that patients treated with corticosteroids had low levels of circulating eosinophils but preserved levels of eosinophils in the BM. PMID- 29981779 TI - No Association Between Screening for Hepatocellular Carcinoma and Reduced Cancer Related Mortality in Patients With Cirrhosis. AB - BACKGROUND & AIMS: Screening patients with cirrhosis for hepatocellular carcinoma (HCC) has been recommended. We conducted a matched case-control study within the US Veterans Affairs (VA) health care system to determine whether screening by abdominal ultrasonography (USS) and/or by measuring serum level of alpha fetoprotein (AFP) was associated with decreased cancer-related mortality in patients with cirrhosis. METHODS: We defined cases (n = 238) as patients with cirrhosis who died of HCC from January 1, 2013 through August 31, 2015 and had been in VA care with a diagnosis of cirrhosis for at least 4 years before the diagnosis of HCC. We matched each case to 1 control (n = 238), defined as a patient with cirrhosis who did not die of HCC and had been in VA care for at least 4 years before the date of the matched case's HCC diagnosis. Controls were matched to cases by year of cirrhosis diagnosis, race and ethnicity, age, sex, etiology of cirrhosis, Model for End-Stage Liver Disease score, and VA medical center. We identified all USS and serum AFP tests performed within 4 years before the date of HCC diagnosis in cases or the equivalent index date in controls and determined by chart extraction (blinded to case or control status) whether these tests were performed for screening. RESULTS: There were no significant differences between cases and controls in the proportions of patients who underwent screening USS (52.9% vs 54.2%), screening measurement of serum AFP (74.8% vs 73.5%), screening USS or measurement of serum AFP (81.1% vs 79.4%), or screening USS and measurement of serum AFP (46.6% vs 48.3%) within 4 years before the index date, with or without adjusting for potential confounders. There also was no difference in receipt of these screening tests within 1, 2, or 3 years before the index date. CONCLUSIONS: In a matched case-control study of the VA health care system, we found that screening patients with cirrhosis for HCC by USS, measurement of serum AFP, either test, or both tests was not associated with decreased HCC-related mortality. We encourage additional case-control studies to evaluate the efficacy of screening for HCC in other health care systems, in which available records are sufficiently detailed to enable identification of the indication for USS and AFP tests. PMID- 29981781 TI - Expression of CCR6 and CXCR6 by Gut-Derived CD4+/CD8alpha+ T-Regulatory Cells, Which Are Decreased in Blood Samples From Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: Faecalibacterium prausnitzii, a member of the Clostridium IV group of the Firmicutes phylum that is abundant in the intestinal microbiota, has anti-inflammatory effects. The relative level of F prausnitzii is decreased in fecal samples from patients with inflammatory bowel diseases (IBDs) compared with healthy individuals. Reduced F prausnitzii was correlated with relapse of Crohn's disease after surgery. We identified, in human colonic mucosa and blood, a population of T regulatory type 1-like T regulatory (TREG) cells that express CD4 and CD8alpha (DP8alpha T cells) and are specific for F prausnitzii. We aimed to determine whether they are altered in patients with IBD. METHODS: We isolated DP8alpha T cells from human colon lamina propria and blood samples and used flow cytometry to detect markers of cells that are of colon origin. We quantified DP8alpha cells that express colon-specific markers in blood samples from 106 patients with IBD, 12 patients with infectious colitis, and 35 healthy donors (controls). We identified cells that respond to F prausnitzii. Cells were stimulated with anti-CD3, and their production of interleukin 10 was measured by enzyme-linked immunosorbent assay. We compared the frequency and reactivity of cells from patients vs controls using the 2-sided Student t test or 1-way analysis of variance. RESULTS: Circulating DP8alpha T cells that proliferate in response to F prausnitzii express the C-C motif chemokine receptor 6 (CCR6) and C X-C motif chemokine receptor 6 (CXCR6). These cells also have features of TREG cells, including production of IL-10 and inhibition of T-cell proliferation via CD39 activity. The proportion of circulating CCR6+/CXCR6+ DP8alpha T cells was significantly reduced (P < .0001) within the total population of CD3+ T cells from patients with IBD compared with patients with infectious colitis or controls. A threshold of <7.875 CCR6+/CXCR6+ DP8alpha T cells/10,000 CD3+ cells discriminated patients with IBD from those with infectious colitis with 100% specificity and 72.2% sensitivity. CONCLUSIONS: We identified a population of gut derived TREG cells that are reduced in blood samples from patients with IBD compared with patients with infectious colitis or controls. These cells should be studied further to determine the mechanisms of this reduction and how it might contribute to the pathogenesis of IBD and their prognostic or diagnostic value. PMID- 29981783 TI - Contrasting dynamics of memory consolidation for novel word forms and meanings revealed by behavioral and neurophysiological markers. AB - Learning novel words is a challenging process for our memory systems; we must be able to recall new word forms and meanings in order to communicate. However, the dynamics of the word memory formation is still unclear. Here, we addressed the temporal profile of two key cognitive markers of memory consolidation in the domain of word learning: i) the susceptibility of recently learned novel words to memory interference; ii) their lexical integration using a semantic judgment task while recording the ERPs responses. Young adults acquired a set of novel picture label-meaning associations. In a first experiment, we performed a temporal gradient of retroactive interference (5 min, 30 min, 4 h and 24 h) and evaluated the memory retention 48 h after learning. In a second experiment, we studied the dynamics of the integration of these novel words, by measuring their N400 modulation when preceded by semantically related words, at 30 min or 48 h after learning. Our results showed that the word-form memory was affected by the interference treatment when it was presented 5 min after learning, but not at later times. On the other hand, only 48 h after learning it was possible to observe a neurophysiological index of semantic-priming (reduced N400 response). These results point to the existence of two contrasting processes that help to build the memory for word forms and meanings. A rapid mechanism would enable word learning while mitigating forgetting, while a slow consolidation would allow the novel meanings to be integrated into previous semantic networks. PMID- 29981785 TI - Modulation of brain response to peer rejection by rejection sensitivity: An exploratory study. AB - A number of studies have explored how rejection sensitivity (RS) affects the neural and physiological responses to stimuli with implicit rejection clues. Peer rejection during social interaction conveys explicit rejection feedback. The current event-related potentials (ERP) study using Chatroom task aimed to test to what extent RS modulated individuals' psychological and neural response to explicit rejection feedback. The subjective ratings mainly demonstrated that RS modulated ostracism distress and negative mood following rejection feedback. The ERP results showed that compared with low RS individuals, both the parietal P3 and left frontal LPP responses towards rejection feedback were enhanced in high RS individuals, indicating that high RS individuals exhibit attentional bias, intense anger experience and lower emotion regulation towards rejection suggested by their neural responses. The current study provides a new insight into neural correlates of RS in the high ecological experimental context. PMID- 29981786 TI - Diosgenin induces genotoxic and mutagenic effects on HepG2 cells. AB - Yam roots and other plants from Dioscorea genus have cultural, nutritional and economic importance to tropical and subtropical regions and have a great amount of diosgenin in its composition. In the present study the cytotoxic, genotoxic and mutagenic potential of diosgenin on HepG2 cells was investigated. Cytotoxicity was assessed using MTT and clonogenic assay. Genotoxic and mutagenic effects were performed using single cell gel electrophoresis and cytokinesis block micronucleus assay, respectively. A reduction on cell viability was observed due to diosgenin treatment at concentrations higher than 30 MUM. A genotoxic effect was shown by comet assay and CBMN. Besides, an increase in micronucleus frequency along with a significant cytostatic effect were observed. Diosgenin elicited DNA damage on HepG2 cells which could not be efficiently repaired contributing to the mutagenic effect observed. Those results suggest that diosgenin deleterious effect could take place through genetic instability, fact that affects the normal cell cycle, leading to cell's death. PMID- 29981784 TI - The relationship between co-speech gesture production and macrolinguistic discourse abilities in people with focal brain injury. AB - Brain damage is associated with linguistic deficits and might alter co-speech gesture production. Gesture production after focal brain injury has been mainly investigated with respect to intrasentential rather than discourse-level linguistic processing. In this study, we examined 1) spontaneous gesture production patterns of people with left hemisphere damage (LHD) or right hemisphere damage (RHD) in a narrative setting, 2) the neural structures associated with deviations in spontaneous gesture production in these groups, and 3) the relationship between spontaneous gesture production and discourse level linguistic processes (narrative complexity and evaluation competence). Individuals with LHD or RHD (17 people in each group) and neurotypical controls (n = 13) narrated a story from a picture book. Results showed that increase in gesture production for LHD individuals was associated with less complex narratives and lesions of individuals who produced more gestures than neurotypical individuals overlapped in frontal-temporal structures and basal ganglia. Co-speech gesture production of RHD individuals positively correlated with their evaluation competence in narrative. Lesions of RHD individuals who produced more gestures overlapped in the superior temporal gyrus and the inferior parietal lobule. Overall, LHD individuals produced more gestures than neurotypical individuals. The groups did not differ in their use of different gesture forms except that LHD individuals produced more deictic gestures per utterance than RHD individuals and controls. Our findings are consistent with the hypothesis that co-speech gesture production interacts with macro-linguistic levels of discourse and this interaction is affected by the hemispheric lateralization of discourse abilities. PMID- 29981787 TI - Are wild and cultivated flowers served in restaurants or sold by local producers in Denmark safe for the consumer? AB - New Nordic Food has within the last decade received much media coverage with chefs of top restaurants using wild plants for foods. As part of a control campaign, the Danish Veterinary and Food Administration visited 150 restaurants and local food producers from May-October 2016 and investigated their use of plants picked from the wild, cultivated in private gardens or market gardens. Among the species used were the flowers from 23 plants. Here we present a safety evaluation of these flowers based on published phytochemical investigations and toxicological data in humans, farm animals, pets, or experimental animals. Of the 23 flowers reviewed, nine contained compounds with toxic or potentially toxic effects if eaten, two contained unidentified toxic compound(s), and four were flowers from plants with potentially toxic compounds present in other plant parts or related species. Many of the flowers may be considered novel, since a use to a significant degree in Europe prior to 15 May 1997 before Regulation (EC) 258/97 on novel food and novel food ingredients came into force could not be established. In conclusion, this review illuminates a striking lack of chemical and toxicological data of many of the proposed wild or cultivated flowers for food use. PMID- 29981788 TI - Bioaccessibility and decomposition of cylindrospermopsin in vegetables matrices after the application of an in vitro digestion model. AB - Research on the human exposure to Cylindrospermopsin (CYN) via consumption of contaminated food is of great interest for risk assessment purposes. The aim of this work is to evaluate for the first time the CYN bioaccessibility in contaminated vegetables (uncooked lettuce and spinach, and boiled spinach) after an in vitro digestion model, including the salivar, gastric and duodenal phases and, colonic fermentation under lactic acid bacteria. The results obtained showed that the digestion processes are able to diminish CYN levels, mainly in the colonic phase, especially in combination with the boiling treatment, decreasing CYN levels in a significant way. Moreover, the potential decomposition products in a pure CYN solution and in CYN-contaminated vegetables were evaluated using UHPLC-MS/MS Orbitrap. Under the conditions assayed, only two diastereoisomers of the same fragment with m/z 292.09617 have been detected in all the analysed samples, with the exception of digested vegetables. Therefore, in terms of risk assessment, the digestion seems to play an important role in reducing the final bioaccesibility of CYN, and the consumption of cooked vegetables (spinach) would be safer in comparison to raw vegetables. PMID- 29981790 TI - Multi-level prevention of human trafficking: The role of health care professionals. AB - As a major public health issue, human trafficking (HT) affects individuals, families, communities, and societies around the world. A public health approach to combating HT has been advocated. Such an approach seeks to prevent HT by engaging diverse stakeholder groups in addressing risk factors at multiple levels. As a key stakeholder group, health care professionals (HCPs) play a critical role in HT prevention. Herein, we use the Centers for Disease Control (CDC) Social-Ecological Model as a framework to present potential HT prevention strategies for health care professionals. As clinicians, HCPs may deliver tailored interventions to patients and families to address individual- and relationship-level risk factors for HT in the health care setting. As educators, advocates, and researchers, HCPs may collaborate across sectors to implement community- and society-level prevention strategies. Such strategies may include enhancing awareness of HT through education; advocating for local and national policies that promote community health and wellness; combating social or cultural norms that contribute to HT; and building a strong evidence-base to guide future HT prevention programs. Guided by the CDC Social-Ecological Model, we recommend that HCPs use their diverse skills to target risk factors for HT at multiple levels and thereby expand their impact in preventing this form of exploitation. PMID- 29981791 TI - How confident can we be in the current guidelines for exiting cervical screening? AB - Current US guidelines recommend against cervical screening beyond age 65 in women who have had adequate negative screening. In anticipation of the next round of evidence review and guideline updates, we provide a critical review of the evidence supporting the exiting recommendation in the US, highlighting both practice changes and new insights into the epidemiology and natural history of HPV and cervical cancer. Current recommendations are based, by necessity, on cytology alone, and will be limited in generalizability to evolving screening strategies with co-testing and primary HPV testing. The lack of empirical data to define what constitutes 'adequate recent screening with negative results' is compounded by difficulties in predicting future risk without consideration of concepts of HPV latency and cohort effects of changing sexual behaviour in US women over time. We urge caution in extrapolating past risk experience in post menopausal women to today's population, and suggest study designs to strengthen the evidence base in well-screened older women. We further recommend building the qualitative evidence base to better define the harms and benefits of screening among older women. Extending the lifetime of screening is a matter of finding the appropriate balance of benefits of cancer reduction and limitation of harms and costs of 'overscreening'. This will require moving beyond current emphasis on number of colposcopies as the metric of harm. Our commentary is meant to stimulate intellectual debate regarding the certainty of our existing knowledge base and set clear research priorities for the future. PMID- 29981789 TI - Protective effects of (-)-epicatechin and the colonic metabolite 3,4 dihydroxyphenylacetic acid against glucotoxicity-induced insulin signalling blockade and altered glucose uptake and production in renal tubular NRK-52E cells. AB - Glucotoxicity (high levels of glucose) is a major cause in the pathogenesis of diabetes. Evidences indicate that (-)-epicatechin (EC) and colonic metabolites derived from flavonoid intake could possess antidiabetic effects, but the mechanisms for their preventive activities related to glucose homeostasis and insulin signalling in the kidney remain largely unknown. This work is aimed to investigate the effect of EC and main colonic phenolic acids derived from flavonoid intake, i.e. 2,3-dihydroxybenzoic-acid, 3,4-dihydroxyphenylacetic-acid (DHPAA) and 3-hydroxyphenylpropionic-acid, on insulin signalling, and glucose production and uptake in renal tubular proximal NRK-52E cells treated with high glucose. Pre-treatment with EC or DHPAA prevented the decreased tyrosine phosphorylated and total levels of IR caused by high glucose. EC and DHPAA pre treatment also avoided the inactivation of the PI3K/AKT pathway and AMPK, and the elevation of PEPCK levels induced by high glucose. Additionally, EC and DHPAA pre treatment alleviated the altered glucose uptake and production caused by high glucose, although this protective effect was abrogated when AKT and AMPK were inhibited. These results suggest EC and DHPAA prevent or delay a potential dysfunction of NRK-52E cells treated with high glucose through the attenuation of the insulin signalling blockade and the modulation of glucose homeostasis via AKT and AMPK. PMID- 29981792 TI - Violence against women increases cancer diagnoses: Results from a meta-analytic review. AB - The purpose of this project was to assess the magnitude of the relationship between violence against women and cancer; to identify the exposures and cancers for which this relationship was particularly robust; to identify the effect of violence exposure on cancer screening. We conducted a meta-analysis of 36 studies to determine the relationship between violence against women and cancer outcomes, including screening, in 2017. Results from this review provide evidence of a significant, positive relationship between violence and cancer diagnoses, particularly for cervical cancer. Women who were victims of intimate partner violence and sexual abuse were more likely to be diagnosed with cancer compared with non-victims. Violence against women did not appear to be related to cancer screening practices and routine clinical service utilization; however, violence was associated with greater odds of abnormal pap test results. Victims of intimate partner violence and women who suffered physical abuse were more likely to have abnormal pap test results. In conclusion, use of screening tools for violence against women in clinical settings may improve the breadth and quality of research on violence against women and cancer. Investigators should consider how to creatively apply case-control and retrospective cohort designs to investigate the complex mechanisms and moderators of the relationship between violence against women and cancer. PMID- 29981794 TI - Repurposed FDA-Approved drug sorafenib reduces replication of Venezuelan equine encephalitis virus and other alphaviruses. AB - The New World alphaviruses -Venezuelan, eastern, and western equine encephalitis viruses (VEEV, EEEV, and WEEV respectively) - cause a febrile disease that is often lethal in equines and children and leads to long-term neurological sequelae in survivors. Endemic to the Americas, epizootic outbreaks of the three viruses occur sporadically in the continental United States. All three viruses aerosolize readily, replicate to high titers in cell culture, and have low infectious doses. Additionally, there are no FDA-approved vaccines or therapeutics for human use. To address the therapeutic gap, a high throughput assay utilizing a luciferase reporter virus, TC83-luc, was performed to screen a library of commercially available, FDA-approved drugs for antiviral activity. From a group of twenty compounds found to significantly decrease luminescence, the carcinoma therapeutic sorafenib inhibited replication of VEEV-TC83 and TrD in vitro. Additionally, sorafenib inhibited replication of EEEV and two Old World alphaviruses, Sindbis virus and chikungunya virus, at 8 and 16 h post-infection. Sorafenib caused no toxicity in Vero cells, and coupled with a low EC50 value, yielded a selectivity index of >19. Mechanism of actions studies suggest that sorafenib inhibited viral translation through dephosphorylation of several key proteins, including eIF4E and p70S6K, leading to a reduction in viral protein production and overall viral replication. PMID- 29981793 TI - Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors and status of novel antivirals, 2016-2017. AB - A total of 13672 viruses, collected by World Health Organization recognised National Influenza Centres between May 2016 and May 2017, were assessed for neuraminidase inhibitor susceptibility by four WHO Collaborating Centres for Reference and Research on Influenza and one WHO Collaborating Centre for the Surveillance Epidemiology and Control of Influenza. The 50% inhibitory concentration (IC50) was determined for oseltamivir and zanamivir for all viruses, and for peramivir and laninamivir in a subset (n = 8457). Of the viruses tested, 94% were obtained from the Western Pacific, Americas and European WHO regions, while limited viruses were available from the Eastern Mediterranean, African and South East Asian regions. Reduced inhibition (RI) by one or more neuraminidase inhibitor was exhibited by 0.2% of viruses tested (n = 32). The frequency of viruses with RI has remained low since this global analysis began (2015/16: 0.8%, 2014/15: 0.5%; 2013/14: 1.9%; 2012/13: 0.6%) but 2016/17 has the lowest frequency observed to date. Analysis of 13581 neuraminidase sequences retrieved from public databases, of which 5243 sequences were from viruses not included in the phenotypic analyses, identified 58 further viruses (29 without phenotypic analyses) with amino acid substitutions associated with RI by at least one neuraminidase inhibitor. Bringing the total proportion to 0.5% (90/18915). This 2016/17 analysis demonstrates that neuraminidase inhibitors remain suitable for treatment and prophylaxis of influenza virus infections, but continued monitoring is important. An expansion of surveillance testing is paramount since several novel influenza antivirals are in late stage clinical trials with some resistance already having been identified. PMID- 29981795 TI - Aldehyde dehydrogenase 2 activation ameliorates cyclophosphamide-induced acute cardiotoxicity via detoxification of toxic aldehydes and suppression of cardiac cell death. AB - Cyclophosphamide (CY)-induced acute cardiotoxicity is a common side effect which is dose dependent. It is reported that up to 20% of patients received high dose of CY treatment suffered from acute cardiac dysfunction. However, the effective intervention strategies and related mechanisms are still largely unknown. We aimed to investigate the effects of aldehyde dehydrogenase 2 (ALDH2), an important endogenous cardioprotective enzyme, on CY-induced acute cardiotoxicity and the underlying mechanisms. It was found that ALDH2 knockout (KO) mice were more sensitive to CY-induced acute cardiotoxicity, presenting as higher serum levels of creatine kinase-MB isoform and lactate dehydrogenase, and significantly reduced myocardial contractility compared with C57BL/6 (WT) mice. In addition, cardiac cell death, especially necrosis, was obviously increased in ALDH2 KO mice compared with WT mice after CY treatment. Furthermore, accumulation of toxic aldehydes such as acrolein and 4-HNE and reactive oxygen species (ROS) in the myocardium were significantly elevated after CY in ALDH2 KO mice. Importantly, ALDH2 activation by Alda-1 pretreatment markedly attenuated CY-induced accumulation of toxic aldehydes, cardiac cell death and cardiac dysfunction, without affecting CY's anti-tumor efficacy. In conclusion, the cardioprotective effects of ALDH2 activation against CY-induced acute cardiotoxicity are exerted via reducing toxic aldehydes accumulation and potentially interrupting the acrolein-ROS-aldehydes vicious circles, and thus alleviates myocardial cell death, without antagonizing the anti-tumor efficacy of CY. Therefore, ALDH2 might be a promising prevention and treatment target for CY-induced acute cardiotoxicity. PMID- 29981796 TI - TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. AB - Persistent inflammation promotes development and progression of heart failure (HF). TWEAK (TNF-Related WEAK Inducer Of Apoptosis), a NF-kappaB- and/or AP-1 responsive proinflammatory cytokine that signals via TWEAK receptor (TWEAKR), is expressed at high levels in human and preclinical models of HF. Since the adapter molecule TRAF3IP2 (TRAF3 Interacting Protein 2) is an upstream regulator of various proinflammatory pathways, including those activated by NF-kappaB and AP 1, we hypothesized that targeting TRAF3IP2 inhibits TWEAK-induced proinflammatory and pro-fibrotic responses in vitro and in vivo. Consistent with the hypothesis, forced expression of TRAF3IP2 upregulated TWEAK and its receptor expression in cultured adult mouse cardiac fibroblasts (CF). Further, exogenous TWEAK upregulated TRAF3IP2 expression in a time- and dose-dependent manner, suggesting a positive-feedback regulation of TRAF3IP2 and TWEAK. TWEAK also promoted TRAF3IP2 nuclear translocation. Confirming its critical role in TWEAK signaling, silencing TRAF3IP2 inhibited TWEAK autoregulation, TWEAKR upregulation, p38 MAPK, NF-kappaB and AP-1 activation, inflammatory cytokine expression, MMP and TIMP1 activation, collagen expression and secretion, and importantly, proliferation and migration. Recapitulating these in vitro results, continuous infusion of TWEAK for 7 days increased systolic blood pressure (SBP), upregulated TRAF3IP2 expression, activated p38 MAPK, NF-kappaB and AP-1, induced the expression of multiple proinflammatory and pro-fibrotic mediators, and interstitial fibrosis in hearts of wild type mice. These proinflammatory and pro-fibrotic changes occurred in conjunction with myocardial hypertrophy and contractile dysfunction. Importantly, genetic ablation of TRAF3IP2 inhibited these TWEAK-induced adverse cardiac changes independent of increases in SBP, indicating that TRAF3IP2 plays a causal role, and thus a therapeutic target, in chronic inflammatory and fibro proliferative diseases. PMID- 29981797 TI - Mineralocorticoid receptor antagonism improves diastolic dysfunction in chronic kidney disease in mice. AB - Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD. PMID- 29981799 TI - Aptamers: Uptake mechanisms and intracellular applications. AB - The structural flexibility and small size of aptamers enable precise recognition of cellular elements for imaging and therapeutic applications. The process by which aptamers are taken into cells depends on their targets but is typically clathrin-mediated endocytosis or macropinocytosis. After internalization, most aptamers are transported to endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and occasionally mitochondria and autophagosomes. Intracellular aptamers, or "intramers," have versatile functions ranging from intracellular RNA imaging, gene regulation, and therapeutics to allosteric modulation, which we discuss in this review. Immune responses to therapeutic aptamers and the effects of G-quadruplex structure on aptamer function are also discussed. PMID- 29981798 TI - Etiology-dependent impairment of relaxation kinetics in right ventricular end stage failing human myocardium. AB - BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the beta-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction. PMID- 29981800 TI - Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. AB - Cutaneous wound healing in adult mammals is a complex multi-step process involving overlapping stages of blood clot formation, inflammation, re epithelialization, granulation tissue formation, neovascularization, and remodelling. Re-epithelialization describes the resurfacing of a wound with new epithelium. The cellular and molecular processes involved in the initiation, maintenance, and completion of epithelialization are essential for successful wound closure. A variety of modulators are involved, including growth factors, cytokines, matrix metalloproteinases, cellular receptors, and extracellular matrix components. Here, we focus on cellular mechanisms underlying keratinocyte migration and proliferation during epidermal closure. Inability to re epithelialize is a clear indicator of chronic non-healing wounds, which fail to proceed through the normal phases of wound healing in an orderly and timely manner. This review summarizes the current knowledge regarding the management and treatment of acute and chronic wounds, with a focus on re-epithelialization, offering some insights into novel future therapies. PMID- 29981801 TI - Bacteriophage T4 nanoparticles for vaccine delivery against infectious diseases. AB - Subunit vaccines containing one or more target antigens from pathogenic organisms represent safer alternatives to whole pathogen vaccines. However, the antigens by themselves are not sufficiently immunogenic and require additives known as adjuvants to enhance immunogenicity and protective efficacy. Assembly of the antigens into virus-like nanoparticles (VLPs) is a better approach as it allows presentation of the epitopes in a more native context. The repetitive, symmetrical, and high density display of antigens on the VLPs mimic pathogen associated molecular patterns seen on bacteria and viruses. The antigens, thus, might be better presented to stimulate host's innate as well as adaptive immune systems thereby eliciting both humoral and cellular immune responses. Bacteriophages such as phage T4 provide excellent platforms to generate the nanoparticle vaccines. The T4 capsid containing two non-essential outer proteins Soc and Hoc allow high density array of antigen epitopes in the form of peptides, domains, full-length proteins, or even multi-subunit complexes. Co-delivery of DNAs, targeting molecules, and/or molecular adjuvants provides additional advantages. Recent studies demonstrate that the phage T4 VLPs are highly immunogenic, do not need an adjuvant, and provide complete protection against bacterial and viral pathogens. Thus, phage T4 could potentially be developed as a "universal" VLP platform to design future multivalent vaccines against complex and emerging pathogens. PMID- 29981803 TI - Personality and meat consumption: The importance of differentiating between type of meat. AB - Recent research has shown that sociodemographic factors and the Big Five personality traits are related to people's overall level of meat consumption. However, there are important differences among various types of meat (e.g., red meat, poultry, and fish) that might lead to differential patterns in how the consumption of specific types of meat is associated with personality and sociodemographic factors. To disentangle these general and specific relationships, we conducted two studies using two large-scale representative samples from different countries: Germany (N = 13,062) and Australia (N = 15,036). Mostly consistent with our expectations, personality and sociodemographic variables showed specific associations with meat consumption, depending on type of meat. For example, in both studies, openness was negatively associated with red meat consumption but positively related to fish consumption, whereas it was unrelated to poultry consumption and overall meat consumption in hierarchical regression analyses in which we controlled for sociodemographic factors. By contrast, extraverted people reported both more consumption of each individual type of meat and more overall meat consumption. In sum, results were largely consistent between the samples, but effect sizes were generally small. Taken together, these two studies underscore the importance of differentiating between meat types when examining individual differences in meat consumption. Implications and future avenues for investigating the link between personality and dietary habits are discussed. PMID- 29981802 TI - Longitudinal factor analysis of the Comprehensive Feeding Practices Questionnaire among parents of preschool-aged children. AB - INTRODUCTION: The Comprehensive Feeding Practices Questionnaire (CFPQ) assesses 12 specific parent feeding practices (Musher-Eizenman & Holub, 2007). However, the original 12-factor structure may not be consistent across age groups, and no studies have yet evaluated the factor structure of the CFPQ over time. Therefore, the aim of the current study is to evaluate the model fit of the original and alternative CFPQ factor structures at two time points in early childhood. METHOD: Mothers (n = 260) of preschoolers completed validated surveys assessing parent feeding practices and child eating behaviors when children were on average 37 months of age at Time 1 (T1), and 57 months of age at Time 2 (T2). Confirmatory Factor Analysis (CFA) and Exploratory Factor Analysis (EFA) procedures were used to evaluate the original CFPQ factor structure, and to identify and evaluate modified factor structures at both time points. RESULTS: The original 12-factor CFPQ model did not adequately fit the data at T1 or T2. EFA identified a 7-factor model at T1, and a 5-factor model at T2. Bivariate correlations provided preliminary evidence for the validity of the modified scales. DISCUSSION: Overall, these findings suggest that parent feeding measures should the developmental significance of specific feeding practices, and/or that parents' reliance on certain feeding practices may shift as children age. Thus, a developmental framework to conceptualize how feeding changes during early childhood is sorely needed. PMID- 29981804 TI - The effect of attentional bias modification on eating behavior among women craving high-calorie food. AB - In individuals with healthy weight and overweight, the level of food cravings experienced is closely related to the individual's attentional bias to food cues. Furthermore, an attentional bias toward food cues, especially high-calorie food cues, is often accompanied by poor eating habits, overweight or obesity, eating disorders, and other problems. Therefore, this study aimed to explore the effect of attentional bias modification on the eating behavior of women craving high calorie food. Sixty-five female college students with a high level of craving for high-calorie foods were randomly assigned to a training group (attended to images of low-calorie food) and a control group (attended equally to images of high- and low-calorie food). An attentional re-training paradigm was used in the training session to modify the participants' attentional bias to these food cues. Compared to the control group, attentional bias to high-calorie food cues in the training group was significantly reduced after training (p < 0.05). The training group consumed less high-calorie food and more low-calorie food than the control group (p < 0.05) in a post-training taste test. However, there was no significant difference between the groups in their level of food cravings (p > 0.05). These findings suggest that attentional bias modification training is a promising brief intervention to improve eating behavior and develop healthy eating habits. PMID- 29981806 TI - Treating insect bite hypersensitivity in horses by using active vaccination against IL-5. PMID- 29981805 TI - Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series. PMID- 29981807 TI - Urinary PGDM, a prostaglandin D2 metabolite, is a novel biomarker for objectively detecting allergic reactions of food allergy. PMID- 29981808 TI - An integrated model of alopecia areata biomarkers highlights both TH1 and TH2 upregulation. PMID- 29981809 TI - Deficiency of parkin suppresses melanoma tumor development and metastasis through inhibition of MFN2 ubiquitination. AB - Parkin, a critical gene of Parkinson's disease, is involved in the development of numerous cancers. However, the effect of parkin deficiency on melanoma growth and metastasis has not been reported. We showed that the tumor size and number of surface lung metastases, and expression of tumor growth and metastasis marker proteins were significantly lower in parkin-KO mice than those observed in non transgenic controls. In an in vitro study, we also showed that parkin siRNA inhibited cell growth and migration of B16F10 and SK-Mel-28 cells. Parkin specific ubiquitination of mitofusin-2 (MFN2) was decreased in tumors and metastasized lung tissues of parkin-KO mice. Moreover, we showed that parkin directly binds and ubiquitinates MFN2. Knockdown of MFN2 decreased the expression of Bax and apoptotic cell death, but increased that of Bcl2 and apoptotic cancer cell death. However, these effects were reversed by knockdown of parkin. Conversely, inhibitory effects on melanoma growth and migration of parkin siRNA were reversed by MFN2 siRNA. These data indicate that melanoma development was inhibited in parkin-KO mice through maintaining of MFN2 level by inhibition of ubiquitinating ability of parkin. PMID- 29981810 TI - The dual role of mast cells in tumor fate. AB - The exact role of mast cells in tumor growth is not clear and multifaceted. In some cases, mast cells stimulate while in others inhibit this process. This dual role may be explained to some extent by the huge number of bioactive molecules stored in mast cell granules, as well as differences between tumor microenvironment, tumor type, and tumor phase of development. PMID- 29981811 TI - Prolactin signaling drives tumorigenesis in human high grade serous ovarian cancer cells and in a spontaneous fallopian tube derived model. AB - The pathways responsible for tumorigenesis of high grade serous ovarian cancer (HGSOC) from the fallopian tube epithelium (FTE) are still poorly understood. A human prolactin (PRL) like gene, Prl2c2 was amplified >100 fold in a spontaneous model of FTE-derived ovarian cancer (MOEhigh - murine oviductal epithelium high passage). Prl2c2 stable knockdown in MOEhigh cells demonstrated a significant reduction in cell proliferation, 2-dimensional foci, anchorage independent growth, and blocked tumor formation. The overall survival of ovarian cancer patients from transcriptome analysis of 1868 samples was lower when abundant PRL and prolactin receptors (PRL-R) were expressed. A HGSOC cell line (OVCAR3) and a tumorigenic human FTE cell line (FT33-Tag-Myc) were treated with recombinant PRL and a significant increase in cellular proliferation was detected. A CRISPR/Cas9 mediated PRL-R deletion in OVCAR3 and FT33-Tag-Myc cells demonstrated significant reduction in cell proliferation and eliminated tumor growth using the OVCAR3 model. PRL was found to phosphorylate STAT5, m-TOR and ERK in ovarian cancer cells. This study identified Prl2c2 as a driver of tumorigenesis in a spontaneous model and confirmed that prolactin signaling supports tumorigenesis in high grade serous ovarian cancer. PMID- 29981812 TI - Advances in oncolytic adenovirus therapy for pancreatic cancer. AB - Survival rates for pancreatic cancer patients have remained unchanged for the last four decades. The most aggressive, and most common, type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which has the lowest 5-year survival rate of all cancers globally. The poor prognosis is typically due to late presentation of often non-specific symptoms and rapid development of resistance to all current therapeutics, including the standard-of-care cytotoxic drug gemcitabine. While early surgical intervention can significantly prolong patient survival, there are few treatment options for late-stage non-resectable metastatic disease, resulting in mostly palliative care. In addition, a defining feature of pancreatic cancer is the immunosuppressive and impenetrable desmoplastic stroma that blocks access to tumour cells by therapeutic drugs. The limited effectiveness of conventional chemotherapeutics reveals an urgent need to develop novel therapies with different mechanisms of action for this malignancy. An emerging alternative to current therapeutics is oncolytic adenoviruses; these engineered biological agents have proven efficacy and tumour-selectivity in preclinical pancreatic cancer models, including models of drug-resistant cancer. Safety of oncolytic adenoviral mutants has been extensively assessed in clinical trials with only limited toxicity to normal healthy tissue being reported. Promising efficacy in combination with gemcitabine was demonstrated in preclinical and clinical studies. A recent surge in novel adenoviral mutants entering clinical trials for pancreatic cancer indicates improved efficacy through activation of the host anti-tumour responses. The potential for adenoviruses to synergise with chemotherapeutics, activate anti-tumour immune responses, and contribute to stromal dissemination render these mutants highly attractive candidates for improved patient outcomes. Currently, momentum is gathering towards the development of systemically-deliverable mutants that are able to overcome anti-viral host immune responses, erythrocyte binding and hepatic uptake, to promote elimination of primary and metastatic lesions. This review will cover the key components of pancreatic cancer oncogenesis; novel oncolytic adenoviruses; clinical trials; and the current progress in overcoming the challenges of systemic delivery. PMID- 29981813 TI - Severe haemolysis and spherocytosis in a dog envenomed by a red-bellied black snake (Pseudechis porphyriacus) and successful treatment with a bivalent whole equine IgG antivenom and blood transfusion. AB - This case report describes a dog envenomed by a red-bellied black snake (RBBS; Pseudechis porphriacus) that experienced severe and life-threatening haemolysis. The dog presented with hypersalivation, facial swelling, mildly prolonged activated clotting time and the absence of neurological deficits. Envenomation was confirmed by positive identification of the snake and retrospective measurement of RBBS specific venom antigen (24 ng/mL) in serum. The dog was initially hospitalised, treated with intravenous fluids and one vial of tiger brown snake antivenom which is recommended for RBBS envenomation in Australia. However, after 3.5 d the dog's PCV had declined to 15% and the dog was dull and tachycardic. A second vial of tiger-brown antivenom followed by a packed red blood cell transfusion was administered. A rapid clinical improvement within 12 h was observed. No free RBBS venom was detected in serum at any time point after the first vial of antivenom. Longitudinal haematology and biochemical profiling was performed to 62 d post-envenomation and revealed a gradual recovery in the haematocrit to normal reference range. Spherocyte numbers on blood smear were highest at 5 d post-envenomation and gradually declined to undetectable after 62 d. This case highlights the potential for unpredictable, severe and life threatening anaemia resulting from RBBS envenomation in dogs. PMID- 29981814 TI - Arizona Ridge-nosed rattlesnake envenomation: Case report of a personal encounter with the official state reptile of Arizona, Crotalus willardi willardi. AB - This case report describes the effects of an envenomation from one of the most infrequently encountered species of rattlesnake in the United States, Crotalus willardi willardi (C. w. willardi), the Arizona Ridge-nosed Rattlesnake. A previously healthy 57-year-old male sustained a bite to his non-dominant hand from a C. w. willardi. The most pronounced effect from the envenomation was edema and progression of edema that extended from his hand to the mid bicep. He also experienced erythema and tenderness to palpation in the affected limb, and some diminished range of motion in the hand. He expressed only minimal pain. Other than a mildly positive D-Dimer and leukocytosis, he had no significant hematologic effects and no systemic effects. He was treated with standard doses of Crotalidae Polyvalent Immune Fab (Ovine). He reported complete recovery from the envenomation within three days of the bite. Although envenomation from rattlesnakes is somewhat common in Arizona, knowing the exact species of snake is not. Confirmed documentation is exceedingly rare as most people do not recognize the different rattlesnake species. In addition, some species of rattlesnake (such as C. w. willardi) are especially reclusive and found only in isolated mountainous regions. Being able to confirm an envenomation by C. w. willardi would require not only someone knowledgeable in herpetology, but also, preferably, photographic evidence. This case has both. PMID- 29981815 TI - Developing recombinant phospholipase D1 (rPLD1) toxoid from Iranian Hemiscorpius lepturus scorpion and its protective effects in BALB/c mice. AB - Hemiscorpius lepturus (H. lepturus) is one of the most dangerous scorpions and the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation, including dermonecrosis, hematuria, renal failure and early death, are attributed to phospholipase D activity. This study was conducted to develop a novel recombinant phospholipase D1 (rPLD1) toxoid and investigate its immunogenicity and protective effects against the lethality of H. lepturus venom. The lethal protein recombinant phospholipase D1 was expressed from PLD H. lepturus venom gland. The rPLD1 toxin was converted into toxoid (the first toxoid of H. lepturus PLD) with a 0.25% concentration of formalin and stored for ten days at room temperature. In the toxicity test, the lethal activity of recombinant phospholipase D1 was fully inhibited. When it reached up to 3 times higher than the maximal effective concentration of the purified toxin (11.1 MUg), rPLD1 toxoid was used. The sphingomyelinase activity was inhibited when up to 5.4 times of the LD100 of the purified toxin (20 MUg), toxoid was used. It was then used to produce an antibody in BALB/c as an antigen and the mice were then challenged with rPLD1 toxin and the whole venom. The immunogenicity of rPLD1 toxoid was evaluated and the maximum titer of the raised antibodies was determined by ELISA assay. The optimum titer for anti-rPLD1 toxoid sera was obtained at the third intraperitoneal injection of rPLD1 toxoid, and a high titer was reached at the fourth injection in the mice. This toxoid increased the amount of antibodies and produced a protective antiserum against the whole venom of H. lepturus and rPLD1 toxin. The in-vivo test results showed that the mice were completely resistant against 200 times the LD100 of recombinant phospholipase D1 and the whole venom of H. lepturus. To conclude, rPLD1 can be used in toxoid form as an immunogen in the production of a new generation of neutralizing antibodies against the lethality and toxicity of H. lepturus whole venom. PMID- 29981816 TI - EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers. AB - Neuroendocrine/Aggressive Variant Prostate Cancers are lethal variants of the disease, with an aggressive clinical course and very short responses to conventional therapy. The age-adjusted incidence rate for this tumor sub-type has steadily increased over the past 20 years in the United States, with no reduction in the associated mortality rate. The molecular networks fueling its emergence and sustenance are still obscure; however, many factors have been associated with the onset and progression of neuroendocrine differentiation in clinically typical adenocarcinomas including loss of androgen-receptor expression and/or signaling, conventional therapy, and dysregulated cytokine function. "Tumor-plasticity" and the ability to dedifferentiate into alternate cell lineages are central to this process. Epithelial-to-mesenchymal (EMT) signaling pathways are major promoters of stem-cell properties in prostate tumor cells. In this review, we examine the contributions of EMT-induced cellular-plasticity and stem-cell signaling pathways to the progression of Neuroendocrine/Aggressive Variant Prostate Cancers in the light of potential therapeutic opportunities. PMID- 29981817 TI - Umbilical cord milking in preterm neonates requiring resuscitation: A randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of cord milking on short term morbidity and hematologic parameters at 6 weeks in preterm neonates requiring resuscitation. METHODS: This trial randomized preterm infants requiring resuscitation to milking group and no milking group. Multiple pregnancy, Rh negative mothers, hydrops, cord abnormalities were excluded. The primary outcome was hemoglobin and serum ferritin at 6 weeks of life. Secondary outcomes were common preterm morbidities and mortality. RESULTS: 60 neonates were included in the study. Infants in the milking group had higher hemoglobin (10.07 g/dl vs 8.9 g/dl; p 0.003) and higher serum ferritin level (244.8 ng/ml vs 148.5 ng/ml; p 0.04) compared to no milking group. CONCLUSIONS: In preterm neonates requiring resuscitation, umbilical cord milking results in higher hemoglobin and ferritin at 6 weeks of life. It can be a used as a placental transfusion strategy in preterm neonates requiring resuscitation with no significant adverse effects. CLINICAL TRIAL REGISTRATION: Clinical trials registry -India CTRI/2015/01/005436, www.ctri.nic.in. PMID- 29981818 TI - Persistence of cortical neuronal activity in the dying brain. PMID- 29981819 TI - Usefulness of early plasma S-100B protein and Neuron-Specific Enolase measurements to identify cerebrovascular etiology of out-of-hospital cardiac arrest. AB - BACKGROUND: While S-100B protein and Neuron-Specific Enolase (NSE) dosages have been extensively investigated for neurological prognostication after cardiac arrest (CA), there is no data about their ability to detect a cerebrovascular cause of CA. We assessed the utility of plasma S-100B protein and NSE measurements for early diagnosis of primary neurological cause in resuscitated CA patients. PATIENTS AND METHODS: Case control study based on two prospectively acquired CA databases. Patients with a primary cerebrovascular etiology were compared with randomly selected CA of non-neurological cause. S-100B protein and NSE were measured at ICU admission in all patients. RESULTS: CA was due to a cerebrovascular etiology in 18 patients (subarachnoid hemorrhage, n = 15; ischemic stroke, n = 3), with an ICU mortality of 100%. Comparative group was constituted with 66 patients (cardiac etiology n = 45, respiratory etiology n = 21), with an ICU mortality of 71%. Admission S-100B protein concentration was 2.0 [0.63-7.15] MUg/L in the cerebrovascular group and 0.45 [0.24-1.95] in the non cerebrovascular group (p < 0.001). In contrast, NSE concentration was similar in cerebrovascular and non-cerebrovascular etiologies (35 [25-103] MUg/L vs. 27 [19 47] respectively, p = 0.16). Area under ROC curves for S-100B protein and NSE to predict cerebrovascular cause of CA was 0.75 [95% CI: 0.64-0.87] and 0.61 [95% CI: 0.45-0.76], respectively. CONCLUSIONS: Even if S-100B protein dosage performs slightly better than NSE, early dosages of these biomarkers are poorly predictive of a cerebrovascular etiology of CA. Our results suggest that early measurement of brain biomarkers should not be recommended to tailor the imaging strategy employed to investigate the CA cause. PMID- 29981820 TI - Differential expression and molecular interactions of chromosome region maintenance 1 and calreticulin exportins in breast cancer cells. AB - Chromosome region maintenance 1 (CRM-1) and calreticulin (CALR) are two proteins that act as exportins for some nuclear receptors, in addition to other critical functions for cellular homeostasis. In several cancer types, CRM-1 and CALR are upregulated suggesting an imbalance in their functions. However, the regulation of CRM-1 and CALR, and their biological implications, are not completely known. Here, we evaluated the interplay between the levels of CRM-1 and CALR, and estrogen receptor alpha (ERalpha) status, in breast cancer cells. CRM-1 and CALR were upregulated in mammary tumors relative to normal mammary tissue. Furthermore, the mRNA and protein levels of CRM-1 and CALR were higher in breast cancer cells lacking ERalpha, in comparison with those that express ERalpha. Additionally, both proteins were distributed in the nucleus and cytoplasm in the two cell types. Importantly, we identified novel interactions for these exportins. First, we showed an interaction between CRM-1 and CALR, and then we identified that SUN1 and SUN2, two proteins localized in the nuclear envelop, were able to interact specifically with CRM-1, but not CALR. Interestingly, SUN1 and SUN2 expression seemed to be decreased in breast cancer, thereby affecting the interactions of these proteins with CRM-1, and possibly its actions as an exportin. Thus, our data suggest that expression levels for CRM-1 and CALR, the interaction between these exportins, and specific interactions of SUN1 and SUN2 with CRM-1 but not CALR, may be central elements in nucleo-cytoplasmic transport. Furthermore, deregulation of these elements may have serious implications in the progression of breast and other types of cancer. PMID- 29981821 TI - Controlled-release in-situ gel forming formulation of tramadol containing chitosan-based pro-nanogels. AB - Chronic pain is one of the most prevalent health problems worldwide. Tramadol is a synthetic semi-opioid analgesic, interacting with serotonergic, adrenergic and opioid receptors to reduce the pain but its short half-life in vivo may reduce patient compliance in case of chronic pains. To overcome this problem, novel drug delivery systems have been investigated. This study focuses on a chitosan based thermoresponsive in-situ gel forming formulation intended to subcutaneous injection. To evaluate further drug release, a reversed phase high performance liquid chromatography method was developed. Then two formulations (with and without TPP) were optimized by D-optimal plan using Design-Expert statistical software and were characterized in terms of morphology, release phenomenon, texture, swelling and stability as well as in vivo response. AFM images show approximately spherical nanocavities in the homogenous TPP containing gel structure, which explain the different patterns of drug release between the two formulations. This implies that changing TPP concentration can control formation of these cavities and hence drug release rate and kinetics. Not present in the sol state, nanostructures lead to emerge of a new concept: pro-nanogels. Finally, the formulations with proper texture qualities, stability and rapid sol-gel transition in vivo could be a candidate for controlled release of therapeutic agents following subcutaneous injection. PMID- 29981822 TI - Immobilization of xylanase and xylanase-beta-cyclodextrin complex in polyvinyl alcohol via electrospinning improves enzyme activity at a wide pH and temperature range. AB - Xylanase (EC 3.2.1.8) is a key enzyme for degradation of xylan. A limitation of xylanase application in food and beverage industries is the low enzyme activity and stability at a wide pH and temperature range. In the present study, different levels of pure xylanase (XY) and xylanase-beta-cyclodextrin (XY-beta-CD) inclusion complex were immobilized in polyvinyl alcohol (PVA) via electrospinning. Morphological and structural characteristics of obtained fibers were investigated by Fourier-transformed infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and X-ray diffraction (XRD) analyzes. Inclusion complex formation was evaluated by FTIR, XRD, and differential scanning calorimetry (DSC) analyzes. Obtained electrospun fibers showed a smooth surface with average diameter from around 200 to 600 nm. Greater diameters were observed at higher xylanase levels. In addition, inclusion complex provided thicker fibers than pure xylanase. Optimum xylanase activity changed from 60 to 70 degrees C when enzyme was immobilized in PVA. FTIR results suggest a more efficient enzyme conformation after immobilization. The greatest xylanase efficiency of immobilization was achieved at 0.5%-XY, with specific activity of 59.73 MUM/min/mg of immobilized xylanase. Xylanase immobilized in PVA fibers exhibited higher activity at extremer pH conditions (4, 5, 7, and 8), as compared to free xylanase. PMID- 29981823 TI - Molecular insight into multiple RpoB clinical mutants of Mycobacterium tuberculosis: An attempt to probe structural variations in rifampicin binding site underlying drug resistance. AB - Rifampicin (RMP) resistant strains are still persisting as a threat to the global TB control program. Therefore, understanding the RMP resistant mechanism is need of the hour. The current study has investigated the role of each RMP binding site (RBS) residues, deploying computational alanine scanning mutagenesis (CASM) to unravel the critical and non-critical binding site residues. In addition, conformational shifts in RBS cavity of different RNAP beta-subunit (RpoB) systems have also been analyzed. Our initial findings showed that in addition to reported mutational sites, Q510, Q513, R529, P564 and P566 were also critical binding site residues, which upon mutation destabilize the RMP binding. Study also indicated that R3, R4 and R5 regions of RpoB were very significant for the functioning of RMP. The concerted interactions of these regions with RMP hold it into the centre position of RBS and restrict the entrance of elongating RNA transcript. Whereas, after mutation, due to repositioning of RMP and changes in its interactions, the overall cavity becomes significantly hollow which may confer space for phosphodiester bond formation during transcription elongation. Our findings provide valuable details to forestall RMP resistance and may help in the development of new leads against the RMP resistant strains. PMID- 29981824 TI - Silver nanoparticle functionalized CS-g-(CA-MA-PZA) carrier for sustainable anti tuberculosis drug delivery. AB - Recently, drug functionalized biodegradable polymers have been appreciated to be imperative to fabricate multi-drug delivery nanosystems for sustainable drug release. In this work, amphiphilic chitosan-grafted-(cetyl alcohol-maleic anhydride-pyrazinamide) (CS-g-(CA-MA-PZA)) was synthesized by multi-step reactions. The incorporation of rifampicin (RF) and entrapment of silver nanoparticles (Ag NPs) on CS-g-(CA-MA-PZA) polymer was carried out by dialysis technique. From the FT-IR experiment, the polymer modification, incorporation of drugs and the entrapment of Ag NPs on micelles were confirmed. The surface morphology of Ag NPs, polymeric system and drug loaded micelles was described by SEM, TEM and AFM techniques. In addition, the controlled release behaviour of CS g-(CA-MA-PZA) micelles was studied by UV-Vis spectroscopy. In vitro cell viability, cell apoptosis and cellular uptake experiments shows that multi-drug delivery system could enhance the biocompatibility and higher the cytotoxicity effect on the cells. Since the prepared amphiphilic polymeric micelles exhibit spotty features and the system is a promising strategy for a novel candidate for immediate therapeutically effects for alveolar macrophages. PMID- 29981825 TI - In situ production of bacterial cellulose to economically improve recycled paper properties. AB - This study focusses on the in-situ production of bacterial cellulose in recycled pulps to increase the quality of fibers in the suspension. The effect of different dosages of the upgraded pulp on the mechanical, physical and optical properties of handsheets was assessed. Papers produced with pulps cultivated in agitation exhibited increments in both tensile and tear indexes of 12.2% and 14.2%, respectively. Thus, flexibility of the paper was also improved. On the other hand, pulps enhanced with static culture fail to improve tensile index of paper, while tear index was increased by 12.4%. The production mechanism for both types of culture was proposed. In agitated culture, bacteria were found to coat the primary fibers, improving their quality. In the case of static culture, heterogeneous systems were observed since recycled fibers tended to sediment while bacteria moved to the surface of the culture broth in search of oxygen. Hence, the in situ production of BC with recycled fibers can, therefore, be an alternative to replace conventional paper strengthening agents. The results attained indicate that the in-situ production of upgraded pulps can be implemented in paper mills cultivating pulp streams sterilized through low cost, non-exhaustive operations, such as ozone or ultraviolet radiation. PMID- 29981826 TI - Usage of GD-95 and GD-66 lipases as fusion partners leading to improved chimeric enzyme LipGD95-GD66. AB - Lipases are used as biocatalysts in industrial processes mainly because of their stability at broad temperature and pH range, resistance to organic solvents and wide spectrum of substrates. The usage of several lipolytic domains, each with different activity and resistance profiles, enables both the flexibility and efficiency of industrial processes. In this study, GD-95 and GD-66 lipases produced by Geobacillus sp. 95 and Geobacillus sp. 66, respectively, were used as fusion partners to create a new fused lipolytic enzyme LipGD95-GD66. Chimeric LipGD95-GD66 lipase displayed tenfold increase in activity (200 U/mg) compared to parental GD-66 lipase, improved Vmax (10 MUmol/min mg-1) and catalytic efficiency (2 * 105 min-1 mM-1) for p-NP palmitate as a substrate and increased activity at 70-75 degrees C compared to both parental lipases. All three lipases also retained >50% of their lipolytic activity after incubation with methanol, n hexane, ethanol and DMF for longer than three weeks, highlighting a great prospect for application in industrial processes. Moreover, transesterification results revealed the capability of parental GD-95 lipase to be the most promising biocatalyst for production of methyl and ethyl esters through eco-friendly transesterification using argan oil and ethanol/methanol as acceptors of acyl group. PMID- 29981827 TI - Carboxylic acids of different nature induces aggregation of hemoglobin. AB - Misfolded proteins that escape cellular quality control check lay the foundation for several progressively widespread neurodegenerative diseases, diabetes and others. Here, crotonic and citric acid are employed to study aggregation behaviour of hemoglobin (Hb). A systematic investigation on varying concentrations of acids from 0 to 60 mM on Hb gives an idea that transition is taking place in the vicinity of 10-30 mM. Hb showed increased intrinsic Trp fluorescence in the presence of both acids. A red shift of 10 nm in presence of citric acid contrary to a blue shift of 5 nm in presence of crotonic acid is observed. ANS and ThT fluorescence marked aggregation at 50 mM, supported by Congo red and Soret absorbance spectroscopy. CD, RLS and DLS studies also validate the findings. Molecular docking analysis exhibited the binding mode of Hb with acids. Aggregates were dense, beaded structure as visualised under TEM. Crotonic and citric acid at 20 and 30 mM, respectively, induced structural changes in Hb which transmutes to aggregate at higher concentration. These alterations remained almost constant and no significant changes were observed on increasing concentration further. Also, crotonic acid is more noxious, as it instigates conformational alterations at lower concentration than citric acid. PMID- 29981828 TI - Fabrication and characterisation of starch/chitosan/flax fabric green flame retardant composites. AB - The study reveals the fabrication of eco-friendly bio-composites by employing natural, widely available biopolymers such as starch, chitosan (CS) and flax fabric (FF). In a typical process, starch was used in the form of thermoplastic starch prepared via mechano ball milling and subsequently, composites were fabricated via compression with CS and FF. The nature of the composites was analysed using FTIR. Good compatibility and homogeneous dispersion of reinforcements was corroborated using FESEM (EDX). The influence of CS (3, 6, & 9 wt%) on the mechanical (UTM) and thermal (TGA) properties, biodegradability (soil burial test), and flammability (horizontal burning test (UL94), limited oxygen index (LOI)) of the composites was investigated. An improvement in tensile strength from 16.45 to 20.78 MPa, thermal stability 10 wt% @ 800 degrees C (N2 atmosphere) and flame retardancy showed remarkable withstandability (UL94 = Vo & LOI = 40) of the composites with flame and flame self-annihilate were speculated to arise from the dense char formed by the carbonaceous agent CS. A delay in biodegradation was observed for CS composites, indicating longer durability of the composites. PMID- 29981829 TI - Penetration monitoring of drugs and additives by ATR-FTIR spectroscopy/tape stripping and confocal Raman spectroscopy - A comparative study. AB - Vibrational spectroscopy is a useful tool for analysis of skin properties and to confirm the penetration of drugs and other formulation compounds into the skin. In particular, attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and confocal Raman spectroscopy (CRS) have been optimised for skin analysis. Despite an impressive amount of data on these techniques, a comparative methodological assessment for skin penetration monitoring of model substances is still amiss. Thus, in vitro skin penetration studies were conducted in parallel using the same porcine material and four model substances, namely sodium laureth sulfate (SLES), sodium dodecyl sulfate (SDS), sulfathiazole sodium (STZ) and dimethyl sulfoxide (DMSO). ATR-FTIR spectroscopy in combination with tape stripping and CRS were employed to evaluate the skin penetration of the applied substances. In addition, the skin hydration status or change in skin hydration after application was investigated. The results show that both methods provide valuable information on the skin penetration potential of applied substances. The penetration profiles determined by CRS or ATR-FTIR/tape stripping were comparable for all substances; a slow decrease in relative substance concentration was visible from the skin surface inwards within the stratum corneum (SC). In general, deeper penetration into the SC was observed with CRS, which may be related to the depth resolution of the employed device. However, when related to the respective total SC thickness of each experiment, the penetration depths determined by parallel CRS and ATR-FTIR analysis were in good agreement for all model substances. The observed order of the penetration depth was DMSO > SDS > SLES > STZ with both techniques. A decrease of the relative concentration to 10% of the maximum value was found approximately between 34 and 89% of total SC thickness. Summarising these findings, advantages and drawbacks of the two techniques for in vitro skin penetration studies are discussed. PMID- 29981830 TI - Hydrogen sulfide inhibits ATP-induced neuroinflammation and Abeta1-42 synthesis by suppressing the activation of STAT3 and cathepsin S. AB - Neuroinflammation and excessive beta-amyloid1-42 (Abeta1-42) generation contribute to the pathogenesis of Alzheimer's disease (AD). Emerging evidence has demonstrated that hydrogen sulfide (H2S), an endogenous gasotransmitter, produces therapeutic effects in AD; however, the underlying mechanisms remain largely elusive. In the present study, we investigated the effects of H2S on exogenous ATP-induced inflammation and Abeta1-42 production in both BV-2 and primary cultured microglial cells and analyzed the potential mechanism(s) mediating these effects. Our results showed that NaHS, an H2S donor, inhibited exogenous ATP stimulated inflammatory responses as manifested by the reduction of pro inflammatory cytokines, ROS and activation of nuclear factor-kappaB (NF-kappaB) pathway. Furthermore, NaHS also suppressed the enhanced production of Abeta1-42 induced by exogenous ATP, which is probably due to its inhibitory effect on exogenous ATP-boosted expression of amyloid precursor protein (APP) and activation of beta- and gamma-secretase enzymes. Thereafter, we found that exogenous ATP-induced inflammation and Abeta1-42 production requires the activation of signal transducer and activator of transcription 3 (STAT3) and cathepsin S (Cat S) as inhibition of the activity of either proteins attenuated the effect of exogenous ATP. Intriguingly, NaHS suppressed exogenous ATP-induced phosphorylation of STAT3 and the activation of Cat S. In addition, we observed that NaHS led to the persulfidation of Cat S at cysteine-25. Importantly, mutation of cysteine-25 into serine attenuated the activity of Cat S stimulated by exogenous ATP and subsequent inflammation and Abeta1-42 production, indicating its involvement in H2S-mediated effect. Taken together, our data provide a novel understanding of H2S-mediated effect on neuroinflammation and Abeta1-42 production by suppressing the activation of STAT3 and Cat S. PMID- 29981831 TI - Characterization of sickness behavior in zebrafish. AB - In a previous study we showed a clear relationship between immune system and behavior in zebrafish and we hypothesized that the immune system is capable of inducing behavioral changes. To further investigate this subject and to address our main question, here we induced an inflammatory response in one group of fish by the inoculation of formalin-inactivated Aeromonoas hydrophila bacterin and compared their social and exploratory behavior with control groups. After the behavioral tests, we also analyzed the expression of cytokines genes and markers of neuronal activity in fish brain. In the bacterin-inoculated fish, the locomotor activity, social preference and exploratory behavior towards a new object were reduced compared to the control fish while the expression of proinflammatory cytokines in the brain was upregulated. With this study we demonstrated for the first time that the immune system is capable of causing behavioral changes that are consistent with the sickness behavior observed in mammals. PMID- 29981832 TI - Global gene expression analysis identifies Mef2c as a potential player in Wnt16 mediated transcriptional regulation. AB - Wnt16 is a major Wnt ligand involved in the regulation of postnatal bone homeostasis. Previous studies have shown that Wnt16 promotes bone formation and inhibits bone resorption, suggesting that this molecule could be targeted for therapeutic interventions to treat bone thinning disorders such as osteoporosis. However, the molecular mechanisms by which Wnt16 regulates bone metabolism is not yet fully understood. To better understand the molecular mechanisms by which Wnt16 promotes bone formation and to identify the target genes regulated by Wnt16 in osteoblasts, we treated calvarial osteoblasts purified from C57Bl/6 mice with recombinant Wnt16 and profiled the gene expression changes by RNA-seq at 24 h post-treatment. We also compared gene expression profiles of Wnt16-treated osteoblasts to canonical Wnt3a- and non-canonical Wnt5a-treated osteoblasts. This study identified 576 genes differentially expressed in Wnt16-treated osteoblasts compared to sham-treated controls; these included several members of Wnt pathway (Wnt2b, Wnt7b, Wnt11, Axin2, Sfrp2, Sfrp4, Fzd5 etc.) and TGF-beta/BMP signaling pathway (Bmp7, Inhba, Inhbb, Tgfb2 etc.). Wnt16 also regulated a large number of genes with known bone phenotypes. We also found that about 37% (215/576) of the Wnt16 targets overlapped with Wnt3a targets and ~15% (86/576) overlapped with Wnt5a targets, suggesting that Wnt16 activates both canonical and non-canonical Wnt signaling targets in osteoblasts. Transcription factor binding motif enrichment analysis in the promoter regions of Wnt16 targets identified noncanonical Wnt/JNK pathway activated transcription factors Fosl2 and Fosl1 as two of the most significantly enriched transcription factors associated with genes activated by Wnt16 while Mef2c was the most significantly enriched transcription factor associated with genes repressed by Wnt16. We also found that a large number of Mef2c targets overlapped with genes down-regulated by Wnt16 and Mef2c itself was transcriptionally repressed by Wnt16 suggesting that Mef2c plays a role in Wnt16-mediated transcriptional regulation. PMID- 29981833 TI - Placental iron transport: The mechanism and regulatory circuits. AB - As the interface between the fetal and maternal circulation, the placenta facilitates both nutrient and waste exchange for the developing fetus. Iron is essential for healthy pregnancy, and transport of iron across the placenta is required for fetal growth and development. Perturbation of this transfer can lead to adverse pregnancy outcomes. Despite its importance, our understanding of how a large amount of iron is transported across placental membranes, how this process is regulated, and which iron transporter proteins function in different placental cells remains rudimentary. Mechanistic studies in mouse models, including placenta-specific deletion or overexpression of iron-related proteins will be essential to make progress. This review summarizes our current understanding about iron transport across the syncytiotrophoblast under physiological conditions and identifies areas for further investigation. PMID- 29981834 TI - Erythropoietic regulators of iron metabolism. AB - Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders. PMID- 29981835 TI - Knee thrust prevalence and normative hip-knee-ankle angle deviation values among healthy individuals across the lifespan. AB - OBJECTIVE: To report the prevalence of varus thrust and normative values for hip knee-ankle (HKA) angle deviation across the lifespan, and to explore associations between HKA angle deviation and selected clinical factors. DESIGN: This was a cross-sectional observational study of 572 participants from the 1000 Norms Project, aged 3-101 years and who self-reported as being healthy. Video recordings (2D) of frontal plane gait were reviewed by physiotherapists for presence of knee thrust and quantification of HKA angle deviation (the difference between HKA angle at initial contact and mid-stance). Age and sex-stratified normative HKA angle deviation values were presented as means and 95% confidence intervals (CIs). Correlations were calculated between HKA angle and clinical measures (age, sex, body mass index (BMI), alignment, knee and hip strength, Knee Injury and Osteoarthritis Outcomes Scores (KOOS), foot posture index, temporo spatial gait, and hypermobility). RESULTS: Overall, 31% of the cohort had varus thrust, most prevalent among adults older than 60 years (42%) and children aged 3 9 (41%). Varus thrust was common in adolescents (25%) and adults aged 20-59 (23%). Mean HKA angle deviation for the entire cohort was 1.2 degrees (95%CI: 1.07, 1.36) towards varus, and 2.1 degrees (95%CI: 1.84, 2.36) among people with clinical varus thrust. Weak associations were identified between HKA angle deviation and BMI, stride width, and KOOS-Sports among adolescents, and in adults weakly associated with height. CONCLUSIONS: Prevalence of varus thrust is common across the lifespan. Normative values established here can be readily used by clinicians and researchers in monitoring this gait deviation. PMID- 29981836 TI - Mechanisms of stress-related muscle atrophy in fish: An ex vivo approach. PMID- 29981837 TI - Konzo: a distinct neurological disease associated with food (cassava) cyanogenic poisoning. AB - Epidemics of neurodegenerative diseases putatively caused by food toxins have been reported in the tropics with no clear understanding of their pathogenetic mechanisms. These diseases include the disease named Konzo that has been well documented in sub-Sahara Africa, mostly among children and women of childbearing age. Outbreaks of Konzo have occurred in the Democratic Republic of Congo, Mozambique, Tanzania, Central African Republic, Angola, Cameroun, and most recently in Zambia. The main clinical picture consists of a symmetrical, permanent and irreversible spastic paraparesis (motor neuron disease) with no signs of sensory or genitourinary impairments. Recently, cognitive impairments and neurodevelopmental delays have been reported among school-aged and very young children. The exact pathogenetic mechanisms of the disease remain unknown. Epidemiological studies consistently show an association between outbreaks of the disease and chronic dietary reliance on insufficiently processed cyanogenic cassava (manioc or tapioca). Biochemical and toxicological studies suggest that the metabolites of linamarin (alpha-Hydroxyisobutyronitrile beta-D glucopyranoside, the main cassava cyanogen), notably cyanide (mitochondrial toxin), thiocyanate (AMPA chaotropic agent), and cyanate (protein carbamoylating agent) may play an important role in the pathogenesis of Konzo. Experimental data suggest that thiol-redox and protein- folding mechanisms may also be perturbed. Factors of susceptibility including genetics, poor nutrition, poverty and dietary cyanogen exposure, or their interactions have been suggested. Serological studies have ruled out the role of retroviruses such as the human lymphotropic viruses HIV-I/II or HTLV-I/II. Because there is no cure for Konzo, prevention of the disease remains of paramount importance. Prospects for cognitive rehabilitation still need to be explored and tested. PMID- 29981839 TI - MiR-26b-3p regulates osteoblast differentiation via targeting estrogen receptor alpha. AB - BACKGROUND: Understanding of the molecular mechanisms of miRNAs involved in osteoblast differentiation is important for the treatment of bone-related diseases. METHODS: MC3T3-E1 cells were induced to osteogenic differentiation by culturing with bone morphogenetic protein 2 (BMP2). After transfected with miR 26b-3p mimics or inhibitors, the osteogenic differentiation of MC3T3-E1 cells was detected by ALP and ARS staining. Cell viability was analyzed by MTT. The expressions of miR-26b-3p and osteogenic related markers and signaling were examined by qPCR and western blot. Direct binding of miR-26b-3p and ER-alpha were determined by dual luciferase assay. RESULTS: miR-26b-3p was significantly down regulated during osteoblast differentiation. Overexpression of miR-26b-3p inhibited osteoblast differentiation, while inhibition of miR-26b-3p enhanced osteoblast differentiation. Further studies demonstrated miR-26b-3p inhibited the expression of estrogen receptor alpha (ER-alpha) by directly targeting to the CDS region of ER-alpha mRNA. Overexpression of ER-alpha rescued the suppression effects of miR-26b-3p on osteoblast differentiation, while knockdown of ER-alpha reversed the upregulation of osteoblast differentiation induced by knockdown of miR-26b-3p. CONCLUSION: Our study demonstrates that miR-26b-3p suppresses osteoblast differentiation of MC3T3-E1 cells via directly targeting ER-alpha. PMID- 29981838 TI - Characterization of Clostridium difficile isolates collected during a phase 2b clinical study with SYN-004 (ribaxamase) for the prevention of C. difficile infection. AB - During a Phase 2b study with SYN-004 (ribaxamase) for prevention of Clostridium difficile infection (CDI) conducted in North America and Eastern Europe, 45 C. difficile isolates from subjects with laboratory-confirmed CDI and or colonized with C. difficile were collected and characterized. Several C. difficile PCR ribotypes, including 027 and 198, were identified. PMID- 29981840 TI - Single particle reconstruction and validation using Bsoft for the map challenge. AB - The Bsoft package is aimed at processing electron micrographs for the determination of the three-dimensional structures of biological specimens. Recent advances in hardware allow us to solve structures to near atomic resolution using single particle analysis (SPA). The Map Challenge offered me an opportunity to test the ability of Bsoft to produce reconstructions from cryo-electron micrographs at the best resolution. I also wanted to understand what needed to be done to work towards full automation with validation. Here, I present two cases for the Map Challenge using Bsoft: beta-galactosidase and GroEL. I processed two independent subsets in each case with resolution-limited alignment. In both cases the reconstructions approached the expected resolution within a few iterations of alignment. I further validated the results by coherency-testing: i.e., that the reconstructions from real particles give better resolutions than reconstructions from the same number of aligned noise images. The key operations requiring attention for full automation are: particle picking, faster accurate alignment, proper mask generation, appropriate map sharpening, and understanding the amount of data needed to reach a desired resolution. PMID- 29981841 TI - Hormesis of mercuric chloride-human serum albumin adduct on N9 microglial cells via the ERK/MAPKs and JAK/STAT3 signaling pathways. AB - Mercury chloride (HgCl2), a neurotoxicant that cannot penetrate the blood-brain barrier (BBB). Although when the BBB are got damaged by neurodegenerative disorders, the absorbed HgCl2, mainly in form of Hg (II)-serum albumin adduct (Hg HSA) in human plasma, can penetrate BBB and affect central nervous system (CNS) cells. Current study planned to evaluate the effect of Hg-HSA on the physiological function of N9 microglial cells. At low dosage (15 ng/mL) of Hg HAS, the observed outcomes was: promoted cell propagation, Nitric Oxide (NO) and intracellular Ca2+ levels enhancement, suppressed the release of TNF-alpha and IL 1beta and inhibited cell proliferation. At high dosage (15 MUg/mL) we observed decline in NO and intracellular Ca2+ levels, and increment in the release of TNF alpha and IL-1beta. These biphasic effects are similar to hormesis, and the hormesis, in this case, was executed through ERK/MAPKs and JAK/STAT3 signaling pathways. Study of quantum chemistry revealed that Hg2+ could form stable coordination structures in both Asp249 and Cys34 sites of HSA. Although five coordination structure in Asp249 site is more stable than four-coordination structure in Cys34 site but four-coordination structure is formed easily in-vivo in consideration of binding-site position in spatial structure of HSA. PMID- 29981842 TI - Autophagy and mitophagy in ALS. AB - Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting this pathway as a therapeutic strategy in neurodegenerative disease. PMID- 29981843 TI - Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice. AB - GPR40 (Free fatty acid receptor 1) has emerged as an important therapeutic target for diabetes. Several studies have demonstrated the association of comorbid psychiatric conditions with decreased n-3 polyunsaturated fatty acids, which may act as an agonist for GPR40. In this study, we for the first time provide evidence of reduced GPR40 signaling in the hippocampus and cortex which may be a critical underlying mechanism mediating cognitive deficits in diabesity (diabetes and obesity together). Specifically, we showed decreased GPR40 and brain-derived neurotrophic factor (BDNF) expression in the brain regions of high-fat-diet induced obese and db/db mice. Next, we demonstrated that chronic treatment with docosahexaenoic acid (DHA) or the synthetic GPR40 agonist, GW9508, significantly alleviates cognitive functions in mice, which correlates with increased BDNF expression in the hippocampus. This supports the hypothesis that DHA improves cognitive function in diabesity via GPR40 agonism. We also showed that DHA specifically activates GPR40 and modulates BDNF expression in primary cortical neurons mediated by the extracellular receptor kinase (ERK) and P38-mitogen activated protein kinase (MAPK) pathways. Finally, the central nervous system (CNS)-specific blockade of GPR40 signaling abrogated the memory potentiating effects of DHA, and induction of BDNF expression in the hippocampus. Thus, we provided evidence that DHA stimulation of GPR40 mediate some of DHA's beneficial effects in metabolic syndrome and identify GPR40 as a viable therapeutic target for the treatment of CNS-related comorbidities associated with diabesity. PMID- 29981844 TI - Do GST polymorphisms influence in the pathogenesis of diabetic nephropathy? AB - Diabetic patients often develop Diabetic Nephropathy (DN) despite severe long lasting hyperglycemia, while others develop DN even under intensive insulin therapy. This indicates that factors other than chronic hyperglycemia may also contribute to the susceptibility to the development of DN. The purpose of this case-control study was to investigate the possible role of GSTM1 and GSTT1 deletion polymorphisms, and Single Nucleotide Polymorphism (SNP), GSTP1 313 A > G (Ile105Val), in DN susceptibility. Multiple logistic regression analysis revealed that the occurrence of GST polymorphisms in the Central Brazilian population was not associated with increased risk of DN. However, the presence GSTT1 null genotype suggest an increase trend in systolic blood pressure and opposite inference was observed for the GSTP1 genotype (Ile/Val or Val/Val). On the order hand, other studies may clarify the relationship of these polymorphisms with DN and help in the prevention of this disease. PMID- 29981845 TI - Biliverdin reductase-A impairment links brain insulin resistance with increased Abeta production in an animal model of aging: Implications for Alzheimer disease. AB - Brain insulin resistance is associated with an increased Abeta production in AD although the molecular mechanisms underlying this link are still largely unknown. Biliverdin reductase-A (BVR-A) is a unique Ser/Thr/Tyr kinase regulating insulin signalling. Studies from our group, demonstrated that BVR-A impairment is among the earliest events favoring brain insulin resistance development. Furthermore, reported a negative association between BVR-A protein levels/activation and BACE1 protein levels in the parietal cortex of aged beagles (an animal model of AD), thus suggesting a possible interaction. Therefore, we aimed to demonstrate that BVR-A impairment is a molecular bridge linking brain insulin resistance with increased Abeta production. Age-associated changes of BVR-A, BACE1, insulin signalling cascade and APP processing were evaluated in the parietal cortex of beagles and experiments to confirm the hypothesized mechanism(s) have been performed in vitro in HEK293APPswe cells. Our results show that BVR-A impairment occurs early with age and is associated with brain insulin resistance. Furthermore, we demonstrate that BVR-A impairment favors CK1-mediated Ser phosphorylation of BACE1 (known to mediate BACE1 recycling to plasma membrane) along with increased Abeta production in the parietal cortex, with age. Overall, our results suggest that the impairment of BVR-A is an early molecular event contributing to both (I) the onset of brain insulin resistance and (II) the increased Abeta production observed in AD. We, therefore, suggest that by targeting BVR-A activity it could be possible to delay the onset of brain insulin resistance along with an improved regulation of the APP processing. PMID- 29981846 TI - Expression of 5T4 extracellular domain fusion protein and preparation of anti-5T4 monoclonal antibody with high affinity and internalization efficiency. AB - 5T4, a membrane protein, is overexpressed in many tumor tissues but rarely expressed in normal tissues. Here, CHO-5T4+ cells were generated and served as the antigen to immunize mice. Hybridoma techniques were employed to produce monoclonal antibodies (mAbs). The recombinant protein of human IgG Fc-fused extracellular domain of 5T4 (5T4 ECD-Fc) was obtained from transient expression in HEK293F cells. The fusion protein 5T4 ECD-Fc and CHO-5T4+ cells were respectively utilized to screen anti-5T4 antibodies that could bind to the native antigen. In preliminary screening, three hundred and fifty mAbs were obtained. Via surface plasmon resonance and flow cytometry screening, seven anti-5T4 mAbs stood out. Among them, H6 showed a high affinity (KD = 1.6 * 10-11 M) and internalization percentage (36% for 1 h and 80% for 4 h). The molecular weight and isoelectric point of H6 were determined by LC-MS and iCIEF. Moreover, the specific reactivity of H6 was demonstrated by western blotting, flow cytometry, and immunohistochemistry, respectively. In conclusion, we produced human recombinant protein of 5T4 extracellular domain and developed high-affinity internalizing monoclonal antibodies which may be applied in the 5T4-targeting ADC therapy and basic research. PMID- 29981847 TI - Antidiabetic potential of the ethyl acetate extract of Physalis alkekengi and chemical constituents identified by HPLC-ESI-QTOF-MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The edible plant Physalis alkekengi (PA) is used in traditional medicine to treat diabetes. However, the anti-diabetic effects and constituents of the fruit and aerial parts of this plant have not been studied extensively. AIM OF THE STUDY: The purpose of this study was to investigate the antidiabetic potential of Physalis alkekengi and identify its chemical constituents. MATERIALS AND METHODS: In the present study, the in vitro glucose uptake capacity was tested using the 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4 yl)amino]-2-deoxy-d-glucose (2-NBDG) assay in HepG2 cells. Secondly, the anti diabetes effects of the ethyl acetate extracts of the aerial parts/fruit (EAP/EAF) of P. alkekengi were evaluated in high-fat diet-fed and streptozotocin induced diabetic rats (seven groups, n = 7) daily at doses of 300 and 600 mg/kg for 28 days. Fasting blood glucose (FBG) was measured with a glucometer and the levels of total cholesterol (TC), triglyceride (TG), glycated serum protein (GSP), and fasting insulin (FINS) were measured by ELISA. Furthermore, insulin sensitivity index (ISI) and homeostasis model assessment-insulin resistance index (HOMA-IR) were calculated based on FBG and FINS. Changes in blood glucose concentration were assessed after an oral glucose challenge in diabetic rats treated with EAF and EAP extracts. In all assays, rosiglitazone, a current antidiabetic drug and insulin sensitizer, was also tested. Finally, the compounds in EAP were identified by HPLC-ESI-QTOF-MS analysis. RESULTS: EAP increased the uptake of 2-NBDG, a measure of direct glucose uptake, in HepG2 cells. Next, in diabetic rats treated with P. alkegenki extracts for 28 days, the levels of FBG, TC, TG and GSP and were lowered effectively, while FINS was increased significantly. EAP/EAF enhanced insulin sensitivity significantly as measured by ISI and HOMA-IR along with oral glucose tolerance test analysis. The EAP generally exerted the greatest effects. Lastly, a HPLC-ESI-Q-TOF-MS analysis identified 50 compounds, including 26 physalins, 10 flavonoids, and 9 phenolic acids, with 21 compounds found for the first time in P. alkekengi. CONCLUSIONS: The results support the merit of P. alkekengi as an antidiabetic herbal medicine or dietary supplement. PMID- 29981848 TI - A Prospective Trial of Extracorporeal Photopheresis for Chronic Graft-versus-Host Disease Reveals Significant Disease Response and No Association with Frequency of Regulatory T Cells. AB - Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic, .09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to .14 mg/kg, P < .001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD. PMID- 29981849 TI - Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients. AB - Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post transplantation cyclophosphamide (PTCy) was performed previously in adults using a nonmyeloablative conditioning regimen and bone marrow as a graft source. In an effort to reduce relapse rates, myeloablative conditioning regimens with higher intensities are now used. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing in children for effective myeloablation and to reduce toxicity. Here, we report the retrospective results of 34 patients (median age 11.1 years) who underwent haplo-HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen and peripheral blood as a stem cell source. The donor-type neutrophil engraftment rate was 97.1%, and the cumulative incidence rates of grade II to IV and grade III to IV acute and extensive chronic graft-versus-host disease were 38.2%, 5.9%, and 9.1%, respectively. The overall survival and event-free survival rates, and treatment-related mortality were 85.0%, 79.4%, and 2.9%, respectively. Based on the subgroup analysis of patients with malignancies (n = 23), the relapse incidence rate was 21.7%. Haplo-HSCT using PTCy with targeted busulfan-based myeloablative conditioning and peripheral blood as a stem cell source was a safe and promising therapeutic option for children. PMID- 29981850 TI - Use of animal models in IPF research. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a poor prognosis and limited treatment options. Many compounds have shown efficacy in preclinical models of this condition, but only pirfenidone and nintedanib have been approved for clinical use. It is widely accepted that the current animal models of IPF need to be improved and in this review we have critically evaluated the current state of play of preclinical models of IPF and discuss the challenges facing this field. The popular model of a single intratracheal (I.T.) administration of bleomycin could be adapted to provide a more progressive fibrosis as is thought to occur in humans. Furthermore, currently the majority of new drugs are investigated in preclinical models of IPF are dosed using a prophylactic dosing regimen, whereas patients are almost always treated after the fibrosis is well established. Using a therapeutic dosing regimen in preclinical models would be a better way to establish potential efficacy of new drugs. The most popular endpoints examined in pre-clinical models of IPF are histological scoring and lung collagen content. However in IPF patients imaging and lung function tests are more commonly used as end points. We propose that examining more clinically relevant endpoints in pre-clinical models could also provide give a better indication of a compound's potential efficacy on endpoints measured in patients. PMID- 29981851 TI - A novel insertion (c.1098dupT) in the albumin gene causes analbuminemia in a consanguineous family. AB - Congenital analbuminemia (OMIM # 616000) is an extremely rare autosomal recessive disorder, caused by variations in the albumin gene (ALB), which is generally thought to be a relatively benign condition in adulthood, but seems to be potentially life threatening in the pre- and peri-natal period. The subject of our study was a consanguineous family, in which we identified two analbuminemic individuals. Mutation analysis of ALB revealed that both are homozygous for a previously unreported insertion in exon 9 (c.1098dupT), causing a subsequent frame-shift with the generation of a premature stop codon, and an aberrant truncated putative protein product, p.Val367fsTer12. This variation is present in heterozygous condition in several other members of the family. The phenotype and the molecular genetics of CAA are discussed. PMID- 29981852 TI - Early onset developmental delay and epilepsy in pediatric patients with WDR45 variants. AB - BACKGROUND: Developmental delay (DD) is a neurological disorder that presents with defects in gross motor, fine motor, language and cognition functions. WD repeat domain 45 (WDR45) is one of the disease-causing genes of DD. Previously, WDR45 de novo mutations were reported in certain adult and pediatric patients due to iron accumulation. CLINICAL REPORT: We report five pediatric female patients with DD and epilepsy. Their ages were below 3 years at the first consultation, and precise diagnoses were difficult based on the available clinical information and phenotype. METHODS: Children with DD and/or epilepsy presenting to the molecular diagnostic center of Children's Hospital of Fudan University between May 2016 and May 2017 were enrolled. The patients and their parents were subjected to whole-exome sequencing (WES), and we characterized the phenotypes of the patients carrying WDR45 variants. Furthermore, we overexpressed the candidate variants in HeLa cells and evaluated their effect on autophagy through Western blot and immunofluorescence staining with confocal microscopy. RESULTS: Five WDR45 de novo mutations, namely, c.19C > T (p.Arg7*), c.401G > C (p.Arg134Pro), c.503G > A (p.Gly168Glu), c.700C > T (p.Arg234*), and c.912delT (p.Ala305Leufs*25), were detected in 623 enrolled pediatric patients (274 females; 487 patients younger than 6 years). All five patients with WDR45 variants presented with DD and epilepsy. Compared with the control HeLa cells, the cells with the p. Arg134Pro and p. Gly168Glu missense mutations showed accumulation of LC3-containing autophagic structures and an abnormally enlarged cell volume, and Western blotting revealed a significant increase in LC3II/GAPDH. CONCLUSION: The identification of WDR45 mutations provides further evidence that WES plays an important role in the diagnosis of neurological disorders with common phenotypes and that WDR45 mutations are associated with neurological disorders and are not very rare in Chinese female pediatric patients with DD and/or epilepsy. The diagnosis of patients with WDR45 mutations would enable more precise genetic counseling for the parents of these children. PMID- 29981853 TI - Inactivation of some pathogenic bacteria and phytoviruses by ultrasonic treatment. AB - High intensity ultrasound is becoming important and more widely used in the food industry for microorganisms decontamination. This sterilization technique has been evaluated to improve food safety and to replace common processing with chemical additive compounds. The efficiency of a horn-type power ultrasound treatment (300 W and 600 W, 28 kHz, 10-30 min) on Listeria monocytogenes, Bacillus cereus, Escherichia coli, Salmonella typhimurium bacteria suspensions and phytoviruses was examined in this study. The results of this study showed that ultrasonic treatment can be used to eliminate vegetative cells of gram positive and gram-negative bacteria from 1.59 to 3.4 log in bacterial suspensions and some phytoviruses in fruits. PMID- 29981855 TI - Provision of Parent Feedback via the Communication Assessment Tool: Does It Improve Resident Communication Skills? AB - OBJECTIVE: To determine the impact of a curriculum that included parent feedback, via the Communication Assessment Tool (CAT), on resident communication skills. METHODS: In a prospective, controlled study, categorical pediatric residents in continuity clinic were divided into control and intervention groups based on clinic day. Parent feedback was obtained for all residents at the beginning and end of the year using the CAT, a validated survey to assess physician communication. Intervention residents participated in learning conferences that reviewed communication best practices and received parental feedback via individual and group CAT scores. Scores were dichotomized as 5 (excellent) versus 1 to 4 (less than excellent) and reported as percentage of items rated excellent. Curriculum impact was assessed by comparing score changes between groups. Residents' scores in both arms were combined to assess changes from the beginning of the year to the end. Statistical testing was performed using generalized linear mixed-effects models. RESULTS: All residents (N = 68) participated. Intervention (n = 38) and control (n = 30) residents received at least 10 CATs at the beginning and end of the year. The percentage of parents rating all items as excellent increased by similar percentages in intervention and control groups (60.9%-73.8% vs 61.1%-69.8; P = .38). When scores of residents in both arms were combined, improvement was found from the beginning to the end of the year for all CAT items (P < .001). CONCLUSIONS: A curriculum including parent feedback from CATs did not significantly impact communication skills. However, communication skills improved over the year in intervention and control groups, suggesting that communication training occurs in multiple settings. PMID- 29981854 TI - Genome-wide MicroRNA Expression Profiles in COPD: Early Predictors for Cancer Development. AB - Chronic obstructive pulmonary disease (COPD) significantly increases the risk of developing cancer. Biomarker studies frequently follow a case-control set-up in which patients diagnosed with a disease are compared to controls. Longitudinal cohort studies such as the COPD-centered German COPD and SYstemic consequences COmorbidities NETwork (COSYCONET) study provide the patient and biomaterial base for discovering predictive molecular markers. We asked whether microRNA (miRNA) profiles in blood collected from COPD patients prior to a tumor diagnosis could support an early diagnosis of tumor development independent of the tumor type. From 2741 participants of COSYCONET diagnosed with COPD, we selected 534 individuals including 33 patients who developed cancer during the follow-up period of 54 months and 501 patients who did not develop cancer, but had similar age, gender and smoking history. Genome-wide miRNA profiles were generated and evaluated using machine learning techniques. For patients developing cancer we identified nine miRNAs with significantly decreased abundance (two-tailed unpaired t-test adjusted for multiple testing P < 0.05), including members of the miR-320 family. The identified miRNAs regulate different cancer-related pathways including the MAPK pathway (P = 2.3 * 10-5). We also observed the impact of confounding factors on the generated miRNA profiles, underlining the value of our matched analysis. For selected miRNAs, qRT-PCR analysis was applied to validate the results. In conclusion, we identified several miRNAs in blood of COPD patients, which could serve as candidates for biomarkers to help identify COPD patients at risk of developing cancer. PMID- 29981856 TI - Opioids in Adolescents' Homes: Prevalence, Caregiver Attitudes, and Risk Reduction Opportunities. AB - OBJECTIVE: The most common source of misused opioids is pain relievers prescribed for family and friends. This study was conducted to assess knowledge, attitudes, and behaviors of adolescents' caregivers regarding prescribed opioids in the home. METHODS: The self-administered survey was completed by caregivers in the waiting rooms of 12 pediatric practices in the Midwest. Eligibility required living in a home where youth age >=10 years were frequently present. Out of 793 eligible caregivers, 700 (88.3%) completed the survey, 76.8% of whom were the parent. RESULTS: Among the 700 caregiver respondents, 34.6% reported opioids in the home (13.6% active prescriptions, 12.7% leftover medications, 8.3% both). Of those with an active prescription, 66.0% intended to keep any leftover medications for future needs (for the patient, 60.1%; for someone else, 5.9%). Of those with leftover medications, 60.5% retained them for the same reason (for the patient, 51.0%; for someone else, 9.5%). Others kept medications unintentionally, either because they never got around to disposing of them (30.6%), they did not know how to dispose of them properly (15.7%), or it never occurred to them to dispose of the medications (7.5%). Many caregivers were unaware that adolescents commonly misuse opioids (30.0%) and use them to attempt suicide (52.3%), and that opioid use can lead to heroin addiction (38.6%). According to the surveys, 7.1% would give leftover opioid medications to an adolescent to manage pain and 5.9% might do so. CONCLUSIONS: Opioids are prevalent in homes in our community, and many parents are unaware of the risks they pose. Study findings can inform strategies to educate parents about opioid risk and encourage and facilitate timely, safe disposal of unused medications. PMID- 29981857 TI - Selective intradural dorsal rhizotomy for persistent radicular leg pain: a contemporary series. AB - BACKGROUND: Lumbar disc surgery for radicular leg pain is one of the most frequently performed spine procedures. In approximately 20% of patients poor outcome is achieved. The most complex cases have persistent leg pain without residual nerve root compression. Treatment for refractory cases is limited to medical pain management, spinal cord stimulation (SCS), and dorsal root ganglion stimulation. For the latter two, fair to good results are obtained in only 50% of patients and costs and complication rates are high. An alternative surgical procedure is selective intradural dorsal rhizotomy (SIDR). This procedure has been largely abandoned, likely due to poor historic results and readily available modern alternatives. PURPOSE: The goal of this paper is to report our results for SIDR for persistent monoradicular leg pain without residual nerve root compression and to compare the results with those of SCS. STUDY DESIGN: Prospectively followed case series. PATIENT SAMPLE: Consecutive patients with persistent monoradicular leg pain without residual nerve root compression. OUTCOME MEASURES: Visual Analogue Scale (VAS) for leg pain, Roland Disability Questionnaire, and Likert Scale for leg pain were recorded. Complications were documented and patients were asked if, in retrospect, they would undergo the procedure again. METHODS: In Haaglanden Medical Center, SIDR was performed on eight consecutive patients with persistent monoradicular leg pain without residual nerve root compression between December 2013 and September 2017. Patients were followed prospectively and VAS for leg pain, Roland Disability Questionnaire (RDQ), and Likert Scale for leg pain were recorded at intake, 8 weeks and 1 year after surgery and yearly after that. Minimal clinically important differences (MCID) for VAS and RDQ were predefined. Means and ranges were calculated and due to the small sample size further analysis was limited to descriptive analysis. RESULTS: Mean follow-up was 20 months. VAS for leg pain improved from 80mm at intake to 34mm at latest follow-up. Five out of eight patients (63%) had good Likert Scale outcome (complete or near complete recovery of leg pain). Patients scored 19, 5 on the RDQ at intake and 12, 7 at the end of follow-up. Four patients (57%) reached a MCID for VAS at 1 year post surgery and one reached borderline MCID. Five patients (71%) reached a MCID for RDQ at 1 year post surgery. Six patients (75%) would undergo the procedure again. CONCLUSIONS: SIDR is a safe and effective procedure in strictly selected patients with persistent monoradicular leg pain without residual nerve root compression. Considering the high costs and complication rates of SCS, the results of this study warrant a randomized controlled trial comparing the cost-effectiveness of SIDR and SCS. PMID- 29981858 TI - Adaptive expansion of biomarker populations in phase 3 clinical trials. AB - It is well documented in this genomic era that an investigational new drug may have greater treatment effect in a biomarker positive population than in the biomarker negative population. However, limited by preclinical data and early phase clinical data, a lot of Phase 3 confirmatory trials are initiated without fully understanding the biomarker effect. In this article, we will investigate the impact of adaptive population expansion on the overall Type I error in two statistical designs. The endpoint for making the adaptive decision can be different from the primary endpoint of the study. The first design allows expansion of study population from biomarker positive patients to all-comers if the treatment effect in the biomarker positive population is more impressive than expected, suggesting broader activity of the study drug. We show that, under this design, the trial outcome can be tested at the desired alpha level without inflating the Type I error when the adaptive decision is based on the primary endpoint of the study or based on an endpoint non-negatively correlated with the primary endpoint, an assumption that generally holds in practice. The second design allows addition of biomarker positive patients in an all-comer study if the treatment effect in the biomarker negative population is less impressive than expected, suggesting lower probability of success in the all-comer population. We show that, under this design, the trial outcome can always be tested at the desired alpha level without inflating the Type I error. PMID- 29981859 TI - Maxillary metastasis from a hepatocellular carcinoma: Report of an uncommon presentation and literature review. AB - INTRODUCTION: Oral metastases from hepatocellular carcinoma (HCC) are very rare, and predominate in the mandible. We report an exceptional case of maxillary metastasis revealing HCC. CASE REPORT: A 56-year-old man with a previous medical history of alcohol abuse presented to our department with a 3-week evolving oral mass. Physical examination showed a left maxillary tumor. The biopsy revealed a HCC and a multi-metastatic HCC with portal thrombosis and a pulmonary embolism was discovered following a CT-scan. A state of advanced malnutrition contraindicated sorafenib chemotherapy. Thus, external irradiation was proposed, without success. The patient subsequently died 50 days later. DISCUSSION: Maxillary HCC metastases are extremely rare. The average age of HCC jaw metastases appearance in patients has been reported to be approximately 57 years, men are more affected than women are, and the mean life expectancy is 12 months following the diagnosis. These patients require palliative treatment. Local recurrences occur very early after possible surgery, and expose the patient to life-threatening bleeding. PMID- 29981860 TI - Tissular tumor of the floor of the mouth in a child: Differential diagnoses. PMID- 29981861 TI - Combined Assessment of Serum Periostin and YKL-40 May Identify Asthma-COPD Overlap. AB - BACKGROUND: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) has been proposed as a different diagnosis from asthma and COPD. However, little is known about the role of serum biomarkers in ACO. OBJECTIVE: To evaluate serum periostin, a type 2 biomarker, and serum chitinase-3-like protein 1 (YKL-40), a useful biomarker for COPD, in Japanese patients with asthma, ACO, or COPD, and investigate the role of these biomarkers in identifying ACO. METHODS: Subjects included Japanese patients with asthma (n = 177), ACO (n = 115), or COPD (n = 61). Serum periostin, YKL-40, and total IgE, blood eosinophils, and fractional exhaled nitric oxide were measured and compared among the patients. RESULTS: Serum periostin was high in both asthma and ACO, but not in COPD, whereas serum YKL-40 was high in both COPD and ACO, but not in asthma. Serum periostin levels correlated weakly with eosinophil counts in asthma, ACO, and COPD. Multivariate linear regression analysis revealed that older age, lower body mass index, higher eosinophil counts, higher total IgE, and the absence of the diagnosis of COPD were significantly associated with higher periostin levels. Based on cutoff values derived by receiver operating characteristic analysis (periostin: 55.1 ng/mL; YKL-40: 61.3 ng/mL), patients were classified into high or low groups. The proportion of patients with both high serum periostin and YKL-40 levels was significantly higher in ACO than in asthma or COPD. CONCLUSIONS: Serum periostin levels were comparable between asthma and ACO, whereas YKL-40 was comparable between ACO and COPD. Combined assessment of serum periostin and YKL-40 may identify ACO. PMID- 29981863 TI - Intermittent anticoagulation guided by continuous atrial fibrillation burden monitoring using dual-chamber pacemakers and implantable cardioverter defibrillators: Results from the Tailored Anticoagulation for Non-Continuous Atrial Fibrillation (TACTIC-AF) pilot study. AB - BACKGROUND: Chronic anticoagulation is recommended for atrial fibrillation (AF) patients with thromboembolic risk factors regardless of AF duration/frequency. Continuous rhythm assessment with pacemakers (PMs)/implantable cardioverter defibrillators (ICDs) and use of direct-acting oral anticoagulants (DOACs) may allow anticoagulation only around AF episodes, reducing bleeding without increasing thromboembolic risk. OBJECTIVE: The purpose of this study was to evaluate the feasibility/safety of intermittent DOAC use guided by continuous remote AF monitoring via dual-chamber PMs or ICDs. METHODS: Patients with nonpermanent AF, current DOAC use, CHADS2 score <=3, St. Jude Medical dual chamber PM or ICD, and rare AF episodes were followed with biweekly and AF-alert based remote transmissions. Patients free of AF episodes lasting >=6 minutes with a total AF burden <6 hours/day for 30 consecutive days discontinued DOAC. If AF burden surpassed these limits, DOAC was restarted and/or continued. Total days on DOAC and adverse events were assessed. RESULTS: Among 48 patients (mean age 71.3 years; 65% male; 79% paroxysmal AF; 87% CHADS2 score 1-2), 14,826 days of monitoring were completed. Patients used DOACs for 3763 days, representing a 74.6% reduction in anticoagulation time compared to chronic administration. Adverse events included 2 gastrointestinal bleeds (both on DOAC), 1 fatal intracerebral bleed (off DOAC), and no thromboembolic/stroke events. CONCLUSION: Among patients with rare AF episodes and low-to-moderate stroke risk, PM/ICD guided DOAC administration is feasible and decreased anticoagulation utilization by 75%. Few adverse events occurred, although the study was not powered to assess these outcomes. PM/ICD-guided DOAC administration may prove a viable alternative to chronic anticoagulation. Future studies are warranted. PMID- 29981864 TI - A case-only genome-wide association study on gene-sex interaction in allergic rhinitis. PMID- 29981862 TI - Campylobacter infection in adult patients with primary antibody deficiency. PMID- 29981865 TI - CasPER, a method for directed evolution in genomic contexts using mutagenesis and CRISPR/Cas9. AB - Here we describe a method for robust directed evolution using mutagenesis of large sequence spaces in their genomic contexts. The method employs error-prone PCR and Cas9-mediated genome integration of mutant libraries of large-sized donor variants into single or multiple genomic sites with efficiencies reaching 98-99%. From sequencing of genome integrants, we determined that the mutation frequency along the donor fragments is maintained evenly and successfully integrated into the genomic target loci, indicating that there is no bias of mutational load towards the proximity of the double strand break. To validate the applicability of the method for directed evolution of metabolic gene products we engineered two essential enzymes in the mevalonate pathway of Saccharomyces cerevisiae with selected variants supporting up to 11-fold higher production of isoprenoids. Taken together, our method extends on existing CRISPR technologies by facilitating efficient mutagenesis of hundreds of nucleotides in cognate genomic contexts. PMID- 29981866 TI - Comprehensive Validation of Cytology Specimens for Next-Generation Sequencing and Clinical Practice Experience. AB - Biopsy specimens are subjected to an expanding portfolio of assays that regularly include mutation profiling via next-generation sequencing (NGS). Specimens derived via fine-needle aspiration, a common biopsy technique, are subjected to a variety of cytopreparatory methods compared with surgical biopsies that are almost uniformly processed as formalin-fixed, paraffin-embedded tissue. Therefore, the fine-needle aspiration-derived specimens most commonly accepted for molecular analysis are cell blocks (CBs), because they are processed most similarly to surgical biopsy tissue. However, CB preparations are fraught with challenges that risk unsuccessful sequencing and repeat biopsies, with the potential to further increase health care costs and delay clinical care. The diversity of cytopreparations and the resource-intensive clinical validation of NGS pose significant challenges to more consistent use of non-CB (NCB) cytology specimens. As part of clinical validation of a targeted NGS assay, DNA subjected to nine cytopreparatory methods was evaluated for sequencing performance and was shown to be uniformly acceptable for clinical NGS. Of the 379 clinical cases analyzed after validation, the majority (56%) were derived from NCB cytology specimens. This specimen class had the lowest DNA insufficiency rate (1.5%) and showed equivalent sequencing performance to surgical and CB formalin-fixed, paraffin-embedded tissue. NCB cytology specimens are valuable sources of tumor nucleic acid and are the preferred specimen type for clinical NGS at our institution. PMID- 29981867 TI - Multiple Ways to Detect IDH2 Mutations in Angioimmunoblastic T-Cell Lymphoma from Immunohistochemistry to Next-Generation Sequencing. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma associated with chemoresistance and a poor prognosis. Various nonsynonymous mutations in the R172 residue of IDH2 are present in 20% to 30% of AITL patients. In addition to their diagnostic value, these mutations are potentially targetable, especially by isocitrate dehydrogenase (IDH) 2 inhibitor, and therefore their identification in a routine setting is clinically relevant. However, in AITL, the neoplastic cells may be scarce, making the identification of molecular anomalies difficult. We evaluated the diagnostic value of different methods to detect IDH2 mutations in formalin-fixed, paraffin-embedded tumor samples. Immunohistochemistry with an anti-IDH2 R172K antibody, Sanger sequencing, high-resolution melting PCR, allele-specific real-time quantitative PCR, and next-generation sequencing (NGS) were applied to biopsy specimens from 42 AITL patients. We demonstrate that the IDH2 R172K antibody is specific to this amino acid substitution and highly sensitive for the detection of the IDH2R172K variant, the most frequent substitution in this disease. In our study, NGS and allele-specific real-time quantitative PCR displayed a good sensitivity, detecting 96% and 92% of IDH2 mutations, respectively, in contrast to Sanger sequencing and high-resolution melting PCR, which showed a significantly lower detection rate (58% and 42%, respectively). These results suggest that a combination of immunohistochemistry and AS-PCR or NGS should be considered for the identification of IDH2 mutations in AITL in a routine setting. PMID- 29981868 TI - Re: 'Accuracy of quick Sequential Organ Failure Assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria for predicting mortality in hospitalized patients with suspected infection' by Som, et al. PMID- 29981869 TI - Hepatitis C virus (HCV) genotype 1 NS5A resistance-associated variants are associated with advanced liver fibrosis independently of HCV-transmission clusters. AB - OBJECTIVES: The aim of the study was to characterize the differences in the frequencies of NS3 and NS5A resistance-associated variants (RAVs) among Polish therapy-naive genotype 1 (G1) hepatitis C virus (HCV)-monoinfected and human immunodeficiency virus (HIV)/HCV-coinfected patients including clustering patterns and association of RAV frequency with liver fibrosis. METHODS: NS3/NS5A RAVs were identified by population sequencing in 387 directly acting antiviral treatment-naive G1-infected individuals (54 with genotype 1a (G1a) and 333 with genotype 1b (G1b)). Liver fibrosis was assessed based on histopathology or ultrasound elastography. Phylogenetic clusters were identified using maximum likelihood models. For statistics, chi-squared or two-sided Fisher's exact tests and multivariate logistic regression models were used, as appropriate. RESULTS: NS3 RAVs were found in 33.33% (18/54) for G1a and 2.62% (8/297) for G1b whereas NS5A variants were present in 5.55% (3/54) G1a and 9.31% (31/333) G1b sequences. Variations in NS5A 31 and 93 codon positions were found only in G1b (4.2% (14/333) for L31I/F/M and 5.39% (17/333) for Y93H). NS5A RAVs were more frequent among patients with advanced liver fibrosis (17.17% (17/99) for F3-F4 versus 6.94% (17/245) for F0-F2; p 0.004) or liver cirrhosis (20.34% (12/59) for F4 versus 7.72% (22/285) for F0-F3; p 0.003). Liver cirrhosis (F4) was associated with higher odds ratio of the NS5A RAVs among HCV-infected patients (odds ratio 2.34, 95% CI 1.004-5.291; p 0.049). NS5A RAVs were less frequent among sequences forming clusters and pairs (5.16% (8/155) versus 11.21% (26/232); p 0.039). CONCLUSIONS: Presence of NS5A RAVs correlated with progression of liver fibrosis and represents de novo selection of variants rather than transmission of drug resistance. Hence, the presence of NS5A RAVs may be a predictor for a long lasting HCV infection. PMID- 29981870 TI - Statistical power of clinical trials increased while effect size remained stable: an empirical analysis of 136,212 clinical trials between 1975 and 2014. AB - OBJECTIVES: To study the statistical power of randomized clinical trials and examine developments over time. STUDY DESIGN AND SETTING: We analyzed the statistical power in 136,212 clinical trials between 1975 and 2014 extracted from meta-analyses from the Cochrane database of systematic reviews. We determined study power to detect standardized effect sizes, where power was based on the meta-analyzed effect size. Average power, effect size, and temporal patterns were examined for all meta-analyses and a subset of significant meta-analyses. RESULTS: The number of trials with power >=80% was low (7%) but increased over time: from 5% in 1975-1979 to 9% in 2010-2014. In significant meta-analyses, the proportion of trials with sufficient power increased from 9% to 15% in these years (median power increased from 16% to 23%). This increase was mainly due to increasing sample sizes, while effect sizes remained stable with a median Cohen's h of 0.09 (interquartile range 0.04-0.22) and a median Cohen's d of 0.20 (0.11 0.40). CONCLUSION: This study demonstrates that sufficient power in clinical trials is still problematic, although the situation is slowly improving. Our data encourage further efforts to increase statistical power in clinical trials to guarantee rigorous and reproducible evidence-based medicine. PMID- 29981871 TI - Diagnostic test guidelines based on high-quality evidence had greater rates of adherence: a meta-epidemiological study. AB - OBJECTIVES: To determine the association between the quality of guidelines for diagnostic tests (both the quality and reporting and the quality of the evidence underpinning recommendations) and nonadherence. STUDY DESIGN AND SETTING: We conducted a meta-epidemiological study. We previously published a systematic review that quantified the percentage of test use that was nonadherent with guidelines. For the present study, we assessed these guidelines using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. We then assessed the quality of evidence underpinning recommendations within these guidelines using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Linear models were then constructed to determine the association between guideline nonadherence and (1) AGREE II score and (2) GRADE score. RESULTS: There was no significant association between AGREE II score and nonadherent testing (P = 0.09). There was a significant association between GRADE score and nonadherence: recommendations based on low-quality and very low-quality evidence had 38% (P < 0.01) and 24% (P = 0.02) more nonadherent testing, compared with recommendations based on high-quality evidence. CONCLUSION: Diagnostic test guideline recommendations based on high-quality evidence are adhered to more frequently. PMID- 29981872 TI - Extending PubMed searches to ClinicalTrials.gov through a machine learning approach for systematic reviews. AB - OBJECTIVES: Despite their essential role in collecting and organizing published medical literature, indexed search engines are unable to cover all relevant knowledge. Hence, current literature recommends the inclusion of clinical trial registries in systematic reviews (SRs). This study aims to provide an automated approach to extend a search on PubMed to the ClinicalTrials.gov database, relying on text mining and machine learning techniques. STUDY DESIGN AND SETTING: The procedure starts from a literature search on PubMed. Next, it considers the training of a classifier that can identify documents with a comparable word characterization in the ClinicalTrials.gov clinical trial repository. Fourteen SRs, covering a broad range of health conditions, are used as case studies for external validation. A cross-validated support-vector machine (SVM) model was used as the classifier. RESULTS: The sensitivity was 100% in all SRs except one (87.5%), and the specificity ranged from 97.2% to 99.9%. The ability of the instrument to distinguish on-topic from off-topic articles ranged from an area under the receiver operator characteristic curve of 93.4% to 99.9%. CONCLUSION: The proposed machine learning instrument has the potential to help researchers identify relevant studies in the SR process by reducing workload, without losing sensitivity and at a small price in terms of specificity. PMID- 29981873 TI - Chemical composition and biological activities of the essential oil from Cleome rutidosperma DC. AB - Cleome rutidosperma DC, commonly known in Jamaica as 'consumption-weed' is a plant traditionally used in folklore for treating tuberculosis and other infectious and chronic ailments. We evaluate for the first time the chemical composition and biological activities of the essential oil components of the complete aerial parts of this plant. The essential oil obtained by steam distillation (0.02%) was analyzed by a combination of gas chromatography-flame ionization detector (GC-FID), gas chromatography-mass spectroscopy (GC-MS) and retention index (RI). The volatile oil of C. rutidosperma was dominated by oxygenated diterpenes (67.6%); with (Z)-phytol (65.1%) being the single most abundant constituent. C. rutidosperma aerial essential oil exhibited moderate inhibition against the activity of recombinant arylamine N-acetyltransferase (NAT) from Mycobacterium marinum (IC50 22.20 +/- 1.80 MUg/MUL), while, racemic phytol had an inhibition with an IC50 of 22.33 MUg/MUL +/- 0.50 MUg/MUL, thus accounting for the NAT inhibition imparted by the crude oil. Inhibition of NAT, a key enzyme in mycobacterial growth may be the pathway in which phytol, shown in this study to interact with the active site using in-silico methods, renders its previously demonstrated anti-tubercular properties. The phytol rich essential oil also demonstrated antimicrobial activity against all nine human pathogenic bacteria and the fungus strain assayed, with the most significant inhibitory activity against Bacillus cereus and justifies the need for further evaluation and development of the essential oils from this plant. PMID- 29981874 TI - Rapid profiling and pharmacokinetic studies of multiple potential bioactive triterpenoids in rat plasma using UPLC/Q-TOF-MS/MS after oral administration of Ilicis Rotundae Cortex extract. AB - Triterpenoids, the major bioactive ingredients of Ilicis Rotundae Cortex, contributes a significant cardiovascular protection activity. Although many studies about the total saponins have been reported, the absorption triterpenoids and pharmacokinetic behaviors were unclear. Thus, the present study aims to comprehensive elucidate the absorption triterpenoids and their pharmacokinetics in rats after oral administration the crude extract using UPLC/Q-TOF-MS/MS. A total of forty-two triterpenoids were successfully characterized from the rat plasma, and thirty-two of them were validated by the reference substances, while the others were tentatively identified based on the mass spectral fragmental patterns. Furthermore, the plasma concentrations of six absorption bioactive triterpenoids (rotundinoside C, ilexoside O, pedunculoside, rotundic acid, rotundanonic acid and ilexgenin A) were simultaneously quantified by selected reaction monitoring in negative ionization mode. All analytes exhibited good linearity with correlation coefficients values greater than 0.99 and the LLOQ ranged from 1.2 to 3.2 ng/mL, and method validation for selectivity, precision, accuracy, recovery, matrix effect and stability were reckoned acceptable. The results were successfully applied for the multiple-component pharmacokinetic study of the six bioactive triterpenoids. PMID- 29981875 TI - Evaluation of in vitro growth-inhibitory effect of carvacrol and thymol combination against Staphylococcus aureus in liquid and vapour phase using new broth volatilization chequerboard method. AB - Carvacrol and thymol, both plant-derived volatile compounds, have extensively been studied individually as well as in combination with other agents for their antimicrobial activity in liquid phase. However, in contrast to well-established assays for testing of antimicrobial combinatory effects in liquid media, there are no standardized methods for evaluation of interactions between volatile compounds in vapour phase. The objective of this study was to verify new broth volatilization chequerboard method by testing the combination of carvacrol and thymol and to determine in vitro inhibitory effect of these compounds in liquid and vapour phase against twelve Staphylococcus aureus strains. The new method, based on combination of standard microdilution chequerboard and new broth volatilization tests allowing calculation of fractional inhibitory concentrations (FICs), was used. Combination of carvacrol and thymol produced the additive antimicrobial effect against all strains tested. In several cases, they reached SigmaFIC values lower than 0.6, which can be considered as a strong additive interaction. The best result was found in vapour phase against one standard strain at combination of 128 MUg/mL of carvacrol and 16-256 MUg/mL of thymol (SigmaFIC = 0.51) and in liquid phase against one clinical isolate at combination of 256 MUg/mL of carvacrol and 256 MUg/mL of thymol (SigmaFIC = 0.53). The study verified that the new technique is suitable for simple and rapid high-throughput combinatory antimicrobial screening of volatile compounds simultaneously in vapour and liquid phase and that it allows determination and comparison of MIC and FIC values in both, liquid and solid media. PMID- 29981876 TI - Plasma transferrin level correlates with the tremor-dominant phenotype of Parkinson's disease. AB - Accumulating evidence suggests that iron metabolism may be involved in the pathophysiology of Parkinson's disease (PD), and particularly in motor phenotype. This investigation aimed to examine plasma iron metabolism related indicators in patients with tremor-dominant phenotype of PD and determine less invasive, potential markers from plasma, which could partially reflect pathophysiological mechanisms of the brain. Seventy-six PD patients were recruited and thirty-three of them were classified into the tremor-dominant PD (TD-PD) group and forty-three into the non-tremor dominant PD (NT-PD) group, as determined by clinical characteristics. Plasma iron, ceruloplasmin, transferrin and ferritin levels were measured using Beckman Coulter AU biochemical assays, immune transmission turbidimetry method, scatter turbidimetry method and chemiluminescence method, respectively. Spearman's correlation analysis and multiple linear regression analysis were used for further study. Compared to healthy controls, TD-PD patients exhibited lower plasma iron level (p = 0.006) and higher transferrin level (p < 0.001). Plasma transferrin level was much higher in the TD-PD as compared to NT-PD (p = 0.003). Furthermore, plasma transferrin level was positively correlated with the severity of tremor in TD-PD (r = 0.358, p = 0.041). Multiple linear regression further demonstrated significant associations of plasma transferrin level with severity of tremor in TD-PD (regression coefficient = 0.253, P = 0.016), independently from other confounding factors. The elevated plasma transferrin level, combining with decreased plasma iron level might be given considerable weight in the recognition of parkinsonian tremor. PMID- 29981877 TI - Ethanol exacerbates manganese - induced functional alterations along the hypothalamic-pituitary-gonadal axis of male rats. AB - Manganese (Mn) exposure has been reported to induce reproductive dysfunction in animal and humans. Studies have shown that a large percentage of adolescent and adult populations tend to consume alcohol in a binge pattern. However, there is no information on the influence of alcohol on Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis. This study aimed to evaluate the influence of ethanol (EtOH) on Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis. Rats were exposed to Mn alone at 30 mg/kg body weight or co-expose with EtOH at 1.25 and 5 g/kg body weight for 35 consecutive days. Results showed that EtOH exposure significantly (p <= 0.05) exacerbated Mn - induced decrease in antioxidant enzymes activities, glutathione level and increased oxidative stress biomarkers in the hypothalamus, testes an epididymis of the exposed rats. Moreover, induction of inflammation was associated with disruption of histo-architecture of the hypothalamus, testes and epididymis of rats treated with Mn alone, EtOH alone or in combination. Furthermore, EtOH significantly exacerbated Mn - induced diminution in reproductive hormones and marker enzymes of testicular functions coupled with decreased sperm quantity and quality. Taken together, EtOH exacerbates Mn - induced functional alteration along the hypothalamic - pituitary - gonadal axis in rats via mechanisms involving induction of oxidative/nitrosative stress, lipid peroxidation and inflammation in rats. PMID- 29981878 TI - An ERP study of the processing of epistemic modality adverbs yexu and yiding in Mandarin Chinese. AB - Numerous studies have demonstrated that word frequency influences sentence processing. However, the impact of frequently used epistemic modality adverbs on sentence processing is less clear. The aim of the present study is to investigate the processing of Chinese epistemic modality adverbs by means of ERPs (event related potentials) based on degrees of modal certainty encoded by different orthographic forms of two epistemic adverbs yexu (possibly) and yiding (surely) co-occurred with two psychological verbs guji (estimate) and quexin (convince) in Mandarin Chinese sentences as Wo guji Xiaolin yexu hui jingxuan banzhang (I estimate Xiaolin possibly future compete monitor). Two conditions (i.e. agreed and disagreed conditions) are constructed through manipulating the agreement of the certainty degree between the psychological verbs and the epistemic adverbs. Twenty-four enrolled Chinese college students took part in the ERP experiment. The results showed that the epistemic adverb yexu (possibly) in disagreed sentences (quexin &yexu) relative to agreed sentences (guji &yexu), elicited a monophasic P600 effect with a centro-parietal distribution, indicating extra syntactic costs in processing the epistemic adverb in sentences with modal uncertainty. The absence of N400 was observed for processing yexu (possibly) in the agreed and disagreed sentences, suggesting that little semantic processing difficulty of the epistemic adverb happens in sentences with modal certainty and/or uncertainty. While for the epistemic adverb yiding (surely) in the agreed and disagreed sentences, the absence of P600 and N400 indicates that little difficulty in syntactic and/or semantic processing of the epistemic adverb happens in sentences with modal certainty and/or uncertainty. PMID- 29981879 TI - A subtype-specific neuropeptide FF receptor antagonist attenuates morphine and nicotine withdrawal syndrome in the rat. AB - Considerable evidence suggests the Neuropeptide FF (NPFF) and related peptides exert pro-nociceptive and anti-opiate actions, particularly at the supra-spinal level, which may contribute to opiate dependence. The FF1 receptor subtype appears to be primarily responsible for anti-opiate effects. In contrast, stimulation of the FF2 receptor primarily induces pro-opiate effects. AC-262620 is a small molecule, systemically active, selective FF1 receptor antagonist. An initial experiment showed that 10 mg/kg i.p. AC-262620 significantly reduced subsequent naloxone-precipitated somatically expressed withdrawal signs in rats infused s.c. for seven days with 0.3 mg/kg/hr morphine sulfate. A second experiment showed that the same dose of AC-262620 significantly reduced subsequent spontaneous withdrawal signs 23.75 h after termination of seven days s.c. infusion of 0.6 mg/kg/hr morphine sulfate. Chronic nicotine intake may contribute to dependence by overstimulating opiate receptors through release of opiate peptides. By analogy to opiate dependence, it was hypothesized that FF1 receptor activation contributes to nicotine dependence and withdrawal syndrome. AC-262620 significantly reduced somatically expressed withdrawal signs precipitated by the nicotinic antagonist mecamylamine in rats infused for seven days with nicotine bitartrate. Taken together, these findings suggest that NPFF or related neuropeptides contribute to opiate, as well as nicotine, dependence and withdrawal syndrome through the FF1 receptor. PMID- 29981880 TI - Feeding European sea bass (Dicentrarchus labrax) juveniles with a functional synbiotic additive (mannan oligosaccharides and Pediococcus acidilactici): An effective tool to reduce low fishmeal and fish oil gut health effects? AB - The aim of this study was to assess the effects of dietary mannan oligosaccharides (MOS), Pediococcus acidilactici or their conjunction as a synbiotic in low fish meal (FM) and fish oil (FO) based diets on European sea bass (Dicentrarchus labrax) disease resistance and gut health. For that purpose, sea bass juveniles were fed one of 6 diets containing different combinations of MOS (Biomos(r) and Actigen(c); Alltech, Inc., Kentucky, USA) and Pediococcus acidilactici (BAC, Bactocell(r); Lallemand Inc., Cardiff, UK) replacing standard carbohydrates as follows (MOS (%)/BAC (commercial recommendation): high prebiotic level (HP) = 0.6/0, low prebiotic level (LP) = 0.3/0, only probiotic (B) = 0/+, high prebiotic level plus probiotic (HPB) = 0.6/+, low prebiotic level plus probiotic (LPB) = 0.3/+, control (C) = 0/0 for 90 days. After 60 and 90 days of feeding trial, fish were subjected to an experimental infection against Vibrio anguillarum. Additionally, inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNFalpha) gut patterns of immunopositivity and major histocompatibility complex class II (MHCII), transforming growth factor beta (TGF beta), regulatory T-cell subset (CD4+T lymphocytes) and effector T cell (CD8alpha+T lymphocytes) gene expression patterns in gut by in situ hybridization were evaluated after 90 days of feeding. The effects of both additives on posterior gut through Gut Associated Lymphoid Tissue (GALT) gene expression was also studied. Fish fed the prebiotic and its combination with P. acidilactici presented increased weight regardless of the dose supplemented after 90 days of feeding, however no effect was detected on somatic indexes. For posterior gut, morphometric patterns and goblet cells density was not affected by MOS, P. acidilactici or its combination. Anti-iNOS and anti-TNFalpha gut immunopositivity patterns were mainly influenced by MOS supplementation and not by its combination with P. acidilactici. MHCII-beta, TCR-beta, CD4 and CD8-alpha positive cells distribution and incidence was not affected by diet. Fish fed HP dose presented a clear up-regulation of TNF-alpha, cyclooxygenase-2 (COX-2), CD4 and IL10, whereas P. acidilactici dietary supplementation increased the number of interleukin-1beta (IL1beta) and COX-2 gene transcripts. Synbiotic supplementation resulted in a reduction of MOS-induced gut humoral proinflammatory response by increasing the expression of some cellular-immune system related genes. Fish mortality after V. anguillarum infection was reduced in fish fed LPB and LP diets compared to fish fed the non-suppelmented diet after 90 days of feeding. Thus, overall pointing to the combination of a low dose of MOS and P. acidilactici as synbiont (LPB) as a viable tool to potentiate European sea bass juvenile's growth and disease resistance when supplemented in low FM and FO diets. PMID- 29981881 TI - The synergic impacts of TiO2 nanoparticles and 17beta-estradiol (E2) on the immune responses, E2 accumulation, and expression of immune-related genes of the blood clam, Tegillarca granosa. AB - The extensive use of TiO2 nanoparticles (nTiO2) in industrial products has led to their release into the marine environment, thereby posing a potential risk to marine organisms. However, in addition to affecting marine organisms through its inherent properties, nTiO2 can also act as a vehicle for other toxic pollutants due to their strong adsorption ability through the "Trojan horse" effect. Due to their potential hazard, the endocrine disrupting chemicals (EDCs) such as 17beta estradiol (E2), have been considered as one of the most serious anthropogenic threats to biodiversity and ecosystem health. However, there is still a lack of knowledge regarding the possible synergistic effects of nTiO2 and endocrine disrupting chemicals (EDCs) on marine organisms to date. Therefore, the combined effects of nTiO2 and 17beta-estradiol (E2) on the immune responses of the blood clam, Tegillarca granosa, were investigated in this study. After 10 days of treatment, the total number, phagocytic activity, red granulocytes ratio, and the phagocytosis of hemocytes were significantly reduced in almost all treatment groups. Furthermore, expressions of genes from NFkappabeta and Toll-like receptor signaling pathways were significantly altered after exposure to nTiO2 and/or E2, indicating a reduced sensitivity to pathogen challenges. In addition, compared to exposure to E2 alone, co-exposure to E2 and nTiO2 led to a significant increase in the content of alkali-labile phosphate (ALP) in hemolymph, suggesting an enhanced E2 bioconcentration in the presence of nTiO2. In general, the present study demonstrated that nTiO2 enhanced the immunotoxicity of E2 to the blood clam, which may be due to the increased E2 uptake in the presence of nTiO2. PMID- 29981882 TI - Nile tilapia fry fed on antimicrobial peptide Epinecidin-1-expressing Artemia cyst exhibit enhanced immunity against acute bacterial infection. AB - Artemia are often used as a live feed for fry in aquaculture. We have previously demonstrated that supplementing adult zebrafish feed with Artemia, which express an Epinephelus coioides-derived antimicrobial peptide, Epinecidin-1 (Epi-1), protects against bacterial infection. Thus, Artemia may serve as a bioreactor for producing biofunctional molecules. However, the application of Epi-1 transgenic Artemia in larval aquaculture of commercial fish species has not been investigated. Here we used a Tol2-transposon system to generate stable Epi-1 expressing Artemia. Nile tilapia (Oreochromis niloticus) fry were then fed with decapsulated transgenic cysts and acutely challenged with Gram-positive Streptococcus iniae or Gram-negative Vibrio vulnificus (204). Survival analysis revealed that tilapia fry fed with Epi-1 transgenic cysts were resistant to acute bacterial infection. Immune-related gene expression profiling showed that S. iniae and V. vulnificus inoculations produced distinct immunomodulatory effects in the tilapia fry. Upon S. iniae infection, tilapia fry fed on control diet exhibited an immune response dominated by Tlr-7/MyD88, wherein Tnf-alpha, Il-8 and Cxcl-10 expression were all induced; conversely, the tilapia fry fed with Epi 1 transgenic cysts showed a Tlr-2/Tlr-5-dominant immune response, marked by the induction of Il-1beta, Il-8 and Il-12 expression. However, after V. vulnificus (204) infection control fry exhibited a Tlr-2/MyD88/Traf-6-dominant response with activation of Tnf-alpha and Il-8 expression; meanwhile tilapia fry fed on Epi-1 transgenic cyst showed a dominant Tlr-2/Tlr-5-mediated immune response, including induction of Il-1beta, Il-8, Il-12, and Cxcl-10 expression. These findings suggest that feeding larval fish fry with Epi-1 transgenic Artemia cysts confers enhanced immunity toward bacterial challenge. Epi-1 transgenic cysts should therefore be considered as a potential functional feed for larval aquaculture. PMID- 29981883 TI - Proliferation and differentiation of circulating haemocytes of Ruditapes philippinarum as a response to bacterial challenge. AB - Ultrastructural investigation confirmed the presence of four cell types (granulocytes, hyalinocytes, serous cells, and haemoblasts) in the haemolymph of the Manila clam, Ruditapes philippinarum. Granulocytes were characterised by numerous electron-dense granules, whereas hyalinocytes had a considerable number of small clear vesicles. Serous cells exhibited large vacuoles, which filled the cytoplasm, and haemoblasts (the undifferentiated cells) were small roundish cells characterised by a high nucleus/cytoplasm ratio. The presence of circulating haemoblasts was observed at various phases of mitosis. Updated data concerning the proliferation and differentiation of circulating haemocytes were obtained after both in vitro and in vivo bacterial challenge. The results demonstrated that cell proliferation occurred within 15 h of exposure, and most haemocyte types responded to the stimuli. The number of granulocytes significantly decreased after massive phagocytosis and ultrastructural observations confirmed that they were active phagocytic cells against both Gram-positive and Gram negative bacteria, which were rapidly engulfed into large phagosomes. Granulocyte lysis may represent a protection response against bacterial proliferation inside phagosomes. The number of serous cells significantly increased, suggesting a previously unreported pivotal immune role during bacterial infection. A panel of lectins was used as probes to further characterise haemocytes and their relationships. Only hyalinocytes were not positive for the lectins assayed, whereas all lectins labelled serous cells, suggesting that these cells have a variety of specific carbohydrates, which are shared with certain haemoblasts. The hypothesis of the existence of a prospective haemoblast for serous cell origin is discussed. PMID- 29981884 TI - Identification of an intercellular cell adhesion molecule-1 homologue from grass carp: Evidence for its involvement in the immune cell adhesion in teleost. AB - Intercellular cell adhesion molecule-1 (ICAM-1) is a single-chain transmembrane glycoprotein which plays key roles in transendothelial migration of leukocytes and interaction between antigen presenting cells and T cells. In teleost, information of cell adhesion-related molecules is still lacking. In this study, we identified a gene from grass carp sharing similar exon and intron organization with human ICAM-1. Cloning and in silico analysis of its homologues in zebrafish and other two cyprinid fishes, respectively demonstrated the existence of the gene in these fishes. Moreover, the molecular features of these genes in fishes were conserved compared with human ICAM-1. In grass carp, the transcripts of this gene were detected with high levels in heart and liver and its mRNA expression in headkidney leukocytes was induced by Il-1beta. Overexpression of this molecule in COS-7 cells could increase the adhesion of the cells with grass carp peripheral blood lymphocytes (PBLs), and the adhesion was further enhanced by lipopolysaccharide stimulation on PBLs. Further studies revealed that the mRNA levels of lymphocyte function-associated antigen-1, a ligand for ICAM-1, were much higher in the PBLs adhering to the COS-7 cells with overexpressing this molecule than in the PBLs alone. These results collectively showed that the newly cloned cDNA encodes grass carp intercellular cell adhesion molecule-1 (Icam-1) and it can mediate the adhesion of PBLs. This provides functional evidence for the existence of Icam-1 in teleost and will facilitate investigation on the transendothelial migration of leukocytes in fish species. PMID- 29981885 TI - A decision support system for antibiotic prescription based on local cumulative antibiograms. AB - BACKGROUND: Local cumulative antibiograms are useful tools with which to select appropriate empiric or directed therapies when treating infectious diseases at a hospital. However, data represented in traditional antibiograms are static, incomplete and not well adapted to decision-making. METHODS: We propose a decision support method for empiric antibiotic therapy based on the Number Needed to Fail (NNF) measure. NNF indicates the number of patients that would need to be treated with a specific antibiotic for one to be inadequately treated. We define two new measures, Accumulated Efficacy and Weighted Accumulated Efficacy in order to determine the efficacy of an antibiotic. We carried out two experiments: the first during which there was a suspicion of infection and the patient had empiric therapy, and the second by considering patients with confirmed infection and directed therapy. The study was performed with 15,799 cultures with 356,404 susceptibility tests carried out over a four-year period. RESULTS: The most efficient empiric antibiotics are Linezolid and Vancomycin for blood samples and Imipenem and Meropenem for urine samples. In both experiments, the efficacies of recommended antibiotics are all significantly greater than the efficacies of the antibiotics actually administered (P < 0.001). The highest efficacy is obtained when considering 2 years of antibiogram data and 80% of the cumulated prevalence of microorganisms. CONCLUSION: This extensive study on real empiric therapies shows that the proposed method is a valuable alternative to traditional antibiograms as regards developing clinical decision support systems for antimicrobial stewardship. PMID- 29981886 TI - Joint dyadic action: Error correction by two persons works better than by one alone. AB - We investigated how two people learn to coordinate their movement to achieve a joint goal. Pairs of participants oscillated a joystick with their dominant hand whilst looking at a common feedback, a Lissajous figure, where each participant controlled either the vertical or horizontal coordinate of a moving dot. In the absence of specific instructions, inter-personal coordination was highly variable, punctuated by intermittent phase locking. When participants were required to produce a circular Lissajous figure, coordination variability decreased while accuracy, transfer entropy and the incidence of stable coordinative solutions (fixed points, including bi-stability) increased as a function of practice trials. When one partner closed his/her eyes, so that the other one received the full control of error correction, the stability and accuracy of coordination decreased. A questionnaire showed that partners experienced the feeling of we-control. The results were interpreted in terms of a disturbance ~ correction challenge: joint action is enhanced by having a flexibly adjusting co-actor rather than a more predictable, but not adjusting, partner. At transfer, partners were able to produce a new, never-practiced Lissajous pattern, evidencing the generalisability of joint learning. PMID- 29981887 TI - Solution structure and dynamics of glia maturation factor from Caenorhabditis elegans. AB - BACKGROUND: The GMF class of the ADF-H domain family proteins regulate actin dynamics by binding to the Arp2/3 complex and F-actin through their Site-1 and Site-2, respectively. CeGMF of C. elegans is analogous to GMFgamma of human and mouse and is 138 amino acids in length. METHODS: We have characterized the solution structure and dynamics of CeGMF by solution NMR spectroscopy and its thermal stability by DSC. RESULTS: The solution structure of CeGMF shows canonical ADF-H fold with two additional beta-strands in the beta4-beta5 loop region. The Site-1 of CeGMF is well formed and residues of all three regions of Site-1 show dynamic flexibility. However, the beta4-beta5 loop of Site-2 is less inclined towards the C-terminal, as the latter is truncated by four residues in comparison to GMF isoforms of human and mouse. Regions of Site-2 show motions on ns-ps timescale, but dynamic flexibility of beta4-beta5 loop is low in comparison to corresponding F-loop region of ADF/cofilin UNC-60B. A general difference in packing of alpha3 and alpha1 between GMF and ADF/cofilins was noticed. Additionally, thermal stability of CeGMF was significantly higher than its ADF/cofilin homologs. CONCLUSION: We have presented the first solution structure of GMF from C. elegans, which highlights the structural differences between the Site-2 of CeGMF and mammalian GMF isoforms. Further, we have seen the differences in structure, dynamics, and thermal stability of GMF and ADF/cofilin. GENERAL SIGNIFICANCE: This study provides a useful insight to structural and dynamics factors that define the specificity of GMF towards Arp2/3 complex. PMID- 29981888 TI - Establishment of a human induced stem cell line (FUi002-A) from Dravet syndrome patient carrying heterozygous R1525X mutation in SCN1A gene. AB - De novo mutations in SCN1A are the most common cause of Dravet syndrome (DS), an infantile-onset epileptic encephalopathy. In this study, human induced pluripotent stem cell (hiPSC) line FUi002-A was generated from skin fibroblasts obtained from a clinically diagnosed 26-year-old male DS patient with the R1525X variant of the SCN1A gene. Skin fibroblasts were reprogrammed using OriP/EBNA-1 based episomal plasmids expressing reprogramming factors expressing OCT4, SOX2, KLF-4, L-MYC, LIN28, and p53 shRNA. The transgene-free FUi002-A showed pluripotency, three germ layer differentiation capacity in vitro, and a normal karyotype. The resulting hiPSCs were heterozygous for the mutation in the SCN1A gene. PMID- 29981889 TI - Coronary artery disease in renal transplant recipients: an angiographic study. AB - BACKGROUND: Cardiovascular disease is the leading cause of mortality in renal transplant recipients (RT). Coronary artery disease (CAD) in such patients is poorly studied. METHODS: During 2012-2017, 50 patients with a renal graft (functioning for a minimum of 6 months) were subjected to coronary angiography in our institution. They were matched (for age, gender, diabetes, and indication for angiography) with 50 patients with end-stage renal disease (ESRD) undergoing chronic dialysis and 50 patients with normal renal function who were subjected to coronary angiography during the same period. The extent and severity of CAD were assessed by using the SYNTAX score. RESULTS: RT had a significantly longer duration of ESRD than patients on dialysis (17.5+/-7.1 vs. 8.5+/-8.7 years, p<0.01). Mean SYNTAX score was 13.3+/-12.0 in RT, 20.6+/-17.5 in patients on dialysis, and 9.4+/-9.2 in control patients (p<0.01). At least one significantly calcified lesion was present in 75.7% of RT recipients, 92.1% of patients on dialysis, and 15.8% of control patients (p<0.01). Percutaneous coronary intervention (PCI) was successful in 93.8% of the attempted cases in RT, 75% of patients on chronic dialysis, and 100% of control patients (p=0.04). In the RT group, SYNTAX score significantly correlated with smoking (p=0.02) and the total vintage of ESRD (p=0.04). CONCLUSIONS: In this angiographic study, CAD was less severe in RT than in patients on long-term dialysis despite a longer duration of ESRD. Coronary artery calcification was highly prevalent after renal transplantation. PCI in RT had a high rate of angiographic success. PMID- 29981890 TI - Study on process parameters and optimization of microencapsulation based on phase separation. AB - As surfactants are capable of influencing the droplet formation, our study primarily aims the investigation of the effect of a nonionic surfactant e.g. Polysorbate 80 on the formation of microspheres on the course of vibrating nozzle method with coacervation. The experiments also concern the impact of the different process parameters (e.g. vibration frequency, feed rate and voltage) on the shape and size distribution of microspheres characterized by laser diffraction size determination completed with particle image analysis. The calcium-alginate microspheres were processed using freeze-drying to ensure solid state with better drug carrier capability. Addition of isomalt was advantageous in the formation of freeze-dried microspheres at low alginate concentration, which was explained by micro-CT analysis of the constructed particle structure. The internal three-dimensional network of calcium alginate demonstrated a more cancellous architecture ameliorating the roundness of microparticles. PMID- 29981891 TI - A novel biocompatible NiII tethered moiety as a glucose uptake agent and a hit against methicillin-resistant Staphylococcus aureus. AB - In the efforts to develop a biocompatible transition metal complex as a drug alike for some of the prevailing non-communicable diseases (NCDs) and communicable diseases (CDs), a novel binuclear NiII compound [{NiII(hpdbal sbdt)}2] (2) has been synthesized by the reaction of Ni(OAc)2.4H2O and H2hpdbal sbdt (1) [1 is a dibasic tridentate ONS2- donor Schiff base ligand obtained by the condensation of 2-hydroxy-5-(phenyldiazenyl)benzaldehyde (Hhpdbal) and S benzyldithiocarbazate (Hsbdt)]. Both ligand 1 and compound 2 were structurally characterized in the solid and solution state using various spectroscopic techniques like ATIR, 1H NMR, 13C NMR, TGA, FESEM, EDS and CHNS analysis. The antidiabetic activity of H2hpdbal-sbdt (1) and [{NiII(hpdbal-sbdt)}2] (2) were assessed using 2-NBDG uptake assay. The assay results showed 85% and 95% of fluorescent glucose uptake by insulin resistant HePG2 cells treated with compounds 1 and 2 respectively. The 2-NBDG uptake by the cells treated with the compound 2 was observed to be comparable to the standard antidiabetic drug metformin. Compounds 1 and 2 were also tested against five bacterial and two fungi strains in order to evaluate pathogen killing activity. Compound 2 showed significant inhibitory action towards the methicillin-resistant Staphylococcus aureus (MRSA) strain with an MIC value of 2 MUg/mL whereas the ligand 1 was found to be inactive. Furthermore, the interactive nature of compound 2 with a model serum carrier protein bovine serum albumin (BSA) was studied using a multi spectroscopic approach which provided an insight into the nature and extent of binding, conformational changes and the quenching of amino acid residues of the protein. PMID- 29981892 TI - I-131 doping of silver nanoparticles platform for tumor theranosis guided drug delivery. AB - Nanotechnology may be applied in medicine where the utilization of nanoparticles (<=100 nm) for the delivery and targeting of theranostic agents is at the forefront of projects in cancer nano-science. This study points a novel one step synthesis approach to build up polyethylene glycol capped silver nanoparticles doped with I-131 radionuclide (131I-doped Ag-PEG NPs). The formula was prepared with average hydrodynamic size 21 nm, zeta potential - 25 mV, radiolabeling yield 98 +/- 0.76%, and showed good in-vitro stability in saline and mice serum. The in vitro cytotoxicity study of cold Ag-PEG NPs formula as a drug carrier vehicle showed no cytotoxic effect on normal cells (WI-38 cells) at a concentration below 3 MUL/104 cells. The in-vivo biodistribution pattern of 131I-doped Ag-PEG NPs in solid tumor bearing mice showed high radioactivity accumulation in tumor tissues with maximum uptake of 35.43 +/- 1.12 and 63.8 +/- 1.3% ID/g at 60 and 15 min post intravenous (I.V.) and intratumoral injection (I.T.), respectively. Great potential of T/NT ratios were obtained throughout the experimental time points with maximum ratios 45.23 +/- 0.65 and 92.46 +/- 1.02 at 60 and 15 min post I.V. and I.T. injection, respectively. Thus, 131I-doped Ag-PEG NPs formulation could be displayed as a great potential tumor nano-sized theranostic probe. PMID- 29981893 TI - Inhibition of multidrug resistance-associated protein 2 (MRP2) activity by the contraceptive nomegestrol acetate in HepG2 and Caco-2 cells. AB - Multidrug resistance-associated protein 2 (MRP2) plays a key role in hepatic and intestinal disposition of endo- and xenobiotics. Several therapeutic agents modulate MRP2 activity resulting in pharmacological interactions. Nomegestrol acetate (NMGA) is a progestogen increasingly used in contraceptive formulations. The aim of this work was to evaluate the effect of NMGA on MRP2 activity in HepG2 and Caco-2 cells as models of human hepatocytes and enterocytes, respectively. NMGA (5, 50 and 500 nM; 48 h) decreased MRP2-mediated transport of 2,4 dinitrophenyl-S-glutathione in HepG2 cells, with no effect on MRP2 protein expression. Acute exposure (1 h) to the same concentrations of NMGA failed to affect MRP2 activity, ruling out an inhibitory action directly induced by the drug. In contrast, acute incubation with a lysate of HepG2 cells pre-treated with NMGA, containing potential metabolites, reproduced MRP2 inhibition. Preincubation of lysates with sulfatase but not with beta-glucuronidase abolished the inhibitory action, strongly suggesting participation of NMGA sulfated derivatives. Western blot studies in plasma vs. intracellular membrane fractions ruled out internalization of MRP2 to be responsible for the impairment of transport activity. MRP2-mediated transport of 5(6)-carboxy-2',7' dichlorofluorescein was not affected in Caco-2 cells incubated for 48 h with either 5, 50 or 500 nM NMGA. Conversely, acute exposure (1 h) of Caco-2 cells to NMGA-treated HepG2 lysates decreased MRP2 activity, being this effect also prevented by pre-treatment of the lysates with sulfatase. Taken together, these findings demonstrate an inhibitory effect of NMGA sulfated metabolites on hepatic and intestinal MRP2 function. Extrapolated to the in vivo situation, they suggest the possibility of pharmacological interactions with coadministered drugs. PMID- 29981894 TI - Population, basicity and partition of short-lived conformers. Characterization of baclofen and pregabalin, the biaxial, doubly rotating drug molecules. AB - Populations, protonation constants and octanol-water partition coefficients were determined and assigned specifically to fast interconverting individual conformers, exemplified in baclofen and pregabalin, the GABA-related drug molecules of biaxial, double rotations. Rotamer statuses along both axes in water and octanol were elucidated from 1H NMR vicinal coupling constants. Conformer abundances were obtained by the appropriate combination of the rotamer populations in the two adjacent moieties in the molecule. The bulky aromatic group in baclofen versus the aliphatic side chain of pregabalin explains why baclofen exists mainly in trans-trans conformeric form, throughout the pH range, unlike pregabalin that has no any highly dominant form. Characteristically enough, for pregabalin, the lipophilicity of the conformers is primarily influenced by the conformation state. Conformers in gauche state are of higher lipophilicity. The conformers of the two compounds were ranked by their membrane influx and -outflow propensities. PMID- 29981895 TI - Lipid-coated superparamagnetic nanoparticles for thermoresponsive cancer treatment. AB - Poor aqueous solubility, chemical instability, and indiscriminate cytotoxicity have limited clinical development of camptothecin (CPT) as potent anticancer therapeutic. This research aimed at fabricating thermoresponsive nanocomposites that enhance solubility and stability of CPT in aqueous milieu and enable stimulus-induced drug release using magnetic hyperthermia. 1,2-Dipalmitoyl-sn glycero-3-phosphocholine (DPPC) and l-alpha-dipalmitoylphosphatidyl glycerol (DPPG) (1:1, mol/mol) were immobilized on the surface of superparamagnetic Fe3O4 nanoparticles (SPIONs) via high affinity avidin-biotin interactions. Heating behavior was assessed using the MFG-1000 magnetic field generator. Encapsulation efficiency and drug release were quantified by fluorescence spectroscopy. Anticancer efficacy of medicated nanoparticles was measured in vitro using Jurkat cells. The results revealed that drug incorporation did not significantly alter particle size, zeta potential, magnetization, and heating properties of lipid coated SPIONs. Drug loading efficiency was 93.2 +/- 5.1%. Drug release from medicated nanoparticles was significantly faster at temperatures above the lipid transition temperature, reaching 37.8 +/- 2.6% of incorporated payload after 12 min under therapeutically relevant hyperthermia (i.e., 42 degrees C). Medicated SPIONs induced greater cytotoxicity than CPT in solution suggesting synergistic activity of magnetically-induced hyperthermia and drug-induced apoptosis. These results underline the opportunity for thermoresponsive phospholipid-coated SPIONs to enable clinical development of highly lipophilic and chemically unstable drugs such as CPT for stimulus-induced cancer treatment. PMID- 29981896 TI - A stimuli-responsive insulin delivery system based on reversible phenylboronate modified cyclodextrin with glucose triggered host-guest interaction. AB - Injection of insulin is an effective therapy to treat most patients with the type I diabetes and some with type II diabetes. Additionally, the release of insulin under specific conditions has attracted widespread interest. In this study, a smart drug carrier that can release insulin depending on the changes in blood glucose levels was designed. Combining two popular molecules through facile synthetic processes, a drug carrier of reversible phenylboronate group modified cyclodextrin (beta-CD-EPDME) was fabricated. The drug carrier is composed of cyclodextrin, which can encapsulate insulin, and phenylboronate, which is sensitive to the cis-diols in some saccharides. Moreover, beta-CD-EPDME can successfully encapsulate insulin and almost completely release insulin in the presence of glucose. The detached phenylboronic acid moiety triggered by glucose can attack the beta-CD cavity and form a host-guest complex, which can force out the encapsulated insulin within the cavity. In addition, the insulin released from the beta-CD-EPDME@Insulin complex retains its secondary structure, and the drug carrier has been proven to have low cytotoxicity. Thus, this safe and glucose-responsive drug carrier shows the potential for use in the therapy of diabetes. PMID- 29981897 TI - Amorphous magnesium carbonate nanoparticles with strong stabilizing capability for amorphous ibuprofen. AB - Formulating active pharmaceutical ingredients (APIs) in the amorphous state can increase their apparent aqueous solubility and dissolution rate and consequently improve their bioavailability. This study demonstrates, for the first time, the ability to stabilize an API in the amorphous state using a solid dispersion of magnesium carbonate nanoparticles within the API. Specifically, high proportions of ibuprofen were able to be stabilized in the amorphous state using as little as 17% wt/wt amorphous magnesium carbonate nanoparticles, and drug release rates 83 times faster than from the crystalline state were achieved. Biocompatibility of the nanoparticles was demonstrated in vitro using human dermal fibroblasts and stability of the nanocomposite formulation was verified with a storage time of six months. The success of this novel formulation provides a promising approach for achieving improved apparent solubility and enhanced bioavailability of drugs. PMID- 29981898 TI - Ablation of N-acetylglucosaminyltransferases in Caenorhabditis induces expression of unusual intersected and bisected N-glycans. AB - The modification in the Golgi of N-glycans by N-acetylglucosaminyltransferase I (GlcNAc-TI, MGAT1) can be considered to be a hallmark of multicellular eukaryotes as it is found in all metazoans and plants, but rarely in unicellular organisms. The enzyme is key for the normal processing of N-glycans to either complex or paucimannosidic forms, both of which are found in the model nematode Caenorhabditis elegans. Unusually, this organism has three different GlcNAc-TI genes (gly-12, gly-13 and gly-14); therefore, a complete abolition of GlcNAc-TI activity required the generation of a triple knock-out strain. Previously, the compositions of N-glycans from this mutant were described, but no detailed structures. Using an off-line HPLC-MALDI-TOF-MS approach combined with exoglycosidase digestions and MS/MS, we reveal that the multiple hexose residues of the N-glycans of the gly-12;gly-13;gly-14 triple mutant are not just mannose, but include galactoses in three different positions (beta-intersecting, beta bisecting and alpha-terminal) on isomeric forms of Hex4-8HexNAc2 structures; some of these structures are fucosylated and/or methylated. Thus, the N-glycomic repertoire of Caenorhabditis is even wider than expected and exhibits a large degree of plasticity even in the absence of key glycan processing enzymes from the Golgi apparatus. PMID- 29981900 TI - The methodology study of three-dimensional (3D) genome research. AB - Multiple dimensions of genome organization play critical roles in the regulation of non-coding regions in gene expression in cell/organ development and pathogenesis. Precise measurements of multi-dimensional genome structure ensure data quality and fully depend upon the study design. We here overview the number of methodologies used in the detection and analysis of genome structure and compare advantages and disadvantages of 3C-based, PCR amplification-based, and sequencing-based measurements. We discuss about the optimization of various techniques according to targeted genomic sites, the required resolution, and possible technique biases. Comparison of different analysis tools and computational system-based automatic analysis is evaluated to define more opportunities and challenges of data analysis in 3D genome research. The genome structure is visualized in levels of single genome organized by enhancer-promoter interactions, TAD, and intra-chromosomal and inter-chromosomal interactions between TADs. Thus, methodologies of genome organization multi-dimensions are not only critical in studies on 3D genome-regulated transcriptions, but also in the discovery of disease-specific biomarkers and targets for diagnosis and therapies. PMID- 29981899 TI - Plasma N-glycome composition associates with chronic low back pain. AB - BACKGROUND: Low back pain (LBP) is the symptom of a group of syndromes with heterogeneous underlying mechanisms and molecular pathologies, making treatment selection and patient prognosis very challenging. Moreover, symptoms and prognosis of LBP are influenced by age, gender, occupation, habits, and psychological factors. LBP may be characterized by an underlying inflammatory process. Previous studies indicated a connection between inflammatory response and total plasma N-glycosylation. We wanted to identify potential changes in total plasma N-glycosylation pattern connected with chronic low back pain (CLBP), which could give an insight into the pathogenic mechanisms of the disease. METHODS: Plasma samples of 1128 CLBP patients and 760 healthy controls were collected in clinical centers in Italy, Belgium and Croatia and used for N glycosylation profiling by hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) after N-glycans release, fluorescent labeling and clean-up. Observed N-glycosylation profiles have been compared with a cohort of 126 patients with acute inflammation that underwent abdominal surgery. RESULTS: We have found a statistically significant increase in the relative amount of high branched (tri-antennary and tetra-antennary) N-glycan structures on CLBP patients' plasma glycoproteins compared to healthy controls. Furthermore, relative amounts of disialylated and trisialylated glycan structures were increased, while high-mannose and glycans containing bisecting N acetylglucosamine decreased in CLBP. CONCLUSIONS: Observed changes in CLBP on the plasma N-glycome level are consistent with N-glycosylation changes usually seen in chronic inflammation. GENERAL SIGNIFICANCE: To our knowledge, this is a first large clinical study on CLBP patients and plasma N-glycome providing a new glycomics perspective on potential disease pathology. PMID- 29981901 TI - Multilocus sequence typing and population genetic structure of Cryptosporidium cuniculus in rabbits in Heilongjiang Province, China. AB - Multilocus sequence typing (MLST) tools have been used widely to characterize population genetic structure of some Cryptosporidium species. To understand MLST subtypes and population genetic structure of Cryptosporidium cuniculus from rabbits in Heilongjiang Province, China, 34 C. cuniculus DNA specimens were collected including VbA21 (n = 6), VbA28 (n = 2), VbA29 (n = 18) and VbA32 (n = 8). They were analyzed by nested-PCR amplification and sequencing at seven microsatellite, minisatellite and polymorphic loci including CP47, CP56, ML2, DZ HRGP, MSC6-5, MSC6-7 and RPGR. The CP47, CP56, MSC6-5 and MSC6-7 loci were monomorphic. The remaining loci were polymorphic, with two, three and two subtypes being found at ML2, DZ-HRGP and RPGR loci, respectively. Six MLST subtypes were obtained based on sequence information of 29 DNA specimens successfully amplified at all eight loci including gp60 locus. Linkage disequilibrium (LD) analysis showed a clonal population structure of C. cuniculus in the investigated areas. STRUCTURE, neighbor-joining and network analyses indicated the presence of two distinct groups, corresponding to VbA21 subtype and VbA28, VbA29 and VbA32 subtypes. This is the first report of MLST analysis of C. cuniculus. A clonal population structure of C. cuniculus suggested the prevalence of C. cuniculus in Heilongjiang Province is not attributed to the introduction of rabbits. Thus, prevention and control strategies should be focused on making stricter measures to avoid occurrence of cross-transmission and re-infection among rabbit individuals. Based on the previous findings of VbA21 subtype only in rabbits and VbA28, VbA29 and VbA32 subtypes both in rabbits and humans, the results of subpopulation analyses might be used to assess zoonotic potential of C. cuniculus subtypes in Vb family. These data will be helpful to explore source attribution of infection/contamination of C. cuniculus and understand its transmission dynamics in humans and rabbits in the investigated areas. PMID- 29981902 TI - Unexplored deep sea habitats in active volcanic Barren Island, Andaman and Nicobar Islands are sources of novel halophilic eubacteria. AB - Deep Sea sediment cores were collected from the surrounding of active volcanic Barren Island, Andaman & Nicobar Islands. A total of 24 halophilic eubacteria were isolated and identified based on their biochemical and 16S rDNA sequences. Three major classes (Gamma-Proteobacteria, Alpha-Proteobacteria and Bacilli) of bacteria were detected in the deep sea sediments of active volcanic Barren Island. Among those, 37% of isolates exhibited antimicrobial activity against all tested Gram positive and Gram negative clinical pathogens. 60% of isolates revealed the presence of either PKS or NRPS genes and 65% isolates disclosed medium to higher level of cytotoxicity in MB-231 breast cancer cell line. Majority of the isolates revealed excellent potential for bioprospecting of novel byproducts with industrial and pharmaceutical importance. PMID- 29981903 TI - Divergence from osteoporosis screening guidelines in older breast cancer patients treated with anti-estrogen therapy: A population-based cohort study. AB - PURPOSE: Older Breast Cancer (BC) survivors are an increased risk of osteoporosis due to natural aging and long-term cancer treatment-related toxicity. It is well known that anti-estrogen therapy (AET), especially aromatase inhibitors (AI), is associated with rapid bone loss and thus increases the risk of osteoporosis. This study characterizes patterns and predictors of receiving guideline-recommended bone densitometry (BD) screening at AET initiation. METHODS: A retrospective cohort study (1998-2012) of all women >=65 years of age initiating AET was designed using claims data from Quebec's universal health care. Associations with BD screening were estimated using a generalized estimating equations regression model, adjusting for clustering of patients within physicians. RESULTS: Among 16,480 women initiating AET, 36.1% received a baseline BD. Among AI users, the rate was 58.4%. In the multivariate analysis, age, lower socioeconomic status, tamoxifen use, lack of periodic health exam and having a general practitioner as the AET prescriber were associated with lower odds of BD screening. In terms of quality of care-related variables, lack of guideline-appropriate radiotherapy (OR: 0.69 (95% CI, 0.57-0.83), or chemotherapy consideration (0.82 (95% CI, 0.71 0.94)) and non-adherence to AET (0.76 (95% CI, 0.68-0.84)) were associated with lower odds of receiving BD screening. Women diagnosed with BC after 2003 had significantly better odds of being screened. CONCLUSION: Despite an increase in rates since 2003, BD screening remains suboptimal, especially for women at higher risk of osteoporosis. Coordination of health care and service-delivery monitoring can potentially optimize long-term management of treatment-related toxicity in older BC survivors. PMID- 29981904 TI - Physical exercise increases overall brain oscillatory activity but does not influence inhibitory control in young adults. AB - Extant evidence suggests that acute exercise triggers a tonic power increase in the alpha frequency band at frontal locations, which has been linked to benefits in cognitive function. However, recent literature has questioned such a selective effect on a particular frequency band, indicating a rather overall power increase across the entire frequency spectrum. Moreover, the nature of task-evoked oscillatory brain activity associated to inhibitory control after exercising, and the duration of the exercise effect, are not yet clear. Here, we investigate for the first time steady state oscillatory brain activity during and following an acute bout of aerobic exercise at two different exercise intensities (moderate-to high and light), by means of a data-driven cluster-based approach to describe the spatio-temporal distribution of exercise-induced effects on brain function without prior assumptions on any frequency range or site of interest. We also assess the transient oscillatory brain activity elicited by stimulus presentation, as well as behavioural performance, in two inhibitory control (flanker) tasks, one performed after a short delay following the physical exercise and another completed after a rest period of 15' post-exercise to explore the time course of exercise-induced changes on brain function and cognitive performance. The results show that oscillatory brain activity increases during exercise compared to the resting state, and that this increase is higher during the moderate-to-high intensity exercise with respect to the light intensity exercise. In addition, our results show that the global pattern of increased oscillatory brain activity is not specific to any concrete surface localization in slow frequencies, while in faster frequencies this effect is located in parieto-occipital sites. Notably, the exercise-induced increase in oscillatory brain activity disappears immediately after the end of the exercise bout. Neither transient (event-related) oscillatory activity, nor behavioural performance during the flanker tasks following exercise showed significant between-intensity differences. The present findings help elucidate the effect of physical exercise on oscillatory brain activity and challenge previous research suggesting improved inhibitory control following moderate-to-high acute exercise. PMID- 29981905 TI - Impulse response timing differences in BOLD and CBV weighted fMRI. AB - Recent advances in BOLD fMRI scan techniques have substantially improved spatial and temporal resolution, currently reaching to sub-millimeter and sub-second levels respectively. Unfortunately, there remain physiological barriers that prevent achieving this resolution in practice. BOLD contrast relies on the hemodynamic response to neuronal activity, whose associated cerebral blood oxygenation (CBO) changes may spread over several millimeters and last several seconds. Recent reports have suggested that significant improvements may be possible with cerebral blood volume (CBV)-weighted fMRI, which highlights the CBV changes rather than the BOLD changes associated with the hemodynamic response. Nevertheless, quantitative comparisons between CBV and BOLD are sparse, in particular regarding their temporal characteristics in human brain. To address this, we studied a cohort of subjects that received injection of ferumoxytol, an intravascular iron-oxide based contrast agent that introduces strong CBV contrast. An event-related visual stimulus paradigm was used to compare the impulse response (IR) for CBV and BOLD contrast, obtained with and without ferumoxytol, respectively. Experiments performed at 7 T (n = 5) at 1.2-1.5 mm spatial and 1 s temporal resolution showed that the onset time and time-to-peak of the CBV IR averaged 0.8 and 3.5 s respectively, both 0.6 s shorter than the BOLD IR. While significant, these improvements are relatively small and not expected to lead to practical advantages for the extraction of temporal information about neural activity. Nonlinearities in the observed IR were also compared and found to be similar between the CBV and BOLD, indicating that these are likely not caused by a 'ceiling' effect in the CBO response, but rather support a previously proposed model of vascular compliance, in which changes in vascular tone elicited by a preceding stimulus affect the IR. PMID- 29981906 TI - Neuroplasticity in the cerebello-thalamo-basal ganglia pathway: A longitudinal in vivo MRI study in male songbirds. AB - Similar to human speech, bird song is controlled by several pathways including a cortico-basal ganglia-thalamo-cortical (C-BG-T-C) loop. Neurotoxic disengagement of the basal ganglia component, i.e. Area X, induces long-term changes in song performance, while most of the lesioned area regenerates within the first months. Importantly however, the timing and spatial extent of structural neuroplastic events potentially affecting other constituents of the C-BG-T-C loop is not clear. We designed a longitudinal MRI study where changes in brain structure were evaluated relative to the time after neurotoxic lesioning or to vocal performance. By acquiring both Diffusion Tensor Imaging and 3-dimensional anatomical scans, we were able to track alterations in respectively intrinsic tissue properties and local volume. Voxel-based statistical analyses revealed structural remodeling remote to the lesion, i.e. in the thalamus and, surprisingly, the cerebellum, both peaking within the first two months after lesioning Area X. Voxel-wise correlations between song performance and MRI parameters uncovered intriguing brain-behavior relationships in several brain areas pertaining to the C-BG-T-C loop supervising vocal motor control. Our results clearly point to structural neuroplasticity in the cerebellum induced by basal ganglia (striatal) damage and might point to the existence of a human-like cerebello-thalamic-basal ganglia pathway capable of modifying vocal motor output. PMID- 29981907 TI - Successful Management of Angiographically Occult Spinal Dural Arteriovenous Fistula with Multiple Draining Veins. AB - Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal arteriovenous malformation and frequently cause progressive myelopathy. Early detection and surgical or endovascular intervention are important to preventing permanent neurologic impairment. Selective spinal angiography is still the gold standard for the diagnosis and localization of the SDAVF. Occasionally, these lesions may be angiographically occult. Here we report a case of an angiographically occult SDAVF, which was localized using magnetic resonance angiography. The lesion was successfully treated by direct surgery. PMID- 29981908 TI - Multicentric Cryptococcomas Mimicking Neoplasia in Immunocompetent Patient. AB - BACKGROUND: Fungal mass lesions in the central nervous system are, as a group, extremely rare. In this group cryptococcomas are the most common mass lesions seen. These cryptococcomas/mucinous pseudocysts are commonly only 3-10 mm in diameter and occur almost exclusively in the basal ganglia through contiguous spread from a basal meningitis through the Virchow-Robbin perivascular spaces. In rare cases a chronic granulomatous process may lead to formation of mass lesions that have a tumoral appearance. CASE DESCRIPTION: A 19-year-old male presented to our Neurosurgical Unit with a 5-month history of progressive morning headaches. He also complained of progressive weakness of his R upper limb of 3 months' duration. The patient was found to be human immunodeficiency virus negative with a CD4 count of 1763. The patient had no other medical problems. Examination revealed a monoplegia of his R upper limb. While being optimized for surgery, the patient demonstrated progression of his upper limb monoplegia despite preoperative steroid therapy aimed at decreasing the perilesional vasogenic edema. He was booked for emergency resection of 2 lobar mass lesions. Histopathology analysis revealed the 2 specimens had similar features. These specimens were representative of gliotic brain parenchyma involved by extensive cryptococcosis. CONCLUSIONS: Diagnosing the tumoral form of cryptococcosis in immunocompetent patients is a challenge. Primary and secondary brain tumors are usually the first hypotheses in these cases. Thorough preoperative investigation through cerebrospinal fluid sampling and detailed magnetic resonance imaging may lead to consideration of this diagnosis before the histopathologic analysis has been conducted. PMID- 29981909 TI - Cystic Lymphocytic Hypophysitis Mimicking Pituitary Apoplexy: Daunting Challenge. AB - BACKGROUND: Inflammatory lesions of the pituitary gland including hypophysitis are poorly understood, and it is difficult to make a correct diagnosis on the basis of only clinical and radiologic findings. CASE DESCRIPTION: An otherwise healthy 68-year-old man presented with sudden onset of headache, visual impairment, and pituitary insufficiency. Magnetic resonance imaging revealed a pituitary mass with cystic component showing changing intensity on follow-up images. Also, changing density of the lesion was demonstrated on computed tomography over a short period of time. These findings suggested a hemorrhagic lesion, and a preoperative diagnosis of pituitary apoplexy associated with a preexisting pituitary adenoma was made on the basis of clinical and radiologic findings. In the endoscopic endonasal approach for tumor resection, there was neither hematoma nor adenoma. Histopathologic diagnosis was lymphocytic hypophysitis. CONCLUSIONS: To the best of our knowledge, this is the first case report of hypophysitis with radiologic signal changes over a short period. Vigilant attention regarding the clinical diagnosis of such rare entity is paramount. PMID- 29981910 TI - Effectiveness of Bi-Needle Technique (Hybrid Yeung Endoscopic Spine System/Transforaminal Endoscopic Spine System) for Percutaneous Endoscopic Lumbar Discectomy. AB - OBJECTIVE: The bi-needle technique is a new technique for percutaneous endoscopic lumbar discectomy. This technique combines the advantages of Yeung endoscopic spine system (YESS) and transforaminal endoscopic spine system (TESSYS) techniques. The aim of this study was to evaluate effectiveness of the bi-needle technique for percutaneous endoscopic lumbar discectomy and compare it with the TESSYS technique. METHODS: We reviewed 86 patients with single-level lumbar disc herniation treated by percutaneous endoscopic lumbar discectomy in our hospital from June 2013 to December 2015. Bi-needle technique was used in 49 patients (30 men, 19 women; average age 40.4 +/- 5.2 years). TESSYS technique was used in 37 patients (19 men, 18 women; average age 42.8 +/- 6.4 years). Clinical results were evaluated and compared between the 2 groups. RESULTS: Symptoms in both groups were significantly improved at the last follow-up (P < 0.01). There was no statistical difference in visual analog scale and lumbar Japanese Orthopaedic Association scores between bi-needle and TESSYS groups at last follow-up (P = 0.69 and P = 0.33, respectively). Operative time was shorter in the bi-needle group (P < 0.01). Recurrence rate and reoperation rate were lower in the bi needle group (P = 0.04 and P = 0.03, respectively). Discitis was diagnosed in 2 patients in the TESSYS group. There were no patients with postoperative discitis in the bi-needle group. CONCLUSIONS: The bi-needle technique is safe and effective for treatment of lumbar disc herniation. Compared with TESSYS technique, operative time is shorter, and recurrence and reoperation rates are lower. PMID- 29981911 TI - Giant Pediatric Rhabdoid Meningioma Associated with a Germline BAP1 Pathogenic Variation: A Rare Clinical Case. AB - BACKGROUND: Rhabdoid meningiomas are rare World Health Organization grade 3 tumors that tend to follow an aggressive course, with an increased likelihood for local recurrence, remote metastasis, and cerebrospinal fluid dissemination. Genetic testing has found certain genes associated with reduced time to tumor recurrence. BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene that is associated with multiple tumors, including rhabdoid meningiomas. CASE DESCRIPTION: We present a case of a pediatric patient who presented with a rhabdoid meningioma occurring in the right tentorium and invading multiple venous structures, including the right jugular vein. The patient underwent 5 separate operations for management of this tumor. The first surgery was an intracranial tumor debulking with reconstruction of venous structures. Postoperatively, the patient was unable to have the ventricular catheter removed and underwent placement of a ventriculoperitoneal shunt. Significant recurrence of the intracranial portion of tumor was found during preoperative imaging for her second stage procedure. She underwent a second craniotomy for resection of the tumor. Her postoperative magnetic resonance imaging showed significant residual tumor and the patient therefore underwent a third craniotomy for total tumor resection, which involved reconstruction of the superior sagittal sinus. She did well after this surgery, with no new neurologic deficits. Her final operation involved resection of the residual tumor in the neck and chest by both otolaryngology and cardiothoracic surgery. This surgery involved opening the jugular vein and resecting residual tumor from the intima. Pathologic results from all surgeries were consistent with rhabdoid meningioma; however, the tissue from the biopsy and first craniotomy lacked the high-grade features that were found on subsequent resections. Genetic analysis found loss of both BAP1 tumor suppressor genes. Peripheral blood testing showed that this patient was a germline carrier of a pathogenic BAP1 variant. DISCUSSION: Pediatric rhabdoid meningiomas represent a rare disease and are found on recurrent tumors in conjunction with lower-grade meningioma disease. Our patient presented with what was initially believed to be a low-grade meningioma with rhabdoid features, which then transformed into a World Health Organization grade III rhabdoid meningioma on recurrence. This tumor was discovered to have a biallelic loss of BAP-1 mutation and the patient was found to have a germline mutation in 1 of her BAP-1 alleles. Germline mutations in BAP-1 are associated with a cancer syndrome that involves uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors, and clear-cell renal cell carcinoma. Patients with this mutation are encouraged to undergo annual eye examinations starting at the age of 11 years. The BAP-1 tumor predisposition syndrome is most commonly an inherited mutation associated with incomplete penetrance and variation with nonoverlapping tumor types. CONCLUSIONS: Rhabdoid meningiomas are unlikely to be found in children and have a high rate of local recurrence. Gross total resection has to be balanced with risk of postoperative deficit. Genetic testing of this rare entity should be performed to identify any hereditary germline mutations. PMID- 29981912 TI - Prospective Study of Nonbeneficial Care in Neurocritical Care Unit. AB - OBJECTIVE: We sought to determine whether a set of simple criteria can identify patients in the neuroscience intensive care unit (NICU) at high risk of poor outcome and delivery of nonbeneficial care early in the course of their illness. Secondarily, factors affecting limitation of care protocols were assessed. METHODS: We prospectively identified patients who were admitted to the NICU with partial loss of brainstem reflexes persisting for >24 hours due to an intrinsic lesion of the brain (trauma, stroke, hemorrhage, etc.). RESULTS: The study included 102 patients. Seventy-two of them died after a mean of 16 days (median: 8 days), and 23 remained comatose, locked-in, or in a vegetative state. Four were conscious and following commands, while 3 were minimally conscious, episodically obeying simple commands. Three out of 4 conscious patients were young males with traumatic brain injuries. Patients who remained full code spent a mean of 22.2 days in the NICU, compared with 10.4 for those who had withdrawal of care (P = 0.022) and 11.9 for patients who received a do-not-resuscitate order (P = 0.045). Time to death did not differ significantly between the groups. Overall, institution of various limitations of care protocols correlated positively with older age (odds ratio [OR] = 1.07, P = 0.0008), being treated on the neurology service (OR = 4.4, P = 0.043), and having health insurance (OR = 5.4, P = 0.03). CONCLUSIONS: We identified simple criteria that can be used to identify patients in the NICU setting for whom continued aggressive care is likely nonbeneficial. Our analysis revealed demographic, social, and economic factors correlating with proxies' willingness to consider limitation of care. PMID- 29981913 TI - Surgical Management of Sphenoid Sinus Lateral Recess Cerebrospinal Fluid Leaks: A Single Neurosurgical Center Analysis of Endoscopic Endonasal Minimal Transpterygoid Approach. AB - OBJECTIVE: To review the results of sphenoid sinus lateral recess (SSLR) cerebrospinal fluid (CSF) leaks treated with the endoscopic endonasal minimal transpterygoid approach (EEMTPA) and to discuss the surgical technique and outcomes. METHODS: We performed a retrospective analysis of 13 cases who underwent SSLR CSF leak repair through the EEMTPA in our clinic between September 2008 and December 2017. Demographic and etiological features with reconstruction and surgical outcomes were examined. Mean follow-up time was 6.1 years. RESULTS: In regard to etiology, the SSLR CSF leaks included 9 patients with spontaneous, 2 patients with traumatic, and 2 with iatrogenic causes. CSF leak was at the left lateral recess in 8 cases and at right lateral recess in 5 cases. Nine patients had empty sella syndrome, and 11 patients had meningoencephaloceles in addition to SSLR CSF leaks. All patients underwent surgery through the EEMTPA, and a multilayer closure with tissue overlay grafts were used for reconstruction. A pedicled nasoseptal flap and/or pedicled middle turbinate flap were applied to the area of the leak in all cases. One patient had a persistent CSF leak and another had recurrence, both of which required revision surgery. Our overall success rate was 100%. CONCLUSIONS: EEMTPA is a safe and effective method that can be used to treat challenging pathologies at the SSLR, including CSF leaks accompanying meningoencephaloceles. Furthermore, the success rate of EEMTPA for SSLR CSF leaks can be increased by applying endoscopic skull base reconstruction techniques such as the pedicled nasoseptal flap and pedicled middle turbinate flap. PMID- 29981915 TI - Interval Recovery of Syringomyelia in Chiari I Malformation Patient with Acute Cervical Trauma After Anterior Decompression: Case Report and Review of Literature. AB - BACKGROUND: Syringomyelia in the cervical spinal cord is a complex pathology that is commonly associated with Chiari I malformation or spinal cord trauma. In both cases the development of syringomyelia has been linked to multiple anatomic and molecular elements including epidural compression. Literature has mainly reported posterior cervical decompressive procedures or shunting of the cyst as options to address this pathology. Anterior decompression is rarely recommended. CASE DESCRIPTION: We present the case of a 19-year-old female who suffered a motor vehicle accident causing a cervical subluxation with mild new-onset neurologic deficits. Preoperative workup showed a large incidental cervical syringomyelia associated with a Chiari I malformation. Anterior cervical decompression at the subluxated cervical segment with a concomitant anterior and posterior fusion was performed. Postoperative workup revealed a significant interval reduction in the size of the syrinx cavity with concomitant neurologic improvement. CONCLUSIONS: Anterior decompression may be considered as an option in select cases of syringomyelia. The findings of this case support the theory of epidural compression as one of the inciting events for the development of syringomyelia. PMID- 29981914 TI - Prognosis of Symptoms and Complications After Microvascular Decompression for Hemifacial Spasm: A Single-Center Experience. AB - OBJECTIVE: The aim of this study was to identify potential prognostic factors of hemifacial spasm (HFS) after microvascular decompression (MVD), to establish the appropriate way to tackle postprocedure symptoms and complications (PPSCs), and to find the incidence and duration of PPSCs. METHODS: Two hundred and forty-eight patients with HFS were monitored between December 2009 and December 2014. The mean follow-up duration was 24 months (range, 6-67 months). We divided patients based on their PPSC status and investigated the following factors: age, sex, spasm side, facial nerve block before MVD (botulinum toxin treatment), acupuncture before MVD, duration of HFS, hypertension, diabetes, hepatitis B virus (HBV) infection status, herpes simplex virus infection status, smoking status and alcohol use, offending vessels, Chiari malformation, electrophysiologic monitoring results, and postoperative HFS. Univariable analysis and multivariate logistic regression were used to find potential risk factors. Kaplan-Meier analysis was used to show the duration of postprocedure facial palsy. RESULTS: Age (odds ratio [OR], 1.037; 95% confidence interval [CI], 1.004-1.072; P = 0.03) and HBV status (OR, 18.256; 95% CI, 2.723-122.415; P = 0.03) were positive predictors of PPSCs. Postoperative HFS (OR, 0.249; 95% CI, 0.084-0.0739; P = 0.012) may be a protective factor for postprocedure facial palsy. Most PPSCs related to cranial nerves recovered spontaneously in 3 months. Infections and cerebrospinal fluid leakages were controlled by medical intervention in 1-2 weeks. The permanent complication rate was only 4.8%. CONCLUSIONS: Although the incidence of PPSCs after MVD is very high, most PPSCs related to cranial nerves recovered spontaneously in several days. Permanent complications after MVD for HFS are rare. Age may relate to the occurrence of PPSCs, and postoperative HFS may be a protective factor for patients with facial palsy after MVD. PMID- 29981917 TI - Taking Theory to Practice: Quality Improvement for Pancreaticoduodenectomy and Development and Integration of the Fistula Risk Score. AB - BACKGROUND: Improvements in surgical outcomes are predicated on recognizing effective practices with subsequent adaptation. It is unknown whether risk assessment for pancreatic fistula (clinically relevant postoperative pancreatic fistula [CR-POPF]) after pancreaticoduodenectomy (PD) translates to improved patient outcomes at the practice level. STUDY DESIGN: A prospectively collected, single-surgeon career experience (2003 to 2018) of 455 consecutive pancreatectomies (303 PDs and 152 distal pancreatectomies) was examined. Analysis occurred during 4 eras of practice: learning curve for PD (n = 50); development of the Fistula Risk Score (n = 48); reactive, data-driven adjustments of anastomotic stent use (n = 94); and omission of prophylactic octreotide with adoption of selective drainage (n = 111). Observed to expected ratios of CR-POPF were calculated using a multi-institutional derivation set (5,379 PDs). RESULTS: After adjustment for increasing fistula risk across the 4 eras (p = 0.016), the risk-adjusted CR-POPF rate declined significantly (observed to expected ratio 1.42->1.28->1.01->0.30; p < 0.001). Literature-driven changes in fistula mitigation strategies likewise led to reductions in the overall complication burden (Postoperative Morbidity Index: 0.20->0.24->0.25->0.15; p = 0.015) and resource use (therapeutic antibiotics: p = 0.019; hospital readmission: p = 0.006; postoperative transfusion: p = 0.007). In contrast, the CR-POPF rate after distal pancreatectomy, for which no validated risk-adjustment process exists, did not vary (approximately 12%; p = 0.878). CONCLUSIONS: Patient outcomes for PD can be optimized by risk-adjusted evaluation and deliberate modification of practice. PMID- 29981916 TI - Dural and Pial Arteriovenous Fistulas Connected to the Same Drainer in the Middle Cranial Fossa: A Case Report. AB - BACKGROUND: Dural arteriovenous fistulas (AVFs) in the middle cranial fossa are rare. Pial AVFs are similarly rare but differ from dural AVFs in that they derive their arterial supply from pial or cortical arterial vessels and do not lie within the intradural region. We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. CASE DESCRIPTION: In a 58-year-old man with a subcortical hemorrhage in the right temporal lobe, digital subtraction angiography showed a dural AVF in the middle cranial fossa fed by the middle meningeal artery (MMA) and draining into the sphenopetrosal vein. A combination with a small pial AVF connected to the same sphenopetrosal vein was suspected. Open surgery was performed to directly observe the shunt points. Transarterial indocyanine green (ICG) angiography using the MMA via the superficial temporal artery on a skin flap was performed to repeatedly and distinctly evaluate the dural shunt points and to prevent cerebral thromboembolism. Although the dural supply was completely disconnected, the sphenopetrosal vein remained arterialized. ICG angiography revealed pial AVF, which was fed by the cortical arteries draining into the same drainer. The pial supply was completely disconnected, and disappearance of the dural and pial AVF was confirmed. CONCLUSIONS: We report an extremely rare case of dural and pial AVF connected to the same drainer in the middle cranial fossa. To our knowledge, this is the first such case report described in the literature. PMID- 29981918 TI - Surgeon-Reported Complications vs AHRQ Patient Safety Indicators: A Comparison of Two Approaches to Identifying Adverse Events. AB - BACKGROUND: Traditionally, clinicians present complications at surgical morbidity and mortality (M&M) conferences, and the AHRQ Patient Safety Indicators (PSIs) use inpatient administrative data to identify certain adverse outcomes. Although both methods are used to identify adverse events and inform quality improvement efforts, these 2 methods might not overlap. STUDY DESIGN: This is a retrospective observational study of all hospitalizations at a single academic department of surgery (including subspecialties) in 2016 involving a PSI-defined event (PSIs 03, 05 to 15) identified by surgery faculty and residents for review by departmental M&M conference or administrative data (according to AHRQ, version 6.0). Pediatric cases were excluded. We analyzed the degree to which these 2 processes captured PSI-defined events and reasons for exclusion by each process. RESULTS: Among 6,563 surgical hospitalizations, 647 hospitalizations (9.9%) had at least 1 complication identified by the M&M process or the PSIs (or both). Of these hospitalizations, 116 had at least 1 PSI-defined event (for a total of 149 PSI-defined events) captured by either M&M or the PSIs. Most complications (n = 82 [88.2%]) identified by M&M alone were excluded by PSI criteria (as intended), but 11 true PSI events (ie false negatives) were identified by M&M only. In contrast, pressure ulcers and central venous catheter-related bloodstream infections were detected exclusively by the PSIs and not reported via M&M. There was limited overlap, with 18 events (12.1%) captured by both processes. CONCLUSIONS: Surgical M&M and the PSIs are complementary approaches to identifying complications. Both case-finding processes should be used to inform quality improvement efforts. PMID- 29981919 TI - The cardenolides strophanthidin, digoxigenin and dihydroouabain act as activators of the human RORgamma/RORgammaT receptors. AB - Two isoforms of a ligand-activated nuclear receptor, RORgamma and RORgammaT, have been implicated in various physiological functions, including energy metabolism, circadian rhythm and immune system development. Using a stably transfected reporter cell line, we screened two chemical libraries and identified three cardenolides (natural, plant-derived pesticides) as activators of RORgamma dependent transcription. These compounds increased G6PC and NPAS2 expression in HepG2 cells, accompanied by increased occupancy of RORgamma within the promoters of these genes. Further, strophanthidin, digoxigenin and dihydroouabain upregulated IL17A and IL17F expression and enhanced IL17 secretion in Th17 human lymphocytes. Molecular docking analyses of these compounds to the RORgamma LBD showed favorable docking scores, suggesting that cardenolides may act as agonists of the receptor. Thus, our results provide new chemical structures for further development of RORgamma-selective modulators with virtual therapeutic potential. PMID- 29981920 TI - Fluorochloridone perturbs blood-testis barrier/Sertoli cell barrier function through Arp3-mediated F-actin disruption. AB - There are reports of fluorochloridone (FLC)-induced male reproductive toxicity, but the underlying toxicological mechanisms remain unknown. In this study, we looked at how FLC exposure affected the integrity of the blood-testis barrier (BTB) and the Sertoli cell barrier and studied the molecular mechanisms. Male rats received gavage administration of FLC (30 mg/kg/d) for 14 consecutive days with sample collection at the 7th and 14th day; and primary cultured Sertoli cells were treated with 0-10 MUM FLC in vitro for 24 h. Our in vivo findings revealed that FLC exposure caused time-dependent testicular injuries, sperm quality decrease as well as adverse changes in BTB integrity, F-actin organization, and expressions of claudin-11 and Arp3. In Sertoli cells isolated from FLC-treated rat testis, Sertoli cell barrier tightness was increased. In Sertoli cells in vitro exposed to FLC, abnormal changes in the barrier permeability were also observed, and the protein expressions of occludin, claudin 11, ZO-1, connexin-43, and Arp3 were significantly decreased in a dose- and time dependent manner. Furthermore, the FLC-induced adverse changes in Sertoli cell barrier and F-actin were partly alleviated by the induction of Arp3 overexpression. In conclusion, our findings revealed that FLC perturbed BTB/Sertoli cell barrier function through Arp3-mediated F-actin disorganization. PMID- 29981921 TI - Prenatal nicotine exposure retards osteoclastogenesis and endochondral ossification in fetal long bones in rats. AB - This study investigated the mechanisms underlying the retarded development of long bone in fetus by prenatal nicotine exposure (PNE) which had been demonstrated by our previous work. Nicotine (2.0 mg/kg.d) or saline was injected subcutaneously into pregnant rats every morning from gestational day (GD) 9 to 20. Fetal femurs or tibias were harvested for analysis on GD 20. We found massive accumulation of hypertrophic chondrocytes and a delayed formation of primary ossification center (POC) in the fetal femur or tibia of rat fetus after PNE, which was accompanied by a decreased amount of osteoclasts in the POC and up regulated expression of osteoprotegerin (OPG) but by no obvious change in the expression of receptor activator of NF-kappaB ligand (RANKL). In primary osteoblastic cells, both nicotine (0, 162, 1620, 16,200 ng/ml) and corticosterone (0, 50, 250, 1250 nM) promoted the mRNA expression of OPG but concentration dependently suppressed that of RANKL. Furthermore, blocking alpha4beta2-nicotinic acetylcholine receptor (alpha4beta2-nAChR) or glucocorticoid receptor rescued the above effects of nicotine and corticosterone, respectively. In conclusion, retarded osteoclastogenesis may contribute to delayed endochondral ossification in long bone in fetal rats with PNE. The adverse effects of PNE may be mediated via the direct effect of nicotine and indirect effect of maternal corticosterone on osteoblastic cells. PMID- 29981922 TI - Poly (ADP-ribose) glycohydrolase silencing-mediated maintenance of H2A and downregulation of H2AK9me protect human bronchial epithelial cells from benzo(a)pyrene-induced carcinogenesis. AB - Poly (ADP-ribosylation) is a key post-translational modification (PTM), and poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme that hydrolyzes poly (ADP ribose) in eukaryotic organisms. Our previous findings suggested that knockdown of PARG attenuates benzo(a)pyrene (BaP) carcinogenesis. However, the mechanisms underlying PARG-mediated protective effects remain limited. In this study, the expression levels of histones were analyzed by Western blotting and immunofluorescence. Histone H2A levels were abnormally decreased by BaP-induced carcinogenesis, but were maintained by knockdown of PARG in the 16HBE human bronchial epithelial cell line. The interaction between poly (ADP-ribose) and H2A was confirmed by co-immunoprecipitation. PARG-related modifications in H2A were profiled by immune antibody enrichment coupled with mass spectrometry. H2AK5ac, H2AK9ac, H2AK13ac, H2A.ZK4K7K11ac, and H2AK9me were expressed in BaP-transformed 16HBE (BTC-16HBE) cells, but were not detectable in normal 16HBE or BaP transformed 16HBE cells with knockdown of PARG (BTC-shPARG). Further verification by Western blotting indicated that H2AK9me was elevated in BTC-16HBE cells but decreased in BTC-shPARG cells. These findings suggest that knockdown of PARG protects against BaP-induced carcinogenesis in 16HBE cells by downregulating H2AK9me. Our in vivo studies confirmed that PARG silencing decreased H2AK9me levels, thereby countering the carcinogenic teratogenic effects induced by BaP. PMID- 29981923 TI - In-silico approach for drug induced liver injury prediction: Recent advances. AB - Drug induced liver injury (DILI) is the prime cause of liver disfunction which may lead to mild non-specific symptoms to more severe signs like hepatitis, cholestasis, cirrhosis and jaundice. Not only the prescription medications, but the consumption of herbs and health supplements have also been reported to cause these adverse reactions resulting into high mortality rates and post marketing withdrawal of drugs. Due to the continuously increasing DILI incidences in recent years, robust prediction methods with high accuracy, specificity and sensitivity are of priority. Bioinformatics is the emerging field of science that has been used in the past few years to explore the mechanisms of DILI. The major emphasis of this review is the recent advances of in silico tools for the diagnostic and therapeutic interventions of DILI. These tools have been developed and widely used in the past few years for the prediction of pathways induced from both hepatotoxic as well as hepatoprotective Chinese drugs and for the identification of DILI specific biomarkers for prognostic purpose. In addition to this, advanced machine learning models have been developed for the classification of drugs into DILI causing and non-DILI causing. Moreover, development of 3 class models over 2 class offers better understanding of multi-class DILI risks and at the same time providing authentic prediction of toxicity during drug designing before clinical trials. PMID- 29981924 TI - Activity of Brigatinib in the Setting of Alectinib Resistance Mediated by ALK I1171S in ALK-Rearranged Lung Cancer. PMID- 29981925 TI - The Incidence of Brain Metastases in Stage IV ROS1-Rearranged Non-Small Cell Lung Cancer and Rate of Central Nervous System Progression on Crizotinib. AB - INTRODUCTION: Central nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1-positive NSCLC and the rate of CNS progression during crizotinib therapy. METHODS: A retrospective review of 579 patients with stage IV NSCLC between June 2008 and December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK receptor tyrosine kinase gene [ALK], EGFR, KRAS, BRAF, and others) were recorded. We measured progression-free survival and time to CNS progression in ROS1-positive and ALK-positive patients who were taking crizotinib. RESULTS: We identified 33 ROS1-positive and 115 ALK positive patients with stage IV NSCLC. The incidences of brain metastases for treatment-naive, stage IV ROS1-positive and ALK-positive NSCLC were 36% (12 of 33) and 34% (39 of 115), respectively. There were no statistically significant differences in incidence of brain metastases across ROS1, ALK, EGFR, KRAS, BRAF, or other mutations. Complete survival data were available for 19 ROS1-positive and 83 ALK-positive patients. The median progression-free survival times for ROS1 positive and ALK-positive patients were 11 and 8 months, respectively (p = 0.304). The CNS was the first and sole site of progression in 47% of ROS1 positive (nine of 19) and 33% of ALK-positive (28 of 83) patients, with no statistically significant differences between these groups (p = 0.610). CONCLUSIONS: Brain metastases are common in treatment-naive stage IV ROS1 positive NSCLC, though the incidence does not differ from that in other oncogene cohorts. The CNS is a common first site of progression in ROS1-positive patients who are taking crizotinib. This study reinforces the importance of developing CNS penetrant tyrosine kinase inhibitors for patients with ROS1-positive NSCLC. PMID- 29981926 TI - A Longitudinal Investigation of Internalized Stigma, Constrained Disclosure, and Quality of Life Across 12 Weeks in Lung Cancer Patients on Active Oncologic Treatment. AB - INTRODUCTION: Internalized lung cancer stigma (i.e., feelings of regret, shame, and self-blame about one's lung cancer) is related to poorer psychological outcomes. Less is known about how internalized stigma relates to physical and functional outcomes or how constrained disclosure (i.e., avoidance of or discomfort about disclosing one's lung cancer status to others) relates to well being. Furthermore, no study has examined whether internalized stigma and constrained disclosure predict changes in well-being for lung cancer patients. This longitudinal study characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional outcomes. METHODS: Participants (N = 101, 52.4% male, 63.4% currently/formerly smoked) were lung cancer patients on active medical treatment who completed questionnaires on stigma and well-being at study entry and at 6- and 12-week follow-up. Multivariable linear regressions characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional well being at study entry and across time. RESULTS: Participants who currently or formerly smoked reported higher levels of internalized stigma (but not constrained disclosure), compared to never smokers (p < 0.001). Higher internalized stigma and constrained disclosure were uniquely associated with poorer emotional and physical/functional well-being at study entry (all p < 0.05), beyond sociodemographic characteristics, time elapsed since diagnosis, and smoking status. Higher internalized stigma predicted significant declines in emotional well-being across 6 and 12 weeks (all p < 0.01) and declines in physical/functional well-being across 6 weeks (p < 0.05). CONCLUSIONS: Internalized lung cancer stigma and constrained disclosure relate to emotional and physical/functional maladjustment. Findings carry implications for provider- and patient-focused interventions to reduce internalized stigma and promote well being. PMID- 29981927 TI - Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of NSCLC. AB - INTRODUCTION: EGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR-activating alterations relatively insensitive to first- and second generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer-generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GAs) present in NSCLC. METHODS: Hybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of greater than 650X for 236 or 315 cancer-related genes. RESULTS: Of 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263 of 2251) of cases with EGFR mutations. Sixty-four unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57 of 263). The most common co-occurring GAs effected tumor protein p53 (TP53) (56%), cyclin dependent kinase inhibitor 2A (CDKN2A) (22%), cyclin dependent kinase inhibitor 2B (CDKN2B) (16%), NK2 homeobox 1 (NKX2-1) (14%) and RB transcriptional corepressor 1 (RB1) (11%); co-occurring GAs in other known lung cancer drivers were rare (5%). Average tumor mutational burden was low (mean 4.3, range 0 to 40.3 mutations/Mb). Clinical outcomes to first- and second generation EGFR TKIs were obtained for five patients and none responded. CONCLUSIONS: In the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes showed lack of response to EGFR TKIs. Tumor mutational burden was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions. PMID- 29981929 TI - Strabismus surgery outcomes without removal of scleral buckle in patients with previous retinal detachment repair. AB - PURPOSE: To report the motor and sensory outcomes of strabismus surgery following scleral buckle procedure for retinal detachment (RD) without removal of the scleral buckle. METHODS: The medical records of patients who underwent strabismus surgery without removal of scleral buckle following RD surgical repair at a tertiary referral center between 2002 and 2015 were reviewed retrospectively. Demographic data were recorded, and rates of surgical motor success (defined as horizontal deviation of <=10Delta and vertical deviation of <=4Delta) and sensory success (resolution of diplopia) were calculated. RESULTS: A total of 23 patients (mean age, 58.4 +/- 24.4 years; 12 males) were included. The average time between the RD surgery and onset of strabismus was 11.05 +/- 10.95 months (range, 1-42 months). The strabismus was horizontal in 6 patients, vertical in 2, and combined in 15. Eighteen patients (78%) presented with diplopia. Adjustable sutures were used in 18 patients. Final motor surgical success was achieved in 17 of 23 patients (74%), and diplopia improved in 17 of 18 patients (94%) who had preoperative fusional capability. There was no statistically significant difference in age, number of RD surgeries, macular status, time to strabismus surgery, visual acuity in the worse eye, or magnitude of preoperative horizontal and vertical deviation with regard to motor success rate and with persistence of diplopia postoperatively. CONCLUSIONS: In our study cohort, strabismus surgery without removal of the scleral buckle resulted in motor success and alleviated diplopia in the majority of patients with prior RD repair. PMID- 29981928 TI - Lung Cancer Stigma across the Social Network: Patient and Caregiver Perspectives. AB - OBJECTIVE: To examine the personal experiences of people with lung cancer and their caregivers and how stigma is manifested throughout a patient's social network. METHODS: A qualitative thematic analysis of interviews with 28 patients with lung cancer and their caregivers was conducted. Telephone interviews were conducted and transcribed verbatim. Data analysis was guided by contemporary stigma theory. RESULTS: Patients and caregivers reported feeling high levels of felt stigma and concomitant psychological distress in response to the diagnosis of lung cancer. Three overarching themes emerged: the nexus of lung cancer and smoking, moralization, and attacking the link between lung cancer and smoking. Stigma was inevitably linked to smoking, and this formed the hub around which the other themes were organized. Caregivers reported feeling invisible and noted a lack of support systems for families and caregivers. In addition, there was evidence that caregivers experienced stigma by association as members of the patients' close networks. Both groups responded ambivalently to stigmatizing antismoking advertisements. CONCLUSIONS: The qualitative analysis demonstrated the complex interplay of the social and personal domains in the experience and outcomes of stigma in lung cancer. There is a significant potential for caregivers of patients with lung cancer to experience exacerbations of psychosocial distress as a consequence of widely shared negative views about lung cancer and its prognosis. It remains for researchers and practitioners to incorporate such complexity in addressing stigma and psychosocial distress in both patients and caregivers. PMID- 29981930 TI - Microtubule nucleation and organization without centrosomes. AB - Centrosomes play various critical roles in animal cells such as microtubule nucleation and stabilization, mitotic spindle morphogenesis, and spindle orientation. Land plants have lost centrosomes and yet must execute many of these functions. Recent studies have revealed the crucial roles played by morphologically distinct cytoplasmic microtubule-organizing centers (MTOCs) in initiating spindle bipolarity and maintaining spindle orientation robustness. These MTOCs resemble centrosomes in many aspects, implying an evolutionary divergence of MT-organizing structures in plants. However, their functions rely on conserved nucleation and amplification mechanisms, indicating a similarity in MT network establishment between animals and plants. Moreover, recent characterization of a plant-specific MT minus-end tracking protein suggests that plants have developed functionally equivalent modules to stabilize and organize MTs at minus ends. These findings support the theory that plants overcome centrosome loss by utilizing modified but substantially conserved mechanisms to organize MT networks. PMID- 29981931 TI - Getting physical: invasive growth events during plant development. AB - Plant cells are enclosed in cell walls that weld them together, meaning that cells rarely change neighbours. Nonetheless, invasive growth events play critical roles in plant development and are often key hubs for the integration of environmental and/or developmental signalling. Here we review cellular processes involved in three such events: lateral root emergence, pollen tube growth through stigma and style tissues, and embryo expansion through the endosperm (Figures 1 3). We consider processes such as regulation of water fluxes and cell turgor (driving growth), cell wall modifications (e.g. cell separation) and cell death (for creating space) within these three contexts with the aim of identifying key mechanisms implicated in providing a chemical and biophysical environments permitting invasive growth events. PMID- 29981932 TI - A well-resolved fern nuclear phylogeny reveals the evolution history of numerous transcription factor families. AB - Ferns account for 80% of nonflowering vascular plant species and are the sister lineage of seed plants. Recent molecular phylogenetics have greatly advanced understanding of fern tree of life, but relationships among some major lineages remain unclear. To better resolve the phylogenetic relationships of ferns, we generated transcriptomes from 125 ferns and two lycophytes, with three additional public datasets, to represent all 11 orders and 85% of families of ferns. Our nuclear phylogeny provides strong supports for the monophyly of all four subclasses and nearly all orders and families, and for relationships among these lineages. The only exception is Gleicheniales, which was highly supported as being paraphyletic with Dipteridaceae sister to a clade with Gleicheniaceae + Hymenophyllales. In addition, new and strongly supported phylogenetic relationships are found for suborders and families in Polypodiales. We provide the first dated fern phylogenomic tree using many nuclear genes from a large majority of families, with an estimate for separation of the ancestors of ferns and seed plants in early Devonian at ~400 Mya and subsequent gradual divergences of fern orders from ~380 to 200 Mya. Moreover, the newly obtained fern phylogeny provides a framework for gene family analyses, which indicate that the vast majority of transcription factor families found in seed plants were already present in the common ancestor of extant vascular plants. In addition, fern transcription factor genes show similar duplication patterns to those in seed plants, with some showing stable copy number and others displaying independent expansions in both ferns and seed plants. This study provides a robust phylogenetic and gene family evolution framework, as well as rich molecular resources for understanding the morphological and functional evolution in ferns. PMID- 29981933 TI - Genomic evaluations of Wolbachia and mtDNA in the population of coconut hispine beetle, Brontispa longissima (Coleoptera: Chrysomelidae). AB - Wolbachia pipientis is a diverse, ubiquitous and most prevalent intracellular bacterial group of alpha-Proteobacteria that is concerned with many biological processes in arthropods. The coconut hispine beetle (CHB), Brontispa longissima (Gestro) is an economically important pest of palm cultivation worldwide. In the present study, we comprehensively surveyed the Wolbachia-infection prevalence and mitochondrial DNA (mtDNA) polymorphism in CHB from five different geographical locations, including China's Mainland and Taiwan, Vietnam, Thailand, Malaysia and Indonesia. A total of 540 sequences were screened in this study through three different genes, i.e., cytochrome oxidase subunit I (COI), Wolbachia outer surface protein (wsp) and multilocus sequencing type (MLST) genes. The COI genetic divergence ranges from 0.08% to 0.67%, and likewise, a significant genetic diversity (pi = 0.00082; P = 0.049) was noted within and between all analyzed samples. In the meantime, ten different haplotypes (H) were characterized (haplotype diversity = 0.4379) from 21 different locations, and among them, H6 (46 individuals) have shown a maximum number of population clusters than others. Subsequently, Wolbachia-prevalence results indicated that all tested specimens of CHB were found positive (100%), which suggested that CHB was naturally infected with Wolbachia. Wolbachia sequence results (wsp gene) revealed a high level of nucleotide diversity (pi = 0.00047) under Tajima's D test (P = 0.049). Meanwhile, the same trend of nucleotide diversity (pi = 0.00041) was observed in Wolbachia concatenated MLST locus. Furthermore, phylogenetic analysis (wsp and concatenated MLST genes) revealed that all collected samples of CHB attributed to same Wolbachia B-supergroup. Our results strongly suggest that Wolbachia bacteria and mtDNA were highly concordant with each other and Wolbachia can affect the genetic structure and diversity within the CHB populations. PMID- 29981934 TI - Mycobacterium tuberculosis acyl carrier protein inhibits macrophage apoptotic death by modulating the reactive oxygen species/c-Jun N-terminal kinase pathway. AB - Mycobacterial acyl carrier protein (AcpM; Rv2244) is a meromycolate extension acyl carrier protein of Mycobacterium tuberculosis (Mtb), which participates in multistep mycolic acid biosynthesis. However, the function of AcpM in host mycobacterium interactions during infection remains largely uncharacterized. Here we show that AcpM inhibits host cell apoptosis during mycobacterial infection. To examine the function of AcpM during infection, we generated a recombinant Mycobacterium smegmatis (M. smegmatis) strain overexpressing AcpM (Ms_AcpM) and a strain transformed with an empty vector (Ms_Vec). Ms_AcpM promoted intracellular survival of M. smegmatis and led to a significant decrease in the death rate of primary bone marrow-derived macrophages (BMDMs). Importantly, Ms_AcpM showed significantly decreased reactive oxygen species (ROS) generation and activation of c-Jun N-terminal kinase (JNK) signaling compared with Ms_Vec. In addition, treatment of BMDMs with recombinant AcpM significantly inhibited the apoptosis and ROS/JNK signaling induced by M. smegmatis. Moreover, recombinant AcpM enhanced intracellular survival of Mtb H37Rv. Taken together, these results indicate that AcpM plays a role as a virulence factor by modulating host cell apoptosis during mycobacterial infection. PMID- 29981935 TI - The relative effects of abstract versus concrete rumination on the experience of post-decisional regret. AB - rumination is characteristic of depressed individuals, as is the tendency to experience post-decisional regret. We conducted two studies to test whether (i) abstract rumination is associated with post-decisional regret, and (ii) inducing the converse style of thinking, namely concrete rumination, would reduce post decisional regret. In Study 1, participants identified a personally important decision that they regretted having made in the past 6 months, were instructed to think in either an abstract (n = 29) or concrete (n = 29) way about their decision, then rated the extent to which they regretted the decision. Participants in the abstract condition reported more regret than did participants in the concrete condition. Employing the same methodology used in Study 1, we replicated this finding in Study 2 (abstract condition: n = 34; concrete condition: n = 36). In both studies we additionally tested the prediction that abstract rumination leads to more counterfactual thoughts than concrete rumination. Neither study yielded evidence to support this hypothesis. Overall, the current research indicates that abstract rumination could play an important role in contributing to post-decisional regret and raises the clinical possibility that encouraging depressed individuals to engage in concrete rumination might alleviate post-decisional regret. PMID- 29981936 TI - Enhancing extinction learning: Occasional presentations of the unconditioned stimulus during extinction eliminate spontaneous recovery, but not necessarily reacquisition of fear. AB - BACKGROUND: Fears underlying anxiety disorders are commonly treated with exposure based therapies, which are based on the principles of extinction learning. While these treatments are efficacious, fears may return after successful treatment. Past research suggested that post-extinction recovery of fear could be reduced through extinction training that involves occasional presentations of the aversive unconditioned stimulus (US), paired with the conditioned stimulus (CS). Here, we examined whether extinction training with occasionally paired or unpaired US presentations is superior in the reduction of fear recovery to non reinforced extinction. METHOD: Following differential fear conditioning to neutral cues, participants (N = 72; M age = 21.61 years, SD = 3.95) underwent either non-reinforced, partially reinforced, or unpaired extinction training. RESULTS: Extinction involving paired or unpaired US presentations, but not non reinforced extinction, eliminated spontaneous recovery of differential skin conductance responses (SCRs). Results further suggested that unpaired, but not paired, US presentations may guard against rapid reacquisition of differential SCRs. No benefits of US presentations during extinction were found on the reinstatement of SCRs or recovery of differential negative CS+ valence. CONCLUSION: Presenting USs during extinction training was more effective than non reinforced extinction in the reduction of fear recovery, as indexed by SCRs, with unpaired extinction being more effective than partially reinforced extinction. PMID- 29981937 TI - Predictors of remission from panic disorder, agoraphobia and specific phobia in outpatients receiving exposure therapy: The importance of positive mental health. AB - Positive mental health has been shown to predict remission from anxiety disorders in community samples. However, it is unclear, whether positive mental health is also predictive of symptom severity and remission from anxiety disorders in patients receiving exposure therapy. A total of 130 adult outpatients suffering from panic disorder, agoraphobia, or specific phobia received manualized exposure therapy. Positive mental health was considered as a predictor of symptom severity and remission at the post-treatment assessment and at the follow-up assessment six months after treatment termination - controlling for depression, anxiety, anxiety cognitions, bodily sensations, number of treatment sessions, age and gender. Pre-treatment positive mental health was the only predictor of post treatment symptom severity and remission status. Post-treatment positive mental health and avoidance behavior predicted symptom severity and remission status at the follow-up assessment. In conclusion, the current study highlights the importance of positive mental health in understanding remission from anxiety disorders. PMID- 29981938 TI - Exploring the boundaries of post-retrieval extinction in healthy and anxious individuals. AB - Over a dozen studies have examined the efficacy of post-retrieval extinction (PRE) in healthy adults in the fear conditioning laboratory, with a recent meta analysis reporting an overall small-moderate effect on attenuating the return of fear compared to standard extinction. The current study was designed to extend PRE effects to a mixed sample of healthy and anxious individuals, explore potential moderators, and examine the benefit of PRE for a memory conditioned over multiple days. Healthy (n = 49) and anxious (n = 43) adults received either one day of acquisition followed by PRE, one day of acquisition followed by extinction, or three days of acquisition followed by PRE. Comparing participants who received one day of acquisition followed by PRE or extinction, no significant effect of PRE was observed on differential skin conductance response reinstatement or reactivity to the conditioned stimulus alone. Anxiety symptoms did not moderate outcomes. There was no difference in return of fear for anxious participants who received three days of acquisition followed by PRE versus one day of acquisition followed by PRE. These results further highlight the variability of findings in the PRE literature and need for further examination of individual difference factors that may moderate PRE effects. PMID- 29981939 TI - Pathologic complete response implies a fewer number of lymph nodes in specimen of rectal cancer patients treated by neoadjuvant therapy and total mesorectal excision. AB - : Studies have suggested that the use of neoadjuvant chemoradiation results in a lower lymph nodes yield in rectal cancer patients. OBJECTIVE: To evaluate factors associated with less than 12 lymph nodes harvested on patients with rectal cancer treated with preoperative chemoradiotherapy followed by total mesorectal excision. PATIENTS: This was a cohort/retrospective single cancer center study. Low and mid locally advanced rectal cancer or T2N0 under risk of sphincter resection underwent chemoradiotherapy followed by total mesorectal excision with curative intent. Chemotherapy consisted of 5-FU and leucovorin IV. Total dose of pelvic radiation was 5040 Gys. All patients were staged and restaged by digital rectal examination, proctoscopy, colonoscopy, CT of abdomen and chest, and MRI of the pelvis. Patients were stratified in two groups: >=12 and < 12 L N retrieved. The possible factors affecting number of LN were analyzed. RESULTS: 95 patients met the inclusion criteria. Mean LN harvest was 23.2 (3-67). 81 patients (85%) had >=12 L N. Gender, age, tumor size, tumor stage, tumor location, length of specimen, presence of LN involvement, type of surgery, and surgical access showed no association with number of LN retrieved. Only pathological complete response showed a statistically significant association with <12 L N on univariate (p = 0.004) and multivariate analyses (p = 0.002). LIMITATIONS: Data were collected retrospectively. The number of patients disparity between the two groups. CONCLUSIONS: Complete pathologic response is associated with <12 L N harvested. Thus, the number of lymph nodes should not be used as a surrogate for oncologic adequacy of resection in patients with pathologic complete response. PMID- 29981940 TI - Aberrant functional connectivity between the thalamus and visual cortex is related to attentional impairment in schizophrenia. AB - Resting-state (rs) functional magnetic resonance imaging (fMRI) studies have revealed dysfunctional thalamocortical functional connectivity (FC) in schizophrenia. However, the relationship between thalamocortical FC and cognitive impairment has not been thoroughly investigated. We hypothesized that aberrant thalamocortical FC is related to attention deficits in schizophrenia. Thirty eight patients with schizophrenia and 38 matched healthy controls underwent rs fMRI and task fMRI while performing a Flanker task. We observed decreased left thalamic activation in patients with schizophrenia using task fMRI to determine the thalamic seed. A seed-based analysis using this seed was performed in the whole brain to assess differences in thalamocortical FC between the groups. Significantly worse performance was observed in the patient group. The rs-fMRI analysis revealed significantly increased FC between the left thalamus seed and the occipital cortices/postcentral gyri in patients when compared to controls. In the patient group, significant positive correlations were observed between the degree of FC from the left thalamus to the bilateral occipital gyri, which correspond to the visual cortex, and the Flanker effect. No significant correlation was detected in the control group. These results indicate that aberrant FC between the left thalamus and the visual cortex is related to attention deficits in schizophrenia. PMID- 29981941 TI - Association of excessive social media use with abnormal white matter integrity of the corpus callosum. AB - Borrowing from findings regarding other problematic behaviors, we posit that excessive social media use (ESMU) can relate to impaired inter-hemispheric connections. These are often reflected in impaired white matter integrity (decreased fractional anisotropy and increased mean diffusivity) of the corpus callosum. We test this idea with diffusion tensor imaging (DTI) data from 20 normal social media users with varying degrees of ESMU. The findings of a Regions of Interest analysis focusing on the corpus callosum indicate that ESMU is associated with increased mean diffusivity in the body and splenium sub-regions of the corpus callosum. Whole-brain Tract Based Spatial Statistics analysis revealed that ESMU is positively associated with mean diffusivity of left superior and inferior longitudinal fasciculi as well as left forceps minor; and that ESMU is positively associated with the fractional anisotropy of the right Corticospinal Tract. It is concluded that inter-hemispheric white matter deficits in the corpus callosum extended to forceps minor, as well as along the ventral semantic path can be associated with ESMU. PMID- 29981942 TI - Acute harms associated with inhalant misuse: Co-morbidities and trends relative to age and gender among ambulance attendees. AB - BACKGROUND: Inhalant misuse is the deliberate inhalation of products containing toluene to induce intoxication. Chronic harms associated with inhalant misuse are well described; including alcohol and other drug use, mental health disorders, and suicidal behaviours. However, the nature of the acute harms from inhalants and characteristics of people who experience those harms are not well understood. Therefore, this study aimed to identify the acute harms associated with inhalant misuse attendances, and to determine whether these differ by age or gender. METHODS: Ambulance attendance data (Victoria, Australia) from January 2012 to June 2017 were extracted from a database of coded ambulance records. 779 ambulance attendances involving inhalant misuse were identified. Attendance characteristics were categorised by age and gender. Co-morbidities of current mental health, self-harm and suicidal behaviour were assessed, plus the involvement of alcohol and other drugs. RESULTS: Overall, attendances related to the acute harms of inhalant misuse have decreased over time, although that trend has reversed from January 2015. Gender differentiated the acute harms associated with inhalant misuse. Males were older and presented with concurrent alcohol and other drug use. Females were younger and presented with concurrent suicidal ideation and self-injury. Attendances for under 15-year-olds are increasing; this age group was over-represented, predominantly female, with a strong association with self-injury. CONCLUSIONS: Ambulance presentations related to inhalant misuse were associated with acute and serious harms. This study highlights that the acute treatment needs of those misusing inhalants are complex and may need to be tailored to gender and age groups. PMID- 29981943 TI - Sociodemographic factors, prescription history and opioid overdose deaths: a statewide analysis using linked PDMP and mortality data. AB - BACKGROUND: Opioid overdose deaths have continued to rise in Tennessee (TN) with fentanyl emerging as a major contributor. Current data are needed to identify at risk populations to guide prevention strategies. We conducted a large statewide observational study among TN adult decedents (2013-2016) to evaluate the association of sociodemographic factors and prescribing patterns with opioid overdose deaths. METHODS: Among drug overdose decedents identified using death certificate data (n = 5483), we used logistic regression to estimate adjusted odds ratios and 95% confidence intervals for characteristics associated with prescription opioid (PO) (excluding fentanyl), fentanyl, and heroin alone overdoses. Among decedents linked to TN's Prescription Drug Monitoring Database using deterministic algorithms, we obtained prescription history in the year before death (n = 3971), which was evaluated by type of overdose using descriptive statistics. RESULTS: Younger, non-White decedents had lower odds of PO overdose, while females and benzodiazepines as a contributing cause were associated with increased odds of PO overdose. Younger age, Non-Hispanic Black race/ethnicity, greater than high school education, and cocaine/other stimulants as a contributing cause were associated with increased odds of fentanyl or heroin overdoses. Over 55% of PO, 39.2% of fentanyl, and 20.7% of heroin overdoses had an active opioid prescription at death. For PO, fentanyl, and heroin decedents, respectively, 46.0%, 30.5%, and 26.2% had an active prescription for benzodiazepines at death. CONCLUSIONS: Prescription opioid overdose deaths were associated with different sociodemographic profiles and prescribing history compared to fentanyl and heroin overdose deaths in TN. Data can guide prevention strategies to reduce opioid overdose mortality. PMID- 29981944 TI - Ebola vaccine development: Systematic review of pre-clinical and clinical studies, and meta-analysis of determinants of antibody response variability after vaccination. AB - OBJECTIVES: For Ebola vaccine development, antibody response is a major endpoint although its determinants are not well known. We aimed to review Ebola vaccine studies and to assess factors associated with antibody response variability in humans. METHODS: We searched PubMed and Scopus for preventive Ebola vaccine studies in humans or non-human primates (NHP), published up to February 2018. For each vaccination group with Ebola Zaire antibody titre measurements after vaccination, data about antibody response and its potential determinants were extracted. A random-effects meta-regression was conducted including human groups with at least 8 individuals. RESULTS: We reviewed 49 studies (202 vaccination groups including 74 human groups) with various vaccine platforms and antigen inserts. Mean antibody titre was slightly higher in NHP (3.10, 95% confidence interval [293; 327]) than in humans (2.75 [257; 293]). Vaccine platform (p<0.001) and viral strain used for antibody detection (p<0.001) were associated with antibody response in humans, but adjusted heterogeneity remained at 95%. CONCLUSIONS: Various platforms have been evaluated in humans, including Ad26, Ad5, ChimpAd3, DNA, MVA, and VSV. In addition to platforms, viral strain used for antibody detection influences antibody response. However, variability remained mostly unexplained. Therefore, comparison of vaccine immunogenicity needs randomised controlled trials. PMID- 29981945 TI - Incidence of suicide among military police officers in South Brazil: An 11-year retrospective cohort study. AB - BACKGROUND: Suicide is known to be the leading cause of death among police officers (PO) worldwide. However, most studies were conducted in developed countries, with no data from Brazil. The present study aimed to evaluate the incidence and the sociodemographic profile of suicide among a military PO subpopulation in South Brazil. METHODS: This retrospective cohort evaluated 31,110 military PO with available data on cause of death from 2006 to 2016. Participants were monitored for an average of 18.8 +/- 9.6 years following the date of entry into the military police. RESULTS: Mean age at the end of the follow up time was 41.4 +/- 9.1 years, with 90.7% males. A total of 650 participants died (2.1%), with 43 suicides (6.6% of all deaths) - cumulative incidence of 138/100,000. Bivariate analysis revealed a significant association (p < 0.05) between suicide and age (HR = 0.70, 95%CI = 0.66-0.74), females (HR = 1.67, 95%CI = 1.08-2.60) and enlisted military rank (HR = 14.9, 95%CI = 2.05 108.5). Multivariate models showed an independent association between suicide and age (HR = 0.71, 95%CI = 0.67-0.74) and enlisted military rank (HR = 9.96, 95%CI = 1.30-76.3). CONCLUSIONS: The incidence of suicide among military PO in South Brazil was high, compared to the national suicide rate. Younger age and lower military rank were independent predictors of suicide in this subpopulation. PMID- 29981946 TI - Pulsed electromagnetic fields and platelet rich plasma alone and combined for the treatment of wear-mediated periprosthetic osteolysis: An in vivo study. AB - : Wear-mediated osteolysis is a common complication occurring around implanted prosthesis, which ultimately leads to bone loss with mechanical instability and the need for surgical revision. At the moment, revision surgery is the only effective treatment. The aim of this study was to assess the efficacy of pulsed electromagnetic fields (PEMFs) and platelet rich plasma (PRP), alone and in association, in a clinically relevant in vivo model of periprosthetic osteolysis. Titanium alloy pins were implanted intramedullary in distal femurs of male inbred rats and, after osseointegration, polyethylene particles were injected intra articularly to induce osteolysis. Animals were divided in four groups of treatment: PEMFs, PRP, PEMFs + PRP and no treatment. Microtomography was performed during the course of experiments to monitor bone stock and microarchitecture. Histology, histomorphometry, immunohistochemistry and biomechanics were evaluated after treatments. Biophysical and biological stimulations significantly enhanced bone to implant contact, bone volume and bone microhardness and reduced fibrous capsule formation and the number of osteoclasts around implants. Among treatments, PEMFs alone and in association with PRP exerted better results than PRP alone. Present data suggest that biophysical stimulation, with or without the enrichment with platelet derived growth factors, might be a safe, mini-invasive and conservative therapy for counteracting osteolysis and prompting bone formation around implants. STATEMENT OF SIGNIFICANCE: Pulsed electromagnetic fields (PEMFs) and platelet rich plasma (PRP) show anabolic and anti-inflammatory effects and they are already been used in clinical practice, but separately. To date, there are no preclinical in vivo studies evaluating their combined efficacy in periprosthetic osteolysis, in bone tissue microarchitecture and in biomechanics. The aim of the present study was to evaluate the effects of PEMFs and PRP in vivo, when administered individually and in combination in the treatment of periprosthetic wear mediated ostelysis, and in restoring the osteogenetic properties of perimplant bone tissue and its biomechanical competence. The combination of PEMFs and PRP could be employed for counteracting the ostelysis process in a conservative and non surgical manner. PMID- 29981947 TI - Development of an apoptosis-assisted decellularization method for maximal preservation of nerve tissue structure. AB - : Preservation of tissue structure is often a primary goal when optimizing tissue and organ decellularization methods. Many current protocols nonetheless rely on detergents that aid extraction of cellular components but also damage tissue architecture. It may be more beneficial to leverage an innate cellular process such as apoptosis and promote cell removal without the use of damaging reagents. During apoptosis, a cell detaches from the extracellular matrix, degrades its internal components, and fragments its contents for easier clearance. We have developed a method that leverages this process to achieve tissue decellularization using only mild wash buffers. We have demonstrated that treating peripheral nerve tissue with camptothecin induced both an early marker of apoptosis, cleaved caspase-3 expression, as well as a late stage marker, TUNEL+ DNA fragmentation. Clearance of the cellular components was then achieved in an apoptosis-dependent manner using a gentle wash in hypertonic phosphate buffered saline followed by DNase treatment. This wash paradigm did not significantly affect collagen or glycosaminoglycan content, but it was sufficient to remove any trace of the cytotoxic compound based on conditioned media experiments. The resulting acellular tissue graft was immunogenically tolerated in vivo and exhibited an intact basal lamina microarchitecture mimicking that of native, unprocessed nerve. Hence, ex vivo induction of apoptosis is a promising method to decellularize tissue without the use of harsh reagents while better preserving the benefits of native tissue such as tissue-specific composition and microarchitecture. STATEMENT OF SIGNIFICANCE: Tissue decellularization has expanded the ability to generate non-immunogenic organ replacements for a broad range of health applications. Current technologies typically rely on the use of harsh agents for clearing cellular debris, altering the tissue structure and potentially diminishing the pro-regenerative effects. We have developed a method for effectively, yet gently, removing cellular components from peripheral nerve tissue while preserving the native tissue architecture. The novelty of this process is in the induction of programmed cell death - or apoptosis - via a general cytotoxin, thereby enabling antigen clearance using only hypertonic wash buffers. The resulting acellular nerve scaffolds are nearly identical to unprocessed tissue on a microscopic level and elicit low immune responses comparable to an isograft negative control in a model of subcutaneous implantation. PMID- 29981948 TI - Additively manufactured biodegradable porous iron. AB - : Additively manufactured (AM) topologically ordered porous metallic biomaterials with the proper biodegradation profile offer a unique combination of properties ideal for bone regeneration. These include a fully interconnected porous structure, bone-mimicking mechanical properties, and the possibility of fully regenerating bony defects. Most of such biomaterials are, however, based on magnesium and, thus, degrade too fast. Here, we present the first report on topologically ordered porous iron made by Direct Metal Printing (DMP). The topological design was based on a repetitive diamond unit cell. We conducted a comprehensive study on the in vitro biodegradation behavior (up to 28 days), electrochemical performance, time-dependent mechanical properties, and biocompatibility of the scaffolds. The mechanical properties of AM porous iron (E = 1600-1800 MPa) were still within the range of the values reported for trabecular bone after 28 days of biodegradation. Electrochemical tests showed up to ~12 times higher rates of biodegradation for AM porous iron as compared to that of cold-rolled (CR) iron, while only 3.1% of weight loss was measured after 4 weeks of immersion tests. The biodegradation mechanisms were found to be topology-dependent and different between the periphery and central parts of the scaffolds. While direct contact between MG-63 cells and scaffolds revealed substantial and almost instant cytotoxicity in static cell culture, as compared to Ti-6Al-4V, the cytocompatibility according to ISO 10993 was reasonable in in vitro assays for up to 72 h. This study shows how DMP could be used to increase the surface area and decrease the grain sizes of topologically ordered porous metallic biomaterials made from metals that are usually considered to degrade too slowly (e.g., iron), opening up many new opportunities for the development of biodegradable metallic biomaterials. STATEMENT OF SIGNIFICANCE: Biodegradation in general and proper biodegradation profile in particular are perhaps the most important requirements that additively manufactured (AM) topologically ordered porous metallic biomaterials should offer in order to become the ideal biomaterial for bone regeneration. Currently, most biodegradable metallic biomaterials are based on magnesium, which degrade fast with gas generation. Here, we present the first report on topologically ordered porous iron made by Direct Metal Printing (DMP). We also conducted a comprehensive study on the biodegradation behavior, electrochemical performance, biocompatibility, and the time evolution of the mechanical properties of the implants. We show that these implants possess bone-mimicking mechanical properties, accelerated degradation rate, and reasonable cytocompatibility, opening up many new opportunities for the development of iron-based biodegradable materials. PMID- 29981949 TI - Nanoengineering of nanorattles for tumor treatment by CT imaging-guided simultaneous enhanced microwave thermal therapy and managing inflammation. AB - Usually the tumor thermal therapy is accompanied with inflammatory reactions, which in turn promote tumor growth and metastasis meanwhile. Herein, we prepared novel trifunctional PEG-IL/ZrO2-Ag@SiO2 nanorattles, which can be used for CT imaging-guided simultaneous tumor microwave thermal therapy and resistance to bacterial infection. Under the microwave irradiation, the nanorattles present excellent microwave thermal properties. Simultaneously, the nanorattles have good antibacterial effect in vitro and in vivo, which can restrain bacterial growth effectively and reduce inflammation response during the microwave thermal therapy. In addition, the nanorattles also have the function of CT imaging, which can monitor the tumor therapy in real time. The strategy of simultaneous microwave thermal therapy and inflammation management effectively inhibits tumor growth in mice with a good anti-tumor effect (96.4%). This proof-of-concept investigation provides a simple and reliable strategy for tumor treatment and inhibiting inflammatory reaction using a multifunctional nanomaterial, indicating the great application prospect in tumor treatment by simultaneous eradicating tumor tissue and managing inflammation. PMID- 29981950 TI - pH-sensitive radiolabeled and superfluorinated ultra-small palladium nanosheet as a high-performance multimodal platform for tumor theranostics. AB - Radiolabeled nanomaterials, especially those with ultra-small structures, have been the research focus in recent years, and thus may open up new prospects for clinical diseases theranostics. Herein, fluorinated Pd nanosheets labeled with Gd or radionuclides are developed as multimodal platforms for tumor theranostics. These nanomaterials decorated by functional polyethylene glycol demonstrate ultrahigh 19F MRI signal, ultrasmall size and good dispersibility. These ultrasmall materials exhibit good biocompatibility and easily to be modified for multimodal imaging (SPECT/MRI/PAI) by assembling the functional groups like building blocks. Furthermore, with high accumulation in tumor sites, under the guidance of multimodal imaging, combined photothermal therapy and radiotherapy are performed and synergistic effects are obtained. By comparing the in vivo behaviors of nanostructures labeled by different nuclides, the present study suggests the pH-sensitive radioiodinated Pd nanosheet which has unexpected T/NT ratio (>4-fold tumor-to-muscle ratio) in SPECT imaging and solves the critical high background issue of nanoprobes, could improve diagnostic accuracy and guide combination therapy. In summary, this functionalized nanoplatform with promising imaging and therapeutic efficacy has great potential for precision theranostic nanomedicines. PMID- 29981951 TI - Parental views on special educational needs provision: Cross-syndrome comparisons in Williams Syndrome, Down Syndrome, and Autism Spectrum Disorders. AB - BACKGROUND: The current study examined parents' views about their child's educational provision for children with Williams syndrome (WS), Down syndrome (DS), and Autism Spectrum Disorders (ASD). AIMS: This cross-syndrome comparison explored the specific and general difficulties that parents of children with neurodevelopmental disorders experience about their child's educational provision. METHODS AND PROCEDURES: Parents of children aged 4-18;11 years old, including 99 with WS, 88 with DS, and 82 with ASD completed a survey. OUTCOMES AND RESULTS: Children with DS were more likely to access mainstream settings and 1-to-1 support compared to those with WS and ASD. Parental satisfaction was lowest for those with ASD but all parents mentioned concerns about professionals' knowledge of how to support children with special educational needs and disabilities (SEND). There were also group differences for access to specialist support but overall access to occupational therapy and mental health was low. CONCLUSIONS AND IMPLICATIONS: In contrast to previous studies, educational provision and satisfaction with educational provision are syndrome-specific. These results also highlight the need for training and raising awareness about the specific needs of children with neurodevelopmental disorders. In addition, our findings suggest improved communication between parents and the school is required about the type of support children with SEND are receiving. PMID- 29981952 TI - Systematic review of the economic impact of cerebral palsy. AB - BACKGROUND: Cerebral palsy (CP) and its associated conditions can pose a significant economic burden on families, the health care system and the general economy. The boundary for inclusion of costs in research can vary substantially across studies. AIMS: To summarize the evidence for burden of disease for CP including the impacts on the health system, the community and carers. METHODS: Literature was identified from Ovid Medline, Embase, CINHAL, PsyInfo, Econlit, Health Economic Evaluation Database (HEED) and NHS Economic Evaluation Database (NHS EED) in the Cochrane Library. The search was restricted to articles published in English between 1970 and April 2016. All costs were converted to $USD 2016 price. RESULTS: Twenty-two articles were included. Studies varied from snapshot cost descriptions to more complex lifetime estimates, from prevalence based to incidence-based studies, and from inclusion to exclusion of non-medical costs. There was a strong positive relationship between CP severity and expenditure. Significant costs were incurred by families and the welfare system to facilitate school and community engagement. CONCLUSION: Facilitating participation for people with CP involves substantial expense. The size, nature and distribution of the economic burden emphasises the importance of finding effective strategies to reduce the risk and severity of CP, together with how it is financed. PMID- 29981953 TI - LGBT people and suicidality in youth: A qualitative study of perceptions of risk and protective circumstances. AB - Evidence suggests that lesbian, gay, bisexual and trans (LGBT) people are more likely to attempt to take their own lives in their youth when compared to heterosexual and/or cisgender people. This study draws on in-depth interviews with 17 LGBT individuals living in England, and explores the narratives used by participants to better understand their perceptions of risk and protective circumstances to explain suicide attempts in youth. Using a Goffman-informed thematic analysis, results identified three key themes that were linked to attempts to end life in youth. The first theme considers the conflicts resulting from first disclosure of sexual orientation and/or gender identity/trans status and being 'out' to others. The second theme explores participants' accounts of their concurrent mental health issues and how diagnoses of the mental health issues helped them make sense of their own experiences of attempted suicide. The final theme explores the experience of grieving over lost relationships and how that grief is received by others, including health professionals. Our results indicate that some LGBT individuals have effectively, although often arduously, navigated suicidal crises by utilising various approaches to coping. We provide a rich and layered picture of LGBT suicide risk in youth and potential resilience scenarios, although these are a reflection of our specific group of participants' experiences and realities. We argue that it is important to understand how LGBT individuals with a history of suicide attempts narrate and make sense of their experiences in early life and we suggest that the early negative experiences continue to have an effect on LGBT adults today. PMID- 29981954 TI - Behavioral and electrophysiological evidence for GABAergic modulation through transcutaneous vagus nerve stimulation. AB - OBJECTIVE: Transcutaneous vagus nerve stimulation (tVNS) has been hypothesized to modulate gamma-aminobutyric (GABA) transmission in the human brain. GABA in the motor cortex is highly correlated to measures of automatic motor inhibition that can be obtained in simple response priming paradigms. To test the effects of tVNS on GABA transmission, we measured tVNS-induced alterations in behavioral and electrophysiology during automatic motor inhibition. METHODS: Participants were 16 young, healthy adults (8 female). We combined a subliminal response priming paradigm with tVNS and EEG measurement. In this paradigm, automatic motor inhibition leads to a reversal of the priming effect, a phenomenon referred to as the negative compatibility effect (NCE). We compute the NCE separated by response hands, hypothesizing a modulation of the left-hand NCE. Using EEG we measured readiness potentials, an established electrophysiological index of cortical motor preparation. RESULTS: As hypothesized, for the ipsilateral hand/contralateral hemisphere, compared to sham stimulation, tVNS increased the NCE and modulated the electrophysiological readiness potentials. CONCLUSION: Our results indicate that tVNS is selectively affecting the GABAergic system in the motor system contralateral to the stimulated ear as reflected in a behavioral and electrophysiological modulation. SIGNIFICANCE: We provide first combined behavioral and electrophysiological evidence for direct GABAergic neuromodulation through tVNS. PMID- 29981955 TI - Betweenness centrality of intracranial electroencephalography networks and surgical epilepsy outcome. AB - OBJECTIVE: We sought to determine whether the presence or surgical removal of certain nodes in a connectivity network constructed from intracranial electroencephalography recordings determines postoperative seizure freedom in surgical epilepsy patients. METHODS: We analyzed connectivity networks constructed from peri-ictal intracranial electroencephalography of surgical epilepsy patients before a tailored resection. Thirty-six patients and 123 seizures were analyzed. Their Engel class postsurgical seizure outcome was determined at least one year after surgery. Betweenness centrality, a measure of a node's importance as a hub in the network, was used to compare nodes. RESULTS: The presence of larger quantities of high-betweenness nodes in interictal and postictal networks was associated with failure to achieve seizure freedom from the surgery (p < 0.001), as was resection of high-betweenness nodes in three successive frequency groups in mid-seizure networks (p < 0.001). CONCLUSIONS: Betweenness centrality is a biomarker for postsurgical seizure outcomes. The presence of high-betweenness nodes in interictal and postictal networks can predict patient outcome independent of resection. Additionally, since their resection is associated with worse seizure outcomes, the mid-seizure network high betweenness centrality nodes may represent hubs in self-regulatory networks that inhibit or help terminate seizures. SIGNIFICANCE: This is the first study to identify network nodes that are possibly protective in epilepsy. PMID- 29981956 TI - Retinal ganglion cell function in recovered optic neuritis: Faster is not better. AB - OBJECTIVE: To assess residual retinal ganglion cell (RGC) function in patients with recovered optic neuritis (ON) and multiple sclerosis (MS). METHODS: Age matched controls (C, n = 32) and MS patients (n = 17) with history of ON in one eye but normal visual acuity and color vision were tested with steady-state Pattern Electroretinogram (PERG). Light Emitting Diodes (LED)-generated bar gratings, robust signal averaging and Fourier analysis were used to assess response amplitude and latency. RESULTS: PERG amplitude was similar for C, ON and fellow eyes (FE) (P = 0.4), but PERG latency was shortened in ON by 3.2 ms (P = 0.002) and in FE by 2.0 ms (P = 0.02) and was correlated (P < 0.01) with both Retinal Nerve Fiber Layer (RNFL) and Ganglion Cell Inner Plexiform Layer (GCIPL) thicknesses. PERG latency shortening could be simulated in control subjects (n = 8) by dioptrically blurring the edges of gratings (high spatial frequencies), which reduced activity of parvocellular RGCs with smaller/slower axons. The blurred PERG latency was shorter than baseline by 2.9 ms (P = 0.01). CONCLUSIONS: PERG latency is shortened in both eyes of MS patients with recovered unilateral ON, suggesting relative dysfunction of RGCs with slower axons and sparing of RGCs with faster axons. SIGNIFICANCE: Assessment of PERG latency in MS and ON may help identifying and monitoring RGC dysfunction. PERG latency shortening in FE suggests primary retinopathy in MS. PMID- 29981957 TI - Diagnostic value of somatosensory evoked potential changes during carotid endarterectomy for 30-day perioperative stroke. AB - OBJECTIVES: Somatosensory evoked potentials (SSEPs) have proven useful as an intraoperative modality to predict perioperative stroke during carotid endarterectomy (CEA). However, the predictive value of SSEPs for predicting stroke 30 days postoperatively remains unclear. The primary objective is to evaluate the efficacy of intraoperative SSEP change in predicting the risk of stroke in the postoperative period beyond 24 h but within 30 days. Our secondary aim is to evaluate the predictive value of each subcategory of SSEP change. METHODS: We performed a meta-analysis of 25 prospective/retrospective studies from PubMed, Web of Science, and Embase regarding SSEP monitoring for postoperative outcomes in symptomatic and asymptomatic CEA patients. RESULTS: A 8307-patient cohort composed the total sample population, of which 54.17% had symptomatic CS. For SSEP change and stroke greater than 24 h but within 30 days, the diagnostic odds ratio was 8.68. The diagnostic odds ratio was 3.88 for transient SSEP change and stroke; 49.29 for persistent SSEP change and stroke; 36.45 for transient SSEP loss and stroke; and 281.35 for persistent SSEP loss and stroke. CONCLUSIONS: Patients with SSEP changes are at increased risk of perioperative stroke within the entire 30-day period. There is a noticeable step wise increase in the predicted risk of stroke with the severity of SSEP changes. SIGNIFICANCE: SSEP changes can serve as a predictor for 30-day perioperative stroke during CEA. PMID- 29981958 TI - Visual rehabilitation training alters attentional networks in hemianopia: An fMRI study. AB - OBJECTIVE: Hemianopia is a visual field defect following post-chiasmatic damage. We now applied functional magnetic resonance imaging (fMRI) in hemianopic patients before and after visual rehabilitation training (VRT) to examine the impact of VRT on attentional function networks. METHODS: Seven chronic hemianopic patients with post- chiasmatic lesions carried out a VRT for five weeks under fixation control. Before vs. after intervention, we assessed the area of residual vision (ARV), contrast sensitivity function (CSF) and functional MRI data and correlated them with each other. RESULTS: VRT significantly improved the visual function of grating detection at the training location. Using fMRI, we found that the training led to a strengthening of connectivity between the right temporoparietal junction (rTPJ) to the insula and the anterior cingulate cortex (ACC), all of which belong to the cortical attentional network. However, no significant correlation between alterations of brain activity and improvements of either CSF or ARV was found. CONCLUSION: Visual rehabilitation training partially restored the deficient visual field sectors and could improve attentional network function in hemianopia. SIGNIFICANCE: Our MRI results highlight the role of attention and the rTPJ activation as one, but not the only, component of VRT in hemianopia. PMID- 29981959 TI - Impact of radiotracer injection latency and seizure duration on subtraction ictal SPECT co-registered to MRI (SISCOM) performance in children. AB - OBJECTIVE: We evaluated the impact of radiotracer injection latency and post injection seizure duration on subtraction ictal SPECT co-registered to MRI (SISCOM) test performance in identifying the epileptogenic zone (EZ) in children with drug-resistant epilepsy who had undergone a resective epilepsy surgery. METHODS: SISCOM concordance with the EZ was retrospectively reviewed to evaluate its performance in 113 children. The impact of radiotracer injection latency and post-injection seizure duration was evaluated for their predictive value of SISCOM localization accuracy. RESULTS: The overall sensitivity and specificity of SISCOM in identifying an EZ was 64.8% (95%CI = 50.6-77.3) and 40.7% (95%CI = 28.1 54.3). The positive likelihood ratio and diagnostic odd ratio was 1.09 (95%CI = 0.80-1.48) and 1.26 (95%CI = 0.59-2.71), respectively. Logistic regression showed that injection latency and post-injection seizure duration did not significantly predict the probability of true positive SISCOM (p-value = 0.45 and 0.29, respectively). CONCLUSION: Radiotracer injection latency and post-injection seizure duration were not shown to have a statistical significant impact on SISCOM performance in identifying the EZ. SIGNIFICANCE: This study demonstrates that further study of factors contributing to the performance of SISCOM in EZ identification in children is needed. PMID- 29981961 TI - Systematic review of cognitive event related potentials in euthymic bipolar disorder. AB - Cognitive deficits are critical features of bipolar disorder (BD), greatly impacting quality of life. The aim is to systematically review and critically evaluate underlying event related potential (ERP) features in euthymic BD relating to differences in sensory processes, attention, inhibition and conflict monitoring compared with healthy controls. 911 unique articles were identified using the PubMed database and 14 studies met the inclusion criteria. Individuals with BD in a euthymic state have reduced P50 sensory gating and reduced P100 amplitudes compared with healthy controls. Many studies demonstrated reduced P300 amplitudes and normal P300 latencies in BD. In addition, reduced NoGo N2 and abnormal NoGo P3 activity were observed in BD. Finally, there is some evidence of reduced error-related negativity amplitudes in BD. Importantly, ERP modulations vary with stimulus factors and clinical profile. The functional significance of these findings and clinical implications are discussed. ERP differences in BD arise at various stages of cognitive processing, specifically in early auditory and visual processing, attention allocation, context updating, inhibition and conflict monitoring. Treating these deficits and their underlying neurobiological disturbances corresponding to abnormal performance on cognitive tasks may aid functional remission. This knowledge might enable personalized treatment interventions targeting specific cognitive deficits. PMID- 29981960 TI - Somatosensory temporal discrimination in Parkinson's disease, dystonia and essential tremor: Pathophysiological and clinical implications. AB - OBJECTIVE: To investigate whether changes in the somatosensory temporal discrimination threshold (STDT) in Parkinson's disease (PD) and dystonia reflect the involvement of specific neural structures or mechanisms related to tremor, and whether the STDT can discriminate patients with PD, dystonia or essential tremor (ET). METHODS: We tested STDT in 223 patients with PD, dystonia and ET and compared STDT values in patients with PD and dystonia with tremor with those of PD and CD without tremor. Data were compared with those of age-matched healthy subjects. RESULTS: STDT values were high in patients with dystonia and PD but normal in ET. In PD, STDT values were similar in patients with resting or postural/action tremor and in those without tremor. In dystonia, STDT values were higher in patients with tremor than in those without tremor. The ROC curve showed that STDT discriminates tremor in dystonia from ET. CONCLUSIONS: In PD, STDT changes likely reflect basal ganglia abnormalities and are unrelated to tremor mechanisms. In dystonia, the primary somatosensory cortex and cerebellum play an additional role. SIGNIFICANCE: STDT provides information on the pathophysiological mechanisms of patients with movement disorders and may be used to differentiate patients with dystonia and tremor from those with tremor due to ET. PMID- 29981962 TI - Which obesity index is the best predictor for high cardiovascular disease risk in middle-aged and elderly population? AB - BACKGROUND AND AIMS: The aim was to investigate the relationships between visceral fat rating scale (VFR), waist circumference (WC), body mass index (BMI) and cardiovascular disease (CVD) risk. METHODS: In this cross-sectional, community-based study, participants completed questionnaire that included personal and medical history, and underwent anthropometric measurement and blood sampling. The 2008 general CVD risk model was used to predict CVD risk. Associations between CVD risk and VFR, WC, BMI were evaluated by means of analysis of covariance (ANCOVA) with gender as covariate, Chi-squared test, Pearson's correlation, Cochran-Armitage test, multivariate logistic regression and receiver operating characteristic curves. RESULTS: A total of 377 people were enrolled. A significant association was identified between VFR, WC, BMI, and CVD risk, with coefficient of determination (r2) of 0.32 (p < 0.001), 0.18 (p < 0.001) and 0.03 (p = 0.001), respectively. There was a trend toward increasing prevalence of high CVD risk as VFR, WC, and BMI increased (all p values <0.05). Multivariate logistic regression revealed VFR (OR = 1.21; 95%CI = 1.02-1.24), WC (OR = 1.07; 95%CI = 1.04-1.11) and BMI (OR = 1.11; 95%CI = 1.02-1.21) to be independent predictors of high CVD risk. In male, the area under curves of VFR and WC are greater than BMI: 0.641, 0.647 and 0.562. In female, the area under curves of VFR and WC are also greater than BMI: 0.656, 0.688 and 0.601. CONCLUSIONS: VFR and WC were more strongly associated with high CVD risk than BMI among middle-aged and elderly persons in Taiwan. PMID- 29981963 TI - Prevalence of geriatric depression in a community sample in Ghana: Analysis of associated risk and protective factors. AB - BACKGROUND: Ageing comes with its own associated physical and psychosocial challenges. Depression is reported as one of the most prevalent psychopathology found among elderly people. However, there is dearth of literature in Ghana regarding mental health and its associated risk and protective factors among Ghanaians who are aged 65years and above. This study examined the prevalence and factors associated with depression among the aged in Ghana. METHODS: A cross sectional survey design was employed and a total of 262 elderly people (65+years) were sampled. The Geriatric Depression Scale, Brief COPE and demographic questionnaires were administered to the participants. RESULTS: There was 37.8% prevalence of depression among the participants. Socio-demographic characteristics such as religion, living status and presence of chronic illness independently predicted depression among the participants. The use of religion, acceptance and active coping were the most commonly reported coping strategies among the participants while denial, behavioural disengagement and substance use were the least used coping strategies among the participants. The use of active coping predicted decreased depression levels whereas the use of behavioural disengagement and self-blame significantly predicted increased depression levels among the participants. CONCLUSIONS: Depression is a major challenge among the aged in this study and therefore, mental health screening should form part of the routine health screening practices for the elderly. The findings call for interventions aimed at promoting healthy ageing among the elderly in Ghana. PMID- 29981964 TI - Mental states modulate gaze following, but not automatically. AB - A number of authors have suggested that the computation of another person's visual perspective occurs automatically. In the current work we examined whether perspective-taking is indeed automatic or more likely to be due to mechanisms associated with conscious control. Participants viewed everyday scenes in which a single human model looked towards a target object. Importantly, the model's view of the object was either visible or occluded by a physical barrier (e.g., briefcase). Results showed that when observers were given five seconds to freely view the scenes, eye movements were faster to fixate the object when the model could see it compared to when it was occluded. By contrast, when observers were required to rapidly discriminate a target superimposed upon the same object no such visibility effect occurred. We also employed the barrier procedure together with the most recent method (i.e., the ambiguous number paradigm) to have been employed in assessing the perspective-taking theory. Results showed that the model's gaze facilitated responses even when this agent could not see the critical stimuli. We argue that although humans do take into account the perspective of other people this does not occur automatically. PMID- 29981965 TI - The relationship between parental mental-state language and 2.5-year-olds' performance on a nontraditional false-belief task. AB - A growing body of evidence suggests that children succeed in nontraditional false belief tasks in the first years of life. However, few studies have examined individual differences in infants' and toddlers' performance on these tasks. Here we investigated whether parental use of mental-state language (i.e. think, understand), which predicts children's performance on elicited-response false belief tasks at older ages, also predicts toddlers' performance on a nontraditional task. We tested 2.5-year-old children in a verbal nontraditional false-belief task that included two looking time measures, anticipatory looking and preferential looking, and measured parents' use of mental-state language during a picture-book task. Parents' use of mental-state language positively predicted children's performance on the anticipatory-looking measure of the nontraditional task. These results provide the first evidence that social factors relate to children's false-belief understanding prior to age 3 and that this association extends to performance on nontraditional tasks. These findings add to a growing number of studies suggesting that mental-state language supports mental state understanding across the lifespan. PMID- 29981966 TI - Intention, attention and long-term memory for visual scenes: It all depends on the scenes. AB - Humans have an ability to remember up to 10,000 previously viewed scenes with apparently robust memory for visual detail, a phenomenon that has been interpreted as suggesting a visual memory system of massive capacity. Attempts at explanation have largely focused on the nature of the stimuli and been influenced by theoretical accounts of object recognition. Our own study aims to supplement this by considering two observer-based aspects of visual long-term memory, one strategic, whether the observers are aware or not that their memory will subsequently be tested and the other executive, based on the amount of attentional capacity available during encoding. We describe six studies involving visual scenes ranging in difficulty from complex manmade scenes (d' = 2.54), to door scenes with prominent features removed (d' = 0.79). To ensure processing of the stimuli, all participants have to make a judgement of pleasantness (Experiments 1 and 2) or of the presence or absence of a dot (Experiment 3). Intention to learn influence performance only in the most impoverished condition comprising doors with prominent features removed. Experiments 4-6 investigated the attentional demands of visual long-term memory using a concurrent task procedure. While the demanding task of counting back in threes clearly impaired performance across the range of materials, a lighter load, counting back in ones influences only the most difficult door scenes. Detailed analysis of error patterns indicated that clear differences in performance level between manmade and natural scenes and between unmodified and modified door scenes was reflected in false alarm scores not detections, while concurrent task load affected both. We suggest an interpretation in terms of a two-level process of encoding at the visual feature rather than the whole scene level, with natural images containing many features encoded richly, rapidly and without explicit intent. Only when scenes are selected from a single category and with distinctive detail minimised does memory depend on intention to remember and on the availability of substantial executive capacity. PMID- 29981967 TI - Communicative intent modulates production and comprehension of actions and gestures: A Kinect study. AB - Actions may be used to directly act on the world around us, or as a means of communication. Effective communication requires the addressee to recognize the act as being communicative. Humans are sensitive to ostensive communicative cues, such as direct eye gaze (Csibra & Gergely, 2009). However, there may be additional cues present in the action or gesture itself. Here we investigate features that characterize the initiation of a communicative interaction in both production and comprehension. We asked 40 participants to perform 31 pairs of object-directed actions and representational gestures in more- or less- communicative contexts. Data were collected using motion capture technology for kinematics and video recording for eye-gaze. With these data, we focused on two issues. First, if and how actions and gestures are systematically modulated when performed in a communicative context. Second, if observers exploit such kinematic information to classify an act as communicative. Our study showed that during production the communicative context modulates space-time dimensions of kinematics and elicits an increase in addressee-directed eye-gaze. Naive participants detected communicative intent in actions and gestures preferentially using eye-gaze information, only utilizing kinematic information when eye-gaze was unavailable. Our study highlights the general communicative modulation of action and gesture kinematics during production but also shows that addressees only exploit this modulation to recognize communicative intention in the absence of eye-gaze. We discuss these findings in terms of distinctive but potentially overlapping functions of addressee directed eye-gaze and kinematic modulations within the wider context of human communication and learning. PMID- 29981968 TI - I remember emotional content better, but I'm struggling to remember who said it! AB - The joint impact of emotion and production on conversational memory was examined in two experiments where pairs of participants took turns producing verbal information. They were instructed to produce out loud sentences based on either neutral or emotional (Experiment 1: negative; Experiment 2: positive) words. Each participant was then asked to recall as many words as possible (content memory) and to indicate who had produced each word (reality monitoring). The analyses showed that both self-production and emotion boost content memory, although emotion also impairs reality monitoring. This study sheds light on how both factors (emotion and production) may constrain language interaction memory through information saliency. PMID- 29981969 TI - The effect of saline-alkaline and water stresses on water use efficiency and standing biomass of Phragmites australis and Bolboschoenus planiculmis. AB - Salt marsh plants in the West Songnen Plain, northern China, are threatened by increasing soil salinity and alkalinity since the late 20th century. To explore how these wetland ecosystems respond to such environmental changes, we examined the effect of saline-alkaline stresses and water stress (flooding/drought) on water use efficiency (WUE, assessed with stable carbon isotopes) and standing biomass of Phragmites australis and Bolboschoenus planiculmis under both greenhouse and field conditions. In the field, sodium bicarbonate (NaHCO3) was the main saline-alkaline component, and the soil total ion content was negatively related to water level. Higher soil ion content decreased standing biomass of P. australis and B. planiculmis in the field and greenhouse, and increased WUE in the greenhouse. With higher water level, standing biomass of P. australis increased, while that of B. planiculmis decreased in both the field and greenhouse. Alkaline stress exerted the greatest negative influence on growth of P. australis, but only under high ion content. Low alkaline ion content promoted growth of B. planiculmis. Soil ion content exerted the strongest influence on foliar delta13C (and thus WUE) and standing biomass of both species compared to water level and stress type. Our findings suggest that under high ion contents, P. australis is more tolerant to flooding stress while B. planiculmis is more tolerant to drought stress. Moreover, P. australis has a high ability to modulate and increase WUE to resist its adverse environment. Our study will contribute to a better understanding of the influence of climate change and increasingly serious human disturbances on the distribution and productivity of these two important wetland species. PMID- 29981970 TI - Black carbon particles and ozone-oxidized black carbon particles induced lung damage in mice through an interleukin-33 dependent pathway. AB - Black carbon (BC) is a key component of atmospheric particles which has adverse effects on human health. Oxidation could lead to chemical property and toxicity potency changes of BC. The key cytokines participating in lung damage in mice induced by BC and ozone-oxidized BC (oBC) particles have been investigated in this study. It was concluded that oBC has stronger potency of inducing lung damage in mice comparing to BC. IL-6 and IL-33 were hypothesized to play important roles in this damage. Accordingly, IL-6 and IL-33 neutralizing antibodies were used to explore which cytokine might play a key role in lung inflammation induced by BC and oBC. As a result, IL-6 neutralizing antibody did not alleviate the lung damage induced by BC and oBC. However, IL-33 neutralizing antibody prevented BC and oBC induced lung damage. Furthermore, IL-33 neutralizing antibody treatment reduced IL-6 mRNA expression. It is hypothesized that MAPK and PI3K-AKT pathways might be involved in the oBC particles caused lung damage. It was concluded that IL-33 plays a key role in BC and oBC induced lung damage in mice. PMID- 29981971 TI - Olive pomace as a valuable source of bioactive compounds: A study regarding its lipid- and water-soluble components. AB - Olive pomace is a major output of olive oil processing. This by-product is a valuable source of bioactive compounds with well-recognized benefits for human health and well-being. In this work, the proximate composition and the profiles of vitamin E (HPLC-DAD-FLD), fatty acids (GC-FID) and phenolics (HPLC-DAD-FL/MSn) were determined. Additionally, a sustainable process for antioxidants extraction Multi-frequency Multimode Modulated (MMM) ultrasonic technique - was compared to a conventional solid-liquid extraction. The total phenolics content and antioxidant activity (ferric reducing antioxidant power and DPPH scavenging ability) of the extracts were analysed to assess the efficacy of both extraction methodologies. The vitamin E profile of the olive pomace comprised the vitamers alpha-tocopherol, beta-tocopherol, alpha-tocotrienol and gamma-tocopherol. alpha Tocopherol was the major form (2.63 mg/100 g), while the other vitamers were present in amounts lower than 0.1 mg/100 g. The lipid fraction was especially rich in oleic acid (75%), followed by palmitic (10%), linoleic (9%), and stearic (3%) acids. Hydroxytyrosol and comsegoloside represented ~79% of the total phenolics present in olive pomace. Hydroxytyrosol content was 83.6 mg/100 g, while tyrosol was present in lower amounts (3.4 mg/100 g). Concerning the antioxidants extraction, the MMM technique allowed a faster and higher recovery (p < 0.05) of the compounds, compared to the conventional solid-liquid extraction. By this way, it seems to be a very promising eco-friendly and effective methodology to extract antioxidants from this and other matrices. PMID- 29981972 TI - Effects of land use and spatial processes in water and surface sediment of tropical reservoirs at local and regional scales. AB - The effects of land use and connectivity on the characteristics of aquatic ecosystems are thought to be scale-dependent. This study aimed to evaluate the relationships between land use and reservoir characteristics at two spatial scales, after controlling for spatial processes. Water and surface sediment samples were collected from 31 sites (7 reservoirs) in the Paiva Castro and Piracicaba River basins (Cantareira System, Sao Paulo State, Brazil), during austral summer and winter. The dataset included 15 water quality variables and 6 surface sediment variables. Land use variables (natural areas, pasture, agriculture and urban areas) were obtained at two spatial scales (buffer and watershed) in each reservoir. Spatial variables were calculated using Moran's Eigenvectors Maps and Asymmetric Eigenvector Maps. The strengths of the relationships between land use and sediment variables were stronger than those between land use and water quality variables. The strengths of some of the relationships were scale-dependent. Finally, spatial processes, mostly hydrological connectivity, play an important role in water-sediment quality and should be considered in landscape management programs. PMID- 29981973 TI - Changes in soil water repellency after prescribed burnings in three different Mediterranean forest ecosystems. AB - Prescribed burnings reduce the biomass and the risk of wildfires but can also alter soil water repellency. The objective of this study is to evaluate the impact of several prescribed burnings in soil water repellency (SWR). In spring 2016, prescribed burns were carried out at three forest sites located in: (i) Beteta in a pure forest of Pinus nigra Arnold ssp. salzmannii; (ii) El Pozuelo in mixed forest stands of Pinus pinaster Aiton and Pinus nigra Arnold ssp. salzmannii; (iii) Lezuza in mixed forest stands of Pinus halepensis Miller and Pinus pinaster Aiton. Six plots were established in each study area: three burned and three unburned. SWR was measured before and immediately after prescribed burns following a 1-year periodic evaluation. There were seven sampling dates at Beteta and El Pozuelo and nine at Lezuza with six plots and six measurement transects in each plot (36 measurement transects on each date). Soil water content (SWC), soil temperature (ST) and soil organic matter (SOM) were also measured. Our results showed that SWR increased after burning to quickly return to normal values in Lezuza, after 1 month in El Pozuelo and after 1 year in Beteta. Moreover, a significant positive relationship between SWR and both SOM and ST, but a negative one with SWC, were observed, which led SWR to increase after fire passage, also in the summer months. Continuous monitoring of these study sites is recommended to determine if low-intensity burnings promote mid- to long-term changes in soil characteristics. PMID- 29981974 TI - Space-based observations of crustal deflections for drought characterization in Brazil. AB - Widespread environmental impacts of frequent drought episodes in Brazil have resulted in several drought-related diagnostics studies. However, the potential of many "opportunistic sensors", such as the Global Positioning System (GPS), has not yet been considered in hydrological hazard monitoring in Brazil. In this study, the response of the Earth's crust to Brazil's 2012-2015 drought event in different structural provinces is analyzed by comparing GPS-observed vertical crustal deformations (VCDs) with the terrestrial water storage (TWS) derived from the Gravity Recovery and Climate Experiment (GRACE). The results indicate that there is no spatial correlation between annual amplitudes of the TWS and VCDs in different structural provinces apart from the purely elastic response of the crust to TWS dynamics, at almost all the 39 GPS stations that were analyzed. However, approximately 15% of the monitoring stations show that VCD leads TWS with a phase lag of 2-4 months. Errors associated with VCD and TWS are within the accepted range for space geodetic techniques (i.e., GPS and GRACE) and despite the need for further investigation, the phase lead seems to be associated with rainfall, which impacts the TWS through the hydrographs. Overall, the GPS-based drought index (DIVCD) reflects the water depletion in many regions of Brazil, which agrees with the GRACE-based DITWS in terms of the Spearman correlation coefficient (ranging from 0.4 to 0.9) in the Amazon, Tocantins, La Plata, and Sao Francisco river basins. This agreement confirms the drought persistence during the study period and that DIVCD can be used to monitor hydrological droughts. In regions in which DITWS sufficiently agrees with DIVCD (48% of the sites), near real-time drought monitoring is feasible. This could be useful in the optimization of models for the forward prediction of drought events in other regions worldwide, where GPS vertical displacements strongly correlate with hydrological GRACE signals. PMID- 29981975 TI - Assessing the effects of rainfall, groundwater downward leakage, and groundwater head differences on the development of cover-collapse and cover-suffosion sinkholes in central Florida (USA). AB - Cover-collapse and cover-suffosion sinkholes are widely distributed in central Florida (USA) karst terrains and have been recognized as the primary geo-hazard threatening human lives and destroying infrastructure. Previous studies indicated that the development of cover-collapse and cover-suffosion sinkholes in central Florida might be related to hydrologic/hydrogeologic conditions such as rainfall, groundwater downward leakage and groundwater hydraulic head differences (groundwater level differences between the water tables in unconfined aquifer and the potentiometric levels in confined aquifer). Here, a case study in central Florida urban areas is conducted to quantify the effects of rainfall, groundwater downward leakage and groundwater head differences on the development of cover collapse and cover-suffosion sinkholes in central Florida with a focus on the timing of their occurrences. Results indicate that heavy rainfall/storm(s) and rapid increase of head differences within a relatively short period of time are major factors affecting the timing of sinkhole occurrences, and the spatial variation of groundwater downward leakage rate can be used to generate sinkhole susceptibility zonation maps for serving as a useful indicator of the likelihood of sinkhole development at certain areas. Results caution that the groundwater pumping and mining dewatering rate should be setup properly and the starting time of groundwater pumping and/or mining dewatering should be selected carefully in central Florida, i.e., the activities should be put into abeyance after a heavy rainfall/storm(s) to reduce the probability of sinkhole occurrences. PMID- 29981976 TI - Application of silica-supported Ir and Ir-M (M = Pt, Pd, Au) catalysts for low temperature hydrodechlorination of tetrachloromethane. AB - Herein, it is presented a catalytic system for gas-phase hydrodechlorination of tetrachloromethane at low temperature and atmospheric pressure, using iridium supported on silica as parent catalyst. Iridium electronic configuration is suitable to catalyse the hydrodechlorination reactions, however, it has been rarely used in this reaction to date. The catalytic abilities were significantly improved when a second transition metal was added. Catalysts' stability and selectivity to the desired products (i.e. C1-C4 hydrocarbons) improved compared to conventional activation in hydrogen when catalysts were activated shortly with microwave irradiation. Microwave irradiation of catalysts favourably influences the homogeneity of the metallic active phase, both in terms of the size of metal crystals and the homogeneity of bimetallic systems. Addition of platinum to the 'parent' iridium catalyst improved its catalytic properties and decreased deactivation. Fresh and spent catalysts were comprehensively characterized using several techniques (BET, CO-chemisorption, XRD, XPS, electron microscopy and mass spectrometry) to determine structure-activity relationships and potential causes for catalyst deactivation. No significant changes in crystalline size or bimetallic phase composition were observed for spent catalysts (with the exception of Ir-Pd catalysts which underwent bulk carbide during the reaction). PMID- 29981977 TI - Distribution and transport of heavy metals in estuarine-inner shelf regions of the East China Sea. AB - This study analyzes the distribution and transportation of heavy metals in surface sediments by determining the concentrations of 6 heavy metals (Cr, Zn, Ni, Pb, Cu, and Cd) based on 164 surface sediments collected from the East China Sea (ECS). The results indicated that concentrations of heavy metals were higher in the south than the north with a clear boundary near 30 degrees N. The distributions of the six heavy metals could be divided into four groups that corresponded well with different sediment components, suggesting that hydrodynamic sorting processes play an important role in the selective transportation of sedimentary heavy metals. In addition, the spatial distributions of heavy metals were more consistent with fine-grained sediments having a grain size lower than 32 MUm. Heavy metal concentrations were slightly higher than found in previous studies conducted from 2002 to 2010. In addition, their spatial patterns have changed drastically compared to data from 2006, suggesting that intensive inland human activities have had a profound impact on heavy metal transportation and distribution in the estuarine & inner-shelf regions of the ECS. PMID- 29981978 TI - Biofouling in ultrafiltration process for drinking water treatment and its control by chlorinated-water and pure water backwashing. AB - We investigated biofouling in ultrafiltration (UF) for drinking water treatment and its control by backwashing with chlorinated-water or pure water. By using sodium azide to suppress biological growth, the relative contribution of biofouling to total fouling was estimated, and its value (5.3-56.0%) varied with the feed water, and increased with the increases of filtration time and membrane flux. The biofouling layer could partially remove biodegradable organic matter and ammonia (32.9-74.2%). Backwashing using chlorinated-water partly inactivated the microorganisms (23.8%) but increased the content of extracellular polymeric substances (7.7%) in the biofouling layer. In contrast, backwashing using pure water led to a looser and more porous fouling layer according to optical coherence tomography observation. Consequently, the latter was more effective in reducing fouling resistance (33.41% reduction) compared to backwashing by chlorinated-water (8.6%). These findings reveal the critical roles of biofouling in pollutants removal in addition to membrane permeability, which has important implications for addressing seasonal ammonia pollution. PMID- 29981979 TI - Carbonaceous nanomaterial-initiated reductive transformation of silver ions in the aqueous environment under sunlight. AB - The aquatic systems are among the major sinks for discharged substances, and these substances will likely associate with each other. The present work, therefore, aims to study the transformation of metal ions to nanoparticles by discharged carbonaceous materials of emerging concern (e.g., carbon nanotubes (CNTs)) coexisting in the aqueous environment. Here we undertook a systematic study of the reduction of silver ions by CNT suspensions under sunlight irradiation. The formation rate of silver nanoparticles (AgNPs) is suppressed by an increasing amount of dissolved oxygen or strong solution acidity, as well as the presence of other cations. The photoreduction of Ag+ by CNTs involves a charge transfer process between Ag+ and the CNTs. The way in which carbonaceous nanomaterial properties influence the formation kinetics, size, and morphology of the AgNPs was examined. An enhanced sunlight-driven formation of AgNPs with highly monodispersity was observed in CNTs with nitrogen-containing functional groups due to their active electrochemical and stabilizing nature. The compiled results reveal the importance of an understanding of not only the inherent environmental behaviors of individual substances but also their interactions with concurrent substances in the environment. We demonstrated that the transformation of silver under sunlight by carbonaceous materials with different characteristics could alter the properties and potential risks of metallic species in aquatic environments. PMID- 29981980 TI - Discrimination of typical cyclic compounds and selection of toxicity evaluation bioassays for coal gasification wastewater (CGW) based on toxicity mechanism of actions (MOAs). AB - This paper originally investigated toxicity discrimination of typical cyclic compounds and bioassays selection on toxicity evaluation for coal gasification wastewater (CGW) effluent with mechanism-oriented investigation. Initially, representative cyclic toxicants were selected and classified with quantitative structure-toxicity relationship (QSTR). Nitrogen heterocyclic compounds (NHCs) and polycyclic aromatic hydrocarbons (PAHs) were basically discriminated as nonpolar narcotics with significant correlation to hydrophobicity (p < 0.05, R2 = 0.8668-0.9635), while phenols were regarded as polar narcotics and reactive compounds due to slight correlation to hydrophobicity (p > 0.05, R2 < 0.5). Furthermore, specific mechanism of actions (MOAs) to various organisms revealed that phenols were discriminated as critical source of acute toxicity in CGW, with short-term visible and irreversible damage. However, NHCs and PAHs, which exerted accumulation toxicity rather than acute toxicity, might result in potential mutagenicity and unpredictable risk along the food chain. Afterwards, based on species sensitivity to typical toxicants and application in real CGW effluent, non-applicability of Chlorella vulgaris (C. vulgaris) was validated in toxicity evaluation. While Daphnia magna (D. magna) was suggested as a toxicity bioassay in entire effluent due to the highest sensitivity and applicability. Tetrahymena thermophile (T. pyriformis) might be applicable in effluent with low biodegradability due to similar evaluation results (TU = 8.90) to D. magna (TU = 6.67) in aerobic effluent. Finally, the relationship between toxicity and bioavailability based on typical pollutants and model species illustrated necessity for dualism toxicity-biodegradability investigation on CGW. PMID- 29981981 TI - Selective removal of heavy metals from landfill leachate by reactive granular filters. AB - The pre-treatment of landfill leachate prior to its co-treatment in the municipal plants of waste water processing could represent an appropriate and cost effective solution for its management. Pre-treatment is necessary especially to remove heavy metals, which may be transferred to the excess sludge preventing its valorisation. In the present paper, we propose a chemical-physical pre-treatment of leachate using four different granular reactive media able to selectively remove the contaminants present in the leachate. The efficiency of these materials was investigated using synthetic leachate through batch tests and a column test. In the latter case the four materials were placed in two columns connected in series and fed an under constant upward flow (0.5 mL/min). The first column was filled half (50 cm) with a granular mixture of zero valent iron (ZVI) and pumice and half (50 cm) with a granular mixture of ZVI and granular activated carbon (GAC). The second column, which was fed with the effluent of the first column, was filled half with zeolite (chabazite) and half with GAC. Heavy metals were mainly removed by the ZVI/pumice and ZVI/GAC steps with a removal efficiency that was higher than 98, 94 and 90% for copper, nickel and zinc, respectively, after 70 days of operation. Ammonium was removed by zeolite with a removal efficiency of 99% up to 23 days. The average reduction of the chemical oxygen demand (COD) was of 40% for 85 days, whereas chloride and sulphate removal was negligible. PMID- 29981982 TI - Assessing the effects of field-relevant pesticide mixtures for their compliance with the concentration addition model - An experimental approach with Daphnia magna. AB - The environmental risk assessment of pesticides is mainly performed on individual active ingredients. In surface waters within the agricultural landscape, however, contamination is usually characterized by complex pesticide mixtures. To estimate the joint effects caused by these complex mixtures, mathematical models have been proposed. Among these, the model of concentration addition (CA) is suggested as default model for the risk assessment of chemical mixtures as it is considered protective for mixtures composed of similar and dissimilar acting substances. Here we assessed the suitability of CA predictions for seven field relevant pesticide mixtures using acute (immobility) and chronic (reproduction) responses of the standard test species Daphnia magna. Pesticide mixtures indicated largely additive or less than additive effects when using CA model predictions as a reference. Moreover, we revealed that deviations from CA predictions are lower for chronic (up to 3.2-fold) relative to acute (up to 7.2-fold) response variables. Additionally, CA predictions were in general more accurate for complex mixtures relative to those composed of only a few pesticides. Thus, this study suggests CA models as largely protective for the risk assessment of pesticide mixtures justifying its use as default model. At the same time, extrapolating conclusions about the joint effects of pesticides from acute to chronic responses is uncertain, due to partly large discrepancies with regards to the deviation of model prediction and observed effects between exposure scenarios. PMID- 29981983 TI - Metal(oid) mobility in a hypersaline salt marsh sediment (Secovlje Salina, northern Adriatic, Slovenia). AB - In this research, sediments from the Secovlje Salina (northern Adriatic, Slovenia) were geochemically investigated in order to decode the mobility of metal(oid)s in the hypersaline environment. The results demonstrated that the concentrations of As, Co, Cu, Mo, Ni, Pb, Sb, Sn and Zn were comparable to those detected in various similar coastal background areas, as well as in the Secovlje salt marsh core sample. The estimated mobility potential of metal(oid)s in sediment decreases in the following order: Mo > As > Cu > Sb > Sn > Co > Pb > Ni > Zn. Since the hypersaline sediment (e.g. healing mud) is used as a healing factor (it can be applied directly on human skin), the study of metal(oid) bioavailability in an interaction between the hypersaline sediments and the artificial sweat was also performed. It is significant that the metal(oid) contents are leached in very low concentrations and are treated as nontoxic for humans according to international norms for cosmetic products. The study provides information in order to assess the role of metal mobility on the potential health impact of the application of natural healing mud. PMID- 29981984 TI - Effects of free nitrous acid treatment conditions on the nitrite pathway performance in mainstream wastewater treatment. AB - Inline sludge treatment using free nitrous acid (FNA) was recently shown to be effective in establishing the nitrite pathway in a biological nitrogen removal system. However, the effects of FNA treatment conditions on the nitrite pathway performance remained to be investigated. In this study, three different FNA treatment frequencies (daily sludge treatment ratios of 0.22, 0.31 and 0.38, respectively), two FNA concentrations (1.35 mgN/L and 4.23 mgN/L, respectively) and two influent feeding regimes (one- and two-step feeding) were investigated in four laboratory-scale sequencing batch reactors. The nitrite accumulation ratio was positively correlated to the FNA treatment frequency. However, when a high treatment frequency was used e.g., daily sludge treatment ratio of 0.38, a significant reduction in ammonia oxidizing bacteria (AOB) activity occurred, leading to poor ammonium oxidation. AOB were able to acclimatise to FNA concentrations up to of 4.23 mgN/L, whereas nitrite oxidizing bacteria (NOB) were limited by an FNA concentration of 1.35 mgN/L over the duration of the study (up to 120 days). This difference in sensitivity to FNA could be used to further enhance nitrite accumulation, with 90% accumulation achieved at an FNA concentration of 4.23 mgN/L and a daily sludge treatment ratio of 0.31 in this study. However, this high level of nitrite accumulation led to increased N2O emission, with emission factors of up to 3.9% observed. The N2O emission was mitigated (reduced to 1.3%) by applying two-step feeding resulting in a nitrite accumulation ratio of 45.1%. Economic analysis showed that choosing the optimal FNA treatment conditions depends on a combination of the wastewater characteristics, the nitrogen discharge standards, and the operational costs. This study provides important information for the optimisation and practical application of FNA-based sludge treatment technology for achieving the mainstream stable nitrite pathway. PMID- 29981985 TI - High serum levels of p,p'-DDE are associated with an accelerated decline in GFR during 10 years follow-up. AB - Over the past 20 years, the global incidence of chronic kidney disease (CKD) has been increasing and organochlorine pesticides (such as DDT) is a suspected etiological factor. The present study examines the associations between low level background exposure to p,p'-DDE (1-dichloro-2,2-bis (p-chlorophenyl) ethylene), the main DDT metabolite, and kidney function during a 10-year follow-up. Data was analysed from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (n = 1016, 50% women, all aged 70 years). Serum levels of p,p'-DDE was measured by gas chromatography coupled to high-resolution mass spectrometry (GC/HRMS) at baseline (i.e. age of 70 years). Glomerular filtration rate (GFR) was estimated using serum creatinine and cystatin C at 70, 75 and 80 years of age. A significant decline in GFR was seen during the 10-year follow-up (-24 ml/min/1.73 m2, p < 0.0001). A significant negative interaction was seen between baseline p,p'-DDE levels and change in GFR over time (p < 0.0001) following adjustment for sex, systolic blood pressure, diabetes, BMI, smoking and education level at age 70. Subjects with the lowest levels of p,p'-DDE levels at age 70 showed the lowest decline in GFR over 10 years, while subjects with the highest p,p'-DDE levels showed the greatest decline. Baseline levels of p,p'-DDE were related to an accelerated reduction in GFR over 10 years suggesting a nephrotoxic effect of DDT/p,p'-DDE. These findings support a potential role for DDT in the epidemic of CKD of unknown etiology (CKDu) in agricultural communities of Sri Lanka and Central America where DDT was previously used. PMID- 29981986 TI - Occurrence and distribution of microplastics in an urban river: A case study in the Pearl River along Guangzhou City, China. AB - Microplastics, as emerging contaminants in the global environment, have become a cause for concern for both academics and the public. The present understanding of microplastic pollution is primarily focused on marine environments, and less attention has been given to freshwater environments, in particular, to urban rivers. In this study, microplastics were sampled from surface water and sediments in 14 sites located in the lower course of the Pearl River. These sampling sites are located along Guangzhou of South China, with built-up areas being the dominant land use. The abundances of microplastics in surface water and sediments ranged from 379 to 7924 items.m-3 and 80 to 9597 items.kg-1, respectively. Polyethylene and polypropylene were the common types of microplastics, together accounting for 64.3% and 73.8% of surface water and sediment samples, respectively. Fibers were the dominant microplastic shapes in both water and sediment samples. The abundances of microplastics varied in surface water and sediments with each site, which might be affected by multiple factors. Our results indicated that wastewater treatment plants (WWTP) could reduce microplastics from municipal sewage which was finally discharged into the Pearl River along Guangzhou. PMID- 29981987 TI - Interactions between arsenic adsorption/desorption and indigenous bacterial activity in shallow high arsenic aquifer sediments from the Jianghan Plain, Central China. AB - Exposure to arsenic in the environment is hazardous to biota. Three types of sediments from a shallow, high arsenic aquifer were collected from Jianghan Plain, Central China to investigate interactions between indigenous bacterial activity and arsenic adsorption/desorption. For the same level of bacterial activity, the As(III) or As(V) adsorption rate in sediments decreased from clay loam to loamy sand to silty sand. However, the arsenic desorption rate from these sediments followed the reverse sequence. For the same arsenic speciation and content, bacterial activity decreased from clay loam to loamy sand to silty sand. Overall, arsenic adsorption/desorption rates were related to both bacterial activity and sediment texture. The bacteria present could reduce As(V) to As(III), thereby favoring its release from sediment into solution and increasing the ratio of As(III) to total arsenic. These results indicate indigenous bacteria strongly affect the adsorption/desorption and oxidation-reduction of arsenic, and are actively involved in the dynamic equilibrium of arsenic between sediment and groundwater in this shallow aquifer. PMID- 29981988 TI - Photo-Fenton abatement of aqueous organics using metal-organic frameworks: An advancement from benchmark zeolite. AB - A new and environmentally benign photocatalyst is introduced in this study, which was synthesized via incipient wetness impregnation onto MIL-47(V) using an ethanolic Fe(III) chloride solution. The resultant materials were characterized by XRD, FE-SEM, and HR-TEM analyses. The photocatalytic capability of Fe/MIL-47 towards removal of methylene blue (MB) was evaluated in comparison to MIL-53(Al), Cu/MIL-47, and Fe/zeolite-Y. The unmodified MIL-47 achieved 55% MB removal after 20-min exposure to UV/H2O2, through photodegradation as the dominant mechanism. Incorporation of Fe species into MIL-47 significantly increased the MB removal rate by 2.4-fold and accomplished nearly complete removal (98.2%) in 60 min, outcompeting the performance of Cu/MIL-47 and Fe/zeolite-Y. Based on the results of XRD, the impregnation of Fe retained the crystalline characteristics of MIL 47. The significance of temperature, catalyst dose, pH, and molar ratio of H2O2:MB was also evaluated in governing the photocatalytic activity of Fe/MIL-47. The reusability of Fe/MIL-47 was evidenced through its repetitive uses in MB photodegradation. The current work highlighted the potential of Fe impregnation for modification of MOFs in order to fabricate highly efficient and water-stable heterogeneous photocatalyst for degradation of organic pollutants. With the use of an economical and environmentally safe reagent (i.e., Fe), robust photocatalyst can exhibit high sustainability to warrant clean environmental remediation. PMID- 29981989 TI - Efficacy of carbon-based materials for remediating polychlorinated biphenyls (PCBs) in sediment. AB - Polychlorinated biphenyls (PCBs) are persistent hydrophobic compounds that are present widely in the environment. Due to poorly maintained hazardous waste sites, electrical equipment leakage, and illegal disposal, PCBs were deposited in sediments present in bays and estuaries. PCBs continuously partition into the overlying water posing a long-term exposure risk to the environment and human health. This study demonstrates the efficacy of carbon-based materials in reducing the partitioning of PCBs from sediment to the water column. Both existing carbon-based materials [activated carbon (AC), black carbon (BC)] and emerging nanomaterials [graphene (GE), graphene oxide (GO), carbon nanotube (CNT)] were tested to determine their efficacy to bind PCBs in sediment. The comparison between the sorbents was accomplished by examining their distribution coefficient (Ks). The magnitude of Ks provides an idea about the bioavailable fraction of PCBs in the system; the higher the Ks, the greater the strength of sorption by the sorbent and therefore, the lower the PCB bioavailability. Results from the sorption experiment indicated that CNT performed the best overall followed by AC, BC, GO and GE. Results indicated that the Ks value for CNT was 1.16, 1.15, 1.13 and 1.04 log units greater than GE, GO, BC, and AC. PMID- 29981990 TI - Compound specific stable isotope determination of methylmercury in contaminated soil. AB - Rice is one of the main sources of methylmercury (MeHg) to humans, and soil is the main source of MeHg to rice grains. Determining the Hg isotope composition in environmental samples is a good way of characterizing sources of Hg pollution and investigating environmental processes. We developed a new compound-specific method for determining stable Hg isotopes in MeHg in contaminated soil and sediment. The method involved HNO3 leaching/solvent extraction, chemical ethylation, and separation by gas chromatography with a solenoid valve optimized to enrich MeHg. The method was optimized by using MeHg standard solution, certified reference materials and paddy soil samples. The delta202Hg precision for replicate MeHg isotope analyses was 0.140/00 (2 * standard deviation, n = 11), and no fractionation of Hg stable isotopes was found during the separation processes. The delta202Hg values for MeHg in paddy soils were -1.780/00 to 1.300/00, which were lower than the delta202Hg values for total Hg (-1.320/00 to 0.440/00). The results indicated that methylation (rather than demethylation) was the dominant process in the paddy soils. The method developed in this study can help us to better understand MeHg migration and transformation processes in paddy soil-rice ecosystem. PMID- 29981991 TI - Heat wave and the risk of intimate partner violence. AB - BACKGROUND: A high number of women report experiencing intimate partner violence (IPV). It is of utmost importance to identify possible factors that precipitate IPV and incorporate them into police protocols for evaluating IPV risk. Scientific evidence shows that environmental temperature is associated with a risk of violent behavior. OBJECTIVES: To analyze the effect and impact of heat waves on the risk of IPV. METHODS: Ecological, longitudinal time series study. The dependent variables are: intimate partner femicides (IPF), reports of IPV and 016 IPV telephone help line calls in the Community of Madrid from 05/01 to 09/30 in the years 2008-2016. The principal independent variable is the daily maximum temperature in Celsius (Tmax) above the heat wave threshold of 34 degrees C. A binomial negative regression was used for calls and reports and a Poisson regression was used for IPF. The attributable risk among those exposed (AR%) and the number of attributable cases was calculated for each variable. RESULTS: The risk of IPF increased three days after the heat wave, [RR(IC95%):1.40(1.00 1.97)], police reports of IPV increased one day after [RR (IC95%):1.02(1.00-1.03) and help line calls increased five days after [RR(IC95%):1.01(1.00-1.03)]. The AR% was 28.8% (IC95%: 0.3%-49.2%) for IPF, 1.7% (IC95%:0.3%-3.1%) for police reports and 1.43% (IC95:0.1%;2.8%) for help line calls. CONCLUSIONS: Our results suggest that heat waves are associated with an increase in IPV. The effect of an increase in IPV is delayed in time, with differences according to the violence indicators analyzed. PMID- 29981992 TI - Environmental correlates of food-chain length, mean trophic level and trophic level variance in invaded riverine fish assemblages. AB - Examining how the trophic structure of biotic assemblages is affected by human impacts, such as habitat degradation and the introduction of alien species, is important for understanding the consequences of such impacts on ecosystem functioning. We used general linear mixed models and hierarchical partitioning analyses of variance to examine for the first time the applicability of three hypotheses (ecosystem-size, productivity and disturbance) for explaining food chain length (FCL) in invaded fish assemblages. We used Fishbase trophic level (TL) estimates for 16 native and 18 alien fish species in an extensive riverine system in north-eastern Spain (99,700 km2, 15 catchments, 530 sites). The FCL of assemblages ranged from 2.7 to 4.42. Ecosystem size-related variables (Strahler stream order, physical habitat diversity) and human-disturbance (conductivity) made the largest contribution to the explained variance in the FCL model after accounting for spatial confounding factors and collinearity among predictors. Within-assemblage TL also was positively associated with Strahler stream order, suggesting that large rivers have the highest trophic diversity. High conductivity was negatively associated with FCL, as did with the mean TL of fish assemblages. However, an inverse association was found between mean TL and Strahler stream order, possibly because the presence of fish species of high TL may be offset by larger numbers of alien species of lower TL in large rivers. Given that there may be trophic replacements among native and alien species, this inference needs to be addressed with detailed trophic studies. However, reducing water conductivity by improved wastewater treatment and better agricultural practices probably would help to conserve the fish species on the apices of aquatic food-webs. PMID- 29981993 TI - Crystal violet and toxicity removal by adsorption and simultaneous photocatalysis in a continuous flow micro-reactor. AB - A continuous flow micro-reactor irradiated by UV-LEDs was employed to treat coloured wastewater by adsorption and simultaneous photocatalysis. Zinc oxide (ZnO) immobilized on commercial zeolites pellets in spherical shape (ZEO) was used as catalytic material in a micro-reactor maximizing the photocatalyst exposition to light sources, irradiating uniformly the entire solution volume and improving the mass transfer phenomena. Experimental tests were carried out on crystal violet dye (CV) as one of the main dying agent present in textile wastewater. The comparison between adsorption and adsorption/photocatalytic tests showed that UV irradiation can achieve a steady state CV concentration value corresponding to an equilibrium condition between adsorption and photocatalytic oxidation. The higher removal efficiency (i.e. 93%) was observed with a liquid flow rate of 1.1 mL/min (contact time = 4.7 min; CV = 10 mg/L) under UV light irradiation. In the steady state, CV removal remained constant for the overall testing time. Bioassays evidenced that toxicity was not completely removed (i.e. final effluent ranked as "slight acute toxic") from wastewater suggesting its suitability for sewage collection discharge. A Dubinin Radushkevich (D-R) isotherm model was applied for studying the adsorption behaviour of ZnO/ZEO sample. CV adsorption constants were evaluated from experimental data carried out in dark conditions in a batch system. Kinetic expression of CV removal and the D R adsorption were incorporated in the CV mass balance estimating the kinetic parameter. The model was validated comparing the calculated CV conversion with the experimental tests collected at different CV inlet concentration. PMID- 29981994 TI - Seasonal patterns of canopy photosynthesis captured by remotely sensed sun induced fluorescence and vegetation indexes in mid-to-high latitude forests: A cross-platform comparison. AB - Characterized by the noticeable seasonal patterns of canopy photosynthesis, mid to-high latitude forests are sensitive to climate change and crucial for understanding the global carbon cycle. To monitor the seasonal cycle of the canopy photosynthesis from space, several remotely sensed indexes, such as normalized difference vegetation index (NDVI), enhanced vegetation index (EVI), and leaf area index (LAI) have been implemented within the past decades. Recently, satellite-derived sun-induced fluorescence (SIF) has shown great potential of providing retrievals that are more related to photosynthesis process. However, the potentials of different canopy measurements have not been thoroughly assessed in the context of recent advances of new satellites and proposals of improved indexes. At 15 forested sites, we present a cross-platform intercomparison of one emerging remote sensing based index of phenology index (PI) and two SIF datasets against the conventional indexes such as NDVI, EVI, and LAI to capture the seasonal cycles of canopy photosynthesis. NDVI, EVI, LAI, and PI were calculated from Moderate Resolution Imaging Spectroradiometer (MODIS) measurements, while SIF were evaluated from Global Ozone Monitoring Experiment-2 (GOME-2) and Orbiting Carbon Observatory-2 (OCO-2) observations. Results indicated that GOME-2 SIF was highly correlated with gross primary production (GPP) and absorbed photosynthetically active radiation during the growing seasons. The SIF-GPP relationship can generally be considered linear at the 16 day scale. Key phenological metrics such as start of the seasons and end of the seasons captured by SIF from GOME-2 and OCO-2 matched closely with photosynthesis phenology as inferred by GPP. However, the applications of OCO-2 SIF for phenological studies may be limited only for a small range of sites (at site level) due to a limited spatial sampling. Among the MODIS estimations, PI and NDVI provided most reliable predictions of start of growing seasons, while no indexes accurately captured the end of growing seasons. PMID- 29981995 TI - Estimation of soil organic carbon stocks of two cities, New York City and Paris. AB - In cities, the strong heterogeneity of soils, added to the lack of standardized assessment methods, serves as a barrier to the estimation of their soil organic carbon content (SOC), soil organic carbon stocks (SOCS; kgC m-2) and soil organic carbon citywide totals (SOCCT; kgC). Are urban soils, even the subsoils and sealed soils, contributing to the global stock of C? To address this question, the SOCS and SOCCT of two cities, New York City (NYC) and Paris, were compared. In NYC, soil samples were collected with a pedological standardized method to 1 m depth. The bulk density (Db) was measured; SOC and SOCS were calculated for 0-30 cm and 30-100 cm depths in open (unsealed) soils and sealed soils. In Paris, the samples were collected for 0-30 cm depth in open soils and sealed soils by different sampling methods. If SOC was measured, Db had to be estimated using pedotransfer functions (PTFs) refitted from the literature on NYC data; hence, SOCS was estimated. Globally, SOCS for open soils were not significantly different between both cities (11.3 +/- 11.5 kgC m-2 in NYC; 9.9 +/- 3.9 kgC m-2 in Paris). Nevertheless, SOCS was lower in sealed soils (2.9 +/- 2.6 kgC m-2 in NYC and 3.4 +/- 1.2 kgC m-2 in Paris). The SOCCT was similar between both cities for 0-30 cm (3.8 TgC in NYC and 3.5 TgC in Paris) and was also significant for the 30-100 cm layer in NYC (5.8 TgC). A comparison with estimated SOCCT in agricultural and forest soils demonstrated that the city's open soils represent important pools of organic carbon (respectively 110.4% and 44.5% more C in NYC and Paris than in agricultural soils, for 0-30 cm depth). That was mainly observable for the 1 m depth (146.6% more C in NYC than in agricultural soils). The methodology to assess urban SOCS was also discussed. PMID- 29981996 TI - Glomalin-related soil protein influences the accumulation of polycyclic aromatic hydrocarbons by plant roots. AB - Studies have demonstrated that the inoculation of soil with arbuscular mycorrhizal fungi (AMF) enhances the content of glomalin-related soil protein (GRSP), which in turn elevates the availability of polycyclic aromatic hydrocarbons (PAHs) in soil. However, few studies have examined the influence of GRSP on PAH accumulation by plants and their tissues. Understanding of this issue would provide new perspectives on the role of GRSP in PAH uptake by plants at contaminated sites. This investigation was the first observational study of the GRSP-influenced PAH accumulation in roots of ryegrass (Lolium multiflorum Lam.). GRSP (0-120 mg/L) enhanced the root PAH accumulation in a GRSP-concentration dependent manner, based on the observed root concentrations and root concentration factors (RCFs). The greatest enhancement of SigmaPAH accumulation appeared at 40 mg/L of the total GRSP (T-GRSP) and 80 mg/L of the easily extracted GRSP (EE-GRSP), respectively. The weakly and strongly adsorbed fractions accounted for 88.8-94.4%, while the absorbed fraction contributed no >11.2% of total PAH accumulation in roots. The capacity of PAH adsorption on roots was enlarged in the presence of GRSP (0-120 mg/L). As the adsorbed fraction dominated the total PAH contents in roots overwhelmingly, the GRSP-induced changes in root PAH accumulation were ascribed to GRSP-affected PAH sorption by roots. PMID- 29981997 TI - Editorial of special issue on climate change impact on water environment. PMID- 29981998 TI - Decision-making skills improve with critical care training: Using simulation to measure progress. AB - PURPOSE: Health care professionals are expected to acquire decision-making skills during their training, but few methods are available to assess progress in acquiring these essential skills. The purpose of this study was to determine whether a simulation methodology could be used to assess whether decision-making skills improve during critical care training. MATERIALS AND METHODS: Sixteen simulated scenarios were designed to assess a critical care provider's ability to make decisions in the care of a critical ill patient. Seventeen (17) critical care providers managed 8 of the scenarios early during their training and then managed a second set of 8 scenarios (T2) at the conclusion of their training. RESULTS: Provider's mean global scenario scores (0-9) increased significantly fromT1 and T2 (5.64 +/- 0.74) and (6.54 +/- 0.64) with a large effect size (1.3). Acute care nurse practitioners and fellows achieved similar overall scores at the conclusion of their training (ACNP 6.43 +/- 0.57; Fellows 6.64 +/- 0.72). CONCLUSIONS: These findings provide evidence to support the validity of a simulation-based method to assess progress in decision-making skills. A simulation methodology could be used to establish a performance standard that determined a provider's ability to make independent decisions. PMID- 29981999 TI - Serum total antioxidant capacity during the first week of sepsis and mortality. AB - PURPOSE: Higher circulating total antioxidant capacity (TAC) concentrations have been found in non-survivor than in survivor septic patients at moment of sepsis diagnosis. The objectives of this study were to determine whether serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and whether could be used as a prognostic biomarker. METHODS: This prospective and observational study with 319 septic patients admitted to Intensive Care Units was carried out in 8 Spanish hospitals. We determined serum concentrations of malondialdehyde (to estimate lipid peroxidation) and TAC at days 1, 4 and 8 of sepsis. Mortality at 30 days was the end-point study. RESULTS: We found that serum TAC concentrations at days 1, 4 and 8 could predict 30-day mortality according to ROC curve analyses (p < 0.001), that were associated with 30-day mortality according to regression analyses (p < 0.001), and that were associated with serum levels of malondialdehyde and SOFA score. CONCLUSIONS: The new findings of our study were that serum TAC levels during the first week of sepsis are associated with lipid peroxidation, sepsis severity, and sepsis mortality, and that could be used as a prognostic biomarker. PMID- 29982000 TI - An assessment of the effectiveness of UK building regulations for new homes in Radon Affected Areas. AB - Radon, a naturally occurring radioactive gas generated underground by radioactive decay of nuclides contained in certain types of rocks, can concentrate inside buildings, where it poses the second-largest risk factor for lung cancer, after smoking. The highest concentrations of domestic radon in the UK occur in the south-western counties of Devon and Cornwall, but certain areas in Northamptonshire and surrounding counties in the English Midlands also have high levels. It has been shown that it is possible both to reduce the radon concentrations in existing houses and to build new homes with appropriate protection. Since 1999, the UK's Building Regulations have specified that all new homes should be built with a combined radon-proof/damp-proof membrane plus, in Radon Affected Areas, a sump under the building. However, the building regulations do not require that the radon level is measured once the house is built and so there is little information on the effectiveness of these measures. Builders generally do not mention radon, and when asked, just confirm that their houses are built to current standards. To better understand the efficacy or otherwise of the currently mandated radon-protection measures, a cross-sectional investigation was carried out in 26 new housing developments in high-radon areas in Northamptonshire. In a targeted mail-shot, 1056 householders were invited to apply for a free radon test; 124 replied (11.7%). In total, 94 pairs of detectors were returned (70.1% of responders), of which two were spoiled, giving a total of 92 results. Following processing and seasonal correction, the arithmetic mean radon concentration in the target houses was 45% of the arithmetic mean radon concentration in existing houses in the postcode sectors where the houses were built and were approximately log-normally distributed. No results exceeded the UK Action Level of 200 Bq. m-3 but three were above the Target Level of 100 Bq. m-3. The results suggest that the radon-proof membranes in general ensure that radon concentrations in new homes constructed in accordance with the Building Regulations in Radon Affected Areas (RAAs) are satisfactorily low. However, there is a very small statistical probability that levels in a small number of homes will be close to or above the Action Level, particularly in areas of high radon potential. As a result, the Public Health England (PHE) recommendation for testing in the first year of occupation should be adopted as a legal requirement. PMID- 29982001 TI - Six-year monitoring of the vertical distribution of radiocesium in three forest soils after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - After the Fukushima Dai-ichi Nuclear Power Plant accident on March 2011, several studies showed that the downward migration of 137Cs from litter to mineral soil is more rapid in forests in Fukushima than in forests affected by the Chernobyl accident. Therefore, the downward migration within mineral soil layers is more important for predicting long-term dynamics of 137Cs in forest ecosystems in Fukushima. In the present study, we monitored the detailed vertical distribution of 137Cs in litter and soil layers for 6 y (2011-2017) following the previous study (2011-2012), and found that temporal changes in those distributions were different among mixed forest (MF), mature cedar (MC) and young cedar (YC) forests. The 137Cs concentrations and inventories in the litter layer exponentially decreased with time for all sites, with more than 80-95% of the deposited 137Cs on the forest floor distributed in mineral soil layers by 2017. The percentage of 137Cs inventory in the litter layer to the total 137Cs inventory in litter and mineral soil layers was well fitted by a single exponential equation with decreasing rate of 0.22-0.44 y-1. The slower migration was observed in the YC site, probably because of higher initial interception of 137Cs fallout by dense canopy. As the downward migration from litter to mineral soil progressed, the 137Cs concentration in the first few cm of mineral soil surface gradually increased and became higher than the 137Cs concentration in the litter within 2-3 y of the accident. The 137Cs concentration in mineral soil layers exponentially decreased with depth throughout survey period, and an exponential equation fitted well. The relaxation depth of 137Cs concentration in mineral soil layers estimated by the exponential equation were constantly increasing in the MC and YC sites with 0.08 cm y-1. In contrast, there was no temporal increase in the relaxation depth in the MF site, indicating little migration to subsurface soil layer from not only litter layer but also surface soil layer. Further studies are necessary to identify the forests prone to the downward migration of 137Cs and its factors regarding both forest and soil characteristics. PMID- 29982002 TI - Determination of the gross activity of uranium, plutonium, americium and strontium in environmental samples using solid-state scintillation. AB - Rapid determination of selected gross alpha and beta emitters in environmental matrices by solid-state scintillation technique is discussed. This method is based on sample treatment using microwave reactor and direct measurement of digested products using powder scintillator and alkaline solution as a substitute for traditional liquid scintillation cocktail. The selected group of radionuclides was chosen with respect to their use in nuclear industry, high radiotoxicity, and the possibility of potential misuse. The work aimed at verifying the connection of microwave decomposition using alkaline solution with solid-state scintillation using a powder scintillator YAP:Ce together with an alkaline medium. PMID- 29982003 TI - Presence of artificial radionuclides in samples from potable water and wastewater treatment plants. AB - Human activity, such as the operation of nuclear power plants (NPPs) and the use of radionuclides in nuclear medicine, results in the presence of artificial radionuclides in surface waters, which may even reach potable water treatment plants (PWTPs) and wastewater treatment plants (WWTPs). In this study, water and sludge samples from a PWTP are radiologically monitored. The incoming water of the plant is influenced by the presence of an NPP upstream. Two WWTPs receiving wastewater from medical centres and other origins are also studied. As a result, 131I, 60Co and 137Cs have been determined in the dewatered sludge samples from the PWTP, while 131I, 99mTc, 67Ga and 111In were detected in the sludge samples from the WWTPs. The radionuclide activities in the influent water from the WWTPs studied were lower than the minimum detectable activity values. Therefore, on the basis of our results, the analysis of sludge samples is very useful as it enables the concentration of any radionuclides that may be present in the incoming water. Lastly, as higher activity of 131I was detected in the samples studied, the total effective dose was assessed for WWTP workers, as they handle dewatered sludge containing this radionuclide. It can be concluded that there is no risk in terms of total exposure. PMID- 29982004 TI - A study of temporal variations of 7Be and 210Pb concentrations and their correlations with rainfall and other parameters in the South West Coast of India. AB - As a part of establishing a regional database on natural radioactivity, the atmospheric concentrations of 210Pb and 7Be were measured over a three and half year period (2014-2017) in Mangalore and Kaiga in the South West Coast of India. A total of 99 air samples, collected in the different months of the year, were analysed in this study. The mean activity concentrations of 7Be and 210Pb were found to be 5.5 +/- 3.1 mBq m-3 and 1.1 +/- 0.73 mBq m-3, respectively. Both the radionuclides exhibited strong seasonal variations, with maximum concentration of 7Be occurring in the summer and that of 210Pb in the winter season. The concentration of both the radionuclides was minimum in the rainy season. Higher 210Pb concentration during winter was attributed to the ingression of continental air masses due to the wind regime from the North East. The sunspot number index of the solar activity also plays an important role in the increase and decrease of 7Be concentration in the air. A clear trend of increased and lowered concentration of 7Be with lower and higher solar activity (low and high sunspot number), respectively, in accordance with the 11-year solar cycle, was observed in this study. The temporal variation of PM10 concentration was also studied and it showed maximum value in the winter and minimum in the rainy season with an average of 56.9 MUg m-3. Statistically significant positive correlation was observed between the PM10 and 210Pb activity concentration, whereas a weak correlation was observed between PM10 and 7Be. This is due to the fact that 7Be is largely associated with sub-micrometer size particles, whereas PM10 is contributed by larger sizes. The dependence of the activity concentrations of 7Be and 210Pb with meteorological parameters such as rainfall, temperature, and humidity was studied through linear regression analysis. A significant correlation was observed between 7Be and 210Pb concentrations with rainfall intensity (with identical correlation coefficients), which suggested that the removal mechanisms of these two radionuclides were similar. 7Be showed a strong correlation with temperature, whereas 210Pb with humidity. A comparison of the data obtained in the present study for the South West Coast of India with the global literature values of 7Be and 210Pb in aerosols showed that the values did not reflect the well-known latitudinal dependence of the 7Be tropospheric fluxes. Overall, the study provides an improved understanding of the correlation and variability of 210Pb and 7Be concentrations in the atmosphere in the South West Coast of India. PMID- 29982005 TI - Distribution and fate of 129I in the seabed sediment off Fukushima. AB - In this study, seabed sediment was collected from 26 stations located within 160 km from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) during the 2 years which followed the FDNPP accident of March 2011 and the concentrations of 129I and 137Cs were measured. By comparing the distribution of these two radionuclides with respect to their different geochemical behaviors in the environment, the transport of accident-derived radionuclides near the seafloor is discussed. The concentration of 129I in seabed sediment recovered from offshore Fukushima in 2011 ranged between 0.02 and 0.45 mBq kg-1, with 129I/137Cs activity ratios of (1.9 +/- 0.5) * 10-6 Bq Bq-1. The initial deposition of 129I to the seafloor in the study area was 0.36 +/- 0.13 GBq, and the general distribution of sedimentary 129I was established within 6 months after the accident. Although iodine is a biophilic element, the accident-derived 129I negligibly affects the benthic ecosystem. Until October 2013, a slight increase in activity of 129I in the surface sediment along the shelf-edge region (bottom depth: 200-400 m) was observed, despite that such a trend was not observed for 137Cs. The preferential increase of the 129I concentrations in the shelf-edge sediments was presumed to be affected by the re-deposition in the shelf-edge sediments of 129I desorbed from the contaminated coastal sediment. The results obtained from this study indicate that 129I/137Cs in marine particles is a useful indicator for tracking the secondary transport of accident-derived materials, particularly biophilic radionuclides, from the coast to offshore areas. PMID- 29982006 TI - Accumulation of U(VI) on the Pantoea sp. TW18 isolated from radionuclide contaminated soils. AB - Pantoea sp. TW18 isolated from radionuclide-contaminated soils was used for the bioremediation of radionuclides pollution. Accumulation mechanism of U(VI) on Pantoea sp. TW18 was investigated by batch experiments and characterization techniques. The batch experiments revealed that Pantoea sp. TW18 rapidly reached accumulation equilibrium at approximately 4 h with a high accumulation capacity (79.87 mg g-1 at pH 4.1 and T = 310 K) for U(VI). The accumulation data of U(VI) onto Pantoea sp. TW18 can be satisfactorily fitted by pseudo-second-order model. The accumulation of U(VI) on Pantoea sp. TW18 was affected by pH levels, not independent of ionic strength. Analysis of the FT-IR and XPS spectra demonstrated that accumulated U(VI) ions were primarily bound to nitrogen- and oxygen containing functional groups (i.e., carboxyl, amide and phosphoryl groups) on the Pantoea sp. TW18 surface. This study showed that Pantoea sp. TW18 can be considered as a promising sorbent for remediation of radionuclides in environmental cleanup. PMID- 29982007 TI - Mechanical, thermal and fire performance of an inorganic-organic insulation material composed of hollow glass microspheres and phenolic resin. AB - HYPOTHESIS: Organic foamy materials possess good thermal insulation properties and inorganic materials are non-combustible. Hence, it is possible to develop a kind of organic-inorganic lightweight thermal insulation materials with excellent fire safety. EXPERIMENTS: Hollow glass microsphere (HGM), as one kind of lightweight noncombustible inorganic material, was chosen as the filling material. Phenolic resin (PR), as the flame retardant polymeric material, was used as binding material. A series of HGM/PR composites with various PR/HGM mass ratio were prepared. Properties, such as apparent density, microstructure, mechanical strength, thermal conductivity, burning behavior and flame retardancy of the specimens were determined, respectively. FINDINGS: The results show that the surface of HGM particles is coated by a layer of cured PR and the HGM powder is glued together firmly from the scanning electron microscope (SEM) images. With the increase of PR/HGM mass ratio, both of apparent density and mechanical strength of HGM/PR composites increase, but thermal conductivity and limiting oxygen index (LOI) values decrease, all of the specimens still possess high LOI value (>50%). What's more, no flaming combustion (merely partial carbonization) and hardly any smoke can be observed during the burning process, which indicates the HGM/PR composites possess excellent flame retardant property and fire safety. PMID- 29982008 TI - Facile synthesis of cerium oxide nanoparticles decorated flower-like bismuth molybdate for enhanced photocatalytic activity toward organic pollutant degradation. AB - One of the great challenges in the field of photocatalysis is to develop novel photocatalysts with excellent solar-light-harvesting capacity and separation efficiency of photo-induced charge. Herein, novel CeO2/Bi2MoO6 heterojunctions were fabricated through in-situ precipitation of CeO2 nanoparticles (size: ~26 nm) on the surface of flower-like Bi2MoO6 superstructures (diameter: 2.1-3.5 MUm) by a simple method. The as-prepared photocatalysts were systematically characterized by a range of techniques. The photocatalytic degradation of rhodamine B (RhB) dye, methyl orange (MO) dye and tetracycline (TC) antibiotic by this novel photocatalyst was investigated under visible-light irradiation. The CeO2/Bi2MoO6 heterojunction with a CeO2/Bi2MoO6 weight ratio of 0.05 (0.05Ce-Bi) exhibited the highest photocatalytic activity with the RhB degradation efficiency of 100% in 75 min, which was considerably higher than those of pristine CeO2 (26.8%) and Bi2MoO6 (80.3%) as well as their physical mixtures (74.8%). The more efficient separation of electron-hole pairs was identified as the primary reason of the enhanced photocatalytic activity. Moreover, the synthesized material maintained satisfactory activity even after 6 recycling runs, indicating its high photocatalytic stability. Therefore, our finding offers a new avenue for development of stable and efficient heterojunction photocatalysts for environmental purification. PMID- 29982009 TI - Free-standing graphene/NiMoS paper as cathode for quasi-solid state dye sensitized solar cells. AB - Highly catalytic two dimensional and metal-doped two-dimensional nanomaterials (MoS2 and NiMoS) were deposited over free-standing graphene (FSG) paper using electrodeposition method and subsequently used as a counter electrode in quasi solid-state dye-sensitized solar cells (q-DSSCs). The replacement of FTO by FSG facilitates high electrical conductivity and electrodeposited metal sulphides provide electrocatalytic activity. The morphology, structural phase formation and chemical composition of FSG-MoS2 and FSG-NiMoS were investigated using FESEM, XRD, Raman and XPS analysis. The electrochemical behavior of metal sulphide decorated FSG cathodes is investigated using an electrochemical workstation and their effects on the photo-conversion efficiency of DSSCs were assessed. NiMoS with FSG substrate is an intriguing counter electrode material that can be utilized at low fabrication cost than the conventional platinum-based counter electrodes. FSG along with the metallic-two dimensional nanoparticles (NiMoS) functions as an effective catalytic material thereby allowing DSSCs to achieve enhanced efficiency of ~7% to provide better alternative of FTO and Pt. PMID- 29982010 TI - Synthesis of defect-rich palladium-tin alloy nanochain networks for formic acid oxidation. AB - Unique and novel Pd4Sn nanochain networks were successfully synthesized with an average diameter of 5 nm, rendering a modified Pd electronic structure with rich defects such as atomic corners, steps or ledges as catalytic active sites for great enhancement of charge transfer and electrode kinetics. The prepared Pd4Sn nanochain networks held an electrochemically active surface area as high as 119.40 m2 g-1, and exhibited higher catalytic activity and stability toward formic acid oxidation compared with Pd3Sn nanochain networks, Pd5Sn nanochain networks, Pd4Sn dendrites and Pd/C. The fundamental insight of the enhancement mechanism is discussed, and this work offers a novel, less expensive but highly active catalyst for direct formic acid fuel cells. PMID- 29982011 TI - Dicyandiamide and iron-tannin framework derived nitrogen-doped carbon nanosheets with encapsulated iron carbide nanoparticles as advanced pH-universal oxygen reduction catalysts. AB - The development of an efficient and cost-effective electrocatalyst toward the oxygen reduction reaction (ORR) is of critical importance for diverse renewable electrical energy techniques. Herein, a dicyandiamide and iron-tannin framework derived nitrogen-doped carbon nanosheet with encapsulated iron carbide nanoparticle (Fe3C/N-CNS) is developed. Particularly, dicyandiamide is the key to achieve this two-dimensional nitrogen-doped lamellar carbon nanosheet. Owing to the synergistic characteristics including composition and structure, the optimal catalyst exhibits the comparable or even better catalytic activity, as well as superior methanol tolerance and stability compared with platinum/carbon catalyst over the whole pH range. More notably, the current approach can be potentially extended to synthesize additional two-dimensional structured transition metal/carbon composites for various energy conversion and storage technologies. PMID- 29982012 TI - Electrochemical determination of purine and pyrimidine bases using copper doped cerium oxide nanoparticles. AB - Deoxyribonucleic acid (DNA), a primary unit of heredity in all types of organisms, consists of purine and pyrimidine bases in such a way that the amount of guanine (GU) is equal to cytosine (CY) and the amount of adenine (AD) is equal to thymine (TY). Any abnormalities in the concentration of these four bases will have significant influence on disease diagnosis, crime detection and biocomputing applications of DNA. Hence, identification and quantification of either individual or group of these DNA bases are important for diagnosis of certain diagnosis and genetic disorders. In the present work, we report the fabrication of an efficient electrochemical sensor for simultaneous determination of purine (GU, AD) and pyrimidine (CY, TY) bases using Cu doped CeO2 nanoparticles modified glassy carbon electrode (Cu-CeO2/GCE). The direct electrocatalytic activities of DNA bases have been studied using voltammetric techniques in phosphate buffer solution (PBS, pH 7.0) without any enzyme or mediator. 3 wt% Cu doped CeO2 modified GCE showed two well defined anodic peaks each towards the oxidation of purine and pyrimidine bases with significant peak to peak potential separation of 312 mV (AD-GU) and 200 mV (TY-CY) which were large enough for the selective and simultaneous determination of these bases in their mixture. Under optimum conditions, calibration plots for the simultaneous detection of the purine and pyrimidine bases were linear in the concentration range of 0.1-500 MUM for AD, 1 650 MUM for GU, 1-300 MUM for TY and 1-250 for CY with the lowest detection limit values of 0.021, 0.031, 0.024, and 0.038 MUM respectively. Additionally, the developed sensor exhibited good repeatability, reproducibility, sufficient stability and good anti-interference ability and was successfully applied for simultaneous detection of AD, GU, TY and CY in denatured DNA sample with satisfactory results. PMID- 29982013 TI - Synthesis of graphene/thorns-like polyaniline/alpha-Fe2O3@SiO2 nanocomposites for lightweight and highly efficient electromagnetic wave absorber. AB - alpha-Fe2O3@SiO2 nanoparticles have been successfully enveloped in graphene nanosheets/thorns-like polyaniline matrix (RGO/thorns-like PANI/alpha-Fe2O3@SiO2 nanocomposites) by some facile strategies. The measured electromagnetic parameters indicate that the interfacial polarization, the charge transfer, the multiple reflections and scatterings, the Debye dipolar relaxation processes, the magnetic loss, the quarter-wavelength matching and the well-matched characteristic impedance all play significant roles in improving the electromagnetic wave absorption performance. The maximum reflection loss of RGO/thorns-like PANI/alpha-Fe2O3@SiO2 nanocomposites reaches -50.06 dB at 14.4 GHz with a matching thickness of only 2.3 mm, and the absorption bandwidth with reflection loss less than -10 dB is in the 4.0-18.0 GHz range for the absorber thickness of 1.5-5.5 mm. Moreover, the adding quantity of nanocomposites in the paraffin matrix is only 16.7 wt%. Consequently, it is believed that the nanocomposites could be used as an excellent electromagnetic wave absorber with lightweight, thin thickness, broad bandwidth and strong absorption. PMID- 29982014 TI - Effect of electrowetting induced capillary oscillations on coalescence of compound droplets. AB - HYPOTHESIS: Coalescence time depends on the drainage rate of the fluid-bridge separating the droplets. Drainage rate is determined by external forcing and properties of the surrounding fluid. Modulating external forcing using electrowetting induced interface motion should allow control of the drainage rate, thereby affecting the coalescence time. Hence, quick coalescence or prolonged non-coalescence can be obtained for compound droplets on the microfluidic lab-on-chip systems. EXPERIMENTS: Using high-speed imaging, we have investigated the effect of electrowetting induced capillary oscillations on the coalescence of compound droplets consisting of water core encapsulated in an oil shell. A systematic study was performed by varying the shell viscosity and actuation parameters (i.e. amplitude, frequency and waveform). FINDINGS: For actuated interface, we observed specific regimes of coalescence or non coalescence, whereas in absence of actuation, coalescence was observed in finite time. Non-coalescence was attributed to the continuous modulation of the oil bridge width, which was caused by the interface motion. Oil-bridge width modulation was seen to be dependent on the amplitude and shape of the excited capillary modes (axisymmetric and non-axisymmetric). These modes were tuned by the actuation parameters. This is the first report of controlling coalescence dynamics by using electrowetting induced interface motion. PMID- 29982015 TI - Zeolitic imidazolate frameworks (ZIFs)-derived NixCo3-xO4/CNTs nanocomposites with enhanced electrochemical performance for supercapacitor. AB - Coupling Co-Ni bimetallic oxides with carbon nanotubes (CNTs) is recognized an effective strategy to enhance the performance of supercapacitors. In this work, porous NixCo3-xO4/CNTs nanocomposites are prepared through in situ growth of ZIF 67 precursor onto CNTs followed by subsequent annealing. The obtained NixCo3 xO4/CNTs combine the promising high storage performance of porous NixCo3-xO4 with the excellent conductivity of CNTs. When test in three-electrode system, the electrode materials exhibit a high specific capacitance of 668 F/g at 1 A g-1, a good rate capability of 91.60% retention from 1 to 10 A g-1 and good cycling stability of 91.20% retention after 3500 cycles in 2.0 M KOH electrolyte. Furthermore, the NixCo3-xO4/CNTs are tested in two-electrode configuration, showing a high energy density of 23.56 Wh kg-1 at power density of 800.15 W kg-1 and outstanding cycling stability of 93.75% retention after 3000 cycles. The excellent electrochemical performance of the designed nanomaterials can be ascribed to the synergy between the CNTs and NixCo3-xO4. PMID- 29982016 TI - Physicochemical properties of cationic nanoemulsions and liposomes obtained by microfluidization complexed with a single plasmid or along with an oligonucleotide: Implications for CRISPR/Cas technology. AB - In this study, we investigated the effects of the association of a single plasmid or its co-complexation along with an oligonucleotide on the physicochemical properties of cationic nanoemulsions and liposomes intended for gene editing. Formulations composed of DOPE, DOTAP, DSPE-PEG (liposomes), MCT (nanoemulsions), and water were obtained by microfluidization. DSPE-PEG was found to play a crucial role on the size and polydispersity index of nanocarriers. Nucleic acids were complexated by adsorption at different charge ratios. No significant differences were noticed in the physicochemical properties of nanocarriers (i.e. droplet size, polydispersity index, or zeta potential) when a single plasmid or both plasmid and oligonucleotide were adsorbed to the formulations. Transmission electron microscopy photomicrographs suggested round nanostructures with the nucleic acids and DSPE-PEG enfolding the surface. Complexes at +4/-1 charge ratio protected nucleic acids against DNase I degradation. The oligonucleotide seemed to be released from the liposomal complexes, while nanoemulsions only released the plasmid after 24 and 48 h of incubation in DMEM supplemented or not. In vitro experiments demonstrated that complexes were highly tolerable to human fibroblasts, Hep-G2, and HEK-293 cells, demonstrating also an uptake ability of about 30%, 30%, and 90%, respectively, no matter what the formulation or the combination of nucleic acids used. Transfection efficiency of the formulations was around 25% in human fibroblasts, 32% in HEK-293, and 15% in Hep-G2 cells. The overall results demonstrated the behavior of liposomes and nanoemulsions complexed with a plasmid or a mixture of a plasmid and an oligonucleotide, and demonstrated that the association with one or two nucleic acids sequences of different length does not seem to interfere in the physicochemical characteristics of complexes or in the uptake capacity by three different types of cells. PMID- 29982017 TI - Strong coupling effect at the interface of cobalt phosphate-carbon dots boost photocatalytic water splitting. AB - Hydrogen and oxygen produced by water splitting under solar energy are ideal future energy sources. At present, obtaining the efficient, stable and inexpensive photocatalyst for photocatalytic overall water splitting is still a huge challenge. Cobalt phosphate (Co3PO4, CoPi) possesses proper band positions for water splitting. However, the fast recombination of photogenerated electron and hole pairs for CoPi restricts its application. Herein, strongly coupling Co3PO4-carbon dots (CoPi-CDs) composite was constructed as an effective strategy to depress the fast recombination behavior of photogenerated electron and hole pairs. CoPi-CDs show superior photocatalytic water splitting activity than that of single CoPi. When the concentration of CDs in the composite is 0.002 gCDs/gcatalyst, the hydrogen production rate was obtained for approximately 0.592 MUmol h-1, as well as the oxygen evolution rate about 0.258 MUmol h-1 (with 2:1 stoichiometry), which are both nearly 33 times than that of pristine CoPi. This enhanced photocatalytic activity of CoPi-CDs should ascribe to the efficient coupling effect between CoPi and CDs, which allows fast electron transfer at the interface of CoPi and CDs and thus effectively boosts the photocatalytic water splitting. The strongly coupling nanocomposites should be inspiring for further nanocomposite building for photocatalytic overall water splitting. PMID- 29982018 TI - In-situ developed carbon spheres function as promising support for enhanced activity of cobalt oxide in oxygen evolution reaction. AB - Highly active, stable electrocatalyst for oxygen evolution reaction (OER) is sincerely required for the practical application of water splitting to get rid from the sluggish reaction kinetics and the stability issue. Here, Co3O4 is studied as OER catalyst and to improve the electrocatalytic activity, carbon is chosen as the conducting support. A simple and cost-effective synthetic route is developed for the synthesis of Co3O4 on carbon support following hydrothermal route using various hydrolyzing agents. The heterostructure 'Co3O4/C' perform well in OER as a non-precious metal catalyst. The best Co3O4/C electrocatalyst can generate 10 and 30 mA/cm2 current densities upon application of 1.623 V and 1.678 V vs. RHE whereas, bare Co3O4 can generate current density of 10 and 30 mA/cm2 upon application of 1.677 and 1.754 V vs. RHE. Carbon in the heterostructure helps to improve the conductivity and at the same time enhances the charge transfer ability which further leads to increase current density and stability to the catalyst. Co3O4/C can generate unaltered current density up to 1000 cycles. PMID- 29982019 TI - Bioinspired superhydrophilic-hydrophobic integrated surface with conical pattern shape for self-driven fog collection. AB - It is well recognized by the scientific community that the fog can be deposited and transported on asymmetric surfaces, thus numerous efforts have been made to create such surfaces. However, it is still challenging to design a surface capable of fast deposition and rapid transportation simultaneously. Herein, inspired by the asymmetric structure of cactus spines and the cooperative hydrophilic/hydrophobic regions of desert beetles, a superhydrophilic-hydrophobic integrated conical stainless steel needle (SHCSN) is fabricated by a facile method. This integrated needle surface combines the merits of the fast deposition of fog on hydrophobic region and then rapid transportation on superhydrophilic surface. The droplet average transportation velocity on SHCSN is greater than other types of surfaces because of large Laplace pressure and self-driven phenomenon at its superhydrophilic-hydrophobic boundary. The best fog harvest efficiency was realized by optimizing the length of the hydrophobic region using theoretical modeling and experimental exploration, whereas the robust superhydrophilic needle surface induced the increase of collection time. This SHCSN was realized to be more efficient in fog collection than uniform superhydrophilic, uniform hydrophobic/superhydrophobic needle surfaces. PMID- 29982020 TI - Combining active phase and support optimization in MnO2-Au nanoflowers: Enabling high activities towards green oxidations. AB - Among the several classes of chemical reactions, the green oxidation of organic compounds has emerged as an important topic in nanocatalysis. Nonetheless, examples of truly green oxidations remain scarce due to the low activity and selectivity of reported catalysts. In this paper, we present an approach based on the optimization of both the support material and the active phase to achieve superior catalytic performances towards green oxidations. Specifically, our catalysts consisted of ultrasmall Au NPs deposited onto MnO2 nanoflowers. They displayed hierarchical morphology, large specific surface areas, ultrasmall and uniform Au NPs sizes, no agglomeration, strong metal-support interactions, oxygen vacancies, and Audelta+ species at their surface. These features led to improved performances towards the green oxidations of CO, benzene, toluene, o-xylene, glucose, and fructose relative to the pristine MnO2 nanoflowers, commercial MnO2 decorated with Au NPs, and other reported catalysts. We believe that the catalytic activities, stabilities, and mild/green reaction conditions described herein for both gas and liquid phase oxidations due to the optimization of both the support and active phase may inspire the development of novel catalytic systems for a wealth of sustainable transformations. PMID- 29982021 TI - Preparation of alpha-CaSO4.1/2H2O with tunable morphology from flue gas desulphurization gypsum using malic acid as modifier: A theoretical and experimental study. AB - Huge amount of flue gas desulphurization (FGD) gypsum not only occupies the farmland but also causes severe pollution to the surrounding environment. The most effective way to achieve a high-value utilization of FGD gypsum is to prepare short columnar alpha-calcium sulfate hemihydrate (alpha-HH) since short columnar crystals show better mechanical strength than needle-like ones. Here, malic acid, a prolific, inexpensive and environment-friendly modifier was explored for the first time to effectively tune the crystal morphology of alpha HH prepared from FGD gypsum in glycerol-water-NaCl solutions. When the concentration of malic acid reached 18.54 * 10-4 mol/kg, alpha-HH crystals with an average aspect (length-to-diameter) ratio of 1.9 (compared to 29.4 in the absence of malic acid) were prepared. The selective complexation of malic acid with Ca active sites on different alpha-HH crystal planes played a dominant role in the alpha-HH crystal morphology transformation, which was then explained by the surface broken bonds theory for the first time. The broken bond number per active Ca atom (Nbper Ca) and broken bond density of Ca atoms (DbCa) on the (2 0 4) end plane were larger than those on the (0 2 0) or (2 0 0) side planes. Therefore, the (2 0 4) end plane was more reactive with organics, resulting in the preferential adsorption of malic acid on the end planes, which reduced the specific surface energy of (2 0 4) and led to an increased exposure of this plane and a decreased exposure of (0 2 0) or (2 0 0) side planes in the final alpha-HH crystals. Consequently, using malic acid as modifier, the alpha-HH crystal gradually transformed from a needle-like shape to a short columnar one. This work provided important insights into and perspectives for the selection of crystal modifiers and explanation of the mechanism during the preparation of calcium containing crystals with controllable morphology. PMID- 29982022 TI - Bifunctional supported ionic liquid-based smart films for dyes adsorption and photodegradation. AB - Herein, novel bifunctional smart films containing poly(styrene-butyl acrylate ionic liquids) (P(S-BA-ILs)) and TiO2 were first prepared by a simple cast method and then used to demonstrate a superior bifunction of adsorption/desorption for dyes due to the property of reversible wettability switching and photodegradation under ultraviolet (UV) irradiation due to the addition of TiO2. The glass transition temperature (Tg) of P(S-BA-ILs) latex was characterized using a differential scanning calorimeter (DSC). The surface properties of films (P(S-BA ILs)-TiO2) were characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), attenuated total (internal) reflection Fourier transform infrared spectroscopy (ATR-FTIR), and water contact angle (WCA) measurements. The results showed that the films displayed reversible wettability switching of hydrophobicity (124.5 +/- 2 degrees )/hydrophilicity (10.5 +/- 2 degrees ) and hydrophobicity (35.1 +/- 2 degrees )/hydrophilicity (93.1 +/- 2 degrees ) triggered by pH and temperature, respectively. Additionally, the films exhibited large adsorption capacities for pollutants at different pH: brilliant red (BR) (6.6 mg cm-3) at pH 1, methylene blue (MB) (12.4 mg cm-3) and phenol (1.1 g cm-3) at pH 11, and metal ions As, Mo and Sb (1.11, 1.57, and 1.25 mg cm 3) at pH 1, as well as superior reusability and excellent in situ photodegradation performance. The convenient preparation of the smart films as well as the good bifunction of adsorption and photodegradation for dyes predicts potential for application to curb water pollution. PMID- 29982024 TI - Carbon-nanotube-based rhodium nanoparticles as highly-active catalyst for hydrolytic dehydrogenation of dimethylamineborane at room temperature. AB - In this study, we present a carbon nanotube-based Rh nanomaterial as a highly active catalyst for the hydrolytic dehydrogenation of dimethylamine - borane (DMAB) at room temperature. The prepared multi-walled carbon nanotube based Rh nanoparticles, called Rh NPs@ MWCNT, was readily prepared, stabilized and effectively used for the hydrolytic dehydrogenation of DMAB under ambient conditions. Monodisperse Rh NPs@ MWCNT nanocatalyst was characterized by using advanced analytical methods such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HR-TEM) etc. These analytical methods revealed that Rh nanoparticles on the surface of MWCNT were well dispersed and the average particle size was found to be 1.44 +/- 0.17 nm. The catalytic experiments revealed that the new Rh NPs@MWCNT nanocatalyst has a high catalytic effect to obtain hydrogen in 3.0 equation from DMAB, and the record catalytic TOF value for the catalytic reaction catalyzed by Rh NPs@MWCNT nanocatalyst was found to be 3010.47 h-1 at room temperature. The current study presents the detailed kinetic studies of the hydrolytic dehydrogenation of DMAB catalyzed by Rh NPs@MWCNT, the results of catalytic experiments were performed at different temperatures, substrate and catalyst concentrations, the Rh NPs@MWCNT nanocatalyst was effectively used in the completion of the hydrolytic dehydrogenation of DMAB, and activation energy, enthalpy and entropy parameters. The experimental results showed that monodisperse Rh NPs@MWCNT nanocatalyst have record catalytic activity with TOF value of 3010.47 h-1, and Rh(0) nanoparticles were well dispersed on the multi-walled carbon nanotubes. PMID- 29982023 TI - Ordered high aspect ratio nanopillar formation based on electrical and thermal reflowing of prepatterned thin films. AB - Creating well-ordered, submicron-sized pillars have been stated as main limitation for electrically induced patterning of nanofilms (thickness <100 nm) [1]. In our previous works, it was shown that the aspect ratio of formed nanopillars was increased to about 0.35 when thermocapillary induced instabilities (Thermally Induced Patterning, TIP) is combined with electrodynamics instabilities (Electrically Induced Patterning, EIP). However, further reduction of pillar size resulted in a coarse and randomly distributed pillars [2,3]. Here, the reflowing of initially prepatterned nanofilms are examined in the EIP and combined EIP-TIP process to create a well-ordered and high aspect ratio nanopillar arrays without sacrificing the fidelity of the final structure. The long-wave approximation is used to simplify the governing equations and boundary conditions leading to a fourth order nonlinear partial differential equation called thin film equation that describes the spatio temporal evolution of the interface. The mechanism of pattern reflowing is discussed for both linear (initial) and nonlinear (long-term) deformations in EIP and EIP-TIP process. The optimum initial pattern width, height and the center-to center distance is found based on the characteristic wavelength for growth of instabilities predicted by linear stability analysis and nonlinear simulation results. PMID- 29982025 TI - Quantitative assessment of paraoxon adsorption to amphiphilic beta-sheet peptides presenting the catalytic triad of esterases. AB - Organophosphate compounds that are used as pesticides affect the nervous system by binding irreversibly to the active site of the enzyme acetylcholine esterase (AChE) and disrupting neuro-signaling nerve cells. In this study we characterized adsorption of paraoxon to a set of designed peptides that present different arrangements of the three amino acids of the AChE catalytic site: histidine, glutamic-acid and serine. The peptides set included two beta-strands with no net charge and three beta-hairpins that differ in their net charge. Circular dichroism, Thioflavin T assays and TEM images provided only qualitative insights on paraoxon binding to the different peptides. Paraoxon binding to the different peptides was measured with dialysis membrane tubes filled with the peptide solutions and suspended in a reservoir of paraoxon solution. Among all the tested peptides, the single strand peptide, denoted ssESH exhibited at 100 MUM in random conformation prefibrillar state, the maximum paraoxon adsorption, with a binding mol ratio of one paraoxon per two peptides and an estimated equilibrium binding constant 5 * 104 M-1. The three beta-hairpin peptides demonstrated that a net negative charge is unfavorable for paraoxon adsorption. Surface enhanced Raman spectroscopy measurements with ssESH enabled the detection of nanomolar adsorbed concentrations of paraoxon. PMID- 29982026 TI - Hierarchical porous carbon prepared from biomass through a facile method for supercapacitor applications. AB - The porous carbon with angstrom-sized pores is important in supercapacitor applications, because of its high pack density and high specific capacitance. In this paper, a facile method is proposed for the preparation of hierarchical porous carbon with high-volume angstrom-sized pores. Onion, as the typical biomass in this research, is used as carbon precursor. First, onion was etched by KOH to obtain a water-soluble lignin-potassium-salt/cellulose composite. This composite was further pyrolyzed under N2 atmosphere to obtain onion derived porous carbon (OPC). The morphology and porous structure of OPC were characterized by scanning electron microscope and N2 adsorption/desorption. The supercapacitive performances of OPC were investigated by cyclic voltammetry, electrochemical impedance spectroscopy, and galvanostatic charge-discharge. OPC shows high specific surface area with high-volume angstrom-sized pores in carbon matrix. When used as supercapacitor electrode materials, OPC shows high specific capacitance and good cycling stability. This paper opens a general way to prepare porous carbon from biomasses, which will promote the development of biomass utilization, preparation of porous carbon and supercapacitors. PMID- 29982027 TI - Immobilization of ultrafine Ag nanoparticles on well-designed hierarchically porous silica for high-performance catalysis. AB - Catalyst immobilization is of much significance not only for maintaining the high activity of the ultrafine catalyst, but also for the separation of catalyst during the practical application. Herein, a novel support material, three dimensional hierarchically porous silica (HPS) with interconnected micro-meso macro pores and high specific surface area was successfully fabricated though a freeze-drying technique in the presence of poly(vinyl alcohol) (PVA) and subsequent calcination process. A series of characterizations revealed that the specific surface area of HPS can be well adjusted by changing the addition of PVA. The specific surface area of HPS was as high as 360 m2 g-1, which was 211 fold higher than HPS-0 (silica prepared without using PVA). To demonstrate the potential application of such novel support material, highly dispersed silver nanoparticles (AgNPs) were immobilized on the surfaces of HPS and HPS-0 through in-situ reduction. By contrast, the catalytic activity of AgNPs anchored on HPS (531 s-1 g-1) was about 42-fold higher than that of AgNPs anchored on HPS-0 (12.67 s-1 g-1). The significantly enhanced catalytic activity of AgNPs/HPS was believed to be related to their high specific surface area and interconnected macroporous scaffolds, which could provide numerous reactive sites and mass transfer routes for the reactants. PMID- 29982028 TI - Microstructured prealloyed Titanium-Nickel powder as a novel nonenzymatic hydrogen peroxide sensor. AB - At present, commercial pure Titanium (Ti) and microstructured pre-alloyed Titanium-Nickel (TiNi) powders are employed as a sensitive electrochemical hydrogen peroxide (H2O2) sensor. Surface characterization of these materials are performed by x-ray diffraction (XRD) and scanning electron microscopy (SEM). The electrochemical characterization is achieved via cyclic voltammetry (CV), chronoamperometry (CA), and electrochemical impedance spectroscopy (EIS) on Ti and TiNi modified glassy carbon electrode (GCE). The electrochemical behavior of H2O2 at the pure Ti/GCE and microstructure pre-alloyed TiNi/GCE are studied by CV in 0.1 M phosphate buffer solution (PBS) containing as the supporting electrolyte. In addition, CA is employed for the determination of H2O2 at the applied potential of 0 V vs. Ag/AgCl. The sensor has a linear response range of 0.5-17.5 mM with a sensitivity of 280 uA mM-1 cm-2. Moreover, the limit of detection (LOD) and limit of quantification (LOQ) are 0.5 uM and 1.7 uM, respectively. The electrochemical sensor exhibits fast and selective responses to H2O2 concentration. The applicability of the sensor is checked using a hair coloring as a real sample with satisfactory results. PMID- 29982030 TI - Deposition of sticky spheres in channel flow: Modeling of surface coverage evolution requires accurate sphere-sphere collision hydrodynamics. AB - We analyzed the role of hydrodynamic interactions in a microfluidic channel flow containing a dilute suspension of micron-scale colloidal spheres (0.03%, 0.1%, 0.3% volume fraction) engineered to adhere onto a collector patch on the channel wall at wall shear rates of 9.3-930 s-1. Particle-wall adhesion was mediated by single-stranded DNA oligomers grafted onto the spheres and the glass channel wall, producing well-defined interactions via DNA strand base pairing. Particle positions in the flow were evolved using Brownian dynamics simulations in which hydrodynamic interactions between moving particles and the channel walls and/or adhered particles were computed off-line using a series of local simulations that explicitly resolve the fluid flow at the particle scale. By systematically varying the nature of hydrodynamic interactions captured in the Brownian dynamics simulations, we find that the interactions between moving and adhered particles represents the single most important physical element in such models. Once captured sufficiently accurately, the resulting models are able to predict coarse variables such as the overall particle coverage evolution, as well as more subtle characteristics, such as the microstructural distribution of the adhered particles. PMID- 29982029 TI - Flower-like Bi2S3 nanostructures grown on nitrogen-doped reduced graphene oxide for electrochemical determination of hydrogen peroxide. AB - This paper reports a facile solvothermal method for the synthesis of Bi2S3 flower like nanostructures grown in situ on a nitrogen-doped reduced graphene oxide (Bi2S3@N-G) surface. Thiourea was used as the nitrogen source and reducing agent for graphene oxide. The surface morphology of the as-prepared Bi2S3@N-G composites was analyzed by field emission scanning electron microscopy and transmission electron microscopy. The crystalline structure and surface chemical states were examined by X-ray diffraction and X-ray photoelectron spectroscopy, respectively. The as-prepared Bi2S3@N-G composite was deposited on a glassy carbon (GC) electrode, and the modified electrode was employed for the electrocatalytic detection of H2O2. The calculated diffusion coefficient and catalytic rate constant of the Bi2S3@N-G modified electrode were 4.9 * 10-6 cm2 s 1 and 5671 M-1 s-1, respectively. The Bi2S3@N-G/GC electrode demonstrated a wide concentration range for H2O2, from 10 to 42,960 MUM, with a sensitivity of 0.1535 MUA MUM-1 and an obtained limit of detection of 1.9 MUM. PMID- 29982031 TI - Facile solvothermal fabrication of polypyrrole sheets supported dendritic platinum-cobalt nanoclusters for highly efficient oxygen reduction and ethylene glycol oxidation. AB - Herein, uniform dendritic PtCo nanoclusters supported on sheet-like polypyrrole (PtCo NCs/PPy) were prepared by a facile one-pot solvothermal method. Cetyltrimethylammonium chloride (CTAC) and pyrrole worked as the capping agent and reductant, respectively, and pyrrole was in-situ polymerized to form PPy sheets under solvothermal conditions. The dendritic PtCo NCs/PPy had the enlarged electrochemically active surface area (EASA, 30.95 m2g-1), and showed the superior catalytic performance and durability towards oxygen reduction reaction (ORR) and ethylene glycol oxidation reaction (EGOR) in comparison with Pt1Co3 nanoparticles (NPs), Pt3Co1 NPs and commercial Pt/C catalysts. This work displays a new strategy for rational design and synthesis of advanced functional nanocomposites as electrocatalysts in fuel cells. PMID- 29982032 TI - Controlled charge-dynamics in cobalt-doped TiO2 nanowire photoanodes for enhanced photoelectrochemical water splitting. AB - In this study, we report for the first time the controlled Co-doping in TiO2 nanowire (NW) arrays grown on the FTO substrate for highly efficient photoelectrochemical (PEC) water splitting. The Co/TiO2 and pristine TiO2 are single crystalline with a tetragonal rutile structure, while the primary peaks were transformed to (0 0 2) with the adding of Co. Compared to pristine TiO2 NW photoanode, the photocurrent of as-prepared Co/TiO2 NW arrays electrodes show a higher PEC activity with up to ~150% of photocurrent density increase under simulated solar radiation. The Co-doping enabled to control the charge dynamics in TiO2 photoanode and thus can achieve an enhanced photocurrent density. The electrochemical impedance measurement indicates that the density of photogenerated carriers can be significantly increased by the Co doping. The Co/TiO2 NW photoanodes exhibit high stability in photoelectrochemical conversion and show great potential for a variety of solar energy driven applications. PMID- 29982033 TI - A DFT study of inclusion complexes of substituted calix[n]arenes with dasatinib and lapatinib. AB - Herein, we have presented the results of Density Functional Theory (DFT) based calculations of inclusion complexes of lapatinib and dasatinib with calix[n]arene macrocycles. A total of 48 calix [n]arene complexes were modeled via considering varied ring sizes (n = 4,5,6,8) and upper-rim functionalization viz. SO3H, tert Butyl, iso-Propyl, COOH, C2H5OH, and C2H5NH2. From the results of multilevel molecular docking, DFT energetics, and reactivity descriptors; it has been demonstrated that dasatinib form optimal complexes with calix 4f, 3f (-35 to -40 kcal/mol). Moreover, for lapatinib, hosts 3f, 4a, 1f, 3d have the capability to generate promising complexes (>35 kcal/mol). Based on counterpoise corrected binding energies (Ebind) and global reactivity descriptors, we anticipate that the proposed complexes can vitally be used as analogous to carrier-mediated-drug delivery. PMID- 29982034 TI - Female sexual function and urinary incontinence in nulliparous athletes: An exploratory study. AB - OBJECTIVES: To estimate the prevalence of Female Sexual Dysfunction (FSD) and Urinary Incontinence (UI) symptom in nulliparous athletes and analyze the risk factors for these dysfunctions. DESIGN: A cross-sectional study. SETTING: The International Consultation on Incontinence Questionnaire-Short Form (ICIQ-UI-SF) and the Female Sexual Function Index (FSFI) were applied to assess the UI and the FSD. PARTICIPANTS: 50 athletes with >=18 years old. RESULTS: We found a prevalence of 48% of UI and 44% of FSD among nulliparous athletes. The rate of athletes having concomitant FSD and UI was 24%. We found a significant difference between high and low impact sports in the ICIQ-UI-SF score (p = 0.028). Hours of training (p = 0.007; R2 = 0.21) was found to be a risk factor for UI. Incontinent athletes demonstrated a Relative Risk of 2.7 to develop sexual desire problem when compared to the continents (p = 0.04; 95% CIs: 1.50-4.89). CONCLUSIONS: This study found a high prevalence of both UI and FSD among nulliparous athletes. Furthermore, nulliparous athletes practicing high-impact modalities are the most susceptible to UI. The hours of training per day was considered a risk factor to develop UI, and incontinent athletes have more chances of showing difficulties in sexual desire. PMID- 29982035 TI - Current injury monitoring and player education practices in Irish amateur rugby union. AB - OBJECTIVES: To ascertain current injury surveillance and player education practices in Irish amateur rugby union. DESIGN: Cross-sectional survey. SETTING: Amateur rugby clubs in Ireland. PARTICIPANTS: Medical professionals and rugby coaches of the top 58 amateur rugby clubs in Ireland. MAIN OUTCOME MEASURES: The survey investigated the current injury and training load monitoring practices in operation in Irish amateur rugby. It also explored whether player education sessions regarding injury prevention and concussion recognition and management were conducted in these clubs. RESULTS: Forty-four clubs completed the survey, giving an overall response rate of 76%. Ninety-one percent of the responding clubs monitored injuries. Sixty-four percent of these clubs operated return to play protocols for all injuries, while 36% operated return to play protocols for concussion only. Injury prevention education was conducted by 71% of these clubs and 82% educated players on concussion recognition and management. CONCLUSIONS: Implementing effective injury monitoring strategies in both amateur and professional sport settings may aid in minimizing injury risk. In Ireland, 91% of the responding clubs monitored injuries and 71% educated players on injury prevention. By implementing one centralized injury surveillance system for Irish amateur rugby, injury trends can be effectively monitored and used to guide prevention strategies. PMID- 29982036 TI - Comparison of lumbopelvic and dynamic stability between dancers and non-dancers. AB - OBJECTIVE: To compare lumbopelvic stability between dancers and non-dancers by assessing lumbopelvic motor control, abdominal muscles automatic-activation, lumbar range of motion and dynamic stability. DESIGN: Cross-sectional. SETTING: University/superior-dance-conservatory. PARTICIPANTS: Twenty-two dancers and 22 non-dancers. MAIN OUTCOME MEASUREMENTS: The active straight leg raise test (ASLR) was used to test lumbopelvic motor control with pressure feedback (mmHg). Transversus, rectus anterior and internal oblique muscles thicknesses were measured at rest and ASLR. For dynamic stability, the modified Star Excursion Balance Test (mSEBT) was employed. RESULTS: Significant differences were revealed in lumbopelvic motor control between groups (p < 0.001). Abdominal muscles automatic-activation showed no differences between the groups. There were significant differences in the mSEBT for most of the test's directions, with dancers performing better than the non-dancers (p < 0.05). For the dancers, there were positive associations between motor control and dynamic stability, and between abdominal muscle thickness and mSEBT. For non-dancers, the rectus anterior activation correlated with the mSEBT. CONCLUSIONS: The dancers had better lumbopelvic motor control, dynamic stability and lumbar movements except in terms of extension, as compared with non-dancers. Therefore, this novel study could stimulate a new line of research to determine the influence of these outcomes on sports performance, prevention and injury rehabilitation. PMID- 29982037 TI - Changes in the spatial spread of attention with ageing. AB - Spatial attention is a necessary cognitive process, allowing for the direction of limited capacity resources to varying locations in the visual field for improved visual processing. Thus, understanding how ageing influences these processes is vital. The current study explored the relationship between the spatial spread of attention and healthy ageing using an inhibition of return task to tap visual attention processing. This task allowed us to measure the spatial distribution of inhibition, and thus acted as a marker for attentional spread. Past research has indicated minimal age differences in inhibitory spread. However, these studies used placeholder stimuli, which may have restricted the range over which age differences could be reliably measured. To address this, in Experiment One, we measured the relationship between the spatial spread of inhibition and healthy ageing using a method which did not employ placeholders. In contrast to past research, an age difference in inhibitory spread was observed, where in comparison to younger adults, older adults exhibited a relatively restricted spread of attention. Experiment Two then confirmed these findings, by directly comparing inhibitory spread for placeholder present and placeholder absent conditions, across younger and older adults. Again, it was found that age differences in inhibitory spread emerged, but only in the placeholder absent condition. Possible reasons for the observed age differences in attention are discussed. PMID- 29982038 TI - Bouba or kiki with and without vision: Shape-audio regularities and mental images. AB - 95% of the world's population associate a rounded visual shape with the spoken word 'bouba', and an angular visual shape with the spoken word 'kiki', known as the bouba/kiki-effect. The bouba/kiki-effect occurs irrespective of familiarity with either the shape or word. This study investigated the bouba/kiki-effect when using haptic touch instead of vision, including the role of visual imagery. It also investigated whether the bouba/kiki shape-audio regularities are noticed at all, that is, whether they affect the bouba/kiki-effect itself and/or the recognition of individual bouba/kiki shapes, and finally what mental images they produce. Three experiments were conducted, with three groups of participants: blind, blindfold, and vision. In Experiment 1, the participants were asked to pick out the tactile/visual shape that they associated with the auditory bouba/kiki. Experiment 1 found that the participants who were blind did not show an instant bouba/kiki-effect (in Trial 1), whereas the blindfolded and the fully sighted did. It also found that the bouba/kiki shape-audio regularities affected the bouba/kiki-effect when using haptic touch: Those who were blind did show the bouba/kiki-effect from Trial 4, and those who were blindfolded no longer did. In Experiment 2, the participants were asked to name one tactile/visual shape and a segment of audio together as either 'bouba' or 'kiki'. Experiment 2 found that corresponding shape and audio improved the accuracy of both the blindfolded and the fully sighted, but not of those who were blind - they ignored the audio. Finally, in Experiment 3, the participants were asked to draw the shape that they associated with the auditory bouba/kiki. Experiment 3 found that their mental images, as depicted in their drawings, were not affected by whether they had experienced the bouba/kiki shapes by haptic touch or by vision. Regardless of their prior shape experience, that is, tactile or visual, their mental images included the most characteristic shape feature of bouba and kiki: curve and angle, respectively, and typically not the global shape. When taken together, these experiments suggest that the sensory regularities and mental images concerning bouba and kiki do not have to be based on, or even include visual information. PMID- 29982039 TI - Enhancement of sugar recovery and ethanol production from wheat straw through alkaline pre-extraction followed by steam pretreatment. AB - To improve sugar recovery and ethanol production from wheat straw, a sequential two-stage pretreatment process combining alkaline pre-extraction and acid catalyzed steam treatment was investigated. The results showed that alkaline pre extraction using 8% (w/w) sodium hydroxide at 80 degrees C for 90 min followed by steam pretreatment with 3% (w/w) sulfur dioxide at 151 degrees C for 16 min was sufficient to prepare a substrate that could be efficiently hydrolyzed at high solid loadings. Moreover, alkaline pre-extraction reduced the process severity of steam pretreatment and decreased the generation of inhibitory compounds. During enzymatic hydrolysis, increasing solid loading decreased the yield of monomeric sugars. Enzymatic hydrolysis at 25% (w/v) solid loading, the yields of approximately 80% of glucose and 65% of xylose could be reached with an enzyme dosage of 25 mg protein/g glucan. Following fermentation of hydrolysate with sugar concentration of approximately 120 g/L, an ethanol concentration of 54.5 g/L was achieved. PMID- 29982040 TI - Effect of the electric supply interruption on a microbial electrosynthesis system converting inorganic carbon into acetate. AB - Microbial electrosynthesis (MES) technology relies on the direct use of electrons to convert CO2 into long chain organic chemicals. Therefore, MES has been proposed to be coupled to the renewable electricity supply, mainly from solar and wind sources. However, those energies suffer fluctuations and interruptions of variable duration, which can have an adverse effect on MES performance. Such effects on MES has been evaluated for the first time under different interruptions time. H-cell-MES reactors were disconnected from power supply during 4, 6, 8, 16, 32 and 64 h. Interruptions affected the acetate production rate, causing a decrease of until 77% after 64 h off. However, after all the interruptions, the acetate production was restored, taking between 7 and 16 h for the reduction current to turn steady. Therefore, microbial community on MES proved to be resilient and able to recover the electro-autotrophic activity despite the duration of current supply interruptions. PMID- 29982042 TI - Revamping downdraft gasifier to minimize clinker formation for high-ash garden waste as feedstock. AB - The conventional downdraft gasifier, when used with garden waste pellets (ash ~10%) as feedstock, exhibits formation of clinker due to hardening of softened ash, which results in discontinuous flame and intermittent operation. The design and operation protocol of the gasifier was appropriately modified to circumvent this problem. The effects of parameters such as grate movement, equivalence ratio (ER), and ratio of air entering at combustion and drying zones (split ratio) were systematically studied to maximize the lower heating value (LHV) of gas and minimize the amount of clinker. The grate movement of once in 20 min, ER of 0.32, and air split ratio of 0:100 together proved to be the best for garden waste pellets. The producer gas LHV and cold gas efficiency were 3.59 MJ/Nm3 and 62.61%, respectively, and comparable to the producer gas obtained from other biomass resources such as rice husk, wheat straw, and cotton stalks. PMID- 29982041 TI - Selectivity control of nitrite and nitrate with the reaction of S0 and achieved nitrite accumulation in the sulfur autotrophic denitrification process. AB - The characteristics of reaction between S0 and NO2--N or NO3--N in the sulfur autotrophic denitrification (SADN) process were studied using S0 as an electron donor and NO2--N and NO3--N as electron acceptors. The effect of changes in pH and temperature on the processes of NO2--N and NO3--N reduction were also studied to identify the optimum control parameters for strengthening the preference of S0 on NO3--N; thus, achieving the efficient accumulation of NO2--N. The results showed that the affinity of S0 for NO3--N was considerably higher than that for NO2--N. The optimum pH values for the reductions of NO2--N and NO3--N were 7.0 and 8.5, respectively, and both optimum temperatures were 35 degrees C. By controlling different pH, the NO3--N conversion efficiency reached 90%, at which time the accumulation of NO2--N was more than 95%. Microbial community analysis showed that Thiobacillus, Sulfurimonas, and Thioahalobacter were the main genera in the S0-SADN process. PMID- 29982044 TI - Co-hydrothermal carbonization of lignocellulosic biomass and swine manure: Hydrochar properties and heavy metal transformation behavior. AB - Co-hydrothermal carbonization (HTC) of lignocellulosic biomass and swine manure (SM) was conducted, and the hydrochar properties and transformation behavior of heavy metals (HMs) were investigated in this study. The results showed that co HTC with lignocellulosic biomass promoted the dehydration of SM and enhanced the aromatization of the hydrochar. Compared to the hydrochar from SM, the carbon content, higher heating value and energy yield of the hydrochar from co-HTC were significantly increased, reaching the maximum of 57.05%, 24.20 kJ/kg and 80.17%, respectively. Significant synergy occurred between lignocellulosic biomass and SM during co-HTC and different lignocellulosic biomass exhibited similar influence on the synergy. Additionally, the concentration and bioavailability of HMs in the hydrochar from co-HTC were decreased in comparison to SM. These findings suggested that co-HTC with lignocellulosic biomass offered an effective approach to convert SM into clean solid fuel with remarkably improved fuel properties. PMID- 29982043 TI - Single pot bioconversion of prairie cordgrass into biohydrogen by thermophiles. AB - The aim of the present work was to use a thermophilic consortium for H2 production using lignocellulosic biomass in a single pot. The thermophilic consortium, growing at 60 degrees C utilized both glucose and xylose, making it an ideal source of microbes capable of utilizing and fermenting both hexose and pentose sugars. The optimization of pH, temperature, and substrate concentration increased the H2 production from 1.07 mmol H2/g of prairie cordgrass (PCG) to 2.2 mmol H2/g PCG by using the thermophilic consortium. A sequential cultivation of a thermostable lignocellulolytic enzyme producing strain Geobacillus sp. strain WSUCF1 (aerobic) with the thermophilic consortium (anaerobic) further increased H2 production with PCG 3-fold (3.74 mmol H2/g PCG). A single pot sequential culturing of aerobic and anaerobic microbes can be sustainable and advantageous for industrial scale production of biofuels. PMID- 29982045 TI - Designing continuous flow reaction of xylan hydrolysis for xylooligosaccharides production in packed-bed reactors using xylanase immobilized on methacrylic polymer-based supports. AB - The present study focuses on the development and optimization of a packed-bed reactor (PBR) for continuous production of xylooligosaccharides (XOS) from xylan. For this purpose, three different methacrylic polymer-based supports (Relizyme R403/S, Purolite P8204F and Purolite P8215F) activated with glyoxyl groups were morphologically characterized and screened for the multipoint covalent immobilization of a xylanase. Based on its physical and mechanical properties, maximum protein loading and thermal stability, Relizyme R403/S was selected to set up a PRB for continuous production of XOS from corncob xylan. The specific productivity for XOS at 10 mL/min flow rate was 3277 gXOS genzyme-1 h-1 with a PBR. This PBR conserved >90% of its initial activity after 120 h of continuous operation. PMID- 29982046 TI - Enhanced methanogenic co-degradation of propionate and butyrate by anaerobic microbiome enriched on conductive carbon fibers. AB - Recent studies have shown that the addition of conductive materials can promote direct interspecies electron transfer (DIET) between bacteria and methanoarchaea. This study demonstrated that carbon fibers could significantly stimulate methanogenic conversion of propionate and butyrate as co-substrate, while only butyrate was completely degraded in the unamended control bioreactor. In the carbon fibers-amended bioreactor, specific methane production (mL-CH4/g CODInitial) and methanogenesis rate (d-1) increased by around 2.4 and 6.7 times, respectively. Various electroactive bacteria were abundant in the carbon fibers amended bioreactor, whereas different known fermentative bacteria were abundant in the control. Moreover, carbon fibers substantially increased the abundance of Methanosaeta species. These results suggest that electroactive bacteria could be involved in DIET with Methanosaeta species enabling co-degradation of propionate and butyrate. Additionally, electrical conductivities of the biomass were comparable in both configurations, indicating that carbon fibers were the primary route for DIET. PMID- 29982047 TI - Vermi-sanitization of toxic silk industry waste employing Eisenia fetida and Eudrilus eugeniae: Substrate compatibility, nutrient enrichment and metal accumulation dynamics. AB - Detoxification of silk processing effluents and sludge (SPES) through composting approaches is a new idea. This study examined the biodegradation potential of two epigeic earthworms (Eisenia fetida and Eudrilus eugeniae) in different SPES and cow dung (CD) mixtures in comparison with composting. N, P, S, Fe and Mn availability significantly increased upon vermicomposting compared to aerobic composting. The alkaline pH of the feedstocks satisfactorily neutralized under vermicomposting. The Ca-K availability and cation exchange dynamics readily stabilized due to vermicomposting. Interestingly, Eisenia fetida exhibited greater adaptability towards the toxic SPES materials than Eudrilus eugeniae, which was accompanied by 60-70% reduction of Cd, Cr, Zn and Pb levels in Eisenia system, whereas metal accumulation ability of Eudrilus eugeniae was remarkable. Moreover, both the species equally contributed in augmentation of beneficial (N fixing and P-solubilizing) microorganisms in the feedstocks. Overall, nutrient enrichment and sanitizing potency of vermitechnology was explicitly manifested in SPES + CD (1:1) combination. PMID- 29982048 TI - Evaluation of the clean characteristics and combustion behavior of hydrochar derived from food waste towards solid biofuel production. AB - This study investigated the clean properties and combustion behavior of hydrochar from food waste (FW). The hydrochar was characterized by proximate analysis and HHVs, and the chemical forms were investigated by FTIR, XPS (Sulfur), and XANES (Chlorine). TG-FTIR was used to assess the combustion behaviors, and XRF was used to assess the fouling and slagging inclinations. Results showed that increasing temperature from 180 degrees C to 260 degrees C enhanced the removal of N, S, and Cl for hydrochar. Especially, aromatic-S and sulfate-S increased in contrast to sulfoxide-S, and more inorganic-S was produced in hydrochar; all samples had mainly inorganic-chlorine. Additionally, the release of HCl, SO2, and NO of hydrochar combustion were significantly reduced and the SI and FI index decreased to ranges of 0.18-0.16 and 0.32-0.17, respectively. However, hydrochar produced at temperature above 220 degrees C led increased NO emission possibly due to formation of more pyridine-N and quaternary-N. PMID- 29982049 TI - Microwave pyrolysis of moso bamboo for syngas production and bio-oil upgrading over bamboo-based biochar catalyst. AB - Microwave pyrolysis of moso bamboo over bamboo-based biochar catalyst was conducted to achieve the bio-oil upgrading and high quality syngas production. The influence of the biochar on bamboo pyrolysis involving the temperature rise, product yield, and bio-oil and gas compositions was studied. The gas production was facilitated by the biochar mainly at the cost of the bio-oil, indicating the biochar had an excellent activity for the bio-oil cracking. The main compositions in bio-oil were acetic acid and phenol with the total contents ranging from 73.145% to 82.84% over the biochar catalysts, suggesting the upgrading of the bio oil were achieved. The biochar exerted a positive effect on the syngas (CO + H2) production with the maximum content reaching up to 65.13 vol% at the 20 wt% addition amount of biochar under microwave condition. The biochar became more effective on the bio-oil upgrading and syngas production under microwave heating than conventional heating. PMID- 29982050 TI - Comparative performance evaluation of novel polystyrene membrane with ultrex as Proton Exchange Membranes in Microbial Fuel Cell for bioelectricity production from food waste. AB - The present research envisages developing a novel polystyrene membrane as Proton Exchange Membrane (PEM) which was prepared by using thermocol packaging waste material. The performance of this novel membrane was evaluated by comparing it with the commonly used ultrex membrane in two-chambered Microbial Fuel Cell (MFC) treating food waste leachate. The COD concentrations were varied from 500 mg/L to 2000 mg/L. The maximum power density and current density when polystyrene and ultrex membranes were used were found to be 29.19 mW/m2 and 38.39 mW/m2; and 174.61 mA/m2 and 238.27 mA/m2 respectively at 1500 mg/L COD concentration. The maximum Columbic Efficiency (CE) was found to be 10.29% for polystyrene and 11.80% for ultrex membrane respectively. SEM, EDS and FTIR analysis techniques were used to determine the characteristics of the membrane. PMID- 29982051 TI - Lewis-Bronsted acid catalysed ethanolysis of the organic fraction of municipal solid waste for efficient production of biofuels. AB - A combined Lewis-Bronsted acid ethanolysis of sugars was thoroughly investigated with the aim of producing ethyl levulinate (EL) in a single step. Ethanolysis carried out at 453 K for 4 h using H2SO4 (1 wt%) and AlCl3.6H2O (30 mol % with respect to sugars) produced a yield of 60 mol % of EL respect to glucose and starch. Such optimised conditions were positively applied directly on different food waste, preliminarily characterised and found to be mainly composed by simple (10-15%) and relatively complex sugars (20-60%), besides proteins (6-10%) and lipids (4-10%), even in their wet form. The catalytic system resulted robust enough to the point that the copresence of proteins, lignin, lipids and mineral salts not only did not negatively affect the overall reactivity, but resulted efficiently converted into soluble species, and specifically, into other liquid biofuels of different nature. PMID- 29982052 TI - Hydrothermal hydrolysis pretreatment of microalgae slurries in a continuous reactor under subcritical conditions for large-scale application. AB - Biofuel production from microalgae biomass via fermentation is promising as a renewable technology. Hydrothermal hydrolysis pretreatment of microalgae slurry prior to fermentation is an efficient method to enhance the biogas production. Herein, we report, for the first time, the hydrothermal hydrolysis pretreatment of microalgae slurries in a continuous reactor under subcritical conditions (temperature <200 degrees C, pressure ~2 MPa). The results show that the yield of carbohydrates from microalgae slurries first increased and then decreased with increasing average outlet temperature, which reached a maximum value at 160 degrees C for 10 min. This phenomenon was caused by the combined effects of the release of organics and biochemical reactions. Notably, the radial temperature distribution of microalgae slurries, influenced by the mass fraction and the flow rate during the heating process, had effects on the yield of organics (carbohydrates, proteins) in aqueous solution. This study provides useful information for the operating conditions in large-scale applications. PMID- 29982053 TI - Butylated hydroxytoluene induces astaxanthin and lipid production in Haematococcus pluvialis under high-light and nitrogen-deficiency conditions. AB - The aim of this study was to investigate the effects of butylated hydroxytoluene (BHT) on the production of astaxanthin and lipids in Haematococcus pluvialis LUGU under high-light and nitrogen-deficiency conditions. Astaxanthin and lipid contents were increased by 71.13% and 10.71%, respectively, in algal cells treated with 2 mg L-1 BHT. The maximal contents of astaxanthin and lipids were 3.17% and 46%, respectively. The levels of reactive oxygen species (ROS) in the presence of BHT were lower than in the control, and this effect involved strong activation of several antioxidases. Additionally, BHT application upregulated endogenous nitric oxide (NO) production. These results showed that this approach is useful for stimulating production of astaxanthin and lipids in H. pluvialis and that exogenous BHT induces astaxanthin and lipid production, which is responsible for the signalling molecule responses against abiotic stress conditions in H. pluvialis. PMID- 29982054 TI - An integrated green biorefinery approach towards simultaneous recovery of pectin and polyphenols coupled with bioethanol production from waste pomegranate peels. AB - An integrated biorefinery, incorporating hydrothermal processing of waste pomegranate peels (WPP), was proposed for the acid and organic solvent-free simultaneous recovery of pectin and phenolics with bioethanol production. The hydrothermal treatment (HT) was optimized using Box-Behnken design and the maximum recovery of pectin (18.8-20.9%) and phenolics (10.6-11.8%) were obtained by hydrothermal treatment at 115 degrees C for 40 min with a liquid-solid ratio of 10. The WPP pectin was characterized by IR, 1H NMR, and TGA which showed close similarity to commercial pectin. Depending on WPP cultivar type the degree of esterification, galacturonic acid content and molecular weight of pectin were in the range of 68-74%, 71-72%, and 131,137-141,538 Da, respectively. The recovered phenolics contained 57-60% punicalagin. Enzyme digestibility of WPP improved using HT with 177 g glucose produced per kg dry mass which was fermented to obtain 80 g ethanol with 88% of theoretical yield. PMID- 29982055 TI - Novel investigation of the performance of continuous packed bed bioreactor (CPBBR) by isolated Bacillus sp. M4 and proteomic study. AB - The present study reveals the benzene degrading potential of bacterial species isolated from petroleum contaminated soil. Genomic analysis suggests that Bacillus sp. M4 was found to be dominating species. The process parameters were optimized and found to be pH 7.0 +/- 0.2, temperature 32 +/- 5 degrees C, immobilization time (20 days) and benzene concentration 400 mg/L. The maximum removal efficiency of benzene was calculated and found to be 93.13% at elimination capacity156 (mg/L/day) and inlet loading rate 192 (mg/L/day) achieved in 54th days of operation. In the study, the residual metabolites were analyzed by GC/MS analysis and identified as benzene-1,2-diol. In order to identify the responsible protein involved in the process of benzene biodegradation The proteomic study was performed and proteins were identified by MALDI-TOF analysis. The molecular docking was confirmed by the benzene biodegradation. PMID- 29982056 TI - A novel low cost microalgal harvesting technique with coagulant recovery and recycling. AB - In this study, a novel low cost and sustainable microalgal harvesting technique was developed using the concept of coagulant recovery concentration and recycling. Al3+ can be recovered from harvested Scenedesmus acuminatus biomass with 0.1 M HCl, at an acid solution-biomass ratio of 250 ml g-1. The residual Al3+ content in the purified biomass was reduced to 0.11 +/- 0.0006 mg g-1, while a higher content of 59.74 +/- 3.11 mg g-1 was found in the coagulation harvested biomass. The recovered Al3+ solution was concentrated 25 times and then reused for the harvesting of S. acuminatus. The Al3+ recovery and reuse were repeated 5 times, and the harvesting efficiencies were found higher than the fresh Al3+ as a result of the presence of extracellular polymeric substances in the recovered coagulant solution which aided the coagulation process. According to the technical-economic analysis, the cost of chemicals decreased 50% after 5 times recycling. PMID- 29982057 TI - Integrated anaerobic digestion and algae cultivation for energy recovery and nutrient supply from post-hydrothermal liquefaction wastewater. AB - Post-hydrothermal liquefaction wastewater (PHWW), which contains approximately 80% of original feedstock resources, shows great potential to achieve sustainable development of an environment-enhancing energy system. A combination of anaerobic digestion and algae cultivation was proposed for methane recovery and nutrient supply from PHWW. Granular activated carbon (GAC) and ozone were used to enhance energy recovery from the PHWW. The results indicated that with GAC addition, the maximum methane yield increased by 67.7%-228 mL/g CODremoval. In addition, Chlorella vulgaris displayed optimal growth in a 5-fold diluted digestate with a 2.32 g/L maximum biomass content and 180 mg/(L.d) biomass production rate. The total energy yield was 565 kJ/g COD, which was 27.4 times higher than that without GAC. Integration of anaerobic digestion and algae cultivation, particularly with GAC addition during fermentation, is a feasible and advantageous process for energy recovery from PHWW. PMID- 29982058 TI - Physicochemical, structural and combustion characterization of food waste hydrochar obtained by hydrothermal carbonization. AB - A solid carbon-rich product hydrochar, was prepared using hydrothermal carbonisation of food waste at temperatures of 200, 250 and 300 degrees C. To acquire detailed insight into physicochemical and structural properties, hydrochar samples were characterised using a range of techniques. The carbon content and higher heating value of food waste increased considerably from 39 to 73% and 15 to 31 MJ/kg corresponding to the heating temperature. The blends of hydrochar and coal prepared in three different ratios (5%, 10% and 15%) exhibited different thermal behaviour. The overall results of co-combustion study showed that the activation energy of hydrochar samples decreased from 56.78 KJ/mol to 29.80 KJ/mol with increase in temperature. Hydrochar prepared at 300 degrees C with coal blending ratio of 10% exhibited the lowest activation energy of 19.45 KJ/mol. Additionally thermal gravimetric analysis of the samples showed that high temperature carbonization can increase the combustion properties of hydrochar. PMID- 29982059 TI - Effects of CO on hydrogenotrophic methanogenesis under thermophilic and extreme thermophilic conditions: Microbial community and biomethanation pathways. AB - Coke oven gas is considered as a potential hydrogen source for biogas bio upgrading. In this study, the effects of CO on biomethanation performance and microbial community structure of hydrogenotrophic mixed cultures were investigated under thermophilic (55 degrees C) and extreme-thermophilic (70 degrees C) conditions. 5% (v/v) CO did not inhibit hydrogenotrophic methanogenesis during semi-continuous operation, and 83-97% CO conversion to CH4 was achieved. Methanothermobacter thermoautotrophicus was the dominant methanogen at both temperatures and was the main functional archaea associated with CO biomethanation. Specific methanogenic activity test results showed that long-term 5% CO acclimation shortened the lag phase from 5 h to 1 h at 55 degrees C and 15 h to 3 h at 70 degrees C. CO2 was the preferred carbon source over CO for hydrogenotrophic methanogens and CO consumption only started when CO2 was completely depleted. M. thermoautotrophicus dominated mixed cultures showed a great potential in simultaneous hydrogenotrophic methanogenesis and CO biomethanation. PMID- 29982060 TI - High-efficiency nutrients reclamation from landfill leachate by microalgae Chlorella vulgaris in membrane photobioreactor for bio-lipid production. AB - Using microalgae to treat landfill leachate is a promising approach due to the effective nutrients reclamation ability and additional profit of bio-lipid production. To offset the negative effect of landfill leachate on microalgae cells, a membrane photobioreactor (m-PBR) was adopted in the study, in which microalgae biomass concentration was improved from 0.66 in traditional photobioreactor (T-PBR) to 0.95 g/L. Nutrients reclamation efficiencies of leachate were analyzed according to elemental balance, and the results showed that nitrogen reclamation efficiency was generally lower than 50% while phosphorus reclamation efficiency was higher than 70% due to elemental availability. The nitrogen and phosphorus reclamation efficiencies in the m-PBR were much higher than that in the T-PBR. Besides, lipid produced from the m-PBR had a high cetane number of 60.96% and low linolenic acid content of 8.32%, which demonstrated good combustion properties of the microalgae-based lipid when using landfill leachate as nutrients source. PMID- 29982061 TI - A comprehensive comparison of five different carbon-based cathode materials in CO2 electromethanogenesis: Long-term performance, cell-electrode contact behaviors and extracellular electron transfer pathways. AB - Each carbon-based material, due to the discrepancy in critical properties, has distinct capability to enrich electroactive microbes able to electrosynthesize methane from CO2. To optimize electromethanogenesis process, this study physically prepared and examined several carbon-based cathode materials: carbon stick (CS), CS twined by Ti wire (CS-Ti) or covered with carbon fiber (CS-CF), graphite felt (CS-GF) and carbon cloth (CS-CC). CS-GF electrode had constantly stable methane production (75.8 mL/L/d at -0.9 V vs. Ag/AgCl) while CS-CC showed a suppressed performance over time caused by the desposition of inorganic shell. Electrode material properties affected biofilms growth, cell-electrode contact behaviors and electron exchange. Methane formation with CS-CC biocathode was H2 concnetration dependent; CS-GF cathode possessed high antifouling properties and extensive space, enriching the microorganisms capable of catalyzing electromethanogenesis through more efficient non-H2 route. This study re interpreted the application potentials of carbon-based materials in CO2 electroreduction and electrofuel recovery, providing valuable guidance for materials' selection. PMID- 29982062 TI - Combustion behaviors of spent mushroom substrate using TG-MS and TG-FTIR: Thermal conversion, kinetic, thermodynamic and emission analyses. AB - The present study systematically investigated the combustion characteristics of spent mushroom substrate (SMS) using TG-MS (thermogravimetric/mass spectrometry) and TG-FTIR (thermogravimetric/Fourier transform infrared spectrometry) under five heating rates. The physicochemical characteristics and combustion index pointed to SMS as a promising biofuel for power generation. The high correlation coefficient of the fitting plots and similar activation energy calculated by various methods indicated that four suitable iso-conversional methods were used. The activation energy varied from 130.06 to 192.95 kJ/mol with a mean value of 171.49 kJ/mol using Flynn-Wall-Ozawa and decreased with the increased conversion degree. The most common emissions peaked at the range of 200-400 degrees C corresponding to volatile combustion stage, except for CO2, NO2 and NO. The peak CO2 emission occurred at 439.11 degrees C mainly due to the combustion of fixed carbon. PMID- 29982063 TI - An efficient Photobioreactors/Raceway circulating system combined with alkaline CO2 capturing medium for microalgal cultivation. AB - High efficiency of microalgal growth and CO2 fixation in a Photobioreactors (PBRs)/Raceway circulating (PsRC) system combined with alkaline-CO2 capturing medium and operation was established and investigated. Compared with a pH 6 medium, the average biomass productivity of Chlorella sp. AT1 cultured in a pH 11 medium at 2 L min-1 circulation rate for 7 days increased by about 2-fold to 0.346 g L-1 d-1. The maximum amount of CO2 fixation and CO2 utilization efficiency of Chlorella sp. AT1 could be obtained at a PBRs to Raceway ratio of 1:10 in an indoor-simulated PsRC system. A similar result was also shown in an outdoor PsRC system with a 10-ton scale for microalgal cultivation. Under the appropriate circulation rate, the stable growth performance of Chlorella sp. AT1 cultured by long-term semi-continuous operation in the 10-ton outdoor PsRC system was observed, and the total amount of CO2 fixation was approximately 1.2 kg d-1 with 50% CO2 utilization efficiency. PMID- 29982064 TI - Evolved gas analysis and slow pyrolysis mechanism of bamboo by thermogravimetric analysis, Fourier transform infrared spectroscopy and gas chromatography-mass spectrometry. AB - Slow pyrolysis of bamboo is an important conversion pathway to produce biofuels and chemicals such as biomass-derived fertilizer precursor (biochar). In this study, evolved gas analysis during pyrolysis of bamboo was conducted by a combination of TG, FTIR and GC-MS to establish a detailed pyrolysis mechanism of bamboo biomass. The main decomposition temperature zones were 300-400 degrees C and it reached the maximum mass loss intensity at 350 degrees C based on DTG curves. The main functional groups escaped from biomass during pyrolysis were OH, -CH2, -CH3, CO, C-O, and -COOH. The main compounds during pyrolysis of bamboo were acetic acid and 2-propenoic acid, ethenyl ester at 300 degrees C, 2-oxo propanoic acid and 1-hydroxy-2-propanone at 350 degrees C and acetic acid and acetic acid ethenyl ester at 400 degrees C. Evolved gas analysis indicated that components in bamboo occurred in different temperatures and pyrolysis mechanisms and resulted in distinguishing pyrolysis product emission characteristics. PMID- 29982065 TI - Improving mechanisms of biohydrogen production from grass using zero-valent iron nanoparticles. AB - This paper investigated the improving mechanisms and microbial community dynamics of using zero-valent iron nanoparticles (Fe0 NPs) in hydrogen fermentation of grass. Results showed that Fe0 NPs supplement improved microbial activity and changed dominant microbial communities from Enterobacter sp. to Clostridium sp., which induced a more efficient metabolic pathway towards higher hydrogen production. Meanwhile, it is also proposed that Fe0 NPs could accelerate electron transfer between ferredoxin and hydrogenase, and promote the activity of key enzymes by the released Fe2+. The maximal hydrogen yield and hydrogen production rate were 64.7 mL/g-dry grass and 12.1 mL/h, respectively at Fe0 NPs dosage of 400 mg/L, which were 73.1% and 128.3% higher compared with the control group. Fe0 NPs also shorten the lag time and facilitated the hydrolysis and utilization of grass. This study demonstrated that Fe0 NPs could effectively improve hydrogen production and accelerate the fermentation process of grass. PMID- 29982066 TI - Pork ham and belly quality can be estimated from loin quality measurements? AB - The aim of the study was to determine the relationships between the quality evaluation of loin and the quality evaluation of ham and belly from the same carcasses for trying to predict the quality parameters of ham and belly based on measurements made on the loin. The research material consisted of 105 pork carcasses, from which three elements were cut and marked: loin, ham and belly. Quality evaluation included: pH, color, water holding capacity (WHC), cooking loss (CL), and sensory analysis. All designated quadratic equations were characterized by low R2 values from 0.06 to 0.43 for ham and from 0.00 to 0.28 for belly. However, it is possible to predict the quality parameters of ham or belly with different levels of accuracy (R2 from 0.50 to 0.92 - depending on the measurement and the element), using measurements selected from all those tested on the loin. Those loin quality measurements most frequently used in equations were chewiness and CL. PMID- 29982067 TI - Attitudes towards, and purchasing of, Scottish beef and beef products in Scotland - A short communication. AB - Attitudes and preferences of the main shopper in households (n = 203) across Scotland towards beef and beef products that were produced in Scotland were assessed by questionnaire. Consumer panel purchase data from the preceding six months were collected for those households by Kantar Worldpanel. Beef products from Scotland accounted for 39% (by value) of all beef purchases, with an additional 46% from Great Britain and 9% from Ireland. Participants tended to report that being locally produced was an important factor when they bought beef and beef products, although this was not reflected in higher proportions of these products being purchased. Participants who rated local production of higher importance did not buy a higher proportion of beef from Scotland than did participants who rated it as less important (41% and 37% respectively, P = 0.448). Stated preferences for locally produced beef and beef products are not translated into higher amounts purchased. PMID- 29982068 TI - Fast and dynamic descriptive techniques (Flash Profile, Time-intensity and Temporal Dominance of Sensations) for sensory characterization of dry-cured loins. AB - The present study aimed to evaluate the influence of NaCl replacement by KCl (15, 20 and 25%) on the sensory characteristics of dry-cured loins. A rapid descriptive method called Flash Profile (FP) was used for sensory evaluation in order to verify if this technique allow to discriminate between these kinds of meat products in a rapid way. The sensory results obtained by FP were complemented with those obtained applying dynamic sensory techniques as time intensity (TI) and Temporal Dominance of Sensations (TDS). FP clearly discriminates between dry-cured loins samples with different salt replacement level whereas TI and TDS techniques contributed with additional dynamic sensory information. Moreover, TDS technique which is a multi-attribute temporal method provided an interesting information about the interactions among attributes along consumption. Significant differences in the temporal perception of the flavor and texture attributes evaluated were detected, especially between normal samples and dry-cured loins with higher salt replacement levels (20 and 25%). PMID- 29982069 TI - Addition of herbal extracts to the Holstein-Friesian bulls' diet changes the quality of beef. AB - Twenty four Holstein-Friesian bulls were randomly assigned to one of three dietary treatments: a control diet, diet O (supplemented with Optirum herbal extracts improving the functioning of the gastrointestinal tract of cattle), and diet OS (containing two herbal preparation: Optirum and Stresomix, used to reduce stress). The quality of longissimus lumborum (LL) and semimembranosus (SM) muscles were determined after 14 days of wet ageing. The diet influenced proximate composition, pH, water holding capacity, colour, shear force and some sensory quality attributes of beef, although the influence depended on the muscle type. The supplementation of the bulls' diet with two herbal preparations (OS diet) had a beneficial impact on technological properties and sensory tenderness of LL muscles. The herbal extracts O and OS had no negative effect on lipid oxidation or the sensory attributes of beef. Thus, it is recommended to use a combination of these two products in cattle feeding. PMID- 29982070 TI - Assessing cattle welfare at slaughter - Why is it important and what challenges are faced? AB - The welfare of animals in the meat industry, especially at the time of slaughter, has become an area of increasing public scrutiny and has prompted research on its assessment, and enhancement. Fundamental factors such as the effects of transport, reactions of the animals to novel environments and underlying commercial pressures which impose 'speed' and 'robustness of action' in the way animals are handled, can pose a challenge when establishing a valid, reliable and feasible welfare assessment protocol for use at slaughter. The purpose of this review is to assess published work on animal welfare at slaughter, with a focus on the current methods used to assess cattle welfare in the slaughterhouse, which are outlined in the scientific and trade literature, and how these relate to the interaction between the environment, the animal, and slaughterhouse personnel. PMID- 29982071 TI - Genetics of growth, carcass and meat quality in rabbits. AB - This paper reviews the current knowledge on the genetics of growth, carcass and meat traits in rabbits. There is a great variety in size of rabbit breeds, from which commercial production uses medium size breeds for does and large breeds as terminal sires. Selection experiments for growth and feed efficiency have been successful. Selection for residual feed intake did not modify growth rate, acting on reducing the appetite. Selection for growth rate increased adult weight and led to poorer carcass yield when comparing selected and unselected animals at the same commercial weight, but not at the same age, near the same maturity stage. The results on meat/bone ratio do not show a clear pattern. Negative effects on intramuscular fat and some sensorial traits have been found in lines selected for growth rate, but meat quality in general does not seem to be affected. PMID- 29982072 TI - Effects of high pressure treatment on lipolysis-oxidation and volatiles of marinated pork meat in soy sauce. AB - To investigate the effect of high pressure (HP) treatment (150 and 300 MPa for 15 min at 20 degrees C) on lipolysis-oxidation and volatile profile of marinated pork meat in soy sauce, the changes of lipase, phospholipase and lipoxygenase (LOX) activities, TBARS, free fatty acids and volatiles composition in control and HP treated samples were analyzed. Acid and neutral lipase activities and free fatty acids content decreased, while LOX activity and TBARS increased after HP treatment. Phospholipase had well stability under HP. The levels of volatile compounds from lipid oxidation and brine increased under HP and then contributed 73.16-78.25% of the typical aroma, while volatile compounds from carbohydrate fermentation, especially acetic acid, decreased with the pressure increasing. The decrease of free fatty acids during pressurization was probably attributed to the decline of lipase activity and the increase of LOX activity. These findings indicated that HP (150-300 MPa/15 min) promoted lipid oxidation and the permeation of brine, but inhibited carbohydrate fermentation. PMID- 29982073 TI - Sensory quality characteristics with different beef quality grades and surface texture features assessed by dented area and firmness, and the relation to muscle fiber and bundle characteristics. AB - The main objective of this study was to compare the eating quality among the groups categorized by the Korean beef quality grade and texture feature of exposed muscle surface assessed by extent of dented areas and firmness. Additionally, this study also investigated the effects of fiber and bundle characteristics on texture feature to establish the cause of differences in muscle surface texture. Significant differences were observed in the sensory quality characteristics among the quality grades mainly determined by marbling score (P < 0.05). However, the coarse texture group with a dented surface required a higher initial force to penetrate meat (P < 0.001), was more difficult to break meat into fragments (P < 0.001), and had a higher amount of perceptible residue in the mouth (P < 0.01) compared to the fine texture group. These differences in the surface texture features between the fine and coarse groups could be explained by bundle area and fiber number per each bundle. PMID- 29982074 TI - Novel genetic polymorphisms associated with carcass traits in grazing Texel sheep. AB - Improving meat production traits has increased its importance in sheep breeding. We report novel associations of SNP present in genes related to lipid metabolism and growth with several carcass traits in purebred Texel lambs. Expected progeny differences (EPD) predictions from 461 animals from the Central Progeny Testing of Texel breed in Uruguay were used for the association analysis. Live weights at different stages, ultrasound and post-mortem traits were analyzed. Markers in several genes were associated with growth, carcass and meat quality traits. Among others: PPARGC1A with valuable cuts weight, hot carcass weight and carcass fatness; DGAT1 with live weights, fat thickness, rib-eye area and shoulder weight; CAST with birth weight and fat thickness; GHR with birth weight and carcass fatness, and GHRHR with live weights and fat thickness. Genotypic effects ranged from 0.035 to 0.923 (DGAT1 vs. weaning weight) units of phenotypic SD. Most of the associations described are novel in sheep breeding, deserving further analyses. PMID- 29982075 TI - Label-free quantitative proteomic analysis reveals muscle contraction and metabolism proteins linked to ultimate pH in bovine skeletal muscle. AB - The purpose of this research was to investigate the causes and consequences of pHu variations in beef cattle. A group of 176 Nellore beef cattle was evaluated and classified into two different pHu groups: High (>=6.0, N = 17) and Normal (<5.8, N = 159). Plasma concentrations of cortisol and adrenocorticotropic hormone, lactate and glycogen muscular content, meat color, shear force and Longissimus thoracis muscle proteomic profile were evaluated and compared between pHu groups. Muscle glycogen content, meat color and shear force statistically differed between pHu groups. Label-free quantitative proteomic analysis revealed ten differentially abundant proteins between pHu groups, involved in metabolic processes and muscle contraction, which also were significantly correlated with pHu. Thirty-six and 31 proteins were exclusively present in Normal and High pHu group, respectively, which were related to TCA cycle, cortisol production, calcium regulation, and antioxidant function. The MYH7, UGP2, H2AFJ and VDAC3 were identified as potential indicators of pHu variations. CALM and NNT appeared to be interesting proteins to understand the metabolic pathways behind pHu. Data are available via ProteomeXchange with identifier PXD009320. PMID- 29982076 TI - Loin eye muscle physico-chemical attributes, sensory evaluation and proximate composition in Korean Hanwoo cattle subjected to slaughtering along with stunning with or without pithing. AB - Korean Hanwoo Cattle (KHC) were utilized to compare existing and modified methods of slaughtering. Carcass traits, loin eye muscle color coordination, physico chemical attributes, sensory evaluation and proximate composition were assessed. Twelve KHC were slaughtered following 1) CSNHS: non-halal way neck cutting as following captive bolt stunning with pithing and 2) CSHS: halal way neck cutting as following captive bolt stunning without pithing. Loin eye muscle color coordination, physico-chemical attributes and sensory evaluation did not differ significantly subjected to slaughter types (P > 0.05). However, loin eye muscle crude ash content was higher in CSHS group relative to CSNHS (P < 0.05). Pearson's correlation analysis indicated that several traits were affected by slaughter types. Overall, CSHS ensures no negative impact on meat yield and qualitative traits rather led a higher loin eye muscle crude ash content. Therefore, CSHS could be adopted in Korean slaughterhouses with modification of existing practice. PMID- 29982077 TI - Improving pork quality traits by a short-term dietary hydroxy methionine supplementation at levels above growth requirements in finisher pigs. AB - The effects of dietary methionine (Met) supplies above growth requirements on tissue biology and pork quality were studied. At 70 kg, 45 crossbred pigs were fed a control (CONT) diet adequate in Met (0.22% Met) up to 105 kg. For the last 14 days before slaughter, pigs were fed with the CONT diet or with diets where the Met level was increased to Met3 (0.66% Met) or Met5 (1.10% Met). Growth performance and carcass composition did not change with the treatment. Pigs fed the Met5 treatment displayed lower TBARS and higher glutathione levels (P <= .05), along with higher ultimate pH (P < .01) and lower drip, lightness and hue (P <= .10) in the longissimus muscle, compared to the CONT and Met3 pigs. Extra dietary Met improved ham's technological quality in the Met3 and Met5 groups (P <= .05). Thus, dietary Met supplementation improves pork quality without impairing growth or carcass traits. PMID- 29982078 TI - Thermal inactivation of actinidin as affected by meat matrix. AB - Actinidin from kiwifruit can tenderise meat and add value to low-value meat cuts. However, as with other proteases, over-tenderisation of meat will occur if the reaction of actinidin is not controlled. We describe a process to control the enzyme activity by heat denaturation after the desired degree of meat tenderisation has been achieved. The thermal inactivation kinetics of actinidin in both fresh (KE) and commercial (CEE) green kiwifruit enzyme extract, were studied, with enzyme alone and with enzyme combined with homogenised meat. Both KE and CEE were inactivated at moderate sous vide temperatures (60 and 65 degrees C) in <5 min. However, the inactivation times increased considerably (up to 24 h at 60 and 65 degrees C) when these extracts were mixed with homogenised meat. The thermal inactivation kinetics in meat homogenates were used as a guide to optimise processing parameters for actinidin application to beef steaks, which will be described in a companion paper. PMID- 29982079 TI - Application of plant extracts to improve the shelf-life, nutritional and health related properties of ready-to-eat meat products. AB - Plant extracts are increasingly becoming important additives in food industry due to their antimicrobial and antioxidant abilities that delay the development of off-flavors and improve the color stability in ready-to-eat (RTE) meat products. Due to their natural origin, they are excellent candidates to replace synthetic molecules, which are generally considered to have toxicological and carcinogenic effects. The efficient extraction of these antioxidant molecules from their natural sources, along with the determination of their activity in the commercialized products, have been a great challenge for researchers and food chain contributors. The objective of this review is to highlight the application of plant extracts to improve the shelf-life, nutritional and health-related properties of RTE meat products. The sensory effects of these extracts on RTE meat products as well as the possible synergistic effects of a combination of extracts are discussed. PMID- 29982080 TI - Actinidin pretreatment and sous vide cooking of beef brisket: Effects on meat microstructure, texture and in vitro protein digestibility. AB - The application of actinidin to beef brisket followed by thermal inactivation (by sous vide cooking) was studied for its effects on textural attributes, microstructure and protein digestibility under simulated gastric conditions. The optimal processing of meat was achieved by injecting 5% of a 3 mg/mL solution of commercial actinidin extract (ActazinTM from Anagenix Ltd.) into brisket steaks, followed by vacuum tumbling and cooking under sous vide conditions at 70 degrees C for 30 min. This cooking time is considerably less than sous vide cooking times normally used in the food service industry. The actinidin-treated meat had no change in pH, colour and cook loss, but showed improved sensory scores for tenderness, juiciness and flavour compared with the untreated meat. Transmission electron micrographs showed considerable breakdown of the myofibrillar structure, particularly around the Z-discs. An enhanced initial rate of muscle protein breakdown under simulated gastric conditions was observed using SDS-PAGE, demonstrating positive effects of the actinidin treatment on meat protein digestibility. PMID- 29982081 TI - Quality characteristics of Warthog (Phacochoerus africanus) meat. AB - Warthogs are hunted for trophies and damage reprisal whilst the meat is consumed. Little is known about the quality profile of the meat, therefore, this study investigated the effect of age (yearlings and adult) and sex on the sensory, physical, and chemical attributes of cooked meat. The meat was high in protein (~32%) and low in total fat (< 2%), while the meat from yearlings tended to be tenderer than adults. Age appeared to have a more pronounced influence than sex on the sensory attributes. Warthog meat had a pork aroma and flavour. Undesirable odours and flavours were described as sour/sweaty and fishy, and adults differed from yearlings regarding sour/sweaty (P = .025) and fishy aromas (P = .006), and fishy flavours (P = .045). Small differences (< 0.5 mg/g) in palmitoleic (P = .047) and arachidonic (P = .038) acids were found between adults and yearlings. Warthog meat can be regarded as a lean and healthy source of protein. PMID- 29982082 TI - Botulinum toxin therapy of bipolar depression: A case series. AB - We and others have recently found that botulinum toxin injected into the brow muscles has significant antidepressant properties as compared to placebo in randomized controlled trials in patients with major depressive disorder. However, data for the treatment of bipolar depression with botulinum toxin is lacking. We report here six patients with bipolar disorder experiencing moderate to severe depressive episodes who were treated on a compassionate basis with botulinum toxin given their persistent depressive symptoms and adverse side effects from medications. Four of six patients with bipolar depression experienced a remission following treatment with botulinum toxin, and the other two patients experienced a reduction of depressive symptoms. When the effect of botulinum toxin on the frown muscles began to wear off, depressive symptoms returned and retreatment with botulinum toxin provided successful relief of depressive symptoms again. PMID- 29982083 TI - Neural circuitry changes associated with increasing self-efficacy in Posttraumatic Stress Disorder. AB - Cognitive models suggest that posttraumtic stress disorder (PTSD) is maintained, in part, as a result of an individual's maladaptive beliefs about one's ability to cope with current and future stress. These models are consistent with considerable findings showing a link between low levels of self-efficacy and PTSD. A growing body of work has demonstrated that perceptions of self-efficacy can be enhanced experimentally in healthy subjects and participants with PTSD, and increasing levels of self-efficacy improves performance on cognitive, affective, and problem-solving tasks. This study aimed to determine whether increasing perceptions of self-efficacy in participants with PTSD would be associated with changes in neural processing. Combat veterans (N = 34) with PTSD were randomized to either a high self-efficacy (HSE) induction, in which they were asked to recall memories associated with successful coping, or a control condition before undergoing resting state fMRI scanning. Two global network measures in four neural circuits were examined. Participants in the HSE condition showed greater right-lateralized path length and decreased right-lateralized connectivity in the emotional regulation and executive function circuit. In addition, area under receiver operating characteristics curve (AUC) analyses found that average connectivity (.71) and path length (.70) moderately predicted HSE group membership. These findings provide further support for the importance of enhancing perceived control in PTSD, and doing so may engage neural targets that could guide the development of novel interventions. PMID- 29982084 TI - Social cognitive impairments in individuals with schizophrenia vary in severity. AB - Social cognitive deficits are a hallmark feature of schizophrenia and have been confirmed by several meta-analyses; however, the uniformity of these impairments across individuals remains unknown. The present study evaluated the heterogeneity of social cognitive impairment. A secondary aim was to identify a subset of measures to quickly identify those individuals who are most in need of remediation. Two independent samples of people with schizophrenia (n = 176; n = 178) and their respective healthy control groups (n = 104; n = 154) were selected from two phases of the Social Cognition Psychometric Evaluation (SCOPE) project, which assessed multiple domains of social cognition. Latent profile analysis was utilized to identify sub-clusters of performance within each patient sample. Receiver operator curve and discriminant analysis were implemented to identify tasks suitable as screening tools. Three clusters were identified in each sample that differed primarily in severity of impairment. The first showed no social cognitive impairment (~25% of patients). The second consisted of patients with mild impairment (~40% of each sample), and the third showed severe SC impairment (~32%). Patients in the severe cluster were older, less educated, more neurocognitively impaired, and lower functioning. Using the Bell Lysaker Emotion Recognition Task (BLERT) for screening provided sensitivity of 80.15% and specificity 89.13%. Combining BLERT with the Reading the Mind in the Eyes task yielded sensitivity of 91.60% and specificity 75.00% for identifying impaired individuals. These results illustrate the existence of distinct degrees of social cognitive impairment in schizophrenia and indicate that remediation efforts may not be necessary for all individuals. PMID- 29982085 TI - Reciprocal amygdala-prefrontal interactions in learning. AB - Animals constantly evaluate their environment in order to avoid potential threats and obtain reward in the form of food, shelter and social interactions. In order to appropriately respond to sensory cues from the environment, the brain needs to form and store multiple cue-outcome associations. These can then be used to form predictions of the valence of sounds, smells and other sensory inputs arising from the surroundings. However, these associations must be subject to constant update, as the environment can rapidly change. Failing to adapt to such change can be detrimental to survival. Several systems in the mammalian brain have evolved to perform these important behavioral functions. Among these systems, the amygdala and prefrontal cortex are prominent players. Although the amygdala has been shown to form strong cue-outcome associations, the prefrontal cortex is essential for modifying these associations through extinction and reversal learning, and synaptic plasticity occurring in the strong reciprocal connections between these structures is thought to underlie both adaptive and maladaptive learning. Here we review the synaptic organization of the amygdala-prefrontal circuit, and summarize the physiological and behavioral evidence for its involvement in appetitive and aversive learning. PMID- 29982086 TI - The insomnia of Franz Kafka. AB - OBJECTIVE: To characterize the insomnia suffered by Franz Kafka (1883-1924), one of the most important literary figures of the 20th century. METHODS: We read Kafka's diaries and private correspondence to his fiancee, friends, editors and relatives looking for references to his insomnia. RESULTS: We found 292 references to insomnia indicating that Kafka suffered from chronic insomnia disorder that originated from and was maintained by the following predisposing and precipitating factors: (1) a complex personality predisposing to an increased arousal level, (2) intrusive thoughts and ruminations at bedtime, (3) excessive worrying about sleep loss and its daytime consequences, and (4) an extraordinary intolerance to noise. Since he could not sleep at night and felt the necessity to compose his literary works in an absolutely quiet environment, Kafka deliberately changed his sleep-wake schedule so he could write at night and nap in the afternoon. These maladaptive sleep habits perpetuated his insomnia and led to chronic sleep deprivation resulting in fatigue, lack of concentration and sleep related auditory, tactile and visual hallucinations. Kafka sought help in alternative medicine however this was ineffective in improving his insomnia. CONCLUSIONS: Kafka suffered from chronic insomnia disorder and had inadequate sleep hygiene resulting in chronic sleep deprivation. These sleep problems impaired Kafka's quality of life. PMID- 29982087 TI - The association between sleep disturbance and second-hand smoke exposure: a large scale, nationwide, cross-sectional study of adolescents in Japan. AB - OBJECTIVE: This study investigated the association between secondhand-smoke (SHS) exposure and sleep disturbance symptoms. METHODS: This study was a cross sectional survey of junior and senior high school students throughout Japan. A total of 85,931 adolescents responded, and 84,988 questionnaires were included in the analysis. RESULTS: Adolescents who had never smoked accounted for 88.0% of respondents; among that group 39.1% reported having been exposed to SHS over the previous week. The results of multiple logistic regression analyses indicated that the adjusted odds ratios for insomnia symptoms such as difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS) and early morning awakening (EMA), as well as sleep disturbance symptoms such as subjectively insufficient sleep and short sleep duration (<6 h), tended to be higher both among never smoking adolescents with SHS exposure and among smoking adolescents, as compared with never-smoking adolescents without SHS exposure. When adolescents with one or more of DIS, DMS, and EMA were defined as having insomnia, the adjusted odds ratio for insomnia was highest for adolescents who smoked, followed in descending order by those exposed to SHS both inside and outside the home, those exposed to SHS only inside the home, those exposed to SHS only outside the home, and never smoking adolescents without SHS exposure (p < 0.001). CONCLUSIONS: The present study has revealed that SHS exposure is associated with sleep disturbance. Thus, in addition to smoking cessation programs, it is also necessary to endorse measures to protect adolescents from SHS exposure in order to promote good sleep in this population. PMID- 29982088 TI - Circadian preference and sleep timing from childhood to adolescence in relation to genetic variants from a genome-wide association study. AB - OBJECTIVE: Recent genome-wide association studies (GWASs) have revealed new genetic variants behind self-reported individual circadian preference, a distinct biological trait that is fairly stable during adulthood. In this study we analyze whether these genetic variants associate with objectively measured sleep timing from childhood to adolescence, over a nine-year period, with self-reported circadian preference during late adolescence. METHODS: The participants (N = 100, 61% girls) came from a community cohort from Finland born in 1998. Sleep midpoint was measured with actigraphy at 8, 12 and 17 years. Circadian preference was self reported at the age of 17 years. Single nucleotide polymorphisms (SNPs) were extracted at 12 years of age from the Illumina OmniExpress Exome 1.2 bead array data. Weighted polygenic risk scores (PRSs) were calculated based on top SNPs from a recent GWAS for morningness-eveningness in an adult population. RESULTS: The PRS for circadian preference towards morningness was associated with earlier sleep midpoint from childhood to adolescence. When the time points were analyzed separately, the association between genetic tendency towards morning preference and earlier sleep midpoint was strongest among the 17-year-olds. Furthermore, the shift towards later sleep rhythm from early to late adolescence was milder for those with a higher PRS for morning preference. PRS for morning preference was also associated with self-reported circadian preference towards morningness in late adolescence. CONCLUSION: Our results suggest that genetic variants found for circadian preference in adults are already associated with objective sleep timing during childhood and adolescence, and predict individual developmental sleep trajectories from childhood onwards. PMID- 29982089 TI - Sleep and psycho-behavioral problems in internally displaced children in Georgia. AB - OBJECTIVE: The aim of this study was to examine sleep and psycho-behavioral variables in Georgian Internally Displaced (ID) Children and their population based controls. METHODS: One hundred and sixty one children (10.85 +/- 0.9) from ID families escaped from Shida Kartli, Georgia, and 161 non-ID children (10.94 +/ 0.9) were studied after seven years of displacement. Children completed the Pre Sleep Arousal Scale, Buss-Perry Aggression Questionnaire (BPAQ), Children's Depression Inventory (CDI), and the Child Trauma Screening Questionnaire (CTSQ). In addition, we assessed the children's appraisal of the family environment. Moreover, parents reported socio-demographic information, their children's academic excellence, and completed the Sleep Disturbance Scale for Children (SDSC), Beck Depression Inventory II (BDI), and Perceived Stress Scale (PSS). RESULTS: Compared with the control group, ID children had a lower level of academic excellence and family environment (p < 0.01) as well as higher scores in all SDSC dimensions with the significant difference for breathing (p < 0.001), hyperhidrosis and SDSC total scores (p < 0.05). Cognitive pre-sleep arousal was significantly higher in non-IDs (p < 0.01), while there was no difference between groups in somatic pre-sleep arousal level. All BPAQ component and total scores were higher in IDs than in non-IDs but the difference was significant only in Physical Aggression (p < 0.01). Mean scores for BDI and PSS were significantly higher in ID than non-ID parents (p < 0.001). Both cognitive and somatic pre sleep arousal predicted SDSC total score in non-IDs (p < 0.01) while cognitive but not somatic arousal was significant predictor in IDs (p < 0.01). CONCLUSION: Sleep and psycho-behavioral problems are noticeable even in those ID children who were very young at the time of displacement. Psycho-social environment in which children are growing up warrants major consideration in ID population. PMID- 29982090 TI - The association of sleep duration and quality with all-cause and cause-specific mortality in the Women's Health Initiative. AB - BACKGROUND/OBJECTIVE: Many studies have shown a U-shaped association of sleep duration with mortality; however, this association is difficult to interpret owing to possible reverse causation, residual confounding, and measurement issues. We used data from the Women's Health Initiative to examine the associations of sleep duration, insomnia, and use of sleep aids with death from cardiovascular disease (CVD), cancer, "other" causes, and all causes combined. METHODS: Cox proportional hazards models were used in the analysis of baseline data and in time-dependent analyses of repeated measures to estimate associations of sleep-related factors with mortality. Among 158,203 women with information regarding sleep, 30,400 total deaths, 8857 CVD deaths, 9284 cancer deaths, and 11,928 other deaths were ascertained over a median of 17.8 years. RESULTS: In both baseline and time-dependent analyses, both short (<=5 h) and long sleep (>=9 h) durations were associated with increased risk of total, CVD, and "other" deaths, but not with cancer deaths. Insomnia showed no association with mortality, whereas use of sleep medications was associated with an increased mortality risk. CONCLUSIONS: While our findings showed a small but robust association of sleep duration with mortality in postmenopausal women, studies including objective measurements of sleep quality and efficiency are needed to clarify these associations. PMID- 29982091 TI - Pulse wave amplitude and heart period variability in children with upper airway obstruction. AB - OBJECTIVE: The aim of this study was to assess cardiovascular autonomic modulation in children with upper airway obstruction (UAO), to compare this modulation to that of non-snoring children and to investigate the effect of adenotonsillectomy (AT). METHODS: ECG and finger photoplethysmographic signals obtained from overnight polysomnographic (PSG) recordings of 31 children with mild-to-moderate UAO and 34 non-snoring children were analysed. The extent of autonomic modulation was assessed by symbolic analysis of heart period (HP), pulse wave amplitude (PWA), and their joint dynamics during non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. RESULTS: Children with UAO showed more frequent patterns of monotonically increasing and decreasing HP in NREM sleep and monotonically increasing and decreasing joint PWA-HP patterns in REM and NREM sleep at baseline compared to controls, even when considering only periods of sleep free of discrete respiratory events. Following AT, HP, and joint PWA-HP dynamics significantly altered towards levels observed in the control group. CONCLUSIONS: In children with mild-to-moderate UAO, cardiovascular autonomic modulation is more prevalent, even during quiet, event-free sleep. AT appears to reverse this pattern. PMID- 29982092 TI - Validating the Persian Adolescent Sleep Hygiene Scale-Revised (ASHSr) using comprehensive psychometric testing methods. AB - BACKGROUND: This study translated the Adolescent Sleep Hygiene Scale-revised (ASHSr) into Persian and aimed to validate its psychometric properties using classical test theory and Rasch analyses. METHODS: Adolescents aged 14-18 (n = 389; 199 males) and their parents in Iran participated in the study. Each adolescent wore a wrist actigraphy device during sleep time and completed the ASHSr, the Depression Anxiety Stress Scale (DASS), the General Health Questionnaire (GHQ), the Pediatric Daytime Sleepiness Scale (PDSS), and the Pittsburgh Sleep Quality Index (PSQI). A parent of each adolescent completed the Sleep Disturbance Scale for Children (SDSC). RESULTS: The construct validity of the ASHSr was supported by both classical test theory (factor loadings from confirmatory factor analysis [CFA] = 0.64 to 0.88; corrected item-total correlations = 0.70 to 0.92; test-retest reliability = 0.72 to 0.90) and Rasch analyses (infit mean square = 0.73 to 1.30; outfit mean square = 0.74 to 1.32). ASHSr had significantly negative associations with DASS subscales (beta = -0.15 to -0.42, ps < 0.001) and GHQ (beta = -0.663, p < 0.001). Known-group validity was demonstrated by the significant differences between poor and good sleep hygiene based on ASHSr in the actigraphy measure and scores of PDSS, PSQI, and SDSC. The multigroup CFA and differential item functioning in Rasch analyses suggested that all the participants interpreted the ASHSr similarly, regardless of their gender or living in a private room. CONCLUSIONS: The Persian ASHSr demonstrated good reliability and validity in assessing sleep hygiene among Iranian adolescents. Healthcare providers may use it to assess the effectiveness of sleep hygiene programs. PMID- 29982093 TI - The carotenoid Bixin found to exhibit the highest measured carotenoid oxidation potential to date consistent with its practical protective use in cosmetics, drugs and food. AB - The electrochemical oxidation potentials of cis bixin correspond to the production of the carotenoid radical cation, Car+ and dication Car++. The oxidation is a two-electron process with oxidation potentials at ~0.94 and ~1.14 V vs SCE (reference to ferrocene at 0.528 V) in THF. These potentials are higher than that of symmetrical canthaxanthin at 0.775 V and 0.972 V and for beta carotene at 0.634 V and 0.605 V respectively. The second oxidation potential for canthaxanthin is higher by 0.20 V than the first. Similar difference is observed for bixin. In contrast, the second oxidation potential for beta-carotene is lower by 30 mV than that of the first. Reduction potentials were found to occur at ~ 0.69 and ~-1.22 V vs SCE. The lifetime of the radical cation of cis bixin, Car+, is short and decays rapidly at ambient temperature. The suggested scavenging ability of cis bixin towards reactive oxidative oxygen species is estimated to be 44. On the other hand, that of beta-carotene, symmetrical canthaxanthin and the dicyano substituted carotenoid which exhibit oxidation potentials of 0.634 V, 0.775 V and 0.833 V vs SCE were measured to be 0.64, 1.96 and 23.60 respectively. The non-reversible electrochemical measurements suggest the tendency for bixin to react with trace amounts of reactive oxygen species (OH, O2-, OOH). PMID- 29982094 TI - Influence of darkness on pigments of Tetraselmis indica (Chlorodendrophyceae, Chlorophyta). AB - In the photic zone, phytoplankton experience diurnal variation in light intensity. However, prolonged exposure to aphotic condition influences their physiological state. Pigment composition is a useful biomarker to decipher cells physiological state and adaptive response to changing environmental conditions. Chlorophyll, a natural pigment, is biosynthesised even in darkness and studies have shown this ability is determined by genetic characteristics of an organism. The purpose of this study was to examine the influence of darkness on pigments and chlorophyll autofluorescence of Tetraselmis indica. Dark exposure (up to 6 months) had no significant impact on chlorophyll a and b concentration, whereas carotenoids were enhanced. Upon re-illumination pigments gradually recovered to pre-dark phase condition. These adaptive survival strategies of T. indica by altering pigment concentration in response to prolonged darkness are interesting. The absence of loroxanthin and loroxanthin esters in T. indica is reported in a first Tetraselmis species so far. In addition, the evaluation of autofluorescence and cellular chlorophyll concentration pointed out that they are not interdependent in this species. Hence, careful consideration of these two factors is needed when either of them is used as a proxy for other. The results obtained encourage a thorough study of pigment analysis, especially when subjected to darkness, to elucidate potential role in the evolution, chemotaxonomy, and survivability of species. PMID- 29982096 TI - Differing clinical pharmacy service models: Quantitative and qualitative analysis of nurse perceptions of support from pharmacists. AB - BACKGROUND: In the last decade interdisciplinary teamwork and collaboration are increasingly favoured as strategies to improve healthcare delivery. The need for collaboration is especially evident in acute care medical-surgical wards of hospitals. Doctors, nurses, pharmacists, doctors and other healthcare professionals work in shifts to provide a multiplicity of services to a rapidly changing caseload of patients. Traditionally, pharmacists have been assigned to a ward or wards for which they provided all clinical services. An alternative clinical pharmacy service model which aligns pharmacists with medical teams is being introduced into Australian hospitals. This newer model, teambased pharmacy, is intended to provide better clinical services overall to patients, but the effect on the working relationship between pharmacists and nurses has not been examined. OBJECTIVE: To compare nurses' perceptions of the pharmacist's role, collaboration with and support for nurses for two models of clinical pharmacy: wardbased pharmacy and teambased pharmacy. DESIGN: Quantitative and qualitative analysis of survey data from nurses. SETTINGS AND PARTICIPANTS: A total of 90 nurses from five acute-care wards located in two tertiary hospitals in Sydney, Australia participated in the survey. METHODS: Statistical comparison of quantitative data from Likert-type questionnaire, and qualitative thematic analysis of nurses' written responses to an open-ended question. RESULTS: The qualitative data analysis indicated that the team-based pharmacy clinical service model, resulted in a perceived increase in nursing workload and a decreased collaboration with pharmacists. These findings were corroborated by the quantitative data analysis findings of statistically significant perceived reductions in collaboration. CONCLUSIONS: Efforts to align pharmacists with medical teams by replacing the traditional ward-based pharmacy model with an alternative model resulted in a perceived reduction in collaboration with and support for nursing teams. Evaluation of the impact of new pharmacy service models should involve all health professionals contributing to the safe and effective use of medicines. Intervention is recommended to provide resources to satisfy nurses' needs for information and education about medication for hospitals that operate team-based clinical pharmacy services. PMID- 29982095 TI - MiR-340/iASPP axis affects UVB-mediated retinal pigment epithelium (RPE) cell damage. AB - Long-term exposure to ultraviolet B (UVB) light increases the risk of UVB damage due to increased UVB absorption by the retina and may further lead to age-related eye diseases. The retinal pigment epithelium (RPE) cell is a main target of UVB reaching the retina; its degeneration is an essential event in UVB-mediated age related macular degeneration (AMD). Herein, we first evaluated the expression and effect of iASPP, an inhibitory regulator of apoptosis, in UVB-induced RPE cell damage. Through the mechanism of RNA interference at the post-transcriptional level, miRNA affects a variety of cellular processes, including UVB-mediated cell damage. We next screened for upstream candidate miRNAs that may regulate iASPP expression. Among 8 candidate miRNAs, UVB significantly increased miR-340 levels. We also confirmed the direct binding of miR-340 to the 3'UTR of iASPP, and assessed the combined effect of miR-340 and iASPP on UVB-induced RPE cell damage. Taken together, we demonstrated the possible mechanisms involved in UVB-induced retinal damage. In RPE cells, UVB irradiation inhibits iASPP expression through inducing miR-340 expression, thereby promoting RPE cell apoptosis and suppressing cell viability via affecting p53, p21 and caspase-3 protein expression. Targeting miR-340 to rescue iASPP expression in RPE cells may help treat UVB-mediated retinal damage. PMID- 29982097 TI - Handgrip exercise reduces peripherally-inserted central catheter-related venous thrombosis in patients with solid cancers: A randomized controlled trial. AB - BACKGROUND: Peripherally-inserted central catheter-related venous thrombosis has serious complications including the loss of vascular access, recurrent venous thrombosis, and post-thrombotic syndrome. Current guidelines recommend non pharmacological strategies to prevent peripherally-inserted central catheter related venous thrombosis. There is little evidence for the effectiveness of handgrip exercise on the prevention of peripherally-inserted central catheter related venous thrombosis. OBJECTIVES: To examine the effectiveness of handgrip exercise using an elastic ball to prevent peripherally-inserted central catheter related venous thrombosis in patients with solid cancers. DESIGN: A randomized controlled trial. SETTINGS: One teaching hospital in Nanjing, China. PARTICIPANTS: In total, 120 subjects with solid cancers were eligible; each had a new peripherally-inserted central catheter. They were recruited and randomly assigned into two exercise groups and one control group. METHODS: Subjects from exercise groups 1 and 2 performed a 3-week, 25-repetition handgrip exercise, 3 and 6 times daily, respectively. The control group subjects performed a gentle limb exercise with no frequency and intensity requirements. Ultrasound was used to detect venous thrombosis development and examine axillary vein blood flow over the three points. RESULTS: There were 32 cases of peripherally-inserted central catheter-related venous thrombosis detected. Two venous thrombosis cases in the control group were symptomatic, but all venous thrombosis cases in the exercise groups were asymptomatic. All venous thromboses were partial. There were significant differences in the incidence of venous thrombosis among the three groups (chi2 = 12.813, p = 0.002; chi2 = 9.340, p = 0.009; chi2 = 11.480, p = 0.003; and chi2 = 10.534, p = 0.005, respectively) at days 2, 3 and 21. The incidence of venous thrombosis in the two exercise groups was lower than that in the control group over the 3 time points (all, p < 0.05). The between-group effects and interaction effect in vein maximum velocity and time-mean flow velocity showed significant differences (F = 4.180, p = 0.025; F = 4.010, p = 0.045; and F = 2.928, p = 0.025) at days 2, 3, and 21, respectively. The axillary vein blood flow parameters in the control group were lower than those in the two exercise groups at day 21 (all, p < 0.05). However, no significant differences occurred in the incidence of venous thrombosis and axillary vein blood flow parameters between the two exercise groups. CONCLUSION: Handgrip exercise using an elastic ball daily for three weeks could decrease the incidence of peripherally-inserted central catheter-related venous thrombosis. The method is simple, with no negative consequence reported. Further studies are required to confirm this conclusion and to explore the optimal frequency of handgrip exercise. PMID- 29982098 TI - Does sleep deprivation increase the vulnerability to acute psychosocial stress in young and older adults? AB - Sleep loss and psychosocial stress often co-occur in today's society, but there is limited knowledge on the combined effects. Therefore, this experimental study investigated whether one night of sleep deprivation affects the response to a psychosocial challenge. A second aim was to examine if older adults, who may be less affected by both sleep deprivation and stress, react differently than young adults. 124 young (18-30 years) and 94 older (60-72 years) healthy adults participated in one of four conditions: i. normal night sleep & Placebo-Trier Social Stress Test (TSST), ii. normal night sleep & Trier Social Stress Test, iii. sleep deprivation & Placebo-TSST, iv. sleep deprivation & TSST. Subjective stress ratings, heart rate variability (HRV), salivary alpha amylase (sAA) and cortisol were measured throughout the protocol. At the baseline pre-stress measurement, salivary cortisol and subjective stress values were higher in sleep deprived than in rested participants. However, the reactivity to and recovery from the TSST was not significantly different after sleep deprivation for any of the outcome measures. Older adults showed higher subjective stress, higher sAA and lower HRV at baseline, indicating increased basal autonomic activity. Cortisol trajectories and HRV slightly differed in older adults compared with younger adults (regardless of the TSST). Moreover, age did not moderate the effect of sleep deprivation. Taken together, the results show increased stress levels after sleep deprivation, but do not confirm the assumption that one night of sleep deprivation increases the responsivity to an acute psychosocial challenge. PMID- 29982099 TI - Associations of NT-proBNP and parameters of mental health in depressed coronary artery disease patients. AB - Natriuretic peptides (NP) are involved in the regulation of blood pressure and blood volume, and are elevated in patients with coronary artery disease (CAD). They are used as markers for illness severity, but their role in mental health is not well understood. Recently, A-type NP (ANP) has been associated with reduced anxiety in studies on cardiac patients; however, this study is the first to assess this effect for B-type NP (BNP) and for further dimensions of well-being and mental health. Depression, anxiety, and distress are more common in CAD patients than in the general population and are most likely not only influenced by psychological adaptation but also by neurobiological processes. We used baseline N-terminal proBNP (NT-proBNP) samples and psychometric assessments of 529 at least mildly depressed (Hospital Anxiety and Depression Scale, depression score >= 8) CAD patients from the multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial. Psychosocial status was assessed using standardized self-rating questionnaires on anxiety, depression, coping with illness, vital exhaustion, type D personality, and quality of life. Separate linear regression models for each psychometric scale revealed significant negative correlations of NT-proBNP with anxiety, depression, vital exhaustion, depressive coping, and negative affectivity. Moreover, patients with higher levels of NT-proBNP experienced less bodily pain and had a better self-rated mental health, despite worse physical functioning. Linear regression adjusted for age, sex, and physical functioning (Short Form Health Survey [SF 36]) revealed NT-proBNP to be a significant predictor for all tested measures of the patients' psychosocial status. These results indicate that NT-proBNP is not only positively associated with greater disease severity in mildly to moderately depressed CAD patients but also with better psychosocial status and mental well being. Possible mechanisms of this effect are discussed. PMID- 29982101 TI - Plasma Protein Profiling Reveal Osteoprotegerin as a Marker of Prognostic Impact for Colorectal Cancer. AB - BACKGROUND: Due to difficulties in predicting recurrences in colorectal cancer stages II and III, reliable prognostic biomarkers could be a breakthrough for individualized treatment and follow-up. OBJECTIVE: To find potential prognostic protein biomarkers in colorectal cancer, using the proximity extension assays. METHODS: A panel of 92 oncology-related proteins was analyzed with proximity extension assays, in plasma from a cohort of 261 colorectal cancer patients with stage II-IV. The survival analyses were corrected for disease stage and age, and the recurrence analyses were corrected for disease stage. The significance threshold was adjusted for multiple comparisons. RESULTS: The plasma proteins expression levels had a greater prognostic relevance in disease stage III colorectal cancer than in disease stage II, and for overall survival than for time to recurrence. Osteoprotegerin was the only biomarker candidate in the protein panel that had a statistical significant association with overall survival (P = .00029). None of the proteins were statistically significantly associated with time to recurrence. CONCLUSIONS: Of the 92 analyzed plasma proteins, osteoprotegerin showed the strongest prognostic impact in patients with colorectal cancer, and therefore osteoprotegerin is a potential predictive marker, and it also could be a target for treatments. PMID- 29982100 TI - Clinicopathologic Factors Related to the Histological Tumor Grade of Breast Cancer in Western China: An Epidemiological Multicenter Study of 8619 Female Patients. AB - BACKGROUND AND PURPOSE: Breast cancer is now recognized as a clinically heterogeneous disease with a wide spectrum of epidemiological and clinicopathologic features. We aimed to evaluate whether epidemiological and clinicopathologic features are associated with the histological tumor grade of breast carcinomas in Western China. METHODS: We retrospectively collected data from the Western China Clinical Cooperation Group and assessed associations between clinicopathologic factors and histological tumor grade in 8619 female breast cancer patients. Patients were divided into two groups: Group I (tumor grade I/II) and Group II (tumor grade III). Univariable analysis and multivariable logistic regression models were used to analyze the relationships between clinicopathologic factors and tumor grade. RESULTS: Patients presenting with positive axillary lymph nodes, large tumor size (>2 cm), lymphovascular invasion, hormone receptor negativity, human epidermal growth factor receptor 2 (HER-2) positivity, and triple negativity tended to have an increased risk of a high tumor grade. However, the number of pregnancies or births was inversely correlated with the risk of a high tumor grade. In addition, patients presenting with grade III tumors were more likely to receive aggressive treatment, such as adjuvant chemotherapy, anti-HER-2 therapy, and level III axillary lymph node dissection. CONCLUSIONS: Our results suggested that several clinicopathologic factors were associated with high tumor grade of breast cancer patients in Western China. PMID- 29982102 TI - PSP1, a Phosphatidylserine-Recognizing Peptide, Is Useful for Visualizing Radiation-Induced Apoptosis in Colorectal Cancer In Vitro and In Vivo. AB - Accurate and timely visualization of apoptotic status in response to radiation is necessary for deciding whether to continue radiation or change to another mode of treatment. This is especially critical in patients with colorectal cancer, which requires a delicate combination of surgery, radiation, and chemotherapy in order to achieve optimal outcome. In this study, we investigated the potential of phosphatidylserine-recognizing peptide 1 (PSP1) as an apoptosis-targeting probe, which identifies phosphatidylserine on cell surfaces. We first screened colon cancer cell lines for their sensitivity to radiation and selected two cell lines: HCT116 and HT29. Cell binding assay using fluorescence-activated cell sorting and optical imaging showed that HCT116 cells had better binding to PSP1 than HT29 cells. Thus, mouse xenograft model using HCT116 cells was generated and was topically irradiated with either single or fractionated dose of radiation followed by systemic administration of PSP1 for subsequent molecular optical imaging. We confirmed that the PSP1 probe was selectively bound to apoptosis induced tumor in a radiation dose-dependent manner. We also observed that fractionated radiation regimen, which is recently being used in clinical situation, was more effective in inducing tumor apoptosis than corresponding single-dose radiation treatment. We then evaluated the correlation between tumor targeting of PSP1 and suppression effect of tumor development and found that tumor volume and fluorescence intensity were correlated before (correlation coefficient r2 = 0.534) and after (r2 = 0.848) radiation therapy. Our study shows that PSP1 peptide is an efficient index probe for deciding "go or no-go" for radiation therapy in colorectal cancer. PMID- 29982104 TI - NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo. AB - Currently, glioma treatment is limited by two main factors: timely detection at onset or relapse and restriction of drugs by the blood-brain barrier (BBB) from entering the brain and influencing tumor growth. However, a safe BBB-traversing drug delivery system has brought new hope to glioma treatment. Exosomes have strong cargo-loading capacity and have the ability to cross the BBB. They can also be conferred with the ability for targeted delivery. Therefore, exosomes have great promise to be a targeted drug delivery vehicles. In this study, we firstly loaded superparamagnetic iron oxide nanoparticles (SPIONs) and curcumin (Cur) into exosomes and then conjugated the exosome membrane with neuropilin-1 targeted peptide (RGERPPR, RGE) by click chemistry to obtain glioma-targeting exosomes with imaging and therapeutic functions. When administered to glioma cells and orthotopic glioma models, we found that these engineered exosomes could cross the BBB smoothly and provided good results for targeted imaging and therapy of glioma. Furthermore, SPION-mediated magnetic flow hyperthermia (MFH) and Cur mediated therapy also showed a potent synergistic antitumor effect. Therefore, the diagnostic and therapeutic effects on glioma were significantly improved, while reducing the side effects. We have designed a new type of glioma-targeting exosomes, which can carry nanomaterials and chemical agents for simultaneous diagnosis and treatment of glioma, thus providing a potential approach for improving the diagnosis and treatment effects of intracranial tumors. PMID- 29982103 TI - Small Molecules Identified from a Quantitative Drug Combinational Screen Resensitize Cisplatin's Response in Drug-Resistant Ovarian Cancer Cells. AB - Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with IC50s under 1 MUM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC 101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells. PMID- 29982105 TI - Trunk control: The essence for upper limb functionality in patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) involves impaired trunk control, leading to impaired upper-limb functionality, dexterity, and independence. Deciding early on a comprehensive approach pointing of functional disturbances and personal needs is essential for a multimodal, individualized, goal-oriented assessment and treatment program, recognizing the broad range of symptoms and disabilities associated with MS. In clinical practice, postural control of the trunk is purported to be an important contributor to voluntary upper-limb function, including motor control and dexterity. The objective of this study was to point out the impairments of and relationship between trunk control and comprehensive upper-limb functions in individuals with MS. METHODS: Tasks that were sought are optimal screening for deterioration in trunk control (Trunk Control Test [TCT] and Trunk Impairment Scale [TIS]) and upper-limb functionality by comparing them with the Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (NHPT), Duruoz's Hand Index (DHI), and Functional Independence Measurement (FIM) results of 49 well-defined relapsing-remitting MS (RRMS) participants with those of 49 age-gender matched healthy subjects. RESULTS: Significant differences between the groups were evident across all tasks of the clinical tests studied (p < 0.05), except the TCT-balance in sitting position subscore. EDSS, NHPT, DHI, and FIM scores were highly correlated with the TCT subscores (rolling to weak side, sitting up from lying down) and TCT-total score, as well as TIS subscores (dynamic and coordination) and TIS total score (p <= 0.005). While TIS subscores were highly correlated with almost all parameters, just TIS-static subscore did not correlate with the DHI and FIM-cognitive scores. Also, DHI-hygiene subscore correlated poorly just with the TIS-coordination and TCT-coming to sitting position (p < 0.05). CONCLUSION: We found that patients with MS would present impaired upper-limb movement and decreased trunk control with high correlation between them, even in RRMS and in the very mild form of the disease. Identifying trunk control deficits provides better insight into dexterous difficulties of patients with MS and allows a more targeted neurorehabilitation focusing on upper limbs. In future studies, it would be of interest to examine the prognostic value of trunk control and upper-limb functionality in patients with MS using a longitudinal approach. PMID- 29982106 TI - Access to social security benefits among multiple sclerosis patients in Italy: A cross-sectional study. AB - BACKGROUND: Knowledge concerning the predictors of social security benefits and the proportion of Multiple Sclerosis (MS) patients receiving these benefits is very limited. OBJECTIVE: To estimate the likelihood of receiving social security benefits for Italian MS patients. METHODS: From September 2014 to November 2015, we interviewed MS outpatients from two Italian MS clinics to collect information regarding their personal data, clinical and working history, and access to social security benefits. We performed both univariate and multivariable analyses to evaluate the predictors for receiving social security benefits. RESULTS: We interviewed 297 patients, with a mean age of 49.5 (+/- 10.7) years; 71.4% were females. About 73% of patients had a relapsing-remitting (RR) course and the median EDSS score was 2.5 (IQR 1.5-6). About 75% of MS patients received a full exemption from co-payments, while the proportions of people who enjoyed each of the other social security benefits were lower, ranging from 8.8% (car adaptation) to 32% (disable badge). At multivariable analysis, the probability of obtaining each of the benefits was significantly associated with the EDSS score: walking aids (OR 3.9), care allowance (OR 3.6), disabled badge (OR 2.4), exemption from co-payment (OR 1.6) and allowed off work permit (OR 1.7). Only the probability of obtaining an allowed off work permit was also influenced by comorbidities (OR 2.9) and a higher education (OR 2.2). CONCLUSION: Except for full exemption from co-payments, the proportions of MS patients who enjoyed social security benefits seem to be limited in our study sample. The EDSS score is the strongest predictor of the probability of receiving all the benefits. Only a small proportion of patients received care allowance and working permits, probably because such benefits are only granted to people with a high level of disability. On the other hand, the low proportion of patients who enjoyed fiscal benefits for home and car adaptations could have been influenced by the way such benefits are granted in our country. PMID- 29982107 TI - Efficacy and safety of natalizumab extended interval dosing. AB - OBJECTIVE: It is postulated that extending the dosing interval of natalizumab (NTZ) from 4 to 5-8 weeks might decrease the risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to assess the effect of extended interval dosing (EID) on the therapeutic efficacy of natalizumab. METHODS: We reviewed 85 patients treated at two MS centers in the Middle East with natalizumab for at least 6 months using EID. Patients were shifted after an initial treatment period at standard interval dosing (SID) to an EID ranging from 5-8 weeks. RESULTS: The mean treatment duration on SID and EID was 15.4 +/- 11.9 and 11.8 +/- 7.0 months, respectively. By the end of SID and EID treatment 95.3% and 93.9% of patients were free of relapses (P = 0.41) with an annualized relapse rate (ARR) of 0.0006 and 0.001 respectively (P = 0.42). The mean EDSS at the end of SID and EID periods was 2.56 +/- 1.62 and 2.59 +/- 1.61 respectively (P = 0.84). A total of 97.6% and 94.7% of patients had no enhancing lesions on MRI during the SID and EID periods respectively (P = 0.18). There were no cases of PML and the rate of infections was lower during the EID period. CONCLUSION: In patients treated with natalizumab, shifting from SID to EID has no negative effect on efficacy as evidenced by relapse rate, disability progression and MRI activity. PMID- 29982108 TI - White matter hyperintensities in myotonic dystrophy type 2: Not always another expression of the disease. AB - Myotonic dystrophy type 2(DM2), inherited in an autosomal, dominant manner, is clinically characterized by muscle weakness, variable myotonia, cataract and multiorgan involvement, including the Central Nervous System. Recent data from literature indicate a possible autoimmune susceptibility of patients with DM2, while white matter abnormalities are a common feature of the disease. We report herein the case of a 38-year old woman, with the rare co-existence of DM2 and MS and argue about the challenging differential diagnosis if CNS involvement is present in DM2 patients. Thus, is it another expression of a multisystem disorder or an unfortunate pure coincidence? PMID- 29982109 TI - Teeth loss after teriflunomide treatment: Casual or causal? A short case series. AB - BACKGROUND: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) with a consistent safety profile in clinical trials. We report three cases of multiple teeth loss during teriflunomide treatment. CASE REPORTS: Case 1: a 39 year-old woman started teriflunomide for RRMS, switching from interferon beta. Four months later she complained about mandibular pain followed by the sudden loss of 4 teeth, in the absence of bleeding or trauma. Suspecting a causal role, we discontinued teriflunomide and started the accelerated elimination procedure with cholestyramine. Orthopantomography and a subsequent dental CT scan showed diffuse alveolar atrophy and periapical bone loss in several residual roots. Investigating retrospectively the patient's dental history, and revising previous orthopantomographies dating from 2009, we highlighted a chronic and progressive dental pathology with several cavities and teeth loss. Case 2: A 52-year-old woman affected by multiple sclerosis (MS) since 1988, switched from interferon beta to teriflunomide treatment due to poor tolerability. One year later she experienced the sudden loss of five teeth in the absence of traumatic events. Dental assessment and orthopantomography confirmed moderate chronic periodontitis. Teriflunomide was discontinued and the accelerated elimination procedure with cholestyramine was performed. Case 3: A 56-year-old woman affected by MS for thirty years. She switched from interferon beta to teriflunomide due to injection site reactions. After eighteen months she experienced hypermobility of several teeth without gum inflammation or pain, followed by sudden loss of twelve teeth. No dental examination is available. Teriflunomide was discontinued without accelerated elimination procedure. DISCUSSION: Odontogenic infections (periodontal disease and dental caries) are common and can cause teeth loss if left untreated as in case 1. It is conceivable that local infections favoured by teriflunomide accelerated pulpitis, endodontic infections and periapical reactions followed by teeth loss in predisposed subjects. Poor oral hygiene is common in MS patients and might favour dental infections. CONCLUSIONS: We underline the importance to assess concomitant teeth morbidity and to recommend accurate oral hygiene before and during teriflunomide treatment. PMID- 29982110 TI - Cardiac autonomic function during postural changes and exercise in people with multiple sclerosis: A cross-sectional study. AB - BACKGROUND: People with multiple sclerosis (PwMS) often develop an autonomic dysfunction (AD), which onset should be assessed early at a subclinical level, as it may interfere with pharmacological treatments and exercise. OBJECTIVE: To evaluate basal cardiac autonomic tone, its modulations during sit-to-stand, sub maximal exercise and recovery in PwMS without clinical overt AD and its relationships with fatigue perception. METHODS: Twenty-three PwMS (55 +/- 8 yrs [mean +/- SD]; EDSS score 5.7 +/- 1.3) and 20 age-matched healthy controls (HC; 55 +/- 8yrs) were enrolled. ECG was digitally acquired during:1) sitting at rest (low sympathetic activation); 2) standing (light sympathetic activation); and 3) during light exercise (moderate sympathetic activation) and recovery. Parasympathetic and sympatho-vagal parameters of heart rate (HR) variability in time and frequency domains were calculated from beat series. RESULTS: HR was slightly but not significantly higher in PwMS compared to HC in all experimental conditions. Parasympathetic indexes were significantly lower (p < 0.05) in PwMS compared to HC during baseline sitting and post-exercise recovery, whereas sympathovagal parameters were similar in both groups. No correlation between autonomic tone and perceived fatigue was observed. CONCLUSION: Parasympathetic tone appears to be impaired in PwMS basal and post-exercise conditions, but not during postural challenge and exercise. In addition, AD does not affect perceived fatigue. PMID- 29982111 TI - Effects of exercise training on cytokines and adipokines in multiple Sclerosis: A systematic review. AB - BACKGROUND: Physical activity, particularly exercise training, is an evidence based approach for managing symptoms, restoring function and improving overall wellness in people with multiple sclerosis (MS). Several recent studies have argued for a potential disease modifying effect of exercise in people with MS, and among the potential mediating mechanisms are exercise training effects on both cytokines and adipokines. The objectives of this study were to perform a systematic review of exercise training effects on cytokine and adipokine profiles in persons with MS. METHODS: We conducted open-dated searches of PubMed, Cochrane Library, EMBASE and PEDro using the terms 'Multiple sclerosis' or 'MS' AND 'exercise' OR 'training' OR 'physical activity' AND 'cytokine' OR 'inflammatory' OR 'immune' OR 'adipokine'. Included studies were written in English; comprised of humans with MS, and evaluated the effects of regular physical activity or exercise on pro-inflammatory, anti-inflammatory cytokines or adipokines. Two authors independently scanned titles and abstracts, and read the studies included. All studies were rated on the PEDro scale and further classified based on American Academy of Neurology criteria. RESULTS: Twelve studies were included of which 10 studies focused on cytokines, 1 study focused on adipokines, and 1 study included both cytokines and adipokines. The selected studies included 3 Class I studies, 7 Class II studies, and 2 Class IV studies and had average PEDro scores of 6.9 +/- 1.6. Studies included endurance (n = 5), resistance (n = 3), combined (n = 3), and vibration (n = 1) training. Overall, there is a general lack of standardization of procedures across studies and inconsistent evidence for the effects of physical activity and exercise on cytokine and adipokine profiles in MS, with a general pattern indicating a lack of effect. CONCLUSION: Research regarding the effects of exercise training on cytokines and adipokines in MS is in its infancy, but exercise represents an adjuvant therapy in MS, and future studies are essential for clarifying the role of exercise on cytokines and adipokines in MS. PMID- 29982112 TI - Psychometric properties of the Prolonged Grief Disorder-13 (PG-13) in bereaved Swedish parents. AB - This study aimed to validate the Swedish version of the Prolonged Grief Disorder 13 tool (PG-13) by examining its psychometric properties, including factor structure, discriminant and concurrent validity. The PG-13 was assessed in a sample of Swedish parents who had lost a child to cancer 1-5 years previously. The sample included 225 parents (133 mothers and 92 fathers) with a mean age of 46.02 years (SD = 8.15) and 16.0% met the criteria for Prolonged Grief Disorder (PGD). A principal component analysis was performed, and the results supported a one-factor structure of the PG-13. The PG-13 was shown to have high internal consistency and intelligible associations with concurrent psychological symptoms and grief rumination as well as with known risk factors for PGD. These results indicate satisfactory psychometric properties of the instrument, thus supporting the use of the PG-13 as a valid measure of PGD. PMID- 29982113 TI - Nanoparticle stripe sensor for highly sensitive and selective detection of mercury ions. AB - Mercury and its compounds are emitted during industrial processes and are extremely harmful for eco systems and human health. Therefore, the detection of mercury ions (Hg2+) in our living and working environment is of great importance for the society and especially for the health of human beings. Here we demonstrate a proof of concept nanoparticle stripe sensor for highly sensitive and selective detection of Hg2+. This sensor is based on the changes of the charge transport between the neighboring nanoparticles in the nanoparticle stripe. The addition of Hg2+ induces a chelation between Hg2+ and carboxylic groups on the surface modification molecules and thus facilitates the charge transport, causing an increase of conductivity in the nanoparticle stripe. These nanoparticle stripes with a few layers in height and several micrometers in width possess large surface area, which increases their exposure to ions and improves the ability to detect Hg2+ at low concentrations. Besides, we studied the effect of molecular length on the sensitivity of the sensor. It is shown that the length of surface modification molecules is positively correlated with the sensitivity of the sensor. The fabricated devices exhibit a detection limit as low as 0.1 nM and a specific response towards Hg2+ ions. PMID- 29982114 TI - A microfluidic electrochemical aptasensor for enrichment and detection of bisphenol A. AB - Bisphenol A (BPA) is an organic monomer used to make common consumer goods such as plastic containers, sports equipment, and cosmetics which are heavily produced worldwide. A growing interest has been drawn to general public as BPA is one of the major endocrine disrupting chemicals threating human health. To date, numerous BPA sensors have been attempted to be developed but important challenges still remained such as limited linearity range, easy to use, and long term response time. To address the present issues, a microfluidic channel should be integrated into an electrochemical aptasensor and it is called Geometrically Activated Surface Interaction (GASI) chip. The vigorous generation of the micro vortex in the GASI fluidic chamber provides the high collision chances between BPA and anti-BPA aptamer (BPAPT) and consequently more BPA molecules can be captured on the aptasensor surface, which finally results in high sensitivity of the aptasensor. To construct the integrated aptasensor, a miniaturized gold electrode is fabricated using shadow mask and e-beam evaporation process. Afterward, BPAPT is immobilized on a nanostructured gold electrode via thiol chemistry, and other terminus of the aptamer is labeled with a ferrocene (Fc) redox probe. Then, the microfluidic channel is mounted over the miniaturized gold electrode to introduce and enrich BPA to the aptasensor. Upon the specific interaction between BPA and its aptamer, configuration of aptamer is changed so that Fc tag approaches to the electrode surface and direct oxidation signal of Fc and BPA are followed as analytical signals. The unique microfluidic integrated electrochemical aptasensor delivers a wide linear dynamic range over 5 * 10-12 to 1 * 10-9 M, with a limit of detection 2 * 10-13 M. This aptasensor provides a precise platform for simple, selective and more importantly rapid detection of BPA. Such kind of sensing platforms can serve as a fertile ground for designing miniaturized portable sensors. PMID- 29982115 TI - The eLoaD platform endows centrifugal microfluidics with on-disc power and communication. AB - In this paper we present a comprehensive description of the design, fabrication and operation of an electrified Lab-on-a-Disc (eLoaD) system. The smart platform is developed to extend conventional Lab-on-a-Disc applications with an electronic interface, providing additional flow control and sensing capabilities to centrifugal microfluidics platforms. Wireless power is transferred from a Qi compliant transmitter to the eLoaD platform during rotation. An Arduino-based microcontroller, a Bluetooth communication module, and an on-board SD-card are integrated into the platform. This generalises the applicability of the eLoaD and its modules for performing a wide range of laboratory unit operations, procedures, or diagnostic assays, all controlled wirelessly during spinning. The lightweight platform is fully reusable and modular in design and construction. An interchangeable and non-disposable application disc is fitted with the necessary sensors and/or actuators for a specific assay or experiment to be performed. A particular advantage is the ability to continuously monitor and interact with LoaD experiments, overcoming the limitations of stroboscopy. We demonstrate the applicability of the platform for three sensing experiments involving optical, electrochemical, and temperature detection, and one actuation experiment involving controlled heating/cooling. The complete electronic designs and example programming codes are extensively documented in the supplementary material for easy adaptation. PMID- 29982116 TI - Homogeneous electrochemical aptasensor for mucin 1 detection based on exonuclease I-assisted target recycling amplification strategy. AB - A sensitive and homogeneous electrochemical aptasensor was fabricated for the detection of mucin 1 (MUC1) by combining a well-designed DNA bulge-loop (L-DNA) structure with high-efficient exonuclease I (Exo I)-assisted target recycling amplification strategy. The L-DNA probe was constructed via the hybridization of the MUC1 aptamer and methylene blue (MB) labeled complementary DNA (cDNA) (cDNA MB) and hence could not diffuse freely to the negatively charged ITO electrode surface due to the strong electrostatic repulsion, so small electrochemical signal was detected. The addition of MUC1 caused the dissociation of L-DNA structure due to the specificity between aptamer and MUC1. Then Exo I was implemented to digest the released cDNA-MB into mononucleotides and then produced short MB-labeled mononucleotides fragments (MB-MFs). As the MB-MFs contained few negative charges, it diffused easily to the negatively charged ITO electrode surface and resulted in the enhanced electrochemical signal. Meanwhile, the MUC1 aptamer complex was also specifically digested by Exo I, resulting in the liberation of MUC1 and hence realized the target recycling and then caused the amplification of the electrochemical signal. The enhanced electrochemical signal has a good linear relationship with logarithm of MUC1 concentration in the range of 1.0 pg mL-1-50 ng mL-1 with a limit of detection of 0.40 pg mL-1 (S/N = 3). Additionally, the fabricated aptasensor has been successfully applied to detect MUC1 in serum samples with satisfactory results and thereby it exhibits great potential in the practical application of clinical diagnosis. PMID- 29982117 TI - Magnetic force assisted electrochemical sensor for the detection of thrombin with aptamer-antibody sandwich formation. AB - A magnetic force assisted electrochemical aptamer-antibody sandwich assay (MESA) was developed for the detection of thrombin as a model protein in serum samples. The MESA using the formation of sandwich complexes on the electrochemical sensor probe for reaction and the removal of unbound bioconjugates from the sensor surface without washing are controlled by a magnetic field. Thrombin was determined by the cathodic currents of a toluidine blue O (TBO) attached with thrombin antibody modified magnetic nanoparticle (MNP) at the sensor surface. To detect thrombin in a serum sample, we applied a thrombin-specific aptamer as the capture molecule bound to the functionalized conducting polymer layer (poly (2,2':5',5"-terthiophene-3'-p-benzoic acid) (pTBA)), and streptavidin and starch coated-MNP was conjugated with biotinylated thrombin antibodies (Ab) and TBO as the bioconjugate (MNP@Ab-TBO). The characterization of MNP@Ab-TBO and sensor probe was performed using voltammetry, impedance spectroscopy, XPS, and UV-VIS spectroscopy. The experimental conditions were optimized in terms of pH, binding time, removal time of unbound bioconjugates, and applied potential. The dynamic ranges of thrombin were from 1.0 to 500 nM with detection limit of 0.49 ( +/- 0.06) nM. The recovery test demonstrates the reliability of the proposed sensing system for a handheld device. PMID- 29982118 TI - A novel electrochemical aptasensor for detection of aflatoxin M1 based on target induced immobilization of gold nanoparticles on the surface of electrode. AB - In this study, a novel electrochemical aptasensor was developed for detection of AFM1 aflatoxin M1 (AFM1) based on the hairpin-shaped structure of AFM1 aptamer (Apt), gold nanoparticles (AuNPs) and complementary strand of the aptamer (CS). The conformational change of hairpin structure of Apt in the presence and absence of AFM1 and also negatively charged AuNPs allowed detection of AFM1 with high sensitivity and selectivity. In the absence of the AFM1, the hairpin structure of the Apt was intact. So, a weak peak current was obtained. However, addition of AFM1 could disassemble the hairpin structure of the Apt. Thus, the CS-modified AuNPs came to close proximity of the surface of electrode and a strong current signal was recorded upon the addition of methylene blue as redox agent. The aptasensor allowed determination of AFM1 with a detection limit of 0.9 ng/L. Finally, the aptasensor was successfully applied for detection of AFM1 in real samples, including milk and serum samples. PMID- 29982119 TI - Integrated electrochemical Chip-on-Plant functional sensor for monitoring gene expression under stress. AB - The ability to interact with plants, both to sense and to actuate, would open new opportunities for precision agriculture. These interactions can be achieved by using the plant as part of the sensing system. The present work demonstrates real time monitoring of beta-glucuronidase (GUS) expression in transgenic tobacco plants using its activity as a biomarker for functional sensing. As "proof of concept", we demonstrated GUS enzyme biosensing under constitutive expression in Msk8 tomato cells and transgenic tobacco plants and in heat shock inducible BY2 tobacco cells and tobacco plants. The sensing was done using a three-electrode microchip in Msk8 or BY2 cell culture or in tobacco plant leaves. The electrode microchip was used to transduce the expression of the GUS enzyme by chronoamperometry to a measurable electrical current signal. For the constitutive expression of GUS in Msk8 cells, the system sensitivity was 0.076 mA/mM-cm2 and the limit of detection was 0.1 mM. For the heat shock inducible BY2 cells the GUS enzyme activity was detected 12-26 h after the heat shock was applied (40 degrees C for 2 h) using two different substrates: p-nitrophenyl-beta-glucuronide (with sensitivity of 0.051 mA/mM-cm2) and phenolphthalein-beta-glucuronide (with sensitivity of 0.029 mA/mM-cm2). PMID- 29982120 TI - Bioelectrocatalytic and electrochemical cascade for phosphate sensing with up to 6 electrons per analyte molecule. AB - Despite the availability of numerous electroanalytical methods for phosphate quantification, practical implementation in point-of-use sensing remains virtually nonexistent because of interferences from sample matrices or from atmospheric O2. In this work, phosphate determination is achieved by the purine nucleoside phosphorylase (PNP) catalyzed reaction of inosine and phosphate to produce hypoxanthine which is subsequently oxidized by xanthine oxidase (XOx), first to xanthine and then to uric acid. Both PNP and XOx are integrated in a redox active Os-complex modified polymer, which not only acts as supporting matrix for the bienzymatic system but also shuttles electrons from the hypoxanthine oxidation reaction to the electrode. The bienzymatic cascade in this second generation phosphate biosensor selectively delivers four electrons for each phosphate molecule present. We introduced an additional electrochemical process involving uric acid oxidation at the underlying electrode. This further enhances the anodic current (signal amplification) by two additional electrons per analyte molecule which mitigates the influence of electrochemical interferences from the sample matrix. Moreover, while the XOx catalyzed reaction is sensitive to O2, the uric acid production and therefore the delivery of electrons through the subsequent electrochemical process are independent of the presence of O2. Consequently, the electrochemical process counterbalances the O2 interferences, especially at low phosphate concentrations. Importantly, the electrochemical uric acid oxidation specifically reports on phosphate concentration since it originates from the product of the bienzymatic reactions. These advantageous properties make this bioelectrochemical-electrochemical cascade particularly promising for point-of-use phosphate measurements. PMID- 29982121 TI - Ultra-sensitive electrochemical detection of oxidative stress biomarker 8-hydroxy 2'-deoxyguanosine with poly (L-arginine)/graphene wrapped Au nanoparticles modified electrode. AB - An innovative electrochemical sensor assembly relying on a simple "green" electrochemical reduction route is presented for the sensitive detection of 8 hydroxy-2'-deoxyguanosine (8-OHdG), the most abundant oxidative product of DNA. The sensing film consisted of poly (L-arginine) and graphene wrapped Au nanoparticles was fabricated on glassy carbon electrode (GCE/P-Arg/ErGO-AuNPs) using subsequent 'layer-by-layer' regime through electrochemical technique. The proposed method was also successfully applied for the quantification of 8-OHdG in the presence of interfering biomolecules like ascorbic acid and uric acid. Scanning electron microscopy (SEM) was utilized to characterize the surface morphology of the composite electrode. Electrochemical characterizations of the bare and modified electrodes were carried out via cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). According to differential pulse voltammetry (DPV) results, there were linear relationships between the peak currents and the concentrations in the ranges of 1.0-100 nM (R2 = 0.996), and 0.5 10 uM (R2 = 0.990), with a detection limit (S/N = 3) of 1.0 nM. Furthermore, the proposed sensor was successfully applied for the determination of target analyte in human urine samples and a very high recovery percentage was obtained. PMID- 29982122 TI - Hierarchical hematite/TiO2 nanorod arrays coupled with responsive mesoporous silica nanomaterial for highly sensitive photoelectrochemical sensing. AB - The photoelectrochemical (PEC) technique has resulted in substantial progress in chemical sensing applications. However the complicated photoelectrode modification procedures would enable undesired background noise and decreasing sensitivity. Hence, it is important to explore a new approach alternative to inconvenient substrate modification. Herein, inspired by the stimuli-responsive drug delivery systems, an innovative PEC system is developed for efficiently microRNA-21 (miRNA-21) tracing. Hierarchical nanocomposites based on hematite (alpha-Fe2O3) coated self-ordered titanium dioxide nanorod arrays (TiO2 NRAs) exhibited enhanced response to solar light, promoted charge carrier separation and transfer efficiency was adopted as photoelectrode directly. Functional mesoporous silica nanomaterial (MSN) is prepared as nanocarriers for efficient loading of Cu2+, further capped with miRNA-21 responsive capture RNA probe. Thereafter, the capture RNA probe endows the functional MSN with responsiveness to miRNA-21. With the presence of miRNA-21, this system is thus triggered and a quickly release of capped Cu2+ occurs due to the dissociation of capture RNA probe presented on the MSN surface via base-pair hybridization. The released Cu2+ was then served as electron acceptor reduced to Cu degrees at the counter electrode to enhance electron-hole pair separation efficiency, leading to a promoted photocurrent response. Consequently, the miRNA-21 can be accurately quantified. Taking advantage of its sensitivity and specificity, this versatile strategy demonstrates a new route for the design PEC sensing approach without any photoelectrode modification procedure, and holds great potential for biosensing and clinical diagnosis. PMID- 29982123 TI - Sequentially multiplexed amperometry for electrochemical biosensors. AB - Multiplexed electrochemical biosensors are intriguing due to their capability to permit high-throughput and low-cost assays. While commercial single-chip potentiostats are one promising approach for rapidly prototyping portable and low cost electrochemical biosensors, it is still challenging to utilize them to achieve parallel multiplexing due to the limited resources integrated onto the chips. In this paper, we provide a methodology for incorporating multiplexing into commercial single-chip potentiostats by using a sequential architecture. In the sequential architecture, the multiplexed biosensors are interfaced to the single-chip potentiostat via single-pole single-throw switches, and the measurements alternate across the sensors. We build analytical and finite element models to investigate the behavior of the sensors, particularly when they are disconnected from the potentiostat, and find that we can take advantage of the dynamics of the sensors to achieve improved sensitivity over conventional chronoamperometry. We also investigate and compare different strategies to interface the multiplexed sensors to the single-chip potentiostat. Using the proposed multiplexing architecture, we demonstrate the implementation of 16-fold multiplexed amperometry, which is validated using ferricyanide measurement. Finally, the sequential multiplexing methodology is applied to a multiplexed bead based electronic enzyme-linked immunosorbent assays of human interleukin-6. PMID- 29982124 TI - A rapid readout for many single plasmonic nanoparticles using dark-field microscopy and digital color analysis. AB - The integration of plasmonic nanoparticles into biosensors has the potential to increase the sensitivity and dynamic range of detection, through the use of single nanoparticle assays. The analysis of the localized surface plasmon resonance (LSPR) of plasmonic nanoparticles has allowed the limit of detection of biosensors to move towards single molecules. However, due to complex equipment or slow analysis times, these technologies have not been implemented for point-of care detection. Herein, we demonstrate an advancement in LSPR analysis by presenting a technique, which utilizes an inexpensive CMOS-equipped digital camera and a dark-field microscope, that can analyse the lambdamax of over several thousand gold nanospheres in less than a second, without the use of a spectrometer. This improves the throughput of single particle spectral analysis by enabling more nanoparticles to be probed and in a much shorter time. This technique has been demonstrated through the detection of interleukin-6 through a core-satellite binding assay. We anticipate that this technique will aid in the development of high-throughput, multiplexed and point-of-care single nanoparticle biosensors. PMID- 29982125 TI - CLASP (Continuous lifestyle awareness through sweat platform): A novel sensor for simultaneous detection of alcohol and glucose from passive perspired sweat. AB - Wearable- IOT based low- cost platforms can enable dynamic lifestyle monitoring through enabling promising and exciting opportunities for wellness and chronic- disease management in personalized environments. Diabetic and pre- diabetic populations can modulate their alcohol intake by tracking their glycemic content continuously to prevent health risks through these platforms. We demonstrate the first technological proof of a combinatorial biosensor for continuous, dynamic monitoring of alcohol and glucose in ultra- low volumes (1-5 uL) of passive perspired sweat towards developing a wearable- IOT based platform. Non-invasive biosensing in sweat is achieved by a unique gold- zinc oxide (ZnO) thin film electrode stack fabricated on a flexible substrate suitable for wearable applications. The active ZnO sensing region is immobilized with enzyme complexes specific for the detection of alcohol and glucose through non- faradaic electrochemical impedance spectroscopy (EIS) and chronoamperometry (CA). Biomolecular interactions occurring at the electrode- sweat interface are represented by the impedance and capacitive current changes in response to charge modulations arising in the double layer. We also report the detection of alcohol concentrations of 0.01-100 mg/dl and glucose concentrations of 0.01-50 mg/dl present in synthetic sweat and perspired human sweat. The limit of detection obtained for alcohol and glucose was found to be 0.1 mg/dl in perspired human sweat. Cross- reactivity studies revealed that glucose and alcohol did not show any signal response to cross- reactive molecules. Furthermore, the stable temporal response of the combinatorial biosensor on continuous exposure to passive perspired human sweat spiked with alcohol and glucose over a 120-min duration was demonstrated. PMID- 29982126 TI - Evolving trends in bio/chemical sensor fabrication incorporating bimetallic nanoparticles. AB - Biosensor designing took a giant leap in its path of evolution after its merger with a wing of nanotechnology. Dramatic properties like high surface area to volume ratio, enhanced chemical and optical properties of nanoscale materials have revolutionized sensor technology in terms of their analytical performance. Many metallic nanoparticles (MeNPs) like gold, silver, platinum, palladium nanoparticles, etc. have been tremendously exploited for improving sensor performance. Over the years, there has been slow but steady shift in nanoscience research with an aim to explore composite MeNPs like bimetallic, trimetallic nanoparticles, etc. So far, these engineered nanoparticles are shown to possess multifunctional properties which are providing several advantages over monometallic nanoparticles (mono-NPs). As a result of these properties, composite MeNPs, particularly bimetallic nanoparticles (BNPs), have sought the attention of sensor engineers and since then there has been rapid rise in the number of reports of sensors incorporating BNPs within a brief period of time. Keeping this pivotal fact in consideration, we have complied this review to give readers a clear insight in the possible ways BNPs can be synthesized that would render them to possess crucial characteristics desired for bio/chemical sensor fabrication and their applications. We have also discussed different characterization techniques that have been applied to investigate various properties of the BNPs along with a table that gives information on how each technique is different and in what ways they complement each other. Moreover, a comprehensive report on the incorporation of different BNPs in sensor fabrication for detection of hydrogen peroxide (H2O2), glucose, pesticides, nucleic acids, proteins, cancerous and bacterial cells has been described. The comparison of analytical performance of the biosensor design incorporating mono-NPs and BNPs, in terms of linear range (LR), limit of detection (LOD), sensitivity, and specificity, has also been discussed to show the importance of BNPs in sensing matrix. PMID- 29982127 TI - A recyclable biointerface based on cross-linked branched DNA nanostructures for ultrasensitive nucleic acid detection. AB - The detection of specific nucleic acids is becoming increasingly important in the discovery of genetic diseases and clinical molecular diagnostics. Here we report a DNA nanostructure-based platform which enables a recyclable biointerface for ultra-sensitive detection of nucleic acid. We created a chemically cross-linked branched DNA nanostructure (CCLB-DNA) as the probe DNA to engineer the biointerfaces, thereby increasing probe distance, exposing more DNA probes from the interface into the solution phase, and thus enhancing the signal dramatically. In addition, DNA functionalized Fe3O4 nanoparticles were utilized for further signal amplification. The detection limit could go as low as 500 fM. Moreover, CCLB-DNA could endure denaturation conditions without disruption of duplex integrity; as a result, the recognition layer could be easily regenerated and the biointerface could be reused. Our CCLB-DNA represents an excellent prospect in the engineering of recyclable biointerface, which will be beneficial to many biosensing systems. PMID- 29982129 TI - Short- and long-term exposure to ambient air pollution and circulating biomarkers of inflammation in non-smokers: A hospital-based cohort study in South Korea. AB - Despite increasing epidemiological evidence of an association between air pollution and adverse health outcomes, the detailed mechanisms underlying the adverse effects of air pollution on medical conditions remain unclear. We evaluated the effects of short- and long-term exposure to ambient air pollution on key inflammatory markers in non-smoking subjects. Serum fibrinogen, C-reactive protein, ferritin, and white blood cell counts were repeatedly measured 3 times in 6589 subjects at the Samsung Medical Center (Seoul, South Korea) between 2010 and 2016. Both short- (<=8-day averages) and long-term (annual averages) exposure measures of 6 air pollutants (particles < 2.5 MUm, particles < 10 MUm, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide) were estimated for each subject based on available residential addresses. Linear mixed-effects models were used to relate interquartile range increases in pollutant concentrations to inflammatory marker levels. Short-term exposure to air pollution was associated with increased fibrinogen and ferritin levels. Long-term exposure to air pollution was associated with increased fibrinogen levels and white blood cell counts. The largest short- and long-term associations were observed for ferritin in response to nitrogen dioxide exposure (1.4%, 95% confidence interval [CI] 0.3 2.5) and fibrinogen exposed to particles < 2.5 MUm (3.4%, 95% CI 3.0-3.8), respectively. Significantly higher associations were observed among subjects with elevated levels of inflammatory markers (upper 25th percentile), including C reactive protein, and those with cardiac infarction, chronic obstructive pulmonary disease, cerebral infarction, or diabetes. We found clear associations between short- and long-term exposure to air pollution and inflammatory markers, especially among vulnerable subgroups. Our findings provide evidence in support of the hypothesis that air pollution increases systemic inflammation, particularly among susceptible subgroups. PMID- 29982128 TI - Multi-generational impacts of arsenic exposure on genome-wide DNA methylation and the implications for arsenic-induced skin lesions. AB - As a nonmutagenic human carcinogen, arsenic (As)'s carcinogenic activity is likely the result of epigenetic changes, particularly alterations in DNA methylation. While increasing studies indicate a potentially important role for timing of As exposure on DNA methylation patterns and the subsequent differential risks for As toxicity and carcinogenesis, there is a lack of research that tackles these critical questions, particularly in human based populations. Here we reported a family-based study including three generations, in which each generation living in the same household had a distinctive timing of As exposure: in adulthood, in utero and during early childhood, and in germlines exposure for grandparents, parents, and grandchildren, respectively. We generated genome-wide DNA methylation data for 18 As-exposed families, nine control families, as well as 18 arsenical skin lesion patients. Our analysis showed that As exposure may leave detectable DNA methylation changes even though exposure occurred decades ago, and the most significant changes of global DNA methylation were observed among patients afflicted with arsenical skin lesions. As exposure across generations shared common differentially methylated DNA loci and regions (744 DML and 15 DMRs) despite the distinctive exposure timing in each generation. Importantly, based on these DML, clustering analysis grouped skin lesion patients together with grandparents in exposed families in the same cluster, separated from grandparents in control families. Further analysis identified a number of DML and several molecular pathways that were significantly distinguished between controls, exposed populations, as well as skin lesion patients. Finally, our exploratory analysis suggested that some of these DML altered by As exposure, may have the potential to be inherited affecting not only those directly exposed but also later generations. Together, our results suggest that common DML and/or DMRs associated with an increased risk for disease development could be identified regardless of when exposure to As occurred during their life span, and thus may be able to serve as biomarkers for identifying individuals at risk for As-induced skin lesions and possible cancers. PMID- 29982130 TI - Corrigendum to "Associations between ambient air pollution and daily mortality in a cohort of congestive heart failure: Case-crossover and nested case-control analyses using a distributed lag nonlinear model" [Environ. Int. 133 (2018) 313 324]. PMID- 29982131 TI - (Eco)toxicological maps: A new risk assessment method integrating traditional and in silico tools and its application in the Ledra River (Italy). AB - Contaminants giving rise to emerging concern like pharmaceuticals, personal care products, pesticides and Endocrine Disrupting Chemicals (EDCs) have been detected in wastewaters, as reported in the literature, but little is known about their (eco)toxicological effects and consequent human health impact. The present study aimed at overcoming this lack of information through the use of in silico methods integrated with traditional toxicological risk analysis. This is part of a pilot project involving the management of wastewater treatment plants in the Ledra River basin (Italy). We obtained data to work up a global risk assessment method combining the evaluations of health risks to humans and ecological receptors from chemical contaminants found in this specific area. The (eco)toxicological risk is expressed by a single numerical value, permitting the comparison of different sampling sites and the evaluation of future environmental and technical interventions. PMID- 29982132 TI - Comparison of background parenchymal enhancement and fibroglandular density at breast magnetic resonance imaging between BRCA gene mutation carriers and non carriers. AB - OBJECTIVE: High background parenchymal enhancement and amount of fibroglandular tissue on breast magnetic resonance imaging are related to increased breast cancer risk. This study sought to compare these parameters between BRCA mutation carriers and non-carriers and to evaluate the potential implications of the findings for short term follow-up. MATERIALS AND METHODS: Magnetic resonance imaging studies of known BRCA mutation carriers, were compared to age-matched non carrier studies performed in the same center during the same period. The groups were compared for qualitative background parenchymal enhancement and amount of fibroglandular tissue using the Breast Imaging Reporting and Data System (BI RADS). RESULTS: Breast parenchymal enhancement was high in up to one-third of the cohort: 22% of carriers and 33% of controls (p = 0.013). These results were sustained on separate analysis of menstrual-cycle-timed examinations. Amount of fibroglandular tissue was high in most cases: 62% of carriers and 75% of controls (p = 0.004). A BI-RADS final assessment score of 3 was more common in patients with high parenchymal enhancement, especially controls. CONCLUSION: BRCA mutation carriers demonstrated lower levels of breast parenchymal enhancement and amount of fibroglandular tissue than age-matched non-carriers. These differences are probably influenced by hormonal status, as well as highlight different risks in distinctive subgroups of breast cancer (hormone-enriched, mutation-associated defective DNA damage repair), affecting considerations of preventive medical treatment. Differences in the indications for imaging between the carrier and non carrier groups (screening for mutations and breast cancer evaluation, respectively) probably accounted for the higher rate of BI-RADS 3 in the control group. PMID- 29982133 TI - Low-voltage (80-kVp) abdominopelvic computed tomography allows 60% contrast dose reduction in patients at risk of contrast-induced nephropathy. AB - PURPOSE: The purpose of this study was to evaluate the quality of image in abdominopelvic late phase computed tomography (CT) with a low tube voltage plus low dose contrast medium (CM) protocol (80-kVp, 60% CM). A compared with the conventional protocol (120-kVp, 100% CM) B in the same patients. MATERIAL AND METHODS: This study included with 22 patients {36 to 77 kg (mean: 55.5 kg)} who had renal insufficiency and had experience of performance conventional CT without renal insufficiency during pre-18 months. The CT value of the portal vein, liver parenchyma, abdominal aorta, psoas muscle was measured. The estimated mean CNR (contrast-to-noise ratios), FOM (figure of merit), DLP (dose length product) and ED (effective dose) were compared between protocol A and B. Moreover, two radiologists assessed the visual quality of the CT images. RESULTS: The mean DLP and ED in the protocol B was about 50% lower than that in the protocol A (p < 0.01). The mean CT value of the portal vein and abdominal aorta in the protocol B were significantly higher than that in the protocol A (p < 0.01). All of the FOM in the protocol B was significantly higher than that in the protocol A (p < 0.01). However, there was no significant difference in the mean CNR and visual quality between protocol A and B. CONCLUSION: Performance of abdominopelvic CT using a low tube voltage plus reduced CM dose (80-kVp, 60% CM) achieved reduction of the radiation dose without impairing image quality in relatively light weight group. CLINICAL RELEVANCE/APPLICATION: In abdominopelvic CT, protocol of low tube voltage (80-kVp) plus iodine dose reduction (60%) is able to provide the same quality of traditional protocols, also able to reducing radiation exposure (50%). PMID- 29982134 TI - Antral follicular count is a tool that may allow the selection of more precocious Bradford heifers at weaning. AB - Although antral follicle count is a repeatable parameter across life that is positively associated with fertility, its use at weaning as a tool to discard less fertile heifers has not been extensively evaluated. The hypotheses of this work are: 1) maximum antral follicle count (MAFC) is repeatable between weaning and pre breeding evaluations, allowing selection of more fertile heifers at an early age, 2) heifers with high MAFC have growth and development parameters linked to an earlier puberty and pregnancy, 3) MAFC has a positive correlation with AMH concentrations, so that both could be used inter changeably. In this study, Hereford (n = 42 and n = 50) and Braford (n = 40 and n = 50) females were used in years 1 and 2; respectively, in a completely randomized experimental design. Heifers were examined for five to ten days at two different moments (post weaning and pre service), to determine MAFC. The concentrations of Anti mullerian hormone (AMH) were evaluated on the day of MAFC assessment. Growth and development parameters were evaluated post weaning and pre service. The repeatability of MAFC between post weaning and pre service evaluations was poor in three cases (Hereford Year 1 = 0.36 and 2 = 0.39 and Braford, Year 2 = 0.32) but it was high for Braford in Year 2 (0.72). The AMH repeatability between post weaning and pre service evaluations was high in one case (Braford Year 2 = 0.72) and moderate in the others (Year 1, Hereford = 0.50 and Braford = 0.52 and Year 2, Hereford = 0.50). In Year 2, Braford heifers with greater MAFC attained puberty at an earlier age (r2 = 0.129; P = 0.0196). Also, diminished MAFC corresponded with decreased growth and development, thus less Braford heifers with low MAFC were inseminated (2/16), compared to those with medium (12/17) and high MAFC (7/17; P < 0.01). Moreover, Braford heifers with low AFC had less progesterone in the cycle post insemination but pregnancy rate was not affected. In Braford heifers in Year 2, there was a high correlation between MAFC and AMH concentrations (0.85 P < 0.001). The results of these experiments indicate that post weaning MAFC and AMH concentrations may be applied to select those Braford heifers that attain puberty at an early age, but these tools are not useful in Hereford heifers. PMID- 29982135 TI - Identification of biomarker candidates for fertility in spermatozoa of crossbred bulls through comparative proteomics. AB - Associations between expression of some proteins in spermatozoa and fertility have been sought in recent years to identify the male fertility markers. Since the incidence of sub-fertility is high in crossbred bulls, the present investigation was carried out on high- and low-fertile crossbred bulls to identify fertility markers in spermatozoa through proteomics approach. Sperm proteome of high-fertile bulls were compared with low-fertile bulls using 2D-DIGE and MALDI-TOF-MS techniques and the results were validated with immuno-blotting. The proteins MDH2, ENO1, RIBC1, CAPN7, ATP5D, LacA like protein-2 like, NCAPD3, DECR1, GCNT2, GDI2, TOP and USP12 were over expressed in high-fertile spermatozoa, whereas DST like isoform 1, TMEM43 and BSP1 were over expressed in low-fertile spermatozoa (P < 0.05). The differential expression ranged from 1.57 (GDI2) to 5.1 (BSP1) fold between the two groups. Based on the GO annotation, majority of them were involved in cellular and metabolic processes, with catalytic and binding activities, and localized in cell and organelles. Among these proteins, ENO1 and BSP1 were selected based on the degree of differential expression and reliability in identification, for further validation. Immuno blotting studies indicated that ENO1expression was positively correlated (P < 0.05) while the expression of BSP1 was negatively (P < 0.01) correlated with bull fertility. The proportion of capacitated spermatozoa in frozen thawed spermatozoa of low-fertile bulls was higher (P < 0.05) as compared to high-fertile bulls. Collectively, the study identified some potential molecules in spermatozoa of bulls, which may act as a panel of biomarkers for fertility. PMID- 29982136 TI - A new, simple and efficient liquid nitrogen free method to cryopreserve mouse spermatozoa at -80 degrees C. AB - The mouse is widely used for biomedical research and an increasing number of genetically altered models are currently generated, therefore centralized repositories are essentials to secure the important mouse strains that have been developed. We have previously reported that spermatozoa of wild type and mutant strains frozen using standard laboratory protocols can be transported in dry ice (-79 degrees C) for 7 days and safely stored in a -80 degrees C freezer for up to two years. The objective of this new study was to compare the effects of the freezing techniques using LN2 or -80 degrees C freezer on fertility of frozen thawed mouse spermatozoa. After thawing, sperm fertility was comparable (P > 0,05) between the LN2 and the -80 degrees C samples for at least 1 year. Furthermore, we showed that it is possible to freeze and store mouse semen directly at -80 degrees C and eventually transfer it to LN2 irrespective of storage time. This study is relevant because it shows for the first time that mouse spermatozoa can be efficiently frozen and stored at -80 degrees C with no use of liquid nitrogen for a long period of time. A new, simple, efficient and flexible, liquid nitrogen free, method was developed for freezing and maintaining spermatozoa of wild type and mutant C57BL/6N lines. Lines on this genetic background are used in collaborative research infrastructures for systematic phenotyping, e.g. the International Mouse Phenotyping Consortium (IMPC) and therefore largely cryopreserved in repositories like EMMA/Infrafrontier. The importance of this finding will be especially useful for small laboratories with no or limited access to liquid nitrogen and for laboratories generating many mouse mutant lines by CRISPR/Cas9 who do not want to saturate the limited space of a LN2 tank, using a more accessible -80 degrees C freezer. This study underlines, once more, that mouse spermatozoa are very resistant and can be frozen, transported, shared and stored at -80 degrees C for a long time without a significant loss of viability. This new approach simplifies the freezing process and facilitates the long term storage of mouse spermatozoa at -80 degrees C, always allowing the transfer to LN2 for indefinite storage without noticeable detrimental effects. PMID- 29982137 TI - Analysis of alternative splicing events by RNA sequencing in the ovaries of Xiang pig at estrous and diestrous. AB - Alternative splicing (AS) is an important mechanism for controlling gene expression, which regulates multiple biological processes in higher organisms. Chinese indigenous Xiang pig has distinctive biological characteristics, such as small size, early sexual maturity, lower litter size and not very clear exhibition of estrous behaviors. To further understand how AS responds to estrous cycles in Xiang pig, the genome-wide analysis of AS events was performed by RNA seq method in Xiang pig ovaries at diestrous and estrous. Using ASprofile program, we analyzed twelve basic AS events in Xiang pig ovaries and identified 68,775 AS events in 15,142 genes from diestrous ovaries and 69,493 AS events in 15,291 genes from the estrous ovaries with average 4.54 splicing events. 94.4 95.5% of expressed genes underwent alternative splicing in this tissues. The frequencies of AS events were similar to each other at diestrous and estrous. Transcription start site (TSS) was the predominant type of AS events, followed by transcription terminal site (TTS), and skipped exon (SKIP). The remaining type of AS events, e.g., intron retention (IR) and alternative exon ends (AE), showed the lower frequencies. Further comparison analysis of gene expression indicated that 4,433 genes had at least one splice variant differentially expressed during estrous, whereas only 2,382 of them were differentially expressed at gene level. Numerous genes involved in gonad development and hormone metabolism were differentially regulated through AS. Twelve genes with different types of alternatively splicing were validated by using RT-PCR method. The GO annotation and KEGG pathway analysis clearly revealed that a lot of DEGs (differentially expressed genes) and DSGs (differentially spliced genes) were involved in follicular development and ovarian steroid biosynthesis. A large number of DSGs, although not differentially expressed, were enriched in circadian rhythm and several signaling pathways. These pathways potentially regulated the female animal reproductive function in gene and/or AS level. Our results suggested that alternative splicing play an essential role in regulation of gene expression in female pigs during estrous. Numerous genes involved in gonad development, hormone metabolism, circadian rhythm were differentially regulated through alternative splicing. PMID- 29982138 TI - Is electroejaculation a safe procedure in cats? An endoscopic and histological prospective blinded study. AB - Transrectal electrostimulation is a technique used for semen collection in several animals including felids, but also in humans with spinal cord injuries and in specific cases of anejaculation. To the authors' knowledge, safety and innocuity on rectal mucosa has not yet been assessed histologically. A prospective study was performed on 10 European cats in order to determine the impact of electroejaculation on the rectal mucosa, by performing endoscopic and histological evaluation of the rectal mucosa. Endoscopic evaluation was performed before and after semen collection. Standardized biopsy specimens were collected immediately after semen collection, on the site of electrostimulation and on the proximal part of the descending colon as a control, for further double-blinded histopathological evaluation. The degree of inflammation was evaluated following the criteria from the WSAVA Gastrointestinal Standardization Group. Semen collection by electrostimulation did not induce significant histological and endoscopic lesions. Electrostimulation may therefore be considered as a safe technique to collect semen in cats. PMID- 29982139 TI - Influence of GnRH supplementation at CIDR removal on estrus expression and interval to estrus in beef cattle. AB - Previous research has indicated that multiple small doses of GnRH following CIDR removal increased circulating concentrations of estradiol. Therefore, our objective was to determine if a single small dose of GnRH (5 MUg or 10 MUg) at CIDR removal would impact expression of estrus and/or interval to estrus. Beef cows and heifers (n = 1620; n = 1057 cows, n = 563 heifers) were synchronized using the 7-day CO-Synch + CIDR protocol, and randomly assigned to one of three treatments (0, 5, or 10 MUg of a GnRH analog at CIDR removal). Animals were inseminated following detection in estrus. Interval to estrus was calculated for each animal that exhibited estrus (INTERVAL 1). Animals that did not exhibit estrus were administered 100 MUg of GnRH at the time of AI and their interval to estrus was designated at 120 h (INTERVAL 2). There was a treatment by age interaction (P = 0.05) on INTERVAL 1. Heifers treated with 5 MUg of GnRH tended to have a shorter interval to estrus (P = 0.07; 47 +/- 1.4 h) compared to 0 MUg (50 +/- 1.5 h) and did have a shorter interval compared to 10 MUg (P < 0.01; 52 +/- 1.5 h). There were no differences between treatments in interval to estrus among cows (P > 0.34). When animals that did not exhibit estrus by 120 h were included in the analysis there was no treatment by age interaction (P = 0.49). This is likely due to the fact that treatment (P < 0.01), but not age (P = 0.96) or treatment by age (P = 0.74) influenced expression of estrus. In addition, there tended to be a treatment by estrus interaction (P = 0.08) on pregnancy success. There was no difference in pregnancy success between treatments among animals that exhibited estrus (P > 0.30). In summary, 5 MUg of GnRH at CIDR removal tended to decrease the interval to estrus and increased expression of estrus among heifers but not cows, and 10 MUg of GnRH at CIDR removal did not improve estrus expression and lengthened the interval to estrus in comparison to the control. PMID- 29982140 TI - Antimicrobial peptide expression in swine granulosa cells in response to lipopolysaccharide. AB - Antimicrobial peptides (AMP) are host defense peptides present in all species examined. The objective of the current study was to characterize the expression of a group of antimicrobial peptides in ovarian cells, and to investigate their expression response to pathogen ligands. It was found that while PG1 transcript was not detected in the ovary, the expression of BD2 is the highest in small follicle derived granulosa cells (SGC), and its expression decreases during follicular development to large follicle stage (LGC; p < 0.05). The expression of BD2 in cumulus cells also decreased from GV to MII stage of oocyte maturation. ANG4 expression increased in granulosa cells during follicular development from SGC to LGC stage (p < 0.05), although no significant difference was observed in cumulus cells from different stages of oocyte maturation. We further examined AMP expression in follicle cells treated with different toll-like receptor (TLR) ligands which mimic pathogen exposure in the ovary. Of the four TLR ligands examined, lipopolysaccharide (LPS) exposure resulted in a 11.5 fold increase of BD2 expression, and a significant decrease of LYZ in LGC. A similar response pattern in BD2 and LYZ expression was also observed in SGC. These responses of AMP expression to LPS are associated with increased TLR4 signaling pathway component in mRNA and protein level, such as MyD88 and NFkB, and pro-inflammatory cytokines/chemokines, such as IL-6, TNFalpha and IL-8 (p < 0.05). Our data suggest that AMPs may play a role in innate defense as well as other physiological functions during ovarian follicular development and oocyte maturation. PMID- 29982141 TI - Characterization and cryopreservation of Amur leopard cats (Prionailurus bengalensis euptilurus) semen collected by urethral catheterization. AB - The Amur leopard cat (Prionailurus bengalensis euptilurus) is a globally endangered species, and there is thus an urgent need to increase its population. The objectives of this study were to: (1) confirm the utility of urethral catheterization (UC) for semen collection from Amur leopard cats; (2) investigate proper dilution media for fresh semen; and (3) investigate the effectiveness of sperm cryopreservation, including examining the effect of glycerol concentration. Six adult males in captivity (mean weight 5.03 +/- 0.44 kg, aged 2-6 years) were included. All study procedures were performed during the breeding season (February to April) over two consecutive years. Semen samples (n = 28) were collected four or five times from each animal (four times for two animals and five times for four animals) by UC under general anaesthesia, and their characteristics (including sperm motility) were evaluated. First, the sperm motility in semen diluted in Ham's F-10 or phosphate buffer saline (PBS) was compared. Next, semen diluted with TEST-yolk buffer containing 2%, 4%, or 6% glycerol was frozen in a liquid nitrogen tank, and sperm motility and acrosome integrity were evaluated after thawing. No difference in motility was observed between sperm diluted in Ham's F-10 and PBS. The percentages of sperm motility and kinetic values in semen frozen in 2% or 4% glycerol were higher than those in semen stored in 6% glycerol. In conclusion, the UC method for semen collection is recommendable for Amur leopard cats and should be useful for artificial insemination. Although sperm motility decreased after thawing, samples thus preserved may be usable for advanced reproductive techniques, such as intracytoplasmic sperm injection or in-vitro fertilization. PMID- 29982142 TI - Adipose tissue fatty acid composition and cognitive impairment. AB - OBJECTIVE: The aim of this study was to examine the association among adipose tissue eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and the ratios of EPA to AA and DHA to AA with impaired cognitive function. METHODS: This cross-sectional analysis comprised 481 men participating in the Cohort of Swedish Men-Clinical and for whom adipose tissue fatty acid composition and results from a telephone-based cognitive test were available. Impaired cognitive function was defined using a predefined cutoff on the cognitive test. Binomial log-linear regression models were used to estimate prevalence ratios. In secondary analyses, Cox proportional hazards models were used to estimate relative risk for incident dementia ascertained by linkage with population-based registers. RESULTS: We observed a graded reduction in the prevalence of impaired cognitive function across tertiles of adipose tissue EPA/AA- ratio (Ptrend = 0.01); compared with the lowest tertile, the multivariable-adjusted prevalence ratios were, respectively, 0.89 (95% confidence interval [CI], 0.67-1.17) and 0.64 (95% CI, 0.45-0.91) for the second and third tertiles. EPA, DHA, and the DHA/AA ratio showed similar patterns of association; however, the CIs included the null. AA alone was not associated with impaired cognitive function. Although with lower precision, estimates obtained from the prospective analysis were broadly consistent with the main analysis. CONCLUSIONS: Findings from this study suggest that a high ratio of EPA to AA in adipose tissue may be associated with better cognitive function. A similar association was observed with EPA, DHA, and the ratio of DHA to AA, but the results did not exclude a null association. PMID- 29982143 TI - Modulatory effects of taurine on metabolic and oxidative stress parameters in a mice model of muscle overuse. AB - OBJECTIVE: The aim of this study was to investigate the regulatory effects of taurine on the biochemical parameters of muscle injury by overuse. METHODS: Male Swiss mice were divided into four groups: control (Ctrl), overuse (Ov), taurine (Tau), and overuse plus taurine (OvTau). High-intensity exercise sessions were administered for 21 d with concomitant subcutaneous injections of taurine (150 mg/kg). The mice were then sacrificed. The quadriceps muscles were surgically removed for subsequent histologic analysis and evaluation of mitochondrial function, oxidative stress parameters, tissue repair, and DNA damage markers. RESULTS: The Ov group showed significant differences compared with the Ctrl group (all P <0.05). The fiber area decreased by 49.34%, whereas the centralized nuclei contents (Ctrl = 1.33%; Ov = 28.67%), membrane potential (Ctrlsuc = 179.05 arbitrary fluorescence units (AFUs), Ctrlsuc+ADP = 198.11 AFUs; Ovsuc = 482.95 AFUs, Ovsuc+ADP = 461.6 AFUs), complex I activity (Ctrl = 20.45 nmol ? min ? mg protein, Ov = 45.25 nmol ? min ? mg protein), hydrogen peroxide (Ctrlsuc = 1.08 relative fluorescence unit (RFU) ? sec ? mg protein, Ctrlsuc+ADP = 0.23 RFU ? sec ? mg protein; Ovsuc = 5.02 RFU ? sec ? mg protein, Ovsuc+ADP = 0.26 RFU ? sec ? mg protein) and malondialdehyde (Ctrl = 0.03 nmol ? mg ? protein, Ov = 0.06 nmol ? mg ? protein) levels, and DNA damage (Ctrlfreq = 7.17%, Ovfreq = 31.17%; Ctrlindex = 4.17, Ovindex = 72.5) were increased. Taurine administration reduced the number of centralized nuclei (OvTau = 5%), hydrogen peroxide levels (OvTausuc = 2.81 RFU ? sec ? mg protein, OvTaussuc+ADP = 1.54 RFU ? sec ? mg protein), membrane potential (OvTausuc = 220.18 AFUs, OvTaussuc+ADP = 235.28 AFUs), lipid peroxidation (OvTau = 0.02 nmol/mg protein), and DNA damage (OvTaufreq = 21.33%, OvTauindex = 47.83) and increased the fiber area by 54% (all P <0.05). CONCLUSION: Taken together, these data suggest that taurine supplementation modulates various cellular remodeling parameters after overuse-induced muscle damage, and that these positive effects may be related to its antioxidant capacity. PMID- 29982144 TI - Protective effect of the riboflavin-overproducing strain Lactobacillus plantarum CRL2130 on intestinal mucositis in mice. AB - OBJECTIVES: Intestinal mucositis (IM) is a local inflammatory response that causes alterations of the intestinal structure that in turn affect nutrient absorption and a side effect that is commonly associated with cancer treatments. Lactobacillus plantarum CRL2130 is a riboflavin-overproducing strain that has previously been shown to provide antiinflammatory properties. The objective of this study was to evaluate the effects of this riboflavin-producing strain in a chemically induced murine mucositis model. METHODS: Mucositis was induced by daily injections of 5-fluororacil (5-FU) after which mice were either given L. plantarum CRL2130, CRL725 (strain from which CRL2130 was derived that does not overproduce riboflavin), or commercial riboflavin twice daily during 6 d of chemotherapy agent injections. The effect of the strains and riboflavin was also evaluated in vitro using Caco-2 intestinal cancer cell cultures to determine if they interfere with 5-FU's anticancer activity. RESULTS: The administration of L. plantarum CRL2130 significantly attenuated the pathologic changes induced by 5-FU in mice such as body weight loss, diarrhea, shortening of villus height, increases in proinflammatory cytokine concentrations, and elevated production of interleukin 10. In vitro assays using Caco-2 cells showed that the effectiveness of 5-FU was not affected by L. plantarum CRL2130 and that this strain exerted an inhibitory mechanism against oxidative stress. CONCLUSIONS: These results indicate that the riboflavin-overproducing strain L. plantarum CRL2130 could be useful to prevent mucositis during cancer treatments and would not affect the primary treatment. PMID- 29982146 TI - Exploring the association between polycyclic aromatic hydrocarbons and diabetes among adults in the United States. AB - OBJECTIVE: To explore the association between polycyclic aromatic hydrocarbons (PAHs) and diabetes and to determine whether effects are heterogeneous when examined by body mass index (BMI). METHODS: Cross-sectional data from 8664 participants were analyzed from the National Health and Nutrition Examination Survey for years 2005-2014. Multivariable logistic regression was used to explore the association between urinary biomarkers of PAHs and diabetes. All models were adjusted for age, sex, race, poverty-income ratio, and serum cotinine. RESULTS: When compared with the lowest quintiles of exposure, the highest quintiles of exposure to 2-hydroxynaphthalene, 2-hydroxyfluorene, 9-hydroxyfluorene, 2 hydroxyphenanthrene, and a summed variable of all low molecular weight PAHs (aOR = 1.73; 95% CI: 1.17-2.55) showed a positive association with diabetes. Stratified analyses by BMI indicated that the positive association between PAHs and diabetes was found among both normal weight and obese participants. CONCLUSIONS: High levels of exposure to PAHs are positively associated with diabetes in the U.S. general population and these effects are modified by BMI. These findings suggest the importance of strong environmental regulation of PAHs to protect population health. PMID- 29982147 TI - Short-and medium-term associations of particle number concentration with cardiovascular markers in a Puerto Rican cohort. AB - Air pollution has been linked to adverse cardiovascular outcomes; however, susceptibility may vary by population. Puerto Rican adults living in the US may be a susceptible group due to a high rate of adverse cardiovascular events. We evaluated the effect of changes in ambient particle number concentration (PNC, a measure of ultrafine particles) and effects on biomarkers of cardiovascular risk in the Boston Puerto Rican Health Study (BPRHS), a longitudinal cohort (n = 1499). Ambient PNC was measured at a fixed site between 2004 and 2013 and daily mean concentrations were used to construct PNC metrics, including lags of 0, 1 and 2 days and moving averages (MAs) of 3, 7 and 28 days. We examined the association of each metric with C-reactive protein (CRP) and blood pressure. Each model included subject-specific random intercepts to account for multiple measurements. An interquartile range (IQR) increase in PNC was associated with CRP for all metrics, notably a 3-day increase in PNC was associated with a 7.1% (95% CI: 2.0%, 12.2%) increase in CRP. Significant associations with CRP were seen in women, but not men; with current and former (but not non-) smokers; participants younger (but not older) than 65 y; those without diabetes (but not with), and those with (but not without), hypertension. Our study extends knowledge about the health effects of air pollution to a vulnerable population that has been understudied. PMID- 29982148 TI - Chronic toxicity of nanodiamonds can disturb development and reproduction of Acheta domesticus L. AB - : The use of nanodiamonds in numerous materials designed for industry and medicine is growing rapidly. Consequently health and environmental risks associated with the exposure of humans and other biota to nanodiamonds-based materials are of the utmost importance. Scarcity of toxicological data for these particles led us to examine the potentially deleterious effects of nanodiamonds in model insect species, Acheta domesticus (Orthoptera) chronically exposed to ND in its diet. Organism-level end-point indices (lifespan, body weight, consumption, caloric value of faeces, reproduction) revealed adverse changes in the treated crickets in comparison with the control. Preliminary studies of oxidative stress level in the offspring of ND-treated crickets suggest toxicity of these particles limited to the exposed individuals. EPR analysis showing increase of radical signal in the faeces of ND-fed crickets led us to propose novel mechanism of nanodiamonds toxicity that is discussed in the light of literature data. CAPSULE: Development and reproduction of Acheta domesticus can be disturbed by the chronic exposure to nanodiamonds. PMID- 29982149 TI - Assessment of heat- and cold-related emergency department visits in cities of China and Australia: Population vulnerability and attributable burden. AB - BACKGROUND: Non-optimal ambient temperature has detrimental impacts on mortality worldwide, but little is known about the difference in population vulnerability to non-optimal temperature and temperature-related morbidity burden between developing and developed countries. OBJECTIVES: We estimated and compared the associations of emergency department visits (EDV) with non-optimal temperature in terms of risk trigger temperature, the average slope of exposure-risk function and attributable risk in 12 cities from China and Australia. METHODS: We modelled the associations of EDV with heat during warm season and with cold during cold season, separately, using generalized additive model. Population vulnerability within a given region was quantified with multiple risk trigger points including minimum risk temperature, increasing risk temperature and excessive risk temperature, and average coefficient of exposure-risk function. Fraction of EDV attributable to heat and cold was also calculated. RESULTS: We found large between- and within-country contrasts in the identified multiple risk trigger temperatures, with higher heat and cold trigger points, except excessive risk temperature, observed in Australia than in China. Heat was associated with a relative risk (RR) of 1.009 [95% confidence interval (CI):1.007, 1.011] in China, which accounted for 5.9% of EDV. Higher RR of heat was observed in Australia (1.014, 95% CI: 1.010, 1.018), responsible for 4.0% of EDV. For cold effects, the RR was similar between two countries, but the attributable fraction was higher in China (9.6%) than in Australia (1.5%). CONCLUSIONS: Exposure to heat and cold had adverse but divergent impacts on EDV in China and Australia. Further mitigation policy efforts incorporating region-specific population vulnerability to temperature impacts are necessary in both countries. PMID- 29982150 TI - Association between exposure to desalinated sea water and ischemic heart disease, diabetes mellitus and colorectal cancer; A population-based study in Israel. AB - BACKGROUND: Drinking water (DW) is an important dietary source of magnesium. Recently, Israel has increased its use of desalinated seawater (DSW) as DW country-wide. Its negligible magnesium content, however, raises concern that consumption of DSW may be associated with hypomagnesemia and increase the risk of ischemic heart disease (IHD), diabetes mellitus (DM), and colorectal cancer (CRC). OBJECTIVES: We tested whether there was a change in incidence of negative health outcomes (IHD, DM, and CRC) following the introduction of DSW supply in a population-based ecologic study in Israel. METHODS: A historical prospective analysis was applied to members aged 25-76 during 2004-2013 of Clalit Health Services (Clalit), the largest healthcare provider in Israel, using its electronic medical record database. Multivariable analyses were adjusted for age, sex, socioeconomic status, smoking status, and body mass index. RESULTS: An increased odds ratio was found for IHD (0.96, 95% CI 0.93-0.99 at baseline and 1.06, 95% CI 1.02-1.11 at the end of the follow-up period), but no time trend was observed. CONCLUSIONS: We found that the risk for IHD increased during the study period. The risks for DM and CRC were unchanged. Long term studies are needed for assessing the risk for CRC due to the long latency. The higher risk for IHD has practical public health implications and raise the need to add magnesium to DSW. PMID- 29982145 TI - Association of proinflammatory diet with low-grade inflammation: results from the Moli-sani study. AB - OBJECTIVES: The association between diet and inflammation is well documented. Yet, no evidence exists on the relationship between the inflammatory potential of the diet and low-grade inflammation (LGI) as measured by a composite score of plasma and cellular biomarkers. The aim of this study was to assess the association between the Dietary Inflammatory Index (DII(r)) and LGI in a large population-based cohort. METHODS: Cross-sectional analyses were conducted on data from 20 823 adults (age >=35 y; 48% male) without acute inflammation, who were recruited within the general population of the Moli-sani study from 2005 to 2010. LGI was measured by using a composite score (INFLA-score) including platelet and leukocyte counts, the granulocyte to lymphocyte ratio, and C-reactive protein. DII scores were computed based on dietary intake assessed by the EPIC food frequency questionnaire. Multivariable linear regression models were fit to produce adjusted regression coefficients and 95% confidence intervals (CIs). RESULTS: Higher DII scores were associated with increased LGI (beta = 0.131; 95% CI, 0.089-0.174 for the highest versus lowest quintile of DII) after adjusting for age, sex, lifestyle, prevalence of chronic diseases, and health conditions. A higher DII score also was positively associated with each single biomarker of inflammation included in the INFLA-score, unhealthy behaviors (smoking, sedentary lifestyle), and insulin. CONCLUSIONS: Higher DII scores, indicating greater inflammatory potential of the diet, were directly associated with LGI, as measured by a composite score of plasma and cellular biomarkers of inflammation. These findings are consistent with the contributing role of diet-mediated inflammation in increasing risk for inflammation-related chronic diseases. PMID- 29982151 TI - The health benefits of the great outdoors: A systematic review and meta-analysis of greenspace exposure and health outcomes. AB - BACKGROUND: The health benefits of greenspaces have demanded the attention of policymakers since the 1800s. Although much evidence suggests greenspace exposure is beneficial for health, there exists no systematic review and meta-analysis to synthesise and quantify the impact of greenspace on a wide range of health outcomes. OBJECTIVE: To quantify evidence of the impact of greenspace on a wide range of health outcomes. METHODS: We searched five online databases and reference lists up to January 2017. Studies satisfying a priori eligibility criteria were evaluated independently by two authors. RESULTS: We included 103 observational and 40 interventional studies investigating ~100 health outcomes. Meta-analysis results showed increased greenspace exposure was associated with decreased salivary cortisol -0.05 (95% CI -0.07, -0.04), heart rate -2.57 (95% CI -4.30, -0.83), diastolic blood pressure -1.97 (95% CI -3.45, -0.19), HDL cholesterol -0.03 (95% CI -0.05, <-0.01), low frequency heart rate variability (HRV) -0.06 (95% CI -0.08, -0.03) and increased high frequency HRV 91.87 (95% CI 50.92, 132.82), as well as decreased risk of preterm birth 0.87 (95% CI 0.80, 0.94), type II diabetes 0.72 (95% CI 0.61, 0.85), all-cause mortality 0.69 (95% CI 0.55, 0.87), small size for gestational age 0.81 (95% CI 0.76, 0.86), cardiovascular mortality 0.84 (95% CI 0.76, 0.93), and an increased incidence of good self-reported health 1.12 (95% CI 1.05, 1.19). Incidence of stroke, hypertension, dyslipidaemia, asthma, and coronary heart disease were reduced. For several non-pooled health outcomes, between 66.7% and 100% of studies showed health-denoting associations with increased greenspace exposure including neurological and cancer-related outcomes, and respiratory mortality. CONCLUSIONS: Greenspace exposure is associated with numerous health benefits in intervention and observational studies. These results are indicative of a beneficial influence of greenspace on a wide range of health outcomes. However several meta-analyses results are limited by poor study quality and high levels of heterogeneity. Green prescriptions involving greenspace use may have substantial benefits. Our findings should encourage practitioners and policymakers to give due regard to how they can create, maintain, and improve existing accessible greenspaces in deprived areas. Furthermore the development of strategies and interventions for the utilisation of such greenspaces by those who stand to benefit the most. PMID- 29982152 TI - Legionella pneumophila recurrently isolated in a Spanish hospital: Two years of antimicrobial resistance surveillance. AB - OBJECTIVES: The aim of this study was to monitor the spread, persistence and antibiotic resistance patterns of Legionella spp. strains found in a hospital water distribution system. These environmental studies are intended to help detect the presence of antibiotic resistant strains before they infect patients. METHODS: Antimicrobial surveillance tests were performed at 27 different sampling points of the water network of a large Spanish hospital over two years. Water samples were screened for Legionella according to ISO 11731:2007. Legionella spp. isolates were identified by serotyping and by mass spectrometry (MALDI-ToF). Epidemiological molecular typing was done by Pulse-Field Gel Electrophoresis (PFGE) and by Sequence-Based Typing (SBT). Antibiotic susceptibility tests were performed using disk diffusion and ETEST(r). RESULTS: Legionella spp. were recurrently isolated for 2 years. All isolates belonged the same group, L. pneumophila serogroups 2-14. Isolates were all attributed by SBT to sequence type (ST) ST328, although PFGE revealed 5 different patterns. No significant change in antibiotic susceptibility could be observed for this study period, irrespectively of the method used. CONCLUSION: Colonization of water systems by Legionella spp. is still occurring, although all the prevention rules were strictly followed. Antibiotic resistance monitoring may help us to find resistance in bacteria with environmental reservoirs but difficult to isolate from patients. The knowledge of the antibiotic susceptibility in environmental strains may help us to predict changes in clinical strains. This study might also help reconsidering Legionnaires' disease (LD) diagnostic methods. L. pneumophila serogroups 2-14 present all along the time of the investigation in the water distribution system can cause LD. However, they may not be detected by routine urine tests run on patients, thereby missing an ongoing LD infection. PMID- 29982153 TI - Comments on "Structural, optical and electrical properties of Zr-doped In2O3 thin films" by C. Manoharan, M. Jothibas, S. Johnson Jeyakumar, S. Dhanapandian published in Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 145 (2015) 47-53. PMID- 29982154 TI - A novel chromone and rhodamine derivative as fluorescent probe for the detection of Zn(II) and Al(III) based on two different mechanisms. AB - In this study, a novel fluorescent probe, 6-hydroxychromone-3-carbaldehyde (rhodamine B carbonyl) hydrazine (L), for Zn2+ and Al3+ was designed and synthesized. Initially, this probe L exhibited inferior fluorescence emission peak centered at 488 nm in EtOH/HEPES solution (3/1, 10.0 MUM HEPES, pH 7.4) when excited at 421 nm. After the addition of Zn2+, this probe L displayed excellent selectivity towards Zn2+ with obvious fluorescence color change from colorless to yellow, which might be attributed to the formation of a 1:1 ligand-metal complex resulting in the inhibition of photo-induced electron transfer phenomenon. Whereas, the prepared Zn2+ complex of L could be used as a ratiometric fluorescent probe to detect Al3+ on the basis of fluorescence resonance energy transfer mechanism. This ligand-metal complex of Zn2+ (LZn) showed high selectivity towards Al3+ with obvious enhancement in fluorescence emission intensity at 580 nm and remarkable decrease in fluorescence emission intensity at 488 nm, and the fluorescence color also changed from yellow to pink. Furthermore, the detection limit of the probe L, LZn towards Zn2+, Al3+ were 1.25 * 10-7 M and 3.179 * 10-6 M, respectively. Additionally, the complexation properties of L towards Zn2+ and LZn towards Al3+ were studied in detail. PMID- 29982155 TI - Insight into the interaction of human serum albumin with folic acid: A biophysical study. AB - Folic acid (FA) is a water soluble bioactive food constituent from the vitamin B family complex (B9). FA deficiency can lead to a variety of human health problems, while a high intake of FA can reduce the cytotoxicity of natural killer cells. The main goal of this study was to investigate the interaction of FA with human serum albumin (HSA) at physiological pH using ATR-FTIR, fluorescence spectroscopy, cyclic voltammetry and electrochemical impedance spectroscopy in order to understand the role of HSA as a blood transporter for FA in aqueous solution that can be used in different therapies. The quenching of HSA in the presence of FA was followed and the binding constant (Kb) was determined. The variation of electrochemical parameters proved that the FA binds to immobilized HSA and the binding constant was ten times than the value obtained when the interaction takes place between free molecules in solution when studied by fluorescence quenching. The results can be used in future studies to improve drug delivery systems or cellular uptake of folic acid and food components conjugated to HSA nanoparticles or nanocapsules. PMID- 29982156 TI - Dual-functional probe based on rhodamine for sequential Cu2+ and ATP detection in vivo. AB - A rhodamine-based fluorescent probe for Cu2+ and ATP has been designed. The fluorescence intensity/absorbance was significantly enhanced upon the addition of Cu2+ owning to the opening of the spiro-ring of rhodamine, which quickly returned to the original level due to the reconstruction of the probe by the reacting with ATP. Cu2+/ATP-induced fluorescent intensity/aborbance changes showed a good linear relationship with the concentration of Cu2+/ATP in the range of 2-20 MUM/0 10 MUM with a detection limit of 0.1 MUM/1.0 MUM. The proposed method is simple in design and fast in operation, and is suitable for the reversible monitoring of Cu2+ and ATP in bioanalytical applications. PMID- 29982157 TI - Structures of aniline(pyrrole)+, aniline(ethanol)+, and aniline-(benzene). AB - Molecular structures of aniline(pyrrole)+, aniline(ethanol)+, and aniline(benzene)+ produced via resonance two-photon ionization at 266 nm were analyzed by infrared predissociation spectroscopy coupled with tandem mass spectrometry. Structural optimization and frequency calculation using density functional theory were carried out to suggest the most probable isomers which are in good agreement with the observed infrared absorption spectra. Intermolecular bonds in the cluster ions were formed such that the electronegative oxygen atom of the solvent molecule or the pi electron of the aromatic ring forms a hydrogen bonding to NH of aniline. PMID- 29982158 TI - Development of mini-spectrophotometer for determination of plasma glucose. AB - This work demonstrates a novel compact spectrophotometer, "Mini spectrophotometer", designed for plasma glucose detection. Unlike conventional spectrophotometer, a light source of the mini spectrophotometer is replaced by a light-emitting diode (LED), and a fabricated polymer-based microwell is used as a cuvette. To validate the downsizing spectrophotometer prototype, the efficiency and reliability for glucose determination are investigated. Using a certain light intensified from LED, the within-run precision of mini-spectrophotometer is found to be 3.9-8.4% while the between-run precision is 6.7-10.8%. The linearity for the quantification of glucose was up to 500 mg dL-1 and the recovery 99.1 +/- 3.4% is obtained. The sensitive and selective detection of glucose has been observed; with limit of detection (LOD) of 13.5 mg dL-1 and limit of quantification (LOQ) of 46.2 mg dL-1, respectively. Hemoglobin and triglyceride at high concentration slightly interferes with the proposed instrument. From comparative studies, there are no significant differences between the glucose concentration measured by mini-spectrophotometer and Shimadzu (r2 = 0.9862) or CECIL spectrophotometer (r2 = 0.9853). Using Passing-Bablok regression analysis, the results obtained from mini-spectrophotometer are in close agreement with the two conventional spectrophotometers. Furthermore, using microwell, the sample volume and reagent used in the process can be reduced. The in-house developed mini-spectrophotometer is capable of detecting plasma glucose while maintaining a compact system, demonstrating the potential of high performance, cost-effective, and portable spectrophotometer for clinical chemistry analysis in small routine, research, and teaching medical laboratory technologist. PMID- 29982159 TI - Derivative synchronous spectrofluorimetry: Application to the analysis of two binary mixtures containing codeine in dosage forms. AB - Two binary mixtures containing codeine (COD) with either ibuprofen (IBU), mixture 1, or with phenylephrine hydrochloride (PE), mixture 2, were analyzed using three simple eco-friendly spectrofluorimetric methods without the need to a prior separation step. The first method is derivative emission spectrofluorimetry using lambdaex = 236 nm and 275 nm for mixtures 1 and 2, respectively. The second method is constant-wavelength synchronous spectrofluorimetry using ?lambda = 100 nm and 60 nm for mixtures 1 and 2, respectively. The last method is constant energy synchronous spectrofluorimetry where a wave number interval of -7000 cm-1 was used for the analysis of the two binary mixtures. All measurements were performed in acetate buffer pH 5 and thus no toxic volatile solvents were used increasing method greenness. High sensitivity was attained for the three studied drugs where the lower limits of quantitation of COD, IBU and PE reached 0.064, 0.512 and 0.087 MUg/mL, respectively. Analysis of the two binary mixtures in their tablet and liquid dosage forms was performed with good accuracy and precision using the developed methods. The results of the proposed and reported methods were statistically evaluated using one-way ANOVA test and no significant difference among them was obtained. In addition, all aspects of ICH guidelines on analytical method validation were conducted. PMID- 29982160 TI - Optical properties and antiangiogenic activity of a chalcone derivate. AB - Chalcones and their derivatives exhibit numerous pharmacological activities such as antibacterial, antifungal, cytotoxic, antinociceptive and anti-inflammatory. Recently, they have been assessed aiming for novel application in nonlinear optics and in the treatment of immune diseases and cancers. In this study, we investigate the optical properties of synthetic chalcona 1E,4E-1-(4-chlorophenyl) 5-(2,6,6-trimethylcyclohexen-1-yl)penta-1,4-dien-3-one (CAB7beta) and its antiangiogenic potential using the chorioallantoic membrane (CAM) with the S180 sarcoma cell line. Experimental and theoretical results show intense absorption in the UVA-UVC region, which is associated with a pi -> pi* transition with intramolecular charge transfer from the trimethyl-cyclohexen-1-yl ring to the chlorophenyl ring. Quantum chemical calculations of the first hyperpolarizability, accounting for both solvent and frequency dispersion effects, are in very good concordance with hyper-Rayleigh scattering measurements. In addition, two-photon absorption allowed band centered at 650 nm was observed. Concerning antiangiogenic activity, CAB7beta causes a significant reduction in the total number, junctions, length and caliber of blood vessels stimulated by S180 cells reducing the presence of blood vessels, inflammatory cells and others elements related to angiogenic process. It is found that CAB7beta is a versatile compound and a promising candidate for linear and nonlinear optical applications, in therapy against sarcoma and phototherapy. PMID- 29982161 TI - Temperature dependent time resolved mid-IR photoacoustic spectroscopy of a nerve gas simulant DMMP. AB - The paper reports the temperature dependent pulsed photoacoustic spectroscopy of Dimethyl methylphosphonate (DMMP) a nerve gas simulant between 50 and 180 degrees C temperature range. The time domain PA spectra are recorded using two mid-IR wavelengths i.e. 3374 nm, 3495 nm of pulse duration 1.5 ns at 1 kHz repetition rate obtained from optical parametric oscillator. Two anti-symmetric stretching vibrational modes of (CH3P) and (CH3O) groups of DMMP molecules have very strong vibrational peaks at 2861.2 cm-1 (3495 nm) and 2963.8 cm-1 (3374 nm), respectively. In addition, we have also recorded the PA spectra of acetone at the vibrational frequency 3115.2 cm-1 (3210 nm), which is the strong vibrational mode of CH band. The comparison of two PA spectra of DMMP and acetone recorded using similar PA cavity help us to understand the effect of other functional groups with respect to different excitation wavelengths. The presence of additional acoustic modes in the PA spectra of DMMP (3374 nm) above the boiling point confirms the slow process of thermal decomposition. Finally, the low level detection limit of DMMP in air is of the of the order of 0.91 ppbV. PMID- 29982162 TI - New enhanced spectrofluorimetric approach for picogram detection of Fenoterol hydrobromide through Von Pechman synthesis of coumarins. AB - A new, specific, precise and very sensitive spectrofluorimetric methodology has been established and approved for determination of Fenoterol hydrobromide (FEN) in its pharmaceutical forms and spiked plasma. The strategy utilized the phenolic nature of FEN and its capacity to undergo Von Pechman synthesis of coumarin. In this study, Fenoterol hydrobromide reacts with ethyl acetoacetate in presence of concentrated sulfuric acid to form an extremely fluorescent coumarin derivative measured at 480 nm (lambdaex: 420 nm). Different reaction variables affecting development and stability of the formed coumarin derivative were precisely examined and enhanced to guarantee greatest sensitivity of the strategy. The recommended procedure was found to obey Beer's law in concentration range of (300 2000) pg mL-1 with quantitation limit 130 pg mL-1, revealing high sensitivity of the suggested method. The proposed procedure was completely examined and approved through the ICH guidelines and was efficiently applied for the determination of the cited drug in spiked plasma and its dosage forms. PMID- 29982163 TI - Spectroscopic and molecular modelling studies on glycation modified bovine serum albumin with cyanidin-3-O-glucoside. AB - In this study, we report the glycation mediated effect of bovine serum albumin (BSA) on the molecular interaction mechanism of cyanidin-3-O-glucoside (C3G) by molecular modelling, Uv-visible spectroscopy, transmission electron microscopy (TEM), fluorescence spectroscopy, and circular dichroism spectroscopy studies. The structures of advanced glycation end-products (AGEs) modified BSA were modelled, energy minimized and analyzed for binding affinity by molecular docking studies using Autodock Vina. Glycation experiments are carried out using glucose and methylglyoxal to validate the molecular modelling results on the interaction of modified BSA with C3G. The modified structures were characterized by reduction in the binding pocket volume, surface, depth, hydrophobicity, and hydrogen bond donors/acceptors. Arg-194, Arg-196, Arg-198, Arg-217, Arg-409, Lys-114, Lys-116, Lys-204, Lys 221, and Lys-439 were found to be crucial in the context of glycation of BSA. TEM images represented the formation of unique globular aggregates in the event of glycation. Uv-visible spectroscopic studies showed the formation of new chromophores between 300 and 400 nm in the event of glycation. Fluorescence quenching was observed in a differential manner in the presence of C3G on glycation modified BSA. Circular dichroism studies suggested the loss of helical structure and formation of beta-sheeted structure upon glycation, but subsequent C3G binding has resulted in the increase towards helical structure. Our findings suggested that drug binding affinity has been certainly impaired due to glycation and subsequent AGE modification. Arg-p modification has more austere impact on the structure and would affect the binding properties. We conclude that C3G had differential modulation of binding properties on glycated BSA which can help to protect the stability and bioavailability that has been impaired due to glycation mediated structural changes. PMID- 29982164 TI - The role of the transient receptor potential melastatin5 (TRPM5) channels in the pancreatic beta-cell electrical activity: A computational modeling study. AB - The TRPM5 channels are transient receptor potential channels whose presence in the human pancreatic beta-cell has been confirmed. The sensitivity of these channels to membrane voltage, temperature and intracellular calcium concentration and their possible role in insulin secretion has made them a focal point in research in the past decade. While experimental researches have confirmed the role of the TRPM5 channels in insulin secretion, but the underlying mechanism is still unclear. In this study, based on the experimental results of other studies, a mathematical description of the TRPM5 channel activity has been proposed which correlates the TRPM5 electrical activity to the voltage and intracellular calcium concentration. The resulting expression has been added to the existing mathematical model of the human beta-cell and the enhanced model has been used for investigating the effect of the TRPM5 channel on the beta-cell electrical activity. The results of our study show that the TRPM5 influences other ion channel activities through speeding up membrane depolarization. In addition, we have shown that the TRPM5 increases the amplitude and firing rate of action potentials by possibly affecting the Na+ and gamma-Aminobutyric acid related currents. The results also confirm the prominent effect of the TRPM5 channels in glucose-stimulated condition. PMID- 29982165 TI - Molecular dynamics study of TMPA mediated dissociation of Nur77-LKB1 complex. AB - LKB1 protein is involved in the regulation of cell polarity by phosphorylating the AMPK under energetic stress conditions. LKB1 protein is expressed in both cytoplasm and nucleus. In the nucleus, LKB1 interacts with orphan nuclear receptor protein Nur77. It is reported that the interaction of LKB1 with Nur77 is disrupted by the small molecular ligand TMPA (ethyl 2-[2,3,4-trimethoxy-6-(1 octanoyl)phenyl]acetate), such that the LKB1 is enabled to play its role in cytoplasm and further to regulate/reduce the blood glucose level. In the present study, atomistic molecular dynamics simulations are performed to understand the dissociation mechanism of Nur77-LKB1 complex. The present study reveals that TMPAs induce an open-close motion of Nur77 which further decrease the stability of Nur77-LKB1 complex. As a consequence, the interface region in LKB1-Nur77 complex is more exposed for solvation and further releases the interactions existing between Nur77 and LKB1. Altogether, this study explains the TMPAs mediated Nur77-LKB1 complex dissociation. PMID- 29982166 TI - Computational study of FaEXPA1, a strawberry alpha expansin protein, through molecular modeling and molecular dynamics simulation studies. AB - Changes in the cellulose-hemicellulose fraction take place during ripening of strawberry fruit and are associated with the activity of a set of proteins and hydrolytic enzymes. Expansins are proteins located in the cell wall with no catalytic activity. In this context, FaEXPA1 was previously reported to have a high accumulation rate during fruit ripening in three different strawberry cultivars. In order to understand at the molecular level the expansin mechanism mode, a 3D model of FaEXPA1 protein was built by comparative modeling. FaEXPA1 protein model displayed two domains, a cellulose-binding domain with a beta sandwich structure, and a second domain that included a HFD motif with a similar structure to the catalytic core of endoglucanase V from Humicola insolens. Additionally, in the center of the structure, an open groove was formed. Finally, using a cellulose polymer as a ligand, the protein-ligand interaction was evaluated by molecular dynamic (MD) simulation. Two MD simulations showed that FaEXPA1 can interact with cellulose via the flat aromatic surface of its binding domain D2, composed mainly of residues Trp99 and Trp225. In addition, FaEXPA1 formed a high number of hydrogen bonds with the glycan chain and the Asn81, Phe114 and Asn211 residues. PMID- 29982167 TI - Coloured Hybrid Petri Nets: An adaptable modelling approach for multi-scale biological networks. AB - Coloured Petri nets are an excellent choice for exploring large biological models, particularly when there are repetitions of components. Such models can be easily adapted by slight modifications of parameter values related to colours. Similarly, multi-scale models could involve multiple spatial scales in addition to multiple time scales. Thus, they require the full interplay between stochastic as well as deterministic processes. In this paper we take these two aspects into account and present a modelling and simulation approach for multi-scale biochemical networks using Coloured Generalised Hybrid Petri Nets (GHPNC). GHPNC are a Petri net class that associates colours to Generalised Hybrid Petri Nets (GHPN), which incorporate discrete and continuous places in addition to stochastic and continuous transitions. Moreover, we present two case studies to illustrate typical applications taking advantage of such a Petri net class. PMID- 29982168 TI - Deciphering transcriptome profiles of tetraploid Artemisia annua plants with high artemisinin content. AB - To investigate on the effects of autopolyploidization on growth and artemisinin biosynthesis in Artemisia annua, we performed a comprehensive transcriptomic characterization of diploid and induced autotetraploid A. annua. The polyploidization treatment not only enhanced photosynthetic capacity and endogenous contents of indole-3-acetic acid (IAA), abscisic acid (ABA) and jasmonic acid (JA), oxidative stress, but increased the average level of artemisinin in tetraploids from 42.0 to 63.6%. The obvious phenotypic alterations in tetraploids were observed including shorter stems, larger size of stomata and glandular secretory trichomes (GSTs), larger leaves, more branches and roots. A total of 8763 (8.85%) differentially expressed genes (DEGs) were identified in autotetraploids and mainly involved in carbohydrate metabolic processes, cell wall organization and defense responses. Both the up-regulated expression of DNA methylation unigenes and enhanced level of DNA methylation in autotetraploids indicated a possible role of DNA methylation on transcriptomic remodeling and phenotypic alteration. The up-regulated genes were enriched in response to extracellular protein biosynthesis, photosynthesis and hormone stimulus for cell enlargement and phenotypic alteration. The genomic shock induced by chromosome duplication stimulated the expression of transcripts related to oxidative stress, biosynthesis and signal transduction of ABA and JA, and key enzymes in artemisinin biosynthetic pathway, leading to the increased accumulation of artemisinin. This is the first transcriptomic research that identifies DEGs involved in the polyploidization of A. annua. The results provide novel information for understanding the complexity of polyploidization and for further identification of the factors and genes involve in artemisinin biosynthesis. PMID- 29982169 TI - Genotypic and environmental effects on the level of ascorbic acid, phenolic compounds and related gene expression during pineapple fruit development and ripening. AB - Pineapple (Ananas comosus (L.) Merr.) is a non-climacteric tropical fruit whose ripening could be accompanied by oxidative processes and the concurrent activation of enzymatic and non-enzymatic reactive oxygen species (ROS) scavenging systems. To better understand the variability of these processes among climatic environments or genotypes in pineapple, the temporal expression dynamics for genes encoding oxidative and antioxidative stress enzymes were analyzed by real-time RT-PCR during fruit development and ripening, among three cultivars: Queen Victoria, Flhoran 41 and MD-2 hybrid, and in two climatic areas. Pineapple development and ripening involved changes in the levels of transcripts encoding for polyphenol oxidase and transcripts involved in the first steps of the phenylpropanoid pathway and in the balance of ROS, especially those encoding for ascorbate peroxydase and metallothioneins, regardless of the cultivar. Our results confirm the same dynamic in gene expression from the two environmental crop areas, however climatic conditions influenced the level of the expression of the major transcripts studied that were linked to these oxidative and antioxidant metabolisms. MT3a and MT3b transcripts were not influenced by genetic factor. The genetic effect was not significant on the various transcripts linked to the first steps of the phenylpropanoid pathway and to phenol oxidation, except 4CL ones. In ripe pineapple, highly significant relationships were found between the contents in antioxidant metabolites, i.e., ascorbic acid and total phenolic compounds, and the transcript levels of genes involved in the enzymatic ROS-scavenging system and in the biosynthesis or regeneration of ROS-scavenging compounds, like phenylpropanoids, ascorbic acid, metallothioneins. PMID- 29982170 TI - Water stress alleviation by polyamines and phenolic compounds in Scrophularia striata is mediated by NO and H2O2. AB - Plants respond to water stress through a variety of mechanisms, depending on metabolites preferences and their available resources. This work was performed to elucidate the cross-talk between signaling molecules (polyamines (PAs), hydrogen peroxide (H2O2) and nitric oxide (NO)), phenolic compounds and osmolytes (phenylethanoid glycosides (PhGs), phenolic acids, flavonoids, soluble sugars and amino acids) under water stress in Scrophularia striata plants. The results revealed that PAs, NO levels were enhanced in the plants, earlier in response to polyethylene glycol-induced water stress. The antioxidative mechanisms with increased activity of catalase (CAT), guaiacol peroxidase (GPX) and superoxide dismutase (SOD) and also phenylalanine ammonia-lyase (PAL), tyrosine ammonia lyase (TAL), as key enzymes in phenolic pathway were deployed in response to the stress. Mannose, glucose, xylose/rhamnose which are involved in PhGs biosynthesis as well as in serving osmotic adjustment were modulated. The elevated content of arginine and methionine as PAs precursors and tyrosine and phenylalanine as PhGs precursors was enhanced by water stress and was significantly associated with PAs and PhGs accumulations. Metabolic profiling revealed new information about relationship between stress signal molecules; PAs, NO and H2O2, osmolytes (sugers, PhGs) and phenolic compounds which involved in the improvement of water stress tolerance in S. striata. PMID- 29982171 TI - Zinc oxide nanoparticles (ZnO NP) mediated regulation of bacosides biosynthesis and transcriptional correlation of HMG-CoA reductase gene in suspension culture of Bacopa monnieri. AB - Bacopa monnieri (L.) Wettst. is a well documented nootropic plant, extensive known for alleviating symptoms of neurological disorder, along with other symptomatic relief. This property is attributed to the active phytocompounds, saponins (bacoside A) present in the plant. However, lack of stringent validation guidelines in most of the countries bring to the market, formulations differing in phytocompounds yield, thereby suggesting possible variation in therapeutic efficacy. The in-vitro suspension cultures of the Bacopa monnieri, provide an ease of scale-up, but regulating saponin yield is a stringent task. The aim of the study is to explore the effects of different concentrations (0, 0.25, 0.50, 0.75 and 1.0 ppm) of zinc oxide nanoparticles (ZnO NP) (24 nm in size), in regulating growth rate, bacoside yield and transcriptional profile of HMG CoA reductasegene in the suspension cells of Bacopa monnieri. Results showed a linear correlation between Bacoside A yield and ZnO NP concentrations with around 2 fold increase in total bacoside A concentration at 1 ppm. Also, ZnO NP supplemented suspension cells showed variation in the specific growth rate. Neuroprotective properties, analyzed using methanolic extracts of suspension cells again obtrude the extract of ZnO NP supplemented (0.75 ppm and 1 ppm) culture for better response in alleviating oxidative stress mediated damage to neuronal cells. ZnO NP supplemented system showed lower expression of HMG CoA reductasegene (the rate limiting step in bacoside A biosynthesis) but higher concentration of bacoside A, suggesting possible role of ZnO NP in isoprenoid pathway than MVA pathways. PMID- 29982172 TI - Is mid-upper arm circumference in Dutch children useful in identifying obesity? AB - BACKGROUND: Mid-upper arm circumference (MUAC) is suggested as being a valid measure in detecting overweight/obesity in children and adolescents, due to the strong relation with weight. We examined this relation and compared MUAC to body mass index (BMI) according to the International Obesity Task Force (IOTF) in children. METHODS: Anthropometric data including MUAC were collected in 2009 by trained healthcare professionals in the context of the fifth Dutch Nationwide Growth Study, in a sample of 6167 children (2891 boys and 3276 girls) aged 2-18 years of Dutch origin. We propose MUAC SDS cut-off values for overweight and obesity, and compared MUAC with BMI IOTF in sex-specific and age-specific categories (2-5, 6-11, 12-18 years). RESULTS: The area under the curve is used as a measure of diagnostic accuracy; the explained variance (R2) is good to excellent (0.88-0.94). Sensitivity ranges from 51.8% to 95.3% and specificity from 71.4% to 93.8%. Across age and gender groups, 65.1% to 89.0% participants are classified by both MUAC and BMI as normal weight, overweight or obese. We constructed three equations to predict weight using MUAC, with small differences between observed and predicted weight with an explained variance ranging from 0.88 to 0.94. CONCLUSIONS: Compared with BMI, MUAC is a valid measure for detecting overweight and obesity and thus a good alternative for BMI. When weight has to be estimated, it can be accurately predicted using MUAC. Based on our observations, we recommend developing diagrams with international (IOTF) cut-offs for MUAC SDS similar to BMI. PMID- 29982173 TI - Multiplex PCR reveals a high prevalence of multiple pathogens in traveller's diarrhoea in children. AB - OBJECTIVE: Traveller's diarrhoea (TD) is one of the most frequent illnesses affecting children returning from tropical countries. The purpose of this study was to assess the distribution of pathogens associated with TD in children using a multiplex PCR assay on stool samples. DESIGN: All the children admitted for TD in two university hospitals from 1 August to 15October during 2014 and 2015 were included in a prospective study. Stool samples were tested by a multiplex PCR FilmArray GI panel detecting 22 pathogens. Performances for the detection of major enteropathogenic bacteria (Salmonella, Shigella and Campylobacter spp) by multiplex PCR and conventional culture methods were compared. The prevalence of extended spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae was also determined. RESULTS: Fifty-nine children were included. In 58 cases (98%), at least one pathogen was identified, including 9 different enteropathogenic bacteria, 5 viruses and 2 parasites. Multiplex PCR enhanced the enteropathogenic bacteria detection by 25%. The most frequent pathogens were enteroaggregative Escherichia coli (n=32), enteropathogenic E. coli (n=26), enterotoxigenic E. coli (n=19), Salmonella enterica, enteroinvasive E. coli/Shigella (n=16 each), Cryptosporidium, sapovirus (n=11 each), Campylobacter jejuni, norovirus (n=10 each), rotavirus (n=9), Giardia (n=8) and Shiga-toxin-producing E. coli (n=4). Fifty-two coinfections were observed, notably including bacteria and viruses (n=21), multiple bacteria (n=14), or bacteria and parasites (n=10). ESBL were detected in 28 cases. Multiplex PCR could optimise the number of treated patients by 27% compared with stool cultures. CONCLUSION: Multiplex PCR on stools revealed a high prevalence of diverse enteric pathogens and coinfections in children with TD. Major enteropathogenic bacteria were more frequently detected by multiplex PCR compared with conventional culture. Finally, this technique allows the start of appropriate and early antibiotic treatment and seems to optimise the number of correctly treated patients. PMID- 29982174 TI - Fair, just and compassionate: A pilot for making allocation decisions for patients requesting experimental drugs outside of clinical trials. AB - Patients have received experimental pharmaceuticals outside of clinical trials for decades. There are no industry-wide best practices, and many companies that have granted compassionate use, or 'preapproval', access to their investigational products have done so without fanfare and without divulging the process or grounds on which decisions were made. The number of compassionate use requests has increased over time. Driving the demand are new treatments for serious unmet medical needs; patient advocacy groups pressing for access to emerging treatments; internet platforms enabling broad awareness of compelling cases or novel drugs and a lack of trust among some that the pharmaceutical industry and/or the FDA have patients' best interests in mind. High-profile cases in the media have highlighted the gap between patient expectations for compassionate use and company utilisation of fair processes to adjudicate requests. With many pharmaceutical manufacturers, patient groups, healthcare providers and policy analysts unhappy with the inequities of the status quo, fairer and more ethical management of compassionate use requests was needed. This paper reports on a novel collaboration between a pharmaceutical company and an academic medical ethics department that led to the formation of the Compassionate Use Advisory Committee (CompAC). Comprising medical experts, bioethicists and patient representatives, CompAC established an ethical framework for the allocation of a scarce investigational oncology agent to single patients requesting non-trial access. This is the first account of how the committee was formed and how it built an ethical framework and put it into practice. PMID- 29982175 TI - 'Depletion of the susceptibles' taught through a story, a table and basic arithmetic. PMID- 29982177 TI - Catheterisation of a persistent left superior vena cava. AB - We present a case of a 62-year-old woman with end-stage renal disease who displayed a persistent left superior vena cava detected following placement of haemodialysis catheter through the left internal jugular vein (IJV). The diagnosis was confirmed by left internal jugular vein cathetogram, computed tomography (CT) thorax and transthoracic echocardiography. The catheter was removed without immediate complications. She remained well during the outpatient follow-up. PMID- 29982176 TI - Respiratory failure caused by lipoid pneumonia from vaping e-cigarettes. AB - A young female vaper presented with insidious onset cough, progressive dyspnoea on exertion, fever, night sweats and was in respiratory failure when admitted to hospital. Clinical examination was unremarkable. Haematological tests revealed only thrombocytopenia, which was long standing, and her biochemical and inflammatory markers were normal. Chest radiograph and high-resolution CT showed diffuse ground-glass infiltrates with reticulation. She was initially treated with empirical steroids and there was improvement in her oxygenation, which facilitated further tests. Since the bronchoscopy and high-volume lavage was unyielding, a video-assisted thoracoscopicsurgical biopsy was done later and was suggestive of lipoid pneumonia. The only source of lipid was the vegetable glycerine found in e-cigarette (EC). Despite our advice to quit vaping, she continued to use EC with different flavours and there is not much improvement in her clinical and spirometric parameters. PMID- 29982178 TI - Atypical presentation of cat scratch disease: Parinaud's oculoglandular syndrome with facial nerve paresis. AB - A 28-year-old man presented to our clinic over the course of 3 weeks with symptoms that progressed from mild headaches to fever, fatigue, myalgia and an enlarged right preauricular lymph node with ipsilateral conjunctivitis and upper eyelid weakness. Our differential included Epstein Barr Virus/Cytomegalovirus mononucleosis, bacterial conjunctivitis and lymphoma. We evaluated with CBC, EBV IgM Ab, lactate dehydrogenase level and a CMV IgG Ab which were all within normal limits. During his third visit, we discovered our patient had been scratched by two stray kittens he had adopted 2 months prior. We confirmed the diagnosis with a positive Bartonella henselae IgG level and diagnosed him with cat scratch disease presenting as Parinaud's oculoglandular syndrome. He was treated with a 5 day course of Azithromycin 250 mg with definitive improvement. PMID- 29982179 TI - MRI diagnosis of megarectum in pregnant women. PMID- 29982180 TI - Arterial fragility in kyphoscoliotic Ehlers-Danlos syndrome. AB - Pathogenic variants in the lysyl-hydroxylase-1 gene (PLOD1) are responsible for the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS). The disease is classically responsible for severe hypotonia at birth, progressive kyphoscoliosis, generalised joint hypermobility and scleral fragility. Arterial fragility is an important feature of the disease, but its characterisation remains limited. We report the clinical history of a 41-year-old woman who presented repeated arterial accidents, which occurred in previously normal medium size arteries within a limited time span of 2 years. Molecular investigations revealed compound heterozygosity for two PLOD1 gene deletions of exons 11-12 and 14-15. Arterial fragility is an important characteristic of kyphoscoliotic EDS. It manifests as spontaneous arterial rupture, dissections and dissecting aneurysms which may occur even during early childhood. This fragility is particularly likely to manifest during surgical intervention. Early medical management and surveillance may be indicated, but its modalities remain to be defined. PMID- 29982181 TI - Plane palsy: a case of transient facial weakness during an aircraft flight. AB - Changes in atmospheric pressure have been reported to cause a transient lower motor neuron weakness of the facial nerve. We report the case of a passenger on an international flight who developed a unilateral facial weakness after take-off which resolved within 45 min. The effect is thought to be due to an ischaemic neuropraxia of the facial nerve caused by increased middle ear pressure compressing the facial nerve in an exposed facial canal. The condition has been commonly reported in scuba-divers but less frequently in airline passengers. Treatment is not necessary. PMID- 29982182 TI - IgG4-related disease coexisting with autoimmune haemolytic anaemia. AB - An 85-year-old man presented with a pale appearance and generalised pruritic papules. Laboratory investigations disclosed eosinophilia, autoimmune haemolytic anaemia, mixed hyperbilirubinaemia, cholestasis and elevated serum IgG4 levels. Abdominal sonography and CT showed progressive dilatation of biliary trees, with diffuse pancreatic enlargement and a subtle capsule-like low-density rim around the pancreatic head and body. Endoscopic retrograde cholangiopancreatography found no stone-related biliary obstruction, while endoscopic transpapillary biopsy demonstrated chronic inflammation only. Nevertheless, the diagnosis of IgG4-related disease with coexisting autoimmune haemolytic anaemia was presumed. The clinical picture and laboratory abnormalities improved after administration of moderate dose of methylprednisolone. PMID- 29982183 TI - Gastrointestinal beriberi: a forme fruste of Wernicke's encephalopathy? AB - Gastrointestinal symptoms, such as anorexia, nausea, vomiting and abdominal pain, are very common in patients with Wernicke's encephalopathy (WE). Mild thiamine deficiency may have only gastrointestinal symptoms. We are reporting two patients with thiamine deficiency who predominantly had gastrointestinal symptoms. Case 1: a 38-year-old man had gastrointestinal problems for about 2-3 years. It gradually became severe. The patient came to the neurology outpatient department for his recent-onset vertigo and headache. Clinical examinations fulfilled Caine's criteria of WE. Gastrointestinal symptoms responded dramatically to intravenous thiamine. Case 2: a 21-year-old woman developed drug-induced hepatitis and gastritis. Associated nausea, vomiting and abdominal pain progressively increased over the weeks. The patient responded only to intravenous thiamine administration.We suggest that a suspicion for gastrointestinal beriberi should arise if gastrointestinal symptoms (anorexia, nausea, vomiting and abdominal pain) are refractory to the usual therapies. PMID- 29982184 TI - Perimesencephalic non-aneurysmal subarachnoid haemorrhage. PMID- 29982186 TI - Papillary thyroid cancer nodal metastases mimicking a slow-flow lymphatic malformation. PMID- 29982185 TI - Hungry bone syndrome secondary to prostate cancer successfully treated with radium therapy. AB - A 50-year-old man with a history of prostate cancer with extensive bone metastasis and hypocalcaemia presented with muscle aches and cramps. Physical exam was significant for Chvostek's and Trousseau's sign. Laboratory assessment was consistent with profound hypocalcaemia. This was believed to be due to hungry bone syndrome secondary to advanced prostate cancer. He was treated with intravenous calcium, vitamin D and calcitriol. He also received three doses of radium223 therapy. After therapy, hypocalcaemic episodes resolved. Follow-up after 2.5 years showed continued resolution of hypocalcaemia. PMID- 29982187 TI - Hypomelanosis of Ito with gynaecomastia and dental anomaly. AB - Hypomelanosis of Ito is a rare neurocutaneous syndrome. Cutaneous involvement is characterised by streaks and swirls of hypopigmentation arranged in a Blaschkoid pattern. Neural involvement along with other systemic features are seen. We report a case of a 13-year-old boy who presented with the characteristic skin involvement of hypomelanosis of Ito, mental retardation, teeth abnormalities and gynaecomastia along with psoriasis. PMID- 29982188 TI - Management of prematurely erupted teeth in newborns. AB - The majority of natal and neonatal teeth are prematurely erupted primary teeth, whereas few are supernumerary in origin. They most commonly occur in mandibular central incisor region and often can lead to difficulty to the mother during breast feeding and tongue ulceration in newborn. Moreover, since majority of these have poorly developed roots and are mobile, there is always a fear of aspiration into respiratory passage. Extraction therefore is the most commonly rendered treatment for these teeth. This paper comprises cases of natal and neonatal teeth describing about their clinical characteristics and sequel. This paper has also highlighted the factor which needs to be considered during the management of natal/neonatal teeth and protocol followed at our centre. PMID- 29982189 TI - Laws of attraction: management of magnetic foreign body ingestion. PMID- 29982190 TI - Squamous cell carcinoma of scrotum mimicking as scrotal abscess. PMID- 29982191 TI - Emergency preparedness: Ionising radiation incidents and medical management. AB - Military personnel risk being exposed to ionising radiation through a variety of means, including industrial accidents with Ministry of Defence equipment, inadvertent exposure while on operations, terrorist activities and nuclear war. The aim of this review is to outline the possible acute health effects and immediate management of radiation casualties in the context of different exposure scenarios. It emphasises the most important principles for managing irradiated, and/or contaminated casualties, in the operational environment, as well as providing details of key references and other sources of reach-back support. PMID- 29982192 TI - Proton pump inhibitors and suppression of duodenal eosinophilia in functional dyspepsia. PMID- 29982193 TI - The association between systolic blood pressure and in-hospital mortality in older emergency department patients who are hospitalised with a suspected infection. AB - OBJECTIVE: In existing risk stratification and resuscitation guidelines for sepsis, a hypotension threshold of systolic blood pressure (SBP) below 90-100 mmHg is typically used. However, for older patients, the clinical relevance of a SBP in a seemingly 'normal' range (>100 mmHg) is still poorly understood, as they may need higher SBP for adequate tissue perfusion due to arterial stiffening. We therefore investigated the association between SBP and mortality in older emergency department (ED) patients hospitalised with a suspected infection. METHODS: In this observational multicentre study in the Netherlands, we interrogated an existing prospective database of consecutive ED patients hospitalised with a suspected infection between 2011 and 2016. We investigated the association between SBP categories (<=100, 101-120, 121-139, >=140 mmHg) and in-hospital mortality in patients of 70 years and older. We adjusted for demographics, comorbidity, disease severity and admission to ward/intensive care using multivariable logistic regression. RESULTS: In the 833 included older patients, unadjusted in-hospital mortality increased from 4.7% (n=359) in SBP >=140 mmHg to 20.8% (n=96) in SBP <=100 mmHg. SBP categories were linearly associated with case-mix-adjusted in-hospital mortality. The adjusted ORs (95% CI) for <=100, 101-120 and 121-139 mmHgcompared with the reference of >=140 mmHg were 3.8 (1.8 to 7.8), 2.8 (1.4 to 5.5) and 1.9 (0.9 to 3.7), respectively. CONCLUSION: In older ED patients hospitalised with a suspected infection, we found an inverse linear association between SBP and case-mix-adjusted in-hospital mortality. Our data suggest that the commonly used threshold for hypotension is not clinically meaningful for risk stratification of older ED patients with a suspected infection. PMID- 29982194 TI - Managing accidental hypothermia: progress but still some way to go. PMID- 29982195 TI - Increased attention should be paid to perinatal mental health and to the need of dedicated services. PMID- 29982196 TI - Towards a demographic risk profile for sedentary behaviours in middle-aged British adults: a cross-sectional population study. AB - OBJECTIVES: In response to a call from the American Heart Association to more clearly identify the demographic factors associated with sedentary behaviours, this study aimed to identify the hierarchy of demographic characteristics associated with the sedentary behaviours of television viewing, recreational computer use and driving. DESIGN: Cross-sectional analysis of baseline data collected as part of the UK Biobank. The UK Biobank is a population cohort recruited from 22 centres across the UK. Participants aged between 37 and 73 years were recruited between 2006 and 2010. METHODS: Decision tree models were generated for the sedentary behaviour outcomes of hours/day spent television viewing, recreational computer use and all driving; a sum of time spent in these sedentary behaviours ('overall') was computed. Age, sex, race, college attendance, employment, shift-work, urban versus rural residence as well as physical activity were considered as predictors. RESULTS: The analytic sample comprised 415 666 adults who were mostly female (54.2%), white (95.2%), non college attendee (64.5%), employed (61.7%), lived in an urban centre (85.5%), with a mean age of 56.6 (SD=8.1) years. Television viewing was most common sedentary behaviour (2.7 hour/day vs 1.1 for recreational computer use and 1.0 for all driving). Males (tier 1), who did not attend college (tier 2) were the highest risk group for overall sedentary time. Adults with no college attendance (tier 1) and were retired (tier 2) were the most high-risk demographic group for television viewing. College attendees (tier 1) were highest risk for recreational computer use. Adults who were employed (tier 1), male (tier 2) and did not attend college (tier 3) were most at risk for driving CONCLUSIONS: Daily time spent in different sedentary behaviours varies by sex, employment status and college attendance status. The development of targeted interventions to reduce sedentary behaviour in different demographic subgroups is needed. PMID- 29982197 TI - Association between ATP2B1 and CACNB2 polymorphisms and high blood pressure in a population of Lithuanian children and adolescents: a cross-sectional study. AB - OBJECTIVES: Recently, genome-wide associated studies have identified several genetic loci that are associated with elevated blood pressure and could play a critical role in intracellular calcium homeostasis. The aim of this study was to assess the associations of ATP2B1 rs2681472 and CACNB2 rs12258967 gene polymorphisms with high blood pressure (HBP) among Lithuanian children and adolescents aged 12-15 years. STUDY DESIGN AND PARTICIPANTS: This was a cross sectional study of a randomly selected sample of 646 12-15-year-old adolescents who participated in the survey 'The Prevalence and Risk Factors of HBP in 12-15 Year-Old Lithuanian Children and Adolescents (from November 2010 to April 2012)'. Anthropometric parameters and BP were measured. The participants with HBP were screened on two separate occasions. Subjects were genotyped ATP2B1 rs2681472 and CACNB2 rs12258967 gene polymorphisms using real-time PCR method. RESULTS: The prevalence of HBP was 36.7%, significantly higher for boys than for girls. In the multivariate analysis, after adjustment for body mass index and waist circumference, boys with CACNB2 CG genotype, CACNB2 GG genotype and CACNB2 CG +GG genotype had higher odds of having HBP in codominant (adjusted OR (aOR)=1.92; 95% CI 1.16 to 3.18, p=0.011; and aOR=2.64; 95% CI 1.19 to 5.90, p=0.018) and in dominant (aOR=2.05; 95% CI 1.27 to 3.30, p=0.003) inheritance models. Girls carrying CACNB2 CG genotype and CACNB2 CG +GG genotype had increased odds of HBP in codominant (aOR=1.82; 95% CI 1.02 to 3.24, p=0.044) and in dominant (aOR=1.89; 95% CI 1.09 to 3.28, p=0.023) inheritance models. Furthermore, significant associations were found in additive models separately for boys (aOR=1.72; 95% CI 1.20 to 2.46, p=0.003) and girls (aOR=1.52; 95% CI 1.05 to 2.20, p=0.027). No significant association was found between ATP2B1 gene polymorphism and the odds of HBP. CONCLUSIONS: Our results indicate that CACNB2 gene polymorphism was significantly associated with higher odds of HBP in Lithuanian adolescents aged 12-15 years. PMID- 29982199 TI - Association between QTc prolongation and mortality in patients with suspected poisoning in the emergency department: a transnational propensity score matched cohort study. AB - OBJECTIVES: Poisoning is a frequent cause of admission to the emergency department (ED) and may involve drugs known to prolong the QT interval. This study aims to describe the prevalence of QTc prolongation among ED patients with suspected poisoning and to calculate the absolute and relative risk of mortality or cardiac arrest associated with a prolonged QTc interval. METHODS: We performed a register-based cohort study, including all adult first-time contacts with suspected poisoning to the ED of two Swedish hospitals (January 2010-December 2014) and two Danish hospitals (March 2013-April 2014). We used propensity score matching to calculate HRs for all-cause mortality or cardiac arrest (combined endpoint) within 30 days after contact comparing patients with a prolonged QTc interval (>=450 ms men, >=460 ms women) with patients with a QTc interval of <440 ms. RESULTS: Among all first-time contacts with suspected poisoning that had an ECG recorded within 4 hours after arrival (n=3869), QTc prolongation occurred in 6.5%. The overall mortality after a 30-day follow-up period was 0.8% (95% CI 0.6 to 1.2), with an absolute risk of mortality or cardiac arrest in patients with QTc prolongation of 3.2% (95% CI 1.4 to 6.1). A prolonged QTc interval on arrival was associated with a HR of 3.6 (95% CI 1.0 to 12.2). CONCLUSION: In the ED, a prolonged QTc interval in patients arriving with suspected poisoning seems to be associated with a threefold increased risk of 30-day all-cause mortality or cardiac arrest. PMID- 29982198 TI - Alterations in maternally perceived fetal movement and their association with late stillbirth: findings from the Midland and North of England stillbirth case control study. AB - OBJECTIVE: To report perception of fetal movements in women who experienced a stillbirth compared with controls at a similar gestation with a live birth. DESIGN: Case-control study. SETTING: 41 maternity units in the UK. PARTICIPANTS: Cases were women who had a late stillbirth >=28 weeks gestation (n=291) and controls were women with an ongoing pregnancy at the time of the interview (n=733). Controls were frequency matched to cases by obstetric unit and gestational age. METHODS: Data were collected using an interviewer-administered questionnaire which included questions on maternal perception of fetal movement (frequency, strength, increased and decreased movements and hiccups) in the 2 weeks before the interview/stillbirth. Five fetal movement patterns were identified incorporating the changes in strength and frequency in the last 2 weeks by combining groups of similar pattern and risk. Multivariable analysis adjusted for known confounders. PRIMARY OUTCOME MEASURE: Association of maternally perceived fetal movements in relation to late stillbirth. RESULTS: In multivariable analyses, women who reported increased strength of movements in the last 2 weeks had decreased risk of late stillbirth compared with those whose movements were unchanged (adjusted OR (aOR) 0.18, 95% CI 0.13 to 0.26). Women with decreased frequency (without increase in strength) of fetal movements were at increased risk (aOR 4.51, 95% CI 2.38 to 8.55). Daily perception of fetal hiccups was protective (aOR 0.31, 95% CI 0.17 to 0.56). CONCLUSIONS: Increased strength of fetal movements and fetal hiccups is associated with decreased risk of stillbirth. Alterations in frequency of fetal movements are important in identifying pregnancies at increased risk of stillbirth, with the greatest risk in women noting a reduction in fetal activity. Clinical guidance should be updated to reflect that increase in strength and frequency of fetal movements is associated with the lowest risk of stillbirth, and that decreased fetal movements are associated with stillbirth. TRIAL REGISTRATION NUMBER: NCT02025530. PMID- 29982200 TI - Patient safety initiatives in obstetrics: a rapid review. AB - OBJECTIVES: This review was commissioned by WHO, South Africa-Country office because of an exponential increase in medical litigation claims related to patient safety in obstetrical care in the country. A rapid review was conducted to examine the effectiveness of quality improvement (QI) strategies on maternal and newborn patient safety outcomes, risk of litigation and burden of associated costs. DESIGN: A rapid review of the literature was conducted to provide decision makers with timely evidence. Medical and legal databases (eg, MEDLINE, Embase, LexisNexis Academic, etc) and reference lists of relevant studies were searched. Two reviewers independently performed study selection, abstracted data and appraised risk of bias. Results were summarised narratively. INTERVENTIONS: We included randomised clinical trials (RCTs) of QI strategies targeting health systems (eg, team changes) and healthcare providers (eg, clinician education) to improve the safety of women and their newborns. Eligible studies were limited to trials published in English between 2004 and 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: RCTs reporting on patient safety outcomes (eg, stillbirths, mortality and caesarean sections), litigation claims and associated costs were included. RESULTS: The search yielded 4793 citations, of which 10 RCTs met our eligibility criteria and provided information on over 500 000 participants. The results are presented by QI strategy, which varied from one study to another. Studies including provider education alone (one RCT), provider education in combination with audit and feedback (two RCTs) or clinician reminders (one RCT), as well as provider education with patient education and audit and feedback (one RCT), reported some improvements to patient safety outcomes. None of the studies reported on litigation claims or the associated costs. CONCLUSIONS: Our results suggest that provider education and other QI strategy combinations targeting healthcare providers may improve the safety of women and their newborns during childbirth. PMID- 29982201 TI - Care pathway and organisational features driving patient experience: statistical analysis of large NHS datasets. AB - OBJECTIVE: The aim of this study was to identify the care pathway and organisational factors that predict patient experience. DESIGN: Statistical analysis of large National Health Service (NHS) datasets. SETTING ANDPARTICIPANTS: England; acute NHS organisational-level data. PRIMARY AND SECONDARY OUTCOME MEASURES: The relationship of care pathway and organisational variables to organisation-level patient experience. RESULTS: A framework of 18 care pathway and organisational variables were created based on the existing literature. 11 of these correlated to patient experience in univariate analyses. Multicollinearity tests resulted in 1 of the 11 variables holding a correlation to another variable larger than r=0.70. A significant multilinear regression equation, including the final 10 variables, was found (F(10,108)=6.214, p<0.00), with an [Formula: see text] of 0.365. Two variables were significant in predicting better in patient experience: Amount of support to clinical staff (beta=0.2, p=0.02) and the proportion of staff who would recommend the trust as a place to work or receive treatment (beta=0.26, p=0.01). Two variables were significant in predicting a negative impact on the patient's rating of their experience: Number of patients spending over 4 hours from decision to admit to admission (beta=-1.99, p=0.03) and the percentage of estates and hotel services contracted out (beta=-0.23, p=0.01). CONCLUSIONS: These results indicate that augmenting clinical support and investing in the mechanisms that facilitate positive staff experience is essential to delivering appropriate, informative and patient-centric care. Reducing wait times and the extent of external contracting within hospitals is also likely to improve patient ratings of experience. Understanding the relationship between patient experience and objective, measurable organisational features promote a more patient-centric interpretation of quality and compel a better use of patient experience feedback to drive improvement. PMID- 29982202 TI - Is mortality-to-incidence ratio associated with health disparity in pancreatic cancer? A cross-sectional database analysis of 57 countries. AB - OBJECTIVE: The colorectal cancer mortality-to-incidence ratio (MIR) can reflect healthcare disparities. However, a similar association has not yet been established between the MIR of pancreatic cancer and healthcare disparities. METHODS: In this study, the incidence and mortality rates of pancreatic cancer were obtained from the GLOBOCAN 2012 database. The WHO rankings and total expenditures on health/gross domestic product (e/GDP) were obtained from a public database. Linear regression was performed to determine correlations between the variables. RESULTS: 57 countries met the inclusion criteria according to the data quality. Developed regions (Europe and the Americas) had high pancreatic cancer incidence and mortality rates. The MIRs were over 0.90 in all regions. No significant correlation was found between MIRs and the WHO rankings, e/GDP or per capita total expenditure on health for analysis in the 57 countries, indicating no association between MIRs and cancer care disparities for pancreatic cancer. CONCLUSIONS: The MIR variations for pancreatic cancer do not correlate with healthcare disparities among countries. Further investigation is necessary to confirm this observation with secondary analysis of databases. PMID- 29982203 TI - Framework to construct and interpret latent class trajectory modelling. AB - OBJECTIVES: Latent class trajectory modelling (LCTM) is a relatively new methodology in epidemiology to describe life-course exposures, which simplifies heterogeneous populations into homogeneous patterns or classes. However, for a given dataset, it is possible to derive scores of different models based on number of classes, model structure and trajectory property. Here, we rationalise a systematic framework to derive a 'core' favoured model. METHODS: We developed an eight-step framework: step 1: a scoping model; step 2: refining the number of classes; step 3: refining model structure (from fixed-effects through to a flexible random-effect specification); step 4: model adequacy assessment; step 5: graphical presentations; step 6: use of additional discrimination tools ('degree of separation'; Elsensohn's envelope of residual plots); step 7: clinical characterisation and plausibility; and step 8: sensitivity analysis. We illustrated these steps using data from the NIH-AARP cohort of repeated determinations of body mass index (BMI) at baseline (mean age: 62.5 years), and BMI derived by weight recall at ages 18, 35 and 50 years. RESULTS: From 288 993 participants, we derived a five-class model for each gender (men: 177 455; women: 111 538). From seven model structures, the favoured model was a proportional random quadratic structure (model F). Favourable properties were also noted for the unrestricted random quadratic structure (model G). However, class proportions varied considerably by model structure-concordance between models F and G were moderate (Cohen kappa: men, 0.57; women, 0.65) but poor with other models. Model adequacy assessments, evaluations using discrimination tools, clinical plausibility and sensitivity analyses supported our model selection. CONCLUSION: We propose a framework to construct and select a 'core' LCTM, which will facilitate generalisability of results in future studies. PMID- 29982204 TI - Barriers to uptake of referral services from secondary care to tertiary care and its associated factors in L V Prasad Eye Institute network in Southern India: a cross-sectional study. AB - OBJECTIVE: To examine barriers to the uptake of referral services from secondary care centres to higher level tertiary care centres. DESIGN: Cross-sectional study. SETTING: Secondary care hospital in Khammam District in the Telangana state of India. PARTICIPANTS: Nine hundred and three patients who were referred from a secondary care centre to tertiary care centres between June 2011 and December 2012, were over the age of 18 and lived within 50 km of the secondary care centre were identified. Six hundred and sixteen (68.2%) of these patients were successfully contacted, and 611 (99%) of those contacted consented to participation in the study. INTERVENTIONS: Those who attended at higher centres after referral (compliant) and those who failed to attend (non-compliant) were interviewed with a standard questionnaire designed for the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcome measures were barriers to the uptake of eye care services for the non-compliant participants and the associated risk factors for non-compliance. RESULTS: Of the contacted patients, 418 (68.4%) were compliant and 193 (31.6%) were non-compliant. The mean age of interviewed patients was 48.4 years (SD: 17.9 years) and 365 (59.7%) were male. Of those who did not comply with their referral, the major identified barriers were 'cannot afford treatment cost' (30%) and 'able to see adequately' (20.7%). Multivariable analysis showed that participants in the non-compliant group were more likely to have had only one prior visit to the centre (OR: 2.5, 95% CI 1.6 to 3.9), be referred for oculoplastic services (OR: 3.0, 95% CI 1.0 to 8.8) and to be the main earning member of the family (OR: 1.9, 95% CI 1.2 to 2.8). CONCLUSIONS: Non compliance with referrals in this population is largely attributable to economic and attitudinal reasons. Focusing on these specific barriers and targeting groups at higher risk of non-compliance could potentially improve uptake of referral services. PMID- 29982205 TI - Community factors associated with stunting, overweight and food insecurity: a community-based mixed-method study in four Andean indigenous communities in Ecuador. AB - OBJECTIVES: We aimed to implement participatory research to answer a question posed by four Kichwa indigenous communities in Andean Ecuador about what actionable factors are associated with childhood stunting, overweight and food insecurity among their people. DESIGN: We used mixed methods including household questionnaires, discussion groups with respondents of the questionnaires and anthropometric measurement of children (6 months to 12 years) from surveyed households. SETTING: The study involved four Andean indigenous communities transitioning from traditional to Western lifestyles. They subsist mainly on small-scale agriculture and have a rich cultural heritage including their traditional language. PARTICIPANTS: Anthropometric data were collected from 298 children from 139 households in four communities; all households completed the questionnaire. We held five discussion groups (6-10 participants each): three composed of mothers and two of farmers. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were stunting, overweight, food insecurity and their relationship with demographics, dietary habits and agricultural habits. RESULTS: Of 298 children, 48.6% were stunted and 43.3% overweight for age. Stunted children were more likely to live in households that sold livestock (ORa 1.77, 95% CIa 1.06 to 2.95) and with illiterate primary caretakers (ORa 1.81, 95% CIa 1.07 to 3.06), but were less likely to live in households with irrigation (ORa 0.47, 95% CIa 0.27 to 0.81). Overweight children were more likely to be male (ORa 1.87, 95% CIa 1.02 to 3.43) and live in a household that sold livestock (ORa 2.14, 95% CIa 1.14 to 4.02). Some 67.8% of children lived in a household with food insecurity, more frequently in those earning below minimum wage (ORa 2.90, 95% CIa 1.56 to 5.41) and less frequently in those that ate quinoa in the past 24 hours (ORa 0.17, 95% CIa 0.06 to 0.48). Discussion groups identified irrigation and loss of agricultural and dietary traditions as important causes of poor childhood nutrition. CONCLUSION: Many indigenous communities face tumultuous cultural, nutritional and epidemiological transitions. Community-based interventions on factors identified here could mitigate negative health outcomes. PMID- 29982206 TI - Media use and excess body weight among women in Nigeria: a cross-sectional study. AB - OBJECTIVES: To investigate the (1) time trends in body mass index (BMI) and (2) relationship between media use and body weight status among adult women in Nigeria. We hypothesise that higher frequency of media use is associated with higher likelihood of being overweight and obesity among adult women. STUDY DESIGN: Cross-sectional. SETTING: Urban and rural settings in Nigeria. PARTICIPANTS: Adult non-pregnant women aged between 15 and 49 years. METHODS: Data were derived from Nigeria Demographic and Health Surveys conducted in 2003, 2008 and 2013. The outcome variable was excess body weight (overweight and obesity), and main explanatory variables were frequency of reading newspaper, listening to radio and television (TV) viewing. Datasets were merged to perform pooled analysis, and were analysed using bivariate and multivariable regression techniques. RESULTS: Of the 69 401 participants, 16.2% had a BMI of 25.0-29.9 kg/m2 (95% CI 15.8 to 16.6) and 6.6% had >30 kg/m2 (95% CI 6.3 to 6.9). Between 2003 and 2013, the prevalence of overweight women increased by 4.1%, and that of obesity by 2.2%. Overall, radio was the most popular media followed by TV and newspaper. Respectively, 15.6% and 11.7% of the women reported using radio and TV almost every day and 30.6% and 25.1% at least once a week. In multivariable analysis, watching TV almost every day and at least once a week were associated with, respectively, 1.6 and 1.2 times higher odds of being overweight, and 2.7 and 1.5 times higher odds of being obese compared with those who never used radio. Similarly, significant associations were observed for newspaper and radio use as well. CONCLUSION: The prevalence of overweight and obesity is noticeably high among Nigerian women and has been increasing steadily over the past decade. A statistically significant association exists between BMI and the use of newspaper, radio and TV. Further studies are required to develop a better understanding of the mechanisms that underlie this relationship. PMID- 29982207 TI - Does nephrotic syndrome without chronic kidney disease increase the risk of Parkinson's disease and secondary parkinsonism? A nationwide population-based study in Taiwan. AB - OBJECTIVES: Previous research has shown that patients with nephrotic syndrome (NS) have a higher risk of cognitive impairment, dementia or neurodegenerative disorder. The present study aimed to examine a relationship, if any exists between NS and Parkinson's disease (PD), a neurodegenerative disorder and secondary parkinsonism (sPS). METHODS: A nationwide retrospective observational study conducted using data from the 2000-2010 Taiwan National Health Insurance Research Database. This study included 3663 patients with NS and 14 652 randomly selected, age-matched and sex-matched patients without NS. A Cox multivariable proportional hazards model was used to evaluate the risk of PD and sPS (PDsPS) in the NS cohort. RESULTS: This study identified a positive association between NS and the risk of PDsPS in both men and women and in all age groups (adjusted HR 1.51; 95% CI 1.37 to 1.66). Compared with patients without NS and comorbidities, those with NS with two or more comorbidities exhibited an 8.23-fold higher risk of PDsPS (95% CI 6.22 to 10.9) and patients with NS and one comorbidity exhibited a 2.93-fold higher risk of PDsPS (95% CI 2.37 to 3.63). CONCLUSIONS: Patients with NS have an increased risk of PDsPS. This increased risk may be related to brain vascular damage or blood-brain barrier impairment. Further research is necessary to explore the underlying relationship between NS and PDsPS. PMID- 29982208 TI - Initial use of supplementary oxygen for trauma patients: a systematic review. AB - OBJECTIVE: This systematic review aimed to identify and describe the evidence for supplementary oxygen for spontaneously breathing trauma patients, and for high (0.60-0.90) versus low (0.30-0.50) inspiratory oxygen fraction (FiO2) for intubated trauma patients in the initial phase of treatment. METHODS: Several databases were systematically searched in September 2017 for studies fulfilling the following criteria: trauma patients (Population); supplementary oxygen/high FiO2 (Intervention) versus no supplementary oxygen/low FiO2 (Control) for spontaneously breathing or intubated trauma patients, respectively, in the initial phase of treatment; mortality, complications, days on mechanical ventilation and/or length of stay (LOS) in hospital/intensive care unit (ICU) (Outcomes); prospective interventional trials (Study design). Two independent reviewers screened and identified studies and extracted data from included studies. RESULTS: 6142 citations were screened with an inter-rater reliability (Cohen's kappa) of 0.88. One interventional trial of intubated trauma patients was included. 68 trauma patients were randomised to receive an FiO2 of 0.80 (intervention group) or 0.50 (control group) during mechanical ventilation (first 6 hours). There was no significant difference in hospital or ICU LOS between the groups. No patient died in either group. Another interventional trial, not strictly fulfilling the inclusion criteria, was presented for descriptive purposes. 21 trauma patients were alternately assigned to two types of mechanical ventilation (first 48 hours), both aiming at an FiO2 of 0.40, but resulted in estimated mean FiO2s of 0.45 (intervention group) and 0.60 (control group). No difference in days on mechanical ventilation was found. Two patients in the control group died, none in the intervention group. No prospective, interventional trials on spontaneously breathing trauma patients were identified. CONCLUSIONS: Evidence for the use of supplementary oxygen for spontaneously breathing trauma patients is lacking, and the evidence for low versus high FiO2 for intubated trauma patients is limited. PROSPERO REGISTRATION NUMBER: 42016050552. PMID- 29982209 TI - Emotional reserve and prolonged post-concussive symptoms and disability: a Swedish prospective 1-year mild traumatic brain injury cohort study. AB - OBJECTIVE: Prolonged post-concussive symptoms (PCS) affect a significant minority of patients withmild traumatic brain injury (mTBI). The aetiology is multifactorial depending on preinjury as well as peri-injury and postinjury factors. In this study, we examine outcome from an emotional reserve perspective. DESIGN: Prospective cohort study. SETTING: Patients were recruited from three emergency departments in major university hospitals in Stockholm, Sweden. Follow up data were collected in an outpatient setting at one of the recruiting hospitals. PARTICIPANTS: 122 patients with a history of blunt head trauma (aged 15-65 years; admitted for mTBI within 24 hours after trauma (Glasgow Coma Scale score of 14-15, loss of consciousness <30 min and/or post-traumatic amnesia <24 hours). Exclusion criteria were other significant physical injury and other major neurological disorder, including previous significant head injury. PROCEDURE: Recruitment in three emergency departments. Initial assessments were made within 1 week after the injury. Patients were mailed the follow-up questionnaires 1 year postinjury. OUTCOME MEASURES: A psychiatric assessment was performed at 1 week post injury. The participants also completed a personality inventory, measures of psychological resilience, depression, anxiety and post-traumatic symptoms. One year outcome was measured by the Rivermead Post Concussion Symptoms and the Rivermead Head Injury Follow-Up questionnaires. RESULTS: The psychiatric assessment revealed more symptoms of anxiety, depression and post-traumatic symptoms in the acute stage for patients who later developed PCS.After 1 year, 94 participants were still in the programme (male/female 57/37) and 12% matched the extended criteria for PCS (>=3 symptoms and >=2 disabilities). PCS patients reported more preinjury and concurrent psychiatric problems, lower level of functioning before the injury and experienced more stress. They showed higher somatic trait anxiety, embitterment, mistrust and lower level of psychological resilience than recovered participants. CONCLUSION: Intrapersonal emotional reserve shape the emergence and persistence of PCS after mTBI. PMID- 29982210 TI - A systematic review of barriers and enablers to South Asian women's attendance for asymptomatic screening of breast and cervical cancers in emigrant countries. AB - OBJECTIVES: The aim of this review was to identify the cultural, social, structural and behavioural factors that influence asymptomatic breast and cervical cancer screening attendance in South Asian populations, in order to improve uptake and propose priorities for further research. DESIGN: A systematic review of the literature for inductive, comparative, prospective and intervention studies. We searched the following databases: MEDLINE/In-Process, Web of Science, EMBASE, SCOPUS, CENTRAL, CDSR, CINAHL, PsycINFO and PsycARTICLES from database inception to 23 January 2018. The review included studies on the cultural, social, structural and behavioural factors that influence asymptomatic breast and cervical cancer screening attendance and cervical smear testing (Papanicolaou test) in South Asian populations and those published in the English language. The framework analysis method was used and themes were drawn out following the thematic analysis method. SETTINGS: Asymptomatic breast or cervical screening. PARTICIPANTS: South Asian women, including Bangladeshi, Indian, Pakistani, Sri Lankan, Bhutanese, Maldivian and Nepali populations. RESULTS: 51 included studies were published between 1991 and 2018. Sample sizes ranged from 25 to 38 733 and participants had a mean age of 18 to 83 years. Our review showed that South Asian women generally had lower screening rates than host country women. South Asian women had poorer knowledge of cancer and cancer prevention and experienced more barriers to screening. Cultural practices and assumptions influenced understandings of cancer and prevention, emphasising the importance of host country cultures and healthcare systems. CONCLUSIONS: High-quality research on screening attendance is required using prospective designs, where objectively validated attendance is predicted from cultural understandings, beliefs, norms and practices, thus informing policy on targeting relevant public health messages to the South Asian communities about screening for cancer. PROSPERO REGISTRATION NUMBER: CSD 42015025284. PMID- 29982211 TI - Risk of pleural empyema in patients with schizophrenia: a nationwide propensity matched cohort study in Taiwan. AB - OBJECTIVE: Thoracic infection and pneumonia are prevalent in patients with schizophrenia; however, it is unclear whether patients with schizophrenia are at an increased risk of developing pleural empyema. DESIGN: A retrospective cohort study with propensity-matched cohorts with and without schizophrenia. SETTING: Using the National Health Insurance Research Database of Taiwan. PARTICIPANTS: We identified 55 888 patients with schizophrenia newly diagnosed in 2000-2011 and same number of individuals without schizophrenia as the comparison cohort, frequency matched by propensity scores estimated using age, sex, occupation, income, urbanisation, year of diagnosis and comorbidities. PRIMARY OUTCOME MEASURES: We assessed incident pleural empyema by the end of 2011 and used the Cox proportional hazards model to calculate the schizophrenia cohort to comparison cohort HR of pleural empyema. RESULTS: The overall incidence of pleural empyema was 2.44-fold greater in the schizophrenia cohort than in the comparison cohort (4.39vs1.80 per 10 000 person-years), with an adjusted HR of 2.87(95% CI 2.14 to 3.84). Stratified analyses by age, sex, occupation, income, urbanisation and comorbidity revealed significant hazards for pleural empyema associated with schizophrenia in all subgroups. CONCLUSIONS: Patients with schizophrenia are at an increased risk of developing pleural empyema and require greater attention and appropriate support. PMID- 29982212 TI - Protocol for a meta-integration: investigating positive aspects of caregiving in dementia. AB - INTRODUCTION: The current work describes the protocol for a meta-integration investigating the positive aspects of providing care to someone living with dementia. We aim to understand the position of positive aspects in the caregiver experience as well as identify how positive aspects are commonly conceptualised, investigated and measured in literature. METHODS AND ANALYSES: Meta-integration is a method of investigation that synthesises findings from meta-analysis or systematic review of quantitative studies and meta-synthesis of qualitative studies, to provide a coherent and holistic account of a phenomenon. As a relatively new method, terminology and methodological approaches are varied. The current work describes the process of conducting an advanced convergent meta integration, including protocol for systematic search, inclusion/exclusion screening phases, intramethod analysis synthesis and intermethod synthesis on quantitative, qualitative and mixed methods research pertaining to the positive aspects of providing care to someone living with dementia. ETHICS AND DISSEMINATION: There are no ethics or safety concerns about dissemination, which includes plans for a conference presentation and publication. PMID- 29982213 TI - Sipjeondaebo-tang in patients with breast cancer with fatigue: a protocol for a pilot, randomised, double-blind, placebo-controlled, cross-over trial. AB - INTRODUCTION: Cancer-related fatigue is a frequent symptom in patients with cancer and one of the most distressing symptoms in patients with breast cancer. Sipjeondaebo-tang (Juzen-taiho-to in Japanese or Shi-Quan-Da-Bu-Tang in Chinese) is a widely used herbal medicine for the treatment of fatigue in Korea, China and Japan. The purpose of the present study is to evaluate the feasibility of Sipjeondaebo-tang for cancer-related fatigue. METHODS AND ANALYSIS: The present study is a randomised, double-blind, placebo-controlled, cross-over study. Forty eight patients with breast cancer who are indicated for doxorubicin and cyclophosphamide will be recruited. The participants will receive 3 g of Sipjeondaebo-tang or a placebo three times a day for 56 days. The primary outcome measurement is the change in the Brief Fatigue Inventory scores. The secondary outcome measurements include the changes in the Visual Analogue Scale (VAS) of fatigue, and quality of life measured by the European Organization for Research and Treatment of Cancer-QLQ-C30 and QLQ-BR23. VAS of fatigue will be measured on every visit, and other outcomes will be measured on visits 2, 4, 6 and 7. The total study period is 14 weeks. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of the Catholic Kwandong University International St Mary's Hospital (reference IS16MNSI0011). The results of this study will be published in a peer-reviewed journal and presented at a scientific conference. TRIAL REGISTRATION NUMBER: NCT02858856; Pre-results. PMID- 29982214 TI - Different but similar: personality traits of surgeons and internists-results of a cross-sectional observational study. AB - OBJECTIVES: Medical practice may attract and possibly enhance distinct personality profiles. We set out to describe the personality profiles of surgical and medical specialties focusing on board-certified physicians. DESIGN: Prospective, observational. SETTING: Online survey containing the Ten-Item Personality Inventory (TIPI), an internationally validated measure of the Five Factor Model of personality dimensions, distributed to board-certified physicians, residents and medical students in several European countries and Canada. Differences in personality profiles were analysed using multivariate analysis of variance and Canonical Linear Discriminant Analysis on age standardised and sex-standardised z-scores of the personality traits. Single personality traits were analysed using robust t-tests. PARTICIPANTS: The TIPI was completed by 2345 board-certified physicians, 1453 residents and 1350 medical students, who also provided demographic information. RESULTS: Normal population and board-certified physicians' personality profiles differed (p<0.001). The latter scored higher on conscientiousness, extraversion and agreeableness, but lower on neuroticism (all p<0.001). There was no difference in openness to experience. Board-certified surgical and medical doctors' personality profiles were also different (p<0.001). Surgeons scored higher on extraversion (p=0.003) and openness to experience (p=0.002), but lower on neuroticism (p<0.001). There was no difference in agreeableness and conscientiousness. These differences in personality profiles were reproduced at other levels of training, that is, in students and training physicians engaging in surgical versus medical practice. CONCLUSION: These results indicate the existence of a distinct and consistent average 'physician personality'. Despite high variability within disciplines, there are moderate but solid and reproducible differences between surgical and medical specialties. PMID- 29982216 TI - Registration and publication of emergency and elective randomised controlled trials in surgery: a cohort study from trial registries. AB - OBJECTIVES: Emergency surgical practice constitutes 50% of the workload for surgeons, but there is a lack of high quality randomised controlled trials (RCTs) in emergency surgery. This study aims to establish the differences between the registration, completion and publication of emergency and elective surgical trials. DESIGN: The clinicaltrials.gov and ISRCTN.com trials registry databases were searched for RCTs between 12 July 2010 and 12 July 2012 using the keyword 'surgery'. Publications were systematically searched for in Pubmed, MEDLINE and EMBASE. PARTICIPANTS: Results with no surgical interventions were excluded. The remaining results were manually categorised into 'emergency' or 'elective' and 'surgical' or 'adjunct' by two reviewers. PRIMARY OUTCOME MEASURES: Number of RCTs registered in emergency versus elective surgery. SECONDARY OUTCOME MEASURES: Number of RCTs published in emergency versus elective surgery; reasons why trials remain unpublished; funding, sponsorship and impact of published articles; number of adjunct trials registered in emergency and elective surgery. RESULTS: 2700 randomised trials were registered. 1173 trials were on a surgical population and of these, 414 trials were studying surgery. Only 9.4% (39/414) of surgical trials were in emergency surgery. The proportion of trials successfully published did not significantly differ between emergency and elective surgery (0.46 vs 0.52; mean difference (MD) -0.06, 95% CI -0.24 to 0.12). Unpublished emergency surgical trials were statistically equally likely to be terminated early compared with elective trials (0.33 vs 0.16; MD -0.18, 95% CI -0.06 to 0.41). Low accrual accounted for a similar majority in both groups (0.43 vs 0.46; MD -0.04, 95% CI 0.48 to 0.41). Unpublished trials in both groups were statistically equally likely to still be planning publication (0.52 vs 0.71; MD -0.18, 95% CI -0.43 to 0.07). CONCLUSION: Fewer RCTs are registered in emergency than elective surgery. Once trials are registered both groups are equally likely to be published. PMID- 29982215 TI - Rationale and design for the detection and neurological impact of cerebrovascular events in non-cardiac surgery patients cohort evaluation (NeuroVISION) study: a prospective international cohort study. AB - OBJECTIVES: Covert stroke after non-cardiac surgery may have substantial impact on duration and quality of life. In non-surgical patients, covert stroke is more common than overt stroke and is associated with an increased risk of cognitive decline and dementia. Little is known about covert stroke after non-cardiac surgery.NeuroVISION is a multicentre, international, prospective cohort study that will characterise the association between perioperative acute covert stroke and postoperative cognitive function. SETTING AND PARTICIPANTS: We are recruiting study participants from 12 tertiary care hospitals in 10 countries on 5 continents. PARTICIPANTS: We are enrolling patients >=65 years of age, requiring hospital admission after non-cardiac surgery, who have an anticipated length of hospital stay of at least 2 days after elective non-cardiac surgery that occurs under general or neuraxial anaesthesia. PRIMARY AND SECONDARY OUTCOME MEASURES: Patients are recruited before elective non-cardiac surgery, and their cognitive function is measured using the Montreal Cognitive Assessment (MoCA) instrument. After surgery, a brain MRI study is performed between postoperative days 2 and 9 to determine the presence of acute brain infarction. One year after surgery, the MoCA is used to assess postoperative cognitive function. Physicians and patients are blinded to the MRI study results until after the last patient follow-up visit to reduce outcome ascertainment bias.We will undertake a multivariable logistic regression analysis in which the dependent variable is the change in cognitive function 1 year after surgery, and the independent variables are acute perioperative covert stroke as well as other clinical variables that are associated with cognitive dysfunction. CONCLUSIONS: The NeuroVISION study will characterise the epidemiology of covert stroke and its clinical consequences. This will be the largest and the most comprehensive study of perioperative stroke after non-cardiac surgery. TRIAL REGISTRATION NUMBER: NCT01980511; Pre-results. PMID- 29982217 TI - Oral propranolol for prevention of threshold retinopathy of prematurity (ROPROP): protocol of a randomised controlled trial. AB - INTRODUCTION: Retinopathy of prematurity (ROP) is a disease observed in extremely premature infants characterised by visioning-threatening retinal vessel proliferation. Propranolol, a drug used for decades in newborn infants with heart diseases, hypertension and thyrotoxicosis and licenced for infantile haemangiomas, may be effective in halting progression of ROP to severe stages, as suggested by preliminary data from small studies. METHODS AND ANALYSIS: ROPROP is an investigator-initiated, multicentre, placebo-controlled double-blind, randomised controlled trial aiming to assess the safety and efficacy of orally administered propranolol to reduce the risk of threshold ROP (stage 3) in extremely preterm infants at 48 weeks postmenstrual age (primary objective) and the rate of infants requiring local interventions for severe ROP (secondary objective). Key inclusion criteria: gestational age <28 weeks, birth weight <1250 g, postmenstrual age >=31 and <37 weeks, incipient ROP (stage 1 or 2, with or without plus disease) and written informed consent by parents or legal guardian. Key exclusion criteria: requirement for open-label propranolol treatment, major congenital malformations (including those with cerebrovascular malformations), known chromosomal anomalies, colobomas and other eye malformations, atrioventricular block grade 2 or 3 and comedication with antiarrhythmics, clonidine, insulin (pharmacodynamic interaction), phenobarbital or rifampicin (pharmacokinetic interaction). The intervention consists of oral propranolol hydrochloride (1.6 mg/kg/day in three to four divided dosages) or placebo until discharge, for a maximum of 10 weeks. Analysis is by intention to treat. ETHICS AND DISSEMINATION: The protocol has received ethical and regulatory approval. Results will be published after peer review irrespective of the study outcome. TRIAL REGISTRATION NUMBERS: NCT03083431 , EudraCT# 2017-002124-24 (EUCTR), 00013730 (DRKS); Pre-results. PMID- 29982218 TI - Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT): a protocol for a randomised factorial, double-blind, placebo-controlled trial of azithromycin, nitazoxanide and nicotinamide. AB - INTRODUCTION: In many developing areas in the world, a high burden of enteric pathogens in early childhood are associated with growth deficits. The tryptophan kynurenine-niacin pathway has been linked to enteric inflammatory responses to intestinal infections. However, it is not known in these settings whether scheduled antimicrobial intervention to reduce subclinical enteric pathogen carriage or repletion of the tryptophan-kynurenine-niacin pathway improves linear growth and development. METHODS AND ANALYSIS: We are conducting a randomised, placebo-controlled, factorial intervention trial in the rural setting of Haydom, Tanzania. We are recruiting 1188 children within the first 14 days of life, who will be randomised in a 2*2 factorial design to administration of antimicrobials (azithromycin and nitazoxanide, randomised together) and nicotinamide. The nicotinamide is administered as a daily oral dose, which for breast-feeding children aged 0-6 months is given to the mother and for children aged 6-18 months is given to the child directly. Azithromycin is given to the child as a single oral dose at months 6, 9, 12 and 15; nitazoxanide is given as a 3-day course at months 12 and 15. Mother/child pairs are followed via monthly in-home visits. The primary outcome is the child's length-for-age Z-score at 18 months. Secondary outcomes for the child include additional anthropometry measures; stool pathogen burden and bacterial microbiome; systemic and enteric inflammation; blood metabolomics, growth factors, inflammation and nutrition; hydrogen breath assessment to estimate small-intestinal bacterial overgrowth and assessment of cognitive development. Secondary outcomes for the mother include breastmilk content of nicotinamide, other vitamins and amino acids; blood measures of tryptophan-kynurenine-niacin pathway and stool pathogens. ETHICS AND DISSEMINATION: This trial has been approved by the Tanzanian National Institute for Medical Research, the Tanzanian FDA and the University of Virginia IRB. Findings will be presented at national and international conferences and published in peer-review journals. PROTOCOL VERSION: 5.0, 4 December 2017. PROTOCOL SPONSOR: Haydom Lutheran Hospital, Haydom, Manyara, Tanzania. TRIAL REGISTRATION NUMBER: NCT03268902; Pre-results. PMID- 29982219 TI - Maintenance use of non-steroidal anti-inflammatory drugs and risk of gastrointestinal cancer in a nationwide population-based cohort study in Sweden. AB - OBJECTIVES: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are potential candidates for chemoprevention of gastrointestinal cancer. We aimed to assess the association between contemporary NSAID use (>=180 days) and gastrointestinal cancer. DESIGN: Nationwide Swedish population-based cohort study (2005-2012). SETTING: Sweden PARTICIPANTS: All adults exposed to maintenance NSAIDs use (aspirin, n=783 870; unselective NSAIDs, n=566 209, selective cyclo oxygenase (COX)-2 inhibitors, n=17 948) compared with the Swedish background population of the same age, sex and calendar period. OUTCOME MEASURES: The risk of different gastrointestinal cancer types expressed as standardised incidence ratios (SIR) and 95% CIs, taking into account concurrent proton pump inhibitors (PPIs) and statins usage. RESULTS: The SIR for gastrointestinal cancer for aspirin use was 1.02 (95% CI 1.00 to 1.04), with clearly reduced risk for long term users (SIR=0.31, 95% CI 0.30 to 0.33 for 5.5-7.7 years), but an increased risk for short-term users (SIR=2.77, 95% CI 2.69 to 2.85), and stronger protective effect for low-dose aspirin (SIR=0.86, 95% CI 0.85 to 0.88). Users of non-selective NSAIDs showed an overall decreased risk of gastrointestinal cancer (SIR=0.79, 95% CI 0.77 to 0.82), in particular for cancer of the stomach, colorectum and oesophagus, and the SIRs were further decreased among long-term users. Users of selective COX-2 inhibitors showed a SIR=0.89 (95% CI 0.73 to 1.09) for gastrointestinal cancers. Both aspirin and unselective NSAIDs users who also were using PPIs, had higher risks for all gastrointestinal cancer types; and lower risk if using statins. CONCLUSION: Long-term use of (low-dose) aspirin and non-selective NSAIDs was associated with a decreased risk of all gastrointestinal cancer types. PMID- 29982220 TI - Influence of health literacy on acceptance of influenza and pertussis vaccinations: a cross-sectional study among Spanish pregnant women. AB - OBJECTIVES: Immunisations against influenza and Bordetella pertussis infection are recommended to pregnant women in Valencia (Spain), yet vaccination rates remain low. Health literacy (HL) appears as a crucial factor in vaccination decision-making. We explored the relation between HL of pregnant women and decisions to receive influenza and pertussis immunisations. SETTING: University hospital in Valencia (Spain). PARTICIPANTS: 119 women who gave birth at a hospital in Valencia (Spain) between November 2015 and May 2016. Women in the immediate postpartum period (more than 27 weeks of gestation), between November 2015 and May 2016 were included in the study. Women with impairments, language barriers or illiteracy which prevented completion of the questionnaires, or those who were under 18 years were excluded from enrolment. PRIMARY AND SECONDARY OUTCOME MEASURES: HL level; influenza and pertussis immunisation rate; reasons for rejection of vaccination. RESULTS: 119 participants were included (mean age 32.3+/-5.5 years, 52% primiparous, 95% full-term deliveries). A higher education level was associated with Short Assessment of Health Literacy for Spanish Adults _50 (adjusted R2=0.22, p=0.014) and Newest Vital Sign (adjusted R2=0.258, p=0.001) scores. Depending on the scale, 56%-85% of participants had adequate HL. 52% (62/119) and 94% (112/119) of women received influenza and pertussis immunisation, respectively. Women rejecting influenza vaccine had a higher HL level (measured by SALHSA_50 tool) than those accepting it (Kruskal-Wallis test p=0.022). 24% of women who declined influenza vaccination felt the vaccine was unnecessary, and 23% claimed to have insufficient information. CONCLUSIONS: Influenza vaccination rate was suboptimal in our study. Women with high HL were more likely to decline immunisation. Information from professionals needs to match patients' HL levels to reduce negative perceptions of vaccination. PMID- 29982221 TI - Anticholinergic and sedative drug burden in community-dwelling older people: a national database study. AB - OBJECTIVES: The Drug Burden Index (DBI) tool quantifies individual exposure to anticholinergic and sedative medications. The DBI has been internationally validated against adverse health outcomes in older people. DBI exposure has not been reported in the Irish older population. This study aimed to: (1) develop a list of drugs with clinically significant anticholinergic and/or sedative effects (DBI medications) relevant to Ireland; (2) examine, using the DBI formula, the prevalence of exposure to DBI medications in Irish older people and (3) explore patient factors associated DBI exposure. DESIGN: A cross-sectional national pharmacy claims database study. SETTING: Community setting using the General Medical Services (GMS) scheme pharmacy claims database maintained by the Health Service Executive Primary Care Reimbursement Services. PARTICIPANTS: Irish older individuals (aged >=65 years) enrolled in the GMS scheme and dispensed at least one prescription item in 2016 (n=428 516). MAIN OUTCOME MEASURES: Prevalence of exposure to DBI medications and patient factors associated with DBI exposure. RESULTS: 282 874 (66%) of the GMS population aged >=65 years were exposed to at least one DBI medication in 2016. Prevalence of exposure to DBI medications was significantly higher in females than males (females 71.6% vs males 58.7%, adjusted OR 1.65, 95% CI 1.63 to 1.68). Prevalence of DBI exposure increased progressively with the number of chronic drugs used, rising from 42.7% of those prescribed 0-4 chronic drugs to 95.4% of those on >=12 chronic drugs (adjusted OR 27.8, 95% CI 26.7 to 29.0). The most frequently used DBI medications were codeine/paracetamol combination products (20.1% of patients), tramadol (11.5%), zopiclone (9.5%), zolpidem (8.5%), pregabalin (7.9%) and alprazolam (7.8%). CONCLUSIONS: The majority of older people in Ireland are exposed to medications with anticholinergic and/or sedative effects, particularly females and those with multiple comorbidities. The high use of low-dose codeine/paracetamol combination products, Z-drugs and benzodiazepines, suggests there are opportunities for deprescribing. PMID- 29982222 TI - Effect of albumin-globulin score and albumin to globulin ratio on survival in patients with heart failure: a retrospective cohort study in China. AB - OBJECTIVE: To investigate the combined effect of albumin (ALB) and globulin (GLB) on the overall survival (OS) of patients with heart failure (HF). DESIGN: Retrospective cohort study. SETTING: A hospital. PARTICIPANTS: 404 patients first diagnosed with HF. MEASUREMENTS: Serum ALB and GLB were measured within 3 days after admission. The albumin to globulin ratio (AGR) was calculated as the ALB divided by the GLB. The receiver operating characteristic curve was used to calculate the cut-off points for ALB, GLB and AGR. Patients with low ALB levels (<=35.3 g/L) and high GLB levels (>27.0 g/L) were assigned an albumin-globulin score (AGS) of 2, those with only one of the two abnormalities were assigned an AGS of 1 and those with neither of the two abnormalities were assigned an AGS of 0. RESULTS: The mean age of the 404 patients was 62.69+/-15.62, and 54.5% were male. 14 patients were lost to follow-up. 120 patients died from HF and 211 patients were readmitted to the hospital for worsening HF. Multivariate Cox regression analysis showed that higher AGR was significantly associated with favourable OS (HR, 0.61, 95% CI 0.38 to 0.98, p=0.040) but not AGS. CONCLUSION: Serum levels of ALB and GLB are objective and easily measurable biomarkers which can be used in combination to predict the survival of patients with HF. PMID- 29982224 TI - 'Plug and pipe' strategy for treatment of ruptured intracranial aneurysms. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage is a potentially devastating condition, and among the first priorities of treatment is aneurysm occlusion to prevent re-hemorrhage. An emerging strategy to treat patients whose aneurysms are not ideal for surgical or endovascular treatment is subtotal coiling followed by flow diversion in the recovery phase or 'plug and pipe'. However, data regarding the safety and efficacy of this strategy are lacking. METHODS: A retrospective cohort study was performed to evaluate the efficacy and safety of 'plug and pipe'. All patients with a ruptured intracranial aneurysm intentionally, subtotally treated by coiling in the acute stage followed by flow diversion after recovery, were included. The primary outcome was re-hemorrhage. Secondary outcomes included aneurysm occlusion and functional status. Complications were reviewed. RESULTS: 22 patients were included. No patient suffered a re hemorrhage, either in the interval between coiling and flow diversion or in follow-up. The median interval between aneurysm rupture and flow diversion was 3.5 months. Roy-Raymond (R-R) class I or II occlusion was achieved in 91% of target aneurysms at the last imaging follow-up (15/22(68%) R-R 1 and 5/22(23%) R R 2). Complications occurred in 2 (9%) patients, 1 of which was neurological. CONCLUSIONS: Overall, these data suggest that subtotal coiling of ruptured intracranial aneurysms followed by planned flow diversion is both safe and effective. Patients who may most benefit from 'plug and pipe' are those with aneurysms that confer high operative risk and those whose severity of medical illness increases the risk of microsurgical clip ligation. PMID- 29982225 TI - Serum androgen levels are positively correlated with athletic performance and competition results in elite female athletes. PMID- 29982223 TI - Evaluating latent tuberculosis infection diagnostics using latent class analysis. AB - BACKGROUND: Lack of a gold standard for latent TB infection has precluded direct measurement of test characteristics of the tuberculin skin test and interferon gamma release assays (QuantiFERON Gold In-Tube and T-SPOT.TB). OBJECTIVE: We estimated test sensitivity/specificity and latent TB infection prevalence in a prospective, US-based cohort of 10 740 participants at high risk for latent infection. METHODS: Bayesian latent class analysis was used to estimate test sensitivity/specificity and latent TB infection prevalence among subgroups based on age, foreign birth outside the USA and HIV infection. RESULTS: Latent TB infection prevalence varied from 4.0% among foreign-born, HIV-seronegative persons aged <5 years to 34.0% among foreign-born, HIV-seronegative persons aged >=5 years. Test sensitivity ranged from 45.8% for the T-SPOT.TB among foreign born, HIV-seropositive persons aged >=5 years to 80.7% for the tuberculin skin test among foreign-born, HIV-seronegative persons aged >=5 years. The skin test was less specific than either interferon-gamma release assay, particularly among foreign-born populations (eg, the skin test had 70.0% specificity among foreign born, HIV-seronegative persons aged >=5 years vs 98.5% and 99.3% specificity for the QuantiFERON and T-SPOT.TB, respectively). The tuberculin skin test's positive predictive value ranged from 10.0% among foreign-born children aged <5 years to 69.2% among foreign-born, HIV-seropositive persons aged >=5 years; the positive predictive values of the QuantiFERON (41.4%) and T-SPOT.TB (77.5%) were also low among US-born, HIV-seropositive persons aged >=5 years. CONCLUSIONS: These data reinforce guidelines preferring interferon-gamma release assays for foreign-born populations and recommending against screening populations at low risk for latent TB infection. TRIAL REGISTRATION NUMBER: NCT01622140. PMID- 29982226 TI - Whole of community pain education for back pain. Why does first-line care get almost no attention and what exactly are we waiting for? PMID- 29982227 TI - Predictive Ability of Novel Cardiac Biomarkers ST2, Galectin-3, and NT-ProBNP Before Cardiac Surgery. AB - BACKGROUND: Current preoperative models use clinical risk factors alone in estimating risk of in-hospital mortality following cardiac surgery. However, novel biomarkers now exist to potentially improve preoperative prediction models. An assessment of Galectin-3, N-terminal pro b-type natriuretic peptide (NT ProBNP), and soluble ST2 to improve the predictive ability of an existing prediction model of in-hospital mortality may improve our capacity to risk stratify patients before surgery. METHODS AND RESULTS: We measured preoperative biomarkers in the NNECDSG (Northern New England Cardiovascular Disease Study Group), a prospective cohort of 1554 patients undergoing coronary artery bypass graft surgery. Exposures of interest were preoperative levels of galectin-3, NT ProBNP, and ST2. In-hospital mortality and adverse events occurring after coronary artery bypass graft were the outcomes. After adjustment, NT-ProBNP and ST2 showed a statistically significant association with both their median and third tercile categories with NT-ProBNP odds ratios of 2.89 (95% confidence interval [CI]: 1.04-8.05) and 5.43 (95% CI: 1.21-24.44) and ST2 odds ratios of 3.96 (95% CI: 1.60-9.82) and 3.21 (95% CI: 1.17-8.80), respectively. The model receiver operating characteristic score of the base prediction model (0.80 [95% CI: 0.72-0.89]) varied significantly from the new multi-marker model (0.85 [95% CI: 0.79-0.91]). Compared with the Northern New England (NNE) model alone, the full prediction model with biomarkers NT-proBNP and ST2 shows significant improvement in model classification of in-hospital mortality. CONCLUSIONS: This study demonstrates a significant improvement of preoperative prediction of in hospital mortality in patients undergoing coronary artery bypass graft and suggests that biomarkers can be used to identify patients at higher risk. PMID- 29982228 TI - Contemporary Burden and Correlates of Symptomatic Paroxysmal Supraventricular Tachycardia. AB - BACKGROUND: Contemporary data about symptomatic paroxysmal supraventricular tachycardia (PSVT) epidemiology are limited. We characterized prevalence and correlates of symptomatic PSVT within a large healthcare delivery system and estimated national PSVT burden. METHODS AND RESULTS: We identified adults with an encounter for potential PSVT between 2010 and 2015 in Kaiser Permanente Northern California, excluding those with prior known atrial fibrillation or atrial flutter. We adjudicated medical records, ECGs, and other monitoring data to estimate positive predictive values for targeted International Classification of Diseases (ICD), 9th and 10th Revisions codes in inpatient, emergency department, and outpatient settings. Combinations of diagnosis codes and settings were used to calculate PSVT prevalence, and PSVT correlates were identified using multivariable regression. We estimated national rates by applying prevalence estimates in Kaiser Permanente to 2010 US Census data. The highest positive predictive values included codes for "PSVT" in the emergency department (82%), "unspecified cardiac dysrhythmia" in the emergency department (27%), "anomalous atrioventricular excitation" as a primary inpatient diagnosis (33%), and "unspecified paroxysmal tachycardia" as a primary inpatient diagnosis (23%). Prevalence of symptomatic PSVT was 140 per 100 000 (95% confidence interval, 100 179) and was higher for individuals who were older, women, white or black, or who had valvular heart disease, heart failure, diabetes mellitus, lung disease, or prior bleeding. We estimate the national prevalence of symptomatic PSVT to be 168 per 100 000 (95% confidence interval, 120-215). CONCLUSIONS: Selected diagnostic codes in inpatient and emergency department settings may be useful to identify symptomatic PSVT episodes. We project that at least 0.168% of US adults experience symptomatic PSVT, and certain characteristics can identify people at higher risk. PMID- 29982229 TI - Ascending Aortic Strain Analysis Using 2-Dimensional Speckle Tracking Echocardiography Improves the Diagnostics for Coronary Artery Stenosis in Patients With Suspected Stable Angina Pectoris. AB - BACKGROUND: Arterial stiffening and atherosclerosis tend to coexist. Strain imaging, using a 2-dimensional speckle tracking (2D-ST) method, has been used for arterial stiffness assessment and early identification of atherosclerosis. We investigated whether the ascending aortic strain assessed by 2D-ST echocardiography at rest can predict the presence of coronary artery disease (CAD). METHODS AND RESULTS: Two hundred seventy-one consecutive patients with suspected stable angina pectoris sequentially underwent exercise treadmill testing, 2-dimensional echocardiography, M-mode echocardiography, 2D-ST echocardiography, and coronary angiography. Circumferential ascending aortic strain (CAAS) and radial ascending aortic strain were assessed by 2D-ST echocardiography. Ninety-two patients with coronary lumen area stenosis >=70% were categorized as having significant CAD. Global CAAS was significantly lower in patients with significant CAD (7.41+/-2.30% versus 11.54+/-4.03%; P<0.001) and remained an independent predictor of significant CAD (odds ratio, 0.64 [0.54 0.75]; P<0.001) after multivariate regression. Based on the receiver operating characteristic curve for diagnosing significant CAD, the optimal cut-off value of global CAAS was <=9.22% (sensitivity, 86%; specificity, 70%; area under curve=0.82; P<0.001). Global CAAS decreased with increasing severity of CAD and was significantly associated with 3-vessel disease (odds ratio, 0.58 [0.42-0.79]; P<0.001). Diagnostics for significant CAD were remarkably better for global CAAS combined with exercise treadmill testing than for exercise treadmill testing alone (area under curve=0.88 versus 0.78; P<0.001). CONCLUSIONS: Global CAAS assessed by 2D-ST echocardiography at rest was able to predict the presence of significant CAD and identify multivessel disease. In addition, global CAAS combined with exercise treadmill testing remarkably improved the diagnostics for significant CAD. PMID- 29982230 TI - Transcatheter Aortic and Mitral Valve-in-Valve Implantation Using the Edwards Sapien 3 Heart Valve. PMID- 29982231 TI - Endovascular Thrombectomy for Acute Basilar Artery Occlusion: A Multicenter Retrospective Observational Study. AB - BACKGROUND: Despite the recent acceptance of thrombectomy as the standard of care in patients with acute anterior circulation stroke, the benefits of thrombectomy remain uncertain for patients with acute basilar artery occlusion (BAO). This study aimed to evaluate the effectiveness and safety of thrombectomy and to identify predictors of outcomes in a large cohort of patients with acute BAO. METHODS AND RESULTS: This study included 212 consecutive patients with acute BAO who underwent either stent-retriever or contact aspiration thrombectomy as the first-line approach between January 2011 and August 2017 at 3 stroke centers. Clinical and radiologic data were prospectively collected and stored in a database at each center. Multivariable ordinal logistic regression was performed to assess the association between each characteristic and 90-day modified Rankin scale scores. Reperfusion was successful in 91.5% (194/212) of patients; 44.8% (95/212) of patients achieved 90-day modified Rankin scale 0 to 2. The symptomatic hemorrhage rate was 1.9% (4/212) and mortality was 16% (34/212). In a multivariable ordinal regression, younger age, lower National Institute of Health stroke scale on admission, and absence of diabetes mellitus and parenchymal hematoma were significantly associated with a favorable shift in the overall distribution of 90-day modified Rankin scale scores. Treatment outcomes were similar between patients who received stent-retriever thrombectomy and contact aspiration thrombectomy as the first-line technique. CONCLUSIONS: Endovascular thrombectomy was effective and safe for treating patients with acute BAO. Age, the baseline National Institute of Health stroke scale, diabetes mellitus, and parenchymal hematoma were associated with better outcomes. This study showed no superiority of the stent-retriever over the aspiration thrombectomy for treating acute BAO. PMID- 29982232 TI - International Validation of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention in Post-MI Patients: A Collaborative Analysis of the Chronic Kidney Disease Prognosis Consortium and the Risk Validation Scientific Committee. AB - BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS2 degrees P), a 0-to-9-point system based on the presence/absence of 9 clinical factors, was developed to classify the risk of major adverse cardiovascular events (MACE) (a composite of cardiovascular death, recurrent myocardial infarction, or ischemic stroke) among patients with a recent myocardial infarction. Its performance has not been examined internationally outside of a clinical trial setting. METHODS AND RESULTS: We evaluated the performance of TRS2 degrees P for predicting MACE in 53 599 patients with recent myocardial infarction in 5 international cohorts from New Zealand, South Korea, Sweden, and the United States participating in the Chronic Kidney Disease Prognosis Consortium. Overall, there were 19 444 cases of MACE across 5 cohorts over a mean follow-up of 5 years, and the overall MACE rate ranged from 5.0 to 18.4 (per 100 person-years). The TRS2 degrees P showed modest calibration (Brier score ranged from 0.144 to 0.173) and discrimination (C-statistics >0.61 in all studies except 1 from Korea with 0.55) across cohorts relative to its original Brier score of 0.098 and C-statistic of 0.67 in the derived data set. Although there was some heterogeneity across cohorts, the 9 predictors in the TRS2 degrees P were generally associated with higher MACE risk, with strongest associations observed (meta-analyzed adjusted hazard ratio 1.6-1.7) for history of heart failure, age >=75 years, and prior stroke, followed by peripheral artery disease, kidney dysfunction, diabetes mellitus, and hypertension (hazard ratio 1.3-1.4). Prior coronary bypass graft surgery and smoking did not reach statistical significance (hazard ratio ~1.1). CONCLUSIONS: TRS2 degrees P, a simple scoring system with 9 routine clinical factors, was modestly predictive of secondary events when applied in patients with recent myocardial infarction from diverse clinical and geographic settings. PMID- 29982233 TI - Body Mass Index and Sudden Cardiac Death in Japanese Patients After Acute Myocardial Infarction: Data From the JCAD Study and HIJAMI-II Registry. AB - BACKGROUND: Although an "obesity paradox" exists in patients after myocardial infarction, the association between obesity and the risk of sudden cardiac death (SCD) is limited. The aim of this study was to determine whether obesity is associated with an increased risk of SCD in Japanese survivors of acute myocardial infarction. METHODS AND RESULTS: Pooled data from 2 cohort studies in Japan, JCAD (Japanese Coronary Artery Disease) study and the Heart Institute of Japan Acute Myocardial Infarction-II (HIJAMI-II) registry, comprising of 6216 patients (mean age 65+/-11 years, 75.2% male) with acute myocardial infarction who were discharged alive, were studied. The patients were categorized into the following body mass index (BMI) groups at baseline according to the World Health Organization classification for Asian populations: BMI <18.5 kg/m2 (n=335), 18.5 to 23 kg/m2 (n=2371), 23 to 27.5 kg/m2 (n=2823), and >=27.5 kg/m2 (n=687). The main outcomes were all-cause mortality and SCD. During an average follow-up period of 3.6+/-1.4 years, all-cause mortality was 10.1%, and SCD was 1.2%. Patients with BMI <18.5 kg/m2 had the highest rate of all-cause mortality (adjusted hazard ratio, 1.61; 95% confidence interval, 1.20-2.16), but high BMI (>=27.5 kg/m2) was not associated with mortality compared with patients in the group with BMI >=18.5 and <23 kg/m2. However, the long-term risk of SCD was increased in the group with BMI >=27.5 kg/m2 (adjusted hazard ratio, 2.97; 95% confidence interval, 1.24-7.15). Multivariate analysis revealed that BMI >=27.5 kg/m2 was associated with an increased risk of SCD (hazard ratio, 2.78; 95% confidence interval, 1.35-5.74). CONCLUSIONS: Obesity (BMI >=27.5 kg/m2) was associated with the risk of SCD in Japanese patients after myocardial infarction, although an obesity paradox was found for all-cause mortality. PMID- 29982234 TI - Breast tumour resembling tall cell variant of papillary thyroid carcinoma: case presentation (in a patient with Lynch syndrome). PMID- 29982235 TI - Harmonization in laboratory medicine: Blowin' in the wind. PMID- 29982236 TI - Semantics for an Integrative and Immersive Pipeline Combining Visualization and Analysis of Molecular Data. AB - The advances made in recent years in the field of structural biology significantly increased the throughput and complexity of data that scientists have to deal with. Combining and analyzing such heterogeneous amounts of data became a crucial time consumer in the daily tasks of scientists. However, only few efforts have been made to offer scientists an alternative to the standard compartmentalized tools they use to explore their data and that involve a regular back and forth between them. We propose here an integrated pipeline especially designed for immersive environments, promoting direct interactions on semantically linked 2D and 3D heterogeneous data, displayed in a common working space. The creation of a semantic definition describing the content and the context of a molecular scene leads to the creation of an intelligent system where data are (1) combined through pre-existing or inferred links present in our hierarchical definition of the concepts, (2) enriched with suitable and adaptive analyses proposed to the user with respect to the current task and (3) interactively presented in a unique working environment to be explored. PMID- 29982237 TI - From Virtual Reality to Immersive Analytics in Bioinformatics. AB - Bioinformatics-related research produces huge heterogeneous amounts of data. This wealth of information includes data describing metabolic mechanisms and pathways, proteomics, transcriptomics, and metabolomics. Often, the visualization and exploration of related structural - usually molecular - data plays an important role in the aforementioned contexts. For decades, virtual reality (VR)-related technologies were developed and applied to Bioinformatics problems. Often, these approaches provide "just" visual support of the analysis, e.g. in the case of exploring and interacting with a protein on a 3D monitor and compatible interaction hardware. Moreover, in the past these approaches were limited to cost intensive professional visualization facilities. The advent of new affordable, and often mobile technologies, provides high potential for using similar approaches on a regular basis for daily research. Visual Analytics is successfully being used for several years to analyze complex and heterogeneous datasets. Immersive Analytics combines these approaches now with new immersive and interactive technologies. This publication provides a short overview of related technologies, their history and Bioinformatics-related approaches. Six new applications on the path from VR to Immersive Analytics are being introduced and discussed. PMID- 29982238 TI - Three new Brazilian cases of 17alpha-hydroxylase deficiency: clinical, molecular, hormonal, and treatment features. AB - BACKGROUND: Deficiency of 17alpha-hydroxylase (17OHD) is a rare form of adrenal hyperplasia. Diagnosis is generally delayed, impairing appropriate treatment. CASE PRESENTATION: Here, we report the clinical, molecular, hormonal, and treatment data of three unrelated 17OHD patients, aged 14-16 years with hypergonadotrophic hypogonadism; uncontrolled hypertension; primary adrenal insufficiency; and high progesterone, low to normal potassium, and low dehydroepiandrosterone, androstenedione, and testosterone levels. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) at baseline and after an adrenocorticotropic hormone test showed low cortisol and cortisone and high deoxycorticosterone (DOC) and corticosterone levels; both DOC/21 deoxycortisol and costicosterone/cortisol ratios were very high. Patient 2 had 46,XX karyotype and patients 1 and 3, had 46,XY. A molecular analysis showed that two of the patients were homozygous for p.W406R mutation and the other patient was compound heterozygous for p.W406R and p.P428L. Hypertension was controlled only after the administration of both prednisone and mineralocorticoid antagonist. CONCLUSIONS: Hypertension in young women must lead to diagnostic suspicion, even in the pre-pubertal period. The basal level of progesterone is an indicator of 17OHD. Mineral and glucocorticoid ratios obtained from LC-MS/MS can reinforce the diagnosis. Hypertension can be controlled using glucocorticoid replacement therapy and mineralocorticoid antagonist. PMID- 29982239 TI - Symptomatic Rathke cleft cyst in paediatric patients - clinical presentations, surgical treatment and postoperative outcomes - an analysis of 38 cases. AB - BACKGROUND: Rathke cleft cysts (RCC) are benign, epithelium-lined intrasellar and/or suprasellar cysts believed to originate from the remnants of the Rathke pouch. The aim of this study was to analyse the symptoms and surgical outcome of patients with the diagnosis of RCC verified in a histopathological examination of the postoperative material. METHODS: The study is a retrospective analysis of 38 cases of children who underwent a neurosurgical treatment due to RCC at the Children's Memorial Health Institute in Warsaw, Poland, between 1994 and 2015. RESULTS: At diagnosis, the mean age was 13 years and 8 months (6 years and 11 months-17 years and 10 months, sex ratio was 1:0.9 with a female prevalence). The most common symptoms were the following: headache (50%), hypothyroidism (50%), short stature and/or decreased growth velocity (47%), delayed puberty and menstrual abnormalities (37%), diabetes insipidus or polydipsia and polyuria (26%), adrenal dysfunction (26%), sleepiness and general weakness (13%) and visual disturbances (11%). Due to the gravity of symptoms and size of the lesion, all the patients underwent a surgical treatment. All but one were successful (one patient died due to postoperative neurosurgical complications). The most common postoperative complications were the following: adenohypopituitarism (67%) and diabetes insipidus (45%). CONCLUSIONS: RCC can present with serious symptoms that significantly deteriorate patients' quality of life. Despite a successful neurosurgical treatment in most of the analysed cases, patients required long term pharmacological treatment. PMID- 29982240 TI - The natural environment as a reservoir of pathogenic and non-pathogenic Acinetobacter species. PMID- 29982241 TI - Evaluation of implicit associations between back posture and safety of bending and lifting in people without pain. AB - Background and aims Despite lack of support from recent in vivo studies, bending and lifting (especially with a round-back posture) are perceived as dangerous to the back. In light of this view, it has been proposed that pain-free people may hold a common implicit belief that is congruent with the idea that bending and lifting with a round-back represents danger to a person's back, however this has not been evaluated. The aims of this study were: (1) to evaluate implicit associations between back posture and safety related to bending and lifting in pain-free people; (2) to explore correlations between the implicit measure and explicit measures of back beliefs, fear of movement and safety of bending; (3) to investigate self-reported qualitative appraisal of safe lifting. Methods Exploratory cross-sectional study including 67 pain-free participants (no pain, or average pain <=3/10 for less than one week over the previous 12 months) (52% male), who completed an online survey containing demographic data and self reported measures of: fear of movement (Tampa Scale for Kinesiophobia for General population - TSK-G), back beliefs (Back Pain Attitudes Questionnaire BackPAQ), and bending beliefs (Bending Safety Belief - BSB - a pictorial scale with images of a person bending/lifting with round and straight back postures). Implicit associations between back posture and safety related to bending and lifting were evaluated with the Implicit Association Test (IAT). A qualitative assessment of descriptions of safe lifting was performed. Results An implicit association between "danger" and "round-back" bending/lifting was evident in all participants (IATD-score=0.65 (SD=0.45; 95% CI [0.54, 0.76]). Participants' profile indicated high fear of movement, unhelpful back beliefs, and perceived danger to round-back bending and lifting (BSBThermometer: 5.2 (SD=3.8; 95% CI [4.26, 6.13] range -10 to 10; t(67)=11.09, p<0.001). There was a moderate correlation between IAT and BSBThermometer (r=0.38, 95% CI [0.16, 0.62]). There were weaker and non statistically significant correlations between IAT and TSK-G (r=0.28, 95% CI [ 0.02, 0.47]), and between IAT and BackPAQDanger (r=0.21, 95% CI [-0.03, 0.45]). Qualitative assessment of safe lifting descriptions indicated that keeping a "straight back" and "squatting" when lifting were the most common themes. Conclusions Pain-free people displayed an implicit bias towards bending and lifting with a "round-back" as dangerous. Our findings support the idea that pain free people may have a pre-existing belief about lifting, that the back is in danger when rounded. Research to evaluate the relationship between this implicit bias and lifting behaviour is indicated. Implications The findings of this study may have implications for ergonomic guidelines and public health information related to bending and lifting back postures. Additionally, clinicians may need to be aware of this common belief, as this may be reflected in how a person responds when they experience pain. PMID- 29982242 TI - Implementation of Intravenous Drip Infusion Therapy with Peripheral Venous Catheters and the Incidence of Related Complications in Home-Based Medical Care Settings in Japan. AB - BACKGROUND/AIMS: Home-based medical care is rapidly expanding in Japanese health care settings. We aimed to clarify the implementation status of drip injection with peripheral venous catheters (PVCs) and the incidence of related complications. METHODS: We investigated the number of patients who required intravenous drip infusion therapy at home. We also examined the incidence rate of PVC-related complications and their statistical correlation with patients' characteristics. RESULTS: Of 139 patients, 30 (21.6%) received intravenous drip infusion therapy through PVCs at home. Patients' activities of daily living (bed ridden) and the presence of underlying disease (terminal cancer) were significantly correlated with the requirement for drip infusion therapy (p < 0.0001 and p < 0.0001, respectively). A high incidence of PVC-related complications (75%: 15 out of 20 patients) was observed. More than 50% of patients experienced multiple needling due to difficulty in securing venous access. CONCLUSIONS: This is the first report to reveal the relatively high incidence of PVC-related complications in home-based medical care settings. Safer vascular devises should be incorporated for more stable intervention. PMID- 29982243 TI - Cerebrovascular Accident Risk in a Population with Periodic Limb Movements of Sleep: A Preliminary Meta-Analysis. AB - BACKGROUND AND PURPOSE: Periodic limb movements of sleep (PLMS) are usually comorbid with hypertension, tachycardia, and coronary arterial diseases, which are also risk factors for cerebrovascular accidents (CVA). However, evidence about the relationship between CVA and PLMS is still weak. The aim of this study was to investigate (1) the prevalence of CVA in patients with PLMS, and (2) the severity of PLMS in patients with or without CVA through a meta-analysis. METHODS: The electronic databases of PubMed, Embase, ScienceDirect, ClinicalKey, Cochrane Library, ProQuest, Web of Science, and ClinicalTrials.gov were searched. The inclusion criteria were (1) articles investigating comorbidity between PLMS and CVA, and (2) clinical trials in humans. RESULTS: This meta-analysis included (1) 9,823 patients with PLMS and 9,416 controls from 5 studies to analyze the prevalence of CVA in PLMS, and (2) 158 patients with PLMS with CVA and 88 PLMS controls without CVA from 3 studies to analyze the severity of PLMS with and without CVA. The results showed (1) significantly higher comorbidity rates of CVA in the patients with PLMS than in the controls without PLMS (OR 1.267, p = 0.019), and (2) higher PLM index in the patients with CVA than in the controls (Hedges' g = 0.860, p = 0.001; means difference: 4.435, p = 0.016). CONCLUSIONS: The results revealed (1) a worse severity of PLMS in the patients with CVA, and (2) increased prevalence of CVA in the patients with PLMS. Based on our results, the patients had a higher prevalence of CVA within 8 years of a diagnosis of PLMS compared to those without PLMS by about 1.3-fold. Whether (1) patients with PLMS receiving treatment have a similar incidence of stroke to those without PLMS, and (2) secondary stroke prevention can lower the severity of PLMS or whether those with severe PLMS have a higher risk of stroke is still inconclusive. Future studies investigating the prevalence of CVA in patients with PLMS should use a follow-up period of over 8 years. PMID- 29982244 TI - Challenges in Diagnosing Myelodysplastic Syndromes in the Era of Genetic Testing: Proceedings of the 13th Workshop of the European Bone Marrow Working Group. AB - The 13th workshop of the European Bone Marrow Working Group in Utrecht, The Netherlands, was devoted to studying myelodysplastic syndromes (MDS) and their boundaries. The panel received 44 cases submitted to the 3 invited categories, which included: reactive cytopenias with dysplasia, idiopathic cytopenia of undetermined significance, clonal haematopoiesis of indeterminate potential, idiopathic dysplasia of uncertain significance and overt MDS. For this summary, we have selected 17 cases that highlight difficulties in separating true MDS from other causes of cytopenia and the intricate relationship between clonal haematopoiesis and true MDS. In addition, cases of overt MDS with challenging features were also selected. All cases were stained for p53 expression. Using instructive submitted cases we discuss the following: (1) cytopenia with clonal haematopoiesis not fulfilling MDS criteria, (2) cytopenia and/or dysplasia with germline mutations and/or familial history suggesting an underlying gene defect, (3) MDS based on a recurrent chromosomal abnormality and (4) overt MDS with diagnostic difficulties due to concurrent treatment or disease. The lively discussion in the open forum of the workshop illustrated the need for better integrative understanding of the evolution of acquired genetic abnormalities in haematopoiesis, and the challenge of diagnosing true MDS in cytopenic patients with genetic abnormalities, either germline or acquired. PMID- 29982245 TI - Treatment of Chronic Pulmonary Aspergillosis: Current Standards and Future Perspectives. AB - Chronic pulmonary aspergillosis (CPA) complicates conditions including tuberculosis, chronic obstructive pulmonary disease and sarcoidosis, and is associated with high morbidity and mortality. Surgical cure should be considered where feasible; however, many patients are unsuitable for surgery due to extensive disease or poor respiratory function. Azoles are the only oral drug with anti-Aspergillus activity and itraconazole and voriconazole are considered as first-line drugs. A randomized controlled trial demonstrated improvement or stability in three-quarters of patients given 6 months of itraconazole, but a quarter relapsed on stopping therapy. Long-term treatment may therefore be required in some cases. Itraconazole, voriconazole and posaconazole require therapeutic drug monitoring. No published data are yet available for isavuconazole. Adverse drug effects of azoles are common, including peripheral neuropathy, heart failure, elevated liver enzymes, QTc prolongation and sun sensitivity. Many serious drug-drug interactions occur, including major interactions with rifamycins, simvastatin, warfarin, clopidogrel, immunosuppressant drugs like sirolimus. Furthermore, drug resistance occurs, including cross-resistance to all azoles, but the true prevalence is not yet determined. Intravenous therapy is possible with echinocandins or amphotericin B, but long-term use is challenging. Hemoptysis complicates CPA and can be fatal. Tranexamic acid should be given acutely to reduce bleeding. Bronchial artery embolization can stop acute bleeds. In some circumstances, emergency surgery may be necessary to resect the source of the bleed. Current CPA treatments can be beneficial but have many drawbacks. New oral anti-Aspergillus agents are needed, along with optimization of currently available treatments. PMID- 29982246 TI - Ranolazine Prevents Levosimendan-Induced Atrial Fibrillation. AB - OBJECTIVES: Levosimendan is a calcium sensitizer that is used as positive inotropic drug in acute decompensated heart failure. An increased incidence of atrial fibrillation after levosimendan-treatment was observed in clinical and experimental studies. Due to the limited range of antiarrhythmic drugs, the aim of the present study was to assess potential antiarrhythmic effects of ranolazine in levosimendan-pretreated isolated rabbit hearts. METHODS: Twelve rabbit hearts were excised and retrogradely perfused employing the Langendorff setup. Left and right atrial catheters were used to record monophasic action potentials and to obtain cycle length-dependent atrial action potential durations (aAPD90) and effective refractory periods (aERP). After obtaining baseline data, 0.5 umol/L levosimendan was infused. Subsequently, 10 umol/L ranolazine was administered. RESULTS: Infusion of levosimendan led to a reduction of aAPD90 (-9 ms, p < 0.05) and aERP (-13 ms, p < 0.05). Additional treatment with ranolazine prolonged aAPD90 (+23 ms, p < 0.01) and aERP (+30 ms, p < 0.05). Under baseline conditions, a predefined pacing protocol induced 77 episodes of atrial fibrillation. Infusion of levosimendan enhanced the vulnerability to atrial fibrillation (132 episodes, p = 0.14). Further treatment with ranolazine had a significant antiarrhythmic effect (61 episodes, p < 0.05). CONCLUSIONS: In this study, ranolazine seems to prevent atrial fibrillation in levosimendan-pretreated hearts. Underlying mechanism is a prolongation of atrial repolarization and aERP. PMID- 29982247 TI - Biochemical and Molecular Mechanisms of Platelet-Rich Plasma in Ameliorating Liver Fibrosis Induced by Dimethylnitrosurea. AB - BACKGROUND/AIMS: Hepatic fibrosis is a wound-healing process in the chronically injured liver. Clinical application of platelet-rich plasma (PRP) is of considerable interest for wound healing and regeneration. In view of the regeneration effect of PRP, we designed this study to explore the hypothesis that PRP could play a role in improving the biochemical and molecular changes that occur in liver fibrosis induced by dimethylnitrosamine (DMN) in rats. METHODS: Four groups were studied: control, PRP control, DMN (liver fibrosis), and DMN+PRP groups. Serum liver enzymes (alanine amino transferase ALT, aspartate amino transferase AST, gamma glutamyl transferase GGT, and lactate dehydrogenase LDH), and liver hydroxyproline content were measured colorimetrically.Interleukin-8 (IL 8) and B-cell lymphoma (Bcl2) were determined by enzyme-linked immunosorbent assay. And the expression levels of alpha-smooth muscle actin (alpha-SMA) ,transforming growth factor (TGF-beta), and nuclear factor kappa B1(NF-?B1) were evaluated by quantitative real-time polymerase chain reaction. RESULTS: Our results showed that PRP markedly improved the DMN-induced changes in liver enzymes accompanied by a significant decrease in liver hydroxyproline content and IL-8 level induced by DMN, and an increase in the anti-apoptotic marker Bcl-2. PRP also showed significant down-regulation of fibrosis-related genes alpha-SMA and TGF-beta and a significant decrease in the inflammatory marker NF-?B1. CONCLUSION: Based on these encouraging results, we consider that PRP could be a promising new agent for liver regeneration and alleviation of fibrosis. PMID- 29982248 TI - Comparison of 2 Perioperative Management Protocols and Their Influence on Postoperative Recovery after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Standard Parenteral Nutrition, Selective Bowel Decontamination and Suprapubic Catheters? AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is associated with considerable postoperative morbidity, including ileus and infectious complications. Perioperative care is believed to be an important factor for the development and treatment of postoperative morbidity. PATIENTS AND METHODS: Data on case-matched patients from a retrospective database of 2 Dutch HIPEC centres was compared. Patient selection and procedures were identical in both hospitals although perioperative management items differ slightly. In centre B, immediate total parenteral nutrition (TPN), suprapubic urine bladder catheter placement (SPCs) and selective decontamination of the digestive-tract are standard care for CRS-HIPEC patients, while in centre A, they are not. RESULTS: From a total of 223 patients, 68 consecutive patients from centre B were compared to 68 matched patients from centre A. TPN was administered to 54.4% of patients in centre A because of prolonged ileus, whereas it was standard of care in centre B. In all, 105 (77.2%) patients experienced postoperative complications including 17.6% who had a grades III-IV complication. The incidence of grade III-V complications was 18 (26.4%) in centre A and 8 (11.8%) in centre B (p = 0.03). Median hospital stay was 12 days (7-84) in A and 11(6-80) in centre B (p = 0.546). CONCLUSIONS: Gastrointestinal recovery after CRS-HIPEC seems to take longer as compared to other surgical procedures. Between the 2 centres, a significant difference in severe complications was found, while standard TPN, selective bowel decontamination and SPCs were the only identified differences in perioperative care. PMID- 29982249 TI - Study on the Association between the Fibroblast Growth Factor Receptor 4 Expression and High-Risk Human Papillomavirus Infection in Cervical Cancer and Precancerous Lesions. AB - AIMS: To discuss the correlation between the expression of fibroblast growth factor receptor 4 (FGFR4) and human papillomavirus (HPV) infection in cervical cancer and precancerous lesions. METHODS: One hundred and sixty four cases of cervical lesions tissue samples were collected (60 cases of cervical cancer, 38 cases of cervical intraepithelial neoplasia [CIN] stage I, 32 cases of CIN II, 34 cases of CIN III). HPV infection status and expression strength of FGFR4 of all samples were detected and compared among different groups. The correlation between the HPV infection and the expression strength of FGFR4 was analyzed. RESULTS: There were differences of the HPV infection status and type distribution and FGFR4 expression strength among the 4 groups; The infection rate of high-risk HPV in cervical cancer group was higher than that of the 3 CIN groups. The FGFR4 positive expression rate of the cervical cancer group was also obviously higher than that of the 3 CIN groups; HPV infection was correlated with the FGFR4 expression strength and the FGFR4 expression was stronger when infected with high risk type HPV. CONCLUSION: The expression of FGFR4 in the cervical cancer and CIN tissues was correlated with the HPV infection and the FGFR4 may be involved in the development of the HPV-infected cervical lesions. PMID- 29982250 TI - Genetic Factors and Molecular Mechanisms of Vitamin D and Obesity Relationship. AB - Vitamin D (vitD) deficiency is associated with a wide range of chronic diseases and conditions, including obesity, and with an increasing severity of metabolic dysregulation, such as insulin resistance, hyperlipidemia, liver disease, and hypertension, both in children and adults. However, the nature of the association between low vitD status and obesity remains unclear. This fact has motivated the scientific community to conduct genetic association analyses between 25 hydroxyvitamin D (25[OH]D)-related genes and obesity traits. In this line, the variation in the vitD receptor (VDR) gene represents the bulk of the findings. Specifically, polymorphisms in the VDR gene have been associated with obesity traits in some but not all, studies. Thus, results regarding this matter remain inconclusive. Other genes aside from VDR have also been investigated in relation to obesity-related traits. However, again, findings have been inconsistent. In general, results point to the fact that the DBP/GC gene could be an important protein-linking obesity and vitD status. On the other hand, several studies have attempted to determine the molecular mechanism of the relationship between 25(OH) D levels and obesity. Some of these studies suggest that vitD, due to its fat soluble characteristic, is retained by the adipose tissue and has the capacity to metabolize 25(OH)-D locally, and this can be altered during obesity. Additionally, vitD is capable of regulating the gene expression related to adipogenesis process, inflammation, oxidative stress, and metabolism in mature adipocytes. Therefore, the aim of the present review was to evaluate the association between obesity and vitD deficiency describing the main molecular mechanism of the relationship and the link with genetic factors. Key Messages: Low serum 25(OH)-D is positively associated with obesity or BMI in adults and children. Circulating vitD concentrations are, at least, partially determined by genetic factors. VitD plays an important role in the adipogenesis process and inflammation status in adipocytes and adipose tissue. PMID- 29982251 TI - Clinical Outcomes and Predictors of Satisfaction in Patients with Improved Lithium Disilicate All-Ceramic Crowns. PMID- 29982252 TI - The Expression of MAS1, an Angiotensin (1-7) Receptor, in the Eutopic Proliferative Endometria of Endometriosis Patients. AB - BACKGROUND/AIM: We demonstrated that AT1 and AT2 are expressed and both pathways balance the renin-angiotensin system in endometriosis. MAS1, a specific receptor of angiotensin (1-7), opposes AT1 pathway-associated tissue remodelling. It is not known whether MAS1 has an effect on the pathogenesis of endometriosis or not. MATERIALS AND METHODS: Ovarian endometriotic tissues (endo-Ov) and eutopic endometrial tissues (endo-Em) were obtained from 29 patients with endometrial cysts. Normal endometrial tissues (cont-Em) were obtained from patients without endometriosis. Immunohistochemical staining was performed for MAS1, AT1 and AT2 in the endometriosis-associated tissues. The mRNA levels of these receptors were examined by quantitative reverse transcription PCR. RESULTS: MAS1 was immune positive at the apical side of the glandular epithelium in the endometriotic lesions. The MAS1 mRNA levels in endo-Ov were increased significantly, irrespective of the menstrual cycle phase. The MAS1 mRNA levels were significantly higher in the proliferative-tissues of the endometriosis patients than in those of the controls. The ratio of the MAS1 to the AT1 mRNA in the proliferative tissues was increased predominantly in the endometriosis patients compared with that in the controls. CONCLUSION: High MAS1 expression in the endometrium might promote the initiation of endometriosis via migration of proliferative tissue. PMID- 29982253 TI - Immunomodulatory and Kidney-Protective Effects of the Human Chorionic Gonadotropin Derivate EA-230. AB - The systemic inflammatory response following infectious or non-infectious insults is related to morbidity (including acute kidney injury) and mortality. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230, a linear tetrapeptide (Alanine-Glutamine-Glycine-Valine), derived from the beta-chain of the human chorionic gonadotropin hormone, has shown immunomodulatory and renoprotective properties in several pre-clinical animal models of systemic inflammation. Furthermore, an excellent safety profile of EA 230 was observed in phase 1 studies in humans, and the immunomodulatory effects of EA-230 were recently demonstrated in a phase IIa study during human experimental endotoxemia. A prospective double-blind placebo-controlled randomized trial in 180 patients undergoing elective CABG-surgery with or without valve surgery is currently conducted to investigate the immunomodulatory and renoprotective properties of EA-230. PMID- 29982255 TI - Effect of Prone and Supine Positioning on Computed Tomography Urography Examination. AB - OBJECTIVES: The aim of this study is to evaluate the effects of performing computed tomography (CT) urogram in the prone position in terms of diagnosis. METHODS: CT urograms of 208 patients imaged randomly in the prone and supine positions were included in this study. A total of 199 patients and 370 collecting systems were examined in total. Axial raw data and reconstructed coronal thin and thick MIP images with a slice thickness of 5 mm were evaluated by 2 independent radiologists blinded to the initial diagnosis. Renal collecting system, ureters, and bladder were included in radiological evaluation. Anatomically, the renal collecting system was separated into 7 regions. Filling and dilatation of collecting systems were evaluated via images at urogram phase by scoring. RESULTS: Filling in lower pole infundibulum (p = 0.006), distal ureter (p = 0.006); and highly dilated lower pole calyx (p = 0.020), pelvis (p = 0.006), and bladder (p < 0.001) were determined to be better in images in the prone position compared to the supine position. There were no statistical differences in other regions. CONCLUSION: Better contrast material filling is achieved in dilated or non-dilated lower pole collecting system, dilated renal pelvis, non-dilated distal ureter of kidney, and in the bladder only by imaging the urogram phase in the prone position compared to the supine position. Additionally, presence of dilatation is a factor that could adversely affect filling. Studies in the future may investigate the contribution of prone positioning to CT urogram with larger series comparing it with other methods and modalities. PMID- 29982254 TI - The Impact of Pregnancy on Hemorrhagic Stroke in Young Women. AB - BACKGROUND: Pregnancy is a sex-specific risk factor for causing hemorrhagic stroke (HS) in young adults. Unique physiological characteristics during pregnancy may alter the relative risk for HS in pregnant/postpartum (PP) women compared to HS in other young women. We compared patient characteristics and HS subtypes between young non-pregnant and PP women. METHODS: We reviewed the medical records of all women 18-45 years old admitted to our center with HS from October 15, 2008 through March 31, 2015, and compared patient characteristics and stroke mechanisms using logistic regression. RESULTS: Of the 130 young women with HS during the study period, 111 were non-PP women, and 19 PP women. PP women had lower proportions of vascular risk factors such as hypertension, prior stroke, and smoking, and a higher proportion of migraine (36.8 vs. 14.4%, p = 0.01). After adjusting for hypertension, smoking, migraine, prior stroke and prior myocardial infarction, PP women had lower odds of having an underlying vascular lesion (OR 0.14, 95% CI 0.04-0.44, p = 0.0009) and a higher proportion of the reversible cerebral vasoconstriction syndrome (RCVS) as cause of their HS. CONCLUSIONS: Women with pregnancy-associated HS had fewer cerebrovascular risk factors, lower odds of having -underlying vascular lesions, and higher proportion of -migraine and RCVS compared with similar-aged non--pregnant women. Pregnancy associated HS appears to represent a unique pathophysiological process, requiring targeted study. PMID- 29982256 TI - Erratum. PMID- 29982257 TI - Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects. AB - BACKGROUND: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. METHODS: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5-25 mg) or ramipril (n = 9, 2.5-10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. RESULTS: CSF reached 4.1% (interquartile ranges 2.5-5%) of total serum concentrations for HCT and 2.3% (1.7-5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. CONCLUSION: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain. PMID- 29982258 TI - Cyanidin Protects SH-SY5Y Human Neuroblastoma Cells from 1-Methyl-4 Phenylpyridinium-Induced Neurotoxicity. AB - Cyanidin is an anthocyanidin extracted from a variety of fruits and vegetables. Cyanidin showed benefits against diabetes, cancer, and atherosclerosis. However, the potential neuroprotective effects of cyanidin against Parkinson's disease (PD) have not been examined. Indicated concentrations of cyanidin (1, 3, 10, and 30 MUmol/L) were incubated together with 0.5 mmol/L 1-methyl-4-phenylpyridinium (MPP+) to human neuroblastoma SH-SY5Y cells. We found cyanidin prevented MPP+ induced cell demise in a concentration-dependent manner. Cyanidin significantly reduced MPP+-induced apoptosis, this is reflected by decreased TdT-mediated dUTP nick-end labeling staining and caspase-3 expressions. Further, MPP+ increased the Bax/Bcl-2 ratio, which was partly reversed by cyanidin. We also found cyanidin attenuated the MPP+-induced mitochondrial oxidative stress as revealed by decreased MitoSOX staining. Taken together, these data for the first time indicated the -neuroprotective effects of cyanidin against MPP+-induced -SH-SY5Y cell death. These findings shed light on the potential implications of cyanidin for PD treatment. PMID- 29982259 TI - Iron Homeostasis Pathways as Therapeutic Targets in Acute Kidney Injury. AB - BACKGROUND: Iron is critical for fundamental biologic functions such as cell division and mitochondrial electron transport. However, by the virtue of its ability to donate electrons, iron is probably the most effective oxidant in biologic systems. SUMMARY: To avoid damage from iron-mediated oxidative injury or ferroptosis, multiple defense mechanisms exist including iron binding proteins and robust glutathione-dependent intracellular pathways. Hepcidin, through its ability to sequester iron within macrophages and induce H-ferritin, serves as an endogenous protective molecule against ferroptosis. Key Messages: Recent studies have demonstrated the protective role of hepcidin in both ischemic reperfusion injury and heme-mediated models of acute kidney injury (AKI). Ferroptosis inhibiting drugs and hepcidin offer exciting novel prospects to treat AKI. PMID- 29982260 TI - Comparison of Serum A Disintegrin and Metalloproteinase with Thrombospondin Motifs-19 Levels in Different Fertility Situations: Could It Be a Serum Marker of Ovarian Function and Oocyte Pool? AB - BACKGROUND/AIMS: A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) enzymes take part in extracellular matrix (ECM) remodeling which has been shown to contribute to the ovulation and follicular functions. We aimed to compare serum levels of ADAMTS-19 in patients with different fertility situations. METHODS: A total of 86 women were enrolled to this cross sectional and case-control study. Four groups were constituted with respect to women's clinical and hormonal status: group 1, women with premature ovarian failure (POF; n = 21); group 2, women with natural menopause (n = 21); group 3, women with polycystic ovary syndrome (PCOS; n = 22); and group 4, healthy fertile controls. Serum ADAMTS-19 levels and individual characteristics were compared among groups. RESULTS: -ADAMTS-19 levels were found as 36.7 +/- 10.2, 40.1 +/- 12.6, 46.7 +/- 16.1, and 51.0 +/- 18.8 ng/mL in POF, fertile, natural menopause, and PCOS groups, respectively (p = 0.012). Especially, ADAMTS-19 levels in the PCOS group were significantly higher than the POF group, as found in dual comparisons (p = 0.010). CONCLUSIONS: ADAMTS-19 was found to be higher in PCOS patients than in POF patients. This work provides a novel vantage point for function of ECM within the ovary. ADAMTS-19 may have a potential for being an important marker of ovarian function and oocyte pool. PMID- 29982261 TI - The Role of MiR-132 in Regulating Neural Stem Cell Proliferation, Differentiation and Neuronal Maturation. AB - BACKGROUND/AIMS: microRNAs are of vital importance in neural development. As a brain-specific miRNA, miR-132 has been well studied in mature neurons. However, its role in neural stem cells (NSCs) remains unclear. In this study, we investigated the role of miR-132 in regulating NSCs proliferation, differentiation and neuronal maturation. METHODS: NSCs were obtained from fetal mice spinal cord. Proliferation, cell cycle, cell apoptosis, cell motility were measured through CCK-8, BrdU, AnnexinV-FITC/PI and migration assay respectively. The expression of synaptic proteins and ERK1/2 pathway were detected by western blot. The inactivation of Notch pathway was checked using qPCR. The neurite outgrowth was recorded using Image J software and Neuron J software. Dendritic length was further analyzed through sholl analysis. Fate determination of NSCs, developmental synapse formation was assessed by immunostaining. RESULTS: miR-132 negatively regulated NSCs proliferation by affecting the cell cycle and promoting apoptosis. Inactivated Notch-Hes1pathway was observed in miR-132 overexpression cells. miR-132 was significantly increased in differentiating NSCs following activation of ERK1/2 pathway. miR-132 could impair neuronal differentiation but promote glial cell differentiation by regulating Mecp2 expression. miR-132 was implicated in neurite outgrowth but slightly inhibited postsynaptic PSD-95 expression. The differentiated neurons exhibited normal electrophysiological characteristics, and already interacted with other neurons to form synaptic-like structures. CONCLUSION: miR-132 was demonstrated as a negative regulator for NSCs self-renewal, neuronal differentiation but promoted glial cell differentiation and neurite outgrowth. PMID- 29982262 TI - Mastocytic Enterocolits and the Role of Mast Cells in Functional and Inflammatory Intestinal Disorders: A Systematic Review. AB - BACKGROUND: Chronic diarrhoea affects 5-10% of the adult population. Histologic lesions of possible diagnostic significance are found under normal colonoscopy in approximately 30% of patients affected by chronic diarrhoea. Mastocytic enterocolitis is characterized by an increase in the number of mucosal mast cells (MC) in the gut of patients with chronic intractable diarrhoea, detected by immunohistochemical staining, responding to mast-cell targeted drugs. The question arises whether to search for MC infiltration in specific subsets of patients as a matter of routine clinical practice. SUMMARY: A systematic electronic search of the English literature up to December 2017 was performed, using Medline, EMBASE, Web of Science, Scopus, and the Cochrane Library. This revealed 9 studies reporting an increased number of MC in the gut mucosa of patients with chronic diarrhoea. No consensus was found, however, on the actual cutoff point, the overlap in range between patients and controls being too great to be of clinical significance. The available evidence does not therefore justify the routine evaluation of MC count. Key Messages: More studies are needed to better define MC count and the significance of MC degranulation in normal and pathological settings. Until these become available, the search for MC infiltration in specific subsets of patients should be restricted to research settings. PMID- 29982263 TI - Upregulation of BCL2 19 kD Protein-Interacting Protein 3 (BNIP3) is Predictive of Unfavorable Prognosis in Uveal Melanoma. AB - BACKGROUND BCL2 19 kD protein-interacting protein 3 (BNIP3) is a BH3-containing protein of the BCL-2 family; it can regulate cell death, autophagy, and cytoprotection. The upregulation of BNIP3 has been reported to relate to progression and poor prognosis in different cancer types. However, the clinical significance of BNIP3 in uveal melanoma (UM) is still unknown. MATERIAL AND METHODS In our study, 47 patients with UM were enrolled; the expression of BNIP3 was detected with immunohistochemistry. According to BNIP3 immunohistochemical scores, the patients were divided into BNIP3 high- and low-expression subgroups. The correlation between the expression of BNIP3 and clinicopathological factors was evaluated with Fisher's test; the associations with survival rates were analyzed with log-rank test. The independent prognostic factors were identified with the Cox-regression model. RESULTS BNIP3 was mainly localized in the cytoplasm, and high expression of BNIP3 accounted for 31.9% (15/47) of the patients in our study. High expression of BNIP3 was demonstrated to be significantly associated with more pigment (P=0.018) and deeper scleral invasion (P=0.013). High expression of BNIP3 was also correlated with lower overall survival rate (P=0.006). Multivariate analysis confirmed positive ciliary body involvement and lymphatic infiltration as independent prognostic factors. CONCLUSIONS High expression of BNIP3 was significantly associated with poor prognosis of patients with UM, indicating that BNIP3 detection could help stratify high-risk patients and identify new therapies targeting BNIP3 as a promising approach to treat UM. PMID- 29982264 TI - Involvement of T-Helper 9 Activation in a Mouse Model of Allergic Rhinitis. AB - BACKGROUND We aimed to investigate the role of T-Helper (TH) 9 cells in the pathogenesis of allergic rhinitis (AR) in mice. MATERIAL AND METHODS An AR model was produced in BALB/c mice, and the viral encoding interleukin (IL)-9 silencing sequence was used to reduce IL-9 expression. The experiment was divided into a control group, an AR group, an IL-9 shRNA+AR group, and a vector+AR group. Hematoxylin and eosin (H&E) staining was used to detect pathological changes. The cytokine expression was detected by ELISA method. Cellular typing was detected by flow cytometry. RESULTS Cells in the control group were regularly arranged, with clear layers and no congestion, edema, or necrosis observable. By contrast, in the AR model group and the vector treatment group, nasal mucosa showed clear hyperemia and edema in upper tissues and infiltration of inflammatory cells, which were ameliorated by IL-9 silencing. Compared with the control group, interferon-gamma (IFN-gamma) was significantly down-regulated, while IL-4, IL-17, and IL-9 were significantly elevated in the AR model group. TH1 cells in nasal mucosa, lymph, nasal lavage, spleen, and peripheral blood were significantly reduced, while TH2, TH9, TH17, and Treg cells were significantly elevated in the AR group compared with the control group. Importantly, all these changes in AR model were ameliorated by IL-9 silencing. CONCLUSIONS AR is related to the changes of cytokines in TH1, TH2, TH9, TH17, and Treg, which are improved by IL-9 silencing. Activation of TH9 cells is involved in the pathogenesis of AR. PMID- 29982265 TI - Pre-Pregnancy Health Status and Risk of Preterm Birth: A Large, Chinese, Rural, Population-Based Study. AB - The aim of this study was to estimate the incidence of preterm birth (PTB) and identify maternal risk factors before pregnancy in rural China, and to determine their population-attributable fractions (PAFs). A prospectively population-based study was conducted in the city of Fuyang, China. Surveillance locations were randomly selected by cluster sampling based on administrative areas and geographic characteristics. Data were collected through interview questionnaires and medical examination records from the participants, then follow-up until discharge, fetus death, or at a maximum of 6 weeks postpartum, whichever came first. We used logistic regression analysis to identify the associated factors. PAFs were also estimated to examine the impact of risk factors. The incidence of PTB was 3.86% in this study. Multivariate analyses showed that risk factors for PTB were economic pressure (aOR=2.98, 95% CI, 2.40-3.71), hypertension (aOR=3.45, 95% CI, 2.23-5.36), hypoglycemia (aOR=2.07, 95% CI, 1.58, 2.72), hyperglycemia (aOR=1.69, 95% CI, 1.09, 2.62), serum creatinine (<44 MUmol/L) (aOR=1.78, 95% CI, 1.13-2.40), hypothyroidism (aOR=1.37, 95% CI, 1.06-1.78), positivity for anti-CMV IgM (aOR=2.57, 95% CI, 1.21-5.45), multiple pregnancy (aOR=3.35, 95% CI, 1.87 6.00), and parity (>=3 times) (aOR=1.67, 95% CI, 1.05-2.64). Economic pressure was the most significant contributor (11.57%), while parity was the lowest (0.10%). This study demonstrated the relatively high burden of PTBs in a rural Chinese area. A broader focus on the risk factors prior to pregnancy amenable to interventions of women may reduce the incidence of PTB. PMID- 29982266 TI - Genetic loss of GluN2B in D1-expressing cell types enhances long-term cocaine reward and potentiation of thalamo-accumbens synapses. AB - Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B-/- mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories. PMID- 29982267 TI - Dietary sodium intake in urban and rural Malawi, and directions for future interventions. AB - Background: High dietary sodium intake is a major risk factor for hypertension. Data on population sodium intake are scanty in sub-Saharan Africa, despite a high hypertension prevalence in most countries. Objective: We aimed to determine daily sodium intake in urban and rural communities in Malawi. Design: In an observational cross-sectional survey, data were collected on estimated household level per capita sodium intake, based on how long participants reported that a defined quantity of plain salt lasts in a household. In a subset of 2078 participants, 24-h urinary sodium was estimated from a morning spot urine sample. Results: Of 29,074 participants, 52.8% of rural and 50.1% of urban individuals lived in households with an estimated per capita plain salt consumption >5 g/d. Of participants with urinary sodium data, 90.8% of rural and 95.9% of urban participants had estimated 24-h urinary sodium >2 g/d; there was no correlation between household per capita salt intake and estimated 24-h urinary sodium excretion. Younger adults were more likely to have high urinary sodium and to eat food prepared outside the home than were those over the age of 60 y. Households with a member with previously diagnosed hypertension had reduced odds (OR: 0.59; 95% CI: 0.51, 0.68) of per capita household plain salt intake >5 g/d, compared with those where hypertension was undiagnosed. Conclusions: Sodium consumption exceeds the recommended amounts for most of the population in rural and urban Malawi. Population-level interventions for sodium intake reduction with a wide focus are needed, targeting both sources outside the home as well as home cooking. This trial was registered at clinicaltrials.gov as NCT03422185. PMID- 29982269 TI - Hip fractures: are we asking the right questions? PMID- 29982268 TI - Effects of copper and zinc on ischemic heart disease and myocardial infarction: a Mendelian randomization study. AB - Background: Despite great progress in prevention and control, ischemic heart disease (IHD) remains a leading cause of global morbidity and mortality. Diet plays a key role in IHD, but a comprehensive delineation of the role of dietary factors in IHD is not yet quite complete. Objective: The aim of this study was to test the long-standing hypothesis that copper is protective and zinc harmful in IHD. Design: We used separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization). We obtained single nucleotide polymorphisms (SNPs) from a genome wide association study, strongly (P value < 5 * 10-8) and independently associated with erythrocyte copper and zinc. We applied these genetic predictors of copper and zinc to the largest, most extensively genotyped IHD case (n <= 76014)-control (n <= 264785) study, based largely on CARDIoGRAMplusC4D 1000 Genomes and the UK Biobank SOFT CAD, to obtain SNP specific Wald estimates for the effects of copper and zinc on IHD, which were combined through the use of inverse variance weighting. Sensitivity analysis included use of the MR-Egger method, and reanalysis including SNPs independently associated with erythrocyte copper and zinc at P value < 5 * 10-6. Results: Genetically instrumented copper was negatively associated with IHD (OR: 0.94; 95% CI: 0.90, 0.98). Genetically instrumented zinc was positively associated with IHD (OR: 1.06; 95% CI: 1.02, 1.11). Sensitivity analysis via MR-Egger gave no indication of unknown pleiotropy; less strongly associated SNPs gave similar results for copper. Conclusion: Genetic validation of a long-standing hypothesis suggests that further investigation of the effects, particularly of copper, on IHD may provide a practical means of reducing the leading cause of mortality and morbidity. PMID- 29982270 TI - A Systematic Review of Full-Shift, Noise Exposure Levels Among Construction Workers: Are We Improving? AB - Context: Construction industry workers are at high risk of occupational noise exposure. Although regulations and guidelines for this industry specify the use of noise controls, workers continue to be exposed to hazardous noise levels. Objectives: The objectives of this study were (i) to collate and describe full shift noise exposure experienced by construction workers; (ii) to review trends in full-shift exposure over time and between countries; and (iii) to identify any occupational categories within the construction industries that have higher levels of exposure. Results: Of the 1171 studies found using key terms, 25 contained noise exposure measurements that met our inclusion criteria. Sample populations were predominantly from large construction sites and primarily comprised occupations known to engage in noisy workplace activities. Studies spanned over 36 years with all having average full-shift noise exposure over 85 A weighted decibels (dBA). No time trend in full-shift noise exposure levels for construction workers was observed. Construction workers in the subgroup occupations of mason, sheet metal workers, carpenters, concrete workers, and operating engineers consistently had mean LAeq,8h over the 85 dBA limit. Conclusion: Studies spanning 36 years in 10 countries consistently show construction workers have been exposed to hazardous noise levels. There has been no significant change over time of the average full-shift exposure levels of construction workers, including in all occupational subgroups except iron workers. Some variability in full-shift measures is due to sampling methods and population characteristics and to a lesser extent, methods used to derive exposure levels. PMID- 29982271 TI - Predictors for Increased and Reduced Rat and Mouse Allergen Exposure in Laboratory Animal Facilities. AB - Introduction: Exposure to rat and mouse allergens during work in laboratory animal facilities represents a risk for being sensitized and developing allergic diseases, and it is important to keep the exposure level as low as possible. The objective of this study was to characterize the personal Mus m 1 and Rat n 1 exposure during work in laboratory animal facilities, and to investigate the effect of identified predictors of increased and reduced exposure. Methods: Mus m 1 and Rat n 1 were analysed in whole day or task-based personal air samples by enhanced sensitivity sandwich enzyme-linked immunosorbent assay. Information about cage-and-rack systems, tasks, and other conditions known to influence the allergen exposure was registered. Predictors for allergen exposure were identified by multiple linear regression analyses. Results: The median allergen exposure was 3.0 ng m-3 Mus m 1 and 0.5 ng m-3 Rat n 1, with large task-dependent variations among the samples. The highest exposed job group were animal technicians. Cage emptying and cage washing in the cage washroom represented the highest exposure, whereas animal experiments in the lab/operation room represented the lowest exposure, with laminar airflow bench being an exposure reducing determinant. Cage changing was the highest exposed task in the animal room, where individually ventilated cages (IVCs) were predictors of reduced exposure for both Mus m 1 and Rat n 1, whereas cage-rack systems with open shelves and sliding doors were predictors of increased Rat n 1 exposure. Cages of IVC type with positive air pressure (IVC+) as well as open shelves and sliding doors were strong predictors of increased exposure during cage emptying and cage washing. Conclusions: Significant different exposure levels depending on type of work and task imply different risks of sensitization and allergy development. The fact that IVC+ cages have opposite impact on Mus m 1 and Rat n 1 exposure during different tasks may have positive clinical implications when taken into account. PMID- 29982272 TI - Hip fracture-great steps forward but we still need better evidence. A commentary on NICE CG124 and QS16 on fractured neck of femur. AB - The National Institute for Health and Care Excellence (NICE) updated its Clinical Guideline and its Quality Standard on hip fracture in 2017. Three quality statements relate to the organisation of care-having a multidisciplinary hip fracture programme, and both operating and starting rehabilitation without delay while three relate to surgical aspects, the most recent being the requirement to offer total hip replacement rather than hemiarthroplasty for those with displaced intracapsular fractures who could mobilise outdoors with a stick. Some evidence exists to support this, but the timely provision of this more complex and specialised operation presents a logistical challenge to many units. The evidence for many more general aspects of the care of hip fracture patients is still extrapolated from other populations, and more research is needed to guide the care of this specific group. PMID- 29982274 TI - What type of man against machine? PMID- 29982275 TI - Association Between Heart Rate Variability and Home Blood Pressure: The Toon Health Study. AB - BACKGROUND: Although blood pressure (BP) is regulated by the autonomic nervous system, it is not fully understood how autonomic activity affects BP at home in the general population. METHODS: Subjects were enrolled from 2009 to 2012 and included 1,888 men and women aged 30-79 years. We measured casual BP in the morning during health checkups and asked participants to monitor BP at home twice in the morning and evening for 1 week. The mean of the two measurements of mean arterial pressure (MAP) was calculated. Five-minute recordings of the pulse wave from a fingertip sensor were used to determine the following indices of heart rate variability (HRV): standard deviation of normal-to-normal RR intervals (SDNN), root mean square of successive differences in RR intervals (RMSSD), high frequency (HF) power, low frequency (LF) power, and LF/HF. RESULTS: Sex- and age adjusted means of casual MAP, and morning and evening MAP at home were significantly different among quartiles of SDNN, RMSSD, and HF. When further adjusted for smoking, alcohol drinking, medication for hypertension, diabetes, sleeping hours, snoring, and mental health status, the associations were somewhat attenuated. Inverse relationships were found between the means of morning home MAP, and RMSSD (P = 0.02) and HF (P = 0.051) after adjustment for confounders. The association between MAP and RMSSD, or MAP and HF was evident in individuals <65 years old. CONCLUSION: Low HF and RMSSD, which reflect impaired parasympathetic nervous system activity, were associated with increased home MAP in the morning rather than in the evening. PMID- 29982276 TI - Orthostatic Hypotension in the Hypertensive Patient. AB - Orthostatic hypotension (OH) is an important and common medical problem, particularly in the frail elderly with multiple comorbidities and polypharmacy. OH is an independent risk factor for falls and overall mortality. Hypertension is among the most common comorbidities associated with OH, and its presence complicates the management of these patients because treatment of one can worsen the other. However, there is evidence that uncontrolled hypertension worsens OH so that both should be managed. The limited data available suggest that angiotensin receptor blockers and calcium channel blockers are preferable antihypertensives for these patients. Patients with isolated supine hypertension can be treated with bedtime doses of short-acting antihypertensives. Treatment of OH in the hypertensive patients should focus foremost on the removal of drugs that can worsen OH, including ones that are easily overlooked, such as tamsulosin, tizanidine, sildenafil, trazodone, and carvedilol. OH and postprandial hypotension can be prevented with abdominal binders and acarbose, respectively, without the need to increase baseline blood pressure. Upright blood pressure can be improved by harnessing residual sympathetic tone with atomoxetine, which blocks norepinephrine reuptake in nerve terminals, and pyridostigmine, which facilitates cholinergic neurotransmission in autonomic ganglia. Oral water bolus acutely but transiently increases blood pressure in autonomic failure patients. If traditional pressor agents are needed, midodrine and droxidopa can be used, administered at the lowest dose and frequency that improves symptoms. Management of OH in the hypertensive patient is challenging, but a management strategy based on understanding the underlying pathophysiology can be effective in most patients. PMID- 29982273 TI - Harmonization of Respiratory Data From 9 US Population-Based Cohorts: The NHLBI Pooled Cohorts Study. AB - Chronic lower respiratory diseases (CLRDs) are the fourth leading cause of death in the United States. To support investigations into CLRD risk determinants and new approaches to primary prevention, we aimed to harmonize and pool respiratory data from US general population-based cohorts. Data were obtained from prospective cohorts that performed prebronchodilator spirometry and were harmonized following 2005 ATS/ERS standards. In cohorts conducting follow-up for noncardiovascular events, CLRD events were defined as hospitalizations/deaths adjudicated as CLRD-related or assigned relevant administrative codes. Coding and variable names were applied uniformly. The pooled sample included 65,251 adults in 9 cohorts followed-up for CLRD-related mortality over 653,380 person-years during 1983-2016. Average baseline age was 52 years; 56% were female; 49% were never-smokers; and racial/ethnic composition was 44% white, 22% black, 28% Hispanic/Latino, and 5% American Indian. Over 96% had complete data on smoking, clinical CLRD diagnoses, and dyspnea. After excluding invalid spirometry examinations (13%), there were 105,696 valid examinations (median, 2 per participant). Of 29,351 participants followed for CLRD hospitalizations, median follow-up was 14 years; only 5% were lost to follow-up at 10 years. The NHLBI Pooled Cohorts Study provides a harmonization standard applied to a large, US population-based sample that may be used to advance epidemiologic research on CLRD. PMID- 29982277 TI - Rate of appearance of amino acids after a meal regulates insulin and glucagon secretion in patients with type 2 diabetes: a randomized clinical trial. AB - Background: Meal composition regulates the postprandial response of pancreatic and gastrointestinal hormones and plays an important role in patients with type 2 diabetes (T2D). Proteins have glucagon and insulinotropic effects, which may differ depending on amino acid composition, form of intake, and rate of digestibility and absorption. Objective: The aim of this study was to test effects of isolated pea protein-based (PP) compared with casein protein-based (CP) meals differing in amino acid compositions on endocrine responses to meal tolerance tests (MTTs) in patients with T2D. Design: Thirty-seven individuals with T2D [mean +/- SD age: 64 +/- 6 y; mean +/- SD body mass index (kg/m2): 30.2 +/- 3.6; mean +/- SD glycated hemoglobin: 7.0% +/- 0.6%] were randomly assigned to receive either high-animal-protein (~80% of total protein) or high-plant protein (~72% of total protein) diets (30% of energy from protein, 40% of energy from carbohydrate, 30% of energy from fat) for 6 wk. MTTs were performed at study onset and after 6 wk. Participants received standardized high-protein (30% of energy) meals 2 times/d containing either CP-rich (~85% wt:wt) or PP-rich (~95% wt:wt) foods. Results: The CP and PP meals produced differences in insulin, C peptide, glucagon, and glucose-dependent insulinotropic peptide (GIP) release. Total areas under the curve after CP were significantly lower than after the PP lunch by 40% for insulin and 23% for glucagon. Indexes of insulin sensitivity and secretion were significantly improved for the second CP MTT. This was accompanied by differential rates of appearance of amino acids. The ingestion of PP resulted in significant increases in amino acids after both meals, with a decline between meals. By contrast, CP intake resulted in increases in most amino acids after breakfast, which remained elevated but did not increase further after lunch. Conclusions: PP elicits greater postprandial increases in glucagon than does CP and consequently requires higher insulin to control glucose metabolism, which appears to be related to the rate of amino acid appearance. The metabolic impact of protein quality could be used as a strategy to lower insulin needs in patients with T2D. This trial was registered at www.clinicaltrials.gov as NCT02402985. PMID- 29982278 TI - MetaboRank: network-based recommendation system to interpret and enrich metabolomics results. AB - Motivation: Metabolomics has shown great potential to improve the understanding of complex diseases, potentially leading to therapeutic target identification. However, no single analytical method allows monitoring all metabolites in a sample, resulting in incomplete metabolic fingerprints. This incompleteness constitutes a stumbling block to interpretation, raising the need for methods that can enrich those fingerprints. We propose MetaboRank, a new solution inspired by social network recommendation systems for the identification of metabolites potentially related to a metabolic fingerprint. Results: MetaboRank method had been used to enrich metabolomics data obtained on cerebrospinal fluid samples from patients suffering from hepatic encephalopathy. MetaboRank successfully recommended metabolites not present in the original fingerprint. The quality of recommendations was evaluated by using literature automatic search, in order to check that recommended metabolites could be related to the disease. Complementary mass spectrometry experiments and raw data analysis were performed to confirm these suggestions. In particular, MetaboRank recommended the overlooked alpha-ketoglutaramate as a metabolite which should be added to the metabolic fingerprint of hepatic encephalopathy, thus suggesting that metabolic fingerprints enhancement can provide new insight on complex diseases. Availability: Method is implemented in the MetExplore server and is available at www.metexplore.fr. A tutorial is available at https://metexplore.toulouse.inra.fr/com/tutorials/MetaboRank/2017-MetaboRank.pdf. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 29982280 TI - PepBDB: a comprehensive structural database of biological peptide-protein interactions. AB - Summary: A structural database of peptide-protein interactions is important for drug discovery targeting peptide-mediated interactions. Although some peptide databases, especially for special types of peptides, have been developed, a comprehensive database of cleaned peptide-protein complex structures is still not available. Such cleaned structures are valuable for docking and scoring studies in structure-based drug design. Here, we have developed PepBDB-a curated Peptide Binding DataBase of biological complex structures from the Protein Data Bank (PDB). PepBDB presents not only cleaned structures but also extensive informationabout biologicalpeptide-proteininteractions, and allows users to search the database with a variety of options and interactively visualize the search results. Availability and implementation: PepBDB is available at http://huanglab.phys.hust.edu.cn/pepbdb/. PMID- 29982281 TI - GATK PathSeq: A customizable computational tool for the discovery and identification of microbial sequences in libraries from eukaryotic hosts. AB - Summary: We present an updated version of our computational pipeline, PathSeq, for the discovery and identification of microbial sequences in genomic and transcriptomic libraries from eukaroyotic hosts. This pipeline is available in the Genome Analysis Toolkit (GATK) as a suite of configurable tools that can report the microbial composition of DNA or RNA short-read sequencing samples and identify unknown sequences for downstream assembly of novel organisms. GATK PathSeq enables sample analysis in minutes at low cost. In addition, these tools are built with the GATK engine and Apache Spark framework, providing robust, rapid parallelization of read quality filtering, host subtraction, and microbial alignment in workstation, cluster, and cloud environments. Availability: These tools are available as a part of the GATK at https://github.com/broadinstitute/gatk. Supplementary information: Supplementary data are available at Bioinformatics online. Detailed descriptions of the PathSeq tools, introductory tutorial, and a resource bundle of pre-built references are available at https://software.broadinstitute.org/gatk/documentation/ and https://software.broadinstitute.org/gatk/download/bundle/. PMID- 29982279 TI - Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). AB - Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as <=10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival. PMID- 29982282 TI - Simulation: An Effective Method of Teaching Cosmetic Botulinum Toxin Injection Technique. AB - Background: Learning to inject botulinum toxin for cosmetic purposes is difficult for beginners, given the nature of the procedure and patient population. Simulation training is an effective modality for medical professionals to acquire skills in an environment that provides low stress and ample opportunity for questions and correction of mistakes. Objectives: Compare posttraining comfort, knowledge, and practical botulinum toxin injection scores among trainees who underwent simulation vs video training only. Methods: A total of 20 nurse practitioners, physician assistants, and resident physicians underwent cosmetic botulinum toxin injection training either through lecture and video, or lecture and hands-on simulation training. Comfort, knowledge, and practical test scores were recorded and compared between the groups. Results: There was no evidence of a statistically significant difference in comfort or knowledge scores between simulation and video groups. The median (range) practical score was significantly higher in the simulation group compared to the video group (59.0 [31-60] vs 44.5 [27-57]; P < 0.01). Conclusions: Despite feeling similarly comfortable and having similar written knowledge test scores, the trainees who underwent simulation training had significantly higher hands-on practical test scores compared to trainees who underwent video training only for cosmetic botulinum toxin injections. PMID- 29982283 TI - Erratum to: Physical Properties of Silicone Gel Breast Implants. PMID- 29982284 TI - Commentary on: Micro-Autologous Fat Transplantation for Treating a Gummy Smile. PMID- 29982285 TI - Interactions between TLR4 methylation and alcohol consumption on subjective responses to an alcohol infusion. AB - Aims: Converging evidence has implicated perturbed inflammatory signaling in alcohol use disorders (AUDs), and both animal and human studies suggest that alcohol-induced inflammatory signaling is mediated by Toll-Like Receptor 4 (TLR4). We previously demonstrated that TLR4 is hypermethylated in subjects with AUD compared to control individuals. Examining the relationship between TLR4 methylation and subjective alcohol responses could shed light on the role of TLR4 in promoting AUDs, thereby highlighting its potential as a treatment target. Short summary: Significant interactions were demonstrated between Toll-like Receptor 4 (TLR4) methylation and human alcohol consumption patterns, such that greater methylation was associated with decreased positive and negative self reported arousal during an alcohol infusion among light-to-moderate drinkers, but increased self-reported positive arousal and physiological arousal (i.e. systolic blood pressure) among heavy drinkers. Methods: Latent growth models were used to examine the relationship between TLR4 methylation and subjective responses and physiological measures of arousal during an alcohol infusion across 222 drinkers. Results: We observed significant interactions of TLR4 methylation and alcohol use (drinks per week) on intercepts for self-report and physiological arousal measures. Specifically, light-to-moderate drinkers had positive associations between methylation and stimulation and tension (r's = 0.21-0.24), and heavy drinkers had negative associations (r's = -0.15 to -0.21). There were also significant interaction effects on changes in tension (beta = 0.31, P < 0.01), systolic blood pressure (beta = 0.74, P < 0.01) and marginal effects on stimulation (beta = 0.15, P = 0.07) during the infusion, such that methylation was associated with decreased arousal among light-to-moderate drinkers (r's = 0.12 to -0.25) but stable or increased arousal among heavy drinkers (r's = 0.05 0.19). Conclusions: Findings suggest that the relationship between TLR4 methylation and subjective and physiological arousal during acute alcohol intoxication depends upon on self-reported alcohol use. These data demonstrate the influence of TLR4 on subjective responses to alcohol, thereby supporting the need for further research on its potential as a pharmacological treatment target. PMID- 29982286 TI - Winter plant phenology in the alpine meadow on the eastern Qinghai-Tibetan Plateau. AB - Background and Aims: There is no knowledge of winter plant phenology and its controlling factors on the Qinghai-Tibetan Plateau (QTP). Thus, we conducted a 4 year winter phenology and growth dynamics study in the alpine meadow on the eastern QTP. Methods: From November 2013 to March 2017, the phenology of the 'winter-growth' and 'winter-green' species was recorded every 5 d. In November February from 2014 to 2015, the above-ground biomass (AGB) in random plots was calculated to distinguish different growth patterns among winter growing species. The percentage of winter abundance relative to the summer population for forbs and the percentage of absolute coverage for grasses (W/S) were calculated to describe the importance of the winter population to the summer population. The soil moisture (SM) and soil temperature (ST) were used to explore the controlling factors on the AGB. Pearson's correlation analysis between winter phenology data and environmental variables, including air temperature (Tair), snow cover fraction (SCF), SM and ST, was used to investigate the factors affecting winter phenology during November-February from 2014 to 2017. Key Results: There were 107 species in total in the sites, including ten 'winter-growth' species and four 'winter-green' species. Among the 'winter-green' species, Festuca ovina and Deschampsia cespitosa were the dominant species in the sites. The 'winter-growth' species grew new leaves or ramets or transitioned to reproductive growth. Gentiana spathulifolia even flowered in winter. 'Winter-growth' made important contributions to the annual AGB, e.g. winter growth of G. spathulifolia accounted for 23.26 % of its annual AGB, while 14.74 % of the annual AGB of G. crassuloides was from winter growth. In addition, winter warming and snowfall reduction under global climate change on the eastern QTP may decrease the AGB increment of the 'winter-growth' and delay the green-up onset date of 'winter-green' species. Also, winter warming and snowfall reduction may advance the first flowering date of 'winter-growth' species. Conclusions: In contrast to previous views that plants on the QTP were generally considered to remain dormant in winter, our study revealed that alpine meadow plants had strong winter growth which suggested the importance of re-evaluating the dynamics of ecosystem function of alpine meadow, including its contribution to the global carbon balance. It was also shown that soil moisture availability is more important than warmer temperature in controlling the green-up onset of 'winter-green' species on the eastern QTP, which contrasts with the traditional view that warmer winters could advance green up. As snowmelt is the only source of soil water in winter, the prediction of the green-up trend may be further complicated by snowfall variation in winter. PMID- 29982287 TI - Detecting brain injury related to hypertension at mid-life: a key to interventions for preventing dementia in older age. PMID- 29982288 TI - SATurn: A modular bioinformatics framework for the design of robust maintainable web-based and standalone applications. AB - Summary: SATurn is a modular, open-source, bioinformatics platform designed to specifically address the problems of maintenance and longevity commonly associated with the development of simple tools funded by academic research grants. Applications developed in SATurn can be deployed as web-based tools, standalone applications, or hybrid tools which have the benefits of both. Within the Structural Genomics Consortium (SGC) we have utilized SATurn to create a bioinformatics portal which routinely supports a diverse group of scientists including those interested in structural biology, cloning, glycobiology & chemical biology. Supplementary information: . PMID- 29982289 TI - Interpretation of Endocervical Cells With Gastric-Type Mucin on Pap Smears: A Proposal for a Cytologic Category "Atypical Endocervical Cells With Gastric-Type Mucin". AB - Objectives: Early detection of endocervical adenocarcinoma is especially important for cancers that are human papillomavirus (HPV) negative. We investigated the clinicopathologic significance of yellow gastric-type mucin observed on Papanicolaou smears. Methods: We described "atypical endocervical cells with gastric-type mucin" (AEC-GAM) when yellow mucin was observed in endocervical cells. We retrieved AEC-GAM samples from 58,752 cervical smears performed at Yamanashi University Hospital during our study period and reviewed clinical, cytologic, and pathologic features. Results: We detected AEC-GAM in 172 (0.29 %) smears from 65 patients, and 41 of these 65 patients were histologically diagnosed with lobular endocervical glandular hyperplasia (LEGH) (43%) or pyloric gland metaplasia (20%). The prevalence of adenocarcinoma was 25% (7/28) in LEGH cases and 11% (7/65) in AEC-GAM smears. Conclusions: Yellow mucin is a diagnostic clue for endocervical glandular lesions with gastric differentiation. We recommend describing AEC-GAM on cytologic reports to improve cytologic screening for HPV-negative cervical cancers. PMID- 29982290 TI - Pro-arrhythmic RyR2 channels in heart failure: do their localisation and mechanism of activation really matter? PMID- 29982291 TI - Interleukin-10 Treatment Attenuates Sinus Node Dysfunction Caused by Streptozotocin-induced Hyperglycemia in Mice. AB - Aims: Diabetes, characterized by hyperglycemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycemia in streptozotocin (STZ)-induced diabetic mice. Methods and Results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ induced hyperglycemia for 8 weeks significantly depressed serum levels of IL-10, but increased several pro-inflammatory cytokines in WT mice. STZ-induced hyperglycemia reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration, and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycemia-induced apoptotic and pro-fibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation. PMID- 29982292 TI - Reply: A novel MCM3AP mutation in a Lebanese family with recessive Charcot-Marie Tooth neuropathy. PMID- 29982294 TI - Effects of caloric restriction on cardiorespiratory fitness, fatigue, and disability responses to aerobic exercise in older adults with obesity: A randomized controlled trial. AB - Background: Obesity compounds aging-related declines in cardiorespiratory fitness (CRF), with accompanying fatigue and disability. This study determined the effects of two different levels of caloric restriction (CR) during aerobic training on CRF, fatigue, physical function and cardiometabolic risk. Methods: The INFINITE study was a 20-week randomized trial in 180 older (65-79 years) men and women with obesity (BMI= 30-45 kg/m2). Participants were randomly assigned to aerobic training (EX; treadmill 4 days/week for 30 minutes at 65-70% of heart rate reserve), 2) EX with moderate (-250 kcal/d) CR (EX+Mod-CR), or 3) EX with more intensive (-600 kcal/d) CR (EX+High-CR). CRF (peak aerobic capacity, VO2peak, primary outcome) was determined during a graded exercise test. Results: 155 participants returned for 20-week data collection (87% retention). VO2peak increased by 7.7% with EX, by 13.8% with EX+Mod-CR, and by 16.0% with EX+High-CR and there was a significant treatment effect (EX+High-CR= 21.5 ml/kg/min, 95%CI=19.8-23.2; EX+Mod-CR= 21.2 ml/kg/min, 95%CI=19.4-23.0; EX=20.1 ml/kg/min, 95%CI=18.4-21.9). Both CR groups exhibited significantly greater improvement in self-reported fatigue and disability, and in glucose control, compared to EX. Conclusion: Combining aerobic exercise with even moderate CR is more efficacious for improving CRF, fatigue and disability, and glucose control than exercise alone, and is as effective as higher dose CR. PMID- 29982295 TI - A novel MCM3AP mutation in a Lebanese family with recessive Charcot-Marie-Tooth neuropathy. PMID- 29982296 TI - Identifying patients who may benefit from oxaliplatin-containing perioperative chemo(radio)therapy for rectal cancer. PMID- 29982297 TI - Functions of short lifetime biological structures at large: the case of intrinsically disordered proteins. AB - Although for more than a century a protein function was intimately associated with the presence of unique structure in a protein molecule, recent years witnessed a skyrocket rise of the appreciation of protein intrinsic disorder concept that emphasizes the importance of the biologically active proteins without ordered structures. In different proteins, the depth and breadth of disorder penetrance are different, generating an amusing spatiotemporal heterogeneity of intrinsically disordered proteins (IDPs) and intrinsically disordered protein region regions (IDPRs), which are typically described as highly dynamic ensembles of rapidly interconverting conformations (or a multitude of short lifetime structures). IDPs/IDPRs constitute a substantial part of protein kingdom and have unique functions complementary to functional repertoires of ordered proteins. They are recognized as interaction specialists and global controllers that play crucial roles in regulation of functions of their binding partners and in controlling large biological networks. IDPs/IDPRs are characterized by immense binding promiscuity and are able to use a broad spectrum of binding modes, often resulting in the formation of short lifetime complexes. In their turn, functions of IDPs and IDPRs are controlled by various means, such as numerous posttranslational modifications and alternative splicing. Some of the functions of IDPs/IDPRs are briefly considered in this review to shed some light on the biological roles of short-lived structures at large. PMID- 29982298 TI - Spontaneous Switching of Future Dominance to a Smaller Follicle: Commonality among Monovular Species?. AB - Selection of a dominant follicle from a wave of follicles is manifested by diameter deviation between future dominant (F1) and largest subordinate (F2) follicles. On day-1 or 0 (day 0 = beginning of deviation) growth rate of F1 continues and growth rate of F2 decreases. Deviation occurs during the decline in the wave stimulating FSH surge when F1 reaches means of 8.5, 10.5, and 22.5 mm in heifers, women, and mares, respectively. Diameter of F1 at the FSH peak vs at deviation is proportionally similar among these monovular species. In conventional deviation, F1 usually emerges first. In F1, F2-switched deviation, F2 is usually first to emerge and to reach a diameter characteristic of deviation. On day-1 or 0, the larger F2 and the smaller F1 switch so that the formerly larger F2 becomes subordinate and the formerly smaller F1 becomes dominant. In heifers and mares, the profile and prominence of the FSH surge are similar between deviation classes. Surge location relative to deviation differs so that the surge ends earlier in switched deviation. When the larger F2 reaches a diameter characteristic of deviation, FSH concentration is too low for continued growth of F2. The decrease in FSH ceases (heifers) or increases (mares) presumably from a decrease in FSH inhibitors; therefore, F1 continues to grow and becomes dominant. The frequency of switched deviation (eg, 16 to 37% among species) can be problematic in follicle-selection research. Switching is a natural model for study of the interplay between follicles and FSH. PMID- 29982299 TI - Differential pollinator response underlies plant reproductive resilience after fires. AB - Background and aims: Assessing the resilience of plant-animal interactions is critical to understanding how plant communities respond to habitat disturbances. Most ecosystems experience some level of natural disturbance (e.g. wildfires) to which many organisms are adapted. Wildfires have structured biotic communities for millennia; however, the effects of fire on interactions such as pollination have only recently received attention. A few studies have shown that generalist plants can buffer the impact of fires by pollinator replacement, suggesting that the resilience to disturbance could depend on the level of specialization of the interactions. Here, we hypothesize that (1) fires could impose negative effects on plants with specialized pollination systems, and (2) in large wildfires, these negative effects will be stronger with increasing distance inside the burnt area because pollinators will need more time to recolonize. Methods: These questions were tested in the specialized pollination system of a widespread Mediterranean palm, Chamaerops humilis. The post-fire pollination resilience was assessed in replicated wildfires representing three post-fire ages by measuring the abundance of beetle pollinators and by estimating fruit set (i.e. the proportion of flowers setting fruits) in burnt and unburnt areas. To test for distance effects, plants were sampled along transects inside the burnt area. Key Results: Despite a marked post-fire decline in the specialist pollinator, exacerbated by the distance from the fire's edge, the palm's fruit set was barely affected. The temporary replacement by a sap beetle at burnt sites - an effective pollinator that had not been previously recognized - provided post-fire reproductive resilience. Conclusions: Differential pollinator responses to disturbance can ensure plant success even in plants with only two functionally similar pollinators. This highlights the importance of pollinator replacement and dynamics for the resilience of interactions and ultimately of plant reproduction in disturbance prone ecosystems. PMID- 29982300 TI - Maladaptive Schemas Among People Addicted to Alcohol: Heterogeneity but not Specificity? AB - Aims: Early maladaptive schemas described by Young theoretically underlie the development of psychopathology, including substance use. The key assumption is that the schemas do not act in isolation but create configurations that are, at least to a certain extent, distinctive for specific disorders. Thus, the aim of the current study was to examine whether a schema profile specific to alcohol addiction can be identified when compared to profiles obtained from a non clinical sample. Short Summary: Early maladaptive schemas are cognitive and behavioral patterns related to a wide spectrum of psychopathology, including alcohol addiction. However, the assumption that the configuration of schemas varies across disorders still needs verification. In the sample of alcohol addicted people, only heterogeneity was noted, without any specific profile that may differentiate them from healthy adults. Methods: The study included two samples: 108 alcohol-dependent patients beginning stationary treatment and 1529 healthy adults. All participants completed the Young Schema Questionnaire-Short Form 3 (YSQ-S3). Results: Multiple-group latent profile analysis was used to compare clinical and non-clinical sample profiles. In both groups, four profiles were identified. These were similar in terms of schema means and variances across groups, differing only in size. Specifically, people addicted to alcohol were over-represented in the highest profile and under-represented in the lowest profile. Also, the only distinguishable difference between profiles was their height, not shape. Conclusion: The findings indicate a heterogeneity but not specificity of maladaptive schema profiles within the studied sample of people addicted to alcohol. PMID- 29982301 TI - Conflicting vascular and metabolic impact of the IL-33/sST2 axis. AB - Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naive. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases. PMID- 29982302 TI - Epidemiology of nontuberculous mycobacteria infection in children and young people with cystic fibrosis: analysis of UK Cystic Fibrosis Registry. AB - Background: Infection with nontuberculous mycobacteria (NTM) is of growing clinical concern in people with cystic fibrosis (CF). The epidemiology of infection in children and young people remains poorly understood. We wished to investigate the epidemiology of NTM infection in the paediatric age-group using data from the United Kingdom CF Registry. Methods: Data from 2010-2015 for children and young people aged <16 years (23,200 observations from 5,333 unique individuals) were obtained. Univariate analysis of unique individuals comparing all key clinical factors and health outcomes to NTM status was performed. Identified significant factors were used to generate a multivariate logistic regression model, which following step-wise removal generated a final parsimonious model. Results: The prevalence of individuals with a NTM positive respiratory culture increased every year from 2010 (45 [1.3%]) to 2015 (156 [3.8%]). Allergic bronchopulmonary aspergillosis (OR 2.66, P = 5.0x10-8), age (OR 1.08, P = 3.4x10-10) and intermittent Pseudomonas aeruginosa infection (OR 1.51, P = 0.004) were significantly associated with NTM infection. Conclusions: NTM infection is of increasing prevalence in the UK paediatric CF population. This study highlights the urgent need for work to establish effective treatment and prevention strategies for NTM infection in young people with CF. PMID- 29982303 TI - A systematic review and meta-analysis of ventilator associated pneumonia in adults in Asia; an analysis of national income level on incidence and etiology. AB - Ventilator associated pneumonia (VAP) is the commonest hospital acquired infection (HAI) in intensive care. In Asia, VAP is increasingly caused by resistant Gram-negative organisms. Despite the global antimicrobial resistance crisis, the epidemiology of VAP is poorly documented in Asia.We systematically reviewed literature published on Ovid MEDLINE, Embase Classic and Embase from 1st January 1990 to 17th Aug 2017 to estimate incidence, prevalence, and etiology of VAP. We performed meta-analysis of pooled data to give overall rates and rates by country income level.Pooled incidence density of VAP was high in low- and middle income countries and lower in high-income countries (18.5, 15.2 and 9.0/1000 ventilator days respectively).Acinetobacter baumannii and Pseudomonas aeruginosa (26%, N=3687; 22%, N=3176) were leading causes of VAP, Staphylococcus aureus caused 14% (N=1999). Carbapenem resistance was common (57.1%).VAP remains a common cause of HAI, especially in low and middle income countries and antibiotic resistance is common. PMID- 29982304 TI - Developing and assessing the feasibility of a home-based PrEP monitoring and support program. AB - We piloted PrEP@Home, a system of remote laboratory and behavioral monitoring designed to replace routine quarterly follow-up visits with home care to reduce the patient and provider burden. The system was highly acceptable and in-demand for future use, and over one-third reported greater likelihood of persisting in care if available. PMID- 29982305 TI - Reversed-Phase High-Performance Liquid Chromatography and High-Performance Thin layer Liquid Chromatography Methods for Simultaneous Determination of Theophylline, Guaifenesin and Guaifenesin Impurity (Guaiacol) in Their Bulk Powders and in Dosage Form. AB - Two simple, rapid chromatographic methods were developed for the simultaneous determination of Theophylline (THP), Guaifenesin (GUI) and Guaifenesin impurity namely Guaiacol (GUA). The first method is an isocratic reversed-phase high performance liquid chromatography (RP-HPLC) method, where separation of THP, GUI and GUA was achieved on C18 column using methanol:water (containing 0.1% triethylamine):acetonitrile (30:60:10, by volume) as a mobile phase with a flow rate of 0.7 mL /min and UV detection at 275 nm. The separation was achieved at retention times (Rt 3.76, 6.76 and 8.79 for THP, GUI and GUA, respectively). The calibration plots were linear over the concentration range of 2-25, 2-37 and 0.5 10 MUg /mL for THP, GUI and GUA, respectively. The second method is high pressure thin layer liquid chromatography method, which was developed using silica gel plates 60F254 as a stationary phase with ethyl acetate:hexane:methanol:ammonia (65:35:10:2, by volume) as a developing system. The densitometric measurements were performed at 275 nm with good Rf values (0.13, 0.35 and 0.8) for THP, GUI and GUA, respectively. The calibration plots showed good correlation over the range (0.4-2 MUg/band) for both THP and GUI, and (0.4-1.2 MUg/band) for GUA. The two proposed methods were validated according to ICH guidelines. The results for the two methods were statistically compared to those obtained by a reported high performance liquid chromatography method and no significant difference was found regarding accuracy and precision. PMID- 29982306 TI - Imprinting of a Nonpheromonal Cue and Its Protective Effect on Alien Male-Induced Implantation Failure in Mice. AB - Bruce effect or alien male-induced implantation failure is a well-studied phenomenon in mice. The presence of stud male during exposure to an alien male protects the female from implantation failure. The pheromones of the stud male are imprinted in the female at the time of mating and act as a luteotrophic agent. We tested whether a nonpheromonal cue exposed to the female during pericopulatory sensitive period could protect pregnancy in newly inseminated females exposed to alien males. Virgin females were allowed to mate in the presence of a cotton ball smeared with groundnut oil as a nonpheromonal cue. When these females were exposed to alien males in the presence of groundnut oil, the majority of the females retained their pregnancy. We evidenced that a nonpheromonal cue could possibly protect the female from alien male-induced implantation failure. The majority of the females exposed to the nonpheromonal cue during the pre-or postcopulatory interactions with the males, exhibited higher rate of pregnancy failure on reexposure to the same cue at the time of exposure to alien males. The protective effect of the nonpheromonal cue is observed only when the female is exposed to it during the pericopulatory sensitive period. PMID- 29982307 TI - Reply to ST McSorley et al. PMID- 29982308 TI - Comment on the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project. PMID- 29982309 TI - Use of people-first language with regard to obesity. PMID- 29982311 TI - Rethinking apolipoprotein A-II in lipid metabolism. PMID- 29982312 TI - Another indication for the use of oral vitamin B-12 supplementation. PMID- 29982310 TI - Plasma trimethylamine-N-oxide and related metabolites are associated with type 2 diabetes risk in the Prevencion con Dieta Mediterranea (PREDIMED) trial. AB - Background: The role of trimethylamine-N-oxide (TMAO) in type 2 diabetes (T2D) is currently partially understood and controversial. Objective: The aim of this study was to investigate associations between TMAO and related metabolites with T2D risk in subjects at high risk of cardiovascular disease. Design: This is a case-cohort design study within the Prevencion con Dieta Mediterranea (PREDIMED) study, with 251 incident T2D cases and a random sample of 694 participants (641 noncases and 53 overlapping cases) without T2D at baseline (median follow-up: 3.8 y). We used liquid chromatography-tandem mass spectrometry to measure plasma TMAO, l-carnitine, betaine, lyso-phosphatidylcholine (LPC) and lyso phosphatidylethanolamine (LPE) species, phosphocholine, alpha glycerophosphocholine, and choline at baseline and after 1 y. We examined associations with the use of weighted Cox proportional hazard models, accounting for the weighted case-cohort design by the Barlow method. Results: After adjustment for recognized T2D risk factors and multiple testing, individuals in the highest quartile of baseline TMAO and alpha-glycerophosphocholine had a lower risk of T2D [HR (95% CI): 0.52 (0.29, 0.89) and 0.46 (0.24, 0.89), respectively]. The HR (95% CI) comparing the extreme quartiles of betaine was 0.41 (0.23, 0.74). Similar trends were observed for C16:0 LPC, C18:1 LPC, C18:0 LPC, C20:4 LPC, C22:6 LPC, C18:1 LPC plasmalogen, and C16:0 LPE. After correcting for multiple comparisons, participants in the highest quartile of 1-y changes in oleic acid LPC plasmalogen concentrations had a lower T2D risk than the reference quartile. Conclusion: Whether the associations between plasma TMAO and certain metabolite concentrations with T2D risk reflect its pathophysiology or represent an epiphenomenon needs to be elucidated. This trial is registered at http://www.controlled-trials.com as ISRCTN35739639. PMID- 29982313 TI - Supported liquid extraction and LC-MS-MS determination of iloperidone and olanzapine in rat plasma: Application to a pharmacokinetic study. AB - A sensitive, selective rapid bioanalytical assay method was developed and quantification of iloperidone (ILP) and olanzapine (OLZ) in rat plasma was done by mass spectrometry. Systematic sample preparation and extraction procedure were carried out by supported liquid extraction using dichloromethane to extract both the eluents (ILP and OLZ) from rat plasma samples. The extorted samples were injected on a selective Waters XTerra(r) C18 reverse-phase bonded column (250 * 4.6 mm i.d., 5 MUm) using acetonitrile and 15 mM ammonium formate containing 0.05% trifluoroacetic acid (60:40 v/v) for isocratic elution mode and detected by mass spectrometry. Calibration curves were drawn with the respective assay statistical data and showed linear regression coefficients greater than 0.9996 over the concentration ranges 2-5,000 ng/mL for ILP and OLZ, respectively. The absolute mean recoveries were found to be in the replicate range of 87.12-94.47%, respectively. The obtained results by the method revealed good intra and interday assay performance in terms of 1.70-5.90% precision and 0-5% accuracy. The validated bioassay method has been successfully applied to the pharmacokinetics in rats. PMID- 29982314 TI - On the power of epigenome-wide association studies using a disease-discordant twin design. AB - Motivation: Many studies have investigated the association between DNA methylation alterations and disease occurrences using two design paradigms, traditional case-control and disease-discordant twins. In the disease-discordant twin design, the affected twin serves as the case and the unaffected twin serves as the control. Theoretically the twin design takes advantage of controlling for the shared genetic make-up, but it is still highly debatable if and how much researchers may benefit from such a design over the traditional case-control design. Results: In this study, we investigate and compare the power of both designs with simulations. A liability threshold model was used assuming that identical twins share the same genetic contribution with respect to the liability of complex human diseases. Varying ranges of parameters have been used to ensure that the simulation is close to real-world scenarios. Our results reveal that the disease-discordant twin design implies greater statistical power over the traditional case-control design. For diseases with moderate and high heritability (>0.3), the disease-discordant twin design allows for large sample size reductions compared to the ordinary case-control design. Our simulation results indicate that the discordant twin design is indeed a powerful tool for epigenetic association studies. Availability and implementation: Computer scripts are available at https://github.com/zickyls/EWAS-Twin-Simulation. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982315 TI - Metabolic influence on the differentiation of suppressive myeloid cells in cancer. AB - New evidences indicate that the metabolic instruction of immunity (immune metabolism) results from the integration of cell metabolism and whole-body metabolism, which are both influenced by nutrition, microbiome metabolites and disease-driven metabolism (e.g. cancer metabolism). Cancer metabolism influences the immunological homeostasis and promotes immune alterations that support disease progression, hence influencing the clinical outcome. Cancer cells display increased glucose uptake and fermentation of glucose to lactate, even in the presence of completely functioning mitochondria. A major side effect of this event is immunosuppression, characterized by limited immunogenicity of cancer cells and restriction of the therapeutic efficacy of anticancer immunotherapy. Here, we discuss how the metabolism of myeloid cells associated with cancer contributes to the differentiation of their suppressive phenotype and therefore to cancer immune evasion. PMID- 29982317 TI - Next-generation sequencing technologies accelerate advances in T-cell therapy for cancer. AB - Next-generation sequencing has produced a large quantity of DNA or RNA sequences related to the processes occurring within tumors and their microenvironment in a reasonable time and cost. These data have been used to guide the identification of neoantigens and to determine their specific T-cell receptors. Furthermore, adoptive T-cell therapy targeting neoantigens is under development for cancer treatment. In this review, we first provide an overview of sequencing technologies and the updated findings concerning neoantigens related to adoptive T-cell therapy and then summarize the methods and principles underlying the development of next-generation sequencing-based neoantigen-reactive T-cell therapy for cancer. PMID- 29982316 TI - The Value of T-Cell Receptor gamma (TRG) Clonality Evaluation by Next-Generation Sequencing in Clinical Hematolymphoid Tissues: A Descriptive Study of 41 Cases From a Single Institution. AB - Objectives: To evaluate feasibility of assessing T-cell receptor gamma (TRG) clonality by next-generation sequencing (NGS) in hematolymphoid tissues. Methods: We evaluated TRG clonality using NGS and polymerase chain reaction (PCR) assays in blood, bone marrow, and formalin-fixed, paraffin-embedded tissues in 41 archived cases, including 21 benign cases with no history of any lymphoproliferative disorders (LPDs), 16 LPDs (nine mature T-cell neoplasms, seven mature B-cell neoplasms and immune dysregulation-associated LPDs), and four atypical LPDs from 22 females and 19 males with a median age of 58 (range, 9-87) years. Results: (1) NGS analyzed TRG sequence and peak ratios, and it had a greater sensitivity than PCR. (2) NGS identified small clones, including biallelic or monoallelic, and minimum clonal percentages (range, ~2.4% to ~69%) within all T cells. (3) We provide our strategy and criteria for evaluating NGS results. (4) We describe every case, with definitive evaluation of TRG clonality in 100% cases by NGS. Conclusions: TRG clonality evaluation by NGS provides greater clinical utility than PCR. PMID- 29982319 TI - Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer. PMID- 29982318 TI - Sepsis and Risk of Cancer Among Elderly Adults in the United States. AB - Background: Sepsis is an important cause of mortality among older adults in the United States. The association between sepsis and subsequent risk of cancer is poorly understood. Methods: We conducted a case-control study in US adults using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. We included 1,801,156 cases with a first cancer diagnosis in SEER during 1992 2013 (ages 66-115 years) and 200,000 cancer-free controls from a 5% random sample of Medicare beneficiaries. Sepsis was identified using inpatient Medicare claims. Associations with sepsis were estimated using logistic regression. Results: After correction for multiple comparisons, sepsis was significantly associated with increased risk for cancers of the colon (adjusted OR=1.12), rectum (1.13), liver (1.47), lung (1.17), and cervix (1.52), as well as acute myeloid leukemia (AML, 1.19), chronic myeloid leukemia (1.54), and myelodysplastic syndrome (1.30). Inverse associations were observed for cancers of the breast (adjusted OR=0.86), prostate (0.75), kidney (0.90), and thyroid (0.68), and melanoma (0.83), diffuse large B-cell lymphoma (0.89) and follicular lymphoma (0.65). Sepsis was significantly associated with 9 of these cancers in the period >5 years following sepsis diagnosis: cancers of thyroid, prostate, colon, rectum, lung, and liver, and follicular lymphoma, melanoma, and AML. Conclusions: Sepsis is associated with increased or decreased risks for a small group of cancers. Factors that may explain these associations include etiologic effects of bacterial infections, inflammation, or use of antibiotics. Other associations may reflect the presence of precursor conditions (e.g., cirrhosis, colorectal polyps) or patterns in ascertainment of cancer and screening. PMID- 29982320 TI - COMBO dual-therapy stent: non-inferior to drug-eluting stents or stepping back to bare metal stents? PMID- 29982321 TI - FSH Receptor Signaling: Complexity of Interactions and Signal Diversity. AB - FSH is synthesized in the pituitary by gonadotrope cells. By binding to and interacting with its cognate receptor [FSH receptor (FSHR)] in the gonads, this gonadotropin plays a key role in the control of gonadal function and reproduction. Upon activation, the FSHR undergoes conformational changes leading to transduction of intracellular signals, including dissociation of G protein complexes into components and activation of several associated interacting partners, which concertedly regulate downstream effectors. The canonical Gs/cAMP/protein kinase A pathway, considered for a long time as the sole effector of FSHR-mediated signaling, is now viewed as one of several mechanisms employed by this receptor to transduce intracellular signals in response to the FSH stimulus. This complex network of signaling pathways allows for a fine-tuning regulation of the gonadotropic stimulus, where activation/inhibition of its multiple components vary depending on the cell context, cell developmental stage, and concentration of associated receptors and corresponding ligands. Activation of these multiple signaling modules eventually converge to the hormone-integrated biological response, including survival, proliferation and differentiation of target cells, synthesis and secretion of paracrine/autocrine regulators, and, at the molecular level, functional selectivity and differential gene expression. In this mini-review, we discuss the complexity of FSHR-mediated intracellular signals activated in response to ligand stimulation. A better understanding of the signaling pathways involved in FSH action might potentially influence the development of new therapeutic strategies for reproductive disorders. PMID- 29982322 TI - Impact of Peanut Depth and Container Size on the Parasitism of Diapausing and Nondiapausing Larvae of Indian Meal Moth (Lepidoptera: Pyralidae) by Habrobracon hebetor (Hymenoptera: Braconidae). AB - Host mortality and progeny production by the ectoparasitoid, Habrobracon hebetor Say (Hymenoptera: Braconidae) on diapausing and nondiapausing larvae of Plodia interpunctella Hubner (Lepidoptera: Pyralidae) were investigated in response to peanut depths and free space at standard environmental conditions. The free space was created by having four different quantities of peanuts in glass containers of fixed volume or same quantity of peanut in containers of different sizes. Host mortality caused by the parasitoids was significantly higher for diapausing larvae compared with nondiapausing larvae at corresponding peanut depth. Differences in peanut depth affected mortality of nondiapausing larvae exposed to parasitoids but diapausing larvae experienced the same level of mortality. Regardless of container sizes, host mortality was higher than 90.0% for both types of larvae. When equivalent peanut depths were compared, more F1 parasitoids were produced on diapausing larvae than on nondiapausing larvae. Reduced peanut depth affected the sex ratio of parasitoid progeny reared on nondiapausing larvae but not those reared on diapausing larvae. Parasitoid progeny resulting from reduced peanut depth was male-biased and this was more evident with parasitoids that emerged from diapausing host larvae than nondiapausing larvae. Progeny production by H. hebetor was not influenced by container size. This study underscores the fact that host mortality caused by H. hebetor at different peanut depths was significantly different for nondiapausing host larvae, but was not so for diapausing larvae. The container sizes did not affect the performance of H. hebetor in killing P. interpunctella. The entire study emphasizes the potential of diapausing larvae for the rearing of H. hebetor. PMID- 29982323 TI - Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer. PMID- 29982324 TI - Effects of Nymphal Diet and Adult Feeding on Allocation of Resources to Glassy Winged Sharpshooter Egg Production. AB - The glassy-winged sharpshooter is an invasive insect capable of transmitting the bacterial pathogen Xylella fastidiosa. Pre-oviposition periods of laboratory reared glassy-winged sharpshooters are variable. Here, two questions were addressed: does nymphal diet affect pre-oviposition period and how do allocation patterns of resources differ for females that produce eggs versus females that do not? Nymphs were reared on one of three host plant species: cowpea, sunflower, or sorghum. Half of the females were sacrificed at emergence. The remaining adult females were held on cowpea, a host plant species known to support egg maturation via adult feeding. Females were sacrificed on the day of first oviposition or after 9 wk if no eggs were deposited. Females reared as nymphs on sorghum had longer development times and were smaller (head capsule width and hind tibia length) than females reared as nymphs on cowpea and sunflower. However, nymphal diet did not affect percentage of dry weight that was lipid at emergence. Further, nymphal diet did not affect time to deposition of the first egg mass or total number of eggs matured at the time of first oviposition. Egg production reduced the allocation of resources to insect bodies, with body lipid content decreasing with increasing egg production. In general, females increased wet weight 1.4-fold during the first week after adult emergence, with wet weights plateauing over the remaining 9 wk that adults were monitored. Thus, it seems reasonable to hypothesize that resources required for egg production were acquired via adult feeding during the first week after adult emergence. PMID- 29982325 TI - Functional significance of the optical properties of flowers for visual signalling. AB - Background: Flower coloration is a key enabler for pollinator attraction. Floral visual signals comprise several components that are generated by specific anatomical structures and pigmentation, and often have different functions in pollinator attraction. Anatomical studies have advanced our understanding of the optical properties of flowers, and evidence from behavioural experiments has elucidated the biological relevance of different components of floral visual signals, but these two lines of research are often considered independently. Scope: Here, we review current knowledge about different aspects of the floral visual signals, their anatomical and optical properties, and their functional significance in plant-pollinator visual signalling. We discuss common aspects, such as chromatic and achromatic contrast, hue, saturation and brightness, as well as less common types of visual signals, including gloss, fluorescence, polarization and iridescence in the context of salience of floral colour signals and their evolution, and highlight promising avenues for future research. PMID- 29982326 TI - Prospective Postimplementation Study of Solana Group A Streptococcal Nucleic Acid Amplification Test vs Conventional Throat Culture. AB - Objectives: We evaluated the Solana Group A Streptococcus Assay (Quidel, San Diego, CA), a nucleic acid amplification test (NAAT), as a substitute for backup culture on throat specimens with a negative rapid group A Streptococcus (GAS) antigen assay. Methods: During October 2016, all throat swabs from patients with a negative GAS antigen assay from local urgent care centers were processed by NAAT and conventional culture in real time. Results: The overall agreement of the 2,090 tested throat swab specimens of the NAAT with the culture was 2,050 (98%) of 2,090. Sensitivity, specificity, positive predictive value, and negative predictive value were 91.4%, 98.5%, 78.0%, and 99.5%, respectively. Conclusions: In summary, this postimplementation study supported high sensitivity and specificity of the GAS NAAT as a backup test for negative rapid GAS antigen tests. PMID- 29982327 TI - Clinical Utility of Classical and Nonclassical Monocyte Percentage in the Diagnosis of Chronic Myelomonocytic Leukemia. AB - Objectives: To determine if a clinically applicable flow cytometry methodology could identify chronic myelomonocytic leukemia (CMML) cases. Methods: Monocyte subset screening (CD14/CD16 expression) was performed on 68 blood and 25 bone marrow specimens with a monocytosis and/or flagged as possible CMML. Fifty thousand total events were obtained per case. Cases were categorized as CMML, atypical chronic myeloid leukemia (aCML), or non-CMML + non-aCML by clinicopathologic diagnosis. Results: The methodology differentiated blood and bone marrow CMML cases from non-CMML + non-aCML but not three aCML cases in the clinical setting. Furthermore, a decreased percentage of nonclassical monocytes (CD14dimCD16+) showed better sensitivity than the previously described approach that relied on increased percentage of classical monocytes (CD14brightCD16-). Conclusions: Quantification of monocyte subsets is useful in clinical practice as a diagnostic marker of CMML in blood and bone marrow specimens. The percentage of nonclassical monocytes should be included in analysis of monocyte subsets. PMID- 29982328 TI - The Effect of Feeding and Mate Presence on the Pheromone Production of the Spruce Beetle (Coleoptera: Curculionidae). AB - Dendroctonus rufipennis (Kirby, Coleoptera: Curculionidae) uses pheromone blends containing aggregative components (frontalin, verbenene, 1-methyl-2-cyclohexen-1 ol [MCOL], and seudenol) and an anti-aggregative component (3-methyl-2-cyclohexen 1-one [MCH]) to coordinate attacks against host trees, but little is known about the influence of external stimuli on pheromone production. We conducted feeding experiments followed by pheromone extractions to determine if feeding duration and mate presence affected pheromone production in D. rufipennis. Unfed beetles of both sexes produced very little of any pheromone component. Females fed for 48 h produced significantly more MCH and MCOL compared to those which fed for 24 h. Males fed for 48 h produced significantly less seudenol than those which fed for 24 h. Male presence did not significantly affect female pheromone production. We propose that the pheromone blend produced by beetles transitions from aggregative to anti-aggregative shortly after colonizing a host, regardless of mate presence. PMID- 29982329 TI - Cell line-based xenograft mouse model of paediatric glioma stem cells mirrors the clinical course of the patient. AB - The leading cause of cancer-related mortality among children is brain tumour, and glioblastoma multiforme (GBM) has the worst prognosis. New treatments are urgently needed, but with few cases and clinical trials in children, pre-clinical models such as patient-derived tumour xenografts (PDTX) are important. To generate these, tumour tissue is transplanted into mice, but this yields highly variable results and requires serial passaging in mice, which is time-consuming and expensive. We therefore aimed to establish a cell line-based orthotopic mouse model representative of the patient tumour. Glioma stem cell (GSC) lines derived from paediatric GBM were orthotopically transplanted into immunodeficient mice. Overall survival data were collected and histological analysis of the resulting neoplasias was performed. Genome-wide DNA methylation arrays were used for methylation and copy-number alterations (CNA) profiling. All GSC lines initiated tumours on transplantation and the survival of the mice correlated well with the survival of the patients. Xenograft tumours presented histological hallmarks of GBM, and were also classified as GBM by methylation profiling. Each xenograft tumour clustered together with its respective injected GSC line and patient tumour based on the methylation data. We have established a robust and reproducible cell line-based xenograft paediatric GBM model. The xenograft tumours accurately reflected the patient tumours and mirrored the clinical course of the patient. This model can therefore be used to assess patient response in pre-clinical studies. PMID- 29982330 TI - Compound-protein Interaction Prediction with End-to-end Learning of Neural Networks for Graphs and Sequences. AB - Motivation: In bioinformatics, machine learning-based methods that predict the compound-protein interactions (CPIs) play an important role in the virtual screening for drug discovery. Recently, end-toend representation learning for discrete symbolic data (e.g., words in natural language processing) using deep neural networks has demonstrated excellent performance on various difficult problems. For the CPI problem, data are provided as discrete symbolic data, i.e., compounds are represented as graphs where the vertices are atoms, the edges are chemical bonds, and proteins are sequences in which the characters are amino acids. In this study, we investigate the use of end-to-end representation learning for compounds and proteins, integrate the representations, and develop a new CPI prediction approach by combining a graph neural network (GNN) for compounds and a convolutional neural network (CNN) for proteins. Results: Our experiments using three CPI datasets demonstrated that the proposed end-to-end approach achieves competitive or higher performance as compared to various existing CPI prediction methods. In addition, the proposed approach significantly outperformed existing methods on an unbalanced dataset. This suggests that data driven representations of compounds and proteins obtained by end-to-end GNNs and CNNs are more robust than traditional chemical and biological features obtained from databases. Although analyzing deep learning models is difficult due to their black-box nature, we address this issue using a neural attention mechanism, which allows us to consider which subsequences in a protein are more important for a drug compound when predicting its interaction. The neural attention mechanism also provides effective visualization, which makes it easier to analyze a model even when modeling is performed using real-valued representations instead of discrete features. Availability: https://github.com/masashitsubaki. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982331 TI - Transcriptome profiling reveals an integrated mRNA-lncRNA signature with predictive value of early relapse in colon cancer. AB - The purpose of our study was to develop a multigene signature based on transcriptome profiles of both mRNAs and lncRNAs to identify a group of patients who are at high risk of early relapse in stages II-III colon cancer. Firstly, propensity score matching was conducted between patients in early relapse group and long-term survival group from GSE39582 training series (N = 359) and patients were matched 1:1. Global transcriptome analysis was then performed between the paired groups to identify tumor specific mRNAs and lncRNAs. Finally, using LASSO Cox regression model, we built a multigene early relapse classifier incorporating 15 mRNAs and three lncRNAs. The prognostic and predictive accuracy of the signature was internally validated in 102 colon cancer patients and externally validated in other 241 patients. In the training set, patients with high risk score were more likely to suffer from relapse than those with low risk score (HR: 2.67, 95% CI: 2.07-3.46, P < 0.001). The results were validated in the internal validation set (HR: 2.23, 95% CI: 1.23-3.78, P = 0.003) and external validation (HR 1.88, 95% CI 1.42-2.48; P < 0.001) set. Time-dependent receiver operating curve at 1 year showed that the integrated mRNA-lncRNA signature [area under curve (AUC) = 0.742] had better prognostic accuracy than AJCC TNM stage (AUC = 0.615) in the entire 702 patients. In addition, survival decision curve analyses at 12 months revealed a good clinical usefulness of the integrated mRNA-lncRNA signature. In conclusion, we successfully developed an integrated mRNA-lncRNA signature that can accurately predict early relapse. PMID- 29982332 TI - Trends in the development of miRNA bioinformatics tools. AB - MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression via recognition of cognate sequences and interference of transcriptional, translational or epigenetic processes. Bioinformatics tools developed for miRNA study include those for miRNA prediction and discovery, structure, analysis and target prediction. We manually curated 95 review papers and ~1000 miRNA bioinformatics tools published since 2003. We classified and ranked them based on citation number or PageRank score, and then performed network analysis and text mining (TM) to study the miRNA tools development trends. Five key trends were observed: (1) miRNA identification and target prediction have been hot spots in the past decade; (2) manual curation and TM are the main methods for collecting miRNA knowledge from literature; (3) most early tools are well maintained and widely used; (4) classic machine learning methods retain their utility; however, novel ones have begun to emerge; (5) disease-associated miRNA tools are emerging. Our analysis yields significant insight into the past development and future directions of miRNA tools. PMID- 29982333 TI - Insights into the phylogeny of false-branching heterocytous cyanobacteria with the description of Scytonema pachmarhiense sp. nov. isolated from Pachmarhi Biosphere Reserve, India. AB - A false branching cyanobacterium (strain 10A1_PS) was isolated from a freshwater body of the Pachmarhi Biosphere Reserve, India and was characterised using the polyphasic approach. The detailed morphological examination indicated that the strain belonged to the complex genus Scytonema as it exhibited typical false branching character whose frequency increased with age of the culture. As the family Scytonemataceae and the genus Scytonema has been shown to be polyphyletic in many studies, we provide deep insights into the phylogenetic complexities within the family Scytonemataceae based on 16S rRNA gene phylogeny along with complete morphological, molecular and phylogenetic characterisation of the strain. The 16S rRNA gene phylogenetic tree inferred by Bayesian Inference, Neighbor-Joining and Maximum Parsimony methods showed that the strain clustered within the Scytonema sensu stricto clade. The phylogenetic distance and the positioning of the strain clearly indicated it to be different from other Scytonema species. Further analysis using rbcL phylogeny, folded secondary structures of the 16S-23S ITS, p-distance and percentage pairwise similarity matrix clearly distinguished the strain 10A1_PS from the other closely related species. In accordance with the International Code of Nomenclature for Algae, Fungi and Plants, we propose the name of the new species to be Scytonema pachmarhiense. PMID- 29982334 TI - Whole-Exome Sequencing Identifies Novel Recurrent Somatic Mutations in Sporadic Parathyroid Adenomas. AB - Primary hyperparathyroidism is commonly caused by excess production of parathyroid hormone from sporadic parathyroid adenomas. However, the genetic architecture of sporadic primary hyperparathyroidism remains largely uncharacterized, especially in the Chinese population. To identify genetic abnormalities that may be involved in the etiology of sporadic parathyroid adenomas and to determine the mutation frequency of previously identified genes in the Chinese population, we performed whole-exome sequencing of 22 blood-tumor pairs from sporadic parathyroid adenomas. The most important finding is the recurrently mutated gene, ASXL3, which has never been reported in parathyroid tumors before. Moreover, we identified two different somatic mutations in the CDC73 gene and one somatic mutation in the EZH2 gene. The Y54X mutation in the CDC73 gene was previously identified in parathyroid carcinomas, which proved that parathyroid adenomas and carcinomas might possess similar molecular signatures. No mutations in the MEN1 or CCND1 genes were observed in our study. Thus, our data provide insights into the genetic pathogenesis of sporadic parathyroid adenomas and are valuable for the development of diagnostic and therapeutic approaches for sporadic primary hyperparathyroidism. PMID- 29982335 TI - Educating in antimicrobial resistance awareness: adaptation of the Small World Initiative program to service-learning. AB - The Small World Initiative (SWI) and Tiny Earth are a consolidated and successful education programs rooted in the USA that tackle the antibiotic crisis by a crowdsourcing strategy. Based on active learning, it challenges young students to discover novel bioactive-producing microorganisms from environmental soil samples. Besides its pedagogical efficiency to impart microbiology content in academic curricula, SWI promotes vocations in research and development in Experimental Sciences and, at the same time, disseminates the antibiotic awareness guidelines of the World Health Organization. We have adapted the SWI program to the Spanish academic environment by a pioneering hierarchic strategy based on service-learning that involves two education levels (higher education and high school) with different degrees of responsibility. Throughout the academic year, 23 SWI teams, each consisting of 3-7 undergraduate students led by one faculty member, coordinated off-campus programs in 22 local high schools, involving 597 high school students as researchers. Post-survey-based evaluation of the program reveals a satisfactory achievement of goals: acquiring scientific abilities and general or personal competences by university students, as well as promoting academic decisions to inspire vocations for science- and technology oriented degrees in younger students, and successfully communicating scientific culture in antimicrobial resistance to a young stratum of society. PMID- 29982336 TI - Transitioning into spousal caregiving: contribution of caregiving intensity and caregivers' multiple chronic conditions to functional health. AB - Background: both caregiving intensity and caregivers' multiple chronic conditions (MCCs) are important aspects of caregiving that might affect the health and well being of older spousal caregivers, but few investigations have simultaneously modelled their impact during the transition into spousal caregiving. Objective: to examine the differential effects of caregiving intensity and caregivers' MCCs on functional health over time among individuals entering the spousal caregiver role. Methods: a total of 1,866 non-caregivers at the baseline were followed over a 4-year period (2011-2015). The effects of transitioning into caregiving (transitioned into low-intensity and transitioned into high-intensity versus never-caregiver) and caregivers' MCCs (reported before and during the transitioning period versus no MCCs) on functional health at the follow-up were estimated using mixed-effects regression models. Results: transitioning into spousal caregiving was associated with a decline in functional health, particularly for those transitioned into high-intensity caregiving, and for those who reported MCCs when transitioning into the caregiver role. The association between transitioning into spousal caregiving and functional decline was strongest for high-intensity caregivers reporting MCCs when transitioning into caregiving, followed by low-intensity caregivers reporting MCCs when transitioning into caregiving. Conclusion: the results highlight the contribution of transitioning into high-intensity caregiving and caregivers' MCCs to the functional health decline of spousal caregivers. Caregiver support interventions should target spousal caregivers who have newly entered a demanding caregiving role; clinical attention should be emphasised for the development of caregivers' own MCCs coinciding with the transitioning period. PMID- 29982337 TI - ATAC-pipe: general analysis of genome-wide chromatin accessibility. AB - Availability: https://github.com/QuKunLab/ATAC-pipe. PMID- 29982338 TI - Amenable mortality in the EU-has the crisis changed its course? AB - Background: Did the global financial crisis and its aftermath impact upon the performance of health systems in Europe? We investigated trends in amenable and other mortality in the EU since 2000 across 28 EU countries. Methods: We use WHO detailed mortality files from 28 EU countries to calculate age-standardized deaths rates from amenable and other causes. We then use joinpoint regression to analyse trends in mortality before and after the onset of the economic crisis in Europe in 2008. Results: Amenable and other mortality have declined in the EU since 2000, albeit faster for amenable mortality. We observed increases in amenable mortality following the global financial crisis for females in Estonia [from -4.53 annual percentage change (APC) in 2005-12 to 0.03 APC in 2012-14] and Slovenia (from -4.22 APC in 2000-13 to 0.73 in 2013-15) as well as males and females in Greece(males: from -2.93 APC in 2000-10 to 0.01 APC in 2010-13; females: from -3.48 APC in 2000-10 to 0.06 APC in 2010-13). Other mortality continued to decline for these populations. Increases in deaths from infectious diseases before and after the crisis played a substantial part in reversals in Estonia, Slovenia and Greece. Conclusion: There is evidence that amenable mortality rose in Greece and, among females in Estonia and Slovenia. However, in most countries, trends in amenable mortality rates appeared to be unaffected by the crisis. PMID- 29982339 TI - Effects of Lifestyle Modifications on Elevated Blood Pressure and Excess Weight in a Population of Italian Children and Adolescents. AB - BACKGROUND: Children's excess weight is a common problem due to low-quality diet and poor physical activity and is a risk factor associated with hypertension. Aim of this study was to assess the effect of a nonpharmacological multidisciplinary intervention on blood pressure (BP) and body weight in a population of children with excess weight and/or elevated BP. METHODS: Children consecutively referred to a Prevention of Cardiovascular Risk Clinic by the primary care pediatrician from 2009 to 2015 were assessed at baseline and followed up over time. RESULTS: Out of 273 children (median age 11.4 years, 55% male), 61% were excess weight only, 7% had elevated BP only, and 32% showed both conditions. The probability of reaching the clinical target (normal weight and BP values) at 1 year of follow-up was 19% (confidence interval [CI]: 14%; 24%) and increased up to 38% (CI: 28%; 47%) at 3 years. At 1 year of follow-up, in the overall population both body mass index (BMI) and systolic BP z-scores decreased significantly from 1.77 to 1.47 and from 0.99 to 0.52, respectively (P < 0.0001). BP was significantly reduced in both children with elevated BP only (reduction = 0.91, P = 0.0157) and subjects with excess weight and elevated BP (reduction = 0.89, P < 0.0001). Variables significantly related with systolic BP z-score at 1 year of follow-up were baseline systolic BP z-score and BMI z-score reduction during follow-up (P < 0.001 and P = 0.0003, respectively). CONCLUSION: Our data demonstrate the efficacy of lifestyles modification on weight and BP in children, both when elevated BP and excess weight were present as distinct clinical problems and in the case of their association. PMID- 29982340 TI - Older age is associated with less cancer treatment: a longitudinal study of English cancer patients. AB - Background: making informed decisions about cancer care provision for older cancer patients can be challenging and complex. Evidence suggests cancer care varies by age, however the relationship between age and care experiences from diagnosis to death for cancer patients within the UK has not previously been examined in detail. Patients and methods: retrospective cohort linking cancer registry and secondary care data for 13,499 adult cancer patients who died between January 2005 and December 2011. Cancer therapies (chemotherapy, radiotherapy, surgery), hospital palliative care referrals, hospital admissions and place of death were compared between age groups using multivariable regression models. Trends in cancer care over time, overall and within age groups were also assessed. Results: compared with adult patients under 60 years, patients aged 80 years and over were less likely to receive chemotherapy, radiotherapy, a hospital palliative care referral; or be admitted to hospital but were more likely to die in a care home. Overall, the percentage of patients receiving chemotherapy, surgery, hospital palliative care referrals and hospital admissions have increased while deaths in hospital have decreased. Deaths at home have increased for patients aged 80 years and over. Conclusion: older patients are less likely to receive cancer therapies or hospital palliative care before death. Further research is needed to identify the extent to which these results reflect unmet need. PMID- 29982341 TI - Neuronal Mechanisms Recording the Stream of Consciousness-A Reappraisal of Wilder Penfield's (1891-1976) Concept of Experiential Phenomena Elicited by Electrical Stimulation of the Human Cortex. AB - Research on memory has been a major focus in the neurosciences over the past decades. An important advance was achieved by Wilder Penfield at the Montreal Neurological Institute, who reported from the 1930s to the 1950s about experiential phenomena induced by electrical brain stimulation in humans, implying neuronal causation of memory. Since then, neuroscientists have addressed the topic of memory from a range of subdisciplines; however, these reports by Penfield and his group as well as those on patient H. M. by Brenda Milner at the same institution continue to be referenced as groundbreaking. Further experimental work by Nobel laureates Eric Kandel and John O'Keefe, as well as by Edvard and May-Britt Moser related Penfield's patient documentation to experiential phenomena. However, our reassessment of Penfield's original patient documentation questions the stance that he had uncovered the "storehouse of memories." Human memory must be regarded more as context sensitive and as representative of an active reconstructive process, than as a simple recording of events. Hence, strategies aiming at naturalizing all phenomena of mind (including memory) to cellular and molecular mechanisms cannot convincingly refer to Penfield's electrophysiological studies alone as evidence that memories are solely caused by neuronal firing patterns. PMID- 29982342 TI - Source and localization of ovulation-inducing factor/nerve growth factor in male reproductive tissues among mammalian species. AB - The objectives of the study were to compare the presence and localization of OIF/NGF in male reproductive organs and determine the abundance in ejaculates of species representative of both spontaneous- and induced-ovulators. We hypothesized that the protein is a widely conserved component of semen among mammals, but is most abundant in camelids. Immuno-histochemical analysis was performed on tissues from the male reproductive system of llamas, rats, cattle, bison, elk, and white-tailed deer (n = 2 males/species), and the abundance of OIF/NGF in the seminal plasma of camelids (llamas and alpacas), cattle, horses and pigs (n = 69, 53, 24 and 16 ejaculates, respectively) were quantified by radioimmunoassay. Based on immuno-reactivity in both the glandular epithelium and glandular lumen, the prostate gland was the main source of seminal OIF/NGF in llamas, the vesicular gland and ampullae in bovids (cattle and bison), and the ampullae and prostate in cervids (elk and white-tailed deer). Camelid and bovine seminal plasma induced dendritic growth in the PC12 differentiation bioassay, but no effect was observed with equine or porcine seminal plasma. The concentration of OIF/NGF was 10 times higher in camelid than bovine seminal plasma (1.2 +/- 0.21 vs. 0.10 +/- 0.03; P < 0.05); OIF/NGF was not detected in equine or porcine ejaculates by radio-immunoassay. Based on, tissue localization, abundance and bioactivity, we conclude that OIF/NGF is a common protein within the male accessory glands among species, and its abundance in camelids, bovids and cervids suggests an important role in the mechanisms of ovulation in both induced- and spontaneous-ovulators. PMID- 29982344 TI - The role of eating behavior traits in mediating genetic susceptibility to obesity. AB - Background: Genome-wide association studies (GWASs) have identified several genes associated with obesity. The mechanisms through which these genes affect body weight are not fully characterized. Recent studies suggest that eating behavior (EB) traits could be involved, but only a few EB traits were investigated. Objective: This study aimed to investigate whether genetic susceptibility to obesity is mediated by EB traits (cognitive restraint, disinhibition, hunger) and their subscales. We hypothesized that EB traits, and their subscales, partly mediate this association. Design: Adult individuals (n = 768) who participated in the Quebec Family Study were included in this cross-sectional study. A genetic risk score (GRS) of obesity was calculated based on the 97 genetic variants recently identified in a GWAS meta-analysis of body mass index (BMI). EB traits and their subscales were assessed with the use of the Three-Factor Eating Questionnaire. Regression analyses with age and sex as covariates were used to investigate the associations between GRS, EB traits, BMI, and WC and whether the association between GRS and obesity is mediated by EB traits, which represents the indirect effect of GRS on obesity. Results: The GRS of obesity was positively associated with BMI (beta = 0.19 +/- 0.04, P < 0.0001) and WC (beta = 0.46 +/- 0.10, P < 0.0001). Regression analyses also revealed that the association between GRS of obesity and BMI was partly mediated by disinhibition and susceptibility to hunger (betaindirect = 0.09 +/- 0.03, P = 0.0007, and betaindirect = 0.04 +/- 0.02, P = 0.02, respectively). Habitual and situational susceptibility to disinhibition (betaindirect = 0.08 +/- 0.03, P = 0.002 and betaindirect = 0.05 +/ 0.02, P = 0.003, respectively) as well as internal and external locus of hunger (betaindirect = 0.03 +/- 0.02, P = 0.03 for both) were also found to mediate the association between GRS of obesity and BMI. The same trends were observed with WC. Conclusions: The results of this study indicate that the genetic susceptibility to obesity is partly mediated through undesirable EB traits, which suggests that they could be targeted in obesity treatment and prevention. This trial was registered at clinicaltrials.gov as NCT03355729. PMID- 29982343 TI - Genome-wide characterization of DNA methylation, small RNA expression, and histone H3 lysine nine di-methylation in Brassica rapa L. AB - Epigenetic gene regulation is crucial to plant life and can involve dynamic interactions between various histone modifications, DNA methylation, and small RNAs. Detailed analysis of epigenome information is anticipated to reveal how the DNA sequence of the genome is translated into the plant's phenotype. The aim of this study was to map the DNA methylation state at the whole genome level and to clarify the relationship between DNA methylation and transcription, small RNA expression, and histone H3 lysine 9 di-methylation (H3K9me2) in Brassica rapa. We performed whole genome bisulfite sequencing, small RNA sequencing, and chromatin immunoprecipitation sequencing using H3K9me2 antibody in a Chinese cabbage inbred line, RJKB-T24, and examined the impact of epigenetic states on transcription. Cytosine methylation in DNA was analysed in different sequence contexts (CG, CHG, and CHH) (where H could be A, C, or T) and position (promoter, exon, intron, terminator, interspersed repeat regions), and the H3K9me2 and 24 nucleotide small interfering RNAs (24 nt-siRNA) were overlaid onto the B. rapa reference genome. The epigenome was compared with that of Arabidopsis thaliana and the relationship between the position of DNA methylation and gene expression, and the involvement of 24 nt siRNAs and H3K9me2 are discussed. PMID- 29982345 TI - Revisiting bacterial volatile-mediated plant growth promotion: lessons from the past and objectives for the future. AB - Background: Bacterial volatile compounds (BVCs) are important mediators of beneficial plant-bacteria interactions. BVCs promote above-ground plant growth by stimulating photosynthesis and sugar accumulation and by modulating phytohormone signalling. These compounds also improve below-ground mineral uptake and modify root system architecture. Scope: We review advances in our understanding of the mode of action and practical applications of BVCs since the discovery of BVC mediated plant growth promotion in 2003. We also discuss unanswered questions about the identity of plant receptors, the effectiveness of combination of two or more BVCs on plant growth, and the potential side effects of these compounds for human and animal health. Conclusion: BVCs have good potential for use as biostimulants and protectants to improve plant health. Further advances in the development of suitable technologies and preparing standards and guidelines will help in the application of BVCs in crop protection and health. PMID- 29982347 TI - Are serum concentrations of vitamin B-12 causally related to cardiometabolic risk factors and disease? A Mendelian randomization study. AB - Background: Several observational studies have shown that low serum vitamin B-12 is associated with increased body mass index (BMI) and adverse cardiometabolic outcomes. However, it is unclear if these associations reflect a causal effect of vitamin B-12 on cardiometabolic risk factors and diseases, latent confounding, or reverse causality. Objectives: The aims of this study were to investigate 1) the possible causal relation between vitamin B-12 and indicators of body fat, lipid, and glucose variables; type 2 diabetes (T2D); and cardiovascular disease by using a 2-sample Mendelian randomization (MR) method and 2) the possible pleiotropic role of fucosyltransferase 2 (FUT2). Design: We selected 11 single nucleotide polymorphisms (SNPs) robustly associated with serum concentrations of vitamin B 12 in a previous genomewide association study (GWAS) in 45,576 individuals. We performed 2-sample MR analyses of the relation between vitamin B-12 and cardiometabolic risk factors and diseases with the use of publicly available GWAS summary statistics for 15 outcomes in <=339,224 individuals. The robustness of results was tested with sensitivity analyses by using MR Egger regression and weighted-median estimation, and by performing additional analyses excluding a variant in the FUT2 gene, which may be pleiotropic. Results: We found a suggestive causal relation between vitamin B-12 and fasting glucose and beta cell function [homeostatic model assessment (HOMA) of beta cell function (HOMA-B)]. However, we found no evidence that serum concentrations of vitamin B-12 were causally related to BMI, waist-to-hip ratio, plasma leptin, body fat, fasting insulin, insulin resistance (from HOMA of insulin resistance), glycated hemoglobin, triglycerides, T2D, coronary artery disease, or HDL, LDL, or total cholesterol. Conclusions: We found no evidence that serum concentrations of vitamin B-12 are causally related to body weight or the majority of cardiometabolic outcomes investigated. However, vitamin B-12 may have a causal effect on fasting glucose and HOMA-B, although these results will require replication in large independent data sets. This trialwas registered at http://www.isrctn.com/ISRCTN47414943 as ISRCTN47414943. PMID- 29982348 TI - The effects of cigarette smoking on the associations between sitting time and all cause mortality: a meta-analysis. AB - Background: Sedentary behavior is recognized as an independent risk factor for mortality, but it remains unclear whether cigarette smoking will aggravate the detrimental effects of prolonged sitting on mortality. This study examined the impact of cigarette smoking on the relationship between sitting time and all cause mortality in adults. Methods: Electronic database searches were conducted in PubMed, Web of Science, and the EMBASE up to 1 June 2017. Prospective studies that reported sitting time, percent of current smokers, and all-cause mortality were included. Data were extracted independently by two authors. Results: Ten prospective studies met the inclusion criteria. These studies included 850990 adults who were followed up for 2-15.7 years, during which 64 781 died (7.6%). Generally, during follow-up sitting time showed a dose-response relationship with all-cause mortality, with each 1 h increment of sitting time per day accounting for hazard ratio (HR) of mortality 1.02 (95%CI, 1.02-1.03). The relationship remained significant when stratified by the quartiles of smoking populations (<=8.4%, 8.5%-12.6%, 12.7%-27.9%, and >=28.0%), and the risk of sitting time related mortality increased parallel to the increment of the percent of smoking populations, with HRs 1.02 (95%CI, 1.02-1.03), 1.03 (95%CI, 1.02-1.03), 1.04 (95%CI, 1.03-1.04) and 1.06 (95%CI, 1.06-1.06), respectively. The associations between the risk of prolonged sitting-related mortality and the percent of smoking populations were linear (P = 0.032). Conclusions: Cigarette smoking significantly aggravated the detrimental effects of sitting time on all-cause mortality. Our findings provided further evidence on the harmful effects of smoking combing prolonged sitting on adult health. PMID- 29982346 TI - A role for plant science in underpinning the objective of global nutritional security? AB - Background: The challenges of achieving global food security have become more demanding as scientists have realized that not only calorie content but also food composition and colonic microbial content impact our health and well-being, dramatically. The ways that the nutrients we consume affect our health are highly complex due to the diversity of what we eat, the varying digestibility of what we eat, the changing composition and functioning of each individual's gut microbiota, the differences in absorption and bioavailability of the nutrients we eat, the differences in responses between individuals to what they eat and the multi-fold mechanisms of action that nutrients have on our health. Perspective and Conclusions: It has been accepted for more than 50 years that diets rich in plants, particularly fruit and vegetables, protect health, and yet such diets have declined, with lower fruit and vegetable content and much more cheap, sugary, oily, processed foods, over the same period. These dietary shifts have had a marked impact on the incidence of chronic diseases: obesity, metabolic diseases, type 2 diabetes and cardiovascular diseases. Greater support for research into the ways that plant-based foods impact health will be essential for changing dietary patterns to protect health and to achieve global nutritional security. PMID- 29982349 TI - The growing vaccine hesitancy: exploring the influence of the internet. AB - Background: Vaccination coverage is dropping in several countries, including Slovenia. More and more people hesitate or even reject vaccinations. As the influence of the internet grows, the question becomes how to communicate about vaccination to parents in order to prevent this drop in vaccination coverage among children. Methods: For the first time in Europe, the Situational Theory of Publics (STOP) has been used in the field of vaccination to segment mothers to subpublics, and to prescribe a clearly defined form of communication for each of the segmented groups. In the survey, 1704 mothers participated who gave birth in 2014 and 2015 in Slovenia. Results: The study showed that mothers react passively to information on vaccination no matter whether they come across it coincidentally or intentionally. Most often, they seek information about vaccination from friends or online. The more concerned they are about the safety of vaccines, the more they search for information about vaccination, and their communication is consequently more active. The mothers that problematize the safety of vaccines more, and are afraid of their adverse events tend to be in favour of alternative options. Conclusions: Our research demonstrated that the STOP can be applied to the field of vaccination. There is a huge need for intensive professional communication about vaccination on the internet and social media. The improvement of the communicational competences of doctors and healthcare workers is essential to achieve better communication with parents and the media, and needs to be focused on mothers and pregnant women. PMID- 29982350 TI - Acute Exacerbations of Chronic Obstructive Pulmonary Disease with a Low Procalcitonin: Impact of Antibiotic Therapy. AB - Background: Patients admitted with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) often are prescribed antibiotics. Studies have shown that the use of procalcitonin (PCT) to guide the decision to initiate antibiotic therapy in AECOPD has resulted in less antibiotic use and similar outcomes compared to standard of care. We evaluated patients with AECOPD and low PCT concentrations to determine whether antibiotic therapy was associated with improved outcomes. Methods: We retrospectively evaluated adult patients admitted with AECOPD who had a peak PCT concentration <0.25ug/mL. Patients were evaluated based on their antibiotic exposure: <= 24 hours vs > 24 hours. We also evaluated outcomes based upon the duration of azithromycin therapy: <= 24 hours vs > 24 hours. The primary outcome was all-cause 30-day readmissions. Secondary outcomes included length of stay (LOS) and COPD-related 30-day readmissions. Results: 161 and 195 patients received <= 24 hours vs > 24 hours of antibiotic therapy, respectively. The cohort with <= 24 hours of antibiotics had a shorter LOS (2.8 vs. 3.7 days; P=0.01). There was no differences in all-cause 30-day readmissions (15.5% vs. 17.4%; P=0.63) or COPD-related 30-day readmissions (11.2% vs. 12.3%; P=0.74). Additionally, patients receiving <= 24 hours of azithromycin had a shorter LOS (3.0 vs. 3.8 days; P=0.01) and there were no differences in all-cause 30-day readmissions (16.2% vs. 17.1%; P=0.82) or COPD-related 30-day readmissions (11.9% vs.11.6%; P=0.94). Conclusions: For adult patients hospitalized with non severe AECOPD and low PCT concentrations, antibiotic therapy beyond 24 hours did not improve outcomes. PMID- 29982351 TI - Simultaneous Determination of Quercitrin, Afzelin, Amentoflavone, Hinokiflavone in Rat Plasma by UFLC-MS-MS and Its Application to the Pharmacokinetics of Platycladus orientalis Leaves Extract. AB - Leaves of Platycladus orientalis have been used as blood cooling and homeostatic therapy for thousands of years in traditional Chinese medicine. Emerging evidences of modern pharmacology have proved flavonoids as the key elements responsible for the efficacies. However, there has been no report on pharmacokinetic study of the flavonoids from Platycladus orientalis leaves extract. In this study, a sensitive and rapid ultra-flow liquid chromatography tandem mass spectrometry method was established and validated for the simultaneous determination of amentoflavone, afzelin, hinokiflavone and quercitrin in rat plasma. The four flavonoids and luteolin (internal standard, IS) were recovered from rat plasma by methanol-ethyl acetate (v:v, 50:50). Chromatographic separation was performed on a C18 column with gradient elution. Our results showed that the recoveries from spiked control samples were more than 85% for all analytes and IS. The relative standard deviations of intra-day and inter-day precision were within 15% while the REs ranged from -6.6% to 8.0%. The validated method in this study was successfully applied to pharmacokinetic study in healthy rats after oral administration of P. orientalis leaves extract. PMID- 29982352 TI - Cardiomyocyte-Specific Deficiency of HSPB1 Worsens Cardiac Dysfunction by Activating NFkappaB-Mediated Leukocyte Recruitment After Myocardial Infarction. AB - Aim: Inadequate healing after myocardial infarction (MI) leads to heart failure and fatal ventricular rupture, while optimal healing requires timely induction and resolution of inflammation. This study tested the hypothesis that heat shock protein B1 (HSPB1), which limits myocardial inflammation during endotoxemia, modulates wound healing after MI. Methods and results: To test this hypothesis, cardiomyocyte-specific HSPB1 knockout (Hspb1-/-) mice were generated using the Cre-LoxP recombination system. MI was induced by ligation of the left anterior descending coronary artery in Hspb1-/- and wild-type (WT) littermates. HSPB1 was upregulated in cardiomyocytes of WT animals in response to MI, and deficiency of cardiomyocyte HSPB1 increased MI-induced cardiac rupture and mortality within 21 days after MI. Serial echocardiography showed more aggravated remodeling and cardiac dysfunction in Hspb1-/- mice than in WT mice at 1, 3, and 7 days after MI. Decreased collagen deposition and angiogenesis, as well as increased MMP2 and MMP9 activity, were also observed in Hspb1-/- mice compared with WT controls after MI, using immunofluorescence, polarized light microscopy, and zymographic analyses. Notably, Hspb1-/- hearts exhibited enhanced and prolonged leukocyte infiltration, enhanced expression of inflammatory cytokines, and enhanced TLR4/MyD88/NFkappaB activation compared with WT controls after MI. In-depth molecular analyses in both mice and primary cardiomyocytes demonstrated that cardiomyocyte-specific knockout of HSPB1 increased NFkappaB activation, which promoted the expression of proinflammatory mediators. This led to increased leukocyte recruitment and thereby to excessive inflammation, ultimately resulting in adverse remodeling, cardiac dysfunction, and cardiac rupture following MI. Conclusions: These data suggest that HSPB1 acts as a negative regulator of NFkappaB-mediated leukocyte recruitment and the subsequent inflammation in cardiomyocytes. Cardiomyocyte HSPB1 is required for wound healing after MI and could be a target for myocardial repair in MI patients. PMID- 29982353 TI - Corrigendum: A miRNA-145/TGF-beta1 negative feedback loop regulates the cancer associated fibroblast phenotype. PMID- 29982354 TI - Selecting patients with triple negative breast cancer for platinum-based therapy: we still haven't found what we're looking for. PMID- 29982355 TI - Evaluating Mobility in Advanced Dementia: A Scoping Review and Feasibility Analysis. AB - Background and Objectives: Mobility decline is a symptom of advanced dementia that affects function, safety, caregiving, and quality of life. Monitoring mobility status is essential for initiating timely and targeted interventions aimed at preventing excess disability in people with dementia (PWD). The physical, cognitive, and behavioral symptoms of dementia however, present unique challenges for mobility assessment. The goals of this review were to (a) identify and describe measures of mobility used for PWD and (b) assess measures' feasibility for use in people with advanced dementia; a group whose degree of cognitive impairment results in severe functional deficits. Research Design and Methods: Electronic searches of Medline, Embase, CINAHL, and PsychInfo databases were conducted using keywords related to dementia, mobility, measurement, and validation. Descriptive characteristics were extracted and measures coded for mobility components. Tools were also evaluated for feasibility of use in advanced dementia and those deemed feasible, screened for psychometric strength. Results: Thirty-eight measures were included and 68% of these tools were performance based. Elements of mobility evaluated were walking (53% of measures), postural transitions (42%), standing (40%), mobility-related behavioral/psychological symptoms (24%), transfers (10%), bed mobility (5%), and wheeled mobility (3%). 36% of studies included people with advanced dementia. Only 18% of tools received high scores for feasibility. Discussion and Implications: Existing measures provide only partial information regarding mobility and few target elements that become relevant as dementia progresses. Most measures are not feasible for people with advanced dementia, and the psychometric evaluation of these measures is limited. Further research is needed to develop a comprehensive, dementia specific, mobility assessment tool. PMID- 29982356 TI - Comments on "Paradoxical Adipose Hypertrophy (PAH) After Cryolipolysis". PMID- 29982357 TI - Starmerella bombicola, an industrially relevant, yet fundamentally underexplored yeast. AB - In this review, we focus on one of the most important microbial producers of biosurfactants, Starmerella bombicola. Emphasis is laid on the discovery, taxonomy, habitat, cellular characteristics, biochemistry and genetics of this non-pathogenic yeast. Biosurfactants are natural surface-active compounds produced by several types of microorganisms and have been considered an interesting alternative to synthetic surfactants. The sophorolipids produced by S. bombicola are promising biosurfactants, with application potential in food, pharmaceutical, cosmetic and cleaning industries. The fundamental knowledge described in this review is of crucial interest to optimize production of these promising compounds. Furthermore, it can be translated to produce novel non native bioactive molecules with S. bombicola, and to deepen fundamental knowledge on other non-conventional yeast species and in the end to broaden their application potential as well. PMID- 29982358 TI - Prognostic gene expression signatures in sarcoma: finding clarity in complexity. PMID- 29982359 TI - Re: 'Application of the key characteristics of carcinogens in cancer hazard evaluation': response to Goodman, Lynch and Rhomberg. PMID- 29982360 TI - Analysis of Fatty Acids in Trichosanthes kirilowii Maxim by MSPD and Fluorescence Derivatization. AB - The extraction and analysis of free fatty acids (FFAs) in the whole natural plants are reported. The aminopropyl-functionalized SBA-15 was designed to increase the efficiency of the matrix solid-phase dispersion (MSPD) extraction method. MSPD extraction was performed using to extract FFAs via acid-base interactions. The optimum parameters for the MSPD extraction were N-SBA-15 30 mg, grinding time 120 s and elution solvent methanol-HCl (6:4, v/v). After extraction, the FFAs were analyzed by HPLC with fluorescent labeling. The reaction of the labeling agent, 2-(9-oxoacridin-10(9 H)-yl) acetohydrazide, with FFAs proceeded easily and quickly (within 20 min) in the presence of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride as the condensing agent. The derivatives had excellent fluorescence properties with excitation and emission wavelengths of 260 and 430 nm, respectively. Good linear correlations were observed for all FFAs, with correlation coefficients >0.996. When 20 mg of sample were used for the analysis, the detection limits at a signal-to-noise ratio of 3 were in the range 0.21-1.20 MUg g-1. The FFAs in the roots, stems, leaves and peel of Trichosanthes kirilowii Maxim were determined using the developed method. PMID- 29982361 TI - Comparative Accuracy of Bowel Ultrasound Versus Magnetic Resonance Enterography in Combination With Colonoscopy in Assessing Crohn's Disease and Guiding Clinical Decision-making. AB - Background: The comparative accuracy of bowel ultrasound [US] versus magnetic resonance enterography [MRE] in combination with colonoscopy [CS] in assessing Crohn's disease [CD] and influencing the decision-making process is unknown. Methods: Consecutive ileo-colonic CD patients seen in a tertiary referral centre were prospectively assessed by MRE, CS, and bowel US, within 1 week. Sensitivity, specificity, accuracy, positive predictive value [PPV], and negative predictive value [NPV] of bowel US in assessing localisation, enhancement [presence of vascularisation at Power Doppler], active disease [presence of ulcers at colonoscopy], strictures, fistulas, and abscesses were calculated using CS + MRE findings together as a reference standard. Two blinded inflammatory bowel disease [IBD] specialists reviewed MRE and bowel US findings and were asked to decide the therapeutic strategy [continue versus change therapy]. Kappa agreement with clinical decision was calculated. Results: Sixty CD patients [36 with endoscopic disease activity, 28 with complications] were enrolled. For localisation, sensitivity, specificity, accuracy, PPV, and NPV of bowel US were 88%, 96%, 91%, 96%, and 85%, respectively; for enhancement, 87%, 92%, 89%, 93%, and 86%; for activity, 92%, 100%, 96%, 100%, and 94%; for strictures, 75%, 86%, 81%, 78%, and 83%; for fistulas, 100%, 98%, 98%, 66%, and 100%; for abscesses, 100%, 96%, 96%, 33%, and 100%. The concordance of management of CD patients based on bowel US or MRE findings, alone, compared with clinical decision, was 0.768 and 0.767, respectively [p <0.001]. The concordance between bowel US and MRE on management of CD patients was 0.800 [p <0.001]. Conclusions: Bowel US is very accurate in assessing CD and is a non-invasive, easy-to-use tool to manage CD patients in clinical practice. PMID- 29982362 TI - Pathological phenotypes of LDL particles. PMID- 29982363 TI - Co-optimization of axial root phenotypes for nitrogen and phosphorus acquisition in common bean. AB - Background and Aims: Root architecture is a primary determinant of soil resource acquisition. We hypothesized that root architectural phenes will display both positive and negative interactions with each other for soil resource capture because of competition for internal resources and functional trade-offs in soil exploration. Methods: We employed the functional-structural plant model SimRoot to explore how interactions among architectural phenes in common bean determine the acquisition of phosphate and nitrate, two key soil resources contrasting in mobility. We evaluated the utility of basal root whorl number (BRWN) when basal root growth angle, hypocotyl-borne roots and lateral root branching density (LRBD) were varied, under varying availability of phosphate and nitrate. Key Results: Three basal root whorls were optimal in most phenotypes. This optimum shifted towards greater values when LRBD decreased and to smaller numbers when LRBD increased. The maximum biomass accumulated for a given BRWN phenotype in a given limiting nutrient scenario depended upon root growth angle. Under phosphorus stress shallow phenotypes grew best, whereas under nitrate stress fanned phenotypes grew best. The effect of increased hypocotyl-borne roots depended upon BRWN as well as the limiting nutrient. Greater production of axial roots due to BRWN or hypocotyl-borne roots reduced rooting depth, leading to reduced biomass under nitrate-limiting conditions. Increased BRWN as well as greater LRBD increased root carbon consumption, resulting in reduced shoot biomass. Conclusions: We conclude that the utility of a root architectural phenotype is determined by whether the constituent phenes are synergistic or antagonistic. Competition for internal resources and trade-offs for external resources result in multiple phenotypes being optimal under a given nutrient regime. We also find that no single phenotype is optimal across contrasting environments. These results have implications for understanding plant evolution and also for the breeding of more stress-tolerant crop phenotypes. PMID- 29982364 TI - Parvalbumin Interneurons Shape Neuronal Vulnerability in Blunt TBI. AB - Excessive excitation has been hypothesized to subsume a significant part of the acute damage occurring after traumatic brain injury (TBI). However, reduced neuronal excitability, loss of neuronal firing, and a disturbed excitation/inhibition balance have been detected. Parvalbumin (PV) interneurons are major regulators of perisomatic inhibition, principal neurons firing, and overall cortical excitability. However, their role in acute TBI pathogenic cascades is unclear. We exploited the chemogenetic Pharmacologically Selective Activation Module and Pharmacologically Selective Effector Module control of PV Cre+ neurons and the Designer Receptors Exclusively Activated by Designer Drug (DREADD) control of principal neurons in a blunt model of TBI to explore the role of inhibition in shaping neuronal vulnerability to TBI. We demonstrated that inactivation of PV interneurons at the instance or soon after trauma enhances survival of principal neurons and reduces gliosis at 7 dpi whereas, activation of PV interneurons decreased neuronal survival. The protective effect of PV inactivation was suppressed by expressing the nuclear calcium buffer PV-nuclear localisation sequence in principal neurons, implying an activity-dependent neuroprotective signal. In fact, protective effects were obtained by increasing the excitability of principal neurons directly using DREADDs. Thus, we show that sustaining neuronal excitation in the early phases of TBI may reduce neuronal vulnerability by increasing activity-dependent survival, while excess activation of perisomatic inhibition is detrimental to neuronal integrity. PMID- 29982365 TI - Delirium, dementia and in-hospital mortality: the results from the Italian Delirium Day 2016, a national multicenter study. AB - Background: There is little evidence about the prevalence of cognitive disorders and their effect on in-hospital mortality in large multicenter studies. The objectives of the 2016th edition of the "Italian Delirium Day", a large multicenter study on in-hospital older patients, were to assess: 1) the point prevalence of cognitive impairment/no dementia, dementia, delirium and delirium superimposed on dementia, DSD; and 2) the effect of these conditions on in hospital mortality. Methods: This multicenter study and included 2037 older patients (aged >=65 years) admitted to acute medical and surgical wards across 205 acute hospitals. The four cognitive disorders groups were defined with a structured approach including the 4 AT and the presence of a documented diagnosis of dementia. The outcome measure was in hospital mortality, as reported by the researchers involved in the study in each center. Results: The mean age was 81.17+/-7.7 years. Overall, 893 patients (43.8%) had neither delirium, nor dementia nor cognitive impairment, 483 (23.7%) had cognitive impairment/no dementia, 230 (11.3%) dementia alone, 187 (9.2%) delirium alone and 244 (12.0%) DSD. Overall, 99 (4.8%) patients died. Participants with delirium alone (Odds Ratio, O.R. 2.56, 95% Confidence interval, C.I. 1.29-5.09) and those with DSD (OR. 2.60, 95% C.I. 1.39-4.85) had higher mortality risk compared to the reference group of patients with "no cognitive impairment". Conclusions: Delirium and DSD were highly prevalent among older hospitalized patients and significantly increased in-hospital mortality. Clinicians should systematically assess these conditions and recognize them as markers of critical conditions and predictors of imminent death. PMID- 29982366 TI - Caffeine consumption during early pregnancy impairs oviductal embryo transport, embryonic development and uterine receptivity in mice. AB - Caffeine consumption has been widely used as a central nervous system stimulant. Epidemiological studies, however, have suggested that maternal caffeine exposure during pregnancy is associated with increased abnormalities, including decreased fertility, delayed conception, early spontaneous abortions and low birth weight. The mechanisms underlying the negative outcomes of caffeine consumption, particularly during early pregnancy, remain unclear. In present study, we found that pregnant mice treated with moderate (5mg/kg) or high (30mg/kg) dosage of caffeine (intraperitoneally or orally) during preimplantation resulted in retention of early embryos in the oviduct, defective embryonic development and impaired embryo implantation. Transferring normal blastocysts into the uteri of caffeine-treated pseudopregnant females also showed abnormal embryo implantation, thus indicates impaired uterine receptivity by caffeine administration. The remaining embryos that managed to implant after caffeine treatment also showed increased embryo resorption rate and abnormal development at mid-term stage, and decreased weight at birth. In addition to a dose-dependent effect, significant variations between individual mice under the same caffeine dosage were also observed, suggesting different sensitivities to caffeine, similar to that observed in human populations. Collectively, our data revealed that caffeine exposure during early pregnancy impaired oviductal embryo transport, embryonic development, and uterine receptivity, which are responsible for abnormal implantation and pregnancy loss. The study raises the concern of caffeine consumption during early stages of pregnancy. PMID- 29982367 TI - Establishing the cell biology of apomictic reproduction in diploid Boechera stricta (Brassicaceae). AB - Background and aims: In the Brassicaceae family, apomictic development is characteristic of the genus Boechera. Hybridization, polyploidy and environmental adaptation that arose during the evolution of Boechera may serve as (epi)genetic regulators of apomictic initiation in this genus. Here we focus on Boechera stricta, a predominantly diploid species that reproduces sexually. However, apomictic development in this species has been reported in several studies, indicating non-obligate sexuality. Methods: A progressive investigation of flower development was conducted using three accessions to assess the reproductive system of B. stricta. We employed molecular and cyto-embryological identification using histochemistry, transmission electron microscopy and Nomarski and epifluorescence microscopy. Key Results: Data from internal transcribed spacer (ITS) and chloroplast haplotype sequencing, in addition to microsatellite variation, confirmed the B. stricta genotype for all lines. Embryological data indicated irregularities in sexual reproduction manifested by heterochronic ovule development, longevity of meiocyte and dyad stages, diverse callose accumulation during meiocyte-to-gametophyte development, and the formation of triads and tetrads in several patterns. The arabinogalactan-related sugar epitope recognized by JIM13 immunolocalized to one or more megaspores. Furthermore, pollen sterility and a high frequency of seed abortion appeared to accompany reproduction of the accession ES512, along with the initiation of parthenogenesis. Data from flow cytometric screening revealed both sexual and apomictic seed formation. Conclusion: These results imply that B. stricta is a species with an underlying ability to initiate apomixis, at least with respect to the lines examined here. The existence of apomixis in an otherwise diploid sexual B. stricta may provide the genomic building blocks for establishing highly penetrant apomictic diploids and hybrid relatives. Our findings demonstrate that apomixis per se is a variable trait upon which natural selection could act. PMID- 29982368 TI - Overall and Sex-Specific Associations Between Fetal Adversity and Child Development at Age 1 Year: Evidence From Brazil. AB - A growing body of epigenetic research suggests that in-utero adaptations to environmental changes display important sex-specific variation. We tested this heterogeneous adaptation hypothesis using data from 900 children born at the University Hospital in Sao Paulo, Brazil, between October 2013 and April 2014. Crude and adjusting linear models were used to quantify the associations between prematurity, being small for gestational age, and children's physical and mental development at 12 months of age. Prematurity was negatively associated with neuropsychological development in final models (z score difference, -0.42, 95% confidence intervals: -0.71, -0.14), but associations did not vary significantly by sex. For being small for gestational age, associations with height-for-age, weight-for-age, and neuropsychological development were also negative, but they were systematically larger for male than for female infants (P < 0.05 for all). These results suggest that male fetuses may be more vulnerable to intrauterine adversity than female fetuses. Further research will be needed to better understand the mechanisms underlying these sex-specific associations. PMID- 29982369 TI - Sterile marginal flowers increase visitation and fruit set in the hobblebush (Viburnum lantanoides, Adoxaceae) at multiple spatial scales. AB - Background and Aims: Enlarged sterile flowers on the periphery of inflorescences increase the attractiveness of floral displays, and previous studies have generally demonstrated that these have positive effects on insect visitation and/or reproductive success. However, experiments have not specifically been designed to examine the benefits of sterile flowers under conditions that reflect the early stages in their evolution, i.e. when plants that produce sterile flowers are at low frequency. Methods: Over three years, three experiments were performed in natural populations of Viburnum lantanoides, which produces sterile marginal flowers (SMFs). The first experiment established that fruit production in V. lantanoides increases with the receipt of outcross pollen. The second tested the role of SMFs under extant conditions, comparing fruit production in two populations composed entirely of intact plants or entirely of plants with the SMFs removed. The third was designed to mimic the presumed context in which SMFs first evolved; here, SMFs were removed from all but a few plants in a population, and rates of insect visitation and fruit set were compared between plants with intact and denuded SMFs. Key Results: In comparing whole populations, the presence of SMFs nearly doubled fruit set. Under simulated 'ancestral' conditions within a population, plants with intact SMFs received double the insect visits and produced significantly more fruits than denuded plants. There was no significant effect of the number of inflorescences or fertile flowers on insect visitation or fruit set, indicating that the presence of SMFs accounted for these differences. Conclusions: The presence of SMFs significantly increased pollinator attraction and female reproductive success both in contemporary and simulated ancestral contexts, indicating that stabilizing selection is responsible for their maintenance, and directional selection likely drove their evolution when they first appeared. This study demonstrates a novel approach to incorporating historically relevant scenarios into experimental studies of floral evolution. PMID- 29982370 TI - The putative transcription factor CaMaf1 controls the sensitivity to lithium and rapamycin and represses RNA polymerase III transcription in Candida albicans. AB - Maf1 is a repressor of RNA polymerase (Pol) III transcription for tRNA. Nutrient deprivation and environmental stress repress Pol III transcription through Maf1 in Saccharomyces cerevisiae. The sole Candida albicans homolog CaMaf1 is a protein of 380 amino acids with conserved domains and motifs of the eukaryotic Maf1 family. Here, we show that C. albicans cells lacking CaMAF1 show elevated levels of tRNA. Deletion of CaMAF1 increases the sensitivity of C. albicans cells to lithium cation and SDS as well as tolerance to rapamycin and azole. In addition, deletion of CaMAF1 reduces the level of filamentation and alters the surface morphology of colonies. CaMaf1 is localized in the nucleus of log-phase growing cells. However, a dynamic change of subcellular localization of CaMaf1 exists during serum-induced morphological transition, with CaMaf1 being localized in the nuclei of cells with germ tubes and short filaments but outside of the nuclei of cells with long filaments. In addition, CaMaf1 is required for rapamycin-induced repression of CaERG20, encoding the farnesyl pyrophosphate synthetase involved in ergosterol biosynthesis. Therefore, CaMaf1 plays a role as a general repressor of Pol III transcription in C. albicans. PMID- 29982371 TI - Changes in facial expressions following functional orthopaedic treatment for Class II division 1 malocclusion: a prospective controlled study. AB - Objective: The aim of this study was to quantify changes in facial expressions in children with Class II division 1 malocclusion treated with functional appliances. Materials and methods: A prospective controlled study was carried out evaluating 20 children with Class II division 1 malocclusion (ages 9-13) treated with a functional appliance for 12 months (treatment group). Age- and gender matched children without immediate orthodontic treatment need were followed up without treatment for 12 months (control group). A frame-mode video sequence was taken of each subject at the beginning and end of the 12-month study period, during which 5 distinct facial expressions (posed smile, spontaneous smile, aggressive smile, lip pucker, and maximal mouth opening) were recorded. Frames at which each facial expression was at its peak were analysed. Changes in horizontal and vertical facial anthropometric distances brought about by performing each facial expression were measured. Intragroup differences following treatment were assessed using paired t-tests, whereas intergroup differences were assessed using unpaired t-tests. Results: All treated children showed an improvement in dentoalveolar relationships. Initial facial expressions differed between groups, with the treatment group showing less marked changes during lip pucker and more marked changes during maximal mouth opening. In contrast, no statistically significant differences were found between groups for the final facial expressions. Conclusions: This study suggests that functional appliance use in growing children with Class II division 1 malocclusion tends to normalize soft tissue movements during facial expressions. PMID- 29982372 TI - Pre- and post-pericardiocentesis echo-Doppler features of effusive-constrictive pericarditis compared with cardiac tamponade and constrictive pericarditis. AB - Aims: To review 2D and Doppler findings in patients diagnosed with effusive constrictive pericarditis (ECP) and compare these to patients with cardiac tamponade and patients with surgically-proven constrictive pericarditis (CP). Methods and results: We identified 22 patients diagnosed with ECP at Mayo Clinic, MN, USA between 2002 and 2016 who had persistent elevation of jugular venous pressure post-pericardiocentesis. We compared them to 30 patients with CP and 30 patients with cardiac tamponade who had normalization of venous pressure post pericardiocentesis. All patients were in sinus rhythm. Mean age was 57 +/- 18 years in the ECP group; 36% were females. Most ECP and cardiac tamponade cases were idiopathic (41% and 33%, respectively). Prior to pericardiocentesis, medial and lateral e' velocities were higher in ECP compared with tamponade; both ECP and tamponade patients had markedly decreased hepatic vein diastolic forward flow velocities. Inspiratory and expiratory mitral E/A ratios were higher in ECP compared with tamponade, but lower than those observed in CP. Post pericardiocentesis, hepatic vein diastolic forward flow velocities increased in both ECP and tamponade. Hepatic vein diastolic reversal velocities decreased in tamponade but were unchanged in ECP. During median follow-up of 481 days, three patients required pericardiectomy for CP; they were all in the ECP group (14% of ECP cases). Conclusion: ECP may have unique echo-Doppler features that distinguish it from both CP and tamponade. Our findings suggest that ECP could be diagnosed by echocardiography even prior to pericardiocentesis. ECP appears to have a good prognosis, particularly in patients presenting acutely. PMID- 29982373 TI - Determination of the effect of polyamines on an oil-degrading strain of Yarrowia lipolytica using an odc minus mutant. AB - Yarrowia lipolytica is an ascomycetous dimorphic yeast with immense potential for industrial applications, including bioremediation of crude oil-contaminated environments. It has been shown that a dimorphic marine isolate of Y. lipolytica (var. indica) has significant capacity to degrade fatty acids and alkanes, when in its yeast morphology. It has also been demonstrated that polyamines play an important role in the yeast-to-mycelium transition of different strains of Y. lipolytica that are unable to utilize those carbon sources. To determine the role of polyamines on their capacity to utilize oils and hydrocarbons, on the dimorphic transition, and also on other characteristics of the var. indica strain of Y. lipolytica, we proceeded to obtain ornithine decarboxylase minus (odc-) mutants. These mutants behaved as yeasts independently of the concentrations of putrescine added. Further, they conserved the oil-degrading capacity of the parent strain. The odc- mutant can thus be used in fatty acid degradation, and oil spill remediation with distinct advantages. PMID- 29982375 TI - What if they don't have tuberculosis? The consequences and trade-offs involved in false-positive diagnoses of tuberculosis. AB - To find the millions of missed tuberculosis (TB) cases, national TB programmes are under pressure to expand TB disease screening, and target populations with lower disease prevalence. Together with imperfect performance and application of existing diagnostic tools, including empirical diagnosis, broader screening risks placing individuals without TB on prolonged treatment. These false-positive diagnoses have profound consequences for TB patients and prevention efforts, yet are usually overlooked in policy decision-making.In this paper we describe the pathways to a false-positive TB diagnosis, including trade-offs involved in the development and application of diagnostic algorithms. We then consider the wide range of potential consequences for individuals, households, health systems, and reliability of surveillance data. Finally, we suggest practical steps that the TB community can take to reduce the frequency and potential harms of false-positive TB diagnosis and to more explicitly assess the trade-offs involved in the screening and diagnostic process. PMID- 29982374 TI - Targeted Estimation of the Relationship Between Childhood Adversity and Fluid Intelligence in a US Population Sample of Adolescents. AB - Many studies have shown inverse associations between childhood adversity and intelligence, although most are based on small clinical samples and fail to account for the effects of multiple co-occurring adversities. Using data from the 2001-2004 National Comorbidity Survey Adolescent Supplement, a cross-sectional US population study of adolescents aged 13-18 years (n = 10,073), we examined the associations between 11 childhood adversities and intelligence, using targeted maximum likelihood estimation. Targeted maximum likelihood estimation incorporates machine learning to identify the relationships between exposures and outcomes without overfitting, including interactions and nonlinearity. The nonverbal score from the Kaufman Brief Intelligence Test was used as a standardized measure of fluid reasoning. Childhood adversities were grouped into deprivation and threat types based on recent conceptual models. Adjusted marginal mean differences compared the mean intelligence score if all adolescents experienced each adversity to the mean in the absence of the adversity. The largest associations were observed for deprivation-type experiences, including poverty and low parental education, which were related to reduced intelligence. Although lower in magnitude, threat events related to intelligence included physical abuse and witnessing domestic violence. Violence prevention and poverty reduction measures would likely improve childhood cognitive outcomes. PMID- 29982376 TI - Antimicrobial Stewardship and Intensive Care Unit (ICU) Mortality: A systematic review. AB - Background: Antimicrobial stewardship programs (ASP) using audit and feedback in the intensive care unit setting (ICU) can reduce harms related to inappropriate antibiotic use. However, inappropriate discontinuation or narrowing of antibiotic treatment could increase infection-related mortality in this population. Individual ASP studies are underpowered to detect mortality differences. Methods: We conducted a systematic review and meta-analysis of audit and feedback in the ICU setting using mortality as our outcome. Results: Of 2447 citations, 11 studies met our inclusion criteria. Although a variety of study designs were used to assess reductions in antibiotic utilization, mortality was analyzed using an uncontrolled before-after study design in all studies. Five studies directed audit and feedback at all or most ICU patients on antibiotics and measured overall ICU mortality. In the meta-analysis of these studies, the pooled relative risk of ICU mortality was 1.03 (95% CI, 0.93 - 1.14). A second meta-analysis of three smaller studies that evaluated mortality only in patients directly assessed by the ASP found a pooled relative risk of ICU mortality of 1.06 (95% CI, 0.80 to 1.4). Three studies were not appropriate for meta-analysis, but their results were consistent with our overall findings. Conclusion: Our systematic review did not identify a change in mortality associated with antimicrobial stewardship using audit and feedback in the ICU setting. These results increase our confidence that audit and feedback can be safely implemented in this setting. Future studies should report standardized estimates of mortality and use more robust study designs to assess mortality, when feasible. PMID- 29982377 TI - Assisted reproductive technology and the risk of unplanned peripartum hysterectomy: analysis using propensity score matching. AB - STUDY QUESTION: Is there an increased risk of unplanned peripartum hysterectomy in pregnancies with assissted reproductive technology compared to those without ART? SUMMARY ANSWER: Although the absolute risks are low, there is an almost five fold increased risk of unplanned peripartum hysterectomy and 1.7 more unplanned peripartum hysterectomies occur per 1000 deliveries in pregnancies with ART compared to those without ART. WHAT IS KNOWN ALREADY: It has been reported that pregnancies with ART was associated with increased risk of peripartum hysterectomy in one case-control study and in one cohort study. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was conducted using a birth cohort from 2014 and 2015 in the United States, which includes more than 7 million births. Propensity score (PS) matching was used to control for confounding. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects were divided into two groups: pregnancies with and without ART. We calculated PSs with demographic, clinical and socioeconomic variables, and subjects were matched using the PS with a 1:1 ratio. Subjects comprised 43868 ART pregnancies and 43868 non-ART pregnancies after PS matching. The primary outcome of interest was the risk of unplanned peripartum hysterectomy which was compared by evaluating the relative risk and the risk difference between the two groups after PS matching. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline characteristics were similar between groups after PS matching. The risk of peripartum hysterectomy in women with ART was 4.947 times that of those without ART (0.0021 [94/43868] vs 0.0004 [19/43868]; 95% confidence interval [CI] 3.022-8.098). The risk difference between two groups was 0.0017 (95% CI 0.0012-0.0022). LIMITATIONS, REASONS FOR CAUTION: There is a possibility of bias due to unmeasured confounding such as fibroids, previous history of uterine surgery and intrauterine procedures. Misclassification of the exposure and/or the outcome could also influence the results. WIDER IMPLICATIONS OF THE FINDINGS: Although we found a five-fold increased risk of unplanned peripartum hysterectomy in pregnancies with ART compared to those without ART, the results should be interpreted with caution in a clinical context as the overall number and the absolute risk of unplanned peripartum hysterectomy are very low in either group (1/2325 in the non-ART group, and 1/468 in the ART group). However, it would be appropriate as future research agenda to explore mechanisms and/or etiology underlying this finding. STUDY FUNDING/COMPETING INTEREST(S): No external funding was used and there are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 29982378 TI - Malignant mesothelioma diagnosed at a younger age is associated with heavier asbestos exposure. AB - Asbestos exposure is the main etiology of malignant mesothelioma, but there are conflicting data on whether the intensity of exposure modulates the development of this disease. This study considered 594 patients with malignant mesothelioma for whom count data on asbestos bodies and fibers (per gram of wet lung tissue) were available. The relationships between age at diagnosis (a time-to-event outcome variable) and these two measures of internal asbestos exposure, along with other possible modulating factors (sex, tumor location, histological subtype and childhood exposure), were assessed on multivariable Cox proportional hazard models, stratifying by decade of birth year. For both measures of asbestos in lung tissue, younger age at diagnosis was associated with higher internal measures of exposure to asbestos. Stratified Cox analyses showed that for each doubling in asbestos body count patients were 1.07 times more likely to be diagnosed at a younger age [hazard ratio (HR) = 1.07; 95% confidence interval (CI), 1.04-1.09; P = 2.2 * 10-7] and for each doubling in asbestos fiber count patients were 1.13 times more likely to be diagnosed at a younger age (HR = 1.13; 95% CI, 1.09-1.17; P = 8.6 * 10-11). None of the other variables considered were associated with age at diagnosis. Our finding that tumors become clinically apparent at a younger age in heavily exposed subjects suggests that asbestos is involved not only in the malignant mesothelioma tumor initiation but, somehow, also in the progression of the disease. PMID- 29982379 TI - iS-CellR: a user-friendly tool for analyzing and visualizing single-cell RNA sequencing data. AB - Summary: Interactive platform for single-cell RNA-sequencing (iS-CellR) is a web based Shiny application that is designed to provide user-friendly, comprehensive analysis of single-cell RNA sequencing data. iS-CellR has the capability to run on any modern web browser and provides an accessible graphical user interface that enables the user to perform complex single-cell RNA-sequencing analysis without requiring programming skills. Availability and implementation: iS-CellR is open source and available through GitHub at https://github.com/immcore/iS CellR. iS-CellR is implemented in Docker and can be launched on any operating system with Docker installed. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982380 TI - Differential coexpression in human tissues and the confounding effect of mean expression levels. AB - Motivation: Differential coexpression - the alteration of gene coexpression patterns observed in different biological conditions - has been proposed to be a mechanism for revealing rewiring of transcription regulatory networks. Despite wide use of methods for differential coexpression analysis, the phenomenon has not been well-studied. In particular, in many applications, differential coexpression is confounded with differential expression, that is, changes in average levels of expression across conditions. This confounding, despite affecting the interpretation of the differential coexpression, has rarely been studied. Results: We constructed high-quality coexpression networks for five human tissues and identified coexpression links (gene pairs) that were specific to each tissue. Between 3 and 32% of coexpression links were tissue-specific (differentially coexpressed) and this specificity is reproducible in an external dataset. However, we show that up to 75% of the observed differential coexpression is substantially explained by average expression levels of the genes. "Pure" differential coexpression independent from differential expression is a minority and is less reproducible in external datasets. We also investigated the functional relevance of pure differential coexpression. Our conclusion is that to a large extent, differential coexpression is more parsimoniously explained by changes in average expression levels and pure links have little impact on network-based functional analysis. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982382 TI - Epidemiology of meningococcal disease outbreaks in the United States, 2009-2013. AB - Background: Although incidence of meningococcal disease is low in the United States, outbreaks remain a serious public health concern. In this evaluation, we identify and describe outbreaks of meningococcal disease. Methods: A retrospective review of all meningococcal disease cases reported from January 1, 2009 to December 31, 2013 was performed by state health departments and CDC to identify meningococcal disease outbreaks. An outbreak was defined as 2 or more primary cases of the same serogroup in less than three months in an organization, or an at-least two-fold increase in disease rates in a community. Results: From 2009 to 2013, 3,686 cases of meningococcal disease were reported in the United States. Among these, 180 primary cases (4.9%) occurred as part of 36 outbreaks (17 organization-based and 19 community-based). Serogroup B accounted for 8 (47.1%) organization-based outbreaks, including 6 of 8 university outbreaks. Serogroup C accounted for 10 (52.6%) community-based outbreaks, including both of the 2 outbreaks identified among men who have sex with men. Organization- and community-based outbreaks differed in predominant serogroup, age distribution of cases, and clinical syndrome. Among 33 outbreaks with known information, a vaccination and/or expanded chemoprophylaxis campaign were conducted in 16 (48.5%). Conclusions: Outbreak-associated cases account for approximately 5% of all meningococcal disease cases in the United States. Serogroup B is the primary cause of organization-based outbreaks, with the majority of university outbreaks due to serogroup B, while serogroup C is the primary cause of community-based outbreaks. PMID- 29982383 TI - Uninterrupted direct oral anticoagulants vs. uninterrupted vitamin K antagonists during catheter ablation of non-valvular atrial fibrillation: a systematic review and meta-analysis of randomized controlled trials. AB - Aims: To assess the incremental benefit of uninterrupted direct oral anticoagulants (DOACs) vs. uninterrupted vitamin K antagonists (VKA) for catheter ablation (CA) of non-valvular atrial fibrillation (NVAF) on three primary outcomes: major bleeding, thrombo-embolic events, and minor bleeding. A secondary outcome was post-procedural silent cerebral infarction (SCI) as detected by brain magnetic resonance imaging. Methods and results: A systematic review of Medline, Cochrane, and Embase was done to find all randomized controlled trials (RCTs) in which uninterrupted DOACs were compared against uninterrupted VKA for CA of NVAF. A fixed-effect model was used, with the exception of the analysis regarding major bleeding events (I2 > 25), for which a random effects model was used. The benefit of uninterrupted DOACs over VKA was analysed from four RCTs that enrolled a total of 1716 patients (male: 71.2%) with NVAF. Of these, 1100 patients (64.1%) had paroxysmal atrial fibrillation. No significant benefit was seen in major bleeding events [risk ratio (RR) 0.54, 95% confidence interval (95% CI) 0.29-1.00; P = 0.05]. No significant differences were found in minor bleeding events (RR 1.11, 95% CI 0.82-1.52; P = 0.50), thrombo-embolic events (RR 0.74, 95% CI 0.26-2.11; P = 0.57), or post-procedural SCI (RR 1.06, 95% CI 0.74-1.53; P = 0.74). Conclusion: An uninterrupted DOACs strategy for CA of NVAF appears to be as safe as uninterrupted VKA without a significantly increased risk of minor or major bleeding events. There was a trend favouring DOACs in terms of major bleeding. Given their ease of use, fewer drug interactions and a similar security and effectiveness profile, DOACs should be considered first line therapy in patients undergoing CA for NVAF. PMID- 29982384 TI - Using the consolidated framework for implementation research to understand safety net health system efforts to increase colorectal cancer screening rates. AB - Guided by the Consolidated Framework for Implementation Research (CFIR), this study aimed to identify factors that influence implementation of evidence-based provider and client-oriented strategies to promote colorectal cancer (CRC) screening in safety net health systems. Site visits and key informant interviews (n=33) were conducted with project leaders and staff in five health systems funded by an American Cancer Society grants program. Within- and cross-site analyses identified CFIR constructs that influenced implementation of provider and client-oriented strategies to promote CRC screening through colonoscopies and fecal immunochemical tests. Of the five CFIR domains, constructs within four CFIR domains (inner setting, outer setting, individual characteristics and process domains) were particularly salient in discussions of implementation while constructs within one CFIR domain (characteristics of the intervention) were not. This study provides a detailed description of how facilitating and inhibiting factors influenced the implementation of evidence-based practices related to CRC screening within safety net health systems. These findings can inform future efforts to promote evidence-based strategies to increase CRC screening rates in safety net health systems. PMID- 29982381 TI - Whole Genome Sequencing of the Pirarucu (Arapaima gigas) Supports Independent Emergence of Major Teleost Clades. AB - The Pirarucu (Arapaima gigas) is one of the world's largest freshwater fishes and member of the superorder Osteoglossomorpha (bonytongues), one of the oldest lineages of ray-finned fishes. This species is an obligate air-breather found in the basin of the Amazon River with an attractive potential for aquaculture. Its phylogenetic position among bony fishes makes the Pirarucu a relevant subject for evolutionary studies of early teleost diversification. Here, we present, for the first time, a draft genome version of the A. gigas genome, providing useful information for further functional and evolutionary studies. The A. gigas genome was assembled with 103-Gb raw reads sequenced in an Illumina platform. The final draft genome assembly was ~661 Mb, with a contig N50 equal to 51.23 kb and scaffold N50 of 668 kb. Repeat sequences accounted for 21.69% of the whole genome, and a total of 24,655 protein-coding genes were predicted from the genome assembly, with an average of nine exons per gene. Phylogenomic analysis based on 24 fish species supported the postulation that Osteoglossomorpha and Elopomorpha (eels, tarpons, and bonefishes) are sister groups, both forming a sister lineage with respect to Clupeocephala (remaining teleosts). Divergence time estimations suggested that Osteoglossomorpha and Elopomorpha lineages emerged independently in a period of ~30 Myr in the Jurassic. The draft genome of A. gigas provides a valuable genetic resource for further investigations of evolutionary studies and may also offer a valuable data for economic applications. PMID- 29982385 TI - New potassium binders reduce the risk of hyperkalaemia in patients treated with renin-angiotensin-aldosterone system inhibitors. PMID- 29982386 TI - Endoscopic submucosal dissection for superficial esophageal cancer. AB - Endoscopic submucosal dissection (ESD) has evolved into a viable treatment modality for superficial esophageal cancer. ESD offers a distinct advantage given the ability to perform en bloc resection enabling accurate histopathologic assessment. Data from published literature has established ESD as the preferred option in the treatment of superficial squamous cell carcinoma with complete resection rates of 78-100%, and a low rate recurrence of 0-2.6%. En bloc resection for esophageal SCC is curative for tumors with M1 (intrapethelial) or M2 (invasion into the lamina propria) involvement with no lymphovascular invasion. Tumors that contain lymphovascular invasion or submucosal invasion greater than 200 MUm should be treated as advanced carcinomas due to the increased risk of lymph node metastasis. In contrast, the role of ESD in Barrett's esophagus is more limited due to the high rate of efficacy of EMR. A randomized control trial comparing EMR and ESD strategies found a higher R0 resection rate for ESD, but no significant difference in complete remission from neoplasia at 3 month follow up. Endoscopic ultrasound (EUS) has a limited role in the evaluation of superficial esophageal cancer. Alternatively, detailed endoscopic assessment along with magnification endoscopy or narrow band imaging, may provide greater utility than EUS. The most common adverse events of ESD in the esophagus include perforation and stricture. Perforation can often be managed by defect closure along with non-operative conservative management. Steroid administration with either topical or local injection can be effective management in stricture prevention. Continued refinement of ESD technique and innovation will overcome some of the current limitations of ESD and enable curative resection of superficial esophageal cancer as an alternative to invasive surgery. PMID- 29982387 TI - Statistical tests for detecting variance effects in quantitative trait studies. AB - Motivation: Identifying variants, both discrete and continuous, that are associated with quantitative traits, or QTs, is the primary focus of quantitative genetics. Most current methods are limited to identifying mean effects, or associations between genotype or covariates and the mean value of a quantitative trait. It is possible, however, that a variant may affect the variance of the quantitative trait in lieu of, or in addition to, affecting the trait mean. Here, we develop a general methodology to identify covariates with variance effects on a quantitative trait using a Bayesian heteroskedastic linear regression model (BTH). We compare BTH with existing methods to detect variance effects across a large range of simulations drawn from scenarios common to the analysis of quantitative traits. Results: We find that BTH and a double generalized linear model (dglm) outperform classical tests used for detecting variance effects in recent genomic studies. We show BTH and dglm are less likely to generate spurious discoveries through simulations and application to identifying methylation variance QTs and expression variance QTs. We identify four variance effects of sex in the Cardiovascular and Pharmacogenetics study. Impact: Our work is the first to offer a comprehensive view of variance identifying methodology.We identify shortcomings in previously used methodology and provide a more conservative and robust alternative. We extend variance effect analysis to a wide array of covariates that enables a new statistical dimension in the study of sex and age specific quantitative trait effects. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982388 TI - pH level has a strong impact on population dynamics of the yeast Yarrowia lipolytica and oil micro-droplets in multiphasic bioreactor. AB - The oleaginous yeast Yarrowia lipolytica has the ability to use oils and fats as carbon source, making it a promising cell factory for the design of alternative bioprocesses based on renewable substrates. However, such a multiphasic bioreactor design is rather complex and leads to several constraints when considering emulsification of the oil-in-water mixture, foaming and cell growth/physiology on hydrophobic substrate. This study aims to shed light on the effect of pH changes on the physico-chemical properties of the cultivation medium and on cell physiology. It was indeed observed that at a pH value of 6, cell growth rate and intracellular lipid accumulation were optimized. Additionally, foaming was significantly reduced. In order to avoid over foaming in bioreactor, without impairing cell physiology, the use of alternative processes that can only act on the physical structure of culture medium, seems to be an effective alternative to usual chemical anti-foam agents. PMID- 29982390 TI - Sparse Labeling and Neural Tracing in Brain Circuits by STARS Strategy: Revealing Morphological Development of Type II Spiral Ganglion Neurons. AB - Elucidating axonal and dendritic projection patterns of individual neurons is a key for understanding the cytoarchitecture of neural circuits in the brain. This requires genetic approaches to achieve Golgi-like sparse labeling of desired types of neurons. Here, we explored a novel strategy of stochastic gene activation with regulated sparseness (STARS), in which the stochastic choice between 2 competing Cre-lox recombination events is controlled by varying the lox efficiency and cassette length. In a created STARS transgenic mouse crossed with various Cre driver lines, sparse neuronal labeling with a relatively uniform level of sparseness was achieved across different brain regions and cell types in both central and peripheral nervous systems. Tracing of individual type II peripheral auditory fibers revealed for the first time that they undergo experience-dependent developmental refinement, which is impaired by attenuating external sound input. Our results suggest that STARS strategy can be applied for circuit mapping and sparse gene manipulation. PMID- 29982391 TI - Trajectories of limitations in instrumental activities of daily living in frail older adults with vision, hearing, or dual sensory loss. AB - Background: The present study investigated the trajectories of decline in individual instrumental activities of daily living (IADL) with aging and the effect of hearing (HL) , vision (VL), or dual sensory loss (DSL) on these trajectories in community-living frail older persons. Method: This longitudinal population-based study was conducted in 9,319 community-living frail Dutch persons aged 60 years and older. Self-reported HL, VL, or DSL and nine IADLs were assessed in fifteen studies of the Dutch National Care for the Elderly Program (TOPICS-MDS). Probabilities of limitations in IADLs, odds ratios (per five-years) for binary and rate ratios (per five years) for score outcomes were calculated using mixed logistic and negative binomial models with age as the underlying time scale, stratified by sensory loss (SL), and corrected for confounders. Results: At baseline, the number of IADL-limitations was higher in DSL (2.00 [IQR 1.00 - 4.00]) and VL (2.00 [IQR 1.00 - 4.00]) compared to no SL (NSL) (1.00 [IQR 0.00 - 2.00]) or HL (1.00 [IQR 0.00 - 3.00]). Trajectories of individual IADLs showed an increase in limitations in all IADLs with age. Household tasks, traveling, shopping, preparing a meal, and walking showed the most rapid decline. Handling finances, traveling, and walking followed a different pattern of decline based on SL-status. Conclusions: The age-effect on limitations in IADL appears to be similar across all types of SL, with the exception of handling finances, traveling, and walking. At baseline, persons with self-reported SL had higher levels of self-reported functional limitations. Trajectories depict a decline in IADL-competence with age. PMID- 29982389 TI - Spreading of Tau Pathology in Sporadic Alzheimer's Disease Along Cortico-cortical Top-Down Connections. AB - By using AT8-immunocytochemistry that visualizes hyperphosphorylated tau protein, we examined neurofibrillary changes related to sporadic Alzheimer's disease (AD) in N = 40 individuals at neurofibrillary tangle (NFT) stages I-IV. We report the presence of abnormal tau changes within solitary pyramidal neurons in layers III and V of the neocortex. These pyramidal cells showed pathology in different cell compartments (dendritic, somatic, axonal) that appeared to occur sequentially: Tau pathology was seen in distal segments of the basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected neurons. These findings are remarkable in that they point to the existence of neurofibrillary changes in regions routinely associated with later NFT stages. In addition, they lend support to the idea that it may be the axons of cortico cortical top-down neurons in neocortical fields involved in AD that carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells following directly in the neuronal chain, thereby sustaining further tau-seeded templating. PMID- 29982392 TI - LigVoxel: Inpainting binding pockets using 3D-convolutional neural networks. AB - Motivation: Structure-based drug discovery methods exploit protein structural information to design small molecules binding to given protein pockets. This work proposes a purely data driven, structure-based approach for imaging ligands as spatial fields in target protein pockets.We use an end-to-end deep learning framework trained on experimental protein-ligand complexes with the intention of mimicking a chemist's intuition at manually placing atoms when designing a new compound. We show that these models can generate spatial images of ligand chemical properties like occupancy, aromaticity and donor-acceptor matching the protein pocket. Results: The predicted fields considerably overlap with those of unseen ligands bound to the target pocket. Maximization of the overlap between the predicted fields and a given ligand on the Astex diverse set recovers the original ligand crystal poses in 70 out of 85 cases within a threshold of 2 A RMSD. We expect that these models can be used for guiding structure-based drug discovery approaches. Availability: LigVoxel is available as part of the PlayMolecule.org molecular web application suite. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29982393 TI - Role of Kisspeptin and Neurokinin B Signaling in Male Rhesus Monkey Puberty. AB - Despite the well-established concept that an increase in pulsatile GnRH release triggers puberty, the precise signaling mechanism responsible for the pubertal increase in GnRH release remains unclear. A recent study indicates that developmental changes in the network formation between kisspeptin and neurokinin B (NKB) signaling greatly contribute to the pubertal increase in GnRH release in female monkeys. It is, however, unknown whether similar developmental changes in the kisspeptin and NKB network are involved in male puberty. In the current study, we first characterized the pubertal stages in male rhesus monkeys by assessing physiological and hormonal changes during sexual development. Subsequently, we examined the role of the kisspeptin and NKB signaling network in the pubertal increase in GnRH release. Results suggest that while collaborative kisspeptin and NKB signaling to GnRH neurons was active before puberty onset, after initiation of puberty the role of NKB signaling in GnRH neurons diminished and kisspeptin signaling assumed the primary stimulatory role in the regulation of GnRH release in male monkeys. These findings in males differ from those seen in females. PMID- 29982394 TI - Immediate effects of a brief intervention to prevent alcohol and medication interactions among older adults. AB - Risk of experiencing alcohol and medication interactions (AMI) is significant among older adults due to the substantial prevalence of alcohol and medication use in this segment of the population. Given the lack of community-level AMI prevention interventions for older adults, this study aimed to examine the immediate effects of a brief, pharmacy-based intervention to prevent AMI among older adults, as well as assess differential effects by past-month drinking status. A convenience sample of 134 adults aged 59 and older was recruited from four pharmacies in rural Virginia. Participants were assessed on their AMI awareness, intentions and importance prior to and immediately after exposure to intervention materials. Findings support immediate, positive intervention effects on AMI awareness, intentions and perceived importance of AMI messaging. Changes from pre to post-test did not differ by drinking status, but participants who consumed alcohol were less likely than non-drinkers to recognize the potential consequential severity of alcohol and medication interactions at both time points. Recommendations and future research to prevent AMI are discussed. PMID- 29982395 TI - Meeting Report of the International Life Science Integration Workshop 2018. PMID- 29982396 TI - Adipose-Derived Stem Cells in Aesthetic Surgery. AB - Adipose-derived stem cells (ADSC) have come to be viewed as a ubiquitous solution for aesthetic and reconstructive problems involving loss of tissue volume and age or radiation-induced loss of tissue pliability and vascularity. As the theoretical potential of "stem cell therapy" has captured the public imagination, so the commercial potential of novel therapies is being exploited beyond scientifically sound, hypothesis-driven paradigms and in the absence of evidence establishing clinical efficacy and safety. Moreover, with variations in methods of isolation, manipulation and reintroduction described, it is unclear how the practitioner with an interest in ASDC can harness the clinical potential in reproducible and scientifically measurable ways. This Continuing Medical Education (CME) article presents a summary of our understanding of what ADSC are, their utility within the field of aesthetic surgery and the current and future directions for adipose stem cell research. PMID- 29982397 TI - Commentary on: Treatment to External Labia and Vaginal Canal With CO2 Laser for Symptoms of Vulvovaginal Atrophy in Postmenopausal Women. PMID- 29982398 TI - Microbial distribution and turnover in Antarctic microbial mats highlight the relevance of heterotrophic bacteria in low-nutrient environments. AB - Maritime Antarctica has shown the highest increase in temperature in the Southern Hemisphere. Under this scenario, biogeochemical cycles may be altered, resulting in rapid environmental change for Antarctic biota. Microbes, that drive biogeochemical cycles often form biofilms or microbial mats in continental meltwater environments. Limnetic microbial mats from the Fildes Peninsula were studied using high-throughput 16S rRNA gene sequencing. Mat samples were collected from fifteen meltwater stream sites, comprising a natural gradient from ultraoligotrophic glacier flows to meltwater streams exposed to anthropogenic activities. Our analyses show microbial structure differences between mats are explained by environmental NH4+, NO3-, DIN, soluble reactive silicon and conductivity. Microbial mats living under ultraoligotrophic meltwater conditions did not exhibit a dominance of cyanobacterial photoautotrophs, as it has been documented for other Antarctic limnetic microbial mats. Instead, ultraoligotrophic mat communities were characterized by the presence of microbes recognized as heterotrophs and photoheterotrophs. This suggests that microbial capabilities for recycling may be a key factor to dwell in ultra-low nutrient conditions. Our analyses show that phylotype level assemblages exhibit coupled distribution patterns in environmental oligotrophic inland waters. The evaluation of these microbes suggests the relevance of reproductive and structural strategies to pioneer these psychrophilic ultraoligotrophic environments. PMID- 29982399 TI - Smoking in bars in eight European countries in 2010 and 2016: an observational comparative study. AB - Background: Most European countries established laws against smoking in public places. We aimed to describe the prevalence of smoking in bars in 2010 and 2016 in eight European countries and to characterise those bars in which smoking still occurred in 2016. Methods: Smoking in bars was studied in 16 cities in 8 European countries (Austria, Belgium, Czech Republic, Denmark, England, France, Germany and the Netherlands). In 2010, 96 bars were visited. In 2016, 51 bars were revisited and 45 new bars were visited. Smoking indoors and characteristics of bars, terrace and customers were observed using a standard observation template. Associations between bar characteristics and smoking were analyzed using logistic regression. Results: Overall prevalence of in-bar smoking was 39.6% in 2010 and 34.4% in 2016. Prevalence in bars covered by smoke-free legislation decreased from 24.2 to 13.0% between 2010 and 2016 whereas prevalence in bars where smoking was legally allowed increased from 73.3 to 88.9%. In-bar smoking almost exclusively occurred in countries with partial smoke-free legislation compared with more comprehensive legislation. Smoking was more prevalent in bars for locals, with a counter for drinks, slot-machines, no outside seating and no food service. Size of the bar, comfort of the terrace and the presence of cigarette vending machines were not associated with in-bar smoking. Conclusions: Whereas comprehensive smoke-free legislation resulted in high compliance, smoking increased in bars in countries with partial or no smoke-free legislation. This study confirms that comprehensive smoke-free legislation is needed to protect customers and personnel against second-hand-smoke exposure in all bars. PMID- 29982400 TI - Gender disparities in fenestrated and branched endovascular aortic repair. AB - OBJECTIVES: Gender disparities in risk factors and outcomes following aortic repair are important issues in healthcare. To date, no large-scale multicentre study addresses this topic in complex endovascular aortic repair. We aimed to determine the outcomes following fenestrated or branched endovascular aortic repair of aneurysms and dissections in female and male patients. METHODS: Health insurance claims data of Germany's third largest insurance provider, DAK Gesundheit, were used to investigate gender disparities in elective fenestrated or branched endovascular aortic repair of thoraco-abdominal or abdominal aortic aneurysms or dissections performed between 2008 and 2017. Elixhauser comorbidities and the linear van Walraven score were used to adjust for confounders in the multivariable analyses. RESULTS: There were 959 patients in the cohort, in whom 163 (17%) were female. The mean age was 73 +/- 8 years with no differences between females and males. No gender disparities were observed regarding the van Walraven comorbidity score (6.9 vs 6.8, P = 0.83), but complications occurred more frequently in females. Acute renal failure (relative risk 1.71, 95% confidence interval 1.06-2.77), paraplegia (relative risk 2.71, 95% confidence interval 1.28-5.77) and bleeding or anaemia requiring transfusion (relative risk 1.76, 95% confidence interval 1.39-2.22) were more common in women. In multivariable models, female patients were at a higher risk of in hospital death (odds ratio 3.206, P < 0.001). Consequently, female gender was associated with lower long-term survival (hazard ratio 1.506, P = 0.006). CONCLUSIONS: In complex endovascular aortic repair, females are more likely to experience complications and have worse in-hospital and, consequently, long-term survival when compared to males. Future studies should include anatomic parameters to determine the impact of anatomy on outcome disparities. PMID- 29982401 TI - Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis. AB - STUDY QUESTION: How does hypoxia-mediated downregulation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) promote angiogenesis in endometriosis? SUMMARY ANSWER: Suppression of COUP-TFII by hypoxia stimulates angiogenesis through induction of angiogenin (ANG). WHAT IS KNOWN ALREADY: The level of COUP-TFII is downregulated in endometriotic tissues, and downregulation of COUP-TFII contributes to the development of endometriosis. STUDY DESIGN, SIZE, DURATION: Twenty-seven patients of reproductive age with endometriosis were recruited in this study. Eutopic endometrial and ectopic endometriotic stromal cells were isolated, cultured and subjected to various treatments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Microarray hybridization, quantitative RT-PCR, and Western blot were used to detect gene expression in normal and endometriotic samples. A luciferase reporter assay and chromatin immunoprecipitation in normoxia- or hypoxia-treated primary cultures of human endometrial stromal cells were performed. Tube formation analysis was performed using primary human umbilical vein endothelial cells (HUVECs). MAIN RESULTS AND THE ROLE OF CHANCE: Protein level of COUP-TFII was downregulated by hypoxia (P < 0.05, normoxia versus hypoxia). Loss of COUP-TFII increased the angiogenic capacity of endometrial stromal cells (P < 0.05, COUP-TFII knockdown versus knockdown control). A novel COUP-TFII target gene, ANG, was identified through microarray analysis. Chromatin immunoprecipitation and promoter activity assays demonstrated that the ANG promoter was bound and suppressed by COUP-TFII (P < 0.05, COUP-TFII overexpression versus empty vector). The levels of ANG mRNA and protein were elevated in ectopic endometriotic stromal cells and negatively correlated with COUP-TFII (P < 0.05, endometrial versus endometriotic tissues/stromal cells). Both knockdown and forced-expression of COUP-TFII further demonstrated that ANG expression and ANG-mediated angiogenic activity were negatively regulated by COUP-TFII (P < 0.05, COUP-TFII knockdown versus knockdown control, and COUP-TFII overexpression versus empty vector). LIMITATIONS, REASONS FOR CAUTION: This study was conducted in primary human endometrial stromal cell cultures and HUVECs, therefore, may not fully reflect the situation in vivo. LARGE SCALE DATA: The raw data were submitted to Gene Expression Omnibus (GSE107469). WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to highlight that the aberrant expression of ANG in endometriotic lesions is mediated by hypoxia-suppressed COUP-TFII expression, which reveals an as yet unidentified molecular pathogenesis of endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by research grants (MOST 105-2314-B-006-059 MY3 to M.H.W. and MOST 104-2320-B-006-036-MY3 to S.J.T.) from the Ministry of Science and Technology, Taiwan. The authors declare that there is no conflict of interest. PMID- 29982402 TI - Waldenstrom's macroglobulinaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 29982403 TI - Neonatal exchange transfusions at a tertiary care centre in north India: an investigation of historical trends using change-point analysis and statistical process control. AB - Background: The need for exchange transfusion (ET) as a treatment modality for neonatal hyperbilirubinaemia declined in developed countries with the advent of effective phototherapy. The trends of ET from India are unknown. Our objective was to investigate the trends of ET in India. Methods: Retrospective data (January 2006-December 2016) was collected on total outborn neonatal admissions and ET procedures from a centre in north India. A combination of change-point analysis (CPA) and statistical process control (SPC) was used to investigate the trends of ET. Results: During the study period, a total of 39 217 outborn neonates were admitted and 1575 (4%) underwent 1816 ET procedures. The CPA unravels four critical change points (October 2009, May 2011, September 2011 and November 2014) in ET rates. An SPC chart showed a decline in mean ET rate from 89.3 (upper control limit [UCL] 176.9, lower control limit [LCL] 1.7)/1000 neonatal admissions at the start of the study to 7.7 (UCL 34.6, LCL 0)/1000 at the end of the study. The greatest decline in ET rate was witnessed in October 2009, from 89.3 (UCL 176.9, LCL 1.7)/1000 neonatal admissions to 34.8 (UCL 87.1, LCL 0)/1000 neonatal admissions. Conclusions: Our study demonstrated a progressive decline in the number of neonatal ET procedures over 11 y. PMID- 29982404 TI - HPLC Method for Simultaneous Determination of Bisphenol-A-Diglycidyl Ether and Some of Its Reaction Products in Canned Foods Using Photodiode Array Detector. AB - Gradient reversed-phase high-performance liquid chromatography with photodiode array detection was used for separation, detection and quantification of bisphenol-A-diglycidyl ether (BADGE) and some of its reaction products, namely, BADGE.HCl.H2O, BADGE.H2O and BADGE.2HCl in pure form and in canned foods, where canned beans and tuna were used as representatives of aqueous and oil-in-water food matrices, respectively. The proposed method had a linear range of 0.01-0.5 MUg g-1 for BADGE.HCl.H2O, BADGE.H2O, BADGE.2HCl and 0.02-0.7 MUg g-1 for BADGE in aqueous food matrices. In oil-in-water matrices, the method was proven to be sensitive over a linear range of 0.01-0.5 MUg g-1 for BADGE.HCl.H2O, BADGE.H2O and 0.02-0.7 MUg g-1 for BADGE.2HCl and BADGE. The limits of detection and quantification ranged from 0.24 to 1.22 ng g-1 and 0.73 to 14.07 ng g-1, respectively. Excellent intraday and interday precision (n = 9) were obtained with RSD% of 0.84-2.19% and 1.88-2.52%, respectively. Accuracy was measured at five concentration levels and the recoveries ranged from 96.31% to 98.76% with an acceptable variation of +/-0.9-2.87. Results suggest that the proposed method could be applied for the routine analysis of the studied compounds in their laboratory-prepared mixtures and in various types of canned foods following the limits and regulations of the European Union. PMID- 29982406 TI - Interferences With Thyroid Function Immunoassays: Clinical Implications and Detection Algorithm. AB - Automated immunoassays used to evaluate thyroid function are vulnerable to different types of interference that can affect clinical decisions. This review provides a detailed overview of the six main types of interference known to affect measurements of thyroid stimulating hormone (TSH), free thyroxine (T4) and free triiodothyronine (T3): macro-TSH, biotin, antistreptavidin antibodies, anti ruthenium antibodies, thyroid hormone autoantibodies, and heterophilic antibodies. Because the prevalence of some of these conditions has been reported to approach 1% and the frequency of testing for thyroid dysfunction is important, the scale of the problem might be tremendous. Potential interferences in thyroid function testing should always be suspected whenever clinical or biochemical discrepancies arise. Their identification usually relies on additional laboratory tests, including assay method comparison, dilution procedures, blocking reagents studies, and polyethylene glycol precipitation. Based on the pattern of thyroid function test alterations, to screen for the six aforementioned types of interference, we propose a detection algorithm, which should facilitate their identification in clinical practice. The review also evaluates the clinical impact of thyroid interference on immunoassays. On review of reported data from more than 150 patients, we found that >=50% of documented thyroid interferences led to misdiagnosis and/or inappropriate management, including prescription of an unnecessary treatment (with adverse effects in some situations), inappropriate suppression or modification of an ongoing treatment, or use of unnecessary complementary tests such as an I123 thyroid scan. Strong interaction between the clinician and the laboratory is necessary to avoid such pitfalls. PMID- 29982407 TI - Whose income is more important: mine, yours or ours? Income inequality and mental health in northern Sweden. AB - Background: Three main explanations of the relationship between income and population health have been identified: the absolute, the contextual and the relative income hypotheses. The evidence about their relevance particularly in egalitarian societies is, however, inconsistent. This study aimed to test the three hypotheses in relation to psychological distress in northern Sweden. Methods: Data come from the 2014 cross-sectional survey from the four northern most counties in Sweden, and included people aged 25-84 years (n = 21 004). Psychological distress was measured by the General Health Questionnaire-12 and income information came from population registers. Absolute income was operationalized by individual disposable income, contextual income as the municipal-level Gini coefficient and relative income by the Yitzhaki index. Prevalence ratios (PR) were calculated from log-binomial regression analyses. Results: A gradient in poor mental health was observed across quintiles of individual income, with the poorest substantially more likely to report poor health compared with the highest quintile (PR = 1.56; 95% CI = 1.19, 2.04). Second, municipalities in the quintiles 2-3 of the Gini coefficient had a better mental health compared with those in the most equal municipalities. Third, a gradient in poor mental health across quintiles of relative deprivation was also found, with the most deprived quintile the most likely to report poor health (PR = 1.37; 95% CI = 1.06, 1.76). Conclusion: This study suggests a strong, moderate and lack of support for the absolute, relative and contextual income effect hypotheses, respectively. Interventions targeting a reduction in the individual income gap may be necessary in order to reduce psychosocial distress differences in northern Sweden. PMID- 29982405 TI - A 10 year study of hospitalized atrial fibrillation-related stroke in England and its association with uptake of oral anticoagulation. AB - Aims: To determine whether changing patterns of anticoagulant use in atrial fibrillation (AF) have impacted on stroke rates in England. Methods and results: English national databases, 2006-2016, were interrogated to assess stroke admissions and oral anticoagulant use. The number of patients with known AF increased linearly from 692 054 to 983 254 (prevalence 1.29% vs. 1.71%). Hospital episodes of AF-related stroke/100 000 AF patients increased from 80/week in 2006 to 98/week in 2011 and declined to 86/week in 2016 (2006-2011 difference 18.0, 95% confidence interval (CI) 17.9-18.1, 2011-2016 difference -12.0, 95% CI -12.1 to -11.9). Anticoagulant use amongst patients with CHA2DS2-VASc >=2 increased from 48.0% to 78.6% and anti-platelet use declined from 42.9% to 16.1%; the greatest rate of change occurred in the second 5 year period (for anticoagulants 2006-2011 difference 4.8%, 95% CI 4.5-5.1%, 2011-2016 difference 25.8%, 95% CI 25.5-26.1%). After adjustment for AF prevalence, a 1% increase in anticoagulant use was associated with a 0.8% decrease in the weekly rate of AF-related stroke (incidence rate ratio 0.992, 95% CI 0.989-0.994). Had the use of anticoagulants remained at 2009 levels, 4068 (95% CI 4046-4089) more strokes would have been predicted in 2015/2016. Conclusion: Between 2006 and 2016, AF prevalence and anticoagulant use in England increased. From 2011, hospitalized AF-related stroke rates declined and were significantly associated with increased anticoagulant uptake. PMID- 29982408 TI - Corrigendum: Non-adherence to Anti-TNF Therapy is Associated with Illness Perceptions and Clinical Outcomes in Outpatients with Inflammatory Bowel Disease: Results from a Prospective Multicentre Study. PMID- 29982409 TI - Platelet Survival in Hematology Patients Assessed by the Corrected Count Increment and Other Formulas. AB - Objectives: To compare the performance of the corrected count increment (CCI) and three other formulas to assess 24-hour posttransfusion platelet survival in hematology patients. Methods: Twenty-four-hour posttransfusion platelet counts were analyzed after apheresis platelet transfusion. Platelet increment (PI), percent platelet recovery (PPR), and percentage platelet increment (PPI) were compared with CCI by receiver operating characteristic analysis. Clinical factors that influence platelet survival were assessed by logistic regression. Results: In total, 142 apheresis platelet transfusions in 85 hematology patients were studied. Mean (SD) CCI at 24 hours was 11,869 (10,125). Compared with CCI, the sensitivity of other formulas ranged from 89.4% to 95.7% and specificity from 94.7% to 100%. Cutoff values were 15.7 * 103/uL for PI, 11.4% for PPR, and 17% for PPI. For ABO-compatible vs incompatible transfusions, CCI was 14,070/uL vs 9,176/uL (P = .007). Negative factors for all formulas were sepsis, hypotension, and amphotericin B. Conclusions: PI, PPR, and PPI are comparable to CCI for assessing 24-hour platelet survival. PMID- 29982410 TI - cAMP regulated EPAC1 supports microvascular density, angiogenic and metastatic properties in a model of triple negative breast cancer. AB - Breast cancer is a leading cause of cancer-related mortality in women. Triple negative breast cancer (TNBC; HER2-, ER-/PR-) is an aggressive subtype prone to drug resistance and metastasis, which is characterized by high intratumor microvascular density (iMVD) resulting from angiogenesis. However, the mechanisms contributing to the aggressive phenotypes of TNBC remain elusive. We recently reported that down-regulation of exchange factor directly activated by cyclic AMP (cAMP), also known as EPAC1, leads to a reduction in metastatic properties including proliferation and cell migration in TNBC cell lines. Here, we report that EPAC1 supports TNBC-induced angiogenesis, tumor cell migration and invasiveness as well as pro-metastatic phenotypes in endothelial cells induced through the tumor secretome. Using an approach that integrates proteomics with bioinformatics and gene ontologies, we elucidate that EPAC1 supports a tumor secreted network of angiogenic, cell adhesion and cell migratory pathways. Using confocal microscopy, we show that signaling molecules involved in focal adhesion, including Paxillin and MENA, are down-regulated in the absence of EPAC1, and electric cell substrate impedance sensing technique confirmed a role for EPAC1 on TNBC-induced endothelial cell permeability. Finally, to provide a translational bridge, we studied iMVD and therapy response using a primary human tumor explant assay, CANscriptTM, which suggests a link between therapy-modulated neovascularization and drug sensitivity. These data provide mechanistic insight into the role of EPAC1 in regulating the tumor microenvironment, iMVD and cancer cell-induced angiogenesis, a dynamic mechanism under drug pressure that may associate to treatment failure. PMID- 29982412 TI - G9a/GLP Complex Acts as a Bidirectional Switch to Regulate Metabotropic Glutamate Receptor-Dependent Plasticity in Hippocampal CA1 Pyramidal Neurons. AB - Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is conventionally considered to be solely dependent on local protein synthesis. Given the impact of epigenetics on memory, the intriguing question is whether epigenetic regulation influences mGluR-LTD as well. G9a/GLP histone lysine methyltransferase complex is crucial for brain development and goal-directed learning as well as for drug-addiction. In this study, we analyzed whether the epigenetic regulation by G9a/GLP complex affects mGluR-LTD in CA1 hippocampal pyramidal neurons of 5-7 weeks old male Wistar rats. In hippocampal slices with intact CA1 dendritic regions, inhibition of G9a/GLP activity abolished mGluR-LTD. The inhibition of this complex upregulated the expression of plasticity proteins like PKMzeta, which mediated the prevention of mGluR-LTD expression by regulating the NSF-GluA2-mediated trafficking of AMPA receptors towards the postsynaptic site. G9a/GLP inhibition during the induction of mGluR-LTD also downregulated the protein levels of phosphorylated-GluA2 and Arc. Interestingly, G9a/GLP inhibition could not impede the mGluR-LTD when the cell-body was severed. Our study highlights the role of G9a/GLP complex in intact neuronal network as a bidirectional switch; when turned on, it facilitates the expression of mGluR-LTD, and when turned off, it promotes the expression of long-term potentiation. PMID- 29982411 TI - Neofunctionalization in Ligand Binding Sites of Ant Olfactory Receptors. AB - Chemical communication is fundamental for the operation of insect societies. Their diverse vocabulary of chemical signals requires a correspondingly diverse set of chemosensory receptors. Insect olfactory receptors (ORs) are the largest family of chemosensory receptors. The OR family is characterized by frequent expansions of subfamilies, in which duplicated ORs may adapt to detect new signals through positive selection on their amino acid sequence. Ants are an extreme example with ~400 ORs per genome-the highest number in insects. Presumably, this reflects an increased complexity of chemical communication. Here, we examined gene duplications and positive selection on ant ORs. We reconstructed the hymenopteran OR gene tree, including five ant species, and inferred positive selection along every branch using the branch-site test, a total of 3326 tests. We find more positive selection in branches following species-specific duplications. We identified amino acid sites targeted by positive selection, and mapped them onto a structural model of insect ORs. Seventeen sites were under positive selection in six or more branches, forming two clusters on the extracellular side of the receptor, on either side of a cleft in the structure. This region was previously implicated in ligand activation, suggesting that the concentration of positively selected sites in this region is related to adaptive evolution of ligand binding sites or allosteric transmission of ligand activation. These results provide insights into the specific OR subfamilies and individual residues that facilitated adaptive evolution of olfactory functions, potentially explaining the elaboration of chemical signaling in ant societies. PMID- 29982413 TI - Six-Month Effectiveness of Remote Activity Monitoring for Persons Living With Dementia and Their Family Caregivers: An Experimental Mixed Methods Study. AB - Background and Objectives: This study aimed to evaluate if and how remote activity monitoring (RAM) improves caregiver outcomes for family members providing care for persons living with Alzheimer's disease or a related dementia (ADRD). Research Design and Methods: We conducted an embedded experimental mixed methods study of 132 persons living with ADRD and their family caregivers (n = 64 randomly assigned to RAM treatment condition). In addition to baseline and 6 month quantitative survey data on context of care, primary objective stressors, resources, self-efficacy/competence, and distress collected from caregivers, 6 month RAM review checklists contained open-ended, qualitative information on perceived acceptability of the technology. Results: The RAM system did not exert statistically significant effects on caregiving outcomes over a 6-month period. However, qualitative analyses identified several potential moderators of RAM technology effectiveness that were subsequently tested in post-hoc repeated measures analyses of variance. Caregivers who utilized RAM technology and cared for relatives with: (a) less severe cognitive impairment; and (b) difficulty navigating around the home were more likely to indicate statistically significant increases in competence and self-efficacy, respectively. Discussion and Implications: We found that the early months spent calibrating and modifying RAM are potentially challenging for families, which may prevent this technology from improving caregiving outcomes during initial months of use. Remote activity monitoring may work optimally for caregivers of persons living with ADRD in specific situations (e.g., earlier stages of dementia; wandering risk), which suggests the need for appropriate needs assessments that can better target such innovations. PMID- 29982414 TI - Feasibility and safety of combined percutaneous coronary intervention among high risk patients with severe aortic stenosis undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis. AB - : OBJECTIVES: Recent reports indicated that percutaneous coronary intervention (PCI) may be correlated with increased mortality in patients undergoing transcatheter aortic valve implantation (TAVI). Therefore, we performed a meta analysis to determine the feasibility and safety of combined PCI in high-risk patients with severe aortic stenosis undergoing TAVI. METHODS: A comprehensive literature search was performed using PubMed, Embase and the Cochrane Central Register of Controlled trials through June 2016. RESULTS: Five clinical trials including 1634 patients were identified. The pooled analysis revealed no significant differences in 30-day all-cause mortality [odds ratio (OR) 1.25, 95% confidence interval (CI) 0.52-3.05; P = 0.62], 30-day cardiovascular mortality rate (OR 1.59, 95% CI 0.52-4.88; P = 0.41) and 1-year mortality rate (OR 1.16, 95% CI 0.85-1.59; P = 0.34) among the patients assigned to TAVI and those undergoing TAVI+PCI. The incidence of myocardial infarction (OR 2.96, 95% CI 1.03 8.45; P = 0.04) was slightly higher in the TAVI+PCI group. Other complications, such as stroke, kidney injury, bleeding and vascular complications, were not significantly increased in the TAVI+PCI group. Patients treated with a staged procedure of TAVI and PCI but not simultaneous TAVI+PCI showed higher 30-day all cause mortality as compared to those undergoing isolated TAVI. CONCLUSIONS: Combined TAVI+PCI showed similar rates of death from any cause at 30 days and 1 year as compared to isolated TAVI. Except for myocardial infarction, the rate of operative complications in the TAVI+PCI group was not detrimental as compared to the isolated TAVI group. The simultaneous treatment of significant coronary artery lesions may be preferred in selected patients undergoing TAVI. PMID- 29982415 TI - Increased sharing and collaboration can decrease barriers to progress in Microbiology. PMID- 29982417 TI - Combined total mitral and tricuspid valve reconstruction with the use of CorMatrix in an adult. AB - The article confirms the possibility of simultaneous implementation of custom made mitral and tricuspid valve prostheses together with their subvalvular apparatuses from extracellular matrix. Both prostheses were implanted in a 43 year-old man experiencing severe mitral and tricuspid regurgitation, decreased left ventricle ejection fraction, acromegaly, macrocardia and a history of undiagnosed infective process. Postoperative echocardiography showed good haemodynamic function of implanted valves. On postoperative day 11, a paravalvular leak of mitral valve was noticed and required reoperation. The predischarge echocardiography showed no paravalvular leak. The patient was discharged in good condition 52 days after the surgery. The custom-made extracellular matrix valves do not require postoperative anticoagulation. They also serve as prostheses of subvalvular apparatus and, therefore, ameliorate the functioning of ventricles. They prevent the postoperative adverse ventricular remodelling as well. Despite good early haemodynamic results, extracellular matrix mitral valve prosthesis requires further study to assess its long-term function. PMID- 29982418 TI - alpha1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction. AB - Aims: Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of alpha1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment. Methods and results: We generated a mouse strain with alpha1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x alpha1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in alpha1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli. Conclusions: In summary, alpha1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease. PMID- 29982416 TI - Mild SMN missense alleles are only functional in the presence of SMN2 in mammals. AB - Spinal muscular atrophy (SMA) is caused by reduced levels of full-length SMN (FL SMN). In SMA patients with one or two copies of the Survival Motor Neuron 2 (SMN2) gene there are a number of SMN missense mutations that result in milder than-predicted SMA phenotypes. These mild SMN missense mutation alleles are often assumed to have partial function. However, it is important to consider the contribution of FL-SMN as these missense alleles never occur in the absence of SMN2. We propose that these patients contain a partially functional oligomeric SMN complex consisting of FL-SMN from SMN2 and mutant SMN protein produced from the missense allele. Here we show that mild SMN missense mutations SMND44V, SMNT74I or SMNQ282A alone do not rescue mice lacking wild-type FL-SMN. Thus, missense mutations are not functional in the absence of FL-SMN. In contrast, when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish. Here we demonstrate that the heteromeric SMN complex formed with FL-SMN is functional and sufficient to rescue small nuclear ribonucleoprotein assembly, motor neuron function and rescue the SMA mice. We conclude that mild SMN missense alleles are not partially functional but rather they are completely non functional in the absence of wild-type SMN in mammals. PMID- 29982419 TI - Bone Marrow as a Source of Cells for Paroxysmal Nocturnal Hemoglobinuria Detection. AB - Objectives: To determine fluorescently labeled aerolysin (FLAER) binding and glycophosphatidylinositol-anchored protein expression in bone marrow (BM) cells of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) detected in peripheral blood (PB); compare PNH clone size in BM and PB; and detect PNH in BM by commonly used antibodies. Methods: Flow cytometry analysis of FLAER binding to leukocytes and expression of CD55/CD59 in erythrocytes. Analysis of CD16 in neutrophils and CD14 in monocytes in BM. Results: FLAER binds to all normal BM leukocytes, and binding increases with cell maturation. In PNH, lymphocytic clones are consistently smaller than clones of other BM cells. PNH clones are detectable in mature BM leukocytes with high specificity and sensitivity using common antibodies. Conclusions: PNH clone sizes measured in mature BM leukocytes and in PB are comparable, making BM suitable for PNH assessment. We further demonstrate that commonly used reagents (not FLAER or CD55/CD59) can reliably identify abnormalities of BM neutrophils and monocytes consistent with PNH cells. PMID- 29982420 TI - Identification of phenol- and p-cresol-producing intestinal bacteria by using media supplemented with tyrosine and its metabolites. AB - To identify intestinal bacteria that produce phenols (phenol and p-cresol), we screened 153 strains within 152 species in 44 genera by culture-based assay using broth media supplemented with 200 uM each of tyrosine and its predicted microbial metabolic intermediates (4-hydroxyphenylpyruvate, DL-4-hydroxyphenyllactate, 3-(p hydroxyphenyl)propionate, 4-hydroxyphenylacetate and 4-hydroxybenzoate). Phenol producing activity was found in 36 strains and p-cresol-producing activity in 55 strains. Sixteen strains had both types of activity. Phylogenetic analysis based on the 16S rRNA gene sequences of strains that produced 100 uM or more of phenols revealed that 16 phenol producers belonged to the Coriobacteriaceae, Enterobacteriaceae, Fusobacteriaceae and Clostridium clusters I and XIVa; four p cresol-producing bacteria belonged to the Coriobacteriaceae and Clostridium clusters XI and XIVa; and one strain producing both belonged to the Coriobacteriaceae. A genomic search for protein homologs of enzymes involved in the metabolism of tyrosine to phenols in 10 phenol producers and four p-cresol producers, the draft genomes of which were available in public databases, predicted that phenol producers harbored tyrosine phenol-lyase or hydroxyarylic acid decarboxylase, or both, and p-cresol producers harbored p hydroxyphenylacetate decarboxylase or tyrosine lyase, or both. These results provide important information about the bacterial strains that contribute to production of phenols in the intestine. PMID- 29982421 TI - "The Same Thing That Makes You Live Can Kill You in the End": Exploring the Effects of Growth Rates and Longevity on Cellular Metabolic Rates and Oxidative Stress in Mammals and Birds. AB - All aerobic organisms are subjected to metabolic by-products known as reactive species (RS). RS can wreak havoc on macromolecules by structurally altering proteins and inducing mutations in DNA, among other deleterious effects. To combat accumulating damage, organisms have an antioxidant system to sequester RS before they cause cellular damage. The balance between RS production, antioxidant defences, and accumulated cellular damage is termed oxidative stress. Physiological ecologists, gerontologists, and metabolic biochemists have turned their attention to whether oxidative stress is the principal, generalized mechanism that mediates and limits longevity, growth rates, and other life history trade-offs in animals, as may be the case in mammals and birds. At the crux of this theory lies the regulation and activities of the mitochondria with respect to the organism and its metabolic rate. At the whole-animal level, evolutionary theory suggests that developmental trajectories and growth rates can shape the onset and rate of aging. Mitochondrial function is important for aging since it is the main source of energy in cells, and the main source of RS. Altering oxidative stress levels, either increase in oxidative damage or reduction in antioxidants, has proven to also decrease growth rates, which implies that oxidative stress is a cost of, as well as a constraint on, growth. Yet, in nature, many animals exhibit fast growth rates that lead to higher loads of oxidative stress, which are often linked to shorter lifespans. In this article, I summarize the latest findings on whole-animal life history trade-offs, such as growth rates and longevity, and how these can be affected by mitochondrial cellular metabolism, and oxidative stress. PMID- 29982422 TI - Age Modulates the Association of Caffeine Intake With Cognition and With Gray Matter in Elderly Diabetics. AB - Background: The association between caffeine and cognitive performance has not been tested in older individuals with type 2 diabetes (T2D). Its association with brain volume in T2D has been tested only in animals. Methods: We examined the association of caffeine with cognitive function and brain volume in a sample of elderly diabetics participating in the Israel Diabetes and Cognitive Decline Study (n = 638) and the moderating effect of age on this association. In a subsample (n = 185) with magnetic resonance imaging, we also examined these associations with gray and white matter volumes (GM/WM). Results: Using linear regression adjusting for cognition-related covariates, we found that higher caffeine intake was associated with better function in overall cognition (p = .018), attention/working memory (p = .002), executive functioning (p = .047), and semantic categorization (p = .026). Interaction analyses of caffeine intake with age were significant for semantic categorization (p = .025), and approached significance for overall cognition (p = .066). This association was driven by the older group (above-median) for whom the association of caffeine intake with semantic categorization (p = .001), attention/working memory (p = .007), executive functioning (p = .005), and overall cognition (p = .002) were significant. In the magnetic resonance imaging subsample, there was an interaction (p = .034) of caffeine intake with age for GM volume; in the older group, higher caffeine intake was associated with greater GM volume (beta = .198, p = .033). Conclusions: Caffeine intake may have a beneficial role in cognitive functioning of elderly adults with T2D, which may be moderated by age. Greater GM volume may be a mechanism underlying the association of higher caffeine intake with better cognitive function. PMID- 29982423 TI - Contact force and ablation assessment of surgical bipolar radiofrequency clamps in the treatment of atrial fibrillation. AB - OBJECTIVES: Atrial fibrillation is treated surgically by creating conduction block lesions. Radiofrequency (RF) lesions have reduced efficacy compared to 'cut and-sew'. Catheter ablation studies demonstrate a relationship between lesion depth and contact force. We hypothesized that contact force and lesion depth are dependent on design of the bipolar surgical RF clamps. METHODS: Hinged and parallel jaw style RF clamps were studied. Muscle samples were clamped with pressure-sensitive film at increasing tissue thicknesses. Films were analysed determining clamp pressure profiles. A sheep model was utilized for ablation testing using each clamp style until the device indicated transmurality. Separate muscle areas had 1, 2 or 3 burns applied. The muscle was excised, sectioned every 1 cm and stained for lesion depth and fat thickness analysis. RESULTS: Pressure profiling comparing the proximal and distal segments of each clamp style demonstrated only one statistically significant difference in the parallel clamp; the hinged clamp had statistically significant differences (P <= 0.03) for all tissue thicknesses. There was no evidence for differences in the proximal lesion depth of both clamps (P = 0.13) but deeper distally in the parallel clamp (10.17 mm vs 8.02 mm, P = 0.003). The logistic regression analysis demonstrated increased odds of transmurality with parallel clamps at 1, 2 or 3 burns (P = 0.03, P = 0.003 and P = 0.002). Every 1 mm increase in overlying fat decreased likelihood of transmurality by 11% (P < 0.05). CONCLUSIONS: The parallel and hinged clamps have different pressure profiles with higher likelihood of transmurality using the parallel clamp. Fat reduces the ability of RF to deliver a transmural lesion. These findings have implications for optimal surgical RF ablation technique. PMID- 29982425 TI - Nitric oxide-donating aspirin (NO-Aspirin) suppresses lung tumorigenesis in vitro and in vivo and these effects are associated with modulation of the EGFR signaling pathway. AB - Although regular aspirin use has been shown to lower the risk of colorectal cancer, its efficacy against lung cancer is weak or inconsistent. Moreover, aspirin use increases the risk of ulcers and stomach bleeding. In this study, we determined the efficacy of nitric oxide-donating aspirin (NO-Aspirin), a safer form of aspirin in which the parent drug is linked to a nitric oxide-releasing moiety through a spacer, to suppress lung tumorigenesis. Under in vitro conditions, NO-Aspirin significantly reduced the proliferation and survival of tumorigenic bronchial cell line (1170) and non-small cell lung cancer (NSCLC) cell lines (A549, H1650, H1975 and HCC827) and colony formation by NSCLC cells at sub- or low micromolar concentrations (<=1 uM for 1170 cells and <=6 uM for NSCLC cells) in a COX-2 independent manner. These effects were paralleled by suppression of phospho-epidermal growth factor receptor (EGFR), -STAT3, -Akt and ERK and enhanced caspase 3 and PARP cleavage. Among NSCLC cells, EGFR mutant cells (H1650, H1975 and HCC827) were more sensitive than cells expressing wild type EGFR (A549) and H1650 cells were the most sensitive. Moreover, NO-Aspirin sensitized H1650 and H1975 cells to the antiproliferative effects of erlotinib, a tyrosine kinase inhibitor. In in vivo studies using 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) + lipopolysaccharide (LPS)-induced model of lung tumorigenesis, NO-Aspirin significantly reduced the number and size of lung tumors, expression of phospho-EGFR and -Akt as well as the pro-inflammatory molecules TNF-alpha and interferon-gamma. Overall, these results indicate the potential of NO-Aspirin for the chemoprevention of lung cancer in high risk populations. PMID- 29982424 TI - Localizing parkinsonism based on focal brain lesions. AB - Bradykinesia, rigidity, and tremor frequently co-occur, a clinical syndrome known as parkinsonism. Because this syndrome is commonly seen in Parkinson's disease, symptoms are often attributed to cell loss in the substantia nigra. However, parkinsonism occurs in several other neurological disorders and often fails to correlate with nigrostriatal pathology, raising the question of which brain region(s) cause this syndrome. Here, we studied cases of new-onset parkinsonism following focal brain lesions. We identified 29 cases, only 31% of which hit the substantia nigra. Lesions were located in a variety of different cortical and subcortical locations. To determine whether these heterogeneous lesion locations were part of a common brain network, we leveraged the human brain connectome and a recently validated technique termed lesion network mapping. Lesion locations causing parkinsonism were functionally connected to a common network of regions including the midbrain, basal ganglia, cingulate cortex, and cerebellum. The most sensitive and specific connectivity was to the claustrum. This lesion connectivity pattern matched atrophy patterns seen in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy, suggesting a shared neuroanatomical substrate for parkinsonism. Lesion connectivity also predicted medication response and matched the pattern of effective deep brain stimulation, suggesting relevance as a treatment target. Our results, based on causal brain lesions, lend insight into the localization of parkinsonism, one of the most common syndromes in neurology. Because many patients with parkinsonism fail to respond to dopaminergic medication, these results may aid the development of alternative treatments. PMID- 29982426 TI - Comparative Genomic Analysis of Two Chilean Renibacterium salmoninarum Isolates and the Type Strain ATCC 33209T. AB - Renibacterium salmoninarum, a slow-growing facultative intracellular pathogen belonging to the high C + G content Actinobacteria phylum, is the causative agent of bacterial kidney disease, a progressive granulomatous infection affecting salmonids worldwide. This Gram-positive bacterium has existed in the Chilean salmonid industry for >30 years, but little or no information is available regarding the virulence mechanisms and genomic characteristics of Chilean isolates. In this study, the genomes of two Chilean isolates (H-2 and DJ2R) were sequenced, and a search was conducted for genes and proteins involved in virulence and pathogenicity, and we compare with the type strain ATCC 33209 T genome. The genome sizes of H-2 and DJ2R are 3,155,332 bp and 3,155,228 bp, respectively. They genomes presented six ribosomal RNA, 46 transcription RNA, and 25 noncodingRNA, and both had the same 56.27% G + C content described for the type strain ATCC 33209 T. A total of 3,522 and 3,527 coding sequences were found for H-2 and DJ2R, respectively. Meanwhile, the ATCC 33209 T type strain had 3,519 coding sequences. The in silico genome analysis revealed a genes related to tricarboxylic acid cycle, glycolysis, iron transport and others metabolic pathway. Also, the data indicated that R salmoninarum may have a variety of possible virulence-factor and antibiotic-resistance strategies. Interestingly, many of genes had high identities with Mycobacterium species, a known pathogenic Actinobacteria bacterium. In summary, this study provides the first insights into and initial steps towards understanding the molecular basis of antibiotic resistance, virulence mechanisms and host/environment adaptation in two Chilean R. salmoninarum isolates that contain proteins of which were similar to those of Mycobacterium. Furthermore, important information is presented that could facilitate the development of preventive and treatment measures against R. salmoninarum in Chile and worldwide. PMID- 29982427 TI - Vaccine and antibody production in plants: developments and computational tools. AB - Plants as bioreactors have been widely used to express efficient vaccine antigens against viral, bacterial and protozoan infections. To date, many different plant based expression systems have been analyzed, with a growing preference for transient expression systems. Antibody expression in diverse plant species for therapeutic applications is well known, and this review provides an overview of various aspects of plant-based biopharmaceutical production. Here, we highlight conventional and gene expression technologies in plants along with some illustrative examples. In addition, the portfolio of products that are being produced and how they relate to the success of this field are discussed. Stable and transient gene expression in plants, agrofiltration and virus infection vectors are also reviewed. Further, the present report draws attention to antibody epitope prediction using computational tools, one of the crucial steps of vaccine design. Finally, regulatory issues, biosafety and public perception of this technology are also discussed. PMID- 29982428 TI - Antibiotic resistant bacteria and resistance genes in the bottom sediment of a small stream and the potential impact of remobilization. AB - River sediments are regarded as hot spots of bacterial density and activity. Moreover, high bacterial densities and biofilm formation are known to promote horizontal gene transfer, the latter playing a vital role in the spread of antimicrobial resistance. It can thus be hypothesized that sediments act as a reservoir of antibiotic resistant bacteria (ARB) and resistance genes (ARGs), particularly in rivers receiving microbes and drug residues from treated sewage. We analyzed the phenotypic susceptibility of 782 Escherichia coli isolates against 24 antimicrobials and we measured the relative abundances of five ARGs in water and sediment extracts of a small stream. We did not find evidence for a general increase in the proportion of resistant E. coli isolated from sediments as compared to those found in stream water. For most antimicrobials, the likelihood of detecting a resistant isolate was similar in water and sediment or it was even lower in the latter compartment. The mean relative abundance of ARGs was moderately increased in sediment-borne samples. Generally, absolute abundances of resistant cells and resistance genes in the sediment exceeded the pelagic level owing to higher bacterial densities. The river bottom thus represents a reservoir of ARB and ARGs that can be mobilized by resuspension. PMID- 29982429 TI - Analysis of temporal fecal microbiota dynamics in weaner pigs with and without exposure to enterotoxigenic Escherichia coli. AB - The primary aim of this work was to study potential effects of sub-clinical enterotoxigenic Escherichia coli (ETEC) exposure on porcine fecal microbiota composition, with a secondary aim of profiling temporal shifts in bacterial communities over the weaning transition period. 16S rRNA gene metabarcoding and quantitative PCR (qPCR) were used to profile the fecal microbiota and quantify ETEC excretion in the feces, respectively. Temporal shifts in fecal microbiota structure and stability were observed across the immediate post-weaning period (P < 0.05), including significant shifts in the relative levels of specific bacterial phylotypes (P < 0.05). ETEC exposure did not change the fecal microbiota structure (P > 0.05), but significant variations in fecal community structure and stability were linked to variations in ETEC excretion level at particular time points (P < 0.05). In this study, marked temporal changes in microbiota structure and stability were evident over the short weaning transition period, with a relationship between ETEC excretion level and fecal microbiota composition being observed. This study has provided a detailed analysis of fecal microbiota dynamics in the pig, which should help to inform the development of novel management strategies for enteric disorders based on an improved understanding of microbial populations during the challenging post-weaning period. PMID- 29982430 TI - Effects of conscious sedation on tachycardia inducibility and patient comfort during ablation of supraventricular tachycardia: a double blind randomized controlled study. AB - Aims: Sedation is not consistently used during electrophysiology procedures because of concerns regarding effects on tachycardia inducibility. We designed this study to assess the effect of conscious sedation on tachycardia inducibility and patient comfort during supraventricular tachycardia ablation. Methods and results: Patients with narrow QRS tachycardia and no pre-excitation undergoing an electrophysiology study were randomly assigned to sedation or placebo group. Patients in the sedation group received intermittent doses of midazolam and fentanyl, while those in the placebo group received normal saline as placebo. The physician and the patient were blinded to the allocation. Information was collected on tachycardia inducibility, patient discomfort, and complications. A total of 103 patients were included in the study. Proportion of patients with difficult tachycardia induction (27.4% vs. 32.7%) or with non-inducibility (5.8% vs. 3.8%) were not different between the sedation and placebo groups. Patient discomfort as measured by the Wong-Baker scale was significantly less in the sedation group (1.45 +/- 1.08 vs. 2.24 +/- 1.2, P < 0.0007) compared to the placebo group. There was no difference in incidence of hypotension or hypoxia between the two groups. Conclusions: Conscious sedation with intermittent midazolam- and fentanyl-reduced patient discomfort during electrophysiology study and ablation of supraventricular tachycardia without affecting tachycardia inducibility. Sedation administered in the absence of an anaesthetist was safe. PMID- 29982432 TI - The Hog1 positive regulated YCT1 gene expression under cadmium tolerance of budding yeast. AB - Cadmium (Cd) is a heavy metal that is the cause of irreversible hazards to living organisms. Cadmium ions can induce the phosphorylation of MAPKs pathway molecules such as Hog1 and Slt2, but downstream effectors and potential activation pathways are still unclear. In this study, the RNA-seq data analysis in Cd-stressed yeast was performed to predict and screen the signal transduction pathway and the potential effect molecules regulated by MAPKs. Based on differentially expressed genes and Venn diagrams, 31 genes regulated by Hog1p and two genes induced by Slt2p, which related to carbohydrate metabolism, oxidative damage, DNA replication stress and detoxification, were characterized under Cd exposure to yeast. A cysteine-specific transporter (Yct1) modulated by Hog1 was confirmed via RNA-seq results. Meanwhile, we tested the Cd-sensitivity, intracellular Cd concentrations and beta-galactosidase assay, and results indicated that the hypersensitivity of the hog1 mutant to Cd was partly abrogated in YCT1 gene deletion, induction of YCT1 was dependent on Hog1 and its transcription factors, and Yct1p would be epistatic to the Hog1p in Cd-tolerance. The investigation of the transcriptome of MAPKs under Cd stress provided valuable information for future molecular studies of Cd-tolerance. PMID- 29982431 TI - Cumulative blood pressure from early adulthood to middle age is associated with left atrial remodelling and subclinical dysfunction assessed by three-dimensional echocardiography: a prospective post hoc analysis from the coronary artery risk development in young adults study. AB - Aims: To evaluate the association of cumulative blood pressure (BP) from young adulthood to middle age with left atrial (LA) structure/function as assessed by three-dimensional echocardiography (3DE) in a large longitudinal bi-racial population study. Methods and results: We conducted a prospective post hoc analysis of individuals enrolled at the Coronary Artery Risk Development in Young Adults, which is a multi-centre bi-racial cohort with 30 years of follow-up. Cumulative systolic and diastolic BP levels were defined by summing the product of average millimetres of mercury and the years between each two consecutive clinic visits over 30 years of follow-up. Multivariable linear regression analyses were used to assess the relationship between cumulative systolic and diastolic BP with 3DE LA structure and function, adjusting for demographics and traditional cardiovascular risk factors. A total of 1033 participants were included, mean age was 55.4 +/- 3.5 years, 55.2% women, 43.9% blacks. Cumulative systolic BP had stronger correlations than cumulative diastolic BP. Higher cumulative systolic BP was independently associated with higher 3D LA volumes: maximum (beta = 1.74, P = 0.004), pre-atrial contraction (beta = 1.87, P < 0.001), minimum (beta = 0.76, P = 0.04), total emptying (beta = 0.98, P = 0.006), active emptying (beta = 1.12, P < 0.001), and lower magnitude 3D LA early diastolic strain rate (beta = 0.05, P = 0.02). Higher cumulative diastolic BP was independently associated with higher 3D LA active emptying volume (beta = 0.66, P = 0.002), lower magnitude 3D LA early diastolic strain rate (beta = 0.05, P = 0.004), and higher magnitude 3D LA late diastolic strain rate (beta = -0.04, P = 0.05). Conclusion: Higher cumulative BP from early adulthood throughout middle age was associated with adverse LA remodelling evaluated by 3D echocardiography. PMID- 29982433 TI - Serbian primary care physicians' perspectives on adolescents' right to confidentiality in sexual and reproductive healthcare-a qualitative interview study. AB - Background: In prominent international documents and professional position papers, confidentiality was recognized as a necessary condition for effective reproductive healthcare of adolescents. Although legally guaranteed, it is questionable if the right to confidentiality of adolescents is respected in healthcare practice in Serbia. Objectives: To assess primary care physicians' perspectives on the legal right of minors to confidentiality in sexual and reproductive healthcare, as well as their experiences in practice. Methods: Qualitative, semi-structured face-to-face interviews with 12 primary care pediatricians and gynecologists at several municipalities of the city of Belgrade were performed. Interview transcripts were analyzed using qualitative content analysis method. Results: Most interviewees were aware of their legal obligations and support the general idea of granting adolescents the right to confidentiality. They recognized that the lack of confidentiality assurances prevents adolescents' access to sensitive care. However, physicians expressed concerns regarding medical situations when parents should be notified, which was reflected in their inconsistent respect of said right in actual practice. Several organizational obstacles were emphasized by interviewees, including insufficient number of physicians, time constraints, poor access to gynecological services and vague definitions of legal provisions. Conclusion: If the aim is for adolescents' right to confidentiality to be consistently respected in practice, primary care physicians need to be systematically educated about legal provisions and given comprehensive clinical guidelines. The general positive attitude towards confidentiality expressed by the primary care physicians implies that a possibility exists to engage them as main advocates for improvements in access to the necessary health care. PMID- 29982434 TI - Critical role of histone demethylase Jumonji domain-containing protein 3 in the regulation of neointima formation following vascular injury. AB - Aims: Jumonji domain-containing protein 3 (JMJD3), also called lysine specific demethylase 6B (KDM6b), is an inducible histone demethylase which plays an important role in many biological processes, however, its function in vascular remodelling remains unknown. We aim to demonstrate that JMJD3 mediates vascular neointimal hyperplasia following carotid injury, and proliferation and migration in platelet-derived growth factor BB (PDGF-BB)-induced vascular smooth muscle cells (VSMCs). Methods and results: By using both genetic and pharmacological approaches, our study provides the first evidence that JMJD3 controls PDGF-BB induced VSMCs proliferation and migration. Furthermore, our in vivo mouse and rat intimal thickening models demonstrate that JMJD3 is a novel mediator of neointima formation based on its mediatory effects on VSMCs proliferation, migration, and phenotypic switching. We further show that JMJD3 ablation by small interfering RNA or inhibitor GSK J4 can suppress the expression of NADPH oxidase 4 (Nox4), which is correlated with H3K27me3 enrichment around the gene promoters. Besides, deficiency of JMJD3 and Nox4 prohibits autophagic activation, and subsequently attenuates neointima and vascular remodelling following carotid injury. Above all, the increased expression of JMJD3 and Nox4 is further confirmed in human atherosclerotic arteries plaque specimens. Conclusions: JMJD3 is a novel factor involved in vascular remodelling. Deficiency of JMJD3 reduces neointima formation after vascular injury by a mechanism that inhibits Nox4-autophagy signalling activation, and suggesting JMJD3 may serve as a perspective target for the prevention and treatment of vascular diseases. PMID- 29982436 TI - Correction. PMID- 29982435 TI - Engineered Functional Redundancy Relaxes Selective Constraints upon Endogenous Genes in Viral RNA Genomes. AB - Functional redundancy, understood as the functional overlap of different genes, is a double-edge sword. At the one side, it is thought to serve as a robustness mechanism that buffers the deleterious effect of mutations hitting one of the redundant copies, thus resulting in pseudogenization. At the other side, it is considered as a source of genetic and functional innovation. In any case, genetically redundant genes are expected to show an acceleration in the rate of molecular evolution. Here, we tackle the role of functional redundancy in viral RNA genomes. To this end, we have evaluated the rates of compensatory evolution for deleterious mutations affecting an essential function, the suppression of RNA silencing plant defense, of tobacco etch potyvirus (TEV). TEV genotypes containing deleterious mutations in presence/absence of engineered functional redundancy were evolved and the pattern of fitness and pathogenicity recovery evaluated. Genetically redundant genotypes suffered less from the effect of deleterious mutations and showed relatively minor changes in fitness and pathogenicity. By contrast, nongenetically redundant genotypes had very low fitness and pathogenicity at the beginning of the evolution experiment that were fully recovered by the end. At the molecular level, the outcome depended on the combination of the actual mutations being compensated and the presence/absence of functional redundancy. Reversions to wild-type alleles were the norm in the nonredundant genotypes while redundant ones either did not fix any mutation at all or showed a higher nonsynonymous mutational load. PMID- 29982437 TI - In vitro activity of meropenem combined with vaborbactam against KPC-producing Enterobacteriaceae in China. AB - Background: Vaborbactam is a novel inhibitor of serine beta-lactamases, including KPCs, which predominate in China. It is being developed in combination with meropenem. Methods: Using the broth microdilution method, the in vitro activity of meropenem/vaborbactam against 128 KPC-producing Enterobacteriaceae from China was investigated. Results: Meropenem alone showed no activity (MIC50 and MIC90 >64 mg/L), but the addition of vaborbactam potentiated meropenem in a dose dependent manner with MIC90 decreasing from >64 to 0.5 mg/L in the presence of increasing concentrations of vaborbactam. MIC50 and MIC90 of meropenem with 8 mg/L vaborbactam (MV8) were reduced to 0.5 and 8 mg/L, respectively. MV8 (4 mg/L meropenem) inhibited 76.6% of Klebsiella pneumoniae and 100% of Escherichia coli isolates. Seventy-three (77.7%) of the K. pneumoniae isolates belonged to ST11; the remaining 22.3% of isolates were represented by 12 different STs. Of the ST11 and non-ST11 isolates, 71.2% and 95.2%, respectively, were inhibited by MV8 (4 mg/L meropenem). In 14 strains characterized for intrinsic resistance mechanisms, MV8 MIC was increased in isolates with defects in both OmpK35 and OmpK36. The highest MV8 MIC was observed in the strain that had both non-functional porins and increased expression of blaKPC and acrB. Conclusions: Our findings suggest that meropenem/vaborbactam has good activity against KPC-producing Enterobacteriaceae from China. However, a higher percentage of K. pneumoniae isolates for which MV8 MIC was elevated compared with other geographical areas is noteworthy. This might be due to clonal dissemination of ST11 KPC-producing isolates that are defective in both major porins, OmpK35 and OmpK36. PMID- 29982438 TI - Are compound leaves more complex than simple ones? A multi-scale analysis. AB - Background and Aims: The question of which cellular mechanisms determine the variation in leaf size has been addressed mainly in plants with simple leaves. It is addressed here in tomato taking into consideration the expected complexity added by the several lateral appendages making up the compound leaf, the leaflets. Methods: Leaf and leaflet areas, epidermal cell number and areas, and endoreduplication (co-) variations were analysed in Solanum lycopersicum considering heteroblastic series in a wild type (Wva106) and an antisense mutant, the Pro35S:Slccs52AAS line, and upon drought treatments. All plants were grown in an automated phenotyping platform, PHENOPSIS, adapted to host plants grown in 7 L pots. Key Results: Leaf area, leaflet area and cell number increased with leaf rank until reaching a plateau. In contrast, cell area slightly decreased and endoreduplication did not follow any trend. In the transgenic line, leaf area, leaflet areas and cell number of basal leaves were lower than in the wild type, but higher in upper leaves. Reciprocally, cell area was higher in basal leaves and lower in upper leaves. When scaled up at the whole sympodial unit, all these traits did not differ significantly between the transgenic line and the wild type. In response to drought, leaf area was reduced, with a clear dose effect that was also reported for all size-related traits, including endoreduplication. Conclusions: These results provide evidence that all leaflets have the same cellular phenotypes as the leaf they belong to. Consistent with results reported for simple leaves, they show that cell number rather than cell size determines the final leaf areas and that endoreduplication can be uncoupled from leaf and cell sizes. Finally, they re-question a whole-plant control of cell division and expansion in leaves when the Wva106 and the Pro35S:Slccs52AAS lines are compared. PMID- 29982440 TI - Transmission dynamics and disease severity in children infected with East Central South African or ECSA-diverged clades of chikungunya virus. PMID- 29982439 TI - Clinker: visualizing fusion genes detected in RNA-seq data. AB - Background: Genomic profiling efforts have revealed a rich diversity of oncogenic fusion genes. While there are many methods for identifying fusion genes from RNA sequencing (RNA-seq) data, visualizing these transcripts and their supporting reads remains challenging. Findings: Clinker is a bioinformatics tool written in Python, R, and Bpipe that leverages the superTranscript method to visualize fusion genes. We demonstrate the use of Clinker to obtain interpretable visualizations of the RNA-seq data that lead to fusion calls. In addition, we use Clinker to explore multiple fusion transcripts with novel breakpoints within the P2RY8-CRLF2 fusion gene in B-cell acute lymphoblastic leukemia. Conclusions: Clinker is freely available software that allows visualization of fusion genes and the RNA-seq data used in their discovery. PMID- 29982441 TI - Autologous adoptive T-cell therapy for recurrent or drug-resistant cytomegalovirus complications in solid organ transplant patients: A single-arm open-label phase I clinical trial. AB - Background: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of anti-viral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. While adoptive T-cell therapy has been successfully used in haematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus specific T-cell response in vivo, and the perceived risk of graft rejection. Methods: In this prospective study, 22 SOT recipients (13 renal, 8 lung and 1 heart) with recurrent or ganciclovir-resistant CMV infection were recruited and of these, 13 patients were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms and immune reconstitution. Results: Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20 cases. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the thirteen treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia, CMV-associated end organ disease and/or the cessation or reduced use of anti-viral drugs. Furthermore, many of these patients showed co-incident increased frequency of CMV-specific T cells in peripheral blood following completion of T-cell therapy. Conclusions: The data presented here demonstrate for the first time the clinical safety of CMV specific adoptive T-cell therapy and its potential therapeutic benefit for SOT patients with recurrent and/or drug-resistant CMV infection or disease. PMID- 29982442 TI - Gonadotropins and Their Analogs: Current and Potential Clinical Applications. AB - The gonadotropin receptors LH receptor and FSH receptor play a central role in governing reproductive competency/fertility. Gonadotropin hormone analogs have been used clinically for decades in assisted reproductive therapies and in the treatment of various infertility disorders. Though these treatments are effective, the clinical protocols demand multiple injections, and the hormone preparations can lack uniformity and stability. The past two decades have seen a drive to develop chimeric and modified peptide analogs with more desirable pharmacokinetic profiles, with some displaying clinical efficacy, such as corifollitropin alfa, which is now in clinical use. More recently, low-molecular weight, orally active molecules with activity at gonadotropin receptors have been developed. Some have excellent characteristics in animals and in human studies but have not reached the market-largely as a result of acquisitions by large pharma. Nonetheless, such molecules have the potential to mitigate risks currently associated with gonadotropin-based fertility treatments, such as ovarian hyperstimulation syndrome and the demands of injection-based therapies. There is also scope for novel use beyond the current remit of gonadotropin analogs in fertility treatments, including application as novel contraceptives; in the treatment of polycystic ovary syndrome; in the restoration of function to inactivating mutations of gonadotropin receptors; in the treatment of ovarian and prostate cancers; and in the prevention of bone loss and weight gain in postmenopausal women. Here we review the properties and clinical application of current gonadotropin preparations and their analogs, as well as the development of novel orally active, small-molecule nonpeptide analogs. PMID- 29982444 TI - Is it time to move from treating risk factors of the disease to treating the disease? PMID- 29982443 TI - Transcriptome Sequencing Reveals Candidate NF-kappaB Target Genes Involved in Repeated Cocaine Administration. AB - Background: Drug-induced alterations in gene expression play an important role in the development of addictive behavior. Numerous transcription factors have been implicated in mediating the gene expression changes that occur in drug addiction. Nuclear factor kappa B is an inducible transcription factor complex that is rapidly activated by diverse stimuli. Methods: We performed next-generation high throughput sequencing of the prefrontal cortex in a mouse model of repeated cocaine administration combined with pharmacological nuclear factor kappa B inhibition to identify nuclear factor kappa B target genes that participate in the cocaine addiction process. Results: We found that the nuclear factor kappa B antagonist sodium diethyldithiocarbamate trihydrate significantly reversed the cocaine-induced expression changes of the amphetamine addiction pathway. Genes that demonstrated differential expression in response to cocaine treatment that was also reversed by sodium diethyldithiocarbamate trihydrate were enriched for the axon guidance pathway. Furthermore, the nuclear factor kappa B homo-dimer motif could be mapped to 86 of these sodium diethyldithiocarbamate trihydrate reversed genes, which were also enriched for axon guidance. Conclusions: We suggest that nuclear factor kappa B directly modifies the expression of axon guidance pathway members, leading to cocaine sensitization. Our findings reveal the role of prefrontal cortex nuclear factor kappa B activity in addiction and uncover the molecular mechanisms by which nuclear factor kappa B drives changes in the addicted brain. PMID- 29982445 TI - The use of controls in interrupted time series studies of public health interventions. AB - Interrupted time series analysis differs from most other intervention study designs in that it involves a before-after comparison within a single population, rather than a comparison with a control group. This has the advantage that selection bias and confounding due to between-group differences are limited. However, the basic interrupted time series design cannot exclude confounding due to co-interventions or other events occurring around the time of the intervention. One approach to minimizse potential confounding from such simultaneous events is to add a control series so that there is both a before after comparison and an intervention-control group comparison. A range of different types of controls can be used with interrupted time series designs, each of which has associated strengths and limitations. Researchers undertaking controlled interrupted time series studies should carefully consider a priori what confounding events may exist and whether different controls can exclude these or if they could introduce new sources of bias to the study. A prudent approach to the design, analysis and interpretation of controlled interrupted time series studies is required to ensure that valid information on the effectiveness of health interventions can be ascertained. PMID- 29982446 TI - Dissecting the chromosomal composition of mutagen-induced micronuclei in Brachypodium distachyon using multicolour FISH. AB - Background and Aims: Brachypodium distachyon (Brachypodium) is a model species for temperate cereals and other economically important grasses. Its favourable cytogenetic features and advanced molecular infrastructure make it a good model for understanding the mechanisms of instability of plant genomes after mutagenic treatment. The aim of this study was to qualitatively and quantitatively assess the composition and origin of micronuclei arising from genomic fracture, and to detect possible 'hot spots' for mutagen-induced DNA breaks. Methods: Seeds of Brachypodium were treated with maleic hydrazide (MH) or X-rays. The structure of mutagen-induced micronuclei was analysed in root-tip meristematic cells using multicolour fluorescence in situ hybridization (mcFISH) with various repetitive (5S rDNA, 25S rDNA, telomeric, centromeric) and low-repeat [small and large pools of bacterial artificial chromosome (BAC) clones specific for chromosome Bd1] DNA sequences. Key Results: The majority of micronuclei derive from large, acentric fragments. X-rays caused more interstitial DNA breaks than MH. Double-strand breaks rarely occurred in distal chromosome regions. Bd1 contributed to the formation of more mutagen-induced micronuclei than expected from random chromosome involvement. Conclusions: mcFISH with chromosome-specific BAC clones offers insight into micronuclei composition, in so far as it allows their origin and formation to be determined more specifically. A reliable assay for micronuclei composition is crucial for the development of modern genotoxicity tests using plant cells. The combination of mutagenic treatments and well developed cytomolecular resources in Brachypodium make this model species very promising for plant mutagenesis research. PMID- 29982448 TI - Dietary flavonoids and the prevalence and 15-y incidence of age-related macular degeneration. AB - Background: The majority of research performed to date has examined the effects of commonly known antioxidants such as vitamins C, E, and A and carotenoids on age-related macular degeneration (AMD) risk and progression. To date, there is limited research on promising phytochemicals with antioxidant and anti inflammatory properties, including flavonoids. Objective: In this exploratory study, we aimed to assess the independent associations between dietary intake of total flavonoids and common flavonoid classes with the prevalence and 15-y incidence of AMD. Design: In this population-based cohort study, 2856 adults aged >=49 y at baseline and 2037 followed up 15 y later were included in prevalence and incidence analyses, respectively. Dietary intake was assessed by using a semiquantitative food-frequency questionnaire (FFQ). Estimates of the flavonoid content of foods in the FFQ were assessed by using the USDA Flavonoid, Isoflavone, and Proanthocyanidin databases. AMD was assessed from retinal photographs. Results: In cross-sectional analysis, each 1-SD increase in total overall flavonoid intake was associated with a reduced likelihood of any AMD (multivariable-adjusted OR: 0.76; 95% CI: 0.58, 0.99). Each 1-SD increase in dietary intake of total flavonols and total flavanones was associated with reduced odds of the prevalence of any AMD [multivariable-adjusted OR (95% CI): 0.75 (0.58, 0.97) and 0.77 (0.60, 0.99), respectively]. A marginally significant trend (P = 0.05) was observed between increasing the intake of total flavanone and hesperidin (from the first to the fourth quartile) and reduced likelihood of incident late AMD, after multivariable adjustment. Participants who reported >=1 serving of oranges/d compared with those who never consumed oranges at baseline had a reduced risk of late AMD 15 y later (multivariable-adjusted OR: 0.39; 95% CI: 0.18, 0.85). Conclusions: Our findings suggest an independent and protective association between dietary intake of flavonoids and the likelihood of having AMD. Additional prospective cohort studies are needed to validate these findings. PMID- 29982449 TI - Efficacy and safety of continuous infusions with elastomeric pumps for outpatient parenteral antimicrobial therapy (OPAT): an observational study. AB - Objectives: This study aimed to evaluate the efficacy and safety of continuous antimicrobial infusion using elastomeric pumps in an outpatient setting, while simultaneously documenting circulating antibiotic concentration exposure achieved with this mode of administration. Methods: Clinical outcomes, adverse events and antibiotic plasma concentrations were recorded for all patients treated by continuous infusion with elastomeric pumps at the outpatient parenteral antimicrobial therapy (OPAT) unit of the University Hospital of Lausanne between December 2013 and January 2017. The study was registered under ClinicalTrials.gov identifier NCT03221140. Results: One hundred and fifty outpatients were treated by continuous intravenous infusions using flucloxacillin (70 patients), cefepime (36), vancomycin (32) and piperacillin/tazobactam (12). The calculated free fractions of each antibiotic were above the epidemiological cut-off values for resistance (ECOFF) of the treated microorganisms in 92% of measurements. Cure was achieved in 143 patients (95%) 3 months after the end of treatment. Four patients needed unexpected readmission and three had a relapse. In none of the patients with unsuccessful treatment was the ratio of free antibiotic plasma concentration/ECOFF <1. Sixteen patients (11%) had an adverse event, none of them being of severity grade 4 or 5. Conclusions: Continuous infusions of flucloxacillin, cefepime, vancomycin and piperacillin/tazobactam using elastomeric pumps seem to be an effective and safe approach to treat outpatients. The number of treatment successes was very high and adverse events occurred at a similar rate as reported by other OPAT centres. The measured antibiotic plasma concentrations confirmed adequate drug concentration exposure for the vast majority of patients. PMID- 29982450 TI - Bitter Fruit: Inverse Associations Between PTC and Antidesma bunius Perception. AB - Ability to perceive the bitter compound phenylthiocarbamide (PTC) is inherited via a dominant "taster" allele of the TAS2R38 gene, whereas inability is inherited via a recessive "non-taster" allele. This raises a question: Is the non taster allele functionless, or does it mediate perception of compounds other than PTC? New evidence supports speculation that it is indeed functional. Associations between TAS2R38 mutations and bitter sensitivity to the tropical berry Antidesma bunius are the inverse of those PTC, suggesting that the non-taster allele enables perception to compounds in the fruit. PMID- 29982451 TI - Reply to Gerardin, et al. PMID- 29982452 TI - Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica. AB - Complex I deficiency is a common cause of mitochondrial disease, resulting from mutations in genes encoding structural subunits, assembly factors or defects in mitochondrial gene expression. Advances in genetic diagnostics and sequencing have led to identification of several variants in NUBPL (nucleotide binding protein-like), encoding an assembly factor of complex I, which are potentially pathogenic. To help assign pathogenicity and learn more about the function of NUBPL, amino acid substitutions were recreated in the homologous Ind1 protein of the yeast model Yarrowia lipolytica. Leu102Pro destabilized the Ind1 protein, leading to a null-mutant phenotype. Asp103Tyr, Leu191Phe and Gly285Cys affected complex I assembly to varying degrees, whereas Gly136Asp substitution in Ind1 did not impact on complex I levels nor dNADH:ubiquinone activity. Blue-native polyacrylamide gel electrophoresis and immunolabelling of the structural subunits NUBM and NUCM revealed that all Ind1 variants accumulated a Q module intermediate of complex I. In the Ind1 Asp103Tyr variant, the matrix arm intermediate was virtually absent, indicating a dominant effect. Dysfunction of Ind1, but not absence of complex I, rendered Y. lipolytica sensitive to cold. The Ind1 Gly285Cys variant was able to support complex I assembly at 28 degrees C, but not at 10 degrees C. Our results indicate that Ind1 is required for progression of assembly from the Q module to the full matrix arm. Cold sensitivity could be developed as a phenotype assay to demonstrate pathogenicity of NUBPL mutations and other complex I defects. PMID- 29982453 TI - Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin. AB - Objectives: In the context of cystic fibrosis, Pseudomonas aeruginosa biofilms often develop in the vicinity of airway mucus, which acts as a protective physical barrier to inhaled matter. However, mucus can also adsorb small drug molecules administered as aerosols, including antibiotics, thereby reducing their bioavailability. The efficacy of antibiotics is typically assessed by determining the MIC using in vitro assays. This widespread technique, however, does not consider either bacterial biofilm formation or the influence of mucus, both of which may act as diffusion barriers, potentially limiting antibiotic efficacy. Methods: We grew P. aeruginosa biofilms in the presence or absence of human tracheal mucus and tested their susceptibility to tobramycin and colistin. Results: A significant reduction of tobramycin efficacy was observed when P. aeruginosa biofilms were grown in the presence of mucus compared with those grown in the absence of mucus. Diffusion of tobramycin through mucus was reduced; however, this reduction was more pronounced in biofilm/mucus mixtures, suggesting that biofilms in the presence of mucus respond differently to antibiotic treatment. In contrast, the influence of mucus on colistin efficacy was almost negligible and no differences in mucus permeability were observed. Conclusions: These findings underline the important role of mucus in the efficacy of anti infective drugs. PMID- 29982454 TI - Letter to the editor re: Guyton et al. (2018), 'Application of the key characteristics of carcinogens in cancer hazard identification'. PMID- 29982455 TI - Open chromatin profiling of human postmortem brain infers functional roles for non-coding schizophrenia loci. PMID- 29982457 TI - Fecundity and Egg Laying in Helicoverpa armigera (Lepidoptera: Noctuidae): Model Development and Field Validation. AB - Models can be useful to help understand population dynamics of insects under diverse environmental conditions and in developing strategies to better manage pest species. Adult longevity and fecundity of Helicoverpa armigera (Hubner) were evaluated against a wide range of constant temperatures (15, 20, 25, 30, 35, and 37.5 degrees C). The modified Sharpe and DeMichele model described adult aging rate and was used to estimate adult physiological age. Maximum fecundity of H. armigera was 973 eggs per female at 25 degrees C decreasing to 72 eggs per female at 37.5 degrees C. The relationship between adult fecundity and temperature was well described by an extreme value function. Age-specific cumulative oviposition rate and age-specific survival rate were well described by a two-parameter Weibull function and sigmoid function, respectively. An oviposition model was developed using three temperature-dependent components: total fecundity, age specific oviposition rate, and age-specific survival rate. The oviposition model was validated against independent field data and described the pattern of field occurrence of H. armigera egg numbers very well. Our model will be a useful component for population modeling of H. armigera and can be independently used for the timing of sprays in management programs targeting this key pest species. PMID- 29982456 TI - Patterns of Nucleotide Deletion and Insertion Inferred from Bacterial Pseudogenes. AB - Pseudogenes are a paradigm of neutral evolution and their study has the potential to reveal intrinsic mutational biases. However, this potential is mitigated by the fact that pseudogenes are quickly purged from bacterial genomes. Here, we assembled a large set of pseudogenes from genomes experiencing reductive evolution as well as functional references for which we could establish reliable phylogenetic relationships. Using this unique dataset, we identified 857 independent insertion and deletion mutations and discover a pervasive bias towards deletions, but not insertions, with sizes multiples of 3 nt. We further show that selective constraints for the preservation of gene frame are unlikely to account for the observed mutational bias and propose that a mechanistic bias in alternative end-joining repair, a recombination-independent double strand break DNA repair mechanism, is responsible for the accumulation of 3n deletions. PMID- 29982458 TI - Attitudes Toward Computers Across Adulthood From 1994 to 2013. AB - Background and Objectives: Regardless of the increased deployment of technologies in everyday living domains, barriers remain that hamper technology adoption by older adults. Understanding barriers to adoption such as individual differences in attitudes toward computers is important to the design of strategies to reduce age-related digital disparities. Research Design and Methods : This article reports a time-sequential analysis of data from the Edward R. Roybal Center on Human Factors and Aging Research and the Center for Research and Education on Aging and Technology Enhancement (CREATE) on computer attitudes among a large (N = 3,917), diverse sample of community-dwelling adults aged from 18 to 98 years. The data were gathered from 1994 to 2013. Results: The findings indicated that there are still age disparities in attitudes; older adults report less comfort with and less efficacy about using computers than younger people. We also found a cohort (birth year) effect; attitudes are generally more positive among more recent birth cohorts. Those who have more education and experience with computers also have more positive attitudes. Males generally have more positive attitudes than females; however, the gender difference decreases with increased age. Discussion and Implications: Technology affords potential benefits for older people, but lack of uptake in technology clearly puts older adults at a disadvantage in terms of negotiating today's digital world. This article provides insight into attitudinal barriers that may affect on technology uptake among older adults. The findings have implications for the design of technology training programs, design of technology systems, and policy. PMID- 29982459 TI - Articulating citizen participation in national anti-microbial resistance plans: a comparison of European countries. AB - Background: National action plans determine country responses to anti-microbial resistance (AMR). These plans include interventions aimed at citizens. As the language used in documents could persuade certain behaviours, we sought to assess the positioning and implied responsibilities of citizens in current European AMR plans. This understanding could lead to improved policies and interventions. Methods: Review and comparison of national action plans for AMR (NAP-AMR) obtained from the European Centre for Disease Prevention and Control (plans from 28 European Union and four European Economic Area/European Free Trade Association countries), supplemented by European experts (June-September 2016). To capture geographical diversity, 11 countries were purposively sampled for content and discourse analyses using frameworks of lay participation in healthcare organization, delivery and decision-making. Results: Countries were at different stages of NAP-AMR development (60% completed, 25% in-process, 9% no plan). The volume allocated to citizen roles in the plans ranged from 0.3 to 18%. The term 'citizen' was used by three countries, trailing behind 'patients' and 'public' (9/11), 'general population' (6/11) and 'consumers' (6/11). Increased citizen awareness about AMR was pursued by ~2/3 plans. Supporting interventions included awareness campaigns (11/11), training/education (7/11) or materials during clinical encounters (4/11). Prevention of infection transmission or self-care behaviours were much less emphasized. Personal/individual and social/collective role perspectives seemed more frequently stimulated in Nordic countries. Conclusion: Citizen roles in AMR plans are not fully articulated. Documents could employ direct language to emphasise social or collective responsibilities in optimal antibiotic use. PMID- 29982460 TI - Multiple Rounds of Artificial Selection Promote Microbe Secondary Domestication The Case of Cachaca Yeasts. AB - The study of microbe domestication has witnessed major advances that contribute to a better understanding of the emergence of artificially selected phenotypes and set the foundations of their rational improvement for biotechnology. Several features make Saccharomyces cerevisiae an ideal model for such a study, notably the availability of a catalogue of signatures of artificial selection and the extensive knowledge available on its biological processes. Here, we investigate with population and comparative genomics a set of strains used for cachaca fermentation, a Brazilian beverage based on the fermentation of sugar cane juice. We ask if the selective pressures posed by this fermentation have given rise to a domesticated lineage distinct from the ones already known, like wine, beer, bread, and sake yeasts. Our results show that cachaca yeasts derive from wine yeasts that have undergone an additional round of domestication, which we define as secondary domestication. As a consequence, cachaca strains combine features of wine yeasts, such as the presence of genes relevant for wine fermentation and advantageous gene inactivations, with features of beer yeasts like resistance to the effects of inhibitory compounds present in molasses. For other markers like those related to sulfite resistance and biotin metabolism our analyses revealed distributions more complex than previously reported that support the secondary domestication hypothesis. We propose a multilayered microbe domestication model encompassing not only transitions from wild to primarily domesticated populations, as in the case of wine yeasts, but also secondary domestications like those of cachaca yeasts. PMID- 29982461 TI - Fear Odor Facilitates the Detection of Fear Expressions Over Other Negative Expressions. PMID- 29982463 TI - Is patient loyalty associated with quality of care? Results of a patient survey over primary care in Switzerland. AB - Objective: The study aimed to evaluate quality of care and to determine which aspects are associated with the willingness to recommend the general practitioner (GP) as a part of patient loyalty. Design: This was an exploratory study which collected patient data from ambulatory care in the German part of Switzerland between 2013 and 2016. Setting: Primary care in Switzerland. Participants: Included patients from 79 primary care practices who volunteered to participate in the quality management system European Practice Assessment. Patients were afterwards asked to complete the European Task Force on Patient Evaluations of General Practice Care instrument. Interventions: Describing influencing factors of quality of care on recommendation of the GP from the perspective of the patients. Main outcome measures: Patient perspective on quality of care. Results: Survey respondent rate was 81.3%. Over 69% of the respondents were willing to recommend their GP. 'Listening to you' (94.2%) and 'interest in your personal situation' (93.0%) as a part of the domain 'relationship and communication' were rated as the highest quality criteria. The lowest rate was found for 'being able to speak to the GP on the telephone' (30.0%) and 'waiting time in the waiting room' (50.6%). Patient loyalty, in terms of willingness to recommend the GP, was strongly associated with most of the items under the 'relationship and communication' section but also with having more physician's assistants in the practice. Conclusions: The results are important for understanding patients' priorities with regard to general practice care. Patient assessment allows us to identify possible areas for quality improvement within the practice and could provide feedback. PMID- 29982462 TI - Pharmacological and physiological activation of AMPK improves the spliceopathy in DM1 mouse muscles. AB - Myotonic dystrophy type 1 (DM1) is a debilitating multisystemic disorder caused by a triplet repeat expansion in the 3' untranslated region of dystrophia myotonica protein kinase mRNAs. Mutant mRNAs accumulate in the nucleus of affected cells and misregulate RNA-binding proteins, thereby promoting characteristic missplicing events. However, little is known about the signaling pathways that may be affected in DM1. Here, we investigated the status of activated protein kinase (AMPK) signaling in DM1 skeletal muscle and found that the AMPK pathway is markedly repressed in a DM1 mouse model (human skeletal actin long repeat, HSALR) and patient-derived DM1 myoblasts. Chronic pharmacological activation of AMPK signaling in DM1 mice with 5-aminoimidazole-4-carboxamide-1 beta-D-ribofuranoside (AICAR) has multiple beneficial effects on the DM1 phenotype. Indeed, a 6-week AICAR treatment of DM1 mice promoted expression of a slower, more oxidative phenotype, improved muscle histology and corrected several events associated with RNA toxicity. Importantly, AICAR also had a dose-dependent positive effect on the spliceopathy in patient-derived DM1 myoblasts. In separate experiments, we also show that chronic treatment of DM1 mice with resveratrol as well as voluntary wheel running also rescued missplicing events in muscle. Collectively, our findings demonstrate the therapeutic potential of chronic AMPK stimulation both physiologically and pharmacologically for DM1 patients. PMID- 29982464 TI - The In-House Manufacture of Sterilizable, Scaled, Patient-Specific 3D-Printed Models for Rhinoplasty. AB - Background: Rhinoplasty relies on clear patient communication and precise execution of a three-dimensional (3D) plan to achieve optimal results. As 3D imaging and printing continue to grow in popularity within the medical field, rhinoplasty surgeons have begun to leverage these resources as an aid to preoperative planning, patient communication, and the technical performance of this challenging operation. Objective: Utilizing departmentally-available resources and open access 3D imaging platforms, we have developed an affordable, reproducible protocol for rapid in-house virtual surgical planning (VSP) and subsequent manufacture of 3D-printed rhinoplasty models. Methods: Preoperative 3D photographic images underwent virtual rhinoplasty using a freely-available 3D imaging and sculpting program (BlenderTM [Version 2.78, Amsterdam, The Netherlands]). Once the ideal postoperative result was digitally achieved, scaled, sterilizable and patient-specific 3D models of the preoperative and ideal postoperative result were manufactured in-house using a departmentally-owned 3D printer. Results: 3D-printed models have successfully been manufactured and employed for 12 patients undergoing rhinoplasty. The average time to prepare a set of pre- and postoperative models was 3 hours, while the printing process required 18-24 hours per model. Each set of surgical models can be manufactured at a total materials cost of approximately $5.00. Conclusions: We describe an affordable means to construct sterilizable, scaled, patient-specific 3D-printed models for rhinoplasty. This technique may become of increasing interest to academic and cosmetic centers as hardware costs of 3D printers continues to fall. PMID- 29982465 TI - Patients With Autoimmune Thyroiditis Show Diminished Levels and Defective Suppressive Function of Tr1 Regulatory Lymphocytes. AB - Context: T regulatory type 1 (Tr1) cells are a subpopulation of T lymphocytes (CD4+CD49+LAG-3+IL-10+) that exert a considerable immunosuppressive effect. However, their possible role in autoimmune thyroid disease (AITD) has not been explored so far. Purpose: To analyze the levels and function of Tr1 cells in peripheral blood and thyroid tissue of patients with AITD. Design: Cases and controls, observational study. Setting: Department of Endocrinology, Hospital Universitario de la Princesa, Madrid, Spain. Patients: Thirty-eight patients with AITD (23 with Graves disease and 15 with Hashimoto thyroiditis) and 26 controls. Intervention: Multiparametric flow cytometry and immunofluorescence techniques were used to analyze the levels in peripheral blood (n = 38) and thyroid mononuclear cells (n = 5). An in vitro assay of suppression of cellular activation and cytokine release was performed to study the function of Tr1 cells. Main Outcome Measure: Levels and function of Tr1 cells in patients with AITD and controls. Results: Levels of Tr1 cells were significantly diminished in peripheral blood from patients with AITD. Functional studies showed that Tr1 cells from patients with AITD exhibit a diminished suppressive function compared with healthy controls. Tr1 levels were associated with disease severity, including longer duration of the disease and ophthalmopathy activity, and with autoantibody titers. Conclusions: The low levels of Tr1 cells and their diminished function may have a relevant role in the defective immune-regulatory function characteristic of patients with AITD. PMID- 29982466 TI - Workshop on Synergies Between Alzheimer's Research and Clinical Gerontology and Geriatrics: Current Status and Future Directions. AB - Age is the strongest risk factor for physical disability and Alzheimer's disease (AD) and related dementias. As such, other aging-related risk factors are also shared by these two health conditions. However, clinical geriatrics and gerontology research has included cognition and depression in models of physical disability, with less attention to the pathophysiology of neurodegenerative disease. Similarly, AD research generally incorporates limited, if any, measures of physical function and mobility, and therefore often fails to consider the relevance of functional limitations in neurodegeneration. Accumulating evidence suggests that common pathways lead to physical disability and cognitive impairment, which jointly contribute to the aging phenotype. Collaborations between researchers focusing on the brain or body will be critical to developing, refining, and testing research paradigms emerging from a better understanding of the aging process and the interacting pathways contributing to both physical and cognitive disability. The National Institute of Aging sponsored a workshop to bring together the Claude D. Pepper Older Americans Independence Center and AD Center programs to explore areas of synergies between the research concerns of the two programs. This article summarizes the proceedings of the workshop and presents key gaps and research priorities at the intersection of AD and clinical aging research identified by the workshop participants. PMID- 29982467 TI - Impact of orthodontic treatment on the integrity of endodontically treated teeth. AB - Aim: The purpose of this study was to evaluate the periapical status of endodontically treated teeth and the integrity of endodontic treatment before and after orthodontic treatment. Materials and methods: This retrospective study was conducted by evaluating 128 teeth with root canal treatment (RCT). The teeth were obtained from 72 patients (23 males, 49 females) who had undergone fixed orthodontic treatment. Panoramic radiographs were taken and were evaluated before the start and after the completion of orthodontic treatment. Apical periodontitis (AP) was evaluated by the periapical index (PAI) and the probability index (PRI) of periapical bone destruction. Other variables related to the quality of root canal fillings were included, such as RCT quality index, length, and homogeneity, and coronal restoration. Results: According to the PRI, the proportion of teeth with periapical bone destruction was significantly higher after orthodontic treatment. Overall, there was no significant change in the PAI scores after orthodontic treatment. However, the quality of the endodontic treatment moderated the change in the PAI score, as well as the change in the PRI. There was no significant increase in PAI and PRI scores after orthodontic treatment for adequately treated teeth. However, the risk for periapical lesions and bone destruction after orthodontic treatment was significantly increased for teeth receiving inadequate endodontic treatment compared with those receiving adequate endodontic treatment. Conclusion: Increased PAI and PRI after orthodontic treatment correlated with the quality of endodontic treatment. PMID- 29982468 TI - Predicting Risk of Postoperative Disease Recurrence in Crohn's Disease: Patients With Indolent Crohn's Disease Have Distinct Whole Transcriptome Profiles at the Time of First Surgery. AB - Background: Assessing risk of Crohn's disease (CD) recurrence following ileocolic resection (ICR) is necessary to optimize medical management and prevent long-term complications. This study aimed to identify noninvasive markers that could predict postoperative disease activity. Methods: Inclusion criteria were a diagnosis of CD, first ICR, interval colonoscopy, and whole transcriptome array meeting quality control standards. Demographic and clinical data were obtained from the electronic medical record. RNA extraction and human transcriptome microarray were performed on noninflamed ileal margins from operative specimens. Clinical data and random forest were analyzed in R. Principal components analysis, hierarchical clustering, and pathway enrichment were performed in Partek. Results: Sixty-five patients completed the study, and 5 were excluded from analysis due to extreme variability on whole transcriptome analysis. Unsupervised hierarchical clustering revealed that patients with an i0 Rutgeerts score generally segregated from all others. In anti-TNF-naive patients, unsupervised hierarchical clustering revealed complete segregation of patients with an i0 score. Reduced escalation in therapy and continued mucosal remission, consistent with indolent disease, were seen in the 4 years following surgery. Random forest identified 30 transcripts differentiating i0 patients from the other groups. Pathway enrichment highlighted toll-like receptor, NOD-like receptor, and TNF signaling. This transcriptome signature did not identify i0 anti-TNF-exposed patients. However, anti-TNF-exposed patients with indolent postoperative courses were found to have a transcriptome signature distinct from those with aggressive disease. Conclusions: Anti-TNF-naive and -exposed patients have unique expression profiles at the time of surgery, which may offer predictive value in assessing the risk of nonrecurrence. 10.1093/ibd/izy228_video1izy228.video15804852517001. PMID- 29982470 TI - Opening chronic coronary total occlusions: light in the tunnel or sleeping in Seattle? PMID- 29982469 TI - Impact of repeated lipopolysaccharide administration on ovarian signaling during the follicular phase of the estrous cycle in post-pubertal pigs. AB - Increased circulating lipopolysaccharide (LPS) results from heat stress (HS) and bacterial infection, both of which are associated with reduced female fertility. Specific effects of low-level, repeated LPS exposure on the ovary are unclear, as many studies utilize a bolus model and/or high dosage paradigm. To better understand the effects of chronic LPS exposure on ovarian signaling and function, post-pubertal gilts (n = 20) were orally administered altrenogest for 14 d to synchronize the beginning of the follicular phase of the ovarian cycle. For 5 d after synchronization, gilts (163 +/- 3 kg) received IV administration of LPS (0.1 ug/kg BW, n = 10) or saline (CT, n = 10) 4* daily. Blood samples were obtained on days 1, 3, and 5 of LPS treatment. Follicular fluid was aspirated from dominant follicles on day 5, and whole ovarian homogenate was used for transcript and protein abundance analysis via quantitative real-time PCR and western blotting, respectively. There were no treatment differences detected in rectal temperature on any day (P >= 0.5). Administering LPS increased plasma insulin (P < 0.01), LPS-binding protein (LBP; P < 0.01), and glucose (P = 0.08) on day 1, but no treatment differences thereafter were observed (P = 0.66). There were no treatment differences in follicular fluid concentration of LBP or 17beta estradiol (P = 0.42). Gilts treated with LPS had increased abundance of ovarian TLR4 protein (P = 0.01), but protein kinase B (AKT) and phosphorylated AKT (pAKT) were unchanged and no effect of LPS on components of the phosphatidylinositol 3 kinase (PI3K) pathway were observed. There was no impact of LPS on ovarian abundance of STAR or CYP19A1, nor ESR1, LDLR, CYP19A1, CYP17A1, or 3BHSD. In conclusion, repeated, low-level LPS administration alters inflammatory but not steroidogenic or PI3K signaling in follicular phase gilt ovaries. PMID- 29982471 TI - Conscious sedation for diagnostic electrophysiology and catheter ablation of supraventricular tachycardia. PMID- 29982472 TI - Effects of solid-state fermentation with three higher fungi on the total phenol contents and antioxidant properties of diverse cereal grains. AB - Three culinary-medicinal fungi and mushrooms (Agaricus bisporus AS2796, Helvella lacunosa X1 and Fomitiporia yanbeiensis S. Guo & L. Zhou) were individually inoculated into different cereal grains (wheat, rice, oat, corn, millet, quinoa, buckwheat, soybean, pea and sorghum) and the antioxidant properties of fungus fermented products after solid-state fermentation (SSF) (0, 7, 14, 21, 28 and 35 days; 25 degrees C) were studied. The results showed that the total phenol contents (TPCs) of the fermented cereals varied with fermentation time and the starter organisms. According to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity, reducing power, ferrous ion chelating ability and superoxide anion radical scavenging ability of ethanolic extracts from the fungus-fermented products (35 days), it was shown that the antioxidant properties of all the products were significantly stronger than uninoculated grains. It revealed that SSF on cereal grains by dietary fungi is a biotechnological strategy, which may enhance the antioxidant properties of the substrate. The three medicinal mushroom and fungi-fermented products were relatively effective in the antioxidant properties assayed and might be potential antioxidants for application in food products. PMID- 29982473 TI - Urine volume and nitrogen excretion are altered by feeding birdsfoot trefoil compared to alfalfa in lactating dairy cows. AB - Legumes that contain condensed tannins may have lower ruminal protein degradation than alfalfa. The present study investigated the effects of feeding birdsfoot trefoil (Lotus corniculatus L.) hay on lactational performance and N utilization and excretion. Eight multiparous Holstein cows in mid-lactation (150 +/- 22.3 d in-milk) were randomly assigned to two treatments [alfalfa hay-based total mixed ration (AHT) or birdsfoot trefoil hay-based total mixed ration (BHT)] in a crossover design with two experimental periods. Each experimental period lasted 17 d (14 d of adaptation and 3 d of sampling and total collection). Hays comprised approximately 50% of DM in experimental diets. There were no treatment effects on dry matter intake (DMI; 21.4 vs. 20.7 kg/d), milk yield (29.4 vs. 28.1 kg/d), milk fat concentration (3.20 vs. 3.21%), and milk protein concentration (3.20 vs. 3.16%) for AHT and BHT, respectively. In addition, dietary treatments did not affect milk yield/DMI or energy-corrected milk yield/DMI. In contrast, apparent crude protein digestion decreased in cows fed BHT compared to those fed AHT (60.7 vs. 69.1%). Concentration of milk urea-N decreased by feeding BHT compared with AHT (11.9 vs. 13.3 mg/100 mL), whereas total N excretion did not differ between AHT and BHT diets. However, cows fed BHT excreted more N in feces (194 vs. 168 g/d), while urinary N excretion was lower compared with cows fed AHT. Shift of N to feces resulted in a decrease in urinary-N:fecal-N ratio in cows fed BHT relative to those fed AHT. Overall results in the current study suggest that feeding birdsfoot trefoil in dairy diets shifts routes of N from urine to feces compared with feeding alfalfa hay, with little effect on lactational performance. Reduction in urinary N and any impact on environment may be attributed to functional effect of condensed tannins in birdsfoot trefoil hay. PMID- 29982474 TI - Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts. AB - Background: Individuals with low cardiovascular risk factor profiles experience lower rates of cardiovascular diseases, but associations with geriatric syndromes are unclear. We tested whether individuals with low cardiovascular disease risk, aged 60-69 years old at baseline in two large cohorts, were less likely to develop aging-related adverse health outcomes. Methods: Data were from population representative medical records (Clinical Practice Research Datalink [CPRD] England, n = 239,591) and healthy volunteers (UK Biobank [UKB], n = 181,820), followed for <=10 years. A cardiovascular disease risk score (CRS) summarized smoking status, LDL-cholesterol, blood pressure, body mass index, fasting glucose and physical activity, grouping individuals as low (ie, all factors near ideal), moderate, or high CRS. Logistic regression, Cox models, and Fine and Grey risk models tested the associations between the CRS and health outcomes. Results: Low CRS individuals had less chronic pain (UKB: baseline odds ratio = 0.52, confidence interval [CI] = 0.50-0.54), lower incidence of incontinence (CPRD: subhazard ratio [sub-HR] = 0.75, 0.63-0.91), falls (sub-HR = 0.82, CI = 0.73 0.91), fragility fractures (sub-HR = 0.78, CI = 0.65-0.93), and dementia (vs. high risks; UKB: sub-HR = 0.67, CI = 0.50-0.89; CPRD: sub-HR = 0.79, CI = 0.56 1.12). Only 5.4% in CPRD with low CRS became frail (Rockwood index) versus 24.2% with high CRS. All-cause mortality was markedly lower in the low CRS group (vs. high CRS; HR = 0.40, 95% CI = 0.35-0.47). All associations showed dose-response relationships, and results were similar in both cohorts. Conclusions: Persons aged 60-69 years with near-ideal cardiovascular risk factor profiles have substantially lower incidence of geriatric conditions and frailty. Optimizing cardiovascular disease risk factors may substantially reduce the burden of morbidity in later life. PMID- 29982475 TI - Origin and parental genome characterization of the allotetraploid Stylosanthes scabra Vogel (Papilionoideae, Leguminosae), an important legume pasture crop. AB - Backgrounds and Aims: The genus Stylosanthes includes nitrogen-fixing and drought tolerant species of considerable economic importance for perennial pasture, green manure and land recovery. Stylosanthes scabra is adapted to variable soil conditions, being cultivated to improve pastures and soils worldwide. Previous studies have proposed S. scabra as an allotetraploid species (2n = 40) with a putative diploid A genome progenitor S. hamata or S. seabrana (2n = 20) and the B genome progenitor S. viscosa (2n = 20). We aimed to provide conclusive evidence for the origin of S. scabra. Methods: We performed fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) experiments and Illumina paired-end sequencing of S. scabra, S. hamata and S. viscosa genomic DNA, to assemble and compare complete ribosomal DNA (rDNA) units and chloroplast genomes. Plastome- and genome-wide single nucleotide variation detection was also performed. Key Results : GISH and phylogenetic analyses of plastid DNA and rDNA sequences support that S. scabra is an allotetraploid formed from 0.63 to 0.52 million years ago (Mya), from progenitors with a similar genome structure to the maternal donor S. hamata and the paternal donor S. viscosa. FISH revealed a non additive number of 35S rDNA sites in S. scabra compared with its progenitors, indicating the loss of one locus from A genome origin. In S. scabra, most 5S rDNA units were similar to S. viscosa, while one 5S rDNA site of reduced size most probably came from an A genome species as revealed by GISH and in silico analysis. Conclusions: Our approach combined whole-plastome and rDNA assembly with additional cytogenetic analysis to shed light successfully on the allotetraploid origin of S. scabra. We propose a Middle Pleistocene origin for S. scabra involving species with maternal A and paternal B genomes. Our data also suggest that variation found in rDNA units in S. scabra and its progenitors reveals differences that can be explained by homogenization, deletion and amplification processes that have occurred since its origin. PMID- 29982476 TI - Hypothalamic-Pituitary and Growth Disorders in Survivors of Childhood Cancer: An Endocrine Society Clinical Practice Guideline. AB - Objective: To formulate clinical practice guidelines for the endocrine treatment of hypothalamic-pituitary and growth disorders in survivors of childhood cancer. Participants: An Endocrine Society-appointed guideline writing committee of six medical experts and a methodologist. Conclusions: Due to remarkable improvements in childhood cancer treatment and supportive care during the past several decades, 5-year survival rates for childhood cancer currently are >80%. However, by virtue of their disease and its treatments, childhood cancer survivors are at increased risk for a wide range of serious health conditions, including disorders of the endocrine system. Recent data indicate that 40% to 50% of survivors will develop an endocrine disorder during their lifetime. Risk factors for endocrine complications include both host (e.g., age, sex) and treatment factors (e.g., radiation). Radiation exposure to key endocrine organs (e.g., hypothalamus, pituitary, thyroid, and gonads) places cancer survivors at the highest risk of developing an endocrine abnormality over time; these endocrinopathies can develop decades following cancer treatment, underscoring the importance of lifelong surveillance. The following guideline addresses the diagnosis and treatment of hypothalamic-pituitary and growth disorders commonly encountered in childhood cancer survivors. PMID- 29982478 TI - An FEVR-associated mutation in ZNF408 alters the expression of genes involved in the development of vasculature. AB - Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disorder hallmarked by an abnormal development of retinal vasculature. A missense mutation in ZNF408 (p.H455Y) was reported to underlie autosomal dominant FEVR in a large Dutch family, and ZNF408 was shown to play a role in the development of vasculature. Nonetheless, little is known about the molecular mechanism of ZNF408 associated FEVR. To investigate this, an in vitro model of ZNF408-associated FEVR was generated by overexpressing wild-type and p.H455Y ZNF408 in human umbilical vein endothelial cells. Cells overexpressing mutant ZNF408 were unable to form a capillary-like network in an in vitro tube formation assay, thereby mimicking the clinical feature observed in patients with FEVR. Intriguingly, transcriptome analysis revealed that genes involved in the development of vasculature were deregulated by the p.H455Y mutation. Chromatin immunoprecipitation showed that p.H455Y ZNF408 has reduced DNA-binding ability, as compared to the wild-type protein. The fact that the p.H455Y mutation disrupts the expression of genes important for the development of vasculature sheds further light on the molecular mechanisms underlying ZNF408-associated FEVR. PMID- 29982477 TI - Severe maternal morbidity in women with high BMI in IVF and unassisted singleton pregnancies. AB - STUDY QUESTION: Is there a synergistic risk of severe maternal morbidity (SMM) in overweight/obese women who conceived by IVF compared to normal-weight women without IVF? SUMMARY ANSWER: SMM was more common in IVF pregnancies, and among overweight/obese women, but we did not detect a synergistic effect of both factors. WHAT IS KNOWN ALREADY: While much is known about the impact of overweight and obesity on success rates after IVF, there is less data on maternal health outcomes. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study of 114 409 singleton pregnancies with conceptions dating from 11 January 2013 until 10 January 2014 in Ontario, Canada. The data source was the Canadian Assisted Reproductive Technologies Register (CARTR Plus) linked with the Ontario birth registry (BORN Information System). PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women who delivered at >=20 weeks gestation, and excluded those younger than 18 years or with twin pregnancies. Women were classified according to the mode of conception (IVF or unassisted) and according to pre pregnancy BMI (high BMI (>=25 kg/m2) or low-normal BMI (<25 kg/m2)). The main outcome was SMM, a composite of serious complications using International Classification of Diseases, 10th revision (ICD-10) codes. Secondary outcomes were gestational hypertension, pre-eclampsia, gestational diabetes and cesarean delivery. Adjusted risk ratios (aRR) with 95% CI were estimated using log binomial regression, adjusted for maternal age, parity, education, income and baseline maternal comorbidity. MAIN RESULTS AND THE ROLE OF CHANCE: Of 114 409 pregnancies, 1596 (1.4%) were IVF conceptions. Overall, 41.2% of the sample had high BMI, which was similar in IVF and non-IVF groups. We observed 674 SMM events (rate: 5.9 per 1000 deliveries). IVF was associated with an increased risk of SMM (rate 11.3/1000; aRR 1.89, 95% CI: 1.06-3.39). High BMI was modestly associated with SMM (rate 7.0/1000; aRR 1.23, 95% CI: 1.04-1.45) There was no interaction between the two factors (P = 0.22). We noted supra-additive effects of high BMI and IVF on the risk of pre-eclampsia and gestational diabetes, but not gestational hypertension or cesarean delivery. LIMITATIONS, REASONS FOR CAUTION: We were unable to assess outcomes according to reason for treatment. Type II error (beta ~25%) may affect our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results support previous data indicating a greater risk of SMM in IVF pregnancies, and among women with high BMI. However, these factors do not interact. Overweight and obese women who seek treatment with IVF should be counseled about pregnancy risks. The decision to proceed with IVF should be based on clinical judgment after considering an individual's chance of success and risk of complications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Research Institute of the McGill University Health Centre (grant 6291) and also supported by the Trio Fertility (formerly Lifequest) Research Fund. The authors report no competing interests. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 29982479 TI - The maize secondary metabolism glycosyltransferase UFGT2 modifies flavonols and contributes to plant acclimation to abiotic stresses. AB - Background and Aims: Nowadays, the plant family 1 glycosyltransferases (UGTs) are attracting more and more attention since members of this family can improve the properties of secondary metabolites and have significantly enriched the chemical species in plants. Over the past decade, most studies on UGTs have been conducted in Arabidopsis thaliana and they were proved to play diverse roles during the plant life cycle. The Zea mays (maize) GT1 family comprises a large number of UDP glycosyltransferase (UGT) members. However, their enzyme activities and the biological functions are rarely revealed. In this study, a maize flavonol glycosyltransferase, UFGT2, is identified and its biological role is characterized in detail. Methods: The UFGT2 enzyme activity, the flavonol and glycoside levels in planta were examined by high- performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). The functions of UFGT2 in modifying flavonols, mediating flavonol accumulation and improving stress tolerance were analysed using two ufgt2 mutants and transgenic arabidopsis plants. Key Results: By in vitro enzyme assay, the maize UFGT2 was found to show strong activity towards two flavonols: kaemferol and quercetin. Two ufgt2 knockout mutants, Mu689 and Mu943, exhibited obvious sensitivity to salt and drought stresses. The endogenous quercetin and kaempferol glycosides, as well as the total flavonol levels were found to be substantially decreased in the two ufgt2 mutants, with declined H2O2-scavenging capacity. In contrast, ectopic expression of UFGT2 in arabidopsis led to increased flavonol contents and enhanced oxidative tolerance. Moreover, expression of typical stress-related genes in arabidopsis and maize were affected in UFGT2 overexpression plants or knockout mutants in response to abiotic stresses. UFGT2 was also transferred into the arabidopsis ugt78d2 mutant and it was found to recover the deficient flavonol glycoside pattern in the ugt78d2 mutant, which confirmed its catalysing activity in planta. Conclusion: It is demonstrated in our study that a maize glycosyltransferase, UFGT2, involved in modifying flavonols, contributes to improving plant tolerance to abiotic stresses. PMID- 29982480 TI - Intestinal Inflammation and Tumor Burden as Determinants for Bone Fragility in APC-Driven Tumorigenesis. AB - Background: Colorectal cancer (CRC) is a major cause of cancer-related deaths, and tumor-related comorbidities additionally lower life quality and survival. Mutations in the tumor suppressor adenomatous polyposis coli (APC) are associated with sporadic CRC and familial adenomatous polyposis (FAP), which results in the growth of multiple intestinal cancer lesions. In some cases, inflammatory bowel diseases (IBDs) are additionally observed in CRC patients. Although APC mutations have been shown to increase bone mineral density (BMD), inflammation is associated with reduced BMD and an elevated fracture risk in IBD patients. Methods: To determine the consequences of APC-driven intestinal tumorigenesis and additional inflammation on bone parameters, we utilized an APC1638N/+ mouse model. We treated 1 cohort of APC wild-type and mutant animals with dextran sodium sulfate (DSS) to induce colorectal inflammation. All mice were killed at the same age and stratified according to their tumor burden. Results: As expected, a heterozygous APC mutation increased intestinal tumor numbers and the cortical BMD. This effect on bone was abrogated in mice with high intestinal tumor numbers. Moreover, we found that high tumor burden elevated bone fragility in APC-mutated mice. After DSS treatment, there were no significant changes in bone parameters of control mice. In contrast, in combination with inflammation, bone biomechanical properties severely deteriorated at high tumor burdens in APC1638N/+ animals. Conclusions: Together, not only were bone parameters affected by APC status and inflammation, but also high intestinal tumor numbers, especially when combined with inflammation, were associated with an osteoporotic phenotype. PMID- 29982481 TI - Dispersion and Optimization of Sequential Sampling Plans for Coffee Berry Borer (Coleoptera: Curculionidae) Infestations in Hawaii. AB - Coffee berry borer, Hypothenemus hampei (Ferrari, Coleoptera: Curculionidae) is a serious pest of coffee in most coffee-growing areas of the world. This beetle was first detected in Big Island of Hawaii in 2010 and has since spread to other islands. Being an invasive pest that causes serious economic damage, efforts are in progress in Hawaii to develop an integrated approach to manage this pest. In this study, we sampled commercial coffee orchards from representative coffee growing regions in the Big Island, Hawaii, to understand dispersion of the pest in the field and develop a reliable sampling plan based on the dispersion characteristics. Analysis of data collected from 12 commercial fields over three growing seasons suggests an aggregated pattern of dispersion of the pest in the field. Two fixed-precision sequential sampling plans based on berry cluster and branch as sample units were modeled and validated using Resampling for Validation of Sampling Plans software. The models suggest that infestation density can be estimated reliably for integrated pest management (IPM) practices with minimal sampling effort by sampling berry clusters or branches using sequential sampling plans. Sequential sampling plan based on berry cluster requires detection of fewer infested berries compared to branch sampling for a reliable estimation of mean density of infested berries and IPM decision making. PMID- 29982482 TI - Statin Use Is Associated With Decreased Osteoporosis and Fracture Risks in Stroke Patients. AB - Context: Poststroke osteoporosis and consequent fractures increase the risk of morbidity and mortality and cause considerable socioeconomic burden. Objective: To evaluate the association between statin use and risks of osteoporosis and fracture in stroke patients. Design: Population-based propensity score-matched cohort study. Setting: Taiwan's National Health Insurance Research Database. Patients: Patients newly diagnosed with a stroke between 2000 and 2012 were identified. After propensity score matching, 5254 patients were included, with 2627 patients in the statin and nonstatin cohorts, respectively. Main Outcome Measures: Hazard ratios (HRs) for poststroke osteoporosis, hip fracture, and vertebral fracture (together, the primary outcome) were calculated using Cox proportional hazards regression models according to statin use status. Results: Poststroke statin use was associated with a lower overall risk of the primary outcome [adjusted hazard ratio (aHR) = 0.66; P < 0.001]. In subanalyses, statin use was associated with a decreased risk of all individual outcomes, including osteoporosis (aHR = 0.68; P < 0.001), hip fracture (aHR = 0.59; P < 0.001), and vertebral fracture (aHR = 0.73; P = 0.003). A dose-effect relationship was identified. The aHRs for developing the primary outcome were 0.96, 0.86, and 0.34 for patients who used 1 to 90, 91 to 365, and >365 cumulative defined daily doses of statins, respectively. These dose-effect relationships were maintained on subgroup analyses stratified by age, sex, and stroke type and sensitivity analyses conducted without propensity score matching. Conclusions: Statin use is associated with decreased risks of osteoporosis, hip fracture, and vertebral fracture in stroke patients. PMID- 29982484 TI - Plasma EBV-load as an early biomarker and prognostic factor of HIV-related lymphomas. AB - Background: Epstein-Barr virus (EBV) has been implicated in lymphomagenesis and can be found infecting tumor cells and in plasma at lymphoma diagnosis, especially in HIV-infected patients. Our aim was to evaluate the usefulness of plasma EBV-load as biomarker and prognostic factor in HIV-related lymphomas. Methods: EBV-load was measured by polymerase chain reaction (PCR) in plasma samples of 81 HIV-related lymphomas at different moments: within one year before lymphoma diagnosis, at diagnosis and at complete response (CR). Control samples included HIV-negative patients with lymphoma and HIV-infected patients without neoplasia or opportunistic infections. Results: Patients with HIV-related lymphoma had more frequently detectable EBV-load at lymphoma diagnosis (53%) than both, HIV-negative with the same lymphoma type (16%) (p<0.001) and HIV-infected individuals without neoplasia or opportunistic infection (1,2%) (p<0.001). HIV related lymphoma patients with detectable EBV-load in plasma at lymphoma diagnosis had a statistically significant decrease of EBV-load at CR. High EBV load (>5000 copies/mL) at lymphoma diagnosis was an independent negative prognostic factor for overall survival and progression-free survival in patients with HIV-related lymphoma. Detectable plasma EBV-load identified HIV-infected subjects eventually developing lymphoma (area under the curve [AUC] 82%, 95%CI: 0.67-0.96). Conclusions: Plasma EBV-load can be used as biomarker and as prognostic factor in HIV-related lymphomas. The presence of EBV-load in plasma can be an early predictor of HIV-related lymphoma development. PMID- 29982485 TI - Relations of laterality and chewing sidedness in twins. AB - Objectives: To study, whether there are associations between chewing side preference and other lateralities, whether there is a genetic origin for preferred chewing side (PCS), relations to sex, birth order and orthodontic treatment. Materials and Methods: The study included 113 twin pairs, 57 pairs monozygotic, 47 pairs same sex dizygotic and 9 pairs of opposite sex. The lateralities of preferred chewing side, footedness and eyedness were assessed by functional tests and handedness was checked by asking. Results: Right-handed, footed and -eyed as separated groups, and true-right sided (combined), were evenly distributed by preferred chewing side. By contrast, left-handed, -footed, eyed and non-right sided used more left or both sides when chewing. Birth order affected preferred chewing side among monozygotic: the first-born twin was more likely to have the preferred chewing side on the non-right, whereas second-born twins used right side. Gender, zygosity and orthodontic treatment were not statistically significant factors. Limitations: Examination of chewing sidedness could have been done in several different ways to provide a definite result. Sample size of opposite sex twins was very small. Conclusions: Preferred chewing side generally seemed to follow the side where other lateralities occur; however, monozygotic twins seemed to be more receptive to it. True-right sided were more evenly distributed than non-right sided by the preferred chewing side. PMID- 29982483 TI - Light modulation ameliorates expression of circadian genes and disease progression in spinal muscular atrophy mice. AB - Physiology and behaviour are critically dependent on circadian regulation via a core set of clock genes, dysregulation of which leads to metabolic and sleep disturbances. Metabolic and sleep perturbations occur in spinal muscular atrophy (SMA), a neuromuscular disorder caused by loss of the survival motor neuron (SMN) protein and characterized by motor neuron loss and muscle atrophy. We therefore investigated the expression of circadian rhythm genes in various metabolic tissues and spinal cord of the Taiwanese Smn-/-;SMN2 SMA animal model. We demonstrate a dysregulated expression of the core clock genes (clock, ARNTL/Bmal1, Cry1/2, Per1/2) and clock output genes (Nr1d1 and Dbp) in SMA tissues during disease progression. We also uncover an age- and tissue-dependent diurnal expression of the Smn gene. Importantly, we observe molecular and phenotypic corrections in SMA mice following direct light modulation. Our study identifies a key relationship between an SMA pathology and peripheral core clock gene dysregulation, highlights the influence of SMN on peripheral circadian regulation and metabolism and has significant implications for the development of peripheral therapeutic approaches and clinical care management of SMA patients. PMID- 29982486 TI - Dual-organ transplantation in older recipients: outcomes after heart-kidney transplant versus isolated heart transplant in patients aged >=65 years. AB - OBJECTIVES: Combined heart-kidney transplantation has successful outcomes. With an increasing number of patients with end-stage heart disease, there is a high incidence of significant renal insufficiency that may necessitate combined heart kidney transplant. Outcomes for heart-kidney transplant recipients aged >=65 years are not well described. METHODS: Between 2010 and 2015, 163 recipients >=65 years of age were transplanted in a single centre: 12 heart-kidney and 151 isolated heart transplants. Outcomes assessed were estimated glomerular filtration rate at 1, 6 and 12 months after transplant, the need for dialysis, 1 year survival, 1-year freedom from rejection, 1-year freedom from cardiac allograft vasculopathy and 1-year freedom from non-fatal major adverse cardiac events. RESULTS: Recipient ages were 67.8 +/- 1.6 and 69.0 +/- 2.8 years for heart-kidney transplant and isolated heart transplant, and pretransplant estimated glomerular filtration rates were 26.6 +/- 9.4 vs 55.2 +/- 18.9, respectively. At 1 month (66.3 +/- 31.4 vs 67.2 +/- 28.0, P = 0.92), 6 months (68.1 +/- 21.3 vs 60.5 +/- 19.6, P = 0.20) and 12 months (58.6 +/- 21.5 vs 52.4 +/- 18.5, P = 0.27) post-transplant, estimated glomerular filtration rate was similar for heart-kidney transplant versus isolated heart transplant. There was a trend towards reduced 1-year freedom from temporary dialysis after heart-kidney transplant relative to isolated heart transplant (75.0% vs 90.4%, P = 0.06) without a difference in 1-year freedom from chronic dialysis (100% vs 95.2%, P = 0.46). There were no differences in 1-year survival, 1-year freedom from any treated rejection, acute cellular rejection, antibody-mediated rejection, cardiac allograft vasculopathy and non-fatal major adverse cardiac events. CONCLUSIONS: For patients >=65-year old, heart-kidney transplant can achieve outcomes on par with heart transplant alone. PMID- 29982488 TI - Cohort Profile: The National Longitudinal Survey of Youth 1979 (NLSY79). PMID- 29982487 TI - Chronic Kidney Disease Risk in African and Caribbean Populations With HIV. AB - We conducted an observational cohort study of end-stage kidney disease (ESKD) in >7000 African and Caribbean people with HIV in the UK. Using Poisson regression and East Africans as the reference group, the adjusted incidence rate ratio (95% confidence interval) of ESKD was 3.14 (1.26-7.84) in Southern Africans, 6.35 (2.53-15.96) in West Africans, and 5.26 (1.91-14.43) in Caribbeans. Higher CD4 cell count and suppressed HIV replication were associated with reduced risk of ESKD. The risk of ESKD varied among HIV-positive people of African heritage, with the highest rates observed in those of West African descent. PMID- 29982489 TI - Physical activity and generalized anxiety disorder: results from The Irish Longitudinal Study on Ageing (TILDA). AB - Background: Generalized anxiety disorder (GAD) is prevalent and costly. Physical activity (PA) may protect against other mental health disorders, including depression, but its protective effect on GAD remains under-studied in the general population and unstudied among older adults. Therefore, the present study examines associations between meeting World Health Organization PA guidelines (i.e. >=150 min of moderate PA, >=75 min of vigorous PA or >=600MET min of moderate and vigorous PA weekly) and the prevalence of probable GAD and incidence of GAD. Methods: Participants (n = 3950; 56.2% female) aged >=50 years completed the short-form International Physical Activity Questionnaire and the abbreviated Penn State Worry Questionnaire at baseline and the Composite International Diagnostic Interview - Short Form to clinically assess GAD 2 years later. Prospective analyses included participants without probable GAD at baseline (n = 3236). Results: Prevalence and incidence of GAD were 18.1% (n = 714) and 0.9% (n = 29), respectively. More respondents with GAD were female (72.2% vs 52.7%), aged 50-59 years (51.7% vs 38.7%), had normal waist circumference (52.7% vs 47.8) and smoked (20.4% vs 13.3%; all P <0.05). Meeting PA guidelines was associated with 25% and 63% lower odds of prevalent [odds ratio (OR) = 0.75, 95% confidence interval: 0.64 to 0.88] and incident (OR = 0.37, 0.17 to 0.85) GAD, respectively, in crude models, and 17% and 57% lower odds of prevalent (OR = 0.83, 0.70 to 0.98) and incident (OR = 0.43, 0.19 to 0.99) GAD, respectively, following adjustment for age, sex, waist circumference, social class and smoking. Conclusions: In addition to established physical health benefits of PA, the present findings support the importance of increasing PA at the population-level for mental health. PMID- 29982490 TI - Factors That Influence Flight Propensity in Anoplophora glabripennis (Coleoptera: Cerambycidae). AB - The effects of mating status, sex, beetle age, host quality, temperature, and wind speed on the propensity of Anoplophora glabripennis (Motschulsky) (Coleoptera: Cerambycidae) to take flight were evaluated using a free flight test in the laboratory. Time to initiate flight, the angle of flight, and flight capability (when beetles were enticed to take flight) were also evaluated. Host quality, mating status, beetle age, sex, temperature, and the interactions between one or more of these were all found to be significant predictors of flight in A. glabripennis in one or more of the experiments. Female flight propensity peaked at sexual maturity and declined thereafter. Both sexes had a higher propensity to take flight from a stem section of dry host material than from a fresh one. Most (78%) males flew at least once during the four mating status/ages tested from a fresh host stem section, while only 43% of the females flew at least once after chewing an oviposition pit. Flight propensity and distance flown increased with temperature and there was no voluntary flight at 15 degrees C. Flight propensity did not increase with wind speeds 0.0-1.0 m/s, but no ascending flight was observed at 0.5 or 1.0 m/s. Time to flight initiation did not vary with the factors evaluated. Implications these results could have on the success of eradication programs are discussed. Specifically, what factors increase the propensity of mated females to disperse, effectively expanding the infestation zone. PMID- 29982491 TI - Left extralobar pulmonary sequestration and a right aorto-to-pulmonary vein fistula in a newborn: a 3-mm thoracoscopic monolateral approach. AB - An extralobar pulmonary sequestration (EPS) associated with a contralateral aorto to-pulmonary vein fistula is rare. We report the case of a female newborn with left EPS fed by an artery originating from the distal thoracic aorta and, symmetrically on the controlateral side, an artery shunting in the inferior right pulmonary vein. Echocardiography showed dilatation of the left atrium. On the 34th day since birth (weight 4500 g), the patient was operated on thoracoscopically. The EPS was closed with a 3-mm sealing system, divided and removed. A window in the mediastinal pleura was created, and the origin of the fistula was identified and sealed. The postoperative course was uneventful. The patient was discharged on Day 4 with no echocardiographic signs of persistence of the fistula and of the congestive heart failure. This is the first case report of a thoracic large systemic circulation-to-pulmonary vein fistula causing heart failure associated with EPS. The thoracoscopic monolateral approach and the availability of 3-mm instruments guaranteed a maximum level of minimal invasiveness. PMID- 29982493 TI - The Ankle-Brachial Index Is Associated with Cerebral Beta-Amyloid Deposition in Cognitively Normal Older Adults. AB - Background: Although ankle-brachial index (ABI), an indicator of atherosclerosis or arterial stiffness, has been associated with dementia and Alzheimer's disease, no information is yet available for its contribution to AD pathologies. We investigated the relationship between the ABI and in vivo beta-amyloid (Abeta) deposition and AD-specific neurodegeneration in cognitively normal (CN) elderly individuals. Methods: A total of 256 CN elderly subjects who participated in the Korean Brain Aging Study for the Early Diagnosis & Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort study, were included. All subjects underwent comprehensive clinical and neuropsychological assessments, ABI measurement, apolipoprotein E (APOE) genotyping, [11C]Pittsburgh Compound B (PiB) positron emission tomography (PET), [18F]-fludeoxyglucose PET, and magnetic resonance imaging. Results: A significant positive association was found between the ABI and global cerebral Abeta retention measured by PiB-PET, even after controlling for age, sex, and APOE epsilon4. When three stratified ABI subgroups (ABI < 1.00, 1.00-1.29, and >= 1.30) were compared, the highest ABI subgroup (i.e., ABI >= 1.30) showed significantly higher Abeta deposition than that of the other subgroups. This relationship between Abeta deposition and the ABI was significant only in APOE epsilon4 carriers, but not in non-carriers. No significant association was observed between the ABI and neurodegeneration in the AD-signature regions. Conclusion: Our findings suggest that a high ABI, possibly related to arterial stiffness, is associated with elevated brain Abeta burden in cognitively healthy elderly individuals, particularly in APOE epsilon4 carriers. PMID- 29982494 TI - Environmental Endocrinology: Insights into the Diversity of Regulatory Mechanisms in Life Cycles. AB - All organisms must time their life cycles appropriately and organize life history stages into temporal sequences that enhance fitness in a changing environment. The endocrine system plays a major regulatory role in transducing information from the environment into morphological, physiological, and behavioral responses appropriate for the time of year. The perception, transduction, response pathways via neural and endocrine mechanisms are beginning to be explored and underscore the critical regulatory roles they play. Whereas many conserved mechanisms (evolutionary constraints hypothesis) are emerging, there is a growing realization that there may be alternate pathways unique to populations and individuals (evolutionary flexibility hypothesis). Field investigations (field endocrinology) over the past 45 years have revealed patterns of hormonal responses to environmental changes, physical and social, that could not have been anticipated from laboratory investigations alone. These patterns include differences at population and individual levels that have enabled new insights into acclimation and adaptation to environmental transitions. The number of species studied under natural conditions has grown exponentially in recent years to include all vertebrate classes and some invertebrates as well. These data are now driving evolutionary perspectives and with the advent of comparative genomics a new and exciting era of evolutionary/ecological endocrinology is developing. This article gives a brief overview of where the field stands now and where it is likely to go in the future especially in relation to the networks of regulatory pathways and how they can be modulated to enable acclimation of individuals as well as populations. One illustrative example, mechanisms underlying modulation of the adrenocortical responses to environmental stress, is the focus of this communication. These "coping" mechanisms will be key for acclimation and adaptation to global change. PMID- 29982495 TI - Neural Basis of Sensorimotor Plasticity in Speech Motor Adaptation. AB - When we speak, we get correlated sensory feedback from speech sounds and from the muscles and soft tissues of the vocal tract. Here we dissociate the contributions of auditory and somatosensory feedback to identify brain networks that underlie the somatic contribution to speech motor learning. The technique uses a robotic device that selectively alters somatosensory inputs in combination with resting state fMRI scans that reveal learning-related changes in functional connectivity. A partial correlation analysis is used to identify connectivity changes that are not explained by the time course of activity in any other learning-related areas. This analysis revealed changes related to behavioral improvements in movement and separately, to changes in auditory perception: Speech motor adaptation itself was associated with connectivity changes that were primarily in non-motor areas of brain, specifically, to a strengthening of connectivity between auditory and somatosensory cortex and between presupplementary motor area and the inferior parietal lobule. In contrast, connectively changes associated with alterations to auditory perception were restricted to speech motor areas, specifically, primary motor cortex and inferior frontal gyrus. Overall, our findings show that during adaptation, somatosensory inputs result in a broad range of changes in connectivity in areas associated with speech motor control and learning. PMID- 29982496 TI - Longitudinal associations between having an adult child migrant and depressive symptoms among older adults in the Mexican Health and Aging Study. AB - Background: Migration may impact the mental health of family members who remain in places of origin. We examined longitudinal associations between having an adult child migrant and mental health, for middle-aged and older Mexican adults accounting for complex time-varying confounding. Methods: Mexican Health and Aging Study cohort (N = 11 806) respondents >=50 years completed a 9-item past week depressive symptoms scale; scores of >=5 reflected elevated depressive symptoms. Expected risk differences (RD) for elevated depressive symptoms at each wave due to having at least one (versus no) adult child migrant in the US or in another Mexican city were estimated with longitudinal targeted maximum likelihood estimation. Results: Women with at least one adult child in the US had a higher adjusted baseline prevalence of elevated depressive symptoms (RD: 0.063, 95% CI: 0.035, 0.091) compared to women with no adult children in the US. Men with at least one child in another Mexican city at all three study waves had a lower adjusted prevalence of elevated depressive symptoms at 11-year follow-up (RD: 0.042, 95% CI: -0.082, -0.003) compared to those with no internal migrant children over those waves. For men and women with <=3 total children, adverse associations between having an adult child in the US and depressive symptoms persisted beyond baseline. Conclusions: Associations between having an adult child migrant and depressive symptoms varied by respondent gender, family size, and the location of the child migrant. Trends in population aging and migration bring new urgency to examining associations with other outcomes and in other settings. PMID- 29982497 TI - Organophosphate and Organochlorine Resistance in Larval Stage of Aedes albopictus (Diptera: Culicidae) in Sabah, Malaysia. AB - The present study aims to investigate the susceptibility status of Aedes albopictus (Skuse) collected from residential areas in Sabah, Malaysia towards eight WHO-recommended dosages of larvicides representing the classes of organophosphates and organochlorines. Field and reference strains of Ae. albopictus larvae were bioassayed in accordance to WHO standard methods using diagnostic dosages of bromophos, malathion, fenthion, fenitrothion, temephos, chlorpyrifos, dichlorodiphenyltrichloroethane (DDT), and dieldrin. The results revealed that Ae. albopictus was resistant (mortality < 90%) towards malathion, temephos, and DDT. In addition, most of the Ae. albopictus strains exhibited a wide range of susceptibilities against bromophos, with mortality ranged from 49.33 to 93.33%. On the contrary, only dieldrin was able to induce 100% mortality against all strains of Ae. albopictus. Tolerance to fenitrothion, fenthion, and chlorpyrifos, with mortality ranging from 81.33 to 97.33%, was also observed in this study. PMID- 29982498 TI - The role of alkalinization-induced Ca2+ influx in sperm motility activation of a viviparous fish Redtail Splitfin (Xenotoca eiseni). AB - Mechanisms regulating sperm motility activation are generally known in oviparous fishes, but are poorly understood in viviparous species. The mechanism of osmotic shock induced signaling for oviparous fishes is not suitable for viviparous fishes which activate sperm motility within an isotonic environment. In addition, the presence of sperm bundles in viviparous fishes further complicates study of sperm activation mechanisms. The goal of this study was to establish methodologies to detect intracellular Ca2+ signals from sperm cells within bundles, and to investigate the signaling mechanism of sperm activation of viviparous fish using Redtail Splitfin (Xenotoca eiseni) as a model. Motility was assessed by classification of bundle dissociation and computer-assisted sperm analysis, and intracellular Ca2+ was assessed using the fluorescent probe Fura-2 AM. Bundle dissociation and sperm motility increased with extracellular Ca2+ and pH levels. Intracellular Ca2+ signals were detected from sperm within bundles, and increased significantly with extracellular Ca2+ and pH levels. Major channel blockers known to inhibit Ca2+ influx (NiCl2, ruthenium red, GdCl3, SKF-96365, nimodipine, verapamil, methoxyverapamil, mibefradil, NNC 55-0396, omega-Conotoxin MVIIC, bepridil, and 2-APB) failed to inhibit Ca2+ influx, except for CdCl2, which partially inhibited the influx. We propose a novel mechanism for motility regulation of fish sperm: an alkaline environment in the female reproductive tract opens Ca2+ channels in the sperm plasma membrane without osmotic shock, and the Ca2+ influx functions as a second messenger to activate motor proteins controlling flagella movement. PMID- 29982499 TI - Cortical Neuron Migration and Dendrite Morphology are Regulated by Carboxypeptidase E. AB - Higher brain function relies on proper development of the cerebral cortex, including correct positioning of neurons and dendrite morphology. Disruptions in these processes may result in various neurocognitive disorders. Mutations in the CPE gene, which encodes carboxypeptidase E (CPE), have been linked to depression and intellectual disability. However, it remains unclear whether CPE is involved in early brain development and in turn contributes to the pathophysiology of neurocognitive disorders. Here, we investigate the effects of CPE knockdown on early brain development and explore the functional significance of the interaction between CPE and its binding partner p150Glued. We demonstrate that CPE is required for cortical neuron migration and dendrite arborization. Furthermore, we show that expression of CPE-C10 redistributes p150Glued from the centrosome and that disruption of CPE interaction with p150Glued leads to abnormal neuronal migration and dendrite morphology, suggesting that a complex between CPE and p150Glued is necessary for proper neurodevelopment. PMID- 29982500 TI - Effects of Substance Use and Sex Practices on the Intestinal Microbiome During HIV-1 Infection. AB - Background: Human immunodeficiency virus type 1 (HIV-1) infection alters the human intestinal microbiome; however, behavioral factors driving these changes remain poorly defined. Here we examine the effects of substance use and sex behavior on the microbiome during HIV-1 infection. Methods: Archival rectal swab specimens, urine drug test results, and responses to substance use and sex behavior questionnaires were obtained from 37 HIV-positive participants at 2 time points, separated by 6 months, in a cohort examining the effects of substance use in men who have sex with men (MSM). Microbiome profiling was performed using 16S ribosomal RNA gene sequencing, and associations with behavioral factors were examined using 0-inflated negative binomial regression. Further analysis of selected variables of interest was performed using propensity scores to account for multiple confounders. Results: Using permutational multivariate analysis of variance, we found that receptive anal intercourse, methamphetamine use, and marijuana use were among the most important drivers of microbiome variation. Propensity score-adjusted analyses revealed that methamphetamine use and marijuana use displayed unique associations; methamphetamine use was associated with an increased abundance of Porphyromonas and Granulicatella organisms and a decreased abundance of Ruminococcus, Collinsella, and Parabacteroides organisms, whereas marijuana use was associated with an increased abundance of Ruminococcus, Clostridium cluster IV, Solobacterium, and Fusobacterium organisms and a decreased abundance of Acidaminococcus, Prevotella, Dialister, Anaerostipes, and Dorea organisms. Conclusions: Drug use and sex behavior are important factors associated with intestinal dysbiosis during chronic HIV-1 infection among young MSM. PMID- 29982502 TI - Healthcare resource use and attributable cost of Clostridium difficile infection: a micro-costing analysis comparing first and recurrent episodes. AB - Objectives: Accurate and sufficiently detailed data on the economic burden of Clostridium difficile infection (CDI) are lacking. We performed a micro-costing study to determine the health resource utilization of patients with a first episode of CDI (fCDI) and those with a recurrent episode of CDI (rCDI). Patients and methods: Forty-five adult and paediatric inpatients with rCDI were matched by age, sex and date of diagnosis with control patients with fCDI. Total length of hospital stay, length of stay in the ICU and several cost parameters differentiated into fixed and variable components were measured and compared across both groups. Results: The mean total length of stay for rCDI patients was 33 days (95% CI 19-46) compared with 17 days (95% CI 12-21) for fCDI patients; P = 0.0259. ICU length of stay was also longer for rCDI patients than for fCDI patients (mean 2.5 versus 0.7 days). Mean total variable costs for fCDI and rCDI were L2382 (95% CI 1750-3014) and L4683 (95% CI 3051-6311), respectively; P = 0.009. Mean fixed costs for fCDI and rCDI were L10 328 (95% CI 7555-13 101) and L26 438 (95% CI 16 135-36 742), respectively; P = 0.003. Mean total costs for fCDI and rCDI were L12 710 (95% CI 9652-15 769) and L31 121 (95% CI 19 792-42 447), respectively; P < 0.002. Conclusions: The healthcare resource use and financial burden attributable to CDI is significant. Most excess cost is driven by additional length of hospital stay. These costs may have been underestimated in previous studies that have not accounted for several difficult-to-measure parameters or have used averaged tariff-based estimates. PMID- 29982501 TI - Nighres: processing tools for high-resolution neuroimaging. AB - With recent improvements in human magnetic resonance imaging (MRI) at ultra-high fields, the amount of data collected per subject in a given MRI experiment has increased considerably. Standard image processing packages are often challenged by the size of these data. Dedicated methods are needed to leverage their extraordinary spatial resolution. Here, we introduce a flexible Python toolbox that implements a set of advanced techniques for high-resolution neuroimaging. With these tools, segmentation and laminar analysis of cortical MRI data can be performed at resolutions up to 500 MUm in reasonable times. Comprehensive online documentation makes the toolbox easy to use and install. An extensive developer's guide encourages contributions from other researchers that will help to accelerate progress in the promising field of high-resolution neuroimaging. PMID- 29982503 TI - Effective Deaf Access to Justice. AB - This article reports on findings from a qualitative study that explored the experiences of eight deaf participants in interacting with the justice system in Northern Ireland. The study was spurred by anecdotal evidence of challenges facing members of the Deaf community in obtaining access to solicitors. The UN Convention on the Rights of Persons with Disabilities, to which the United Kingdom is a State Party, requires providers of goods, facilities, and services, which include solicitors, to provide effective communication access to deaf people seeking their services on an equal basis with non-disabled people. The Disability Discrimination Act comes into play, requiring service providers like solicitors to make a "reasonable adjustment" in order to provide access to deaf clients. Eight participants provided narratives from which three thematic categories emerged: (a) Barriers to Access, (b) The Contested Meaning of "Reasonable Adjustment," and PMID- 29982504 TI - Effect of spatial origin and hydrocarbon composition on bacterial consortia community structure and hydrocarbon biodegradation rates. AB - Oil reserves in deep-sea sediments are currently subject to intense exploration, with associated risks of oil spills. Previous research suggests that microbial communities from deep-sea sediment (>1000m) can degrade hydrocarbons (HCs), but have a lower degradation ability than shallow (<200m) communities, probably due to in situ temperature. This study aimed to assess the effect of marine origin on microbial HC degradation potential while separating the influence of temperature, and to characterise associated HC-degrading bacterial communities. Microbial communities from 135 and 1000 m deep sediments were selectively enriched on crude oil at in situ temperatures and both consortia were subsequently incubated for 42 days at 20 degrees C with two HC mixtures: diesel fuel or model oil. Significant HC biodegradation occurred rapidly in the presence of both consortia, especially of low molecular weight HCs and was concomitant with microbial community changes. Further, oil degradation was higher with the shallow consortium than with the deep one. Dominant HC-degrading bacteria differed based on both spatial origin of the consortia and supplemented HC types. This study provides evidence for influence of sediment spatial origin and HC composition on the selection and activity of marine HC-degrading bacterial communities and is relevant for future bioremediationdevelopments. PMID- 29982506 TI - The unexpected diversity of microbial communities associated with black corals revealed by high-throughput Illumina sequencing. AB - The microbes associated with black corals remain poorly studied. The present study is the first attempt to investigate microbial community structure in the black corals Antipathes ceylonensis and A. dichotoma from the South China Sea by using high-throughput Illumina sequencing. A total of 52 bacterial and 3 archaeal phyla were recovered in this study, suggesting the black corals harboured highly diverse microbial communities. Among the 55 microbial phyla, Proteobacteria, Firmicutes, Bacteroidetes, Chloroflexi, Acidobacteria and Actinobacteria dominated in the two black corals from the South China Sea. Although most of the microbial phyla recovered from the two black corals have been reported in previous studies on coral-associated microbes, eight bacterial phyla including Synergistetes, Thermi, AncK6, GNO2, NKB19, NC10, WWE1 and GAL15, and the archaeal phylum Parvarchaeota are reported for the first time from corals in this study, which expands our knowledge about the diversity of coral-associated microbes. The comparison of microbial communities in the different black coral species indicated that A. ceylonensis harboured few abundant bacterial genera such as Citrobacter and Pseudomonas, whereas a high diversity of rare bacterial genera (<1% abundance), such as Winogradskyella and Rubricoccus, was detected only in A. dichotoma. These results suggested that the microbial community in black corals exhibited species-specific variation. PMID- 29982505 TI - Adult Cellular Neuroadaptations Induced by Adolescent THC Exposure in Female Rats Are Rescued by Enhancing Anandamide Signaling. AB - Background: In rodent models, chronic exposure to cannabis' psychoactive ingredient, Delta9-tetrahydrocannabinol, during adolescence leads to abnormal behavior in adulthood. In female rats, this maladaptive behavior is characterized by endophenotypes for depressive-like and psychotic-like disorders as well as cognitive deficits. We recently reported that most depressive-like behaviors triggered by adolescent Delta9-tetrahydrocannabinol exposure can be rescued by manipulating endocannabinoid signaling in adulthood with the anandamide inactivating enzyme FAAH inhibitor, URB597. However, the molecular mechanisms underlying URB597's antidepressant-like properties remain to be established. Methods: Here we examined the impact of adult URB597 treatment on the cellular and functional neuroadaptations that occurred in the prefrontal cortex and dentate gyrus of the hippocampus upon Delta9-tetrahydrocannabinol during adolescence through biochemical, morphofunctional, and electrophysiological studies. Results: We found that the positive action of URB597 is associated with the rescue of Delta9-tetrahydrocannabinol-induced deficits in endocannabinoid mediated signaling and synaptic plasticity in the prefrontal cortex and the recovery of functional neurogenesis in the dentate gyrus of the hippocampus. Moreover, the rescue property of URB597 on depressive-like behavior requires the activity of the CB1 cannabinoid receptor. Conclusions: By providing novel insights into the cellular and molecular mechanisms of URB597 at defined cortical and hippocampal circuits, our results highlight that positive modulation of endocannabinoid-signaling could be a strategy for treating mood alterations secondary to adolescent cannabis use. PMID- 29982507 TI - Definition of hidden drug cardiotoxicity: paradigm change in cardiac safety testing and its clinical implications. AB - Unexpected cardiac adverse effects are the leading causes of discontinuation of clinical trials and withdrawal of drugs from the market. Since the original observations in the mid-90s, it has been well established that cardiovascular risk factors and comorbidities (such as ageing, hyperlipidaemia, and diabetes) and their medications (e.g. nitrate tolerance, adenosine triphosphate-dependent potassium inhibitor antidiabetic drugs, statins, etc.) may interfere with cardiac ischaemic tolerance and endogenous cardioprotective signalling pathways. Indeed drugs may exert unwanted effects on the diseased and treated heart that is hidden in the healthy myocardium. Hidden cardiotoxic effects may be due to (i) drug induced enhancement of deleterious signalling due to ischaemia/reperfusion injury and/or the presence of risk factors and/or (ii) inhibition of cardioprotective survival signalling pathways, both of which may lead to ischaemia-related cell death and/or pro-arrhythmic effects. This led to a novel concept of 'hidden cardiotoxicity', defined as cardiotoxity of a drug that manifests only in the diseased heart with e.g. ischaemia/reperfusion injury and/or in the presence of its major comorbidities. Little is known on the mechanism of hidden cardiotoxocity, moreover, hidden cardiotoxicity cannot be revealed by the routinely used non-clinical cardiac safety testing methods on healthy animals or tissues. Therefore, here, we emphasize the need for development of novel cardiac safety testing platform involving combined experimental models of cardiac diseases (especially myocardial ischaemia/reperfusion and ischaemic conditioning) in the presence and absence of major cardiovascular comorbidities and/or cotreatments. PMID- 29982508 TI - Identification of a Novel Hepatitis C Virus Genotype From Punjab, India: Expanding Classification of Hepatitis C Virus Into 8 Genotypes. AB - Background: Hepatitis C virus (HCV) exhibits great genetic diversity and is classified into 7 genotypes (GTs), with varied geographic prevalence. Until the recent development of pangenotypic direct-acting antiviral regimens, the determination of HCV GT was necessary to inform optimal treatment. Methods: Plasma samples with unresolved GT using standard commercial genotyping methods were subjected to HCV full-genome sequencing, and phylogenetic analysis was performed to assign GT. Results: Four patients, previously classified as GT5 by LiPA or Abbott RealTime polymerase chain reaction assays, were identified as infected with a novel HCV GT. This novel HCV GT, GT8, is genetically distinct from previously identified HCV GT1-7 with >30% nucleotide sequence divergence to the established HCV subtypes. All 4 patients were originally from Punjab, India, but now reside in Canada and are epidemiologically unlinked. Despite presence of baseline resistance-associated substitutions within the GT8 virus of all 4 patients (NS3: V36L, Q80K/R; NS5A: Q30S, Y93S), all patients achieved a sustained virologic response; 2 treated with sofosbuvir/velpatasvir/voxilaprevir for 8 weeks, 1 with sofosbuvir/ledipasvir plus ribavirin for 24 weeks and 1 with sofosbuvir plus daclatasvir for 12 weeks. Conclusions: The discovery of a novel HCV GT8 confirms the circulation of this newly identified lineage in the human population. PMID- 29982509 TI - Blood Telomere Length Changes After Ritonavir-Boosted Darunavir Combined With Raltegravir or Tenofovir-Emtricitabine in Antiretroviral-Naive Adults Infected With HIV-1. AB - Background: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown. Methods: NEAT001/ANRS143 is a randomized trial that showed noninferiority over 96 weeks of ritonavir-boosted darunavir plus raltegravir versus tenofovir disoproxil fumarate/emtricitabine in 805 antiretroviral antiretrovrial-naive HIV-infected adults. We compared changes in whole-blood telomere length measured with quantitative polymerase chain reaction in 201 randomly selected participants (104 raltegravir and 97 tenofovir disoproxil fumarate/emtricitabine). We performed multivariable estimative and predictive linear regression. Results: At week 96, participants receiving tenofovir disoproxil fumarate/emtricitabine had a statistically significant higher gain in telomere length than participants receiving raltegravir. Difference in mean telomere length change between groups (tenofovir disoproxil fumarate/emtricitabine minus raltegravir) from baseline to week 96 adjusted by baseline telomere length was 0.031 (P = .009). This difference was not significantly confounded by age, gender, known duration of HIV infection, CD4 (baseline/nadir), CD8 cells, CD4/CD8 ratio, HIV viral load (baseline/week 96), tobacco and alcohol consumption, statins, or hepatitis C. Conclusion: Antiretroviral-naive HIV-infected adults receiving ritonavir-boosted darunavir and tenofovir disoproxil fumarate/emtricitabine had a significant higher gain in blood telomere length than those receiving ritonavir-boosted darunavir and raltegravir, suggesting a better initial recovery from HIV-associated immunosenescence. PMID- 29982510 TI - Cardioscopy resection of a multiple papillary fibroelastoma attached to the anterior interventricular septum. PMID- 29982511 TI - Identifying surgical site infections in electronic health data using predictive models. AB - Objective: The objective was to prospectively derive and validate a prediction rule for detecting cases warranting investigation for surgical site infections (SSI) after ambulatory surgery. Methods: We analysed electronic health record (EHR) data for children who underwent ambulatory surgery at one of 4 ambulatory surgical facilities. Using regularized logistic regression and random forests, we derived SSI prediction rules using 30 months of data (derivation set) and evaluated performance with data from the subsequent 10 months (validation set). Models were developed both with and without data extracted from free text. We also evaluated the presence of an antibiotic prescription within 60 days after surgery as an independent indicator of SSI evidence. Our goal was to exceed 80% sensitivity and 10% positive predictive value (PPV). Results: We identified 234 surgeries with evidence of SSI among the 7910 surgeries available for analysis. We derived and validated an optimal prediction rule that included free text data using a random forest model (sensitivity = 0.9, PPV = 0.28). Presence of an antibiotic prescription had poor sensitivity (0.65) when applied to the derivation data but performed better when applied to the validation data (sensitivity = 0.84, PPV = 0.28). Conclusions: EHR data can facilitate SSI surveillance with adequate sensitivity and PPV. PMID- 29982512 TI - A systematic assessment of the availability and clinical drug information coverage of machine-readable clinical drug data sources for building knowledge translation products. AB - Objective: To identify and describe clinical drug data sources that have the potential to serve as a repository of information for developing drug knowledge translation products. Methods: Two reviewers independently screened citations from PubMed and Embase, websites from the web search engine Google, and references from selected journals. Publicly licensed or non-proprietary data sources containing clinical drug information accessible in a machine-readable format were eligible. Data sources were assessed for their coverage across 18 pre specified domains and 74 elements of clinical drug information. Results: Of the 3369 unique citations or webpages screened, 44 drug information data sources were identified. Of these, 22 data sources met the study inclusion criteria. There was a mean of 4.5 (SD = 5.19) domains covered by each source and a mean of 10.9 (SD = 18) elements covered by each source. None of the data sources covered all domains and eight elements were not addressed by any source. All of the data sources identified by the study are government or academic databases. Conclusion: Our study demonstrated the availability of machine-readable clinical drug data that could help facilitate the creation of novel drug knowledge translation products. However, we identified clinical content gaps in the available non-proprietary drug information sources. Further evaluation of the quality of each data source would be necessary prior to incorporating these sources into any knowledge translation products intended for clinical use. PMID- 29982513 TI - N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene. AB - Cardiomyopathy caused by lamin A/C gene (LMNA) mutations (hereafter referred as LMNA cardiomyopathy) is an anatomic and pathologic condition associated with muscular and electrical dysfunction of the heart, often leading to heart failure related disability. There is currently no specific therapy available for patients that target the molecular pathophysiology of LMNA cardiomyopathy. We showed here an increase in oxidative stress levels in the hearts of mice carrying LMNA mutation, associated with a decrease of the key cellular antioxidant glutathione (GHS). Oral administration of N-acetyl cysteine, a GHS precursor, led to a marked improvement of GHS content, a decrease in oxidative stress markers including protein carbonyls and an improvement of left ventricular structure and function in a model of LMNA cardiomyopathy. Collectively, our novel results provide therapeutic insights into LMNA cardiomyopathy. PMID- 29982514 TI - Clinical and bacteriological efficacy of pivmecillinam treatment for uncomplicated urinary tract infections caused by ESBL-producing Escherichia coli: a prospective, multicentre, observational cohort study. AB - Objectives: To compare the clinical and bacteriological outcomes of pivmecillinam treatment for community-acquired urinary tract infections (UTIs) caused by ESBL producing Escherichia coli versus non-ESBL-producing E. coli in an outpatient setting. Methods: A prospective, multicentre, observational cohort study of women aged >=16 years, with pivmecillinam-treated community-acquired UTIs caused by E. coli with or without ESBL production, recruited from primary care, was conducted in the period from April 2013 to August 2016. Eighty-eight women (mean age 49.4 years) with community-acquired UTIs caused by ESBL-producing E. coli were compared with a control group of 74 women (mean age 50.1 years). Trial registration: Regional Committees for Medical and Health Research Ethics (REC) in Norway, ID 2011/2214, and ClinicalTrials.gov, ID NCT01531023. Results: The median time until symptom resolution after treatment initiation was 5 days for the ESBL cases and 3 days for the non-ESBL controls (P < 0.01). The proportion of women warranting a second antibiotic prescription in the follow-up period was higher for the ESBL cases [30/88 (34.1%) versus 10/72 (13.9%), P < 0.01]. Persistent bacteriuria was non-significantly more common among ESBL cases than in the control group [15/81 (18.5%) versus 6/67 (9.0%), P = 0.10]. A pivmecillinam dosage of 200 mg given three times daily for <=5 days was associated with treatment failure (OR 4.77, 95% CI 1.40-19.44, P = 0.03) for the ESBL E. coli group. For the subgroup treated with 400 mg of pivmecillinam given three times daily there was no significantly increased OR for treatment failure between ESBL cases and the control group irrespective of treatment duration. Conclusions: Pivmecillinam given at 400 mg three times daily gave comparable clinical and bacteriological cure rates in women with community-acquired E. coli UTIs irrespective of ESBL production. PMID- 29982515 TI - A systematic review of mental health and wellbeing outcomes of group singing for adults with a mental health condition. AB - Background: A growing body of research has found that participating in choir singing can increase positive emotions, reduce anxiety and enhance social bonding. Consequently, group singing has been proposed as a social intervention for people diagnosed with mental health problems. However, it is unclear if group singing is a suitable and effective adjunct to mental health treatment. The current paper systematically reviews the burgeoning empirical research on the efficacy of group singing as a mental health intervention. Methods: The literature searched uncovered 709 articles that were screened. Thirteen articles representing data from 667 participants were identified which measured mental health and/or wellbeing outcomes of group singing for people living with a mental health condition in a community setting. Results: The findings of seven longitudinal studies, showed that while people with mental health conditions participated in choir singing, their mental health and wellbeing significantly improved with moderate to large effect sizes. Moreover, six qualitative studies had converging themes, indicating that group singing can provide enjoyment, improve emotional states, develop a sense of belonging and enhance self confidence in participants. Conclusion: The current results indicate that group singing could be a promising social intervention for people with mental health conditions. However, these studies had moderate to high risk of bias. Therefore, these findings remain inconclusive and more rigorous research is needed. PMID- 29982516 TI - Evaluation of moderate to high elevation effects on pulmonary arterial pressure measures in Angus cattle. AB - Altitude-induced pulmonary hypertension is a disease once thought to only occur at extremely high elevations (> 1,600 m), but recently it has been observed at moderate elevations of 1200 to 1600 m. Pulmonary arterial pressure (PAP) has been used as an indicator of tolerance to high altitude in mountainous beef production systems for over 30 years. The trait is typically measured on yearling bulls and heifers with values <= 41 mm Hg being favorable. These observations were historically only considered valid when they were recorded at elevations >= 1,600 m; however, if observations from lower (i.e., moderate) elevations were reliable indicators, a greater number of cattle records could be used in genetic improvement programs for high altitude beef systems. The objectives of this study were to evaluate the relationship between PAP and elevation, as well as to determine if PAP measures obtained at moderate elevations (ME) less than 1,600 m have a genetic relationship with PAP observations obtained at high elevations (HE) 1,600 m or greater. Elevation and PAP data from purebred Angus cattle (n = 14,665) from 349 contemporary groups were used in the analyses. Elevation and PAP averaged 1,887 +/- 1.8 m and 43.0 +/- 0.1 mm Hg, respectively. A univariate model containing the effects of sex, age, elevation category (HE vs ME), elevation (continuous), elevation category by elevation interaction along with a random direct genetic effect was utilized to determine the relationship between PAP and elevation. In this model, all main effects were found to be significant contributors of variation in PAP (P < 0.001). The interaction between elevation category and elevation was not a significant contributor to variability of PAP (P > 0.05). A bivariate animal model was then used to evaluate the relationship between PAP observations obtained between HE and ME groups. Heritability estimates for these two groups were 0.34 0.03 and 0.29 0.09, respectively, and their genetic correlation was 0.83 0.15. Even though this is a strong genetic relationship, results of this study support the hypothesis that PAP observations collected at HE and ME are not perfectly, genetically related. Results suggest that PAP measures collected from 1,219 to 1,600 m may be useful as a correlated trait in a multi-trait genetic evaluation to produce EPD useful for selection of animals with reduced susceptibility to pulmonary hypertension. PMID- 29982517 TI - Improved Trap Designs and Retention Mechanisms for Halyomorpha halys (Hemiptera: Pentatomidae). AB - Current monitoring systems for the invasive Halyomorpha halys (Stal) (Hemiptera; Pentatomidae) in orchard agroecosystems rely on ground-deployed tall black pyramid traps baited with the two-component H. halys aggregation pheromone and pheromone synergist. Pyramid traps are comparatively costly, require considerable time to deploy and service, and may not be best suited to grower needs. Therefore, we evaluated other traps for H. halys, including modified pyramid traps (lures deployed on the outside), a canopy-deployed small pyramid, a pipe trap, delta traps, and yellow sticky cards in 2015 and 2016 in commercial apple and peach orchards. We also compared various H. halys killing agents for use in standard pyramid trap collection jars, including VaporTape kill strips, cattle ear tags, and plastic netting treated with various pyrethroids. Finally, we evaluated the effect of positioning the lures inside versus outside the collection jar on standard pyramid traps on overall captures. Among trap types, modified pyramid and pipe traps were most effective, capturing more adults than all other trap designs. Adult captures in small canopy-deployed pyramid, delta, and yellow sticky traps were lower, but significantly correlated with the standard black pyramid. Placing lures on the outside of collection jars on pyramid traps resulted in significantly greater captures and insecticide impregnated netting was as effective for retaining bugs as VaporTape strips. These studies demonstrate that trapping systems for H. halys can be simplified and improved by modifying the trap design, lure deployment location, and/or killing agent. PMID- 29982518 TI - Refusal to provide healthcare to sub-Saharan migrants in France: a comparison according to their HIV and HBV status. AB - Background: In this study, we aim to measure and compare the frequency of reported denial of care in sub-Saharan African migrants living in the Paris area, according to their HIV and HBV status and social and migration characteristics. Methods: The ANRS-PARCOURS study is a life-event survey conducted in 2012-13 in healthcare facilities in the Paris area, among three groups of sub-Saharan migrants recruited in primary care centres (N = 760; reference group), in dedicated centres for HIV care (N = 922; HIV group) and in centres for chronic hepatitis B care (N = 777; CHB group). Characteristics associated with refusal of care since arrival in France were identified using a logistic regression model. Results: Compared to the reference group (6%, P < 0.001), the reported refusal of care was twice as high in the HIV group (12%) and the CHB group (10%). In the multivariate analysis, men and women living with HIV were at greater risk of being denied care (aOR = 2.20[1.14-4.25] and 2.24[1.25-4.01]). Women covered by the specific health insurance (HI) for precarious or undocumented migrants were also at higher risk (aOR = 2.07[1.10-3.89] and 2.69[1.18-6.10], respectively). The risk was also increased in men who remained for at least one year without permit of residence or without HI and among those who were threatened in their country. Conclusion: Refusals to provide healthcare are frequent and deleterious situations especially for migrants living with HIV. Health decision makers, public insurance bodies and health professional councils must address this issue to improve equity in the healthcare system. PMID- 29982519 TI - The future burden of lung cancer attributable to current modifiable behaviours: a pooled study of seven Australian cohorts. AB - Background: Knowledge of preventable disease and differences in disease burden can inform public health action to improve health and health equity. We quantified the future lung cancer burden preventable by behavioural modifications across Australia. Methods: We pooled seven Australian cohort studies (n = 367 058) and linked them to national registries to identify lung cancers and deaths. We estimated population attributable fractions and their 95% confidence intervals (CIs) for modifiable risk factors, using risk estimates from the cohort data and risk factor exposure distribution from contemporary national health surveys. Results: During the first 10-year follow-up, there were 2025 incident lung cancers and 20 349 deaths. Stopping current smoking could prevent 53.7% (95% CI, 50.0-57.2%) of lung cancers over 40 years and 18.3% (11.0-25.1%) in 10 years. The smoking-attributable burden is highest in males, those who smoke <20 cigarettes per day, are <75 years of age, unmarried, of lower educational attainment, live in remote areas or are healthy weight. Increasing physical activity and fruit consumption, if causal, could prevent 15.6% (6.9-23.4%) and 7.5% (1.3-13.3%) of the lung cancer burden, respectively. Jointly, the three behaviour modifications could prevent up to 63.0% (58.0-67.5%) of lung cancers in 40 years, and 31.2% (20.9-40.1%) or 43 300 cancers in 10 years. The preventable burden is highest among those with multiple risk factors. Conclusions: Smoking remains responsible for the highest burden of lung cancer in Australia. The uneven burden distribution distinguishes subgroups that could benefit the most from activities to control the world's deadliest cancer. PMID- 29982520 TI - Using wearable technology to predict health outcomes: a literature review. AB - Objective: To review and analyze the literature to determine whether wearable technologies can predict health outcomes. Materials and methods: We queried Ovid Medline 1946 -, Embase 1947 -, Scopus 1823 -, the Cochrane Library, clinicaltrials.gov 1997 - April 17, 2018, and IEEE Xplore Digital Library and Engineering Village through April 18, 2018, for studies utilizing wearable technology in clinical outcome prediction. Studies were deemed relevant to the research question if they involved human subjects, used wearable technology that tracked a health-related parameter, and incorporated data from wearable technology into a predictive model of mortality, readmission, and/or emergency department (ED) visits. Results: Eight unique studies were directly related to the research question, and all were of at least moderate quality. Six studies developed models for readmission and two for mortality. In each of the eight studies, data obtained from wearable technology were predictive of or significantly associated with the tracked outcome. Discussion: Only eight unique studies incorporated wearable technology data into predictive models. The eight studies were of moderate quality or higher and thereby provide proof of concept for the use of wearable technology in developing models that predict clinical outcomes. Conclusion: Wearable technology has significant potential to assist in predicting clinical outcomes, but needs further study. Well-designed clinical trials that incorporate data from wearable technology into clinical outcome prediction models are required to realize the opportunities of this advancing technology. PMID- 29982521 TI - Can public financing of the private sector defeat antimicrobial resistance? AB - Public financing to incentivise private sector innovation in antimicrobial pharmaceuticals is believed by many to be necessary to defeat growing threats from antimicrobial resistance. Large cash incentives from the public sector are said to be essential to stimulate 'normal' market forces capable of unleashing much-needed innovation. However, there is little evidence to suggest that lack of innovation in drug development is peculiar to antimicrobials or that current deficits in the supply of antimicrobials is due to unique inefficiencies in the antimicrobial market. Neither the history of drug development in general nor of antimicrobial innovation in particular supports economic interventions intended to stimulate private sector supply of new antimicrobials. On the contrary, public underwriting of the private sector, which by definition is compelled to prioritise profit, risks dire consequences for future global health. PMID- 29982522 TI - Different Olfactory Percepts Evoked by Orthonasal and Retronasal Odorant Delivery. AB - The Duality of Smell hypothesis suggests odorants delivered orthonasally elicit different sensations compared with those delivered retronasally despite activating the same receptors in the olfactory epithelium. Presently, we investigated this further using a matching paradigm free from odorant or semantic memory bias. Subjects were asked to evaluate an aroma delivered in one condition (orthonasal or retronasal delivery) and match the same aroma from 4 unknowns evaluated in the same or different delivery conditions. Panelists matched flavors in 4 delivery conditions: orthonasal-orthonasal, retronasal-retronasal, retronasal-orthonasal, and orthonasal-retronasal. For orthonasal presentation, panelists smelled samples using their nostrils, and for retronasal presentation, panelists swallowed aqueous flavors. In Experiment 1, panelists were instructed to match familiar flavors (banana, grape, orange, raspberry). In Experiments 2 and 3, panelists used the same experimental design with either 4 unfamiliar flavors (kinnow, longan, pawpaw, prunus) or 4 distinct subtypes of a strawberry flavor (woody, green, ripe, candy). In Experiment 1, the number of correct matches in each condition did not significantly differ suggesting stability in the perceptual construct across delivery routes. However, in Experiments 2 and 3, significantly more samples were correctly matched in the orthonasal-orthonasal and retronasal-retronasal conditions compared with the retronasal-orthonasal or orthonasal-retronasal conditions suggesting aroma perception is dependent on delivery route. Additionally, across the 4 delivery methods, the ability to correctly match flavors decreased as flavor familiarity decreased or similarity increased and may reflect the different cognitive strategies employed by subjects when matching these stimuli. Our results suggest odorant percepts are route dependent and consistent with the Duality of Smell phenomenon. PMID- 29982523 TI - Effectiveness of provider price display in computerized physician order entry (CPOE) on healthcare quality: a systematic review. AB - Objective: To study the association between Electronic Health Record (EHR)/Computerized Physician Order Entry (CPOE) provider price display, and domains of healthcare quality (efficiency, effective care, patient centered care, patient safety, equitable care, and timeliness of care). Methods: Randomized and non-randomized studies assessing the relationship between healthcare quality domains and EHR/CPOE provider price display published between 1/1/1980 to 2/1/2018 were included. MEDLINE, Web of Science, and Embase were searched. Assessment of internal validity of the included studies was performed with a modified Downs-Black checklist. Results: Screening of 1118 abstracts was performed resulting in selection of 41 manuscripts for full length review. A total of 13 studies were included in the final analysis. Thirteen studies reported on efficiency domain, one on effectiveness and one on patient safety. Studies assessing relationship between provider price display and patient centered, equitable and timely care domains were not retrieved. Quality of the studies varied widely (Range 6-12 out of a maximum possible score of 13). Provider price display in electronic health record environment did not consistently influence domains of healthcare quality such as efficiency, effectiveness and patient safety. Conclusions: Published evidence suggests that price display tools aimed at ordering providers in EHR/CPOE do not influence the efficiency domain of healthcare quality. Scant published evidence suggests that they do not influence the effectiveness and patient safety domains of healthcare quality. Future studies are needed to assess the relationship between provider price display and unexplored domains of healthcare quality (patient centered, equitable, and timely care). Registration: PROSPERO registration: CRD42018082227. PMID- 29982524 TI - Geographical and temporal clustering of OXA-48-producing Escherichia coli ST410 causing community-onset urinary tract infection in Christchurch, New Zealand. PMID- 29982526 TI - Corrigendum to Reviewing the Risk of Colorectal Cancer in Inflammatory Bowel Disease After Liver Transplantation for Primary Sclerosing Cholangitis. PMID- 29982527 TI - Will a Single-Cycle Adenovirus Vaccine Be Effective Against Ebola Virus? PMID- 29982528 TI - Defining Endoscopic Remission in Ileocolonic Crohn's Disease: Let's Start from Scratch. AB - Endoscopic remission is the cornerstone of drug development and the guidance for daily clinical practice in Crohn's disease [CD]. However, although scoring systems for endoscopic activity in CD have been available for more than three decades, no consensus exists on the definition of endoscopic remission. In this viewpoint we describe the shortcomings of the current definition of endoscopic remission in ileocolonic CD and the essential requirements for a newly developed endoscopic scoring tool for endoscopic remission in CD. PMID- 29982529 TI - Associations Between Soluble LDLR and Lipoproteins in a White Cohort and the Effect of PCSK9 Loss-of-Function. AB - Context: Elevated circulating cholesterol-rich low-density lipoprotein (LDL) particles increase coronary artery disease risk. Cell-surface hepatic LDL receptors (LDLRs) clear 70% of these particles from circulation. The ectodomain of LDLR is shed into circulation, preventing it from removing LDL particles. The role that LDLR ectodomain shedding plays as a regulatory mechanism is unknown. Objective: We describe LDLR shedding via the relationships between circulating soluble LDLRs (sLDLRs) and serum lipoproteins, serum proprotein convertase subtilin/kexin type 9 (PCSK9; a negative regulator of LDLR), and clinical parameters in a white Canadian population. Design: Population-based, cross sectional study. Settings: Clinical Research Center, The Ottawa Hospital, and Faculty of Medicine, University of Ottawa. Participants: Two hundred seventy three white Canadians. Intervention: None. Main Outcome Measures: sLDLR measured by ELISA; serum lipids and PCSK9, PCSK9 genotypes, and clinical parameters from previous analyses. Results: sLDLRs correlated strongly with triglycerides (TG; r = 0.624, P < 0.0001) and moderately with LDL cholesterol (r = 0.384, P < 0.0001), and high-density lipoprotein cholesterol (r = -0.307, P = 0.0003). Only TG correlations were unaffected by PCSK9 variations. sLDLR levels were significantly elevated in those with TG >50th or LDL cholesterol >75th percentiles. Conclusions: Serum sLDLR levels correlate with several lipoprotein parameters, especially TG, and the presence of PCSK9 loss-of-function variants alters sLDLR levels and correlations, except for TG. Ectodomain LDLR shedding has a role in LDL metabolism, distinct from PCSK9, with interplay between these two pathways that regulate cell-surface LDLRs. Findings suggest alteration of LDLR shedding could emerge as a target to treat dyslipidemia. PMID- 29982530 TI - The influence of sigma factors and ribosomal recognition elements on heterologous expression of cyanobacterial gene clusters in Escherichia coli. AB - Cyanobacterial natural products offer new possibilities for drugs and lead compounds but many factors can inhibit the production of sufficient yields for pharmaceutical processes. While Escherichia coli and Streptomyces sp. have been used as heterologous expression hosts to produce cyanobacterial natural products, they have not met with resounding success largely due to their inability to recognize cyanobacterial promoter regions. Recent work has shown that the filamentous freshwater cyanobacterium Anabaena sp. strain PCC 7120 recognizes various cyanobacterial promoter regions and can produce lyngbyatoxin A from the native promoter. Introduction of Anabaena sigma factors into E. coli might allow the native transcriptional machinery to recognize cyanobacterial promoters. Here, all 12 Anabaena sigma factors were expressed in E. coli and subsets were found to initiate transcription from several cyanobacterial promoters based on transcriptional fusions to the chloramphenicol acetyltransferase (CAT) reporter. Expression of individual Anabaena sigma factors in E. coli did not result in lyngbyatoxin A production from its native cyanobacterial gene cluster, possibly hindered by deficiencies in recognition of cyanobacterial ribosomal binding sites by native E. coli translational machinery. This represents an important step toward engineering E. coli into a general heterologous expression host for cyanobacterial biosynthetic gene cluster expression. PMID- 29982532 TI - Boosting of Mucosal Immunity After Fractional-Dose Inactivated Poliovirus Vaccine. AB - Background: Inactivated poliovirus vaccine (IPV) boosts mucosal immunity in persons previously vaccinated with oral poliovirus vaccine (OPV). We assessed whether fractional-dose IPV (fIPV, 1/5th of full dose) administered intradermally also boosts mucosal immunity. Methods: Children 10-12 years old were enrolled in Sri Lanka and randomized to receive one dose IPV, fIPV, or no IPV vaccine. One month later, they received OPV challenge. Blood was collected at enrolment and before challenge; stool was collected at 3, 7, and 14 days post-challenge. Sera were analysed for presence of poliovirus neutralizing antibodies; stool was analysed for poliovirus. Results: We analysed 304/309 (98%) enrolled subjects. There were 16/97 (16%), 9/99 (9%), and 72/95 (76%) subjects excreting poliovirus after challenge in the IPV, fIPV and "No IPV Vaccine" study arms, respectively (P < .001 for comparison of IPV [or fIPV] vs "No IPV Vaccine"; P = .1 for comparisons of fIPV vs IPV). Relative decrease in excretion prevalence was 80% and 88% to IPV and fIPV, respectively, compared with the "No IPV Vaccine" control arm. Conclusions: Single fIPV dose boosted mucosal immunity to a similar degree as single full dose of IPV. This finding provides further evidence in support of fIPV for poliovirus outbreak response at the time of IPV global supply shortage. Clinical trials registration: Australia New Zealand Clinical Trial Registry ACTRN12616000124437p. PMID- 29982525 TI - Novel Concepts for Inducing Final Oocyte Maturation in In Vitro Fertilization Treatment. AB - Infertility affects one in six of the population and increasingly couples require treatment with assisted reproductive techniques. In vitro fertilization (IVF) treatment is most commonly conducted using exogenous FSH to induce follicular growth and human chorionic gonadotropin (hCG) to induce final oocyte maturation. However, hCG may cause the potentially life-threatening iatrogenic complication "ovarian hyperstimulation syndrome" (OHSS), which can cause considerable morbidity and, rarely, even mortality in otherwise healthy women. The use of GnRH agonists (GnRHas) has been pioneered during the last two decades to provide a safer option to induce final oocyte maturation. More recently, the neuropeptide kisspeptin, a hypothalamic regulator of GnRH release, has been investigated as a novel inductor of oocyte maturation. The hormonal stimulus used to induce oocyte maturation has a major impact on the success (retrieval of oocytes and chance of implantation) and safety (risk of OHSS) of IVF treatment. This review aims to appraise experimental and clinical data of hormonal approaches used to induce final oocyte maturation by hCG, GnRHa, both GnRHa and hCG administered in combination, recombinant LH, or kisspeptin. We also examine evidence for the timing of administration of the inductor of final oocyte maturation in relationship to parameters of follicular growth and the subsequent interval to oocyte retrieval. In summary, we review data on the efficacy and safety of the major hormonal approaches used to induce final oocyte maturation in clinical practice, as well as some novel approaches that may offer fresh alternatives in future. PMID- 29982531 TI - Genome Evolution of Bartonellaceae Symbionts of Ants at the Opposite Ends of the Trophic Scale. AB - Many insects rely on bacterial symbionts to supply essential amino acids and vitamins that are deficient in their diets, but metabolic comparisons of closely related gut bacteria in insects with different dietary preferences have not been performed. Here, we demonstrate that herbivorous ants of the genus Dolichoderus from the Peruvian Amazon host bacteria of the family Bartonellaceae, known for establishing chronic or pathogenic infections in mammals. We detected these bacteria in all studied Dolichoderus species, and found that they reside in the midgut wall, that is, the same location as many previously described nutritional endosymbionts of insects. The genomic analysis of four divergent strains infecting different Dolichoderus species revealed genes encoding pathways for nitrogen recycling and biosynthesis of several vitamins and all essential amino acids. In contrast, several biosynthetic pathways have been lost, whereas genes for the import and conversion of histidine and arginine to glutamine have been retained in the genome of a closely related gut bacterium of the carnivorous ant Harpegnathos saltator. The broad biosynthetic repertoire in Bartonellaceae of herbivorous ants resembled that of gut bacteria of honeybees that likewise feed on carbohydrate-rich diets. Taken together, the broad distribution of Bartonellaceae across Dolichoderus ants, their small genome sizes, the specific location within hosts, and the broad biosynthetic capability suggest that these bacteria are nutritional symbionts in herbivorous ants. The results highlight the important role of the host nutritional biology for the genomic evolution of the gut microbiota-and conversely, the importance of the microbiota for the nutrition of hosts. PMID- 29982533 TI - Human peroxidasin 1 promotes angiogenesis through ERK1/2, Akt and FAK pathways. AB - Aims: The term angiogenesis refers to sprouting of new blood vessels from pre existing ones. The angiogenic process involves cell migration and tubulogenesis requiring interaction between endothelial cells and the extracellular matrix. Human peroxidasin 1 (hsPxd01) is a multidomain heme peroxidase found embedded in the basement membranes. As it promotes the stabilization of extracellular matrix, we investigated its possible role in angiogenesis both in vitro and in vivo. Methods and Results: We analyzed the effects of peroxidasin 1 gene silencing and supplementation by recombinant hsPxd01 in TeloHAEC endothelial cells on cell migration, tubulogenesis in matrigel and intracellular signal transduction as assessed by kinase phosphorylation and expression of pro-angiogenic genes as measured by qRT-PCR. We further evaluated the angiogenic potential of recombinant peroxidasin in a chicken chorioallantoic membrane model. RNA silencing of endogenous hsPxd01 significantly reduced tube formation and cell migration, whereas supplementation by the recombinant peroxidase promoted tube formation in vitro and stimulated vascularization in vivo through its catalytic activity. Moreover, recombinant hsPxd01 promoted phosphorylation of Extracellular signal Regulated Kinases (ERK1/2), Protein kinase B (Akt) and Focal Adhesion Kinase (FAK), and induced the expression of pro-angiogenic downstream genes: Platelet Derived Growth Factor Subunit B (PDGFB), endothelial-derived Heparin Binding EGF like growth factor (HB-EGF), CXCL-1, Hairy-Related Transcription Factor 1 (HEY 1), DNA-binding protein inhibitor (ID-2), Snail Family Zinc Finger 1 (SNAI-1), as well as endogenous hsPxd01. However, peroxidasin silencing significantly reduced Akt and FAK phosphorylation but induced ERK1/2 activation after supplementation by recombinant hsPxd01. While hsPxd01 silencing significantly reduced expression of HEY-1, ID-2, and PDGFB, it did not affect expression of SNAI-1, HB-EGF and CXCL-1 after supplementation by recombinant hsPxd01. Conclusion: Our findings suggest a role of enzymatically active peroxidasin 1 as a pro-angiogenic peroxidase and a modulator of ERK1/2, Akt and FAK signaling. PMID- 29982534 TI - Inulin-Type Fructan Supplementation of 3- to 6-Year-Old Children Is Associated with Higher Fecal Bifidobacterium Concentrations and Fewer Febrile Episodes Requiring Medical Attention. AB - Background: Inulin-type fructans used in formula have been shown to promote microbiota composition and stool consistency closer to those of breastfed infants and to have beneficial effects on fever occurrence, diarrhea, and incidence of infections requiring antibiotic treatment in infants. Objectives: The primary study aim was to explore whether prophylactic supplementation with prebiotic fructans is able to influence the frequency of infectious diseases in kindergarten children during a winter period. A secondary objective was to ascertain the effect on the intestinal microbiota. Methods: 142 boys and 128 girls aged 3-6 y were randomly allocated to consume 6 g/d fructans or maltodextrin for 24 wk. At baseline, stool samples were collected for microbiota analysis and anthropometric measurements were made. During the intervention period diagnoses were recorded by physicians, whereas disease symptoms, kindergarten absenteeism, dietary habits, and stool consistency were recorded by parents. Baseline measurements were repeated at wk 24. Results: In total 219 children finished the study. Both the relative abundance of Bifidobacterium (P < 0.001) and that of Lactobacillus (P = 0.014) were 19.9% and 7.8% higher, respectively, post data normalization, in stool samples of children receiving fructans as compared with those of controls at wk 24. This was accompanied by significantly softer stools within the normal range in the prebiotic group from wk 12 onwards. The incidence of febrile episodes requiring medical attention [0.65 +/- 1.09 compared with 0.9 +/- 1.11 infections/(24 wk * child), P = 0.04] and that of sinusitis (0.01 +/- 0.1 compared with 0.06 +/- 0.25, P = 0.03) were significantly lower in the prebiotic group. The number of infectious episodes and their duration reported by parents did not differ significantly between the 2 intervention groups. Conclusions: Prebiotic supplementation modified the composition of the intestinal microbiota and resulted in softer stools in kindergarten-aged children. The reduction in febrile episodes requiring medical attention supports the concept of further studies on prebiotics in young children. This trial was registered at clinicaltrials.gov as NCT03241355. PMID- 29982535 TI - Lower Spine Volumetric Bone Density in Patients With a History of Epidural Steroid Injections. AB - Context: Epidural steroid injections (ESIs) are a common, effective treatment of lumbar radiculopathy and sciatica. Although the negative skeletal effects of oral glucocorticoids are well established, little is known about the impact of ESI on bone quality. Objective: To investigate the relationship between ESI exposure and volumetric bone mineral density (vBMD) at the lumbar spine (LS) using central quantitative CT. Design: Retrospective study. Setting: University hospital outpatient facility. Patients: All patients had CT scans of the LS between 2011 and 2016. Cases received at least three ESIs prior to the date of CT (n = 121). Controls were matched for age and sex (n = 121). Main Outcome Measures: Cumulative ESI dose was calculated. vBMD was measured at T12 through L5 using QCT Pro phantomless software (MindWays). Results: Mean age of subjects was 65 +/- 14 years, and 49% were women. Median number of ESIs was 4 (range: 3 to 16). Median cumulative ESI dosage was 340 mg of triamcinolone or equivalent (range: 150 to 1400 mg). Compared with controls, ESI subjects had lower vBMD at each vertebral level. Higher cumulative dose was associated with lower mean vBMD at T12 to L5 (r = -0.22, P = 0.02). Conclusions: Greater cumulative ESI dose was related to lower vBMD at the LS. To our knowledge, this is the first study to measure vBMD in patients treated with ESIs. Prospective studies are needed to confirm these findings and to help identify the best strategies for preventing bone loss in this population. PMID- 29982536 TI - PANCOSMA COMPARATIVE GUT PHYSIOLOGY SYMPOSIUM: ALL ABOUT APPETITE REGULATION: Effects of diet and gonadal steroids on appetite regulation and food intake of companion animals. AB - The prominent incidence of overweight and obese pet animals not only results in higher morbidity and mortality, but also poses a threat for the quality of life, longevity, and well-being of dogs and cats. To date, strategies to prevent BW gain or to induce weight loss have had modest success in the pet population. In part, due to the complexity and the multifactorial nature of this disease, which involves pet-human interaction, environmental and dietary factors, and an intertwined metabolic process that still is not fully understood. As such, research methods to investigate the role of physiological hormones and dietary management on mechanisms related to the control of feelings of satiety and hunger in pet animals is warranted. Increasing interest exists in exploring gut chemosensing mechanisms, the crosstalk between metabolic-active tissues, and the interface between the gut microbiota and the nervous system (gut-brain axis). The noninvasive nature of research conducted in companion animals focuses on systemic approaches to develop environmental, nutritional, or therapeutic interventions that can be translated from research settings to pet-owned households. Because the majority of the pet population is spayed or neutered, it is important to determine the effect that sex hormones might have on appetite regulation and fasting metabolic rate of these animals. In general, studies have revealed that gonadectomy may establish a new "set point" characterized by increased food intake and BW, accompanied by physiological and behavioral changes. Some studies have also shown associations between gonadectomy and alterations in appetite related hormones (e.g., ghrelin, leptin, adiponectin, glucagon-like peptide-1). Manipulation of macronutrients in diets of dogs and cats have also been investigated as a mean to improve satiety. Most of the research in this area has focused on high-protein diets, predominantly, for cats, and the use of dietary fiber sources of contrasting fermentability and viscosity profiles. Dietary fibers may affect the production of fermentative end products and gut microbiome, digestive and absorptive processes, appetite-related hormones, and promote "gut fill" and satiety. More recent studies have reported profound effects of dietary manipulation on the phylogeny and functional capacity of gut microbial communities of dogs and cats. PMID- 29982537 TI - East Asian variant of aldehyde dehydrogenase 2 is related to worse cardioprotective results after coronary artery bypass grafting. AB - OBJECTIVES: Aldehyde dehydrogenase 2 activity is associated with cardioprotection. Individuals carrying an East Asian variant of the ALDH2 genotype (ALDH2*2) have significantly reduced aldehyde dehydrogenase 2 activity. No previous studies have determined the effect of the ALDH2*2 genotype on cardioprotective results after coronary artery bypass grafting (CABG). METHODS: In total, 207 patients who underwent selective off-pump CABG were prospectively enrolled. Their baseline characteristics and clinical results were collected. Preoperative and postoperative circulating oxidative stress levels (serum malondialdehyde adducts and hydroxynonenal adducts) were measured. After genotyping, the oxidative stress levels and clinical results were compared between the ALDH2*2 carriers and non-carriers. RESULTS: ALDH2*2 carriers exhibited higher levels of malondialdehyde (P = 0.02) and hydroxynonenal (P = 0.03) adducts after CABG. ALDH2*2 carriers had higher postoperative troponin I levels (P = 0.01) and 24-h inotropic scores (P = 0.02). The intensive care unit time (P = 0.03) and postoperative length of stay (P = 0.03) were longer in ALDH2*2 carriers. The postoperative pulmonary infection rate was higher (P = 0.03) in ALDH2*2 carriers. CONCLUSIONS: Patients with the ALDH2*2 genotype had higher postoperative oxidative stress levels and poorer clinical results after CABG. Special cardioprotective techniques should be considered for patients with a history of 'facial flushing' when performing CABG. PMID- 29982538 TI - Physiological Glucocorticoid Replacement in Adrenal Insufficiency: Does It Fix the Broken Clock? PMID- 29982539 TI - Care Recipient Multimorbidity and Health Impacts on Informal Caregivers: A Systematic Review. AB - Background and Objectives: Caregiving outcomes have often been reported in terms of care recipients of single disease, rather than multiple health conditions. A systematic review was conducted to outline caregiving health outcomes and its association with care recipient multimorbidity for informal caregivers of older adults. Research Design and Methods: A search strategy was applied in six databases and grey literature. Inclusion criteria were primary observational studies on informal caregiving for care recipients aged 60 years and above, in the English language. Informal caregivers were those not formally hired and multimorbidity referred to presence of at least two health conditions. From a total of 2,101 titles, 230 abstracts were screened, and 19 articles were included. Quality assessment was conducted with application of the Newcastle Ottawa-Scale. Results: Health-related and caregiving-related outcomes have been assessed for informal caregivers of older adults with multimorbidity. Caregiver subjective burden was most commonly evaluated and often reported to be low to moderate. In association with care recipient multimorbidity, caregiver burden, quality of life, and perceived difficulty in assisting the older adults were examined in 14 of the studies with mixed results. Studies were heterogeneous, with nonuniform definitions of informal caregivers and multimorbidity as well as measurement tools. Discussion and Implications: This narrative review found that caring for older adults with multimorbidity impacts caregivers, although overall evidence is not conclusive. Despite caregiving-related outcomes being most commonly assessed among the caregivers, particularly subjective burden, findings suggest that it is worthwhile to examine other outcomes to enrich the evidence base. PMID- 29982540 TI - Simultaneous Determination of Amphetamine-Related New Psychoactive Substances in Urine by Gas Chromatography-Mass Spectrometry. AB - Despite the efforts to prevent the spread of new psychoactive substances (NPS) such as synthetic amphetamine derivatives, it is apparent that newer types of NPS are still emerging on the market in recent years. Due to high potential for their abuse, reliable analytical methods are required to determine these substances in biological samples. The objective of this study was to develop and validate the gas chromatography-mass spectrometric (GC-MS) method for the simultaneous determination of 13 amphetamine-related NPS (amphetamine; AP, 4 fluoroamphetamine; 4FA, methamphamine; MA, 4-fluoromethamphetamine; 4FMA, 4 chloroamphetamine; 4CA, para-methoxyamphetamine; PMA, 4-chloromethamphetamine; 4CMA, 6-(2-aminopropyl)benzofuran; 6APB, 4-methylenedioxyamphetamine; MDA, para methoxymethamphetamine; PMMA, 6-(2-methylaminopropyl)benzofuran; 6MAPB, 3,4 methylenedioxymethamphetamine; MDMA, 5,6-methylenedioxy-2-aminoindane; MDAI) in urine. The analytes were extracted at pH 7.4 by liquid-liquid extraction prior to their trifluoroacetyl derivatives and then analyzed by GC-MS. The validation parameters included selectivity, linearity, lower limits of quantification (LLOQ), intra and interday precision and accuracy, recovery and stability. The linear ranges were 2-100 ng/mL for AP, 4FA, 4FMA, 4CA, PMA, 6APB, MDA, and MDAI, 2-250 ng/mL for 4CMA, PMMA, and 6MAPB and 25-1,000 ng/mL for MA and MDMA, with acceptable coefficients of determination (r2 > 0.9963). The intra and interday precision were within 11.9 and 12.5%, while the intra and interday accuracies ranged from -10.6% to 13.0% and -11.0% to 6.8% for the nominal concentration at all studied levels, respectively. The LLOQs for each analyte were 2.0-25 ng/mL. The recoveries ranged from 69.3% to 96.4%. The short- and long-term variations of the analytes in urine were lower than 8.5 and 12.7%, indicating that the analytes are stable at least for 16 h at room temperature and for 7 days at 4 degrees C, respectively. The applicability of the method was examined by analyzing urine samples from drug abusers and was determined to be effective for detecting multiple drug use. PMID- 29982541 TI - Corrigendum: Chronic Inflammatory Pain Impairs mGluR5-Mediated Depolarization Induced Suppression of Excitation in the Anterior Cingulate Cortex. PMID- 29982542 TI - Continuity of GP care after the last hospitalization for patients who died from cancer, chronic obstructive pulmonary disease or heart failure: a retrospective cohort study using administrative data. AB - Background: Discharge from hospital to home can be a stressful experience for patients and carers. Contact with the GP is important to ensure continuity of care. Objectives: To investigate timing of contact with the GP and locum after the last hospitalization in the last year of life and to investigate patient and care characteristics related to contact with the GP within 2 days after discharge. Methods: Health insurance data were combined with data from Statistics Netherlands on patients who mainly received care at home in the last 4 months of life. Patients who died from cancer (n = 3014), chronic obstructive pulmonary disease (COPD, n = 195) or heart failure (n = 171) were compared. Results: First contact after hospital discharge was within 2 days for 51.7% of patients and within a week for 77.8% of patients. Patients who died from COPD or heart failure had contact less often than patients with cancer. Characteristics related to having contact within 2 days after discharge were older age, cause of death cancer, home death, timing of last hospitalization closer to death and contact with a locum in the week after discharge. Conclusion: Results may indicate that the GP is likely to visit patients with more care needs sooner. This would be in accordance with the finding that contact with the GP was more likely after a hospitalization closer to death and that contact within 2 days was related to contact with a locum within a week after discharge. Proactive care is necessary. This is a joint responsibility of GPs and medical specialists. PMID- 29982544 TI - High-dose omega-3 Fatty Acid Plus Vitamin D3 Supplementation Affects Clinical Symptoms and Metabolic Status of Patients with Multiple Sclerosis: A Randomized Controlled Clinical Trial. AB - Background: Combined omega-3 fatty acid and vitamin D supplementation may improve multiple sclerosis (MS) by correcting metabolic abnormalities and attenuating oxidative stress and inflammation. Objective: This study aimed to determine the effects of omega-3 fatty acid and vitamin D cosupplementation on the disability score and metabolic status of patients with MS. Methods: This was a randomized, placebo-controlled clinical trial with Expanded Disability Status Scale (EDSS) score and inflammation as primary outcomes and oxidative stress biomarkers and metabolic profile as secondary outcomes. Patients, aged 18-55 y, were matched for disease EDSS scores, gender, medications, BMI, and age (n = 53) and randomly received a combined 2 * 1000 mg/d omega-3 fatty acid and 50,000 IU/biweekly cholecalciferol supplement or placebo for 12 wk. The placebos were matched in colour, shape, size, packaging, smell, and taste with supplements. Fasting blood samples were collected at baseline and end of intervention to measure different outcomes. Multiple linear regression models were used to assess treatment effects on outcomes adjusting for confounding variables. Results: Patients taking omega-3 fatty acid plus vitamin D supplements showed a significant improvement in EDSS (beta -0.18; 95% CI: -0.33, -0.04; P = 0.01), compared with placebo. Serum high sensitivity C-reactive protein (beta -1.70 mg/L; 95% CI: -2.49, -0.90 mg/L; P < 0.001), plasma total antioxidant capacity (beta +55.4 mmol/L; 95% CI: 9.2, 101.6 mmol/L; P = 0.02), total glutathione (beta +51.14 umol/L; 95% CI: 14.42, 87.87 umol/L; P = 0.007), and malondialdehyde concentrations (beta -0.86 umol/L; 95% CI: -1.10, -0.63 umol/L; P < 0.001) were significantly improved in the supplemented group compared with the placebo group. In addition, omega-3 fatty acid and vitamin D cosupplementation resulted in a significant reduction in serum insulin, insulin resistance, and total/HDL-cholesterol, and a significant increase in insulin sensitivity and serum HDL-cholesterol concentrations. Conclusion: Overall, taking omega-3 fatty acid and vitamin D supplements for 12 wk by patients with MS had beneficial effects on EDSS and metabolic status. This trial was registered at the Iranian website (www.irct.ir) for registration of clinical trials as IRCT2017090133941N20. PMID- 29982543 TI - A Bibliometric Analysis of the Landscape of Cancer Rehabilitation Research (1992 2016). AB - Cancer rehabilitation research has accelerated as great attention has focused on improving survivorship care. Recent expert consensus has attempted to prioritize research needs and suggests greater focus on studying physical functioning of survivors. However, no analysis of the publication landscape has substantiated these proposed needs. This manuscript provides an analysis of PubMed indexed articles related to cancer rehabilitation published between 1992 and 2017. A total of 22 171 publications were analyzed using machine learning and text analysis to assess publication metrics, topic areas of emphasis, and their interrelationships through topic similarity networks. Publications have increased at a rate of 136 articles per year. Approximately 10% of publications were funded by the National Institutes of Health institutes and centers, with the National Cancer Institute being the most prominent funder. The greatest volume and rate of publication increase were in the topics of Cognitive and Behavioral Therapies and Psychological Interventions, followed by Depression and Exercise Therapy. Four research topic similarity networks were identified and provide insight on areas of robust publication and notable deficits. Findings suggest that publication emphasis has strongly supported cognitive, behavioral, and psychological therapies; however, studies of functional morbidity and physical rehabilitation research are lacking. Three areas of publication deficits are noted: research on populations outside of breast, prostate, and lung cancers; methods for integrating physical rehabilitation services with cancer care, specifically regarding functional screening and assessment; and physical rehabilitation interventions. These deficits align with the needs identified by expert consensus and support the supposition that future research should emphasize a focus on physical rehabilitation. PMID- 29982545 TI - Bone Mass, Microstructure, and Strength Can Discriminate Vertebral Fracture in Patients on Long-Term Steroid Treatment. AB - Context: Measurement of areal bone mineral density (aBMD) by dual-energy x-ray absorptiometry (DXA) was able to predict fracture risk. High-resolution peripheral quantitative computed tomography (HR-pQCT) yields additional information about volumetric bone mineral density (vBMD), microarchitecture, and strength that may increase our understanding of fracture susceptibility. Objective: To ascertain whether vBMD, microarchitecture, and estimated bone strength derived from HR-pQCT can discriminate vertebral fractures in patients with glucocorticoid-induced osteoporosis (GIOP) independent of aBMD. Design: A cross-sectional case-control study. Setting: Seven regional hospitals in Hong Kong. Patients: A total of 110 patients on long-term glucocorticoids with vertebral fracture, determined radiographically, and 110 patients on long-term glucocorticoids without fracture. Main Outcome Measures: We assessed vBMD, microarchitecture, and bone strength; aBMD; and fracture risk assessment tool (FRAX). Results: Patients with vertebral fracture had lower total vBMD and a thinner cortex at the distal tibia after adjustment for age, sex, and aBMD or FRAX. In the antiresorptive treatment-naive subgroup, patients with vertebral fracture also had lower total vBMD at both the distal radius and the tibia after adjustment for covariates. Lower total vBMD and a thinner cortex were also noticed in the nonosteoporotic or FRAX score of <10% subgroups with vertebral fracture and were also associated with increasing prevalence of vertebral fracture. Conclusion: Patients with GIOP and vertebral fracture have a significant reduction in total vBMD and cortical thinning independent of aBMD and FRAX. These changes may help identify high-risk patients in the subgroups currently considered to have low fracture risk as assessed by DXA or FRAX. PMID- 29982546 TI - Investigating the long-term stability of protein immunogen(s) for whole recombinant yeast-based vaccines. AB - Even today vaccine(s) remains a mainstay in combating infectious diseases. Many yeast-based vaccines are currently in different phases of clinical trials. Despite the encouraging results of whole recombinant yeast and yeast display, the systematic study assessing the long-term stability of protein antigen(s) in yeast cells is still missing. Therefore, in the present study, I investigate the stability of heterologous protein antigen in the cellular environment of Saccharomyces cerevisiae through Escherichia coli surface protein (major curlin or CsgA). Present biochemical data showed that the stationary-phase yeast cells were able to keep the antigen stable for almost 1 year when stored at 2 degrees C 8 degrees C and 23 degrees C-25 degrees C. Further, iTRAQ-based quantitative proteomics of yeast whole cell lysate showed that the level of heterologous fusion protein was low in cells stored at 23 degrees C-25 degrees C compared to those at 2 degrees C-8 degrees C. In the end, I also proposed a workable strategy to test the integrity or completeness of heterologous protein in the yeast cell. I believe that the observations made in the present study will be really encouraging for those interested in the development of a whole recombinant yeast based vaccine(s). PMID- 29982547 TI - Sign Language Skills Assessed Through a Sentence Reproduction Task. AB - The aim of this study is to analyze Italian Sign Language (LIS) linguistic skills in two groups of deaf signing children at different ages, and to compare their skills with those of a group of deaf signing adults. For this purpose, we developed a new Sentence Reproduction Task (SRT) for Italian Sign Language (LIS SRT), which we administered to 33 participants. Participants' scores and type of errors were analyzed to investigate similarities and differences related to both chronological age and age of LIS acquisition. Results showed that signs tended to be omitted more frequently by the younger children than both the older children and adults and that non-manual components produced simultaneously with manual components appear to be the most difficult linguistic elements to be acquired and mastered. Our results are compared to those of previous studies using SRTs for other signed languages. PMID- 29982549 TI - A usability and safety analysis of electronic health records: a multi-center study. AB - To characterize the variability in usability and safety of EHRs from two vendors across four healthcare systems (2 Epic and 2 Cerner). Twelve to 15 emergency medicine physicians participated from each site and completed six clinical scenarios. Keystroke, mouse click, and video data were collected. From the six scenarios, two diagnostic imaging, laboratory, and medication tasks were analyzed. There was wide variability in task completion time, clicks, and error rates. For certain tasks, there were an average of a nine-fold difference in time and eight-fold difference in clicks. Error rates varied by task (X-ray 16.7% to 25%, MRI: 0 to 10%, Lactate: 0% to 14.3%, Tylenol: 0 to 30%; Taper: 16.7% to 50%). The variability in time, clicks, and error rates highlights the need for improved implementation optimization. EHR implementation, in addition to vendor design and development, is critical to usable and safe products. PMID- 29982550 TI - Development of a genetic transformation toolkit for Brettanomyces bruxellensis. AB - Brettanomyces bruxellensis is usually considered a spoilage microorganism, responsible for significant economic losses during the production of fermented beverages such as wine, beer and cider, though for some styles of beer its influence is essential. In recent years, the competitiveness of this yeast in bioethanol production processes has brought to attention its broader biotechnological potential. Furthermore, the species has evolved key fermentation traits in parallel with Saccharomyces cerevisiae. Attempts to better understand B. bruxellensis physiology through genomics-driven research have been hampered by a lack of functional genomics tools. Genetic transformation for B. bruxellensis has only been developed recently and with limited efficiency. Here we describe gene transformation cassettes tailored for B. bruxellensis, which provide multiple drug-resistant markers and the ability to tag B. bruxellensis with different fluorescent proteins. All marker cassettes resulted in increased transformation efficiency compared to the maximum reported in literature, with one cassette, TDH1p natMX, showing five times greater efficiency. Transformation cassettes encoding fluorescent proteins enabled discrimination between subpopulations of transformed B. bruxellensis cells by flow cytometry and fluorescent microscopy. Thus, the genetic transformation toolkit described here unlocks several molecular applications such as strain tagging, insertional mutagenesis and potentially targeted gene deletion. PMID- 29982548 TI - Effect of UV irradiation on Sulfolobus acidocaldarius and involvement of the general transcription factor TFB3 in the early UV response. AB - Exposure to UV light can result in severe DNA damage. The alternative general transcription factor (GTF) TFB3 has been proposed to play a key role in the UV stress response in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. Reporter gene assays confirmed that tfb3 is upregulated 90-180 min after UV treatment. In vivo tagging and immunodetection of TFB3 confirmed the induced expression at 90 min. Analysis of a tfb3 insertion mutant showed that genes encoding proteins of the Ups pili and the Ced DNA importer are no longer induced in a tfb3 insertion mutant after UV treatment, which was confirmed by aggregation assays. Thus, TFB3 plays a crucial role in the activation of these genes. Genome wide transcriptome analysis allowed a differentiation between a TFB3-dependent and a TFB3-independent early UV response. The TFB3-dependent UV response is characterized by the early induction of TFB3, followed by TFB3-dependent expression of genes involved in e.g. Ups pili formation and the Ced DNA importer. Many genes were downregulated in the tfb3 insertion mutant confirming the hypothesis that TFB3 acts as an activator of transcription. The TFB3-independent UV response includes the repression of nucleotide metabolism, replication and cell cycle progression in order to allow DNA repair. PMID- 29982551 TI - Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications. AB - Children born small for gestational age (SGA), defined as a birth weight and/or length below -2 SD score (SDS), comprise a heterogeneous group. The causes of SGA are multifactorial and include maternal lifestyle and obstetric factors, placental dysfunction, and numerous fetal (epi)genetic abnormalities. Short-term consequences of SGA include increased risks of hypothermia, polycythemia, and hypoglycemia. Although most SGA infants show catch-up growth by 2 years of age, ~10% remain short. Short children born SGA are amenable to GH treatment, which increases their adult height by on average 1.25 SD. Add-on treatment with a gonadotropin-releasing hormone agonist may be considered in early pubertal children with an expected adult height below -2.5 SDS. A small birth size increases the risk of later neurodevelopmental problems and cardiometabolic diseases. GH treatment does not pose an additional risk. PMID- 29982552 TI - Effects of Plant Diversity, Vegetation Composition, and Habitat Type on Different Functional Trait Groups of Wild Bees in Rural Beijing. AB - The loss of flower-rich habitats and agricultural intensification have resulted in significant losses of wild bee diversity from agricultural landscapes that is increasingly threatening the pollination of zoochorous agricultural crops and agricultural sustainability. However, the links of different wild bee functional trait groups with habitat types and plant resources in agricultural landscapes remain poorly understood, thus impeding the formulation of effective policies for bee conservation. We therefore analyzed how bees representing different functional groups responded to variations in habitat type, vegetation composition and plant diversity. Natural shrubland sustained the highest diversity in bees overall, in large-sized bees, solitary bees and belowground-nesting bees, while each habitat harbored unique species. In half of the functional bee groups, species were negatively linked to tree coverage and herb coverage, respectively, while plant diversity was positively related to all functional groups except large-sized bees and aboveground-nesting bees. Overall bee abundance was positively related to abundance of plants in the Sympetalae, and negatively related to abundance of plants in the Archichlamydeae. Different bee functional groups showed distinct preferences for different plant communities. In order to conserve the diversity of wild bees across functional groups to optimize associated pollination services, a diverse habitat mosaic, and particularly plant species in Sympetalae need to be promoted in agricultural landscapes. Future studies should aim to enhance our understanding of plant-pollinator associations and specific food requirement of different wild bee species for their effective conservation. PMID- 29982553 TI - Insights and Implications of Genome-Wide Association Studies of Height. AB - Context: In the last decade, genome-wide association studies (GWASs) have catalyzed our understanding of the genetics of height and have identified hundreds of regions of the genome associated with adult height and other height related body measurements. Evidence Acquisition: GWASs related to height were identified via PubMed search and a review of the GWAS catalog. Evidence Synthesis: The GWAS results demonstrate that height is highly polygenic: that is, many thousands of genetic variants distributed across the genome each contribute to an individual's height. These height-associated regions of the genome are enriched for genes in known biological pathways involved in growth, such as fibroblast growth factor signaling, as well as for genes expressed in relevant tissues, such as the growth plate. GWASs can also uncover previously unappreciated biological pathways, such as the STC2/PAPPA/IGFBP4 pathway. The genes implicated by GWASs are often the same genes that are the genetic causes of Mendelian growth disorders or skeletal dysplasias, and GWAS results can provide complementary information about these disorders. Conclusions: Here, we review the rationale behind GWASs and what we have learned from GWASs for height, including how it has enhanced our understanding of the underlying biology of human growth. We also highlight the implications of GWASs in terms of prediction of adult height and our understanding of Mendelian growth disorders. PMID- 29982554 TI - Cardiac tamponade in catheter ablation of atrial fibrillation: German-wide analysis of 21 141 procedures in the Helios atrial fibrillation ablation registry (SAFER). AB - Aims: Catheter ablation is an established therapy in patients with symptomatic atrial fibrillation (AF) with increasing popularity. Pericardial effusion requiring intervention (PE) is one of the most threatening adverse outcomes. The aim of this study was to examine rates of PE after catheter ablation in a large 'real-world' data set in a German-wide hospital network. Methods and results: Using ICD and OPS codes, administrative data of 85 Helios hospitals from 2010 to 2017 was used to identify AF catheter ablation cases [Helios atrial fibrillation ablation registry (SAFER)]. PE occurred in 0.9% of 21 141 catheter ablation procedures. Patients with PE were significantly older, to a higher percentage female, had more frequently hypertension, mild liver disease, diabetes with chronic complications, and renal disease. Low hospital volume (<50 procedures per year) and radiofrequency ablation (vs. cryoablation) were significantly associated with PE. Using two logistic regression models, age, female gender, hypertension, mild liver disease, diabetes with chronic complications, renal disease, low hospital volume, and radiofrequency ablation remained independent predictors for PE. Conclusion: Overall PE rate was 0.9%. Predictors for PE occurrence involved factors ascribed to the patient (age, gender, comorbidities), the type of catheter ablation (radiofrequency), and the institution (low-volume centres). PMID- 29982555 TI - GH Therapy in Childhood Cancer Survivors: A Systematic Review and Meta-Analysis. AB - Background: GH deficiency (GHD) is common among childhood cancer survivors (CCSs) with history of tumors, surgery, and/or radiotherapy involving the hypothalamus pituitary region. We aimed to evaluate the effects of GH therapy (GHT) in CCSs on adult height, risk of diabetes mellitus, abnormal lipids, metabolic syndrome, quality of life, secondary tumors, and disease recurrence. Methods: We searched multiple databases for randomized and observational studies. Pairs of reviewers independently selected studies and collected data. Random effects meta-analysis was used to pool outcomes across the studies. Results: We included 29 observational studies at moderate to high risk of bias. Sixteen studies compared CCSs on GHT with those not on GHT (512 patients, GH dose: 0.3 to 0.9 IU/kg/week). GHT was significantly associated with height gain [standard deviation score, 0.61; 95% CI, 0.08 to 1.13] and was not significantly associated with the occurrence of secondary tumors [odds ratio (OR), 1.10; 95% CI, 0.72 to 1.67] or tumor recurrence (OR, 0.57; 95% CI, 0.31 to 1.02). Thirteen studies compared CCSs on GHT with normal age- or sex-matched controls or controls with idiopathic GHD or short stature. GHT was associated with either improved or unchanged risk of diabetes, lipid profiles, and metabolic syndrome. GHT was associated with improvements in quality of life. Conclusion: CCSs treated with GHT gain height compared with the untreated controls. GHT may improve lipid profiles and quality of life and does not appear to increase the risk of diabetes or the development of secondary tumors, although close monitoring for such complications remains warranted due to uncertainty in the current evidence. PMID- 29982556 TI - Dementia: is it time for targeted national screening? PMID- 29982557 TI - Compatibility of Maximum-Containment Virus-Inactivation Protocols With Identification of Bacterial Coinfections by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry. AB - Diagnostics and research analyses involving samples containing maximum containment viruses present unique challenges, and inactivation protocols compatible with downstream testing are needed. Our aim was to identify a validated viral inactivation protocol compatible with bacterial identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We assessed a panel of bacteria with 6 validated maximum containment virus-inactivation protocols and report that inactivation with TRIzol or gamma-irradiation is compatible with MALDI-TOF MS. The availability, simplicity, and rapidity of TRIzol inactivation make this method the more suitable choice. PMID- 29982558 TI - Improved biomedical term selection in pseudo relevance feedback. AB - Biomedical information retrieval systems are becoming popular and complex due to massive amount of ever-growing biomedical literature. Users are unable to construct a precise and accurate query that represents the intended information in a clear manner. Therefore, query is expanded with the terms or features that retrieve more relevant information. Selection of appropriate expansion terms plays key role to improve the performance of retrieval task. We propose document frequency chi-square, a newer version of chi-square in pseudo relevance feedback for term selection. The effects of pre-processing on the performance of information retrieval specifically in biomedical domain are also depicted. On average, the proposed algorithm outperformed state-of-the-art term selection algorithms by 88% at pre-defined test points. Our experiments also conclude that, stemming cause a decrease in overall performance of the pseudo relevance feedback based information retrieval system particularly in biomedical domain.Database URL: http://biodb.sdau.edu.cn/gan/. PMID- 29982559 TI - A database of wild rice germplasm of Oryza rufipogon species complex from different agro-climatic zones of India. AB - Rice is a staple food for the people of Asia that supplies more than 50% of the food energy globally. It is widely accepted that the crop domestication process has left behind substantial useful genetic diversity in their wild progenitor species that has huge potential for developing crop varieties with enhanced resistance to an array of biotic and abiotic stresses. In this context, Oryza rufipogon, Oryza nivara and their intermediate types wild rice germplasm/s collected from diverse agro-climatic regions would provide a rich repository of genes and alleles that could be utilized for rice improvement using genomics assisted breeding. Here we present a database of detailed information on 614 such diverse wild rice accessions collected from different agro-climatic zones of India, including 46 different morphological descriptors, complete passport data and DNA fingerprints. The information has been stored in a web-based database entitled 'Indian Wild Rice (IWR) Database'. The information provided in the IWR Database will be useful for the rice geneticists and breeders for improvement of rice cultivars for yield, quality and resilience to climate change.Database URL: http://nksingh.nationalprof.in: 8080/iwrdb/index.jsp. PMID- 29982560 TI - Mobility of Adult Tribolium castaneum (Coleoptera: Tenebrionidae) and Rhyzopertha dominica (Coleoptera: Bostrichidae) After Exposure to Long-Lasting Insecticide Incorporated Netting. AB - Stored products represent an enormous economic output, but insects regularly immigrate into stored products from the surrounding landscape throughout the postharvest supply chain. Long-lasting insecticide-incorporatednetting (LLIN), which usually contains an incorporated pyrethroid, has been used as part of a strategy to reduce the spread of malaria in tropical regions since the 1990s and has only recently been considered for its application in pre- and postharvest agricultural contexts. The goal of this study was to determine how short-term exposure to LLINs in the laboratory impacts the locomotory behavior and mortality for adult Tribolium castaneum (Herbst), (Coleoptera: Tenebrionidae) red flour beetle, and Rhyzopertha dominica (Fauvel), (Coleoptera: Bostrichidae) lesser grain borer, at different periods of time after exposure. Exposure to LLINs resulted in multiple-fold reductions in the distance moved and elevated angular velocity in both species that quickly took effect and persisted even after 168 h compared with adults exposed to control netting. R. dominica was somewhat more susceptible than T. castaneum to LLINs. Finally, the dispersal capacity of both species, measured as ability to move to a remote resource patch, was significantly impaired or absent after exposure to LLINs compared to adults exposed to control netting. Our results demonstrate that LLINs are a promising new technology for reducing infestation by stored product insects since even short exposures limit movement and ultimately lead to knockdown and death. PMID- 29982561 TI - Livable Environments and the Quality of Life of Older People: An Ecological Perspective. AB - Background and Objectives: The WHO "Framework for Policy for Healthy Ageing' (2015) focuses on the broader environment and the support it provides for everyday functioning of older people. The concept of "livability" supports this framework by providing a conceptualization of environments that support good quality of life. Research Design and Methods: This observational study used an ecological framework of livability to assess cross-sectional relationships between living environments and perceived quality of life among 4,028 respondents, aged 50-89 years who were surveyed in 2016. A 4-step hierarchical model regressed quality of life on individual resources (health, chronic conditions, SES), contextual variables (distance to health care; rural/urban setting), perceptions of housing and neighborhood environments (housing satisfaction, neighborhood quality, neighborhood social cohesion), and interactions between these levels of the ecological model. Results: As predicted, housing and neighborhood perceptions contributed an additional 5% variance to the model which explained 49% of quality of life. There were significant interactions between the contextual variables and qualities of housing and neighborhood. Discussion and Implications: These findings support the importance of material and social provisions of housing and neighborhoods to quality of life among older people. The ecological model highlights critical information provided by taking different levels of the environment and personal circumstances into account. The concept of "livability," focusing on perceptions of the environment, can assist a shift from seeking the universal ideal neighborhood toward understanding the ways in which different communities may achieve quality of housing and neighborhood facilities that meet community members' needs. PMID- 29982562 TI - Uninterrupted vs. interrupted periprocedural direct oral anticoagulants for catheter ablation of atrial fibrillation: a prospective randomized single-centre study on post-ablation thrombo-embolic and haemorrhagic events. AB - Aims: This prospective, randomized, single-centre study aimed to directly compare the safety and efficacy of uninterrupted and interrupted periprocedural anticoagulation protocols with direct oral anticoagulants (DOACs) in patients undergoing catheter ablation of non-valvular atrial fibrillation (NVAF). Methods and results: We randomly assigned 846 NVAF patients receiving DOACs prior to ablation to uninterruption (n = 422) or interruption (n = 424) of the DOACs on the day of the procedure. The primary endpoint was a composite of symptomatic thromboembolisms and major bleeding events within 30 days after the ablation. Secondary endpoints included symptomatic and silent thromboembolisms and major and minor bleeding events. The primary endpoint occurred in 0.7% of the uninterrupted DOAC group [1 transient ischaemic attack (TIA) and 2 major bleeding events] and 1.2% of the interrupted DOAC group (1 TIA and 4 major bleeding events) (P = 0.480). The incidence of major and minor bleeding was comparable between the two groups (0.5% vs. 0.9%, P = 0.345; 5.9% vs. 5.4%, P = 0.753). Silent cerebral ischaemic lesions (SCILs) were observed in 138 (20.9%) of the 661 patients undergoing post-ablation magnetic resonance (MR) imaging. The uninterrupted and interrupted DOAC groups revealed a similar incidence of SCILs (19.8% vs. 22.0%, P = 0.484) and percentage of SCILs with disappearance on follow up MR imaging (77.8% vs. 82.1%, P = 0.428). Conclusion: Both the uninterrupted and interrupted DOAC protocols revealed a low risk of symptomatic thromboembolisms and major bleeding events and similar incidence of SCILs and minor bleeding events and may be feasible for periprocedural anticoagulation in NVAF patients undergoing catheter ablation. PMID- 29982563 TI - Maternal and paternal preconception exposure to bisphenols and size at birth. AB - STUDY QUESTION: Are maternal and paternal preconception urinary bisphenol A (BPA) or bisphenol S (BPS) concentrations associated with offspring birth size? SUMMARY ANSWER: Maternal-but not paternal-preconception urinary BPA concentrations were associated with lower birth size among couples seeking fertility evaluation. WHAT IS KNOWN ALREADY: Prenatal BPA exposure has been previously associated with reduced birth size in some but not all epidemiologic studies. However, the potential effect of BPA exposure before conception in either parent is unknown. Data on BPS is practically absent. STUDY DESIGN, SIZE, DURATION: Ongoing prospective preconception cohort of women and men seeking fertility evaluation between 2005 and 2016 in a large fertility center in an academic hospital in Boston, MA, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the association between maternal and paternal preconception, as well as maternal prenatal urinary BPA and BPS concentrations, and size at birth among 346 singletons from couples recruited in the Environment and Reproductive Health (EARTH) Study using multivariable linear regression. Infant birth weight and head circumference were abstracted from delivery records. Mean preconception and prenatal exposures were estimated by averaging urinary ln-BPA and ln-BPS concentrations in multiple maternal and paternal urine samples collected before pregnancy, and maternal pregnancy samples collected in each trimester. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal preconception urinary BPA concentrations were inversely associated with birth weight and head circumference in adjusted models: each ln-unit increase was associated with a decrease in birth weight of 119 g (95% CI: -212, -27), and a head circumference decrease of 0.72 cm (95% CI: 1.3, -0.1). Additional adjustment by gestational age or prenatal BPA exposure modestly attenuated results. Women with higher prenatal BPA concentrations had infants with lower mean birth weight (-75 g, 95% CI: -153, 2) although this did not achieve statistical significance. Paternal preconception urinary BPA concentrations were not associated with either birth weight or head circumference. No consistent patterns emerged for BPS concentrations measured in either parent. LIMITATIONS, REASONS FOR CAUTION: We observed a strong negative association between maternal-but not paternal-preconception BPA concentrations and offspring birth size among a subfertile population. Although these results are overall consistent with prior studies on prenatal BPA exposure, these findings may not be generalizable to women without fertility concerns. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that the unexplored maternal preconception period may be a sensitive window for BPA effects on birth outcomes. STUDY FUNDING/COMPETING INTEREST(S): Work supported by Grants (ES R01 009718, ES 022955 and ES 000002) from the National Institute of Environmental Health Sciences (NIEHS). C.M. was supported by a post-doctoral fellowship award from the Canadian Institutes of Health Research. There are no competing interests to declare. PMID- 29982564 TI - Reduced Susceptibility of Homalodisca vitripennis (Hemiptera: Cicadellidae) to Commonly Applied Insecticides. AB - Pest management for the glassy-winged sharpshooter, Homalodisca vitripennis Germar (Hemiptera: Cicadellidae), in Kern County, California relies on the application of insecticides. These treatments have contributed to low H. vitripennis field counts since applications were initiated in 2001. However, densities have been high in recent years despite continued management, prompting efforts to evaluate the susceptibility of current populations to insecticides. H. vitripennis adults were subjected to bioassays with five commonly applied insecticides, and the results were compared to baseline toxicities determined in 2002. Two neonicotinoids, imidacloprid and thiamethoxam, were evaluated using systemic uptake bioassays. Contact toxicities of the neonicotinoid acetamiprid and pyrethroids bifenthrin and fenpropathrin were estimated using leaf dip bioassays. Dose-mortality responses were analyzed by probit analysis. For each compound, there was no significant difference in annual LC50 values determined over 2 yr. Compared to baseline toxicities, acetamiprid and bifenthrin were found to be significantly less toxic to H. vitripennis. The LC50 values of these two compounds increased sevenfold and 152-fold, respectively. Tests with the neonicotinoids revealed a trend of decreasing susceptibility levels within each season followed by reversion back to early season LC50 estimates in the following year. In addition, data showed seasonal and site variation in susceptibility to imidacloprid, possibly due to differential applications in nearby fields. PMID- 29982565 TI - Activity of dalbavancin and comparator agents against Gram-positive cocci from clinical infections in the USA and Europe 2015-16. AB - Background: Many infections due to Gram-positive cocci (GPC; staphylococci, streptococci and enterococci) regularly involve prolonged systemic antibiotic use. Dalbavancin has demonstrated activity against GPC isolates and has been approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults. Objectives: To evaluate the activity of dalbavancin against GPC isolated from a variety of infection types in the USA and Europe. Methods: A total of 14 319 Staphylococcus aureus, 1992 CoNS, 3269 beta-haemolytic streptococci (BHS), 2071 Enterococcus faecalis, 936 Enterococcus faecium, 71 Enterococcus gallinarum/casseliflavus and other Enterococcus spp., 3487 Streptococcus pneumoniae and 1063 viridans group streptococci (VGS) causing clinical infections were consecutively collected (2015-16) and tested for susceptibility by broth microdilution methods. Results: All S. aureus (36.4% MRSA) isolates were susceptible to dalbavancin, teicoplanin and vancomycin, while daptomycin and linezolid showed susceptibility rates of >99.9% (according to CLSI criteria). Dalbavancin MIC results were at least 16-fold lower than these comparators against all S. aureus. Dalbavancin was the most potent agent against CoNS [62.2%/59.6% methicillin-resistant (CLSI/EUCAST)], followed by daptomycin, linezolid and vancomycin. All vancomycin-susceptible E. faecalis isolates were inhibited by dalbavancin at <=0.25 mg/L (FDA susceptible breakpoint). Dalbavancin was very active against BHS (MIC90 0.03 mg/L) and the most active agent against S. pneumoniae and VGS (highest MIC 0.25 mg/L). Ceftriaxone, daptomycin, levofloxacin and vancomycin were also active (93.5%-100.0% susceptible) against VGS, whereas clindamycin, erythromycin, penicillin and tetracycline had lower activity. Conclusions: Dalbavancin appears to be a viable candidate for treating serious infections caused by GPC. PMID- 29982566 TI - Deriving Economic Models for Pea Aphid (Hemiptera: Aphididae) as a Direct-Pest and a Virus-Vector on Commercial Lentils. AB - The pea aphid, Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae), presents a dual threat to commercial pulse growers because it can inflict direct injury through feeding and indirect injury as a vector of two important viruses, Pea enation mosaic virus (PEMV) and Bean leafroll virus (BLRV). A decision support system is needed to help producers manage both of these threats in pulses. To address these gaps in lentil, Lens culinaris (Medikus) (Fabales: Fabaceae), we conducted field experiments near Moscow, Idaho in 2011 and 2012 with three objectives: 1) determine economic injury levels (EILs) for pea aphid in lentil based on the direct effects of their feeding on yield, 2) develop economic guidelines for treating aphids carrying PEMV or BLRV based on the impact on yield of virus inoculation at different times after crop emergence, and 3) provide a framework for using both of these decision tools as part of a comprehensive approach to pea aphid management in lentil. EILs were determined based on data from replicated field cage trials over 2 yr. Windows of economic vulnerability to viruses were determined based on artificial inoculation with viruses at different days after crop emergence over 2 yr. Both direct and indirect injury support tools can be parameterized with potential yields, market prices, and the costs of insecticide applications to guide treatment decisions. Together, the two tools comprise a decision support system for managing pea aphid acting as both a direct pest and as a vector of the viruses in lentils in the Palouse region of northern Idaho and southeastern Washington State. PMID- 29982567 TI - Mutation of FOP/FGFR1OP in mice recapitulates human short rib-polydactyly ciliopathy. AB - Skeletal dysplasias are a clinically and genetically heterogeneous group of bone and cartilage disorders. A total of 436 skeletal dysplasias are listed in the 2015 revised version of the nosology and classification of genetic skeletal disorders, of which nearly 20% are still genetically and molecularly uncharacterized. We report the clinical and molecular characterization of a lethal skeletal dysplasia of the short-rib group caused by mutation of the mouse Fop gene. Fop encodes a centrosomal and centriolar satellite (CS) protein. We show that Fop mutation perturbs ciliogenesis in vivo and that this leads to the alteration of the Hedgehog signaling pathway. Fop mutation reduces CSs movements and affects pericentriolar material composition, which probably participates to the ciliogenesis defect. This study highlights the role of a centrosome and CSs protein producing phenotypes in mice that recapitulate a short rib-polydactyly syndrome when mutated. PMID- 29982568 TI - Assessing the incidence trend and characteristics of eosinophilic esophagitis in children in Olmsted County, Minnesota. AB - Previous studies reported increased eosinophilic esophagitis (EoE) incidence in children. It is unclear whether this reported increased EoE incidence is true or due to increased recognition and diagnostic endoscopy among children. A population-based study that evaluated EoE incidence in OC, Minnesota, from 1976 to 2005 concluded that EoE incidence increased significantly over the past three 5-year intervals (from 0.35 [range: 0-0.87] per 100,000 person-years for 1991 1995 to 9.45 [range: 7.13-11.77] per 100,000 person-years for 2001-2005). The aim of this study is to assess the change of incidence and characteristics of EoE in children in the same population between 2005 and 2015 and compare the findings to those reported in the previous study. We retrospectively reviewed the electronic medical records from Olmsted Medical Center and Mayo Clinic between 2005 and 2015, using Rochester Epidemiology Project (REP) resources. All children with EoE diagnosis based on the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) guidelines were included. The incidence and characteristics of children with EoE during the study period were compared to those diagnosed between 1995 and 2005. The incidence of EoE in children adjusted for age and sex was 5.31 per 100,000 population person-years in 1995, 15.2 in 2005, and 19.2 in 2015. Change in annual incidence and seasonal variation were not significant, (P = .48) and (P = .32), respectively. Between 2005 and 2015, 73 children received an EoE diagnosis (boys 49; 67%) compared to 16 children (boys 10; 62.5) between 1995 and 2005. Mean (SD) age at diagnosis was 7.5 (5.2) and 12.8 (4.3) years, respectively. Symptoms differed by age of presentation, with vomiting the most common in children younger than 5 years (41.1% and 43.5%) and dysphagia in those older than 5 years (35.6% and 60.9%). The incidence of EoE was not increased for any specific age-group during the study period (P = .49). This study showed increased incidence of EoE in children in Olmsted County between 2005 and 2015 compared to the incidence between 1995 and 2005 (5.31 per 100,000 population person-years in 1995, 15.2 in 2005, and 19.2 in 2015). However, between 2005 and 2015, the change of incidence was not statically significant, (P = .48) despite the steady increase of EGD performed during the same time frame (64 in 2005 to 144 in 2015). By comparing children diagnosed between 2005 and 2015 to those diagnosed between 1995 and 2005, the mean age at diagnosis was younger in the former group, 7.5 versus 12.8 years. Vomiting replaced dysphagia as the most common clinical presentation. Otherwise, the presenting symptom of EoE in children remained consistent across specific age groups. PMID- 29982570 TI - Antimicrobial susceptibility testing of invasive isolates of Streptococcus pneumoniae from Canadian patients: the SAVE study, 2011-15. AB - Objectives: To assess antimicrobial susceptibility for 14 agents tested against 6001 invasive isolates of Streptococcus pneumoniae cultured from invasive patient samples from 2011 to 2015 as a part of the annual SAVE study. Methods: Isolates of S. pneumoniae were tested using the standard CLSI broth microdilution method (M07-A10, 2015) with MICs interpreted by CLSI M100 27th Edition (2017) MIC breakpoints. Results: From 2011 to 2015, small but significant increases (P <= 0.05) in the percentage susceptibility for penicillin (interpreted by all three CLSI MIC breakpoint criteria) (increase of 1.7%-3.2%), clindamycin (3.1%) and ceftriaxone (interpreted by non-meningitis and meningitis CLSI MIC breakpoint criteria) (1.1%-1.5%) were observed. Susceptibility rates for clarithromycin and other commonly tested antimicrobial agents remained unchanged (P > 0.05) over the 5 year period. Isolates with an MDR phenotype (resistance to three or more antimicrobial agent classes) decreased significantly (P < 0.001) from 8.5% in 2011 to 5.6% in 2015. Antimicrobial susceptibility rates were not generally associated (P > 0.05) with patient gender (exception: clarithromycin) but were associated (P <= 0.05) with patient age (chloramphenicol and clindamycin) or specimen source (penicillin, doxycycline, trimethoprim/sulfamethoxazole and clindamycin), as well as geographic location in Canada and concurrent resistance to penicillin or clarithromycin. Conclusions: The in vitro susceptibility of invasive isolates of S. pneumoniae in Canada to penicillin, clindamycin and ceftriaxone increased from 2011 to 2015, coincident with a significant decrease in MDR phenotypes. PMID- 29982569 TI - MORC Domain Definition and Evolutionary Analysis of the MORC Gene Family in Green Plants. AB - Microrchidia (MORC) proteins have been described as epigenetic regulators and plant immune mediators in Arabidopsis. Typically, plant and animal MORC proteins contain a hallmark GHKL-type (Gyrase, Hsp90, Histidine kinase, MutL) ATPase domain in their N-terminus. Here, 356 and 83 MORC orthologues were identified in 60 plant and 27 animal genomes. Large-scale MORC sequence analyses revealed the presence of a highly conserved motif composition that defined as the MORC domain. The MORC domain was present in both plants and animals, indicating that it originated in the common ancestor before the divergence of plants and animals. Phylogenetic analyses showed that MORC genes in both plant and animal lineages were clearly classified into two major groups, named Plants-Group I, Plants-Group II and Animals-Group I, Animals-Group II, respectively. Further analyses of MORC genes in green plants uncovered that Group I can be subdivided into Group I-1 and Group I-2. Group I-1 only contains seed plant genes, suggesting that Group I-1 and I-2 divergence occurred at least before the emergence of spermatophytes. Group I-2 and Group II have undergone several gene duplications, resulting in the expansion of MORC gene family in angiosperms. Additionally, MORC gene expression analyses in Arabidopsis, soybean, and rice revealed a higher expression level in reproductive tissues compared with other organs, and showed divergent expression patterns for several paralogous gene pairs. Our studies offered new insights into the origins, phylogenetic relationships, and expressional patterns of MORC family members in green plants, which would help to further reveal their functions as plant epigenetic regulators. PMID- 29982571 TI - Introduction to the SAVE study (2011-15): Streptococcus pneumoniae serotyping and antimicrobial susceptibility: Assessment for Vaccine Efficacy in Canada after the introduction of PCV-13. AB - Streptococcus pneumoniae continues to be an important bacterial pathogen associated with invasive (e.g. bacteraemia) and non-invasive (e.g. community acquired respiratory tract) infections worldwide. Surveillance studies conducted nationally and globally can assist in determining trends across geographical areas and allow comparisons between countries. SAVE is an ongoing, annual, national study focused on characterizing invasive isolates of S. pneumoniae obtained across Canada. This Supplement documents the initial 5 years of the SAVE study (2011-15) during which 6207 invasive isolates of S. pneumoniae were evaluated. The three manuscripts in this Supplement provide a comprehensive examination of the changing patterns of invasive S. pneumoniae obtained across Canada over a 5 year period. The data highlight the evolution of S. pneumoniae antimicrobial resistance and multidrug resistance, serotype distribution, genotypic relatedness and virulence under pressure by vaccination and antimicrobial usage. This allows both clinicians and researchers nationally and globally to view the current status of invasive pneumococcal infections in Canada. PMID- 29982572 TI - Analysis of multidrug resistance in the predominant Streptococcus pneumoniae serotypes in Canada: the SAVE study, 2011-15. AB - Objectives: This study assessed MDR invasive isolates of Streptococcus pneumoniae, in relation to serotype evolution in Canada between 2011 and 2015 as part of the annual SAVE study. Methods: As part of a collaboration between the Canadian Antimicrobial Resistance Alliance and Public Health Agency of Canada National Microbiology Laboratory, 6207 invasive isolates of S. pneumoniae were evaluated. All isolates were serotyped and had antimicrobial susceptibility testing performed, in accordance with CLSI guidelines (M07-A10, 2015). Complete susceptibility profiles were available for 6001 isolates. MDR was defined as resistance to three or more classes of antimicrobial agents (with penicillin MIC >=2 mg/L defined as resistant). Results: The overall rate of MDR S. pneumoniae was 6.2% (372/6001) in SAVE, decreasing significantly from 8.5% in 2011 to 5.6% in 2015 (P = 0.0041). MDR was observed in 32 serotypes, with serotypes 15A and 19A predominating (26.6% and 41.7% of the MDR isolates, respectively). The overall proportion of serotypes 19A, 7F and 33A decreased significantly (P < 0.0001) throughout the study. The annual proportion of serotypes 7C, 8, 9N, 10A, 20, 24F, 29, 31, 33F, 35B and 38 increased throughout the study; however, among these increasing serotypes, MDR was only notable (>5%) for 24F and 33F. Conclusions: In 2015, 56.3% of invasive MDR S. pneumoniae were serotypes included in the PCV-13 vaccine. PCV-13 includes the most commonly identified serotype, 19A; however, other increasingly important MDR serotypes, such as 15A, 24F and 33F, are notably not in the currently used vaccines. PMID- 29982573 TI - Molecular characterization of predominant Streptococcus pneumoniae serotypes causing invasive infections in Canada: the SAVE study, 2011-15. AB - Objectives: This study characterized the 11 most predominant serotypes of invasive Streptococcus pneumoniae infections collected by the annual SAVE study in Canada, between 2011 and 2015. Methods: A subset of the 11 most predominant serotypes (7F, 19A, 22F, 3, 12F, 11A, 9N, 8, 33F, 15A and 6C) collected by the SAVE study was analysed using PFGE and MLST, as well as PCR to identify pilus encoding genes. WGS analyses were performed on a subset of the above isolates plus a random selection of background strains. Results: Of the predominant serotypes analysed, 7F, 33F and 19A were obtained more commonly from children <6 years of age, whereas 15A, 6C, 22F and 11A were more common in adults >65 years of age. Pneumococcal pilus PI-1 was identified in antimicrobial-susceptible serotype 15A (61/212) and <10% of 6C isolates (16/188). PI-2 was found in serotype 7F (683/701) and two-thirds of 11A isolates (162/241). Only serotype 19A ST320 possessed both pili. Molecular and phylogenetic analyses identified serotypes 19A, 15A, 6C, 9N and 33F as highly diverse, whereas 7F, 22F and 11A demonstrated clonality. Antimicrobial resistance determinants were common within diverse serotypes, and usually similar within a clonal complex. Conclusions: Despite successful use of conjugate vaccines, S. pneumoniae remains a highly diverse organism in Canada. Several predominant serotypes, both antimicrobial susceptible and MDR, have demonstrated rapid clonal expansion or an increase in diversity. As S. pneumoniae continues to evolve in Canada, WGS will be a necessary component in the ongoing surveillance of antimicrobial-resistant and expanding clones. PMID- 29982574 TI - Evaluating a Health Care Disparity Among Marine Recruits Treated for Acute Appendicitis. AB - Introduction: One of the most common emergent surgical diseases encountered within the active duty (AD) military population is acute appendicitis, yet the rate of perforation among military members is lower than age-matched civilians in the USA. Among all demographics, a delay in presentation to surgical care has been associated with an increase in perforation rates and postoperative complications. A subset of the U.S. military population, the Marine Corps recruits (MCRs), are subjected to a unique and vigorous training environment which may result in delayed medical care. This retrospective study aims to evaluate if there is a delay in presentation and to investigate the surgical outcomes in MCR as compared with AD personnel and military health system beneficiaries with appendicitis. Materials and methods: A retrospective review was conducted on all MCRs, AD military personnel, and military health system beneficiaries between the ages of 17 and 25 who underwent surgical treatment of appendicitis between October 2006 and June 2013 at a single military hospital. Data collected included demographics, time from symptom onset to presentation, clinical and pathologic severity of appendicitis, postoperative complications, and length of stay. The primary outcome was the clinical severity of appendicitis. Secondary outcomes include length of stay and postoperative complications. An analysis of the data was performed using basic statistical methods, to include Fisher's exact, one-way ANOVA, and Kruskal-Wallis. Results: Of the 577 patients that were reviewed, there were 393 (68%) AD military and reserve members, 139 (24%) military health system beneficiaries, and 45 (8%) MCR. The population was 67% male and 68% Caucasian. The mean age was 21.6 years (SD 2.2). The rate of perforated appendicitis was significantly higher among MCR than among AD and beneficiaries (25% vs. 7% vs. 6%, respectively; p < 0.0001). MCR experienced significantly longer hospital lengths of stay (3.1 days vs. 1.7 days, p < 0.0001). Rates of readmission (20% vs. 6% vs. 4%; p = 0.002) and complications (40% vs. 8% vs. 9%; p < 0.0001) were higher among MCR. Among patients with perforated appendicitis (n = 47), MCR had longer delay to presentation for treatment than AD and beneficiaries, but this was not statistically significant (59.4 hours vs. 45.7 hours vs. 35 hours, respectively; p = 0.2). Conclusion: This retrospective review identifies that MCRs have a higher incidence of perforated appendicitis as compared with AD members and military health system beneficiaries. This distinguishes a unique health care disparity found within MCR which military health care providers must recognize. Identification of potential social factors, education of military health care providers, and earlier surgical evaluation may lead to improved outcomes. PMID- 29982575 TI - Effects of Treatment Delay on Efficacy of Tecovirimat Following Lethal Aerosol Monkeypox Virus Challenge in Cynomolgus Macaques. AB - Background: Tecovirimat (ST-246) is being developed as an antiviral therapeutic for smallpox for use in the event of an accidental or intentional release. The last reported case of smallpox was 1978 but the potential for use of variola virus for biowarfare has renewed interest in smallpox antiviral therapeutics. Methods: Cynomolgus macaques were challenged with a lethal dose of monkeypox virus (MPXV) by aerosol as a model for human smallpox and treated orally with 10 mg/kg tecovirimat once daily starting up to 8 days following challenge. Monkeys were monitored for survival, lesions, and clinical signs of disease. Samples were collected for measurement of viremia by quantitative real-time polymerase chain reaction, and for white blood cell counts. Results: Survival in animals initiating treatment up to 5 days postchallenge was 100%. In animals treated starting 6, 7, or 8 days following challenge, survival was 67%, 100%, and 50%, respectively. Treatment initiation up to 4 days following challenge reduced severity of clinical manifestations of infection. Conclusions: Tecovirimat treatment initiated up to 8 days following a lethal aerosol MPXV challenge improves survival and, when initiated earlier than 5 days after challenge, provides protection from clinical effects of disease, supporting the conclusion that it is a promising smallpox antiviral therapeutic candidate. PMID- 29982576 TI - A Positive Urine Alcohol with Negative Urine Ethyl-Glucuronide. AB - Urine ethanol is a common finding in urine drug-screening results. An unexpected finding of alcohol in urine can have serious implications for patients who have committed to pain-management contracts or are being counseled for substance abuse. Although laboratory screening for urine ethanol is highly specific and sensitive, the source of the ethanol can sometimes be unclear. This case report describes a 44-year-old Caucasian man with positive urine ethanol results who reported having abstained from alcohol. A test for urine ethyl-glucuronide and ethyl sulfate was used to validate the information in the patient history stating that the patient had not consumed alcohol for 1 year. Evaluation of the urinalysis results from the patient revealed fermentation in the context of glucosuria as the source of the urine ethanol. PMID- 29982577 TI - Perspectives on Expanded Scope of Practice in Cytotechnology. AB - Introduction: In an effort to identify professional trends while offering meaningful resources to support decision making in the cytopathology community, the ASC/ASCP Workgroup: Focusing on Emerging Roles in Cytopathology conducted several data collection activities to assess the current state and professional trends of cytotechnologist (CT) practice. This information is intended to inform evidence- based development of education and workforce model(s). Materials and Methods: Research was conducted through mixed-method data collection processes. These included the ASCP Board of Certification (BOC) Practice Analysis, focus groups used to gather qualitative data regarding the perceptions and experiences of current stakeholders in cytopathology through face-to-face discussion, and a RAND Delphi study conducted to gather qualitative data regarding the perspectives and "pulse" of decision makers influencing cytopathology practice. Results: Research findings reveal that practice patterns with new and emerging technologies are changing the workplace for many cytotechnologists. Cytotechnologists are increasingly performing tasks within the laboratory that extend beyond their formal training and are looking to professional societies to bridge the gap. Although many laboratory leaders embrace the use of cytotechnologists in expanded roles, regulatory restrictions and reimbursement rules are among acknowledged barriers to change. Conclusions: This study examines current marketplace needs and cytotechnologists' perceptions of their evolving workplace demands through qualitative data collection. This study provides a snapshot of the cur- rent climate of cytopathology and data that will help direct future education, personnel training needs, and staffing decisions. PMID- 29982578 TI - Changing Practice Patterns for Cytotechnologists: A Comparative Analysis of Data from the 2009 and 2015 ASCP BOC Practice Analysis Surveys. AB - Background: The American Society for Clinical Pathology (ASCP) Board of Certification (BOC) surveys US certified cytotechnologists (CTs) at approximately 5-year intervals to gain information about current practice patterns. Although the purpose of this survey is to inform valid content development for the BOC CT examination, comparative longitudinal analysis of the survey data provides information about changes in cytotechnology practice. Materials and Methods: BOC Practice Analysis Survey data for 2009 and 2015 were examined, comparing survey demographics and performance of laboratory tasks. The 2015 survey added tasks not previously surveyed and considered them emerging when performed by a majority of respondents. Results: Two hundred thirty-five participants completed the survey in 2015 and 151 in 2009. Respondents reported an overall decrease in performing conventional Papanicolaou tests (-25.3%). Respondents reported increases in morphologic tasks such cytologyehistology correlation (17.5%), cell-block interpretation (17.5%), and preliminary interpretation of histochemical stains (e.g., mucin and Grocott's methenamine silver stain) (16.7%), as well as quality assurance tasks. Majority-performed, newly surveyed tasks included touch prep preparation (57.8%) and interpretation (59.2%) and ancillary test triage (59.6%). Molecular tasks such as tumor identification (6.8%) and preparation of cytology specimens for oncology molecular testing (9.4%) did not meet majority reporting thresholds. Conclusions: Although performance of the Papanicolaou test is declining, CTs report increases in additional morphologic as well as other laboratory tasks. Emerging tasks (2015) focus on FNA specimens. Knowledge of cytology practice patterns will help guide development of education and training resources toward maintaining an appropriately trained workforce. PMID- 29982579 TI - Voices from the Field: Supporting the Educational Needs of Cytotechnologists. AB - Introduction: Sustaining a well-trained, competitive, and marketable cytotechnology workforce is a major goal of the American Society of Cytopathology/American Society for Clinical Pathology Workgroup Focusing on Emerging Roles in Cytopathology (ASC/ASCP Workgroup). This article describes the data collection initiatives performed by the Workgroup to confirm cytotechnologist (CT) perceived educational needs to keep pace with emerging practice changes in the workplace. In response to data collected, the Workgroup created Advanced Cytopathology Education (ACE)da unique, innovative educational resource designed to fulfill this need. Materials and Methods: Data collection efforts included annual needs assessment surveys to gauge CT participants' preferred topics and learning modalities. These data were used to design and prioritize ACE topics. Program evaluations were also administered to evaluate participants' perceptions of program quality and effectiveness at meeting their educational needs. Results: Research findings reveal CT education needs to align with emerging practice areas as reported in other Workgroup data collection efforts. The incorporation of new entry-level competencies in cytotechnology training programs prepares new CT graduates, but there is no standardized mechanism for formal, robust, and recognized ongoing education for other practicing CTs. Conclusions: This article highlights the educational endeavors carried out by the Workgroup in fulfilling the educational needs of practicing CTs as communicated through various data collection efforts. As CT responsibilities evolve, ASC and Workgroup efforts will continue to focus on providing educational support for current practicing CTs who need training in emerging practice areas. PMID- 29982580 TI - Serological Evidence for the Circulation of Ebolaviruses in Pigs From Sierra Leone. AB - Many human ebolavirus outbreaks have been linked to contact with wildlife including nonhuman primates and bats, which are assumed to serve as host species. However, it is largely unknown to what extent other animal species, particularly livestock, are involved in the transmission cycle or act as additional hosts for filoviruses. Pigs were identified as a susceptible host for Reston virus with subsequent transmission to humans reported in the Philippines. To date, there is no evidence of natural Ebola virus (EBOV) infection in pigs, although pigs were shown to be susceptible to EBOV infection under experimental settings. To investigate the potential role of pigs in the ecology of EBOV, we analyzed 400 porcine serum samples from Sierra Leone for the presence of ebolavirus-specific antibodies. Three samples reacted with ebolavirus nucleoproteins but had no neutralizing antibodies. Our results (1) suggest the circulation of ebolaviruses in swine in Sierra Leone that are antigenically related but not identical to EBOV and (2) could represent undiscovered ebolaviruses with unknown pathogenic and/or zoonotic potential. PMID- 29982581 TI - Low Rate of Return to Impact Activity Following Core Decompression for Femoral Head AVN in Military Servicemembers. AB - Introduction: Femoral head avascular necrosis (AVN) is a debilitating disease with core decompression commonly performed for early stage disease. However, the ability to return to high-activity levels following treatment is largely unknown. Materials and Methods: Active military patients undergoing core decompression for femoral head AVN were reviewed. Demographic variables were identified and visual analog pain data was collected at a minimum of 2-year post-surgery or prior to total hip arthroplasty (THA). Patient outcomes, need for THA, and ability to remain on active service were recorded from chart review. Imaging studies were reviewed to classify the lesion stage and size for correlation with progression to THA or discharge from military service. Results: A total of 29 active duty patients met inclusion criteria (22 male, 7 female; 32.3 years). Seven patients (24%) progressed to THA and they were more likely to have bilateral disease (86%) and be older (35.4 years versus 31.2 years). At final follow-up, 86% of patients had significant hip-related activity restrictions, with only 6 (21%) remaining on active military service. Neither Steinberg stage nor modified Kerboul necrotic angle was associated with progression to THA or military discharge. Conclusion: Military servicemembers undergoing core decompression for femoral head AVN experienced mild clinical improvement with moderate survivorship from THA (74%) at mid-term follow-up. However, servicemembers have a low likelihood of returning to preoperative physical function and running activities (13.7%). Older patients and those with bilateral disease were at a higher risk of progressing to THA. PMID- 29982582 TI - EpsN from Bacillus subtilis 168 has UDP-2,6-dideoxy 2-acetamido 4-keto glucose aminotransferase activity in vitro. AB - The gene epsN of Bacillus subtilis 168 was cloned and overexpressed in Escherichia coli. Purified recombinant EpsN is shown to be a pyridoxal 5' phosphate (PLP)-dependent aminotransferase by absorption spectroscopy, l cycloserine inhibition and reverse phase HPLC studies. EpsN catalyzes the conversion of UDP-2,6-dideoxy 2-acetamido 4-keto glucose to UDP-2,6-dideoxy 2 acetamido 4-amino glucose. Lys190 was found by sequence comparison and site directed mutagenesis to form Schiff base with PLP. Mutagenesis studies showed that, in addition to Lys190, Ser185, Glu164, Gly58 and Thr59 are essential for aminotransferase activity. PMID- 29982583 TI - Hydrocortisone Affects Fatigue and Physical Functioning Through Metabolism of Tryptophan: A Randomized Controlled Trial. AB - Context: Hydrocortisone (HC) treatment influences health-related quality of life (HRQOL) in secondary adrenal insufficiency (AI). Glucocorticoids regulate tryptophan metabolism through the kynurenine pathway, which modulates mood and energy homeostasis. Objective: This study investigated whether tryptophan metabolism mediated the effect of HC dose on HRQOL in patients with secondary AI. Design, Setting, and Patients: Forty-seven patients with secondary AI participated in this double-blind randomized controlled cross-over trial in the University Medical Center Groningen. Intervention: Patients were treated for two 10-week periods with a daily HC dose of 0.2 to 0.3 mg/kg and 0.4 to 0.6 mg/kg body weight, respectively. Main Outcome Measures: Diary data and questionnaires were used to assess HRQOL. Tryptophan, kynurenine and 3-hydroxykynurenine were measured in serum and dialyzed plasma and the kynurenine-to-tryptophan ratio (Kyn/Trp ratio) ratio was calculated. Results: A higher dose HC was associated with increased levels of tryptophan (95% CI for mean difference 0.37 to 12.5, P = 0.038), reduced levels of kynurenine (95% CI, -0.49 to -0.10, P = 0.004) and 3 hydroxykynurenine (95% CI, -10.6 to -2.35, P = 0.003), and a reduced Kyn/Trp ratio (95% CI, -0.84 to -0.50, P < 0.001). The Kyn/Trp ratio mediated the effect of a higher dose HC on fatigue (P = 0.041) and physical functioning (P = 0.005). Conclusion: Metabolism of tryptophan through the kynurenine pathway is reduced after a 10-week treatment with a higher dose HC and plays a role in the effect of HC on fatigue and physical functioning in patients with secondary AI. PMID- 29982584 TI - Interstitial Stereotactic Laser Anterior Corpus Callosotomy: A Report of 2 Cases with Operative Technique and Effectiveness. AB - BACKGROUND AND IMPORTANCE: Corpus callosotomy is an effective palliative treatment for medically intractable Lennox-Gastaut syndrome (LGS) that disrupts the interhemispheric synchronization of epileptiform discharges. However, traditional open corpus callosotomy carries a significant risk of surgical complications associated with craniotomy and a parafalcine approach to the corpus callosum. Here, we report 2 cases of anterior corpus callosotomy using MRI-guided stereotactic laser interstitial thermal therapy (LITT) as a minimally invasive technique for mitigating the risks of craniotomy while achieving favorable outcomes. CLINICAL PRESENTATION: Two patients with medically intractable LGS underwent stereotactic laser anterior corpus callosotomy using a 2 laser-fiber approach. Ablation of 70%-80% of the corpus callosum was confirmed by postoperative MRI diffusion tensor imaging and volumetric analysis. Marked reduction of epileptiform activity was observed in both patients during postoperative video-EEG studies as compared to preoperative video-EEG studies. Freedom from disabling seizures including drop attacks was achieved in 1 patient for 18 mo, and more than a 90% reduction of disabling seizures was achieved in the other patient for 7 mo with cognitive improvement and without surgical complications. CONCLUSION: These early data demonstrate the technical feasibility, safety, and favorable outcomes of MRI-guided stereotactic laser anterior corpus callosotomy in patients with LGS, making it a potentially safe and effective alternative to traditional open corpus callosotomy and other stereotactic methods including radiofrequency ablation and radiosurgery due to the ability to monitor the ablation in real time with MRI. PMID- 29982585 TI - Role of Fractional-Dose Intradermal Inactivated Poliovirus Vaccine in Halting Polio Transmission: Finding the Missing Piece for Global Polio Eradication. PMID- 29982587 TI - Glyco-Forum. PMID- 29982588 TI - Antigenic Drift of H7N9 Viral Hemagglutinin. AB - Background: Since its emergence in 2013, there have been five H7N9 influenza epidemic waves in China. However, evolution of the hemagglutinin (HA) antigenicity has not been systematically investigated. Methods: To better understand how antigenic drift in HA proteins of H7N9 occurs, 902 H7N9 HA sequences from public database were retrieved and analyzed. 53 mutants with single amino acid substitutions in HA were introduced into pseudoviruses and their antigenic characteristics were analyzed using pseudovirus-based assays. Results: Nine mutations incrementally increased over the past 5 years, with mutations identified at multiple sites. While mean neutralization titers of most variants remain unchanged, three mutations, A143V, A143T and R148K displayed a median 4-fold lower susceptibility to neutralization by antisera against A/Anhui/1/2013(H7N9) (A/Anhui). Notably, A143V and A143T were located outside the previously reported antigenic sites. The most dominant variant (A143V/R148K) in the most recent season constitutes 74.11% of all mutations and demonstrated a 10 fold reduction in its reactivity to A/Anhui antisera. Importantly, compared to DNA construct without the corresponding HA mutation, DNA vaccine encoding A143V/R148K mutant induced a 5-fold increase in the neutralizing activity against this circulating virus. Conclusions: Appropriate vaccine strain should be considered in response to increasing antigenic drift in H7N9 HA. PMID- 29982586 TI - Factors related to the participation and detection of lesions in colorectal cancer screening programme-based faecal immunochemical test. AB - Background: The overall aim of this study was to describe trends in participation rates and detection of lesions in a colorectal cancer (CRC) screening programme, during three rounds, using faecal immunochemical test (FIT). Methods: National registers were used to collect data on invitations for CRC screening in the Basque Country (Spain) from 2009 to 2014. Information about participation, age, gender and lesions in each round were collected. Results: A total of 961.533 individuals were included in the analysis; respectively, 584.950, 298.143 and 78.440 in the first, second and third rounds. The average participation rate was 68.4% (66.8, 70.4 and 72.3%, respectively by round; P < 0.001) and the positivity rate was 6.3% (7, 5.5 and 5.4%, respectively by round; P < 0.001). The participation rate increased significantly with age and was found to be higher in women versus men. A total of 15.144 advanced adenomas and 2.131 CRCs were diagnosed, leading to a detection rate of 23.9 and 3.40/00, respectively. Regarding gender, men had the highest rates in all periods and rounds. The detection rate of advanced neoplasia was lower in the regular when compared with irregular paricipants. Conclusions: In a CRC screening, this organization obtained high FIT participation rates. Older participants and women were associated with a higher participation. The detection rate of lesions was higher in men, independent on age and round. PMID- 29982589 TI - Rpd3L HDAC links H3K4me3 to transcriptional repression memory. AB - Transcriptional memory is critical for the faster reactivation of necessary genes upon environmental changes and requires that the genes were previously in an active state. However, whether transcriptional repression also displays 'memory' of the prior transcriptionally inactive state remains unknown. In this study, we show that transcriptional repression of ~540 genes in yeast occurs much more rapidly if the genes have been previously repressed during carbon source shifts. This novel transcriptional response has been termed transcriptional repression memory (TREM). Interestingly, Rpd3L histone deacetylase (HDAC), targeted to active promoters induces TREM. Mutants for Rpd3L exhibit increased acetylation at active promoters and delay TREM significantly. Surprisingly, the interaction between H3K4me3 and Rpd3L via the Pho23 PHD finger is critical to promote histone deacetylation and TREM by Rpd3L. Therefore, we propose that an active mark, H3K4me3 enriched at active promoters, instructs Rpd3L HDAC to induce histone deacetylation and TREM. PMID- 29982591 TI - Immune Responses and Hepatitis B Surface Antigen Loss After Cessation of Direct Antiviral Therapy in Hepatitis B e Antigen-Negative Patients. PMID- 29982590 TI - PbbHLH4 regulates floral monoterpene biosynthesis in Phalaenopsis orchids. AB - Floral scent is an important factor in attracting pollinators and repelling florivores. In Phalaenopsis bellina (Orchidaceae), the major floral scent components are monoterpenoids. Previously, we determined that expression of GERANYL DIPHOSPHATE SYNTHASE (PbGDPS) is highly correlated with monoterpene biosynthesis in Phalaenosis orchids. Here, we found that both cis- and trans regulation were present on the GDPS promoters, with trans-regulation playing a key role. To investigate the regulation of biosynthesis of floral scent, we compared the transcriptomic data of two Phalaenopsis orchids with contrasting scent phenotypes. Eight transcription factors (TFs) that exhibited sequential elevation in abundance through floral development in P. bellina were identified, and their transcript levels were higher in the scented orchid than the scentless one. Five of these TFs transactivated several structural genes involved in monoterpene biosynthesis including PbbHLH4, PbbHLH6, PbbZIP4, PbERF1, and PbNAC1. Ectopic transient expression of each of these TFs in scentless orchids resulted in stimulation of terpenoid biosynthesis. PbbHLH4 most profoundly induced monoterpene biosynthesis, with a 950-fold increase of monoterpenoid production in the scentless orchid. In conclusion, we determined that biosynthesis of orchid floral monoterpenes was sequentially regulated, with PbbHLH4 playing a crucial role for monoterpene biosynthesis. PMID- 29982592 TI - PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. AB - Aims: PCSK9 loss of function genetic variants are associated with lower low density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association. Methods and results: Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20 weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion. Conclusion: PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9. PMID- 29982593 TI - Black-White Breast Cancer Incidence Trends: Effects of Ethnicity. AB - Recent reports of converging black and white breast cancer incidence rates have gained much attention, potentially foreshadowing a worsening of the black-white breast cancer mortality disparity. However, these incidence rates also reflect the sum of non-Hispanics and Hispanics that may mask important ethnicity-specific trends. We therefore assessed race- and ethnicity-specific breast cancer trends using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 13 Registries Database (1992-2014). Age-period-cohort models projected rates for 2015-2030. Results confirmed merging of age-standardized incidence rates for blacks and whites circa 2012, but not for non-Hispanic black (NHB) and non-Hispanic white (NHW) women. Incidence rates were highest for NHW women (n = 382 290), followed by NHB women (n = 51 074), and then Hispanic white women (n = 48 651). The sample size for Hispanic blacks was too small for analysis (n = 693). Notably, future incidence rates are expected to slowly increase (2015 through 2030) among NHW women (0.24% per year, 95% confidence interval [CI] = 0.17 to 0.32) and slowly decrease for NHB women (-0.14% per year, 95% CI = -0.15 to -0.13). A putative worsening of the black-white mortality disparity, therefore, seems unlikely. Ethnicity matters when assessing race-specific breast cancer incidence rates. PMID- 29982594 TI - RBPJ binds to consensus and methylated cis elements within phased nucleosomes and controls gene expression in human aortic smooth muscle cells in cooperation with SRF. PMID- 29982595 TI - A Replicating Single-Cycle Adenovirus Vaccine Against Ebola Virus. AB - Recent West African Ebola virus (EBOV) epidemics have led to testing different anti-EBOV vaccines, including a replication-defective adenovirus (RD-Ad) vector (ChAd3-EBOV) and an infectious, replication-competent recombinant vesicular stomatitis virus expressing the EBOV glycoprotein (rVSV-EBOV; also known as rVSV ZEBOV). While RD-Ads elicit protection, when scaled up to human trials, the level of protection may be much lower than that of vaccines containing viruses that can replicate. Although a replication-competent Ad (RC-Ad) vaccine might generate a level of protection approximating that of rVSV, this infectious vector would also risk causing adenovirus disease. We recently described a "single-cycle" adenovirus (SC-Ad) vector that amplifies antigen genes like RC-Ad, but that avoids the risk of adenovirus infection. Here we have tested an SC-Ad6 vector expressing the glycoprotein (GP) from a 2014 EBOV strain in mice, hamsters, and rhesus macaques. We show that SC-Ad6-EBOV GP induces a high level of serum antibodies in all species and mediates significant protection against pseudo challenge with rVSV-EBOV expressing luciferase in mice and hamsters. These data suggest that SC-Ad6-EBOV GP may be useful during future EBOV outbreaks. PMID- 29982596 TI - Epididymal more than testicular abnormalities are associated with the occurrence of antisperm antibodies as evaluated by the MAR test. AB - STUDY QUESTION: Is there any association between mixed antiglobulin reaction (MAR) test positivity and clinical features or genital tract ultrasound (US) parameter values in males of infertile and fertile couples? STUDY ANSWER: In males of infertile and fertile couples MAR test positivity was associated with clinical and US features suggestive of chronic epididymal inflammation. WHAT IS KNOWN ALREADY: MAR test positivity has been more often reported in males of infertile couples than in fertile men. A positive MAR test has been detected in men with a history of testicular or post-testicular damage. No previous study has reported US alterations related to MAR test positivity. This is the first study that has systematically evaluated associations between a positive MAR test and clinical, seminal and US characteristics of the entire male genital tract. STUDY DESIGN, SIZE, DURATION: This cross-sectional analysis included 109 fertile men and 699 consecutive subjects seeking medical care for couple infertility from September 2012 to September 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent, in our outpatient clinic, a complete physical, endocrine, scrotal and transrectal US evaluation and semen analysis (including sIL-8) on the same day. Of the 699 males of infertile couples, 181 (age 38.6 +/- 6.6 years) had an assessable MAR test, whereas the test was assessable in all 109 fertile men (age 36.6 +/- 5.2 years). The associations among MAR test positivity and the other studied parameters were investigated on a caseload of 290 men (patients + fertile men) and in the two cohorts of males of infertile and fertile couples. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 181 men of infertile couples studied, 20 (11%) had a positive MAR test, including 12 (6.6%) who had a MAR test >= 50%, which is considered as a pathological threshold according to the WHO. Of the 109 fertile men, four (3.7%) had a positive MAR test, of which one (0.9%) had a MAR test >= 50%. MAR test positivity was therefore found more often in men of infertile couples (P < 0.05). In the entire caseload (n = 290) of males of both infertile and fertile couples, no correlations between MAR test positivity and seminal characteristics were observed. A positive MAR test was associated with epididymal US abnormalities, particularly with the mean size of the epididymal body and tail (both P < 0.0001), and in infertile men, a positive MAR test was also associated with an abnormal epididymal echotexture. In addition, subjects with a positive MAR test more frequently showed a history of epididymitis and high sIL-8 levels. Considering endocrine parameters, only a positive correlation between MAR test positivity and LH levels was observed, even after adjusting for age and life-style factors (adj. r = 0.232, P < 0.0001), while no associations with testosterone and FSH levels were found. LIMITATIONS, REASONS FOR CAUTION: Antisperm antibodies (ASA) were detected in this study by using the SpermMAR test IgG, but other tests are available. In addition, for technical reasons, the MAR test is not assessable in subjects with severe oligo-astheno-zoospermia and, therefore, this test may lead to an intrinsic selection bias. Finally, owing to the cross-sectional nature of the study, neither a causality hypothesis nor mechanistic models can be inferred. WIDER IMPLICATIONS OF THE FINDINGS: First, our results indicate that MAR test positivity is associated with clinical and US signs suggestive of chronic epididymal inflammation and not testicular damage. Hence, when investigating a subject with a positive MAR test, the epididymis and not just the testis should be evaluated. Furthermore, MAR test positivity was more often detected in males of infertile couples than in fertile men, but it was not associated with conventional semen parameter values. Our data support a role of ASA in couple infertility, regardless of the conventional sperm analysis. How ASA affects couple fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTEREST(S): Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A. PMID- 29982597 TI - Spatial Distribution of Necrophagous Flies of Infraorder Muscomorpha in Iran Using Geographical Information System. AB - Medically important flies that majority of them are classified to synanthropic flies can be mechanical vectors for some of contagious diseases to human and many animals. Also some species of their larvae are cause of myiasis in human and livestock animals. The aim of this study was to determine the geographical distribution of medically important flies in Iran using Geographical Information System (GIS). All published English and Persian documents on medically important flies of Iran from reliable medical sciences resources were gathered. A database was then designed in Excel format, including all available information regarding flies. The valid data were transferred to ArcGIS 10.3 to prepare the first spatial database of medically important flies and human myiasis foci of Iran. The Iran Medical Important Flies base includes 71 papers and three PhD/MSc theses, reporting studies conducted during 1977-2017. This database contains different available data covering their faunistic and all myiasis data reports related to flies of 102 species in nine families of medical important flies in Iran. Twenty three out of the 31 provinces of Iran, had some reports of medically important flies. However, these flies have high species diversity, wide geographical distribution and with various ecological niches in different provinces in Iran. Besides that, there are many high-risk foci of human myiasis in a number of provinces of Iran. PMID- 29982598 TI - MicroRNA Expression Profiling in Adrenal Myelolipoma. AB - Introduction: Adrenal myelolipoma (AML) is the second most common and invariably benign primary adrenal neoplasm. Due to the variable proportion of fat and hematopoietic elements and its often large size, it can cause differential diagnostic problems. Several reports confirmed the utility of miRNAs in the diagnosis of tumors, but miRNA expression in AML has not yet been investigated. Materials and Methods: Next-generation sequencing (NGS) was performed on 30 formalin-fixed, paraffin-embedded (FFPE) archived tissue samples [10 each of AML, adrenocortical adenoma (ACA), and adrenocortical carcinoma (ACC)]. Validation was performed by real-time quantitative reverse transcription polymerase chain reaction on a cohort containing 41 further FFPE samples (15 AML, 14 ACA, and 12 ACC samples). Circulating miRNA counterparts of significantly differentially expressed tissue miRNAs were studied in 33 plasma samples (11 each of ACA, ACC, and AML). Results: By NGS, 256 significantly differentially expressed miRNAs were discovered, and 8 of these were chosen for validation. Significant overexpression of hsa-miR-451a, hsa-miR-486-5p, hsa-miR-363-3p, and hsa-miR-150-5p was confirmed in AML relative to ACA and ACC. hsa-miR-184, hsa-miR-483-5p, and hsa-miR-183-5p were significantly overexpressed in ACC relative to ACA but not to AML. Circulating hsa-miR-451a and hsa-miR-363-3p were significantly overexpressed in AML, whereas circulating hsa-miR-483-5p and hsa-miR-483-3p were only significantly overexpressed in ACC vs ACA. Conclusions: We have found significantly differentially expressed miRNAs in AML and adrenocortical tumors. Circulating hsa-miR-451a might be a promising minimally invasive biomarker of AML. The lack of significantly different expression of hsa-miR-483-3p and hsa-miR 483-5p between AML and ACC might limit their applicability as diagnostic miRNA markers for ACC. PMID- 29982599 TI - Treponema denticola transcriptional profiles in serum-restricted conditions. AB - Treponema denticola is a major pathogen in periodontal disease, and is frequently isolated from the lesions of patients with chronic periodontitis. T. denticola utilizes serum components as nutrient sources so as to colonize and proliferate in the gingival crevice. However, the mechanisms of serum utilization remain unclear. Therefore, the aim of the present study was to identify T. denticola serum utilization genes. Precultured T. denticola cells were suspended in a tryptone-yeast extract-gelatin-volatile fatty acids medium containing 0, 1%, and 10% serum, respectively, and incubated anaerobically for 17 h. Total RNA was isolated, and T. denticola gene expression was compared by microarray and reverse transcription-polymerase chain reaction. In serum-depleted conditions, the expression levels of a potential hydroxylamine reductase, several ABC transporters, and phosphoenolpyruvate synthase were increased, while those of genes encoding methyl-accepting chemotaxis proteins and a transcriptional regulator were decreased. These results suggest that T. denticola may uptake serum components mainly through the action of ABC transporters. In particular, the decrease in the dmcA expression level with decreasing serum concentration suggests its involvement in chemotaxis toward serum-rich environments. PMID- 29982600 TI - Reflection on modern methods: selection bias-a review of recent developments. AB - Selection bias remains a more difficult bias to understand than confounding or measurement error. Past definitions have not always been illuminating and a simple method (such as the change-in-estimate method for confounding) has not been available to determine its presence and magnitude in the study sample. A better understanding of the nature of the bias has led to the definition of endogenous selection bias. It is the result of conditioning on a collider variable, itself caused by two other variables; the latter variables become spuriously associated. Conditioning on a variable in the analysis that is a collider or on an indicator of sample selection has the same effect. Note that selection bias is possible even in the absence of a collider, but in the presence of endogenous selection bias, the concern is whether it is possible to identify a causal effect in the sample. Conditions have been outlined to determine that. However, even if conditions are met to identify a causal effect in the study sample, its generalization to a defined target population is not a given.We discuss the concept of endogeneity and the sources of endogenous selection bias in observational studies. We then briefly address the terms generalizability, target population (or alternative formulations) and transportability. We outline the explicit conditions to identify causal effects in studies affected by selection bias: they involve exchangeability between exposed and unexposed and exchangeability between sampled and unsampled. We briefly describe methods to generalize estimated causal effects to the target population. The latter usually require data from the target population. Finally we discuss sensitivity analyses; some are limited to providing an indication of the presence and direction of the bias and others can provide corrected estimates with user-supplied selection bias parameters. PMID- 29982601 TI - Clinicopathologic features and BRCA mutations in primary fallopian tube cancer in Japanese women. AB - Objective: The present study aimed to clarify the clinicopathological features, including the level of p53 protein expression and BRCA mutations, of primary fallopian tube cancer (PFTC) in Japanese women. Methods: A multicenter clinical survey was conducted at three Japanese institutions. Clinical data in patients with PFTC between 1998 and 2016 were collected. Immunohistochemical staining of p53 and BRCA mutation analysis by exome sequence using paraffin-embedded surgical resected specimens were performed. Results: A total of 40 patients with PFTC were enrolled in the study. The median age was 58 years (range: 38-78 years); 31 patients were menopausal. Thirty-four (85.0%) patients were diagnosed with serous adenocarcinoma (high grade, 33; low grade, 1). PFTC was classified into ampulla type, fimbriae type and undeterminable type by tumor-occupying lesion; ampulla type and fimbriae type occurred with the same frequency. Among 30 patients with high-grade serous adenocarcinoma, 6 patients showed germline mutations of BRCA1 (stop-gain 4 and frameshift deletion 2) and 2 patients showed germline mutation of BRCA2 (stop-gain 1 and frameshift deletion 1). However, only 1 patient had familial history of breast or ovarian cancer. Patients with BRCA mutations in the germline were frequently observed in ampulla type and FIGO stage I/II cancers, but no significant difference in the frequency of p53 overexpression and overall survival was observed. Conclusions: Among Japanese patients with PFTC, 26.7% presented with BRCA mutations in the germline. Additionally, p53 was important for the carcinogenesis in fallopian tubes, independent of the specific BRCA mutation. PMID- 29982602 TI - Susceptibility of low-density lipoprotein particles to aggregate depends on particle lipidome, is modifiable, and associates with future cardiovascular deaths. AB - Aims: Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results: We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion: Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD. PMID- 29982604 TI - Dystonin-A3 upregulation is responsible for maintenance of tubulin acetylation in a less severe dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI. AB - Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) is a recessive human disease that arises from mutations in the dystonin gene (DST; also known as Bullous pemphigoid antigen 1 gene). A milder form of HSAN-VI was recently described, resulting from loss of a single dystonin isoform (DST-A2). Similarly, mutations in the mouse dystonin gene (Dst) result in severe sensory neuropathy, dystonia musculorum (Dstdt). Two Dstdt alleles, Dstdt-Tg4 and Dstdt-27J, differ in the severity of disease. The less severe Dstdt-Tg4 mice have disrupted expression of Dst-A1 and -A2 isoforms, while the more severe Dstdt-27J allele affects Dst-A1, -A2 and -A3 isoforms. As dystonin is a cytoskeletal-linker protein, we evaluated microtubule network integrity within sensory neurons from Dstdt-Tg4 and Dstdt-27J mice. There is a significant reduction in tubulin acetylation in Dstdt-27J indicative of microtubule instability and severe microtubule disorganization within sensory axons. However, Dstdt-Tg4 mice have no change in tubulin acetylation, and microtubule organization was only mildly impaired. Thus, microtubule instability is not central to initiation of Dstdt pathogenesis, though it may contribute to disease severity. Maintenance of microtubule stability in Dstdt-Tg4 dorsal root ganglia could be attributed to an upregulation in Dst-A3 expression as a compensation for the absence of Dst-A1 and -A2 in Dstdt-Tg4 sensory neurons. Indeed, knockdown of Dst-A3 in these neurons resulted in a decrease in tubulin acetylation. These findings shed light on the possible compensatory role of dystonin isoforms within HSAN-VI, which might explain the heterogeneity in symptoms within the reported forms of the disease. PMID- 29982603 TI - Comparative Genomics of Nonoutbreak Pseudomonas aeruginosa Strains Underlines Genome Plasticity and Geographic Relatedness of the Global Clone ST235. AB - Pseudomonas aeruginosa is an important opportunistic pathogen in hospitals, responsible for various infections that are difficult to treat due to intrinsic and acquired antibiotic resistance. Here, 20 epidemiologically unrelated strains isolated from patients in a general hospital over a time period of two decades were analyzed using whole genome sequencing. The genomes were compared in order to assess the presence of a predominant clone or sequence type (ST). No clonal structure was identified, but core genome-based single nucleotide polymorphism (SNP) analysis distinguished two major, previously identified phylogenetic groups. Interestingly, most of the older strains isolated between 1994 and 1998 harbored exoU, encoding a cytotoxic phospholipase. In contrast, most strains isolated between 2011 and 2016 were exoU-negative and phylogenetically very distinct from the older strains, suggesting a population shift of nosocomial P. aeruginosa over time. Three out of 20 strains were ST235 strains, a global high risk clonal lineage; these carried several additional resistance determinants including aac(6')Ib-cr encoding an aminoglycoside N-acetyltransferase that confers resistance to fluoroquinolones. Core genome comparison with ST235 strains from other parts of the world showed that the three strains clustered together with other Brazilian/Argentinean isolates. Despite this regional relatedness, the individuality of each of the three ST235 strains was revealed by core genome based SNPs and the presence of genomic islands in the accessory genome. Similarly, strain-specific characteristics were detected for the remaining strains, indicative of individual evolutionary histories and elevated genome plasticity. PMID- 29982605 TI - Reference Ranges and Determinants of Thyroid Function During Early Pregnancy: The SELMA Study. AB - Context: Establishing reference ranges as well as identifying and quantifying the determinants of thyroid function during pregnancy is important for proper clinical interpretation and optimizing research efforts. However, such data are sparse, specifically for triiodothyronine measurements, and most studies do not take into account thyroid antibodies or human chorionic gonadotropin. Objective: To determine reference ranges and to identify/quantify determinants of TSH, free T4 (FT4), free triiodothyronine (FT3), total T4 (TT4), and total triiodothyronine (TT3). Design, Setting, and Participants: This study included 2314 participants of the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study, a population-based prospective pregnancy cohort of mother-child pairs. Reference ranges were calculated by 2.5th to 97.5th percentiles after excluding thyroperoxidase antibody (TPOAb)-positive and/or thyroglobulin antibody (TgAb) positive women. Intervention: None. Main Outcome Measures: TSH, FT4, FT3, TT4, and TT3 in prenatal serum. Results: After exclusion of TPOAb-positive women, reference ranges were as follows: TSH, 0.11 to 3.48 mU/L; FT4, 11.6 to 19.4 pmol/L; FT3, 3.72 to 5.92 pg/mL; TT4, 82.4 to 166.2 pmol/L; and TT3, 1.28 to 2.92 nmol/L. Additional exclusion of TgAb-positive women did not change the reference ranges substantially. Exposure to tobacco smoke, as assessed by questionnaires and serum cotinine, was associated with lower TSH and higher FT3 and TT3. Body mass index (BMI) and gestational age were the main determinants of TSH (only for BMI), FT4, FT3, TT4, and TT3. Conclusions: We show that the exclusion of TgAb positive women on top of excluding TPOAb-positive women hardly affects clinical reference ranges. We identified various relevant clinical determinants of TSH, FT4, FT3, TT4, and TT3 that could reflect endocrine-disrupting effects and/or effects on thyroid hormone transport or deiodination. PMID- 29982606 TI - Validation of the Spanish Version of the Psychosocial Assessment Tool (PAT) in Pediatric Cancer. AB - Objective: Family psychosocial risk screening is an important initial step in delivering evidence-based care and in addressing health disparities. There is currently no validated measure of family psychosocial risk in Spanish. The Psychosocial Assessment Tool (PAT) is a brief parent report screener based on the trilevel Pediatric Preventative Psychosocial Risk Model (PPPHM; Universal, Targeted, and Clinical). The current article validates a Spanish version of the PAT (Version 3.0) in pediatric oncology. Method: Spanish-speaking Hispanic primary caregivers of 79 children newly diagnosed with cancer participated in this 4-institution multisite investigation, completing Spanish versions of the PAT and validation measures using REDCap. Results: Over 60% of the sample had a high school or lower level of education and they primarily identified as Hispanic in terms of acculturation. Internal consistency for the total score (KR20 = 0.76) and the Social Support, Child Problems, Sibling Problems, and Family Problems subscales was strong (KR20 = 0.69-0.79). Stress Reactions, Family Structure, and Family Beliefs subscales were lower (KR20 = 0.43-0.55). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Nearly two-thirds of the sample scored in the Targeted or Clinical range of the PPPHM. The PAT was successful in identifying clinical cases. Conclusions: The Spanish version of the PAT can be used with families of children newly diagnosed with cancer. Elevated psychosocial risks were found and warrant particular attention in providing psychosocial care attentive to the needs of Spanish-speaking families. PMID- 29982607 TI - Glycosuria amount in response to hyperglycaemia and risk for diabetic kidney disease and related events in Type 1 diabetic patients. AB - Background: Hyperglycaemia impairs tubulo-glomerular feedback. We tested whether variable tubulo-glomerular feedback during hyperglycaemia contributes to renal risk heterogeneity seen in Type 1 diabetes. Methods: During the period 1990-92, we studied the tubulo-glomerular feedback in Type 1 diabetic patients at high or low renal risk [21 of 54 with glomerular hyperfiltration and/or microalbuminuria against 11 of 55 with normal glomerular filtration rate (GFR) and urinary albumin despite uncontrolled diabetes]. The GFR, effective renal plasma flow, mean arterial pressure and fractional reabsorptions of glucose, osmols, sodium and lithium were measured sequentially during normo- and hyperglycaemia. All patients were followed up until 2016 for incident proteinuria, estimated GFR <60 mL/min/1.73 m2, doubling of serum creatinine, end-stage renal disease or all cause death. Results: Glycaemia increased from 6.1 +/- 1.3 to 15.1 +/- 1.9 mmol/L in both high-risk and low-risk patients. Glycosuria was lower in the high- versus low-risk patients: 0.34 +/- 0.25 versus 0.64 +/- 0.44 mmol/min (P = 0.03). Both groups displayed similar kidney function during normoglycaemia. Hyperglycaemia increased more importantly GFR and fractional reabsorptions, and pre-glomerular vasodilatation in the high- than in the low-risk patients (all P < 0.05). Over 21 years, 31.5% high- versus 12.7% low-risk patients developed endpoints (adjusted P = 0.006). In a multi-adjusted survival analysis of patients having undergone renal tests, each 0.10 mmol/min glycosuria during hyperglycaemia reduced the outcome risk by 0.72 (95% confidence interval 0.49-0.97, P = 0.03). Conclusions: Reduced tubulo-glomerular feedback and glycosuria during hyperglycaemia indicate high renal risk for Type 1 diabetic patients. Inter-individual variability in tubulo-glomerular feedback activity determines renal risk in Type 1 diabetes. PMID- 29982609 TI - Corrigendum. PMID- 29982608 TI - Angiotensin-related genetic determinants of cardiovascular disease in patients undergoing hemodialysis. AB - Background: Cardiovascular mortality in patients receiving dialysis remains unacceptably high, with unexplained ancestry differences suggesting a genetic component. Methods: We analyzed DNA samples from 37% of subjects enrolled in the EValuation Of Cinacalcet Hydrochloride (HCl) Therapy to Lower CardioVascular Events (EVOLVE) trial, a randomized trial conducted in patients receiving hemodialysis with secondary hyperparathyroidism, comparing cinacalcet to placebo on a background of usual care. DNA was analyzed for single-nucleotide polymorphisms (SNPs) in the genes encoding the angiotensin-converting enzyme receptor type I (AGTR1) and angiotensin-converting enzyme (ACE). Survival analyses were conducted separately in European Ancestry (EA) and African Ancestry (AfAn) due to known differences in cardiovascular events, minor alleles for the same variant and the frequency of minor alleles. Our primary determination was a meta-analysis across both races. Results: Meta-analysis showed significant associations between rs5186 in AGTR1 and increased rates by 25-34% for the primary endpoint (composite of death or nonfatal myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event), all-cause mortality, cardiovascular mortality and heart failure; all P < 0.001. Three correlated SNPs in ACE were associated with lower rates of sudden cardiac death (SCD) in EA samples. One ACE SNP, rs4318, only found in the AfAn samples, was associated with a lower rate of SCD in the AfAn samples. Conclusions: The C allele in rs5186 in AGTR1 was associated with higher rates of death and major cardiovascular events in a meta-analysis of EA and AfAn patients with end-stage kidney disease. SNPs in ACE were associated with SCD. PMID- 29982610 TI - Vegetarian diets and chronic kidney disease. AB - While dietary restriction of protein intake has long been proposed as a possible kidney-protective treatment, the effects of changes in the quality of ingested proteins on the prevalence and risk of progression of chronic kidney disease (CKD) have been scarcely studied; these two aspects are reviewed in the present article. The prevalence of hypertension, type 2 diabetes and metabolic syndrome, which are the main causes of CKD in Western countries, is lower in vegetarian populations. Moreover, there is a negative relationship between several components of plant-based diets and numerous factors related to CKD progression such as uraemic toxins, inflammation, oxidative stress, metabolic acidosis, phosphate load and insulin resistance. In fact, results from different studies seem to confirm a kidney-protective effect of plant-based diets in the primary prevention of CKD and the secondary prevention of CKD progression. Various studies have determined the nutritional safety of plant-based diets in CKD patients, despite the combination of a more or less severe dietary protein restriction. As observed in the healthy population, this dietary pattern is associated with a reduced risk of all-cause mortality in CKD patients. We propose that plant-based diets should be included as part of the clinical recommendations for both the prevention and management of CKD. PMID- 29982611 TI - Inferring Ancient Relationships with Genomic Data: A Commentary on Current Practices. AB - Contemporary phylogeneticists enjoy an embarrassment of riches, not only in the volumes of data now available, but also in the diversity of bioinformatic tools for handling these data. Here, I discuss a subset of these tools I consider well suited to the task of inferring ancient relationships with coding sequence data in particular, encompassing data generation, orthology assignment, alignment and gene tree inference, supermatrix construction, and analysis under the best fitting models applicable to large-scale datasets. Throughout, I compare and critique methods, considering both their theoretical principles and the details of their implementation, and offering practical tips on usage where appropriate. I also entertain different motivations for analyzing what are almost always originally DNA sequence data as codons, amino acids, and higher-order recodings. Although presented in a linear order, I see value in using the diversity of tools available to us to assess the sensitivity of clades of biological interest to different gene and taxon sets and analytical modes, which can be an indication of the presence of systematic error, of which a few forms remain poorly controlled by even the best available inference methods. PMID- 29982612 TI - Influenza A (H7N9) virus evolution: Which genetic mutations are antigenically important? PMID- 29982613 TI - The Influenza Vaccine Mess. PMID- 29982615 TI - Impact of Powdered Vancomycin on Preventing Surgical Site Infections in Neurosurgery: A Systematic Review and Meta-analysis. AB - BACKGROUND: Surgical site infections (SSIs) after spine and brain surgery present a major burden to patients and hospitals by increasing morbidity, mortality, and healthcare costs. OBJECTIVE: To review available literature investigating the role of intrawound powdered vancomycin against SSIs after neurosurgical operations. METHODS: All randomized and observational English language studies of intrawound powdered vancomycin use in spinal and cranial surgery were included and analyzed using random-effects modeling. RESULTS: In spine surgery (25 studies with 16 369 patients), patients in the vancomycin group had a significantly lower risk for any SSI (odds ratio [OR]: 0.41; 95% confidence interval [CI]: 0.30-0.57; P < .001; I2 = 47%). However, when separate analyses were conducted for superficial and deep SSIs, a significant difference was found only for deep (OR: 0.31; 95% CI: 0.22-0.45; P < .001; I2 = 29%). Subgroup analyses for different vancomycin powder dosages (1 g vs 2 g vs composite dose) did not point to any dose-related effect of vancomycin. In cranial surgery (6 studies with 1777 patients), use of vancomycin was associated with a significantly lower risk for SSIs (OR: 0.33; 95% CI: 0.18-0.60; P = .0003; I2 = 45%). In meta-regression analysis, trial-level variability of diabetes had no influence on the association of vancomycin powder use with SSIs. CONCLUSION: Use of vancomycin powder in spinal and cranial surgery might be protective against SSIs, especially against deep SSIs. No dose-related effect of vancomycin powder was identified. However, caution is needed in the clinical interpretation of these results, owing to the observational design of the included studies in this meta-analysis. PMID- 29982614 TI - Copper and zinc sources and levels of zinc inclusion influence growth performance, tissue trace mineral content, and carcass yield of broiler chickens. AB - A 35-d experiment was conducted in broilers to study the effect of supplementation of sulfate or hydroxychloride forms of Zn and Cu at 2 supplemental Zn levels on growth performance, meat yield, and tissue levels of Zn. On day 0, 900 male Ross 308 broiler chicks (45 +/- 1.10 g) were allocated to 4 treatments in a randomized complete block design and 2 * 2 factorial arrangement of treatments. The factors were 2 sources (sulfate or hydroxychloride) of Zn and Cu and 2 levels (low or high) of Zn. The Zn sources were zinc sulfate monohydrate (ZSM) or hydroxychloride Zn. Copper sources were copper (II) sulfate pentahydrate or hydroxychloride Cu. Each of the 4 treatments had 15 replicates and 15 birds per replicate. Birds were weighed on days 0, 21, and 35 for growth performance. On day 35, left tibia bone, liver, and blood were collected from 4 randomly selected birds per pen. In addition, 7 birds per pen were used for carcass evaluation. There was no significant source * level interaction on any of the growth performance response. Broiler chickens receiving hydroxychloride Zn and Cu had greater (P < 0.05) gain: feed, whereas broiler chickens receiving lower Zn level had greater (P < 0.01) weight gain. There was no source * level interaction on meat yield. Broiler chickens receiving hydroxychloride Zn and Cu had greater (P < 0.05) % breast yield than those receiving sulfate Zn and Cu. Higher level of Zn, irrespective of source, produced greater (P < 0.01) tibia and plasma Zn levels, whereas liver Cu was greater (P < 0.05) in broiler chickens receiving hydroxychloride Zn and Cu. It was concluded that hydroxychloride Zn and Cu were more efficacious than sulfate Zn and Cu in promoting growth performance and enhancing meat yield in the current study. PMID- 29982616 TI - The RCR and ATP/O Indices Can Give Contradictory Messages about Mitochondrial Efficiency. AB - Mitochondrial efficiency is typically taken to represent an animal's capacity to convert its resources into ATP. However, the term mitochondrial efficiency, as currently used in the literature, can be calculated as either the respiratory control ratio, RCR (ratio of mitochondrial respiration supporting ATP synthesis to that required to offset the proton leak) or as the amount of ATP generated per unit of oxygen consumed, ATP/O ratio. The question of how flexibility in mitochondrial energy properties (i.e., in rates of respiration to support ATP synthesis and offset proton leak, and in the rate of ATP synthesis) affects these indices of mitochondrial efficiency has tended to be overlooked. Furthermore, little is known of whether the RCR and ATP/O ratio vary in parallel, either among individuals or in response to environmental conditions. Using data from brown trout Salmo trutta we show that experimental conditions affect mitochondrial efficiency, but the apparent direction of change depends on the index chosen: a reduction in food availability was associated with an increased RCR (i.e., increased efficiency) but a decreased ATP/O ratio (decreased efficiency) in liver mitochondria. Moreover, there was a negative correlation across individuals held in identical conditions between their RCR and their ATP/O ratio. These results show that the choice of index of mitochondrial efficiency can produce different, even opposing, conclusions about the capacity of the mitochondria to produce ATP. Neither ratio is necessarily a complete measure of efficiency of ATP production in the living animal (RCR because it contains no assessment of ATP production, and ATP/O because it contains no assessment of respiration to offset the proton leak). Consequently, we suggest that a measure of mitochondrial efficiency obtained nearer to conditions where respiration simultaneously offsets the proton leak and produce ATP would be sensitive to changes in both proton leakage and ATP production, and is thus likely to be more representative of the state of the mitochondria in vivo. PMID- 29982618 TI - Low-voltage SEM contrasts of steel surface studied by observations and electron trajectory simulations for GEMINI lens system. AB - Scanning electron microscopy (SEM) is a powerful tool for observing the surface of materials. Modern SEM systems have multiple detectors with different geometries. Consequently, the SEM image contrast depends on the instrument and experimental conditions even for the same sample. Understanding the SEM imaging mechanism is necessary to clarify SEM contrast. In this paper, low-voltage (LV) SEM image contrast is investigated by comparing LV-SEM images and electron trajectory simulation results. Surface observations of oxides on a steel surface, positive charging contrast and topographic contrast in the image systematically changed with the working distance (WD). The electron trajectory simulation revealed the sharing of emitted electrons by the in-lens and Everhart-Thornley detectors, and systematic changes in the electron sharing caused by changes in WD. The image contrast was reasonably explained by the kinetic energy and take off angle (acceptance plots) of the detected electrons derived by the electron trajectory simulations. This approach is essential to understanding the SEM image contrast obtained by SEM systems with multiple detectors. Thorough image simulations based on acceptance plots are required in future work. PMID- 29982617 TI - Time-lapse imaging of molecular evolution by high-throughput sequencing. AB - High-throughput sequencing of in vitro selection could artificially provide large quantities of relic sequences from known times of molecular evolution. Here, we demonstrate how it can be used to reconstruct an empirical genealogical evolutionary (EGE) tree of an aptamer family. In contrast to classical phylogenetic trees, this tree-diagram represents proliferation and extinction of sequences within a population during rounds of selection. Such information, which corresponds to their evolutionary fitness, is used to infer which sequences may have been mutated through the selection process that led to the appearance and spreading of new sequences. This approach was validated by the re-analysis of an in vitro selection that had previously identified an aptamer against Annexin A2. It revealed that this aptamer might be the descendant of a sequence that was more highly amplified in early rounds. It also succeeded in predicting improved variants of this aptamer and providing a means to understand the influence of selection pressure on evolution. This is the first demonstration that HTS can provide time-lapse imaging of the evolutionary pathway that is taken by a macromolecule during in vitro selection to evolve by successive mutations through better fitness. PMID- 29982619 TI - Transport and metabolic engineering of the cell factory Corynebacterium glutamicum. AB - Corynebacterium glutamicum has a long and successful history in the biotechnological production of the amino acids l-glutamate and l-lysine. In the recent years, C. glutamicum has been engineered for the production of a broad catalog of value-added compounds including organic acids, vitamins, terpenoids and proteins. Moreover, this bacterium has been engineered to realize a flexible carbon source concept enabling product formation from various second generation feedstocks without competing uses in human and animal nutrition. In this review, we highlight transport engineering to improve product export and substrate uptake or to avoid loss of intermediates by excretion as well as the application of new metabolic engineering concepts for C. glutamicum strain development including the use of designed synthetic Escherichiacoli-C. glutamicum consortia. As examples, pathway extension of l-lysine and l-glutamate biosynthesis to produce derived value-added chemicals is described. The described examples of C. glutamicum strain engineering reflect strategies to cope with the increasing complexity of biotechnological processes that are required for successful applications in the bioeconomy. PMID- 29982620 TI - Dietary Intake in Relation to Military Dietary Reference Values During Army Basic Combat Training; a Multi-center, Cross-sectional Study. AB - Introduction: The military dietary reference intakes (MDRIs), outlined in Army Regulation 40-25, OPNAVINST 10110.1/MCO10110.49, AFI 44-141, establish standards intended to meet the nutrient requirements of Warfighters. Therefore, the purpose of this study was to comprehensively compare the revised MDRIs, published in 2017, with estimated dietary intakes in U.S. military personnel. Materials and Methods: During this cross-sectional study, Block food frequency questionnaires were administered at the end of the 9-week basic combat training course to estimate dietary intake during basic combat training in male (n = 307) and female (n = 280) recruits. The cut-point method was used to determine nutrient adequacy in comparison to the MDRIs. This study was approved by the Institutional Review Board of the U.S. Army Research Institute of Environmental Medicine. Results: Recruits consumed an adequate amount of vitamins A, C and K, as well as the B vitamins, and phosphorus, selenium, zinc, and protein and carbohydrate as a percentage of total calories when compared with MDRI standards. Vitamin D was the short-fall nutrient affecting the greatest number of participants, as 55 and 70% of males and females, respectively, consumed less than 33% of the MDRI. In addition, less than 50% of males met the MDRI for linoleic and alpha-linolenic acid, fiber, vitamin E, magnesium, and potassium, and less than 50% of females met the MDRI for alpha-linolenic acid, fiber, vitamin E, calcium, iron, magnesium, and potassium. In contrast, fat and sodium were over-consumed by both males (78 and 87%, respectively) and females (73 and 72%, respectively). Conclusion: The main findings of this study were that vitamins D and E, magnesium, potassium, alpha-linolenic acid, and fiber were under consumed by male and female recruits while males also did not consume adequate linoleic acid and females did not consume adequate calcium and iron. Future prospective research studies are needed to determine possible health and performance impacts that may be associated with suboptimal intake of these nutrients. PMID- 29982621 TI - Group A Streptococcal Virulence: New Lessons. PMID- 29982622 TI - Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status. AB - T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 cells of mice and humans. This is achieved simply by resting Th1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-beta). We named the resulting Th1-derived Foxp3+ cells Th1reg cells. Mouse Th1reg cells showed an inducible Treg-like phenotype and suppressive ability both in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed mouse Th1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-beta-induced phosphorylation of Smad2/3 in Th1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with Th1reg cells. PMID- 29982623 TI - Towards the synthetic design of camelina oil enriched in tailored acetyl triacylglycerols with medium-chain fatty acids. AB - The ability to manipulate expression of key biosynthetic enzymes has allowed the development of genetically modified plants that synthesise unusual lipids that are useful for biofuel and industrial applications. By taking advantage of the unique activities of enzymes from different species, tailored lipids with a targeted structure can be conceived. In this study we demonstrate the successful implementation of such an approach by metabolically engineering the oilseed crop Camelina sativa to produce 3-acetyl-1,2-diacyl-sn-glycerols (acetyl-TAGs) with medium-chain fatty acids (MCFAs). Different transgenic camelina lines that had been genetically modified to produce MCFAs through the expression of MCFA specific thioesterases and acyltransferases were retransformed with the Euonymus alatus gene for diacylglycerol acetyltransferase (EaDAcT) that synthesises acetyl TAGs. Concomitant RNAi suppression of acyl-CoA:diacylglycerol acyltransferase increased the levels of acetyl-TAG, with up to 77 mole percent in the best lines. However, the total oil content was reduced. Analysis of the composition of the acetyl-TAG molecular species using electrospray ionisation mass spectrometry demonstrated the successful synthesis of acetyl-TAG containing MCFAs. Field growth of high-yielding plants generated enough oil for quantification of viscosity. As part of an ongoing design-test-learn cycle, these results, which include not only the synthesis of 'designer' lipids but also their functional analysis, will lead to the future production of such molecules tailored for specific applications. PMID- 29982624 TI - Characterization and Identification of Methods for Phenotyping Soybean Populations With Tolerance to the Soybean Aphid (Hemiptera: Aphididae). AB - The development of soybeans tolerant to the soybean aphid [Aphis glycines Matsumura (Hemiptera: Aphididae)] remains unexplored. The objectives of this research were to determine the susceptibility of two high-yielding soybean [Glycine max (L.) Merrill (Fabales: Fabaceae)] genotypes involved in a breeding platform to develop aphid-tolerant recombinant inbred lines (RILs); characterize the peroxidase activity and relative expression of peroxidase transcripts in the parents of RILs; and identify an assay to phenotype aphid-tolerant RILs. Enzyme kinetic assays documented the total peroxidase activity for tolerant (KS4202), susceptible (SD76R), and two high-yielding (U09-105007 and U11-611112) soybeans during two vegetative stages (V1 and V3) at three sampling days (D4, D6, and D8 after aphid introduction). Enzyme kinetic assays showed that V3 infested tolerant and U11-611112 plants had significantly higher peroxidase activity than their respective control plants at D4, and infested tolerant plants were also higher than control plants at D6. There were no apparent trends when comparing the expression of peroxidase-specific transcripts in the absence of aphids (basal levels) in both V1 and V3. Relative expression analyses of two peroxidase transcripts (PRX52 and PRX2) performed to compare differences among the soybean genotypes indicated that, despite basal levels being similar for the treatments analyzed, tolerant soybeans had a tendency for a higher expression of PRX52 in the presence of aphids. Based on the different patterns observed and the feasibility of analyses performed in this study, enzyme kinetics using V3 infested plants may be a marker for screening RILs in a breeding program targeting the development of aphid-tolerant soybeans. PMID- 29982626 TI - DA-6 promotes germination and seedling establishment from aged soybean seeds by mediating fatty acid metabolism and glycometabolism. AB - Soybean seeds contain higher concentrations of oil (triacylglycerol) and fatty acids than do cereal crop seeds, and the oxidation of these biomolecules during seed storage significantly shortens seed longevity and decreases germination ability. Here, we report that diethyl aminoethyl hexanoate (DA-6), a plant growth regulator, increases germination and seedling establishment from aged soybean seeds by increasing fatty acid metabolism and glycometabolism. Phenotypic analysis showed that DA-6 treatment markedly promoted germination and seedling establishment from naturally and artificially aged soybean seeds. Further analysis revealed that DA-6 increased the concentrations of soluble sugars, during imbibition of aged soybean seeds. Consistently, the concentrations of several different fatty acids in DA-6-treated aged seeds were higher than those in untreated aged seeds. Subsequently, qPCR analysis indicated that DA-6 induced the transcription of several key genes involved in the hydrolysis of triacylglycerol to sugars in aged soybean seeds. Furthermore, the activity in aged seeds of invertase, which catalyzes the hydrolysis of sucrose to form fructose and glucose, increased following DA-6 treatment. Altogether, DA-6 promotes germination and seedling establishment from aged soybean seeds by enhancing the hydrolysis of triacylglycerol and the conversion of fatty acids to sugars. PMID- 29982625 TI - SVEngine: an efficient and versatile simulator of genome structural variations with features of cancer clonal evolution. AB - Background: Simulating genome sequence data with variant features facilitates the development and benchmarking of structural variant analysis programs. However, there are only a few data simulators that provide structural variants in silico and even fewer that provide variants with different allelic fraction and haplotypes. Findings: We developed SVEngine, an open-source tool to address this need. SVEngine simulates next-generation sequencing data with embedded structural variations. As input, SVEngine takes template haploid sequences (FASTA) and an external variant file, a variant distribution file, and/or a clonal phylogeny tree file (NEWICK) as input. Subsequently, it simulates and outputs sequence contigs (FASTAs), sequence reads (FASTQs), and/or post-alignment files (BAMs). All of the files contain the desired variants, along with BED files containing the ground truth. SVEngine's flexible design process enables one to specify size, position, and allelic fraction for deletions, insertions, duplications, inversions, and translocations. Finally, SVEngine simulates sequence data that replicate the characteristics of a sequencing library with mixed sizes of DNA insert molecules. To improve the compute speed, SVEngine is highly parallelized to reduce the simulation time. Conclusions: We demonstrated the versatile features of SVEngine and its improved runtime comparisons with other available simulators. SVEngine's features include the simulation of locus-specific variant frequency designed to mimic the phylogeny of cancer clonal evolution. We validated SVEngine's accuracy by simulating genome-wide structural variants of NA12878 and a heterogeneous cancer genome. Our evaluation included checking various sequencing mapping features such as coverage change, read clipping, insert size shift, and neighboring hanging read pairs for representative variant types. Structural variant callers Lumpy and Manta and tumor heterogeneity estimator THetA2 were able to perform realistically on the simulated data. SVEngine is implemented as a standard Python package and is freely available for academic use . PMID- 29982627 TI - Clinical decision support directed to primary care patients and providers reduces cardiovascular risk: a randomized trial. AB - Objective: To test the hypothesis that use of a clinical decision support (CDS) system in a primary care setting can reduce cardiovascular (CV) risk in patients. Materials and Methods: Twenty primary care clinics were randomly assigned to usual care (UC) or CDS. For CDS clinic patients identified algorithmically with high CV risk, rooming staff were prompted by the electronic health record (EHR) to print CDS that identified evidence-based treatment options for lipid, blood pressure, weight, tobacco, or aspirin management and prioritized them based on potential benefit to the patient. The intention-to-treat analysis included 7914 adults who met high CV risk criteria at an index clinic visit and had at least one post-index visit, accounted for clustering, and assessed impact on predicted annual rate of change in 10-year CV risk over a 14-month period. Results: The CDS was printed at 75% of targeted visits, and providers reported 85% to 98% satisfaction with various aspects of the intervention. Predicted annual rate of change in absolute 10-year CV risk was significantly better in CDS clinics than in UC clinics (-0.59% vs. +1.66%, -2.24%; P < .001), with difference in 10-year CV risk at 12 months post-index favoring the CDS group (UC 24.4%, CDS 22.5%, P < .03). Discussion: Deploying to both patients and providers within primary care visit workflow and limiting CDS display and print burden to two mouse clicks by rooming staff contributed to high CDS use rates and high provider satisfaction. Conclusion: This EHR-integrated, web-based outpatient CDS system significantly improved 10-year CV risk trajectory in targeted adults. PMID- 29982628 TI - E. coli strain engineering for the production of advanced biopharmaceutical products. AB - Since the emergence of the biopharmaceutical industry in the 1980's, Escherichia coli, has played an important role in the industrial production of recombinant proteins and plasmid DNA for therapeutic use. Currently, advanced biopharmaceutical products, including rationally designed recombinant proteins and viral-vector gene therapies, offer unprecedented promise for the long-term management, and even cure of disease. As such, E. coli remains an important production host for the biopharmaceutical industry. This review provides insight into the industrially relevant strain engineering approaches used to enhance both the quantity and quality of these therapeutic products. PMID- 29982629 TI - Comparison of metabolite networks from four German population-based studies. AB - Background: Metabolite networks are suggested to reflect biological pathways in health and disease. However, it is unknown whether such metabolite networks are reproducible across different populations. Therefore, the current study aimed to investigate similarity of metabolite networks in four German population-based studies. Methods: One hundred serum metabolites were quantified in European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (n = 2458), EPIC-Heidelberg (n = 812), KORA (Cooperative Health Research in the Augsburg Region) (n = 3029) and CARLA (Cardiovascular Disease, Living and Ageing in Halle) (n = 1427) with targeted metabolomics. In a cross-sectional analysis, Gaussian graphical models were used to construct similar networks of 100 edges each, based on partial correlations of these metabolites. The four metabolite networks of the top 100 edges were compared based on (i) common features, i.e. number of common edges, Pearson correlation (r) and hamming distance (h); and (ii) meta-analysis of the four networks. Results: Among the four networks, 57 common edges and 66 common nodes (metabolites) were identified. Pairwise network comparisons showed moderate to high similarity (r = 63-0.96, h = 7-72), among the networks. Meta analysis of the networks showed that, among the 100 edges and 89 nodes of the meta-analytic network, 57 edges and 66 metabolites were present in all the four networks, 58-76 edges and 75-89 nodes were present in at least three networks, and 63-84 edges and 76-87 edges were present in at least two networks. The meta analytic network showed clear grouping of 10 sphingolipids, 8 lyso phosphatidylcholines, 31 acyl-alkyl-phosphatidylcholines, 30 diacyl phosphatidylcholines, 8 amino acids and 2 acylcarnitines. Conclusions: We found structural similarity in metabolite networks from four large studies. Using a meta-analytic network, as a new approach for combining metabolite data from different studies, closely related metabolites could be identified, for some of which the biological relationships in metabolic pathways have been previously described. They are candidates for further investigation to explore their potential role in biological processes. PMID- 29982630 TI - Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. AB - Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene coding for alpha-galactosidase A (alpha-GalA). The deleterious mutations lead to accumulation of alpha-GalA substrates, including globotriaosylceramide (Gb3) and globotriaosylsphingosine. Progressive glycolipid storage results in cellular dysfunction, leading to organ damage and clinical disease, i.e. neuropathic pain, impaired renal function and cardiomyopathy. Many Fabry patients are treated by bi-weekly intravenous infusions of replacement enzyme. While the only available oral therapy is an alpha-GalA chaperone, which is indicated for a limited number of patients with specific 'amenable' mutations. Lucerastat is an orally bioavailable inhibitor of glucosylceramide synthase (GCS) that is in late stage clinical development for Fabry disease. Here we investigated the ability of lucerastat to lower Gb3, globotriaosylsphingosine and lysosomal staining in cultured fibroblasts from 15 different Fabry patients. Patients' cells included 13 different pathogenic variants, with 13 cell lines harboring GLA mutations associated with the classic disease phenotype. Lucerastat dose dependently reduced Gb3 in all cell lines. For 13 cell lines the Gb3 data could be fit to an IC50 curve, giving a median IC50 [interquartile range (IQR)] = 11 MUM (8.2-18); the median percent reduction (IQR) in Gb3 was 77% (70-83). Lucerastat treatment also dose dependently reduced LysoTracker Red staining of acidic compartments. Lucerastat's effects in the cell lines were compared to those with current treatments-agalsidase alfa and migalastat. Consequently, the GCS inhibitor lucerastat provides a viable mechanism to reduce Gb3 accumulation and lysosome volume, suitable for all Fabry patients regardless of genotype. PMID- 29982631 TI - Continuous Clinical Response Is Associated With a Change of Disease Course in Patients With Moderate to Severe Ulcerative Colitis Treated With Golimumab. AB - Background: Responders to induction treatment sustain continuous clinical response (CCR) through 1 year in about 50% of patients in PURSUIT-M trial with golimumab maintenance in ulcerative colitis (UC). This post hoc analysis of PURSUIT-M describes the 1-year clinical, endoscopic, quality of life (QoL), and biomarker and 4-year clinical outcome in patients with sustained response to golimumab therapy for UC. Methods: We compared clinical, endoscopic, QoL, and calprotectin outcomes in CCR and non-CCR patients through 54 weeks in PURSUIT-M. Persistence on golimumab therapy and clinical response at 4 years was assessed for CCR and non-CCR patients. The relationship of colectomy with CCR status was determined. Results: Among patients receiving golimumab maintenance, greater proportions of patients with vs without CCR at week 54 achieved clinical remission (67.1% vs 1.9%), corticosteroid-free remission (61.6% vs 1.9%), endoscopic remission (Mayo endoscopy score 0 [47.9% vs 1.3%]), and normal QoL (inflammatory bowel disease questionnaire score >=170 [75.0% vs 24.4%]). CCR but not non-CCR patients maintained normalized calprotectin levels during maintenance. Among patients who entered the long-term extension study, a greater proportion of patients with vs without CCR maintained PGA 0 through week 216 (58% vs 42%). Colectomy was performed in 47 induction nonresponders and in 13 induction responders. None of the patients going onto colectomy achieved CCR through 54 weeks in PURSUIT-M. Conclusions: Continuous clinical response is associated with favorable short- and long-term clinical, endoscopic, QoL, and biomarker responses that may result in changing the course of disease and may prevent colectomy in patients with moderate to severe UC treated with golimumab. 10.1093/ibd/izy229_video1izy229.video15806022773001. PMID- 29982632 TI - The Calcium Channel Blocker Bepridil Demonstrates Efficacy in the Murine Model of Marburg Virus Disease. AB - No therapeutics are approved for the treatment of filovirus infections. Bepridil, a calcium channel blocker developed for treating angina, was identified as a potent inhibitor of filoviruses in vitro, including Ebola and Marburg viruses, and Ebola virus in vivo. We evaluated the efficacy of bepridil in a lethal mouse model of Marburg virus disease. A dose of 12 mg/kg bepridil once or twice daily resulted in 80% or 90% survival, respectively. These data confirm bepridil's broad-spectrum anti-filovirus activity warranting further investigation of bepridil, or improved compounds with a similar mechanism, as a pan-filovirus therapeutic agent. PMID- 29982633 TI - SAG12, a Major Cysteine Protease Involved in Nitrogen Allocation during Senescence for Seed Production in Arabidopsis thaliana. AB - SAG12 is the most widely used senescence-associated reference gene for characterizing leaf senescence, and the increase in SAG12 protein during leaf senescence is remarkable. However, the role of this cysteine protease in N remobilization and the leaf senescence process remains unclear. The role of SAG12 has been poorly investigated and the few reports dealing with this are somewhat controversial. Indeed, sag12 Arabidopsis mutants have not shown any phenotype, while OsSAG12-1 and OsSAG12-2 overexpression in rice moderates senescence progression. Therefore, this study aims at clarifying the role of the SAG12 cysteine protease during the entire plant life span and during leaf senescence. Arabidopsis thaliana plants knocked-out for the SAG12 gene (sag12) did not exhibit any special phenotypic traits when grown under optimal nitrogen supply (HN), suggesting that other cysteine proteases could provide compensatory effects. Moreover, for the first time, this study shows that aspartate protease activity is significantly increased in sag12. Among the putative aspartate proteases involved, a CND41-like aspartate protease has been identified. Under low nitrogen (LN) availability, when inducible proteolytic systems are not sufficient to cope with SAG12 depletion, a decrease in yield is observed. Altogether, these results show that SAG12 (and perhaps also aspartate proteases) could be involved in RuBisCO degradation during the leaf senescence associated with seed filling. PMID- 29982634 TI - NPO Prior to Interventional Spine Procedures. PMID- 29982635 TI - Chromosomal over-replication in Escherichia coli recG cells is triggered by replication fork fusion and amplified if replichore symmetry is disturbed. AB - Chromosome duplication initiates via the assembly of replication forks at defined origins. Forks proceed in opposite directions until they fuse with a converging fork. Recent work highlights that fork fusions are highly choreographed both in pro- and eukaryotic cells. The circular Escherichia coli chromosome is replicated from a single origin (oriC), and a single fork fusion takes place in a specialised termination area opposite oriC that establishes a fork trap mediated by Tus protein bound at ter sequences that allows forks to enter but not leave. Here we further define the molecular details of fork fusions and the role of RecG helicase in replication termination. Our data support the idea that fork fusions have the potential to trigger local re-replication of the already replicated DNA. In DeltarecG cells this potential is realised in a substantial fraction of cells and is dramatically elevated when one fork is trapped for some time before the converging fork arrives. They also support the idea that the termination area evolved to contain such over-replication and we propose that the stable arrest of replication forks at ter/Tus complexes is an important feature that limits the likelihood of problems arising as replication terminates. PMID- 29982636 TI - Quantifying antimicrobial access and usage for paediatric diarrhoeal disease in an urban community setting in Asia. AB - Objectives: Antimicrobial-resistant infections are a major global health issue. Ease of antimicrobial access in developing countries is proposed to be a key driver of the antimicrobial resistance (AMR) epidemic despite a lack of community antimicrobial usage data. Methods: Using a mixed-methods approach (geospatial mapping, simulated clients, healthcare utilization, longitudinal cohort) we assessed antimicrobial access in the community and quantified antimicrobial usage for childhood diarrhoea in an urban Vietnamese setting. Results: The study area had a pharmacy density of 15.7 pharmacies/km2 (a pharmacy for every 1316 people). Using a simulated client method at pharmacies within the area, we found that 8% (3/37) and 22% (8/37) of outlets sold antimicrobials for paediatric watery and mucoid diarrhoea, respectively. However, despite ease of pharmacy access, the majority of caregivers would choose to take their child to a healthcare facility, with 81% (319/396) and 88% (347/396) of responders selecting a specialized hospital as one of their top three preferences when seeking treatment for watery and mucoid diarrhoea, respectively. We calculated that at least 19% (2688/14427) of diarrhoea episodes in those aged 1 to <5 years would receive an antimicrobial annually; however, antimicrobial usage was almost 10 times greater in hospitals than in the community. Conclusions: Our data question the impact of community antimicrobial usage on AMR and highlight the need for better education and guidelines for all professionals with the authority to prescribe antimicrobials. PMID- 29982637 TI - SMA1, a homolog of the splicing factor Prp28, has a multifaceted role in miRNA biogenesis in Arabidopsis. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that repress gene expression. In plants, the RNase III enzyme Dicer-like (DCL1) processes primary miRNAs (pri-miRNAs) into miRNAs. Here, we show that SMALL1 (SMA1), a homolog of the DEAD-box pre-mRNA splicing factor Prp28, plays essential roles in miRNA biogenesis in Arabidopsis. A hypomorphic sma1-1 mutation causes growth defects and reduces miRNA accumulation correlated with increased target transcript levels. SMA1 interacts with the DCL1 complex and positively influences pri-miRNA processing. Moreover, SMA1 binds the promoter region of genes encoding pri-miRNAs (MIRs) and is required for MIR transcription. Furthermore, SMA1 also enhances the abundance of the DCL1 protein levels through promoting the splicing of the DCL1 pre-mRNAs. Collectively, our data provide new insights into the function of SMA1/Prp28 in regulating miRNA abundance in plants. PMID- 29982638 TI - Regional Differences in the Prevalence of Coronary Heart Disease and Stroke in Patients With Type 2 Diabetes in China. AB - Background: There are large regional variations in the prevalence and mortality of cardiovascular disease in general populations in China. It remains uncertain whether the prevalence in type 2 diabetes mellitus (T2DM) varies by region in China. Methods: We analyzed data of 219,522 Chinese patients with T2DM retrieved from the China National HbA1c Surveillance System in 2012. We used the Chinese population distribution in 2010 to standardize prevalence of coronary heart disease (CHD), stroke, and composite of both in 30 provinces and seven geological regions. Multivariable logistic regression was performed to obtain ORs and CIs of provinces/geological regions for CHD, stroke, and composite of both. Results: Age and sex standardized prevalence of CHD, stroke, and composite of both was, respectively, 4.59% (95% CI, 4.58 to 4.60), 1.79% (1.79 to 1.80), and 5.85% (5.84 to 5.86), in contrast to 0.60% of CHD, 0.80% of stroke, and 1.37% of composite of both in the general population in China. After adjustment for traditional risk factors, Northeast had the highest risks of CHD, stroke, and composite of both, and North had the second highest risks of CHD, stroke, and composite of both among the seven regions, both being higher than any other regions (all P values < 0.05). The ORs of Northeast vs Southwest were up to 2.60 (2.35 to 2.88) for CHD, 2.49 (2.15 to 2.88) for stroke, and 2.61 (2.38 to 2.86) for composite of both. Conclusions: There were large variations in risks of CHD, stroke, and composite of both in T2DM in China with Northeast and North having the highest risks. PMID- 29982639 TI - Reduced engagement of the anterior cingulate cortex in the dishonest decision making of incarcerated psychopaths. AB - A large body of research indicates that psychopathic individuals lie chronically and show little remorse or anxiety. Yet, little is known about the neurobiological substrates of dishonesty in psychopathy. In a sample of incarcerated individuals (n = 67), we tested the hypothesis that psychopathic individuals show reduced activity in the anterior cingulate cortex (ACC) when confronted with an opportunity for dishonest gain, reflecting dishonest behavior that is relatively unhindered by response conflict. During functional magnetic resonance imaging, incarcerated offenders with different levels of psychopathy performed an incentivized prediction task wherein they were given real and repeated opportunities for dishonest gain. We found that while incarcerated offenders showed a high rate of cheating, levels of psychopathic traits did not influence the frequency of dishonesty. Higher psychopathy scores predicted decreased activity in the ACC during dishonest decision-making. Further analysis revealed that the ACC was functionally connected to the dorsolateral prefrontal cortex, and that ACC activity mediated the relationship between psychopathic traits and reduced reaction times for dishonest behavior. These findings suggest that psychopathic individuals behave dishonestly with relatively low levels of response conflict and that the ACC may play a critical role in this pattern of behavior. PMID- 29982640 TI - Fumigating broiler hatching eggs with lysozyme product (Inovapure) to reduce eggshell microbial load. AB - Experiments were conducted to evaluate the effectiveness of a lysozyme product (InovapureTM) (LP) against E. coli penetrating eggshells. In the first microbiological experiment, 60 agar-filled eggs were inoculated with E. coli suspension, then fumigated with distilled water, 1.5% or 3.0% LP or a quaternary ammonium product (QA) at 0.125% for 10 min. In the second microbiological experiment, another 60 agar-filled eggs were fumigated with the same sanitizer treatments first, then inoculated with the E. coli suspension. Eggshells were candled and visual colonies were counted after 48 h incubation. An animal experiment was conducted to evaluate LP applied to the surface of 2080 broiler hatching eggs on hatching and growth performance. Hatching eggs were submerged in an E. coli suspension. After drip drying, eggs were randomly divided into four fumigation treatments, each with four subsets of 150 eggs. Fumigation treatments were the same as in the microbiological experiments. Eggs were incubated in 8 incubators (2 replicate incubators per treatment) and the broilers were grown to 33 d of age. In the microbiological experiments, inoculated eggs fumigated with 3.0% LP and 0.125% QA reduced (P < 0.05) the total amount of E. coli to 11 cfu/egg and 10 cfu/egg, respectively. When eggs were sanitized prior to inoculation, 3.0% LP demonstrated (P < 0.05) ongoing bactericidal action to prevent E. coli penetration. No differences in hatchability, fertility rate or egg weight loss percent were found among sanitation treatments. At hatch, body weight or the ratio of yolk sac weight to yolk-free body weight were not affected by the sanitation treatments. However, the application of sanitizers decreased (P < 0.05) the presence of E. coli in the yolk sac of newly hatched chicks. Feed consumption, body weight and feed conversion ratio were not affected by sanitation treatments. However, average daily body weight gain was lower (P < 0.05) following QA. Overall, 3.0% LP demonstrated acceptable activity against E. coli on eggshells, and provided ongoing bactericidal action to prevent E. coli penetration without negatively affecting growth performance. PMID- 29982642 TI - The Preventable Shunt Revision Rate: A Multicenter Evaluation. AB - BACKGROUND: The Preventable Shunt Revision Rate (PSRR) was recently introduced as a novel quality metric. OBJECTIVE: To evaluate the PSRR across multiple centers and determine associated variables. METHODS: Nine participating centers in North America provided at least 2 years of consecutive shunt operations. Index surgery was defined as new shunt implantation, or revision of an existing shunt. For any index surgery that resulted in a reoperation within 90-days, index surgery information (demographic, clinical, and procedural) was collected and a decision made whether the failure was potentially preventable. The 90-day shunt failure rate and PSRR were calculated per institution and combined. Bivariate analyses were performed to evaluate individual effects of each independent variable on preventable shunt failure followed by a final multivariable model using a backward model selection approach. RESULTS: A total of 5092 shunt operations were performed; 861 failed within 90 days of index operation, resulting in a 16.9% combined 90-day shunt failure rate and 17.6% median failure rate (range, 8.7% 26.9%). Of the failures, 307 were potentially preventable (overall and median 90 day PSRR, 35.7% and 33.9%, respectively; range, 16.1%-55.4%). The most common etiologies of avoidable failure were infection (n = 134, 44%) and proximal catheter malposition (n = 83, 27%). Independent predictors of preventable failure (P < .05) were lack of endoscopy (odds ratio [OR] = 2.26), recent shunt infection (OR = 3.65), shunt type (OR = 2.06) and center. CONCLUSION: PSRR is variable across institutions, but can be 50% or higher. While the PSRR may never reach zero, this study demonstrates that overall about a third of early failures are potentially preventable. PMID- 29982643 TI - Comparing Older Persons' Human Rights: Exploratory Study of the International Older Persons' Human Rights Index (IOPHRI). AB - Background and Objectives: Over the last 2 decades, several international indices have been developed to describe the status of older persons. None, however, have examined their human rights. The International Older Persons' Human Rights Index (IOPHRI) fills in this gap by analyzing the formal legislative foundation of human rights for older people. The objective of this exploratory study is to examine the IOPHRI while comparing the legislation in 6 countries. Research Design and Methods: A comparative international exploratory study comparing the human rights legislation of 6 countries: United States, Chile, Ireland, South Africa, India, and Australia in 5 different human rights domains: constitutional, protection, familial and informal support, planning, and empowerment. Results: The findings suggest that the actual relationship between formal human rights of older persons and the real world is complex: for example, while the IOPHRI index places South Africa in first place, it is far behind compared with all other participants in the Global AgeWatch Index (which measures objective elements such as life expectancy at 60, or poverty rates in old age). Discussion and Implications: Measuring and indexing human rights of older persons reveal significant methodological issues. Beyond these methodological challenges, comparing the ranking of the IOPHRI to nonlegalistic indices raises significant questions about the relationship between formal human rights and the actual living experiences of older persons. PMID- 29982641 TI - The potential use of rifabutin for treatment of patients diagnosed with rifampicin-resistant tuberculosis. AB - Background: Use of the Xpert MTB/RIF assay has increased the number of people diagnosed with rifampicin-resistant tuberculosis (RR-TB), especially in South Africa where Xpert is now the initial diagnostic for individuals with TB symptoms. We hypothesized that a proportion of RR-TB patients determined by Xpert can be treated with a rifabutin-containing regimen. Methods: Rifabutin susceptibility by rpoB mutation was assessed in 349 individuals from South Africa and 172 from Belgium. rpoB polymorphisms were identified by Sanger sequencing. Rifampicin and rifabutin susceptibility was assessed phenotypically. A systematic review was performed to comprehensively collate information on rifabutin susceptibility by rpoB polymorphism. Rifabutin susceptibility was assigned to rpoB polymorphisms based on their positive likelihood ratios and ORs. Results: One hundred and twelve rpoB polymorphisms (67.9% from literature) were identified from all 2045 RR-TB patients, of which 17 polymorphisms could be classified as susceptible/resistant to rifabutin. Eleven polymorphisms were associated with rifabutin susceptibility. The 516GTC mutation was the most common, representing 70% (South Africa) and 76% (Belgium) of all rifabutin-susceptible isolates. At a population level, the 11 polymorphisms associated with rifabutin susceptibility occurred in 33.2% and 16.6% of all South African and Belgian patients diagnosed with RR-TB, respectively. Conclusions: Identification of the exact rpoB polymorphism leading to the diagnosis of RR-TB has the potential to allow inclusion of rifabutin in the treatment regimen of a substantial proportion of RR TB patients. A randomized controlled trial evaluating the efficacy of a rifabutin containing TB treatment regimen in these selected patients is needed to provide the evidence required for a change in policy. PMID- 29982644 TI - Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar-Kyoto rats through anti-inflammatory effects. AB - Background: Since recombinant human soluble thrombomodulin (RH-TM) has anti inflammatory properties through neutralizing high-mobility group box 1 protein (HMGB1), the protective effects of RH-TM were examined in anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in Wistar-Kyoto rats. Methods: Rats were injected with nephrotoxic serum (NTS) to induce anti-GBM GN on Day 0, and were given either RH-TM or vehicle from Day 0 to Day 6. Rats were sacrificed 7 days after NTS injection. Results: RH-TM-treated rats had decreased proteinuria and serum creatinine level. RH-TM significantly reduced the percentage of glomeruli with crescentic features and fibrinoid necrosis. In addition, RH-TM treated rats had significantly reduced glomerular ED1+ macrophage accumulation as well as reduced renal cortical proinflammatory cytokine expression. Furthermore, RH-TM had a potent effect in reducing intercellular adhesion molecule-1 (ICAM-1) expression in kidneys and urine. RH-TM significantly reduced renal cortical mRNA levels for toll-like receptor -2 and -4, known as receptors for HMGB1, and their downstream adopter protein, myeloid differentiation primary respond protein 88 (MyD88). Conclusions: We showed for the first time that anti-inflammatory effects, which were characterized by reduced glomerular macrophage influx concomitant with a marked reduction in proinflammatory cytokines, were involved in the mechanism of attenuating experimental anti-GBM GN by RH-TM. The observed effects might be attributable to the downregulation of ICAM-1 by reducing the HMGB1/TLR/MyD88 signaling pathway. PMID- 29982647 TI - Does Bariatric Surgery Affect Breast-Milk Composition? PMID- 29982646 TI - Frequency of Herpes Zoster Vaccination Among Inflammatory Bowel Disease Patients. AB - Background: Inflammatory bowel disease (IBD) patients are at an increased risk of herpes zoster (HZ). Our aim was to determine the frequency of HZ vaccination and the factors associated with it among eligible IBD patients. Methods: We conducted a retrospective cohort study among IBD patients who were followed in the nationwide Veterans Affairs Healthcare system. Among this cohort, we identified patients who were the age of 60 years after the introduction of the vaccination. The outcome of interest was vaccination for HZ. For all patients, follow-up began on January 1, 2008, and ended at incident HZ diagnosis, HZ vaccination, death, June 30, 2016, or loss to follow-up, whichever was earlier. The exposure to different medication groups at any time after the onset of the study period was also evaluated, as were the demographic features. Results: We found that among 18,825 IBD patients who were eligible for vaccination, only 3946 (20.96%) patients were vaccinated at any time during their follow-up. Within the first 5 years of follow-up, 11.7% of the total eligible population was vaccinated. Furthermore, ulcerative colitis patients and Caucasians were more likely to get vaccinated, whereas patients ever exposed to steroids, thiopurines, or anti-tumor necrosis factor medications and those with older age and a higher Charlson comorbidity index were less likely to be vaccinated. Conclusions: The vaccination rates for HZ in a nationwide IBD cohort without insurance constraints were extremely low. Concerted efforts should be made to improve them, and HZV should be considered among the quality of care indicators. PMID- 29982645 TI - Identification of a novel tRNA wobble uridine modifying activity in the biosynthesis of 5-methoxyuridine. AB - Derivatives of 5-hydroxyuridine (ho5U), such as 5-methoxyuridine (mo5U) and 5 oxyacetyluridine (cmo5U), are ubiquitous modifications of the wobble position of bacterial tRNA that are believed to enhance translational fidelity by the ribosome. In gram-negative bacteria, the last step in the biosynthesis of cmo5U from ho5U involves the unique metabolite carboxy S-adenosylmethionine (Cx-SAM) and the carboxymethyl transferase CmoB. However, the equivalent position in the tRNA of Gram-positive bacteria is instead mo5U, where the methyl group is derived from SAM and installed by an unknown methyltransferase. By utilizing a cmoB deficient strain of Escherichia coli as a host and assaying for the formation of mo5U in total RNA isolates with methyltransferases of unknown function from Bacillus subtilis, we found that this modification is installed by the enzyme TrmR (formerly known as YrrM). Furthermore, X-ray crystal structures of TrmR with and without the anticodon stemloop of tRNAAla have been determined, which provide insight into both sequence and structure specificity in the interactions of TrmR with tRNA. PMID- 29982648 TI - Stevia Leaf to Stevia Sweetener: Exploring Its Science, Benefits, and Future Potential. AB - Steviol glycoside sweeteners are extracted and purified from the Stevia rebaudiana Bertoni plant, a member of the Asteraceae (Compositae) family that is native to South America, where it has been used for its sweet properties for hundreds of years. With continued increasing rates of obesity, diabetes, and other related comorbidities, in conjunction with global public policies calling for reductions in sugar intake as a means to help curb these issues, low- and no calorie sweeteners (LNCSs, also known as high-potency sweeteners) such as stevia are gaining interest among consumers and food manufacturers. This appeal is related to stevia being plant-based, zero calorie and with a sweet taste that is 50-350 times sweeter than sugar, making it an excellent choice for use in sugar- and calorie-reduced food and beverage products. Despite the fact that the safety of stevia has been affirmed by several food regulatory and safety authorities around the world, insufficient education about stevia's safety and benefits, including continuing concern with regard to the safety of LNCSs in general, deters health professionals and consumers from recommending or using stevia. Therefore, the aim of this review and the stevia symposium that preceded this review at the ASN's annual conference in 2017 was to examine, in a comprehensive manner, the state of the science for stevia, its safety and potential health benefits, and future research and application. Topics covered included metabolism, safety and acceptable intake, dietary exposure, impact on blood glucose and insulin concentrations, energy intake and weight management, blood pressure, dental caries, naturality and processing, taste and sensory properties, regulatory status, consumer insights, and market trends. Data for stevia are limited in the case of energy intake and weight management as well as for the gut microbiome; therefore, the broader literature on LNCSs was reviewed at the symposium and therefore is also included in this review. PMID- 29982649 TI - Rickettsia Species Isolated from Dermacentor occidentalis (Acari: Ixodidae) from California. AB - The Pacific Coast tick (Dermacentor occidentalis Marx, 1892) is one of the most widely distributed and frequently encountered tick species in California. This tick is the primary vector of an unclassified spotted fever group rickettsial pathogen, designated currently as Rickettsia 364D, the etiologic agent of a recently recognized tick-borne rickettsiosis known as Pacific Coast tick fever. Despite intensified interest in this pathogen, important questions remain regarding its taxonomic status and possible variations in genotype among different strains that could influence its pathogenicity. Only the extensively passaged prototypical isolate (strain 364-D) is widely available to rickettsiologists and public health scientists worldwide. To achieve a larger, more geographically diverse, and contemporary collection of strains, 1,060 questing adult D. occidentalis ticks were collected from 18 sites across six counties in northern and southern California in 2016 and 2017. Fourteen ticks (1.3%) yielded DNA of Rickettsia 364D and from these, 10 unique isolates from Lake and Orange counties were obtained. Additionally, Rickettsia rhipicephali was detected in 108 (10.2%) ticks, from which eight isolates were obtained, and Rickettsia bellii in six (0.6%), from which three isolates were obtained. The panel of recently acquired, low-passage strains of Rickettsia 364D derived from this study could enhance opportunities for investigators to accurately determine the taxonomic standing of this agent and to develop specific diagnostic assays for detecting infections with Rickettsia 364D in ticks and humans. PMID- 29982650 TI - The effects of ultimate pH and color on sensory traits of pork loin chops cooked to a medium-rare degree of doneness. AB - The objective was to determine the effects of pH and color on sensory characteristics of boneless pork loin chops cooked to an internal endpoint temperature of 63C. Center cut loins (296 total) from barrows and gilts, 5 different sire lines, and a range in pH of 5.36 through 6.23 were used. Previously, ultimate pH was correlated with sensory characteristics of chops cooked to a medium (71 degrees C) degree of doneness. Additionally, increasing ultimate pH improved sensory tenderness and juiciness of loin chops cooked to a medium degree of doneness. However, in 2011, the USDA Food Safety and Inspection Service reduced the recommended final internal cooking temperature of pork chops from 71 degrees C to 63 degrees C (followed by a 3 min rest). The effects of ultimate pH on sensory traits of pork chops cooked to a medium-rare (63 degrees C) degree of doneness are not known. Therefore, loins were categorized using historical categories based on ultimate pH: >5.95, n = 22; 5.80 to 5.95, n = 75; 5.65 to 5.80, n = 102; 5.50 to 5.65, n = 91; <5.50, n= 6. On 1 d postmortem, loins were evaluated for CIE instrumental L*, a*, b*, visual color, marbling, and subjective firmness. Then, loins were aged in vacuum packages at 4 degrees C until 16 d postmortem. After aging, loins were cut into 2.54 cm thick chops, vacuum-packaged and frozen until sensory or instrumental tenderness analysis. One chop was also used to determine extractable lipid. Chops were weighed, cooked to 63 degrees C, cooled to approximately 23 degrees C, weighed again to determine cook loss, and then evaluated for Warner-Bratzler shear force. Another chop was cooked to 63 degrees C internal temperature and served warm to trained panelists to determine sensory traits. Coefficients of determination (R2) were calculated to determine the predictability of ultimate pH and instrumental color on sensory tenderness, juiciness, and flavor. A one-way ANOVA and means separation test was used to determine specific differences among pH categories. Ultimate pH explained less than 5% of the variation in tenderness and less than 1% of the variation in juiciness or flavor. Further, sensory tenderness did not differ (P > 0.05) among pH categories, except for chops with an ultimate pH >5.95. Chops with a pH >5.95 were at least 9.1% more tender (P < 0.05) than chops with a pH <5.95. Visual and instrumental color were not predictive (R2 <= 0.03) of any sensory traits. Overall, pH does not influence sensory traits of pork chops cooked to medium-rare degree of doneness unless pH is at least 5.95. PMID- 29982651 TI - H2A.Z.1 crosstalk with H3K56-acetylation controls gliogenesis through the transcription of folate receptor. AB - Astrocytes play crucial roles in the central nervous system, and defects in astrocyte function are closely related to many neurological disorders. Studying the mechanism of gliogenesis has important implications for understanding and treating brain diseases. Epigenetic regulations have essential roles during mammalian brain development. Here, we demonstrate that histone H2A.Z.1 is necessary for the specification of multiple neural precursor cells (NPCs) and has specialized functions that regulate gliogenesis. Depletion of H2A.Z.1 suppresses gliogenesis and results in reduced astrocyte differentiation. Additionally, H2A.Z.1 regulates the acetylation of H3K56 (H3K56ac) by cooperating with the chaperone of ASF1a. Furthermore, RNA-seq data indicate that folate receptor 1 (FOLR1) participates in gliogenesis through the JAK-STAT signaling pathway. Taken together, our results demonstrate that H2A.Z.1 is a key regulator of gliogenesis because it interacts with ASF1a to regulate H3K56ac and then directly affects the expression of FOLR1, which acts as a signal-transducing component of the JAK-STAT signaling pathway. PMID- 29982654 TI - Corrigendum to Evaluation of the Quality of Semen and Sexual Function in Men with Inflammatory Bowel Disease. PMID- 29982653 TI - De novo and secondary anaplastic meningiomas: natural history, prognosis, and the TERT promoter. PMID- 29982655 TI - Informal Support, Health, and Burden Among Parents of Adult Children With Autism. AB - Background and Objectives: Many adults with autism spectrum disorders require lifelong reliance on caregiver support. As these caregivers age and experience health challenges, social support can be critical. This study seeks to understand if caregiver health moderates the relationship between informal social support and caregiver burden. Research Design and Methods: A total of 320 parents (age 50+ years) of adult children diagnosed with ASD were recruited from autism organizations and support groups and completed a web-based survey. Separate moderation analyses were used to determine if caregiver health was moderating the relationship between informal social support and composite caregiver burden, as well as the separate domains of developmental, time dependence, emotional burden, and impact of caregiving on finances. For each analysis, perceptions of available informal social support were the independent variable, composite and domains of caregiver burden were dependent variables, and parents' self-reported general health was the moderating variable. Results: Caregiver health had a statistically significant moderating effect when predicting the relationships between informal social support and composite caregiver burden, as well as time dependence burden and impact of caregiving on finances. Discussion and Implications: Increased attention should be focused on supporting the current and future needs of both aging caregivers and their adult children with ASD. Future research on the dynamics of social support, health, and burden is also urgently needed to address the growing number of aging caregivers of adults diagnosed with ASD. PMID- 29982656 TI - Unhealthy Dietary Patterns Established in Infancy Track to Mid-Childhood: The EU Childhood Obesity Project. AB - Background: Dietary habits established in infancy may persist into adulthood and determine long-term health. Objectives: The aims of this work were to describe dietary patterns, predictors of adherence to them, and their tracking from ages 1 to 8 y in European children. Methods: Three-day food diaries were prospectively collected at ages 1, 2, 3, 4, 5, 6 and 8 y. Foods were allocated to 1 of 29 food groups, which were included in exploratory factor analyses at each children's age. The tracking of patterns through childhood was assessed by an estimated general equation model. Results: At age 1 y (n = 633), 2 patterns were identified. One was labeled "core foods" (CORE), since it was positively loaded for vegetables, fish, olive oil, and white and red meat, and negatively loaded for ready-to-eat infant products, sugar, and confectioneries. The other was positively loaded for saturated spreads, sugar, fruit juices, and confectioneries, and negatively loaded for olive oil, fish, and cow milk; this was labeled as the "poor-quality fats and added sugars" (F&S) pattern. From ages 2 to 8 y, 3 patterns were repeatedly identified: CORE, F&S, and a "high protein sources" (PROT) pattern that was positively loaded for milk, flavored milks, fish, eggs, white and processed meat, chips, and olive oil, and negatively loaded for fresh fruits at almost all time points. Of those children in the highest quartiles of the CORE, F&S, and PROT patterns at 2 y, 45%, 72%, and 36%, respectively, remained in the highest quartile at 8 y [OR = 2.01 (1.08, 3.8), OR = 3.6 (1.5, 8.4) and OR = 0.80 (0.4,1.6), respectively; P = 0.510]. Conclusions: Dietary patterns are established between 1 and 2 y of age and track into mid childhood. A dietary pattern characterized by added sugars, unhealthy fats, and poor consumption of fish and olive oil was the most stable throughout childhood. Further analyses will reveal whether those dietary patterns are associated with metabolic disease risk. PMID- 29982657 TI - Selenium Supplementation Alters Hepatic Energy and Fatty Acid Metabolism in Mice. AB - Background: Human and animal studies have raised concerns that supplemental selenium can increase the risk of metabolic disorders, but underlying mechanisms are unclear. Objective: We used an integrated transcriptome and metabolome analysis of liver to test for functional pathway and network responses to supplemental selenium in mice. Methods: Male mice (8-wk-old, C57BL/6J) fed a standard diet (0.41 ppm Se) were given selenium (Na2SeO4, 20 MUmol/L) or vehicle (drinking water) for 16 wk. Livers were analyzed for selenium concentration, activity of selenoproteins, reduced glutathione (GSH) redox state, gene expression, and high-resolution metabolomics. Transcriptomic and nontargeted metabolomic data were analyzed with biostatistics, bioinformatics, pathway enrichment analysis, and combined transcriptome-metabolome-wide association study (TMWAS). Results: Mice supplemented with selenium had greater body mass gain from baseline to 16 wk (55% +/- 5%) compared with controls (40% +/- 3%) (P < 0.05); however, no difference was observed in liver selenium content, selenoenzyme transcripts, or enzyme activity. Selenium was higher in the heart, kidney, and urine of mice supplemented with selenium. Gene enrichment analysis showed that supplemental selenium altered pathways of lipid and energy metabolism. Integrated transcriptome and metabolome network analysis showed 2 major gene-metabolite clusters, 1 centered on the transcript for the bidirectional glucose transporter 2 (Glut2) and the other centered on the transcripts for carnitine-palmitoyl transferase 2 (Cpt2) and acetyl-CoA acyltransferase (Acaa1). Pathway analysis showed that highly associated metabolites (P < 0.05) were enriched in fatty acid metabolism and bile acid biosynthesis, including acylcarnitines, triglycerides and glycerophospholipids, long-chain acyl-coenzyme As, phosphatidylcholines, and sterols. TMWAS of body weight gain confirmed changes in the same pathways. Conclusions: Supplemental selenium in mice alters hepatic fatty acid and energy metabolism and causes increases in body mass. A lack of effect on hepatic selenium content suggests that signaling involves an extrahepatic mechanism. PMID- 29982658 TI - Are birthweight and postnatal weight gain in childhood associated with blood pressure in early adolescence? Results from a Ugandan birth cohort. AB - Background: In Africa, where low birthweight (LBW), malnutrition and high blood pressure (BP) are prevalent, the relationships between birthweight (BW), weight gain and BP later in life remain uncertain. We examined the effects of early life growth on BP among Ugandan adolescents. Methods: Data were collected prenatally from women and their offspring were followed from birth, with BP measured following standard protocols in early adolescence. Weight-for-age Z-scores (WAZ) were computed using World Health Organization references. Linear regression was used to relate BW, and changes in WAZ between birth and 5 years, to adolescents' BP, adjusting for confounders. Results: Among 2345 live offspring, BP was measured in 1119 (47.7%) adolescents, with mean systolic BP 105.9 mmHg and mean diastolic BP 65.2 mmHg. There was little evidence of association between BW and systolic [regression coefficient beta = 0.14, 95% confidence interval (CI) ( 1.00, 1.27)] or diastolic [beta = 0.43, 95% CI (-0.57, 1.43)] BP. Accelerated weight gain between birth and 5 years was associated with increased BP: systolic beta = 1.17, 95% CI (0.69, 1.66) and diastolic beta = 1.03, 95% CI (0.59, 1.47). Between birth and 6 months of age, effects of accelerated weight gain on adolescent BP were strongest among the LBW (both premature and small-for gestational-age) children [BW < 2.5 kg: beta = 2.64, 95% CI (0.91, 4.37), BW>=2.5 kg: beta = 0.58, 95% CI (0.01, 1.14), interaction P-value = 0.024]. Conclusions: Findings from this large tropical birth cohort in Uganda suggest that postnatal weight gain rather than BW is important in the developmental programming of BP, with fast-growing LBW children at particular risk. Efforts to control BP should adopt a life course approach. PMID- 29982659 TI - OpenNotes and shared decision making: a growing practice in clinical transparency and how it can support patient-centered care. AB - Objective: Prior studies suggest inviting patients to read their visit notes (OpenNotes) has important benefits for patient engagement. We utilized survey data to investigate our hypothesis that patients who read more notes would report greater shared decision making (SDM). Materials and Methods: Our survey focused on the safety and quality implications of OpenNotes. 24 722 patients at an urban healthcare organization were invited to complete the survey, which included an item assessing the number of notes read and the CollaboRATE scale to measure SDM. We used log-binomial regression to estimate the relative probability of top CollaboRATE scores across number of notes read while controlling for several covariates. Results: 6913 patients responded (28% response rate). Patients reading 4+ clinical notes in the past 12 months were 17% more likely to have top CollaboRATE scores when compared to patients who had not read a note in the previous 12 months (RR: 1.17, 95%CI: 1.04-1.32). Discussion: There is a clear relationship between what SDM requires and the transparency OpenNotes provides. Access to clinicians' notes can support the SDM model, which relies on efficient information exchange between clinicians and well-informed patients. Conclusion: Our study showed evidence of a relationship between note reading and perceived SDM. Implementation of SDM is likely to expand, given its association with improved patient satisfaction, adherence, and medical decision making. Findings from this study highlight OpenNotes as a policy that institutions can implement as a facilitator of SDM and a manifestation of their commitment to patient autonomy and transparency. PMID- 29982660 TI - Susceptibility of ESBL Escherichia coli and Klebsiella pneumoniae to fosfomycin in the Netherlands and comparison of several testing methods including Etest, MIC test strip, Vitek2, Phoenix and disc diffusion. AB - Objectives: Fosfomycin susceptibility testing is complicated and prone to error. Before using fosfomycin widely in patients with serious infections, acquisition of WT distribution data and reliable susceptibility testing methods are crucial. In this study, the performance of five methods for fosfomycin testing in the routine laboratory against the reference method was evaluated. Methods: Ten laboratories collected up to 100 ESBL-producing isolates each (80 Escherichia coli and 20 Klebsiella pneumoniae). Isolates were tested using Etest, MIC test strip (MTS), Vitek2, Phoenix and disc diffusion. Agar dilution was performed as the reference method in a central laboratory. Epidemiological cut-off values (ECOFFs) were determined for each species and susceptibility and error rates were calculated. Results: In total, 775 E. coli and 201 K. pneumoniae isolates were tested by agar dilution. The ECOFF was 2 mg/L for E. coli and 64 mg/L for K. pneumoniae. Susceptibility rates based on the EUCAST breakpoint of <=32 mg/L were 95.9% for E. coli and 87.6% for K. pneumoniae. Despite high categorical agreement rates for all methods, notably in E. coli, none of the alternative antimicrobial susceptibility testing methods performed satisfactorily. Due to poor detection of resistant isolates, very high error rates of 23.3% (Etest), 18.5% (MTS), 18.8% (Vitek2), 12.5% (Phoenix) and 12.9% (disc diffusion) for E. coli and 22.7% (Etest and MTS), 16.0% (Vitek2) and 12% (Phoenix) for K. pneumoniae were found. None of the methods adequately differentiated between WT and non-WT populations. Conclusions: Overall, it was concluded that none of the test methods is suitable as an alternative to agar dilution in the routine laboratory. PMID- 29982661 TI - Risk of Different Cancers Among First-degree Relatives of Pancreatic Cancer Patients: Influence of Probands' Susceptibility Gene Mutation Status. AB - Background: Increased risk of malignancies other than pancreatic cancer (PC) has been reported among first-degree relatives (FDRs) of PC patients; however, the roles of susceptibility gene mutations are unclear. We assessed risk for 15 cancers among FDRs of unselected PC probands. Methods: Data on 17 162 FDRs, with more than 336 000 person-years at risk, identified through 2305 sequential PC probands enrolled at Mayo Clinic (2000-2016) were analyzed. Family history data were provided by the probands. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated, comparing malignancies observed among the FDRs with that expected using Surveillance, Epidemiology, and End Results (SEER) data. Genetic testing was performed among a subset of probands (n = 2094), enabling stratified analyses among FDRs based on whether the related proband tested positive or negative for inherited mutation in 22 sequenced cancer susceptibility genes. All statistical tests were two-sided. Results: Compared with SEER, PC risk was twofold higher among FDRs of PC probands (SIR = 2.04, 95% CI = 1.78 to 2.31, P < .001). Primary liver cancer risk was elevated among female FDRs (SIR = 2.10, 95% CI = 1.34 to 3.12, P < .001). PC risk was more elevated among FDRs of mutation-positive probands (SIR = 4.32, 95% CI = 3.10 to 5.86) than FDRs of mutation-negative probands (SIR = 1.77, 95% CI = 1.51 to 2.05, between group P < .001). FDR PC risk was higher when the related proband was younger than age 60 years at diagnosis and mutation-positive (SIR = 5.24, 95% CI = 2.93 to 8.64) than when the proband was younger than age 60 years but mutation-negative (SIR = 1.76, 95% CI = 1.21 to 2.47, between-group P < .001). Breast (SIR = 1.29, 95% CI = 1.01 to 1.63) and ovarian (SIR = 2.38, 95% CI = 1.30 to 4.00) cancers were elevated among FDRs of mutation-positive probands. Conclusions: Our study substantiates twofold risk of PC among FDRs of PC patients and suggests increased risk for primary liver cancer among female FDRs. FDRs of susceptibility mutation carriers had substantially increased risk for PC and increased risk for breast and ovarian cancers. PMID- 29982662 TI - High in vivo levels of adipsin lead to increased knee tissue degradation in osteoarthritis: data from humans and animal models. AB - Objective: This study explored the role of the adipokine adipsin in OA. Methods: Control and OA articular tissues, cells and serum were obtained from human individuals. Serum adipsin levels of human OA individuals were compared with cartilage volume loss as assessed by MRI at 48 months. Human adipsin expression was determined by PCR, its production in tissues by immunohistochemistry, and in SF and serum by a specific assay. OA was surgically induced in wild-type (Df+/+) and adipsin-deficient (Df-/-) mice, and synovial membrane and cartilage processed for histology and immunohistochemistry. Results: Adipsin levels were significantly increased in human OA serum, SF, synovial membrane and cartilage compared with controls, but the expression was similar in chondrocytes, synoviocytes and osteoblasts. Multivariate analysis demonstrated that human serum adipsin levels were significantly associated (P = 0.045) with cartilage volume loss in the lateral compartment of the knee. Destabilization of the medial meniscus-Df-/- mice showed a preservation of the OA synovial membrane and cartilage lesions (P ? 0.026), the latter corroborated by the decreased production of cartilage degradation products and proteases (P ? 0.047). The adipsin effect is likely due to a deficient alternative complement pathway (P ? 0.036). Conclusion: In human OA, higher serum adipsin levels were associated with greater cartilage volume loss in the lateral compartment, and adipsin deficiency led to a preservation of knee structure. Importantly, we documented an association between adipsin and OA synovial membrane and cartilage degeneration through the activation of the complement pathway. This study highlights the clinical relevance of adipsin as a valuable biomarker and potential therapeutic target for OA. PMID- 29982663 TI - Reflections and Future Directions on Extending Physical Therapist Scope of Practice to Improve Quality of Care and Preserve Health Care Resources. PMID- 29982664 TI - EPH receptor signaling as a novel therapeutic target in NF2-deficient meningioma. AB - Background: Meningiomas are the most common primary brain tumor in adults, and somatic loss of the neurofibromatosis 2 (NF2) tumor suppressor gene is a frequent genetic event. There is no effective treatment for tumors that recur or continue to grow despite surgery and/or radiation. Therefore, targeted therapies that either delay tumor progression or cause tumor shrinkage are much needed. Our earlier work established mammalian target of rapamycin complex mTORC1/mTORC2 activation in NF2-deficient meningiomas. Methods: High-throughput kinome analyses were performed in NF2-null human arachnoidal and meningioma cell lines to identify functional kinome changes upon NF2 loss. Immunoblotting confirmed the activation of kinases and demonstrated effectiveness of drugs to block the activation. Drugs, singly and in combination, were screened in cells for their growth inhibitory activity. Antitumor drug efficacy was tested in an orthotopic meningioma model. Results: Erythropoietin-producing hepatocellular receptor tyrosine kinases (EPH RTKs), c-KIT, and Src family kinase (SFK) members, which are biological targets of dasatinib, were among the top candidates activated in NF2-null cells. Dasatinib significantly inhibited phospho-EPH receptor A2 (pEPHA2), pEPHB1, c-KIT, and Src/SFK in NF2-null cells, showing no cross-talk with mTORC1/2 signaling. Posttreatment kinome analyses showed minimal adaptive changes. While dasatinib treatment showed some activity, dual mTORC1/2 inhibitor and its combination with dasatinib elicited stronger growth inhibition in meningiomas. Conclusion: Co-targeting mTORC1/2 and EPH RTK/SFK pathways could be a novel effective treatment strategy for NF2-deficient meningiomas. PMID- 29982666 TI - Commentary: Peritumoral Edema/Tumor Volume Ratio: A Strong Survival Predictor for Posterior Fossa Metastases. PMID- 29982665 TI - Natural History and Outcomes of Cytologically Benign Thyroid Nodules in Children. AB - Context: Most pediatric thyroid nodules are cytologically benign, but few data exist to guide treatment. Objective: To describe the natural history and outcomes of cytologically benign, pediatric thyroid nodules. Design: Cohort study. Setting: Multidisciplinary thyroid clinic at an academic medical center. Patients: Consecutive pediatric patients (<=18 years old) with cytologically benign thyroid nodules evaluated between 1998 and 2016. Results: Cytologically benign nodules (N = 237) in 181 patients were followed by ultrasound (median follow-up, 3.4 years; range, 0.5 to 13.9 years) or to resection. Thyroid cancer was diagnosed in six nodules (2.5%), and all six patients were disease free after median follow-up of 4.9 years. Malignancy was more common in nodules >4 cm (15.4%; P = 0.037) or that grew during follow-up (6.0%; P = 0.048). The likelihood of nodule growth (+/-SE) was 15% +/- 3%, 24% +/- 4%, and 49% +/- 10% at 6, 12, and 24 months, respectively. Among nodules >2 cm, those with >=25% cystic content grew more slowly than nodules <25% cystic; nodules <2 cm grew similarly regardless of cystic content. Conclusion: Benign cytology in pediatric thyroid nodules has a low false-negative rate similar to that in adults, and prognosis is excellent in the rare cases of malignancy. Resection of nodules >4 cm, combined with surveillance of smaller nodules and repeated aspiration for growth, detects most false-negative results. Follow-up ultrasound in 12 months is appropriate for most cytologically benign pediatric nodules, but delaying surveillance up to 24 months may be reasonable in large, predominantly cystic nodules. PMID- 29982667 TI - Causal Inference for Observational Studies. PMID- 29982668 TI - Urinary peptidomic biomarkers of renal function in heart transplant recipients. AB - Background: Chronic kidney disease (CKD) is common in patients after heart transplantation (HTx). We assessed whether in HTx recipients the proteomic urinary classifier CKD273 or sequenced urinary peptides revealing the parental proteins correlated with the estimated glomerular filtration rate (eGFR). Methods: In 368 HTx patients, we measured the urinary peptidome and analysed CKD273 and 48 urinary peptides with a detectable signal in >95% of participants. After 9.1 months (median), eGFR and the urinary biomarkers were reassessed. Results: In multivariable Bonferroni-corrected analyses of the baseline data, a 1 SD increase in CKD273 was associated with a 11.4 [95% confidence interval (CI) 7.25-15.5] mL/min/1.73 m2 lower eGFR and an odds ratio of 2.63 (1.56-4.46) for having eGFR <60 mL/min/1.73 m2. While relating eGFR category at follow-up to baseline urinary biomarkers, CKD273 had higher (P = 0.007) area under the curve (0.75; 95% CI 0.70-0.80) than 24-h proteinuria (0.64; 95% CI 0.58-0.69), but additional adjustment for baseline eGFR removed significance of both biomarkers. In partial least squares analysis, the strongest correlates of the multivariable adjusted baseline eGFR were fragments of collagen I (positive) and the mucin-1 subunit alpha (inverse). Associations between the changes in eGFR and the urinary markers were inverse for CKD273 and mucin-1 and positive for urinary collagen I. Conclusions: With the exception of baseline eGFR, CKD273 was more closer associated with imminent renal dysfunction than 24-h proteinuria. Fragments of collagen I and mucin-1-respectively, positively and inversely associated with eGFR and change in eGFR-are single-peptide markers associated with renal dysfunction. PMID- 29982669 TI - Association Between Diabetic Retinopathy and Parkinson Disease: The Korean National Health Insurance Service Database. AB - Context: Studies have shown an association between diabetes and Parkinson disease (PD). The retina is a part of the central nervous system; it was proposed that diabetic retinopathy (DR) and PD share common pathophysiology of dopamine deficiency. However, no epidemiologic studies have investigated the relationship between these two diseases. Objective: We assessed the association between DR and incident PD using a population-based database. Design/Setting/Participants: Using the Korean National Health Insurance Service database, 14,912,368 participants who underwent regular health checkup from 2005 to 2008 were included. Subjects were classified into non-diabetes, diabetes without DR, and diabetes with DR groups at baseline and followed up until the date of PD incidence, death, or 31 December 2013. Cox proportional hazards regression analysis was used to evaluate the association between DR and incident PD. Results: During the period, 34,834 subjects were newly diagnosed with PD. The incidence of PD was 2.74, 8.39, and 15.51 per 10,000 person-years for the non-diabetes, diabetes without DR, and diabetes with DR groups, respectively. In multivariate Cox proportional hazard models, DR groups were associated with significantly higher risk of PD than non diabetes or diabetes without DR groups even after adjusting for age, sex, fasting plasma glucose level, insulin usage, and other possible risk factors. Conclusion: Concurrent DR was associated with an increased risk of incident PD. Future studies are necessary to investigate the mechanism of increased risk of PD in DR including dopamine deficiency in the central nervous system and long-lasting poor glycemic control. PMID- 29982670 TI - Alveolar macrophage functions during the transition phase to active immunity in calves. AB - The first three to six months of the life of calves is the period during which active immunity is established. During this period, greater morbidity and mortality is caused by bronchopneumonia, because of the immaturity of the pulmonary immune system or the exaggerated cytotoxic response at subsequent infection. The aim of this study was to examine the maturity of the immune system during this phase of activation of acquired immunity in calves. For this purpose, the functions of phagocytosis and the reactive oxygen species (ROS) of alveolar macrophages CD14+ were evaluated. Further, the classes of immunoglobulins and the cytokines implicated in lymphocyte response patterns Th1 and Th2 in 10 healthy Holstein calves were quantified. Samples were taken from calves every 15 days, from the third to the sixth month of life. The alveolar macrophage CD14+ functions increased progressively until 150 days of age (phagocytosis, P=0.02, ROS, P=0.05), IgG1 and IgG2 isotype secretion reached an equilibrium, and the cytokine profiles were compatible with the Th1 response. At 165 days of age, there was a decrease in cellular function (phagocytosis P=0.02, ROS P=0.04) and an increase in IgG1 titers (P= 0.005) and IL-10 mRNA expression (P=0.09). At 180 days of life, we observed an IgG1 and IgG2 secretion balance, a decrease in IL 10mRNA expression, and an increase in IL-12 mRNA (P=0.04)and TNF-alpha mRNA expressions(P=0.0003) and alveolar macrophage oxidative metabolism were observed. These results indicate that the calves had an active immune response that was distinctive for the age group. The CD14+ response is more reactive at 150 days. A regulatory and/or humoral response begins at 165 days of life as the equilibrium of Th1 and Th2 profiles is reached at 180 days of life. This may be clinically relevant for the development of specific therapies and prophylactic measures for bronchopneumonia in calves at 135 to180 days of life. PMID- 29982671 TI - TESTING DIFFERENT AREA DOSEMETERS CONCERNING THEIR BEHAVIOUR IN PULSED RADIATION FIELDS. AB - In Germany, authorised experts are required to measure around an X-ray facility to determine supervised and controlled areas within the scope of a legal regulatory procedure. For this purpose, they have to use area dosemeters which are nationally type-approved by the PTB according to the German measurement and verification act. To date, all available type-approved area dosemeters are only tested in continuous radiation fields, and therefore the technical data of the measuring instruments are valid only for continuous radiation. In practice, however, the majority of facilities use pulsed radiation X-rays. Since no other measuring equipment is available, the authorised experts use supposedly unsuitable dosemeters. But is this really so? In the scope of this article, instruments typically used for these measurements were tested to investigate their behaviour in pulsed radiation fields. The approach is similar to that of Friedrich et al. PMID- 29982674 TI - Commentary: Mean 6-Year Follow-up of Magnetically Controlled Growing Rod Patients With Early Onset Scoliosis: A Glimpse of What Happens to Graduates. PMID- 29982672 TI - Influence of a specific amino acid pattern in the diet on the course of an experimental Campylobacter jejuni infection in broilers. AB - Campylobacter jejuni (C. jejuni) is one of the most important zoonotic pathogens worldwide. In Europe, the majority of the cases are caused by consuming contaminated poultry meat. The objective of the present study was to investigate potential effects of different crude protein levels in complete diets for broilers on infection dynamics of C. jejuni after experimental infection. In total, 300 commercial broilers line Ross 308 were divided into 4 different groups, including 5 replications of 15 chickens each. The chickens were fed a conventional diet (212 g CP/kg DM) and a protein-reduced test diet (190 g CP/kg DM) supplemented with essential amino acids. This resulted simultaneously in lower amino-acid concentrations preferentially utilized by C. jejuni, such as aspartate, glutamate, proline, and serine. One group of each feeding concept was infected artificially with C. jejuni at day 21 by applying an oral C. jejuni inoculum containing 4.17 +/- 0.09 log10 cfu of C. jejuni to 3 of 15 chickens, called "seeders." Feeding the test diet resulted in a significant reduction (P < 0.001) in CP intake (31.5 +/- 1.20 g CP/broiler/day and 27.7 +/- 0.71 g CP/broiler/day, respectively), a significant decrease (P < 0.05) in crude mucin in excreta (55.7 +/- 8.23 g/kg DM and 51.9 +/- 7.62 g/kg DM, respectively), and in goblet cell number in cecal crypts (P < 0.05; 15.1 +/- 5.71 vs. 13.6 +/- 5.91 goblet cells/crypt). In groups receiving the test diet, the excretion of C. jejuni was significantly reduced in seeders by 1.9 log10 cfu/g excreta at day 23 (3.38a +/- 2.55 vs. 1.47b +/- 2.20; P = 0.033). At day 25, prevalence of C. jejuni in cloacal swabs amounted to 53.3% in the group fed the test diet and 75.7% in the control group, respectively (P < 0.05). In summary, a definite amino acid pattern in the broiler diets could contribute to a development of an effective feeding strategy to reduce the prevalence of C. jejuni infection in chickens (Patent No 17187659.2-1106). PMID- 29982673 TI - Long-term effects of childhood cancer treatment on hormonal and ultrasound markers of ovarian reserve. AB - STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti Mullerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922. PMID- 29982675 TI - How to empower patients? A systematic review and meta-analysis. AB - Patient empowerment, a concept focused on patient-centeredness and patients autonomy, is a well-discussed topic in health literature. However, translating theory into practice is a challenge. The purpose of this study was to assess the effectiveness of interventions on patient empowerment and to identify and compare the modalities of these interventions. For this systematic review including meta analysis, eligibility criteria were as follows: (i) adult participants with one or more chronic somatic diseases, (ii) "patient empowerment" was explicitly measured (i.e., outcome or measuring instrument), (iii) randomized controlled designs, and (iv) written in English, French, Dutch, or German. A systematic search strategy was applied in five online databases (last search: March 29, 2017). Thirty-two studies were included in this review, of which 23 studies could be included in the meta-analysis. Overall effect estimate was significant in favor of the intervention; however, heterogeneity was high. Subgroup analyses revealed that the effect estimate was higher in studies with interventions that comprised individual sessions. The most recurrent behavioral change technique identified in our review was "knowledge", though this is not sufficient to empower. "Goal setting" and "action planning" were more likely to be applied in successful interventions. "Knowledge" could be combined with "goal setting" and "action planning" to empower. Thorough understanding of the concept of patient empowerment remains necessary. Future research should focus on somatic chronic diseases other than diabetes, a consensus definition for patient empowerment, and clinimetric properties of instruments. PMID- 29982676 TI - Three metronidazole-resistant Prevotella bivia strains harbour a mobile element, encoding a novel nim gene, nimK, and an efflux small MDR transporter. AB - Objectives: In this study we assess the antibiotic resistance genes in three metronidazole-resistant Prevotella bivia clinical isolates. Methods: Strains were whole-genome sequenced. De novo assembly was performed and genes were annotated in RAST. Manual adjustments were made, when required, to the annotation and length of the genes. Results: In all three strains a novel nim gene, nimK, was encountered located on a mobile genetic element (MGE). The nimK gene was associated with an IS1380 family transposase. On the same MGE, genes encoding an efflux small MDR (SMR) transporter were present and were associated with a crp/fnr regulator. Conclusions: This is the first description of the presence of a novel nim gene in metronidazole-resistant P. bivia clinical isolates. This gene is co-located with an efflux SMR transporter on an MGE, which has been named Tn6456 (MG827401). The identification of these resistance genes on an MGE is worrisome, since this indicates the horizontal gene transfer of antibiotic and/or biocide resistance from one strain to the other. PMID- 29982678 TI - Two convergent pathways of DNA knotting in replicating DNA molecules as revealed by theta-curve analysis. AB - During DNA replication in living cells some DNA knots are inadvertently produced by DNA topoisomerases facilitating progression of replication forks. The types of DNA knots formed are conditioned by the 3D organization of replicating DNA molecules. Therefore, by characterizing formed DNA knots it is possible to infer the 3D arrangement of replicating DNA molecules. This topological inference method is highly developed for knotted DNA circles. However, partially replicated DNA molecules have the form of theta-curves. In this article, we use mathematical formalism of theta-curves to characterize the full possibilities of how knotting can occur during replication of DNA molecules in vivo. To do this, we reanalyze earlier experimental studies of knotted, partially replicated DNA molecules and the previously proposed pathway of their formation. We propose a general model of knotting in replication intermediates, and demonstrate that there is an additional, equally important, parallel knotting pathway that also explains how DNA topoisomerases can produce experimentally observed knotted theta-curves. Interestingly, both pathways require intertwining of freshly replicated sister duplexes (precatenanes). PMID- 29982677 TI - Abscisic acid influences tillering by modulation of strigolactones in barley. AB - Strigolactones (SLs) represent a class of plant hormones that are involved in inhibiting shoot branching and in promoting abiotic stress responses. There is evidence that the biosynthetic pathways of SLs and abscisic acid (ABA) are functionally connected. However, little is known about the mechanisms underlying the interaction of SLs and ABA, and the relevance of this interaction for shoot architecture. Based on sequence homology, four genes (HvD27, HvMAX1, HvCCD7, and HvCCD8) involved in SL biosynthesis were identified in barley and functionally verified by complementation of Arabidopsis mutants or by virus-induced gene silencing. To investigate the influence of ABA on SLs, two transgenic lines accumulating ABA as a result of RNAi-mediated down-regulation of HvABA 8' hydroxylase 1 and 3 were employed. LC-MS/MS analysis confirmed higher ABA levels in root and stem base tissues in these transgenic lines. Both lines showed enhanced tiller formation and lower concentrations of 5-deoxystrigol in root exudates, which was detected for the first time as a naturally occurring SL in barley. Lower expression levels of HvD27, HvMAX1, HvCCD7, and HvCCD8 indicated that ABA suppresses SL biosynthesis, leading to enhanced tiller formation in barley. PMID- 29982680 TI - Mortality of Sugarcane Aphid, Melanaphis sacchari (Zehntner, Hemiptera: Aphididae), at Low Temperatures. AB - We conditioned colonies of Melanaphis sacchari (Zehntner, Hemiptera: Aphididae) to three different temperature regimes over a period of 2 mo: 30 degrees C, 25 degrees C, and a cycle of 18/8 degrees C (L:D), all under a diurnal photoperiod of 12:12 (L:D). Plants of susceptible sorghum, 85Y40, were grown to the five-leaf stage in 4-liter pots, 2 per pot, and then infested with mixtures of second fourth instar M. sacchari nymphs, either 50 (18/8 degrees C treatment) or 100 (25 and 30 degrees C treatments) aphids per plant. In each run of the experiment, a series of two to four plants of each treatment group were lowered to the desired cold temperature (4.0, 2.0, 0.0, -2.0, and -4.0 degrees C) in a climate controlled chamber and then evaluated for aphid survival after 12 h in complete darkness. Results revealed substantial survival of aphids from the 18/8 and 25 degrees C conditioned treatments, even at -4.0 degrees C, a temperature sufficient to kill the plants, and >90 and 60% survival, respectively, at 0.0 degrees C. In contrast, aphids conditioned to 30 degrees C experienced about 50% mortality at 4.0 degrees C, and complete mortality at 0.0 degrees C. Our results indicate that M. sacchari is able to survive periods of sub-freezing temperatures quite easily and will not suffer 'cold-shock' mortality unless subjected to a rapid drop in temperature from very warm conditions (e.g., 30 degrees C or higher). Therefore, only temperatures that are cold enough to kill sorghum plants are likely to kill all apterous virginoparae of M. sacchari. PMID- 29982681 TI - Smoking decisions: Altered reinforcement learning signals induced by nicotine state. AB - Introduction: Alterations in dopamine signaling play a key role in reinforcement learning and nicotine addiction, but the relationship between these two processes have not been well characterized. We investigated this relationship in young adult smokers using a combination of behavioral and computational measures of reinforcement learning. Methods: We asked moderately dependent smokers to engage in a reinforcement learning task three times: smoking as usual, smoking abstinence, and cigarette consumption. Participants' trial-to-trial training choices were modeled using a reinforcement learning model that calculates separate learning rates associated with positive and negative prediction errors. Results: We found that learning from positive prediction error signals are reduced during smoking abstinence and enhanced following cigarette consumption. By contrast, learning from negative prediction error signals was enhanced during smoking abstinence and reduced following cigarette consumption. Finally, when tested with novel pairs of stimuli, participants were relatively better at selecting the positive feedback predicting stimuli than avoiding the negative feedback predicting stimuli during the smoking as usual session, a pattern that reversed following cigarette consumption. Conclusions: These findings provide a specific computational account of altered reinforcement learning induced by smoking state (abstinence and consumption) and may represent a unique target for treatment of nicotine addiction. IMPLICATIONS: The present study illustrates the potential of computational psychiatry for understanding reinforcement learning deficits associated with substance use disorders in general and nicotine addiction in particular. We found that learning from positive prediction error signals is reduced during smoking abstinence and enhanced following cigarette consumption. By contrast, learning from negative prediction error signals was enhanced during smoking abstinence and reduced following cigarette consumption. By highlighting important computational differences between three states of smoking, these findings hold out promise for integrating experimental, computational, and theoretical analyses of decision making function together with research on addiction-related disorders. PMID- 29982679 TI - Biophysical analysis of sialic acid recognition by the complement regulator Factor H. AB - Complement factor H (FH), an elongated and substantially glycosylated 20-domain protein, is a soluble regulator of the complement alternative pathway (AP). It contains several glycan binding sites which mediate recognition of alpha2-3 linked sialic acid (FH domain 20) and glycosaminoglycans (domains 6-8 and 19-20). FH also binds the complement C3-activation product C3b, a powerful opsonin and focal point for the formation of C3-convertases of the AP feedback loop. In freely circulating FH the C3b binding site in domains 19-20 is occluded, a phenomenon that is not fully understood and could be mediated by an intramolecular interaction between FH's intrinsic sialylated glycosylation and its own sialic acid binding site. In order to assess this possibility, we characterized FH's sialylation with respect to glycosidic linkage type and searched for further potential, not yet characterized sialic acid binding sites in FH and its seven-domain spanning splice variant and fellow complement regulator FH like-1 (FHL-1). We also probed FH binding to the sialic acid variant Neu5Gc which is not expressed in humans but on heterologous erythrocytes that restrict the human AP and in FH transgenic mice. We find that FH contains mostly alpha2-6-linked sialic acid, making an intramolecular interaction with its alpha2 3-sialic acid specific binding site and an associated self-lock mechanism unlikely, substantiate that there is only a single sialic acid binding site in FH and none in FHL-1, and demonstrate direct binding of FH to the nonhuman sialic acid Neu5Gc, supporting the use of FH transgenic mouse models for studies of complement-related diseases. PMID- 29982682 TI - Gut microbiota correlates with fiber and apparent nutrients digestion in goose. AB - To explore the relationship among the level of fiber, gut microbiota, and nutritional substances, we applied the next generation sequencing technology for the identification of the composition and structure of microbiota in the gastrointestinal tract. In this study, a total of 25 phyla and 298 genera were identified from the gastrointestinal tract; Firmicutes, Bacteroidetes, and Proteobacteria were the predominant phyla. The ability of cecum in carbohydrate metabolism was significantly higher than that of the gizzard and ileum (P < 0.05). The bacterial community structure in various stages of the development of the cecum was different. In the different growth stages of cecum, the increase in the microbiota structure of the fiber level elevates the ability of carbon hydration. Second, the apparent metabolic rates of the other nutrients were affected by the fiber and period except for acid detergent fiber (P < 0.05); the apparent utilization rate of the nutrients increased with time. However, with the increase in the fiber level, the apparent utilization of nutrients was initially increased, followed by a decrease. Therefore, a correlation was established between the fiber level and gastrointestinal microbiota and apparent nutrient utilization rate of the 3 phyla. Our results suggest that the fiber level and growth stages could impact the composition of gut microbiota. PMID- 29982683 TI - Sustained virological response to direct-acting antiviral regimens reduces the risk of hepatocellular carcinoma in HIV/HCV-coinfected patients with cirrhosis. AB - Objectives: To assess the impact of all-oral direct-acting antiviral agent (DAA) regimens on the risk of hepatocellular carcinoma (HCC) in HIV/HCV-coinfected patients with cirrhosis. Methods: This was a multicentre prospective cohort study recruiting HIV/HCV-coinfected patients with a new diagnosis of compensated cirrhosis. Patients were followed up until HCC, death or the censoring date (March 2017). The primary endpoint was the emergence of HCC. The incidence rate (IR) (95% CI) of HCC in different groups was computed. Time-to-event analyses were performed to identify predictors of HCC emergence. Results: The study included 495 HIV/HCV-coinfected patients with cirrhosis. After a median (IQR) follow-up of 59 (27-84) months, 22 (4.4%; 95% CI 2.6-6.3) patients developed an HCC. The IR (95% CI) of HCC was 0.93 (0.06-1.42) per 100 person-years (PY). Three hundred and three (61%) patients achieved sustained virological response (SVR) during follow-up, 79 after interferon (IFN)-based regimens and 224 after an all oral DAA regimen. The IR (95% CI) of HCC after all-oral DAA was 0.35 (0.14-0.85) per 100 PY whereas it was 1.79 (1.11-2.88) per 100 PY in the remaining cohort (P = 0.0005). When only patients with SVR were considered, the IR (95% CI) of HCC after all-oral DAA was 0.32 (0.12-0.86) whereas it was 0 per 100 PY among those with SVR after IFN-based therapies (P = 0.27). Achieving SVR with an all-oral DAA regimen during follow-up was independently associated with a lower risk of HCC emergence (subhazard ratio 0.264; 95% CI 0.070-0.991; P = 0.049). Conclusions: SVR with all-oral DAA regimens reduces the risk of HCC in HIV/HCV-coinfected patients with compensated cirrhosis. PMID- 29982684 TI - Gene Body Methylation Involved in Leaf Development. PMID- 29982685 TI - Predictors of Survival in Adrenocortical Carcinoma: An Analysis From the National Cancer Database. AB - Context: Adrenocortical carcinoma (ACC) is rare; knowledge about prognostic factors and survival outcomes is limited. Objective: To describe predictors of survival and overall survival (OS) outcomes. Design and Patients: Retrospective analysis of data from the National Cancer Database (NCDB) from 2004 to 2015 on 3185 patients with pathologically confirmed ACC. Main Outcome Measures: Baseline description, survival outcomes, and predictors of survival were evaluated in patients with ACC. Results: Median age at ACC diagnosis was 55 (range: 18 to 90) years; did not differ significantly by sex or stage of the disease at diagnosis. On multivariate analysis, increasing age, higher Charlson-Deyo comorbidity index score, high tumor grade, and no surgical therapy (all P < 0.0001); and stage IV disease (P = 0.002) and lymphadenectomy during surgery (P = 0.02) were associated with poor prognosis. Patients with stage I-III disease treated with surgical resection had significantly better median OS (63 vs 8 months; P < 0.001). In stage IV disease, better median OS occurred in patients treated with surgery (19 vs 6 months; P < 0.001), and postsurgical radiation (29 vs 10 months; P < 0.001) or chemotherapy (22 vs 13 months; P = 0.004). Conclusion: OS varied with increasing age, higher comorbidity index, grade, and stage of ACC at presentation. There was improved survival with surgical resection of primary tumor, irrespective of disease stage; postsurgical chemotherapy or radiation was of benefit only in stage IV disease. PMID- 29982686 TI - Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis. AB - Background: Active inflammatory bowel disease increases the risk of adverse pregnancy outcomes. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). As a small molecule, tofacitinib is likely to cross the placental barrier; however, information on the effects of tofacitinib on pregnancy outcomes is limited. We report pregnancy and newborn outcomes among patients in UC clinical studies with prenatal (maternal/paternal) exposure to tofacitinib. Methods: Pregnancies with maternal/paternal exposure to tofacitinib were identified and outcomes reported in 5 tofacitinib UC interventional studies (up to March 2017). Outcomes from tofacitinib rheumatoid arthritis (RA), psoriasis, and psoriatic arthritis interventional studies, and RA noninterventional postapproval safety studies, spontaneous adverse event reporting, and registry data are also reported. Results: Of 1157 patients enrolled in the UC interventional studies, 301 were women of childbearing age. Eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy were identified. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations, 2 spontaneous abortions, and 2 medical terminations. Outcomes across other tofacitinib studies and postmarketing cases were consistent, with a healthy newborn being the most common outcome and no fetal deaths. Conclusions: Based on the limited data available, pregnancy and newborn outcomes among patients with prenatal (maternal/paternal) exposure to tofacitinib in UC studies appear similar to those reported for other tofacitinib clinical study populations and the general population. PMID- 29982687 TI - Assessing the impact of health system organizational structure on hospital electronic data sharing. AB - Objective: Horizontal consolidation in the hospital industry has gained momentum in the United States despite concerns over rising costs and lower quality. Hospital systems frequently point to potential gains in interoperability and electronic exchange of patient information as consolidation benefits. We sought to assess whether hospitals in different health system structures varied in their interoperable data sharing. Materials and methods: We created a cross-sectional national hospital sample from the 2014 AHA Annual Survey and 2015 IT Supplement. We combined the existing taxonomy of health system organizational forms and the ONC's functionality-based, technology-agnostic definition of interoperability. We used logistic regression models to assess the relationship between health systems' organizational forms and interoperability engagement, controlling for hospital characteristics. Results: We found that interoperability engagement varied greatly across hospitals in different health system structures, with facilities in more centralized health systems more likely to be interoperable. Hospitals in one system type, featuring centralized insurance product development but diverse service offerings across member organizations, had significantly higher odds of being engaged in interoperable data sharing in our multivariate regression results. Discussion: The heterogeneity in health system interoperability engagement indicates that incentives to share data vary greatly across organizational strategies and structures. Our results suggest that horizontal consolidation in the hospital industry may not bring significant gains in interoperability progress unless that consolidation takes a specific business alignment form. Conclusion: Policymakers should be wary of claims that horizontal consolidation will lead to interoperability gains. Future research should explore the specific mechanisms that lead to greater interoperability in certain health system organizational structures. PMID- 29982689 TI - Patterns and Associations of Shoulder Motion, Strength, and Function in MARSOC Personnel Without History of Shoulder Injury. AB - Introduction: Military personnel are at an increased risk of shoulder injuries due to training and deployment demands, however, there is a lack of information on the tactical athlete's upper extremity profile. Therefore, the purpose of this study was to examine shoulder musculoskeletal characteristics, including range of motion (ROM), strength, and function, and the relationships between these measures in Marine Corps Forces Special Operations Command (MARSOC) personnel without history of shoulder injury. Materials and Methods: Participants included 195 full-duty male MARSOC personnel (age: 25.38 +/- 2.85 yr; height: 1.79 +/- 0.06 m, mass: 82.79 +/- 7.88 kg) without history of shoulder injury. Measurements of ROM, strength, and function were obtained bilaterally. Shoulder internal rotation (IR) and external rotation (ER) ROM were summed to calculate total arc of motion (ARC). Shoulder IR and ER strength were assessed using an isokinetic dynamometer. Function was evaluated with an explosive push-up. Results: MARSOC personnel present with significantly increased ER ROM, and decreased IR ROM and ARC in their dominant shoulder. They demonstrated greater IR strength and peak force during the explosive push-up on the dominant side but no bilateral differences in average or peak rate were found. Correlation analyses suggest a weak inverse relationship between strength and ARC (r = -0.15 to -0.24). Positive relationships between strength and function were identified except for dominant IR strength and push-up variables. Those with the greatest ARC demonstrated significantly weaker IR and ER strength compared to those with less motion. Conclusions: MARSOC personnel demonstrate shoulder ROM and strength symmetry patterns similar to overhead athletes. Increased dominant shoulder strength does appear to translate to a bilateral functional performance, but overall performance may be limited by the weaker nondominant upper extremity. As ARC increases, IR and ER rotation strength decrease. Repetitive, increased loading of the dominant shoulder during functional movements and training may increase risk of chronic, overuse-type injuries, common to the military. Unilateral exercises and movement analysis should be incorporated to encourage proper development of bilateral shoulder strength, which may be particularly important in those with high ranges of ARC. PMID- 29982690 TI - GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women. AB - Context: GlaxoSmithKline (GSK) 2881078 is a nonsteroidal, selective androgen receptor modulator (SARM) under investigation by GSK for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses. Objective: This was a phase 1b study intended to explore across a dose range the pharmacokinetics (PK) pharmacodynamics relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on PK of GSK2881078. Methods: This was a randomized, placebo-controlled, parallel-group, repeat-dose, dose-escalation study in healthy older males and postmenopausal females. A total of three cohorts of males and three cohorts of females were studied. Dosing at each dose level was twice daily for the first 3 days followed by once daily for up to 53 days. Repeated dual-energy X-ray absorptiometry and MRI cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort. Results: GSK2881078 was generally well tolerated and no serious adverse events were reported. Compared with placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than did males. Transient elevations of alanine aminotransferase were observed. The effect of CYP3A4 inhibition on GKS2881078 PK was unlikely to be of clinical significance. Conclusions: GSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated. PMID- 29982688 TI - Histone H1 acetylation at lysine 85 regulates chromatin condensation and genome stability upon DNA damage. AB - Linker histone H1 has a key role in maintaining higher order chromatin structure and genome stability, but how H1 functions in these processes is elusive. Here, we report that acetylation of lysine 85 (K85) within the H1 globular domain is a critical post-translational modification that regulates chromatin organization. H1K85 is dynamically acetylated by the acetyltransferase PCAF in response to DNA damage, and this effect is counterbalanced by the histone deacetylase HDAC1. Notably, an acetylation-mimic mutation of H1K85 (H1K85Q) alters H1 binding to the nucleosome and leads to condensed chromatin as a result of increased H1 binding to core histones. In addition, H1K85 acetylation promotes heterochromatin protein 1 (HP1) recruitment to facilitate chromatin compaction. Consequently, H1K85 mutation leads to genomic instability and decreased cell survival upon DNA damage. Together, our data suggest a novel model whereby H1K85 acetylation regulates chromatin structure and preserves chromosome integrity upon DNA damage. PMID- 29982691 TI - Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype. AB - Background: Podocyte injury plays a pathogenic role in the development of lupus nephritis (LN). Mesenchymal stem cells (MSCs) have shown promising therapeutic potential for LN. However, whether MSCs can prevent podocyte injury in LN remains unknown. Methods: Human umbilical cord-derived MSCs (UC-MSCs) were infused into lupus-prone B6.MRL-Faslpr (B6.lpr) mice to investigate the influences of UC-MSCs on podocyte injury in LN. Podocytes and macrophages were co-cultured with UC-MSCs in vitro to study the mechanism by which UC-MSC protect podocytes. We further explored the effects of UC-MSCs on macrophage polarization. Results: We found that UC-MSCs promoted the expression of podocyte-specific markers, podocin and synaptopodin, in lupus-prone B6.lpr mice, along with the improvement of lupus renal pathology in terms of reduced IgG and C3 deposition in glomeruli and decreased anti-dsDNA antibody level. Besides, UC-MSC treatment decreased podocyte foot process effacement, as UC-MSCs-treated macrophages led to less podocyte injury in vitro. Interestingly, we further found that UC-MSCs-treated macrophages exhibited an anti-inflammatory phenotype with higher expression of CD206, and lower expression of tumor necrosis factor-alpha and interleukin-1beta. Additionally, UC-MSCs-treated lupus mice showed reduced renal macrophage infiltration and elevated CD206 expression in kidney. Conclusions: Our results demonstrated that UC-MSCs ameliorated LN by preventing podocyte injury possibly through reducing macrophage infiltration and polarizing macrophage into an anti inflammatory phenotype. PMID- 29982692 TI - m6A Demethylase FTO Regulates Dopaminergic Neurotransmission Deficits Caused by Arsenite. AB - Arsenite exposure is known to increase the risk of neurological disorders via alteration of dopamine content, but the detailed molecular mechanisms remain largely unknown. In this study, using both dopaminergic neurons of the PC-12 cell line and C57BL/6J mice as in vitro and in vivo models, our results demonstrated that 6 months of arsenite exposure via drinking water caused significant learning and memory impairment, anxiety-like behavior and alterations in conditioned avoidance and escape responses in male adult mice. We also were the first to reveal that the reduction in dopamine content induced by arsenite mainly resulted from deficits in dopaminergic neurotransmission in the synaptic cleft. The reversible N6- methyladenosine (m6A) modification is a novel epigenetic marker with broad roles in fundamental biological processes. We further evaluated the effect of arsenite on the m6A modification and tested if regulation of the m6A modification by demethylase fat mass and obesity-associated (FTO) could affect dopaminergic neurotransmission. Our data demonstrated for the first time that arsenite remarkably increased m6A modification, and FTO possessed the ability to alleviate the deficits in dopaminergic neurotransmission in response to arsenite exposure. Our findings not only provide valuable insight into the molecular neurotoxic pathogenesis of arsenite exposure, but are also the first evidence that regulation of FTO may be considered as a novel strategy for the prevention of arsenite-associated neurological disorders. PMID- 29982693 TI - Chronic heat stress affects muscle hypertrophy, muscle protein synthesis and uptake of amino acid in broilers via insulin like growth factor-mammalian target of rapamycin signal pathway. AB - Heat stress markedly impairs the growth performance of broilers, such as the reduction of breast muscle mass and yield. The aim of this study was to examine the molecular mechanism of depressed muscle mass and yield caused by heat stress. A total of 144 (28-day-old) male broilers were allocated randomly into 3 treatment groups: (1) the normal control group (environment temperature was 22 degrees C), (2) the heat stress group (environment temperature was 32 degrees C), (3) the pair-fed group (environment temperature was 22 degrees C and pair-fed to heat stress group). The experiment lasted for 14 d (from the age of 28 to 42 d). After 14 d of heat exposure, heat stress decreased (P < 0.05) broiler average daily gain, breast muscle mass, and muscle yield, and increased (P < 0.05) feed to gain ratio. After 14 d of heat exposure, heat stress increased (P < 0.05) the activities of aspartate aminotransferase and the concentrations of uric acid and most amino acids in serum, and reduced (P < 0.05) the concentration of insulin like growth factor 1 (IGF-1) in serum. Additionally, heat stress decreased (P < 0.05) the mRNA expressions of IGF-1, IGF-1 receptor, insulin receptor substrate 1, mammalian target of rapamycin (mTOR), the 70 kD ribosomal protein S6 kinase, myogenic differentiation, myogenin, solute carrier family 38 member 2, solute carrier family 7 member 5, and solute carrier family 3 member 2 of the breast muscle. In conclusion, chronic heat stress resulted in lower breast muscle mass and yield, and decreased muscle protein synthesis and amino acid transportation by downregulating IGFs-mTOR signal pathway. These findings have important practical significance in discovering effective means to alleviate muscle loss caused by chronic heat stress. PMID- 29982694 TI - Family Functioning and Medical Adherence Across Children and Adolescents With Chronic Health Conditions: A Meta-Analysis. AB - Objectives: A meta-analysis examined family functioning and medical adherence in children and adolescents with chronic health conditions. Family functioning was evaluated at the level of the family unit, as well as parent-child interactions. Methods: We conducted literature searches using PubMed, PsycINFO, SCOPUS, Web of Science, and Cochrane. After reviewing 764 articles, 62 studies met eligibility criteria. Pearson's r correlations were the effect size of interest. We conducted both omnibus and domain-specific (e.g., family conflict, cohesion) meta-analyses. Meta-regressions examined whether relevant covariates related to the magnitude of the effect. Results: The omnibus meta-analysis showed that family functioning was significantly related to medical adherence across a variety of pediatric chronic health conditions. Lower family conflict, greater family cohesion, greater family flexibility, more positive communication, and better family problem-solving were each associated with better adherence. There were no significant differences in the magnitude of the omnibus effect based on child age, measurement features (subjective vs. objective or bioassay adherence; family unit vs. parent-child interactions), or study quality. Conclusions: Consistent with social-ecological frameworks, findings supported links between family functioning and medical adherence. This study highlights several limitations of the extant research, including absence of a guiding theoretical framework and several methodological weaknesses. We offer clinical and research recommendations for enhancing scientific understanding and promotion of adherence within the family context. PMID- 29982695 TI - Physicochemical and biochemical parameters of chicken breast meat influenced by stunning methods. AB - The influence of stunning methods on the physicochemical and biochemical parameters of chicken breast meat, as indicators of bird stress, was investigated. A total of 200 Cobb broiler chickens aged from 42 to 48 d were submitted to gas or electrical stunning and slaughtered according to the standard industry practice. Pectoralis major muscles (24 h post-mortem) from broilers stunned by electronarcosis exhibited a higher L* and R-value and lower pH45min than did those from gas stunning, indicating modification of the glycolytic rate. Protease activity, measured as the myofibril fragmentation index, and the sarcoplasmic Ca2+ concentration were highest in samples from broilers stunned by electronarcosis, suggesting the greatest activity of the calpain system. In the fatty acid profile, a higher ratio of polyunsaturated fatty acids was observed in samples from broilers stunned by electronarcosis. These characteristics are related to phospholipase A2 activity, which is higher in animal stress conditions. These results indicated that the gas-stunning method produced less bird stress than electrical stunning. PMID- 29982696 TI - Postexposure Protective Efficacy of T-705 (Favipiravir) Against Sudan Virus Infection in Guinea Pigs. AB - Filoviruses such as Ebola virus (EBOV), Marburg virus (MARV), and Sudan virus (SUDV) cause deadly viral hemorrhagic fever in humans, with high case-fatality rates; however, no licensed therapeutic agent or vaccine has been clinically approved to treat or prevent infection. T-705 (favipiravir) is a novel antiviral drug that has been approved for the treatment of influenza in Japan. T-705 exhibits broad-spectrum antiviral activity against different viruses, including MARV and EBOV, and here, we are the first to report the in vitro and in vivo antiviral activity of T-705 against SUDV. T-705 treatment reduced SUDV replication in Vero E6 cells. Subcutaneous administration of T-705, beginning 1-4 days after infection and continuing for 7 days, significantly protected SUDV infected guinea pigs, with a survival rate of 83%-100%. Viral RNA replication and infectious virus production were also significantly reduced in the blood, spleen, liver, lungs, and kidney. Moreover, early administration of low-dose T-705 and late administration (at 5 days after infection) of higher-dose T-705 also showed partial protection. Overall, our study is the first to demonstrate the antiviral activity of T-705 against SUDV, suggesting that T-705 may be a potential drug candidate for use during outbreaks. PMID- 29982697 TI - Host Gene Expression Kinetics During Treatment of Tuberculosis in HIV-Coinfected Individuals Is Independent of Highly Active Antiretroviral Therapy. AB - Background: Limitations in diagnostic tools to discriminate between active tuberculosis and latent Mycobacterium tuberculosis infection and for monitoring antituberculosis treatment responses are major challenges in tuberculosis control, especially in human immunodeficiency virus (HIV)-coinfected individuals. Methods: Expression levels of 105 immune-related genes were determined in 131 HIV infected patients with active tuberculosis (n = 48), patients with latent M. tuberculosis infection (LTBI; n = 37), and controls with no M. tuberculosis infection (n = 46) in Addis Ababa, Ethiopia, using focused gene expression profiling with a dual-color reverse-transcription multiplex ligation-dependent probe amplification assay. Results: Within the cohort of HIV-positive subjects, the expression profiles of 7 genes at baseline (FCGR1A, RAB24, TLR1, TLR4, MMP9, NLRC4, and IL1B) could accurately discriminate between active tuberculosis and both latent and no M. tuberculosis infection, largely independently of (in)eligibility for highly active antiretroviral therapy (HAART). Six months after antituberculosis treatment, biomarker profiles of patients with tuberculosis became indistinguishable from those of patients with LTBI and controls. Importantly, host gene expression kinetics during antituberculosis treatment in HIV-coinfected individuals was found to be independent of HAART use. Conclusions: Blood transcriptomic profiles can potentially be used as biomarkers to discriminate the different clinical stages of tuberculosis in HIV-coinfected individuals and to monitor tuberculosis treatment responses in both HAART recipients and untreated individuals. PMID- 29982698 TI - In Reply: Superficial Temporal Artery: Distal Posterior Cerebral Artery Bypass Through the Subtemporal Approach: Technical Note and Pilot Surgical Cases. PMID- 29982699 TI - Evaluation of Cyanarox Insecticidal Bait Against Stable Flies (Diptera: Muscidae). AB - Most scatter or granular toxic fly baits are intended to be used against house flies, Musca domestica L. (Diptera: Muscidae). Attractants have been developed to make baits house fly-specific to avoid wasting bait on nontarget flies. Cyanarox Insecticidal Bait (IB) (formerly Zyrox Granular Fly Bait) appeared on the market recently and field reports suggested that stable flies, Stomoxys calcitrans (L.) (Diptera: Muscidae), were being attracted to the bait. There was little doubt that the toxicant, cyantraniliprole, which is formulated to kill house flies, should readily kill stable flies if enough is consumed, but it seemed highly unusual that blood-feeding stable flies would be attracted to the bait. Proof of concept tests were conducted to determine if stable flies would feed on Cyanarox IB. When confined in small cages, mortality exceeded 90% after a 3-d exposure. Stable flies (200) were released in each of two large windowless rooms and Cyanarox IB was placed in small containers at the label rate at floor level in four locations per room. Mortality reached 90% after a 5-d exposure, which indicated that stable flies were attracted to the bait, actively found it and fed on it. The Cyanarox IB Material Safety Data Sheet lists an undisclosed amount of sucrose as part of the bait composition. Stable flies are known to feed on many sugar sources in the environment and the sucrose associated with the Cyanarox IB may explain why stable flies find it attractive. PMID- 29982700 TI - Projected costs associated with school-based screening to inform deployment of Dengvaxia: Vietnam as a case study. AB - Background: After new analysis, Sanofi Pasteur now recommends their dengue vaccine (Dengvaxia) should only be given to individuals previously infected with dengue and the World Health Organization's recommendations regarding its use are currently being revised. As a result, the potential costs of performing large scale individual dengue screening and/or dengue serosurveys have become an important consideration for decision making by policymakers in dengue-endemic areas. Methods: We used an ingredients-based approach to estimate the financial costs for conducting both a school-based dengue serosurvey and school-based individual dengue screening within a typical province in Vietnam, using an existing commercial indirect immunoglobulin G enzyme-linked immunosorbent assay kit. This costing is hypothetical and based on estimates regarding the resources that would be required to perform such activities. Results: We estimated that performing a school-based individual screening of 9-year-olds would cost US$9.25 per child tested or US$197,827 in total for a typical province. We also estimated that a school-based serosurvey would cost US$10,074, assuming one class from each of the grades that include 8- to 11-year-olds are sampled at each of the 12 selected schools across the province. Conclusions: The study indicates that using this vaccine safely on a large-scale will incur noteworthy operational costs. It is crucial that these be considered in future cost-effectiveness analyses informing how and where the vaccine is deployed. PMID- 29982701 TI - How Many Patients With Schizophrenia Do Not Respond to Antipsychotic Drugs in the Short Term? An Analysis Based on Individual Patient Data From Randomized Controlled Trials. AB - Objective: An important clinical question is how many patients with acute schizophrenia do not respond to antipsychotics despite being treated for adequate time and with an effective dose. However, up to date, the exact extent of the phenomenon remains unclear. Methods: We calculated the nonresponse and nonremission percentages using individual patient data from 16 randomized controlled trials (RCTs). Six thousand two hundred twenty-one patients were assigned to one antipsychotic (amisulpride, flupenthixol, haloperidol, olanzapine, quetiapine, risperidone, or ziprasidone) at an adequate dose; the response was assessed at 4-6 weeks. As various definitions of nonresponse have been used in the literature, we applied 4 different cut-offs covering the whole range of percent Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) reduction (<=0%, <25%, <50%, <75%).For symptomatic remission, we used the definition proposed by Andreasen without employing the time criterion. Results: The overall nonresponse for the cut-off of <=0% PANSS/BPRS reduction was 19.8% (18.8%-20.8%); for the cut-off of <25% reduction it was 43% (41.7%-44.3%); for the cut-off of <50% reduction it was 66.5% (65.3%-67.8%); and for the cut-off of <75% reduction it was 87% (86%-87.9%). The overall percentage of no symptomatic remission was 66.9% (65.7%-68.1%). Earlier onset of illness, lower baseline severity and the antipsychotic used were significantly associated with higher nonresponse percentages. Conclusions: Nonresponse and nonremission percentages were notably high. Nevertheless, the patients in our analysis could represent a negative selection since they came from short-term RCTs and could have been treated before study inclusion; thus, further response may not have been observed. Observational studies on this important question are needed. PMID- 29982702 TI - Improving the identification and treatment of depression in low-income primary care clinics: a qualitative study of providers in the VitalSign6 program. AB - Quality problem: Despite its global burden and prevalence, Major Depressive Disorder often goes undetected and untreated, and is particularly pervasive in the primary care setting. Initial assessment: One in four Texans lack health insurance, and people with behavioral health disorders are disproportionately affected. It is possible to provide high-quality depression treatment in primary care settings with outcomes equal to those provided by specialty care. The Center for Depression Research and Clinical Care offered an opportunity to transform service delivery practices in underserved primary care practices to improve quality, health status, patient experience and coordination. Choice of solution: A point-of-care, web-based, self-report based software program, VitalSign6, was developed to provide universal depression screening in primary care practices and assist providers in monitoring and treating patients' symptoms using principles of Measurement-Based Care. Implementation: Implementation included a multi faceted training program designed to build confidence and competence in participating clinics' medical providers and staff as well as ongoing performance improvement delivered by the VitalSign6 team. Evaluation: Primary care providers (N = 11) were interviewed, using a semi-structured interview guide, with a focus on barriers and challenges to full integration, perceptions of the most/least valuable aspects of the program, and the program's impact on knowledge, attitudes and behaviors about depression screening and treatment. Lessons learned: More efficient technology is needed to reduce time wasted, as is training to reduce stigma and correct misconceptions about antidepressant medications. Provider buy in is essential. Conclusions: Despite barriers, VitalSign6 increased knowledge, changed attitudes and enhanced providers' depression screening and treatment skills over time. PMID- 29982703 TI - Early post-hatch survival and humoral immune response of layer chickens when in ovo vaccinated with strain F Mycoplasma gallisepticum,. AB - Commercial layer hens reared on multi-age hen complexes are vaccinated during pullet rearing to combat production losses due to the bacteria Mycoplasma gallisepticum (MG). In this study, the potential to in ovo vaccinate layer chickens against MG was investigated. Layer embryos were administered a dosage of a live attenuated strain F MG (FMG) vaccine at 18 d of incubation and raised for 6 wk for initial post-hatch evaluation in 2 replicate trials. Treatments included control non-injected eggs, eggs injected with diluent, a non-diluted dosage, a 10 2 dilution, a 10-4 dilution, and a 10-6 dilution. A subset of chicks were swabbed for detection of FMG in the trachea at hatch. At 6 wk of age, birds were swabbed again for FMG detection and a blood sample was tested for MG antibody production. Hatch was depressed in the non-diluted dose group (P < 0.0001). Strain F MG was detected at hatch in the trachea in each FMG injection treatment, with decreasing numbers of positive chicks in the lower dosage groups. Mortality during the first 2 wk post-hatch was 3.5% (trial 1) and was 11.7% (trial 2) in the 10-6 dilution treatment, with all other FMG treatments experiencing a high rate of mortality (>50%). Birds in the in ovo FMG treatments had detectable FMG and antibody production at 6 wk. There were no differences in percentage positive birds (P > 0.3 for all tests) or ELISA titers (P = 0.079) between the FMG treatments. Body weight at 6 wk of age was diminished with increasing FMG dose (P < 0.0001). The lowest dose tested was found to be the most practical, causing the least mortality, least weight loss, and a humoral immune response in the majority of the birds. Further work is needed to evaluate how this in ovo vaccine, promoting immunity earlier, would compare to a standard post-hatch vaccination against an MG challenge scenario through a lay cycle. PMID- 29982704 TI - Effect of Dietary Carbohydrate Type on Serum Cardiometabolic Risk Indicators and Adipose Tissue Inflammatory Markers. AB - Context and Objective: Direct comparisons between types of dietary carbohydrate in terms of cardiometabolic risk indicators are limited. This study was designed to compare the effects of an isocaloric exchange of simple, refined, and unrefined carbohydrates on serum cardiometabolic risk indicators, adipose tissue inflammatory markers, and peripheral blood mononuclear cell (PBMC) fractional cholesterol efflux. Design, Participants, and Measures: Participants [postmenopausal women and men (N = 11), 65 +/- 8 years, body mass index 29.8 +/- 3.2 kg/m2, low-density lipoprotein (LDL) cholesterol >=2.6 mmol/L] were provided with diets (60% energy from total carbohydrate, 15% from protein, 25% from fat) for 4.5 weeks in a randomized crossover design, with 2-week washout periods. The variable component was an isocaloric exchange of simple, refined, or unrefined carbohydrate-containing foods. Serum lipoprotein, glucose, insulin, and inflammatory marker concentrations were measured. Abdominal subcutaneous adipose tissue was aspirated to assess macrophage and inflammatory marker gene expression and ex vivo cytokine secretion, and PBMCs were isolated to assess ex vivo fractional cholesterol efflux. Results: Fasting serum LDL and non-high-density lipoprotein (HDL) cholesterol concentrations were higher after the refined compared with simple or unrefined carbohydrate-enriched diets (P < 0.01). Other serum measures, ex vivo fractional cholesterol efflux and adipose tissue gene expression and ex vivo cytokine secretion, were similar between diets. Conclusions: Diets enriched in refined compared with simple or unrefined carbohydrate resulted in higher fasting serum LDL and non-HDL cholesterol concentrations but had little effect on other cardiometabolic risk indicators. This small study raises the intriguing possibility that refined carbohydrate may have unique adverse effects on cardiometabolic risk indicators distinct from simple and unrefined carbohydrate. PMID- 29982705 TI - Generating genomic platforms to study Candida albicans pathogenesis. AB - The advent of the genomic era has made elucidating gene function on a large scale a pressing challenge. ORFeome collections, whereby almost all ORFs of a given species are cloned and can be subsequently leveraged in multiple functional genomic approaches, represent valuable resources toward this endeavor. Here we provide novel, genome-scale tools for the study of Candida albicans, a commensal yeast that is also responsible for frequent superficial and disseminated infections in humans. We have generated an ORFeome collection composed of 5099 ORFs cloned in a GatewayTM donor vector, representing 83% of the currently annotated coding sequences of C. albicans. Sequencing data of the cloned ORFs are available in the CandidaOrfDB database at http://candidaorfeome.eu. We also engineered 49 expression vectors with a choice of promoters, tags and selection markers and demonstrated their applicability to the study of target ORFs transferred from the C. albicans ORFeome. In addition, the use of the ORFeome in the detection of protein-protein interaction was demonstrated. Mating-compatible strains as well as GatewayTM-compatible two-hybrid vectors were engineered, validated and used in a proof of concept experiment. These unique and valuable resources should greatly facilitate future functional studies in C. albicans and the elucidation of mechanisms that underlie its pathogenicity. PMID- 29982706 TI - Behavior, Electrophysiology, and Robotics Experiments to Study Lateral Line Sensing in Fishes. AB - The lateral line system is a sensory system unique to fishes and amphibians. It is composed of distributed mechanosensory hair cell organs on the head and body (neuromasts), which are sensitive to pressure gradients and water movements. Over the last decade, we have pursued an interdisciplinary approach by combining behavioral, electrophysiology, and robotics experiments to study this fascinating sensory system. In behavioral and electrophysiology experiments, we have studied the larval lateral line system in the model genetic organism, zebrafish (Danio rerio). We found that the lateral line system, even in 5-day-old larvae, is involved in an array of behaviors that are critical to survival, and the deflection of a single neuromast can elicit a swimming response. In robotics experiments, we used a range of physical models with distributed pressure sensors to better understand the hydrodynamic environments from the local perspective of a fish or robot. So far, our efforts have focused on extracting control-related information for a range of application scenarios including characterizing unsteady flows such as Karman vortex streets for station holding. We also used robot models to test biological hypotheses on how morphology and movement of fishes affect lateral line sensing. Overall, with this review we aim to increase the visibility and accessibility of this multi-disciplinary research approach. PMID- 29982708 TI - Discussing modern poultry farming systems-insights into citizen's lay theories. AB - A growing public concern, especially about animal welfare problems in poultry farming systems in the EU, has been addressed by numerous (mostly quantitative) studies. However, in-depth research about the underlying reasons for the lack of acceptance concerning modern poultry farming is rare. Debates on animal welfare are often polarized. Thus, this study involved 8 exploratory focus group discussions in 4 German cities. To understand the different positions and to simulate controversial debates on animal welfare, the study includes vegetarians/vegans (as a critical and involved group) and meat eaters. The actual level of knowledge about modern poultry production among participants was heterogeneous, varying between detailed specialized knowledge and misinformation. It was found that improvements for poultry animal welfare that have already been achieved, such as the ban of conventional cages for laying hens in the EU, were not yet recognized by the wider public. A central finding was that participants mostly use lay theories and conclude that the actual poultry husbandry systems make a high use of antibiotics necessary, which has a negative influence on the meat products and, thus, endangers consumer health. The results also indicate that an industrialized agri-food system (rather than farmers) is held primarily responsible for the perceived problems in the poultry value chain. Furthermore, participants are aware of their responsibility and also blame their buying behavior. PMID- 29982707 TI - Antibodies to PfsEGXP, an Early Gametocyte-Enriched Phosphoprotein, Predict Decreased Plasmodium falciparum Gametocyte Density in Humans. AB - Background: Antigametocyte-specific immune responses may regulate Plasmodium falciparum gametocyte density, providing the rationale for pursuing transmission blocking vaccines (TBVs) that target gametocytes in the human host. Methods: To identify novel antigametocyte TBV antigens, we interrogated the gametocyte proteome with our whole proteome differential screening method using plasma from a treatment-reinfection study conducted in western Kenya. At the start of the high-transmission season, 144 males (12-35 years) were enrolled and treated with quinine and doxycycline, peripheral venous blood samples were obtained, volunteers were observed, and weekly blood films were obtained for 18 weeks to quantify gametocytemia. Using plasma pooled from individuals with low versus high gametocyte carriage, we differentially screened a P falciparum gametocyte stage complementary deoxyribonucleic acid expression library. Results: We identified 8 parasite genes uniquely recognized by gametocyte-resistant but not by gametocyte susceptible individuals. Antibodies to one of these antigens, PfsEGXP, predicted lower gametocytemia measured over the 18-week transmission season (P = .021). When analyzed dichotomously, anti-PfsEGXP responders had 31% lower gametocyte density over 18 weeks of follow-up, compared with nonresponders (P = .04). Conclusions: PfsEGXP is one of the first reported gametocyte-specific target of antibodies that predict decreased gametocyte density in humans and supports our novel TBV antigen discovery platform. PMID- 29982709 TI - Combined inhibition of tumour necrosis factor-alpha and interleukin-12/23 for long-standing, refractory psoriatic disease: a differential role for cytokine pathways? PMID- 29982710 TI - Characteristics of adult cigarette smokers who "relight" and the effects of exposure to tobacco smoke constituents. AB - Introduction: About half of smokers relight their cigarette, a habit that is a risk factor for chronic bronchitis and possibly lung cancer. Little is known about the characteristics of smokers who relight and their dependence on nicotine. It is unknown whether relighting affects exposure to tobacco smoke constituents. This study examined the characteristics of relighters of usual brand cigarettes and whether relighting affects exposure to selected tobacco smoke constituents. Methods: We explored relighting status and frequency, using baseline data from 248 adult smokers participating in studies of reduced nicotine cigarettes in relation to demographic and cigarette characteristics, smoking behaviors, nicotine dependence, biomarkers of exposure (exhaled carbon monoxide, blood cotinine), and biomarkers of oxidative stress (ratio of oxidized/reduced glutathione). Results: 69.4% (n=172) of subjects reported relighting, and they relit an average of 5 cigarettes out of 20. Both relighters and non-relighters smoked a mean of 20 CPD (p=0.6). Relighting was significantly associated with higher nicotine dependence, use of longer rod cigarettes, older age, lower income, and unemployment. There were no significant associations between relighting and blood cotinine, exhaled carbon monoxide or measures of oxidized/reduced blood glutathione. Conclusions: The majority of subjects were relighters, who had higher levels of nicotine dependence than non-relighters. Relighters had similar levels of plasma cotinine and exhaled carbon-monoxide to non-relighters. Implications: No study has compared the cigarette characteristics and biomarkers of exposure of adult cigarette smokers who relight with those who do not. Relighting behavior was common in our sample and was associated with low income, not currently working, higher nicotine dependence, cigarette rod length, daily cigarette use years, and a lifetime history of depressed mood. PMID- 29982711 TI - Evaluation of Bone Mineral Density Using DXA and cQCT in Postmenopausal Patients Under Thyrotropin Suppressive Therapy. AB - Purpose: This study aimed to examine the discrepancy in osteoporosis diagnoses between central quantitative computed tomography (cQCT) and dual-energy X-ray absorptiometry (DXA) and evaluated correlations among volumetric bone mineral density (vBMD), areal bone mineral density (aBMD), and trabecular bone score(TBS) in postmenopausal women who were undergoing TSH suppressive therapy. Methods: We enrolled a total of 81 postmenopausal patients [median age: 58 years; interquartile range (IQR): 57 to 60 years] receiving TSH suppressive therapy with levothyroxine after undergoing total thyroidectomy for papillary thyroid cancer. Patients were diagnosed by their bone mineral density (BMD) T-score and categorized according to a vBMD threshold of 120 mg/cm3 for osteopenia and a threshold of 80 mg/cm3 for osteoporosis. Results: When DXA and cQCT were compared, the BMD evaluation results differed in 76% of patients (n = 62; P < 0.001), and the detection rate of osteoporosis was 30.9% for cQCT and 21.0% for DXA. Sixty-two patients had discordant results; in 46 of these patients (74%) whose DXA T-scores were normal, the diagnosis shifted to osteopenia (n = 35) and osteoporosis (n = 11) according to the vBMD on cQCT (P < 0.001), and their vBMD values were significantly correlated with TBS (r = 0.293; P = 0.008). However, aBMD was not significantly correlated with TBS (r = 0.080; P = 0.480). TBS was significantly lower in patients with osteopenia (median: 1.35; IQR: 1.18 to 1.47) and osteoporosis (median: 1.28; IQR: 1.07 to 1.47) than in those with a normal BMD value (median: 1.37; IQR: 1.25 to 1.49; P = 0.041) on cQCT. There was no significant difference in TBS according to DXA BMD status (P = 0.200). Conclusions: DXA and cQCT yielded inconsistent results, and detection of osteopenia and osteoporosis was higher using cQCT. TBS showed a more significant correlation with vBMD than with aBMD. PMID- 29982712 TI - Serum immunoglobulin free light chains are sensitive biomarkers for monitoring disease activity and treatment response in primary Sjogren's syndrome. AB - Objectives: Serum immunoglobulin free light chains (FLCs) are frequently elevated in B-cell-mediated autoimmune diseases, including primary SS (pSS). The objective of this study was to assess if serum FLCs can contribute to classification, mucosa-associated lymphoid tissue (MALT) lymphoma detection, monitoring of disease activity and treatment response in pSS. Methods: Serum samples of 100 consecutive patients suspected of pSS were included. Forty-five patients fulfilled ACR-EULAR criteria for pSS. Additionally, samples of 17 pSS patients with MALT lymphoma and longitudinal samples of pSS patients treated with rituximab (n = 20), placebo (n = 10) or abatacept (n = 15) were included. Serum FLCkappa/FLClambda was measured by nephelometry or turbidimetry. Results: At diagnosis, FLCkappa and FLClambda serum levels were significantly higher in pSS compared with non-SS sicca patients. The FLCkappa/FLClambda ratio was abnormal in 11% of pSS patients. In established MALT-pSS patients, without recent rituximab treatment (n = 12), 50% had abnormal FLCkappa/FLClambda ratios. FLC measurement had no additional value for pSS classification, compared with IgG and anti-SSA. FLC levels correlated significantly with systemic disease activity, assessed by EULAR SS Disease Activity Index (ESSDAI) and clinical ESSDAI, both cross sectionally and longitudinally following treatment. Treatment with rituximab or abatacept significantly lowered FLC levels. FLCs show a large sensitivity to change and relative changes induced by treatment were higher compared with IgG. Conclusion: Serum FLCs are elevated in pSS, and abnormal FLCkappa/FLClambda ratios may be indicative for the presence of MALT lymhoma. FLC levels can be used as a biomarker for systemic disease activity and monitoring treatment responses. FLCs are sensitive to change and have more favorable kinetics than IgG. PMID- 29982713 TI - Genetic Characterization of Toxoplasma gondii DNA Samples Isolated From Humans Living in North America: An Unexpected High Prevalence of Atypical Genotypes. AB - Background: Whereas in Europe most of Toxoplasma gondii genotypes belong to the type II lineage, in Latin America, type II is rare and atypical strains predominate. In North America, data on T. gondii genotypes in humans are scarce. Methods: In this study, T. gondii DNA samples from 67 patients with diagnosed toxoplasmosis in the United States were available for genotyping. Discriminant analysis of principal components was used to infer each atypical genotype to a geographic area where patients were probably infected. Associations between genotype, disease severity, immune status, and geographic region were also estimated. Results: Of 67 DNA samples, 41 were successfully genotyped: 18 (43.9%) and 5 (12.2%) were characterized as types II and III, respectively. The remaining 18 genotypes (43.9%) were atypical and were assigned to a geographic area. Ten genotypes originated from Latin America, 7 from North America, and 1 from Asia (China). In North America, unlike in Europe, T. gondii atypical genotypes are common in humans and, unlike in Latin America, type II strains are still present with significant frequency. Conclusions: Clinicians should be aware that atypical genotypes are common in North America and have been associated with severe ocular and systemic disease and unusual presentations of toxoplasmosis in immunocompetent patients. PMID- 29982714 TI - First-year estimated glomerular filtration rate variability after pre-end-stage renal disease program enrollment and adverse outcomes of chronic kidney disease. AB - Background: Scarce evidence associates the first-year estimated glomerular filtration rate (eGFR) variability and longitudinal change scales concomitantly to the risk of developing end-stage renal disease (ESRD), acute coronary syndrome (ACS) and death following pre-ESRD program enrollment in chronic kidney disease (CKD). Methods: We conducted a prospective cohort study of 5092 CKD patients receiving multidisciplinary care between 2003 and 2015 with careful ascertainment of ESRD, ACS and death during the follow-up. First-year eGFR variability and longitudinal change scales that were based on all first-year eGFR measurements included coefficient of variation of eGFR (eGFR-CV), percent change (eGFR-PC), absolute difference (eGFR-AD), slope (eGFR-slope) and area under the curve (AUC). Results: A total of 786 incident ESRD, 292 ACS and 410 death events occurred during the follow-up. In the multiple Cox regression, the fully adjusted hazard ratios (HRs) of progression to ESRD for each unit change in eGFR-CV, eGFR-PC, eGFR-AD, eGFR-slope, eGFR-AUC were 1.03 [95% confidence interval (CI) 1.02-1.04], 1.04 (1.03-1.04), 1.16 (1.14-1.18), 1.16 (1.14-1.17) and 1.04 (1.03-1.04), respectively. The adjusted HRs for incident ESRD comparing the extreme with the reference quartiles of eGFR-CV, eGFR-PC, eGFR-AD, eGFR-slope and eGFR-AUC were 2.67 (95% CI 2.11-3.38), 8.34 (6.33-10.98), 19.08 (11.89-30.62), 13.08 (8.32 20.55) and 6.35 (4.96-8.13), respectively. Similar direction of the effects on the risk of developing ACS and mortality was observed. In the 2 * 2 risk matrices, patients with the highest quartile of eGFR-CV and concomitantly with the most severely declining quartiles of any other longitudinal eGFR change scale had the highest risk of all outcomes. Conclusions: The dynamics of eGFR changes, both overall variability and longitudinal changes, over the first year following pre-ESRD program enrollment are crucial prognostic factors for the risk of progression to ESRD, ACS and deaths among patients with CKD. A risk matrix combining the first-year eGFR variability and longitudinal change scales following pre-ESRD enrollment is a novel approach for risk characterization in CKD care. Randomized trials in CKD may be required to ascertain comparable baseline eGFR dynamics. PMID- 29982715 TI - A positive legacy of trauma? A study on the impact of natural disasters on medical utilization. AB - Objective: The impact of natural disasters on medical utilization is largely unknown and often overlooked how it affects bereaving and non-bereaving survivors. The aim of this study is to determine the medical utilization between both survivor groups and long-term effects. Study design: A 10-year 1999-2009 population-based retrospective study by using the National Health Insurance claim database and the Household Registration database from the Department of Health, Executive Yuan, Taiwan. Settings: Taiwan 1999 Chi-Chi earthquake-affected areas. Participants: A total of 49 834 individuals which included 1183 bereaving survivors and 48 651 non-bereaving earthquake survivors. Intervention(s): None. Main Outcome Measures: Medical utilization of bereaving and non-bereaving survivors. Results: The results showed that bereaving survivors had significantly more outpatient visits before the earthquake, within 3-month period and 1 year after earthquake (odds ratio (OR) = 1.11, 1.16 and 1.08). However, after 1 year after earthquake their outpatient visits were not significantly different from non-bereaving, and even significantly less in some years. Inpatient visits of bereaving survivors had similar trend to outpatient visits, i.e. visits were more both before earthquake and within 3-month period after earthquake (OR = 1.59 and 1.89), however, they were not significantly higher than non-bereaving survivors for the following years of the study. Conclusion: Our study reveals that compared to non-bereaving survivors, bereaving survivors slightly had higher medical utilization in the beginning stage of earthquake, i.e. for the first 3-month period or 1 year after earthquake. However, there were no differences between these two groups in medical utilization including outpatient and inpatient visits in long run. PMID- 29982716 TI - Limitations of the 2015 ATA Guidelines for Prediction of Thyroid Cancer: A Review of 1947 Consecutive Aspirations. AB - Background: The 2015 American Thyroid Association (ATA) guidelines have been proposed to aid in the management of thyroid nodules by determining whether fine needle aspiration is indicated. Objective: To determine whether the ATA guidelines contribute to the overdiagnosis of thyroid cancer. Patients and Methods: This was a retrospective cohort study of ultrasound-imaged thyroid nodules (n = 1947) consecutively aspirated at a tertiary care center from 1 October 2009 to 22 February 2016. Nodules were retrospectively reviewed, assigned a 2015 ATA morphology, and placed into one of five 2015 ATA categories of risk (ATA-1, <1% risk of malignancy; ATA-2, <3% risk; ATA-3, 5% to 10% risk, ATA-4: 10% to 20% risk; ATA-5, >70% to 90% risk) by a reader who was blinded to cytology. ATA category was compared with cytopathology. The positive predictive value (PPV) of each ATA category was calculated with respect to cancer. Numbers needed to aspirate and Pearson correlations were calculated. Interrater agreement for ATA category across five readers was assessed. Results: The PPV for cancer increased by ATA category [category 1 to 5, respectively: 0% (0/14), 2% (4/249), 5% (36/733), 12% (104/850), 28% (28/101)]. The number needed to sample to detect one papillary cancer was 125 (ATA-2), 49 (ATA-3), 13 (ATA-4), and 5 (ATA-5). The overall interrater agreement for ATA score across all five readers was fair (intraclass correlation coefficient 0.460). Conclusions: The 2015 ATA guidelines stratify risk for thyroid cancer; however, the stratification system is overly optimistic regarding cancer detection rates for the higher-risk nodules, and there is only fair interrater agreement. PMID- 29982717 TI - Hyperphosphataemia: which phosphate binder? PMID- 29982718 TI - Efficacy of Human Monoclonal Antibody Monotherapy Against Bundibugyo Virus Infection in Nonhuman Primates. AB - Background: The 2013-2016 Ebola virus disease (EVD) epidemics in West Africa highlighted a need for effective therapeutics for treatment of the disease caused by filoviruses. Monoclonal antibodies (mAbs) are promising therapeutic candidates for prophylaxis or treatment of virus infections. Data about efficacy of human mAb monotherapy against filovirus infections in preclinical nonhuman primate models are limited. Methods: Previously, we described a large panel of human mAbs derived from the circulating memory B cells from Bundibugyo virus (BDBV) infection survivors that bind to the surface glycoprotein (GP) of the virus. We tested one of these neutralizing mAbs that recognized the glycan cap of the GP, designated mAb BDBV289, as monotherapy in rhesus macaques. Results: We found that recombinant mAb BDBV289-N could confer up to 100% protection to BDBV-infected rhesus macaques when treatment was initiated as late as 8 days after virus challenge. Protection was associated with survival and decreased viremia levels in the blood of treated animals. Conclusions: These findings define the efficacy of monotherapy of lethal BDBV infection with a glycan cap-specific mAb and identify a candidate mAb therapeutic molecule that could be included in antibody cocktails for prevention or treatment of ebolavirus infections. PMID- 29982720 TI - Barriers to treatment adjustment within a treat to target strategy in rheumatoid arthritis: a secondary analysis of the TRACTION trial. AB - Objectives: Adherence to a treat to target (TTT) strategy is a recommended paradigm for RA; however, research shows there are many barriers to implementation. We conducted a trial to improve TTT implementation, and herein examine barriers to treatment adjustment within TTT among patient visits not in agreement with the TTT paradigm. Methods: Chart review assessed TTT implementation based on documentation of four items: designation of a treatment target, recording a disease activity measure, shared-decision making when applicable and adjusting treatment when disease activity was not at target. A treatment decision not in agreement with the TTT paradigm was defined as lack of treatment adjustment when disease activity was not at the pre-determined treatment target. Providers were encouraged to report the barriers to treatment change; these were categorized and analysed by study staff. Multiple barriers were possible for one visit. Results: Eighty-three visits not in agreement with the TTT strategy were observed in 74 patients, during which 90 reported barriers to treatment adjustment were noted. Common barriers to adjusting treatment included patient preference in 37.1% of visits and elevated disease activity measure despite no objective evidence of active RA in 38.6% of visits. Conclusion: An elevated disease activity measure not reflective of RA disease activity and patient preference are the two leading barriers to treatment adjustment to TTT in RA. Understanding barriers to adherence should guide interventions aimed at using better markers of disease activity and improving alignment with patient preference, with the overarching goal of enhancing TTT adherence. PMID- 29982719 TI - A novel dual-cytokine-antibody fusion protein for the treatment of CD38-positive malignancies. AB - A novel dual-cytokine-antibody fusion protein, consisting of an antibody directed against CD38 [a tumor-associated antigen mainly expressed on the surface of multiple myeloma (MM) cells], simultaneously fused to both tumor necrosis factor ligand superfamily member 10 (TRAIL) and interleukin-2 (IL2), was designed, expressed and purified to homogeneity. The novel fusion protein, termed IL2 alphaCD38-alphaCD38-scTRAIL, was able to selectively recognize its cognate antigen expressed on the surface of MM and lymphoma cell lines, as evidenced by flow cytometry analysis. Moreover, the targeted version of TRAIL was able to induce cancer cell death in vitro, both with MM cell lines and with fresh isolates from the bone marrow of MM patients. The experiments provide a rationale for possible future applications of IL2-alphaCD38-alphaCD38-scTRAIL for the treatment of patients with MM or other CD38-positive malignancies. PMID- 29982721 TI - Improved sgRNA design in bacteria via genome-wide activity profiling. AB - CRISPR/Cas9 is a promising tool in prokaryotic genome engineering, but its success is limited by the widely varying on-target activity of single guide RNAs (sgRNAs). Based on the association of CRISPR/Cas9-induced DNA cleavage with cellular lethality, we systematically profiled sgRNA activity by co-expressing a genome-scale library (~70 000 sgRNAs) with Cas9 or its specificity-improved mutant in Escherichia coli. Based on this large-scale dataset, we constructed a comprehensive and high-density sgRNA activity map, which enables selecting highly active sgRNAs for any locus across the genome in this model organism. We also identified 'resistant' genomic loci with respect to CRISPR/Cas9 activity, notwithstanding the highly accessible DNA in bacterial cells. Moreover, we found that previous sgRNA activity prediction models that were trained on mammalian cell datasets were inadequate when coping with our results, highlighting the key limitations and biases of previous models. We hence developed an integrated algorithm to accurately predict highly effective sgRNAs, aiming to facilitate CRISPR/Cas9-based genome engineering, screenings and antimicrobials design in bacteria. We also isolated the important sgRNA features that contribute to DNA cleavage and characterized their key differences among wild type Cas9 and its mutant, shedding light on the biophysical mechanisms of the CRISPR/Cas9 system. PMID- 29982722 TI - Entheseal involvement in patients with systemic lupus erythematosus: an ultrasound study. AB - Objectives: The main objective of this study is to explore the prevalence and distribution of entheseal US changes in a cohort of SLE patients, taking as controls a group including both PsA patients and healthy subjects. The secondary objective is to investigate the correlation between the US findings and the clinical and serological data in SLE patients. Methods: Clinical and US assessment of quadriceps, patellar and Achilles tendons, and plantar fascia entheses were performed by independent rheumatologists on 65 patients with SLE, 50 patients with PsA and 50 healthy subjects. US findings were identified according to the OMERACT definitions. In SLE patients, the correlation between the US changes and the clinical and laboratory findings was evaluated. Results: US revealed one or more abnormalities in at least one enthesis in 44 out of 65 SLE patients (67.7%), 47 out of 50 PsA patients (94.0%) and 22 out of 50 healthy subjects (44.0%). In SLE patients, US findings indicating active inflammation were significantly more frequently detected than in healthy subjects (P < 0.001). The distal enthesis of the patellar tendon was the most commonly involved. The presence of power Doppler signal at the enthesis was an independent predictor of SLE disease activity (SLEDAI-2k P < 0.001, beta = 0.52; musculoskeletal-BILAG P < 0.001, beta = 0.56). Conclusion: The burden of entheseal sonographic changes was significantly higher in SLE patients than in healthy subjects, especially as regards active inflammation. The presence of power Doppler signal at the enthesis may represent a potential biomarker of SLE disease activity. PMID- 29982723 TI - Consumption of a Carbonated Beverage with High-Intensity Sweeteners Has No Effect on Insulin Sensitivity and Secretion in Nondiabetic Adults. AB - Background: The effects of the regular intake of beverages containing high intensity sweeteners on insulin sensitivity in healthy individuals remain controversial. Objective: This trial compared the effects of the consumption of a carbonated beverage containing aspartame and acesulfame K (high-intensity sweeteners beverage-HISB) with those of an unsweetened, no-calorie carbonated beverage (UB) on insulin sensitivity and secretion in nondiabetic adults. Methods: SEDULC was a randomized, double-blind, crossover study. Nondiabetic adults [mean age 31 y, 44% men, body mass index (BMI; kg/m2) 19-29] who did not consume high-intensity sweeteners were randomized 1:1 to drink 1 of the 2 carbonated beverages, 2 cans (330 mL each)/d, for 12 wk. After a 4-wk washout period, participants were switched to the opposite beverage for 12 wk. The primary outcome tested was the change in insulin sensitivity as assessed by the Matsuda Insulin Sensitivity Index (MISI) after an oral glucose load. Secondary outcomes were indexes of insulin secretion. Results: Sixty individuals were enrolled and 50 completed the study (28 nonoverweight and 22 overweight participants). The change in MISI from baseline did not significantly differ between beverages and noninferiority was demonstrated (difference = -0.23; 95% CI: -1.31, 0.85; P < 0.0001). The change in insulinogenic (means +/- SEMs: 0.23 +/- 0.14 for HISB compared with 0.08 +/- 0.1 for UB) and disposition indexes (2.70 +/- 0.99 for HISB compared with 1.62 +/- 0.90 for UB) did not differ, and no differences in insulin secretion estimates were confirmed by the Stumvoll indexes. Consuming the high-intensity sweeteners did not affect body weight, self reported dietary consumption, or self-reported physical activity. Conclusions: These findings suggest that the daily consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 wk has no significant effect on insulin sensitivity and secretion in nondiabetic adults. This trial was registered at clinicaltrials.gov as NCT02031497. PMID- 29982725 TI - Development of the Concept for Stem Cell-Based Developmental Neurotoxicity Evaluation. AB - Human brain development consists of a series of complex spatiotemporal processes that if disturbed by chemical exposure causes irreversible impairments of the nervous system. To evaluate a chemical disturbance in an alternative assay, the concept evolved that the complex procedure of brain development can be disassembled into several neurodevelopmental endpoints which can be represented by a combination of different alternative assays. In this review article, we provide a scientific rationale for the neurodevelopmental endpoints that are currently chosen to establish assays with human stem/and progenitor cells. Assays covering these major neurodevelopmental endpoints are thought to assemble as building blocks of a DNT testing battery. PMID- 29982724 TI - Diet-Quality Indexes Are Associated with a Lower Risk of Cardiovascular, Respiratory, and All-Cause Mortality among Chinese Adults. AB - Background: Diet-quality indexes have been associated with a lower risk of chronic disease mortality in Western populations, but it is unclear whether these indexes reflect protective dietary patterns in Asian populations. Objective: We examined the association between Alternative Healthy Eating Index-2010 (AHEI 2010), alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Healthy Diet Indicator (HDI) scores and the risk of all cause cardiovascular disease (CVD), cancer, and respiratory disease mortality. Methods: We used data from a prospective cohort of 57,078 Singapore Chinese men and women (aged 45-74 y) who were free of cancer and CVD at baseline (1993-1998) and who were followed up through 2014. The diet-quality index scores were calculated on the basis of data from a validated 165-item food-frequency questionnaire. Cox regression models with adjustment for potential confounders including sociodemographic and lifestyle variables, body mass index, and medical history were used to estimate HRs and 95% CIs. Results: During a total of 981,980 person-years of follow-up, 15,262 deaths (CVD: 4871; respiratory: 2690; and cancer: 5306) occurred. Comparing the highest with the lowest quintiles, the multivariable adjusted HRs (95% CIs) for all-cause mortality were 0.82 (0.78, 0.86) for AHEI-2010, 0.80 (0.76, 0.85) for aMED, 0.80 (0.75, 0.84) for DASH, and 0.88 (0.83, 0.92) for HDI scores (all P-trend < 0.001). Higher diet index scores were associated with a 14-28% lower risk of CVD and respiratory mortality, but only a 5-12% lower risk of cancer mortality. Higher consumption of vegetables, fruit, nuts, and long-chain n-3 (omega-3) fatty acids, lower consumption of red meat, and avoidance of high alcohol consumption were the diet index components associated with a lower risk of mortality. Conclusion: Adherence to several recommended dietary patterns that emphasize healthy plant-based foods was associated with a substantially lower risk of chronic disease mortality in an Asian population. The Singapore Chinese Health Study was registered at www.clinicaltrials.gov as NCT03356340. PMID- 29982726 TI - The role of a health protection scheme in health services utilisation among community-dwelling older persons in Ghana. AB - Objectives: This study examines the relationships between National Health Insurance Scheme (NHIS) enrollment and the frequency and 'timing' of health services utilisation among community-dwelling older Ghanaians. It also investigates whether the NHIS policy has improved equity in access to healthcare in later life. Methods: Cross-sectional data were derived from an Ageing, Health, Psychological Wellbeing and Health-seeking Behaviour Study collected between August 2016 and January 2017 (N = 1200). Descriptive and bivariate analyses described the sample. Generalised Poisson and logit regression models respectively estimated the predictors of frequency of health services utilisation and time from onset of illness to health facility use and during last illness episode. Results: Older persons with active NHIS membership frequently used health facilities (beta = 0.237, SE = 0.0957, p ? 0.005), but the association was largely a function of health-related factors. The NHIS enrollees were more likely to attend health facility earlier (beta = 1.347, SE = 0.3437, p ? 0.001) compared with non-enrollees, after adjusting for theoretically relevant covariates. Moreover, given the NHIS enrollment, the rich (ebeta = 2.149, SE = 0.240, p ? 0.005), social support recipients (ebeta = 1.366, SE = 0.162, p ? 0.05) and those living with relevant others (ebeta = 2.699, SE = 0.175, p ? 0.001) were more likely to consume health services. Discussion: Ghana's NHIS policy generally increases health services utilisation but at present lacks the capability to improve equitable access to healthcare, especially between poor and non-poor older adults. This may hamper the progress towards universal health coverage (UHC), indicating the need for further refinements in the policy including ways to improve the health status of older persons. PMID- 29982727 TI - Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo Controlled Trial. AB - Background: GEN-003 is a candidate therapeutic vaccine for genital herpes simplex virus type 2 (HSV-2). We compared virologic and clinical impact of varying GEN 003 doses. Methods: Adults with symptomatic HSV-2 received placebo or GEN-003 (30 or 60 ug antigen with 25, 50, or 75 ug adjuvant). Viral shedding and lesion rates before vaccination were compared with those measured immediately after vaccination, then at weeks 29-33 and 53-57 after last dose. Results: Compared with baseline shedding rates, the rate ratios for viral shedding immediately after treatment were as follows: 0.82 (95% confidence interval [CI], 0.49-1.36), 30 ug antigen/25 ug adjuvant (30/25) dose; 0.64 (95% CI, 0.45-0.92), 30/50 dose; 0.63 (95% CI, 0.37-1.10), 30/75 dose; 0.56 (95% CI, 0.36-0.88), 60/25 dose; 0.58 (95% CI, 0.38-0.89), 60/50 dose; 0.45 (95% CI, 0.16-0.79), 60/75 dose; and 0.98 (95% CI, 0.76-1.26), placebo. Lesion rate reductions by GEN-003 ranged from 31% to 69%, but lesion rates also decreased among placebo recipients (62%). Reductions in shedding and lesion rate were durable for 12 months for the 60 ug antigen plus 50 or 75 ug adjuvant groups. No serious adverse events occurred with vaccination. Conclusions: The most efficacious vaccine combinations for GEN-003 were the 60 ug/50 ug and 60 ug/75 ug doses. PMID- 29982728 TI - Flavored Versus Non-Flavored Waterpipe Tobacco: A Comparison of Toxicant Exposure, Puff Topography, Subjective Experiences and Harm Perceptions. PMID- 29982729 TI - Dysconnectivity of Large-Scale Functional Networks in Early Psychosis: A Meta analysis. AB - Objective: Increasingly, studies have identified abnormalities in the functional connectivity (FC) of large-scale neural networks in early psychosis, but the findings thus far have been inconclusive. Therefore, the aim of this study was to identify robust alterations in FC of the default mode (DMN), salience (SN), and central executive networks (CEN), in patients with first-episode psychosis (FEP) using a meta-analytic approach. Methods: Included studies were required to be resting-state, seed-to-whole brain, FC neuroimaging studies, comparing FEP patients to healthy controls (HC), with seeds within the boundaries of the region of-interest networks. Peak effect coordinates and peak t, z, or p values were meta-analyzed using Seed-based d Mapping software. Results: The DMN seeds primarily displayed within-network hypoconnectivity (largest clusters including the middle orbital gyrus; and ventral anterior cingulate gyrus). The SN seeds displayed hypoconnectivity with regions in the DMN and CEN (largest clusters located in the bilateral middle temporal gyri). Review of the limited CEN data revealed hypo- and hyperconnectivity across the networks. Negative symptoms were positively correlated with all DMN FC abnormalities in the FEP group. Antipsychotic-treated patients displayed greater hypoconnectivity than antipsychotic-naive patients between both the DMN/SN seeds and prefrontal regions. Conclusions: These findings provide substantial evidence of widespread resting-state FC abnormalities of the DMN, SN, and CEN in early psychosis; particularly implicating DMN and SN dysconnectivity as a core deficit underlying the psychopathology of psychosis. Additionally, we highlight the importance of disentangling connectivity abnormalities resulting from disease processes, from those that result from antipsychotic treatment. PMID- 29982731 TI - Dysfunction of Circulating Natural Killer T Cells in Patients With Scrub Typhus. AB - Background: Human natural killer T (NKT) cells are known to serve as regulatory and/or effector cells in infectious diseases. However, little is known about the role of NKT cells in Orientia tsutsugamushi infection. Accordingly, the objective of this study was to examine the level and function of NKT cells in patients with scrub typhus. Methods: This study included 62 scrub typhus patients and 62 healthy controls (HCs). NKT cell level and function in peripheral blood samples were measured by flow cytometry. Results: Proliferation of NKT cells and their ability to produce interferon-gamma and interleukin-4 (IL-4) were significantly lower in scrub typhus patients compared to those in HCs. However, circulating NKT cell levels were comparable between patients and HCs. Expression levels of CD69, programmed death-1 (PD-1), lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin domain and mucin domain-containing molecule-3 (TIM-3) were significantly increased in scrub typhus patients. Elevated expression of CD69, PD 1, LAG-3, and TIM-3, impaired proliferation, and decreased IL-4 production by NKT cells were recovered in the remission phase. Conclusions: This study demonstrates that circulating NKT cells are numerically preserved but functionally impaired in scrub typhus patients. In addition, NKT cell dysfunction is recovered in the remission phase. PMID- 29982730 TI - Characterization of strain of fowl adenoviruses circulating in Morocco. AB - Infection of fowl with adenoviruses raises concerns for poultry production, thus making the detection of adenovirus infection crucial. Fowl adenovirus is the causal agent of inclusion body hepatitis (IBH) and other avian syndromes that affect the production; since the epidemiological point of view it is important to differentiate the serotype of the virus. Between September 2016 and February 2017 several cases of IBH in broiler flocks were reported in Morocco. Molecular detection of the fowl adenovirus and sequencing also allowed determining the strain of the virus. The strain detected was identified as fowl adenovirus closely related to serotype 11 and 8a based on nucleotide sequence analyses of hexon gene loop 1. This is the first time that FadV has been detected in Morocco. PMID- 29982732 TI - High Frequency of Cardiovascular Complications in Tunisian Kawasaki Disease Patients: Need for a Further Awareness. AB - Background: The outcome of Kawasaki disease (KD) depends on cardiovascular complications (CVCs). Objectives: This study aimed to explore diagnostic features and CVCs in Tunisian patients with KD. Methods: In total, 33 Tunisian patients (age, 2.9 +/- 2.2 years) fulfilling the diagnosis criteria of KD, were retrospectively reviewed. Nonparametric tests were used to compare the two groups with regards to coronary complications (CCs). Results: Diagnosis of KD was established at day 11 +/- 5.1 from the beginning of the fever. Apyrexia was obtained in an average of 29 h after completion of intravenous immunoglobulin. CVCs were identified in 52% of cases: CC in 15 patients (giant aneurysm >8 mm in five patients) and non-CCs in 6 patients (severe in three patients). CCs were more frequently associated with the male sex (p = 0.037), fever lasting >8 days (p = 0.028) and longer time to apyrexia (p = 0.031). Conclusion: In Tunisia, better knowledge and monitoring of KD are warranted. PMID- 29982733 TI - Illumination semiangle of 10-9 rad achieved in a 1.2-MV atomic resolution holography transmission electron microscope. AB - The coherency of a 1.2-MV transmission electron microscope was evaluated through illumination semiangles calculated from lengths over which Fresnel fringes can be observed. These lengths were determined from the diameters of circular holes fully filled with Fresnel fringes, i.e. this method allows lengths to be accurately measured even if micrographs are subjected to distortions. The smallest illumination semiangle of 4.0 * 10-9 rad was obtained for a circular hole with a diameter of 191 MUm. In addition, electron beam brightness was estimated to be approximately 3 * 1014 A/m2.sr from the obtained illumination semiangle values and current densities. The results provide us with essential information that can be referred to in future electron holography studies aimed at detecting weak electromagnetic fields in materials. PMID- 29982734 TI - In vitro antileishmanial activity of ravuconazole, a triazole antifungal drug, as a potential treatment for leishmaniasis. AB - Objectives: Leishmaniasis, one of the most significant neglected diseases around the world, is caused by protozoan parasites of the Leishmania genus. Nowadays, the available aetiological treatments for leishmaniasis have variable effectiveness and several problems such as serious side effects, toxicity, high cost and an increasing number of resistance cases. Thus, there is an urgent need for safe, oral and cost-effective drugs for leishmaniases. Previously, our group has shown the effect of the ergosterol biosynthesis inhibitors on Leishmania amazonensis. Herein, we showed the effect of ravuconazole against L. amazonensis; ravuconazole is a second-generation triazole antifungal drug that has good bioavailability after oral administration and a long terminal half-life in humans, a broad activity spectrum, high effectiveness in treatment of mycosis and negligible side effects. Methods: Several methodologies were used: cell culture, fluorescence and electron microscopy, high-resolution capillary GC coupled with MS, fluorimetry and flow cytometry. Results: Our results showed that ravuconazole was able to inhibit the proliferation of L. amazonensis promastigotes and intracellular amastigotes in vitro, with single-digit to sub-micromolar IC50 values, causing several alterations in the morphology, ultrastructure, cell viability and physiology of the parasites. The mitochondrion was significantly affected by the treatment, resulting in a collapse of the mitochondrial transmembrane potential that consequently led to inhibition of ATP production, combined with an increase in reactive oxygen species and mitochondrial superoxide production; by transmission electron microscopy, the organelle displayed a completely altered ultrastructure. The treatment changed the lipid profile, showing a profound depletion of the 14-desmethyl endogenous sterol pool. Conclusions: These results suggest that ravuconazole could be an alternative option for the treatment of leishmaniasis. PMID- 29982735 TI - 'Capacity for Discernment' and Euthanasia on Minors in Belgium. AB - In 2014, the Belgian Euthanasia Law was amended so as to extend the possibility of obtaining euthanasia to minors who have the capacity for discernment. The amendment led to considerable debate among Belgian legal experts, health care professionals and ethicists, in large part due to concerns about the scope and assessment of the minor's 'capacity for discernment', a concept first introduced in Belgian medical law by the amendment. This article offers a critical legal analysis of the concept of 'capacity for discernment' and its implications for euthanasia practice in Belgium. We do so by focusing on a ruling of the Belgian Constitutional Court of 29 October 2015, where the concept figured prominently in the examination of the constitutionality of the amendment. This approach also allows us to shed light on the interpretation of several core aspects of the original 2002 Euthanasia Law and its 2014 amendment. PMID- 29982736 TI - Timing and mode of simulated ungulate herbivory alter aspen defense strategies. AB - Timing of herbivory or selection of specific plant tissues (mode of herbivory) by different ungulate herbivore species are likely to have important influences on plant defense strategies. In this study, we devised two different modes of simulated herbivory, representing a selective ungulate feeding strategy (defoliation: leaf tissue removal only) and a bulk feeding strategy (clipping: leaves, twigs and meristems taken together). We applied these contrasting herbivory treatments to juvenile aspen suckers (Populus tremuloides Michx.) regenerating underneath aspen stands in early summer (June), late summer (August) or at both times to determine the effects of herbivory mode, timing and frequency on regenerating aspen. In response to the simulated herbivory treatments, we measured traits related to three plant defense strategies: tolerance (aboveground biomass and stem diameter), resistance (foliar phenolic glycosides) and vertical escape (sucker height and average leader length). There was no evidence that mode, timing or frequency of simulated herbivory induced or repressed phenolic glycoside production. Early summer herbivory was more detrimental than late summer herbivory on aspen tolerance and escape. Repeat herbivory in late summer did not amplify the negative effects of early summer herbivory. Clipping and defoliation tended to have similar effects on tolerance but clipping was more detrimental than defoliation on vertical escape. These results suggest that different ungulate herbivore species may have disparate impacts on the plant communities by selecting different tissues of the same plant, or browsing the plant at different times in the growing season. PMID- 29982737 TI - Reduced Incidence of Hepatocellular Carcinoma with Tenofovir in Chronic Hepatitis B Patients with and without Cirrhosis - a Propensity Score Matched Study. AB - Background: The effect of newer oral anti-HBV medication, tenofovir disoproxil (TDF), on liver related outcomes among Asians is limited. We examined the effect of TDF on incidence of hepatocellular carcinoma (HCC) within an Asian chronic hepatitis B (CHB) population. Methods: Retrospective cohort study: 6914 adult, non-transplant, CHB mono-infected patients recruited from 6 U.S. referral, community medical centers, and a community based Taiwan cohort: 774 patients received TDF; 6140 not treated. Propensity score matching [(PSM); age, sex, HBeAg, HBV DNA, ALT, baseline cirrhosis status, follow-up time] balanced the groups (n=591, treated vs. untreated). Kaplan-Meier estimated cumulative risk of HCC. Cox proportional hazards models estimated HCC risk between groups. Results: The eight-year cumulative HCC incidence was significantly higher in PSM untreated group (20.13% vs 4.69%, p<0.0001). Cirrhosis was a significant predictor for HCC (aHR: 5.36; 95% CI: 2.73 - 10.51, p<0.001). On multivariate analysis adjusting for age, sex, HBV DNA, ALT and study site, TDF was associated with a 77% [0.23 (0.56 - 0.92)] HCC risk reduction in patients with cirrhosis and 73% [0.27 (0.07 0.98)] reduction in patients without cirrhosis. Conclusions: Among cirrhotic and non-cirrhotic Asian CHB patients, TDF therapy was significantly associated with an eight-year HCC cumulative incidence rate reduction. PMID- 29982738 TI - Retrospective and Cross-sectional Analysis of Physical Training-Related Musculoskeletal Injuries in Slovenian Armed Forces. AB - Introduction: Injury registration is an important first step of the musculoskeletal injury (MSI) prevention process that helps establish the magnitude of the problem and focus prevention on the body parts that are most frequently injured. However, an injury definition used in that process may influence the reported prevalence of MSI, causing some injuries to be under reported which in turn alters the prevention efforts. The primary goal of our study was to identify the 10-year prevalence of MSI in members of the Slovenian Armed Forces (SAF), to help plan and implement preventive measures for the reduction of MSI. Our secondary goal was to compare MSI data collected using two different approaches. The first one was prospective approach where only time-loss injuries were collected during a 10-year period, and the second one was a cross sectional approach where at one point in time soldiers were asked about any musculoskeletal complaint. Materials and Methods: The study was an introductory part of trial that was registered in the U.S. Clinical Trials Registry (clinical.trials.gov) under the identifier number NCT03415464. For the retrospective analysis, injury data from the Department of Safety and Occupational Safety of the SAF were used for a 10-year period (2006-2015) where only injuries that cause a soldier to be absent from duty for three or more working days are registered. For cross-sectional analysis, 129 members (N = 129) of an infantry SAF regiment (118 males, 11 females) volunteered to participate in the study. A modified Oslo Sports Trauma Research Centre (OSTRC) injury report form was used to collect injury data about current musculoskeletal complaints. Results: The 10-year prevalence of MSI in SAF was 4.9%, with significantly (p = 0.0004) lower prevalence in females (3.1%) than males (5.4%). The most frequently injured body parts were ankles (23%) and knees (21%). The cross-sectional analysis has shown a much higher MSI prevalence of 48.8% (50.8% in males and 27.7% in females), demonstrating that some MSIs are probably under-reported. For all reported injuries in a cross-sectional analysis, a previous injury was a strong and significant injury risk factor (p < 0.001 for all instances). Conclusions: To the best of our knowledge, this is the first comprehensive analysis of MSI among SAF members showing that the currently used injury surveillance system in SAF, that reports only the prevalence of time-loss injuries (4.9%), is probably underestimating the true and overall MSI prevalence (48.8%) in SAF members, suggesting a need for a better injury registration process. Based on the most frequent injury locations, preventive measures in SAF should focus on knee and ankle injuries in males with previous lower limb injuries. A best preventive approach would probably be to train smarter and harder to develop the physical capability to better protect against those injuries. PMID- 29982739 TI - Soil Type Mediates the Effectiveness of Biological Control Against Limonius californicus (Coleoptera: Elateridae). AB - Wireworms, the larval stage of click beetles (Coleoptera: Elateridae), are a considerable threat to cereal and vegetable production in the Pacific Northwest and Intermountain regions of the United States. As insecticides are generally ineffective, alternative controls are needed to improve wireworm management. Wireworms are continuously exposed to a wide range of subterranean pathogenic organisms in the soil; identifying these organisms and determining their impact would contribute to the development of biological control for wireworms. Here, we evaluated the efficacy of an entomopathogenic nematode, Steinernema carpocapsae (Weiser) (Rhabditida: Steinernematidae), and a fungus, Metarhizium brunneum Petch (strain F52) (Hypocreales: Clavicipitaceae), for control of the Pacific Northwest predominant wireworm species Limonius californicus, in two different soil media. We also examined whether diatomaceous earth (DE) increases the efficacy of entomopathogens through facilitating their penetration into the host integument. Treatments containing M. brunneum (F52) resulted in the highest rates of wireworm mortality, indicating that the fungus may be more effective than the nematode at reducing population size. However, results were impacted by soil media. In peatmoss-dominated medium, M. brunneum-containing treatments were more effective in reducing feeding damage than treatments containing S. carpocapsae. However, in sand-dominated medium, treatments with S. carpocapsae provided relatively better seedling protection. No consistent effect of DE was detected. Our results suggest that the effectiveness of wireworm biological control agents depends on soil media, such that the application of biological control against wireworms must be made with knowledge of field soil type. PMID- 29982740 TI - Copy number profiling across glioblastoma populations has implications for clinical trial design. AB - Background: Copy number alterations form prognostic molecular subtypes of glioblastoma with clear differences in median overall survival. In this study, we leverage molecular data from several glioblastoma cohorts to define the distribution of copy number subtypes across random cohorts as well as cohorts with selection biases for patients with inherently better outcome. Methods: Copy number subtype frequency was established for 4 glioblastoma patient cohorts. Two randomly selected cohorts include The Cancer Genome Atlas (TCGA) and the German Glioma Network (GGN). Two more selective cohorts include the phase II trial ARTE in elderly patients with newly diagnosed glioblastoma and a multi-institutional cohort focused on paired resected initial/recurrent glioblastoma. The paired initial/recurrent cohort also had exome data available, which allowed for evaluation of multidimensional scaling analysis. Results: Smaller selective glioblastoma cohorts are enriched for copy number subtypes that are associated with better survival, reflecting the selection of patients who do well enough to enter a clinical trial or who are deemed well enough to undergo resection at recurrence. Adding exome data to copy number data provides additional data reflective of outcome. Conclusions: The overall outcome for diffuse glioma patients is predicted by DNA structure at initial tumor resection. Molecular signature shifts across glioblastoma populations reflect the inherent bias of patient selection toward longer survival in clinical trials. Therefore it may be important to include molecular profiling, including copy number, when enrolling patients for clinical trials in order to balance arms and extrapolate relevance to the general glioblastoma population. PMID- 29982742 TI - Skeletal muscle growth characteristics and myogenic stem cell activity in broiler chickens affected by wooden breast. AB - The degenerative myopathy known as wooden breast (WB) has been increasingly observed in the breast muscle (PM) of commercial broilers during the last decade. Previous research has demonstrated that WB may be induced or ameliorated by modulating dietary digestible Lys (dLys) concentrations. Two concurrent experiments (Exp) were conducted to verify the effects of feeding 2 diets formulated to 75% and 100% of recommended dLys concentrations from 15 to 25 d of age on production responses and WB incidence (Exp 1), and the characterization of muscle stem cell activity in broilers affected by WB (Exp 2). At 25 and 43 d of age, birds were injected with 5?-bromo-2?-deoxyuridine (BrdU) prior to the collection of PM tissue to label mitotically active cells. Muscle samples were processed for cryosectioning and immunofluorescence staining and microscopy in order to determine myofiber cross-sectional area (CSA), to enumerate Myf-5+ and Pax7+ myogenic stem cell populations, and to determine the mitotic activity (BrdU+) of these populations. The reduced dLys diet produced broilers with differing (P < 0.001) incidences of WB within the same flock (Exp 1), with some detrimental effects on performance and processing characteristics. In Exp 2, broilers with severe WB had increased numbers (P = 0.016) and proportions (P = 0.022) of mitotically active, myogenic stem cells, as well as increased proportions (P < 0.05) of large CSA myofibers relative to broilers unaffected by WB at 25 d of age. At 43 d of age, broilers affected by severe WB had a greater (P = 0.011) total population of myogenic stem cell types (Myf-5+, Pax7+, or Myf 5+:Pax7+) and a concurrent increase (P = 0.007) in the mitotic activity (Myf 5+:BrdU+, and Pax7+:BrdU+, and Myf-5+:Pax7+:BrdU+) of these cells. Additionally, a greater (P < 0.05) proportion of small CSA myofibers was observed in broilers with severe WB. These results provide evidence that myofiber CSA, as well as the heterogeneity and mitotic activity of myogenic stem cell populations were altered in the presence of WB. PMID- 29982741 TI - Developmental Exposure to Low Concentrations of Organophosphate Flame Retardants Causes Life-Long Behavioral Alterations in Zebrafish. AB - As the older class of brominated flame retardants (BFRs) are phased out of commercial use because of findings of neurotoxicity with developmental exposure, a newer class of flame retardants have been introduced, the organophosphate flame retardants (OPFRs). Presently, little is known about the potential for developmental neurotoxicity or the behavioral consequences of OPFR exposure. Our aim was to characterize the life-long neurobehavioral effects of 4 widely used OPFRs using the zebrafish model. Zebrafish embryos were exposed to 0.1% DMSO (vehicle control); or one of the following treatments; isopropylated phenyl phosphate (IPP) (0.01, 0.03, 0.1, 0.3 uM); butylphenyl diphenyl phosphate (BPDP) (0.003, 0.03, 0.3, 3 uM); 2-ethylhexyl diphenyl phosphate (EHDP) (0.03, 0.3, 1 uM); isodecyl diphenyl phosphate (IDDP) (0.1, 0.3, 1, 10 uM) from 0- to 5-days postfertilization. On Day 6, the larvae were tested for motility under alternating dark and light conditions. Finally, at 5-7 months of age the exposed fish and controls were tested on a battery of behavioral tests to assess emotional function, sensorimotor response, social interaction and predator evasion. These tests showed chemical-specific short-term effects of altered motility in larvae in all of the tested compounds, and long-term impairment of anxiety-related behavior in adults following IPP, BPDP, or EHDP exposures. Our results show that OPFRs may not be a safe alternative to the phased-out BFRs and may cause behavioral impacts throughout the lifespan. Further research should evaluate the risk to mammalian experimental models and humans. PMID- 29982743 TI - The 70th anniversary of glucocorticoids in rheumatic diseases: the second youth of an old friend. AB - Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit-risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations. PMID- 29982744 TI - Do patients with and without a regular primary care physician have their psychological distress looked after differently? AB - Background: While qualitative studies suggested that continuity of care by primary care physicians (PCPs) facilitated consultations for psychological problems, there was limited quantitative evidence. This survey compared management of psychological distress between patients with and without a regular PCP. Methods: A questionnaire survey was conducted with 1626 adult primary care attenders from 13 private and 6 public clinics in Hong Kong. Management of psychological distress between respondents with a regular PCP and those without were compared. Effects of demographic factors were adjusted for by multivariable logistic regression. Results: Among the 1626 respondents, 650 (40.0%) reported that they had ever experienced psychological distress. Of the 650 respondents experienced distress, 307 (47.2%) had a regular PCP. A significantly higher proportion of patients with a regular PCP than those without reported: (i) their PCPs sometimes/often asked about psychological problems [37.7 versus 20.1%, adjusted OR = 2.241]; (ii) they sometimes/often mentioned their psychological problems to PCPs [45.2 versus 24.9%, adjusted OR = 2.503]; and (iii) their distress had been treated by PCPs [22.1 versus 13.4%, adjusted OR = 1.702]. Conclusion: Patients with a regular PCP have around double odds of receiving mental health care. Continuity of care by PCPs should be emphasized in mental health care delivery. PMID- 29982745 TI - Energy partitioning by broiler breeder pullets in skip-a-day and precision feeding systems. AB - An empirical nonlinear mixed model was derived to describe metabolizable energy (ME) partitioning in Ross 308 broiler breeder pullets. Its coefficients described ME used for total heat production (HP) and growth. A total of 630 pullets were randomly and equally assigned to 2 treatments: precision feeding (PF) and conventional skip-a-day feeding (CON) from 10 to 23 wk of age. The PF system allowed birds to enter voluntarily at any time, weighed them, and provided access to feed for 60 s if their BW was less than the target BW. Birds in the CON treatment were fed as a group on alternate days. Energetic efficiency of pullets was evaluated using residual total heat production (RHP), defined as the difference between observed and predicted total HP. Additionally, ME intake (MEI), ADG, HP, and cumulative feed conversion ratio (FCR) were calculated for the entire experimental period. The energy partitioning model (P < 0.05) predicted MEI = (120+u)BW0.68 + 1.52(ADG) + epsilon. Total HP was (120 kcal/kg0.68 + u); the energy requirement for each g of BW gain was 1.52 kcal/d. The random variable u ~ N (0, sigmau2) indicated a pen level HP standard deviation sigmau = 12.1 kcal/kg0.68. Over the experimental period, for CON and PF treatments, respectively, MEI was 194 and 174 kcal/d (P < 0.001); ADG was 15.3 and 15.4 g/d (P = 0.94); HP was 129 and 111 kcal/kg0.68 (P < 0.001); FCR was 4.888 and 4.057 (P < 0.001); and RHP was 0.12 and -0.12 kcal/kg0.68 (P = 0.73). The CON pullets had similar ADG, but higher MEI relative to PF, consistent with levels of heat production predicted by RHP. The PF pullets had lower cumulative FCR compared to CON pullets. The PF pullets lost less energy as heat, likely because they were fed continuously, reducing the need to store and mobilize nutrients compared to CON pullets. Thus, increased feeding frequency likely increased PF pullet efficiency. PMID- 29982746 TI - Informal employees in the European Union: working conditions, employment precariousness and health. AB - Background: The aim of this study is to estimate the prevalence of informal workers and their working conditions and employment precariousness in the EU-27; and to explore the association of different contract arrangements with health outcomes and how they are influenced by working and employment conditions. Methods: A sample of 27 245 working-age employees from the fifth European Working Condition Survey of 2010 was analysed. Logistic regression models were fitted to estimate the contribution of different contract arrangement (permanent, temporary and informal) and working and employment precariousness variables on health outcomes (psychosocial well-being and self-rated health). Results: Prevalence of informal employees in the EU-27 is 4.1% among men and 5.1% among women. Although informal employees have the poorest working conditions and employment precariousness, they did not seem to reflect poorer health. Precariousness employment variables have a greater impact than working conditions variables in reducing the association between health outcomes and type of contract arrangement, especially in the case of informal employees. Conclusions: Informal employment in the EU-27 is characterized by worse working conditions and employment precariousness than the conditions for formal employees. There is no evidence at all that being in informal employment implies better health outcomes compared to permanent employees. PMID- 29982747 TI - Examining the impact of a multimedia intervention on treatment decision-making among newly diagnosed prostate cancer patients: results from a nationwide RCT. AB - Men diagnosed with early stage prostate cancer face multiple treatment options, each with distinctive side effects that have significant implications for post treatment quality of life. Healing Choices for Men with Prostate Cancer is a multimedia educational and decision aid program. This nation-wide randomized controlled trial evaluated the impact of Healing Choices on reducing decisional conflict and distress. Eligible prostate cancer patients who called the National Cancer Institute's Cancer Information Service (CIS) were invited to participate. After a baseline interview, participants were randomized to usual personalized consultation with a CIS specialist (comparison condition) or CIS personalized consultation plus the Healing Choices program (intervention condition). The Decision Conflict Scale and Impact of Event Scale assessed decisional conflict about prostate cancer treatment and cancer-related distress, respectively. Analyses evaluated group differences at 2 months postenrollment. Hypothesized moderation of intervention effects by demographic and clinical characteristics were evaluated. The final sample consisted of N = 349 participants (intervention: n = 181; comparison n = 168). Men were on average 64 years old, primarily White, and well educated. The difference in total decisional conflict was not significant (DCS total score; F[1,311] = .99, p = .32). The difference in cancer related distress at 2 months between the intervention and the comparison groups was not significant (F[1,337] = .01, p = .93). Evaluation of specific decision processes indicated a significant effect on levels of perceived decisional support (intervention, M = 34.8, SD = 15.7; comparison, M = 38.3, SD = 16.1; F[1,337] = 3.74, p = .05). The intervention effect was greatest for nonwhite minority participants (b = -9.65, SE = 4.67) and those with lower educational attainment (b = 3.87, SE = 2.21). This interactive, comprehensive education and decision aid program may be most effective for a subset of prostate cancer patients in need of educational and decisional support. PMID- 29982748 TI - Colonization of a commercial broiler line by Campylobacter is under limited genetic control and does not significantly impair performance or intestinal health. AB - Campylobacter is the leading bacterial cause of foodborne diarrheal illness in humans and source attribution studies unequivocally identify handling or consumption of poultry meat as a key risk factor. Campylobacter colonizes the avian intestines in high numbers and rapidly spreads within flocks. A need therefore exists to devise strategies to reduce Campylobacter populations in poultry flocks. There has been a great deal of research aiming to understand the epidemiology and transmission characteristics of Campylobacter in poultry as a means to reduce carriage rates in poultry and reduce infection in humans. One potential strategy for control is the genetic selection of poultry for increased resistance to colonization by Campylobacter. The potential for genetic control of colonization has been demonstrated in inbred populations following experimental challenge with Campylobacter where quantitative trait loci associated with resistance have been identified. Currently in the literature there is no information of the genetic basis of Campylobacter colonization in commercial broiler lines and it is unknown whether these QTL are found in commercial broiler lines. The aim of this study was to estimate genetic parameters associated with Campylobacter load and genetic correlations with gut health and production traits following natural exposure of broiler chickens to Campylobacter.The results from the analysis show a low but significant heritability estimate (0.095 +/- 0.037) for Campylobacter load which indicates a limited genetic basis and that non genetic factors have a greater influence on the level of Campylobacter found in the broiler chicken.Furthermore, through examination of macroscopic intestinal health and absorptive capacity, our study indicated that Campylobacter has no detrimental effects on intestinal health and bird growth following natural exposure in the broiler line under study. These data indicate that whilst there is a genetic component to Campylobacter colonization worthy of further investigation, there is a large proportion of phenotypic variance under the influence of non-genetic effects. As such the control of Campylobacter will require understanding and manipulation of non-genetic host and environmental factors. PMID- 29982749 TI - Better is possible. PMID- 29982750 TI - Evaluation of Insect Succession Patterns and Carcass Weight Loss for the Estimation of Postmortem Interval. AB - This study assesses the succession of insects on rabbit carcass. The study was conducted in sunny and shaded sites in the west of Iran during four seasons in 2016 and 2017. Based on the results of this study, various factors such as body size, carcass location, and carcass injury could affect the pattern of insect succession on carcass. In this study, we estimated the elapsed time since death (R2 > 0.98, P = 0.00) based on carcass weight loss during the stages of decomposition and the cubic method. Jaccard analysis was performed to determine the similarity of insect taxa during decomposition of rabbit carrion in two different sites during a period of four seasons. Succession pattern analysis for necrophagous insects in both habitats showed a similarity between bloat and decay stages for each habitat. On the other hand, pairwise similarities in taxa were low at the fresh and dry stages, however increased at bloat and decay stages of decomposition. This study shows that succession has some limitations in determining the elapsed time of death. Therefore, the use of source of information such as a weight loss model seems to be essential. PMID- 29982752 TI - Transcriptome profile analysis identifies candidate genes for the melanin pigmentation of breast muscle in Muchuan black-boned chicken. AB - Melanin-based coloration in the meat of black-boned chicken is a major economic issue in China. Variation in the pigmentation (hypopigmentation) of chicken muscle causes direct economic losses every year. To determine the molecular mechanisms involved in the melanogenesis of muscle tissue, this study used high throughput sequencing to compare differences in the transcriptome between black (BM) and white (WM) chicken breast muscles. We constructed 6 cDNA libraries from BM and WM groups in Muchuan black-boned chickens. A comparison between the BM and WM groups revealed 264 differentially expressed genes, of which 152 were upregulated, whereas 112 were downregulated in black muscle. Gene ontology and a Kyoto Encyclopedia of Genes and Genomes pathway analysis identified several differentially enriched biological functions and processes of the 2 muscles. Seven promising candidate genes [PMEL, Ras-related protein RAB29, and 5 solute carrier superfamily genes: SLC6A9, SLC38A4, SLC22A5, SLC35F3, and SLC16A3] may play an important role in the melanogenesis of chicken muscle. Our data provide a valuable resource for identifying genes whose functions are critical for muscle melanogenesis, and will assist studies of the molecular mechanisms of melanogenesis regulation in chicken muscle. PMID- 29982753 TI - Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers. AB - Background: Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). Methods: We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP 3) measurements compared with GH dynamic testing. Results: We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). Conclusion: The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population. PMID- 29982751 TI - Effects of phytogenic feed additives on cellular oxidative stress and inflammatory reactions in intestinal porcine epithelial cells. AB - Due to increasing concerns about the use of antibiotic growth promoters (AGP) in livestock production and their complete ban in the European Union in 2006, suitable alternatives are urgently needed. Among others, anti-inflammatory activities of AGP are discussed as their putative mode of action. As numerous phytochemicals are known to modulate the cellular antioxidant capacity and immune response, we studied the antioxidative and anti-inflammatory properties of a phytogenic (plant-derived) feed additive (PFA) in intestinal porcine epithelial cells (IPEC-J2). The effects of the PFA were compared with those of selected phytogenic ingredients (grape seed extract (GRS), licorice extract (LIC), menthol (MENT), methyl salicylate (MES), oak bark extract (OAK), oregano essential oil (ORE), and a plant powder mix (PLA)), and with the effects of the AGP tylosin (TYL). Oxidative or inflammatory stress was induced by stimulating IPECJ2 with hydrogen peroxide (H2O2; 0.5 mM) or tumor necrosis factor alpha (TNF-alpha; 10 ng/mL), respectively. The antioxidative effects of feed additives were assessed with a reactive oxygen species (ROS)-sensitive probe and by measuring the expression of six antioxidative target genes via quantitative real-time PCR (RTqPCR). Anti-inflammatory potential was analyzed using a nuclear factor kappa light-chain-enhancer of activated B cells (NF-kappaB) reporter gene assay. Moreover, the expression levels of six NF-kappaB target genes were measured using RT-qPCR analysis, and the release of IL-6 was analyzed via ELISA. Significant decreases in cellular ROS upon H2O2 treatment were observed for the PFA (P < 0.001), LIC (P < 0.001), ORE (P < 0.05), and GRS (P < 0.01). No significant changes in the expression of antioxidative genes were found. NF-kappaB activation upon TNF-alpha treatment was significantly inhibited by the PFA (P < 0.05) and by ORE (P < 0.001). Moreover, the PFA and ORE significantly reduced the gene expression of IL-6 (P < 0.001), IL-8 (P < 0.001), and C-C motif chemokine ligand 2 (CCL2; P < 0.05), as well as the release of IL-6 (P < 0.05). The other phytogenic compounds as well as the AGP TYL did not significantly affect any of the inflammatory parameters. In summary, we revealed the antioxidative properties of the PFA, LIC, ORE, and GRS, as well as anti-inflammatory properties of the PFA and ORE in IPEC-J2, providing a better understanding of the mode of action of this PFA under our experimental conditions. PMID- 29982754 TI - Neurocognitive Sequelae in Adult Childhood Leukemia Survivors Related to Levels of Phosphorylated Tau. AB - Central nervous system-directed prophylactic chemotherapy increases survival in childhood leukemia, but possible late neurocognitive sequelae remain a concern. We compared intellectual performance (WAIS IV), memory (AVLT), and executive functioning (ANT) between adult leukemia survivors (n = 31) and control individuals (n = 35). In survivors, cerebrospinal fluid (CSF) levels of phosphorylated Tau (p-Tau) during treatment and total intrathecal methotrexate dose correlated with adult intellectual performance (Pearson's and Spearman's coefficients, respectively). Long-term memory and attentional control, both maturing before survivors' mean age at diagnosis, were unaffected (P > .05 on all four subtests), in contrast to cognitive flexibility and information processing (P < .05 for eight of the subtests), which mature during adolescence. CSF p-Tau and methotrexate dose negatively correlated with intellectual performance (r = 0.414, P = .04 and r = -0.484, P = .007, respectively), but not with each other (r = 0.219, P = .29). These data identify CSF p-Tau as a predictor of late neurocognitive sequelae (in addition to methotrexate dose). Early identification of children at risk could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae. PMID- 29982755 TI - RE: Personalized Prognostic Prediction Models for Breast Cancer Recurrence and Survival Incorporating Multidimensional Data. PMID- 29982756 TI - Response. PMID- 29982757 TI - Editorial: Radiomics: The New World or Another Road to El Dorado? PMID- 29982758 TI - What's Next for Patient-Derived Xenograft Modeling? PMID- 29982759 TI - Updates to the National Cancer Institute's PDQ Information from Recently Published Oncology Research. PMID- 29982760 TI - Thyroid Cancer's Overdiagnosis Problem. PMID- 29982761 TI - New Guidelines Allow Some Patients With Chronic Myeloid Leukemia To Go Off Treatment. PMID- 29982762 TI - National Incidence Rates for Men, 2009-2013. PMID- 29982763 TI - Rapid Communication: Reduced maternal nutrition during early- to mid-gestation elevates newborn lamb plasma cortisol concentrations and eliminates the neonatal leptin surge. AB - Human epidemiological and animal studies show that maternal nutrient reduction (MNR) and maternal overnutrition/obesity (MO) alter fetal growth and development, predisposing offspring (F1) to endocrine and appetite dysregulation. Compared to F1 of control-fed ewes, F1 of MO ewes display hypercortisolemia at birth and fail to exhibit the neonatal leptin surge implicated in lifelong appetite regulation. Here, we determined if MNR also elevates newborn lamb plasma cortisol and eliminates the neonatal leptin surge. Starting 30 d prior to conception, nulliparous control (CON, n = 6) ewes ate 100% NRC recommendations through parturition. Nutrient-reduced (NR, n = 6) ewes ate a CON diet through day 27 of gestation. From gestational days 28 to 78, NR ewes ate 50% of the CON diet before realimentation to 100% NRC recommendations. Jugular blood was collected daily from lambs from birth (day 0) through postnatal day 10, to determine plasma cortisol and leptin. Newborn NR plasma cortisol concentrations were increased (P < 0.0001) vs. CON and were similar to concentrations in MO lambs. Plasma leptin concentrations were similar between groups through postnatal day 7. The leptin surge, seen in CON lambs on postnatal days 8 to 10 was not present in NR lambs. These data show that, similar to MO lambs, early pregnancy MNR elevates newborn lamb plasma cortisol and eliminates the neonatal leptin surge. In the light of the similar elevation of neonatal cortisol in MNR and MO lambs, we conclude that cortisol plays a central role in regulating the neonatal lamb leptin surge. PMID- 29982764 TI - First Observations of Initial Blow Fly (Diptera: Calliphoridae) Activity on Lava Fields and in Subterranean Environments in Sicily in Cool Temperatures. AB - In criminal cases involving the recovery of human remains, as well as in cases of myiasis and pest management, the expertise of a forensic entomologist has been requested more and more frequently in Sicily. Recently, research on the insect species of forensic interest in Sicily has been investigated. The aim of this research was to raise awareness of this discipline and to build a Sicilian entomofauna checklist during cool temperatures. The predominant species observed in this study was Calliphora vicina (Robineau-Desvoidy) (Diptera, Calliphoridae), the first to colonize the carcasses; Lucilia spp. (Diptera, Calliphoridae) were also present. We wanted to explore the potential insect activity on decaying matter both on lava fields, exposed to sunlight, and in dark subterraneous environments. No activity was observed in our dark environment for 20 d; then, C. vicina was observed on one of the carcasses, laying eggs in complete darkness at a temperature of 6.4 degrees C. Larval development under these conditions was delayed and the mortality rate was high. This preliminary trial allowed us to improve our experimental design and helped map new sites where we can expand our research to collect new data on insect distribution and their activity in caves. PMID- 29982765 TI - Strengths-Based, Clinic-Integrated Nonrandomized Pilot Intervention to Promote Type 1 Diabetes Adherence and Well-Being. AB - Objective: Given persistent challenges achieving optimal diabetes outcomes in adolescence, new interventions to support disease self-management and emotional well-being are needed. Approaches that emphasize adolescents' positive behaviors and attitudes ("strengths") are designed to incorporate positive provider communications into clinical encounters to encourage youths' engagement in adherence behaviors and enhance well-being. Methods: This pilot study tested the feasibility, acceptability, and preliminary outcomes of a brief, strengths-based behavioral intervention for adolescents with type 1 diabetes. Adolescents (age 12 17 years) and parents were recruited, consented, and completed baseline and postintervention questionnaires. There was no randomization to a control group, and all participants received the pilot intervention. At the start of two clinic visits, diabetes care providers followed a semi-structured script to reinforce adolescents' diabetes-related strengths and adherence behaviors. Results: Of 116 eligible families, 84 consented and 64 completed baseline (M age = 15.0 +/- 1.8 years, 56% female, 69% White, M HbA1c = 8.6 +/- 1.6%). Providers reported the intervention usually (95%) took <10 min to deliver. Participants and providers enjoyed the intervention and would like to see it as part of routine clinical care. Pre-post data indicated significant improvements in youth-rated diabetes strengths, adherence, burden, and relationship with provider, parent-reported diabetes burden, and provider-rated relationship with family (p < .05). Objectively measured adherence and glycemic control did not change. Conclusions: This brief strengths-based, clinic-integrated intervention was feasible to conduct and stakeholders were satisfied. This intervention holds promise to have a positive impact on adolescents' diabetes adherence, well-being, and provider relationships. Lessons were learned to improve implementation and participant experience for a larger study. PMID- 29982766 TI - Management of inflammatory rheumatic conditions in the elderly. AB - The number of elderly people with chronic inflammatory rheumatic diseases is increasing. This heterogeneous and comorbid population is at particular risk of cardiovascular, neoplastic, infectious and iatrogenic complications. The development of biotherapies has paved the way for innovative therapeutic strategies, which are associated with toxicities. In this review, we have focused on the scientific and therapeutic changes impacting the management of elderly patients affected by RA, SpA or PsA. A multidimensional health assessment resulting in an integrated therapeutic strategy was identified as a major research direction for improving the management of elderly patients. PMID- 29982767 TI - Neonatal Murine Engineered Cardiac Tissue Toxicology Model: Impact of Metallothionein Overexpression on Cadmium-Induced Injury. AB - Engineered cardiac tissues (ECTs) serve as robust in vitro models to study human cardiac diseases including cardiac toxicity assays due to rapid structural and functional maturation and the ability to vary ECT composition. Metallothionein (MT) has been shown to be cardioprotective for environmental toxicants including heavy metals. To date, studies on the role of cardiomyocyte (CM)-specific MT expression and function have occurred in dissociated single cell assays or expensive in vivo small animal models. Therefore, we generated 3D ECTs using neonatal mouse ventricular cells from wild-type (WT) and the CM-specific overexpressing MT-transgenic (MT-TG) to determine the effect of MT overexpression on ECT maturation and function. Because Cadmium (Cd) is an environmentally prevalent heavy metal toxicant with direct negative impact on cardiac structure and function, we then determined the effect of MT overexpression to reduce Cd mediated CM toxicity within ECTs. We found: (1) structural and functional maturation was similar in WT and MT-TG ECTs; (2) Cd exposure negatively impacted ECT cell survival, maturation, and function; and (3) MT-ECTs showed reduced Cd toxicity as defined by reduced cleaved caspase 3, reduced Bax/Bcl2 ratio, reduced TdT-mediated dUTP nick-end labeling positive cells, reduced CM loss after Cd treatment, and delayed onset of cardiac dysfunction after Cd treatment. Thus, neonatal murine ECTs can serve as a robust in vitro model for heavy metal toxicity screening and as a platform to evaluate the role cardioprotective mechanisms, such as the MT-TG model, on environmentally relevant toxicants. PMID- 29982768 TI - The role of spacer sequence in modulating turn-on fluorescence of DNA-templated silver nanoclusters. AB - Guanine activation of fluorescence in DNA templated silver nanoclusters (AgNCs) is an interesting physical phenomenon which has yet to be fully understood to date. While the individual role of cytosine and guanine has been established, there is still a knowledge gap on how the AgNC-DNA system switches from dark to bright state. Here, we present evidence on the universal role of the DNA spacer sequence in physically separating two Ag+-binding cytosine sites to maintain the dark state while holding them together for structural re-organization by the guanine-rich strand to activate the bright state. The extent of turn-on signal could be modulated by adjusting the spacer length and composition. The ATATA spacer sequence was found to have negligible dark state fluorescence and a turn on effect of 2440-fold, which was almost five times of the highest factor reported to date. PMID- 29982769 TI - Key insomnia symptoms and incident pain in older adults: direct and mediated pathways through depression and anxiety. AB - Pain is common among older adults and negatively impacts functioning. Sleep disturbances and mood disorders, specifically depression and anxiety, are closely associated with pain in older individuals, but the directionality of these associations remains unclear. In this study, we deconstruct long-term temporal effects of two key insomnia symptoms on incident pain into direct and indirect pathways, with focus on depression and anxiety symptoms, within a nationally representative sample. We utilized 2011-2013 data from the National Health and Aging Trends Study, a longitudinal survey of 2239 community-dwelling Medicare beneficiaries. Participants completed annual in-person interviews with assessments of sleep initiation and maintenance; depression, and anxiety (using the Patient Health Questionnaire-2 [PHQ-2] and the Generalized Anxiety Disorder Scale-2 [GAD-2] respectively); and bothersome pain. Causal mediation analysis was applied to examine direct effects of the two insomnia symptoms at baseline on incident pain, and their indirect effects through depression and anxiety symptoms. Almost one-third of the study participants were 69 years old or younger. A similar proportion reported bothersome pain in 2013. The two baseline insomnia symptoms predicted the development of pain. Adjusted analyses suggested that compared to older adults without the two baseline insomnia symptoms, participants with sleep initiation or maintenance difficulties had 24% (95% confidence interval [CI] 2%,51%) and 28% (95% CI 4%,55%) higher odds of incident pain, respectively. Anxiety symptoms partially mediated the relationship between the insomnia symptoms and incident pain, accounting for up to 17% of the total effect, but depressive symptoms did not. These results suggest that improved sleep or anxiety could reduce the risk for future pain. PMID- 29982770 TI - Regional variation in chronic kidney disease and associated factors in hypertensive individuals in rural South Asia: findings from control of blood pressure and risk attenuation-Bangladesh, Pakistan and Sri Lanka. AB - Background: We aimed to determine the prevalence of chronic kidney disease (CKD) and its cross-country variation among hypertensive individuals in rural Bangladesh, Pakistan and Sri Lanka. We also explored the factors associated with CKD in these populations. Method: We studied baseline data from the Control of Blood Pressure and Risk Attenuation-Bangladesh, Pakistan and Sri Lanka (COBRA BPS) trial, an ongoing cluster randomized controlled trial on 2643 hypertensive adults >=40 years of age from 30 randomly selected rural clusters, 10 in each of the three countries. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (UACR) >=30 mg/g. Determinants for CKD were assessed using logistic regression analysis. Results: The overall prevalence of CKD was 38.1% (95% confidence interval 36.2-40.1%): 21.5% with eGFR <60 mL/min/1.73 m2 and 24.4% with UACR >=30 mg/g. CKD prevalence varied across the three countries (58.3% in Sri Lanka, 36.4% Bangladesh and 16.9% Pakistan; P <0.001). The factors independently associated with higher odds of CKD were older age, being unmarried, higher 24-h urinary sodium excretion, presence of diabetes, elevated systolic blood pressure, diuretic use and living in Bangladesh or Sri Lanka (versus Pakistan). Conclusions: The prevalence of CKD is alarmingly high in community-dwelling hypertensive adults, with significant cross country variation in South Asia. Our findings underscore the urgency for further research into the etiology of CKD and address associated factors in targeted public health strategies with hypertension care outreach services in rural South Asia. ClinicalTrials.gov: NCT02657746. PMID- 29982771 TI - Opening an onconephrology clinic: recommendations and basic requirements. AB - Onconephrology is a rapidly evolving subspeciality that covers all areas of renal involvement in cancer patients. The complexity of the field may benefit from well defined multidisciplinary management administered by a dedicated team. Since there is an increasing need to address the needs of this population in dedicated outpatient clinics, it is critical to highlight basic characteristics and to suggest areas of development. In this brief perspective article, we analyse the requirements of an onconephrology clinic in terms of logistics, critical mass of patients and building a multidisciplinary team. We will further discuss which patients to refer and which conditions to treat. The last part of the article is dedicated to education and performance indicators and to analysis of the potential advantages of applying the hub-and-spoke model to this field. The ultimate aim of this experience-based article is to initiate debate about what an onconephrology outpatient clinic might look like in order to ensure the highest quality of care for this growing population of patients. PMID- 29982773 TI - Impact of Age on the Biological Activities of Sitophilus zeamais (Coleoptera: Curculionidae) Adults on Stored Maize: Implications for Food Security and Pest Management. AB - The present work was undertaken in three successive years in three different regions of Nigeria to study the impact of age on the postharvest biological performance of maize weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae) adults infesting maize grain. Eight different age groups of S. zeamais adults which ranged from 1 to 56 d were used. The study assessed important parameters and was carried out using standard methods at mean temperature and relative humidity of 28.2 degrees C and 87.5%, respectively. Results indicated that age affected bionomics of S. zeamais adult infesting maize grain in storage. The minimum age threshold for prolific oviposition in the females was 8 d. Weevils in the age groups 8-14 and 15-21 d showed highest fecundity. There was no effect of age on progeny emergence and development time for weevils younger than 36 d. Consequent upon infestation, only S. zeamais adults of <=35 d old caused great damage and loss to grains in storage. The susceptibility of infesting weevil to cypermethrin was not greatly influenced by weevil age except at an elderly age of >=43 d. Observations signal that weevil adults are physiologically fittest at <=14 d old but indicate that adults of <=35 d old pose the highest food security threat. The S. zeamais ecotype studied showed resistance to the pyrethroid insecticide at 24 h evaluation period and that also has implications for food security. PMID- 29982772 TI - The PXDLS linear motif regulates circadian rhythmicity through protein-protein interactions. PMID- 29982774 TI - Preadolescent Phthalate (DEHP) Exposure Is Associated With Elevated Locomotor Activity and Reward-Related Behavior and a Reduced Number of Tyrosine Hydroxylase Positive Neurons in Post-Adolescent Male and Female Rats. AB - Phthalate administration to male rats has been shown to negatively impact neural development while development of the female rat brain is less affected. Because a number of exogenous agents have been shown to interfere with dopamine function, we evaluated post-adolescent behavioral (operant conditioning for food reward and locomotor activity), histological (tyrosine hydroxylase; TH), and genetic (mRNA levels) outcomes of preadolescent (postnatal days [PND] 16-22) phthalate exposure. Male and female Long-Evans rats were administered 4 doses (0, 1, 10, or 20 mg/kg) of di-(2-ethylhexyl)phthalate (DEHP) i.p. from PND16 to 22. Rats were trained on an operant task to bar press for chocolate-flavored pellets from PND55 63 then euthanized on PND78. The 10 mg/kg DEHP dose was associated with elevated bar pressing for food reward during acquisition and extinction while the 20 mg/kg dose was associated with elevated locomotor activity in both males and females. Stereological analysis revealed reduced TH+ densities in the SNc in DEHP- (10 and 20 mg/kg) treated male and female rats. In the VTA, TH+ staining was reduced in male rats treated with 10 or 20 mg/kg DEHP while in females, the TH: CV ratio was higher at the 10 mg/kg dose compared with controls. An examination of Th mRNA showed a main effect of sex with females showing increased Th expression at all DEHP doses. The present results show that preadolescent phthalate exposure results in detrimental dopaminergic system development impacting neurobehavioral function in post-adolescent rats. PMID- 29982775 TI - CACNA1C: Association With Psychiatric Disorders, Behavior, and Neurogenesis. AB - Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this increased risk. This review presents an overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning. The impact of reduced gene dosage of Cacna1c on adult hippocampal neurogenesis is also assessed, including new data from a novel Cacna1c+/- rat model. PMID- 29982776 TI - Autophagy induces protein carbamylation in fibroblast-like synoviocytes from patients with rheumatoid arthritis. AB - Objectives: Autophagy is a homeostatic and physiological process that promotes the turnover of proteins and organelles damaged in conditions of cellular stress. We previously demonstrated that autophagy represents a key processing event creating a substrate for autoreactivity, which is involved in post-translational changes and generation of citrullinated peptides, recognized by the immune system in RA. In this study, we analysed whether autophagy is involved in other post translational changes that can generate autoantigens, focusing on carbamylation processes. Carbamylation is a nonenzymatic post-translational modification, in which homocitrulline is generated by the reaction of cyanate with the primary amine of lysine residues; carbamylated peptides may accumulate during inflammation conditions. Methods: The role of autophagy in the generation of carbamylated proteins was evaluated in vitro in fibroblasts as well as in synoviocytes from RA patients, treated with 5 MUM tunicamycin or 200 nM rapamycin; the correlation between autophagy and carbamylated proteins was analysed in mononuclear cells from 30 naive early-active RA patients. Results: Our results demonstrated that cells treated with tunicamycin or rapamycin showed a significant increase of carbamylated proteins. Immunoblotting and immunoprecipitation experiments identified vimentin as the main carbamylated protein. Furthermore, a correlation was found between autophagy and carbamylation levels in mononuclear cells of naive RA patients. Conclusion: These data indicate that autophagy is able to induce in vitro carbamylation processes, and in vivo appears to be related to an increase in carbamylation during RA. These observations introduce a new pathogenetic mechanism of disease, which could contribute to more accurate monitoring of patients. PMID- 29982777 TI - Pathogenesis of giant-cell arteritis: how targeted therapies are influencing our understanding of the mechanisms involved. AB - GCA is a chronic granulomatous vasculitis that affects large- and medium-sized vessels. Both the innate and the adaptive immune system are thought to play an important role in the initial events of the pathogenesis of GCA. Amplification cascades are involved in the subsequent development and progression of the disease, resulting in vascular inflammation, remodelling and occlusion. The development of large-vessel vasculitis in genetically modified mice has provided some evidence regarding potential mechanisms that lead to vascular inflammation. However, the participation of specific mechanistic pathways in GCA has not been fully established because of the paucity and limitations of functional models. Treatment of GCA is evolving, and novel therapies are being incorporated into the GCA treatment landscape. In addition, to improve the management of GCA, targeted therapies are providing functional proof of concept of the relevance of particular pathogenic mechanisms in the development of GCA and in sustaining vascular inflammation. PMID- 29982778 TI - Large-vessel giant cell arteritis: diagnosis, monitoring and management. AB - GCA is a chronic, idiopathic, granulomatous vasculitis of medium and large arteries. It comprises overlapping phenotypes including classic cranial arteritis and extra-cranial GCA, otherwise termed large-vessel GCA (LV-GCA). Vascular complications associated with LV-GCA may be due, in part, to delayed diagnosis, highlighting the importance of early identification and prompt initiation of effective therapy. Advancements in imaging techniques, including magnetic resonance angiography, CT angiography, PET and colour duplex ultrasonography, have led to improvements in the diagnosis of LV-GCA; however, the role imaging modalities play in the assessment of disease activity and long-term outcomes remains unclear. Glucocorticoids are the mainstay of therapy in LV-GCA, but their prolonged use is associated with multiple, sometimes serious, adverse effects. Recent data suggest that biologic therapies, such as tocilizumab, may be effective and safe steroid-sparing options for patients with GCA. However, data specifically evaluating the management of LV-GCA are limited. PMID- 29982779 TI - Prevention of glucocorticoid morbidity in giant cell arteritis. AB - Glucocorticoids are the mainstay of treatment for GCA. Patients often require long-term treatment that may be associated with numerous adverse effects, depending on the dose and the duration of treatment. Trends in recent decades for glucocorticoid use in GCA suggest increasing cumulative doses and longer exposures. Common adverse events (AEs) reported in glucocorticoid-treated GCA patients include osteoporosis, hypercholesterolaemia, hypertension, posterior subcapsular cataract, infections, diabetes mellitus, Cushingoid appearance, adrenal insufficiency and aseptic necrosis of bone. AEs considered most worrisome by patients and rheumatologists include weight gain, psychological effects, osteoporosis, cardiometabolic complications and infections. The challenge is to maximize the benefit-risk ratio by giving the maximum glucocorticoid treatment necessary to control GCA initially and then to prevent relapse but to give the minimum treatment possible to avoid glucocorticoid-related AEs. We discuss the safety issues associated with long-term glucocorticoid use in patients with GCA and strategies for preventing glucocorticoid-related morbidity. PMID- 29982780 TI - Ultrasound in the diagnosis and management of giant cell arteritis. AB - US has become an important diagnostic tool for musculoskeletal diseases. Because of its wide availability in rheumatology practice, US has also been applied in other rheumatic diseases such as GCA. In acute GCA, US displays a non compressible, hypoechoic, most commonly concentric arterial wall thickening. Temporal and axillary arteries should be examined in patients with suspected GCA and PMR. Additionally, almost all other large arteries, with the exception of the thoracic aorta, can be easily delineated by US. Many studies and several meta analyses have been conducted to evaluate the diagnostic performance of US. US is more sensitive than temporal artery biopsy (TAB) because TAB evaluates only a limited anatomical region in a systemic disease. Most US studies arrive at specificities between 90 and 100% compared with the final clinical diagnosis. Reliability for reading US images and videos is excellent and comparable to reliability for reading TAB specimens. The advantage of US over other imaging techniques in GCA is its availability, safety and tolerability and its high resolution of 0.1 mm. Rheumatology departments are increasingly establishing fast track clinics. Physicians can refer patients with suspected GCA within 24 h. Patients receive clinical and US examination by experienced specialists, establishing a clear diagnosis either before TAB or without the need for TAB. The introduction of fast-track clinics has led to a significant reduction of permanent vision loss. Furthermore, a process that primarily includes US is significantly more cost-effective than TAB. PMID- 29982781 TI - Physiological effects of modulating the interleukin-6 axis. AB - IL-6 is a pleiotropic cytokine involved in many biological functions that affect tissues beyond the immune system and the vasculature. This multifunctional cytokine exerts its actions via the classic signalling pathway when it binds to the transmembrane IL-6 receptor (IL-6R) or via the trans-signalling pathway upon binding to the soluble form of IL-6R (sIL-6R). In general, classic IL-6 signalling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signalling is responsible for the pro-inflammatory actions of IL-6. As a result, dysregulation of the IL-6 axis can lead to the onset or development of several disease states, particularly autoimmune and inflammatory disorders, including RA and GCA. This pathological role of IL-6 means that pharmacologic modulation of the IL-6 axis is a rational therapeutic approach; however, multiple predictable, but often underappreciated, effects on tissues and organs beyond the blood vessels may also occur. PMID- 29982782 TI - Why do temporal arteries go wrong? Principles and pearls from a clinician and a pathologist. AB - Early diagnosis and treatment of GCA is essential to prevent complications of the disease, including permanent vision loss. Temporal artery biopsy has been intrinsically linked with the diagnosis of GCA for several decades. A negative predictive value of > 90% has been reported for temporal artery biopsy; however, a negative result does not reliably indicate the absence of GCA because inflammation of the temporal artery is not always evident because of segmental involvement or other reasons. This is demonstrated by a case study of a patient hospitalized following acute vision loss to the right eye whose glucocorticoid treatment was suspended after temporal artery biopsy revealed no evidence of GCA. The patient subsequently lost sight in the left eye 6 weeks after stopping glucocorticoid therapy. The specificity of temporal artery biopsy for the diagnosis of GCA is variable and influenced by many factors, including length of biopsy specimens, vasculitis in vessels other than the temporal artery (ophthalmic, retinal and posterior ciliary vessels), unilateral versus bilateral biopsy, expertise of the surgeon, interpretation of histology, effects of treatment and confounding factors such as atherosclerosis or other non-GCA diseases that can affect the temporal artery. Considering the limitations of temporal artery biopsy, collaboration and education between the clinician, the pathologist and the patient, taking into account a thorough examination of patient history, recognizing signs and symptoms, and potentially involving newer imaging studies with trained technicians and physicians, are essential in confirming or eliminating diagnosis of GCA. PMID- 29982783 TI - Foreword: clinical challenges of diagnosing and managing giant cell arteritis. PMID- 29982785 TI - Reply to Liaw. PMID- 29982784 TI - Loose ends: almost one in five human genes still have unresolved coding status. AB - Seventeen years after the sequencing of the human genome, the human proteome is still under revision. One in eight of the 22 210 coding genes listed by the Ensembl/GENCODE, RefSeq and UniProtKB reference databases are annotated differently across the three sets. We have carried out an in-depth investigation on the 2764 genes classified as coding by one or more sets of manual curators and not coding by others. Data from large-scale genetic variation analyses suggests that most are not under protein-like purifying selection and so are unlikely to code for functional proteins. A further 1470 genes annotated as coding in all three reference sets have characteristics that are typical of non-coding genes or pseudogenes. These potential non-coding genes also appear to be undergoing neutral evolution and have considerably less supporting transcript and protein evidence than other coding genes. We believe that the three reference databases currently overestimate the number of human coding genes by at least 2000, complicating and adding noise to large-scale biomedical experiments. Determining which potential non-coding genes do not code for proteins is a difficult but vitally important task since the human reference proteome is a fundamental pillar of most basic research and supports almost all large-scale biomedical projects. PMID- 29982786 TI - Effects of Feeding Honey Bees (Hymenoptera: Apidae) With Industrial Sugars Produced by Plants Using Different Photosynthetic Cycles (Carbon C3 and C4) on the Colony Wintering Ability, Lifespan, and Forage Behavior. AB - In the study, 130 honey bee colonies fed with different levels (5, 20, and 100 liters/colony) of various industrial commercial sugars, including High-Fructose Corn 85 (Fructose-85), High-Fructose Corn 55 (Fructose-55), Glucose Monohydrate (Glucose), Bee feed, and Sucrose syrups, for 2 mo were compared with colonies fed with no sugar (control) in terms of their colony development of worker bee population, hive weight, wax production, wintering ability, foraging behavior, and lifespan of worker bee. Utilization of industrial sugars by honey bee colonies showed differences in terms of colony performance and behavior parameters. Honey bees did not use Glucose heavily, resulting in 4% increase in worker bee loss in winter and 46% decrease in marked worker bee numbers over time when compared to the control. Sucrose syrup had a positive effect on wintering ability, wax production, and hive weight. While Sucrose had a positive effect (3 4%) on wintering ability, the 100 liters/colony sugar syrups of all other sugars had negative effects (6-15%). Sugars containing high levels of monosaccharide were not used effectively by honey bee colonies, whereas the sugars containing fructose and glucose at rates of 40 and 30% (Bee feed and Fructose-55), were utilized effectively. The lifespan of worker bees decreased over time in the 100 liters/colony of all sugars syrup. In conclusion, except Glucose, other industrial sugars can be used for promoting colonies at the beginning of the season (in spring). Industrial sugars except sucrose should not be used in order to meet carbohydrate needs of the colonies in winter. PMID- 29982787 TI - Causes of renal allograft failure in the UK: trends in UK Renal Registry and National Health Service Blood and Transplant data from 2000 to 2013. AB - Background: Improvement in long-term renal allograft survival is impeded by incomplete or erroneous coding of causes of allograft loss. This study reports 13 year trends in causes of graft failure across the UK. Methods: National Health Service Blood and Transplant (NHSBT) and UK Renal Registry data were linked to describe UK kidney patients transplanted in 2000-13. NHSBT graft failure categories were used, with 'other' recoded when free text was available. Adjusted analyses examined the influence of age, ethnicity and donor type on causes of graft failure. Results: In 22 730 recipients, 5389 (23.7%) grafts failed within a median follow-up of 5 years. The two most frequent causes were death with a functioning graft (40.8%) and alloimmune pathology (25.0%). Graft survival was higher in recipients who were younger (mean 47.3 versus 50.7 years), received a pre-emptive transplant (20.2% versus 10.4%), spent less time on dialysis (median 1.6 versus 2.4 years) and received a living donor transplant (36.3% versus 22.2%), with no differences by sex, ethnicity or human leucocyte antigen mismatch. Allograft failure within 2 years of transplantation fell from 12.5% (2000-4) to 9.8% (2009-13). Surgical- and alloimmune-related failures decreased over time while death with a functioning graft became more common. Age, ethnicity and donor type were factors in recurrent primary disease and alloimmune pathology. Conclusions: Since 2000 there have been reductions in surgical and alloimmune graft failures in the UK. However, graft failure codes need to be revised if they are to remain useful and effective in epidemiological and quality improvement trials. PMID- 29982788 TI - Chronic Pain, Opioid Therapy, Sexual Desire, and Satisfaction in Sexual Life: A Population-Based Survey. AB - Objectives: Associations between chronic pain, opioid use, and sexual problems are acknowledged, but population-based investigations are sparse. Our study aimed at investigating the associations between chronic noncancer pain (CNCP), opioid use, lack of/low sexual desire, and dissatisfaction with sexual life. Subjects: In 2013, 11,517 randomly selected individuals of the Danish population (18-74 years old without cancer) completed a self-administered questionnaire. Methods: We classified CNCP: pain lasting six months or longer, short-term opioid use: one or more prescriptions the previous year, long-term opioid use: one or more prescriptions per month for six months the previous year. Sexual problems were assessed by four closed-ended questions. Data on dispensed opioids were retrieved from the Danish National Prescription Registry. Multiple logistic regression analysis was used to examine associations between CNCP, opioid use, and lack of/low sexual desire, and dissatisfaction in sexual life, presented as odds ratios (95% confidence intervals [CIs]). Results: Compared with individuals without CNCP, individuals with CNCP in the long-term and short-term opioid use group and in the nonopioid use group were more likely to report a lack of/low sexual desire (OR = 2.64, 95% CI = 1.80-3.88; OR = 1.82, 95% CI = 1.39-2.38; OR = 1.46, 95% CI = 1.28-1.67, respectively) and dissatisfaction with sex life (OR = 1.69, 95% CI = 1.07-2.67; OR = 1.35, 95% CI = 1.00-1.82; OR = 1.38, 95% CI = 1.22 1.58, respectively). Compared with CNCP patients not using opioids, long-term opioid users with CNCP had statistically significant higher odds of reporting a lack of/low sexual desire (OR = 1.81, 95% CI = 1.23-2.68). Conclusions: Long-term opioid therapy for CNCP requires special attention due to its potential in suppressing sexual desire. PMID- 29982789 TI - Improving Laboratory Processes with Total Laboratory Automation. AB - Background: To further improve workflow efficiency, our laboratory implemented a total laboratory automation (TLA) system that connected our preanalytic processing system with various testing (hematology, coagulation, and chemistry). Methods: Detailed time and motion studies were performed to create process flow maps before and after TLA. The before maps identified opportunities for workflow improvements. We used postimplementation studies to quantify efficiency gains. Results: The implementation of our TLA system resulted in 86% fewer discrete processing steps in specimen handling, even when starting from a partially automated laboratory. Instrument consolidation reduced the testing footprint by 45% and reduced the number of testing personnel by 2.5 full-time employees (FTEs). An 82% reduction in hands-on time associated with add-on processes was achieved. Combining STAT and outreach work on the testing system did not impact turnaround time. Conclusions: With careful planning, a TLA system can effectively optimize laboratory processes and efficiency. PMID- 29982790 TI - Transmission of dynamic supercoiling in linear and multi-way branched DNAs and its regulation revealed by a fluorescent G-quadruplex torsion sensor. AB - DNA supercoiling is an important regulator of gene activity. The transmission of transcription-generated supercoiling wave along a DNA helix provides a way for a gene being transcribed to communicate with and regulate its neighboring genes. Currently, the dynamic behavior of supercoiling transmission remains unclear owing to the lack of a suitable tool for detecting the dynamics of supercoiling transmission. In this work, we established a torsion sensor that quantitatively monitors supercoiling transmission in real time in DNA. Using this sensor, we studied the transmission of transcriptionally generated negative supercoiling in linear and multi-way DNA duplexes. We found that transcription-generated dynamic supercoiling not only transmits along linear DNA duplex but also equally diverges at and proceeds through multi-way DNA junctions. We also show that such a process is regulated by DNA-protein interactions and non-canonical DNA structures in the path of supercoiling transmission. These results imply a transcription-coupled mechanism of dynamic supercoiling-mediated intra- and inter-chromosomal signal transduction pathway and their regulation in DNA. PMID- 29982792 TI - Please Release Me, Let Me Go: How the Failure to Discuss and Treat OIC Can Result in Adverse Medico-Legal Outcomes. PMID- 29982791 TI - Commentary: Clinical Outcomes of Upfront Stereotactic Radiosurgery Alone for Patient With 5 to 15 Brain Metastases. PMID- 29982793 TI - Less safety for more efficiency: water relations and hydraulics of the invasive tree Ailanthus altissima (Mill.) Swingle compared with native Fraxinus ornus L. AB - Invasion of natural habitats by alien trees is a threat to forest conservation. Our understanding of fundamental ecophysiological mechanisms promoting plant invasions is still limited, and hydraulic and water relation traits have been only seldom included in studies comparing native and invasive trees. We compared several leaf and wood functional and mechanistic traits in co-occurring Ailanthus altissima (Mill.) Swingle (Aa) and Fraxinus ornus L. (Fo). Aa is one of the most invasive woody species in Europe and North America, currently outcompeting several native trees including Fo. We aimed at quantifying inter-specific differences in terms of: (i) performance in resource use and acquisition; (ii) hydraulic efficiency and safety; (iii) carbon costs associated to leaf and wood construction; and (iv) plasticity of functional and mechanistic traits in response to light availability. Traits related to leaf and wood construction and drought resistance significantly differed between the two species. Fo sustained higher structural costs than Aa, but was more resistant to drought. The lower resistance to drought stress of Aa was counterbalanced by higher water transport efficiency, but possibly required mechanisms of resilience to drought-induced hydraulic damage. Larger phenotypic plasticity of Aa in response to light availability could also promote the invasive potential of the species. PMID- 29982794 TI - Phosphorus acquisition efficiency and phosphorus remobilization mediate genotype specific differences in shoot phosphorus content in grapevine. AB - Crop productivity is limited by phosphorus (P) and this will probably increase in the future. Rootstocks offer a means to increase the sustainability and nutrient efficiency of agriculture. It is known that rootstocks alter petiole P concentrations in grapevine. The objective of this work was to determine which functional processes are involved in genotype-specific differences in scion P content by quantifying P uptake, P remobilization from the reserves in the cutting and P allocation within the plant in three grapevine genotypes. Cuttings of two American rootstocks and one European scion variety were grown in sand and irrigated with a nutrient solution containing either high P (0.6 mM) or low P (0 mM). The high P solution was labelled with 32P throughout the experiment. The grapevine genotypes studied show variation in the inhibition of shoot and root biomass in response to low P supply, and P supply also affected shoot, but not root, P concentrations. Genotype-specific differences in total P content were related to differences in P acquisition and utilization efficiencies (PAE and PUE, respectively). Phosphorus allocation within the plant was not affected by genotype or P supply. The rootstock genotype known to confer high petiole P content in the vineyard was associated with a high PAE under high P, and a high PUE under low P. This suggests that the petiole P concentrations in the vineyard are related to genotype-specific differences in PAE and PUE, and that these traits could be used for rootstock selection programmes in the future. PMID- 29982795 TI - Active neurocysticercosis at the Hospital for Tropical Diseases, London: a clinical case series. AB - Background: Neurocysticercosis is the commonest infectious cause of epilepsy in endemic countries, and accounts for a greater number of cases worldwide than any other single pathology. Infection is associated with long-term exposure in low income countries, although acquisition after travel has been recognized. The standard of care in the UK is inpatient treatment with anti-helminthic drugs and steroids. Methods: The authors reviewed all cases of neurocysticercosis managed at the Hospital for Tropical Diseases in London, England, between 2001 and 2015. Active disease was defined as evidence of either viable cysts or involuting cysts with associated parenchymal inflammation. Results: Of 26 active cases, 65.4% were migrants from nine different countries; 34.6% were UK-born travellers who had visited 19 countries across South and Central America, sub-Saharan Africa, South and South-east Asia; India was the commonest country of exposure in both groups. Only 73.1% presented with seizures; two diagnoses were made through brain imaging of patients with peripheral cysticerci; 53.8% had a single cyst. Migrants were more likely to be seropositive than travellers (p=0.033). Only two patients had seizures during admission, one of whom had multiple seizures prior to diagnosis. Conclusions: Neurocysticercosis presents in a non-endemic setting in both migrants and travellers. Travellers are less likely to be sero-positive. Not all cases of neurocysticercosis present with seizures. Outpatient management could be considered for selected patients. PMID- 29982796 TI - Prostaglandin E2 receptor EP2 mediates the effect of cyclooxygenase 2 on secondary parathyroid hyperplasia in end-stage renal disease. AB - Background: Secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease (ESRD) is characterized by hyperplasia of the parathyroid glands (PTGs), while the underlying mechanism is not completely understood. Previously we demonstrated a relationship between cyclooxygenase 2 (COX2) overexpression and parathyroid hyperplasia and here we investigate the role of COX2 downstream metabolic product prostaglandin E2 (PGE2) and its receptor EP2 in the pathogenesis of SHPT. Methods: PTGs isolated from ESRD patients with advanced SHPT were used to test the expression of COX2-microsomal prostaglandin E synthase 1 (mPGES-1)-EP2 pathway. A diffuse proliferative section of the PTGs was used for tissue culture and treated with high phosphate (HPi) medium, COX2-PGE2-EP2 pathway inhibitors or agonists. EP2 short hairpin RNA (shRNA) lentivirus was locally applied to treat an SHPT rat model. Results: In PTGs isolated from ESRD patients, enhanced immunoactivities of COX2, mPGES-1 and EP2 were observed. In primary cultured PTG tissues, HPi induced intact parathyroid hormone (iPTH) secretion, proliferating cell nuclear antigen (PCNA) expression and COX2 activity, while COX2 and EP2 inhibitors attenuated hyperparathyroidism promoted by HPi. Furthermore, PGE2 or EP2 agonist (butaprost) directly stimulated hyperparathyroidism, whereas EP2 receptor antagonist or cyclic adenosine monophosphate inhibitor attenuated the hyperparathyroidism promoted by PGE2 or butaprost. EP2 shRNA treatment significantly reduced excessive expressions of EP2 and PCNA in the PTGs of nephrectomy rats fed an HPi diet, diminished the size of PTGs and downregulated serum iPTH levels. Conclusions: The COX2 downstream PGE2 and its receptor EP2 may play an important role in HPi-induced parathyroid hyperplasia and may serve as a potential therapeutic target for SHPT in ESRD. PMID- 29982798 TI - The Hepatotoxicity of Palmitic Acid in Zebrafish Involves the Intestinal Microbiota. AB - Background: Palmitic acid (PA) is the main saturated fatty acid naturally occurring in animal fats and vegetable oils. In recent decades, palm oil, an alternative lipid source containing high amounts of PA, has been widely used to replace fish oil in aquafeed. Objective: We investigated the hepatotoxicity of PA in zebrafish and the underlying mechanism. Methods: One-month-old zebrafish fed a high-fat diet (HFD) containing 16% soybean oil and 3 PA-incorporated HFDs [4%, 8%, and 12% PA (12PA)] for 2 wk (experiment 1) and 4 wk (experiment 2) were used to evaluate PA-induced liver damage and endoplasmic reticulum (ER) stress. Germ free (GF) zebrafish fed low-fat, high-fat, or 12PA diets for 5 d were used to study the direct effects of PA on liver damage (experiment 3). GF zebrafish colonized with HFD or 12PA microbiota for 48 h were used to elucidate the indirect effects of PA-altered microbiota on liver damage (experiment 4). Last, GF zebrafish colonized with HFD or 12PA microbiota were used to evaluate the effects of different microbiotas on PA absorption (experiment 5). Results: In experiment 1, the proportion of PA in the liver linearly increased as its percentage in dietary lipid increased (r2 = 0.83, P < 0.05). In experiment 2, the expression of glucose-regulated protein 78 (Grp78) and C/EBP-homologous protein (Chop) was higher in the 12PA group than in the HFD group (2.2- and 2.7-fold, respectively; P < 0.05). The activity of caspase-12 was increased by 61.1% in the 12PA group compared with the HFD group (P < 0.05). In experiment 3, caspase-12 activity was higher in the 12PA group than in the HFD group (P < 0.05). In experiment 4, GF zebrafish colonized with PA-altered microbiota had higher caspase-12 activity (P < 0.05) than those colonized by HFD microbiota. In experiment 5, PA-altered microbiota promoted PA absorption (P < 0.05) and aggravated ER stress and liver damage in the context of high-PA feeding. Conclusions: The PA-altered microbiota indirectly induced ER stress and liver damage in zebrafish. Moreover, the PA microbiota promoted the absorption of PA, leading to enhanced PA overflow into the liver and aggravated hepatotoxicity of PA in zebrafish. PMID- 29982797 TI - Surfactant protein-D, a potential mediator of inflammation in axial spondyloarthritis. AB - Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects. Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography. Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures. Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA. PMID- 29982799 TI - Stereoelectroencephalography for Refractory Epileptic Patients Considered for Surgery: Systematic Review, Meta-Analysis, and Economic Evaluation. AB - BACKGROUND: Stereoelectroencephalography (SEEG) has been shown to be a valuable tool for the anatomoelectroclinical definition of the epileptogenic zone (EZ) in patients with medically refractory epilepsy considered for surgery (RES patients). In Spain, many of those patients are not offered this diagnostic procedure. OBJECTIVE: To evaluate the effectiveness, safety, and cost effectiveness of SEEG to define the EZ in RES patients compared to no SEEG intervention, ie, remaining with further antiepileptic drugs. METHODS: We undertook a systematic review with meta-analyses on the effectiveness and safety of SEEG. A cost-effectiveness analysis was conducted using a Markov model, which simulates the costs and health outcomes of individuals for a lifetime horizon from the perspective of the Spanish National Health Service. The effectiveness measure was quality-adjusted life years (QALYs). We ran extensive sensitivity analyses, including a probabilistic sensitivity analysis. RESULTS: The EZ was found in 92% of patients who underwent SEEG (95% confidence interval [CI]: 0.87 0.96); 72% were eligible for epilepsy surgery (95% CI: 0.66-0.78) and 33% were free of seizures after surgery (95% CI: 0.27-0.42). Of the patients who underwent surgery, 47% were free of seizures after surgery (95% CI: 0.37-0.58). Complications related to implantation and monitoring of SEEG and the subsequent intervention occurred in 1.3% of patients (95% CI: 0.01-0.02). In the base case analysis, SEEG led to higher QALYs and healthcare costs with an estimated incremental cost-effectiveness ratio of 10 368 EUR per QALY (95% CI: dominant-113 911), making the probability of cost-effectiveness between 75% and 88%. Further sensitivity analyses showed that the results of the study were robust. CONCLUSION: SEEG is a cost-effective technology in RES patients when compared to no SEEG intervention. PMID- 29982800 TI - Prevalence and Epidemiologic Profile of Oral Infection with Alpha, Beta, and Gamma Papillomaviruses in an Asian Chinese Population. AB - Background: Knowledge of the prevalence of and risk factors for oral human papillomavirus (HPV) infection, especially cutaneous types, is limited. Methods: A population-based study using next-generation sequencing consecutively recruited asymptomatic individuals aged 18-64 years from a proportional sampling of the general population of Hong Kong, according to age groups, gender, and regions of residence. We examined associations of alpha-, beta-, and gamma-HPVs from oral rinse samples with participants' sociodemographics by logistic regression models. Results: The prevalence of oral HPV infection among 1426 ethnic Chinese was 15.5% (95% confidence interval [CI], 13.7%-17.5%), 2.5% (95% CI, 1.8%-3.5%), 11.9% (95% CI, 10.3%-13.6%), and 2.9% (95% CI, 2.1%-3.9%) for any type, alpha-, beta-, and gamma-HPV, respectively. Prevalence of any high-risk HPV was 0.8% (95% CI, 0.4% 1.4%), and that of HPV-16 was 0.4% (95% CI, 0.2%-0.8%). HPV-8 and HPV-98 were the most common beta types detected, while HPV-4 and HPV-SD2R were the most common gamma types. Prevalence of alpha- and beta/gamma-HPV infection showed a similar pattern of increase with age, and was higher in men than women. Smoking, drinking, oral sex, and more sexual partners were associated with alpha-HPV. Teeth brushing before sleep was protective for beta/gamma-HPVs. Discussion: The epidemiologic factors associated with oral infection with alpha-HPVs are different from those of beta/gamma-HPVs, suggesting different modes of acquisition and persistence. PMID- 29982801 TI - Erratum. PMID- 29982802 TI - Erratum. PMID- 29982803 TI - Effects of drinking water synbiotic supplementation in laying hens challenged with Salmonella. AB - This experiment was conducted to study the effects of drinking water supplementation of synbiotic product PoultryStar(r)sol (containing Lactobacillus reuteri, Bifidobacterium animalis, Pediococcus acidilactici, Enterococcus faecium, and fructo-oligosaccharide) in laying hens with and without a Salmonella challenge. A total of 384 one-day-old layer chicks were randomly distributed to the drinking water synbiotic supplementation or control groups. At 14 wk of age, the birds were vaccinated with a Salmonella vaccine, resulting in a 2 (control and synbiotic) X 2 (non-vaccinated and vaccinated) factorial arrangement. At 24 wk of age, half of the birds in the vaccinated groups and all the birds that were not vaccinated were challenged with Salmonella Enterica serotype Enteritidis, resulting in a 3 (vaccinated, challenged, vaccinated+challenged) X 2 (control and synbiotic) factorial arrangment. At 8 d post-Salmonella challenge, synbiotic supplementation decreased (P = 0.04) cecal S. Enteritidis in the challenge group compared to the un-supplemented challenge group. Birds that were supplemented with synbiotic in the vaccine + challenge group had significantly greater cecal B. animalis and P. acidilactici percentage at 10 d post-Salmonella challenge than the birds in the vaccine + challenge group without synbiotic supplementation. At 3 d post-Salmonella challenge, birds that were supplemented with synbiotic in the challenge group had significantly greater cecal L. reuteri percentage than the birds in the challenge group without synbiotic supplementation. At 17 d post Salmonella challenge, synbiotic supplementation increased bile anti-Salmonella IgA in the challenge group compared to the birds in the challenge group without synbiotic supplementation by 76.0%. At 10 d (P < 0.01) and 30 d (P = 0.05) post Salmonella challenge, synbiotic supplementation decreased LITAF mRNA expression compared to the un-supplemented groups. At 3 d post-Salmonella challenge, synbiotic supplementation in the vaccine group had longer jejunal villi compared to the vaccine group without synbiotic supplementation. This experiment demonstrated that drinking water supplementation of the synbiotic product evaluated can significantly manipulate immune response and intestinal microbiota of laying hens post-Salmonella challenge to handle the challenge effectively. PMID- 29982804 TI - Letter: Superficial Temporal Artery: Distal Posterior Cerebral Artery Bypass Through the Subtemporal Approach: Technical Note and Pilot Surgical Cases. PMID- 29982806 TI - A Collaborative Approach to Decision Making Through Developmental Monitoring to Provide Individualized Services for Children With Cerebral Palsy. PMID- 29982805 TI - Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial. AB - Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR amplified rGBM. Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naive. Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6 month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406). PMID- 29982807 TI - Editorial: The 16th annual Nucleic Acids Research web server issue 2018. PMID- 29982808 TI - Exacerbation of Type 1 Diabetes in Perinatally Genistein Exposed Female Non-Obese Diabetic (NOD) Mouse Is Associated With Alterations of Gut Microbiota and Immune Homeostasis. AB - Despite various hypothesized benefits of dietary isoflavone genistein (GEN) from soy-based products, many questions surrounding GEN's immunotoxic effects, especially during perinatal exposure, have yet to be answered. The objective of the study was to determine if there existed a sex-specific effect of GEN on type 1 diabetes (T1D) following perinatal exposure. We exposed offspring of non-obese diabetic (NOD) mice to GEN per oral at a physiological dose (20 mg/kg body weight) from embryonic day 7 to postnatal day (PND) 21. In female offspring, perinatal GEN dosing significantly increased the incidence of T1D at early time points, and the exacerbation was associated with decreased serum levels of interleukin (IL)-10, IgG2a, and IgM. In male offspring dosed with GEN, a decrease in serum IgG1 was also observed. Flow cytometric analysis in females suggested an increased pro-inflammatory splenic CD5+CD24- and CD4-CD8+ cell counts, while both %T cells and %CD4+ T cells were significantly decreased in males, suggesting an anti-inflammatory effect. Gut microbiota (GMB) analysis indicated that fecal microbiota from PND 90 female offspring exhibited an increased level of Enterobacteriales (suggesting a pro-inflammatory response), while the similar changes were not found in PND 30 females. Moreover, RNA sequencing showed that intestinal alpha-defensin expression was down-regulated in GEN-treated females, supporting a pro-inflammatory response. However, perinatal GEN administration perturbed GMB toward an anti-inflammatory response in PND 90 males. Taken together, a strong sex-specific effect was found in the perinatal GEN exposure window, and the T1D exacerbation in NOD females was associated with GMB-related immunomodulatory mechanisms. PMID- 29982809 TI - Differential Diagnosis of a Patient with Lysosomal Acid Lipase Deficiency: A Case Report. AB - Background: We describe the differential diagnosis of an obese 12-year-old boy of Mexican origin who presented with a 6-year history of abnormal lipid profile and elevated liver transaminase levels. Methods: The patient underwent routine clinical testing, an abdominal ultrasound and, ultimately, a liver biopsy. Based on the histologic findings, a serum leukocyte lysosomal acid lipase (LAL) assay and DNA sequencing of the lipase A (LIPA) gene were performed. Results: Liver biopsy revealed diffuse microvesicular steatosis with clusters of foamy histiocytes in the lobules and portal areas. Our differential diagnosis included nonalcoholic fatty liver disease; medication-induced hepatotoxicity; glycogenic hepatopathy; medium-chain acyl coenzyme A dehydrogenase or long-chain acyl coenzyme A dehydrogenase deficiency; and lysosomal storage disorders, including Niemann-Pick disease and lysosomal acid lipase deficiency (LAL-D). Serum LAL activity was absent, and DNA sequencing confirmed homozygous mutation in LIPA. Conclusions: Although it occurs rarely, LAL-D should be considered in the differential diagnosis of microvesicular steatosis for a timely diagnosis. PMID- 29982810 TI - Effect of Dietary Protein and Carbohydrates on Survival and Growth in Larvae of the Henosepilachna vigintioctopunctata (F.) (Coleoptera: Coccinellidae). AB - The ratio of protein and carbohydrate in an insect's nutritional regime can significantly influence its survival, growth, and fecundity. The effects of 11 different artificial diets containing protein (p): carbohydrate (c) ratios were determined in larvae of the phytophagus ladybug, Henosepilachna vigintioctopunctata (F.) (Coleoptera: Coccinellidae). We recorded the developmental times and survival rates of the larvae and weighed their pupae. When the concentration of carbohydrates was kept constant while the concentration of proteins was increased (p29:c20, p31:c20, p33:c20, and p35:c20), H. vigintioctopunctata could successfully complete the larval and pupal stages. The highest survival rate and greatest pupal mass of H. vigintioctopunctata were 72% and 19.5 mg, respectively, when reared on the p33:c20 diet. H. vigintioctopunctata larvae, however, were unable to develop into adults when the concentration of protein remained constant while the level of carbohydrates was increased (p20:c23, p20:c25, p20:c27, and p20:c29), or when the total amount (p + c) was kept at 48% (p22:c26, p 24:c24, p26:c22). Evidently, changing the availability of quality diet, especially the total protein levels, can significantly affect the performance to H. vigintioctopunctata. Our results indicated that the maximum development and survival of H. vigintioctopunctata larvae occurred within a narrow range-when the p:c ratio was (33:20). PMID- 29982811 TI - Nesting Biology of Xylocopa xinjiangensis (Hymenoptera: Apidae: Xylocopinae). AB - Xylocopa, an important genus in Hymenoptera: Apidae, is of great significance in research on the early stages of insect social evolution. Most species in this genus burrow into wooden structures. Only the Proxylocopa subgenus nests in the soil. Here, we report the nesting behavior of Xylocopa xinjiangensis (Hymenoptera: Apidae: Xylocopinae), which is distributed only in Western China. During July 2013 and August 2016, we observed the nest architecture and nest building process of X. xinjiangensis. X. xinjiangensis is solitary and nests in the soil walls of gullies, mounds, and cliffs in the Manas area, Xinjiang, multiplying at the rate of one generation a year. Newly emerged females eclose in the fall and build wintering nests first. The next spring, outbound wintering females build breeding nests, although a few wintering females may use the breeding nests built by their mothers. The location and structure of X. xinjiangensis wintering nests are different from those of the breeding nests. The wintering nest is simple in structure, consisting of a tunnel leading perpendicularly from the surface to the interior. The structure of the breeding nest may be either a branching tunnel or a straight-chain tunnel. The first cell that X. xinjiangensis builds in the breeding nest is closest to the entrance, which is a significant difference from the behavior of carpenter bees that construct nests in wood structures. The results of this study lay the foundation for the utilization and protection of X. xinjiangensis resources and facilitate a better understanding of the evolution of the Xylocopa population. PMID- 29982812 TI - The wooden breast condition results in surface discoloration of cooked broiler pectoralis major. AB - Published studies have shown that the wooden breast (WB) condition affects the macroscopic appearance, quality, and functionality of raw broiler breast fillets (pectoralis major) as well as the texture of both raw and cooked fillets. In this study, we demonstrated for the first time that the WB condition also significantly affects the color and appearance of cooked breast fillets. Fresh broiler breast fillets (deboned at 3 h post-mortem) were collected from a commercial plant and sorted into normal (no WB) and severe WB condition categories based on palpable hardness and rigidity throughout the breast fillets. The fillets were either cooked directly from a fresh state, after marination with a target concentration of 0.75% NaCl and 0.45% phosphate at the end, or after storage at -20 degrees C. Samples were cooked to 76 degrees C in individual cooking bags in a combi-steam oven. Color measurements (CIEL*a*b*) on both the ventral and dorsal surfaces of cooked fillets were assessed using a Minolta spectrophotometer CM-700d. There were no significant CIE color value differences on the dorsal surfaces (bone side) of cooked fillets (P > 0.01). However, on the cooked ventral surfaces (skin side), the WB condition caused increases (P < 0.01) in a* and b* values and a decrease (P < 0.01) in the L* value regardless of marination treatment or frozen storage. The average L* values of cooked WB fillets were more than 6 units lower than in cooked normal fillets. After cooking, WB fillets showed higher a* and b* values by more than 0.5 and 2 units, respectively, than normal fillets. Data demonstrate that the WB condition can negatively influence the ventral surface color of cooked broiler breast fillets. The cooked surface of WB fillets was darker, redder, and more yellow than that of fillets without the WB condition. The detrimental effect of WB on the surface color and appearance of cooked breast fillets was noticeable and was not eliminated by marination or frozen storage. PMID- 29982813 TI - Implementation of a unique hepatitis C care continuum model in Rwanda. AB - Background: There has been an evolution in the treatment of chronic hepatitis C (HCV) due to highly effective direct-acting antivirals, however, restriction of treatment to medical specialists hinders escalation of HCV treatment. This is particularly true in resource-limited settings (RLS), which disproportionately represent the burden of HCV worldwide. The ASCEND study in Washington, DC, demonstrated that complete task-shifting can safely and effectively overcome a low provider-to-patient ratio and expand HCV treatment. However, this model has not been applied internationally to RLS. Method: The validated ASCEND model was translated to an international clinical program in Kigali, Rwanda, aimed at training general medicine providers on HCV management and obtaining HCV prevalence data. Results: The didactic training program administered to 11 new HCV providers in Rwanda increased provider's knowledge about HCV management. Through the training program, 26% of patients seen during the follow-up period were screened for HCV and a prevalence estimate of 2% was ascertained. Of these patients, 30% were co-infected with hepatitis B. Conclusion: The ASCEND paradigm can be successfully implemented in RLS to escalate HCV care, in a self-sustaining fashion that educates more providers about HCV management, while increasing the public's awareness of HCV and access to treatment. PMID- 29982815 TI - Daily Control Beliefs and Cognition: The Mediating Role of Physical Activity. AB - Objectives: Recent work suggests that physical activity may underlie the positive relationship between control beliefs and cognition. Despite the well-known cognitive benefits, most adults do not engage in enough physical activity, perhaps due to low perceived control. The current study aimed to expand upon past work by investigating these constructs over the short-term by studying the intraindividual variability in daily control beliefs, physical activity, and cognition. We examined whether these constructs were related on a day-to-day basis and if daily physical activity mediated the relationship between control beliefs and cognition. Method: Over seven consecutive days, 145 participants (M= 50.54 years) completed daily diaries to measure domain-specific control beliefs, wore an ActiGraph to capture objective physical activity, and were administered two tasks each day via phone to measure cognition. Results: Using Multilevel Structural Equation Modeling, our results indicated that on days with higher control beliefs cognition was also higher and this relationship was mediated by one's level of physical activity. Discussion: These findings demonstrate the role of physical activity in linking control beliefs and cognition on a daily level using a within-person approach to investigate the dynamic processes in beliefs and cognition. PMID- 29982814 TI - Psychotic Experiences and Related Distress: A Cross-national Comparison and Network Analysis Based on 7141 Participants From 13 Countries. AB - Psychotic experiences (PEs) are common in the general population but do not necessarily reflect a risk status if they occur in relative isolation or are not distressing. Emerging evidence suggests that PEs might be experienced as more benign for individuals from collectivistic low- and middle-income countries (LAMIC) compared with individualistic high-income countries (HIC). The aim of this study was to determine whether: (1) self-reported PEs are less distressing in community samples from LAMIC than from HIC; (2) the network of PEs is significantly less connected in a sample from LAMIC than from HIC. Adults from 8 HIC (n = 4669) and 5 LAMIC (n = 2472) were compared. The lifetime frequency of PEs and related distress were assessed with the Community Assessment of Psychic Experiences. We analyzed the associations of PEs with distress and country type. The interconnection of PEs was visualized by a network analysis and tested for differences in global connection strengths. The average endorsement rates of PEs were significantly higher in LAMIC than in HIC (chi2 = 1772.87, P < .01, Phicramer = 0.50). There was a universal positive correlation between higher frequency of PEs and more distress, but the distress levels controlled for frequency were significantly higher in HIC (R2 = 0.11; b = 0.26; SE = 0.01; T = 17.68; P < .001). Moreover, the network of PEs was significantly less connected in LAMIC (S = 0.40, P < .05). The findings indicate that PEs are of less clinical relevance in LAMIC compared with HIC. The universal use of current high-risk criteria might thus not be adequate without consideration of associated distress and cultural values. PMID- 29982817 TI - Multiple Deprivation, the Inner City, and the Fracturing of the Welfare State: Glasgow, c. 1968-78. AB - From 1968, the central government established a series of area-based initiatives that operated on the basis of 'positive discrimination' towards the social needs of local residents. Over the course of the next 10 years, this area-based positive discrimination became an increasingly important part of social policy in Britain. This article uses Glasgow as a case study to show, first, how both the local and the central government attempted to define the problem of 'multiple deprivation' in the 1970s. Second, it shows how social studies were used to locate multiply deprived communities within urban areas, thereby feeding into the identification of the 'inner city' as a policy problem. Finally, this article shows how evidence of the concentration of multiple deprivation and the adoption of area-based strategies contributed to the fracturing of the welfare state, eroding the universalist principles upon which post-war social policy had been based. PMID- 29982816 TI - A comparative study of acute-phase protein concentrations in historical and modern broiler breeding lines. AB - Acute-phase proteins (APP) are secreted from the liver as a result of inflammation or infection and are measurable in serum and plasma. To determine whether the constitutive APP serum amyloid A (SAA), alpha-1-acid glycoprotein (AGP), ceruloplasmin (Cp), and ovotransferrin (Ovt) have changed as a result of selection for improved production and growth characteristics over the last 40 yr two historical broilers lines were compared to a modern line of the same lineage. Serum was harvested from blood samples taken from the 3 broiler lines on days 10, 17, and 20, and the APP concentrations were determined using immunoassay methods. Most of the significant changes observed were age related, with SAA and Cp having significantly lower concentrations at day 20 than days 10 and 17 in all lines. The only significant difference between lines was observed at day 20 on which both Cp (P = 0.01) and AGP (P = 0.03) were significantly higher in the modern line than the 90s line, though no significant differences were noted between the modern and 70s line. When evaluating the difference in APP concentrations between males (Cx) and females (Px) across all 3 lines, females had a higher SAA at day 17 and lower SAA at day 20, P = 0.0078 and 0.0327 respectively, and males had a significantly higher Ovt on days 17 and 20 (P = 0.0002 and P = 0.003 respectively). These results reveal that APP concentrations fluctuate over this early period of growth and that the changes in APP serum concentration appear uniform between 3 lines with very contrasting selection history, suggesting the improvements made in meat production efficiency since the 1970s have not affected the circulating concentrations of these constitutively expressed APP. PMID- 29982818 TI - Bibliometric analysis of literature in AIDS-related stigma and discrimination. AB - Stigma and discrimination are major barriers in the global fight against human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). The aim of this study was to create an analytical inventory of worldwide research output in AIDS-related stigma and discrimination. SciVerse Scopus was used for the study period from 1980 to 2017 to retrieve literature in AIDS-related stigma and discrimination. Results were presented as bibliometric tables and maps. In total, 2,509 documents were retrieved. Approximately 40% (n = 990) of the retrieved documents were published in the last 5 years (2013-2017). Retrieved documents received an average of 19.8 citations per article and had an average of 3.2 authors per article. The Hirsh index of the retrieved documents was 94. Most frequently encountered topics were mental health, adherence, adolescents, women, disclosure, and Africa. The USA contributed to 1,226 (48.9%) documents while the African region contributed to 531 (21.2%) documents. Research collaboration among most active countries was relatively low. Authors and institutions from the USA dominated this field. AIDS Care was the most active journal in publishing documents in this field with 307 (13.4%) documents while documents published in Social Medicine journal received the highest citations. Research in AIDS-related stigma and discrimination had witnessed a noticeable increase in the past decade, but the overall number of publications is considered insignificant relative to the size of the problem and the global number of infected people. There was a relative underpresentation of literature from African region despite the fact that more than two-thirds of HIV-infected people in the world are living in Africa. PMID- 29982819 TI - Liquorice, Liddle, Bartter or Gitelman-how to differentiate? AB - Hypokalaemia with alkalosis can suggest excess aldosterone. Aldosterone stimulates the collecting duct mineralocorticoid receptor (MR) to upregulate the epithelial sodium channel (ENaC) and stimulate electrogenic sodium reabsorption, with secretion of potassium and protons. Gitelman, Bartter and Liddle syndrome, and liquorice ingestion all cause hypokalaemic alkalosis. This mini-review outlines the pathophysiology of these conditions as well as how to differentiate them. PMID- 29982820 TI - Developing a questionnaire to assess the health effects of bioaerosols. AB - Background: Bioaerosol exposure occurs in several industries including green waste recycling, poultry farming, grain, animal feed and cotton production. Whilst several studies have investigated exposure and health effects in compost workers, the best questions to ask about health are uncertain. Aims: This study aimed to develop a questionnaire to assess health symptoms in compost workers. Methods: A 46-item questionnaire to ascertain possible symptoms of occupational illness related to bioaerosol exposure in a cohort of UK industrial compost workers and delivery in an interviewer-led format. The reliability of the questionnaire was assessed using Cronbach's alpha. A principal component analysis (PCA) was conducted to condense the questionnaire for practical purposes. Results: One hundred and eleven (89%) workers completed the questionnaire. All items showed very good reliability (Cronbach's alpha = 0.83). After removing perfectly correlated questions from the data set, the PCA was conducted on a reduced data set of 28 items to explore underlying themes. Nine components were identified that explained 77% of the total variation. Nine of the questions removed prior to PCA due to perfect correlation were reintroduced because they added clinical value. The final questionnaire therefore consisted of 37 items and retained very adequate reliability (Cronbach's alpha = 0.76). Conclusions: Our health questionnaire has demonstrated adequate reliability when used within this industrial composting workforce. Further applications may include health surveillance, investigating outbreaks of occupational disease or research. Future work should examine the predictive validity of the questionnaire in these settings. PMID- 29982821 TI - Members of the Arabidopsis FORKED1-LIKE gene family act to localize PIN1 in developing veins. AB - The reticulate leaf vein pattern typical of angiosperms is proposed to have been a driving force for their evolutionary success. Vein pattern is established through auxin canalization via the auxin efflux protein PINFORMED1 (PIN1). During formation of vein loops, PIN1 cellular localization is increasingly restricted to either the basal side of cells in the lower domain or to the apical side in the upper domain. We previously identified the gene FORKED1 (FKD1) to be required for PIN1 asymmetric localization and for the formation of closed vein loops. FKD1 encodes a plant-specific protein with a domain of unknown function (DUF828) and a Pleckstrin-like homology domain. The Arabidopsis genome encodes eight similar proteins, which we term the FORKED1-LIKE (FL) gene family. Five FL family members localize primarily to the trans-Golgi network or the Golgi, and several co localize with FKD1-green flourescent protein (GFP) and RABA1c, suggesting action in the secretory pathway. While single FL gene family mutations do not result in vein pattern defects, triple mutants with mutations in FKD1, FL2, and FL3 result in a more symmetric PIN1 localization and a highly disconnected vein pattern. Our data suggest that FL genes act redundantly with FKD1 in the secretory pathway to establish appropriate PIN1 localization in provascular tissue. PMID- 29982822 TI - Treatment of small intestinal bacterial overgrowth in systemic sclerosis: a systematic review. AB - Objectives: Almost all patients with SSc have gastrointestinal manifestations. Small intestinal bacterial overgrowth (SIBO) occurs in 30-60% of patients and leads to malnutrition and impaired quality of life. Recent systematic reviews have reported efficacy of treatments for SIBO, but these are not specific to patients with SSc. We conducted a systematic review of the evidence for all possible SIBO treatments in the SSc population. Methods: The following databases were searched: MEDLINE, EMBASE and the Cochrane Library, from database inception to 1 January 2017. All evidence for all possible SIBO treatments including antibiotics, prokinetics, probiotics and alternative treatments was included. Treatment outcomes included symptomatic relief or demonstrated SIBO eradication. Results: Of 5295 articles, five non-randomized studies were reviewed with a total of 78 SSc patients with SIBO. One trial assessed octreotide while the remaining four trials investigated the effectiveness of ciprofloxacin, rifaximin, norfloxacin and metronidazole, and the combination of amoxicillin, ciprofloxacin and metronidazole. Studies were generally of low quality and most were un controlled. Conclusion: Data indicate that, for some SSc patients, antibiotics can eradicate SIBO. There is a paucity of data reporting the effectiveness of either prokinetics or probiotics in SSc. PMID- 29982823 TI - What the brain 'Likes': neural correlates of providing feedback on social media. AB - Evidence increasingly suggests that neural structures that respond to primary and secondary rewards are also implicated in the processing of social rewards. The 'Like'-a popular feature on social media-shares features with both monetary and social rewards as a means of feedback that shapes reinforcement learning. Despite the ubiquity of the Like, little is known about the neural correlates of providing this feedback to others. In this study, we mapped the neural correlates of providing Likes to others on social media. Fifty-eight adolescents and young adults completed a task in the MRI scanner designed to mimic the social photo sharing app Instagram. We examined neural responses when participants provided positive feedback to others. The experience of providing Likes to others on social media related to activation in brain circuity implicated in reward, including the striatum and ventral tegmental area, regions also implicated in the experience of receiving Likes from others. Providing Likes was also associated with activation in brain regions involved in salience processing and executive function. We discuss the implications of these findings for our understanding of the neural processing of social rewards, as well as the neural processes underlying social media use. PMID- 29982824 TI - Coupled catabolism and anabolism in autocatalytic RNA sets. AB - The ability to process molecules available in the environment into useable building blocks characterizes catabolism in contemporary cells and was probably critical for the initiation of life. Here we show that a catabolic process in collectively autocatalytic sets of RNAs allows diversified substrates to be assimilated. We modify fragments of the Azoarcus group I intron and find that the system is able to restore the original native fragments by a multi-step reaction pathway. This allows in turn the formation of catalysts by an anabolic process, eventually leading to the accumulation of ribozymes. These results demonstrate that rudimentary self-reproducing RNA systems based on recombination possess an inherent capacity to assimilate an expanded repertoire of chemical resources and suggest that coupled catabolism and anabolism could have arisen at a very early stage in primordial living systems. PMID- 29982825 TI - The Spectre of Too Many Species. AB - Recent simulation studies examining the performance of Bayesian species delimitation as implemented in the BPP program have suggested that BPP may detect population splits but not species divergences and that it tends to over-split when data of many loci are analyzed. Here we confirm these results and provide the mathematical justifications. We point out that the distinction between population and species splits made in the protracted speciation model has no influence on the generation of gene trees and sequence data, which explains why no method can use such data to distinguish between population splits and speciation. We suggest that the protracted speciation model is unrealistic as its mechanism for assigning species status assumes instantaneous speciation, contradicting prevailing taxonomic practice. We confirm the suggestion, based on simulation, that in the case of speciation with gene flow, Bayesian model selection as implemented in BPP tends to detect population splits when the amount of data (the number of loci) increases. We discuss the use of a recently proposed empirical genealogical divergence index (gdi) for species delimitation and illustrate that parameter estimates produced by a full likelihood analysis as implemented in BPP provide much more reliable inference under the gdi than the approximate method phrapl. We distinguish between Bayesian model selection and parameter estimation, and suggest that the model selection approach is useful for identifying sympatric cryptic species while the parameter estimation approach may be used to implement empirical criteria for determining species status among allopatric populations. PMID- 29982826 TI - Rapid inflammation and early degeneration of bone and cartilage revealed in a time-course study of induced haemarthrosis in haemophilic rats. AB - Objectives: Detailed knowledge of the sequential cell and tissue responses following haemarthrosis is important for a deep understanding of the pathological process initiated upon extensive bleeding into the joint causing haemophilic arthropathy (HA). The underlying pathobiology driving haemarthrosis towards HA has been difficult to establish in detail, although animal models have shed light on some processes. Previous studies have focused on a single or a few distant time points and often only characterizing one tissue type of the joint. The objective of this study was, therefore, to carefully map early onset of synovitis and HA following induced haemarthrosis. Methods: One hundred and thirty haemophilia A rats were subjected to induced haemarthrosis or a sham procedure in full anaesthesia and euthanized from 30 min to 7 days after the procedure. Pathological changes of the joints were visualized using micro-computed tomography, histology and immunohistochemistry. Results: Synovitis developed within 24 h and was dominated by myeloid cell infiltrations. Cartilage and bone pathology were evident as early as 48-96 h after haemarthrosis, and the pathology rapidly progressed with extensive periosteal bone formation and formation of subchondral cysts. Conclusion: Fast, extensive and simultaneous cartilage and bone degeneration developed shortly after haemarthrosis, as shown by the detailed mapping of the early pathogenesis of HA. The almost immediate loss of cartilage and the pathological bone turnover suggest a direct influence of blood on these processes and are unlikely to be attributed simply to an indirect effect of inflammation. PMID- 29982827 TI - Sensitivity to Physical Activity: Identifying Important Predictors and Outcomes in Pain-Free Older Adults Using a Simple Activity-Related Measure. PMID- 29982828 TI - Autophage as a control measure for Salmonella in laying hens. AB - Notwithstanding the National Salmonella Control Programs, the latest data published by the European Food Safety Authority show an increase in Salmonella Enteritidis prevalence in laying hen flocks. For this reason, the implementation of innovative techniques such as phage therapy is needed to control Salmonella at farm level. Most common bacteriophage applications are a cocktail of 2 or more bacteriophages, as it has been described that cocktails could remove different Salmonella serotypes, thus providing cross efficacy. Nevertheless, resistance to the bacteriophage cocktail has been reported, resulting in a decrease in their effectiveness. Along these lines, some authors have reported the possibility of using autophage when commercial bacteriophage cocktails are not active against field strains. To our best knowledge, no autophage (bacteriophage isolated from the same environment where the pathogen is isolated) has been found to control Salmonella in laying hens. In this context, the aim of this study was to assess the application of autophage in reducing Salmonella Enteritidis in environmental and fecal samples in a layer farm. To this end, the bacteriophage was isolated from the same farm where the bacteria was present and was applied onto the facility installations and the animals, at 2 different times. After bacteriophage challenges, swab cloths from facility surfaces and feces samples were collected at 3 times according to the time spent after the bacteriophage challenge. The results obtained in our study showed that all the surface samples collected from the farm facilities after phage therapy were negative for Salmonella. Concerning faces samples, statistical differences were found in Salmonella counts, with the strongest decrease (1.78log10) occurring after the second challenge. Otherwise, depending of the moment of sampling, the results obtained were 2.34log10, 1.39log10, 0.56log10, and 0.97log10 cfu/g for T0, T1, T2, and T3 respectively. The study highlights the use of autophage therapy not only for Salmonella Enteritidis control in animals, but as a sanitizer in cleaning and disinfection. PMID- 29982829 TI - Cyclic di-GMP integrates functionally divergent transcription factors into a regulation pathway for antioxidant defense. AB - Cyclic diguanylate monophosphate (c-di-GMP) is a global signaling molecule that modulates diverse cellular processes through its downstream receptors. However, no study has fully clarified the mechanisms by which c-di-GMP organizes functionally divergent regulators to drive the gene expression for coping with environmental stress. Here, we reported that c-di-GMP can integrate two functionally opposite receptor transcription factors, namely, LtmA and HpoR, into a pathway to regulate the antioxidant processes in Mycobacterium smegmatis. In contrast to HpoR, LtmA is an activator that positively regulates the expression of redox gene clusters and the mycobacterial H2O2 resistance. LtmA can physically interact with HpoR. A high level of c-di-GMP stimulates the positive regulation of LtmA and boosts the physical interaction between the two regulators, further enhancing the DNA-binding ability of LtmA and reducing the inhibitory activity of HpoR. Therefore, upon exposure to oxidative stress, c-di-GMP can orchestrate functionally divergent transcription factors to trigger antioxidant defense in mycobacteria. This finding presents a noteworthy example of how a bacterium remodels its transcriptional network via c-di-GMP in response to environmental stress. PMID- 29982830 TI - Current Availability of Stem Cell-Based In Vitro Methods for Developmental Neurotoxicity (DNT) Testing. AB - There is evidence that chemical exposure during development can cause irreversible impairments of the human developing nervous system. Therefore, testing compounds for their developmentally neurotoxic potential has high priority for different stakeholders: academia, industry, and regulatory bodies. Due to the resource-intensity of current developmental neurotoxicity (DNT) in vivo guidelines, alternative methods that are scientifically valid and have a high predictivity for humans are especially desired by regulators. Here, we review availability of stem-/progenitor cell-based in vitro methods for DNT evaluation that is based on the concept of neurodevelopmental process assessment. These test methods are assembled into a DNT in vitro testing battery. Gaps in this testing battery addressing research needs are also pointed out. PMID- 29982831 TI - Clinical Outcomes of Upfront Stereotactic Radiosurgery Alone for Patients With 5 to 15 Brain Metastases. AB - BACKGROUND: The role of primary stereotactic radiosurgery (SRS) for patients with >4 brain metastases (BM) remains controversial. OBJECTIVE: To compare the outcomes of patients treated with upfront SRS alone for 1, 2 to 4, and 5 to 15 BM and assess for predictors of clinical outcomes in the 5 to 15 BM group. METHODS: A total of 478 patients treated with upfront SRS were stratified by number of lesions: 220 had 1 BM, 190 had 2 to 4 BM, and 68 patients had 5 to 15 BM. Overall survival and whole brain radiotherapy-free survival were estimated using the Kaplan-Meier method. The cumulative incidences of local failure and distant brain failure (DBF) were estimated using competing risks methodology. Clinicopathologic and dosimetric parameters were evaluated as predictors of survival and DBF in patients with 5 to 15 BM using Cox proportional hazards. RESULTS: Median overall survival was 8.0, 6.3, and 4.7 mo for patients with 1, 2 to 4, and 5 to 15 BM, respectively (P = .14). One-year DBF was 27%, 44%, and 40%, respectively (P = .01). Salvage SRS and whole brain radiotherapy rates did not differ. Progressive extracranial disease and gastrointestinal primary were associated with poor survival while RCC primary was associated with increased risk of DBF. No evaluated dose-volume parameters predicted for death, neurologic death or toxicity. CONCLUSION: SRS for 5 to 15 BM is well tolerated without evidence of an associated increase in toxicity, treatment failure, or salvage therapy. Further prospective, randomized studies are warranted to clarify the role of SRS for these patients. PMID- 29982832 TI - Predicting ascites incidence in a simulated altitude-challenge using single nucleotide polymorphisms identified in multi-generational genome wide association studies. AB - Assessing pedigreed broiler lines for ascites resistance in an industry setting is time consuming. Further, the use of sibling selection implies study subjects are not used in the breeding program, and instead, siblings take their place in pedigree systems, which reduces overall genetic accuracy. The purpose of this study is to evaluate the effectiveness of prediction models produced with SNP with the goal of predicting ascites incidence. Ascites is the manifestation of a series of adverse changes in a broiler beginning with hypoxia. Increased blood pressure, accumulation of fluid in the abdominal cavity, and death can result. Ascites results in losses estimated at $100 million/year in the USA. A multi generational genome wide association study in an unselected line maintained at the University of Arkansas since the 1990s identified chromosomal regions associated with ascites incidence in males when challenged at high altitude. From the identified regions of significance 20 SNP were selected to construct a predictive model (8 SNP on chromosome 11, and 12 SNP on chromosome Z). Ascites phenotype and genotype data were obtained for 295 male and female individuals from the REL line. Five modeling techniques were compared for their ascites predictive ability using a 70/30 split between training and validation. For both males and females, the artificial neural network model was the best fit prediction model due to the large area under the curve value of 0.997 and 0.997, respectively, as well as a low misclassification ratio of 0.027 and 0.037, respectively. Using a parameter decreasing method, the total number of SNP inputs used to construct artificial neural network (ANN) models was reduced. A 13 SNP male ANN model and an 18 SNP female ANN model were constructed with equally high levels of prediction accuracy compared with the 20 SNP input models. The construction of predictive ANN models indicates that we have found the genetic predictors to ascites outcome in male and female broilers from an elite line of the 1990s with a high level of accuracy. PMID- 29982833 TI - Functional xylem anatomy of aspen exhibits greater change due to insect defoliation than to drought. AB - The study of tree rings can reveal long-term records of a tree's response to the environment. This dendroecological approach, when supplemented with finer-scale observations of the xylem anatomy, can provide novel information about a tree's year-to-year anatomical and hydraulic adjustments. Here we use this method in aspen (Populus tremuloides Michx.) to identify xylem response to drought and insect defoliation. Surprisingly, we found that precipitation influenced vessel diameter mostly in the trees' youth, while this correlation was less pronounced at maturity. This is likely due to a reduction in stress the stand experiences as it ages, and reflects an ability to mediate drought stress as trees mature. Defoliation events caused consistent and profound changes in fiber anatomy likely leading to reduced structural support to vessels. We therefore expect that in years of defoliation trees may be vulnerable to drought-induced cavitation when leaf area recovers. This study highlights how the inclusion of cellular level measurements in tree ring studies provides additional information on how stress events may alter tree functioning through alterations in structure. PMID- 29982834 TI - Actigraphy in the digital health revolution: still asleep? PMID- 29982835 TI - Back to the Future: Examining Age Differences in Processes Before Stressor Exposure. PMID- 29982837 TI - Improvements in semen quality, sperm fatty acids, and reproductive performance in aged Ross breeder roosters fed a diet supplemented with a moderate ratio of n-3: n-6 fatty acids. AB - The purpose of this study was to evaluate the effects of dietary n-3: n-6 fatty acid (FA) ratios and vitamin E (vitE) on the semen quality, FA composition, hormonal responses, and reproductive performance of aged roosters. Thirty-six Ross broiler breeder roosters were assigned to a 3 * 2 factorial design with 3 n 3: n-6 FA ratios (0.09, 0.16, and 0.23) based on the inclusion of 3 oil sources (canola, canola/fish, and fish) and 2 vitE levels (0 and 200 mg/kg). During the 60 d of treatment, semen parameters, FAs composition of sperm, lipid peroxidation, and hormonal responses were monitored. Reproductive performance using artificial insemination was also evaluated at the end of experiment (on day 60). Results showed that the 0.16 and 0.23 dietary ratios increased docosahexaenoic acid and n-3 polyunsaturated FA and decreased docosatetraenoic acid and arachidonic acid in rooster sperm (P < 0.05). The 0.16 dietary ratio supplemented with 200 mg vitE improved total sperm motility (P < 0.05) than the 0.09 and 0.23 ratios, both with and without vitE. Progressive motility, membrane functionality, and viability were significantly (P < 0.05) improved in the 0.16 and 0.23 ratios supplemented with vitE. The highest concentration of testosterone was observed in the roosters fed a diet ratio of 0.16 (P < 0.05). Compared with no supplementation of vitE, 200 mg/kg vitE reduced the lipid peroxidation of rooster sperm (P < 0.05). In the artificial insemination, the higher significant percentage of fertility rate (P = 0.02) was observed in the 0.16 ratio group that was supplemented with vitE compared to other groups. It can be concluded that supplementation of aged roosters' diet with 0.16 ratio of n-3: n-6 can be a beneficial strategy for improvement of their fertility. PMID- 29982836 TI - Melatonin receptor type 1A gene linked to Alzheimer's disease in old age. AB - Disruption of the circadian rhythms is a frequent preclinical and clinical manifestation of Alzheimer's disease. Furthermore, it has been suggested that shift work is a risk factor for Alzheimer's disease. Previously, we have reported association of intolerance to shift work (job-related exhaustion in shift workers) with a variant rs12506228A, which is situated close to melatonin receptor type 1A gene (MTNR1A) and linked to MTNR1A brain expression levels. Here, we studied association of that variant with clinical and neuropathological Alzheimer's disease in a Finnish whole-population cohort Vantaa 85+ (n = 512, participants over 85 years) and two follow-up cohorts. Rs12506228A was associated with clinical Alzheimer's disease (p = 0.000073). Analysis of post-mortem brain tissues showed association with higher amount of neurofibrillary tangles (p = 0.0039) and amyloid beta plaques (p = 0.0041). We then followed up the associations in two independent replication samples. Replication for the association with clinical Alzheimer's disease was detected in Kuopio 75+ (p = 0.012, n = 574), but not in the younger case-control sample (n = 651 + 669). While melatonin has been established in regulation of circadian rhythms, an independent role has been also shown for neuroprotection and specifically for anti-amyloidogenic effects. Indeed, in vitro, RNAi mediated silencing of MTNR1A increased the amyloidogenic processing of amyloid precursor protein (APP) in neurons, whereas overexpression decreased it. Our findings suggest variation close to MTNR1A as a shared genetic risk factor for intolerance to shift work and Alzheimer's disease in old age. The genetic associations are likely to be mediated by differences in MTNR1A expression, which, in turn, modulate APP metabolism. PMID- 29982838 TI - Recruitment and effectiveness by cohort in a case management intervention among American Indians and Alaska Natives with diabetes. AB - In real-world settings, eligible populations and intervention effectiveness for a translational intervention likely vary across time. To determine the optimal strategies for effective large-scale implementation of evidence-based interventions, it is critical to investigate these potential variabilities. The purpose of this study is to evaluate whether patient characteristics and intervention effectiveness differed by year of enrollment in a multiyear evidence based translational intervention. The Special Diabetes Program for Indians Healthy Heart (SDPI-HH) Demonstration Project is an intensive case management intervention designed to reduce cardiovascular disease risk among American Indians and Alaska Natives with diabetes. SDPI-HH participants recruited from 2006 through 2008 were included. Baseline characteristics were compared by year of enrollment. We also evaluated the differences in improvements in clinical and behavioral risk factors for cardiovascular disease among participants recruited in different years. The baseline characteristics of the three cohorts significantly differed in demographics, diabetes duration, health behaviors, level of motivation, and clinical measures. Improvements in 13 clinical and behavioral outcomes also differed by enrollment year with the 2006 cohort having the greatest number of significant improvements and the highest rates of participation and retention. Further investigation into the ways to modify the intensive case management model to address differences in levels of motivation and participation is warranted to improve the management of chronic disease in Indian health. Given the evolving nature of translational initiatives of this kind, our analysis results highlight the need to understand and adapt during the natural progression of health behavioral interventions. PMID- 29982839 TI - How I Made the Decision Not to Have Children. PMID- 29982840 TI - Distribution of particulate matter and ammonia and physicochemical properties of fine particulate matter in a layer house. AB - High concentrations of particulate matter (PM) and ammonia (NH3) in poultry houses have adverse effects on the health of workers and animals. The present study investigated the distribution of the PM in different size fractions and NH3, as well as analyzing the physicochemical properties of fine particulate matter (PM2.5) in an enclosed layer house. The detection was taken from 5:00 to 21:00 in every 2 h for a 7-d continuous monitoring using a DustTrak II model 8532 aerosol monitor for PM concentrations and a JK40-IV portable gas detector for NH3 concentrations. The concentrations of inhalable particulate matter (PM10), total suspended particles (TSP), and NH3 were significantly higher in the rear of the chicken house compared to the front (P < 0.05). The PM10, TSP, and NH3 concentrations inside the layer house were significantly higher than outside (P < 0.001). The concentrations of PM10 and TSP were both highest at the first feeding time at 7:00. The PM2.5/PM10, PM2.5/TSP, and PM10/TSP concentration ratios at 5:00 were highest with 0.84, 0.62, and 0.74, respectively. Airflow speed showed a significant correlation with other measured microclimatic variables. Organic carbon was the primary constituent of PM2.5 collected from the layer house. It was also observed that mass percentage of elements C and O were both the highest by energy spectrum diagrams of PM2.5. The ultrastructure of PM2.5 revealed that there were mineral particles derived from feed, feces, or the ground and that smoke polymers came from ambient air. In conclusion, air quality was better at the front than at the middle and rear of the layer house. Air quality outside was better than that inside the house. Chicken activities primarily caused the PM10 and TSP concentrations to increase in the chicken house. The main components of PM2.5 in the layer house were organic matter and minerals, which were mostly derived from feed, feces, and ground dust. PMID- 29982841 TI - Resolving Repression. PMID- 29982842 TI - Trends and topics in occupational diseases over the last 60 years from PubMed. AB - Objectives The purpose of this study was to provide an analysis of scientific production on occupational diseases (OD) during the period 1945-2015 in order to describe publication trends on that topic and identify the major diseases as well as the predominant actors (journals, countries) involved in this field. Methods A PubMed search was carried out to extract articles related to occupational diseases during the period 1 January 1945 to 31 December 2015 using a specific query. Data were downloaded from PubMed in Extensible Markup Language (XML) and processed through a dedicated parser. Results A total of 160 025 articles were retrieved from 7127 journals. One third of these articles were published in 39 journals: the core journals according to Bradford's law. Following exponential growth, OD publications reached a plateau in 2007. The overall dynamics of the OD field are heterogeneous with differences between subfields: psychological diseases emerged in the 1990s while "traditional" OD are less studied nowadays. Despite a sharp decrease in the proportion of publications, the most productive country remains the USA with 14.5% of the OD publications over the period but Scandinavian countries are, proportionally, the most active in research and publication on OD. Conclusions The proportion of publications on OD is decreasing in Medline, except for specific subfields of OD. This is discrepant with the global burden of occupational diseases. PMID- 29982843 TI - Comparison of hemodynamic responses between normotensive and untreated hypertensive men under simulated long working hours. AB - Objectives The present study examined hemodynamic responses of normotensive and untreated hypertensive participants under simulated long working hours (LWH) - 13 hours - in an experimental laboratory study. Methods Thirty-five men participated in this study. Twenty-two of these participants were categorized into the normotensive group (systolic blood pressure (SBP) <=140 mmHg and diastolic blood pressure (DBP) <=90 mmHg); one participant was excluded due to missing data, leaving twenty-one participants with a mean age of 49.2 years. Another thirteen participants were categorized into the high blood pressure group (SBP=140-160 mmHg or DBP=90-100 mmHg) with a mean age of 51.9 years. The hemodynamic responses at the resting state from 09:00-09:10 hours (baseline) and during LWH from 09:10 22:00 hours (12 sessions) were measured. In each session, participants performed mental tasks. Changes in the hemodynamic response (Delta) were calculated by subtracting the individual values at each session from the baseline values. Results The values for the DeltaSBP, DeltaDBP, and Deltamean arterial pressure increased with work time. Additionally, we found a significant interaction between the group and sessions for the DeltaSBP (P<0.05, partial eta 2=0.086). Although DeltaSBP values did not differ between the groups at first (09:10-14:30 hours), the values in later sessions (14:40-21:50 hours) were significantly higher in the high blood pressure compared to the normotensive group. Conclusions Our study found that LWH increases BP, with a larger increase in SBP in the later working hours among individuals with untreated hypertension, whereas other hemodynamic responses did not differ between groups as a function of the LWH. PMID- 29982844 TI - Influence of full range of motion vs. equalized partial range of motion training on muscle architecture and mechanical properties. AB - PURPOSE: The purpose of this study was to determine the effect of a 15-week partial range of motion (ROM) resistance training program on the vastus lateralis (VL) architecture and mechanical properties, when the time under tension (TUT) was equalized. METHODS: Nineteen untrained male subjects were randomly assigned to a control (Control; n = 8) or training (TG; n = 11) group. In the TG, the dominant and nondominant legs were randomly selected to be trained with a full ROM (FULL) or a partial ROM (PART) in an isokinetic dynamometer. Training volume was equalized based on the TUT by manipulating sets and repetitions. The VL muscle architecture was assessed by B-mode ultrasonography at rest and during maximal isometric knee extension contractions (MVCs) at ten knee angles. The VL fascicle force and specific tension were calculated from the MVCs with superimposed stimuli, accounting for the moment arm length, muscle architecture, and antagonist coactivation. RESULTS: The FULL training induced changes in fascicle length (FL) (4.9 +/- 2.0%, P < 0.001) and specific tension (25.8 +/- 18.7%, P < 0.001). There was a moderate effect of PART training on the physiological cross-sectional area (PCSA) (7.8 +/- 4.0%, P < 0.001, dav = 0.6) and torque-angle adaptations (average increase 17.7 +/- 3.9%, P < 0.05). CONCLUSIONS: These results provide evidence that crucial architectural and mechanical muscle adaptations are dependent on the ROM used in strength training. It seems that muscle FL and specific tension can be increased by pure concentric training if greater ROM is used. Conversely, restricting the ROM to shorter muscle lengths promotes a greater PCSA and angle-specific strength adaptations. PMID- 29982845 TI - Early treatment response evaluation using FET PET compared to MRI in glioblastoma patients at first progression treated with bevacizumab plus lomustine. AB - BACKGROUND: The goal of this prospective study was to compare the value of both conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response evaluation in glioblastoma patients treated with bevacizumab plus lomustine (BEV/LOM) at first progression. METHODS: After chemoradiation with concomitant and adjuvant temozolomide, 21 IDH wild-type glioblastoma patients at first progression (age range, 33-75 years; MGMT promoter unmethylated, 81%) were treated with BEV/LOM. Contrast-enhanced MRI and FET-PET scans were performed at baseline and after 8-10 weeks. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios. Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the post-progression overall survival (OS) <=/>9 months as the reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning OS using uni- and multivariate survival estimates. RESULTS: Early treatment response as assessed by RANO criteria was not predictive for an OS>9 months (P = 0.203), whereas relative reductions of all FET-PET parameters significantly predicted an OS>9 months (P < 0.05). The absolute MTV at follow-up enabled the most significant OS prediction (sensitivity, 85%; specificity, 88%; P = 0.001). Patients with an absolute MTV below 5 ml at follow-up survived significantly longer (12 vs. 6 months, P < 0.001), whereas early responders defined by RANO criteria lived only insignificantly longer (9 vs. 6 months; P = 0.072). The absolute MTV at follow-up remained significant in the multivariate survival analysis (P = 0.006). CONCLUSIONS: FET-PET appears to be useful for identifying responders to BEV/LOM early after treatment initiation. PMID- 29982846 TI - Phospholipids and inositol phosphates linked to the epigenome. AB - Even though the majority of knowledge about phospholipids comes from their cytoplasmic functions, in the last decade, it has been shown that nuclear phospholipids and their building blocks, inositol phosphates, have many important roles in the cell nucleus. There are clear connections of phospholipids with the regulation of gene expression and chromatin biology, however, this review focuses on less known functions of nuclear phospholipids in connection with the epigenome regulation. In particular, we highlight the roles of nuclear phospholipids and inositol phosphates that involve histone modifications, such as acetylation or methylation, tightly connected with the cell physiology. This demonstrates the importance of nuclear phospholipids in the regulation of cellular processes, and should encourage further research of nuclear phospholipids and inositol phosphates. PMID- 29982848 TI - Identifying molecular markers suitable for Frl selection in tomato breeding. AB - Modern plant breeding heavily relies on the use of molecular markers. In recent years, next generation sequencing (NGS) emerged as a powerful technology to discover DNA sequence polymorphisms and generate molecular markers very rapidly and cost effectively, accelerating the plant breeding programmes. A single dominant locus, Frl, in tomato provides resistance to the fungal pathogen Fusarium oxysporum f. sp. radicis-lycopersici (FORL), causative agent of Fusarium crown and root rot. In this study, we describe the generation of molecular markers associated with the Frl locus. An F2 mapping population between an FORL resistant and a susceptible cultivar was generated. NGS technology was then used to sequence the genomes of a susceptible and a resistant parent as well the genomes of bulked resistant and susceptible F2 lines. We zoomed into the Frl locus and mapped the locus to a 900 kb interval on chromosome 9. Polymorphic single-nucleotide polymorphisms (SNPs) within the interval were identified and markers co-segregating with the resistant phenotype were generated. Some of these markers were tested successfully with commercial tomato varieties indicating that they can be used for marker-assisted selection in large-scale breeding programmes. PMID- 29982849 TI - Prevalence of motion sickness in various vestibular disorders: a study on 749 patients. PMID- 29982847 TI - Voltage-gated sodium currents in cerebellar Purkinje neurons: functional and molecular diversity. AB - Purkinje neurons, the sole output of the cerebellar cortex, deliver GABA-mediated inhibition to the deep cerebellar nuclei. To subserve this critical function, Purkinje neurons fire repetitively, and at high frequencies, features that have been linked to the unique properties of the voltage-gated sodium (Nav) channels expressed. In addition to the rapidly activating and inactivating, or transient, component of the Nav current (INaT) present in many types of central and peripheral neurons, Purkinje neurons, also expresses persistent (INaP) and resurgent (INaR) Nav currents. Considerable progress has been made in detailing the biophysical properties and identifying the molecular determinants of these discrete Nav current components, as well as defining their roles in the regulation of Purkinje neuron excitability. Here, we review this important work and highlight the remaining questions about the molecular mechanisms controlling the expression and the functioning of Nav currents in Purkinje neurons. We also discuss the impact of the dynamic regulation of Nav currents on the functioning of individual Purkinje neurons and cerebellar circuits. PMID- 29982850 TI - Coincidence of lymphomatoid granulomatosis, chronic myelomonocytic leukemia, and anaplastic T cell lymphoma after methotrexate therapy for rheumatoid arthritis. PMID- 29982851 TI - Successful treatment of refractory/relapsed acquired pure red cell aplasia with sirolimus. AB - Acquired pure red cell aplasia (aPRCA) is a kind of anemia characterized by severe reticulocytopenia and obvious bone marrow erythroblastic cells decreased. Some patients are refractory or intolerant to the first-line therapy (cyclosporine A with/without steroids). The effects of the second-line therapy are not satisfactory and sometimes not available. In this study, we analyzed the efficacy and side effect of sirolimus on refractory/relapsed aPRCA and investigated the possible mechanism of sirolimus on immune regulation. Twenty-one patients with refractory/relapsed aPRCA were enrolled in this study and were administered with sirolimus. Totally, 76.2% of patients responded to the sirolimus with 42.9% complete response during the experimental period. The median time for reaction was 4 months. Side effects were tolerable including infections; mild oral mucositis; sinus tachycardia, the increase of creatinine, transaminase, triglyceride, or cholesterol; and thrombocytopenia. Most patients stayed in remission or remained stable during the follow-up period. Early drug withdrawal may lead to quick relapse. Compared with healthy control, Treg levels in patients with aPRCA reduced significantly before sirolimus but recovered after successful treatment. Level of Treg cells correlated with hemoglobin level after effective sirolimus treatment. Thus, sirolimus was effective and tolerable for refractory/relapsed aPRCA. Effective sirolimus treatment may lead to the upregulation of Treg cells which may partly explain the underlying mechanism. PMID- 29982853 TI - Incidence of rotator cuff tears in the setting of calcific tendinopathy on MRI: a case controlled comparison. AB - OBJECTIVE: To compare the incidence of rotator cuff tears on shoulder MRI in patients who have rotator cuff calcific tendinopathy with that in patients without calcific tendinopathy in a frequency-matched case-control study. MATERIALS AND METHODS: Retrospective review shoulder MRIs of 86 patients with rotator cuff calcific tendinopathy and an 86-patient age-, gender-, and laterality-matched control group using frequency matching. RESULTS: No statistically significant difference (odds ratio: 0.72, 95% confidence interval: 0.38-1.38, p = 0.32) was found in the incidence of rotator cuff tear in the calcific tendinopathy (27.9%) and control groups (34.9%). A significant (p < 0.001) difference in the size of rotator cuff tear was seen between the two groups, with 12.5% of tears being full-thickness in the calcific tendinopathy group and 63.3% of tears being full-thickness in the control group. Only 3 of the 24 (12.5%) rotator cuff tears present in the calcific tendinopathy group occurred at the site of tendon calcification. CONCLUSION: Patients presenting with indeterminate shoulder pain and rotator cuff calcific tendinopathy are not at increased risk for having a rotator cuff tear compared with similar demographic patients without calcific tendinopathy presenting with shoulder pain. Calcific tendinopathy and rotator cuff tears likely arise from different pathological processes. PMID- 29982852 TI - MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways. AB - MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid beta peptide (Abeta) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3beta, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders. PMID- 29982854 TI - Sonoelastographic evaluation of the sciatic nerve in patients with unilateral lumbar disc herniation. AB - OBJECTIVE: The aim of this study was to compare strain elastography (SE) and shear wave elastography (SWE) findings of the sciatic nerve in patients with unilateral lumbar disc herniation (LDH) and healthy control subjects. MATERIALS AND METHODS: The study group included patients with complaints of unilateral sciatica for 3-12 months, with foraminal stenosis due to one level of LDH (L4-L5 or L5-S1). An age- and gender-matched control group was formed of healthy subjects. Evaluations were performed on both the axial and longitudinal planes from the bilateral gluteal region using a 5-9 MHz multifrequency convex probe. RESULTS: There were 40 patients (20 male, 20 female) with a mean age of 43.1 +/- 12.7 years in the study group, and 40 healthy subjects (22 male, 18 female) with a mean age of 42.9 +/- 10.7 years in the control group (p > 0.05). The sciatic nerve stiffness assessed on both the axial (12.3 +/- 3.7 kPA) and longitudinal (14.3 +/- 3.8 kPA) planes of the involved side was significantly higher than non involved side (axial: 6.8 +/- 2.1 and longitudinal: 8.3 +/- 2.3 kPA) in the patient group (p < 0.001). CONCLUSIONS: Patients with unilateral LDH have increased stiffness of the sciatic nerve compared to healthy control subjects. Although the findings in this preliminary study show that shear wave elastography can detect a change in sciatic nerve stiffness in patients with unilateral LDH, larger studies are required to determine the clinical utility of this technique. PMID- 29982855 TI - Patterns of tendon retraction in full-thickness rotator cuff tear: comparison of delaminated and nondelaminated tendons. AB - OBJECTIVE: To analyze full-thickness rotator cuff tears, compare retraction patterns in delaminated and nondelaminated tendons, and correlate retraction distances with anteroposterior tear lengths. MATERIALS AND METHODS: In 483 MR examinations reported as showing full-thickness cuff tear, two musculoskeletal radiologists independently characterized tendons as delaminated or nondelaminated. Tendon delamination was defined as either horizontal intra substance splitting of bursal and articular layers by an intervening plane of fluid, or differential retraction of bursal and articular layers. In a subset of 144 shoulders with surgically proven full-thickness cuff tears (45 delaminated, 99 nondelaminated tendons), matched cohorts (n = 45) were further analyzed to compare tendon retraction distance, anteroposterior tear length and retraction ratios (retraction distance/anteroposterior length). RESULTS: Delamination was present in 13% of 483 total tears, and 31% of 144 operated tears (p = 0.001). In nondelamination and delamination cohorts, mean anteroposterior tear length measured 30.0 and 31.5 mm respectively (p = 0.6). Although nondelaminated tendons showed mean retraction 31.5 mm, articular and bursal layers of delaminated tendons showed mean retractions 36.3 mm and 21 mm respectively (p < 0.0001). Anteroposterior tear length and retraction distance were significantly associated in all cuff tears (p < 0.0001). Retraction ratio for nondelaminated tendons (1.05) was significantly different from retraction ratios for articular (1.21) and bursal (0.70) layers of delaminated tendons (p < 0.0001). CONCLUSION: In full thickness rotator cuff tear, delaminated and nondelaminated tendons show significant differences in retraction distances, despite similarities in anteroposterior dimensions. Delaminated tendons are important to identify and report because they are more likely to fail conservative treatments and undergo operative repairs. PMID- 29982856 TI - Characteristics and risk factors for proximal junctional kyphosis in adult spinal deformity after correction surgery: a systematic review and meta-analysis. AB - There are still controversies on characteristics and risk factors for proximal junctional kyphosis (PJK) in adult spinal deformity (ASD) patients. The objective of this study is to explore the characteristics and risk factors for PJK in ASD. A systematic online search in databases including PubMed, EMBASE, Web of Science, and the Cochrane Library was performed to identify eligible studies. OR and weight mean difference with 95% CI were used to evaluate characteristics and risk factors. A total of 31 studies were finally included. ASD patients with PJK had larger proximal junctional angle (PJA), thoracic kyphosis (TK), pelvic incidence minus lumbar lordosis (PI-LL), and sagittal alignment. Age, female gender, and low BMD/osteoporosis were demographic risk factors for PJK. Using hooks at upper instrumented vertebra (UIV) and the selection of UIV above T8 could reduce the occurrence of PJK, while pelvic fixation was significantly associated with increased occurrence of PJK. Preoperative LL, preoperative pelvic tilt (PT), preoperative LL-TK, preoperative PI-LL, preoperative sagittal vertical axis (SVA), preoperative global spine alignment (GSA), postoperative PJA, change in PJA, postoperative TK, change in LL, change in SVA, and postoperative GSA were identified as risk factors for PJK. In conclusion, PJK patients had larger PJA, larger TK, smaller PI-LL, and larger sagittal alignment. Older female ASD patients with low BMD/osteoporosis are more likely to suffer from PJK. We recommend the following: (1) using hooks at UIV; (2) UIV should be chosen above T8, and pelvic fixation should be avoided if possible; (3) ideal correction of sagittal alignment should be performed to prevent the occurrence of PJK. PMID- 29982857 TI - Pitfalls of skull base reconstruction in endoscopic endonasal approach. AB - Various skull base reconstruction techniques have been developed in endoscopic endonasal approach (EEA) for skull base lesions to prevent postoperative cerebrospinal fluid (CSF) leakage. This study was performed to evaluate the efficacy and pitfalls of our method of skull base reconstruction after EEA. A total of 123 patients who underwent EEA (127 surgeries) between October 2014 and May 2017 were reviewed. Our algorithm for skull base reconstruction in EEA was categorized based on intraoperative CSF leakage graded as follows: grade 0 was excluded from this study; grade 1, dural suturing with abdominal fat graft or packing of gelatin sponge into the cavity; grade 2, method for grade 1 with addition of mucosal flap or nasoseptal flap (NSF); and grade 3, duraplasty in fascia patchwork closure with NSF. Bony reconstruction was not mandatory, and there was no postoperative bed rest or initial lumbar drainage (LD) insertion in any of the cases. Postoperative CSF leakage after EEA was mostly prevented (96.3%) by our algorithm without postoperative initial LD or bed rest. On the other hand, reconstruction surgery was required for postoperative CSF leakage in two cases-one with prior multitranssphenoidal surgery and radiotherapy and another patient with poor compliance due to communication difficulties. Both of the latter patients were obese. Greater care with regard to postoperative CSF leakage is required in patients with prior EEA with radiotherapy and obesity. In such high-risk patients, initial LD or bed rest may be required to prevent postoperative CSF leakage. It is also important to restrict activities that result in increased intracranial pressure. PMID- 29982858 TI - Correction to: A large-scale multiomics analysis of wheat stem solidness and the wheat stem sawfly feeding response, and syntenic associations in barley, Brachypodium, and rice. AB - The original version of this article contained a mistake. The word "RefSeq v.1" was incorrectly inserted on page 7. The correct sentence should be: To identify the differentially regulated transcripts, clean RNA-Seq reads were mapped onto the T. aestivum Chinese Spring chromosome 3B pseudomolecule. PMID- 29982860 TI - A genetic algorithm survey on closed-shell atomic nitrogen clusters employing a quantum chemical approach. AB - The DFT potential energy hypersurfaces of closed-shell nitrogen clusters up to ten atoms are explored via a genetic algorithm (GA). An atom-atom distance threshold parameter, controlled by the user, and an "operator manager" were added to the standard evolutionary procedure. Both B3LYP and PBE exchange-correlation functionals with 6-31G basis set were explored using the GA. Further evaluation of the structures generated were performed through reoptimization and vibrational analysis within MP2 and CCSD(T) levels employing larger correlation consistent basis set. The binding energies of all stable structures found are calculated and compared, as well as their energies relative to the dissociation into N2, [Formula: see text] and [Formula: see text] molecules. With the present approach, we confirmed some previously reported polynitrogen structures and predicted the stability of new ones. We can also conclude that the energy surface profile clearly depends on the calculation method employed. PMID- 29982859 TI - Leishmania phosphatase PP5 is a regulator of HSP83 phosphorylation and essential for parasite pathogenicity. AB - Leishmania parasites are responsible for important neglected diseases in humans and animals, ranging from self-healing cutaneous lesions to fatal visceral manifestations. During the infectious cycle, Leishmania differentiates from the extracellular flagellated promastigote to the intracellular pathogenic amastigote. Parasite differentiation is triggered by changes in environmental cues, mainly pH and temperature. In general, extracellular signals are translated into stage-specific gene expression by a cascade of reversible protein phosphorylation regulated by protein kinases and phosphatases. Though protein kinases have been actively studied as potential anti-parasitic drug targets, our understanding of the biology of protein phosphatases in Leishmania is poor. We have previously reported the principal analysis of a novel protein phosphatase 5 (PP5) in Leishmania species. Here, we assessed the role of PP5 in parasite pathogenicity, where we uncovered, using transgenic PP5 over-expressing and PP5 null-mutant parasites, its importance in metacyclogeneisis, maintaining HSP83 phosphorylation homeostasis and virulence. All together, our results indicate the importance of PP5 in regulating parasite stress and adaptation during differentiation, making this protein an attractive potential target for therapeutic intervention. PMID- 29982861 TI - Prognostic importance of the preoperative modified systemic inflammation score for patients with gastric cancer. AB - BACKGROUND: The systemic inflammation score (SIS), based on preoperative serum albumin (Alb) level and lymphocyte-to-monocyte ratio (LMR), has been shown to be a novel prognostic score for some tumors. We investigate the prognostic value of the SIS in patients with resectable gastric cancer (GC). METHODS: Patients with GC who underwent curative resection between December 2008 and December 2013 were included. Time-dependent receiver operating characteristics analysis (t-ROC), concordance index (C-index) and AUC were used to compare the prognostic impact. RESULTS: Totally, 1786 patients with resectable GC were included in the study. By multivariate analysis, the SIS was not an independent prognostic factor. However, the normal Alb level (>= 40 g/l) and LMR >= 3.4 both remained independent protective factors for GC (both P < 0.05). Due to the similar survival of patients with LMR >= 3.4 and LMR < 3.4 in the normal Alb group, we combined the two subgroups to establish the modified SIS (mSIS). Multivariate analysis revealed that the mSIS was the only significant independent biomarker (P < 0.05). The t-ROC curve and C-index for the mSIS were superior to those of the SIS throughout the observation period. Furthermore, the AUC of the mSIS was significantly greater than that of the SIS at 3 and 5 years after operation (both P < 0.05). CONCLUSION: The preoperative mSIS is a novel, simple and useful prognostic factor for postoperative survival in patients with GC and can be used as a part of the preoperative risk stratification process to improve the prediction of clinical outcomes. PMID- 29982862 TI - Assessing the cellulase enzyme heterogeneity of bacterial strains and their feedback to cattle manure degradation in a greenhouse model of in vivo pond ecosystem. AB - The responses of cellulase enzymes of three bacterial isolates and their impacts on cattle manure decomposition were assessed in a greenhouse model in vivo pond ecosystem. Fifty grams of fresh cattle manure was placed in a fastened nylon bag (mesh size ~ 50 MUm dia.) and placed in triplicate in a plastic bucket with 10 l of pond water which was hung inside the enclosed polyhouse, semi-closed and open systems for 4 weeks. Samples of manure residue directly from nylon bag and water from manure leached bucket water, water, and soil from the enclosed polyhouse were collected for enzymatic assays, enumeration of aerobic cellulose decomposing and heterotrophic bacteria, and determination of water and soil quality parameters. Responses of cellulases to different temperatures in situ were also elucidated. The values of test bacteria, endoglucanase, exoglucanase and beta glucosidase, and organic carbon were significantly (P ? 0.05) higher in the closed system compared to semi-closed or open system. Priming of all the enzymes coupled with the peak of aerobic cellulose decomposing bacteria and heterotrophic bacterial populations occurred on the day 14 or 21 in vivo. Since the peaks of three cellulases of bacterial isolates (KUPH1, KUPH6, and KUPH8) were demonstrated between 35 and 40 degrees C, and that temperature coincided with temperature of the greenhouse model, this temperature range appeared to favor the growth of cellulose decomposing bacterial populations and involved cellulase enzymes. PMID- 29982864 TI - Family Inclusion in Mental Health Service Planning and Delivery: Consumers' Perspectives. AB - Family inclusion in treatment planning and delivery for people living with mental illness is advocated in government policy but is yet to be widely translated into practice. While external barriers have been identified, including concerns about consumers' best interests, little is known about consumers' own views. This study explores consumers' experiences and perspectives of including family in treatment. Semi-structured interviews were conducted with 13 adult consumers who could identify supportive family members. Data were analysed using constant comparative analysis. The findings indicated that the outcomes reported from family inclusion depended on who, how, how much and when family were included, and the degree of choice consumers had regarding these features For consumers to have real choice around these features, family inclusion needed to be accessible, families needed to be willing, and all parties needed to agree upon a consumer centred purpose. Findings can aid health professionals to facilitate consumer choice. PMID- 29982863 TI - SDH and EDH in children up to 18 years of age-a clinical collective in the view of forensic considerations. AB - Providing concise proof of child abuse relies heavily on clinical findings, such as certain patterns of injury or otherwise not plausibly explainable trauma. Subdural hemorrhaging has been identified as a common occurrence in abused children whereas epidural hemorrhaging is related to accidents. In order to explore this correlation, we retrospectively analyzed clinical data of children under 19 years of age diagnosed with either injury. Reviewing 56 cases of epidural and 38 cases of subdural bleeding, it was shown that subdural bleeding is more common in young children and extremely often a result of suspected abuse in children under 2 years of age. Epidural hemorrhaging however never was found in the context of suspected abuse, was unrelated to other injuries typical for abuse, and did not see a statistically significant increase in any age group. In conformity with currently theorized mechanisms of injury for both types of bleeding, we found that subdural hemorrhaging in young children is closely associated with abuse whereas epidural bleeding is not. PMID- 29982865 TI - Shutting Down Acute Myeloid Leukemia and Myelodysplastic Syndrome with BCL-2 Family Protein Inhibition. AB - PURPOSE OF REVIEW: Apoptosis results from the interaction between pro- and anti apoptotic proteins, mediated by BCL-2 homology 3 (BH3) proteins. B cell lymphoma 2 (BCL-2) is an inhibitor of apoptosis which stabilizes the mitochondria, resulting in the prevention of activation of the pro-apoptotic proteins. In addition, BCL-2 is overexpressed in the leukemic stem cell (LSC) population, and its inhibition may lead to selective LSC eradication. Herein, we will discuss the mechanism and rationale of BCL-2 inhibition in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) with an overview of the selective BCL-2 inhibitor venetoclax. RECENT FINDINGS: Venetoclax has activity against AML and has displayed synergistic activity with hypomethylating agents in the preclinical setting. In the clinical setting, although it has only modest activity as a single agent in relapsed and refractory AML, in the older, treatment-naive population, in combination with either a hypomethylator or low-dose cytarabine, it is well tolerated with impressive efficacy. In addition, BCL-2 inhibition may also have activity in MDS, and although clinical trials are in their early phases, this may be an effective strategy in both the up-front and relapsed setting. BCL-2 inhibition with venetoclax is well tolerated and active in older patients with newly diagnosed AML and in the relapsed setting has activity that may be improved in combination with other therapies. It may prove to be effective in MDS and is an exciting treatment strategy for myeloid malignancies. PMID- 29982866 TI - Economic Impact of Oral Therapies for Chronic Lymphocytic Leukemia-the Burden of Novelty. AB - PURPOSE OF REVIEW: Small molecule tyrosine kinase inhibitors (TKIs) and BCL2 inhibitors are oral targeted therapies that have changed the treatment approach to patients with chronic lymphocytic leukemia (CLL). The aim of this review is to summarize the relevant literature on the economic impact of oral novel therapies for the treatment of CLL and discuss the underlying factors and suggested solutions for high drug prices. RECENT FINDINGS: The cost of therapy for CLL has increased substantially since the introduction of oral therapies. This increase in cost is caused by multiple factors including cost of drug development, alternate reimbursement patterns, lack of transparency, and lack of free market competition. Oral therapies for CLL have dramatically increased costs for both patients and payers. Some solutions to overcome this include value-based pricing, transparency, and legal action that allow Medicare to negotiate drug prices with manufacturers. PMID- 29982867 TI - Pyrolysis Temperature-Dependent Changes in the Characteristics of Biochar-Borne Dissolved Organic Matter and Its Copper Binding Properties. AB - The dissolved organic matter (DOM) samples from biochars produced from Jerusalem artichoke stalks by pyrolysis at 300, 500, and 700 degrees C were characterized using a combination of spectroscopic techniques. Additionally, the binding affinities (long KM) and the complexation capacities (CL) of the DOM samples with Cu(II) were calculated to assess their Cu binding properties. The biochar-borne DOM contained mainly humic-like components (C1-C3) with a small amount of a protein-like component (C4). As the charring temperature increased, the concentrations of released DOM decreased. The low temperature biochar-borne DOM was found to have more carboxyl groups than its high temperature counterparts, and thus it had larger CL values. In contrast, the high temperature biochar-borne DOM had larger long KM values. Low temperature biochars, if applied in a large quantity, would alter copper mobility in the environment because of their high DOM contents and large copper binding capacities. PMID- 29982868 TI - Arthroscopic Bankart repair for the acute anterior shoulder dislocation: systematic review and meta-analysis. AB - BACKGROUND: The ideal treatment of acute anterior shoulder dislocation remains one of the topics that spark debate over the value of primary repair for the first-time anterior shoulder dislocation. The high rate of complications especially in young adults, such as recurrent instability, residual pain, and inability to return to sports, has led to the quest for an ideal management of such injuries. OBJECTIVE: In this meta-analysis, we compare between the immediate arthroscopic repair and conservative treatment of primary anterior shoulder dislocation as well as arthroscopic reconstruction of recurrent anterior shoulder dislocation. Outcome measures were failure rate (dislocation, subluxation, and instability) and revision rates. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched several database including PubMed, MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov through August 2017 to identify observational and experimental randomized controlled trials comparing the outcomes of immediate arthroscopic repair and conservative treatment of primary shoulder dislocations as well as arthroscopic reconstruction of recurrent dislocation. The primary outcome was failure rate, whereas, secondary outcomes were revision rate and functional outcomes. RESULTS: Out of the 710 studies identified, 12 were eligible for meta analysis. The estimated pooled failure rate was 13.7% (7.7%-19.6%), whereas, the pooled revision rate was 7.1% (3.8%-10.4%) in immediate arthroscopic repair of primary shoulder dislocation. The odd ratio (OR) of failure and revision rates were significantly lower in arthroscopic repair of primary shoulder dislocation compared to conservative treatment (OR 0.103, 95% CI [0.052, 0.201]), (OR 0.217, 95% CI [0.078, 0.607]), respectively. The odd ratio (OD) of failure and revision rates were lower in arthroscopic repair of primary shoulder dislocation compared to arthroscopic reconstruction of the recurrent shoulder dislocation; however, the difference was statistically insignificant (OR 0.423, 95% CI [0.117, 1.522]) and (OR 0.358, 95% CI [0.044, 2.920]) respectively. CONCLUSION: The outcome of immediate arthroscopic repair of primary anterior shoulder dislocation is superior and encouraging with significant reduction in failure and revision rates compared to conservative treatment. Nevertheless, the failure and revision rates are statistically insignificant compared to arthroscopic reconstruction of recurrent dislocation. Hence, there is evidence to support immediate arthroscopic repair option for primary anterior shoulder dislocations over conservative treatment in young active patients, in order to reduce the risk of failure and revision rates. However, the evidence is inconclusive compared to arthroscopic reconstruction of recurrent dislocation. PMID- 29982869 TI - Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-beta plaques. AB - Age-associated deposition of amyloid-beta in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-beta plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-beta targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-beta1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99 m complexes are likely to be isostructural to their rhenium oxo analogues. PMID- 29982870 TI - Randomized, prospective, comparative study on the effects and safety of sorafenib vs. hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis. AB - BACKGROUND/AIMS: Treatment responses of advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) remain unacceptably low and treatment modalities are limited. We compared the efficacy and safety of sorafenib and hepatic arterial infusion chemotherapy (HAIC). METHODS: In this randomized, prospective, comparative study, data on 58 patients with advanced HCC with PVTT, with Child-Turcotte-Pugh (CTP) scores of 5-7, were collected from six university hospitals between January 2013 and October 2015. Twenty-nine patients were treated with sorafenib and twenty-nine with HAIC. RESULTS: The median overall survival (OS) and time to progression (TTP) were significantly longer in the HAIC group than in the sorafenib group (14.9 vs.7.2 months, p = 0.012 and 4.4 vs. 2.7 months, p = 0.010). The objective response (OR) rates were 27.6 and 3.4% in the HAIC and sorafenib groups, respectively (p = 0.001). In univariate analysis, sex, main portal vein invasion and treatment modality were significant prognostic factors of OS (p = 0.044, 0.040, 0.015), whereas cause of HCC, tumor number, tumor location and treatment modality were significant prognostic factors of TTP (p = 0.040, 0.002, 0.034, 0.014). In multivariate analysis, sex and treatment modality were significant prognostic factors of OS (p = 0.008, 0.005), whereas cause of HCC, tumor number, tumor location and treatment modality were significant prognostic factors of TTP (p = 0.038, 0.038, 0.015, 0.011). Major complications included hyperbilirubinemia (44.8%), AST elevation (34.5%), ascites (13.8%) and catheter-related complications (3.4%) in the HAIC group and hyperbilirubinemia (34.5%), hand-foot syndrome (31.0%) and AST elevation (27.6%) in the sorafenib group. CONCLUSIONS: For managing advanced HCC with PVTT, HAIC may be a valuable treatment modality. PMID- 29982871 TI - Aptamer-based fluorometric lateral flow assay for creatine kinase MB. AB - A group of aptamers possessing high specificity and affinity for creatine kinase MB (CKMB) was obtained by magnetic systematic evolution of ligands by exponential enrichment. Two aptamers (referred to as C.Apt.21 and C.Apt.30) were found to possess adequately low Kd values. They form a well suited pair for CKMB binding. By using fluorescent microspheres, an aptamer-based lateral flow assay was developed. It is portable, economical, and sensitive. The limit of detection for CKMB is as low as 0.63 ng.mL-1, and the assay works in the 0.005 - 2 MUg.mL-1 CKMB concentration range. The method is specific for CKMB, and biomarkers for AMI (such as cardiac troponin I and myoglobin) and serum do not interfere. The strip is highly accurate as shown by analysis of spiked serum samples which gave recoveries ranging between 88 and 117%. Graphical Abstract Schematic of the test strip and sandwich aptamer-based fluorometric lateral flow assay for creatine kinease. The detection is based on the specific affinity between CKMB and selected aptamers to form a sandwich structure. PMID- 29982872 TI - A missing piece? Neuropsychiatric functioning in untreated patients with tumors within the cerebellopontine angle. AB - PURPOSE: To date, little is known about neuropsychiatric symptoms in patients with tumors within the cerebellopontine angle (CPA). These, however, might be of clinical relevance. Aim of this study was thus to assess possible impairment in cognition, elevation in mood symptoms, and fatigue in this specific patient group. METHODS: Forty-five patients with an untreated CPA tumor (27 vestibularis schwannoma, 18 meningioma) were tested within a cross-sectional observational study in a single institution prior to neurosurgical treatment. Patients were administered a multifaceted battery comprising of widely-used tests for assessment of neuropsychiatric functioning. RESULTS: The majority of the included patients (69%) showed neurocognitive impairment, most frequently in the areas of attention and visuo-motor speed (e.g., alertness) (62%) as well as visuo construction (44%). Impaired structural integrity of the brain stem was accompanied by more serious neurocognitive deficits. About one-third of the sample reported clinically relevant depression and/or anxiety and an even higher proportion (48%) described high levels of fatigue. Cognitive and affective symptoms as well as fatigue contributed significantly to patients' Quality of Life, indicating the clinical relevance of neuropsychiatric symptoms in patients with CPA tumors. CONCLUSIONS: Although patients with untreated CPA tumors often suffer from devastating and prominent physical symptoms, neuropsychiatric problems are also frequent. Including these aspects in the routine clinical assessment and initiating treatment accordingly might thus improve clinical management of the patients and improve Quality of Life. PMID- 29982873 TI - Hypoglycaemia induces recruitment of non-classical monocytes and cytotoxic lymphocyte subsets in type 1 diabetes. PMID- 29982874 TI - Evaluation of testicular function in prepubertal children. AB - INTRODUCTION: The assessment of testicular function is not currently performed in childhood. The aim of this review was to address the usefulness of serum Anti Mullerian Hormone (AMH), inhibin B, and testicular volume (TV) evaluation in children. REVIEW: Serum AMH and inhibin B levels reflect Sertoli cells (SCs) health and number, SCs maturation degree and their exposure to FSH and to intra tubular testosterone (T). These hormones might be helpful in discriminating between congenital central hypogonadism (cHH) and constitutional delay in growth and puberty (CDGP) and in case of clinical suspicious of precocious puberty. Furthermore, low AMH and/or inhibin B levels have been observed in children with primary testicular disorders, suggesting the existence of SC dysfunction. TV also provides useful information on testicular health. Recently, a medical calculator, requiring testis length and the stage of genital development, has been developed to easily derive TV. CONCLUSIONS: The evidence supports the usefulness of AMH, inhibin B and TV evaluation for the early diagnosis of puberty disorders and primary testicular damage. We suggest the measurement of TV by using the medical calculator in all children and to reserve AMH and inhibin B measurements to those cases of no testicular growth, clinical suspicious of puberty disorders or in children at risk for spermatogenesis damage. This work-up might allow the early detection of testicular tubular damage which, in turn, may be useful to prevent the oncoming male infertility in adulthood. PMID- 29982876 TI - Pocket-size ultrasound device in cholelithiasis: diagnostic accuracy and efficacy of short-term training. AB - Pocket-size ultrasound devices (PSUD) are now widely available becoming a useful tool for diagnostic and therapeutic purposes. We aim to investigate the accuracy of PSUD in diagnosing cholelithiasis as compared to traditional ultrasonography. Moreover, we tested the reliability of PSUD when performed by inexperienced internal medicine residents after a short-term training. We consecutively enrolled inpatients and outpatients referred to undergo abdominal ultrasonography for signs or symptoms of gallbladder diseases in two different hospitals. Every patient underwent two independent examinations with PSUD by both expert (EXPPSUD) and nonexpert operators (N-EXPPSUD), and a conventional examination with traditional abdominal ultrasound (AUS). Every naive operator underwent a short term training with a 2-h theoretical lesson, and a practical training focused on gallbladder under expert operator supervision. Overall, 146 patients were consecutively enrolled. Considering conventional AUS as the reference standard, sensitivity and specificity of EXPPSUD were, respectively, 93.75 and 100%. Sensitivity and specificity of N-EXPPSUD were, respectively, 75 and 91.25%. Nevertheless, when considering outpatients, PSUD has a high diagnostic accuracy even when performed by N-EXPPSUD with sensitivity of 93% and specificity of 88%. PSUD is a reliable tool for the diagnosis of cholelithiasis when used by expert operators potentially reducing the need for further diagnostic tests. It can even be successfully used by non-expert operators in outpatients setting after a short focussed training. PMID- 29982875 TI - European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents. AB - Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders. PMID- 29982877 TI - Use of genomic and functional analysis to characterize patients with steroid resistant nephrotic syndrome. AB - BACKGROUND: Children with genetic causes of steroid-resistant nephrotic syndrome (SRNS) usually do well after renal transplantation, while some with idiopathic SRNS show recurrence due to a putative podocyte-toxic factor. Distinguishing different forms of SRNS based on clinical criteria has been difficult. The aim of our study was to test a novel approach that allows categorization of patients into clinically useful subgroups. METHODS: Seventeen patients with clinically confirmed SRNS were analyzed by next-generation sequencing (NGS) of 37 known SRNS genes and a functional assay of cultured human podocytes, which indirectly tests for toxicity of patients' sera by evidenced loss of podocyte focal adhesion complex (FAC) number. RESULTS: We identified a pathogenic mutation in seven patients (41%). Sera from patients with monogenic SRNS caused mild loss of FAC number down to 73% compared to untreated controls, while sera from seven of the remaining ten patients with idiopathic SRNS caused significant FAC number loss to 43% (non-overlapping difference 30%, 95% CI 26-36%, P < 0.001). All patients with recurrent SRNS (n = 4) in the graft showed absence of podocyte gene mutations but significant FAC loss. Three patients had no mutation nor serum podocyte toxicity. CONCLUSIONS: Our approach allowed categorization of patients into three subgroups: (1) patients with monogenic SRNS; (2) patients with idiopathic SRNS and marked serum podocyte toxicity; and (3) patients without identifiable genetic cause nor evidence of serum podocyte toxicity. Post-transplant SRNS recurrence risk appears to be low in groups 1 and 3, but high in group 2. PMID- 29982878 TI - Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings. AB - BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome (SRNS) due to focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) is a leading cause of end-stage kidney disease in children. Recurrence of primary disease following transplantation is a major cause of allograft loss. The clinical determinants of disease recurrence are not completely known. Our objectives were to determine risk factors for recurrence of FSGS/MCD following kidney transplantation and factors that predict response to immunosuppression following recurrence. METHODS: Multicenter study of pediatric patients with kidney transplants performed for ESKD due to SRNS between 1/2006 and 12/2015. Demographics, clinical course, and biopsy data were collected. Patients with primary-SRNS (PSRNS) were defined as those initially resistant to corticosteroid therapy at diagnosis, and patients with late-SRNS (LSRNS) as those initially responsive to steroids who subsequently developed steroid resistance. We performed logistic regression to determine risk factors associated with nephrotic syndrome (NS) recurrence. RESULTS: We analyzed 158 patients; 64 (41%) had recurrence of NS in their renal allograft. Disease recurrence occurred in 78% of patients with LSRNS compared to 39% of those with PSRNS. Patients with MCD on initial native kidney biopsy had a 76% recurrence rate compared with a 40% recurrence rate in those with FSGS. Multivariable analysis showed that MCD histology (OR; 95% CI 5.6; 1.3-23.7) compared to FSGS predicted disease recurrence. CONCLUSIONS: Pediatric patients with MCD and LSRNS are at higher risk of disease recurrence following kidney transplantation. These findings may be useful for designing studies to test strategies for preventing recurrence. PMID- 29982880 TI - Qualitative evaluation of hybrid layer formation using Er:YAG laser in QSP mode for tooth cavity preparations. AB - The purpose of this study was to evaluate the thickness and qualitative characteristics of the hybrid layer after two cavity preparation methods, using Er:YAG laser in QSP mode and conventional carbide burs. Additionally, two different adhesive techniques were investigated using etch-and-rinse and self etch adhesive systems. Sixty sound human third molars were used and were randomly divided into four groups (n = 15). In the first two groups, large (4 mm length, 3 mm wide, and 3 mm deep) class I cavities were prepared using Er:YAG laser (2.94 MUm) in QSP mode, while in the other two groups, the cavities were prepared using carbide burs. After cavity preparations, two different adhesive techniques with GLUMA(r) 2 Bond (etch-and-rinse) and ClearfilTM Universal Bond Quick (self-etch) were applied. For the qualitative evaluation of the formed hybrid layer, photomicrographs were taken using SEM, and elemental semi-quantitative analysis was performed using EDS to confirm the extent of the hybrid layer. One-way ANOVA was applied to verify the existence of statistically significant differences, followed by Tukey test for post hoc comparisons (Bonferroni corrected), and the level of significance was set at a = 0.05. The laser-treated groups exhibited higher hybrid layer thickness than bur-treated groups (p < 0.001). Between the laser-treated groups, etch-and-rinse technique presented higher hybrid layer thickness than self-etch technique (p < 0.001), while between the bur-treated groups, no significant differences were detected (p = 0.366). Er:YAG laser cavity preparations in QSP mode may be advantageous for adhesion of composite restorations, but more data are necessary to confirm its clinical effectiveness. PMID- 29982879 TI - FUS(1-359) transgenic mice as a model of ALS: pathophysiological and molecular aspects of the proteinopathy. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (DeltaFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells. Second, we applied RNA-seq to evaluate changes in the gene expression profile encompassing the pre-symptomatic and the symptomatic stages of disease progression in motor neurons and the surrounding microglia of the spinal cord. The resulting data show that FUS-mediated proteinopathy is virtually asymptomatic in terms of both the clinical symptoms and the molecular aspects of neurodegeneration until it reaches the terminal stage of disease progression (120 days from birth). After this time, the pathological process develops very rapidly, resulting in the formation of massive FUS-positive inclusions accompanied by a transcriptional "burst" in the spinal cord cells. Specifically, it manifests in activation of a pro-inflammatory phenotype of microglial cells and malfunction of acetylcholine synapse transmission in motor neurons. Overall, we assume that the highly reproducible course of the pathological process, as well as the described accompanying features, makes DeltaFUS(1-359) mice a convenient model for testing potential therapeutics against proteinopathy-induced decay of motor neurons. PMID- 29982881 TI - Erythropoietin-mediated activation of aquaporin-4 channel for the treatment of experimental hydrocephalus. AB - OBJECTIVE: In this study, we investigate a neuroprotective agent, erythropoietin (EPO), in animal hydrocephalus model and its potential reversal effects on hydrocephalus by altering the expression of aquaporin-4 (AQP4). METHODS: Obstructive hydrocephalus was induced in 2-week-old rat pups by injecting kaolin (50 MUl, 10 mg/ml in saline) into the cisterna magna, while the control pups received only saline. Kaolin-injected pups were divided into two groups on the fifth day after kaolin injection; one group received intra-peritoneal (i.p.) EPO (1 MUg/pup) for 5 consecutive days, while other group received i.p. saline for 5 days. The effects of EPO on hydrocephalus were investigated by studying cerebral ventricle size and structural ependymal changes. We examined also the EPO effects on AQP4 expression and microRNA expression. RESULTS: EPO treatment significantly reduced dilation of the cerebral ventricle and denudation of ependymal line in hydrocephalic pups comparing with the control group. Increased expression of AQP4 in periventricular ependymal lining and cultured astrocytes and increased vascular formation were noted after EPO treatment. Additionally, we identified miR-668 as an endogenous regulator of AQP4 in response to EPO. Anti-miR-668 dampened EPO-induced activation of AQP4 expression. CONCLUSIONS: Together, our results show that EPO-mediated upregulation of AQP4 significantly reduces dilation of the cerebral ventricles in obstructive hydrocephalus pups and may lead to potential therapeutic options for hydrocephalus. PMID- 29982882 TI - Theoretical study on the structure and reactions of uranium fluorides. AB - The gas-phase mechanisms of UF4 and UF5 conversion into UF6 at different electronic states have been investigated using density functional theory (DFT) calculations, including relativistic effects and without the frozen core approximation. New geometries and electronic states of the isolated molecules were obtained, and their reactions were predicted to occur without a potential energy barrier. Our calculations show that UF4+F2 collision will most likely produce UF5+F in the gas phase. Relevant surface crossings between different electronic states are also obtained and their roles in collision dynamics are discussed. PMID- 29982884 TI - Effect of Processing on Bioactive Compounds, Physicochemical and Rheological Characteristics of Jucara, Banana and Strawberry Smoothie. AB - This study aimed to evaluate the effect of processing steps on bioactive compounds and physicochemical and rheological characteristics of a jucara, banana and strawberry smoothie. The product was obtained by mixing the pulps of these fruits in previously defined proportions. The mixture was standardized in a pilot disintegrator, homogenized at 60 MPa in continuous mode and pasteurized at 90 degrees C for 35 s. The homogenization step increased the concentration of cyanidin-3-O-glucoside and cyanidin-3-O-rutinoside, major anthocyanins in the smoothie. However, these anthocyanins, as well as perlagonidin-3-O-glucoside, have been reduced (p<0.05) after the pasteurization step. The pasteurization also affected the instrumental color of the smoothie, expressed by Hue angle (p<0.05). Regarding to the rheological behavior, the smoothie, in all processing steps, presented a non-Newtonian fluid behavior with pseudoplastic characteristics (n<1). After homogenization, the smoothie became more fluid and homogeneous. Thus, despite the negative impact of pasteurization on the smoothie's color, the pasteurized product preserves the bioactive compounds such as flavonoids and phenolic acids that are of great importance to human health. Furthermore, the development of this product contributes to add value to the jucara agro-chain and Atlantic Forest preservation. PMID- 29982885 TI - An environmental flow assessment of a river's blocking effect on a lake in a river-lake system: application in the Yangtze-Poyang system. AB - Hydrologic regimes are essential to riverine, lacustrine, and wetland ecosystems, and every component of a hydrologic regime has a specific ecological environmental function. In an outflow lake-river system, water levels are reduced by a reservoir constructed at the river, which interferes with the river-lake interrelationships by impairing the river's blocking effect. This increases the lake-river hydraulic gradient and accelerates the lake's drainage to the river, resulting in shrinkage of the lake and damaging environmental issues. To respond to these issues, we propose an environmental flow assessment that considers the river's blocking effect on the lake. This novel methodology consists of four steps: data preparation, assessment of the lake's environmental water level, assessment of the river's environmental water level, and environmental flow assessment. We estimated the river's environmental water level through a hydraulic correlation between the lake and the river, and found that the river's blocking effect could be sustained. The Yangtze-Poyang system was selected as a case study to illustrate the methodology's procedures and applicability. The impoundment of the Three Gorges Reservoir, during the fall retreating season, decreased the Yangtze's water level and weakened the Yangtze's blocking effect on Poyang Lake. Poyang Lake's environmental water level, which ranges from 11.71 to 15.81 m in the month of October, was used to estimate the Yangtze's environmental water level as falling in a range of 11.95 to 16.17 m, which corresponds to an environmental flow range of 16,822 to 32,371 m3/s. This study offers a solution for reservoir-induced accelerated lake drainage, which may be helpful in mitigating the negative impacts of reservoirs and sustaining natural rive-lake interactions. PMID- 29982883 TI - Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications. AB - The misbehaving attitude of Ca2+ signaling pathways could be the probable reason in many muscular disorders such as myopathies, systemic disorders like hypoxia, sepsis, cachexia, sarcopenia, heart failure, and dystrophy. The present review throws light upon the calcium flux regulating signaling channels like ryanodine receptor complex (RyR1), SERCA (Sarco-endoplasmic Reticulum Calcium ATPase), DHPR (Dihydropyridine Receptor) or Cav1.1 and Na+/Ca2+ exchange pump in detail and how remodelling of these channels contribute towards disturbed calcium homeostasis. Understanding these pathways will further provide an insight for establishing new therapeutic approaches for the prevention and treatment of muscle atrophy under stress conditions, targeting calcium ion channels and associated regulatory proteins. PMID- 29982886 TI - Learning curve analysis of 3D-fluoroscopy image-guided pedicle screw insertions in lumbar single-level fusion procedures. AB - INTRODUCTION: The implementation of 3D-navigation in the operating theater is reported to be complex, time consuming, and radiation intense. This prospective single-center cohort study was performed to objectify these assumptions by determining navigation-related learning curves in lumbar single-level posterior fusion procedures using 3D-fluoroscopy for real-time image-guided pedicle screw (PS) insertions. MATERIALS AND METHODS: From August 2011 through July 2016, a total of 320 navigated PSs were inserted during 80 lumbar single-level posterior fusion procedures by a single surgeon without any prior experience in image guided surgery. PS misplacements, navigation-related pre- and intraoperative time demand, and procedural 3D-radiation dose (dose-length-product, DLP) were prospectively recorded and congregated in 16 subgroups of five consecutive procedures to evaluate improving PS insertion accuracy, decreasing navigation related time demand, and reduction of 3D-radiation dose. RESULTS: After PS insertion and intraoperative O-arm control scanning, 11 PS modifications were performed sporadically without showing "learning curve dependencies" (PS insertion accuracies in subgroups 96.6 +/- 6.3%). Average navigation-related pre surgical time from patient positioning on the operating table to skin incision decreased from 61 +/- 6 min (subgroup 1) to 28 +/- 2 min (subgroup 16, p < 0.00001). Average 3D-radiation dose per surgery declined from 919 +/- 225 mGycm (subgroup 1) to 66 +/- 4 mGycm (subgroup 16, p < 0.0001). CONCLUSIONS: In newly inaugurated O-arm based image-guidance, lumbar PS insertions can be performed at constantly high accuracy, even without prior experience in navigated techniques. Navigation-related time demand decreases considerably due to accelerating workflow preceding skin incision. Procedural 3D-radiation dose is reducible to a fraction (13.2%) of a lumbar diagnostic non-contrast-enhanced computed tomography scan's radiation dose. PMID- 29982887 TI - Ketogenic diet delays spinal fusion and decreases bone mass in posterolateral lumbar spinal fusion: an in vivo rat model. AB - BACKGROUND: Ketogenic diet (KD), a low-carbohydrate-and-high-fat diet, causes a metabolic state of ketogenesis and has been used to treat drug-resistance epilepsy. Our recent studies showed KD neuroprotective after spinal cord injury and causing bone loss. Effects of KD on spinal fusion were still unknown. This study was aimed to evaluate effects of KD on spinal fusion in rats. METHODS: Thirty-two Sprague-Dawley rats were randomly divided into KD and standard diet (SD) groups. The KD group was fed with food of 1:4 carbohydrates to fat. All rats were subjected to L4/5 posterolateral lumbar spinal fusion. The blood ketone, and serum calcium, phosphorus, and insulin-like growth factor-1 (IGF-1) were measured, as well as the fusion rates, bone mass (BV), and bone mineral contents (BMC) of fusion sites were estimated at 4 and 8 weeks. RESULTS: There was no significant difference in serum calcium or phosphorus levels between groups at 4 or 8 weeks. However, there was a significant increase of blood ketone (1.02 mmol/L vs 0.38 mmol/L at 4 weeks; 0.83 mmol/L vs 0.32 mmol/L, at 8 weeks) and decrease of serum IGF-1 (339.4 ng/mL vs 630.6 ng/mL at 4 weeks; 418.8 ng/mL vs 628.6 ng/mL, at 8 weeks) in the KD group compared with the SD group. The spinal fusion occurred less in the KD group (1/16 vs 6/16 at 4 weeks; 7/16 vs 10/16, at 8 weeks), particularly at 4 weeks after surgery. The BV and BMC were lower in the KD group than that in the SD group at 4 weeks, but not different between groups at 8 weeks. CONCLUSIONS: This study demonstrated that KD delayed spinal fusion and decreased bone mass in posterolateral lumbar spinal fusion in rats. PMID- 29982888 TI - Unruptured intracranial aneurysms in patients over 80 years: natural history and management implications. AB - PURPOSE: Patients over the age of 80 years when diagnosed with an unruptured intracranial aneurysm (UIA) pose unique decision-making challenges due to shortened life-expectancy and increased risk of treatment. Thus, we investigated the risk of rupture and survival of a consecutive series of patients who were diagnosed with an UIA after the age of 80 years. METHODS: Data of consecutive patients with an UIA were reviewed, and patients were included in our study if they were first evaluated for a UIA by the senior author during their ninth decade of life. Outcomes were aneurysm rupture and overall survival after diagnosis. Survival was estimated from a Kaplan-Meier survival curve. Incidence of risk factors was compared to a population of patients less than 65 years who were seen by the senior author over the same time period. RESULTS: Eighty-three patients who were over 80 years when diagnosed with a UIA were included in this study. In our population, there is a risk of rupture of 3.2% per patient-year. One-, three-, and five-year survival rates for our population were estimated to be 92, 64, and 35%, respectively. When compared to patients under 65 years diagnosed with a UIA, "over 80" patients had a significantly higher incidence of hypertension, and a significantly lower incidence of smoking history and familial aneurysm history. CONCLUSIONS: In our study population, UIAs greater than 7 mm carry a non-negligible risk of rupture of 3.2% per patient-year, and further studies investigating the risk-to-benefit ratio of treatment in this population are warranted. PMID- 29982889 TI - Adrenal Insufficiency in Young Children: a Mixed Methods Study of Parents' Experiences. AB - Research into adrenal insufficiency (AI) and congenital adrenal hyperplasia (CAH) in children has focused largely on clinical consequences for patients; and until recently, the wider experience of the condition from the perspective of other family members has been neglected. In a mixed methods study, we captured the experiences of parents of young children affected by AI/CAH, including their views on the psychosocial impact of living with and managing the condition. Semi structured interviews were carried out in the UK and an online survey was developed, translated and disseminated through support groups (UK and the Netherlands) and outpatient endocrinology clinics (Germany). Challenges associated with diagnosis, treatment, support and the future were identified. For UK parents, the diagnosis period was characterised by a lack of awareness amongst healthcare professionals and occurrences of adrenal crisis. Parents reported burden, anxiety and disruption associated with the intensive treatment regimen. Parents adjusted and gained confidence over time yet found delegating responsibility for medication difficult and worried about the future for their child. Access to psychological support and contact with other families was reported as highly beneficial. The findings of the study provide critical context for future studies and for informing how parents and families can be better supported. Prenatal genetic counselling for parents who already have an affected child will include an explanation of recurrence risk but should also focus on providing information and reassurance about diagnostic testing and care for their newborn. PMID- 29982890 TI - Mitochondrial activity in different regions of the brain at the onset of streptozotocin-induced diabetes in rats. AB - Diabetes affects a variety of tissues including the central nervous system; moreover, some evidence indicates that memory and learning processes are disrupted. Also, oxidative stress triggers alterations in different tissues including the brain. Recent studies indicate mitochondria dysfunction is a pivotal factor for neuron damage. Therefore, we studied mitochondrial activity in three brain regions at early type I-diabetes induction. Isolated mitochondria from normal hippocampus, cortex and cerebellum revealed different rates of oxygen consumption, but similar respiratory controls. Oxygen consumption in basal state 4 significantly increased in the mitochondria from all three brain regions from diabetic rats. No relevant differences were observed in the activity of respiratory complexes, but hippocampal mitochondrial membrane potential was reduced. However, ATP content, mitochondrial cytochrome c, and protein levels of beta-tubulin III, synaptophysin, and glutamine synthase were similar in brain regions from normal and diabetic rats. In addition, no differences in total glutathione levels were observed between normal and diabetic rat brain regions. Our results indicated that different regions of the brain have specific metabolic responses. The changes in mitochondrial activity we observed at early diabetes induction did not appear to cause metabolic alterations, but they might appear at later stages. Longer-term streptozotocin treatment studies must be done to elucidate the impact of hyperglycemia in brain metabolism and the function of specific brain regions. PMID- 29982891 TI - Positive selection adaptation of two-domain arginine kinase (AK) from cold seep Vesicomyidae clams. AB - Arginine kinase (AK) is an important member of Phosphagen kinases which engage in energy metabolism process, and AKs from cold seep clams may develop an effective mechanism to adapt a special habitat (e.g. low temperature). Three Vesicomyidae clams and seven Veneridae clams (belong to the same Order Veneroida) were chosen to analyze the evolution of two-domain AKs. In the present study, ten two-domain AKs were identified and Neighbor-joining tree showed that AKs were divided into two groups. Branch-site model indicated that two-domain AKs were subjected to strong positive selection (omega2a = 17.5058). 16 positively selective sites were detected and five of them showed posterior probabilities of 0.95 or more. Comparative analysis found that domain 2 might be suffered from more evolutionary selection pressure than domain 1, as most positively sites were located at domain 2. Residue Pro (positively selective site) (587P in ApAK) in domain 2 from all Vesicomyidae AKs might participate in change of the synergism and in the function of its cold-adapted characteristics. In conclusion, our studies provide evidence of positive Darwinian selection in the two-domain AKs family of Vesicomyidae clams, and may contribute to a better understanding of its adaptation mechanisms to cold seep habitats. PMID- 29982892 TI - Genotyping DNA isolated from UV irradiated human bloodstains using whole genome amplification. AB - Analysis of DNA polymorphisms are the primary technique used for personal identification in forensic cases. However, DNA samples collected as evidence from crime scenes are usually degraded by environmental, physical, and chemical factors, which may interfere with the PCR analysis and, consequently, personal identification. Whole genome amplification (WGA) is a useful method to amplify genomic DNA from samples containing low quantity and poor quality of DNA, and it approach that shows promise to overcome the limited small fragments based upon random fragmentation by universal priming sites. In this study, we describe the use of WGA to genotype 15 short tandem repeat (STR) loci from dried blood samples irradiated with different types of ultraviolet (UV) light (UVA, UVB, and UVC). The result showed that UVC was the most damaging to DNA, followed by UVB and UVA. Samples exposed to UVA could be genotyped for all STR loci with or without WGA. For UVB and UVC irradiated blood samples, a greater number of STR loci could be genotyped after WGA. Although it hard to amplified a few higher molecular weight alleles, overall, the WGA method was useful in genotyping template DNA of poor quality but low quantity. PMID- 29982893 TI - "Life is Much More Difficult to Manage During Periods": Autistic Experiences of Menstruation. AB - Although menarche and menstruation are perceived to be overwhelmingly negative events for developmentally-disabled women, women's health issues remain under researched in autism. Here, we conducted a preliminary investigation of the experiences of post-menarcheal autistic (n = 123) and non-autistic (n = 114) respondents to a brief online survey. Although autistic respondents reported many overlapping issues and experiences with non-autistic respondents, they also highlighted distinct-and sometimes-distressing-issues relating to menstruation, especially a cyclical amplification of autistic-related challenges, including sensory differences and difficulties with regulating emotion and behavior, which had a significant, negative impact on their lives. These initial findings call for systematic research on the potential causes, correlates and consequences of menstrual-related problems in autistic individuals-across the spectrum and the lifespan. PMID- 29982894 TI - Understanding Friendship Sex Heterophily and Relational Characteristics to Optimize the Selection of Peer Models for Children with Autism Spectrum Disorder. AB - This study used social network analysis to evaluate whether sex heterophily, the degree to which peers are different in sex, between 126 children with autism (ages 5-12 years) and their peers affected social network connectivity. Results indicate that: (1) the quantity and sex of friends were more important in predicting social network connectivity than the relational characteristics of the friends (friendship nominations and social network salience/popularity); and (2) sex heterophily is an important factor in predicting social network connectivity. For males with autism, having friends of the same sex was associated with better social network connectivity; this was not true for females with autism. These findings have important implications for the selection of peer models for elementary-aged children with autism. PMID- 29982895 TI - Timing of the Diagnoses of Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder in Taiwan. AB - ADHD comorbidity has been associated with delayed diagnosis of ASD, but no study has investigated this association in an Asian country. Children with ASD were included and divided into three groups: ADHD before ASD, ADHD same/after ASD, and ASD only. Timing of ASD and ADHD diagnoses were assessed. The logistic regression model was performed to investigate the likelihood of being diagnosed with ASD after 6 years of age between three groups. ADHD before ASD (OR 10.93) group was more likely to being diagnosed with ASD after 6 years of age compared with ADHD same/after ASD (OR: 1.37) and ASD only groups. ADHD comorbidity would delay the diagnosis of ASD in the general clinical settings in Taiwan. PMID- 29982896 TI - Expanding the Capacity of Primary Care to Treat Co-morbidities in Children with Autism Spectrum Disorder. AB - We examined barriers and facilitators to expanding primary care's capacity to manage conditions associated with autism spectrum disorder (ASD). We conducted semi-structured interviews with specialists, primary care providers (PCPs), primary care staff, and parents of children with ASD, discussing health/behavior problems encountered, co-management, and patient/family experience. Participants endorsed primary care as the right place for ASD-associated conditions. Specialists advising PCPs, in lieu of referrals, efficiently uses their expertise. PCPs' ability to manage ASD-associated conditions hinged on how behavioral aspects of ASD affected care delivery. Practices lacked ASD-specific policies but made individual-level accommodations and broader improvements benefitting children with ASD. Enhancing access to specialty expertise, particularly around ASD-associated behaviors, and building on current quality improvements appear important to expanding primary care. PMID- 29982897 TI - Prevalences of segmentation errors and motion artifacts in OCT-angiography differ among retinal diseases. AB - PURPOSE: To assess the prevalences of segmentation errors and motion artifacts in optical coherence tomography angiography (OCT-A) in different retinal diseases METHODS: In a retrospective analysis, multimodal retinal imaging including OCT-A was performed in one eye of 57 healthy controls (50.96 +/- 22.4 years) and 149 patients (66.42 +/- 14.1 years) affected by different chorioretinal diseases: early/intermediate age-related macular degeneration (AMD; n = 26), neovascular AMD (nAMD; n = 22), geographic atrophy due to AMD (GA; n = 6), glaucoma (n = 28), central serous chorioretinopathy (CSC; n = 14), epiretinal membrane (EM; n = 26), retinal vein occlusion (RVO; n = 11), and retinitis pigmentosa (RP; n = 16). Central 3 * 3 mm2 OCT-A imaging was performed with active eye-tracking (AngioVue, Optovue). Best-corrected visual acuity (BCVA) and signal strength index (SSI) were recorded. Images were independently evaluated by two graders using the OCT-A motion artifact score (MAS; scores I-IV) as well as a newly introduced segmentation accuracy score (SAS; score I-IIB). RESULTS: Mean SSI was 63.67 +/- 9.2 showing a negative correlation with increasing age (rSp = - 0.42, p < 0.001, n = 206). In the healthy cohort, mean MAS was 1.45 +/- 0.8 and segmentation was accurate (SAS I) in all eyes. In eyes with retinal pathologies, mean MAS was 2.1 +/- 0.9 (p < 0.001). Lowest MAS was observed in GA (2.67 +/- 0.5) and RVO (2.45 +/- 1.1). Compared to an accurate segmentation in 100% in healthy subjects, 34.2% (n = 51) of all patients showed highest segmentation quality (p < 0.001). 63.8% showed segmentation errors in more than 5% of all single b-scans in one (SAS IIA, n = 58) or at least two (SAS IIB, n = 40) segmentation boundaries. Highest percentages of inaccurate segmentation (SAS IIA or IIB) were observed in the nAMD group (90.1%). The inner plexiform layer was the segmentation boundary most prone to inaccurate segmentation in all pathologies compared to the inner limiting membrane (ILM) and retinal pigment epithelium (RPE) segmentation layer. Incorrect ILM segmentation was only seen in patients with EM. CONCLUSIONS: Prior to both qualitative and quantitative analysis, OCT-A images must be carefully reviewed as motion artifacts and segmentation errors in current OCT-A technology are frequent particularly in pathologically altered maculae. PMID- 29982898 TI - Transmission electron microscopy study of undescribed material at the anterior lens capsule in exfoliation syndrome. AB - PURPOSE: In the present study, we aimed to examine the anterior lens capsule using transmission electron microscopy (TEM) and compare the findings in patients with and without exfoliation syndrome (XFS). METHODS: Eighteen patients with senile cataract, including 10 with XFS, were included. Anterior capsule specimens were obtained from patients during phacoemulsification through continuous curvilinear capsulorrhexis, and were examined via TEM. RESULTS: In the XFS group, in addition to the typical fibrillar material above the basement membrane of the lens capsule, another unknown, microgranular, electron-dense, unbound material was observed beneath the lens epithelium. Larger formations appeared to detach from the surface of the epithelial cells, and oval or crescent-shaped structures of an electron-denser material were less commonly observed on the apical side of the epithelium. Membranous structures were occasionally attached to epithelial cells that often exhibited thicker or ruptured cell membranes on their apical free side, along with deposits of electron-dense material. Degenerative lesions of various severities were observed at the epithelium in both groups. CONCLUSION: The anterior lens capsule epithelium in patients with XFS exhibits a highly irregular and rough margin on its free side, with unbound material over its membrane, which probably contributes to loose contact with the underlying lens and leads to different clinical behaviors in XFS eyes during cataract surgery. PMID- 29982899 TI - Retinal pigmental epithelium elevation and external limiting membrane interruption in myopic choroidal neovascularization: correlation with activity. AB - PURPOSE: To describe the morphological changes in myopic choroidal neovascularization (mCNV) on spectrum domain optical coherence tomography (SD OCT) and to find a new strategy to evaluate their activity. METHODS: Characteristics of SD-OCT and fundus fluorescein angiography (FFA) before and after ranibizumab treatment of 52 eyes with active mCNV were analyzed. SD-OCT parameters associated with mCNV activity and the clinical significance of their sensitivity and specificity were analyzed using FFA as a standard reference. Retinal pigment epithelium (RPE) elevation was noted as highly correlated to the mCNV activity. RESULTS: Intraobserver agreement was substantial for all OCT parameters. However, interobserver agreement was low for intraretinal fluid (IRF). To evaluate the CNV activity, sensitivity of presence of subretinal fluid (SRF) and interruption of ellipsoid zone (EZ) was 23.9 and 82.1%, and specificity was 97.5 and 19.8%. External limiting membrane (ELM) interruption showed high sensitivity (97.0%) but low specificity (55.6%) due to the development of RPE elevation. A novel two-step procedure using ELM interruption and RPE elevation was developed to evaluate mCNV activity with sensitivity 92.5% and specificity 95.1%, respectively. Final agreement was as high as 93.9%, with a kappa value of 0.877 (P < 0.001). CONCLUSIONS: A novel two-step diagnostic procedure combining ELM interruption with RPE elevation is considered a valuable guide for diagnosis and monitoring of mCNV. PMID- 29982901 TI - Examining the effect of 5-HTTLPR on depressive symptoms in postmenopausal women 1 year after initial breast cancer treatment. AB - BACKGROUND: Depression following the diagnosis of breast cancer has been well documented, and occurs in as many as 40% of women. The serotonin transporter gene SLC6A4 and its functional polymorphism 5-HTTLPR have been extensively studied as factors in the development of depression. Many research studies have demonstrated conflicting results, and the contribution of 5-HTTLPR to depression is unclear. PURPOSE: The purpose of this study was to compare the relationship between depressive symptoms and serotonin transporter gene polymorphisms between women with early-stage breast cancer 1 year following initial diagnosis and surgery and matched controls. METHODS: Participants (N = 125), included postmenopausal women following breast cancer surgery (n = 80) and age-and education-matched healthy controls (n = 45). The genetic elements of interest were the long (LA) and short (S) alleles of 5-HTTLPR, as well as the single nucleotide polymorphism rs25531 A > G within the L-allele (LG). DNA was extracted from either blood or saliva and analyzed for the SLC6A4 polymorphisms. The outcome measures for this longitudinal study included Beck Depression Inventory scores and physical function domain scores from the Medical Outcome Study Short Form 36. RESULTS: Women with breast cancer demonstrated greater depressive symptomatology and decreased physical function compared to healthy controls. The LA/LA genotype was associated with increased depressive symptomatology in the overall sample and within the controls. The LA/LA genotype appeared with greater frequency in the experimental group, but the relationship with increased depressive symptoms was not observed. Physical function was a significant (p < 0.00) predictor of depressive symptoms in both groups at 12 months. CONCLUSION: The relationship between 5-HTTLPR and depressive symptomatology in breast cancer patients remains unclear. A potential clinical application includes monitoring physical function and addressing increased depressive symptoms as physical function declines. PMID- 29982900 TI - New insights in radiation-induced leukoencephalopathy: a prospective cross sectional study. AB - BACKGROUND: Radiation-induced leukoencephalopathy (RIL) is the most threatening delayed complication of cerebral radiotherapy (RT) and remains roughly defined by cognitive dysfunction associated with diffuse FLAIR MRI white matter hyperintensities after brain irradiation. We documented clinical, neuropsychological, and radiological aspects of RI in order to refine diagnostic criteria. METHODS: Patients referred to our center for deterioration in cognitive complaint at least 6 months after completing a focal or whole brain RT underwent a systematic cross-sectional assessment including clinical examination, neuropsychological tests, and a standardized MRI protocol. Patients with progressive tumor were excluded. RESULTS: Forty patients were prospectively enrolled. Of these, 26 had received a focal RT, median dose of 53 Gy (range 50 to 60), and 14 had received a whole brain RT, median dose of 30 Gy. Cognitive complaints, gait apraxia, and urinary troubles were reported in 100, 67, and 38% of cases, respectively. On neuropsychological examination, patients displayed a global and severe cognitive decline through a subcortical frontal mode. The cognitive changes observed were not hippocampic, but related to executive dysfunction. On MRI, 68% of the patients had extensive FLAIR hyperintensities with anterior predominance, 87% had brain atrophy, and 21% had intraparenchymal cysts. T2*-weighted MRI showed small asignal areas in 53% of the patients. These abnormalities are evocative of cerebral small vessel disease. Fractional anisotropy in the corpus callosum correlated with the cognitive evaluation. No differentiation in terms of cognitive and MRI features could be made between patients treated with focal brain RT (glioma) and patients treated with WBRT (for brain metastases or PCNSL). CONCLUSIONS: RIL can be defined by clinical symptoms (subcortical frontal decline, gait apraxia, urinary incontinence) and MRI criteria (cortico-subcortical atrophy, spread FLAIR HI, T2* asignals). This condition mimics a diffuse progressive cerebral small vessel disease triggered by RT, independent of RT protocol. PMID- 29982902 TI - Development and prospective evaluation of CAPLET, a cancer ambulatory patient physical function longitudinal evaluation tool for routine clinical practice. AB - PURPOSE: A patient's physical function is a critical outcome variable for measuring and improving chronic care management. However, patient-reported outcome measures of physical function are not routinely assessed in cancer outpatients, in part due to limitations of tools available. This study presents the development and evaluation of the Cancer Ambulatory Patient Physical Function Longitudinal Evaluation Tool (CAPLET) as an adaptive response tool for routinely screening for physical dysfunction in oncology clinical practice. METHODS: In phase 1, 407 adult outpatients at Princess Margaret Cancer Centre completed the World Health Organization Disability Assessment Schedule (WHODAS) 2.0, Health Assessment Questionnaire Disability Index (HAQ-DI), EuroQuol-5D-3L ( EQ-5D-3L), and patient-reported outcome (PRO)-Eastern Cooperative Oncology Group (ECOG). CAPLET was developed based on a branching logic algorithm navigating patients to appropriate domains of HAQ-DI/WHOAS using their responses to the PRO-ECOG/EQ-5D 3L as screeners. Sensitivity/specificity of CAPLET screeners for HAQ-DI/WHODAS items were reported. In phase 2, CAPLET vs the WHODAS/HAQ-DI were alternatively administrated to 318 adult outpatients in a two-arm trial comparing time to completion and acceptability between the tools. RESULTS: Using a patient's ECOG status and the sum of the mobility, self-care, and usual activity dimensions of the EQ-5D-3L to dichotomize patients as with or without difficulty, CAPLET achieved a sensitivity > 90% against recommended WHODAS and HAQ-DI cutoffs for significant dysfunction. Sensitivity of screeners for capturing dysfunction in individual WHODAS/HAQ-DI items ranged from 85 to 100%. Compared to the HAQ DI/WHODAS, CAPLET was associated with a 50% reduction in administration times and improved patient acceptability, while reducing question burden by 84% for half the sample population. CONCLUSIONS: CAPLET improves the feasibility of capturing detailed assessments of patient-reported physical function in cancer outpatients. PMID- 29982904 TI - Robot-assisted bladder diverticulectomy sequentially followed by robot-assisted radical prostatectomy: a case series. AB - We aimed to describe a case series of robot-assisted bladder diverticulectomy followed by radical prostatectomy for prostate cancer in a single surgical procedure. Three cases of robot-assisted bladder diverticulectomy and radical prostatectomy were completed between 2013 and 2016. Charts of the three cases were reviewed and analyzed for perioperative and postoperative outcomes. All patients presented with lower urinary tract symptoms, and bladder diverticulum or diverticula was revealed after further evaluation of the patients. In addition, elevated prostate-specific antigen levels were noted. All patients were diagnosed with prostate carcinoma on the basis of subsequent multiparametric MRI studies and biopsies. Three patients underwent da Vinci robot-assisted diverticulectomy followed by radical prostatectomy using a transperitoneal approach. All patients had Foley catheters removed postoperatively after negative cystogram, and no substantial complications were noted. Sequential robot-assisted bladder diverticulectomy-radical prostatectomy is an effective and safe procedure. PMID- 29982903 TI - Myocardium segmentation from DE MRI with guided random walks and sparse shape representation. AB - PURPOSE: For patients with myocardial infarction (MI), delayed enhancement (DE) cardiovascular magnetic resonance imaging (MRI) is a sensitive and well-validated technique for the detection and visualization of MI. The myocardium viability assessment with DE MRI is important in diagnosis and treatment management, where myocardium segmentation is a prerequisite. However, few academic works have focused on automated myocardium segmentation from DE images. In this study, we aim to develop an automatic myocardium segmentation algorithm that targets DE images. METHODS: We propose a segmentation framework based on both prior shape knowledge and image intensity. Instead of the strong request of the pre segmentation of cine MRI in the same session, we use the sparse representation method to model the myocardium shape. Data from the Cardiac MR Left Ventricle Segmentation Challenge (2009) are used to build the shape template repository. The method of guided random walks is used to integrate the shape model and intensity information. An iterative approach is used to gradually improve the results. RESULTS: The proposed method was tested on the DE MRI data from 30 MI patients. The proposed method achieved Dice similarity coefficients (DSC) of 74.60 +/- 7.79% with 201 shape templates and 73.56 +/- 6.32% with 56 shape templates, which were close to the inter-observer difference (73.94 +/- 5.12%). To test the generalization of the proposed method to routine clinical images, the DE images of 10 successive new patients were collected, which were unseen during the method development and parameter tuning, and a DSC of 76.02 +/- 7.43% was achieved. CONCLUSION: The authors propose a novel approach for the segmentation of myocardium from DE MRI by using the sparse representation-based shape model and guided random walks. The sparse representation method effectively models the prior shape with a small number of shape templates, and the proposed method has the potential to achieve clinically relevant results. PMID- 29982905 TI - Simplified robot-assisted partial nephrectomy: step-by-step technique and perioperative outcomes. AB - Controversies have been raised and still exist regarding several technical aspects of robot-assisted partial nephrectomy (RAPN). While the "perfect RAPN" has still to be determined, we aimed to report a simplified technique of RAPN in a step-by-step fashion and the perioperative outcomes of a single-center series. A simplified technique of RAPN was developed, refined and standardized over the past 7 years in an academic department of urology to make it as safe and as reproducible as possible, the main goal being to make it an "easy to learn" technique for fellows. This technique is presented in 12 key steps. The patients' characteristics and perioperative outcomes were prospectively collected and are reported herein. Since the first case performed in our department in 2010, 406 patients have undergone RAPN with a standardized and stable simplified technique after the first 30 cases, involving several key steps including systematic use of the transperitoneal approach, minimal visceral mobilization of the colon, systematic psoas exposure and ureter identification, minimal dissection of the perinephric fat, arterial clamping with early unclamping, no use of hemostatic agents or drain. The majority of RAPN were performed by surgeons with either low experience (i.e., < 20 procedures; 46.3%) or intermediate experience (i.e., 20-50 procedures; 17.2%). The mean warm ischemia time was 15.3 min. Conversions to an open approach and to radical nephrectomy were required in 14 (3.5%) and 21 (5.2%) cases, respectively. From 132 patients who experienced post-operative complications (32.5%), 47 experienced a major complication (11.6%). The positive surgical margin rate was 5.6%. The simplified technique of RAPN was feasible and reproducible with satisfactory perioperative outcomes. Most of the key steps have been assessed through single-center and multicenter clinical studies. PMID- 29982906 TI - Factors controlling organic matter composition and trophic state in seven tropical estuaries along the west coast of India. AB - To understand the organic matter (OM) sources and trophic states, spatial and seasonal (post-monsoon and pre-monsoon) variation in sedimentary OM compositions was investigated in seven tropical estuaries of the state of Maharashtra along the central west coast of India. Based on the result of cluster analysis, estuaries were segregated into two distinct groups: Northern Maharashtra and Southern Maharashtra owing to dissimilarity in OM characteristics potentially constrained by geomorphology and catchment properties. Enrichment of Corg and major biochemical compounds (lipids, carbohydrates and proteins) in the middle zone of most estuaries highlighted towards the addition of allochthonous OM. Results of principal component analysis highlighted the similar source of OM in most of the estuaries during both seasons and their distribution largely constrained by grain size change. The benthic trophic state indicated the prevalence of eutrophic state in the middle zone of the investigated estuaries, which may be sporadic and dependent upon anthropogenic activities in the study area. PMID- 29982907 TI - Application of enrichment factor, geoaccumulation index, and ecological risk index in assessing the elemental pollution status of surface sediments. AB - Sediment can accumulate trace elements in the environment. This study profiled the magnitude of As, Ba, Cd, Co, Cu, Cr, Ni, Pb, Se, and Zn pollution in surface sediments of the west coast of Peninsular Malaysia. Trace elements were digested using aqua regia and were analyzed using the inductively coupled plasma-mass spectrometry. The extent of elemental pollution was evaluated using with the enrichment factor (EF) and geoaccumulation index (Igeo). This study found that the elemental distribution in the sediment in descending order was Zn > Ba > Cr > Pb > Cu > As > Ni > Co > Se > Cd. Zn concentrations in all samples were below the interim sediment quality guideline (ISQG) (124 mg/kg). In contrast, Cd concentrations (2.34 +/- 0.01 mg/kg) at Station 31 (Merlimau) exceeded the ISQG (0.70 mg/kg), and the concentrations of As in the samples from Station 9 (Tanjung Dawai) exceeded the probable effect level (41.60 mg/kg). The Igeo and EF revealed that Station 9 and Station 31 were extremely enriched with Se and Cd, respectively. All stations posed low ecological risk, except Station 31, which had moderate ecological risk. The outputs from this study are expected to provide the background levels of pollutants and help develop regional sediment quality guideline values. This study is also important in aiding relevant authorities to set priorities for resources management and policy implementation. PMID- 29982908 TI - Non-photochemical quenching-dependent acclimation and thylakoid organization of Chlamydomonas reinhardtii to high light stress. AB - Light is essential for all photosynthetic organisms while an excess of it can lead to damage mainly the photosystems of the thylakoid membrane. In this study, we have grown Chlamydomonas reinhardtii cells in different intensities of high light to understand the photosynthetic process with reference to thylakoid membrane organization during its acclimation process. We observed, the cells acclimatized to long-term response to high light intensities of 500 and 1000 umol m-2 s-1 with faster growth and more biomass production when compared to cells at 50 umol m-2 s-1 light intensity. The ratio of Chl a/b was marginally decreased from the mid-log phase of growth at the high light intensity. Increased level of zeaxanthin and LHCSR3 expression was also found which is known to play a key role in non-photochemical quenching (NPQ) mechanism for photoprotection. Changes in photosynthetic parameters were observed such as increased levels of NPQ, marginal change in electron transport rate, and many other changes which demonstrate that cells were acclimatized to high light which is an adaptive mechanism. Surprisingly, PSII core protein contents have marginally reduced when compared to peripherally arranged LHCII in high light-grown cells. Further, we also observed alterations in stromal subunits of PSI and low levels of PsaG, probably due to disruption of PSI assembly and also its association with LHCI. During the process of acclimation, changes in thylakoid organization occurred in high light intensities with reduction of PSII supercomplex formation. This change may be attributed to alteration of protein-pigment complexes which are in agreement with circular dichoism spectra of high light-acclimatized cells, where decrease in the magnitude of psi-type bands indicates changes in ordered arrays of PSII-LHCII supercomplexes. These results specify that acclimation to high light stress through NPQ mechanism by expression of LHCSR3 and also observed changes in thylakoid protein profile/supercomplex formation lead to low photochemical yield and more biomass production in high light condition. PMID- 29982909 TI - Arbuscular Mycorrhizal fungi (AMF) protects photosynthetic apparatus of wheat under drought stress. AB - Drought stress (DS) is amongst one of the abiotic factors affecting plant growth by limiting productivity of crops by inhibiting photosynthesis. Damage due to DS and its protection by Arbuscular Mycorrhizal fungi (AMF) was studied on photosynthetic apparatus of wheat (Triticum aestivum) plants in pot experiments. DS was maintained by limiting irrigation to the drought stressed (DS) and AMF + DS plants. Relative Water content (RWC) was measured for leaf as well as soil to ensure drought conditions. DS plants had minimum RWC for both leaf and soil. AMF plants showed increased RWC both for leaf and soil indicating that AMF hyphae penetrated deep into the soil and provided moisture to the plants. In Chl a fluorescence induction curve (OJIP), a declined J-I and I-P phase was observed in DS plants. Efficacy of primary photochemistry declined in DS plants as result of DS, while AMF plants showed maximum photochemistry. DS leads to declined quantum efficiency of PSI and PSII in DS plants while it was restored in AMF + DS plants. Electron transport (ETRI and ETRII) decreased while quantum yield of non photochemical quenching Y(NPQ) increased as a result of drought stress. CEF around PSI increased in DS-stressed plants. Efficient PSI complexes decreased in DS plants while in case of AMF plants PSI complexes were able to perform PSI photochemistry significantly. Thus, it is concluded that drought stress-induced damage to the structure and function of PSII and PSI was alleviated by AMF colonization. PMID- 29982910 TI - Frequency and distribution of foot lesions identified during cattle hoof trimming in the Province of Antioquia, Colombia (2011-2016). AB - Lameness is a severe welfare problem in cattle and has a detrimental effect on longevity, productivity, and reproductive performance. This study aimed to describe the frequency and distribution of foot lesions in cattle using hoof trimming records over a period of 6 years in the Province of Antioquia (Colombia). The data collection instrument enabled differentiation between limbs, digits, and views. The Claw Lesion Identification in Dairy Cattle brochure was the reference for foot lesion identification. A total of 1814 foot lesions observations, recorded from 1120 cows in 71 herds, were analyzed and 11 different foot lesions were identified. Non-infectious foot lesions were more common than infectious (94.4 vs 5.6%). White line disease was more frequently observed in the hind limbs (79.6%) compared to the front limbs (20.4%), and more frequent in medial claws of the front limbs (70.3%) compared to lateral claws (29.7%). In hind limbs, the lateral claws were more commonly affected (65.7%) compared to the medial claws (34.3%). Claw zone 3 was affected in 61.3% of the cases, followed by zones 2 (21.7%) and 1 (17%). Although our data are from a limited area of the country, they are consistent with published and anecdotal reports of foot lesions in cattle in Colombia and worldwide. Our results suggest that there is need for additional prospective research under Colombian dairy cattle management conditions to better understand the lameness and benefit of trimming intervention. PMID- 29982911 TI - A review on ambulance offload delay literature. AB - Ambulance offload delay (AOD) occurs when care of incoming ambulance patients cannot be transferred immediately from paramedics to staff in a hospital emergency department (ED). This is typically due to emergency department congestion. This problem has become a significant concern for many health care providers and has attracted the attention of many researchers and practitioners. This article reviews literature which addresses the ambulance offload delay problem. The review is organized by the following topics: improved understanding and assessment of the problem, analysis of the root causes and impacts of the problem, and development and evaluation of interventions. The review found that many researchers have investigated areas of emergency department crowding and ambulance diversion; however, research focused solely on the ambulance offload delay problem is limited. Of the 137 articles reviewed, 28 articles were identified which studied the causes of ambulance offload delay, 14 articles studied its effects, and 89 articles studied proposed solutions (of which, 58 articles studied ambulance diversion and 31 articles studied other interventions). A common theme found throughout the reviewed articles was that this problem includes clinical, operational, and administrative perspectives, and therefore must be addressed in a system-wide manner to be mitigated. The most common intervention type was ambulance diversion. Yet, it yields controversial results. A number of recommendations are made with respect to future research in this area. These include conducting system-wide mitigation intervention, addressing root causes of ED crowding and access block, and providing more operations research models to evaluate AOD mitigation interventions prior implementations. In addition, measurements of AOD should be improved to assess the size and magnitude of this problem more accurately. PMID- 29982912 TI - Interferon-stimulated genes: new platforms and computational approaches. AB - Interferon-stimulated genes (ISGs) are the effectors of interferon (IFN) actions and play major roles in innate immune defense against microbial infection. During virus infection, ISGs impart antiviral actions to control virus replication and spread but can also contribute to disease pathology if their expression is unchecked. Antiviral ISGs have been identified by a variety of biochemical, genetic, and virologic methods. New computational approaches are expanding and redefining ISGs as responders to a variety of stimuli beyond IFNs, including virus infection, stress, and other events that induce cytokines. These studies reveal that the expression of ISG subsets link to interferon regulatory factors (IRF)s, NF-kB, and other transcription factors that impart gene expression in specific cell types independently of IFNs, including stem cells and other cell types where ISGs are constitutively expressed. Here, we provide a broad overview of ISGs, define virus-induced genes (VSG)s, and discuss the application of computational approaches and bioinformatics platforms to evaluate the functional role of ISGs in epigenetics, immune programming, and vaccine responses. PMID- 29982913 TI - Development and effect of antibodies to anakinra during treatment of severe CAPS: sub-analysis of a long-term safety and efficacy study. AB - Anakinra is an effective, well-tolerated, long-term anti-inflammatory treatment for cryopyrin-associated periodic syndromes (CAPS), yet evidence shows that it can induce the development of anti-drug antibodies (ADA). This analysis aims to determine ADA occurrence in CAPS patients and elucidate their effects on anakinra dosing and drug efficacy. A post hoc analysis was performed on data from a long term safety and efficacy study in patients with severe CAPS. Patients were initiated on an anakinra dose of 1.0-2.4 mg/kg once daily subcutaneously, which was increased (in 0.5-1.0 mg/kg increments) to 2.0-5.0 mg/kg/day according to clinical need (median 3.1 mg/kg/day). ADA, serum amyloid A (SAA), and C-reactive protein (CRP) levels were measured at various time points, and pharmacokinetic (PK) parameters at 1 and 3 months. Efficacy was evaluated using a diary symptom sum score (DSSS), and SAA and CRP levels were evaluated as proxies of efficacy. Safety was evaluated by an analysis of adverse events (AEs). Anakinra dose levels were unrelated to ADA status. A high proportion of patients with at least one post-baseline assessment developed ADA (83%), the majority (79%) within 3 months. However, anakinra treatment markedly improved symptoms and was effective regardless of the presence of ADA; the annual rates of AEs were comparable between ADA-negative and ADA-positive patients. While ADA are likely to occur in CAPS patients treated with anakinra, our evidence shows that chronic daily subcutaneous treatment with anakinra is safe and effective regardless of the development and presence of ADA. PMID- 29982914 TI - Three-Year Outcomes of Aflibercept Treatment for Neovascular Age-Related Macular Degeneration: Evidence from a Clinical Setting. AB - INTRODUCTION: To report 3-year treatment outcomes with intravitreal aflibercept injections for neovascular age-related macular degeneration (nAMD) in routine clinical practice. METHODS: This was a retrospective, single-centre, non randomized interventional case series analysis. Data from treatment-naive patients with nAMD treated between 1 October 2013 and 31 February 2014 were included in the analysis. Data including age, gender, vision acuity (VA) measured on Early Treatment of Diabetic Retinopathy Study charts (ETDRS) and injection numbers were recorded. Spectral domain optical coherence tomography (SD-OCT) data including presence or absence of macular fluid and automated central subfield macular thickness (CSMT) at year 1, 2 and 3 were also recorded. RESULTS: Of the 157 eyes of 148 patients treated, data from 108 eyes of 102 patients were available at 3-year follow-up. The mean (+/- SD) age was 80.6 +/- 8.3 years with a mean of 154.5 +/- 5.4 weeks follow-up. The mean VA changed from 54.4 +/- 16 letters at baseline to 60.3 +/- 18.1 letters (VA gain 5.9 +/- 13.8 letter gain) at 1 year, to 60.8 +/- 17.4 letters (VA gain 6.4 +/- 14.9 letters) at 2 years and to 61.0 +/- 16.6 letters (VA gain 6.6 +/- 15.4 letters) at 3 years. The reduction in CSMT was 77.9 +/- 101.4 um with absence of macular fluid in 71% of eyes. The total mean number of injections was 15.9 +/- 6.1 at year 3. CONCLUSION: The results suggest that good long-term morphological and functional treatment outcomes can be achieved using aflibercept for nAMD in a clinical setting. PMID- 29982916 TI - Antioxidant activities of Moringa oleifera leaf extract against pendimethalin induced oxidative stress and genotoxicity in Nile tilapia, Oreochromis niloticus (L.). AB - To assess the ameliorative effects of Moringa oleifera (MO) leaf extract on haematological and biochemical changes, liver DNA damage and oxidative stress biomarkers in Nile tilapia (Oreochromis niloticus) exposed to a sublethal concentration (0.52 mg/l) of pendimethalin (PM). Tilapia fish were allocated into four equal groups in tri-replicates as follows: first group was the control group, second group was treated with MO (20 ml/30 l water), third group was exposed to 0.52 mg PM/l and fourth group was exposed to 0.52 mg PM/l and treated with MO leaf extract (20 ml/30 l water) for 28 days. At the end of this period, blood and liver tissue samples were collected and haematological and biochemical changes, hepatic DNA fragmentation and oxidative stress biomarkers were analysed. Pendimethalin caused significant reduction in haematological profile [White blood cells (WBCs) and red blood cells (RBCs) counts, haemoglobin (Hb) concentration and haematocrit (Ht) level]; meanwhile, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, uric acid, glucose, cortisol, cholesterol and lactate dehydrogenase (LDH) were significantly increased. On the other hand, serum total protein, albumin, globulin and acetylcholinesterase (AChE) were decreased. Significant reduction in hepatic superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC) and glutathione peroxidase (GSH-Px) levels and marked increments of hepatic malondialdehyde (MDA) and DNA fragmentation were observed in PM-exposed fish compared to the control group. The addition of Moringa oleifera leaf extract into the water could overcome the negative impacts of pendimethalin and normalise the examined parameters nearly to the control values. Moringa oleifera was used for the first time to protect tilapia fish against PM-induced toxicity. The present study revealed that Moringa oleifera has potent antioxidant and antigenotoxic actions against pendimethalin toxicity. PMID- 29982915 TI - Impact of Energy Drinks on Health and Well-being. AB - PURPOSE OF REVIEW: Energy drinks and energy shots are functional supplements with higher caffeine content marketed toward adolescents and young adults with the intention of boosting energy. Parallel to its rising popularity, there are safety concerns with the consumption of these beverages. Herein, we reviewed the impact these supplements produce on health and well-being. RECENT FINDINGS: Most of the promoted benefits of the beverages can be attributed to caffeine. The physiologic effects, if any, of other ingredients such as vitamins and herbal extracts are unclear. The presence of a higher caffeine content as compared to soft drinks may predispose to caffeine intoxication in susceptible individuals. Also, the practice of co-ingestion of these beverages with alcohol is still prevalent and associated with serious consequences. Strict regulations (restriction of sales, clear warning labels, capping caffeine levels) and public education may help prevent the adverse outcomes from these beverages. PMID- 29982918 TI - Correction to: Two class I genes of the chicken MHC have different functions: BF1 is recognized by NK cells while BF2 is recognized by CTLs. AB - The Figure 3 in the original version of this article was incorrectly published. In this article the top panel of Figure 3 that describes the amino acid sequence alignment is now added. The original article has been corrected. PMID- 29982917 TI - Complex Spike Wars: a New Hope. AB - The climbing fiber-Purkinje cell circuit is one of the most powerful and highly conserved in the central nervous system. Climbing fibers exert a powerful excitatory action that results in a complex spike in Purkinje cells and normal functioning of the cerebellum depends on the integrity of climbing fiber-Purkinje cell synapse. Over the last 50 years, multiple hypotheses have been put forward on the role of the climbing fibers and complex spikes in cerebellar information processing and motor control. Central to these theories is the nature of the interaction between the low-frequency complex spike discharge and the high frequency simple spike firing of Purkinje cells. This review examines the major hypotheses surrounding the action of the climbing fiber-Purkinje cell projection, discussing both supporting and conflicting findings. The review describes newer findings establishing that climbing fibers and complex spikes provide predictive signals about movement parameters and that climbing fiber input controls the encoding of behavioral information in the simple spike firing of Purkinje cells. Finally, we propose the dynamic encoding hypothesis for complex spike function that strives to integrate established and newer findings. PMID- 29982919 TI - Denoising of 3D magnetic resonance images with multi-channel residual learning of convolutional neural network. AB - PURPOSE: To test if the proposed deep learning based denoising method denoising convolutional neural networks (DnCNN) with residual learning and multi-channel strategy can denoise three dimensional MR images with Rician noise robustly. MATERIALS AND METHODS: Multi-channel DnCNN (MCDnCNN) method with two training strategies was developed to denoise MR images with and without a specific noise level, respectively. To evaluate our method, three datasets from two public data sources of IXI dataset and Brainweb, including T1 weighted MR images acquired at 1.5 and 3 T as well as MR images simulated with a widely used MR simulator, were randomly selected and artificially added with different noise levels ranging from 1 to 15%. For comparison, four other state-of-the-art denoising methods were also tested using these datasets. RESULTS: In terms of the highest peak-signal-to noise-ratio and global of structure similarity index, our proposed MCDnCNN model for a specific noise level showed the most robust denoising performance in all three datasets. Next to that, our general noise-applicable model also performed better than the rest four methods in two datasets. Furthermore, our training model showed good general applicability. CONCLUSION: Our proposed MCDnCNN model has been demonstrated to robustly denoise three dimensional MR images with Rician noise. PMID- 29982920 TI - Speciated VOCs emission estimate for a typical petrochemical manufacturing plant in China using inverse-dispersion calculation method. AB - Volatile organic compounds (VOCs) play a key role in air pollution of China. Among various sources, petrochemical industry is one of the important contributors, but its VOC emission estimate still exists a big uncertainty. Therefore, this study developed an inverse-dispersion calculation method (IDM), and applied it in a typical petrochemical plant that manufactures ethylene (170 kt/year), polyethylene (100 kt/year), and polypropylene (61 kt/year), and determined the VOC emission amount for this complex industrial area source. Firstly, this study monitored VOC concentrations around this plant in April of 2017, and found that the VOCs at downwind receptors was obviously higher than the level at background, higher by 20.7 ppb on average. This VOC increment was mainly contributed by ethylene (30.4%), propylene (17.8%), pentanes (16.4%), and butanes (13.4%), which is consistent with the knowledge of VOC components emitted from the manufacturing of ethylene, polyethylene, and polypropylene. Then, by using the inverse-dispersion calculation method (IDM), we determined the relationship coefficient gamma between source emission rate and ambient concentration for each receptor of each test based on an assumed source emission rate, combined gamma with the actual VOC concentrations measured in monitoring tests, and estimated the average VOCs emission of 666.0 tons/year for this plant, including 18.1 tons for ethane, 21.1 tons for propane, 61.6 tons for isobutane, 44.3 tons for n butane, 79.3 tons for isopentane, 56.8 tons for n-pentane, 115.4 tons for ethylene, 102.5 tons for propylene, 92.7 tons for benzene, and 74.1 tons for toluene. Our IDM estimate was in the same order with the traditional emission factor method estimate (916.4 tons VOCs per year for this plant), and we believed the IDM can be applied to effectively estimate the VOCs emissions for those complicated industrial sources. PMID- 29982921 TI - What stops practitioners discussing medication breaks in children and adolescents with ADHD? Identifying barriers through theory-driven qualitative research. AB - National and international guidelines on the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents call for annual reviews to assess continuing need for medication by considering brief periods without medication, referred to as 'Drug holidays'. However, drug holidays are reactively initiated by families, or recommended by practitioners if growth has been suppressed by medication rather than proactively to check the need. There is little evidence of planned, practitioner-initiated drug holidays from methylphenidate. The aim of this study was to identify what stops practitioners from routinely discussing planned drug holidays from methylphenidate with children, adolescents, and their parents. Practitioners involved in shared-care prescribing for children and adolescents with ADHD in one UK County were included. Interviews with 8 general practitioners (GPs) and 8 Child and Adolescent Mental Health Service (CAMHS) practitioners were conducted. Transcripts were analysed qualitatively against the components of the Capability Opportunity-Motivation-Behaviour (COM-B) model. Possible interventions for increasing prescribers' engagement with planned drug holidays were considered in response. Multiple barriers to practitioner engagement in planned drug holidays from methylphenidate were identified. Capability, in terms of knowledge and skills, was not a barrier identified for CAMHS practitioners but was for GPs. Opportunity was a main barrier for both groups, who reported lack of time and the absence of educational material about drug holidays. Motivation was more complex to define, with CAMHS practitioners questioning the need for drug holidays and GPs being more accepting due to worries about long-term medication side effects as well as cost savings. 'Education' and 'enablement' interventions were identified as key activities targeting all three components, which could feasibly increase uptake of practitioner-initiated planned drug holidays from methylphenidate. The application of the COM-B system identified a number of key barriers to practitioner engagement with drug holidays in children and adolescents with ADHD. Accordingly, a number of interventions could be developed to facilitate change. For example, educating and training GPs about ADHD management and drug holidays, and developing a decision aid to help families make informed decisions about whether or not to implement drug holidays could be used. PMID- 29982923 TI - Production and properties of bacterial cellulose by the strain Komagataeibacter xylinus B-12068. AB - A strain of acetic acid bacteria, Komagataeibacter xylinus B-12068, was studied as a source for bacterial cellulose (BC) production. The effects of cultivation conditions (carbon sources, temperature, and pH) on BC production and properties were studied in surface and submerged cultures. Glucose was found to be the best substrate for BC production among the sugars tested; ethanol concentration of 3% (w/v) enhanced the productivity of BC. Optimization of medium and cultivation conditions ensures a high production of BC on glucose and glycerol, up to 2.4 and 3.3 g/L/day, respectively. C/N elemental analysis, emission spectrometry, SEM, DTA, and X-ray were used to investigate the structure and physical and mechanical properties of the BC produced under different conditions. MTT assay and SEM showed that native cellulose membrane did not cause cytotoxicity upon direct contact with NIH 3T3 mouse fibroblast cells and was highly biocompatible. PMID- 29982924 TI - Progress in the gut microbiota in exploring shrimp disease pathogenesis and incidence. AB - It is now recognized that gut microbiota contributes indispensable roles in safeguarding host health. Shrimp is being threatened by newly emerging diseases globally; thus, understanding the driving factors that govern its gut microbiota would facilitate an initial step to reestablish and maintain a "healthy" gut microbiota. This review summarizes the factors that assemble the shrimp gut microbiota, which focuses on the current progresses of knowledge linking the gut microbiota and shrimp health status. In particular, I propose the exploration of shrimp disease pathogenesis and incidence based on the interplay between dysbiosis in the gut microbiota and disease severity. An updated research on shrimp disease toward an ecological perspective is discussed, including host bacterial colonization, identification of polymicrobial pathogens and diagnosing disease incidence. Further, a simple conceptual model is offered to summarize the interplay among the gut microbiota, external factors, and shrimp disease. Finally, based on the review, current limitations are raised and future studies directed at solving these concerns are proposed. This review is timely given the increased interest in the role of gut microbiota in disease pathogenesis and the advent of novel diagnosis strategies. PMID- 29982922 TI - Inhibition of alpha-ketoglutarate dehydrogenase activity affects adventitious root growth in poplar via changes in GABA shunt. AB - MAIN CONCLUSION: Blocking alpha-ketoglutarate dehydrogenase results in up regulation of gamma-aminobutyric acid (GABA) shunt activity, and inhibits the growth of poplar adventitious roots (ARs), indicating that AR growth is closely associated with GABA shunt. gamma-Aminobutyric acid (GABA) shunt starts from alpha-ketoglutarate in the tricarboxylic acid cycle, which is thought to represent the cross road between carbon and nitrogen metabolism. Previous studies (Araujo et al. 2012b, Plant Cell 24: 2328-2351) have shown that blocking alpha ketoglutarate dehydrogenase (alpha-KGDH) affects the GABA shunt activity, and inhibits growth. However, its effects on the growth of adventitious roots (ARs) are unclear. In this study, the growth of ARs in tissue-cultured 84K poplar (Populus alba * Populus glandulosa cv. '84K') was significantly inhibited when succinyl phosphate (SP), a specific inhibitor of alpha-KGDH, was supplied. The inhibition of ARs was associated with significant changes in the levels of soluble sugars, organic acids, and amino acids, and was coupled with the up regulation of the GABA shunt activity at the transcriptional and translational levels. Exogenous GABA also inhibited AR growth following the increase of the endogenous GABA level. Transcriptomic analyses further showed that genes related to cell wall carbon metabolism and phytohormone (indoleacetic acid, ABA, and ethylene) signaling were affected by the changes of GABA shunt activity, resulting from the alpha-KGDH inhibition. Thus, our study indicates that the inhibition of poplar AR growth by blocking alpha-KGDH is closely associated with GABA shunt, which would benefit a better understanding of GABA's roles in plant development and stress response. PMID- 29982925 TI - Consortia of cyanobacteria/microalgae and bacteria in desert soils: an underexplored microbiota. AB - Desert ecosystem is generally considered as a lifeless habitat with extreme environmental conditions although it is colonized by extremophilic microorganisms. Cyanobacteria, microalgae, and bacteria in these habitats could tolerate harsh and rapidly fluctuating environmental conditions, intense ultraviolet radiation, and lack of water, leading to cell desiccation. They possess valuable metabolites withstanding extreme environmental conditions and make them good candidates for industrial applications. Moreover, most natural microorganisms in these extreme habitats exist as consortia that provide robustness and extensive metabolic capabilities enabling them to establish important relationships in desert environments. Engineering of such consortia of cyanobacteria, microalgae, and bacteria would be functional in the sustainable development of deserts through improving soil fertility, water preservation, primary production, pollutant removal, and maintaining soil stability. Modern tools and techniques would help in constructing highly functional cyanobacterial/microalgal-bacterial consortia that are greatly useful in the establishment of vegetation in deserts as well as in biotechnological applications. PMID- 29982926 TI - Plantaricin NC8 from Lactobacillus plantarum causes cell membrane disruption to Micrococcus luteus without targeting lipid II. AB - Plantaricin NC8, a two-peptide non-lantibiotic class IIb bacteriocin composed of PLNC8alpha and PLNC8beta and derived from Lactobacillus plantarum ZJ316, has been shown to be highly potent against a range of bacteria and fungi. In this study, we assessed the antimicrobial mechanism of plantaricin NC8 against the most sensitive bacterial strain, Micrococcus luteus CGMCC 1.193. The results showed that plantaricin NC8 induced membrane permeabilization and caused cell membrane disruption to M. luteus CGMCC 1.193 cells, as evidenced by electrolyte efflux, loss of proton motive force, and ATP depletion within a few minutes of plantaricin NC8 treatment. Furthermore, scanning and transmission electron microscopy showed that plantaricin NC8 had a drastic impact on the structure and integrity of M. luteus CGMCC 1.193 cells. In addition, we found that either PLNC8alpha or PLNC8beta alone exhibited membrane permeabilization activity, but that PLNC8beta had higher permeabilization activity, and their individual effects were not as strong as that of the combined compounds as plantaricin NC8. Finally, we showed that lipid II is not the specific target of plantaricin NC8 against M. luteus CGMCC 1.193. Our study reveals the antimicrobial mechanism of plantaricin NC8 against M. luteus CGMCC 1.193. PMID- 29982927 TI - Harnessing fungi to mitigate CH4 in natural and engineered systems. AB - Methane (CH4) is a powerful greenhouse gas emitted from natural and anthropogenic sources, and its emission rates vary among sources as a function of environment, microbial respiration, and feedbacks. Biological CH4 flux from natural and engineered systems is typically represented simply as generation of CH4 by methanogens minus oxidation by methanotrophs. In many cases, however, CH4 flux is modulated by transport and solubility mechanisms that occur before oxidation or other chemical transformation. The ability of fungi to directly oxidize CH4 remains unclear; however, their hydrophobic growths extending above microbial biofilms can improve surface area and sorption of hydrophobic gases. This can improve overall oxidation rates in a biofilm simply by improving phase transfer dynamics and bioavailability to bacterial or archaeal associates. This indirect facilitation is not necessarily intuitive, but there has been a recent emerging interest in harnessing these fungal abilities in engineering bioreactors and filtration systems designed to capture and oxidize CH4. These dynamics may be playing a similar facilitative role in natural CH4 oxidation, where fungi may indirectly influence carbon mineralization and methanogen/methanotroph communities, and/or directly oxidize and dissolve gaseous CH4. This review highlights these unique roles for fungi in determining net CH4 oxidation rates, and it summarizes the potential to harness fungi to mitigate CH4 emissions. PMID- 29982928 TI - A microbial community snapshot of windrows from a commercial composting facility. AB - The effect of depth on compost microbial communities is unclear but could be relevant to the management of windrows at commercial facilities. DNA extracted from 64 compost samples from seven windrows at a commercial facility were analyzed via deep 16S rRNA gene sequencing. The relative abundance of eight to nine genera was affected by depth during the transition from cooling to maturation phases between 4 and 6 months, whereas very few genera (0-1) showed a depth dependence in young, actively managed windrows or in mature windrows older than 10 months. Seven novel bacterial operational taxonomic units (OTUs) were detected in compost DNA and also in publicly available compost metagenomes. A compost metagenome was used to construct a metagenome-assembled genome for most of the abundant uncharacterized OTU in our samples and suggests its involvement in carbon cycling. PMID- 29982929 TI - Speciation analysis of Tl(I) and Tl(III) after magnetic solid phase extraction using a magnetite nanoparticle composite modified with aminodibenzo-18-crown-6 functionalized MIL-101(Cr). AB - The authors describe a magnetic metal-organic framework nanocomposite consisting of aminodibenzo-18-crown-6 magnetite nanoparticles and MIL-101(Cr). It was employed to the speciation analysis of Tl(I) and Tl(III) ions. The sorbent is capable of selectively extracting Tl(I) while Tl(III) remains in solution. The total amount of thallium was then determined by reducing Tl(III) to Tl(I) by hydroxylamine hydrochloride and also extracting it. The extraction parameters were optimized by employing design of experiments methodology. Thallium was quantified by ET-AAS. Under optimized conditions, the detection limit is as low as 1.5 ng L-1, the quantification limit is 5.0 ng L-1, the linear range extends from 5 to 400 ng L-1, and the relative standard deviation is <12% (for n = 5 at levels of 5, 50 and 250 ng L-1). The recoveries of real samples analysis were in the range of 90-106%. The method was successfully applied to the analysis of a certified reference material (NIST SRM 1643d water sample) and to various real water samples. Graphical abstract A novel metal-organic framework nanocomposite consisting of aminodibenzo-18-crwon-6 magnetite nanoparticles (Fe3O4@ADB18C6) and MIL-101(Cr) was synthesized, characterized and employed to speciation analysis of Tl(I) and Tl(III). PMID- 29982930 TI - Sustained release of basic fibroblast growth factor using gelatin hydrogel improved left ventricular function through the alteration of collagen subtype in a rat chronic myocardial infarction model. AB - OBJECTIVE: Chronic myocardial infarction (CMI) tends to be resistant to treatments possibly due to extensive solid fibrotic scar, hypoxia mediated by poorly vascularized environment, and/or inflammation and apoptosis. Here we aimed to testify the therapeutic effects of sustained release of basic fibroblast growth factor (bFGF) using gelatin hydrogel (GH) in a rat chronic MI model and to elucidate the therapeutic mechanism including the alteration of extracellular matrix component. METHODS: CMI model rats are prepared by the permanent ligation of proximal left anterior descending coronary artery. After 4 weeks, GH sheets (GHSs) with bFGF (100 ug) (bFGF group) or with phosphate-buffered saline (Vehicle group) were implanted to the CMI models to evaluate the effect of bFGF-GHS on chronic scar tissue. Sham operation group was also prepared (n = 5 for each). RESULTS: 4 weeks after implantation, bFGF-GHS significantly improved cardiac contractile function (fractional shortening: 21.8 +/- 1.1 vs 21.5 +/- 1.3 vs 29.7 +/- 1.8%; P < 0.001/fractional area change: 33.0 +/- 1.4 vs 34.1 +/- 2.3 vs 40.6 +/- 1.8%; P < 0.001) (Sham vs Vehicle vs bFGF) accompanied with neovascularization. Immunohistochemical studies revealed that bFGF-GHS increased collagen III/I ratio indicating the alteration of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I mRNA expression within border MI zone. CONCLUSIONS: The implantation of bFGF-GHS altered the collagen subtype of the fibrotic scar more suitable for tissue repair. The treatment of sustained release bFGF may be promising for ischemic heart disease through chronic pathology. PMID- 29982931 TI - Chiral and molecular recognition of monosaccharides by photoexcited tryptophan in cold gas-phase noncovalent complexes as a model for chemical evolution in interstellar molecular clouds. AB - Chiral and molecular recognition between amino acid and sugar molecules and their implications for chemical evolution were investigated using a tandem mass spectrometer equipped with an electrospray ionization source and a cold ion trap. Ultraviolet photodissociation of mass-selected and temperature-controlled gas phase noncovalent complexes of protonated tryptophan (Trp) and monosaccharide enantiomers, such as aldohexose, aldopentose, and deoxyhexose, was examined as a model for chemical evolution in interstellar molecular clouds. Upon photoexcitation of noncovalent heterochiral H+(L-Trp)(D-aldohexose) complexes, NH2CHCOOH loss from protonated Trp via Calpha-Cbeta bond cleavage occurred. Conversely, in homochiral H+(L-Trp)(L-aldohexose), the energy absorbed by Trp was released through the detachment of aldohexose, and dissociation of the amino acid was suppressed. In the photodissociation mass spectra of protonated Trp with aldopentose and deoxyhexose, which lacks the OH group of aldohexose, no dissociation of the molecules in the complexes or differences between enantiomers were observed. These results indicate that the OH groups in monosaccharides contribute to enantiomer-selective photodissociation in molecular clouds. The differences observed between enantiomers in the photodissociation mass spectra were applied to distinguishing and quantifying aldohexose enantiomers in solution using L-Trp as a chiral probe. The enantiomeric excesses of aldohexoses in solution could be determined from a single photodissociation mass spectrum by reference to the relative ion intensities for the NH2CHCOOH-elimination product and H+(L-Trp) formed via detachment of aldohexose. This analysis method could also distinguish and quantify two D-aldohexose mixtures, where L-Trp was employed as an isomer probe. Graphical abstract ?. PMID- 29982932 TI - Immunoassay and amperometric biosensor approaches for the detection of deltamethrin in seawater. AB - The study of an enzyme-linked immunosorbent assay (ELISA) and an amperometric biosensor for the detection of the pyrethroid deltamethrin in seawater is reported. The preparation of specific polyclonal antibodies is addressed using two immunizing haptens based on deltamethrin and cypermethrin compounds, with a spacer arm placed at the cyano residue in the pyrethroid structure. Different conjugates based on bovine serum albumin and aminodextran are prepared depending on the lipophilic profile of the competitor haptens studied. A reproducible and sensitive indirect competitive ELISA is developed, reaching a limit of detection of 1.2 +/- 0.04 MUg L-1 and an IC50 value of 21.4 +/- 0.3 MUg L-1 (both n = 3). For validation of the assays described, artificial seawater samples fortified with deltamethrin are analyzed. For the ELISA assay, these accuracy studies reported a slope of 0.904. An amperometric immunosensor is developed using the same immunoreagents and achieving a comparable detectability in terms of LOD of 4.7 MUg L-1, measuring seawater without any pretreatment. These results suggest that both techniques can be used as rapid and simple analytical methods for deltamethrin quantification in seawater samples, which are great candidates for initial environmental screening programs. Graphical abstract ?. PMID- 29982933 TI - Development of immunosorbents for the analysis of forchlorfenuron in fruit juices by ion mobility spectrometry. AB - The advantages of using smart materials as immunosorbents in the analysis of complex matrices by ion mobility spectrometry (IMS) have been highlighted in this study. A novel analytical method has been proposed for the sensitive, selective, and fast determination of residues of the plant growth regulator forchlorfenuron in fruit juices. Three different monoclonal antibodies (s3#22, p2#21, and p6#41) were employed for the production of immunosorbents, based on Sepharose gel beads, which were characterized in terms of loading capacity, solvent resistance, and repeatability for its use in solid-phase extraction (SPE). Immunosorbents that were prepared with antibody p6#44 provided the best performance, with a loading capacity of 0.97 MUg, a 10% (v/v) 2-propanol tolerance, and a reusability of at least eight uses. The SPE procedure involved the use of a column with 0.15 g Sepharose beads, containing 0.5 mg antibody, which was loaded to 20 mL of the sample, washed with 2 mL of water plus 2 mL of 10% (v/v) 2-propanol, and eluted with 2 mL of 2-propanol. The cleaned extract was directly analyzed by IMS, giving a limit of detection of 2 MUg L-1 with a relative standard deviation of 7.6%. Trueness was assessed by the analysis of blank grape and kiwifruit juice samples spiked with forchlorfenuron concentrations from 10 to 400 MUg L-1, with recoveries from 80 to 115%. The analytical performance of the proposed immunosorbent was compared with conventional extraction and cleanup methods, such as QuEChERS and C18-based SPE, giving the cleanest extracts for accurate determinations of forchlorfenuron by IMS. Graphical abstract ?. PMID- 29982934 TI - Isolation of transferrin by imprinted nanoparticles with magnetic deep eutectic solvents as monomer. AB - Transferrin (TrF) is a very important human body glycoprotein and a clinical biomarker which controls the body's iron ion channels and iron ion balance. Any change in TrF concentration and isoform also reflects the emergence of some diseases. In this work, we prepared magnetic molecularly imprinted nanoparticles (deep eutectic solvent-molecular imprinting polymers [DES-MIPs]) with a deep eutectic solvent (DES) as a functional monomer to separate TrF in human serum. The DES dosage for MIP, pH value, and time for adsorption have been optimized, and these materials show special adsorption properties for TrF. The maximum adsorption capacity (Qmax) and dissociation constant KL of the MIP by the Langmuir adsorption curve (R2 = 0.9949) were 37.5 mg/g and 0.015 g/L, respectively. The imprinting factor of the MIP is 3.50 with relative standard deviation (5.63%). In summary, the use of DES as a functional monomer in molecular imprinting technology provides a novel, efficient, and biocompatible method for the isolation and purification of proteins. Graphical abstract ?. PMID- 29982935 TI - Anaerococcus jeddahensis sp. nov., a New Bacterial Species Isolated From Healthy Nomadic Bedouin Woman From Saudi Arabia. AB - An understanding of the microbial diversity of the human body has generated significant interest in recent years. With the advent of MALDI-TOF mass spectrometry, high-speed sequencing, and the rebirth of microbial culture, knowledge of human microbiota is growing. Using culturomics, a strategy to explore the microbial diversity of samples, coupled with a taxono-genomic strategy, we isolated a new bacterium named Anaerococcus jeddahensis sp. nov. strain SB3T. This strain was isolated from the stool sample of a healthy nomadic Bedouin woman from Saudi Arabia. Here, we describe the characteristics of this organism, and the complete genome sequence and annotation. Strain SB3T is a Gram positive obligate anaerobic coccus which is non-motile and non-spore forming. Fatty acid analysis shows that the major fatty acid is by far hexadecanoic acid (C16:0; 52%). Its genome is 1,903,534 bp long and has 29.70 mol% of G+C content. It contains 1756 protein-coding genes and 53 RNA genes. These results show that strategy provides a better understanding of the microorganism and that is a good methodology for microbial identification and characterization. PMID- 29982936 TI - Primatology: the beginning. AB - The journal Primates was founded by Kinji Imanishi (1902-1992) in 1957: It is the oldest and longest-running international primatology journal in the world. In this series of dialogues between Tetsuro Matsuzawa, Editor-in-Chief of Primates and the General Director of the Japan Monkey Centre (JMC) and Juichi Yamagiwa, former Editor-in-Chief of Primates and the Museum Director of the JMC, we look back at the achievements of our spiritual ancestors in primate research and talk about the back story of Imanishi and his fellow primatologists: founding the JMC as a research institute focused on primates and launching this journal. What was their motivation? What challenges did they face? What is their continued influence on the field right up to the present? What will be the legacy of our influence on the discipline? PMID- 29982938 TI - Knowledge of Hepatitis C Risk Factors is Lower in High Incidence Regions. AB - Despite ambitious goals to eliminate hepatitis C virus (HCV) in the United States by 2030, the majority of those infected are not aware of their diagnosis, and only a small minority have been cured. A lack of knowledge regarding risk factors and treatment may contribute to low cure rates. We aimed to evaluate HCV knowledge and the association of risk factor knowledge with HCV incidence. In fall 2017, a survey regarding HCV knowledge was disseminated through social media, web link, and in person throughout the state of Virginia. The survey was completed by 613 individuals. Residents of high-incidence counties identified fewer risk factors (5.6 vs 6.1 of 9, p = 0.04), a difference that remained significant when controlling for education and age (p = 0.03). Fewer participants in the high-incidence group recognized snorting drugs to be a risk factor (25% vs 36%, p = 0.01). Only 38% of all respondents correctly identified HCV to be curable. Knowledge of HCV risk factors is lower in high incidence regions. These results identify a critical knowledge gap in the general population at a time of ongoing HCV transmission. Public health interventions must target these gaps in high-incidence regions as part of comprehensive disease prevention programs. PMID- 29982937 TI - Thalidomide remodels developing heart in chick embryo: discovery of a thalidomide mediated hematoma in heart muscle. AB - Despite of medical disaster caused by thalidomide in 1960s, the drug came to clinical use again for the treatment of erythema nodosum leprosum (ENL) and multiple myeloma. Recently, a new generation of children affected by thalidomide intake by their mothers during pregnancy has been identified in Brazil. In the past few years, there is the great enhancement in our understanding of the molecular mechanisms and targets of thalidomide with the help of modern OMICS technologies. However, understanding of cardiac-specific anomalies in fetus due to thalidomide intake by the respective mother has not been explored fully. At organ level, thalidomide causes congenital heart diseases, limb deformities in addition to ocular, and neural and ear abnormalities. The period of morning sickness and cardiogenesis is synchronized in pregnant women. Therefore, thalidomide intake during the first trimester could affect cardiogenesis severely. Thalidomide intake in pregnant women either causes miscarriage or heart abnormalities such as patent ductus arteriosus, ventricular septal defect (VSD), atrial septal defect (ASD), and pulmonary stenosis in survivors. In the present study, we identified a novel morphological defect (lump) in the heart of thalidomide-treated chick embryos. We characterized the lump at morphological, histo-pathological, oxidative stress, electro-physiological, and gene expression level. To our knowledge, here, we report the very first electrophysiological characterization of embryonic heart affected by thalidomide treatment. PMID- 29982939 TI - Leukocyte- and platelet-rich fibrin: a new graft material in endoscopic repair of spontaneous CSF leaks. AB - BACKGROUND: Spontaneous CSF leak is a challenging condition, with frequent recurrences following attempted surgical closure. The selection of graft materials depends on the experience of the operating surgeon. Leukocyte- and platelet-rich fibrin (L-PRF) is a second-generation platelet concentrate that has currently invaded every surgical specialty. To our knowledge, no previous reports about the use of L-PRF in repair of CSF leak were published. The study was conducted to assess the potential role of L-PRF in spontaneous CSF leaks repair. METHODS: This prospective controlled study was conducted on 40 patients who were randomly divided into 2 groups: In group A, L-PRF was used in addition to another layer, while patients in group B underwent multilayer repair using traditional graft materials. RESULTS: Preoperative HRCT scan showed bony dehiscence (n = 30) and opacity in a nearby sinus (n = 9). MRI findings varied between empty sella in 28 patients, and meningocele in 19 patients. Mean preoperatively measured CSF pressure was 26.6 cm H2O. Cribriform plate was identified as the commonest site of leaks. Multiple skull defects were detected in 2 cases. Failure of repair was found in 3 patients (15%) of group B and 1 patient (5%) of group A, this difference was statistically insignificant (P value = 0.28). Significance correlation between recurrence of CSF leak and elevated intracranial pressure was observed (P value; 0.04). CONCLUSION: L-PRF was found to be a good adjunct material in endoscopic spontaneous CSF leaks repair. It helps in decreasing the number of layers needed for defect closure. PMID- 29982940 TI - A fluorometric clenbuterol immunoassay based on the use of organic/inorganic hybrid nanoflowers modified with gold nanoclusters and artificial antigen. AB - Organic/inorganic hybrid nanoflowers were synthesized from calcium phosphate and protein modified fluorescent gold nanoclusters and antigens. These nanoflowers are shown to be well suited labels for bioassay because they fulfill the functions of biological recognition and signal output. A fluorometric immunoassay was developed that was combined with immunomagnetic separation. In the detection system, the red fluorescence of the supernatant (measured at excitation/emission wavelengths of 360/640 nm) is found to be proportional to the clenbuterol (Clen) concentration after two immunomagnetic separations. The assay has a linear response in the 0.5 MUg L-1 to 40 MUg L-1 Clen concentration range, and 0.167 MUg L-1 limit of detection. This makes it well suited for food safety monitoring. The average recoveries from spiked samples range from 92.7 to 109.1% (intra-assay) and 101.2 to 125.7% (inter-assay) with relative standard deviations of <11.6%. Spiked swine urine samples were analyzed by this method, and the results correlated well with data obtained by LC-MS/MS. Graphical abstract Fluorescent hybrid nanoflowers were fabricated with gold nanoclusters (BSA-AuNCs) and antigens. A fluorometric immunoassay based on the use of such nanoflowers and based on immunomagnetic separation was developed to detect clenbuterol residues in swine urine with satisfactory recoveries and acceptable accuracy. PMID- 29982941 TI - New challenges in the application of advanced oxidation processes. PMID- 29982942 TI - Enhanced degradation of isoproturon in soil through persulfate activation by Fe based layered double hydroxide: different reactive species comparing with activation by homogenous Fe(II). AB - Phenylurea herbicide residuals in soil may continuously contaminate surface water and groundwater due to unregulated and improper use. Herein, we reported a stable and active oxidation system including heterogeneous Fe-based layered double hydroxide materials as persulfate (PS) activators. Under mild conditions, 1% LDH in weight and 70 mM PS can completely degrade 500 mg/kg isoproturon in soil within 10 h, during which less than 0.1 ppm heavy metal leaching was detected. This remarkable performance was consistent in a broad pH range (3~11) and was resistant to various inorganic anions (Cl-, Br-, NO3-, HCO3-) and humic acid. Mechanism studies from scavenging tests, EPR, and fluorescence spectra collectively proved that besides *OH and *SO4-, singlet oxygen (1O2) and superoxide (*O2-) were also generated and were accounted for the oxidative degradation. This unique mechanism of generating diverse radicals was clearly distinguished from classic Fe(II)/PS system, significantly reduced the influence of varying parameters in water and soil matrix, and was suggestive to chemical oxidation system in soil remediation to avoid scavenging effects by background electrolytes or other components in water/soil matrix. Graphical abstract ?. PMID- 29982943 TI - Performance and recovery of a completely separated partial nitritation and anammox process treating phenol-containing wastewater. AB - Anammox process is considered as a promising technology for removing total nitrogen from low-strength ammonium and phenol-containing wastewater. However, it is still a challenge for the anammox process to treat high-strength ammonium and phenol-containing wastewater. A completely separated partial nitritation and anammox (CSPN/A) process was developed to remove total nitrogen from high strength phenol-containing wastewater. About 92% of COD, 100% of phenol, and 82.4% of total nitrogen were successfully removed at a NH4+-N concentration of 200 mg L-1 with a phenol/NH4+-N mass ratio of 0.5 in the CSPN/A process. Furthermore, a shock loading of 300 mg phenol L-1 with a phenol/NH4+-N mass ratio of 1.5 led to a complete failure of partial nitritation, but the performance was rapidly recovered by the increase of NH4+-N concentration. Although the activities of ammonium-oxidizing bacteria and anammox bacteria were severely inhibited at a phenol/NH4+-N mass ratio of 1.5, the enrichment of efficient phenol degraders in the CSPN stage could strengthen the performance robustness of partial nitritation and anammox process. Therefore, this study presented a new insight on the feasibility of the anammox process for treating high-strength ammonium and phenol-containing wastewater. PMID- 29982944 TI - Forecasting riverine total nitrogen loads using wavelet analysis and support vector regression combination model in an agricultural watershed. AB - In the context of non-point source pollution management and algal blooms control, the reliable nutrient forecasting is of critical importance. Considering the highly stochastic, non-linear, and non-stationary natures involved in riverine total nitrogen (TN) load time series data, some traditional statistical and artificial intelligence models are inherently unable to give accurate nutrient forecasts due to their mechanism and structure characteristics. In this study, based on the wavelet analysis (WA) and support vector regression (SVR), a promising combined WA-SVR model was proposed for forecasting riverine TN loads. The data pro-processing tool WA was employed to decompose the time series data of riverine TN load for revealing its dominator. Subsequently, all wavelet components were used as inputs to SVR for WA-SVR model. The continuous riverine TN loads during 2004-2012 in the ChangLe River watershed of eastern China were estimated by using a calibrated Load Estimator model. Performance criteria, namely, determination coefficient (R2), Nash-Sutcliffe model efficiency (NS), and mean square error (MSE) were applied to assess the performance of the developed models. The effects of different mother wavelets on the efficiency of the conjunction model were investigated. The results demonstrated that the mother wavelet played a crucial role for the successful implementation of the WA-SVR model. Among the 23 selected mother wavelet functions, dmey wavelet performed best in forecasting the daily and monthly TN loads. Furthermore, the performance of the optimal WA-SVR model was compared with that of single SVR model without wavelet decomposition. The comparison indicated that the hybrid model provided better accuracy than that of single SVR model. For daily riverine TN loads, the R2, NS, and MSE values of WA-SVR model during the test stage were 0.9699, 0.9658, and 0.4885 * 107 kg/day, respectively. For monthly riverine TN loads, the R2, NS, and MSE values of the model during the test stage were 0.9163, 0.9159, and 0.3237 * 1010 kg/month, respectively. The overall results strongly suggested that the combined WA-SVR method can successfully forecast riverine TN loads in agricultural watersheds. PMID- 29982945 TI - Fluoride removal studies using virgin and Ti (IV)-modified Musa paradisiaca (plantain pseudo-stem) carbons. AB - The preparation of carbons in virgin and Ti-modified forms under controlled conditions at low temperature from plantain pseudo-stem (Musa paradisiaca) was achieved. These prepared carbons were characterized for instrumental studies such as BET, FTIR, XRD, SEM with EDS and TGA to understand the chemistry and modification. The determination of IEP and pHZPC established the presence of positive surface sites on the virgin (VMPC) and Ti-modified (TiMPC) carbons to facilitate the sorption of fluoride. The fluoride removal efficiency as a function of time, pH, dose, initial fluoride concentration, temperature, and co ion intervention was studied. The maximum fluoride removal of about 81.2 and 97.7% was achievable with VMPC and TiMPC, respectively, after 20 min at the pH of 2.04 and continued for the equilibrium of 60 min. Temperature was found to be influential both by way of initial increase followed by a decrease in the fluoride uptake of MPCs. Regeneration was very consistent up to 7 cycles with the residual fluoride concentration below the WHO guide line of 1.5 mg L-1. Highest intervention due to hydrogen carbonate ions was observed during the fluoride removal process. Kinetic (pseudo-first-order, pseudo-second-order, and intra particle diffusion) and isotherm models (Langmuir, Freundlich, and DKR) were checked for their compliance with the present sorption system. These low temperature synthesized MPCs are found to be effective candidates in the process of fluoride abatement in water. PMID- 29982946 TI - Defining the effects of urban expansion on land use/cover change: a case study in Kastamonu, Turkey. AB - In addition to the growing world population, continuous migration from rural areas to city centers leads to rapid population growth in urban centers, bringing with it a change in land use/cover in those areas. This change usually manifests itself as an increase in artificial surfaces and a decrease in agricultural areas and forestlands. However, agricultural areas and forests in the vicinity of city centers contain sensitive ecosystems that require careful monitoring. It is crucial that the impact of population growth in the city centers on these areas is determined. This study aims to determine the changes in the land cover in Kastamonu city center between 1999 and 2014. As part of the study, changes in the population of the city center, as well as in the use of urban spaces within the past 15 years, were investigated to determine how population growth affected land use/cover. Changes in land use/cover were assessed under 12 classes with the use of remote sensing methods on stand-type maps created by the aerial photos. According to the results of the study, a 519.5-ha agricultural area and a 86-ha forest area became artificial surfaces in 1999 and 2014. PMID- 29982947 TI - Mental distress and sexual harassment in Italian university students. AB - Only a few studies have analyzed the association between sexual harassment (SH) and mental health controlling for other types of violence. The aim of this study was to describe SH among male and female university students and analyze the association between harassment and mental distress controlling for sexual violence. An observational survey was conducted at Trieste University (Italy). Students answered an anonymous questionnaire about harassment that included three domains-sexual harassment, gender harassment, cyber harassment-and three psychological health indicators. The global harassment index was computed, with three levels: 0, no harassment; level 1, harassment in at least one of the three domains; and level 2, harassment in two or three domains. The symptoms of mental distress were measured by the 12-item General Health Questionnaire (GHQ) for depressive symptoms; a question about panic symptoms; and a question about general health. The sample included 759 students (412 women; 18 to 29 years old). After adjustment for age, birth country, couple relationship, employment status, mother's education, and previous sexual violence, the risk of mental distress was increased with harassment exposure. Men were affected in perceived health and depressive symptoms (GHQ score >= 6); women were affected in panic symptoms. Harassment has a strong negative impact on the mental health of victims; in some cases, men may be more affected than women. Clinicians should be aware of the negative impact of SH also on men. PMID- 29982948 TI - Looking on the "brite" side exercise-induced browning of white adipose tissue. AB - The need for effective and convenient ways of combatting obesity has created great interest in brown adipose tissue (BAT). However, because adult humans have relatively little amounts of BAT, the possibility of browning white adipose tissue (WAT), i.e., switching the metabolism of WAT from an energy storing to energy burning organ, has gained considerable attention. Exercise has countless health benefits, and has consistently been shown to cause browning in rodent white adipose tissue. The purpose of this review is to provide an overview of recent studies examining the effects of exercise and other interventions on the browning of white adipose tissue. The role of various endocrine factors, including catecholamines, interleukin-6, irisin, and meteorin-like in addition to local re-esterification-mediated mechanisms in inducing the browning of WAT will be discussed. The physiological importance of browning will be discussed, as will discrepancies in the literature between human and rodent studies. PMID- 29982951 TI - Female genital cosmetic surgery: the good, the bad, and the ugly. PMID- 29982950 TI - Long-term endurance running activity causes pulmonary changes depending on the receptor for advanced glycation end-products. AB - The receptor for advanced glycation end-products (RAGE) is an immunoglobulin superfamily cell adhesion molecule predominantly expressed in the lung, but its pulmonary importance is incompletely understood. Since RAGE alters the respiratory mechanics, which is also challenged by endurance running activity, we studied the RAGE-dependent effect of higher running activity on selected lung parameters in a long-term animal model using wild-type (WT) and RAGE knockout (RAGE-KO) mice. Higher long-term running activity of mice was ensured by providing a running wheel for 8 months. Recording the running activity revealed that RAGE-KO mice are more active than WT mice. RAGE-KO caused an increased lung compliance which additionally increased after long-term running activity with minor limitation of the expiratory flow, whereas the respiratory mechanics of WT mice remained constant. Although RAGE-KO mice had a less dense alveolar-capillary barrier for immune cells, higher long-term running activity led only in WT mice to more leukocyte infiltrations in the lung tissue and aggregations of lymphoid cells in the airways. In this regard, WT mice of the activity group were also more sensitive to ventilation-mediated airway damages. In contrast to RAGE-KO mice of the activity group, lungs of WT mice did not show an increase in the cAMP response element-binding protein, a transcription factor regulating many pro survival genes. Our findings suggest an important role of RAGE in the physical capability due to its effect on the lung compliance as well as RAGE as a mediator of airway damages caused by higher long-term running activity. PMID- 29982952 TI - Assessment of the long-term outcome of TVT procedure for stress urinary incontinence in a female population: results at 17 years' follow-up. AB - INTRODUCTION AND HYPOTHESIS: To assess the outcome of the tension-free vaginal tape (TVT) procedure in female patients with urodynamic stress urinary incontinence at 17 years follow-up. METHODS: We carried out a prospective study at the 2nd Department of Obstetrics and Gynecology, Aretaieio Hospital, University of Athens, Greece. Patients who had undergone a TVT procedure 17 years ago. The follow-up assessment included gynecological examination, urinalysis, cough stress test in the lithotomy and/or upright position, filling and voiding cystometry, and uroflow. Also, all patients were required to complete the Patient Satisfaction Questionnaire (PSQ). RESULTS: Out of the 61 initial patients, 56 were available for follow-up. Objective cure rate was 83.9% (47/56) at 17 years follow-up. Subjective cure rate was 78.6% (44/56), subjective improvement was 8.9%, and failure rate was 12.5%. Frequency was present in 39.3% of patients, overactive bladder symptoms were present in 30.3% of patients and urge urinary incontinence was reported by 12.5% of patients. Difficulty emptying the bladder was reported by 10 patients (17.8%) and recurrent urinary tract infection was seen in 3.5% of patients. There was one case of TVT erosion to the vaginal mucosa, which was managed conservatively. CONCLUSIONS: The TVT procedure for the management of stress urinary incontinence in women maintains its efficacy in the long term, having an objective cure rate of 83.9% and a subjective cure rate of 78.6% at 17 years' follow-up, with a very low complications rate. PMID- 29982949 TI - Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective. AB - Cellular organelles form multiple junctional complexes with one another and the emerging research area dealing with such structures and their functions is undergoing explosive growth. A new research journal named "Contact" has been recently established to facilitate the development of this research field. The current consensus is to define an organellar junction by the maximal distance between the participating organelles; and the gap of 30 nm or less is considered appropriate for classifying such structures as junctions or membrane contact sites. Ideally, the organellar junction should have a functional significance, i.e. facilitate transfer of calcium, sterols, phospholipids, iron and possibly other substances between the organelles (Carrasco and Meyer in Annu Rev Biochem 80:973-1000, 2011; Csordas et al. in Trends Cell Biol 28:523-540, 2018; Phillips and Voeltz in Nat Rev Mol Cell Biol 17:69-82, 2016; Prinz in J Cell Biol 205:759 769, 2014). It is also important to note that the junction is not just a result of a random organelle collision but have active and specific formation, stabilisation and disassembly mechanisms. The nature of these mechanisms and their role in physiology/pathophysiology are the main focus of an emerging research field. In this review, we will briefly describe junctional complexes formed by cellular organelles and then focus on the junctional complexes that are formed by mitochondria with other organelles and the role of these complexes in regulating Ca2+ signalling. PMID- 29982953 TI - L-Homoarginine and its AGXT2-metabolite GOCA in chronic kidney disease as markers for clinical status and prognosis. AB - Plasma concentrations of L-homoarginine (hArg) are an emerging marker for clinical status and prognosis in renal and cardiovascular disease. Lowered hArg concentrations are associated with higher risk for these conditions, although a clear pathophysiological explanation for this association has not been established. Baseline plasma samples of patients with different stages of chronic kidney disease (CKD) (n = 527) were obtained from the CARE FOR HOMe study and were analyzed for hArg and, for the first time, its metabolite 6-guanidino-2 oxocaproic acid (GOCA) by isotope dilution LC-MS/MS methods. GOCA is converted from hArg by the enzyme alanine:glyoxylate aminotransferase 2 (AGXT2), which is also in the focus of current cardiovascular research. hArg levels ranged from 0.20-4.01 umol/L with a median of 1.42 umol/L, whereas GOCA levels were 0.08 25.82 nmol/L with a median of 1.45 nmol/L. hArg levels in the highest tertile (>= 1.71 umol/L) were associated with significantly lower risk for reaching the renal (hazard ratio 0.369, 95% confidence interval 0.028-0.655) or cardiovascular (HR 0.458, CI 0.295-0.712) endpoints in univariate Cox regression analysis. Inversely, GOCA levels in the highest tertile (>= 2.13 nmol/L) were associated with increased renal (HR 3.807, CI 1.963-7.381) and cardiovascular (HR 1.611, CI 1.041-2.495) risk. A decreased ratio between hArg and GOCA predicted even more pronounced the risks for renal (HR 0.178, CI 0.087-0.363) and cardiovascular (HR 0.447, CI 0.281-0.709) events. However, adjustment for the confounders eGFR and albuminuria attenuated these findings. A pathophysiological role of an increased activity of AGXT2 in CKD should be evaluated in future clinical studies. PMID- 29982955 TI - Can diffusion weighting replace gadolinium enhancement in magnetic resonance enterography for inflammatory bowel disease in children? AB - BACKGROUND: Contrast-enhanced MRI is often used for diagnosis and follow-up of children with inflammatory bowel disease. OBJECTIVE: To compare the accuracy of diffusion-weighted MRI (DWI) to contrast-enhanced MRI in children with known or suspected inflammatory bowel disease. MATERIALS AND METHODS: This retrospective, consecutive study included 55 children. We used ileo-colonoscopy and histology as the reference standard from the terminal ileum to the rectum, and contrast enhanced MRI as the reference standard proximal to the terminal ileum. DWI and contrast-enhanced MRI sequences were independently reviewed and compared per patient and per segment to these reference standards and to the follow-up for each child. RESULTS: We obtained endoscopic data for 340/385 colonic and ileal segments (88%). The rate of agreement per segment between DWI and endoscopy was 64%, and the rate of agreement between contrast-enhanced MRI and endoscopy was 59%. Per patient, sensitivity and specificity of bowel wall abnormalities as compared to the endoscopy were 87% and 100% for DWI, and 70% and 100% for contrast-enhanced MRI, respectively. Positive and negative predictive values were, respectively, 100% and 57% for DWI, and 96% and 41% for contrast-enhanced MRI. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of DWI compare to contrast-enhanced MRI in the segments proximal to the terminal ileum were 90%, 98%, 90%, 98% and 96%, respectively. CONCLUSION: The diagnostic performance of DWI is competitive to that of contrast enhanced MRI in children with known or suspected inflammatory bowel disease. PMID- 29982957 TI - The Development and Content of the Vocational Advice Intervention and Training Package for the Study of Work and Pain (SWAP) Trial (ISRCTN 52269669). AB - Purpose There are substantial costs associated with sickness absence and struggling at work however existing services in the UK are largely restricted to those absent from work for greater than 6 months. This paper details the development of an early Vocational Advice Intervention (VAI) for adult primary care consulters who were struggling at work or absent due to musculoskeletal pain, and the structure and content of the training and mentoring package developed to equip the Vocational Advisors (VAs) to deliver the VAI, as part of the Study of Work and Pain (SWAP) cluster randomised trial. Methods In order to develop the intervention, we conducted a best-evidence literature review, summarised evidence from developmental studies and consulted with stakeholders. Results A novel early access, brief VAI was developed consisting of case management and stepped care (three steps), using the Psychosocial Flags Framework to identify and overcome obstacles associated with the health-work interface. Four healthcare practitioners were recruited to deliver the VAI; three physiotherapists and one nurse (all vocational advice was actually delivered by the three physiotherapists). They received training in the VA role during a 4-day course, with a refresher day 3 months later, along with monthly group mentoring sessions. Conclusions The process of development was sufficient to develop the VAI and associated training package. The evidence underpinning the VAI was drawn from an international perspective and key components of the VAI have the potential to be applied to other settings or countries, although this has yet to be tested. PMID- 29982956 TI - Ultrasound assessment of pubertal breast development in girls: intra- and interobserver agreement. AB - BACKGROUND: Clinical assessment of pubertal breast development using Tanner staging is subjective. This has led to the introduction of ultrasound (US), aiming for a more objective analysis. However, information regarding its reliability is lacking. OBJECTIVE: To examine intra- and interobserver agreement of breast maturity staging using US and to examine the precision of direct measurements of the gland. MATERIALS AND METHODS: Fifty-seven healthy girls (mean age: 10.9 years, range: 6.1 to 15.9 years) were examined independently by two observers using US of the left breast to score the glandular maturity stage on a 0-5 scale, and to measure the depth and diameter. One observer repeated the examination after 20 to 35 min to assess intra-observer agreement. Cohen's kappa with linear weights was used to examine intra- and interobserver agreement of the US staging, while the measurement precision was analyzed using Bland-Altman plots and 95% limits of agreement. RESULTS: The agreement of US staging on a 0-5 scale was very good (kappa 0.84; 95% confidence interval [CI] 0.78-0.91) for intra observer observation and good (kappa 0.71; 95% CI 0.62-0.80) for interobserver observation. Measurements of glandular depth and diameter were unbiased for a single observer, but the variances were large both within and between observers. CONCLUSION: US using a scale from 0 to 5 is a reliable method to stage the development of glandular breast tissue during puberty in healthy girls. Measurements of glandular depth and diameter were found to be imprecise. PMID- 29982958 TI - Genetic features of Pseudomonas aeruginosa isolates associated with eye infections referred to Farabi Hospital, Tehran, Iran. AB - BACKGROUND: Pseudomonas is the most common cause of microbial keratitis especially in people who use contact lens. The virulence of Pseudomonas aeruginosa in different eye infections is associated with different virulence factors . METHODS: In this study, 54 P. aeruginosa isolates including 39 isolates from keratitis and 15 isolates from conjunctivitis were evaluated for their ability to form biofilm, production of protease, elastase, alkaline protease and their antibiotic-resistant patterns. The distribution of the exoS and exoU genes in the test strains were determined using PCR assays. RESULTS: Most of the eye infections (90.74%) were seen in people who used contact lenses, and in most of patients (72.22%), the infection was presented as keratitis. None of the isolates were resistant to a single antibiotic as tested. Multidrug resistance (MDR) was detected in two isolates (3.5%) which were resistant to more than one category of antibiotics. The exoU+/exoS+ isolates were in majority although in total, compared to exoS, there were more exoU in a greater number of samples. Most of the strains produce elastase but among all of ocular isolates, only 5.8% of the strains showed alkaline protease activity. Most of the ocular isolates were not capable of producing biofilm. CONCLUSIONS: In our study, a high prevalence of virulence factors was observed in P. aeruginosa isolates from contact lens wearer with keratitis. As the P. aeruginosa isolates from different infection origins and different geographic region may have different virulence factors, having a better perception of these differences could help to improve development of clinical instructions for the control of keratitis. PMID- 29982959 TI - Survival outcomes of locally advanced prostate cancer in patients aged < 50 years after local therapy in the contemporary US population. AB - PURPOSE: To assess survival outcomes of locally advanced prostate cancer (LAPC) in patients aged < 50 years after local therapy (LT), as compared to that in the older patients (>= 50 years). Moreover, effectiveness of postoperative radiation therapy (PRT) after radical prostatectomy (RP) was also assessed in patients aged < 50 years. METHODS: Within the Surveillance, Epidemiology, and End results database (2004-2014), non-metastatic cT3-4 LAPC patients treated with LT (RP, RT or RP+RT) were identified. After propensity score matching (PSM), cancer-specific mortality (CSM), overall survival (OS), and other-cause mortality (OCM) rates were assessed. Multivariable competing risk regression (MVA CRR) model was also used in our analysis. RESULTS: 1507 younger (< 50 years) and 34833 older (>= 50 years) LAPC patients treated with LT were identified. Younger patients with LAPC had overall more aggressive disease features than their older counterparts. After PSM, younger patients yielded higher cumulative CSM rates than the older patients (P = 0.046). However, OS and cumulative OCM rates were significantly higher (P = 0.038 and P < 0.0001, respectively) in the older cohort. In the MVA CRR model, younger patients yielded higher CSM (P = 0.02). Specifically, younger patients resulted in higher CSM in Gleason score 8-10, cT3b/4 stage, cN1 stage, and patients treated with RP. No statistically significant differences were found in patients treated with RP versus RP+PRT in all parameters. CONCLUSIONS: LAPC patients aged < 50 years yielded higher CSM after LT, specifically after RP, compared with the older counterparts (>= 50 years). No significant differences were observed in RP versus RP+PRT regarding survival outcomes in our analysis. PMID- 29982960 TI - Assessment of boundary conditions for CFD simulation in human carotid artery. AB - Computational fluid dynamics (CFD) is an increasingly used method for investigation of hemodynamic parameters and their alterations under pathological conditions, which are important indicators for diagnosis of cardiovascular disease. In hemodynamic simulation models, the employment of appropriate boundary conditions (BCs) determines the computational accuracy of the CFD simulation in comparison with pressure and velocity measurements. In this study, we have first assessed the influence of inlet boundary conditions on hemodynamic CFD simulations. We selected two typical patients suspected of carotid artery disease, with mild stenosis and severe stenosis. Both patients underwent digital subtraction angiography (DSA), magnetic resonance angiography, and the invasive pressure guide wire measured pressure profile. We have performed computational experiments to (1) study the hemodynamic simulation outcomes of distributions of wall shear stress, pressure, pressure gradient and (2) determine the differences in hemodynamic performances caused by inlet BCs derived from DSA and Womersley analytical solution. Our study has found that the difference is related to the severity of the stenosis; the greater the stenosis, the more the difference ensues. Further, in our study, the two typical subjects with invasively measured pressure profile and thirty subjects with ultrasound Doppler velocimeter (UDV) measurement served as the criteria to evaluate the hemodynamic outcomes of wall shear stress, pressure, pressure gradient and velocity due to different outlet BCs based on the Windkessel model, structured-tree model, and fully developed flow model. According to the pressure profiles, the fully developed model appeared to have more fluctuations compared with the other two models. The Windkessel model had more singularities before convergence. The three outlet BCs models also showed good correlation with the UDV measurement, while the Windkessel model appeared to be slightly better ([Formula: see text]). The structured-tree model was seen to have the best performance in terms of available computational cost and accuracy. The results of our numerical simulation and the good correlation with the computed pressure and velocity with their measurements have highlighted the effectiveness of CFD simulation in patient-specific human carotid artery with suspected stenosis. PMID- 29982961 TI - Enzyme-linked immunosorbent assay and agar gel immunodiffusion assay for diagnosis of equine infectious anemia employing p26 protein fused to the maltose binding protein. AB - A codon-optimized equine infectious anemia virus p26 gene was fused to a maltose binding protein (MBP) and expressed in Escherichia coli for use as an antigen in agar gel immunodiffusion (AGID) and enzyme-linked immunosorbent assay (ELISA) for diagnosis of equine infectious anemia. An analysis of analytical sensitivity and specificity showed that the antigen MBP-p26rec reacted positively with a reference World Organization for Animal Health serum and demonstrated no cross reaction against sera from vaccinated animals in either test. The diagnostic characteristics were evaluated and presented excellent values. The AGIDrec showed 100% sensitivity and specificity, and the ELISArec showed 100% sensitivity and 99.64% specificity. In addition, MBP-p26rec was stabile after three years of storage at 4 degrees C, maintaining its immunoreactivity. PMID- 29982962 TI - Novel Anti-arthritic Mechanisms of Polydatin in Complete Freund's Adjuvant Induced Arthritis in Rats: Involvement of IL-6, STAT-3, IL-17, and NF-kB. AB - Articular manifestations are the main hall mark for rheumatoid arthritis; inflammation and oxidative stress are involved in its pathogenesis. This study was designed to figure out the possible therapeutic potential of polydatin on experimentally induced arthritis in rats. Polydatin (POLY) was administered (200 mg/kg, p.o.) for 21 days to complete Freund's adjuvant (CFA; 0.1 ml, s.c.) induced arthritic rats. Meanwhile, methotrexate (MTX; 0.75 mg/kg, i.p.) was given as a reference standard disease-modifying anti-rheumatic drug (DMARD). Both POLY and MTX significantly attenuated articular damage associated with CFA-induced arthritis. This was manifested by reducing levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-17 (IL-17), and matrix metalloproteinase-3 (MMP-3), paralleled with marked decrease in hind paw and ankle diameters. Moreover, POLY and MTX downregulated gene expressions of receptor activator of nuclear factor kappa-B ligand (RANKL) as well as signal transducer and activator of transcription-3 (STAT3) besides hampering immunohistochemical staining of vascular endothelial growth factor (VEGF) and nuclear factor kappa-B (NF-kappaB). Furthermore, substantial decline in myeloperoxidase (MPO) activity and malondialdehyde (MDA) level associated with significant rise in reduced glutathione content (GSH) was observed. These findings provide an innovative therapeutic approach of POLY as a natural anti arthritic drug through modulating IL-6/STAT-3/IL-17/NF-kB cascade. Graphical Abstract ?. PMID- 29982963 TI - Gracilis muscle transposition for the treatment of recurrent rectovaginal and pouch-vaginal fistula: is Crohn's disease a risk factor for failure? A prospective cohort study. AB - BACKGROUND: The surgical management of rectovaginal fistulae associated with Crohn's disease is often frustrated by poor results regardless of the different techniques. The outcomes of the gracilis muscle transposition (GMT) for the treatment of recurrent Crohn's-associated fistulae are still debated. The aim of the study is to determine whether the success rate of GMT is similar in Crohn's disease patients and in a control group. MATERIALS AND METHODS: All patients undergoing GMT for rectovaginal or pouch-vaginal fistula were collected from a prospectively maintained database (2005-2016). The primary study outcome was the comparison of the success rate of GMT in Crohn's disease and control group patients. RESULTS: Twenty-one patients with a rectovaginal fistula due to Crohn's disease (8, 38.1%) or other etiologies (13, 61.9%) were included. The groups had similar characteristics and postoperative outcomes. After a median follow-up time of 81 and 57 months (p 0.34), the success rate of GMT was 75% in patients with Crohn's disease and 68.4% in control group (p 0.6). The median time to recurrence was 3.5 months (1-12). The success rate in patients who had more than two previous attempts of repair was lower regardless of the etiology (50 vs 79.4%, p 0.1). CONCLUSION: GMT is associated with a high success rate, especially in Crohn's disease-related rectovaginal fistula. In consideration of the low morbidity rate and the fact that an increasing number of previous local operations might be associated with failure, the procedure should be considered as a first line of treatment for recurrent rectovaginal fistulae. PMID- 29982965 TI - Adipose Tissue Expression of PACAP, VIP, and Their Receptors in Response to Cold Stress. AB - Obesity arises from disrupted energy balance and is caused by chronically higher energy intake compared to expenditure via basal metabolic rate, exercise, and thermogenesis. The brown adipose tissue (BAT), the primary thermogenic organ, has received considerable attention as a potential therapeutic target due to its ability to burn lipids in the production of heat. Pituitary adenylate cyclase activating polypeptide (PACAP) has been identified as a key regulator of the physiological stress response both centrally and peripherally. While PACAP has been shown to increase thermogenesis by acting at the hypothalamus to increase sympathetic output to BAT, a peripheral role for PACAP-activated thermogenesis has not been studied. We identified PACAP receptor (PAC1, VPAC1/2) expression for the first time in murine BAT and confirmed their expression in white adipose tissues. PAC1 receptor expression was significantly altered in all three adipose tissues studied in response to 3.5-week cold acclimation, with expression patterns differing by depot type. In primary cell culture, VPAC1 was increased in differentiated compared to non-differentiated brown adipocytes, and the same trend was observed for the PACAP-specific receptor PAC1 in gonadal white fat primary cultures. The primary PAC1R mRNA splice variant in interscapular BAT was determined as isoform 2 by RNA-Seq. These results show that PACAP receptors are present in adipose tissues and may have important functional roles in adipocyte differentiation, lipid metabolism, or adipose sensitization to sympathetic signaling in response to thermogenic stimuli. PMID- 29982966 TI - Event segmentation and the temporal compression of experience in episodic memory. AB - Recent studies suggest that episodic memory represents the continuous flow of information that constitutes daily life events in a temporally compressed form, but the nature and determinants of this compression mechanism remain unclear. In the present study, we used wearable camera technology to investigate whether the temporal compression of experience in episodic memory depends on event segmentation. Participants experienced a series of events during a walk on a university campus and were later asked to mentally replay these events. The temporal compression of events in memory and grain size of event segmentation were estimated based on records of participants' experience taken by the camera. The results showed that the temporal compression of events in memory (i.e., the density of recalled moments of experience per unit of time of the actual event duration) closely corresponded to the grain size of event segmentation. Specifically, grain sizes of event segmentation and temporal compression rates were four to five times lower when remembering events that involved goal-directed actions compared to other kinds of events (e.g., spatial displacements). Furthermore, temporal compression rates in memory were significantly predicted by the grain size of event segmentation and event boundaries were more than five times more likely to be remembered than other parts of events. Together, these results provide new insights into the mechanism of temporal compression of events in episodic memory. PMID- 29982964 TI - Prion-Like Propagation of Post-Translationally Modified Tau in Alzheimer's Disease: A Hypothesis. AB - The microtubule-associated protein Tau plays a key role in the neuropathology of Alzheimer's disease by forming intracellular neurofibrillary tangles. Tau in the normal physiological condition helps stabilize microtubules and transport. Tau aggregates due to various gene mutations, intracellular insults and abnormal post translational modifications, phosphorylation being the most important one. Other modifications which alter the function of Tau protein are glycation, nitration, acetylation, methylation, oxidation, etc. In addition to forming intracellular aggregates, Tau pathology might spread in a prion-like manner as revealed by several in vitro and in vivo studies. The possible mechanism of Tau spread can be via bulk endocytosis of misfolded Tau species. The recent studies elucidating this mechanism have mainly focussed on the aggregation and spread of repeat domain of Tau in the cell culture models. Further studies are needed to elucidate the prion-like propagation property of full-length Tau and its aggregates in a more intense manner in vitro as well as in vivo conditions. Varied post translational modifications can have discrete effects on aggregation propensity of Tau as well as its propagation. Here, we review the prion-like properties of Tau and hypothesize the role of glycation in prion-like properties of Tau. This post-translationally modified Tau might have an enhanced propagation property due to differential properties conferred by the modifications. PMID- 29982967 TI - Biodentine and MTA modulate immunoinflammatory response favoring bone formation in sealing of furcation perforations in rat molars. AB - OBJECTIVES: Evaluate the tissue reaction of periodontium subjacent to furcation perforations in rat molars sealed with Biodentine or mineral trioxide aggregate (MTA). MATERIALS AND METHODS: The pulp chamber floor of right upper first molars of 60 rats was perforated and filled with Biodentine, MTA, or cotton pellet (sham); the left first molars were used as control. After 7, 15, 30, and 60 days, maxillary fragments were processed for paraffin-embedding. The periodontal space (PS), volume density of inflammatory cells (VvIC) and fibroblasts (VvFb), number of osteoclasts, and collagen content were obtained. Interleukin-6 (IL-6) and osterix (osteoblast marker) were detected by immunohistochemistry. The data were submitted to ANOVA and Tukey's test (p <= 0.05). RESULTS: At 7 days, high values in VvIC, IL-6-immunolabeled cells, and osteoclasts were accompanied by reduced collagen content in enlarged PS of experimental groups. At all periods, VvIC, number of osteoclasts and IL-6, and PS were higher in sham than in Biodentine and MTA (p < 0.0001). From 7 to 60 days, significant reduction in VvIC, IL-6 immunoexpression, and osteoclasts was accompanied by significant increase in VvFb, osteoblasts, and collagen in Biodentine and MTA groups. At 60 days, significant differences in VvIC, PS, IL-6, osteoclasts, and osteoblasts were not found between Biodentine and MTA. Significant differences in the osteoclast number were not observed among Biodentine, MTA, and control groups while osteoblasts number was higher in Biodentine and MTA groups. CONCLUSIONS: Despite the initial inflammatory reaction and bone resorption, the sealing of furcation perforations with Biodentine and MTA favors the repair of periodontal tissues. CLINICAL RELEVANCE: Biodentine and MTA exhibit potential as repair material in the treatment of furcation perforations. PMID- 29982968 TI - Treatment of symptomatic benign migratory glossitis: a systematic review. AB - OBJECTIVE: The aim of this systematic review is to summarize the results of all published studies on symptomatic benign migratory glossitis and evaluate the best available treatment. METHODS: We searched the Cochrane Library, EMBASE, LILACS, PubMed, Scopus, and Web of Science for articles published up to September 2017, with no time restriction. We considered only articles published in English that evaluated the treatment of symptomatic benign migratory glossitis in children and adults. The protocol for this systematic review was registered at the international prospective register of systematic reviews (PROSPERO) as CRD42017074096. RESULTS: Of the 840 identified studies, 11 were included in our sample. Multiple treatment modalities were described for the treatment of symptomatic benign migratory glossitis. CONCLUSIONS: There is a very low level of evidence for the treatment of symptomatic benign migratory glossitis, with substantial methodological heterogeneity among the evaluated studies. In summary, we could identify no specific treatment for symptomatic benign migratory glossitis. CLINICAL RELEVANCE: In clinical practice, at the outpatient clinic of oral medicine, we attend to many patients diagnosed with benign migratory glossitis, with varying intensity of pain ranging from mild to severe. Treating this disease is a formidable challenge for clinicians. Therefore, we performed a systematic review of benign migratory glossitis to identify the best evidence based treatment available for this condition. We believe that this article may be useful in guiding clinicians on the choice of treatment. PMID- 29982969 TI - Intratubular decontamination ability and physicochemical properties of calcium hydroxide pastes. AB - OBJECTIVE: This in vitro study compared the penetration, pH, calcium ion release, solubility, and intradentinal decontamination capacity of calcium hydroxide (CH) pastes with different vehicles and additives. MATERIALS AND METHODS: Infected standard bovine dentine contaminated with Enterococcus faecalis were treated with propolis extract, chlorhexidine, and camphorated paramonochlorophenol (CPMC) loaded in CH paste for the bacterial viability evaluation made by confocal laser scanning microscopy (CLSM) and microbiological culture. Beside this, 50 acrylic teeth were filled with the previously mentioned pastes to evaluate the pH and calcium ion release (pHmeter and atomic absorption spectrophotometer at time intervals of 7, 15, and 30 days) and solubility (micro-computed tomographic imaging before and after 15 days). RESULTS: After treatment, all samples decreased intra-dentinal contamination, specially, the CH paste with CPMC. There was no statistically significant difference between the groups when evaluating the intra-canal paste penetration. In the pH measurements, CH with distilled water showed the smallest pH values. Regardless the solubility percentage of the pastes, the paste of CH + PG presented the highest values. CONCLUSION: The vehicles and additives tested may increase CH antimicrobial effect, but with small differences. In general, all CH pastes tested here were effective in reducing Enterococcus faecalis and were similar in the penetration, pH, calcium ion release, and solubility of calcium hydroxide when compared to distilled water. CLINICAL RELEVANCE: The use of calcium hydroxide pastes as intracanal medication with an aqueous or viscous vehicle, as propylene glycol, can be useful, since all formulations of the tested pastes resulted in great bacterial reduction inside root canals. PMID- 29982970 TI - Letter to the Editor regarding the article "The heart failure burden of type 2 diabetes mellitus-a review of pathophysiology and interventions". PMID- 29982971 TI - Thanks for the Memories! PMID- 29982972 TI - Clinical Characteristics of Roux-en-Y Gastric Bypass Patients with Death from Accidental Overdose or Intentional Self-Harm: a Descriptive Study. AB - PURPOSE: The objective of this descriptive study was to identify clinical characteristics of Roux-en-Y gastric bypass (RYGB) patients who died from intentional self-harm or accidental overdose postoperatively. MATERIALS AND METHODS: This retrospective, descriptive study included RYGB patients from a large rural medical center that completed surgery between January 2004 and December 2014 and died from intentional self-harm or accidental overdose through December 2015. Specific causes of death were obtained from the National Death Index and clinical data from electronic health records. Clinical characteristics explored were age, sex, time to surgery, weight loss expectations, postoperative weight loss, medication, diagnoses, psychiatric histories (diagnoses, self-harm, suicidal ideation and behaviors, medications, substance use, preoperative Beck Depression Inventory-II scores), pain, social support, and reported life stressors. RESULTS: Overall, 22 patients of 146 total deceased patients died from intention self-harm (n = 6) or accidental overdose (n = 16) over the study period (77.3% female, mean age at time of surgery = 38.4 +/- 9.1 years). Younger age (< 40 years), history of self-harm or depression, preoperative pain, and use of opioids at the time of surgery emerged as common characteristics in weight loss surgery patients who died from intentional self-harm or accidental overdose. No trends regarding social support, life stressors, or actual or expected weight loss were identified. CONCLUSION: Certain weight loss surgery patients may be at risk for death from self-harm or overdose and may benefit from greater surveillance postoperatively. PMID- 29982974 TI - Economic Pressure and Loneliness in Migrant Children in China: The Mediating Roles of Parent-Child Communication and Parental Warmth. AB - The purpose of the current study was to examine the mediating roles of parent child communication and parental warmth in the relationship between economic pressure and loneliness in a sample of migrant children in China. A total of 437 participants were selected from two public schools for migrant children in Zhejiang Province, China. All participants were asked to complete four measures, including the Perceived Economic Strain Scale, the Parent-Child Communication Questionnaire, the Parental Warmth Scale, and the Children's Loneliness Scale. The results showed that economic pressure was positively and directly related to loneliness. Furthermore, parent-child communication and parental warmth partially mediated the relationship between economic pressure and loneliness in migrant children. Thus, parent-child communication and parental warmth play important roles in reducing the negative effect of economic pressure on loneliness in migrant children. PMID- 29982973 TI - Association of Adverse Childhood Experiences and Food Addiction to Bariatric Surgery Completion and Weight Loss Outcome. AB - INTRODUCTION/PURPOSE: Adverse childhood experiences (ACEs) are known risk factors for obesity and poor outcomes following weight loss interventions. ACEs are also associated with addictive behaviors and, potentially, food addiction (FA). This study examined the relationship between ACEs and FA, and their association to undergoing bariatric surgery and post-surgical weight loss outcomes. MATERIALS AND METHODS: Between June 2013 and January 2016, 1586 bariatric-surgery-seeking patients completed a psychological evaluation. During their evaluation, the patients were administered measures including the ACE questionnaire and the Yale Food Addiction Scale. RESULTS: 19.2% of those seeking bariatric surgery reported being the victim of childhood sexual abuse, and 22.1% reported being the victim of childhood physical abuse. An elevated ACE score corresponded to increased likelihood of screening positive for FA and more severe FA. When the type of ACE was analyzed separately, ACE was not associated with bariatric surgery completion or percent total weight loss (%TWL). Screening positive for FA corresponded to less %TWL 1 year post-surgery as the total number of ACEs increased, yet there was no association with %TWL 2 years post-surgery. The participants were classified into two groups, those positive for an ACE or FA versus those negative for both. Those who screened positive were significantly less likely to undergo bariatric surgery. CONCLUSION: Screening positive for experiencing ACEs was related to severity of FA, and screening positive for being the victim of either childhood abuse or FA reduced the likelihood of completing bariatric surgery. More research is needed to determine how these psychosocial factors might influence bariatric surgery outcomes. PMID- 29982975 TI - Partner relationship satisfaction, partner conflict, and maternal cardio metabolic health in the year following the birth of a child. AB - Intimate partner relationship quality during the child-bearing years has implications for maternal health. The purpose of this study was to test whether partner satisfaction, partner conflict, and their interaction predicted maternal cardio-metabolic health at 12-months postpartum. Women were recruited in 5 U.S. sites. Partner conflict and satisfaction were measured at 6-months postpartum, and cardio-metabolic indicators (blood pressure, waist-hip ratio, glycosylated hemoglobin, total cholesterol:HDL ratio) were assessed at 6- and 12-months. Cardio-metabolic indices were scored continuously (CM risk) and using clinical risk cutoffs (CM scores). A significant conflict-by-satisfaction interaction emerged for the CM risk, b(SE) = .043 (.016), p = .006, and CM scores, b(SE)= .089 (.028), p = .002, such that when partner satisfaction was low, low partner conflict was associated with poorer postpartum cardio-metabolic health. This is the first study to examine close relationships and cardio-metabolic health during the child-bearing years, an issue warranting further attention. PMID- 29982976 TI - Echocardiography-based pressure-volume loop assessment in the evaluation for the effects of indoxyl sulfate on cardiovascular function. AB - BACKGROUND: Indoxyl sulfate (IS), a uremic toxin, has been reported to have hypertrophic effects on the heart. Previous studies, however, have shown no association between elevated IS levels and cardiovascular outcomes in hemodialysis patients. We hypothesized that, despite left ventricular (LV) hypertrophy, myocardial contractility and ventricular-arterial coupling would remain preserved, and that this would explain the reason for the absence of prognostic impact of IS. METHODS: We evaluated the association of IS with LV structure, contractility, vascular function, and mechanical efficiency (ventricular-arterial coupling and stroke work/pressure volume area) in 154 patients on hemodialysis, using echocardiography-based pressure-volume loop assessment. RESULTS: As expected, subjects in the high IS group (IS >= 33.8 MUg/mL) had greater LV mass index and end-diastolic volume index compared to subjects in the low IS group (IS < 33.8 MUg/mL). These differences remained significant after adjusting for age, sex, body mass index, diabetic nephropathy, duration of hemodialysis, and NT-proBNP levels, suggesting a potential role of elevated IS levels in LV remodeling. However, no differences in LV contractility (preload recruitable stroke work, peak power index, and systolic mitral annular velocity) and mechanical efficiency (ventricular-arterial coupling and stroke work/pressure volume area) were observed between the groups. CONCLUSIONS: Deleterious effects of IS on LV remodeling are not accompanied by impaired LV contractility or mechanical efficiency, which could contribute to the absence of cardiovascular prognostic impact observed in previous studies performed on hemodialysis patients. PMID- 29982977 TI - Scirtothrips dorsalis (Thysanoptera: Thripidae): a Newly Introduced Polyphagous Pest in Northeastern Brazil. AB - We report for the first time the detection of Scirtothrips dorsalis Hood (Thysanoptera: Thripidae) in Brazil and describe the occurrence of the thrips on leaves of ungrafted dwarf-cashew Anacardium occidentale Linnaeus 1753 (Anacardiaceae), maintained into a greenhouse, in the northeastern state of Ceara. This exotic polyphagous species listed as absent quarantine pest in the country is originated in Asia, but since the beginning of this century, it has readily dispersed despite the strict quarantine regulations currently in several countries. Individuals of S. dorsalis identified in Brazil are similar to specimens found in South Africa rather than Asia by virtue of the absence of conspicuous reticulation on the posterior half of the metanotum and the presence of complete lines of microtrichia restricted to the posterior part of the abdominal sternites. Scirtothrips dorsalis is a particularly invasive pest and its introduction represents a potential threat to various crops in Brazil, especially mango. PMID- 29982978 TI - Ants Associated with Turnera subulata (Turneraceae): Elaiosome Attraction, Seed Dispersion and Germination. AB - Symbiosis between plants and ants include examples in which the plant provides shelter and/or food for ants that, in turn, act in the defense or in the dispersion of seeds from the host plant. Although traditionally referred as mutualistic, the results of these interactions may vary with the ecological context in which patterns are involved. A range of species have facultative association with Turnera subulata (Turneraceae). Here, using behavioral bioassays, we investigated the effects of the most frequent ant species associated with T. subulata (Brachymyrmex sp.1, Camponotus blandus (Smith), Dorymyrmex sp.1, Crematogaster obscurata Emery, and Solenopsis invicta Buren) in the dispersion of plant host seeds and in the number of seedlings around the associated ant nests. We also evaluated the effects of these ant species in the germination of T. subulata seeds, in the consumption of elaiosome, and in the attractiveness to elaiosome odor. Our results showed that the ant species associated with T. subulata presented variation in the attraction by the odor and in the rate of consumption of the elaiosomes. However, none of the ant species studied contributed significantly to the increase of seed germination and seedling growth. Our results suggest that the consumption of the elaiosome by ant species is not a determinant factor to the success of germination of T. subulata. However, such species could contribute indirectly to seed germination by carrying seeds to sites more fertile to germination. In general, our results help to elucidate the results of ecological interactions involving ants and plants. PMID- 29982979 TI - Is there a need for standardized postoperative radiographs after operative treatment of wrist or ankle fractures? AB - PURPOSE: The purpose of this study was to evaluate the frequency of changes in treatment plan due to standardized postoperative radiographs. A secondary aim was to compare our results with a national benchmark. METHODS: This is a single center retrospective case series of 167 consecutive patients, operated with open reduction and internal fixation (ORIF) for distal radius or ankle fractures in 2014. Changes in the treatment protocol were defined as additional CT-imaging, reoperation or other changes as stated in the postoperative instructions. In addition, a national survey was conducted assessing differences between surgeons in different hospitals concerning revision rates. RESULTS: In 7.2% (12/167) of the patients, a change in the treatment plan was recorded after the standardized postoperative radiographs. 10 patients (6%) were reoperated (three without additional imaging, seven after additional imaging with CT). The results from our survey showed a good assessment concerning the quality of intraoperative imaging (7.85 on a scale from 0 to 10). Concerning the revision rate, there was a trend to lower revision rate of 8.1% in the six observers. CONCLUSIONS: Standard postoperative radiographs could improve quality of care. Intraoperative standardized radiographic documentation is needed and the perception and acceptance of quality may vary between hospitals. PMID- 29982981 TI - Myostatin Is Associated With Cognitive Decline in an Animal Model of Alzheimer's Disease. AB - With aging, there are progressive functional declines in multiple organ systems. One of the major physiological problems observed in aged people is skeletal muscle loss. This age-related muscle loss causes muscle weakness and disability, which in turn might reduce the quality of life in older adults and lead to the progression of several diseases, particularly Alzheimer's disease (AD). Some researchers have hypothesized that loss of muscle mass and strength is linked to the risk of developing AD. In addition, unintended weight loss often occurs in AD patients and might reflect dementia severity. However, the causal relationship between muscle atrophy and cognitive deficits in AD is unclear. We found that double transgenic amyloid precursor protein and presenilin 1 (APP/PS1) mice that co-express APP and PS1 at older ages exhibited lower body weight and lean tissue mass than sex- and age-matched wild-type (WT) mice. In addition, muscle atrophy and the extent of memory decline were strongly correlated in APP/PS1 mice. Myostatin levels in the gastrocnemius (GAS) muscle of 12-month-old APP/PS1 mice were elevated. We determined that the cellular and molecular mechanism of muscle atrophy was through the ubiquitin-proteasome pathway. Furthermore, myostatin knockdown in the GAS muscles increased grip strength and muscle mass, leading to memory improvement in myostatin short-hairpin RNA-treated APP/PS1 mice. We conclude that high-level myostatin expression might mediate or trigger muscle atrophy and cognitive deficits. PMID- 29982980 TI - MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss. AB - While recent studies have revealed a substantial portion of the genes underlying human hearing loss, the extensive genetic landscape has not been completely explored. Here, we report a loss-of-function variant (c.72delA) in MPZL2 in three unrelated multiplex families from Turkey and Iran with autosomal recessive nonsyndromic hearing loss. The variant co-segregates with moderate sensorineural hearing loss in all three families. We show a shared haplotype flanking the variant in our families implicating a single founder. While rare in other populations, the allele frequency of the variant is ~ 0.004 in Ashkenazi Jews, suggesting that it may be an important cause of moderate hearing loss in that population. We show that Mpzl2 is expressed in mouse inner ear, and the protein localizes in the auditory inner and outer hair cells, with an asymmetric subcellular localization. We thus present MPZL2 as a novel gene associated with sensorineural hearing loss. PMID- 29982982 TI - Endothelial Cell Dysfunction and Injury in Subarachnoid Hemorrhage. AB - In the brain, vascular endothelial cells conserve blood viscosity, control blood flow, and form the interface between central nervous system and circulating blood. Clinical outcome after aneurysmal subarachnoid hemorrhage is linked to early brain injury, cerebral vasospasm, and other causes of delayed cerebral ischemia. The cerebral vasculature remains a unique target for therapies since it becomes rapidly disrupted after subarachnoid hemorrhage, and damage to the blood vessels continues into the delayed injury phase. The current failure of therapies to improve clinical outcome warrants a re-evaluation of current therapeutic approaches. The mechanisms of endothelial cell injury and blood-brain barrier breakdown are critical to the pathway of cerebral injury, and an improved understanding of these mechanisms may lead to novel therapeutic targets. This review provides an update on the current understanding of endothelial cell injury following aneurysmal subarachnoid hemorrhage, including blood-brain barrier dysfunction. PMID- 29982983 TI - Pathological Modification of TDP-43 in Amyotrophic Lateral Sclerosis with SOD1 Mutations. AB - Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset, progressive neurodegenerative disorder with no known cure. Cu/Zn-superoxide dismutase (SOD1) was the first identified protein associated with familial ALS (fALS). Recently, TAR DNA-binding protein 43 (TDP-43) has been found to be a principal component of ubiquitinated cytoplasmic inclusions in neurons and glia in ALS. However, it remains unclear whether these ALS-linked proteins partly have a shared pathogenesis. Here, we determine the association between mutant SOD1 and the modification of TDP-43 and the relationship of pathologic TDP-43 to neuronal cytotoxicity in SOD1 ALS. In this work, using animal model, human tissue, and cell models, we provide the evidence that the association between the TDP-43 modification and the pathogenesis of SOD1 fALS. We demonstrated an age-dependent increase in TDP-43 C-terminal fragments and phosphorylation in motor neurons and glia of SOD1 mice and SOD1G85S ALS patient. Cytoplasmic TDP-43 was also observed in iPSC-derived motor neurons from SOD1G17S ALS patient. Moreover, we observed that mutant SOD1 interacts with TDP-43 in co-immunoprecipitation assays with G93A hSOD1-transfected cell lines. Mutant SOD1 overexpression led to an increase in TDP-43 modification in the detergent-insoluble fraction in the spinal cord of SOD1 mice and fALS patient. Additionally, we showed cellular apoptosis in response to the interaction of mutant SOD1 and fragment forms of TDP-43. These findings suggest that mutant SOD1 could affect the solubility/insolubility of TDP 43 through physical interactions and the resulting pathological modifications of TDP-43 may be involved in motor neuron death in SOD1 fALS. PMID- 29982984 TI - Physical Exercise During Pregnancy Prevents Cognitive Impairment Induced by Amyloid-beta in Adult Offspring Rats. AB - Alzheimer's disease (AD) is the main aging-associated neurodegenerative disorder and is characterized by mitochondrial dysfunction, oxidative stress, synaptic failure, and cognitive decline. It has been a challenge to find disease course modifying treatments. However, several studies demonstrated that regular physical activity and exercise are capable of promoting brain health by improving the cognitive function. Maternal lifestyle, including regular exercise during pregnancy, has also been shown to influence fetal development and disease susceptibility in adulthood through fetal metabolism programming. Here, we investigated the potential neuroprotective role of regular maternal swimming, before and during pregnancy, against amyloid-beta neurotoxicity in the adult offspring. Behavioral and neurochemical analyses were performed 14 days after male offspring received a single, bilateral, intracerebroventricular (icv) injection of amyloid-beta oligomers (AbetaOs). AbetaOs-injected rats of the sedentary maternal group exhibited learning and memory deficits, along with reduced synaptophysin, brain-derived neurotrophic factor (BDNF) levels, and alterations of mitochondrial function. Strikingly, the offspring of the sedentary maternal group had AbetaOs-induced behavioral alterations that were prevented by maternal exercise. This effect was accompanied by preventing the alteration of synaptophysin levels in the offspring of exercised dams. Additionally, offspring of the maternal exercise group exhibited an augmentation of functional mitochondria, as indicated by increases in mitochondrial mass and membrane potential, alpha-ketoglutarate dehydrogenase, and cytochrome c oxidase enzymes activities. Moreover, maternal exercise during pregnancy induced long-lasting modulation of fusion and fission proteins, Mfn1 and Drp1, respectively. Overall, our data demonstrates a potential protective effect of exercise during pregnancy against AbetaOs-induced neurotoxicity in the adult offspring brain, by mitigating the neurodegenerative process triggered by Alzheimer-associated AbetaOs through programming the brain metabolism. PMID- 29982985 TI - Growth Factors and Neuroglobin in Astrocyte Protection Against Neurodegeneration and Oxidative Stress. AB - Neurodegenerative diseases, such as Parkinson and Alzheimer, are among the main public health issues in the world due to their effects on life quality and high mortality rates. Although neuronal death is the main cause of disruption in the central nervous system (CNS) elicited by these pathologies, other cells such as astrocytes are also affected. There is no treatment for preventing the cellular death during neurodegenerative processes, and current drug therapy is focused on decreasing the associated motor symptoms. For these reasons, it has been necessary to seek new therapeutical procedures, including the use of growth factors to reduce alpha-synuclein toxicity and misfolding in order to recover neuronal cells and astrocytes. Additionally, it has been shown that some growth factors are able to reduce the overproduction of reactive oxygen species (ROS), which are associated with neuronal death through activation of antioxidative enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and neuroglobin. In the present review, we discuss the use of growth factors such as PDGF-BB, VEGF, BDNF, and the antioxidative enzyme neuroglobin in the protection of astrocytes and neurons during the development of neurodegenerative diseases. PMID- 29982986 TI - Predictive Narrow-Band Imaging of Colonic Polyps: The Optics Are Good. PMID- 29982987 TI - Checkpoint Inhibitors: Conquering Cancer with a Little (T)-Help from Our Microbial Friends. PMID- 29982988 TI - Hispanics Coming to the US Adopt US Cultural Behaviors and Eat Less Healthy: Implications for Development of Inflammatory Bowel Disease. AB - INTRODUCTION: The incidence of inflammatory bowel disease (IBD) among US Hispanics is rising. Adoption of an American diet and/or US acculturation may help explain this rise. AIMS: To measure changes in diet occurring with immigration to the USA in IBD patients and controls, and to compare US acculturation between Hispanics with versus without IBD. Last, we examine the current diet of Hispanics with IBD compared to the diet of Hispanic controls. METHODS: This was a cross-sectional study of Hispanic immigrants with and without IBD. Participants were recruited from a university-based GI clinic. All participants completed an abbreviated version of the Stephenson Multi-Group Acculturation Scale and a 24-h diet recall (the ASA-24). Diet quality was calculated using the Healthy Eating Index (HEI-2010). RESULTS: We included 58 participants: 29 controls and 29 IBD patients. Most participants were Cuban or Colombian. Most participants, particularly those with IBD, reported changing their diet after immigration (72% of IBD and 57% of controls). IBD participants and controls scored similarly on US and Hispanic acculturation measures. IBD patients and controls scored equally poorly on the HEI-2010, although they differed on specific measures of poor intake. IBD patients reported a higher intake of refined grains and lower consumption of fruits, whereas controls reported higher intake of empty calories (derived from fat and alcohol). CONCLUSION: The majority of Hispanics change their diet upon immigration to the USA and eat poorly irrespective of the presence of IBD. Future studies should examine gene-diet interactions to better understand underlying causes of IBD in Hispanics. PMID- 29982989 TI - Reproducibility of standardized uptake values of same-day randomized 68Ga-PSMA-11 PET/CT and PET/MR scans in recurrent prostate cancer patients. AB - OBJECTIVE: Positron emission tomography in association with magnetic resonance imaging (PET/MR) and 68Ga-PSMA-11 has shown superior detection in recurrent prostate cancer patients as compared to PET/computed tomography (PET/CT). There are, however, several technological differences between PET/CT and PET/MR systems which affect the PET image quality. The objective of this study was to assess the reproducibility of PET/CT and PET/MR SUV's in recurrent prostate cancer patients. We randomized the patients regarding the order of the PET/CT and PET/MR scans to reduce the influence of tracer uptake as a function of time. METHODS: Thirty patients, all with biochemical recurrence after radical prostatectomy, underwent whole-body PET/CT and PET/MR scans after intravenous injection of a single dose of 68Ga-PSMA-11. Fifteen patients underwent PET/CT first and 15 patients underwent PET/MR first. Volumes of interest on tumor lesions were outlined and maximum standardized uptake value (SUVmax) corrected for lean body mass was calculated. Correlation and agreement between scans were assessed by generalized linear mixed-effects models and Bland-Altman analysis. The association between SUV, patient characteristics and imaging parameters was assessed. RESULTS: Eighteen of the 30 evaluated patients had at least one positive lesion, giving an overall detection rate of 60%. In total, there were 34 visible lesions: 5 local recurrences, 22 lymph node metastases and 7 bone metastases. One group acquired PET/CT and PET/MR at median time points of 63.0 and 159.0 min, while the other group acquired PET/MR and PET/CT at median time points of 92.0 and 149.0 min. SUVmax between scans was linearly correlated, described by the equation Y(PET/CT SUVmax) = 0.75 + 1.00 * (PET/MR SUVmax), on average 20% higher on PET/CT than on PET/MR. SUV associated significantly only with type of lesion, scan time post injection and acquisition time per bed position. CONCLUSIONS: SUVmax from PET/CT and PET/MR are linearly correlated, on average 20% higher on PET/CT than on PET/MR and should, therefore, not be used interchangeably in patient follow-up. PMID- 29982990 TI - Prognostic role of pretreatment 18F-FDG PET/CT in primary brain lymphoma. AB - OBJECTIVE: Primary brain lymphoma is an aggressive extranodal non-Hodgkin lymphoma with poor prognosis. Many possible prognostic factors are investigated with controversial results, but possible prognostic role of 18fluorine fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) features remains unclear. Our aim was to study the metabolic behavior of brain lymphoma at 18F-FDG PET/CT and the prognostic impact of qualitative and semiquantitative PET/CT parameters. METHODS: Between 2006 and 2018, 52 patients (26 females and 26 males; mean age: 61 years) with histologically confirmed diagnosis of brain lymphoma who underwent 18F-FDG PET/CT for staging before any treatment were included. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determinate the relation between qualitative and semiquantitative PET/CT features and OS and PFS. RESULTS: Thirty-nine patients had positive 18F-FDG PET/CT showing 18F-FDG uptake (mean SUVbw of 18.2; SUVlbm of 13.9; SUVbsa of 5; MTV of 14.8; TLG of 153) at the corresponding cerebral lesion; the remaining 13 were not 18F-FDG avid. Relapse or progression of disease occurred in 22 patients with an average time of 9.7 months; death occurred in 18 patients with an average of 7.9 months. There was no difference in PFS and OS between baseline PET/CT positive and negative groups or considering SUVbw, SUVlbm, and SUVbsa. PFS and OS was significantly shorter in patients with MTV >= 9.8 cm3 (p = 0.037 and p = 0.022, respectively) and TLG >= 94 (p = 0.045 and p = 0.0430, respectively). CONCLUSIONS: 18F-FDG avidity was noted in 75% of cases. Only metabolic tumor parameters (MTV and TLG) were independently correlated with PFS and OS. PMID- 29982991 TI - Extended compatibility of fentanyl and ketamine in dextrose 5. AB - BACKGROUND: There are no published studies that report on fentanyl and ketamine compatibility in dextrose 5% solution as commonly practiced in hospital settings. METHODS: This study assessed the compatibility of fentanyl and ketamine after their reconstitution in dextrose 5% under ambient temperature and humidity conditions in a hospital setting. Each sample of fentanyl and ketamine was prepared in triplicate by adding dextrose 5% to a prefilled syringe until final concentrations of 9.8 MUg mL-1 for fentanyl and 192 MUg mL-1 for ketamine were achieved. The solutions were stored in syringes at an ambient temperature ranging 26-28 degrees C either under a mixture of daylight and ambient lighting. A sample was taken from the syringes at the following times: 0, 8, 24, 72, 120, and 168 hours. The samples from each solution were checked for physical changes, pH and their concentration assessed by high-performance liquid chromatography. RESULTS: The solutions were clear and no physical changes were seen. The pH of fentanyl and ketamine decreased dramatically after 72 hours. The concentrations of fentanyl remained 90-110% only for 24 hours, while ketamine remained 90-110% for 168 hours. CONCLUSION: Solutions of fentanyl and ketamine in dextrose 5% may be used in prefilled syringes only up to 24 hours and 72 hours after reconstitution, respectively. PMID- 29982992 TI - Marine sponge-derived smenospongine preferentially eliminates breast cancer stem like cells via p38/AMPKalpha pathways. AB - Breast cancer stem cells (CSCs) have been postulated as responsible for therapeutic failure of breast cancer. Novel agents effectively targeting breast CSCs are urging to be discovered to overcome cancer relapse and metastasis. We recently established a CSC-like model through ectopic expression Nanog, a core pluripotency factor, in breast cancer cells and validated induced CSC-like (MCF7 Nanog) model acquired stem-like properties. Using this model, we found that smenospongine (Sme), a natural sesquiterpene aminoquinone isolated from marine sponge Spongia pertusa Esper, preferentially inhibited the induced CSC-like cells proliferation by inducing G0/G1 arrest and intrinsic apoptosis via increasing the phosphorylation level of p38 and AMPKalpha. Importantly, Sme exhibited the ability to abrogate CSC-like cells associated with a downregulation of stem cell markers including Nanog, Sox2, and Bmi1. Functionally, Sme inhibited the ability of MCF7-Nanog cells to form tumor sphere in vitro and develop tumor in vivo. Significant antitumor effects are observed in Sme-treated mouse xenograft tumor models, with no apparent toxicity to mice. Taken together, our findings provide a CSC-like model to identify novel CSC-targeting drugs and identify Sme as a candidate natural agent for treatment of breast cancer. PMID- 29982993 TI - Valvular involvement in granulomatosis with polyangiitis: Case report and systematic review of literature. AB - BACKGROUND: Granulomatosis with polyangiitis (GPA) is a systemic inflammatory condition; however, patients with GPA rarely experience endocardial valve lesions. METHODS: We report a GPA case with tricuspid valve destruction together with a systematic review to highlight the characteristics of all previously reported GPA cases with valvular involvement. RESULTS: Among 36 cases included, the aortic valve was involved in 15 (41.7%) cases while the mitral valve was involved in 9 (25%) subjects. Combined lesion of both aortic and mitral valves was reported in 9 (25%) patients. CONCLUSION: We recommend routine echocardiography examination to rule out any cardiac valve lesion once GPA is suspected. PMID- 29982994 TI - Cloning and characterization of short-chain N-acyl homoserine lactone-producing Enterobacter asburiae strain L1 from lettuce leaves. AB - In gram-negative bacteria, bacterial communication or quorum sensing (QS) is achieved using common signaling molecules known as N-acyl homoserine lactones (AHL). We have previously reported the genome of AHL-producing bacterium, Enterobacter asburiae strain L1. In silico analysis of the strain L1 genome revealed the presence of a pair of luxI/R genes responsible for AHL-type QS, designated as easIR. In this work, the 639 bp luxI homolog, encoding 212 amino acids, have been cloned and overexpressed in Escherichia coli BL21 (DE3)pLysS. The purified protein (~25 kDa) shares high similarity to several members of the LuxI family among different E asburiae strains. Our findings showed that the heterologously expressed EasI protein has activated violacein production by AHL biosensor Chromobacterium violaceum CV026 as the wild-type E. asburiae. The mass spectrometry analysis showed the production of N-butanoyl homoserine lactone and N-hexanoyl homoserine lactone from induced E. coli harboring the recombinant EasI, suggesting that EasI is a functional AHL synthase. E. asburiae strain L1 was also shown to possess biofilm-forming characteristic activity using crystal violet binding assay. This is the first report on cloning and characterization of the luxI homolog from E. asburiae. PMID- 29982995 TI - The diagnostic role and dynamic changes in cerebrospinal fluid neopterin during treatment of patients with primary central nervous system lymphoma. AB - This study aimed at evaluating the diagnostic and prognostic role of neopterin (Npt) concentration in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma (PCNSL). Ninety-nine patients were enrolled in this retrospective study; these included patients with PCNSL (n = 21), other brain tumors (n = 44), and inflammatory diseases (n = 34). CSF Npt concentration was measured using ELISA. Receiver operating characteristic (ROC) curve analysis was performed to assess the discriminative ability of CSF Npt concentration for the diagnosis of PCNSL. CSF Npt concentration in patients with PCNSL was significantly higher than that in patients with other brain tumors and inflammatory diseases (P < .001). On ROC curve analysis, the optimal cutoff CSF Npt level of 10.77 ng/mL for the diagnosis of PCNSL and the diagnostic yield of MRI were increased when used in conjunction with CSF Npt concentration. The CSF Npt concentrations in PCNSL patients with multiple lesions were significantly higher than those in patients with a single lesion. Changes in CSF Npt concentration were consistent with post-treatment changes in tumor sizes. The CSF Npt concentration may be a good biomarker for the diagnosis, for monitoring of disease course, and for prognostic evaluation of patients with PCNSL. PMID- 29982997 TI - Root metabolic plasticity underlies functional diversity in mycorrhiza-enhanced stress tolerance in tomato. AB - Arbuscular mycorrhizal (AM) symbioses can improve plant tolerance to multiple stresses. We compared three AM fungi (AMF) from different genera, one of them isolated from a dry and saline environment, in terms of their ability to increase tomato tolerance to moderate or severe drought or salt stress. Plant physiological parameters and metabolic profiles were compared in order to find the molecular mechanisms underlying plant protection against stress. Mycorrhizal growth response was determined, and ultrahigh-performance LC-MS was used to compare the metabolic profile of plants under the different treatments. All AMF increased plant tolerance to stress, and the positive effects of the symbiosis were correlated with the severity of the stress. The AMF isolated from the stressful environment was the most effective in improving plant tolerance to salt stress. Differentially accumulated compounds were identified and the antistress properties of some of them were confirmed. We demonstrate that AM symbioses increase plant metabolic plasticity to cope with stress. Some responses were common to all AMF tested, while others were specifically related to particular isolates. Important metabolism reprograming was evidenced upon salt stress, and we identified metabolic pathways and compounds differentially accumulated in mycorrhizas that may underlie their enhanced tolerance to stress. PMID- 29982996 TI - Subdiffraction-resolution live-cell imaging for visualizing thylakoid membranes. AB - The chloroplast is the chlorophyll-containing organelle that produces energy through photosynthesis. Within the chloroplast is an intricate network of thylakoid membranes containing photosynthetic membrane proteins that mediate electron transport and generate chemical energy. Historically, electron microscopy (EM) has been a powerful tool for visualizing the macromolecular structure and organization of thylakoid membranes. However, an understanding of thylakoid membrane dynamics remains elusive because EM requires fixation and sectioning. To improve our knowledge of thylakoid membrane dynamics we need to consider at least two issues: (i) the live-cell imaging conditions needed to visualize active processes in vivo; and (ii) the spatial resolution required to differentiate the characteristics of thylakoid membranes. Here, we utilize three dimensional structured illumination microscopy (3D-SIM) to explore the optimal imaging conditions for investigating the dynamics of thylakoid membranes in living plant and algal cells. We show that 3D-SIM is capable of examining broad characteristics of thylakoid structures in chloroplasts of the vascular plant Arabidopsis thaliana and distinguishing the structural differences between wild type and mutant strains. Using 3D-SIM, we also visualize thylakoid organization in whole cells of the green alga Chlamydomonas reinhardtii. These data reveal that high light intensity changes thylakoid membrane structure in C. reinhardtii. Moreover, we observed the green alga Chromochloris zofingiensis and the moss Physcomitrella patens to show the applicability of 3D-SIM. This study demonstrates that 3D-SIM is a promising approach for studying the dynamics of thylakoid membranes in photoautotrophic organisms during photoacclimation processes. PMID- 29982998 TI - Targeting platelet EPCR for better therapeutic factor VIIa activity. PMID- 29982999 TI - An allelic series at the KARRIKIN INSENSITIVE 2 locus of Arabidopsis thaliana decouples ligand hydrolysis and receptor degradation from downstream signalling. AB - Karrikins are butenolide compounds present in post-fire environments that can stimulate seed germination in many species, including Arabidopsis thaliana. Plants also produce endogenous butenolide compounds that serve as hormones, namely strigolactones (SLs). The receptor for karrikins (KARRIKIN INSENSITIVE 2; KAI2) and the receptor for SLs (DWARF14; D14) are homologous proteins that share many similarities. The mode of action of D14 as a dual enzyme receptor protein is well established, but the nature of KAI2-dependent signalling and its function as a receptor are not fully understood. To expand our knowledge of how KAI2 operates, we screened ethyl methanesulphonate (EMS)-mutagenized populations of A. thaliana for mutants with kai2-like phenotypes and isolated 13 new kai2 alleles. Among these alleles, kai2-10 encoded a D184N protein variant that was stable in planta. Differential scanning fluorimetry assays indicated that the KAI2 D184N protein could interact normally with bioactive ligands. We developed a KAI2 active version of the fluorescent strigolactone analogue Yoshimulactone Green to show that KAI2 D184N exhibits normal rates of ligand hydrolysis. KAI2 D184N degraded in response to treatment with exogenous ligands, suggesting that receptor degradation is a consequence of ligand binding and hydrolysis, but is insufficient for signalling activity. Remarkably, KAI2 D184N degradation was hypersensitive to karrikins, but showed a normal response to strigolactone analogues, implying that these butenolides may interact differently with KAI2. These results demonstrate that the enzymatic and signalling functions of KAI2 can be decoupled, and provide important insights into the mechanistic events that underpin butenolide signalling in plants. PMID- 29983000 TI - The UPF1 interactome reveals interaction networks between RNA degradation and translation repression factors in Arabidopsis. AB - The RNA helicase UP-FRAMESHIFT (UPF1) is a key factor of nonsense-mediated decay (NMD), a mRNA decay pathway involved in RNA quality control and in the fine tuning of gene expression. UPF1 recruits UPF2 and UPF3 to constitute the NMD core complex, which is conserved across eukaryotes. No other components of UPF1 containing ribonucleoproteins (RNPs) are known in plants, despite its key role in regulating gene expression. Here, we report the identification of a large set of proteins that co-purify with the Arabidopsis UPF1, either in an RNA-dependent or RNA-independent manner. We found that like UPF1, several of its co-purifying proteins have a dual localization in the cytosol and in P-bodies, which are dynamic structures formed by the condensation of translationally repressed mRNPs. Interestingly, more than half of the proteins of the UPF1 interactome also co purify with DCP5, a conserved translation repressor also involved in P-body formation. We identified a terminal nucleotidyltransferase, ribonucleases and several RNA helicases among the most significantly enriched proteins co-purifying with both UPF1 and DCP5. Among these, RNA helicases are the homologs of DDX6/Dhh1, known as translation repressors in humans and yeast, respectively. Overall, this study reports a large set of proteins associated with the Arabidopsis UPF1 and DCP5, two components of P-bodies, and reveals an extensive interaction network between RNA degradation and translation repression factors. Using this resource, we identified five hitherto unknown components of P-bodies in plants, pointing out the value of this dataset for the identification of proteins potentially involved in translation repression and/or RNA degradation. PMID- 29983001 TI - PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway: comment. PMID- 29983003 TI - Quantifying construction vibration effects on daily radiotherapy treatments. AB - The existing two-story parkade is being replaced by a four-story parkade on a hospital campus. The parkade is across a two-lane access road from a cancer center with a nine-linear accelerator radiotherapy department in the basement. The new parkade is supported by over 280 drilled and cased pilings installed at depths between 10 and 25 m depending on the underlying soil strata and varying diameters, up to 1.5 m. The construction work in such close proximity to the radiation therapy department resulted in significant vibrations being felt in the simulation and treatment vaults. The amplitude and frequency of the vibration was measured. Using vendor supplied documentation, the total vibratory amplitude of the linear accelerators in use within the department was calculated. The results fell outside of specification, resulting in changes to the way the project preceded following discussion with the project management team. PMID- 29983002 TI - Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters. AB - Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic contrast-enhanced MRI (DCE-MRI) using extravascular extracellular agent (Gd DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region-dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment-induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and alpha caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment. PMID- 29983005 TI - Plant carbon metabolism and climate change: elevated CO2 and temperature impacts on photosynthesis, photorespiration and respiration. AB - Contents Summary 32 I. The importance of plant carbon metabolism for climate change 32 II. Rising atmospheric CO2 and carbon metabolism 33 III. Rising temperatures and carbon metabolism 37 IV. Thermal acclimation responses of carbon metabolic processes can be best understood when studied together 38 V. Will elevated CO2 offset warming-induced changes in carbon metabolism? 40 VI. No plant is an island: water and nutrient limitations define plant responses to climate drivers 41 VII. Conclusions 42 Acknowledgements 42 References 42 Appendix A1 48 SUMMARY: Plant carbon metabolism is impacted by rising CO2 concentrations and temperatures, but also feeds back onto the climate system to help determine the trajectory of future climate change. Here we review how photosynthesis, photorespiration and respiration are affected by increasing atmospheric CO2 concentrations and climate warming, both separately and in combination. We also compile data from the literature on plants grown at multiple temperatures, focusing on net CO2 assimilation rates and leaf dark respiration rates measured at the growth temperature (Agrowth and Rgrowth , respectively). Our analyses show that the ratio of Agrowth to Rgrowth is generally homeostatic across a wide range of species and growth temperatures, and that species that have reduced Agrowth at higher growth temperatures also tend to have reduced Rgrowth , while species that show stimulations in Agrowth under warming tend to have higher Rgrowth in the hotter environment. These results highlight the need to study these physiological processes together to better predict how vegetation carbon metabolism will respond to climate change. PMID- 29983006 TI - Evaluation of a Fluorescence-aided Identification Technique (FIT) for removal of composite bonded trauma splints. AB - BACKGROUND/AIM: Accurate removal of composite bonded titanium trauma splints (TTS) can be challenging. The aim of this study was to evaluate a Fluorescence aided Identification Technique (FIT) compared with a conventional light source (CT) for removal of trauma splints regarding loss of tooth substance, residual composite, and time taken. MATERIALS AND METHODS: Twenty maxillary models with six bovine teeth (13 - 23) were fabricated. An optical three-dimensional impression was taken and a TTS was applied from 12 to 22 with two bonding sites on every tooth under standardized conditions using an etch-and-rinse adhesive and resin composite. Two operators removed 10 splints each (5x FIT and 5x CT). For FIT, a 405 nm light-emitting headlamp was used. Time was recorded. A post operative scan was superimposed on the pre-operative scan using OraCheck software. A qualitative and quantitative analysis of tooth defects and composite remnants was performed by two operators and statistically analyzed. RESULTS: Compared with the CT, FIT led to significantly fewer and smaller enamel defects (mean volume: -0.04 mm3 vs -0.33 mm3 ) (P < 0.001), significantly less composite remained (mean volume: 0.02 mm3 vs 0.28 mm3 ) (P < 0.001), and the removal procedure with FIT was significantly quicker (mean: 162 seconds vs 268 seconds) (P < 0.001), CONCLUSIONS: FIT facilitated the removal of composite used to bond trauma splints leading to less time-consuming as well as less invasive treatment. It left fewer composite residues on enamel surfaces. PMID- 29983007 TI - Anesthesia Considerations in Modified Osteo-odonto-keratoprosthesis. AB - PURPOSE: The purpose of this study was to elucidate anesthesia-related challenges in 74 cases who underwent modified osteo-odonto-keratoprosthesis (MOOKP). DESIGN: Retrospective cohort study. METHODS: Medical records of 74 consecutive patients who underwent MOOKP surgery between January 2007 and January 2015 were studied. Data such as demographic details, systemic comorbidities, indications for MOOKP, anesthesia techniques, and postoperative events in various stages of MOOKP were collected and analyzed. RESULTS: The mean age of the patients was 29.7 +/- 9.13 years. Of the 74 patients, 47 were men. The most common indication for MOOKP was found to be Stevens-Johnson syndrome (53%) followed by chemical injury (38%). In all stages of the MOOKP procedure, 94.6% of cases were found to have American Society of Anesthesiologists (ASA) score grade II, whereas 4.6% had grade III. Mallampati score of 1 was found in 79.7% of cases in stage 1, 82.4% of cases in stage 1B + 1C, and 81% of cases in stage 2. Recovery grade of 10 was noted in all the cases at all stages of the MOOKP procedure. Intubation in the second attempt was carried out in 8 cases and oral intubation in stage 1B + 1C was performed in 4 cases. Difficulty in intubation was noted in 3 cases in stage 1A, 4 cases in stage 1B + 1C, and 1 case in stage 2. CONCLUSIONS: In patients undergoing MOOKP, a good preanesthetic evaluation and intraoperative anesthesia plan before each stage could help in successful administration of anesthesia in these patients. PMID- 29983004 TI - Patients' perceived needs for allied health, and complementary and alternative medicines for low back pain: A systematic scoping review. AB - OBJECTIVES: Allied health and complementary and alternative medicines (CAM) are therapeutic therapies commonly accessed by consumers to manage low back pain (LBP). We aimed to identify the literature regarding patients' perceived needs for physiotherapy, chiropractic therapy and CAM for the management of LBP. METHODS: A systematic scoping review of MEDLINE, EMBASE, CINAHL and PsycINFO (1990-2016) was conducted to identify studies examining patients' perceived needs for allied health and CAM for LBP. Data regarding study design and methodology were extracted. Areas of patients' perceived need for allied health and CAM were aggregated. RESULTS: Forty-four studies from 2202 were included: 25 qualitative, 18 quantitative and 1 mixed-methods study. Three areas of need emerged: (i) physiotherapy was viewed as important, particularly when individually tailored. However, patients had concerns about adherence, adverse outcomes and correct exercise technique. (ii) Chiropractic therapy was perceived to be effective and needed by some patients, but others were concerned about adverse outcomes. (iii) An inconsistent need for CAM was identified with some patients perceiving a need, while others questioning the legitimacy and short-term duration of these therapies. CONCLUSIONS: Our findings regarding patients' perceived needs for allied health and CAM for LBP may assist in informing development of more patient centred guidelines and service models for LBP. Understanding patients' concerns regarding active-based physiotherapy, which is recommended in most guidelines, and issues surrounding chiropractic and CAM, which are generally not, may help inform management that better aligns patient's perceived needs with effective treatments, to improve outcomes for both patients and the health-care system. PMID- 29983008 TI - Intra-Articular Injection of Bone Marrow-Derived Mesenchymal Stem Cells Leading to Better Clinical Outcomes without Difference in MRI Outcomes from Baseline in Patients with Knee Osteoarthritis. AB - Purpose: Bone marrow (BM) is frequently used as a source of mesenchymal stem cells (MSCs) because they have a high potential for differentiation. However, it is unclear whether BM-derived MSCs lead to better clinical and magnetic resonance imaging (MRI) outcomes postoperatively. Materials and Methods: This meta-analysis compared the clinical and MRI outcomes in patients with knee osteoarthritis (OA) treated with BM-derived MSCs. Eight studies comparing the clinical and MRI outcomes assessed with various measurement tools in patients with knee OA treated with BM-derived MSCs were included. Results: The range of motion (95% confidence interval [CI], -13.05 to 4.24; p=0.32) and MRI outcomes (95% CI, -0.16 to 1.40; p=0.12) did not differ significantly between the baseline and final follow-up. In contrast, pain (95% CI, 0.89 to 1.87; p<0.001) and functional outcomes (95% CI, 0.70 to 2.07; p<0.001) were significantly improved at the final follow-up when compared to the baseline. Conclusions: This meta-analysis found no significant difference in the tested range of motion and MRI outcomes between the baseline and the final follow-up in patients treated with BM-derived MSCs, whereas significant functional improvement and pain relief were noted when compared with the baseline. Thus, BM-derived MSCs appear to be a viable alternative for patients with knee OA, although long-term and high-quality randomized controlled trials are needed to confirm the clinical benefits. PMID- 29983009 TI - [Prevalence, incidence and factors associated with adverse reactions to foods in Cuban infants. A population-based cohort study]. AB - BACKGROUND: The prevalence of asthma and allergic diseases in Cuban children is high, but little is known about adverse reactions to foods. OBJECTIVE: To determine the prevalence, incidence and risk factors for adverse reaction to foods in children. METHODS: Population-based cohort study carried out in Havana, Cuba, in a three-year period. Parents of 1543 children provided medical and lifestyle information from the first to the third year of age, which was collected using a questionnaire. An adverse reaction to foods was defined by medical diagnosis reported by the parents or caregivers. RESULTS: Annual cumulative incidence was 5.7%, 1.9% and 0.8%, whereas annual prevalence was 5.7%, 4% and 2.5% at 1, 2 and 3 years of age, respectively; 8% of infants had experienced an adverse reaction to foods when they turned 3 years of age. Cow milk was the most commonly implicated food. Main risk factors were allergenic food consumption, use of antibiotics, factors related to the presence of allergens, maternal history of overweight during pregnancy and allergy to insect bites. CONCLUSIONS: Adverse reaction to food is a significant clinical problem in children from Havana. Modifiable risk factors were identified, the understanding of which will help to direct effective intervention strategies. PMID- 29983010 TI - [Latex sensitization and allergy in Hospital General de Mexico surgery residents]. AB - BACKGROUND: The prevalence of latex allergy ranges from 0.8 to 6.5% and is the second cause of perioperative anaphylaxis. The main risk factors are being a health worker or latex producer, hours of latex gloves or products usage, exposure to other hand irritants, history of atopy, neural tube closure defects or numerous surgeries at early age. OBJECTIVE: To determine the frequency of latex sensitization in resident physicians of the Hospital General de Mexico surgical area. METHODS: Prospective, cross-sectional, descriptive study where skin prick tests were applied to residents of the surgical area of the Hospital General de Mexico, which depends on the Ministry of Health and is located in Mexico City. RESULTS: Ninety-two subjects were included and had skin tests practiced, with 11 surgical specialties participating. Latex sensitization in this population was 11.9%, whereas the presence of latex allergy was 10.8%. CONCLUSIONS: A high frequency of latex sensitization and allergy was demonstrated in Hospital General de Mexico surgery residents, which indicates the need for policies and procedures to be developed for health workers with latex allergy, as well as continuous training of employees on latex allergy. PMID- 29983011 TI - [Prevalence of allergic rhinitis, and symptoms as indicators of risk in schoolchildren of the Puebla Northern Mountain Range]. AB - BACKGROUND: According to the ISAAC study, the prevalence of allergy disease is reported to have increased. OBJECTIVE: To determine the prevalence of allergic rhinitis diagnosis, its symptoms and the magnitude of the association of symptoms with the disease as risk indicators. METHODS: A study on allergic rhinitis prevalence was carried out, where 3446 questionnaires were applied to schoolchildren in Zacatlan, Puebla, using a validated instrument. RESULTS: According to the questionnaire results, 413 children (12 %) were positive for allergic rhinitis diagnosis, while 3033 (88 %) were negative; 263 (7.6 %) of the cases with allergic rhinitis diagnosis were females. Overall, the prevalence of symptoms was higher than the prevalence of allergic rhinitis diagnosis. Recurrent catarrhal symptoms had the highest magnitude of association with the disease, followed by symptoms of morning and nocturnal predominance. CONCLUSIONS: The prevalence of allergic rhinitis was 12 %; recurrent nasal symptoms showed higher association with allergic rhinitis than in the general population. PMID- 29983012 TI - [Epidemiological, clinical and diagnostic characterization of children with eosinophilic gastroenteropathy. A retrospective study of three high complexity health institutions]. AB - BACKGROUND: Eosinophilic gastrointestinal disorders (EGID) are uncommon. In Colombia there are no studies in the pediatric population. OBJECTIVE: To describe the epidemiological, clinical and diagnostic characteristics of a pediatric population with EGID. METHODS: Observational, retrospective study in children aged between 0 and 12 years, assessed in three high complexity hospitals in Medellin, Colombia, between 2010 and 2015. RESULTS: Out of 151 children, 74 (49%) had eosinophilic esophagitis, 35 (23.2%) had eosinophilic gastritis, 20 (13.2%), eosinophilic duodenitis, and 65 (43%) eosinophilic ileitis or colitis; 60.9% were males, and median age was 5 years; 66.9% had a history of allergic disease, and 78.8% had involvement of a single segment of the gastrointestinal tract. Main symptoms were abdominal pain and vomiting. Maximum eosinophil count per high power field (HPF) in the esophagus, stomach, duodenum, ileum and colon was 34, 21, 42, 45 and 60, respectively. Peripheral eosinophilia was more common in patients with esophageal and stomach involvement. The most sensitizing foods were egg, milk, shrimp, wheat and chicken. Proton pump inhibitors, steroids or immunosuppressants, as well as food-exclusion diets were used. CONCLUSIONS: EGID can compromise multiple segments, and its symptoms are unspecific; multidisciplinary management is required. PMID- 29983013 TI - [Sleep and immune system]. AB - Sleep is a process that occupies one third part of the life of the human being, and it is essential in order for the individual to be able to maintain body homeostasis. It emerges as an important regulator of the immune system since, during sleep, the necessary functions to maintain its balance are carried out. On the other hand, decreased sleep has deleterious effects that alter the metabolism and produce an increase in the secretion of C-reactive protein, interleukin (IL) 6 and tumor necrosis factor (TNF). These cytokines activate NF-kappaB; therefore, sleep disturbance can be a risk factor for the development of chronic inflammatory and metabolic diseases. Pro-inflammatory cytokines IL-1, IL-6 and TNF increase non-rapid eye movement sleep, whereas anti-inflammatory cytokines such as IL-4 and IL-10 decrease it. Sleep can modify the immune system function by inducing changes in the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system. In turn, the circadian rhythm of hormones such as cortisol and adrenaline, which have a nocturnal decrease, favors different activities of the immune system. The purpose of the present review is to address different aspects of sleep and their relationship with the immune system. PMID- 29983014 TI - [Common variable immunodeficiency and its association with memory B-cell defects]. AB - Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency in adulthood. CVID diagnosis is by exclusion and should be considered in patients of any age who have hypogammaglobulinemia of unknown origin. Numerous patients with CVID show alterations in the development of B lymphocytes, both in plasma cells and memory cells. The absence of memory B cells suggests an insufficient germinal reaction, which can be associated with a blockade of the transition of T1 cells into T2 in patients with IDCV, owing to B cell activating factor (BAFF) receptor deficiency. In patients with IDCV, memory B cell alterations with isotype change favor the development of concomitant comorbidities such as lymphadenopathy, splenomegaly, autoimmunity and granulomatous disease, and multiple classifications that use memory B cells in common have therefore been made trying to generate a classification of patients with IDCV, as well as to establish prognostic factors. PMID- 29983015 TI - [Experimental studies: research designs for the evaluation of interventions in clinical settings]. AB - Experimental studies are used to assess the efficacy and effectiveness of therapeutic (pharmacological or surgical), preventive (such as vaccination or lifestyle changes) or educational interventions (e.g., workshops to improve quality and healthcare). There are different experimental studies but, currently, randomized controlled trial (RCT) is recognized as the type of study that provides the highest level of evidence. When this type of research cannot be carried out, there are quasi-experimental studies, where there may be no randomization or a control group; however, this type of studies has a lower degree of validity. This article describes the way different types of RCT and quasi-experimental studies are performed; their advantages and disadvantages are also explained. PMID- 29983016 TI - [Adverse reaction to food additives in a pediatric patient]. AB - BACKGROUND: Food additives are intentionally-added ingredients in order to modify physical, chemical, biological, or sensory characteristics of foods. Allergic reactions caused by additives are uncommon in children, and their prevalence is not known; however, they can be severe. CASE REPORT: An 8-year-old male presented with anaphylaxis and recurrent anaphylactic shocks due to multiple triggering factors such as food additives and medications. Point-of-care skin tests were performed with several additives, with positive results. Personalized emergency treatment was indicated in view of the possibility of anaphylaxis (adrenaline, diphenhydramine and dexamethasone) and environmental care for aeroallergens. Owing to a history of adverse reaction to salbutamol (giant or generalized urticaria), formoterol dry powder was indicated, which was well tolerated. Organic food exclusive consumption was recommended. CONCLUSIONS: The diagnosis of allergy to additives should be suspected when the patient has a suggestive medical history, allergy to multiple foods or medications, reaction with manufactured foods, unrelated to organic products. PMID- 29983017 TI - [Long-term efficacy of omalizumab in patients with conventional treatment resistant vernal keratoconjunctivitis]. AB - BACKGROUND: In vernal keratoconjunctivitis, traditional treatments are sometimes insufficient for symptom control; the results with omalizumab are promising in resistant cases. CASE REPORT: 15-year-old female adolescent with vernal keratoconjunctivitis who had received multiple ophthalmic treatments, immunotherapy and systemic steroids with no clinical response. She attended a clinical immunology and allergy department where she was started on omalizumab 225 mg every 2 weeks. After 6 months, she showed a decrease in pruritus and photophobia; two years later, both papillae and Horner-Trantas dots had disappeared. She remained symptom-free, and the use of ophthalmic drugs was therefore reduced. The patient missed omalizumab application on 4 occasions; however, symptoms recurred, and the papillae reappeared, but remitted upon drug re-initiation. CONCLUSION: There is a temporal relationship between omalizumab administration and ocular symptom con-trol, with evidence of relapse upon discontinuation. PMID- 29983018 TI - Pattern of infection with Parapharyngodon riojensis Ramallo, Bursey, Goldberg 2002 (Nematoda: Pharyngodonidae) in the lizard Phymaturus extrilidus from Puna region, Argentina AB - The pattern of infection with the nematode Parapharyngodon riojensis in the lizard Phymaturus extrilidus in a Puna area, central-west Argentina was studied. No significant prevalence differences were found between sexes or seasons sampled. However, there were differences in mean intensity between the summer (dry period) and autumn (wet period) seasons. Mean intensity was higher in the moistest season, associated with low body condition in P. extrilidus. The genus Parapharyngodon has a direct life cycle, and environmental moisture could favor higher intensity in the rainy period. The present study provides the first data on the parasitic ecology of P. extrilidus from Argentina. PMID- 29983019 TI - Microfilariae Onchocerca alcis Bain et Rehbinder, 1986 - a new parasite of moose Alces alces (L.) in Poland AB - Onchocerca alcis Bain et Rehbinder, 1986 belongs to the subfamily Onchocercinae. Mature nematodes of O. alcis are located on the surface of hindlimb tendons. The aim of this article was to describe the occurrence of microfilariae of O. alcis in the skin of moose from Kampinos Forest. This is the first report of O. alcis in moose from Poland and the third finding of this rare species in the world. PMID- 29983020 TI - Molecular identification of Buxtonella sulcata from associated-diarrhea in water buffaloes (Bubalus bubalis) in the Philippines AB - Sixty suspected protozoan oocysts were demonstrated from 260 fecal samples collected from water buffaloes aged one month to seven years old with clinical signs of diarrhea in four provinces in the Philippines after conventional methods of isolation, sporulation, morphological characteristics and Kinyoun Acid Fast Staining techniques. The recovered protozoan oocysts were subjected to molecular analysis. Amplification of DNA extractedfrom recovered Eimeria oocysts using universal primers for the ITS-1 region of 18S rRNA revealed PCR products with 348 bp size demonstrated by samples collected from Benguet, La Union and Nueva Ecija provinces in the Philippines while DNA extracted from oocysts of suspected Cryptosporidium spp. samples that applied primers for the SSU of 18S rRNA registered PCR products but no genes were amplified from diarrheic water buffaloes from these provinces. Alignment of the DNA sequences of the suspected Eimeria and Cryptosporidium species revealed sequences for threeisolates of Buxtonella sulcata with product lengths that varied from 235 to 252 bp. This is an initial observation on the involvement of B. sulcata in diarrhea condition of water buffaloes in the Philippines. Phylogenetic analysis of the three local isolates of B. sulcata revealed no similarity with other protozoan constructed according to Neighbor-Joining method. PMID- 29983021 TI - Trichodina amblypharyngodoni sp. n. and Trichodina hoffmani Wellborn, 1967 (Ciliophora: Trichodinidae) from the freshwater fishes in the Baikka Beel of Moulvibazar district in Sylhet division, Bangladesh AB - During a survey on species diversity of trichodinid ciliates from freshwater fishes in the Baikka Beel of Moulvibazar district in Sylhet division from January to December 2015, two species of ciliates were identified, of which one is new to science. Trichodina hoffmani Wellborn, 1967 is collected from the gills of Mystus tengara, and Trichodina amblypharyngodoni sp. n. is described from Amblypharyngodon mola using the silver nitrate impregnation method. T. amblypharyngodoni sp. n. is characterized by having a large, darkly stained central area; rectangularly-rounded butterspoon-shaped blade with very narrow interblade space and blunt tangent point; indistinct anterior and posterior blade apophysis, but a rounded apex near the base of the central part of denticle; slender, sometimes slightly triangular central part with rounded tip; and filamentous, curved, anteriorly directed rays with inflated tip and indistinct central groove. Based on these characters and the unique shape and absence of variability of the denticles among the silver impregnated specimens of the present species, it may be said that to a lesser extent, it resembles Trichodina prowazeki Grupcheva and Lom, 1980. PMID- 29983022 TI - Demodecid mites (Acariformes, Demodecidae) in brown longeared bat Plecotus auritus (Chiroptera, Vespertilionidae) - second record in the world and systematic status of Demodex chiropteralis Hirst, 1921 AB - As many as 26 species of parasitic mites of the Demodecidae family have thus far been described in the Chiroptera, of which only three have been found in bats from Europe. The first of the latter group was Demodex chiropteralis Hirst, 1921, described on the basis of only two females originating from one bat from Great Britain; an observation which has never been made since. The present study reports the discovery of both male and female D. chiropteralis in Poland, together with other unknown demodecid mites which may well belong to new species. The present study confirms the existence of D. chiropteralis after nearly one hundred years from its original description, as well as the first determination of representatives of the Demodecidae in the Chiroptera of Central Europe. PMID- 29983023 TI - Endoparasites of pet reptiles based on coprosopic methods AB - Due to the growing popularity of reptiles as a household animals and the development of numerous reptile farms, they have become a common sight in veterinary clinics. As parasitic infections represent a serious problem among pet reptiles obtained by captive breeding and from pet shops, the purpose of the present study was to determine the species composition of parasites present in reptiles bred privately or in Cracow Zoological Garden, and those obtained from pet shops. Fecal samples collected from 91 reptiles (30 turtles, 40 lizards, and 21 snakes) were examined using the quantitative McMaster method. Parasite eggs or protozoan oocysts were identified in 59.3% of samples. These included the eggs of the Pharyngodonidae, Ascarididae and Rhabditoidea (Nematoda), and Trematoda, as well as oocysts of Isospora and Eimeria. In addition, pseudoparasites belonging to the Mesostigmata, Demodecidae and Myobiidae were found. PMID- 29983024 TI - Parasites community of Astronotus crassipinnis (Cichlidae), a fish from the Brazilian Amazon AB - We provide the first study on the diversity and community of parasites in Astronotus crassipinnis from the lower Amazon River, in Brazil. Of 35 hosts examined, 100% were infected with one or more species of parasites, such as Gussevia asota, Gussevia astronoti, Gussevia rogersi, Posthodiplostomum sp., Contracaecum sp., Gorytocephalus sp. and Dolops longicauda. Gussevia asota, G. astronoti and G. rogersi were dominant, and, in total, 9788 parasites were collected. The richness of parasite species (4.9+/-0.7), Brillouin diversity (0.46+/-0.28) and evenness (0.29+/-0.17) were low. Parasites had aggregated dispersion, parasitism did not affect the host condition factor, and host size did not influence abundance, species richness and parasite diversity. The parasitic fauna was characterized by the presence of few species of parasites with high prevalence and low abundance, specifically the endoparasites, besides dominance of ectoparasites. The presence of endoparasites indicates that the diet of A. crassipinnis consists mostly of mollusks and microcrustaceans. This fish species is an intermediate host for Posthodiplostomum sp., Contracaecum sp. and Gorytocephalus sp., parasites found in larval stage. Finally, the behavior and availability of infective stages, which are intermediate hosts for endoparasites, were factors structuring the communities of endoparasites. PMID- 29983025 TI - Prevalence of endoparasites in captive snakes of Kerala, India AB - The objective of the study was to evaluate the status of parasitic infections in captive snakes of Kerala. Faecal samples were collected from captive snakes of State Museums and Zoos of Thrissur and Thiruvananthapuram. Parasites were screened by direct smear, sedimentation, simple floatation and Shaether's sugar floatation method. Fortynine snakes from 15 species were screened and 35 (71.4%) were found to be positive. While 80% of the snakes from Thrissur were found to be positive for parasitic infections, 70.6% of the samples from Thiruvananthapuram zoo were positive. Strongyloides sp. was the most prominent infection, accounting for 25.7% of all infections, followed by Capillaria sp. (22.8%) and Strongyles (20%). The preliminary investigation of captive Green Anaconda samples from Thiruvananthapuram zoo revealed mites, non-sporulated Coccidia of the genus Eimeria sp. and Cryptosporidium sp. It is understood that most of the infections of the captive snakes were acquired through the feeding and handling of the snakes, therefore periodical sampling is needed for both the snakes and their prey. PMID- 29983026 TI - Tetrameres globosa (Linstow, 1879) (Nematoda, Tetrameridae) - a nematode of the Eurasian coot Fulica atra (Linnaeus, 1758) recorded for the first time in Poland AB - During parasitological studies of 23 Eurasian coot Fulica atra (Linnaeus, 1758), 91 nematodes were isolated. Three of them, found in the proventriculus, were identified as Tetrameres globosa (Linstow, 1879). This paper presents the morphological characteristics of the discovered males of T. globosa. PMID- 29983027 TI - Urszula Gabriela Czaplinska primo voto Dzieszuk (1950-2016), Chemical Engineer PMID- 29983028 TI - Radiation induced secondary malignancies: a review article. AB - Radiation-induced second malignancies (RISM) is one of the important late side effects of radiation therapy and has an impact on optimal treatment decision making. Many factors contribute to the development of RISM such as age at radiation, dose and volume of irradiated area, type of irradiated organ and tissue, radiation technique and individual and family history of cancer. Exact mechanism of RISM is unknown. But nowadays, it is a growing concern in oncology because of the increased number of cancer survivors and efforts are being made to prevent or decrease the incidence of RISM. The primary search for articles was carried via Google Scholar and PubMed with keywords included 'radiation induced malignancies, second malignancies, and chemotherapy induced malignancies'. Additional papers were found through references from relevant articles. In this review article, we have discussed about the pathogenesis, factors contributing to RISM, screening and prevention strategies of RISM. PMID- 29983029 TI - Prognostic value of FDG PET/CT during radiotherapy in head and neck cancer patients. AB - PURPOSE: To evaluate the prognostic value of 18F-fluorodeoxyglucose positron emission tomography (FDG PET) with computed tomography (CT) before and during radiotherapy (RT) in patients with head and neck cancer. METHODS: Twenty patients with primary head and neck squamous cell carcinoma were enrolled in this study, of whom 6 had oropharyngeal cancer, 10 had hypopharyngeal cancer, and 4 had laryngeal cancer. Fifteen patients received concurrent cisplatin and 2 received concurrent cetuximab chemotherapy. FDG PET/CT was performed before RT and in the 4th week of RT. The parameters of maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) of the primary tumor were measured, and the prognostic significance of each was analyzed with the Cox proportional hazards model. RESULTS: Higher TLG (>19.0) on FDG PET/CT during RT was a poor prognostic factor for overall survival (OS) (p = 0.001) and progression-free survival (PFS) (p = 0.007). In the multivariate analysis, TLG during RT as a continuous variable was significantly associated with OS and PFS rate (p = 0.023 and p = 0.016, respectively). Tumor response worse than partial remission at 1 month after RT was another independent prognostic factor for PFS (p = 0.024). Conclusions: Higher TLG of the primary tumor on FDG PET/CT during RT was a poor prognostic factor for OS and PFS in patients with head and neck cancer. PMID- 29983030 TI - Treatment outcomes of radiotherapy for anaplastic thyroid cancer. AB - PURPOSE: Anaplastic thyroid cancer (ATC) is a rare tumor with a lethal clinical course despite aggressive multimodal therapy. Intensity-modulated radiotherapy (IMRT) may achieve a good therapeutic outcome in ATC patients, and the role of IMRT should be assessed. We retrospectively reviewed outcomes for ATC treated with three-dimensional conformal radiotherapy (3D-CRT) or IMRT to determine the optimal treatment option and explore the role of radiotherapy (RT). Materials and. METHODS: Between December 2000 and December 2015, 41 patients with pathologically proven ATC received RT with a sufficient dose of >=40 Gy. Among them, 21 patients (51%) underwent surgery before RT. Twenty-eight patients received IMRT, and 13 received 3D-CRT. Overall survival (OS) and progression-free survival (PFS), patterns of failure, and toxicity were examined. RESULTS: The median follow-up time for survivors was 38.0 months. The median and 1-year OS and PFS rates were 7.2 months and 29%, 4.5 months and 15%, respectively. Surgery significantly improved the prognosis (median OS: 10.7 vs. 3.9 months, p = 0.001; median PFS: 5.9 vs. 2.5 months, p = 0.007). IMRT showed significantly better PFS and OS than 3D-CRT, even in multivariate analysis (OS: hazard ratio [HR] = 0.30, p = 0.005; PFS: HR = 0.33, p = 0.005). Significantly higher radiation dose could be delivered with IMRT than 3D-CRT (EQD210 66 vs. 60 Gy, p = 0.005). Only 2 patients had grade III dermatitis after IMRT. No other severe toxicity >=grade III occurred. CONCLUSION: Patients with ATC showed better prognosis through multimodal treatment. Furthermore, IMRT could achieve favorable survival rates by safely delivering higher dose than 3D-CRT. PMID- 29983031 TI - Maximum diameter versus volumetric assessment for the response evaluation of vestibular schwannomas receiving stereotactic radiotherapy. AB - PURPOSE: To explore the feasibility of maximum diameter as a response assessment method for vestibular schwannomas (VS) after stereotactic radiosurgery or fractionated stereotactic radiotherapy (RT), we analyzed the concordance of RT responses between maximum diameters and volumetric measurements. Materials and. METHODS: Forty-two patients receiving curative stereotactic radiosurgery or fractionated stereotactic RT for VS were analyzed retrospectively. Twelve patients were excluded: 4 did not receive follow-up magnetic resonance imaging (MRI) scans and 8 had initial MRI scans with a slice thickness >3 mm. The maximum diameter, tumor volume (TV), and enhanced tumor volume (ETV) were measured in each MRI study. The percent change after RT was evaluated according to the measurement methods and their concordances were calculated with the Pearson correlation. The response classifications were determined by the assessment modalities, and their agreement was analyzed with Cohen kappa statistics. RESULTS: Median follow-up was 31.0 months (range, 3.5 to 86.5 months), and 90 follow-up MRI studies were analyzed. The percent change of maximum diameter correlated strongly with TV and ETV (r(p) = 0.85, 0.63, p = 0.000, respectively). Concordance of responses between the Response Evaluation Criteria in Solid Tumors (RECIST) using the maximum diameters and either TV or ETV were moderate (kappa = 0.58; 95% confidence interval, 0.32-0.85) or fair (kappa = 0.32; 95% confidence interval, 0.05-0.59), respectively. Conclusions: The percent changes in maximum diameter and the responses in RECIST were significantly concordant with those in the volumetric measurements. Therefore, the maximum diameters can be used for the response evaluation of VS following stereotactic RT. PMID- 29983032 TI - Positional uncertainties of cervical and upper thoracic spine in stereotactic body radiotherapy with thermoplastic mask immobilization. AB - PURPOSE: To investigate positional uncertainty and its correlation with clinical parameters in spine stereotactic body radiotherapy (SBRT) using thermoplastic mask (TM) immobilization. Materials and. METHODS: A total of 21 patients who underwent spine SBRT for cervical or upper thoracic spinal lesions were retrospectively analyzed. All patients were treated with image guidance using cone beam computed tomography (CBCT) and 4 degrees-of-freedom (DoF) positional correction. Initial, pre-treatment, and post-treatment CBCTs were analyzed. Setup error (SE), pre-treatment residual error (preRE), post-treatment residual error (postRE), intrafraction motion before treatment (IM1), and intrafraction motion during treatment (IM2) were determined from 6 DoF manual rigid registration. RESULTS: The three-dimensional (3D) magnitudes of translational uncertainties (mean +/- 2 standard deviation) were 3.7+/-3.5 mm (SE), 0.9+/-0.9 mm (preRE), 1.2+/-1.5 mm (postRE), 1.4+/-2.4 mm (IM1), and 0.9+/-1.0 mm (IM2), and average angular differences were 1.1 degrees +/-1.2 degrees (SE), 0.9 degrees +/-1.1 degrees (preRE), 0.9 degrees +/-1.1 degrees (postRE), 0.6 degrees +/-0.9 degrees (IM1), and 0.5 degrees +/-0.5 degrees (IM2). The 3D magnitude of SE, preRE, postRE, IM1, and IM2 exceeded 2 mm in 18, 0, 3, 3, and 1 patients, respectively. No association were found between all positional uncertainties and body mass index, pain score, and treatment location (p > 0.05, Mann-Whitney test). There was a tendency of intrafraction motion to increase with overall treatment time; however, the correlation was not statistically significant (p > 0.05, Spearman rank correlation test). CONCLUSION: In spine SBRT using TM immobilization, CBCT and 4 DoF alignment correction, a minimum residual translational uncertainty was 2 mm. Shortening overall treatment time and 6 DoF positional correction may further reduce positional uncertainties. PMID- 29983033 TI - Is higher dose always the right answer in stereotactic body radiation therapy for small hepatocellular carcinoma? AB - PURPOSE: This study was conducted to compare clinical outcomes and treatment related toxicities after stereotactic body radiation therapy (SBRT) with two different dose regimens for small hepatocellular carcinomas (HCC) <=3 cm in size. Materials and. METHODS: We retrospectively reviewed 44 patients with liver confined HCC treated between 2009 and 2014 with SBRT. Total doses of 45 Gy (n = 10) or 60 Gy (n = 34) in 3 fractions were prescribed to the 95% isodose line covering 95% of the planning target volume. Rates of local control (LC), intrahepatic failure-free survival (IHFFS), distant metastasis-free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: Median follow-up was 29 months (range, 8 to 64 months). Rates at 1 and 3 years were 97.7% and 95.0% for LC, 97.7% and 80.7% for OS, 76% and 40.5% for IHFFS, and 87.3% and 79.5% for DMFS. Five patients (11.4%) experienced degradation of albumin-bilirubin grade, 2 (4.5%) degradation of Child-Pugh score, and 4 (9.1%) grade 3 or greater laboratory abnormalities within 3 months after SBRT. No significant difference was seen in any oncological outcomes or treatment related toxicities between the two dose regimens. Conclusions: SBRT was highly effective for local control without severe toxicities in patients with HCC smaller than 3 cm. The regimen of a total dose of 45 Gy in 3 fractions was comparable to 60 Gy in efficacy and safety of SBRT for small HCC. PMID- 29983034 TI - External validation of IBTR! 2.0 nomogram for prediction of ipsilateral breast tumor recurrence. AB - PURPOSE: IBTR! 2.0 nomogram is web-based nomogram that predicts ipsilateral breast tumor recurrence (IBTR). We aimed to validate the IBTR! 2.0 using an external data set. Materials and. METHODS: The cohort consisted of 2,206 patients, who received breast conserving surgery and radiation therapy from 1992 to 2012 at our institution, where wide surgical excision is been routinely performed. Discrimination and calibration were used for assessing model performance. Patients with predicted 10-year IBTR risk based on an IBTR! 2.0 nomogram score of <3%, 3%-5%, 5%-10%, and >10% were assigned to groups 1, 2, 3, and 4, respectively. We also plotted calibration values to observe the actual IBTR rate against the nomogram-derived 10-year IBTR probabilities. RESULTS: The median follow-up period was 73 months (range, 6 to 277 months). The area under the receiver operating characteristic curve was 0.607, showing poor accordance between the estimated and observed recurrence rate. Calibration plot confirmed that the IBTR! 2.0 nomogram predicted the 10-year IBTR risk higher than the observed IBTR rates in all groups. High discrepancies between nomogram IBTR predictions and observed IBTR rates were observed in overall risk groups. Compared with the original development dataset, our patients had fewer high grade tumors, less margin positivity, and less lymphovascular invasion, and more use of modern systemic therapies. Conclusions: IBTR! 2.0 nomogram seems to have the moderate discriminative ability with a tendency to over-estimating risk rate. Continued efforts are needed to ensure external applicability of published nomograms by validating the program using an external patient population. PMID- 29983035 TI - Adjuvant external beam radiation and brachytherapy for vaginal resection margin positive cervical cancer. AB - PURPOSE: To evaluate the treatment outcomes of adjuvant external beam radiation therapy (EBRT) and vaginal brachytherapy (VB) following radical hysterectomy in cervical cancer patients with involved vaginal resection margin (VRM). Materials and. METHODS: We retrospectively reviewed the medical records of 21 patients treated with postoperative EBRT and VB for positive VRM FIGO stage IB-IIA cervical cancer between 2003 and 2015. Concurrent platinum-based chemotherapy was administered to all patients. RESULTS: The median whole pelvis EBRT dose was 50.4 Gy (range, 45 to 50.4 Gy). In the VB, the median dose per fraction, number of fractions, and total dose delivered were: 4 Gy (range, 3.0 to 4.0 Gy), 4 fractions (range, 3 to 5 fractions), and 16 Gy (range, 12 to 20 Gy), respectively. At a median follow-up of 46 months (range, 9 to 122 months), local recurrence was observed in 2 patients, and distant metastasis was present in 7 patients. All patients with local recurrence subsequently developed distant metastases. The 5-year local control, disease-free survival, and overall survival rates were 89.1%, 65.9%, and 62.9%, respectively. Of the 21 patients, 7 patients (33.3%) reported grade 2 acute toxicity; however, there were no grade 3 or higher acute adverse events. Grade 1-2 late toxicities were observed in 8 patients. Late grade 3 urinary toxicity was reported in 1 patient. Conclusions: Adjuvant EBRT and VB showed excellent local control and low toxicity in cervical cancer patients with positive VRM. Although limited by its retrospective nature, the findings from our study provide evidence supporting the use of additional VB in pathologically involved VRM. PMID- 29983036 TI - Clinical outcomes and prognostic factors in patients with mycosis fungoides who underwent radiation therapy in a single institution. AB - PURPOSE: We aimed to evaluate clinical outcomes including progression-free survival (PFS), overall survival (OS), partial response, and complete response in patients who underwent radiation therapy (RT) for mycosis fungoides (MF). Also, we sought to find prognostic factors for clinical outcomes. Materials and. METHODS: Total 19 patients confirmed with MF between 1999-2015 were retrospectively reviewed. Clinical and treatment characteristics, clinical outcomes, and and toxicities were analyzed. RESULTS: Eleven patients were treated with total skin electron beam radiotherapy (TSEBT) and 8 patients with involved field radiation therapy (IFRT) with median dose of 30 Gy, respectively. The median time interval from diagnosis to RT was 2.6 months (range, 0.4 to 87.3 months). The overall response rate was 100%; 11 patients (57.9%) had a complete response and 8 patients (42.1%) a partial response. The presence of positive lymph node at the time of consultation of RT was associated with lower OS (p = 0.043). In multivariate analysis, PFS was significantly lower for patients with increased previous therapies experienced following RT (p = 0.019) and for patients showing PR during RT (p = 0.044). There were no reported grade 3 or more skin toxicities related with RT. CONCLUSION: Both IFRT and TSEBT are effective treatment for MF patients. Patients with short disease course before RT or complete response during RT are expected to have longer PFS. Positive lymph node status at the initiation of RT was associated woth poor OS, suggesting other treatment modalities such as low-dose RT for patients with low life-expectancy. PMID- 29983037 TI - Correction: Intensity-modulated radiation therapy: a review with a physics perspective. PMID- 29983038 TI - Treatment of livestock carcasses in soil using Corynebacterium glutamicum and lysosomal application to livestock burial. AB - A method of rapidly decaying livestock carcasses is sought through Corine glutamicum, and furthermore, lysosomes are used to remove toxic microorganisms from livestock carcasses. The landfill was constructed on a laboratory scale. Optimized growth conditions of C. glutamicum that could quickly decay livestock carcasses were determined. Lysosomes were extracted from egg whites and used to treat contaminated soil to confirm their antimicrobial activities. Condition of C. glutamicum was activated, regardless both anaerobic and aerobic conditions, soil exists and, to be close to the optimum conditions as possible temperatures, moisture content was about 1/10 of the culture. Lysosomes were found to be effective in clearing soil contamination. C. glutamicum can accelerate the decay of livestock carcasses. A combination of C. glutamicum and lysomes could be used to treat soil contamination caused by decomposition of livestock. PMID- 29983039 TI - Body Weight Perception and Weight Loss Practices among Private College Students in Kelantan State, Malaysia. AB - BACKGROUND: Body image is associated with the perception of people on themselves. Influencing factors are generated internally and/or externally. The most common issue pertaining to body image is body weight and weight loss. This study aimed to determine the association between body weight perception and weight loss practices among college students. METHODS: A cross-sectional study was conducted involving 297 college students from private nursing colleges in the state of Kelantan, Malaysia. A self-administered questionnaire was used to assess sociodemographic characteristics, body weight perception, and weight loss methods. Weight and height were measured, and body mass index (BMI) was calculated based on weight and height measurement. The World Health Organization BMI cutoffs were applied in the study. RESULTS: More than half (54.2%) of college students perceived their weight correctly as per actual measured BMI. A total of 51.5% of participants had tried various methods to reduce their weight. Body weight perception is associated with weight loss practices (odds ratio, 0.31; 95% confidence interval, 0.19-0.50; P<0.001) adjusted for sex, marital status, and status of having obese family members. Those who had correct body weight perception were less likely to engage in weight loss practice. Food intake restriction (42.4%) is the most popular weight reduction method among students in nursing colleges. Over a quarter of the participants chose physical exercise (25.3%) to reduce their weight, and a small number engaged in unhealthy weight loss practices. CONCLUSION: Body weight perception is an important factor that influences the practice to reduce weight especially among young adult group and college students. PMID- 29983041 TI - The Cutoff Pericardial Adipose Tissue Volume Associated with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MS) is a well-known risk factor of cardiovascular diseases that is focused on central obesity. Recent studies have reported the association between pericardial adipose tissue (PAT) volume and MS. However, no studies have demonstrated the cutoff PAT volume that represents the best association with MS. METHODS: The data of 374 subjects were analyzed cross sectionally to compare PAT, measured on coronary multidetector computed tomography, and various metabolic parameters according to MS. After PAT volumes were divided into tertiles, various metabolic parameters were compared among tertiles; furthermore, the odds ratio for developing MS was calculated. Finally, we demonstrated the cutoff PAT volume that represented the best association with MS by using the receiver-operating characteristic curve. RESULTS: We found that 27.5% of the subjects had MS, and the mean PAT volume was 123.9 cm3 . PAT showed a significant positive correlation with body mass index, waist circumference, and levels of glucose, triglyceride, high-sensitivity C-reactive protein, uric acid, and homocysteine, but a negative correlation with high-density lipoprotein cholesterol. Furthermore, after dividing into tertiles, PAT volume was also significantly associated with various metabolic parameters. The odds ratio for having MS was 4.19 (95% confidence interval, 2.27-7.74) in the top tertile of PAT volumes after adjusting for age, sex, and smoking. The cutoff PAT volume that represented the best association with MS was 142.2 cm3 . CONCLUSION: PAT was significantly associated with MS and various metabolic parameters. The cutoff PAT volume of 142.2 cm3 showed the best association with MS. PMID- 29983040 TI - Time-Lapse Live-Cell Imaging Reveals Dual Function of Oseg4, Drosophila WDR35, in Ciliary Protein Trafficking. AB - Cilia are highly specialized antennae-like organelles that extend from the cell surface and act as cell signaling hubs. Intraflagellar transport (IFT) is a specialized form of intracellular protein trafficking that is required for the assembly and maintenance of cilia. Because cilia are so important, mutations in several IFT components lead to human disease. Thus, clarifying the molecular functions of the IFT proteins is a high priority in cilia biology. Live imaging in various species and cellular preparations has proven to be an important technique in both the discovery of IFT and the mechanisms by which it functions. Live imaging of Drosophila cilia, however, has not yet been reported. Here, we have visualized the movement of IFT in Drosophila cilia using time-lapse live imaging for the first time. We found that NOMPB-GFP (IFT88) moves according to distinct parameters depending on the ciliary segment. NOMPB-GFP moves at a similar speed in proximal and distal cilia toward the tip (~0.45 MUm/s). As it returns to the ciliary base, however, NOMPB-GFP moves at ~0.12 MUm/s in distal cilia, accelerating to ~0.70 MUm/s in proximal cilia. Furthermore, while live imaging NOMPB-GFP, we observed one of the IFT proteins required for retrograde movement, Oseg4 (WDR35), is also required for anterograde movement in distal cilia. We anticipate our time-lapse live imaging analysis technique in Drosophila cilia will be a good starting point for a more sophisticated analysis of IFT and its molecular mechanisms. PMID- 29983042 TI - Association between Breastfeeding and Prevalence of Diabetes in Korean Parous Women: The Korea National Health and Nutrition Examination Survey, 2010-2014. AB - BACKGROUND: It is well known that breastfeeding has a significant impact on the health of mothers and children. With the growing importance of breastfeeding, the present study aimed to investigate the relationship between breastfeeding and the prevalence of diabetes in Korean parous women. METHODS: The data of 5,448 premenopausal parous women aged 20-49 years who agreed to participate in the 5th- 6th Korea National Health and Nutrition Examination Survey were analyzed in this study. Control group included women who had not breastfed. The subjects who had breastfed were classified into three groups based on the duration of breastfeeding: 0-6 months, 6-12 months, and >12 months. The variables included age, body mass index, education level, income, alcohol drinking, smoking, family history of diabetes, use of oral contraceptives, the number of pregnancies, and regular exercise. RESULTS: Among the subjects, the prevalence of diabetes was significantly lower in women who had breastfed compared to those who had not, with an odds ratio of 0.534 (95% confidence interval [CI], 0.289-0.976) in women who breastfed for 0-6 months and 0.575 (95% CI, 0.321-0.990) in women who breastfed for 6-12 months (both P<0.05). CONCLUSION: The present study found a reduced prevalence of diabetes in women who had breastfed compared to those who had not. However, no association between the duration of breastfeeding and the prevalence of diabetes could be found. PMID- 29983044 TI - Controlling the Reaction of Nanoparticles for Hollow Metal Oxide Nanostructures. AB - Hollow nanostructures of metal oxides have found broad applications in different fields. Here, we reported a facile and versatile synthetic protocol to prepare hollow metal oxide nanospheres by modulating the chemical properties in solid nanoparticles. Our synthesis design starts with the precipitation of urea containing metal oxalate, which is soluble in water but exists as solid nanospheres in ethanol. A controlled particle hydrolysis is achieved through the heating-induced urea decomposition, which transforms the particle composition in an outside-to-inside style: The reaction starts from the surface and then proceeds inward to gradually form a water-insoluble shell of basic metal oxalate. Such a reaction-induced solubility difference inside nanospheres becomes highly efficient to create a hollow structure through a simple water wash process. A following high temperature treatment forms hollow nanospheres of different metal oxides with structural features suited to their applications. For example, a high performance anode for Li-ion intercalation pseudocapacitor was demonstrated with the hollow and mesoporous Nb2O5 nanospheres. PMID- 29983043 TI - Dissection, Optimization, and Structural Analysis of a Covalent Irreversible DDAH1 Inhibitor. AB - Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1) can control endogenous nitric oxide production. A time-dependent covalent inactivator of DDAH1, N5-(1-imino-2-chloroethyl)-l-ornithine ( KI = 1.3 MUM, kinact = 0.34 min-1), was conceptually dissected into two fragments and each characterized separately: l-norvaline ( Ki = 470 MUM) and 2-chloroacetamidine ( KI = 310 MUM, kinact = 4.0 min-1). This analysis suggested that the two fragments were not linked in a manner that allows either to reach full affinity or reactivity, prompting the synthesis and characterization of three analogues: two that mimic the dimethylation status of the substrate, N5-(1-imino-2 chloroisopropyl)-l-ornithine ( kinact /KI = 208 M-1 s-1) and N5-(1-imino-2 chlorisopropyl)-l-lysine ( kinact /KI = 440 M-1 s-1), and one that lengthens the linker beyond that found in the substrate, N5-(1-imino-2-chloroethyl)-l-lysine (Cl-NIL, KI = 0.19 MUM, kinact = 0.22 min-1). Cl-NIL is one of the most potent inhibitors reported for DDAH1, inactivates with a second order rate constant (1.9 * 104 M-1 s-1) larger than the catalytic efficiency of DDAH1 for its endogenous substrate (1.6 * 102 M-1 s-1), and has a partition ratio of 1 with a >100 000 fold selectivity for DDAH1 over arginase. An activity-based protein-profiling probe is used to show inhibition of DDAH1 within cultured HEK293T cells (IC50 = 10 MUM) with cytotoxicity appearing only at higher concentrations (ED50 = 118 MUM). A 1.91 A resolution X-ray crystal structure reveals specific interactions made with DDAH1 upon covalent inactivation by Cl-NIL. Dissecting a covalent inactivator and analysis of its constituent fragments proved useful for the design and optimization of this potent and effective DDAH1 inhibitor. PMID- 29983045 TI - Biokinetic Modeling of Cd Bioaccumulation from Water, Diet and Sediment in a Marine Benthic Goby: A Triple Stable Isotope Tracing Technique. AB - Aquatic animals are often simultaneously exposed to metals through multiple routes in the natural environment. This study explored a triple stable isotope tracing method to quantify simultaneous cadmium (Cd) uptake biokinetics by yellow stripe goby from water (traced by 110Cd), sediment (traced by 111Cd), and diet (traced by 113Cd) when the fish were exposed to Cd for 24 h. The simultaneous uptake of Cd from multiple routes during 4 weeks was then predicted by the modified biokinetic model. The results demonstrated that the uptake rate constant of waterborne 110Cd, sediment-associated 111Cd, and dietary 113Cd was 3.1 L kg-1 d-1, 2.2 * 10-4 g g-1 d-1, and 3.3 * 10-3 g g-1 d-1 in the fish. Sedimentary Cd was less bioavailable than the waterborne and dietary Cd; however, sediment could become the predominant Cd source of the total Cd bioaccumulation when the partition coefficient of Cd between sediment and seawater ( Kd) is larger than 6 * 104 L kg-1. The simultaneous uptake of Cd from the three routes could be successfully predicted by the modified model. The model revealed that the Cd bioaccumulation generally increased with the increase of ambient Cd concentration in all the three routes. Overall, our findings demonstrated that the multiple stable isotopes tracing method and the modified biokinetic model have a wide generality and applicability for predicting Cd bioaccumulation under multiple routes of metal exposure scenario and may have application to other metals. PMID- 29983046 TI - Visible-Light-Activated Quinolone Carbon-Monoxide-Releasing Molecule: Prodrug and Albumin-Assisted Delivery Enables Anticancer and Potent Anti-Inflammatory Effects. AB - The delivery of controlled amounts of carbon monoxide (CO) to biological targets is of significant current interest. Very few CO-releasing compounds are currently known that can be rigorously controlled in terms of the location and amount of CO released. To address this deficiency, we report herein a new metal-free, visible light-induced CO-releasing molecule (photoCORM) and its prodrug oxidized form, which offer new approaches to controlled, localized CO delivery. The new photoCORM, based on a 3-hydroxybenzo[ g]quinolone framework, releases 1 equiv of CO upon visible-light illumination under a variety of biologically relevant conditions. This nontoxic compound can be tracked prior to CO release using fluorescence microscopy and produces a nontoxic byproduct following CO release. An oxidized prodrug form of the photoCORM is reduced by cellular thiols, providing an approach toward activation in the reducing environment of cancer cells. Strong noncovalent affinity of the nonmetal photoCORM to albumin enables use of an albumin:photoCORM complex for targeted CO delivery to cancer cells. This approach produced cytotoxicity IC50 values among the lowest reported to date for CO delivery to cancer cells by a photoCORM. This albumin:photoCORM complex is also the first CO delivery system to produce significant anti-inflammatory effects when introduced at nanomolar photoCORM concentration. PMID- 29983047 TI - UV-Assisted Cataluminescent Sensor for Carbon Monoxide Based on Oxygen Functionalized g-C3N4 Nanomaterials. AB - Cataluminescence (CTL) is one of the most important sensing-transduction principles for the real-time monitoring of atmospheric pollutants. Highly sensitive CTL-based CO detection still remains a challenge because of the relatively poor reactivity of CO and the low catalytic efficiency of the catalysts. Herein, combining ultraviolet (UV)-light activation and chemical modification of the sensing element, we have successfully established a UV assisted CTL sensor for gaseous CO based on g-C3N4 with high sensitivity, selectivity, and stability. UV irradiation can efficiently activate CO molecules and induce the generation of reactive oxygen species (ROS) for CO oxidation. Furthermore, carboxyl groups greatly facilitate the chemisorption of CO on functionalized g-C3N4 nanomaterials, thus enhancing the CTL sensitivity. The influences of experimental conditions and the possible catalytic mechanism of CO on functionalized g-C3N4 have been investigated in detail. Under the optimal experimental conditions, the proposed CTL sensor presents a detection limit (3sigma) toward CO of 0.008 MUg mL-1, which is much lower than the maximum allowable emission concentration of CO in atmospheric conditions (0.030 MUg mL 1). The UV-CTL system is green, sensitive, stable, and low cost, and thus it possesses great potential application in gas sensing. PMID- 29983048 TI - Nonfullerene/Fullerene Acceptor Blend with a Tunable Energy State for High Performance Ternary Organic Solar Cells. AB - Ternary blending is an effective strategy for broadening the absorption range of the active layer in bulk heterojunction polymer solar cells and for constructing an efficient cascade energy landscape at the donor/acceptor interface to achieve high efficiencies. In this study, we report efficient ternary blend solar cells containing an acceptor alloy consisting of the indacenodithiophene-based nonfullerene material, IDT2BR, and the fullerene material, phenyl-C71-butyric acid methyl ester (PC71BM). The IDT2BR materials mix fully with PC71BM materials, and the energy state of this phase can be tuned by varying the blending ratio. We performed photoluminescence and external quantum efficiency studies and found that the ternary charge cascade structure efficiently transfers the photogenerated charges from the polymer to IDT2BR and finally to PC71BM materials. Ternary blend devices containing the IDT2BR:PC71BM acceptor blend and various types of donor polymers were found to exhibit power conversion efficiencies (PCEs) improved by more than 10% over the PCEs of the binary blend devices. PMID- 29983049 TI - Ag(I)-C-H Activation Enables Near-Room-Temperature Direct alpha-Arylation of Benzo[ b]thiophenes. AB - The first example of near-room-temperature alpha-arylation of benzo[ b]thiophenes is reported. The discovery rests on the observation of a switch in alpha-/beta regioselectivity at different loadings of Pd2(dba)3.CHCl3 in the coupling between benzo[ b]thiophene and 4-iodotoluene. We show that this unprecedented regioselectivity switch is driven by a Ag(I)-mediated C-H activation at the alpha C-H position, which becomes the dominant mode of reactivity at low concentrations of Pd. Competition experiments, kinetic studies, KIE, and D/H scrambling experiments have been carried out supporting this mechanism. PMID- 29983050 TI - Thermodynamics of Hg(II) Bonding to Thiol Groups in Suwannee River Natural Organic Matter Resolved by Competitive Ligand Exchange, Hg LIII-Edge EXAFS and 1H NMR Spectroscopy. AB - A molecular level understanding of the thermodynamics and kinetics of the chemical bonding between mercury, Hg(II), and natural organic matter (NOM) associated thiol functional groups (NOM-RSH) is required if bioavailability and transformation processes of Hg in the environment are to be fully understood. This study provides the thermodynamic stability of the Hg(NOM-RS)2 structure using a robust method in which cysteine (Cys) served as a competing ligand to NOM (Suwannee River 2R101N sample) associated RSH groups. The concentration of the latter was quantified to be 7.5 +/- 0.4 MUmol g-1 NOM by Hg LIII-edge EXAFS spectroscopy. The Hg(Cys)2 molecule concentration in chemical equilibrium with the Hg(II)-NOM complexes was directly determined by HPLC-ICPMS and losses of free Cys due to secondary reactions with NOM was accounted for in experiments using 1H NMR spectroscopy and 13C isotope labeled Cys. The log K +/- SD for the formation of the Hg(NOM-RS)2 molecular structure, Hg2+ + 2NOM-RS- = Hg(NOM-RS)2, and for the Hg(Cys)(NOM-RS) mixed complex, Hg2+ + Cys- + NOM-RS- = Hg(Cys)(NOM-RS), were determined to be 40.0 +/- 0.2 and 38.5 +/- 0.2, respectively, at pH 3.0. The magnitude of these constants was further confirmed by 1H NMR spectroscopy and the Hg(NOM-RS)2 structure was verified by Hg LIII-edge EXAFS spectroscopy. An important finding is that the thermodynamic stabilities of the complexes Hg(NOM RS)2, Hg(Cys)(NOM-RS) and Hg(Cys)2 are very similar in magnitude at pH values <7, when all thiol groups are protonated. Together with data on 15 low molecular mass (LMM) thiols, as determined by the same method ( Liem-Ngyuen et al. Thermodynamic stability of mercury(II) complexes formed with environmentally relevant low molecular-mass thiols studied by competing ligand exchange and density functional theory . Environ. Chem. 2017 , 14 , ( 4 ), 243 - 253 .), the constants for Hg(NOM RS)2 and Hg(Cys)(NOM-RS) represent an internally consistent thermodynamic data set that we recommend is used in studies where the chemical speciation of Hg(II) is determined in the presence of NOM and LMM thiols. PMID- 29983051 TI - Heterogeneously Catalyzed Aerobic Oxidation of Sulfides with a BaRuO3 Nanoperovskite. AB - A rhombohedral BaRuO3 nanoperovskite, which was synthesized by the sol-gel method using malic acid, could act as an efficient heterogeneous catalyst for the selective oxidation of various aromatic and aliphatic sulfides with molecular oxygen as the sole oxidant. BaRuO3 showed much higher catalytic activities than other catalysts, including ruthenium-based perovskite oxides, under mild reaction conditions. The catalyst could be recovered by simple filtration and reused several times without obvious loss of its high catalytic performance. The catalyst effect, 18O-labeling experiments, and kinetic and mechanistic studies showed that substrate oxidation proceeds with oxygen species caused by the solid. The crystal structure of ruthenium-based oxides is crucial to control the nature of the oxygen atoms and significantly affects their oxygen transfer reactivity. Density functional theory calculations revealed that the face-sharing octahedra in BaRuO3 likely are possible active sites in the present oxidation in sharp contrast to the corner-sharing octahedra in SrRuO3, CaRuO3, and RuO2. The superior oxygen transfer ability of BaRuO3 is also applicable to the quantitative conversion of dibenzothiophene into the corresponding sulfone and gram-scale oxidation of 4-methoxy thioanisole, in which 1.20 g (71% yield) of the analytically pure sulfoxide could be isolated. PMID- 29983052 TI - Computational Kinetics of Hydroperoxybutylperoxy Isomerizations and Decompositions: A Study of the Effect of Hydrogen Bonding. AB - Hydroperoxyalkylperoxy (OOQOOH) radicals are important intermediates in combustion chemistry. The conventional isomerization of OOQOOH radicals to form ketohydroperoxides has been long believed to be the most important chain branching reaction under the low-temperature combustion conditions. In this work, the kinetics of competing pathways (alternative isomerization, concerted elimination, and H-exchange pathways) to the conventional isomerization of different beta-, gamma- and Delta-OOQOOH butane isomers are investigated. Six- and seven-membered ring conventional isomerizations are found to be the dominant pathways, whereas alternative isomerizations are more important than conventional isomerization, when the latter proceeded via a more strained transition state ring. The oxygen atoms in OOQOOH radicals introduce intramolecular hydrogen bonding (HB) that significantly affects the energies of reacting species and transition states, ultimately influencing chemical kinetics. Conceptually, HB has a dual effect on the stability of chemical species, the first being the stabilizing effect of the actual intramolecular HB force, and the second being the destabilizing effect of ring strain imposed by the HB conformer. The overall effect can be quantified by determining the difference between the minimum energy conformers of a chemical species or transition state that have HB and that do not have HB (non-hydrogen bonding (NHB)). The stabilization effect of HB on the species and transition sates is assessed, and its effect on the calculated rate constants is also considered. Our results show that, for most species and transition states, HB stabilizes their energies by as much as 2.5 kcal/mol. However, NHB conformers are found to be more stable by up to 2.7 kcal/mol for a few of the considered species. To study the effect of HB on rate constants, reactions are categorized into two groups ( groups one and two) based on the structural similarity of the minimum energy conformers of the reactant and transition state, for a particular reaction. For cases where the reactant and transition state conformers are similar (i.e., both HB or NHB structures), group one, the effect of HB on reaction kinetics is major only if the magnitudes of the stabilization energy of the reactant and transition state are quite different. Meanwhile, for group two, where the reactant and transition state prefer different conformers (one HB and the other NHB), HB affects the kinetics when the stabilization energy of the reactant or transition state is significant or the entropy effect is important. This information is useful in determining corrections accounting for HB effects when assigning rate parameters for chemical reactions using estimation and/or analogy, where analogies usually result in inaccuracies when modeling atmospheric and combustion processes. PMID- 29983053 TI - High-Pressure Methane Adsorption in Porous Lennard-Jones Crystals. AB - Decades of research have yet to yield porous adsorbents that meet the U.S. Department of Energy's methane storage targets. To better understand why, we calculated high-pressure methane adsorption in 600 000 randomly generated porous crystals, or "pseudomaterials," using atomistic grand canonical Monte Carlo (GCMC) simulations. These pseudomaterials were periodic configurations of Lennard Jones spheres whose coordinates in space, along with corresponding well depths and radii, were all chosen at random. GCMC simulations were performed for pressures of 35 and 65 bar at a temperature of 298 K. Methane adsorption was compared for all materials against a range of other properties: average well depths and radii, number density, helium void fraction, and volumetric surface area. The results reveal structure-property relationships that resemble those previously observed for metal-organic frameworks and other porous materials. We contend that our computational methodology can be useful for discovering useful structure-property relationships related to gas adsorption without requiring experimentally accessible structural data. PMID- 29983055 TI - Surface-Engineered PtNi-O Nanostructure with Record-High Performance for Electrocatalytic Hydrogen Evolution Reaction. AB - Hydrogen holds the potential of replacing nonrenewable fossil fuel. Improving the efficiency of hydrogen evolution reaction (HER) is critical for environmental friendly hydrogen generation through electrochemical or photoelectrochemical water splitting. Here we report the surface-engineered PtNi-O nanoparticles with enriched NiO/PtNi interface on surface. Notably, PtNi-O/C showed a mass activity of 7.23 mA/MUg at an overpotential of 70 mV, which is 7.9 times higher compared to that of the commercial Pt/C, representing the highest reported mass activity for HER in alkaline conditions. The HER overpotential can be lowered to 39.8 mV at 10 mA/cm2 when platinum loading was only 5.1 MUgpt/cm2, showing exceptional HER efficiency. Meanwhile, the prepared PtNi-O/C nanostructures demonstrated significantly improved stability as well as high current performance which are well over those of the commercial Pt/C and demonstrated capability of scaled hydrogen generation. PMID- 29983054 TI - Bioinformatic Expansion and Discovery of Thiopeptide Antibiotics. AB - Thiopeptides are members of the ribosomally synthesized and post-translationally modified peptide family of natural products. Most characterized thiopeptides display nanomolar potency toward Gram-positive bacteria by blocking protein translation with several being produced at the industrial scale for veterinary and livestock applications. Employing our custom bioinformatics program, RODEO, we expand the thiopeptide family of natural products by a factor of four. This effort revealed many new thiopeptide biosynthetic gene clusters with products predicted to be distinct from characterized thiopeptides and identified gene clusters for previously characterized molecules of unknown biosynthetic origin. To further validate our data set of predicted thiopeptide biosynthetic gene clusters, we isolated and characterized a structurally unique thiopeptide featuring a central piperidine and rare thioamide moiety. Termed saalfelduracin, this thiopeptide displayed potent antibiotic activity toward several drug resistant Gram-positive pathogens. A combination of whole-genome sequencing, comparative genomics, and heterologous expression experiments confirmed that the thioamide moiety of saalfelduracin is installed post-translationally by the joint action of two proteins, TfuA and YcaO. These results reconcile the previously unknown origin of the thioamide in two long-known thiopeptides, thiopeptin and Sch 18640. Armed with these new insights into thiopeptide chemical-genomic space, we provide a roadmap for the discovery of additional members of this natural product family. PMID- 29983056 TI - Permanent CO2 Trapping through Localized and Chemical Gradient-Driven Basalt Carbonation. AB - Recent laboratory and field studies have demonstrated that basalt formations may present one of the most secure repositories for anthropogenic CO2 emissions through carbon mineralization. In this work, a series of high-temperature, high pressure core flooding experiments was conducted to investigate how transport limitations, reservoir temperature, and brine chemistry impact carbonation reactions following injection of CO2-rich aqueous fluids into fractured basalts. At 100 degrees C and 6.3 mM [NaHCO3], representative of typical reservoir conditions, carbonate precipitates were highly localized on reactive mineral grains contributing key divalent cations. Geochemical gradients promoted localized reaction fronts of secondary precipitates that were consistent with 2D reactive transport model predictions. Increasing [NaHCO3] to 640 mM dramatically enhanced carbonation in diffusion-limited zones, but an associated increase in clays filling advection-controlled flow paths could ultimately obstruct flow and limit sequestration capacity under such conditions. Carbonate and clay precipitation were further enhanced at 150 degrees C, reducing the pre-reaction fracture volume by 48% compared to 35% at 100 degrees C. Higher temperature also produced more carbonate-driven fracture bridging, which generally increased with diffusion distance into dead-end fractures. In combination, the results are consistent with field tests indicating that mineralization will predominate in buffered diffusion-limited zones adjacent to bulk flow paths and that alkaline reservoirs with strong geothermal gradients will enhance the extent of carbon trapping. PMID- 29983057 TI - Large Out-of-Plane Deformations of Two-Dimensional Covalent Organic Framework (COF) Sheets. AB - Flexibility and deformability are important factors influencing the assembly and application of two-dimensional covalent organic frameworks (2D COFs). On one hand, the formation of stable, extended 2D sheets is a prerequisite for the fabrication of high-quality 2D crystals. On the other hand, characterizing these properties will eventually provide a path toward the inclusion of electron vibration couplings when evaluating their electronic properties such as their band structures. Here, atomistic molecular dynamics simulations are used to investigate the mechanical properties of 2D COF sheets, taking the prototypical COF-5 as a representative example. Large out-of-plane deformations are found, about 400% higher than those encountered in graphene. In addition, structural defects lead to significantly larger twists and deformations, which underlines the challenges in fabricating stand-alone, large-size 2D COF sheets. Stacking, on the other hand, effectively reduces the out-of-plane deformations and suppresses the role of defects, two aspects beneficial to the lateral extension of 2D COF sheets. PMID- 29983058 TI - Carbonate Facilitated Mobilization of Uranium from Lacustrine Sediments under Anoxic Conditions. AB - Sorbed U(IV) species can be major products of U(VI) reduction in natural reducing environments as sediments and waterlogged soils. These species are considered more labile than crystalline U(IV) minerals, which could potentially influence uranium migration in natural systems subjected to redox oscillations. In this study, we examined the role of oxygen and carbonate on the remobilization of uranium from lake sediments, in which ~70% of the 150-300 ppm U is under the form of mononuclear U(IV) sorbed species. Our results show that both drying and oxic incubation only slightly increase the amount of remobilized U after 8 days, compared to anoxic drying and anoxic incubation. In contrast, the amount of remobilized U increases with the quantity of added bicarbonate even under anoxic conditions. Moreover, U LIII-edge XANES data show that a significant amount of the solid U(IV) is mobilized in such conditions. Thermodynamic speciation calculations based on the supernatant composition indicates the predominance of aqueous UO2(CO3)34- and, to a lesser extent, CaUO2(CO3)32- complexes. These results suggest that monomeric U(IV) species could be oxidized into aqueous U(VI) carbonate complexes even under anoxic conditions via carbonate promoted oxidative dissolution, which emphasizes the need for considering such a process when modeling U dynamics in reducing environments. PMID- 29983059 TI - Epimerization of Tertiary Carbon Centers via Reversible Radical Cleavage of Unactivated C(sp3)-H Bonds. AB - Reversible cleavage of C(sp3)-H bonds can enable racemization or epimerization, offering a valuable tool to edit the stereochemistry of organic compounds. While epimerization reactions operating via cleavage of acidic C(sp3)-H bonds, such as the Calpha-H of carbonyl compounds, have been widely used in organic synthesis and enzyme-catalyzed biosynthesis, epimerization of tertiary carbons bearing a nonacidic C(sp3)-H bond is much more challenging with few practical methods available. Herein, we report the first synthetically useful protocol for the epimerization of tertiary carbons via reversible radical cleavage of unactivated C(sp3)-H bonds with hypervalent iodine reagent benziodoxole azide and H2O under mild conditions. These reactions exhibit excellent reactivity and selectivity for unactivated 3 degrees C-H bonds of various cycloalkanes and offer a powerful strategy for editing the stereochemical configurations of carbon scaffolds intractable to conventional methods. Mechanistic study suggests that the unique ability of N3* to serve as a catalytic H atom shuttle is critical to reversibly break and reform 3 degrees C-H bonds with high efficiency and selectivity. PMID- 29983060 TI - Formation and Diffusion of Subsurface Adsorbates at Electrodes. AB - We report direct observation of the formation of a subsurface species at metal electrodes in liquid electrolytes and of its migration within the solid's surface layer, below a chemisorbed electrochemical double layer. Using in situ video-rate scanning tunneling microscopy, we find for adsorbed sulfide on bromide-covered Ag(100) electrodes reversible transitions between adsorption sites on top of the surface and within a vacancy in the first Ag layer. In the latter state, the sulfide surface diffusion can be enhanced by orders of magnitude, which we attribute to vacancy-mediated diffusion underneath the bromide adlayer. The high dynamics within the surface layer, indicated by these observations, may open up alternative pathways in electrocatalytic reactions and growth processes. PMID- 29983061 TI - Covalent Post-assembly Modification Triggers Multiple Structural Transformations of a Tetrazine-Edged Fe4L6 Tetrahedron. AB - Covalent post-assembly modification (PAM) reactions are useful synthetic tools for functionalizing and stabilizing self-assembled metal-organic complexes. Recently, PAM reactions have also been explored as stimuli for triggering supramolecular structural transformations. Herein we demonstrate the use of inverse electron-demand Diels-Alder (IEDDA) PAM reactions to induce supramolecular structural transformations starting from a tetrazine-edged FeII4L6 tetrahedral precursor. Following PAM, this tetrahedron rearranged to form three different architectures depending on the addition of other stimuli: an electron rich aniline or a templating anion. By tracing the stimulus-response relationships within the system, we deciphered a network of transformations that mapped different combinations of stimuli onto specific transformation products. Given the many functions being developed for self-assembled three-dimensional architectures, this newly established ability to control the interconversion between structures using combinations of different stimulus types may serve as the basis for switching the functions expressed within a system. PMID- 29983062 TI - Rhodamine 6G-Labeled Pyridyl Aroylhydrazone Fe(II) Complex Exhibiting Synergetic Spin Crossover and Fluorescence. AB - Here, we use a pyridinecarbaldehyde rhodamine 6G hydrazone ligand (L) to synthesize an Fe(II) complex 1 for the search of new fluorescent-spin crossover (SCO) materials. Single-crystal structural determinations suggest that the Fe(II) ion is chelated by two ring-opened ligands (L-o) to form a FeN4O2 coordination environment, and intermolecular pi---pi contacts of the xanthene groups connect the adjacent molecules to form a supramolecular one-dimensional chain. Magnetic susceptibility measurements on complex 1 show that three-step SCO takes place in the temperature range of 120-350 K, and its desolvated form 1-d exhibits SCO around room temperature ( Tc? = 343 K and Tc? = 303 K) with a wide hysteresis loop of 40 K. Moreover, complex 1-d displays light-induced excited spin-state trapping phenomenon. Intriguingly, the fluorescence intensity of the maximum emission at 560 nm for complex 1-d displays discontinuous variation in the range of 250-400 K, indicative of the occurrence of synergetic fluorescence and SCO. PMID- 29983063 TI - Atomistic Picture of Fluorescent Probes with Hydrocarbon Tails in Lipid Bilayer Membranes: An Investigation of Selective Affinities and Fluorescent Anisotropies in Different Environmental Phases. AB - By reverting to spectroscopy, changes in the biological environment of a fluorescent probe can be monitored and the presence of various phases of the surrounding lipid bilayer membranes can be detected. However, it is currently not always clear in which phase the probe resides. The well-known orange 1,1' dioctadecyl-3,3,3',3'-tetramethylindodicarbo-cyanine perchlorate (DiI-C18(5)) fluorophore, for instance, and the new, blue BODIPY (4,4-difluoro-4-bora-3 a,4 a diaza- s-indacene) derivative were experimentally seen to target and highlight identical parts of giant unilamellar vesicles of various compositions, comprising mixtures of dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine (DOPC), sphingomyelin (SM), and cholesterol (Chol). However, it was not clear which of the coexisting membrane phases were visualized (Bacalum et al., Langmuir. 2016, 32, 3495). The present study addresses this issue by utilizing large-scale molecular dynamics simulations and the z-constraint method, which allows evaluating Gibbs free-energy profiles. The current calculations give an indication why, at room temperature, both BODIPY and DiI-C18(5) probes prefer the gel (So) phase in DOPC/DPPC (2:3 molar ratio) and the liquid-ordered (Lo) phase in DOPC/SM/Chol (1:2:1 molar ratio) mixtures. This study highlights the important differences in orientation and location and therefore in efficiency between the probes when they are used in fluorescence microscopy to screen various lipid bilayer membrane phases. Dependent on the lipid composition, the angle between the transition-state dipole moments of both probes and the normal to the membrane is found to deviate clearly from 90 degrees . It is seen that the DiI-C18(5) probe is located in the headgroup region of the SM/Chol mixture, in close contact with water molecules. A fluorescence anisotropy study also indicates that DiI C18(5) gives rise to a distinctive behavior in the SM/Chol membrane compared to the other considered membranes. The latter behavior has not been seen for the studied BODIPY probe, which is located deeper in the membrane. PMID- 29983064 TI - Measuring the Interactions between Protein-Coated Microspheres and Polymer Brushes in Aqueous Solutions. AB - Hydrophilic or zwitterionic polymer-functionalized surfaces have become attractive biomaterials in bioscience and technology due to their excellent protein-resistant ability. Understanding the fundamental interactions between proteins and polymers plays an essential role in the surface design of biomaterials. In this work, we studied the interactions between bovine serum albumin (BSA) and two sorts of polymer brushes including zwitterionic poly(carboxybetaine methacrylate) (PCBMA) and hydrophilic poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) in NaCl aqueous solutions directly with a self-established total internal reflection microscope (TIRM) to provide a better understanding of the underlying nonfouling mechanism of polymers. Our results indicate that both the surface charge and brushes length can affect protein adsorption through electrostatic and steric repulsions, respectively. Both PCBMA- and POEGMA-coated surfaces display negative charge properties due to incomplete coverage and ionic adsorption. As a result, strong electrostatic repulsions between proteins and negatively charged polymer-coated surfaces could contribute to the resistance of protein-coated particles in solutions with low ionic strength (0.1, 0.5, and 1 mM) and disappear in solutions with high ionic strength (10 mM). The measured interaction profiles demonstrate that PCBMA brushes could provide apparent steric forces only at high ionic strength (10 mM), where zwitterionic brushes exhibit a relatively extended conformation with a lack of electrostatic forces between intra- and interpolymers. In contrast, the steric repulsion between proteins and POEGMA brushes appears when particles diffuse at low positions in all salt concentrations (0.1-10 mM) with similar steric decay lengths, which results from the unresponsiveness of POEGMA brushes to the salt stimulus. PMID- 29983065 TI - Continuous Uptake or Saturation-Investigation of Concentration and Surface Packing-Specific Hemin Interaction with Lipid Membranes. AB - Drug design and targeted delivery in cells serve as a flourishing area not only for scientific inquiry, owing to numerous clinical applications, but also for understanding cell interaction with exogenous materials. The membrane localization of heme and its analog hemin, one of the most biologically relevant planar organic molecule, is very important to understand the molecular mechanism of intercalation and adsorption of this cytotoxic molecule after its dissociation from proteins such as hemoglobin. Herein, we investigate the differential behavior of hemin on the soft membrane surfaces of phospholipids by synchrotron based X-ray scattering techniques, Langmuir monolayer measurements, and molecular dynamics simulation. A continuous hemin uptake from the subphase and intercalation into and/or adsorption on to the membrane surface have been witnessed in a strong membrane surface packing-specific manner. Competitive interactions between hemin-membrane and hemin-hemin are proposed to be responsible for the critical hemin concentration. Up to the limit, a continuous hemin uptake is possible and beyond that the hemin-hemin interaction dominates, effectively reducing the hemin intercalation into the membrane. This structural model of the hemin-uptake process can be generalized to understand the localization and transport across membranes and also for the development and design of new drugs. PMID- 29983066 TI - Synthesis of Fluorescent and Water-Dispersed Germanium Nanoparticles and Their Cellular Imaging Applications. AB - In recent years, Ge nanomaterials have aroused a great deal of attention because of their unique physical and chemical properties. However, the current synthesis methods bear some disadvantages, such as high reaction temperature, dangerous reagents, and inert atmospheres. In this paper, we developed a facile one-step route for preparing fluorescent and water-dispersed germanium nanoparticles (Ge NPs) by utilizing organogermanes as the precursor, operated at mild reactive conditions. The as-synthesized Ge NPs have an average diameter of 2.6 +/- 0.5 nm and intense blue-green fluorescence (FL). Furthermore, the as-synthesized Ge NPs show remarkable water dispersibility, favorable biocompatibility, outstanding photostability, excellent storage stability, and low cytotoxicity. More importantly, these Ge NPs can act as a satisfactory FL probe and successfully be applied to cellular imaging of HeLa. The present study offers a simple and moderate strategy for the preparation of Ge NPs and expedites Ge NPs for bioimaging applications. PMID- 29983067 TI - Self-Assembly of TiO2 Nanofiber-Based Microcapsules by Spontaneously Evolved Multiple Emulsions. AB - We demonstrate hierarchical nest/crust-like colloidosomes composed of interlocked titanium dioxide (TiO2) nanofibers using spontaneously evolved n-butanol/water/ n butanol (B/W/B) emulsions. We find two mechanisms to produce colloidosomes from B/W/B droplets due to their mutual solubility and dewetting discrepancy. Porous TiO2 colloidal capsules with loosely intertwined nanofibers were obtained after the dewetting of nanofiber-coated B/W/B droplets, while crustlike TiO2 colloidosomes with a thin shell and large hollow interior are developed from amphiphilic polymer-stabilized B/W/B droplets. We further investigate the effect of experimental parameters, including the initial droplet size, the nanofiber concentration, and the water/butanol ratios in butanol phases, on the droplet-to colloidosome evolution and resultant morphology of colloidosomes. Our simple and versatile approach for fabricating TiO2 colloidosomes can be extended to a range of irregular colloidal particles, and the products have great potential to act as host systems in electrochemical catalysis, photothermal therapy, or filtration materials. PMID- 29983068 TI - Interchain Overlap Affects Formation of Silk Fibroin Secondary Structures on Hydrophobic Polystyrene Surface Detected via Achiral/Chiral Sum Frequency Generation. AB - Silk fibroin (SF) has been engineered in the biomedical applications on account of its structural robustness, biocompatibility, and biodegradability. However, in situ study is still lacking with respect to the formation of SF secondary structures at the interface. In this paper, by using methanol as an inducing agent, the formation of SF secondary structures at the polystyrene (PS)/SF solution interfaces was detected with achiral and chiral sum frequency generation (SFG) vibrational spectroscopy. SF solutions with two concentrations above and below the critical overlapping concentration ( C*) of SF (~1.8 mg/mL) were chosen, namely, 90 and 1 mg/mL. We found that above C*, before adding methanol to the protein solution, no ordered SF secondary structures could be detected at the PS/SF solution interface; oppositely, after adding methanol to the protein solution, ordered SF secondary structure, for example, antiparallel beta-sheet, could be formed at the PS/protein solution interface. Below C*, both before and after adding methanol to the SF solution, ordered SF secondary structure such as antiparallel beta-sheet could be formed. Besides, the addition of methanol could induce the formation of an extended helical structure, verified by the achiral and chiral characteristic bands. Because C* represents a critical solution concentration above which the SF chains can interact with each other and below which the SF chains are isolated in the solution, this achiral/chiral SFG study emphasizes the importance of the chain-chain interaction or spatial confinement on the formation of the protein secondary structures, which provides an additional dimension for the future study of interfacial protein folding. PMID- 29983069 TI - Interfacial Polymerization of Zwitterionic Building Blocks for High-Flux Nanofiltration Membranes. AB - A simple scalable strategy is proposed to fabricate highly permeable antifouling nanofiltration membranes. Membranes with a selective thin polyamide layer were prepared via interfacial polymerization incorporating building blocks of zwitterionic copolymers. The zwitterionic copolymer, poly(aminopropyldimethylaminoethyl methacrylate)- co-poly(sulfobetaine methacrylate) with an average molecular weight of 6.1 kg mol-1, was synthesized in three steps: (i) polymerization of dimethylaminoethyl methacrylate to yield the base polymer by atom transfer radical polymerization (ATRP), (ii) fractional sulfobetainization via quaternization, and (iii) amination via quaternization. The effect of the zwitterionic polymer content on the polyamide surface characteristics, fouling resistance, and permeance is demonstrated. The zwitterion-modified membrane becomes more hydrophilic with lower surface roughness, as the zwitterionic polymer fraction increases. The excellent fouling resistance of the zwitterion-modified membrane was confirmed by the negligible protein adsorption and low bacteria fouling compared to a pristine membrane without zwitterionic segments. In addition, the zwitterion-modified membranes achieve a water permeation around 135 L m-2 h-1bar-1, which is 27-fold higher than that of the pristine membrane, along with good selectivity in the nanofiltration range, confirmed by the rejection of organic dyes. This permeance is about 10 times higher than that of other reported loose nanofiltration membranes with comparable dye rejection. The newly designed membrane is promising as a highly permeable fouling resistant cross-linked polyamide network for various water treatment applications. PMID- 29983070 TI - CO2-Responsive Surfactant-Free Microemulsion. AB - A surfactant-free microemulsion (SFME) with CO2 stimuli responsive properties was prepared. The oil and the water phases were N, N-dimethylcyclohexylamine (DMCHA) and deionized water, respectively, and N, N-dimethylethanolamine was used as an amphisolvent. The single-phase and multiphase zones were measured by the ternary phase diagram, and the microstructure of the SFME was determined by measuring the change trend of the electrical conductivity of the system with increasing DMCHA content. While using methyl orange as a probe, the microstructure of the SFME was further confirmed by an UV-visible spectrometer. The microstructures of water-in oil (SFME-I) and oil-in-water (SFME-II) microemulsions were obtained by changing the DMCHA content in the system. The SFME-I system has a significant phase separation after the action of CO2. However, with the continuous introduction of CO2, the upper phase of DMCHA is gradually protonated and dissolves in the aqueous phase, resulting in a gradual decrease in the volume of the upper phase, and eventually in an aqueous solution of ammonium bicarbonate. For SFME-II, CO2 does not directly cause phase separation, but eventually it becomes an aqueous solution of ammonium bicarbonate with the addition of CO2. Both the water-in-oil structure SFME-I and the oil-in-water structure SFME-II have excellent CO2 stimuli responsive performance. PMID- 29983071 TI - Kinetically Stable Triglyceride-Based Nanodroplets and Their Interactions with Lipid-Specific Proteins. AB - Understanding of the interactions between proteins and natural and artificially prepared lipid membrane surfaces and embedded nonpolar cores is important in studies of physiological processes and their pathologies and is applicable to nanotechnologies. In particular, rapidly growing interest in cellular droplets defines the need for simplified biomimetic lipid model systems to overcome in vivo complexity and variability. We present a protocol for the preparation of kinetically stable nanoemulsions with nanodroplets composed of sphingomyelin (SM) and cholesterol (Chol), as amphiphilic surfactants, and trioleoylglycerol (TOG), at various molar ratios. To prepare stable SM/Chol-coated monodisperse lipid nanodroplets, we modified a reverse phase evaporation method and combined it with ultrasonication. Lipid composition, zeta-potential, gyration and hydrodynamic radius, shape, and temporal stability of the lipid nanodroplets were characterized and compared to extruded SM/Chol large unilamellar vesicles. Lipid nanodroplets and large unilamellar vesicles with theoretical SM/Chol/TOG molar ratios of 1/1/4.7 and 4/1/11.7 were further investigated for the orientational order of their interfacial water molecules using a second harmonic scattering technique, and for interactions with the SM-binding and Chol-binding pore-forming toxins equinatoxin II and perfringolysin O, respectively. The surface characteristics (zeta-potential, orientational order of interfacial water molecules) and binding of these proteins to the nanodroplet SM/Chol monolayers were similar to those for the SM/Chol bilayers of the large unilamellar vesicles and SM/Chol Langmuir monolayers, in terms of their surface structures. We propose that such SM/Chol/TOG nanoparticles with the required lipid compositions can serve as experimental models for monolayer membrane to provide a system that imitates the natural lipid droplets. PMID- 29983072 TI - Multiform Sulfur Adsorption Centers and Copper-Terminated Active Sites of Nano CuS for Efficient Elemental Mercury Capture from Coal Combustion Flue Gas. AB - Nanostructured copper sulfide synthesized with the assistance of surfactant with nanoscale particle size and high Brunauer-Emmett-Teller surface area was for the first time applied for the capture of elemental mercury (Hg0) from coal combustion flue gas. The optimal operation temperature of nano-CuS for Hg0 adsorption is 75 degrees C, which indicates that injection of the sorbent between the wet flue gas desulfurization and the wet electrostatic precipitator systems is feasible. This assures that the sorbent is free of the adverse influence of nitrogen oxides. Oxygen (O2) and sulfur dioxide exerted a slight influence on Hg0 adsorption over the nano-CuS. Water vapor was shown to moderately suppress Hg0 capture efficiency via competitive adsorption. The simulated adsorption capacities of nano-CuS for Hg0 under pure nitrogen (N2), N2 + 4% O2, and simulated flue gas reached 122.40, 112.06, and 89.43 mgHg0/g nano CuS, respectively. Compared to those of traditional commercial activated carbons and metal sulfides, the simulated adsorption capacities of Hg0 over the nano-CuS are at least an order of magnitude higher. Moreover, with only 5 mg loaded in a fixed-bed reactor, the Hg0 adsorption rate reached 11.93-13.56 MUg/g min over nano-CuS. This extremely speedy rate makes nano-CuS promising for a future sorbent injection technique. The anisotropic growth of nano-CuS was confirmed by X-ray diffraction analysis and provided a fundamental aspect for nano-CuS surface reconstruction and polysulfide formation. Further X-ray photoelectron spectroscopy and Hg0 temperature-programmed desorption tests showed that the active polysulfide, S-S dimers, and copper-terminated sites contributed primarily to the extremely high Hg0 adsorption capacity and rate. With these advantages, nano-CuS appears to be a highly promising alternative to traditional sorbents for Hg0 capture from coal combustion flue gas. PMID- 29983073 TI - Morphology Evolution of Stimuli-Responsive Triblock Copolymer Modulated by Polyoxometalates. AB - Polyoxometalate (POM) H3PMo12O40 was coassembled with stimuli-responsive triblock copolymer poly(ethylene oxide)- block-polystyrene- block-poly(2 (dimethylamino)ethyl methacrylate) (PEO- b-PS- b-PDMAEMA) by electrostatic interactions. Depending on the POM contents, the hybrid complexes can self assemble into a series of morphologies: micelles, rods, toroids, and vesicles. Unlike traditional morphology transition of amphiphilic block copolymer derived from a broad range of hydrophobic volume fractions, POM-induced morphology transitions just occurred in a narrow range of volume fractions. The length of rod micelles exponentially decreased with solvent compositions (tetrahydrofuran/H2O). The hybrid assemblies showed acid-base responsibility due to the PDMAEMA block. Rod micelles could further assemble and disassemble reversibly upon adding acid/base. Fluorescent polyoxometalate Na9EuW10O36 was also complexed with PEO- b-PS- b-PDMAEMA to prepare fluorescent vesicles. The vesicles showed off-on switchable fluorescence behavior accompanied with reversible vesicle-to-micelle transformation in response to pH stimuli. PMID- 29983074 TI - Synthesis of a Scalable Two-Dimensional Covalent Organic Framework by the Photon Assisted Imine Condensation Reaction on the Water Surface. AB - An atomically thin two-dimensional (2D) covalent organic framework (COF) was successfully synthesized via the photon-assisted imine condensation reaction within 1 h from the highly uniform and homogeneous precursor solution layer floating on the water surface. The polarity optimization of the precursor solution was the key step for the successful formation of the high-quality 2D COF because only the precursor solution consisting of polarity-controlled solvents allows ideal floating on the water surface. The polarity-controlled solution not only prohibits the agglomeration of the organic precursors on the water surface but also facilitates the wafer scale and layer number-controllable synthesis of the 2D COF. The resulting 2D COF has a uniform porous structure and highly oriented layered structure along the out-of-plane direction as observed by microscopy analysis and X-ray diffraction, respectively. In addition, we successfully fabricated field effect transistor type polyimine-based COF (pi-COF) electronic devices to demonstrate the prompt electrical responses to photo exposure and water vapor exposure, suggesting the potential applications of the pi-COF in electrical photodetector or moisture-detector devices. PMID- 29983075 TI - Impact of Glycolipid Hydrophobic Chain Length and Headgroup Size on Self-Assembly and Hydrophobic Guest Release. AB - Encapsulation of a hydrophobic guest molecule inside a micelle and its stimuli sensitive release is a useful strategy for target-specific drug delivery. Herein, nine biobased glycolipids were derived from plant sources. The influence of headgroup on the stability and aggregation pattern in water with different alkyl chain lengths was investigated to deduce the structure-property relationship. External factors, such as temperature, pH, and NaCl and urea concentrations, were employed to explore stimuli response of glycolipid nanoassemblies. Furthermore, solvatochromic dyes, such as pyrene, N-phenyl-1-naphthylamine, and curcumin, were utilized to examine hydrophobe loading capacities of these glycolipid assemblies. A fluorescence study was performed to investigate the enzyme-sensitive hydrophobe release. Interestingly, the pH-sensitive hydrophobic guests showed pH-responsive release from dynamic micelles. Finally, the synthesized glycolipids revealed their nanoassemblies as smart carriers for hydrophobic cargo. PMID- 29983076 TI - Antifouling Photograftable Zwitterionic Coatings on PDMS Substrates. AB - The foreign body response (FBR) to implantable materials can negatively impact performance of medical devices such as the cochlear implant. Engineering surfaces that resist the FBR could lead to enhanced functionality including potentially improving outcomes for cochlear implant recipients through reduction in fibrosis. In this work, we coat poly(dimethylsiloxane) (PDMS) surfaces with two zwitterionic polymers, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA), using a simultaneous photografting/photo-cross-linking process to produce a robust grafted zwitterionic hydrogel. reduce nonspecific protein adsorption, the first step of the FBR. The coating process uses benzophenone, a photografting agent and type II photoinitiator, to covalently link the cross-linked zwitterionic thin film to the PDMS surface. As the concentration of benzophenone on the surface increases, the adhesive strength of the zwitterionic thin films to PDMS surfaces increases as determined by shear adhesion. Additionally, with increased concentration of the adsorbed benzophenone, failure of the system changes from adhesive delamination to cohesive failure within the hydrogel, demonstrating that durable adhesive bonds are formed from the photografting process. Interestingly, antifouling properties of the zwitterionic polymers are preserved with significantly lower levels of nonspecific protein adsorption on zwitterion hydrogel-coated samples compared to uncoated controls. Fibroblast adhesion is also dramatically reduced on coated substrates. These results show that cross-linked pSBMA and pCBMA hydrogels can be readily photografted to PDMS substrates and show promise in potentially changing the fibrotic response to implanted biomaterials. PMID- 29983077 TI - Corrigendum. PMID- 29983078 TI - Communicative Predictors of Older Adults' Successful Aging, Mental Health, and Alcohol Use. AB - We examined how older adults' communication about age-related topics is related to aging efficacy, successful aging, and well-being. Guided by the communicative ecology model of successful aging, three profiles of "environmental chatter"-that is, patterns of accommodation and overaccommodation older adults received from relational partners-were identified: positive, mixed-positive, and negative. Four profiles of individuals' own age-related communication were identified, including a new profile: gloomy agers. Chatter profile membership and own age-related communication profile membership indirectly predicted successful aging, depressive symptoms, loneliness, and perceptions of unhealthy alcohol consumption via aging efficacy, but not self-reported alcoholic drinks consumed. Communication by both older adults and their relational partners may be consequential to experiences of successful aging and well-being. PMID- 29983079 TI - Barriers to Healthcare Participation in Persons With Disabilities in Appalachia: A Qualitative Pilot Study. AB - OBJECTIVES:: A study exploring facility-related barriers to healthcare participation (the level to which an individual is engaged or involved in their own healthcare activities from simply keeping appointments to following treatment regimens) in persons with disabilities in Appalachia from the perspectives of four stakeholder groups, (1) adults with disabilities, (2) caregivers of persons with disabilities, (3) advocates for persons with disabilities, and (4) providers who treat persons with disabilities. BACKGROUND:: Persons with disabilities potentially face additional barriers to healthcare participation than those without disabilities. Understanding and addressing the barriers to participation could assist in improving healthcare outcomes among the disabled population. METHODS:: A qualitative study was conducted involving scripted focus groups with four stakeholder groups with expertise/experience in disabilities. The objective was to assess perceptions of impacts of clinical design elements on healthcare participation. RESULTS:: Participants identified and characterized six major categories of facility- and nonfacility-related barriers they felt impacted healthcare participation, with priority differences reported between each group. CONCLUSIONS:: The healthcare facility is perhaps the most visible tool the provider has at his or her disposal to deliver effective healthcare. Understanding the interactions persons with different disabilities have with the physical facility and the messages, both intentional and unintentional, the state of the facility sends can provide useful insights into delivering more effective healthcare to this population. PMID- 29983080 TI - Influence of pre-heating and ceramic thickness on physical properties of luting agents. AB - PURPOSE: The objective of this in vitro study was to evaluate the influence of ceramic thickness and pre-heating of luting agents on their physical properties. MATERIALS AND METHODS: The materials RelyX Arc, RelyX Ultimate, RelyX Veneer, and Filtek Z350 Flow were handled at different temperatures (23 degrees C or 54 degrees C), inserted into matrix, and photoactivated through ceramic disks (0.75 mm or 1.5 mm). The following tests were performed ( n=8): degree of conversion, Knoop Hardness, cross-link density, water sorption, solubility, and ultimate tensile strength. Data were analyzed using three-way analysis of variance and Tukey's test (alpha=0.05). RESULTS: Regarding ceramic thickness, the thinnest ceramic resulted in higher values of Knoop Hardness ( p=0.027). The lowest temperature (23 degrees C) resulted in a higher solubility ( p=0.0257), and water sorption ( p=0.0229) values. There was also statistical difference among the materials: RelyX Arc showed a higher degree of conversion and ultimate tensile strength, followed by RelyX Veneer, RelyX Ultimate, and Filtek Z350 Flow. For Knoop Hardness and cross-link density tests, RelyX Ultimate showed the highest values, followed by RelyX Arc, RelyX Veneer, and Filtek Z350 Flow. For water sorption and solubility, RelyX Veneer showed the highest values, followed by RelyX Arc, RelyX Ultimate, and Filtek Z350 Flow. CONCLUSION: Pre-heating interfered with water sorption and solubility, whereas ceramic thickness only affected Knoop Hardness; the physical properties of the materials are dependent on their composition. PMID- 29983081 TI - Lumbar Cerebrospinal Fluid Evolution in Childhood Tuberculous Meningitis. AB - As early diagnosis of childhood tuberculous meningitis cannot rely on mycobacterial confirmation, clinical, cerebrospinal fluid and neuroimaging features are essential. We aimed to describe the evolution of serially analyzed lumbar cerebrospinal fluid parameters. We performed a retrospective observational study including children <13 years with suspected tuberculous meningitis at Tygerberg Hospital, Cape Town, South Africa. Cerebrospinal fluid parameters at admission and weeks 1, 2, and 3 were analyzed. Of 318 children with suspected tuberculous meningitis, 53 (17%) had "definite" tuberculous meningitis and 265 (83%) "probable" tuberculous meningitis. Longitudinal clustering revealed 3 distinct profiles, with 1 group atypically demonstrating initial increase in lymphocyte count, neutrophil count, and protein concentration. The decreasing cerebrospinal fluid glucose trend remained uniform among all groups. A gradual decline in cerebrospinal fluid lymphocyte, neutrophil and protein count, and rise in cerebrospinal fluid glucose concentration is expected; however, normal variability exists. PMID- 29983083 TI - Using professor Harden's four principles of learning for improving bedside teaching in infectious disease ward at Shiraz Medical School. PMID- 29983082 TI - Orexin-A protects SH-SY5Y cells against H2O2-induced oxidative damage via the PI3K/MEK1/2/ERK1/2 signaling pathway. AB - Orexin-A elicits multiple potent effects on a variety of tumor cells via different signaling pathways. However, it is unknown whether it has a neuroprotective effect on SH-SY5Y human neuroblastoma cells. This study investigated the neuroprotective effect of Orexin-A against hydrogen peroxide (H2O2)-induced oxidative damage in SH-SY5Y cells and the underlying mechanism. H2O2 treatment decreased the viability of SH-SY5Y cells, induced apoptosis, and decreased superoxide dismutase activity. Orexin-A attenuated these effects, indicating that it protects SH-SY5Y cells against H2O2-induced oxidative damage. Pre-treatment with Orexin-A also attenuated H2O2-induced increases in phosphorylation of MEK1/2 and ERK1/2. Moreover, these effects of Orexin-A were reduced in the presence of the PI3K inhibitor LY294002. Finally, pre-treatment with LY294002 abrogated attenuation of the H2O2-induced decrease in cell viability and increase in caspase-3/7 activity by Orexin-A. These results show that the PI3K/MEK1/2/ERK1/2 signaling pathway is involved in the neuroprotective effects of Orexin-A against H2O2-induced oxidative damage in SH-SY5Y cells. Our findings provide insight into the neuroprotective effects of Orexin-A and the underlying mechanism, which will be useful for the treatment of nervous system diseases. PMID- 29983084 TI - Therapists' experience of the cognitive orientation to daily occupational performance (CO-OP) approach: Shifting from conventional practice. AB - BACKGROUND: The CO-OP ApproachTM has been increasingly used in research and practice, yet its critical elements and implementation challenges are largely undescribed. Obtaining therapists' perspectives on CO-OP may reveal insights into potential critical and mediating factors. AIM/OBJECTIVE: To explore the experiences of CO-OP therapists by understanding their perceptions on the approach compared with conventional practice, and by identifying mediating factors in its implementation. MATERIAL AND METHOD: This exploratory study utilized a qualitative descriptive design. A purposive sample of occupational therapists (n = 3) was interviewed. Data were analyzed using thematic analysis and themes were validated within a focus group. RESULTS/FINDINGS: Three themes were identified: 'CO-OP works,' 'CO-OP delivery is mediated by contextual factors,' and 'CO-OP shifts the therapeutic approach.' Therapists perceived CO-OP to be efficacious for client-centred goal attainment. Guided discovery and the problem-solving strategy were identified as unique and challenging CO-OP elements. Mediating factors such as level of cognitive impairment and quality of family member involvement may affect CO-OP efficacy. CONCLUSIONS: Therapists found CO-OP to be efficacious and adopted unique elements into their professional approaches. SIGNIFICANCE: This is the first study to investigate CO-OP therapists' experiences. Future research is recommended to enhance training of therapists in key CO-OP features. PMID- 29983085 TI - Mexiletine rescues a mixed biophysical phenotype of the cardiac sodium channel arising from the SCN5A mutation, N406K, found in LQT3 patients. AB - INTRODUCTION: Individual mutations in the SCN5A-encoding cardiac sodium channel alpha-subunit usually cause a single cardiac arrhythmia disorder, some cause mixed biophysical or clinical phenotypes. Here we report an infant, female patient harboring a N406K mutation in SCN5A with a marked and mixed biophysical phenotype and assess pathogenic mechanisms. METHODS AND RESULTS: A patient suffered from recurrent seizures during sleep and torsades de pointes with a QTc of 530 ms. Mutational analysis identified a N406K mutation in SCN5A. The mutation was engineered by site-directed mutagenesis and heterologously expressed in HEK293 cells. After 48 hours incubation with and without mexiletine, macroscopic voltage-gated sodium current (INa) was measured with standard whole-cell patch clamp techniques. SCN5A-N406K elicited both a significantly decreased peak INa and a significantly increased late INa compared to wide-type (WT) channels. Furthermore, mexiletine both restored the decreased peak INa of the mutant channel and inhibited the increased late INa of the mutant channel. CONCLUSION: SCN5A-N406K channel displays both "gain-of-function" in late INa and "loss-of function" in peak INa density contributing to a mixed biophysical phenotype. Moreover, our finding may provide the first example that mexiletine exerts a dual rescue of both "gain-of-function" and "loss-of-function" of the mutant sodium channel. PMID- 29983087 TI - Can Poly (ADP-Ribose) Polymerase Inhibitors Palliate Paclitaxel-Induced Peripheral Neuropathy in Patients With Cancer? AB - BACKGROUND: Paclitaxel-treated patients can suffer from years of peripheral neuropathy with pain, numbness, and tingling. Promising preclinical data with poly (ADP-ribose) polymerase (PARP) inhibitors led us to explore this class of agents to palliate this neuropathy. METHODS: We relied on a completed trial that tested the antineoplastic effects of veliparib (NCT01012817). Data from patients who had been enrolled on NCT01012817, who previously received paclitaxel, and who had completed a validated pain assessment instrument were evaluated for improvement in their pain scores. RESULTS: All 34 eligible patients were women, and all had a metastatic gynecological malignancy. On a 10-point scale (higher numbers indicative of worse pain), the average baseline score was 3.6 (range: 0 7). Seven patients (21%; 95% confidence interval: 9%-38%) manifested a drop in pain score (1 score lower than baseline followed by at least one consecutive value also below baseline). Of note, no patients initiated other therapy for neuropathy while on NCT01012817. CONCLUSION: The PARP inhibitors merit further study for chemotherapy-induced peripheral neuropathy. For patients suffering from peripheral neuropathy, these putative palliative effects might prompt earlier consideration of a PARP inhibitor as part of cancer treatment. PMID- 29983086 TI - Influence of andrographolide on the pharmacokinetics of warfarin in rats. AB - CONTEXT: Andrographolide and warfarin are often used together in clinics in China. However, the herb-drug interaction between andrographolide and warfarin is still unknown. OBJECTIVE: This study investigates the herb-drug interaction between andrographolide and warfarin in vivo and in vitro. MATERIALS AND METHODS: A sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in male Sprague-Dawley rats plasma, and then the pharmacokinetics of orally administered warfarin (0.5 mg/kg) with or without andrographolide (30 mg/kg/day for 7 days) pretreatment was investigated. In addition, Sprague-Dawley rat liver microsomes incubation systems were used to support the in vivo pharmacokinetic data and investigate its potential mechanism. RESULTS: The method validation results showed that a sensitive and reliable LC-MS/MS method was developed for the determination of warfarin in rat plasma samples. The pharmacokinetic results indicated that co-administration of andrographolide could increase the systemic exposure of warfarin significantly, including area under the curve (118.92 +/- 18.08 vs. 60.58 +/- 9.46 MUg * h/mL), maximum plasma concentration (3.32 +/- 0.41 vs. 2.35 +/- 0.25 MUg/mL) and t1/2 (22.73 +/- 3.28 vs. 14.27 +/- 2.67 h). Additionally, the metabolic stability of warfarin increased from 23.5 +/- 4.7 to 38.7 +/- 6.1 min with the pretreatment of andrographolide, and the difference was significant (p < 0.05). DISCUSSION AND CONCLUSION: In conclusion, andrographolide could increase the systemic exposure of warfarin in rats when andrographolide and warfarin were co-administered, and possibly by slowing down the metabolism of warfarin in rat liver by inhibiting the activity of CYP3A4 or CYP2C9. PMID- 29983088 TI - Thank you Reviewers. PMID- 29983089 TI - Mothers' experiences of their work as healthcare assistants for their chronic disabled child. AB - BACKGROUND: To the best of our knowledge, no research of the work situation of full-time, paid, parental HC assistants has been done. AIM: To examine how parents experienced their work as HC assistants for their chronic disabled child. METHODS: Semi-structured interviews based on the Work Environment Impact Scale (WEIS-S) were done with nine mothers who had a child aged 8-17 years old with a cognitive or/and physical chronic disability. Content analysis was used with the Model Of Human Occupation as a framework. RESULTS: The studied mothers always needed to be stand-by for their child, and they highlighted physical and psychological health problems caused by their work situation. There were several difficulties working in different environments because of the child's need of technical devices. Further they described the support from their employers as important and in general the participants perceived a lack of understanding about their work situation in the society. CONCLUSION: The mothers in the present study had unclear job descriptions, they often worked more than full-time, and had low occupational balance. SIGNIFICANCE: Occupational therapists could improve the HC assistants' work place focusing on the physical and psycho-social work environment as well as on their occupational balance. PMID- 29983090 TI - Child Sexual Abuse and Criminal Offending: Gender-Specific Effects and the Role of Abuse Characteristics and Other Adverse Outcomes. AB - This study sought to enhance knowledge of the link between child sexual abuse (CSA) and long-term criminality by investigating gender-specific effects and the role of index sexual abuse characteristics, revictimization, and serious mental health problems. An Australian sample of 2,759 documented cases of sexual abuse and 2,677 community controls were linked to statewide police records and public mental health service databases, with a follow-up period of 13-44 years. Four key findings emerged from the analysis: (1) CSA victims were more likely than controls to engage in all types of criminal behaviors including violent, sexual, and other offending; (2) gender moderated the relationship between CSA and criminal offending, with stronger associations found among females for general and violent offending, and among males for sexual offending; (3) certain features of the index sexual abuse (i.e., developmental period, number of perpetrators, relation to perpetrator), further victimization experiences, and the development of serious mental health problems were all associated with an increased likelihood of criminal behavior among CSA victims; (4) CSA victims who engaged in criminal offending were more likely to present with cumulative risks than victims not engaging in criminal offending. Implications for future research and clinical practice are discussed. PMID- 29983091 TI - Graft-Recipient Anteroposterior Mismatch Does Not Affect the Midterm Clinical Outcomes of Osteochondral Allograft Transplantation of the Femoral Condyle. AB - BACKGROUND: For the treatment of femoral condyle cartilage defects with osteochondral allograft transplantation (OCA), many surgeons have relaxed their graft-recipient size-matching criteria given the limited allograft supply. However, since the anteroposterior (AP) length is typically correlated with the radius of curvature for a given condyle, a large mismatch in graft-recipient AP length can indicate a corresponding mismatch in the radius of curvature, leading to articular incongruity after implantation. PURPOSE: To evaluate the association between femoral condyle graft-recipient AP mismatch and clinical outcomes of OCA. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective review was conducted of patients treated with OCA for femoral condyle chondral defects from 2000 to 2015. Graft characteristics, including AP and mediolateral dimensions, were gathered from vendor-specific allograft offering documents. Patient condyle dimensions were measured on preoperative magnetic resonance imaging. Reoperations and patient responses to validated outcome measures were reviewed. Failure was defined by any partial removal/revision of the allograft or conversion to knee arthroplasty. A multivariable logistic regression model was fitted to examine the association of AP mismatch with OCA failure while adjusting for patient age and number of previous ipsilateral knee surgical procedures. RESULTS: A total of 69 knees from 69 patients (mean age, 35.7 years; 71% male) met the inclusion criteria. Mean duration of follow-up was 4 years (range, 2-16 years). The mean absolute graft-recipient AP mismatch was 6.7 mm (range, 0-20 mm; P < .01). At final follow-up, 19 knees had failed. There was no significant difference in the mean absolute AP mismatch between failures (8.1 mm) and nonfailures (6.2 mm; P = .17). Multivariate logistic regression revealed that AP mismatch was not associated with graft failure ( P = .14). At final follow-up, significant improvements were noted in the 36-Item Short Form Health Survey, International Knee Documentation Committee subjective form, and Knee Outcome Survey-Activities of Daily Living ( P < .01 for all). Magnitude of AP mismatch was not associated with postoperative outcome scores or achievement of minimal clinically significant differences in outcome scores. CONCLUSION: Magnitude of graft-recipient AP mismatch was not associated with midterm OCA failure rates or patient-reported outcome scores, suggesting that AP length mismatch within the limits measured here is not a contraindication for graft acceptance. PMID- 29983092 TI - Acidic stress induces protective autophagy in SGC7901 cells. AB - Objective To investigate the effect of acidity on gastric cancer SGC7901 cells in terms of autophagy and provide a new strategy for therapeutically targeting gastric cancer autophagy in an acidic environment. Methods Transmission electron microscopy (TEM) and confocal laser scanning microscopy were used to examine the effect of an acidic environment on autophagosome formation. Light chain 3 (LC3) and p62 levels in SGC7901 cells exposed to acidic conditions were measured using Western blot analysis. To explore changes in autophagy flux, the cells were treated with an inhibitor of autophagy bafilomycin A1. The CCK-8 assay was performed to determine if inhibiting acid-induced autophagy affected cell proliferation. Results Increased autophagosome formation was observed by TEM. Punctate LC3 structures were observed in cells cultured under acidic conditions, whereas untreated cells exhibited diffuse and weak staining for punctate LC3 structures. Cytoplasmic LC3-I translocated to the autophagic membrane (LC3-II) levels increased under acidic conditions, whereas p62 levels decreased. The bafilomycin A1-induced inhibition of autophagy caused by the acidic environment inhibited cell proliferation. Conclusion The acidic environment upregulates autophagy in SGC7901 cells. In long-term culture, a stable and high level of autophagy is maintained in an acidic environment, which has a protective effect on cells. PMID- 29983093 TI - Long noncoding RNA signature in predicting metastasis following tamoxifen treatment for ER-positive breast cancer. AB - AIM: We aimed to develop a long noncoding RNA (lncRNA) expression signature that can predict response to tamoxifen. MATERIALS & METHODS: LncRNA expression profiling was mined in two cohorts from Gene Expression Omnibus (GSE6532, GSE9195, n = 412). RESULTS: A set of lncRNAs (LINC01191, RP4-639F20.1 and CTC 429P9.3) associated with distant metastasis-free survival was established. Estrogen receptor-positive breast cancer patients in the training series could be classified into high- and low-risk groups with significantly different distant metastasis-free survival values based on this signature (hazard ratio [HR]: 5.11; p = 7.28 * 10-8). The prognostic ability of this signature was confirmed in validation sets 1 (HR: 2.58; p = 1.54 * 10-2) and 2 (HR: 10.06; p = 6.85 * 10-3). CONCLUSION: The lncRNA signature may have possible clinical implications in the selection of high-risk patients for tamoxifen therapy. PMID- 29983094 TI - Individual differences in the emotional modulation of gaze-cuing. AB - Gaze-cuing refers to the spontaneous orienting of attention towards a gazed-at location, characterised by shorter response times to gazed-at than non-gazed at targets. Previous research suggests that processing of these gaze cues interacts with the processing of facial expression cues to enhance gaze-cuing. However, whether only negative emotions (which signal potential threat or uncertainty) can enhance gaze-cuing is still debated, and whether this emotional modulation varies as a function of individual differences still remains largely unclear. Combining data from seven experiments, we investigated the emotional modulation of gaze cuing in the general population as a function of participant sex, and self reported subclinical trait anxiety, depression, and autistic traits. We found that (i) emotional enhancement of gaze-cuing can occur for both positive and negative expressions, (ii) the higher the score on the Attention to Detail subscale of the Autism Spectrum Quotient, the smaller the emotional enhancement of gaze-cuing, especially for happy expressions, and (iii) emotional modulation of gaze-cuing does not vary as a function of participant anxiety, depression or sex, although women display an overall larger gaze-cuing effect than men. PMID- 29983095 TI - Microwave-Assisted Ablation Improves the Prognosis of Patients With Hepatocellular Carcinoma Undergoing Liver Resection. AB - OBJECTIVE: We evaluated microwave-assisted liver resection for hepatocellular carcinoma. PATIENTS AND METHODS: We enrolled 79 patients in this study, and microwave ablation was used for liver resection. Patients were randomized to group A (50.6%; n = 40), liver resection without microwave ablation, or group B (49.4%; n = 39), liver resection performed using microwave ablation. Data were analyzed for statistical significance. RESULTS: Of the participants enrolled, 60 were male, and the participant's average age was 59.32 +/- 10.34 years. The mean overall tumor diameter was 4.39 (2.00) cm, and this did not differ between groups. Intraoperative blood loss in group B was significantly less than that in group A ( P < .001). No differences were reported between the 2 groups regarding surgical time ( P = .914), postoperative morbidity ( P = .718), and late postoperative complications ( P = .409). Postoperative drainage volume for group B was less than that of group A on the first ( P = .005) and third ( P = .019) day after surgery. The time of postoperative hospitalization in group B was significantly shorter than that in group A ( P < .001). Local recurrence was noted in 18.99% of cases (n = 15) in group B, which is less than that of group A ( P = 0.047), while in group B distant metastasis is less but not statistically significant ( P = 0.061). The 1-year and 3-year cumulative survival rates were 57% and 93.7%, respectively. CONCLUSIONS: The curative effects of liver resection combined with microwave ablation during operation are superior to only liver resection in the treatment of primary liver cancer. PMID- 29983096 TI - Clinical Outcomes of Stereotactic Body Radiotherapy for Patients With Stage I Small-Cell Lung Cancer: Analysis of a Subset of the Japanese Radiological Society Multi-Institutional SBRT Study Group Database. AB - Stereotactic body radiotherapy (SBRT) is widely used as a curative treatment option for stage I non-small-cell lung cancer, but for patients with stage I small-cell lung cancer, the role of stereotactic body radiotherapy is unclear. In this study, we retrospectively analyzed the outcomes of a subset of patients with stage I small-cell lung cancer treated with stereotactic body radiotherapy in the database of the Japanese Radiological Society-Multi-Institutional stereotactic body radiotherapy Study Group. The 43 patients treated with stereotactic body radiotherapy for stage I small-cell lung cancer between 2004 and 2012 at 11 Japanese institutions were studied: median age = 77 years; 32 (74%) males and 11 females; and 80% were medically inoperable. The clinical stage was IA in 31 and IB in 12. In all patients, the lung tumors were pathologically proven as small cell lung cancer. A total dose of 48 to 60 Gy was administered in 4 to 8 fractions. The median biologically effective dose (alpha/beta = 10 Gy) was 105.6 Gy. Chemotherapy and prophylactic cranial irradiation were administered in only 8 patients, respectively. The median follow-up time was 23.2 months. The 2-year overall survival, progression-free survival, and distant metastasis-free survival rates were 72.3%, 44.6%, and 47.2%, respectively. The 2-year local control was 80.2%. Regarding the patterns of failure, distant metastasis, lymph node metastasis, and local recurrence were observed in 47%, 28%, and 16% of patients, respectively. No >=grade 3 stereotactic body radiotherapy-related toxicities were observed. Although stereotactic body radiotherapy was thus revealed to be effective for the local control of stage I small-cell lung cancer, the incidence of distant metastases was high. Further investigations of larger cohorts are needed, including analyses of the effects of combined chemotherapy. PMID- 29983097 TI - Intuitive and Instrumental Grief: A Study of the Reliability and Validity of the Grief Pattern Inventory. AB - A convenience sample of 209 participants completed the Grief Pattern Inventory (GPI) together with the Hogan Grief Reaction Checklist (HGRC), the Integration of Stressful Life Events Scale (ISLES), and the Myers-Briggs Type Indicator (MBTI). Alpha coefficients of the GPI's intuitive and instrumental subscales were improved by eliminating low-performing items and empirically reassigning items from the GPI dissonant subscale. The two modified scales showed a near zero intercorrelation indicating they were independent constructs in this sample, a conclusion further verified by factor analysis. Both styles correlated with distress measures from the HGRC and correlated negatively with adaptation indicators from the ISLES, though the findings were stronger for intuitive grievers. MBTI findings revealed that intuitive grievers endorsed significantly more "feeling" in how processing occurs while grievers who preferred sensing/thinking functions more often identified with the instrumental grief pattern. Implications of these findings for scholars and clinicians are discussed. PMID- 29983098 TI - Salvage CyberKnife-Based Reirradiation of Patients With Recurrent Prostate Cancer: The Single-Center Experience. AB - The aim of this study was to evaluate CyberKnife-based radioablation as a salvage treatment for prostate cancer postirradiation relapses based on a group of patients disqualified from available conventional methods of salvage treatment. Thirty-eight patients were treated with a fraction dose varying from 5.5 to 10 Gy (median 7.35) to a total dose of 18 to 36.25 Gy (median 36.25). In all, 55.3% of patients had androgen deprivation therapy during this time. Nine patients had oligometastases in the salvage time. The follow-up varied from 1.6 to 46.4 months (mean 19.7, median 14.4). In all, 92.6% to 97.4% of patients had no gastrointestinal acute adverse effects; no effects higher than G1 were noted. There were particular (up to 4.8%) G2 late gastrointestinal effects. The percentage without genitourinary acute effects varied from 59.1% to 78.9%; 3.7% had G3 toxicity. G3 late genitourinary toxicity appeared 3 times, the maximal percentage being 12.5% (24 months after salvage treatment). The nadir of prostate specific antigen median was 0.24 ng/mL (9 months after treatment). Twelve (31.6%) patients failed in the timeline of 6 to 42 months after salvage treatment (mean 18.7, median 16.5)-5 due to dissemination. In 2 cases, progression in existing metastases was identified. Five (13.2%) patients had biochemical failure without additional metastases (local relapses); hence, local control was 86.8%. The failure risk is strongly influenced by initial disease stage and presalvage prostate-specific antigen concentration. The obtained results permit us to conclude that such a treatment could be an effective and safe option for prostate cancer postirradiation relapse salvage treatment. PMID- 29983099 TI - Essentials of maxillary sinus augmentation. PMID- 29983100 TI - Decellularization and genipin crosslinking of amniotic membrane suitable for tissue engineering applications. AB - Amniotic membrane has the potential to be used as scaffold in various tissue engineering applications. However, increasing its biostability at the same time maintaining its biocompatibility is important to enhance its usage as a scaffold. This studied characteristics genipin-crosslinked amniotic membrane as a bioscaffold. Redundant human amniotic membranes (HAM) divided into native (nAM), decellularized (dAM) and genipin-crosslinked (clAM) groups. The dAM and clAM group were decellularized using thermolysin (TL) and sodium hydroxide (NaOH) solution. Next, clAM group was crosslinked with 0.5% and 1.0% (w/v) genipin. The HAM was then studied for in vitro degradation, percentage of swelling, optical clarity, ultrastructure and mechanical strength. Meanwhile, fibroblasts isolated from nasal turbinates were then seeded onto nAM, dAM and clAM for biocompatibility studies. clAM had the slowest degradation rate and were still morphologically intact after 30 days of incubation in 0.01% collagenase type 1 solution. The dAM had a significantly highest percentage of swelling than other groups (p < 0.05). Besides, the dAM retained the collagen content at similar level of nAM. Although the dAM had highest mechanical strength compared to the rest of the groups, the differences were statistically insignificant. Cell attachment on dAM and 0.5% clAM was higher compared to that on nAM and 1.0% clAM. In conclusion, clAM have better biostability and biocompatibility compared to the nAM and dAM. Together with other suitable characteristics of the clAM such as percentage of swelling, structural integrity and ECM content, clAM is suitable as scaffold for various tissue engineering applications. PMID- 29983101 TI - Power output in traditional and ballistic bench press in elite athletes: Influence of training background. AB - This study aimed to compare the power production in traditional bench-press (TBP) and ballistic bench-throw (BBT) exercises. Furthermore, we assessed the differences in velocity, force, and power outputs between TBP and BBT. Finally, we tested the differences between the loads used to optimize power (optimum power load; OPL) in both exercises, using three distinct power-variables: mean power (MP), mean propulsive power (MPP), and peak power (PP). Sixty athletes from different sports were divided into two groups, according to their training characteristics: hypertrophy-based trained athletes (HTA), thirty-one athletes performing hypertrophy training programmes for (at least) 12-weeks; and power based trained athletes (PTA), twenty-nine athletes performing power-oriented training sessions for (at least) 12-weeks. Magnitude-based inferences were used to test for differences between groups. Independent of the variable analyzed (MP, MPP, or PP), the PTA produced greater power values in BBT, whereas the HTA generated higher outputs during TBP. The OPL in the HTA was likely heavier in TBP than in BBT, whereas no differences related to this variable were found in the PTA. Despite the apparent superiority of ballistics to produce power, it seems that in elite athletes, the strength-power training routine might affect the ability to apply high forces at very-high velocities. PMID- 29983102 TI - Issues impacting on enrolled nurse education for Aboriginal and Torres Strait Islander students: a discussion. AB - BACKGROUND: Achieving increased participation of Aboriginal and Torres Strait Islander peoples in Australia's health workforce, particularly nursing, is federal government policy imperative. However, the uptake of Aboriginal and Torres Strait Islander students into nursing has stalled and their attrition from tertiary nursing courses is considerably higher than for other students. AIM: To alert the profession to issues impacting enrolled nursing education for Aboriginal and Torres Strait Islander students. DESIGN: Discussion paper. RESULTS: Studies of Aboriginal and Torres Strait Islander students mainly focus on tertiary education for registered nurses whereas vocational education and training (VET) for enrolled nurses is usually overlooked. It is generally assumed that the issues influencing the recruitment, attrition, and retention of Aboriginal and Torres Strait Islander students in higher education universities and other institutions similarly impact enrolled nursing students in the VET sector. CONCLUSION: Research that contributes robust evidence-based knowledge specifically on strategies addressing issues in enrolled nursing education for Aboriginal and Torres Strait Islander students and their employment uptake is required. PMID- 29983103 TI - Giant intercostal nerve schwannoma in a patient with neurofibromatosis type 2. AB - PURPOSE: To describe a case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2. METHODS: A 44-year-old woman, with a history of neurofibromatosis type 2, presented with chest discomfort and mild dyspnea. She had undergone a recent resection of a large frontal parasagittal benign meningioma. Radiologic examinations showed a large lesion (9*12*9 cm) of the left hemithorax causing a complete atelectasis of left upper lobe. Bronchoscopy did not show any endobronchial alterations, apart from an ab estriseco compression of the left upper bronchial tree. A transthoracic needle biopsy was then performed and microscopic examination revealed a mesenchymal tumor composed of spindle-like cells. RESULTS: A video-assisted thoracoscopic surgery procedure was proposed. The tumor mass appeared to be tenaciously adherent to the parietal pleura in its anterolateral aspect, confirming the radiologic appearance. No invasion of the lung parenchyma or parietal pleural metastases were visible. Therefore, a left posterolateral thoracotomy at the fifth intercostal space was performed and a macroscopic complete resection was carried out. The recovery was uneventful and the patient was discharged on postoperative day 5. The histologic examination revealed a moderate cellular proliferation of spindle-shaped and oval to polygonal cells with frequent Verocay bodies; mitotic figures were rare. The tumor cells were strongly S-100 positive. The microscopic features were consistent with benign intercostal schwannoma. Eight years later, the patient is disease-free and asymptomatic. CONCLUSIONS: An unusual case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2 is described. PMID- 29983104 TI - [Longer oral contraception history as a possible preventive factor against fetal trisomy 21 in advanced maternal age pregnancies]. AB - Down syndrome is the most common autosomal chromosomal abnormality. According to the classical interpretation, it is the result of meiotic nondisjunction. Its occurrence is more common in advanced maternal age. Despite intensive research, pathophysiology of this genetic disorder is not fully understood. According to recent studies, a different kind of mechanism may be found in the background of trisomy 21 than was previously considered. Based on the ovarian mosaicism model, the cause of trisomy 21 (or any common trisomy) is a segregation error of a chromosome in premeiotic mitosis. The cell entering meiosis will be an oocyte with preexisting trisomy, where its (so-called "secondary") nondisjunction is essential. Maturation of the trisomic oocytes appears to fall behind the disomic oocytes, resulting in their relative accumulation in the ovaries as time progresses. The ratio of trisomic/disomic cells becomes less favorable in maternal maturity. If ovulation is inhibited - although the number of oocytes will continue to decline due to apoptosis - it can be assumed that the trisomic/disomic oocyte ratio remains more favorable with the progression of age. In our summary report, presenting and updating our previous data, we would like to propose that - according to ovarian mosaicism model - long-term oral contraception in the anamnesis may be beneficial in pregnancies with advanced maternal age. Orv Hetil. 2018; 159(28): 1146-1152. PMID- 29983106 TI - [Assembly of the Hungarian Physicians and Nature-Scientists in Keszthely in 1922]. PMID- 29983105 TI - [Potential relationship between juice cleanse diets and eating disorders. A qualitative pilot study]. AB - INTRODUCTION AND AIM: There are two notable eating behaviors that are not far from having their own category as a mental disorder: the purging disorder, that is already among the DSM-5 non-specific eating disorders, and orthorexia nervosa, when a person is fixating too much on healthy foods. Our purpose is to describe how these can be observed in recreational juice cleanse camps, which are very popular today as an alternative health trend. METHOD: The first author recorded her data during multisited ethnographic observations in two Hungarian juice cleanse camps. Based on the diary logs, notes and interviews collected, we will present the motives of eating anomalies that the participants had shown. RESULTS: The main motive of the camp is "detoxification". The lack of solid food, drastically low calorie intake and lots of physical activity will bring an inevitable change in the body, that is interpreted as toxins leaving the body. Participants have also included deliberate use of laxatives in their everyday routines, with which they associate positive connotations and are linked to the spiritual processes of "letting it go" and "renewal" in the spirit of a holistic approach. The use of symbols in the physiological processes was highly noticeable. Rapid weight loss due to diuresis, the desire for "clean" meals, and "self-rewarding" borrowed from the esoteric-self-help culture are also common motives. Due to the refeeding complications, so far two deaths have been reported by camp organizers. CONCLUSIONS: Both purging disorder and orthorexia nervosa can be well-identified in our observations. This shows that also in the non-clinical environment, there is an institutionalization of eating habits that are dangerous to the health. This "detox" is not only physiologically harmful, but it is not proved to provide long-term help in mental health either. As a solution, we advocate developing an appropriate health communication plan for misconceptions about healthy lifestyle and eating, and also a promotion of psychotherapeutic opportunities. Orv Hetil. 2018; 159(28): 1153-1157. PMID- 29983107 TI - [Significance of whole exome sequencing in the diagnostics of rare neurological diseases - own experiences through a case presenting with ataxia]. AB - Next generation sequencing (NGS) technologies reshape the diagnostics of rare neurological diseases. In the background of certain neurological symptoms, such as ataxia, many acquired and genetic causes may be present. Variations in a given gene can present with variable phenotypes, too. Because of this phenomenon, the conventional one gene sequencing approach often fails to identify the genetic background of a disease. Next generation sequencing panels allow to sequence 50 100 genes simultaneously, and if the disease stratification is not possible based on the clinical symptoms, whole exome sequencing can help in the diagnostic of genetic disorders with atypical presentation. This case study is about the exome sequencing of a patient with cerebellar ataxia. Genetic investigations identified rare variants in the SPG11 gene in association with the clinical phenotype, which gene was originally described in the background of hereditary spastic paraparesis. Our article highlights that in certain cases the variability of the leading presenting symptom makes it hard to select the correct gene panel. In our case the variants in the gene, formerly associated to hereditary spastic paraparesis, resulted in cerebellar ataxia initially, so even an ataxia NGS gene panel would not detect those. Orv Hetil. 2018; 159(28): 1163-1169. PMID- 29983108 TI - [Novel mechanisms in the initiation and maintenance of atrial fibrillation: tailored individual treatment]. AB - Atrial fibrillation affects approximately three percent of the adults. Ablation strategies targeting the isolation of the pulmonary veins are the up-to-date cornerstones for atrial fibrillation ablations. However, a one-year success rate of repeated interventions is not more than 70%. Long-term efficacy of catheter ablation is presumably limited by electrical and structural remodeling of the atria, which results in a progressive increase in the duration of atrial fibrillation to become sustained. The potential pathophysiological importance of the epicardial adipose tissue, atrial fibrosis, autonomic nervous system and arrhythmogenic foci are documented by several studies. Increased volume, inflammation induced transformation to fibrosis and myocardial infiltration of atrial subepicardial fat in obese patients result in higher risk of atrial fibrillation development. Changes in atrial autonomic innervation under some conditions including regular physical exercise strongly promote arrhythmogenesis via the mechanism of enhanced triggered activity or abbreviated atrial refractoriness. Individualized management of possible trigger and substrate mechanisms are proposed to provide a novel basis for the effective treatment of atrial fibrillation. Pro-fibrotic signalling pathways can be inhibited by the suppression of renin-angiotensin-aldosterone system. Neuromodulation strategies include renal sympathetic denervation and ganglionic plexi ablation. Anticoagulation therapy has also been shown to reduce the burden of abnormal atrial remodeling. Possible novel catheter ablation techniques are used for right or left atrial linear lesions, scar homogenization and catheter ablation of complex fractionated atrial electrograms, rotors or ectopic foci. Beside these new management strategies, clinical consideration of factors of particular risks as obesity, hyperlipidaemia, hypertension, diabetes and obstructive sleep apnoe are also essential. Orv Hetil. 2018; 159(28): 1135-1145. PMID- 29983109 TI - Opioid Prescribing to Adolescents in the United States From 2005 to 2016. AB - OBJECTIVE: This study assessed trends in days' supply for opioid prescriptions filled by adolescents with commercial insurance and Medicaid. METHODS: IBM MarketScan commercial and Medicaid pharmacy claims data were used to measure days' supply among adolescents (2005-2016) and to determine whether there were differences between patients with commercial insurance or Medicaid coverage. RESULTS: The 2-3 days' supply decreased from 50.5% (2005) to 36.7% of fills (2016), while 4-5 days' supply increased from 30.2% to 37.7%. Fills of 6-7 and 8 15 days increased slightly. Fills of over 30 days remained near 0.0%, and one-day fills remained at 1.0-2.0% until 2016, when they increased to 3.6% Conclusions: For adolescents, fills of prescription opioids generally exceeded three days. Efforts to reduce opioid prescribing through guidelines, prescription drug monitoring programs, and limits on days' supply do not appear to have affected prescribing for adolescents as much as desired. PMID- 29983110 TI - Depression Screening Patterns, Predictors, and Trends Among Adults Without a Depression Diagnosis in Ambulatory Settings in the United States. AB - OBJECTIVE:: This study examined national patterns, predictors, and trends in depression screening among adults without a diagnosis of depression in the United States. METHODS:: A cross-sectional design utilizing pooled data from the National Ambulatory Medical Care Survey (2005-2015) was used. The study sample consisted of ambulatory care visits to nonpsychiatrists among adults (>=18 years) without a depression diagnosis. Depression screening was the dependent variable. Descriptive statistics, logistic regression, and piecewise regression analyses were conducted to achieve the study objectives. RESULTS:: The national-level depression screening rate was 1.4% of all adult ambulatory care visits. Year, gender, physician specialty, geographic region, and time spent with physician were significantly associated with depression screening. Piecewise regression analysis revealed a statistically significant (p<.001) interaction between year and change in depression screening rate, where screening rates increased significantly after 2009. CONCLUSIONS:: Although screening rates have increased significantly after 2009, screening remains low among adults without a depression diagnosis. PMID- 29983111 TI - Barriers to Service Utilization and Child Mental Health Treatment Attendance Among Poverty-Affected Families. AB - OBJECTIVE:: The majority of children who initially engage in mental health treatment in the United States drop out prematurely, a problem further exacerbated among children living in poverty. This study examined the relationships between sociodemographic characteristics, barriers to treatment use, and session attendance. METHODS:: Data were obtained from participants (N=225) in the 4R2S field trial. Barriers were measured using the Kazdin Barriers to Treatment Participation Scale. RESULTS:: Barriers endorsed by families attending less treatment primarily aligned with practical rather than perceptual obstacles. Critical events linked to lower attendance included moving too far away from the clinic, a job change, and a child's moving out of the home. CONCLUSIONS:: Child mental health programs serving low-income families may consider structural modifications to allow for greater family support as well as flexibility in treatment delivery by leveraging technology. Future research is needed to evaluate barriers to treatment and alternate modalities in relation to service utilization. PMID- 29983112 TI - Legislators' Sources of Behavioral Health Research and Preferences for Dissemination: Variations by Political Party. AB - OBJECTIVES:: This study sought to characterize primary sources of behavioral health research and dissemination preferences of state legislators and assess differences by political party. METHODS:: A 2017 cross-sectional survey of state legislators (N=475) assessed where legislators seek, and the most important features of, behavioral health research. Bivariate analyses and multivariate logistic regression were conducted. RESULTS:: Advocacy organizations (53%), legislative staff (51%), and state agencies (48%) were identified most frequently as sources of behavioral health research. Universities were identified by significantly more Democrats than Republicans (34% versus 19%; adjusted odds ratio=1.79). Data about budget impact and cost-effectiveness were most frequently rated as very important, but by significantly fewer Democrats than Republicans (77% versus 87% and 76% versus 89%, respectively). CONCLUSIONS:: To reach legislators and satisfy their information preferences, behavioral health researchers should target diverse audiences, partner with intermediary organizations, and craft messages that include economic evaluation data. PMID- 29983113 TI - Can community health worker home visiting improve care-seeking and maternal and newborn care practices in fragile states such as Afghanistan? A population-based intervention study. AB - BACKGROUND: The effects of community health worker (CHW) home visiting during the antenatal and postnatal periods in fragile- and conflicted-affected countries such as Afghanistan are not known. METHODS: We conducted a non-randomised population-based intervention study from March 2015 to February 2016. Two intervention and two control districts were selected. All female CHWs in the intervention districts were trained to provide eight home visits and behaviour change communication messages from pregnancy to 28 days postpartum. The primary outcome was the proportion of women who reported delivering in a health facility. Secondary outcomes were the proportion of women who reported attending a health facility for at least one antenatal and one postnatal visit. Outcomes were analysed at 12 months using multivariable difference-in-difference linear regression models adjusted for clustering. RESULTS: Overall, 289 female CHWs in the intervention districts performed home visits and 1407 eligible women (less than 12 months postpartum) at baseline and 1320 endline women provided outcome data (94% response rate). Facility delivery increased in intervention villages by 8.2% and decreased in the control villages by 6.3% (adjusted mean difference (AMD) 11.0%, 95% confidence interval (CI) 4.0-18.0%, p = 0.002). Attendance for at least one antenatal care visit (AMD 10.5%, 95% CI 4.2-16.9%, p = 0.001) and postnatal care visit (AMD 7.2%, 95% CI 0.2-14.2%, p = 0.040) increased in the intervention compared to the control districts. CONCLUSIONS: CHW home visiting during the antenatal and postnatal periods can improve health service use in fragile- and conflict-affected countries. Commitment to scale-up from Ministries and donors is now needed. TRIAL REGISTRATION: This trial was retrospectively registered at the Australian and New Zealand Clinical Trial Registry ( ACTRN12618000609257 ). PMID- 29983114 TI - Five year trends in the serve size, energy, and sodium contents of New Zealand fast foods: 2012 to 2016. AB - BACKGROUND: The nutritional composition of foods and beverages consumed away from the home has important implications for population health. Our objective was to determine if the serve size, energy, and sodium contents of fast foods sold at chain restaurants in New Zealand (NZ) changed between 2012 and 2016. METHODS: Serve size and nutrient data were collected in annual cross-sectional surveys of all products sold at 10 major fast food chains. Changes over time may occur due to alterations in product availability or individual product reformulation. Linear regression adjusting for food group and chain was used to estimate overall changes in serve size and nutrients. Random effects mixed models were used to estimate reformulation changes on same products available for two or more years. RESULTS: Across all products (n = 5468) increases were observed in mean serve size (+ 9 (3, 15) g, + 5%), energy density (+ 54 (27, 81) kJ/100 g, + 6%), energy per serve (+ 178 (125, 231) kJ, + 14%), and sodium per serve (+ 55 (24, 87) mg, + 12%). Sodium density did not change significantly. Four of 12 food groups (Desserts, Pizza, Sandwiches, and Salads) and four of 10 fast food chains (Domino's, Hell Pizza, Pizza Hut, and Subway) displayed large, undesirable changes for three or more (of five) outcomes (>=10%; p < 0.05). One food group (Asian) and one chain (St Pierre's) displayed large, desirable changes for two or more outcomes. The only significant reformulation change was a drop in sodium density (- 22 (- 36, - 8) mg/100 g, - 7%). CONCLUSIONS: The serve size and energy density of NZ fast food products has increased significantly over the past 5 years. Lower sodium concentration in new and reformulated products has been offset by overall increases in serve size. Continued monitoring and development and implementation of Government-led targets for serve size and nutrient content of new and existing fast food products are required. PMID- 29983115 TI - Prevalence and distribution of soil-transmitted helminth infections in Nigerian children: a systematic review and meta-analysis. AB - BACKGROUND: Soil transmitted helminth (STH) infections still remain a notable health problem in resource-limited countries due to difficulties in the implementation of control measures. In Nigeria for instance, despite several community-based and provincial reports, national data on prevalence, burdens and risk zones (RZs) for STH infections are lacking. METHODS: The present study employed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to determine the prevalence, distribution and RZs for STH infections among Nigerian children through a meta-analysis of data published between 1980 and 2015. Pooled prevalence estimate (PPE) was determined by the random-effects model while heterogeneity was evaluated using the Cochran's Q-test. RESULTS: A total of 18 901 of the 34 518 Nigerian children aged 0-17 years examined across 19 Nigerian states during the period under review were infected with one or more species of STHs. The overall PPE for STH infections was 54.8% (95% CI: 54.2-55.3). PPEs for sub-groups ranged between 13.2% (95% CI: 11.5 15.1) and 80.9% (95% CI: 80.0-81.7). Highest PPEs for STH infections were observed among children within community settings (59.0%, 95% CI: 57.7-60.4) and school-aged children (54.9%, 95% CI: 54.3-55.5). Ascaris lumbricoides was the most prevalent species (44.6%, 95% CI: 44.0-45.2). Over 36% (15/41) of the studies were published from south-western Nigeria. South-western region was the only high risk zone (HRZ) for STH infections while the rest of the regions were low risk zones (LRZs). CONCLUSIONS: STH infections involving Ascaris lumbricoides, Strongyloides stercoralis, Trichuris trichiura and hookworms are highly prevalent across Nigeria. Strategic use of anthelmintics, health education and adequate sanitation, taking into account this epidemiologic information will help in the control of these infections in Nigeria. PMID- 29983117 TI - Association of medullary sponge kidney and hyperparathyroidism with RET G691S/S904S polymorphism: a case report. AB - BACKGROUND: Medullary sponge kidney is a rare renal malformation, which usually manifests as nephrocalcinosis, renal tubular acidosis, and recurrent urinary tract infections. Medullary sponge kidney is often associated with renal developmental anomalies and tumors, and its exact pathogenesis is not yet clearly explained. Given the key role of the interaction of glial cell line-derived neurotrophic factor gene, GDNF, and the "rearranged during transfection" proto oncogene, RET, in kidney and urinary tract development, variations in these genes are proposed to be candidates for medullary sponge kidney. Hyperparathyroidism is observed in a few patients with medullary sponge kidney, but the exact pathogenesis of this association is unknown. This case report highlights the coexistence of these two conditions associated with RET polymorphism, which contributes toward the understanding of the pathogenesis of medullary sponge kidney. CASE PRESENTATION: A 52-year-old Chinese woman with recurrent renal stones presented to our hospital. Subsequently she was diagnosed as having medullary sponge kidney and tertiary hyperparathyroidism and underwent parathyroidectomy. Genomic DNA was isolated from lymphocytes and the GDNF and RET genes were determined by Sanger sequencing. Two RET polymorphisms were found in our patient, one was nonsynonymous c.2071G>A (G691S; rs1799939) located in exon 11, the other was synonymous c.2712C>G. (p.S904S; rs1800863) located in exon 15. CONCLUSIONS: We demonstrated a case of medullary sponge kidney combined with tertiary hyperparathyroidism, which contributes to further understanding of the pathogenesis of this disease. Besides, we also found RET G691S/S904S polymorphism in this patient, but additional studies are required to explore the role of the RET gene in medullary sponge kidney with hyperparathyroidism. PMID- 29983116 TI - Horizontal transfer of BovB and L1 retrotransposons in eukaryotes. AB - BACKGROUND: Transposable elements (TEs) are mobile DNA sequences, colloquially known as jumping genes because of their ability to replicate to new genomic locations. TEs can jump between organisms or species when given a vector of transfer, such as a tick or virus, in a process known as horizontal transfer. Here, we propose that LINE-1 (L1) and Bovine-B (BovB), the two most abundant TE families in mammals, were initially introduced as foreign DNA via ancient horizontal transfer events. RESULTS: Using analyses of 759 plant, fungal and animal genomes, we identify multiple possible L1 horizontal transfer events in eukaryotic species, primarily involving Tx-like L1s in marine eukaryotes. We also extend the BovB paradigm by increasing the number of estimated transfer events compared to previous studies, finding new parasite vectors of transfer such as bed bug, leech and locust, and BovB occurrences in new lineages such as bat and frog. Given that these transposable elements have colonised more than half of the genome sequence in today's mammals, our results support a role for horizontal transfer in causing long-term genomic change in new host organisms. CONCLUSIONS: We describe extensive horizontal transfer of BovB retrotransposons and provide the first evidence that L1 elements can also undergo horizontal transfer. With the advancement of genome sequencing technologies and bioinformatics tools, we anticipate our study to be a valuable resource for inferring horizontal transfer from large-scale genomic data. PMID- 29983118 TI - The role of gender in patient preference for breast surgical care - a comment on equality. AB - Gender preference among patients seeking medical care is an issue that is not well understood. It warrants exploration, particularly for patients undergoing sensitive physical exams. In a recent IJHPR article, Groutz et al. reported a survey study that explored patient preferences in selecting a breast surgeon. They found that a third of patients preferred a female surgeon for their breast examination. However, surgical ability was the primary factor in selecting a surgeon for their breast surgery. This commentary discusses these findings in the context of patient-centered care and issues of gender equality in medical education.Gender equality is considered an important societal movement in achieving human rights for everyone based on their ability, rather than their gender and opportunity. This commentary argues that the goal of gender equality is why women should be encouraged to enter surgical professions, recognizing that patient preferences will be shaped by societal norms. Gender preferences for the performance of sensitive physical examinations by some patients are likely multifactorial and they warrant more exploration to deliver ideal patient centered care. PMID- 29983120 TI - Radiation exposure in transcatheter patent ductus arteriosus closure: time to tune? -CORRIGENDUM. PMID- 29983119 TI - Fully automated, inline quantification of myocardial blood flow with cardiovascular magnetic resonance: repeatability of measurements in healthy subjects. AB - BACKGROUND: Non-invasive assessment of myocardial ischaemia is a cornerstone of the diagnosis of coronary artery disease. Measurement of myocardial blood flow (MBF) using positron emission tomography (PET) is the current reference standard for non-invasive quantification of myocardial ischaemia. Dynamic myocardial perfusion cardiovascular magnetic resonance (CMR) offers an alternative to PET and a recently developed method with automated inline perfusion mapping has shown good correlation of MBF values between CMR and PET. This study assessed the repeatability of myocardial perfusion mapping by CMR in healthy subjects. METHODS: Forty-two healthy subjects were recruited and underwent adenosine stress and rest perfusion CMR on two visits. Scans were repeated with a minimum interval of 7 days. Intrastudy rest and stress MBF repeatability were assessed with a 15 min interval between acquisitions. Interstudy rest and stress MBF and myocardial perfusion reserve (MPR) were measured for global myocardium and regionally for coronary territories and slices. RESULTS: There was no significant difference in intrastudy repeated global rest MBF (0.65 +/- 0.13 ml/g/min vs 0.62 +/- 0.12 ml/g/min, p = 0.24, repeatability coefficient (RC) =24%) or stress (2.89 +/- 0.56 ml/g/min vs 2.83 +/- 0.64 ml/g/min, p = 0.41, RC = 29%) MBF. No significant difference was seen in interstudy repeatability for global rest MBF (0.64 +/- 0.13 ml/g/min vs 0.64 +/- 0.15 ml/g/min, p = 0.80, RC = 32%), stress MBF (2.71 +/ 0.61 ml/g/min vs 2.55 +/- 0.57 ml/g/min, p = 0.12, RC = 33%) or MPR (4.24 +/- 0.69 vs 3.73 +/- 0.76, p = 0.25, RC = 36%). Regional repeatability was good for stress (RC = 30-37%) and rest MBF (RC = 32-36%) but poorer for MPR (RC = 35-43%). Within subject coefficient of variation was 8% for rest and 11% for stress within the same study, and 11% for rest and 12% for stress between studies. CONCLUSIONS: Fully automated, inline, myocardial perfusion mapping by CMR shows good repeatability that is similar to the published PET literature. Both rest and stress MBF show better repeatability than MPR, particularly in regional analysis. PMID- 29983121 TI - Grass silage particle size when fed with or without maize silage alters performance, reticular pH and metabolism of Holstein-Friesian dairy cows. AB - The particle size of the forage has been proposed as a key factor to ensure a healthy rumen function and maintain dairy cow performance, but little work has been conducted on ryegrass silage (GS). To determine the effect of chop length of GS and GS:maize silage (MS) ratio on the performance, reticular pH, metabolism and eating behaviour of dairy cows, 16 multiparous Holstein-Friesian cows were used in a 4*4 Latin square design with four periods each of 28-days duration. Ryegrass was harvested and ensiled at two mean chop lengths (short and long) and included at two ratios of GS:MS (100:0 or 40:60 dry matter (DM) basis). The forages were fed in mixed rations to produce four isonitrogenous and isoenergetic diets: long chop GS, short chop GS, long chop GS and MS and short chop GS and MS. The DM intake (DMI) was 3.2 kg/day higher (P<0.001) when cows were fed the MS than the GS-based diets. The short chop length GS also resulted in a 0.9 kg/day DM higher (P<0.05) DMI compared with the long chop length. When fed the GS:MS based diets, cows produced 2.4 kg/day more (P<0.001) milk than when fed diets containing GS only. There was an interaction (P<0.05) between chop length and forage ratio for milk yield, with a short chop length GS increasing yield in cows fed GS but not MS-based diets. An interaction for DM and organic matter digestibility was also observed (P<0.05), where a short chop length GS increased digestibility in cows when fed the GS-based diets but had little effect when fed the MS-based diet. When fed the MS-based diets, cows spent longer at reticular pH levels below pH 6.2 and pH 6.5 (P<0.01), but chop length had little effect. Cows when fed the MS-based diets had a higher (P<0.05) milk fat concentration of C18 : 2n-6 and total polyunsaturated fatty acids compared with when fed the GS only diets. In conclusion, GS chop length had little effect on reticular pH, but a longer chop length reduced DMI and milk yield but had little effect on milk fat yield. Including MS reduced reticular pH, but increased DMI and milk performance irrespective of the GS chop length. PMID- 29983122 TI - A pilot study on the foraging behaviour of heifers in intensive silvopastoral and monoculture systems in the tropics. AB - Intensive silvopastoral systems (ISS) are a sustainable alternative to monoculture systems (MS). The presence of trees and legumes improves animal welfare due to the increased food quality and quantity and the presence of shade while providing a variety of environmental services. As cattle behaviour is greatly affected by environmental conditions, knowledge on the behavioural trade offs that cattle make to meet their demands while foraging in different grazing systems is important, as this will help us understand the perceived advantages of ISS. This pilot study assessed the behaviour of heifers in an ISS (n=8 heifers) and MS (n=8 heifers) in the Mexican tropics during the dry and rainy seasons, and its relationship with forage availability, mean travelled distance and the temperature humidity index (THI). In both seasons, daily foraging times were longer in the MS than the ISS (P<0.01). The duration of rumination was higher for ISS (P<0.01) and the duration of lying was higher for the dry season (P<0.05). The decrease in foraging times in relation to THI was significantly higher in the ISS than in the MS (mean slope+/-SE: ISS=-4.64+/-0.34; MS=-2.34+/-0.22; t=-14.20, P<0.001). The results suggest that the forage availability and access to shade in the ISS allow cattle to rest longer and increase rumination, whereas cattle in MS spend more time searching for food and foraging at times of the day were the temperatures were higher as a compensatory strategy, which potentially decreases cattle's welfare and production qualities when compared with the ISS. In conclusion, ISS are likely to generate positive behavioural trade-offs that result in better welfare conditions and higher productive potential. PMID- 29983123 TI - Effect of different dietary tannin extracts on lamb growth performances and meat oxidative stability: comparison between mimosa, chestnut and tara. AB - Little information is available on the effects of different sources of tannins on ruminant product quality. Nowadays several tannin-rich extracts, produced from different plants, are available and contain tannins belonging to different chemical groups, but most of these have not been used so far as feed supplements. The present study aimed at comparing the effects of feeding three tannin extracts (one containing condensed tannins and two containing hydrolysable tannins) to lambs on growth performances and meat oxidative stability. Comisana male lambs were divided into four groups (n=9 each) and were fed for 75 days: a concentrate based diet (CON), or CON supplemented with 4% tannin extracts from either mimosa ( MI; Acacia mearnsii, De Wild; condensed tannins), chestnut (CH; Castanea sativa, Mill; hydrolysable ellagitannins) or tara (TA; Cesalpinia spinosa, (Molina) Kuntze; hydrolysable gallotannins). Only CH reduced growth rate, final weight, carcass weight and feed intake (P0.05). The TA diet increased (P<0.001) the concentration of gamma-tocopherol in muscle and tended to increase that of alpha-tocopherol (P=0.058). Oxidative stability of raw and cooked meat, or of meat homogenates incubated with pro-oxidants, was not affected by the extracts. These results, compared with those reported in the literature, highlight that some effects of tannins cannot be easily generalized, but may strictly depend on their specific characteristics and on conditions inherent to the basal diet and the metabolic status of the animals. PMID- 29983125 TI - A review of select minerals influencing the haematopoietic process. AB - Micronutrients are indispensable for adequate metabolism, such as biochemical function and cell production. The production of blood cells is named haematopoiesis and this process is highly consuming due to the rapid turnover of the haematopoietic system and consequent demand for nutrients. It is well established that micronutrients are relevant to blood cell production, although some of the mechanisms of how micronutrients modulate haematopoiesis remain unknown. The aim of the present review is to summarise the effect of Fe, Mn, Ca, Mg, Na, K, Co, iodine, P, Se, Cu, Li and Zn on haematopoiesis. This review deals specifically with the physiological requirements of selected micronutrients to haematopoiesis, showing various studies related to the physiological requirements, deficiency or excess of these minerals on haematopoiesis. The literature selected includes studies in animal models and human subjects. In circumstances where these minerals have not been studied for a given condition, no information was used. All the selected minerals have an important role in haematopoiesis by influencing the quality and quantity of blood cell production. In addition, it is highly recommended that the established nutrition recommendations for these minerals be followed, because cases of excess or deficient mineral intake can affect the haematopoiesis process. PMID- 29983124 TI - Imagery-Focused Cognitive Therapy (ImCT) for Mood Instability and Anxiety in a Small Sample of Patients with Bipolar Disorder: a Pilot Clinical Audit. AB - BACKGROUND: Despite the global impact of bipolar disorder (BD), treatment success is limited. Challenges include syndromal and subsyndromal mood instability, comorbid anxiety, and uncertainty around mechanisms to target. The Oxford Mood Action Psychology Programme (OxMAPP) offered a novel approach within a cognitive behavioural framework, via mental imagery-focused cognitive therapy (ImCT). AIMS: This clinical audit evaluated referral rates, clinical outcomes and patient satisfaction with the OxMAPP service. METHOD: Eleven outpatients with BD received ImCT in addition to standard psychiatric care. Mood data were collected weekly from 6 months pre-treatment to 6 months post-treatment via routine mood monitoring. Anxiety was measured weekly from start of treatment until 1 month post-treatment. Patient feedback was provided via questionnaire. RESULTS: Referral and treatment uptake rates indicated acceptability to referrers and patients. From pre- to post-treatment, there was (i) a significant reduction in the duration of depressive episode relapses, and (ii) a non-significant trend towards a reduction in the number of episodes, with small to medium effect size. There was a large effect size for the reduction in weekly anxiety symptoms from assessment to 1 month follow-up. Patient feedback indicated high levels of satisfaction with ImCT, and underscored the importance of the mental imagery focus. CONCLUSIONS: This clinical audit provides preliminary evidence that ImCT can help improve depressive and anxiety symptoms in BD as part of integrated clinical care, with high patient satisfaction and acceptability. Formal assessment designs are needed to further test the feasibility and efficacy of the new ImCT treatment on anxiety and mood instability. PMID- 29983126 TI - Transcriptome changes in muscle of Nellore cows submitted to recovery weight gain under grazing condition. AB - The aim of this study was to evaluate transcriptome changes in the muscle tissue of Bos taurus indicus cull cows subjected to recovery weight gain under grazing conditions. In all, 38 Nellore cull cows were divided randomly into two different management groups: (1) Maintenance (MA) and (2) Recovery gain (RG) from weight loss by moderate growth under high forage availability. After slaughter, RNA analysis was performed on the Longissimus thoracis muscle. Semaphorin 4A, solute carrier family 11 member 1, and Ficolin-2 were expressed in the RG, which may indicate an inflammatory response during tissue regrowth. Signaling factors, such as Myostatin, related to fibroblast activation, negative control of satellite cell proliferation in adults and muscle protein synthesis were less abundant in the RG group. The only gene related to anabolic processes that were more abundant in the MA group was related to fat deposition. The genes that were differentially expressed in the experiment showed muscle repair-related changes during RG based on the greater expression of genes involved in inflammatory responses and the lower expression of negative regulators of muscle cell proliferation and hypertrophy. PMID- 29983128 TI - The Acceptability, Feasibility and Potential Outcomes of an Individual Mindfulness-Based Intervention for Hearing Voices. AB - BACKGROUND: A prominent area of advancement in the psychological treatment for people with persisting psychosis has been the application of mindfulness-based therapies. Recent literature has recommended the investigation of focused mindfulness interventions for voices (auditory hallucinations) as a specific experience. To date, only mindfulness programs in group format have been examined. AIMS: This non-randomized pilot study aimed to assess the acceptability, feasibility and potential outcomes of an individual mindfulness program for persistent voices on the negative impact of voices on the subjective experience of mental health and wellbeing, depression and voice-related distress and disruption. Also, it aimed to identify potential psychological and neurocognitive mechanisms of change. METHOD: A new 4-week individual Mindfulness Program for Voices (iMPV) was developed, and piloted with a group of 14 participants with a schizophrenia-spectrum disorder and persisting voices. Participants completed clinical and neurocognitive measures pre- and post intervention and at 2-month follow-up. RESULTS: Results revealed low attrition rates, high formal practice engagement levels and positive participant feedback. Pre-post outcomes suggested small to moderate effects for a reduction in the negative impact of voices on experience, depression and disruption. Large effects for changes in mindful responding and attentional switching were also identified. CONCLUSIONS: Our findings suggest that this novel treatment protocol is appropriate, engaging and safe for persistent voice hearers. Findings for mindful responding and attentional switching suggest these to be potential mechanisms of change for further investigation. Further RCTs are warranted to ascertain the feasibility and efficacy for focused mindfulness interventions for voices of individual format. PMID- 29983127 TI - Characteristics and Outcomes of Patients in Rehabilitation with Hip Fracture: A Retrospective Chart Review. AB - ABSTRACTHip fracture rehabilitation has two streams: high tolerance short duration (HTSD) and low tolerance long duration (LTLD). This study examined patient characteristics and outcomes in HTSD and LTLD associated with length of stay (LOS) and discharge destination. We retrospectively examined patients' medical charts following hip fracture surgery and collected demographic, functional, and health characteristics. A statistical analysis was done to describe the differences between HTSD (n = 73) and LTLD (n = 57) patient characteristics and their relationship with LOS and discharge destination. Those in LTLD were significantly older, less independent with prefracture bathing and instrumental activities of daily living, had lower Functional Independence Measure (FIM) admission scores, and more co-morbidities. Higher FIM motor score on admission in HTSD and greater change in FIM total score in LTLD was significantly correlated with discharge home. Diabetes in LTLD and lower total admission FIM in HTSD was significantly associated with increased LOS. PMID- 29983129 TI - Water footprint assessment of sheep farming systems based on farm survey data. AB - Water scarcity is among the main challenges making vulnerable the livestock farming systems in drylands. The water footprint (WF) indicator was proposed as a metric to measure the impacts of livestock production on freshwater resources. Therefore, this study aimed to assess water use in five different Tunisian sheep production systems using the Water Footprint Network methodology. The primary data were obtained from 1050 sheep farms located in 13 Tunisian provinces. A multivariate analysis was performed to characterize the different farming systems. A validation step of the WF modeled values of sheep meat was conducted in 12 sheep farms belonging to two different farming systems. This was done through year-round monitoring of on-farm practices using water metres and recording equipment's taking into account the direct and indirect water use. The typology analysis came up with five sheep farming systems that are the mixed sheep-cereal (MSC), the agro-sylvo-pastoral (ASP), the agro-pastoral (AP), the extensive agro-pastoral (EAP) and the mixed sheep-olive tree farming systems. The WF of sheep meat produced under the target farming systems ranged from 8654 to 13 056 l/kg live weight. The evaluation of WF of five different sheep production systems figured out that sheep raised under the EAP farming system had the greatest WF per ton of live animal. However, the ASP farming system exhibited the lowest WF. Water used to grow feedstuffs for sheep production accounts for 98% of the total WF of sheep. The green WF accounts for more than 92% of the total WF in all farming systems. Results of monitoring water use at farm scale show that the modeled values of WF are overestimated by an average of 23.3% and 24.1% for the selected farms assigned to the MSC and AP farming systems, respectively. Water use for sheep production is high in most of the Tunisian farms. Therefore, the general assumption that 'meat production is a driver of water scarcity' is supported and should be considered as an important focal point in agricultural and water policies. Particular attention should be given to forage crops with low WFs and high contribution to dry matter to provide ration with low WF. The efficient use of green water along the meat value chain is essential to minimize the depletion of blue water resources and to reduce the economic dependency on virtual water through the import of feedstuffs. PMID- 29983130 TI - Follicular development of sows at weaning in relation to estimated breeding value for within-litter variation in piglet birth weight. AB - In this study we aimed to identify possible causes of within-litter variation in piglet birth weight (birth weight variation) by studying follicular development of sows at weaning in relation to their estimated breeding value (EBV) for birth weight variation. In total, 29 multiparous sows (parity 3 to 5) were selected on their EBV for birth weight variation (SD in grams; High-EBV: 15.8+/-1.6, N=14 and Low-EBV: -24.7+/-1.5, N=15). The two groups of sows had similar litter sizes (15.7 v. 16.9). Within 24 h after parturition, piglets were cross-fostered to ensure 13 suckling piglets per sow. Sows weaned 12.8+/-1.0 and 12.7+/-1.0 piglets, respectively, at days 26.1+/-0.2 of lactation. Blood and ovaries were collected within 2 h after weaning. The right ovary was immediately frozen to assess average follicle size and percentage healthy follicles of the 15 largest follicles. The left ovary was used to assess the percentage morphologically healthy cumulus-oocyte complexes (COCs) of the 15 largest follicles. To assess the metabolic state of the sows, body condition and the circulating metabolic markers insulin, IGF1, non-esterified fatty acid, creatinine, leptin, urea and fibroblast growth factor 21 were analysed at weaning. No significant differences were found in any of the measured follicular or metabolic parameters between High EBV and Low-EBV. A higher weight loss during lactation was related to a lower percentage healthy COCs (beta= -0.65, P=0.02). Serum creatinine, a marker for protein breakdown, was negatively related to average follicle size (beta= -0.60, P=0.05). Backfat loss during lactation was related to a higher backfat thickness at parturition and to a higher average follicle size (beta=0.36, P<0.001) at weaning. In conclusion, we hypothesise that modern hybrid sows with more backfat at the start of lactation are able to mobilise more energy from backfat during lactation and could thereby spare protein reserves to support follicular development. PMID- 29983131 TI - Characterisation of white and black merino wools: a proteomics study. AB - Wool is an important agricultural commodity with merino wool being rated alongside the finest quality fibres, which include the goat fibres Mohair and Cashmere. Although pigmented wool merinos have become extremely rare, the market for this wool is increasing. In Portugal, there are two merino breeds: white and black, descendants of animals originally bred on the Iberian Peninsula. These breeds have the potential to assist in our understanding of how protein expression relates to wool traits of importance to the textile industry. Herein, we study the characteristics and protein expression profiles of wool from ewes of the Portuguese black and white merino (n=15). Both breeds had very similar results for fibre diameter (25 um) and curvature (105 to 111 degrees /mm). Significant between-breed differences were found in the two types of keratin associated proteins (KAPs): high-sulphur proteins (HSPs) and high-glycine tyrosine proteins (HGTPs). The expression of HSPs, KAP2-3 and KAP2-4, decreased expression in the pigmented animals, whereas KAP13-1 was found in higher amounts. Likewise, the expression of the ultra-high-sulphur proteins, KAP4-3 and KAP4-7 like, was reduced in black sheep to half the levels of the white wools, whereas the HGTPs, KAP6, KAP6-1, KAP6-2 and KAP16-2, were more abundant in black sheep. These results suggest structural differences between the black and white merino wool, because of differences among some KAPs. These differences have important implications for the textile industry. PMID- 29983132 TI - Analysing innovations among cattle smallholders to evaluate the adequacy of breeding programs. AB - Many breeding programs have been implemented in developing countries, many of which have been unsuccessful. To better understand the failure of these breeding programs, it is proposed to analyze their adequacy with innovations that are actually adopted by smallholders. The proposed methodology takes account of these innovations, the reasons for their adoption and the objectives of livestock keeping. The N'Dama cattle-breeding program in Senegal was used as a case study. Surveys were carried out among 54 farmers: 27 breeders who participated in this program, 17 of whom recently resigned, and 27 breeders who have never participated. Feeding was the most frequently cited area of innovation, followed by infrastructure. Genetics, animal health and reproduction held the third rank. Milk production appeared as an important objective of breeders, although the context remains one of strong multifunctionality. Principal component analysis highlighted three categories of breeders according to the innovations they adopted: institutional, modernizing, and integrating innovators. The groups of institutional and modernizing innovators dominate, gathering each 41% of the farmers. In the first category, breeders have organized themselves in an association and use N'Dama sires, livestock aiming at an insurance objective. In the second category, artificial insemination with exotic breeds and other technical innovations (cowshed, vaccination, urea treatment of straw) are used to improve production of milk and meat. The third group is termed 'integrating innovators,' since their innovations aim at integrating livestock and crop production. Gathering 18% of the sampled breeders, this group presents intermediate features between the two previous groups, using animals as draught power and for manure production. These results indicate that a process of intensification is at play and that the genetic improvement through the selection of N'Dama cattle for production criteria does not meet the breeders' demand. However, the N'Dama's adaptive traits justify its use as part of the breeding strategy of farmers, either in pure-breeding or in crossbreeding. The study thus tends to show the interactive link between genetic improvement and other innovations. It suggests that the success of a breeding program depends on its adequate positioning within the set of innovations adopted by breeders and proposes a method to inform breeding programs accordingly. PMID- 29983133 TI - Thymol supplementation effects on adrenocortical, immune and biochemical variables recovery in Japanese quail after exposure to chronic heat stress. AB - Chronic heat stress (CHS) exposure negatively impairs avian' immunoneuroendocrine interplay. Thymol has shown several bioactive properties including antioxidant, bactericidal, antifungal and gamma-aminobutyric acid modulator activities. Indeed, supplementation with thymol has been used with positive effects on poultry production and immune-related variables. This study evaluates whether a thymol dietary supplementation can be used as a new functional feed strategy to mitigate CHS deleterious effects on endocrine, biochemical and immune-related variables. Starting at 100 days of age, 24 fully adult Japanese quail were fed with a diet supplemented with thymol (~80 mg/quail per day) and other 24 quail remained non-supplemented (control diet). Between 119 and 127 days of age, half of the quail within those groups were submitted to a CHS by increasing environmental temperature from 24 degrees C to 34 degrees C during the light phase and the other half remained at 24 degrees C (non-stressed controls). A period of 3 days after CHS ended (during the recovery period), corticosterone, albumin, total proteins and globulins and glucose concentrations, inflammatory response, antibody production and heterophil to lymphocyte (H/L) ratio were assessed. No differences between groups were found in basal corticosterone concentrations. Total proteins, total globulins and glucose concentrations were found elevated in the previously CHS group compared with their control counterparts. Regardless of the previous CHS exposure, thymol supplementation increased albumin concentrations and inflammatory responses and decreased antibody titers. An interaction between thymol supplementation and prior CHS exposure was found on the H/L ratio. Quail previously exposed to CHS and supplemented with thymol showed similar H/L values than their control non stressed counterparts, suggesting that thymol has a stress preventive effect on this variable. The present findings together with the already reported thymol bioactive properties, suggest that feed supplementation with this compound could be a useful strategy to help overcoming some of the CHS induced alterations. PMID- 29983134 TI - Travel distance and human movement predict paths of emergence and spatial spread of chikungunya in Thailand. AB - Human movement contributes to the probability that pathogens will be introduced to new geographic locations. Here we investigate the impact of human movement on the spatial spread of Chikungunya virus (CHIKV) in Southern Thailand during a recent re-emergence. We hypothesised that human movement, population density, the presence of habitat conducive to vectors, rainfall and temperature affect the transmission of CHIKV and the spatiotemporal pattern of cases seen during the emergence. We fit metapopulation transmission models to CHIKV incidence data. The dates at which incidence in each of 151 districts in Southern Thailand exceeded specified thresholds were the target of model fits. We confronted multiple alternative models to determine which factors were most influential in the spatial spread. We considered multiple measures of spatial distance between districts and adjacency networks and also looked for evidence of long-distance translocation (LDT) events. The best fit model included driving-distance between districts, human movement, rubber plantation area and three LDT events. This work has important implications for predicting the spatial spread and targeting resources for control in future CHIKV emergences. Our modelling framework could also be adapted to other disease systems where population mobility may drive the spatial advance of outbreaks. PMID- 29983135 TI - Effects of whole linseed supplementation and treatment duration on fatty acid profile and endogenous bioactive compounds of beef muscle. AB - Diet supplementation with oilseeds is known to improve the fatty acid profile of meat, but few studies have been carried out to determine the time required for the incorporation of a significant quantity of n-3 polyunsaturated fatty acids (PUFA) into meat from steers. Therefore, the present study aimed to assess the effects of linseed supplementation and feeding duration on the fatty acid profile, cholesterol and bioactive compounds of bovine meat. In total, 54 Friesian steers were randomly allocated during the finishing period into six experimental treatments following a 2*3 factorial design. The six treatments consisted of two diets, the control diet (CO) with no supplemental fat and the linseed diet (LS) containing 10% whole linseed, fed 40, 75 or 120 days before slaughter. At the end of each finishing period, steers from the CO and LS groups were slaughtered. After 8 days of ageing chemical analysis, the fatty acid profile, cholesterol content and bioactive compounds were determined from the longissimus thoracis muscle. Including linseed in the diet increased the content of monounsaturated fatty acids, CLA and n-3 PUFA, and reduced the proportion of saturated fatty acids and n-6 PUFA. The percentage of myristic fatty acid increased with the duration of feeding, regardless of diet and a decrease in PUFA and n-6 PUFA was observed in the CO and LS diets, respectively. Furthermore, meat from steers fed linseed showed an increased percentage of n-3 PUFA, linolenic acid, and EPA from 40 to 75 days of feeding, whereas vaccenic acid, CLA 9c,11t, and total CLA increased from 40 and 75 days but declined at 120 days. Beef from the linseed group had a higher content of bioactive substances such as creatine, carnosine and anserine than beef from the control group. The duration of feeding significantly affected the creatine concentrations, with an increase in the LS group from 40 to 75 days of feeding. Feeding linseed did not modify the cholesterol content, on average and the lowest cholesterol content was found in meat after 75 days of linseed administration. This study demonstrates that a short-term diet manipulation is sufficient to improve the nutritional properties of meat, including n-3 PUFA and bioactive compounds. PMID- 29983136 TI - Early intervention with faecal microbiota transplantation: an effective means to improve growth performance and the intestinal development of suckling piglets. AB - Recent studies indicate that early postnatal period is a critical window for gut microbiota manipulation to optimise the immunity and body growth. This study investigated the effects of maternal faecal microbiota orally administered to neonatal piglets after birth on growth performance, selected microbial populations, intestinal permeability and the development of intestinal mucosal immune system. In total, 12 litters of crossbred newborn piglets were selected in this study. Litter size was standardised to 10 piglets. On day 1, 10 piglets in each litter were randomly allotted to the faecal microbiota transplantation (FMT) and control groups. Piglets in the FMT group were orally administrated with 2ml faecal suspension of their nursing sow per day from the age of 1 to 3 days; piglets in the control group were treated with the same dose of a placebo (0.1M potassium phosphate buffer containing 10% glycerol (vol/vol)) inoculant. The experiment lasted 21 days. On days 7, 14 and 21, plasma and faecal samples were collected for the analysis of growth-related hormones and cytokines in plasma and lipocalin-2, secretory immunoglobulin A (sIgA), selected microbiota and short chain fatty acids (SCFAs) in faeces. Faecal microbiota transplantation increased the average daily gain of piglets during week 3 and the whole experiment period. Compared with the control group, the FMT group had increased concentrations of plasma growth hormone and IGF-1 on days 14 and 21. Faecal microbiota transplantation also reduced the incidence of diarrhoea during weeks 1 and 3 and plasma concentrations of zonulin, endotoxin and diamine oxidase activities in piglets on days 7 and 14. The populations of Lactobacillus spp. and Faecalibacterium prausnitzii and the concentrations of faecal and plasma acetate, butyrate and total SCFAs in FMT group were higher than those in the control group on day 21. Moreover, the FMT piglets have higher concentrations of plasma transforming growth factor-beta and immunoglobulin G, and faecal sIgA than the control piglets on day 21. These findings indicate that early intervention with maternal faecal microbiota improves growth performance, decreases intestinal permeability, stimulates sIgA secretion, and modulates gut microbiota composition and metabolism in suckling piglets. PMID- 29983137 TI - Dietary essential oils improve feed efficiency and hepatic antioxidant content of broiler chickens. AB - The aim of this study was to test the hypothesis of an improved growth, dietary nutrient availability and overall health of broiler chickens reared on recycled litter when fed a standardised combination of essential oils (EO; carvacrol, cinnamaldehyde and capsicum oleoresin). To assess the effect of dietary treatments, feed intake, weight gain, feed efficiency, availability of dietary nutrients and energy, villus morphometry, excreta sialic acid concentration, hepatic antioxidants and serum amyloid A (SAA) when fed to broiler chickens were evaluated. Counts of Eimeria spp. oocysts were also determined in excreta samples. Four experimental diets were offered, including two basal control diets based on either wheat or maize that contained 215 g CP/kg and 12.13 MJ/kg metabolisable energy and another two diets using the basal control diets supplemented with the EO combination at 100 mg/kg diet. Each diet was fed to eight floor pens, containing two birds each, following randomisation. Birds fed the EO-supplemented diets had an improved (P0.05) were observed in villus morphometry, sialic acid secretion, number of oocysts and SAA. Feeding the EO improved (P<0.05) the retention of dietary Ca and Na. Compared with maize, feeding wheat-based diets improved the retention coefficients for Ca, P and Na (P<0.05). Feeding dietary EO improved (P<0.05) the concentrations of the hepatic antioxidants, including carotene, coenzyme Q10 and total vitamin E. The hepatic concentration of carotene of the maize-fed birds was 55.6% greater (P<0.05) compared with the wheat-fed birds. These results demonstrated that the addition of a standardised combination of EO in wheat- and maize-based diets provided benefits in terms of feed efficiency, mineral retention and antioxidant status of the birds when reared on recycled litter. PMID- 29983138 TI - Homeless adults' access to dental services and strategies to improve their oral health: a systematic literature review. AB - Homeless people have poor oral health and high treatment needs, yet tend to make problem-based dental visits. This review aimed to determine how and where homeless adults receive oral health care, the barriers that prevent homeless adults accessing dental care and find strategies to promote oral health to homeless adults. The databases MEDLINE via OvidSP, PubMed, CINAHL and Scopus were searched using the keywords: homeless, roofless, houseless, rough sleeper, couch surfer, shelter, hostel, dental and oral health. The inclusion criteria were: participants over the age of 17 years, studies written in English, based in developed countries and published after 2003. Selected articles were assessed using the Mixed Methods Appraisal Tool and data extracted were thematically analysed. Twenty-two studies met the inclusion criteria. Five main themes were found: how homeless people accessed dental care; factors affecting the uptake of care; strategies used to improve access to care; the effect of non-dental staff on dental care; and challenges with providing care to homeless people. Dental care for homeless adults was affected by numerous factors. Improving their access to dental services requires collaboration between support service providers, dental care to be near homeless populations and flexibility by dental services. PMID- 29983139 TI - CircRNA-9119 regulates the expression of prostaglandin-endoperoxide synthase 2 (PTGS2) by sponging miR-26a in the endometrial epithelial cells of dairy goat. AB - Circular RNAs (circRNAs) have been found to play important functional roles in epigenetic regulation under certain physiological and pathological conditions. However, knowledge of circRNAs during the development of receptive endometrium (RE) from pre-RE is limited. In the RE of dairy goats, higher circRNA-9119 levels, with lower miR-26a and higher prostaglandin-endoperoxide synthase 2 (PTGS2) levels, were detected. Further study showed that circRNA-9119 decreased levels of miR-26a by acting as a microRNA sponge, and that miR-26a downregulated the expression of PTGS2 via the predicted target site in endometrial epithelial cells (EECs) of dairy goats in vitro. In this way, circRNA-9119 functioned as a competing endogenous RNAs (ceRNA) that sequestered miR-26a, thereby protecting PTGS2 transcripts from miR-26a-mediated suppression in dairy goat EECs in vitro. Furthermore, PTGS2 participated in the regulation of some protein markers for endometrial receptivity in dairy goat EECs in vitro. Thus, a circRNA-9119-miR-26a PTGS2 pathway in the endometrium was identified, and modulation of circRNA-9119 miR-26a-PTGS2 expression in EECs may emerge as a potential target to regulate the development of RE. PMID- 29983140 TI - Shining light on spindle positioning. AB - Optogenetic approaches are leading to a better understanding of the forces that determine the plane of cell division. PMID- 29983141 TI - Imaging Evaluation and Interpretation for Vascular Access for Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for aortic stenosis in patients who are at intermediate and high surgical risk. Vascular access remains critical to the success of the TAVR procedure. This article reviews the use of imaging in planning and executing TAVR access. PMID- 29983142 TI - Imaging Evaluation for the Detection of Leaflet Thrombosis After Transcatheter Aortic Valve Replacement. AB - Subclinical leaflet thrombosis has been increasingly recognized as a common imaging finding after surgical or transcatheter aortic valve replacement (TAVR) in recent studies. This finding has raised concerns over TAVR valve durability and debates on optimal postprocedural antithrombotic regime. Hypoattenuated leaflet thickening (HALT) and the associated reduced leaflet motion (RELM) were noted as computed tomography hallmarks of the phenomenon. The coexistence of HALT and significant RELM has been suggested as a threshold for reporting of subclinical leaflet thrombosis. This methodology may contribute to the standardization of reporting for research collaboration, hence the better understanding and management of this common yet largely unknown phenomenon. PMID- 29983143 TI - Computed Tomography Assessment for Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement has become a mainstream therapeutic option for patients with severe aortic stenosis who are at intermediate risk or high risk for surgical valve replacement. Computed tomography (CT) is now the standard imaging modality for preoperative vascular access planning an aortic annular sizing. This article reviews the established and potential future roles of CT in transcatheter aortic valve replacement. PMID- 29983144 TI - Intravascular Ultrasound for Guidance and Optimization of Percutaneous Coronary Intervention. AB - Percutaneous coronary intervention (PCI) remains the mainstay management of symptomatic obstructive stable coronary artery disease (despite optimal medical treatment) and acute coronary syndrome. Intravascular ultrasound (IVUS) has emerged as an adjunct to angiography, permitting better assessment of the coronary lesion and stent apposition. Data from multiple studies have demonstrated improved clinical and procedural outcomes with IVUS-guided PCI. This review discusses the use of IVUS, with emphasis on technique, parameters, and applications during coronary interventions. In addition, the clinical outcomes data are highlighted with IVUS compared with conventional angiography-guided PCI. PMID- 29983145 TI - Algorithmic Approach for Optical Coherence Tomography-Guided Stent Implantation During Percutaneous Coronary Intervention. AB - Intravascular imaging plays a key role in optimizing outcomes for percutaneous coronary intervention (PCI). Optical coherence tomography (OCT) utilizes a user friendly interface and provides high-resolution images. OCT can be used as part of daily practice in all stages of a coronary intervention: baseline lesion assessment, stent selection, and stent optimization. Incorporating a standardized, algorithmic approach when using OCT allows for precision PCI. PMID- 29983146 TI - Computed Tomography Fractional Flow Reserve to Guide Coronary Angiography and Intervention. AB - Computed tomography angiography (CTA) has played a significant role in evaluation of coronary artery disease in the last decade and has demonstrated high sensitivity and negative predictive values. However, the positive predictive value as compared with invasive fractional flow reserve (FFR) is limited. CT-FFR has emerged as a disruptive noninvasive technology with higher specificity and diagnostic accuracy for detection of hemodynamically significant coronary lesions as compared with invasive FFR than conventional coronary CTA. CT-FFR has been shown to be cost-effective as a gate-keeper to invasive coronary angiography and has the potential to limit unnecessary invasive angiography studies. PMID- 29983148 TI - Computed Tomography for Left Atrial Appendage Occlusion Case Planning. AB - Prevention of thromboembolism in atrial fibrillation has been investigated in light of the high numbers of patients unable to be treated with effective anticoagulation. Therefore, endovascular mechanical occlusion of the left atrial appendage (LAA) has been developed as a substitute for thromboprophylaxis. Initial clinical trials demonstrated high rates of procedural complications. Using computed tomography (CT), one can ascertain accurate left atrial appendage dimensions, appendage morphology; predict radiograph gantry angles; and produce physical models for ex vivo device and catheter fitting. This is an overview of available evidence for using CT and the clinical impact of CT on endovascular LAA occlusion. PMID- 29983147 TI - Myocardial Viability Testing to Guide Coronary Revascularization. AB - Left ventricular dysfunction remains one of the best prognostic determinants of survival in patients with coronary artery disease. Revascularization has been shown to improve survival compared with medical therapy alone. Viability testing can help direct patients who will benefit the most from revascularization. Single photon emission computed tomography, dobutamine stress echo, cardiac MRI, and PET imaging with F18-fluorodeoxyglucose are the most common modalities for assessing myocardial viability. Viability testing can help differentiate which patients benefit most from chronic total occlusion interventions. PMID- 29983149 TI - Multimodality Imaging of the Tricuspid Valve for Assessment and Guidance of Transcatheter Repair. AB - The tricuspid valve is a highly complex structure, with variability in the number of leaflets and scallops. The mechanism of regurgitation is multifactorial in etiology, a mix of functional and degenerative tricuspid regurgitation. Iatrogenic tricuspid regurgitation is becoming more common secondary to pacemaker wire impingement of leaflet function and coaptation. Echocardiographic imaging of the tricuspid valve is particularly challenging given its anatomic location and other interfering structures, including pacemaker wires. Preprocedural planning and intraprocedural guidance for transcatheter intervention relies on a comprehensive understanding of tricuspid anatomy and the use of 3-dimensional transesophageal echocardiography. The incorporation of computed tomography and cardiac magnetic resonance imaging likely will provide increasing accuracy and optimization of procedural success. PMID- 29983150 TI - Identification and Quantification of Degenerative and Functional Mitral Regurgitation for Patient Selection for Transcatheter Mitral Valve Repair. AB - Chronic mitral regurgitation (MR), whether due to valve degeneration or secondary to myocardial disease, affects an increasing proportion of the aging population. Percutaneous mitral valve interventions, including edge-to-edge repair, are emerging as feasible and effective therapy for patients with severe MR at high or prohibitive surgical risk. Imaging with echocardiography is crucial for patient selection by evaluating mitral anatomy, the mechanism of dysfunction, and MR severity. In this article, the authors review the imaging characteristics for identifying and quantifying degenerative and functional MR for transcatheter mitral valve repair. PMID- 29983151 TI - Percutaneous Balloon Mitral Valvuloplasty: Echocardiographic Eligibility and Procedural Guidance. AB - Rheumatic mitral stenosis remains a common disease in the developing world. Percutaneous mitral balloon valvuloplasty is an important therapy for rheumatic mitral stenosis. Echocardiography plays a critical role in the diagnosis of rheumatic mitral stenosis and the assessment of suitability for and guidance of percutaneous mitral valvuloplasty. PMID- 29983152 TI - Three-Dimensional Printing for Planning of Structural Heart Interventions. AB - Three-dimensional (3D) printing is a process leading to the creation of a physical 3D model used for teaching, patient education, device evaluation, and procedural planning. 3D printed models of patient-specific anatomy can be generated from 3D transesophageal, cardiac MRI, or cardiac computed tomographic datasets. This article discusses the potential advantages of 3D printing, reviews the different modalities to acquire a 3D dataset, and highlights the application of 3D printing to enhance patient screening and procedural planning in structural heart intervention. PMID- 29983153 TI - Imaging in Intervention. PMID- 29983154 TI - Psoriasis and Pitiriasis Versicolor: Together But Separate. PMID- 29983155 TI - Epidermal Nevi and Related Syndromes -- Part 1: Keratinocytic Nevi. AB - Epidermal nevi are hamartomatous lesions derived from the epidermis and/or adnexal structures of the skin; they have traditionally been classified according to their morphology. New variants have been described in recent years and advances in genetics have contributed to better characterization of these lesions and an improved understanding of their relationship with certain extracutaneous manifestations. In the first part of this review article, we will look at nevi derived specifically from the epidermis and associated syndromes. PMID- 29983156 TI - Over 100 years of Krapina: New insights into the Neanderthal thorax from the study of rib cross-sectional morphology. AB - The Krapina costal sample was studied by Gorjanovic-Kramberger in the early twentieth century. He pointed out unique features in the sample such as the rounder rib cross-section, which was recently confirmed in other Neanderthal specimens. Round rib cross-sections are characteristic of Homo ergaster, suggesting this may be plesiomorphic for Pleistocene Homo, but it is unknown whether Homo antecessor also had this rib shape. Furthermore, the influence of allometry on the cross-sectional shape of ribs is still unknown. The large costal sample from Krapina allows us to address these issues. We quantified cross section morphology at the midshaft throughout a closed curve of one landmark and nine sliding semilandmarks in the Krapina costal remains (n = 7), as well as in other Neanderthals (n = 50), H. antecessor (n = 3) and modern humans, both fossil (n = 12) and recent (n = 160). We used principal components analysis and mean comparisons to explore interspecific differences, regression analysis to investigate allometry, and partial least squares analysis to examine covariation of cross-section shape and overall rib morphology. Neanderthal cross-sections tended to be larger than those of recent humans except for the Krapina and Tabun remains. Regarding shape, inter-group differences were found only in the diaphragmatic thorax, where Neanderthal and H. antecessor ribs were statistically significantly rounder than those of modern humans. Allometry accounted for covariation of size on shape, but the Neandertal and modern human trajectories had different slopes. While our results based on the Krapina costal sample are similar to previous findings, we also make several new insights: 1) the cross section morphology observed in Neanderthals was probably present in H. antecessor, albeit less marked; 2) the distinct roundness of Neanderthal cross sections is not related to size; 3) rounder cross-sections are correlated with ribs presenting less curvature in cranial view and a low degree of torsion in recent humans. These results are important for the interpretation of fragmentary Neanderthal costal remains, and the fact that the differences are marked only in the diaphragmatic thorax could have implications for breathing kinematics. PMID- 29983157 TI - Calculating brain perfusion of primates. PMID- 29983158 TI - Risk factors for prolonged need for percutaneous endoscopic gastrostomy (PEG) tubes in adult trauma patients: Experience of a level 1 trauma. AB - BACKGROUND: Percutaneous endoscopic gastrostomy tubes are a means of providing an alternative enteric route of nutrition. This study sought to identify risk factors for the prolonged need of a percutaneous endoscopic gastronomy tube (>=90 days) in adult trauma patients. METHODS: The trauma database of a level 1 trauma center was queried retrospectively to identify patients who had percutaneous endoscopic gastronomy tubes placed. RESULTS: A total of 9,772 charts were reviewed with 282 patients (2.9%) undergoing successful percutaneous endoscopic gastronomy tube placement. On review of discharged living patients, 195 had adequate clinical documentation to allow for analysis. The mean age was 57.5 years, admission serum albumin was 3.7 g/dL, and Charlson Comorbidity Index score was 1.1. The first recorded mean Glasgow Coma Scale was 10.7, and their Injury Severity Score was 23.2. The mean duration of total hospital stay was 23.8 days, intensive care unit stay was 16.5 days, and in-hospital ventilator days was 11.5. Of the 272 patients, 77 (41.4%) required percutaneous endoscopic gastronomy tubes for >90 days. Statistically significant characteristics on univariate analysis included increasing age, a greater Charlson Comorbidity Index score, and a greater number of in-hospital ventilator days. On logistic regression, a Charlson Comorbidity Index score >1 (odds ratio 1.27, 95% confidence interval 1.03-1.56, P = .02) and greater in-hospital ventilator days (odds ratio 1.05, 95% confidence interval 1.02-1.09, P < .01) were predictive of the need for prolonged percutaneous endoscopic gastronomy tube placement. CONCLUSION: A Charlson Comorbidity Index score >1 and prolonged in-hospital ventilator days were risk factors for the necessity of a percutaneous endoscopic gastronomy tube for >=90 days after placement. This observation may assist patients/surrogates in decision making when needing alternative routes for nutrition. PMID- 29983160 TI - Approaches to reduce noise from ships operating in important killer whale habitats. AB - Shipping is key to global trade, but is also a dominant source of anthropogenic noise in the ocean. Chronic noise from ships can affect acoustic quality of important whale habitats. Noise from ships has been identified as one of three main stressors-in addition to contaminants, and lack of Chinook salmon prey-in the recovery of the endangered southern resident killer whale (SRKW) population. Managers recognize existing noise levels as a threat to the acoustical integrity of SRKW critical habitat. There is an urgent need to identify practical ways to reduce ocean noise given projected increases in shipping in the SRKW's summertime critical habitat in the Salish Sea. We reviewed the literature to provide a qualitative description of mitigation approaches. We use an existing ship source level dataset to quantify how some mitigation approaches could readily reduce noise levels by 3-10 dB. PMID- 29983159 TI - Numerical encoding in early visual cortex. AB - The ability to estimate numerosity in a visual array arose early in evolution, develops early in human development, and is correlated with mathematical ability. Previous work with visually presented arrays indicates that the intraparietal sulcus (IPS) represents number. However, it is not clear if the number signal originates in IPS or is propagated from earlier visual areas. Previous work from our group has demonstrated a rapidly instantiated representation of number in low level regions of visual cortex using the high temporal resolution of event related electro-encephalography (EEG). Here, we use a rapid event-related functional magnetic resonance imaging (fMRI) paradigm and find convergent evidence for a number signal in low-level visual cortex (areas V1, V2, and V3). Employing a stringent set of stimulus controls, we demonstrate that this signal cannot be explained by the total extent of the array, the density of the items in the array, the aggregate visual area of the items, the size of individual items, the proportion of the array covered by items, nor the overall scale of the array and items. Our findings thus provide strong support for the hypothesis that number is rapidly and directly encoded early in the visual processing stream. PMID- 29983161 TI - Asymptomatic bacteriuria in emergency. A frequent cause of diagnostic error. PMID- 29983162 TI - Aspergillosis, nocardiosis and scleroderma, a fatal and infrequent association. PMID- 29983163 TI - Rescue surgery in a patient with metastatic melanoma and BRAF V600E mutation. PMID- 29983164 TI - In recognition of this special journal issue on real-world emissions on CARB's leadership and central role in uncovering and resolving the environmental violations from Volkswagen's use of illegal diesel defeat devices. PMID- 29983165 TI - Use of real-world connected vehicle data in identifying high-risk locations based on a new surrogate safety measure. AB - Traditional methods for the identification of high-risk locations rely heavily on historical crash data. Rich information generated from connected vehicles could be used to obtain surrogate safety measures (SSMs) for risk identification. Conventional SSMs such as time to collision (TTC) neglect the potential risk of car-following scenarios in which the following vehicle's speed is slightly less than or equal to the leading vehicle's but the spacing between two vehicles is relatively small that a slight disturbance would yield collision risk. To address this limitation, this study proposes time to collision with disturbance (TTCD) for risk identification. By imposing a hypothetical disturbance, TTCD can capture rear-end conflict risks in various car following scenarios, even when the leading vehicle has a higher speed. Real-world connected vehicle pilot test data collected in Ann Arbor, Michigan is used in this study. A detailed procedure of cleaning and processing the connected vehicle data is presented. Results show that risk rate identified by TTCD can achieve a higher Pearson's correlation coefficient with rear-end crash rate than other traditional SSMs. We show that high-risk locations identified by connected vehicle data from a relatively shorter time period are similar to the ones identified by using the historical crash data. The proposed method can substantially reduce the data collection time, compared with traditional safety analysis that generally requires more than three years to get sufficient crash data. The connected vehicle data has thus shown the potential to be used to develop proactive safety solutions and the risk factors can be eliminated in a timely manner. PMID- 29983166 TI - Separation and identification of phospholipids by hydrophilic interaction liquid chromatography coupled to tandem high resolution mass spectrometry with focus on isomeric phosphatidylglycerol and bis(monoacylglycero)phosphate. AB - Changes in lipid composition of cells or tissue are often linked to various diseases. Studies indicate alterations of bis(monoacylglycero)phosphate (BMP) species in diseases such as cancer. Therefore, an extended phospholipid profiling method based on hydrophilic interaction liquid chromatography (HILIC) coupled to high-resolution mass spectrometry (MS) and data-dependent MS/MS acquisition was developed to separate and unambiguously identify BMP species. Lipid species identification was based on retention time, accurate mass and specific MS/MS fragments. The developed method was applied in a proof of concept study to lipid extracts of a cell culture model of conditional oncogene overexpression in MCF 7/NeuT breast cancer cells. Comparison of control and oncogene-induced MCF-7/NeuT breast cancer cells showed changes in BMP species distribution. Thereby, a shift from long-chain to shorter-chain fatty acid composition in BMP species was detected. PMID- 29983167 TI - Separation of highly charged compounds using competing ions with hydrophilic interaction liquid chromatography - Application to assay of cellular nucleotides. AB - Separation of highly charged compounds has always been a challenge in chromatography. Ion-pair reversed phase chromatography has been the most successful approach to date. Although polar reversed phase and HILIC columns have been introduced, they have limitations with highly charged compounds. Competing ions have been used, in addition to ion-pair reagent, to achieve better resolution with reversed phase columns. Herein, we explored the use of competing ions with HILIC columns to demonstrate the effects on retention and separation of mono-, di-, and tri-nucleotides, introducing a new tool to improve resolution with HILIC columns. HILIC columns that had irreversibly retained highly charged tri-nucleotides became capable of successfully separating the same compounds, by using this approach. The optimised method was used to successfully resolve a mixture of 12 nucleotides with charges ranging from 1- to 3-. The method was applied to quantify nucleotides in blood cell extracts. PMID- 29983168 TI - Resolution and signal-to-noise in analysis of carbohydrate isomers by graphitised carbon chromatography with charged aerosol detection. AB - The effects of co-eluents and additives on separation and signal-to-noise ratio in analyses of monosaccharides by graphitised carbon chromatography (GCC) in combination with charged aerosol detection were studied. Design of experiments was used to model and predict the elution of two monosaccharide isomers, galactose and glucose and the corresponding amine at varying isocratic conditions, including concentration of water-soluble co-eluent, flow and temperature. The study confirmed the well-known order of eluent strength of the co-eluents investigated but showed that the eluent strength of MeOH was significantly lower than that of ACN, and at co-eluent concentrations >=5% (v/v) IPA approached that of THF. Addition of NH3 increased retention and improved both peak shape and separation but the detector response decreased with increasing NH3 concentration lowering the signal-to-noise ratio. The best combination of response, retention and separation was obtained at 0.1% NH3. Increasing column temperature in the range of 15-50 degrees C resulted in decreased retention times and resolution. The corresponding Van't Hoff correlations showed negative adsorption enthalpies indicating an exothermic adsorption process driven by a decrease in entropy minimising the surface energy of the system. Isocratic elution with MeOH as co-eluent offered limited possibilities for optimisation of resolution due to the opposite effects of changes in co-eluent concentration and changes in flow rate. Elution with acetonitrile as co-eluent showed possibilities for optimisation of the resolution within the range of flow rates of 0.6 0.95mL/min and co-eluent concentrations of 0.1-0.3%, with the highest resolution predicted at 0.1% acetonitrile and a flow rate of 0.81mL/min. Saccharides in the size range DP1-4, including amino, acetamido, and deoxy sugars, were separated using a binary gradient method. Higher retention was observed for increasing degree of polymerisation (DP) and N-acetylated saccharides were retained longer than non-substituted saccharides of corresponding DP. Partial resolution of two lacto-N-tetrasaccharide positional isomers was obtained. PMID- 29983169 TI - Preparation of porous zinc ferrite/carbon as a magnetic-assisted dispersive miniaturized solid phase extraction sorbent and its application. AB - In this study, porous ZnFe2O4/carbon, derived from Zn-Fe zeolitic imidazolate framework (Zn-Fe-ZIF), was employed as a novel sorbent for magnetic-assisted dispersive miniaturized solid phase extraction (M-DMUSPE). The Zn-Fe-ZIF derived magnetic porous ZnFe2O4/carbon was easily prepared using a one-pot solvothermal method, and its morphology, structure and magnetic characteristics were evaluated via scanning electron microscopy, powder X-ray diffraction, Raman spectroscopy and vibrating sample magnetometry. The extraction ability of ZnFe2O4/carbon is evaluated by different kinds of compounds including organochlorine pesticides, pyrethroid insecticides, aldehydes, nerolidol, benzoic acid and sorbic acid. A M DMUSPE method was developed for the analysis of organochlorine pesticides. Several parameters affecting the extraction efficiency were systematically investigated. The calibration curves ranged from 0.05 to 100 ng g-1 and the limits of detection were 0.005-0.3 ng g-1. The intra-day and inter-day relative standard deviations were lower than 2.3 and 5.2%. The recoveries of spiked organochlorine pesticides were in the range of 86.1-109.4%. PMID- 29983170 TI - The use of chemical probes to detect the proteomics of renal tubular injury induced by maleic acid. AB - Maleic acid (MA), an industrial raw material, was found to be illegally added to edible starch-based food products in Taiwan in 2013, a practice unheard of in most of the world. MA has been associated with renal dysfunction in many experimental animal studies. In this study, we developed chemical probes to investigate protein-protein interactions between MA and renal proteins. In the fabrication of the MA probes, we used silicon dioxide (SiO2) modified with a silanized linker (3-aminopropyl triethoxyslane, APTES) to generate MA with APTES SiO2 particles. The probes were then incubated with the cell lysates of normal human kidney cell lines (HK-2) and subjected to MS/MS for identifying several MA related proteins, including nucleophosmin, neutral alpha-glucosidase AB, translocon-associated protein subunit alpha, elongation factor 1-gamma, 60S acidic ribosomal protein P0-like, and heat shock protein (HSP 90-alpha and beta). Based on our findings, we believed that the probe can potentially be used to identify and detect the target proteins and help characterize a network of MA protein-protein interactions. PMID- 29983171 TI - Hip fractures in the non-elderly-Who, why and whither? AB - Nonelderly hip fracture patients have gathered little scientific attention, and our understanding of the group may be biased by patient case-mix and lack of follow-up. Preconceptions may thwart adequate investigation of bone health and other comorbidities. This literature review focusses on who these patients between 20 and 60 years are, how to treat them and how to evaluate the outcome. 2 11% of the hip fractures occur in non-elderly, equally common in men and women. Every second to forth patient smoke, have chronic diseases, and abuse alcohol. Poor self-rated health, sleep disturbances, low cognitive function and education are associated with increased hip fracture risk in young adults. Bone health is poorly investigated, but literature suggest young patients to have lower bone mineral density regardless of trauma mechanism. Studies contradict on whether surgery within 8-12 h reduce the risk of avascular necrosis in femoral neck fractures (FNF). Based on rationality, surgery ought to be performed promptly, in order to reduce pain and permit rehabilitation. There is no convincing support from the existing literature to use open reduction. Good reduction is mandatory, preferably using a closed reduction technique. The failure rate following internal fixation of displaced FNF in younger patients can be as high as 59%. In some cases a displaced FNF is better treated with a primary arthroplasty; in case of rheumatoid arthritis or osteoarthritis for example. Complications after extracapsular fractures vary from 6 to 23%. The relatively few studies looking at functional outcome in non-elderly use a multitude of outcome measures, precluding comparisons. Many non-elderly patients seem not to fully recover. While some non elderly hip fracture patients are healthy individuals sustaining high energy trauma, others have low-energy fractures and comorbidities including reduced bone strength (either as a primary or secondary condition). i.e. non-delaying medical optimization, proper surgical technique, bone health investigation and secondary fracture prevention is necessary. Younger hip fracture patients are at risk of permanent loss of function, and negative socioeconomic and psychological consequences. High-energy trauma does not exclude the presence of osteopenia. A hip fracture in adulthood and middle-age is very seldom caused by bad luck only! PMID- 29983172 TI - A global call to action to improve the care of people with fragility fractures. AB - The ageing of society is driving an enormous increase in fragility fracture incidence and imposing a massive burden on patients, their families, health systems and societies globally. Disrupting the status quo has therefore become an obligation and a necessity. Initiated by the Fragility Fracture Network (FFN) at a "Presidents' Roundtable" during the 5th FFN Global Congress in 2016 several leading organisations agreed that a global multidisciplinary and multiprofessional collaboration, resulting in a Global Call to Action (CtA), would be the right step forward to improve the care of people presenting with fragility fractures. So far global and regional organisations in geriatrics/internal medicine, orthopaedics, osteoporosis/metabolic bone disease, rehabilitation and rheumatology were contacted as well as national organisations in five highly populated countries (Brazil, China, India, Japan and the United States), resulting in 81societies endorsing the CtA. We call for implementation of a systematic approach to fragility fracture care with the goal of restoring function and preventing subsequent fractures without further delay. There is an urgent need to improve: To address this fragility fracture crisis, the undersigned organisations pledge to intensify their efforts to improve the current management of all fragility fractures, prevent subsequent fractures, and strive to restore functional abilities and quality of life. PMID- 29983174 TI - [Sleep related dissociative disorder: A case complicated by a suicide attempt]. PMID- 29983173 TI - Abundance of saccharides and scarcity of glycosaminoglycans in the soft tissue of clam, Meretrix meretrix (Linnaeus). AB - We investigated presence and distribution of glycosaminoglycans (GAGs) in Meretrix meretrix soft tissue by determining GAG composition in the different parts, namely, mantle edge, foot, gill, adductor muscle, and viscera. The occurrence of glycan ingredients was examined by histochemistry, whereas GAG and general polysaccharide contents in clam tissue were qualified through extraction and determination. Tissue sections stained with alcian blue or periodic acid Schiff demonstrated the general existence of saccharides and trifling generation of GAGs in clam tissues. GAGs coexisting with glycogens appeared to be primarily produced in the mantle and foot tissues in mucus form by visualization. The GAG content of the polysaccharide extract ranged from 16.8 to 75.8 mg in 10 g of 5 dried tissue materials in comparison with total carbohydrate level in the range of 500-1760 mg, thereby indicating that GAGs were not the major components of polysaccharide extracts. GAG composition only accounted for approximately 4% of total glycan components, which consist of the determinations of amino sugar and uronic acid. The soft tissues of clam contained abundant saccharide compounds but sparse amounts of GAGs. The results will benefit the subsequent development of products made from the polysaccharide components of M. meretrix. PMID- 29983175 TI - [Living and housing conditions of patients seen in the sectorized psychiatric hospitals in Paris on a given day]. PMID- 29983176 TI - [Physical activity in patients with schizophrenia: From neurobiology to clinical benefits]. AB - Schizophrenia is a severe chronic mental disorder that mainly manifests by positive symptoms, negative symptoms, disorganized behavior and thought and cognitive impairments. Taken together, these symptoms have substantial impact on quality of life, well-being and functional outcome. Patients with schizophrenia have dramatically higher levels of cardiovascular and metabolic morbidity than the general population due to poor physical fitness and to sedentary lifestyle. They have a reduced life expectancy, and an excess mortality being two or three times more than that in the general population. Moreover, despite major therapeutic advances in the overall management of these patients, some symptomatic dimensions, and more specifically the negative and cognitive ones, remain to be resistant to the usual pharmacological approaches. Moreover, antipsychotics can also reinforce the global cardiovascular risk due to side effects and low neurometabolic tolerance. The benefits of physical activity on health are now well described in the general population and in many medical diseases. More recently, physical activity has also found its place as an adjuvant therapy in severe mental illnesses, particularly in schizophrenia. In the literature physical activity programs, in addition to pharmacological treatments, appear to be feasible in patients and improve both physical and mental health as well as functional outcome. Clinical benefits of physical activity would be underpinned by biological and cerebral mechanisms, which remain unclear. In this review, we propose to present a state of the art and to present an update of the interests of physical activity in the management of patients with schizophrenia. We emphasize the clinical benefits of physical activity regarding the different symptomatic dimensions and its impact specifically on cognitive deficits. Finally, we describe the various underlying pathophysiological mechanisms in particular in the neurobiological, cerebral and physiological fields. We then discuss the barriers, facilitators and motivating factors towards physical activity to enhance health promotion initiatives, to optimize resource allocation when delivering physical activity programs in clinical practice, and to maximize physical activity participation. Physical activity appears to be an original and novel adjunctive therapeutic approach in the management of patients with schizophrenia and would both reduce schizophrenic symptoms and act like pro-cognitive therapy, improve quality of life and long term functioning in daily life and reduce cardiovascular comorbidities. However, efforts are still needed to increase the motivating factors and adherence towards physical activity participation for people with schizophrenia. PMID- 29983177 TI - Crossed prevalence results between subtypes of eating disorder and bipolar disorder: A systematic review of the literature. AB - OBJECTIVE: To assess the association between sub-types of bipolar disorder (BD) (types I and II) and sub-types of eating disorders (EDs) (Anorexia Nervosa, Bulimia Nervosa, Binge-eating disorders) as well as their relative order of occurrence. METHODOLOGY: A systematic review of articles estimating prevalence rates for BD among patients with ED and vice versa. We also analysed all articles assessing their relative order of occurrence. RESULTS: Comorbid BD is common among patients with an ED. From 0.6 to 33.3% of bipolar subjects have an eating disorder. Conversely, from 0 to 35.8% of subjects with an ED can present a BD. This co-occurrence has mostly been observed among patients with anorexia of the bulimic/purging type, with bulimia or with binge-eating disorders. The association is less frequent in cases of anorexia of the restrictive type. In contrast, the BD sub-type does not seem to have an impact on the association with EDs. Whilst age at BD onset is earlier in case of a comorbid ED, age at ED onset does not seem to be impacted by the presence of an associated BD. There has been little data on the relative order of occurrence of the two disorders or on the impact of the thymic phase on the expression of EDs. CONCLUSIONS: EDs and BD are frequently comorbid, suggesting the need for crossed screening of these pathologies, in particular for EDs with purging behaviours and for patients with early BD onset. PMID- 29983178 TI - [Involuntary hospitalization: A survey of liberty and custody judges]. AB - The procedure of involuntary hospitalization in France has been recently modified by the law of 5 July 2011. Since that time, a liberty and custody judge has been appointed to guarantee the rights of psychiatric inpatients and to prevent abusive hospitalizations. Currently, for one involuntary hospitalization in ten a release is decided by the liberty and custody judge although psychiatrists consider that psychiatric care is necessary. In order to improve our understanding of the role of liberty and custody judges, and how they make their decisions, we conducted a qualitative survey of liberty and custody judges in the Tribunal de Grande Instance of Lille. Three judges were questioned, based on a semi-structured interview. Judges' responses have highlighted the need for psychiatrists to strictly respect the legal procedures and to accurately describe the clinical signs and symptoms that justify the procedure of involuntary hospitalization in the medical certificates. The intervention of liberty and custody judges for patients with psychiatric disorders represents a breakthrough for patients' rights in France, reflecting that they are considered as citizens, with the same rights as others. Nonetheless, this new mission needs a progressive learning, based on mutual exchanges with doctors and caregivers. PMID- 29983179 TI - [Influence of a therapeutic patient education (TPE) program on quality of life in bipolar disorder: Preliminary results]. AB - INTRODUCTION: Bipolar disorder is a mental illness that is associated with a long term impairment in psychosocial functioning and quality of life. The objective of this study was to evaluate the influence of a therapeutic education program on the quality of life of patients with bipolar disorder (type 1 or 2). METHOD: This study included 18 patients with bipolar disorder (type 1 or 2) following the therapeutic education program on bipolar disorder which includes 8 sessions of 2hours each. The assessment of quality of life and mood, self-esteem, insight and global functioning was performed before and after the program using the following tools: World Health Organization Quality Of Life questionnaire in short version (WHOQOL-Bref), Hamilton Depression Rating Scale, Young Mania Rating Scale, Rosenberg Self-Esteem Scale, Birchwood Insight Scale and Global Assessment of Functioning Scale. The total score of WHOQOL-Bref constitutes the primary study outcome. The under-scores of WHOQOL-Bref as insight, self-esteem, functioning, depression and mania scores constitute secondary outcomes. RESULTS: Our results show an improvement in quality of life, regarding global and main dimension scores of WHOQOL-Bref. The mean total scores for quality of life at the beginning and the end of the program were respectively 55.47/100 (standard deviation=14.11) and 60.03/100 (standard deviation=12.62). However, the difference was still not significant even after statistical adjustment with depression, mania and functioning scores. Self-esteem was significantly improved (P=0.0469). Quality of life and self-esteem evolutions were strongly related (correlation coefficient=0.80, P=0.0006). At the end of the program, the less depressed the patients were, the better their quality of life was (correlation coefficient=0.67, P=0.0090). We did not find any correlation between quality of life and mania intensity or global functioning level at the end of the program. CONCLUSION: This study suggests a need to focus on self-esteem perception in order to understand and ameliorate the quality of life of patients with bipolar disorders. Going further, the use of bipolar disorder specific scales to assess quality of life would be more relevant. PMID- 29983180 TI - [The profil of Moroccan elderly psychiatric inpatients]. PMID- 29983183 TI - [Ultrasound-guided thoracic paravertebral block for closed loop ileostomy repair in severe COPD: a case report]. AB - BACKGROUND AND OBJECTIVES: Ultrasound-guided thoracic paravertebral block is usually considered a good alternative to epidural thoracic for anesthesia and pain control in thoracic and breast surgery. Furthermore it has also been used during abdominal surgery lately, especially hepatic and renal surgery. However, its role is poorly defined in this context. The purpose of this report was to highlight the role of thoracic paravertebral block in providing effective anesthesia and analgesia during both the abdominal surgical intervention and pain control in post-operative period, avoiding possible complications which general anesthesia may arise, which are fairly common in patients with chronic obstructive pulmonary disease and similar comorbidities. CASE REPORT: The authors present a case of abdominal surgery successfully performed on a woman affected by severe chronic obstructive pulmonary disease requiring closed loop ileostomy repair performed with ultrasound guided thoracic paravertebral block without any complications. CONCLUSIONS: Thoracic paravertebral block may be a safe anesthetic method for abdominal surgery in those patients who would undergo potential severe complications by using general anesthesia. PMID- 29983186 TI - The efficacy of surgical shunts to treat severe portal hypertension after a Kasai procedure for biliary atresia. AB - BACKGROUND: To assess the outcome of patients with biliary atresia (BA) who underwent a surgical shunt (SS) for severe portal hypertension (PH) following a Kasai procedure. METHODS: We collected and analyzed the data and outcomes of patients with BA who underwent SS for severe PH following a Kasai procedure between 1974 and 2014, focusing on complications related to the procedure, overall survival (OS), and transplant-free survival (TFS). RESULTS: SS was performed at a median age of 5.5 years [2-13.5] in 38 patients. Conjugated bilirubin level (cBL) was <=20 MUmol/l in 24 patients at time of SS. Median follow-up was 15 years [1-32]. OS at 5 and 10 years was 91% and 87% respectively. TFS at 5 and 10 years was 84% and 70% respectively. Long-term complications included hepatic encephalopathy in 9 patients, and hepatopulmonary syndrome in 3. At last follow-up, 10/14 patients without LT and 18/ 24 who had a delayed LT at a median delay of 11 years [1.5-22] were alive. CONCLUSION: Surgical shunt for severe portal hypertension in biliary atresia may delay the need for liver transplantation. However complications are indications for transplantation. LEVEL OF EVIDENCE: Type of study: Therapeutic. Level of evidence III. PMID- 29983187 TI - Foley catheters are not routinely necessary in children treated with patient controlled analgesia following perforated appendicitis. AB - BACKGROUND: Patient-controlled analgesia (PCA) is often used in children with perforated appendicitis. To prevent urinary retention, some providers also routinely place Foley catheters. This study examines the necessity of this practice. METHODS: We retrospectively reviewed all children (<=18 years old) with perforated appendicitis and postoperative PCA from 7/2015 to 6/2016 at two academic children's hospitals. Urinary retention was defined as the inability to spontaneously void requiring straight catheterization or placement of a Foley catheter. RESULTS: Of 313 patients who underwent appendectomy for perforated appendicitis (Hospital 1: 175, Hospital 2: 138), 129 patients received an intraoperative Foley (Hospital 1: 22 [13%], Hospital 2: 107 [78%], p < 0.001). Age, gender, and BMI were similar between those with an intraoperative Foley and those without. There were no urinary tract infections in either group. Urinary retention rate in patients with an intraoperative Foley following removal on the inpatient unit (n = 3, 2%) and patients without an intraoperative Foley (n = 10, 5%) did not reach significance (p = 0.25). On univariate analysis, demographics, intraoperative findings, PCA specifics, postoperative abscess formation, and postoperative length of stay, were not significant risk factors for urinary retention. CONCLUSIONS: The risk of urinary retention in this population is low despite the use of PCA. Children with perforated appendicitis do not require routine Foley catheter placement to prevent urinary retention. LEVEL OF EVIDENCE: II. PMID- 29983188 TI - Management of suspected thyroglossal duct cysts. PMID- 29983189 TI - Antibiotic ointment versus a silver-based dressing for children with extremity burns: A randomized controlled study. AB - INTRODUCTION: Antibiotic or silver-based dressings are widely used in burn wound care. Our standard method of dressing pediatric extremity burn wounds consists of an antibiotic ointment or nystatin ointment-impregnated nonadherent gauze (primary layer), followed by rolled gauze, soft cast pad, plaster and soft casting tape (3MTM ScotchcastTM, St. Paul, MN). The aim of this study was to compare our standard ointment-based primary layer versus Mepitel Ag(r) (Molnlycke Health Care, Gothenburg, Sweden) in the management of pediatric upper and lower extremity burn wounds. METHODS: Children with a new burn injury to the upper or lower extremities, who presented to the burn clinic were eligible. Eligible children were enrolled and randomized, stratified by burn thickness, to be dressed in an ointment-based dressing or Mepitel Ag(r). Study personnel and participants were not blinded to the dressing assignment after randomization. Dressings were changed approximately once or twice per week, until the burn wound was healed or skin-grafted. The primary outcome was time to wound healing and p value < 0.05 was considered significant. RESULTS: Ninety-six children with 113 upper or lower extremity burns were included in the analysis. Mepitel Ag(r) (hazard ratio [HR] 0.57 (95% Confidence Interval (CI) 0.40-0.82); p = 0.002) significantly reduced the rate of wound healing, adjusting for burn thickness and fungal wound infection. The incidence of fungal wound infections and skin grafting was similar between the two groups. Children randomized to standard ointment dressings were significantly less likely to require four or more burn clinic visits than those in the Mepitel Ag(r) (4% versus 27%; p = 0.004). CONCLUSION: Our study shows that our standard ointment-based dressing significantly increases the rate of wound healing compared to Mepitel Ag(r) for pediatric extremity burn injuries. LEVEL OF EVIDENCE: Treatment study; Level 1. PMID- 29983191 TI - Removal treatments alter the recruitment dynamics of a global marine invader - Implications for management feasibility. AB - Frameworks designed to prioritise the management of invasive non-native species (INNS) must consider many factors, including their impacts on native biodiversity, ecosystem services, and human health. Management feasibility should also be foremost in any prioritisation process, but is often overlooked, particularly in the marine environment. The Asian kelp, Undaria pinnatifida, is one of the most cosmopolitan marine INNS worldwide and recognised as a priority species for monitoring in the UK and elsewhere. Here, experimental monthly removals of Undaria (from 0.2 m2 patches of floating pontoon) were conducted at two marinas to investigate their influence on recruitment dynamics and the potential implications for management feasibility. Over the 18-month experiment there was no consistent reduction in Undaria recruitment following removals. Cleaning of pontoon surfaces (i.e. removal of all biota) led to significant short term reductions in recruitment but caused a temporal shift in normal recruitment patterns. Non-selective removal (i.e. all macroalgae) generally promoted recruitment, while selective removal (i.e. Undaria only) had some limited success in reducing overall recruitment. The varied results indicate that the feasibility of limiting Undaria is likely to be very low at sites with established populations and high propagule pressure. However, where there are new incursions, a mixture of cleaning of invaded surfaces prior to normal periods of peak recruitment followed by selective removal may have some potential in limiting Undaria populations within these sites. Multi-factorial experimental manipulations such as this are useful tools for gathering quantitative evidence to support the prioritisation of management measures for marine INNS. PMID- 29983192 TI - Transcriptomic, lipid, and histological profiles suggest changes in health in fish from a pesticide hot spot. AB - Barramundi (Lates calcarifer) were collected at the beginning (1st sampling) and end (2nd sampling) of the wet season from Sandy Creek, an agriculturally impacted catchment in the Mackay Whitsundays region of the Great Barrier Reef catchment area, and from Repulse Creek, located approximately 100 km north in Conway National Park, to assess the impacts of pesticide exposure. Gill and liver histology, lipid class composition in muscle, and the hepatic transcriptome were examined. The first sample of Repulse Creek fish showed little tissue damage and low transcript levels of xenobiotic metabolism enzymes. Sandy Creek fish showed altered transcriptomic patterns, including those that regulate lipid metabolism, xenobiotic metabolism, and immune response; gross histological alterations including lipidosis; and differences in some lipid classes. The second sampling of Repulse Creek fish showed similar alterations in hepatic transcriptome and tissue structure as fish from Sandy Creek. These changes may indicate a decrease in health of pesticide exposed fish. PMID- 29983193 TI - A multi-criteria decision approach for ranking unmet needs in healthcare. AB - Early temporary reimbursement (ETR) schemes for new interventions targeting high unmet needs are increasingly applied in pharmaceutical policy. Crucial for these schemes is the assessment of unmet healthcare needs of patients and society. This study develops and tests a multi-criteria decision approach (MCDA) for assessing therapeutic and societal needs. The Belgian unmet needs commission, responsible for creating a list of unmet needs for the ETR programme, has tested this methodology to assess the needs in eight health conditions. For therapeutic need, three criteria were included (impact of the condition on quality of life and on life expectancy and inconvenience of current treatment); for societal need two criteria (condition-related healthcare expenditures per patient, prevalence). The results show that the proposed MCDA is feasible and acceptable for the unmet needs commission. Clear definitions of the criteria and regular repetition of these is needed to avoid variable interpretation of the criteria by the commission members. Quality assessment of the evidence is desired. Rankings resulting from the application have face validity. Considering therapeutic need separately from societal need is considered appropriate. Policy makers should consider the use of MCDA in assessing healthcare needs. MCDA improves the transparency and accountability of the decision making processes and is practical and feasible. PMID- 29983194 TI - Health expenditure data for policy: Health accounts, national accounts or both? AB - Compatibility of statistical frameworks and comparability of data are aspects of statistical quality. This paper explores comparability of data from National Accounts (NA) and Care Accounts/health accounts (CA&HA) of the Netherlands. Although based on the same sources, differences result from specificities of each framework, making data adjustments necessary. Data comparison of major aggregates and household spending is a means for verification and for triangulation of sources. Monitoring household spending on health is one of the Sustainable Development Goals. The usability of NA data for household consumption estimates is key to judge plausibility of household spending levels. However, definitions, coverage and valuation in NA and CA&HA should be understood to benefit from the use of NA data for HA. More than in the concepts used the strength of NA is the way NA are usually produced compared with HA. Key is the integrated analysis including supply and demand to verify the comprehensiveness and consistency. It is concluded that SUT data of NA on consumption of human health and social care can be used for judging plausibility of HA household spending estimates, and, in the absence of the latter, NA data can directly be used. The case of the Netherlands shows that policy measures can have a large impact on the validity of using NA for the estimation of household spending. PMID- 29983195 TI - Results of the Andalusian Cystic Fibrosis Neonatal Screening Program, 5 Years After Implementation. AB - INTRODUCTION: Cystic fibrosis neonatal screening (CFNS), based on double determination of immunoreactive trypsinogen ([IRT] [IRT1/IRT2]), has been available in Andalusia since May 2011. If screening is positive, a sweat test is performed, and if that is positive or inconclusive, genetic testing is requested. OBJECTIVE: To analyze CFNS, based on results from the first 4.5 years of the program. MATERIALS AND METHODS: Prospective descriptive study of neonates undergoing CFNS. IRT levels, sweat chloride, and mutations were recorded. Statistical analysis was performed using SPSS 12.0. RESULTS: Between May 2011 and December 2016, 474,953 neonates underwent CFNS. Of these, 1,087 (0.23%) had elevated IRT2. Since CFNS was introduced, 73 cases of cystic fibrosis were diagnosed; 60 were diagnosed by positive CFNS, and 13 were diagnosed by other means. In one case, the patient developed a typical clinical picture of cystic fibrosis, but had not undergone CFNS at the decision of the parents; the remaining 12 had a negative CFNS (false negatives). Of these, one patient was diagnosed before symptoms developed, as his twin brother had a positive CFNS result; another had chloride at the upper limit of normal, and was subsequently diagnosed with genetic testing before symptoms appeared; and 10 patients developed clinical signs and symptoms. Excluding patients with meconium ileus, sensitivity and specificity of the CFNS program were 85.71% and 99.78%, respectively. The incidence of the disease in Andalusia is 1/6,506 live births. CONCLUSION: These results are a basis for reflection on possible areas for improvement of the CFNS algorithm, and thought may be given to the introduction of genetic studies to increase sensitivity and reduce false positives. PMID- 29983196 TI - A Complex Pulmonary Vascularization: Bilateral Meandering Pulmonary Veins. PMID- 29983197 TI - Prone positioning before extracorporeal membrane oxygenation for severe acute respiratory distress syndrome: A retrospective multicenter study. AB - OBJECTIVE: To evaluate the clinical outcomes of patients with severe acute respiratory distress syndrome (ARDS) subjected to prone positioning before extracorporeal membrane oxygenation (ECMO). DESIGN: A retrospective analysis of a multicenter cohort was carried out. SETTING: Patients admitted to the Intensive Care Units of 11 hospitals in Korea. PATIENTS: Patients were divided into those who underwent prone positioning before ECMO (n=28) and those who did not (n=34). INTERVENTIONS: None. VARIABLES OF INTEREST: Thirty-day mortality, ECMO weaning failure rate, mechanical ventilation weaning success rate, mechanical ventilation free days at day 60. RESULTS: The prone group had lower median peak inspiratory pressure and lower median dynamic driving pressure before ECMO. Thirty-day mortality was 21% in the prone group and 41% in the non-prone group (p=0.098). The prone group also showed a lower ECMO weaning failure rate, and a higher mechanical ventilation weaning success rate and more mechanical ventilation-free days at day 60. In the non-prone group, median dynamic compliance marginally decreased shortly after ECMO, but no significant change was observed in the prone group. CONCLUSIONS: Prone positioning before ECMO was not associated to increased mortality and tended to exert a protective effect. PMID- 29983198 TI - Sodium chloride triggers Th17 mediated autoimmunity. AB - The detrimental effects of a high-salt diet on human health have received much attention in the past few years. While it has been well established that high dietary salt intake is related to cardiovascular diseases, there is growing evidence that excess salt also affects the immune system and might be considered as a risk factor in autoimmune diseases such as multiple sclerosis (MS). Several studies have implicated T helper 17 cells (Th17) in the pathogenesis of MS. We and others recently demonstrated that excessive salt enhances the differentiation of Th17 cells, inducing a highly pathogenic phenotype that aggravates experimental neuroinflammation. Moreover, a diet rich in sodium affects intestinal microbiota alongside increased intestinal Th17 cells, thus linking the detrimental effects of high salt consumption to the gut-immune axis. First human studies revealed an association of increased MS disease activity with elevated sodium chloride consumption, while more recent epidemiology studies in larger cohorts suggest no correlation between salt intake and MS. However, it is known that ordinary urinary sodium analyses and nutritional questionnaires do not necessarily correspond to the actual sodium load and more sophisticated analyses are needed. Moreover, studies revealed that sodium can temporarily be stored in the body. This review summarizes recent findings on the impact of salt on the immune system and discusses potential challenges investigating dietary salt intake as a risk factor in MS. PMID- 29983190 TI - Factors associated with poor anticoagulation control with vitaminK antagonists among outpatients attended in Internal Medicine and Neurology. The ALADIN study. AB - OBJECTIVE: To identify factors associated with poor anticoagulation control with vitaminK antagonists (VKA) among outpatients with nonvalvular atrial fibrillation (NVAF) attended in Neurology and Internal Medicine in Spain. METHODS: Cross sectional and multicenter study, from the ALADIN database, of outpatients with NVAF treated with VKA and attended in Internal Medicine and Neurology in Spain. Rates of anticoagulation control were determined with the direct and Rosendaal methods, considering data from the 6months before the inclusion. RESULTS: Out of 1,337 patients included in the ALADIN study, 750 were taking VKA, and complete information about INR values in the last 6months was available in 383 patients. Mean scores of Charlson Index, CHADS2, CHA2DS2-VASc and HAS-BLED were 1.94+/ 1.54; 3.10+/-1.26; 4.63+/-1.54, and 2.20+/-0.90, respectively. 46.2% and 47.0% of patients had an adequate anticoagulation control according to the direct and Rosendaal methods, respectively. Inadequate anticoagulation control according to the direct method was associated with diabetes (OR: 2.511; 95%CI: 1.144-5.659), prior labile INR (OR: 35.371; 95%CI: 15.058-83.083) and the determination of >6INR controls in the last 6months (OR: 4.747; 95%CI: 2.094-10.759), and according to the Rosendaal method, with prior labile INR (P<.001) and HAS-BLED score (OR: 3.991; 95%CI: 2.520-6.319). CONCLUSIONS: Despite the high thromboembolic risk, only a little more than a half of patients were well controlled. Factors associated with poor anticoagulation control were diabetes, labile INR, >6INR controls and HAS-BLED. PMID- 29983199 TI - Helicobacter pylori infection and demyelinating disease of the central nervous system. AB - Helicobacter pylori (H. pylori) colonize >50% of the entire human population. Generally, H. pylori infect the human stomach in infancy when parietal cells secreting gastric acids, which reduce the survival of H. pylori, are not well matured. Once acquired, the bacterium persists for life. Thus, H. pylori infection reflects sanitary conditions during childhood. >10 studies performed in various Eastern and Western countries as well as two meta-analyses collectively indicated the H. pylori infection rate is significantly lower in patients with multiple sclerosis (MS) than in healthy controls. Thus, the bacterium might be a protective factor for MS, especially in low prevalence countries and younger generations that grew up in the low prevalence era. The protective effects of H. pylori might be explained by the hygiene hypothesis-encountering generic infection early in life facilitates development of the immunoregulatory system, which suppresses overactivity of autoimmune T cells later in life. However, no influence of common childhood infections on MS risk was reported by large MS cohort studies. Direct attenuation of autoreactive Th1 and Th17 cells by H. pylori infection was found in experimental autoimmune encephalomyelitis, an animal model of MS. These observations may underscore the direct protective effects of H. pylori on MS rather than generic infection in childhood. By contrast, several studies reported that H. pylori infection rates are significantly higher in anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD) than in healthy controls. H. pylori strongly activate Th17 cells via the induction of IL-23, resulting in neutrophil mobilization and activation. H. pylori neutrophil-activating protein (NAP) is a major proinflammatory protein responsible for the pathology of H. pylori-related gastric inflammatory diseases. Anti-H. pylori-NAP antibody levels were positively correlated with final EDSS scores and myeloperoxidase levels in anti-AQP4 antibody-positive NMOSD patients. Given that spinal cord lesions of NMOSD are heavily infiltrated with myeloperoxidase-positive neutrophils, H. pylori-NAP, which can be absorbed and presented to the host immune system, may exacerbate NMOSD. Thus, H. pylori infection and its proinflammatory proteins, such as NAP, may contribute to the pathology of anti-AQP4 antibody-related neural damage, by activating neutrophils. It is interesting that two representative demyelinating diseases of the central nervous system are differentially modulated by chronic H. pylori infection. The direct effects of H. pylori infection on MS and NMOSD warrant future studies. PMID- 29983201 TI - ["Visiting friends and relatives". New risk group in the primary care consulta]. PMID- 29983200 TI - [Daily activities assessed by a high-tech pattern-recognition monitor in older adults: preliminary findings from the IMPACT65+ study]. AB - INTRODUCTION: Physical activity and physical inactivity patterns can affect health status. In the elderly people, their study is relevant given the importance that they have on the morbidity and mortality. OBJECTIVE: To present preliminary data on activity and inactivity patterns of a sub-sample of older adults from the IMPACT65+ Study. MATERIAL AND METHODS: The sample included the first 84 participants (57% women) over 65 years (age 70.7+/-4.7). Time spent in activity and inactivity patterns was obtained from an Intelligent Device for Energy Expenditure and Activity monitor over a continuous period of 24hours. The patterns analysed were: standing, lying down, sitting or reclining, and the transition between them. The physical activity patterns analysed were; walking, step up or step down, running, and jumping. RESULTS: Time spent in inactivity patterns like reclining, lying down, and sitting was 16.1+/-1.9hours (67% day), while the amount of time spent in activity patterns was 2.4+/-1.9hours (10% day). Differences were observed between men and women in the amount of hours sitting (9.7+/-3 men vs. 7.5+/-2.7 women) and standing (4.5+/-1.4 men vs. 5.6+/-2.7 women). These differences were greater in the older participants. CONCLUSIONS: Preliminary results show that older adults spend a great part of day in inactivity patterns like sitting, and that gender is the only factor analysed that affects the time spent in the activity patterns analysed. PMID- 29983202 TI - Screening is caring: Community-based non-invasive diagnosis and treatment strategies for hepatitis C to reduce liver disease burden. PMID- 29983203 TI - Reply to: "NASH-related and cryptogenic cirrhosis similarities extend beyond cirrhosis": Cryptogenic cirrhosis should not be equated with NASH cirrhosis based on UNOS data mining and Bayesian 'doctrine of chances'. PMID- 29983204 TI - Autoimmune hepatitis and coeliac disease. Simultaneous onset of both diseases. PMID- 29983205 TI - Investigating heavy metal bioaccumulation by macrofauna species from different feeding guilds from sandy beaches in Rio de Janeiro, Brazil. AB - The relationship between metal accumulation and feeding behavior of macrofauna species is a key concept to understand the bioavailability of different metals in the marine environment. We examined and compared the concentrations of eight heavy metals (Cr, Zn, Pb, Ni, Cu, Cd, Co and V) in different feeding guilds of macrofauna species, from a data set including 68 sandy beaches along the Rio de Janeiro coast. For this purpose, macrofauna species were classified in five feeding guild categories: carnivorous, herbivorous, detritivorous, suspensivorous and filter feeders. The coast of Rio de Janeiro was divided into seven regions according to environmental characteristics and historical human activities. For each region, generalized linear models were adjusted to test for differences between feeding guild abundances. Redundancy Analysis was performed to explore the relationship among the feeding guilds composition and the environmental variables. We found high variability in abundance and composition among feeding guilds, linked with environmental heterogeneity. In general, carnivorous species showed a higher heavy metal concentrations compared to other trophic guilds evaluated. However, bioaccumulation across the feeding guild was not the rule and patterns varied across regions. Our hypothesis is that variations are probably related to the different magnitudes of metal contamination along the coast as also in to the trophic structure found in each beach. This data highlighted the crucial role of the relationship between variability of environmental drivers and bioaccumulation in macrofauna species in sandy beaches ecosystem. PMID- 29983206 TI - Radium-223 (Xofigo) with concurrent abiraterone or enzalutamide: predictive biomarkers of improved overall survival in a clinically advanced cohort. AB - PURPOSE: Radium-223 (Xofigo) is the first therapy with bone tropism for metastatic castrate-resistant prostate cancer (mCRPC) that has been shown to improve overall survival (OS). Although radium-223 has a positive effect on OS in men with mCRPC, there has been a paucity of reports from community practitioners, especially with regard to concurrent abiraterone and enzalutamide therapy. Significant differences in patient characteristics encountered may exist. PATIENTS AND METHODS: We conducted a retrospective study of men with mCRPC who received at least 1 cycle of radium-223 (n = 35). Baseline pain and ECOG PS as well as concurrent usage of abiraterone or enzalutamide were recorded. Side effect profiles for each patient throughout treatment were noted. RESULTS: Baseline cohort characteristics include a median age of 75 years. 37% had an ECOG PS >= 2 and 23% reported severe pain at baseline. 31% received concomitant enzalutamide 31% concomitant abiraterone. Patients treated concurrently with either abiraterone or enzalutamide did not display additional toxicity. Median cohort OS was 10 months. Patients with no or mild pain had longer median OS than those with moderate or severe pain, 14 versus 7 months (P = 0.028). Patients with ECOG PS < 2 had longer median OS than those with ECOG PS >= 2, 13 versus 10 months (P = 0.0233). CONCLUSION: This study highlights key differences in patient characteristics encountered by community practitioners. In this population, which presented with clinically advanced disease, there was an improved survival benefit for those treated earlier in their disease. Radium-223 was well tolerated and concurrent treatment with abiraterone or enzalutamide did not add additional toxicity. These 2 points seem to advocate for aggressive and early treatment of patients with radium-223 in the community. PMID- 29983207 TI - [Retinal vein occlusion in a young patient: Where does intraocular hypertension come from?] AB - INTRODUCTION: Retinal vein occlusion presents as an acute, painless and unilateral sight loss. We report two cases of retinal vein occlusion (CRVO) in which the etiology was unusual. CASE REPORTS: Case 1. A 54-year-old woman without any significant past medical history presented with an acute loss of vision. Medical history taking revealed the practice of yoga with headstand posture like "Sirsana". Case 2. A 35-year-old woman presented with an acute loss of vision related to a retinal vein occlusion. The investigation found prolonged and repeated vomiting the days before the retinal vein occlusion. CONCLUSION: Cardiovascular assessment is recommended in the investigation of CRVO. Furthermore, especially in young patients, a situation causing an increase of intraocular pressure as the practice of yoga with taking reverse "head down" body positions or even repeated vomiting efforts may be the cause of slower circulation of blood flow in the retinal veins. PMID- 29983208 TI - [Diffuse calcifications]. PMID- 29983209 TI - Assessment of the origin and transport of four selected emerging micropollutants sucralose, Acesulfame-K, gemfibrozil, and iohexol in a karst spring during a multi-event spring response. AB - The assessment of vulnerability in karst systems reveals to be extremely challenging since it varies significantly with time and highly depends on the identification of diffuse and concentrated infiltration from surface karst features. The origin, consumed loads, and transport mode of selected micropollutants (MPs) including two artificial sweeteners (ASWs) Sucralose (SUC) and Acesulfame-K (ACE-K), in addition to other less investigated pharmaceuticals such as the lipid regulator Gemfibrozil (GEM), and the contrast media Iohexol (IOX) were investigated in a karst system under dynamic conditions. A detailed analysis of selected spring responses' chemograph and hydrograph following a multi precipitation event shows that three of the tracked MPs, especially ACE-K, and to the exception of IOX, can be used as specific indicators for point source domestic wastewater in karst systems. They have revealed to be persistent, source specific, conservative, and highly correlated with in-situ parameters easily measurable at the spring (chloride and turbidity). Even if the selected MPs are found in the system during low flow periods, they are mostly transported to the spring through fast flow pathways from flushed wastewater with surface water or flood rainwater. The highest mass inflow of ACE-K, IOX and GEM originated from a sinking stream, while SUC infiltrated exclusively through fast infiltration points (dolines). Their breakthrough curves coincide with the arrival of new waters and turbidity peaks. Unlike IOX, the mass fluxes of ASWs, and GEM to a lesser extent, can be linearly correlated with chloride mass fluxes and turbidity flux. Moreover, the variance of the normalized breakthrough curves of the MPs with respect to a mean transit time, increases in that order IOX10 indicating moderate depression and 57 (88%) improved to <10 postoperatively (P = .0012). Ten patients had a PHQ-9 score >20 indicating severe depression and 9 (90%) improved to <10 postoperatively (P = .10). Of the 65 patients who had a PHQ-9 score >10 preoperatively, the median postoperative Hip Disability and Osteoarthritis Outcome Score (N = 40) was 92.3, while the median postoperative Knee Injury and Osteoarthritis Outcome Score (N = 25) was 84.6. The median postoperative Hip Disability and Osteoarthritis Outcome Score and Knee Injury and Osteoarthritis Outcome Score in nondepressed patients were 96.2 and 84.6, respectively (P = .9041). CONCLUSION: By diminishing pain and improving function through arthroplasty, depression symptoms improve significantly. Patients with depressive symptoms preoperatively had similar postoperative outcome scores compared to non-depressed patients. Patients should not be denied surgical intervention through optimization programs that include a depression scale threshold. LEVEL OF EVIDENCE: III. PMID- 29983219 TI - Prognostic factors for digital range of motion after intrasynovial flexor tendon injury and repair: Long-term follow-up on 273 patients treated with active extension-passive flexion with rubber bands. AB - STUDY DESIGN: Observational cohort study. INTRODUCTION: Investigating prognostic factors using population-based data may be used to improve functional outcome after flexor tendon injury and repair. PURPOSE OF THE STUDY: The aim of this study is to investigate the effect of concomitant nerve transection, combined flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS) tendon transection and the age of the patient, on digital range of motion (ROM) more than 1 year after FDP tendon transection and repair in zone I and II. METHODS: Two hundred seventy-three patients with a total of 311 fingers admitted for FDP injury in zone I and II were treated with active extension-passive flexion with rubber bands and followed for at least 1 year. We compared outcome by evaluating digital mobility using Strickland's evaluation system. RESULTS: At 12 months 72% of patients aged > 50 had fair or poor ROM compared to 17% of patients aged 0-25 years. At 24 months the results for patients aged > 50 had improved to 33% with fair or poor ROM, whereas no improvement had occurred for patients aged 0-25 (17% with fair or poor ROM). Concomitant nerve transection and FDS tendon transection had no negative effects on digital mobility. DISCUSSION: Age above 50 was significantly associated with impaired digital ROM during the first year after flexor tendon injury and repair but not at 2 years follow-up. Concomitant nerve transection and combined transection of FDP and FDS do not affect digital mobility. CONCLUSIONS: Older patients are likely to have a slower healing process and impaired digital ROM during the first year after surgery. PMID- 29983220 TI - IL-1beta promotes the migration of olfactory epithelium neural stem cells through activating matrix metalloproteinase expressions. AB - BACKGROUND: To investigate the effects of IL-1beta on the migration of olfactory epithelium neural stem cells (OENSCs), and to assess the mechanisms. METHODS: The effects of different concentrations of IL-1beta on cell proliferation, apoptosis and migration were evaluated by cell counting assay, flow cytometry and transwell migration assay, respectively. Matrix metalloproteinase (MMP)-2 and MMP-9 expression in both protein and mRNA levels were detected. Small interfering RNA (siRNA) technique was employed to knockdown MMP-2 and MMP-9 expression. Additionally, c-Jun N-terminal kinase (JNK) and nuclear factor-kappaB (NF-kappaB) inhibitors were applied to assess the potential signaling pathways involved in the effects of IL-1beta on cell migration. RESULTS: IL-1beta promoted cell migration of OENSCs in a concentration-dependent manner at the concentration range of 0-80 ng/ml, but did not affect cell proliferation and apoptosis. Mechanically, IL-1beta promoted MMP-2 and MMP-9 expressions. Knockdown of MMP-2 or MMP-9 could significantly reduce IL-1beta-induced cell migration. IL-1beta activated JNK, NF-kappaB, Extracellular Signal-Regulated Kinase (ERK) and p-65 phosphorylation. Finally, we evidenced that inhibition of JNK or NF-kappaB significantly inhibited cell migration. CONCLUSION: Our study demonstrated that IL-1beta promoted the migration of OENSCs through activating MMP expression. Moreover, JNK and NF-kappaB signaling pathways were involved in the regulation. This study provides important experimental evidence for the application of OENSCs in the transplantation therapy. PMID- 29983221 TI - Cigarette Smoke Exposure to Pig Larynx in an Inhalation Chamber. AB - OBJECTIVES: This study investigated the effects of cigarette smoke exposure on the pig larynx using an inhalation chamber. Specifically, we compared the effects of cigarette smoke exposure from either 3 cigarettes per day (3cd) or 15 cigarettes per day (15cd) for 20days. STUDY DESIGN: In vivo prospective design. METHODS: Female pigs were exposed via an inhalation chamber to cigarette smoke (3R4F research cigarettes) from 3cd (n = 6) or 15cd (n = 6) for 20days. Outcomes included histopathology of vocal fold and airway tissues; gene expression of interleukins, TNF-alpha, and VEGF; protein levels of TNF-alpha and IL-6; and number of coughs recorded in the chamber. RESULTS: Pigs exposed to cigarette smoke from 15cd exhibited mild vocal fold edema as compared to the 3cd group on histopathological evaluation. There was also minimal inflammation of nasal and tracheal tissue characterized by presence of more granulocytes in the 15cd group compared to the 3cd group. Cough frequency was significantly greater for the 15cd group compared to the 3cd group. CONCLUSIONS: A custom-designed large animal inhalation chamber successfully challenged pigs repeatedly, to varying levels of cigarette smoke. Future studies will combine such low levels of smoke exposure with other common challenges such as acid reflux to understand the multifactorial causation of laryngeal pathologies. PMID- 29983222 TI - Direct bilirubin is associated with low-density lipoprotein subfractions and particle size in overweight and centrally obese women. AB - BACKGROUND AND AIMS: Bilirubin has antioxidant and anti-inflammatory properties; serum bilirubin levels have been known to be inversely associated with cardiovascular disease. However, the effects of different bilirubin subtypes on cardiometabolic traits are unknown. In this study, we aimed to determine whether direct bilirubin is more strongly correlated with small, dense low-density lipoprotein (sdLDL) compared to other bilirubin subtypes. We also investigated which LDL subfractions exhibited the highest correlation with direct bilirubin. METHODS AND RESULTS: A total of 288 overweight and centrally obese women were included in this study. The Pearson correlation and Steiger's Z test were used to compare the correlation coefficients between bilirubin subtypes and lipoproteins. Multiple linear regression analyses were used to evaluate the independent association between direct bilirubin and mean LDL particle size. Only direct bilirubin levels were significantly associated with the sdLDL subfraction and mean LDL particle size. Mean LDL particle size exhibited a significantly stronger correlation with direct bilirubin than sdLDL, percent sdLDL, and the sdLDL:large LDL ratio. Regression analysis showed that direct bilirubin was significantly associated with mean LDL particle size, according to both the stepwise method (beta = 11.445, P value = 0.002) and the enter method (beta = 11.655, P value = 0.002). CONCLUSIONS: Direct bilirubin is more strongly correlated with the sdLDL subfraction compared with total and indirect bilirubin, and is independently associated with mean LDL particle size in overweight and centrally obese women. PMID- 29983223 TI - Corrigendum to "In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis" [Int. J. Pharm. 535 (2018) 113-119]. PMID- 29983224 TI - Assessing skeletal muscle dysfunction in sepsis utilizing muscle ultrasound in search for pathways to improve ICU survivor's functional outcomes. PMID- 29983225 TI - [Non-allergenic impact of indoor mold exposure]. AB - The proportion of moldy housing in France is around 20%. It is not simple to establish that a health impact of mold is not allergic, because the identification of allergy is itself difficult. Moreover, exposure to molds and their metabolites may have a protective effect. Non-allergic health impacts may occur due to the multiple aerocontaminants found in damp or mold-containing dwellings: glucans, microbial volatile organic compounds, mycotoxins, bacteria and endotoxins. The heath impacts of indoor mold have been addressed by numerous toxicologic and epidemiologic investigations, the results of which have been summarized in three notable reports. These conclude that mold exposure is linked to a risk of ENT and bronchial symptoms, both the genesis and exacerbation of asthma and, lastly, hypersensitivity pneumonitis. Finally, other studies highlight the protective role of fungal metabolites with respect to asthma and allergy. Pulmonologists should be aware of these data, which can be useful in clinical practice and also in legal work. PMID- 29983226 TI - Symptoms of alcohol abuse: The first warning sign of cancer development risk. PMID- 29983227 TI - Selective depolymerization of lignosulfonate via hydrogen transfer enhanced in an emulsion microreactor. AB - An efficient emulsion microreactor was constructed for selective conversion of lignosulfonate via hydrogen transfer reaction based on the self-surfactivity of this natural aromatic polymer. Industrial Raney Ni and isopropanol were used as catalyst and hydrogen donor, respectively. The results showed that the emulsion microreactor has a remarkable process intensification effect on the lignosulfonate depolymerization. Under mild condition of 473 K for 2.0 h, 116.1 mg g-1 of volatile phenolic monomer can be obtained, which is twice of that from other investigated processes without emulsion of this work. In particular, 39.3 mg g-1 of which is composed of 4-ethyl guaiacol, an important and versatile chemical currently from petrochemical industry. Furthermore, the solvent separates to two phases automatically after reaction due to the consumption of lignosulfonate, which makes handy products enrichment and separation. Additionally, the emulsion microreactor is significantly affected by hydrogen donor and is efficient for other lignin sources as well. PMID- 29983228 TI - A review of membrane fouling and its control in algal-related membrane processes. AB - Membrane technologies have received much attention in microalgae biorefinery for nutrients removal from wastewater, carbon dioxide abatement from the air as well as the production of value-added products and biofuel in recent years. This paper provides a state-of-the-art review on membrane fouling issues and its control in membrane photobioreactors (MPBRs) and other algal-related membrane processes (harvesting, dewatering, and biofuel production). The mechanisms of membrane fouling and factors affecting membrane fouling in algal-related membrane processes are systematically reviewed. Also, strategies to control membrane fouling in algal-related membrane processes are summarized and discussed. Finally, the gaps, challenges, and opportunities in membrane fouling control in algal-related membrane technologies are identified and discussed. PMID- 29983229 TI - The Importance of the Full Blood Count in Cerebral Ischemia: A Review of 609 Consecutive Young Patients with Stroke and Transient Ischemic Attacks. AB - BACKGROUND: Almost half of ischemic strokes in young individuals are cryptogenic. Thrombophilia testing is routinely sent despite limited evidence linking to arterial cerebrovascular events. A full blood count may identify underlying hematological disorder. METHODS: We retrospectively reviewed all patients younger than 60 years with stroke and transient ischemic attack (TIA) presenting to a regional hyperacute stroke unit and daily TIA clinic from January 2015 to August 2016. We examined hematocrit level and platelet count, and whether abnormalities were further investigated. We examined if primary hematological disorders associated with stroke were considered, specifically myeloproliferative diseases (MPDs) and thrombotic thrombocytopenic purpura (TTP). RESULTS: Of 609 patients who presented with stroke or TIA, there were 161 abnormalities in hematocrit level or platelet count in 153 patients (25.1%). One hundred sixteen patients had high hematocrit levels (19%), 19 had thrombocytosis (3.1%), 26 had thrombocytopenia (4.3%), and 8 had abnormalities in both lineages (1.3%). A total of 119 patients had repeat testing (74%). Molecular investigations for MPD were warranted in 19 patients (3.1%), performed in 3 patients (.5%) with 2 patients subsequently diagnosed. ADAMTS13 analysis was indicated in 10 patients with thrombocytopenia, performed in 2 patients with 1 diagnosed with TTP thereafter. CONCLUSIONS: One quarter of our cohort (n = 153) had abnormalities in hematocrit and/or platelets. MPD or TTP was present in 3 of the 5 patients specifically investigated. At least 22 patients (14%) merited further investigation. Although primary hematological disorders are rare in stroke aetiology, the full blood count is important to exclude known causes of arterial cerebrovascular events in young patients. PMID- 29983230 TI - Resveratrol reduces albuminuria in diabetic nephropathy: A randomized double blind placebo-controlled clinical trial. AB - AIM: Albuminuria is the most important indicator of diabetic nephropathy (DN). Resveratrol, a natural compound found in grape skins and red wine, has antioxidant effects. This study aimed to evaluate the effects of resveratrol on DN. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients with type 2 diabetes and albuminuria were randomly assigned to receive either resveratrol (500mg/day) or placebo for 90 days. Losartan (12.5mg/day) was also administered to all participants. Primary outcomes were urinary albumin/creatinine ratio, estimated glomerular filtration rate (eGFR) and serum creatinine levels. Secondary outcomes were oxidative stress markers, and anthropometric and biochemical measures. RESULTS: Mean urine albumin/creatinine ratio was significantly reduced in the resveratrol group vs placebo (-46.4mg/g, 95% CI: -64.5 to -28.3 vs 29.9mg/g, 95% CI: 4.9 to 54.9; P<0.001), whereas eGFR (1.7mL/min/1.73m2, 95% CI: -3.4 to 6.8 vs -4.0, 95% CI: -8.2 to 0.2; P=0.08) and serum creatinine (-0.3mg/dL, 95% CI: -0.1 to 0.1 vs 0.1mg/dL, 95% CI: -0.0 to 0.1; P=0.13) were unchanged. Serum antioxidant enzymes were significantly increased with resveratrol. After adjusting for confounding variables, the effect of resveratrol in reducing urinary albumin excretion was still significant (P<0.001). Regression analysis revealed that every 1-cm decrease in waist circumference and 1-MUmol/L increase in nitric oxide (NO) was associated with 9.4mg/g and 4.0mg/g reductions, respectively, of urine albumin/creatinine ratio. CONCLUSION: This clinical trial has shown that resveratrol may be an effective adjunct to angiotensin receptor blockers (ARBs) for reducing urinary albumin excretion in patients with DN (ClinicalTrials.gov: NCT02704494). PMID- 29983231 TI - Extragonadal Effects of Follicle-Stimulating Hormone on Osteoporosis and Cardiovascular Disease in Women during Menopausal Transition. AB - The risk of osteoporosis and cardiovascular disease increases significantly in postmenopausal women. Until recently, the underlying mechanisms have been primarily attributed to estrogen decline following menopause. However, follicle stimulating hormone (FSH) levels rise sharply during menopausal transition and are maintained at elevated levels for many years. FSH receptor has been detected in various extragonadal sites, including osteoclasts and endothelial cells. Recent advances suggest FSH may contribute to postmenopausal osteoporosis and cardiovascular disease. Here, we review the key actions through which FSH contributes to the risk of osteoporosis and cardiovascular disease in women as they transition through menopause. Advancing our understanding of the precise mechanisms through which FSH promotes osteoporosis and cardiovascular disease may provide new opportunities for improving health-span for postmenopausal women. PMID- 29983232 TI - Diagnostic Usefulness of the Protein Energy Wasting Score in Prevalent Hemodialysis Patients. AB - OBJECTIVE: To study whether the score proposed by the International Society of Renal Nutrition and Metabolism to define the protein energy wasting (PEW) syndrome has diagnostic validity in patients undergoing dialysis. DESIGN AND METHODS: Cross-sectional study including 468 prevalent hemodialysis patients from Canary Islands, Spain. Individual PEW syndrome criteria and the number of PEW syndrome categories were related to other objective markers of PEW using linear and logistic regression analyses: subjective global assessment, handgrip strength, bioimpedance-assessed body composition, and levels of high-sensitivity C-reactive protein. RESULTS: Study participants (34% women) had a median age of 66 years, 37 months of maintenance dialysis, and 50% were diabetics. About 23% of patients had PEW (>=3 PEW categories), and 68% were at risk of PEW (1-2 PEW categories). Low prealbumin was the most frequently found derangement (52% of cases), followed by low albumin (46%), and low protein intake (35%). Across higher number of PEW syndrome categories, patients showed a longer dialysis vintage and had lower creatinine, triglycerides, and transferrin (P for trend <.001 for all). All nutritional assessments not included in the PEW definition worsened across higher number of PEW categories. In multivariable regression analyses, there was a linear inverse relationship between muscle and fat mass as well as handgrip strength with the number of PEW syndrome categories. Likewise, the proportion of subjective global assessment-defined malnutrition and serum concentration of C-reactive protein gradually increased despite adjustment for confounders (P for trend <.05 for all). CONCLUSION: The PEW score reflects systemic inflammation, malnutrition and wasting among dialysis patients and may thus be used for diagnostic purposes. PMID- 29983233 TI - Sequence-based identification, genotyping and virulence factors of Trichosporon asahii strains isolated from urine samples of hospitalized patients (2011-2016). AB - INTRODUCTION: Trichosporon asahii is the most common species that causes trichosporonosis. MATERIALS AND METHODS: In the present study, a collection of 68T. asahii strains recovered from hospitalized patients urine samples between 2011 and 2016 was examined. T. asahii strains were identified by sequencing the intergenic spacer 1 region (IGS1) and genotyped. In addition, proteinase, phospholipase, esterase, haemolytic activity, and biofilm formation of a total of T. asahii strains were investigated. RESULTS: The predominant genotype was 1 (79.3%) and followed by 5 (8%), 3 (6.9%), 6 (3.4%), 4 (1.1%), 9 (1.1%). In none of the 68 strains, proteinase and phospholipase activities could be detected, while all were found to be esterase positive. Biofilm production and hemolytic activity were detected in 23.5 and 97% respectively. DISCUSSION: Our results indicated that six genotypes were (1, 5, 3, 6, 4, 9) present among T. asahii strains and no property was found to associate with a genotype, in terms of virulence factors. PMID- 29983234 TI - Effects of ripasudil, a ROCK inhibitor, on retinal edema and nonperfusion area in a retinal vein occlusion murine model. AB - Rho-associated coiled-coil containing protein kinase (ROCK) inhibitors are used to treat glaucoma patients and have protective effects on ischemic states. However, it is poorly understood how the ROCK pathway affects the pathological signs of retinal vein occlusion (RVO). In this study, we evaluated the effects of ripasudil, a ROCK inhibitor, on a murine RVO model. In vivo, RVO was induced by retinal vein laser irradiation in mice, and evaluated with ripasudil. In vitro, the effects of ripasudil were examined on tight junction protein integrity in human retinal microvascular endothelial cells (HRMECs). Moreover, we investigated the expression level of the phosphorylated myosin phosphatase target protein (MYPT)-1 after administration of ripasudil. Ripasudil significantly prevented deterioration, such as retinal edema, reduced the size of the nonperfusion area, and improved retinal blood flow. Ripasudil treatment inhibited disintegration of ZO-1 in HRMECs. Administration of ripasudil suppressed retinal phosphorylation of MYPT-1 in a murine RVO model. These findings indicate that ripasudil might be as a possible therapeutic agent for RVO. PMID- 29983236 TI - The prevalence of pre-exposure prophylaxis use and the pre-exposure prophylaxis to-need ratio in the fourth quarter of 2017, United States. AB - PURPOSE: The number of individuals who have started a regimen for HIV pre exposure prophylaxis (PrEP) in the United States is not well characterized but has been on the rise since 2012. This analysis assesses the distribution of PrEP use nationally and among subgroups. METHODS: A validated algorithm quantifying tenofovir disoproxil fumarate/emtricitabine for PrEP in the United States was applied to a national prescription database to determine the quarterly prevalence of PrEP use. HIV diagnoses from 2016 were used as an epidemiological proxy for PrEP need. The PrEP-to-need ratio (PnR) was defined as the number of PrEP users divided by new HIV diagnoses. RESULTS: A total of 70,395 individuals used PrEP in the fourth quarter of 2017: 67,166 males and 3229 females. Nationally, prevalence of PrEP use was 26/100,000 (range across states per 100,000 [RAS/100k]: 4-73) and the PnR was 1.8 (RAS: 0.5-6.6). Prevalence of PrEP use among males and females, respectively, was 50/100,000 and 2/100,000 (RAS/100k: 7-143 and 0.3-7) and PnR was 2.1 and 0.4 (RAS: 0.6-7.1 and 0.1-4.0). Prevalence of PrEP use was lowest among individuals aged less than or equal to 24 and more than or equal to 55 years (15/100,000 and 6/100,000, RAS/100k: 1-45 and 0.4-14), with PnR 0.9 and 1.5 (RAS: 0.2-5.6 and 0.3-7.0). The Northeast had the highest PnR (3.3); the South had the lowest (1.0). States with Medicaid expansion had more than double the PnR than states without expansion. CONCLUSIONS: Available data suggest that females, individuals aged less than or equal to 24 years and residents of the South had lower levels of PrEP use relative to epidemic need. These results are ecological, and misclassification may attenuate results. PnR is useful for future assessments of HIV prevention strategy uptake. PMID- 29983235 TI - Effect of a SGLT2 inhibitor on the systemic and intrarenal renin-angiotensin system in subtotally nephrectomized rats. AB - We aimed to examine the effects of a sodium glucose co-transporter 2 (SGLT2) inhibitor on systemic and intrarenal renin-angiotensin system (RAS) in subtotally nephrectomized non-diabetic rats, a model of chronic kidney disease (CKD). Oral administration of the selective SGLT2 inhibitor, TA-1887 (10 mg/kg/day), for 10 weeks induced glycosuria. However, plasma renin activity, plasma angiotensinogen levels, kidney angiotensin II contents and renal injury were not significantly affected by TA-1887. These data indicate that chronic treatment with an SGLT2 inhibitor does not activate the systemic and intrarenal RAS in subjects with non diabetic CKD. PMID- 29983237 TI - Anaphylaxis caused by lipid transfer proteins: an unpredictable clinical syndrome. AB - INTRODUCTION: Lipid transfer proteins (LTPs) are panallergens found in many plant foods. They are a common cause of food-induced anaphylaxis (FIA) in adults living in the Mediterranean area. LTPs have also been proposed as a main cause of food dependent exercise-induced anaphylaxis (FDEIA). OBJECTIVES: Describe clinical characteristics and allergen sensitization profiles in patients with FIA related to LTP. MATERIALS AND METHODS: Forty-three patients were included, aged 3-52 years with a clinical history of FIA and proven sensitization to LTP. Patients were tested with a multiple plant food and pollen panel and specific IgE to LTP allergens. LTP sensitization was assessed by in vivo (Pru p 3, LTP extract) and/or by in vitro tests (specific IgE, ImmunoCAP/ISAC(r)). RESULTS: Median age of first anaphylactic episode was 24 years (range 2-51), 44% had asthma, 74% were atopic and 42% had pollinosis (olive, mugwort, plane tree, wall pellitory and cypress). Co-sensitization to profilins was found in 22%. Overall in our center, LTP-induced anaphylaxis represents 17% of all causes of FIA. Foods implicated in anaphylactic reactions were: fresh fruits 51%, tree nuts 42%, vegetables (including peanut) 40% and seeds 14%. Seven patients had FDEIA. CONCLUSIONS: LTPs are important allergens of FIA in Portugal. Clinical reactivity to several taxonomically unrelated plant foods may raise suspicion toward LTP sensitization. The association of LTP-induced anaphylaxis with pollinosis is relevant in our country. The unpredictable clinical expression depends on the effect of cofactors such as exercise. The management of avoidance plans can be challenging due to LTP being a widely cross-reacting allergen in plant foods. PMID- 29983238 TI - Rosmarinic acid affects immunological and inflammatory mediator levels and restores lung pathological features in asthmatic rats. AB - BACKGROUND: The effects of rosmarinic acid (RA) on immunological and inflammatory mediator levels in bronchoalveolar lavage fluid (BALF) as well as lung pathological changes in asthmatic rats were investigated. METHODS: The levels of IFN-gamma, IL-4, IFN-gamma/IL-4 ratio, IgE, PLA2, and total protein (TP) in BALF and pathological changes in the lung were evaluated in control group (C), asthma group (sensitized to ovalbumin) (A), asthma groups treated with RA and dexamethasone. RESULTS: Compared to the control group, asthmatic rats showed increased levels of IL-4, IgE, PLA2, and TP as well as all pathological scores with decreased levels of IFN-gamma and IFN-gamma/IL-4 ratio (P<0.05 to P<0.001). The levels of IL-4, IgE, PLA2, and TP significantly reduced in groups treated with all concentrations of RA compared to asthma group (P<0.001 for all cases). IFN-gamma was significantly decreased in groups treated with two lower concentrations of RA but IFN-gamma/IL-4 ratio was increased in groups treated with two higher concentrations of RA compared to asthma group (P<0.05 to P<0.001). Treatment with all doses of RA led to significant improvement in pathological scores in asthmatic animals (P<0.05 to P<0.001). Most measured parameters were also significantly improved in dexamethasone-treated animals (P<0.01 to P<0.001) but IFN-gamma/IL-4 ratio and the scores of interstitial fibrosis, bleeding and epithelial damage did not change in this group. CONCLUSION: The results indicated a preventive effect for RA on immunological and inflammatory mediators as well as lung pathological changes in asthmatic rats which were comparable or even more potent than that of dexamethasone. PMID- 29983239 TI - Impulse oscillometry in the assessment of children's lung function. AB - PURPOSE: To review available evidence in the literature on impulse oscillometry in the assessment of lung function in children with respiratory diseases, especially asthma. DATA COLLECTION: Research in the Medline, PubMed, and Lilacs databases, with the keywords forced oscillation, impulse oscillometry, asthma and impulse oscillometry. RESULTS: The Impulse Oscillometry System (IOS) allows the measurement of resistance and reactance of airways and is used as a diagnostic resource. A significant association between the findings of the IOS and those of spirometry is observed. In asthma, the IOS has already been used to assess the bronchodilator response and the therapeutic response to different drugs and has shown to be a sensitive technique to evaluate disease control. There are limitations to this assessment, such as children with attention deficit and in some cases it is difficult to interpret the results from a clinical point of view. CONCLUSION: The IOS is a useful tool for the measurement of the lung function of children. It is an easy test, although its interpretation is not straightforward. PMID- 29983240 TI - What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events. AB - Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL 1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors. PMID- 29983242 TI - Corrigendum to "Emodin ameliorates ulcerative colitis by the flagellin-TLR5 dependent pathway in mice" [Int. Immunopharmacol. 59 (2018) 269-275]. PMID- 29983241 TI - The mysteries of sleep and waking unveiled by Michel Jouvet. AB - A great pioneer in sleep research, Michel Jouvet applied rigorous scientific methods to the study of sleep-wake states and associated changes in consciousness which, with his vivid imagination and creative mind, he unveiled as the mysteries of sleep and waking such as to inspire a generation of researchers in the field. His initial discovery of a third state distinguished from waking (W) and slow wave sleep (SWS) by the paradoxical association of W-like cortical activity with sleep-like behavior and muscle atonia that he accordingly called "paradoxical sleep" (PS) began his investigation over some 50 years of the mechanisms of these three sleep-wake states. Using primarily lesion and pharmacological manipulations, he sought the systems which are necessary and sufficient, and he thereby provided an early blueprint of how the neuromodulatory systems could determine the sleep-wake states. With the application of increasingly more selective lesion and other advanced techniques including, notably, single unit recording combined with histochemical identification of recorded units, the monoamines and acetylcholine, together with peptidergic systems have been revealed to play modulatory, yet not essential, roles acting upon other intermingled glutamatergic and GABAergic neurons that are the effector neurons of the sleep-wake states and their cortical and behavioral correlates. PMID- 29983243 TI - Narrowing Health Disparities: One Health System's Efforts Toward Equity for Underserved Populations. PMID- 29983244 TI - ACR Neck Imaging Reporting and Data Systems (NI-RADS): A White Paper of the ACR NI-RADS Committee. AB - Imaging surveillance after treatment for head and neck cancer is challenging because of complicated resection and reconstruction surgery, in addition to posttreatment changes from radiation and chemotherapy. The posttreatment neck is often a source of anxiety for diagnostic radiologists, leading to suboptimal reporting and no standardized guidance for next management steps. Nevertheless, imaging is critical for detecting submucosal recurrences in a timely manner, so that patients remain candidates for salvage surgery. In 2016, the ACR convened the Neck Imaging Reporting and Data Systems (NI-RADS) Committee with the goals to (1) provide recommendations for surveillance imaging; (2) produce a lexicon to distinguish between benign posttreatment change and residual or recurrent tumor in the posttreatment neck; and (3) propose a NI-RADS template for reporting on the basis of this lexicon with defined levels of suspicion and management recommendations. In this article, the authors present the ACR NI-RADS Committee's recommendations, which provide guidance regarding the management of patients after treatment for head and neck cancer. PMID- 29983245 TI - WocEA: The visualization of functional enrichment results in word clouds. PMID- 29983246 TI - The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress. AB - Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated. PMID- 29983247 TI - Cocaine- and amphetamine-regulated transcript (CART) peptide in the enteric nervous system of the porcine esophagus. AB - Cocaine- and amphetamine-regulated transcript peptide (CART) is widely distributed within the central and peripheral nervous system. In the brain, CART is considered as the main anorectic peptide involved in the regulation of food intake. Contrary to the central nervous system, a lot of aspects connected with the distribution and functions of CART within the enteric nervous system (ENS) still remain unknown. The aim of the present study was to investigate, for the first time, the population of CART-like immunoreactive (CART-LI) neurons within the porcine esophagus and the denotation of their neurochemical coding. During this experiment, the distribution of CART-LI neurons and the colocalization of CART with other neuronal active substances were examined using standard double- and triple-immunofluorescence techniques in enteric plexuses of cervical, thoracic, and abdominal esophagus fragments. The obtained results showed that CART is present in a relatively high percentage of esophageal neurons (values fluctuated from 45.2+/-0.9% in the submucous plexus of the thoracic esophagus to 58.1+/-5.0% in the myenteric plexus of the same fragment of the esophagus). Moreover, CART colocalized with a wide range of other active neuronal substances, mainly with the vesicular acetylcholine transporter (VAChT, a marker of cholinergic neurons), neuronal isoform of nitric oxide synthase (nNOS, a marker of nitrergic neurons), vasoactive intestinal polypeptide (VIP) and galanin (GAL). The number of CART-positive neuronal cells and their neurochemical coding clearly depended on the fragment of esophagus studied and the type of enteric plexus. The obtained results suggest that CART may play important and multidirectional roles in the neuronal regulation of esophageal functions. PMID- 29983248 TI - Safety and efficacy of the reducer: A multi-center clinical registry - REDUCE study. AB - BACKGROUND: The coronary sinus (CS) Reducer is a novel device designed to aid in the management and to improve quality of life of patients with severe angina symptoms refractory to optimal medical and interventional therapies. This study aims to assess the safety and efficacy of the Reducer in a real-world cohort of patients presenting with refractory angina. METHODS: One hundred forty-one consecutive patients were treated with CS Reducer implantation. The primary efficacy endpoint was reduction in angina symptoms from baseline as assessed by Canadian Cardiovascular Society (CCS) class status and Seattle Angina Questionnaire (SAQ) scores. The primary safety endpoint was successful Reducer device delivery and deployment in the absence of any device-related events. RESULTS: Procedural success was achieved in 139 (98.6%) patients. Reducer implantation was not obtained in 2 (1.4%) patients because of unfavorable anatomy of the CS. There were no CS perforations, cardiac tamponade, peri-procedural death or myocardial infarction during a median follow-up of 14 months (range from 6- to 70-month). In patients undergoing Reducer implantation, mean CCS class improved from 3.05 +/- 0.53 at baseline to 1.63 +/- 0.98 at follow-up (p < 0.001). Overall, 113 (81%) patients experienced at least 1 CCS improvement, and 63 (45%) patients at least 2 CCS-class improvement. All SAQ items improved significantly (p < 0.001 for all) and translated into a significant reduction in the mean number of anti-ischemic drugs prescribed (2.37 +/- 0.97 vs 2.17 +/- 0.95; p = 0.003). CONCLUSIONS: In a real-world multi-center experience, implantation of the CS Reducer appears safe, and efficacious in reducing symptoms of angina and improving quality of life. PMID- 29983249 TI - Corrigendum to "Epidemiology of lower extremity artery disease in a rural setting in Benin, West Africa: the TAHES study" [Int. J. Cardiol. 267 (2018) 198-201]. PMID- 29983250 TI - Arrhythmogenic right ventricular cardiomyopathy as a hidden cause of paediatric myocarditis presentation. PMID- 29983252 TI - Erratum to "Routine use of bilateral internal thoracic artery grafting in women does not increase in-hospital mortality and could improve long-term survival" [Int. J. Cardiol. 266 (2018) 43-49]. PMID- 29983251 TI - Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy. AB - BACKGROUND AND OBJECTIVE: We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS: For 672 enrolled patients, we collected history, LVEF, EP study and T wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS: The 635 patients included in the final analyses were 63 +/- 13 years old, 81% were male, LVEF averaged 40 +/- 14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 +/- 1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS: In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks. PMID- 29983253 TI - Long-term follow-up of BVS from a prospective multicenter registry: Impact of a dedicated implantation technique on clinical outcomes. AB - OBJECTIVES: The aim of this study was to evaluate the impact of a consistent and dedicated implantation strategy on long-term outcomes after implantation of bioresorbable vascular scaffold (BVS) in a real-world cohort of patients with a high prevalence of complex lesions. BACKGROUND: Bioresorbable vascular scaffolds may result in a reduced incidence of late and very-late scaffold thrombosis (ScT) after the complete reabsorption of the scaffold, but this hypothesis is hampered by data from RCTs that showed a higher than expected incidence of late events. However, these studies did not adopt a dedicated implantation technique, that proved to be fundamental in reducing the incidence of adverse events. METHODS: 573 consecutive patients (912 lesions) treated with bioresorbable scaffolds between May 2012 and December 2014 were enrolled in 3 high-volume centers that used a dedicated implantation strategy from the beginning. Primary endpoints were target-lesion failure (TLF) and definite and probable ScT. Secondary endpoints included myocardial infarction, target-lesion and target-vessel revascularization. RESULTS: The registry enrolled a high complexity subset of lesions (69.4% of type B2 or C lesions; 10.3% of severe calcific lesions; 26.1% of bifurcations). Predilatation was performed in almost all cases (99.2%); intracoronary imaging was liberally adopted (37.3%). Mean scaffold length was 42.9 +/- 27.4 mm per patient, and post-dilation with a 1:1 high-pressure (22 +/- 3.5 atm) balloon was performed in 99.9% of lesions. Median follow-up (available for 98.6% of patients) was 981 days (IQR 802-1133). Overall incidence of ScT was reassuringly low: three thrombotic events occurred during the first year (0.5%), while only one event ensued in the second year of follow-up, and ScT rate remained stable thereafter up to the fourth year (0.7%). Cumulative TLF rates at 1, 2, 3 and 4 years were 3.0%, 6.0%, 7.8% and 12.2%. CONCLUSIONS: These long-term results from a complex "real-world" population appear to be reassuring as regards to the incidence of ScT and TLF when BVS are implanted by experienced operators with a dedicated implantation technique. PMID- 29983255 TI - The use of eHealth with immunizations: An overview of systematic reviews. AB - BACKGROUND: eHealth interventions may help increase vaccination uptake and health literacy related to immunization and improve immunization program efficiency. OBJECTIVES: To see where and how eHealth technologies have had a positive impact on immunization practices-using eHealth strategies to increase vaccination uptake, improve immunization program efficiency and advance heath literacy related to immunizations. METHODS: An overview of systematic reviews was conducted, searching PubMed, Scopus, Embase, and Web of Science for systematic reviews published through August 2017 for eHealth and immunizations (using pre determined concepts for each). Two independent reviewers selected studies based on a priori criteria; disagreement was resolved by consensus. The quality of the included studies was evaluated using the Measurement Tool to Assess Systematic Reviews (AMSTAR). RESULTS: The primary search identified 198 results. After eliminating duplicates 158 remained. Upon applying the a priori set criteria to these, six articles were left to analyze. Four articles showed a positive relationship (a demonstrated benefit, improvement, increase in vaccination uptake, etc. when using eHealth technologies for immunization), one showed a promising relation / with potential, and one showed unknown effects as it focused on the difficulty of analyzing cost-benefits of immunization information systems (IIS). CONCLUSION: The review leads to a recommendation of using eHealth technologies to encourage immunizations and increase vaccination adherence and uptake and to continue assessing and documenting the use of eHealth for immunization. PMID- 29983254 TI - Three-dose HPV vaccine completion among sexual and gender minority young adults at a Boston community health center. AB - BACKGROUND: Disparities in human papillomavirus (HPV) vaccination completion have been noted among sexual and gender minority (SGM) people. Little is known about factors associated with HPV vaccination among SGM people. This study examines factors linked with completion of HPV vaccination among SGM patients. METHODS: We collected cross-sectional data from electronic health records (EHRs) of SGM patients receiving primary care at a Boston community health center specialized in SGM health. We employed a binomial logistic regression model to identify factors associated with 3-dose HPV vaccine completion. RESULTS: Patients were 70.3% white, with mean age of 26.3 years (SD = 2.48), 26.9% identifying as gender minorities and 79% as sexual minorities, 48.9% with 4-year college or graduate degrees, 59.4% employed, 65.9% with private insurance, 39.1% living at or below the federal poverty level, and 8.3% living with HIV. Seventy-seven percent of patients who were offered HPV vaccination had completed the series. Factors significantly associated with HPV vaccine completion included: 4-year college or graduate degree (OR: 2.87; 95% CI = 1.26-6.53), completion of primary care appointments (OR: 1.03; 95% CI: 1.01-1.05), Hepatitis A or B vaccine completion (OR: 2.59; 95% CI: 1.2-5.59), and visits for a sexually transmitted infection (STI) screen (OR: 1.22; 95% CI: 1.03-1.43). CONCLUSION: Vaccine completion was higher among SGM with higher levels of education, Hepatitis A or B vaccination, and completed health visits. These findings highlight potential ways to increase HPV vaccination, such as offering tailored HPV vaccine education, bundling with other vaccines, and incorporating HPV vaccination with STI screenings. PMID- 29983256 TI - Response to pneumococcal vaccine in interstitial lung disease patients: Influence of systemic immunosuppressive treatment. AB - BACKGROUND: Interstitial lung diseases (ILD) are severe respiratory diseases, and ILD patients are treated with corticosteroid and immunosuppressive agents. However, it is unclear whether these medications influence the response of pneumococcal vaccine. OBJECTIVES: We examined the immunogenicity of pneumococcal vaccines (PPSV23 and PCV13) in ILD patients undergoing immunosuppressive treatment. METHODS: ILD patients who were regularly followed at the outpatient clinic were enrolled. Sera were collected before and 4-8 weeks after vaccination. Serotype-specific immunoglobulin G (IgG) concentrations against pneumococcal serotype 19F were measured by ELISA. RESULTS: IgG concentrations to serotype 19F were increased in all groups in response to the vaccine. Both PCV13 and PPSV23 induced IgG concentrations in patients immunized for the first time. Response rates for the ILD group were comparable with those for the ILD group undergoing corticosteroid therapy. Only idiopathic pulmonary fibrosis patients undergoing immunosuppressive therapy had a significantly lower response. PMID- 29983257 TI - An environmental scan to examine stakeholder perspectives on human papillomavirus vaccination: A mixed methods study. AB - PURPOSE: Human papillomavirus (HPV) vaccine series completion rates among females and males remain low in Florida (46.4% and 34.5%, respectively). Multiple stakeholders influence vaccination uptake, including health care providers (HCPs), public health professionals (PHPs), and members of professional organizations. We examined stakeholder efforts related to increasing vaccine uptake and education among parents/adolescents and HCPs. METHODS: We conducted an environmental scan of stakeholder efforts and identified stakeholders using our professional networks and a snowball sampling approach. Stakeholders (n = 46) completed a survey about involvement in and barriers to vaccination promotion efforts. A subset (n = 12) of stakeholders participated in follow-up interviews further exploring vaccination efforts and barriers. Survey data were analyzed using descriptive statistics. Interview data were analyzed using deductive analysis and coded using constructs from the PRECEDE-PROCEED model. RESULTS: The majority of our survey sample was PHPs (50.0%) and HCPs (32.6%). Stakeholder efforts were focused on adolescent/parent/HCP education including providing: educational materials for HCPs (55.8%) and adolescents/parents (59.6%), one-on one consultations for adolescents/parents (55.3%), and HCP education (54.7%). Lack of knowledge/understanding and education/information were barriers reported across almost all groups/areas. Office staff/HCP education and distribution of patient education materials were efforts described as important during qualitative interviews. Stakeholders also noted HCP discomfort when recommending HPV vaccine, parental perceptions that the vaccine is unnecessary, and a lack of education/understanding among parents and HCPs. CONCLUSIONS: Results suggest the need for parent/adolescent education, specifically targeting key areas we identified: importance and benefits of HPV vaccine, and education and skill building in vaccine communication for HCPs. PMID- 29983258 TI - National cervical cancer prevention program in the Arab States: Strategies and cost-minimization study of the Tunisian case. AB - BACKGROUND: The Arab states geographic region is marked by a low to moderate cervical cancer screening coverage rates and the absence of national human papillomavirus (HPV) vaccination programs, except for the United Arab Emirates. Knowing that the HPV prevalence among Tunisian woman is estimated to 4.9/100 000 according to the "HPV Center" data, this study aims to estimate the cost of a national cervical cancer prevention program in Tunisia using either the primary prevention method (the two-dose schedule anti-HPV vaccine according to the WHO recommendation for young adolescents) or the secondary prevention method (the Pap smear test according to three time-lapse periodicity). METHODS: The mean incremental cost of one avoided cervical cancer case was calculated for each prevention scenario. RESULTS: The ascending incremental costs by avoided cervical cancer case are: 1- the national vaccination program through the GAVI support ($ 1803), 2- the cervical cancer screening according to 10-year periodicity ($ 8219), 3- the cervical cancer screening according to 5-year periodicity ($ 14,567), 4- the cervical cancer screening according to 3-year periodicity ($ 20,479), 5- and finally the national vaccination program according to the manufacturer marketed price ($ 36,854). CONCLUSION: Currently, the anti-HPV national vaccination program combined with cervical cancer screening according to 5-year periodicity present the best cost-effective strategy for cervical cancer prevention in Tunisia. This study gives Tunisian decision makers a basis for structured planning and cost apportionment to ensure effective roll-out of the cervical cancer prevention strategies. PMID- 29983259 TI - Impact of radiotherapy underutilisation measured by survival shortfall, years of potential life lost and disability-adjusted life years lost in New South Wales, Australia. AB - BACKGROUND AND PURPOSE: Despite evidence of the benefits of radiotherapy (RT) in the treatment of cancer patients, its underutilisation has been reported for various tumour sites. The aim of this study was to estimate survival shortfall, 'years of potential life lost' (YPLL) and 'disability-adjusted life years lost' (DALY) to demonstrate the impact of radiotherapy underutilisation in Australia. MATERIALS AND METHODS: Optimal and actual RT utilisation (RTU) was compared to assess RT underutilisation to estimate 5-year overall survival shortfall using 2006 data from New South Wales (NSW) for 26 common tumour sites. 5-year overall survival shortfall is defined as number of people not surviving for 5-years due to RT underutilisation [=benefit proportion * shortfall [(optimal-actual RTU)/optimal RTU] proportion * No. of new cases]. YPLL = survival shortfall * estimated years of life lost per person (overall life expectancy - median age at death for specific cancer). DALY = (Years lived with disability + Years of life lost) * survival shortfall. RESULTS: The total number of new cases with cancer in 2006 in NSW was 20,741. Optimal RTU was 48% while actual RTU was 26%, resulting in estimated of 411 deaths due to underutilisation. Each death resulted in an average of 10.4 YPLL and 17.5 DALY. It was estimated RT underutilisation resulted in a total of 4,289 YPLL and 7,192 DALY overall. CONCLUSION: This study illustrates the value of considering different mortality statistics, which include measures of the burden of cancer deaths on both the population and patients. PMID- 29983260 TI - Comparison of SUVmax and SUVpeak based segmentation to determine primary lung tumour volume on FDG PET-CT correlated with pathology data. AB - PURPOSE: The aim of the study was to compare simple SUVmax and SUVpeak based segmentation methods for calculating the lung tumour volume, compared to a pathology ground truth. METHODS: Thirty patients diagnosed with early stage Non Small Cell lung cancer (NSCLC) underwent surgical resection in the Netherlands between 2006 and 2008. FDG PET-CT scans for these patients were acquired within a median of 20 days before surgery. The tumour volume for each percentage SUVmax and SUVpeak threshold, with and without background correction, was calculated for each patient. The percentage threshold that provided the tumour volume that corresponded best with the pathology volume was considered to be the optimal threshold. The optimal thresholds were plotted as a function of tumour volume using a power law function and cross validated using the leave-one-out technique. RESULTS: The mean optimal percentage threshold was 50% +/- 10% and 62% +/- 15% for the SUVmax and SUVpeak without background correction respectively and 47% +/- 10% and 60 +/- 15% for the SUVmax and SUVpeak with background correction respectively. The optimal threshold curves could be fitted well with power law function. After cross validation the correlation between the effective tumour diameter in pathology and autosegmentation was 0.900 and 0.905 for the SUVmax and SUVpeak without background correction respectively and 0.913 and 0.908 for the SUVmax and SUVpeak with background correction respectively. CONCLUSION: No benefit was shown on clinical data for the SUVpeak based segmentation method over a SUVmax based one. Both methods can be used to determine the tumour volumes in resected NSCLC tumours. PMID- 29983261 TI - Bilirubin, a new therapeutic for kidney transplant? AB - In patients with end-stage renal disease, kidney transplantation has been associated with numerous benefits, including increased daily activity, and better survival rates. However, over 20% of kidney transplants result in rejection within five years. Rejection is primarily due to a hypersensitive immune system and ischemia/reperfusion injury. Bilirubin has been shown to be a potent antioxidant that is capable of potentially reversing or preventing damage from reactive oxygen species generated from ischemia and reperfusion. Additionally, bilirubin has several immunomodulatory effects that can dampen the immune system to promote organ acceptance. Increased bilirubin has also been shown to have a positive impact on renal hemodynamics, which is critical post-transplantation. Lastly, bilirubin levels have been correlated with biomarkers of successful transplantation. In this review, we discuss a multitude of potentially beneficial effects that bilirubin has on kidney acceptance of transplantation based on numerous clinical trials and animal models. Exogenous bilirubin delivery or increasing endogenous levels pre- or post-transplantation may have therapeutic benefits. PMID- 29983262 TI - Developing a competency framework for pharmacy technicians: Perspectives from the field. AB - BACKGROUND: Within the last decade and given the context of ever-growing complexity in pharmaceutical care the new profession of Pharmacy Technicians (PT) was added to the pharmacy team. Until now, pharmaceutical organizations worldwide are searching for the best way to educate and employ future PTs. OBJECTIVE: This empirical study set out to gain insight into the knowledge, skills and attitudes required to perform as a PTs. A further aim was to develop a PT competency framework on the basis of experiences and opinions of stakeholders from the Dutch pharmaceutical field. METHODS: A multi-method qualitative research design was used to develop a competency framework between 2015 and 2017. Data were collected using focus group interviews. Iterative thematic analysis led to an initial framework, which was refined using a modified Delphi-method. A competency domain was considered relevant if a minimum of 70% consensus was reached. RESULTS: Both PTs (n = 27) and pharmacists (n = 12) participated in the focus groups. The Delphi-panel consisted of PTs (n = 8), pharmacists (n = 12) and representatives of other stakeholders like patient organizations, health policy makers and all levels of pharmacy education (n = 14). The developed competency framework comprises 6 domains: Communication in patient care, Interdisciplinary collaboration, Pharmaceutical expertise, Organization of care practice, Collaborative leadership and Personal development. A detailed description about the practical implications of each domain was added to the framework. CONCLUSION: The PT competency framework provides a solid foundation for both PT training and curriculum development and is based on several rounds of scientific research. The proposed competency framework may help understand the PT role and how to best prepare for practice within pharmaceutical care. PMID- 29983263 TI - Detection of tick-borne pathogens in ticks from dogs and cats in different European countries. AB - Ticks are known to transmit pathogens which threaten the health and welfare of companion animals and man globally. In the present study, mainly adult ticks were collected from dogs and cats presented at their local veterinary practice in Hungary, France, Italy, Belgium (dogs only) and Germany (cats only), and identified based on tick morphology. If more than one tick was collected from a host animal, ticks were pooled by tick species for DNA extraction and subsequent PCR examination for the presence of tick-borne pathogens. Out of 448 tick samples, 247 (95 from dogs and 152 from cats) were Ixodes ricinus, 26 (12 from dogs and 14 from cats) were I. hexagonus, 59 (43 from dogs and 16 from cats) were Dermacentor reticulatus and 116 (74 from dogs and 42 from cats) were Rhipicephalus sanguineus sensu lato (s.l.). In 17% of the I. ricinus samples Anaplasma phagocytophilum was found. Borrelia spp. were mainly identified in I. ricinus collected from cats (18%) and to a lesser extent in dog-sourced ticks (1%), with Borrelia afzelii (n = 11), B. garinii (n = 7), B. valaisiana (n = 5), B. lusitaniae (n = 3) and B. burgdorferi sensu stricto (n = 3) being identified. One I. hexagonus sample collected from a cat in France tested positive for B. afzelii. Babesia canis was detected in 20% of the D. reticulatus samples, mainly from Hungary. Rhipicephalus sanguineus s.l. was found positive for Hepatozoon canis (3%), A. platys (5%) and three Rickettsia species (7%; R. massiliae; R. raoultii and R. rhipicephali). Furthermore, a total of 66 R. sanguineus s.l. ticks were subjected to molecular analysis and were identified as R. sanguineus sp. II-temperate lineage, with seven haplotypes recorded. Amongst them, the most prevalent sequence types were haplotype XIII (n = 24; 69%) and haplotype XIV (n = 16; 52%) in France and in Italy, respectively, found both in cats and dogs. Although differences related to both country and host, were observed, the results of this study indicate that cats and dogs are exposed to tick-borne pathogen infected ticks, which may represent a medical risk to these host animals. PMID- 29983264 TI - Preventive Effects of Renin-angiotensin System Inhibitors on Oxaliplatin-induced Peripheral Neuropathy: A Retrospective Observational Study. AB - PURPOSE: Oxaliplatin-induced peripheral neuropathy has remained an unresolved issue in clinical practice. Our previous study hypothesized that inhibition of the renin-angiotensin system (RAS) may produce a preventive effect on oxaliplatin induced neuropathy. The aim of this study was to clarify whether RAS inhibitors prevent oxaliplatin-induced peripheral neuropathy. METHODS: This study retrospectively analyzed data from cancer patients who had received chemotherapy including oxaliplatin and were treated with or without RAS inhibitors. This retrospective observational study was conducted at Ehime University Hospital using electronic medical records from May 2009 to December 2016. The primary end point was the incidence of severe peripheral neuropathy during or after oxaliplatin treatment, according to the Common Terminology Criteria for Adverse Events, version 4.0. A multivariate Cox proportional hazards model analysis was used to identify risk factors. FINDINGS: A total of 150 patients were included in the study. The estimated incidence of peripheral neuropathy was 36.9% and 91.7% in the RAS inhibitor group and the non-RAS inhibitor group, respectively. The multivariate analysis using a Cox proportional hazards model showed that the RAS inhibitor group was slightly associated with a decreased risk of neurotoxicity (adjusted hazard ratio, 0.42 [95% CI, 0.18-0.99]; P = 0.048). IMPLICATIONS: The present findings suggest that RAS inhibitors have the ability to prevent oxaliplatin-induced peripheral neuropathy. PMID- 29983266 TI - Hepatitis C Management Simplification From Test to Cure: A Framework for Primary Care Providers. AB - This article proposes a strategy for primary care providers to begin treating patients with hepatitis C virus (HCV). We are motivated by the need to expand HCV treatment and by developments that have simplified treatment for most patients. This article presents 5 steps to achieving quality HCV treatment in the primary care setting: (1) accurate diagnosis via reflex testing; (2) risk stratification and identifying comorbidities via pretreatment evaluation; (3) simple, once daily, pan-genotypic HCV treatment regimens; (4) minimized on-treatment monitoring: and (5) posttreatment monitoring and high-quality care for comorbidities such as cirrhosis and injection drug use. We provide indications for referral to specialists: notably children, patients with genotype 3 and cirrhosis, advanced liver or kidney disease, previous treatment failures, drug interactions with recommended regimens, and hepatitis B co-infection. Finally, potential barriers for providers are discussed, as well as further research findings and policy interventions that can promote HCV treatment in the primary care setting. We believe that a substantial portion of patients with HCV can be treated safely and effectively by nonspecialists and that the engagement of primary care providers is critical to efforts to end the HCV epidemic. PMID- 29983267 TI - Maternal and paternal cannabis use during pregnancy and the risk of psychotic like experiences in the offspring. AB - Cannabis use continues to increase among pregnant women. Gestational cannabis exposure has been associated with various adverse outcomes. However, it remains unclear whether cannabis use during pregnancy increases the risk for offspring psychotic-like experiences. In this prospective cohort, we examined the relationship between parental cannabis use during pregnancy and offspring psychotic-like experiences. Comparisons were made between maternal and paternal cannabis use during pregnancy to investigate causal influences of intra-uterine cannabis exposure during foetal neurodevelopmental. This study was embedded in the Generation R birth cohort and included N = 3692 participants. Maternal cannabis exposure was determined using self-reports and cannabis metabolite levels from urine. Paternal cannabis use during pregnancy was obtained by maternal report. Maternal cannabis use increased the risk of psychotic-like experiences in the offspring (ORadjusted = 1.38, 95% CI 1.03-1.85). Estimates were comparable for maternal cannabis use exclusively before pregnancy versus continued cannabis use during pregnancy. Paternal cannabis use was similarly associated with offspring psychotic-like experiences (ORadjusted = 1.44, 95% CI 1.14-1.82). We demonstrated that both maternal and paternal cannabis use were associated with more offspring psychotic-like experiences at age ten years. This may suggest that common aetiologies, rather than solely causal intra-uterine mechanisms, underlie the association between parental cannabis use and offspring psychotic-like experiences. These common backgrounds most likely reflect genetic vulnerabilities and shared familial mechanisms, shedding a potential new light on the debated causal path from cannabis use to psychotic-like phenomena. Our findings indicate that diagnostic screening and preventative measures need to be adapted for young people at risk for severe mental illness. PMID- 29983268 TI - Striatal cerebral blood flow, executive functioning, and fronto-striatal functional connectivity in clinical high risk for psychosis. AB - BACKGROUND: Patients at clinical high risk (CHR) for psychosis exhibit increased striatal cerebral blood flow (CBF) during the resting state and impaired cognitive function. However, the relation between CBF and cognitive impairment is unknown. We therefore studied the association between striatal CBF and executive functioning and evaluated the functional connectivity (FC) between dorsal striatum and the frontal cortex in CHR. METHODS: In total, 47 participants [29 with CHR, 18 matched clinical controls (CC)] were assessed for ultra-high-risk criteria and basic symptoms and were tested for executive functioning using the trail making test-B (TMT-B). Resting state mean CBF and FC were calculated from arterial spin labeling 3T MRI data. RESULTS: Striatal CBF was highest in CHR patients with TMT-B deficits and was significantly higher than that in CC with and without TMT-B impairment. Further, a significantly lower CBF FC between the dorsal striatum and the anterior cingulate cortex was revealed in CHR. CONCLUSIONS: Our study suggests that higher striatal CBF might represent focal pathology in CHR and is associated with disrupted cingulo-striatal FC and executive dysfunctions. PMID- 29983265 TI - Elimination of Vertical Transmission of Hepatitis B in Africa: A Review of Available Tools and New Opportunities. AB - PURPOSE: This review article focuses on preventing vertical transmission of hepatitis B virus (HBV) among pregnant women living in sub-Saharan Africa (SSA), where disease is endemic and the estimated maternal HBV seroprevalence is >8%. Available interventions that have been studied in low- and middle-income countries are compared in terms of efficacy and effectiveness in clinical practice. Global disease-elimination targets, barriers to HBV-prevention efforts, and critical research gaps are discussed. METHODS: A PubMed literature search in February 2018 identified relevant studies of interventions to reduce or prevent the transmission of HBV during pregnancy or in the peripartum period. Studies that focused on interventions that are currently available or could be made available in SSA were included. Trials conducted in SSA and other low-income countries were prioritized, although studies of interventions in middle- and high income countries were included. FINDINGS: Among 127 studies and reports included in the review, 60 included data from SSA. The most cost-effective intervention to reduce HBV infection rates in SSA is timely birth-dose vaccination followed by completion of the 3-dose infant-vaccination series. The identification and treatment of pregnant women with elevated HBV viral load to further reduce the risk for vertical transmission in SSA show promise, but efficacy and tolerability trials in Africa are lacking. IMPLICATIONS: Scale-up of currently available tools is required to reach HBV disease-elimination goals in SSA. Many countries in SSA are in the process of rolling out national birth-dose vaccination campaigns; this roll out provides an opportunity to evaluate and improve processes in order to expand coverage. Early antenatal care, promotion of facility deliveries, and increased awareness of HBV prevention are also key components of prevention success. Future studies in SSA should identity an HBV-prevention package that is effective, well tolerated, and feasible and can be administered in the antenatal clinic and tailored to vertical-transmission risk. PMID- 29983269 TI - Schizophrenia and epilepsy as a result of maternally inherited CNTN6 copy number variant. AB - BACKGROUND: Copy number variants have made important contributions to understanding neuropsychiatric disorders, including schizophrenia. Deletions in genes encoding neuronal cell adhesion molecules have identified widely varied neurodevelopmental phenotypes. CASE SUMMARY: A 27-year old woman presented with schizophrenia, borderline intellectual functioning and shortened metacarpal bones. Subsequent electroencephalogram confirmed genetic generalised epilepsy and microarray analysis found a 0.2 megabase deletion of chromosome 3p26.3. CONCLUSIONS: We report the first case of schizophrenia in a proband with a CNTN6 deletion. Schizophrenia has been reported in relatives of probands with this deletion but not in probands themselves. This finding further contributes to the evolving literature regarding schizophrenia pathogenesis. PMID- 29983270 TI - Quality of life among older adults in China and India: Does productive engagement help? AB - Individuals in developing countries often engage in paid and unpaid work till late in life due to low household savings and limited welfare provisions. Yet, physical disabilities associated with aging can limit their ability to work. While work can be beneficial for economic and psychological well-being, this paper investigates whether engagement in paid and unpaid work mediates the impact of physical disabilities on quality of life for older adults. We exploit the different levels of health services and social security in rural and urban China and India to examine the effect of public provisions in the process. We use nationally representative data of individuals aged 50 and above from the World Health Organization Study on Global Ageing and Adult Health Wave 1, conducted in 2008-10 in China and in 2007-08 in India. Using a causal mediation analysis framework, we find that paid work plays a minor role in mediating the effect of physical disabilities on quality of life in all societies, and the mediated effect is smaller in urban China than in other societies. Unpaid work is beneficial only in urban China, and it does not mediate the impact of physical disabilities on quality of life elsewhere. The findings indicate that promoting productive engagement alone, without improving basic public provisions, will have limited impact on improving quality of life of the aging population in developing countries. PMID- 29983271 TI - Examining longitudinal associations between the recreational physical activity environment, change in body mass index, and obesity by age in 8864 Yorkshire Health Study participants. AB - The environment may lead to lower body mass index (BMI) and obesity risk by providing opportunities to be physically active. However, while intuitively appealing, associations are often inconsistent in direction and small scale. This longitudinal study examined if change in BMI and obesity was associated with the availability of physical activity (PA) facilities and parks and explored if these associations differed by age. Longitudinal data (n = 8,864, aged 18-86 years) were provided at baseline (wave I: 2010-2012) and follow up (wave II: 2013-2015) of the Yorkshire Health Study. BMI was calculated using self-reported height (cm) and weight (kg) (obesity = BMI>=30.00). To define availability, home addresses were geocoded based on postcode zone centroids and neighbourhood was defined as a 2 km radial buffer. PA facilities were sourced from Ordnance Survey Points of Interest (PoI) and parks were sourced from OpenStreetMap. Environmental data temporally matched individual-level baseline data collection. PA facilities (b = 0.006 [-0.015, 0.003]) and parks (b = -0.001 [-0.015, 0.013]) at baseline were not associated with change in BMI. Change in obesity was unrelated to parks (OR = 0.994 [0.975, 1.015]) and while PA facilities were related (OR = 0.979 [0.965, 0.993]), effects were small. A combined measure of the recreational PA environment including parks and PA facilities was unrelated to change in BMI and obesity. Despite this, statistically significant interactions were found for both PA facilities, parks, and change in obesity by age. Based on the premise that an individual's mobility varies with age, and although effects were small, this offers tentative evidence which suggests it may be useful for policymakers in Public Health and Planning to consider the impact of environmental interventions across the life course. PMID- 29983272 TI - Selective Inhibition of Sialic Acid-Based Molecular Mimicry in Haemophilus influenzae Abrogates Serum Resistance. AB - Pathogens such as non-typeable Haemophilus influenzae (NTHi) evade the immune system by presenting host-derived sialic acids. NTHi cannot synthesize sialic acids and therefore needs to utilize sialic acids originating from host tissue. Here we report sialic acid-based probes to visualize and inhibit the transfer of host sialic acids to NTHi. Inhibition of sialic acid utilization by NTHi enhanced serum-mediated killing. Furthermore, in an in vitro model of the human respiratory tract, we demonstrate efficient inhibition of sialic acid transfer from primary human bronchial epithelial cells to NTHi using bioorthogonal chemistry. PMID- 29983274 TI - A Quantitative Chemoproteomic Platform to Monitor Selenocysteine Reactivity within a Complex Proteome. AB - Mammalian selenocysteine (Sec)-containing proteins, selenoproteins, are important to (patho)physiological processes, including redox homeostasis. Sec residues have been recalcitrant to mass spectrometry-based chemoproteomic methods that enrich for reactive cysteine (Cys) residues with electrophilic chemical probes, despite confirmed reactivity of Sec with these electrophiles. Highly abundant Cys peptides likely suppress low-abundant Sec peptides. By exploiting the decreased pKa of Sec relative to Cys, we have developed a chemoproteomic platform that relies on low pH (pH 5.75) electrophile labeling, reducing Cys reactivity and enhancing identification of Sec-containing peptides across mouse tissues and cell lines. The utility of this Sec-profiling platform is underscored by evaluation of the selectivity of auranofin, an inhibitor of the selenoprotein, thioredoxin reductase, against both reactive Cys- and Sec-containing proteins. Platform limitations pertain to the non-physiological low-pH conditions that could perturb protein structure and function. Future work necessitates the discovery of Sec selective electrophiles that function at physiological pH. PMID- 29983273 TI - Synthetic Immunotherapeutics against Gram-negative Pathogens. AB - While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system toward Escherichia coli and Pseudomonas aeruginosa. More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum. We established that the spacer length played a significant role in hapten display within the bacterial cell surface, a result that was confirmed both experimentally and via molecular dynamics simulations. Most importantly, we demonstrated the specific killing of bacteria by our agent in the presence of human serum. By enlisting the immune system, these agents have the potential to pave the way for a potent antimicrobial modality. PMID- 29983275 TI - Incidence and survival trends for gastric neuroendocrine neoplasms: An analysis of 3523 patients in the SEER database. AB - BACKGROUND: The aim of this study is to investigate trends in the incidence and survival of patients with gastric neuroendocrine neoplasms (g-NENs). METHODS: and methods: Patients diagnosed with g-NENs (n = 3523) were identified from the Surveillance, Epidemiology and End Results (SEER) database. Patients diagnosed with g-NENs (n = 199) in our department were designated as a validation dataset. Nomograms were adopted to predict disease-specific survival (DSS) and overall survival (OS). RESULTS: The incidence of g-NENs is steadily increasing over time at a rate higher than any other cancer [annual percentage change (APC) = 6.3%, 95% confidence interval (CI) 5.6-7.0]. The 1-, 3-, and 5-year DSS rates were 87%, 78.6% and 70.6%, respectively, and the corresponding OS rates were 84.3%, 71.9%, and 53.7%, respectively. The multivariate analysis identified age, sex, T stage, M stage, and histological type as independent prognostic factors for both DSS and OS (all P < .05). The concordance indexes of the nomograms for DSS and OS in the training dataset were superior to those of the traditional tumor-node-metastasis (TNM) staging system [0.899 and 0.849 versus 0.864 and 0.783]. Calibration plots of the nomograms showed that the probability of DSS and OS closely corresponded to the actual observations in both the SEER-based training dataset and our inpatient validation dataset. CONCLUSION: The incidence of g-NENs has been steadily increasing at a rapid rate over the past four decades. The nomograms based on the analysis of the SEER database were superior to the TNM staging system in predicting the clinical outcomes for g-NEN patients. PMID- 29983276 TI - [Compliance to the color codes protocol according to the indication of cesarean and to the decision-to-delivery interval]. AB - OBJECTIVE: Evaluation of the compliance of the color codes protocol according to the indication of ceasarean section and on the decision-to-delivery interval according to the color code, the operator and the period. METHODS: This is a retrospective monocentric study including women who had to undergo an emergency cesarean section after 37 weeks of amenorrhea in the Jeanne-de-Flandre hospital between 2015 and 2017. Three groups were created: cesarean section with green code, orange code and red code. We compared population characteristics and obstetrical data, then drew up a reassessed color code and analyzed the correspondence between the initial color code and the reassessed one. Finally, we considered the respect of decision-to-delivery interval according to color code, operator level and period. RESULTS: Eight hundred and eighty-one patients were included, amongst which 303 (34%) fell into the green c-section, 353 (40%) into the orange c-section and 225 (26%) into the red c-section. In the three groups, there was a significant consistency between the initial color code and the reassessed one, with a kappa agreement test of 95% 0.95 (0.93-0.97). The average decision-to-delivery interval was 37+/-20min for the green c-section, 20+/-6min for the orange c-section and 12+/-3min for the red c-section with a significant respect of the decision-to-delivery interval according to color code P<0.001. The decision-to-delivery interval was similar considering the operator level and the period. CONCLUSION: In our study, we observed the compliance with color code regarding the indication of ceasarean section and the respect of the decision-to delivery interval whatever the time of occurrence and the operator. PMID- 29983277 TI - Accuracy of a novel marker tracking approach based on the low-cost Microsoft Kinect v2 sensor. AB - Microsoft Kinect for Windows v2 is a motion analysis system that features a markerless human pose estimation algorithm. Given its affordability and portability, Kinect v2 has potential for use in biomechanical research and within clinical settings; however, recent studies suggest high inaccuracy of the markerless algorithm compared to marker-based motion capture systems. A novel tracking method was developed using Kinect v2, employing custom-made colored markers and computer vision techniques. The aim of this study was to test the accuracy of this approach relative to a conventional Vicon motion analysis system, performing a Bland-Altman analysis of agreement. Twenty participants were recruited, and markers placed on bony prominences near hip, knee and ankle. Three dimensional coordinates of the markers were recorded during treadmill walking and running. The limits of agreement (LOA) of marker coordinates were narrower than - 10 and 10 mm in most conditions, however a negative relationship between accuracy and treadmill speed was observed along Kinect depth direction. LOA of the surrogate knee angles were within - 1.8 degrees , 1.7 degrees for flexion in all conditions and - 2.9 degrees , 1.7 degrees for adduction during fast walking. The proposed methodology exhibited good agreement with a marker-based system over a range of gait speeds and, for this reason, may be useful as low-cost motion analysis tool for selected biomechanical applications. PMID- 29983278 TI - Concentrations of non-permeable cryoprotectants and equilibration temperatures are key factors for stallion sperm vitrification success. AB - Vitrification is based on rapid freezing by direct exposure of sperm to liquid nitrogen (LN2). This study evaluated the effect of non-permeable CPAs and equilibration temperature on stallion sperm quality after vitrification. In Experiment 1, different concentrations of sucrose (20, 50, 100 mM; mmol/L) and bovine serum albumin (BSA 1%, 5%, 10%) were compared including different temperatures for the equilibration (~22 degrees C or 5 degrees C). Vitrification was performed dropping 30 MUl sperm suspension directly into LN2. In Experiment 2, conventional sperm freezing using 2.2% of glycerol in 0.5 ml straws, frozen in LN2 vapours, was compared to the sucrose and BSA extenders (and its combination) producing the most desirable results. Sperm motility, plasma membrane and acrosome integrity were statistically compared between treatments. Vitrification after sperm cooling at 5 degrees C with sucrose 20 mM (S20) or BSA 1% (BSA1) resulted in the greatest values (mean +/- SEM) for most of the sperm variables assessed. With use of the combination (S20 + BSA1/5 degrees C), there were greater values (P<0.001) than freezing with glycerol for total (55.67 +/- 2.99 vs 35.41 +/- 2.96) and progressive sperm motility (38.32 +/- 3.05 vs 14.42 +/- 1.80), plasma membrane integrity (66.61 +/- 2.69 vs 49.16 +/- 2.60), intact acrosomes (49.19 +/- 2.60 vs 14.91 +/- 1.57) and most of the kinetics assessed, respectively. In conclusion, stallion sperm can be vitrified after cooling at 5 degrees C using a combination of 20 mM sucrose and 1% BSA based extender and this is a promising alternative compared with conventional sperm freezing using glycerol. PMID- 29983279 TI - Glossopharyngeal (IXth) cranial nerve palsy associated with postural change after accidental dural puncture. PMID- 29983280 TI - The synthesis and evaluation of phenoxyacylhydroxamic acids as potential agents for Helicobacter pylori infections. AB - Two series of omega-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that omega-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4 dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50 = 0.061 +/- 0.003 MUM) and intact cell (IC50 = 0.89 +/- 0.05 MUM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively. Non-linear fitting of experimental data (V-[S]) suggested a mixed-type inhibition mechanism and a dual site binding mode of these compounds. PMID- 29983281 TI - Polysaccharide deacetylases serve as new targets for the design of inhibitors against Bacillus anthracis and Bacillus cereus. AB - Peptidoglycan N-acetylglucosamine (GlcNAc) deacetylases (PGNGdacs) from bacterial pathogens are validated targets for the development of novel antimicrobial agents. In this study we examined the in vitro inhibition of hydroxamate ligand N hydroxy-4-(naphthalene-1-yl)benzamide (NHNB), a selective inhibitor of histone deacetylases-8 (HDAC8), against two PGNGdacs namely BC1974 and BC1960 from B. cereus, highly homologous to BA1977 and BA1961 of B. anthracis, respectively. Kinetic analysis showed that this compound functions as a competitive inhibitor of both enzymes with apparent Ki's of 8.7 MUM (for BC1974) and 66 MUM (for BC1960), providing thus the most potent CE4 inhibitor reported to date. NHNB was tested in antibacterial assays and showed bactericidal activity against both examined pathogens acting as a multi-target drug. This compound can serve as lead for the development of inhibitors targeting the conserved active sites of the multiple polysaccharide deacetylases (PDAs) of both pathogens. PMID- 29983282 TI - Forewords BMC. PMID- 29983283 TI - Corrigendum to "Synthesis, structure-activity relationship and molecular docking studies of 3-O-flavonol glycosides as cholinesterase inhibitors" [Bioorg. Med. Chem. 26 (12) (2018) 3696-3706]. PMID- 29983284 TI - Sameuramide A, a new cyclic depsipeptide isolated from an ascidian of the family Didemnidae. AB - Sameuramide A (1), a new cyclic depsipeptide encompassing one each of alanine, N methyl alanine, N-methyl dehydroalanine, N,O-dimethyl threonine, phenyllactic acid, three beta-hydroxy leucines, and two propionates, was isolated from a didemnid ascidian collected at the northern part of Japan. The planar structure was established based on the interpretation of MS and NMR data. The absolute configuration of the subunits was determined by the advanced Marfey's method and the chiral LC-MS analysis. Compound 1 exhibited the activity of maintaining colony formation of murine embryonic stem (mES) cells without leukemia inhibitory factor (LIF). Down regulation of the gene expression of Kruppel-like transcription factor 4 (Klf4) indicated that 1 itself was not able to maintain the undifferentiated state of the mES cells. However, the expression levels of the marker genes (Nestin, T, Sox17) for three germ layers were upregulated in embryoid bodies (EBs) after treatment of 1 together with LIF, suggesting that 1 plays a supportive role for LIF in maintaining the multipotency of mES cells. PMID- 29983285 TI - Antiplasmodial activity of hydroxyethylamine analogs: Synthesis, biological activity and structure activity relationship of plasmepsin inhibitors. AB - Malaria, particularly in endemic countries remains a threat to the human health and is the leading the cause of mortality in the tropical and sub-tropical areas. Herein, we explored new C2 symmetric hydroxyethylamine analogs as the potential inhibitors of Plasmodium falciparum (P. falciparum; 3D7) in in-vitro cultures. All the listed compounds were also evaluated against crucial drug targets, plasmepsin II (Plm II) and IV (Plm IV), enzymes found in the digestive vacuole of the P. falciparum. Analog 10f showed inhibitory activities against both the enzymes Plm II and Plm IV (Ki, 1.93 +/- 0.29 uM for Plm II; Ki, 1.99 +/- 0.05 uM for Plm IV). Among all these analogs, compounds 10g selectively inhibited the activity of Plm IV (Ki, 0.84 +/- 0.08 uM). In the in vitro screening assay, the growth inhibition of P. falciparum by both the analogs (IC50, 2.27 +/- 0.95 uM for 10f; IC50, 3.11 +/- 0.65 uM for 10g) displayed marked killing effect. A significant growth inhibition of the P. falciparum was displayed by analog 12c with IC50 value of 1.35 +/- 0.85 uM, however, it did not show inhibitory activity against either Plms. The hemolytic assay suggested that the active compounds selectively inhibit the growth of the parasite. Further, potent analogs (10f and 12c) were evaluated for their cytotoxicity towards mammalian HepG2 and vero cells. The selectivity index (SI) values were noticed greater than 10 for both the analogs that suggested their poor toxicity. The present study indicates these analogs as putative lead structures and could serve as crucial for the development of new drug molecules. PMID- 29983286 TI - Evaluation of the CRE and ESBL ELITe MGB(r) kits for the accurate detection of carbapenemase- or CTX-M-producing bacteria. AB - As carbapenemase-producing Enterobacteriaceae (CPE) and extended-spectrum beta lactamase-producing Enterobacteriaceae (ESBL-E) are becoming a major public health issue, there is an urgent need for accurate and fast diagnostic tests. The ELITe InGenius is a fully automated sample-to-result system designed for the extraction and detection by multiplex real-time polymerase chain reaction of carbapenemases KPC, NDM, VIM, IMP, and OXA-48-like variants and CTX-M group 1 and 9-producers from diverse sample matrices such as colonies, positive blood cultures, and rectal swabs. CRE and ESBL ELITe MGB(r) kits were evaluated on 153 cultured colonies of enterobacterial isolates with characterized beta-lactamase content, on 30 spiked blood cultures, and the CRE kit was also evaluated on 53 clinical rectal swabs collected prospectively during a 3-month period and 10 spiked rectal swabs. CRE ELITe MGB(r) kit's performances reached 100% sensitivity and 100% specificity, while for the ESBL ELITe kit, 100% sensitivity and 96.6% specificity were observed, with a sample to result of less than 3 h and a total percentage of agreement with expected results of 99.6% (255/256). PMID- 29983287 TI - Sequence heterogeneity of the PenA carbapenemase in clinical isolates of Burkholderia multivorans. AB - Multidrug-resistant gram-negative pathogens are a significant health threat. Burkholderia spp. encompass a complex subset of gram-negative bacteria with a wide range of biological functions that include human, animal, and plant pathogens. The treatment of infections caused by Burkholderia spp. is problematic due to their inherent resistance to multiple antibiotics. The major beta-lactam resistance determinant expressed in Burkholderia spp. is a class A beta-lactamase of the PenA family. In this study, significant amino acid sequence heterogeneity was discovered in PenA (37 novel variants) within a panel of 48 different strains of Burkholderia multivorans isolated from individuals with cystic fibrosis. Phylogenetic analysis distributed the 37 variants into 5 groups based on their primary amino acid sequences. Amino acid substitutions were present throughout the entire beta-lactamase and did not congregate to specific regions of the protein. The PenA variants possessed 5 to 17 single amino acid changes. The N189S and S286I substitutions were most prevalent and found in all variants. Due to the sequence heterogeneity in PenA, a highly conserved peptide (18 amino acids) within PenA was chosen as the antigen for polyclonal antibody production in order to measure expression of PenA within the 48 clinical isolates of B. multivorans. Characterization of the anti-PenA peptide antibody, using immunoblotting approaches, exposed several unique features of this antibody (i.e., detected <500 pg of purified PenA, all 37 PenA variants in B. multivorans, and Pen-like beta lactamases from other species within the Burkholderia cepacia complex). The significant sequence heterogeneity found in PenA may have occurred due to selective pressure (e.g., exposure to antimicrobial therapy) within the host. The contribution of these changes warrants further investigation. PMID- 29983288 TI - Collaboration between an antimicrobial stewardship team and the microbiology laboratory can shorten time to directed antibiotic therapy for methicillin susceptible staphylococcal bacteremia and to discontinuation of antibiotics for coagulase-negative staphylococcal contaminants. AB - BACKGROUND: Rapid identification of Gram-positive cocci in clusters (GPCC) in positive blood cultures (pBC) may limit exposure to unnecessary or inappropriate antibiotics. METHODS: Inpatients with pBC showing GPCC between October 2013 and December 2017 were included. In the baseline period (BL), final ID and susceptibility results were reported in the electronic medical record (EMR) within 48 h of telephoned Gram stain report. The laboratory introduced rapid phenotypic identification and direct susceptibility testing (INT1), later replaced by PCR (INT2). In the last Intervention (INT3), Antimicrobial Stewardship Response Team (ASRT) contacted providers with PCR results and recommendations. RESULTS: Time to directed therapy (TDT) for MSSA and coagulase negative Staphylococci (CoNS) decreased from BL to INT3 (48.5-17.9 h, 50.3-16.4 h, respectively). Time to ID from BL to INT3 for MSSA and CoNS also decreased (23.2-1.9 h, 44.7-2.8, respectively). CONCLUSIONS: TDT can be improved by modification of reporting methods with utilization of an ASRT. PMID- 29983290 TI - UK Training in Clinical Oncology: The Trainees' Viewpoint. PMID- 29983289 TI - Familiarity with social sounds alters c-Fos expression in auditory cortex and interacts with estradiol in locus coeruleus. AB - When a social sound category initially gains behavioral significance to an animal, plasticity events presumably enhance the ability to recognize that sound category in the future. In the context of learning natural social stimuli, neuromodulators such as norepinephrine and estrogen have been associated with experience-dependent plasticity and processing of newly salient social cues, yet continued plasticity once stimuli are familiar could disrupt the stability of sensorineural representations. Here we employed a maternal mouse model of natural sensory cortical plasticity for infant vocalizations to ask whether the engagement of the noradrenergic locus coeruleus (LC) by the playback of pup-calls is affected by either prior experience with the sounds or estrogen availability, using a well-studied cellular activity and plasticity marker, the immediate early gene c-Fos. We counted call-induced c-Fos immunoreactive (c-Fos-IR) cells in both LC and physiologically validated fields within the auditory cortex (AC) of estradiol or blank-implanted virgin female mice with either 0 or 5-days prior experience caring for vocalizing pups. Estradiol and pup experience interacted both in the induction of c-Fos-IR in the LC, as well as in behavioral measures of locomotion during playback, consistent with the neuromodulatory center's activity being an online reflection of both hormonal and experience-dependent influences on arousal. Throughout core AC, as well as in a high frequency sub-region of AC and in secondary AC, a main effect of pup experience was to reduce call-induced c Fos-IR, irrespective of estradiol availability. This is consistent with the hypothesis that sound familiarity leads to less c-Fos-mediated plasticity, and less disrupted sensory representations of a meaningful call category. Taken together, our data support the view that any coupling between these sensory and neuromodulatory areas is situationally dependent, and their engagement depends differentially on both internal state factors like hormones and external state factors like prior experience. PMID- 29983296 TI - O 089 - A soft robotic exosuit assisting the paretic ankle in patients post stroke: Effect on muscle activation during overground walking. AB - This study compared overground walking with and without exosuit assistance in post-stroke patients. Exosuit-assisted walking was found to improve paretic propulsion and ground clearance during swing, two common gait deviations in stroke patients. No changes in leg muscle activity was found, motivating further study of the exosuit as a tool for gait training during stroke rehabilitation. PMID- 29983306 TI - Three-dimensional accuracy of mandibular reconstruction by patient-specific pre bent reconstruction plates using an "in-house" 3D-printer. AB - PURPOSE: The purpose of this study was to compare the three-dimensional accuracy of mandibular reconstruction following mandible continuity resection in patients treated with patient-specific, pre-bent reconstruction plates, using an 'in house' 3D printer, with that in patients treated with conventional, intraoperatively bent plates. PATIENTS AND METHODS: We retrospectively analyzed 42 alloplastic mandibular reconstructions following continuity resection. 21 patients received patient-specific, pre-bent reconstruction plates using an in house 3D printer. The control group consisted of 21 patients provided with intraoperatively bent reconstruction plates. Distances between corresponding anatomical landmarks on the mandibular angle and condyle (A-A', BB', CC', BC'), as well as the intercondylar angle (ICA), were measured and compared on the pre- and postoperative CT scans. RESULTS: Multivariate analysis of variance (MANOVA) showed significant multivariate main effect of group (F(5, 36) = 5.58, p = 0.001; Wilks lambda 0.564; partial eta2 = 0.436), indicating more accurate postoperative results for the pre-bent group. Post-hoc comparison revealed significantly larger postoperative deviation in the distances between the mandibular angle and the intercondylar angle (ICA) for the intraoperatively bent group in comparison with the pre-bent group. However, there was no significant effect on the distance between the condyles. CONCLUSIONS: Mandibular reconstructions employing patient specific, pre-bent reconstruction plates made using an in-house 3D printer show significantly better three-dimensional accuracy compared with intraoperatively bent plates. The described method prevents rotational error of the mandibular angle and improves restoration of the physiological intercondylar angle in mandible reconstruction after continuity resection. PMID- 29983307 TI - Enhanced radiographic visualization of resorbable foils for orbital floor reconstruction: A proof of principle. AB - PURPOSE: Despite the advantages and broad applications of alloplastic resorbable implants, postoperative radiological control is challenging due to its radiolucency. The aim of the present study was to evaluate the radiographic visibility of newly developed materials for orbital floor reconstruction. MATERIALS AND METHODS: The radiographic visibility of four different material combinations consisting of poly-(L-lactic acid)/poly-glycolic acid (PLLA/PGA) or poly(D,L-lactic acid) (PDLLA) enriched with magnesium (Mg), hydroxyapatite (HA) or beta-tricalcium phosphate (beta-TCP) with various layers of thicknesses (0.3, 0.6, and 1 mm), surgically placed above the orbital floor of a human head specimen, was evaluated using computed tomography (CT) and cone beam computed tomography (CBCT). The visibility was rated on a scale of 0-10 in CT/CBCT and by Hounsfield Units in CT for each subject. RESULTS: All of the materials were clearly detectable in CT scans. Visibility was significantly higher (p < 0.001) in the standard soft tissue window (mean score: 7.3, ranging from 2 to 10) in comparison to the standard bone window (mean score: 5.2, ranging from 1 to 10). In CBCT (mean score: 3.3, ranging from 0 to 7), there was significantly lower but still sufficient visibility of the materials compared to the CT soft tissue window (p < 0.001) and CT bone window (p < 0.001). Comparing the different materials' visibility among the group of same layer thicknesses with each other, in the majority of cases, PDLLA enriched with beta-TCP appeared to be most visible in both CT and CBCT. CONCLUSION: The incorporation of radiopaque elements to PLLA/PGA and PDLLA polymers is a promising strategy to improve their visibility in CT and CBCT. Our data suggest that the reconstruction of the orbital floor with these new materials could provide an advantageous postoperative radiographic control. PMID- 29983308 TI - Cystic masses of the lateral neck - Proposition of an algorithm for increased treatment efficiency. AB - Preoperative discrimination of solitary cervical branchial cleft cysts from cystic lymph node metastasis often is challenging. Surgical excision of the cystic formation and consecutive histopathological examination of tissue specimens are the only means resulting in the correct diagnosis. However, in case of malignancies surgery on the lateral neck prior to the definitive treatment is considered to negatively influence the patients' outcome. The rate of cystic lymph node metastasis in patients presenting with a lateral branchial cleft cyst, localization of the primary tumour and oncological outcome were investigated. Retrospective chart review of 131 patients presenting clinically with solitary lateral cervical cysts between. A malignant tumour was detected in 12 patients (9.2%). Malignant tumours were significantly more frequent in patients older than 40 years of age (22.0%; p = 0.0001). In patients older than 40 years of age with solitary lateral cervical cysts a malignancy should be presumed. PMID- 29983309 TI - Osteonecrosis of the jaw in patients treated with denosumab: A multicenter case series. AB - PURPOSE: Osteonecrosis of the jaw has been recently reported in patients receiving denosumab for the treatment of metastatic bone disease and osteoporosis. It is essential to investigate this disease as a new osteonecrosis entity in order to recognize its optimal management strategies. MATERIALS AND METHODS: A total of 63 cases of denosumab-related osteonecrosis of the jaw (DRONJ) diagnosed at two clinical centres were retrospectively reviewed. Demographics, comorbidities, antiresorptive medication use, local preceding event, location, DRONJ stage, treatment and treatment outcomes were analyzed. RESULTS: In all, 69 MRONJ lesions in 63 patients were diagnosed. The mean patient age was 70 +/- 9 years. Denosumab was the only received antiresorptive medication in 50.8% of the patients. Discontinuation of denosumab prior to treatment was recorded for 66.7% of the patients, with a mean period of 6 +/- 3.4 months. Stage 2 was the most common stage of the disease (71%). The lesions were predominantly located in the mandible (63.5%). The most common preceding local event was extraction (55.6%). Surgical treatment was performed in 95.7% of the cases, while purely conservative treatment was performed in 4.3%. DRONJ healed after surgical treatment in 71.7% of the treated lesions. Complete mucosal healing was achieved in 77.2% of the lesions treated with fluorescence-guided surgery (17/22). Clinical characteristics and treatment outcomes were not significantly different between patients with and without previous intake of bisphosphonates. CONCLUSION: DRONJ is more prevalent at extraction and local infection sites in cancer patients. Within the limitation of this study, surgical treatment, particularly fluorescence-guided surgery, appears to be effective for the management of DRONJ. The prior use of bisphosphonates does not seem to affect severity nor the treatment success rate of DRONJ. PMID- 29983310 TI - Diseases of ganglioside biosynthesis: An expanding group of congenital disorders of glycosylation. AB - Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distinct mutations in the B4GALNT1 gene, encoding GM2/GD2/GA2 synthase. Patients suffering from ST3GAL5 deficiency present a devastating syndrome characterized by early onset and dramatic neurological and cognitive impairment, sometimes associated with dyspigmentation and an increased blood lactate concentration. On the other hand, B4GALNT1 mutations give rise to a form of complicated hereditary spastic paraplegia (HSP), previously referred to as HSP26. It is characterized by the late onset of lower limb weakness and mild to moderate intellectual impairment, which is usually not progressive. In addition to the most typical signs, some patients present ocular and endocrine signs, pes cavus, and psychiatric illness. Since the nineties, mice lacking genes for single glycosyltransferases involved in ganglioside biosynthesis, including ST3GAL5 and B4GALNT1, were created and studied. The resulting phenotypes were frequently mild or very mild, so double knock-out animals were created to effectively study the function of gangliosides. The main clinical and biochemical features of patients suffering from GM3 synthase or GM2/GD2/GA2 synthase deficiency, compared with the phenotypes described in mice that are null for single or multiple glycosyltransferase genes, provide suggestions to improve the recognition of novel mutations and potentially related disorders. PMID- 29983311 TI - The Role of Association in Pre-schoolers' Solutions to "Spoon Tests" of Future Planning. AB - Imagining the future is a powerful tool for making plans and solving problems. It is thought to rely on the episodic system which also underpins remembering a specific past event [1-3]. However, the emergence of episodic future thinking over development and evolution is debated [4-9]. One key source of positive evidence in pre-schoolers and animals is the "spoon test" or item choice test [4, 10], in which participants encounter a problem in one context and then a choice of items in another context, one of which is the solution to the problem. A majority of studies report that most children choose the right item by age 4 [10 15, cf.16]. Apes and corvids have also been shown to pass versions of the test [17-19]. However, it has been suggested that a simpler mechanism could be driving choice: the participant simply chooses the item that has been assigned salience or value, without necessarily imagining the future event [16, 20-23]. We developed a new test in which two of the items offered to children were associated with positive outcomes, but only one was still useful. We found that older children (5-, 6-, and 7-year-olds) chose the correct item at above chance levels, but younger children (3- and 4-year-olds) did not. In further tests, 4 year-olds showed an intact memory for the encoding event. We conclude that positive association substantially impacts performance on item choice tests in 4 year-olds and that future planning may have a more protracted developmental trajectory than episodic memory. PMID- 29983312 TI - The Rise and Fall of African Rice Cultivation Revealed by Analysis of 246 New Genomes. AB - African rice (Oryza glaberrima) was domesticated independently from Asian rice. The geographical origin of its domestication remains elusive. Using 246 new whole genome sequences, we inferred the cradle of its domestication to be in the Inner Niger Delta. Domestication was preceded by a sharp decline of most wild populations that started more than 10,000 years ago. The wild population collapse occurred during the drying of the Sahara. This finding supports the hypothesis that depletion of wild resources in the Sahara triggered African rice domestication. African rice cultivation strongly expanded 2,000 years ago. During the last 5 centuries, a sharp decline of its cultivation coincided with the introduction of Asian rice in Africa. A gene, PROG1, associated with an erect plant architecture phenotype, showed convergent selection in two rice cultivated species, Oryza glaberrima from Africa and Oryza sativa from Asia. In contrast, a shattering gene, SH5, showed selection signature during African rice domestication, but not during Asian rice domestication. Overall, our genomic data revealed a complex history of African rice domestication influenced by important climatic changes in the Saharan area, by the expansion of African agricultural society, and by recent replacement by another domesticated species. PMID- 29983313 TI - Motor Error in Parietal Area 5 and Target Error in Area 7 Drive Distinctive Adaptation in Reaching. AB - Errors in reaching drive trial-by-trial adaptation to compensate for the error. Parietal association areas are implicated in error coding, but whether the parietal error signals directly drive adaptation remains unknown. We first examined the activity of neurons in areas 5 and 7 while two monkeys performed rapid target reaching to clarify whether and how the parietal error signals drive adaptation in reaching. We introduced random errors using a motor-driven prism device to augment random motor errors in reaching. Neurons in both regions encoded information on the target position prior to reaching and information on the motor error after reaching. However, post-movement microstimulation caused trial-by-trial adaptation to cancel the motor error only when it was delivered to area 5. By contrast, stimulation to area 7 caused trial-by-trial adaptation so that the reaching endpoint was adjusted toward the target position. We further hypothesized that area 7 would encode target error that is caused by a target jump during the reach, and our results support this hypothesis. Area 7 neurons encoded target error information, but area 5 neurons did not encode this information. These results suggest that area 5 provides signals for adapting to motor errors and that area 7 provides signals to adapt to target errors. PMID- 29983314 TI - gamma-TuRC Heterogeneity Revealed by Analysis of Mozart1. AB - Microtubules are essential for various cell processes [1] and are nucleated by multi-protein gamma-tubulin ring complexes (gamma-TuRCs) at various microtubule organizing centers (MTOCs), including centrosomes [2-6]. Recruitment of gamma TuRCs to different MTOCs at different times influences microtubule array formation, but how this is regulated remains an open question. It also remains unclear whether all gamma-TuRCs within the same organism have the same composition and how any potential heterogeneity might influence gamma-TuRC recruitment. MOZART1 (Mzt1) was recently identified as a gamma-TuRC component [7, 8] and is conserved in nearly all eukaryotes [6, 9]. Mzt1 has so far been studied in cultured human cells, yeast, and plants; its absence leads to failures in gamma-TuRC recruitment and cell division, resulting in cell death [7, 9-15]. Mzt1 is small (~8.5 kDa), binds directly to core gamma-TuRC components [9, 10, 14, 15], and appears to mediate the interaction between gamma-TuRCs and proteins that tether gamma-TuRCs to MTOCs [9, 15]. Here, we use Drosophila to investigate the function of Mzt1 in a multicellular animal for the first time. Surprisingly, we find that Drosophila Mzt1 is expressed only in the testes and is present in gamma TuRCs recruited to basal bodies, but not to mitochondria, in developing sperm cells. mzt1 mutants are viable but have defects in basal body positioning and gamma-TuRC recruitment to centriole adjuncts; sperm formation is affected and mutants display a rapid age-dependent decline in sperm motility and male fertility. Our results reveal that tissue-specific and MTOC-specific gamma-TuRC heterogeneity exist in Drosophila and highlight the complexity of gamma-TuRC recruitment in a multicellular animal. PMID- 29983315 TI - Electric Fields Elicit Ballooning in Spiders. AB - When one thinks of airborne organisms, spiders do not usually come to mind. However, these wingless arthropods have been found 4 km up in the sky [1], dispersing hundreds of kilometers [2]. To disperse, spiders "balloon," whereby they climb to the top of a prominence, let out silk, and float away. The prevailing view is that drag forces from light wind allow spiders to become airborne [3], yet ballooning mechanisms are not fully explained by current aerodynamic models [4, 5]. The global atmospheric electric circuit and the resulting atmospheric potential gradient (APG) [6] provide an additional force that has been proposed to explain ballooning [7]. Here, we test the hypothesis that electric fields (e-fields) commensurate with the APG can be detected by spiders and are sufficient to stimulate ballooning. We find that the presence of a vertical e-field elicits ballooning behavior and takeoff in spiders. We also investigate the mechanical response of putative sensory receivers in response to both e-field and air-flow stimuli, showing that spider mechanosensory hairs are mechanically activated by weak e-fields. Altogether, the evidence gathered reveals an electric driving force that is sufficient for ballooning. These results also suggest that the APG, as additional meteorological information, can reveal the auspicious time to engage in ballooning. We propose that atmospheric electricity adds key information to our understanding and predictive capability of the ecologically important mass migration patterns of arthropod fauna [8]. VIDEO ABSTRACT. PMID- 29983316 TI - Recovery of "Lost" Infant Memories in Mice. AB - Hippocampus-dependent, event-related memories formed in early infancy in human and non-human animals are rapidly forgotten. Recently we found that high levels of hippocampal neurogenesis contribute to accelerated rates of forgetting during infancy. Here, we ask whether these memories formed in infancy are permanently erased (i.e., storage failure) or become progressively inaccessible with time (i.e., retrieval failure). To do this, we developed an optogenetic strategy that allowed us to permanently express channelrhodopsin-2 (ChR2) in neuronal ensembles that were activated during contextual fear encoding in infant mice. We then asked whether reactivation of ChR2-tagged ensembles in the dentate gyrus was sufficient for memory recovery in adulthood. We found that optogenetic stimulation of tagged dentate gyrus neurons recovered "lost" infant memories up to 3 months following training and that memory recovery was associated with broader reactivation of tagged hippocampal and cortical neuronal ensembles. PMID- 29983317 TI - Ion Channels Regulate Nyctinastic Leaf Opening in Samanea saman. AB - The circadian leaf opening and closing (nyctinasty) of Fabaceae has attracted scientists' attention since the era of Charles Darwin. Nyctinastic movement is triggered by the alternate swelling and shrinking of motor cells at the base of the leaf. This, in turn, is facilitated by changing osmotic pressures brought about by ion flow through anion and potassium ion channels. However, key regulatory ion channels and molecular mechanisms remain largely unknown. Here, we identify three key ion channels in mimosoid tree Samanea saman: the slow-type anion channels, SsSLAH1 and SsSLAH3, and the Shaker-type potassium channel, SPORK2. We show that cell-specific circadian expression of SsSLAH1 plays a key role in nyctinastic leaf opening. In addition, SsSLAH1 co-expressed with SsSLAH3 in flexor (abaxial) motor cells promoted leaf opening. We confirm the importance of SLAH1 in leaf movement using SLAH1-impaired Glycine max. Identification of this "master player" advances our molecular understanding of nyctinasty. PMID- 29983318 TI - Noradrenaline Modulates Visual Perception and Late Visually Evoked Activity. AB - An identical sensory stimulus may or may not be incorporated into perceptual experience, depending on the behavioral and cognitive state of the organism. What determines whether a sensory stimulus will be perceived? While different behavioral and cognitive states may share a similar profile of electrophysiology, metabolism, and early sensory responses, neuromodulation is often different and therefore may constitute a key mechanism enabling perceptual awareness. Specifically, noradrenaline improves sensory responses, correlates with orienting toward behaviorally relevant stimuli, and is markedly reduced during sleep, while experience is largely "disconnected" from external events. Despite correlative evidence hinting at a relationship between noradrenaline and perception, causal evidence remains absent. Here, we pharmacologically down- and upregulated noradrenaline signaling in healthy volunteers using clonidine and reboxetine in double-blind placebo-controlled experiments, testing the effects on perceptual abilities and visually evoked electroencephalography (EEG) and fMRI responses. We found that detection sensitivity, discrimination accuracy, and subjective visibility change in accordance with noradrenaline (NE) levels, whereas decision bias (criterion) is not affected. Similarly, noradrenaline increases the consistency of EEG visually evoked potentials, while lower noradrenaline levels delay response components around 200 ms. Furthermore, blood-oxygen-level dependent (BOLD) fMRI activations in high-order visual cortex selectively vary along with noradrenaline signaling. Taken together, these results point to noradrenaline as a key factor causally linking visual awareness to external world events. VIDEO ABSTRACT. PMID- 29983319 TI - Co-polymers of Actin and Tropomyosin Account for a Major Fraction of the Human Actin Cytoskeleton. AB - Tropomyosin proteins form stable coiled-coil dimers that polymerize along the alpha-helical groove of actin filaments [1]. The actin cytoskeleton consists of both co-polymers of actin and tropomyosin and polymers of tropomyosin-free actin [2]. The fundamental distinction between these two types of filaments is that tropomyosin determines the functional capability of actin filaments in an isoform dependent manner [3-9]. However, it is unknown what portion of actin filaments are associated with tropomyosin. To address this deficit, we have measured the relative distribution between these two filament populations by quantifying tropomyosin and actin levels in a variety of human cell types, including bone (U2OS); breast epithelial (MCF-10A); transformed breast epithelial (MCF-7); and primary (BJpar), immortalized (BJeH), and Ras-transformed (BJeLR) BJ fibroblasts [10]. Our measurements of tropomyosin and actin predict the saturation of the actin cytoskeleton, implying that tropomyosin binding must be inhibited in order to generate tropomyosin-free actin filaments. We find the majority of actin filaments to be associated with tropomyosin in four of the six cell lines tested and the portion of actin filaments associated with tropomyosin to decrease with transformation. We also discover that high-molecular-weight (HMW), unlike low molecular-weight (LMW), tropomyosin isoforms are primarily co-polymerized with actin in untransformed cells. This differential partitioning of tropomyosins is not due to a lack of N-terminal acetylation of LMW tropomyosins, but it is, in part, explained by the susceptibility of soluble HMW tropomyosins to proteasomal degradation. We conclude that actin-tropomyosin co-polymers make up a major fraction of the human actin cytoskeleton. PMID- 29983320 TI - Mettl1/Wdr4-Mediated m7G tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation. AB - tRNAs are subject to numerous modifications, including methylation. Mutations in the human N7-methylguanosine (m7G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation, yet the molecular and cellular function in mammals is not well understood. We developed m7G methylated tRNA immunoprecipitation sequencing (MeRIP-seq) and tRNA reduction and cleavage sequencing (TRAC-seq) to reveal the m7G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs is modified at a "RAGGU" motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs, implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m7G tRNA methylome and highlights its essential role in ESCs with links to human disease. PMID- 29983322 TI - A Modular Organization of LRR Protein-Mediated Synaptic Adhesion Defines Synapse Identity. AB - Pyramidal neurons express rich repertoires of leucine-rich repeat (LRR) containing adhesion molecules with similar synaptogenic activity in culture. The in vivo relevance of this molecular diversity is unclear. We show that hippocampal CA1 pyramidal neurons express multiple synaptogenic LRR proteins that differentially distribute to the major excitatory inputs on their apical dendrites. At Schaffer collateral (SC) inputs, FLRT2, LRRTM1, and Slitrk1 are postsynaptically localized and differentially regulate synaptic structure and function. FLRT2 controls spine density, whereas LRRTM1 and Slitrk1 exert opposing effects on synaptic vesicle distribution at the active zone. All LRR proteins differentially affect synaptic transmission, and their combinatorial loss results in a cumulative phenotype. At temporoammonic (TA) inputs, LRRTM1 is absent; FLRT2 similarly controls functional synapse number, whereas Slitrk1 function diverges to regulate postsynaptic AMPA receptor density. Thus, LRR proteins differentially control synaptic architecture and function and act in input-specific combinations and a context-dependent manner to specify synaptic properties. PMID- 29983321 TI - The Importance of Poly(ADP-Ribose) Polymerase as a Sensor of Unligated Okazaki Fragments during DNA Replication. AB - Poly(ADP-ribose) is synthesized by PARP enzymes during the repair of stochastic DNA breaks. Surprisingly, however, we show that most if not all endogenous poly(ADP-ribose) is detected in normal S phase cells at sites of DNA replication. This S phase poly(ADP-ribose) does not result from damaged or misincorporated nucleotides or from DNA replication stress. Rather, perturbation of the DNA replication proteins LIG1 or FEN1 increases S phase poly(ADP-ribose) more than 10 fold, implicating unligated Okazaki fragments as the source of S phase PARP activity. Indeed, S phase PARP activity is ablated by suppressing Okazaki fragment formation with emetine, a DNA replication inhibitor that selectively inhibits lagging strand synthesis. Importantly, PARP activation during DNA replication recruits the single-strand break repair protein XRCC1, and human cells lacking PARP activity and/or XRCC1 are hypersensitive to FEN1 perturbation. Collectively, our data indicate that PARP1 is a sensor of unligated Okazaki fragments during DNA replication and facilitates their repair. PMID- 29983324 TI - OLMalpha2 Cells Bidirectionally Modulate Learning. AB - Inhibitory interneurons participate in mnemonic processes. However, defined roles for identified interneuron populations are scarce. A subpopulation of oriens lacunosum-moleculare (OLM) interneurons genetically defined by the expression of the nicotinic receptor alpha2 subunit has been shown to gate information carried by either the temporoammonic pathway or Schaffer collaterals in vitro. Here we set out to determine whether selective modulation of OLMalpha2 cells in the intermediate CA1 affects learning and memory in vivo. Our data show that intermediate OLMalpha2 cells can either enhance (upon their inhibition) or impair (upon their activation) object memory encoding in freely moving mice, thus exerting bidirectional control. Moreover, we find that OLMalpha2 cell activation inhibits fear-related memories and that OLMalpha2 cells respond differently to nicotine in the dorsoventral axis. These results suggest that intermediate OLMalpha2 cells are an important component in the CA1 microcircuit regulating learning and memory processes. VIDEO ABSTRACT. PMID- 29983323 TI - De Novo Mutation in Genes Regulating Neural Stem Cell Fate in Human Congenital Hydrocephalus. AB - Congenital hydrocephalus (CH), featuring markedly enlarged brain ventricles, is thought to arise from failed cerebrospinal fluid (CSF) homeostasis and is treated with lifelong surgical CSF shunting with substantial morbidity. CH pathogenesis is poorly understood. Exome sequencing of 125 CH trios and 52 additional probands identified three genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 * 10-7), SMARCC1 (p = 8.15 * 10-10), and PTCH1 (p = 1.06 * 10-6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 * 10-4). Together, these probands account for ~10% of studied cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate. These results implicate impaired neurogenesis (rather than active CSF accumulation) in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications. PMID- 29983325 TI - Luminance Changes Drive Directional Startle through a Thalamic Pathway. AB - Looming visual stimuli result in escape responses that are conserved from insects to humans. Despite their importance for survival, the circuits mediating visual startle have only recently been explored in vertebrates. Here we show that the zebrafish thalamus is a luminance detector critical to visual escape. Thalamic projection neurons deliver dim-specific information to the optic tectum, and ablations of these projections disrupt normal tectal responses to looms. Without this information, larvae are less likely to escape from dark looming stimuli and lose the ability to escape away from the source of the loom. Remarkably, when paired with an isoluminant loom stimulus to the opposite eye, dimming is sufficient to increase startle probability and to reverse the direction of the escape so that it is toward the loom. We suggest that bilateral comparisons of luminance, relayed from the thalamus to the tectum, facilitate escape responses and are essential for their directionality. PMID- 29983326 TI - Motivation, Perception, and Chance Converge to Make a Binary Decision. AB - We reveal a central role for chance neuronal events in the decision of a male fly to court, which can be modeled as a coin flip with odds set by motivational state. The decision is prompted by a tap of a female with the male's pheromone receptor-containing foreleg. Each tap evokes competing excitation and inhibition onto P1 courtship command neurons. A motivating dopamine signal desensitizes P1 to the inhibition, increasing the fraction of taps that successfully initiate courtship. Once courtship has begun, the same dopamine tone potentiates recurrent excitation of P1, maintaining the courtship of highly motivated males for minutes and buffering against termination. Receptor diversity within P1 creates separate channels for tuning the propensities to initiate and sustain courtship toward appropriate targets. These findings establish a powerful invertebrate system for cue-triggered binary decisions and demonstrate that noise can be exploited by motivational systems to make behaviors scalable and flexible. PMID- 29983328 TI - Inflammatory bowel disease and risk of Parkinson's disease in medicare beneficiaries. PMID- 29983327 TI - A Distance-Dependent Distribution of Presynaptic Boutons Tunes Frequency Dependent Dendritic Integration. AB - How presynaptic inputs and neurotransmitter release dynamics are distributed along a dendritic tree is not well established. Here, we show that presynaptic boutons that form onto basal dendrites of CA1 pyramidal neurons display a decrease in active zone (AZ) size with distance from the soma, resulting in a distance-dependent increase in short-term facilitation. Our findings suggest that the spatial distribution of short-term facilitation serves to compensate for the electrotonic attenuation of subthreshold distal inputs during repeated stimulation and fine-tunes the preferred input frequency of dendritic domains. PMID- 29983329 TI - Mirror movements and blepharoclonus as novel phenomena in hereditary diffuse leukoencephalopathy with spheroids. PMID- 29983330 TI - National consensus on the definition, investigation, and classification of meniscal lesions of the knee. AB - BACKGROUND: The aim of this study was to deliver standardised terminology for the identification and stratification of patients with meniscal lesions of the knee. METHODS: A national group of expert surgeons was convened by the British Association for Surgery of the Knee (BASK) and a formal consensus process was undertaken following a validated methodology. A combination of nominal group techniques and an iterative Delphi process was used to develop and refine relevant definitions. Where appropriate, definitions were placed into categories to facilitate use in clinical practice and guideline development. RESULTS: A degenerative meniscus develops progressively with degradation of meniscal tissue and this may be revealed by intra-meniscal high signal on magnetic resonance imaging (MRI). A meniscal tear was defined as a defect or split in the meniscocapsular complex, which can occur in a degenerative or non-degenerative meniscus. Degenerative meniscal lesions (high signal or tear) are frequent in the general population and are often incidental findings on knee MRI. Symptoms were defined and classified into three groups: (1) strongly suggestive of a treatable meniscal lesion, (2) potentially suggestive of a treatable meniscal lesion, (3) osteoarthritic. A strategy for radiological imaging (radiograph +/- MRI) was agreed for the investigation of the patients with a possible meniscal tear. Meniscal lesions and tear patterns on MRI imaging were defined and classified with reference to potential treatability: (1) target, (2) possible target, (3) no target. CONCLUSIONS: The agreed terminology will enable patients with meniscal lesions to be identified and stratified consistently in clinical practice, research and guideline development. PMID- 29983331 TI - Giant cavernous malformations: A single center experience and literature review. AB - Intracranial giant cavernous malformations (GCMs) are rarely reported because of their extremely low incidence. Knowledge of GCM is poor. The goals of this study were to analyze the epidemiological characteristics, clinical manifestations, radiological findings, microsurgical treatment, and neurological outcomes of GCMs. From January of 2003 to December 2016, nine GCM patients who underwent neurosurgical treatment at Beijing Tiantan Hospital were chosen for analysis and their records were reviewed. We also performed an exhaustive literature search and identified all previously reported GCMs. The study population consisted of three males and six females (mean age, 25.1 years). The mean diameter of the malformations was 6.7 cm (range, 6.0-8.4 cm). The most common clinical manifestations were the symptoms caused by mass effect. Radiologically, all GCMs showed mixed T1 and T2 signals; five of them exhibited minimal enhancement after contrast administration. Gross total resection was achieved in all patients without surgical mortality. Postoperatively, three patients developed new surgical complications, including left limbs weakness and left side paralysis. The mean follow-up period after diagnosis was 69.3 months (range, 16-149 months); five patients (55.6%) had achieved full recovery and the remaining four cases (44.4%) were improved to some extent. GCM is a rare subgroup of vascular malformations; it is more prone to occur in children and adolescents. Microsurgical resection should be the treatment of choice for GCMs, and despite their giant size, excellent surgical outcomes after total removal could be achieved. PMID- 29983332 TI - The Goldilocks principle. Oxygen in the delivery room: When is it too little, too much, and just right? AB - Oxygen has been used to stabilize newborn infants for more than a century. Over the last two decades, a paradigm shift towards using less oxygen has occurred but without firm evidence of benefit. Using lower levels of oxygen has also added new conundrums to clinical care. Can oxygen delivery to sick newborn babies meet the Goldilocks principle, of being "just right"? This review discusses the history of oxygen use in the delivery room and the impetus to change from the long established practice of using pure oxygen to using lower oxygen concentrations. The review also highlights knowledge gaps, particularly for oxygen exposure and monitoring, as well as the sequelae of oxygen administration, including short- and long-term outcomes. PMID- 29983333 TI - Retro-peritoneal paraganglioma, diagnosis and management. AB - INTRODUCTION: Paragangliomas, defined as extra-adrenal chromaffin-cells tumors, are rarely located in the retro-peritoneum. Clinical presentation is similar to pheochromocytoma, and mainly depends on the producing character of the tumor. Positive diagnosis requires plasmatic and urinary hormonal assays. Radiological and isotopic explorations are essential before surgery. The only curative therapeutic strategy is surgical, associated to peri-operative prevention and monitoring of the frequently reported hemodynamic and cardiovascular disorders. Outcome depends of the metastatic character of the tumor, the presence of tumor remnant after surgical resection. Genetic study is recommended; the risk of recurrence and association to other neoplasm is more described in genetic forms. MATERIAL AND METHODS: Authors report 5cases of retro-peritoneal paraganglioma, operated in the department of urology of Hospital, between 2013 and 2017. Observations are about 2men and 3women. Clinical presentation is not always specific and paraganglioma may be discovered fortuitously. Two patients have been operated by coelioscopic approach, midline incision was performed in two other cases, and dorsal lumbotomy associated to a Rutherford-Morrison incision in a patient. RESULTS: Two patients presented resistant hypertension and palpitation associated to suspect retro-peritoneal masses in imagery and elevated urinary methoxylated derivates before surgery. One patient was asymptomatic and the tumor was discovered in imagery. Per-operative hypertensive crisis and sinus tachycardia occurred in a case. The average follow-up period is 22.8months. Hypertension and palpitation disappeared after surgery. There was no recurrence for all the operated patients. CONCLUSION: Retro-peritoneal paraganglioma is a rare condition. Symptoms are not specific and clinical presentation may be similar to pheochromocytoma. Abdominal CT-scan and MRI, in association with MIBG scintigraphy are strongly evocative. Histological examination ensures diagnosis. Per-operative cardio-vascular disorders are to consider and must prevented and managed by anesthesiologists. Complete surgical resection is the only curative treatment and avoids recurrences. PMID- 29983334 TI - Human monocytes stimulated by Shiga toxin 1a via globotriaosylceramide release proinflammatory molecules associated with hemolytic uremic syndrome. AB - The life-threatening sequela of hemorrhagic colitis induced by Shiga toxins (Stx) producing Escherichia coli (STEC) infections in humans is hemolytic uremic syndrome (HUS), the main cause of acute renal failure in early childhood. The key step in the pathogenesis of HUS is the appearance of Stx in the blood of infected patients because these powerful virulence factors are capable of inducing severe microangiopathic lesions in the kidney. During precocious toxemia, which occurs in patients before the onset of HUS during the intestinal phase, Stx bind to several different circulating cells. An early response of these cells might include the release of proinflammatory mediators associated with the development of HUS. Here, we show that primary human monocytes stimulated with Shiga toxin 1a (Stx1a) through the glycolipid receptor globotriaosylceramide released larger amounts of proinflammatory molecules (IL-1beta, TNFalpha, IL-6, G-CSF, CXCL8, CCL2, CCL4) than Stx1a-treated neutrophils. The mediators (except IL-1beta) are among the top six proinflammatory mediators found in the sera from patients with HUS in different studies. The molecules appear to be involved in different pathogenetic steps of HUS, i.e. sensitization of renal endothelial cells to the toxin actions (IL-1beta, TNFalpha), activation of circulating monocytes and neutrophils (CXCL8, CCL2, CCL4) and increase in neutrophil counts in patients with poor prognosis (G-CSF). Hence, a role of circulating monocytes in the very early phases of the pathogenetic process culminating with HUS can be envisaged. Impairment of the events of precocious toxemia would prevent or reduce the risk of HUS in STEC-infected children. PMID- 29983335 TI - Seeing the Light after 25 Years of Retinal Gene Therapy. AB - The retina has been at the forefront of translational gene therapy. Proof-of concept that gene therapy could restore vision in a large animal led to the initiation of the first successful clinical trials and, in turn, to the recent approval of the first gene therapy product for an ocular disease. As dozens of clinical trials of retinal gene therapy have begun, new challenges are identified, which include delivery of large genes, counteracting gain-of-function mutations, and safe and effective gene transfer to diseased retinas. Advancements in vector design, improvements of delivery routes, and selection of optimal timing for intervention will contribute to extend the initial success of retinal gene therapy to an increasing number of inherited blinding conditions. PMID- 29983337 TI - Cardiovascular magnetic resonance imaging for amyloidosis: The state-of-the-art. AB - Amyloidosis results from insoluble precursor proteins being deposited in the extracellular compartment. The prognosis of the disease is predominantly determined by cardiac involvement due to amyloid accumulation that contributes to cardiac dysfunction and disturbed conduction of cardiac electrical signals. The clinical and radiological manifestations of amyloidosis are often non-specific, making amyloidosis a diagnostic challenge both for clinicians and radiologists. Cardiovascular magnetic resonance imaging, including conventional sequences, late gadolinium enhancement, T1 mapping and determination of extracellular volume fraction is a multi-dimensional modality for the assessment and diagnosis of cardiac amyloidosis and, in addition, is an excellent tool for risk stratification and disease tracking. PMID- 29983336 TI - A Switch-like Activation Relay of EGFR-ERK Signaling Regulates a Wave of Cellular Contractility for Epithelial Invagination. AB - The dynamics of extracellular signal-regulated kinase (ERK) signaling underlies its versatile functions in cell differentiation, cell proliferation, and cell motility. Classical studies in Drosophila established that a gradient of epidermal growth factor receptor (EGFR)-ERK signaling is essential for these cellular responses. However, we challenge this view by the real-time monitoring of ERK activation; we show that a switch-like ERK activation is essential for the invagination movement of the Drosophila tracheal placode. This switch-like ERK activation stems from the positive feedback regulation of the EGFR-ERK signaling and a resultant relay of EGFR-ERK signaling among tracheal cells. A key transcription factor Trachealess (Trh) permissively regulates the iteration of the relay, and the ERK activation becomes graded in trh mutant. A mathematical model based on these observations and a molecular link between ERK activation dynamics and myosin shows that the relay mechanism efficiently promotes epithelial invagination while the gradient mechanism does not. PMID- 29983338 TI - Development of an asthma risk factors scale (ARFS) for risk assessment asthma screening in children. AB - BACKGROUND: The study objective was to create asthma risk factors scale (ARFS) score that would be correlated with the increased risk of asthma in Lebanese children. This scale would eventually be used both to identify children at risk and assess early diagnosis of asthma. METHODS: A case-control study (study 1) of 1276 children (976 controls and 300 cases) and a cross-sectional study (study 2) of 1000 children were conducted using a parental questionnaire. Children aged between 3 and 16 years were screened for possible enrollment. The ARFS was created by combining the following risk factors: child's exposure to pesticides, detergent mixing, alcohol, smoking and drug intake during pregnancy and breastfeeding, the actual paternal and maternal smoking status and history of asthma, and the types of food the child consumes. RESULTS: There was a significant increase in the risk assessment screening for asthma per 15 points increments of ARFS (p < 0.001 for trend). The score category 0-14.99 best represented control individuals (88.8% controls), while a score higher than 45 represented asthmatic children best (98.4% asthmatics). The positive predictive value (disease positive/all positive by scale) came out as 94.02%, whereas the negative predictive value (disease negative/all negative by scale) was found to be 90.47%. These results were confirmed in the second study sample. CONCLUSION: The ARFS is a simple and easy-to-use tool, composed of 15 questions, for the clinician risk assessment of asthma in children, taking into account the environmental exposure, parental history of asthma and dietary habits of the child. Its value for asthma diagnosis remains to be confirmed in future prospective studies, especially in children with chronic respiratory symptoms. PMID- 29983339 TI - Association of body mass index and season with histamine skin reactivity in Chinese children with allergic rhinitis. AB - BACKGROUND: To investigate the association between histamine skin reactivity and body mass index (BMI) and other clinical factors, 526 children (3-6 years old) who underwent a skin-prick test (SPT) to diagnose allergic rhinitis were enrolled. METHODS: The SPT was carried out using 43 common allergens (commercial kit). The wheal size was analyzed. The associations between histamine reactivity and age, gender, BMI, atopy, parental smoking history, and testing season were examined. RESULTS: Mean age was 4.6 +/- 1.1 years. Among all 526 children, 202 (38.4%) had intermittent allergic rhinitis (IAR), 164 (32.1%) had IAR + persistent allergic rhinitis (PER), and 160 (30.4%) had PER. The size of the histamine skin wheal and maximum diameter for positive allergens showed significant seasonal differences (P = 0.001 and P = 0.02, respectively). Children with biparental allergy history had a higher BMI (P = 0.006). BMI (P < 0.001), summer testing (P = 0.001), and autumn testing (P < 0.001) were independently associated with the size of the histamine skin wheal. Only winter testing was independently associated with the maximal diameter for positive allergens (P = 0.002). CONCLUSIONS: Higher histamine skin reactivity was associated with higher BMI and summer or autumn testing. Subject BMI and season should be considered for better interpretation of the SPT. The mechanisms underlying these associations require further study. PMID- 29983340 TI - Dose-response effects of years of self-reported physical activity on old females' motor and cognitive function. AB - BACKGROUND: There is a poor understanding of the dose-response relationship between years of physical activity and motor and cognitive function. We determined the dose-response effects of physical activity duration in years on motor and cognitive function and their relationship in healthy old females. OBJECTIVES: To determine the dose-effects of physical activity duration in years on motor and cognitive function and their relationship in health aging adults. METHODS: We conducted a retrospective observational study with 201 old (age 69 years; SD=5.9) and 12 young (mean age 21 years; SD=1.9) females, with sub-groups based on number of years of self-reported physical activity. Aerobic capacity, mobility, functional reach, standing balance, global cognition, episodic memory, executive function, and processing speed were assessed with performance-based tests. We analyzed sub-group differences quantitatively and qualitatively and performed regression and mediation analyses to determine predictors and mediators of physical activity effects. RESULTS: Based on physical activity of minimal (0.3 y, n=29), short (2.4 y, n=77), moderate (6.2 y, n=36) and long (16.6 y, n=59) duration, physical activity for at least 2.4 years affords old adults benefits in body mass index with peak dose-effects present in aerobic capacity and mobility at 6.2 years without additional benefits after 16.6 years of physical activity. Physical activity for any duration had no effects on functional reach, balance, executive function, episodic memory, and processing speed. Although weakly mobility predicted global cognition and executive function. CONCLUSION: Performing physical activity up to 6.2 years on average had favorable effects on body mass index, aerobic capacity and mobility. The data strengthen current recommendations for an active lifestyle in adulthood to prevent aging-related motor and cognitive decline. PMID- 29983341 TI - Tinnitus evaluation: relation among pitch matching and loudness, visual analog scale and tinnitus handicap inventory. AB - INTRODUCTION: Tinnitus is a subjective auditory symptom usually associated with a sound, even in the absence of external sound sources. Its diagnosis is complex, and some of the forms of measurement alone or in combination, include self assessment questionnaires, such as the tinnitus handicap inventory, the visual analog scale and/or pitch and loudness matching. OBJECTIVE: To analyze the correlation among three tinnitus measurement methods: tinnitus handicap inventory, visual analog scale and pitch and loudness matching. METHODS: The study consisted of 148 patients complaining of chronic tinnitus. An otorhinolaryngological evaluation, anamnesis directed to tinnitus, audiometry (pure tone and speech), imitanciometry, tinnitus handicap inventory, visual analog scale, and pitch and loudness matching were performed. The study was registered in the Ethics Committee of the Institution with no. 0129/12. RESULTS: Regarding the frequency of tinnitus handicap inventory responses, a higher occurrence of the mild degree was observed. An average of 6 points was observed on the visual analog scale. The mean loudness matching in the right ear was 20dBNS, and in the left ear was 17dBNS. As for the type of stimulus, the most found was continuous pure tone. The frequency of the pitch sensation was 6000Hz in the largest number of cases. Regarding the measures of tinnitus handicap inventory and the visual analogical scale, a significant correlation was observed, and as one value increases the other also increases. Pitch and loudness matching and the visual analogical scale results are also significant. CONCLUSION: There was a significant correlation between the values measured by the tinnitus handicap inventory, visual analogical scale (annoyance) and loudness matching in the evaluation of tinnitus. The selection of any one of the three evaluative methods for tinnitus investigation provides different dimensions of the tinnitus and complements the others. PMID- 29983343 TI - Fruquintinib for previously treated metastatic colorectal cancer. PMID- 29983344 TI - Enzalutamide and metastasis risk in prostate cancer. PMID- 29983342 TI - Advancing the public health applications of Chlamydia trachomatis serology. AB - Genital Chlamydia trachomatis infection is the most commonly diagnosed sexually transmitted infection. Trachoma is caused by ocular infection with C trachomatis and is the leading infectious cause of blindness worldwide. New serological assays for C trachomatis could facilitate improved understanding of C trachomatis epidemiology and prevention. C trachomatis serology offers a means of investigating the incidence of chlamydia infection and might be developed as a biomarker of scarring sequelae, such as pelvic inflammatory disease. Therefore, serological assays have potential as epidemiological tools to quantify unmet need, inform service planning, evaluate interventions including screening and treatment, and to assess new vaccine candidates. However, questions about the performance characteristics and interpretation of C trachomatis serological assays remain, which must be addressed to advance development within this field. In this Personal View, we explore the available information about C trachomatis serology and propose several priority actions. These actions involve development of target product profiles to guide assay selection and assessment across multiple applications and populations, establishment of a serum bank to facilitate assay development and evaluation, and development of technical and statistical methods for assay evaluation and analysis of serological findings. The field of C trachomatis serology will benefit from collaboration across the public health community to align technological developments with their potential applications. PMID- 29983345 TI - Refametinib in RAS-mutated hepatocellular cancer. PMID- 29983346 TI - Surgical Simulation: Markers of Proficiency. AB - OBJECTIVE: Surgical simulation has become an integral component of surgical training. Simulation proficiency determination has been traditionally based upon time to completion of various simulated tasks. We aimed to determine objective markers of proficiency in surgical simulation by comparing novel assessments with conventional evaluations of technical skill. DESIGN: Categorical general surgery residents completed 10 laparoscopic cholecystectomy modules using a high-fidelity simulator. We recorded and analyzed simulation task times, as well as number of hand movements, instrument path length, instrument acceleration, and participant affective engagement during each simulation. Comparisons were made to Objective Structured Assessment of Technical Skill (OSATS) and Accreditation Council for Graduate Medical Education Milestones, as well as previous laparoscopic experience, duration of laparoscopic cholecystectomies performed by participants, and postgraduate year. Comparisons were also made to Fundamentals of Laparoscopic Surgery task times. Spearman's rho was utilized for comparisons, significance set at >0.50. SETTING: University of Missouri, Columbia, Missouri, an academic tertiary care facility. PARTICIPANTS: Fourteen categorical general surgery residents (postgraduate year 1-5) were prospectively enrolled. RESULTS: One hundred forty simulations were included. The number of hand movements and instrument path lengths strongly correlated with simulation task times (rho 0.62 0.87, p < 0.0001), FLS task completion times (rho 0.50-0.53, p < 0.0001), and prior real-world laparoscopic cholecystectomy experience (rho -0.51 to -0.53, p < 0.0001). No significant correlations were identified between any of the studied markers with Accreditation Council for Graduate Medical Education Milestones, Objective Structured Assessment of Technical Skill evaluations, total previous laparoscopic experience, or postgraduate year level. Neither instrument acceleration nor participant engagement showed significant correlation with any of the conventional markers of real-world or simulation skill proficiency. CONCLUSIONS: Simulation proficiency, measured by instrument and hand motion, is more representative of simulation skill than simulation task time, instrument acceleration, or participant engagement. PMID- 29983347 TI - Associations of vitamin D status and metabolic dyslipidemia and hypertriglyceridemic waist phenotype in apparently healthy adults. AB - BACKGROUND: Recent studies have shown that Vitamin D deficiency is very common globally. Vitamin D deficiency is associated with lipid metabolism. A relationship between vitamin D levels and waist circumference (WC) has been observed. The purpose of this study is to evaluate the relationship between vitamin D status and metabolic dyslipidemia and the hypertriglyceridemic waist phenotype. METHODS: This cross-sectional study was conducted on 265 healthy Tehran adults. Hypertriglyceridemic waist phenotype (HTGWP) was described as serum triacylglycerol concentrations >150 mg/dL and concurrent WC > 88 cm (women) and >102 cm (men). Dyslipidemia was defined as: 1) TG level of >150 mg/dL 2) HDL > 40 mg/dL for men or >50 mg/dL for women, as has been previously described. RESULTS: Current study's results demonstrated that HTGWP was significantly associated with weight, age, WC, hip, fat percent, TG, lipid profile, ALT and BMI. We found 77% reduction in the chances of developing metabolic dyslipidemia in suficient satus of vitamin D in compare to deficiency, although the significancy was mariginal, OR: 0.33, 95% CI of 0.09 to 1.21, P = 0.09. However, our results revealed that vitamin D deficiency, compared with normal status, can increase the risk of phenotype 1 (high TG/high WC); OR: 3.86 and 95% CI from 0.86 to 0.99, p for trend = 0.05. CONCLUSIONS: Significant associations were found between vitamin D status and HTGWP. In addition, there was a relationship between vitamin D and lipid profiles. There is a direct correlation between TG and waist circumference in insulin resistance in healthy Tehran adults. PMID- 29983348 TI - Evaluation of GWAS-Identified Genetic Variants for Gastric Cancer Survival. AB - BACKGROUNDS: Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS identified genetic variants could serve as robust prognostic biomarkers for GC. METHODS: A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log rank P was calculated by the log-rank test with the Kaplan-Meier method. RESULTS: We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223. INTERPRETATION: This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation. PMID- 29983351 TI - 70 years of the NHS-time to grow up? PMID- 29983349 TI - Short-Term Hypoxia Dampens Inflammation in vivo via Enhanced Adenosine Release and Adenosine 2B Receptor Stimulation. AB - Hypoxia and inflammation are closely intertwined phenomena. Critically ill patients often suffer from systemic inflammatory conditions and concurrently experience short-lived hypoxia. We evaluated the effects of short-term hypoxia on systemic inflammation, and show that it potently attenuates pro-inflammatory cytokine responses during murine endotoxemia. These effects are independent of hypoxia-inducible factors (HIFs), but involve augmented adenosine levels, in turn resulting in an adenosine 2B receptor-mediated post-transcriptional increase of interleukin (IL)-10 production. We translated our findings to humans using the experimental endotoxemia model, where short-term hypoxia resulted in enhanced plasma concentrations of adenosine, augmentation of endotoxin-induced circulating IL-10 levels, and concurrent attenuation of the pro-inflammatory cytokine response. Again, HIFs were shown not to be involved. Taken together, we demonstrate that short-term hypoxia dampens the systemic pro-inflammatory cytokine response through enhanced purinergic signaling in mice and men. These effects may contribute to outcome and provide leads for immunomodulatory treatment strategies for critically ill patients. PMID- 29983350 TI - Anti-Tumour Necrosis Factor Therapy for Dupuytren's Disease: A Randomised Dose Response Proof of Concept Phase 2a Clinical Trial. AB - BACKGROUND: Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. METHODS: Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for alpha-smooth muscle actin (ACTA2). Secondary outcomes included levels of alpha-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). FINDINGS: We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of alpha-SMA protein expression in patients treated with 40 mg adalimumab (1.09 +/- 0.09 ng per MUg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 +/- 0.09 ng/MUg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 +/- 84 pg/MUg total protein) compared with placebo (817 +/- 78 pg/MUg). There were two serious adverse events, both considered unrelated to the study drug. INTERPRETATION: In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of alpha-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease. FUNDING: Health Innovation Challenge Fund (Wellcome Trust and Department of Health) and 180 Therapeutics LP. PMID- 29983352 TI - Use of a comprehensive frailty assessment to predict morbidity in patients with multiple myeloma undergoing transplant. AB - : Multiple myeloma (MM) is a disease of aging adults and autologous stem cell transplant (ASCT) is considered the standard of care. As the population ages a growing number of older adults will undergo ASCT and an objective approach to estimate physiologic reserve and transplant morbidity risk is warranted. Here, we evaluate assess p16INK4a (p16), a molecular aging biomarker, along with geriatric metrics to determine risk of transplant toxicity. METHODS: We prospectively evaluated 100 MM patients for frailty before and after ASCT using a Geriatric Assessment (GA) and collected T-cells for analysis of p16 using a custom nanostring codeset. RESULTS: Pre-transplant physical function was predicative of hospital length of stay (LOS). Each one-unit increase in physical function score, the average LOS decreased by 0.52 days (95% CI, -1.03-0.02); p = .04). Similarly, higher self-report of ADL/IADL (Human Activity Profile was associated with shorter LOS (0.65 less days (95% CI -1.15 to -0.15), p = .01). Patients with anxiety/depression (OR = 1.10 (95% CI 1.00-1.22), p = .056), lower handgrip strength (OR = 0.90 (95% CI 0.82-0.98), p = .02), falls (OR = 1.60 (95% CI 1.07 2.38), p = .02), or weight loss (OR = 5.65 (95% CI 1.17-25.24), p = .03) were more likely to be re-admitted. The estimated EFS at 1-year was 85% (95% CI, 75 91) with median follow-up of 15.7 months. Weight loss was a significant predictor of EFS (HR = 3.13 (95% CI 1.15-8.50), p = .03). Frailty assessment by self reported fatigue minimally correlated with T-cell p16 expression (r = 0.28; p = .02). Age, Karnofsky Performance Status (KPS), or Hematopoietic cell transplantation-specific Co-Morbidity Index (HCT-CI) did not predict hospital LOS or readmissions. CONCLUSIONS: Our data illustrate that a GA can identify individuals with MM who are at greater risk for morbidity following ASCT. PMID- 29983353 TI - Incomplete circle of Willis is associated with a higher incidence of neurologic events during carotid eversion endarterectomy without shunting. AB - OBJECTIVE: A complete circle of Willis (CoW) is considered an important collateral network to maintain blood flow during cross-clamping in carotid endarterectomy (CEA). The aim of this study was to evaluate the impact of an incomplete CoW with isolated middle cerebral artery (iMCA) on immediate neurologic events (INEs) after CEA. METHODS: We prospectively collected the clinical data and outcomes of 902 patients who underwent CEA under general anesthesia between 2013 and 2015. All patients had preoperative computed tomography angiography of the extracranial and intracranial cerebral circulation. Indications were asymptomatic (52%) and symptomatic (48%) carotid artery disease. Patients who had CEA with shunt (n = 35) and those with inadequate intracranial imaging to assess CoW were excluded (n = 322) only. Computed tomography angiography images were reviewed retrospectively and independently by two vascular radiologists who were blinded for treatment outcomes. Imaging assessment included the vertebral and carotid circulation and each segment of the CoW, which was classified as normal, hypoplastic (diameter < 0.8 mm) or absent. The ipsilateral MCA was considered isolated if there was an absence of the anterior and posterior communicating branches from the contralateral carotid or posterior circulations. INE was defined as any transient ischemic attack (TIA) and stroke diagnosed immediately after the procedure. RESULTS: Of the 545 included patients (331 males; mean age, 69 +/- 8 years), 12 (2.2%) had a stroke in the postoperative period. There were 20 INEs (8 strokes and 12 TIAs). A complete CoW was rare; it was only detected in 19 patients (3.5%) and an iMCA was found in 34 patients (6.3%). When at least one collateral circulation was complete (in 330 patients), we observed only four INEs (1.2%). Of the 34 patients with an iMCA, 8 (24%) had INE (6 TIAs and 2 strokes). Overall, iMCA was an independent predictor of INEs (odds ratio, 11.12; 95% confidence interval, 3.57-35.87; P < .001). With logistic regression, the model included hypertension, smoking, diabetes, hyperlipidemia, carotid clamping time (minutes), contralateral significant internal carotid artery stenosis of greater than 90%, ipsilateral significant internal carotid artery stenosis of greater than 90%, preoperative symptoms in 6 months, and iMCA; above iMCA only symptomatic patients had significant risk (odds ratio, 3.34; 95% confidence interval, 1.19-9.73; P = .02), whereas all other parameters were not significant. CONCLUSIONS: An iMCA carries more than a 10-fold higher the risk of INEs after CEA with cross-clamping without shunt protection. In these patients, routine shunting is recommended to prevent INEs. PMID- 29983354 TI - Movement profile influences systemic stress and biomechanical resilience to high training load exposure. AB - OBJECTIVES: Determine the influence of movement profile on systemic stress and mechanical loading before and after high training load exposure. DESIGN: Cross sectional cohort study. METHODS: 43 physically active, college-aged field or court sport female athletes participated in this study. Participants were assigned to a "excellent" (n=22; age=20.5+/-1.9yrs, height=1.67+/-0.67m, mass=64.5+/-7.8kg) or "poor" (n=21; age=20.4+/-1.3yrs, height=1.69+/-0.67m, mass=60.9+/-6.1kg) movement group defined by The Landing Error Scoring System. Participants completed five cycles of high training load exercise of 5-min treadmill-running at a speed coincident with 100-120% ventilatory threshold and 10 jump-landings from a 30-cm box. Jump-landing vertical ground reaction force and serum cortisol were evaluated prior to and following exercise. Vertical ground reaction force ensemble averages and 95% confidence interval waveforms were generated for pre-exercise, post-exercise, and pre-post exercise changes. A two-way mixed model ANOVA was used to evaluate the effect of movement profile on systemic stress before and after exercise. RESULTS: There was no significant difference in changes in serum cortisol between the poor and excellent groups (p=0.69) in response to exercise. Overall, individuals in the poor group exhibited a higher serum cortisol level (p<0.05, d=0.85 [0.19,1.48]). The poor group exhibited higher magnitude vertical ground reaction force prior to (d=1.02 1.26) and after exercise (d=1.15) during a majority of the stance phase. CONCLUSIONS: Individuals with poor movement profiles experience greater mechanical loads compared to individuals with excellent movement profiles. A poor movement profile is associated with greater overall concentrations of circulating cortisol, representative of greater systemic stress. PMID- 29983355 TI - Italian and North American dietary intake after ivacaftor treatment for Cystic Fibrosis Gating Mutations. AB - BACKGROUND: In patients with cystic fibrosis (CF), ivacaftor treatment results in significant weight gain and the impact on diet has not been explored. METHODS: A study in 22 subjects (6.1-61.6 years) compared diet, energy balance, weight gain, and body composition, before and after three months of treatment in Italians and North Americans with CFTR gating mutations. RESULTS: With no differences between groups in energy or macronutrient intake at baseline, fat intake increased in all subjects, and both fat and energy intake increased in Italians. Height, weight, BMI, lean and fat mass, and % body fat increased and resting energy expenditure decreased after treatment. Weight gain was associated with energy and fat intake. CONCLUSIONS: Fat intake increased with treatment, possibly due to the recommendation to take ivacaftor with high fat meals. Increased energy and fat intake correlated with weight gain. Regional dietary patterns differed. PMID- 29983356 TI - Interleukin-6 as a "metabolic hormone". AB - Interleukin 6 (IL-6) is a cytokine that is involved in divers immune responses and implicated in a number of diseases. However, this cytokine has other non immune functions. Within this review, we highlight selected effects on metabolic pathways, which are mediated, controlled or modified by the IL-6. Importantly, putting spotlight on such concepts could allow us to classify IL-6 among the metabolic hormones and further study it to both deepen our knowledge on disorders involving metabolic or energy imbalances such as obesity and develop novel therapeutic strategies. Furthermore, potential explanations related to IL-6 roles in both physiology and pathology as well as relevant implications and applications on both research and therapeutic fields are also pointed as consequences of the involvement of IL-6 in the energy and metabolic homeostasis via its "endocrine" roles. PMID- 29983357 TI - The correlation between serum adipokines levels and metabolic indicators in girls with Turner syndrome. AB - OBJECTIVE: The following study investigated the serum adiponectin, chemerin and vaspin levels and their relationship with body mass index (BMI), glucose and lipid metabolism in girls with Turner Syndrome (TS). METHODS: A total of 64 girls with TS (mean age, 12.22 +/- 3.98 years; mean BMI, 18.90 +/- 3.45 kg/m2) were ascertained by chromosome analysis. Height, weight, waist circumference, hip circumference and blood pressure were measured, as well as the levels of fasting plasma glucose (FPG), fasting plasma insulin, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and triglyceride (TG). The BMI, BMI standard deviation score (SDS), waist to hip ratio, waist to height ratio and insulin resistance index (HOMA-IR) were calculated. The TS group and the control group were subdivided into non-puberty or puberty subgroup. RESULTS: The TS group had higher waist to hip ratio and waist to height ratio compared to the control group. There was no significant difference in FPG, fasting plasma insulin, HOMA IR, blood lipid and blood pressure between the two groups. Significantly higher serum levels of adioponectin (12.51 +/- 4.58 MUg/ml) and chemerin (173.71 +/- 37.88 ng/ml) and significantly lower levels of vaspin (0.67 +/- 0.47 ng/ml) were found in the TS group compared to the control group (9.30 +/- 3.17 MUg/ml, 159.43 +/- 23.19 ng/ml and 1.06 +/- 0.49 ng/ml, respectively) (all P < 0.05). In the TS group, adiponectin levels were negatively correlated with age, BMI and TG (r = 0.251, -0.247, -0.294, P < 0.05 for all). In the control group, adiponectin levels were negatively correlated with BMI and BMI SDS (r = -0.416 and -0.315, P < 0.05 for both), while vaspin levels were positively correlated with age, fasting plasma insulin and HOMA-IR (r = 0.257, 0.273 and 0.282, P < 0.05 for all). In addition, significantly higher levels of adiponectin were found in the non-puberty subgroup (13.88 +/- 4.49) MUg/ml compared to puberty subgroup (9.72 +/- 3.39) MUg/ml (P < 0.05), while no significant differences in chemerin and vaspin were found between the two TS subgroups. CONCLUSIONS: Elevated adiponectin and chemerin levels and significantly reduced vaspin were found in girls with TS. Puberty or estrogen replacement therapy may reduce adiponectin in girls with TS. PMID- 29983358 TI - MMP-12 and S100s in saliva reflect different aspects of periodontal inflammation. AB - Matrix metalloproteinase (MMP)-12, S100A8/A9, and S100A12 are involved in innate immune responses. We addressed whether different aspects of oral health and non disease-related covariates influence their levels in saliva. 436 participants were clinically examined, completed a health questionnaire, and provided stimulated saliva. Salivary levels of MMP-12, S100A8/A9, and S100A12 were determined by enzyme-linked immunosorbent assays. Lower MMP-12 levels were observed in individuals 40-64 years old (yo) compared to < 40 yo, and higher S100A8/A9 levels were found in individuals > 64 yo compared to 40-64 yo. Smokers exhibited lower MMP-12 and S100A12 levels compared to non-smokers. All three proteins were elevated in individuals with bleeding on probing (BOP) > 20% compared to those with BOP <= 20%, and the S100A8/A9 levels were higher in individuals having >= 10% gingival pocket depths (PPD) >= 4 mm compared to the ones with shallow pockets < 4 mm. The extent of alveolar bone loss or presence of manifest caries did not alter any of the markers. MMP-12, S100A8/A9, and S100A12 levels were higher in participants with high periodontal inflammatory burden. All three proteins correlated positively to BOP, PPD, and to several inflammatory mediators. The explanatory variables for MMP-12 in saliva were age, smoking, presence of any tumor, and percentage of PPD >= 4 mm. The determinant of salivary S100A8/A9 was percentage of BOP, while S100A12 levels were associated with percentage of BOP and presence of any tumor. Taken together, MMP-12 and the S100/calgranulin levels in saliva reflect different aspects of periodontal inflammation. Smoking and age should be taken into account in further investigation of these proteins as biomarker candidates of periodontal disease. PMID- 29983359 TI - [Vein of Galen aneurysmal malformation. A case series]. PMID- 29983360 TI - Assessment of Skeletal Muscle Mass in Older People: Comparison Between 2 Anthropometry-Based Methods and Dual-Energy X-ray Absorptiometry. AB - OBJECTIVES: Sarcopenia is a common geriatric syndrome, whose diagnosis implies the assessment of muscle mass. Dual-energy x-ray absorptiometry (DXA) is the reference method for clinical practice, but it is not universally available. We compared DXA with 2 anthropometry-based methods to assess muscle mass in older adults. DESIGN: Cross-sectional. SETTING: Ambulatory patients. PARTICIPANTS: 148 (87 female and 61 male) white older adults. MEASUREMENTS: Mid-arm muscle circumference (MAMC), whole skeletal muscle mass estimated by the Lee's formula (eTSMM), and relative skeletal muscle index (RSMI). RESULTS: Men and women did not differ for MAMC and RSMI, whereas eTSMM was higher (P < .001) in men. MAMC and eTSMM correlated with RSMI, in the whole sample as in men and women separately (P < .001). According to the McNemar test, the frequencies of older men and women with low muscle mass identified by eTSMM did not differ from those detected by RSMI (P = .066) at variance with MAMC. Using EWGSOP (European Working Group on Sarcopenia in Older People) criteria for RSMI as standard reference, the receiver operating characteristic (ROC) curves provided redefined cut-offs of reduced muscle mass: 18.6 cm in women and 22.3 cm in men for MAMC, and 17.7 kg in women and 28.3 kg in men for eTSMM. The areas under the ROC curves (AUCs) for MAMC were 0.882 in women (sensitivity 89%, specificity 84%) and 0.826 in men (sensitivity 94%, specificity 67%). The AUCs for eTSMM were 0.8913 in women (sensitivity 95%, specificity 81%) and 0.878 in men (sensitivity 97%, specificity 67%). No significant difference was found between the ROC curves of MAMC and eTSMM in both sexes. CONCLUSION: Two simple anthropometric methods, possibly used in every clinical setting, could be valuable screening tools for low muscle mass in older subjects. PMID- 29983361 TI - Socioeconomic and Geographic Disparities in Accessing Nursing Homes With High Star Ratings. AB - OBJECTIVES: The Centers for Medicare & Medicaid Services Nursing Home Compare (NHC) serves as the most comprehensive repository of Medicaid- and/or Medicare certified nursing homes providing services to approximately 1.4 million US residents. A gap in the literature exists in understanding on the national level whether residents from socioeconomically disadvantaged counties experience disparities in the access to nursing homes with higher NHC star ratings. The study aimed to examine nursing home quality variations with regard to county level socioeconomic, geographic, and metropolitan status, while adjusting for nursing home facility-level characteristics. DESIGN: Cross-sectional ecological study. SETTING AND PARTICIPANTS: 15,090 Medicaid/Medicare-certified nursing homes with nonmissing star ratings. MEASURES: Study outcomes were NHC overall, health inspection survey, nurse staffing, and quality measure star ratings. County-level measures included SES index, geographic regions, and metropolitan status. Facility-level characteristics included ownership, chain affiliation, type and length of Medicaid/Medicare certification, hospital affiliation, continuing care retirement community status, number of certified beds, and occupancy. RESULTS: Counties with average adjusted overall, nurse staffing, and quality measure star ratings below 3 stars appeared to be clustered in the South. Nursing homes located in counties with lower SES were associated with lower overall star ratings [adjusted mean stars: 3.66 to 3.84, 95% confidence interval (CI): (3.54, 3.79) to (3.73, 3.95)]. A similar pattern was observed in staffing [adjusted mean stars: 3.75 to 4.23, 95% CI: (3.54, 3.97) to (4.10, 4.35)] and quality ratings [adjusted mean stars: 3.29 to 3.52, 95% CI: (3.12, 3.47) to (3.35, 3.69)]. CONCLUSIONS: Residents in socioeconomically disadvantaged counties experience disparities in accessing nursing homes with higher star ratings. These areas may lack sufficient resources to adequately staff the facility and deliver care that meets industry quality standards. These issues are likely to persist and possibly even worsen for the lower- and middle-class geriatric population given the current uncertainty around healthcare reform. PMID- 29983362 TI - The Effect of Xerostomic Medication on Oral Health in Persons With Dementia. AB - OBJECTIVES: Medication-induced hyposalivation can increase the risk for oral complications, including dental caries and tooth loss. This problem is particularly important in people with dementia because of their declining ability to maintain oral care. The objective of this study was to describe the association between the number of xerostomic medications used and tooth loss and restorative and dental preventive treatment in a population of persons with dementia. DESIGN: A longitudinal population-based register study with a 3-year follow-up was conducted. Data were extracted from the Swedish Dementia Registry (SveDem), the Swedish Prescribed Drug Register (SPDR), the Swedish National Patient Register (SNPR), and the Dental Health Register (DHR). SETTING AND PARTICIPANTS: Participants were persons with dementia who were registered in the SveDem at the time of their dementia diagnosis. MEASURES: The exposure was continuous use of xerostomic medications over the 3 years prior to dementia diagnosis (baseline). The outcomes were the incidence of tooth extractions, tooth restorations, and dental preventive procedures. Poisson regression models were used to estimate incidence rate ratios (IRRs) for the association between the exposure and outcomes, adjusting for relevant confounders. RESULTS: A total of 34,037 persons were included in the analysis. A dose-response relationship between the exposure and tooth extractions was observed. Compared with nonusers of xerostomic medication, the rate of tooth extractions increased with increasing number of xerostomic medications used (IRR = 1.03, 1.11, and 1.40 for persons using an average >0-1, >1-3, and >3 xerostomic medications, respectively). However, the risk for having new dental restorations and receiving preventive procedures did not differ between groups. CONCLUSION: Continuous use of xerostomic medications can increase the risk for tooth extraction in people with dementia. This study highlights the importance of careful consideration when prescribing xerostomic medications to people with dementia, and the need for regular and ongoing dental care. PMID- 29983363 TI - Comment on: Laparoscopic sleeve gastrectomy in patients with heart failure and left ventricular assist devices as a bridge to transplant. PMID- 29983364 TI - Donor skin allograft survival after bone marrow transplantation: Case report and systematic review of the literature?. AB - BACKGROUND: We present a case of skin allograft survival in a patient who previously received a bone marrow transplant from the same HLA-matched donor. DNA fingerprinting of skin biopsies showed mixed cellularity originating from the donor and recipient (68% and 32% donor DNA in the allograft skin and the native recipient's skin, respectively). Histologic sections demonstrated both grade 3/4 rejection and graft-versus-host-disease. We have conducted a systematic review in search for other cases of donor skin allograft survival after a bone marrow or hematopoietic stem cell transplantation. METHODS: All reported cases in English, Spanish, French, and German were captured using the electronic databases. Bibliographies of relevant articles were manually searched. RESULTS: Nineteen patients (12 females) who received skin allografts from their bone marrow or hematopoietic stem cell donors were identified. Average age was 27.2 years (range: 5 months to 64 years). Skin allografts were used to treat graft-versus host-disease, Herlitz junctional epidermolysis bullosa, and to test tolerance before a kidney transplantation from the same donor. Eight cases were not receiving immunosuppressive therapy. Allografts survived in all patients. In three patients, skin punch biopsies were taken, and these biopsies demonstrated mixed donor and recipient cellularity. The pathology result is specified in two more cases, with no signs of rejection. CONCLUSIONS: The same donor skin allografts may be a safe option to treat severe cutaneous conditions in recipients of a bone marrow/hematopoietic stem cell transplantation. However, future studies are needed to confirm these results. PMID- 29983365 TI - Comparing transversus abdominus release and anterior component separation techniques in reconstructing midline hernias: A cadaveric study. PMID- 29983366 TI - Diagnostic value and safety of dynamic MRI of contralateral breast and axilla in subjects with tissue expander. AB - INTRODUCTION: To verify the diagnostic value of contrast-enhanced breast and axillary MRI in patients with tissue expander labeled as "MR-unsafe" and to confirm its safety. PATIENTS AND METHODS: Breast MRI examinations performed in patients with tissue expander in the period from August 2010 to December 2017 were reviewed after IRB approval. In the case of breast lesion or lymph node, breast MRI exams after definitive prosthetic replacement were used for comparison. Breast MRI was performed using 1.5 T equipment with a dedicated coil. The protocol included axial STIR sequence and axial dynamic sequence with fat suppression (1 pre-contrast and 4 post-contrast phases). Two radiologists experienced in breast imaging reviewed images using six parameters for image quality evaluation. t-Test for dependent samples, Wilcoxon and Sign test were used. RESULTS: Twenty-three patients (49 +/- 9 years, range 34-68 years) with tissue expander who underwent contrast-enhanced MRI were reviewed. Thirteen breast lesions (12.92 +/- 4.84 mm) and eleven lymph nodes (11.00 +/- 4.29 mm) were found. In breast MRI examinations used for comparison no significant difference was observed in breast lesions (12.69 +/- 4.71 mm, P = 0.707) or lymph node dimensions (10.58 +/- 3.00 mm, P = 0.538). No significant difference was observed in lesion classification. A significantly lower visibility was observed for vascular maps (P < 0.001). None of the patients reported sensations of heating or skin burns. None of the patients revealed any clinical effects or signs of pathology after MRI examination. CONCLUSION: When necessary, after adequate information and preparation, contrast-enhanced breast MRI can be performed in patients with tissue expanders maintaining its diagnostic value and safety. PMID- 29983368 TI - Predisposing factors that increase trigger digit incidence in carpal tunnel syndrome patients: A national, population-based study. PMID- 29983367 TI - Selective non-operative management for penetrating extremity trauma: A paradigm shift in management? AB - BACKGROUND: Selective non-operative management (SNOM) has been proposed as a safe and adequate strategy for penetrating extremity trauma (PET) management. This may reduce unwarranted surgical exploration and enhance cost-effectiveness. Our experience at a UK major trauma centre advocates SNOM-PET as a viable and safe strategy for selected patients. A PET management algorithm is proposed. METHODS: A retrospective review was undertaken for isolated PET from October 2015 to October 2016. Examination findings were recorded as positive if neurovascular or tendon deficits were elicited. Surgical exploration was recorded as positive if neurovascular or tendon injuries were found. Diagnostic statistics were employed for upper limb (UL) and lower limb (LL) examinations. RESULTS: One hundred sixty patients [112 UL and 48 LL PET injuries] were included. Fifty-six out of 112 (50%) patients with UL PET had no examination findings. Twenty-three out of 56 (41%) patients had negative surgical explorations and 33 of 56 (59%) patients had positive surgical explorations. Thirty-four out of 48 patients with LL PET had no examination findings. All 34 patients had negative surgical explorations. The sensitivity (0.61 vs 1.00, p = 0.005), specificity (0.82 vs 0.97, p = 0.043) and negative predictive value (NPV; 0.41 vs 1.00, p < 0.001) were lower for UL PET than for LL PET examinations. There were no statistically significant differences in sensitivity, specificity as well as NPV and positive predictive value between plastic surgery residents and emergency medicine residents for UL and LL examinations. CONCLUSION: This is the first UK evaluation of SNOM-PET. It may be safely utilised for LL PET. UL PET should be surgically explored. SNOM-PET may avoid unwarranted surgical exploration, associated complications and cost. PMID- 29983369 TI - Reply to the Editor: The pedicled internal pudendal artery perforator (PIPAP) flap for ischial pressure sore reconstruction: Technique and long-term outcome of a cohort study. PMID- 29983370 TI - Real-World Treatment Patterns, Overall Survival, and Occurrence and Costs of Adverse Events Associated With Second-Line Therapies for Medicare Patients With Advanced Non-Small-Cell Lung Cancer. AB - INTRODUCTION: Real-world data on current treatment practices for non-small-cell lung cancer (NSCLC) are needed to understand the place in therapy and potential economic impact of newer therapies. PATIENTS AND METHODS: This retrospective cohort study identified patients >= 65 years old in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database with first-time diagnosis of stage IIIB/IV NSCLC from 2007-2011 who received second-line therapy after first-line platinum-based chemotherapy from 2007 through mid-2013. Second line regimens, health care resource use, adverse events (AEs), and associated costs were analyzed descriptively. Overall survival was determined by Kaplan Meier test. Costs were adjusted to 2013 US dollars. RESULTS: We identified 4033 patients with advanced NSCLC who received second-line therapy (47% of those who received first-line platinum-based chemotherapy). Mean (SD) age was 73 (5) years, 2246 (56%) were male; 1134 (28%) and 2899 (72%) had squamous and nonsquamous NSCLC, respectively. The 4 most common second-line regimens were pemetrexed (22%), docetaxel (12%), carboplatin/paclitaxel (11%), and gemcitabine (7%). Median overall survival from second-line therapy initiation was 7.3 months (95% confidence interval, 7.0-7.7). Dyspnea and anemia were the most common AEs of interest, affecting 29% and 26% of patients, respectively; atypical pneumonia was associated with the highest AE-related costs (mean, $5339). The mean total per patient-per-month cost was $10,885; AE-related per-patient-per-month costs totaled $1036 (10%). Costs were highest for pemetrexed-treated patients. CONCLUSION: These real-world data illustrate the variety of second-line regimens, poor prognosis, and high cost of second-line chemotherapy for patients with advanced NSCLC treated before the approval of immunotherapies for these patients. PMID- 29983371 TI - Transient elastography for alcoholic liver disease: a step forward. PMID- 29983372 TI - Non-invasive diagnosis of liver fibrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data meta-analysis. AB - BACKGROUND: The value of transient elastography for the non-invasive diagnosis of alcohol-related liver fibrosis is subject to debate. We did an individual patient data (IPD) meta-analysis to determine specific diagnostic cutoff values for liver stiffness in alcohol-related fibrosis, and to assess the effect of aminotransferase concentrations, bilirubin concentrations, and presence of asymptomatic and non-severe alcoholic hepatitis on liver stiffness. METHODS: We searched for studies that included patients with alcohol-related liver disease, liver biopsy, and transient elastography, and with a statistical method for determining the diagnostic cutoffs for alcohol-induced liver fibrosis on the basis of the FibroScan results, in PubMed between Jan 1, 2000, and Sept 30, 2017. Native data bases were obtained from corresponding authors in an Excel form. Pooled diagnostic cutoffs for the various fibrosis stages were determined in a two-stage, random-effects meta-analysis. The effects of aspartate aminotransferase (AST) concentrations, bilirubin concentrations, and histological features of asymptomatic and non-severe alcoholic hepatitis on liver stiffness cutoff were assessed in one-stage, random-effects meta-analysis. FINDINGS: Of 188 studies assessed, ten studies comprising 1026 patients were included in the meta analysis, yielded liver stiffness cutoffs of 7.0 kPa (area under the receiver operating characteristic curve 0.83 [SE 0.02; 95% CI 0.79-0.87]) for F>=1 fibrosis, 9.0 kPa (0.86 [0.02; 0.82-0.90]) for F>=2, 12.1 kPa (0.90 [0.02; 0.86 0.94]) for F>=3, and 18.6 kPa (0.91 [0.04; 0.83-0.99]) for F=4. AST and bilirubin concentrations had a significant effect on liver stiffness, with higher concentrations associated with higher liver stiffness values (p<0.0001), and with significantly higher cutoff values for diagnosis of all fibrosis stages but F>=1. The presence of histological features of asymptomatic and non-severe alcoholic hepatitis was associated with increased liver stiffness (p<0.0001). In a multivariate analysis, AST (p<0.0001) and bilirubin (p=0.0002) concentrations, and prothrombin activity (p=0.01), were independently associated with the presence of histological features of asymptomatic and non-severe alcoholic hepatitis. Lastly, specific liver stiffness cutoffs were determined on the basis of concentrations of AST and bilirubin. Liver stiffness cutoff values increased in patients with increased AST concentrations, bilirubin concentrations, or both. INTERPRETATION: This IPD meta-analysis highlights the link between liver stiffness and the histological features of asymptomatic and non-severe alcoholic hepatitis, reflected by AST and bilirubin concentrations. In alcohol-related liver disease, FibroScan assessments of liver fibrosis should take into account AST and bilirubin concentrations through the use of specifically adjusted liver stiffness cutoffs. FUNDING: None. PMID- 29983374 TI - Architectural Features of Human Mitochondrial Cysteine Desulfurase Complexes from Crosslinking Mass Spectrometry and Small-Angle X-Ray Scattering. AB - Cysteine desulfurase plays a central role in mitochondrial iron-sulfur cluster biogenesis by generating sulfur through the conversion of L-cysteine to L-alanine and by serving as the platform for assembling other components of the biosynthetic machinery, including ISCU, frataxin, and ferredoxin. The human mitochondrial cysteine desulfurase complex consists of two copies each of NFS1, ISD11, and acyl carrier protein. We describe results from chemical crosslinking coupled with tandem mass spectrometry and small-angle X-ray scattering studies that are consistent with a closed NFS1 dimer rather than an open one for both the cysteine desulfurase-ISCU and cysteine desulfurase-ISCU-frataxin complexes. We present a structural model for the cysteine desulfurase-ISCU-frataxin complex derived from chemical crosslinking restraints in conjunction with the recent crystal structure of the cysteine desulfurase-ISCU-zinc complex and distance constraints from nuclear magnetic resonance. PMID- 29983375 TI - Engineering of a Polydisperse Small Heat-Shock Protein Reveals Conserved Motifs of Oligomer Plasticity. AB - Small heat-shock proteins (sHSPs) are molecular chaperones that bind partially and globally unfolded states of their client proteins. Previously, we discovered that the archaeal Hsp16.5, which forms ordered and symmetric 24-subunit oligomers, can be engineered to transition to an ordered and symmetric 48-subunit oligomer by insertion of a peptide from human HspB1 (Hsp27). Here, we uncovered the existence of an array of oligomeric states (30-38 subunits) that can be populated as a consequence of altering the sequence and length of the inserted peptide. Polydisperse Hsp16.5 oligomers displayed higher affinity to a model client protein consistent with a general mechanism for recognition and binding that involves increased access of the hydrophobic N-terminal region. Our findings, which integrate structural and functional analyses from evolutionarily distant sHSPs, support a model wherein the modular architecture of these proteins encodes motifs of oligomer polydispersity, dissociation, and expansion to achieve functional diversity and regulation. PMID- 29983373 TI - Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. AB - The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase domain in its non phosphorylated state, revealing a fully resolved atypically long activation segment that blocks substrate binding and stabilizes a non-productive position of helix alphaC. Consistent with an auto-inhibitory function, mutations within the activation segment of NDR1 dramatically enhance in vitro kinase activity. Interestingly, NDR1 catalytic activity is further potentiated by MOB1 binding, suggesting that regulation through modulation of the activation segment and by MOB1 binding are mechanistically distinct. Lastly, deleting the auto-inhibitory activation segment of NDR1 causes a marked increase in the association with upstream Hippo pathway components and the Furry scaffold. These findings provide a point of departure for future efforts to explore the cellular functions and the mechanism of NDR1. PMID- 29983376 TI - Description of YESHealth: A consumer-directed intervention in a randomized trial of methods to improve quality of care for persons with disability. AB - BACKGROUND: Persons leading their own evaluations of care quality offers the promise of generating maximally meaningful information to ensure person-centered care. OBJECTIVES: To describe an intervention where persons with disability engage other persons with disability, develop their own metrics to assess their care, and provide these care evaluations directly to primary care practitioners, with the goal of improving care. The context was a research study involving One Care, a Massachusetts demonstration program with capitated reimbursement for individuals ages 18-64 dually eligible for Medicare and Medicaid. METHODS: Individuals with serious mental illness or significant physical disability designed and implemented "YESHealth: Your Experience, Speak up for better health care." To solicit and communicate with YESHealth members, they mailed postcards announcing YESHealth to potential participants, created a website, sponsored a Facebook group, and staffed telephones in English and Spanish. YESHealth also involved reaching out to numerous disability advocacy organizations, developing and conducting short quarterly surveys about quality concerns they identified, and reporting survey results to YESHealth members and their primary care practitioners. RESULTS: Over 12 months, YESHealth staff visited 60 community organizations to recruit participants. Recruiting participants was challenging and ultimately required offering monetary compensation. Participants preferred telephone to online communication. Efforts to engage targeted primary care practitioners had very limited success. CONCLUSIONS: Despite these challenges, YESHealth represents a unique model for consumers' voices to try to affect change in care delivery. A randomized trial has evaluated whether the YESHealth intervention affected care quality for One Care members with disability. PMID- 29983377 TI - A systematic review and meta-analysis on the clinical outcome of zirconia implant restoration complex. AB - PURPOSE: This systematic review evaluates the clinical outcome of zirconia implant-associated survival and success rates, marginal bone loss, and implant restoration complex integrity. STUDY SELECTION: Using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, studies including >=10 patients restored with zirconia implants supporting single crowns (SCs) or fixed dental prostheses (FDPs) prior to January 2017 were identified. Primary outcomes were survival rates and marginal bone loss around one and two piece zirconia implants and the associated implant-restoration complex integrity. RESULTS: 1349 studies were selected; after duplicate removal and title screening, 36 remained for full-text screening. 17 studies met the inclusion criteria: 2 randomized controlled clinical studies, 11 prospective clinical studies and 4 retrospective studies. In total, 1704 implants from 1002 patients were evaluated, including 1521 one-piece and 183 two-piece zirconia implants with follow-up between 1 and 7 years. The mean survival rate was 95% (95% CI 91-97%). The overall mean marginal bone loss was 0.98mm (95% CI 0.79-1.18); the mean marginal bone loss after 1year was 0.89mm (95% CI 0.60-1.18). No meta-analysis regarding prosthetic outcomes was possible. CONCLUSIONS: Survival and marginal bone loss values after one year for one-piece zirconia implants are acceptable, but long term studies are required to support their clinical use. No particular restoration material can be recommended; this decision is apparently based on clinicians' preferences. Results from two-piece implants do not provide sufficient data to support their clinical use and no abutment or cementing materials for two-piece zirconia implants can be recommended. PMID- 29983379 TI - Diagnostic Value of Contrast-Enhanced Spectral Mammography for Screening Breast Cancer: Systematic Review and Meta-analysis. AB - BACKGROUND: Contrast-enhanced spectral mammography (CESM) is a new image examination technology that has developed over the past few years. As CESM technology keeps improving, a current meta-analysis review is needed to systematically evaluate the potential diagnostic value of CESM. METHODS: A total of 18 studies were included in the review. Sensitivity, specificity, and other important parameters of CESM accuracy for breast cancer diagnosis were pooled and analyzed using random-effects models. Summary receiver operating characteristic curves were calculated for overall accuracy estimation. RESULTS: The summary estimates for CESM in the diagnosis of breast cancer were as follows: the pooled sensitivity and specificity were 0.89 (95% confidence interval [CI], 0.88-0.91) and 0.84 (95% CI, 0.82-0.85), respectively. Positive likelihood ratio was 3.73 (95% CI, 2.68-5.20), negative likelihood ratio was 0.10 (95% CI, 0.06-0.15), and diagnostic odds ratio was 71.36 (95% CI, 36.28-140.39). The area under the curve was 0.96 (standard error = 0.011). CONCLUSION: CESM has a high diagnostic accuracy for evaluating breast cancer and can be considered as a useful test for initial assessment of breast lesions. PMID- 29983380 TI - Conservative Management of Positive Axilla After Neoadjuvant Systemic Therapy-The Need for, and Review of, Techniques Used for Lymph Node Localization. AB - Involvement of axillary lymph nodes is an important prognostic factor in relationship to the management of breast cancer. However, the use of neoadjuvant systemic therapy is widespread in the treatment of positive axilla and such treatment leads to downstaging of axillary disease. Hence, the role of targeted axillary lymph node biopsy appears to play a vital role after primary systemic therapy. Given that this is a relatively novel approach, we have discussed the evidence for this approach and the different techniques currently available for localization of biopsy-proven metastatic axillary lymph nodes. We have also highlighted the need for universal guidelines for conservative management of positive axilla after systemic therapy. PMID- 29983378 TI - Influence of polymerization time on properties of dual-curing cements in combination with high translucency monolithic zirconia. AB - PURPOSE: The aim of this in vitro study was to assess conversion degree (DC), micro-hardness (MH) and bond strength of two dual-curing resin cements employed under translucent monolithic zirconia irradiated with different time protocols. METHODS: 84 square shaped samples of 1mm thickness were prepared from high translucency zirconia blocks and divided into two groups (n=24) according to the cement employed: (1) Rely-X Ultimate; (2) Panavia SA. Each group was further divided into 3 subgroups (n=8) according to the irradiation time: (a) no light; (b) 20s; (c) 120s. Light curing was performed 60s after the sample was placed on the diamond support of a FT-IR spectrophotometer with a high power multiLED lamp. Final DC% were calculated after 10min. After 24h, Vickers Test on the cement layer was performed. The same protocol was used to lute composite cylinders in order to evaluate microshear bond-strength test. ANOVA and Bonferroni tests were performed to find differences between MH and bond-strength to zirconia, while for DC% the Scheirer-Ray-Hare two-way test was used. RESULTS: The two cements reached higher DC% in subgroup (b) and (c). As concern MH, statistics showed an increase in curing time was able to improve MH significantly. Bond-strength was not affected by irradiation time only for Panavia SA. CONCLUSIONS: The first null hypothesis has to be rejected since DC% and MH of the dual-cements tested were influenced by the curing time. The second null hypothesis is partially rejected since the bond strength was influenced by the curing time only for Rely-X Ultimate. PMID- 29983381 TI - Buried esophageal adenocarcinoma after radiofrequency ablation. PMID- 29983382 TI - Prognostic Significance of BCL-2 and BCL-6 Expression in MYC-positive DLBCL. AB - BACKGROUND: Double-expression lymphoma (DEL) is a rare subgroup of diffuse large B-cell lymphoma (DLBCL), which has coexpression of MYC and BCL-2. Coexpression of MYC and BCL-2 is considered a prognostic marker portending poor outcomes. However, the prognostic effect of BCL-2 and BCL-6 expression in DLBCL remains controversial. MATERIALS AND METHODS: Immunohistochemical staining was performed to detect MYC, BCL-2 and BCL-6 expression in 212 patients with newly diagnosed DLBCL and assess the prognostic effects of BCL-2 and BCL-6 expression. The DLBCL patients were treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone)-like regimens. RESULTS: Retrospective analysis revealed that BCL-2+ and BCL-2+/MYC+ were prognostic factors indicative of poor outcomes. Patients with BCL-2+ and/or MYC+ expression had a poorer prognosis than that of patients with BCL-2- and/or MYC- expression. Patients with BCL-2+/MYC- expression showed a trend toward poorer survival than those with BCL-2-/MYC+ expression, suggesting that BCL-2 plays a more important role than MYC. Also, patients with BCL-6-/MYC+ expression had poorer progression-free survival than those with BCL-6+/MYC+ expression. In addition, patients with BCL-2+/MYC+/BCL-6- expression had the worst prognosis, suggesting that BCL-6- is a prognostic factor for poor outcomes for MYC+ DLBCL patients. Altogether, our findings have shown that BCL-2 is an independent prognostic factor and possibly plays a more important role than MYC in MYC+ DLBCL patients. Furthermore, we found that BCL-6- expression could also be a prognostic factor portending poor outcomes for MYC+ DLBCL patients. PMID- 29983383 TI - Role of testing standards in smoke-free product assessments. AB - Testing standards for tobacco and related products are an important basis for product science-based regulation. The recent emergence and rapid growth of products offering an alternative to continued smoking for adult smokers who would otherwise continue to smoke, urgently calls for the establishment of quality and assessment standards relevant for these products. The two main categories of products under consideration are electronic cigarettes and heated tobacco products, which both deliver nicotine in the aerosol that is not smoke, because tobacco is not burned in the process, and in particular no solid particles are generated as a result. In the case of electronic cigarettes the need for new testing and product standards is well recognized and relevant initiatives are underway, whereas no testing standards specific for heated tobacco products are currently under development. In the present manuscript, a critical review of the applicability of existing testing standards - which were mainly developed for cigarettes, is provided, and a framework approach is proposed toward developing relevant testing standards to be able to compare aerosol yields across different product categories (cigarettes, e-cigarettes, heated tobacco products). PMID- 29983384 TI - Development of nutritional risk assessment platform in Korea. AB - Risk assessment has been used to prevent health problems associated with eating habits in response to increased interest in a balanced diet. For nutritional risk assessment (NRA), it is important to 1) consider personal nutrition status based on year-round dietary intake, 2) organize core datasets such as food composition, intake, and health based guidance value (HBGV) datasets with public confidence, and 3) assess and predict the effects by using the computerized NRA tool. Our research staff constructed an integrated database system by compiling and organizing core datasets produced sporadically by different organizations and with different formats and developed a nutritional exposure and risk assessment system called Nutri-Risk (NUTRItional RISK assessment platform), which contained the database. Nutri-Risk is not only capable of NRA, but also contains additional data service functions. Here, the compilations and organization of an integrated database are outlined. In addition, the overall architectures of Nutri-Risk and dietary modeling are described and predictive simulation functions to support the regulatory decisions related to nutritional fortification or reduction policy were demonstrated. PMID- 29983385 TI - An hPSC-Derived Tissue-Resident Macrophage Model Reveals Differential Responses of Macrophages to ZIKV and DENV Infection. AB - Zika virus (ZIKV) and dengue virus (DENV) are two closely related flaviviruses that lead to different clinical outcomes. The mechanism for the distinct pathogenesis of ZIKV and DENV is poorly understood. Here, we investigate ZIKV and DENV infection of macrophages using a human pluripotent stem cell (hPSC)-derived macrophage model and discover key virus-specific responses. ZIKV and DENV productively infect hPSC-derived macrophages. DENV, but not ZIKV, infection of macrophages strongly activates macrophage migration inhibitory factor (MIF) secretion and decreases macrophage migration. Neutralization of MIF leads to improved migratory ability of DENV-infected macrophages. In contrast, ZIKV infected macrophages exhibit prolonged migration and express low levels of pro inflammatory cytokines and chemokines. Mechanistically, ZIKV disrupts the nuclear factor kappaB (NF-kappaB)-MIF positive feedback loop by inhibiting the NF-kappaB signaling pathway. Our results demonstrate the utility of hPSC-derived macrophages in infectious disease modeling and suggest that the distinct impact of ZIKV and DENV on macrophage immune response may underlie different pathogenesis of Zika and dengue diseases. PMID- 29983386 TI - Distinct Molecular Signatures of Quiescent and Activated Adult Neural Stem Cells Reveal Specific Interactions with Their Microenvironment. AB - Deciphering the mechanisms that regulate the quiescence of adult neural stem cells (NSCs) is crucial for the development of therapeutic strategies based on the stimulation of their endogenous regenerative potential in the damaged brain. We show that LeXbright cells sorted from the adult mouse subventricular zone exhibit all the characteristic features of quiescent NSCs. Indeed, they constitute a subpopulation of slowly dividing cells that is able to enter the cell cycle to regenerate the irradiated niche. Comparative transcriptomic analyses showed that they express hallmarks of NSCs but display a distinct molecular signature from activated NSCs (LeX+EGFR+ cells). Particularly, numerous membrane receptors are expressed on quiescent NSCs. We further revealed a different expression pattern of Syndecan-1 between quiescent and activated NSCs and demonstrated its role in the proliferation of activated NSCs. Our data highlight the central role of the stem cell microenvironment in the regulation of quiescence in adult neurogenic niches. PMID- 29983387 TI - An Immune System-Modified Rat Model for Human Stem Cell Transplantation Research. AB - Due to its lack of both innate and acquired immune responses to human cells, the NODSCIDIl2rgamma-/- (NSG) mouse model has become an important tool for human stem cell research. When compared with the mouse, the rat is physiologically more similar to humans and offers advantages in preclinical efficacy studies on human stem cells, particularly in evaluating neural, hepatic, and cardiac functions. Therefore, we generated a human SIRPalpha+Prdkc-/-Il2rgamma-/- rat model, denoted NSG-like (NSGL) rat, which expresses human SIRPalpha and is abolished in the development of B, T, and natural killer cells. When compared with Prdkc-/ Il2rgamma-/- (SG) rats, NSGL rats allow more efficient engraftment of human cancer cells and human pluripotent stem cells. In addition, only NSGL rats, but not SG rats, can be engrafted with human hematopoietic stem cells to reconstitute the human immune system. Therefore, NSGL rats represent an improved xenotransplantation model for efficacy studies of human stem cells. PMID- 29983388 TI - FGF2 Induces Migration of Human Bone Marrow Stromal Cells by Increasing Core Fucosylations on N-Glycans of Integrins. AB - Since hundreds of clinical trials are investigating the use of multipotent stromal cells (MSCs) for therapeutic purposes, effective delivery of the cells to target tissues is critical. We have found an unexplored mechanism, by which basic fibroblast growth factor (FGF2) induces expression of fucosyltransferase 8 (FUT8) to increase core fucosylations of N-linked glycans of membrane-associated proteins, including several integrin subunits. Gain- and loss-of-function experiments show that FUT8 is both necessary and sufficient to induce migration of MSCs. Silencing FUT8 also affects migration of MSCs in zebrafish embryos and a murine bone fracture model. Finally, we use in silico modeling to show that core fucosylations restrict the degrees of freedom of glycans on the integrin's surface, hence stabilizing glycans on a specific position. Altogether, we show a mechanism whereby FGF2 promotes migration of MSCs by modifying N-glycans. This work may help improve delivery of MSCs in therapeutic settings. PMID- 29983390 TI - High detection rate and genetic diversity of picobirnavirus in a sheep flock in Brazil. AB - This study reports the detection by RT-PCR and molecular characterization of partial RdRp gene of picobirnavirus (PBV) dsRNA in fecal samples (n = 100) from a meat sheep flock in southern Brazil. The analysis of the results allowed the identification of two important characteristics of PBV infection. The first was the high frequency of infection in the sheep flock evaluated where 62% of the analyzed fecal samples were PBV-positive. The second was the high genetic variability found in field strains of ovine PBV genogroup I circulating in animals of the same sheep flock. PMID- 29983389 TI - Status of KRAS in iPSCs Impacts upon Self-Renewal and Differentiation Propensity. AB - Oncogenic KRAS mutations in hematopoietic stem cells cause RAS-associated autoimmune lymphoproliferative syndrome-like disease (RALD). KRAS plays essential roles in stemness maintenance in some types of stem cells. However, its roles in pluripotent stem cells (PSCs) are poorly understood. Here, we investigated the roles of KRAS on stemness in the context of induced PSCs (iPSCs). We used KRAS mutant (G13C/WT) and wild-type isogenic (WT/WT) iPSCs from the same RALD patients, as well as wild-type (WTed/WT) and heterozygous knockout (Deltaed/WT) iPSCs, both obtained by genome editing from the same G13C/WT clone. Compared with WT iPSCs, G13C/WT iPSCs displayed enforced retention of self-renewal and suppressed capacity for neuronal differentiation, while Deltaed/WT iPSCs showed normalized cellular characteristics similar to those of isogenic WTed/WT cells. The KRAS-ERK pathway, but not the KRAS-PI3K pathway, was shown to govern these G13C/WT-specific phenotypes, indicating the strong impact of the KRAS-ERK signaling upon self-renewal and differentiation propensity in human iPSCs. PMID- 29983391 TI - Reconsolidation of human motor memory: From boundary conditions to behavioral interventions-How far are we from clinical applications? AB - The memory reconsolidation hypothesis states that a previously consolidated and stable memory can return to a temporary labile state after retrieved, requiring a new stabilization process. During the labile period, the memory trace is vulnerable to modification, which provides a potential therapeutic opportunity to weaken, updated or strengthen that memory. As such, reconsolidation has been the subject of numerous studies in different domains of human memory that seek strategies to treat post-traumatic disorders and erase or modify pathological memories. A few studies have also investigated the impairment effects of behavioral interferences on motor memory. However, very little has been researched and written about the possibility of using reconsolidation to enhance motor skill learning. Here, we present a critical review of the literature and trace possible applications for human motor memory reconsolidation. We discuss the boundary conditions and the mechanisms to trigger the reconsolidation process, as well as the effects of behavioral interventions in modifying the performance of motor skills. PMID- 29983392 TI - Disturbances of postural sway components in cannabis users. AB - INTRODUCTION: A prominent effect of acute cannabis use is impaired motor coordination and driving performance. However, few studies have evaluated balance in chronic cannabis users, even though density of the CB1 receptor, which mediates the psychoactive effects of cannabis, is extremely high in brain regions critically involved in this fundamental behavior. The present study measured postural sway in regular cannabis users and used rambling and trembling analysis to quantify the integrity of central and peripheral nervous system contributions to the sway signal. METHODS: Postural sway was measured in 42 regular cannabis users (CB group) and 36 non-cannabis users (N-CB group) by asking participants to stand as still as possible on a force platform in the presence and absence of motor and sensory challenges. Center of pressure (COP) path length was measured, and the COP signal was decomposed into rambling and trembling components. Exploratory correlational analyses were conducted between sway variables, cannabis use history, and neurocognitive function. RESULTS: The CB group had significantly increased path length and increased trembling in the anterior posterior (AP) direction. Exploratory correlational analyses suggested that AP rambling was significantly inversely associated with visuo-motor processing speed. DISCUSSION: Regular cannabis use is associated with increased postural sway, and this appears to be predominantly due to the trembling component, which is believed to reflect the peripheral nervous system's contribution to the sway signal. PMID- 29983393 TI - Defining the plateau point: When are further attempts futile in out-of-hospital advanced airway management? AB - BACKGROUND: We sought to characterize the number of attempts required to achieve advanced airway management (AAM) success. METHODS: Using 4 years of data from a national EMS electronic health record system, we examined the following subsets of attempted AAM: 1) cardiac arrest intubation (CA-ETI), 2) non-arrest medical intubation (MED-ETI), 3) non-arrest trauma intubation (TRA-ETI), 4) rapid sequence intubation (RSI), 5) sedation-assisted ETI (SAI), and 6) supraglottic airway (SGA). We determined the first pass and overall success rates, as well as the point of additional attempt futility ("plateau point"). RESULTS: Among 57,209 patients there were 64,291 AAM. CA-ETI performance was: first-pass success (FPS) 71.4% (95% CI: 70.9-71.9%), 4 attempts to reach 91.5% (91.2-91.9%) success plateau. MED-ETI performance was: FPS 66.0% (95% CI: 65.1-67.0%), 3 attempts to reach 79.2% (78.4-80.0%) success plateau. TRA-ETI performance was: FPS 61.6% (95% CI: 59.3-63.9%), 3 attempts to reach 75.8% (73.7-77.8%) success plateau. RSI performance was: FPS 76.1% (95% CI: 75.1-77.1%), 5 attempts to reach 95.8% (95.3 96.2%) success plateau. SAI performance was: FPS 66.9% (95% CI: 65.1-68.6%), 3 attempts to 85.3% (83.9-86.6%) success plateau. SGA performance was: FPS 88.7% (95% CI: 88.0-89.3%), 5 attempts to reach 92.8% (92.3-93.4%) success plateau. CONCLUSION: Multiple attempts are often needed to accomplish successful AAM. The number of attempts needed to accomplish AAM varies with AAM technique. These results may guide AAM practices. PMID- 29983394 TI - Repeated mild shaking of neonates induces transient cerebral microhemorrhages and anxiety-related behavior in adult rats. AB - Growing evidence suggests that neonatal cerebral microhemorrhages (MHs) are implicated in neuropsychiatric diseases in adults. Although animal studies have identified the progression of the underlying mechanisms of MHs, few studies have investigated the histopathology and behavioral outcomes. In this study, we created an experimental rat model of MHs using a new experimental device for repeated mild shaking brain injury (SBI) in the neonatal period and examined temporal changes in MHs using susceptibility weighted imaging (SWI) and iron histochemistry. SWI demonstrated transient MHs in the gray matter of the cerebral cortex and hippocampus in injured rats. Iron histochemical staining demonstrated leakage of iron and iron-positive cells surrounding MHs. This staining pattern lasted for a long time and continued after disappearance of hemorrhagic signals on SWI. These data suggested the presence of iron-associated gray matter injury after MHs. In the open field test, these injured rats showed anxiety-related behavior as adults. This model may be useful for exploring the underlying mechanisms of changes that occur after MHs and the behavioral outcomes of repeated mild SBI in early development. PMID- 29983395 TI - CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS. AB - Chronic immune activation and systemic inflammation are underlying causes of acquired immunodeficiency syndrome (AIDS). Products of virus replication and microbial translocation, co-infection or opportunistic pathogens, and danger associated molecular patterns have been reported to contribute to chronic immune activation and inflammation in human immunodeficiency virus type-1/simian immunodeficiency virus (HIV-1/SIV) infection or other disease. To develop new strategies and therapies for HIV-1/AIDS, we tested if the CD24 and Fc fusion protein (CD24Fc), which interacts with danger-associated molecular patterns and sialic acid binding Ig-like lectin to attenuate inflammation, can protect Chinese rhesus macaques (ChRMs) with SIV infection. We found that CD24Fc treatment decreased weight loss, wasting syndrome, intractable diarrhea, and AIDS morbidity and mortality, while it was well tolerated by SIV-infected animals. Corresponding to the elimination of intractable diarrhea, CD24Fc significantly reduced the expression of IL-6 and indoleamine 2, 3-dioxygenase-1 in peripheral blood mononuclear cell and inflammation in the ileum, colon and rectum based on the reduction of inflammatory cells, pathological scores and expression of inflammatory cytokines. Furthermore, although CD24Fc did not restore CD4+ T cell number or significantly change T cell subsets or CD4+ T cell activation, it maintained low levels of plasma soluble CD14, CD8+ T cell activation, viral load and proviral load in the peripheral blood mononuclear cells and marrow. These results suggested that CD24Fc confers protection to SIV-infected ChRMs against progression to AIDS. It was also implied that CD24Fc may be a potential therapeutic approach for the control of HIV-1/AIDS. PMID- 29983396 TI - Considerations in preparing for clinical studies of inhaled rifampicin to enhance tuberculosis treatment. AB - Drug delivery via the inhaled route has advantages for treating local and systemic diseases. Pulmonary drug delivery may have potential in treating tuberculosis (TB), which is mainly localised in the lung (pulmonary tuberculosis ~75%) while also affecting other organs (extra-pulmonary tuberculosis). Currently, rifampicin, a first-line anti-tubercular drug, is given orally and the maximum daily oral dose is the lesser of 10 mg/kg or 600 mg. Since only a small fraction of this dose is available in the lung, concentrations may frequently fail to reach bactericidal levels, and therefore, contribute to the development of multi-drug resistant pulmonary TB. Pulmonary delivery of rifampicin, either alone or in addition to the standard oral dose, has the potential to achieve a high concentration of rifampicin in the lung at a relatively low administered dose that is sufficient to kill bacteria and reduce the development of drug resistance. As yet, no clinical study in humans has reported the pharmacokinetics or the efficacy of pulmonary delivery of rifampicin for TB. This review discusses the opportunities and challenges of rifampicin delivery via the inhaled route and important considerations for future clinical studies on high dose inhaled rifampicin are illustrated. PMID- 29983397 TI - Multitargeted kinase inhibitors imatinib, sorafenib and sunitinib perturb energy metabolism and cause cytotoxicity to cultured C2C12 skeletal muscle derived myotubes. AB - Tyrosine kinase inhibitors (TKIs) have advanced cancer treatment and prognosis but have also resulted in adverse effects such as fatigue, diarrhea, hypothyroidism, and other toxicities. We investigated TKI effects on skeletal muscle as a possible explanation of TKI induced fatigue. Changes in mitochondrial function due to inhibition of oxidative phosphorylation complexes, generation of superoxides, and inhibition of key transporters involved in uptake of glucose and/or nucleosides may result in alteration of energy metabolism and/or mitochondrial function. We investigated effects of imatinib, sorafenib and sunitinib on these processes in cultured C2C12 murine skeletal muscle cells. Imatinib, sorafenib and sunitinib were cytotoxic to C2C12 cells with IC50 values of 20, 8 and 8 uM, respectively. Imatinib stimulated glucose uptake and inhibited complex V activity by 35% at 50 uM. Sorafenib inhibited complex II/III and V with IC50 values of 32 and 28 uM, respectively. Sorafenib caused activation of caspase 3/7 and depolarization of mitochondrial membranes occurred very rapidly with complete loss at 5-10 uM. Sunitinib inhibited Complex I with an IC50 value of 38 uM and caused ATP depletion, caspase 3/7 activation, an increase in reactive oxygen species (ROS), and decreased nucleoside and glucose uptake. In conclusion, imatinib, sunitinib and sorafenib caused changes in mitochondrial complex activities, glucose and nucleoside uptake leading to decreased energy production and mitochondrial function in a skeletal muscle cell model, suggesting that these changes may play a role in fatigue, one of the most common adverse effects of TKIs. PMID- 29983398 TI - Level of NO/nitrite and 3-nitrotyrosine in seminal plasma of infertile men: Correlation with sperm number, motility and morphology. AB - Nitric oxide (NO) is a signaling molecule responsible for initiation of molecular events that influence sperm functionality in a concentration-dependent manner. It is still not fully understood how seminal plasma NO contributes to sperm pathologies. The aim of this study was to elucidate whether and how NO is implicated in etiology of different sperm abnormalities. To this end we determine NO, nitrite and 3-nitrotyrosine (3-NT) content in seminal plasma of infertile men with specific pathologies (terato-, oligoterato- and oligoasthenoteratospermia) and relate it to infertile normospermic samples. To gain further understanding of NO metabolism in seminal plasma we determine protein expression of endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Here we show that NO, nitrite and 3-NT levels in seminal plasma of men with suboptimal semen parameters are significantly lower compared to normospermic men. An increase in protein expression of eNOS and no change in protein expression of iNOS is observed in men with sperm pathologies. Association of seminal plasma 3 NT level with functional sperm parameters is observed - positive correlation with sperm count, motility and morphology in normospermia, teratospermia and oligoteratospermia, as well as negative correlation with sperm morphology and motility in oligoasthenoteratospermia. Present study revealed that suboptimal seminal plasma NO content is found in all examined sperm pathologies. This result unequivocally shows the importance of NO for sperm function and involvement of suboptimal NO level in etiology of sperm abnormalities. Lower seminal plasma 3-NT level and its significant association with sperm parameters, found in pathologies, strongly indicates that protein nitration is important for spermatozoa function and that failure to establish this post-translational protein modification might be involved in etiology of sperm abnormalities. According to our results, NO measurement can discriminate infertile men with sperm pathologies from infertile normospermic men but is not indicative of a specific type of sperm pathology. PMID- 29983399 TI - The essential role of hypothalamic paraventricular nucleus nNOS in the modulation of autonomic control in exercised rats. AB - Nitric oxide (NO), an intercellular signaling molecule is relevant for circulatory autonomic control. Brain NO synthase (NOS) and NO levels were downregulated in pathological conditions, but rescued after exercise training. We hypothesized that exercise training was also able to improve NO modulation within the hypothalamic paraventricular nucleus (PVN) of healthy rats. Male Wistar rats were submitted to two 4-weeks protocols: i) swimming training (T) or kept sedentary (S), ii) l-arginine (62,5 mg/mL, 1 mL/day p. o.) or vehicle supplementation. Rats underwent stereotaxic surgery (PVN bilateral guide cannulas) and chronic catheterization of artery/vein. Arterial pressure (AP), heart rate (HR) and baroreflex sensitivity were recorded in conscious rats at rest and following a selective nNOS inhibitor (Nw-Propyl-l-Arginine, 4 nmol/100 nL) within the PVN. Rats were deeply anesthetized for brain perfusion/harvesting after respiratory arrest. In separate groups (T and S, l-arginine and Vehicle supplemented) not submitted to PVN cannulation, fresh and fixed brains were obtained for gene and protein nNOS expression (qPCR and immunohistochemistry) and nitrite levels (Griess reaction). T and l-arginine treatment were accompanied by resting bradycardia, augmented parasympathetic and reduced sympathetic activity to heart and vessels (power spectral analysis) and increased baroreflex sensitivity (?P < 0.05). In contrast, PVN nNOS inhibition blocked/attenuated these effects in addition to significantly increase in resting MAP and HR (with larger effects in T and l-arginine treated rats vs. respective controls, ?P < 0.05). T increased nNOS gene and protein expression within the ventromedial and posterior PVN nuclei (?P < 0.05). PVN nitirite levels were also increased in T and l-arginine groups (?P < 0.05). Data strongly suggest that training by increasing NO availability within PVN preautonomic nuclei favors both the slow down of sympathetic and the augmentation of parasympathetic activity and facilitates baroreflex control, therefore improving autonomic regulation of the heart in healthy rats. PMID- 29983400 TI - Gender differences in the relationships between chronic kidney disease, asymmetric dimethylarginine, and sleep quality: The HEIJO-KYO cohort. AB - The association between chronic kidney disease (CKD), serum levels of asymmetric dimethylarginine (ADMA), and sleep quality has not been studied in large populations. In this cross-sectional study of 1115 elderly individuals (mean age, 71.9 years), we measured serum levels of ADMA, and objective and subjective sleep quality using actigraphy and a standardized self-reported questionnaire, respectively. Multivariable analysis adjusted for potential confounders revealed that in females, compared with the non-CKD/low-ADMA group (n=312), sleep efficiency was significantly lower in the CKD/high-ADMA group (n=52) by 3.5% for objective sleep quality [95% confidence interval (CI), 1.1-5.9] and by 4.2% (95% CI, 0.3-8.0) for subjective sleep quality but not in the non-CKD/high-ADMA (n=179) and CKD/low-ADMA (n=36) groups. In males, no significant associations between CKD, ADMA levels, and sleep quality were observed. Wake time after sleep onset was significantly longer by 11.3 min (95% CI, 3.0-19.6) for objective sleep quality and by 25.9 min (95% CI, 4.9-46.9) for subjective sleep quality in the CKD/high-ADMA group than in the non-CKD/low-ADMA group in females but not in males. Mediation analysis revealed a significant effect of serum ADMA levels on the association between renal function and parameters of sleep quality among females. In conclusions, both objective and subjective sleep quality were poorer in elderly females with CKD/high-ADMA than in those with non-CKD/low-ADMA, but not in males. Association between CKD and sleep disturbances might be mediated by ADMA levels. PMID- 29983401 TI - Demodicidosis Accompanying Acute Cutaneous Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation PMID- 29983402 TI - Does minimally invasive surgery reduce anxiety? AB - Objective: To evaluate whether there were any differences in preoperative and postoperative anxiety in patients who underwent total laparoscopic hysterectomy (TLH) (n=37) and total abdominal hysterectomy (TAH) (n=37). Material and Methods: All premenopausal patients who underwent TLH or TAH because of benign uterine disorders were enrolled. Anxiety status was assessed 6 hours before and after the operation using standardized validated questionnaires: State-Trait Anxiety Inventory. Results: In the TAH group, the state anxiety level of the patients significantly increased, whereas there was a significant decrease in the TLH group. For the trait anxiety level, there was a statistically significant increase in the TAH group postoperatively. In the TLH group, trait anxiety levels decreased postoperatively. In the analysis of between-group differences, pre and postoperative the state anxiety level was higher in the TAH group. A statistically significant difference was determined between the groups in respect of the postoperative state anxiety levels (p<0.05), but not in the preoperative state anxiety levels (p>0.05). Statistically significant differences were determined between the groups in respect of education, occupation, and curettage rates (p<0.05). Conclusion: Women undergoing TLH for benign uterine disease may have lower levels of preoperative and postoperative anxiety than women undergoing TAH. PMID- 29983403 TI - Light chain myeloma with highly atypical plasma cells and extensive Auer rod-like inclusions. PMID- 29983404 TI - Skeletal Muscle Diffuse Large B-Cell Lymphoma in the Gluteal Region PMID- 29983405 TI - Congress report of the 23rd AGE annual meeting from 26th - 28th April 2018 in Hamburg AB - The Study Group of Gynecological Endoscopy (AGE) has a growing number of members each year. This is an acknowledgment as well as a challenge for the study group. The challenges were faced in the form of exemplary cooperative work by the core members of AGE, the Velen Study Group for Ambulant Surgery (VAAO), the Foundation of Endometriosis Research (SEF), the Study Group of Urogynecology and Plastic Pelvic Floor Reconstruction (AGUB), the Study Group for Robotic-assisted Surgery in Gynecology (ARCGyn), and the Study Group of Gynecological Oncology (AGO). More than 1500 AGE members have been able to create significant effects preemptively by designing a Congress program that was prepared interactively. The program of live surgery was designed in the course of two days on the basis of an online inquiry. The first transmission of laparoscopy on a body donor and anatomic demonstrations on formalin-fixed specimens were especially significant in this context. Sessions of general gynecology, including myoma therapy, endometriosis and infertility treatment, and gynecologic oncology and urogynecology covered the entire spectrum of minimally invasive surgical techniques. Individual topics were addressed in specific courses. The Congress was preceded by an optional certified basic course (MIC I) of the AGE. Far more than 500 congress attendees from all German-speaking countries were spirited away to a paramedical steep face, which was ascended together with a renowned German extreme climber. The keynote lecture was especially impressive and held by the pioneer and founder of the neuropelveology. The world's leading expert in this field described the responsibilities of our specialty in a visionary manner and motivated all of the listeners strongly in regard of their actions and efforts. PMID- 29983406 TI - Recent Progress in Pathology and Genetics of Pilocytic and Pilomyxoid Astrocytomas. AB - Pilocytic and Pilomyxoid Astrocytomas constitute one of the most common gliomas in children and young adults, and are considered indolent neoplasms with long overall survival probability. The genetic characteristics of these neoplasms have been well characterized, and the deeper understanding of molecular alterations has led to novel treatment strategies and approaches. Currently, we can account for some of the unusual behavior of these neoplasms such as oncogene-induced senescence and associated spontaneous regression, anaplastic transformation and cerebrospinal dissemination. However, there are still enigmatic issues with these tumors that are often considered "chronic diseases". We review the classical and less common clinical pathological and genetic features of these indolent gliomas. PMID- 29983407 TI - Early Direct Antiglobulin Test Negativity after Bendamustine and Rituximab Treatment in Chronic Lymphocytic Leukemia: Two Cases PMID- 29983408 TI - A Novel Mutation In A Child With Atypical Wiskott-Aldrich Syndrome Complicated by Cytomegalovirus Infection. PMID- 29983409 TI - Origin and Efficacy of Hyaluronan Injections in Knee Osteoarthritis: Randomized, Double-Blind Trial. AB - BACKGROUND Several hyaluronan preparations are available that have different dosage forms, origins, and concentrations. The objective of the study was to compare the efficacy of intra-articular chemically cross-linked hyaluronan (CCH) and avian-derived hyaluronan (ADH) injections in knee osteoarthritis (KOA) patients. MATERIAL AND METHODS In total, 258 patients were randomized into 2 groups of 129 each: patients who received CCH injection (CCH group) and patients who received ADH injection (ADH group). Radiographic Kellgren-Lawrence score, visual analog scale (VAS) pain score, Lequesne index score, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, single-limb stance (SLS) test, and timed "Up-and-Go" (TUG) test were performed. The Mann-Whitney U test or independent t-test following Bonferroni adjustment was performed for statistical analysis at 95% of confidence level. RESULTS The CCH group had improved VAS pain score (P<0.0001, q=54.803), total WOMAC score (P<0.0001, q=4.753), Lequesne index score (P<0.0001, q=3.208), and SLS time (P<0.0001, q=8.76) at the end of 6 months as compared to those in the ADH group. After 6 months of follow-up, the ADH group had improved TUG time (P=0.0148, q=3.385) as compared to baseline. Both groups of patients had the similar improvement in Kellgren-Lawrence score and mild to moderate adverse effects after 6 months. CONCLUSIONS CCH injection was superior to ADH injection. PMID- 29983410 TI - A Fatal Case of Non-Uremic Calciphylaxis: A Case Report and Literature Review. AB - BACKGROUND Calciphylaxis is a rare cutaneous disease, also known as calcific uremic arteriolopathy, that occurs most frequently in patients with advanced chronic kidney disease and on long-term hemodialysis. CASE REPORT We describe the case of a 61-year-old female patient with worsening chronic kidney disease not on dialysis therapy, who presented with severe progressive calciphylaxis on both lower limbs. CONCLUSIONS Calcific uremic arteriolopathy is a rare fatal condition that requires prompt diagnosis and treatment. It is classically described in patients with end-stage kidney disease on long-term renal replacement therapy but can present in patients with an earlier stage of kidney disease. Non-uremic calciphylaxis should be suspected in patients with earlier stages of kidney disease, especially in those with other concurrent risk factors or co-morbid conditions, to avoid the high risk of morbidity and mortality associated with such cases. PMID- 29983411 TI - Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. AB - BACKGROUND: Rituximab, a monoclonal antibody targeting B lymphocytes, effectively sustains remission in steroid-dependent nephrotic syndrome (SDNS). We studied its effects on lymphocyte subsets and urinary CD80 excretion (uCD80) in patients with SDNS. METHODS: Blood and urine samples were collected from 18 SDNS patients before rituximab, and after 1 month and 1 year or at first relapse. T and B lymphocytes and uCD80 were determined by flow cytometry and ELISA, respectively. RESULTS: Treatment was associated with reduction in counts of Th17, Th2, and memory T cells, and increased T-regulatory (Treg) cells. The Th17/Treg ratio declined from baseline (median 0.6) to 1 month (0.2, P = 0.006) and increased during relapse (0.3, P = 0.016). Ratios of Th1/Th2 cells at baseline, 1 month after rituximab, and during relapse were 7.7, 14.0 (P = 0.0102), and 8.7, respectively. uCD80 decreased 1 month following rituximab (45.5 vs. 23.0 ng/g creatinine; P = 0.0039). B lymphocytes recovered earlier in relapsers (60.0 vs.183.0 days; P < 0.001). Memory B cells were higher during relapse than remission (29.7 vs.18.0 cells/uL; P = 0.029). CONCLUSION: Rituximab-induced sustained remission and B-cell depletion was associated with reduced numbers of Th17 and Th2 lymphocytes, and increased Treg cells; these changes reversed during relapses. Recovery of B cells and memory B cells predicted the occurrence of a relapse. PMID- 29983412 TI - Improving pharmaceutical trials for children: a call to the pediatric academic community. PMID- 29983413 TI - Increased right ventricular power and ductal characteristic impedance underpin higher pulmonary arterial blood flow after betamethasone therapy in fetal lambs. AB - BACKGROUND: The glucocorticosteroid betamethasone is routinely administered prior to anticipated preterm birth to enhance lung maturation. While betamethasone also increases fetal pulmonary blood flow and reduces pulmonary vascular resistance (PVR), we investigated whether alterations in right ventricular (RV) function and ductal characteristic impedance (Zc) additionally contributed to rises in pulmonary flow. METHODS: Anesthetized preterm fetal lambs with (n = 10) or without (n = 8) betamethasone pretreatment were instrumented with a pulmonary trunk micromanometer and ductus arteriosus and left pulmonary artery (PA) flow probes to calculate Zc, and obtain RV output and hydraulic power. RESULTS: Betamethasone (1) increased systolic and pulse arterial pressures (P <= 0.04), heart rate (P = 0.02), and lowered PVR (P = 0.04), (2) increased mean (P = 0.008) and systolic (P = 0.004), but not diastolic PA flow or PA Zc, (3) increased ductal Zc (P < 0.05), but not ductal flow, (4) increased RV output (P = 0.03) and the proportion of PT flow distributed to the lungs (P = 0.02), and (5) increased RV power (P <= 0.002). CONCLUSION: An increased fetal PA blood flow after betamethasone therapy was confined to the systole and underpinned not only by decreased PVR, but also greater RV power and preferential distribution of an augmented RV systolic outflow to the lungs due to higher ductal Zc. PMID- 29983414 TI - Caffeine: an evidence-based success story in VLBW pharmacotherapy. AB - Apnea of prematurity (AOP) is a common and pervasive problem in very low birth weight infants. Methylxanthines were reported >40 years ago to be an effective therapy and, by the early 2000s, caffeine had become the preferred methylxanthine because of its wide therapeutic index, excellent bioavailability, and longer half life. A clinical trial to address unresolved questions and toxicity concerns, completed in 2004, confirmed significant benefits of caffeine therapy, including shorter duration of intubation and respiratory support, reduced incidence of chronic lung disease, decreased need for treatment of patent ductus arteriosus, reduced severity of retinopathy of prematurity, and improved motor and visual function. Cohort studies have now further delineated the benefits of initiation of therapy before 3 days postnatal age, and of higher maintenance doses to achieve incremental beneficial effects. This review summarizes the pivotal and in particular the most recent studies that have established the safety and efficacy of caffeine therapy for AOP and other respiratory and neurodevelopmental outcomes. Caffeine has a very favorable benefit-to-risk ratio, and has become one of the most prescribed and cost-effective pharmacotherapies in the NICU. PMID- 29983415 TI - The relationship between parental locus of control and adolescent obesity: a longitudinal pre-birth cohort. AB - OBJECTIVES: To investigate whether parental external locus of control (ELOC) measured in pregnancy is related to obesity in their adolescent offspring and whether the child's own ELOC measured at age 8 contributes. To determine whether associations are due to types of behaviour used by externally oriented participants. SUBJECTS/METHODS: Longitudinal pre-birth cohort study (Avon Longitudinal Study of Parents & Children (ALSPAC)) set in south-west England. Families whose adolescent offspring had their fat mass measured using DXA scans at any of ages 9, 11, 13, 15 or 17 (range, n = 7329 at 9 to n = 4850 at 17). The primary outcome measures were mean fat mass, and obesity measured as >=85th centile of fat mass at each age. RESULTS: We found that parent and child externality was associated with greater fat mass [e.g., mean difference at age 15 associated with maternal ELOC was 1.70 kg (+1.17, +2.24), paternal ELOC 1.49 kg (+0.89, +2.09) and child's ELOC 1.50 kg (+0.93, +2.06) (P < 0.0001)]. Further analyses showed that factors associated with parent behaviour such as smoking in pregnancy, failure to breast feed, and early introduction of solids accounted for a third of the excess fat mass associated with maternal externality, whereas aspects of diet and energetic activity in later childhood were not. Further analyses demonstrated that the child's own ELOC only became independently important for adolescent obesity from age 13, whereas the mothers' and to a lesser extent the fathers' ELOC were associated at each age. CONCLUSIONS: There is increased interest in determining factors that may be involved in the aetiology and maintenance of excessive weight in adolescents. We demonstrate that parental locus of control is a promising candidate. We suggest interventions to change parents' locus of control towards internality in pregnancy might have long term preventative benefits on the likelihood of obesity in the offspring. PMID- 29983417 TI - Prolonged antepartum hospitalization: no time for rest. AB - OBJECTIVE: To characterize sleep patterns among pregnant women undergoing prolonged antepartum hospitalization. STUDY DESIGN: We conducted a prospective cohort study of women undergoing prolonged antepartum hospitalization after 20 weeks' gestation. Women were recruited to wear an Actigraph, complete a sleep log for 7 consecutive days, and complete a sleep survey at the end of the study period. Actigraphy was used to determine rest and sleep intervals, sleep onset latency, and wake time after sleep onset. RESULTS: A total of 40 participants were recruited, and 28 had >= 5 nights of data for a total of 177 nights of antepartum sleep data. Mean gestational age was 30 weeks. Median sleep duration was 7.05 h +/- 1.71 h. In all, 43.5% of women had an average sleep duration of <7 h per night. In all, 28.2% of the study nights had a bedtime between midnight and 5 am. Going to bed between midnight and 5 am was significantly associated with sleep durations of <7 h (70.7 vs. 32.5%, p < .001). Participants reported an average of 2.4 awakenings per night due to hospital-related events. CONCLUSIONS: Prolonged antepartum hospitalization has a negative impact on sleep duration and quality. PMID- 29983416 TI - p38 MAPK pathway and its interaction with TRF2 in cisplatin induced chemotherapeutic response in head and neck cancer. AB - TRF2 is a telomere binding protein, a component of the shelterin complex that plays a major role in maintaining the integrity of the genome. TRF2 is over expressed in a number of human cancers including Head and Neck cancer and might play a key role in tumor initiation and development. p38 MAPK signaling pathway is strongly activated in response to various environmental and cellular stresses and thus overexpressed in most of the Head and Neck cancer cases. In this study, we investigated potential interactions of TRF2 with p38 in HNSCC cells and patient samples. Using in silico experiments, we identified interface polar residue Asp-354 of p38 and Arg-492, Arg-496 of TRF2 as protein-protein interaction hotspots. In addition to these interactions, Arg-49 residue of p38 was also found to interact with Glu-456 of TRF2. A detailed understanding of how phosphorylated and unphosphorylated state of p38 protein can influence the stability, specificity and to some extent a conformational change of p38-TRF2 binding is presented. Silencing of TRF2 significantly decreased the phosphorylation of p38 in HNSCC cells which was confirmed by western blot, immunofluorescence and co-immunoprecipitation and alternatively inhibiting p38 using p38 inhibitor (SB 203580) decreased the expression of TRF2 in HNSCC cells. Furthermore, we checked the effect of TRF2 silencing and p38 inhibition in cisplatin induced chemosensitivity of SCC-131 cells. TRF2 silencing and p38 inhibition chemosensitize HNSCC cells to cisplatin. Thus, targeting TRF2 in combinatorial therapeutics can be a treatment modality for Head and Neck cancer which involves inhibition of p38 MAPK pathway. PMID- 29983418 TI - Serum exosomes contain ECRG4 mRNA that suppresses tumor growth via inhibition of genes involved in inflammation, cell proliferation, and angiogenesis. AB - Esophageal cancer related gene-4 (Ecrg4) has been shown to be a tumor suppressor in many organs. Exosomes are naturally secreted nanosized particles that carry signal molecules including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) among others. Upon internalization, exosomes unload their cargos that in turn modulate the biology of the recipient cells. Mounting evidence has shown that exosomal miRNAs are functional. However, reports that exosomes carry functional mRNAs remain scarce. We found that serum exosomes contain ECRG4 open reading frame. To simulate serum exosomal ECRG4, stable cell line expressing ECRG4 was created, from which exosomes were isolated and characterized, and the internalization and the resulting biological effects of exosomal ECRG4 were evaluated. Results showed that serum exosomes contain higher levels of ECRG4 mRNA in healthy individuals than their cancer counterparts. Exosomal ECRG4 can be internalized and unload the encapsulated ECRG4 into recipient cells, which subsequently suppressed cell proliferation in vitro, and inhibited tumor growth in a xenograft mouse model. Mechanistically, ECRG4 containing exosomes, when internalized, suppressed the expression of genes commonly implicated in inflammation, cell proliferation, and angiogenesis. Given that exosome is an ideal vehicle for therapeutics delivery and that ECRG4 is a tumor suppressor gene, the exosomal ECRG4 can be exploited as a formulation for cancer gene therapy. PMID- 29983419 TI - Correction: Hyperbaric oxygen can induce angiogenesis and recover erectile function. AB - This has been corrected in both the PDF and HTML versions of the Article. PMID- 29983420 TI - Need of National Indexing System: Challenges and Way Forward. AB - NA. PMID- 29983421 TI - Tuberculosis and Diabetes Mellitus Comorbidity among the Ageing Population: A Threat to the Public Health System of Nepal. AB - Ageing population is attributable to the growing trend of diabetes mellitus. Diabetic patients are three times greater risk of developing tuberculosis. The review aims to describe the state of tuberculosis and diabetes mellitus comorbidity, risk factors for the comorbidity from the perspective of the ageing in Nepal. It is a systematic narrative review of literature in Google Scholar and Pubmed. At first, title and abstract of an article was reviewed for relevance, and then full article was reviewed for validity. The secondary data was retrieved from the Central Bureau of Statistics of Nepal and WHO, and analysed in the Ms Excel. In Nepal, the population is ageing. The risk factors associated with diabetes are escalating. On the other hand, tuberculosis is endemic and about 45% of the Nepalese people are infected with tuberculosis bacteria. These circumstances have laid the foundation that fosters tuberculosis and diabetes co epidemic in the future. The clinical management of patients with the comorbid condition is a difficult task because diabetes and tuberculosis interact with each other, one worsening the other. The upsurge of the co-morbidity needs the provision of more health services threatening the public health system of Nepal. It is fundamental to create a mechanism to integrate diabetes and tuberculosis program such as screening, diagnosis and management of the both diseases at the all levels of health service delivery. Furthermore, increase awareness of healthy lifestyle and the prevention of the risk factors for tuberculosis and diabetes could reduce the occurrence of the comorbidity in the future. PMID- 29983422 TI - Price Variation and Availability of Free Medicine for Non-communicable Diseases. AB - BACKGROUND: Nepal is witnessing rise in non-communicable chronic diseases. Costs of the medicine, availability of the medicine for free in public health sectors and variation of price of medicines may play an important role in the management of chronic disease. The study was undertaken to find out the variation in price of drugs used for treating non communicable diseases among private pharmacies and availability of free essential medicines in public facilities. METHODS: Randomly selected 33 public health centers and 13 pharmacies were included for the study. Availability of free essential medicines for treating selected chronic diseases was assessed in public health centers and percentage price variation in various branded drugs used for treating these diseases was assessed at the consumer level. RESULTS: Out of 89 different formulations, variations between maximum and minimum priced brands of more than 100% were observed in 37 formulations and that of > 200% in 22 formulations. Thirty-seven formulations had more than 100% inter pharmacy variation. The most commonly available free essential medicines was 4 mg salbutamol (88.57%) while the least available free essential drug was levothyroxine 5 mg (9.0%). CONCLUSIONS: Considerable variation in prices is seen among similar drugs and in prices of same drug in different pharmacies. These factors may have implications in the management of chronic disease in Nepal offsetting the government's effort to control chronic diseases. PMID- 29983423 TI - Barriers to Dietary Salt Reduction among Hypertensive Patients. AB - BACKGROUND: Despite knowing the ill consequences of high salt intake, many hypertensive patients in Nepal continue to consume high levels of salt in their diet. Hence, this study aims to reveal the barriers to dietary salt reduction among hypertensive patients in Nepal. METHODS: A barrier analysis was conducted in the outpatient department of Sahid Gangalal National Heart Center, Nepal among 180 hypertensive patients under physician advice to reduce salt in their diet. A logistic regression modeling was used to calculate odds ratios (ORs) for the barriers. RESULTS: Low self-efficacy (OR=0.04; 95%CI: 0.01-0.24) was a significant barrier to dietary salt reduction among study participants, as well as lack of taste (23.3% Compliant vs. 53.3% Non-Compliant) and lack of family support (5.6% compliant vs. 27.8% noncompliant).Difficulty in remembering to eat low salt (OR=3.89; 95%CI: 1.28-11.87) was a barrier for males. There were differences seen by gender in barriers: among female participants, low perceived social acceptability (OR=0.05; 95%CI: 0.01-0.32), and living in a joint rather than nuclear family (OR=0.21; 95%CI: 0.06-0.77) were significant barriers to dietary salt reduction. Presence of a son (7.8% Compliant vs.30.0% Non-Compliant) and/or husband (1.1% Compliant vs. 11.1% Non-Compliant) had an influence on females' decisions to reduce salt. CONCLUSIONS: Perceived self-efficacy, reminder to action, social acceptability, and family structure were barriers to dietary salt reduction among hypertensive patients in Nepal. Presence of a son and/or husband had an influence on females' decisions to reduce salt. Addressing the modifiable barriers identified in this study is important for successful salt reduction initiatives in Nepal. The inclusion of a son and/or husband in nutritional counseling may be beneficial to achieve salt reduction in this population. PMID- 29983424 TI - Scenario of Neonatal Respiratory Distress in Tertiary Hospital. AB - BACKGROUND: Respiratory distress is one of the most common reasons for admission in Neonatal Intensive Care Unit. However, studies of newborn admitted with respiratory distress in our setup are limited. This study aims to look for incidence of neonatal respiratory distress in our setup, to analyze the common causes of respiratory distress and to determine possible strategic plan needed for better clinical outcome. METHODS: A cross sectional study was conducted from March 2013 to December 2014 in Nepal Medical College and Teaching Hospital. Data of all the neonates with respiratory distress admitted during this period were analyzed. RESULTS: Total 317 (13.4%) neonates were admitted to Neonatal Intensive Care Unit during the study period.109 neonates developed respiratory distress comprising 34.3% of all Neonatal Intensive Care Unit admissions. Incidence of neonatal respiratory distress was 4.6%. The common causes of respiratory distress in our study were meconium aspiration syndrome in 21.1%, septicemia in 16.5%, transient tachypnea of newborn in 15.5%, pneumonia in 14.6%, birth asphyxia and hyaline membrane disease were in each 11.9% of the neonates. Caesarean section was the most common predisposing factor associated with the development of transient tachypnea of newborn in 82.3% newborns (p=.001). The overall mortality rate due to respiratory distress was 12.8%. CONCLUSIONS: Meconium aspiration syndrome, septicemia and hyaline membrane disease are the most important causes of respiratory distress in our setup. Good obstetric care, proper training of health care personnel in neonatal resuscitation and early recognition of potential risk factors of respiratory distress will be helpful. PMID- 29983425 TI - Antibacterial and Antifungal Property of Actinomycetes Isolates from Soil and Water of Nepal. AB - BACKGROUND: Human pathogens are rapidly acquiring resistance to antibiotics leading to treatment failure. We carried out this study to isolate and screen actinomycetes strains that have potential to kill bacterial and fungal pathogens. METHODS: In this descriptive study 288 soil and water samples were processed by standard microbiological techniques at Central Department of Microbiology,Tribhuvan University from 2013 to 2015. Screened actinomycetes were cultivated for bioactive metabolite production and minimum inhibitory concentration (MIC) of metabolites were determined against bacterial pathogens including multidrug resistant bacteria and fungi. RESULTS: One hundred twenty isolates having antimicrobial property were screened. Out of them, four most potent strains, Nocardiopsis prasina, Streptomyces violarus, Streptomyces krainskii and Streptomyces tsusimaensis were identified all having both antibacterial and anti-fungal property.Highest zone of inhibition (ZOI)was given by N. prasina against Candida albicans(41.33 +/-1.15mm) and among bacteria, maximum ZOI was against Acinetobacter baumannii(31.33+/-3.05mm). MIC value of metabolite of N.prasina was 0.125mg/ml for E.coli and C. albicans. It was 2.5 mg/ml each for methicillin resistant Staphylococcus aureus (MRSA), A. baumannii and Salmonella Typhi and 0.625 mg/ml for Bacillus Subtilis. CONCLUSIONS: Bioactive metabolite producing actinomycetes were recovered from soil and tested against human pathogenic bacteria and fungiand found to have antibacterial and antifungal property. PMID- 29983426 TI - Attitude of Treating Psychiatrist Towards Personality Disorder. AB - BACKGROUND: Worldwide mental health professionals have negative attitude towards personality disorder. Aim of this study was to assess the attitudes toward personality disorder among Nepalese psychiatrists. METHODS: A cross-sectional survey study was done. Survey questionnaire was developed which consisted of 10 questions to explore the feeling and views regarding personality disorder. It was distributed via e-mail to 80 registered psychiatrist who were randomly selected and responses were analyzed. RESULTS: Results showed only 50% of psychiatrist assessed for personality disorders whereas only 55.6% diagnosed it. Cluster 'B'personality disorders were most commonly diagnosed personality disorder, 36.1% felt helpless for those patients, 75% felt overall treatment for personality disorder was very difficult and 50% reported they were not competent to care for personality disorder patients. CONCLUSIONS: Nepalese psychiatrists were not optimistic towards personality disorder in terms of its recognition, diagnosis and its overall management. Thus, future researches are needed to explore such attitudes in depth in same population. PMID- 29983427 TI - Barrett's Esophagus in Patients with Gastroesophageal Reflux Disease. AB - BACKGROUND: Barrett's esophagus a is metaplasia of normal squamous cells that line the lower part of the esophagus and carries a major risk for adenocarcinoma of esophagus. In Asian population, the prevalence of Barrett's esophagus and adenocarcinoma are less common than in Western countries but has been increasing. METHODS: This is a hospital based descriptive study comprising of 120 consecutive patients with symptoms of gastroesophagial reflux disease belonging to both sexes of any age group. The diagnosis of gastroesophagial reflux disease was based on the symptoms like heart burn and regurgitation. Upper gastrointestinal endoscopy was done in all the patients. Four quadrant biopsies were taken from the esophagogastric junction in suspected case of Barrett's esophagus. The diagnosis of Barrett's esophagus was confirmed histopathologically. RESULTS: There were 44.2% males and 55.8% females, age ranging from 22 to 85 years mean being 44.33+13.37. Of them, gastroesophagial reflux disease was mild in 54.16%, moderate in 21.16% and severe in 16.66%. Upper Gastrointestinal endoscopy revealed non erosive gastroesophagial reflux disease in 50%, erosive in 45%, hiatal hernias in 5% and Barrett's esophagus in 1.6%. Both patients with Barrett's esophagus were elderly and had short segment (<3cm) involvement with no evidence of dysplasia or adenocarcinoma histopathologically. CONCLUSIONS: Endoscopic surveillance with detailed inspection and systematic biopsies is recommended for most patients with Barrett's esophagus. Esophageal carcinoma if detected should be treated at the earliest. PMID- 29983428 TI - Assesssment of Health Facilities for Implementation of Non-communicable Disease Package. AB - BACKGROUND: Non-communicable Diseases are an alarming public health emergency in Nepal. Owing to the risk of NCD's in Nepal, Government of Nepal has developed a Multisectoral Action Plan for Non-communicable Disease 2014-2020 and has adopted the World Health Organization Package of Essential Non-communicable Disease protocol. Prior for its implementation in Nepal, baseline study has been carried out to assess the status of health facilities in Nepal. METHODS: A descriptive cross-sectional study was carried out in Kailali and Ilam district encompassing a total of 92 health facilities. A set of structured questionnaire and interview guideline was used to obtain the data. Collected data was transferred to Microsoft Excel, cleaned and analyzed in SPSS 16.0. Descriptive analysis was performed to express the frequencies and relative frequencies Results: Of the total health facilities, 49 and 43 health facilities of Ilam and Kailali were interviewed. The hospital of Ilam consisted all the procedure, equipment and medicine for the management of NCDs whilst, health posts lacked Oxygen services. Only 592 posts were fulfilled out of 704 sanctioned post in both the districts of which only 161 were trained in management of NCDs. Atotal of 231 patients were diagnosed with NCDs before the day of study in all the health facilities of both districts. CONCLUSIONS: Study reveals the gaps in capacity of health institution and system in terms of training, supply, equipments, and diagnostics. However, training of health workers, supply of essential medicines and improvising the service delivery would supplement the effective implementation of PEN in Nepal. PMID- 29983429 TI - Work Related Injury among Welders Working in Metal Workshops of Dharan Municipality, Nepal. AB - BACKGROUND: Injuries are a problem worldwide in all occupations. Welders are exposed to many hazards at work resulting in a variety of health problems including injuries at work. This study was conducted to find out the prevalence and factors associated with injuries among welders in Dharan city of eastern Nepal. METHODS: A cross sectional study was conducted among 86 welders in Dharan city. Occurrence of injury in past 2 weeks and past 12 months were recorded. Data regarding sociodemographic along with occupational characteristics was collected using semi structured questionnaire. Data analysis was done using SPSS version 17. RESULTS: All the welders in this study were male with almost half of the welders under the age of 25 years and about a fifth (21.1%) of the welders having received some form of welding training. In the past 12 months, 21.1% of the welders suffered from work related injuries. More than 95% welders used at least one personal protective equipment in this study. More injuries were seen among welders with age ?35 years, working experience ? 5 years, not received training and not using of PPE at work. However, these factors were not found to be statistically significant. CONCLUSIONS: Work related injuries are high among welders of Dharan. Further research is required to explore the relationship between age, literacy, training and use of personal protective equipment with the occurrence of injuries among the welders. PMID- 29983430 TI - Situation of Water, Sanitation and Hygiene and Diarrhoeal Diseases After Open Defecation Free Declaration. AB - BACKGROUND: Makwanpur district was declared Open Defecation Free in 2013 as the movement started in Nepal since 2003 to address the high burden of diarrhoeal disease among under five children. As the water supply, sanitation and hygiene situation of the district is not known after the declaration, the need for this study was visualized. METHODS: It was a cross sectional study among randomly sampled 178 households using interview and observation. Water, sanitation and hygiene situation was assessed in terms of related facilities, knowledge and practices of mothers. Results were compared with the standard open defecation free criteria of Nepal. Five years trend of diarrhoeal disease was analysed from the health facility records to assess the impact of declaration. RESULTS: Of the total households 92% had toilets and 90% had access to improved water source. About 79% mothers had high knowledge on safe water, sanitation and hygiene and 43% practiced hand washing with soap at critical times. Proper disposal of solid and liquid waste was found among 32% and 46% of households respectively. About 68% of households had good water, sanitation and hygiene situation and was found to be significantly associated with related knowledge among mothers irrespective of their economic status. Diarrhoeal disease among under five children was found declining after open defecation free declaration. CONCLUSIONS: Water, sanitation and hygiene status in the study area is found lower than the criteria for open defecation free declaration. However, diarrhoeal disease among children under five is declining after the declaration. PMID- 29983431 TI - Management and Outcome of Severe Sepsis and Septic Shock Patients. AB - BACKGROUND: Severe sepsis and septic shock are major causes of morbidity and mortality worldwide and need immediate medical attention. Early recognition, fluid resuscitation and early antimicrobials are the mainstays of sepsis therapy. This study analyzed the management strategies of severe sepsis and septic shock and evaluated its impact. METHODS: A prospective study was conducted on patients admitted through emergency department of Tribhuvan University Teaching Hospital of Nepal, who were diagnosed with severe sepsis and septic shock. RESULTS: A total of 85 patients were diagnosed as severe sepsis and septic shock with 45 female patients and mean age 47.69 years ranging from 18 to 83 years. Pneumonia (45.9%) was found to be the major source of infection. The most commonly prescribed antibiotics and vassopressor at emergency department were ceftriaxone (24.7%) and norepinephrine (44.7%) respectively. The mean length of stay in Emergency department was 13.01 +/- 7.03 h, while it was 11.27 +/- 5.26 days in hospital. A total of 31 (36.5%) septic patients died. Deceased patients were found to have greater age, higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score and presence of co-morbid conditions. CONCLUSIONS: This study looked in-depth on management and outcome of patients with severe sepsis and septic shock. Mortality from severe sepsis and septic shock were high, but similar to other studies. PMID- 29983432 TI - Prevalence of Methicillin Resistant Staphylococcus aureus and Antibiotic Susceptibility Pattern in a Tertiary Hospital in Nepal. AB - BACKGROUND: Methicillin resistant Staphylococcus aureus is a global health challenge nowadays creating problem in antibiotic therapy. This study was aimed to generate resistance pattern of Methicillin resistant Staphylococcus aureus to various antibiotics in order to formulate antibiotic policy for control of Methicillin resistant Staphylococcus aureus in Nepal. METHODS: This was a cross sectional study conducted at the department of Clinical Microbiology, Nepal Medical College Teaching Hospital, from April 2015 to March 2016. A total of 142 S. aureus isolated from various clinical specimens. were screened for Methicillin resistant Staphylococcus aureus by cefoxitin disc method according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Out of 142 S. aureus isolates, 30 (21.1%) were detected as Methicillin resistant Staphylococcus aureus by cefoxitin disc method. Most of the Methicillin resistant Staphylococcus aureus (25/30) were isolated from pus which were collected from OPD patients. Antibiotic sensitivity pattern showed all Methicillin resistant Staphylococcus aureus isolates were sensitive to vancomycin. CONCLUSIONS: Prevalence of Methicillin resistant Staphylococcus aureus was found to be 21.1%, and all Methicillin resistant Staphylococcus aureus appear 100% sensitive to vancomycin. PMID- 29983433 TI - Atherogenic Index of Plasma in Postmenopausal Women. AB - BACKGROUND: Hyperlipidemia is one of the important risk factor for development of cardiovascular disease in post menopausal women.Our study compared the serum lipid profile and atherogenic index of plasma between premenopausal and post menopausal women. METHODS: This was a cross sectional study conducted in Kathmandu Medical College. A total number of 194 women in the age group 30 to 60 years were studied. They include 108 postmenopausal women and 86 premenopausal controls. Total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides were determined. RESULTS: The mean value of total cholesterol, low-density lipoprotein cholesterol and triglyceride were significantly increased in postmenopausal women when compared to premenopausal women. There was increase in high-density lipoprotein cholesterol in postmenopausal women but the difference was not significant. The atherogenic index of plasma was increased in postmenopausal women (0.22 +/- 0.25 mmol/l). This shows that postmenopausal women in our setting are at medium risk of developing cardiovascular disease. Atherogenic index of plasma was positively and significantly correlated with age (r= 0.29, p<0.05), body mass index (r=0.24, p<0.05), systolic blood pressure (r=0.20, p<0.05) and diastolic blood pressure (r=0.45, p<0.05). CONCLUSIONS: Postmenopausal women were at greater risk for developing cardiovascular disease when compared to premenopausal women due to increase in atherogenic lipid profile. There was a significant correlation of atherogenic index of plasma with age, body mass index, systolic blood pressure and diastolic blood pressure. PMID- 29983434 TI - Biofilm Production and Antimicrobial Resistance among Uropathogens in Pediatric Cases: a Hospital Based Study. AB - BACKGROUND: The study was designed to provide account of etiological agents of urinary tract infection in pediatric patients and the antimicrobial resistance pattern plus biofilm producing profile of the isolates. METHODS: The prospective study was conducted in Alka Hospital, Nepal with 353 clean catch urine samples from children. It was obtained during July 2014 to January 2015 which were first cultured by semi-quantitative method, followed by antimicrobial susceptibility testing and biofilm production assay on Congo red agar. Multidrug- resistance, extensively drug- resistance and pandrug- resistance among isolates were considered as per international consensus. RESULTS: Out of 353 samples, 64 (18.13%) showed positive growth in culture, confirming urinary tract infection. E. coli, 44 (68.8%) was the predominant organism followed by Klebsiella spp. 6 (14.1%). Most E. coli were sensitive to amikacin (93.2%) followed by nitrofurantoin (86.4%), and highly resistant to ampicillin (95.5%). Of 64 isolates, 23 (35.93%) were found to be multidrug- resistant strains. Biofilm was produced by 36 (56.25%) isolates. CONCLUSIONS: This study showed higher biofilm production and resistance to in-use antibiotics rendering ineffective for empirical use. Regular surveillance of resistance patterns should be done to regulate multidrug- resistant bugs and to ensure effective management of urinary tract infection in children in a tertiary care setups. PMID- 29983435 TI - Perceived Burden in Caregivers of Children with Autism Spectrum Disorder. AB - BACKGROUND: Autism Spectrum Disorder is a lifelong developmental disorder that affects children and results in deficit in social interaction, communication and display of unusual pattern of behavior. Though caregiving is a normal parental duty, providing intensive care to a child with long-term problem is burdensome and impacts both physical and mental health of caregivers. The aim of this study was to obtain a picture of burden among caregivers raising children with Autism Spectrum Disorder. METHODS: We conducted a descriptive cross-sectional study to assess the burden of caregiving among sixty one parents of children with Autism Spectrum Disorder in the Kathmandu Valley, Nepal, using purposive sampling technique. The burden perceived by caregivers was assessed using standard tool Zarit Burden Interview-22. RESULTS: Average burden score was 41.49+/-12.25 which indicates that caregivers experienced moderate to severe range of burden. Level of education, anxiety and depression was found to be significantly associated with burden of caregiving. CONCLUSIONS: The study concluded that the burden of caregiving is most remarkably associated with emotional status and social life of the caregivers. PMID- 29983436 TI - Complications among Mothers and New Born Due to Delivery Process in Rupandehi District Nepal. AB - BACKGROUND: Child birth is a universally celebrated occasion, yet everyday for thousands of women child birth is experienced not as a joyful event as it should be, but as a private hell that may even end in death. The objective of this study is to determine the complications of normal delivery and cesarean section on the mothers and new born. METHODS: A descriptive study was conducted in two selected hospitals of Rupandehi district, Nepal. Data was collected as per pretested structured proforma from 550 respondents who were the mothers and new born delivered normally and through cesarean section randomly till the completion of sample size and analyzed by using SPSS, MANOVA and Chi-square test to determine associations between categorical variables. RESULTS: In a total of 550 deliveries,25.8% were cesarean delivery, 42.7% motherssuffered from delivery related complications, common were PPH (21.1%), prolonged labour (8.5%) and wound infection (7.6%). 35.5% of newborn had complications, common were respiratory distress (6.3%) and neonatal jaundice (4.2%). CONCLUSIONS: Delivery related complications were higher among Lower segment cesarean section compared to vaginal delivery in mothers and newborn. PMID- 29983437 TI - Anxiety and Depression among Pregnant Women and Mothers of Children Under one Year in Sindupalchowk District. AB - BACKGROUND: Common mental disorders such as anxiety and depression among mothers of young children and expectants can silently deteriorate the health of the mother with significant impact on the newborn. The primary aims were to determine the proportion of pregnant women and mothers of children under one year with anxiety and depression and their associated factors in Sindhupalchowk. METHODS: We used the Hopkins Symptom Checklist 25 and a structured questionnaire in a cross-sectional study to collect information from 778 women (164 pregnant women, 614 mothers of children under one year) selected through multi-stage sampling. RESULTS: Among pregnant women, the study found that 21.3%(95%CI:15.7-28.3) had anxiety and 23.8% (95%CI:17.8-31.0) had depression. Being from the Dalit ethnic group was independently associated with anxiety and depression. Among mothers of children under one year, 18.7% (95%CI:15.7-22.1) had anxiety and 15.2% (95%CI:12.4-18.4) had depression. Among these women, low education level; primary source of family income being agriculture, animal husbandry or labour; history of unplanned pregnancy; and use of tobacco were independently associated with anxiety and history of unplanned pregnancy and use of tobacco were independently associated with depression. CONCLUSIONS: A substantial proportion of women had anxiety and depression with higher odds of anxiety and depression in certain group of women. Targeted health system interventions are needed for improving the psychological well being of women, including pregnant women, as well as newborn health and wellbeing. PMID- 29983438 TI - Obesity and Its Risk Factors of among School Children in Sylhet, Bangladesh. AB - BACKGROUND: Childhood obesity is found in affluent society, less physical activity and changes in food pattern. This study was designed to see prevalence and risk factors of childhood obesity among school children of Sylhet city. METHODS: Students of class five and six of two schools of Sylhet city were randomly selected. Demographic and anthropometric data were collected and recorded in predesigned data sheet. BMI and percentile were calculated using official centre for disease control growth chart for 2 to 20 years. Logistic regression analysis was done to see association of various factors with childhood obesity. P value of ?0.05 was taken as significant. RESULTS: Total 288 children were included in this study. Age varied from 10 to 14 years. Among them 5.6% and 8.7% were found to be obese and overweight respectively. Obesity was significantly higher among girls (6.8% vs3.6%).Prevalence of obesity and overweight (p=0.001) was more among those who spent less time in physical exercise and outdoor games. Food habit, television watching, computer gaming and duration of sleep were not found as significant predictor of obesity. CONCLUSIONS: Obesity was significantly higher among girls (6.8% vs3.6%). Girls with less physical activity were mainly associated with overweight and obesity. PMID- 29983439 TI - Maternal Attitude and Knowledge towards Modes of Delivery. AB - BACKGROUND: Whether a mother should be allowed to choose between the modes of delivery is a matter of concern among practicing obstetricians. This study aims to explore the knowledge of the Nepalese women attending a tertiary care center about the benefits and complications of vaginal and caesarean delivery and their attitude and preference for the method of delivery. METHODS: The study was a hospital based cross sectional questionnaire survey conducted in Nepal Medical College teaching Hospital, Jorpati from 1stShrawan 2074 to 31st Ashoj 2074. All pregnant women who were 36 weeks or more in gestation attending the clinic during the study period were included in the study. A questionnaire was made of 10 questions for knowledge assessment regarding mode of delivery consisting of the indications, the possible complications and advantages of vaginal and caesarean delivery. RESULTS: A total of 256 pregnant women participated in the study. The knowledge of the mode of delivery, their benefit and complications was medium to good in approximately 90% of the mothers attending the antenatal OPD. Overall attitude for vaginal delivery was positive in 93% of women and negative or neutral in 6.6%.Overall attitude for caesarean delivery was positive in 24% and negative or neutral in 75.8%. CONCLUSIONS: Women in our setup agree that vaginal delivery is a natural and acceptable method of delivery and would prefer to have a vaginal delivery. PMID- 29983440 TI - Tobacco Use among Health Professional Students in Chitwan, Nepal. AB - BACKGROUND: Health professional students play a critical role in tobacco control by providing services, advocating for policies and serving as role models for social change. This study aimed to estimate the prevalence of tobacco use and determine the attitude and behavior regarding tobacco use among health professional students. METHODS: A cross-sectional study was conducted among third year medical, dental, nursing and pharmacy undergraduates using GHPSS questionnaire. RESULTS: A total of 16.3% students were current cigarette smokers. 33.2% students had ever smoked cigarettes, and 57.0% had smoked first cigarettes during adolescence life. Cigarette smoking consumption was higher than the use of other tobacco products like chewing tobacco, snuff, bidis, hookah, cigar or pipes and. 10.0%students were current users of other tobacco products.22.1%students had ever used other tobacco products.31.6% were exposed to second-hand smoke at home and 48.9% were exposed to second-hand smoke at public places. CONCLUSIONS: The prevalence of smoking and exposure to second-hand was high among medical students. Medical educators should consider revising the medical curricula to focus on tobacco cessation training/counseling in medical schools. PMID- 29983441 TI - Correlation of Hormonal Profile and Lipid Levels with Female Adult Acne in a Tertiary Care Center of Nepal. AB - BACKGROUND: Acne beyond 25 years of age is frequently associated with hormonal derangement in women. Hormonal association provides the impetus for hormonal therapy as well as underpins the need for blood investigations in this population. Hence, we aim to estimate the presence of hormonal derangement and lipid alteration in female adult acne. METHODS: A prospective, observational study was conducted in Dhulikhel Hospital from July 2015 to February 2016. Females older than 25 years with acne were taken in the study after informed consent. Total 100 patients were enrolled after sample size estimation. Hormonal paneland lipid profile were measured. Hormones tested were androgens, C-peptide and thyroid stimulating hormone.Data analysis was done with SPSS-23. Bivariate analysis was done by chi-square test for categorical data. RESULTS: In this study, majority of patients were younger than 30 years (70.5%) and perioral area most commonly involved. Hormonal alteration was seen in 37.2% patients, among which17.9% had hyperandrogenism, 15.4% had abnormal thyroid level and 10.3% had high C-peptides respectively. Lipid profile was altered in 15.4% patients. Hormonal alteration had significant association with irregular menstruation (P<0.05) but not acne severity. CONCLUSIONS: We observed hormonal alteration frequently in females with adult acne, which comprised of various hormonal parameters including hyperandrogenism.Hormonal alteration reflects deranged metabolic milieu and we suggest that wide hormonal panel should be done in female adult acne. Relationship of hormones with menstrual irregularity but not with acne severity, suggest that clinical symptoms should lead hormonal investigations in all grades of acne. PMID- 29983442 TI - Antimicrobial Sensitivity Trend in Blood Culture Positive Enteric Fever. AB - BACKGROUND: For diagnosis of enteric fever, the culture of the organism from different body fluids is the gold standard. After diagnosis, it is important to treat with the right antibiotic before any complications can occur. The retrospective study is designed to explore the antibiotic sensitivity trend in blood culture positive typhoid fever cases and the extent of drug resistance before treatment is administered. METHODS: A retrospective study was carried out for culture isolated enteric fever patients admitted in Kathmandu Model Hospital. The discharged records from January 2012 to December 2016 were analyzed. The patients above 15 years and with culture isolated enteric fever were included in the study. RESULTS: One hundred fifty-nine strains of Salmonella typhi and paratyphi were isolated from Jan 2012 to Dec 2016 at Kathmandu Model Hospital. Out of 159 isolated, 125 (78.6%) were Salmonella typhi and 34 (21.4%) were paratyphi. Among them co-trimoxazole, chloramphenicol, ceftriaxone, cefotaxime, cefixime, and ofloxacin demonstrated 100% sensitivity. Similarly, amoxicillin sensitivity was 98.1% (n=156) while ciprofloxacin was sensitive in 6.3% (n=10), intermediately sensitive in 49.1% (n=78) and resistance in 44.7% (n=71).The newer quinolone levofloxacin showed 78.5% (n=11) sensitivity. Azithromycin was sensitive in 99.2% (n=132) of total isolated Salmonella species both typhi and paratyphi. CONCLUSIONS: A high degree of sensitivity was noted to chloramphenicol and co-trimoxazole, showing sensitivity has returned to conventional antibiotics. The drug-like ofloxacin is still the best responding drug in our contest whereas ciprofloxacin resistance is still high, but five years patterns show a trend of rollback of sensitivity. PMID- 29983443 TI - Managing Ureterovaginal Fistulas following Obstetric and Gynecological Surgeries. AB - BACKGROUND: Iatrogenic ureteric injuries leading to fistula are rare but devastating complications of obstetric and gynecological surgeries. The aim of the study was to review the demography of ureterovaginal fistula (UVF) and its surgical outcome in Kathmandu Model Hospital. METHODS: This is a review of 15 patients of ureterovaginal fistula who were referred to department of Obstetrics and Gynaecology of Kathmandu Model Hospital from Feb 2014 to Sept 2017. We reviewed the demography, causes and surgical outcome of ureterovaginal fistula (UVF). Ten patients who had complete blind end at the distal ureter, underwent Lich-Gregoir extravesical ureteroneocystostomy. In other five patients, guide wire was successfully negotiated beyond the fistula site, however retrograde double J stenting could be done in only four patients. RESULTS: All the patients had distal ureteric injury close to vesicoureteric junction leading to ureterovaginal fistula. Among them, majority were due to post-hysterectomy in 60% (n=9) followed by obstetrical procedures in 40% (n=6). Fourteen patients (93%) had successful closure of the fistula with complete preservation of renal function. Retrograde double J stenting was possible in patients who were referred earlier within two weeks of the onset of injury. CONCLUSIONS: Iatrogenic injury to the distal ureter during surgery was the leading cause for the ureterovaginal fistula. Endoscopic management with ureteric stents was still possible if the patients were referred earlier following primary surgery. PMID- 29983444 TI - Prospective Validation of a Decision Tree Model for Prediction of Severity in Acute Pancreatitis. AB - BACKGROUND: Early identification of severe acute pancreatitis is important for early stratification, goal directed fluid therapy, rationalizing level of care to improve outcome. Various clinical, laboratory and imaging scoring system has been used to identify severe acute pancreatitis with variable results. Recently a decision tree model was proposed using serum creatinine, serum lactate dehydrogenase and oxygenation index to predict severe acute pancreatitis. This system is easy and usable at our centre. Hence, we conducted the study to validate the decision tree model prospectively. METHODS: Patients admitted with a diagnosis of acute pancreatitis were included in the study. Decision tree model was used to identify patients at high and low risk for severe acute pancreatitis. Sensitivity and specificity were calculated for prediction of the decision tree model. RESULTS: Fifty-three patients were included in the study. Fourty-one (77.4 %) patients with mild acute pancreatitis, five (9.4 %) patients had moderately severe pancreatitis and seven (13.2 %) patients had severe acute pancreatitis. Sensitivity and specificity of decision tree model to predict severity of pancreatitis was 97.83%(95 % CI - 88.47% to 99.94%) and 71.43 % % (95 % CI - 29.04% to 96.33%) respectively with positive and negative predictable value of 95.74 % % (95 % CI - 87.45% to 98.64%) and 83.33 % % (95 % CI - 40.49% to 97.35%) respectively. CONCLUSIONS: Decision tree model with serum creatinine, lactate dehydrogenase, and oxygenation index is an easy and useful tool to predict patients at high risk of developing severe acute pancreatitis. PMID- 29983445 TI - Fibrodysplasia Ossificans Progressiva: A Case Report. AB - Fibrodysplasia ossificans progressiva is a genetic disorder of the connective tissue differentiation characterized by congenital malformation of the big toes and progressive heterotopic ossification in the extra skeletal tissues like tendons, ligaments, fascia and skeletal muscles leading to permanent disability. The prevalence is one in two million people. During childhood, it may be asymptomatic but in later life, progressive stiffness of major joints renders movement of the individual impossible. Currently, there is no effective treatment for this debilitating disease. Here, we present a case of 27 year old male with clinical and radiological features of fibrodysplasia ossificans progressiva. PMID- 29983446 TI - Continuous Fascia Iliaca Compartment Block for Post Operative Analgesia in Fracture Femur. AB - The postoperative pain management in the elderly is challenging due to comorbidities and change in physiology due to age itself. This limit the use of medication which include pain medication also. The fascia iliaca compartment block has been described in the literature for fracture of femur. It has even been safely used by non anaesthesiologist also. To our knowledge, we did not find any case report of continuous fascia iliaca compartment block published in Nepal. This is our first experience of successful continous fasicia iliaca compartment block in case of 89 year old lady with multiple co morbidities in whom traditional pain medication might be difficult to use. We encourage to practice this block which is both safe and easy to perform with good results. PMID- 29983447 TI - Rotational spectrum of methoxyamine up to 480 GHz: a laboratory study and astronomical search. AB - Aims: Methoxyamine is a potential interstellar amine that has been predicted by gas-grain chemical models for the formation of complex molecules. The aim of this work is to provide direct experimental frequencies of its ground-vibrational state in the millimeter- and submillimeter-wave regions to achieve its detection in the interstellar medium. Methods: Methoxyamine was chemically liberated from its hydrochloride salt, and its rotational spectrum was recorded at room temperature from 75 to 480 GHz using the millimeter-wave spectrometer in Valladolid. Many observed transitions revealed A-E splitting caused by the internal rotation of the methyl group, which had to be treated with specific internal rotation codes. Results: Over 400 lines were newly assigned for the most stable conformer of methoxyamine, and a precise set of spectroscopic constants was obtained. Spectral features of methoxyamine were then searched for in the Orion KL, Sgr B2, B1-b, and TMC-1 molecular clouds. Upper limits to the column density of methoxyamine were derived. PMID- 29983448 TI - Detection of interstellar HCS and its metastable isomer HSC: new pieces in the puzzle of sulfur chemistry. AB - We present the first identification in interstellar space of the thioformyl radical (HCS) and its metastable isomer HSC. These species were detected toward the molecular cloud L483 thanks to observations carried out with the IRAM 30m telescope in the lambda 3 mm band. We derive beam-averaged column densities of 7 * 1012 cm-2 for HCS and 1.8 * 1011 cm-2 for HSC, which translate to fractional abundances relative to H2 of 2 * 10-10 and 6 * 10-12, respectively. Although the amount of sulfur locked by these radicals is low, their detection allows to put interesting constraints on the chemistry of sulfur in dark clouds. Interestingly, the H2CS/HCS abundance ratio is found to be quite low, ~ 1, in contrast with the oxygen analogue case, in which the H2CO/HCO abundance ratio is around 10 in dark clouds. Moreover, the radical HCS is found to be more abundant than its oxygen analogue, HCO. The metastable species HOC, the oxygen analogue of HSC, has not been yet observed in space. These observational constraints are confronted with the outcome of a recent model of the chemistry of sulfur in dark clouds. The model underestimates the fractional abundance of HCS by at least one order of magnitude, overestimates the H2CS/HCS abundance ratio, and does not provide an abundance prediction for the metastable isomer HSC. These observations should prompt a revision of the chemistry of sulfur in interstellar clouds. PMID- 29983449 TI - High-resolution observations of IRAS 08544-4431: Detection of a disk orbiting a post-AGB star and of a slow disk wind. AB - Aims: In order to study the effects of rotating disks in the post-asymptotic giant branch (post-AGB) evolution, we observe a class of binary post-AGB stars that seem to be systematically surrounded by equatorial disks and slow outflows. Although the rotating dynamics had only been well identified in three cases, the study of such structures is thought to be fundamental to the understanding of the formation of disks in various phases of the late evolution of binary stars and the ejection of planetary nebulae from evolved stars. Methods: We present ALMA maps of 12CO and 13CO J=3-2 lines in the source IRAS 08544-4431, which belongs to the above mentioned class of objects. We analyzed the data by means of nebula models, which account for the expectedly composite source and can reproduce the data. From our modeling, we estimated the main nebula parameters, including the structure and dynamics and the density and temperature distributions. We discuss the uncertainties of the derived values and, in particular, their dependence on the distance. Results: Our observations reveal the presence of an equatorial disk in rotation; a low-velocity outflow is also found, probably formed of gas expelled from the disk. The main characteristics of our observations and modeling of IRAS 08544-4431 are similar to those of better studied objects, confirming our interpretation. The disk rotation indicates a total central mass of about 1.8 M?, for a distance of 1100 pc. The disk is found to be relatively extended and has a typical diameter of ~ 4 1016 cm. The total nebular mass is ~ 2 10-2M?, of which ~ 90% corresponds to the disk. Assuming that the outflow is due to mass loss from the disk, we derive a disk lifetime of ~ 10000 yr. The disk angular momentum is found to be comparable to that of the binary system at present. Assuming that the disk angular momentum was transferred from the binary system, as expected, the high values of the disk angular momentum in this and other similar disks suggest that the size of the stellar orbits has significantly decreased as a consequence of disk formation. PMID- 29983450 TI - Miniemulsion ARGET ATRP via Interfacial and Ion-Pair Catalysis: From ppm to ppb of Residual Copper. AB - It was recently reported that copper catalysts used in atom transfer radical polymerization (ATRP) can combine with anionic surfactants used in emulsion polymerization to form ion pairs. The ion pairs predominately reside at the surface of the monomer droplets, but they can also migrate inside the droplets and induce a controlled polymerization. This concept was applied to activator regenerated by electron transfer (ARGET) ATRP, with ascorbic acid as reducing agent. ATRP of n-butyl acrylate (BA) and n-butyl methacrylate (BMA) was carried out in miniemulsion using CuII/tris(2-pyridylmethyl)amine (TPMA) as catalyst, with several anionic surfactants forming the reactive ion-pair complexes. The amount and structure of surfactant controlled both the polymerization rate and the final particle size. Well-controlled polymers were prepared with catalyst loadings as low as 50 ppm, leaving only 300 ppb of Cu in the precipitated polymer. Efficient chain extension of a poly(BMA)-Br macroinitiator confirmed high retention of chain-end functionality. This procedure was exploited to prepare polymers with complex architectures such as block copolymers, star polymers, and molecular brushes. PMID- 29983451 TI - Protection of opening lids: very high catalytic activity of lipase immobilized on core-shell nanoparticles. AB - Various hydrophobic supports have been used for lipase immobilization since the active site of lipase can be opened in a hydrophobic environment. Nevertheless, the increase of lipase activity is still limited. This study demonstrates a hyperactivation-protection strategy of lipase after immobilization on poly(n butyl acrylate)-polyaldehyde dextran (PBA-PAD) core-shell nanoparticles. The inner hydrophobic PBA domain helps to rearrange lipase conformation to a more active form after immobilization into the PAD shell. More importantly, the outer PAD shell with dense polysaccharide chains prevents the immobilized lipase from contact with outside aqueous medium and revert its conformation back to an inactive form. As a result, under optimal conditions the activity of lipase immobilized in PBA-PAD nanoparticles was enhanced 40 times over the free one, much higher than in any previous report. Furthermore, the immobilized lipase retained more than 80 % of its activity after 10 reaction cycles. PMID- 29983453 TI - One-pot synthesis of triazines as potential agents affecting cell differentiation. AB - Abstract: This paper outlines the synthesis of a number of structural analogs of 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic acid which represent compounds with potential cardiogenetic activity. A one-pot protocol was developed for swift functionalization of the 1,3,5-triazine core without the need of isolating intermediates. The developed route starts from readily available 2,4,6-trichloro 1,3,5-triazine, displacing the chlorine atoms sequentially by aryloxy, arylamino, or arylthio moieties to enable access to molecules with three different substituents of this type in good yields. To facilitate purification, tert-butyl, methyl, and ethyl ester derivatives of the target compounds were initially synthesized. The tert-butyl esters could be readily hydrolyzed to the desired compounds, while reduction of the methyl and ethyl esters gave the corresponding benzylic alcohols in high yields, thereby expanding the substrate scope for future relevant cell assays. Graphical abstract: PMID- 29983454 TI - A practical guide for using lithium halocarbenoids in homologation reactions. AB - Abstract: Lithium halocarbenoids are versatile reagents for accomplishing homologation processes. The fast alpha-elimination they suffer has been considered an important limitation for their extensive use. Herein, we present a series of practical considerations for an effective employment in the homologation of selected carbon electrophiles. Graphical abstract: PMID- 29983452 TI - Modifications of quinolones and fluoroquinolones: hybrid compounds and dual action molecules. AB - Abstract: This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents. Graphical abstract: PMID- 29983455 TI - Lewis Acid Mediated Cyclizations: Diastereoselective Synthesis of Six- to Eight Membered Substituted Cyclic Ethers. AB - Cyclic ethers are widely abundant in natural products. Cyclic ether templates are also utilized in drug design and medicinal chemistry. Although the synthetic processes for this class of compounds have been studied extensively with respect to five- and six-membered rings, medium-sized cyclic ethers are synthetically more challenging due to a variety of factors. Herein, we report our results on the Lewis acid catalyzed synthesis of medium-sized cyclic ethers in a diastereoselective manner. PMID- 29983456 TI - Precipitation Estimation Using L-Band and C-Band Soil Moisture Retrievals. AB - An established methodology for estimating precipitation amounts from satellite based soil moisture retrievals is applied to L-band products from the Soil Moisture Active Passive (SMAP) and Soil Moisture and Ocean Salinity (SMOS) satellite missions and to a C-band product from the Advanced Scatterometer (ASCAT) mission. The precipitation estimates so obtained are evaluated against in situ (gauge-based) precipitation observations from across the globe. The precipitation estimation skill achieved using the L-band SMAP and SMOS datasets is higher than that obtained with the C-band product, as might be expected given that L-band is sensitive to a thicker layer of soil and thereby provides more information on the response of soil moisture to precipitation. The square of the correlation coefficient between the SMAP-based precipitation estimates and the observations (for aggregations to ~100 km and 5 days) is on average about 0.6 in areas of high rain gauge density. Satellite missions specifically designed to monitor soil moisture thus do provide significant information on precipitation variability, information that could contribute to efforts in global precipitation estimation. PMID- 29983458 TI - The Impact of Contraceptive Use and Abortion on Fertility in sub-Saharan Africa: Estimates for 2003-2014. PMID- 29983459 TI - Epidemiology of cancer in Colombia. PMID- 29983457 TI - Electroactive polymers for tissue regeneration: Developments and perspectives. AB - Human body motion can generate a biological electric field and a current, creating a voltage gradient of -10 to -90 mV across cell membranes. In turn, this gradient triggers cells to transmit signals that alter cell proliferation and differentiation. Several cell types, counting osteoblasts, neurons and cardiomyocytes, are relatively sensitive to electrical signal stimulation. Employment of electrical signals in modulating cell proliferation and differentiation inspires us to use the electroactive polymers to achieve electrical stimulation for repairing impaired tissues. Electroactive polymers have found numerous applications in biomedicine due to their capability in effectively delivering electrical signals to the seeded cells, such as biosensing, tissue regeneration, drug delivery, and biomedical implants. Here we will summarize the electrical characteristics of electroactive polymers, which enables them to electrically influence cellular function and behavior, including conducting polymers, piezoelectric polymers, and polyelectrolyte gels. We will also discuss the biological response to these electroactive polymers under electrical stimulation. In particular, we focus this review on their applications in regenerating different tissues, including bone, nerve, heart muscle, cartilage and skin. Additionally, we discuss the challenges in tissue regeneration applications of electroactive polymers. We conclude that electroactive polymers have a great potential as regenerative biomaterials, due to their ability to stimulate desirable outcomes in various electrically responsive cells. PMID- 29983460 TI - Cancer incidence estimates and mortality for the top five cancer in Colombia, 2007-2011. AB - Objectives: To describe the incidence and mortality for the five main types of cancer in Colombia, from 2007-2011. Methods: We estimated cases and cancer incidence rates standardised by age, based on incidence/mortality ratios; and we calculated the observed deaths and mortality rates standardised by age in Colombia, both differentiated by province, type of cancer and sex. Incidence estimates were generated based on information from four cancer population registries (Cali, Pasto, Bucaramanga and Manizales), published in Cancer Incidence in Five Continents, volume X, and the official mortality and population information of the National Administrative Province of Statistics (DANE, for its initials in Spanish). Results: The annual number of expected cases (all cancers) was 62,818 in men and women; and there were 32,653 recorded deaths. The main incidental cancers were prostate (46.5 per 100,000 person-years) in men, and breast (33.8 per 100,000 person-years) in women. The highest mortality figures were for stomach cancer in men (14.2); and breast cancer in women (9.9). Conclusions: The highest incidence and mortality estimates in Colombia were for breast and prostate cancers, as well as a proportion of infection-related cancers, such as stomach and cervical cancer. These four neoplasms were responsible for more than 50% of the burden of the disease. Only through good quality, long-duration cancer registries, can information be obtained about the changes in incidence trends. PMID- 29983462 TI - Trends in cancer incidence and mortality over three decades in Quito - Ecuador. AB - Introduction: The National Registry of Tumors has collected, processed, analyzed and regularly disseminated information on new cases of cancer diagnosed in the city of Quito, Ecuador over the last three decades. Aim: This article analyzed the trend of cancer incidence and mortality rates for the period 1985-2013. Methods: Incidence and mortality rates standardized by age were estimated by the direct method, using the world standard population. Analysis of the time trends, from selected locations, the joinpoint regression was used. Results: A decrease in the incidence and mortality rates of cervical and stomach cancers were documented. There was an increase in breast and colorectal cancer rates. The increase of the incidence rate of thyroid cancer in women was notorious. Lung cancer also increased in women while in men their values remained stable. Conclusion: There are important variations in the evolution of cancer in Quito; the information presented is an instrument for monitoring and evaluating the interventions that are developed in the Country. PMID- 29983461 TI - Reliable information for cancer control in Cali, Colombia. AB - Background: The Cali Population Cancer Registry (RPCC) has been in continuous operation since 1962 with the objective of producing valid statistics on the incidence of cancer, its patterns, trends and survival rates. Methods: During the period 2008-2012, 23,046 new cases were registered and during 2011-2015 there were 12,761 cancer deaths. The trend of the rates was described with the APC average annual change rate and with the Joinpoint analysis. We analyzed the individual data of 38,671 adults (15-99 years) diagnosed with cancer between 1995 2009, and we calculated the standardized net survival by age for the 14 most common cancer body sites, using the Pohar-Perme method. Results: Prostate and breast cancer were the first cause of cancer morbidity. The incidence rates in these were susceptible to early detection, tumors stabilized after decades of growth, while an increase in the incidence of colon cancer and papillary thyroid carcinoma was observed. The incidence rates of cervical and stomach cancer and conditions related to infectious agents decreased, although the number of absolute cases increased, due to the growth and aging of the population. Gastric cancer was responsible for the highest number of cancer related deaths. The types of cancer related to tobacco consumption (lung, oral cavity, esophagus, pancreas, urinary bladder) showed low numbers and a tendency to decrease. During the period 2000-2004, the 5-year net survival improved for cancers of the breast, cervix, prostate, melanoma and thyroid, although in the period 2005-2009 a stagnation was observed. In stomach, liver and lung cancer, the 5-year net survival was less than 15%. The 5-year overall survival in children was 51.0% (95% CI: 47.5, 54.3) and in adolescents 44.6% (95% CI: 36.0, 52.8). Comment: RPCC has been an advisor to the Colombian government in the evaluation of CPRs in the country and its data has contributed significantly to different aspects of cancer control in Colombia. PMID- 29983464 TI - Cancer incidence and mortality in Barranquilla, Colombia. 2008-2012. AB - Objective: To describe cancer incidence and mortality during the 2008-2012 period in the District of Barranquilla. Methods: Cancer incident cases were collected, analyzed and processed by the Barranquilla Population Cancer Registry during the study period. Population structure was obtained from the Departamento Administrativo Nacional de Estadisticas (DANE) and mortality from the Sistema de Informacion de Cancer en Colombia. The total and specific crude and specific incidence rates and mortality by age and gender were estimated, as well as by-age standardized incidence rates. Statistical analysis were performed with SPSS V24 and Canreg5. Results: 8,182 cases of cancer were identified, excluding non melanoma skin cancer (62.8% in women). 83.0% of the tumors had histological verification and only 5.2% were DCO. The adjusted incidence rate for all tumors was 116.5 per 100,000 in men and 155.4 per 100,000 in women. The most frequent locations were prostate and trachea-bronchi-lung in men, while in women, breast and cervix occupied the first places. Breast and prostate had the highest mortality rates in women and men, respectively. Conclusion: Specific behavior of cancer incidence and mortality in Barranquilla has important increases for the main types of tumors (breast and prostate) when compared to the country and other population registries. To provide data is key to showing a representative behavior of the Colombian Caribbean. PMID- 29983463 TI - Trends on cancer incidence and mortality in Pasto, Colombia. 15 years experience. AB - Introduction: In Colombia it is necessary to continue producing quality and continuously updated information on the magnitude of cancer, derived from population-based cancer registries to contribute to decision making, and implementation of strategies for health promotion, prevention and treatment of cancer in order to reduce the impact on the population. Objective: To describe the incidence, mortality and cancer trends in Pasto-Colombia from 1998 to 2012. Methods: Observational descriptive study of morbi - mortality due to malignant tumours in Pasto. The collection, processing and systematization of the data, was carried out according to international standards for population-based cancer registries. The incidence and mortality rates were calculated by period, sex, age and tumour site. Results: During the period 1998-2012 there were 8,010 new cases of cancer, of them, 57.7% occurred in females. There were 4,214 deaths reported, 52.0% in females. The incidence (p men= 0.7, p females= 0.3) and mortality (p males= 1.0, p females= 0.0) did not present significant changes over 15 years of observation and the tumours that cause greater morbi-mortality affect the stomach, cervix uteri, breast and prostate. Conclusions: Cancer in general, continues to be a serious health problem for the population of Pasto. The global behaviour of cancer incidence and mortality, identify the need to promote and strengthen promotion and prevention programs, especially focused on tumours of the stomach, prostate, breast and cervix uteri that produce greater morbidity and mortality in the population. PMID- 29983465 TI - Health inequities and cancer survival in Manizales, Colombia: a population-based study. AB - Objective: To analyze differences in survival of breast, cervical, lung, prostate and stomach cancer by health insurance regime (HIR) and socioeconomic position (SEP) in an intermediate city in a middle-income country. Methods: All patients with breast, cervix uteri, lung, prostate and stomach cancer diagnosed between 2003 and 2007 and characterized by the Manizales population-based Cancer Registry (MCR) were included and followed up to a maximum of 5 years for identifying deaths. Survival probabilities estimated by HIR were defined according to the type of affiliation at the date of diagnosis, and by socioeconomic stratification of residence (SS) as indicator of SEP, stratifying for other prognostic factors using Kaplan-Meier methods. Cox proportional hazard models were fitted for multivariate analysis. Results: A total of 1,384 cases and 700 deaths were analyzed. Five-year observed survival was 71.0% (95% IC: 66.1-75.3) for breast, 51.4% (95% IC: 44.6-57.9) for cervix, 15.4% (95% IC: 10.7-20.8) for lung, 71.1% (95% IC: 65.3-76.1) for prostate and 23.8% (95% IC: 19.3-28.6) for stomach. Statistically significant differences in survival by HIR were observed for breast, lung, prostate, and stomach - with poorer survival for the subsidized and uninsured patients. Differences by SS were observed for lung and prostate. Differences in survival by HIR were independent of SS, and viceversa. Conclusions: Important inequities in cancer survival exist related to HIR and SEP. Possible explanations include underlying comorbidities, late stage at diagnosis, or barriers to timely and effective treatment. PMID- 29983466 TI - Cancer incidence and mortality in Bucaramanga, Colombia. 2008-2012. AB - Introduction: Cancer is a burden in the world, especially for the least developed countries. The Population Registries of Cancer are fundamental in order to know the territorial profiles of cancer, and to evaluate the impact of their control programs. Objective: To estimate the incidence and mortality from cancer in the Metropolitan Area of Bucaramanga in the period 2008-2012. Methods: A descriptive population study of cancer incidence and mortality in the Metropolitan Area of Bucaramanga was conducted. Primary invasive cancer cases from the 2008-2012 period was obtained from the RPC-AMB base. Population and death data were provided by the National Administrative Department of Statistics (DANE, for its initials in Spanish). Crude rates of global and specific incidence and mortality were estimated by sex, and standardized incidence and mortality rates. Results: During the five-year period, 8,775 incidents of cancer were recorded (excluding non-melanoma skin cancer). The global standardized incidence rates per 100,000 person-years were 151.7 in men and 157.2 in women. The main locations were prostate, stomach and colorectal, in men; breast, thyroid and colorectal in women. The standardized mortality rate per 100,000 person-years was 94.8 in men and 78.0 in women. Conclusion: The incidence and mortality rates in most locations are lower than the national ones and those in the previous quinquennium in the Metropolitan Area of Bucaramanga. Thyroid cancer, colorectal cancer, and leukemia show a tendency to increase, which demands further investigation. PMID- 29983467 TI - Cancer incidence and mortality in Medellin-Colombia, 2010-2014. AB - Background: This study provides information on cancer incidence and mortality in a Colombian population during 2010-2014, based on the data and methodology of the Population-based Cancer Registry of Antioquia to facilitate the implementation of cancer control strategies. Methods: This is a descriptive study of cancer incidence and mortality in a population, residing in the urban area of the municipality of Medellin. The cancers included in the study are those prioritized in the cancer control plan for Colombia (PDCC-cancers). The collection, processing and systematization of the data were performed in accordance with internationally standardized parameters for population cancer registries. Incidence and mortality rates were calculated by gender, age and tumor location. Results: During 2010-2014 there were 22,379 new cancer cases recorded in the urban area of the municipality of Medellin, of which 43.5% corresponded to the PDCC-cancers. During the same period, 14,922 cancer deaths were reported, 23.5% related to the PDCC-cancers, 53.5% in women. Prostate cancer and breast cancer were the principal cause of morbidity in men and women, respectively, and lung cancer was the principal cause of death for both sexes. Conclusion: Cancer is a health problem for the population of Medellin. It is necessary to emphasize research and monitor risk factors, the health response and the capacity of the health provider network when facing the growing demand caused by this epidemic. PMID- 29983468 TI - Oncology services supply in Colombia. AB - Objective: To characterize the current status of oncological services supply in Colombia. Methods: A descriptive analysis of oncological services for cancer care in the adult and infant population that meet the requirements for operation according to the Special Register of Health Service Providers was carried out. The case - by - provider ratio was calculated based on the cancer incidence estimated for Colombia by the National Cancer Institute. Results: Were identified 1,780 qualified oncology health services in the country related to specialties for providing care to cancer patients. Twenty five providers nationwide had all three qualified services: chemotherapy, radiotherapy and surgery. Nearly 50% of the offer was concentrated in Bogota, Antioquia and Valle del Cauca. Putumayo and the Amazonas group departments, with the exception of Vaupes, did not show any oncological services. Healthcare Providers were responsible for 87.8%, and independent professionals provided 12.2%. Outpatient services were 66.7% of oncology services, 17.4% was diagnostic support services and therapeutic complementation, and 15.9% was surgical services. 87.9% of the oncological service offer in Colombia takes place in the private sector. Conclusions: The ratio between the service groups is asymmetric, with few providers jointly offering the basic services for oncology treatment, which reflects how provision is fragmented. It is necessary to redefine the concept of oncology service under a comprehensive care approach and the importance of enabling functional units, comprehensive treatment centers and other forms of care. PMID- 29983469 TI - Pediatric oncology services in Colombia. AB - : In low-income countries, a child diagnosed with cancer has an 80% chance of dying, while in high-income countries more than 80% survive the disease. In Colombia, a middle-income country, the government issued new legislation that promotes the generation of comprehensive care units; nevertheless, seven years after its expedition, no institution has been recognized as such by the Ministry of Health. The objective of this study was to characterize the current offer of oncological services for cancer care in children and to identify the institutions that can be constituted in Units of Comprehensive Care of Childhood Cancer in Colombia. Methods: descriptive study of secondary source, the Special Register of Health Providers of the Ministry of Health and Social Protection was consulted, in order to identify the institutions that had enabled hospitalization services of medium or high complexity, chemotherapy, specialized consultation, emergencies, oncological surgery, and radiotherapy or nuclear medicine. The information is reported in absolute frequencies. Results: Seventy one institutions have hematology-oncology consultation, 39 institutions have chemotherapy and hospitalization services of medium or high complexity, and 18 have radiotherapy enabled. Only nine of the institutions include all the services that are necessary for comprehensive care. Conclusion: Colombia has a sufficient supply of services for the care of children with cancer. Only a minority are in institutions that have the capacity to guarantee the integrality of the attention. PMID- 29983470 TI - Breast and cervical cancer survival at Instituto Nacional de Cancerologia, Colombia. AB - Objective: to provide and compare estimations of two-year overall survival for cervical and female breast cancer in three cohorts (first treated in 2007, 2010, 2012) at the Instituto Nacional de Cancerologia of Colombia. Methods: All patients first treated at the Instituto Nacional de Cancerologia for breast or cervical cancer in the years 2007, 2010, 2012, without a prior cancer diagnosis, were included for the study. The hospital-based cancer registry was cross linked with governmental databases to obtain follow-up information on all patients. Probability of surviving 24 months since the date of entry at the hospital was estimated using Kaplan-Meier methods, using the log-rank test to evaluate differences between groups. Results: We analyzed 1,928 breast cancer cases and 1,189 cervical cancer cases, resulting in an overall survival probability at 24 months of 79.6% (95% CI: 77.8-81.4) for BC and of 63.3% (95% CI: 60.6- 66.0) for cervical cancer, there were no differences in survival for year of entry. Advanced clinical stage substantially affected overall survival, being 32.2% (95% CI: 28.4-44.0) for stage IV breast cancer and 22.6% (95% CI: 11.4-33.8) for stage IV cervical cancer. Conclusions: Breast cancer was the cancer with the best survival rates at Instituto Nacional de Cancerologia; cervical cancer was the one with the lowest survival rates. Overall survival did not change over the years for any of the cancers. PMID- 29983471 TI - Cali cancer registry methods. AB - Background: The Population Cancer Registry of Cali (RPCC) has operated since 1962, disseminating high quality information to provide a framework to assess and control the burden of cancer in Cali. Methods: The collection of new cancer cases in permanent residents of Cali is done through active search in and notification from hospitals, and public and private laboratories. The Secretary of Municipal Public Health provides individual information on general mortality and death from cancer. Tumors are coded with ICDO-3 and mortality with ICD-10. Presented rates are standardized by age and trends are assessed by estimating the percentage annual change using the regression analysis in JoinPoint. The 5-year net survival was analyzed with the Pohar-Perme estimator. Results: The 88.5% of the registered cancers had morphological verification (MV). The proportion of unknown primary site represented 5% and the death certificate only cases (DCO) varied between 0 to3% depending on the cancer site. All deaths were certified by a physician, 94.2% of cancer deaths were correctly certified. The ill-defined site proportion was 5.3% and that of uterine cancer not specified (C55) was 0.5%. For survival analysis, existing data collection procedure and infrastructure ensures assessment of the patient's vital status and follow-up, with an average lost to follow-up of 13.2%. Comment: The information has been published in the eleven volumes of "Cancer Incidence in Five Continents" confirming high quality of the collected data. The RPCC PCRC has also participated in the Concord Study and is participating in SURVCAN-3. PMID- 29983473 TI - Cancer risk management in Colombia, 2016. AB - Objective: To describe the outcomes of risk management indicators for five types of cancer in population that is affiliated to the General System of Social Security in Health, in six cities of Colombia. Methods: Based on the data from the administrative cancer registry for the period 2016, the High Cost Disease Fund (CAC in Spanish) as a technical organization of the Colombian health system, processed and analyzed the data for the calculation of risk management indicators established in consensus based on the evidence found in six cities. Results: There is a diversity in the indicators results found among the different cities, evidencing strengths and weaknesses in each of them for the different types of cancer. From the set of indicators, those with the best results presented are related to the greater detection of cancer in early stages or in situ, as well as a decrease in mortality, especially in colorectal and in gastric cancer. Most indicators in gastric cancer showed optimal results. Important measurements such as the opportunity for diagnosis and treatment are below the proposed standard for most types in all the six cities. Conclusions: The descriptive analysis of cancer risk management indicators shows certain weaknesses in the quality and timeliness of the care of cancer patients, the standards agreed upon in the consensus with the different actors of the system are not being reached, situation which may be due to a reality of problems of the Colombian health system, as well as deficiencies in the quality of the report to the CAC. PMID- 29983472 TI - Quality of death certification in Colombia. AB - Objective: To evaluate the quality of the certification of general death and cancer in Colombia. Methods: Validity indicators were described for each province and the cities of Bogota, Cali, Manizales, Pasto and Bucaramanga. A factorial analysis of principal components was carried out in order to identify non-obvious relationships. Results: Were analyzed 984,159 deaths, among them there were 164,542 deaths due to cancer. 93.7% of the general mortality was well certified. The predominant errors were signs, symptoms and ill-defined conditions. 92.8% of cancer mortality was well certified. The predominant errors were due to poorly defined cancer sites. Conclusions: Certification of quality indicators in Colombia has improved. Given the good performance of the quality indicators for certificating general death and cancer, it is considered that this is a valid input for the estimation of cancer incidences. PMID- 29983474 TI - Empathic Understanding: Benefits of Perspective-Taking and Facial Mimicry Instructions are Mediated by Self-Other Overlap. AB - The current study sought to better understand the utility of two strategies - perspective-taking and facial mimicry - proposed to increase empathic responding. Thirty-seven female participants were presented an interpersonal situation (a betrayal) that would elicit the use of empathic responding to achieve conflict resolution between friends. Each participant was given instructions to partake in either perspective-taking, facial mimicry, or to remain neutral (control condition). The results demonstrated that individuals who engaged in perspective taking reported significantly higher state empathy than the control condition, but there was no significant difference in state empathy between the mimicry and control condition. Also, those who engaged in either strategy reported significantly higher self-other overlap relative to those not instructed to engage in a particular strategy. Importantly, self-other overlap mediated the association between the instructional sets and state empathy. Both strategies are arguably means of enhancing interpersonal understanding. PMID- 29983475 TI - Mixture models with a prior on the number of components. AB - A natural Bayesian approach for mixture models with an unknown number of components is to take the usual finite mixture model with symmetric Dirichlet weights, and put a prior on the number of components-that is, to use a mixture of finite mixtures (MFM). The most commonly-used method of inference for MFMs is reversible jump Markov chain Monte Carlo, but it can be nontrivial to design good reversible jump moves, especially in high-dimensional spaces. Meanwhile, there are samplers for Dirichlet process mixture (DPM) models that are relatively simple and are easily adapted to new applications. It turns out that, in fact, many of the essential properties of DPMs are also exhibited by MFMs-an exchangeable partition distribution, restaurant process, random measure representation, and stick-breaking representation-and crucially, the MFM analogues are simple enough that they can be used much like the corresponding DPM properties. Consequently, many of the powerful methods developed for inference in DPMs can be directly applied to MFMs as well; this simplifies the implementation of MFMs and can substantially improve mixing. We illustrate with real and simulated data, including high-dimensional gene expression data used to discriminate cancer subtypes. PMID- 29983476 TI - Parents' Preferences for Sex of Children in Sweden: Attitudes and Outcomes. AB - It has been argued that preferences for the sex of children would be small or non existing in relatively gender equal societies. However, previous studies have suggested that a stronger preference for having daughter exists in Scandinavian countries, which are frequently noted for being among the most gender equal societies in the world. Combining new register data on birth rates by sex of the previous children and recent survey data on couples' stated preferences for the sex of children, we show that the preference for daughters has increased in Sweden over the last decade. In addition to the stronger preference for having daughters among two-child mothers documented in previous research, our findings show that during the previous decade this preference was noticeable also among one-child parents. Despite Swedish society being known for holding gender equal social norms, interviewed parents openly expressed some degree of preference for having daughters over sons. PMID- 29983477 TI - Mad Cows, French Foxes and Other Rabid Animals in Britain, 1800 to the Present. PMID- 29983478 TI - A novel oligo-pyrazole-based thin film: synthesis, characterization, optical and morphological properties. AB - Pyrazole-3,4-dicarboxylic acid 2 was synthesized via the hydrolysis of pyrazole-3 carboxylic acid 1 and subsequently heated with thionyl chloride to give the novel pyrazole-3,4-dicarbonyl dichloride 3, which was easily converted into oligo pyrazole 4 upon its reaction with p-phenylene-diamine. These newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and FT-IR spectroscopy, and gel permission chromatography (GPC). Three novel oligo-pyrazole thin films were prepared using oligo-pyrazole 4 with these respective values of thickness: 20, 21, and 24 MUm. The optical properties of the films, including the absorbance, transmittance, and optical band gap, were determined using UV-vis spectroscopy. The Eg values of the films were found to be 1.426, 1.537, and 1.648 eV for the 20, 21, and 24 MUm thick organic films, respectively. Atomic force microscopy (AFM) was used to examine the surface morphology and properties of the organic films. In the AFM images, a few black regions were observed and several yellow regions appeared over a large area, and the surface of the oligo-pyrazole films had an extremely low roughness value. The as-synthesized oligo-pyrazole has great potential in optoelectronic applications according to the optical properties of the as-prepared films. Graphical abstract. PMID- 29983479 TI - Differences Between Household Income from Surveys and Registers and How These Affect the Poverty Headcount: Evidence from the Austrian SILC. AB - We take advantage of the fact that for the Austrian SILC 2008-2011, two data sources are available in parallel for the same households: register-based and survey-based income data. Thus, we aim to explain which households tend to under- or over-report their household income by estimating multinomial logit and OLS models with covariates referring to the interview situation, employment status and socio-demographic household characteristics. Furthermore, we analyze source specific differences in the distribution of household income and how these differences affect aggregate poverty indicators based on household income. The analysis reveals an increase in the cross-sectional poverty rates for 2008-2011 and the longitudinal poverty rate if register data rather than survey data are used. These changes in the poverty rate are mainly driven by differences in employment income rather than sampling weights and other income components. Regression results show a pattern of mean-reverting errors when comparing household income between the two data sources. Furthermore, differences between data sources for both under-reporting and over-reporting slightly decrease with the number of panel waves in which a household participated. Among the other variables analyzed that are related to the interview situation (mode, proxy, interview month), only the number of proxy interviews was (weakly) positively correlated with the difference between data sources, although this outcome was not robust over different model specifications. PMID- 29983480 TI - Comparison of ZnO surface modification with gas-phase propiolic acid at high and medium vacuum conditions. AB - Recent advances in preservation of the morphology of ZnO nanostructures during dye sensitization required the use of a two-step preparation procedure. The first step was the key for preserving ZnO materials morphology. It required exposing clean ZnO nanostructures to a gas-phase prop-2-ynoic acid (propiolic acid) in vacuum. This step resulted in the formation of a robust and stable surface-bound carboxylate with ethynyl groups available for further modification, for example, with click chemistry. This paper utilizes spectroscopic and microscopic investigations to answer several questions about this modification and to determine if the process can be performed under medium vacuum conditions instead of high vacuum procedures reported earlier. Comparing the results of the preparation process at medium vacuum of 0.5 Torr base pressure with the previously reported investigations of the same process in high vacuum of 10-5 Torr suggests that both processes lead to the formation of the same surface species, confirming that the proposed modification scheme can be widely applicable for ZnO sensitization procedures and does not require the use of high vacuum. Additional analysis comparing the computationally predicted surface structures with the results of spectroscopic investigations yields the more complete description of the surface species resulting from this approach. PMID- 29983481 TI - The relationship between boundary layer stability and cloud cover in the post cold frontal region. AB - Using NASA-Aqua MODIS and AIRS data, the relationship between low-level cloud cover (cloud top below the 700 hPa level) and boundary layer stability is explored in post-cold frontal conditions. A linear relationship is found between seasonal cloud cover and two separate measures of inversion strength, the lower tropospheric stability (LTS) and the estimated inversion strength (EIS), for two specific regions in the north Atlantic and Pacific in quiescent and weakly subsiding conditions. The relationship barely changes when considering dynamically active and subsiding post-cold frontal conditions for the same regions. To explore the generality of this result and increase sample size, cold front centered composites of cloud cover and stability are constructed. The northern and southern hemisphere seasonal cloud cover and stability distributions in the post-cold frontal regions are then compared. A fairly good correlation between cloud cover and EIS is found in both hemispheres across all seasons, suggesting that a linear relationship between cloud cover and inversion strength proposed for quiescent conditions exists also in more dynamically active subsiding post-cold frontal conditions. However, for a given season and hemisphere, the correlation between cloud cover and EIS degrades in post-cold frontal regions, especially in the northern hemisphere. At these scales, other large scale factors tend to correlate better with cloud cover. PMID- 29983482 TI - One-Dimensional NMR Imaging of High-Temperature First-Drying in Monolithics. AB - In this study a specialized high-temperature nuclear magnetic resonance (NMR) setup is presented for measuring free moisture in monolithic refractory castables during one-sided heating (100-300 degrees C). This setup makes use of a high thermal-stability Birdcage-coil for measuring the quantitative moisture content at high-temperatures, while also utilizing a mini-coil for calibrating transverse relaxation changes, as a function of temperature and hydration state, taking place in the sample throughout a drying experiment. We employ a high-temperature correction scheme that calibrates the effects of rising temperatures on the NMR signal. With this configuration, we can non-destructively measure moisture and temperature profiles continuously and achieve a spatial resolution of 2-3 mm for samples as long as 74 mm. After applying the NMR correction, we can extract information about the physical and chemical components of water as they are released from the porous matrix during first heat up. As a model material, we demonstrate the capability of our setup with a conventional castable after it has been cast and cured for 48 h. PMID- 29983483 TI - Plasma generation and processing of interstellar carbonaceous dust analogs. AB - Interstellar (IS) dust analogs, based on amorphous hydrogenated carbon (a-C:H) were generated by plasma deposition in RF discharges of CH4 + He mixtures. The a C:H samples were characterized by means of secondary electron microscopy (SEM), infrared (IR) spectroscopy and UV-visible reflectivity. DFT calculations of structure and IR spectra were also carried out. From the experimental data, atomic compositions were estimated. Both IR and reflectivity measurements led to similar high proportions (~ 50%) of H atoms, but there was a significant discrepancy in the sp2/sp3 hybridization ratios of C atoms (sp2/sp3 = 1.5 from IR and 0.25 from reflectivity). Energetic processing of the samples with 5 keV electrons led to a decay of IR aliphatic bands and to a growth of aromatic bands, which is consistent with a dehydrogenation and graphitization of the samples. The decay of the CH aliphatic stretching band at 3.4 um upon electron irradiation is relatively slow. Estimates based on the absorbed energy and on models of cosmic ray (CR) flux indicate that CR bombardment is not enough to justify the observed disappearance of this band in dense IS clouds. PMID- 29983484 TI - Molecular modeling, docking and protein-protein interaction analysis of MAPK signalling cascade involved in Camalexin biosynthesis in Brassica rapa. AB - Phytoalexins are small antimicrobial molecules synthesized and accumulated by plants upon exposure to pathogens. Camalexin is an indole-derived phytoalexin, which is accumulated in plants including Arabidopsis thaliana, and other Brassicaceae, which plays a major role in disease resistance against fungal pathogens. The productivity of Brassica crops is adversely affected by Alternaria blight disease, which is caused by Alternaria brassicae. In Arabidopsis thaliana, MAP kinase signalling cascade is known to be involved in synthesis of camalexin, which contributes to disease resistance against a necrtrophic fungal pathogen, Botrytis cinerea. In the present study, MAPK signalling cascade leading to biosynthesis of camalexin that triggers defense responses in B. rapa upon exposure to the most devastating nectrophic fungus, Alternaria brassicae has been elucidated with the help of previously reported MAPK cascade in Arabidopsis thaliana, Molecular modelling, docking, and protein-protein interaction analysis of MAP kinases retrieved from Brassica rapa genome have been carried out to reveal the above cascade. The tertiary structure prediction of MAPKs obtained through molecular modelling revealed that all the protein models fulfil the criteria of being the stable structures. The molecular docking of predicted models for elucidating potential partners of MAPKs revealed strong interactions between MKK1, MKK4, MKK5, MAPK3 and MAPK6 with MKK9. The MAPK signalling cascade also shows different genes that express and play major role in camalexin biosynthesis in B. rapa during defense response to A. brassicae. The understanding of MAPK defense signaling pathway in B. rapa against devastating fungal pathogen Alternaria brassicae would help in devising strategies to develop disease resistance in Brassica crops. PMID- 29983485 TI - Biomarker Identification from RNA-Seq Data using a Robust Statistical Approach. AB - Biomarker identification by differentially expressed genes (DEGs) using RNA sequencing technology is an important task to characterize the transcriptomics data. This is possible with the advancement of next-generation sequencing technology (NGS). There are a number of statistical techniques to identify DEGs from high-dimensional RNA-seq count data with different groups or conditions such as edgeR, SAMSeq, voom-limma, etc. However, these methods produce high false positives and low accuracy in presence of outliers. We describe a robust t statistic method to overcome these drawbacks using both simulated and real RNA seq datasets. The model performance with 61.2%, 35.2%, 21.6%, 6.9%, 74.5%, 78.4%, 93.1%, 35.2% sensitivity, specificity, MER, FDR, AUC, ACC, PPV, and NPV, respectively at 20% outliers is reported. We identified 409 DE genes with p values<0.05 using robust t-test in HIV viremic vs avirmeic state real dataset. There are 28 up-regulated genes and 381 down-regulated genes estimated by log2 fold change (FC) approach at threshold value 1.5. The up-regulated genes form three clusters and it is found that 11 genes are highly associated in HIV- 1/AIDS. Protein-protein interaction (PPI) of up-regulated genes using STRING database found 21 genes with strong association among themselves. Thus, the identification of potential biomarkers from RNA-seq dataset using a robust t statistical model is demonstrated. PMID- 29983486 TI - ASBAAC: Automated Salt-Bridge and Aromatic-Aromatic Calculator. AB - : Biological systems are made of complex networks non-covalent interactions observed among protein-protein, protein-DNA, proteinlipid complexes using hydrogen-bonds, salt-bridges, aromatic-aromatic, van der Waals (vdW), hydrophobic interactions and several others using distance criteria. Hence, large-scale data analysis is required to understand the principles of biological complex formation. Therefore, it is of interest to analyze non-covalent interaction namely, salt-bridge and aromatic-aromatic contacts in known and modeled protein complex structures. Here, we describe ASBAAC for automatic calculation of salt bridges and aromatic-aromatic contacts in protein complexes. This software tool is fast, robust and user-friendly for large-scale analysis of inter-chain salt bridges and aromatic-aromatic contact in protein complexes. Availability: ASBAAC is available for free at http://sourceforge.net/projects/asbaac. PMID- 29983488 TI - LSAT: Liliaceae Simple Sequences Analysis Tool, a web server. AB - : LSAT is a web-based microsatellite SSR marker designer tool specific for the Liliaceae family. It is developed using HTML, CSS, PHP, Perl and Java scripts. It works without extra add-ons on standard browsers. LSAT provides SSR primer designing service using the web interface. It helps in SSR mining and primer design. LSAT is user friendly with customizable search parameters producing visual output having download options. The current version of LSAT is backed by two data sets, namely, lily EST (Expressed Sequence Tag) from NCBI and lily nr (non redundant) with 4,099 and 216,768 unigenes, respectively. LSAT will be updated regularly upon availability of additional data (either EST and/or transcriptome) on Liliaceae. Availability: LSAT is available for free at http://210.110.86.160/Lsat/Lsat.html. PMID- 29983489 TI - Erratum: Folliculotropic Mycosis Fungoides in 20 Korean Cases: Clinical and Histopathologic Features and Response to Ultraviolet A-1 and/or Photodynamic Therapy. AB - [This corrects the article on p. 192 in vol. 30, PMID: 29606817.]. PMID- 29983490 TI - Erratum: Disseminated Superficial Actinic Porokeratosis in a Patient with Psoriasis, after Long-Term Narrowband Ultraviolet B Phototherapy. AB - [This corrects the article on p. 211 in vol. 30, PMID: 29606819.]. PMID- 29983487 TI - Computer-Aided Multi-Target Management of Emergent Alzheimer's Disease. AB - Alzheimer's disease (AD) represents an enormous global health burden in terms of human suffering and economic cost. AD management requires a shift from the prevailing paradigm targeting pathogenesis to design and develop effective drugs with adequate success in clinical trials. Therefore, it is of interest to report a review on amyloid beta (Abeta) effects and other multi-targets including cholinesterase, NFTs, tau protein and TNF associated with brain cell death to be neuro-protective from AD. It should be noted that these molecules have been generated either by target-based or phenotypic methods. Hence, the use of recent advancements in nanomedicine and other natural compounds screening tools as a feasible alternative for circumventing specific liabilities is realized. We review recent developments in the design and identification of neuro-degenerative compounds against AD generated using current advancements in computational multi target modeling algorithms reflected by theragnosis (combination of diagnostic tests and therapy) concern. PMID- 29983491 TI - Erratum: Fibrous Plaque of the Eyelid in a Patient with Tuberous Sclerosis Responding to Everolimus. AB - [This corrects the article on p. 247 in vol. 30, PMID: 29606832.]. PMID- 29983492 TI - Ultra-fast, low dose high-pitch (FLASH) versus prospectively-gated coronary computed tomography angiography: Comparison of image quality and patient radiation exposure. AB - Background: Coronary computed tomography angiography (CCTA) is increasingly being used for the evaluation of coronary artery disease; however, radiation exposure remains a major limitation of its use. Objective: To compare image quality and radiation exposure in two groups of patients undergoing CCTA using a 256-slice dual-source helical computed tomography scanner with high-pitch (FLASH) or prospective [step-and-shoot (SAS)] gating protocols. Methods: A prospective, single-center study was performed in our cardiac center. In total, 162 patients underwent CCTA with either FLASH or SAS scanning protocols. Subjective image quality was graded on the basis of a four-point grading system (1, non diagnostic; 2, adequate; 3, good; 4, excellent). Objective image quality was assessed using image signal, noise, and signal-to-noise ratio (SNR). The effective radiation dose was also estimated. Results: The clinical and demographic characteristics of the patients in both groups were similar. The median age of the patients in both groups was 48.43 years, and males accounted for 63% and 68.7% of the FLASH and SAS groups, respectively. We found that the subjective image quality obtained with the FLASH protocol was superior to that obtained with the SAS protocol (3.35 +/- 0.6 mSv vs. 2.82 +/- 0.61 mSv; p < 0.001). Image noise was higher in the FLASH group but was not statistically significant (25.0 +/- 6.13 vs. 24.0 +/- 6.8; p = 0.10), whereas the signal and SNR was significantly higher with the FLASH protocol than with the SAS protocol [(469 +/- 116 vs. 397 +/- 106; p > 0.001) and (21.6 +/- 8.7 mSv vs. 16.6 +/- 7.7 mSv; p < 0.001), respectively]. Radiation exposure was 62% lower in the FLASH protocol than in the SAS protocol, (1.9 +/- 0.4 mSv vs. 5.12 +/- 1.8 mSv; p < 0.001). Conclusion: The use of 256-slice CCTA performed with the FLASH protocol has a better objective and subjective image quality as well as lower radiation exposure when compared with the use of prospective electrocardiography gating. PMID- 29983494 TI - ASD device closure in pediatrics: 3-Dimensional transthoracic echocardiography perspective. AB - Objective: Real-time three-dimensional echocardiography, using both reconstruction methods and RT3D, has been used as an extra helping tool in several forms of congenital heart diseases. Our aim was to understand the relation of the ASD device to all surrounding structures by 3-dimensional echocardiography (3D). Methods: This prospective study included 37 patients diagnosed as ASD secundum by transthoracic (TTE) and transesophageal echocardiography (TEE) referred for transcatheter closure from October 2013 to July 2016. Follow-up for 1 year using 2D and 3D-echocardiography was performed to assess the relations of the device to the surrounding structures. Results: Transcatheter ASD closure and echocardiographic examinations were successfully performed for all patients. By 3D echocardiography, 16 patients (43.24%) had their ASD device close to the aortico-mitral continuity plane without apparent regurgitation, while the rest of our patients (56.75%) the devices were away from this plane. The following variables were significantly different between the two groups; body surface area, atrioventricular rim (AV), device size, left disc size and ratio of left disc to interatrial septum. A cut-off AV rim length not less than 8 mm was found optimal to avoid device encroachment on the sensitive surrounding structures. New Formula was constructed to aid in device choice. Conclusion: Use of 3D before and after ASD closure is of value to determine the device relation to the surrounding structures. AV rim by TEE is an important rim to avoid eventual encroachment on the mitral valve and aorta. PMID- 29983493 TI - A quality improvement project to reduce door-to-electrocardiogram time: A multicenter study. AB - Objective: To improve compliance with a target door-to-electrocardiogram (EKG) time of 10 minutes or less in patients presenting with symptoms concerning for acute coronary syndrome. Methods: A pre-post study was performed between January 2014 and May 2016 at five emergency departments (EDs) in Saudi Arabia. Patients who presented to ED with symptoms concerning for acute coronary syndrome were included in the study. The primary outcome of interest was whether EKG was completed within 10 minutes after the patient arrival to ED. Quality improvement interventions consisted of human resources adjustments, education, technological improvements, and improved interdepartmental collaboration. Multivariate analysis was used to model the percentage of EKGs that were completed within the targeted time. Results: During the study period, 11,518 patients received EKGs. Prior to the intervention, compliance with a door-to-EKG time of 10 minutes or less was found to be 62.6%. Post intervention, compliance improved to 87.7%. On multivariate analysis, male patients were significantly more likely to receive EKG within 10 minutes than female patients (odds ratio = 1.231, 95% confidence interval = 1.113-1.361; p < 0.001). Conclusion: A quality improvement project can successfully increase the percentage of patients receiving EKG within 10 minutes of presentation to ED. Further research is required to demonstrate the clinical significance of improved door-to-EKG times. PMID- 29983495 TI - Prognostic value of homocysteine and highly sensitive cardiac troponin T in children with acute heart failure. AB - Objective: Heart failure (HF) is a progressive disorder in children. Many HF biomarkers have been identified to assess its severity and predict its course. The aim of this study was to evaluate the prognostic value of plasma levels of homocysteine (HCY) and highly sensitive cardiac troponin T (hs-cTnT) in children with HF. Materials and Methods: Eighty children with acute HF were enrolled in this study as the patient group and 80 healthy children of matched age and sex served as the control group. HCY and hs-cTnT serum levels were measured before and after HF treatment; additionally, echocardiographic examinations were performed before and after therapy. All patients were followed up for 3 months. Results: Plasma levels of HCY and hs-cTnT were significantly higher in children with HF before treatment, compared with their levels in children with HF after treatment and with the control group. This increase in serum levels of both biomarkers was associated with increased severity of HF according to the Ross classification of HF. HCY had higher specificity, positive predictive value, and accuracy than hs-cTnT. Serum levels of both biomarkers had a significant positive correlation with cardiomegaly and a significant negative correlation with left ventricular ejection fraction and fraction shortening. Marked elevation of both serum biomarkers was significantly associated with poor outcome with mortality rate of 10%. Conclusion: Plasma HCY and serum hs-cTnT levels have a good prognostic value in children with congestive heart failure (CHF) and their levels significantly correlated with clinical and echocardiographic data, severity of HF, and adverse outcome in children with CHF. PMID- 29983496 TI - Determining the factors causing delayed referral for fetal echocardiography at a tertiary care hospital. AB - Objective: To determine the factors causing delayed referral for fetal echocardiography at a tertiary care hospital. Background: Timely referral for fetal echocardiogram is considered essential for identification of congenital heart diseases, interventions, and counseling of parents. The present study highlights the factors associated with delayed referral for fetal echocardiography. Material and methods: This prospective study includes a total of 200 pregnant females who were referred for fetal echocardiography. The data collected included referral indications, gestational age, maternal age, educational status, referral personale, and final diagnosis on echocardiography. Results: The mean gestational age of presentation was found to be 33 weeks [standard deviation (SD), 4.8 weeks]. Among 200 females, 24% were referred at second trimester, 69% presented at third trimester, and 6% of the females presented at term. No female presented before 18 weeks of gestation. Our results showed that most of the females (94%) were referred by their gynecologist. Eighty nine percent of the females were booked since the first trimester. The most common indication for referral was unexplained death of children (60%). Of 200 pregnant women, 40% were found to be illiterate and 60% were educated. However, the mean gestational age of presentation of illiterate females was 32.9 weeks (SD, 4.2 weeks), and for educated women it was 33 weeks (SD, 5 weeks). Congenital heart disease was diagnosed in 12% of the cases. Conclusion: On the basis of the results, it could be concluded that delayed presentation for fetal echocardiography was not associated with the educational status of females. By contrast, referral personnel were found to be responsible for the delayed referral of females. Therefore, we strongly recommend that both pregnant women and gynecologists be educated about the importance of timely diagnosis for identification of congenital heart diseases. PMID- 29983497 TI - Baseline characteristics, management practices, and long-term outcomes among patients with first presentation acute myocardial infarction in the Second Gulf Registry of Acute Coronary Events (Gulf RACE-II). AB - Background and objectives: Limited data are available highlighting the different clinical aspects of acute coronary syndrome (ACS) patients, especially in Gulf countries. In this study, we aimed to compare patients who presented with acute myocardial infarction (AMI) as the first presentation of patients who have a history of ACS in terms of initial presentation, medical history, laboratory findings, and overall mortality. Methods: We used the Second Gulf Registry of Acute Coronary Events (Gulf RACE-II), which is a multinational observational study of 7930 ACS patients. Results: Among all patients, 4723 (59.6%) patients presented with AMI. First presentation AMI patients were older (mean age, 55 years vs. 53 years; p < 0.001) and had lower risk factors than patients with a history of ACS. Higher laboratory readings of cardiac markers and all aspects of mortality were significantly higher among patients with first presentation AMI. After adjustments for baseline variables, congestive heart failure [odds ratio (OR) = 1.08; 95% confidence interval (CI), 0.73-1.57], reinfarction (OR = 1.16; 95% CI, 0.58-2.30), cardiogenic shock (OR = 1.51; 95% CI, 0.74-3.08), stroke (OR = 2.30; 95% CI, 0.29-17.99), and overall mortality (OR = 1.16; 95% CI = 0.74 1.83) were independent predictive factors for first presentation AMI. Conclusions: First presentation AMI patients tend to be older and to have lower rates of risk factors. Adverse clinical outcomes such as congestive heart failure, reinfarction, cardiogenic shock, and stroke were higher among patients with first presentation AMI compared to patients with a history of ACS. PMID- 29983498 TI - Correlates of memory loss and depression among myocardial infarction patients in Al-Qassim, Saudi Arabia. AB - Background: After myocardial infarction (MI), patients have an elevated risk for depression, which has a negative impact on morbidity and mortality for patients. As depression and memory function are associated, we examined them in the context of one another. Our objectives were to determine the proportion of patients with either depression only, memory loss only, or both depression and memory loss and to examine the correlates with each outcome. Methods: This study was a cohort of 264 patients who had myocardial infarction. Data sources included medical records and phone interviews. Results: The participants' mean age was 62 +/- 12.2 years and mean body mass index was 28.4 +/- 5.8 kg/m2. Of the participants, 6.4% had memory loss alone, 23.17% had depression alone, and 6.1% had combined memory loss and depression. Activity level and poor health were significantly associated with depression only (p < 0.05). Poor health was significantly associated with combined memory loss and depression (p < 0.05). Conclusion: Activity level and poor health were identified as correlates of depression as well as combined memory loss and depression. Future studies should aim to improve screening for depression among post-MI patients and develop appropriate interventions to raise the level of activity. PMID- 29983499 TI - Incidence and causes of prolonged mechanical ventilation in children with Down syndrome undergoing cardiac surgery. AB - Introduction: Trisomy 21 is the most common syndrome in children with a 30-50% association with congenital heart disease (CHD). Cardiac surgeries are required in the majority of Down syndrome (DS) with CHD cases. Because of the distinctive abnormalities in their respiratory system, children with DS may require longer positive pressure ventilation after cardiac surgery. The aim of this study is to investigate the incidence and possible risk factors for prolonged mechanical ventilation (PMV) need in DS patients undergoing cardiac surgery. Methods: We conducted a prospective study on all DS children who underwent cardiac surgery from 2013 to 2016. Demographic and perioperative data were collected including the duration of mechanical ventilation, respiratory risk factors such as previous infection, evidence of pulmonary hypertension during the intensive care unit (ICU) stay, the presence of lung collapse, secretion and wheezy chest, inotropes score, sedation score, arrhythmias, and low cardiac output syndrome. Based on the duration of mechanical ventilation, cases were divided into two groups: the control group, comprising of children who required mechanical ventilation for less than 72 hours, and the PMV group, which consisted of children who required mechanical ventilation for 72 hours or more. Risk factors were compared and analyzed between both groups. Results: A total of 102 participants fulfilled the inclusion criteria, 90 of whom were assigned to the control group and 12 to the PMV group (11.7%). Compared with the control group, the PMV group had a higher incidence of pulmonary hypertension at a younger age (83% vs. 23%, p = 0.012) and 50% of them required chronic treatment for pulmonary hypertension upon home discharge. Pneumonia during ICU stay was encountered more frequently in the PMV group (33.3% vs. 2.2%, p = 0.0042). In addition, the PMV group had more frequent signs of low cardiac output syndrome after surgery (25% vs. 2.2%, p = 0.019), longer ICU stays (7 +/- 0.3 days vs. 15.6 +/- 2.1 days, p = 0.0001), needed more days of inotropes infusion (7.5 +/- 0.4 days vs. 11.1 +/- 1.6 days, p = 0.0045), and required more sedative and paralytic agents postoperatively (6 +/- 0.6 days vs. 8.7 +/- 1 days, p = 0.022). Conclusion: Overall, 11.7% of DS patients required prolonged ventilation after cardiac surgery. Pulmonary hypertension was seen more frequently in cases requiring PMV, and half of PMV cases required antipulmonary hypertension medication upon discharge. Early recognition of pulmonary hypertension and proper perioperative management are recommended to avoid serious complication and comorbidity after cardiac surgery. PMID- 29983500 TI - Endovascular repair of a leaking aortic-arch pseudoaneurysm using graft stent combined with chimney protection to left common carotid artery: Case report and review of literature. AB - Aortic pseudoaneurysm (PsA) is a rare but serious condition that has high mortality and morbidity rates if untreated. We report a rare case of leaking aortic-arch PsA repaired by thoracic endovascular aortic repair using graft stent with the chimney technique to protect the left common carotid artery. Unlike other cases in the literature, our case was unique, having leaking PsA not related to previous cardiac surgery or aortic dissection. The successful management of this patient using thoracic endovascular aortic repair combined with the chimney technique suggests that this approach may be an attractive therapeutic alternative to treat aortic-arch PsA. PMID- 29983501 TI - Is baseline cerebral oximetry a better predictor than carotid scan for postoperative delirium in cardiac surgery? AB - Guidelines recommend screening patients for carotid-artery stenosis, but unfortunately, measurement of baseline cerebral oximetry levels is still not a routine practice prior to cardiac surgery. We report a 41-year-old woman who presented with a normal carotid scan and unexpectedly low baseline cerebral oximetry levels. She had delayed postoperative recovery and discharge from hospital following her coronary-artery bypass surgery. This case report reiterates the prognostic significance of cerebral oximetry in the preoperative checkup and the association of low intraoperative values to postoperative cerebral impairment. It can also be identified as a comparatively better tool for preventing cognitive disturbances after cardiac surgery. PMID- 29983502 TI - Percutaneous retrieval of a shard of metal from the right ventricular apex after an industrial accident. AB - A 29-year-old man suffered from an industrial accident as a piece of metal of a die-cutter burst and shards of metal penetrated his right upper arm. One shard was localized via x-ray and computer tomography within the apex of the right ventricle. Here we report on a successful retrieval of this shard of metal by aspirating it via a 6F multipurpose (MP) catheter. PMID- 29983503 TI - Multimodality imaging of a rare type of coronary cameral fistula. AB - Coronary artery fistulas are defined as abnormal vascular connections between one or more coronary arteries and the cardiac chamber [coronary cameral fistula (CCF)] or a great thoracic vessel. Here, we present multimodality imaging findings of a rare case with CCF between the sinoatrial nodal artery and the left atrium. PMID- 29983504 TI - Huge right ventricular mass revealing a testicular nonseminomatous germ cell tumor. AB - Background: Cardiac intracavitary metastases from a testicular cancer are very unusual, and intra-cardiac metastasis is exceptionally the first expression of a noncardiac primary neoplasm. We report a case of a young patient for whom a cardiac symptom led to the diagnosis of a metastatic testicular cancer. Case presentation: Our presentation describes an unusual case of a 32 years-old male patient admitted for dyspnea, in whom full examination and tests led to the diagnosis of a huge right ventricular mass revealing a testicular malignant teratoma. As the mass was huge and obstructing the root of pulmonary artery, we had decided to opt for surgical treatment in order to remove the obstruction of the pulmonary trunk. Subsequently, the patient has received systemic adjuvant chemotherapy. Conclusions: Here, we describe the world's first reported case of intraventricular metastasis from a nonseminomatous germ cell tumor of the testis which occupies almost all the right ventricular volume and extending to the root of pulmonary artery that underwent surgical resection of the ventricular mass before chemotherapy. PMID- 29983505 TI - Samter-Beer triad presenting as Kounis type I variant of syndrome. PMID- 29983506 TI - Hydroclimatic Variability and Predictability: A Survey of Recent Research. AB - Recent research in large-scale hydroclimatic variability is surveyed, focusing on five topics: (i) variability in general, (ii) droughts, (iii) floods, (iv) land atmosphere coupling, and (v) hydroclimatic prediction. Each surveyed topic is supplemented by illustrative examples of recent research, as presented at a 2016 symposium honoring the career of Professor Eric Wood. Taken together, the recent literature and the illustrative examples clearly show that current research into hydroclimatic variability is strong, vibrant, and multifaceted. PMID- 29983507 TI - What Factors Affect Health Seeking Behavior? PMID- 29983508 TI - Health Seeking Behavior of Patients Diagnosed with Cervical Cancer in Addis Ababa, Ethiopia. AB - Background: Cervical cancer is increasingly recognized as one of the public health problems among women in developing countries. Most women with cervical cancer are seen in the health care system late with advanced stage of cancer. This study aims to explore the care seeking behavior of women with cervical cancer. Methods: A qualitative study was conducted to explore the health seeking behavior of women with cervical cancer for patients who were admitted with cervical cancer in Tikur Anbessa Hospital. In-depth interviews were conducted with purposively selected participants. Interviews were transcribed verbatim and then translated into English and analyzed using a content analysis approach. The study period was from October 2013 to April 2014. Results: The study found that women diagnosed with cervical cancer lack prior awareness about cervical cancer and availability of screening services. Moreover, decision making to seek medical care up on experiencing early symptoms seems to be delayed. Women reported the first symptom was unusual vaginal bleeding that forces them to seek care. The bleeding could be profound and accompanied by offensive odor. Fear of stigmatization could make women reluctant to seek timely care. Once treatment is started most women found it shockingly expensive. Conclusion: Women lack general awareness about the nature and symptoms of cervical cancer. All health services providers serving women need to sensitize women to seek timely screening services and timely treatment services if cervical cancer is confirmed. PMID- 29983509 TI - Susceptibility of Selected Multi-Drug Resistant Clinical Isolates to Leaves of Carpolobia lutea. AB - Background: The decline in the production of new effective antibiotics coupled with the constantly evolving antimicrobial resistance remains a public health concern. This study thus evaluated the antibacterial and antifungal effects of the ethanolic, n-hexane and hot aqueous extracts of Carpolobialutea leaves. Methods: The extracts were tested using agar well diffusion method against selected clinical isolates: Pseudomonas aeruginosa, Salmonella typhi, Escherichia coli, Staphylococcus aureus and Candida albicans. Antibiogram profile of the isolates were deduced by disc diffusion method. Results: Multi-drug resistance was confirmed in all bacteria with a notable pandrug resistance in Pseudomonas aeruginosa. Ofloxacin, Erythromycin and Gentamicin were effective on two or three organisms, notably on Salmonella typhi and Escherichia coli. The preliminary antibacterial assay marked the efficacy of the ethanol and n-hexane extracts except on E. coli, with zero activity for hot water extracts at the stock concentration (200 mg/ml). Pseudomonas aeruginosaand Candida albicans were susceptible to lesser concentrations of the ethanol extracts at 5 mg/ml and 25 mg/ml respectively. None of the isolates showed sensitivity to lesser concentrations of n-hexane extract. Carpolobia lutea leaves proved to be effective over the use of antibiotics in inhibiting the activity of Pseudomonas aeruginosa which was resistant to the latter. The Minimum Inhibitory concentration of the ethanolic extract was considerably low (<=5mg/ml for P. aeruginosa and 25mg/ml for C. albicans). However, there was no Minimum Bactericidal concentration for the extracts against the clinical isolates. Conclusion: Carpolobia lutea shelters bioactive components with pharmacological potentials that could show efficiency in the treatment of bacterial infections. PMID- 29983510 TI - Assessment of Healthcare Waste Generation Rate and Its Management System in Health Centers of Bench Maji Zone. AB - Background: It is known that the basic role of healthcare system is to preserve the health of patients and protect the public from diseases. However, in the process of performing these activities, health facilities generate hazardous waste that could be potentially harmful to healthcare workers, the public and the environment if there is insufficient handling, treatment and disposal of those wastes. Unfortunately, healthcare waste management is, in many regions, not yet carried out with a satisfactory degree of safety. Therefore, the aim of this study was to assess healthcare waste generation rate and its management system in health centers of Bench Maji Zone. Methods: A cross-sectional study was conducted from February to August, 2016. Observational checklist, key informant interview guide and weight scale were used to assess healthcare waste generation rate and its management system in selected health centers. Training, pre-test, instrument calibration and daily meeting were used to improve data quality. The Data was entered, compiled and analyzed using EpiData version 3.1 and SPSS version 21. The results on waste management system were reported using different descriptive statistics. Results: Out of the total HCW generated in health centers, more than half (57.9%) was general or non-risk HCW, and the remaining 42.1% was hazardous healthcare waste. The amount of HCW generated in the studied health centers was different from WHO's norm which may be attributed to different factors such as economy, patient flow, difference in services provided, poor waste segregation practice, available waste management system and seasonal factors. Conclusion: HCW was not adequately managed which is characterized by lack of HCW segregation at source of generation and inadequate facilities to manage HCW. Therefore, it is important to develop a HCW management plan for keeping human health as well environmental sustainability. PMID- 29983511 TI - Identification of Prognostic and Susceptibility Markers in Chronic Myeloid Leukemia Using Next Generation Sequencing. AB - Background: Incidence of Chronic Myeloid Leukemia (CML) is continuously increasing and expected to reach 100,000 patients every year by 2030. Though the discovery of Imatinib Mesylate (IM) has brought a paradigm shift in CML treatment, 20% patients show resistance to this tyrosine kinase inhibiter (TKI). Therefore, it is important to identify markers, which can predict the occurrence and prognosis of CML. Clinical Exome Sequencing, panel of more than 4800 genes, was performed in CML patients to identify prognostic and susceptibility markers in CML. Methods: Enrolled CML patients (n=18) were segregated as IM responders (n=10) and IM failures (n=8) as per European Leukemia Net (ELN), 2013 guidelines. Healthy controls (n=5) were also enrolled. DNA from blood of subjects was subjected to Next Generation Sequencing. Rare mutations present in one patient group and absent in another group were considered as prognostic markers, whereas mutations present in more than 50% patients were considered as susceptibility markers. Result: Mutations in genes associated with cancer related functions were found in different patient groups. Four variants: rs116201358, rs4014596, rs52897880 and rs2274329 in C8A, UNC93B1, APOH and CA6 genes, respectively, were present in IM responders; whereas rs4945 in MFGE8 was present in IM failures. Mutations in HLA-DRB1 (rs17878951), HLA-DRB5 (rs137863146), RPHN2 (rs193179333), CYP2F1 (rs116958555), KCNJ12 (rs76684759) and FUT3 (rs151218854) were present as susceptibility markers. Conclusion: The potential genetic markers discovered in this study can help in predicting response to IM as frontline therapy. Susceptibility markers may also be used as panel for individuals prone to have CML. PMID- 29983512 TI - Prevalence of Opportunistic Intestinal Parasites and Associated Factors among HIV Patients while Receiving ART at Arba Minch Hospital in Southern Ethiopia: A Cross sectional Study. AB - Background: Opportunistic Intestinal Parasites (OIPs) commonly cause morbidity in HIV/AIDS patients due to the decline of CD4+T-cells. The burden of Opportunistic Intestinal Parasitic Infections (OIPIs) in Ethiopia is expected to be high due to poor sanitation and co-pandemicity of HIV/AIDs. Therefore, frequent assessment of the magnitude and associated factors for intestinal parasitosis is essential for the management of HIV/AIDS patients. Methods: A hospital based cross-sectional study was conducted among patients attending Arba Minch Hospital Antiretroviral Therapy (ART) Clinic from March to June 2016. Stool specimens were processed for parasitological examination using direct wet mount, formol-ether sedimentation and modified Ziehl-Neelsen staining techniques. CD4+ T-cell count data were taken from patients' medical records. A structured questionnaire was used to collect data on socio-demographic characteristics and possible associated factors for OIPIs. All the data were analyzed using SPSS version 20. Results: Two hundred and twenty ART patients participated in the study. The overall prevalence of intestinal parasitic infections was 28.18% while that of OIPIs alone was 17.72%. Among identified intestinal parasites, Cryptosporidium species accounts for the highest frequency (19/220, 8.63%), followed by Cyclospora species (13/220, 5.90%). Presence of domestic animals (AOR=2.07, 95%CI:1.07-8.40, P= 0.032) and CD4+ T-cell count <500cell/ul (AOR=4.66, 95%CI:1.17-5.35, P= 0.001) were significantly associated with OIPIs. Conclusion: The study indicated that co infection rate of OIPs is high among ART patients. It also found that contact with domestic animals and having CD4+ count <500 cell/ul predict for the presence of OIPs. PMID- 29983513 TI - Implementation Requirements for Patient Discharge Planning in Health System: A qualitative study in Iran. AB - Background: Effective discharge planning plays a vital role in care continuity and integrated care. Identifying and providing infrastructures for discharge planning can reduce avoidable hospital readmissions and finally lead to improvement of quality of care. The current study aimed to identify the requirements of discharge planning from the perspective of professionals in the health system of Iran. Methods: For the purposes of this qualitative study, semi structured interviews and sessions of focus group discussions with experts in the field were conducted. The data were analyzed using a thematic and framework analyses method. The study population was 51 participants including health policy makers, hospital and health managers, faculty members, nurses, practitioners, community medicine specialists and other professionals of the Ministry of Health andMedical Education (MOHME). Results: According to the control knobs (health reforms levels), recruitments of effective hospital discharge planning were divided into four areas, behavior (ofpolicy makers, service providers, recipients services), organization, payment and financing and regulation (themes), in which there were 3, 7, 2 and 3 sub-themes respectively. Based on the findings of the interviews, they were categorized into the following main themes: behavior (policy makers, providers and patients), organizational change, financing and payment system and rules and regulations. Conclusions: According to the results of the present study, it appears to be essential for health managers and policy makers to pay attention to essential requirements of effective discharge planning. PMID- 29983515 TI - Infection Prevention Practices and Associated Factors among Healthcare Workers in Governmental Healthcare Facilities in Addis Ababa. AB - Background: Failure to follow proper infection prevention practices puts healthcare workers, patients and communities at risk. Despite the increases of highly contagious infections, infection prevention practices among healthcare workers is unknown in many developing countries. The need to understand infection prevention practices is important for prevention and control of nosocomial infections. Therefore, the objective of this study was to assess infection prevention practices and associated factors among healthcare workers in governmental healthcare facilities in Addis Ababa, Ethiopia. Methods: A facility based cross-sectional study design was conducted from February to March 2016, in Addis Ababa among 629 healthcare workers who were selected by multistage sampling technique from 30 governmental healthcare facilities. Data were collected using pre-tested interviewer administered structured questionnaire. Data were entered into Epi -data 3.1 and exported to SPSS version 20 for analysis. Multivariable logistic regression model was used to identify factors associated with infection prevention practices.. Findings were presented using odds ratios with their 95% confidence intervals., A p-value less than 0.05 were used to declare statistical significance. Results: Six hundred five (96.2%) healthcare workers participated in the study. Four hundred (66.1%, (95%CI: 62.1%-70.1%)) health care workers had good infection prevention practices. Having good knowledge on infection prevention meausures (AOR =1.53, 95%CI: 1.05-2.22), having positive attitude towards infection prevention practices (AOR=2.03, 95%CI: 1.26-3.26), having awareness on availability of standard operating procedures (AOR=1.97, 95%CI: 1.34 2.93) and presence of continuous water supply (AOR=1.68, 95%CI: 1.11-2.56) were predictors of good infection prevention practices. Conclusion: Two-third of the healthcare workers had good infection prevention practices. Having good knowledge on infection prevention measures, having positive attitude towards infection prevention practices, having awareness on availability of standard operating procedures and presence of continuous water supply were predictors of good infection prevention practices. To sustain good practices, adequate pre-service and in-service training should be in place to equip and update health care workers about infection prevention precautions. The need for continuous supervision should be implemented to strengthen adherence for infection prevention practices among workers along with sustainable and reliable water supply is crucial. PMID- 29983514 TI - Goitre-Related Factors for Predicting Difficult Intubation in Patients Scheduled for Thyroidectomy in a Resource-Challenged Health Institution in North Central Nigeria. AB - Background: Airway management problems may arise when intubating patients with goitre scheduled for thyroidectomy. Goitres are not uncommon in sub-Saharan Africa, thyroidectomy being the main treatment. The aim of this study was to determine incidences of difficult intubation (DI), failed intubation (FI) and predictors of DI using a modified intubation difficulty score (IDS). Methods: One hundred and twenty-five consenting patients with goitre scheduled for thyroidectomy were recruited. Goitre-related factors (GRF) of duration of illness, diagnosis, neck circumference, tracheal deviation and narrowing and retrosternal extension were recorded as well as Mallampati classification and BMI. At intubation, modified IDS was determined for each patient. Patients with modified IDS <= 5 were categorized as easy intubation group (E), and those with modified IDS >5 were categorized as difficult intubation group (D). The GRF of all patients in group D were compared with matched patients in group E. Results: Incidence of DI was 13.6% with 2 (1.6%) cases of failed intubation. Comparing groups D and E, duration of illness was 4.28 +/- 3.78 years in group D versus 7.44 +/- 7.63 years group E, p = 0.1353. Neck circumference was 41.42 +/-5.30 cm in group D versus 37.43+/-2.68 cm in group E, p = 0.0200. Tracheal deviation, narrowing and retrosternal extension, and surgical diagnosis were not significantly different among both groups. Conclusion: Incidence of DI was 13.6% and that of FI was 1.6%. Neck circumference was found to be a predictor of difficult intubation in goitre patients scheduled for thyroidectomy using the modified IDS. PMID- 29983516 TI - Pediatric Urinary Tract Infection as a Cause of Outpatient Clinic Visits in Southern Ethiopia: A Cross Sectional Study. AB - Background: Failure to timely diagnose and treat urinary tract infections is associated with grave long term consequences. The objectives of this study included assessing the proportion and predictors of Urinary Tract Infection (UTI) as a cause of pediatric outpatient department (OPD) visits and determining common uropathogens with antimicrobial susceptibility pattern. Methods: A cross sectional study was conducted from May to September 2015 among children of less than 15 years old at a tertiary center in Hawassa, Ethiopia. Children who fulfilled predefined eligibility criteria were recruited to undergo urine culture and urine analysis. Results: A total of 863 children visited the OPD during the study period among which 269(31.2%) fulfilled the predefined eligibility criteria. Urine culture was positive for 74/269(27.5%) of the clinically suspected children. Male uncircumcision (adjusted odds ratio (aOR) 3.70; 95% CI 1.34-10.16) and under nutrition (aOR 5.41; 95%CI 2.64-11.07) were independent predictors of culture positivity. More than 5 WBC per high power field (aOR 4.7, 95% CI 1.8-12.7) on microscopy, urine PH > 5.0 (aOR 2.6, 95%CI 1.2-5.8), and positive leukocyte esterase (aOR 9.9, 95%CI 4.1-25.7) independently predicted positive growth on urine culture. Escherichia coli (34/74, 45.9%) and Klebsiella spp (18/74, 24.3%) were the most frequent isolates. High resistance was noted against amoxicillin (70.6%) and cotrimoxazole (97.1%) by E. coli. Conclusion: UTI accounted for a tenth of total OPD visits. Commonly used first line antibiotics showed high level resistance to common etiologies of UTI. UTI should be suspected in febrile children, and antibiograms should be done to tailor prescription of antibiotics. PMID- 29983517 TI - Isolation and Antimicrobial Susceptibility Profile of Shigella and Salmonella Species from Children with Acute Diarrhoea in Mekelle Hospital and Semen Health Center, Ethiopia. AB - Background: Salmonella and Shigella remain the major contributors to acute enteric infections and diarrhoea. Hence, the objective of this study was to isolate and determine the antimicrobial susceptibility pattern of Shigella and Salmonella species from children with acute diarrhoea in Mekelle Hospital and Semen Health Center. Methods: A cross sectional study was conducted among 260 children with acute diarrhoea from November 2011 to March 2012 in Mekelle, Ethiopia. Stool specimen was collected from all study participants who presented with acute diarrhoea. Microscopy, culture and confirmatory identification were done by the pattern of biochemical reactions using a standard bacterial identification system (API 20E, BioMerieux, Marcy-l'Etoile, France) and polyvalent (Poly O and H) antiseras for Salmonella species and Vi for S.typhi. Isolated colonies were assessed for antimicrobial susceptibility profile using disk diffusion method. Data was entered and analyzed using SPSS version 16.0 software. Results: Out of the 260 study participants, 145(55.8%) were males while 115(44.2%) were females. The majority of the patients (44.2%) were of children under five years old. A total of 120 enteropathogens were isolated. The frequency of isolation was 19(7.3%), 18(6.9%) and 83(31.9%) for Salmonella species, Shigella species and intestinal parasites respectively. Most of the Shigella isolates were resistant to ampicillin (88.9%), Tetracycline (77.8), cotrimoxazole (55.6%) and chloramphenicol (55.6%). Among the Salmonella isolates, the highest resistance was observed to ampicillin (89.5%), Tetracycline (89.5%), chloramphenicol (78.9%) and cotrimoxazole (57.9%). Multi-drug resistance was noted in 19(100%) and 16(88.9%) of Salmonella and Shigella species respectively. Conclusions: Shigella and Salmonella are still challenging pathogens in children < 5 years of age. High antibiotic resistance was observed among both isolates to ampicillin, tetracycline, chloramphenicol and cotrimoxazole. PMID- 29983518 TI - Utilization and Associated Factors of Modern Contraceptives During Extended Postpartum Period among Women Who Gave Birth in the Last 12 Months in Gondar Town, Northwest Ethiopia. AB - Background: The postpartum period is a critical period for addressing widespread unmet needs in family planning and for reducing the risks of closely spaced pregnancies. However, many women do not realize that they are at risk for pregnancy during this period. Therefore, the aim of this study was to assess utilization and associated factors of modern contraceptives during extended post partum period. Methods: Institutional based cross-sectional study was conducted from March to April, 2015 in six health institutions among women who gave birth in the last 12 months prior to the study period in Gondar Town, Northwest Ethiopia. A systematic random sampling technique was used to select the study participants. Data were analyzed using SPSS version 20. Bivariate and multivariate logistic regression models were fitted to identify the determinants of postpartum modern contraceptive use. Adjusted odds ratios with 95% confidence intervals were calculated, and p-values <0.05 were considered to indicate statistical significance. Result: Of the total 404 participants, 45.8% mothers used modern contraceptives during postpartum period. Injectable contraceptive was the most frequently used method. Menstruating [AOR =3.84, 95% CI: (2.33, 6.35)], resumption of sex [AOR= 3.17, 95% CI: (1.80, 5.58)], 37-51 weeks of postpartum period [AOR= 2.48, 95% CI: (1.11, 5.55)], husband approval of contraceptive [AOR= 2.10, 95% CI: (1.16, 3.82)] and current knowledge on FP [AOR= 5.01, 95% CI: (2.23, 11.24)] were factors affecting contraceptive use in postpartum period. Conclusion: Utilization of modern contraceptive during the postpartum period was significantly decreased placing women at risk for a pregnancy in the extended postpartum period. Menstruating, resumption of sex, variation on postpartum period and husband approval of contraceptive were factors associated with contraceptive use. Strengthening FP counseling service at the ANC clinic and postnatal care would improve contraceptive use during the postpartum period. PMID- 29983519 TI - Analysis of the Effect of Health Education Activities on Selected Child Health Determinants in Two Communities of Ile Ife, Nigeria. AB - Background: Child survival in Nigeria is threatened not just by the direct causes of childhood mortality such as the common childhood diseases but also by the associated child health determinants. Health education activities as part of community integrated management of childhood illness have the potential to improve these child health determinants. The objective of this study was to assess the effect of community level health education activities on selected child health determinants in Ile Ife, Nigeria. Methods: A cross-sectional comparative study was carried out among 722 caregivers in two LGAs of Osun State, Nigeria, using a multistage cluster sampling method. Data were collected from mothers of index children aged 0-59 months using an interviewer-administered questionnaire. Results: Vitamin A supplementation before the study was received by 89.1% and 79.8% of the children aged 9 months old and above in implementing and non-implementing LGAs (p=0.002). Amongst children age 12-23 months in the implementing LGA, 93.4% received DPT3, (91.8%) received measles compared with non implementing LGA in which 66.7% received DPT and (64%) measles. Children in the CIMCI implementing LGA were three times more likely to receive DPT Vaccine (Adjusted odds ratio (AOR) 3.02, 95% confidence interval (CI) 1.55-7.98), and five and half times more likely to receive measles vaccine (AOR 5.56, 95% CI 2.76 12.54). Conclusion: The study concluded that community level health education activities have a positive effect on child health practices and determinants. PMID- 29983520 TI - Level of Faecal Coliform Contamination of Drinking Water Sources and Its Associated Risk Factors in Rural Settings of North Gondar Zone, Ethiopia: A Cross Sectional Community Based Study. AB - Background: Today, close to a billion people mostl living in the developing world do not have access to safe and adequate water. Several studies in Ethiopia indicate that the majority of the drinking water sources had coliform count beyond the WHO standard. Therefore, Regular quality control mechanisms need to be in place. The objective of this study is therefore to determine the level of faecal coliform contamination of drinking water and its associated factors in North Gondar Zone, Ethiopia. Methods: A community-based cross-sectional study was conducted in rural parts of North Gondar Zone from April to July, 2016. Water samples were taken from water sources using standardized water sampling techniques. Face-to-face interview with structured questionnaires were used to collect socio-economic and behavioral data. Univariate and multivariate analyses were done using logistic regression models. Results: A total of 736 households participated in the study. The prevalence of positive faecal coliform at water sources in North Gondar Zone was found to be 56.5% (n=416) with [95% CI (53-60)]. In multivariate analysis, educational status [(AOR): 0.28, 95% CI (0.1-0.8], sanitary risk of contamination [AOR): 513, 95%CI (51-511)] and water shortage experience [AOR: 0.25, 95% CI (0.12-0.5)] are variables identified as predictors for faecal coliform contamination of water in the source. Conclusion: In this study, the prevalence of positive faecal coliform at water source was high. Educational status, sanitary Risk of contamination at the water source, water shortage experience had significant associations with the presence of faecal coliform in drinking water sources. PMID- 29983521 TI - Errors in the Total Testing Process in the Clinical Chemistry Laboratory at the University of Gondar Hospital, Northwest Ethiopia. AB - Background: Laboratory services have been described as the major processes contributing to safe patient care in the modern healthcare sector. However, occurrences of errors in the overall testing processes impair the clinical decision-making process. Such errors are supposed to be high in resource-poor countries, like Ethiopia. The objective of this study was to assess errors in the total testing process in the Clinical Chemistry laboratory of the University of Gondar Hospital, Northwest Ethiopia. Methods: A cross-sectional study was conducted at the University of Gondar Hospital from February to March 2016. All the required data were collected using established quality indicators. Data were analyzed using SPSS version 20. Frequencies and cross-tabulations were used to summarize descriptive statistics. Results: A total of 3259 samples and corresponding laboratory request forms were received for analysis. The analysis of the overall distribution of errors revealed that 89.6% were pre-analytical errors, 2.6% were analytical, and 7.7% were post-analytical errors. Of the pre analytical errors, incomplete request form filling was the most frequent error observed, followed by sample rejection rate (3.8%). Analytical errors related to internal and external quality control exceeding the target range, (14.4%) and (51.4%) respectively, were reported. Excessive turnaround time and unreported critical value cases were the major defects in the post-analytical phase of quality assurance. Conclusion: The present finding showed relatively high frequency of errors, which alarms the importance of quality indicators to assess errors in the total testing process. The University of Gondar Hospital laboratory should improve the quality of healthcare services based on these findings using laboratory standards. PMID- 29983522 TI - Split Calvarial Graft and Titanium Mesh for Reconstruction of Post-Craniotomy Frontal Bone Defect. AB - Background: The goal of cranioplasty is to achieve a lifelong, stable and structural reconstruction of the cranium covered by a healthy skin and scalp flap. We present two cases of large frontal bone defect following a accident. Cases: We describe the utilization of autogenous local split calvarial graft and titanium mesh for the reconstruction of the post trauma frontal bone defect. Conclusion: Cranioplasty using split calvarial bone grafting for restoring large cranial defects resulting from a trauma is a useful technique, and allows the surgeon to reconstruct a moderate to large cranial defect without rifting the inner cortical plate. PMID- 29983523 TI - How Can Ethiopia Mitigate the Health Workforce Gap to Meet Universal Health Coverage? PMID- 29983524 TI - Trends and Outcomes of Emergency Pediatric Surgical Admissions from a Tertiary Hospital in Ethiopia. AB - Background: Pediatric surgical emergency condition is a broad spectrum of surgical pathologies/disorders occurring in pediatric age group requiring proper emergency surgical care as the only option of management to salvage life, avoid/minimize disability or palliation. The objective of this study is to analyze the pattern and outcome of pediatric surgical emergencies managed at Tikur Anbesa Hospital and the factors associated with outcome. Methods: Retrospective analysis of medical records of patients was conducted to assess the pattern, outcome and factors associated with outcome of pediatric surgical emergencies admitted and managed at Tikur Anbesa Specialized Hospital, from January 1, 2015 to December 31, 2015. Data was checked for completeness and entered into SPSS version 20 for statistical analysis. Results: A total of 454 patients' medical records were analyzed. The presentation was after 5 days of illness in 182(40%), and >3 days in 243(53.4%), while only 89(19.6%) of them come within 24 hours of the illness. The etiologies were abdominal/gastrointestinal emergencies 210(46.3%), foreign body in aero digestive system in 133(29.3%), urogenital surgical emergencies in 27(5.9%). The other causes include superficial and deep tissue abscess collections in 22(4.8%), trauma /injury related cases in 24(5.3%) and others in 38(8.4%) respectively while congenital malformations were only 57(12.6%) of the cases. Finally, 439(96.7%) were discharged cured or improved without major disabilities documented, while 9(2%) died. Conclusions: Delayed presentation, unstable condition on arrival, younger age group and the nature of underlying pathology could have contributed for the death, but this needs further study. PMID- 29983525 TI - Anemia among School-Age Children: Magnitude, Severity and Associated Factors in Pawe Town, Benishangul-Gumuz Region, Northwest Ethiopia. AB - Background: Anemia is a global public health problem associated with increased mortality and morbidity. The cause of anemia in school-age children is multifactorial and has been associated with delayed psychomotor development, poor cognitive performance, impaired immunity and decrease working capacity. The aim of this study was to determine the magnitude, severity and determinant factors of anemia among school-age children (5-15 years) in Pawe Town, Northwest Ethiopia. Methods: A community based cross-sectional study was conducted from March 20 to June 19, 2015 in Pawe Town. A total of 422 school-age children were included in this study. Sociodemographic and related data were collected using structured questionnaire. Anthropometric data were collected from each study participant. Hemoglobin concentration was measured using HemoCue(r) Hb 201+ System (HemoCue, Angelholm, Sweden). Blood film for malaria diagnoses and stool examination for intestinal parasites were also performed. Data were analyzed using SPSS version 20.0. Results: The overall prevalence of anemia among school-age children was 33.9%. Mothers' illiteracy (AOR=7.5, 95% CI: 2.6-16.3), being from a family with low income (AOR=4.8, 95% CI: 1.3-10.9), being stunted (AOR=7.1, 95% CI: 2.9 11.9), being underweight (AOR=5.3, 95% CI: 2.1-13.3), infection with intestinal parasites (AOR=5.2, 95% CI: 2.1-12.6), and malaria infection (AOR=8.2, 95% CI: 1.8-14.5) were identified as associated factors of anemia. Conclusion: In this study, anemia is a moderate public health problem among school-age children. School health strategies and interventions targeting nutritional deficiencies and parasitic infections might be very important. PMID- 29983526 TI - Postnatal Care Utilization and Associated Factors among Married Women in Benchi Maji Zone, Southwest Ethiopia: A Community Based Cross-Sectional Study. AB - Background: In Ethiopia, maternal health service utilization is very low, especially postnatal care (PNC). The percentage of mothers who receive care within two days of childbirth has shown little progress, from 2.4% in 2000 to 13% in 2014. However, it is very far below the expected level as compared to other sub-Saharan regions. Therefore, the aim of this study was to assess PNC services utilization and its associated factors among married women in Benchi-Maji Zone, Southwest Ethiopia. Method: A cross-sectional study was conducted from June 15 to August 15, 2015. A total of 801 married women was sampled from randomly selected districts in the zone. Semi-structured questionnaire was used to collect, data and informed consent was obtained from participants. The collected data were entered into the computer using Epi-data version 3.0, and then exported to SPSS Windows version 20.0 for analysis. Logistic regression was used to identify important predictors of PNC utilization. Result: Out of 765 participants, 392(51.24%) of married women who attended PNC in this study. Out of them, more than two-third 305(77.8%) attended mainly to immunize their baby. The vast majority, 251(86.3%), of respondents mentioned lack of information as a main reason for not following PNC, and of them, the majority mentioned that they were appointed to come after 45 days for Family Planning(FP). In comparison with house wives, farmer women were less likely (AOR 0.3, 95 % CI 0.2-0.7) to attend for PNC. Awareness of problems during postnatal period showed the strongest association in which those who knew the problems were about nine times (AOR 8.7 95 % CI 5.6-13.4) more likely to attend PNC. Similarly, married women who followed antenatal care (ANC) were more likely (AOR 2.2 95 % CI 1.1-4.6) to attend PNC in comparison with those who did not attend ANC at all. Conclusion: Residence, ANC follow-up, maternal occupation, awareness about problems of postnatal period had effects on use of PNC. In light of this study, providing deep counselling about PNC at the time of ANC visit and discharge after delivery is strongly recommended. Furthermore, targeting more of rural married women may increase PNC utilization. PMID- 29983527 TI - Trend of Malaria Cases in Hana and Keyafer Health Centers, South Omo Zone, Southern Ethiopia. AB - Background: Data registered in health facilities about malaria are vital source of information regarding the trend and pattern of the disease. Moreover the data also used to evaluate the impact of the intervention methods and to plan malaria control accordingly. The aim of this study was to assess the number of malaria cases in the service providing health institutions of South Omo Zone, SNNPR, over a period of seven years, 2008-2014. Methods: A retrospective review of routinely collected and recorded data on malaria was conducted at Hana and Keyafer health centers located in South OmoZone, during December-March/2014. Result: This retrospective study examined records of 54,160 presumptive and confirmed malaria cases registered over seven years (January 2008-December 2014). Among the registered, a total of 22,494 laboratory confirmed malaria cases were reported. The mean annual prevalence of malaria was 3213, with total slide positivity rate (SPR) of 41.53%. The seven years' overall trend of malaria occurrence in the study sites showed a fluctuating trend from 2008 to 20114. P. falciparum was the predominant species with no trend shift in seven years period. Plasmodium falciparum accounted for 61.03% and Plasmodium vivax for 32.44%. Most of the confirmed cases were males (63.26%) and most were above 15 years old (70.7%). Rainfall at lag of one month was significantly predicting number of cases at Hana Health center (P< 0.001), though it was found to be not significant in case of Keyafer Health Center. Conclusion: The finding of the retrospective study revealed that malaria still remains as a public health problem in the study areas. The deadly species P. falciparium was most predominant, and the age group above 15 was more infected. Hence, malaria intervention methods should be scaled up in the study sites. PMID- 29983528 TI - Teenage Pregnancy and Its Associated Factors among School Adolescents of Arba Minch Town, Southern Ethiopia. AB - Background: Teenage pregnancy has long been a worldwide social, economic and educational concern for the developed, developing and underdeveloped countries. Studies on adolescent sexuality and pregnancy are very limited in our country. Therefore, this study aims to assess the prevalence of teenage pregnancy and its associated factors among school adolescents of Arba Minch Town. Methods: Institution-based, cross-sectional study was conducted from 20-30 March 2014. Systematic sampling technique was used to select a total of 578 students from four schools of the town. Data were collected by trained data collectors using a pre-tested, self-administered structured questionnaire. Analysis was made using SPSS version 20.0 statistical packages. Multivariate logistic regression was used to identify the predictors of teenage pregnancy. Results: The prevalence of teenage pregnancy among school adolescents of Arba Minch Town was 7.7%. Being grade 11 student (AOR=4.6;95%CI:1.4,9.3), grade 12 students (AOR=5.8;95% CI:1.3,14.4), not knowing the exact time to take emergency contraceptives (AOR=3.3;95%CI:1.4,7.4), substance use (AOR=3.1;95%CI:1.1,8.8), living with either of biological parents (AOR=3.3;95%CI:1.1,8.7) and poor parent-daughter interaction (AOR=3.1;95%CI:1.1,8.7) were found to be significant predictors of teenage pregnancy. Conclusions: This study revealed high level of teenage pregnancy among school adolescents of Arba Minch Town. A significant number of adolescent female students were at risk of facing the challenges of teenage pregnancy in the study area. School-based reproductive health education and strong parent-daughter relationships are recommended. PMID- 29983529 TI - Mutations of rpob Gene Associated with Rifampin Resistance among Mycobacterium Tuberculosis Isolated in Tuberculosis Regional Reference Laboratory in Northeast of Iran during 2015-2016. AB - Background: Drug resistance is a leading concern in control of TB. Resistance against rifampin as one of the most important drugs in the treatment of Mycobacterium tuberculosis is caused by mutations in the 81-base pair region of the rpoB gene encoding the beta-subunit of RNA polymerase. This study aimed to characterize the mutations in the rpoB gene associated with rifampin resistance among M. tuberculosis. Methods: This study was conducted on referred samples of patients who did not respond to anti-TB treatment, in Tuberculosis Regional Reference Laboratory at Shariati Hospital. Drug susceptibility of M. tuberculosis isolates was surveyed using a proportional method on LJ medium. The isolates with resistant to rifampin were reconfirmed and then the rpoB gene was amplified and sequenced. Results: Among 27 resistant cases, 8, 11 and 8 people were from Iran, Afghanistan, and Turkmenistan, respectively. In 26 out of 27 isolates, rpoB gene mutations were observed. The most prevalent mutations belonged to the codon 53. The most prevalent mutations belonged to the TCG (Ser) 531TTG (leu) with prevalence 51.8% (n=14), and GAC (Asp)516TAC (Tyr), CAC (His) 526GAC (Asp) and CAC (His) 526TAC(Tyr) mutations with prevalence 14.8%(n=4). Twenty-three isolates had just one mutation. Conclusion: The use of rpoB gene sequencing led to the lack of the need for growth of the organism in the culture medium, the direct use of clinical samples, reduction of biological risks and a detection about 96.3% of MDR TB cases lowering the cost of the treatment. PMID- 29983530 TI - An Evidence-Based Framework for Evidence-Based Management in Healthcare Organizations: A Delphi Study. AB - Background: Evidence-based management (EBMgt) is a growing literature concept in management sciences which claims that management decision-making must be based on the best available evidence. The aim of this paper is to present and provide an evidence-based framework for EBMgt to improve decision-making in healthcare organizations. Methods: A two-round Delphi survey was used to collect the factors affecting EBMgt. Purposive and snowball sampling methods were used in both rounds. In round 1, we conducted a systematic review and a series of semi structured interviews (n=45). In round 2, a specific questionnaire with four main parts was designed. The experts (n=21) were asked to rate on a 9-point Likert scale the importance of each factor. The data was collected through Google Forms (n=11) and paper forms (n=10). Results: Participants were mostly men (73%). Overall, 126 factors were selected in round 1. Factors were classified into 4 categories: facilitators, barriers, the sources of evidence and EBMgt process that consisted of 48, 46, 22 and 10 factors, respectively. In round 2, based on median scores, many factors (n=114) were found to be very important. Only, 12 factors have a median score of less than 3 and were excluded from the study. Finally, 114 factors were confirmed. Conclusions: Confirmed factors played significant roles in affecting the practice of EBMgt among healthcare managers. We tried to facilitate interaction between these factors in the framework. Depending on the type of problem, using six steps of EBMgt process, managers will select the best evidence among six sources of evidence. PMID- 29983531 TI - Asymptomatic Malaria Infection and Associated Factors among Blood Donors Attending Arba Minch Blood Bank, Southwest Ethiopia. AB - Background: It is well known that malaria can be transmitted via blood transfusion. However, it is not documented in the national donor screening protocol. Magnitude of asymptomatic malaria among donors would be the key to decide on the need of donor screening. Despite this, there is lack of such data in Ethiopia. The aim of this study was thus to estimate the prevalence of asymptomatic malaria and associated factors among blood donors. Methods: An institution based cross-sectional study was conducted in Arba Minch blood bank from February to June, 2015. Data was collected from donors who passed the clinical donor selection criteria and recruited by systematic random sampling technique. A structured questionnaire was used to capture data on socio demographic characteristics. Giemsa stained blood films were examined for plasmodium parasites. Magnitude of asymptomatic malaria was calculated and association of factors with malaria was assessed by multivariable logistic regressions using SPSS version 20.0. Results: A total of 416 donors participated in the study. The proportion of infected donors was 4.1% (17/416). Eight donors were infected with Plasmodium falciparum while 9 donors were infected with Plasmodium vivax. Most positive blood films (13/17) were with parasite loads ranging from 100 - 500 parasites/ul. Donors with blood group O were more susceptible to malaria parasitemia compared to all other ABO blood groups together (AOR=6.899, 95%CI=1.951-24.391, p=0.003). Conclusion: Magnitude of malaria parasitemia in the present study was high as compared to the national malaria prevalence. Hence, in malaria endemic areas of Ethiopia, blood should be screened before donation. PMID- 29983532 TI - Magnitude of Severe Head Injury and Its Associated Factors among Head Injury Patients in Gedeo Zone, Southern Ethiopia: A Two-Year Retrospective Study. AB - Background: Severe head injury is a major public health threat that is the main cause of morbidity and mortality in all age groups of the world's populations including Ethiopia. In view of this, this study was assessed the severity of head injury and its contributing factors. Methods: A Two-year retrospective study was conducted at Dilla University Referral Hospital, from December 2014 to November 2016. All head injury patients admitted to the surgical ward were included. Bivariate and multivariate regression analyses were used to identify factors associated with severity of head injury. Results: A total of 106 eligible head injury patient charts were reviewed. The magnitude of severe head injury was 32.1%. Young populations, mainly males, were the highest risk groups, and road traffic accident was the main cause of severe head injury. In adjusted analysis, age interval greater than 45 years (aOR, 5.41; 95% CI:1.05-29.09), alcohol consumption before the trauma (aOR, 4.16, 95%CI: 1.18, 14.61), delayed presentation (beyond 24 hours) after injury (aOR, 4.717; 95% CI: 1.02-21.81), and respiratory rate greater than 30 breaths per minute (aOR, 7.34; 95% CI: 1.88 28.73) were significantly associated with severe head injury. Conclusions: Severe head injury remains an important public health problem. Young adults were the highest risk groups of populations. Prevention of road traffic accidents, continuous awareness creation about the consequences of road traffic accident and close neurological monitoring offered by neuro-intensive care unit are recommended. PMID- 29983533 TI - Biochemical Profiles of Pregnant and Non-pregnant Women Attending at the University of Gondar Hospital, Northwest Ethiopia: A Comparative Cross-sectional Study. AB - Background: Pregnancy is a natural physiological statement with hormonal and metabolic changes that helps the growth and survival of the fetus. However, biochemical profiles derangement may lead to pregnancy complications. Therefore, there is a need for determining biochemical profiles among pregnant women. Methods: A comparative cross-sectional study was conducted among pregnant and non pregnant women at the University of Gondar Hospital, from February to April, 2015. Fasting blood sample was collected from 139 pregnant and 139 age matched non-pregnant women using systematic random sampling technique. Interviewer administered questionnaire was used to collect socio-demographic and clinical data. Fasting blood glucose and lipid profile were measured by A25 Biosytemchemistry analyzer using enzymatic calorimetric methods. Data analysis was done using SPSS version 20. Level of significance between groups was analyzed using independent student t-test and Mann-Whitney U test. A p-value of <0.05 was considered as statistically significant. Result: Pregnant women as compared to non-pregnant had significantly increased glucose (96.35+/-14.45 and 81.12+/-9.86 mg/dl), total cholesterol (211.9+/-40.88 and 172.40+/-29.64 mg/dl) [p<0.05], respectively. It had also significantly high triglycerides (190.81+/-81.04 and 107.43+/-45.80 mg/dl) and low-density lipoprotein cholesterol (116.03+/-37.26 and 86.12+/-27.29mg/dl) [p<05] in pregnant as compared to non-pregnant women. The level of high-density lipoprotein cholesterol was significantly lower in pregnant women (59.58+/-14.26) than control (63.63+/-11.4, P <0.05). Conclusion: There were statistically significant increment in glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol and decrement in high-density lipoprote in cholesterol levels among pregnant women compared with non-pregnant women. Therefore, pregnant women have to be monitored closely for their biochemical profiles to avoid adverse pregnancy outcomes. PMID- 29983535 TI - Prevalence of Tuberculosis and Treatment Outcomes of Patients with Tuberculosis among Inmates in Debrebirhan Prison, North Shoa Ethiopia. AB - Background: Prevalence of tuberculosis in vulnerable groups such as prisoners is usually high, and the problem is worsened by poor treatment outcomes. In spite of this, there is limited information regarding tuberculosis in prisons of Ethiopia. Hence, this study was aimed to assess the prevalence of tuberculosis and treatment outcomes of patients with tuberculosis among inmates of Debrebirhan prison in North Shoa, Ethiopia. Methods: A retrospective cross-sectional study was conducted among inmates of Debrebirhan prison. Data were collected by reviewing the medical charts and other records of prison inmates diagnosed and treated for tuberculosis between September 2010 and August 2015. Data were entered and analyzed using SPSS version 21.0. Results: A total of 162 patients with tuberculosis were registered and treated at Debrebirhan prison health center within the five years study period. The overall average prevalence was found to be 32 per 1538 (2139 per 100,000) prison inmates. Regarding treatment outcome, 44(27.2%) were cured, 59(36.42%) completed treatment, 2(1.24%) were treatment failures, 6(3.72%) died and 51(31.5%) were not evaluated. The five year's treatment success rate was found to be 63.62%. Area of residence (AOR= 3.59; 95% CI: 1.44, 8.93), duration of imprisonment (AOR = 3.67; 95% CI: 1.53, 8.78) and history of tuberculosis were significantly associated with treatment outcome of tuberculosis. Conclusion: This study showed high prevalence of tuberculosis in Debrebirhan prison. It also revealed that the treatment success rate of patients with tuberculosis was lower than the target set by World Health Organization. PMID- 29983534 TI - Testing Psychometrics of Healthcare Empowerment Questionnaires (HCEQ) among Iranian Reproductive Age Women: Persian Version. AB - Background: Producing high quality data needs an accurate measurement in any fields of study. This study aimed to test psychometrics of the Persian version Healthcare Empowerment Questionnaire (HCEQ) in relation to personal care among Iranian reproductive age women and to validate the instrument for future use. Methods: A cross-sectional study was conducted on 549 reproductive age women in a health centers affiliated to Tehran University of Medical Sciences producing a response rate of 100%. Content validity was established using translation and backtranslation procedures, pilot testing, and getting views of expert panel. Construct validity was measured using explanatory factor analysis. Cronbach's alpha was used to measure internal consistency, and intra-class correlation coefficients were used to confirm stability. Results: The results indicated that explanatory factor analysis of 10 items in three dimensions explained 63.2% of the total variance. Validity and reliability of the 10-items of HCEQ with two response scales (perception of control and motivation of being empowered) assessed for internal quality showed the reliability of internal consistency (alpha=0.70; range=0.62-0.76). The correlation between convert (10 items) and apparent (3 factors) variables was 0.5 times higher than the revealed convergent validity. Conclusion: The findings of this study supported the reliability and validity of the Persian version of HCEQ to assess the degree of individual empowerment in relation to personal healthcare and services among reproductive age women. Therefore, the HCEQ-Persian version could be a useful, comprehensive, and culturally sensitive scale for assessing healthcare empowerment among reproductive age women. PMID- 29983536 TI - Contextualizing Ottawa Charter Frameworks for Type 2 Diabetes Prevention: A Professional Perspective as a Review. AB - Background: Type 2 Diabetes remains one of the deadliest non-communicable diseases in the world. Systematically articulating the health issues with emerging policies is very important in preventing chronic diseases like diabetes. This article aims to integrate Ottawa Charter frameworks in prevention of Type 2 diabetes and the way the charter's application should bring amicable changes if applied as planned. Method: We used the aim of the study as a method derivative. Then, we applied the five actions of Ottawa Charter frameworks. We also described and stated the existing scientific literature (knowledge) about the prevention of diabetes. After thoroughly reviewing, possible intervention strategies were included with a brief discussion by comparing different literatures. In our case, diabetes prevention is facilitated by those actions and conditions. Evidence: Setting appropriate goals, lifestyle modifications, appropriate self-monitoring of blood glucose, medications, regular monitoring for complications, and laboratory assessment are important factors to be endorsed within Ottawa Charter five actions. Lifestyle interventions and physical activities are the most important factors recommended in different reviews and interventions. However, none of the studies had integrated disease prevention with existing policy. Conclusion: Type 2 Diabetes directed health promotion interventions implemented in various countries were not integrated into Ottawa charter frameworks. As field experts, we believe that applying all the basic principles of health promotion and the idea of Ottawa Charter articulation is very important in disease prevention and behavioral change. Therefore, field specialists should figure out the problem of policy integration through policy evaluation researches. PMID- 29983537 TI - Letter to the Editor. PMID- 29983539 TI - On-line EEG Denoising and Cleaning Using Correlated Sparse Recovery and Active Learning. AB - We have developed two new methods that use sparse recovery and active learning techniques for near real-time artifact identification and removal in EEG recordings. The first algorithm, called Correlated Sparse Signal Recovery (CSSR) addresses the problem of structured sparse signal recovery when statistical rather than exact properties describing the structure of the signal are appropriate, as in the elimination of eye movement artifacts; such tasks cannot be done efficiently using structured models that assume a common sparsity profile of fixed groups of components. Our algorithm learns structured sparse coefficients in a Bayesian paradigm. Using it, we have successfully identified and subtracted eye movement (structured) artifacts in real EEG recordings resulting in minimal data loss. Our method outperforms ICA and standard sparse recovery algorithms by preserving both spectral and complexity properties of the denoised EEG. Our second method uses a new active selection algorithm that we call Output-based Active Selection (OAS). When applied to the task of detection of EEG epochs containing other non-structured artifacts from an ensemble of detectors, OAS boosts accuracy of the ensemble from 91% to 97.5% with only 10% active labels. Our methods can also be applied to real-time artifact removal in magnetoencephalography (MEG) and blood pressure signals. PMID- 29983538 TI - A Screening Rule for l1-Regularized Ising Model Estimation. AB - We discover a screening rule for l1-regularized Ising model estimation. The simple closed-form screening rule is a necessary and sufficient condition for exactly recovering the blockwise structure of a solution under any given regularization parameters. With enough sparsity, the screening rule can be combined with various optimization procedures to deliver solutions efficiently in practice. The screening rule is especially suitable for large-scale exploratory data analysis, where the number of variables in the dataset can be thousands while we are only interested in the relationship among a handful of variables within moderate-size clusters for interpretability. Experimental results on various datasets demonstrate the efficiency and insights gained from the introduction of the screening rule. PMID- 29983540 TI - Ranking Coal Ash Materials for Their Potential to Leach Arsenic and Selenium: Relative Importance of Ash Chemistry and Site Biogeochemistry. AB - The chemical composition of coal ash is highly heterogeneous and dependent on the origin of the source coal, combustion parameters, and type and configuration of air pollution control devices. This heterogeneity results in uncertainty in the evaluation of leaching potential of contaminants from coal ash. The goal of this work was to identify whether a single leaching protocol could roughly group high leaching potential coal ash from low-leaching potential coal ash, with respect to arsenic (As) and selenium (Se). We used four different leaching tests, including the Toxicity Characteristic Leaching Protocol (TCLP), natural pH, aerobic sediment microcosms, and anaerobic sediment microcosms on 10 different coal ash materials, including fly ash, lime-treated ash, and flue gas desulfurization materials. Leaching tests showed promise in categorizing high and low-leaching potential ash materials, indicating that a single point test could act as a first screening measure to identify high-risk ash materials. However, the amount of contaminant leached varied widely across tests, reflecting the importance of ambient conditions (pH, redox state) on leaching. These results demonstrate that on-site geochemical conditions play a critical role in As and Se mobilization from coal ash, underscoring the need to develop a situation-based risk assessment framework for contamination by coal ash pollutants. PMID- 29983541 TI - C-reactive protein may be useful to differentiate idiopathic orbital inflammation and orbital cellulitis in cases with acute eyelid erythema and edema. AB - Purpose: Idiopathic orbital inflammation (IOI) and orbital cellulitis can present similar clinical features, and the diagnoses of these two disorders are sometimes confused. The purpose of the present study was to determine whether or not inflammatory markers in the blood can be useful to differentiate between IOI and orbital cellulitis in cases with acute eyelid erythema and edema. Subjects and methods: In this retrospective single-institute study, we reviewed the medical records spanning the past 10 years at the Department of Ophthalmology, Osaka Medical College Hospital, Takatsuki, Osaka, Japan, and found 45 cases, with patients >15 years of age, with presumed IOI. Their blood samples were obtained within 5 days after the onset of IOI. Of those cases, 15 patients (10 males, 5 females, mean age of 56.9 years; range 38-76 years) presented acute eyelid erythema and edema, and were initially misdiagnosed as orbital cellulitis. Thus, inflammatory markers in the blood (ie, white blood cells [WBCs] and C-reactive protein [CRP]) of those 15 patients were analyzed with 17 patients (10 males, 7 females) having orbital cellulitis. The receiver operating characteristic curve analysis was performed to determine the optimal cut-off values. Results: The mean +/- standard error (SE) levels of the WBC were 6.80+/-0.70*103/MUL in the IOI patients, and 8.54+/-0.91*103/MUL in the orbital cellulitis patients, and no significant differences were observed (P=0.15, Student's t-test). However, the mean +/- SE levels of CRP were 1.04+/-0.43 mg/dL in the IOI patients, yet were significantly increased to 4.65+/-1.21 mg/dL in the orbital cellulitis patients (P=0.01, Student's t-test). The area under the curve value was 0.80 and the optimal cut-off value was 0.43 for orbital cellulitis, with sensitivity and specificity being 82% and 73%, respectively. Conclusion: The findings of this study indicate that CRP may be useful in distinguishing patients with idiopathic orbital inflammation from those with orbital cellulitis. PMID- 29983542 TI - The assessment of autofluorescence of the crystalline lens in diabetic patients and healthy controls: can it be used as a screening test? AB - Background: Our purpose was to demonstrate if measuring lens autofluorescence (AF) with a scanning confocal biomicroscope may be used to identify subjects with undiagnosed type II diabetes mellitus (DM), and hence, for it to be used as a marker for the severity of diabetic retinopathy in diabetic patients. Patients and methods: In this cross-sectional, comparative study, lens AF was measured with scanning confocal lens fluorescence biomicroscope in diabetic and healthy groups. Full ophthalmological examination was performed. Blood tests of fasting plasma glucose, and glycosylated hemoglobin were also analyzed. The correlation between lens AF results and blood tests was evaluated in both groups. The cutoff value for the diagnosis of DM using lens AF was investigated. Results: The study included 191 subjects with a mean age of 52.09+/-6.75 years. One hundred and seven (56.0%) subjects were female, and 84 (44.0%) were male. Eighty-two (42.9%) patients had type II DM, and 109 (57.1%) subjects self-reported as normal. The fluorescence ratio (FR) values ranged from 0.09 to 0.46 (0.23+/-0.06) in the total group. Mean FR measurements of diabetic subjects were significantly higher (0.27+/-0.06) than those without DM (0.20+/-0.05), (p=0.001). A statistically significant correlation was found between glycosylated hemoglobin, fasting plasma glucose, and FR. The cutoff point for the FR according to the presence of DM was found to be 0.24 and above (p=0.001), with a sensitivity of 71.95% and a specificity of 80.73%. Conclusion: Measuring AF of human lens as an indirect evidence of increased advanced glycaton end products may helpful in detecting impaired glucose metabolism. Our results show highly significant correlation between possibility of DM and FR. PMID- 29983543 TI - Senkyunolide A protects neural cells against corticosterone-induced apoptosis by modulating protein phosphatase 2A and alpha-synuclein signaling. AB - Background: Depression is characterized by a pathological injury to the hippocampal neurons. Senkyunolide A (SenA) is one of the major active components of Dan-zhi-xiao-yao-san, which is widely used in the treatment of depression related disorders. Materials and methods: In the present study, it was hypothesized that the antidepressant effect of Dan-zhi-xiao-yao-san depended on the function of SenA and the authors attempted to reveal the molecular mechanism associated with the treatment. An in vitro depression model was induced using corticosterone (Cort), and the effect of SenA on the cell viability, apoptosis, and protein phosphatase 2A/alpha-synuclein (PP2A/alpha-syn) signaling was detected. To validate the mechanism driving the therapeutic effect of SenA, activity of PP2A and alpha-syn was modulated and the effect on neural cells was evaluated. Results: The results showed that SenA protects Cort-induced cell apoptosis in PC12 cells. In addition, SenA increased Cort-induced reduction of PP2A activity, while it decreased the expression of p-PP2A, alpha-syn, and p alpha-syn (Ser129). Further, modulation of PP2A activity with specific inhibitor okadaic acid (OA) increased Cort-induced cell apoptosis, while PP2A activator D erythro-sphingosine (SPH) exhibited an opposite effect. The neuroprotective effects of SenA on neural cells also depended on inhibition of alpha-syn function, the regulation of which would influence the activity of PP2A in a negative loop. Conclusion: Collectively, the results suggested that the neuroprotective effects of SenA were exerted by modulating activities of PP2A activities and alpha-syn. The findings partially explained the mechanism associated with the neuroprotective effect of SenA. PMID- 29983544 TI - Modes of cell death induced by tetrahydroisoquinoline-based analogs in MDA-MB-231 breast and A549 lung cancer cell lines. AB - Background: A and B rings of the steroidal microtubule disruptor, 2 methoxyestradiol, and its analogs can be mimicked with a tetrahydroisoquinoline (THIQ) core. THIQs are cytotoxic agents with potential anticancer activities. The aim of this in vitro study was to investigate the modes of cell death induced by four nonsteroidal THIQ-based analogs, such as STX 2895, STX 3329, STX 3451 and STX 3450, on MDA-MB-231 metastatic breast and A549 epithelial lung carcinoma cells. Materials and methods: Cytotoxicity studies determined the half-maximal growth inhibitory concentration of the analogs to be at nanomolar concentrations without the induction of necrosis. Light and fluorescent microscopy determined that compounds caused microtubule depolymerization and displayed morphological hallmarks of apoptosis. Results: Flow cytometric analyses confirmed apoptosis induction as well as an increased G2/M phase on cell cycle analysis. Furthermore, intrinsic pathway signaling was implicated due to increased cytochrome c release and a decrease in mitochondrial transmembrane potential. Potential involvement of autophagy was observed due to increased acidic vacuole formation and increased aggresome activation factor. Conclusion: Thus, it can be concluded that these four THIQ-based analogs exert anti-proliferative and antimitotic effects, induce apoptosis and involve autophagic processes. Further investigation into the efficacy of these potential anticancer drugs will be conducted in vitro and in vivo. PMID- 29983545 TI - The mechanism of botulinum A on Raynaud syndrome. AB - Background: Botulinum neurotoxin type A (BoNT/A) is emerging as a treatment modality for Raynaud's phenomenon (RP). However, the mechanism of the role of BoNT/A in antagonizing the constriction of arteriola in RP remains unclear. Materials and methods: We tested the constriction of arteriole diameter and the distribution of adrenergic receptors on the rat cremaster modle. Moreover, we measured the secretion of norepinephrine (NE), protein level changes and related receptors on cultured rat superior cervical ganglia neurons(SCGNs), a model of sympathetic neuron. Results: Based on our results, the inhibition of arteriole vasoconstriction was increased with increasing doses of BoNT/A. BoNT/A, prazosin, and BQ123 treatment can result in significant inhibition of arteriole vasoconstriction with the same electrical stimulation. The inhibition effect of prazosin was equivalent to BoNT/A, while BQ123 has a synergistic effect with BoNT/A. After treating SCGNs using BoNT/A for 30 min, the decrease in fluorescence intensity of FM1-43 slowed down which was correlated with the doses of BoNT/A. Furthermore, release of NE in the supernatant was significantly decreased as measured by enzyme-linked immunosorbent assay, 24 h after a high dose of BoNT/A (25 u/mL). Cleaved-SNAP-25 was detected by Western blotting 24 h following BoNT/A (50 u/mL) treatment. Moreover, receptor SV2C, GM1, and FGFR3 were detected on sympathetic neurons, similarly to cholinergic neurons. Conclusion: Our study showed that BoNT/A could significantly inhibit electrical stimulation-induced arteriole vasoconstriction through the sympathetic pathway. The mechanism was similar to the cholinergic one, in which the vesicle release of sympathetic neurons could be inhibited by cleavage of SNAP-25. The end result was blocked vesicle fusion with the presynaptic membrane after BoNT/A treatment, inhibiting the release of the NE. PMID- 29983546 TI - Electroporation-enhanced transdermal diclofenac sodium delivery into the knee joint in a rat model of acute arthritis. AB - Purpose: Since electroporation (EP) can increase the permeability of biological membranes, we hypothesized that it offers an opportunity to enhance the transdermal delivery of drugs for intra-articular indications. Our aim was to compare the anti-inflammatory and analgesic efficacy of EP-combined topical administration of diclofenac sodium hydrogel (50 mg mL-1 in 230 uL volume) with that of an equivalent dose of oral (75 mg kg-1) and simple topical administration. Methods: Arthritis was induced with the injection of 2% lambda carrageenan and 4% kaolin into the right knee joints of male Sprague Dawley rats. EP was applied for 8 min with 900 V high-voltage pulses for 5 ms followed by a 20 ms break. Drug penetration into the synovial fluid and plasma was detected by high-performance liquid chromatography. Leukocyte-endothelial interactions were visualized by intravital videomicroscopy on the internal surface of the synovium. Inflammation-induced thermal and mechanical hyperalgesia reactions, knee joint edema, and inflammatory enzyme activities were assessed at 24 and 48 h after arthritis induction. Results: EP significantly increased the plasma level of diclofenac as compared with the topical controls 10 min after the 2% lambda carrageenan and 4% kaolin injection. Increased leukocyte-endothelial interactions were accompanied by joint inflammation, which was significantly reduced by oral and EP diclofenac (by 45% and by 30%, respectively) and only slightly ameliorated by simple topical diclofenac treatment (by 18%). The arthritis-related secondary hyperalgesic reactions were significantly ameliorated by oral and EP-enhanced topical diclofenac treatments. The knee cross-section area (which increased by 35%) was also reduced with both approaches. However, simple topical application did not influence the development of joint edema and secondary hyperalgesia. Conclusion: The study provides evidence for the first time of the potent anti inflammatory and analgesic effects of EP-enhanced topical diclofenac during arthritis. The therapeutic benefit provided by EP is comparable with that of oral diclofenac; EP is a useful alternative to conventional routes of administration. PMID- 29983547 TI - Computer-aided drug design and inhibitive effect of a novel nitrogenous heterocyclic compound and its mechanism on glioma U251 cells and breast cancer MCF-7 cells. AB - Background: Glioma and breast cancer are severe malignant cancerous tumors that highlight the importance of developing new anti-cancer drugs. The aim of this study was to explore the effects of a novel nitrogenous heterocyclic compound on glioma and breast cancer cells and to determine its mechanism of action. Methods: We designed and synthesized a novel nitrogenous heterocyclic compound, 3-(4-amino 1H-benzo[d]imidazole-2-carboxamido)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5] tetrazine-8-carboxamide, based on alkylglycerone phosphate synthase (AGPS) using computer-aided drug design (CADD), and we measured its effect on the proliferation, invasion, cell cycle and apoptosis of U251 glioma and MCF-7 breast cancer cells. In addition, the compound's effect on the expression of tumor related mRNA, circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) was explored. Results: It was found that the nitrogenous heterocyclic compound could induce cell cycle arrest at the G2/M phase of U251/MCF-7 cells and activate apoptosis. Real-time PCR showed that the expression levels of tumor-related mRNA, circRNAs and lncRNAs were impacted. Conclusion: We concluded that the nitrogenous heterocyclic compound inhibits the proliferation and invasion of U251 glioma and MCF-7 breast cancer cells through the induction of apoptosis and cell cycle arrest by regulating tumor-related genes. PMID- 29983548 TI - Mechanism of Yanghe Pingchuan granules treatment for airway remodeling in asthma. AB - Purpose: Yanghe Pingchuan granules (YPG), a hospital preparation developed by The First Affiliated Hospital, Anhui University of Chinese Medicine, has been used for the clinical treatment of bronchial asthma (BA) for several decades. This study aimed to explore the mechanism of action of YPG in the treatment of BA. Materials and methods: Male Sprague Dawley rats (n=60) were randomly divided into six groups (n=10 per group): control, a BA model, positive drug control (Guilong Kechuanning capsules; a proven effective treatment for BA), and model rats treated with a high, medium, or low dose of YPG. H&E staining was used to detect pathological changes in the bronchial tubes. The mRNA expression levels of PI3K, PKB, PCNA, and AR were determined by real-time PCR, and the protein levels of phospho- (p-)PI3K, p-PKB, p-PCNA, and p-AR were detected by Western blotting. ELISAs were used to detect the expression of PIP2, PIP3 IL-6, IL-8, IL-1beta, and epinephrine (EPI). Results: H&E staining demonstrated that BA can be ameliorated using YPG. Real-time PCR, Western blotting, and ELISA indicated that use of YPG decreased expression of the phosphoinositide 3-kinase (PI3K) signaling pathway and PCNA, and can also ameliorate the condition kidney Yang deficiency, which is associated with BA in Chinese traditional medicine. Conclusion: YPG can attenuate BA therapeutically in a dose-dependent manner. The mechanism underlying its therapeutic effect comprises influences on three features that contribute to BA: the PI3K signaling pathway, cell proliferation, and "kidney-Yang deficiency". PMID- 29983549 TI - The dynamics of self-care in the course of heart failure management: data from the IN TOUCH study. AB - Introduction: Self-care is an important patient-reported outcome (PRO) for heart failure (HF) patients, which might be affected by disease management and/or telemonitoring (TM). The number of studies reporting the influence of TM on self care is limited. Aims: This study aimed: to assess whether TM, in addition to information-and-communication-technology (ICT)-guided disease management system (ICT-guided DMS), affects self-care behavior; to evaluate the dynamics of self care during the study; to investigate factors contributing to self-care changes; and to identify a patient profile that predisposes the patient to improvement in self-care. Methods: In the INnovative ICT-guided-DMS combined with Telemonitoring in OUtpatient clinics for Chronic HF patients (IN TOUCH) study, 177 patients were randomized to either ICT-guided DMS or TM+ICT-guided DMS, with a follow-up of 9 months. The current analysis included 118 participants (mean age: 69+/-11.5 years; 70% male) who filled the following PRO instruments: the nine-item European Heart Failure Self-care Behaviour scale (EHFScBs), Hospital Anxiety and Depression scale (HADs), and Minnesota Living with HF Questionnaire (MLHFQ). Results: The baseline level of self-care was better in the TM+ICT-guided-DMS group (n=58) compared to ICT-guided-DMS group (n=60, p=0.023). Self-care behavior improved in the ICT-guided-DMS group (p<0.01) but not in the TM+ICT-guided-DMS group. Factors associated with self-care worsening were as follows: higher physical subscale of MLHFQ (per 10 points, p<0.05), lower left ventricular ejection fraction (LVEF) (per 5%, p<0.05), lower New York Heart Association (NYHA) class (class III vs class II, p<0.05). The subgroups of patients who had an initial EHFScBs total score >28, or from 17 to 28 with concomitant HADs depression subscale (HADs_D) score <=8, demonstrated the greatest potential to improve self-care during the study. Conclusion: TM did not have an advantage on self-care improvement. Poor physical aspect of quality of life, lower LVEF, and lower NYHA class were associated with self-care worsening. The greatest self-care improvement may be achieved in those patients who have low or medium initial self care level in the absence of depression. PMID- 29983550 TI - Psychometric properties of the Arabic version of the EUROPEP questionnaire. AB - Background: The evaluation of quality of primary health care from the perspective of refugees is very underdeveloped. It depends mainly on the availability of instruments in the language of the refugees. The aim of this study was to translate, culturally adapt, and examine the psychometric properties especially the internal consistency and convergent construct validity of the Arabic version of the European Project on Patient Evaluation of General Practice Care (EUROPEP) questionnaire. Methods: The German version of the EUROPEP questionnaire was translated into Arabic language. In total, 619 Arabic-speaking people were invited to participate in this study. Refugees who lived in collective living quarters in the German federal state of Schleswig-Holstein were recruited. The EUROPEP questionnaire is a multidimensional instrument that comprises 23 items, each with a 5-point Likert-type response. Cronbach's alpha, descriptive statistics, and principal component analysis were used to assess a part of psychometric properties. Convergent construct validity was assessed with the validated questionnaire on satisfaction with ambulatory care - quality from the patient perspective (ZAP questionnaire) by using Spearman rank-order correlation test. Results: A total of 136 questionnaires of refugees were returned (response rate 22%). Of these respondents, 95 participants who had visited a general practitioner were included in the validation study. The exploratory factor analysis extracted four factors, namely, "medical care," "physician-patient relationship," "coordination of care," and "accessibility to care." The internal consistency ranged between alpha=0.942 for "medical care" and alpha=0.869 for "coordination of care." The convergent construct validity is supported by a significant positive correlation between the overall score of the EUROPEP questionnaire and the overall score of the ZAP questionnaire (rrho=0.820; p<0.01). Conclusion: The Arabic version of the EUROPEP questionnaire shows appropriate internal consistency and convergent construct validity. The availability of this instrument in Arabic language encourages further research in the field of outcome quality from refugees' perspective in other health service research projects. PMID- 29983551 TI - Whose advocacy counts in shaping elderly patients' satisfaction with physicians' care and communication? AB - Purpose: The purpose of this article was to examine the relative importance of patients' self-advocacy and perceived physicians' advocacy for impacting patients' satisfaction in terms of physician communication and physician-patient relationship. We also examine the influence of physicians' emotional support and patients' demographic as well as health characteristics on patients' satisfaction. Sample: Our sample includes interviews with 806 community dwelling older adults (mean age =77.82 years, SD=8.41). The sample included residents of a large retirement community in Clearwater, FL, USA. Respondents were also included from representative samples of older adults living in Orlando and Miami, FL, USA, and Cleveland, OH, USA. Methods and results: Using multiple hierarchical regression analyses, we found that patients' age and functional limitations were negatively associated with their care satisfaction. When compared with White patients, African-American patients were less satisfied with their physicians while Latino patients expressed greater satisfaction with their medical care. We found limited evidence of patients' self-advocacy and such advocacy did not serve as a significant predictor of satisfaction with physicians. In contrast, patients' perception of physicians' readiness to act as patient advocates was a significant predictor of patients' satisfaction. Emotional support of physicians was also associated with patients' satisfaction. Conclusion: These findings raise questions about consumer empowerment among older adults and underscore their desire for and appreciation of physicians' advocacy. Findings are discussed in the context of power imbalance between elderly patients and their doctors. PMID- 29983552 TI - Cost and outcome of occupation-based practice for community dwelling frail elderly: a pilot study. AB - Purpose: The purpose of this pilot study was to determine the effectiveness and costs of the occupation-based practice for community dwelling frail elderly. Design: Pilot pre-post design without a control group. Setting: A care management center involving 37 local elderly. Subject: The final analysis included 26 frail elderly in a community dwelling center. Intervention: The intervention was occupation-based practice involving setting of client-centered goals, observation of real living situations, and provision of advice on the individual problem of real occupation. Outcome: The outcome was the Frenchay Activities Index (FAI), which is used to evaluate the instrumental activities of daily living (IADL). Additionally, the frequency, duration, and cost of the intervention were calculated. Results: Regarding the FAI score before and after the interventions, there were significant improvements in all items except work (P<0.05, effect size [r]: 0.67-0.93). A total of 15 people out of 26 (57.7%) showed improvement in activities of daily living. The frequency of interventions was 3.7 (95% confidence interval [CI]: 2.83-4.48), and the duration was 7.4 weeks (95% CI: 5.27-9.42). The average intervention cost was $258 (95% CI: 200.4-317.4). Conclusion: The results of this study showed that occupation-based practice has a potential to improve IADL in frail elderly, with low frequency of intervention, within a short-term, and direct cost reduction. We believe that this pilot study will contribute to future clinical studies for frail elderly, and the findings can be easily applied to daily clinical intervention. A well-designed prospective randomized-controlled trial is necessary to verify these results. PMID- 29983553 TI - Gender-related differences in the progression of carotid stiffness with age and in the influence of risk factors on carotid stiffness. AB - Background: In recent years, there has been growing interest in the impact of gender-related factors on the function and structure of the arterial tree. The aim of our study was to identify gender-specific differences in the progression of carotid stiffness parameters with age and in the impact of risk factors on carotid stiffness. Subjects and methods: The study group included 256 subjects (mean age: 54.7 years): 134 women (52%) and 122 men (48%) with cardiovascular risk factors: hypertension, type 2 diabetes mellitus, dyslipidemia, smoking, and obesity. Local parameters of carotid stiffness: beta stiffness index (beta), Peterson's elastic modulus (Ep), pulse wave velocity beta (PWV-beta) and arterial compliance (AC) were determined with ultrasound echo-tracking software application. Results: Women were characterized by lower AC than men (women: 0.57 mm2/kPa vs men: 0.69 mm2/kPa, p < 0.001) and the subanalysis in three age groups revealed that the difference in AC value between genders became significant over the age of 45 years. Although no significant difference in the value of beta, Ep and PWV-beta were found between genders in the whole study group, women <45 years were characterized by lower values of beta and Ep than their men counterparts (beta: women: 5.4 vs men: 6.6, p = 0.002; Ep: women: 72 kPa vs men: 84 kPa, p = 0.015). Among analyzed risk factors, the significant determinants of carotid stiffness were age, blood pressure components (pulse pressure and mean arterial pressure), type 2 diabetes mellitus and heart rate. The relationship between carotid stiffness and pulse pressure was observed only in women and between carotid stiffness and heart rate - only in men. Conclusion: There are gender related differences in the progression of carotid stiffness parameters with age and in the influence of risk factors on carotid stiffness. PMID- 29983554 TI - Coronary lesions in patients with COPD (Global Initiative for Obstructive Lung Disease stages I-III) and suspected or confirmed coronary arterial disease. AB - Background: Systemic inflammation is the pathophysiological link between coronary artery disease (CAD) and COPD. However, the influence of subclinical COPD on patients with suspected or diagnosed CAD is largely unknown. Thus, this study was designed to evaluate the degree of coronary involvement in patients with COPD and suspected or confirmed CAD. Methods: In this cross-sectional study, carried out between March 2015 and June 2017, 210 outpatients with suspected or confirmed CAD were examined by both spirometry and coronary angiography or multidetector computed tomography. These patients were divided into two groups: with and without COPD. Size, site, extent, and calcification of the coronary lesions, and the severity of COPD were analyzed. Results: COPD patients (n = 101) presented with a higher frequency of obstructive coronary lesions >=50% (n = 72, 71.3%), multivessels (n = 29, 28.7%), more lesions of the left coronary trunk (n = 18, 17.8%), and more calcified atherosclerotic plaques and higher Agatston coronary calcium score than the patients without COPD (P < 0.0001). The more severe the COPD in the Global Initiative for Obstructive Lung Disease stages, the more severe the CAD and the more calcified coronary plaques (P < 0.0001). However, there was no difference between the two groups with respect to the main risk factors for CAD. In the univariate analysis, COPD was an independent predictor of obstructive CAD (odds ratio [OR] 4.78; 95% confidence interval: 2.21-10.34; P < 0.001). Conclusion: In patients with suspected CAD, comorbid COPD was associated with increased severity and extent of coronary lesions, calcific plaques, and elevated calcium score independent of the established risk factors for CAD. In addition, the more severe the COPD, the greater the severity of coronary lesions and calcification present. PMID- 29983555 TI - Trends in intensive care unit admissions of COPD patients from 2003 to 2013 in Taiwan. AB - Objective: The objective of this study was to investigate the trends in COPD patients admitted to the intensive care unit (ICU) in Taiwan from 2003 to 2013. Patients and methods: A retrospective study was conducted to analyze the available data in the National Health Insurance Research Database compiled by the Taiwan Department of Health. We selected patients admitted to the ICU nationwide from 2003 to 2013. Patients older than 40 years with a diagnosis of COPD were enrolled. The ICU admission date was used as the index date. Baseline comorbidities existing before the index date were identified. The comorbidities of interest included diabetes, hypertension, diabetes mellitus, coronary artery disease, stroke, dyslipidemia, cancer, and end-stage renal disease. Results: The number of COPD patients in the ICU increased from 12,384 in 2003 to 13,308 in 2013 (P<0.0001). The mean age of patients and SD was 76.66+/-9.48 and 78.32+/ 10.59 in 2003 and 2013, respectively. The percentage of COPD patients aged $70 years in the ICU decreased markedly. COPD patients per 10,000 ICU patients decreased for both males and females. The length of ICU stays, and in-hospital mortality increased from 21.58 to 23.14 days and 14.97% to 30.98% from 2003 to 2013, respectively. Conclusion: The number of COPD patients admitted to the ICU in Taiwan increased over the 11-year study period. Increased mean patient age, length of ICU stays, hospital mortality, and comorbidities were observed. The use of a nationwide population-based database allowed for a sufficient sample size, generalizability, and statistical power to analyze COPD patients admitted to the ICU in Taiwan. PMID- 29983556 TI - Exercise assessments and trainings of pulmonary rehabilitation in COPD: a literature review. AB - Skeletal muscle dysfunction leads to reduction in activity in patients with COPD. As an essential part of the management of COPD, pulmonary rehabilitation (PR) alleviates dyspnea and fatigue, improves exercise tolerance and health-related quality of life, and reduces hospital admissions and mortality for COPD patients. Exercise is the key component of PR, which is composed of exercise assessment and training therapy. To evaluate PR's application in clinical practice, this article summarizes the common methods of exercise measurement and exercise training for patients with COPD. Exercise assessments should calculate patients' symptoms, endurance, strength, and health-related quality of life. After calculation, detailed exercise therapies should be developed, which may involve endurance, strength, and respiratory training. The detailed exercise training of each modality is mentioned in this review. Although various methods and therapies of PR have been used in COPD patients, developing an individualized exercise training prescription is the target. More studies are warranted to support the evidence and examine the effects of long-term benefits of exercise training for patients with COPD in each stage. PMID- 29983557 TI - Enhance the biocompatibility and osseointegration of polyethylene terephthalate ligament by plasma spraying with hydroxyapatite in vitro and in vivo. AB - Purpose: This study was designed to evaluate the biocompatibility and osseointegration of polyethylene terephthalate ligament after coating with hydroxyapatite (PET/HA) by using the plasma spraying technique in vitro and in vivo. Methods: In this study, PET/HA sheets were prepared by using the plasma spraying technique. The characterization, the viability of bone marrow stromal cells (BMSCs), and the mRNA expression of bone formation-related genes were evaluated in vitro. The osseointegration in vivo was investigated in the rabbit anterior cruciate ligament (ACL) reconstruction model by micro-computed tomography (micro-CT) analysis, histological evaluation, and biomechanical tests. Results: Scanning electron microscopy (SEM) results showed that the surface of polyethylene terephthalate (PET) becomes rough after spraying with hydroxyapatite (HA) nanoparticles, and the water contact angle was 75.4 degrees +/-10.4 degrees in the PET/HA-plasma group compared to 105.3 degrees +/-10.9 degrees in the control group (p<0.05). The cell counting kit-8 counting results showed that the number of BMSCs significantly increased in the PET/HA-plasma group (p<0.05). Reverse transcription polymerase chain reaction (RT-PCR) results showed that there was an upregulated mRNA expression of bone formation-related genes in the PET/HA-plasma group (p<0.05). Micro-CT results showed that the transactional area of tibial tunnels and femoral tunnels was smaller in the PET/HA-plasma group (p<0.05). The histological evaluation scores of the PET/HA-plasma group were significantly superior to those of the PET control group at 8 and 12 weeks (p<0.05). The biomechanical tests showed an increased maximum load to failure and stiffness in the PET/HA-plasma group compared to those in the control group at 8 and 12 weeks. Conclusion: Both in vitro and in vivo results demonstrated in this study suggest that the biocompatibility and osseointegration of PET/HA ligament were significantly improved by increasing the proliferation of cells and upregulating the expression of bone formation-related genes. In a word, the PET/HA-plasma ligament is a promising candidate for ACL reconstruction in future. PMID- 29983559 TI - Erratum: Development and blood compatibility assessment of electrospun polyvinyl alcohol blended with metallocene polyethylene and plectranthus amboinicus (PVA/mPE/PA) for bone tissue engineering [Corrigendum]. AB - [This corrects the article on p. 2777 in vol. 13, PMID: 29785105.]. PMID- 29983558 TI - Lumbrokinase/paclitaxel nanoparticle complex: potential therapeutic applications in bladder cancer. AB - Background: Lumbrokinase (LK) is an enzyme complex with antithrombotic, antioxidant, antitumor, and immunomodulatory effects. It has been extensively studied and used in clinical anti-tumor therapy. However, its half-life is short, its bioavailability is low, and its toxicity and side effects are great, which greatly limit its clinical application. Therefore, LK is often combined with other drugs (such as immune agents, hormones, or Chinese herbal medicine) to reduce its dosage and side effects and to improve its anti-tumor effects. Methods and results: Here, we described an LK/paclitaxel (PTX) nanocarrier based on poly(ethylene glycol)-b-(poly(ethylenediamine l-glutamate)-g-poly(epsilon benzyoxycarbonyl-l-lysine)-r-poly(l-lysine)) (PEG-b-(PELG-g-(PZLL-r-PLL))). In the present study, LK and PTX were loaded by electrostatic and/or hydrophobic effects under mild conditions, thereby increasing the half-life and bioavailability of the drugs via the sustained release and enhancement of tumor site enrichment by the LK/PTX/PEG-b-(PELG-g-(PZLL-r-PLL)) complex through passive targeting. In this study, using bladder cancer cells (J82 cells) and rat bladder cancer model as the object, the structure of the nanocarrier, the relationship between drugs composition and antitumor properties were systematically studied. Conclusion: We propose that the block copolymer PEG-b-(PELG-g-(PZLL-r-PLL)) may function as a potent nanocarrier for augmenting anti-bladder cancer pharmacotherapy, with unprecedented clinical benefits. PMID- 29983560 TI - Evaluation of highly carbonated hydroxyapatite bioceramic implant coatings with hierarchical micro-/nanorod topography optimized for osseointegration. AB - Background: Optimal osseointegration has been recognized as a pivotal factor in determining the long-term success of biomedical implants. Materials and methods: In the current study, highly carbonated hydroxyapatite (CHA) with carbonate contents of 8, 12 and 16 wt% and pure hydroxyapatite (HA) were fabricated via a novel hydrothermal method and deposited on the titanium substrates to generate corresponding CHA bioceramic coatings (designated as C8, C12 and C16, respectively) and HA bioceramic coatings (designated as C0). Results: C8, C12 and C16 were endowed with nanoscale, hierarchical hybrid micro-/nanoscale and microscale surface topographies with rod-like superstructures, respectively. Compared with C0, the micro-/nanotextured CHA bioceramic coatings (C8, C12 and C16) possessed excellent surface bioactivity and biocompatibility, as well as better wettability, which mediated improved protein adsorption, giving rise to simultaneous enhancement of a biological cascade of events of rat bone-marrow derived mesenchymal stem cells including cell adhesion, proliferation, osteogenic differentiation and, notably, the production of the pro-angiogenic growth factor, vascular endothelial growth factor-A. In particular, C12 with biomimetic hierarchical hybrid micro-/nanorod topography exhibited superior fractal property and predominant performance of protein adsorption, cell adhesion, proliferation and osteogenesis concomitant with angiogenesis. Conclusion: All these results suggest that the 12 wt% CHA bioceramic coating with synergistic modification of surface chemistry and topography has great prospect for future use as implant coating to achieve optimum osseointegration for orthopedic and dental applications. PMID- 29983561 TI - Fabrication of multifunctional triple-responsive platform based on CuS-capped periodic mesoporous organosilica nanoparticles for chemo-photothermal therapy. AB - Introduction: For an ideal drug delivery system, the outstanding drug-loading capacity and specific control of the release of therapeutics at the desired lesions are crucial. In this work, we developed a triple-responsive nanoplatform based on copper sulfide (CuS)-capped yolk-shell-structured periodic mesoporous organosilica nanoparticles (YSPMOs) for synergetic chemo-photothermal therapy. Methods: Herein, the YSPMOs were employed as a drug carrier, which exhibited a high doxorubicin (DOX) loading capacity of 386 mg/g. In this controlled-release drug delivery system, CuS serves as a gatekeeper to modify YSPMOs with reduction cleavable disulfide bond (YSPMOs@CuS). CuS could not only avoid premature leakage in the delivery process, but also endowed the excellent photothermal therapy (PTT) ability. Results: Upon entering into cancer cells, the CuS gatekeeper was opened with the breaking of disulfide bonds and the DOX release from YSPMOs(DOX)@CuS in response to the intracellular acidic environment and external laser irradiation. Such a precise control over drug release, combined with the photothermal effect of CuS nanoparticles, is possessed by synergistic chemo photothermal therapy for cancer treatment. Both in vitro and in vivo experimental data indicated that the synergistic effect of YSPMOs(DOX)@CuS showed efficient antitumor effect. In addition, low systemic toxicity was observed in the pathologic examinations of liver, spleen, lungs, and kidneys. Conclusion: This versatile nanoplatform combination of PTT, chemotherapeutics, and gating components shows general potential for designing multifunctional drug delivery systems. PMID- 29983562 TI - Self-assembled biodegradable polymeric micelles to improve dapoxetine delivery across the blood-brain barrier. AB - Background: Dapoxetine (DPX) is the drug of choice for the specific treatment of premature ejaculation. DPX is characterized by relatively low bioavailability (42%) and short half-life (1.5 h). The aim of this study was to improve DPX bioavailability and delivery across the blood-brain barrier (BBB) using a nanostructured DPX formulation for improved DPX efficacy and patient satisfaction. Materials and methods: DPX-loaded polymeric micelles (PMs) formulations (F1-F3) were characterized for particle sizes, entrapment efficiencies, and Fourier transform infrared spectroscopic and transmission electron microscopic evaluations. In addition, diffusion profiles of the prepared formulations were investigated. Animal model pharmacokinetic parameters in plasma and brain tissues were investigated and compared with commercial DPX tablets. Results: Particle size analysis revealed that formulations of DPX PMs showed a narrow range of 62.7+/-9.3-45.45+/-9.1 nm for F1-F3. In addition, DPX PMs showed a sustained release pattern with 91.27%+/-7.64%, 79.43%+/-7.81%, and 63.78%+/ 5.05% of DPX content permeated after 24 h for F1, F2, and F3, respectively. Plasma pharmacokinetic parameters for DPX PMs showed significant increase (P<0.05) for the area under drug concentration-time curves in plasma and brain tissues compared with commercial DPX tablets. Conclusion: DPX formulations in the form of PMs improved bioavailability and efficacy across the BBB. This DPX formulation provided improved brain delivery in order to enhance the convenience and compliance of patients. PMID- 29983563 TI - Development of a thermostable nanoemulsion adjuvanted vaccine against tuberculosis using a design-of-experiments approach. AB - Background: Adjuvants have the potential to increase the efficacy of protein based vaccines but need to be maintained within specific temperature and storage conditions. Lyophilization can be used to increase the thermostability of protein pharmaceuticals; however, no marketed vaccine that contains an adjuvant is currently lyophilized, and lyophilization of oil-in-water nanoemulsion adjuvants presents a specific challenge. We have previously demonstrated the feasibility of lyophilizing a candidate adjuvanted protein vaccine against Mycobacterium tuberculosis (Mtb), ID93 + GLA-SE, and the subsequent improvement of thermostability; however, further development is required to prevent physicochemical changes and degradation of the TLR4 agonist glucopyranosyl lipid adjuvant formulated in an oil-in-water nanoemulsion (SE). Materials and methods: In this study, we took a systematic approach to the development of a thermostable product by first identifying compatible solution conditions and stabilizing excipients for both antigen and adjuvant. Next, we applied a design-of experiments approach to identify stable lyophilized drug product formulations. Results: We identified specific formulations that contain disaccharide or a combination of disaccharide and mannitol that can achieve substantially improved thermostability and maintain immunogenicity in a mouse model when tested in accelerated and real-time stability studies. Conclusion: These efforts will aid in the development of a platform formulation for use with other similar vaccines. PMID- 29983565 TI - Erratum: Biophysical and biological contributions of polyamine-coated carbon nanotubes and bidimensional buckypapers in the delivery of miRNAs to human cells [Corrigendum]. AB - [This corrects the article on p. 1 in vol. 13, PMID: 29296082.]. PMID- 29983564 TI - Doxorubicin and anti-VEGF siRNA co-delivery via nano-graphene oxide for enhanced cancer therapy in vitro and in vivo. AB - Background: Graphene oxide (GO) has attracted intensive interest in biological and medical fields in recent years due to its unique physical, chemical, and biological properties. In our previous work, we proved that GO could deliver small interfering RNA (siRNA) into cells and downregulate the expression of the desired gene. Methods: This study investigated the potential of a modified GO nanocarrier for co-delivery of siRNA and doxorubicin (DOX) for enhanced cancer therapy. Fourier transform infrared spectroscopy, laser particle size analyzer, UV-visible spectroscopy, gel electrophoresis retardation, and in vitro release assay were studied. Results: The results of real-time polymerase chain reaction revealed that the expression of vascular endothelial growth factor (VEGF) mRNA was decreased 46.84%+/-3.72% (mean +/- SD). Enzyme-linked immunosorbent assay indicated that the expression of VEGF protein was down-regulated to 52.86%+/ 1.10% (mean +/- SD) in vitro. In vivo tumor growth assay GO-poly-l-lysine hydrobromide/folic acid (GPF)/DOX/siRNA exhibited gene silencing and tumor inhibition (66.95%+/-2.35%, mean +/- SD) compared with naked siRNA (1.62%+/ 1.47%, mean +/- SD) and DOX (33.63%+/-5.85%, mean +/- SD). GPF/DOX/siRNA exhibited no testable cytotoxicity. Conclusion: The results indicated that co delivery of siRNA and DOX by GPF could be a promising application in tumor clinical therapy. PMID- 29983566 TI - Direct modulation of myelin-autoreactive CD4+ and CD8+ T cells in EAE mice by a tolerogenic nanoparticle co-carrying myelin peptide-loaded major histocompatibility complexes, CD47 and multiple regulatory molecules. AB - Purpose: Numerous nanomaterials have been reported in the treatment of multiple sclerosis or experimental autoimmune encephalomyelitis (EAE). But most of these nanoscale therapeutics deliver myelin antigens together with toxins or cytokines and underlay the cellular uptake and induction of tolerogenic antigen-presenting cells by which they indirectly induce T cell tolerance. This study focuses on the on-target and direct modulation of myelin-autoreactive T cells and combined use of multiple regulatory molecules by generating a tolerogenic nanoparticle. Materials and methods: Poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) were fabricated by co-coupling MOG40-54/H-2Db-Ig dimer, MOG35-55/I-Ab multimer, anti-Fas, PD-L1-Fc and CD47-Fc and encapsulating transforming growth factor beta1. The resulting 217 nm tolerogenic nanoparticles (tNPs) were administered intravenously into MOG35-55 peptide-induced EAE mice, which was followed by the investigation of therapeutic outcomes and the in vivo mechanism. Results: Four infusions of the tNPs durably ameliorated EAE with a marked reduction of clinical score, neuroinflammation and demyelination. They were distributed in secondary lymphoid tissues, various organs and brain after intravenous injection, with retention over 36 h, and made contacts with CD4+ and CD8+ T cells. Two injections of the tNPs markedly decreased the MOG35-55-reactive Th1 and Th17 cells and MOG40 55-reactive Tc1 and Tc17 cells, increased regulatory T cells, inhibited T cell proliferation and elevated T cell apoptosis in spleen. Transforming growth factor beta1 and interleukin-10 were upregulated in the homogenates of central nervous system and supernatant of spleen cells. Conclusion: Our data suggest a novel therapeutic nanoparticle to directly modulate autoreactive T cells by surface presentation of multiple ligands and paracrine release of cytokine in the antigen specific combination immunotherapy for T cell-mediated autoimmune diseases. PMID- 29983567 TI - Clinician-delivered cognitive training for children with attention problems: effects on cognition and behavior from the ThinkRx randomized controlled trial. AB - Purpose: The impact of attention problems on academic and social functioning coupled with the large number of children failing to respond to stimulant medication or behavioral therapy makes adjunctive therapies such as cognitive training appealing for families and clinicians of children with attention difficulties or childhood attention deficit hyperactivity disorder. However, the results of cognitive training studies have failed to find far transfer effects with this population. This study examined the quantitative cognitive effects and parent-reported behavioral effects of a clinician-delivered cognitive training program with children who have attention problems. Patients and methods: Using a randomized controlled study design, we examined the impact of a clinician delivered cognitive training program on processing speed, fluid reasoning, memory, visual processing, auditory processing, attention, overall intelligence quotient score, and behavior of students (n=13) aged 8-14 years with attention problems. Participants were randomly assigned to either a waitlist control group or a treatment group for 60 hours of cognitive training with ThinkRx, a clinician delivered intervention that targets multiple cognitive skills with game-like, but rigorous mental tasks in 60-90-minute training sessions at least 3 days per week. Results: Results included greater mean pretest to posttest change scores on all variables for the treatment group versus the control group with statistically significant differences noted in working memory, long-term memory, logic and reasoning, auditory processing, and intelligence quotient score. Qualitative outcomes included parent-reported changes in confidence, cooperation, and self discipline. Conclusion: Children with attention problems who completed 60 hours of clinician-delivered ThinkRx cognitive training realized both cognitive and behavioral improvements. PMID- 29983568 TI - The direct and indirect effects of alpha-synuclein on microtubule stability in the pathogenesis of Parkinson's disease. AB - Despite decades of research, the mechanism of Parkinson's disease pathogenesis remains unclear. Studies have focused heavily on the protein alpha-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson's on the cellular level. While the roles of alpha synuclein in causing mitochondrial dysfunction and disruptions to the proteasomal system have been well documented, recently, its role in effecting microtubule dynamics has been investigated as a potential source of pathogenicity. Here, we evaluate the evidence for and against the role of alpha-synuclein in destabilizing microtubules, causing axonal transport deficits and eventually neurodegeneration. We present evidence for a model where alpha-synuclein has both a direct and indirect effect on microtubule stability. Directly, it may act as a microtubule-associated protein, binding to microtubules and directly effecting their dynamics. Indirectly, it may promote the hyperphosphorylation of the microtubule stabilizing protein, tau, leading to tau aggregation with other microtubule stabilizing proteins, hence indirectly causing microtubule destabilization. This model provides insights into the function of alpha synuclein and tau in Parkinson's disease pathogenesis and raises the possibility that this role that may also be conserved in Alzheimer's disease. PMID- 29983569 TI - A case of developing progressive multifocal leukoencephalopathy while using rituximab and mycophenolate mofetil in refractory systemic lupus erythematosus. AB - Progressive multifocal leukoencephalopathy (PML) is a central nervous system infection caused by John Cunningham (JC) virus reactivation in an immunocompromised patient. PML has various neurologic symptoms and has very poor prognosis. A 36-year-old man developed transverse myelitis and had a psychiatric disorder at the age of 26. He was diagnosed with systemic lupus erythematosus (SLE) and neuropsychiatric SLE (NPSLE), on the basis of leukopenia and presence of anti-DNA and anti-nuclear antibodies. Treatment with glucocorticoid (GC) was started, and remission was introduced. Six months before PML onset, his condition was complicated with hemophagocytic lymphohistiocytosis (HLH) due to exacerbation of SLE. Remission re-induction therapy by GC, cyclosporine-A, intravenous cyclophosphamide, and rituximab (RTX) was initiated and HLH improved. However, interleukin-6 levels of the cerebrospinal fluid (CSF) continued to rise. We thought that the disease activity of NPSLE worsened; thus, we introduced mycophenolate mofetil (MMF) 4 months before the PML onset. He developed progressive dysarthria and right hemiplegia. He was diagnosed with PML via magnetic resonance imaging and JC virus polymerase chain reaction in CSF. Considering that immunosuppressants, including RTX and MMF, are precipitating factors of PML, we discussed the RTX removal using plasma exchange (PEx), but we did not introduce PEx, because it was expected that the concentration of RTX was already lowered when he was diagnosed with PML. Treatment for PML with mefloquine and mirtazapine saved his life, but severe residual disabilities remained. This is the first report of a patient who developed PML during combination therapy with RTX and MMF. PMID- 29983570 TI - Erratum: A restrictive dose of crystalloids in patients during laparoscopic cholecystectomy is safe and cost-effective: prospective, two-arm parallel, randomized controlled trial [Corrigendum]. AB - [This corrects the article on p. 741 in vol. 14, PMID: 29719401.]. PMID- 29983571 TI - Long-term health complications following snake envenoming. AB - Background: Snakebite is an important public health problem in tropical regions of the world. Although devastating effects of envenoming such as kidney failure, tissue necrosis, bleeding diathesis, and neurotoxicity are well known in the acute stage following a snakebite, the long-term effects of snake envenoming have not been adequately studied. Materials and methods: A population-based study was conducted among 8707 residents in a rural district in Sri Lanka to assess the long-term sequelae following snakebite. Health-related complaints that snakebite victims had developed immediately or within 4 weeks of the bite and persisted for more than 3 months, were assessed by interviewer-administered questionnaire and in-depth interviews, and further evaluated by physical examination and relevant investigations. Results: Of the 816 participants who were identified as ever snakebite victims, 112 (13.7%) presented with at least one snakebite-related long term health complication. Among them, "migraine-like-syndrome" characterized by headache vertigo, and photosensitivity to sunlight was found in 46 (5.6%); musculoskeletal disorders such as pain, local swelling, muscle weakness, deformities, contractures, and amputations were found in 26 (3.2%); visual impairment in 21 (2.6%); acute kidney injury in 4 (0.5%); skin blisters at the bite site in 5 (0.6%); psychological distress in 2 (0.2%); hemiplegia in 1 (0.1%); right-side facial nerve palsy in 1 (0.1%); paresthesia over bite site in 1 (0.1%); generalized shivering in 1 (0.1%); and chronic nonhealing ulcer in 1 (0.1%). Interestingly, 31 (3.8%) reported nonspecific somatic symptoms such as abdominal colic, chest tightness, wheezing, receding gums, excessive hair loss, and lassitude with body aches following the bite. The average duration of symptoms since snakebite was 12.7 years (SD=11.7). Conclusion: This study highlights that a significant proportion of snakebite victims suffer disabling chronic health sequelae. There is a need to place systems to address these unmet health needs. PMID- 29983572 TI - A randomized placebo-controlled trial of paroxetine for the management of anxiety in chronic obstructive pulmonary disease (PAC Study). AB - Background: Despite the high prevalence of anxiety in COPD patients and its impact on quality of life, evidence to support the effectiveness of various anxiety treatment options is insufficient, leading to the need for further research in this field. Aim: The aim of this study was to assess the efficacy and safety of paroxetine for the management of anxiety in COPD and the impact of treatment on patients' quality of life and rate of hospitalization. Patients and methods: In a double-blind, randomized, controlled trial, COPD patients were allocated into groups that either received paroxetine 20 mg or placebo pills daily, for four months. Differences in outcomes were assessed based on an intention-to-treat analysis using linear mixed effects models. A chi-square test was used to compare the number of COPD-related admissions. Results: Thirty-eight participants were recruited. Twenty-two of these completed the trial. A clinically and statistically significant reduction was noted in anxiety symptoms after four months of treatment compared to the placebo. Clinically important improvement was noted in depression symptoms, with no statistically significant differences in walking distance or quality-of-life measure outcomes. The intervention group had less COPD-related admissions compared to the placebo group but experienced medication-related side effects. Conclusion: Treatment with paroxetine significantly improved anxiety levels, but this difference did not translate into improved quality of life at four months follow-up. PMID- 29983573 TI - Evaluation of Two Strategies for Community-Based Safety Monitoring during Seasonal Malaria Chemoprevention Campaigns in Senegal, Compared with the National Spontaneous Reporting System. AB - Background: Seasonal malaria chemoprevention (SMC) using sulfadoxine pyrimethamine plus amodiaquine has been introduced in 12 African countries. Additional strategies for safety monitoring are needed to supplement national systems of spontaneous reporting that are known to under represent the incidence of adverse reactions. Objectives: This study aimed to determine if adverse event (AE) reporting could be improved using a smartphone application provided to village health workers, or by active follow-up using a symptom card provided to caregivers. Methods: Two strategies to improve reporting of AEs during SMC campaigns were evaluated, in comparison with the national system of spontaneous reporting, in 11 health post areas in Senegal. In each health post, an average of approximately 4000 children under 10 years of age received SMC treatment each month for 3 months during the 2015 malaria transmission season-a total of 134,000 treatments. In three health posts (serving approximately 14,000 children), caregivers were encouraged to report any adverse reactions to the nurse at the health post or to a community health worker (CHW) in their village, who had been trained to use a smartphone application to report the event (enhanced spontaneous reporting). In two health posts (approximately 10,000 children), active follow-up of children at home was organized after each SMC campaign to ask about AEs that caregivers had been asked to record on a symptom card (active surveillance). Six health posts (approximately 23,000 children) followed the national system of spontaneous reporting using the national reporting (yellow) form. Each AE report was assessed by a panel to determine likely association with SMC drugs. Results: The incidence of reported AEs was 2.4, 30.6, and 21.6 per 1000 children treated per month, using the national system, enhanced spontaneous reporting, and active surveillance, respectively. The most commonly reported symptoms were vomiting, fever, and abdominal pain. The incidence of vomiting, known to be caused by amodiaquine, was similar using both innovative methods (10/1000 in the first month, decreasing to 2.5/1000 in the third month). Despite increased surveillance, no serious adverse drug reactions were detected. Conclusion: Training CHWs in each village and health facility staff to report AEs using a mobile phone application led to much higher reporting rates than through the national system. This approach is feasible and acceptable, and could be further improved by strengthening laboratory investigation and the collection of control data immediately prior to SMC campaigns. PMID- 29983574 TI - Prognostic impact of the number of lymph nodes examined in different stages of colorectal mucinous adenocarcinoma. AB - Background: Mucinous adenocarcinoma (MC) is a special kind of colorectal adenocarcinoma that occurs more frequently in young patients and females, but the prognostic effect of lymph nodes in MC patients is unclear. This population-based study was conducted to analyze the prognostic value of the number of lymph nodes examined in different stages of colorectal MC. Methods: We included 17,001 MC patients from the Surveillance, Epidemiology, and End Results program database between 2003 and 2013, of which 12,812 (75%) had >12 lymph nodes examined. Results: Compared to the group with insufficient lymph nodes examined, patients with more lymph nodes (>12) examined tended to come from east and central America, were more frequently female and young, were diagnosed after 2008, had larger-sized tumors of less differentiated grade and in later stages, had not received radiation therapy and had more positive nodal status. Patients with more lymph nodes (>12) examined demonstrated significantly better survival than those with insufficient lymph nodes examined only in stages II and III (stage II: overall, P<0.001; cancer-specific, P<0.001; stage III: overall, P=0.093; cancer specific, P=0.032), even though the overall (P<0.001) and cancer-specific survival (P<0.001) showed significant differences between the two groups. Both univariate (overall, HR=0.739, 95% CI=0.703-0.777, P<0.001; cancer-specific, HR=0.742, 95% CI=0.698-0.788, P<0.001) and multivariate (overall, HR=0.601, 95% CI=0.537-0.673, P<0.001; cancer-specific, HR=0.582, 95% CI=0.511-0.664, P<0.001) Cox proportional hazards models verified the association between >12 lymph nodes examined and better survival. Conclusion: More number of lymph nodes (.12) examined significantly increased the survival probability of MC patients in stages II and III, but had no significant influence on patients in stages I and IV, indicating the effect of number of lymph nodes examined was a stage-dependent prognostic factor in clinical utility. PMID- 29983575 TI - CAT3, a prodrug of 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine, circumvents temozolomide-resistant glioblastoma via the Hedgehog signaling pathway, independently of O6-methylguanine DNA methyltransferase expression. AB - Purpose: Glioblastoma multiforme (GBM) is a malignant high-grade glioma with a poor clinical outcome. Temozolomide (TMZ) is the first-line GBM chemotherapy; however, patients commonly develop resistance to its effects. Materials and methods: We investigated the antitumor activity of CAT3 in TMZ-resistant glioblastoma cell lines U251/TMZ and T98G. Orthotopic and subcutaneous mice tumor models were used to investigate the effects of various treatment regimes. Results: We found that PF403, the active metabolite of CAT3, inhibited proliferation of both cell lines. PF403 repressed the Hedgehog signaling pathway in the U251/TMZ cell line, reduced O6-methylguanine DNA methyltransferase (MGMT) expression, and abolished the effects of the Shh pathway. Moreover, PF403 blocked the Hedgehog signaling pathway in T98G MGMT-expressing cells and downregulated the expression of MGMT. CAT3 suppressed growth in the U251/TMZ orthotopic and T98G subcutaneous xenograft tumor models in vivo. We also demonstrated that inhibition of the Hedgehog pathway by PF403 counteracted TMZ resistance and enhanced the antitumor activity of TMZ in vitro and in vivo. Conclusion: These results indicate that CAT3 is a potential therapeutic agent for TMZ-resistant GBM. PMID- 29983577 TI - Impact of smoking on efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer patients: a meta-analysis. AB - Background: Smoking status is associated with the efficacy of non-small cell lung cancer (NSCLC) treatment. Latest clinical trials have depicted the difference in the effectiveness of programmed death-1 (PD-1) and programmed death-ligand 1 (PD L1) inhibitors in smokers and nonsmokers. However, the lack of statistical power in these trials prevented a final conclusion. The authors postulated that the efficacy of PD-1/PD-L1 inhibitors correlated with smoking status. Materials and methods: Clinical trials evaluating PD-1 inhibitors versus chemotherapies in smokers and nonsmokers were included. The hazard ratios (HRs) and 95% confidence intervals (CIs) of overall survival (OS) and progression-free survival (PFS) were used. Results: A total of 1,981 patients from three Phase III randomized controlled trials (RCTs) were included. PD-1/PD-L1 inhibitors significantly prolonged the OS (HR, 0.69; 95% CI, 0.60-0.78) and PFS (HR, 0.55; 95% CI, 0.43 0.67; P = 0.027) in smoking patients versus chemotherapy. However, among nonsmoking patients, no significant improved OS and PFS were observed compared with chemotherapy. Conclusion: PD-1 inhibitors were more efficacious in smoking NSCLC patients compared with chemotherapy. No better survival of nonsmoking patients was observed in the treatment of PD-1 inhibitors than chemotherapy. Difference in the efficacy of PD-1 treatment should be taken into consideration in the future guidelines and clinical practice. PMID- 29983576 TI - An uncommon granulocytic sarcoma of the breast: a case report and literature review. AB - Granulocytic sarcoma (GS) is an uncommon extramedullary manifestation of acute myeloid leukemia. GS is often likely to be clinically misdiagnosed as another type of primary breast cancer due to its rarity. We report an uncommon case of breast GS in a patient and review the relevant literature. PMID- 29983578 TI - Chemotherapy with or without pemetrexed as second-line regimens for advanced non small-cell lung cancer patients who have progressed after first-line EGFR TKIs: a systematic review and meta-analysis. AB - Purpose: The development of acquired resistance to the first-line epidermal growth factor-tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC) is inevitable, and most of these patients needed second-line chemotherapy. Furthermore, the optimum chemotherapeutic regimen is unclear. The aim of this meta-analysis was to evaluate the chemotherapeutic regimens "with pemetrexed" versus "non-pemetrexed" in advanced NSCLC patients who had progressed after first-line EGFR-TKIs. Materials and methods: We searched PubMed, Embase, Cochrane Library, and the Web of science for relevant clinical trials. Outcomes analyzed were response rate (RR), disease control rate (DCR), 1-year survival rate (1-year SR), progression-free survival (PFS), and overall survival (OS). Results: One randomized controlled trial (RCT) and three retrospective studies were included in this meta-analysis, covering a total of 354 patients. The results showed that there was no significant difference between with-pemetrexed arm and non-pemetrexed arm in RR (OR 1.43, 95% CI 0.85-2.41, P=0.18), DCR (OR 1.5, 95% CI 0.94-2.39, P=0.09), and 1-year SR (OR 1.47, 95% CI 0.79-2.74, P=0.22). But the with-pemetrexed chemotherapeutic regimens significantly improved the PFS (HR 0.61, 95% CI 0.46-0.81, P=0.0005) and OS (HR 0.62, 95% CI 0.42-0.90, P=0.01). Conclusion: The second-line with-pemetrexed chemotherapeutic regimens provided significantly longer PFS and OS than non-pemetrexed chemotherapeutic regimens. These findings indicate that the with-pemetrexed chemotherapeutic regimen may be an optimal second-line chemotherapeutic regimen for patients with advanced NSCLC following EGFR-TKI failure. PMID- 29983579 TI - Targeted therapy and immunotherapy for platinum-refractory advanced ovarian adenosquamous carcinoma: a case report. AB - Background: Ovarian adenosquamous carcinoma is an extremely rare type of ovarian histology. Platinum-refractory disease is also uncommon, but can be fatal because of the lack of available treatment options. To date, there is no study or case report on platinum-refractory ovarian adenosquamous carcinoma or its relevant treatment. Case presentation: Herein, we report the case of a 38-year-old Chinese woman with platinum-refractory advanced ovarian adenosquamous carcinoma who received clinical benefit from poly adenosine diphosphate ([ADP] ribose) polymerase and programmed death-1 inhibitors after failure of prior multiline chemotherapies and antiangiogenic agents. The targeted therapy and immunotherapy controlled disease deterioration and improved performance status. Thus far, the patient has survived longer than 15 months, and she is taking nivolumab as maintenance treatment. Conclusion: Targeted therapy and immunotherapy may be options for rare categories of ovarian cancer, but this warrants more clinical evidence of efficacy and toxicity. PMID- 29983580 TI - Updates on the clinical diagnosis and management of ocular sebaceous carcinoma: a brief review of the literature. AB - Ocular sebaceous carcinoma (SC) is an exceedingly rare but aggressive malignancy that can impair patients' visual acuity or even cause tumor-specific mortality. This tumor usually mimics chronic benign eyelid lesions, thus leading to delayed diagnosis, thereby causing high recurrence and metastasis. Ophthalmologists should be more aware of SC in order to offer correct diagnosis and treatment at the onset of symptoms. Prompt surgical excision with frozen section margin control is the mainstay of SC management after patient evaluation and accurate biopsy. Mohs micrographic surgery has been associated with better tumor control outcomes than wide local excision. Radiation therapy should be considered as adjuvant treatment for locally advanced (stage T3a or higher) or high-risk (pagetoid spread) SC, nodal metastasis, or palliative care. Cryotherapy and topical chemotherapy are used for pagetoid spread. Targeted therapy has an emerging role in more complicated cases. For lymph node and distant metastasis, combination treatments should be provided, including lymph node and neck dissection, radiation therapy, systemic chemotherapy, and even orbital exenteration. The rarity of ocular SC precludes a comprehensive perspective on standard treatment. This paper offers a brief review of recent advances in the clinical diagnosis and management of ocular SC based on current scientific literature. PMID- 29983581 TI - Sofosbuvir-daclatasvir improves hepatitis C virus-induced mixed cryoglobulinemia: Upper Egypt experience. AB - Background and aims: Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations such as cryoglobulinemia and accounts for up to 90% of all cases of mixed cryoglobulinemia (MC). The present study aimed to evaluate the effect of sofosbuvir-daclatasvir therapy on symptomatic HCV-related MC and sustained virologic response (SVR) achievement. Patients and methods: This prospective cohort study was carried out on 120 patients with chronic HCV infection, clinically suspected to have MC, but only 63 of whom were positive for cryoglobulins. HCV-MC patients were treated with sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months. The serum cryoglobulins levels, complement 3 (C3), complement 4 (C4) (using ELISA assay kits) and rheumatoid factor (RF) (using immunoturbidimetric assay kit), were measured in the included HCV infected patients (to confirm HCV-MC diagnosis), in addition to quantitave HCV-RNA assays, using real time PCR. All these measurements have been done before stating therapy and 12, 24 weeks post-therapy for assessments of immunological recovery, viral load and SVR. Results: Significant increase in the serum cryoglobulin levels and RF with significant decrease in C3 and C4 serum levels were detected in only 63 out of 120 included HCV infected patients, upon whom the study has been completed. They showed significant decrease in their mean cryoglobulin levels from 41.47 ug/mL +/-12.32 SD to 5.12 ug/mL +/-3.59 SD then to 5.09 ug/mL +/-3.02 SD, 12 to 24 weeks post-therapy respectively (p<0.001), with significant decline in RF concentrations and rise in C3 and C4 serum levels approaching the normal values. There were improvements in the presenting HCV-MC clinical manifestations in variable degrees, ranging from 5 (71.42%) in patients with glomerulonephritis to 62 (98.4%) in patients with purpura. Eighty-seven percent of the included patients showed complete response (clinical, virological and immunological recovery) and 13% showed partial response (virological and immunological recovery without clinical improvement of cryoglobulinemia associated manifestations). Conclusion: A combined therapy of sofosbuvir 400 mg and daclatasvir 60 mg once daily for 3 months was associated with a significant decrease in serum cryoglobulin levels and appears as a reasonable treatment option for HCV-associated MC. PMID- 29983582 TI - Evaluation of statin utilization in the Republic of Macedonia during 2013-2016. AB - Purpose: A rational use of statins has a major and increasing importance in public health and allocation of financial resources by the health insurance funds (HIFs). The aim of this study was to evaluate the market share and utilization trends of statins in the Republic of Macedonia (R. Macedonia) from 2013 to 2016. Materials and methods: A retrospective analysis and data comparison for the utilization of HMG-CoA inhibitors (C10AA) in R. Macedonia from 2013 to 2016 were conducted. The data obtained from HIF, IMS Health, pharmaceutical industry and marketing authorization holders (MAHs) were evaluated through defined daily doses per 1000 insurers per day (DDD/TID). Results: Cardiovascular drugs are the most commonly prescribed and utilized drugs in R. Macedonia. The HIF cost for cardiovascular disease (CVD) increased to ?2,243,777.00 in the period from 2013 to 2016. Since 2012, the reimbursement shows that atorvastatin accounts for the highest expenditure reaching ?2,162,958.00 while rosuvastatin reached ?1,645,860.00 in 2016. The increased consumption of statins is confirmed from the records obtained from IMS Health databases in the evaluated period in R. Macedonia suggesting increased expenditures with total growth of 35.65% reaching ?4,421,280.24 in 2016. Evident growth of statin consumption is confirmed from the data obtained from the pharmaceutical industry and MAH. The statin use increased from 42.347 DDD/TID in 2013 to 71.697 DDD/TID in 2016, although it is lower in comparison to other European Union (EU) countries (1.1-2.5-fold). Conclusion: The rapid increase in the consumption of statins can be attributed mostly to an increase in the consumption volume. It is inevitable to widen the price reduction concept with initiatives that may control statin consumption amounts with measures such as educational programs for rational drug utilization and targeting eligible population. PMID- 29983583 TI - Post-lumbar discectomy reoperations that are associated with poor clinical and socioeconomic outcomes can be reduced through use of a novel annular closure device: results from a 2-year randomized controlled trial. AB - Introduction: Lumbar discectomy patients with large annular defects are at a high risk for reherniation and reoperation, which could be mitigated through the use of an annular closure device (ACD). To identify the most effective treatment pathways for this high-risk population, it is critical to understand the clinical outcomes and socioeconomic costs among reoperated patients as well as the utility of ACD for minimizing reoperation risk. Methods: This was a post hoc analysis of a prospective, multicenter, randomized controlled trial (RCT) designed to investigate the safety and efficacy of an ACD. All 550 patients (both ACD treated and control) from the RCT with follow-up data through 2 years were included in this analysis (69 reoperated and 481 non-reoperated). Reoperations were defined as any revision surgery of the index level, regardless of indication. Equivalent U.S. Medicare expenditures for reoperations were estimated through cost multipliers derived from the commercially available PearlDiver database. Results: A significantly greater number of control patients (45/278; 16%) compared to ACD patients (24/272; 9%) underwent a revision surgery at the index level within 2 years of followup (p=0.01). At 2 years of follow-up, the reoperated patients had significantly worse Oswestry Disability Index scores and visual analog scale for leg and back pain scores compared to their non-reoperated counterparts (p<0.0001). The total estimated direct medical costs for reoperation were US $952,348 ($13,802 per reoperated patient), with control patients accounting for the majority of this cost burden ($565,188; 59%). Conclusion: Post-discectomy reoperation is associated with significantly increased patient morbidity, missed work, and direct treatment costs in a population at high risk for reherniation. Annular closure helped minimize this clinical and socioeconomic burden by reducing the incidence of reoperation by nearly 50% (16% control vs 9% ACD). PMID- 29983584 TI - Comparing efficacy of lumen-apposing stents to plastic stents in the endoscopic management of mature peripancreatic fluid collections: a single-center experience. AB - Introduction: Mature peripancreatic fluid collection (MPFC) is a known and often challenging consequence of acute pancreatitis and often requires intervention. The most common method accepted is the "step-up approach," which consists of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy. Our paper aims to distinguish between plastic stents and lumen-apposing stents in the endoscopic management of MPFC in terms of morbidity, mortality, and haste of fluid collection resolution. Methods: A retrospective analysis was performed at UMass Memorial Medical Center in patients with a diagnosis of MPFC. Utilizing medical records, clinical data, radiology, as well as endoscopic evidence, patients were differentiated by stent type used (plastic versus lumen-apposing) for the management of the MPFC. The primary outcome of the study was to assess the time to MPFC resolution following the placement of either plastic or lumen-apposing stents (on endoscopic ultrasound or computerized tomography scan) using a multivariate analysis with a logistic regression model. Results: A total of 54 patients were included in this study from UMass Memorial Medical Center between 2012 and 2015. Twelve (22%) of these patients received lumen-apposing stents and 42 (78%) of these patients received plastic pigtail stents. For the lumen-apposing stent group, the mean interval between stent placement and resolution of MPFC was 57 days as compared to 102 days for plastic pigtail stents (p=0.02). The mean interval for placement/removal of lumen-apposing stents was 48 days as compared to 81 days for plastic pigtail stents (p=0.01). Stent migration was seen in 5 patients (11%) who received a plastic pigtail stent compared to 0 (0%) patients who received a lumen-apposing stent. Discussion: Our study demonstrates that lumen-apposing stents result in a significant reduction in the interval between stent placement and MPFC resolution as well as the time from stent placement to removal, when compared to plastic pigtail stents, the prior standard-of-care. Our study reached similar conclusions regarding the number of stents placed. However, we did not find a significant difference between the complication rates, specifically peri- and postprocedural bleeding or perforation, between the 2 study groups, as demonstrated in prior papers. PMID- 29983585 TI - Predictors of the analgesic efficacy of pulsed radiofrequency treatment in patients with chronic lumbosacral radicular pain: a retrospective observational study. AB - Background: Pulsed radiofrequency (RF) targeting the adjacent dorsal root ganglion (DRG) is one treatment option for lumbosacral radicular pain. However, the analgesic efficacy of this procedure is not always guaranteed. The aim of this retrospective study was to identify the predictors of the analgesic efficacy of pulsed DRG RF treatment in patients with chronic lumbosacral radicular pain. Methods: Patients who underwent pulsed DRG RF treatment from 2006 to 2017 at our clinic were enrolled. Positive response was defined as a >=50% reduction in pain score from baseline at day 30. Patient demographics, pain-related factors, and clinical factors were evaluated using logistic regression analysis to identify the predictors of a positive response to the treatment. Results: A total of 60 patients satisfied the study protocol requirements. Twenty-eight patients (46.7%) had a positive outcome. Multivariate logistic regression analysis revealed that the absence of comorbid musculoskeletal pain (OR=0.518, 95% CI=0.029-0.858, P=0.033) and positive response to previous epidural steroid injection (OR=3.269, 95% CI=1.046-10.215, P=0.042) were independent predictors of the analgesic efficacy of pulsed DRG RF treatment. Conclusion: Comorbid musculoskeletal pain and previous epidural injection response appear to affect the outcome of pulsed DRG RF treatment in patients with chronic lumbosacral radicular pain. PMID- 29983586 TI - The analgesic effect of intravenous methylprednisolone on acute neuropathic pain with allodynia due to central cord syndrome: a retrospective study. AB - Background: Central cord syndrome (CCS) may be associated with severe neuropathic pain that often resists to conventional pain therapy regimens and affects the patients' quality of life (QoL) seriously. Current treatments for CCS-associated neuropathic pain have limited evidence of efficacy. This retrospective study was performed to present the effects of early treatment with methylprednisolone (MP) on acute neuropathic pain relief and the QoL in CCS patients. Patients and methods: Data were collected from the medical records of CCS patients who suffered from acute neuropathic pain with allodynia. All the patients received intravenous MP treatment for up to 1 week. Patients were evaluated with standard measures of efficacy: neuropathic pain intensity, the area of allodynia, and the QoL at baseline, daily treatment, and at 1 and 3 months after the end of MP treatment. Results: Thirty-four eligible patients were enrolled in our study. By the end of MP treatment, the proportion of patients who gained total or major (visual analog scale [VAS] score decreased by 50% or more) allodynia relief from the treatment was 91.18%, and a decrease in spontaneous pain was also observed. Moreover, this study showed MP could significantly improve the QoL of patients based on McGill Pain Questionnaire Short Form and EuroQol Five Dimensions Questionnaire. Four patients (11.76%) during MP treatment experienced mild or moderate side effects. None of the patients manifested CCS-associated neuropathic pain recurrence and MP-associated side effects at follow-up. Conclusion: The current results suggested that MP offered an effective therapeutic alternative for relieving CCS-associated acute neuropathic pain with allodynia. Given the encouraging results of this study, it would be worthwhile to confirm these results in randomized placebo-controlled clinical trials. PMID- 29983587 TI - Intra-articular injection of botulinum toxin type A for shoulder pain in glenohumeral osteoarthritis: a case series summary and review of the literature. AB - Introduction: Shoulder pain is one of the most common musculoskeletal diseases, and can be due to glenohumeral osteoarthritis, rotator cuff tear, impingement, tendinitis, adhesive capsulitis, and subacromial bursitis. Several therapies have been proposed, including steroids, nonsteroidal anti-inflammatory drugs, intra articular injections, and physical therapies. Many published studies have reported on the employment of botulinum toxin type A (BoNT-A) to reduce pain in subjects with neurological and musculoskeletal diseases by inhibiting substance P release and other inflammatory factors. Methods: In the present article, we briefly update current knowledge regarding intra-articular BoNT therapy, reviewing existing literature on intra-articular use of BoNT-A, including nonrandomized and randomized prospective and retrospective cohort studies and case series published from December 1989 to November 2017. We also describe a case series of six subjects treated with intra-articular injection of incobotulinumtoxin A for the treatment of pain deriving from osteoarthritis. Conclusion: Intra-articular BoNT-A is effective and minimally invasive. Pain reduction with an increase in shoulder articular range of motion in our experience confirms the effectiveness of BoNT-A injection for the management of this syndrome. PMID- 29983588 TI - Effects of propofol anesthesia versus sevoflurane anesthesia on postoperative pain after radical gastrectomy: a randomized controlled trial. AB - Purpose: After a radical gastrectomy, patients may experience severe pain. Some studies have reported that the use of propofol significantly reduced postoperative pain, while others have argued that this effect was not significant. Thus, we aimed to assess whether anesthesia with propofol could help to reduce pain after an open radical gastrectomy procedure. Patients and methods: Sixty patients who were scheduled to undergo a laparotomy for radical gastrectomy were randomly assigned to either the propofol or sevoflurane group (n=30 each). A target-controlled infusion of propofol or inhalation of sevoflurane, titrated to bispectral index of 40-60, was maintained. All patients were administered a standardized multimodal analgesic plan, including intraoperative dexmedetomidine, dexamethasone, and postoperative flurbiprofen axetil, as well as patient controlled fentanyl. Hemodynamics, pain scores, fentanyl consumption, adverse events, and the incidence of chronic pain 1 month and 3 months following hospital discharge were recorded. Results: The intensity of postoperative pain was relatively low to moderate in all the patients. The propofol group showed lower pain scores, at rest and while coughing, up to 48 h postoperatively compared to the sevoflurane group (P<0.05). Cumulative fentanyl consumption 0-24 h after surgery was lower for the propofol group (364.4 +/- 139.1 vs. 529.3 +/- 237.9 ug; P=0.002). However, for fentanyl consumption 0-48 h, the difference between the two groups was not significant (710.9 +/- 312.8 vs. 850.9 +/- 292.0 ug; P=0.078). There were no differences in the incidences of adverse events or chronic pain between the groups. Conclusions: Overall, the multimodal analgesic approach reduced postoperative pain after an open radical gastrectomy procedure in all patients anesthetized with either propofol or sevoflurane. Furthermore, our results indicated better analgesic outcome for the propofol group, especially in the early postoperative period. PMID- 29983589 TI - miRNA-146a rs2910164 C>G polymorphism increased the risk of esophagogastric junction adenocarcinoma: a case-control study involving 2,740 participants. AB - Purpose: The miRNA-146a rs2910164 C>G polymorphism may contribute to the development of cancer. However, the association between this polymorphism and the risk of esophagogastric junction adenocarcinoma (EGJA) remains unclear. In the present study, we carried out a case-control study to explore the potential relationship between miRNA-146a rs2910164 C>G polymorphism and EGJA risk. Patients and methods: In total, 1,063 EGJA patients and 1,677 cancer-free controls were enrolled. The SNPscanTM genotyping assay, a patented technology, was used to test the genotyping of miRNA-146a rs2910164 C>G polymorphism. Results: We found that miRNA-146a rs2910164 C>G polymorphism was associated with a risk of developing EGJA (additive model: adjusted odds ratio (OR), 1.27; 95% CI, 1.07-1.51; P=0.006; homozygote model: adjusted OR, 1.31; 95% CI, 1.03-1.65; P=0.027 and dominant model: adjusted OR, 1.36; 95% CI, 1.15-1.60; P<0.001). After adjustment for the Bonferroni correction, these associations were also found in additive and dominant genetic models. In the subgroup analyses, after adjustment by sex, age, alcohol consumption, and smoking status, results of multiple logistic regression analysis indicated that miRNA-146a rs2910164 C>G polymorphism increased the risk of EGJA in males, females, <64 years old, >=64 years old, never smoking, and never drinking subgroups. Conclusion: The current study highlights that the miRNA-146a rs2910164 C>G polymorphism increased the risk of EGJA in eastern Chinese Han population. PMID- 29983590 TI - A retrospective study of concurrent chemoradiotherapy plus S-1 adjuvant chemotherapy on curative effect for treatment of patients with N3 stage nasopharyngeal carcinoma. AB - Introduction: The purpose of this study was to analyze the efficacy and safety of concurrent chemoradiotherapy plus S-1 adjuvant chemotherapy for N3 stage nasopharyngeal carcinoma (NPC). Methods: This study included 44 N3 stage NPC patients treated with concurrent chemoradiotherapy plus S-1 adjuvant chemotherapy. The intensity-modulated radiation therapy doses were planning target volume (PTV) 70-72 Gy for gross disease in the nasopharynx and 66-70 Gy for positive lymph nodes. The doses for high-risk- and low-risk region PTV were 60-62 and 54-56 Gy in 31-33 fractions. All patients received a concurrent chemotherapy program consisting of cisplatin 100 mg/m2, day 1, and the cycle repetition was every 21 days. The adjuvant chemotherapy program consisted of 4 cycles of S-1. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m2; 50 mg twice a day for 1.25 m2<=BSA<1.5 m2; and 60 mg twice a day for BSA >=1.5 m2. S-1 was given on days 1-28, given 6 weeks apart. Results: All 44 patients completed at least 2 cycles of concurrent chemotherapy and 4 cycles of adjuvant chemotherapy. The total efficiency of therapy was 100.0%. The 3-year overall survival (OS), distant metastasis-free survival (DMFS), local-regional control, and progression-free survival rates were 86.4%, 84.1%, 97.7%, and 81.8%, respectively. There were no differences in the OS, DMFS, and efficiency between fast-fading group (reaching partial response before the second cycle of concurrent chemotherapy) and general-fading group (the rest of the group). The incidence of rash in the entire group was low, and there was also no association with prognosis. Conclusion: In patients with N3 stage NPC, concurrent chemoradiotherapy plus S-1 adjuvant chemotherapy yielded an excellent survival benefit, and the toxicities were mild and tolerable. Distant metastasis was the main cause of treatment failure. PMID- 29983591 TI - The prognostic value of differentially expressed CYP3A subfamily members for hepatocellular carcinoma. AB - Objective: The activities of four cytochrome P3A (CYP3A) subfamily members (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) are well documented in drug metabolism. However, the association between CYP3A subfamily members and hepatocellular carcinoma (HCC) remains unclear. This study investigated the prognostic value of CYP3A subfamily mRNA expression levels with HCC prognosis. Materials and methods: Data from a total of 360 HCC patients were retrieved from The Cancer Genome Atlas database, and data from 231 HCC patients were retrieved from the Gene Expression Omnibus database. Kaplan-Meier analysis and Cox regression models were utilized to determine median survival, overall survival, and recurrence-free survival. Hazard ratios and 95% CI were calculated. Results: Low expression of CYP3A4, CYP3A5, and CYP3A43 in the tumor tissue was associated with short median survival (crude p=0.004, 0.001, and 0.001; adjusted p=0.022, 0.005, and 0.013, respectively). Joint-effects combination analysis of CYP3A4, CYP3A5/CYP3A4, CYP3A43/CYP3A5, and CYP3A43 revealed that high expression groups of two genes (group C, group c, group 3) were associated with a reduced risk of death, as compared to low expression of two genes (group A, group a, group 1), and the adjusted p values were 0.001, 0.004, and 0.001, respectively. Joint-effects analysis of CYP3A4, CYP3A5, and CYP3A43 showed that groups III and IV had a reduced risk of death, as compared to group I (adjusted p=0.024 and 0.002, respectively). Conclusion: CYP3A4, CYP3A5, and CYP3A43 mRNA expression levels are potential prognostic markers of HCC. PMID- 29983592 TI - The prognosis and effects of local treatment strategies for orbital embryonal rhabdomyosarcoma: a population-based study. AB - Introduction: Orbital embryonal rhabdomyosarcoma is a rare childhood malignancy with a good prognosis, but the optimal treatment remains unclear. Using a population-based cancer registry, we assessed the prognoses and survival outcomes of patients with orbital embryonal rhabdomyosarcoma according to the local treatment strategy. Patients and methods: Patients diagnosed with orbital embryonal rhabdomyosarcoma between 1988 and 2012 as part of the Surveillance Epidemiology and End Results program were included. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors associated with cause-specific survival (CSS) and overall survival (OS). Results: In total, 102 patients were included; their median age was 6 years, 78.4% were white, and 56.9% were male. The median tumor size was 30 mm. Of 20 patients with an available histologic grade, the tumors of 90% were poorly differentiated/undifferentiated. Of 92 patients with available surgical and radiotherapy (RT) statuses, 50 (54.3%), 36 (39.1%), and 6 (6.5%) received surgery and RT, primary RT, and primary surgery, respectively. Ninety-five patients (93.1%) received chemotherapy. The 5- and 10-year CSSs of the entire cohort were 94.3% and 92.2%, respectively. The 5- and 10-year OSs were 93.3% and 91.3%, respectively. In 95 patients who were followed up for at least 12 months, there were no significant prognostic factors related to CSS and OS. Furthermore, the local treatment strategy did not significantly affect CSS (P=0.29) or OS (P=0.468). Conclusion: There is no local treatment of choice for orbital embryonal rhabdomyosarcoma in terms of survival. However, RT is a reasonable alternative treatment to surgery. PMID- 29983594 TI - A panel containing PD-1, IL-2Ralpha, IL-10, and CA15-3 as a biomarker to discriminate breast cancer from benign breast disease. AB - Introduction: Programmed cell death protein 1 (PD-1), an immune checkpoint molecule, has recently been recognized as a predictive and prognostic biomarker in several malignant tumors, but its diagnostic value remains largely unknown. We aimed to investigate the differential diagnostic efficiency of PD-1 and other immune molecules and propose a panel of immune molecules combined with cancer antigen 15-3 (CA15-3) to distinguish breast cancer (BC) from benign breast disease (BBD). Patients and methods: Ninety-one eligible BC patients and 31 BBD patients were enrolled. Pretreatment peripheral blood was collected and tested for mRNA expression of PD-1, cytotoxic T lymphocyte antigen 4, forkhead box P3, transforming growth factor beta, interleukin-10 (IL-10), IL-2 receptor alpha (IL 2Ralpha), and cluster of differentiation 28 by quantitative reverse transcription PCR. Results: The diagnostic areas under curve (AUCs) of PD-1, IL-2Ralpha, and IL 10 for BC-BBD discrimination were 0.764, 0.758, and 0.743, respectively. The diagnostic efficiencies of these three parameters in distinguishing early-stage or advanced BC from BBD were consistent with a role in BC-BBD discrimination. A panel of PD-1 + IL-10 + IL-2Ralpha + CA15-3 showed the highest AUC (0.862), with a sensitivity of 0.933 and a specificity of 0.724, for BC-BBD discrimination. In addition, for early-stage BC discrimination, this panel also had the highest AUC (0.811), with a sensitivity of 0.933 and a specificity of 0.614, while for advanced BC discrimination, a panel of PD-1 + IL-10 + CA15-3 exhibited the highest AUC (0.896), with a sensitivity of 0.933 and a specificity of 0.783. Conclusion: These data indicate that the panel containing PD-1, IL-2Ralpha, IL 10, and CA15-3 can effectively discriminate BC from BBD with a high efficiency. After further confirmation, it could be used to complement conventional imaging modalities, especially in discriminating early-stage BC from BBD. PMID- 29983595 TI - Decreased expression of peroxisome proliferator-activated receptor alpha indicates unfavorable outcomes in hepatocellular carcinoma. AB - Introduction: Hepatocellular carcinoma (HCC) has a close relationship with lipid metabolism. Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a crucial role in the regulation of fatty acid oxidation in the liver. However, the role of PPARalpha in HCC remains unclear. Methods: A total of 804 HCC specimens were collected to construct a tissue microarray and for immunohistochemical analysis. The relationship between PPARalpha expression and clinical features of HCC patients was analyzed. Kaplan-Meier analysis was conducted to assess the prognostic value of PPARalpha expression levels. Results: The expression of PPARalpha in HCC was noticeably decreased in HCC tissues. HCC patients with high levels of PPARalpha expression in cytoplasm had smaller tumors (P=0.027), less vascular invasion (P=0.049), and a higher proportion of complete involucrum (P=0.038). Kaplan-Meier analysis showed that HCC patients with low PPARalpha expression in the cytoplasm had significantly worse outcomes in terms of overall survival (P<0.001), disease-free survival (P=0.024), and the probability of recurrence (P=0.037). Similarly, overall survival was significantly shorter in HCC patients with negative PPARalpha expression in the nucleus (P=0.034). Multivariate Cox analyses indicated that tumor size (P=0.001), TNM stage (P<0.001), vascular invasion (P<0.001), and PPARalpha expression in the cytoplasm (P<0.001) were found to be independent prognostic variables for overall survival. Conclusion: Our data revealed that PPARalpha expression was decreased in HCC samples. High PPARalpha expression was correlated with longer survival times in HCC patients, and served as an independent factor for better outcomes. Our study therefore provides a promising biomarker for prognostic prediction and a potential therapeutic target for HCC. PMID- 29983593 TI - Disparities in survival for right-sided vs. left-sided colon cancers in young patients: a study based on the Surveillance, Epidemiology, and End Results database (1990-2014). AB - Purpose: To investigate whether young patients exhibit different characteristics and survival according to tumor location and stage using data from the Surveillance, Epidemiology, and End Results (SEER) database. Patients and methods: Young patients (20-49 years old) with stage I-III colon cancers were identified from the SEER program from 1990 to 2014. Kaplan-Meier survival analysis and Cox proportional hazards regression were used to analyze the data. Subset analyses were also done among different age and stage subgroups. Results: Of 8197 patients, 3709 (45.2%) had right-sided colon cancers (RCCs). Patients with RCCs were more likely to be male, to be younger, and to have more poorly differentiated and more advanced tumors. The Kaplan-Meier survival curves and univariate survival models revealed that left-sided colon cancers (LCCs) had lower mortality for all stages combined and stage III, but higher mortality for stage II, compared with right-sided tumors. However, multivariate Cox regression models showed no significant survival differences by location for all patients (adjusted hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.86-1.05; P=0.34) or for stage I (adjusted HR, 1.47; 95% CI, 0.82-2.63; P=0.20). Stage II left-sided cancers had higher mortality (adjusted HR, 1.24; 95% CI, 1.00-1.54; P=0.048), whereas stage III left-sided cancers had lower mortality (adjusted HR, 0.86; 95% CI, 0.77-0.97; P=0.01). For 20- to 39-year-old patients, a significant difference was only found in stage II disease, with a higher mortality for left sided tumors (adjusted HR, 1.82; 95% CI, 1.12-2.97; P=0.02). However, for 40- to 49-year-old patients, a significant difference was only found in stage III disease, with a lower mortality for left-sided tumors (adjusted HR, 0.83; 95% CI, 0.72-0.95; P=0.008). Conclusion: In patients younger than 50 years, there were no significant differences in mortality between RCCs and LCCs for all stages combined after adjusting for multiple clinicopathological features. However, RCCs had lower mortality in stage II (especially in 20- to 39-year-old patients) and higher mortality in stage III (especially in 40- to 49-year-old patients). PMID- 29983596 TI - Elevated pre-surgical CA15-3: does it predict the short-term disease-free survival of breast cancer patients without distant metastasis? AB - Background: CA15-3 is the most commonly used tumor marker in breast cancer. Its prognostic role has been described in the metastatic setting, but the role of pre surgical CA15-3 in the assessment of patients with breast cancer without metastasis has not been substantiated yet. Methodology: From February 2014 for a 2-year period, this prospective study included all patients who were diagnosed with primary breast cancer and underwent surgery at a tertiary care hospital. The serum level of CA15-3 was assessed on a pre-surgical blood sample and later at the 3-, 6-, 9-, and 12-month follow-up by enzyme-linked immunosorbent assay. Disease-free survival (DFS) was analyzed with a Kaplan-Meier model and log-rank test. Results: We enrolled 195 patients (mean age +/- SD 57.84 years +/-13.819, range, 28-95) with breast cancer. The prevalence of elevated (>=30 U/mL) pre surgical CA15-3 was 35.9%, and it reduced to 14.3% at 3 months after mastectomy. Pre-surgical CA15-3 had a significant association only with the size of the tumor (p=0.047). Patients who did not have elevated pre-surgical CA15-3 (>=30 U/mL) had the best short-term DFS, and it was worst when the pre-surgical CA15-3 was >100 U/mL (p=0.041). Conclusion: Elevated pre-surgical CA15-3 is a predictor of poor short-term DFS of patients with breast cancer without distant metastasis. PMID- 29983597 TI - Safety and neutralizing rabies antibody in healthy subjects given a single dose of rabies immune globulin caprylate/chromatography purified. AB - Background: Rabies immune globulin (RIG) and vaccination series are necessary for postexposure prophylaxis. A new formulation of RIG (human) purified by caprylate/chromatography (RIG-C) was evaluated. Trial registration: ClinicalTrials.gov identifier: NCT02139657. Materials and methods: This open label, single-arm study in healthy subjects evaluated neutralizing rabies antibody concentrations produced from a single 20 IU/kg intramuscular (IM) dose of RIG-C as measured by rapid fluorescent focus inhibition test (50% neutralization endpoint) 1-hour postdose and on days 1, 2, 4, 6, 8, 10, 14, 18, and 21. Results: Twelve subjects were enrolled into the study. No discontinuations, serious adverse events (AEs), or treatment-emergent clinically significant changes in laboratory parameters were observed. All AEs resolved and were mild except 1 moderate AE of oropharyngeal pain. Injection site pain (4 subjects) was most commonly reported. RIG-C produced a rapid increase in neutralizing rabies antibody: mean value 0.113 IU/mL at 24 hours after IM injection, peak on day 4 (0.132 IU/mL), persisting through day 21 (0.116 IU/mL). The mean reciprocal titer was 11.5 by day 2; the peak value of 12.1 was achieved on day 4; and a mean value >=10.6 was maintained through day 21. Conclusion: RIG C was well tolerated and provided neutralizing rabies antibodies, which combined with vaccine series after rabies exposure, should result in effective prophylaxis per World Health Organization/Centers for Disease Control and Prevention guidelines. PMID- 29983598 TI - Development of an advanced injection time model for an autoinjector. AB - Background: This work describes an advanced physics-based mathematical model that accurately predicts autoinjector injection time. Autoinjectors are a well established technology for parenteral drug delivery and quantifying the probability to achieve a given injection time is critical to the successful development and commercial launch of the autoinjector. Method: Each parameter that can influence injection time was treated as a statistical variable with an appropriate distribution function. Monte Carlo simulation was used to obtain the probability of achieving the required injection time. Sensitivity analyses were performed to identify those parameters most critical in contributing to the overall injection time. To validate the model, a number of experiments were conducted on autoinjectors, with key contributors to injection time measured and characterized. Results: The results showed excellent agreement between modeled and measured injection time. The modeling error for all investigated device configurations was smaller than 12% and the error range was less than 6%. The consistent over-estimation of injection time suggests a small bias in the model which could be accounted for by reducing internal friction. Conclusion: This work provides evidence that the selected modeling approach, which aims for a simple yet computationally inexpensive model, is accurate and enables running comprehensive statistical simulations to determine the full range of expected injection times due to component variability. PMID- 29983599 TI - Review of lung sealant technologies for lung volume reduction in pulmonary disease. AB - Emphysema is an incurable and underdiagnosed disease with obstructive ventilatory impairment of lung function. Despite decades of research, medical treatments available so far did not significantly improve the survival benefits. Different bronchoscopic methods for lung volume reduction (LVR) in emphysema were used in the past 2 decades aiming to close the airways serving the hyperinflated lung regions and to allow the gas in the more distal bullas to be absorbed. Sealants and adhesives can be natural/biological, synthetic and semisynthetic. In lung surgery, lung sealants are used to treat prolonged air leak, which is the most common complication. Sealants can also be applied in bronchoscopic lung volume reduction (BLVR) as they administer into the peripheral airways where they polymerize and act as tissue glue on the surface of the lung to seal the target area to cause durable permanent absorption atelectasis. Initial studies analyzed the efficacy of bronchoscopic instillation of a fibrinogen-thrombin complex solution in advanced emphysema. Future studies will analyze the effects of adding chondroitin sulfate and poly-L-lysine to thrombin-fibrinogen complex thus promoting fibroblast attachment, proliferation and scarring, causing bronchial fibrostenosis and preventing ventilation of the affected part of the lung. Modifications of these methods were later developed, and the efficacy of BLVR with other sealants was analyzed in clinical studies. Results from current studies using this treatment method are promising showing that it is effective in improving exercise tolerance and quality of life in patients with advanced emphysema. It seems that subjective benefits in dyspnea scores and quality of life are more marked than improvements in lung function tests. The safety profile of sealant techniques in BLVR was mostly acceptable in clinical studies. The definite conclusions about the effectiveness of sealant in BLVR could be difficult because only a small population was involved in the current studies. More randomized large controlled studies are needed in establishing the definite role of biological BLVR in the bronchoscopic treatment of emphysema. PMID- 29983600 TI - Hematological abnormalities in HIV-antiretroviral therapy naive clients as seen at an immune suppression syndrome clinic at Mbarara Regional Referral Hospital, southwestern Uganda. AB - Aim/objective: To assess the common hematological abnormalities among HIV antiretroviral therapy (ART) naive clients attending an immune suppression syndrome (ISS) clinic at Mbarara Regional Referral Hospital (MRRH), southwestern Uganda. Patients and methods: This was a cross-sectional study carried out during the months of March to August 2016 at the ISS clinic of MRRH. We collected approximately 4.0 mL of EDTA anticoagulated blood samples, which were assayed for complete blood count, CD4+ cell count and thin film examination. Correlation of the hematological abnormalities with CD4+ cell counts was done using correlation coefficient (r) and analysis of variance (F), and the p-value was set at <=0.05. Results: A total of 141 clients were enrolled. Of these, 67.38% (95/141) were anemic, 26.24% (40/141) had thrombocytopenia while 26.95% (38/141) had leucopenia. Of the 95 participants with anemia, 89.47% (85/95) presented with normocytic-normochromic anemia, 8.42% (8/95) with microcytic-hypochromic anemia and 2.11% (2/95) with macrocytic-hypochromic anemia. Anemia was not different across the several World Health Organization (WHO) stages of HIV infection disease progression (p>0.05). Statistically significant differences were present among participants with leucopenia (p<0.05). Also, leucopenia was more prevalent (11/38) among participants in WHO stage 4 of HIV infection. CD4+ cell counts correlated with thrombocytopenia (r=0.24, p<0.05) and leucopenia (r=0.15, p<0.05). Conclusion: People living with HIV/AIDS (PLWHIV/AIDS) ought to be routinely monitored and treated for the occurrence of hematological abnormalities. Early initiation of ART can help to prevent some hematological abnormalities. PMID- 29983601 TI - Designing and developing a continuing interprofessional education model. AB - Background: Interprofessional education is considered as one of the approaches in educating learners in the health system that increases interprofessional collaboration and improves the quality of patient care. Purpose: This study sought to design an interprofessional continuing education model. Methods: This study was conducted in three stages. In the first stage, a systematic review of literature and search of databases were conducted to identify the common models of interprofessional continuing education and to extract the elements used in these models. In the second stage, specialists in interprofessional continuing education were interviewed in relation to the features of elements derived from the first stage. In the third stage, the model of interprofessional continuing education was designed using the results of the first and second stages. Results: Seven models were obtained. Five themes, including the subject of interprofessional continuing education, objectives, content, learning strategy, and evaluation strategies, were extracted from them. Specialists stated interprofessional collaboration, needs of community and learners, focus on patient, using interactive teaching methods, and feedback as the main features of these five themes. Conclusion: The results of this study showed that providing a framework and model regulated in interprofessional continuing education programs can help design these programs. PMID- 29983602 TI - Bridging the gap between physician and medical student education: using the Train the Trainer model to improve cultural competence training in the clerkship years of medical school. AB - Cultural competence (CC) training has become a required part of medical education to create future physicians dedicated to decreasing health disparities. However, current training seems to be inadequate as research has demonstrated gaps between CC training and clinical behaviors of students. One aspect that is potentially contributing to this gap is the lack of physician education of CC. Without it being something not only taught in the classroom, but also modeled and taught in the clinical setting, CC will continue to be a theoretical concept instead of a skill set that changes the way that future physicians interact with patients and make decisions about patient care. To change this, we propose the implementation of a Train the Trainer model in which the preclinical professor in charge of CC education trains Clerkship and Residency Directors who then can train and supervise the physicians and residents in their departments on CC to better implement it into the formal and informal curriculum of clerkships. PMID- 29983603 TI - Learning preferences in higher education: a medical student's perspective. PMID- 29983604 TI - The role of interviews in predicting student OSCE performance: medical students' perspective. PMID- 29983605 TI - Functional role of ginseng-derived compounds in cancer. AB - Ginseng is a natural product best known for its curative properties in diverse physiological processes such as cancer, neurodegenerative disorders, hypertension, and maintenance of hemostasis in the immune system. In previous decades, there have been some promising studies into the pharmacology and chemistry of ginseng components and the relationship between their structure and function. The emerging use of modified ginseng and development of new compounds from ginseng for clinical studies have been topics of study for many researchers. The present review deals with the anticancer, anti-inflammatory, antioxidant, and chemopreventive effects, and recent advances in microRNA technology related to red ginseng. The review also summarizes the current knowledge on the effect of ginsenosides in the treatment of cancer. PMID- 29983606 TI - Gut microbiota-mediated pharmacokinetics of ginseng saponins. AB - Orally administered ginsengs come in contact with the gut microbiota, and their hydrophilic constituents, such as ginsenosides, are metabolized to hydrophobic compounds by gastric juice and gut microbiota: protopanxadiol-type ginsenosides are mainly transformed into compound K and ginsenoside Rh2; protopanaxatriol-type ginsenosides to ginsenoside Rh1 and protopanaxatriol, and ocotillol-type ginsenosides to ocotillol. Although this metabolizing activity varies between individuals, the metabolism of ginsenosides to compound K by gut microbiota in individuals treated with ginseng is proportional to the area under the blood concentration curve for compound K in their blood samples. These metabolites such as compound K exhibit potent pharmacological effects, such as antitumor, anti inflammatory, antidiabetic, antiallergic, and neuroprotective effects compared with the parent ginsenosides, such as Rb1, Rb2, and Re. Therefore, to monitor the potent pharmacological effects of ginseng, a novel probiotic fermentation technology has been developed to produce absorbable and bioactive metabolites. Based on these findings, it is concluded that gut microbiota play an important role in the pharmacological action of orally administered ginseng, and probiotics that can replace gut microbiota can be used in the development of beneficial and bioactive ginsengs. PMID- 29983607 TI - Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. AB - Panax ginseng, also called Asian or Korean ginseng, has long been traditionally used in Korea and China to treat various diseases. The major active ingredients of P. ginseng are ginsenosides, which have been shown to have a variety of therapeutic effects, including antioxidation, anti-inflammatory, vasorelaxation, antiallergic, antidiabetic, and anticancer. To date, approximately 40 ginsenoside components have been reported. Current research is concentrating on using a single ginseng compound, one of the ginsenosides, instead of the total ginseng compounds, to determine the mechanisms of ginseng and ginsenosides. Recent in vitro and in vivo results show that ginseng has beneficial effects on cardiac and vascular diseases through efficacy, including antioxidation, control of vasomotor function, modulation of ion channels and signal transduction, improvement of lipid profiles, adjustment of blood pressure, improvement in cardiac function, and reduction in platelet adhesion. This review aims to provide valuable information on the traditional uses of ginseng and ginsenosides, their therapeutic applications in animal models and humans, and the pharmacological action of ginseng and ginsenosides. PMID- 29983608 TI - Chemical transformation and target preparation of saponins in stems and leaves of Panax notoginseng. AB - Background: Notoginsenoside Ft1 is a promising potential candidate for cardiovascular and cancer disease therapy owing to its positive pharmacological activities. However, the yield of Ft1 is ultralow utilizing reported methods. Herein, an acid hydrolyzing strategy was implemented in the acquirement of rare notoginsenoside Ft1. Methods: Chemical profiles were identified by ultraperformance liquid chromatography coupled with quadruple-time-of-flight and electrospray ionization mass spectrometry (UPLC-Q/TOF-ESI-MS). The acid hydrolyzing dynamic changes of chemical compositions and the possible transformation pathways of saponins were monitored by ultrahigh-performance LC coupled with tandem MS (UHPLC-MS/MS). Results and conclusion: Notoginsenoside Ft1 was epimerized from notoginsenoside ST4, which was generated through cleaving the carbohydrate side chains at C-20 of notoginsenosides Fa and Fc, and vina ginsenoside R7, and further converted to other compounds via hydroxylation at C 25 or hydrolysis of the carbohydrate side chains at C-3 under the acid conditions. High temperature contributed to the hydroxylation reaction at C-25 and 25% acetic acid concentration was conducive to the preparation of notoginsenoside Ft1. C-20 epimers of notoginsenoside Ft1 and ST4 were successfully separated utilizing solvent method of acetic acid solution. The theoretical preparation yield rate of notoginsenoside Ft1 was about 1.8%, which would be beneficial to further study on its bioactivities and clinical application. PMID- 29983609 TI - Remarkable impact of steam temperature on ginsenosides transformation from fresh ginseng to red ginseng. AB - Background: Temperature is an essential condition in red ginseng processing. The pharmacological activities of red ginseng under different steam temperatures are significantly different. Methods: In this study, an ultrahigh-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry was developed to distinguish the red ginseng products that were steamed at high and low temperatures. Multivariate statistical analyses such as principal component analysis and supervised orthogonal partial least squared discrimination analysis were used to determine the influential components of the different samples. Results: The results showed that different steamed red ginseng samples can be identified, and the characteristic components were 20-gluco-ginsenoside Rf, ginsenoside Re, ginsenoside Rg1, and malonyl-ginsenoside Rb1 in red ginseng steamed at low temperature. Meanwhile, the characteristic components in red ginseng steamed at high temperature were 20R-ginsenoside Rs3 and ginsenoside Rs4. Polar ginsenosides were abundant in red ginseng steamed at low temperature, whereas higher levels of less polar ginsenosides were detected in red ginseng steamed at high temperature. Conclusion: This study makes the first time that differences between red ginseng steamed under different temperatures and their ginsenosides transformation have been observed systematically at the chemistry level. The results suggested that the identified chemical markers can be used to illustrate the transformation of ginsenosides in red ginseng processing. PMID- 29983610 TI - Korean Red Ginseng extract reduces hypoxia-induced epithelial-mesenchymal transition by repressing NF-kappaB and ERK1/2 pathways in colon cancer. AB - Background: The incidence of colorectal cancer (CRC) is increasing, with metastasis of newly diagnosed CRC reported in a large proportion of patients. However, the effect of Korean Red Ginseng extracts (KRGE) on epithelial to mesenchymal transition (EMT) in CRC is unknown. Therefore, we examined the mechanisms by which KRGE regulates EMT of CRC in hypoxic conditions. Methods: Human CRC cell lines HT29 and HCT116 were incubated under hypoxic (1% oxygen) and normoxic (21% oxygen) conditions. Western blot analysis and real-time PCR were used to evaluate the expression of EMT markers in the presence of KRGE. Furthermore, we performed scratched wound healing, transwell migration, and invasion assays to monitor whether KRGE affects migratory and invasive abilities of CRC cells under hypoxic conditions. Results: KRGE-treated HT29 and HCT116 cells displayed attenuated vascular endothelial growth factor (VEGF) mRNA levels and hypoxia-inducible factor-1alpha (HIF-1alpha) protein expression under hypoxic conditions. KRGE repressed Snail, Slug, and Twist mRNA expression and integrin alphaVbeta6 protein levels. Furthermore, hypoxia-repressed E-cadherin was restored in KRGE-treated cells; KRGE blocked the invasion and migration of colon cancer cells by repressing NF-kappaB and ERK1/2 pathways in hypoxia. Conclusions: KRGE inhibits hypoxia-induced EMT by repressing NF-kappaB and ERK1/2 pathways in colon cancer cells. PMID- 29983611 TI - An investigation of Panax ginseng Meyer growth promotion and the biocontrol potential of antagonistic bacteria against ginseng black spot. AB - Background: Ginseng black spot disease resulting from Alternaria panax Whuetz is a common soil-borne disease, with an annual incidence rate higher than 20-30%. In this study, the bacterial strains with good antagonistic effect against A. panax are screened. Methods: A total of 285 bacterial strains isolated from ginseng rhizosphere soils were screened using the Kirby-Bauer disk diffusion method and the Oxford cup plate assay. We analyzed the antifungal spectrum of SZ-22 by confronting incubation. To evaluate the efficacy of biocontrol against ginseng black spot and for growth promotion by SZ-22, we performed pot experiments in a plastic greenhouse. Taxonomic position of SZ-22 was identified using morphology, physiological, and biochemical characteristics, 16S ribosomal DNA, and gyrB sequences. Results: SZ-22 (which was identified as Brevundimonas terrae) showed the strongest inhibition rate against A. panax, which showed 83.70% inhibition, and it also provided broad-spectrum antifungal effects. The inhibition efficacies of the SZ-22 bacterial suspension against ginseng black spot reached 82.47% inhibition, which is significantly higher than that of the 25% suspension concentrate azoxystrobin fungicide treatment (p < 0.05). Moreover, the SZ-22 bacterial suspension also caused ginseng plant growth promotion as well as root enhancement. Conclusion: Although the results of the outdoor pot-culture method were influenced by the pathogen inoculum density, the cropping history of the field site, and the weather conditions, B. terrae SZ-22 controlled ginseng black spot and promoted ginseng growth successfully. This study provides resource for the biocontrol of ginseng black spot. PMID- 29983612 TI - Effects of fermented ginseng root and ginseng berry on obesity and lipid metabolism in mice fed a high-fat diet. AB - Background: Previous studies have shown that both ginseng root and ginseng berry exhibit antiobesity and antidiabetic effects. However, a direct comparison of the efficacy and mechanisms between the root and the berry after oral administration remains to be illuminated. Methods: In this study, we observed the effects of fermented ginseng root (FGR) and fermented ginseng berry (FGB) on obesity and lipid metabolism in high-fat diet induced obese mice. Results: FGR and FGB significantly inhibited the activity of pancreatic lipase in vitro. Both FGR and FGB significantly suppressed weight gain and excess food intake and improved hypercholesterolemia and fatty liver, while only FGR significantly attenuated hyperglycemia and insulin resistance. Both FGR and FGB significantly inhibited the mRNA expression of Ldlr and Acsl1 while FGR also significantly inhibited expression of Cebpa and Dgat2 in liver. FGR significantly decreased the epididymal fat weight of mice while FGB significantly inhibited the mRNA expression of genes Cebpa, Fas, Hsl, Il1b, and Il6 in adipose tissue. Conclusion: Saponin from both FGR and FGB had a beneficial effect on high-fat diet-induced obesity. Compared to FGB, FGR exhibited more potent antihyperglycemic and antiobesity effect. However, only FGB significantly inhibited mRNA expression of inflammatory markers such as interleukins 1beta and 6 in adipose tissue. PMID- 29983613 TI - Oxidative stability of extracts from red ginseng and puffed red ginseng in bulk oil or oil-in-water emulsion matrix. AB - Background: Explosive puffing can induce changes in the chemical, nutritional, and sensory quality of red ginseng. The antioxidant properties of ethanolic extracts of red ginseng and puffed red ginseng were determined in bulk oil and oil-in-water (O/W) emulsions. Methods: Bulk oils were heated at 60 degrees C and 100 degrees C and O/W emulsions were treated under riboflavin photosensitization. In vitro antioxidant assays, including 2,2-diphenyl-1-picrylhudrazyl, 2,2' azinobis-3-ethyl-benzothiazoline-6-sulfonic acid, ferric reducing antioxidant power, total phenolic content, and total flavonoid content, were also performed. Results: The total ginsenoside contents of ethanolic extract from red ginseng and puffed red ginseng were 42.33 mg/g and 49.22 mg/g, respectively. All results from above in vitro antioxidant assays revealed that extracts of puffed red ginseng had significantly higher antioxidant capacities than those of red ginseng (p < 0.05). Generally, extracts of puffed red and red ginseng had high antioxidant properties in riboflavin photosensitized O/W emulsions. However, in bulk oil systems, extracts of puffed red and red ginseng inhibited or accelerated rates of lipid oxidation, depending on treatment temperature and the type of assay used. Conclusion: Although ethanolic extracts of puffed red ginseng showed stronger antioxidant capacities than those of red ginseng when in vitro assays were used, more pro-oxidant properties were observed in bulk oils and O/W emulsions. PMID- 29983614 TI - Applications of Panax ginseng leaves-mediated gold nanoparticles in cosmetics relation to antioxidant, moisture retention, and whitening effect on B16BL6 cells. AB - Background: Bioactive compounds in plant extracts are able to reduce metal ions to nanoparticles through the process of green synthesis. Panax ginseng is an oriental medicinal herb and an adaptogen which has been historically used to cure various diseases. In addition, the P. ginseng leaves-mediated gold nanoparticles are the value-added novel materials. Its potential as a cosmetic ingredient is still unexplored. The aim of this study was to evaluate the antioxidant, moisture retention and whitening properties of gold nanoparticles (PgAuNPs) in cosmetic applications. Methods: Cell-free experiments were performed to evaluate PgAuNP's antioxidant and moisture retention properties and inhibition activity on mushroom tyrosinase. Furthermore, in vitro cell cytotoxicity was evaluated using normal human dermal fibroblast and murine B16BL6 melanoma cells (B16) after treatment with increasing concentrations of PgAuNPs for 24 h, 48 h, and 72 h. Finally, in vitro cell assays on B16 cells were performed to evaluate the whitening effect of PgAuNPs through reduction of cellular melanin content and tyrosinase activity. Results: In vitro DPPH radical scavenging assay results revealed that PgAuNPs exhibited antioxidant activity in a dose-dependent manner. PgAuNPs exhibited moisture retention capacity and effectively inhibited mushroom tyrosinase. In addition, 3-(4,5-dimethyl-thiazol-2yl)-2,5-diphenyl tetrazolium bromide results revealed that PgAuNPs were not toxic to human dermal fibroblast and B16 cells; in addition, they significantly reduced melanin content, tyrosinase activity, and mRNA expression of melanogenesis-associated transcription factor and tyrosinase in B16 cells. Conclusion: Our study is the first report to provide evidence supporting that P. ginseng leaves-capped gold nanoparticles could be used as multifunctional ingredients in cosmetics. PMID- 29983615 TI - Investigating chemical features of Panax notoginseng based on integrating HPLC fingerprinting and determination of multiconstituents by single reference standard. AB - Background: Panax notoginseng is a highly valued medicine and functional food, whose quality is considered to be influenced by the size, botanical parts, and growth environments. Methods: In this study, a HPLC method integrating fingerprinting and determination of multiconstituents by single reference standard was established and adopted to investigate the chemical profiles and active constituent contents of 215 notoginseng samples with different sizes, from different botanical parts and geographical regions. Results: Chemical differences among main root, branch root, and rotten root were not distinct, while rhizome and fibrous root could be discriminated from other parts. The notoginseng samples from Wenshan Autonomous Prefecture and cities nearby were similar, whereas samples from cities far away were not. The contents of major active constituents in main root did not correlate with the market price. Conclusion: This study provided comprehensive chemical evidence for the rational usage of different parts, sizes, and growth regions of notoginseng in practice. PMID- 29983616 TI - A proteomic approach reveals the differential protein expression in Drosophila melanogaster treated with red ginseng extract (Panax ginseng). AB - Background: Red ginseng is a popularly used traditional medicine with antiaging effects in Asian countries. The present study aimed to explore the changes in protein expression underlying the mechanisms of life span extension and antiaging caused by red ginseng extract (RGE) in Drosophila melanogaster. Methods: A proteomic approach of two-dimensional polyacrylamide gel electrophoresis (2-DE) was used to identify the differential abundance of possible target proteins of RGE in D. melanogaster. The reliability of the 2-DE results was confirmed via Western blotting to measure the expression levels of selected proteins. Proteins altered at the expression level after RGE treatment (1 mg/mL) were identified by matrix-assisted laser desorption/ionization-time of flight tandem mass spectrometry and by searching against the National Center for Biotechnology nonredundant and Uniprot protein databases. The differentially expressed proteins were analyzed using bioinformatics methods. Results: The average survival life span of D. melanogaster was significantly extended by 12.60% with RGE treatment (1 mg/mL) compared to untreated flies. This followed increased superoxide dismutase level and decreased methane dicarboxylic aldehyde content. Based on the searching strategy, 23 differentially expressed proteins were identified (16 up regulated and 7 down-regulated) in the RGE-treated D. melanogaster. Transduction pathways were identified using the Kyoto Encyclopedia of Genes and Genomes database, and included the hippo and oxidative phosphorylation pathways that play important roles in life span extension and antiaging process of D. melanogaster. Conclusion: Treatment with RGE in D. melanogaster demonstrated that mechanisms of life span extension and antiaging are regulated by multiple factors and complicated signal pathways. PMID- 29983617 TI - Alleviation of diabetic complications by ginsenoside Rg3-enriched red ginseng extract in western diet-fed LDL-/- mice. AB - In this study, we precisely showed how the Rg3-enriched red ginseng extract (Rg3 RGE) lowers glucose, triglyceride, and low-density lipoprotein (LDL) levels in LDL-/- mice. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase), alanine aminotransferase /serum glutamate-pyruvate transaminase, and steatohepatitis were found to be reduced, and atheroma formation was inhibited by Rg3-enriched red ginseng extract. PMID- 29983618 TI - Micro-/nano-sized delivery systems of ginsenosides for improved systemic bioavailability. AB - Ginsenosides, dammarane-type triterpene saponins obtained from ginseng, have been used as a natural medicine for many years in the Orient due to their various pharmacological activities. However, the therapeutic potential of ginsenosides has been largely limited by the low bioavailability of the natural products caused mainly by low aqueous solubility, poor biomembrane permeability, instability in the gastrointestinal tract, and extensive metabolism in the body. To enhance the bioavailability of ginsenosides, diverse micro-/nano-sized delivery systems such as emulsions, polymeric particles, and vesicular systems have been investigated. The delivery systems improved the bioavailability of ginsenosides by enhancing solubility, permeability, and stability of the natural products. This mini-review aims to provide comprehensive information on the micro /nano-sized delivery systems for increasing the bioavailability of ginsenosides, which may be helpful for designing better delivery systems to maximize the versatile therapeutic potential of ginsenosides. PMID- 29983619 TI - Multitarget effects of Korean Red Ginseng in animal model of Parkinson's disease: antiapoptosis, antioxidant, antiinflammation, and maintenance of blood-brain barrier integrity. AB - Background: Ginsenosides are the main ingredients of Korean Red Ginseng. They have extensively been studied for their beneficial value in neurodegenerative diseases such as Parkinson's disease (PD). However, the multitarget effects of Korean Red Ginseng extract (KRGE) with various components are unclear. Methods: We investigated the multitarget activities of KRGE on neurological dysfunction and neurotoxicity in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model of PD. KRGE (37.5 mg/kg/day, 75 mg/kg/day, or 150 mg/kg/day, per os (p.o.)) was given daily before or after MPTP intoxication. Results: Pretreatment with 150 mg/kg/day KRGE produced the greatest positive effect on motor dysfunction as assessed using rotarod, pole, and nesting tests, and on the survival rate. KRGE displayed a wide therapeutic time window. These effects were related to reductions in the loss of tyrosine hydroxylase-immunoreactive dopaminergic neurons, apoptosis, microglial activation, and activation of inflammatory factors in the substantia nigra pars compacta and/or striatum after MPTP intoxication. In addition, pretreatment with KRGE activated the nuclear factor erythroid 2-related factor 2 pathways and inhibited phosphorylation of the mitogen-activated protein kinases and nuclear factor-kappa B signaling pathways, as well as blocked the alteration of blood-brain barrier integrity. Conclusion: These results suggest that KRGE may effectively reduce MPTP-induced neurotoxicity with a wide therapeutic time window through multitarget effects including antiapoptosis, antiinflammation, antioxidant, and maintenance of blood-brain barrier integrity. KRGE has potential as a multitarget drug or functional food for safe preventive and therapeutic strategies for PD. PMID- 29983620 TI - Antimelanogenesis and skin-protective activities of Panax ginseng calyx ethanol extract. AB - Background: The antioxidant effects of Panax ginseng have been reported in several articles; however, little is known about the antimelanogenesis effect, skin-protective effect, and cellular mechanism of Panax ginseng, especially of P. ginseng calyx. To understand how an ethanol extract of P. ginseng berry calyx (Pg C-EE) exerts skin-protective effects, we studied its activities in activated melanocytes and reactive oxygen species (ROS)-induced keratinocytes. Methods: To confirm the antimelanogenesis effect of Pg-C-EE, we analyzed melanin synthesis and secretion and messenger RNA and protein expression levels of related genes. Ultraviolet B (UVB) and hydrogen peroxide (H2O2) were used to induce cell damage by ROS generation. To examine whether this damage is inhibited by Pg-C-EE, we performed cell viability assays and gene expression and transcriptional activation analyses. Results: Pg-C-EE inhibited melanin synthesis and secretion by blocking activator protein 1 regulatory enzymes such as p38, extracellular signal-regulated kinases (ERKs), and cyclic adenosine monophosphate response element-binding protein. Pg-C-EE also suppressed ROS generation induced by H2O2 and UVB. Treatment with Pg-C-EE decreased the expression of matrix metalloproteinases, mitogen-activated protein kinases, and hyaluronidases and increased the cell survival rate. Conclusion: These results suggest that Pg-C-EE may have antimelanogenesis properties and skin-protective properties through regulation of activator protein 1 and cyclic adenosine monophosphate response element-binding protein signaling. Pg-C-EE may be used as a skin-improving agent, with moisture retention and whitening effects. PMID- 29983621 TI - Structural equation modeling to identify the risk factors of diabetes in the adult population of North India. AB - Background: A non-communicable disease risk factor survey (based on World Health Organization STEP approach to Surveillance, i.e., WHO-STEPS) was done in the state of Punjab, India in a multistage stratified sample of 5127 individuals. The study subjects were administered the WHO STEPS questionnaire and also underwent anthropometric and biochemical measurements. This study aimed at exploring the risk factors of diabetes using a Structural Equation Modeling (SEM) approach in the North Indian state of Punjab. Results: Overall prevalence of diabetes mellitus among the study participants was found out to be 8.3% (95% CI 7.3-9.4%). The final SEM had excellent fit considering the model parameters. The following risk factors deemed to have a direct statistically significant effect on blood sugar status: family history of diabetes (4.5), urban residence (3.1), triglycerides (0.46), increasing waist circumference (0.18), systolic blood pressure (0.11), and increasing age (0.05). There are specific indirect effects of alcohol use (1.43, p = 0.001), family h/o diabetes (0.844, p = 0.001), age (0.156, p < 0.001), waist circumference (0.028, p = < 0.001) and weekly fruit intake (- 0.009, p = 0.034) on fasting blood glucose. Indirect effects of waist circumference, alcohol intake and age on blood sugar levels are mediated by raised blood pressure. Waist circumference mediates the indirect effects of age, family h/o of diabetes, alcohol intake and weekly fruit intake on blood sugar levels. Triglycerides also mediated the indirect effects between age and diabetes. Conclusions: Family history of diabetes, urban residence, alcohol use, increasing age, and waist circumference are the key variables affecting diabetes status in the Indian population. The results of this study further strengthens the evidence that lifestyle changes in the form of physical activity and healthy diet are required to prevent and control diabetes. Those with family h/o diabetes constitute a high risk group and should be targeted with regular screening and lifestyle intervention package. PMID- 29983622 TI - EFFECTS OF HIGH-DOSE VITAMIN C AND HYALURONIC ACID ON TENDON HEALING. AB - Objective: To assess the histopathologic and biomechanical effects of hyaluronic acid (HA) and high-dose vitamin C (VC) on rat Achilles tendon healing. Methods: Forty-eight Sprague-Dawley rats were randomized to HA and VC and control groups with equal numbers. Each group was further divided into two subgroups to be sacrificed on Day 15 (n=8) and Day 30 (n=8). The Achilles tendons were cut and repaired. While the control rats remained untreated, HA and VC were administered after repair. The repaired tendons were removed for biomechanical and histopathologic analyses. In the biomechanical tests, the tendons were stretched to failure and maximum forces were measured. For histopathologic examination, the specimens were interpreted semiquantitatively using Movin's grading scale and Bonar scores. Results: The highest mean forces were obtained in the HA group on Day 15 and in the VC group on Day 30, with a significant difference between HA and VC on Day 15 between control and VC on Day 30 (p<0.05). Histological examination showed both Movin and Bonar scores decreased in all groups on Day 30, with significant improvements in the HA and VC groups (p<0.05). Conclusion: Our results demonstrated that both VC and HA had therapeutic effects on tendon healing, especially in the late phase. Level of Evidence I; High quality randomized trial with statistically significant difference. PMID- 29983623 TI - CLINICAL MUSCULAR EVALUATION IN PATELLOFEMORAL PAIN SYNDROME. AB - Objective: To define a profile of the muscle groups affected by patellofemoral pain syndrome (PFPS) to determine a pattern of functional weaknesses around the knee. Methods: Sixty-three female patients were randomly selected, and 17 included in this study, receiving a clinical evaluation with pre-established protocol which evaluated the quadriceps, abductors, range of motion in the internal rotators and ankle dorsiflexors, pelvic tilt, and dynamic valgus. Results: Losses were seen in abductor strength and ankle dorsiflexor range of motion in comparison with the contralateral limb (0.031 and 0.040, respectively). There was a loss of quadriceps strength and decreased amplitude of internal hip rotation when compared to the Kujala score (0.032 and 0.002, respectively). Dynamic valgus and pelvic fall were greater in comparison with the Kujala score (0.668 and 0.567, respectively). Conclusion: Clinical evaluation showed deficits in the quadriceps and abductor muscle groups, as well as decreased range of motion in the internal hip rotators and ankle dorsiflexors and increased dynamic valgus and pelvic drop. Level of Evidence IV; Case series. PMID- 29983624 TI - TECHNICAL VARIATION IN AFFIXING HAMSTRING GRAFTS TO THE TIBIA IN ACL RECONSTRUCTION. AB - Purpose: To present a technical variation in tibial fixation of quadruple hamstring grafts during anatomic reconstruction of the anterior cruciate ligament (ACL). The secondary purpose was to decrease the costs associated with this procedure. Methods: Twenty patients who underwent ACL reconstruction were selected. A tibial tunnel was constructed using standard techniques, and a femoral tunnel was anatomically created using the outside-in technique. The hamstring autograft was passed (with its bend) into the tibial tunnel and affixed to the tibia using the suspensory technique and a simple staple. Femoral fixation was performed using a titanium interference screw. The patients underwent postoperative evaluations at 0, 3, 6 and 12 months using the subjective International Knee Documentation Committee (IKDC) form and Lysholm knee scores. Results: The IKDC and Lysholm score results improved over time (p<0.001) without major complications. The cost of the procedure could be reduced by using lower cost hardware (staples). Conclusion: The proposed technique for anatomic ACL reconstruction using inverted hamstring grafts with their bend in the tibial tunnel, suspension-type fixation using a staple demonstrated good to excellent results after 1 year of follow up, with lower aggregate costs. Level of Evidence IV; Case series. PMID- 29983625 TI - PATIENT-DERIVED XENOGRAFTS AS A PRECLINICAL MODEL FOR BONE SARCOMAS. AB - Objective: The purpose of this study was to reproduce a mouse model of bone sarcomas for use in cancer research. Methods: A fresh sample of the tumor tissue was implanted subcutaneously into nude mice. When the patient-derived xenograft (PDX) reached a volume of 1500 mm3, it was harvested for re-implantation into additional mice. Histology was used to compare the morphological characteristics of different generations of sarcoma xenografts with the primary tumor. Results: Sixteen sarcoma tissue samples were engrafted into nude mice. Nine patients were diagnosed with osteosarcoma, two with chondrosarcoma, two with malignant peripheral nerve sheath tumor, one with synovial sarcoma, one with pleomorphic sarcoma, and one with Ewing's sarcoma. PDX tumors were generated in 11 of the 16 implanted specimens (69% success rate in P1). Six P1 tumors grew sufficiently for transfer into additional mice, producing the P2 generation, and three P2 tumors established the P3 generation. Conclusion: PDX tumors generated from bone sarcomas were successfully established in immunodeficient mice and reproduced the characteristics of the primary tumor with a high degree of fidelity. The preclinical PDX model described herein may represent an important tool for translational oncology research and for evaluating therapeutic strategies for bone sarcomas. Level of Evidence I; Experimental study. PMID- 29983626 TI - PRIMARY BONE LYMPHOMAS: RETROSPECTIVE ANALYSIS OF 42 CONSECUTIVE CASES. AB - Objective: It is difficult to define parameters for management and factors associated with primary bone lymphoma (PBL). This article presents the experience in a single institution with 42 patients with PBL over a 16-year period (2000 2016). Methods: Fifty-five patients were retrospectively evaluated, and forty-two were included (76.3%). Results: Median age at diagnosis was 51.5 years, and median follow-up was 102.7 months. One patient had HIV. Pain in the affected site was the most prevalent symptom. The average time between symptom onset and diagnosis was 5.4 months. The vertebrae were most affected (n=16, 33.3%). According to the International Prognostic Index Score (IPI), 64.3% of the patients were classified as having low-grade lymphoma and 25.7% as low intermediate. The most common histology was diffuse large B cell lymphoma (DLBCL) (85.7%). Immunophenotyping was CD20 positive in 93.5% of patients, and 11 patients had pathological fracture. All patients received chemotherapy and 30% of the regimens included rituximab. Thirty-eight percent of patients received radiation therapy. Overall survival was 50%, and survival median time was 80 months. Age and chemotherapy regimen influenced patient survival. Younger patients and patients who received RCHOP had better prognoses. Conclusions: The choice of chemotherapy regimen associated with age influenced survival for patients with PBL. Level of Evidence IV; Case series. PMID- 29983627 TI - INCIDENCE OF PEDESTRIAN TRAFFIC INJURY IN SAO PAULO, BRAZIL, IN 2016. AB - Objective: Globally, more than 1.2 million people die from traffic accidents each year. In order to reduce the rate of traffic accidents and their subsequent social consequences in Sao Paulo, Brazil, the aim of this study was to characterize pedestrian victims of traffic accidents and occurrences. Methods: This is a cross-sectional, quantitative, descriptive and retrospective epidemiological study of 2723 pedestrians injured in traffic accidents during 2016 in Sao Paulo. Results: Of the total sample, 37.3% participants were female and 62.7% male; incidence was highest in the 10-19 year old age group (19.9%) and lower limb injuries were most frequent (28.6%). Of the cases attended in urgent health care units, 75.6% progressed to hospital discharge. Accidents were more frequent in the afternoon (44.6%), and most commonly involved cars (47.2%). Conclusions: This study showed the importance of making detailed records of traffic accidents to guide the government in intensive education efforts to develop a healthy society and respect for traffic regulations, to promote urban improvements involving signage and pavement, and to maintain pre-hospital and hospital care teams in strategic locations to minimize the time elapsed between the accident and care provided to the victim. Level of Evidence II; Retrospective study. PMID- 29983628 TI - PROFILE OF PATIENTS WITH OSTEOPOROTIC FRACTURES AT A TERTIARY ORTHOPEDIC TRAUMA CENTER. AB - Objective: To evaluate the profile of patients with osteoporotic fractures treated at a tertiary orthopedic hospital. Methods: Using questionnaires, 70 patients with osteoporotic fractures (OF) were compared with 50 outpatients with multiple osteoarthritis (OA) followed through an outpatient clinic. Results: The OF group was older (p <0.001), less heavy (p=0.003), had lower BMI (p=0.006), was more likely to be white (p=0.011), was less likely to be married (p=0.008), and had previous falls, previous fractures, old fractures (>1 year), falls in the last 12 months, fractures due to falls, and needed more assistance (p<0.05). They also had lower Lawton & Brody Instrumental Activities of Daily Living scores (p <0.05) and reported less lower limb disability, foot pathology, muscle weakness, hypothyroidism, and vitamin D intake than patients in the OA group. White race, previous falls, and previous fractures increase the risk of osteoporotic fractures by 10.5, 11.4, and 4.1 times, respectively. The chance of fracture dropped 29% for each one-unit increase in Lawton & Brody IADL score. Married participants had fewer fractures than participants with other marital status. Conclusion: Together, race, marital status, previous falls, foot pathologies, previous fractures, and IADL scores define the profile of patients with osteoporotic fractures. Level of Evidence III; Case control study. PMID- 29983629 TI - TRAUMATIC INJURIES OF THE CERVICAL SPINE: CURRENT EPIDEMIOLOGICAL PANORAMA. AB - Objective: To collect data from patients with cervical fracture who were treated surgically in a tertiary health service, in order to better understand the current scenario of this kind of injury in our population. Methods: This retrospective survey examined consecutive cases of patients with cervical spine trauma who received surgical treatment during 2013 and 2014. The data were subjected to descriptive statistical analysis. Results: Fifty-two patients were treated with surgery during 2013 and 2014. All patients classified as Frankel A and B developed respiratory failure. Patients classified as Frankel A, B, and C had significantly higher rates for postoperative complications (p < 0.01) than patients classified as Frankel D and E, except for the rate of postoperative infections (p = 0.717). Hospitalization time was also longer in the first group (p < 0.01). Conclusion: Patients with cervical trauma who present with neurological deficit at hospital admission should receive special attention, since the rate of postoperative complications is higher and hospital stays are lengthier in this group. In addition, patients with Frankel A and B classification should be monitored in an intensive care unit. Level of Evidence III; Retrospective comparative study. PMID- 29983630 TI - ROLE OF ARTERIOVENOUS VASCULAR LOOPS IN MICROSURGICAL RECONSTRUCTION OF THE EXTREMITIES. AB - Objective: To analyze 10 consecutive cases of microsurgical arteriovenous loops created to reconstruct complex injuries from March 2011 to May 2012. Methods: This observational cohort-type study conducted by the Hand and Microsurgery Group at the HC-FMUSP included patients who were candidates for microsurgical reconstruction as a last alternative to amputation of the limb with proven absence of adequate recipient vessels for primary microsurgical anastomosis, in a prospective and consecutive manner. We analyzed 14 variables (epidemiological, clinical, procedure-related, and outcome) in patients who underwent reconstruction using an arteriovenous loop utilizing a single-stage or two-stage procedure. Results: The injuries were mostly traumatic (80%). The success rate of the single-stage procedure was 75%, and 17% for the two-stage procedure. The rate of preservation for the injured limb was 44%. Conclusion: This study reinforces the more recent understanding that the indication for single-stage or two-stage reconstruction should be individualized; our findings favor the single-stage reconstruction. This technique should be used in selected cases, as a last reconstructive alternative before amputation, and further studies are necessary to confirm its safety and efficacy in our practice. Level of Evidence IV; Case series. PMID- 29983631 TI - USE OF MAGNETIC RESONANCE IMAGING TO DIAGNOSE BRACHIAL PLEXUS INJURIES. AB - Objective: To compare magnetic resonance imaging and intraoperative findings in patients diagnosed with traumatic injury to the brachial plexus. Methods: Patients with a diagnosis of traumatic injury to the brachial plexus admitted to the hand and microsurgery outpatient consult of the Hospital das Clinicas at the University of Sao Paulo were selected during December 2016. A total of three adult patients with up to six months of injury who underwent surgical treatment were included in the study. A diffusion-weighted sequence magnetic resonance protocol and fluid-sensitive volumetric reformatting sequence were applied. The magnetic resonance results were compared with the diagnoses obtained from the injuries observed during the surgery. The study was double-blind (surgeon and radiologist). Results: A descriptive correlation was found between the magnetic resonance imaging results and the diagnostic findings from the surgeries, for both pre- and post-ganglionic injuries. Conclusion: Magnetic resonance imaging has shown to be a promising diagnostic method in preoperative assessment of brachial plexus lesions; it is less invasive than other common methods, showing not only avulsion lesions but also localized postganglionic lesions in the supra- and infraclavicular region. Level of Evidence III; Diagnostic studies - Investigating a diagnostic test. PMID- 29983632 TI - WEIGHT-BEARING COMPUTED TOMOGRAPHY OF THE FOOT AND ANKLE: AN UPDATE AND FUTURE DIRECTIONS. AB - Spatial understanding of osteoarticular deformities of the foot and ankle is vital to correct diagnosis and therapeutic decision making. Poor reproducibility in conventional standing radiography in three orthogonal views has driven the development of weight-bearing computed tomography (WBCT) technology over the last decade. We analyzed the available literature on WBCT imaging in patients with foot and ankle disorders by performing a literature review of relevant clinical studies in multiple databases including PubMed, MedLine, and Scopus from January 1999 to October 2017. WBCT imaging allows correct evaluation of foot and ankle anatomy with the patient in a standing position, providing images with high spatial resolution, short image acquisition time, low dose of radiation, and costs which are similar to other available imaging technologies. This diagnostic tool can be used for decision making in the treatment of deformities of the ankle, hindfoot, midfoot, and forefoot. Level of Evidence III; Systematic review of level III studies. PMID- 29983633 TI - CONTRALATERAL PATELLAR TENDON AUTOGRAFT IN ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION. AB - Objective: To conduct a systematic review of literature about the use of contralateral patellar tendon autograft in anterior cruciate ligament reconstructions and present the results. Methods: The LILACS, MEDLINE, Cochrane, PubMed, Scielo and Google Scholar databases were searched without date restrictions for the keywords "anterior cruciate ligament reconstruction" combined with "contralateral" in the article title. After the studies were identified, two independent evaluators collected the qualitative characteristics of the studies and classified them according to clinical outcomes of these grafts as positive, neutral, or negative. Results: A total of 755 articles were found initially, and after detailed evaluation of all references, followed by a screening process and assessment of quality, a total of 11 studies were determined to be eligible for inclusion in this systematic review. Of these, 72.72% were level II studies, the most common level of evidence among the results. Positive results for this type of graft were found in 63.63% of the studies. Conclusion: Based on the literature review, most of the included articles (63.63%) presented positive results for the use of contralateral patellar tendon grafts. Level of Evidence III; Systematic review. PMID- 29983635 TI - A questionnaire using vocal symptoms in quality control of phonosurgery: vocal surgical questionnaire. AB - Background: Quality control after phonosurgery is important and may be time consuming. Often questionnaires focusing on quality of life are applied. We aimed at investigating the use of organ specific symptoms, such as hoarseness and voice failure with the use of self-reported visual analogue scales (VAS) and Likert scales. Methods: A vocal surgical questionnaire using VAS and Likert-scales for hoarseness, voice failure and factors that could influence voice quality was given twice consecutively to a group of healthy volunteers (n = 57, 45 female) and a group of voice patients (n = 34, 21 females) for a test/re-test study. Secondly, a group of patients undergoing surgery (n = 90, 61females) answered the questionnaire preoperatively and postoperatively. The difference between test/retest, healthy volunteers and patients, and between pre- and postoperative results were compared. Results: There was no significant difference in the test/retest results in healthy volunteers nor in the patient group. There was statistically significant difference between the healthy volunteers and patients, and between the preoperative and postoperative results after phonosurgery. Conclusion: This short and organ specific questionnaire clearly demonstrates the effect of phonosurgery, making it an easy and relevant tool in quality control and potentially reducing the need of postoperative controls in the outpatient clinic. PMID- 29983634 TI - Reduction of Glucocorticoid Receptor Function in Chronic Fatigue Syndrome. AB - Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n = 48), primary Sjogren's syndrome (a disease group control) (n = 27), and sedentary healthy controls (HCs) (n = 20), and to investigate its relationship with clinical measures. In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFalpha, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined. CFS patients had reduced LPS-induced IL-6 and TNFalpha production compared to both control groups and reduced suppression of TNFalpha by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score. The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression. PMID- 29983636 TI - The burden of chronic rhinosinusitis and its effect on quality of life among patients re-attending an otolaryngology clinic in south western Uganda. AB - Background: Worldwide, the burden of chronic rhinosinusitis (CRS) is variable, but not known in Uganda. CRS has significant negative impact on quality of life (QOL) and as such QOL scores should guide adjustments in treatment strategies. However, most of these studies have been done in the west. Our hypothesis was that QOL scores of the majority of CRS patients in low- to- middle income countries are poorer than those among patients without CRS. The aim of this study was to determine the burden of CRS among patients re-attending the Otolaryngology clinic and whether CRS is related to poor QOL. Methods: A cross sectional study was conducted at Mbarara Regional Referral Hospital Otolaryngology clinic. One hundred and twenty-six adult re-attendees were consecutively recruited. Data was collected using a structured questionnaire and the Sinonasal Outcome Test 22 (SNOT 22) questionnaire measured QOL. Results: The proportion of re-attendees with CRS was 39.0% (95% CI 30-48%). Majority of CRS patients had poor quality of life scores compared to non-CRS (88% versus 20% p < 01). The poor quality of life scores on the SNOT 22 were almost solely as a result of the functional, physical and psychological aspects unique to CRS. Conclusions: CRS is highly prevalent among re-attendees of an Otolaryngology clinic at a hospital in resource limited settings and has a significant negative impact on the QOL of these patients. PMID- 29983637 TI - Student evaluation of the impact of changes in teaching style on their learning: a mixed method longitudinal study. AB - Background: Maternal and Child Health Aides are the largest nursing cadre in Sierra Leone providing maternal and child health care at primary level. Poor healthcare infrastructure and persistent shortage of suitably qualified health care workers have contributed to high maternal and newborn morbidity and mortality. In 2012, 50% of the MCHAides cohort failed their final examination and the Government of Sierra Leone expressed concerns about the quality of teaching within the programmes. Lack of teaching resources and poor standards of teaching led to high failure rates in final examinations reducing the number of newly qualified nurses available for deployment. Methods: A mixed-methods approach using semi-structured observations of teaching sessions and completion of a questionnaire by students was used. Fourteen MCHAide Training Schools across all districts of Sierra Leone, 140 MCHAide tutors and 513 students were included in the study. In each school, teaching was observed by two researchers at baseline, 3 and 6 months after the tutor training programme. Students completed a questionnaire on the quality of teaching and learning in their school at the same time points. Results: A total of 513 students completed the questionnaire, 120 tutors took part in the training and 66 lessons across all schools were observed. There was a statistically significant (p < 0.05) improvement in mean student evaluation of teaching and learning in 12/19 areas tested at follow-up compared to baseline. Observation of 66 teaching sessions demonstrated an increase in the number of student-focused, interactive teaching methods used. Conclusion: Prior to the teaching and learning workshops there was little student-focused learning within the schools. Teaching was conducted predominantly using lectures even for practical sessions. Training tutors to move away from didactic teaching towards a more student-focused approach leads to increased student satisfaction with teaching and learning within the schools. PMID- 29983638 TI - Systematic development of CHEMO-SUPPORT, a nursing intervention to support adult patients with cancer in dealing with chemotherapy-related symptoms at home. AB - Background: Given the great symptom burden associated with chemotherapy on the one hand and generally poor self-management of symptoms by cancer patients on the other hand, our aim was to develop a nursing intervention to reduce symptom burden in adult cancer patients treated with chemotherapy and to support them in dealing with their various symptoms at home. Methods: Development of the intervention was guided by the Intervention Mapping Approach and included following steps: needs assessment, formulation of proximal programme objectives, selection of methods and strategies, production of programme components, and planning for implementation and evaluation of the intervention. A panel of multidisciplinary healthcare professionals (n = 12) and a panel of patients and family caregivers (n = 7) were actively involved developing the intervention at each stage. Results: For the intervention, four patient performance objectives relating to self-management were advanced. Self-efficacy and outcome expectations were selected as key determinants of dealing with chemotherapy-related symptoms. As methods for supporting patients, motivational interviewing and tailoring were found to fit best with the change objectives and determinants. Existing patient information materials were re-designed after panel input to reinforce the new intervention approach. Conclusion: The intervention mapping approach, including active involvement of the intervention providers and receivers, informed the design of this nursing intervention with two or more contacts. Further evaluation is needed to gain insight into the potential effects, feasibility and mechanisms of this complex intervention. PMID- 29983639 TI - The nuclear transcription factor RelB functions as an oncogene in human lung adenocarcinoma SPC-A1 cells. AB - Background: Lung cancer is a leading public health issue worldwide. Although therapeutic approaches have improved drastically in the last decades, the prognosis of lung cancer patients remains suboptimal. The canonical nuclear transcription factor kappa B (NF-kappaB) signalling pathway is critical in the carcinogenesis of lung cancer. The non-canonical NF-kappaB signalling pathway (represented by RelB) has attracted increasing attention in the pathogenesis of haematological and epithelial malignancies. However, the function of RelB in non small cell lung cancer (NSCLC) is still unclear. Recently, high expression of RelB has been detected in NSCLC tissues. We have also demonstrated that RelB expression is an independent prognostic factor in NSCLC patients. Methods: The mRNA and protein expression of RelB in NSCLC tissues were detected by qRT-PCR and IHC assay. The cell growth of SPC-A1 cells was detected in real-time using the x Celligence system and xenograft tumour assays. The proliferation capability of cells was detected using a CFSE assay. Cell apoptosis was measured using Annexin V/PI staining, cell cycle was analyzed by the cytometry. Cell migration abilities were detected using the x-Celligence system and wound healing assays. The relative amounts of the active and inactive gelatinases MMP-2 and MMP-9 were examined using gelatin zymography experiments. Apoptosis of RelB depletion SPC-A1 cells after ionizing radiation at 8 Gy. The expression of cellular proliferation signal pathway related-proteins were examined by Western blot analysis. Results: The expression of RelB increases in NSCLC tissues. High RelB expression was significantly correlated with advanced-metastatic stage in patients with NSCLC. RelB-silencing inhibits cell growth in vitro and in vivo. We found that RelB affected cell proliferation by regulating AKT phosphorylation. RelB silencing attenuates the migration and invasion abilities of SPC-A1 cells and is likely related to the down regulation of MMP-9 activity and Integrin beta-1 expression. In addition, RelB modulated radiation-induced survival of NSCLC cells predominantly by regulating Bcl-xL expression. Conclusions: Given the involvement of RelB in cell proliferation, migration, invasion, and radio-resistance, RelB functions as an oncogene in NSCLC cells. Our data here shed light on unexplored aspects of RelB in NSCLC. PMID- 29983640 TI - miR-133a function in the pathogenesis of dedifferentiated liposarcoma. AB - Background: Sarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS. Methods: Real-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice. Results: miR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration. Conclusions: Based on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS. PMID- 29983642 TI - Correction to: Proteomic identification and characterization of hepatic glyoxalase 1 dysregulation in non-alcoholic fatty liver disease. AB - [This corrects the article DOI: 10.1186/s12953-018-0131-y.]. PMID- 29983641 TI - In-depth proteomic analyses of Haliotis laevigata (greenlip abalone) nacre and prismatic organic shell matrix. AB - Background: The shells of various Haliotis species have served as models of invertebrate biomineralization and physical shell properties for more than 20 years. A focus of this research has been the nacreous inner layer of the shell with its conspicuous arrangement of aragonite platelets, resembling in cross section a brick-and-mortar wall. In comparison, the outer, less stable, calcitic prismatic layer has received much less attention. One of the first molluscan shell proteins to be characterized at the molecular level was Lustrin A, a component of the nacreous organic matrix of Haliotis rufescens. This was soon followed by the C-type lectin perlucin and the growth factor-binding perlustrin, both isolated from H. laevigata nacre, and the crystal growth-modulating AP7 and AP24, isolated from H. rufescens nacre. Mass spectrometry-based proteomics was subsequently applied to to Haliotis biomineralization research with the analysis of the H. asinina shell matrix and yielded 14 different shell-associated proteins. That study was the most comprehensive for a Haliotis species to date. Methods: The shell proteomes of nacre and prismatic layer of the marine gastropod Haliotis laevigata were analyzed combining mass spectrometry-based proteomics and next generation sequencing. Results: We identified 297 proteins from the nacreous shell layer and 350 proteins from the prismatic shell layer from the green lip abalone H. laevigata. Considering the overlap between the two sets we identified a total of 448 proteins. Fifty-one nacre proteins and 43 prismatic layer proteins were defined as major proteins based on their abundance at more than 0.2% of the total. The remaining proteins occurred at low abundance and may not play any significant role in shell fabrication. The overlap of major proteins between the two shell layers was 17, amounting to a total of 77 major proteins. Conclusions: The H. laevigata shell proteome shares moderate sequence similarity at the protein level with other gastropod, bivalve and more distantly related invertebrate biomineralising proteomes. Features conserved in H. laevigata and other molluscan shell proteomes include short repetitive sequences of low complexity predicted to lack intrinsic three-dimensional structure, and domains such as tyrosinase, chitin-binding, and carbonic anhydrase. This catalogue of H. laevigata shell proteins represents the most comprehensive for a haliotid and should support future efforts to elucidate the molecular mechanisms of shell assembly. PMID- 29983643 TI - Cost-effectiveness of diagnostic tests for threatened preterm labor in singleton pregnancy in France. AB - Background: Previous studies have showed that the early diagnosis of threatened preterm labor decreases neonatal morbidity and mortality, avoids maternal morbidity induced by antepartum bed rest and unnecessary treatment, and reduces costs. Although there are many diagnostic tests, none is clearly recommended by international guidelines. The aim of our study was to compare seven diagnostic methods in terms of effectiveness and cost using a decision analysis model in singleton pregnancy presenting threatened preterm labor, between 24 and 34 weeks of gestation. Methods: Seven diagnostic strategies based on individual or combined use of the following tests: cervical length, cervical fibronectin test, cervical interleukin test and protein in maternal serum, were compared using a decision analysis model. Effectiveness was expressed in terms of serious adverse neonatal events avoided (neonatal morbidity and mortality) at the hospital discharge. The economic analysis was performed from the health care system perspective. Deterministic and probabilistic analyses were performed to test the robustness of the model. Results: At 24-34 weeks of gestation, the association of cervical length and qualitative fibronectin was the most efficient strategy dominating all alternatives, reducing the perinatal death or severe neonatal morbidity rate up to 15% and the costs up to 31% according to the gestational age. This result was confirmed by the deterministic sensitivity analyses. The probabilistic analysis showed that the association of cervical length and qualitative fibronectin dominated cervical length < 15 mm in more than 90% of the simulations. The comparison with the other tests revealed more uncertainty. Conclusions: A test using cervical length and qualitative fetal fibronectin appears to be the best diagnostic strategy. Decisions regarding its generalization and funding in France in this population of women should take into account the high, lifetime costs induced by prematurity. PMID- 29983644 TI - Primary and secondary prevention interventions for cardiovascular disease in low income and middle-income countries: a systematic review of economic evaluations. AB - Background: Cardiovascular disease (CVD) is the leading cause of deaths globally, with greatest premature mortality in the low- and middle-income countries (LMIC). Many of these countries, especially in sub-Saharan Africa, have significant budget constraints. The need for current evidence on which interventions offer good value for money to stem this CVD epidemic motivates this study. Methods: In this systematic review, we included studies reporting full economic evaluations of individual and population-based interventions (pharmacologic and non pharmacologic), for primary and secondary prevention of CVD among adults in LMIC. Several medical (PubMed, EMBASE, SCOPUS, Web of Science) and economic (EconLit, NHS EED) databases and grey literature were searched. Screening of studies and data extraction was done independently by two reviewers. Drummond's checklist and the National Institute for Health and Care Excellence quality rating scale were used in the quality appraisal for all studies used to inform this evidence synthesis. Results: From a pool of 4059 records, 94 full texts were read and 50 studies, which met our inclusion criteria, were retained for our narrative synthesis. Most of the studies were from middle-income countries and predominantly of high quality. The majority were modelled evaluations, and there was significant heterogeneity in methods. Primary prevention studies dominated secondary prevention. Most of the economic evaluations were performed for pharmacological interventions focusing on blood pressure, cholesterol lowering and antiplatelet aggregants. The greatest majority were cost-effective. Compared to individual-based interventions, population-based interventions were few and mostly targeted reduction in sodium intake and tobacco control strategies. These were very cost-effective with many being cost-saving. Conclusions: This evidence synthesis provides a contemporary update on interventions that offer good value for money in LMICs. Population-based interventions especially those targeting reduction in salt intake and tobacco control are very cost-effective in LMICs with potential to generate economic gains that can be reinvested to improve health and/or other sectors. While this evidence is relevant for policy across these regions, decision makers should additionally take into account other multi sectoral perspectives, including considerations in budget impact, fairness, affordability and implementation while setting priorities for resource allocation. PMID- 29983646 TI - Improved Hydrological Simulation Using SMAP Data: Relative Impacts of Model Calibration and Data Assimilation. AB - The assimilation of remotely sensed soil moisture information into a land surface model has been shown in past studies to contribute accuracy to the simulated hydrological variables. Remotely sensed data, however, can also be used to improve the model itself through the calibration of the model's parameters, and this can also increase the accuracy of model products. Here, data provided by the Soil Moisture Active/Passive (SMAP) satellite mission are applied to the land surface component of the NASA GEOS Earth system model using both data assimilation and model calibration in order to quantify the relative degrees to which each strategy improves the estimation of near-surface soil moisture and streamflow. The two approaches show significant complementarity in their ability to extract useful information from the SMAP data record. Data assimilation reduces the ubRMSE (the RMSE after removing the long-term bias) of soil moisture estimates and improves the timing of streamflow variations, whereas model calibration reduces the model biases in both soil moisture and streamflow. While both approaches lead to an improved timing of simulated soil moisture, these contributions are largely independent; joint use of both approaches provides the highest soil moisture simulation accuracy. PMID- 29983645 TI - Cost effectiveness of mHealth intervention by community health workers for reducing maternal and newborn mortality in rural Uttar Pradesh, India. AB - Background: A variety of mobile-based health technologies (mHealth) have been developed for use by community health workers to augment their performance. One such mHealth intervention-ReMiND program, was implemented in a poor performing district of India. Despite some research on the extent of its effectiveness, there is significant dearth of evidence on cost-effectiveness of such mHealth interventions. In this paper we evaluated the incremental cost per disability adjusted life year (DALY) averted as a result of ReMiND intervention as compared to routine maternal and child health programs without ReMiND. Methods: A decision tree was parameterized on MS-Excel spreadsheet to estimate the change in DALYs and cost as a result of implementing ReMiND intervention compared with routine care, from both health system and societal perspective. A time horizon of 10 years starting from base year of 2011 was considered appropriate to cover all costs and effects comprehensively. All costs, including those during start-up and implementation phase, besides other costs on the health system or households were estimated. Consequences were measured as part of an impact assessment study which used a quasi-experimental design. Proximal outputs in terms of changes in service coverage were modelled to estimate maternal and infant illnesses and deaths averted, and DALYs averted in Uttar Pradesh state of India. Probabilistic sensitivity analysis was undertaken to account for parameter uncertainties. Results: Cumulatively, from year 2011 to 2020, implementation of ReMiND intervention in UP would result in a reduction of 312 maternal and 149,468 neonatal deaths. This implies that ReMiND program led to a reduction of 0.2% maternal and 5.3% neonatal deaths. Overall, ReMiND is a cost saving intervention from societal perspective. From health system perspective, ReMiND incurs an incremental cost of INR 12,993 (USD 205) per DALY averted and INR 371,577 (USD 5865) per death averted. Conclusions: Overall, findings of our study suggest strongly that the mHealth intervention as part of ReMiND program is cost saving from a societal perspective and should be considered for replication elsewhere in other states. PMID- 29983649 TI - Internet: Friend and Foe. PMID- 29983647 TI - Standardized Uptake Values Derived from 18F-FDG PET May Predict Lung Cancer Microvessel Density and Expression of KI 67, VEGF, and HIF-1alpha but Not Expression of Cyclin D1, PCNA, EGFR, PD L1, and p53. AB - Background: Our purpose was to provide data regarding relationships between 18F FDG PET and histopathological parameters in lung cancer. Methods: MEDLINE library was screened for associations between PET parameters and histopathological features in lung cancer up to December 2017. Only papers containing correlation coefficients between PET parameters and histopathological findings were acquired for the analysis. Overall, 40 publications were identified. Results: Associations between SUV and KI 67 were reported in 23 studies (1362 patients). The pooled correlation coefficient was 0.44. In 2 studies (180 patients), relationships between SUV and expression of cyclin D1 were analyzed (pooled correlation coefficient = 0.05). Correlation between SUV and HIF-1alpha was investigated in 3 studies (288 patients), and the pooled correlation coefficient was 0.42. In 5 studies (310 patients), associations between SUV and MVD were investigated (pooled correlation coefficient = 0.54). In 6 studies (305 patients), relationships between SUV and p53 were analyzed (pooled correlation coefficient = 0.30). In 6 studies (415 patients), associations between SUV and VEGF expression were investigated (pooled correlation coefficient = 0.44). In 5 studies (202 patients), associations between SUV and PCNA were investigated (pooled correlation coefficient = 0.32). In 3 studies (718 patients), associations between SUV and expression of PD L1 were analyzed (pooled correlation coefficient = 0.36). Finally, in 5 studies (409 patients), associations between SUV and EGFR were investigated (pooled correlation coefficient = 0.38). Conclusion: SUV may predict microvessel density and expression of VEGF, KI 67, and HIF-1alpha in lung cancer. PMID- 29983648 TI - [18F]ML-10 Imaging for Assessment of Apoptosis Response of Intracranial Tumor Early after Radiotherapy by PET/CT. AB - [18F]ML-10 is a novel apoptosis radiotracer for positron emission tomography (PET). We assess the apoptosis response of intracranial tumor early after CyberKnife (CK) treatment by [18F]ML-10 PET imaging. 29 human subjects (30 lesions), diagnosed with intracranial tumors, underwent CK treatment at 14-24 Gy in 1-3 fractions, had [18F]ML-10 positron emission tomography/computed tomography (PET/CT) before (pre-CK) and 48 hours after (post-CK) CK treatment. Magnetic resonance imaging (MRI) scans were taken before and 8 weeks after CK treatment. Voxel-based analysis was used for the imaging analysis. Heterogeneous changes of apoptosis in tumors before and after treatment were observed on voxel-based analysis of PET images. A positive correlation was observed between the change in radioactivity (X) and subsequent tumor volume (Y) (r=0.862, p < 0.05), with a regression equation of Y=1.018*X - 0.016. Malignant tumors tend to be more sensitive to CK treatment, but the treatment outcome is not affected by pre-CK apoptotic status of tumor cells; [18F]ML-10 PET imaging could be taken as an assessment 48 h after CK treatment. PMID- 29983650 TI - Bariatric Surgery Following Total Shoulder Arthroplasty Increases the Risk for Mechanical Complications Including Instability and Prosthetic Loosening. AB - Background: While extensive literature has been published on the risks and benefits of bariatric surgery (BS) prior to and following lower-extremity arthroplasty, no similar investigations have been performed on the impact of BS prior to total shoulder arthroplasty (TSA). Purpose: The objective of the present study was to compare the incidence of mechanical complications in morbidly obese patients who undergo TSA: those who undergo BS following TSA compared with those who do not undergo BS, and those who undergo BS after TSA compared with those who undergo BS prior to TSA. Methods: A Medicare database was queried for morbidly obese patients who underwent BS either before or after TSA, as well as those who underwent TSA but no BS. Of 12,277 morbidly obese patients who underwent TSA between 2005 and 2014, 304 underwent BS (165 of them prior to TSA and 139 following TSA) and 11,923 did not undergo BS. Rates of mechanical complications were then compared between groups using a logistic regression analysis. Results: Patients who underwent BS after TSA had significantly higher rates of mechanical complications (12.9%) compared to controls (8.8%) or patients who underwent prior BS (7.9%). Patients who underwent BS after TSA had higher rates of both instability (7.9%) and loosening (8.6%) than did controls (5.1 and 4.9%, respectively) or patients who underwent BS before TSA (4.8 and 4.2%, respectively). Conclusions: BS following TSA is associated with increased rates of mechanical complications, including instability and loosening, compared to BS prior to TSA. These findings suggest that it may be prudent to consider performing BS prior to TSA in morbidly obese patients, rather than waiting until after TSA is performed. PMID- 29983651 TI - Effects of Abduction Pillows on Rotator Cuff Repair: A Biomechanical Analysis. AB - Background: After rotator cuff repair, some surgeons use abduction pillows to unload or protect the repair construct, while others do not. Question/Purpose: The aim of this study was to determine which type of sling-one with a small or large abduction pillow or one without a pillow-places the repaired rotator cuff in the best position to reduce tension on the supraspinatus. Methods: An X-ray study was performed on asymptomatic subjects to determine what position the shoulder is placed in when wearing a sling with or without an abduction pillow. Positions were then reproduced in human cadaveric shoulders using a custom-made testing jig, and tension on the repaired supraspinatus was measured. Results: X rays showed that abduction of the glenohumeral joint with a sling was only 4 degrees , with a sling with a small pillow was 13 degrees , and with a sling with a large abduction pillow was 25 degrees . Placing the cadaveric shoulders in the position of a sling with a small abduction pillow caused a reduction in tension on the supraspinatus of 27% anteriorly and 55% posteriorly compared to placing the shoulder in the position of a sling without an abduction pillow; a large abduction pillow caused a further reduction in tension, of 42% anteriorly and 56% posteriorly. Conclusion: These findings show that abduction pillows reduce tension on the repaired supraspinatus tendon. PMID- 29983652 TI - Prevalence of Rotator Cuff Repairs with and Without Concomitant Subacromial Decompressions Has Not Changed. AB - Background: Recent research from the American Board of Orthopaedic Surgery database indicates a decreasing rate of subacromial decompression (SAD) performed with rotator cuff repair (RCR) by younger orthopedic surgeons. Questions/Purposes: The purpose of this study was to determine the rate of RCR with and without SAD and whether the rate of RCR with SAD decreased over time. Further, we set out to determine if there was significant variation in the rate of RCR with SAD by state. Methods: Rates of RCR with and without open or arthroscopic SAD from 2010 to 2012 were determined based upon de-identified data from a national health insurance carrier. Data were normalized per 10,000 insured patients for comparative analysis. Results: Rates of RCR with concomitant SAD were higher than RCR without SAD in each year analyzed. In patients 50 years old and older, this same significant difference was also seen for each year. The rate of RCR with or without SAD did not decrease over the 3-year time period. The rate of RCR performed concomitantly with SAD was significantly higher than RCR performed without SAD in all patient age groups combined. There was wide variation in the rate of RCR with or without concurrent SAD across states. Conclusion: Disproving our hypothesis, the overall rate of RCR with or without SAD did not decrease over the period from 2010 to 2012. There was wide variation in the rate of RCR by state; however, this variation was not seen in the incidence of SAD performed concomitant with the RCR. PMID- 29983653 TI - Characterization and Correction of Symptomatic Hip Impingement in American Football Linemen. AB - Background: Femoroacetabular impingement (FAI) morphology can lead to range-of motion deficits in football players. It is therefore important for physicians treating these players to be aware of the location and implications of FAI morphology. Purpose/Questions: We sought to characterize the radiographic deformity and dynamic impingement observed in a consecutive series of American football linemen with symptomatic, mechanical hip pain who underwent surgical treatment for FAI and to use software analysis to identify the location of impingement and terminal range of motion and the effects of simulated correction. Methods: A retrospective analysis was conducted of 17 hips in 13 football linemen who underwent arthroscopic correction for symptomatic FAI. Computed tomography (CT) scans were used to generate preoperative three-dimensional models of the hips. Femoral and acetabular measurements, maximum hip flexion, abduction, internal rotation at 90 degrees flexion (IR90), and flexion/adduction/internal rotation (FADIR) were determined, and areas of bony collision were defined. Simulated femoral correction was performed and motion analysis was repeated. Results: Mean femoral version was 13.1 degrees (range, 0 to 26 degrees ), while mean femoral neck-shaft angle was 132.1 degrees (range, 123 to 145 degrees ). Mean maximum alpha angle on the radial reformatted CT was 69.2 degrees (range, 48 to 95 degrees ) and was located at the 12:45 clock-face position (range, 11:30 to 2:15). Mean acetabular version values at 1:30 and 3:00 were 1.1 degrees (range, - 11 to 11 degrees ) and 12.7 degrees (range, 2 to 20 degrees ), respectively. Fifty-three percent of hips showed a "crossover" sign. Mean lateral center-edge angle was 31.7 degrees (range, 25 to 44 degrees ). CT-derived motion analysis demonstrated a mean preoperative flexion of 108.2 degrees (range, 73 to 127 degrees ), IR90 of 20.5 degrees (range, 0 to 52 degrees ), and FADIR of 12.3 degrees (range, 0 to 39 degrees ). Simulated correction resulted in significant improvements in flexion (6.6 degrees ), IR90 (11.3 degrees ), and FADIR (10.6 degrees ). Conclusions: While cephalad retroversion was observed in approximately half of the hips, a significant cam deformity was seen maximally at 12:45, a more posterior cam location than that of the general population. Managing this pathology required obtaining preoperative and intraoperative images to characterize lesions and allow for their complete correction. With complete correction of the deformity, simulated range of motion demonstrated significant improvement in flexion, IR90, and FADIR maneuvers. PMID- 29983654 TI - The Incidence of Complications Is Low Following Foot and Ankle Surgery for Which Peripheral Nerve Blocks Are Used for Postoperative Pain Management. AB - Background: The incidence of neurologic complications from foot and ankle surgery utilizing regional anesthesia is not well established. Questions/Purposes: The purpose of this study was to prospectively determine the incidence of neurologic and peripheral nerve block (PNB) site complications on a busy foot and ankle service that utilizes ankle blocks (ABs) and popliteal blocks (POPs). Patients and Methods: This prospective observational study included patients undergoing foot and ankle surgery with ABs or POPs. Block choice was determined by surgeon's preference. Patients were assessed for complications during postoperative visits at 2, 6, and 12 weeks. The relation of each complication to the block was scored by a surgeon and anesthesiologist. Results: From October 2012 to October 2014, 2516 patients underwent 2704 surgeries. There were 195 complications (7.2%) considered neurologic or at the PNB site. The incidence of serious complications was 0.7%. A higher complication rate was reported for POPs (8.8%) than for ABs (2.5%). However, when analysis was limited to forefoot surgery, this difference was not significant. Dexamethasone use was associated with increased complications for POPs. Only 5 of the 195 total complications, and 2 of 20 serious complications, were deemed to have been likely caused by the block by both the surgeon and anesthesiologist reviewer. Conclusions: The incidences of neurologic or block-related complications and serious complications were 7.2 and 0.7%, respectively, most without a clear surgical vs. nerve block etiology. The higher complication rate for POPs using perineural dexamethasone should be interpreted cautiously in light of the lack of randomization and likely confounders. PMID- 29983655 TI - The Root-Ely Modified Test of Rectus Femoris Spasticity Has Reliability in Individuals with Cerebral Palsy. AB - Background: Stiff-knee gait is a common gait deviation in individuals with cerebral palsy (CP) due to rectus femoris (RF) muscle spasticity. The Duncan-Ely test is a velocity-dependent measurement of spasticity that is recorded as positive or negative. At our institution, we use a modification of the Duncan-Ely test, a 5-point ordinal rating scale, which delineates where the catch occurs within the rapid arc of knee flexion. It has been named the Root-Ely test. Questions/Purposes: We sought to determine the intra- and inter-rater reliability of the Duncan-Ely and Root-Ely tests in pediatric patients with CP. Methods: A convenience sample of 20 ambulatory subjects was recruited; mean age was 10.5 +/- 4.5 years, and the Gross Motor Function Classification System (GMFCS) levels were I-III. Five clinicians measured each individual's RF spasticity using the Root Ely protocol during a single visit. Simple kappa statistics with 95% confidence intervals (CI) were utilized for intra-rater reliability and weighted kappa statistics with 95% CI for inter-rater reliability. Results: The Root-Ely scale intra-rater reliability was 0.77 to 0.90 and inter-rater reliability was 0.32 to 0.87. Inter-rater reliability was good to excellent among experienced clinicians and fair to moderate in new clinicians. Conclusion: The Root-Ely 5-point scale has acceptable intra- and inter-rater reliability in pediatric individuals with CP among experienced clinicians. The Root-Ely test allows experienced clinicians to reliably quantify severity of RF spasticity and may give orthopaedic surgeons a clinical tool to better predict ideal candidates for RF transfers in individuals with CP in order to improve stiff-knee gait. PMID- 29983656 TI - An Alternative Macrophage Activation Pathway Regulator, CHIT1, May Provide a Serum and Synovial Fluid Biomarker of Periprosthetic Osteolysis. AB - Background: Periprosthetic osteolysis (PPO) is a frequent indication for total hip replacement (THR) failure. Currently, PPO diagnosis occurs in advanced stages that often necessitate complex revisions due to bone loss. PPO biomarkers could facilitate earlier diagnosis. Alternative macrophage activation pathway regulators, chitotriosidase (CHIT1) and CC chemokine ligand 18 (CCL18), have increased periprosthetic expression in patients undergoing revision THR for osteolysis. We hypothesized that synovial fluid and serum levels of CHIT1 and CCL18 would be increased in patients undergoing revision THR for PPO versus controls without osteolysis. Methods: In this prospective case-control study, 60 patients undergoing revision metal-on-polyethylene THR at Hospital for Special Surgery were screened preoperatively from January 2013 to December 2014. Twenty "osteolysis" patients who underwent revision for PPO (based on imaging and operative reports) and 10 "control" patients (with stable implants) who underwent revision for recurrent dislocation or a mechanical etiology were included. Among osteolysis and control patients, 11/20 and 4/10 were male; average age was 68 and 63 years, respectively; 9/20 and 3/10 had cemented femoral components; and average implant longevity was 15 and 5 years, respectively. Preoperative serum and intraoperative synovial fluid samples were collected. CHIT1 and CCL18 were quantified via enzyme-linked immunosorbent assay. Significance was assessed via nonparametric Mann-Whiney U test. Results: CHIT1 was significantly increased in both synovial fluid (3727 versus 731 nanomoles [nM]) and serum (98 versus 39 nM) in the osteolysis versus control patients. CCL18 levels were also significantly increased in osteolysis versus control patients' synovial fluid (425 versus 180 nM) but not their serum. Conclusions: In this prospective case-control study, CHIT1 was identified as a novel synovial fluid and serum biomarker of PPO. CHIT1 expression is induced during macrophage activation in response to wear debris. CHIT1 monitoring may facilitate early diagnosis of THR PPO. Furthermore, CHIT1 may represent a novel therapeutic target for PPO. PMID- 29983658 TI - Less Midterm Damage and Oxidation Are Seen in Retrieved Highly Crosslinked Ultrahigh-Molecular-Weight Polyethylene Tibial Inserts than in Direct Compression Molded Polyethylene Inserts. AB - Background: Highly crosslinked ultrahigh-molecular-weight polyethylene (XLPE) shows reduced wear in total hip arthroplasty compared to direct compression molded polyethylene (compPE); however, minimal research evaluating polyethylene damage in XLPE tibial inserts in total knee arthroplasty exists. Questions/Purposes: We evaluated damage and material properties in retrieved XLPE components at midterm (>= 2.5 years) follow-up. Methods: We identified 19 XLPE tibial inserts with >= 30 months in vivo using our institutional review board approved implant retrieval system; 19 compPE retrieved inserts were matched based on age at index surgery, body mass index, sex, and length of implantation. Articular surface damage was assessed using a subjective grading system. Swell ratio testing and Fourier-transform infrared spectroscopy were used to measure crosslink density (XLPE) and oxidation (XLPE, compPE), respectively, at loaded and unloaded surface and subsurface regions. Results: CompPE inserts had higher overall damage than XLPE inserts, specifically at the post of posterior stabilized inserts. The XLPE inserts had lower crosslink density at the loaded surface (0.159 mol/dm3) than either unloaded region (0.183 mol/dm3). CompPE peak oxidation index (OI) was greater than XLPE peak OI in the loaded and unloaded surface regions (1.67 vs. 0.61 and 1.38 vs. 0.46, respectively). Conclusions: Surface damage and oxidation are reduced in XLPE inserts compared to compPE at midterm follow-up. Peak OI greater than 1.0 in the compPE group suggests that mechanical-property degradation had occurred, a likely cause for increased damage. Longer-term retrievals will determine whether these trends continue. Based on midterm results, XLPE shows an advantage over compression molded PE in total knee arthroplasty. PMID- 29983657 TI - Firefighters Have a Higher Incidence of Trochlear Chondral Lesions than the Normal Population. AB - Background: Firefighters' knees are subjected to significant dynamic and static forces, resulting in increased knee complaints and a higher relative risk of osteoarthrosis, compared with aged-matched office workers. Firefighters wear or carry a total of 80 to 100 lbs. of gear while performing intensive physical activity. Purpose/Question: The purpose of this study was to determine whether a central femoral trochlear lesion was observed in firefighters undergoing knee arthroscopy for other diagnoses. Methods: A retrospective chart review of 159 knees in 146 firefighters undergoing arthroscopy for treatment of acute meniscal injury or anterior cruciate ligament reconstruction over a 14-year period was undertaken. Patient demographics, physical examination results, trochlear lesion size and grade, and firehouse type (engine vs. ladder company) and firefighter position (seniority) were recorded. Comparisons of characteristics in those with and without trochlear lesions were performed. Results: The average patient age was 42.2 years (range, 27 to 64 years). Ninety-eight knees (62%) had trochlear lesions and 33 knees (51%) had matching patellar lesions. Patients with lesions were older (43.2 vs. 40.5 years). Mean trochlear lesion size was 19.5 +/- 13.7 mm by 18.9 +/- 12.4 mm. Lesion grade distribution was grade 1 or 2 in 24 knees (24%) and grade 3 or 4 in 67 knees (44%). Trochlear lesion presence was associated with a body mass index of over 30. Current engine company members had more advanced lesions. Conclusions: A "firefighter's trochlea" was present in the majority of firefighters undergoing knee arthroscopy. Higher age and longer tenure as a firefighter prior to surgery were associated with more advanced lesions. Firefighters working in engine companies at the time of arthroscopy were at a greater risk of developing low-grade lesions but not high-grade lesions. Firefighters move between ladder and engine companies, thus a definitive association with company type cannot be reached in this retrospective study. This lesion may reflect the increase in patellofemoral biomechanical stresses secondary to the physical demands of the occupation. PMID- 29983659 TI - A Comparison of Femoral Lengthening Methods Favors the Magnetic Internal Lengthening Nail When Compared with Lengthening Over a Nail. AB - Background: Bone lengthening with an internal lengthening nail (ILN) avoids the need for external fixation and requires one less surgical procedure than lengthening over a nail (LON). However, LON has been shown to be superior to femoral internal lengthening using a mechanical nail. The magnetic ILN, a remote controlled and magnet-driven device, may have overcome the weaknesses of earlier internal lengthening technology and may be superior to LON. Questions/Purposes: (1) Is the magnetic ILN more accurate than LON for femoral lengthening? (2) Does the magnetic ILN demonstrate more precise distraction rate control than LON? (3) Does the magnetic ILN result in faster regenerate site healing, with more robust callus, than LON? (4) Does the magnetic ILN result in fewer complications, including impediments to knee motion, than LON? Methods: We conducted a retrospective comparison of the records and radiographs of 21 consecutive patients with 22 femoral lengthenings using LONs and 35 consecutive patients with 40 femoral lengthenings using remote-controlled magnetic ILNs. Primary outcomes measured included accuracy, distraction rate precision, time to bony union, final knee range of motion, regenerate quality, and complications. The minimum follow up times for the LON and ILN cohorts were 13 and 21 months, respectively. Results: Patients treated with ILN had a lower post-treatment residual limb length discrepancy (0.3 mm) than those treated with LON (3.6 mm). The rate of distraction was closer to the goal of 1 mm/day and more tightly controlled for the ILN cohort (1 mm/day) than that for the LON group (0.8 mm/day; SD, 0.2). Regenerate quality was not significantly different between the cohorts. Bone healing index for ILN was not statistically significant. Time to union was shorter in the ILN group (3.3 months) than that in the LON group (4.5 months). A lower percentage of patients experienced a complication in the ILN group (18%) than in the LON group (45%). Knee flexion at the end of distraction was greater for ILN patients (105 degrees ) than that for LON patients (88.8 degrees ), but this difference was no longer observed after 1 year. Conclusions: Femoral lengthening with magnetic ILN was more accurate than with LON. The magnetic ILN comports the additional advantage of greater precision with distraction rate control and fewer complications. Both techniques afford reliable healing and do not significantly affect knee motion at the final follow-up. The magnetic ILN method showed no superiority in regenerate quality and healing rate. PMID- 29983660 TI - Online Patient Ratings Are Not Correlated with Total Knee Replacement Surgeon Specific Outcomes. AB - Background: Despite potential concerns regarding their validity, physician-rating websites continue to grow in number and utilization and feature prominently on major search engines, potentially affecting patient decision-making regarding physician selection. Questions/Purposes: We sought to determine whether patient ratings on public physician-rating websites correlate with surgeon-specific outcomes for high-volume total knee replacement (TKR) surgeons in New York State (NYS) from 2010 to 2012. Methods: Online patient ratings were compared to surgeon specific outcomes from the Statewide Planning and Research Cooperative System (SPARCS) database from the NYS Department of Health. For each surgeon, we determined the infection rate, re-admission rate, and revision surgery rate within the study period, as well as the mean inpatient length of stay, for TKR from the SPARCS database. Online ratings were collected from two physician-rating websites (Vitals.com and HealthGrades.com). Results: One hundred seventy-four high-volume TKR surgeons were identified in NYS from 2010 to 2012. The mean rates of in-hospital infection, 90-day infection, 30-day re-admission, 90-day re admission, and revision surgery were 0.25, 1.00, 4.89, 8.43, and 1.31%, respectively. The mean number of ratings for individual surgeons on HealthGrades.com and Vitals.com were 24.0 (range: 0 to 109) and 19.3 (range: 0 to 114), respectively, and mean overall ratings were 4.2 and 4.1 (out of 5) stars, respectively. As with online patient ratings of individual surgeons, variability was observed in the total adverse event rate distribution for individual surgeons. Despite sufficient variability in both online patient rating and surgeon-specific outcomes for high-volume TKR surgeons in NYS, no correlation was observed. Conclusion: There was no correlation between surgeon-specific TKR outcome measures and online patient ratings. We therefore advise that patients exert caution when interpreting ratings on these websites. PMID- 29983661 TI - Tendon Excision Following Distal Semitendinosus Injury in the Elite Athlete: A Surgical Technique. AB - Background: Hamstring injuries can present in numerous forms, some of which can lead to persistent pain, loss of function, and delay in return to sport. Although most are treated conservatively, proximal and distal tendon avulsion injuries have become more commonly treated with surgery. Distal semitendinosus avulsion injuries have been largely reported in the elite athlete population. While conservative management has been utilized, failure in this group can significantly impact a future career. Purpose: The purpose of the manuscript is to describe our approach of surgical tendon excision for distal semitendinosus injury in an elite athlete. Methods: We highlight a two-incision technique to isolate the avulsed tendon, followed by exteriorization and tendon excision. In addition, we provide insight on clinical and imaging findings to help guide management. Results: This technique provides a reliable and effective surgical option for managing these rare injuries of the distal semitendinosus, along with outlining rehabilitation goals in the postoperative period. Conclusion: In this setting, we present a detailed surgical technique to excise the injured distal semitendinosus tendon to promote recovery and potentially allow for earlier return to play. PMID- 29983662 TI - A Comparison of Two Arthroscopic Techniques for Interpositional Polytetrafluoroethylene Patch Repair for Massive Irreparable Rotator Cuff Tears: Speed and Biomechanics. AB - Background: Interpositional synthetic patch repairs are a novel method of treating massive irreparable rotator cuff tears. However, surgeons experience difficulty in the arthroscopic insertion of these patches. Questions/Purposes: We compared two methods of arthroscopic interpositional synthetic patch repair: the newly devised slide-and-grip technique, using pre-loaded sliding knots and no arthroscopic knots, and the weave technique, using less arthroscopic knot tying than the earlier mattress technique. Study questions were as follows: (1) Would the slide-and-grip technique take less time than the weave technique? (2) Would the biomechanical strength of the two methods be comparable? Methods: Fourteen paired ovine infraspinatus tendon ex vivo models of the degenerative human rotator cuff underwent timed repair with a synthetic polytetrafluoroethylene (PTFE) patch, using either the weave technique (n = 7) or the slide-and-grip technique (n = 7). Each was pulled to failure using a tensile testing machine, the Instron 8874. Results: The time to complete the slide-and-grip repairs was shorter (12 +/- 0.9 min) than that of the weave repairs (23 +/- 1 min). Ultimate load to failure was comparable for the slide-and-grip and weave techniques (211 +/- 27 N vs. 295 +/- 35 N, respectively), and the slide-and-grip was less stiff (14 +/- 1 N/mm vs. 19 +/- 1 N/mm). Conclusions: The slide-and-grip technique took less time than the weave technique for the interpositional patch repair of massive irreparable rotator cuff tears and when correctly performed had comparable biomechanical strength. PMID- 29983663 TI - Patient Satisfaction After Total Knee Replacement: A Systematic Review. AB - Background: The quality and state of satisfaction reporting after total knee replacement (TKR) is variable. Questions/Purposes: The purposes of this systematic review were (1) to examine the available literature on patient satisfaction after TKR, (2) to evaluate the quality of available evidence, and (3) to identify predictors of patient satisfaction after TKR. Methods: A systematic review of the MEDLINE database was performed. The initial search yielded 1219 studies. The inclusion criteria were English language, clinical outcome study with primary outcome related to TKR for osteoarthritis, and patient reported satisfaction included as an outcome measure. Studies were assessed for demographics, methodology for reporting satisfaction, and factors influencing satisfaction. Results: Two hundred eight studies, including 95,560 patients who had undergone TKR, met all inclusion and exclusion criteria; 112 (53.8%) of these studies were published in the past 3 years. Satisfaction was most commonly measured using an ordinal scale. Twenty-seven studies (13%) used a validated satisfaction survey. Eighty-three percent of studies reported more than 80% satisfaction. The most commonly reported predictor of satisfaction was post operative patient-reported functional outcome. Pre-operative anxiety/depression was the most common pre-operative predictor of dissatisfaction. Conclusion: There are numerous studies reporting patient satisfaction after TKR, and publication on the topic has been increasing over the past decade. However, the majority of studies represent lower levels of evidence and use heterogeneous methods for measuring satisfaction, and few studies use validated satisfaction instruments. In general, the majority of studies report satisfaction rates ranging from 80 to 100%, with post-operative functional outcome and relief of pain being paramount determinants for achieving satisfaction. PMID- 29983665 TI - Component Placement Accuracy in Unicompartmental Knee Arthroplasty Is Improved with Robotic-Assisted Surgery: Will It Have an Effect on Outcomes? AB - Bell et al.'s "Improved Accuracy of Component Positioning with Robotic-Assisted Unicompartmental Knee Arthroplasty: Data from a Prospective, Randomized Controlled Study" compared the accuracy of a robotic-assisted unicompartmental knee arthroplasty (UKA) using the MAKO Robotic Interactive Orthopedic Arm (RIO) system to a conventional UKA using standardized instrumentation. This review examines the authors' findings and their relevance to clinical practice. Bell et al. conclude that the MAKO RIO system leads to more accurate implantation of both the tibial and femoral components in UKA in the sagittal, coronal, and axial planes. This well-designed, level I study suggests what many arthroplasty surgeons assume about robotic assistance, which admittedly is of unknown clinical significance at this time. Evaluating this article in the context of the current literature provides valuable insight into areas in need of future investigation. The effect of implant positioning on long-term clinical outcomes and implant survivorship remains unclear. Long-term follow-up studies are needed to determine the role of robotic-assisted arthroplasty in the future. PMID- 29983664 TI - Optimizing Intraoperative Blood Management for One-Stage Bilateral Total Knee Arthroplasty. AB - Background: Effective blood management strategies are a major determinant of successful outcomes after one-stage bilateral total knee arthroplasty (BTKA). Proper patient selection with preoperative optimization and intra- and postoperative interventions can reduce transfusion risk and associated morbidity in these patients. Questions/Purposes: The purpose of this study was to evaluate intraoperative blood management modalities based on three keystone questions: (1) What is the role of the anesthesiologist?, (2) Which are the surgeon-dependent strategies?, and (3) Is there any place for pharmacologic interventions? Methods: We searched the established electronic literature database MEDLINE. After critical appraisal, 94 studies were deemed eligible from which to draw documented evidence. Results: A number of blood-conserving methods are currently implemented in patients undergoing one-stage BTKA. Among them, regional anesthesia, tourniquet use, and tourniquet deflation after wound closure, femoral canal sparing or femoral canal plugging, avoidance of drains, and tranexamic acid use were the intraoperative strategies with documented efficacy in blood conservation. Conclusion: Combined proper intraoperative anesthesiologic, surgical, and pharmacologic interventions reduce blood loss and need for transfusion in BTKA patients. However, contemporary relevant literature is lacking evidence-based guidelines. PMID- 29983667 TI - Analysis of Player Statistics in Major League Baseball Players before and after Achilles Tendon Repair. PMID- 29983666 TI - Adult-Onset Still's Disease and Macrophage-Activating Syndrome Progressing to Lymphoma: A Clinical Pathology Conference Held by the Division of Rheumatology at Hospital for Special Surgery. PMID- 29983668 TI - Analysis of Player Statistics in Major League Baseball Players Before and After Achilles Tendon Repair. PMID- 29983669 TI - Correction to: Shoulder Arthroplasty for Humeral Head Avascular Necrosis Is Associated with Increased Postoperative Complications. AB - [This corrects the article DOI: 10.1007/s11420-017-9562-8.]. PMID- 29983670 TI - CD44 glycoprotein in cancer: a molecular conundrum hampering clinical applications. AB - CD44 is a heavily glycosylated membrane receptor playing a key role in cell adhesion, signal transduction and cytoskeleton remodelling. It is also one of the most studied glycoproteins in cancer, frequently explored for stem cell identification, and associated with chemoresistance and metastasis. However, CD44 is a general designation for a large family of splicing variants exhibiting different degrees of glycosylation and, potentially, functionally distinct roles. Moreover, structural diversity associated with ambiguous nomenclature has delayed clinical developments. Herein, we attempt to comprehensively address these aspects and systematize CD44 nomenclature, setting milestones for biomarker discovery. In addition, we support that CD44 may be an important source of cancer neoantigens, most likely resulting from altered splicing and/or glycosylation. The discovery of potentially targetable CD44 (glyco)isoforms will require the combination of glycomics with proteogenomics approaches, exploring customized protein sequence databases generated using genomics and transcriptomics. Nevertheless, the necessary high-throughput analytical and bioinformatics tools are now available to address CD44 role in health and disease. PMID- 29983672 TI - Isolation and characterization of a new fructophilic Lactobacillus plantarum FPL strain from honeydew. AB - In the present study, a Lactobacillus plantarum FPL strain exhibiting fructophilic behavior has been isolated for the first time from honeydew. It is a probably syntrophic bacterium inhabiting the gastrointestinal tract of Coccus hesperidum L. and taking part in sugar metabolism. The promising growth characteristics and biochemical properties of Lb. plantarum FPL indicate that this may be a facultatively fructophilic species, whose properties are not associated with the loss of the alcohol/acetaldehyde dehydrogenase gene. The article attempts to classify the peculiar behavior of this strain by means of tests that are characteristic for FLAB as well as through a classic identification approach. In this study, we used a reference strain Lb. plantarum NRRL B-4496, which showed no fructophilic properties. With the FLAB group, the new strain shares the habit, such as a fructose-rich environment, the preference of this sugar for growth, and similar growth curves. However, it exceeds FLAB in terms of osmotolerance to high sugar content. The fructophilic Lb. plantarum FPL strain can proliferate and grow on a medium wherein the sugar concentration is 45 and 50% (w/v). Our findings indicate that honeydew can be a promising source of new fructophilic lactic acid bacteria. PMID- 29983671 TI - A review of metabolism-associated biomarkers in lung cancer diagnosis and treatment. AB - INTRODUCTION: Lung cancer continues to be the leading cause of cancer-related mortality worldwide. Early detection has proven essential to extend survival. Genomic and proteomic advances have provided impetus to the effort dedicated to detect and diagnose the disease at an earlier stage. Recently, the study of metabolites associated with tumor formation and progression has inaugurated the era of cancer metabolomics to aid in this effort. OBJECTIVES: This review summarizes recent work regarding novel metabolites with the potential to serve as biomarkers for early lung tumor detection, evaluation of disease progression, and prediction of patient outcomes. METHOD: We compare the metabolite profiling of cancer patients with that of healthy individuals, and the metabolites identified in tissue and biofluid samples and their usefulness as lung cancer biomarkers. We discuss metabolite alterations in tumor versus paired non-tumor lung tissues, as well as metabolite alterations in different stages of lung cancers and their usefulness as indicators of disease progression and overall survival. We evaluate metabolite dysregulation in different types of lung cancers, and those associated with lung cancer versus other lung diseases. We also examine metabolite differences between lung cancer patients and smokers/risk-factor individuals. RESULT: Although an extensive list of metabolites has been evaluated to distinguish between these cases, refinement of methods is further required for adequate patient diagnosis. CONCLUSION: We conclude that with technological advancement, metabolomics may be able to replace more invasive and costly diagnostic procedures while also providing the means to more effectively tailor treatment to patient-specific tumors. PMID- 29983673 TI - Burns in the Third World: an unmet need. AB - Burns continue to present a significant public health problem, resulting in scores of preventable deaths and disability everyyear. The burden of burns disproportionately falls to the world's poor residing in low and middle-income countries (LMICs). Those who are burnt require timely access to acute burns management, including definitive surgical care. The current lack of access to safe and affordable surgical care with anaesthesia worldwide means that some 5 billion people do not have access to acute burns management, including definitive surgical care for burns, when needed most. Major limitations to access to burn care at healthcare facilities in LMICs include a lack of appropriately trained staff (including surgeons), appropriate equipment and resources. Burn prevention measures have been successful in reducing the incidence of burns and deaths in many developed countries, however there is currently a paucity of robust understanding of what works in LMICs to prevent burns. A combined effort to implement proven burn prevention strategies and address the unmet need for access to safe and affordable surgical care with anaesthesia is required to reduce the global burden of burns that still exists. PMID- 29983674 TI - Paediatric burn epidemiology as a basis for developing a burn prevention program. AB - Burn injuries are often seen among the paediatric population. Mortality from burn injuries is high in developing countries. Poor facilities and poverty contribute to this. A look at the epidemiology of burn injuries among children from this part of the world will therefore serve as a means for developing programs for burn injury prevention. A retrospective review of burn injuries among the paediatric population was conducted. The aim was to outline common aetiologies, sex predisposition and sites of injury with a view to recommending possible ways of preventing these injuries. A total of 148 children sustained burn injuries during the period under study. There were 85 (57.4%) boys and 63 (42.6%) girls. Scald was the most common cause of injury, observed in 127 (85.8%) children, followed by flame burn in 18 (12.2%), chemical burn in 2 (1.4%), and friction burn in 1 (0.68%). Almost all of the injuries (144, 98%) occurred at home. Sources of heat were hot water, which caused injury in 109 (73.6%) children, and hot oil, hot soup and hot soya milk which were responsible for 7 (4.7%), 7 (4.7%) and 3 (2.0%) cases, respectively. Other sources were kerosene explosion (7, 4.7%), burning firewood (1, 0.6%) petrol explosion (5, 3.4%), candlelight (3, 2.0%), hot ashes (1, 0.6%), soot (1, 0.6%), burned house, chemicals and friction (1, 0.6%). Preventive methods are suggested based on aetiologies, and include education and certain precautions in the home environment. These will reduce burn injuries and associated morbidity and mortality in developing countries. PMID- 29983675 TI - Epidemiology and clinical pattern of paediatric burns requiring hospitalization in sarajevo canton, bosnia and herzegovina, 2012-2016. AB - We first aimed to investigate the epidemiological characteristics and clinical pattern of hospitalized paediatric burn patients in Sarajevo Canton. Second, we aimed to determine the targets for the paediatric burn prevention program. This descriptive retrospective study was carried out to analyse the demographic, etiologic and clinical data of 73 hospitalized paediatric burn patients in Sarajevo Canton over a 5-year period from January 1, 2012 to December 31, 2016. The differences between various groups were evaluated using the chisquare test. During the course of the study, 73 paediatric burns (37 boys and 36 girls; ratio 1:0.97) were hospitalized. The overall mean age was 3.0 +/- 2.9 years (range: 3 months to 12.5 years). The mean total body surface area burned was 8.4 +/- 8.3%. The most common causes of burns in children were scald injuries (84.9%) followed by contact with a hot object (9.6%). No children were found to have burns caused by chemicals or electricity. A total of 97.3% of paediatric burn injuries occurred at home (p<0.001), and almost all were preventable. Although the most burns were recorded in the spring months (35.6%), there was no significant seasonal variation in burns (p = 0.199). Average length of hospital stay (LOS) was 16.32 +/- 12 days (range: 1 to 65 days). The findings of the current study revealed that the main cause of paediatric burns was scald occurring at home. These data can contribute to the development of a prevention program to protect the paediatric population from burns. PMID- 29983676 TI - Burn injuries from the london suicide bombings: a new classification of blast related thermal injuries. AB - In July 2005, four suicide bombers detonated explosive improvised high explosive devices (IEDs) in three separate underground carriages and a double decker bus in London, resulting in 56 deaths and 775 injured. This study aims to understand the mechanisms and patterns of burn injuries from high explosives, and the related factors that determine mortality. The types and patterns of burn injuries in survivors and fatalities in the confined underground train carriages and the bus were analysed, evaluating injury severity score and the victims' relative position from the detonation point. The data were sourced from collated police witness statements, hospital records, forensic post mortem examinations and forensic examinations at the scene. The detonation of an explosive device in a confined space causes complex injuries to the human body, resulting in blast related direct thermal and radiant burns. Injury patterns and mortality were related to crowd density, enclosure design, position of the victims and proximity to the device. Suicide bombings using IEDs will result in direct thermal burns and radiant burns currently categorised in the quaternary (miscellaneous) blast injury group. We propose a classification of these burns following an analysis of the London bombing data with respect to burns in both the fatalities and survivors. Distance from the device, crowd density and environment influences these burns. PMID- 29983677 TI - Toxic epidermal necrolysis in a female with metastatic breast cancer treated with vinorelbine. AB - Vinorelbine is an anticancer agent with high clinical efficacy for the treatment of metastatic breast cancer. Toxic epidermal necrolysis is a rare but serious cutaneous adverse reaction associated with drug therapy. We hereby present a case report of a patient with metastatic breast cancer, treated with vinorelbine, who developed toxic epidermal necrolysis. To the best of our knowledge, ours is the second case report describing this exceptional dermatologic emergency associated with vinorelbine. In June 2014, a 33-year-old female was treated for localized breast cancer. In December 2016, a brain magnetic resonance imaging revealed cerebral and cerebellar recurrence of the breast cancer. Whole brain radiation therapy was administered and treatment with vinorelbine was subsequently initiated. On day 3 of the first cycle of chemotherapy, she presented a general malaise and an itchy rash with conjunctivitis, oral ulcers and diffuse alopecia. The clinical diagnosis was toxic epidermal necrolysis due to vinorelbine. The patient was transferred to the burn unit. Treatment with intravenous steroids, topical steroids and desloratadine was initiated. She subsequently developed Staphylococcus aureus bacteremia and died of multi-organ failure. Toxic epidermal necrolysis is an extremely rare, acute hypersensitivity reaction involving the skin and mucous membranes. Features more suggestive of toxic epidermal necrolysis are acute onset and rapid worsening of painful lesions of the skin and mucous membranes. Specific treatment with active interventions should be practiced in the context of an international and multicentre clinical study in order to give sufficient power for such trials in this rare disease. PMID- 29983678 TI - ? AB - The traditional brazier remains a means of cooking and warming for thousands of families in isolated rural areas in Morocco. From simple burns due to accidental contact to limb carbonizations, these burns are all the more serious when they are secondary to epileptic seizures or carbon monoxide poisoning. The sequelae are important in the associated forms, mainly because of delay in management and non-adherence to therapeutic protocols by patients of low socioeconomic status. PMID- 29983679 TI - Electrical burns: a retrospective analysis over a 10-year period. AB - Although electrical burns have a rather low incidence, they are considered one of the most devastating injuries. The aim of this retrospective study was to analyse specific aspects of electrical injuries and to delineate a prevention strategy. A retrospective analysis of medical records of all the patients admitted to our Unit with electrical burns over a 10-year period (2006/01/01-2015/12/31) was undertaken. Demographic data, mechanism of injury and electric current voltage, total burn surface area (TBSA), location and depth of burns, acute complications, surgical interventions and length of hospital stay (LOS) were analysed. Out of 1695 burn patients admitted to our Unit, 99 subjects (5.84%) suffered electrical burns. 97% of these patients were male. The mean age was 38.3+/-13.7years and mean TBSA was 11.9%+/-13.2%. The mechanism of injury was occupational in 75 cases. Injuries were classified as low-voltage burns (24.2%), highvoltage burns (30.3%) and flash burns (45.5%). TBSA (p=0.014), mean LOS (p=0.002) and serum creatinine kinase levels (p<0.001) were significantly higher in patients with high-voltage injury in comparison to low-voltage injury, as well as the incidence of escharotomy/ fasciotomy (p=0.049) and flap surgeries (p=0.004). Although there was a higher incidence of amputations in this group (16.7% vs. 12.5%), the difference was not statistically significant (p=0.487). The high prevalence of electrical burns in males and workers emphasizes the need to review occupational safety regulations. Educational efforts regarding potential hazards of electricity and reinforcing compliance with safety measures are essential to avoid these injuri. PMID- 29983680 TI - ? AB - Burns to the upper limb caused by contact with a hot press are associated with a compression trauma of variable severity. These burns are rare, and they mostly occur in the context of accidents at work due to mishandling. They can cause severe multi-tissue injuries requiring urgent multidisciplinary care. Their psycho-social repercussions are considerable, especially as they affect a young population. PMID- 29983681 TI - Predictors of inhalation burn injury using fire site information. AB - Inhalation burn injury (IBI) is a risk factor for mortality in burn patients. However, it is difficult to diagnose IBI using traditional physical examination alone, especially in prehospital settings. Therefore, facial burn patients are usually treated for suspected IBI. In the present study, we investigated whether fire site information could predict IBI as an alternative to traditional physical examination. This retrospective single-centre analysis involved 27 facial burn patients with suspected IBI who were admitted between 2014 and 2016. The patients were divided into two groups (IBI and non-IBI) according to bronchoscopy findings. Fire site information was compared between the two groups. The IBI (n = 13) and non-IBI (n = 14) groups were compared. Domestic fire was more frequent in the IBI group (69% vs. 29%, P = 0.035). The IBI group included one patient with carboxyhemoglobin >=10% on admission. Prehospitalization fire site information, particularly domestic fires, might predict IBI in facial burn patients.. PMID- 29983682 TI - ? AB - White phosphorus injuries are considered both thermal and chemical burns. They should be well known, especially in military and terrorism contexts. This type of burn causes a life-threatening systemic toxicity from hypocalcemia, cardiac arrhythmia and respiratory complications by inhalation of phosphoric acid vapours. We report a case of a non-cardiogenic pulmonary edema complicating a white phosphorus burn in a young serviceman. PMID- 29983683 TI - Infectious complications in adult burn patients and antimicrobial resistance pattern of microorganisms isolated. AB - The objective of this study was to analyze the incidence of hospital acquired infections (HAIs) in burn patients, and to determine the principle infection sites and the sensitivity profile of the microorganisms to antimicrobials. This is a retrospective cohort study, conducted in a specialized centre for the treatment of burns from January 2009 to December 2013. The sample consisted of 404 patients, divided into two groups: the first group comprised 142 patients without infection, and the second group was made up of 262 patients who had acquired HAIs. There was a predominance of males in both groups. Mean age of the patients without infection was 37 years (SD 14.89), and 38 years (SD 15.78) for the patients with HAIs. Of the 523 infections observed in this study, pneumonia was the most frequent with 216 (41%) cases, followed by urinary tract infections with 137 (26%) episodes. The pathogens identified were Acinetobacter baumannii (93, 40%), Pseudomonas aeruginosa (50, 21%) and Klebsiella (pneumoniae/oxytoca) (23, 10%) and were resistant to most common antimicrobials. In the study population, no pathogens resistant to vancomycin were found. The present study describes high rates of infection in burn victims. Pneumonia was the most frequent site of infection, followed by urinary tract infections caused respectively by non-fermenting bacteria with a high frequency of antimicrobial resistance. PMID- 29983684 TI - ? AB - Polyamphoteric washing solutions (PWS) have been used for several years, mainly in industries, for cases of chemical ocular or cutaneous splashes by acid or alkali. We collected 37 cases reporting the use of PWS for ocular and cutaneous chemical splashes from several centres. Among the 37 cases, 55.26% resulted from occupational exposure. Among ocular exposures, initial clinical symptoms included pain (20 cases), blepharospasm (4 cases), hyperaemia (15 cases), palpebral oedema (2 cases) and blurred vision (7 cases). Among cutaneous exposures, 2 injuries were classified as deep, and 11 as superficial. Mean (SD) pain (VAS) before PWS was 6,29 +/- 2,74; mean (SD) pain after PWS was 1,47 +/- 1,73. Early application of PWS to the eye or skin reduces the intensity of pain that is associated with chemical damage. Early application of amphoteric solution appears to reduce the incidence of sequelae, provided its pre-hospital and hospital use is early. However, further studies are needed. PMID- 29983685 TI - ? AB - We report the case of a severe burn patient who presented an asystole during a dermo-epidermal graft of the two upper limbs. Perioperative bleeding, hypovolemia and hypothermia are at the origin of this incident. We review the management of cardiopulmonary arrest in the operating theatre during burns surgery. PMID- 29983686 TI - ? AB - The hands are the most commonly affected area in burn injuries and are involved approximately 80% of the time. Because of the thinness of the skin and superficial location of critical structures, the dorsum of the hand needs an optimal coverage to preserve maximum articular mobility and range of motion. The aim of this article is to detail the therapeutic alternatives to skin graft in cases of very deep burns on the dorsum of the hand, and to specify the indications. We reviewed all articles referenced on PubMed, and included all the original articles related to the management of acute burned hands and their different coverage techniques (dermal substitutes and flaps). We excluded articles that dealt only with skin grafting techniques, as well as articles about secondary management (sequelae and reconstruction). One hundred and sixteen articles were found and twenty of these were selected. Alternatives to full thickness skin grafting are dermal substitutes (Alloderm(r), Matriderm(r), Integra(r)) and flaps. In cases of immediately usable autologous donor sites, the combination Matriderm(r) with a thin skin graft is preferred. Otherwise, we use Integra(r). In cases of deep exposure of critical structures and doubtful vascularization quality on the wound, flaps can be discussed (cross-arm, abdominal wall flap...). PMID- 29983688 TI - Functional reconstruction of acutely burnt achilles tendon with composite anterolateral thigh flap with fascia lata: a case report. AB - Soft tissue defects in the postero-inferior aspect of the leg are still challenging, especially when they affect the Achilles tendon due to its important functional involvement in the normal movement of the ankle. Dorsiflexion and flexion may be affected if proper reconstruction is not achieved, thus limiting daily activities such as walking, climbing stairs or running. Several techniques, including local or regional flaps, combinations of tendon substitutes with free muscular or fasciocutaneous flaps, and free composite flaps with tendon have been described for the reconstruction of complex defects caused by burn sequelae, tumors, trauma, chronic ulcers, etc. The gold standard treatment for moderate to large defects is the anterolateral thigh (ALT) flap with vascularized fascia lata. The ALT flap is reliable because of a long vascular pedicle and a large donor area. Moreover, the fascia lata mimics the Achilles tendon perfectly when rolled on itself. The aim of this article is to present the application of this technique for the first time in a case of an acute burn. The timing of reconstruction with free flaps is critical in acute burns. In our case, it was performed on the 24th day post-burn and no microsurgical complications appeared. More than six months after surgery, the patient showed a normal gait, was able to lift his own weight against gravity and no complications were detected in the donor area. PMID- 29983687 TI - Early free flap reconstruction of blast injuries with thermal component. AB - Modern warfare has seen advances in both weaponry and personnel protective material, thus allowing for better survival of injured individuals. As a result, the medical system is faced with an increasing number and diversity of non-life threatening wounds, to the extremities especially, sustained by multiple mechanisms. These wounds have a thermal injury component regardless of the mechanism, and there is often a delay in them being definitively treated, thus affecting final cosmetic and functional outcomes. Fourteen patients presented to our institution after sustaining blast injuries of different etiologies. Time of admission was between 0-10 days, and time of microvascular reconstruction after initial serial debridement was between 5-28 days. All patients were found to be infected with multiple organisms upon admission. Five patients were reconstructed with free vascularized skin flaps, three with osseous and osseocutaneous free flaps, four with free latissimus dorsi muscle flaps and two by toe-to-hand transfer. The follow-up period ranged from 4 to 52 weeks (mean, 26.7 weeks). Eleven free flaps survived completely. Two patients presented with minor dehiscence and were treated with secondary closure. Two patients developed a hematoma under the flap that required evacuation. One flap failed due to arterial thrombosis. Early free flap reconstruction proves to be a good option for the early reconstruction of blast injuries with thermal components after serial debridement and tangential excision of the wound beds. PMID- 29983690 TI - MBC News. PMID- 29983689 TI - Spontaneous healing and scar control following enzymatic debridement of deep second-degree burns. AB - Scarring after a burn injury remains the greatest unmet challenge in the treatment of functional and psychosocial sequelae of burns. The hypertrophic scar represents the most common type of cicatrix after burns, and it has a prevalence of up to 70%. We present a case of upper and lower extremity partial-thickness burns in a female patient treated in two different modalities. Superficial seconddegree burns on the upper extremities were treated with conservative dressing with fairly early wound closure but they developed hypertrophic scars. Deeper, lower extremity burns were debrided with a new bromelain-based debriding agent, resulting in scar-free healing. The pathophysiology of hypertrophic scar formation is based on the perturbation of collagen production or degradation or both. The duration and magnitude of the inflammatory phase of wound healing also appears to play a role in hypertrophic scarring. Bromelain has demonstrated an anti-angiogenic effect in various cancer cell lines and it has been shown to regulate a variety of pro-angiogenic growth factors. This case raises the classical question of the relationship between time to healing and formation of hypertrophic scars after burn injury, pointing to other potential factors that may play an important role in burn healing. PMID- 29983691 TI - Comparison of Safety Profiles between Non-operating Room Anesthesia and Operating Room Anesthesia: a Study of 199,764 Cases at a Korean Tertiary Hospital. AB - Background: Despite expanding demands for non-operating room anesthesia (NORA) worldwide, studies in this field are scarce. We compared the overall characteristics and the nature of deaths occurring within 48 hours after surgery between NORA and operating room anesthesia (ORA) cases at a Korean tertiary hospital. Methods: We retrospectively analyzed the medical records of patients who underwent surgical procedures under anesthesia services in and outside the operating room from January 2013 to November 2017. All of the mortalities were categorized by principal cause into groups such as patient disease or condition, surgery, anesthesia, and others. Results: Overall, 16,383 NORA cases and 183,381 ORA cases were analyzed. Eighty-six deaths were identified. The mortality rate of NORA cases was similar to that of ORA cases (4.9 per 10,000 cases [95% confidence interval (CI), 2.1-9.6] vs. 4.3 per 10,000 cases [95% CI, 3.4-5.3], respectively). Similar to ORA cases, higher American Society of Anesthesiologists physical status and very young age (< 2 years) were significantly associated with mortality in NORA cases. A patient's disease or condition was the most important cause of mortality (65/86, 75.6%), followed by surgery-related causes (16/86, 18.6%). Two cases of anesthesia-related mortality were only identified in the ORA cases, resulting in an overall anesthesia-related mortality of 0.1 per 10,000 cases (95% CI, 0.0-0.4). Conclusion: Although NORA cases showed an equivalent perioperative mortality rate compared to ORA cases, there may be more room for improving patient safety when considering their favorable characteristics (healthier patients, less invasive and shorter procedures). Trial registry at Clinical Research Information Service, KCT0002719. PMID- 29983692 TI - Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike. AB - Previously, we defined DRD as a syndrome of selective nigrostriatal dopamine deficiency caused by genetic defects in the dopamine synthetic pathway without nigral cell loss. DRD-plus also has the same etiologic background with DRD, but DRD-plus patients have more severe features that are not seen in DRD because of the severity of the genetic defect. However, there have been many reports of dystonia responsive to dopaminergic drugs that do not fit into DRD or DRD-plus (genetic defects in the dopamine synthetic pathway without nigral cell loss). We reframed the concept of DRD/DRD-plus and proposed the concept of DRD look-alike to include the additional cases described above. Examples of dystonia that is responsive to dopaminergic drugs include the following: transportopathies (dopamine transporter deficiency; vesicular monoamine transporter 2 deficiency); SOX6 mutation resulting in a developmentally decreased number of nigral cells; degenerative disorders with progressive loss of nigral cells (juvenile Parkinson's disease; pallidopyramidal syndrome; spinocerebellar ataxia type 3), and disorders that are not known to affect the nigrostriatal dopaminergic system (DYT1; GLUT1 deficiency; myoclonus-dystonia; ataxia telangiectasia). This classification will help with an etiologic diagnosis as well as planning the work up and guiding the therapy. PMID- 29983693 TI - Surgical Strategy for T2 Gallbladder Cancer: Nationwide Multicenter Survey in Korea. AB - Background: Although all guidelines suggest that T2 gallbladder (GB) cancer should be treated by extended cholecystectomy (ECx), high-level scientific evidence is lacking because there has been no randomized controlled trial on GB cancer. Methods: A nationwide multicenter study between 2000 and 2009 from 14 university hospitals enrolled a total of 410 patients with T2 GB cancer. The clinicopathologic findings and long-term follow-up results were analyzed after consensus meeting of Korean Pancreas Surgery Club. Results: The 5-year cumulative survival rate (5YSR) for the patients who underwent curative resection was 61.2%. ECx group showed significantly better 5YSR than simple cholecystectomy (SCx) group (65.4% vs. 54.0%, P = 0.016). For N0 patients, there was no significant difference in 5YSR between SCx and ECx groups (68.7% vs. 73.6%, P = 0.173). Systemic recurrence was more common than locoregional recurrence (78.5% vs. 21.5%). Elevation of cancer antigen 19-9 level preoperatively and lymph node (LN) metastasis were significantly poor prognostic factors in a multivariate analysis. Conclusion: ECx including wedge resection of GB bed should be recommended for T2 GB cancer. Because systemic recurrence was more common and recurrence occurred more frequently in patients with LN metastasis, postoperative adjuvant therapy should be considered especially for the patients with LN metastasis. PMID- 29983694 TI - Five Months Follow-up Study of School-based Crisis Intervention for Korean High School Students Who Experienced a Peer Suicide. AB - Background: The purpose of this study was to examine post-traumatic stress, depression, anxiety, and complicated grief in Korean high school students who experienced a peer suicide. Methods: A total of 956 students were included in the statistical analysis. One week after a peer suicide, a school-based crisis intervention program was conducted. The cohort was followed-up at one week and five months after a peer suicide. The program consists of screening tests, educational sessions, and further interview with psychiatric specialists for the selected group. Screening tests were conducted for all students to measure the Child Report of Post-traumatic Symptoms (CROPS), the post-traumatic stress symptoms (The University of California at Los Angeles post-traumatic stress disorder [PTSD] reaction index; UCLA-PTSD-RI), the anxiety symptoms (The Korean Beck Anxiety Inventory; K-BAI), the depressive symptoms (The Korean-Beck Depression Inventory-II; K-BDI-II), and the complicated grief reaction (The Inventory of Complicated Grief; ICG). For statistical analysis, the SPSS Statistics 21.0 program was used. Results: At baseline and five months follow ups, 8.6% and 2.9% of the students showed post-traumatic stress symptoms. At five months follow-up, there was a statistically significant decline in the post traumatic stress symptoms, anxiety, depression, and complicated grief among the 'trauma group.' A higher proportion of the female students showed post-traumatic stress symptoms after the incident of peer suicide than the male students. Conclusion: School-based crisis intervention helps improvement of trauma-related symptoms. It might be an effective way to prevent suicide spreading among students by alleviating trauma-related symptoms. PMID- 29983695 TI - Letter to the Editor: Individual Researcher and Author Metrics: a Viewpoint from India. PMID- 29983696 TI - Multi-purpose, multi-level feature modeling of large-scale industrial software systems. AB - Feature models are frequently used to capture the knowledge about configurable software systems and product lines. However, feature modeling of large-scale systems is challenging as models are needed for diverse purposes. For instance, feature models can be used to reflect the perspectives of product management, technical solution architecture, or product configuration. Furthermore, models are required at different levels of granularity. Although numerous approaches and tools are available, it remains hard to define the purpose, scope, and granularity of feature models. This paper first reports results and experiences of an exploratory case study on developing feature models for two large-scale industrial automation software systems. We report results on the characteristics and modularity of the feature models, including metrics about model dependencies. Based on the findings from the study, we developed FORCE, a modeling language, and tool environment that extends an existing feature modeling approach to support models for different purposes and at multiple levels, including mappings to the code base. We demonstrate the expressiveness and extensibility of our approach by applying it to the well-known Pick and Place Unit example and an injection molding subsystem of an industrial product line. We further show how our approach supports consistency between different feature models. Our results and experiences show that considering the purpose and level of features is useful for modeling large-scale systems and that modeling dependencies between feature models is essential for developing a system-wide perspective. PMID- 29983697 TI - Synthetic Biology, Tinkering Biology, and Artificial Biology. What are We Learning? AB - While chemical theory cannot yet support an engineering vision that allows molecules, DNA sequences, and proteins to be interchangeable parts in artificial constructs without "tinkering", progress can be made in synthetic biology by pursuing challenges at the limits of existing theory. These force scientists across uncharted terrain where they must address unscripted problems where, if theory is inadequate, failure results. Thus, synthesis drives discovery and paradigm change in ways that analysis cannot. Further, if failures are analyzed, new theories emerge. Here, we illustrate this by synthesizing an artificial genetic system capable of Darwinian evolution, a feature theorized to be universal to life. PMID- 29983698 TI - Orbital Metastases from Breast Cancer with BRCA2 Mutation: A Case Report and Literature Review. AB - Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Of these women, 5-10% have an inherited form of breast cancer with a mutation in a major gene, such as the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Triple negative (the most common subtype of BRCA1 associated breast cancers) and Her2-positive breast cancer patients have more frequently been observed to develop central nervous system (CNS) metastases compared to other molecular subtypes of breast cancers. However, it remains an open question if BRCA2-associated breast cancers also have a higher propensity to develop CNS metastases. Here we report a rare case of recurrent BRCA2-associated breast cancer which manifested as orbital metastases. At the time of this publication, this is one of the first cases of BRCA2-associated breast cancer to present with orbital metastases. In this article, we discuss the diagnostic challenges and review the literature regarding this rare presentation. PMID- 29983699 TI - Isolated Left Ventricular Metastasis from Renal Cell Carcinoma: Diagnostic and Therapeutic Dilemma. AB - Background: The treatment of metastatic renal cell carcinoma (RCC) has been radically changed by the advent of tyrosine kinase inhibitors (TKIs). However, few reports have described their role in cardiac metastases. We present a case of a left ventricular metastasis from RCC that was managed with pazopanib therapy. Case Report: A 74-year-old male with stage I RCC underwent right nephrectomy in 2004 and right lung metastasis resection in 2009. He was well till March 2016, when he presented with chest pain. Cardiac catheterization revealed a highly vascular mass in the apex. Cardiac magnetic resonance imaging revealed a left ventricular mass with full-thickness involvement of the myocardium, and the open cardiac biopsy was consistent with metastatic RCC. The patient was initially treated with pazopanib with response but later developed therapy-related side effects, and the dose was reduced. Due to tumor progression, he is currently on nivolumab instead and is stable. Conclusion: RCC with cardiac metastasis poses unique challenges with regard to diagnosis as well as treatment. The use of TKI therapy is associated with cardiotoxicity and has not been adequately studied in cardiac metastasis. Choosing the right treatment for this subgroup of patients continues to pose an ongoing dilemma. PMID- 29983700 TI - Beneficial Effect of Bendamustine in a Patient with Anti-MAG/SGPG Neuropathy and Bing-Neel Syndrome Associated with Waldenstrom Macroglobulinemia: A Case Report. AB - A 71-year-old man with Waldenstrom macroglobulinemia (WM) presented with a slowly progressive sensory disturbance and mild weakness predominantly affecting the distal portion of the limbs over the course of 6 months. Cervical magnetic resonance imaging (MRI) showed a long hyperintense lesion at the C1-C4 level. Nerve conduction studies (NCS) revealed prolongation of distal latency, slowed conduction velocity, and conduction block. His serum IgM level was increased, and he was positive for anti-myelin-associated glycoprotein (MAG) and anti sulfoglucuronyl paragloboside (SGPG) IgM antibodies. Based on the presence of anti-MAG/SGPG antibodies and a single atypical cell with lymphoplasmacytic character in the cerebral spinal fluid, he was diagnosed as having anti-MAG/SGPG neuropathy and Bing-Neel syndrome (BNS) associated with WM. Following 6 cycles of bendamustine monotherapy, the patient's neurological impairment improved; and the serum IgM level became normalized. Furthermore, NCS findings indicated improvement; and the hyperintense lesion on MRI had almost completely disappeared. The present findings suggest that bendamustine monotherapy is effective not only for WM but also for its associated MAG/SGPG neuropathy and BNS. PMID- 29983701 TI - Severe Nightly Thoracic Pain Presenting during Pregnancy: A Case Report. AB - We present the case of a woman who developed severe nightly thoracic pain during pregnancy without neurological deficits upon examination. Spontaneously after childbirth, the pain was markedly reduced. Further investigation showed that her pain was caused by an ependymoma in the cervicothoracic spinal cord. Gross total resection was accomplished, and the patient has been free of pain ever since. With this case, we want to draw attention to a rare, but possibly very disabling, cause of increasing nightly thoracic pain during pregnancy. Spontaneous improvement after childbirth could erroneously cause postponement of further investigation. PMID- 29983702 TI - Corrigendum: Sliding Mode Tracking Control of a Wire-Driven Upper-Limb Rehabilitation Robot with Nonlinear Disturbance Observer. AB - [This corrects the article DOI: 10.3389/fneur.2017.00646.]. PMID- 29983703 TI - High Frequencies of Caspase-3 Expressing Mycobacterium tuberculosis-Specific CD4+ T Cells Are Associated With Active Tuberculosis. AB - Antigen-specific CD4+ T cell responses to Mycobacterium tuberculosis (Mtb) infection are important for host defense against tuberculosis (TB). However, Mtb specific IFN-gamma-producing T cells do not distinguish active tuberculosis (ATB) patients from individuals with asymptomatic latent Mtb infection (LTBI). We reasoned that the immune phenotype of Mtb-specific IFN-gamma+CD4+ T cells could provide an indirect gauge of Mtb antigen load within individuals. We sought to identify immune markers in Mtb-specific IFN-gamma+CD4+ T cells and hypothesized that expression of caspase-3 Mtb-specific CD4+ T cells would be associated with ATB. Using polychromatic flow cytometry, we evaluated the expression of caspase-3 in Mtb-specific CD4+ T cells from LTBI and ATB as well as from ATB patients undergoing anti-TB treatment. We found significantly higher frequencies of Mtb specific caspase-3+IFN-gamma+CD4+ T cells in ATB compared to LTBI. Caspase-3+IFN gamma+CD4+ T cells were also more activated compared to their caspase-3-negative counterparts. Furthermore, the frequencies of caspase-3+IFN-gamma+CD4+ T cells decreased in response to anti-TB treatment. Our studies suggest that the frequencies of caspase-3-expressing antigen-specific CD4+ T cells may reflect mycobacterial burden in vivo and may be useful for distinguishing Mtb infection status along with other host biomarkers. PMID- 29983704 TI - Clinical Utility of the Cognitive Test for Severe Dementia: Factor Analysis, Minimal Detectable Change, and Longitudinal Changes. AB - Aims: This study sought to conduct additional analyses of the Cognitive Test for Severe Dementia (CTSD) using the COSMIN checklist to ensure the development of adequate outcome measures. Methods: The following analyses were conducted: (1) factor analyses were used to evaluate construct validity; (2) the standard error of measurement (SEM) and minimal detectable change (MDC) were assessed to evaluate reliability and interpretability; and (3) longitudinal change was assessed to evaluate responsiveness. Results: The CTSD factor analysis yielded 2 factors, each of which was dichotomized by the passage rate of each item. We calculated a SEM and MDC of 1.6 and 3.6 points, respectively. Finally, the mean CTSD score showed a significant reduction (p < 0.001) over time, and the change in score exceeded the SEM and MDC. Conclusion: Our results indicate that the CTSD could provide a reliable outcome measure in severe dementia. PMID- 29983705 TI - Exploration on the Interaction Ability of Antitumor Compound Bis-[2,6-difluoro-N (hydroxyl-O)benzamidato-O]dibutylitin(IV) with Human Peroxisome Proliferator-Activated Receptor hPPARgamma. AB - Diorganotin(IV) antitumor compound bis-[2,6-difluoro-N-(hydroxyl O)benzamidato-O] (DBDF2,6T) was one of the novel patent organotin compounds with high antitumor activity and relatively low toxicity. In this study, several methods were used to study the interaction between DBDF2,6T and hPPARgamma protein, including fluorescence quenching, three-dimensional (3D) fluorescence, drug affinity responsive target stability (DARTS), ultrafiltration LC, and molecular docking. According to the experimental results, the quenching process of the hPPARgamma protein was induced by static quenching mode to form a nonradiative ground-state complex with DBDF2,6T spontaneously, mainly through the hydrophobic force. DBDF2,6T could bind to the hPPARgamma protein directly and give the protein the ability of antienzymatic hydrolysis. And the binding mode of DBDF2,6T into hPPARgamma protein appeared to have an orientation towards residues of SER342 and GLY284. In conclusion, these methods could comprehensively reveal the interaction details of DBDF2,6T and the hPPARgamma protein and established a feasible way to preliminarily identify the agonist compounds for the hPPARgamma protein. PMID- 29983706 TI - Test-Retest Reliability of Homeostatic Plasticity in the Human Primary Motor Cortex. AB - Homeostatic plasticity regulates synaptic activity by preventing uncontrolled increases (long-term potentiation) or decreases (long-term depression) in synaptic efficacy. Homeostatic plasticity can be induced and assessed in the human primary motor cortex (M1) using noninvasive brain stimulation. However, the reliability of this methodology has not been investigated. Here, we examined the test-retest reliability of homeostatic plasticity induced and assessed in M1 using noninvasive brain stimulation in ten, right-handed, healthy volunteers on days 0, 2, 7, and 14. Homeostatic plasticity was induced in the left M1 using two blocks of anodal transcranial direct current stimulation (tDCS) applied for 7 min and 5 min, separated by a 3 min interval. To assess homeostatic plasticity, 15 motor-evoked potentials to single-pulse transcranial magnetic stimulation were recorded at baseline, between the two blocks of anodal tDCS, and at 0 min, 10 min, and 20 min follow-up. Test-retest reliability was evaluated using intraclass correlation coefficients (ICCs). Moderate-to-good test-retest reliability was observed for the M1 homeostatic plasticity response at all follow-up time points (0 min, 10 min, and 20 min, ICC range: 0.43-0.67) at intervals up to 2 weeks. The greatest reliability was observed when the homeostatic response was assessed at 10 min follow-up (ICC > 0.61). These data suggest that M1 homeostatic plasticity can be reliably induced and assessed in healthy individuals using two blocks of anodal tDCS at intervals of 48 hours, 7 days, and 2 weeks. PMID- 29983708 TI - Neutrophil to Lymphocyte Ratio as a Predictor of Poor Prognosis in Metastatic Pancreatic Cancer Patients Treated with Nab-Paclitaxel plus Gemcitabine: A Propensity Score Analysis. AB - Background: High neutrophil to lymphocyte ratio (NLR) has shown to be a predictor of poor outcomes in various malignancies, including pancreatic cancer. Methods: We assessed 70 consecutive pts with histologically confirmed mPC who received chemotherapy with nab-paclitaxel/gemcitabine at two different European oncologic centers between January 2012 and November 2015. Variables assessed for prognostic correlations included age >= 66, sex, Karnofsky PS score, primary tumor site, baseline CA19.9 level >= 59xULN, 12-week decrease of the CA19.9 level >= 50% from baseline, basal bilirubin level, baseline NLR, biliary stent implantation, and liver metastasis. Survival analyses were generated according to the Kaplan-Meier method. Univariate and multivariate analyses were performed by a Cox proportional hazard model. Results: According to NLR values, the patients were divided into two groups: high and low. Low group patients showed a better median PFS (7 months versus 5 months) and median OS (13 months versus 7 months) in respect to high group patients. At multivariate analysis, Karnofsky PS < 80% (HR = 0.4; CI 0.2 1.2), liver metastases (HR = 0.4; CI 0.18-0.82), and NLR >= 5 (HR = 2.7; 95% CI 1.4-5.2) were predictors of poorer OS. Based on the presence of one or more independent prognostic factors, three risk categories were identified: good-risk, intermediate-risk and poor-risk. The median OS was 22, 10, and 7 months, respectively. Conclusions: Baseline NLR is an independent predictor of survival of patients with mPC receiving palliative chemotherapy and could be useful to develop a simple clinical score to identify a subgroup of patients with a low chance to benefit from chemotherapy. PMID- 29983707 TI - Function of Connexins in the Interaction between Glial and Vascular Cells in the Central Nervous System and Related Neurological Diseases. AB - Neuronal signaling together with synapse activity in the central nervous system requires a precisely regulated microenvironment. Recently, the blood-brain barrier is considered as a "neuro-glia-vascular unit," a structural and functional compound composed of capillary endothelial cells, glial cells, pericytes, and neurons, which plays a pivotal role in maintaining the balance of the microenvironment in and out of the brain. Tight junctions and adherens junctions, which function as barriers of the blood-brain barrier, are two well known kinds in the endothelial cell junctions. In this review, we focus on the less-concerned contribution of gap junction proteins, connexins in blood-brain barrier integrity under physio-/pathology conditions. In the neuro-glia-vascular unit, connexins are expressed in the capillary endothelial cells and prominent in astrocyte endfeet around and associated with maturation and function of the blood brain barrier through a unique signaling pathway and an interaction with tight junction proteins. Connexin hemichannels and connexin gap junction channels contribute to the physiological or pathological progress of the blood-brain barrier; in addition, the interaction with other cell-cell-adhesive proteins is also associated with the maintenance of the blood-brain barrier. Lastly, we explore the connexins and connexin channels involved in the blood-brain barrier in neurological diseases and any programme for drug discovery or delivery to target or avoid the blood-brain barrier. PMID- 29983709 TI - Comparison of Anthropometric Parameters after Ultralow Anterior Resection and Abdominoperineal Resection in Very Low-Lying Rectal Cancers. AB - Background and Aim: Ultralow anterior resection (uLAR) is a sphincter-saving procedure for very low-lying rectal cancers. This procedure, however, has complications related to defecation which can aggravate the patient's quality of life postoperatively. In this study, we compared the anthropometric and nutritional parameters after uLAR and abdominoperineal resection (APR). Methods: We retrospectively reviewed the data of patients who underwent either uLAR or APR in 2012 for rectal cancers within 3 cm from the anal verge. Data including body weight, body mass index (BMI), levels of total protein, albumin, and hemoglobin and lymphocyte count were analyzed. We compared the changes of these parameters before operations to 3 years after discharge between uLAR and APR groups by ANOVA for repeated measures and Bonferroni comparison method. Results: After 3 years of discharge, the body weight and BMI of the APR group were fully recovered to the preoperative levels; however, those of the uLAR group did not. The hemoglobin level in the APR group was recovered to the preoperative level within 3 months of discharge; however, that in the uLAR group was recovered after 1 year of discharge. Conclusions: Recovery of anthropometric and nutritional status of patients was more stable after APR than after uLAR. These findings might indirectly reflect the low anterior syndrome effect of uLAR and help colorectal surgeons in selecting better surgical methods and in better counseling patients with very low-lying rectal cancer. PMID- 29983710 TI - GnRH Antagonist Improves Pubertal Cyclophosphamide-Induced Long-Term Testicular Injury in Adult Rats. AB - Background: Gonadal injury following chemotherapy is of increasing importance with the continuous improvement of survival rates. The protection of gonadotropin hormone antagonist (GnRHant) in long-term adult survivors of adolescent cancers and some autoimmune diseases has not yet been evaluated. Methods: The present study was aimed at longitudinally exploring whether the GnRHant could alleviate testicular damage induced by cyclophosphamide (CPA) in a rat model. Pubertal male rats were assigned to receive CPA with and without GnRHant. CPA was administrated at a single dose (100 mg/kg). GnRHant was started one hour prior to CPA injection and continued for four weeks (0.1 mg/kg, 3 times a week). Body and testes weights, testicular hormones, histological changes, and expression of androgen receptor (AR) in the testis were analyzed when rats matured into adulthood and completed a round of spermatogenesis. Results: Our results showed that body weight, histological injury, and AR expression in the testis were improved in the GnRHant + CPA group. However, testes weight and testicular hormones (anti Mullerian hormone, inhibin B, and testosterone) did not markedly change. Conclusion: Our results indicate that the GnRHant administration before and after CPA in pubertal rats can protect long-term testicular injury induced by CPA via increased AR expression in the testes. PMID- 29983711 TI - Weight Mobility and Obesity in a Representative Sample of the US Adult Population. AB - Background: Despite the attention given to the prevalence of obesity, surprisingly little is known about the incidence or reduction of obesity. We report the 1-year incidence and remission of obesity in a representative sample of the US population. Methods: Individuals from the Medical Expenditure Panel Survey (MEPS) panel 17 were classified into standard obesity categories at enrollment and one year later. Incidence rates were calculated by age. Results: Although the overall prevalence of obesity remained nearly constant, remission rates from obesity (stratified by age) ranged from 11 to 27% while incidence rates ranged from 6 to 16%. For almost all age levels, the proportion of individuals leaving an obese or overweight state was greater than or equal to the proportion who progressed to a more severe level of overweight or obesity. Overall, 36% of adults lost at least 2.5 kg/m2 in the one-year period; only 8% gained 2.5 kg/m2 or more. Individuals less than 25 years of age had higher rates of leaving overweight (23% versus <16%) and obesity (27% versus 24%) classifications than people of other ages. Conclusions: Prevalence rates of obesity are well documented in the United States, but incidence is understudied. Public health efforts that target young people with overweight or obesity may yield the greatest benefit. PMID- 29983712 TI - TEMPO-Functionalized Nanoporous Au Nanocomposite for the Electrochemical Detection of H2O2. AB - A novel nanocomposite of nanoporous gold nanoparticles (np-AuNPs) functionalized with 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) was prepared; assembled carboxyl groups on gold nanoporous nanoparticles surface were combined with TEMPO by the "bridge" of carboxylate-zirconium-carboxylate chemistry. SEM images and UV Vis spectroscopies of np-AuNPs indicated that a safe, sustainable, and simplified one-step dealloying synthesis approach is successful. The TEMPO-np-AuNPs exhibited a good performance for the electrochemical detection of H2O2 due to its higher number of electrochemical activity sites and surface area of 7.49 m2g-1 for load bigger amount of TEMPO radicals. The TEMPO-functionalized np-AuNPs have a broad pH range and shorter response time for H2O2 catalysis verified by the response of amperometric signal under different pH and time interval. A wide linear range with a detection limit of 7.8 * 10-7 M and a higher sensitivity of 110.403 MUA mM-1cm-2 were obtained for detecting H2O2 at optimal conditions. PMID- 29983713 TI - Inter-Laboratory Validation of Method to Determine Residual Enrofloxacin in Chicken Meat. AB - An inter-laboratory study was performed to evaluate the performance of a method developed for the quantification of enrofloxacin in chicken meat. Liquid-liquid extraction combined with a clean-up procedure based on solid-phase extraction followed by a liquid chromatography-tandem mass spectrometric method was used by three individual laboratories. All the investigated results of calibration curves and limits of quantification were within the acceptable range for regulatory testing of enrofloxacin. The three laboratories received blind a certified reference material to analyze in triplicate and assess using statistical analysis. From the results, no statistical differences were found between the laboratories in the precision of the method. Additionally, all the results of the z-score, which is an indication of fixed interval bias criteria for accuracy from the laboratories, fell within the allowable limits (+/-2sigma). Based on this proficiency testing by inter-laboratory comparisons, the analytical method including the sample preparation step was proven to be applicable. PMID- 29983714 TI - Location, Isolation, and Identification of Mesenchymal Stem Cells from Adult Human Sweat Glands. AB - Sweat glands (SGs) are spread over almost the entire surface of the human body and are essential for thermoregulation. Theoretically, tissue-specific stem cells (TSSCs) are excellent candidate cells for the regeneration of SGs due to their genetic stability and differentiation ability. Herein, we attempted to isolate TSSCs derived from adult human sweat glands (ahSGs). ahSGs were localized and identified by H&E staining, double immunofluorescence staining, transmission electron microscope (TEM), and immuno-TEM. We found a population of cells with stem cell characteristics (SGSCs), located in basal myoepithelial cells of the secretory portion of the solenoid bulb. The SGSCs expressed alpha-smooth muscle actin (alpha-SMA) and showed the typical characteristics of mesenchymal stem cells (MSCs), with a positive antigen profile for CD44, CD73, CD90, and CD105, and had the multilineage differentiation potential to osteoblasts and adipocytes. In addition, the isolated alpha-SMA positive cells remained stably phenotypic and proliferative cycles at passage 12. This is the first report of successful isolation of MSC-like cells from ahSGs, which may contribute to wound repair and SG regeneration. PMID- 29983716 TI - Direct Microscopy of Stool Samples for Determining the Prevalence of Soil Transmitted Helminthic Infections among Primary School Children in Kaduwela MOH Area of Sri Lanka following Floods in 2016. AB - A descriptive cross-sectional school based study was carried out to investigate the prevalence of soil-transmitted intestinal helminths and the associated factors among school children in Kaduwela Medical Officer of Health (MOH) area in the Colombo district, which was affected by floods in 2016. The study was conducted in 9 selected schools in Kaduwela MOH area from September 2016 to March 2017. Permission was obtained from the relevant authorities. Grade 1 students were enrolled in the study after obtaining informed written consent from their parents/guardian. Interviewer based questionnaire was administered to gather demographic data and other relevant information. Stool samples were collected and examined by direct wet saline smear. Study population comprised 53.4% male students. None of stool samples were positive for soil-transmitted helminths but 17.4% of students complained of nocturnal itching and parents of 23% of them had seen worms passing out from their children's anus at night. Fourteen stool samples were found to be positive for cyst of Entamoeba coli. Majority of parents (69%) stated that their children always wash their hands with soap and water before meals, whereas 26% stated that their children practice this sometimes. Majority of students (88%) washed their hands after going to the toilet. Almost all students (86%) used water sealed toilets and very few used pit latrines (14%). In this study, 67% of students had received anti-helminthic drugs after the floods. These findings suggest that zero prevalence of helminthic infections could be due to anti-helminthic prophylaxis and good health practices. Further studies should be done in this area with a large sample size to investigate the true prevalence of helminthic infections. Students and parents should be educated on Enterobius vermicularis infection. The source of water supply should be tested for fecal contamination. PMID- 29983715 TI - SHP2-Mediated Signal Networks in Stem Cell Homeostasis and Dysfunction. AB - Stem cells, including embryonic stem cells (ESCs) and adult stem cells, play a central role in mammal organism development and homeostasis. They have two unique properties: the capacity for self-renewal and the ability to differentiate into many specialized cell types. Src homology region 2- (SH2-) containing protein tyrosine phosphatase 2 (SHP-2), a nonreceptor protein tyrosine phosphatase encoded by protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), regulates multicellular differentiation, proliferation, and survival through numerous conserved signal pathways. Gain-of-function (GOF) or loss-of-function (LOF) SHP2 in various cells, especially for stem cells, disrupt organism self balance and lead to a plethora of diseases, such as cancer, maldevelopment, and excessive hyperblastosis. However, the exact mechanisms of SHP2 dysfunction in stem cells remain unclear. In this review, we intended to raise the attention and clarify the framework of SHP2-mediated signal pathways in various stem cells. Establishment of integrated signal architecture, from ESCs to adult stem cells, will help us to understand the changes of dynamic, multilayered pathways in response to SHP2 dysfunction. Overall, better understanding the functions of SHP2 in stem cells provides a new avenue to treat SHP2-associated diseases. PMID- 29983717 TI - Mode of clinical presentation and delayed diagnosis of Turner syndrome: a single Centre UK study. AB - Background: Early diagnosis of girls with Turner syndrome (TS) is essential to provide timely intervention and support. The screening guidelines for TS suggest karyotype evaluation in patients presenting with short stature, webbed neck, lymphoedema, coarctation of aorta or >= two dysmorphic features. The aim of the study was to determine the age and clinical features at the time of presentation and to identify potential delays in diagnosis of TS. Methods: Retrospective data on age at diagnosis, reason for karyotype analysis and presenting clinical features was collected from the medical records of 67 girls with TS. Results: The mean age of diagnosis was 5.89 (+/-5.3) years ranging from pre-natal to 17.9 years (median 4.6 years). 10% were diagnosed antenatally, 16% in infancy, 54% in childhood (1-12 years) and 20% in adolescence (12-18 years). Lymphoedema (27.3%) and dysmorphic features (27.3%) were the main signs that triggered screening in infancy. Short stature was the commonest presenting feature in both childhood (52.8%) and adolescent (38.5%) years. At least 12% of girls fulfilled the criteria for earlier screening but were diagnosed only at a later age (mean age = 8.78 years). 13.4% of patients had classical 45XO karyotype and 52.3% of girls had a variant karyotype. Conclusion: Majority of girls with TS were diagnosed only after the age of 5 years. Short stature triggered evaluation for most patients diagnosed in childhood and adolescence. Lack of dedicated community height-screening programme to identify children with short stature and lack of awareness could have led to potential delays in diagnosing TS. New strategies for earlier detection of TS are needed. PMID- 29983718 TI - Heat-induced necrosis after bronchial thermoplasty: a new concern? AB - Background: Bronchial thermoplasty (BT) is an endoscopic procedure for the treatment of severe refractory asthma, based on the local airways delivery of radio-frequency at 65 degrees C. Several controlled clinical studies demonstrated the effectiveness of BT on clinical outcomes, particularly the reduction of asthma exacerbations. During procedure or shortly after, significant but transient respiratory adverse events have been reported. Case report: We describe the case of a male, caucasian, 56-year-old, non-smoker patient with non allergic severe asthma. A few days after the second BT session performed in the left lower lobe, persistent haemoptysis appeared requiring patient hospitalization. A chest CT scan showed mild varicoid bronchiectasis and distal parenchymal infiltrate in the basal anterior segment of the left lower lobe. At fibreoptic bronchoscopy two small nodular neoformations were observed in sub segmental areas of the same lobe. Histological examination showed mild non specific inflammation of bronchial mucosa, and some large fragments of peribronchial pulmonary parenchyma with an area of haemorrhagic necrosis. The patient was treated empirically with co-amoxiclav, azithromycin and prednisone. A new chest CT showed a complete resolution of the parenchymal opacity. Finally, the patient underwent the third session of BT, without recurrence of haemoptysis or radiological changes. Discussion: Bronchial thermoplasty is a generally safe procedure. To our knowledge this is the first report of necrosis of the treated bronchus and haemoptysis complicating BT after the second session. The pulmonary damage was most likely determined by a thermal shock induced by BT. One hypothesis could be a structural fragility of the treated bronchus, possibly related to bronchiectasis. A technical malfunction of the BT controller or the catheter, causing an excessive energy delivery could not be excluded. Adverse events following BT deserve particular attention but should not discourage clinicians from the application of this promising procedure. PMID- 29983719 TI - Precise Detection of Wrist Pulse Using Digital Speckle Pattern Interferometry. AB - Pulse diagnosis is one of the four diagnostic methods of traditional Chinese medicine. However it suffers from the lack of objective and efficient detection method. We propose a noncontact optical method to detect human wrist pulse, aiming at the precise determination of the temporal and spatial distributions of pulse. The method uses the spatial-carrier digital speckle pattern interferometry (DSPI) to measure the micro/nanoscale skin displacement dynamically. Significant improvements in DSPI measurement have been made to allow the DSPI to detect the comprehensive information of the arterial pulsation at locations of Cun, Guan, and Chi. The experimental results prove that the spatiotemporal distributions of pulse can be obtained by the proposed method. The obtained data can be further used to describe most of the pulse parameters such as rate, rhythm, depth, length, width, and contour. PMID- 29983720 TI - Modernization of Traditional Oriental Medicine: New Dosage Forms and Medical Instruments. PMID- 29983721 TI - A study on the relationship between waist phenotype, hypertriglyceridemia, coronary artery lesions and serum free fatty acids in adult and elderly patients with coronary diseases. AB - Background: Abdominal obesity is an independent risk factor for coronary heart disease (CHD) and high serum triglyceride (TG) and free fatty acid levels may precipitate or aggravate CHD. Methods: We enrolled patients with coronary heart disease in our hospital from October 2008 to July 2009. Patients with high TG and increased WC, i.e. waist phenotype WP were included in group A. In group B, were included patients with high TG but not WP. Group C consisted of patients with WP but not high TG. Finally, Group D was composed of patients without high TG or WP. Serum FFA levels for all patients were measured by ELISA. The relationship between TG levels, WC, FFA levels, and coronary artery score was analysed by a single variable regression. Results: Group A had a significantly higher FFA level than the other groups. Regression analysis showed that FFA, TG, WC, hip circumference, waist-to-height ratio, systolic blood pressure, pulse pressure index, and low-density lipoprotein cholesterol all positively correlated with CAS (r = 0.160 ~ 0.415, P = 0.000 ~ 0.032). After we controlled for traditional risk factors for cardiovascular disease, FFA levels remained positively correlated to the CAS (r = 0.365, P < 0.001). Conclusion: The serum FFA level for patients with complications of both increased WC and high TG levels was significantly higher than that of patients without either of these complications. The close correlation between the CAS and FFA levels showed by regression analysis suggested that inflammation in these patients was more serious. Increased WC and high TG levels as well as FFA level are valuable for the prediction of cardiovascular disease and can be applied as a clinical guidance for early intervention in the treatment of coronary heart diseases. PMID- 29983722 TI - Cannons and sparrows: an exact maximum likelihood non-parametric test for meta analysis of k 2 * 2 tables. AB - Background: The use of meta-analysis to aggregate multiple studies has increased dramatically over the last 30 years. For meta-analysis of homogeneous data where the effect sizes for the studies contributing to the meta-analysis differ only by statistical error, the Mantel-Haenszel technique has typically been utilized. If homogeneity cannot be assumed or established, the most popular technique is the inverse-variance DerSimonian-Laird technique. However, both of these techniques are based on large sample, asymptotic assumptions and are, at best, an approximation especially when the number of cases observed in any cell of the corresponding contingency tables is small. Results: This paper develops an exact, non-parametric test based on a maximum likelihood test statistic as an alternative to the asymptotic techniques. Further, the test can be used across a wide range of heterogeneity. Monte Carlo simulations show that for the homogeneous case, the ML-NP-EXACT technique to be generally more powerful than the DerSimonian-Laird inverse-variance technique for realistic, smaller values of disease probability, and across a large range of odds ratios, number of contributing studies, and sample size. Possibly most important, for large values of heterogeneity, the pre-specified level of Type I Error is much better maintained by the ML-NP-EXACT technique relative to the DerSimonian-Laird technique. A fully tested implementation in the R statistical language is freely available from the author. Conclusions: This research has developed an exact test for the meta-analysis of dichotomous data. The ML-NP-EXACT technique was strongly superior to the DerSimonian-Laird technique in maintaining a pre-specified level of Type I Error. As shown, the DerSimonian-Laird technique demonstrated many large violations of this level. Given the various biases towards finding statistical significance prevalent in epidemiology today, a strong focus on maintaining a pre-specified level of Type I Error would seem critical. PMID- 29983723 TI - Estimating the agreement between the metabolic rate calculated from prediction equations and from a portable indirect calorimetry device: an effort to develop a new equation for predicting resting metabolic rate. AB - Background: Many studies have been performed over time in order to determine the reliability of metabolic rate prediction equations. Purpose: To evaluate the agreement, in terms of bias, absolute bias and accuracy between metabolic rate prediction equations and measured metabolic rate using indirect calorimetry system (IC), investigating also the factors affecting this agreement. Methods: The anthropometric features of 383 Caucasian participants of all Body Mass Index (BMI) classes were recorded and Resting Metabolic Rate (RMR) was measured by using the IC Fitmate portable device. The resulting values were compared with the predictive values of Harris & Benedict, Schofield, Owen, FAO-WHO-UNU, Mifflin and Harrington equations. Results: A closer approximation in agreement was obtained using the Harrington equation (based on BMI, age and gender). The equations using variables, such as weight, height, age and gender demonstrated higher agreement than the equations using merely weight and gender. Higher educational level was associated with normal weight, while higher calorific ratio was found in the class of normal-weighted individuals. An inverse relationship between BetaMUIota and RMR was also observed and a logarithmic equation for calculating RMR was created, which was differentiated in relation to BMI classes, using the weight and gender variables. Conclusion: A better measurement agreement between RMR prediction equations and IC may be achieved due to BMI consideration. The present findings contributed to a better understanding of the measured parameters, confirming the inverse relationship between BMI and RMR. Age group and gender variables may also exert significant role on the bias response of some RMR equations. PMID- 29983724 TI - Relationship of Internet gaming disorder with dissociative experience in Italian university students. AB - The purpose of this study was twofold: (a) to investigate the prevalence of Internet gaming disorder (IGD) among Italian university students and (b) to explore the associations between the former and dissociative phenomena. The sample included 221 college students, 93 males and 128 females, aged between 18 and 25 (M = 21.56; SD = 1.42). They were asked to state their favourite games choice and were administered a demographic questionnaire, the APA symptom checklist based on the diagnostic criteria of IGD in the DSM-5, the Internet Gaming Disorder Scale Short Form (IGD9-SF) and the Italian version of dissociative experience scale for adolescents and young adults. The different game types used are distributed as follows: Massively Multiplayer Online Role Playing Game (30%), flash games (26%), multiplayer games (24%), and online gambling (23%). The results of the study showed a high incidence of Internet gaming disorder risk in college students (84.61%). Specifically, our data confirmed the literature on the incidence of the male gender bias among online players (M = 28.034; SD = 2.213). Thirty-three subjects (31 male and 2 female) on 221 (14.9%) matched five or more criteria for clinical diagnosis of IGD. The data showed a positive correlation between Internet gaming disorder risk and some dissociative experiences: depersonalisation and derealisation (AbII/item6 r = .311; DD/item6 r = .322); absorption and imaginative involvement (AbII/item2 r = .319; AbII/item8 r = .403) and passive influence (PI/item3 r = .304; PI/item4 r = .366; PI/item9 r = .386). This study shedded light on psychopathological aspects that preceded the spread of IGD and encourages the implementation of a programmatic plan of preventative interventions by Italian public institutions, to prevent and tame the spreading of such addictive behaviours. PMID- 29983725 TI - Coherent control of an opsin in living brain tissue. AB - Retinal-based opsins are light-sensitive proteins. The photoisomerization reaction of these proteins has been studied outside cellular environments using ultrashort tailored light pulses1-5. However, how living cell functions can be modulated via opsins by modifying fundamental nonlinear optical properties of light interacting with the retinal chromophore has remained largely unexplored. We report the use of chirped ultrashort near-infrared pulses to modulate light evoked ionic current from Channelrhodopsin-2 (ChR2) in brain tissue, and consequently the firing pattern of neurons, by manipulating the phase of the spectral components of the light. These results confirm that quantum coherence of the retinal-based protein system, even in a living neuron, can influence its current output, and open up the possibilities of using designer-tailored pulses for controlling molecular dynamics of opsins in living tissue to selectively enhance or suppress neuronal function for adaptive feedback-loop applications in the future. PMID- 29983726 TI - "Areas of Worklife scale" (AWS) short version (Spanish): a confirmatory factor analysis based on a secondary school teacher sample. AB - Background: This study examines the construct validity of the Areas of Worklife Short Scale, a practical instrument to measure employees' perceptions of their work environments in the sample of secondary obligatory education teachers in Spain. Methods: Conducted in 33 centers of secondary obligatory education in Spain (N = 677). Confirmatory Factor analysis for 3 different models for the 29 items version and 1 model for the 18-items version was tested. Results: Results confirmed that the short AWS short version had the best fit to the data than any other model proposed (GFI-Satorra-Bentler scaled chi-squared = 320.19, * 2/df = 2.337) and good fit indices (CFI = 0.911; RMSEA = 0.046). Conclusions: This analysis ultimately supports the appropriateness of AWS short version to explore areas of worklife and therefore can indicate the factors that contribute to burnout in the sample of secondary obligatory education teachers in Spain. Therefore it has been confirmed that this tool is able to assess the 6 domains of work environment of secondary schools teachers. PMID- 29983727 TI - Exploring breastfeeding support on social media. AB - Background: Lack of breastfeeding support is often cited by mothers as one of the key reasons for premature weaning. The experiences and perceptions of breastfeeding mothers in a range of contexts and their support needs have been studied, but there has been little exploration of the specific breastfeeding topics that women are investigating via social networking sites (SNSs) such as Facebook, and how breastfeeding peer supporters respond to queries about breastfeeding concerns on a SNS. Methods: This online ethnography took place in the Australian Breastfeeding Association's (ABA) closed Facebook groups. These groups have been created for breastfeeding mothers to seek and provide support to their peers. All wall posts, comments and images for 15 of these groups were captured over a four-week period between 21 July and 17 August 2013. Results: The data were collected on a total of 778 wall posts with a total of 2,998 comments posted into the initial wall posts. Analysis revealed that 165 (21%) of these wall posts were queries and 72 (44%) of the queries were specific breastfeeding questions. Twelve breastfeeding topic areas were identified, and the top three topic areas were further analysed for not only their content but the nature of informational and emotional support provided to the community members. Conclusions: The closed Facebook groups hosted by the ABA provided both informational and emotional support that appeared to be facilitated by an authentic presence from both trained peer breastfeeding counsellors and other mothers. The group administrators played a vital role in both responding to the queries and overseeing the discussions to ensure they adhered to the ABA's Code of Ethics. PMID- 29983728 TI - Acceptability of donor breast milk banking, its use for feeding infants, and associated factors among mothers in eastern Ethiopia. AB - Background: The first priority for infant feeding is to encourage the use of infant's mother's breast milk, but when this is not possible, donated breast milk is the second best option. In developing countries, very few studies have been conducted on the acceptance of donor breast milk. Hence, this study was planned to discover the acceptability of donor breast milk banking, its use for feeding infants, and associated factors among mothers in eastern Ethiopia. Methods: A mixed method study was conducted in eastern Ethiopia from December 2015 to February 2016. Data were collected through a pre-tested structured interview based questionnaire. A total of 1085 mothers participated in the survey and six focus group discussions were held with 33 mothers. Descriptive statistics have been used to report results from the survey and qualitative data were analyzed using the thematic data analysis approach. Results: The study revealed that 119 (11%) of participants were willing to donate breast milk for banking and 165 (15.2%) of mothers were willing to use for feeding infants. The acceptance of donor milk banking was 5.8 times more likely among the mothers who had heard about donor milk banking previously (Adjusted Odds Ratio [AOR] 5.8; 95% Confidence Interval [CI] 3.1, 10.72), 4.2 times more likely among the mothers who heard about wet-nurses (AOR 4.2; 95% CI 2.5, 6.99) and 2 times more likely among mothers who had visited a neonatal intensive care unit (AOR 2; 95% CI 1.1, 3.73). Conclusions: Generally, this study showed that the acceptance of breast milk donation for banking and its use for feeding infants was very low, due to lack of information and misconceptions about the safety of breast milk. Therefore, before initiation of any donor milk banking program awareness should be created about donor breast milk and its safety. PMID- 29983729 TI - Understanding Dynamic Status Change of Hospital Stay and Cost Accumulation via Combining Continuous and Finitely Jumped Processes. AB - The Coxian phase-type models and the joint models of longitudinal and event time have been extensively used in the studies of medical outcome data. Coxian phase type models have the finite-jump property while the joint models usually assume a continuous variation. The gap between continuity and discreteness makes the two models rarely used together. In this paper, a partition-based approach is proposed to jointly model the charge accumulation process and the time to discharge. The key construction of our new approach is a set of partition cells with their boundaries determined by a family of differential equations. Using the cells, our new approach makes it possible to incorporate finite jumps induced by a Coxian phase-type model into the charge accumulation process, therefore taking advantage of both the Coxian phase-type models and joint models. As a benefit, a couple of measures of the "cost" of staying in each medical stage (identified with phases of a Coxian phase-type model) are derived, which cannot be approached without considering the joint models and the Coxian phase-type models together. A two-step procedure is provided to generate consistent estimation of model parameters, which is applied to a subsample drawn from a well-known medical cost database. PMID- 29983730 TI - The therapeutic effect of scalp acupuncture on natal autism and regressive autism. AB - Background: Autism spectrum disorders (ASD) is a common disease and the incidence has been rising constantly. Acupuncture is one of the most widely used complementary and alternative medicine therapies. Despite studies had been done on the effectiveness of acupuncture on ASD children, how factors such as chronological age and the onset pattern influence the effectiveness of the therapy remains unclear. The aim of this retrospective study is to know how symptomatology of ASD alters upon the introduction of scalp acupuncture and how do age and onset type affect the effectiveness of the therapy. Methods: ASD children aged 2-11 years old were invited to join the study. In the course of the investigation, they received a total of 30 sessions of scalp acupuncture therapy. They were then evaluated to compare the performance on various aspects before and after the treatment. The influence on the therapeutic effect by factors including chorological age and onset pattern were further taken into consideration and analyzed. In addition, investigation on the relationship between allergies and onset pattern of ASD was performed by statistically analyzing the received epidemiologic data from the participants. Results: 68 children with ASD participated in the study. It is found that the significant effective rate of scalp acupuncture on ASD is 97%. Scalp acupuncture can improve verbal communication problems the most while noise sensitivity improves the least. The therapeutic effectiveness decreases with increasing age and children with natal autism benefit more from acupuncture than those with regressive autism. In the latter part of the study, we observe a positive correlation between the family history of allergy and onset pattern. Conclusion: Scalp acupuncture is an effective treatment for alleviating the symptomatology of ASD. The therapeutic effectiveness is expected to be higher for those patients with natal or early onset of the disorder, and at a younger age when they receive the therapy. The study result helps to formulate an ideal regimen for ASD patients and allow therapists and parents to make appropriate expectation towards the therapeutic outcome of acupuncture. Early intervention of scalp acupuncture therapy recommended. The relationship between the family history of allergic disorder and the onset type of ASD hints that the etiologies of natal and regressive ASD are discrete. It shows a great significance in differentiating the onset pattern in carrying out clinical assessments or researches on ASD patients.Trial registration This retrospective study was approved by the Committee on the Use of Human and Animal Subjects in Teaching and Research, Hong Kong Baptist University on 4th Aug 2017. The retrospectively registered number is HASC/Student/17 18/0115. PMID- 29983731 TI - Global ecological regionalization of 15 Illicium species: nature sources of shikimic acid. AB - Background: Illicium plants are relevant officinal and ornamental species that are native in Eastern Asia, and they are the main sources of shikimic acid. Shikimic acid is an important component of Tamiflu, which is recognized for its ability to resist avian influenza by the World Health Organization. To determine areas where 15 Illicium species can be grown and to understand the importance of species diversity, we should enhance the prediction of suitable areas. Methods: In this study, the global potential distribution of 15 Illicium species was predicted using a geographic information system for global medicinal plants. Results: Results showed that the possible suitable areas for these plants in China covered 1357.68 * 104 km2 (56%), and the second-largest area spanning 527.42 * 104 km2 was found in the United States. Illicium verum Hook, an edible species with the highest shikimic acid content among them, grew in areas of 59.92 * 104 (48%), 64.04 * 104 (19%), and 60.53 * 104 km2(18%) in China, the United States, and Brazil, respectively. Illicium.difengpi B. N. Chamg, an endangered species, was distributed in an area of 19.03 * 104 km2 or 95% of the total area in China. Conclusions: This research provided a guarantee for the demand of Tamiflu, presented strategies that helped protect endangered species, and provided a reference for species cultivation and introduction. PMID- 29983732 TI - Corni Fructus: a review of chemical constituents and pharmacological activities. AB - Cornus officinalis Sieb. et Zucc. is part of the genus Cornus of the family Cornaceae. Ripening and dry fruits (Corni Fructus) are recognized as an essential herb medicine in the traditional Chinese medicine (TCM) and have been widely used for over 2000 years. This review provides a comprehensive summary of Corni Fructus (CF), including the botany, phytochemistry, traditional use, and current pharmacological activities. According to the basic theory of TCM, CF usually participates in various Chinese medicinal formulae to exert the essential roles in replenishing liver and kidney, arresting seminal emission and sweat. Based on modern pharmacological studies, about 90 compounds have been isolated and identified from CF. In vivo and in vitro experimental studies indicate that CF exhibits extensive pharmacological activities including hypoglycemic, antioxidant, anti-inflammatory, anticancer, neuroprotective, hepatoprotective, and nephroprotective activities. However, only about 18% of chemical constituents in CF were tested. It means the potential pharmacological activities and clinical values of CF need to be further investigated. PMID- 29983733 TI - Performance-based financing in three humanitarian settings: principles and pragmatism. AB - Background: Performance based financing (PBF) has been increasingly implemented across low and middle-income countries, including in fragile and humanitarian settings, which present specific features likely to require adaptation and to influence implementation of any health financing programme. However, the literature has been surprisingly thin in the discussion of how PBF has been adapted to different contexts, and in turn how different contexts may influence PBF. With case studies from three humanitarian settings (northern Nigeria, Central African Republic and South Kivu in the Democratic Republic of Congo), we examine why and how PBF has emerged and has been adapted to those unsettled and dynamic contexts, what the opportunities and challenges have been, and what lessons can be drawn. Methods: Our comparative case study is based on data collected from a document review, 35 key informant interviews and 16 focus group discussions with stakeholders at national and subnational level in the three settings. Data were analysed in order to describe and compare each setting in terms of underlying fragility features and their implications for the health system, and to look at how PBF has been adopted, implemented and iteratively adapted to respond to acute crisis, deal with other humanitarian actors and involve local communities. Results: Our analysis reveals that the challenging environments required a high degree of PBF adaptation and innovation, at times contravening the so-called 'PBF principles' that have become codified. We develop an analytical framework to highlight the key nodes where adaptations happen, the contextual drivers of adaptation, and the organisational elements that facilitate adaptation and may sustain PBF programmes. Conclusions: Our study points to the importance of pragmatic adaptation in PBF design and implementation to reflect the contextual specificities, and identifies elements (such as, organisational flexibility, local staff and knowledge, and embedded long-term partners) that could facilitate adaptations and innovations. These findings and framework are useful to spark a reflection among PBF donors and implementers on the relevance of incorporating, reinforcing and building on those elements when designing and implementing PBF programmes. PMID- 29983734 TI - Perceptions about pasung (physical restraint and confinement) of schizophrenia patients: a qualitative study among family members and other key stakeholders in Bogor Regency, West Java Province, Indonesia 2017. AB - Background: The UN resolution recommends treating all mentally ill patients with humanity and respect. However, social stigma continues to prevail for patients with schizophrenia. Physical restraint and confinement of the mentally ill is a well-known phenomenon in Indonesia and is termed as pasung. Objective: To explore the perceptions of family members of patients of schizophrenia and other key stakeholders concerning pasung in Bogor Regency, West Java Province 2017. Methods: This qualitative exploratory study was conducted in Bogor Regency, West Java Province from May to June 2017. This study involved 12 key stakeholders including family members, neighbors, community leaders, and mental health officers. In-depth interviews were conducted with family members (n = 3) who practiced pasung for patients with schizophrenia and key informant interviews of neighbors, community leaders (two household heads and one from a health cadre) (n = 3) and mental health officers of puskesmas (three midwives). Data triangulation was performed by interviewing residents and mental health workers. Content analysis was conducted and themes were identified based on valid inference and interpretation. Results: Family members and society in general perceived that pasung is necessary for security reasons due to the patient's aggressive behavior such as physical violence to neighbors, stealing food etc. According to community leaders, families often do not respond to patient's request to be released from pasung. Family members had financial constraints to seek mental healthcare and were also dissatisfied with available services. Healthcare providers highlighted the poor knowledge and prevailing misconceptions about schizophrenia in the community. Conclusion: Concurrent efforts to strengthen basic mental health services and health education regarding schizophrenia, prevalent misconceptions, and importance of timely and appropriate treatment are needed, especially in rural settings. PMID- 29983735 TI - Child and adolescent mental health policy in South Africa: history, current policy development and implementation, and policy analysis. AB - Background: Mental health problems represent the greatest global burden of disease among children and adolescents. There is, however, lack of policy development and implementation for child and adolescent mental health (CAMH), particularly in low- and middle-income countries (LMICs) where children and adolescents represent up to 50% of populations. South Africa, an upper-middle income country is often regarded as advanced in health and social policy-making and implementation in comparison to other LMICs. It is, however, not clear whether this is the case for CAMH. The national child and adolescent mental health policy framework of 2003 was developed to guide the establishment of CAMH policies provincially, using a primary care and intersectoral approach. This policy provided a framework for the nine South African provinces to develop policies and implementation plans, but it is not known whether this has happened. The study sought to examine the history and current state of CAMH policy development and implementation, and to perform a systematic analysis of all available CAMH service-related policies. Methods: A comprehensive search was performed to identify all provincial mental health and comprehensive general health policies across South African provinces. The Walt and Gilson policy triangle framework (1994) was used for analysis. Results: No South African province had a CAMH policy or identifiable implementation plans to support the national CAMH policy. Provincial comprehensive general health policies addressed CAMH issues only partially and were developed mainly to address the challenges with HIV/AIDS, TB, maternal and child mortality and adherence to the millennium development goals. The process of policy development was typically a consultative process with internal and external stakeholders. There was no evidence that CAMH professionals and/or users were included in the policy development process. Conclusions: In spite of South Africa's upper-middle income status, the absence of any publically-available provincial CAMH policy documents was concerning, but in keeping with findings from other LMICs. Our results reinforce the neglect of CAMH even at policy level in spite of the burden of CAMH disorders. There is an urgent need to develop and implement CAMH policies in South Africa and other LMICs. Further research will be required to identify and explore the barriers to policy development and implementation, and to service development and scale-up in CAMH. PMID- 29983737 TI - Biomimicry and Bioinspiration as Tools for the Design of Innovative Materials and Systems. PMID- 29983736 TI - Childhood ADHD and treatment outcome: the role of maternal functioning. AB - Background: Relatively little is known about the role of maternal functioning in terms of attention deficit hyperactivity disorder (ADHD) symptoms, attachment style and resilience as predictive factors for treatment outcome when offspring are diagnosed with ADHD. Objective: To investigate whether maternal functioning is associated with treatment outcome in children with ADHD. Methods: The study formed part of a larger naturalistic observational study of children with ADHD. A battery of self-report measures was used to assess selected factors in maternal functioning at the point of referral (baseline data); adult ADHD-symptoms, adult attachment style and adult resilience. Associations between these domains and child treatment response were subsequently examined in a 1-year follow up. Results: Maternal ADHD-symptoms and degree of resilience were significantly correlated to symptom reduction in offspring diagnosed with ADHD. However, the association between maternal attachment style and child treatment response as measured by the ADHD-RS did not reach statistical significance. Conclusion: To our knowledge, this is the first study to consider potential protective factors along with risk factors in maternal functioning and the impact on child treatment outcome. The study contributes to our knowledge of the potential role of maternal functioning in treatment outcome for children with ADHD. PMID- 29983738 TI - Automated Techniques for the Interpretation of Fetal Abnormalities: A Review. AB - Ultrasound (US) image segmentation methods, focusing on techniques developed for fetal biometric parameters and nuchal translucency, are briefly reviewed. Ultrasound medical images can easily identify the fetus using segmentation techniques and calculate fetal parameters. It can timely find the fetal abnormality so that necessary action can be taken by the pregnant woman. Firstly, a detailed literature has been offered on fetal biometric parameters and nuchal translucency to highlight the investigation approaches with a degree of validation in diverse clinical domains. Then, a categorization of the bibliographic assessment of recent research effort in the segmentation field of ultrasound 2D fetal images has been presented. The fetal images of high-risk pregnant women have been taken into the routine and continuous monitoring of fetal parameters. These parameters are used for detection of fetal weight, fetal growth, gestational age, and any possible abnormality detection. PMID- 29983739 TI - Growth promotion of three microalgae, Chlamydomonas reinhardtii, Chlorella vulgaris and Euglena gracilis, by in situ indigenous bacteria in wastewater effluent. AB - Background: Microalgae are a promising biomass feedstock for biofuels production. The use of wastewater effluent as a nutrient medium would improve the economics of microalgal biofuels production. Bacterial communities in aquatic environments may either stimulate or inhibit microalgal growth. Microalgal productivity could be enhanced if the positive effects of indigenous bacteria could be exploited. However, much is unknown about the effects of indigenous bacteria on microalgal growth and the characteristics of bacterial communities associated with microalgae in microalgae-effluent culture. To assess the effects of the indigenous bacteria in wastewater effluent on microalgal growth, three microalgae, Chlamydomonas reinhardtii, Chlorella vulgaris, and Euglena gracilis, were cultured in two municipal wastewater effluents and one swine wastewater effluent with and without indigenous bacteria for 7 days. Results: All microalgae grew better in all effluents with indigenous bacteria than without bacteria. Biomass production of C. reinhardtii, C. vulgaris, and E. gracilis increased > 1.5, 1.8-2.8, and > 2.1-fold, respectively, compared to the axenic cultures of each microalga. The in situ indigenous bacterial communities in the effluents therefore promoted the growth of the three microalgae during 7-day cultures. Furthermore, the total numbers of bacterial 16S rRNA genes in the 7-day microalgae-effluent cultures were 109-793 times the initial numbers. These results suggest that the three microalgae produced and supplied organic carbon that supported bacterial growth in the effluent. At the phylum and class levels, Proteobacteria (Alphaproteobacteria and Betaproteobacteria) and Bacteroidetes (Sphingobacteriia and Saprospirae) were selectively enriched in all microalgae effluent cultures. The enriched core bacterial families and genera were functions of the microalgal species and effluents. These results suggest that certain members of the bacterial community promote the growth of their "host" microalgal species. Conclusion: To enhance their own growth, microalgae may be able to selectively stimulate specific bacterial groups from among the in situ indigenous bacterial community found in wastewater effluent (i.e., microalgae growth promoting bacteria: MGPB). The MGPB from effluent cultures could be used as "probiotics" to enhance microalgal growth in effluent culture. Wastewater effluent may therefore be a valuable resource, not only of nutrients, but also of MGPB to enable more efficient microalgal biomass production. PMID- 29983740 TI - Stepwise metabolic engineering of Escherichia coli to produce triacylglycerol rich in medium-chain fatty acids. AB - Background: Triacylglycerols (TAGs) rich in medium-chain fatty acids (MCFAs, C10 14 fatty acids) are valuable feedstocks for biofuels and chemicals. Natural sources of TAGs rich in MCFAs are restricted to a limited number of plant species, which are unsuitable for mass agronomic production. Instead, the modification of seed or non-seed tissue oils to increase MCFA content has been investigated. In addition, microbial oils are considered as promising sustainable feedstocks for providing TAGs, although little has been done to tailor the fatty acids in microbial TAGs. Results: Here, we first assessed various wax synthase/acyl-coenzyme A:diacylglycerol acyltransferases, phosphatidic acid phosphatases, acyl-CoA synthetases as well as putative fatty acid metabolism regulators for producing high levels of TAGs in Escherichia coli. Activation of endogenous free fatty acids with tailored chain length via overexpression of the castor thioesterase RcFatB and the subsequent incorporation of such fatty acids into glycerol backbones shifted the TAG profile in the desired way. Metabolic and nutrient optimization of the engineered bacterial cells resulted in greatly elevated TAG levels (399.4 mg/L) with 43.8% MCFAs, representing the highest TAG levels in E. coli under shake flask conditions. Engineered cells were observed to contain membrane-bound yet robust lipid droplets. Conclusions: We introduced a complete Kennedy pathway into non-oleaginous E. coli towards developing a bacterial platform for the sustainable production of TAGs rich in MCFAs. Strategies reported here illustrate the possibility of prokaryotic cell factories for the efficient production of TAGs rich in MCFAs. PMID- 29983741 TI - Effect of overliming and activated carbon detoxification on inhibitors removal and butanol fermentation of poplar prehydrolysates. AB - Background: Biomass prehydrolysates from dilute acid pretreatment contain a considerable amount of fermentable sugars for biofuels production. However, carbonyl degradation compounds present severe toxicity to fermentation microbes. Furans (such as furfural and hydroxymethylfurfural), aliphatic acids (such as acetic acid, formic acid and levulinic acid) and phenolic compounds (such as vanillin and syringaldehyde) have been suggested to be the main inhibitors in biomass prehydrolysates. However, no single compound has been determined as the dominant toxic inhibitor. The effects of various detoxification methods on inhibitors removal have not been fully understood. Results: The effects of overliming and activated carbon (AC) detoxification on the removal of inhibitors and butanol fermentation of the poplar prehydrolysates were investigated. Gas chromatography-mass spectrometry (GC/MS) was used to identify and quantify 46 carbonyl compounds as potential inhibitors. It was observed that overliming and AC treatment alone did not make the prehydrolysates fermentable with Clostridium saccharobutylicum. The sequential overliming and AC resulted in a remarkable fermentability and a high butanol yield at 0.22 g g-1 sugar. The inhibitor removal in the prehydrolysates treated by overliming and AC was also examined by GC/MS. Overliming removed 75.6% of furan derivatives and 68.1% of aromatic monomers. In comparison, AC (5.0% w/v) removed 77.9% of furan derivatives and 98.6% of aromatic monomers. In addition, overliming removed much more 2,5 furandicarboxyaldehyde, 5-ethylfuran-2-carbaldehyde and 2,5-hexanedione than AC did. On the contrary, AC could remove considerably more phenolic acids than overliming. In the sequential detoxification, both dialdehydes/diketones and phenolic acids were extensively removed. This could be the main reason why the sequential detoxification enabled a remarkable ABE fermentation for the prehydrolysates. Conclusions: This study indicated that the effect of overliming and AC treatment on inhibitors removal was related to their chemical structures. Overliming removed more dialdehydes and diketones than AC treatment, while AC removed more phenolic acids than overliming. Sequential overliming and AC treatment were required to make the prehydrolysates fermentable with C. saccharobutylicum. The study also suggested different detoxification method was needed for ABE fermentation of the prehydrolysate as compared to ethanol fermentation. PMID- 29983742 TI - Molecular characterization of a novel chitinase CmChi1 from Chitinolyticbacter meiyuanensis SYBC-H1 and its use in N-acetyl-d-glucosamine production. AB - Background: N-acetyl-d-glucosamine (GlcNAc) possesses many bioactivities that have been used widely in many fields. The enzymatic production of GlcNAc is eco friendly, with high yields and a mild production process compared with the traditional chemical process. Therefore, it is crucial to discover a better chitinase for GlcNAc production from chitin. Results: A novel chitinase gene (Cmchi1) cloned from Chitinolyticbacter meiyuanensis SYBC-H1 and expressed in Escherichia coli BL21(DE3) cells. The recombinant enzyme (CmChi1) contains a glycosyl hydrolase family 18 catalytic module that shows low identity (12-27%) with the corresponding domain of the well-characterized chitinases. CmChi1 was purified with a recovery yield of 89% by colloidal chitin affinity chromatography, whereupon it had a specific activity of up to 15.3 U/mg. CmChi1 had an approximate molecular mass of 70 kDa after the sodium dodecyl sulfate polyacrylamide gel electrophoresis, and its optimum activity for colloidal chitin (CC) hydrolysis occurred at pH 5.2 and 50 degrees C. Furthermore, CmChi1 exhibited kcat/Km values of 7.8 +/- 0.11 mL/s/mg and 239.1 +/- 2.6 mL/s/MUmol toward CC and 4-nitrophenol N,N'-diacetyl-beta-d-chitobioside [p-NP-(GlcNAc)2], respectively. Analysis of the hydrolysis products revealed that CmChi1 exhibits exo-acting, endo-acting and N-acetyl-beta-d-glucosaminidase activities toward N acetyl chitooligosaccharides (N-acetyl CHOS) and CC substrates, behavior that makes it different from typical reported chitinases. As a result, GlcNAc could be produced by hydrolyzing CC using recombinant CmChi1 alone with a yield of nearly 100% and separated simply from the hydrolysate with a high purity of 98%. Conclusion: The hydrolytic properties and good environmental adaptions indicate that CmChi1 has excellent potential in commercial GlcNAc production. This is the first report on exo-acting, endo-acting and N-acetyl-beta-d-glucosaminidase activities from Chitinolyticbacter species. PMID- 29983743 TI - A pyruvate carbon flux tugging strategy for increasing 2,3-butanediol production and reducing ethanol subgeneration in the yeast Saccharomyces cerevisiae. AB - Background: The yeast Saccharomyces cerevisiae is a promising host cell for producing a wide range of chemicals. However, attempts to metabolically engineer Crabtree-positive S. cerevisiae invariably face a common issue: how to reduce dominant ethanol production. Here, we propose a yeast metabolic engineering strategy for decreasing ethanol subgeneration involving tugging the carbon flux at an important hub branching point (e.g., pyruvate). Tugging flux at a central glycolytic overflow metabolism point arising from high glycolytic activity may substantially increase higher alcohol production in S. cerevisiae. We validated this possibility by testing 2,3-butanediol (2,3-BDO) production, which is routed via pyruvate as the important hub compound. Results: By searching for high activity acetolactate synthase (ALS) enzymes that catalyze the important first step reaction in 2,3-BDO biosynthesis, and tuning several fermentation conditions, we demonstrated that a stronger pyruvate pulling effect (tugging of pyruvate carbon flux) is very effective for increasing 2,3-BDO production and reducing ethanol subgeneration by S. cerevisiae. To further confirm the validity of the pyruvate carbon flux tugging strategy, we constructed an evolved pyruvate decarboxylase (PDC)-deficient yeast (PDCDelta) strain that lacked three isozymes of PDC. In parallel with re-sequencing to identify genomic mutations, liquid chromatography-tandem mass spectrometry analysis of intermediate metabolites revealed significant accumulation of pyruvate and NADH in the evolved PDCDelta strain. Harnessing the high-activity ALS and additional downstream enzymes in the evolved PDCDelta strain resulted in a high yield of 2,3-BDO (a maximum of 0.41 g g-1 glucose consumed) and no ethanol subgeneration, thereby confirming the utility of our strategy. Using this engineered strain, we demonstrated a high 2,3 BDO titer (81.0 g L-1) in a fed-batch fermentation using a high concentration of glucose as the sole carbon source. Conclusions: We demonstrated that the pyruvate carbon flux tugging strategy is very effective for increasing 2,3-BDO production and decreasing ethanol subgeneration in Crabtree-positive S. cerevisiae. High activity of the common first-step enzyme for the conversion of pyruvate, which links to both the TCA cycle and amino acid biosynthesis, is likely important for the production of various chemicals by S. cerevisiae. PMID- 29983744 TI - Efficient heterologous expression of an alkaline lipase and its application in hydrolytic production of free astaxanthin. AB - Background: Astaxanthin, a naturally occurring carotenoid pigment molecule, displays strong antioxidant, anti-cancer, and immunity-enhancing properties, and is often utilized in food, biomedical, cosmetic, and other industries. Free astaxanthin has better solubility than astaxanthin esters (Ast-E), and is a useful auxiliary ingredient in health foods and medicines. Our goal was to establish an improved enzymatic method for preparation of free astaxanthin from natural sources (e.g., the microalga Haematococcus pluvialis), to expand the potential applications of free astaxanthin. Results: The alkaline lipase gene proalip and its propeptide were cloned and successfully fusion-expressed in Pichia pastoris X-33. The recombinant lipase was termed Lipase-YH. Through optimization of culture conditions (medium formulation, pH, added methanol concentration), cell growth (OD600) and secreted enzyme activity respectively reached to 280 and 2050 U/mL in a 50-L autofermentor. Activity of Lipase-YH enzyme powder was about 40,000 U/g. Hydrolysis of Ast-E (extracted from H. pluvialis) by Lipase-YH occurred in aqueous phase, and reaction conditions were optimized based on emulsification method and enzyme/substrate ratio. The highest enzymatic reaction rate was observed for substrate concentration 200 MUg/mL, with maximal free astaxanthin yield (80%) at 1 h, and maximal Ast-E hydrolysis rate 96%, as confirmed by TLC, HPLC, and mass spectroscopy. Conclusion: A novel, efficient enzymatic process was developed for production of free astaxanthin through hydrolysis of Ast-E. Lipase activity was enhanced, and production cost was greatly reduced. The unique structure of free astaxanthin allows linkage to various functional compounds, which will facilitate development of novel pharmaceutical and food products in future studies. PMID- 29983745 TI - An improved technical trick for identification of the thoracodorsal nerve during axillary clearance surgery: a cadaveric dissection study. AB - Background: Accurate anatomical landmarks to locate the thoracodorsal nerve are important in axillary clearance surgery. Methods: Twenty axillary dissections were carried out on ten preserved Sri Lankan cadavers. Cadavers were positioned dorsal decubitus with upper limbs abducted to 900. An incision was made in the upper part of the anterior axillary line. The lateral thoracic vein was identified and traced bi-directionally. The anatomical location of the thoracodorsal nerve was studied in relation to the lateral border of pectoralis minor and from a point along the lateral thoracic vein, 2 cm inferior to its confluence with the axillary vein. Results: The lateral thoracic vein was invariably present in all the specimens. All the lateral thoracic veins passed lateral to the lateral border of pectoralis minor except in one specimen, where the lateral thoracic vein passed along its lateral border. The thoracodorsal nerve was consistently present posterolateral to the lateral thoracic vein. The mean distance to the lateral thoracic vein from the lateral border of pectoralis minor was 28.7 +/- 12.6 mm. The mean horizontal distance, depth, and displacement, from a point along the lateral thoracic vein, 2 cm inferior to its confluence with the axillary vein to the thoracodorsal nerve were 14.5 +/- 8.9 mm, 19.7 +/- 7.3 mm and 25 +/- 5 mm respectively. The thoracodorsal nerve was found in a posterolateral direction, at a 540 +/- 120 angle to the horizontal plane, 95% of the time. Conclusions: The lateral thoracic vein is an accurate guide to the thoracodorsal nerve. We recommend exploring for the thoracodorsal nerve from a point 2 cm from the confluence of the lateral thoracic vein and the axillary vein for a distance of 25 +/- 5 mm in a posterolateral direction, at a 540 +/- 120 angle to the horizontal plane. PMID- 29983747 TI - Integrative analysis of gene expression and methylation data for breast cancer cell lines. AB - Background: The deadly costs of cancer and necessity for an accurate method of early cancer detection have demanded the identification of genetic and epigenetic factors associated with cancer. DNA methylation, an epigenetic event, plays an important role in cancer susceptibility. In this paper, we use DNA methylation and gene expression data integration and pathway analysis to further explore and understand the complex relationship between methylation and gene expression. Results: Through linear modeling and analysis of variance, we obtain genes that show a significant correlation between methylation and gene expression. We then examine the functions and relationships of these genes using bioinformatic tools and databases. In particular, using ConsensusPathDB, we analyze the networks of statistically significant genes to identify hub genes, genes with a large number of links to other genes. We identify eight major hub genes, all in strong association with cancer susceptibility. Through further analysis of the function, gene expression level, and methylation level of these hub genes, we conclude that they are novel potential biomarkers for breast cancer. Conclusions: Our findings have various implications for cancer screening, early detection methods, and potential novel treatments for cancer. Researchers can also use our results to develop more effective methods for cancer study. PMID- 29983746 TI - Measuring associations between the microbiota and repeated measures of continuous clinical variables using a lasso-penalized generalized linear mixed model. AB - Background: Human microbiome studies in clinical settings generally focus on distinguishing the microbiota in health from that in disease at a specific point in time. However, microbiome samples may be associated with disease severity or continuous clinical health indicators that are often assessed at multiple time points. While the temporal data from clinical and microbiome samples may be informative, analysis of this type of data can be problematic for standard statistical methods. Results: To identify associations between microbiota and continuous clinical variables measured repeatedly in two studies of the respiratory tract, we adapted a statistical method, the lasso-penalized generalized linear mixed model (LassoGLMM). LassoGLMM can screen for associated clinical variables, incorporate repeated measures of individuals, and address the large number of species found in the microbiome. As is common in microbiome studies, when the number of variables is an order of magnitude larger than the number of samples LassoGLMM can be imperfect in its variable selection. We overcome this limitation by adding a pre-screening step to reduce the number of variables evaluated in the model. We assessed the use of this adapted two-stage LassoGLMM for its ability to determine which microbes are associated with continuous repeated clinical measures.We found associations (retaining a non-zero coefficient in the LassoGLMM) between 10 laboratory measurements and 43 bacterial genera in the oral microbiota, and between 2 cytokines and 3 bacterial genera in the lung. We compared our associations with those identified by the Wilcoxon test after dichotomizing our outcomes and identified a non-significant trend towards differential abundance between high and low outcomes. Our two-step LassoGLMM explained more of the variance seen in the outcome of interest than other variants of the LassoGLMM method. Conclusions: We demonstrated a method that can account for the large number of genera detected in microbiome studies and repeated measures of clinical or longitudinal studies, allowing for the detection of strong associations between microbes and clinical measures. By incorporating the design strengths of repeated measurements and a prescreening step to aid variable selection, our two-step LassoGLMM will be a useful analytic method for investigating relationships between microbes and repeatedly measured continuous outcomes. PMID- 29983748 TI - An anatomically-based masking protocol for the assessment of in-shoe plantar pressure measurement of the forefoot. AB - Background: The area beneath the metatarsal heads is a common location of foot pain, which is often associated with high plantar pressures. Current plantar pressure assessment protocols focus mainly on the gross area of the forefoot with minimal attention paid to specific areas such as the metatarsal heads. The aim of this study was to develop and assess a new anatomically-based masking protocol that is clinically relevant to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. Methods: Initially, we developed a masking protocol to measure forefoot plantar pressure during shod conditions based on the anatomical positions of the metatarsal heads. This new masking protocol divided the forefoot into three sub-areas (proximal, beneath, and distal to the metatarsal heads) as determined by the position of each metatarsal head. Following development of the new masking protocol, we compared the new protocol against a traditional protocol, which defines the forefoot as between 51 and 81% of the foot length. To compare the two masking protocols, we tested two experimental conditions: (i) a control condition (i.e. no metatarsal pad), and (ii) a metatarsal pad condition. We then compared plantar pressure differences between the two experimental conditions for the two masking protocols. Participants for this component of the study included 36 community dwelling older adults (mean age 75.6 years +/-5.4) with a history of forefoot pain. Forefoot plantar pressure data were measured while walking using the pedar(r)-X in-shoe system. Peak pressure, maximum force and contact area at the time of peak pressure were determined and results were compared between the two masking protocols. Results: The traditional masking protocol showed that the metatarsal pad significantly decreased peak pressure and increased contact area in the forefoot area (i.e. within the entire mask area), but maximum force was not significantly different between the two conditions. In contrast, the newly developed anatomically-based masking protocol indicated that the metatarsal pad decreased peak plantar pressures distal to and beneath the metatarsal heads by increasing force and contact area proximal to the metatarsal heads. Conclusions: An anatomically-based masking protocol that is clinically relevant was developed to assess forefoot plantar pressure during shod conditions based on the anatomical positions of metatarsal heads. We propose that the new forefoot masking protocol will provide greater interpretability of forefoot plantar pressure data, which will aid clinicians and researchers for diagnostic, prognostic and therapeutic purposes. PMID- 29983749 TI - Effect of knee unloading shoes on regional plantar forces in people with symptomatic knee osteoarthritis - an exploratory study. AB - Background: Knee 'unloading' footwear can reduce the external knee adduction moment in people with knee osteoarthritis, yet effects of these shoes on regional plantar forces are unknown. We evaluated the effects of unloading shoes on in shoe regional plantar forces, and whether measures of foot posture and/or mobility moderate these effects in people with symptomatic knee osteoarthritis. Methods: In this exploratory study 21 participants underwent testing while wearing knee unloading shoes (ASICS GEL-Melbourne OA) and conventional shoes in random order. Peak total forces were compared across conditions for: lateral heel, medial heel, lateral forefoot, and medial forefoot. Arch index, centre of pressure position and medial-lateral heel peak force ratio were also evaluated. Foot posture, foot mobility magnitude and navicular drop were separately added to the mixed linear model to investigate if these modified the effect of footwear on outcomes. Results: Unloading shoes significantly increased lateral heel and lateral forefoot force (12.9 and 20.2% respectively, all P < 0.001), with concurrent decreases in the medial heel (8.9%, P = 0.001) and medial forefoot (9.9%, P = 0.005). Unloading shoes significantly shifted the centre of pressure anteriorly (4.7%, P < 0.001) and laterally (5.6%, P = 0.034), but did not affect the arch index (8.7%, P = 0.093). Foot posture, foot mobility magnitude and navicular drop did not moderate the effect of footwear on outcomes. Conclusion: Compared to conventional shoes, unloading shoes caused a lateral shift in foot pressure and force patterns. Although these effects were not moderated by foot posture, FMM or navicular drop, variability in the individual increases in lateral heel force suggests participant characteristics other than foot posture may play a role. Trial registration: ACTRN12613000851763. Registered 02 August 2013. PMID- 29983750 TI - ESBL-plasmid carriage in E. coli enhances in vitro bacterial competition fitness and serum resistance in some strains of pandemic sequence types without overall fitness cost. AB - Background: Extended spectrum beta lactamase (ESBL)-producing extraintestinal pathogenic Escherichia coli infections are of global interest because of their clinical and economic impact. The ESBL resistance genes disseminate through plasmids, and are found in successful global lineages such as ST131 and ST648. The carriage of plasmids has been suggested to result in a fitness burden, but recently it was shown that ESBL-plasmids enhanced virulence in pandemic ST131 and ST648 lineages without affecting their fitness. Herein, we investigated the influence of ESBL-plasmids on bacterial competition and serum resistance, both of which are essential characteristics of ExPEC during infections. Methods: Triplets of ESBL-plasmid-carrying wildtype (WT), plasmid-cured variant (PCV) and transformant (T) of five ExPEC strains of ST131 and ST648 were used for bacterial competition experiments with colicin-producing commensal E. coli, competitive adhesion experiments and serum survival. In addition, resilience after SDS, acid, osmotic challenges and RNA sequence data were analyzed. Results: In all five strains tested, ESBL-plasmid carriage did not negatively influence E. coli fitness in direct bacterial competition with commensal E. coli in vitro. That is, WTs did not show any disadvantages when compared to their isogenic plasmid-free PCV. For one strain we even found the opposite as PCV17433 was out-competed by a commensal strain, which suggests an even protective role of the ESBL-plasmid carried by the WT17433. Similarly, in the serum-resistance experiments, the PCVs of two strains (PCV17433 and PCV17887) were more sensitive to serum, unlike WTs and Ts. The observed inter-strain differences could be explained by the different genetic content of plasmids carried in those strains. Conclusions: Overall, we found no compelling evidence for an increased burden resulting from the carriage of ESBL-plasmids in the absence of antimicrobial selection pressure in the strains of pandemic ST131 and ST648; rather, the possession of certain ESBL plasmids was beneficial for some strains in regarding competition fitness and serum survival. PMID- 29983751 TI - Diabetic retinopathy among Brazilian Xavante Indians. AB - Background: To describe the frequency of diabetic retinopathy (DR) and its associated variables in Brazilian Xavante Indians. Methods: A population-based survey carried out in two Xavante Reservations between 2008 and 2012, included 948 Indians aged 20 years or more, identified 246 individuals with type 2 diabetes. A non-probabilistic cluster sample of 140 diabetic individuals were submitted to ophthalmologic examination. Due to operational conditions and to optimize the field work, only the larger Xavante villages were included. Ophthalmologic examinations were performed during one trip to each reservation, in their villages and consisted of measurement visual acuity, anterior segment biomicroscopy, applanation tonometry, and direct and indirect ophthalmoscopy. Results: The frequency of DR was 19.3%, distributed as follows: mild non proliferative retinopathy in nine (33.3%) subjects, moderate in nine (33.3%), severe in six (22.3%), very severe in two (7.4%), and high-risk proliferative DR in one (3.7%). The occurrence of DR was higher among those with a longer duration of diabetes, higher levels of glycated hemoglobin (HbA1c) and fasting glucose, papillary excavation >= 0.5, and among individuals in older age group. Using the log-binomial regression model, diabetes duration > 24 months and HbA1c >= 6.5% were significantly associated with the occurrence of DR. Conclusions: The presence of DR (19.3%) in Xavante Indians is an alert for health care providers for this population, since diabetes is a new disease among them. Its association with disease duration, high levels of HbA1c and blood glucose calls attention for the necessity of more actions to improve diabetes control in this recently contacted ethnic group that needs particular attention. PMID- 29983753 TI - Changing Trends in the Treatment of Mandibular Fracture. PMID- 29983752 TI - Association between dietary protein intake and type 2 diabetes varies by dietary pattern. AB - Background: Epidemiological studies have demonstrated that high total protein intake was related to type 2 diabetes mellitus (T2DM) risks. However, few studies considered the impact of dietary pattern. Objective: We examined the associations between protein intake and T2DM in different dietary patterns. Methods: We used the demographic and dietary information of adults aged 18-75 years from the China Health and Nutrition Survey (2009), consisting of 4113 women and 4580 men. Dietary data was collected by using 24-h recalls combined with a food inventory for 3 consecutive days. Cluster analysis was used to classify subjects into groups, as determined by major sources of protein. Logistic regression models were used to calculate odds ratios (OR) and 95% confidence interval (95% CI) of T2DM according to the energy-adjusted protein intake. Results: All participants were divided into three patterns according to the dietary source of protein (legumes and seafood, red meat, refined grains). Overall, plant protein intake was significantly and inversely associated with T2DM. In the subgroup analysis by dietary patterns, extreme quartile of plant protein intake was also inversely related to T2DM in the "legumes and seafood" group [OR = 0.58, 95% CI (0.33 0.96)]. Total protein intake and animal protein intake were positively related to T2DM in the "red meat" group [OR: 3.12 (1.65-5.91) and 3.48 (1.87-6.60), respectively]. However, the association of animal protein intake was reversed in the "refined grains" group [OR = 0.55, 95% CI 0.32-0.89]. Conclusions: The association between protein intake and T2DM varies by dietary pattern. Dietary pattern may be considered into the recommendation of protein intake for diabetes prevention. PMID- 29983754 TI - Cervical Vestibular-Evoked Myogenic Potentials in Sedated Toddlers. AB - Introduction Cervical vestibular-evoked myogenic potentials (cVEMPs) are difficult to test in toddlers who cannot follow instructions or stay calm. Objective Due to the growing need for vestibular testing in very young children as a part of a delayed walking assessment battery, this study aimed to provide a solution to this problem by recording the cVEMPs in toddlers during sedation. Method The cVEMPs measures were assessed in 30 toddlers aged 12 to 36 months with normal motor milestones. They were sedated with chloral hydrate. Then, the head was retracted ~ 30 degrees backward with a pillow under the shoulders, and turned 45 degrees contralateral to the side of stimulation to put the sternocleidomastoid (SCM) muscle in a state of tension. Results The P13 and N23 waves of the cVEMPs were recordable in all sedated toddlers. The cVEMPs measures resulted in the following: P13 latency of 17.5 +/- 1.41 milliseconds, N23 latency of 25.58 +/- 2.02 milliseconds, and peak-to-peak amplitude of 15.39 +/- 3.45 uV. One-sample t -test revealed statistically significant longer latencies and smaller amplitude of the toddlers' cVEMPs relative to the normative data for adults. Conclusions The difficulty of cVEMPs testing in toddlers can be overcome by sedating them and attaining a position that contracts the SCM muscle. However, the toddlers' recordings revealed delayed latencies and smaller amplitudes than those of adults. PMID- 29983756 TI - Otogenic Lateral Sinus Thrombosis: A Review of Fifteen Patients and Changing Trends in the Management. AB - Introduction Otogenic lateral sinus thrombosis is a rare intracranial complication of otitis media in the modern age of antibiotic treatment, but it is potentially a dangerous complication. Objectives The aim of this study is to focus on the various clinical presentations, management options and sequelae in a series of fifteen patients with otogenic lateral sinus thrombosis. Methods Retrospective chart review of inpatients treated for otogenic lateral sinus thrombosis at our tertiary care institution between 2010 and 2015. Results A total of 15 patients (11 males and 4 females) with ages ranging from 9 to 60 years were diagnosed with otogenic lateral sinus thrombosis. The most commonly reported symptoms were headache, ear discharge and hard of hearing, which were experienced by all 15 (100%) patients. In contrast to previous studies found in the literature, 7 (47%) patients in our series presented with neck pain and neck abscess. Imaging studies and microbiological cultures were performed for all patients, who also underwent a mastoidectomy procedure. Internal jugular vein ligation was performed on 5 (33%) patients. Incision and drainage of the neck abscess was performed on 7 (47%) patients. All patients had a satisfactory resolution of their symptoms, and the mortality rate was of 0%. Conclusions Otogenic lateral sinus thrombosis, though a rare complication, can still occur; therefore, keeping a high level of suspicion is important, especially in developing countries. We also describe the patients with neck abscess associated with this rare condition. Combining parenteral antibiotics with surgical intervention is the treatment of choice. PMID- 29983757 TI - Suspensory Tethers and Critical Point Membrane Displacement in Endolymphatic Hydrops. AB - Introduction Grossly displaced membranes are characteristic of endolymphatic hydrops. The process whereby physiological membrane displacement becomes pathological may be mediated by stress, but the membrane biomechanics underlying this transition are unclear. Objective This study seeks to determine the role of suspensory tethers during pressure-induced membrane displacement in the generation of the membranous lesions seen in this disease entity using a biomechanical model approach. Methods The location of membrane suspensory tethers was identified histologically. The influence of tethers on model membrane configuration during displacement was assessed graphically. The relationship of membrane configuration during displacement to curvature radius was quantified trigonometrically. The relationship of curvature radius to stress susceptibility was determined mathematically. The net effect of suspensory tethers on membrane stress levels for various degrees of membrane distention and displacement was then calculated numerically. Results In the inferior labyrinth, suspensory tethers are found to occur on the membranes' boundaries. Such tethering is found to impose a biphasic effect on membrane curvature with increasing degrees of displacement. As a consequence, tensile stress susceptibility is found to decline with initial membrane displacement to a critical point nadir beyond which stress then increases monotonically. No such effect was found for the superior labyrinth. Conclusion Boundary tethers in the inferior labyrinth are associated with significant tensile stress reductions until a critical point of membrane displacement is reached. Displacements short of the critical point may be physiological and even reversible, whereas such displacements beyond the critical point are apt to be overtly hydropic and irreversible. PMID- 29983755 TI - Holmium Laser for Endoscopic Treatment of Benign Tracheal Stenosis. AB - Introduction Laryngotracheal stenosis is a difficult problem with varied etiology and various treatment options. The holmium laser represents another tool for the treatment of benign tracheal stenosis. Objectives To determine the utility of holmium laser treatment for benign tracheal stenosis with regards to safety and efficacy. Methods This was a retrospective case study examining patients with benign tracheal stenosis from 1998-2016 who underwent holmium laser treatment. Determining the safety of this procedure was the primary goal, and complications were monitored as a surrogate of safety. Results A total of 123 patients who underwent holmium laser treatment for benign tracheal stenosis were identified. In total, 123 patients underwent 476 procedures, with follow-up ranging from 1 month to 14 years. No intraoperative or post-operative complications were identified as a direct result of the use of this particular laser. Conclusions The holmium laser is an effective and safe laser to use for tracheal stenosis treatment. It is a contact laser with a short acting distance, which reduces the risk of injury to distal airway structures. Given the favorable experience reported here, the holmium laser should be considered when tracheal surgery is attempted. PMID- 29983758 TI - The Effect of Methylphenidate on the Hearing of Children with Attention Deficit Hyperactivity Disorder. AB - Introduction There has been a sudden idiopathic hearing loss case presented after methylphenidate treatment in a child with attention deficit hyperactivity disorder (ADHD). Objective This study was performed to reveal the probable ototoxic side effects of methylphenidate use in patients with ADHD. Methods Thirty pediatric patients with ADHD were included in the study. Pure tone audiometry, speech discrimination scores, waves I, III, V absolute latencies and waves I-III, I-V, III-V interpeak latencies at the 80 dB nHL intensity after click stimulus auditory brainstem response (ABR) results were compared before and 3 months after methylphenidate treatment. Results There were no statistically significant difference between pretreatment and posttreatment pure tone and speech audiometry findings and ABR results (p > 0.05 for all parameters). Conclusion Methylphenidate can be regarded as a safe drug regarding ototoxic side effects. Additional studies with a larger sample size and longer follow-up may be needed. PMID- 29983759 TI - Efficacy of Myofunctional Therapy Associated with Voice Therapy in the Rehabilitation of Neurogenic Oropharyngeal Dysphagia: a pilot study. AB - Introduction Dysphagia causes changes in the laryngeal and stomatognathic structures; however, the use of vocal exercises is poorly described. Objective To verify whether the therapy consisting of myofunctional exercises associated with vocal exercises is more effective in rehabilitating deglutition in stroke patients. Methods This is a pilot study made up of two distinct groups: a control group, which performed only myofunctional exercises, and an experimental group, which performed myofunctional and vocal exercises. The assessment used for oral intake was the functional oral intake scale (FOIS). Results The FOIS levels reveal that the pre-therapy median of the experimental group was 4, and increased to 7 after therapy, while in the control group the values were 5 and 6 respectively. Thus, the experimental group had a statistically significant difference between the pre- and post-therapy assessments ( p = 0.039), which indicates that the combination of myofunctional and vocal exercises was more effective in improving the oral intake levels than the myofunctional exercises alone ( p = 0.059). On the other hand, the control group also improved, albeit at a lower rate compared with the experimental group; hence, there was no statistically significant difference between the groups post-therapy ( p = 0.126). Conclusion This pilot study showed indications that using vocal exercises in swallowing rehabilitation in stroke patients was able to yield a greater increase in the oral intake levels. Nevertheless, further controlled blind clinical trials with larger samples are required to confirm such evidence, as this study points to the feasibility of conducting this type of research. PMID- 29983760 TI - Anatomical Variations in Patients with Meniere Disease: A Tomography Study. AB - Introduction The etiology of Meniere disease (MD), a difficult-to-treat condition with great morbidity, remains controversial in the literature. The possible clinical and diagnostic impact of anatomical variations of the temporal bone among patients with MD has been recently studied. Objective To identify anatomical variations of the temporal bone associated with the diagnosis of MD. Methods Thirty-seven patients were included, although each ear was considered separately ( n = 74). A case group ( n A = 33) was composed of the affected ears of patients with definite MD and a control group ( n B = 41) was used consisting of the ears of individuals who did not meet the criteria for MD and of the contralateral ears from patients with unilateral disease. Tomographic images from the individuals included in the study were submitted to a blinded and systematic evaluation regarding a broad variety of anatomical variations of the temporal bone. Obtained data were compared statistically between the groups and after stratifying the study sample. Significance level was set at 0.05. Results Among the affected ears, it was observed an increased number of tomographic scans in which the vestibular aqueduct could not be identified ( p = 0.01, Fisher exact test). No statistically significant differences were observed when comparing the affected and contralateral ears from patients with unilateral MD, between affected ears from patients with unilateral and bilateral disease or between contralateral ears of patients with unilateral affection and patients without the disease. Conclusion Some anatomical variations might be more frequent in the affected ears of patients with MD, such as the lower rates of individualization of the vestibular aqueduct. PMID- 29983761 TI - Applicability of Evoked Auditory Brainstem Responses with Complex Stimuli in Adults with Hearing Loss. AB - Introduction The use of the speech-evoked auditory brainstem response (ABR) shows how the brainstem operates up to the subcortex in a more complex manner than when the click-evoked ABR is used. Objective To study the applicability of the speech-evoked ABR in adults with hearing loss. Methods The sample was composed of a study group of 11 subjects, with ages ranging between 18 and 59 years, and auditory thresholds within normal standards, with loss of up to 65 dB at high frequencies or up to moderately severe symmetric sensorineural hearing loss. The sample underwent a basic audiological assessment, as well as speech evoked ABR and click-evoked ABR, in which waves I, III and V, and V, A, C, D, E, F were respectively marked. The electrophysiological assessments were performed using the SmartEP device (Intelligent Hearing Systems, Miami, FL, US). Results For the speech-evoked ABR, the reference values were used in the identification and analysis of the study group. Those values found for the study group were: V = 8.56; A = 10.97; C = 21.33; D = 29.51; E = 37.93; F = 46.96; and O = 55.97. In the comparison between groups, the study group presented an increase in latency only in wave C. Conclusion The speech-evoked ABR can be performed in subjects with up to moderately severe hearing loss, and the test proved to be appropriate, because, unlike the click-evoked ABR, the former does not suffer influence of peripheral hearing loss. PMID- 29983762 TI - Sudden Sensorineural Hearing Loss: Comparative Study of Different Treatment Modalities. AB - Introduction Idiopathic sudden sensorineural hearing loss (ISSNHL) is hearing loss of at least 30 dB in at least 3 contiguous frequencies within at least 72 hours. There are many different theories to explain it, and many different modalities are used for its management, such as: systemic steroids (SSs), intratympanic steroid injection (ITSI), hyperbaric oxygen therapy (HOT), antiviral drugs, and vasodilators or vasoactive substances. Objectives This study aims to evaluate the efficacy of the combination of the most common treatment modalities of ISSNHL and to compare the results if HOT was not one of the treatment modalities administered. Methods The study was conducted with 22 ISSNHL patients with ages ranging from 34 to 58 years. The patients were divided into 2 groups; group A included 11 patients managed by SSs, ITSI, antiviral therapy, and HOT simultaneously, and group B included 11 patients exposed to the aforementioned modalities, with the exception of HOT. Results After one month, all of the patients in group A showed total improvement in hearing in all frequencies, with pure tone average (PTA) of 18.1 +/- 2.2, while in group B, 5/11 (45.5%) patients showed total improvement, and 6 /11 (54.5%) patients showed partial improvement, with a total mean PTA of 28.1 +/- 8.7. Conclusion The early administration of HOT in combination with other clinically approved modalities (SSs, ITSI, antiviral therapy) provides better results than the administration of the same modalities, with the exception of HOT, in the treatment of ISSNHL. PMID- 29983763 TI - Otitis Externa in Secondary Care: A Change in Our Practice Following a Full Cycle Audit. AB - Introduction Patients presenting with otitis externa are a common thing in otolaryngology units. However, the practice has not been standardized due to a lack of consensus over the management of this condition in secondary care. The National Institute for Health and Care Excellence (NICE) guideline has been published targeting the general practitioners, but it may be relevant in cases of hospital first-time attenders. Objective To conduct an audit of the investigative and prescription practice for hospital first-time attenders in our department against the NICE guideline for otitis externa. Methods The case notes of the patients presenting with otitis externa were reviewed. The data collation included the performance of ear swabs and choice of eardrops. Results An initial audit showed that ear swabs were sent in 14 out of 19 cases, of which 11 grew either Pseudomonas aeruginosa or Staphylococcus aureus (organisms that are sensitive to empirical treatment). A re-audit showed higher adherence to NICE recommendations, with ear swabs sent in only 3 out of 25 cases. The initial audit also demonstrated Sofradex (Sanofi-Aventis, Paris, France) as the most popular empirical eardrop. Following our recommendation, the re-audit showed that Betnesol-N (GSK, Brentford, UK) was administered in 24 out of 25 cases. Conclusion We recommend Betnesol-N due to its cost-effectiveness. Ear swabs should be reserved for refractory cases only. Posters and email reminders are effective means of disseminating information within the hospital. PMID- 29983764 TI - Papillary Thyroid Carcinoma within Thyroglossal Duct Cyst: Case Series and Literature Review. AB - Introduction Thyroglossal duct cyst (TGDC) is the most common congenital anomaly of the neck, and approximately 7% of all the adult population presents it. Ectopic thyroid tissue is found in the thyroglossal duct cyst wall in up to 65% of cases. This thyroid tissue has the potential to develop some type of malignancy, the most common of which is the papillary carcinoma of the thyroid. There are just over 270 cases of thyroglossal duct cyst malignancy reported in the literature. Objectives We aimed to study our population of patients in order to identify cases with thyroglossal duct cyst malignancy. Methods A retrospective chart review was conducted in the section of otolaryngology/head and neck surgery at a hospital in Karachi, Pakistan, from January of 2004 to December of 2014 on patients with the diagnosis of thyroglossal duct cyst. Results Fifty-eight patients were diagnosed with TGDC, two of whom also presented with thyroglossal duct cyst carcinoma. Both patients revealed papillary thyroid carcinoma on histopathology. Case 1 had an open biopsy before undergoing definitive surgery. Both patients underwent subsequent total thyroidectomy after Sistrunk procedure, and case 2 had selective neck dissection revealing lymph node metastasis. Conclusion Thyroglossal duct cyst carcinoma is a rare finding that comes as a surprise to both the patient and the surgeon. We report 2 out of 58 cases diagnosed with thyroglossal duct cyst carcinoma. PMID- 29983765 TI - Efficacy of Drainless Total Thyroidectomy in Intrathyroidal Lesions of Thyroid. AB - Introduction There is difference of opinion about the placement of the drain in thyroid surgeries, and, to the best of our knowledge, the efficacy of drainless total thyroidectomy regarding various parameters of thyroid lesions has not been well-established. Objective To report our experience with drainless total thyroidectomy, and to define an appropriate patient population for its performance. Methods This is a retrospective case analysis of the patients who underwent total thyroidectomy for intrathyroidal lesions with or without central neck dissection in a tertiary referral hospital (number = 74). The patients, who had undergone total thyroidectomy without any drain insertion, were analyzed, and the relationships among various parameters of thyroid lesions were noted in relation to seroma and hematoma formation. Results Seroma formation was noted only in 5 out of 74 patents (6.75%). All of the seromas that occurred were observed in patients with thyroid lesions < 4 cm, and 4 out of 5 seromas were observed in patients with a malignant pathology. There was no statistically significant difference in seroma formation between patients younger or older than 50 years of age. The nature of the lesion, whether benign or malignant, did not affect the formation of seroma. Of interest is the fact that none of the 10 patients who had central neck dissection performed as part of their treatment developed seroma. Conclusions Drainless total thyroidectomy is safe across all age groups for patients harboring either benign or malignant thyroid pathologies. However, caution is to be observed in opting for drainless total thyroidectomy in patients with large lesions (> 5 cm). PMID- 29983766 TI - Evaluation of the Facial Recess and Cochlea on the Temporal Bone of Stillbirths regarding the Percutaneous Cochlear Implant. AB - Introduction The literature shows that there are anatomical changes on the temporal bone anatomy during the first four years of life in children. Therefore, we decided to evaluate the temporal bone anatomy regarding the cochlear implant surgery in stillbirths between 32 and 40 weeks of gestational age using computed tomography to simulate the trajectory of the drill to the scala timpani avoiding vital structures. Objectives To measure the distances of the simulated trajectory to the facial recess, cochlea, ossicular chain and tympanic membrane, while performing the minimally invasive cochlear implant technique, using the Improvise imaging software (Vanderbilt University, Nashville, TN, US). Methods An experimental study with 9 stillbirth specimens, with gestational ages ranging between 32 and 40 weeks, undergoing tomographic evaluation with individualization and reconstruction of the labyrinth, facial nerve, ossicular chain, tympanic membrane and cochlea followed by drill path definition to the scala tympani. Improvise was used for the computed tomography (CT) evaluation and for the reconstruction of the structures and trajectory of the drill. Results Range of the distance of the trajectory to the facial nerve: 0.58 to 1.71 mm. to the ossicular chain: 0.38 to 1.49 mm; to the tympanic membrane: 0.85 to 1.96 mm; total range of the distance of the trajectory: 5.92 to 12.65 mm. Conclusion The measurements of the relationship between the drill and the anatomical structures of the middle ear and the simulation of the trajectory showed that the middle ear cavity at 32 weeks was big enough for surgical procedures such as cochlear implants. Although cochlear implantation at birth is not an indication yet, this study shows that the technique may be an option in the future. PMID- 29983767 TI - Hyoid Bone Suspension as a Part of Multilevel Surgery for Obstructive Sleep Apnea Syndrome. AB - Introduction Since oropharyngeal surgery alone is often insufficient to treat obstructive sleep apnea (OSA), advances have been developed in hypopharyngeal surgery. Objective To assess hyoid suspension surgery as part of a multilevel OSA surgery, also including palatal surgery. Methods The study included patients with OSA symptoms with apnea hypopnea index (AHI) > 15. They were scheduled for hyoid suspension after a nasoendoscopy during Muller maneuver and drug induced sleep endoscopy (DISE). All patients had body mass index (BMI) < 35 kg/m2. Hyoidothyroidopexy combined with tonsillectomy and palatal suspension was performed in all cases. Results The mean AHI dropped significantly ( p < 0.0001) from 68.4 +/- 25.3 preoperatively to 25.6 +/- 9.52 postoperatively. The mean lowest oxygen (O 2 ) saturation level increased significantly from 66.8 +/- 11.3 to 83.2 +/- 2.86 ( p < 0.0001). In addition, the snoring score significantly decreased ( p < 0.0001) from a preoperative mean of 3.4 +/- 0.54 to 2 +/- 0.7 at 6 months postoperatively. In regard to the Epworth sleepiness scale (ESS), it showed significant improvements ( p < 0.0001) as its mean diminished from 13.8 +/- 5.4 preoperatively to 5.2 +/- 1.6 postoperatively. Conclusion Hyoidothyroidopexy using absorbable suture seems to produce a good outcome in treating OSA. It could be effectively and safely combined with other palatal procedures in the multilevel surgery for OSA. PMID- 29983768 TI - Vocal Symptoms and Associated Risk Factors between Male and Female University Teachers. AB - Introduction Many recent studies on teachers warn of the adverse effects that voice problems have on work performance. However, only a few of these studies included university teachers. Objective To compare the vocal symptoms and risk factors between male and female university teachers in a private institution within the city of Sao Paulo. Methods In a cross-sectional survey, a voice self evaluation form prepared by the Ministry of Labor in Brazil was administered to 846 university teachers at a private institution in the city of Sao Paulo. Results The percentage of hoarseness, vocal tract discomfort, neck pain and foreign body sensation was significantly higher in female than in male subjects. A significantly higher percentage of males participated in other professional activities in addition to teaching, reported working in a calm environment compared with working in a moderately or severely tense and stressful environment, and rated themselves as calm, slightly stressed and anxious or moderately stressed and anxious rather than very stressed and anxious. A significantly higher percentage of females spent most of their time teaching compared with performing other professional activities, and rated themselves as chatty or impulsive. Conclusion Among university teachers, a significantly higher percentage of females than males reported hoarseness, vocal tract discomfort, neck pain and foreign body sensation. Some risk factors related to work organization, workplace environment, voice care and quality of life variables were related to this higher prevalence in females. PMID- 29983769 TI - The Middle Turbinate Resection and Its Repercussion in Olfaction with the University of Pennsylvania Smell Identification Test (UPSIT). AB - Introduction Nasal obstruction is a common complaint, and, for some, the middle turbinate resection is still a controversial issue among the surgical options due to the possibility of deleterious effects on olfaction. The University of Pennsylvania smell identification test (UPSIT) is considered the gold standard of smell identification tests, but data about it is still incipient in Brazil. Objective To evaluate if the middle turbinectomy has any repercussion on the sense of olfaction by using the UPSIT as an assessment tool. Methods A prospective study performed between 2013 and 2015 with 27 patients who were treated with middle turbinectomy by the same surgeon and tested with the UPSIT pre- and post-surgery, with a minimum interval of 3 months. Results Twenty-five patients completed the study. The mean age was 27.9 years. There was no statistical correlation between middle turbinectomy and the UPSIT score, or between gender and the UPSIT score. Conclusion There was no clinical repercussion on olfaction from partial middle turbinectomy. PMID- 29983770 TI - Long-Term Evaluation of Nasal Septoplasty Followed by Inferior Turbinate Cauterization for the Treatment of Nasal Obstruction using Objective and Subjective Methods. AB - Introduction Nasal septoplasty is considered the treatment of choice for nasal obstruction due to septal deviation. An ongoing discussion among rhinologists is whether it is reasonable to perform objective measurements of nasal patency pre or postoperatively routinely. Objective The primary aim of this study was to identify the short- and long-term functional benefits for patients undergoing septal surgery, as assessed by acoustic rhinometry (AR). The secondary goal was to evaluate the short- and long-term perception of symptom relief and disease specific quality of life (QoL) outcomes on the part of the patients. Methods This was a prospective observational study in which AR was utilized for the assessment of nasal patency preoperatively and 1, 6 and 36 months after septoplasty. Total 40 patients who underwent septoplasty filled out the Nasal Obstruction Septoplasty Effectiveness (NOSE) questionnaire and the Glasgow Benefit Inventory (GBI) to assess their subjective improvement in nasal obstruction symptoms and the changes in their QoL. Results There were statistically significant improvements in nasal patency, mean postoperative NOSE and GBI scores postoperatively. However, there was no correlation between the mean NOSE and GBI scores and the AR measurements. Furthermore, the GBI scores tended to decrease as the postoperative period increased. Conclusion The present study confirms that septoplasty significantly increases nasal patency and causes a significant subjective improvement in nasal obstruction symptoms. The absence of a statistically significant correlation among the objective measurements, the symptom scores, and the patients' low GBI scores indicates that factors other than the anatomical findings may also contribute to the patients' perception of QoL. PMID- 29983771 TI - Translation to Brazilian Portuguese and Cultural Adaptation of the Craniocervical Dysfunction Index. AB - Introduction Functional disorders of the craniocervical region affect 77.78% of Brazilian teachers. Among the most common instruments used to assess craniocervical disorders in a detailed and objective way, none had been translated to Brazilian Portuguese and adapted to Brazilian culture. Objectives To translate to Brazilian Portuguese and to culturally adapt the Craniocervical Dysfunction Index (CDI). Method The first phase of the study consisted of the translation, synthesis, back-translation, and review of the contents by a committee of experts, who developed a trial version and sent all the steps to the original author. The trial version was applied to 50 teachers of an institution. The reliability and internal consistency were evaluated by Cronbach alpha. For the validation, the Brazilian Portuguese version of the CDI was correlated with the Visual Analogue Scale (VAS) domains for cervicalgia and evaluated by Spearman rho. Result Some expressions were adapted to the Brazilian culture. Among the participants who did not report neck pain in the VAS, 84.21% suffered from craniocervical dysfunction acording to the CDI. Among the participants who reported neck pain in the VAS, 100% suffered from craniocervical dysfunction according to the CDI. The CDI showed good internal consistency and satisfactory reliability measured by Cronbrach alpha (alpha = 0.717). There was a strong correlation between the CDI and the VAS score (rho = 0.735). Conclusion No difficulties were encountered in the translation and back-translation of the CDI, and no problems were observed regarding the trial version developed; therefore, the Brazilian Portuguese version of the CDI is a valid and reliable instrument to evaluate the functional alteration of the craniocervical region. PMID- 29983772 TI - Anatomical Variations of the Middle Turbinate Concha Bullosa and its Relationship with Chronic Sinusitis: A Prospective Radiologic Study. AB - Introduction A pneumatized turbinate, also called concha bullosa, is a normal anatomical variant of the paranasal sinus region. Depending on the site of pneumatization, the concha is classified into extensive, bulbous or lamellar type. The middle turbinate concha bullosa has been implicated as a possible etiological factor in chronic sinusitis. Objectives The aim of this study was to investigate the anatomical variations of the concha bullosa, based on paranasal sinus imaging, and its possible association with sinusitis. Methods This prospective descriptive study was performed at the Department of ENT and Head Neck Surgery over a period of one year, from 2016 to 2017. We studied the computed tomography scans of the nose and paranasal sinuses- in axial, coronal and sagittal planes-of patients who had symptoms of nasal obstruction, or headache and features of chronic sinusitis. Results Out of the 202 scans studied, the prevalence of concha bullosa was 31.7%. The concha was bilateral in 35 (54.7%) patients and unilateral in 29 (45.3%) patients. Out of 99 conchae, 54 were on the right side and 45 were on left side. Ipsilateral sinusitis was found in 40.4% of the sides in the scans of subjects with concha. There was no statistically significant association between any type of middle turbinate concha with sinusitis, but sinusitis was more predominant with the extensive type of concha ( p > 0.05). Conclusion Multiple air cells, mucocele, pyocele and inflammatory mucosal thickenings in the concha are relatively rare. Detailed knowledge of anatomic variations of the concha bullosa is imperative for the radiologists and the operating surgeons. PMID- 29983773 TI - Supracricoid Laryngectomy: The Function of the Remaining Arytenoid in Voice and Swallowing. AB - Introduction Supracricoid laryngectomy still has selected indications; there are few studies in the literature, and the case series are limited, a fact that stimulates the development of new studies to further elucidate the structural and functional aspects of the procedure. Objective To assess voice and deglutition parameters according to the number of preserved arytenoids. Methods Eleven patients who underwent subtotal laryngectomy with cricohyoidoepiglottopexy were evaluated by laryngeal nasofibroscopy, videofluoroscopy, and auditory-perceptual, acoustic, and voice pleasantness analyses, after resuming oral feeding. Results Functional abnormalities were detected in two out of the three patients who underwent arytenoidectomy, and in six patients from the remainder of the sample. Almost half of the sample presented silent laryngeal penetration and/or vallecular/hypopharyngeal stasis on the videofluoroscopy. The mean voice analysis scores indicated moderate vocal deviation, roughness and breathiness; severe strain and loudness deviation; shorter maximum phonation time; the presence of noise; and high third and fourth formant values. The voices were rated as unpleasant. There was no difference in the number and functionality of the remaining arytenoids as prognostic factors for deglutition; however, in the qualitative analysis, favorable voice and deglutition outcomes were more common among patients who did not undergo arytenoidectomy and had normal functional conditions. Conclusion The number and functionality of the preserved arytenoids were not found to be prognostic factors for favorable deglutition efficiency outcomes. However, the qualitative analysis showed that the preservation of both arytenoids and the absence of functional abnormalities were associated with more satisfactory voice and deglutition patterns. PMID- 29983774 TI - Hearing Loss in Acromegaly - A Review. AB - Introduction Acromegaly is a chronic disease caused by growth hormone (GH) excess due to a GH-secreting pituitary adenoma in most cases. There is reasonable data to presume the possible influence of chronic GH and insulin-like growth factor I (IGF-I) hyperproduction on the anatomical structures involved in normal sound perception, and on its conductive and/or sensorineural part. Objectives To review the literature about acromegaly and hearing loss. Data Synthesis A systematic literature search was performed using the MEDLINE database, including hand-searching reference lists from original articles. The search was performed using the terms hearing loss and acromegaly , and only 5 studies were found. Conclusion The results are not consistent, but led to different conclusions. Therefore, more studies with greater numbers of patients with acromegaly are needed. PMID- 29983775 TI - A Review of Traditional Vaccine-Preventable Diseases and the Potential Impact on the Otolaryngologist. AB - Introduction A majority of otolaryngologists have not had direct experience with many vaccine-preventable diseases since the creation of national vaccination programs. Despite the elimination of endemic transmission of some of these diseases in the United States, outbreaks can occur anywhere and still pose a threat to public health around the world. Recent outbreaks and changing trends in exemption rates indicate that it is important for physicians to maintain a working knowledge of how these diseases present and of the recommended treatment guidelines. Objectives This review will evaluate the current state of vaccination rates, vaccine exemption rates and disease incidence in the United States and in the world. It will also examine the clinical presentation and treatment recommendations of these diseases. Data Synthesis United States estimated vaccination rates, vaccine exemption rates and vaccine-preventable disease incidences were obtained from data compiled by the Centers for Disease Control and Prevention. World vaccination rates and disease incidences were obtained from the World Health Organization databases, which compile official figures reported by member states. A PubMed literature review provided information on the current state of vaccination exemptions and outbreaks in the United States. Conclusion Vaccination and vaccine exemption rates continue to put the United States and many areas of the world at risk for outbreaks of vaccine-preventable diseases. Clinical guidelines should be reviewed in the event of a local outbreak. PMID- 29983776 TI - Hearing Disorders in Congenital Toxoplasmosis: A Literature Review. AB - Introduction Several studies show correlations between congenital toxoplasmosis and hearing loss, with a broad diversity of levels of hearing loss and specifications of hearing disorders. Objective To describe the studies found in the literature regarding hearing disorders in congenital toxoplasmosis. Data Synthesis A literature review was conducted on the Lilacs, SciELO, PubMed and Scopus databases by combining the following keywords: congenital toxoplasmosis and hearing . Based on this search strategy, 152 papers were found, the majority published on the Scopus and PubMed databases from 1958 to 2015. After the application of the inclusion criteria, 8 articles published between 1980 and 2015 were included in the present study. Conclusion This review showed a moderate evidence of the association between hearing disorders and congenital toxoplasmosis, which is characterized by sensorineural hearing loss. However, there are gaps in the description of the specific characteristics of the type and level of hearing loss, or of other possible disorders involved in the auditory processing. PMID- 29983777 TI - Evaluation of Access to Long-term Care Services for Old People Ageing in Place in Slovenia. AB - Theory: The quality of long-term care services has an important effect on the quality of life of their users and their informal carers. By identifying gaps between provision of services and users' needs we can suggest adjustments of the long-term care services and advance their development. Method: The data from the first Slovenian national survey of social homecare (SHC) users and their informal carers was utilised. Linear regression analysis was used to evaluate factors that affect assessments of five-dimensional concept of access. Results: On average, affordability was rated the lowest (mean=2.9) and acceptability the highest (4.0), with availability, accessibility and accommodation (mean=3.6) in the middle. Regression analysis explains 15% of variability in affordability, while for other dimensions much less. Caregiver's needs are the most influential predictor of access, negatively influencing the rating of access (availability B=.127, accommodation B=-.113, acceptability B=-.120, affordability B=-.155). Care recipients' needs also affect the rating of affordability (B=-.132). Family income negatively influences the rating of availability (B=-.115), accessibility (B=-.076) and affordability (B=-.270). Residents of rural areas rate availability (B=-.070) and affordability (B=-.067) less favourable. Discussion: This study showed that affordability is rated the least favourable among components of access. Adjustment in private out-of-pocket co-payment mechanism is suggested. PMID- 29983778 TI - Future Teachers' Attitudes and Knowledge Regarding the Management of the Potential Students' Life-threatening Allergic Reactions in Slovenian Schools. AB - Introduction: Poorly developed teachers' competences for managing children's allergies can pose a significant problem for the wellbeing of children in the preschool and school environment. The purpose of this study is to explore the attitudes and theoretical understanding of the management of allergic reactions in children among future teachers. Methods: A total of 572 future teachers participated in the study, 56% of whom were in the 1st year of undergraduate educational programmes, while 44% were in the 4th year. The participants answered the Teachers' Health Competences Development - Allergy Questionnaire. Results: The future teachers showed positive attitudes towards learning more about different child health issues. There was an average understanding of managing allergic reactions in children (59.4%; SD=16.1% success), with no statistically significant difference regarding the duration of education, science background or the students' self-allergy. There was, however, a statistically significant difference in achievement scores between future teachers in different educational programmes (F(3,568)=6.4, p<=.000). A subgroup of future teachers exposed to basic allergy education in the 1st year and tested again in the 4th year showed significantly better knowledge (Mann-WhitneyU=83.0; p=.008). Conclusion: The duration of future education, science background and self-allergy did not influence the level of knowledge regarding the management of allergic reactions in children. A basic educational programme in allergy management had a positive effect on future teachers' knowledge of managing allergic reactions in children. Our study indicates that all future teachers should be included in specific educational programmes in order to develop adequate health competences. PMID- 29983779 TI - Hospital Staff's Risk of Developing Musculoskeletal Disorders, Especially Low Back Pain. AB - Introduction: Health-related absenteeism impacts individuals, companies, and society. Its consequences are reflected in the cost of benefits, substitutes, and reduced productivity. Research shows that musculoskeletal disorders (MSDs) are the most common work-related health problem reported by hospital staff. This study determines the groups at the Ljubljana University Medical Centre that are most susceptible to MSDs, especially low back pain. Methods: Using data from the Health Data Centre of the Slovenian National Public Health Institute and the medical centre, this cross-sectional study analysed absenteeism among medical centre employees. The correlation between MSD / low-back pain risk factors and incidence was determined using logistic regression. An odds ratio was calculated to determine the probability of MSDs, most especially low back pain via sex, age, occupation, and education. Results: Sick leave at the medical centre is higher than 5%, exceeding the Slovenian healthcare sector average. MSDs, as the main reason for absence, is significantly more frequent in women, non-medical staff, and employees with a maximum secondary school education. Among the MSDs, low back pain predominates as a reason for absence and is most frequent among nurses, midwives, and employees of 20 to 44.9 years old. Conclusion: This study offers insight into the health status of medical centre employees. The high percentage of sick leave is mainly due to musculoskeletal disorders, including low back pain. This is an important basis for further monitoring and analysis of sick leave indicators and for planning systematic and continuous workplace health promoting measures to manage ergonomic risk factors and reduce health-related absenteeism. PMID- 29983780 TI - Anticholinergic Burden and Most Common Anticholinergic-acting Medicines in Older General Practice Patients. AB - Introduction: Anticholinergic burden in older adults has been correlated with cognitive decline, delirium, dizziness and confusion, falls and hospitalisations. Nevertheless, anticholinergic-acting medications remain commonly prescribed in up to a third of older adults in primary care population. Our aim was to study the anticholinergic burden in older adults in Slovenian ambulatory setting and explore the most commonly involved medications which could be avoided by the physicians. Methods: A cross-sectional study was conducted in 30 general practices in Slovenia as part of a larger trial. Data on prescribed medications were collected for randomly chosen adults of over 65 years of age visiting general practice, who were taking at least one regularly prescribed medication. Anticholinergic burden was calculated using Duran's scale and Drug Burden Index. Results: Altogether, 622 patients were included, 356 (57.2%) female, average age of 77.2 (+/-6.2), with an average of 5.6 medications. At least one anticholinergic medication was present in 78 (12.5 %) patients. More than half (N=41, 52.6%) of anticholinergic prescriptions were psychotropic medications. Most common individual medications were diazepam (N=10, 1.6%), quetiapine (N=9, 1.4%) and ranitidine (N=8, 1.3%). Conclusions: Though the prevalence of anticholinergic medications was low compared to international research, the most commonly registered anticholinergic prescriptions were medications that should be avoided according to guidelines of elderly prescriptions. It would be probably clinically feasible to further decrease the anticholinergic burden of older adults in Slovenian primary care setting by avoiding or replacing these medications with safer alternatives. PMID- 29983781 TI - What can we Learn from each other about Undergraduate Medical Education in General Practice/Family Medicine? AB - Introduction: There is a dearth of published literature on the organisation of family medicine/general practice undergraduate teaching in the former Yugoslavia. Methods: A semi-structured questionnaire was sent to the addresses of 19 medical schools in the region. Questions covered the structure of Departments of Family Medicine (DFM), organisation of teaching, assessment of students and their involvement in departmental activities. Results: Thirteen medical schools responded, of which twelve have a formal DFM. Few DFM have full-time staff, with most relying upon external collaborators. Nine of 13 medical schools have family doctors teaching other subjects, covering an average of 2.4 years of the medical curriculum (range: 1-5). The total number of hours dedicated to teaching ranged from 30 - 420 (Md 180). Practice-based teaching prevails, which is conducted both in city and rural practices in over half of the respondent schools. Written exams are conducted at all but two medical schools, with the written grade contributing between 30 and 75 percent (Md=40%) of the total score. Nine medical schools have a formal method of practical skills assessment, five of which use Objective Structured Clinical Examinations. Student participation is actively sought at all but three medical schools, mainly through research. Conclusion: Most medical schools of the former Yugoslavia recognise the importance of family medicine in undergraduate education, although considerable variations exist in the organisation of teaching. Where DFM do not exist, we hope our study will provide evidence to support their establishment and the employment of more GPs by medical schools. PMID- 29983782 TI - Empathy and Burnout in Slovenian Family Medicine Doctors: The First Presentation of Jefferson Scale of Empathy Results. AB - Background: Study aimed to assess the burnout prevalence and level of empathic attitude in family medicine doctors (FMDs) and its associations with demographic factors, working conditions and physician health, using the Jefferson Scale of Empathy - Health Professional version (JSE-HP). Methods: Slovenian FMDs (n=316, response rate 56%) completed an online socio-demographic questionnaire, with questions on working conditions, physician health, and the Slovenian versions of the Maslach Burnout Inventory (MBI) and the JSE-HP. Univariate and multivariate analyses were used, applying linear regression to calculate associations between demographic variables, factors of empathy and burnout dimensions, P<0.05 was set as a limit of statistical significance. Results: Of the 316 participants, aged 40+/-10.2 years, 57 (18%) were men. The FMDs achieved mean scores on the JSE-HP (JSEtot of 112.8+/-10.2 and on the MBI 27.8+/-11.6 for EE, 10.8+/-5.5 for D and 33.5+/-6.0 for PA. High burnout was reported in one dimension by 24.8% of participants, in two by 17.2%, and by 6% in all three dimensions. Multivariate analysis revealed a higher EE and D and lower PA in specialists as opposed to trainees. Higher EE was also identified in older physicians having longer work experience, working in a rural setting, dealing with more than 40 patients/day and having a chronic illness. The latter was also associated with higher JSEtot. JSEtot was negatively associated with D, while PA was positively associated with JSEtot and Perspective Taking. Conclusion: The incidence of burnout warns both physicians and decision-makers against too heavy workload, especially in older professionals. PMID- 29983783 TI - The Role of a School Nurse in the Care of a Child with Diabetes Mellitus Type 1 - The Perspectives of Patients and their Parents: Literature Review. AB - Introduction: The aim of this literature review was to explore the views of parents and children with type 1 diabetes mellitus regarding having a school nurse. Methods: Six databases were selected for the analysis. The research strategy was based on the PICO model. The research participants were children with type 1 diabetes mellitus and/or their parents. Results: The present review of research papers includes 12 publications. The majority of works deal with the perspectives of children with type 1 diabetes and their parents on various aspects related to the role of a school nurse in the care of a child with type 1 diabetes:the presence of a school nurse;the role of a school nurse in the prevention and treatment of hypoglycaemia, in performing the measurements of blood glucose, and in insulin therapy;the role of a nurse in improving metabolic control of children with type 1 diabetes;a nurse as an educator for children with type 1 diabetes, classmates, teachers, teacher's assistants, principals, administrators, cafeteria workers, coaches, gym teachers, bus drivers, and school office staff;a nurse as an organiser of the care for children with type 1 diabetes. Conclusions: According to parents and children with type 1 diabetes mellitus, various forms of school nurse support (i.e., checking blood glucose, giving insulin, giving glucagon, treating low and high blood glucose levels, carbohydrate counting) are consistently effective and should have an impact on the condition, improvement of metabolic control, school activity and safety at school. PMID- 29983784 TI - Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice. AB - BACKGROUND: Preclinical studies have demonstrated that renin-angiotensin system (RAS) signalling has strong tumour-promoting effects and RAS inhibition was associated with improvement in the overall survival in some cancer types including hepatocellular carcinoma (HCC). OBJECTIVE: We aimed to investigate the effect of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-II receptor blockers (ARBs) on the survival of mice with diethylnitrosamine (DEN) induced HCC. METHODS: HCC was induced by weekly i.p. administration of DEN. Mice were treated with sorafenib (SO) (30 mg/kg), perindopril (PE) (1 mg/kg), fosinopril (FO) (2 mg/kg), losartan (LO) (10 mg/kg), PE (1 mg/kg) + SO (30 mg/kg), FO (2 mg/kg) + SO (30 mg/kg), or LO (10 mg/kg) + SO (30 mg/kg). Survival analysis was done using the Kaplan-Meier method, and the log-rank test was used for assessing the significance of difference between groups. RESULTS: The administration of PE, FO and LO as monotherapy or as combined with SO resulted in marked improvement in the liver histologic picture with no impact on overall survival of mice. CONCLUSION: Interfering the RAS either through the inhibition of ACE or the blockade of angiotensin II type 1 (AT1) receptors has similar effects on the liver of DEN-induced HCC mice and is not associated with longer survival due to detrimental effects of DEN on other organs. Hence, repetitive administration of DEN in such models of HCC is not suitable for mortality assessment studies. PMID- 29983786 TI - Colonic Stem Cells Expression of Lgr5 and CD133 Proteins as Predictive Markers in Colorectal Cancer among Egyptian Patients. AB - AIM: Colorectal cancer is the fourth common tumour in Egypt after lymphoid, breast and urinary tumours. The study aims to assess the expression of Lgr5 and CD133 in pre-malignant (adenomatous polyps and IBD), malignant colorectal lesions and normal colonic mucosa by immunohistochemical staining. MATERIAL AND METHODS: This prospective study was done on 100 patients presenting with colonic symptoms, patients were divided into four groups; group I including 20 patients in the control group, group II including 20 ulcerative colitis (U.C) patients, group III including 20 patients with adenomatous polyps and group IV including 40 patients with colorectal cancer (CRC). RESULTS: Lgr5 and CD133 expression was significantly higher in carcinoma than in adenomas, IBD and normal mucosa (P < 0.001). Lrg5 and CD133 was positively correlated with histological grade (P = 0.001), depth of invasion (P = 0.001), lymph node metastasis (P < 0.001), distant metastasis (P < 0.004) and TNM stage (P < 0.001). CONCLUSION: Role of Lgr5 and CD133 as stem cell marker was expressed and presented with different expression in the normal colonic mucosa, adenoma and CRC and showed increased expression in an advanced stage of CRC. This may suggest its possible involvement in colorectal tumorigenesis and invasion. PMID- 29983785 TI - Presentation of the Molecular Subtypes of Breast Cancer Detected By Immunohistochemistry in Surgically Treated Patients. AB - INTRODUCTION: The detection of estrogen, progesterone and HER-2 neu receptors on the surface of the tumour cell is a significant prognostic factor, alone or in combination. The presence or absence of receptors on the surface of the tumour cell is associated with the conditional gene expression in the tumour cell itself. Based on these genetically determined expressions of the tumour cell, five molecular subtypes of breast cancer have been classified on the St. Gallen International Expert Consensus in 2011 that can be immunohistochemically detected, with each subtype manifesting certain prognosis and aggression. AIM: Analyzing the presentation of molecular subtypes of breast cancer that are immunohistochemically detected in surgically treated patients at the Clinic for Thoracic and Vascular Surgery. MATERIAL AND METHODS: We used the international classification on molecular subtypes of breast cancer which divides them into: Luminal A (ER+ and/or PR+, HER-2 negative, Ki-67 < 14%), Luminal B with HER-2 negative (ER+ and/or PR+, HER-2 negative, Ki-67 >= 14%), Luminal B with HER-2 positive (ER+ and/or PR+, HER-2+, any Ki-67), HER-2 enriched (ER-, PR-, HER-2+), and basal-like (triple negative) (ER-, PR-, HER-2 negative, CK5/6+ and/or EGFR+). A total of 290 patients, surgically treated for breast cancer, were analysed during 2014. RESULTS: In our analysis, we found that Luminal A was present in 77 (26.55%) patients, Luminal B HER-2 negative was present in 91 (31.38%) patients, Luminal B HER-2 positive was present in 70 (24.14%) patients, HER-2 enriched was present in 25 (8.62%) patients and basal-like (or triple negative) was present in 27 (9.31%) patients. CONCLUSION: Detecting the subtype of breast cancer is important for evaluating the prognosis of the disease, but also for determining and providing an adequate therapy. Therefore, determining the subtype of breast cancer is necessary for the routine histopathological assay. PMID- 29983787 TI - Usefulness of Sunlight and Artificial UV Radiation Versus Chlorine for the Inactivation of Cryptosporidium Oocysts: An in Vivo Animal Study. AB - BACKGROUND: Cryptosporidium is an important waterborne protozoan. AIM: The aim of this study was to investigate the effect of sunlight being the natural source of UV and artificial UV irradiation on Cryptosporidium oocysts versus the effect of chlorination, being the traditional method of water disinfection and to provide an insight into the viability and degree of infectivity of Cryptosporidium oocysts, using an animal model. METHODS: An experimental study including 300 neonatal mice was carried out to investigate the effect of artificial ultraviolet (UV) irradiation and sunlight being the natural source of UV irradiation versus chlorine, the traditionally used water disinfectant on the infectivity of Cryptosporidium oocysts present in water. For each item, nine different exposure times were investigated. Parasitological assessment (Modified Ziehl Neelsen stained stool smears) and histopathological assessment of the excised segments of the small intestine (stained by both Haematoxylin & Eosin and ZN stain) of mice were used to verify the inactivation of oocysts. RESULTS: Cryptosporidium oocysts failed to induce any noticeable infection after 4 hours of artificial UV exposure that provided a UV dose of 10mJ/cm2 and after an 8 hours exposure to sunlight, whereas they showed resistance to disinfection by chlorine. CONCLUSION: The results of the study demonstrate the important role of an 8 hours sunlight exposure of potable water in plastic bottles in achieving complete inactivation of any contaminating Cryptosporidium oocysts, thus offering an applicable, economical and convenient method for the control of cryptosporidiosis especially in developing countries. PMID- 29983788 TI - Isothermal PCR for Feasible Molecular Diagnosis of Primary Toxoplasmosis in Women Recently Experienced Spontaneous Abortion. AB - AIM: The current study aimed to assess the practicability of a simple loop mediated isothermal amplification (LAMP) about real-time quantitative PCR to diagnose primary toxoplasmosis among high-risk pregnant women. METHODS: Cloned Toxoplasma samples were used to calculate the analytical sensitivity while specificity was assessed using pooled DNA samples extracted from other parasitic stages. RESULTS: Both techniques showed 100% sensitivity and specificity and then applied to detect recent Toxoplasma infection in peripheral blood of 77 IgG negative women out of a total 139 women lately experienced spontaneous abortion. The 2 techniques obtained positive results in 8 samples confirming primary toxoplasmosis. CONCLUSION: Generally, LAMP assay is a simple, cost-effective molecular technique can be completed in less than half an hour to diagnose primary Toxoplasma infection. The technique can be applied in a minimally equipped laboratory by ordinary workers to screen the vulnerable groups. Further analysis using larger samples with the quantitative approach is recommended to confirm the sensitivity of this emergent molecular technique. PMID- 29983789 TI - Anatomic Variations of Pancreaticobiliary Union. AB - AIM: This study was designated to evaluate the frequency of anatomic variations of the pancreaticobiliary union. MATERIALS AND METHODS: Our research was observational, comparative and analytical. The investigation was conducted from January 2016-May 2017. This study included 63 patients from Clinic of Gastroenterology and Hepatology - Prishtina, assessed pancreaticobiliary union with Magnetic Resonance cholangiopancreatography. RESULTS: Union of the common bile duct and the major pancreas was biliary-pancreatic type The angle between common bile duct and the major pancreas duct had different sizes average 35.6 degrees . We did not distinguish significant statistical significance in the size of the pancreaticobiliary angle. In men, the union angle was from the average 36.9 degrees , while in females was average 34.3 degrees . No correlation between the age and size of the angle between common bile duct and the major pancreas duct. CONCLUSIONS: The union of the common bile duct and the major pancreas duct was in most cases B-P Type. The common channel and angle between common bile duct and the major pancreas duct were normal in most cases. PMID- 29983790 TI - In Vitro Action of Meconium on Bronochomotor Tonus of Newborns with Meconium Aspiration Syndrome. AB - AIM: Here we studied the role of meconium in the respiratory system on live and exited newborns (weight 250-3000 g). Throughout this study is followed the response of tracheal rings in acetylcholine and histamine in different molar concentrations (10-1, 10-2, 10-3, 10-4 mol/dm3). METHODS: To study the smooth tracheal musculature we used 23 tracheal preparations obtained from the newborns exited from meconium aspiration. RESULTS: Based on the functional analysis of the tracheal specimen we have concluded that the meconium aspiration did not change the smooth musculature response on acetylcholine and histamine when compared to control group, exited from lung inflammatory processes (e.g., pneumonia, bronchopneumonia, atelectasis, cerebral hemorrhage), where tracheal smooth musculature response is significant (P for other causes is not significant (P > 0.01). CONCLUSION: The conclusions suggest that meconium did not potentiate the constrictor action of acetylcholine and histamine in the tracheobronchial system and did not cause modulation of bronchomotor tonus in case of his aspiration. Meconium causes mild relaxation of smooth tracheal musculature with a mechanism which is not mediated by cyclooxygenase products, from tracheal epithelium or proteins. Also, direct activity in the smooth musculature of several tested acids seems to have no significant impact in increasing the tonus of respiratory airway of smooth tracheal musculature. PMID- 29983791 TI - Morphology of the Ovaries in Condition of Inhalation Intoxication with Dust Saline Aerosols of the Aral Sea in Female White Rats. AB - BACKGROUND: After some clinical studies of the reproductive health of the female population of the Aral Sea region, we concluded that it is necessary to confirm by experiment the theory of the direct influence of dust-saline aerosols of the Aral Sea on the reproductive system of female individuals. AIM: The purpose of this work is to study the effect of dust-saline aerosols of the Aral Sea on the folliculogenesis process in rats at inhalation intoxication. METHODS: Inhalation in rats was carried out for 30 days for 4 hours a day for 5 days a week in special inoculating cylindrical chambers with the extra-chamber placement of animals in individual boxes and dynamic aerosol delivery. Morphological changes were assessed using electron microscopy. RESULTS: Ultrastructural changes in the ovaries of the experimental study group were characterised by the pathology of all structures of the cortical substance of the organ. The accumulation of lutein pigment, the utilisation of lipid inclusions and the destruction of the complete cell reflected the pathology of estrogen production-an important factor in the postovulatory phase of the ovarian cycle. CONCLUSIONS: Taking into account the proven effect of dust-saline aerosols on the production of estrogen, the violation of the postovulatory phase of the ovarian cycle, we trace the mechanism of folliculogenesis disturbance. This confirms the data of our previous studies on primary and secondary infertility in women living in the Aral Sea region and the necessity of creation and development of preventive measures for the inhabitants of the region. PMID- 29983792 TI - Tumour Lymphocytic Infiltration, Its Structure and Influence in Colorectal Cancer Progression. AB - BACKGROUND: The role of the immune system in the control of tumour progression has been stressed, recently. Many studies indicate the fact that the immune system can prevent tumour progression in several types of human malignant neoplasms including colorectal cancer. According to some authors, a higher density of "tumour-associated lymphocytes" (TAL), in malignant neoplasms, correlate with prolonged survival of patients. AIM: This study aims to determine the structure and the influence of the immune cells, TAL, in the progression of colorectal cancer (CRC). PATIENTS AND METHODS: The study included 103 patients with CRC operated at the University Clinic of Digestive Surgery in Skopje, whose operative material was analysed at the Institute of Pathology, Medical Faculty in Skopje. The structure of tumor-associated cells and their density were determined and were correlated with neoplasm's grade, local growth (T), positive lymph nodes, lymphatic invasion and stage of the disease. RESULTS: CD4+, CD8+ and CD20+ lymphocytes (Ly) were found in TAL. The density of TAL was significantly different in neoplasms with different T status, lymphatic invasion, patients with and without nodal metastasis and patients with a different stage of the disease. The density of CD4+, CD8+, and CD20+ cells were significantly different in neoplasms with different T. The density of CD8+ and CD20+ lymphocytes was lower in patients with nodal metastasis and higher stage. CONCLUSION: The density of tumor-associated lymphocytes can anticipate the disease progression in patients with colorectal cancer, and the density of TAL influences the control of tumour progression. PMID- 29983793 TI - Serum Markers of Iron Metabolism in Chronic Liver Diseases. AB - BACKGROUND: Disorders in the metabolism of iron in the direction of iron overload are observed not only in primary hemochromatosis but also in some chronic liver diseases other aetiology. Elevation of serum iron, ferritin and transferrin saturation is reported in nonalcoholic fatty liver disease and alcohol, chronic hepatitis C and liver cirrhosis. AIM: Aim of the study was to evaluate and compare the frequency of the iron serum markers in patients with various chronic liver diseases. MATERIAL AND METHODS: The study included a total of 246 persons 186 patients with chronic liver disease without cirrhosis (-115 men, women -71; average age of 50.41 +/- 12.85, from 23 to 77 years) and 60 healthy controls (-30 men, women -30, middle-aged 50.50 +/- 11.31, from 29 to 83 years). Medical history, physical examination and demographic data including height, weight, laboratory and instrumental studies were performed. RESULTS: The highest incidence of elevated serum iron, transferrin saturation and ferritin and decreased serum hepcidin found in cases of alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC). CONCLUSION: Finally, analysis of the changes in serum markers of iron metabolism shows that the difference between healthy and sick with liver disease is primarily due to changes in alcoholic and nonalcoholic fatty liver disease, particularly steatohepatitis, and chronic hepatitis C. PMID- 29983794 TI - Upregulation of Twist2 in Non-Muscle Invasive Urothelial Carcinoma of the Bladder Correlate with Response to Treatment and Progression. AB - BACKGROUND: Twist2 is a transcription factor and an epithelial-to-mesenchymal transition that plays an important role in cell polarity, cell adhesion, and has a role in tumour invasion and metastases. AIM: In this study, we examined the expression of Twist2 in non-muscle invasive bladder carcinoma (NMIBC) and correlated the expression with response to treatment and tumour progression. METHODS: Data of 305 patients with NMIBC of Ta, T1 were retrieved from hospitals archives. Twist2 expression was examined in tissue samples by immunohistochemistry at initial diagnosis and final follow-up, normal control was 10 normal urothelium, 10 patients with muscle-invasive bladder cancer (MIBC) were a positive control. Treatment of NMIBC was implemented according to the European Association of Urology guidelines on NMIBC. The descriptive statistical analysis included means, standard deviation, p-value; Univariate and multivariate Cox regression analyses. RESULTS: Twist2 expression score was identified as negative, low (1-15%); medium (15-40%); and high (40-100%). Patients who had low or low medium scores at the initial diagnosis had a good response and a favourable prognosis. Expression of a high score of Twist2 in patients having high-grade T1 tumours showed non-responsiveness to repeated courses of intravesical bacillus Calmette Guerin (BCG) therapy and was upstaged to MIBC. CONCLUSION: Twist2 expression in tissue samples of NMIBC would indicate the tumour response to therapy, upgrading and upstaging in the follow up after intravesical BCG therapy. PMID- 29983795 TI - Nitric Oxide and Pre-Eclampsia: A Comparative Study in Ghana. AB - BACKGROUND: Preeclampsia is one of the commonest aetiologies of foetal and maternal mortality and morbidity. Though common, the aetiology of preeclampsia has remained unknown with several inconclusive theories surrounding the disease. Recent studies have implicated vascular endothelial dysfunction and possibly nitric oxide in preeclampsia. AIM: To compare plasma nitric oxide levels in pre eclampsia and healthy pregnant women in a large tertiary hospital in Ghana. METHODS: This was a case-control study conducted among pre-eclampsia and healthy pregnant women in Korle-Bu Teaching Hospital over a four-month period. Thirty (30) pre-eclamptic and 30 healthy pregnant women aged 18-35 years with over 30 weeks' gestation were consecutively recruited into the study after obtaining informed consent. Plasma nitric oxide levels were determined using the Griess Reagent system. Data were analysed using Statistical Package for the Social Sciences (SPSS) software version 20.0 and results were compared using the independent t-test. A P-value of <= 0.05 was considered statistically significant. RESULTS: The parity and body mass index (BMI) of the participants were similar. There was a significant difference in the blood pressure of the pre eclamptic compared to healthy pregnant women. There was no statistically significant difference (P-value = 0.160) in the plasma levels of nitric oxide in pre-eclamptic (Mean = 1178.78; SD = 89.70 nM) compared to healthy pregnant women (Mean = 1365.43; SD = 95.46 nM). CONCLUSION: Plasma nitric oxide levels may not play a significant role in the aetiology of pre-eclampsia. PMID- 29983796 TI - Obstetric Outcome in Pregnant Patients with Low Level of Pregnancy-Associated Plasma Protein A in First Trimester. AB - BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A), is a protease which releases Insulin-like growth factor. The role of this factor is stimulation of cell mitosis, differentiation and trophoblastic invasion of deciduas. Identification of patients with low PAPP-A (under 0.4 MoM in the first trimester has an influence on birth weight, attenuation of fetal growth, preeclampsia, birth and fetal demise. AIM: The main issue in the study is evaluating an influence of PAPP-A, calculated in the first trimester on the unfavourable outcome of pregnancy. MATERIAL AND METHODS: Seventy pregnant women with singleton pregnancy underwent first-trimester biochemical screening. The target group were women with PAPP-A below 0.4 MoM, and in control group, PAPP-A were over 0.4 MoM. There was an assessment of the influence on the mode of delivery, gestational week, the presence of intrauterine growth restriction, preeclampsia, temporary birth, intrauterine fetal demise and newborn condition. RESULTS: In target group, consisted of 35 patients, 16 were delivered at term. From 28 to 37 g.w.- were 7 patient, 22-28 g.w.- 4 and 8 patients were under the 22 g.w (all with fetal demise) there were 19 pretemporary deliveries - 9 with Cesarean Section (SC). In the target group: 5 newborn were with IUGR, 6 women had preeclampsia, 1 had placental abruption. In control group were 35 patients: 28 delivered at term, 9 with SC, 26 vaginal deliveries; with IUGR were 4 newborns. Two newborns were hypertrophic. CONCLUSION: There is a significant difference in unfavourable outcome in the cases with PAPP-A under 0.4 Mom, particular in the group, with a PAPP-A value under 0.2 MoM. The patients delivered with SC with the main indications in utero hypoxia, growth restriction and elevated blood pressure had PAPP-A between 0.3-0.4 MoM. The patients with intrauterine fetal death and placental abruption in the most of the cases have PAPP-A value under 0.2 MoM. There is a need to be aware in these pregnancies to achieve the preventions of adverse outcome, to decrease perinatal morbidity and mortality. PMID- 29983797 TI - Evaluation of the Clinical Proficiency of RDTs, Microscopy and Nested PCR in the Diagnosis of Symptomatic Malaria in Ilorin, North-Central, Nigeria. AB - BACKGROUND: Accurate laboratory diagnosis of suspected malaria is the hallmark to the control of the disease. AIM: The clinical proficiency of commercial Rapid Diagnostic test kits (RDTs) using nested PCR as quality control was evaluated among patients attending two public healthcare providing institutions in Ilorin, Kwara state, North-Central, Nigeria. METHOD: A cross-sectional evaluation of finger prick blood samples of volunteer patients were accessed for malaria parasites with pLDH, HRP2, Pf, Pf/PAN and nested PCR molecular assays. The data derived were analysed using standard formulae for diagnostic accuracy, and the obtained predictive values were subjected to a comparison with one-way analysis of variance (ANOVA). RESULT: Three hundred and sixty-eight (368) patients comprising 203 (55%) females and 165 (45%) males participated in this study. Routine microscopy revealed that 54 (32.7%) males and 80 (39.4%) was infected with Plasmodium falciparum. SD Bioline (pLDH) 47.4%; Carestart Malaria (HRP2) 49.8% recorded low sensitivities. Micropoint (pfPAN) 82.8% and Micropoint (Mal. Pf) 64.4% recorded a high sensitivity. SD Bioline (pLDH) 67.4%; Carestart Malaria (HRP2) 85.9%; Micropoint (PfPAN) 62.2% and Micropoint (Mal. Pf) 86.7% had high specificities. The positive predictive value (PPV) ranged from 67.7% to 85.94%, while the negative predictive values (NPV) of 64.4% for SD Bioline (pLDH); 86.7% for Carestart Malaria (HRP2); 89.3% for Micropoint (pfPAN) and 58.5% for Micropoint (Mal. Pf). Agarose gel analysis of P. falciparumssrRNA gene (206 bp) for 28 specimens containing 10% concordant and discordant samples showed that all 12 negative specimens for RDTs and routine microscopy were truly negative for nPCR. However, the remaining 16 specimens were positive for nPCR and showed discrepancies with routine microscopy and RDTs. Cohen's interrater diagnostic measure analysis revealed that the weighted kappa for the RDTs was moderate 0.417 (p=0.027), 95%CI (0.756, 0.078) and good for nPCR 0.720 (p < 0.001), 95%CI (0.963, 0.477). The area under the curve (AUC) specify that nPCR has been more effective than the RDTs (nPCRAUC = 0.875; p < 0.001 and RDTsAUC = 0.708; p = 0.063). CONCLUSION: A thorough large-scale quality control is advocated on all commercial RDTs being used in most sub-Saharan African countries. This is to avoid double jeopardy consequent upon misdiagnosis on unidentified positive cases serving as pool reservoir for the insect vector and cyclical infection and re infection of the populace. PMID- 29983798 TI - Proton Pump Inhibitors Diminish Barrett's Esophagus Length: Our Experience. AB - AIM: Our main objectives were to evaluate the influence of two-year proton pump inhibitors (PPI) therapy in patients with Barrett's oesophagus on its length, in both types, short and long segment. METHODS: In this single-centre, prospective interventional controlled study were analysed data collected prospectively over two years from patients with Barrett's oesophagus diagnosed by endoscopy. Patients who received continuous proton pump inhibitors (PPI) for 2 years were included. At each patient visit symptoms were recorded, and at each endoscopy, the length of Barrett's oesophagus (BE) was measured. Biopsies were taken along the length of the oesophagus at intervals of 1 cm. In total, 50 patients with Barrett's oesophagus were included in the study: 10 of whom had long-segment Barrett's oesophagus, and 40 patients had short-segment Barrett's oesophagus. The mean number of endoscopies performed was 3 per patient. RESULTS: The length of Barrett's esophagus (BE) was influenced by PPI therapy: Circumferential extension in BE patients short-segment Barrett's esophagus (SSBE) (before treatment was 1.5 cm and after treatment was 0.8 cm Maximum proximal extension in SSBE group before treatment was 2.3 cm (SD +/- 1.1 cm), and 1.1 cm (SD +/- 0.9 cm), respectively. Squamous islands were detected in 25% of patients examined after 2 years on PPIs. CONCLUSIONS: PPIs achieve a reduction to the length of Barrett's oesophagus, in both types, and the development of squamous islands is commonly associated with their use. PMID- 29983799 TI - Influence of the Type and Amount of Liver Resection on the Survival of the Patients with Colorectal Metastases. AB - INTRODUCTION: Colorectal liver metastases have a poor prognosis, and only 2% have an average 5-year survival if left untreated. Despite radical resection, the average five-year survival is between 25% and 44%. AIM: To explore the experience of the Clinic in the treatment of colorectal liver metastases, comparing it with data from the literature and based on the comparison to determine the influence of the type and extensity of resection survival after radical surgical treatment of patients. METHODS: This is a retrospective study. The study comprised the period between 01.01.2006 to 31.12.2015. It included a total of 239 cases, of whom: 179 patients underwent radical interventions, 5 palliative and 55 patients underwent explorative interventions due to liver metastases. RESULTS: Radical resection of liver metastases has the impact of the patient survival, and the survival is the smallest in the patients with left hemihepatectomy and the longest in the patients with bisegmentectomy. But no specific technique and the number of resected segments influenced the survival of patients with colorectal liver metastases. CONCLUSION: In patients with colorectal liver metastases only resection has potentially curative character. The type and amount of liver resection has no influence of the survival. PMID- 29983800 TI - Noninvasive Biomarkers in Assessment of Liver Fibrosis in Patients with HBeAg Negative Chronic Hepatitis B. AB - BACKGROUND: Liver biopsy for evaluation of liver fibrosis has several adverse effects, for which reason noninvasive tests have been developed. AIM: To evaluate the usefulness of noninvasive biomarkers, qHBsAg and HBV DNA levels in predicting liver fibrosis in patients with hepatitis Be antigen (HBeAg) negative chronic hepatitis B (CHB). MATERIAL AND METHODS: This prospective study included 50 patients with HBeAg negative CHB. All patients underwent laboratory and serology testing, quantification of HBV DNA and HBs antigen. The liver stiffness was measured with elastography. The patients were analysed for APRI and FIB-4, quantitative hepatitis Bs antigen and HBV DNA. RESULTS: Logistic regression analysis showed that greatest significance in predicting liver fibrosis has FIB-4 (Wald = 3.24, P = 0.07), followed by HBV DNA >= 2 000 IU/ml <= 20 000 IU/ml (Wald = 2.86, P = 0.09), qHBsAg (Wald = 2.17, P = 0.14), HBV DNA > 20 000 IU/ml (Wald = 0.58, P = 0.45), APRI (Wald = 0.04, P = 0.84). CONCLUSION: the FIB-4 index has the greatest value in predicting liver fibrosis while APRI has the lowest; the more advanced liver disease is associated with lower serum level of quantitative HBs antigen. Combination of noninvasive blood biomarkers and imaging tests can provide better diagnostic accuracy and exclude the need for liver biopsy. PMID- 29983801 TI - Apitherapy as a New Approach in Treatment of Palmoplantar Psoriasis. AB - BACKGROUND: Apitherapy is the medical use of honey bee products, "honey, propolis, royal jelly, bee wax, and bee venom to relieve human ailments. Propolis is one of the most well-documented products derived from the honeybee and has always played an important role in traditional folk medicine. AIM: The aim was to justify the consideration of Aloe Vera as an effective remedy for the treatment of psoriasis. METHODS: The study follows (857) patients (354 females, 503 males) with a mean age range from (9 - 62) years, affected with moderate to severe psoriasis in palms and foot soles treated by a combination mixture of propolis and Aloe in the form of an ointment (Aloreed) and Beauty reed cream. The treatment duration was for 12 weeks. Results were evaluated by using clinical, histological and statistical parameters. RESULTS: After the 12 - week treatment, we observed an 86% overall response rate from which 62% showed excellent results and 24% showed good results, therefore proving the efficiency in the use of the mixture of propolis 50% and aloe vera 3% as topically applied ointment in the treatment of mild to moderate psoriasis. CONCLUSION: Patients who have palmoplantar psoriasis, who were treated with a topically applied mixture of propolis (50%) and aloe vera (3%), have shown noteworthy improvement thus proving the efficiency of propolis and aloe vera in the treatment of mild to moderate psoriasis. PMID- 29983802 TI - The Effect of Self-Management Educational Program on Pain Intensity in Elderly Patients with Knee Osteoarthritis: A Randomized Clinical Trial. AB - BACKGROUND: Osteoarthritis is one of the chronic diseases that greatly affect the health and life quality of individuals. AIM: This study aimed to determine the effect of self-management educational program on the pain intensity of the elderly patients with knee osteoarthritis. METHODS: In a randomised clinical trial, a total of 82 elderly patients with knee osteoarthritis were randomly divided into intervention and control groups. The intervention group received six sessions of self-management group education, while the control group received only the routine care during this period. In both groups, patients' pain intensity, with a visual analogue scale (VAS), were assessed before, immediately after and eight weeks after the start of the study. RESULTS: The mean pain intensity scores of the intervention and control groups were not significantly different before the intervention (P = 0.9), but after the intervention, the mean pain intensity score in the intervention group (3.61 +/- 2.36) was significantly lower than that of the control group (4.93 +/- 2.00), (P < 0.0001). CONCLUSION: Implementation of a self-management program for the patients with knee osteoarthritis is useful in reducing their pain intensity and can be used as one of the effective methods for their empowerment. PMID- 29983803 TI - Third and Fourth Degree Perineal Tear in Four-Year Period at Sestre Milosrdnice University Hospital Center, Zagreb, Croatia. AB - OBJECTIVES: Obstetric anal sphincter injury (OASIS) includes the third and fourth degree of perineal injury. The risk for OASIS is about 1% of all vaginal deliveries. If not recognised and treated properly, obstetric anal sphincter injury can have serious consequences for reproductive age woman. MATERIAL AND METHODS: We have retrospectively gathered and analysed data on obstetric anal sphincter injury in a four-year period at our department. The control group in this study included vaginal deliveries in 2012. RESULTS: We recorded 0.34% third and fourth degree of perineal injury in all vaginal deliveries, and 87.9% of those patients were primiparae. Episiotomy was performed in 57.6% of all women with obstetric anal sphincter injury. In 30.3% of cases, newborns were large for gestational age. Gestational diabetes was found in 9.1% of OASIS cases, occipitoposterior position was found in 9.1% of cases. Induced labour took place in 39.4%, and oxytocin infusion was applied in 60.6% of OASIS cases. Vacuum extraction was performed in 12.1% of deliveries with OASIS. The average BMI in 3a and 3b injuries was 29.9. In 3c degree it was 28.0, and in the fourth degree, it was 32.1. In 27.0% of OASIS cases due to the extent of the injury surgeon engagement was necessary. When compared with vaginal deliveries in 2012 we found a significant increase in OASIS in primiparas, large for gestational age, occipitoposterior position, induced labour, vacuum extraction and hypertension (P < 0.01). There is also increased incidence of OASIS in episiotomy and oxytocin use group (P < 0.05). CONCLUSION: Low incidence of OASIS in our department is a result of active management of delivery, manual perineal protection and timely episiotomy. PMID- 29983804 TI - A Study of Nerve Conduction Velocity in Diabetic Patients and its Relationship with Tendon Reflexes (T-Reflex). AB - BACKGROUND: Neuropathy is one of the most common complications of diabetes mellitus. Neuropathy can cause the sensory deficit, neurological disorder, limb ulcers, osteomyelitis, and amputation. Therefore, neurological examinations, determining the nerve conduction velocity and performing sensory and motor tests are important for timely diagnosis and treatment. AIM: The present study aimed to investigate the nerve conduction velocity in diabetic patients and its relationship with tendon reflexes. MATERIAL AND METHODS: The present study was observational-cross sectional research carried out on 77 diabetic patients who were admitted into the EMG/NCV Department of Shariati Hospital in the academic year 1996-1997. In all patients, the medical history of the patient (age, duration of diabetes, gender and age of onset of diabetes), neurological examination, nerve conduction velocity, heat test, vibration test, tendon reflexes, D.L and Amplitude were examined and recorded. Finally, the raw data obtained were entered into the IBM SPSS Statistics software, and the important relationships between these variables were analysed. Moreover, in the present study, the statistical significance level (P-value) was considered less than 0.05. RESULTS: The present study was conducted on a population consisting of 48 women and 29 men with diabetes. The age range of participants was 14-70 years old with an average age of 50.506 +/- 7.50. The results of present study showed that the participants with clinical neuropathy (11.2 +/- 7.2) had a significantly longer duration of diabetes than the normal group and those participants with sub clinical neuropathy (P-value = 0.12). Statistical analyses indicated that increase in age, increase in the duration of diabetes and the gender of male significantly made the nerve conduction velocity abnormal. The analysis of the response to neural reflexes indicated that the ratio of neurological disorders in the five nerves of the ankle and knee was generally higher in the abnormal group (the patients with nerve conduction disorder) compared to the normal (the patients with normal nerve conduction) and in some cases, such as the ulnar motor nerve of ankle (P-value = 0.010), and the ulnar motor nerve of knee motor (P value = 0.002) and also in the peroneal motor nerve of knee (P-value = 0.003) and the sural sensory nerve of knee (P-value = 0.003), increase in neurological disorders was significant. CONCLUSION: Increase in age, increase in the duration of diabetes, and the male gender can significantly increase the risk of abnormal nerve conduction velocity. PMID- 29983805 TI - Comparative Analysis of the Applicability of Island Flap in Primary and Recurrent Basal Cell Carcinomas of Similar Localization. AB - BACKGROUND: Basal cell carcinoma belongs to non-melanoma skin cancers and is the most prevalent neoplasia that shows a tendency to increase over the last few decades. It occurs most often in skin areas exposed to sunlight. It is characterised by slow progression, low tendency to metastasising and good prognosis when the right choice of treatment has been made. The difficulty in the treatment of basal cell carcinomas is determined by their localisation and puts to the test the aesthetic potential of dermatosurgeons. Complete surgical excision is the standard approach in most uncomplicated cases. In relapsing basal cell carcinoma or carcinoma with aggressive or unfavourable histopathological characteristics, the clinician faces the dilemma of identifying the most appropriate method of treatment. To find the decision, help comes from the individualisation of each case and the related risk factors. CASE REPORT: Two cases of basal cell carcinoma of similar localisation are presented, where the carcinomas are removed using island flaps. In spite of the desire to observe the recommended field of surgical security (by the desire for the ultimate esthetic effect for the patient), one of the tumours was not completely removed, and as an alternative, reoperation was proposed using Mohs micrographic surgery (MMS). CONCLUSION: The choice of a surgical technique, which would guarantee a better outcome and could be applied depending on the individual risk factor in each patient, is discussed. PMID- 29983806 TI - A Saudi Infant with Vici Syndrome: Case Report and Literature Review. AB - INTRODUCTION: Vici syndrome, a rare autosomal recessive disorder, was first described in 1988 by Vici et al. Only 78 cases have been reported to date. The syndrome is characterised by agenesis of the corpus callosum, hypopigmentation, cardiomyopathy, progressive failure to thrive, dysmorphic features, immunodeficiency and cataracts. Mutations in the gene epg5 have been identified as the cause of Vici syndrome. CASE DESCRIPTION: The parents are a consanguineous Saudi couple with two other children diagnosed with Gaucher disease. The patient was born at term and in the first 5 months had many hospital admissions for a recurrent chest infection. Physical examination, investigations and imaging studies revealed that the patient had agenesis of the corpus callosum, cataracts, psychomotor delay, immunodeficiency and hypopigmentation. The initial echocardiogram was normal. At 7 months, genetic testing confirmed the diagnosis of Vici syndrome with a c.3693G>Ap (Gln1231Gln) mutation in the gene EPG5. The patient developed a chest infection and was admitted to the pediatric intensive care unit. An echocardiogram was repeated and showed significant left ventricular dilation with a Z-score of 3.1, moderate mitral and tricuspid regurgitation, and depressed ventricular function with a fractional shortening of 17% and ejection fraction 37%. The patient's condition deteriorated, and he died aged 8 months. CONCLUSION: The symptoms of extensive system involvement in Vici syndrome have been present in the majority of reported cases and should prompt careful evaluation of this syndrome when such symptoms are present in an infant. In confirmed cases, close monitoring of the immune status and cardiac function, the two main causes of death among Vici syndrome patients, is vital to prevent rapid deterioration and improve life expectancy. PMID- 29983807 TI - One Step Melanoma Surgery (OSMS) Without Using Ultrasonography for Preoperative Tumour Thickness Measurement? - "A Question that Sometimes Drives Me Hazy: Am I or Are the Others Crazy!" AB - BACKGROUND: One step melanoma surgery is a new surgical approach by which specific groups of patients with cutaneous melanoma may be operated only by or within a single surgical session. Until now, the Bulgarian Society for Dermatologic Surgery (BULSDS) has presented models of clinical behaviour, in which preoperative measurement of tumour thickness in combination with echographic measurement of the locoregional lymph nodes could lead to the conduct of the so-called one-step melanoma surgery. Although this one step surgery currently does not fit in the recommended guidelines, it ensures compliance of the recommended boundaries of operational security while saving patients a repeated excision and relieves the healthcare institutions or the patients themselves financially. CASE REPORT: We at this moment present another case from the Bulgarian Society for Dermatologic Surgery (BULSDS) of one step melanoma surgery with a perfect end result, where the tumour thickness was not preoperatively determined by high-frequency echography. Preoperative assessment of tumour thickness was performed based on the clinical picture and dermatoscopy. The histologically established tumour thickness was identical to the preoperative assessment, i.e. <1 mm. Removal of the melanocytic lesion was performed with operational security field of 1cm in all directions, where, as a rule, no further removal of the draining lymph nodes is required. CONCLUSION: One step melanoma surgery has two significant advantages: 1) it saves a re-excision in certain groups of patients, which in turn is 2) significantly more favourable from a financial point of view. Its applicability in the appropriate groups of patients and the postoperative (although in a limited number of patients) results achieved indicate the need to optimise the current algorithms and direct them individually to each patient. Guidelines may not and should not be unified or set strict limits given the fact that they show a significant level of variability themselves regarding some key moments in the initial surgical treatment of melanoma. More than 10% of the primary melanoma cases refer to thin melanomas, and dermatoscopy and clinics are a sufficient method of optimising the planned surgical excision. PMID- 29983808 TI - Endometrioid Adenocarcinoma Arising in Adenomyoma in a Woman with a Genital Prolapse - Case Report. AB - BACKGROUND: Endometrial cancer is the third-ranked genital malignancy in women and includes 3% of cancer deaths. There is a 2.8% chance of a woman developing endometrial cancer during her lifetime. Low-grade endometrioid adenocarcinomas are often seen along with endometrial hyperplasia, but high-grade endometrioid adenocarcinomas have more solid sheets of less-differentiated tumour cells, which are no longer organised into glands, often associated with surrounded atrophic endometrium. CASE REPORT: We present an unusual case of endometrial adenocarcinoma arising in adenomyoma in 74-year old woman presented with genital prolapse, without other clinical symptoms. Ultrasound evaluation revealed endometrium with 4 mm-thickness and atrophic ovaries. The cervical smear was normal. The patient underwent a total vaginal hysterectomy. The histopathology of the anterior uterine wall revealed an intramural adenomyoma of 4 mm in which some endometrial glands with malignant transformation of well-differentiated endometrioid adenocarcinoma without infiltration in surrounding myometrium and lymphovascular invasion were present. The endometrium lining the uterine cavity was predominantly atrophic, and only one focus of simplex and complex hyperplasia was found, with cell-atypia. According to AJCC/FIGO 2010, the tumour was classified: pTNM = pT1B pNX pMX G1 R0 L0 V0 NG1, Stage I. On dismiss, the near future oncological consultation was recommended. CONCLUSION: We would like to point out the rare occurrence of such type of malignancy and the importance of meticulous histopathology evaluation, even after reconstructive surgery for genital prolapse. PMID- 29983809 TI - Recycling of Previously Transplanted Hair: A Novel Indication for Follicular Unit Extraction. AB - BACKGROUND: Hair transplantation has enhanced the realm of procedural dermatology. Before the advent of follicular transplantation, androgenetic alopecia was a difficult disease to manage, as there is a limited armamentarium of topical and systemic pharmaceuticals. However, as with other novel surgical procedures, there is a steep learning curve, that may result in poor transplantation or cosmesis. CASE REPORT: We present a case of androgenetic alopecia, where previously, poorly implanted hairs were recycled by follicular unit extraction to increase hair density at the vertex of the scalp, which resulted in improved cosmesis and patient satisfaction. CONCLUSION: We have demonstrated that re-transplantation is not only feasible but is effective; therefore redesigning of previous transplantations should be considered as a possible indication follicle unit extraction, particularly in the setting of scarce follicular reserves. The utility of our recycling method may also inspire hope in patients that have undergone failed or unsatisfactory hair transplantations. PMID- 29983810 TI - Surgery Resection of a Massive Thymic Carcinoma during Urgent Coronary Artery Bypass Grafting. AB - BACKGROUND: Thymic carcinoma is a very rare tumour. It is classified as thymoma type C according to World Health Organization classification. There are not many publications of simultaneous surgical treatment of thymoma during cardiac surgery interventions. CASE REPORT: We present a case of simultaneous surgical treatment of incidentally discovered thymic carcinoma during an urgent coronary artery by pass operation. A 55-year-old man with diagnosis three coronary vessel diseases indicated urgent by-pass surgery. The patient underwent triple coronary bypass surgery. During the intervention, it was discovered incidentally a strong mass 15 x 12 cm located in the right pleural space. A tumour was excised totally, and biopsy referred thymoma type C or thymic carcinoma. The patient did very well early postoperatively. He was referred to oncologist clinicians for further treatment. The patient was clinically very good for at least 1.5 years after surgery. CONCLUSION: We think that simultaneous surgical treatment of thymoma, whenever it is encountered during cardiac surgery procedures, is the recommended solution. PMID- 29983811 TI - An Uncommon Occurrence of Pleomorphic Adenoma in the Submandibular Salivary Gland: A Case Report. AB - BACKGROUND: Pleomorphic adenoma is a salivary gland tumour and mostly found in the parotid gland and quite uncommon in the submandibular gland. Pleomorphic tumours are a mixed tumour (benign mixed tumour) consisted of epithelium, myoepithelium, and mesenchyme and made of a view component variation of it. CASE REPORT: We reported a fifty-three years old man with pleomorphic adenoma that has been complaining swelling on the left neck for the last twenty years and treated with surgical excision. Computed tomography of the neck showed soft tissue tumour in the left submandibular. CONCLUSIONS: The best management for pleomorphic adenoma is surgery, the tumour tissue must be removed as a whole because the remaining parts of a tumour can easily become recurrent or turn into a malignant tumour. PMID- 29983812 TI - Associations between Diet, Dietary and Oral Hygiene Habits with Caries Occurrence and Severity in Children with Autism at Dammam City, Saudi Arabia. AB - AIM: The purpose of the study is to achieve the baseline information of the autistic child's oral health status about the diet, dietary and hygiene habits. The association of these factors with dental caries were assessed. MATERIAL AND METHODS: The survey was composed of self-administered questionnaires to parents about their children's' demographic data followed by questions related to diet, dietary and hygiene habits. This is later followed by oral examination for estimating the decayed, missing and filled [dmft] scores as per WHO norms. The variables are analysed using t-tests and ANOVA. Pearson's correlation coefficients were calculated for each of the independent variables to examine for autocorrelation. RESULTS: The mean age for the present study is 5.8 years with more predilections of caries in females. The autistic children prefer soft diet and pouch it in oral cavity resulting in increased caries though not significant. Other foods like nuts and pulses confectioneries and soft drinks resulted in increased caries, and our study shows significant relation. Consumption of sugars between meals and increased quantity of sugar per day also increased dental caries with highly significant results in our study. Hygiene habits also made a difference in the occurrence of caries though, in our study, it's not significant. CONCLUSIONS: The study suggests that the oral health education programs should be conducted for the parents, caregivers and the teachers about the diet, dietary and the hygiene habits and the role they play in maintaining the oral hygiene. PMID- 29983813 TI - Comparative Study Clarifying the Most Suitable Material to Be Used as Partial Denture Clasps. AB - BACKGROUND: Removable partial denture's clasp is of particular importance as it affects the denture longevity during the function. The key of successful clasp selection is to select a direct retainer that will control tipping and torquing forces on the abutment teeth, provide retention against reasonable dislodging forces and are compatible with both tooth and tissue contour and the aesthetic desire of the patient. In this consideration, different materials employed for the clasp construction were compared mechanically. AIM: This study aims to compare the most usable esthetic clasps mechanically to clarify the most suitable material to be used as partial denture clasps. METHODS: Evaluation of surface roughness, retention and deformation has been investigated utilising different in vitro methods. All these techniques provide valuable information regarding the mechanical properties of the materials tested. However, none of the in-vitro techniques can expose the tested materials to conditions similar to that of the oral environment (in-vivo) such as pH value and temperature variations. RESULTS: Most commonly, RPD clasps are fabricated from the same alloy of the metal framework, as cobalt-chromium (CoCr) alloy although it is unaesthetic. Other methods consumed to avoid such esthetic mystery have included coating retainers with tooth-coloured resin or introduction of esthetic materials as Thermoplastic Acetal, Versacryl, and Thermopress. CONCLUSION: It has been concluded that the non-metal Acetal resin retainer reveals superior mechanical properties. PMID- 29983814 TI - Retention of Approximal Guiding Plane Surfaces in Removable Partial Skeletal Prosthesis. AB - BACKGROUND: The morphology of the retention tooth often does not correspond with the required design; hence there is often an indication for enamel recontouring or other restorative procedures. AIM: The study aimed to determine the impact of changing the path of insertion of the prosthesis by reshaping the anatomical and morphological structures of the natural teeth predetermined for the retention of the prosthesis. MATERIAL AND METHODS: The group of 40 patients with Class II, Subclass 1 according to Kennedy was formed, and 120 approximal surfaces of retention teeth were obtained. Two different types of prostheses were made on the models: one group in the zero point position of the model, and another group in the zero position of the model, with changing of the direction of input at an angle of 2 degrees . RESULTS: The difference between the established and theoretical normal distribution of frequencies was tested with the Kolmogorov Smirnov and Lilliefors tests (r < 0.10; r < 0.01). The first group showed a retention force of 0.08 N. In the second group the retention force was 0.94 N. CONCLUSION: It could be concluded that the change in the path of insertion of the dental prosthesis with conservative restorations as composite inlays, as well as the accurate extension of the prosthesis onto guiding plane surfaces, will undoubtedly increase the retention force of the prosthesis. PMID- 29983815 TI - Evaluation of the Masticatory Efficiency at the Patients with New Complete Dentures. AB - BACKGROUND: There are a lot of factors influencing the efficiency of mastication; therefore there are also a lot of methods for testing this efficiency. OBJECTIVE: The study aimed to test the efficiency of mastication and evaluate it in the function of time, based on previous experience with the complete dentures. METHODS: A total of 88 patients (42 female, 46 male, mean age 52.2, SD = 5.76), complete dentures wearers, participated in this study. Masticatory functions were investigated by using the method of electromyography (EMG), analyzing electromyomasticatiogram. For testing the masticator efficiency, the further parameters of the masticatiogram were used: duration of the Standard Masticatory Task (SMT) (t), number of the masticatory cycles within the masticator arch (F) and maximal amplitude within the masticatory arch (F). All data were statistically analysed by using standard software package BMDP (bio-medical Statistical package). Parametric data have been tested using One Way Repeated Measurement of ANOVA test. RESULTS: The changes of the relation A/t are evident in different time intervals in both measured sides: F-DS-time of the measurement = 34.86, P = 0.0000; F-NDS- time of the measurement = 26.1, P = 0.0000. There are also differences of the masticatory index A/t between sexes in both, dominant and non-dominant side: F-DS-gender = 237.05, P = 0.0000; F-NDS-gender = 12.90, P = 0.004. Masticatory index (A/F) varies in time, from first to the sixth measurement in both sides: F-DS-time of the measurement = 32.36, P = 0.0000; F NDS-time of the measurement = 30.53, P = 0.0000. The interaction of the time and gender was also important: F-DS-interaction = 6.95, P = 0.0000; F-NDS-interaction = 14.9, P = 0.0000. CONCLUSION: Masticator indexes are A/F, and A/t are a very important indicator of the masticatory efficiency and the level of the functional adaptation on complete dentures. Both masticator indexes show the same dynamics (reaching the stationary condition after the 15th week after getting new dentures). After the observing period, all examinee express the same degree of masticator efficiency known as functional adaptation. Patients with previous experience with complete dentures reach faster the stationary condition, compared with those non-experienced. PMID- 29983816 TI - The Effect of Orthodontic Intervention on Mental Health and Body Image. AB - AIM: Physical health especially oral and dental health can play a leading role in individuals' mental health status. Therefore, determining the relationship between orthodontics, mental health, and body image can provide solutions for the development of treatment services and provision of greater accessibility of communities to them. METHODS: The present study was natural experimental research conducted to determine the relationship between orthodontic treatment, mental health, and body image. To conduct this research, individuals referring to orthodontic clinics in the city of Kermanshah and meeting the inclusion criteria in the study were selected using convenience sampling method and then they were assessed before and after undergoing orthodontics via the standardised Goldberg's General Health Questionnaire (GHQ) and Multidimensional Body-Self Relations Questionnaire (MBSRQ). RESULTS: The mean scores of mental health problems in the study participants reduced and such a difference calculated by Wilcoxon signed rank test with a 95% confidence level was significant (P = 0.001). Moreover, all the subscales of GHQ in the study participants showed a significant decrease after orthodontics compared to the stage before that (P < 0.05). The mean score of MBSRQ before orthodontics was equal to 171.78 and this value reached 172.51 after that, indicating individuals' increased scores and their high levels of satisfaction with their body image. Nevertheless, the given difference was trivial, and it was not statistically significant (P = 0.751). CONCLUSIONS: The results of the present study showed that orthodontic treatment could significantly increase mental health status in the clients and also improve multidimensional attitudes towards body image. PMID- 29983817 TI - Recent Advances in Material and Geometrical Modelling in Dental Applications. AB - This article touched, in brief, the recent advances in dental materials and geometric modelling in dental applications. Most common categories of dental materials as metallic alloys, composites, ceramics and nanomaterials were briefly demonstrated. Nanotechnology improved the quality of dental biomaterials. This new technology improves many existing materials properties, also, to introduce new materials with superior properties that covered a wide range of applications in dentistry. Geometric modelling was discussed as a concept and examples within this article. The geometric modelling with engineering Computer-Aided-Design (CAD) system(s) is highly satisfactory for further analysis or Computer-Aided Manufacturing (CAM) processes. The geometric modelling extracted from Computed Tomography (CT) images (or its similar techniques) for the sake of CAM also reached a sufficient level of accuracy, while, obtaining efficient solid modelling without huge efforts on body surfaces, faces, and gaps healing is still doubtable. This article is merely a compilation of knowledge learned from lectures, workshops, books, and journal articles, articles from the internet, dental forum, and scientific groups' discussions. PMID- 29983818 TI - Persuading Iranian Women toward Normal Vaginal Delivery: Using Pictorial Perception of the Labour Process. AB - BACKGROUND: Pictorial education could provide an innovative approach for health educators which help to increase health-related information, the attention of individuals, comprehension, and recall. AIM: The purpose of this study was to determine the effect of pictorial perception of labour process by persuading Iranian women toward normal vaginal delivery. MATERIALS AND METHODS: The pre and post non-randomized trial with control group carried out on non-probability sample consisted of 76 pregnant women during the third trimester of pregnancy in the four urban health care centres in Pars-Abad city, Iran, during 2014. Demographic, knowledge, attitude, subjective norms, outcome expectations, self efficacy, and intention to do normal vaginal delivery variables were measured by using self-administered questionnaire and via the self-report method. Data analysis was performed using SPSS-21 software by Independent t-test, repeated measure, paired T-test, ANOVA, chi-square, Cochran's Q, and McNemar test. Manipulation included a pictorial education program to persuade pregnant women toward selecting normal vaginal delivery. RESULTS: The results showed significant improvement in mean scores of knowledge, attitudes, self-efficacy and behavioural intention of labour after manipulation in the intervention group (P < 0.001). It was found about 60% changes for intending to choose normal vaginal delivery, and 27/06% of women in the intervention group reported normal vaginal delivery versus the control group. And 10/81% of women did a cesarean section because of medical reasons during of delivery. Reduction of cesarean section was evident. Additionally, the annual rate of cesarean section decreased about 7% in comparison to the previous year. CONCLUSION: Pictorial education could be effective on the intention of women to choose natural vaginal delivery among pregnant women, and it can be used as an effective training technique for developing health literacy, enhancing self-efficacy and decision-making power of women in the delivery. PMID- 29983819 TI - Trend and Causes of Maternal Mortality in a Nigerian Tertiary Hospital: A 5-year Retrospective Study (2010-2014) at the University of Calabar Teaching Hospital, Calabar, Nigeria. AB - BACKGROUND: Maternal mortality ratios (MMR) are still unacceptably high in many low-income countries especially in sub-Saharan Africa. MMR had been reported to have improved from an initial 3,026 per 100,000 live births in 1999 to 941 in 2009, at the University of Calabar Teaching Hospital (UCTH), Calabar, a tertiary health facility in Nigeria. Post-partum haemorrhage and hypertensive diseases of pregnancy have been the common causes of maternal deaths in the facility. AIM: This study was aimed at determining the trend in maternal mortality in the same facility, following institution of some facility-based intervention measures. METHODOLOGY: A retrospective study design was utilised with extraction and review of medical records of pregnancy-related deaths in UCTH, Calabar, from January 2010 to December 2014. The beginning of the review period coincided with the period the "Woman Intervention Trial" was set up to reduce maternal mortality in the facility. This trial consists of the use of Tranexamic acid for prevention of post-partum haemorrhage, as well as more proactive attendance to parturition. RESULTS: There were 13,605 live births and sixty-one (61) pregnancy-related deaths in UCTH during the study period. This yielded a facility Maternal Mortality Ratio of 448 per 100,000 live births. In the previous 11-year period of review, there was sustained the decline in MMR by 72.9% in the initial four years (from 793 in 2010 to 215 in 2013), with the onset of resurgence to 366 in the last year (2014). Mean age at maternal death was 27 +/- 6.5 years, with most subjects (45, 73.8%) being within 20-34 years age group. Forty-eight (78.7%) were married, 26 (42.6%) were unemployed, and 33 (55.7%) had at least secondary level of education. Septic abortion (13, 21.3%) and hypertensive diseases of pregnancy (10, 16.4%) were the leading causes of death. Over three quarters (47, 77.0%) had not received care from any health facility. Most deaths (46, 75.5%) occurred between 24 and 97 hours of admission. CONCLUSION: Compared with previous trends, there has been a significant improvement in maternal mortality ratio in the study setting. There is also a significant change in the leading cause of maternal deaths, with septic abortion and hypertensive disease of pregnancy now replacing post-partum haemorrhage and puerperal sepsis that was previously reported. This success may be attributable to the institution of the Woman trial intervention which is still ongoing in other parts of the world. There is, however, need to sustain effort at a further reduction in MMR towards the attainment of set sustainable development goals (SDGs), through improvement in the provision of maternal health services in low-income countries. PMID- 29983820 TI - Effect of Exposure to Cement Dust among the Workers: An Evaluation of Health Related Complications. AB - BACKGROUND: Cement contains various types of chemicals in addition to lime and silica, and such chemicals cause different health complications and pathogenesis in addition to respiratory disorders. The most important occupational hazards for cement workers are allergy and complication related to respiratory system. AIM: The current study was performed by analysing the questionnaire distributed among the workers and also by the sputum collected from them to study the general health conditions and other life activities. METHODS: Sputum samples were assayed for cytological analysis by Hematoxylin and Eosin staining. RESULTS: In this study, it was observed that majority of these workers suffered from different types of respiratory complications, such as a cough, asthma and lung infections. In addition to this, few subjects showed allergy and other complication like hypertension, diabetes and backache. Moreover, cytological analysis of the sputum was made, and it was observed that majority of the subjects showed severe inflammation. CONCLUSION: Based on these finding, we concluded that long-term cement dust exposure and inhalation causes respiratory complications due to epithelial tissue damage and that can lead to secondary complications as well. PMID- 29983821 TI - The Correlation between Islamic Lifestyle and Pregnancy-Specific Stress: A Cross Sectional, Correlational Study. AB - BACKGROUND: Pregnancy is associated with great psychological, emotional and physical stress. In addition to undergoing hormonal changes, pregnant women experience a change in their attitude toward life and learn to re-assess their skills and lifestyle. Lifestyle, in general, and Islamic lifestyle, in particular, is concerned with the different psychological, social and physical aspects of the individual's life. AIM: This study was conducted to evaluate the correlation between Islamic lifestyle and pregnancy-specific stress in pregnant women. MATERIAL AND METHODS: This cross-sectional, correlational study was conducted on 300 pregnant women presenting to prenatal care clinics. Data were collected using a demographic, the Islamic lifestyle and the pregnancy-related stress questionnaires. RESULTS: The results showed a statistically significant negative correlation (r = -0.284) between Islamic lifestyle and pregnancy specific stress (P < 0.01). The stepwise regression showed that the mean score obtained in the pregnancy-related stress questionnaire decreased by 0.75 per year of marriage and by 0.14 per point in the Islamic lifestyle questionnaire. CONCLUSION: There was a significant negative correlation between Islamic lifestyle and pregnancy-specific stress. Training mothers, raising their awareness and encouraging them to adopt an Islamic lifestyle may play a significant role in controlling pregnancy-specific stress. PMID- 29983822 TI - Are Resilient Factors Increasing the Risk for Childhood Psychological Victimization? AB - BACKGROUND: Understanding the resilient factors and why some children do well despite early adverse experiences is crucial, because it can inform more effective policies and programs that help more children reach their full potential. AIM: The main objective of the study is to describe the associations between psychological abuse in childhood and resilient risk factors on individual, relational, contextual level among adolescents in the country and see the probability of resiliency to predict psychological victimisation. MATERIAL AND METHOD: Cross-sectional study on two-stage quota sample of 622 university students was applied in the study, including adolescents at first and second year at the main public Ss Cyril and Methodius University of Skopje, from the 12 faculties in the country. Adverse Childhood Experiences Study International Questionnaires was used for collecting information on psychological abuse, while the individual, relational and contextual resilient factors were measured using the Child and Youth Resilience Measure - Youth version. The study was conducted from March to September 2017. Statistical significance was set up at P < 0.05. RESULTS: The results from the study have shown statistically significant negative correlation between exposure to psychological abuse in childhood and individual (rpb = -0.159), relational (rpb = -0.263), contextual factors (rpb = -0.147), and resilience in total (rpb = -0.232). The regressive model presents that 5.2% of the variance of the variable experienced psychological abuse is explained with resilience (F(1, 527) = 28.909; P < 0.001), showing that resilience is negatively significant predictor for being psychologically abused in childhood (beta = 0.228; t = -5.377; P < 0.001). The regressive model explains the individual contribution of the predictor variables for the psychological abuse, presenting that only caregiver resiliency is a significant predictor for psychological abuse (beta = -0.282; t = -4.986; P < 0.001). CONCLUSION: Supporting children through prevention means foster competence and prevent problems. Preventive programmes represent developing protective factors in childhood, increasing competence and skills for the growth of resilience and decreasing the likelihood of developing psychopathology in adolescence and adulthood. It is of common interest of society for implementation of evidence-based interventions with fostering settings and in the long run enabling positive childhood basis for future generations. PMID- 29983823 TI - How to Improve Clinical Outcome of Epileptic Seizure Control Based on Medication Adherence? A Literature Review. AB - Anti-Epileptic Drugs (AEDs) are the main therapy for epilepsy to prevent seizures. Non-adherence situation plays an important factor in the failure of seizure control. Such a condition may generate several impacts on clinical, social, and economic aspect. Several methods are used to measure adherence in epilepsy patients, including direct and indirect measurement. The direct measure involves measurement of drug levels in hair or body fluids such as blood and saliva. Whereas, indirect measure involves the non-biological tools, for example, a self-report measure, pill counts, appointment attendance, medication refills, and seizure frequency. Numerous factors may affect adherence in epilepsy patients, such as age, sex, and seizure aetiology, seizure sites, which are categorised as irreversible factors and hardly to be improved. However, there are factors that can be influenced to improve adherence such as patient knowledge, medication, cultural, health care professionals, and national health policies, which are related to treatment and education factor which is associated with behaviour to be likely adherence. PMID- 29983825 TI - Chronic lymphocytic leukemia at ASH 2017. AB - At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia. PMID- 29983824 TI - Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization during Bone Repair. AB - Introduction: Mesenchymal stem and progenitor cells (MSCs), which normally reside in the bone marrow, are critical to bone health and can be recruited to sites of traumatic bone injury, contributing to new bone formation. The ability to control the trafficking of MSCs provides therapeutic potential for improving traumatic bone healing and therapy for genetic bone diseases such as hypophosphatasia. Methods: In this study, we explored the sphingosine-1-phosphate (S1P) signaling axis as a means to control the mobilization of MSCs into blood and possibly to recruit MSCs enhancing bone growth. Results: Loss of S1P receptor 3 (S1PR3) leads to an increase in circulating CD45-/CD29+/CD90+/Sca1 putative mesenchymal progenitor cells, suggesting that blocking S1PR3 may stimulate MSCs to leave the bone marrow. Antagonism of S1PR3 with the small molecule VPC01091 stimulated acute migration of CD45-/CD29+/CD90+/Sca1+ MSCs into the blood as early as 1.5 hours after treatment. VPC01091 administration also increased ectopic bone formation induced by BMP-2 and significantly increased new bone formation in critically sized rat cranial defects, suggesting that mobilized MSCs may home to injuries to contribute to healing. We also explored the possibility of combining S1P manipulation of endogenous host cell occupancy with exogenous MSC transplantation for potential use in combination therapies. Importantly, reducing niche occupancy of host MSCs with VPC01091 does not impede engraftment of exogenous MSCs. Conclusions: Our studies suggest that MSC mobilization through S1PR3 antagonism is a promising strategy for endogenous tissue engineering and improving MSC delivery to treat bone diseases. PMID- 29983826 TI - Systemic treatment of advanced non-small cell lung cancer: controversies and perspectives. AB - Patients with advanced non-small cell lung cancer receive first-line therapy with chemotherapy, targeted therapies in case of tumors with driver mutations, and more recently also immune checkpoint inhibitors. Important controversies include the role of targeted therapies in combination with chemotherapy, optimal sequencing of treatments, treatment guidance by means of predictive biomarkers, and value-based judgements of treatments. PMID- 29983827 TI - Chimeric antigen receptor T-cell therapy-a hematological success story. AB - Chimeric antigen receptor (CAR) T cells are genetically engineered autologous cells that express an activating receptor targeted towards one or more tumoral antigens. After ex vivo production and re-infusion, they are able to proliferate in the host and to recognize and kill tumor cells. Together with checkpoint inhibition, this new therapy is already being celebrated as a major medical breakthrough in recent years, due to the substantial benefit observed in clinical trials with patients with chemotherapy-refractory B-cell malignancies. These results have led to the recent approval of two CAR T-cell products by the Food and Drug Administration (FDA) in the United States. The list of targetable antigens and possible indications is continuously being expanded, as are the modifications to the CAR structure and the final cell products currently under investigation. In some patients, CAR T-cell therapy may lead to substantial toxicity including the cytokine release syndrome (CRS). In summary, CAR T-cell therapy has already provided clinical benefit to patients with B-cell malignancies unresponsive to conventional treatment. Yet, the therapy is still in an early stage of development, and the many opportunities for improvement in its various aspects as well as its future role in relation to conventional therapy will set the pace in the field of hematology for the next years or even decades. PMID- 29983828 TI - Management of adverse events related to checkpoint inhibition therapy. AB - IO treatments (immuno-oncology treatments) have become reality and are now daily practice or, in some cases, a daily challenge. New recommendations are being made with the prime purpose of increasing alertness and awareness as well as emphasizing standard operating strategies to deal with immune-related adverse events (ir-AEs) in patients treated with immune checkpoint inhibitors (ICI). This brief review refers to systemic reviews, guidelines and meta-analyses, randomized controlled trials and case series published from 2000 to the present. Existing recommendations for optimal management of toxicities vary according to organ systems affected and grading. Grade 1 toxicities (exception to the rule: neurologic, hematologic, cardiac manifestation) require close monitoring. Grade 2 toxicities prompt immediate treatment interruption combined with corticosteroid administration (prednisone or methylprednisolone 0.5-1 mg/kg/day) until the symptoms revert to grade 1 or less. ir-AEs up to grade 3 or 4 justify suspension of treatment together with increased dosage of prednisone or methylprednisolone (1-2 mg/kg/day) combined with close monitoring to continuously adapt the current immunosuppressive strategy. In some cases, a different additional immunosuppressive agent has to be evaluated. Only when all symptoms have disappeared and immunosuppressive treatment produces a response can all immunosuppressive agents be tapered. Endocrinopathies are the exception to the rule and are mostly controllable by hormone replacement, at least in low-grade manifestation. This short review focuses on the main aspects that help manage immune-related side-effects and elucidates all the additional aspects surrounding and contributing to successful treatment and management of cancer patients. PMID- 29983829 TI - Pitfalls in the radiological response assessment of immunotherapy. AB - Immunotherapies comprise of a class of cancer therapies that are increasingly used for treatment of several cancer entities. Active immunotherapies encompassing immune checkpoint inhibitors are the most widespread class of immunotherapies, with indications for melanoma, non-small lung cancer, renal cell carcinoma, urothelial carcinoma, head and neck squamous cell carcinoma, and Hodgkin's lymphoma. Immune checkpoint inhibitors have demonstrated unique response patterns that are not adequately captured by traditional response criteria such das the Response Evaluation Criteria in Solid Tumors (RECIST) and World Health Organization criteria. Consequently, adaptions of these criteria have been released such as the immune-related RECIST and immune RECIST, which account for the specialities of immunotherapies. Immunotherapies can cause a distinct set of adverse events such as pneumonitis, colitis, and hypophysitis. In addition, atypical treatment response patterns termed pseudoprogression have been observed. Thereby, new or enlarging lesions appear after treatment start and mimic tumor progression, which is followed by an eventual decrease in total tumor burden. In this review article we will describe pitfalls in the radiological response assessment of immunotherapies, focusing on pseudoprogression and imaging appearances of common immune-related adverse events. PMID- 29983830 TI - APPLY: A prospective observational study of clinical practice patterns of darbepoetin alfa use in patients with chemotherapy-induced anemia in Romania. AB - Purpose: The primary objective of this study was to evaluate the compliance of Romanian physicians with the national therapeutic protocol and international guidelines on treatment with erythropoiesis-stimulating agents in anemic cancer patients receiving chemotherapy. The secondary objective was to assess the hemoglobin (Hb) level change due to anemia treatment and safety of darbepoetin alfa. Methods: This was a single-arm, prospective, longitudinal, multicenter, observational study in patients with nonmyeloid malignancies and symptomatic chemotherapy-induced anemia treated concomitantly with darbepoetin alfa. Patients were followed for the duration of chemotherapy, but no shorter than three and no longer than eight cycles, irrespective of their exposure to darbepoetin alfa. Results: In this study, 497 patients with a mean age of 60.6 years were analyzed. Most patients (80.7%) were initiated on darbepoetin alfa at a Hb of 9-11 g/dL, congruent with recommendations. The median Hb increased by 0.9 g/dL between baseline and week 12. Hb target achievement was higher among patients treated according to guidelines than those initiated at Hb < 9 g/dL. A similar trend was observed for red blood cell transfusion requirements. No new safety signals were reported for darbepoetin alfa. Conclusions: The majority of patients were treated according to national and international recommendations. Guideline adherence was associated with more frequent achievement of Hb targets and lower red blood cell transfusion requirements compared with patients starting anemia treatment with darbepoetin alfa at lower-than-recommended Hb levels. PMID- 29983831 TI - DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer. AB - Background: High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer. Methods: Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively. Results: We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80-90%), and TIGIT were poorly hypomethylated (20-30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues. Conclusion: Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer. PMID- 29983832 TI - H3K27 acetylation and gene expression analysis reveals differences in placental chromatin activity in fetal growth restriction. AB - Background: Posttranslational modification of histone tails such as histone 3 lysine 27 acetylation (H3K27ac) is tightly coupled to epigenetic regulation of gene expression. To explore whether this is involved in placenta pathology, we probed genome-wide H3K27ac occupancy by chromatin immunoprecipitation sequencing (ChIP-seq) in healthy placentas and placentas from pathological pregnancies with fetal growth restriction (FGR). Furthermore, we related specific acetylation profiles of FGR placentas to gene expression changes. Results: Analysis of H3K27ac occupancy in FGR compared to healthy placentas showed 970 differentially acetylated regions distributed throughout the genome. Principal component analysis and hierarchical clustering revealed complete segregation of the FGR and control group. Next, we identified 569 upregulated genes and 521 downregulated genes in FGR placentas by RNA sequencing. Differential gene transcription largely corresponded to expected direction based on H3K27ac status. Pathway analysis on upregulated transcripts originating from hyperacetylated sites revealed genes related to the HIF-1-alpha transcription factor network and several other genes with known involvement in placental pathology (LEP, FLT1, HK2, ENG, FOS). Downregulated transcripts in the vicinity of hypoacetylated sites were related to the immune system and growth hormone receptor signaling. Additionally, we found enrichment of 141 transcription factor binding motifs within differentially acetylated regions. Of the corresponding transcription factors, four were upregulated, SP1, ARNT2, HEY2, and VDR, and two downregulated, FOSL and NR4A1. Conclusion: We demonstrate a key role for genome-wide alterations in H3K27ac in FGR placentas corresponding with changes in transcription profiles of regions relevant to placental function. Future studies on the role of H3K27ac in FGR and placental-fetal development may help to identify novel targets for therapy of this currently incurable disease. PMID- 29983833 TI - Epigenetic gestational age acceleration: a prospective cohort study investigating associations with familial, sociodemographic and birth characteristics. AB - Background: Gestational age at delivery is associated with health and social outcomes. Recently, cord blood DNA methylation data has been used to predict gestational age. The discrepancy between gestational age predicted from DNA methylation and determined by ultrasound or last menstrual period is known as gestational age acceleration. This study investigated associations of sex, socioeconomic status, parental behaviours and characteristics and birth outcomes with gestational age acceleration. Results: Using data from the Avon Longitudinal Study of Parents and Children (n = 863), we found that pre-pregnancy maternal overweight and obesity were associated with greater gestational age acceleration (mean difference = 1.6 days, 95% CI 0.7 to 2.6, and 2.9 days, 95% CI 1.3 to 4.4, respectively, compared with a body mass index < 25 kg/m2, p < .001). There was evidence of an association between male sex and greater gestational age acceleration. Greater gestational age acceleration was associated with higher birthweight, birth length and head circumference of the child (mean differences per week higher gestational age acceleration: birthweight 0.1 kg, 95% CI 0.1 to 0.2, p < .001; birth length 0.4 cm, 95% CI 0.2 to 0.7, p < .001; head circumference 0.2 cm, 95% CI 0.1 to - 0.4, p < .001). There was evidence of an association between gestational age acceleration and mode of delivery (assisted versus unassisted delivery, odds ratio = 0.9 per week higher gestational age acceleration, 95% CI 0.7, 1.3 (p = .05); caesarean section versus unassisted delivery, odds ratio = 0.6, 95% CI 0.4 to 0.9 per week higher gestational age acceleration (p = .05)). There was no evidence of association for other parental and perinatal characteristics. Conclusions: The associations of higher maternal body mass index and larger birth size with greater gestational age acceleration may imply that maternal overweight and obesity is associated with more rapid development of the fetus in utero. The implications of gestational age acceleration for postnatal health warrant further investigation. PMID- 29983834 TI - Epigenetic signature of preterm birth in adult twins. AB - Background: Preterm birth is a leading cause of perinatal mortality and long-term health consequences. Epigenetic mechanisms may have been at play in preterm birth survivors, and these could be persistent and detrimental to health later in life. Methods: We performed a genome-wide DNA methylation profiling in adult twins of premature birth to identify genomic regions under differential epigenetic regulation in 144 twins with a median age of 33 years (age range 30-36). Results: Association analysis detected three genomic regions annotated to the SDHAP3, TAGLN3 and GSTT1 genes on chromosomes 5, 3 and 22 (FWER: 0.01, 0.02 and 0.04) respectively. These genes display strong involvement in neurodevelopmental disorders, cancer susceptibility and premature delivery. The three identified significant regions were successfully replicated in an independent sample of twins of even older age (median age 66, range 56-80) with similar regulatory patterns and nominal p values < 5.05e-04. Biological pathway analysis detected five significantly enriched pathways all explicitly involved in immune responses. Conclusion: We have found novel evidence associating premature delivery with epigenetic modification of important genes/pathways and revealed that preterm birth, as an early life event, could be related to differential methylation regulation patterns observable in adults and even at high ages which could potentially mediate susceptibility to age-related diseases and adult health. PMID- 29983836 TI - Nasal and Pharyngeal Colonization by Bacterial Pathogens: A Comparative Study between Preclinical and Clinical Sciences Medical Students. AB - Background: Upper respiratory tract is one of the commonest sites for microbial colonization. The colonized individuals are at risk of infections and can be a source of transmission of pathogens. Medical students are frequently exposed to a variety of infectious agents and more likely to get colonized by them. This study was aimed to determine the prevalence and to compare the colonization rates of nasal and pharyngeal bacterial pathogens among preclinical and clinical sciences medical students. Methods: This cross-sectional study was conducted among 100 preclinical and 100 clinical sciences medical students. Isolation, identification, and antibiotic susceptibility testing of the isolates were performed by standard microbiological techniques. Results: The nasal colonization by S. aureus and MRSA was 35% (70/200) and 19.5% (39/200), respectively. The nasal colonization by S. aureus and MRSA was significantly higher among clinical sciences students as compared to preclinical sciences students. Pharyngeal colonization by Haemophilus influenzae was significantly higher among clinical sciences students as compared to preclinical sciences students. The pharyngeal colonization by beta-hemolytic streptococci (nongroup A) was higher among preclinical sciences students than clinical sciences students. Conclusion: The nasal colonization by S. aureus and MRSA was higher among clinical sciences students. Pharyngeal colonization by potential bacterial pathogens was higher among clinical sciences students than preclinical students. Periodic screening of MRSA and potential throat pathogens of clinical sciences students and may reduce the incidences of nosocomial transmission of pathogens. PMID- 29983835 TI - Long non-coding RNAs: implications in targeted diagnoses, prognosis, and improved therapeutic strategies in human non- and triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) has been clinically difficult to manage because of tumor aggressiveness, cellular and histological heterogeneity, and molecular mechanisms' complexity. All this in turn leads us to evaluate that tumor biological behavior is not yet fully understood. Additionally, the heterogeneity of tumor cells represents a great biomedicine challenge in terms of the complex molecular-genetical-transcriptional and epigenetical-mechanisms, which have not been fully elucidated on human solid tumors. Recently, human breast cancer, but specifically TNBC is under basic and clinical-oncology research in the discovery of new molecular biomarkers and/or therapeutic targets to improve treatment responses, as well as for seeking algorithms for patient stratification, seeking a positive impact in clinical-oncology outcomes and life quality on breast cancer patients. In this sense, important knowledge is emerging regarding several cancer molecular aberrations, including higher genetic mutational rates, LOH, CNV, chromosomal, and epigenetic alterations, as well as transcriptome aberrations in terms of the total gene-coding ribonucleic acids (RNAs), known as mRNAs, as well as non-coding RNA (ncRNA) sequences. In this regard, novel investigation fields have included microRNAs (miRNAs), as well as long ncRNAs (lncRNAs), which have been importantly related and are likely involved in the induction, promotion, progression, and/or clinical therapeutic response trackers of TNBC. Based on this, in general terms according with the five functional archetype classification, the lncRNAs may be involved in the regulation of several molecular mechanisms which include genetic expression, epigenetic, transcriptional, and/or post-transcriptional mechanisms, which are nowadays not totally understood. Here, we have reviewed the main dis-regulated and functionally non- and well-characterized lncRNAs and their likely involvement, from a molecular enrichment and mechanistic point of view, as tumor biomarkers for breast cancer and its specific histological subtype, TNBC. In reference to the abovementioned, it has been described that some lncRNA expression profiles correspond or are associated with the TNBC histological subtype, potentially granting their use for TNBC malignant progression, diagnosis, tumor clinical stage, and likely therapy. Based on this, lncRNAs have been proposed as potential biomarkers which might represent potential predictive tools in the differentiated breast carcinomas versus TNBC malignant disease. Finally, elucidation of the specific or multi-functional archetypal of lncRNAs in breast cancer and TNBC could be fundamental, as these molecular intermediary regulator "lncRNAs" are widely involved in the genome expression, epigenome regulation, and transcriptional and post-transcriptional tumor biology, which in turn will probably represent a new prospect in clinical and/or therapeutic molecular targets for the oncological management of breast carcinomas in general and also for TNBC patients. PMID- 29983837 TI - Recent advances and current challenges in magnetophoresis based micro magnetofluidics. AB - The combination of magnetism and microscale fluid flow has opened up a new era for handling and manipulation of samples in microfluidics. In particular, magnetophoresis, the migration of particles in a magnetic field, is extremely attractive for microfluidic handling due to its contactless nature, independence of ionic concentration, and lack of induced heating. The present paper focuses on recent advances and current challenges of magnetophoresis and highlights the key parameters affecting the manipulation of particles by magnetophoresis. The magnetic field is discussed according to their relative motion to the sample as stationary and dynamic fields. The migration of particles is categorized as positive and negative magnetophoresis. The applications of magnetophoresis are discussed according to the basic manipulation tasks such as mixing, separation, and trapping of particles or cells. Finally, the paper highlights the limitations of current approaches and provides the future perspective for this research area. PMID- 29983838 TI - Oscillating dispersed-phase co-flow microfluidic droplet generation: Multi droplet size effect. AB - Controllable generation of microdroplets at desired sizes and throughputs is important in many applications. Many biological assays require size-optimized droplets for effective encapsulation of analytes and reagents. To perform size optimization, different-size droplets must be generated from identical sources of samples to prevent potential cross-sample variations or other sources of error. In this paper, we introduce a novel alteration of the co-flow droplet generation technique to achieve multi-size generation of monodispersed droplets. Using a custom-made mechanism, we oscillate the disperse-phase (d-phase) flow nozzle perpendicular to the continuous phase (c-phase) flow in a co-flow channel. Oscillation of the d-phase nozzle introduces an additional lateral drag force to the growing droplets while exposing them to various levels of axial drag owing to the parabolic velocity distribution of the c-phase flow. Superimposing both effects results in simultaneous and repeatable generation of monodispersed droplets with different sizes. The effect of nozzle oscillation frequency (f = 0 15 Hz) on droplet generation at different d-phase (Qd = 0.05, 0.10, and 0.50 ml/min) and c-phase (Qc = 2, 5, and 10 ml/min) flow rates was studied. A wide range of monodispersed droplets (4nl-4 MUl) were generated using this method. Droplet sizes were directly proportional to the We number and inversely proportional to the Ca number and oscillation frequency. Our technique is promising for applications such as aqueous two-phase systems, where due to inherently low interfacial tension, the d-phase flow forms a long stable jet which can be broken into droplets using the additional oscillatory drag in our device. PMID- 29983839 TI - Virtual vortex gear: Unique flow patterns driven by microfluidic inertia leading to pinpoint injection. AB - An interesting phenomenon that vortices are sequentially generated on a microfluidic chip is investigated in this paper. The direction of every two adjacent vortices is opposite to each other, like a set of gears, and thus is named virtual vortex gear (VVG). Both experiments and computational simulations were conducted in order to make clear the mechanism of VVG. The experimental results show that only the flow from a particular point would form vortices and enter the target chamber. A technique of inverse mapping is proposed based on the phenomenon and it demonstrates that only a pinpoint injection is sufficient to control the contents of a microfluidic chamber. VVG can significantly reduce the volume of chemical usage in biological research and has potential for other on chip applications, such as mixing and valving. PMID- 29983840 TI - Engineering of three-dimensional pre-vascular networks within fibrin hydrogel constructs by microfluidic control over reciprocal cell signaling. AB - Reengineering functional vascular networks in vitro remains an integral part in tissue engineering, since the incorporation of non-perfused tissues results in restricted nutrient supply and limited waste removal. Microfluidic devices are routinely used to mimic both physiological and pathological vascular microenvironments. Current procedures either involve the investigation of growth factor gradients and interstitial flow on endothelial cell sprouting alone or on the heterotypic cell-cell interactions between endothelial and mural cells. However, limited research has been conducted on the influence of flow on co cultures of these cells. Here, we exploited the ability of microfluidics to create and monitor spatiotemporal gradients to investigate the influence of growth factor supply and elution on vascularization using static as well as indirect and direct flow setups. Co-cultures of human adipose-derived stem/stromal cells and human umbilical vein endothelial cells embedded in fibrin hydrogels were found to be severely affected by diffusion limited growth factor gradients as well as by elution of reciprocal signaling molecules during both static and flow conditions. Static cultures formed pre-vascular networks up to a depth of 4 mm into the construct with subsequent decline due to diffusion limitation. In contrast, indirect flow conditions enhanced endothelial cell sprouting but failed to form vascular networks. Additionally, complete inhibition of pre-vascular network formation was observable for direct application of flow through the hydrogel with decline of endothelial cell viability after seven days. Using finite volume CFD simulations of different sized molecules vital for pre vascular network formation into and out of the hydrogel constructs, we found that interstitial flow enhances growth factor supply to the cells in the bulk of the chamber but elutes cellular secretome, resulting in truncated, premature vascularization. PMID- 29983841 TI - Multimode Electron Tomography as a Tool to Characterize the Internal Structure and Morphology of Gold Nanoparticles. AB - Three dimensional (3D) characterization of structural defects in nanoparticles by transmission electron microscopy is far from straightforward. We propose the use of a dose-efficient approach, so-called multimode tomography, during which tilt series of low and high angle annular dark field scanning transmission electron microscopy projection images are acquired simultaneously. In this manner, not only reliable information can be obtained concerning the shape of the nanoparticles, but also the twin planes can be clearly visualized in 3D. As an example, we demonstrate the application of this approach to identify the position of the seeds with respect to the twinning planes in anisotropic gold nanoparticles synthesized using a seed mediated growth approach. PMID- 29983842 TI - Photoelectrochemical Behavior of PEDOT/Nanocarbon Electrodes: Fundamentals and Structure-Property Relationships. AB - In this study, we investigated the photoelectrochemical behavior of poly(3,4 ethylenedioxythiophene) (PEDOT)/carbon nanotube (CNT) and PEDOT/graphene nanocomposite photoelectrodes for the first time. Electrodeposition allowed control of both the composition and the morphology (as demonstrated by both transmission and scanning electron microscopy images) and also ensured an intimate contact between the PEDOT film and the nanocarbon scaffold. The effect of CNT and graphene on the photoelectrochemical behavior of the nanocomposite samples was studied by linear sweep photovoltammetry, incident photon-to-charge carrier conversion efficiency measurements, and long-term photoelectrolysis coupled with gas-chromatographic product analysis. We demonstrated that the nanocarbon framework facilitated efficient charge carrier transport, resulting in a 4-fold increase in the measured photocurrents for the PEDOT/CNT electrode, compared to the bare PEDOT counterpart. The presented results contribute to the better understanding of the enhanced photoelectrochemical behavior of organic semiconductor/nanocarbon electrode assemblies and might encourage other researchers to study these intriguing hybrid materials further. PMID- 29983844 TI - Effects of Hydrogen Contents on Oxidation Behavior of Alloy 690TT and Associated Boron Accumulation within Oxides in High-Temperature Water. AB - The aim of this work is to characterize the oxide layer structure of Alloy 690TT in high-temperature water with different dissolved hydrogen (DH) contents by using an X-ray photoelectron spectroscopy. Under the low DH contents (0.4494 0.8988 mg/kg), the oxide layers were composed of an outermost layer of Ni(OH)2 and Cr(OH)3 enriched in Ni, an intermediate layer of hydroxides and oxides enriched in Cr, and an inner Cr2O3 layer. Outermost NiO coexists with small amount of Cr2O3 layer, while in the inner oxide only Cr2O3 remains. The oxide layers at medium and high DH contents (3.1458- 8.9880 mg/kg) consisted of an outermost layer of Ni(OH)2 and Cr(OH)3 enriched in Cr, an intermediate layer of metallic Ni, hydroxides and oxides enriched in Cr, and an inner Cr2O3 layer. In addition, boron compounds containing B3+ ions were accumulated in the thick and porous NiO layer formed at low DH contents, whereas the accumulation of boron compounds did not occur in the thin and dense polyhedral oxide layer formed at medium and high DH contents. PMID- 29983843 TI - Study of the Partial Substitution of Pb by Sn in Cs-Pb-Sn-Br Nanocrystals Owing to Obtaining Stable Nanoparticles with Excellent Optical Properties. AB - Halide perovskites are revolutionizing the photovoltaic and optoelectronic fields with outstanding performances obtained in a remarkably short time. However, two major challenges remain: the long-term stability and the Pb content, due to its toxicity. Despite the great effort carried out to substitute the Pb by a less hazardous element, lead-free perovskite still remains more unstable than lead containing perovskites and presents lower performance as well. In this work, we demonstrate the colloidal preparation of Cs-Pb-Sn-Br nanoparticles (NPs) where Sn is incorporated up to 18.8%. Significantly, we have demonstrated that the partial substitution of Pb by Sn does not produce a deleterious effect in their optical performance in terms of photoluminescence quantum yield (PLQY). We observed for the first time a positive effect in terms of enhancement of PLQY when Sn partially substitutes Pb in a considerable amount (i.e., higher than 5%). PLQYs as high as 73.4% have been obtained with a partial Pb replacement of 7% by Sn. We present a systematic study of the synthesis process in terms of different growth parameters (i.e., precursor concentration, time, and temperature of reaction) and how they influence the Sn incorporation and the PLQY. This high performance and long-term stability is based on a significant stabilization of Sn2+ in the NPs for several months, as determined by XPS analysis, and opens an interesting way to obtain less Pb-containing perovskite NPs with excellent optoelectronic properties. PMID- 29983845 TI - Finding Some Good in an Invasive Species: Introduction and Assessment of a Novel CURE to Improve Experimental Design in Undergraduate Biology Classrooms. AB - Reports such as Vision and Change in Undergraduate Biology Education call for integration of course-based undergraduate research experiences (CUREs) into biology curricula and less emphasis on "cookbook" laboratories. CUREs, often characterized by a single open-ended research question, allow students to develop hypotheses, design experiments, and collaborate with peers. Conversely, "cookbook" labs incentivize task completion and have pre-determined experimental outcomes. While research comparing CUREs and "cookbook" labs is growing, there are fewer comparisons among CUREs. Here, we present a novel CURE built around an invasive grass, Bromus inermis. We evaluated this CURE's effectiveness in improving students' understanding of the Vision and Change competency relating to the application of the scientific process through development and testing of hypotheses. We did so by comparing changes in pre- and posttest scores on the Experimental Design Ability Test (EDAT) between Brome CURE students and students in a concurrent CURE, SEA-PHAGES. While students in both CUREs showed improvements at the end of the semester, Brome CURE students showed a greater increase in EDAT scores than did SEA-PHAGES CURE students. Additionally, Brome CURE students had significantly higher gains in 6 of the 10 EDAT criteria. We conclude that the Brome CURE is an effective ecological parallel to the SEA PHAGES CURE and can help students gain a meaningful understanding of Vision and Change competencies. Journal of Microbiology & Biology Education. PMID- 29983846 TI - Makgeolli: Rapid Production of an Alcoholic Beverage from the Fermentation of Rice. PMID- 29983847 TI - Simulation of MICROBACT Strip Assay Using Colored Liquids to Demonstrate Identification of Unknown Gram-Negative Organisms in Undergraduate Laboratory. PMID- 29983848 TI - How Undergraduate Science Students Use Learning Objectives to Study. AB - Learning objectives communicate the knowledge and skills that instructors intend for students to acquire in a course. Student performance can be enhanced when learning objectives align with instruction and assessment. We understand how instructors should use learning objectives, but we know less about how students should use them. We investigated students' use and perceptions of learning objectives in an undergraduate science course at a public research university. In this exploratory study, students (n = 185) completed two open-ended assignments regarding learning objectives and we analyzed the content of their answers. We found that students used learning objectives in ways that reflected the recommendations of past and present instructors, suggesting that students are receptive to instruction on how to use learning objectives. Students generally found learning objectives to be useful because the objectives helped them to narrow their focus and organize their studying, suggesting that students may need additional help from instructors in order to self-direct their learning. Students who chose not to use learning objectives often found other resources, such as case studies covered in class, to be more helpful for their learning. Some of these students recognized that the concepts included in case studies and learning objectives overlapped, pointing to a benefit of alignment between instructional activities and learning objectives. These qualitative results provide the data necessary for designing a quantitative instrument to test the extent to which students' use of learning objectives affects their performance. PMID- 29983849 TI - Claw Waving for Sex: An Inquiry-Based Lab to Teach Sexual Dimorphism and Behavior in Fiddler Crabs. PMID- 29983850 TI - Microbiology Education and Infection Control Competency: Offering a New Perspective. AB - Healthcare-associated infections (HAIs) have become a significant and costly problem for healthcare institutions worldwide. Despite the crucial role of infection prevention and control (IC) procedures, there is a substantial body of evidence to indicate that IC knowledge and practices of health professional graduates is, however, sub-optimal. This paper presents a discussion of the critical role microbiology plays in infection control education and practice, arguing that without an ability to apply microbiology knowledge to IC decision making, there is an inherent risk of incorrect application of IC practices and thus a risk to patient (and nurse) safety. The authors propose a re conceptualization of infection control competency, using nursing as an exemplar profession, to reflect practice that is not based on simple memorization of protocols but rather on a sound understanding of microbiology and informed decision-making. The proposal for re-conceptualizing the definition and assessment of IC competence, if adopted, would potentially enhance students' understanding and synthesis of microbiology knowledge and help build students' capacity to apply that knowledge to practice. PMID- 29983851 TI - Investigation of a Stand-Alone Online Learning Module for Cellular Respiration Instruction. AB - With the recent rise of alternative instructional methodologies such as flipped classrooms and active learning, many core concepts are being introduced outside of the classroom prior to scheduled class meeting times. One popular means for external concept introduction in many undergraduate biology courses is the use of stand-alone online learning modules. Using a group of four large introductory biology course sections, we investigate the use of a stand-alone online learning module developed using animations from Virtual Cell Animation Collection as a resource for the introduction of cellular respiration concepts outside of the classroom. Results from four sections of introductory biology (n = 629) randomized to treatments show that students who interacted with the stand-alone online learning module had significantly higher normalized gain scores on a cellular respiration assessment than students who only attended a traditional lecture as a means of concept introduction (p < 0.001, d = 0.59). These findings suggest a superior ability to convey certain introductory cellular respiration topics in a stand-alone manner outside of the classroom than in a more traditional lecture-based classroom setting. PMID- 29983852 TI - Bacterial Production of Gellan Gum as a Do-It-Yourself Alternative to Agar. PMID- 29983853 TI - Student-Designed High-Throughput Assays to Assess Effects of Growth Insults in Budding Yeast. PMID- 29983854 TI - Mutation Rate Simulation by Dice Roll: Practice with the Drake Equation. PMID- 29983856 TI - Cybrid Models of Pathological Cell Processes in Different Diseases. AB - Modelling of pathological processes in cells is one of the most sought-after technologies of the 21st century. Using models of such processes may help to study the pathogenetic mechanisms of various diseases. The aim of the present study was to analyse the literature, dedicated to obtaining and investigating cybrid models. Besides, the possibility of modeling pathological processes in cells and treatment of different diseases using the models was evaluated. Methods of obtaining Rho0 cell cultures showed that, during their creation, mainly a standard technique, based on the use of mtDNA replication inhibitors (ethidium bromide), was applied. Cybrid lines were usually obtained by PEG fusion. Most frequently, platelets acted as donors of mitochondria. According to the analysis of the literature data, cybrid cell cultures can be modeled to study the dysfunction of the mitochondrial genome and molecular cellular pathological processes. Such models can be very promising for the development of therapeutic approaches to the treatment of various human diseases. PMID- 29983855 TI - Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice. AB - Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH. PMID- 29983858 TI - Endothelial cells: The heart attack of the Clones. AB - Neovascularization induced by acute myocardial infarction is mediated by clonal expansion of mature endothelial cells, which is triggered by VEGFR-2 signaling. PMID- 29983857 TI - Transient Receptor Potential Canonical Channels 4 and 5 Mediate Escherichia coli Derived Thioredoxin Effects in Lipopolysaccharide-Injected Mice. AB - Thioredoxin plays an essential role in bacterial antioxidant machinery and virulence; however, its regulatory actions in the host are less well understood. Reduced human Trx activates transient receptor potential canonical 5 (TRPC5) in inflammation, but there is no evidence of whether these receptors mediate bacterial thioredoxin effects in the host. Importantly, TRPC5 can form functional complexes with other subunits such as TRPC4. Herein, E. coli-derived thioredoxin induced mortality in lipopolysaccharide- (LPS-) injected mice, accompanied by reduction of leukocyte accumulation, regulation of cytokine release into the peritoneum, and impairment of peritoneal macrophage-mediated phagocytosis. Dual TRPC4/TRPC5 blockade by ML204 increased mortality and hypothermia in thioredoxin treated LPS mice but preserved macrophage's ability to phagocytose. TRPC5 deletion did not alter body temperature but promoted additional accumulation of peritoneal leukocytes and inflammatory mediator release in thioredoxin administered LPS mice. Thioredoxin diminished macrophage-mediated phagocytosis in wild-type but not TRPC5 knockout animals. TRPC5 ablation did not affect LPS induced responses. However, ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS injected mice. These results suggest that bacterial thioredoxin effects under LPS stimuli are mediated by TRPC4 and TRPC5, shedding light on the additional mechanisms of bacterial virulence and on the pathophysiological roles of these receptors. PMID- 29983859 TI - AHR: A Temple of Tolerance to Toxemia. PMID- 29983860 TI - Maintenance ramucirumab monotherapy after intolerable toxicities following docetaxel plus ramucirumab. PMID- 29983861 TI - BRAF inhibitors stimulate inflammasome activation and interleukin 1 beta production in dendritic cells. AB - Melanoma is the most dangerous form of skin cancer with a growing incidence over the last decades. Fourty percent of all melanomas harbor a mutation in the signaling adaptor BRAF (V600E) that results in ERK hyperactivity as an oncogenic driver. In these cases, treatment with the BRAFV600E inhibitors Vemurafenib (VEM) or Dabrafenib (DAB) coapplied with the MEK1/2 inhibitors Cobimetinib (COB) or Trametinib (TRA) can result in long-term suppression of tumor growth. Besides direct suppression of ERK activity, these inhibitors have been reported to also modulate tumor immune responses, and exert pro-inflammatory side effects such as fever and rash in some patients. Here we asked for potential effects of BRAFV600E inhibitors on dendritic cells (DC) which are essential for the induction of adaptive anti-tumor responses. Both splenic and bone marrow-derived (BM) mouse dendritic cells (DC) up-regulated costimulator expression (CD80, CD86) in response to DAB but not VEM treatment. Moreover, DAB and to lesser extent VEM enhanced IL-1beta (interleukin 1 beta) release by splenic DC, and by LPS stimulated BMDC. We demonstrate that DAB and VEM activated the NLRC4/Caspase-1 inflammasome. At high concentration, DAB also induced inflammasome activation independent of Caspase-1. TRA and COB elevated MHCII expression on BMDC, and modulated the LPS-induced cytokine pattern. Immunomodulatory activity of DAB and VEM was also observed in human monocyte-derived DC, and DAB induced IL-1beta in human primary DC. Altogether, our study shows that BRAFV600E inhibitors upregulate IL-1beta release by mouse and human DC which may affect the DC mediated course of anti-tumor immune responses. PMID- 29983862 TI - IL-23 enhances the malignant properties of hepatoma cells by attenuation of HNF4alpha. AB - Chronic infection with hepatitis B virus (HBV) is one of the major risk factors for hepatocellular carcinoma. HBV infection can induce the expression of IL-23. However, the effects of IL-23 on carcinogenesis are rare and contradictory. To investigate the potential role of IL-23 on malignant properties of hepatoma cells, in the present study, first, we confirmed that HBV drove infected hepatoma cells to produce more IL-23. And then we found that at low concentration, human recombinant IL-23 (hrIL-23) enhanced malignant properties of hepatoma cells through increasing the proportion of stem/progenitor cells, promoting proliferation and colony formation, reducing apoptosis and inducing motility and invasivity of them. Hepatocyte nuclear factor 4 alpha (HNF4alpha), which is essential for liver development and hepatocyte function, was found to be downregulated in HBV integrated or transiently transfected hepatoma cells. Its expression was also decreased in cells treated by hrIL-23 or by HepG2.215 culture supernatant and this decrease could be abolished by supplementation of anti-IL 23p19 antibody. Hence, it is speculated that HBV related IL-23 can enhance malignant properties of hepatoma cells through attenuation of HNF4alpha. The findings identified a potential target of interventional strategies for treating hepatitis B patients through manipulation of the IL-23. PMID- 29983863 TI - Proteomics identification and characterization of MbovP730 as a potential DIVA antigen of Mycoplasma bovis. AB - Mycoplasma bovis (M. bovis) is an important pathogen of cattle. An attenuated live vaccine has recently been developed by this laboratory. However, an effective assay for the differentiation of infected from vaccinated animals (DIVA) is still lacking. Therefore, a comparative immunoproteomics study of the membrane and membrane associated proteins (MAPs) of M. bovis HB0801 and its attenuated strain (M. bovis-150) was aimed to identify potential antigens for DIVA assay. Triton-X-114 fractionated liposoluble proteins of both the virulent and attenuated strains were separated with 2-DE and proteins reacting with sera against the virulent M. bovis strain were detected by MS. A total of 19 differently expressed proteins were identified by MS, among them twelve proteins were detected by MALDI-TOF MS and seven antigenic proteins were identified by short-gun LC-MS/MS. Furthermore, these findings were confirmed at mRNA level by qRT-PCR. The results demonstrated that a putative lipoprotein encoded by functionally unknown gene Mbov_0730 (MbovP730) is a sensitive and specific antigen for DIVA assay. MbovP730 is absent in M. bovis-150 confirmed with Western blot assay and also didn't cross-react with other antisera against common pathogens including infectious bovine rhinotracheitis virus and bovine viral diarrhea virus by iELISA. Thereby rMbovP730-based iELISA was established. For clinical samples, this ELISA provided a sensitivity of 95.7% (95% CI: 90.4%, 98.2%) and specificity was 97.8% (95% CI: 88.4%, 99.6%). Antisera from vaccinated calves (n = 44) were found negative with rMbovP730 based iELISA, while positive with assays based on whole cell proteins of M. bovis-150 and M. bovis HB0801, respectively. In conclusion, this study identified the differential antigen MbovP730 between virulent and attenuated strains and established rMbovP730-based iELISA as a new DIVA method. PMID- 29983864 TI - The human blood DNA methylome identifies crucial role of beta-catenin in the pathogenesis of Kawasaki disease. AB - Kawasaki disease (KD) is a type of acute febrile vasculitis syndrome and is the most frequent cause of cardiac illness in children under the age of five years old. Although the etiology of KD remains largely unknown, some recent genome-wide studies have indicated that epigenetic factors may be important in its pathogenesis. We enrolled 24 KD patients and 24 non-KD controls in this study to access their DNA methylation status using HumanMethylation450 BeadChips. Another 34 KD patients and 62 control subjects were enrolled for expression validation. Of the 3193 CpG methylation regions with a methylation difference >= 20% between KD and controls, 3096 CpG loci revealed hypomehtylation, with only 3% being hypermethylated. Pathway buildup identified 11 networked genes among the hypermethylated regions, including four transcription factors: nuclear factor of activated T-cells 1, v-ets avian erythroblastosis virus E26 oncogene homolog 1, runt related transcription factor 3, and retinoic acid receptor gamma, as well as the activator beta-catenin. Ten of these network-selected genes demonstrated a significant decrease in mRNA in KD patients, whereas only CTNNB1 significantly decreased in correlation with coronary artery lesions in KD patients. Furthermore, CTNNB1-silenced THP-1 monocytic cells drastically increased the expression of CD40 and significantly increased the expression of both CD40 and CD40L in cocultured human coronary artery endothelial cells. This study is the first to identify network-based susceptible genes of hypermethylated CpG loci, their expression levels, and the functional impact of beta-catenin, which may be involved in both the cause and the development of KD. PMID- 29983865 TI - Increased Nrf2 expression by renal cell carcinoma is associated with postoperative chronic kidney disease and an unfavorable prognosis. AB - Chronic kidney disease (CKD) is a worldwide health problem, and prevention of CKD is important for preservation of renal function after kidney surgery. There is evidence that transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has a vital antioxidant and detoxifying role in protecting the kidneys against various diseases. Impaired activation of Nrf2 is associated with oxidative stress related to CKD, and Nrf2 is also a key player in the development of cancer. However, the clinical impact of Nrf2 has not been investigated in patients with renal cell carcinoma (RCC). A retrospective study was performed in 89 patients undergoing nephrectomy for RCC. The estimated glomerular filtration rate (eGFR) and serum uric acid (SUA) were investigated over time after surgery. We investigated Nrf2 protein expression in all tumors and single nucleotide polymorphisms (SNPs) of the Nrf2 gene in 7 tumors. In patients whose tumors showed higher Nrf2 expression, there was a more rapid decrease of eGFR and increase of SUA after nephrectomy. Multivariate analysis confirmed that increased Nrf2 expression was an independent poor prognostic factor related to shorter overall survival. Among the 7 tumor samples, an SNP on exon 5 of the Nrf2 gene in one tumor and three genotypes (C/C, C/A, and A/A) of rs6721961 at the promoter region of the Nrf2 gene were observed. Although the mechanisms underlying the influence of Nrf2 are still unclear, our findings suggested that elevated tumor expression of Nrf2 was associated with postoperative CKD and biologically aggressive RCC with an unfavorable prognosis. PMID- 29983866 TI - Tumor-derived granzyme B-expressing neutrophils acquire antitumor potential after lipid A treatment. AB - Neutrophils are known to possess both pro- and anti-tumor properties, a feature that could be related to the diversity and plasticity of these cells. Here we explored the hypothesis that under an appropriate environment and stimuli, neutrophils could induce an effective response against tumor cells. In a rat and mouse models, we show that a substantial amount of colon tumor associated neutrophils (TAN) expressed the cytolytic enzyme granzyme B, which is absent in spleen or blood circulating neutrophils. This TAN population was also found into tumors of patients with colon cancer. Tumor neutrophil infiltration was correlated with an increase of chemokines known to attract neutrophils in both rat models and patients. These cells were involved in a Lipid A analog-mediated colon tumor regression. Mechanistically, treating the rats with the Lipid A analog triggered granzyme B release from neutrophils in tumor cell vicinity, which was correlated to tumor regression. Alteration of granzyme B function in tumor cells decreased the cytotoxic effect of Lipid A in rat and mouse models. Granzyme B expression in neutrophils could be induced by the lipid A analog but also by some of the cytokines that were detected in the tumor microenvironment. These results identify a subpopulation of neutrophils expressing granzyme B that can act as a key player of lipid A-mediated colon cancer regression in rat and mouse models and the molecular mechanisms involved may provide novel approaches for human therapeutic intervention. PMID- 29983867 TI - MicroRNA analysis of gastroenteropancreatic neuroendocrine tumors and metastases. AB - The incidence of neuroendocrine neoplasias (NEN) continues to increase. Since the primary tumor cannot be diagnosed in some cases of metastatic disease, new biomarkers are clearly needed to find the most probable site of origin. Tissue samples from 79 patients were analyzed and microRNA profiles were generated from a total of 76 primary tumors, 31 lymph node and 14 solid organ metastases. NEN metastases were associated with elevated levels of miR-30a-5p, miR-210, miR-339 3p, miR-345 and miR-660. Three microRNAs showed a strong correlation between proliferation index and metastatic disease in general (miR-150, miR-21 and miR 660). Further, each anatomic location (primary or metastatic) had one or more site-specific microRNAs more highly expressed in these tissues. Comparison between primary tumors and metastases revealed an overlap only in pancreatic (miR 127) and ileal tumors (let-7g, miR-200a and miR-331). This thorough analysis of gastroenteropancreatic neuroendocrine tumors demonstrates site-specific microRNA profiles, correlation with proliferation indices as well as corresponding nodal and distant metastases. Using microRNA profiling might improve NEN diagnostics by linking metastases to a most probable site of origin. PMID- 29983868 TI - MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4. AB - Although microRNA (miR) 199a-3p functions as a tumor suppressor in multiple malignancies, its expression and role in esophageal cancer have not been studied. Based on our previous observation that miR-199a-3p is markedly downregulated in esophageal cancer cell lines relative to esophageal epithelial cells, we examined the function of miR-199a-3p in these cells. MiR-199a-3p is predicted to bind with high affinity to the mRNA of p21 activated kinase 4 (PAK4). This kinase has been shown to be overexpressed in several malignancies and to modulate proliferation and motility. The current study is designed to determine whether miR-199a-3p regulates the expression of PAK4 in esophageal cancer cells and to understand the functional consequences of this interaction. Herein, we demonstrate reduced expression of miR-199a-3p in human esophageal cancer specimens and cell lines compared to esophageal epithelial cells, with associated increased expression of PAK4. Forced expression of miR-199a-3p decreases expression of PAK4 in esophageal cancer cell lines. Mechanistic studies reveal that miR-199a-3p binds to the 3'UTR of PAK4 mRNA. This interaction results in reduced levels of PAK4 mRNA due to decreased mRNA stability. Downregulation of PAK4 leads to decreased cyclin D1 (CD1) transcription and protein expression, resulting in markedly impaired cellular proliferation. When PAK4 expression is rescued, both CD1 transcription and protein return to baseline levels. Our results show that miR-199a-3p functions as a tumor suppressor in esophageal cancer cells through repression of PAK4. These findings suggest that both miR-199a-3p and PAK4 may be novel therapeutic targets in the treatment of esophageal cancer. PMID- 29983869 TI - Cancer-related transcription regulator protein NAC1 forms a protein complex with CARM1 for ovarian cancer progression. AB - NAC1 is a cancer-related transcription regulator protein that is overexpressed in various carcinomas, including ovarian, cervical, breast, and pancreatic carcinomas. NAC1 knock-down was previously shown to result in the apoptosis of ovarian cancer cell lines and to rescue their sensitivity to chemotherapy, suggesting that NAC1 may be a potential therapeutic target, but protein complex formation of intranuclear NAC1 in ovarian cancer cells remain poorly understood. In this study, analysis of ovarian cancer cell lysates by fast protein liquid chromatography on a sizing column showed that the NAC1 peak corresponded to an apparent molecular mass of 300-500 kDa, which is larger than the estimated molecular mass (58 kDa) of the protein. Liquid chromatography-tandem mass spectrometry analysis identified CARM1 as interacting with NAC1 in the protein complex. Furthermore, tissue microarray analysis revealed a significant correlation between CARM1 and NAC1 expression levels. Ovarian cancer patients expressing high levels of NAC1 and CARM1 exhibited poor prognosis after adjuvant chemotherapy. Collectively, our results demonstrate that high expression levels of NAC1 and its novel binding partner CARM1 may serve as an informative prognostic biomarker for predicting resistance to chemotherapy for ovarian cancer. PMID- 29983870 TI - Comparative molecular characterization of typical and exceptional responders in glioblastoma. AB - Glioblastoma (GBM) is the most common and the deadliest type of primary brain tumor, with a median survival time of only 15 months despite aggressive treatment. Although most patients have an extremely poor prognosis, a relatively small number of patients survive far beyond the median survival time. Investigation of these exceptional responders has sparked a great deal of interest and is becoming an important focus in the field of cancer research. To investigate the molecular differences between typical and exceptional responders in GBM, comparative analyses of somatic mutations, copy number, methylation, and gene expression datasets from The Cancer Genome Atlas were performed, and the results of these analyses were integrated via gene ontology and pathway analyses to assess the functional significance of the differential aberrations. Less severe copy number loss of CDKN2A, lower expression of CXCL8, and FLG mutations are all associated with an exceptional response. Typical responders are characterized by upregulation of NF-kappaB signaling and of pro-inflammatory cytokines, while exceptional responders are characterized by upregulation of Alzheimer's and Parkinson's disease pathways as well as of genes involved in synaptic transmission. The upregulated pathways and processes in typical responders are consistently associated with more aggressive tumor phenotypes, while those in the exceptional responders suggest a retained ability in tumor cells to undergo cell death in response to treatment. With the upcoming launch of the National Cancer Institute's Exceptional Responders Initiative, similar studies with much larger sample sizes will likely become possible, hopefully providing even more insight into the molecular differences between typical and exceptional responders. PMID- 29983871 TI - Deferasirox, an oral iron chelator, with gemcitabine synergistically inhibits pancreatic cancer cell growth in vitro and in vivo. AB - Objectives: Iron is an essential element for cell proliferation and growth processes. We have reported that deferasirox (DFX), an oral iron chelator, showed antiproliferative activity against pancreatic cancer cells. This study aimed to elucidate the effects of combination of gemcitabine (GEM), standard chemotherapy for pancreatic cancer, and DFX in vitro and in vivo. Results: GEM+DFX showed antiproliferative activity and induced apoptosis in pancreatic cancer cells in vitro. GEM+DFX suppressed xenograft tumor growth and induced apoptosis without any serious side effects compared with control, GEM, and DFX (average tumor volume: control 697 mm3 vs GEM 372 mm3, p < 0.05; GEM 372 mm3 vs GEM+DFX 234 mm3, p < 0.05). RRM1 and RRM2 protein levels were substantially reduced by DFX in BxPC 3 in vitro. Conclusion: GEM+DFX has significant anticancer effects on pancreatic cancer cell through RR activity suppression. Methods: BxPC-3, a human pancreatic cancer cell line, was used in all experiments. Cellular proliferation rate was measured using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium, inner salt assay. Apoptosis was evaluated by flow cytometry and by measuring caspase 3/7 activity with luminescence assay. In the tumor xenografts in nude mice models, when five weeks after engraftment, drug administration began (day 0). After treatment for 21 days, the mice were sacrificed and the tumors were excised. Apoptotic cells in xenografts were evaluated by terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay. Protein levels of ribonucleotide reductase (RR) subunit 1 (RRM1) and RR subunit 2 (RRM2) in BxPC-3 cells were assessed by western blot in vitro. PMID- 29983872 TI - Silencing NIK potentiates anti-VEGF therapy in a novel 3D model of colorectal cancer angiogenesis. AB - Angiogenesis is essential for colorectal cancer (CRC) progression, as demonstrated by the beneficial clinical effects of therapeutics inhibiting VEGF signaling. However, alternative mechanisms of neovascularization can develop, resulting in treatment failure. Previously we demonstrated NF-kappaB-inducing kinase (NIK) contributes to pathological angiogenesis. Here, we investigate NIK as a therapeutic target in endothelial cells (EC) in CRC. To determine NIK expression levels in CRC tissues, we immunostained both primary colorectal tumors and tumors metastasized to the liver. Additionally, a 3D tumor-stromal cell interaction model was developed including EC, fibroblasts and CRC cells to study tumor angiogenesis. This model tested efficacy of NIK-targeting siRNA (siNIK) in EC alone or in combination with the anti-VEGF antibody, bevacizumab. Both primary CRC and liver metastases contained blood vessels expressing NIK. In patients receiving chemotherapy plus bevacizumab, immature NIK+ vessels (p < 0.05) were increased as compared to chemotherapy alone. Activation of NIK by lymphotoxin beta receptor (LTbetaR) induced increases in pro-angiogenic mediators, including interleukin (IL)-6, IL-8, chemokine (C-X-C motif) ligand (CXCL)1 and CXCL5 in EC and fibroblasts, accompanied by sprouting in the 3D model, which was blocked by siNIK in EC. Treatment with bevacizumab plus siNIK in EC resulted in a synergistic effect and reduced VEGF and bFGF-induced sprouting (p < 0.05). Here, we demonstrate a role for NIK in CRC-associated angiogenesis. Targeting NIK in EC in combination with anti-VEGF antibody bevacizumab may hold therapeutic potential to increase efficiency in blocking tumor neovascularization, either to prevent treatment failure due to activation of accessory pathways such as NF-kappaB signaling or as a rescue treatment. PMID- 29983873 TI - Simultaneous delivery of olaparib and carboplatin in PEGylated liposomes imparts this drug combination hypersensitivity and selectivity for breast tumor cells. AB - Combination regiments involving platinum anticancer drugs and agents with unrelated mechanisms of action are a subject of widespread interest. Here, we show that synergistic toxic action in cancer cells of combinations of antitumor platinum drug carboplatin and effective PARP inhibitor olaparib is considerably improved if these combined drugs are encapsulated into liposomes. Notably, the formation of such nano-formulations, called OLICARB, leads to a marked enhancement of activity in human cancer cell lines (including those resistant to conventional platinum antitumor drugs) and selectivity towards tumor cells. We used immunofluorescence analysis of gammaH2AX expression and examined DNA damage in cancerous cells treated with the investigated compounds. We find that the synergistic toxic effects in cancer cells of both drugs used in combination, nonencapsulated or embedded in the OLICARB nanoparticles, positively correlates with DNA damage. These results also suggest that the enhancement of the toxic effects of carboplatin by olaparib in cancer cells is a consequence of an accumulation of cytotoxic lesions in DNA due to the inhibition of repair of platinated DNA augmented by the synergistic action of olaparib as an effective PARP inhibitor. Our findings also reveal that the combination of olaparib with carboplatin encapsulated in the OLICARB nanoparticles is particularly effective to inhibit the growth of 3D mammospheres. Collectively, the data provide convincing evidence that the encapsulation of carboplatin and olaparib into liposomal constructs to form the OLICARB nanoparticles may represent the viable approach for the treatment of tumors with the aim to eliminate the possible effects of acquired resistance. PMID- 29983874 TI - Role of drug transporters in the sensitivity of acute myeloid leukemia to sorafenib. AB - Background: Chemoresistance often limits the success of the pharmacological treatment in acute myeloid leukemia (AML) patients. Although positive results have been obtained with tyrosine kinase inhibitors (TKIs), such as sorafenib, especially in patients with Fms-like tyrosine kinase 3 (FLT3)-positive AML, the success of chemotherapy is very heterogeneous. Here we have investigated in vitro whether the transportome (set of expressed plasma membrane transporters) is involved in the differential response of AML to sorafenib. Methods: The sensitivity to sorafenib-induced cell death (MTT test and anexin V/7-AAD method) was evaluated in five different cell lines: MOLM-13, OCI-AML2, HL-60, HEL and K 562. The transportome was characterized by measuring mRNA using RT-qPCR. Drug uptake/efflux was determined by flow cytometry using specific substrates and inhibitors. Results: The cytostatic response to sorafenib was: MOLM-13>>OCI AML2>HL-60>HEL~K-562. Regarding efflux pumps, MDR1 was highly expressed in HEL>K 562~MOLM-13, but not in OCI-AML2 and HL-60. BCRP and MPR3 expression was low in all cell lines, whereas MRP4 and MRP5 expression was from moderate to high. Flow cytometry studies demonstrated that MRP4, but not MRP5, was functional. The expression of the organic cation transporter 1 (OCT1), involved in sorafenib uptake, was MOLM-13>OCI-AML2~HL-60 and non detectable in HEL and K-562. Transfection of HEL cells with OCT1 increased the sensitivity of these cells to sorafenib, whereas inactive genetic variants failed to induce this change. Conclusion: Together with changes in the expression/function of receptors targeted by TKIs, the expression of plasma membrane transporters involved in sorafenib uptake/efflux may affect the response of leukemia cells to this drug. PMID- 29983875 TI - Efficacy of a new cancer treatment strategy based on eradication of tumor initiating stem cells in a mouse model of Krebs-2 solid adenocarcinoma. AB - Krebs-2 solid carcinoma was cured using a new "3+1" strategy for eradication of Krebs-2 tumor-initiating stem cells. This strategy was based on synchronization of these cells in a treatment-sensitive phase of the cell cycle. The synchronization mechanism, subsequent destruction of Krebs-2 tumor-initiating stem cells, and cure of mice from a solid graft were found to depend on the temporal profile of the interstrand cross-link repair cycle. Also, the temporal profile of the Krebs-2 interstrand repair cycle was found to have a pronounced seasonal cyclicity at the place of experiments (Novosibirsk, Russia). As a result, the therapeutic effect that is based on application of the described strategy, originally developed for the "winter repair cycle" (November-April), is completely eliminated in the summer period (June-September). We conclude that one of the possible and the likeliest reasons for our failure to observe the therapeutic effects was the seasonal cyclicity in the duration of the interstrand repair cycle, the parameter that is central to our strategy. PMID- 29983876 TI - A bi-specific inhibitor targeting IL-17A and MMP-9 reduces invasion and motility in MDA-MB-231 cells. AB - The cytokine IL-17A is associated with the progression of various cancers, but little is known about the molecular cross-talk between IL-17A and other tumor promoting factors. Previous studies have shown that the IL-17A-mediated invasion of breast cancer cells can be inhibited by selective antagonists of the matrix metalloproteinase 9 (MMP-9), suggesting that the cross-talk between IL-17A and MMP-9 may promote cancer invasiveness and metastasis. Here, we present a novel strategy for developing cancer therapeutics, based on the simultaneous binding and inhibition of both IL-17A and MMP-9. To this end, we use a bi-specific heterodimeric fusion protein, comprising a natural inhibitor of MMPs (N-TIMP2) fused with an engineered extracellular domain (V3) of the IL-17A receptor. We show that, as compared with the mono-specific inhibitors of IL-17A (V3) and MMP-9 (N-TIMP2), the engineered bi-specific fusion protein inhibits both MMP-9 activation and IL-17A-induced cytokine secretion from fibroblasts and exhibits a synergistic inhibition of both the migration and invasion of breast cancer cells. Our findings demonstrate, for the first time, that dual targeting of inflammatory (IL-17A) and extracellular matrix remodeling (MMP) pathways can potentially be used as a novel therapeutic approach against cancer. Moreover, the platform developed here for generating the bi-specific IL-17A/MMP-9 inhibitor can be utilized for generating bi-specific inhibitors for other cytokines and MMPs. PMID- 29983878 TI - Prostate cancer susceptibility gene HIST1H1A is a modulator of androgen receptor signaling and epithelial to mesenchymal transition. AB - In 2018, approximately 165,000 new prostate cancer (PC) cases will be diagnosed, and over 29,000 men will succumb to PC in the U.S. alone. The means of assessing outcome in the clinic are inaccurate, and there is a pressing need to more precisely identify men at risk of aggressive PC. We previously identified HIST1H1A as a susceptibility gene for aggressive PC. HIST1H1A encodes H1.1, a member of the linker histone family that is involved in chromatin organization and compaction. To understand the molecular basis of aggressive PC, we have characterized how germline variation modulates susceptibility to neuroendocrine differentiation, which is a form of aggressive PC. Immunohistochemistry studies revealed that HIST1H1A is over-expressed in normal human prostate tissue compared to prostate adenocarcinoma. Functional characterization of HIST1H1A in prostate LNCaP cells indicated that HIST1HA over-expression increased cell growth, as well as the expression of neuroendocrine and epithelial-to-mesenchymal markers in vitro. Assay for Transposase-Accessible Chromatin (ATAC-seq), which is used to assess chromatin compaction and thus the transcriptional availability of individual genomic regions, demonstrated that H1.1 plays a prominent role in modulating Wnt signaling pathway genes, which are implicated in prostate tumorigenesis. These results demonstrate that HIST1H1A is a modulator of aggressive PC susceptibility. PMID- 29983877 TI - Mutations of p53 decrease sensitivity to the anthracycline treatments in bladder cancer cells. AB - Due to doxorubicin (Dox) cardiotoxicity, the next generation of novel non cardiotoxic anthracyclines, including AD 312 and AD 198, were synthesized and validated. In this study, we assessed the efficacy and mechanisms of anthracyclines-induced apoptosis and inhibition of cell viability in human bladder cancer cells expressing wild-type (wt) p53 (RT4 and SW780) and mutated (mt) p53 (UM-UC-3, 5637, T-24, J82, and TCCSUP) protein. Anthracyclines inhibited cell viability in tested TCC cells, but were less effective in mt-p53 TCC cells, especially in the drug-resistant J82 and TCCSUP cells. Anthracyclines upregulated the expression of wt p53 protein in RT4 and SW780 cells, but had no effect on expression of mt p53 protein in UM-UC-3, 5637, T-24, J82, and TCCSUP cells. The anthracyclines activated caspase 3/7 and cleavage of PARP in wt-p53 RT4 and SW780 cells, and mt-p53 5637, UM-UC-3, and T-24, but not in mt-p53 J82 and TCCSUP cells. The anthracyclines-induced cleavage of PARP was blocked by p53 siRNA in wt p53 RT4 cells. Co-treatment of AD 198 with PRIMA-1 significantly inhibited cell viability of mt-p53 J82 cells, but had no effect in wt-p53 RT4 cells. AD 198 blocked c-myc expression in mt-p53 UM-UC-3, 5637, T-24, and J82 cells, however no expression of c-myc was detected in wt-p53 RT4 and SW780 cells. In conclusion, our results demonstrated that the anthracycline-induced resistance in bladder cancer cells positively correlated with TP53 mutations in the tetramerization domain in J82 and TCCSUP cells. Further, AD 312 and AD 198 are promising chemotherapeutic drugs for bladder cancer, especially in combination with PRIMA 1. PMID- 29983879 TI - Targeting of BMI-1 expression by the novel small molecule PTC596 in mantle cell lymphoma. AB - Despite the development of the novel Bruton tyrosine kinase inhibitor ibrutinib, mantle cell lymphoma (MCL) remains an incurable B-cell non-Hodgkin lymphoma. BMI 1 is required for the self-renewal and maintenance of MCL-initiating stem cells. Upregulation of BMI-1 has been reported in MCL patients, especially in those with refractory/relapsed disease. We studied the effects of a novel small-molecule selective inhibitor of BMI1 expression, PTC596, in MCL cells. Eight MCL cell lines and patient-derived samples were exposed to PTC596. PTC596 induced mitochondrial apoptosis, as evidenced by loss of mitochondrial membrane potential, caspase-3 cleavage, BAX activation, and phosphatidylserine externalization. There was a positive correlation between baseline BMI-1 protein levels and PTC596-induced apoptosis. p53 status did not affect sensitivity to PTC596. PTC596 effectively decreased BMI-1-expressing and tumor-initiating side population MCL cells (IC50: 138 nM) compared with ibrutinib, which modestly decreased side population cells. Interestingly, PTC596, reported to target cancer stem cells, decreased MCL-1 expression levels and antagonized ibrutinib-induced increase in MCL-1 expression, leading to synergistic apoptosis induction in MCL cells. There are currently no drugs that specifically target cancer stem cell fractions, and a reduction in BMI-1 protein by PTC596 may offer a novel therapeutic strategy for MCL. PMID- 29983880 TI - Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. AB - AR-V7-expressing metastatic prostate cancer is an aggressive phenotype with poor progression-free survival (PFS) and overall survival (OS). Preliminary evidence suggests that AR-V7-positive tumors may be enriched for DNA-repair defects, perhaps rendering them more sensitive to immune-checkpoint blockade. We enrolled 15 metastatic prostate cancer patients with AR-V7-expressing circulating tumor cells into a prospective phase-2 trial. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, then maintenance nivolumab 3 mg/kg every 2 weeks. Targeted next-generation sequencing was performed to determine DNA-repair deficiency (DRD) status. Outcomes included PSA response rates, objective response rates (ORR), PSA progression-free survival (PSA-PFS), clinical/radiographic PFS and OS. Median age of participants was 65, median PSA was 115 ng/mL, 67% had visceral metastases, and 60% had >=4 prior systemic therapies. Six of 15 men (40%) had DRD mutations (three in BRCA2, two in ATM, one in ERCC4; none had microsatellite instability). Overall, the PSA response rate was 2/15 (13%), ORR was 2/8 (25%) in those with measurable disease, median PSA PFS was 3.0 (95%CI 2.1-NR) months, PFS was 3.7 (95%CI 2.8-7.5) months, and OS was 8.2 (95%CI 5.5-10.4) months. Outcomes appeared generally better in DRD+ vs. DRD- tumors with respect to PSA responses (33% vs. 0%; P=0.14, nonsignificant), ORR (40% vs. 0%; P=0.46, nonsignificant), PSA-PFS (HR 0.19; P<0.01, significant), PFS (HR 0.31; P=0.01, significant), and OS (HR 0.41; P=0.11, nonsignificant). There were no new safety concerns. Ipilimumab plus nivolumab demonstrated encouraging efficacy in AR-V7-positive prostate cancers with DRD mutations, but not in the overall study population. PMID- 29983881 TI - 2'-deoxy-2'-[18F] fluoro-D-glucose positron emission tomography, diffusion weighted magnetic resonance imaging, and choline spectroscopy to predict the activity of cetuximab in tumor xenografts derived from patients with squamous cell carcinoma of the head and neck. AB - We investigated changes on 2'-deoxy-2'-[18F]fluoro-D-glucose positron emission tomography (18FDG-PET), diffusion-weighted magnetic resonance imaging (DW-MRI), and choline spectroscopy as early markers of cetuximab activity in squamous cell carcinoma of the head and neck (SCCHN). SCCHN patient-derived tumor xenografts models were selected based on their cetuximab sensitivity. Three models were resistant to cetuximab and two were sensitive (one was highly sensitive and the other one was moderately sensitive). Cetuximab was infused on day 0 and 7. Maximal standardized uptake values (SUVmax), apparent diffusion coefficient (ADC), and total choline pool were measured at baseline and at day 8. To investigate the possible clinical relevance of our pre-clinical findings, we also studied the SUVmax and ADC modifications induced by cetuximab in five patients. Cetuximab induced a significant decrease in SUVmax and an increase in ADC at day 8 compared to baseline in the most cetuximab-sensitive model but not in the other models. At day 8, in one resistant model, SUVmax was decreased compared to baseline and was significantly lower than the controls. Choline spectroscopy was not able to predict cetuximab activity. The five patients treated with cetuximab had a 18FDG-PET partial response. One patient had a partial response according to RECISTv1.1. Interestingly, this last had also an increase in ADC value above 25%. Our preclinical data support the use of PDTX to investigate imaging techniques to detect early treatment response. Our pre-clinical and clinical data suggest that DW-MRI and 18FDG-PET should be further investigated to predict cetuximab activity. PMID- 29983883 TI - Thymoquinone challenges UHRF1 to commit auto-ubiquitination: a key event for apoptosis induction in cancer cells. AB - Down-regulation of UHRF1 (Ubiquitin-like containing PHD and Ring Finger 1) in Jurkat cells, induced by natural anticancer compounds such as thymoquinone, allows re-expression of tumor suppressor genes such as p73 and p16INK4A . In order to decipher the mechanisms of UHRF1 down-regulation, we investigated the kinetic of expression of HAUSP (herpes virus-associated ubiquitin-specific protease), UHRF1, cleaved caspase-3 and p73 in Jurkat cells treated with thymoquinone. We found that thymoquinone induced degradation of UHRF1, correlated with a sharp decrease in HAUSP and an increase in cleaved caspase-3 and p73. UHRF1 concomitantly underwent a rapid ubiquitination in response to thymoquinone and this effect was not observed in the cells expressing mutant UHRF1 RING domain, suggesting that UHRF1 commits an auto-ubiquitination through its RING domain in response to thymoquinone treatment. Exposure of cells to Z-DEVD, an inhibitor of caspase-3 markedly reduced the thymoquinone-induced down-regulation of UHRF1, while proteosomal inhibitor MG132 had no such effect. The present findings indicate that thymoquinone induces in cancer cells a fast UHRF1 auto ubiquitination through its RING domain associated with HAUSP down-regulation. They further suggest that thymoquinone-induced UHRF1 auto-ubiquitination followed by its degradation is a key event in inducing apoptosis through a proteasome independent mechanism. PMID- 29983882 TI - The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma. AB - Non-Hodgkin lymphoma (NHL) is one of the most common causes of cancer-related death in the United States and Europe. Although the outcome of NHL patients has improved over the last years with current therapies, the rate of mortality is still high. A plethora of new drugs is entering clinical development for NHL treatment; however, the approval of new treatments remains low due in part to the paucity of clinically relevant models for validation. Canine lymphoma shares remarkable similarities with its human counterpart, making the dog an excellent animal model to explore novel therapeutic molecules and approaches. Histone deacetylase inhibitors (HDACis) have emerged as a powerful new class of anti cancer drugs for human therapy. To investigate HDACi antitumor properties on canine diffuse large B-cell lymphoma, a panel of seven HDACi compounds (CI-994, panobinostat, SBHA, SAHA, scriptaid, trichostatin A and tubacin) was screened on CLBL-1 canine B-cell lymphoma cell line. Our results demonstrated that all HDACis tested exhibited dose-dependent inhibitory effects on proliferation of CLBL-1 cells, while promoting increased H3 histone acetylation. Amongst all HDACis studied, panobinostat proved to be the most promising compound and was selected for further in vitro and in vivo evaluation. Panobinostat cytotoxicity was linked to H3 histone and alpha-tubulin acetylation, and to apoptosis induction. Importantly, panobinostat efficiently inhibited CLBL-1 xenograft tumor growth, and strongly induced acetylation of H3 histone and apoptosis in vivo. In conclusion, these results provide new data validating HDACis and, especially, panobinostat as a novel anti-cancer therapy for veterinary applications, while contributing to comparative oncology. PMID- 29983884 TI - P-Rex1 is dispensable for Erk activation and mitogenesis in breast cancer. AB - Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 1 (P-Rex1) is a key mediator of growth factor-induced activation of Rac1, a small GTP binding protein widely implicated in actin cytoskeleton reorganization. This Guanine nucleotide Exchange Factor (GEF) is overexpressed in human luminal breast cancer, and its expression associates with disease progression, metastatic dissemination and poor outcome. Despite the established contribution of P-Rex1 to Rac activation and cell locomotion, whether this Rac-GEF has any relevant role in mitogenesis has been a subject of controversy. To tackle the discrepancies among various reports, we carried out an exhaustive analysis of the potential involvement of P-Rex1 on the activation of the mitogenic Erk pathway. Using a range of luminal breast cancer cellular models, we unequivocally showed that silencing P-Rex1 (transiently, stably, using multiple siRNA sequences) had no effect on the phospho-Erk response upon stimulation with growth factors (EGF, heregulin, IGF-I) or a GPCR ligand (SDF-1). The lack of involvement of P-Rex1 in Erk activation was confirmed at the single cell level using a fluorescent biosensor of Erk kinase activity. Depletion of P-Rex1 from breast cancer cells failed to affect cell cycle progression, cyclin D1 induction, Akt activation and apoptotic responses. In addition, mammary-specific P-Rex1 transgenic mice (MMTV-P Rex1) did not show any obvious hyperproliferative phenotype. Therefore, despite its crucial role in Rac1 activation and cell motility, P-Rex1 is dispensable for mitogenic or survival responses in breast cancer cells. PMID- 29983885 TI - RIOK1 kinase activity is required for cell survival irrespective of MTAP status. AB - Genotype specific vulnerabilities of cancer cells constitute a promising strategy for the development of new therapeutics. Deletions of non-essential genes in tumors can generate unique vulnerabilities which could be exploited therapeutically. The MTAP gene is recurrently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. Recent studies have uncovered an increased dependency of MTAP-deleted cancer cells on the function of a PRMT5 containing complex, including WDR77, PRMT5 and the kinase RIOK1. As RIOK1 kinase activity constitutes a potential therapeutic target, we wanted to test if MTAP deletion confers increased sensitivity to RIOK1 inhibition. Using CRISPR/Cas9-mediated genome engineering we generated analog sensitive alleles of RIOK1 in isogenic cell lines differing only by MTAP status. While we were able to independently confirm an increased dependency of MTAP deleted cells on PRMT5, we did not detect a differential requirement for RIOK1 kinase activity between MTAP-proficient and deficient cells. Our results reveal that the kinase activity of RIOK1 is required for the survival of cancer cell lines irrespective of their MTAP status and cast doubt on the therapeutic exploitability of RIOK1 in the context of MTAP-deleted cancers. PMID- 29983886 TI - Oral administration of fructose exacerbates liver fibrosis and hepatocarcinogenesis via increased intestinal permeability in a rat steatohepatitis model. AB - Recent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH. PMID- 29983887 TI - Epithelial differentiation with microlumen formation in meningioma: diagnostic utility of NHERF1/EBP50 immunohistochemistry. AB - Meningioma is a primary brain tumor arising from the neoplastic transformation of meningothelial cells. Several histological variants of meningioma have been described. Here we show that NHERF1/EBP50, an adaptor protein required for structuring specialized polarized epithelia, can distinguish meningioma variants with epithelial differentiation. NHERF1 decorates the membrane of intracytoplasmic lumens and microlumens in the secretory variant, consistent with a previously described epithelial differentiation of this subtype. NHERF1 also labels microlumens in chordoid meningioma, an epithelial variant not previously known to harbor these structures, and ultrastructural analysis confirmed the presence of microlumens in this variant. NHERF1 associates with the ezrin-radixin moesin (ERM)-NF2 cytoskeletal proteins, and moesin but not NF2 was detectable in the microlumens. In a meningioma series from 83 patients, NHERF1 revealed microlumens in 87.5% of the chordoid meningioma (n = 25) and meningioma with chordoid component (n = 7) cases, and in 100% of the secretory meningioma cases (n = 12). The most common WHO grade I meningioma variants lacked microlumens. Interestingly, 20% and 66.6% of WHO grades II (n = 20) and III (n = 3) meningiomas, respectively, showed microlumen-like NHERF1 staining of ultrastructural tight microvillar interdigitations, mainly in rhabdoid, papillary like or sheeting areas, revealing a new subset of high grade meningiomas with epithelial differentiation. NHERF1 failed to detect microlumens in 12 additional cases of chordoid glioma of the 3rd ventricle, chordoma and chondrosarcoma, neoplasms that may mimic the histological appearance of chordoid meningioma. This study uncovers features of epithelial differentiation in meningioma and proposes NHERF1 immunohistochemistry as a method of discriminating chordoid meningioma from neoplasms with similar appearance. PMID- 29983889 TI - Advantage of HSP110 (T17) marker inclusion for microsatellite instability (MSI) detection in colorectal cancer patients. AB - Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Microsatellite instability (MSI) is a genetic pathway leading to CRC, associated with particular clinicopathological features, and recently a major biomarker of immunotherapy response. There is little information the frequency MSI among Brazilian CRC patients, and it is still debatable the ideal methodology for MSI screening in countries with limited resources. We proposed to evaluate MSI by molecular and immunohistochemistry (IHC) methods, to compare both methodologies and also to assess the inclusion of a novel microsatellite marker, HSP110 (T17). The molecular MSI evaluation was performed using a PCR-multiplex panel in a total of 1013 CRC patients. Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2) expression were evaluated by IHC. HSP110 (T17) marker was analyzed by fragment analysis. Molecularly, 89.5% of cases were MSI-negative and 10.5% were MSI positive. The IHC showed that 88.9% of cases exhibited MMR-proficient status, 10.2% were MMR-deficient and 0.9% was inconclusive. Genotyping of the HSP110 (T17) in 106 MSI-positive and 215 MSI-negative cases showed its alteration only among the MSI-positive cases. We observed agreement (0.956, Kappa Test) between both molecular and IHC methodologies, with only eight discordant results, and in this subset of cases the HSP110 (T17) corroborate the molecular findings. This study suggests the use of molecular assays over IHC for MSI analysis and proposes the inclusion HSP110 (T17) marker as a complementary analysis in discordant cases. PMID- 29983888 TI - Role for the transcriptional activator ZRF1 in early metastatic events in breast cancer progression and endocrine resistance. AB - Breast cancer is one of the most common malignancies among women which is often treated with hormone therapy and chemotherapy. Despite the improvements in detection and treatment of breast cancer, the vast majority of breast cancer patients are diagnosed with metastatic disease either at the beginning of the disease or later during treatment. Still, the molecular mechanisms causing a therapy resistant metastatic breast cancer are still elusive. In the present study we addressed the function of the transcriptional activator ZRF1 during breast cancer progression. We provide evidence that ZRF1 plays an essential role for the early metastatic events in vitro and acts like a tumor suppressor protein during the progression of breast invasive ductal carcinoma into a more advanced stage. Hence, depletion of ZRF1 results in the acquisition of metastatic behavior by facilitating the initiation of the metastatic cascade, notably for cell adhesion, migration and invasion. Furthermore absence of ZRF1 provokes endocrine resistance via misregulation of cell death and cell survival related pathways. Taken together, we have identified ZRF1 as an important regulator of breast cancer progression that holds the potential to be explored for new treatment strategies in the future. PMID- 29983890 TI - Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus. AB - Intratumoral therapy with oncolytic viruses is increasingly being explored as a strategy to potentiate an immune response against cancer, but it remains unknown whether such therapy should be restricted to cancers sensitive to virus-mediated lysis. Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates. Infection of human and mouse bladder cancer cells with NDV resulted in immunogenic cell death, activation of innate immune pathways, and upregulation of MHC and PD-L1 in all tested cell lines, including the cell lines completely resistant to NDV-mediated lysis. In a bilateral flank NDV-lysis-resistant syngeneic murine bladder cancer model, intratumoral therapy with NDV led to an increase of immune infiltration in both treated and distant tumors and a shift from an inhibitory to effector T cell phenotype. Consequently, combination of intratumoral NDV with systemic PD-1 or CTLA-4 blockade led to improved local and abscopal tumor control and overall survival. These findings encourage future clinical trials combining intratumoral NDV therapy with systemic immunomodulatory agents and underscore the rationale for such treatments irrespective of tumor cell sensitivity to NDV-mediated lysis. PMID- 29983891 TI - Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids. AB - Ulcerative colitis (UC) is a prevalent form of inflammatory bowel disease (IBD) whose pathogenic mechanisms remain unclear. Elucidating these mechanisms is important to reduce UC symptoms and to prevent UC progression into colitis associated colon cancer (CAC). Our goal was to develop and validate faithful, human-derived, UC models and analyze them at histologic, transcriptomic and epigenetic levels to allow mechanistic studies of UC and CAC pathogenesis. We generated patient-derived primary-organoid cultures from UC and non-IBD colonic epithelium. We phenotyped them histologically and used next-generation-sequencing approaches to profile whole transcriptomes and epigenomes of organoids and primary tissues. Tissue organization and expression of mucin 2 (MUC2) and lysozyme (LYZ) demonstrated histologic faithfulness of organoids to healthy and diseased colonic epithelium. Transcriptomic analyses showed increased expression of inflammatory pathways in UC patient-derived organoids and tissues. Profiling for active enhancers using the H3K27ac histone modification revealed UC-derived organoid enrichment for pathways indicative of gastrointestinal cancer, including S100 calcium-binding protein P (S100P), and revealed novel markers for GI cancer, including both LYZ and neuropeptide S receptor 1 (NPSR1). Immunolocalization showed increased levels of LYZ, S100P, and NPSR1 proteins in UC and CAC. In conclusion, primary colonic organoid cultures from UC and non-IBD patients can be established that faithfully represent diseased or normal colonic states. These models reveal precancerous molecular pathways that are already activated in UC. The findings demonstrate the suitability of primary organoids for dissecting UC and CAC pathogenic mechanisms and suggest new targets for therapeutic intervention. PMID- 29983892 TI - Targeting Polo-like kinase 1 and TRAIL enhances apoptosis in non-small cell lung cancer. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells without causing damage to normal cells. However, some tumors are resistant to TRAIL monotherapy and clinical studies assessing targeted agents towards the TRAIL receptor have failed to show robust therapeutic activity. Evidence has shown that standard anti-mitotic drugs can induce synergistic apoptosis upon combination with TRAIL via cell cycle arrest. Polo like kinase-1 (PLK1) plays a critical role in different stages of cell cycle progression and mitosis. A number of investigations have demonstrated that PLK1 inhibition causes cell cycle arrest and mitotic catastrophe in non-small cell lung cancer (NSCLC), and we thus postulated that PLK1 inhibition could enhance TRAIL-induced apoptosis. We demonstrate that the combination of a TRAIL receptor agonist and a PLK1 inhibitor synergistically reduces cell viability, and strongly increases apoptosis in NSCLC cellular models. Consistent with our in vitro observations, this drug combination also significantly reduces tumor growth in vivo. Our data additionally reveal that G2/M cell cycle arrest and downregulation of Mcl-1 and signal transducer and activator of transcription 3 (STAT3) activity following PLK1 inhibition may contribute to the sensitization of TRAIL-induced apoptosis in NSCLC. Together, these data support the further exploration of combined TRAIL and PLK1 inhibition in the treatment of NSCLC. PMID- 29983894 TI - Trends and outcomes of women with synchronous endometrial and ovarian cancer. AB - This retrospective observational study examined trends, characteristics, and survival of women with synchronous endometrial and ovarian cancer (SEOC) in the Surveillance, Epidemiology, and End Results Program between 1973 and 2013. Among 235,454 women with primary endometrial cancer, synchronous ovarian cancer was seen in 4,082 (1.7%) women with the proportion being decreased from 2.0% to 1.6% between 1983 and 2013 (P=0.049); and the proportion of concurrent endometrioid tumors in the two cancer sites has increased from 24.2% to 49.9% among SEOC women (P<0.001). When compared to endometrial cancer without synchronous ovarian cancer, endometrioid histology in the two cancer sites was associated with improved cause-specific survival while non-endometrioid histology in the ovarian cancer was associated with decreased cause-specific survival (adjusted-P<0.01). Among 110,063 women with primary epithelial ovarian cancer, synchronous endometrial cancer was seen in 3,940 (3.6%) women with the proportion being increased from 2.2% to 4.4% between 1973 and 2013 (P<0.001); and the proportion of concurrent endometrioid tumors in the two cancer sites had increased from 24.3% to 50.2% among SEOC women (P<0.001). When compared to primary epithelial ovarian cancer without synchronous endometrial cancer, SEOC was associated with better cause-specific survival if ovarian cancer is endometrioid type or if endometrial cancer is endometrioid type (adjusted-P<0.001). Across the two cohorts, the proportion of SEOC reached to the peak in the late-40 years of age and then decreased significantly (P<0.001). In conclusion, our study suggests that synchronous ovarian cancer has decreased among endometrial cancer whereas synchronous endometrial cancer has increased among epithelial ovarian cancer. PMID- 29983893 TI - Growth hormone-releasing hormone (GHRH) and its agonists inhibit hepatic and tumoral secretion of IGF-1. AB - The role of hypothalamic growth hormone-releasing hormone (GHRH) in the release of growth hormone (GH) from the pituitary is well established. However, direct effects of GHRH and its agonistic analogs on extra-pituitary cells and tissues have not been completely elucidated. In the present study, we first demonstrated that human and rat hepatocytes express receptors for GHRH. We then showed that GHRH(1-29)NH 2 and GHRH agonist, MR-409, downregulated mRNA levels for IGF-1 in human cancer cell lines and inhibited IGF-1 secretion in vitro when these cancer lines were exposed to rhGH. Another GHRH agonist, MR-356, lowered serum IGF-l and inhibited tumor growth in nude mice bearing xenografted NCI-N87 human stomach cancers. GHRH(1-29)NH 2 and MR-409 also suppressed the expression of mRNA for IGF 1 and IGF-2 in rat and human hepatocytes, decreased the secretion of IGF-1 in vitro from rat hepatocytes stimulated with rhGH, and lowered serum IGF-l levels in hypophysectomized rats injected with rhGH. Vasoactive intestinal peptide had no effect on the release of IGF-1 from the hepatocytes. Treatment of C57BL/6 mice with MR-409 reduced serum levels of IGF-l from days 1 to 5. These results show that GHRH and its agonists can, by a direct action, inhibit the secretion of IGF 1 from the liver and from tumors. The inhibitory effect of GHRH appears to be mediated by the GHRH receptor (GHRH-R) and GH receptor (GHR), with the involvement of JAK2/STAT5 pathways. Further studies are required to investigate the possible physiopathological role of GHRH in the control of secretion of IGF 1. PMID- 29983895 TI - Chemical exchange saturation transfer MRI serves as predictor of early progression in glioblastoma patients. AB - Purpose: To prospectively investigate chemical exchange saturation transfer (CEST) MRI in glioblastoma patients as predictor of early tumor progression after first-line treatment. Experimental Design: Twenty previously untreated glioblastoma patients underwent CEST MRI employing a 7T whole-body scanner. Nuclear Overhauser effect (NOE) as well as amide proton transfer (APT) CEST signals were isolated using Lorentzian difference (LD) analysis and relaxation compensated by the apparent exchange-dependent relaxation rate (AREX) evaluation. Additionally, NOE-weighted asymmetric magnetic transfer ratio (MTRasym) and downfield-NOE-suppressed APT (dns-APT) were calculated. Patient response to consecutive treatment was determined according to the RANO criteria. Mean signal intensities of each contrast in the whole tumor area were compared between early progressive and stable disease. Results: Pre-treatment tumor signal intensity differed significantly regarding responsiveness to first-line therapy in NOE-LD (p = 0.0001), NOE-weighted MTRasym (p = 0.0186) and dns-APT (p = 0.0328) contrasts. Hence, significant prediction of early progression was possible employing NOE-LD (AUC = 0.98, p = 0.0005), NOE-weighted MTRasym (AUC = 0.83, p = 0.0166) and dns-APT (AUC = 0.80, p = 0.0318). The NOE-LD provided the highest sensitivity (91%) and specificity (100%). Conclusions: CEST derived contrasts, particularly NOE-weighted imaging and dns-APT, yielded significant predictors of early progression after fist-line therapy in glioblastoma. Therefore, CEST MRI might be considered as non-invasive tool for customization of treatment in the future. PMID- 29983896 TI - Induction chemotherapy reduces extracellular heat shock protein 72 levels, inflammation, lipoperoxidation and changes insulin sensitivity in children and adolescents newly diagnosed with acute lymphoblastic leukemia. AB - Background: Acute lymphoblastic leukemia (ALL) is associated with higher levels of pro-inflammatory cytokines and oxidative stress. Recently, the levels of extracellular heat shock protein 72 (eHSP72) were found to be elevated in ALL, and its elevation associated with poor prognosis. Therefore, considering the possible role of eHSP72 as a modulator of the immunological system and metabolism, the aim of this study was to describe the response of eHSP72 to the induction phase of chemotherapy, along with metabolic, inflammatory and oxidative stress markers, in children and adolescents newly diagnosed with ALL. Methods: Nineteen patients were recruited and analysed before and after the induction phase of chemotherapy (with 28 days of duration). Blood samples were taken for the analysis of C-reactive protein (CRP), levels of lipoperoxidation, insulin (and HOMA-IR), cortisol, glucose, lipid profile and eHSP72. Results: We found that induction phase of chemotherapy leads to a drop in glucose levels (from 101.79+/-19 to 75.8+/-9.7 mg/dL), improvements on inflammation (CRP levels, p<0.01) and oxidative stress (TBARS levels, p<0.01), reduction on eHSP72 (p=0.03) and improved insulin sensitivity (HOMA-IR, p=0.02). Conclusion: Our results indicate that eHSP72 may have an immune and metabolic role and could be used as a marker of the treatment success and metabolic changes in children with ALL. PMID- 29983897 TI - Correction: Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway. AB - [This corrects the article DOI: 10.18632/oncotarget.21882.]. PMID- 29983898 TI - Correction: Targeting Hsp27/eIF4E interaction with phenazine compound: a promising alternative for castration-resistant prostate cancer treatment. AB - [This corrects the article DOI: 10.18632/oncotarget.20469.]. PMID- 29983899 TI - Correction: Combining molecular and immunohistochemical analyses of key drivers in primary melanomas: interplay between germline and somatic variations. AB - [This corrects the article DOI: 10.18632/oncotarget.23204.]. PMID- 29983900 TI - More to the picture of the psychological impact of endocarditis and thoracic aortic pathology. AB - Over the years there has been substantial advanced in the diagnosis and surgical management of complex thoracic aortic disease and complex endocarditis. As these therapies are being offered to a growing segment of patients-and more and more patients are felt to potentially benefit from such therapies, the long-term consequences of these interventions is sometimes poorly understood. While traditional medical complications, such as stroke, renal failure, respiratory failure, and even death are often the focus of outcomes studies, little is known on the impact of these diseases and therapies on mental health. This commentary emphasizes the importance of better understanding the psychologic impact of endocarditis and thoracic aortic pathology as reviewed by Dr. Bagnasco. PMID- 29983901 TI - Patent foramen ovale closure reduces recurrent stroke risk in cryptogenic stroke: A systematic review and meta-analysis of randomized controlled trials. AB - AIM: To investigate if patent foramen ovale (PFO) closure device reduces the risk of recurrent stroke in patients with cryptogenic stroke. METHODS: We searched five databases - PubMed, EMBASE, Cochrane, CINAHL and Web-of-Science and clinicaltrials.gov from January 2000 to September 2017 for randomized trials comparing PFO closure to medical therapy in cryptogenic stroke. Heterogeneity was determined using Cochrane's Q statistics. Random effects model was used. RESULTS: Five randomized controlled trials with 3440 patients were included in the analysis. Mean follow-up was 50 +/- 20 mo. PFO closure was associated with a 41% reduction in incidence of recurrent strokes when compared to medical therapy alone in patients with cryptogenic stroke [risk ratio (RR): 0.59, 95%CI: 0.40 0.87, P = 0.008]. Atrial fibrillation was higher with device closure when compared to medical therapy alone (RR: 4.97, 95%CI: 2.22-11.11, P < 0.001). There was no difference between the two groups with respect to all-cause mortality, major bleeding or adverse events. CONCLUSION: PFO device closure in appropriately selected patients with moderate to severe right-to-left shunt and/or atrial septal aneurysm shows benefit with respect to recurrent strokes, particularly in younger patients. Further studies are essential to evaluate the impact of higher incidence of atrial fibrillation seen with the PFO closure device on long-term mortality and stroke rates. PMID- 29983903 TI - Time to tame necroptosis - viable combat against chemo resistant oral cancer cells. PMID- 29983902 TI - The role of pemetrexed in recurrent epithelial ovarian cancer: A scoping review. AB - Ovarian cancer is the leading cause of mortality among gynecologic malignancies, with most cases diagnosed at an advanced stage. Despite an initial response, most develop a recurrence and subsequent resistance to standard therapies. Pemetrexed (AlimtaTM) is a new generation multi-targeted antifolate initially approved for the treatment of malignant pleural mesothelioma. In recent years, it has shown promise in the treatment of recurrent epithelial ovarian cancer. In this review, we outline the current literature and discuss the future of pemetrexed in the setting of recurrent epithelial ovarian cancer. PMID- 29983904 TI - Adipose and Liver Function in Primate Offspring with Insulin Resistance Induced by Estrogen Deprivation in Utero. AB - Purpose: We recently demonstrated that offspring delivered to baboons deprived of estrogen during the second half of gestation exhibited insulin resistance. Therefore, because skeletal muscle accounts for >80% of insulin dependent glucose disposal, we suggested that estrogen in utero programs factors in fetal skeletal muscle important for insulin sensitivity in offspring. However, liver and adipose are also sites of insulin action and adipose insulin resistance can increase serum free fatty acid (FFA) levels and thereby reduce skeletal muscle insulin sensitivity. Therefore, in the current study we determined whether estrogen deprived offspring exhibit normal adipose and hepatic function. Results: The fasting serum levels of adiponectin, leptin, glucose, and analytes of liver function as well as the basal levels of serum FFA were similar in offspring of estrogen replete/suppressed baboons. Moreover, the normal glucose-induced decline in serum FFA levels measured in untreated offspring was also measured in offspring of letrozole-treated baboons. Fetal serum levels of adiponectin and leptin in late gestation also were similar and expression of nitrotyrosine negligible in fetal liver and adipose of untreated and letrozole-treated animals. Conclusions: These results indicate that offspring of letrozole-treated baboons have normal adipose and liver function and do not exhibit adipose insulin resistance. Therefore, we suggest that the insulin resistance observed in estrogen-deprived offspring primarily reflects a decline in insulin-stimulated glucose clearance by skeletal muscle and which supports our original suggestion that estrogen in utero programs factors in fetal skeletal muscle that promote insulin sensitivity in offspring. PMID- 29983905 TI - Leg Length Discrepancy: Dynamic Balance Response during Gait. AB - Balance in the human body's movement is generally associated with different synergistic pathologies. The trunk is supported by one's leg most of the time when walking. A person with poor balance may face limitation when performing their physical activities on a daily basis, and they may be more prone to having risk of fall. The ground reaction forces (GRFs), centre of pressure (COP), and centre of mass (COM) in quite standing posture were often measured for the evaluation of balance. Currently, there is still no experimental evidence or study on leg length discrepancy (LLD) during walking. Analysis of the stability parameters is more representative of the functional activity undergone by the person who has a LLD. Therefore, this study hopes to shed new light on the effects of LLD on the dynamic stability associated with VGRF, COP, and COM during walking. Eighteen healthy subjects were selected among the university population with normal BMIs. Each subject was asked to walk with 1.0 to 2.0 ms-1 of walking speed for three to five trials each. Insoles of 0.5 cm thickness were added, and the thickness of the insoles was subsequently raised until 4 cm and placed under the right foot as we simulated LLD. The captured data obtained from a force plate and motion analysis present Peak VGRF (single-leg stance) and WD (double-leg stance) that showed more forces exerted on the short leg rather than long leg. Obviously, changes occurred on the displacement of COM trajectories in the ML and vertical directions as LLD increased at the whole gait cycle. Displacement of COP trajectories demonstrated that more distribution was on the short leg rather than on the long leg. The root mean square (RMS) of COP-COM distance showed, obviously, changes only in ML direction with the value at 3 cm and 3.5 cm. The cutoff value via receiver operating characteristic (ROC) indicates the significant differences starting at the level 2.5 cm up to 4 cm in long and short legs for both AP and ML directions. The present study performed included all the proposed parameters on the effect of dynamic stability on LLD during walking and thus helps to determine and evaluate the balance pattern. PMID- 29983906 TI - Discovery of the Ubiquitous Cation NS+ in Space Confirmed by Laboratory Spectroscopy. AB - We report the detection in space of a new molecular species which has been characterized spectroscopically and fully identified from astrophysical data. The observations were carried out with the 30m IRAM telescopea. The molecule is ubiquitous as its J=2->1 transition has been found in cold molecular clouds, prestellar cores, and shocks. However, it is not found in the hot cores of Orion KL and in the carbon-rich evolved star IRC+10216. Three rotational transitions in perfect harmonic relation J' = 2/3/5 have been identified in the prestellar core B1b. The molecule has a 1Sigma electronic ground state and its J=2->1 transition presents the hyperfine structure characteristic of a molecule containing a nucleus with spin 1. A careful analysis of possible carriers shows that the best candidate is NS+. The derived rotational constant agrees within 0.3-0.7% with ab initio calculations. NS+ was also produced in the laboratory to unambiguously validate the astrophysical assignment. The observed rotational frequencies and determined molecular constants confirm the discovery of the nitrogen sulfide cation in space. The chemistry of NS+ and related nitrogen-bearing species has been analyzed by means of a time-dependent gas phase model. The model reproduces well the observed NS/NS+ abundance ratio, in the range 30-50, and indicates that NS+ is formed by reactions of the neutral atoms N and S with the cations SH+ and NH+, respectively. PMID- 29983907 TI - Rapid onset of action and reduced nasal hyperreactivity: new targets in allergic rhinitis management. AB - Background: This article summarizes a EUFOREA symposium, presented during the European Rhinology Research Forum in Brussels (9-10 November 2017; https://www.rhinologyresearch.eu/) which focused on novel pathways and therapeutic approaches in allergic rhinitis (AR). Main body: AR remains under diagnosed, under-estimated and under-treated. A key component in understanding the AR landscape has been the realization of a significant mismatch between how physicians instruct AR patients to manage their disease and what AR patients actually do in real life. Data from the Allergy Diary (developed by MACVIA ARIA) showed that AR patients take their medication prn, rapidly switch treatments, often experience poor control, use multiple therapies and stop treatment when symptoms are controlled. Better control of AR may be achievable by using an AR treatment which has a rapid onset of action and which effectively targets breakthrough symptoms. Indeed, AR patients report complete symptom relief, lack of breakthrough symptoms, rapid onset of action, safety and use on an 'as needed' basis as key targets for new nasal sprays. MP-AzeFlu comprises intranasal azelastine and fluticasone propionate (FP) in a novel formulation delivered in a single device. It is the first AR treatment to break the 5 min onset of action threshold and provides clinically relevant symptom relief in 15 min, much faster than that noted for FP + oral loratadine. MP-AzeFlu also significantly reduces nasal hyperresponsiveness (NHR) which may be responsible for the breakthrough symptoms frequently reported by AR patients. Mechanisms underlying MP-AzeFlu's effect include inhibition of mast cell degranulation, stabilization of the mucosal barrier, synergistic inhibition of inflammatory cell recruitment and a unique desensitization of sensory neurons expressing the transient receptor potential A1 and V1 channels. Conclusion: With the most rapid onset of action and onset of clinically-relevant effect of any AR medication currently available, and proven efficacy in the treatment of NHR, MP-AzeFlu is an AR treatment which provides what patients want, and fits how patients manage their AR in real life. PMID- 29946420 TI - Oral aniracetam treatment in C57BL/6J mice without pre-existing cognitive dysfunction reveals no changes in learning, memory, anxiety or stereotypy. AB - Background: The piracetam analog, aniracetam, has recently received attention for its cognition enhancing potential, with minimal reported side effects. Previous studies report the drug to be effective in both human and non-human models with pre-existing cognitive dysfunction, but few studies have evaluated its efficacy in healthy subjects. A previous study performed in our laboratory found no cognitive enhancing effects of oral aniracetam administration 1-hour prior to behavioral testing in naive C57BL/6J mice. Methods: The current study aims to further evaluate this drug by administration of aniracetam 30 minutes prior to testing in order to optimize any cognitive enhancing effects. In this study, all naive C57BL/6J mice were tested in tasks of delayed fear conditioning, novel object recognition, rotarod, open field, elevated plus maze, and marble burying. Results: Across all tasks, animals in the treatment group failed to show enhanced learning when compared to controls. Conclusions: These results provide further evidence suggesting that aniracetam conveys no therapeutic benefit to subjects without pre-existing cognitive dysfunction. PMID- 29983908 TI - Low back pain: a major global problem for which the chiropractic profession needs to take more care. AB - An important series of papers have been published in the Lancet. These papers provide a comprehensive update for the major global problem of low back pain, and the challenges that low back pain presents to healthcare practitioners and policy makers. Chiropractors are well placed to reduce the burden of low back pain, but not all that chiropractors do is supported by robust, contemporary evidence. This commentary summarises the Lancet articles. We also make suggestions for how the chiropractic profession should most effectively help people with low back pain by implementing practices supported by high quality evidence. PMID- 29983910 TI - Hepatic deletion of p110alpha and p85alpha results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity. AB - BACKGROUND: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110alpha results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85alpha results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110alpha and p85alpha (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. METHODS: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. RESULTS: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. CONCLUSIONS: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110alpha/p85alpha by signaling through other nodes than Akt/Protein Kinase B. PMID- 29983911 TI - Sex/gender differences in cognition, neurophysiology, and neuroanatomy. AB - In this mini-review, I summarize and interpret the current status of sex/gender differences in terms of brain anatomy, brain function, behavior, and cognition. Based on this review and the reported findings, I conclude that most of these sex/gender differences are not large enough to support the assumption of sexual dimorphism in terms of brain anatomy, brain function, cognition, and behavior. Instead, I suggest that many brain and cognitive features are modulated by environment, culture, and practice (and several other influences). These influences interact with the menstrual cycle, the general hormone level, and current gender stereotypes in a way that has not yet been fully understood. PMID- 29983912 TI - Recent advances in understanding and managing contact dermatitis. AB - About 20% of the general population is contact-sensitized to common haptens such as fragrances, preservatives, and metals. Many also develop allergic contact dermatitis (ACD), the clinical manifestation of contact sensitization. ACD represents a common health issue and is also one of the most important occupational diseases. Although this inflammatory skin disease is mediated predominantly by memory T lymphocytes recognizing low-molecular-weight chemicals after skin contact, the innate immune system also plays an important role. Along that line, the presence of irritants may increase the risk of ACD and therefore ACD is often seen in the context of irritant contact dermatitis. In this review article, we discuss recent progress in basic research that has dramatically increased our understanding of the pathomechanisms of ACD and provides a basis for the development of novel diagnostic and therapeutic measures. Current methods for diagnosis as well as treatment options of ACD are also discussed. PMID- 29983913 TI - Recent advances in understanding female gametophyte development. AB - The haploid female gametophyte (embryo sac) is an essential reproductive unit of flowering plants, usually comprising four specialized cell types, including the female gametes (egg cell and central cell). The differentiation of these cells relies on spatial signals which pattern the gametophyte along a proximal-distal axis, but the molecular and genetic mechanisms by which cell identities are determined in the embryo sac have long been a mystery. Recent identification of key genes for cell fate specification and their relationship to hormonal signaling pathways that act on positional cues has provided new insights into these processes. A model for differentiation can be devised with egg cell fate as a default state of the female gametophyte and with other cell types specified by the action of spatially regulated factors. Cell-to-cell communication within the gametophyte is also important for maintaining cell identity as well as facilitating fertilization of the female gametes by the male gametes (sperm cells). PMID- 29983914 TI - Normal Human Lactation: closing the gap. AB - With the exception of infant growth, there are no well-defined parameters describing normal human lactation. This represents a major gap in the continuum of care that does not exist for other major organs. Biological normality occurs naturally and is characterized by well-integrated function. We have proposed a definition that highlights four key elements that describe parameters for biological normality: comfort, milk supply, infant health, and maternal health. Notwithstanding the current limitations, published data have been collated to provide preliminary markers for the initiation of lactation and to describe objective tests once lactation is established. Reference limits have been calculated for maternal markers of secretory activation, including progesterone in maternal blood and total protein, lactose, sodium, and citrate in maternal milk. Objective measurements for established lactation, including 3-hourly pumping and 24-hour milk production, together with pre-feed to post-feed milk fat changes (a useful indicator of the available milk removed by the infant) have been outlined. Considered together with the parameters describing normal function, this information provides a preliminary objective framework for the assessment of human lactation. PMID- 29983915 TI - A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination. AB - Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs) dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop) tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output. PMID- 29983918 TI - Case Report: Case report on multiple extradural thoracic lesions with myelopathy as the clinical presentation in a systemic sarcoidosis- another tale of a lurking entity. AB - Herein, we report a rare case study of a sarcoidosis presenting with the features of compressive myelopathy. There were multiple extra-dural lesions in the thoracic region. Computerized Tomography (CT) of the chest revealed fibrotic changes with a pleural based nodular lesion in the right lung. The patient underwent laminectomy and partial excision of both the lesions. The histology revealed presence of non-caseating granulomas. The patient made a good recovery following adjuvant medical management with steroid and Methotrexate. Repeat CT scan of the chest also confirmed good resolution in the size of the pleural based nodule. PMID- 29983917 TI - Development of a human leukocyte antigen-based HIV vaccine. AB - Human immunodeficiency virus (HIV) carries abundant human cell proteins, particularly human leukocyte antigen (HLA) molecules when the virus leaves host cells. Immunization in macaques with HLAs protects the animals from simian immunodeficiency virus infection. This finding offers an alternative approach to the development of HLA molecule-based HIV vaccines. Decades of studies have enhanced a great deal of our understanding of the mechanisms of allo-immune response-mediated anti-HIV immunity. These include cell-mediated immunity, innate immunity, and antibody response. These studies provided a rationale for the future design of effective HIV vaccines. PMID- 29623192 TI - Classification of processes involved in sharing individual participant data from clinical trials. AB - Background: In recent years, a cultural change in the handling of research data has resulted in the promotion of a culture of openness and an increased sharing of data. In the area of clinical trials, sharing of individual participant data involves a complex set of processes and the interaction of many actors and actions. Individual services and tools to support data sharing are becoming available, but what is missing is a detailed, structured and comprehensive list of processes and subprocesses involved and the tools and services needed. Methods: Principles and recommendations from a published consensus document on data sharing were analysed in detail by a small expert group. Processes and subprocesses involved in data sharing were identified and linked to actors and possible supporting services and tools. Definitions adapted from the business process model and notation (BPMN) were applied in the analysis. Results: A detailed and comprehensive tabulation of individual processes and subprocesses involved in data sharing, structured according to 9 main processes, is provided. Possible tools and services to support these processes are identified and grouped according to the major type of support. Conclusions: The identification of the individual processes and subprocesses and supporting tools and services, is a first step towards development of a generic framework or architecture for the sharing of data from clinical trials. Such a framework is needed to provide an overview of how the various actors, research processes and services could interact to form a sustainable system for data sharing. PMID- 29983916 TI - aPKC: the Kinase that Phosphorylates Cell Polarity. AB - Establishing and maintaining cell polarity are dynamic processes that necessitate complicated but highly regulated protein interactions. Phosphorylation is a powerful mechanism for cells to control the function and subcellular localization of a target protein, and multiple kinases have played critical roles in cell polarity. Among them, atypical protein kinase C (aPKC) is likely the most studied kinase in cell polarity and has the largest number of downstream substrates characterized so far. More than half of the polarity proteins that are essential for regulating cell polarity have been identified as aPKC substrates. This review covers mainly studies of aPKC in regulating anterior-posterior polarity in the worm one-cell embryo and apical-basal polarity in epithelial cells and asymmetrically dividing cells (for example, Drosophila neuroblasts). We will go through aPKC target proteins in cell polarity and discuss various mechanisms by which aPKC phosphorylation controls their subcellular localizations and biological functions. We will also review the recent progress in determining the detailed molecular mechanisms in spatial and temporal control of aPKC subcellular localization and kinase activity during cell polarization. PMID- 29721309 TI - Unraveling endometriosis-associated ovarian carcinomas using integrative proteomics. AB - Background: To elucidate potential markers of endometriosis and endometriosis associated endometrioid and clear cell ovarian carcinomas using mass spectrometry based proteomics. Methods: A total of 21 fresh, frozen tissues from patients diagnosed with clear cell carcinoma, endometrioid carcinoma, endometriosis and benign endometrium were subjected to an in-depth liquid chromatography-tandem mass spectrometry analysis on the Q-Exactive Plus. Protein identification and quantification were performed using MaxQuant, while downstream analyses were performed using Perseus and various bioinformatics databases. Results: Approximately 9000 proteins were identified in total, representing the first in depth proteomic investigation of endometriosis and its associated cancers. This proteomic data was shown to be biologically sound, with minimal variation within patient cohorts and recapitulation of known markers. While moderate concordance with genomic data was observed, it was shown that such data are limited in their abilities to represent tumours on the protein level and to distinguish tumours from their benign precursors. Conclusions: The proteomic data suggests that distinct markers may differentiate endometrioid and clear cell carcinoma from endometriosis. These markers may be indicators of pathobiology but will need to be further investigated. Ultimately, this dataset may serve as a basis to unravel the underlying biology of the endometrioid and clear cell cancers with respect to their endometriotic origins. PMID- 29983921 TI - Role of extracellular matrix in breast cancer development: a brief update. AB - Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and 14 play vital roles degrading the matrix proteins for cancer spread. The beta-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components. PMID- 29983922 TI - Defining "FGF21 Resistance" during obesity: Controversy, criteria and unresolved questions. AB - The term "FGF21 resistance" was first used to describe increased circulating FGF21 levels concomitant to decreased FGF21 receptor complex expression in white adipose tissue of obese mice. Since this initial report, the term has been associated with a wide range of pathological states, including human obesity, in which circulating FGF21 levels are elevated. However, the notion of "FGF21 resistance" has been controversial partly due to difficulty in delineating the mechanisms underlying the physiological versus pharmacological effects of FGF21. Here, key aspects of the term "FGF21 resistance" are discussed including; the origin and experimental context surrounding the term "FGF21 resistance", new criteria for evaluating FGF21 sensitivity in vivo and finally, crucial unresolved questions regarding the function of FGF21 during obesity. PMID- 29862020 TI - Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts. AB - While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000-50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity. PMID- 29983924 TI - eXamine: Visualizing annotated networks in Cytoscape. AB - eXamine is a Cytoscape app that displays set membership as contours on top of a node-link layout of a small graph. In addition to facilitating interpretation of enriched gene sets of small biological networks, eXamine can be used in other domains such as the visualization of communities in small social networks. eXamine was made available on the Cytoscape App Store in March 2014, has since registered more than 7,200 downloads, and has been highly rated by more than 25 users. In this paper, we present eXamine's new automation features that enable researchers to compose reproducible analysis workflows to generate visualizations of small, set-annotated graphs. PMID- 29946443 TI - Comparing protein structures with RINspector automation in Cytoscape. AB - Residue interaction networks (RINs) have been shown to be relevant representations of the tertiary or quaternary structures of proteins, in particular thanks to network centrality analyses. We recently developed the RINspector 1.0.0 Cytoscape app, which couples centrality analyses with backbone flexibility predictions. This combined approach permits the identification of crucial residues for the folding or function of the protein that can constitute good targets for mutagenesis experiments. Here we present an application programming interface (API) for RINspector 1.1.0 that enables interplay between Cytoscape, RINspector and external languages, such as R or Python. This API provides easy access to batch centrality calculations and flexibility predictions, and allows for the easy comparison of results between different structures. These comparisons can lead to the identification of specific and conserved central residues, and show the impact of mutations to these and other residues on the flexibility of the proteins. We give two use cases to demonstrate the interest of these functionalities and provide the corresponding scripts: the first concerns NMR conformers, the second focuses on mutations in a structure. PMID- 29983926 TI - The Cytoscape Automation app article collection. AB - Cytoscape is the premiere platform for interactive analysis, integration and visualization of network data. While Cytoscape itself delivers much basic functionality, it relies on community-written apps to deliver specialized functions and analyses. To date, Cytoscape's CyREST feature has allowed researchers to write workflows that call basic Cytoscape functions, but provides no access to its high value app-based functions. With Cytoscape Automation, workflows can now call apps that have been upgraded to expose their functionality. This article collection is a resource to assist readers in quickly and economically leveraging such apps in reproducible workflows that scale independently to large data sets and production runs. PMID- 29983927 TI - The relationship between cardiopulmonary exercise test variables, the systemic inflammatory response, and complications following surgery for colorectal cancer. AB - Background: Both preoperative cardiopulmonary exercise test (CPET)-derived measures of fitness and postoperative C-reactive protein (CRP) concentrations are associated with complications following surgery for colorectal cancer. The aim of the present pilot study was to examine the relationship between CPET and postoperative CRP concentrations in this patient group. Methods: Patients who had undergone CPET prior to elective surgery for histologically confirmed colorectal cancer in a single centre between September 2008 and April 2017 were included. Preoperative VO2 at the anaerobic threshold (AT) and peak exercise were recorded, along with preoperative modified Glasgow Prognostic Score (mGPS) and CRP on each postoperative day. Results: Thirty-eight patients were included. The majority were male (30, 79%), over 65 years old (30, 79%), with colonic cancer (23, 61%) and node-negative disease (24, 63%). Fourteen patients (37%) had open surgery and 24 (63%) had a laparoscopic resection. A progressive reduction in VO2 at peak exercise was significantly associated with both increasing American Society of Anesthesiology (ASA) grade (median, ml/kg/min: ASA 1 = 22, ASA 2 = 19, ASA 3 = 15, ASA 4 = 12, p = 0.014) and increasing mGPS (median, ml/kg/min: mGPS 0 = 18, mGPS 1 = 16, mGPS 2 = 14, p = 0.039) There was no significant association between either VO2 at the AT or peak exercise and postoperative CRP. Conclusions: The present pilot study reports a possible association between preoperative CPET derived measures of exercise tolerance, and the preoperative systemic inflammatory response, but not postoperative CRP in patients undergoing surgery for colorectal cancer. PMID- 29983928 TI - Comparing the experience of enhanced recovery programme for gynaecological patients undergoing laparoscopic versus open gynaecological surgery: a prospective study. AB - Background: Enhanced recovery has been shown to improve patients' experience after surgery. There are no previous studies comparing patients' experience between those undergoing laparoscopic and open gynaecological surgery. Therefore, the aim of this prospective study is to compare patients' functional recovery based on milestones set by the enhanced recovery programme and patients' satisfaction between the two groups. Methods: All eligible patients undergoing gynaecological surgery within an enhanced recovery after surgery (ERAS) programme from March to August 2014 were involved in this study. All patients received the questionnaires on admission which were then collected prior to discharge. They were followed up by telephone within 7 days. Results: Two hundred sixty-three patients were involved. One hundred forty-four questionnaires were returned (54% response rate). Fifty-one percent (n = 74) were from the laparoscopic group and 49% (n = 70) were from the laparotomy group. In terms of achieving milestones, more patients in the laparotomy group performed the deep breathing exercises (laparoscopic versus open; 66.2% versus 87.1% (p = 0.003). The laparoscopic group were more able to eat on day 0, but by day 1, there was no difference between the groups. Both groups were similar in their ability to drink (p = 0.98), mobilise (p = 0.123) and sit out in a chair (p = 0.511). In the laparoscopic group, the patients' experience was better for pain control (p < 0.0001) and nausea control (p = 0.003) from recovery to day 1, and they were more able to put on their own clothes (p = 0.001) and were more confident in mobilising (p < 0.0001) and in going home (p < 0.0001). The laparoscopic group had greater patient satisfaction with their pain always being well controlled (p < 0.0001) whilst more patients in the laparotomy group reported being satisfied to very satisfied with their overall care on the gynaecology ward (p = 0.04). Both groups were equally satisfied with their care from nursing staff (p = 0.709) and doctors (p = 0.431). Conclusion: The two groups were in general equally able to achieve the majority of the milestones despite differences in symptoms such as pain, nausea and confidence in mobilising and going home. Pre-operative education can empower patients to engage in their recovery. There is a high level of patient satisfaction in both groups. PMID- 29983929 TI - Evaluation of methods for linking household and health care provider data to estimate effective coverage of management of child illness: results of a pilot study in Southern Province, Zambia. AB - Background: Existing population-based surveys have limited accuracy for estimating the coverage and quality of management of child illness. Linking household survey data with health care provider assessments has been proposed as a means of generating more informative population-level estimates of effective coverage, but methodological issues need to be addressed. Methods: A 2016 survey estimated effective coverage of management of child illness in Southern Province, Zambia, using multiple methods for linking temporally and geographically proximate household and health care provider data. Mothers of children <5 years were surveyed about seeking care for child illness. Information on health care providers' capacity to manage child illness, or structural quality, was assessed using case scenarios and a tool modeled on the WHO Service Availability and Readiness Assessment (SARA). Each sick child was assigned the structural quality score of their stated (exact-match) source of care. Effective coverage was calculated as the average structural quality experienced by all sick children. Children were also ecologically linked to providers using measures of geographic proximity, with and without data on non-facility providers, to assess the effects of these linking methods on effective coverage estimates. Results: Data were collected on 83 providers and 385 children with fever, diarrhea, and/or symptoms of ARI in the preceding 2 weeks. Most children sought care from government facilities or community-based agents (CBAs). Effective coverage of management of child illness estimated through exact-match linking was approximately 15-points lower in each stratum than coverage of seeking skilled care due to providers' limited structural quality. Estimates generated using most measures of geographic proximity were similar to the exact-match estimate, with the exception of the kernel density estimation method in the urban area. Estimates of coverage in rural areas were greatly reduced across all methods using facility-only data if seeking care from CBAs was treated as unskilled care. Conclusions: Linking household and provider data may generate more informative estimates of effective coverage of management of child illness. Ecological linking with provider data on a sample of all skilled providers may be as effective as exact-match linking in areas with low variation in structural quality within a provider category or minimal provider bypassing. PMID- 29983930 TI - Correction to: The knowledge, attitudes and practices of doctors regarding antibiotic resistance at a tertiary care institution in the Caribbean. AB - [This corrects the article DOI: 10.1186/s13756-018-0315-3.]. PMID- 29983931 TI - Prevalence of antibiotic resistant Escherichia coli isolates from fecal samples of food handlers in Qatar. AB - Background: It is well documented that food handlers harbor and shed enteric foodborne pathogens causing foodborne disease outbreaks. However, little known on enteric antibiotic resistant (AR) bacteria carriage in food handlers. The objective of this study was to establish a baseline prevalence of fecal AR E. coli among food handlers in Qatar. Methods: Fecal samples were collected from 456 migrant food handlers of different nationalities arriving in Qatar on a work permit between January 2015 and December 2016. These samples (25 g each) were collected based on the availability and examination schedule at the Medical Commission facility from those consented to participate. Isolated E. coli bacteria were tested for antibiotic susceptibility against nine antibiotics using the E-test method and Double Disc Synergy Test (DDST) for extended-spectrum beta lactamase (ESBL) production. Results: From the 78 E. coli positive samples (17.1%, n = 456), 60% of the isolates were resistant to at least one antibiotic, whereas, 27% were multi-drug resistant (MDR). Seven isolates (9%, n = 78) were ESBL producers of which five were MDR. Individual AR E. coli frequencies to the nine antibiotics were not significantly (P > 0.05) different by nationality. Conclusions: Based on our findings, we revealed that individual resistant E. coli and MDR resistant E. coli were common in fecal samples of food handlers in Qatar. This may indicate that food handlers can potentially contaminate foods with AR E. coli, a possible public health concern. PMID- 29983932 TI - Utilizing cocoyam (Xanthosoma sagittifolium) for food and nutrition security: A review. AB - The critical role of indigenous crops in the socioeconomic growth of developing nations has necessitated calls for accelerated exploitation of staples. Cocoyam, Xanthosoma sagittifolium, is food for over 400 million people worldwide and is the most consumed aroid in West Africa. However, it remains an underexploited food resource. This study reviews existing literature and also makes use of primary data from interviews with indigenous cocoyam farmers, processors, consumers, and cocoyam scientists in the research Institutes of Ghana, to provide insight into existing nomenclature of the species, indigenous knowledge on food uses, nutritional value, and potential novel food applications of cocoyam. Adaptable technologies in conformity to new trends in food science that could be employed for in-depth molecular studies and further exploitation of the crop are also discussed. It is envisaged that the provided information would contribute to global efforts aimed at exploiting the full potential of indigenous crops for sustainable food and nutrition security. PMID- 29983933 TI - A comprehensive review on beneficial dietary phytochemicals in common traditional Southern African leafy vegetables. AB - Regular intake of sufficient amounts of certain dietary phytochemicals was proven to reduce the incidence of noncommunicable chronic diseases and certain infectious diseases. In addition, dietary phytochemicals were also reported to reduce the incidence of metabolic disorders such as obesity in children and adults. However, limited information is available, especially on dietary phytochemicals in the commonly available traditional leafy vegetables. Primarily, the review summarizes information on the major phytochemicals and the impact of geographical location, genotype, agronomy practices, postharvest storage, and processing of common traditional leafy vegetables. The review also briefly discusses the bioavailability and accessibility of major phytochemicals, common antinutritive compounds of the selected vegetables, and recently developed traditional leafy vegetable-based food products for dietary diversification to improve the balanced diet for the consumers. The potential exists for better use of traditional leafy vegetables to sustain food security and to improve the health and well-being of humans. PMID- 29983934 TI - Green tea extract and black tea extract differentially influence cecal levels of short-chain fatty acids in rats. AB - Increasing evidence indicates that gut microbiota plays a critical role to maintain the host's health. The biological function of microbially produced short chain fatty acids (SCFA) becomes the focus of attention. This study aimed to compare the effects of green tea extract (GTE) and black tea extract (BTE) on cecal levels of SCFA in rats. Rats consumed an assigned diet of either a control diet, a GTE diet (10 g/kg), or a BTE diet (10 g/kg), for 3 weeks. The dietary addition of GTE significantly reduced the concentrations of acetate and butyrate in cecal digesta compared to the control, but BTE showed an increased trend for a cecal pool. In the GTE group, a significant amount of undigested starch was excreted in feces, but BTE produced no effect. Interestingly, feces of rats fed the BTE diet contained higher bacterial 16S rRNA gene copy numbers for total eubacteria compared to the control diet. Taken together, treatments of the diets with GTE and BTE brought about a different degree of producing SCFA in rat cecum. BTE might advantageously stimulate more SCFA production than GTE by facilitating bacterial utilization of starch. PMID- 29983935 TI - Effect of low thermal pasteurization in combination with carvacrol on color, antioxidant capacity, phenolic and vitamin C contents of fruit juices. AB - Mild thermal treatment in combination with natural antimicrobials has been described as an alternative to conventional pasteurization to ensure fruit juices safety. However, to the best of our knowledge, no study has been undertaken to evaluate what could be its effect on their color and nutritional value. This study therefore aimed at assessing how a low thermal pasteurization in combination with carvacrol could affect these parameters, with orange, pineapple, and watermelon juices as selected fruit juices. The experimental design used had levels ranging from 50 to 90 degrees C, 0 to 60 MUl/L, and 0 to 40 min for temperature, concentration of carvacrol supplemented, and treatment length, respectively. The only supplementation of fruit juices with carvacrol did not affect their color. In comparison with high thermal pasteurization (>70 degrees C), a combined treatment at mild temperatures (50-70 degrees C) better preserved their color, antioxidant capacity (AOC), and vitamin C content, and increased their total phenolic content (TPC). Globally, carvacrol supplementation had a positive impact on the TPC of thermally treated juices and increased the AOC of treated watermelon juice, which was the lowest of the three fruit juices. Mild heat treatment in combination with natural antimicrobials like carvacrol is therefore an alternative to limit the negative effects of conventional pasteurization on fruit juices quality. PMID- 29983936 TI - Effects of Chinese pickled and dried mustard on nutritional quality, sensory quality, and shelf life of steamed pork belly. AB - Steamed pork with pickled and dried mustard (PDM) is a famous Chinese dish. Here, we examined the effects of PDM on nutritional quality, sensory quality, and shelf life of steamed pork belly. Proximate composition, lipid oxidation, fatty acid profiles, protein hydrolysis and oxidation, sensory evaluation, and induction period (IP) of steamed pork belly were determined after addition of different levels (0-100%, WPDM/Wpork belly) of PDM. The results demonstrated that PDM could significantly (p < .05) enhance the loss of moisture and fat, increase the ratio of unsaturated to saturated fatty acids, and decrease lipid and protein oxidation in steamed pork belly. Additionally, IP values and steamed pork belly preservation times increased as the amount of added PDM increased. Best sensory quality was achieved when moderate levels of PDM (40%) were added to steamed pork belly. These findings provide insights into the beneficial effects of PDM on steamed pork belly. PMID- 29983937 TI - Appropriate parboiling steaming time at atmospheric pressure and variety to produce rice with weak digestive properties. AB - Consumers with diabetes mellitus have shown interest in products with low postprandial glucose. To produce rice for this group of consumers, the effect of parboiling steaming time (0, 5, 15, 25, 35, and 45 min) and variety (NERICA1, NERICA7, WITA4, and IR841) on resistant, damaged starch fractions and glycemic response in rats was investigated. Resistant and damaged starch fractions were influenced by variety and steaming time but this was not the case for glycemic index. Nonparboiled NERICA7 and NERICA7 steamed for 25 min recorded the highest (10.07%) and lowest (2.49%) resistant starch fraction, respectively. Resistant starch correlated negatively with protein and sodium and positively with lipids. Damaged starch was high for WITA4 steamed for 45 min (26.80%) and low for nonparboiled NERICA1 (6.59%). Damaged starch correlated positively with lipid content and negatively with ash and total starch content. NERICA7 steamed for 35 min recorded the lowest postprandial glucose level 30 min after feeding (0.16 g/L), while WITA4 steamed for 15, 25, and 35 min and nonparboiled NERICA7 recorded higher levels (0.76, 0.91, 0.84, and 0.76 g/L, respectively). NERICA7 steamed for 35 min recorded both low glycemic and weak digestive properties because the glycemic index was lowest 120 min and increased steadily up to 180 min after feeding. We conclude that the digestive properties of rice depend both on the intrinsic properties of the variety and the parboiling steaming time. PMID- 29983938 TI - Improving antioxidant and antiproliferative activities of colla corii asini hydrolysates using ginkgo biloba extracts. AB - Colla corii asini hydrolysates (ACCH) and ginkgo biloba extracts (EGb) possess more potent antioxidant effects when used in combination than when used alone. The mixture of ACCH and EGb at a dose ratio of 20:4(w:w) showed the highest radical scavenging activity with IC 50 of 0.17 +/- 0.01, 0.43 +/- 0.02 and 1.52 +/- 0.07 mg/ml against DPPH, ABTS and HO . free radicals, respectively. Furthermore, the inhibition of breast cancer cells MCF-7 and MDA-MB-231 proliferation increased when these cell lines were treated with a combination of ACCH and EGb for 72 hr, with IC 50 of 4.32 +/- 0.12 mg/ml and 0.39 +/- 0.01 mg/ml, respectively. The findings indicated that the mixtures of ACCH and EGb could be used to prevent and treat some diseases caused by the excessive free radicals, especially cancer. Therefore, the mixtures of ACCH and EGb might serve as a natural source of desirable antioxidant and anticancer agents for the nutraceutical and pharmaceutical industries. PMID- 29983939 TI - Geographical discrimination of palm oils (Elaeis guineensis) using quality characteristics and UV-visible spectroscopy. AB - This preliminary study demonstrated the possibility of discriminating geographical origin of palm oils using conventional quality characteristics and UV-visible spectroscopy. A total of 60 samples, 20 from each region (North (N), South (S), and Central (C)) of Ondo State Nigeria, were analyzed for their quality characteristics and UV-visible spectra. Principal component analysis (PCA) and orthogonal projection to latent structure discriminant analysis (OPLS DA) were applied to elaborate the data. Models were built on the most informative portion of the spectra (250-550 nm) as: untreated (without pretreatment) and standard normal variate-second-derivative-treated (SNV+2der) data matrices. OPLS DA classification models were validated by independent prediction sets and cross validation. PCA score plots of both chemical and spectral data matrices revealed geographical distinction between the palm oil samples. Significantly high carotene content, free fatty acids, acid value, and peroxide value distinguished Central palm oils. K extinction values, color density, and chlorophyll content were the most important quality parameters separating North oil samples. In the discriminant models, over 95% and 85% percent correct classification were recorded for spectral and chemical data, respectively. These results cannot be considered exhaustive because of the limited sample size used. However, the study suggested a potential analytical technique suitable for geographical origin authentication of palm oils with additional advantages that include the following: speed, low cost, and minimal waste. PMID- 29983940 TI - Effect of addition of processed bambara nut on the functional and sensory acceptability of millet-based infant formula. AB - Fermentation and sprouting have been shown to increase nutrient bioavailability and modify the functional properties of foods. Application of these methods in the preparation of infant foods and complementing cereals with legumes will address nutrient density and viscosity problems associated with infant foods. Infant foods were formulated from blends of treated bambara nut and pearl millet. Functional properties, pasting properties, and sensory acceptability of the blends were studied. Millet and bambara nut were soaked separately in water and allowed to ferment for 48 hr at room temperature. While for sprouting, millet and bambara nut were soaked for 12 and 24 hr, respectively, at room temperature, and soaked seeds were separately sprouted for 48 hr. After fermentation and sprouting, the seeds were oven-dried and then milled into a flour of 0.6 mm size. The flours were formulated to six (A, B, C, D, E, and F) complementary diets. The results show that sample E had the suitable water absorption capacity, while, for oil absorption capacity, various blends showed suitability except samples A and B. In terms of swelling capacity, sample F (6.52 +/- 0.01%) was the suitable at 60 degrees C. Treatment and blending significantly influenced trough, final viscosity, and pasting time. In sensory acceptability, sample B was adjudged the best. This study revealed that sample C was the best in respect to functional and pasting properties for infant food; however, sample B received the best general acceptability. PMID- 29983941 TI - Mining online activity data to understand food consumption behavior: A case of Asian fish sauce among Japanese consumers. AB - Internet search engines and online recipe repositories have become increasingly popular resources among households for recipes and meal planning. Meanwhile, fish sauce's distinct flavor makes it a popular condiment in Southeast Asian countries. Although fish sauce is used as a condiment for traditional cuisine in Japan, it is not popular for general household use. To understand the consumption behavior regarding fish sauce in Japanese households, we analyzed search trends for the words nampla (Thai fish sauce), nuoc mam (Vietnamese fish sauce), and shottsuru (Japanese fish sauce) using Google's search engine and the Japanese online recipe site Cookpad. The results clearly indicate nampla's rising popularity due to the rapid spread of Thai cuisine and an annually increasing traditional consumption of Japanese fish sauce. These results provide insights into the household demand for fish sauce. PMID- 29983942 TI - Guava leaf extract suppresses osteoarthritis progression in a rat anterior cruciate ligament transection model. AB - Guava leaf extract and ellagic acid, one of its polyphenolic components, inhibit the activity of a disintegrin and metalloproteinase with thrombospondin type 5 (ADAMTS-5), which is associated with aggrecan degeneration during the early stage of osteoarthritis (OA). To investigate the efficacy of guava leaf extract for preventing OA, we examined the effect of its dietary intake on cartilage destruction in anterior cruciate ligament-transected (ACLT) rats. Rats were randomly assigned to four groups: ACLT control rats fed with control diet, ACLT rats fed with diet containing 0.2% guava leaf extract, ACLT rats fed with diet containing 0.5% guava leaf extract, and sham-operated rats fed with control diet. Mankin's scores, an index of cartilage damage, were higher in rats that underwent ACLT. Guava leaf extract treatment dose-dependently led to lower Mankin's scores and higher concentrations of ellagic acid in the serum and synovial membrane. Ellagic acid levels in the synovial membrane negatively correlated with cartilage destruction scores. These results suggest that dietary guava leaf extract suppresses OA progression in ACLT rats through ellagic acid-mediated inhibition of early joint destruction. PMID- 29983943 TI - Effects of gamma radiation combined with cinnamon oil on qualities of smoked salmon slices inoculated with Shewanella putrefaciens. AB - Smoked salmon slices inoculated with Shewanella putrefaciens were untreated (CK) or treated with 2 kGy gamma radiation (G), 1% (v/v) cinnamon oil (C), or the combination of them (G+C), and then packaged and stored at 4 degrees C for 10 days. Microbiological and physiochemical analyses were then carried out. All treatments showed a better effect on inhibiting the increase in total viable counts, total volatile basic nitrogen, and thiobarbituric acid-reactive substances than CK, especially the treatment of G+C. In addition, the combination treatment also showed a best effect on retarding the reduction in polyunsaturated fatty acids of salmon samples in all treatments. These results indicated that treatments of gamma radiation and cinnamon oil on salmon samples, especially the combination treatment, can be used to maintain the quality of smoked salmon slices. PMID- 29983944 TI - Effect of drying methods on the retention of bioactive compounds in African eggplant. AB - African eggplants (Solanum aethiopicum L.) are a rich source of bioactive compounds and functional constituents that are beneficial to human health. However, the short shelf life of these vegetables can be a major cause of postharvest losses especially during peak harvesting season. Drying is one of the most convenient technologies for the production of shelf stable food products. However, drying can lead to considerable loss of the available bioactive compounds due to thermal degradation depending on the drying method and temperature conditions. This study investigated the effect of four drying methods (solar, oven, vacuum, and freeze) on the retention of total phenolics, beta carotene, antioxidant capacity, and lycopene in five African eggplant (S. aethiopicum) accessions (sangawili, manyire green, S00047A, AB2, and aubergine blanche). Samples were dried up to ~10% moisture content. The fresh and dried samples were analyzed for total phenolic content, antioxidant capacity, beta carotene content, and the lycopene content. In the fresh state, beta-carotene, total phenolic content, and free radical scavenging activity ranged between 14.75 +/- 0.50 and 29.50 +/- 0.77 mg/100 g db, 751.21 +/- 1.73 and 1,363.95 +/- 2.56 mg/100 g GAE db, and 99.58 and 325.61 mg/ml db IC 50 value, respectively. The accession S00047 showed highest total phenolic content and lowest IC 50 value in the fresh samples. The results also showed that total phenolic content, antioxidant capacity, and beta-carotene contents were significantly (p < .05) affected by drying method and drying temperature with freeze-drying presenting the highest retention. Overall, 36.26%s-95.05% (total phenolics) and 31.44% 99.27% (beta-carotene) were retained during freeze-drying. Lycopene was only detected in the dried samples of the accession manyire green but absent in all the fresh samples of all the accessions. This study demonstrates that freeze drying was the most effective in retaining the highest bioactive compounds in African eggplants. PMID- 29983945 TI - The effect of replacing egg yolk with sesame-peanut defatted meal milk on the physicochemical, colorimetry, and rheological properties of low-cholesterol mayonnaise. AB - Egg yolk was replaced with sesame-peanut meal milk in mayonnaise in the levels of 0, 25%, 50%, 75%, and 100%. The pH was significantly decreased by increasing the percentage of replacement in all three kinds of replacement (p < .05). However, over the whole period, no significant difference was observed in the acidity. The mayonnaise samples, except for the replacements of 50%, were desirable in terms of physical and thermal stability. A significant decrease was seen in lightness (L*) and yellowness (b*) of the samples as a result of an increase in the percentage of replacements (p < .05). In the power law model, the flowing index amount (n) of all samples was in the domain between zero and one, which served as evidence for pseudoplastic behavior (dilatant with shear) of mayonnaise samples. The positive results are employing suitably the sesame-peanut meal milk instead of egg yolk, decreasing the cholesterol of mayonnaise and increasing its nutritional value, proposing mayonnaise factories to make use of the meal of the oil extraction factory as emulsifier, which lead to a decrease in overall costs of producing these products. PMID- 29983946 TI - Nutrient and aflatoxin contents of traditional complementary foods consumed by children of 6-24 months. AB - The nutrient composition and safety of complementary foods have recently become areas of concern, especially with regard to aflatoxin contamination which has been found to adversely affect health outcomes. This study presents the nutrient and aflatoxin contents of complementary foods consumed by children (6-24 months) and infants and young child feeding practices of mothers from two districts in eastern and southern Zambia. A total of 400 mother-child pairs were recruited from Monze and Chipata districts, and data on breastfeeding and complementary feeding practices were collected twice at 3-month interval using a structured questionnaire. Samples of two traditional complementary foods (Maize Nshima and Maize porridge) were collected from the mothers and analyzed for nutrient contents and aflatoxin contamination. The results showed that there is a high level of awareness on exclusive breastfeeding among mothers. Fat, protein, carbohydrate, and ash contents of Maize nshima from Chipata were significantly lower (p < .05) compared to those from Monze district except for starch and sugar. Monze mothers preferred to prepare a thicker Maize nshima and Maize porridge compared to their Chipata counterparts. The aflatoxin contamination showed that the Maize porridge samples from Chipata were the most contaminated with mean aflatoxin content of 5.8 +/- 15.93 mg/100 g, while Maize nshima was the most contaminated of the two complementary foods from Monze districts with mean aflatoxin level of 3.8 +/- 6.41 mg/100 g. There were significant (p < .05) positive correlations between fat and aflatoxin contents for Chipata samples (r = .12409) and for Monze samples (r = .13666). The traditional complementary foods studied were found to be low in fat and protein and high in aflatoxin contamination. Thus, it is imperative that best practices and interventions are designed and introduced to reduce the possible lethal health implications of consumption of such complementary foods by children under 5 years. PMID- 29983947 TI - Hierarchical network modeling with multidimensional information for aquatic safety management in the cold chain. AB - The cold-chain information has characterized by the loss and dispersion according to the different collecting methods. The description for the quality decay factors of aquatic products can be defined as the multidimensional information. A series of nodes with multidimensional information are assembled to be hierarchies aiming at describing the environment conditions and locations in the supply chain. Each of the single hierarchy levels constitutes a sequence of node information in a network, which is applied as internal information analysis. The cross-layer information structure is defined as "bridge" information which is able to record the information transmissions among every hierarchy from the point of view of the whole chain. The study has established a novel structured modeling to describe the cold chain of aquatic products based on a network-hierarchy framework. An organized and sustainable transmission process can be built and recorded by the multidimensional attributes for the whole course of cold chain of aquatic products. In addition, seamless connections among every hierarchy are attainable by the environmental information records continuously to monitor the quality of aquatic products. The quality assessments and shelf life predictions are estimated properly as the risk control in order to monitor and trace the safety of aquatic products under the supply chain perspective. PMID- 29983949 TI - Effect of chitosan edible coating with Laurus nobilis extract on shelf life of cashew. AB - This study tested the effects of the application of Laurus nobilis aqueous extract and edible coating of chitosan had on the chemical, microbial, and sensory attributes of cashew's shelf life. An aqueous extract of L. nobilis leaf (0, 0.5, and 1% w/w) was added to chitosan solution (0, 0.5, 1% w/w) in the cashew's coating. Cashews were dipped into the coating solution and were kept in polyethylene terephthalate containers. The result showed that chitosan and aqueous extract of L. nobilis coating had significant effects on peroxide and thiobarbituric acid value (p < .05). There was significant reduction in the growth of mold/yeast and mesophilic bacteria with higher concentration of chitosan and L. nobilis aqueous extract (p < .05). The results of this study show chitosan aqueous extract of L. nobilis coating could be an effective preservative method for extending shelf life and improving the stability of cashew. PMID- 29983948 TI - Green leafy vegetables from two Solanum spp. (Solanum nigrum L and Solanum macrocarpon L) ameliorate scopolamine-induced cognitive and neurochemical impairments in rats. AB - This study examined the modulatory effect of Black nightshade (Solanum nigrum L) and African eggplant (Solanum macrocarpon L) leaves on cognitive function, antioxidant status, and activities of critical enzymes of monoaminergic and cholinergic systems of neurotransmission in scopolamine-administered rats. Cognitive impairment was induced in albino rats pretreated with dietary inclusions of Black nightshade (BN) and African eggplant (AE) leaves by single administration (i.p.) of scopolamine (2 mg/kg body weight). Prior to termination of the experiment, the rats were subjected to spontaneous alternation (Y-maze) test to assess their spatial working memory. Thereafter, activities of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO), arginase, and antioxidant enzymes (catalase, SOD, and GST) of rat brain homogenate were determined. Also, the malondialdehyde (MDA), nitrite, and GSH contents of the homogenate were determined. The results showed that pretreatment with dietary inclusions of AE and BN significantly reversed the impairment in the rats' spatial working memory induced by scopolamine. Similarly, elevations in activities of AChE, BChE, and MAO induced by scopolamine were significantly reversed in rats pretreated with dietary inclusions of AE and BN. In addition, impaired antioxidant status induced by scopolamine was reversed by pretreatment with dietary inclusions of AE and BN. This study has shown that dietary inclusions of AE and BN could protect against cognitive and neurochemical impairments induced by scopolamine, and hence, these vegetables could be used as a source of functional foods and nutraceuticals for the prevention and management of cognitive impairments associated diseases such as Alzheimer's disease. PMID- 29983950 TI - The antibacterial effect of whey protein-alginate coating incorporated with the lactoperoxidase system on chicken thigh meat. AB - Nowadays, the environmental problems due to the use of synthetic films and packages have caused the production of natural edible coatings or films. The aim of this study was to produce an edible whey protein-alginate coating with different concentrations of lactoperoxidase system to control the microbial load and increase the shelf life of chicken thigh meat stored in refrigerated condition (4 +/- 1 degrees C). So, after the provision of the alginate-whey protein coating incorporated with the lactoperoxidase system (at concentrations of 2%, 4%, and 6% in alginate-whey protein solution), microbial experiments were conducted for the period of 8 days. Three batches of organisms, including total aerobic mesophilic bacteria, Enterobacteriaceae, and Pseudomonas aeruginosa in samples, were tested by culturing in appropriate conditions. Results indicated that the coating had a substantial inhibitory effect on all lots. Also, the antimicrobial activity of coating increased with increase in lactoperoxidase system concentration in alginate-whey protein coating. PMID- 29983951 TI - Occurrence of filamentous fungi in maize destined for human consumption in South Africa. AB - One-hundred maize samples were analyzed for fungal contamination using conventional and molecular methods. The percentage incidence of different genera isolated revealed the predominance of Fusarium (82%), Penicillium (63%), and Aspergillus species (33%) compared to other genera. Fusarium occurred in 90% and 74% of small scale and commercial samples, respectively, while Penicillium occurred in small scale and commercial samples at an incidence rate of 64% and 62%, respectively. However, among the species, Fusarium verticilloides have the highest incidence of 70% and 76% in commercial and small-scale maize, respectively, while Penicillium digitatum has 56% total incidence. Aspergillus fumigatus (27%) were also the most dominant of these genera. Fungal genera isolated included Alternaria and Cladosporium although occurring at a lower incidence level of 30%, 32% and 16%, 20%, respectively, in small-scale and commercial samples. The results emphasize that farmers and consumers should be alerted to the danger of fungal contamination in maize. PMID- 29983952 TI - Optimization of red teff flour, malted soybean flour, and papaya fruit powder blending ratios for better nutritional quality and sensory acceptability of porridge. AB - This study was carried out to optimize the compositions of red teff flour with malted soybean flour and papaya fruit powders for better nutritional quality and sensory acceptability of porridge. Total eleven formulations of the composite flours were determined using D-optimal mixture design with the help of Minitab Version 16 Statistical Software. The three ingredients were considered in the ranges of 55%-70%, 20%-30%, 5%-15% for red teff flour, malted soybean flour, and Papaya fruit powder, respectively. The prepared porridge samples from formulations were analyzed for nutritional composition, antinutritional factors, and sensory acceptability. Results of the study showed the significant difference (p < .05) in ash, fat, fiber, protein, carbohydrate, energy, iron, calcium, zinc, beta-carotene, phytates, tannin, appearance, taste, mouthfeel, and overall acceptability as the composition of ingredients were changed. The overall optimum point was found in a range of red teff flour (60%-70%), malted soybean flour (20% 27.5%), and papaya fruit powder (10%-12.5%). In conclusion, the present approach can help in improve infants dietary quality of complementary foods by developing nutritionally enhanced red teff-based porridge used for intervention of malnutrition. PMID- 29983953 TI - Effect of ethanol extract of boiled breadfruit (Treculia Africana) seed on the oral glucose tolerance, lipid profile, and body weight of normoglycemic albino rats. AB - The effect of ethanol extracts of boiled Treculia africana seed on the oral glucose tolerance (OGTT), lipid profile, and body weight of normoglycemic albino rats was determined. Fifteen male albino rats were used and were divided into three groups of five rats each. Groups 1 and 2 received 100 and 200 mg/kg of the extract, while group 3 (control group) received 1 ml/kg of normal saline. The experiment lasted for 28 days. The body weights of the rats were determined daily. OGTT was determined at week zero (before extract administration) and at weeks 2 and 4, respectively, following extract administration. Glycemic index (GI) of the extracts was calculated from the incremental area under the OGTT curve. The total cholesterol, high-density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and very-low-density lipoprotein (VLDL) cholesterol levels in the sera of the rats were determined using standard techniques. Atherogenic index (AI) and coronary risk index (CRI) of the rats were expressed as ratios of LDL cholesterol to HDL cholesterol and total cholesterol to HDL cholesterol, respectively. Following 2 weeks of the extract administration, the blood glucose for groups 1 and 2 rats declined to values <=100 mg/dl after oral glucose loading. GI for the standard rat feeds and the extracts at 100 and 200 mg/kg by the second week of experimentation were 100, 114, and 96.09, respectively. GI for the extract at 100 mg/kg decreased to 103.63 at the 4th week, while that for the extract at 200 mg/kg increased to 98.07. The extract at 100 mg/kg increased the LDL cholesterol, AI, and CRI of the rats, suggesting that consumption of boiled African breadfruit may expose an individual to the risk of development of cardiovascular diseases. Finally, the study suggested that consumption of T. africana seed by a nondiabetic subject may have no effect on the glucose tolerance of the individual, while it will negatively impact on the glycemic status of a diabetic subject. PMID- 29983954 TI - Effect of ethanol on flavor perception of Rum. AB - This is the first sensory study to evaluate the effects of ethanol concentration on flavor perception of distilled spirits. Dilution series of two rums (R1 and R2) were evaluated to gain insight into the effects of ethanol concentration on the flavor perception of distilled spirits. Rums were diluted 1:2 (v/v) either with pure water to a final alcohol by volume (ABV) of 20% (R1-W and R2-W) or with an aqueous 40% ABV solution (R1-E and R2-E). The later dilution accounted for the flavor dilution effect while keeping the ethanol concentration the same as the original liquors. Descriptive sensory analysis was conducted on both dilution series and the original rums. Twenty-three attributes were evaluated consisting of eight aroma, four aroma-by-mouth, four mouthfeel, two taste, and five aftertaste terms. Results revealed 18 significant attributes for the R1 series. With the exception of silky mouthfeel, all attributes were rated highest in R1 and lowest in R1-E. The R2 series contained sixteen significant attributes, all of which were rated higher in R2 compared with R2-E. The flavor profiles of the original rums and those diluted with water were very similar, with the diluted rums generally having slightly lower attribute intensities. In contrast, the rums diluted with 40% ABV had significantly different flavor profiles than the original rums. Results indicate that diluting spirits with water may reduce the odor suppression effects of ethanol or enhance flavor release which appears to counteract the flavor dilution effect. PMID- 29983955 TI - Preparation of the rainbow trout bone peptides directed by nutritional properties and flavor analyses. AB - Rainbow trout bone proteins were prepared by heating at 121 degrees C for 30 min, followed by filtration, concentration, and lyophilization. Nutritional properties and flavor analyses of hydrolysates digested by five different enzymes were investigated, respectively. Results showed that the crude protein content of rainbow trout bone was 15.90% and had a well-balanced nutritional value. The content of total amino acids was 983.64 mg/g. The amount of free amino acids of hydrolysates digested by alkaline protease, neutral protease, flavourzyme, papain, and trypsin for 3 hr was 207.83, 224.13, 1,001.59, 283.26, and 303.64 mg/g, respectively. During the hydrolysis, the main flavor compounds were identified by GC-MS to be alcohols, aldehydes, ketones, acids, and alkanes. After hydrolysis, the main molecular weight of peptides was focused on the range of 1,000-3,000 Da in all enzymatic hydrolysates. This study provided a theoretical basis to comprehensive utilization of rainbow trout bone in food industry. PMID- 29983956 TI - Chemical, antimicrobial, and molecular characterization of mortino (Vaccinium floribundum Kunth) fruits and leaves. AB - Fruits and leaves of Vaccinium spp. are known for their high content of bioactive compounds, but the chemical and biological characteristics of mortino (Vaccinium floribundum Kunth) have not been fully described. In this study, the levels of polyphenols, antioxidant capacity, anthocyanins, antimicrobial activity, and genetic variability were determined in mortino plants. The Folin-Ciocalteu's, ABTS scavenging, pH differential, and well diffusion methods were used to evaluate the levels of polyphenols, antioxidant capacity, anthocyanins, and antimicrobial activity, respectively. The genetic variability was evaluated by sequencing of the matK and rbcl DNA regions. Polyphenol content was up to 229.81 mg gallic acid equivalents/100 g, the average antioxidant capacity was 11.01 mmol Trolox equivalents/100 g, and anthocyanin content was up to 1,095.39 mg/100 g. Mortino extracts significantly inhibited the growth of Gram-negative bacteria including Burkholderia gladioli, Burkholderia cepacia, Salmonella Typhimurium, Vibrio parahaemolyticus, Vibrio harveyi, Vibrio vulnificus, Escherichia coli, and Pseudomona aeruginosa, as well as Gram-positive bacteria such as Probionibacterium propionicum, Staphylococcus aureus, and Enterococcus faecalis showing greater inhibition halos than those produced by the antibiotic ampicillin. A polymorphic nucleotide was found in position 739 of the matK region. This study shows the potential of mortino for the food and pharmaceutical industries. PMID- 29983957 TI - Leea macrophylla Roxb. leaf extract potentially helps normalize islet of beta cells damaged in STZ-induced albino rats. AB - This research aims to investigate the protective effects Leea macrophylla Roxb polyphenols on streptozotocin-induced diabetic rats. Polyphenolic assays were undertaken through established methods. To conduct animal intervention study, forty Wistar albino male rats (average body weight 188.42 +/- 7.13 g) of different groups were diabetized by streptozotocin (60 mg/kg) only in the animals of diabetic control (DC) and L. macrophylla extract (LM) groups. At the end of 4 weeks of intervention, serum was analyzed for insulin, liver and cardiac enzymes, lipid profiles, uric acid, and creatinine using ELISA method. In vitro alpha amylase inhibition of LM was evaluated and compared with reference drug acarbose. Pancreatic tissues were undertaken for histopathological screening. Food and fluid intake, weekly blood glucose level, liver glycogen, aspartate transaminase (AST), creatinine kinase (CK-MB), cholesterol, and lactate dehydrogenase (LDH) were significantly decreased, whereas oral glucose tolerance (OGTT) ability, serum insulin concentration, and pancreatic islets morphology were significantly improved in the LM300 treatment group compared to the DC group. Alpha-amylase inhibition was not found to be very promising for guiding the alpha-amylase inhibition pathway. Results suggest that L. macrophylla can exert a potential effort to restore pancreatic beta-cell damaged by streptozotocin induction. PMID- 29983958 TI - Shelf-life enhancement of whole rainbow trout (Oncorhynchus mykiss) treated with Reshgak ice coverage. AB - The effect of ice coverage comprised of Reshgak extract and Reshgak essential oil on shelf-life extension of chilled whole rainbow trout (Oncorhynchus mykiss) was evaluated. Chemical (peroxide value (PV), thiobarbituric acids (TBA), total volatile nitrogen base (TVB-N), and free fatty acids (FFA)), microbiological (total viable count (TVC) and psychrotrophic viable count (PVC)), and sensory evaluations (texture, color, flavor, and general acceptance) were investigated every 4 days during a 20-day storage period. Results revealed that the effect of both icing systems led to considerably lower bacterial counts and chemical indices in comparison with the traditional ice coverage without such phytogenic. According to sensory analyses, fish stored in ice containing Reshgak essential oil had a longer shelf-life (>16 days) and those stored in ice medium included with Reshgak extract possessed a shelf-life of 16 days, whereas lot stored in traditional ice showed a shorter shelf-life of 12 days. PMID- 29983959 TI - Safety assessment of Plukenetia volubilis (Inca peanut) seeds, leaves, and their products. AB - Plukenetia volubilis or Inca peanut is a promising plant with high economic value. Its seeds can be pressed for oil production or roasted and served as a snack, while the dried leaves can be used to make a kind of tea. Although the oil from the cold-pressed seeds has been proven to be safe for human consumption, little information is known about the other parts of the plant regarding safety. Thus, the aim of this study was to investigate the naturally occurring phytotoxins, including saponins, total alkaloids, and lectins in fresh and roasted Inca peanut seeds and leaves. In addition, cytotoxicity on several normal cell types including human peripheral blood mononuclear cells, human embryonic kidney cells, human hepatic stellate cells, and mouse fibroblasts as well as in vivo mutagenic properties was studied. This study showed that fresh Inca peanut seeds and leaves contain saponins, alkaloids, and lectins. However, roasting enables the reduction in alkaloids, saponins, and possibly lectins, suggesting that these phytotoxins become unstable under heat. Furthermore, Inca peanut seeds and leaves, especially after roasting, are safe to a variety of normal cell lines and do not induce DNA mutations in Drosophila expressing high biotransformation system. In conclusion, the data in this study indicated that high and chronic consumption of fresh seeds and leaves should be avoided. Heat processing should be applied before the consumption of Inca peanut seeds and leaves in order to reduce phytotoxins and potential health risks. PMID- 29983961 TI - Evaluation of antioxidant properties of lemon verbena (Lippia citriodora) essential oil and its capacity in sunflower oil stabilization during storage time. AB - In this study, lemon verbena essential oil as a natural antioxidant was used to increase the stability of sunflower oil, and stabilization effects in terms of storage conditions were compared with synthetic antioxidant (BHT). For this purpose, the antioxidant activity of the essential oil was determined by DPPH assay and beta-carotene bleaching method. Then, lemon verbena essential oil (0, 400, 800, and 1,600 ppm) was added to sunflower oil without synthetic antioxidant and stored at 60 degrees C for 60 days. Results from different parameters (peroxide value, free fatty acid, iodine value, total polar compound, carbonyl value, conjugated dienes, and oxidative stability index) were in agreement with each other, suggesting that lemon verbena essential oil (1,600 ppm) could act better than BHT in inhibition of lipid oxidation in sunflower oil and can be used as predominant alternative of synthetic antioxidants. PMID- 29983960 TI - Variations in agronomic and grain quality traits of rice grown under irrigated lowland conditions in West Africa. AB - Rice breeding in West Africa has been largely skewed toward yield enhancement and stress tolerance. This has led to the variable grain quality of locally produced rice in the region. This study sought to assess variations in the agronomic and grain quality traits of some rice varieties grown in this region, with a view to identifying sources of high grain yield and quality that could serve as potential donors in their breeding programs. Forty-five varieties were grown under irrigated conditions in Benin and Senegal with two trials in each country. There were wide variations in agronomic and grain quality traits among the varieties across the trials. Cluster analysis using paddy yield, head rice yield, and chalkiness revealed that 68% of the total variation could be explained by five varietal groupings. One group comprising seven varieties (Afrihikari, BG90-2, IR64, Sahel 108, WAT311-WAS-B-B-23-7-1, WAT339-TGR-5-2, and WITA 10) had high head rice yield and low chalkiness. Of the varieties in this group, Sahel 108 had the highest paddy yield in three of the four trials. IR64 and Afrihikari had intermediate and low amylose content, respectively, with the rest being high amylose varieties. Another group of varieties consisting of B6144F-MR-6-0-0, C74, IR31851-96-2-3-2-1, ITA222, Jaya, Sahel 305, WITA 1, and WITA 2 had high paddy yield but poor head rice yield and chalkiness. The use of materials from these two groups of varieties could accelerate breeding for high yielding rice varieties with better grain quality for local production in West Africa. PMID- 29983962 TI - Evaluation of the physicochemical, proximate, and sensory properties of moinmoin from blends of cowpea and water yam flour. AB - Moinmoin is a steamed cowpea seed-based pudding native to Nigeria. This study evaluated the physicochemical, proximate, and sensory properties of moinmoin from a blend of cowpea and water yam flours. The pudding was prepared by varying the proportion of cowpea to water yam flour (CWYP). The blends were in the ratio 75:25% (CWYP1), 50:50% (CWYP2), and 100:0% cowpea flour (CPP) which served as the control. Physicochemical evaluation indicated that the products will have good keeping quality and reconstitute easily. Protein content was 26.90%, 20.10%, and 17.60% for CPP, CWYP1 and CWYP2, respectively, and the presence of water yam significantly (p < .05) increased the crude fiber, ash, and carbohydrate contents of the cowpea/water yam products relative to the control. Pasting properties revealed that regardless of the proportion of water yam in the mixture, the moinmoin samples cooked at approximately the same time; and sensory evaluation showed that CWYP1 was best preferred in terms of taste, flavor, color, and overall acceptability. These findings suggest that the cowpea/water yam pudding can meet the nutritional demands of a meal and that the 75%-25% cowpea/water yam mixture was the most acceptable. The study contributes to the knowledge nutritious products with desirable organoleptic qualities from a blend of cowpea and water yam flour, allowing for up to 50% water yam substitution. It also provides an alternative way of utilizing water yam thus preventing wastage during peak production and ensuring food and nutritional security because of the balanced products obtained. PMID- 29983963 TI - Effects of ethanol combined with ascorbic acid and packaging on the inhibition of browning and microbial growth in fresh-cut Chinese yam. AB - The objective of this study was to investigate the effects of aqueous solutions of ethanol (25%, v/v) and ascorbic acid (AA, 1%, m/v) alone and in combination, along with modified atmosphere packaging (MAP) or vacuum packaging (VP), on the physicochemical properties and microbial quality of fresh-cut Chinese yam slices during 4 degrees C storage. The data showed that ethanol (25%, v/v) combined with AA (1%, m/v) and MAP treatment resulted in the lowest changes for headspace gas composition, color, electrical conductivity, overall visual quality, aerobic plate count population, and mold and yeast population in fresh-cut Chinese yam over 21 days of 4 degrees C cold storage, which was more effective at both inhibiting microbial growth and delaying browning than ethanol or AA alone or a commonly used sanitizer, sodium hypochlorite. The experiment on packaging demonstrated that samples treated with VP and 25% ethanol with 1% (m/v) AA dip can only preserve the sensory qualities of fresh-cut Chinese yam slices up to 7 days at 4 degrees C, but 25% (v/v) ethanol in conjunction with 1% (m/v) AA packed with MAP had antibrowning potential and maintained the quality of fresh-cut Chinese yam slices up to 14 days when stored at 4 degrees C. PMID- 29983964 TI - Using Thymus carmanicus and Myrtus communis essential oils to enhance the physicochemical properties of potato chips. AB - The aim of this study was to evaluate the antioxidant effects of the essential oils of Myrtus communis leaves and Thymus caramanicus aerial parts in order to improve the physicochemical properties of potato chips. Sunflower oil without any antioxidant (control group) was fortified with BHA or TBHQ antioxidants (200 ppm), and M. communis or T. caramanicus essential oils (3,000 ppm). The effects of the antioxidant behavior of these compounds on the physicochemical properties of potato chips were analyzed by measuring peroxide value (PV), acid value (AV), and thiobarbituric acid (TBA). In addition, changes occurring in oxidation stability, texture, and color were evaluated. The results revealed that samples containing either M. communis or T. carmanicus showed a significant decrease in PV, as compared to the control sample. Compared with the control, the extracted oil of potato chips with M. communis or T. carmanicus led to the significant reduction in AV (p < .05). The results also revealed the addition of the essential oils of M. communis or T. carmanicus was obviously effective in preventing the TBA increasing value. Based on the results obtained by the Rancimat test, either T. carmanicus or M. communis essential oils could significantly increase the shelf-life of potato chips, as compared with the control sample (p < .05). The hardness of potato chips was decreased in M. communis or T. carmanicus groups (p < .05), as compared to the control sample. Neither M. communis nor T. carmanicus essential oils had any negative effects on the lightness values, as compared to the control (p > .05). Based on the results, the physicochemical properties of potato chips could be improved with the addition of these essential oils. PMID- 29983965 TI - The influence of fat substitution with kappa-carrageenan, konjac, and tragacanth on the textural properties of low-fat sausage. AB - Reducing the fat content of meat products and producing healthier products is considered as an important matter in politics in prevention of many hazardous diseases and providing consumers' health. The aim of this study was reducing the fat in fatty sausages based on oil reduction and using fat substitutes, including kappa-carrageenan, konjac, and tragacanth, and comparing them according to their texture characteristics. kappa-carrageenan, konjac, and tragacanth gums were used at four different levels (0.0, 0.5, 1.0, and 1.5) as the fat substitutes in producing low-fat sausage with 70% reduction based on formulated oil. Texture profile analysis (Hardness, Gumminess, Springiness, and Chewiness) was performed in this study for analyzing the texture characteristics, in 1-, 10-, 20-, and 30 day time intervals after production. The results showed that producing low-fat sausage was possible using all the three gums, among the low-fat samples of which, the texture samples containing konjac were more favorable. Textural properties indicated that fat reduction increased in firmness and gum addition can partially compensate deficits in rheological properties, although during the storage, low-fat sausages without any gum have highest decline in Hardness. Konjac gum illustrated the best theological properties between treatments. PMID- 29983966 TI - Gelatin versus its two major degradation products, prolyl-hydroxyproline and glycine, as supportive therapy in experimental colitis in mice. AB - Gelatin is an anti-inflammatory dietary component, and its predominant metabolites entering circulation are prolyl-hydroxyproline (Pro-Hyp) and glycine. We evaluated the protective effects of orally administered gelatin, glycine, and Pro-Hyp 10:3:0.8 (w/w/w) against dextran sodium sulfate (DSS)-induced colitis in mice. According to clinical, histological, and biochemical parameters, they exhibited significant activities in the order of gelatin < glycine < Pro-Hyp. Gelatin prevented the DSS-induced increase in interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the colon, rather than in peripheral blood. Glycine and Pro-Hyp attenuated the DSS-induced rise in colonic IL-6 and TNF-alpha, as well as peripheral IL-1beta, IL-6, and TNF alpha. Hematologic results show the attenuation of DSS-induced leukocytosis and lymphocytosis by glycine and Pro-Hyp, rather than gelatin. These findings suggest that glycine and Pro-Hyp constitute the material basis for gelatin's anticolitis efficacy, and they have better anticolitis activities and distinct mechanisms of action when ingested as free compounds than as part of gelatin. PMID- 29983967 TI - Protein-lipid co-oxidation in emulsions stabilized by microwave-treated and conventional thermal-treated faba bean proteins. AB - The course of protein-lipid co-oxidation was investigated in oil-in-water emulsions stabilized with proteins extracted from microwave-treated (MWT) and conventional thermal-treated (CTT) faba beans stored at 37 degrees C for 7 days. Emulsions prepared with proteins from untreated (UT) faba beans and soy protein isolate (SP) were monitored for comparison. Lipid oxidation was detected through formation of primary and secondary oxidation products while protein oxidation was examined via tryptophan fluorescence degradation in interface and aqueous phase. Oxidation of proteins was more emphasized in the interfacial layers of MWT, CTT, and SP emulsions than in UT emulsions due to the prominence of radical chain driven co-oxidation mechanism while lipoxygenase (LOX) activity in UT and MWT emulsions resulted in high amounts of hydroperoxides and abundance in lipid oxidation volatiles. Conventional thermal treatment provided better oxidative stability than microwave treatment reflected in lower levels of hydroperoxides and relative lack of diversity in lipid volatiles. Among detected volatiles, formation of ketones was more distinguished in MWT, CTT, and SP emulsions while UT emulsions contained a more diverse range of alkenals and alkanals. Ketones are known to form mainly through radical recombination reactions which combined with the results of protein oxidation supports that radical transfer reactions between proteins and lipids were the driving force behind oxidation in MWT, CTT, and SP emulsions. Treatments of faba beans resulted in increased oxidative stability of emulsified lipids and lower degradation of aqueous phase proteins. PMID- 29983968 TI - Investigation of antioxidant activities of Pleurotus ostreatus stored at different temperatures. AB - In this study, the antioxidant capacity of oyster mushroom (Pleurotus ostreatus) stored in five different temperature environments was investigated by DPPH (1,1 diphenyl-2-picryl hydrazyl) radical scavenging method. The antioxidant capacity results of oyster mushroom extracts were examined by spectroscopic measurements and expressed as percent of inhibition. The IC50 values of mushroom samples were calculated with DPPH method using calibration equations, and change in antioxidant properties was also tried to decipher by SEM images. The IC50 values of Pleurotus ostreatus for four different concentrations were also found in h+20 degrees C > inh+4 degrees C> inh-10 degrees C> inh-20 degrees C> inh-40 degrees C, respectively. As a conclusion, the temperature factor of oyster mushroom in the range of -40 degrees C to +20 degrees C storage conditions is directly proportional to the change of antioxidant properties. The results have shown the importance of logistics and storage conditions in preserving the antioxidant properties of oyster mushroom and similar food samples. PMID- 29983969 TI - Phytochemicals and syneresis of osmo-dried mulberry incorporated yoghurt. AB - The research was aimed to study the effect of the addition of Osmo-air-dried mulberry (TSS 29.33%) in yoghurt on syneresis and a bioactive component of yoghurt. Two types of yoghurts, with or without Osmo-dried mulberry, were developed using standard culture (Streptococcus thermophilus and Lactobacillus bulgaricus), and changes at refrigerated temperature (<5 degrees C) were studied. Fruit yoghurt showed high total soluble solids (TSSs) and low-fat content (dry basis) (17.67% and 11.84%) compared with normal yoghurt (9.5% and 17.21%). The addition of fruits increased the ascorbic acid (0.77 to 5.96 mg/100 g yoghurt), anthocyanins content (0 to 7.9 mg/100 g yoghurt), total phenol content (TPC) (6.63 to 68.03 mg GAE/100 g yoghurt), and antioxidant activity (20.73% to 47.6% radical scavenging activity) in yoghurt. During 18 days of storage at refrigerated condition (<5 degrees C), the acidity of all samples increased, while pH decreased. Syneresis increased with a storage period in control samples while fruit incorporated yoghurt showed decreased syneresis with time. The viability of lactic acid bacteria (LAB) count went on decreasing at similar rates for both with and without the Osmo-dried mulberry incorporated yoghurt. There is an ample opportunity for utilization of Osmo-air-dried mulberry in yoghurt to prevent syneresis during storage with increased bioactive components. PMID- 29983970 TI - Ultrasound-induced changes in structural and physicochemical properties of beta lactoglobulin. AB - Effect of ultrasound treatment on the physicochemical properties and structure of beta-lactoglobulin were investigated. beta-Lactoglobulin was treated with ultrasound at different amplitudes, temperatures, and durations. The surface hydrophobicity and free sulfhydryl group of beta-lactoglobulin were significantly increased after ultrasound treatment (p < .05). The maximal surface hydrophobicity and free sulfhydryl group were 5,812.08 and 5.97 MUmol/g, respectively. Ultrasound treatment changed the physicochemical properties of beta lactoglobulin including particle size (from 1.21 +/- 0.05 nm to 1.66 +/- 0.03 nm), absolute zeta potential (from 15.47 +/- 1.60 mV to 27.63 +/- 3.30 mV), and solubility (from 84.66% to 95.17%). Ultrasound treatment increased alpha-helix and beta-sheet structures of beta-lactoglobulin. Intrinsic fluorescence intensity of ultrasound-treated beta-lactoglobulin was increased with shift of lambdamax from 334 to 329 nm. UV absorption of beta-lactoglobulin was decreased with shift of lambdamax from 288 to 285 nm after ultrasound treatment. There were no significant changes in high-performance liquid chromatography and protein electrophoretic patterns. These findings indicated that ultrasound treatment had high potential in modifying the physiochemical and structural properties of beta lactoglobulin for industrial applications. PMID- 29983971 TI - Stability of Golden redfish (Sebastes marinus) during frozen storage as affected by raw material freshness and season of capture. AB - Physicochemical changes of Icelandic golden redfish (Sebastes marinus) as affected by seasonal variation (June and November) and raw material freshness (processed 4 and 9 days postcatch) during frozen storage (at -25 degrees C for 20 months) were studied to find optimal conditions for production of high-quality frozen products. Thawing loss, cooking yield, and color of the fillets as well as chemical composition, water holding capacity, pH, total volatile basic nitrogen, lipid oxidation, and hydrolysis of the light and dark muscle were analyzed every 4 months of frozen storage. Lipid hydrolysis was the main degradation process in the light muscle, while the dark muscle was more affected by lipid oxidation. Fish caught in November showed greater instability in the analyzed parameters during storage than fish caught in June, which could be linked to differences in individual poly unsaturated fatty acids between the two seasons. The quality attributes of fish processed on day 9 were similar to fish processed 4 days postcatch, except slightly higher thawing loss and yellowness, were observed in fish processed 9 days postcatch. Stability of golden redfish through frozen storage was higher in the fish caught in June than in November. PMID- 29983973 TI - Thin-layer drying behavior of West Indian lemongrass (Cymbopogan citratus) leaves. AB - The objectives of this study were to investigate the effect of temperature (40, 50, 60, and 70 degrees C), and air velocity (0.5, 1, and 2 m/s) on the drying behavior of West Indian lemongrass (Cymbopogan citratus) leaves. Drying was carried out in a computer-controlled tray dryer. Overall, the effect of temperature was seen to be more important than that of air velocity, but the air velocity did have an effect on drying rates at the start of the drying process at 50-70 degrees C. Drying rate constants, diffusivity values, and activation energy were determined. Twenty-two empirical and semiempirical thin-layer models were tested, and although model fit varied, the Midilli model could be applied to all data with reasonable prediction of MR values. PMID- 29983972 TI - Safety of ready-to-eat chicken in Burkina Faso: Microbiological quality, antibiotic resistance, and virulence genes in Escherichia coli isolated from chicken samples of Ouagadougou. AB - In Burkina Faso, flamed/grilled chickens are very popular and well known to consumers. The aim of this study was to evaluate the microbiological quality, the antibiotic resistance, and the virulence gene from Escherichia coli isolated from these chickens in Ouagadougou. A total of 102 grilled, flamed, and fumed chickens were collected in Ouagadougou and analyzed, using standard microbiological methods. All E. coli isolates were checked with the antimicrobial test and also typed by 16-plex PCR. The mean of aerobic mesophilic bacteria (AMB) and thermo tolerant coliforms (TTC) was found respectively between 6.90 +/- 0.12 * 107 CFU/g to 2.76 +/- 0.44 * 108 CFU/g and 2.4 +/- 0.82 * 107 CFU/g to 1.27 +/- 0.9 * 108 CFU/g. E. coli strains were found to 27.45%. Forty samples (38.24%) were unacceptable based on the AMB load. Fifty-nine samples (57.85%) were contaminated with TTCs. Low resistance was observed with antibiotics of betalactamin family. Diarrheagenic E. coli strains were detected in 21.43% of all samples. This study showed that flamed/grilled chickens sold in Ouagadougou could pose health risks for the consumers. Need of hygienic practices or system and good manufacturing practices is necessary to improve the hygienic quality of flamed/grilled chickens. Our results highlight the need of control of good hygiene and production practices to contribute to the improvement of the safety of the products and also to avoid antibiotic resistance. Slaughter, scalding, evisceration, plucking, bleeding, washing, rinsing, preserving, grilling, and selling may be the ways of contamination. PMID- 29983974 TI - Effect of Oryctolagus cuniculus (rabbit) rennet on the texture, rheology, and sensory properties of white cheese. AB - Calf rennet has long been used in cheese-making. Because of calf rennet shortage and high cost, novel proteases were needed to meet industry's increasing enzyme demand. Recombinant chymosins and camel chymosin were started to be used in the industry. There is no study in the literature subjecting use of rabbit rennet in cheese production. Chemical, rheological, and sensorial characteristics of white cheese made with rabbit rennet were investigated in this study. Quality characteristics of rabbit rennet cheese (RC) were compared to cheeses produced with commercial calf (CC) and camel chymosins (CLC). RC and CLC exhibited higher hardness and dynamic moduli values throughout the storage as compared to CC. Although moisture levels of cheese samples were similar at day 60, CC had much lower hardness and dynamic moduli values than CLC and RC. While the appearance and structure were better for CLC, the highest odor and taste scores were obtained by RC during 60 days of storage. The results of this investigation proposed that rabbit rennet could be a suitable milk coagulant for white cheese production. Our results showed that rabbit rennet has comparable cheese-making performance with camel chymosin and could be a good alternative for calf chymosin. PMID- 29983975 TI - Determination of soybean routine quality parameters using near-infrared spectroscopy. AB - Large differences in quality existed between soybean samples. In order to rapidly detect soybean quality between samples from different areas, we have developed near-infrared spectroscopy (NIRS) models for the moisture, crude fat, and protein content of soybeans, based on 360 soybean samples collected from different areas. Compared with whole kernels, soybean powder with particle sizes of 60 mesh was more suitable for modeling of moisture, crude fat, and protein content. To increase the reproducibility of the prediction model, uniform particle sizes of soybeans were prepared by grinding and sieving soybeans with different sizes and colors. Modeling analysis showed that the internal cross-validation correlation coefficients (Rcv) for the moisture, crude fat, and protein content of soybeans were .965, .941, and .949, respectively, and the determination coefficients (R2) were .966, .958, and .958. NIRS performed well as a rapid method for the determination of routine quality parameters and provided reference data for the analysis of soybean quality using FT-NIRS. PMID- 29983976 TI - Effect of sweet potato endogenous amylase activation on in vivo energy bioavailability and acceptability of soy-enriched orange-fleshed sweet potato complementary porridges. AB - Energy bioavailability can be influenced by food matrix factors and processing conditions or treatments. In this study, the effects of endogenous sweet potato amylase enzyme activation and slurry solids content of soy-enriched orange fleshed sweet potato (OFSP) porridges on in vivo energy bioavailability (energy, weight gain, and feed efficiency ratio) and porridge acceptability were determined. Fifty-six weanling albino rats were randomly assigned to two blocks each having eight groups of seven rats. The rats were housed in individual cages in a well-ventilated animal house. The intervention block had rats fed on activated porridges (held at 75 degrees C for 15 min), while rats in the control block were fed on nonactivated porridges (boiled at 90-95 degrees C for 10 min). The rats were fed for 28 days on 50 ml of porridge per rat per day. The four groups per block were each fed on porridges with varying amounts of total solids content (10%, 15%, 20%, and 25%). Weight gain, energy bioavailability, and feed efficiency ratio were determined at the end of the feeding period. Consumer acceptability of activated and nonactivated porridges at 25% solids content was determined using a nontrained human panel (n = 40). Activation of amylases did not significantly (p > .05) affect the bioavailable energy, cumulative weight gain, and feed efficiency of the rats. Increasing slurry solids content of activated and nonactivated porridges significantly (p < .05) increased feed efficiency ratio (-14.6 +/- 11.7 to 102.3 +/- 2.3), weight gain (-1.4 to 5.6 g +/ 1.9 g), and bioavailable energy (702.8 +/- 16.2 to 1242.8 +/- 12.2 kcal). Activation of amylases reduced porridge viscosity but did not significantly influence the overall acceptability. This work demonstrates the opportunity of utilizing sweet potato amylases to facilitate the preparation of complementary porridges with appropriate viscosity and increased energy density. PMID- 29983978 TI - Scaling-up biofortified beans high in iron and zinc through the school-feeding program: A sensory acceptance study with schoolchildren from two departments in southwest Colombia. AB - Iron and zinc deficiencies are global health problems, affecting mostly pregnant women and young children. In 2016, biofortified iron and zinc beans were introduced in Colombia. The incorporation of biofortified beans into the national school-feeding program could facilitate adoption and potentially improve the nutritional status of large populations. However, biofortified beans have to be accepted in order to be consumed by populations. We therefore studied the sensory acceptability of two biofortified beans, BIO-101 and BIO-107, and local beans at schools with free feeding services in two departments of southwest Colombia. Measured on a five-point Likert scale, the mean overall scores were 3.88 +/- 0.64, 3.79 +/- 0.74, and 3.81 +/- 0.76, for BIO-101, BIO-107, and the local bean varieties, respectively, without significant differences. The children in Piendamo (Cauca) slightly preferred BIO-107 over the local bean (p < .05) based on color, smell, and taste. The children in Caicedonia (Valle del Cauca) slightly favored the local bean over BIO-107 (p < .05), regarding size, smell, and taste. Overall acceptability in schoolchildren was good for all beans without significant differences. This study advocates incorporation of accepted biofortified beans in the school-feeding program, in order to reach large groups of schoolchildren and potentially improve their nutritional statuses. PMID- 29983977 TI - Enhanced yield of oleuropein from olive leaves using ultrasound-assisted extraction. AB - The aim of this study was to optimize the extraction of oleuropein from olive leaves through a systematic study of the effects of different parameters of ultrasound-assisted extraction (USAE) on the oleuropein yield, in comparison with conventional maceration extraction. A range of operational parameters were investigated for both conventional maceration extraction and USAE: solvent type, olive leaf mass-to-solvent volume ratio, and extraction time and temperature. Oleuropein yield was determined using high-performance liquid chromatography, with total phenolics content also determined. The optimized conditions (water ethanol, 30:70 [v/v]; leaf-to-solvent ratio, 1:5 [w/v]; 2 hr; 25 degrees C) provided ~30% greater oleuropein extraction yield compared to conventional maceration extraction. The total phenolics content obtained using the optimized USAE conditions was greater than reported in other studies. USAE is shown to be an efficient alternative to conventional maceration extraction techniques, as not only can it offer increased oleuropein extraction yield, but it also shows a number of particular advantages, such as the possibility of lower volumes of solvent and lower extraction times, with the extraction carried out at lower temperatures. PMID- 29983979 TI - Influence of drying temperature and storage period on the quality of cherry and plum tomato powder. AB - The quality changes of cherry and plum tomatoes dried at different temperatures (60, 65 and 70 degrees C) milled into powder and stored for 8 weeks were assessed in this study. The ascorbic acid and lycopene content of the tomato powders were significantly different with values that ranged from 5.10 to 7.70 mg/100 g and 211.53 to 246.02 mg/kg, respectively. Color parameters redness (a*) and chroma decreased, while lightness (L*), yellowness (b*), and hue increased as the drying temperature increased. In addition, increase was observed in the total fungal load and lightness of the two tomato varieties at all temperatures, while the titratable acidity, pH, ascorbic acid, lycopene, redness, and yellowness increased as the storage period increased to 8 weeks. The 60 degrees C dried plum tomato powder had the best result in terms of quality retention at the end of the storage period. Some quality parameters increased and decreased with drying and storage of plum and cherry tomato powders. PMID- 29983980 TI - Effect of total replacement of egg by soymilk and lecithin on physical properties of batter and cake. AB - The baking industry is interested in finding cost-effective and healthful alternatives for eggs. Therefore, in this study the effects of total replacement of egg by soymilk (SM) in combination with 0-6% soy lecithin (SL) on batter (density, microstructure, viscosity, and texture) and cakes (height, volume, density, texture, color parameters, and sensory attributes) were determined and compared with cakes manufactured with eggs. The results showed that all batters had shear thinning behavior and provided a good fit for the power law model. The egg-free cake in the absence of SL was downgraded because of high density and viscosity, small air bubbles, dark color, firm texture, low volume, and sensory scores. Inclusion of up to 4% SL to the SM was found to be significant in improving cake quality and led to cakes more similar to the control sample; however, higher levels of SL had negative effects on organoleptic properties of cakes. PMID- 29983981 TI - A novel strategy and kinetics analysis of half-fractional high cell density fed batch cultivation of Zygosaccharomyces rouxii. AB - Zygosaccharomyces rouxii is an important microorganism for aroma production in traditional fermented foods. Using Z. rouxii as the original strain, the batch was split after glucose depletion in the culture medium. Half of the volume of the culture medium was released, and fresh culture medium was fed in. The exponential culture kinetics and the formula for the half-fractional fed-batch cultivations were determined to achieve a new strategy for high cell density culturing of Z. rouxii. Based on a full cultivation, three half-fractional fed batch cultivations were performed after every 10 hr of culture. The specific growth rates of Z. rouxii at the different stages were in the order MU X0>MU X1>MU X2>MU X3 (0.525 to 0.229 hr-1). The glucose substrate consumption rates gradually decreased following the order MU S0>MU S1>MU S2>MU S3 (-1.165 to 0.722, g/g). The equation models for cell growth and glucose substrate consumption showed typical exponential behavior. The total cell yield was 1.78 fold higher than the yield from a full cultivation, and this continuous subculture strategy also indicated a higher efficiency than traditional full cultivation. A new strategy for highly efficient culturing of Z. rouxii was achieved in a pilot scale. A foundation with data support for the production and application of Z. rouxii was developed. PMID- 29983982 TI - Sensitivity and specificity of point-of-care circulating Cathodic antigen test before and after praziquantel treatment in diagnosing Schistosoma mansoni infection in adult population co-infected with human immunodeficiency virus-1, North-Western Tanzania. AB - Background: The effect of Human Immunodeficiency Virus-1 (HIV-1) on CD4+ Th2 cells is hypothesized to affect parasitological diagnosis of Schistosoma mansoni using Kato Katz technique. Thus, the use of more sensitive technique such as Point-of-Care Circulating Cathodic Antigen (POC-CCA) test is recommended. However, the sensitivity of this diagnostic test in diagnosing S.mansoni infection and the usefulness of it in monitoring efficacy of praziquantel drug in presence of HIV-1 co-infection remains inconclusive. The Primary objective of the present study was to assess accuracy of the POC-CCA test in diagnosing S.mansoni infection before and after praziquantel treatment in adult population co-infected with HIV -1. Methods: A prospective longitudinal study was conducted among individuals aged 15-55 years at Igalagala village, north-western Tanzania. At baseline and 4 weeks after treatment, a single stool and urine samples were collected from each participants. Kato Katz (KK) technique and Point-of-Care Circulating Cathodic Antigen tests were used for diagnosis of Schistosoma mansoni. Results: At baseline, based on KK and POC-CCA, the prevalence of S.mansoni was 57.8% (95%CI: 52.9-62.4) and 87.5% (95%CI: 83.9-90.4). Based on KK technique and POC-CCA test, 3.6% and 5.7% of the study participants were co infected with S.mansoni and HIV-1. At baseline, in the general population, the sensitivities of POC-CCA test using KK technique and combine gold standard were 96.3%(95%CI: 93.1-98.3) and 97.6%(95%CI:95.5-98.9) respectively. In the HIV-1 seropositive group, at baseline, the sensitivities of POC-CCA test using KK technique and combined gold standards, were 93.3%(95%CI:68.1-99.8) and 96%(95CI%:79.6-99.9). Four weeks after treatment, in general population, the sensitivities of POC-CCA test using KK technique and combined gold standards were 47.8%(95%CI:26.8-69.4) and 84.4%(95%CI:74.4-91.7). In the HIV-1 seropositive group, using KK technique, the sensitivity was 100% (95%CI:2.5-100). Conclusion: The sensitivity of POC-CCA in diagnosing S.mansoni infection was higher than KK technique in adult individuals likely to have low infection intensity and co infected with HIV-1. However, its sensitivity decreases following praziquantel treatment but remained higher than Kato Katz technique. If the goal of the post treatment is to identify uncured individuals, then POC-CCA test offers the best choice. PMID- 29983983 TI - Pulmonary lymphangitic carcinomatosis with ground-glass opacities as presentation of prostate cancer. AB - There is a broad differential diagnosis for interstitial shadows on chest computed tomography in rheumatoid arthritis patients, especially those previously treated with immunosuppressant drugs. We report an immunocompromised rheumatoid arthritis patient in respiratory failure with diffuse ground-glass opacities (GGOs), who was diagnosed with pulmonary lymphangitic carcinomatosis as the initial presentation of prostate cancer. He was successfully treated with chemohormonal androgen deprivation therapy, including bicalutamide, leuprorelin acetate, denosumab, and docetaxel. Metastatic pulmonary lymphangitis, rarely from the prostate, should always be considered in the differential diagnosis of GGOs, even when the patient has no known prior malignancies. PMID- 29983984 TI - BK virus pneumonia following stem cell transplantation against diffuse large B cell lymphoma. AB - The patient, a 70-year-old woman with diffuse large B-cell lymphoma (DLBCL), developed haemorrhagic cystitis associated with the BK virus (BKV) and adenovirus type 11. Moreover, chest computed tomography showed ground-glass opacity (GGO) in the bilateral upper lobe, and we performed bronchoalveolar lavage (BAL). The BKV DNA load was elevated not only in blood but also in BAL fluid (BALF), leading to the diagnosis of BKV pneumonia. After administering cidofovir, the respiratory symptoms and GGO abated. Therefore, detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia. The patient with DLBCL developed BKV pneumonia. We performed BAL, and BKV DNA load was elevated on BALF. The detection of BKV DNA in BALF is useful for diagnosing BKV pneumonia. PMID- 29983985 TI - Recruitment maneuver does not provide any mortality benefit over lung protective strategy ventilation in adult patients with acute respiratory distress syndrome: a meta-analysis and systematic review of the randomized controlled trials. AB - Background: Clinical benefits of recruitment maneuver in ARDS patients are controversial. A number of previous studies showed possible benefits; a large recent study reported that recruitment maneuver and PEEP titration may even be harmful. This meta-analysis was designed to compare the clinical utility of recruitment maneuver with low tidal volume ventilation in adult patients with ARDS. Methods: Randomized controlled trials comparing recruitment maneuver and lung protective ventilation strategy with lung protective strategy ventilation protocol alone in adult patients with ARDS has been included in this meta analysis. PubMed and Cochrane Central Register of Controlled Trials were searched from inception to 10 November 2017 to identify potentially eligible trials. Pooled risk ratio (RR) and standardized mean difference (SMD) were calculated for binary and continuous variables respectively. Results: Data of 2480 patients from 7 randomized controlled trials have been included in this meta-analysis and systemic review. Reported mortality at the longest available follow-up [RR (95% CI) 0.93 (0.80, 1.08); p = 0.33], ICU mortality [RR (95% CI) 0.91 (0.76, 1.10); p = 0.33] and in-hospital mortality [RR (95% CI) 0.95 (0.83, 1.08); p = 0.45] were similar between recruitment maneuver group and standard lung protective ventilation group. Duration of hospital stay [SMD (95% CI) 0.00 (- 0.09, 0.10); p = 0.92] and duration of ICU stays [SMD (95% CI) 0.05 (- 0.09, 0.19); p = 0.49] were also similar between recruitment maneuver group and standard lung protective ventilation group. Risk of barotrauma was also similar. Conclusion: Use of recruitment maneuver along with co-interventions such as PEEP titration does not provide any benefit in terms of mortality, length of ICU, and hospital stay in ARDS patients. PMID- 29983987 TI - First literature review of carbapenem-resistant Providencia. AB - Providencia species are Gram-negative bacteria that belong to the Enterobacteriaceae family. They have intrinsic resistance to colistin and tigecycline, which makes treatment of the multidrug-resistant strains of Providencia challenging. Carbapenem-resistant Providencia species are increasingly reported. In this review, patients' characteristics, resistance mechanisms, treatment and infection control measures of carbapenem-resistant Providencia species in the literature are described. PMID- 29983988 TI - Completion of genome of Aeromonas salmonicida subsp. salmonicida 01-B526 reveals how sequencing technologies can influence sequence quality and result interpretations. AB - Aeromonas salmonicida subsp. salmonicida is a pathogen that primarily infects salmonids. A strain of this bacterium, 01-B526, has been used in several studies as a reference. The genomic sequence of this strain is available, but comes from pyrosequencing and is the second most fragmented assembly for this bacterium. We generated its closed genome sequence and found a pitfall in result interpretations associated with low-quality genomic sequences. PMID- 29983986 TI - Drug conjugates-an emerging approach to treat breast cancer. AB - Breast cancer treatment using a single drug is associated with a high failure rate due, in part, to the heterogeneity of drug response within individuals, nonspecific target action, drug toxicity, and/or development of resistance. Use of dual-drug therapies, including drug conjugates, may help overcome some of these roadblocks by more selective targeting of the cancer cell and by acting at multiple drug targets rather than one. Drug-conjugate approaches include linking drugs to antibodies (antibody-drug conjugates), radionuclides (radioimmunoconjugates), nanoparticles (nanoparticle-drug conjugates), or to other drugs (drug-drug conjugates). Although all of these conjugates might be designed as effective treatments against breast cancer, the focus of this review will be on drug-drug conjugates because of the increase in versatility of these types of drugs with respect to mode of action at the level of the cancer cell either by creating a novel pharmacophore or by increasing the potency and/or efficacy of the drugs' effects at their respective molecular targets. The development, synthesis, and pharmacological characteristics of drug-drug conjugates will be discussed in the context of breast cancer with the hope of enhancing drug efficacy and reducing toxicities to improve patient quality of life. PMID- 29983989 TI - Occurrence of multiclass pesticide residues in tomato samples collected from different markets of Iran. AB - Background: Pesticides are a reason for popular concern due to their possible unfavorable results on human safety. Most pesticide residues are present in food owing to the direct application of a pesticide to a crop. The aims of this study were; development a multiresidue method for analysis of 81 pesticides in tomato using GC/MS, and detection and quantitation of the studied pesticides in tomato samples gathered from various stores of Iran. Methods: The pesticides were assessed concurrently in a single run applying GC/MS after extraction with QuEChERS method. Homogenized tomato samples were weighed into centrifuge tubes. The studied pesticides were extracted using acetonitrile, followed by the addition of a mixture of anhydrous magnesium sulfate and sodium acetate. In order to remove excess water and other components of tomato a combination of primary secondary amine and magnesium sulfate was applied, and then the extracted components were analyzed by GC-MS. Results: The calibration curves for all analytes were linear in the range of 20-200 ng/g with a determination coefficient (R2) in the range between 0.993 and 0.999. The LODs and LOQs were in the range between 2.5-6.7 and 7.5-20 ng/g respectively, and the mean recoveries obtained for three fortification levels (25,50 and 100 ng/g -five replicates each) were 72 116% with RSD < 20%. Six residues were found in 31 (20.7%) samples. Iprodione was the most common detected residues (6.0%), followed by permethrine (4.7%), esfenvalerate (4.7%), chlorpyrifos (3.3%), diazinon (2.0%), and penconazole (1.3%). Conclusions: Among the detected pesticides, only Iprodione, permethrine, chlorpyrifos and diazinon are registered for tomato production in Iran. With exception of Chlorpyrifos and diazinon the concentrations of iprodione and permethrine were found below the maximum residue levels (MRLs) established by Iranian National Standard Organization (INSO). Esfenvalerate and penconazole are not registered for tomato production in Iran. Therefore, it is necessary to control and management of their residues in tomato. PMID- 29983990 TI - Determinants of change in fertility pattern among women in Uganda during the period 2006-2011. AB - Background: Studies on fertility in Uganda have attributed fertility reduction to a shift in the overall characteristics of women of reproductive age. It is not clear whether the reduction in fertility is due to changing socioeconomic and demographic characteristics over time or stems from the shifts in the reproductive behavior of women. In this paper we examine how fertility rates have changed between 2006 and 2011 and whether these changes have resulted from changing characteristics or from changing reproductive behavior of women. Methods: Using the 2006 and 2011 Demographic and Health Survey data for Uganda, Multivariate Poisson Decomposition techniques were applied to evaluate observed changes in fertility. Results: Changing characteristics of women aged 15-49 years significantly contributed to the overall change in fertility from 2006 to 2011. The change observed in older age at first marriage was the major contributor to the changes in fertility. The contribution that can be attributed to changes in reproductive behavior was not significant. Conclusions: This study finds that the major contribution to the reduction in fertility between 2006 and 2011 was from increased education and delayed marriage among women. Continued improvement in secondary school completion, will lead to older age at first marriage and will continue to be an important factor in Uganda's declining fertility rates. PMID- 29983991 TI - Poverty and mental health: the work of the female sanitary inspectors in Bradford (c. 1901-1912). AB - Although there are many excellent studies of the work of pioneer women public health officers, few accounts dwell on mental health issues or discuss any relationship that such staff might have understood to exist between poverty and mental health in the early twentieth century. This is a remarkable omission considering that social and feminist historians have highlighted the problems created by the way early practitioners sought to manage poverty and arguably the poor. Drawing on records created by Female Sanitary Inspectors (FSIs) in Bradford, this study chronicles distressing economic and social conditions but also reveals encounters between the staff and people experiencing mental health problems and mental health crises. The ways in which the FSIs chose to both make and deny links between the abject poverty witnessed in the slum districts and cases of mental disorder forms an important strand to the analysis that follows. Interestingly, it is the well-being of the staff that emerges as a persistent and even over-riding concern. PMID- 29983992 TI - Cognitive remediation therapy (CRT) as a pretreatment intervention for adolescents with anorexia nervosa during medical hospitalization: a pilot randomized controlled trial protocol. AB - Background: Anorexia nervosa (AN) is a severe psychiatric condition characterized by low body weight, fear of weight gain/becoming fat and/or behavior that interferes with weight gain, and body disturbance. Though there have been recent advances in the treatment of AN, there continues to be an urgent need to increase treatment options. Cognitive remediation therapy (CRT) has been successfully used as an adjunctive treatment for individuals with AN. In this study, we pilot the use of CRT plus an innovative parent involvement component as a pre-treatment intervention on a medical unit. We hypothesize that adding CRT with parent involvement to a standard hospital stay is feasible, acceptable by patients and staff, and may improve treatment outcomes post-hospitalization. Methods/design: This is a pilot randomized controlled trial with three arms. Participants are adolescents aged 12-18 with AN; 60 participants will be included. They are randomized into one of three groups: treatment as usual (TAU, standard care at Children's Hospital of Philadelphia), CRT + contact control (known as "Family Fun Time"), and CRT + Teach the Parent. Intervention will occur on an inpatient basis. Follow-up will be outpatient and will continue until 6 months post discharge. Psychosocial, neurocognitive, and behavioral measures will be collected throughout the study, and group differences will be evaluated at 4 weeks, 3 months, and 6 months post-discharge. The study will take place at The Children's Hospital of Philadelphia. Discussion: This pilot randomized controlled trial will inform feasibility of the integration of a pre-treatment intervention into a medical hospital stay for AN. We will assess recruitment procedures, treatment administration, and participant retention. Finally, a comprehensive assessment battery will be evaluated. Secondary goals are to conduct a preliminary evaluation of whether or not CRT with parent involvement increases rate of weight gain and treatment engagement and decreases parental accommodation of symptoms post-discharge. If successful, this pilot study will inform a larger controlled trial fully powered to examine the secondary goals. Trial registration: ClinicalTrials.gov Identifier NCT02883413. PMID- 29983993 TI - Novel patient-reported outcomes (PROs) used in a pilot and feasibility study of a Cognitive Behavioral Coping Skills (CBCS) group intervention for patients with chronic hepatitis C. AB - Background: Patients with chronic hepatitis C virus (HCV) experience reduced quality of life, HCV-associated symptoms, comorbid conditions, and treatment side effects. The Cognitive Behavioral Coping Skills group intervention for HCV (CBCS HCV) was developed using the Stage Model of Behavioral Therapies Research. Intervention development and initial feasibility testing in wave 1 participants were previously reported. The primary objective of this subsequent pilot with wave 2-3 participants was to investigate the effect sizes and clinical improvements in patient-reported outcomes (PROs) and trial and intervention feasibility. Methods: A pilot feasibility two-arm randomized controlled trial using block randomization to assign patients to CBCS-HCV or standard of care was conducted. Participants attended nine group sessions: four before HCV treatment and five during treatment. PRO data were collected at five time points: before the CBCS intervention (T1), immediately before HCV treatment (T2), during HCV treatment (T3, T4), and 1 month post-intervention/post-HCV treatment (T5). PROs included quality of life, perceived stress, HCV symptoms, and medication adherence. Cohen's d was used to estimate within-group changes (WGCs) and between group differences (BGDs), with d > 0.35 considered potentially clinically significant. Potential mechanisms of change were also evaluated. Results: Several WGCs and BGDs (ES > .35) suggest that the CBCS-HCV may promote improvements in PROs: psychological stress, depression, anger, anxiety, sleep disturbance, and fatigue. The intervention did not appear to impact social functioning, pain, or medication adherence. Cognitive behavioral skills and group therapy dynamics, but not HCV treatment self-efficacy, may mediate improvements in PROs. Most aspects of the study trial, including intervention implementation, were feasible. Patient acceptance and retention were exceptional. The greatest feasibility challenge was due to patients needing to initiate treatment as soon as medications were obtained, but often before a full block could be created in wave 3. Challenges with PRO data collection were identified that will be resolved in future studies. Conclusions: The CBCS-HCV intervention warrants future investigation in an efficacy trial to evaluate improvements in selected PROs. The next step is to pilot test the CBCS-HCV delivered via telehealth to an expanded pool of patients to reduce patient barriers, hone technical logistics, and improve intervention reach and effectiveness. Trial registration: NCT03057236 Retrospectively registered. PMID- 29983994 TI - Sharpening the focus: differentiating between focus groups for patient engagement vs. qualitative research. AB - Plain English summary: Patient engagement is an opportunity for people with experience of a health-related issue to contribute to research on that issue. The Canadian Strategy for Patient-Oriented Research (SPOR) highlights patient engagement as an important part of health research. Patient engagement, however, is a new concept for many researchers and research ethics boards, and it can be difficult to understand the differences between patient engagement activities and research activities. Focus groups are one example of how research and patient engagement activities are often confused.We distinguish these two types of activities by using different terms for each. We use focus groups to refer to research activities, and discussion groups to refer to patient engagement activities. In focus groups, researchers collect data by speaking with a group of research subjects about their experiences. Researchers use this information to answer research questions and share their findings in academic journals and gatherings. In patient engagement, discussion groups are a way for patients to help plan research projects. Their contributions are not treated as research data, but instead they help make decisions that shape the research process. We have found that using different language to refer to each type of activity has led to improved clarity in research planning and research ethics submissions. Abstract: Background In patient-oriented research (POR), focus groups can be used as a method in both qualitative research and in patient engagement. Canadian health systems researchers and research ethics boards (REBs), however, are often unaware of the key differences to consider when using focus groups for these two distinct purposes. Furthermore, no one has clearly established how using focus groups for these two purposes should be differentiated in the context of Canada's Strategy for Patient-Oriented Research (SPOR), which emphasizes appropriate patient engagement as a fundamental component of POR. Body Researchers and staff in the Maritime SPOR SUPPORT Unit refer to focus groups in patient engagement as discussion groups for clarity, and have developed internal guidelines to encourage their appropriate use. In this paper, the guidelines comparing and contrasting the design and conduct of focus groups and of discussion groups is described, including: the theoretical framework for each; the need for research ethics board review approval; identifying participants; collecting and analyzing data; ensuring rigour; and disseminating results. Conclusion The MSSU guidelines address an important and current methodological challenge in patient-oriented research, which will benefit Canadian and international health systems researchers, patients, and institutional REBs. PMID- 29983995 TI - Blurred boundaries: sexuality and power in standardised patients' negotiations of the physical examination. AB - Background: Working with standardised or simulated patients (SPs) is now commonplace in Simulated Learning Environments. Embracing the fact that they are not a homogenous group, some literature suggests expansion of learning with SPs in health professional education by foregrounding their personal experiences. Intimate examination teaching, whether with or without the help of SPs, is protected by a particular degree of ceremony given the degree of potential vulnerability. However, other examinations may be equally intrusive for example the close proximity of an eye examination or a chest examination in a female patient. In this study, we looked at SPs' experiences of boundary crossing in any examinations, sensitised by Foucault's concept of the clinical gaze. We wished to problematise power relations that construct and subject SPs as clinical tools within simulation-based education. Methods: We collected data from 22 SPs, through five focus groups. Analysis was an iterative process, using thematic analysis. Data collection and reflexive analysis continued iteratively until concepts were fully developed and all theoretical directions explored. Results: Students and SPs construct simulated teaching consultations by negotiating the unequal distribution of power between them. The SPs themselves discussed how they, perhaps unknowingly, acted in accordance with the discourse of the clinical gaze. However, SPs became disempowered when students deviated from the negotiated terms of consent and they used their agency to resist this. The SPs used strong sexual metaphors to express the subjugation they experienced, as discourses of sexuality and gender played out in the Simulated Learning Environment. Conclusion: We demonstrate that power dynamics and the clinical gaze can have important consequences within the Simulated Learning Environment. Every physical examination can be potentially 'intimate' and can therefore be underpinned by discourses of sexuality and gendered undertones. In partnership with SPs, simulation-based education should create a teaching space that no longer fosters the discourse of the clinical gaze but facilitates students to learn to reflectively navigate, in the moment, the fine line between touching patients versus touching loved ones, and the blurred boundaries that exist in the gulf between sexual contact and benevolent touch. PMID- 29983996 TI - Breast phantom for comparison X-ray and polarimetric optical tomography imaging. AB - Breast phantom made as combination of paraffin and INTRALIPIDTM was tested by use of X-ray classical computed tomography and polarimetric optical tomography. The INTRALIPIDTM is a liquid commonly used for simulation breast tissues optical properties but it is useless as X-ray phantom. During our tests we have observed that X-ray tomography allows to recognize a proper placement of INTRALIPIDTM inclusions inside paraffin medium but we cannot distinguish density of INTRALIPIDTM within each inclusions. On the other hand the polarimetric optical tomography allows to distinguish density of INTRALIPIDTM (0%, 10%, 20%) in inclusions but with relatively low accuracy of their placement. PMID- 29983997 TI - Current Status of Knowledge about Cardiopulmonary Resuscitation among the University Students in the Northern Region of Saudi Arabia. AB - Background: Sudden cardiac arrest is a major public health problem in the world. Immediate initiation of high-quality cardiopulmonary resuscitation (CPR) significantly increased patient survival rate. Therefore, it is very important to train young people and increase public awareness of CPR for the long-term benefit of the community. Objective: We aimed at estimating the level of knowledge and attitude towards cardiopulmonary resuscitation (CPR) among the university students in the northern region of Saudi Arabia. Methodology: A cross-sectional, prospective study was conducted among the students of four northern region universities of Saudi Arabia (Jouf, Hail, Northern Borders, and Tabuk) between March and November 2017. A self-administered questionnaire was prepared in both Arabic and English languages and distributed to all the participants. All the data were collected and analyzed by using SPSS version 21. Results: A total of 947 students from four universities completed the questionnaire: Jouf (57%), Hail (15%), Northern Borders (13%), and Tabuk (15%). Although 72% of students have previous knowledge about CPR, 49% of them lack knowledge about a medical emergency. Moreover, 59% failed to answer regarding CPR where only 41% wrote the ABC steps in the correct sequence. However, 67% of the participants had very poor knowledge, 89% of participants desired to receive additional CPR training course, and 49% of the students thought that CPR training should be a mandatory graduation requirement for all universities. There were no significant differences between male and female students. Students from medicine-related colleges have significantly (p < 0.001) more knowledge and scored better compared with non-medicine-related colleges. Tabuk University scored better compared to the others, but the overall knowledge and attitude scored were low. Conclusions: Overall knowledge about CPR among the university students was not satisfactory; however, attitude towards CRP training was very positive. Our results suggested that there is a need for improvement of CPR education among Saudi university students, which will help to reduce the cardiac arrest mortality rate among the community. PMID- 29983998 TI - Examining the Obesogenic Attributes of the Family Child Care Home Environment: A Literature Review. AB - Childhood obesity is a major public health concern in the US. More than a third of young children 2-5 years old are placed in nonrelative child care for the majority of the day, making the child care setting an important venue to spearhead obesity prevention. Much of the obesity research in child care has focused on center-based facilities, with emerging research on Family Child Care Homes (FCCHs)-child care operated in a home setting outside the child's home. The purpose of this review was to assess the obesogenic attributes of the FCCH environment. A search of the PubMed, Embase, CINHAL, and PsycINFO electronic databases identified 3,281 citations; 35 eligible for full-text review, and 18 articles from 17 studies in the analysis. This review found a lack of comprehensive written nutrition and physical activity policies within FCCHs, lack of FCCH providers trained in nutrition and physical activity best practices, lack of adequate equipment and space for indoor and outdoor playtime activities in FCCHs, inaccurate nutrition-related beliefs and perceptions among FCCH providers, poor nutrition-related communication with families, and poor feeding practices. Future research focusing on interventions aimed at addressing these problem areas can contribute to obesity prevention. PMID- 29983999 TI - Socioeconomic Status and Vulnerability to HIV Infection in Uganda: Evidence from Multilevel Modelling of AIDS Indicator Survey Data. AB - Background: There is controversy on the association between socioeconomic status (SES) and HIV infection. Some evidence claims higher SES is negatively associated with HIV infection while others report the reverse. Objectives: To examine the association between SES and HIV infection in Uganda and to examine whether the SES-HIV relationship varies by gender, rural-urban place of residence, and time (2004-2005 and 2011) in Uganda. Methods: Multilevel analysis was applied to 39,766 individual cases obtained in 887 clusters of Uganda HIV/AIDS Indicators Survey conducted in 2004-2005 and 2011. Results: Household wealth is associated with increased vulnerability in the general population and in rural areas. Compared with no educational attainment, secondary or higher education is associated with reduced vulnerability to the risk of HIV infection by 37% in the general population. However, this effect was stronger in urban than rural areas. Besides individual-level factors, unobserved community factors too play an important role and account for 9% of unexplained variance after individual-level factors are considered. Conclusion: Household wealth increases vulnerability but education reduces it. The social environment influences vulnerability to HIV infection independent of individual-level factors. HIV/AIDS awareness targeting sexual practices of wealthy individuals and those with primary-level educational attainment together with improving educational attainment and addressing contextual factors influencing vulnerability to HIV infection are necessary strategies to reduce HIV infections in Uganda. PMID- 29984000 TI - Effectiveness and Adverse Effect of Intravenous Lacosamide in Nonconvulsive Status Epilepticus and Acute Repetitive Seizures in Children. AB - Nonconvulsive status epilepticus (NCSE) and acute repetitive seizures (ARS) are associated with significant morbidity and mortality. Due to the lack of randomized-controlled trials of intravenous antiepileptic drugs (AEDs) in these conditions, trials of a new generation of AEDs in this aspect are needed. A prospective interventional study was conducted in children under 18 years of age with NCSE or ARS who either had contraindication to or were refractory to first line AEDs and received intravenous lacosamide. Demographic data, the efficacy of treatment, and adverse effects were recorded. Eleven patients with a median age of 11 years, predominantly female (72.7%), were enrolled. Average loading dose was 227 mg (8.3 mg/kg/dose) and average daily maintenance dose was 249 mg (4.6 mg/kg/dose). All patients (100%) experienced a reduction in seizure frequency within 24 hours. Eight of eleven patients (72.7%) experienced a reduction in seizure frequency of more than 50% by the end of the study, and one patient became seizure-free. In terms of adverse events, one patient had a bradycardia without prolongation of the PR interval. Interestingly, there was a case of neuronal ceroid lipofuscinosis in which a significant improvement in seizure control was achieved. The results indicate that intravenous lacosamide may be an alternative treatment for NCSE or ARS in children. To our knowledge, this is the first study on the use of intravenous lacosamide in Asian children. This study is registered to Thai Clinical Trials Registry (TCTR) and the trial registration number is TCTR20180508004. PMID- 29984001 TI - Expert-Performed Endotracheal Intubation-Related Complications in Trauma Patients: Incidence, Possible Risk Factors, and Outcomes in the Prehospital Setting and Emergency Department. AB - The aim of this study was to determine complication rates and possible risk factors of expert-performed endotracheal intubation (ETI) in patients with trauma, in both the prehospital setting and the emergency department. We also investigated how the occurrence of ETI-related complications affected the survival of trauma patients. This single-center retrospective observational study included all injured patients who underwent anesthesiologist-performed ETI from 2007 to 2017. ETI-related complications were defined as hypoxemia, unrecognized esophageal intubation, regurgitation, cardiac arrest, ETI failure rescued by emergency surgical airway, dental trauma, cuff leak, and mainstem bronchus intubation. Of the 537 patients included, 23.5% experienced at least one complication. Multivariable logistic regression analysis revealed that low Glasgow Coma Scale Score (adjusted odds ratio [AOR], 0.93; 95% confidence interval [CI], 0.88-0.98), elevated heart rate (AOR, 1.01; 95% CI, 1.00-1.02), and three or more ETI attempts (AOR, 15.71; 95% CI, 3.37-73.2) were independent predictors of ETI-related complications. We also found that ETI-related complications decreased the likelihood of survival of trauma patients (AOR, 0.60; 95% CI, 0.38-0.95), independently of age, male sex, Injury Severity Score, Glasgow Coma Scale Score, and off-hours presentation. Our results suggest that airway management in trauma patients carries a very high risk; this finding has implications for the practice of airway management in injured patients. PMID- 29984002 TI - Antimalarial Activity of Croton macrostachyus Stem Bark Extracts against Plasmodium berghei In Vivo. AB - There is an increasing need for innovative drug and prophylaxis discovery against malaria. The aim of the present study was to test in vivo antiplasmodial activity of Croton macrostachyus H. (Euphorbiaceae) stem bark extracts from Kenyan folkloric medicine. Inbred Balb/c mice were inoculated with erythrocytes parasitized with Plasmodium berghei (ANKA). Different doses (500, 250, and 100 mg/kg) of C. macrostachyus ethyl acetate, methanol, aqueous, and isobutanol extracts were administrated either after inoculation (Peters' 4-day suppressive test) or before inoculation (chemoprotective test) of the parasitized erythrocytes. All the extracts showed significant suppression of parasitemia compared to control (p < 0.001): for the ethyl acetate extract in the range of 58 82%, for the methanol extract in the range of 27-68%, for the aqueous extract in the range of 24-72%, and for the isobutanol extract in the range of 61-80%. Chemoprotective effect was significant (p < 0.001) and the suppression caused by the ethyl acetate extract was between 74 and 100%, by the methanol extract between 57 and 83%, and by the isobutanol extract between 86-92%. The study showed that it is possible to inhibit the growth of the parasites by various stem bark extracts of C. macrostachyus in Balb/c mice supporting the folkloric use of the plant against malaria. PMID- 29984004 TI - A Rare Case of Complete Heart Block in a Young Patient. AB - Introduction: Complete heart block (CHB) is considered as one of the dangerous rhythms since it can progress to lethal arrhythmias such as ventricular tachycardia. It can be congenital or acquired. Patients may present with frequent palpitations, presyncope, dyspnea, or chest pain but also may remain asymptomatic. Extensive work-up should be conducted to exclude secondary causes such as infections, cardiac ischemia or myopathies, autoimmune diseases, or endocrinological diseases. In our paper, we would like to present a case of CHB in the setting of aortic abdominal thrombus that nearly occluded both renal arteries. The CHB in this case is thought to be caused by hypertensive cardiomyopathy due to ongoing uncontrolled hypertension, which is caused by bilateral renal artery stenosis. Case Presentation: A 31-year-old male with history of active smoking was incidentally found to have high blood pressure, bradycardia, and CHB on electrocardiogram. The patient was admitted to a cardiology ward and extensive work-up revealed hypokinesia of the left ventricle with low ejection fraction and left ventricle concentric hypertrophy, large abdominal aortic thrombus with bilateral renal artery stenosis, and evidence of arterial collateral connections, which suggest chronicity. The patient then was placed on four antihypertensive medications but eventually, he underwent bilateral renal artery stenting and insertion of permanent pacemaker for his CHB. The patient's blood pressure then was under control with only one medication, and subsequent CT angiogram showed no evidence of stenosis of both renal arteries. Conclusion: Uncontrolled hypertension can lead to hypertensive cardiomyopathy, which in turn can cause conduction abnormalities such as CHB. Although hypertension can be secondary to a treatable underlying cause, permanent pacemaker is essential to treat CHB. PMID- 29984003 TI - Personalizing Radiation Treatment Delivery in the Management of Breast Cancer. AB - Long-term data establishes the efficacy of radiotherapy in the adjuvant management of breast cancer. New dose and fractionation schemas have evolved and are available, each with unique risks and rewards. Current efforts are ongoing to tailor radiotherapy to the unique biology of breast cancer. In this review, we discuss our efforts to personalize radiotherapy dosing using genomic data and the implications for future clinical trials. We also explore immune mechanisms that may contribute to a tumor's unique radiation sensitivity or resistance. PMID- 29984005 TI - Heat Stroke with Status Epilepticus Secondary to Posterior Reversible Encephalopathy Syndrome (PRES). AB - Heat stroke is a life threatening, multisystem disorder characterized by severe hyperthermia (core body temperature > 41.1 degrees C) with central nervous system dysfunction and/or other end organ damage. Neurological complications, such as disturbances of consciousness, convulsion, profound mental change, disorientation, or even prolonged coma, were present in almost all cases of exertional heat stroke (EHS). We present a case of EHS with severe rhabdomyolysis and acute oliguric kidney injury in a 20-year-old healthy marathon runner, who developed status epilepticus on Day 4 of his admission. The patient was managed in ICU with renal replacement therapy and aggressive seizure control. He made a full recovery after 2 weeks of ICU stay. Diagnosis of EHS with posterior reversible encephalopathy syndrome (PRES) secondary to acute kidney injury was made. PMID- 29984007 TI - Drug Hypersensitivity due to Azathioprine with Elevated Procalcitonin. AB - We present a case of azathioprine hypersensitivity presenting as sepsis with elevated procalcitonin in a 68-year-old man with myasthenia gravis. The patient presented with fever, chills, nausea, vomiting, and headache. He developed numerous 1 cm erythematous papules over his upper torso. Infectious workup including bacteriological tests and microbial cultures was negative and a skin biopsy was performed which revealed suppurative folliculitis with eosinophils, consistent with drug hypersensitivity. Notably, acute phase reactants including C reactive protein and procalcitonin were elevated upon presentation, likely secondary to drug hypersensitivity. PMID- 29984006 TI - Severe Progressive Diffuse Alveolar Hemorrhage in a Patient with Systemic Lupus Erythematosus. AB - Diffuse alveolar hemorrhage (DAH) refers to the effusion of blood into the alveoli due to damaged pulmonary microvasculature. The ensuing alveolar collapse can lead to severe hypoxemia with poor prognosis. In these cases, it is crucial to provide respiratory care for hypoxemia in addition to treating the underlying disease. Here, we describe our experience with a case involving a 46-year-old woman with severe DAH-induced hypoxemia accompanying systemic lupus erythematosus (SLE). Mechanical ventilation was managed using airway pressure release ventilation (APRV) after intubation. Through APRV-based respiratory care and treatment of the underlying disease, hemoptysis was eliminated and oxygenation improved. The patient did not experience significant barotrauma and was successfully weaned from mechanical ventilation after 25 days in the intensive care unit. This case demonstrates that APRV-based control for respiratory management can inhibit the effusion of blood into the alveoli and achieve mechanical hemostasis, as well as mitigate alveolar collapse. APRV may be a useful method for respiratory care in patients with severe DAH-induced hypoxemia. PMID- 29984008 TI - Asymmetric Bilateral Lichen Striatus: A Rare Presentation following Multiple Blaschko's Lines. AB - Lichen striatus (LS) is an uncommon, acquired, self-limited, and benign linear dermatosis of unknown etiology that most often occurs unilaterally and is confined to the lines of Blaschko. A healthy 7-year-old girl presented to our clinic with bilateral asymmetric LS occurring on the right arm and left leg of 1 year duration. Very few cases of bilateral LS have been previously reported in the literature, with none from clinics within the United States. The etiology of LS is currently unknown; however its confinement to Blaschko's lines, which represent embryologic migration of skin cell clones, does provide insight into a possible pathogenesis. It seems most likely that an individual's development of LS is linked to their genetic predisposition and a subsequent triggering event. Our case serves as a strong example of a rare presentation of LS and facilitates discussion of the clinical diagnostic process and possible pathogenesis of this dermatosis. PMID- 29984009 TI - Cycling Induced Spontaneous Coronary Artery Dissection in a Healthy Male. AB - Introduction: Spontaneous coronary artery dissection (SCAD) is a rare but important cause of acute coronary syndrome with a spectrum of disease that can include unstable angina, acute myocardial infarction, or sudden cardiac death. It has also been found in case reports to be caused by shear stress from physical exertion. We present a rare cycling induced SCAD that occurred in our institution in an otherwise healthy male with no cardiac risk factors. Case Presentation: A 36-year-old male presented to the emergency department with complaints of lightheadedness and diaphoresis after a bicycle fall. In the emergency department, he complained of feeling lightheaded and diaphoretic and having mid back pain. Patient had an ECG performed which showed lateral ST segment elevation and troponin I that was positive. A coronary angiography was subsequently performed demonstrating a spontaneous coronary artery dissection of left anterior descending coronary artery. Conclusion: SCAD is a rare cause of myocardial infarction, occurring in healthy individuals, which is rarely reported in the literature. Nearly 70% are diagnosed in postmortem studies after sudden cardiac death. Only 12 cases have been reported from activities involving physical exertion and no studies to our knowledge demonstrate this. PMID- 29984010 TI - Graves' Disease Presenting with Periodic Paralysis to the Emergency Department. AB - Thyrotoxic periodic paralysis is an infrequent manifestation of hyperthyroidism and an uncommon cause of muscle weakness in western countries. The diagnosis should be considered in the differential when a patient presents with transient and recurrent weakness associated with hypokalaemia. We present a case of a 26 year-old Asian male presenting with sudden onset muscle weakness affecting predominantly his lower limbs on a background of weight loss. Physical examination demonstrated symmetrical proximal muscle weakness with normal sensation and reflexes. Initial biochemical investigations revealed hypokalaemia, hypomagnesaemia, and hyperthyroidism. Intravenous electrolyte replacement was administered in the emergency department. The patient's symptoms resolved during inpatient admission. Subsequent TSH receptor antibody testing and radionuclide thyroid scan confirmed a diagnosis of Graves' disease. The patient was discharged on antithyroid medication with no further episodes of weakness on follow-up. Therefore, thyrotoxic periodic paralysis can be the presenting feature of previously undiagnosed Graves' disease and should be considered in the differential diagnosis in patients presenting with weakness. PMID- 29984011 TI - Dental Impaction in the Cecum: Case Report and Review of Gastrointestinal Foreign Body Impactions. AB - Approximately 20% of the adult population in the United States wears dentures. Foreign body ingestions, including dentures, are not uncommon. Although the majority of all ingested foreign bodies pass spontaneously through the gastrointestinal tract, impaction may occur, especially with physiologic constrictions, angulations, or stenosis. The esophagus is the most common site of impaction, whereas colonic impaction is extremely uncommon. We present a case of an 84-year-old male who was referred to the gastroenterology clinic for denture impaction, which lasted for two weeks. The patient had already failed to pass the denture following conservative treatment with laxatives, and repeated abdominal imaging showed the dental plate in the cecum. Colonoscopy was performed three weeks after the ingestion of his dentures, and tripod forceps were used to dislodge the end of the dental plate and ultimately remove it. The patient was asymptomatic for the entire period. PMID- 29984012 TI - Obstructive Giant Inflammatory Polyposis: Is It Related to the Severity or the Duration of the Inflammatory Bowel Disease? Two Case Reports. AB - We report two cases of giant inflammatory polyposis (GIP) with totally different presentation and evolution. The first patient had two giant pseudopolyps after one year of the diagnosis of UC. The second patient had one obstructive giant pseudopolyp secondary to CD at the level of the transverse colon, being totally asymptomatic years before the presentation. GIP is a rare complication of inflammatory bowel disease (IBD). It consists of numerous filiform polyps that look like a "mass of worms" or a "fungating" mass. Surgical resection is inevitable when GIP presents with obstructive symptoms. PMID- 29984013 TI - Indocyanine-Green Fluorescence-GUIDED Liver Resection of Metastasis from Squamous Cell Carcinoma Invading the Biliary Tree. AB - Background. The concept of fluorescence-guided navigation surgery based on indocyanine green (ICG) is a developing interest in many fields of surgical oncology. The technique seems to be promising also during hepatic resection. Case Presentation. We reported our experience of ICG-fluorescence-guided liver resection of metastasis located at VIII Couinaud's segment from colon squamous cell carcinoma of a 74-year-old male patient. Results. After laparotomy, the fluorescing tumour has been clearly identified on the liver surface. We have also identified that a large area of fluorescent parenchyma that gets from the peripheral of the lesion up to the portal pedicle such as the neoplasia would interest the right biliary tree in the form of neoplastic lymphangitis. This datum was not preoperatively known. Conclusion. Fluorescent imaging navigation liver resection could be a feasible and safe technique helpful in identifying additional characteristics of lesion. It could be a powerful tool but further studies are required. PMID- 29984014 TI - Endoscopic Ultrasound-Guided Hepaticogastrostomy Is Effective for Repeated Recurrent Cholangitis after Surgery: Two Case Reports. AB - We report the cases of two patients who underwent endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) using metallic stents (MS) for recurrent cholangitis due to benign biliary stenosis. The patients had repeatedly undergone double-balloon endoscopy and anastomotic stenosis. Thus, EUS-HGS was performed. The procedures were successful, and placement of a covered metallic stent (C-MS) relieved cholangitis. The occurrence of cholangitis was subsequently considerably reduced. For patients with postoperative recurrent cholangitis, EUS-HGS with MS should be considered because of its efficacy and safety. PMID- 29984015 TI - Bradycardia during Induction Therapy with All-trans Retinoic Acid in Patients with Acute Promyelocytic Leukemia: Case Report and Literature Review. AB - A 41-year-old man with newly diagnosed acute promyelocytic leukemia (APL) received induction chemotherapy, containing all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide. On the 11th day of therapy, he experienced complete atrioventricular (AV) block; therefore, ATRA and arsenic trioxide were immediately postponed. His heart rate partially recovered, and ATRA was rechallenged with a half dose. However, complete AV block as well as differentiation syndrome recurred on the next day. ATRA was immediately discontinued, and a temporary pacemaker was inserted. Two days after discontinuing ATRA, AV block gradually improved, and ATRA was uneventfully rechallenged again. The Naranjo adverse drug reaction probability scale was 7 for ATRA, suggesting it was the probable cause of arrhythmia. A literature search identified 6 other cases of bradycardia during ATRA therapy, and all of them occurred during APL induction therapy, with onset ranging from 4 days to 25 days. Therefore, monitoring vital signs and performing electrocardiogram are highly recommended during the first month of induction therapy with ATRA. ATRA should be discontinued if complete AV block occurs. Rechallenging with ATRA can be considered in fully recovered and clinically stable patients. PMID- 29984016 TI - Melkersson-Rosenthal Syndrome: A Rare Cause of Recurrent Facial Nerve Palsy and Acute Respiratory Distress Syndrome. AB - Melkersson-Rosenthal Syndrome (MRS) is a rare disease characterized by persistent or recurrent orofacial oedema, relapsing peripheral facial paralysis, and furrowed tongue. Pathologically, granulomatosis is responsible for oedema of face, labia, oral cavity, and facial nerve. We present a patient with MRS admitted to our hospital with acute respiratory distress syndrome (ARDS). 45-year old woman was admitted to an emergency department with dyspnea and swelling on her hands and face. She was intubated because of ARDS and accepted to intensive care unit (ICU). After weaning from ventilatory support, peripheral facial paralysis was diagnosed and steroid treatment was added to her therapy. On dermatologic examination, oedema on her face, pustular lesions on her skin, and fissure on her tongue were detected. The patient informed us about her recurrent and spontaneous facial paralysis in previous years. According to her history and clinical findings, MRS was diagnosed. PMID- 29984017 TI - Never Too Old? Occurrence of Medulloblastoma in the Elderly beyond the 70th Year of Life. AB - The occurrence of medulloblastoma (MB) in the elderly is an absolutely rare event. Concerning this issue we report on two MB patients beyond the 70th year of life. Two patients older than 70 years presented with a mass in the posterior fossa without evidence of a preexisting malignant tumor. After careful radiological work-up the suspected diagnosis was metastasis of an unknown primary tumor. Both patients underwent surgery and histopathological analysis revealed MB in both cases (classical MB and desmoplastic type). The two cases presented here represent also one classical MB and one additional desmoplastic MB. To our knowledge we report for the first time that there are different molecular subtypes of MB in the elderly patients that seem to be consistent with those subtypes mainly occurring in young adults. Unfortunately the patients died within one week after surgery due to respiratory insufficiency and an unclear cause. The presented cases show that MB can occur in the elderly. Although this constellation is absolutely rare, MB should be considered in the differential diagnosis, especially when a primary tumor is not known or detected. PMID- 29984019 TI - Optical Coherence Tomography Angiography. PMID- 29984018 TI - The Rising Triad of Cesarean Scar Pregnancy, Placenta Percreta, and Uterine Rupture: A Case Report and Comprehensive Review of the Literature. AB - As the rate of cesarean sections continues to rapidly rise, knowledge of diagnosis and management of cesarean scar pregnancies (CSPs) is becoming increasingly more relevant. CSPs rest on the continuum of placental abnormalities which include morbidly adherent placenta (accreta, increta, and percreta). A CSP poses a clinical challenge which may have significant fetal and maternal morbidity. At this point, no clear management guidelines and recommendations exist. Herein we describe the case of a second trimester CSP with rapid diagnosis and management in a tertiary care center. The case underscores the need for well coordinated mobilization of resources and a multidisciplinary approach. A review of the literature is performed and deficits in universal management principles are underscored. PMID- 29984020 TI - Open Fracture of the Acromion: An Isolated Injury with Oblique-Type Fracture. AB - Open acromial fractures are a rare set of fractures. We report a case of Gustilo IIIA open acromial fracture (14A2 as per OTA scapular fracture classification) that was isolated from any other injury. Our patient had a good recovery and showed excellent clinical outcome after irrigation and screw fixation of the acromial fracture. We also reviewed the literature for other cases of open acromial fracture. PMID- 29984021 TI - Tibia Adamantinoma Resection and Reconstruction with a Custom-Made Total Tibia Endoprosthesis: A Case Report with 8-Year Follow-Up. AB - This case study describes a total tibia resection and reconstruction with a custom-made endoprosthetic replacement (EPR) and a long-term, 8-year follow-up. The patient underwent a total tibia adamantinoma resection in 2009. Reconstruction was performed with a custom-made total tibia EPR, where both the knee joint and ankle joint were reconstructed. Two muscle flaps, latissimus dorsi free flap and a pedicled medial gastrocnemius flap, were used for soft tissue reconstruction. The patient returned to normal life as a kindergarten teacher, without complications for eight years. This case demonstrated the importance of successful multidisciplinary teamwork in close collaboration with industry. In our best knowledge, no over 2 years of follow-up of total tibia replacement reports have been published. PMID- 29984022 TI - Massive Acromioclavicular Joint Cyst with Intramuscular Extension: Case Report and Review. AB - Acromioclavicular cysts are an uncommon manifestation secondary to a massive rotator cuff tear and/or a degenerative osteoarthritic AC joint. We present a case of an 80-year-old female with a symptomatic acromioclavicular cyst that extended intramuscularly into the trapezius. She did not complain of symptoms associated with a massive rotator cuff tear; however, the cyst has been increasing in size and she was interested in having it removed. Intraoperatively, the mass extended into the trapezius muscle and was removed en bloc after dissecting it down to the stalk. A distal clavicle excision was then performed using an oscillating saw. After the cyst was excised, it was incised revealing thick mucoid content. The patient did well postoperatively at the three-month follow-up without signs of recurrence. To our knowledge, this is the first case of AC joint cyst with intramuscular extension that was managed operatively. PMID- 29984023 TI - Utilizing a Cortical Bone Trajectory Pedicle Screw for Lumbar Flexion-Distraction Injury. AB - Spinal flexion-distraction injuries (FDIs) are unstable fractures, commonly located at the thoracolumbar junction. Management of FDIs often necessitates the use of posterior instrumentation and fusion, but long-segment instrumentation surgery decreases postoperative spinal mobility and increases the risk of junctional kyphosis and fracture. We report the case of a patient with FDI showing an L2 vertebral fracture, unilateral L2 pedicle fracture, and disruptions of the posterior ligamentous complex between L1 and L2. After open reduction using L1 and L2 pedicle screws with a conventional trajectory on the right side, a cortical bone trajectory (CBT) pedicle screw was used as an osteosynthesis screw for the fractured left pedicle. This procedure enabled successful single level fusion. Follow-up radiological examination revealed good reduction and complete bone union. To the best of our knowledge, utilizing a CBT technique as an osteosynthesis screw in FDIs has not previously been described. PMID- 29984024 TI - Subscapular Abscess Caused by Panton-Valentine Leukocidin-Positive Staphylococcus aureus: An Atypical Presentation. AB - Subscapular abscess is an uncommon condition which requires early recognition followed by prompt surgical intervention. We present a case of spontaneous subscapular abscess following blunt trauma to the shoulder in a patient with a history of recurrent superficial soft tissue infections, in which Panton Valentine leukocidin-producing S. aureus was identified as the infectious agent. This strain due to its virulence can lead to fatal infections in otherwise healthy individuals; therefore, a high index of suspicion is needed to investigate with an MRI to rule out abscess formation in a patient with acute shoulder girdle pain and negative joint aspirate. Urgent surgical intervention and targeted antimicrobial therapy against PVL-positive S. aureus in accordance with microbiologist yield good outcomes. PMID- 29984025 TI - Septic Infrapatellar Bursitis in an Immunocompromised Female. AB - Bursitis is a relatively common occurrence that may be caused by traumatic, inflammatory, or infectious processes. Septic bursitis most commonly affects the olecranon and prepatellar bursae. Staphylococcus aureus accounts for 80% of all septic bursitis, and most cases affect men and are associated with preceding trauma. We present a case of an 86-year-old female with an atypical septic bursitis involving the infrapatellar bursa. Not only are there very few reported cases of septic infrapatellar bursitis, but also this patient's case is particularly unusual in that she is a female with no preceding trauma who had Pseudomonas aeruginosa on aspirate. The case also highlights the diagnostic workup of septic bursitis through imaging modalities and aspiration. This patient had full resolution of her septic bursitis with appropriate IV antibiotics. PMID- 29984026 TI - Head and Neck Myxoma Presenting as Isolated Laryngeal Polyp. AB - Myxoma is a benign tumour with a propensity for local infiltration and recurrence. Laryngeal myxoma presents as a submucosal polyp. Being an uncommon tumour and mimicking vocal cord polyp, only anecdotal evidence is available in the literature. The literature was reviewed from 1986 onwards using the keywords "myxoma" and "larynx." The databases used were PubMed, Google Scholar, Scopus, and Web of Science. Along with this, we also report our case of vocal fold myxoma. We found a total of 19 studies reporting laryngeal myxoma. Laryngeal myxoma typically affects males in the 6th decade with a history of smoking. Unlike myxomas originating outside the larynx, recurrence is not widely described, and microlaryngeal surgery will usually suffice. Laryngeal myxomas should definitely be kept in the list of differential diagnosis when dealing with a benign-looking vocal fold lesion. PMID- 29984027 TI - Diffuse Neurofibroma in a Patient with Unknown History of NF1. AB - Malignant peripheral nerve sheath tumor (MPNST) is a rare disease in the parotid gland with a poor prognosis in most cases. The disease most often develops in the setting of neurofibromatosis type 1 (NF1) but can also occur sporadically. Herein, we report a rare case of MPNST in the parotid gland, in a patient with no previous history of NF1. Initial investigations of the patient, which consisted of laboratory investigations, ultrasound imaging of the swelling, fine-needle aspiration (FNA), computed tomography (CT) scan, and magnetic resonance imaging (MRI) of the neck and swelling, were compatible with a benign pleomorphic adenoma of the parotid gland. However, intraoperatively, the dissection was challenging as the tumor was adherent to the neighboring tissue. A diagnosis of MPNST arising from a diffuse neurofibroma was established based on clinicopathologic features of the disease. The patient, who exhibited clinical features compatible with (NF1), proceeded for radiotherapy following surgery to continue his treatment. PMID- 29984028 TI - Intracardiac Teratoma in an Infant: Report of a New Case and Literature Review. AB - Primitive intracardiac tumours are rare, especially in childhood, and are often discovered on autopsy. The intracardiac teratoma is the rarest intracardiac tumours of childhood. Herein, we report the case of an 11-month-old infant, which featured recurrent bronchoalveolitis since the age of 3 months, with a thoracic deformation. Physical examination did found discrete respiratory distress signs. Chest radiography showed large mediastinal enlargement. The computed tomography showed a solid cystic-cloisonned mass with fat and central calcification highly suggestive of an intracardiac teratoma. A radical surgical excision was made and the histological examination found a well circumscribed tumour containing elements of the three germ layers confirming the diagnosis of mature well differentiated teratoma, with no need of immunohistochemical support. PMID- 29984029 TI - Misinterpretation of Psychiatric Illness in Deaf Patients: Two Case Reports. AB - The Deaf/hard of hearing population is growing rapidly and the medical community is facing a higher demand for this special needs group. The Deaf culture is unique in that spoken word is via sign language. What one person may see as mania or psychosis is actually a norm with Deaf individuals. The fear of the unknown language often creates immediate conclusions that are false. As such, being culturally sensitive becomes a large component of properly assessing a Deaf patient in any psychiatric situation. In the first case, the patient is a 26-year old prelingually Deaf male, who was placed under an involuntary hold by the emergency room physician for acting erratic and appearing to respond to internal stimuli. The patient was later interviewed with an interpreter and stated he became upset because the staff was not providing him proper care as they lacked an ability to communicate with him. The patient's family was called who corroborated the story and requested he be discharged. Case two presents with a 30-year-old Hispanic male who is also prelingually Deaf. He was admitted involuntary for bizarre behavior and delusions, with a past diagnosis of schizophrenia. Upon interview, the patient endorsed delusions via written language; however, through an ASL-language interpreter he was able to convey a linear and coherent thought process. Caring for special needs patients must be in the repertoire of any trained healthcare professional. Deaf Individuals experience mental illness just like the general population. Symptoms such as auditory hallucinations are not brought up in the same manner and are thought to be a visual construct interpreted by the patient as a vocal expression. It is imperative that these subtle differences are known in order to differentiate out an actual mental illness. In any case where language is a barrier, an interpreter must be present for a thorough assessment. These cases lend further thought into policy reform for Deaf individuals within healthcare. PMID- 29984030 TI - Pervasive Refusal Syndrome in Autistic Spectrum Disorder. AB - Pervasive Refusal Syndrome (PRS) is a rare child psychiatric condition. We describe a case of PRS in a 9-year-old boy with a diagnosis of Autism Spectrum Disorder (ASD) presenting with severe weight loss due to extreme restriction of food and fluids. Other prominent symptoms included total mutism, school refusal, and self-neglect. He was admitted to a specialist Child and Adolescent Mental Health Unit. We discuss the symptoms present in this case and the differential diagnosis of ASD in PRS. Although this differential has briefly been considered one in previous case, there have been no reported cases of PRS with a prior diagnosis of ASD. We explore comorbidity and interaction of the two diagnoses. We discuss the possible impact of ASD as a predisposing factor upon the progression and prognosis of PRS. PMID- 29984031 TI - Diffuse Alveolar Hemorrhage Induced by Vaping. AB - There has been a significant increase in electronic cigarette (e-cigarette) use since its introduction in 2007. Ironically, there remains very few published literature on the respiratory complications of e-cigarettes. The use of personalized vaporizers or commonly known as "vaping" has started to overtake standard e-cigarette. Its dynamic vaporizer customization makes it challenging to assess long-term health effects. Case reports on the pulmonary complications of e cigarettes are limited to bronchiectasis, eosinophilic pneumonia, pleural effusion, and suspected hypersensitivity pneumonitis. Diffuse alveolar hemorrhage (DAH) is bleeding into the alveolar spaces of the lung secondary to disruption of the alveolar-capillary basement membrane. We report a case of young male presenting with subacute respiratory failure. He was later found to have diffuse alveolar hemorrhage syndrome that is likely induced by aggressive vaping. This adds up to the rising concern on the possible serious complications of this innovative technology designed as a safer alternative to traditional cigarettes. PMID- 29984032 TI - Sarcoid of the Upper Humerus Found Incidentally on MR Images Obtained for Work-Up of Rotator Cuff Tear Where Compromised Tissue Quality Was a Concern for Surgical Success. AB - Sarcoidosis is an idiopathic systemic inflammatory disorder characterized histologically by noncaseating granulomas. The pathogenesis likely includes genetic, immunologic, and environmental factors. The lungs, skin, and eyes are most commonly affected. Although bone involvement is possible, sarcoidosis of the humerus is rare, with few cases reported. Furthermore, we are unaware of any reports of sarcoidosis of the upper humerus with a coexisting rotator cuff tear. We report the case of a 50-year-old female with sarcoidosis of the humerus and a coexisting tear of the supraspinatus tendon. Her medical history includes type 2 diabetes, depression, and fatigue. She had chronic shoulder pain that worsened after her dog jerked on the leash. Radiographs were grossly normal. Subsequent magnetic resonance imaging (MRI) demonstrated a possible small full-thickness rotator cuff tear. Multiple rounded lesions were also noted within the proximal humerus. A biopsy demonstrated noncaseating granulomas, confirming the diagnosis of sarcoidosis. There was concern that her sarcoid lesions would compromise bone quality, limiting options for surgical repair of her rotator cuff tear. However, it was determined that her lesion did not involve cortical bone, and surgery was performed. During surgery, the supraspinatus tendon was found to be partially torn and was treated with arthroscopic debridement and acromioplasty. An excellent result was ultimately achieved after her rheumatologist started adalimumab injections. This case demonstrates that there can be a rare incidental finding of osseous sarcoid lesions in the upper humerus where the bone might be compromised in the location of a planned rotator cuff repair. PMID- 29984033 TI - A Rare Adrenal Incidentaloma That Mimics Adrenocortical Carcinoma. AB - Objective: We present a case of an adrenal hemangioma, an uncommon cause of an adrenal mass, and review the clinical presentation, work-up, and management of adrenal incidentalomas. Background: A 64-year-old male was found to have a right adrenal incidentaloma during work-up for elevated liver transaminase levels, later found to be from hepatitis C. The mass was suspicious for adrenocortical carcinoma on CT imaging. Biochemical evaluation revealed no evidence of function. He underwent an open right adrenalectomy. The mass was found to be an adrenal hemangioma on histopathologic analysis. Methods: This is a case report with pertinent review of the diagnosis and management of adrenal incidentalomas. Results: Adrenal hemangiomas are rare, benign, nonfunctional tumors typically found during imaging for other reasons. As illustrated by this case, they appear similar to adrenocortical carcinoma on CT imaging. The diagnosis is usually not made prior to surgical resection. Conclusion: Adrenal hemangioma is a rare nonfunctional adrenal incidentaloma that displays atypical features on CT imaging. The suspicion for adrenocortical carcinoma usually prompts adrenalectomy. PMID- 29984034 TI - Acute Diffuse Peritonitis Caused by Urinary Retention: A Rare Case of Gangrenous Cystitis. AB - Gangrenous cystitis is an umbrella term encompassing conditions from necrosis of the mucosa and submucosa to necrosis of the entire bladder wall that can result in acute peritonitis. Timely diagnosis is challenging as the symptoms are nonspecific and resemble other conditions such as cystitis. We report a case of gangrenous cystitis in a 63-year-old woman who was diagnosed with peritonitis preoperatively by a CT scan of the abdomen. Overdistension of the bladder due to chronic urinary retention was the primary cause. The patient underwent partial cystectomy, excising nonviable detrusor with preservation of the trigone and ureters, but conclusively succumbed. Etiopathology, symptoms, and treatment of this rare disease are also considered. PMID- 29984035 TI - Traumatic Penetrating Neck Injury with Right Common Carotid Artery Dissection and Stenosis Effectively Managed with Stenting: A Case Report and Review of the Literature. AB - Introduction: Penetrating neck injuries (PNI) are common and associated with arterial and other neuronal injuries. Although many authors have written on penetrating and blunt carotid artery injuries as a result of PNI or traumatic neck injuries, no one has reported a case or case series on PNI that resulted in blunt carotid dissection and stenosis. Case Presentation: We present a case of 40 year-old building and construction male worker who slipped and fell on an iron rod that resulted in penetrating wound on the right side of the anterior neck a week prior to presenting at our facility. He pulled out the iron rod immediately. Computer tomography angiography (CTA) done revealed C2-C4 transverse process fractures on the right side and a fracture at the right lamina of C3 and right common carotid artery dissection with stenosis. He was successfully treated with stenting via endovascular approach. Conclusions: We adopt the view that patient should never pull out objects that result in PNI because of complex neurovascular architecture of the neck. The mortality rate of our patient will have doubled if the iron rode penetrated the common carotid artery. The gold standard treatment option for carotid artery dissection and stenosis is endovascular approaches. PMID- 29984036 TI - Inhibition of Mast Cell Function and Proliferation by mTOR Activator MHY1485. AB - Mast cells integrate innate and adaptive immunity and are implicated in pathophysiological conditions, including allergy, asthma, and anaphylaxis. Cross linking of the high-affinity IgE receptor (FcepsilonRI) initiates diverse signal transduction pathways and induces release of proinflammatory mediators by mast cells. In this study, we demonstrated that hyperactivation of mechanistic target of rapamycin (mTOR) signaling using the mTOR activator MHY1485 suppresses FcepsilonRI-mediated mast cell degranulation and cytokine secretion. MHY1485 treatment increased ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation, which are downstream targets of mTOR complex 1 (mTORC1), but decreased phosphorylation of Akt on mTOR complex 2 (mTORC2) target site serine 473. In addition, this activator decreased beta-hexosaminidase, IL-6, and tumor necrosis factor alpha (TNF-alpha) release in murine bone marrow-derived mast cells (BMMCs) after FcepsilonRI stimulation. Furthermore, MHY1485-treated BMMCs showed significantly decreased proliferation when cultured with IL-3. These findings suggested hyperactivation of mTORC1 as a therapeutic strategy for mast cell-related diseases. PMID- 29984038 TI - Role of IL-32 Gamma on Bone Metabolism in Autoimmune Arthritis. AB - IL-32 acts as a pro-inflammatory cytokine by inducing the synthesis of inflammatory molecules as well as promoting the morphological changes involved in the transformation of monocytes into osteoclasts (OCs). Evaluation of the functions of IL-32 has mainly focused on its inflammatory properties, such as involvement in the pathogenesis of various autoimmune diseases. Recently, IL-32 was shown to be involved in bone metabolism, in which it promotes the differentiation and activation of OCs and plays a key role in bone resorption in inflammatory conditions. IL-32gamma also regulates bone formation in conditions such as ankylosing spondylitis and osteoporosis. In this review, we summarize the results of recent studies on the role of IL-32gamma in bone metabolism in inflammatory arthritis. PMID- 29984037 TI - L1 Recombinant Proteins of HPV Tested for Antibody Forming Using Sera of HPV Quadrivalent Vaccine. AB - Virus-like particles (VLPs) derived from human papillomavirus (HPV) L1 capsid proteins were used for HPV quadrivalent recombinant vaccine. The HPV quadrivalent vaccine is administrated in a 3-dose regimen of initial injection followed by subsequent doses at 2 and 6 months to prevent cervical cancer, vulvar, and vaginal cancers. The type 6, 11, 16, or 18 of HPV infection is associated with precancerous lesions and genital warts in adolescents and young women. The HPV vaccine is composed of viral L1 capsid proteins are produced in eukaryotic expression systems and purified in the form of VLPs. Four different the L1 protein of 3 different subtypes of HPV: HPV11, HPV16, and HPV18 were expressed in Escherichia coli divided into 2 fragments as N- and C-terminal of each protein in order to examine the efficacy of HPV vaccine. Vaccinated sera failed to recognize N-terminal L1 HPV type 16 and type 18 by western blot while they detected N terminal L1 protein of HPV type 11. Moreover, the recombinant C-terminal L1 proteins of type 16 was non-specifically recognized by the secondary antibody conjugated with horseradish peroxidase. This expression and purification system may provide simple method to obtain robust recombinant L1 protein of HPV subtypes to improve biochemical analysis of antigens with immunized sera. PMID- 29984039 TI - N-terminal Domain of the Spike Protein of Porcine Epidemic Diarrhea Virus as a New Candidate Molecule for a Mucosal Vaccine. AB - Porcine epidemic diarrhea virus (PEDV) is a contagious coronavirus infecting pigs that leads to significant economic losses in the swine industry. Given that PEDV infection occurs in gut epithelial cells mainly via the fecal-oral route, induction of PEDV-specific immune responses in the mucosal compartment is required for protective immunity against viral infection. However, an effective mucosal vaccine against the currently prevalent PEDV strain is not available. In this study, we demonstrated that the N-terminal domain (NTD) of the spike (S) protein of PEDV represents a new vaccine candidate molecule to be applied via the mucosal route. We first established an Escherichia coli expression system producing the partial NTD (NTD231-501) of the PEDV S protein. Orally administered NTD231-501 protein specifically interacted with the apical area of M cells in the follicle-associated epithelium of Peyer's patch. Additionally, the NTD protein induced antigen-specific immune responses in both the systemic and mucosal immune compartments when administered orally. Collectively, we propose the NTD of the PEDV S protein to be a candidate mucosal vaccine molecule. PMID- 29984041 TI - Association of Chemokines and Chemokine Receptor Expression with Monocytic Myeloid-Derived Suppressor Cells during Tumor Progression. AB - Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells that show increased expression in cancer patients; however, the molecular mechanisms underlying their generation and function are unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer (BC), the presence and relevance of monocytic (Mo)-MDSCs are unknown. Here, we report for the first time increased chemokine and chemokine receptor production by Mo MDSCs in BC patients. A clear population of Mo-MDSCs with the typical cell surface phenotype (human leukocyte antigen-antigen D related [HLA-DR]low/- CD11b+ CD33+ CD14+) increased significantly during disease progression. In addition, the chemokine receptor expression level on Mo-MDSCs in patients with invasive BC was the highest. Furthermore, different chemokine receptor expression patterns were noted in Mo-MDSCs between healthy controls (HC) and BC patients. Additionally, CD4 T cells proliferations were significantly decreased in the invasive BC groups compared with the HC group. However, the ductal carcinoma in situ (DCIS) group had no significantly compared with the HC group. Our data suggest that monitoring chemokine and chemokine receptor production by Mo-MDSCs may represent a novel and simple biomarker for assessing disease progression in BC patients. PMID- 29984043 TI - Our take on 2018 Journal Citation Reports. PMID- 29984040 TI - Epidemiologic Evidence of and Potential Mechanisms by Which Second-Hand Smoke Causes Predisposition to Latent and Active Tuberculosis. AB - Many studies have linked cigarette smoke (CS) exposure and tuberculosis (TB) infection and disease although much fewer have studied second-hand smoke (SHS) exposure. Our goal is to review the epidemiologic link between SHS and TB as well as to summarize the effects SHS and direct CS on various immune cells relevant for TB. PubMed searches were performed using the key words "tuberculosis" with "cigarette," "tobacco," or "second-hand smoke." The bibliography of relevant papers were examined for additional relevant publications. Relatively few studies associate SHS exposure with TB infection and active disease. Both SHS and direct CS can alter various components of host immunity resulting in increased vulnerability to TB. While the epidemiologic link of these 2 health maladies is robust, more definitive, mechanistic studies are required to prove that SHS and direct CS actually cause increased susceptibility to TB. PMID- 29984045 TI - Oral tissue response to soft tissue expanders prior to bone augmentation: in vitro analysis and histological study in dogs. AB - Purpose: To determine whether the swelling and mechanical properties of osmotic self-inflating expanders allow or not the induction of intraoral soft tissue expansion in dogs. Methods: Three different volumes (0.15, 0.25, and 0.42 mL; referred to respectively as the S , M , and L groups) of soft tissue expanders (STEs) consisting of a hydrogel core coated with a silicone-perforated membrane were investigated in vitro to assess their swelling behavior (volume swelling ratio) and mechanical properties (tensile strength, tensile strain). For in vivo investigations, the STEs were subperiosteally inserted for 4 weeks in dogs (n=5). Soft tissue expansion was clinically monitored. Histological analyses included the examination of alveolar bone underneath the expanders and thickness measurements of the surrounding fibrous capsule. Results: The volume swelling ratio of all STEs did not exceed 5.2. In tensile mode, the highest mean strain was registered for the L group (98.03+/-0.3 g/cm), whereas the lowest mean value was obtained in the S group (81.3+/-0.1 g/cm), which was a statistically significant difference (P<0.05). In addition, the S and L groups were significantly different in terms of tensile strength (1.5+/-0.1 g/cm for the S group and 2.2+/-0.1 g/cm for the L group, P<0.05). Clinical monitoring showed successful dilatation of the soft tissues without signs of inflammation up to 28 days. The STEs remained volumetrically stable, with a mean diameter in vivo of 6.98 mm, close to the in vitro post-expansion findings (6.69 mm). Significant histological effects included highly vascularized collagen-rich fibrous encapsulation of the STEs, with a mean thickness of 0.67+/-0.12 mm. The bone reaction consisted of resorption underneath the STEs, while apposition was observed at their edges. Conclusions: The swelling and mechanical properties of the STEs enabled clinically successful soft tissue expansion. A tissue reaction consisting of fibrous capsule formation and bone loss were the main histological events. PMID- 29984042 TI - Dual Effect of Hepatic Macrophages on Liver Ischemia and Reperfusion Injury during Liver Transplantation. AB - Ischemia-reperfusion injury (IRI) is a major complication in liver transplantation (LT) and it is closely related to the recovery of grafts' function. Researches has verified that both innate and adaptive immune system are involved in the development of IRI and Kupffer cell (KC), the resident macrophages in the liver, play a pivotal role both in triggering and sustaining the sterile inflammation. Damage-associated molecular patterns (DAMPs), released by the initial dead cell because of the ischemia insult, firstly activate the KC through pattern recognition receptors (PRRs) such as toll-like receptors. Activated KCs is the dominant players in the IRI as it can secret various pro inflammatory cytokines to exacerbate the injury and recruit other types of immune cells from the circulation. On the other hand, KCs can also serve in a contrary way to ameliorate IRI by upregulating the anti-inflammatory factors. Moreover, new standpoint has been put forward that KCs and macrophages from the circulation may function in different way to influence the inflammation. Managements towards KCs are expected to be the effective way to improve the IRI. PMID- 29984044 TI - The effects of ozone therapy as an adjunct to the surgical treatment of peri implantitis. AB - Purpose: The decontamination procedure is a challenging aspect of surgical regenerative therapy (SRT) of peri-implantitis that affects its success. The purpose of the present study was to determine the impact of additional topical gaseous ozone therapy on the decontamination of implant surfaces in SRT of peri implantitis. Methods: A total of 41 patients (22 males, 19 females; mean age, 53.55+/-8.98 years) with moderate or advanced peri-implantitis were randomly allocated to the test group (ozone group) with the use of sterile saline with additional ozone therapy or the control group with sterile saline alone for decontamination of the implant surfaces in SRT of peri-implantitis. Clinical and radiographic outcomes were evaluated over a period of 12 months. Results: At the 12-month follow-up, the plaque and gingival index values were significantly better in the ozone group (P<0.05). Probing depth decreased from 6.27+/-1.42 mm and 5.73+/-1.11 mm at baseline to 2.75+/-0.7 mm and 3.34+/-0.85 mm at the end of the 12-month observation period in the ozone and control groups, respectively. Similarly, the clinical attachment level values changed from 6.39+/-1.23 mm and 5.89+/-1.23 mm at baseline to 3.23+/-1.24 mm and 3.91+/-1.36 mm at the 12-month follow-up in the ozone and control groups, respectively. According to the radiographic evidence, the defect fill between baseline and 12 months postoperatively was 2.32+/-1.28 mm in the ozone group and 1.17+/-0.77 mm in the control group, which was a statistically significant between-group difference (P<0.05). Conclusions: Implant surface decontamination with the additional use of ozone therapy in SRT of peri-implantitis showed clinically and radiographically significant. Trial registry at ClinicalTrials.gov, NCT03018795. PMID- 29984046 TI - Efficacy of an LED toothbrush on a Porphyromonas gingivalis biofilm on a sandblasted and acid-etched titanium surface: an in vitro study. AB - Purpose: The aim of this study was to evaluate the antimicrobial effect of a newly devised toothbrush with light-emitting diodes (LEDs) on Porphyromonas gingivalis attached to sandblasted and acid-etched titanium surfaces. Methods: The study included a control group, a commercial photodynamic therapy (PDT) group, and 3 test groups (B, BL, and BLE). The disks in the PDT group were placed in methylene blue and then irradiated with a diode laser. The B disks were only brushed, the BL disks were brushed with an LED toothbrush, and the BLE disks were placed into erythrosine and then brushed with an LED toothbrush. After the different treatments, bacteria were detached from the disks and spread on selective agar. The number of viable bacteria and percentage of bacterial reduction were determined from colony counts. Scanning electron microscopy was performed to visualize bacterial alterations. Results: The number of viable bacteria in the BLE group was significantly lower than that in the other groups (P<0.05). Scanning electron microscopy showed that bacterial cell walls were intact in the control and B groups, but changed after commercial PDT and LED exposure. Conclusions: The findings suggest that an LED toothbrush with erythrosine treatment was more effective than a commercial PDT kit in reducing the number of P. gingivalis cells attached to surface-modified titanium in vitro. PMID- 29984047 TI - A radiographic evaluation of graft height changes after maxillary sinus augmentation. AB - Purpose: The aims of the present study were to quantitatively assess graft height changes after sinus lift procedures and to analyze the factors that influenced graft height changes, including the residual bone height before surgery, surgical approach, and tooth type. Methods: A total of 39 maxillary posterior implants placed during a simultaneous sinus lift procedure were evaluated. Panoramic radiographs of all patients were taken immediately after implant installation and at 3 months, 6 months, 1 year, 2 years, and 3 years. To analyze graft height changes over time, we measured the distance between the implant platform and the base of the grafted sinus floor at 3 locations. The radiographs were analyzed by a single examiner. Results: Graft height tended to decrease over time, and a statistically significant difference was observed at 2 years compared to baseline (P<0.05). There was no statistically significant difference in graft height change according to the surgical approach or tooth type. For residual bone height, a statistically significant difference in graft height change was found between those with 4-7 mm of residual bone height and those with >=7 mm (P<0.05). Conclusions: Graft height after sinus lift procedures significantly decreased at 2 years compared to baseline after sinus augmentation. Further studies should be done with controlled variables, and prospective studies with 3-dimensional images are needed to clarify the factors that influence graft height changes. PMID- 29984048 TI - Tissue integration of zirconia and titanium implants with and without buccal dehiscence defects. AB - Purpose: The purpose of the present study was to validate an experimental model for assessing tissue integration of titanium and zirconia implants with and without buccal dehiscence defects. Methods: In 3 dogs, 5 implants were randomly placed on both sides of the mandibles: 1) Z1: a zirconia implant (modified surface) within the bony housing, 2) Z2: a zirconia implant (standard surface) within the bony housing, 3) T: a titanium implant within the bony housing, 4) Z1_D: a Z1 implant placed with a buccal bone dehiscence defect (3 mm), and 5) T_D: a titanium implant placed with a buccal bone dehiscence defect (3 mm). The healing times were 2 weeks (one side of the mandible) and 6 weeks (the opposite side). Results: The dimensions of the peri-implant soft tissue varied depending on the implant and the healing time. The level of the mucosal margin was located more apically at 6 weeks than at 2 weeks in all groups, except group T. The presence of a buccal dehiscence defect did not result in a decrease in the overall soft tissue dimensions between 2 and 6 weeks (4.80+/-1.31 and 4.3 mm in group Z1_D, and 4.47+/-1.06 and 4.5+/-1.37 mm in group T_D, respectively). The bone-to-implant contact (BIC) values were highest in group Z1 at both time points (34.15%+/-21.23% at 2 weeks, 84.08%+/-1.33% at 6 weeks). The buccal dehiscence defects in groups Z1_D and T_D showed no further bone loss at 6 weeks compared to 2 weeks. Conclusions: The modified surface of Z1 demonstrated higher BIC values than the surface of Z2. There were minimal differences in the mucosal margin between 2 and 6 weeks in the presence of a dehiscence defect. The present model can serve as a useful tool for studying peri-implant dehiscence defects at the hard and soft tissue levels. PMID- 29984049 TI - Guided bone regeneration using K-incision technique. AB - Purpose: The present study describes 3 patients with chronic periodontitis and consequent vertical resorption of the alveolar ridge who were treated using implant-based restoration with guided bone regeneration (GBR). Methods: After extraction of a periodontally compromised tooth, vertical bone augmentation using a K-incision was performed at the healed, low-level alveolar ridge. Results: The partial-split K-incision enabled soft tissue elongation without any change in buccal vestibular depth, and provided sufficient keratinized gingival tissue during GBR. Conclusions: Within the limits of this study, the present case series demonstrated that the novel K-incision technique was effective for GBR and allowed normal implant-based restoration and maintenance of a healthy periodontal condition. However, further long-term follow-up and a large-scale randomized clinical investigation should be performed to evaluate the feasibility of this technique. PMID- 29984050 TI - Morphometric study of pulleys of the thumb. AB - Pulleys are thickened regions in flexor tendons sheaths of the digits. They are essential and act as fulcrum for the flexion and extension of the digits. The arrangement and number of pulley system differs greatly between the thumb and other digits. There is paucity of literature regarding the pulley system of thumb. We aimed to study the morphometry of the pulley system of the thumb in Indian cadavers. Dissection was carried out in 55 adult human cadaveric thumbs. The most common morphologic pattern of pulley observed in the thumb is type III (30 thumbs). The least observed is type I (4 thumbs). The mean width and standard deviation of A1, Av, oblique, and A2 pulleys are 5.06+/-0.87, 5.38+/-1.22, 4.68+/ 1.13, and 6.04+/-1.41 mm, respectively. The gap distances between the pulleys were also measured. The results obtained from the present study may be helpful in surgical treatment of trigger thumb with less complication and also in reconstruction of the closed rupture of the pulley of the thumb. PMID- 29984051 TI - Interobserver and intraobserver reliability of different methods of examination for presence of palmaris longus and examination of fifth superficial flexor function. AB - The palmaris longus is harvested as a tendon graft in various surgical procedures. Several tests are used to assess the presence of palmaris longus tendon. In the present study, we attempted to assess the interobserver and intraobserver reliability of five of the most famous methods and also the examination of fifth superficial flexor function. Two observers, who had been trained on the tests and had practiced them, examined 105 volunteers on two separate occasions and in 1-month interval the results were recorded. The reliability of each method was assessed with Kappa measurement. Kappa ranged from 0.541 (moderate reliability) to 0.813 (almost complete agreement) for palmaris. The highest interobserver and intraobserver reliability and also the best agreement with other tests were of Schaeffer. The lowest kappa was for Thompson and the others have good to excellent reliability. Kappa for interobserver and intraobserver reliability for the fifth flexor were 0.415 and 0.500 (moderate reliability), respectively. The tests that were assessed have good reliability except for Thompson that has a moderate one. It seems that the standard test (Schaeffer) is the best method for the assessment of the absence or presence of palmaris longus. The method used for the evaluation of fifth superficial flexor variations assessment has a moderate interobserver and intraobserver reliability. PMID- 29984052 TI - Variations in human pulmonary fissures and lobes: a study conducted in nepalese cadavers. AB - The fissures of lungs are embryologically separating the bronchopulmonary segments, which later on persist in interlobar planes of fully developed lung. Fifty lungs (23 right side and 27 left side), obtained during routine dissection and preserved in formalin constituted the material for present study. In them, variations in fissures and lobes of lung were observed and compared with the previous studies. Seven right sided and 14 left sided lungs showed incomplete oblique fissure. Incomplete horizontal fissure of right lung was observed in eight lungs while it was completely missing in three specimens. A right lung with "lobe of the azygos vein" separated by a supernumerary fissure in medial surface was found. One of the right lung had both superior accessory fissure and inferior accessory fissure and four other right lungs and one left lung presented only with inferior accessory fissure. A vertical notch was found in middle lobe of one right lung. Eight left lungs exhibited with left minor fissure among them two lungs had lingula appearing as a separate lobe. Knowledge of variations in fissures and lobes is of interest to all medical professionals to exactly interpret radiographs, computed tomography scans, to diagnose, plan and modify a surgical procedure depending on the merit of the case and also in certain classical clinical cases pertaining to lung pathologies. PMID- 29984053 TI - Re-definition of position and calculation of safe area for axillary nerve in deltoid muscle with its clinical relevance: a cadaveric study. AB - Several authors have made efforts to define the position of the axillary nerve within deltoid muscle and to calculate the so called safe area for this nerve but it still remains a matter of debate. The primary aim of the study was to investigate the acromio-axillary (AA) distance and its correlation with upper arm length. The secondary aim was to re-define the safe area for axillary nerve within deltoid muscle. Sixty shoulders of thirty adult human cadavers were dissected using standard methods. The distance from the anterior and posterior edge of acromion to the upper border of the course of the axillary nerve was measured and recorded as anterior and posterior AA distance respectively. Correlation analysis was done between the upper arm length and AA distance for each limb. The ratios between anterior and posterior AA distance and upper arm length were calculated and mentioned as anterior index and posterior index, respectively. The mean of anterior and posterior AA distance was 5.22 cm and 4.17 cm, respectively. The mean of upper arm length was 29.30 cm. The means of anterior index and posterior indices were 0.18 and 0.14, respectively. There was a significant correlation between upper arm length and both the anterior and posterior AA distance. The axillary nerve was found to lie at variable distance from the acromion. The minimum AA distance was found to be 3.50 cm. So this should be considered as the maximum permissible length of the deltoid split. Upper arm length has strong correlation with both anterior and posterior AA distances. The ideal safe area for the axillary nerve was found to be a quadrangular area above it and the size of which depends on the length of the upper arm. PMID- 29984054 TI - A mixed method study to validate a two-way feedback between student and faculty to improve learning of anatomy. AB - Although the students are subjected to some formative exams throughout the problem based learning units, feedback is not given appropriately and timely. Students want to know and use the reasoning behind judgments and always complain that assessment criteria need to be explained. The aim of this project is to implement a two-way feedback delivery (TWFD), in which both faculty and students have an opportunity to discuss their reflections on learning and examination processes. An Anatomy formative assessment is introduced to 100 students followed by implementation of TWFD. Faculty members provided the students with a structured and timely feedback on their performance. Also, the students reflected on the whole learning process, including real examination experience. The reaction was measured using quantitative and qualitative instruments through a questionnaire, focus group discussion, and semi-structured interviews. Ninety students (90%) participated in the questionnaire with high satisfaction toward implementation of TWFD. Ninety-four percent (n=85) admitted that the time of the session was appropriate. Ninety percent (n=81) of the students demonstrated that the TWFD helped them to identify their strengths and weaknesses. Eighty-five percent (n=77) of the students admitted that TWFD promotes active reflection on the effectiveness of teaching. Most of the students and teachers' comments in the focus group discussions and the interviews supported these results. TWFD seems to be a good approach to implement an effective and timely feedback process between the faculty and the students. Students and the faculty recommended the implementation of this session in different courses and units. PMID- 29984055 TI - CD57 (Leu-7, HNK-1) immunoreactivity seen in thin arteries in the human fetal lung. AB - CD57 (synonyms: Leu-7, HNK-1) is a well-known marker of nerve elements including the conductive system of the heart, as well as natural killer cells. In lung specimens from 12 human fetuses at 10-34 weeks of gestation, we have found incidentally that segmental, subsegmental, and more peripheral arteries strongly expressed CD57. Capillaries near developing alveoli were often or sometimes positive. The CD57-positive tissue elements within intrapulmonary arteries seemed to be the endothelium, internal elastic lamina, and smooth muscle layer, which corresponded to tissue positive for a DAKO antibody reactive with smooth muscle actin we used. However, the lobar artery and pulmonary arterial trunk as well as bronchial arteries were negative. Likewise, arteries in and along any abdominal viscera, as well as the heart, thymus, and thyroid, did not express CD57. Thus, the lung-specific CD57 reactivity was not connected with either of an endodermal- or a branchial arch-origin. CD57 antigen is a sugar chain characterized by a sulfated glucuronic acid residue that is likely to exist in some glycosphingolipids. Therefore, a chemical affinity or an interaction might exist between CD57-positive arterioles and glycosphingolipids originating from alveoli, resulting in acceleration of capillary budding to make contact with the alveolar wall. CD57 might therefore be a functional marker of the developing air-blood interface that characterizes the fetal lung at the canalicular stage. PMID- 29984056 TI - Histomorphometric demonstration of the effect of chronic use of nonsteroidal anti inflammatory drugs-ibuprofen on mucosa of small intestine. AB - The purpose of this study was to ascertain change in structure of mucosa of small intestine, if any, in small intestine of Swiss albino mice as an effect of chronic use of nonsteroidal anti-inflammatory drugs-Ibuprofen. Longitudinal study conducted on 46 adult Swiss albino mice, 23 as experimental and 23 as control. Ibuprofen was given at a dose of 40 ug/g body weight per day for 6 weeks by intragastric route in experimental group of mice while control group of mice received same volume of distilled water. Mice of both the groups were sacrificed and desired segments of small intestines were dissected out and tissues were subjected to histological processing. Histomorphometry was performed and relevant photomicrographs were obtained. Student's unpaired t test by GraphPad Prism 6 software. Height of villi was not significantly altered but there was significant reduction of the number of goblet and non-goblet cells (enterocytes and other columnar cells) in mucosal lining of the small intestine of experimental group of mice. Percent distribution of the goblet and non-goblet cells was not altered in villi of two groups. Chronic exposure of Ibuprofen in therapeutic dosage caused reduction of the functional cell mass in lining epithelium of villi of middle segment of small intestine. However, there was no evidence of ulcerative or hemorrhagic lesion. PMID- 29984057 TI - Ameliorative effects of Moringa on cuprizone-induced memory decline in rat model of multiple sclerosis. AB - Cuprizone is a neurotoxin with copper-chelating ability used in animal model of multiple sclerosis in which oxidative stress has been documented as one of the cascade in the pathogenesis. Moringa oleifera is a phytomedicinal plant with antioxidant and neuroprotective properties. This study aimed at evaluating the ameliorative capability of M. oleifera in cuprizone-induced behavioral and histopathological alterations in the prefrontal cortex and hippocampus of Wistar rats. Four groups of rats were treated with normal saline, cuprizone, M. oleifera and a combination of M. oleifera and cuprizone, for five weeks. The rats were subjected to Morris water maze and Y-maze to assess long and short-term memory respectively. The animals were sacrificed, and brain tissues were removed for histochemical and enzyme lysate immunosorbent assay for catalase, superoxide dismutase, and nitric oxide. Cuprizone significantly induced oxidative and nitrosative stress coupled with memory decline and cortico-hippocampal neuronal deficits; however, administration of M. oleifera significantly reversed the neuropathological deficits induced by cuprizone. PMID- 29984059 TI - Solitary osteochondroma in the body of the pubic bone: a cadaveric case report. AB - Osteochondromas develop as cartilaginous nodules in the periosteum of bones. They are the commonest benign tumors of the skeleton, generally observed in the long bones. Rarely, they are also found in the axial skeleton, flat bones of skull and facial bones. During a regular dissection, we came across a solitary osteochondroma in posterior surface of the body of the right pubic bone. Histopathology of the bony projection confirmed the typical features of the osteochondroma. The symptomatic osteochondromas are usually evaluated during radiographic examination. Though, the observed osteochondroma is relatively smaller its unusual location is remarkable and knowledge of occurrence of such nodules is clinically important during the diagnosis and planning of treatment. PMID- 29984058 TI - The relationship between low survival and acute increase of tumor necrosis factor alpha expression in the lung in a rat model of asphyxial cardiac arrest. AB - Cardiac arrest (CA) is sudden loss of heart function and abrupt stop in effective blood flow to the body. The patients who initially achieve return of spontaneous circulation (RoSC) after CA have low survival rate. It has been known that multiorgan dysfunctions after RoSC are associated with high morbidity and mortality. Most previous studies have focused on the heart and brain in RoSC after CA. Therefore, the aim of this research was to perform serological, physiological, and histopathology study in the lung and to determine whether or how pulmonary dysfunction is associated with low survival rate after CA. Experimental animals were divided into sham-operated group (n=14 at each point in time), which was not subjected to CA operation, and CA-operated group (n=14 at each point in time), which was subjected to CA. The rats in each group were sacrificed at 6 hours, 12 hours, 24 hours, and 2 days, respectively, after RoSC. Then, pathological changes of the lungs were analyzed by hematoxylin and eosin staining, Western blot and immunohistochemistry for tumor necrosis factor alpha (TNF-alpha). The survival rate after CA was decreased with time past. We found that histopathological score and TNF-alpha immunoreactivity were significantly increased in the lung after CA. These results indicate that inflammation triggered by ischemia-reperfusion damage after CA leads to pulmonary injury/dysfunctions and contributes to low survival rate. In addition, the finding of increase in TNF-alpha via inflammation in the lung after CA would be able to utilize therapeutic or diagnostic measures in the future. PMID- 29984060 TI - Trifurcation of right coronary artery and its huge right ventricular branch: can it be hazardous? AB - The objective of this case report is to alert the cardiologists and radiologists about the possibility of an extremely rare trifurcation of the right coronary artery. During dissection classes, an early trifurcation of the right coronary artery (RCA) was observed in an adult male cadaver aged approximately 65 years. The RCA had a normal origin from the anterior aortic sinus. After a course of just 2 mm, it trifurcated into a conus artery, a huge right ventricular branch and then a main continuation of the RCA. The conus artery entered the myocardium of the conus after a short course. The huge ventricular branch had a downward and left course almost till the apex of the heart. Right marginal artery was absent. No other vascular variations of heart were observed apart from this. Knowledge of this trifurcation could be useful in coronary angioplasty and bypass procedures. PMID- 29984061 TI - Role of Laparoscopic Gastrectomy in Very Elderly Patients with Gastric Cancer Who Have Outlived the Average Lifespan. AB - Purpose: This study aimed to investigate the outcomes of laparoscopic gastrectomy in very elderly patients with gastric cancer, who have outlived the average lifespan of the Korean population (men: >=77 years, women: >=84 years). Materials and Methods: Between 2004 and 2015, 836 patients with gastric cancer underwent a laparoscopic gastrectomy. They were divided into the elderly group (EldG) and non elderly group (nEldG). Propensity score matching for covariates of sex, tumor depth, node status, and extent of resection was performed. Clinicopathologic characteristics, and surgical and survival outcomes were compared between the 2 groups. Results: The EldG had a higher American Society of Anesthesiologists (ASA) score and a higher number of comorbidities. There was no significant difference in the post-operative complications, except for pulmonary complications, which were more frequent in the EldG (5/56, 8.9%) than in the nEldG (0/56, 0%). The EldG had a shorter overall survival (OS), but cancer specific survival was similar for both groups. Among deceased patients, 2 (25%) and 8 patients (50%) died within a year of surgery in the nEldG and EldG, respectively. Univariate and multivariate risk factor analyses for OS showed that age, ASA score, tumor, node, metastasis (TNM) stage, and occurrence of complications were significantly related to deterioration in OS. Conclusions: Laparoscopic gastrectomy can be safely performed in very elderly patients with gastric cancer who have outlived the average lifespan of the Korean population. However, impact of laparoscopic gastrectomy on improving survival is not clear, and careful patient selection is recommended. PMID- 29984062 TI - Feasibility and Effects of a Postoperative Recovery Exercise Program Developed Specifically for Gastric Cancer Patients (PREP-GC) Undergoing Minimally Invasive Gastrectomy. AB - Purpose: Exercise intervention after surgery has been found to improve physical fitness and quality of life (QOL). The purpose of this study was to investigate the feasibility and effects of a postoperative recovery exercise program developed specifically for gastric cancer patients (PREP-GC) undergoing minimally invasive gastrectomy. Materials and Methods: Twenty-four patients treated surgically for early gastric cancer were enrolled in the PREP-GC. The exercise program comprised sessions of In-hospital Exercise (1 week), Home Exercise (1 week), and Fitness Improvement Exercise (8 weeks). Adherence and compliance to PREP-GC were evaluated. In addition, body composition, physical fitness, and QOL were assessed during the preoperative period, after the postoperative recovery (2 weeks after surgery), and upon completing the PREP-GC (10 weeks after surgery). Results: Of the 24 enrolled patients, 20 completed the study without any adverse events related to the PREP-GC. Adherence and compliance rates to the Fitness Improvement Exercise were 79.4% and 99.4%, respectively. Upon completing the PREP GC, patients also exhibited restored cardiopulmonary function and muscular strength, with improved muscular endurance and flexibility (P<0.05). Compared to those in the preoperative period, no differences were found in symptom scale scores measured using the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Quality of Life Questionnaire-Stomach Cancer-Specific Module (QLQ-STO22); however, higher scores for global health status and emotional functioning were observed after completing the PREP-GC (P<0.05). Conclusions: In gastric cancer patients undergoing minimally invasive gastrectomy, PREP-GC was found to be feasible and safe, with high adherence and compliance. Although randomized studies evaluating the benefits of exercise intervention during postoperative recovery are needed, surgeons should encourage patients to participate in systematic exercise intervention programs in the early postoperative period (Registered at the ClinicalTrials.gov NCT01751880). PMID- 29984063 TI - Pancreatic Compression during Lymph Node Dissection in Laparoscopic Gastrectomy: Possible Cause of Pancreatic Leakage. AB - Purpose: Postoperative pancreatic fistula is a serious and fatal complication of gastrectomy for gastric cancer. Blunt trauma to the parenchyma of the pancreas can result from an assistant's forceps compressing and retracting the pancreas, which in turn may result in pancreatic juice leakage. However, no published studies have focused on blunt trauma to the pancreas during laparoscopic surgery. Our aim was to investigate the relationship between compression of the pancreas and pancreatic juice leakage in a swine model. Materials and Methods: Three female pigs were used in this study. The pancreas was gently compressed dorsally for 15 minutes laparoscopically with gauze grasped with forceps. Pancreatic juice leakage was visualized by fluorescence imaging after topical administration of chymotrypsin-activatable fluorophore in real time. Amylase concentrations in ascites collected at specified times was measured. In addition, pancreatic tissue was fixed with formalin, and the histology of the compressed sites was evaluated. Results: Fluorescence imaging enabled visualization of pancreatic juice leaking into ascites around the pancreas. Median concentrations of pancreatic amylase in ascites increased from 46 U/L preoperatively to 12,509 U/L 4 hours after compression. Histological examination of tissues obtained 4 hours after compression revealed necrotic pancreatic acinar cells extending from the surface to deep within the pancreas and infiltration of inflammatory cells. Conclusions: Pancreatic compression by the assistant's forceps can contribute to pancreatic juice leakage. These findings will help to improve the procedure for lymph node dissection around the pancreas during laparoscopic gastrectomy. PMID- 29984064 TI - Modification of the TNM Staging System for Stage II/III Gastric Cancer Based on a Prognostic Single Patient Classifier Algorithm. AB - Purpose: The modification of the cancer classification system aimed to improve the classical anatomy-based tumor, node, metastasis (TNM) staging by considering tumor biology, which is associated with patient prognosis, because such information provides additional precision and flexibility. Materials and Methods: We previously developed an mRNA expression-based single patient classifier (SPC) algorithm that could predict the prognosis of patients with stage II/III gastric cancer. We also validated its utilization in clinical settings. The prognostic single patient classifier (pSPC) differentiates based on 3 prognostic groups (low , intermediate-, and high-risk), and these groups were considered as independent prognostic factors along with TNM stages. We evaluated whether the modified TNM staging system based on the pSPC has a better prognostic performance than the TNM 8th edition staging system. The data of 652 patients who underwent gastrectomy with curative intent for gastric cancer between 2000 and 2004 were evaluated. Furthermore, 2 other cohorts (n=307 and 625) from a previous study were assessed. Thus, 1,584 patients were included in the analysis. To modify the TNM staging system, one-grade down-staging was applied to low-risk patients according to the pSPC in the TNM 8th edition staging system; for intermediate- and high-risk groups, the modified TNM and TNM 8th edition staging systems were identical. Results: Among the 1,584 patients, 187 (11.8%), 664 (41.9%), and 733 (46.3%) were classified into the low-, intermediate-, and high-risk groups, respectively, according to the pSPC. pSPC prognoses and survival curves of the overall population were well stratified, and the TNM stage-adjusted hazard ratios of the intermediate- and high-risk groups were 1.96 (95% confidence interval [CI], 1.41 2.72; P<0.001) and 2.54 (95% CI, 1.84-3.50; P<0.001), respectively. Using Harrell's C-index, the prognostic performance of the modified TNM system was evaluated, and the results showed that its prognostic performance was better than that of the TNM 8th edition staging system in terms of overall survival (0.635 vs. 0.620, P<0.001). Conclusions: The pSPC-modified TNM staging is an alternative staging system for stage II/III gastric cancer. PMID- 29984065 TI - Feasibility and Safety of Totally Laparoscopic Radical Gastrectomy for Advanced Gastric Cancer: Comparison with Early Gastric Cancer. AB - Purpose: Totally laparoscopic gastrectomy (TLG) for advanced gastric cancer (AGC) is a technically and oncologically challenging procedure for surgeons. This study aimed to compare the oncologic feasibility and technical safety of TLG for AGC versus early gastric cancer (EGC). Materials and Methods: Between 2011 and 2016, 535 patients (EGC, 375; AGC, 160) underwent curative TLG for gastric cancer. Clinicopathologic characteristics and surgical outcomes of both patient groups were analyzed and compared. Results: Patients with AGC required a longer operation time and experienced more intraoperative blood loss than those with EGC did. However, patients from both the AGC and EGC groups demonstrated similar short-term surgical outcomes such as postoperative morbidity (14.4% vs. 13.3%, P=0.626), mortality (0% vs. 0.5%, P=0.879), time-to-first oral intake (2.7 days for both groups, P=0.830), and postoperative hospital stay (10.2 days vs. 10.1 days, P=0.886). D2 lymph node dissection could be achieved in the AGC group (95%), with an adequate number of lymph nodes being dissected (36.0+/-14.9). In the AGC group, the 3-year overall and disease-free survival rates were 80.5% and 73.7%, respectively. Conclusions: TLG is as safe and effective for AGC as it is for EGC. PMID- 29984066 TI - Assessment of the Completeness of Lymph Node Dissection Using Near-infrared Imaging with Indocyanine Green in Laparoscopic Gastrectomy for Gastric Cancer. AB - Purpose: This study assessed the feasibility of near-infrared (NIR) imaging with indocyanine green (ICG) in investigating the completeness of laparoscopic lymph node (LN) dissection for gastric cancer. Materials and Methods: Patients scheduled for laparoscopic gastrectomy for treating gastric cancer were enrolled in the study. After intraoperative submucosal ICG injection (0.05 mg/mL), LN dissection was performed under conventional laparoscopic light. After dissection, the LN stations of interest were examined under the NIR mode to locate any extra ICG-stained (E) tissues, which were excised and sent for pathologic confirmation. This technique was tested in 2 steps: infra-pyloric LN dissection (step 1) and review of all stations after proper radical node dissection (step 2). Results: In step 1, 15 patients who underwent laparoscopic pylorus-preserving gastrectomy (LPPG) and 15 patients who underwent laparoscopic distal gastrectomy (LDG) were examined. Seven and 2 E-tissues were obtained during LPPG and LDG, respectively. From the retrieved E-tissues, 1 and 0 tissue obtained during LPPG and LDG, respectively, was confirmed as LN. In step 2, 20 patients were enrolled (13 D1+ dissection and 7 D2 dissection). Six E-tissues were retrieved from 5 patients, and 1 tissue was confirmed as LN in the pathologic review. Overall, 15 E-tissues were detected and removed, and 2 tissues were confirmed as LNs in the pathologic review. Both nodes were from LN station #6, with 1 case each in the LDG and LPPG groups. Conclusions: NIR imaging may provide additional node detection during laparoscopic LN dissection for gastric cancer, especially in the infra-pyloric area. PMID- 29984067 TI - Transition from Conventional to Reduced-Port Laparoscopic Gastrectomy to Treat Gastric Carcinoma: a Single Surgeon's Experience from a Small-Volume Center. AB - Purpose: This study aimed to evaluate the surgical outcomes and investigate the feasibility of reduced-port laparoscopic gastrectomy using learning curve analysis in a small-volume center. Materials and Methods: We reviewed 269 patients who underwent laparoscopic distal gastrectomy (LDG) for gastric carcinoma between 2012 and 2017. Among them, 159 patients underwent reduced-port laparoscopic gastrectomy. The cumulative sum technique was used for quantitative assessment of the learning curve. Results: There were no statistically significant differences in the baseline characteristics of patients who underwent conventional and reduced-port LDG, and the operative time did not significantly differ between the groups. However, the amount of intraoperative bleeding was significantly lower in the reduced-port laparoscopic gastrectomy group (56.3 vs. 48.2 mL; P<0.001). There were no significant differences between the groups in terms of the first flatus time or length of hospital stay. Neither the incidence nor the severity of the complications significantly differed between the groups. The slope of the cumulative sum curve indicates the trend of learning performance. After 33 operations, the slope gently stabilized, which was regarded as the breakpoint of the learning curve. Conclusions: The surgical outcomes of reduced-port laparoscopic gastrectomy were comparable to those of conventional laparoscopic gastrectomy, suggesting that transition from conventional to reduced port laparoscopic gastrectomy is feasible and safe, with a relatively short learning curve, in a small-volume center. PMID- 29984068 TI - Learning Curve of Pure Single-Port Laparoscopic Distal Gastrectomy for Gastric Cancer. AB - Purpose: Despite the fact that there are several reports of single-port laparoscopic distal gastrectomy (SPDG), no analysis of its learning curve has been described in the literature. The aim of this study was to investigate the favorable factors for SPDG and to analyze the learning curve of SPDG. Materials and Methods: A total of 125 cases of SPDG performed from November 2011 to December 2015 were enrolled. All operations were performed by 2 surgeons (surgeon A and surgeon B). The moving average method was used for defining the learning curve. All cases were divided into 10 cases in a sequence, and the mean operative time and estimated blood loss data were extracted from each group. Results: Surgeon A performed 68 cases (female-to-male sex ratio, 91.1%:8.82%), and surgeon B performed 57 cases (female-to-male sex ratio, 61.4%:38.5%). The operative time of surgeon B significantly decreased after 30 cases (157.8+/-38.4 minutes vs. 118.1+/-34.5 minutes, P=0.003); that of surgeon A did not significantly decrease before and after around 30 cases (160.8+/-51.6 minutes vs. 173.3+/-35.2 minutes, P=0.6). The subgroup analysis showed that the operative time significantly decreased in the patients with body mass index (BMI) of <25 kg/m2 (<25 kg/m2:>=25 kg/m2, 159.3+/-41.7 minutes: 194.25+/-81.1 minutes; P=0.001). Conclusions: Although there was no significant decrease in the operative time for surgeon A, surgeon B reached the learning curve upon conducting 30 cases of SPDG. BMI of <25 kg/m2 was found to be a favorable factor for SPDG. PMID- 29984069 TI - Long-Term Nutritional Outcomes of Near-Total Gastrectomy in Gastric Cancer Treatment: a Comparison with Total Gastrectomy Using Propensity Score Matching Analysis. AB - Purpose: This study sought to examine whether near total gastrectomy (nTG) confers a long-term nutritional benefit when compared with total gastrectomy (TG) for the treatment of gastric cancer. Materials and Methods: Patients who underwent nTG or TG for gastric cancer were included (n=570). Using the 1:2 matched propensity score, 25 patients from the nTG group and 50 patients from the TG group were compared retrospectively for oncologic outcomes, including long term survival and nutritional status. Results: The length of the proximal resection margin, number of retrieved lymph nodes and tumor nodes, metastasis stage, short-term postoperative outcomes, and long-term survival were not significantly different between the groups. The body mass index values, and serum total protein and hemoglobin levels of the patients decreased significantly until postoperative 6 months, and then recovered slightly over time (P<0.05); however, there was no difference in the levels between the groups. The prognostic nutritional index values and serum albumin levels decreased significantly until postoperative 6 months and then recovered (P<0.05); the levels decreased more in the nTG group than in the TG group (P<0.05). The mean corpuscular volumes and serum transferrin levels increased significantly until postoperative 1 year and then recovered slightly over time (P<0.05); however, there was no difference between the groups. Serum vitamin B12, iron, and ferritin levels of the patients did not change significantly over time, and no difference existed between the groups. Conclusions: A small remnant stomach after nTG conferred no significant nutritional benefits over TG. PMID- 29984071 TI - Erratum: Is Lymph Node Size a Reliable Factor for Estimating Lymph Node Metastasis in Early Gastric Cancer? AB - [This corrects the article on p. 20 in vol. 18, PMID: 29629217.]. PMID- 29984070 TI - Multiregion Comprehensive Genomic Profiling of a Gastric Mixed Neuroendocrine Nonneuroendocrine Neoplasm with Trilineage Differentiation. AB - Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) are a group of rare tumors previously known as mixed adenoneuroendocrine carcinomas (MANECs). The neuroendocrine component is high-grade and may consist of small-cell carcinoma or large-cell neuroendocrine carcinoma. The nonneuroendocrine component may consist of adenocarcinoma or squamous cell carcinoma. We report a unique case of a MiNEN with trilineage differentiation: large-cell neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma. The reported patient presented with symptoms of an upper gastrointestinal bleed and was ultimately diagnosed with a MiNEN with trilineage differentiation. This is the first report of this exceedingly rare tumor type to include next-generation sequencing of the 3 separate tumor entities. In addition, we review the current literature and discuss the role of next-generation sequencing in classifying and treating MiNEN tumors. PMID- 29984072 TI - Client Satisfaction with Quality of Health Care in a Rural area in Southern India. AB - Background: Client satisfaction is an important method to assess the pattern of utilization of health care services amongst all sectors indirectly reflecting on the quality of services. Most of the clients prefer private over government services due to multiple reasons. Aim: To assess the level of satisfaction of patients attending rural government and private health facilities in rural Andhra Pradesh. Methods: Ten villages were randomly selected from the field practice area of a teaching medical institution, and all patients who visited any facility during the past three months were interviewed using a semi-structured questionnaire focusing on access to care, competence of the providers, quality and cost of the services and overall satisfaction with the services. Data was analysed using Microsoft Access software. Results: One hundred and eight clients who visited different facilities for common ailments, chronic diseases, maternal and child health services were interviewed. The average time to reach the facility was 52.23 +/- 44.52 minutes. The average waiting time was 34.25 +/- 42.47 minutes. More than 80% were satisfied with the clinic hours, cleanliness and comfort of the facility, and privacy maintained during examinations. 40% were satisfied with the cost of services. Conclusion: The client satisfaction with different health care providers in rural areas of Andhra Pradesh is high. Clients expect the quality of services to be better; nevertheless they continue to use the available services without complaining much. PMID- 29984073 TI - Segmentation of vessel structures from photoacoustic images with reliability assessment. AB - Photoacoustic imaging enables the imaging of soft biological tissue with combined optical contrast and ultrasound resolution. One of the targets of interest is tissue vasculature. However, the photoacoustic images may not directly provide the information on, for example, vasculature structure. Therefore, the images are improved by reducing noise and artefacts, and processed for better visualisation of the target of interest. In this work, we present a new segmentation method of photoacoustic images that also straightforwardly produces assessments of its reliability. The segmentation depends on parameters which have a natural tendency to increase the reliability as the parameter values monotonically change. The reliability is assessed by counting classifications of image voxels with different parameter values. The resulting segmentation with reliability offers new ways and tools to analyse photoacoustic images and new possibilities for utilising them as anatomical priors in further computations. Our MATLAB implementation of the method is available as an open-source software package [P. Raumonen, Matlab, 2018]. PMID- 29984074 TI - Quantitative diagnosis of tissue microstructure with wide-field high spatial frequency domain imaging. AB - Non-contact and minimally invasive endoscopic optical imaging is an invaluable diagnostic tool for tissue examination and cancer screening. The point sampling techniques with high sensitivity to the tissue microenvironment are time consuming and often not affordable in clinics. There is a major clinical need for a large field-of-view (FOV) rapid screening method to highlight subtle tissue microstructural alterations. To address this unmet need, we have developed High Spatial Frequency Domain Imaging (HSFDI)-a non-contact imaging modality that spatially maps the tissue microscopic scattering structures over a large field of view (>1cm2). Based on an analytical reflectance model of sub-diffusive light from forward-peaked highly scattering media, HSFDI quantifies the spatially resolved parameters of the light scattering phase function (i.e., the backscattering probability and the light spreading length) from the reflectance of structured light modulated at high spatial frequencies. Enhanced signal to noise ratio (SNR) is achieved at even ultra-high modulation frequencies with single snapshot multiple frequency demodulation (SSMD). The variations in tissue microstructures, including the strength of the background (pudding) refractive index fluctuation and the prominent scattering structure (plum) morphology, can then be inferred. After validation with optical phantoms, measurements of fresh ex vivo tissue samples revealed significant contrast and differentiation of the phase function parameters between different types and disease states (normal, inflammatory, and cancerous) of tissue whereas tissue absorption and reduced scattering coefficients only show modest changes. HSFDI may provide wide-field images of microscopic structural biomarkers unobtainable with either diffuse light imaging or point-based optical sampling. Potential clinical applications include the rapid screening of excised tissue and the noninvasive examination of suspicious lesions during operation. PMID- 29984075 TI - Quantitative characterization of bovine serum albumin thin-films using terahertz spectroscopy and machine learning methods. AB - The development of new spectral analysis methods in bio thin-film detection has generated intense interest in terahertz (THz) spectroscopy and its application in a wide range of fields. In this paper, it is the first time that machine learning methods are applied to the quantitative characterization of bovine serum albumin (BSA) deposited thin-films detected by terahertz time-domain spectroscopy. The spectra data of BSA thin-films prepared by solutions with concentrations ranging from 0.5 to 35 mg/ml are analyzed using the support vector regression method to learn the underlying model of the frequency against the target concentration. The learned mode successfully predicts the concentrations of the unknown test samples with a coefficient of determination R2 = 0.97932. Furthermore, aiming to identify the relevance of each frequency to the concentration, the maximal information coefficient statistical analysis is used and the three most discriminating frequencies in THz frequency are identified at 1.2, 1.1 and 0.5 THz respectively, which means a good prediction for BSA concentration can be achieved by using the top three relevant frequencies. Moreover, the top discriminating frequencies are in good agreement with the frequencies predicted by a long-wavelength elastic vibration model for BSA protein. PMID- 29984077 TI - Super-multiplexed fluorescence microscopy via photostability contrast. AB - Fluorescence microscopy is widely used to observe and quantify the inner workings of the cell. Traditionally, multiple types of cellular structures or biomolecules are visualized simultaneously in a sample by using spectrally distinct fluorescent labels. The wide emission spectra of most fluorophores limits spectral multiplexing to four or five labels in a standard fluorescence microscope. Further multiplexing requires another dimension of contrast. Here, we show that photostability differences can be used to distinguish between fluorescent labels. By combining photobleaching characteristics with a novel unmixing algorithm, we resolve up to three fluorescent labels in a single spectral channel and unmix fluorescent labels with nearly identical emission spectra. We apply our technique to organic dyes, autofluorescent biomolecules and fluorescent proteins. Our approach has the potential to triple the multiplexing capabilities of any digital widefield or confocal fluorescence microscope with no additional hardware, making it readily accessible to a wide range of researchers. PMID- 29984076 TI - Pilot study of freshly excised breast tissue response in the 300-600 GHz range. AB - The failure to accurately define tumor margins during breast conserving surgery (BCS) results in a 20% re-excision rate. The present paper reports the investigation to evaluate the potential of terahertz imaging for breast tissue recognition within the under-explored 300 - 600 GHz range. Such a frequency window matches new BiCMOS technology capabilities and thus opens up the opportunity for near-field terahertz imaging using these devices. To assess the efficacy of this frequency band, data from 16 freshly excised breast tissue samples were collected and analyzed directly after excision. Complex refractive indices have been extracted over the as-mentioned frequency band, and amplitude frequency images show some contrast between tissue types. Principal component analysis (PCA) has also been applied to the data in an attempt to automate tissue classification. Our observations suggest that the dielectric response could potentially provide contrast for breast tissue recognition within the 300 - 600 GHz range. These results open the way for silicon-based terahertz subwavelength near field imager design, efficient up to 600 GHz to address ex vivo life-science applications. PMID- 29984078 TI - Pixel-wise segmentation of severely pathologic retinal pigment epithelium and choroidal stroma using multi-contrast Jones matrix optical coherence tomography. AB - Tissue segmentation of retinal optical coherence tomography (OCT) is widely used in ophthalmic diagnosis. However, its performance in severe pathologic cases is still insufficient. We propose a pixel-wise segmentation method that uses the multi-contrast measurement capability of Jones matrix OCT (JM-OCT). This method is applicable to both normal and pathologic retinal pigment epithelium (RPE) and choroidal stroma. In this method, "features," which are sensitive to specific tissues of interest, are synthesized by combining the multi-contrast images of JM OCT, including attenuation coefficient, degree-of-polarization-uniformity, and OCT angiography. The tissue segmentation is done by simple thresholding of the feature. Compared with conventional segmentation methods for pathologic maculae, the proposed method is less computationally intensive. The segmentation method was validated by applying it to images from normal and severely pathologic cases. The segmentation results enabled the development of several types of en face visualizations, including melano-layer thickness maps, RPE elevation maps, choroidal thickness maps, and choroidal stromal attenuation coefficient maps. These facilitate close examination of macular pathology. The melano-layer thickness map is very similar to a near infrared fundus autofluorescence image, so the map can be used to identify the source of a hyper-autofluorescent signal. PMID- 29984079 TI - Multiwavelength time-resolved near-infrared spectroscopy of the adult head: assessment of intracerebral and extracerebral absorption changes. AB - An optical technique based on diffuse reflectance measurement combined with indocyanine green (ICG) bolus tracking is extensively tested as a method for the clinical assessment of brain perfusion at the bedside. We report on multiwavelength time-resolved diffuse reflectance spectroscopy measurements carried out on the head of a healthy adult during the intravenous administration of a bolus of ICG. Intracerebral and extracerebral changes in absorption were estimated from an analysis of changes in statistical moments (total number of photons, mean time of flight and variance) of the distributions of times of flight (DTOF) of photons recorded simultaneously at 16 wavelengths from the range of 650-850 nm using sensitivity factors estimated by diffusion approximation based on a layered model of the studied medium. We validated the proposed method in a series of phantom experiments and in-vivo measurements. The results obtained show that changes in the concentration of the ICG can be assessed as a function of time of the experiment and depth in the tissue. Thus, the separation of changes in ICG concentration appearing in intra- and extracerebral tissues can be estimated from optical data acquired at a single source-detector pair of fibers/fiber bundles positioned on the surface of the head. PMID- 29984080 TI - Decoding cortical brain states from widefield calcium imaging data using visibility graph. AB - Widefield optical imaging of neuronal populations over large portions of the cerebral cortex in awake behaving animals provides a unique opportunity for investigating the relationship between brain function and behavior. In this paper, we demonstrate that the temporal characteristics of calcium dynamics obtained through widefield imaging can be utilized to infer the corresponding behavior. Cortical activity in transgenic calcium reporter mice (n=6) expressing GCaMP6f in neocortical pyramidal neurons is recorded during active whisking (AW) and no whisking (NW). To extract features related to the temporal characteristics of calcium recordings, a method based on visibility graph (VG) is introduced. An extensive study considering different choices of features and classifiers is conducted to find the best model capable of predicting AW and NW from calcium recordings. Our experimental results show that temporal characteristics of calcium recordings identified by the proposed method carry discriminatory information that are powerful enough for decoding behavior. PMID- 29984081 TI - Effect of spatial light distribution on the thermal response of vascular tissue. AB - The aim of the current study is to investigate the effect of radial and cylindrical light distributions on the response of vascular tissue during 1470-nm irradiation in ex vivo models. Due to a low irradiance (5.3 W/cm2) and wide light distribution, cylindrically diffusing irradiation yielded uniform thermal coagulation while radial irradiation accompanied delamination of layers in leporine veins. Bovine foot model testing verified that the diffusing irradiation was associated with the steady maximum temperature and no tissue attachment, compared with the radial irradiation. The proposed cylindrical light application can be a feasible way to treat varicose veins in an effective manner. PMID- 29984082 TI - Effect of patch size and network architecture on a convolutional neural network approach for automatic segmentation of OCT retinal layers. AB - Deep learning strategies, particularly convolutional neural networks (CNNs), are especially suited to finding patterns in images and using those patterns for image classification. The method is normally applied to an image patch and assigns a class weight to the patch; this method has recently been used to detect the probability of retinal boundary locations in OCT images, which is subsequently used to segment the OCT image using a graph-search approach. This paper examines the effects of a number of modifications to the CNN architecture with the aim of optimizing retinal layer segmentation, specifically the effect of patch size as well as the network architecture design on CNN performance and subsequent layer segmentation. The results demonstrate that increasing patch size can improve the performance of the classification and provides a more reliable segmentation in the analysis of retinal layer characteristics in OCT imaging. Similarly, this work shows that changing aspects of the CNN network design can also significantly improve the segmentation results. This work also demonstrates that the performance of the method can change depending on the number of classes (i.e. boundaries) used to train the CNN, with fewer classes showing an inferior performance due to the presence of similar image features between classes that can trigger false positives. Changes in the network (patch size and or architecture) can be applied to provide a superior segmentation performance, which is robust to the class effect. The findings from this work may inform future CNN development in OCT retinal image analysis. PMID- 29984083 TI - Millisecond cellular labelling in situ with two-photon photoconversion. AB - In situ labeling of cells within living biological tissues using photoconversion has provided valuable information on cellular physiology in their natural environments. However, current photoconvertible probes typically require seconds to minutes of light exposure, limiting their uses in rapid biological processes such as intracellular diffusion and circulating cells. Here, we report that two photon photoconversion of cyanine-based dyes offers unprecedentedly rapid photoconversion down to millisecond timescales per cell. We demonstrate potential biological applications including measuring intracellular diffusion kinetics in a spinal nerve, labeling of rapidly flowing cells in a microfluidic channel, and photoconversion of a circulating cell in vivo. PMID- 29984084 TI - Fundus autofluorescence beyond lipofuscin: lesson learned from ex vivo fluorescence lifetime imaging in porcine eyes. AB - Fundus autofluorescence (FAF) imaging is a well-established method in ophthalmology; however, the fluorophores involved need more clarification. The FAF lifetimes of 20 post mortem porcine eyes were measured in two spectral channels using fluorescence lifetime imaging ophthalmoscopy (FLIO) and compared with clinical data from 44 healthy young subjects. The FAF intensity ratio of the short and the long wavelength emission (spectral ratio) was determined. Ex vivo porcine fundus fluorescence emission is generally less intense than that seen in human eyes. The porcine retina showed significantly (p<0.05) longer lifetimes than the retinal pigment epithelium (RPE): 584 +/- 128 ps vs. 121 +/- 55 ps 498 560 nm, 240 +/- 42 ps vs. 125 +/- 20 ps at 560-720 nm. Furthermore, the lifetimes of the porcine RPE were significantly shorter (121 +/- 55 ps and 125 +/- 20 ps) than those measured from human fundus in vivo (162 +/- 14 ps and 179 +/- 13 ps, respectively). The fluorescence emission of porcine retina was shifted towards a shorter wavelength compared to that of RPE and human FAF. This data shows the considerable contribution of fluorophores in the neural retina to total FAF intensity in porcine eyes. PMID- 29984085 TI - Deep learning for the segmentation of preserved photoreceptors on en face optical coherence tomography in two inherited retinal diseases. AB - The objective quantification of photoreceptor loss in inherited retinal degenerations (IRD) is essential for measuring disease progression, and is now especially important with the growing number of clinical trials. Optical coherence tomography (OCT) is a non-invasive imaging technology widely used to recognize and quantify such anomalies. Here, we implement a versatile method based on a convolutional neural network to segment the regions of preserved photoreceptors in two different IRDs (choroideremia and retinitis pigmentosa) from OCT images. An excellent segmentation accuracy (~90%) was achieved for both IRDs. Due to the flexibility of this technique, it has potential to be extended to additional IRDs in the future. PMID- 29984087 TI - Realistic simulation and experiment reveals the importance of scatterer microstructure in optical coherence tomography image formation. AB - Realistic simulation of image formation in optical coherence tomography, based on Maxwell's equations, has recently been demonstrated for sample volumes of practical significance. Yet, there remains a limitation whereby reducing the size of cells used to construct a computational grid, thus allowing for a more realistic representation of scatterer microstructure, necessarily reduces the overall sample size that can be modelled. This is a significant problem since, as is well known, the microstructure of a scatterer significantly influences its scattering properties. Here we demonstrate that an optimized scatterer design can overcome this problem resulting in good agreement between simulated and experimental images for a structured phantom. This approach to OCT image simulation allows for image formation for biological tissues to be simulated with unprecedented realism. PMID- 29984086 TI - Image reconstruction in fluorescence molecular tomography with sparsity initialized maximum-likelihood expectation maximization. AB - We present a reconstruction method involving maximum-likelihood expectation maximization (MLEM) to model Poisson noise as applied to fluorescence molecular tomography (FMT). MLEM is initialized with the output from a sparse reconstruction-based approach, which performs truncated singular value decomposition-based preconditioning followed by fast iterative shrinkage thresholding algorithm (FISTA) to enforce sparsity. The motivation for this approach is that sparsity information could be accounted for within the initialization, while MLEM would accurately model Poisson noise in the FMT system. Simulation experiments show the proposed method significantly improves images qualitatively and quantitatively. The method results in over 20 times faster convergence compared to uniformly initialized MLEM and improves robustness to noise compared to pure sparse reconstruction. We also theoretically justify the ability of the proposed approach to reduce noise in the background region compared to pure sparse reconstruction. Overall, these results provide strong evidence to model Poisson noise in FMT reconstruction and for application of the proposed reconstruction framework to FMT imaging. PMID- 29984088 TI - Volumetric optical coherence microscopy with a high space-bandwidth-time product enabled by hybrid adaptive optics. AB - Optical coherence microscopy (OCM) is a promising modality for high resolution imaging, but has limited ability to capture large-scale volumetric information about dynamic biological processes with cellular resolution. To enhance the throughput of OCM, we implemented a hybrid adaptive optics (hyAO) approach that combines computational adaptive optics with an intentionally aberrated imaging beam generated via hardware adaptive optics. Using hyAO, we demonstrate the depth equalized illumination and collection ability of an astigmatic beam compared to a Gaussian beam for cellular-resolution imaging. With this advantage, we achieved volumetric OCM with a higher space-bandwidth-time product compared to Gaussian beam acquisition that employed focus-scanning across depth. HyAO was also used to perform volumetric time-lapse OCM imaging of cellular dynamics over a 1mm * 1mm * 1mm field-of-view with 2 MUm isotropic spatial resolution and 3-minute temporal resolution. As hyAO is compatible with both spectral-domain and swept-source beam scanning OCM systems, significant further improvements in absolute volumetric throughput are possible by use of ultrahigh-speed swept sources. PMID- 29984089 TI - Simultaneous arteriole and venule segmentation with domain-specific loss function on a new public database. AB - The segmentation and classification of retinal arterioles and venules play an important role in the diagnosis of various eye diseases and systemic diseases. The major challenges include complicated vessel structure, inhomogeneous illumination, and large background variation across subjects. In this study, we employ a fully convolutional network to simultaneously segment arterioles and venules directly from the retinal image, rather than using a vessel segmentation arteriovenous classification strategy as reported in most literature. To simultaneously segment retinal arterioles and venules, we configured the fully convolutional network to allow true color image as input and multiple labels as output. A domain-specific loss function was designed to improve the overall performance. The proposed method was assessed extensively on public data sets and compared with the state-of-the-art methods in literature. The sensitivity and specificity of overall vessel segmentation on DRIVE is 0.944 and 0.955 with a misclassification rate of 10.3% and 9.6% for arteriole and venule, respectively. The proposed method outperformed the state-of-the-art methods and avoided possible error-propagation as in the segmentation-classification strategy. The proposed method was further validated on a new database consisting of retinal images of different qualities and diseases. The proposed method holds great potential for the diagnostics and screening of various eye diseases and systemic diseases. PMID- 29984090 TI - Prenatal detection of thalassemia by cell-free fetal DNA (cffDNA) in maternal plasma using surface enhanced Raman spectroscopy combined with PCR. AB - Thalassemias are widely occurring genetic hemoglobin disorders; patients with severe thalassemia often require regular blood transfusions for survival. Prenatal detection of thalassemia is currently invasive and carries the risk of miscarriage and infection. A polymerase chain reaction (PCR)-based surface enhanced Raman spectroscopy (SERS) technique was investigated in this paper for the purpose of detecting prenatal alpha-thalassemia Southeast Asian (SEA) type deletion using maternal plasma. Couples with the same SEA thalassemia ( SEA/alphaalpha) were selected, and the quantification of SEA and wild type (WT) alleles in the maternal plasma sample predicted the fetal genotype. PCR was performed using two pairs of fluorescence tag-labeled primers to produce tag labeled PCR products for both the SEA (labeled with R6G) and WT (labeled with Cy3) alleles. Then, the labeled PCR products containing the two fluorescence tags were measured by SERS. The ratios between the R6G and Cy3 tags were obtained using multiple linear regressions (MLR), and these ratios corresponded with the physical ratio of WT and SEA concentrations in maternal plasma. After verifying this technique on DNA mixtures with known SEA and WT ratios, the plasma from 24 pregnant women was screened. An accuracy of 91.7% was achieved for detecting the fetal genotypes of Hb Bart's, alpha-trait, and normal trait. The results indicated that the simple PCR-SERS method may be sensitive enough for use on cell free fetal DNA (cffDNA) in maternal plasma for non-invasive prenatal detection (NIPD). PMID- 29984091 TI - Erratum: Visualization of laser tattoo removal treatment effects in a mouse model by two-photon microscopy: erratum. AB - [This corrects the article on p. 3735 in vol. 8, PMID: 28856046.]. PMID- 29984092 TI - Glare-free retinal imaging using a portable light field fundus camera. AB - We present the retinal plenoptoscope, a novel light field retinal imaging device designed to overcome many of the problems that limit the use of portable non mydriatic fundus cameras, including image quality and lack of stereopsis. The design and prototype construction of this device is detailed and the ideal relationship between the eye pupil, system aperture stop and micro-image separation is investigated. A comparison of the theoretical entrance pupil size, multi-view baseline and depth resolution indicates that a higher degree of stereopsis is possible than with stereo fundus cameras. We also show that the effects of corneal backscatter on image quality can be removed through a novel method of glare identification and selective image rendering. This method is then extended to produce glare-free depth maps from densely estimated depth fields, creating representations of retinal topography from a single exposure. These methods are demonstrated on physical models and live human eyes using a prototype device based on a Lytro Illum consumer light field camera. The Retinal Plenoptoscope offers a viable, robust modality for non-mydriatic color and 3-D retinal imaging. PMID- 29984093 TI - Prediction of the anti-glioma therapeutic effects of temozolomide through in vivo molecular imaging of MMP expression. AB - Currently, there is no effective way to assess the therapeutic response of temozolomide (TMZ) for the glioma. In this study, the human U87MG-fLuc glioma animal models were set up and the antitumor efficacy of TMZ was evaluated using bioluminescence imaging (BLI) and MRI. Then, bioluminescence tomography (BLT) was reconstructed using an adaptive sparsity matching pursuit (ASMP) algorithm. Second, the expression level of the MMP-750 probe was examined with or without TMZ treatment using FMI. Third, the expression of MMP2 and MMP3 was specifically examined after treatment. The results showed that TMZ effectively inhibited glioma growth. The targeted imaging of MMP-750 was decreased during the treatment of glioma with TMZ. Moreover, the MMP2 and MMP3 expression was found to correlate with the inhibition effect of TMZ. Our study indicated that the therapeutic effects of TMZ can be effectively evaluated at an early stage using molecular imaging, and MMP targeting the fluorescence probe could be utilized for the prediction and assessment of the therapeutic effects of TMZ. PMID- 29984094 TI - Automatic quantification of choroidal neovascularization lesion area on OCT angiography based on density cell-like P systems with active membranes. AB - Detecting and quantifying the size of choroidal neovascularization (CNV) is important for the diagnosis and assessment of neovascular age-related macular degeneration. Depth-resolved imaging of the retinal and choroidal vasculature by optical coherence tomography angiography (OCTA) has enabled the visualization of CNV. However, due to the prevalence of artifacts, it is difficult to segment and quantify the CNV lesion area automatically. We have previously described a saliency algorithm for CNV detection that could identify a CNV lesion area with 83% accuracy. However, this method works under the assumption that the CNV region is the most salient area for visual attention in the whole image and consequently, errors occur when this requirement is not met (e.g. when the lesion occupies a large portion of the image). Moreover, saliency image processing methods cannot extract the edges of the salient object very accurately. In this paper, we propose a novel and automatic CNV segmentation method based on an unsupervised and parallel machine learning technique named density cell-like P systems (DEC P systems). DEC P systems integrate the idea of a modified clustering algorithm into cell-like P systems. This method improved the accuracy of detection to 87.2% on 22 subjects and obtained clear boundaries of the CNV lesions. PMID- 29984095 TI - Machine-learning based segmentation of the optic nerve head using multi-contrast Jones matrix optical coherence tomography with semi-automatic training dataset generation. AB - A pixel-by-pixel tissue classification framework using multiple contrasts obtained by Jones matrix optical coherence tomography (JM-OCT) is demonstrated. The JM-OCT is an extension of OCT that provides OCT, OCT angiography, birefringence tomography, degree-of-polarization uniformity tomography, and attenuation coefficient tomography, simultaneously. The classification framework consists of feature engineering, k-means clustering that generates a training dataset, training of a tissue classifier using the generated training dataset, and tissue classification by the trained classifier. The feature engineering process generates synthetic features from the primary optical contrasts obtained by JM-OCT. The tissue classification is performed in the feature space of the engineered features. We applied this framework to the in vivo analysis of optic nerve heads of posterior eyes. This classified each JM-OCT pixel into prelamina, lamina cribrosa (lamina beam), and retrolamina tissues. The lamina beam segmentation results were further utilized for birefringence and attenuation coefficient analysis of lamina beam. PMID- 29984097 TI - Weighting function effects in a direct regularization method for image-guided near-infrared spectral tomography of breast cancer. AB - Structural image-guided near-infrared spectral tomography (NIRST) has been developed as a way to use diffuse NIR spectroscopy within the context of image guided quantification of tissue spectral features. A direct regularization imaging (DRI) method for NIRST has the value of not requiring any image segmentation. Here, we present a comprehensive investigational study to analyze the impact of the weighting function implied when weighting the recovery of optical coefficients in DRI based NIRST. This was done using simulations, phantom and clinical patient exam data. Simulations where the true object is known indicate that changes to this weighting function can vary the contrast by 10%, the contrast to noise ratio by 20% and the full width half maximum (FWHM) by 30%. The results from phantoms and human images show that a linear inverse distance weighting function appears optimal, and that incorporation of this function can generally improve the recovered total hemoglobin contrast of the tumor to the normal surrounding tissue by more than 15% in human cases. PMID- 29984096 TI - DRUNET: a dilated-residual U-Net deep learning network to segment optic nerve head tissues in optical coherence tomography images. AB - Given that the neural and connective tissues of the optic nerve head (ONH) exhibit complex morphological changes with the development and progression of glaucoma, their simultaneous isolation from optical coherence tomography (OCT) images may be of great interest for the clinical diagnosis and management of this pathology. A deep learning algorithm (custom U-NET) was designed and trained to segment 6 ONH tissue layers by capturing both the local (tissue texture) and contextual information (spatial arrangement of tissues). The overall Dice coefficient (mean of all tissues) was 0.91 +/- 0.05 when assessed against manual segmentations performed by an expert observer. Further, we automatically extracted six clinically relevant neural and connective tissue structural parameters from the segmented tissues. We offer here a robust segmentation framework that could also be extended to the 3D segmentation of the ONH tissues. PMID- 29984098 TI - On the dysfunctional hemoglobins and cyanosis connection: practical implications for the clinical detection and differentiation of methemoglobinemia and sulfhemoglobinemia. AB - Methemoglobinemia and sulfhemoglobinemia are potentially life-threatening blood related disorders characterized by similar symptoms and markedly distinct treatment procedures. In this paper, we investigate the causal relationship between these conditions and the onset of cyanosis, which is typically associated with a purple or bluish skin coloration. More specifically, we perform controlled experiments to elicit cyanotic appearances resulting from different severity levels of these disorders and varying physiological conditions. We note that such experiments cannot be induced in living subjects without posing risks to their health. Accordingly, we have resorted to an in silico experimental approach supported by biophysical data reported in the literature. Besides bringing new insights about cyanotic chromatic variations elicited by methemoglobinemia and sulfhemoglobinemia, our investigation provides the basis for the proposition of a cost-effective protocol for the noninvasive detection and differentiation of these disorders. Our experimental results indicate that its sensitivity range is wider than what is provided by similar protocols employed in these tasks. Moreover, it has lower operational requirements than laboratory tests ordered to enable the diagnosis of these conditions. We believe that these aspects make the proposed protocol particularly suitable for deployment at the point of care of medical settings with limited access to laboratory resources. PMID- 29984099 TI - Solving Fourier ptychographic imaging problems via neural network modeling and TensorFlow. AB - Fourier ptychography is a recently developed imaging approach for large field-of view and high-resolution microscopy. Here we model the Fourier ptychographic forward imaging process using a convolutional neural network (CNN) and recover the complex object information in a network training process. In this approach, the input of the network is the point spread function in the spatial domain or the coherent transfer function in the Fourier domain. The object is treated as 2D learnable weights of a convolutional or a multiplication layer. The output of the network is modeled as the loss function we aim to minimize. The batch size of the network corresponds to the number of captured low-resolution images in one forward/backward pass. We use a popular open-source machine learning library, TensorFlow, for setting up the network and conducting the optimization process. We analyze the performance of different learning rates, different solvers, and different batch sizes. It is shown that a large batch size with the Adam optimizer achieves the best performance in general. To accelerate the phase retrieval process, we also discuss a strategy to implement Fourier-magnitude projection using a multiplication neural network model. Since convolution and multiplication are the two most-common operations in imaging modeling, the reported approach may provide a new perspective to examine many coherent and incoherent systems. As a demonstration, we discuss the extensions of the reported networks for modeling single-pixel imaging and structured illumination microscopy (SIM). 4-frame resolution doubling is demonstrated using a neural network for SIM. The link between imaging systems and neural network modeling may enable the use of machine-learning hardware such as neural engine and tensor processing unit for accelerating the image reconstruction process. We have made our implementation code open-source for researchers. PMID- 29984100 TI - Selective retina therapy enhanced with optical coherence tomography for dosimetry control and monitoring: a proof of concept study. AB - Selective treatment of the retinal pigment epithelium (RPE) by using short-pulse lasers leads to a less destructive treatment for certain retinal diseases in contrast to conventional photocoagulation. The introduction of selective retina therapy (SRT) to clinical routine is still precluded by the challenges to reliably monitor treatment success and to automatically adjust dose within the locally varying therapeutic window. Combining micrometer-scale depth resolving capabilities of optical coherence tomography (OCT) with SRT can yield real-time information on the laser-induced changes within the RPE after a laser pulse or even during treatment with a laser pulse train. In the present study, SRT and OCT were combined to treat ex-vivo porcine eyes demonstrating closed-loop dose control. We found a reliable correlation of specific signal changes in time resolved OCT images and physiological lesions in the RPE. First experiments, including 23 porcine eyes, prove the feasibility of the novel treatment concept. PMID- 29984101 TI - Temporally and spatially adaptive Doppler analysis for robust handheld optical coherence elastography. AB - Optical coherence elastography (OCE), a functional extension of optical coherence tomography (OCT), can be used to characterize the mechanical properties of biological tissue. A handheld fiber-optic OCE instrument will allow the clinician to conveniently interrogate the localized mechanical properties of in vivo tissue, leading to better informed clinical decision making. During handheld OCE characterization, the handheld probe is used to compress the sample and the displacement of the sample is quantified by analyzing the OCT signals acquired. However, the motion within the sample inevitably varies in time due to varying hand motion. Moreover, the motion speed depends on spatial location due to the sample deformation. Hence, there is a need for a robust motion tracking method for manual OCE measurement. In this study, we investigate a temporally and spatially adaptive Doppler analysis method. The method described here strategically chooses the time interval (deltat) between signals involved in Doppler analysis to track the motion speed v(z,t) that varies temporally and spatially in a deformed sample volume under manual compression. Enabled by temporally and spatially adaptive Doppler analysis, we report the first demonstration of real-time manual OCE characterization of in vivo tissue to the best of our knowledge. PMID- 29984102 TI - Volumetric non-local-means based speckle reduction for optical coherence tomography. AB - We present a novel tomographic non-local-means based despeckling technique, TNode, for optical coherence tomography. TNode is built upon a weighting similarity criterion derived for speckle in a three-dimensional similarity window. We present an implementation using a two-dimensional search window, enabling the despeckling of volumes in the presence of motion artifacts, and an implementation using a three-dimensional window with improved performance in motion-free volumes. We show that our technique provides effective speckle reduction, comparable with B-scan compounding or out-of-plane averaging, while preserving isotropic resolution, even to the level of speckle-sized structures. We demonstrate its superior despeckling performance in a phantom data set, and in an ophthalmic data set we show that small, speckle-sized retinal vessels are clearly preserved in intensity images en-face and in two orthogonal, cross sectional views. TNode does not rely on dictionaries or segmentation and therefore can readily be applied to arbitrary optical coherence tomography volumes. We show that despeckled esophageal volumes exhibit improved image quality and detail, even in the presence of significant motion artifacts. PMID- 29984103 TI - New fluorescent compounds produced by femtosecond laser surgery in biological tissues: the mechanisms. AB - The femtosecond laser ablation in biological tissue produces highly fluorescent compounds that are of great significance for intrinsically labelling ablated tissue in vivo and achieving imaging-guided laser microsurgery. In this study, we analyzed the molecular structures of femtosecond laser-ablated tissues using Raman spectroscopy and transmission electron microscopy. The results showed that though laser ablation caused carbonization, no highly fluorescent nanostructures were found in the ablated tissues. Further, we found that the fluorescence properties of the newly formed compounds were spatially heterogeneous across the ablation site and the dominant fluorescent signals exhibited close similarity to the tissue directly heated at a temperature of 200 degrees C. The findings of our study indicated that the new fluorescent compounds were produced via the laser heating effect and their formation mechanism likely originated from the Maillard reaction, a chemical reaction between amino acids and reducing sugars in tissue. PMID- 29984104 TI - Real-time localization of the parathyroid gland in surgical field using Raspberry Pi during thyroidectomy: a preliminary report. AB - We created an auto-para viewer, an autofluorescence imaging device, to localize the parathyroid glands during thyroidectomy using an inexpensive Raspberry Pi. A special emission filter in the auto-para viewer was designed to pass 1/100 of visible light and nearly all infrared light longer than 808 nm. With this emission filter, we simultaneously acquired an autofluorescence image of the parathyroid and a visible light image of the surrounding surgical field. The auto para viewer displayed four times brighter autofluorescence of the parathyroid glands compared to the background tissues without operating room light. Additionally, it showed two times brighter autofluorescence than the background tissues simultaneously showing the surgical field illuminated by the visible light from the operating room light. The NOIR camera, using the auto-para viewer, could reduce the camera's exposure time so the parathyroid glands to be viewed in real-time, which is expected to prevent unintentional damage to the parathyroid gland during thyroidectomy. PMID- 29984105 TI - Near-simultaneous quantification of glucose uptake, mitochondrial membrane potential, and vascular parameters in murine flank tumors using quantitative diffuse reflectance and fluorescence spectroscopy. AB - The shifting metabolic landscape of aggressive tumors, with fluctuating oxygenation conditions and temporal changes in glycolysis and mitochondrial metabolism, is a critical phenomenon to study in order to understand negative treatment outcomes. Recently, we have demonstrated near-simultaneous optical imaging of mitochondrial membrane potential (MMP) and glucose uptake in non-tumor window chambers, using the fluorescent probes tetramethylrhodamine ethyl ester (TMRE) and 2-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG). Here, we demonstrate a complementary technique to perform near-simultaneous in vivo optical spectroscopy of tissue vascular parameters, glucose uptake, and MMP in a solid tumor model that is most often used for therapeutic studies. Our study demonstrates the potential of optical spectroscopy as an effective tool to quantify the vascular and metabolic characteristics of a tumor, which is an important step towards understanding the mechanisms underlying cancer progression, metastasis, and resistance to therapies. PMID- 29984107 TI - On-chip light-sheet fluorescence imaging flow cytometry at a high flow speed of 1 m/s. AB - We present on-chip fluorescence imaging flow cytometry by light-sheet excitation on a mirror-embedded microfluidic chip. The method allows us to obtain microscopy grade fluorescence images of cells flowing at a high speed of 1 m/s, which is comparable to the flow speed of conventional non-imaging flow cytometers. To implement the light-sheet excitation of flowing cells in a microchannel, we designed and fabricated a mirror-embedded PDMS-based microfluidic chip. To show its broad utility, we used the method to classify large populations of microalgal cells (Euglena gracilis) and human cancer cells (human adenocarcinoma cells). Our method holds promise for large-scale single-cell analysis. PMID- 29984106 TI - Assessment of the radiotherapy effect for nasopharyngeal cancer using plasma surface-enhanced Raman spectroscopy technology. AB - Nasopharyngeal cancer (NPC) is a malignant tumor of the head and neck, which is extremely sensitive to radiotherapy. The aim of this study is to evaluate the feasibility of a label-free nanobiosensor based on plasma surface-enhanced Raman spectroscopy (SERS) to assess the radiotherapy effect in NPC. Here, SERS measurements were performed on plasma samples from 40 pre-treatment and post treatment NPC as well as 30 healthy volunteers. Results demonstrate that the spectral characteristic of post-treatment samples is obviously different from that of pre-treatment ones, owing to the changes of biomolecules in plasma induced by radiotherapy. Classification sensitivities of 83.3%, 61.8% and 95.1%, and specificities of 91.2%, 67.4% and 93% can be achieved for separating pre- and post-treatment samples, post-treatment and normal samples, and pre-treatment and normal samples, respectively, suggesting the great potential of plasma SERS method as a rapid and convenient tool for radiotherapy assessment and cancer screening in NPC. PMID- 29984108 TI - Visualization of drug distribution of a topical minocycline gel in human facial skin. AB - Acne vulgaris is a common chronic skin disease in young adults caused by infection of the pilosebaceous unit, resulting in pimples and possibly permanent scarring on the skin. Minocycline, a common antibiotic, has been widely utilized as a systemic antimicrobial treatment for acne via oral administration. Recently, a topical minocycline gel (BPX-01) was developed to directly deliver minocycline through the epidermis and into the pilosebaceous unit to achieve localized treatment with lower doses of drug. As the effectiveness of the drug is directly related to its successful delivery, there is a need to evaluate the pharmacokinetics at the cellular level within tissue. Advantageously, minocycline is naturally fluorescent and can be directly visualized using microscopy-based approaches. Due to high endogenous autofluorescence, however, imaging of weakly emitting fluorescent molecules such as minocycline in skin tissue can be challenging. Here, we demonstrate a method for the selective visualization of minocycline within human skin tissue by utilizing two-photon excitation fluorescence (TPEF) microscopy and fluorescence lifetime imaging microscopy (FLIM). To demonstrate the feasibility of this approach, ex vivo human facial skin samples treated with various concentrations of BPX-01 were investigated. From the TPEF analysis, we were able to visualize relatively high levels of drug uptake within facial skin. However, minocycline fluorescence could be overwhelmed by endogenous fluorescence that complicates TPEF quantitative analysis, making FLIM more advantageous for visualizing drug uptake. Importantly, we found a unique signature of minocycline uptake via FLIM analysis that enabled the successful differentiation of the drug and enabled the extraction of drug local distribution from the endogenous fluorescence using a non-Euclidean phasor analysis method. Based on these results, we believe that the drug local distribution visualization method using TPEF and FLIM with phasor analysis can play an important role in studying the pharmacokinetics and pharmacodynamics of a topically applicable drug. PMID- 29984109 TI - Real-time visualization of two-photon fluorescence lifetime imaging microscopy using a wavelength-tunable femtosecond pulsed laser. AB - A fluorescence lifetime imaging microscopy (FLIM) integrated with two-photon excitation technique was developed. A wavelength-tunable femtosecond pulsed laser with nominal pulse repetition rate of 76-MHz was used to acquire FLIM images with a high pixel rate of 3.91 MHz by processing the pulsed two-photon fluorescence signal. Analog mean-delay (AMD) method was adopted to accelerate the lifetime measurement process and to visualize lifetime map in real-time. As a result, rapid tomographic visualization of both structural and chemical properties of the tissues was possible with longer depth penetration and lower photo-damage compared to the conventional single-photon FLIM techniques. PMID- 29984110 TI - Fiber-based visible and near infrared optical coherence tomography (vnOCT) enables quantitative elastic light scattering spectroscopy in human retina. AB - Elastic light scattering spectroscopy (ELSS) has been proven a powerful method in measuring tissue structures with exquisite nanoscale sensitivity. However, ELSS contrast in the living human retina has been relatively underexplored, primarily due to the lack of imaging tools with a large spectral bandwidth. Here, we report a simple all fiber-based setup to implement dual-channel visible and near infrared (NIR) optical coherence tomography (vnOCT) for human retinal imaging, bridging over a 300nm spectral gap. Remarkably, the fiber components in our vnOCT system support single-mode propagation for both visible and NIR light, both of which maintain excellent interference efficiencies with fringe visibility of 97% and 90%, respectively. The longitudinal chromatic aberration from the eye is corrected by a custom-designed achromatizing lens. The elegant fiber-based design enables simultaneous imaging for both channels and allows comprehensive ELSS analysis on several important anatomical layers, including nerve fiber layer, outer segment of the photoreceptors and retinal pigment epithelium. This vnOCT platform and method of ELSS analysis open new opportunities in understanding structure-function relationship in the human retina and in exploring new biomarkers for retinal diseases. PMID- 29984111 TI - Physiological Perspective on Therapies of Lymphatic Vessels. AB - Significance: Growth of distinctive blood vessels of granulation tissue is a central step in the post-developmental tissue remodeling. Even though lymphangiogenesis is a part of the regeneration process, the significance of the controlled restoration of lymphatic vessels has only recently been recognized. Recent Advances: Identification of lymphatic markers and growth factors paved the way for the exploration of the roles of lymphatic vessels in health and disease. Emerging pro-lymphangiogenic therapies use vascular endothelial growth factor (VEGF)-C to combat fluid retention disorders such as lymphedema and to enhance the local healing process. Critical Issues: The relevance of recently identified lymphatic functions awaits verification by their association with pathologic conditions. Further, despite a century of research, the complete etiology of secondary lymphedema, a fluid retention disorder directly linked to the lymphatic function, is not understood. Finally, the specificity of pro-lymphangiogenic therapy depends on VEGF-C transfection efficiency, dose exposure, and the age of the subject, factors that are difficult to standardize in a heterogeneous human population. Future Directions: Further research should reveal the role of lymphatic circulation in internal organs and connect its impairment with human diseases. Pro-lymphangiogenic therapies that aim at the acceleration of tissue healing should focus on the controlled administration of VEGF-C to increase their capillary specificity, whereas regeneration of collecting vessels might benefit from balanced maturation and differentiation of pre-existing lymphatics. Unique features of pre-nodal lymphatics, fault tolerance and functional hyperplasia of capillaries, may find applications outreaching traditional pro-lymphangiogenic therapies, such as immunomodulation or enhancement of subcutaneous grafting. PMID- 29984114 TI - Fungi in the Wound Microbiome. AB - Significance: Culture-independent methods have revealed the diverse and dynamic bacterial communities that colonize chronic wounds. Only recently have studies begun to examine fungal colonization and interactions with the bacterial component of the microbiome, their relationship with the host, and influence on wound outcomes. Recent Advances: Studies using culture-independent sequencing methods reveal that fungi often go undetected in wounds. Candida spp. and Cladosporidium spp. are the most commonly identified fungi in wounds. The wound environment may promote multispecies biofilm formation between bacteria and fungi in wounds, with implications for pathogenicity, treatment, and outcomes. Critical Issues: Identifying microorganisms that are problematic for healing will require a comprehensive understanding of all members of the polymicrobial wound community, including fungi and bacteria. Improved reference databases and bioinformatics tools for studying fungal communities will stimulate further research into the fungal microbiome. Future Directions: Continued study of polymicrobial wound communities using culture-independent methods will further our understanding of the relationships between microbial bioburden, the host response, and impact on healing, complications, and patient outcomes. Future studies should encompass all types of microbiota, including fungi, and focus on potential multi-kingdom interactions that contribute to pathogenicity, biofilm formation, and poor outcomes. PMID- 29984112 TI - Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets. AB - Significance: The immune system plays a central role in orchestrating the tissue healing process. Hence, controlling the immune system to promote tissue repair and regeneration is an attractive approach when designing regenerative strategies. This review discusses the pathophysiology of both acute and chronic wounds and possible strategies to control the immune system to accelerate chronic wound closure and promote skin regeneration (scar-less healing) of acute wounds. Recent Advances: Recent studies have revealed the key roles of various immune cells and immune mediators in skin repair. Thus, immune components have been targeted to promote chronic wound repair or skin regeneration and several growth factors, cytokines, and biomaterials have shown promising results in animal models. However, these novel strategies are often struggling to meet efficacy standards in clinical trials, partly due to inadequate drug delivery systems and safety concerns. Critical Issues: Excess inflammation is a major culprit in the dysregulation of normal wound healing, and further limiting inflammation effectively reduces scarring. However, current knowledge is insufficient to efficiently control inflammation and specific immune cells. This is further complicated by inadequate drug delivery methods. Future Directions: Improving our understanding of the molecular pathways through which the immune system controls the wound healing process could facilitate the design of novel regenerative therapies. Additionally, better delivery systems may make current and future therapies more effective. To promote the entry of current regenerative strategies into clinical trials, more evidence on their safety, efficacy, and cost effectiveness is also needed. PMID- 29984115 TI - Obstructive Sleep Apnea among Players in the National Football League: A Scoping Review. AB - Objective: Obstructive sleep apnea (OSA) is a common sleep-disordered breathing condition that has emerged as a significant public health problem given its increased prevalence over the past decade. The high prevalence of obesity and large waist circumference among NFL players are two risk factors that might contribute to the high susceptibility of football players to develop OSA. National Football League linemen might be particularly vulnerable since they tend to have a higher body mass index. In this scoping review, we aim to bring attention to the limited research regarding OSA among National Football League players and highlight the negative consequences of OSA in an attempt to increase awareness of the urgent need for further research in this area. Methods: Search terms associated with obstructive sleep apnea and football were used to examine Google Scholar, EMBASE, CINAHL, PubMed, ProQuest, and Web of Science Plus for relevant studies. All relevant studies were included and documented. Results: Findings included (n=4) studies of interest. All 4 studies revealed a near or slightly above 50% prevalence of OSA in the investigated cohorts (mostly retired NFL linemen). Most participants in the study (active NFL players) showed symptoms associated with a sleep-disorder breathing condition (snoring). Conclusion: OSA requires more attention from the research and medical community. As suggested by results in the 4 studies included in this paper, OSA and associated symptoms are prevalent in the NFL population. Further research is required to investigate the extent of OSA and OSA risk in this population. There is an urgent need to conduct OSA risk surveillance in the athletic community. PMID- 29984113 TI - Inspired by Nature: Hydrogels as Versatile Tools for Vascular Engineering. AB - Significance: Diseases related to vascular malfunction, hyper-vascularization, or lack of vascularization are among the leading causes of morbidity and mortality. Engineered, vascularized tissues as well as angiogenic growth factor-releasing hydrogels could replace defective tissues. Further, treatments and testing of novel vascular therapeutics will benefit significantly from models that allow for the study of vascularized tissues under physiological relevant in vitro conditions. Recent Advances: Inspired by fibrin, the provisional matrix during wound healing, naturally derived and synthetic hydrogel scaffolds have been developed for vascular engineering. Today, engineers and biologists use commercially available hydrogels to pre-vascularize tissues, to control the delivery of angiogenic growth factors, and to establish vascular diseases models. Critical Issue: For clinical translation, pre-vascularized tissue constructs must be sufficiently large and stable to substitute function-relevant tissue defects and integrate with host vascular perfusion. Moreover, the continuous integration of knowhow from basic vascular biology with innovative, tailorable materials and advanced manufacturing technologies is key to achieving near-physiological tissue models and new treatments to control vascularization. Future Directions: For transplantation, engineered tissues must comprise hierarchically organized vascular trees of different caliber and function. The development of novel vascularization-promoting or -inhibiting therapeutics will benefit from physiologically relevant vessel models. In addition, tissue models representing treatment-relevant vascular tissue functions will increase the capacity to screen for therapeutic compounds and will significantly reduce the need for animals for their validation. PMID- 29984116 TI - Hypertension and its Correlates in the Oldest Old Population Aged 80 Years and Above in Urban South India. AB - Background: Hypertension is a major problem among the geriatric population, presenting the risk of multiple associated co-morbidities and organ system damage. Data related to the epidemiology of controlled and uncontrolled hypertension among the oldest old population is sparse, more so from developing countries. The objectives of the present paper were to identify the prevalence and correlates of hypertension according to gender among the urban community dwelling healthy oldest old population. Methods: 200 healthy people aged 80 years and above were recruited by random selection from Hyderabad city of South India in 2017. A trained investigator collected data on background history, history of hypertension and other co-morbidities, medications and sleep. Participants were tested for muscle strength, gait speed, and SPPB and cognitive impairment. Results: The prevalence of hypertension was 83.5%; 81.6% among men and 84.7% among women. 64.5% was self-reported. Hypertension was controlled with treatment among only 46.2%. In 74.6%, it was controlled even without treatment. The independent correlates were BMI per SD increase (OR: 1.92, 95% CI: 1.17-3.16), diabetes (OR: 6.02, 95% CI: 1.24-29.11) and asthma (OR: 3.59, 95% CI: 1.05 12.29). Among men, BMI per SD increase was significantly associated while hemoglobin per SD increase, height per SD decrease, and arthritis were positively associated among women. Increasing heart rate among total subjects (OR: 0.44, 95% CI: 0.27-0.71), and among women (OR: 0.47, 95% CI: 0.24-0.92) showed a negative association. Conclusion: The prevalence of hypertension was high. The correlates were different for men and women. Subjects were unaware of their control status which posed an increased risk for organ damage, and development of co morbidities. Policies aimed at improving quality of life of the oldest old should place due stress on appropriate hypertension management in developing countries. PMID- 29984117 TI - Reduction of Prolonged Excessive Pressure in Seated Persons With Paraplegia Using Wireless Lingual Tactile Feedback: A Randomized Controlled Trial. AB - Pressure ulcers (PU) are known to be a high-cost disease with a risk of severe morbidity. This paper evaluates a new clinical strategy based on an innovative medical device [Tongue Display Unit (TDU)] that implements perceptive supplementation in order to reduce prolonged excessive pressure, recognized as one of the main causes of PU. A randomized, controlled, and parallel-group trial was carried out with 12 subjects with spinal cord injuries (SCI). Subjects were assigned to the control (without TDU, [Formula: see text]) or intervention (with TDU, [Formula: see text]) group. Each subject took part in two sessions, during which the subject, seated on a pressure map sensor, watched a movie for one hour. The TDU was activated during the second session of the intervention group. Intention-to-treat analysis showed that the improvement in adequate weight shifting between the two sessions was higher in the intervention group (0.84 [0.24; 0.89]) than in the control group (0.01 [-0.01; 0.09]; [Formula: see text]) and that the ratio of prolonged excessive pressure between the two sessions was lower in the intervention group (0.74 [0.37; 1.92]) than in the control group (1.72 [1.32; 2.56]; [Formula: see text]). The pressure map sensor was evaluated as being convenient for use in daily life; however, this was not the case for the TDU. This paper shows that persons with SCI could benefit from a system based on perceptive supplementation that alerts and guides the user on how to adapt their posture in order to reduce prolonged excessive pressure, one of the main causes of PU. PMID- 29984118 TI - Cocaine Induced Bilateral Posterior Inferior Cerebellar Artery and Hippocampal Infarction. AB - Cocaine is one of the most commonly abused recreational drugs, second only to marijuana. It blocks the reuptake of neurotransmitters such as norepinephrine and dopamine, that leads to persistent post-synaptic stimulation responsible for its excitatory effects. Cocaine-related strokes, both ischemic and hemorrhagic, have been well described in the literature and cerebral vasospasm is hypothesized as one of the major mechanisms responsible for the presentation. Although cases of posterior circulation infarction were previously reported, we herein report a rare presentation of a cocaine-induced bilateral posterior inferior cerebellar artery and hippocampal infarction in a middle-aged female. PMID- 29984119 TI - Magnetic Resonance-guided External Beam Radiation and Brachytherapy for a Patient with Intact Cervical Cancer. AB - Radiation treatment verification has improved significantly over the past decades. The field has moved from film X-rays and skin marks to fiducial tracking and daily cone beam computed tomography (CBCT) for tumor localization. We now have the ability to perform daily on-board magnetic resonance imaging (MRI), which provides superior soft tissue contrast compared to computed tomography (CT). In the management of cervical cancer, the brachytherapy literature has demonstrated that MRI allows for better delineation of the high-risk clinical target volume (HR-CTV) and the use of MRI-guided brachytherapy has translated into improved treatment outcomes. Consensus contouring guidelines for intensity modulated radiation therapy (IMRT) for cervical cancer advise including the whole uterus in the target volume and adding large planning target volume (PTV) margins to account for inter-fractional uterine motion and target motion resulting from variable rectal and bladder filling. MRI-guided radiation therapy (MRgRT) systems enable the possibility to precisely delineate the target volume on a daily basis and to perform truly adaptive delivery. This advancement in technology provides the opportunity to explore how external beam treatment volumes could be safely reduced for better sparing of pelvic organs for the benefit of our patients with cervical cancer. We describe the MR-guided definitive external beam radiation therapy and brachytherapy for a 32-year-old woman with intact cervical cancer. We contoured the uterus, bladder, rectum, and gross tumor volume (GTV) on each of her 25 set-up MRIs. We demonstrate a steady reduction in the GTV and increased displacement of the uterus and GTV as the GTV decreased in size. The findings presented suggest that cervical cancer could greatly benefit from an adaptive MRgRT approach. PMID- 29984120 TI - Emergency Department Presentation of a Patient with Altered Mental Status: A Simulation Case for Training Residents and Clinical Clerks. AB - Emergency physicians frequently are required to perform timely assessments on patients who are unable to provide a comprehensive history due to an altered level of responsiveness. The etiology of their altered mental status (AMS) causes a diagnostic dilemma due to its wide differential diagnosis. Physicians must use a timely combination of collateral history, physical examination skills, and investigations to diagnose the cause of the patient's AMS, as many of the potential etiologies can be life-threatening if not quickly managed. For this reason, training learners to perform the required actions accurately and effectively proves difficult during real-life emergencies, where an individual's life may be at risk. Simulation-based education (SBE) offers one solution to this challenge. It allows learners to build confidence by dealing with life threatening conditions in a safe environment and has been shown to be superior to other forms of clinical training. This scenario explores learners' comfort in some less-practiced, but very important, areas of medicine including obtaining consent for treatment from a substitute decision maker (SDM), explaining various goals of care, and eliciting an advanced care directive from the SDM. Learners and physicians in all fields of medicine must be able to confidently discuss these subjects with patients and their families in order to provide individualized and appropriate management. In this simulation, learners will have the opportunity to explore an unusual AMS presentation and develop their clinical and communication skills by working as a team to manage the patient. PMID- 29984122 TI - Can Seasons be an Etiologic Factor for Monosymptomatic Nocturnal Enuresis? AB - Introduction Primary nocturnal enuresis is the most frequent urinary system complaint among pediatric patients. Material and Methods Data compiled from 5,500 children, aged between five to 16 years, diagnosed with enuresis during the period from January 2010 to December 2015 were analyzed. The inclusion criteria were having a diagnosis of monosymptomatic nocturnal enuresis, a birth date known for certain, and complete family history taken. A total of 3,547 children met the inclusion criteria and were included in the study. The study was performed by retrospective analyses. Results Analysis of the results revealed a statistically significant difference among the rates of enuresis with respect to months and seasons (p < 0.001). In our study, we retrospectively reevaluated 3,500 patients for their birth dates and determined a statistically significant difference in the rates of nocturnal enuresis with respect to seasons (p < 0.001). Conclusion As a result of this study, we determined that monosymptomatic nocturnal enuresis in children is more frequent, particularly in those born during the summer months. PMID- 29984121 TI - Percutaneous Radiofrequency Ablation for Painful Spinal Metastases Resulting in Resolution of Epidural Disease: A Case Report. AB - Percutaneous image-guided ablation is used for treatment of both benign and malignant osseous lesions often leading to substantial pain relief and local tumor control. Paired with vertebral augmentation of the affected vertebra, patients can often become functional and experience significant pain reduction. However, bone ablation must be paired with various modalities of treatment as it only provides pain relief and local tumor control and does not address systemic metastatic disease. We describe a case of metastatic prostate cancer with epidural extension treated with percutaneous image-guided radiofrequency ablation and vertebral augmentation leading to substantial pain relief as well as resolution of the epidural disease as evidenced by short-term follow-up magnetic resonance imaging (MRI). To the best of our knowledge, the resolution of epidural disease has not been described before. This case highlights the potential of ablative therapy in metastatic bone disease, particularly in the presence of epidural disease. PMID- 29984123 TI - Role of High-dose Chemotherapy and Autologous Stem Cell Transplantation for Relapsed Ewing's Sarcoma: A Case Report with Focused Review of Literature. AB - We report a case of a patient with relapsed Ewing's sarcoma (ES). After receiving conventional chemotherapy (CC) and noticing chemosensitivity of the disease, we proceeded to give the patient two separate cycles of HDCT consisting of a melphalan/busulfan regimen in the first cycle and etoposide/melphalan in the second cycle. The patient proceeded to get an autologous stem cell transplant (ASCT) after each cycle of HDCT. Our patient, despite multiple poor prognostic factors, including advanced age and multiple sites of disease relapse, showed a one-year event-free survival. Relapsed ES is associated with a poor prognosis. No treatment regimen has yet been established as a standard of care in patients with relapsed ES. We conducted a focused literature review to assess the efficacy of high-dose chemotherapy (HDCT) followed by ASCT in patients with relapsed ES. Given the improved survival outcome with HDCT followed by ASCT in our patient, we propose that its role in relapsed ES needs further assessment through large prospective, randomized controlled studies. PMID- 29984124 TI - Anaphylactic Reaction to Cyanocobalamin: A Case Report. AB - Vitamin B12 is essential for the development of healthy nerves and red blood cells. Vitamin B12 deficiency is becoming widespread and most commonly affects elderly, pregnant women, vegetarians, and patients with renal or intestinal diseases. Either parenteral vitamin B12 treatment or high-dose oral vitamin B12 treatment is an effective therapy regardless of etiology. Parenteral therapy using the intramuscular route is considered the most familiar treatment for vitamin B12 deficiency. Anaphylactic reaction after intramuscular injection is an uncommon and potentially serious side effect. In this study, we are documenting a case of anaphylactic reaction in a 55-year-old woman after her second dose of intramuscular injection of cyanocobalamin. The purpose of this case report is to highlight the need to understand the rare life-threatening side effect of intramuscular cyanocobalamin. Health care providers should be vigilant while administering the intramuscular injection of cyanocobalamin to vitamin B12 deficient patients. PMID- 29984125 TI - Hospitalization Outcomes and Comorbidities of Bulimia Nervosa: A Nationwide Inpatient Study. AB - Objective To evaluate inpatient outcomes and the prevalence of psychiatric and medical comorbidities in bulimia nervosa. Methods We used the Nationwide Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project (HCUP). We identified bulimia nervosa as the primary diagnosis and medical and psychiatric comorbidities using ICD-9-CM codes. The differences in comorbidities were quantified using the Chi-square (chi2) test, and a multinomial logistic regression model was used to quantify associations among comorbidities (odds ratio (OR)). Results The sample consisted of 3,319 inpatient admissions with bulimia nervosa between 2010-2014. Overall, 88% patients were younger than 40 years of age (p < 0.001). Bulimia nervosa was seen in a higher proportion of females (92.5%). The mean inpatient stay was 9.15 days and had a variable trend, whereas inpatient charges have been increasing (p < 0.001), averaging $34,398 (USD). The odds of having a longer hospitalization > 7 days (median) was seen in patients with comorbid fluid/electrolyte disorders (OR = 1.816; p < 0.001) and comorbid depression (OR = 1.745; p < 0.001). The most prevalent psychiatric comorbidities were psychosis (52.4%), followed by depression (23.5%). Females had three times higher odds of comorbid diabetes (OR = 3.374; p < 0.001), hypertension (OR = 2.548; p-value < 0.001), comorbid depression (OR = 1.670; p = 0.002), and drug abuse (OR = 2.008; p < 0.001). Conclusion Our study established psycho-socio-demographic characteristics, hospitalization outcomes, and comorbidities of bulimia nervosa patients. We believe that medical and psychiatric comorbidities of bulimia nervosa should be carefully investigated by clinicians as they can further complicate the management of bulimia nervosa and result in adverse inpatient outcomes. PMID- 29984126 TI - Combining in vitro reporter gene bioassays with chemical analysis to assess changes in the water quality along the Ammer River, Southwestern Germany. AB - Background: Rivers receive water and associated organic micropollutants from their entire catchment, including from urban, agricultural and natural sources, and constitute an important environmental component for catalyzing pollutant turnover. Environmental removal processes were extensively investigated under laboratory conditions in the past but there is still a lack of information on how organic micropollutants attenuate on the catchment scale. The aim of this study was to describe the chemical and toxicological profile of a 4th order river and to characterize in-stream processes. We propose indicator chemicals and indicator in vitro bioassays as screening methods to evaluate micropollutant input and transport and transformation processes of the chemical burden in a river. Carbamazepine and sulfamethoxazole were selected as indicators for dilution processes and the moderately degradable chemicals tramadol and sotalol as indicators for potential in-stream attenuation processes. The battery of bioassays covers seven environmentally relevant modes of action, namely estrogenicity, glucocorticogenic activity, androgenicity progestagenic activity and oxidative stress response, as well as activation of the peroxisome proliferator-activated receptor and the aryl hydrocarbon receptor, using the GeneBLAzer test battery and the AhR-CALUX and AREc32 assays. Results: Both approaches, targeted chemical analysis and in vitro bioassays, identified a wastewater treatment plant (WWTP) as a major input source of organic micropollutants that dominantly influenced the water quality of the river. Downstream of the WWTP the amount of detected chemicals and biological effects decreased along the river flow. The organic indicator chemicals of known degradability uncovered dilution and potential loss processes in certain river stretches. The average cytotoxic potency of the river water decreased in a similar fashion as compounds of medium degradability such as the pharmaceutical sotalol. Conclusions: This study showed that the indicator chemical/indicator bioassay approach is suitable for identifying input sources of a mixture of organic micropollutants and to trace changes in the water quality along small rivers. This method forms the necessary basis for evaluating the natural attenuation processes of organic micropollutants on a catchment scale, especially when combined with enhanced sampling strategies in future studies. PMID- 29984127 TI - Economic growth for ecological conversions: South Korean case. AB - Background: Sprawl has been named as one of the critical reasons for the latest social problems in many parts of the world. This is particularly true for developing countries, as their national status largely depends on economic stability and interacts with the rise and decline of major cities. This study focuses on a detailed notion on environmental impact of physical expansion and answers how to specifically estimate the ecological impact of sprawl using the GIS and ecological valuation method. Especially, South Korean cities are examined to identify how development-oriented growth would affect natural stock and the ecology as a whole. Results: By implementing land cover datasets and an estimation method, value transfer, the authors examine the economic losses of Korean ecological stock between 1980 and 2000. Since 1980, the society has gained a significant amount of growth in its national economics. Specifically, GDP has increased from about $40 billion to $640 billion. However, due to its rapid growth, the entire natural stock has lost about 5% of its total features, using the median economic values. If calculated with the maximum values, it is about a 7% decrease. The results indicate that $2076/person for environmental opportunity costs is estimated as a consequence of rapid urbanization. Conclusions: If we had estimated the ecological consumptions of rapid growth from the beginning and considered $2076/person for environmental opportunity costs, then the development patterns and other associated urban planning agendas would have shifted accordingly to increase the overall sustainability. Like most developing cities in the world, major cities in South Korea and the central government concentrated its main strategy on economic growth. Doing so stimulated national economy and made it possible to level up the quality of life. If this quality of life needs to be sustained for a long term, then we should focus on our usage of ecological features, as their characteristics are completely different from man-made resources. PMID- 29984128 TI - Surgical Decision Making in Preduodenal Portal Vein: Report of Two Cases in Neonates. AB - Preduodenal portal vein (PDPV) is a rare anomaly that can cause duodenal obstruction. PDPV is associated with other congenital anomalies, mainly cardiac and gastrointestinal. Treatment usually consists of bypassing the obstruction by duodenoduodenostomy. We report two cases of PDPV in association with atrial isomerism and malrotation with different surgical management. PMID- 29984129 TI - "If You Hear Hoof Beats, Think Horses, Not Zebras". PMID- 29984130 TI - Natural History of NAFLD/NASH. AB - Purpose of Review: The purpose of this review is to summarize the latest knowledge on the natural history of non-alcoholic fatty liver disease (NAFLD). The review focuses on mortality, liver-related complications, and histological course. Recent Findings: Studies during the last decade have established NAFLD as a potentially progressive liver disease. Age and diabetes are the strongest clinical predictors of progressive disease. Fibrosis stage is the most important histological variable to predict mortality and liver-related complications. So far, no study has been able to show that non-alcoholic steatohepatitis at baseline predicts mortality or future liver-related complications when adjusting for fibrosis. Summary: The outlines of the natural history of NAFLD have become clearer during the last decade. There is limited data on factors that predict clinical progression. Prospective longitudinal studies are needed to help us predict worse outcome in individual patients. PMID- 29984132 TI - A Multimaterial Scaffold With Tunable Properties: Toward Bone Tissue Repair. AB - Polyetheretherketone (PEEK)/beta-tricalcium phosphate (beta-TCP) scaffolds are expected to be able to combine the excellent mechanical strength of PEEK and the good bioactivity and biodegradability of beta-TCP. While PEEK acts as a closed membrane in which beta-TCP is completely wrapped after the melting/solidifying processing, the PEEK membrane degrades very little, hence the scaffolds cannot display bioactivity and biodegradability. The strategy reported here is to blend a biodegradable polymer with PEEK and beta-TCP to fabricate multi-material scaffolds via selective laser sintering (SLS). The biodegradable polymer first degrades and leaves caverns on the closed membrane, and then the wrapped beta-TCP is exposed to body fluid. In this study, poly(l-lactide) (PLLA) is adopted as the biodegradable polymer. The results show that large numbers of caverns form on the membrane with the degradation of PLLA, enabling direct contact between beta-TCP and body fluid, and allowing for their ion-exchange. As a consequence, the scaffolds display the bioactivity, biodegradability and cytocompatibility. Moreover, bone defect repair studies reveal that new bone tissues grow from the margin towards the center of the scaffolds from the histological analysis. The bone defect region is completely connected to the host bone end after 8 weeks of implantation. PMID- 29984131 TI - Environmental Determinants of Insufficient Sleep and Sleep Disorders: Implications for Population Health. AB - Purpose of Review: Sleep is important for overall health and well-being. Insufficient sleep and sleep disorders are highly prevalent among adults and children and therefore a public health burden, particularly because poor sleep is associated with adverse health outcomes. Emerging evidence has demonstrated that environmental factors at the household- and neighborhood-level can alter healthy sleep. This paper will (1) review recent literature on the environmental determinants of sleep among adults as well as children and adolescents; and (2) discuss the opportunities and challenges for advancing research on the environment and sleep. Recent Findings: Epidemiologic research has shown that social features of environments, family, social cohesion, safety, noise, and neighborhood disorder can shape and/or impact sleep patterns; and physical features such as light, noise, traffic, pollution, and walkability can also influence sleep and is related to sleep disorders among adults and children. Prior research has mainly measured one aspect of the environment, relied on self reported sleep, which does not correlate well with objective measures, and investigated cross-sectional associations. Although most studies are conducted among non-Hispanic white populations, there is growing evidence that indicates that minority populations are particularly vulnerable to the effects of the environment on insufficient sleep and sleep disorders. Summary: There is clear evidence that environmental factors are associated with insufficient sleep and sleep disorders. However, more research is warranted to evaluate how and which environmental factors contribute to sleep health. Interventions that target changes in the environment to promote healthy sleep should be developed, tested, and evaluated as a possible pathway for ameliorating sleep health disparities and subsequently health disparities. PMID- 29984133 TI - Psychological Impact of Shift Work. AB - Purpose of review: Technology and globalization have been central forces driving the need for shift work. This review examines recent scientific developments that inform our understanding of how psychological process contribute to and are impacted by shift work. Recent findings: Nascent research is beginning to expand beyond circadian misalignment to elucidate the phenomenology of shift work and the associated psychological impairments. Psychological processes and their interaction with biology are considered in the pathophysiology of shift work sleep disorder. Additionally, a review of the adverse consequences of shift work in the cognitive, emotional, and psychosocial domains are reviewed and discussed. Summary: The phenomenology of shift work encompasses multiple domains of biopsychosocial functioning. As such, interventions to reduce the adverse impact of shift work may benefit from an integrated approach. PMID- 29984134 TI - Lung function in HIV-infected children and adolescents. AB - Background: The advent of antiretroviral therapy has led to the improved survival of human immunodeficiency virus (HIV)-infected children to adulthood and to HIV becoming a chronic disease in older children and adolescents. Chronic lung disease is common among HIV-infected adolescents. Lung function measurement may help to delineate the spectrum, pathophysiology and guide therapy for HIV-related chronic lung disease. Aim: The aim of this study was to review the available data on the spectrum and determinants of lung function abnormalities and the impact of antiretroviral therapy on lung function in perinatally HIV-infected children and adolescents. Methods: Electronic databases "PUBMED", "African wide" and "CINAHL" via EBSCO Host, using the MeSH terms "Respiratory function" AND "HIV" OR "Acquired Immunodeficiency Syndrome" AND "Children" OR "Adolescents", were searched for relevant articles on lung function in HIV-infected children and adolescents. The search was limited to English language articles published between January 1984 and September 2017. Results: Eighteen articles were identified, which included studies from Africa, the United States of America (USA) and Italy, representing 2051 HIV-infected children and adolescents, 68% on antiretroviral therapy, aged from 50 days to 24 years. Lung function abnormalities showed HIV-infected participants had increased irreversible lower airway expiratory obstruction and reduced functional aerobic impairment on exercise, compared to HIV-uninfected participants. Mosaic attenuation, extent of bronchiectasis, history of previous pulmonary tuberculosis or previous lower respiratory tract infection and cough for more than 1 month were associated with low lung function. Pulmonary function tests in children established on antiretroviral therapy did not show aerobic impairment and had less severe airway obstruction. Conclusion: There is increasing evidence that HIV-infected children and adolescents have high prevalence of lung function impairment, predominantly irreversible lower airway obstruction and reduced aerobic function. PMID- 29984135 TI - Association of activity behaviours and patterns with cardiovascular risk factors in Swiss middle-aged adults: The CoLaus study. AB - The impact of the combination between physical activity (PA) and sedentary (SE) levels on cardiovascular health is poorly known. We assessed the association of activity behaviours and patterns with cardiovascular risk factors in the general population (The CoLaus study, Switzerland, 2014-2017). 2605 adults (54.4% women, age range 45-86 years) had PA and SE levels measured for 14 days using wrist-worn accelerometry. Four activity behaviours: "Couch potato": low PA & high SE; "Light mover": low PA & low SE; "Sedentary exerciser": high PA & high SE, and "Busy bee": high PA & low SE; and three activity patterns: "Inactive", "Weekend warrior", and "Regularly active" were defined. Smoking, obesity, hypertension, dyslipidemia and diabetes were assessed. Relative to 'Couch potatoes', 'Sedentary exercisers' and 'Busy bees' had a lower likelihood of smoking: Odds Ratio (95% confidence interval): 0.40 (0.27-0.61) and 0.62 (0.47-0.81), obesity: 0.43 (0.29 0.63) and 0.41 (0.31-0.54), and diabetes: 0.53 (0.30-0.95) and 0.62 (0.42-0.89), respectively. Relative to 'Inactives', 'Weekend warriors' and 'Regularly actives' had a lower likelihood of smoking: 0.58 (0.43-0.78) and 0.56 (0.44-0.72), obesity: 0.41 (0.30-0.56) and 0.41 (0.32-0.53), hypertension: 0.66 (0.51-0.85) and 0.72 (0.59-0.89), and diabetes: 0.61 (0.38-0.98) and 0.60 (0.42-0.86), respectively. High PA is associated with a favourable cardiovascular risk profile, even when concomitant with high SE or when PA is concentrated on weekends. These findings suggest that being "Sedentary exerciser" or "Weekend warrior" might be sufficient to prevent cardiovascular disease. PMID- 29984136 TI - Point-of-sale marketing and context of marijuana retailers: Assessing reliability and generalizability of the marijuana retail surveillance tool. AB - As recreational marijuana expands, standardized surveillance measures examining the retail environment are critical for informing policy and enforcement. We conducted a reliability and generalizability study using a previously developed tool involving assessment of a sample of 25 randomly selected Seattle recreational marijuana retailers (20 recreational; 5 recreational/medical) in 2017. The tool assessed: 1) contextual/neighborhood features (i.e., facilities nearby); 2) compliance/security (e.g., age-of-sale signage, age verification); and 3) marketing (i.e., promotions, product availability, price). We found that retailers were commonly within two blocks of restaurants (n = 23), grocery stores (n = 17), liquor stores (n = 13), and bars/clubs (n = 11). Additionally, two were within two blocks of schools, and four were within two blocks of parks. Almost all (n = 23) had exterior signage indicating the minimum age requirement, and 23 verified age. Two retailers had exterior ads for marijuana, and 24 had interior ads. Overall, there were 76 interior ads (M = 3.04; SD = 1.84), most commonly for edibles (n = 28). At least one price promotion/discount was recorded in 17 retailers, most commonly in the form of loyalty membership programs (n = 10) or daily/weekly deals (n = 10). One retailer displayed potential health harms/warnings, while three posted some health claim. Products available across product categories were similar; we also noted instances of selling retailer branded apparel/ paraphernalia (which is prohibited). Lowest price/unit across product categories demonstrated low variability across retailers. This study documented high inter-rater reliability of the surveillance tool (Kappas = 0.73 to 1.00). In conclusion, this tool can be used in future research and practice aimed at examining retailers marketing practices and regulatory compliance. PMID- 29984137 TI - A community health worker intervention to improve blood pressure among Filipino Americans with hypertension: A randomized controlled trial. AB - Behavioral interventions utilizing community health workers (CHWs) have demonstrated effectiveness in improving hypertension disparities in ethnic minority populations in the United States, but few have focused on Asian Americans. We assessed the efficacy of a CHW intervention to improve hypertension management among Filipino Americans with uncontrolled blood pressure (BP) in New York City (NYC) from 2011 to 2013. A total of 240 Filipino American individuals (112 in the treatment group and 128 in the control group) with uncontrolled hypertension (SBP >= 140 mmHg and/or DBP >= 90 mmHg) were recruited from community-based settings in NYC. Using a community-based participatory research approach, treatment participants received 4 educational workshops and 4 one-on one visits with CHWs over a 4-month period, while control group participants received 1 educational workshop. Main outcome measures included BP control, changes in SBP and DBP, and changes in appointment keeping at 8-months. At 8 months, BP was controlled among a significantly greater percentage of treatment group participants (83.3%) compared to the control group (42.7%). The adjusted odds of controlled BP for the treatment group was 3.2 times the odds of the control group (P < 0.001). Both groups showed decreases in SBP and DBP, with greater decreases among treatment participants. Significant between-group differences were also demonstrated in adjusted analyses (P < 0.001). Individuals in the treatment group showed significant changes in appointment keeping. In conclusion, a community-based intervention delivered by CHWs can help improve BP and related factors among Filipino Americans with hypertension in NYC. PMID- 29984138 TI - Advancing health promotion through massage therapy practice: A cross-sectional survey study. AB - The human resources needed to provide health promotion services to improve health behaviors in populations are currently limited. Health promotion and education is included in the definition of massage therapy, and many within the massage therapy profession understand that health promotion and education are a part of massage therapy practice. However, the amounts and types of health promotion activities in massage therapy practice have not been thoroughly explored. The objective of this study was to investigate the current attitudes, practices, and barriers toward providing health promotion in a national sample of practicing massage therapists. A descriptive cross-sectional survey disseminated May to August 2016 to practicing massage therapists in the United States. The majority (90.2%) of the 182 participants agree or strongly agree that it is important for massage therapists to provide health promotion. Therapists with less favorable attitudes about providing health promotion reported more barriers to providing the messages to their patients. Barriers to providing health promotion included a lack of guidelines, knowledge, and skills. Training and guidelines for massage therapists regarding health promotion would be a reasonable next step for future research development. Utilizing massage therapists as health promoters may provide opportunities to deliver more prevention messages to patients which may impact public health. PMID- 29984139 TI - Measuring the effectiveness of workplace health management programs: An Australian example. AB - The workplace can provide opportunities to support workers in adopting and sustaining health enhancing behaviours. Health promotion programs based at the workplace need not only to achieve this goal but also the continuing support of the employers. This can best be achieved by demonstrating a return on their investment. The aim of this study therefore was to develop an integrated workplace health management program which could be associated with measurable outcomes related to benefitting the institution's "bottom line". This program was based in a metropolitan surgical hospital in Melbourne, Australia from 2006 to 2010 with a total workforce of 1400 employees aged 18-74 years (86% female 14% male), The program followed two key principles of 1) building safe and familiar support networks in order to build a workplace culture where all the workers felt valued. 2) Providing time for individual workers to focus on themselves as a means to achieve early intervention and management of injuries. Insurance data generated by the Workers Compensation Authority identified the following 'bottom line' benefits over three years: injury management costs reduced by 56%; number of compensation Injury claims dropped by 46%; time to return to work post injury reduced by 68%, and; a reduction. in premiums of 43% achieved over a six-year period. Insurers world-wide calculate workers' compensation insurance premiums on injury claims history. It is concluded that such data as these can offer a reliable and 'persuasive' measure of health and injury outcomes, in workplace interventions of this nature. PMID- 29984140 TI - Birth history as a predictor of adverse birth outcomes: Evidence from state vital statistics data. AB - One of the most important predictors of preterm births (PTBs) or low-birth-weight births (LBWBs) is whether a mother has had a history of these birth outcomes. This study examined how different characterizations of birth history (e.g., any previous incidence of PTBs or LBWBs, immediate previous birth that was preterm or of low birth weight, and number of previous PTBs or LBWBs) were associated with PTBs or LBWBs. Based on birth records (n = 98,776) reported to the vital statistics electronic registration system in Nebraska from 2005 to 2014, mothers with a history of PTBs or LBWBs were more likely to have recurrences of these outcomes than those who did not have any history of PTBs or LBWBs. The adjusted odds ratios for recurrent PTBs ranged from 2.82 (95% CI: 2.62, 3.04) to 5.54 (95% CI: 4.67, 6.57) depending on how previous incidence of PTBs or LBWBs were characterized. The corresponding adjusted odds ratio for LBWBs ranged from 1.58 (95% CI: 1.43, 1.74) to 6.75 (95% CI: 4.96, 9.17). Relative to other measures used to characterize birth history, the use of number of previous PTBs or LBWBs allows for identifying mothers most vulnerable to recurrences of these birth outcomes. To help identify mothers at risk for future PTBs or LBWBs, it is beneficial to develop state-wide surveillance of reoccurrences for adverse birth outcomes which is feasible by integrating all separated birth records for the same mother using vital statistics data. PMID- 29984141 TI - Changing multiple health risk behaviors in CHOICES. AB - Multiple health behavior change (MHBC) intervention trials to date have only considered behaviors that were directly targeted. Research has yet to consider how untargeted behaviors can affect change in behaviors directly targeted by an intervention or how changes in targeted behaviors might lead to changes in other, untargeted behaviors. This study addresses these gaps with a secondary analysis of change in risk drinking (targeted behavior) and smoking (behavior that was not addressed) in the efficacy trial of CHOICES, an intervention for the prevention of alcohol-exposed pregnancies. Measures included the Timeline Followback for daily alcohol consumption and questions about smoking behavior. Participants were women of childbearing age who were at risk of alcohol-exposed pregnancy at baseline. Baseline smokers were less likely to change their drinking behavior than baseline non-smokers at nine months (n = 579) with Odds Ratio (OR) of 0.681 (95% CI = 0.471-0.985); 41.1% of smokers vs 50.6% of non-smokers reduced drinking to below risk levels (<5 drinks/day and < 8 drinks per week). Meanwhile, smokers who had changed their drinking behavior were more likely than smokers who had not changed their drinking behavior to have also quit smoking at nine months (OR = 2.769; 95% CI = 1.533-5.000); 19.5% vs. 8.1%, respectively. Together, these findings suggest a natural tendency towards change of multiple related behaviors and indicate that while the presence of unaddressed risk behaviors may make a targeted behavior change more difficult, change in one behavior may facilitate change in related behaviors, even when they are not addressed. PMID- 29984142 TI - Objective measurement of physical activity outcomes in lifestyle interventions among adults: A systematic review. AB - Valid, reliable, and direct measures of physical activity (PA) are critical to assessing the impact of lifestyle PA interventions. However, little is known about the extent to which objective measures have been used to assess the outcomes of lifestyle PA interventions. This systematic review had two aims: 1) evaluate the extent to which PA is measured objectively in lifestyle PA interventions targeting adults and 2) explore and summarize what objective measures have been used and what PA dimensions and metrics have been reported. Pubmed, Cochrane Central Register, and PsychInfo were searched for lifestyle PA interventions conducted between 2006 and 2016. Of the 342 articles that met the inclusion criteria, 239 studies measured PA via subjective measures and 103 studies measured PA via objective measures. The proportion of studies using objective measures increased from 4.4% to 70.6% from 2006 to 2016. All studies measuring PA objectively utilized wearable devices; half (50.5%) used pedometers only and 40.8% used accelerometers only. A majority of the 103 studies reported steps (73.8%) as their PA metric. Incorporating objective measures of PA should continue to be a priority in PA research. More work is needed to address the challenges of comprehensive and consistent collecting, reporting, and analyzing of PA metrics. PMID- 29984143 TI - Prevalence of and factors associated with mammography and prostate-specific antigen screening among World Trade Center Health Registry enrollees, 2015-2016. AB - To compare the prevalence of mammography and prostate-specific antigen (PSA) testing in 9/11-exposed persons with the prevalence among the US population, and examine the association between 9/11 exposures and these screening tests using data from the World Trade Center Health Registry (WTCHR) cohort. We studied 8190 female and 13,440 male enrollees aged >=40 years at survey completion (2015 2016), who had a medical visit during the preceding year, had no self-reported breast or prostate cancer, and did not have screening for non-routine purposes. We computed age-specific prevalence of mammography (among women) and PSA testing (among men), and compared to the general population using 2015 National Health Interview Survey data (NHIS). We also computed the adjusted prevalence ratio (PR) and 95% confidence interval (95% CI) to examine the relationship between 9/11 exposures and screening uptakes using modified Poisson regression. Our enrollees had higher prevalences of mammogram and PSA testing than the US general population. 9/11 exposure was not associated with mammography uptake. Proximity to the WTC at the time of the attacks was associated with PSA testing in the age 60-74 group (PR = 1.06; 95% CI = 1.00-1.12). Among rescue/recovery workers and volunteers (RRW), being a firefighter was associated with higher PSA testing than other RRW across all age groups (40-49: PR = 1.45, 95% CI 1.16-1.81; 50-59: PR = 1.33, 95% CI 1.22-1.44; 60-74: PR = 1.14, 95% CI 1.06-1.23). Screening activities should be considered when studying cancer incidence and mortality in 9/11 exposed populations. PMID- 29984144 TI - Effect of multimodal information delivery for diabetes care on colorectal cancer screening uptake among individuals with type 2 diabetes. AB - Despite the significant increase in the risk of colorectal cancer (CRC), one third of individuals with diabetes who met screening recommendations, reported not being up-to-date on CRC screening in the United States. We determined the means through which individuals with type 2 diabetes (T2DM) learned about diabetes care; we further examined their associations with CRC screening uptake. This was a retrospective study of US adults aged 50-75 years diagnosed with T2DM (sample n = 5595, representing 14,724,933 Americans). Data from the 2011-2014 Medical Expenditure Panel Survey were analyzed to compare CRC screening uptake in four learning groups for diabetes care: (1) did not learn, (2) learning from health providers only, (3) learning from other sources (including online sources and group class), and (4) learning from health providers and other sources together (combined learning group). Overall, 70.4% individuals with T2DM were up to-date with CRC screening during 2011-2014. In multivariate logistic regression analysis, the combined learning group had 1.32 (95% confidence interval, 1.01 1.74) times higher odds of being up-to-date on CRC screening than those who did not learn about diabetes care. The odds of being up-to-date on CRC screening were not significant for other learning groups. Our findings suggest that combined ways of health information delivery for diabetes care is associated with increased odds of being up-to-date on CRC screening among individuals with T2DM. Multimodal health information delivery has the potential to result in unintended, positive consequences in preventive care services use. PMID- 29984145 TI - A national survey of primary care physicians: Perceptions and practices of low dose CT lung cancer screening. AB - Soon after the National Lung Screening Trial, organizations began to endorse low dose computed tomography (LCDT) screening for lung cancer in high-risk patients. Concerns about the risks versus benefits of screening, as well as the logistics of identifying and referring eligible patients, remained among physicians. This study aimed to examine primary care physicians' knowledge, attitudes, referral practices, and associated barriers regarding LDCT screening. We administered a national survey of primary care physicians in the United States between September 2016 and April 2017. Physicians received up to 3 mailings, 1 follow-up email, and received varying incentives to complete the survey. Overall, 293 physicians participated, for a response rate of 13%. We used weighted descriptive statistics to characterize participants and their responses. Over half of the respondents correctly reported that the US Preventive Services Task Force recommends LDCT screening for high-risk patients. Screening recommendations for patients not meeting high-risk criteria varied. Although 75% agreed that the benefits of LDCT screening outweigh the risks, fewer agreed that there is substantial evidence that screening reduces mortality (50%). The most commonly reported barriers to ordering screening included prior authorization requirements (57%), lack of insurance coverage (53%), and coverage denials (31%). The most frequently cited barrier to conducting LDCT screening shared decision making was patients' competing health priorities (42%). Given the impact of physician recommendations on cancer screening utilization, further understanding of physicians' LDCT screening attitudes and shared decision-making practices is needed. Clinical practice and policy changes are also needed to engage more patients in screening discussions. PMID- 29984146 TI - Severe acute respiratory distress syndrome in a liver transplant patient. AB - This case report presents a 46-year old man with a failed liver transplant who presented with malaise and dyspnea. Imaging studies revealed diffuse reticulonodular infiltrates and innumerable miliary nodules and a left upper lobe consolidative mass. Examination of bronchoalveolar lavage fluid demonstrated yeast cells with broad-based budding. He was diagnosed with pulmonary blastomycosis and started therapy with liposomal amphotericin. In spite of therapy, he clinically worsened, developing acute respiratory distress syndrome (ARDS) and eventually expired. PMID- 29984147 TI - Microbiological and immunological characteristics of a lethal pulmonary Aspergillus niger infection in a non-neutropenic patient. AB - Invasive pulmonary aspergillosis is increasingly described in non-neutropenic patients, such as patients with COPD receiving corticosteroids and the critically ill. Here, we present a case of a lethal pulmonary Aspergillus niger infection in a COPD patient. Immunological tests showed an impaired innate and adaptive immune response to Aspergillus. A history of COPD, unresponsiveness to antibiotics and especially a suggestive CT-scan should trigger the clinician to consider diseases caused by Aspergillus. PMID- 29984149 TI - A case of pulmonary infection caused by Mycobacterium asiaticum: Difficulties on diagnostic and therapeutic approaches. AB - A 56-year-old previously healthy female presented with chronic productive cough and fever. Chest X-ray revealed right middle lung opacities. Sputum acid fast bacilli smear was positive, however polymerase chain reaction was negative for Mycobacterium tuberculosis. Further investigations were pursued, which identified Mycobacterium asiaticum. Appropriate therapy with isoniazid, rifampin and clarithromycin for total 18 months (including pyrazinamide and ethambutol for first 4 months) resulted in clinical and radiographic improvement. Recognition of the possibility of this rarely described pulmonary pathogen is essential for successful treatment. PMID- 29984148 TI - Sarcomatoid Carcinoma of the Lung Presenting as Localized Bronchiectasis: A Case Report and Review of Literature. AB - Sarcomatoid carcinoma (SC) of the lung is a rare and aggressive biphasic lung tumor with a 5-year survival of 20%. Early detection and treatment is the only way to improve outcomes in patients with SC of the lung. We present a case of primary SC identified early based on high suspicion. A 56-year-old female with a history of chronic obstructive pulmonary disease (COPD) presented with hemoptysis and exertional dyspnea. Chest X-ray revealed right upper lobe (RUL) opacity and patient was started on antibiotics for pneumonia. Due to the persistence of hemoptysis, a computed tomography scan was performed which showed RUL bronchiectasis with scattered nodular opacities suggestive of an infectious process. The patient underwent bronchoscopy which revealed a pedunculated mass in the RUL biopsy of which was consistent with poorly differentiated SC. Positron emission tomography scan revealed Flourdeoxyglucose-avid right peri-hilar mass and another nodule in the RUL. The patient was not a surgical candidate because of severe COPD and was started on chemoradiation therapy. SC of the lung can have various presentations and is usually detected at a later stage and hence, difficult to treat. Our case highlights the importance of critical thinking and prompt diagnostic evaluation in high-risk patients with localized bronchiectasis even without an obvious lung mass on imaging. PMID- 29984150 TI - Cardiac arrest from massive PE in nephrotic syndrome successfully treated with embolectomy and ECMO. AB - Pulmonary emboli (PE) are commonly encountered events with presentations ranging from benign incidental findings to obstructive shock. We present a case of a 20 year old male with nephrotic syndrome who suffered complete cardiovascular collapse with cardiac arrest in the setting of a massive PE, requiring open surgical embolectomy and ECMO support. We reviewed the literature on massive PE's focusing on the use of ECMO and success of the rarely performed open embolectomy for the treatment of obstructive shock from a massive PE. PMID- 29984151 TI - Recurrent idiopathic pulmonary hemosiderosis after long-term remission presented with Sjogren's syndrome: Idiopathic no more? AB - We report a case of recurrent idiopathic pulmonary hemosiderosis after a long term remission presented with Sjogren's syndrome. The patient was diagnosed with IPH due to repeated pneumonia and blood sputum in his childhood. He was admitted to our hospital due to exertional dyspnea and dry cough with bilateral ground glass opacity in chest computed tomography at the age of 32. Video-assisted thoracoscopic surgery was performed and the specimens showed nonspecific interstitial pneumonia pattern with diffuse, chronic alveolar hemorrhage, suggesting recurrence of IPH. He was also diagnosed with Sjogren's syndrome. Further immunological studies will reveal the pathogenesis of IPH. PMID- 29984152 TI - Association of acute depressive symptoms and functional connectivity of emotional processing regions following sport-related concussion. AB - Acute mood disturbance following sport-related concussion is common and is known to adversely affect post-concussion symptoms and recovery. The physiological underpinnings of depressive symptoms following concussion, however, are relatively understudied. We hypothesized that functional connectivity of the emotional processing network would be altered in concussed athletes and associated with the severity of depressive symptoms following concussion. Forty three concussed collegiate athletes were assessed at approximately one day (N = 34), one week (N = 34), and one month post-concussion (N = 30). Fifty-one healthy contact-sport athletes served as controls and completed a single visit. The Hamilton Rating Scale for Depression (HAM-D) was used to measure depressive symptoms. Resting state fMRI data was collected on a 3 T scanner (TR = 2 s) and functional connectivity was calculated in a meta-analytically derived network of regions associated with emotional processing. Concussed athletes had elevated depressive symptoms across the first month post-concussion relative to control athletes, but showed partial recovery by one month relative to more acute visits (ps < 0.05). Concussed athletes had significantly different connectivity in regions associated with emotional processing at one month post-concussion relative to one day post-concussion (p = 0.002) and relative to controls (p = 0.003), with higher connectivity between default mode and attention regions being common across analyses. Additionally, depressive symptoms in concussed athletes at one day (p = 0.003) and one week post-concussion (p = 7 * 10-8) were inversely correlated with connectivity between attention (e.g., right anterior insula) and default mode regions (e.g., medial prefrontal cortex). Finally, the relationships with HAM-D scores were not driven by a general increase in somatic complaints captured by the HAM-D, but were strongly associated with mood-specific HAM-D items. These results suggest that connectivity of emotional processing regions is associated with acute mood disturbance following sport-related concussion. Increased connectivity between attention and default mode regions may reflect compensatory mechanisms. PMID- 29984153 TI - Baseline multimodal information predicts future motor impairment in premanifest Huntington's disease. AB - In Huntington's disease (HD), accurate estimates of expected future motor impairments are key for clinical trials. Individual prognosis is only partially explained by genetics. However, studies so far have focused on predicting the time to clinical diagnosis based on fixed impairment levels, as opposed to predicting impairment in time windows comparable to the duration of a clinical trial. Here we evaluate an approach to both detect atrophy patterns associated with early degeneration and provide a prognosis of motor impairment within 3 years, using data from the TRACK-HD study on 80 premanifest HD (pre-HD) individuals and 85 age- and sex-matched healthy controls. We integrate anatomical MRI information from gray matter concentrations (estimated via voxel-based morphometry) together with baseline data from demographic, genetic and motor domains to distinguish individuals at high risk of developing pronounced future motor impairment from those at low risk. We evaluate the ability of models to distinguish between these two groups solely using baseline imaging data, as well as in combination with longitudinal imaging or non-imaging data. Our models show improved performance for motor prognosis through the incorporation of imaging features to non-imaging data, reaching 88% cross-validated accuracy when using baseline non-longitudinal information, and detect informative correlates in the caudate nucleus and the thalamus both for motor prognosis and early atrophy detection. These results show the plausibility of using baseline imaging and basic demographic/genetic measures for early detection of individuals at high risk of severe future motor impairment in relatively short timeframes. PMID- 29984154 TI - Basal ganglia involvement in ARX patients: The reason for ARX patients very specific grasping? AB - The ARX (Aristaless Related homeoboX) gene was identified in 2002 as responsible for XLAG syndrome, a lissencephaly characterized by an almost complete absence of cortical GABAergic interneurons, and for milder forms of X-linked Intellectual Disability (ID) without apparent brain abnormalities. The most frequent mutation found in the ARX gene, a duplication of 24 base pairs (c.429_452dup24) in exon 2, results in a recognizable syndrome in which patients present ID without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip, described as developmental Limb Kinetic Apraxia (LKA). In this study, we first present ARX expression during human fetal brain development showing that it is strongly expressed in GABAergic neuronal progenitors during the second and third trimester of pregnancy. We show that although ARX expression strongly decreases towards the end of gestation, it is still present after birth in some neurons of the basal ganglia, thalamus and cerebral cortex, suggesting that ARX also plays a role in more mature neuron functioning. Then, using morphometric brain MRI in 13 ARX patients carrying c.429_452dup24 mutation and in 13 sex- and age-matched healthy controls, we show that ARX patients have a significantly decreased volume of several brain structures including the striatum (and more specifically the caudate nucleus), hippocampus and thalamus as well as decreased precentral gyrus cortical thickness. We observe a significant correlation between caudate nucleus volume reduction and motor impairment severity quantified by kinematic parameter of precision grip. As basal ganglia are known to regulate sensorimotor processing and are involved in the control of precision gripping, the combined decrease in cortical thickness of primary motor cortex and basal ganglia volume in ARX dup24 patients is very likely the anatomical substrate of this developmental form of LKA. PMID- 29984155 TI - Urgent challenges in quantification and interpretation of brain grey matter atrophy in individual MS patients using MRI. AB - Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS. PMID- 29984156 TI - Classification of multi-site MR images in the presence of heterogeneity using multi-task learning. AB - With the advent of Big Data Imaging Analytics applied to neuroimaging, datasets from multiple sites need to be pooled into larger samples. However, heterogeneity across different scanners, protocols and populations, renders the task of finding underlying disease signatures challenging. The current work investigates the value of multi-task learning in finding disease signatures that generalize across studies and populations. Herein, we present a multi-task learning type of formulation, in which different tasks are from different studies and populations being pooled together. We test this approach in an MRI study of the neuroanatomy of schizophrenia (SCZ) by pooling data from 3 different sites and populations: Philadelphia, Sao Paulo and Tianjin (50 controls and 50 patients from each site), which posed integration challenges due to variability in disease chronicity, treatment exposure, and data collection. Some existing methods are also tested for comparison purposes. Experiments show that classification accuracy of multi site data outperformed that of single-site data and pooled data using multi-task feature learning, and also outperformed other comparison methods. Several anatomical regions were identified to be common discriminant features across sites. These included prefrontal, superior temporal, insular, anterior cingulate cortex, temporo-limbic and striatal regions consistently implicated in the pathophysiology of schizophrenia, as well as the cerebellum, precuneus, and fusiform, middle temporal, inferior parietal, postcentral, angular, lingual and middle occipital gyri. These results indicate that the proposed multi-task learning method is robust in finding consistent and reliable structural brain abnormalities associated with SCZ across different sites, in the presence of multiple sources of heterogeneity. PMID- 29984157 TI - Coregistrating magnetic source and magnetic resonance imaging for epilepsy surgery in focal cortical dysplasia. AB - Background: Epilepsy surgery for focal cortical dysplasia type II (FCD II) offers good chances for seizure freedom, but remains a challenge with respect to lesion detection, defining the epileptogenic zone and the optimal resection strategy. Integrating results from magnetic source imaging from magnetoencephalography (MEG) with magnetic resonance imaging (MRI) including MRI postprocessing may be useful for optimizing these goals. Methods: We here present data from 21 adult FCD II patients, investigated during a 10 year period and evaluated including magnetic source imaging. 16 patients had epilepsy surgery, i.e. histopathologically verified FCD II, and a long follow up. We present our analysis of epileptogenic zones including MEG in relation to structural data according to MRI data and relate these results to surgical outcomes. Results: FCD II in our cohort was characterized by high MEG yield and localization accuracy and MEG showed impact on surgical success-rates. MEG source localizations were detected in 95.2% of patients and were as close as 12.3 +/- 8,1 mm to the MRI lesion. After a mean follow up of >3 years, we saw >80% Engel I outcomes, with more favourable outcomes when the MEG source was completely resected (Fishers exact test 0,033). Conclusion: We argue for a high value of conducting a combined MEG-MRI approach in the presurgical workup and the resection strategy in patients with FCD II related epilepsy. PMID- 29984158 TI - Longitudinal structural gray matter and white matter MRI changes in presymptomatic progranulin mutation carriers. AB - Introduction: Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods: Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results: Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions: Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD. PMID- 29984159 TI - Information processing speed in multiple sclerosis: Relevance of default mode network dynamics. AB - Objective: To explore the added value of dynamic functional connectivity (dFC) of the default mode network (DMN) during resting-state (RS), during an information processing speed (IPS) task, and the within-subject difference between these conditions, on top of conventional brain measures in explaining IPS in people with multiple sclerosis (pwMS). Methods: In 29 pwMS and 18 healthy controls, IPS was assessed with the Letter Digit Substitution Test and Stroop Card I and combined into an IPS-composite score. White matter (WM), grey matter (GM) and lesion volume were measured using 3 T MRI. WM integrity was assessed with diffusion tensor imaging. During RS and task-state fMRI (i.e. symbol digit modalities task, IPS), stationary functional connectivity (sFC; average connectivity over the entire time series) and dFC (variation in connectivity using a sliding window approach) of the DMN was calculated, as well as the difference between both conditions (i.e. task-state minus RS; DeltasFC-DMN and DeltadFC-DMN). Regression analysis was performed to determine the most important predictors for IPS. Results: Compared to controls, pwMS performed worse on IPS composite (p = 0.022), had lower GM volume (p < 0.05) and WM integrity (p < 0.001), but no alterations in sFC and dFC at the group level. In pwMS, 52% of variance in IPS-composite could be predicted by cortical volume (beta = 0.49, p = 0.01) and DeltadFC-DMN (beta = 0.52, p < 0.01). After adding dFC of the DMN to the model, the explained variance in IPS increased with 26% (p < 0.01). Conclusion: On top of conventional brain measures, dFC from RS to task-state explains additional variance in IPS. This highlights the potential importance of the DMN to adapt upon cognitive demands to maintain intact IPS in pwMS. PMID- 29984160 TI - Callosal circularity as an early marker for Alzheimer's disease. AB - Background: Although brain atrophy is considered to be a downstream marker of Alzheimer's disease (AD), subtle changes may allow to identify healthy subjects at risk of developing AD. As the ability to select at-risk persons is considered to be important to assess the efficacy of drugs and as MRI is a widely available imaging technique we have recently developed a reliable segmentation algorithm for the corpus callosum (CC). Callosal atrophy within AD has been hypothesized to reflect both myelin breakdown and Wallerian degeneration. Methods: We applied our fully automated segmentation and feature extraction algorithm to two datasets: the OASIS database consisting of 316 healthy controls (HC) and 100 patients affected by either mild cognitive impairment (MCI) or Alzheimer's disease dementia (ADD) and a second database that was collected at the Memory Clinic of Hospital Network Antwerp and consists of 181 subjects, including healthy controls, subjects with subjective cognitive decline (SCD), MCI, and ADD. All subjects underwent (among others) neuropsychological testing including the Mini Mental State Examination (MMSE). The extracted features were the callosal area (CCA), the circularity (CIR), the corpus callosum index (CCI) and the thickness profile. Results: CIR and CCI differed significantly between most groups. Furthermore, CIR allowed us to discriminate between SCD and HC with an accuracy of 77%. The more detailed callosal thickness profile provided little added value towards the discrimination of the different AD stages. The largest effect of normal ageing on callosal thickness was found in the frontal callosal midbody. Conclusions: To the best of our knowledge, this is the first study investigating changes in corpus callosum morphometry in normal ageing and AD by exploring both summarizing features (CCA, CIR and CCI) and the complete CC thickness profile in two independent cohorts using a completely automated algorithm. We showed that callosal circularity allows to discriminate between an important subgroup of the early AD spectrum (SCD) and age and sex matched healthy controls. PMID- 29984161 TI - Effects of multisensory stimuli on inhibitory control in adolescent ADHD: It is the content of information that matters. AB - Even though deficits in inhibitory control and conflict monitoring are well-known in ADHD, factors that further modulate these functions remain to be elucidated. One factor that may be of considerable importance is how inhibitory control is modulated by multisensory information processing. We examined the influence of concurrent auditory conflicting or redundant information on visually triggered response inhibition processes in adolescent ADHD patients and healthy controls. We combined high-density event-related potential (ERP) recordings with source localization to delineate the functional neuroanatomical basis of the involved neurophysiological processes. In comparison to controls, response inhibition (RI) processes in ADHD were compromised in conflicting conditions, but showed no differences to controls when redundant or no concurrent auditory information was presented. These effects were reflected by modulations at the response selection stage (P3 ERP) in the medial frontal gyrus (BA32), but not at the attentional selection (P1, N1 ERPs) or resource allocation level (P2 ERP). Conflicting information during RI exerts its influences in adolescent ADHD via response selection mechanisms, but not via attentional selection. It is not the mere presence of concurrent information, but the presence of conflicting information during RI that may destabilize goal shielding processes in medial frontal cortical regions, by means of increasing the automaticity of response tendencies. The occurring RI deficits might relate to the increased impulsivity in adolescent ADHD and a corresponding vulnerability to react to an increased automaticity of pre-potent response tendencies. ADHD patients show a bias to a specific content of information which can modulate inhibitory control. PMID- 29984162 TI - Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system. AB - Background: Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective: To evaluate the capacity of TBSS-based atlas region-of interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods: Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results: Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions: All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question. PMID- 29984163 TI - The relationship between brain atrophy and cognitive-behavioural symptoms in retired Canadian football players with multiple concussions. AB - Multiple concussions, particularly in contact sports, have been associated with cognitive deficits, psychiatric impairment and neurodegenerative diseases like chronic traumatic encephalopathy. We used volumetric and deformation-based morphometric analyses to test the hypothesis that repeated concussions may be associated with smaller regional brain volumes, poorer cognitive performance and behavioural symptoms among former professional football players compared to healthy controls. This study included fifty-three retired Canadian Football League players, 25 age- and education-matched healthy controls, and controls from the Cambridge Centre for Aging and Neuroscience database for validation. Volumetric analyses revealed greater hippocampal atrophy than expected for age in former athletes with multiple concussions than controls and smaller left hippocampal volume was associated with poorer verbal memory performance in the former athletes. Deformation-based morphometry confirmed smaller bilateral hippocampal volume that was associated with poorer verbal memory performance in athletes. Repeated concussions may lead to greater regional atrophy than expected for age. PMID- 29984164 TI - Beta-band oscillations in the supplementary motor cortex are modulated by levodopa and associated with functional activity in the basal ganglia. AB - We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson's disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that patients with PD off medication had an exaggerated movement-related beta-band (13 30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement. PMID- 29984165 TI - Diffusion MRI tractography for improved transcranial MRI-guided focused ultrasound thalamotomy targeting for essential tremor. AB - Purpose: To evaluate the use of diffusion magnetic resonance imaging (MRI) tractography for neurosurgical guidance of transcranial MRI-guided focused ultrasound (tcMRgFUS) thalamotomy for essential tremor (ET). Materials and methods: Eight patients with medication-refractory ET were treated with tcMRgFUS targeting the ventral intermediate nucleus (Vim) of the thalamus contralateral to their dominant hand. Diffusion and structural MRI data and clinical evaluations were acquired pre-treatment and post-treatment. To identify the optimal target location, tractography was performed on pre-treatment diffusion MRI data between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus. The tractography-identified locations were compared to the lesion location delineated on 1 year post-treatment T2-weighted MR image. Their overlap was correlated with the clinical outcomes measured by the percentage change of the Clinical Rating Scale for Tremor scores acquired pre-treatment, as well as 1 month, 3 months, 6 months and 1 year post-treatment. Results: The probabilistic tractography was consistent from subject-to-subject and followed the expected anatomy of the thalamocortical radiation and the dentatothalamic tract. Higher overlap between the tractography-identified location and the tcMRgFUS treatment-induced lesion highly correlated with better treatment outcome (r = -0.929, -0.75, -0.643, p = 0.00675, 0.0663, 0.139 for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex, the entire ipsilateral motor cortex and the contralateral dentate nucleus, respectively, at 1 year post treatment). The correlation for the tractography between the treated thalamus and the hand-knob region of the ipsilateral motor cortex is the highest for all time points (r = -0.719, -0.976, -0.707, -0.929, p = 0.0519, 0.000397, 0.0595, 0.00675 at 1 month, 3 months, 6 months and 1 year post-treatment, respectively). Conclusion: Our data support the use of diffusion tractography as a complementary approach to current targeting methods for tcMRgFUS thalamotomy. PMID- 29984166 TI - Structural white matter changes in adults and children with posttraumatic stress disorder: A systematic review and meta-analysis. AB - White matter plasticity occurs throughout life due to learning and can be a protective factor against as well as a vulnerability factor for the development of mental disorders. In this systematic review we summarize findings on structural white matter changes in children and adults with posttraumatic stress disorder (PTSD) and relate them to theoretical accounts of the pathophysiology of PTSD with a focus on the disturbed processing of contexts and associated problems in emotional and cognitive processing and PTSD symptomatology. We particularly examine studies reporting fractional anisotropy (FA) measured with diffusion tensor imaging (DTI). We further subdivided the studies in adult-onset PTSD with traumatic experience in adulthood, adult-onset PTSD with traumatic experience in childhood and children with PTSD. We included 30 studies comprising almost 1700 participants with 450 adults and 300 children suffering from PTSD. Our systematic review showed that for children with PTSD and adult-onset PTSD with childhood trauma, a decrease in FA in the corpus collosum, most prominently in the anterior and posterior midbody, the isthmus and splenium were reported. For adult-onset PTSD with traumatic experience in adulthood, changes in FA in the anterior and posterior part of the cingulum, the superior longitudinal fasciculus and frontal regions were found. Using GingerAle, we also performed a coordinate-based meta analysis of 14 studies of adult-onset PTSD with traumatic experience in adulthood and did not find any significant clusters. Our results suggest that changes in white matter microstructure vary depending on traumatic experience and are associated with changes in brain circuits related to the processing of contexts. Finally, we present methodological considerations for future studies. PMID- 29984167 TI - The cerebral hemodynamic response to phonetic changes of speech in preterm and term infants: The impact of postmenstrual age. AB - Higher brain dysfunction, such as language delay, is a major concern among preterm infants. Cerebral substrates of cognitive development in preterm infants remain elusive, partly because of limited methods. The present study focuses on hemodynamic response patterns for brain function by using near-infrared spectroscopy. Specifically, the study investigates gestational differences in the hemodynamic response pattern evoked in response to phonetic changes of speech and cerebral hemispheric specialization of the auditory area in preterm infants (n = 60) and term infants (n = 20). Eighty neonates born between 26 and 41 weeks of gestational age (GA) were tested from 33 to 41 weeks of postmenstrual age (PMA). We analyzed the hemodynamic response pattern to phonemic and prosodic contrasts for multiple channels on temporal regions and the laterality index of the auditory area. Preterm infants younger than 39 weeks of PMA showed significantly atypical hemodynamic patterns, with an inverted response shape. Partial correlation analysis of the typicality score of hemodynamic response revealed a significant positive correlation with PMA. The laterality index of preterm infants from 39 weeks of PMA demonstrated a tendency rightward dominance for prosodic changes similar to term infants. We provide new evidence that alterations in hemodynamic regulation and the functional system for phonemic and prosodic processing in preterm infants catch up by their projected due dates. PMID- 29984168 TI - Short- and long-range synergism disorders in lifelong premature ejaculation evaluated using the functional connectivity density and network property. AB - This study was aimed to investigate brain function connectivity in premature ejaculation (PE) patients using the functional connectivity density (FCD) and network property of resting-state functional magnetic resonance imaging. Twenty PE patients (mean age: 27.95 +/- 4.52 years) and 15 normal controls (mean age: 27.87 +/- 3.78 years) with no self-reported history of neurologic or psychiatric disease were enrolled in this study. International Index of Erectile Function-5 and Chinese Index of Sexual Function for Premature Ejaculation-5 questionnaires and self-reported intravaginal ejaculatory latency time (IELT) were obtained from each participant for symptom assessment. Two-sample t-tests (intergroup comparison) were applied in the short-range FCD (SFCD) analysis, long-range FCD (LFCD) analysis, region of interest-based analysis, and network topological organization analysis. Pearson correlation analysis was performed to correlate IELT with FCD or the network property. The patients with PE showed significantly decreased SFCD in the bilateral middle temporal gyrus, left orbitofrontal cortex, nucleus accumbens, fusiform, caudate, and thalamus (p < 0.05, AlphaSim corrected). Notably, all these aforementioned brain areas are located in the dopamine pathway. In contrast, increased LFCD was observed in the left insula, Heschl's gyrus, putamen, bilateral precuneus, supplementary motor area, middle cingulate cortex, and anterior cingulate cortex in PE patients (p < 0.05, AlphaSim-corrected). In addition, the network topological analysis found reinforced network connectivity between several nodes. The degree of hub nodes increased in the patients with PE. IELT was positively correlated with SFCD and negatively correlated with LFCD or the degree of hub nodes (p < 0.05, Pearson correlation). In summary, our results are important for understanding the brain network in PE patients. The present findings indicate that PE patients have a significant synergism disorder across the region of dopamine pathway, which implied neuronal pathological changes might be related with the change of dopamine. The FCD and network property can serve as new disease severity biomarkers and therapeutic targets in PE. PMID- 29984169 TI - Aerobic training modulates salience network and default mode network metabolism in subjects with mild cognitive impairment. AB - Aerobic training (AT) is a promising intervention to improve cognitive functioning. However, its modulatory effects on brain networks are not yet entirely understood. Sixty-five subjects with mild cognitive impairment performed a moderate intensity, 24-week AT program. Differences in resting regional brain glucose metabolism (rBGM) with FDG-PET were assessed before and after AT on a voxel-by-voxel basis. Structural equation modeling was used to create latent variables based on regions with significant rBGM changes and to test a hypothetical model about the inter-relationships between these changes. There were significant rBGM reductions in both anterior temporal lobes (ATL), left inferior frontal gyrus, left anterior cingulate cortex, right hippocampus, left meddle frontal gyrus and bilateral caudate nuclei. In contrast, there was an increase in rBGM in the right precuneus and left inferior frontal gyrus. Latent variables reflecting the salience network and ATL were created, while the precuneus represented the default mode network. In the model, salience network rBGM was decreased after AT. In contrast, rBGM in the default mode network increased as a final outcome. This result suggested improved salience network efficacy and increased control over other brain functional networks. The ATL network decreased its rBGM and connected to the salience network and default mode network with positive and negative correlations, respectively. The model fit values reached statistical significance, demonstrating that this model explained the variance in the measured data. In mild cognitive impairment subjects, AT modulated rBGM in salience network and default mode network nodes. Such changes were in the direction of the normally expected resting-state metabolic patterns of these networks. PMID- 29984170 TI - Hypometabolism of the posterior cingulate cortex is not restricted to Alzheimer's disease. AB - When differential diagnosis of dementia includes both Alzheimer's disease (AD) and the behavioural variant of frontotemporal dementia (bvFTD), distribution of cerebral glucose metabolism as measured using [18F]-2-fluoro-2-deoxy-d-glucose positron emission tomography ([18F]FDG-PET) may be helpful. One important clue for differentiation is the presence of hypometabolism in the posterior cingulate cortex (PCC), usually associated with AD. PCC hypometabolism however, could also be present in bvFTD. Therefore, the specificity of PCC hypometabolism was examined. Based on visual reading PCC hypometabolism was present in 69-73/81 probable AD patients, in 10-16/33 probable bvFTD patients, and in 0-1/22 cognitive normal (CN) subjects. Findings were validated using a PCC to reference tissue [18F]FDG standard uptake value ratio (SUVr) cut-off, which was derived from the receiver operating characteristic (ROC) separating probable AD from CN, resulting in 9-14/33 bvFTD patients having PCC hypometabolism, depending on the reference tissue used. In conclusion, PCC hypometabolism is not restricted to AD. PMID- 29984171 TI - Non-lesional cerebellar damage in patients with clinically isolated syndrome: DTI measures predict early conversion into clinically definite multiple sclerosis. AB - Background: Today, no specific test for the diagnosis of multiple sclerosis (MS) is available due to the lack of characteristic symptoms at beginning. This circumstance also complicates estimation of disease progression. Recent findings provided evidence for early, non-lesional cerebellar damage in patients with (clinically definite) relapsing-remitting MS. Objective: To investigate if microstructural cerebellar alterations can also serve as early structural biomarker for disease progression and conversion from clinically isolated syndrome (CIS) to MS. Methods: 46 patients diagnosed with CIS and 26 age-matched healthy controls were admitted to high-resolution MRI including diffusion tensor imaging (DTI) to examine atrophy and microstructural integrity of the cerebellum. Microstructural integrity of cerebellar white matter was assessed by fractional anisotropy (FA) as derived from DTI. Results: Although all 46 patients of our CIS cohort showed no cerebellar lesions in structural MRI (T1w, T2w, FLAIR), their mean cerebellar FA was already reduced compared to healthy controls. Significant FA reduction at follow-up DTI 6 months after baseline examination was observed. In 16 patients that converted to MS, we found a correlation between initial cerebellar FA and conversion latency (R = 0.71, p < 0.002). Initial cerebellar FA under FAcrit = 0.352 predicted conversion into relapsing-remitting MS within 24 months (FAcrit: mean cerebellar FA of patients with early MS, determined in another study). Conclusion: DTI seems to reflect early tissue injury in beginning MS, when atrophy and lesions are not yet detectable. Decreased cerebellar FA in patients with CIS might indicate an active and unstable disease stage, resulting in a shorter conversion time into MS. PMID- 29984172 TI - Repetitive transcranial magnetic stimulation directed to a seizure focus localized by high-density EEG: A case report. AB - We demonstrate feasibility of using high-density EEG to map a neocortical seizure focus in conjunction with delivery of magnetic therapy. Our patient had refractory seizures affecting the left leg. A five-day course of placebo stimulation followed a month later by active rTMS was directed to the mapped seizure dipole. Active rTMS resulted in reduced EEG spiking, and shortening of seizure duration compared to placebo. Seizure frequency, however, improved similarly in both placebo and active treatment stages. rTMS-evoked EEG potentials demonstrated that a negative peak at 40 ms - believed to represent GABAergic inhibition - was enhanced by stimulation. PMID- 29984173 TI - Unusual seizure evolution: Focal-general-focal-general. AB - Seizure types have been described that do not conform to traditional classification schemes. We present another unusual type characterized by focal onset with secondary generalization, that is followed immediately by continued focal activity that generalizes again without an intervening break. Better understanding of these seizure types may allow improved targeted therapies and help shed light on the mechanistic underpinnings of epilepsy. PMID- 29984175 TI - Test-retest reliability of the questionnaire in the Sasang constitutional analysis tool (SCAT). AB - Background: The Sasang constitutional analysis tool (SCAT) is an integrated Sasang constitutional analysis system developed by the Korea Institute of Oriental Medicine. This study aimed to evaluate the reliability of a questionnaire for measuring personality and pathophysiological symptoms that is one of the components of the SCAT. Methods: In this study, data were collected from university students in their twenties. Tests were administered twice, with an interval of 4 weeks between tests. Test-retest data from 176 students were collected and used for analysis. Internal consistency reliability was analyzed by using Cronbach's alpha coefficient, and test-retest reliability was analyzed by using Spearman's rank correlation coefficient. Results: Cronbach's alpha coefficient was 0.788 for personality, 0.511 for eating habits, 0.718 for digestion, 0.667 for heat- or cold-wise penchant, and 0.612 for water ingestion. Spearman's rank correlation coefficients, which were used to assess correlations between test and retest results, ranged from 0.444 to 0.828. Conclusion: The internal consistency and test-retest reliability of the SCAT questionnaire were found to be satisfactory. PMID- 29984174 TI - New candidates for treatment and management of carpal tunnel syndrome based on the Persian Canon of Medicine. AB - Carpal tunnel syndrome (CTS) is defined as a compressing median mononeuropathy. CTS is one of the major costly debilitating diseases of the hand. Although CTS is a relatively recent concept in current medicine, some evidences show that medieval physicians in Persian medicine (PM) such as Avicenna were familiar with it. The PM textbook written by Avicenna, the Canon of Medicine, defines the anatomy of carpal tunnel and median nerve, as well as mononeuropathy; it also offers suggestions for the prevention and treatment of carpal tunnel syndrome (called as Vaja al-asab and Khadar) in the chapter of nerve diseases. The book describes not only symptoms including pain, paresthesia, hypoesthesia, tingling, and numbness, but also its etiology such as nerve compression (entrapment neuropathy); nonphysical reasons such as disturbed balance among the four body humors; alteration in the nerve's temperament (Mizaj) that prevents the transmission of nerve impulses; and the others such as nutrition, mental condition, sleep, weather condition, body movements, and proper disposal of body waste. Furthermore, the book suggests a lifestyle modification method based on six factors and 10 prescriptions composed with 85 natural products that are not actively used for CTS treatment in modern times. The medicinal suggestions for CTS in the Canon of Medicine will be good candidates for discovering new treatments besides providing historical significance to the various insights considered 1000 years ago. PMID- 29984176 TI - Effect of partially purified sub-fractions of Pterocarpus mildbraedii extract on carbon tetrachloride intoxicated rats. AB - Background: This study was designed to determine the hepatoprotective effect of partially purified fractions from Pterocarpus mildbraedii extract on carbon tetrachloride (CCl4) intoxicated rats. Methods: The methanol extract of P. mildbraedii was subjected to solvent partitioning using n-hexane, chloroform, ethylacetate and water. Separation of fractions with proven antioxidant activity was achieved by chromatographic techniques. Acute toxicity and hepatoprotective studies of the methanol sub-fraction 6 (Me 6), methanol sub-fraction 7 (Me 7) and methanol sub-fraction 8 (Me 8) from P. mildbraedii extract on carbon tetrachloride (CCl4) intoxicated Wister rats. Results: Intoxication of rats with CCl4 resulted in significant (p < 0.05) increase in the activities of aspartate transferase (AST), alanine transferase (ALT), alkaline phosphatase (ALP), level of malondialdehyde (MDA) while glutathione (GSH) concentration, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities were decreased. Administration of Me6, Me7 and Me8 sub-fractions of P. mildbraedii caused a significant reduction (p > 0.05) in the activities of the liver enzymes, MDA level, total and direct bilirubin in dose-dependent manner. There were significant (p < 0.05) increases in GSH concentration, SOD, CAT, and Gpx activities in the treated groups. The subfractions also restored the damaged hepatic-architecture in the treated groups. Conclusion: Therefore, Me6, Me7 and Me8 leaf sub-fractions of P. mildbraedii extract have hepatoprotective effect. Therefore, this vegetable can further be exploited as a source of drug/supplement development in the prevention and treatment of liver damage. PMID- 29984177 TI - Effect of certain trimethoxy flavones on paclitaxel - induced peripheral neuropathy in mice. AB - Background: The anti - nociceptive effect of 7, 2', 3' - trimethoxy flavone, 7, 2', 4' - trimethoxy flavone, 7, 3', 4' - trimethoxy flavone and 7, 5, 4' - trimethoxy flavone against inflammatory, neurogenic and thermal pain in mice was reported earlier. The present study was designed to investigate the effect of the above trimethoxy flavones in amelioration of peripheral neuropathy induced by paclitaxel. Methods: Peripheral neuropathy was induced in mice by administration of a single i.p. dose (10 mg/kg) of paclitaxel. The manifestations of peripheral neuropathy such as tactile allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later by employing hair aesthesiometer test, acetone bubble test and hot water tail immersion test respectively. Further, the role of inflammatory cytokines like TNF - alpha, IL - 1beta and free radicals in the action of trimethoxy flavones was investigated using in vitro assays. Results: The test compounds dose dependently attenuated paclitaxel - induced tactile allodynia, cold allodynia and thermal hyperalgesia in mice. The test compounds inhibited TNF - alpha, IL - 1beta and free radicals in a concentration dependent manner. Conclusion: The investigated trimethoxy flavones attenuated paclitaxel - induced peripheral neuropathy in mice. The inhibition of cytokines and free radicals in addition to many neuronal mechanisms reported earlier may contribute to this beneficial effect. PMID- 29984178 TI - In vitro and in vivo antidiabetic effect of extracts of Melia azedarach, Zanthoxylum alatum, and Tanacetum nubigenum. AB - Background: To investigate the antidiabetic effect of Himalayan Medicinal plants from India viz. Melia azedarach (Family: Meliaceae), Zanthoxylum alatum (Family: Rutaceae), Tanacetum nubigenum (Family: Asteraceae) using in-vitro as well as in vivo approaches. Methods: Their effects were examined on stimulation of glucose uptake by C2C12 cultured cell line, inhibitory effect on human recombinant Protein tyrosine phosphatase-1B (PTP-1B) and followed by the hypoglycaemic activity of extracts in Streptozotocin (STZ) induced diabetic rats. Results: All prepared extracts had been found to enrich with polyphenolic, flavonoids, terpenoids, anthraquinones and saponins type of compounds. n-Butanol fraction of Zanthoxylum alatum showed maximum PTP-1B inhibition (61.9%) whereas ethanol extract of Tanacetum nubigenum showed strong stimulation of glucose uptake (+61.2%) in C2Cl2 myotubes. In STZ induced Sprague-Dawley rats, significant decrease in blood glucose level was observed in ethanol extract of Melia azaderach treated group as 14.8% (p < 0.01) whereas in the ethanol extract of Tanacetum nubigenum treated group, it was observed as 15.5% (p < 0.01) compare to metformin which showed 26.8% (p < 0.01) lowering of blood glucose in the same time duration of 5 h study. Conclusion: This study demonstrated that these plants have a significant therapeutic value in type-2-diabetes mellitus and related complications thus supporting their traditional uses in Indian traditional system of medicine. PMID- 29984179 TI - In vitro anticancer activities of Withania coagulans against HeLa, MCF-7, RD, RG2, and INS-1 cancer cells and phytochemical analysis. AB - Background: The Pakistani Salt Range has a rich floral diversity including Withania coagulans from the Solanaceae family. Methods: The crude methanolic extracts of the root, leaf, leaf stalk, and fruit of this plant were screened for their cytotoxic activity against human (HeLa, MCF-7, RD) and rat (RG2 and INS-1) cancer cell lines at 20 MUg/mL and compared to methotrexate. The IC50 values indicated that leaf stalk and fruit extracts exert an 80% or higher cytotoxic activity against all cell lines at 24 hours. Results: The leaf stalk extract showed the highest cytotoxic efficacy against all tested cell lines, with IC50 values ranging from 0.96 +/- 0.01 MUg/mL to 4.73 +/- 0.05 MUg/mL followed by the fruit extract with IC50 values of 0.69 +/- 0.01-6.69 +/- 0.06 MUg/mL after 48-72 hours incubation. The leaf stalk and seed extracts were analyzed for polyphenols and flavonoids using RP-HPLC. The total flavonoid content (TFC) was calculated for all tested samples, and the highest TFC was recorded for the root extract (394.34 +/- 1.26 MUg/g). The total phenolic content (TPC) was found in the seed extract (307.86 +/- 9.42 MUg/g) of W. coagulans. The highest contents of myricetin (358.46 +/- 2.91 MUg/g) were noted in the leaf extract, and highest quercetin was recorded in the seed extract (21.43 +/- 0.13 MUg/g). The highest gallic acid concentration (83.62 +/- 0.71 MUg/g) was recorded in leaf stalk extract and p-hydroxybenzoic acid in the seed extract (157.46 +/- 1.43 MUg/g). Conclusion: The present study gives a scientific insight and comparative analysis of various plant parts in this medicinally important plant species from the Salt Range of Pakistan against both human and rat cancer cells. PMID- 29984180 TI - Neutrophil to lymphocyte ratio as a predictor of myocardial damage and cardiac dysfunction in acute coronary syndrome patients. AB - Background: Neutrophil to lymphocyte ratio (NLR) in peripheral blood is established to correlate with the morbidity and mortality of heart disease patients. We aimed to define the severity of inflammation (NLR) by observing the association of NLR with cardiac functions or myocardial damage parameters in patients with acute myocardial infarction. Methods: Data from 715 patients who underwent percutaneous coronary intervention (PCI) within 72 hours of incidence in 2016 were analysed retrospectively. Results: The NLR ranges from 0.50 to 46 (medium +/- SD, 2.76 +/- 2.96) in 715 patients. NLR positively correlated with myocardial damage (NLR vs. CK-mB: p < 0.0001) but negatively correlated with myocardial function (NLR vs. EF: p < 0.0001; NLR vs. FS: p < 0.0001). Myocardial damage markers (CK, CK-mB, ASL, LDH) were significantly increased, and cardiac contractile parameters (EF and FS) were reduced at NLR > 2.76 compared to those of NLR < 2.76. ELISA analysis has shown that IL-10 was significantly increased when NLR >= 4.6 and TGF-beta was increased at NLR > 4. The correlation was diminished between NLR and CK-mB at NLR > 2.76 or at NLR > 4, but that of NLR and EF or FS was maintained in NLR > 2.76 and at NLR > 4. EF and FS were comparable between NLR > 2.76 and NLR > 4. But myocardial damage parameters increased significantly at NLR > 4 compared to those of NLR > 2.76. Conclusion: NLR is a strong predictor of myocardial damage in acute myocardial patients. High NLR are associated with myocardial dysfunction in all the patients. Severe inflammation (NLR) can predict the consequence of the heart in patients with coronary syndrome. PMID- 29984181 TI - Interdisciplinary assessment-oriented treatment of fibromyalgia: a case report. AB - Patients with fibromyalgia (FM) have often tried many outpatient treatments, and breakthrough pain frequently stops them from performing everyday tasks and participating in society. FM-pain that has become chronic, therefore, affects quality of life. This case study describes the administration of interdisciplinary inpatient pain therapy due to a primary diagnosis of fibromyalgia with integrated complementary medicine. The female patient, who had several concomitant disorders and had been suffering from pain for many years, benefited from the holistic treatment approach in terms of a reduction in pain and an improvement in physical functions and mental health. The ability to have a positive effect on pain symptoms in the longer term is essential. Compliance with the treatments used should also be improved, so that a healthier lifestyle and better pain management can continue after discharge from hospital. These results are supported by other study results and should provide the impetus for major studies to evaluate holistic pain therapies in FM. PMID- 29984182 TI - Granulomatous hepatitis caused by Bacillus Calmette-Guerin (BCG) infection after BCG bladder instillation: A case report. PMID- 29984183 TI - Retroperitoneal necrotizing fasciitis with gas gangrene caused by urethral stricture. PMID- 29984184 TI - Scrotal reconstruction on scrotal lymphedema. PMID- 29984185 TI - Rejoinder: multiculturalism and interculturalism: alongside but separate. AB - This rejoinder reacts to the comments I have received of my defence of interculturalism (key-article of this Special Issue). Basically it defends the need to take seriously the distinctiveness between MC and IC, as friends rather than foes. It is also argued that the emergence of IC must be placed in the context of legitimacy crisis of MC and the process of policy paradigm change and formation. Then, it is briefly stated that IC tries to fill the epistemological limits of MC and must be considered as a mainstreaming policy within the "local turn" in migration and diversity studies. Moreover, it is contended that IC is a new public mindset and announces a new public culture in a society of multiple identities. Finally that IC makes diversity workwith a view of diversity as an advantage (which means that it is policy resource for cultivating community cohesion, creativity, economic development, solidarity promotion, xenophobia reduction). Finally, I reckon that IC probably requires a multidimensional theory of contact and a more deep normative reflection in terms of public benefits. PMID- 29984186 TI - Interculturalism: Not a new policy paradigm. AB - The central question of the symposium has been whether interculturalism provides a new paradigm that transcends multiculturalism? I note that, consistent with my own position, none of the commentaries answers this question in the affirmative. I concur with the view that interculturalist approaches suffer from an indeterminacy in the use of concepts such as local, place and proximity. When such concepts are given specification, they can have two different meanings: a) face to face encounters, b) urban life and/or governance. Whilst (a) and (b) can be connected together, a dichotimising logic is employed by interculturalists relation to the micro-macro and the city-national. I conclude by specifying, by reference to my work, the key features of multiculturalism that a replacement paradigm has to engage with. PMID- 29984187 TI - The investigation of effect of alpha lipoic acid against damage on neonatal rat lung to maternal tobacco smoke exposure. AB - This study was carried out to determine the changes in the lungs of the rat pups exposed to tobacco smoke during pregnancy period and to investigate the protective effects of alpha lipoic acid, which is administered during pregnancy, on these changes. Spraque-Dawley female rats were divided into four groups: control, tobacco smoke (TS), tobacco smoke + alpha lipoic acid (TS + ALA) and alpha lipoic acid (ALA). The rats in control group were untreated. Rats were exposed to TS twice a day for one hour starting from eight weeks before mating and during pregnancy. 20 mg / kg of ALA was administered to rats. On 7th and 21st days 7 of the pups from each group were decapitated. Histological, morphometric, biochemical and quantitative real-time RT-PCR analyzes were performed. Histopathological and biochemical changes were observed in TS group. While a significant decrease was observed both in SP-A and VEGF immunoreactivities and mRNA levels, caspase-3 immunoreactivity and TUNEL positive cells were increased in TS group. It is suggested that prenatal TS exposure leads to morphological and histopathological changes on lung development by causing oxidative damage in lungs of neonatal rats and the maternal use of ALA can provide a limited protective effect on the neonatal lung development against this oxidative stress originating from TS. Although pregnant women are increasingly aware on health risks of smoking, environmental tobacco smoke exposure is still a widespread problem. For this reason, it is thought that this damage can be partially reduced by some antioxidant supplements in pregnancy. PMID- 29984188 TI - Safety profile of 40% Garcinol from Garcinia indica in experimental rodents. AB - The present study was taken up to evaluate the single dose acute toxicity, 28 days and 90 days repeated dose toxicity and reproductive/developmental toxicity of standardized 40% Garcinol in experimental rodents. The studies were conducted in compliance with OECD principles of good laboratory practice, guidelines for testing of chemicals no.420, 407, 408 and 421 respectively. Single dose acute oral toxicity was conducted on female Wistar rats as sighting study step-I (300 mg/kg) & sighting study step-II (2000 mg/kg) and main study (2000 mg/kg). Sub acute, sub-chronic and reproductive/developmental studies were conducted in Wistar rats divided equally in vehicle control, 20, 50 and 100 mg/kg dose group along with recovery groups for vehicle control and high dose. Reproductive/developmental study was carried out for minimum of 28 days and in females during pregnancy and 4 days post partum. There were no abnormal clinical signs/behavioural changes, reproductive and developmental parameters, gross and histopathological changes as well as no alteration in the body weight, body temperature, haematology and other biochemical parameters in all the four studies. 40% Garcinol has a low toxicity profile in rodents and had no observed effects under experimental conditions used. PMID- 29984189 TI - Glutathione and Inter-alpha-trypsin inhibitor heavy chain 3 (Itih3) mRNA levels in nicotine-treated Cd44 knockout mice. AB - Cluster of differentiation 44 (Cd44), a hyaluronan receptor, and the secreted hyaluronan-binding protein Inter-alpha-trypsin Inhibitor Heavy chain 3 (Itih3) play an important role in cancer and oxidative stress. Smoking of tobacco reduces Itih3 in the plasma and activates hyaluronan signaling through Cd44, but the impact of Cd44 on Itih3 expression is unknown. Here, we studied changes induced by the tobacco component nicotine on the glutathione (GSH) antioxidant system and Itih3 gene expression in Cd44 knockout mice. Cd44 deficiency decreased baseline total GSH and oxidized glutathione (GSSG) levels in the liver compared to wildtype mice. However, contrary to wildtype mice, chronic oral nicotine administration (200 MUg/ml) failed to further reduce total GSH and GSSG in Cd44 mice. Sex differences with lowered glutathione levels in females was also detectable only in wildtype but not Cd44 knockout mice. Itih3 mRNA levels in the liver and hypothalamus were not affected by nicotine, Cd44 genotype or sex. Nonetheless, the correlation between Itih3 and total GSH levels in the liver (r = 0.42, p < 0.05) suggested a role of Itih3 in glutathione metabolism in WT mice. Again this effect was diminished in Cd44 knockout mice. The disappearance of nicotine effects, sex differences and correlations between Itih3 and total GSH in Cd44 knockout mice compared to wildtype animals suggests an interaction between nicotine, Cd44 and/or sex-dependent signaling in the regulation of glutathione metabolism. PMID- 29984190 TI - Short term exposure to titanium, aluminum and vanadium (Ti 6Al 4V) alloy powder drastically affects behavior and antioxidant metabolites in vital organs of male albino mice. AB - Titanium, Aluminum and Vanadium (Ti 6Al 4V) alloy are frequently used as surgical implant but regarding their compatibility in living systems is limited. Ti 6Al 4V was prepared from high purity constituents and Ti 6Al 4V alloy powder (25 mg/ml solvent/Kg body weight) was gavaged to albino mice for 8 days. A saline treated control group was maintained in parallel. A series of behavioral (rota rod, light and dark box, open field and novel object) test performance, complete blood count, selected serum (HDL cholesterol, LDL cholesterol, creatinine, cholesterol and triglycerides) parameters, antioxidant metabolites from vital organs (superoxide dismutase, catalase and lipid peroxidation) from vital organs and body weight were determined in both treatments. It was observed that rota rod test performance in male (P = 0.05) and novel object recognition capability in female mice (P = 0.04) were significantly reduced as compared to their respective control groups. Body weight, complete blood count and studied serum parameters remained unaffected when compared between two treatments of both genders. Concentration of superoxide dismutase in liver (P = 0.008), heart (P = 0.01) and lungs (P = 0.05) was significantly elevated while catalase concentration in liver (P = 0.001) was significantly decreased in female albino mice that were exposed to 25 mg/ml solvent/kg body weight of Ti 6 A l 4 V alloy powder. In case of male albino mice, superoxide dismutase concentration in lungs was reduced (P = 0.05) in mice exposed to Ti 6 A l 4 V alloy powder. In conclusion, our results indicated that short term exposure to 25 mg/ml solvent/Kg body weight of Ti-6Al 4V alloy powder supplementation had adversely affected selected aspects of behavior of albino mice in a gender specific manner. Analysis of antioxidant parameters in vital organs has demonstrated that the applied dose of Ti-6Al-4V alloy powder can disturb the H2O2 associated metabolic pathways in albino mice, especially in female mice. As this alloy is part of surgical implants, so we recommend that their effects in living systems must be extensively explored under variable dose and exposure time conditions to know more about their biocompatibility. PMID- 29984191 TI - Expert-based controllability assessment of control transitions from automated to manual driving. AB - Up to a level of full vehicle automation, drivers will have to be available as a fallback level and take back manual control of the vehicle in case of system limits or failures. Before introducing automated vehicles to the consumer market, the controllability of these control transitions has to be demonstrated. This paper presents a novel procedure for an expert-based controllability assessment of control transitions from automated to manual driving. A standardized rating scheme is developed that allows trained raters to integrate different aspects of driving performance during control transitions (e.g., quality of lateral and longitudinal control, adequateness of signalling to other road users, etc.) into one global controllability measure based on video material of the driving situation. The method is adapted from an existing assessment procedure that has been successfully applied to assess the criticality of driving situations in manual driving conditions (e.g., assessment of substance-induced impairments, assessment of fitness-to-drive of novice drivers). This paper presents the rating procedure, including instructions of how to code relevant qualities of the drivers' performance with accompanying video-demonstrations, and material used for rater training. *A rating procedure for an expert-based controllability assessment of control transitions from automated to manual driving based on observation of video material was adapted from an existing method used in studies on manual driving.*The advantage of this method consists in an integration of different dimensions of driving performance (e.g., operational and tactical driving behaviour, criticality of the situation) into one global controllability measure.*The method allows an assessment and comparison of diverse take-over scenarios, detached from driver performance variables.*The accompanying video based training material allows reproducible and reliable execution of the rating procedure. PMID- 29984192 TI - A method for freeze-fracture and scanning electron microscopy of isolated mitochondria. AB - Electron microscopy as a methodology for the study of mitochondria based on morphological features is a standard technique that has experienced little evolution over the course of several decades. This technology has identified heterogeneity of mitochondria populations across both whole tissues, as well between individual cells, using primarily ultrathin sections for transmission electron microscopy (TEM). However, this technique constrains the evaluation of a sample to a single two-dimensional plane. To overcome this limitation, scanning electron microscopy (SEM) has been successfully utilized to observe three dimensional mitochondria structures within the complex microenvironment containing total cellular components. In response to these dual technical caveats of existing electron microscopy protocols, we developed a methodology to evaluate the three-dimensional ultrastructure of isolated mitochondria, utilizing a freeze fracture step and rigorous preservation of sample morphology. This protocol allows for a more high-throughput analysis of mitochondria populations from a specimen of interest, as the sample has been previously purified, as well as a finer resolution of complex intra-mitochondrial structures, using the depth of field created by SEM. *Protocol designed for SEM of isolated mitochondria samples.*SEM visualizes mitochondria ultrastructure in 3-D.*Freeze-fracture creates cross-sectional plane for view of interior organelle structures. PMID- 29984193 TI - Optimization of phenol-chloroform RNA extraction. AB - Accurate and reliable analysis of gene expression depends on the extraction of pure and high-quality RNA. However, while the conventional phenol-chloroform RNA extraction is preferable over silica-based columns, particularly when cost is a concern or higher RNA yield is desired, it can result in significant RNA contamination. Contaminants including excess phenol, chloroform, or salts, can have significant impacts on downstream applications, including RNA quantification and reverse transcription, that can skew data collection and interpretation. To overcome the issue of RNA contamination in the conventional phenol-chloroform based RNA extraction method, we have optimized the protocol by adding one chloroform extraction step, and several RNA washing steps. Importantly, RNA quality and purity and accuracy in the quantification of RNA concentration were significantly improved with the modified protocol, resulting in reliable data collection and interpretation in downstream gene expression analysis. *Our protocol is customized by the addition of a second chloroform extraction step. Chloroform is carefully pipetted so as to not disturb the interphase layer. Any contaminants accidentally removed from interphase will be present in subsequent steps and can result in RNA contaminated with protein or phenol. The additional chloroform step increases RNA purity.*Additionally, the addition of 2 additional ethanol washes, initially intended to remove any residual salts from the isopropanol RNA precipitation step, also removed residual phenol contamination, enhancing RNA purity.*In summary, these modifications serve to enhance not only the purity of the RNA but, also increase the accuracy and reliability of RNA quantification. PMID- 29984194 TI - Understanding the medial ulnar collateral ligament of the elbow: Review of native ligament anatomy and function. AB - The medial ulnar collateral ligament complex of the elbow, which is comprised of the anterior bundle [AB, more formally referred to as the medial ulnar collateral ligament (MUCL)], posterior (PB), and transverse ligament, is commonly injured in overhead throwing athletes. Attenuation or rupture of the ligament results in valgus instability with variable clinical presentations. The AB or MUCL is the strongest component of the ligamentous complex and the primary restraint to valgus stress. It is also composed of two separate bands (anterior and posterior) that provide reciprocal function with the anterior band tight in extension, and the posterior band tight in flexion. In individuals who fail comprehensive non operative treatment, surgical repair or reconstruction of the MUCL is commonly required to restore elbow function and stability. A comprehensive understanding of the anatomy and biomechanical properties of the MUCL is imperative to optimize reconstructive efforts, and to enhance clinical and radiographic outcomes. Our understanding of the native anatomy and biomechanics of the MUCL has evolved over time. The precise locations of the origin and insertion footprint centers guide surgeons in proper graft placement with relation to bony anatomic landmarks. In recent studies, the ulnar insertion of the MUCL is described as larger than previously thought, with the center of the footprint at varying distances relative to the ulnar ridge, joint line, or sublime tubercle. The purpose of this review is to consolidate and summarize the existing literature regarding the native anatomy, biomechanical, and clinical significance of the entire medial ulnar collateral ligament complex, including the MUCL (AB), PB, and transverse ligament. PMID- 29984195 TI - Comparison of a simplified skin pointer device compared with a skeletal marker for knee rotation laxity: A cadaveric study using a rotation-meter. AB - AIM: To compare the measurements of knee rotation laxity by non-invasive skin pointer with a knee rotation jig in cadaveric knees against a skeletally mounted marker. METHODS: Six pairs of cadaveric legs were mounted on a knee rotation jig. One Kirscher wire was driven into the tibial tubercle as a bone marker and a skin pointer was attached. Rotational forces of 3, 6 and 9 nm applied at 0 degrees , 30 degrees , 45 degrees , 60 degrees and 90 degrees of knee flexion were analysed using the Pearson correlation coefficient and paired t-test. RESULTS: Total rotation recorded with the skin pointer significantly correlated with the bone marker at 3 nm at 0 degrees (skin pointer 23.9 +/- 26.0 degrees vs bone marker 16.3 +/- 17.3 degrees , r = 0.92; P = 0.0), 30 degrees (41.7 +/- 15.5 degrees vs 33.1 +/- 14.7 degrees , r = 0.63; P = 0.037), 45 degrees (49.0 +/- 17.0 degrees vs 40.3 +/- 11.2 degrees , r = 0.81; P = 0.002), 60 degrees (45.7 +/- 17.5 degrees vs 34.7 +/- 9.5 degrees , r = 0.86; P = 0.001) and 90 degrees (29.2 +/- 10.9 degrees vs 21.2 +/- 6.8 degrees , r = 0.69; P = 0.019) of knee flexion and 6 nm at 0 degrees (51.1 +/- 37.7 degrees vs 38.6 +/- 30.1 degrees , r = 0.90; P = 0.0), 30 degrees (64.6 +/- 21.6 degrees vs 54.3 +/- 15.1 degrees , r = 0.73; P = 0.011), 45 degrees (67.7 +/- 20.6 degrees vs 55.5 +/- 9.5 degrees , r = 0.65; P = 0.029), 60 degrees (62.9 +/- 22.4 degrees vs 45.8 +/- 13.1 degrees , r = 0.65; P = 0.031) and 90 degrees (43.6 +/- 17.6 degrees vs 31.0 +/- 6.3 degrees , r = 0.62; P = 0.043) of knee flexion and at 9 nm at 0 degrees (69.7 +/- 40.0 degrees vs 55.6 +/- 30.6 degrees , r = 0.86; P = 0.001) and 60 degrees (74.5 +/- 27.6 degrees vs 57.1 +/- 11.5 degrees , r = 0.77; P = 0.006). No statistically significant correlation with 9 nm at 30 degrees (79.2 +/- 25.1 degrees vs 66.9 +/- 15.4 degrees , r = 0.59; P = 0.055), 45 degrees (80.7 +/- 24.7 degrees vs 65.5 +/- 11.2 degrees , r = 0.51; P = 0.11) and 90 degrees (54.7 +/- 21.1 degrees vs 39.4 +/- 8.2 degrees , r = 0.55; P = 0.079). We recognize that 9 nm of torque may be not tolerated in vivo due to pain. Knee rotation was at its maximum at 45 degrees of knee flexion and increased with increasing torque. CONCLUSION: The skin pointer and knee rotation jig can be a reliable and simple means of quantifying knee rotational laxity with future clinical application. PMID- 29984196 TI - Detecting CALR Mutations in Splanchnic Vein Thrombosis: Who and How? PMID- 29984197 TI - Shear Stress Regulation of Endothelium: A Double-edged Sword. PMID- 29984198 TI - What a Clinician Should Know About a Renal Replacement Membrane? PMID- 29984199 TI - Hypoxia-inducible Factor may Induce the Development of Liver Fibrosis in Budd Chiari Syndrome by Regulating CD248/endosialin Expression: A Hypothesis. AB - Budd-Chiari syndrome (BCS) leads to the development of liver fibrosis in most of the cases. However, the mechanism of BCS-related liver fibrosis is unclear, and it may be largely different from that induced by chronic viral hepatitis. Hepatic stellate cell (HSC) and its specific marker CD248/endosialin are known to play an important regulatory role in the development of liver fibrosis. Additionally, hypoxia microenvironment and hypoxia-inducible factor (HIF) are involved in the regulation of CD248/endosialin. Therefore, we hypothesize that hypoxia microenvironment which develops due to BCS can regulate the expression of CD248/endosialin in HSC via HIF signaling pathway, which then affects the function of HSC and development of liver fibrosis. To confirm the hypothesis, two major investigations are necessary: (1) in the BCS animal model and clinical studies, the relationship between the severity of liver fibrosis and the expression of HIF and CD248/endosialin in HSC will be explored; and (2) in the in vitro cell system, the effect of hypoxic microenvironment, HIF-1alpha or HIF 2alpha, on the expression of CD248/endosialin in HSC will be explored. It will be important to elucidate whether HIF signaling pathway regulates the expression of CD248/endosialin, thereby inducing the development of BCS-related liver fibrosis. PMID- 29984200 TI - Adenosquamous Carcinoma of the Esophagus: A Literature Review. AB - Adenosquamous carcinoma (ASC) of the esophagus is an uncommon type of esophageal cancer that contains both adenocarcinoma and squamous cell carcinoma elements. Data on this biologically unique type of cancer are limited and mainly stem from case reports and small case series. We performed an audit of the available literature and synthesized a review on the epidemiology, pathogenesis, histopathology, clinical manifestations, diagnosis, treatment and prognosis of ASCs. Adenosquamous carcinoma of the esophagus is a rare type of esophageal cancer. Histological examination is necessary to confirm the diagnosis of ASC and patients usually receive multimodal treatment. Patient outcomes are not well defined and further research could help us better understand the pathophysiology and unique needs of patients with this rare malignancy. PMID- 29984201 TI - Acute Respiratory Distress Syndrome: An Update and Review. AB - Acute respiratory distress syndrome (ARDS) is a life threatening condition characterized by severe hypoxemia due to pulmonary gas exchange failure and was first recognized in 1960s.Since its first description, it has undergone intensive research in the past few decades to understand its pathogenesis and therapies. Despite this, the recommended therapies to decrease mortality in ARDS remain limited and include low-tidal volume mechanical ventilation, prone ventilation and recently, the ECMO rescue therapy in extreme cases. This review article will summarize the key features of ARDS with a brief overview of the therapeutic options in the management of ARDS. PMID- 29984202 TI - Dyspepsia Amongst End Stage Renal Disease Undergoing Hemodialysis: Views from a Large Tertiary Care Center. AB - Background and Objectives: Gastrointestinal symptoms are common in patients with end stage renal disease (ESRD) among which dyspepsia is frequently observed. The aim of the study was to determine the frequency and associations of dyspepsia in ESRD patients using the Leeds questionnaire. Methods: All ESRD patients on maintenance hemodialysis were consecutively enrolled in the study. Leeds questionnaire was used to interrogate the patients for the assessment of dyspepsia. Mean and standard deviation were calculated for age, body mass index (BMI), disease duration and number of hemodialysis sessions. Independent t-test and Chi square tests were used for statistical analysis. Results: Total number of patients was 200, out which 118 (59.3%) were male. The mean age was of 41.4 years. According to the Leeds questionnaire, dyspepsia was present in 62 (63.9%) patients. Younger patients (age 20-40 years) more frequently had dyspeptic symptoms (61.5% patients), retrosternal pain (156 patients, 78.0%), regurgitation (127 patients, 63.5%), dysphagia (67 patients, 33.5%), and nausea (142 patients, 71.0%). Patients presented with intermittent pattern of symptoms in 179 (89.5%) cases, while continuous symptoms in 6 (3.0%). Dyspepsia was associated with aspartate aminotransferase (AST) levels > 25 U/L (P = 0.001), alanine aminotransferase (ALT) levels > 28U/L (P = 0.000) and gamma glutamyl transferase (GGT) levels > 34 U/L (P = 0.002). On multivariate analysis, urea, creatinine, and presenting symptoms of dysphagia and belching showed significant statistical association with dyspepsia. Conclusion: Dyspepsia is a common problem affecting patients with end stage renal disease and is associated with raised serum AST, ALT and GGT in such patients. PMID- 29984203 TI - Hepatitis C Screening in Commercially Insured U.S. Birth-cohort Patients: Factors Associated with Testing and Effect of an EMR-based Screening Alert. AB - Background and Objectives: Hepatitis C virus (HCV) testing rates among U.S. birth cohort patients have been studied extensively, limited data exists to differentiate birth-cohort screening from risk- or liver disease-based testing. This study aims to identify factors associated with HCV antibody (HCV-Ab) testing in a group of insured birth cohort patients, to determine true birth cohort testing rates, and to determine whether an electronic medical record (EMR)-driven Best Practice Alert (BPA) would improve birth cohort testing rates. Methods: All birth-cohort outpatients between 2010 and 2015 were identified. HCV-Ab test results, clinical, and demographic variables were extracted from the EMR, and factors associated with testing were analyzed by logistic regression. True birth cohort HCV screening rates were determined by detailed chart review for all outpatient visits during one calendar month. An automated Best Practice Alert was used to identify unscreened patients at the point of care, and to prompt HCV testing. Screening rates before and after system-wide implementation of the BPA were compared. Results: The historic HCV-Ab testing rate was 11.2% (11,976/106,753). Younger age, female gender, and African American, Asian, or Hispanic ethnicity, and medical comorbidities such as chronic hemodialysis, HIV infection, and rheumatologic and psychiatric comorbidities were associated with higher testing rates. However, during the one-month sampling period, true age cohort-based testing was performed in only 69/10,089 patients (0.68%). Following the system-wide implementation of the HCV BPA, testing rates increased from 0.68% to 10.76% (P<0.0001). Conclusions: We documented low HCV-Ab testing rates in our baby boomers population. HCV testing was typically performed in the presence of known risk factors or established liver disease. The implementation of an EMR based HCV BPA resulted in a marked increase in testing rates. Our study highlights current HCV screening gaps, and the utility of the EMR to improve screening rates and population health. PMID- 29984204 TI - Does Hepatic Impairment Influence Renal Function Parameters in Liver Cirrhosis? PMID- 29984206 TI - Current clinical applications of platelet-rich plasma in various gynecological disorders: An appraisal of theory and practice. AB - The purpose of this paper is to review the current clinical uses of platelet-rich plasma (PRP) in the field of gynecology. All relevant articles published from January 2000 to December 2017 were reviewed and analyzed. The articles on PRP in the field of gynecology were mainly case series, pilot studies, or case reports. PRP is currently considered a new therapeutic modality for some disorders that are refractory to conventional drugs. PMID- 29984207 TI - Differentiation of human male germ cells from Wharton's jelly-derived mesenchymal stem cells. AB - Objective: Recapitulation of the spermatogenesis process in vitro is a tool for studying the biology of germ cells, and may lead to promising therapeutic strategies in the future. In this study, we attempted to transdifferentiate Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) into male germ cells using all-trans retinoic acid and Sertoli cell-conditioned medium. Methods: Human WJ-MSCs were propagated by the explant culture method, and cells at the second passage were induced with differentiation medium containing all-trans retinoic acid for 2 weeks. Putative germ cells were cultured with Sertoli cell-conditioned medium at 36C for 3 more weeks. Results: The gene expression profile was consistent with the stage-specific development of germ cells. The expression of Oct4 and Plzf (early germ cell markers) was diminished, while Stra8 (a premeiotic marker), Scp3 (a meiotic marker), and Acr and Prm1 (postmeiotic markers) were upregulated during the induction period. In morphological studies, approximately 5% of the cells were secondary spermatocytes that had completed two stages of acrosome formation (the Golgi phase and the cap phase). A few spermatid-like cells that had undergone the initial stage of tail formation were also noted. Conclusion: Human WJ-MSCs can be transdifferentiated into more advanced stages of germ cells by a simple two-step induction protocol using retinoic acid and Sertoli cell-conditioned medium. PMID- 29984205 TI - The effects of oral antioxidants on the semen of men with idiopathic oligoasthenoteratozoospermia. AB - It has been estimated that approximately 15% of reproductive-age couples suffer from infertility. Male factors contribute to almost half of infertility cases, and in many patients the underlying cause of oligoasthenoteratozoospermia is unknown. Accumulating evidence suggests that oxidative stress plays a role as a contributing factor to male infertility, and reactive oxygen species have been shown to impair sperm function and motility and to damage sperm membrane and DNA. Therefore, this review explored the evidence provided by studies published from 2002 to 2017 on the impact of oral antioxidants (vitamin C, vitamin E, L carnitine, coenzyme Q10, zinc, selenium, and pentoxifylline) on seminal fluid parameters in men with idiopathic oligoasthenoteratozoospermia. Most of the studies were randomized controlled studies that investigated the effect of single or combined antioxidants and reported improvements in at least one semen parameter. The most noteworthy effect that was found was that the use of multiple antioxidants increased sperm motility and concentration. Nonetheless, there is a lack of agreement on the dose, the duration of treatment, and whether individual or combined oral antioxidants should be used. Therefore, the current review provides evidence supporting the use of oral antioxidants in the treatment of infertile men with idiopathic oligoasthenoteratozoospermia. PMID- 29984208 TI - Evaluation of prooxidant-antioxidant balance in in vitro fertilization-conceived mice. AB - Objective: Concerns about the safety of assisted reproductive technology (ART) have been raised, as some studies have shown elevated incidence rates of childhood cancer, asthma, allergies, and other diseases in ART-conceived babies. Findings regarding the health of ART-conceived babies are controversial. The present study was conducted to evaluate the prooxidant-antioxidant balance (PAB) in in vitro fertilization (IVF)-conceived mice in comparison to naturally conceived offspring. Methods: Mice (6-8 weeks) were divided into two groups (IVF conceived and naturally conceived) matched by sex, age, weight, and litter size. A 1-mL blood sample was taken and the sera were separated. The oxidant antioxidant balance was evaluated using a fast and reliable PAB assay. The results were expressed as mean+/-standard deviation. Results: The mean PAB values (HK units) in the IVF-conceived and naturally conceived groups were 59.70+/-22.30 and 54.70+/-18.22, respectively (p=0.82). Conclusion: Since free radicals contribute to several pathological conditions and antioxidants play an important protective role against oxidative stress, evaluating the oxidant-antioxidant balance is very important. Although the results of this study showed that the quality of the defense mechanism against free radicals was not significantly different between the IVF-conceived and naturally conceived mice, other parameters of metabolic dysfunction need to be measured. PMID- 29984209 TI - Seminal reactive oxygen species and total antioxidant capacity: Correlations with sperm parameters and impact on male infertility. AB - Objective: The aim of this study was to measure reactive oxygen species (ROS) production and total antioxidant capacity (TAC) in the seminal fluid of the male partners in couples undergoing intrauterine insemination and to evaluate correlations between these values and their semen parameters. Methods: The study was conducted at Vamsam Fertility Center, Coimbatore, India and enrolled 110 male patients from whom semen samples were collected. ROS production was measured by a thiobarbituric acid reactive species assay, and TAC was measured by a 2,2 diphenyl-2-picrylhydrazyl free radical assay. The differences in the TAC and malondialdehyde (MDA) levels between the subfertile and fertile groups were analysed. Correlations between sperm parameters and TAC and MDA levels were statistically analysed, and cutoff values with respect to the controls were determined. All hypothesis tests used were two-tailed, with statistical significance assessed at the level of p<0.05. Results: A total of 87 subfertile and 23 fertile men were included in the study. The mean MDA level was significantly higher in the subfertile subjects than in the fertile subjects, and the mean antioxidant level was significantly lower in the subfertile subjects than in the fertile subjects. Seminal MDA levels were negatively associated with sperm concentration, motility, and morphology, whereas the opposite was seen with TAC levels. Conclusion: Measurements of seminal TAC and ROS are valuable for predicting semen quality, and hence predicting the outcomes of fertility treatment. PMID- 29984210 TI - A new biomarker for the early diagnosis of ovarian torsion: SCUBE-1. AB - Objective: Prompt diagnosis and management are essential for saving the adnexal organs from infarction in cases of ovarian torsion (OT). This study aimed to determine the diagnostic significance of signal peptide, complement C1r/C1s, Uegf, and Bmp1 (CUB), and epidermal growth factor-like domain-containing protein 1 (SCUBE-1) levels in cases of OT, an emergent ischemic condition, and the relationship of SCUBE-1 with oxidative stress parameters. Methods: This prospective study was conducted among 15 OT patients and 20 age- and gravidity matched healthy women. SCUBE-1 serum concentrations were determined by using enzyme-linked immunosorbent assays. In addition, oxidative stress was evaluated by measuring the serum levels of advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP), and glutathione (GSH). Results: The SCUBE-1 titers were significantly higher in the patients with OT than in the controls (p=0.008). In addition, serum FRAP and GSH levels were significantly lower in the OT patients than in the controls (p<0.001 for both). Serum AOPP levels were higher in the OT patients, but this trend was not statistically significant (p>0.05). Furthermore, there were no correlations between SCUBE-1 levels and age, gravidity, parity, cyst size, and AOPP, FRAP, or GSH levels (p>0.05). Conclusion: We believe that SCUBE-1 may be a promising biomarker for the early diagnosis of OT. PMID- 29984211 TI - Prevalence of kidney dysfunction in diabetes mellitus and associated risk factors among productive age Indonesian. AB - Background: The prevalence of diabetes mellitus is increasing in Indonesia due to population growth, urbanization, and lifestyle. Diabetes mellitus (DM) is the leading cause of chronic kidney disease that escalates mortality rate, but not all DM develop into chronic kidney disease. Aims: To estimate the prevalence of kidney dysfunction (KD) in DM and the associated dominant risk factors among productive age Indonesian based on the National Health Survey (Riskesdas) 2013. Methods: The statistical data consisted of 15,791 females and 10,349 males, aged 20 to 54, who lived in rural and urban areas. The data was obtained from National Institute of Health Research and Development (NIHRD), Ministry of Health. Data were collected from 33 provinces using cross sectional method. The variables data analyzed were sociodemographic, lifestyle, anthropometric, blood pressure, blood lipid, blood glucose, and creatinine. Kidney dysfunction was defined according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Multivariable logistic regression was used to analyze the dominant associated risk factors. Results: The prevalence of KD in DM was 4% (CI 95% 3.1-5.1) and only 0.6% had been diagnosed. Many associated risk factors could affect DM leading to KD such as age, sex, rural, economic status, sugary food/drinks, salty food, coffee, hypertension, hypercholesterolemia, low HDL, high LDL, and hypertriglyceridemia. The dominant associated risk factors were age, sex, economic status, sugary food/drinks, and low HDL. Conclusion: The prevalence of KD in DM among productive age Indonesian was 4% and only 0.6% had been diagnosed. Early detection of identification of KD in DM is needed in order to slow progression and complications. The dominant associated risk factors of KD in DM were age, sex, economic status, sugary food/drinks, and low HDL. Controlling of risk factors in DM should be done in order to prevent diabetic kidney disease. PMID- 29984212 TI - Role of Wnt/beta-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. AB - Hepatocellular carcinoma (HCC) is one of the most common primary hepatic malignancies and one of the fastest-growing causes of cancer-related mortality in the United States. The molecular basis of HCC carcinogenesis has not been clearly identified. Among the molecular signaling pathways implicated in the pathogenesis of HCC, the Wnt/beta-catenin signaling pathway is one of the most frequently activated. A great effort is under way to clearly understand the role of this pathway in the pathogenesis of HCC and its role in the transition from chronic liver diseases, including viral hepatitis, to hepatocellular adenomas (HCAs) and HCCs and its targetability in novel therapies. In this article, we review the role of the beta-catenin pathway in hepatocarcinogenesis and progression from chronic inflammation to HCC, the novel potential treatments targeting the pathway and its prognostic role in HCC patients, as well as the imaging features of HCC and their association with aberrant activation of the pathway. PMID- 29984213 TI - Treatment Outcomes and Risk Factors for In-Hospital Mortality in Patients with Acute Aortic Occlusion. AB - Purpose: The aims of the present study are to determine the outcomes after acute aortic occlusion (AAO) and analyze the risk factors for in-hospital mortality. Materials and Methods: We retrospectively analyzed 24 patients who were diagnosed with AAO from 2002 to 2017 in our registered data. Demographic and radiologic characteristics of AAOs were retrospectively collected. Perioperative treatment outcomes including in-hospital mortality were also assessed and the risk factors of in-hospital mortality were analyzed. Results: The median symptom duration was 21 hours. Five patients had complete paraplegia and 10 patients (41.7%) were initially evaluated for central nervous system disorders instead of acute arterial occlusion. The etiology was determined to be aortoiliac thrombosis in 17 patients (70.8%) and embolic occlusion in 7. Surgical revascularization was performed in 23 patients, and one patient did not receive any treatment. The overall in-hospital mortality was 34.8% (8/23) and 30-day mortality was 26.1%. In the univariate analysis, age (P=0.040), preoperative renal insufficiency (serum creatinine over 1.5 mg/dL at the time of presentation) (P=0.008), postoperative acute kidney injury (need for dialysis or an increase in serum creatinine of >50.0% within 48 hours) (P=0.006), combined external iliac artery occlusion (P=0.019) and combined bilateral internal iliac artery occlusion (P=0.039) were associated with in-hospital mortality. Conclusion: A substantial number of AAO patients were initially evaluated for a central nervous system lesion, which led to a delay in diagnosis. Thus, vascular examinations should always be performed in every patient presenting with lower limb neurologic deficits. Age, perioperative renal function, and combined iliac artery occlusion were associated with the prognosis of AAOs. PMID- 29984214 TI - Does Catheter-Directed Thrombolysis Prevent Postthrombotic Syndrome? AB - Purpose: The aim of this study is to identify risk factors of postthrombotic syndrome (PTS) and evaluate the efficacy of catheter-directed thrombolysis (CDT) for preventing the development of PTS in patients with lower extremity deep vein thrombosis (DVT). Materials and Methods: From 2005 January to 2013 December, 139 limbs of 126 patients were included in this study who had the first episode of proximal DVT at the affected limb and who had visited our out-patient clinic. CDT was performed on 55 limbs (39.6%). We achieved complete recanalization in 39 limbs (70.9%) and partial recanalization (residual thrombus <50.0%) in 16 limbs (29.1%). We retrospectively reviewed medical records for possible predictors of PTS. Results: Median follow-up duration was 83 months (range, 30-136 months). No differences were found between the CDT and non-CDT group in age, gender, duration of symptom, use of anticoagulation and recurrence of DVT. A significantly higher thrombotic burden was observed in the CDT group (P=0.009). In a binary logistic regression model, patients with PTS had significantly higher body mass index (BMI) (odds ratio [OR], 1.303; 95% confidence interval [CI], 1.079-1.574; P=0.006) and longer thrombotic burden involved in ilio-femoro-popliteal DVT (OR, 3.666; 95% CI, 1.093-12.296; P=0.035). CDT did not influence the risk of PTS (P>0.05). Conclusion: We suggest that CDT is not effective in preventing PTS, while higher BMI and longer thrombotic burden are associated with the development of PTS in patients with DVT. PMID- 29984215 TI - Symptomatic Bilateral Carotid Artery Occlusion: An Uncommon Pattern of Carotid Pathology. AB - We report an unusual case of an 83-year-old man who was admitted with dizziness and repeated drop attacks. He was diagnosed with bilateral carotid artery occlusion and he underwent a left subclavian to left carotid bypass with ringed polytetrafluoroethylene graft. The patient's postoperative course was uneventful and no symptoms presented during a 6-month follow-up. Finally, we discuss on proper management of such patients. PMID- 29984216 TI - Hybrid Surgery to Treat Multiple Visceral Aneurysms Secondary to Polyarteritis Nodosa. AB - A 57-year-old woman presented to vascular surgery clinic with visceral artery aneurysms that were incidentally detected during regular check-up. Imaging studies revealed occlusion of the celiac axis and severe stenosis of the superior mesenteric artery and 3 aneurysms along the posterior and inferior pancreaticoduodenal arteries, as well as the right gastroepiploic artery. Endovascular embolization of all aneurysms was rejected because of the risk of hepatic ischemia. These complicated lesion caused by polyarteritis nodosa were successfully treated using a hybrid operation with coil embolization, aneurysm resection, and antegrade aorto-celiac-superior mesentery artery bypass. PMID- 29984217 TI - Detrimental Effects of Endovascular Intervention in Active Rheumatoid Vasculitis. AB - Balloon angioplasty can cause shear stress and tear of the vascular endothelium during mechanical dilatation, leading to increased inflammation and coagulation reactions of the vascular endothelium. Herein, a worst case of active rheumatoid vasculitis is described, where due to progressing ischemic necrosis of the leg, endovascular intervention was unavoidably performed in the presence of active rheumatoid vasculitis. After percutaneous balloon angioplasty, the patient developed recurrent thrombotic occlusion of the leg arteries, and finally, limb amputation resulted in despite vigorous treatment including medication, immunosuppression, catheter-directed thrombolysis, and post-thrombolysis anticoagulation. This case report indicates that endovascular intervention may be detrimental to the active rheumatoid vasculitis. Until the development of treatment guideline to prevent or control inflammatory reaction, endovascular intervention for the active rheumatoid vasculitis may not be appropriate as a first line therapy even though there is progressing ischemic necrosis. PMID- 29984219 TI - Ruptured Mycotic Aneurysm of the Common Carotid Artery: A Case Report. AB - Mycotic aneurysms of the common carotid artery (CCA) are very rare and warrant surgical treatment to prevent rupture and death. A 89-year-old man who complained of a sore throat and swelling of the right side of neck. He had no history of trauma or neck infection. Physical examination revealed hard and pulsatile mass. Computed tomography showed initially pseudoaneurysm rupture on the right CCA with surrounding inflammation. The emergency operation revealed mycotic aneurysm rupture with CCA necrosis and was successfully done by wide debridement and carotid artery resection with interposition bypass. The resected tissue and blood culture grew growth of Staphylococcus aureus group. We report a rare case of mycotic aneurysm of right CCA that treated by bypass interposition. PMID- 29984218 TI - Endovascular Treatment of a Saccular Aneurysm in the Celiomesenteric Trunk: A Case Report and Review of Literature. AB - To present a world-first case of a successful endovascular treatment of a celiomesenteric trunk (CMT) aneurysm. A 45-year-old man had an asymptomatic saccular aneurysm in a rare anomaly of CMT. Endovascular multiple micro-coil embolization of the common hepatic artery, splenic artery and the aneurysm was done, followed by a stent-graft deployment in the superior mesenteric artery covering the orifice to the aneurysm. Postoperative course was uneventful. Only 21 cases have been previously reported in the literature, and all were treated by open surgeries. Endovascular therapy can be safely done in selected cases of a CMT aneurysm with sufficient collaterals to the liver and spleen. PMID- 29984221 TI - Accuracy and reliability of three-dimensional computer-assisted planning for orthognathic surgery. PMID- 29984220 TI - Positional change in mandibular condyle in facial asymmetric patients after orthognathic surgery: cone-beam computed tomography study. AB - Background: We evaluated change in the mandibular condyle after orthognathic surgery using cone-beam computed tomography (CBCT) in patients with facial asymmetry. Methods: Thirty patients with skeletal class III malocclusion and mandibular prognathism or facial asymmetry were classified into two groups according to the amount of menton deviation (MD) from the facial midline on anteroposterior (AP) cephalogram: group A (asymmetry, MD >= 4 mm; n = 15) and group B (symmetry, MD < 4 mm; n = 15). Position and angle of condylar heads on the axial, sagittal, and coronal views were measured within 1 month preoperatively (T0) and postoperatively (T1) and 6 months (T2) postoperatively. Results: On axial view, both groups showed inward rotation of condylar heads at T1, but at T2, the change was gradually removed and the condylar head returned to its original position. At T1, both groups showed no AP condylar head changes on sagittal view, although downward movement of the condylar heads occurred. Then, at T2, the condylar heads tended to return to their original position. The change in distance between the two condylar heads showed that they had moved outward in both groups, causing an increase in the width between the two heads postoperatively. Analysis of all three-dimensional changes of the condylar head positions demonstrated statistically significant changes in the three different CBCT views in group B and no statistically significant changes in group A. Conclusions: There was no significant difference between the two groups in condylar head position. Because sagittal split ramus osteotomy can be performed without significant change in symmetrical and asymmetrical cases, it can be regarded as an effective method to stabilize the condylar head position in patients with skeletal class III malocclusion and mandibular prognathism or facial asymmetry. PMID- 29984222 TI - HPLC Method Development for Quantification of Doxorubicin in Cell Culture and Placental Perfusion Media. AB - Assessment of drug transport across the placenta is important in understanding the effect of drugs on placental and fetal health. These phenomena can be studied in both in vitro cell lines and ex vivo placental perfusions. We have successfully developed a sensitive yet simple high performance liquid chromatography (HPLC) method coupled with fluorescence detection to determine the concentration of doxorubicin (DXR) in cell culture media for transport studies in human trophoblast cells (BeWo, b30 clone) and in fetal media for placental perfusion experiments. The method was developed based on a protein precipitation technique and was validated in both media types for linearity, intra-day, and inter-day precision and accuracy. The relationship of peak area to concentration was linear with R2 values of 0.99 or greater obtained over the concentration range of 1.5 to 15,000 ng/mL. Despite the high concentrations of albumin in fetal perfusion media (30 mg/mL), the lower limits of detection and quantification for DXR were found to be 1.5 and 5 ng/mL, respectively. This analytical method may be used to study the transport of DXR across BeWo cells and human placenta during placental perfusion studies. PMID- 29984223 TI - Retraction: into the eyes of bone marrow-derived mesenchymal stem cells therapy for myocardial infarction and other diseases. AB - [This retracts the article DOI: 10.21037/sci.2017.08.01.]. PMID- 29984224 TI - Retraction: Engineering of extracellular vesicles as drug delivery vehicles. AB - [This retracts the article DOI: 10.21037/sci.2017.08.07.]. PMID- 29984225 TI - Cell intrinsic regulation of external hematopoietic stem cell stress. PMID- 29984226 TI - The ved protein patterning in zebrafish embryos. AB - Homeobox transcription factors play an essential role in cells differentiation. The function is realized by the proteins (not by the mRNA) and it is necessary to pay more attention to the protein patterns. In this study we were the first to obtain antibodies against the ved protein, tested their specificity by Western blot analysis and performed a whole mount immunostaining of zebrafish embryos. It was shown that the spatial-temporal ved protein pattern did not differ from that of other vent-family factors. And moreover, its synthesis like that of vox and vent did not depend on pou5f3. PMID- 29984228 TI - Mandibular Canal Course and the Position of the Mental Foramen by Panoramic X-Ray in Chilean Individuals. AB - The object of this study was to analyse the morphology and morphometry of the mandibular canal (MC) course and the mental foramen (MF) position in relation to the inferior teeth by panoramic X-ray (PAN). Vertical linear measurements were taken of each hemimandible to obtain the length of the distances analysed. We studied the MF position in relation to inferior premolar roots and the relation between the MC and mandibular teeth roots (MCR). The MF was usually located between the apices of the first and second premolars in younger individuals and immediately below the apex of the inferior second premolar in older individuals. The MC evinced proximity to the third molar, and this relation was not affected by sex or age group. The distances analysed in this study presented a marked difference between gender, with larger values in males than in females. The variations which may occur between individuals and different populations make it essential for dentists and surgeons to plan carefully before procedures involving this region. PMID- 29984227 TI - Evaluation of Lsa46 and Lsa77 Leptospiral Proteins for Their Immunoprotective Activities in Hamster Model of Leptospirosis. AB - Leptospirosis is a neglected tropical disease caused by pathogenic Leptospira spp. The lack of an effective vaccine favors the increase of the disease. Currently, surface-exposed proteins are the main targets for the search of vaccine candidates. In this study, we examined whether the surface Lsa46 and Lsa77 proteins, previously identified as laminin and plasminogen binding proteins, have the capacity of inducing protection and sterilizing immunity against challenge with virulent Leptospira in hamster model. Animals were subcutaneously immunized with Lsa46, Lsa77, or a combination of both in Alum adjuvant and challenged intraperitoneally with L. interrogans serovar Kennewicki strain Pomona Fromm. Hamster immunization with Lsa46 or Lsa77 or both promoted a strong IgG response. Th2- and Th1-biased immune responses were observed when Lsa46 and Lsa77 were individually administered, respectively, as detected by the IgG1/IgG2/3 ratio. Immunized hamsters with the combined proteins induced a Th1 biased immune response. Although the immunization with Lsa46 and Lsa77 stimulated protective immunity with reduction of bacterial burden, when compared to animals individually immunized with the proteins, the data was not statistically significant. Thus, although promising, more studies are needed before the role of these proteins in stimulating sterilizing immunity in mammals is conclusively determined. PMID- 29984229 TI - CD30 Is Highly Expressed in Chronic Obstructive Pulmonary Disease and Induces the Pulmonary Vascular Remodeling. AB - Chronic obstructive pulmonary disease (COPD) is one of the common and underdiagnosed diseases with the highest morbidity and mortality in the world. The development of COPD can lead to pulmonary vascular remodeling and pulmonary hypertension, further causing the occurrence of pulmonary heart disease. Therefore, attenuation of pulmonary vascular remodeling and pulmonary hypertension caused by COPD can significantly delay cardiovascular complications. In the study, we firstly found that the expression of CD30 and CD30L was increased in COPD. Importantly, the serum CD30L levels were significantly higher in patients with stable COPD relative to those with acute exacerbation of COPD (AECOPD). This suggested that CD30 might be related to the development of COPD. In addition, we found that the expression of CD30 in the COPD rat model was significantly increased compared with control group. And treatment with the anti CD30 antibody reduced the serum concentration and tissue expression of CD30 in rat. Importantly, anti-CD30 antibody alleviated pulmonary vascular remodeling in COPD model rats. This suggested that CD30 played an important role in the course of COPD. Finally, we found that, in the HPASMC and HPAEC cell lines, CD30 can affect the cell viability and cell migration and inhibited hypoxia-induced cell apoptosis in a concentration-dependent manner. We also found CD30 induced extracellular matrix formation through decreasing the expression of MMP-2, thus promoting the pulmonary vascular remodeling. The study indicated that CD30 and CD30L were involved in pulmonary vascular remodeling and inflammatory response in COPD. Altogether, CD30 might be a marker for the early diagnosis and progression of COPD. PMID- 29984230 TI - Inhibitory Effects of Compounds and Extracts from Ampelopsis brevipedunculata on IL-6-Induced STAT3 Activation. AB - Ampelopsis brevipedunculata (Maxim.) Trautv. (AB), a traditional East Asian medicine, exhibits protective effects against several inflammatory diseases. Our search for an inhibitor of IL-6-induced JAK2/STAT3 activation revealed that AB ethanolic extract (ABE) had a significant inhibitory effect on IL-6-induced STAT3 expression in Hep3B cells. The isolation and purification of an EtOAc-soluble fraction of ABE (ABEA) using reversed-phase high-performance liquid chromatography (RP-HPLC) afforded 17 compounds. The structures of these compounds (1-17) were elucidated based on 1H and 13C nuclear magnetic resonance (NMR) spectroscopy as well as electrospray-ionization mass spectrometry (ESI-MS) data. ABE and ABEA were screened by a luciferase assay using Hep3B cells transfected with the STAT3 reporter gene. ABEA exhibited potent inhibitory effects on IL-6 induced STAT3 expression; moreover, these effects arose from the inhibition of the phosphorylation of the STAT3, JAK2, and ERK proteins in U266 cells. In addition, the compounds isolated from ABEA were measured for their inhibitory effects on IL-6-stimulated STAT3 expression. Of the compounds isolated, betulin showed the greatest inhibitory effects on IL-6-induced STAT3 activation in the luciferase assay (IC50 value: 3.12 MUM). Because of its potential for inhibiting STAT3 activation, A. brevipedunculata could be considered a source of compounds of pharmaceutical interest. PMID- 29984231 TI - Significance of Methylation of FBP1 Gene in Non-Small Cell Lung Cancer. AB - Because NSCLC has poor overall prognosis and is frequently diagnosed at later stage, we aimed to seek novel diagnosis biomarkers or therapy target of the disease in this study. Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis, which was usually lost in NSCLC due to abnormal methylation in promoter DNA sequence. The clinical data indicated that the methylation rate in FBP1 gene promoter was negatively related to the overall survival of the NSCLC patients. DNA methylation transferase inhibitor 5-aza treatment could significantly increase both expression levels of mRNA and protein in A549 cell line. On the other hand, silence of FBP1 in H460 cell line by using specific siRNA against FBP1 dramatically improved the cell proliferation and cell migration according to the date of FACS and transwell assays. All these findings implied the important roles of FBP1 expression in lung cancer development and progression and the potential use of the methylation status detected in FBP1 promoter region as a novel predictor for prognosis and therapeutic target for NSCLC patients. PMID- 29984232 TI - Implementation of Biological Control to the Integrated Control of Strongyle Infection among Wild Captive Equids in a Zoological Park. AB - The integrated control of strongyles was assayed for a period of three years in wild equids (zebras, European donkeys, and African wild asses) captive in a zoo and infected by strongyles. During three years control of parasites consisted of deworming with ivermectin + praziquantel; equids also received every two days commercial nutritional pellets containing a blend of 104 - 105 spores of the fungi Mucor circinelloides + Duddingtonia flagrans per kg meal. Coprological analyses were done monthly to establish the counts of eggs of strongyles per gram of feces (EPG). The reductions in the fecal egg counts (FECR) and in the positive horses (PHR) were calculated fifteen days after deworming; the egg reappearance period (ERP) and the time elapsed from the previous deworming (TPD) were also recorded. Four anthelmintic treatments were administered during the assay, three times throughout the first 2 yrs, and another treatment during the last one. FECR values of 96-100% and 75-100% for the PHR were recorded. The ERP oscillated between eight and twenty-eight weeks, and the TPD ranged from four to eighteen months, increasing to the end of the trial. No side effects were observed in any of the equids. It is concluded that integrated control of strongyles among equids captive in a zoo can be developed by anthelmintic deworming together with the administration of pellets manufactured with spores of parasiticide fungi every two days. PMID- 29984233 TI - Multi-Fiber-Reinforced Composites for the Coronoradicular Reconstruction of Premolar Teeth: A Finite Element Analysis. AB - A coronoradicular reconstruction (CRR) has conventionally used a metallic inlay core (MIC) or a single-fiber-reinforced composite (sFRC) but extensive dentin removal can lead to root fracture. We propose herein a multi-fiber-reinforced composite (mFRC) based on a bundle of thin flexible fibers that can be adapted to the root anatomy without removing additional dentin. The aim of this study was to compare the mechanical behavior of the root reconstructed with mFRC, MIC, or sFRC using a finite element analysis (FEA). Models with or without a ferrule effect were created using Autodesk(c) software and divided into four parts: root, post, bonding composite or cement, and zirconia crown. For both models, extreme stress values (ESV), stress distribution, and risk of fracture were calculated for an oblique force (45 degrees ) of 100 N applied to the top of the buccal cusp. Results indicated that mFRC and mFRCG present a lower risk of fracture of the root and of the CRR without ferrule and thus could be valuable alternatives for premolar CRR. Further studies are necessary to evaluate the clinical success of these CRR. PMID- 29984234 TI - An Investigation into the High Prevalence of Hepatitis B in a Rural Area of Kerala State, India: Hypothesis on Chrysops sp. (Diptera: Tabanidae) Transmission. AB - Objective: Since 2005 there have been several reports of hepatitis B outbreak in the state of Kerala in southern India. Objective of this study was to analyze such outbreaks and to explore hypothesis pertaining the transmission mode. Methods: Retrospective observational study involving cases of acute hepatitis B acquired between 1 January 2015 and 31 December 2015 and their family members residing in Mazhuvanoor village in Ernakulam district of Kerala State in southern India. Results: 59 houses were included in the survey. The number of patients diagnosed to have acute viral hepatitis B was 59. Majority (66.10%) were over 50 years old. There were no cases below the age of 15 years. All 59 patients claimed to have been bitten frequently by a fly which was identified as "deer fly" belonging to the genus Chrysops. Conclusion: Given the current understanding of mechanical transmission of pathogens in both humans and animals by insects belonging to the Tabanidae family which also includes Chrysops, it is plausible that the same mechanism may hold true for hepatitis B also. However this needs to be proven in further studies both at the laboratory level and at field studies. PMID- 29984235 TI - Jinlida Granules Improve Dysfunction of Hypothalamic-Pituitary-Thyroid Axis in Diabetic Rats Induced by STZ. AB - Objective: We aim to explore the effects and mechanisms of Jinlida granules on the dysfunction of hypothalamic-pituitary-thyroid (HPT) axis in diabetic rats induced by streptozotocin. Methods: A total of 48 SD rats were randomized into normal control group (NC, n = 6) and diabetic group (n = 42). Rats in diabetic group were randomly divided into diabetes mellitus (DM) control group, low, medium, and high doses of Jinlida group (JL, JM, and JH), medium dose of Jinlida plus Tongxinluo group (JM + T), metformin group (Met), and Saxagliptin group (Sax) (n = 6 in each group). Diabetic rats were obtained by intraperitoneal injection of streptozotocin and sacrificed at 8 weeks to examine the function of HPT axis. Results: Levels of fasting blood glucose (P < 0.05), pIkappaB, TNFalpha (P < 0.05), pNF-kappaB, and IL-6 (P < 0.01) in liver tissue and TSHR mRNA expression (P < 0.01) in diabetic group were significantly increased, while levels of serum T3 and T4, thyroid hormone receptor (TR) mRNA and Dio1 mRNA in liver tissue, and sodium iodide symporter (NIS) mRNA in thyroid tissue in diabetic group were significantly decreased compared with those in NC group (P < 0.01). Among diabetic groups, level of fasting blood glucose in JH, JM + T and Met group was lower (P < 0.05) compared with DM group. However, levels of serum T3 and T4, TR mRNA in liver tissue, TSHR, and NIS mRNA in thyroid tissue in JH, JM + T, Met, and Sax group were significantly increased (P < 0.01) compared to DM group. In contrast, levels of Dio1 mRNA, pI-kappaB in Met and JM + T groups, pNF kappaB in JH, JM + T, and Met group, and TNFalpha and IL-6 in JM, JH, JM + T, and Met group were significantly decreased (P < 0.05). HE staining showed reduced thyroid follicular epithelium and follicular area, as well as increased colloid area in DM group, indicating impaired synthesis, reabsorption, and secretory of TH in diabetes, which was significantly improved in JH, JM + T, and Met groups. Conclusion: HPT axis dysfunction in DM could be significantly improved by Jinlida granules. The mechanism might be associated with the anti-inflammatory effects involving NF-kappaB pathway. Our findings suggested the potential benefit of Jinlida granules for patients with HPT axis dysfunction and DM, which was to be verified by more experimental and clinical studies. PMID- 29984236 TI - Effect of Polyvalence on the Antibacterial Activity of a Synthetic Peptide Derived from Bovine Lactoferricin against Healthcare-Associated Infectious Pathogens. AB - Antimicrobial peptides (AMPs) are gaining interest as potential therapeutic agents. Peptides derived from bovine lactoferricin B (LfcinB) have been reported to exhibit antimicrobial activity, and the LfcinB RRWQWR sequence is the smallest known motif that exhibits antibacterial and cytotoxic activity. Our goal was to examine the effect of multicopy arrangements of the RRWQWR motif, on its antibacterial activity against healthcare-associated infections (HCAIs). Linear and branched peptides containing the RRWQWR motif were generated using solid phase peptide synthesis-Fmoc/tBu methodology, purified, and characterized using reverse phase-high performance liquid chromatography and matrix-assisted laser desorption/ionization time of flight mass spectrometry. For each peptide, the antibacterial activity against Staphylococcus aureus (ATCC 25923 and 33591 strains) and Klebsiella pneumoniae (ATCC 13883 and 700603 strains) was assessed by measuring the minimum inhibitory and the minimum bactericidal concentrations, in the exponential phase. Cells were observed by scanning electron microscopy, and the hemolytic activity of the peptides was assessed. The overall results demonstrate that, compared to linear analogues, polyvalent presentation of the RRWQWR motif enhances its antibacterial activity against both Gram-negative and Gram-positive bacteria even on resistant strain. PMID- 29984237 TI - Long-Lasting Alterations in Gene Expression of Postsynaptic Density 95 and Inotropic Glutamatergic Receptor Subunit in the Mesocorticolimbic System of Rat Offspring Born to Morphine-Addicted Mothers. AB - Prenatal exposure to morphine causes altered glutamatergic neurotransmission, which plays an important pathophysiological role for neurobiological basis of opiate-mediated behaviors in such offspring. However, it is still not clear whether such alteration involves gene expression of ionotropic glutamate receptor subunits. In this study, we further studied whether prenatal morphine exposure resulted in long-term changes in the gene expression of alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptor, N-methyl-d-aspartate (NMDA) receptor, and postsynaptic density 95 in the mesocorticolimbic area (an essential integration circuitry for drug craving behavior), nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC), of rat offspring from morphine-addicted mothers. Experimental results showed that prenatal morphine exposure led to a persistent downregulation of gene expression in the AMPA and NMDA receptor subunit, with a differential manner of decreased magnitudes, at the age of postnatal days 14 (P14) and P30. However, in PFC, the gene expression of the AMPA receptor subunit was not synchronized in observed rat offspring subjected to prenatal morphine exposure. An upregulation of gene expression in the AMPA receptor subunit 3 (GluR3) was persistently observed at P14 and P30. Furthermore, the gene expressions of PSD-95 in NAc, VTA, and PFC were all decreased concurrently. Collectively, the results suggest that prenatal exposure to morphine may initiate molecular mechanisms leading to a long-lasting, differential alteration in gene expression of the inotropic glutamate receptor subunit and PSD-95 in the mesocorticolimbic circuitry in rat offspring. This study raises a possibility in which differential changes in gene expression with a long-lasting manner may play a role for the development of nearly permanent changes in opiate-mediated behaviors, at least in part for the neurobiological pathogenesis in offspring. PMID- 29984238 TI - Effects of Cyclic Tensile Strain on Oxidative Stress and the Function of Schwann Cells. AB - Schwann cells (SCs) are significant due to the way in which they sustain and myelinate axons within the peripheral nervous system (PNS). This study has investigated the effect of cyclic tensile strain (CTS) on the oxidative stress and function of SCs derived from the sciatic nerves of an infant rat population. A group of 20 6-day-old Wistar rats was selected, and SCs were separated from the sciatic nerve. The SCs then underwent a 6-hour period of cyclical straining, and ElectroForce 3200 in combination with the BioDynamic chamber was employed to apply 0% and 5% strains at a 0.25 Hz frequency. The results showed that the control group suffered higher oxidative stress than that in 5% strains group (P<0.05). The results RT-PCR analysis indicated a correlation between 5% CTS and a reduction in Netrin-1 expression (P<0.05). Furthermore, there was a significant upregulation in NGF, GDNF, and Slit-2 gene expression (P<0.05). Finally, the results showed that CTS stimulate SCs by increasing the expression of nerve oriented factors, and these importantly caused the decrease of oxidative stress, reconstruction of cell skeleton, the promotion of axonal regrowth, and the augmentation of nerves. PMID- 29984239 TI - Genetic Analysis with Random Amplified Polymorphic DNA of the Multiple Enterocin Producing Enterococcus lactis 4CP3 Strain and Its Efficient Role in the Growth of Listeria monocytogenes in Raw Beef Meat. AB - In this manuscript, a multiple enterocin-producing Enterococcus lactis strain named 4CP3 was used to control the proliferation of Listeria monocytogenes in refrigerated raw beef meat model. Also, the intraspecific genetic differentiation of 4CP3 strain was assessed by Random Amplified Polymorphic DNA Polymerase Chain Reaction (RAPD-PCR) analysis. E. lactis 4CP3 strain was found to produce the enterocins A, B, and P. It displayed activity against L. monocytogenes EGDe 107776 by agar-well diffusion method. The application of E. lactis 4CP3 culture at 107 CFU/g in raw beef meat was evaluated using both ANOVA and ANCOVA linear models in order to examine its effect on the growth of the pathogen L. monocytogenes during refrigerated storage. Hence, a very interesting result in decreasing (P<0.05) and suppressing the growth of L. monocytogenes in refrigerated raw beef meat was shown during 28 days of storage. In conclusion, E. lactis 4CP3 strain might be useful for prevention of the proliferation and survival of L. monocytogenes in raw meat during refrigerated storage. PMID- 29984240 TI - Population Structure of Leishmania tropica Causing Anthroponotic Cutaneous Leishmaniasis in Southern Iran by PCR-RFLP of Kinetoplastid DNA. AB - Iran is one of the six countries with the most cutaneous leishmaniasis (CL) patients. Understanding better the genotypes of the parasite population in relation to geography and climate is critical to achieving better CL control. We aimed to characterise the population structure of Leishmania tropica, the cause of anthroponotic cutaneous leishmaniasis (ACL), from important foci in southeast (Bam and Kerman) and southwest (Shiraz) Iran. A total of 39 L. tropica isolates from ACL patients from southeast (Bam 14, Kerman 12) and southwest (Shiraz 13) Iran were analysed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) of the kinetoplast DNA (kDNA) using restriction enzymes MspI (HpaII) and ClaI. 37 genotypes were identified among south Iran L. tropica isolates. The unweighted pair group method with arithmetic mean (UPGMA) tree obtained from the banding patterns of ClaI digested kDNA RFLP distinguished southeast from and southwest L. tropica isolates with some subclustering but the MspI derived tree showed greater discrimination with greater subclustering and divergence of the two foci of southeast region but with some overlapping. Although a monophyletic structure has been defined for southeast L. tropica, isolates from two foci of southeast Iran were partly discriminated in the current study. PMID- 29984242 TI - Intentional Undercorrection by Implantation of Posterior Chamber Phakic Intraocular Lens With A Central Hole (Hole ICL) For Early Presbyopia. AB - Purpose: To assess visual performance at near to far distances in early presbyopic patients with undercorrection by implantation of an ICL with a central hole (hole ICL). Methods: This prospective study evaluated forty-two eyes of 21 early presbyopic patients (age, 40 to 53 years) with spherical equivalents of 7.37 +/- 3.18 D [mean +/- standard deviation] who underwent hole ICL implantation and whose targeted refraction was set at slight myopia (-0.61 +/- 0.28 D) for both eyes. We assessed the safety, efficacy at near to far distances, predictability, and adverse events of the surgery, during the 6-month observation period. Results: Corrected distance visual acuity did not improve significantly, from -0.17 +/- 0.07 preoperatively to -0.19 +/- 0.08 logMAR postoperatively (p=0.066, Wilcoxon signed-rank test). Uncorrected distance visual acuity was significantly improved from 1.30 +/- 0.24 preoperatively to -0.03 +/- 0.20 logMAR postoperatively (p<0.001). The mean binocular visual acuity was 0.02 logMAR or better at all distances (5.0, 3.0, 2.0, 1.0, 0.7, 0.5, and 0.3 m). All eyes were within +/- 0.5 D of the targeted correction. Neither cataract formation, significant intraocular pressure rise, nor other vision-threatening complications occurred in any case during the 6-month observation period. Conclusions: Our pilot study showed that intentional undercorrection by hole ICL implantation for early presbyopia was safe with predictable refractive results and provided good binocular vision at near to far distances, without developing cataract, suggesting its viability as a surgical presbyopic treatment for such patients. PMID- 29984241 TI - Aryl Hydrocarbon Receptor: A New Player of Pathogenesis and Therapy in Cardiovascular Diseases. AB - The aryl hydrocarbon receptor (AhR) is a DNA binding protein that acts as a nuclear receptor mediating xenobiotic metabolism and environmental responses. Owing to the evolutionary conservation of this gene and its widespread expression in the immune and circulatory systems, AhR has for many years been almost exclusively studied by the pharmacological/toxicological field for its role in contaminant toxicity. More recently, the functions of AhR in environmental adaption have been examined in the context of the occurrence, development, and therapy of cardiovascular diseases. Increasing evidence suggests that AhR is involved in maintaining homeostasis or in triggering pathogenesis by modulating the biological responses of critical cell types in the cardiovascular system. Here, we describe the structure, distribution, and ligands of AhR and the AhR signaling pathway and review the impact of AhR on cardiovascular physiology. We also discuss the potential contribution of AhR as a new potential factor in the targeted treatment of cardiovascular diseases. PMID- 29984243 TI - Geminin Orchestrates Somite Formation by Regulating Fgf8 and Notch Signaling. AB - During somitogenesis, Fgf8 maintains the predifferentiation stage of presomitic mesoderm (PSM) cells and its retraction gives a cue for somite formation. Delta/Notch initiates the expression of oscillation genes in the tail bud and subsequently contributes to somite formation in a periodic way. Whether there exists a critical factor coordinating Fgf8 and Notch signaling pathways is largely unknown. Here, we demonstrate that the loss of function of geminin gave rise to narrower somites as a result of derepressed Fgf8 gradient in the PSM and tail bud. Furthermore, in geminin morphants, the somite boundary could not form properly but the oscillation of cyclic genes was normal, displaying the blurry somitic boundary and disturbed somite polarity along the AP axis. In mechanism, these manifestations were mediated by the disrupted association of the geminin/Brg1 complex with intron 3 of mib1. The latter interaction was found to positively regulate mib1 transcription, Notch activity, and sequential somite segmentation during somitogenesis. In addition, geminin was also shown to regulate the expression of deltaD in mib1-independent way. Collectively, our data for the first time demonstrate that geminin regulates Fgf8 and Notch signaling to regulate somite segmentation during somitogenesis. PMID- 29984244 TI - Rhodiola rosea Improves Lifespan, Locomotion, and Neurodegeneration in a Drosophila melanogaster Model of Huntington's Disease. AB - Huntington's disease (HD) is a dominant, late-onset disease characterized by choreiform movements, cognitive decline, and personality disturbance. It is caused by a polyglutamine repeat expansion in the Huntington's disease gene encoding for the Huntingtin protein (Htt) which functions as a scaffold for selective macroautophagy. Mutant Htt (mHtt) disrupts vesicle trafficking and prevents autophagosome fusion with lysosomes, thus deregulating autophagy in neuronal cells, leading to cell death. Autophagy has been described as a therapeutic target for HD, owing to the key role Htt plays in the cellular process. Rhodiola rosea, a plant extract used in traditional medicine in Europe and Asia, has been shown to attenuate aging in the fly and other model species. It has also been shown to inhibit the mTOR pathway and induce autophagy in bladder cancer cell lines. We hypothesized that R. rosea, by inducing autophagy, may improve the phenotype of a Huntington's disease model of the fly. Flies expressing HttQ93 which exhibit decreased lifespan, impaired locomotion, and increased neurodegeneration were supplemented with R. rosea extract, and assays testing lifespan, locomotion, and pseudopupil degeneration provided quantitative measures of improvement. Based on our observations, R. rosea may be further evaluated as a potential therapy for Huntington's disease. PMID- 29984245 TI - Colour Vignetting Correction for Microscopy Image Mosaics Used for Quantitative Analyses. AB - Image mosaicing permits achieving one high-resolution image, extending the visible area of the sample while keeping the same resolution. However, intensity inhomogeneity of the stitched images can alter measurements and the right perception of the original sample. The problem can be solved by flat-field correcting the images through the vignetting function. Vignetting correction has been widely addressed for grey-level images, but not for colour ones. In this work, a practical solution for the colour vignetting correction in microscopy, also facing the problem of saturated pixels, is described. In order to assess the quality of the proposed approach, five different tonal correction approaches were quantitatively compared using state-of-the-art metrics and seven pairs of partially overlapping images of seven different samples. The results obtained proved that the proposed approach allows obtaining high quality colour flat-field corrected images and seamless mosaics without employing any blending adjustment. In order to give the opportunity to easily obtain seamless mosaics ready for quantitative analysis, the described vignetting correction method has been implemented in an upgraded release of MicroMos (version 3.0), an open-source software specifically designed to automatically obtain mosaics of partially overlapped images. PMID- 29984247 TI - Oncology: Management of Elderly Cancer Patients. PMID- 29984248 TI - Comparative Analysis of ADR on China's National Essential Medicines List (2015 Edition) and WHO Model List of Essential Medicines (19th Edition). AB - Objective: To explore the safety of the essential medicines recorded in China's list through the comparison of the list of essential medicines of China and the World Health Organization (WHO), as well as the analysis of the basic situation and characteristics of adverse drug reactions (ADRs) on the two essential medicines recorded in China's and WHO lists in order to provide a reference for the improvement of China's list. Methods: A retrospective descriptive study was conducted, based on the database in Jiangsu Province ADR Monitoring Center from 2013 to 2015. A total of 266869 cases reports were collected within this period, comparing the differences between the two essential medicines recorded in China's and WHO lists, considering number of ADRs, type of report, and modes of administration. Compare the differences between the two groups of drugs in the presence of new, severe, and new severe adverse events using chi square test. Results: Comparing the two essential medicines list, they have the same 117 species. When comparing ADRs in the two groups, most are antimicrobial, electrolytes, and acid-base balance drugs, regulate water, and are higher in China. In addition, with respect to the number of ADR types in the two groups, there is statistical significance (p<0.001) (total number is 68603 and 47515, new types are 12601 and 7262, the severe are 2714 and 7566, and the new severe are 820 and 716). Conclusion: Compared to the WHO list of essential drugs, China's list is still to be improved. PMID- 29984249 TI - Clinical Influence of Micromorphological Structure of Dental Implant Bone Drills. AB - Background: Considerations about heat generation, wear, and corrosion due to some macrostructural bur components (e.g., cutting lips, rake angle, flute, and helix angle) have been widely reported. However, little is known about how the microstructural components of the implant drill surface can influence the implant drill lifetime and clinical performance. Aim: To investigate accurately the surface morphology of surgical bone drill, by means of multivariate and multidimensional statistical analysis, in order to assess roughness parameters able to predict the evolution of tribological phenomena linked to heat development, wear, and corrosion occurring in clinical use. Materials and Methods: The surfaces of implant drills approximately 2.0mm in diameter made by five manufacturers were examined by means of confocal microscope with white light laser interferometry, obtaining several surface roughness parameters. Statistical multivariate analysis based on discriminant analysis showed, for each cut-off, the parameters which discriminate the manufacturers. Results: The microstructural parameters used by discriminant analysis evidenced several differences in terms of drill surface roughness between the five manufacturers. Conclusions: The observed surface roughness difference of drills is able to predict a different durability and clinical performance especially in heat generation and wear onset. PMID- 29984246 TI - Aging-Induced Biological Changes and Cardiovascular Diseases. AB - Aging is characterized by functional decline in homeostatic regulation and vital cellular events. This process can be linked with the development of cardiovascular diseases (CVDs). In this review, we discussed aging-induced biological alterations that are associated with CVDs through the following aspects: (i) structural, biochemical, and functional modifications; (ii) autonomic nervous system (ANS) dysregulation; (iii) epigenetic alterations; and (iv) atherosclerosis and stroke development. Aging-mediated structural and biochemical modifications coupled with gradual loss of ANS regulation, vascular stiffening, and deposition of collagen and calcium often disrupt cardiovascular system homeostasis. The structural and biochemical adjustments have been consistently implicated in the progressive increase in mechanical burden and functional breakdown of the heart and vessels. In addition, cardiomyocyte loss in this process often reduces adaptive capacity and cardiovascular function. The accumulation of epigenetic changes also plays important roles in the development of CVDs. In summary, the understanding of the aging-mediated changes remains promising towards effective diagnosis, discovery of new drug targets, and development of new therapies for the treatment of CVDs. PMID- 29984250 TI - Influence of Induced Blood Pressure Variability on the Assessment of Cerebral Autoregulation in Patients after Cardiac Arrest. AB - Objective: To determine if increasing variability of blood pressure influences determination of cerebral autoregulation. Methods: A prospective observational study was performed at the ICU of a university hospital in the Netherlands. 13 comatose patients after cardiac arrest underwent baseline and intervention (tilting of bed) measurements. Mean flow velocity (MFV) in the middle cerebral artery and mean arterial pressure (MAP) were measured. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, coherence, gain, and phase were calculated in the very low and low frequency bands. Results: The CV of MAP was significantly higher during intervention compared to baseline. On individual level, coherence in the VLF band changed in 5 of 21 measurements from unreliable to reliable and in 6 of 21 measurements from reliable to unreliable. In the LF band 1 of 21 measurements changed from unreliable to reliable and 3 of 21 measurements from reliable to unreliable. Gain in the VLF and LF band was lower during intervention compared to baseline. Conclusions: For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of cerebral autoregulation. PMID- 29984251 TI - Real-World Results of Aflibercept versus Ranibizumab for the Treatment of Exudative AMD Using a Fixed Regimen. AB - Intravitreal injections of antivascular endothelial growth factors have been considered a milestone in the treatment of neovascular age-related macular degeneration (nAMD). However, the increasing incidence of AMD and the burden of visits and injections overcharge both the patient and the healthcare systems. Real-world solutions depend on treatment protocols aimed at optimizing the number of clinical visits while guaranteeing good functional outcomes. We performed a retrospective analysis of 72 eyes from 63 naive patients diagnosed with nAMD that underwent a fixed intravitreal protocol consisting of bimonthly injections after a three-month loading dose, with either Aflibercept or Ranibizumab (no predefined criteria for treatment selection). Best corrected visual acuity (BCVA) and optical coherence tomography were analyzed at baseline and during follow-up clinical visits (months 3, 6, 12, and 18). From the included participants, 42 followed a fixed regimen with Aflibercept and 30 with Ranibizumab. At the 12 month visit, there was not a statistically significant difference in the mean change of BCVA between the two groups (p=0.121); however, the mean difference in the central retinal thickness was significantly superior in the Aflibercept group (-142.2 versus -51.5, p=0.011). The described fixed regimen seems to be efficient in the treatment of nAMD in a clinical practice setting. PMID- 29984253 TI - Curcumin as Treatment for Bladder Cancer: A Preclinical Study of Cyclodextrin Curcumin Complex and BCG as Intravesical Treatment in an Orthotopic Bladder Cancer Rat Model. AB - Objective: To evaluate the antitumor effect of cyclodextrin-curcumin complex (CDC) on human and rat urothelial carcinoma cells in vitro and to evaluate the effect of intravesical instillations of CDC, BCG, and the combination in vivo in the AY-F344 orthotopic bladder cancer rat model. Curcumin has anticarcinogenic activity on urothelial carcinoma and is therefore under investigation for the treatment of non-muscle invasive bladder cancer. Curcumin and BCG share immunomodulating pathways against urothelial carcinoma. Methods: Curcumin was complexed with cyclodextrin to improve solubility. Four human urothelial carcinoma cell lines and the AY-27 rat cell line were exposed to various concentrations of CDC in vitro. For the in vivo experiment, the AY-27 orthotopic bladder cancer F344 rat model was used. Rats were treated with consecutive intravesical instillations of CDC, BCG, the combination of CDC+BCG, or NaCl as control. Results: CDC showed a dose-dependent antiproliferative effect on all human urothelial carcinoma cell lines tested and the rat AY-27 urothelial carcinoma cell line. Moreover, intravesical treatment with CDC and CDC+BCG results in a lower percentage of tumors (60% and 68%, respectively) compared to BCG (75%) or control (85%). This difference with placebo was not statistically significant (p=0.078 and 0.199, respectively). However, tumors present in the placebo and BCG-treated rats were generally of higher stage. Conclusions: Cyclodextrin-curcumin complex showed an antiproliferative effect on human and rat urothelial carcinoma cell lines in vitro. In the aggressive orthotopic bladder cancer rat model, we observed a promising effect of CDC treatment and CDC in combination with BCG. PMID- 29984252 TI - Cytotoxicity of Air Pollutant 9,10-Phenanthrenequinone: Role of Reactive Oxygen Species and Redox Signaling. AB - Atmospheric pollution has been a principal topic recently in the scientific and political community due to its role and impact on human and ecological health. 9,10-phenanthrenequinone (9,10-PQ) is a quinone molecule found in air pollution abundantly in the diesel exhaust particles (DEP). This compound has studied extensively and has been shown to develop cytotoxic effects both in vitro and in vivo. 9, 10-PQ has been proposed to play a critical role in the development of cytotoxicity via generation of reactive oxygen species (ROS) through redox cycling. This compound also reduces expression of glutathione (GSH), which is critical in Phase II detoxification reactions. Understanding the underlying cellular mechanisms involved in cytotoxicity can allow for the development of therapeutics designed to target specific molecules significantly involved in the 9,10-PQ-induced ROS toxicity. This review highlights the developments in the understanding of the cytotoxic effects of 9, 10-PQ with special emphasis on the possible mechanisms involved. PMID- 29984255 TI - Prevalence and Factors Associated with Contraceptive Use among HIV-Infected Women of Reproductive Age Attending Infectious Disease Clinic at Gulu Regional Referral Hospital, Northern Uganda. AB - Background: Reproductive planning by HIV-infected women is essential, as it helps to prevent transmission of HIV to their unborn babies. Integrating contraceptive services to routine HIV care significantly increases the use of modern contraceptive methods, thus reducing vertical transmission of HIV. Objectives: To determine the prevalence and factors associated with contraceptive use among HIV infected women attending Infectious Disease Clinic (IDC) at Gulu Regional Referral Hospital (GRRH) in Northern Uganda. Methodology: A hospital-based cross sectional study was performed. We used simple random sampling to recruit HIV infected women receiving routine care from IDC, GRRH, into our study. Sample size was estimated using modified Kish-Leslie formula and semistructured questionnaire was used for data collection. Data was entered into EpiData version 3.1 and analysed using Stata v11.0. We used logistic regression model to assess the associations and any factor with p<=0.05 was considered statistically significant. Results: The prevalence of contraceptive use was found to be 36% (95% CI 31 - 40%). Factors which promoted contraceptive use were as follows: being married (aOR=2.68, 95% CI 1.54-4.65, p<0.001) and monthly income of $35 250 (aOR= 2.38, 95% CI: 1.39- 4.09, p=0.002). Factors that hindered contraceptive use were having no child (nulliparity) (aOR= 0.16; 95% CI: 0.05-0.49; p=0.002) and age range of 31-49 years (aOR= 0.53; 95% CI: 0.33 - 0.84; p=0.007). Conclusion: In this study, just over a third of sexually active HIV-infected women reported use of modern contraceptives. This is a low level of usage and, therefore, clinicians and stakeholders should sensitise HIV-infected women on the importance of contraceptive use in the fight against HIV/AIDS and encourage them to use contraceptives to avoid vertical transmission of HIV through unintended pregnancy. PMID- 29984254 TI - Biomechanical Characteristics of Three Baseplate Rotational Arrangement Techniques in Total Knee Arthroplasty. AB - Introduction: Several ongoing studies aim to improve the survival rate following total knee arthroplasty (TKA), which is an effective orthopedic surgical approach for patients with severely painful knee joint diseases. Among the studied strategies, baseplate rotational arrangement techniques for TKA components have been suggested but have been the subject of only simple reliability evaluations. Therefore, this study sought to evaluate comparatively three different baseplate rotational arrangement techniques that are commonly used in a clinical context. Materials and Methods: Three-dimensional (3D) finite element (FE) models of the proximal tibia with TKA were developed and analyzed considering three baseplate rotational arrangement techniques (anterior cortex line, tibial tuberosity one third line, and tibial tuberosity end line) for six activities of daily life (ADLs) among patients undergoing TKA. Mechanical tests based on the ASTM F1800 standard to validate the FE models were then performed using a universal testing machine. To evaluate differences in biomechanical characteristics according to baseplate rotational arrangement technique, the strain and peak von Mises stresses (PVMSs) were assessed. Results: The accuracy of the FE models used in this study was high (94.7 +/- 5.6%). For the tibial tuberosity one-third line rotational arrangement technique, strains <= 50 ustrain (the critical bone damage strain, which may affect bone remodeling) accounted for approximately 2.2%-11.3% and PVMSs within the bone cement ranged from 19.4 to 29.2 MPa, in ADLs with high loading conditions. For the tibial tuberosity end line rotational arrangement, strains <= 50 ustrain accounted for approximately 2.3%-13.3% and PVMSs within the bone cement ranged from 13.5 to 26.7 MPa. For anterior cortex line rotational arrangement techniques, strains <=50 ustrain accounted for approximately 10.6% 16.6% and PVMSs within the bone cement ranged from 11.6 to 21.7 MPa. Conclusion: The results show that the most recently developed frontal cortex line rotational alignment technique is the same or better than the other two rotational alignment techniques in terms of biomechanics. This finding can be, however, dependent on the contact characteristics between the baseplate and the proximal tibia. That is, it is indicated that the optimum baseplate rotational arrangement technique in terms of reducing the incidence of TKA mechanical failure can be achieved by adjusting the characteristics of contact between the baseplate and the proximal tibia. PMID- 29984256 TI - Neuropeptide B and Vaspin as New Biomarkers in Anorexia Nervosa. AB - Introduction: The aim of the study was to assess the correlation between the levels of neuropeptide B (NPB), neuropeptide W (NPW), vaspin (VAS), and the total antioxidant status (TAS) in the blood, as well as nutritional status of patients with anorexia nervosa (AN). Materials and Methods: The study covered a cohort of 76 female teenagers, including 46 females with extreme AN and 30 healthy peers (CONTR) aged 12-17. Results: AN persons were characterized by higher (in comparison to CONTR) NPB and VAS concentrations and lower values of TAS levels, body weight, and anthropometric values. Positive correlations between NPB and VAS levels were noted in the AN group (R=0.33; p<0.001) as well as between concentrations of NPW and VAS in the same group (R=0.49; p<0.001). Furthermore, positive correlations existed between NPB and NPW concentrations across the whole studied population (AN+CONTR; R=0.75; p<0.000001), AN (R=0.73; p<0.000001) and CONTR (R=0.90; p<0.0005). Conclusions: In detailed diagnostics of AN it is worth considering testing NPB and VAS levels. PMID- 29984257 TI - MiR-92a Inhibits the Progress of Osteosarcoma Cells and Increases the Cisplatin Sensitivity by Targeting Notch1. AB - Background: MicroRNAs (miRs) have been implicated in the development and progression of osteosarcoma. Here, we aimed to illustrate the important role of miR-92a on the regulation of OS development which may help to establish a novel strategy for OS diagnosis and treatment. Materials and Methods: Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Cell cycle and apoptosis were assessed by flow cytometry with PI and PI/Annexin-V stain, respectively. The expression of proteins was examined by western blot. qPCR was used to detect the expression of RNA. Cell migration was assayed with transwell assay. Results: MiR-92a inhibited the proliferation and the migration of OS in vitro and reduced the volume of the tumour in vivo. Further, miR-92a enhanced cisplatin sensitivity of OS. MiR-92a directly targeted Notch1. Conclusion: Together, our results indicate that miR-92a inhibited cell growth, migration, and enhanced cisplatin sensitivity of OS cell by targeting Notch1. PMID- 29984258 TI - The Impact of Mindfulness-Based Stress Reduction on Emotional Wellbeing and Glycemic Control of Patients with Type 2 Diabetes Mellitus. AB - Objective: The aim of the study was to determine the effect of mindfulness-based stress reduction (MBSR) intervention on emotion regulation and glycemic control of patients with type 2 diabetes. Materials and Methods: Sixty patients with type 2 diabetes were recruited for this randomized controlled trial from an outpatient clinic at Imam Hospital in Iran. The intervention group participated in 8 sessions of MBSR, and the control group continued the treatment as usual. Fasting blood sugar and HbA1c were measured as two indices of glycemic control. Overall mental health, depression, and anxiety were measured using the General Health Questionnaire (GHQ-28), Hamilton Depression Rating Scale (HDRS), and Hamilton Anxiety Rating Scale (HARS), respectively. All the assessments were performed at baseline and after 8 weeks and 3 months as follow-up. Results: In comparison with the control group, the MBSR intervention group showed a significant reduction on all outcome measures including FBS, HbA1C, HARS, and HDRS scores (p < 0/05). Conclusion: MBSR had a remarkable improvement on emotional wellbeing and glycemic control of patients with type 2 diabetes. PMID- 29984259 TI - Adverse Immunologically Mediated Oral Mucosal Reactions to Systemic Medication: Lichenoid Tissue Reaction/Interface Dermatitis-Stomatitis, Autoimmune Vesiculobullous Disease, and IgE-Dependent and Immune Complex Reactions. AB - Drug-induced hypersensitivity immune reactions are exaggerated immunoinflammatory responses to allergenic components of the medications that occur in genetically susceptible subjects. The type of hypersensitivity immune response generated, whether antibody mediated or T cell mediated, or an immune complex reaction is determined by multiple factors, including the molecular characteristics of the allergen, the route of administration of the medication, the manner of presentation of the allergen by antigen-presenting cells to naive T cells, the repertoire of the T cell receptors, and the cytokine profile within the microenvironment. This review deals with the clinical and histopathological aspects of adverse immunologically mediated oral mucosal reactions to systemic medication. We elaborate on diseases showing features of lichenoid tissue reaction/interface dermatitis-stomatitis, autoimmune vesiculobullous oral lesions, and immunoglobulin E- (IgE-) and immune complex-mediated oral reactions to drugs. PMID- 29984260 TI - Quick Flicks: Association of Paroxysmal Kinesigenic Dyskinesia and Tics. AB - Background: Paroxysmal kinesigenic dyskinesia (PKD) is a rare disorder characterised by brief attacks of chorea, dystonia, or mixed forms precipitated by sudden movement. Methods: Observational study with a cohort of 14 PKD patients and genetic testing for PRRT2 mutations. Results: In a series of 14 PKD patients seen in our clinic at the National Hospital of Neurology, Queen Square, from 2012 2017, we noted tics in 11 patients (79%), which stand in stark contrast to the estimated lifetime prevalence of tics estimated to reach 1%. Conclusions: The two reasons to point out this possible association are the clinical implications and the potential opportunity of a better understanding of shared pathophysiological mechanisms of neuronal hyperexcitability. PMID- 29984262 TI - A man with macroglossia and hemorrhagic bulla. PMID- 29984261 TI - Neuroethological studies of fear, anxiety, and risky decision-making in rodents and humans. AB - Prey are relentlessly faced with a series of survival problems to solve. One enduring problem is predation, where the prey's answers rely on the complex interaction between actions cultivated during its life course and defense reactions passed down by descendants. To understand the proximate neural responses to analogous threats, affective neuroscientists have favored well controlled associative learning paradigms, yet researchers are now creating semi realistic environments that examine the dynamic flow of decision-making and escape calculations that mimic the prey's real world choices. In the context of research from the field of ethology and behavioral ecology, we review some of the recent literature in rodent and human neuroscience and discuss how these studies have the potential to provide new insights into the behavioral expression, computations, and the neural circuits that underlie healthy and pathological fear and anxiety. PMID- 29984263 TI - Blaschkoid hyperkeratotic plaques in a hemi-distribution since infancy. PMID- 29984264 TI - Annular polycyclic plaques on the chest and upper back. PMID- 29984265 TI - Vismodegib-resistant basal cell carcinomas in basal cell nevus syndrome: Clinical approach and genetic analysis. PMID- 29984266 TI - A case series of primary cutaneous coccidioidomycosis after a record-breaking rainy season. PMID- 29984267 TI - Cutaneous Microsphaeropsis arundinis infection in renal transplant recipients-A report of 2 cases and review of the literature. PMID- 29984268 TI - A 13-year-old girl with a linear dark patch on her forehead: A case of scleroderma en coup de sabre in a child with skin of color presenting with a bruise-like appearance. PMID- 29984269 TI - Regression of pigmented lesions in a patient with metastatic melanoma treated with immunotherapy. PMID- 29984270 TI - Disseminated coccidioidomycosis as a harbinger of climate change. PMID- 29984271 TI - A fatal case of parathyroid hormone-related peptide (PTHrP)-producing squamous cell carcinoma arising in the context of long-standing hidradenitis suppurativa. PMID- 29984272 TI - Concurrence of psoriasis vulgaris and atopic eczema in a single patient exhibiting different expression patterns of psoriatic autoantigens in the lesional skin. PMID- 29984273 TI - Late-onset solitary porokeratotic eccrine ostial and dermal duct nevus. PMID- 29984274 TI - Inflammatory sebotropic reaction associated with kava kava ingestion. PMID- 29984275 TI - Unusual presentation of hereditary leiomyomatosis mimicking neurofibromatosis. PMID- 29984276 TI - T helper (Th)17 radiation-induced hidradenitis suppurativa. PMID- 29984277 TI - Treatment of generalized deep morphea and eosinophilic fasciitis with the Janus kinase inhibitor tofacitinib. PMID- 29984278 TI - Pilomatricoma of the scalp mimicking poorly differentiated cutaneous carcinoma on positron emission tomography/computed tomography (PET/CT) scan and fine-needle aspiration (FNA) cytology. PMID- 29984279 TI - Atypical Behcet disease with endocarditis, pyoderma gangrenosum-like ulcers and methicillin-resistant Staphylococcus aureus-positive skin abscesses. PMID- 29984280 TI - Stevens-Johnson syndrome-like eruption from palbociclib in a patient with metastatic breast cancer. PMID- 29984281 TI - Aggressive squamous cell carcinoma in a patient on the Janus kinase inhibitor ruxolitinib. PMID- 29984282 TI - Combined neodymium-doped yttrium aluminum garnet laser and sclerotherapy in Gorham-Stout syndrome. AB - Bone involvement is relatively rare in vascular malformations. Gorham-Stout disease, also referred to as vanishing bone disease, is characterized by osteoclast activation and osteolysis caused by proliferating lymphatic endothelial cells. We present the case of a 12-year-old boy who had Gorham-Stout disease at the age of 8 years. The clinical course was complicated by pathological fractures and localized intravascular consumption coagulopathy. Sclerotherapy and embolization therapy led to normalization of the coagulation parameters and significant improvement of the clinical findings. We speculate that this effect may be attributable to the elimination of lymphatic endothelial cells. PMID- 29984284 TI - A case for histologic verification of the diagnosis of atypical psoriasis before systemic therapy. PMID- 29984283 TI - Inflammation and immune evasion coexist in Treponema pallidum-infected skin. PMID- 29984285 TI - An acneiform eruption secondary to iododerma. PMID- 29984286 TI - Recalcitrant hyperkeratotic verrucae in a renal transplant recipient clearing with cessation of immunosuppression. PMID- 29984288 TI - Paraneoplastic cutaneous small-vessel vasculitis as a presentation of recurrent metastatic breast cancer. PMID- 29984287 TI - A case of genital pyoderma gangrenosum successfully treated with cyclosporine without relapse of established follicular lymphoma. AB - Management of pyoderma gangrenosum in established malignancy is challenging. When vital structures are at risk from ulceration, aggressive management is required; however, immunosuppressive therapy may compromise the prognosis for an underlying malignancy. The optimal management of pyoderma gangrenosum in this setting is unclear. We report on a 64-year-old woman with follicular lymphoma in partial remission, who had severe genital pyoderma gangrenosum. After multidisciplinary evaluation, she was treated with corticosteroids and cyclosporine and healed fully with scarring over 7 weeks. She has required low-dose cyclosporine for 3 years to maintain remission of her genital ulceration; however, she remains well with no relapse of her lymphoma on serial imaging. PMID- 29984289 TI - Crusted scabies in a patient with methamphetamine abuse. PMID- 29984290 TI - Ertapenem rescue therapy in hidradenitis suppurativa. PMID- 29984291 TI - Occupational immediate-type reactions to locusts-A possible cross-reactivity between desert locusts (Schistocerca gregoria) and migratory locusts (Locusta migratoria)? PMID- 29984293 TI - A case series of orf infection after the religious sacrifice feast Eid al-Adha. PMID- 29984292 TI - Repigmentation and new growth of hairs after anti-interleukin-17 therapy with secukinumab for psoriasis. PMID- 29984294 TI - Systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis: An emerging overlap syndrome with cutaneous manifestations. PMID- 29984295 TI - Primary conjunctival sporotrichosis: An atypical presentation of the disease. PMID- 29984296 TI - Secukinumab in pityriasis rubra pilaris: A case series demonstrating variable response and the need for minimal clinical datasets. PMID- 29984297 TI - Myasthenia as a paraneoplastic manifestation of ovarian Cancer. AB - We describe the first case of myasthenia gravis as a possible paraneoplastic manifestation of ovarian cancer preceding its diagnosis. PMID- 29984298 TI - Socioemotional wellbeing of mixed race/ethnicity children in the UK and US: Patterns and mechanisms. AB - Existing literature suggests that mixed race/ethnicity children are more likely to experience poor socioemotional wellbeing in both the US and the UK, although the evidence is stronger in the US. It is suggested that this inequality may be a consequence of struggles with identity formation, more limited connections with racial/ethnic/cultural heritage, and increased risk of exposure to racism. Using data from the UK Millennium Cohort Study (n = 13,734) and the US Early Childhood Longitudinal Study-Birth Cohort (n ~ 6250), we examine differences in the socioemotional wellbeing of mixed and non-mixed 5/6 year old children in the UK and US and explore heterogeneity in outcomes across different mixed groups in both locations. We estimate a series of linear regressions to examine the contribution of factors that may explain any observed differences, including socio-economic and cultural factors, and examine the extent to which these processes vary across the two nations. We find no evidence of greater risk for poor socioemotional wellbeing for mixed race/ethnicity children in both national contexts. We find that mixed race/ethnicity children experience socio-economic advantage compared to their non-mixed minority counterparts and that socio economic advantage is protective for socioemotional wellbeing. Cultural factors do not contribute to differences in socioemotional wellbeing across mixed and non mixed groups. Our evidence suggests then that at age 5/6 there is no evidence of poorer socioemotional wellbeing for mixed race/ethnicity children in either the UK or the US. The contrast between our findings and some previous literature, which reports that mixed race/ethnicity children have poorer socioemotional wellbeing, may reflect changes in the meaning of mixed identities across periods and/or the developmental stage of the children we studied. PMID- 29984299 TI - Staging of amyloid beta, t-tau, regional atrophy rates, and cognitive change in a nondemented cohort: Results of serial mediation analyses. AB - Introduction: Current models posit a sequence of amyloid beta (Abeta), tau, atrophy, and cognitive change leading to Alzheimer's disease, but ambiguities remain. We examined these sequences via serial mediations. Methods: We studied normal controls, early mild cognitive impairment, and late mild cognitive impairment individuals from the Alzheimer's Disease Neuroimaging Initiative 2 database for the mediation of baseline cerebrospinal fluid Abeta effects on 2 year cognitive change via regional longitudinal atrophy rate (AR) alone or AR and tau. Results: In normal controls, Abeta correlated directly with regional ARs and memory loss, with no mediations. In early mild cognitive impairment, tau and lateral temporal ARs serially mediated the influence of Abeta on memory while Abeta affected memory via hippocampal AR. Late mild cognitive impairment consistently showed serial mediations of tau followed by atrophy. However, Abeta effects on memory also continued to be specifically mediated by medial temporal ARs without intermediate tau. Discussion: Biomarker sequences vary by region and disease state, suggesting the need to refine current cascade models. PMID- 29984300 TI - Improving face identification with specialist teams. AB - People vary in their ability to identify faces, and this variability is relatively stable across repeated testing. This suggests that recruiting high performers can improve identity verification accuracy in applied settings. Here, we report the first systematic study to evaluate real-world benefits of selecting high performers based on performance in standardized face identification tests. We simulated a recruitment process for a specialist team tasked with detecting fraudulent passport applications. University students (n = 114) completed a battery of screening tests followed by a real-world face identification task that is performed routinely when issuing identity documents. Consistent with previous work, individual differences in the real-world task were relatively stable across repeated tests taken 1 week apart (r = 0.6), and accuracy scores on screening tests and the real-world task were moderately correlated. Nevertheless, performance gains achieved by selecting groups based on screening tests were surprisingly small, leading to a 7% improvement in accuracy. Statistically aggregating decisions across individuals-using a 'wisdom of crowds' approach-led to more substantial gains than selection alone. Finally, controlling for individual accuracy of team members, the performance of a team in one test predicted their performance in a subsequent test, suggesting that a 'good team' is not only defined by the individual accuracy of team members. Overall, these results underline the need to use a combination of approaches to improve face identification performance in professional settings. PMID- 29984302 TI - HIV-Associated Neurocognitive Disorder (HAND) and the Prospect of Brain Penetrating Protease Inhibitors for Antiretroviral Treatment. AB - The advent of combined active antiretroviral therapy (cART) dramatically improved HIV management and patient care of HIV-infected individuals. This treatment regimen resulted in a significant reduction of HIV/AIDS-related mortality and greatly improved life expectancies of those patients with access to cART. However, among many HIV-related complications, neurocognitive dysfunction, known as HIV-associated neurocognitive disorder (HAND) has been a major issue. While the cART regimen has been effective in reduction of HAND in many patients, the prevalence of HAND is increasing as HIV/AIDS patients live longer. HIV infection and its subsequent manifestation of HAND is complex. It is evident that the brain can serve as a sanctuary for HIV replication and HAND can remain in patients even with cART treatment due to poor blood-brain barrier permeability of the majority of current antiretroviral agents. Conceivably, cART needs to have improved CNS penetration properties for effective treatment and possible prevention of HAND. Therefore, design and development of new antiretroviral agents that can penetrate into the CNS effectively, could block HIV replication and significantly reduce the viral load in cerebrospinal fluid. This may prevent HAND and related symptoms. HIV protease inhibitors (PIs) are a critical component of cART. Over the years, we have designed and synthesized a range of highly potent and novel PIs including the FDA approved drug, darunavir, which is used as a first-line treatment. In an effort to improve CNS penetration, we have been involved in the design and development of potent PIs with improved in vitro brain penetration properties. Herein we provide a brief review that cover insights and discussion of HAND and our work on PI development to ameliorate HIV-associated neurocognitive disorders. PMID- 29984303 TI - A crossbar network for silicon quantum dot qubits. AB - The spin states of single electrons in gate-defined quantum dots satisfy crucial requirements for a practical quantum computer. These include extremely long coherence times, high-fidelity quantum operation, and the ability to shuttle electrons as a mechanism for on-chip flying qubits. To increase the number of qubits to the thousands or millions of qubits needed for practical quantum information, we present an architecture based on shared control and a scalable number of lines. Crucially, the control lines define the qubit grid, such that no local components are required. Our design enables qubit coupling beyond nearest neighbors, providing prospects for nonplanar quantum error correction protocols. Fabrication is based on a three-layer design to define qubit and tunnel barrier gates. We show that a double stripline on top of the structure can drive high fidelity single-qubit rotations. Self-aligned inhomogeneous magnetic fields induced by direct currents through superconducting gates enable qubit addressability and readout. Qubit coupling is based on the exchange interaction, and we show that parallel two-qubit gates can be performed at the detuning-noise insensitive point. While the architecture requires a high level of uniformity in the materials and critical dimensions to enable shared control, it stands out for its simplicity and provides prospects for large-scale quantum computation in the near future. PMID- 29984301 TI - Use-inspired basic research on individual differences in face identification: implications for criminal investigation and security. AB - This journal is dedicated to "use-inspired basic research" where a problem in the world shapes the hypotheses for study in the laboratory. This review considers the role of individual variation in face identification and the challenges and opportunities this presents in security and criminal investigations. We show how theoretical work conducted on individual variation in face identification has, in part, been stimulated by situations presented in the real world. In turn, we review the contribution of theoretical work on individual variation in face processing and how this may help shape the practical identification of faces in applied situations. We consider two cases in detail. The first case is that of security officers; gatekeepers who use facial ID to grant entry or deny access. One applied example, where much research has been conducted, is passport control officers who are asked to match a person in front of them to a photograph shown on their ID. What happens if they are poor at making such face matching decisions and can they be trained to improve their performance? Second, we outline the case of "super-recognisers", people who are excellent at face recognition. Here it is interesting to consider whether these individuals can be strategically allocated to security and criminal roles, to maximise the identification of suspects. We conclude that individual differences are one of the largest documented sources of error in face matching and face recognition but more work is needed to account for these differences within theoretical models of face processing. PMID- 29984304 TI - Consecutive crystallographic reorientations and superplasticity in body-centered cubic niobium nanowires. AB - Plasticity of metallic nanowires is often controlled by the activities of single deformation mode. It remains largely unclear whether multiple deformation modes can be activated in an individual metallic nanowire and how much plasticity they can contribute. In situ nanomechanical testing reveals a superior plastic deformation ability of body-centered cubic (BCC) niobium nanowires, in which a remarkable elongation of more than 269% is achieved before fracture. This superplastic deformation originates from a synergy of consecutively nucleated multiple reorientation processes that occur for more than five times via three distinct mechanisms, that is, stress-activated phase transformation, deformation twinning, and slip-induced crystal rotation. These three coupled mechanisms work concurrently, resulting in sequential reorientations and therefore superplastic deformation of Nb nanowires. Our findings reveal a superior mechanical property of BCC Nb nanowires through the close coordination of multiple deformation modes, which may have some implications in other metallic nanowire systems. PMID- 29984305 TI - Stretching vibration is a spectator in nucleophilic substitution. AB - How chemical reactions are influenced by reactant vibrational excitation is a long-standing question at the core of chemical reaction dynamics. In reactions of polyatomic molecules, where the Polanyi rules are not directly applicable, certain vibrational modes can act as spectators. In nucleophilic substitution reactions, CH stretching vibrations have been considered to be such spectators. While this picture has been challenged by some theoretical studies, experimental insight has been lacking. We show that the nucleophilic substitution reaction of F- with CH3I is minimally influenced by an excitation of the symmetric CH stretching vibration. This contrasts with the strong vibrational enhancement of the proton transfer reaction measured in parallel. The spectator behavior of the stretching mode is supported by both quasi-classical trajectory simulations and the Sudden Vector Projection model. PMID- 29984306 TI - Suppression of photo-oxidation of organic chromophores by strong coupling to plasmonic nanoantennas. AB - Intermixed light-matter quasi-particles-polaritons-have unique optical properties owing to their compositional nature. These intriguing hybrid states have been extensively studied over the past decades in a wide range of realizations aiming at both basic science and emerging applications. However, recently, it has been demonstrated that not only optical but also material-related properties, such as chemical reactivity and charge transport, may be significantly altered in the strong coupling regime of light-matter interactions. We show that a nanoscale system, composed of a plasmonic nanoprism strongly coupled to excitons in a J aggregated form of organic chromophores, experiences modified excited-state dynamics and, therefore, modified photochemical reactivity. Our experimental results reveal that photobleaching, one of the most fundamental photochemical reactions, can be effectively controlled and suppressed by the degree of plasmon exciton coupling and detuning. In particular, we observe a 100-fold stabilization of organic dyes for the red-detuned nanoparticles. Our findings contribute to understanding of photochemical properties in the strong coupling regime and may find important implications for the performance and improved stability of optical devices incorporating organic dyes. PMID- 29984307 TI - Enhancing ferroelectric photovoltaic effect by polar order engineering. AB - Ferroelectric materials for photovoltaics have sparked great interest because of their switchable photoelectric responses and above-bandgap photovoltages that violate conventional photovoltaic theory. However, their relatively low photocurrent and power conversion efficiency limit their potential application in solar cells. To improve performance, conventional strategies focus mainly on narrowing the bandgap to better match the solar spectrum, leaving the fundamental connection between polar order and photovoltaic effect largely overlooked. We report large photovoltaic enhancement by A-site substitutions in a model ferroelectric photovoltaic material, BiFeO3. As revealed by optical measurements and supported by theoretical calculations, the enhancement is accompanied by the chemically driven rotational instability of the polarization, which, in turn, affects the charge transfer at the band edges and drives a direct-to-indirect bandgap transition, highlighting the strong coupling between polarization, lattice, and orbital order parameters in ferroelectrics. Polar order engineering thus provides an additional degree of freedom to further boost photovoltaic efficiency in ferroelectrics and related materials. PMID- 29984308 TI - Nano-kirigami with giant optical chirality. AB - Kirigami enables versatile shape transformation from two-dimensional (2D) precursors to 3D architectures with simplified fabrication complexity and unconventional structural geometries. We demonstrate a one-step and on-site nano kirigami method that avoids the prescribed multistep procedures in traditional mesoscopic kirigami or origami techniques. The nano-kirigami is readily implemented by in situ cutting and buckling a suspended gold film with programmed ion beam irradiation. By using the topography-guided stress equilibrium, rich 3D shape transformation such as buckling, rotation, and twisting of nanostructures is precisely achieved, which can be predicted by our mechanical modeling. Benefiting from the nanoscale 3D twisting features, giant optical chirality is achieved in an intuitively designed 3D pinwheel-like structure, in strong contrast to the achiral 2D precursor without nano-kirigami. The demonstrated nano kirigami, as well as the exotic 3D nanostructures, could be adopted in broad nanofabrication platforms and could open up new possibilities for the exploration of functional micro-/nanophotonic and mechanical devices. PMID- 29984309 TI - Ultrathin graphdiyne film on graphene through solution-phase van der Waals epitaxy. AB - Graphdiyne (GDY) is an ordered two-dimensional (2D) carbon allotrope comprising sp- and sp2-hybridized carbon atoms with high degrees of pi-conjugation, which features a natural band gap and superior electric properties. However, the synthesis of one- or few-layer GDY remains challenging because of the free rotation around alkyne-aryl single bonds and the lack of thickness control. We report the facile synthesis of an ultrathin single-crystalline GDY film on graphene through a solution-phase van der Waals epitaxial strategy. The weak admolecule-substrate interaction at the heterojunction drastically relaxes the large lattice mismatch between GDY and graphene. It allows the fast in-plane coupling of admolecules and slow out-of-plane growth toward the formation of an incommensurately stacked heterostructure, which is composed of single-layer graphene and few-layer ABC-stacked GDY, as directly observed by electron microscopy and identified from Raman fingerprints. This study provides a general route not only to the bottom-up synthesis of intriguing 2D acetylenic carbon allotropes but also to the device fabrication for the direct measurement of their intrinsic electrical, mechanical, and thermal properties. PMID- 29984310 TI - Correction for the Research Article: "High-flux soft x-ray harmonic generation from ionization-shaped few-cycle laser pulses" by A. S. Johnson, D. R. Austin, D. A. Wood, C. Brahms, A. Gregory, K. B. Holzner, S. Jarosch, E. W. Larsen, S. Parker, C. S. Struber, P. Ye, J. W. G. Tisch and J. P. Marangos. AB - [This corrects the article DOI: 10.1126/sciadv.aar3761.]. PMID- 29984311 TI - Correction for the Research Article: "High thermal conductivity in electrostatically engineered amorphous polymers" by A. Shanker, C. Li, G. Kim, D. Gidley, K. P. Pipe and J. Kim. AB - [This corrects the article DOI: 10.1126/sciadv.1700342.]. PMID- 29984312 TI - Simultaneous Estimation of Bias and Resolution in PET Images With a Long-Lived "Pocket" Phantom System. AB - A challenge in multicenter trials that use quantitative positron emission tomography (PET) imaging is the often unknown variability in PET image values, typically measured as standardized uptake values, introduced by intersite differences in global and resolution-dependent biases. We present a method for the simultaneous monitoring of scanner calibration and reconstructed image resolution on a per-scan basis using a PET/computed tomography (CT) "pocket" phantom. We use simulation and phantom studies to optimize the design and construction of the PET/CT pocket phantom (120 * 30 * 30 mm). We then evaluate the performance of the PET/CT pocket phantom and accompanying software used alongside an anthropomorphic phantom when known variations in global bias (+/ 20%, +/-40%) and resolution (3-, 6-, and 12-mm postreconstruction filters) are introduced. The resulting prototype PET/CT pocket phantom design uses 3 long lived sources (15-mm diameter) containing germanium-68 and a CT contrast agent in an epoxy matrix. Activity concentrations varied from 30 to 190 kBq/mL. The pocket phantom software can accurately estimate global bias and can detect changes in resolution in measured phantom images. The pocket phantom is small enough to be scanned with patients and can potentially be used on a per-scan basis for quality assurance for clinical trials and quantitative PET imaging in general. Further studies are being performed to evaluate its performance under variations in clinical conditions that occur in practice. PMID- 29984313 TI - Enhanced Bone Metastases in Skeletally Immature Mice. AB - Bone constitutes the most common site of breast cancer metastases either at time of presentation or recurrent disease years after seemingly successful therapy. Bone metastases cause substantial morbidity, including life-threatening spinal cord compression and hypercalcemia. Given the high prevalence of patients with breast cancer, health-care costs of bone metastases (>$20,000 per episode) impose a tremendous economic burden on society. To investigate mechanisms of bone metastasis, we developed femoral artery injection of cancer cells as a physiologically relevant model of bone metastasis. Comparing young (~6 weeks), skeletally immature mice to old (~6 months) female mice with closed physes (growth plates), we showed significantly greater progression of osteolytic metastases in young animals. Bone destruction increased in the old mice following ovariectomy, emphasizing the pathologic consequences of greater bone turnover and net loss. Despite uniform initial distribution of breast cancer cells throughout the hind limb after femoral artery injection, we observed preferential formation of osteolytic bone metastases in the proximal tibia. Tropism for the proximal tibia arises in part because of TGF-beta, a cytokine abundant in both physes of skeletally immature mice and matrix of bone in mice of all ages. We also showed that age-dependent effects on osteolytic bone metastases did not occur in male mice with disseminated breast cancer cells in bone. These studies establish a model system to specifically focus on pathophysiology and treatment of bone metastases and underscore the need to match biologic variables in the model to relevant subsets of patients with breast cancer. PMID- 29984314 TI - Microbial Community Cohesion Mediates Community Turnover in Unperturbed Aquifers. AB - Microbial ecological processes are frequently studied in the presence of perturbations rather than in undisturbed environments, despite the relatively stable conditions dominating many microbial habitats. To examine processes influencing microbial community structuring in the absence of strong external perturbations, three unperturbed aquifers in Ohio (Greene, Licking, and Athens) were sampled over 2 years and analyzed using geochemical measurements, 16S rRNA gene sequencing, and ecological modeling. Redox conditions ranging from highly reducing to more oxidizing distinguished aquifer geochemistry across the three locations. Distinct microbial communities were present in each aquifer, and overall community structure was related to geochemistry, although community composition was more similar between the Athens and Licking locations. The ecological processes acting upon microbial assemblages within aquifers were varied; geochemical changes affected the Athens location, while time or some unknown factor affected Greene County. Stochastic processes, however, dominated the Licking aquifer, suggesting a decoupling between environmental fluctuations and community development. Although physicochemical differences might be expected to drive variable selection, dispersal limitation (inability to mix) explained differences between Athens and Licking. Finally, community complexity as measured by "cohesion" indicated that less-interconnected communities experienced higher turnover and were more likely to be affected by stochastic processes. Conversely, more-interconnected communities experienced lower turnover and susceptibility to homogenizing selection. Based upon these data, we support the hypothesis that unperturbed environments house dynamic microbial communities due to external and internal forces. IMPORTANCE Many microbial ecology studies have examined community structuring processes in dynamic or perturbed situations, while stable environments have been investigated to a lesser extent. Researchers have predicted that environmental communities never truly reach a steady state but rather exist in states of constant flux due to internal, rather than external, dynamics. The research presented here utilized a combined null model approach to examine the deterministic and stochastic processes responsible for observed community differences in unperturbed, groundwater ecosystems. Additionally, internal dynamics were investigated by relating a recently published measure of community complexity (cohesion) to ecological structuring processes. The data presented here suggest that communities that are more cohesive, and therefore more complex, are more likely affected by homogenizing selection, while less complex communities are more susceptible to dispersal. By understanding the relationship between internal dynamics and community structuring processes, insight about microbial population development in natural systems can be obtained. PMID- 29984315 TI - Fibromyxoid Nephrogenic Adenoma in the Ureter. AB - Background: Nephrogenic adenoma is a benign lesion found in the genitourinary tract, often at sites of prior inflammation, and is characterized by tubular, papillary, or tubulopapillary structures. It is thought to arise from distal migration and implantation of renal tubular cells into the renal pelvis, ureter, bladder, or urethra. These tumors often resemble malignant neoplasms. Morphologic variants include small tubules, signet ring-like pattern, papillary formations, flat pattern, and vessel-like structures. A fibromyxoid variant was first described in 2007. Here, we present the first known cases of fibromyxoid nephrogenic adenoma of the ureter. Case Presentations: A 79-year-old white man presented with asymptomatic right hydroureteronephrosis to the level of the mid ureter with associated right ureteral wall thickening found on surveillance CT scan for lymphoma. A 59-year-old white man presented with a right ureteral stricture after ureteroscopic ureteral injury and underwent effective robotic ureteroureterostomy. Pathology analysis in both cases revealed fibromyxoid nephrogenic adenoma. Conclusion: Fibromyxoid nephrogenic adenoma may occur in the ureter. Knowledge of this rare tumor is important for urologists and pathologists to prevent misdiagnosis and overtreatment of a typically benign process. PMID- 29984316 TI - Successful Ultra-Minimally Invasive Endoscopic Intrarenal Surgery for 2-Year-Old Boy with Bilateral Cystine Kidney Stones Over 2 cm. AB - Background: Treatment of upper urinary tract stones measuring >2 cm in children aged <3 years is challenging. Although adult-sized instruments are usually available, in pediatric populations such instruments seem unreasonable and unfit for children with small kidneys and narrow ureters. We use ultra-miniaturized endoscopes and instruments to reduce the damage to normal tissues in pediatric patients. Case Presentation: We treated a 2-year-old boy with >2-cm bilateral cystine kidney stones. We decided to perform retrograde intrarenal surgery using an ultrathin (4.5F) semi-rigid ureteroscope for the right kidney stone (2.0 * 1.2 cm) in the lithotomy position and super ultra-minimally invasive endoscopy combined with intrarenal surgery with a percutaneous 8.5F to 9.5F tract sheath for the left kidney stone (3.5 * 2.4 cm) under the Barts modified Valdivia position. These procedures were successful for the bilateral kidney stones. Postoperatively, the patient was stone-free without major complications. Conclusion: We believe that ultra-minimally invasive endoscopic intrarenal surgery is safe and efficient in pediatric patients. Furthermore, the Barts modified Valdivia position was safely utilized in our 2-year-old patient with multiple large kidney stones. PMID- 29984317 TI - Efficacy of sodium bicarbonate buffered versus non-buffered lidocaine with epinephrine in inferior alveolar nerve block: A meta-analysis. AB - Introduction: This systematic review evaluated the use of buffered versus non buffered lidocaine to increase the efficacy of inferior alveolar nerve block (IANB). Materials and Methods: Randomized, double-blinded studies from PubMed, Web of Science, Cochrane Library, Embase, and ProQuest were identified. Two of the authors assessed the studies for risk of bias. Outcomes included onset time, injection pain on a visual analog scale (VAS), percentage of painless injections, and anesthetic success rate of IANB. Results: The search strategy yielded 19 references. Eleven could be included in meta-analyses. Risk of bias was unclear in ten and high in one study. Buffered lidocaine showed 48 seconds faster onset time (95% confidence interval [CI], -42.06 to -54.40; P < 0.001) and 5.0 units lower (on a scale 0-100) VAS injection pain (95% CI, -9.13 to -0.77; P=0.02) than non-buffered. No significant difference was found on percentage of people with painless injection (P = 0.059), nor success rate (P = 0.290). Conclusion: Buffered lidocaine significantly decreased onset time and injection pain (VAS) compared with non-buffered lidocaine in IANB. However due to statistical heterogeneity and low sample size, quality of the evidence was low to moderate, additional studies with larger numbers of participants and low risk of bias are needed to confirm these results. PMID- 29984318 TI - Comparative evaluation of the efficacy, safety, and hemostatic effect of 2% lidocaine with various concentrations of epinephrine. AB - Background: We evaluated the changes in mean arterial pressure (MAP) and heart rate (HR), and the anesthetic and hemostatic effects, after injection of 2% lidocaine containing various concentrations of epinephrine in rats and mice to determine the appropriate concentration of epinephrine in various anesthetic mixtures. Methods: Rats and mice were randomly allocated to experimental groups: 2% lidocaine without epinephrine (L0), 2% lidocaine with epinephrine 1:200,000 (L200), 1:100,000 (L100), and 1:80,000 (L80). Changes in MAP and HR after administration of the anesthetic mixture were evaluated using a physiological recording system in rats. Onset and duration of local anesthesia was evaluated by pricking the hind paw of mice. A spectrophotometric hemoglobin assay was used to quantify the hemostatic effect. Results: MAP increased in response to epinephrine in a dose-dependent manner; it was significantly higher in the L80 group than in the L0 group at 5 min post-administration. The HR was relatively lower in the L0 group than in the L80 group. The time required for onset of action was < 1 min in all evaluation groups. The duration of action and hemostatic effect of the local anesthetic were significantly better in the L200, L100, and L80 groups than in the L0 group. Conclusion: L200 demonstrated relatively stable MAP and HR values with satisfactory efficacy and hemostatic effect. L200 might be a better local anesthetic for dental patients in terms of anesthetic efficacy and safety. PMID- 29984319 TI - Effect of a 5% naproxen patch on reducing pain caused by separators prior to fixed orthodontic treatment. AB - Background: The pain involved in orthodontic treatments may involve inflammatory processes. This study evaluated the effect of using a naproxen patch for pain reduction in the separating stage of fixed orthodontic treatment. Methods: In this double-blind, randomized, controlled clinical trial of 35 orthodontic patients (age: 14-19 years) who had pain during separator placement, each patient randomly placed naproxen and placebo patches in the first permanent molar region, in opposite quadrants of the same jaw. Patches were replaced every 8 hours until 3 days after separator placement. Patients recorded their pain perception at 2, 6, and 24 hours, and on days 2 (6 PM), 3 (10 AM and 6 PM), and 7 (10 AM and 6 PM), using a visual analog scale. Mean pain scores were compared for the two patches, and effects of sex and age thereon determined. Results: Data from 29 patients (21 girls, eight boys) were analyzed. Mean pain values decreased over time for both patches (P < 0.001). Recorded pain did not differ significantly between the sexes (P = 0.059) or between those aged <16 and those >=16 years (P = 0.106). Mean pain recorded with naproxen patches was statistically significantly less than that with placebo patches at all time points (P = 0.004). Conclusion: The naproxen patch was more efficient than the placebo patch for reducing pain at all time points. The highest pain score was recorded at 6 hours, and the least pain was recorded at the 7th day after separator placement. PMID- 29984320 TI - Effect of preemptive intravenous ibuprofen on postoperative edema and trismus in third molar tooth extraction: A randomized controlled study. AB - Background: This study aimed to evaluate the anti-inflammatory efficacy of preemptive intravenous ibuprofen on inflammatory complications such as edema and trismus in patients undergoing impacted mandibular third molar surgery. Methods: Sixty patients were included and divided into three groups (800 mg IV ibuprofen + 50 mg dexketoprofen, 800 mg IV ibuprofen, and control). In all patients, preoperative hemodynamic values were recorded before the infusions. The operation was started at 15-min post-infusion. Evaluation of edema size on the face and mouth opening (trismus) was conducted in the preoperative period, and at postoperative 48 h and 1 week. Results: No difference was determined among the groups in trismus and edema size in postoperative measurements (P > 0.05). There was a difference between group 2 and group 3 only in measurement value of tragus corner of the mouth on the postoperative day 2 (P < 0.05). A difference was found between the measurement values of trismus preoperatively and at preoperative day 2, and between postoperative day 2 and 1 week in group 3 based on time (P < 0.05). In group 3, edema on the face on postoperative day 2 increased significantly compared to that in the preoperative period (P < 0.001); in addition, edema increased significantly in groups 1 and 2 in the postoperative period but was less than that in group 3 (P < 0.001). Conclusions: In this study, intravenous ibuprofen was determined to be more effective alone or in combination in alleviating trismus and to better limit the postoperative edema. PMID- 29984321 TI - Comparative randomized study of propofol target-controlled infusion versus sevoflurane anesthesia for third molar extraction. AB - Background: The objective of this study was to compare hemodynamic and recovery characteristics of total intravenous anesthesia using propofol target-controlled infusion (TCI) versus sevoflurane for extraction of four third molar teeth. Methods: One hundred patients undergoing extraction of four third molar teeth under general anesthesia were randomized to one of two groups. Group 1 received propofol TCI-oxygen for induction and propofol TCI-oxygen-air for maintenance. Group II received a propofol bolus of 2 mg/kg for induction and sevoflurane oxygen-air for maintenance. Heart rate, mean arterial pressure (MAP), operating time, time to emergence, nausea and vomiting, and sedation and pain scores were measured in each group. Results: Demographic data, including age, gender, weight, and height, were not significantly different between the two groups. The MAP was significantly higher after intubation (P = 0.007) and injection of anesthesia (P = 0.004) in the propofol group than in the sevoflurane group, with significant reflex bradycardia (P = 0.028). The mean time to emergence from anesthesia using propofol was 25 s shorter than that of sevoflurane (P = 0.02). Postoperatively, the propofol group was less sedated than the sevoflurane group at 30 min (0.02 versus 0.12), but this difference was not significant (P = 0.065). Conclusion: Both propofol TCI and sevoflurane are good alternatives for induction and maintenance of anesthesia for short day-case surgery. However, propofol TCI does not blunt the hemodynamic response to sudden, severe stimuli as strongly as sevoflurane, and this limitation may be a cause for concern in patients with cardiac comorbidities. PMID- 29984322 TI - Delayed paresthesia of inferior alveolar nerve after dental surgery: case report and related pathophysiology. AB - Paresthesia is an altered sensation of the skin, manifesting as numbness, partial loss of local sensitivity, burning, or tingling. The inferior alveolar nerve (IAN) is the third branch of the trigeminal nerve and is very important in dental treatment. IAN paresthesia may occur after various dental procedures such as simple anesthetic injections, surgical procedures, and endodontic treatment, and is reported to range from 0.35% to 8.4%. The altered sensation usually follows immediately after the procedure, and reports of late onset of nerve involvement are rare. This report presents a rare case of delayed paresthesia after dental surgery and discusses the pathophysiology of IAN delayed paresthesia. PMID- 29984323 TI - Airway management in a displaced comminuted fracture of the mandible and atlas with a vertebral artery injury: A case report. AB - Complex cervical spine fractures are a serious complications of maxillofacial trauma and associated with high mortality and neurological morbidity. Strict vigilance in preventing further insult to the cervical spine is a crucial step in managing patients who are at risk for neurologic compromise. We report a rare case of a right transverse process of atlas fracture with right-sided vertebral artery injury that was associated with a comminuted fracture of the body and angle of the mandible, which restricted mouth opening. Airway management was performed by an awake fiber-optic nasotracheal intubation, where neck movement was avoided with a cervical collar. Vertebral artery injuries may have disastrous consequences, such as basilar territory infarction and death, and should be suspected in patients with head and neck trauma. After mandibular plating, the patient was on cervical collar immobilization for 12 weeks and anti-coagulant therapy. PMID- 29984324 TI - Recurrent ST segment elevations in a patient with asymptomatic early repolarization during head and neck surgery: implications of vasospastic angina. AB - A 57-year-old woman scheduled for cochlear implant removal exhibited preoperative electrocardiographic findings of early repolarization (ER). Four episodes of transient ST segment elevations during surgery raised suspicion for vasospastic angina (VA). In the post-anesthetic care unit, the patient complained of chest discomfort and received sublingual nitroglycerin with uncertain effect. The patient refused to proceed with postoperative invasive coronary angiography, resulting in inconclusive diagnosis. Intraoperative circumstances limit the diagnosis of VA, which emphasizes the need for further testing to confirm the diagnosis. When VA is suspected in patients with underlying ER, it is reasonable to consider invasive examination to establish the diagnosis and prevent recurrence of VA. If ST changes are observed during surgery in patients with preoperative ER, careful monitoring is recommended. Due to general anesthesia, the absence of patient symptoms limits the definitive diagnosis of those with suspected VA. Therefore, additional postoperative surveillance is recommended. PMID- 29984325 TI - Letter to the Editor - Response to: The effect of dental scaling noise during intravenous sedation on acoustic respiration rate. PMID- 29984326 TI - Serum circulating cell free DNA as potential diagnostic and prognostic biomarker in non small cell lung cancer. AB - Background: Non-small cell lung cancer (NSCLC) is leading cause of cancer related death and the survival rate for patients with NSCLC remain poor so early diagnosis of NSCLC represents the best opportunity for cure. Cell-free DNA (cf DNA) is extracellular nucleic acids found in cell-free plasma/serum of humans, given the recent approval of a liquid biopsy in lung cancer, the use of circulating tumor DNA as a novel non-invasive diagnostic and prognostic biomarker is promising. Objectives: Studying whether the concentrations of circulating Cell Free DNA in serum can be used as a diagnostic and prognostic biomarker for NSCLC patients. Method: This study was carried out on 140 subjects included 60 patients with non small cell lung cancer,40 patients with Chronic Obstructive Pulmonary Disease (COPD) and 40 healthy controls. Quantitative analysis of serum circulating cf-DNA was done b y AlU-based quantitative real time PCR. Serum level of CEA was measured by ELISA. Results: NSCLC patients demonstrated significantly higher values of each of ALU 215, ALU 247, and DNA integrity than both COPD patients and controls. On ROC curve analysis, the total accuracy of ALU 247, ALU 115, DNA integrity (92.1%, 83.6%, 56.4%) at cutoff points (325, 565 & 0.48) respectively. On combining both DNA integrity and CEA, improved sensitivity to 93.3% was noted. For NSCLC patients, ALU 115 & ALU 247 increased significantly with more advanced stage and highest level was noticed in metastatic patients. Regarding survival there was better overall survival among patients with low DNA integrity. Conclusion: Serum cf-DNA concentrations and integrity index may be valuable tool in early diagnosis of NSCLC and prediction of prognosis of those patients. PMID- 29984328 TI - Design and simulation of an automatic room heater control system. AB - This paper presents the design and simulation of an Automatic Room Heater Control system. This system allows the user to set a desired temperature which is then compared to the room temperature measured by a temperature sensor. With the help of a microcontroller, the system responds by turning ON any of the two (2) loads (Fan or a heater) automatically depending on the temperature difference. The Fan is triggered ON when the room temperature is higher than the set temperature and the heater is triggered ON when the room temperature is lower than the set temperature. The system was designed and simulated using Proteus 8, circuit building software used for building electronics system. Proteus software was used to design and simulate the main circuit, and Micro-C hex file was loaded on the Proteus schematic design. For coding the PIC Microcontroller, Micro-C compiler was used. A 5 V DC power supply was designed in order to provide a biasing voltage to most of the active devices used in the system design circuit. The DC power supply was designed and simulated using Multisim software. The system was simulated and simulation results were in accordance to the design specifications. PMID- 29984327 TI - Anxiolytic and anti-inflammatory role of thymoquinone in arsenic-induced hippocampal toxicity in Wistar rats. AB - Arsenic (As) is a widely existing metalloid in the biosphere. Drinking water contamination by arsenic is a major route of human exposure, either by natural means or through industrial pollution. Numerous evidence form earlier reports suggest that arsenic exposure causes cerebral neurodegeneration which initiates behavioral disturbances concomitant to psychiatric disorders. Also, mood disorders in humans as well as in animals correlate with arsenic exposure; the present study is carried out to implore the neuroprotective potential of thymoquinone (TQ) in arsenic-stressed rats. TQ is an active component of Nigella sativa (Kalonji) seed oil. Arsenic exposure in the form of sodium arsenate (10 mg/kg/day; p.o) caused neurobehavioral deficits as evidenced by changes in locomotion and exploratory behavior in open-field and elevated plus maze tasks. Alongside this, arsenate also elevated hippocampal oxidative stress parameters like lipid peroxidation (TBARS) and protein carbonyl formation with a decrease in superoxide dismutase (SOD) and reduced glutathione (GSH) content. Genotoxicity assessment by Comet assay also showed prominent levels of DNA damage. Furthermore, arsenic also elevated hippocampal cytokine levels, TNF-alpha and INF gamma. However, TQ supplementation (2.5 and 5 mg/kg/day, p.o) preceded three days before arsenic administration, significantly attenuated arsenic-associated anxiogenic changes which majorly attributed to its antioxidant and anxiolytic potential. Also, TQ pre-treated rats expressed positive shifts in the hippocampal oxidative stress and cytokine levels with decreased DNA fragmentation. Thus, this study concludes that TQ might serve as a strong therapeutic agent for management of anxiety and depressive outcomes of arsenic intoxication. PMID- 29984329 TI - Synthesis and characterization of Schiff bases NBBA, MNBA and CNBA. AB - Three Schiff base compounds, N1,N2 -bis(3-nitrobenzylidene)phenylene diamine (NBBA), 2-methyl-N-(3-nitrobenzylidene)aniline (MNBA) and N-(2-chlorobenzylidene) 4-nitroaniline (CBNA) were synthesized, characterised and applied for the first time as potential mild steel (MS) corrosion inhibitors in 1 M HCl at 30 degrees C. Fourier transform infra-red (FTIR), 1H, 13C Nuclear magnetic resonance (NMR) and Mass spectrometry (MS) were used for the characterisation of the compounds. The electrochemical studies and evaluation of corrosion inhibition potency were achieved using potentiodynamic polarization (PDP) and electrochemical impedance spectroscopy (EIS) techniques. Density functional theory (DFT) calculations were further employed to describe the electronic distribution on the molecules and potential sites that aided corrosion inhibition. The results of the employed characterisation techniques confirmed the proposed structures of the compounds with the MS revealing the exact molecular mass of the compounds. Electrochemical results showed that the trend in inhibition efficiency of the three compounds was in the order: MNBA > NBBA > CBNA. MNBA recorded the highest inhibition efficiency at 100 ppm. Corrosion kinetics of the set of inhibitors was found to prefer the Langmuir adsorption isotherm with both physisorption and chemisorption mechanisms as revealed by DeltaG values. In an effort to develop efficient corrosion inhibitors with non-toxic effect, low cost and multiple adsorption centres, these Schiff bases are presented. PMID- 29984330 TI - Understanding antagonism and synergism: A qualitative assessment of weight management in youth with Type 1 diabetes mellitus. AB - Aims: No current clinical guidelines focus on weight management in youth with type 1 diabetes mellitus (T1DM). Our aim was to characterize the patient perceived experience and barriers to weight management in youth with T1DM. Methods: Participants were recruited from the University of North Carolina (n = 16, 56% female, 60% White, 50% insulin pump users, mean age 14.8 years, mean HbA1c 8.5% (69 mmol/mol)) and the University of Colorado (n = 18, 50% female, 80% white, 53% pump users, mean age 15.3 years, mean HbA1c 9.3% (78 mmol/mol)). Focus groups were stratified by sex and weight status (BMI cutoff = 25). Discussions were guided by a standardized set of questions, audio-taped, transcribed, and analyzed thematically using inductive qualitative methods. Results: Youth with T1DM expressed four interrelated themes of antagonism between type 1 diabetes and weight management: dysregulated appetite, disruption of blood glucose levels associated with changing diet/exercise, hypoglycemia as a barrier to weight loss, and the overwhelming nature of dual management of weight and glycemic control, and two interrelated themes of synergism: improvement in shared, underlying heath behaviors and exercise as a tool for weight and glycemic control. Variation in emphasis of specific thematic elements was greatest across sex. Youth identified five major components of a weight management program for T1DM: intensified glucose management, healthy diet with known carbohydrate content, exercise, individualization and flexibility, and psychosocial and peer support. Conclusions: There is critical need for personalized, T1DM-specific weight recommendations to overcome disease-specific barriers to weight management in the context of T1DM. PMID- 29984332 TI - Severe Achromobacter xylosoxidans keratitis with deep corneal involvement. AB - Purpose: To describe a case of Achromobacter xylosoxidans keratitis with deep involvement of the corneal stroma and discuss its management. Observations: A 73 year-old monocular male with infectious keratitis of the right eye was referred to the Wilmer Eye Institute after a month of empiric treatment with besifloxacin. On presentation, slit lamp examination of the right eye demonstrated a diffusely edematous cornea with three areas of corneal infiltrates and an overlying epithelial defect and a 1.3 mm hypopyon in the anterior chamber. The corneal culture performed grew A. xylosoxidans. Empiric antibiotic regimen was adjusted once corneal culture susceptibility results were available. Seven days later, slit lamp examination demonstrated a resolving epithelial defect, stable infiltrates, and resolution of the hypopyon. After approximately two months of follow up with his primary ophthalmologist, he was noted to have recurrent hypopyon and infiltrates and was referred back to Wilmer. Slit lamp examination again demonstrated an epithelial defect, diffuse corneal haze, deep stromal infiltrates, and a 1 mm hypopyon. Corneal infiltrates were too deep to culture. Ultimately, the patient underwent a therapeutic penetrating keratoplasty with anterior chamber washout resulting in improvement of vision. Conclusions and importance: The indolent progression of A. xylosoxidans keratitis may predispose patients to delayed presentation and treatment. This can result in deep stromal infection that complicates management due to poor antibiotic penetration. Deep stromal infections in A. xylosoxidans keratitis warrant the consideration of intrastromal antibiotic injection or early therapeutic penetrating keratoplasty. PMID- 29984331 TI - A case of neglected silicone tube in lacrimal duct for 20 years. AB - Purpose: To report a case of prolonged placement of a lacrimal silicone tube for 20 years, with evaluation of the lacrimal duct using lacrimal micro-endoscopy and inspection of deformation of the lacrimal tube. Observations: This study involved a case of dacryocystitis in which a silicone tube had been placed in the patient 20-years previous and that was treated conservatively. Although granulation tissue formation due to dacryocystitis in the lacrimal duct was observed under lacrimal micro-endoscopy, subjective and objective resolution of symptoms, including granulated tissue formation, was achieved after removal of the silicone tube and conservative medical treatment. Follow-up examinations performed over a 12-month period post treatment revealed no recurrence of epiphora or anatomical obstruction. Inspection of the lacrimal tube using the tension test revealed minimal changes in the tube in situ for 20 years. Conclusions and Importance: The findings in this case suggest both the lacrimal system and the silicone tube are tolerant to prolonged intubation, as long as the tube had been placed properly with careful observation. Our findings may encourage physicians to consider prolonged intubation for select cases of nasolacrimal duct obstruction. PMID- 29984333 TI - Central serous chorioretinopathy as a cause of vision loss in chronic relapsing inflammatory optic neuropathy. AB - Purpose: Chronic relapsing inflammatory optic neuropathy (CRION) is a type of idiopathic recurrent optic neuritis that responds to systemic corticosteroids and relapses on steroid withdrawal or dose reduction. Central serous chorioretinopathy (CSCR) is often associated with glucocorticoid therapy. This paper aims to highlight CSCR as a cause of visual loss in patients being treated with corticosteroids for optic neuritis. Observations: We describe the case of a 42-year-old woman with a history of CRION in her left eye who presented with painful vision loss in the right eye and diffuse right optic disc edema. Steroid therapy was initiated, leading to visual and perimetric improvement. Two months later however, the patient returned with painless visual loss, now related to CSCR. Despite oral steroids being continued, there was spontaneous tomographic and visual recovery after four months. Conclusions and importance: We believe this is the first report of CSCR causing vision loss in a patient with CRION treated with oral corticosteroids. CSCR should be suspected in patients with optic neuritis of any cause who develop vision loss while on treatment with steroids. PMID- 29984334 TI - Bilateral cystoid macular edema misdiagnosed as pars planitis in a patient on sertraline therapy. AB - Purpose: To describe the presentation, clinical course and management of a patient with bilateral maculopathy associated with sertraline. Observations: We report a rare case of bilateral cystoid macular edema and subretinal fluid in a 78-year-old Asian Indian female who was on chronic sertraline therapy. The patient was initially misdiagnosed as intermediate uveitis and started on oral corticosteroids. However, multimodal imaging with fluorescein angiography and optical coherence tomography ruled out ocular inflammation. There was symmetrical bilateral macular involvement and changes on macular electroretinography, which provided clues to the diagnosis of toxic maculopathy. After cessation of sertraline therapy, the retinal pathology reversed with improvement in visual acuity. Conclusions and Importance: Development of cystoid macular edema due to sertraline is a very rare adverse event and must be considered by psychiatrists and ophthalmologists. Our case demonstrates this rare toxicity along with its imaging features, and reversal on cessation of sertraline therapy. PMID- 29984335 TI - New surgical robots on the horizon and the potential role of artificial intelligence. PMID- 29984337 TI - Role of co-expression of estrogen receptor beta and Ki67 in prostate adenocarcinoma. AB - Purpose: To evaluate the expression of estrogen receptor (ER)-beta and Ki67 in prostate cancer and study their relationship. Materials and Methods: We analyzed 101 cases of prostate adenocarcinoma diagnosed from January 2011 to June 2015 in 100 patients. Immunohistochemical staining of ER-beta and Ki67 was analyzed according to Gleason score categorized into prognostic groups of 1 to 5. Double immunofluorescent staining of ER-beta and Ki67 was performed in a total of 20 cases to study the co-expression and the relationship between these markers within the same tumor. Results: A total of 53 of 101 cases (52.5%) were positive for ER-beta expression. There was a positive correlation whereby a high percentage of ER-beta expression was seen in the higher prognostic groups (groups 4 and 5; p=0.007). High Ki67 expression was observed in the higher prognostic group, whereas low Ki67 or negative expression was found in the lower prognostic group (p<0.001). The majority of cases evaluated with double-immunofluorescent staining (14/20) showed co-expression of ER-beta and Ki67 at the individual cell level. Conclusions: ER-beta and Ki67 are independent tumor markers in high prognostic groups. Hence, co-expression of ER-beta and Ki67 indicates a more aggressive tumor with a poorer prognosis. PMID- 29984338 TI - Predictors and outcomes of laparoscopic nephrectomy in autosomal dominant polycystic kidney disease. AB - Purpose: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, and 20% of patients eventually require nephrectomies due to compressive symptoms or renal-related complications. Traditionally, nephrectomies were performed via the open approach in view of space constraints. We evaluate our institution's outcomes for laparoscopic nephrectomy (LN) for ADPKD. Materials and Methods: We retrospectively reviewed 33 patients with ADPKD who underwent nephrectomies from November 2005 to December 2016 at a tertiary institution. Preoperative kidney volume was calculated via the ellipsoid method by using computed tomography scan. Results: The median age was 51.0 years (interquartile range [IQR], 44.5-56.0 years). Sixteen patients (48.5%) underwent open nephrectomy (ON), 15 patients (45.5%) had LNs, and 2 patients (6.1%) had laparoscopic converted to ON due to dense adhesions. Thirteen patients had bilateral while 18 patients had unilateral nephrectomies. Median kidney volume in the open group was 1,042 cm3 (IQR, 753-2,365 cm3) versus 899 cm3 (IQR, 482-1,914 cm3) in the laparoscopy group and did not differ significantly. The operative time was comparable between both groups. Patients who underwent LN had lesser blood loss (350 mL vs. 650 mL; 95% confidence interval [CI], 1.822-3.533; p=0.016) and shorter length of hospital stay (4.0 days vs. 6.5 days; 95% CI, 1.445-5.755; p=0.001) compared to patients who underwent ON. Both groups had similar low morbidity rate and no mortality. Conclusions: LN for ADPKD is a safe and effective alternative to ON independent of kidney size with comparable outcomes and benefits of minimally invasive surgery. PMID- 29984336 TI - Can tumor recurrence be reduced with plasma-kinetic vaporization of the area around the tumor in nonmuscle invasive bladder cancer? AB - Purpose: To investigate the effect on recurrence of vaporization of the tumor surroundings and suspicious areas with a plasma-kinetic (PK) system after transurethral resection (TUR) of nonmuscle invasive bladder cancer. Materials and Methods: The study included 121 patients with a primary superficial bladder tumor who were randomized as those who underwent TUR with the PK system (Group 1, n=62) and those who underwent TUR with the monopolar system (Group 2, n=59). The vaporization procedure was performed by suppressing the cutting option of the PK system for a period, which would accumulate energy sufficient to make swelling waves on the mucosa very close to the area of the loop to be vaporized. Results: A total of 121 patients who met the study criteria were included for evaluation. Recurrence was determined in 21 patients in Group 1 (33.87%) and in 29 patients in Group 2 (49.15%) (p=0.088). Recurrence was close to the old resection site in 6 of 21 patients in Group 1, and in 13 patients in Group 2 (p=0.028); the difference was statistically significant. No statistically significant difference was determined between the two groups with respect to age, gender, number of tumor foci, rate or range of additional treatments applied, cigarette smoking rate, repeat TUR rate and rate of tumor en- countered in repeat TUR, T-stage, and tumor grade. Conclusions: The effect of vaporization on recurrence by the PK system may seem similar to the effect of standard TUR, the recurrence- lowering effect surrounding nonmuscle invasive bladder cancers is better. PMID- 29984339 TI - Intravesical electrical stimulation treatment for overactive bladder: An observational study. AB - Purpose: Intravesical electrical stimulation treatment (IVES) has been successfully used to treat neurogenic bladder. We report the results of an observational study regarding the use of IVES for women with overactive bladder syndrome (OAB) and/or urgency urinary incontinence (UUI). Materials and Methods: IVES was performed in women with OAB (defined by frequency >=8/day, nocturia >=2/night, or >=3 episodes of UUI on 3-day voiding diary) who failed prior medical therapy. Subjects underwent 4 weeks of treatment with an 8-Fr DetrusetTM IVES catheter. Primary outcome was Patient Global Impression of Improvement (PGI I) at 3 months. Secondary outcomes included Visual Analog Scale (VAS), Short Form OAB Questionnaire (OAB-q SF), Pelvic Floor Distress Inventory (PFDI), Pelvic Floor Impact Questionnaire (PFIQ), reduction in frequency and UUI on voiding diary, and adverse effects. Analysis was done with paired t-tests and Wilcoxon signed rank tests. Results: Seventeen subjects completed the study. At 4 weeks post-treatment, 15 improved on PGI-I (11 subjects: 'a little better', 2: 'much better', 2: 'very much better'). There were significant improvements in symptom bother and health-related quality of life as measured by OAB-q SF and pelvic organ prolapse and urinary distress as measured by PFDI. Frequency decreased from 10.3+/-4.3 at baseline to 8.9+/-2.3 (p=0.04) at 3 months. No pain was reported during treatment. There was one urinary tract infection during the study period. No other adverse events were reported. Conclusions: IVES appears to be a safe and effective novel treatment for OAB. Larger comparative studies are needed to investigate its potential for long-term treatment. PMID- 29984340 TI - Measuring urinary 8-hydroxy-2'-deoxyguanosine and malondialdehyde levels in women with overactive bladder. AB - Purpose: In this study, we aimed to explain the role of oxidative stress in women with overactive bladder (OAB) by investigating the levels of 8-hydroxy-2' deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and malondialdehyde (MDA), an indicator of lipid peroxidation. Materials and Methods: A total of 90 women were included in the study: 45 female patients diagnosed with OAB at Hopa State Hospital Urology Polyclinic and 45 healthy women without any metabolic or neurologic disease. Levels of MDA and 8-OHdG were measured in 24-hour urine samples for all subjects. Results: Urinary levels of MDA and 8-OHdG were significantly higher in the OAB group than in the control group (p<0.001). A significant positive correlation (p<0.001) was found between the measurements of 8-OHdG and MDA. Conclusions: Oxidative stress may be important in the pathophysiology of OAB, because levels of 8-OHdG and MDA are increased. Increased levels of 8-OHdG may be due to damaged nuclear and mitochondrial DNA as a result of oxidative attacks caused by free radicals. Nevertheless, further randomized and prospective studies with larger patient populations are needed. PMID- 29984341 TI - Peroxisome proliferator-activated receptor gamma agonist as a novel treatment for interstitial cystitis: A rat model. AB - Purpose: To understand the therapeutic potential of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist with a propensity to cause bladder mucosal proliferation, on interstitial cystitis (IC) in a rat model. Materials and Methods: Using a previously described animal model for IC, Sprague-Dawley rats were treated with biweekly cyclophosphamide injections (35 mg/kg) to induce cystitis. Animals were divided into 4 groups (n=6 for each group): IC plus daily sham saline gavage (IC+Pio-), IC plus daily pioglitazone gavage (15 mg/kg) (IC+Pio+), normal rats with daily pioglitazone (IC-Pio+), and normal rats with neither IC nor pioglitazone (IC-Pio- or Control). At the end of four weeks, urinary frequency and bladder capacity were measured. Histologic examination of urothelial integrity was also performed. Results: Average voids per hour were significantly lower in IC+Pio+ (4.0+/-1.9) vs. IC+Pio- (10.0+/-2.4) rats (p<0.01) and were similar to IC-Pio+ (6.0+/-1.4) and IC-Pio- (6.0+/-1.5) controls. Cystometric capacity was significantly higher in IC+Pio+ (0.945+/-0.122 mL) vs. IC+Pio- rats (0.588+/-0.165 mL, p=0.01) and was comparable to IC-Pio- capacity (0.817+/-0.196 mL) and IC-Pio+ capacity (0.941+/-0.188 mL). Urothelial structural integrity was improved in IC+Pio+ rats versus IC+Pio- rats upon histologic observation. Conclusions: Pioglitazone, a PPAR-gamma agonist, improved bladder function in cyclophosphamide-induced cystitis by both observed urinary frequency and measured cystometric capacity. Urothelial structural integrity was also improved. Pioglitazone, due to a propensity to cause bladder mucosal proliferation, may prove useful for treating IC, and deserves further investigation. PMID- 29984342 TI - Down-regulation of transient receptor potential melastatin member 7 prevents migration and invasion of renal cell carcinoma cells via inactivation of the Src and Akt pathway. AB - Purpose: Transient receptor potential melastatin member 7 (TRPM7), an ion channel and serine/threonine protein kinase, has been linked with distinct human malignancies. However, the role of TRPM7 in renal cell carcinoma (RCC) has not been investigated. The aim of this study is to determine whether TRPM7 regulates the migration and invasion of RCC cells. Its relationship with signal transduction pathways was also studied. Materials and Methods: The human RCC cell lines ACHN and SN12C were chosen for this study. The molecular mechanisms of TRPM7 action were studied using Western blot analysis and small interfering RNA (siRNA)-based knockdown. The effect of TRPM7 knockdown on RCC cells was measured by using Transwell invasion and wound healing migration assays. Results: siRNA induced silencing of TRPM7 notably decreased the migration and invasion of ACHN and SN12C RCC cells. The phosphorylation levels of Src in both cells were obviously reduced after TRPM7 silencing compared with that of the control ACHN and SN12C cells. Furthermore, the phosphorylation levels of Akt were greatly decreased in ACHN cells after siRNA-induced knockdown of TRPM7. Additionally, the treatment of cells with Src and Akt inhibitors clearly limited the migration and invasion of RCC cells. Conclusions: Our data show that TRPM7 regulated ACHN and SN12C RCC cell invasion via the Src/Akt signaling pathway. Therefore, targeting the Src/Akt signaling pathway and/or the expression or function of TRPM7 could be a potential beneficial treatment for patients with RCC. PMID- 29984343 TI - Proof of concept: Exposing the myth of urethral atrophy after artificial urinary sphincter via assessment of circumferential recovery after capsulotomy and intraoperative pressure profiling of the pressure regulating balloon. AB - Purpose: Rate of continence after artificial urinary sphincter (AUS) placement appears to decline with time. After appropriate workup to exclude inadvertent device deactivation, development of urge or overflow incontinence, and fluid loss, many assume recurrent stress urinary incontinence (rSUI) to be secondary to nonmechanical failure, asserting urethral atrophy as the etiology. We aimed to characterize the extent of circumferential urethral recovery following capsulotomy and that of pressure regulating balloon (PRB) material fatigue in men undergoing AUS revision for rSUI. Materials and Methods: Retrospective review of a single surgeon database was performed. Cases of AUS removal/replacement for rSUI involving ventral subcuff capsulotomy and intraoperative PRB pressure profile assessments were identified. Results: The described operative approach involving capsulotomy was applied in 7 patients from November 2015 to September 2017. Mean patient age was 75 years. Mean time between AUS placement and revision was 103 months. Urethral circumference increased in all patients after capsulotomy (mean increase 1.1 cm; range 0.5-2.5 cm). Cuff size increased, remained the same, and decreased in 2, 3, and 2 patients, respectively. Six of 7 patients underwent PRB interrogation. Four of these 6 PRBs (66.7%) demonstrated pressures in a category below the reported range of the original manufacturer rating. Conclusions: Despite visual appearance to suggest urethral atrophy, subcuff capsulotomy results in increased urethral circumference in all patients. Furthermore, intraoperative PRB profiling demonstrates material fatigue. Future multicenter efforts are warranted to determine if capsulotomy, with or without PRB replacement, may simplify surgical management of rSUI with reductions in cost and/or morbidity. PMID- 29984344 TI - Letter to the editor: Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. PMID- 29984345 TI - The authors reply: Safety and feasibility of platelet rich fibrin matrix injections for treatment of common urologic conditions. PMID- 29984346 TI - Corrigendum: Incorrect Spelling of Author's Name: US Preventive Services Task Force prostate-specific antigen screening guidelines result in higher Gleason score diagnoses. AB - [This corrects the article on p. 423 in vol. 58.]. PMID- 29984347 TI - The implications of the hypocitricemic response to surgery and the role of liver function and hepatocyte metabolism: An important, but neglected, clinical relationship. AB - Reported studies more than forty years ago established that all surgery patients exhibit a marked postoperative hypocitricemia within one day following surgery and persists for seven days and longer. Animals also exhibit the postoperative hypocitricemia. The hypocitricemia results from increased liver clearance of plasma citrate, in which the hepatocytes become capable of transporting and utilizing citrate from plasma. This represents a physiologic/metabolic response during the patient recovery from surgery. The extensive hypocitricemia in response to surgery is not manifested by known citricemic hormones, but is initiated via an unidentified putative endocrine hypocitricemic hormone. In addition to the importance relating to surgery patients, the surgical hypocitricemic effects, along with the liver and hepatic cell effects, will impact virtually all human and animal clinical and experimental studies that include surgical intervention; including the conclusions and translational clinical implications. Unfortunately, the hypocitricemic response to surgery has been ignored for the past forty years, and most contemporary clinicians and biomedical investigators are not aware of this clinical relationship. The intent of this review is to inform members of the medical community of the established hypocitricemic response to surgery and the important role of liver clearance and hepatocyte metabolism of plasma citrate; which, hopefully, will generate interest and research that should be integrated into contemporary issues that involve surgical intervention. PMID- 29984349 TI - New Spaces at the University of Detroit Mercy That Inspire Undergraduate Research and Innovation. PMID- 29984350 TI - Cytomegalovirus Infection in One Fetus with Hypoplasia of the Pons in a Diamniotic-Dichorionic Twin Pregnancy. PMID- 29984348 TI - Infant and Young Child Feeding (IYCF) Practices Improved in 2 Districts in Nepal during the Scale-Up of an Integrated IYCF and Micronutrient Powder Program. AB - Background: Three-quarters of the >=50 programs that use micronutrient powders (MNPs) integrate MNPs into infant and young child feeding (IYCF) programs, with limited research on impacts on IYCF practices. Objective: This study assessed changes in IYCF practices in 2 districts in Nepal that were part of a post-pilot scale-up of an integrated IYCF-MNP program. Methods: This analysis used cross sectional surveys (n = 2543 and 2578 for baseline and endline) representative of children aged 6-23 mo and their mothers in 2 districts where an IYCF program added MNP distributions through female community health volunteers (FCHVs) and health workers (HWs). Multivariable log-binomial models estimated prevalence ratios comparing reported IYCF at endline with baseline and at endline on the basis of exposure to different sources of IYCF information. Mothers who received FCHV-IYCF counseling with infrequent (<=1 time/mo) and frequent (>1 time/mo) interactions were compared with mothers who never received FCHV-IYCF counseling. The receipt of HW-IYCF counseling and receipt of MNPs from an FCHV (both yes or no) were also compared. Results: The prevalence of minimum dietary diversity (MDD) and minimum acceptable diet (MAD) was significantly higher at endline than at baseline. In analyses from endline, compared with mothers who never received FCHV counseling, only mothers in the frequent FCHV-IYCF counseling group were more likely to report feeding the minimum meal frequency (MMF) and MAD, with no difference for the infrequent FCHV-IYCF counseling group in these indicators. HW IYCF counseling was not associated with these indicators. Mothers who received MNPs from their FCHV were more likely to report initiating solid foods at 6 mo and feeding the child the MDD, MMF, and MAD compared with mothers who did not, adjusting for HW- and FCHV-IYCF counseling and demographic covariates. Conclusions: Incorporating MNPs into the Nepal IYCF program did not harm IYCF and may have contributed to improvements in select practices. Research that uses experimental designs should verify whether integrated IYCF-MNP programs can improve IYCF practices. PMID- 29984351 TI - Health-related quality of life burden of nonalcoholic steatohepatitis: a robust pragmatic literature review. AB - Objective: Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease (CLD): patients have an increased risk of developing cirrhosis, liver failure, and complications (e.g. hepatocellular carcinoma). NASH has a high clinical burden, and likely impairs patients' health-related quality of life (HRQoL), but there are currently no licensed therapies. The objective of this robust pragmatic literature review was to identify and describe recent studies on the HRQoL burden of NASH from the patient perspective. Methods: English-language primary research studies were identified that measured HRQoL in adults with NASH (population-based studies or clinical trials of pharmacological therapy). Searches were conducted in the following bibliographical databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), and Health Technology Assessment Database (HTA). Abstracts from selected congresses (2015/2016) were hand searched. Articles were assessed for relevance by two independent reviewers, and HRQoL data were extracted. Results: A total of 567 de duplicated abstracts were identified, and 20 full-text articles were reviewed. Eight studies were included: five quantitative, two interventional, and one qualitative. The quantitative and interventional studies measured HRQoL using the Short-Form 36 (SF-36) and the Chronic Liver Disease Questionnaire (CLDQ), and the qualitative study involved focus groups and individual interviews. Overall, the studies showed that NASH affects HRQoL, especially physical functioning, with many patients reporting being fatigued. In quantitative studies, overall, patients with NASH had a reduced HRQoL versus normative populations and nonalcoholic fatty liver disease (NAFLD) patients, but not versus chronic liver diseases. A longitudinal study showed that when weight loss was achieved, HRQoL improvement over 6 months was greater in patients with NASH versus NAFLD. Qualitative research suggested that, in addition to fatigue, other symptoms are also burdensome, having a broad negative impact on patients' lives. The impact of pharmacological treatment on HRQoL was explored in only two included studies. Conclusions: HRQoL is impaired in patients with NASH. Patients experience a range of symptoms, especially fatigue, and the impact on their lives is broad. Further research is needed to understand the HRQoL burden of NASH (e.g. assessing NASH specific impacts not captured by SF-36 and CLDQ) and the impact of future NASH therapies on HRQoL. PMID- 29984352 TI - Cord cross-sectional area at foramen magnum as a correlate of disability in amyotrophic lateral sclerosis. AB - Spinal cord atrophy is one of the hallmarks of amyotrophic lateral sclerosis (ALS); however, it is not routinely assessed in routine clinical practice. In the present study, we evaluated whether spinal cord cross-sectional area measured at the foramen magnum level using a magnetic resonance imaging head scan represents a clinically meaningful measure to be added to the whole-brain volume assessment. Using an active surface approach, we measured the cord area at the foramen magnum and brain parenchymal fraction on T1-weighted three-dimensional spoiled gradient recalled head scans in two groups of subjects: 23 patients with ALS (males/females, 13/10; mean +/- standard deviation [SD] age 61.7 +/- 10.3 years; median ALS Functional Rating Scale-Revised score 39, range 27-46) and 18 age- and sex-matched healthy volunteers (mean +/- SD age 55.7 +/- 10.2 years). Spinal cord area at the foramen magnum was significantly less in patients than in control subjects and was significantly correlated with disability as measured with the ALS Functional Rating Scale-Revised (rho = 0.593, p < 0.005). This correlation remained significant after taking into account inter-individual differences in brain parenchymal fraction (rho = 0.684, p < 0.001). Our data show that spinal cord area at the foramen magnum correlates with disability in ALS independently of whole-brain atrophy, thus indicating its potential as a disease biomarker. PMID- 29984353 TI - Effect of thyroid shielding during mammography: measurements on phantom and patient as well as estimation with Monte Carlo simulation. AB - Background: During mammography, the thyroid is exposed to scattered radiation from breast tissue and the device. This may increase the risk of radiation induced thyroid cancer. Methods: We investigated the scatter radiation exposition of the thyroid and the effect of a tailored thyroid protection in phantom and patient as well as by using Monte Carlo simulation (MCS). The protective effect of a modified thyroid protection, the relevance of the protective effect and acceptance by patients have been investigated. Results: Phantom and patient measurements provided higher values for the surface dose at thyroid position than expected from MCS (phantom 0.32 mGy; patients 0.38 mGy; MCS 0.16 mGy). Phantom measurements indicated scatter contributions from both breast tissue and collimator/tube system. The value found in our patient study is within the range of the literature (0.22-0.39 mGy). The thyroid protection significantly reduced the surface dose but the dose (0.016 mGy) was higher than that expected from the lead equivalent value. However, the impact of the collar to the effective dose was small (< 4%). The collar was not visible on mammograms. Conclusions: Scatter from the collimator/tube system contributed with 50% to the thyroid dose. Due to the relative small fraction of dose deposited in the thyroid when compared to the mean glandular dose to the breast, a collar is not mandatory in general. Not being associated with the risk of obscuring parts of mammograms, such a collar may be used for young women considering their higher radio sensitivity. PMID- 29984355 TI - Evaluating the impact of integrated development: are we asking the right questions? A systematic review. AB - Background: Emerging global transformations - including a new Sustainable Development Agenda - are revealing increasingly interrelated goals and challenges, poised to be addressed by similarly integrated, multi-faceted solutions. Research to date has focused on determining the effectiveness of these approaches, yet a key question remains: are synergistic effects produced by integrating two or more sectors? We systematically reviewed impact evaluations on integrated development interventions to assess whether synergistic, amplified impacts are being measured and evaluated. Methods: The International Initiative for Impact Evaluation's (3ie) Impact Evaluation Repository comprised our sampling frame (n = 4,339). Following PRISMA guidelines, we employed a three-stage screening and review process. Results: We identified 601 journal articles that evaluated integrated interventions. Seventy percent used a randomized design to assess impact with regard to whether the intervention achieved its desired outcomes. Only 26 of these evaluations, however, used a full factorial design to statistically detect any synergistic effects produced by integrating sectors. Of those, seven showed synergistic effects. Conclusions: To date, evaluations of integrated development approaches have demonstrated positive impacts in numerous contexts, but gaps remain with regard to documenting whether integrated programming produces synergistic, amplified outcomes. Research on these program models needs to extend beyond impact only, and more explicitly examine and measure the synergies and efficiencies associated with linking two or more sectors. Doing so will be critical for identifying effective integrated development strategies that will help achieve the multi-sector SDG agenda. PMID- 29984354 TI - The chondrodystrophic dog: A clinically relevant intermediate-sized animal model for the study of intervertebral disc-associated spinal pain. AB - Low back pain (LBP) is the leading cause of disability worldwide, with an estimated 80% of the American population suffering from a painful back condition at some point during their lives. The most common cause of LBP is intervertebral disc (IVD) degeneration (IVDD), a condition that can be difficult to treat, either surgically or medically, with current available therapies. Thus, understanding the pathological mechanisms of IVDD and developing novel treatments are critical for improving outcome and quality of life in people living with LBP. While experimental animal models provide valuable mechanistic insight, each model has limitations that complicate translation to the clinical setting. This review focuses on the chondrodystrophic canine clinical model of IVDD as a promising model to assess IVD-associated spinal pain and translational therapeutic strategies for LBP. The canine IVD, while smaller in size than human, goat, ovine, and bovine IVDs, is larger than most other small animal IVDD models and undergoes maturational changes similar to those of the human IVD. Furthermore, both dogs and humans develop painful IVDD as a spontaneous process, resulting in similar characteristic pathologies and clinical signs. Future exploration of the canine model as a model of IVD-associated spinal pain and biological treatments using the canine clinical model will further demonstrate its translational capabilities with the added ethical benefit of treating an existing veterinary patient population with IVDD. PMID- 29984356 TI - Prevalence and factors associated with burnout among frontline primary health care providers in low- and middle-income countries: A systematic review. AB - Background: Primary health care (PHC) systems require motivated and well-trained frontline providers, but are increasingly challenged by the growing global shortage of health care workers. Burnout, defined as emotional exhaustion, depersonalization, and low personal achievement, negatively impacts motivation and may further decrease productivity of already limited workforces. The objective of this review was to analyze the prevalence of and factors associated with provider burnout in low and middle-income countries (LMICs). Methods: We performed a systematic review of articles on outpatient provider burnout in LMICs published up to 2016 in three electronic databases (EMBASE, MEDLINE, and CAB). Articles were reviewed to identify prevalence of factors associated with provider burnout. Results: A total of 6,182 articles were identified, with 20 meeting eligibility criteria. We found heterogeneity in definition and prevalence of burnout. Most studies assessed burnout using the Maslach Burnout Inventory. All three dimensions of burnout were seen across multiple cadres (physicians, nurses, community health workers, midwives, and pharmacists). Frontline nurses in South Africa had the highest prevalence of high emotional exhaustion and depersonalization, while PHC providers in Lebanon had the highest reported prevalence of low personal achievement. Higher provider burnout (for example, among nurses, pharmacists, and rural health workers) was associated with high job stress, high time pressure and workload, and lack of organizational support. Conclusions: Our comprehensive review of published literature showed that provider burnout is prevalent across various health care providers in LMICs. Further studies are required to better measure the causes and consequences of burnout and guide the development of effective interventions to reduce or prevent burnout. PMID- 29984357 TI - A de-identified database of 11,979 verbal autopsy open-ended responses. AB - As part of the Gates Grand Challenge 13, the Population Health Metrics Research Consortium (PHMRC) collected data to enable the development and validation of methods that measure cause-specific mortality in populations with incomplete or inadequate cause of death coding. This work yielded 11,979 verbal autopsy interviews (VAIs). In each, a field interviewer spoke with an individual familiar with the deceased and their final illness, and used a semi-structured questionnaire to collect information about the symptoms of the deceased in their final illness. The VAI collected demographic characteristics, possible risk factors (such as tobacco use), and other potentially contributing characteristics. It also included the open-ended question, "Could you please summarize, or tell us in your own words, any additional information about the illness and/or death of your loved one?" (open narrative). The VAI data were released in a de-identified format in September 2013 through the Global Health Data Exchange, in files that contain verbal autopsies that were collected at six sites in four countries (India, Mexico, Tanzania, and the Philippines). Due to research interest, we have now created redacted versions of the open narratives from the open-ended question of the questionnaire. We hope that this database will be the source of innovations that increase our knowledge about the causes of ill health and, through this knowledge, produce improvements in health for individuals and populations. PMID- 29984358 TI - Collecting family planning intentions and providing reproductive health information using a tablet-based video game in India. AB - Background: In response to a Grand Challenges in Global Health call for action to collect data about family planning intentions and increase the uptake of family planning methods in India, our team designed, developed, and piloted the My Future Family video game in Karnataka Province. The game educates adolescents about human sexuality and reproduction while asking players when they would like to achieve five important family planning milestones. Participants were also asked to report who influences them the most when making family planning decisions. Methods: Focus groups were conducted and the resulting data used to design the game which was iteratively tested and then piloted in 11 schools in rural and urban areas of southern India. Data was collected throughout gameplay and cross-checked with paper questionnaires. Results: In August 2018, we successfully piloted the game with 382 adolescents and validated its efficacy both as an educational tool and as an innovative means of accurate data collection. Conclusion: It has historically been problematic to gather accurate data about adolescents in India on this culturally sensitive topic for a variety of reasons. These include difficulties obtaining consent, developing appropriate survey methods, and framing questions in language that young people can understand. Our game met these challenges by working within a single school system with approval from senior administration, delivering information via a game environment, which freed players from societal constraints, and communicating information via images and audio in addition to text in both English and Kannada (the local language). PMID- 29984359 TI - Pneumococcal Conjugate Vaccine impact assessment in Bangladesh. AB - The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh's national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3 59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia . This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh. PMID- 29984360 TI - Evidence gap map of performance measurement and management in primary care delivery systems in low- and middle-income countries - Study protocol. AB - Background. For the last two decades there has been growing interest in governmental and global health stakeholders about the role that performance measurement and management systems can play for the production of high-quality and safely delivered primary care services. Despite recognition and interest, the gaps in evidence in this field of research and practice in low- and middle-income countries remain poorly characterized. This study will develop an evidence gap map in the area of performance management in primary care delivery systems in low and middle-income countries. Methods. The evidence gap map will follow the methodology developed by 3Ie, the International Initiative for Impact Evaluation, to systematically map evidence and research gaps. The process starts with the development of the scope by creating an evidence-informed framework that helps identify the interventions and outcomes of relevance as well as help define inclusion and exclusion criteria. A search strategy is then developed to guide the systematic search of the literature, covering the following databases: Medline (Ovid), Embase (Ovid), CAB Global Health (Ovid), CINAHL (Ebsco), Cochrane Library, Scopus (Elsevier), and Econlit (Ovid). Sources of grey literature are also searched. Studies that meet the inclusion criteria are systematically coded, extracting data on intervention, outcome, measures, context, geography, equity, and study design. Systematic reviews are also critically appraised using an existing standard checklist. Impact evaluations are not appraised but will be coded according to study design. The process of map-building ends with the creation of an evidence gap map graphic that displays the available evidence according to the intervention and outcome framework of interest. Discussion. Applications arising from the evidence map will be discussed in a separate paper that will summarize findings and make recommendations for the development of a prioritized research agenda. PMID- 29984362 TI - Use of methylene blue in hepatic arterial infusion pump resulting in serotonin syndrome. A case report. AB - We report a case of a 35 year old woman with colon cancer metastatic to liver and lung who presented for exploratory laparotomy and/placement of hepatic arterial infusion pump for chemotherapy. Surgical course was notable for aberrant hepatic artery anatomy requiring extended dissection time, vascular surgery consultation, and use of substantial methylene blue to aid in visualization. Of note, patient's history was also significant for anxiety and depression, for which she was being treated with the selective serotonin reuptake inhibitor (SSRI) duloxetine (Cymbalta). The patient subsequently developed serotonin syndrome in the postoperative period but fully recovered. Our case highlights the need for close attention to methylene dosing recommendations and improved communication between perioperative care providers (surgery, anesthesia, nursing, and pharmacy) to prevent such occurrences. PMID- 29984363 TI - Automatic Estimation of the Optic Nerve Sheath Diameter from Ultrasound Images. AB - We present an algorithm to automatically estimate the diameter of the optic nerve sheath from ocular ultrasound images. The optic nerve sheath diameter provides a proxy for measuring intracranial pressure, a life threating condition frequently associated with head trauma. Early treatment of elevated intracranial pressures greatly improves outcomes and drastically reduces the mortality rate. We demonstrate that the proposed algorithm combined with a portable ultrasound device presents a viable path for early detection of elevated intracranial pressure in remote locations and without access to trained medical imaging experts. PMID- 29984364 TI - Ultrasound Augmentation: Rapid 3-D Scanning for Tracking and On-Body Display. AB - By using a laser projector and high speed camera, we can add three capabilities to an ultrasound system: tracking the probe, tracking the patient, and projecting information onto the probe and patient. We can use these capabilities to guide an untrained operator to take high quality, well framed ultrasound images for computer-augmented, point-of-care ultrasound applications. PMID- 29984361 TI - The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo. AB - Distinct T follicular helper (TFH) subsets that influence specific class switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary lymphoid organs (SLOs) and tertiary lymphoid organs has not been hitherto demonstrated. IL-4-expressing TFH cells are surprisingly sparse in human SLOs. In contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and SLOs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting TFH cells differ from both PD1hi TFH cells that do not secrete IL-4 and IL-4-secreting non-TFH cells. Unlike IgG4 RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjogren's syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL 4+BATF+ T cells and CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease related TFH subpopulation in human tertiary lymphoid organs and SLOs that is linked to IgG4 class switching. PMID- 29984365 TI - Real-Time Locating Systems and the Effects on Efficiency of Anesthesiologists. AB - Objective: To investigate the impact of Real Time Locating System (RTLS) technology on the perioperative efficiency of anesthesiologists. Methods: A retrospective chart review was performed for all outpatient and short-stay patients who received General Anesthesia care at our institution between January 2016 and October 2017. Patients included were over 18 years and had ASA classification scores of 1, 2, and 3. Only first cases of the day for individual anesthesiologists were included. Duration between two perioperative time points was collected and used as a measure of efficiency. Two groups of anesthesiologists were compared Group 1: Anesthesiologists at Main Campus who do not use RTLSGroup 2: Anesthesiologists at Josie Robertson Surgery Center who use RTLSThe outcome measure collected from patient electronic medical records was defined as DUR: Duration from when patient is admitted to the operating room and initiation of induction only for first case of the day by attending anesthesiologist. The outcome was compared between the two groups using Wilcoxon rank sum test. Results: The duration between admission to the OR and initiation of induction was significantly shorter in JRSC (with RTLS) than main campus (without RTLS); specifically, median (25th, 75th percentile) of the duration was 7.0 (5.0, 10.0) at JRSC vs. 8.0 (6.0, 11.0) at main campus (p < 0.0001, Table 1). Conclusion: In our initial study, we found that anesthesiologists who had access to RTLS at JRSC performed more efficiently in their preoperative evaluation of patients as well as time to induction for general anesthesia cases. Because of various confounding factors that potentially influenced the increase in efficiency of anesthesiologists with access to RTLS, this follow-up study aims to eliminate several confounding factors by assessing only time to induction of general anesthesia for all first cases of the day by anesthesiologists. We continue to find a small yet statistically significant difference in time to induction of anesthesiologists with access to RTLS. This translates directly into increased efficiency in perioperative workflow. Additional investigation and application can help elucidate the true value of RTLS on workflow efficiency in the healthcare setting. PMID- 29984366 TI - The Role of Microparticles in Rheumatic Diseases and their Potentials as Therapeutic Tools. AB - Microparticles (MPs) play important roles in intercellular communication, including adhesion, signal transduction, cell activation, and apoptosis. They possess a wide spectrum of biological effects in the immune responses. MPs could be immunotolerogenic or immunogenic depending on the contents and composition. Elevated levels of MPs have been reported in many forms for rheumatic diseases. This review focuses on the immunopathogenic and therapeutic role of MPs in rheumatic diseases. PMID- 29984368 TI - Editorial: Choosing wisely - it is time for dentistry. PMID- 29984369 TI - Direct and Indirect Restorations for Endodontically Treated Teeth: A Systematic Review and Meta-analysis, IAAD 2017 Consensus Conference Paper. AB - PURPOSE: The primary objective of this systematic review was to compare treatment outcomes of direct and indirect permanent restorations in endodontically treated teeth, and provide clinical suggestions for restoring teeth after endodontic treatment. MATERIALS AND METHODS: Electronic databases (Medline, EMBASE, CENTRAL) and gray literature were screened for articles in English that reported on prospective and retrospective clinical studies of direct or indirect restorations after endodontic treatment with an observation period of at least 3 years. Primary outcomes were determined to be short-term (<= 5 years) and medium-term (> 5 and <= 10 years) survival. Secondary outcomes included restorative and endodontic success of restored teeth. The quality of included studies and risk of bias were assessed using Cochrane Collaboration's tool for RCTs (randomized controlled trials), the Newcastle-Ottawa Scale for cohort studies, and the Agency for Healthcare Research and Quality (AHRQ) methodology checklist for cross sectional studies. The GRADE system was used for assessing collective strength of the overall body of evidence. RESULTS: Of 2547 screened articles, only 9 (2 RCTs, 3 retrospective cohort studies, 3 cross-sectional studies) met the inclusion criteria, and 8 studies were used in the meta-analysis. In general, indirect restorations (mostly full crowns) showed higher 5-year survival (OR 0.28, 95% CI 0.19-0.43, p < 0.00001) and 10-year survival (OR 0.20, 95% CI 0.12-0.31, p < 0.00001) than direct restorations. However, there was no statistical difference in short-term (<= 5-years) restorative success (OR 0.32, 95% CI 0.05-2.12, p = 0.24) and endodontic success (OR 0.88, 95% CI 0.72-1.08, p = 0.22). CONCLUSIONS: Based on current evidence, there is a weak recommendation for indirect restorations to restore endodontically treated teeth, especially for teeth with extensive coronal damage. Indirect restorations using mostly crowns have higher short-term (5-year) and medium-term (10-year) survival than do direct restorations using composite or amalgam (GRADE quality of evidence: low to moderate), but no difference in short-term (<= 5 years) restorative success (low quality) and endodontic success (very low quality). There is a need for high quality clinical trials, especially well-designed RCTs. PMID- 29984370 TI - WORN DENTITION: THE ADHESIVE WAYSave the date ! Bologna, May 11th - 13th, 2019. PMID- 29984367 TI - Advancements in Free-Radical Pathologies and an Important Treatment Solution with a Free-Radical Inhibitor. AB - Unsaturated carbon-carbon double bonds particularly at exposed end groups of nonsolid fluids are susceptible to free-radical covalent bonding on one carbon atom creating a new free radical on the opposite carbon atom. Subsequent reactive secondary sequence free-radical polymerization can then continue across extensive carbon-carbon double bonds to form progressively larger molecules with ever increasing viscosity and eventually produce solids. In a fluid solution when carbon-carbon double bonds are replaced by carbon-carbon single bonds to decrease fluidity, increasing molecular organization can interfere with molecular oxygen (O2) diffusion. During normal eukaryote cellular energy synthesis O2 is required by mitochondria to combine with electrons from the electron transport chain and hydrogen cations from the proton gradient to form water. When O2 is absent during periods of irregular hypoxia in mitochondrial energy synthesis, the generation of excess electrons can develop free radicals or excess protons can produce acid. Free radicals formed by limited O2 can damage lipids and proteins and greatly increase molecular sizes in growing vicious cycles to reduce oxygen availability even more for mitochondria during energy synthesis. Further, at adequate free radical concentrations a reactive crosslinking unsaturated aldehyde lipid breakdown product can significantly support free-radical polymerization of lipid oils into rubbery gel-like solids and eventually even produce a crystalline lipid peroxidation with the double bond of O2. Most importantly, free-radical inhibitor hydroquinone intended for medical treatments in much pathology such as cancer, atherosclerosis, diabetes, infection/inflammation and also ageing has proven extremely effective in sequestering free radicals to prevent chain-growth reactive secondary sequence polymerization. PMID- 29984371 TI - Auditory Lexical Decisions in Developmental Language Disorder: A Meta-Analysis of Behavioral Studies. AB - Purpose: Despite the apparent primacy of syntactic deficits, children with developmental language disorder (DLD) often also evidence lexical impairments. In particular, it has been argued that this population have difficulty forming lexical representations that are detailed enough to support effective spoken word processing. In order to better understand this deficit, a meta-analysis of studies testing children with DLD in the auditory lexical decision task was conducted. The objective was to provide summary effect size estimates for accuracy and response time measures for comparisons to age- and language-matched control groups. Method: Two thousand three hundred seventy-two records were initially identified through electronic searches and expert consultation, with this cohort reduced to 9 through duplicate removal and the application of eligibility and quality criteria. The final study cohort included 499 children aged 3;8-11;4 (years;months). Results: Multivariate analysis suggests that children with DLD were significantly less accurate in the auditory lexical decision task than age-matched controls. For the response time estimate, however, confidence intervals for the same group comparison crossed 0, suggesting no reliable difference between groups. Confidence intervals also crossed 0 for language-matched control estimates for both accuracy and response time, suggesting no reliable difference between groups on either measure. Conclusion: Results broadly support the hypothesis that children with DLD have difficulty in forming detailed lexical representations relative to age- though not language matched peers. However, further work is required to determine the performance profiles of potential subgroups and the impact of manipulating different lexical characteristics, such as the position and degree of nonword error, phonotactic probability, and semantic network size. PMID- 29984372 TI - Children With Dyslexia Benefit From Orthographic Facilitation During Spoken Word Learning. AB - Purpose: Orthographic facilitation describes the phenomenon in which a spoken word is produced more accurately when its corresponding written word is present during learning. We examined the orthographic facilitation effect in children with dyslexia because they have poor learning and recall of spoken words. We hypothesized that including orthography during spoken word learning would facilitate learning and recall. Method: Children with dyslexia and children with typical development (n = 46 per group), 7-9 years old, were matched for grade and nonverbal intelligence. Across 4 blocks of exposure in 1 session, children learned pairings between 4 spoken pseudowords and novel semantic referents in a modified paired-associate learning task. Two of the pairings were presented with orthography present, and 2 were presented with orthography absent. Recall of newly learned spoken words was assessed using a naming task. Results: Both groups showed orthographic facilitation during learning and naming. During learning, both groups paired pseudowords and referents more accurately when orthography was present. During naming, children with typical development showed a large orthographic facilitation effect that increased across blocks. For children with dyslexia, this effect was present initially but then plateaued. Conclusions: We demonstrate for the first time that children with dyslexia benefit from orthographic facilitation during spoken word learning. These findings have direct implications for teaching spoken vocabulary to children with dyslexia. PMID- 29984374 TI - Long-acting Reversible Contraception-Highly Efficacious, Safe, and Underutilized. PMID- 29984373 TI - Short-Term Memory, Inhibition, and Attention in Developmental Stuttering: A Meta Analysis. AB - Purpose: This study presents a meta-analytic review of differences in verbal short-term memory, inhibition, and attention between children who stutter (CWS) and children who do not stutter (CWNS). Method: Electronic databases and reference sections of articles were searched for candidate studies that examined verbal short-term memory, inhibition, and attention using behavioral and/or parent report measures. Twenty-nine studies met the eligibility criteria, which included, among other things, children between the ages of 3 and 18 years and the availability of quantitative data for effect size calculations. Data were extracted, coded, and analyzed, with the magnitude of the difference between the 2 groups of children being estimated using Hedge's g (Hedges & Olkin, 1985). Results: Based on the random-effects model (Hunter & Schmidt, 2004), findings revealed that CWS scored lower than CWNS on measures of nonword repetition (Hedges' g = -0.62), particularly at lengths of 2 and 3 syllables (Hedges' g = 0.62 and - 0.50, respectively), and forward span (Hedges' g = -0.40). Analyses further revealed that the parents of CWS rated their children as having weaker inhibition (Hedges' g = -0.44) and attentional focus/persistence (Hedges' g = 0.36) skills than the parents of CWNS, but there were no significant differences between CWS and CWNS in behavioral measures of inhibition and attention. Conclusion: The present findings were taken to suggest that cognitive processes are important variables associated with developmental stuttering. PMID- 29984375 TI - Depression Before and After Bariatric Surgery in Low-Income Patients: the Utility of the Beck Depression Inventory. AB - BACKGROUND: The prevalence of psychological disorders in bariatric surgery candidates is well established, where anxiety and depression are commonly observed. Depression prevalence and evolution after gastric bypass, and its impact on weight loss, have been less explored, especially among low-income patients. METHODS: A retrospective study with low-income patients undergoing bariatric surgery from 2015 to 2016. A comparative analysis of preoperative depression (the Beck Depression Inventory II) was performed and compared at 6 and 12 months. A demographic and weight loss analysis was also performed. RESULTS: Seventy-three patients were included. Female sex comprised 76.7% of cases, and baseline depression was present in 45.2%, being severe in 2.7%. The analysis at 6 months showed Beck's score improvement (12.3 baseline vs. 4.2 points at 6 months, p = 0.006), as well as for individual items (excepting irritability). At 12 months, the mean score was 5 points, without difference vs. 6 months. At 6 and 12 months, depression (any degree) was present in 9.6 and 8.6%, corresponding to percentage change rates of - 65.8 and - 59.3%. Only one patient (2.7%) presented severe depression. Depression status before surgery had no influence in weight loss amount at 12 months. CONCLUSION: Almost half of bariatric surgery candidates have some degree of depression that improves dramatically soon after bariatric surgery. Such change continues stable during the first year. Improvement was independent of gender, and depression has no influence on weight loss. In low income bariatric patients, depression is lower than reports from developed countries, but similar improvement has been observed. PMID- 29984376 TI - Agreement and repeatability of central corneal thickness measurements by four different optical devices and an ultrasound pachymeter. AB - PURPOSE: To compare the repeatability and agreement of central corneal thickness (CCT) measurements by spectral-domain optical coherence tomography (OCT), corneal topography (CT) with a combined Scheimpflug-Placido system, optical biometry (OB), specular microscopy (SM), and ultrasound pachymetry (UP). METHODS: A single observer measured CCT twice in 150 eyes of 150 subjects with each of five devices: Nidek RS-3000 Advance OCT, CSO Sirius combined Scheimpflug-Placido disc system CT, Nidek AL-Scan partial coherence interferometry-based OB, Tomey EM-3000 SM, and Reichert iPac ultrasonic pachymeter. Pachymetry values corrected by the SM device software were also recorded. Levels of agreement between devices were evaluated by Bland-Altman plots with 95% limits of agreement, and repeatability for each device was analysed with intraclass correlation coefficients. RESULTS: The mean CCTs measured by OCT, CT, OB, SM, corrected SM, and UP were 544.60 +/- 29.56, 536.19 +/- 32.14, 528.29 +/- 29.45, 524.88 +/- 32.38, 537.88 +/- 32.38, and 545.29 +/- 30.75 MUm, respectively. Mean CCT differed significantly between the devices (p < 0.05) apart from between OCT and UP, and between CT and corrected SM. Mean paired differences between devices ranged between 0.68 and 20.41 MUm. Repeatability with all devices was excellent (> 0.99). The range of limits of agreement was the least between OCT and UP. CONCLUSIONS: Different CCT measurement techniques produce quite different results, so CCT evaluation and follow-up should be performed using the same device or devices with close compatibility. PMID- 29984377 TI - Diagnosis of vertical root fracture in teeth close and distant to implant: an in vitro study to assess the influence of artifacts produced in cone beam computed tomography. AB - OBJECTIVES: To evaluate the influence of artifacts produced by zirconium implant on the diagnosis of vertical root fracture (VRF) in teeth close and distant to the implant in cone beam computed tomography (CBCT) images. We also determined if kilovoltage (kVp) and metal artifact reduction (MAR) tool could influence this diagnosis. MATERIALS AND METHODS: Twenty single-root teeth were divided in control and fractured groups (n = 10). The teeth were randomly positioned in the first and second and right and left pre-molar alveoli of a dry human mandible. CBCT exams were acquired using a ProMax 3D unit with varying kVp (70, 80, or 90 kVp), with or without MAR, and with and without a zirconium implant placed in the alveolus of first right molar. The images were evaluated by five observers. The area under the receiver operating characteristic curve (ROC), sensitivity, and specificity were calculated and compared by analysis of variance with a significance level of 5%. RESULTS: In general, ROC and sensitivity were not affected by the factors studied (p > 0.05). The main effects occurred in specificity; when implant was used without MAR, the values were lower for tooth 45 for all kVps (p = 0.0001). CONCLUSIONS: Artifacts produced in the vicinity of teeth with suspected VRF impair the diagnosis by decreasing the specificity, because they can mimic the VRF line generating false positives. However, MAR improves the specificity, being its use recommended when metallic objects are present near teeth with suspected VRF. CLINICAL RELEVANCE: Since nowadays, many patients who undergo CBCT show implants and they definitively produce artifacts, it is important to evaluate the influence of such artifacts in the diagnosis of teeth that are close to the generator-artifact object. PMID- 29984378 TI - Head and neck manifestations of an undiagnosed McCune-Albright syndrome: clinicopathological description and literature review. AB - Craniofacial fibrous dysplasia, characteristic of McCune-Albright syndrome (MAS), is usually present in patients with MAS-related acromegaly. We report here the first case of a patient with an undiagnosed MAS presenting with an acute hydrocephalus. A 21-year-old male with gigantism and craniofacial fibrous dysplasia consulted for rapidly progressive headache. An acute obstructive hydrocephalus due to a 39 * 35-mm cystic lesion in the third ventricle was discovered and operated, obtaining hydrocephalus resolution. Pathology described a colloid cyst material and a growth hormone-secreting pituitary adenoma. Genetic study revealed the mosaic GNAS R201H mutation in the pituitary tissue, confirming a MAS diagnosis. Adequate hormonal control was achieved postoperatively. Our results suggest that long-term untreated growth hormone excess in patients with MAS-related craniofacial fibrous dysplasia might end compromising cerebrospinal fluid flow. A prompt diagnosis and coordinated multidisciplinary treatment may help to avoid long-term deleterious impact of hyperfunctioning endocrinopathies in these patients. PMID- 29984379 TI - Histological changes secondary to wire coil placement in breast tissue and lymph nodes. AB - We describe the histological and immunohistochemical features of the changes produced by spiral coil localization wires in the breast parenchyma and lymph nodes of a total of 100 patients undergoing surgery for different breast lesions. Coil wires produced cystic lesions containing a hyaline, mucous-like, PAS negative fluid. Cavities were lined by cells of variable morphology ranging from synovial-like cells (with a conspicuous epithelial appearance) to mononuclear or multinucleate histiocytic cells that expressed CD68, but were negative for keratins. CD3-positive/CD8-positive T lymphocytes predominated in the inflammatory reaction. Pathologists should be aware of these changes in order to differentiate coil-related lesions from other granulomatous or epithelial lesions, including mucocele-like and ductal carcinoma in situ lesions. PMID- 29984380 TI - Carrageenans from Sarcothalia crispata and Gigartina skottsbergii: Structural Analysis and Interpolyelectrolyte Complex Formation for Drug Controlled Release. AB - The aims of the present study were to characterize for the first time the carrageenan extracted from cystocarpic stage of S. crispata collected in the Patagonian coast of Argentina, and to prepare interpolyelectrolytic complexes (IPECs) between the polysaccharide extracted from cystocarpic stage of Sarcothalia crispata and Gigartina skottsbergii thalli, and basic butylated methacrylate copolymer (Eudragit E), in order to test their potential for the controlled release of ibuprofen as model drug. The structural determination revealed that the polysaccharides extracted from S. crispata and G. skottsbergii were mainly constituted by kappa-carrageenan, particularly in the case of G. skottsbergii; however, significant amounts of iota- and nu-carrageenan were also detected in both polygalactans. The differences in diad composition and possibly in their distribution along the polysaccharide chain of both carrageenans would favor a different arrangement in the resulting IPEC structure. The smaller pores observed by scanning electron microscopy in the IPEC of S. crispata suggest that the kinks in the polysaccharide backbone are evenly distributed, resulting in a slower ibuprofen release compared to the IPEC of G. skottsbergii. PMID- 29984381 TI - Compensation for matrix effects in GC analysis of pesticides by using cucumber extract. AB - Matrix effects (MEs) can adversely affect quantification in pesticide residue analysis using GC. Analyte protectants (APs) can effectively interact with and mask active sites in the GC system, and are added individually or in combination to sample extracts and calibration solutions to minimize errors related to MEs. Unfortunately, APs cannot sufficiently compensate for MEs in all cases. Plant extracts, containing a broad range of natural compounds with AP properties, can also be used for this purpose. In this study, the applicability of cucumber extract as a natural AP mixture was investigated both alone and in combination with traditional APs. Extracts of two selected difficult matrices (onion and garlic) were prepared according to the citrate-buffered QuEChERS (quick, easy, cheap, effective, rugged, and safe) procedure. ME values of 40 representative GC amenable pesticides were compared when calibrating against standards in pure solvent and in cucumber extract, with and without the addition of APs. Using a GC system with a contaminated inlet liner, the use of a cucumber-based calibration solution decreased MEs remarkably. The combination of APs with cucumber raw extract further decreased MEs, resulting in more than 85% of the tested pesticides showing <= 10% ME in onion and <= 20% ME in garlic. These results demonstrate that the preparation of calibration standards based on cucumber extracts (with or without the addition of APs) is a very useful and practical approach to compensate for MEs in pesticide residue analysis using QuEChERS and GC-MS/MS. The use of various internal standards is furthermore critically discussed. PMID- 29984382 TI - Predictive Significance of Mucinous Histology on Pathologic Complete Response Rate Following Capecitabine-Based Neoadjuvant Chemoradiation in Rectal Cancer: a Comparative Study. AB - INTRODUCTION: Currently, neoadjuvant fluoropyrimidine-based chemoradiation followed by surgery is considered the standard of care for locally advanced rectal cancer. The current study aimed to investigate the predictive significance of mucinous histology on the pathologic complete response rate following neoadjuvant chemoradiation in locally advanced rectal cancer and to propose potential new treatment protocol for this specific histology. MATERIAL AND METHOD: This retrospective study was conducted on 403 patients with locally advanced (clinically T3-4 and/or N1-2) rectal adenocarcinoma who had been treated at three tertiary academic hospitals between 2010 and 2015. Among those 403 patients, 46 (11%) had mucinous rectal cancer (MRC) and 358 (89%) had non mucinous rectal cancer (NMRC). All patients underwent neoadjuvant chemoradiation with capecitabine followed by low anterior or abdominoperineal resection. RESULTS: There were 268 men and 135 women with a median age of 55 years (range, 26-82 years). Patients with MRC were younger (p = 0.002) and presented with a larger tumor size (p < 0.001) and a more advanced tumor stage (p = 0.033) compared to the ones with MNRC. In the univariate analysis, female gender (p = 0.009), distal tumor location (p = 0.035), higher tumor stage (p = 0.049), node positivity (p = 0.001), MRC histology (p = 0.017), and high pretreatment CEA level (p = 0.013) were observed to be predictive of a poor pathologic complete response. However, in the multivariate analysis, tumor stage was the single most predictive factor of response to neoadjuvant chemoradiation. CONCLUSION: Mucinous adenocarcinoma is a significant predictive factor for poor pathologic complete response to neoadjuvant capecitabine-based chemoradiation in patients with locally advanced rectal cancer. New treatment modality based on biomarkers may be considered in future prospective studies because of MRC poor prognosis. Immunotherapy combined with chemotherapy and/or radiotherapy may be an attractive option because of the tumor microsatellite instability-high status. PMID- 29984383 TI - ICP monitoring in diffuse brain injury: clarifications. PMID- 29984384 TI - Bone resorption around anular closure device. PMID- 29984385 TI - The potential benefit of adjuvant chemotherapy in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy is not predicted by tumor regression grade. AB - INTRODUCTION: Recommended treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT) followed by surgery and total mesorectal excision (TME). The role of adjuvant chemotherapy (ACT) in this regimen is still debated. Assessment of Dworak's tumor regression grade (TRG) after NACRT could potentially select patients who might benefit from ACT. MATERIALS AND METHODS: Data for patients who underwent NACRT and TME for LARC between 2007 and 2014 were retrieved from the Bordet Institute database. Overall survival (OS) and disease free survival (DFS) were calculated for the whole population, according to whether or not they received ACT, and according to TRG. RESULTS: We included 74 patients (38 males) with a median age of 62.7 years (33-84 years). AJCC stage cIIIb disease was the most frequent (73%). Pathologic complete response (pCR) was achieved in 13 patients (17.6%). ACT was administered to 42 patients (56.8%). Five-year OS and DFS of patients who received ACT or not were 92 and 84.5% (p = ns), and 79.9 and 84.8% (p = ns), respectively. OS was related to TRG (cut-off value of 3) (p = 0.001). ACT administration was not correlated with improved outcomes in any TRG groups. CONCLUSION: TRG is a prognostic factor for both OS and DFS but does not appear to have a significant benefit for the selection of patients with LARC treated with NACRT who might benefit from the administration of ACT. Prospective randomized trials with larger populations are needed to identify factors that predict which patients may benefit from the administration of ACT. PMID- 29984386 TI - Using opinion leaders to address intervention gaps in concussion prevention in youth sports: key concepts and foundational theory. AB - Behavioral interventions to increase disclosure and proper management of concussion in youth sports have unrealized potential when it comes to preventing concussion. Interventions have focused on changing individual athlete behavior and have fallen short of the potential for sustained systemic behavioral change. One potentially critical reason for this shortfall is that other key determinants of risk behaviors at all levels of the socio-ecological model (e.g. interpersonal, community, policy) are not addressed in extant programming. There is a critical need for theory-driven interventions that address concussion prevention and education at the community level and target sustainable culture change. The Popular Opinion Leader (POL) intervention, a multi-level intervention model previously successfully employed in multiple public health contexts, is theoretically well positioned to affect such change. POL is based on the Diffusion of Innovations framework and involves identifying, recruiting, and training well-respected and trusted individuals to personally endorse prevention and risk-reduction within their social networks. Critical behavioral changes related to concussion disclosure and management have been shown to diffuse to others if enough opinion leaders endorse and support the behaviors. This article summarizes the concepts and principles of POL and describes how it could be adapted for and implemented in youth sport settings. For optimal impact, POL needs to adapt to several factors unique to youth sports settings and culture. First, adult involvement may be important, given their direct involvement in the athlete's medical care. However, parents and coaches' opinions on injury care seeking, competition, and safety may affect their perceptions of POL. Second, youth sports are structured settings both physically and socioculturally. Games and practices may provide opportunities for the informal interactions that are critical to the success of POL. However, youth sport setting membership is transient as players get older and move to other sport settings; POL approaches need to be self-sustaining despite this turnover. Moreover, stakeholder value placed on athlete development and competition, alongside safety, must be considered. Formative research is needed to ensure that POL principles are translated into the youth sport setting while maintaining fidelity to the concepts and principles that have made POL successful for other health outcomes. PMID- 29984387 TI - The association between reproductive success with persistent organochlorine pollutants residue in feathers of spur-winged lapwing (Vanellus spinosus L.). AB - The reproductive and breeding success of wader species is negatively affected by various anthropogenic factors, including persistent organochlorine pollutants (POPs). We aimed to study the association of POPs in feathers with the reproductive success of the spur-winged lapwing (Vanellus spinosus). For this purpose, data on reproductive parameters and feather samples were collected from a breeding population consisting of 19 pairs near Bogazkent district in Antalya, Turkey. Mean concentrations of total polychlorinated biphenyls (SigmaPCBs) and organochlorine pesticides (SigmaOCPs) were found to be 54 +/- 16 ng/g and 520 ng/g in all samples, respectively. In particular, PCB 151 and beta hexachlorocyclohexane had a negative association the various reproductive parameters in the species under consideration. Fledgling success (n = 25) was calculated to be 37.4%, which was negatively associated with the SigmaOCP concentrations (r = - 0.99, p = 0.01). According to the results, POP residues are one of the associated factors on the reproductive success of spur-winged lapwing along, with agricultural activity and predation. It is indicated that the species needs a protection plan for prevention declining reproductive success and population size species in Turkey. Besides, our results suggest that bird feathers are a non-destructive bio-monitoring tools to estimate of contamination levels of organic pollutants in a population. PMID- 29984388 TI - Cold plasma treatment and exogenous salicylic acid priming enhances salinity tolerance of Oryza sativa seedlings. AB - The present study was designed to highlight the effects of cold plasma (10 kV) treatment and priming with 2 mM salicylic acid (SA) and their combination (10 kV of plasma + 2 mM SA) on the physiological parameters and metabolism of two cultivars of Oryza sativa, i.e., Zhu Liang You 06 (ZY) and Qian You No. 1 (QY), under salinity stress (150 mM NaCl) and normal growth condition (0 mM NaCl). Seed germination and seedling growth were enhanced by SA priming and cold plasma treatment either alone or in combination under salinity stress. Photosynthetic pigments, photosynthetic gas exchange, and chlorophyll fluorescence were improved by cold plasma treatment and SA priming under salinity stress as compared to the untreated seeds. The activities of antioxidant enzymes were significantly improved by the combination of SA priming and cold plasma treatment in both cultivars under salinity stress. There were rapid changes in the cellular content of sodium (Na+) and calcium (Ca+), where the plants grown under saline conditions accumulate more Na+ and less Ca+ contents resulting in ionic imbalances. Interestingly, cold plasma and SA treatments diminished this action by reducing Na+ accumulation and increasing K+ and Ca+ contents in the plant cell under salinity stress. The activities of enzymes involved in secondary metabolism assimilation were up-regulated with cold plasma and SA priming either alone or combination under salinity stress. An increase in reactive oxygen species (ROS) accumulation and malondialdehyde (MDA) content was also observed under salinity stress condition. On contrast, seed treated with SA and plasma alone or combined resulted in a significant decrease in ROS and MDA contents under salinity stress. Our results indicated that SA priming and cold plasma treatment either alone or combined improved plant uptake of nutrients in both cultivars under stress conditions. The ultrastructural changes were observed to be more prominent in ZY than QY cultivar. Plants without SA priming or cold plasma treatments have a big vacuole due to the movement of ions into the vacuole directly from the apoplast into the vacuole through membrane vesiculation leading to membrane destabilization. However, SA priming and cold plasma treatment alone or combined helped the plants to recover their cell turgidity under salinity stress. PMID- 29984389 TI - Polymorphisms of peroxisome proliferator-activated receptor gamma (PPARgamma) and cluster of differentiation 36 (CD36) associated with valproate-induced obesity in epileptic patients. AB - RATIONALE: Valproate (VPA) is a choice for the treatment of primary generalized epilepsies and partial epilepsies. Unfortunately, weight gain or obesity is one of the most frequent adverse effects of VPA treatment. Genetic factors were shown to be involved in the effect. OBJECTIVE: The aim of this study was to investigate the association of selected single nucleotide polymorphisms (SNPs) of cluster of differentiation 36 (CD36) and peroxisome proliferator-activated receptor gamma (PPARgamma) with VPA-induced weight gain and obesity in epileptic patients. METHODS: A total of 225 Chinese Han epilepsy patients receiving VPA treatment were recruited in the study. Height and weight for the calculation of body mass index (BMI) were measured at the initiation of VPA therapy and in the follow-up examination. A BMI of 25 kg/m2 or higher was defined as obesity on the basis of the World Health Organization (WHO) criteria for Asian populations. Four SNPs in CD36 (rs1194197, rs7807607) and PPARgamma (rs10865710, rs2920502) were genotyped using the Sequenom(r) MassArray iPlex platform. RESULTS: About 19.6% of epileptic patients receiving VPA therapy were found to become obese. After covariate analysis of age, gender, sex, height, initial BMI, and VPA dosage, the CD36 rs1194197 C allele and rs7807607 T allele (OR, 0.31; 95%CI, 0.13-0.72; P = 0.009 and OR, 0.38; 95%CI; 0.18-0.83; P = 0.02, respectively) were identified as protective factors for VPA-induced obesity. The PPARgamma rs10865710 C allele carriers were found to be less likely to suffer from VPA-induced obesity compared with GG genotype carriers (OR, 0.04; 95%CI, 0.01-0.12; P < 0.001). After a Bonferroni correction for multiple comparisons, the genotypic associations of CD36 rs1194197 and PPARgamma rs10865710 and the allelic association of CD36 rs7807607 with obesity remained statistically significant. CONCLUSIONS: Our data first indicated that CD36 and PPARgamma polymorphisms may be associated with VPA induced obesity and weight gain, suggesting that CD36 and PPARgamma may have potential value in predicting VPA-induced obesity in Chinese Han epileptic patients. PMID- 29984390 TI - Raised plasma levels of H2S and nitrate predict intrapulmonary vascular dilations: A preliminary report in patients with cryptogenic cirrhosis. AB - BACKGROUND AND AIMS: The role of vasoactive chemicals in the pathogenesis of hepatopulmonary syndrome (HPS), a disorder characterized by intrapulmonary vascular dilation (IPVD), is only vaguely elucidated. We aimed to study the association between plasma H2S, nitrate levels, and presence and severity of IPVD and HPS. METHODS: Consecutive adult patients with cryptogenic cirrhosis were evaluated for IPVD (by contrast echocardiography) and for hypoxemia (by arterial blood gas analysis). Plasma H2S and nitrate levels were measured in these patients. RESULTS: Fifty-eight patients with cryptogenic cirrhosis (male, 45; median age, range, 45, 16-74 years; Child's class; A, 30; B, 18; C, 10) were enrolled in this study. Thirty-four of the 58 (59%) patients had IPVD and 13 (22%) had HPS (mild, 4; moderate, 5; severe, 2; very severe, 2). Plasma H2S levels were significantly higher in patients with IPVD (19.6, 5.7-83 MUmol/L) as compared to patients who had no IPVD (12.3, 0-47 MUmol/L; p-value 0.03) with an area under receiver operating characteristic curve of 0.68 (95% CI 0.53-0.84). Plasma H2S levels were higher in patients with IPVD irrespective of liver disease severity. There was a trend for higher plasma nitrate levels in patients with IPVD (47, 15.8-126.4 nmol/mL) as compared to patients who had no IPVD (32.3, 6.9 51.4 nmol/mL; p-value 0.1). Raised plasma H2S and nitrate levels had an additive effect on the presence of IPVD. Neither plasma H2S nor plasma nitrate levels correlated with the degree of hypoxemia. CONCLUSION: Raised plasma H2S and nitrate levels predict the presence of IPVD in patients with cryptogenic cirrhosis. PMID- 29984392 TI - Rapid and Sensitive Detection of Staphylococcal Enterotoxin B by Recombinant Nanobody Using Phage Display Technology. AB - Staphylococcal enterotoxin B, from Staphylococcus aureus (S. aureus), is one of the most potent bacterial superantigens with profound toxic effects on the immune system. It is associated with food poisoning, toxic shock, atopic dermatitis, asthma, and nasal polyps in humans. The current diagnostic methods for staphylococcal enterotoxin are mainly based on traditional monoclonal antibodies which hardly meet the requirements for clinical applications, and hybridoma clones lose their ability to secrete antibodies during time. The present study investigates the development of a novel, highly specific, low-cost, and sensitive nanobody capable of being used in immunoassays for Staphylococcal enterotoxin B (SEB) detection in suspicious foods. For this purpose, Camelus dromedarius was immunized against SEB toxin. After obtaining acceptable titration, a high-quality phage display nanobody library (4 * 1010 PFU/ml) was constructed. High-affinity SEB-specific nanobodies were retrieved from constructed libraries. After phage rescue and five round of biopanning, clone screening was performed by phage ELISA. Recombinant nanobodies which were expressed from C7 and C21 clone showed the highest affinity for SEB. The presence of high quality and pure nanobody band at ~ 15 kDa was confirmed by SDS-PAGE and western blotting. The affinity constant which was measured by ELISA was calculated to be around 10-9 M. The results suggest that the proposed detection method by nanobodies is an alternative diagnostic tool enabling a rapid, inexpensive, and specific detection of the SEB. PMID- 29984393 TI - Facemask performance during maxillary protraction: a finite element analysis (FEA) evaluation of load and stress distribution on Delaire facemask. AB - BACKGROUND: To evaluate load and stress distribution on Delaire facemask (FM) during maxillary protraction in class III growing patients by means of finite element analysis (FEA). A three-dimensional geometry of a Delaire FM was reconstructed from the original CAD 3D prototype, using software package (ANSYS 5.7). FM presented forehead and chin supports and stainless steel framework characterized by two lateral vertical bars connected to a crossbar with two pawls for elastic attachment. Two traction intensities (7.8 and 9.8 N) were applied on the FM pawls along three different downward inclined directions with respect to the occlusal plane (0 degrees , 30 degrees , or 50 degrees , respectively). Resulting stresses and deformations were then tested through the von Mises yield criterion in order to underline the FM wear performance. RESULTS: The analysis showed that higher stresses and deformations are mostly related to axial forces of 9.8 N rather than 7.8 N. Stresses also progressively increased with increasing downward force inclinations (0 degrees , 30 degrees , and 50 degrees with respect to the occlusal plane). The overall tensions were inferior to the limit of the elastic behavior (yield point) characterizing the material they are applied on. Thus, the FM structure absorbed the load applied with an elastic deformation of the lateral and horizontal bars. CONCLUSIONS: Resulting stresses and deformations were directly proportional to protraction load amounts and to increasing downward inclination of forces. In all tested conditions, protraction forces were not able to determine plastic deformation on FM structure compromising its performance and efficiency. PMID- 29984394 TI - Catabolism of the groundwater micropollutant 2,6-dichlorobenzamide beyond 2,6 dichlorobenzoate is plasmid encoded in Aminobacter sp. MSH1. AB - Aminobacter sp. MSH1 uses the groundwater micropollutant 2,6-dichlorobenzamide (BAM) as sole source of carbon and energy. In the first step, MSH1 converts BAM to 2,6-dichlorobenzoic acid (2,6-DCBA) by means of the BbdA amidase encoded on the IncP-1beta plasmid pBAM1. Information about the genes and degradation steps involved in 2,6-DCBA metabolism in MSH1 or any other organism is currently lacking. Here, we show that the genes for 2,6-DCBA degradation in strain MSH1 reside on a second catabolic plasmid in MSH1, designated as pBAM2. The complete sequence of pBAM2 was determined revealing that it is a 53.9 kb repABC family plasmid. The 2,6-DCBA catabolic genes on pBAM2 are organized in two main clusters bordered by IS elements and integrase genes and encode putative functions like Rieske mono-/dioxygenase, meta-cleavage dioxygenase, and reductive dehalogenases. The putative mono-oxygenase encoded by the bbdD gene was shown to convert 2,6 DCBA to 3-hydroxy-2,6-dichlorobenzoate (3-OH-2,6-DCBA). 3-OH-DCBA was degraded by wild-type MSH1 and not by a pBAM2-free MSH1 variant indicating that it is a likely intermediate in the pBAM2-encoded DCBA catabolic pathway. Based on the activity of BbdD and the putative functions of the other catabolic genes on pBAM2, a metabolic pathway for BAM/2,6-DCBA in strain MSH1 was suggested. PMID- 29984395 TI - Impact on strain growth and butenyl-spinosyn biosynthesis by overexpression of polynucleotide phosphorylase gene in Saccharopolyspora pogona. AB - Polynucleotide phosphorylase is a highly conserved protein found in bacteria and fungi that can regulate the transcription of related enzymes involved in amino acid metabolism, organic acid metabolism, and cell biosynthesis. We studied the effect of polynucleotide phosphorylase on Saccharopolyspora pogona (S. pogona) growth and the synthesis of secondary metabolites. First, we generated the overexpression vector pOJ260-PermE-pnp via overlap extension PCR. The vector pOJ260-PermE-pnp was then introduced into S. pogona by conjugal transfer, thereby generating the recombination strain S. pogona-Pnp. Results showed that engineering strains possessed higher biomass than those of the wild-type strains. Moreover, the ability of these strains to produce spores on solid medium was stronger than that of the wild-type strains. HPLC results revealed that the butenyl-spinosyn yield in S. pogona-Pnp increased by 1.92-fold compared with that of S. pogona alone. These findings revealed that overexpression of polynucleotide phosphorylase effectively promoted butenyl-spinosyn biosynthesis in S. pogona. This result may be extended to other Streptomyces for strain improvement. PMID- 29984391 TI - The role of CD133 in cancer: a concise review. AB - Despite the abundant ongoing research efforts, cancer remains one of the most challenging diseases to treat globally. Due to the heterogenous nature of cancer, one of the major clinical challenges in therapeutic development is the cancer's ability to develop resistance. It has been hypothesized that cancer stem cells are the cause for this resistance, and targeting them will lead to tumor regression. A pentaspan transmembrane glycoprotein, CD133 has been suggested to mark cancer stem cells in various tumor types, however, the accuracy of CD133 as a cancer stem cell biomarker has been highly controversial. There are numerous speculations for this, including differences in cell culture conditions, poor in vivo assays, and the inability of current antibodies to detect CD133 variants and deglycosylated epitopes. This review summarizes the most recent and relevant research regarding the controversies surrounding CD133 as a normal stem cell and cancer stem cell biomarker. Additionally, it aims to establish the overall clinical significance of CD133 in cancer. Recent clinical studies have shown that high expression of CD133 in tumors has been indicated as a prognostic marker of disease progression. As such, a spectrum of immunotherapeutic strategies have been developed to target these CD133pos cells with the goal of translation into the clinic. This review compiles the current therapeutic strategies targeting CD133 and discusses their prognostic potential in various cancer subtypes. PMID- 29984396 TI - The comorbidity of acute ischemic stroke and splenic infarction resulting from essential thrombocythemia. PMID- 29984397 TI - Prevalence of Haemonchus contortus infection in sheep slaughtered at Jimma town municipal abattoir, Ethiopia. AB - Haemonchus contortus is a parasite of major economic importance of most sheep rearing areas of the world. A cross-sectional study was conducted from November 2015 to March 2016 with objectives of determining the prevalence and associated risk factors of Haemonchus contortus infection in sheep slaughtered at Jimma town municipal abattoir, Ethiopia. Of the total 7000 sheep slaughtered during the study time period, 384 sheep were randomly selected and examined for parasites. The overall prevalence of Haemonchus contortus infection was 264 (68.75%). Infection rate of poor body condition animals was significantly (P = 0.000) higher than good body conditioned animals. The mean packed cell volume (PCV) values (%) of parasitemic and aparasitemic sheep were 23.73 +/- 3.7 SD and 37.66 +/- 4.736 SD, respectively. The prevalence in adult sheep (> 1 year) was insignificantly (P = 0.653) higher than that of young sheep (<= 1 year). The highest prevalence was recorded in sheep that originated from Seka district (73.3%) and the lowest in Kersa district (63.4%) with non-significant variation (P = 0.691). The highest monthly mean worm burdens and prevalence of Haemonchus contortus infection were recorded in November and lowest in March. The current study revealed that Haemonchus contortus infection is an important and common parasitic disease and requires special attention to its control. PMID- 29984398 TI - Effects of berberine on growth, liver histology, and expression of lipid-related genes in blunt snout bream (Megalobrama amblycephala) fed high-fat diets. AB - Fatty liver of cultured fish often correlates closely with poor growth and low harvest yield. Some Chinese herbs can reduce hepatic fat storage. This study aimed to examine lipid-lowering effect of berberine (BBR) in blunt snout bream (Megalobrama amblycephala). Triplicate groups of fish were fed four experimental diets: low-fat diet (LFD, 5% fat), high-fat diet (HFD, 15% fat), and HFD supplemented with 50 or 100 mg BBR/kg diet (BBR50, BBR100). After 8-week feeding, growth performance, liver histology and fat deposition, and hepatic genes expression were examined. The results showed significant reduction of growth performance and feed intake in fish fed HFD compared to those fed the LFD and BBR50 diets. Supplementing 50 mg BBR/kg to the HFD significantly improved weight gain and feed intake. Higher hepatic fat content and histological abnormalities were found in the liver of fish receiving HFD, and BBR50 and BBR100 could attenuate these abnormalities of liver. Expression of CPT I, AOX, ApoB100, ApoE, and PGC-1alpha genes was significantly decreased in fish fed HFD, and 50 and 100 mg/kg BBR supplementation could revert the downregulation of these genes. Also, the expression of FATP, LPL, and LDLR genes was upregulated in HFD-fed fish, and their expression was significantly decreased by 50 and 100 mg/kg BBR supplementation. In conclusion, supplementing BBR to HFD could attenuate liver fat deposition and disorders. The fat-lowering effects of BBR appear to be mediated by activating genes related with fatty acid oxidation and decreasing genes for fatty acid uptake. PMID- 29984399 TI - Dentin pretreatment with Er:YAG laser and sodium ascorbate to improve the bond strength of glass fiber post. AB - Root-filled teeth that received fiber posts most frequently fail at the adhesive interface between resin cement and dentin. The objective of this study is to evaluate the effect of Er:YAG laser and/or sodium ascorbate (SA) on bond strength, microhardness of dentin, and penetration depth of cement into dentinal tubules. Forty-eight bovine incisor roots were endodontically treated, post spaces were prepared and equally divided into four groups (n = 12): G1-distilled water (control); G2-10% SA (10 min); G3-Er:YAG laser (150 mJ/4 Hz/40 s), and G4 Er:YAG laser + 10% SA. Glass fiber posts were cemented and roots sectioned into slices. In the first slice, the push-out bond strength (MPa) and failures were analyzed by confocal laser scanning microscope (CLSM). The second slice was subjected to microhardness test (KHN) and CLSM to assess the cement penetration. ANOVA and Tukey test were used for bond strength and microhardness data and Kruskal-Wallis and Dunn tests for the cement penetration (alpha = .05). The SA treated samples had higher bond strength (10.02 +/- 5.45a), similar to Er:YAG laser (9.91 +/- 4.62a) and Er:YAG laser + SA (8.09 +/- 4.07a). The least values (P < .05) were found on control (4.02 +/- 2.39b). Significant differences were observed on root thirds (P < .05): cervical > middle > apical. There was a predominance of adhesive failures. The microhardness test revealed no differences between groups (P > .05). The experimental groups (G2, G3, and G4) had highest penetration into dentinal tubules when compared to the control (G1). Dentin pretreatments with Er:YAG laser or SA improved bond strength of cement-post dentin interfaces; however, no synergistic effect of both treatments combined was observed. PMID- 29984400 TI - Involvement of Claudin-11 in Disruption of Blood-Brain, -Spinal Cord, and Arachnoid Barriers in Multiple Sclerosis. AB - It is important to understand the molecular mechanisms of barrier disruption in the central nervous system (CNS) of patients with multiple sclerosis (MS). The purpose of the present study was to clarify whether claudin-11 is involved in the disruption of two endothelial barriers (blood-brain barrier (BBB) and blood spinal cord barrier (BSCB)) and two epithelial barriers (blood-arachnoid barrier (BAB) and blood-CSF barrier (BCSFB)) in the CNS in MS. Immunohistochemical analysis revealed that, in both normal human and mouse, claudin-11 is co localized with claudin-5 in the brain and spinal cord capillaries. The absolute protein expression level of claudin-11 was nearly equal to that of claudin-5 in rat brain capillaries, but was 2.81-fold greater in human brain capillaries. The protein expressions of claudin-11 were significantly downregulated in the brain and spinal cord capillaries of an MS patient and experimental autoimmune encephalomyelitis (EAE) mice. Specific downregulation of claudin-11 with siRNA significantly increased the transfer of membrane-impermeable FITC-dextran across human brain capillary endothelial cell (hCMEC/D3) monolayer. As for the epithelial barrier, claudin-11 protein expression was not decreased in choroid plexus epithelial cells forming the BCSFB in EAE mice, whereas it was decreased in brain and spinal cord meninges that form the BAB. Specific downregulation of claudin-11 with siRNA in a rat choroid plexus epithelial cell (TR-CSFB) monolayer significantly increased the permeability of FITC-dextran. In conclusion, our present findings indicate that claudin-11 expression at the BBB, BSCB, and BAB, but not the BCSFB, is downregulated in multiple sclerosis, impairing the functional integrity of these barriers. PMID- 29984401 TI - Expression of the Cerebral Olfactory Receptors Olfr110/111 and Olfr544 Is Altered During Aging and in Alzheimer's Disease-Like Mice. AB - A growing number of studies report the expression of olfactory receptors (ORs) in many non-chemosensory tissues and organs. However, within the brain, very few ectopic ORs are exhaustively documented. Their kinetic expression, cellular localization, and functions remain elusive. Using cDNA microarrays, quantitative PCR, and immunohistochemistry, we studied the cellular and sub-cellular localization of Olfr110/111 and Olfr544 and their timely expression in various brain areas of wild-type and transgenic Alzheimer's disease-like (5xFAD) mice. We observed that Olfr110/111 and Olfr544 proteins are mainly expressed by neurons in cortical and hippocampal regions and, to a lesser extent, by astrocytes, microglia, oligodendrocytes, and endothelial cells. In addition, both ORs are present at the cell membrane and co-expressed with the olfactory Galphaolf protein, suggesting that they can be functional. Remarkably, we also found that the expression of the mRNA encoding for Olfr110/111 tends to increase with age in both the cortex and hippocampus of wild-type and transgenic mice. Moreover, Olfr110/111 transcript expression is markedly impaired in the brain of Alzheimer's disease-like mice. A different profile is noticed for Olfr544, for which an overexpression is observed only in the cortex of 9-month-old animals. In addition, in transgenic mice, olfactory receptors are observed near amyloid plaques. Altogether, our findings indicate that ORs may play a role in brain functioning, in normal and pathological conditions. PMID- 29984402 TI - A systems perspective on placental amino acid transport. AB - Placental amino acid transfer is a complex process that is essential for fetal development. Impaired amino acid transfer causes fetal growth restriction, which may have lifelong health consequences. Transepithelial transfer of amino acids across the placental syncytiotrophoblast requires accumulative, exchange and facilitated transporters on the apical and basal membranes to work in concert. However, transporters alone do not determine amino acid transfer and factors that affect substrate availability, such as blood flow and metabolism, may also become rate-limiting for transfer. In order to determine the rate-limiting processes, it is necessary to take a systems approach which recognises the interdependence of these processes. New technologies have the potential to deliver targeted interventions to the placenta and help poorly growing fetuses. While many factors are necessary for amino acid transfer, novel therapies need to target the rate limiting factors if they are going to be effective. This review will outline the factors which determine amino acid transfer and describe how they become interdependent. It will also highlight the role of computational modelling as a tool to understand this process. PMID- 29984403 TI - CCL20 blockade increases the severity of nephrotoxic folic acid-induced acute kidney injury. AB - The chemokine CCL20 activates the CCR6 receptor and has been implicated in the pathogenesis of glomerular injury. However, it is unknown whether it contributes to acute kidney injury (AKI). We identified CCL20 as upregulated in a systems biology strategy combining transcriptomics of kidney tissue from experimental toxic folic acid-induced AKI and from stressed cultured tubular cells and have explored the expression and function of CCL20 in experimental and clinical AKI. CCL20 upregulation was confirmed in three models of kidney injury induced by a folic acid overdose, cisplatin or unilateral ureteral obstruction. In injured kidneys, CCL20 was expressed by tubular, endothelial, and interstitial cells, and was also upregulated in human kidneys with AKI. Urinary CCL20 was increased in human AKI and was associated with severity. The function of CCL20 in nephrotoxic folic acid-induced AKI was assessed by using neutralising anti-CCL20 antibodies or CCR6-deficient mice. CCL20/CCR6 targeting increased the severity of kidney failure and mortality. This was associated with more severe histological injury, nephrocalcinosis, capillary rarefaction, and fibrosis, as well as higher expression of tubular injury-associated genes. Surprisingly, mice with CCL20 blockade had a lower tubular proliferative response and a higher number of cells in the G2/M phase, suggesting impaired repair mechanisms. This may be related to a lower influx of Tregs, despite a milder inflammatory response in terms of chemokine expression and infiltration by IL-17+ cells and neutrophils. In conclusion, CCL20 has a nephroprotective role during AKI, both by decreasing tissue injury and by facilitating repair. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29984404 TI - Effect of providing sudden unexpected death in epilepsy (SUDEP) information to persons with epilepsy (PWE) and their caregivers-Experience from a tertiary care hospital. AB - OBJECTIVE: The primary objective of present study was to observe the effect of providing SUDEP (Sudden Unexpected Death in Epilepsy) information on drug adherence in persons with epilepsy (PWE). We also looked at impact of disclosing SUDEP information on patient's quality of life and mood. MATERIAL AND METHODS: This prospective study had a pretest/post-test design. A total of 231 consecutive PWE (>15 years) were enrolled. Of these 121 PWE received information about SUDEP in addition to standard epilepsy care. One hundred and ten PWE (control group) received routine standard epilepsy care but did not receive SUDEP information. Follow up assessment was done at 6 months. The primary outcome was a change in drug adherence (measured by Modified Morisky Medication Adherence Scale, MMAS) in PWE following disclosure of SUDEP information. RESULTS: After 6 months, 116 PWE in the SUDEP information group and 106 in control group were available for follow up. A non-significant higher adherence was observed in the SUDEP information group as compared to the control group (Mean MMAS change 0.51 +/- 1.66 vs 0.25 +/ 1.26, P value = 0.194). No significant change was perceived in patient's anxiety and depression levels or quality of life in either group. CONCLUSION: The present study suggests that providing information on SUDEP to PWE and their caregivers may increase drug adherence without adverse effect on quality of life or mood. Well-designed studies with high methodological quality are required to determine the precise effect size associated with disclosure of SUDEP information on drug adherence in PWE. PMID- 29984405 TI - The Solvatofluorochromism of 2,4,6-Triarylpyrimidine Derivatives. AB - Seven new 2,4,6-triarylpyrimidines were synthesized and their solvatofluorochromism investigated in 12 solvents and in an aqueous micellar solution of reduced Triton X-100. A multiparametric analysis of their emission band showed that the solvent dipolarity and basicity were mainly responsible for their solvatofluorochromism, which arose from an internal charge-transfer from a donor fragment to the pyrimidine acceptor, confirmed by theoretical calculations. In the micellar system, quenching of their fluorescence by addition of derivatives of 2,2,6,6-tetramethylpiperidinoxyl (TEMPO) radical was investigated and the results were consistent with the spectral changes brought about by the micro-heterogeneous system. PMID- 29984406 TI - Validation of the Russian version of the Fatigue Impact Scale and Fatigue Severity Scale in multiple sclerosis patients. AB - BACKGROUND: Fatigue is a common complaint in patients with multiple sclerosis (MS), and its detection and monitoring are based on self-reported questionnaires. The objective of this study was to validate the Russian translation of the Fatigue Impact Scale (FIS) and the Fatigue Severity Scale (FSS) in MS patients and controls. METHODS: We included 85 MS patients and 250 age-, sex-, and body mass index (BMI)-matched controls. We ascertained in all subjects levels of education, marital status, and comorbidities, such as sleepiness (using the Epworth Sleepiness Scale, ESS), anxiety and depression (using the Hospital Anxiety and Depression Scale, HADS). The expanded disability status scale (EDSS) reflected physical disability in MS. RESULTS: The Russian versions of the three FIS subscales (cognitive, physical, and psychosocial) and FSS had excellent internal consistencies (Cronbach's alpha coefficients 0.88-0.96), and good test retest stability with intraclass coefficients between 0.78 and 0.89. Both convergent and discriminant validity of the Russian FIS and FSS appeared to be good, as expressed by strong inter-correlations between FIS subscales and FSS, and by absent associations between fatigue scales and BMI. Principal components analysis and scree plots indicated unidimensional structures of the physical and cognitive FIS subscales and FSS, but a multidimensional structure of the psychosocial subscale. We identified EDSS and anxiety scores as independent predictors of more severe fatigue in MS. SIGNIFICANCE: The Russian FIS and FSS represent reliable and valid tools for efficient quantification and monitoring of fatigue severity and its clinical impact in MS. EDSS and anxiety are important contributors to fatigue severity in MS. PMID- 29984407 TI - Wound healing potential of Solanum xanthocarpum in streptozotocin-induced diabetic rats. AB - OBJECTIVES: The objective of the present study was to evaluate wound healing potential of Solanum xanthocarpum extract in streptozotocin-induced diabetic rats. METHODS: Alcoholic extract of the aerial parts (ESX) was subjected to phytochemical estimations and its standardization with chlorogenic acid using HPLC. ESX was then evaluated for wound healing potential in, streptozotocin induced diabetic rats using excision and incision wound models on topical and oral treatment Various biochemical evaluations, such as collagen, hexosamine, hyaluronic acid, protein, DNA along with antioxidant parameters, proinflammatory cytokines, VEGF and histopathological examination were also evaluated. KEY FINDINGS: Extract of S. xanthocarpum depicted the presence of mainly alkaloids, polyphenols, steroids, while content of chlorogenic acid was found to be 8.44% w/w. The maximum effective nature of ESX in healing was observed at 10% gel (topical) and 200 mg/kg (orally) in diabetic rats, where highest healing power was observed when treated both orally and topically. Biochemical evaluations showed significant increase in the levels of collagen, hexosamine, hyaluronic acid, protein, DNA followed by significant decline in the levels of blood glucose, lipid peroxidation, nitric oxide and expression of proinflammatory cytokines, supported by histopathology. CONCLUSIONS: The potential healing effect in diabetic rats may be attributed to the presence of chlorogenic acid in combination with other phytoconstituents. PMID- 29984408 TI - Priming attachment security improves attitudes towards a range of therapies. AB - We sought to understand how attachment orientation influenced attitudes towards different types of psychological therapies. In two studies, we (1) examined attachment orientation as a predictor of attitudes towards different therapies and (2) tested whether attachment security priming could improve attitudes. Study 1 (n = 339) found associations between attachment orientation and attitudes towards, and likelihood of using different therapies. Positive and negative attitudes about different therapies mediated the relationship between attachment avoidance and likelihood of use. Study 2 (n = 412) showed that primed security (vs. neutral prime) improved attitudes towards relational, non-relational and distanced-relational therapies for those with a fearful-avoidant attachment orientation. For relational and distanced-relational therapies, the mechanism of this effect was increased cognitive openness. Attachment orientation is a determinant of therapy attitudes and anticipated help-seeking behaviour. Priming security may promote open-minded decision-making about some therapies. Findings are discussed with relevance to attachment theory, research and clinical practice. PMID- 29984410 TI - A Janeway Lesson. PMID- 29984411 TI - Confidence intervals of the Mann-Whitney parameter that are compatible with the Wilcoxon-Mann-Whitney test. AB - For the two-sample problem, the Wilcoxon-Mann-Whitney (WMW) test is used frequently: it is simple to explain (a permutation test on the difference in mean ranks), it handles continuous or ordinal responses, it can be implemented for large or small samples, it is robust to outliers, it requires few assumptions, and it is efficient in many cases. Unfortunately, the WMW test is rarely presented with an effect estimate and confidence interval. A natural effect parameter associated with this test is the Mann-Whitney parameter, phi = Pr[ XA heteroplasmy is associated with depressive symptoms in the elderly. AB - OBJECTIVES: Mitochondrial DNA (mtDNA) heteroplasmy is a mixture of normal and mutated mtDNA molecules in a cell. High levels of heteroplasmy at several mtDNA sites in complex I lead to inherited neurological neurologic diseases and brain magnetic resonance imaging (MRI) abnormalities. Here, we test the hypothesis that mtDNA heteroplasmy at these complex I sites is associated with depressive symptoms in the elderly. METHODS: We examined platelet mtDNA heteroplasmy for associations with depressive symptoms among 137 participants over age 70 from the community-based Health, Aging and Body Composition Study. Depressive symptoms were assessed using the 10-point version of the Center for Epidemiologic Studies Depression Scale (CES-D 10). Complete mtDNA sequencing was performed and heteroplasmy derived for 5 mtDNA sites associated with neurologic mitochondrial diseases and tested for associations with depressive symptoms. RESULTS: Of 5 candidate complex I mtDNA mutations examined for effects on depressive symptoms, increased heteroplasmy at m.13514A>G, ND5, was significantly associated with higher CES-D score (P = .01). A statistically significant interaction between m.13514A > G heteroplasmy and sex was detected (P = .04); in sex-stratified analyses, the impact of m.13514A>G heteroplasmy was stronger in male (P = .003) than in female (P = .98) participants. Men in highest tertile of mtDNA heteroplasmy exhibited significantly higher (P = .0001) mean +/- SE CES-D 10 scores, 5.37 +/- 0.58, when compared with those in the middle, 2.13 +/- 0.52, and lowest tertiles, 2.47 +/- 0.58. No associations between the 4 other candidate sites and depressive symptoms were observed. CONCLUSIONS: Increased mtDNA heteroplasmy at m.13514A>G is associated with depressive symptoms in older men. Heteroplasmy may represent a novel biological risk factor for depression. PMID- 29984426 TI - Barriers to electronic cigarette use. AB - OBJECTIVE: Recent studies suggest that electronic cigarettes (e-cigarettes) may be a better alternative to traditional smoking cessation therapies for cigarette smokers. This study explores the barriers traditional smokers face when switching to e-cigarettes. DESIGN AND SAMPLE: A convenience sample of adult male and female tobacco and/or e-cigarette smokers (n = 446) were recruited through an online survey. MEASUREMENTS: The survey included questions used to determine the barriers a smoker may experience in regards to their use of e-cigarettes, as well as the characteristics regarding their use of tobacco and/or e-cigarettes. RESULTS: The majority (74%) of tobacco smokers who tried e-cigarettes did not perceive e-cigarettes to be an effective replacement for tobacco cigarettes, and 69% indicated the initial cost and health concerns as reasons to not continue using e-cigarettes. Both current e-cigarette users and those who discontinued use of e-cigarettes noted health or lack of information on side effects as a concern. The majority of e-cigarette users indicated that it took more than a week to settle on a proper dose. We found that for each additional cigarette smoked per day individuals were 4.0% (p = .001) more likely to use e-cigarettes. CONCLUSION: This exploratory study informs future cessation trials involving e-cigarettes about the barriers users face. Given that individuals who smoke a greater number of tobacco cigarettes are more likely to try e-cigarettes, greater attention to nicotine dosing is necessary. PMID- 29984427 TI - Rectal cancer in young patients: Time to take notice. PMID- 29984428 TI - Advances in managing COPD related to alpha1 -antitrypsin deficiency: An under recognized genetic disorder. AB - alpha1 -Antitrypsin deficiency (AATD) predisposes individuals to chronic obstructive pulmonary disease (COPD) and liver disease. Despite being commonly described as rare, AATD is under-recognized, with less than 10% of cases identified. The following is a comprehensive review of AATD, primarily for physicians who treat COPD or asthma, covering the genetics, epidemiology, clinical presentation, screening and diagnosis, and treatments of AATD. For patients presenting with liver and/or lung disease, screening and diagnostic tests are the only methods to determine whether the disease is related to AATD. Screening guidelines have been established by organizations such as the World Health Organization, European Respiratory Society, and American Thoracic Society. High-risk groups, including individuals with COPD, nonresponsive asthma, bronchiectasis of unknown etiology, or unexplained liver disease, should be tested for AATD. Current treatment options include augmentation therapy with purified AAT for patients with deficient AAT levels and significant lung disease. Recent trial data suggest that lung tissue is preserved by augmentation therapy, and different dosing schedules are currently being investigated. Effective management of AATD and related diseases also includes aggressive avoidance of smoking and biomass burning, vaccinations, antibiotics, exercise, good diet, COPD medications, and serial assessment. PMID- 29984429 TI - Time-course analysis of salicylic acid effects on ROS regulation and antioxidant defense in roots of hulled and hulless barley under combined stress of drought, heat and salinity. AB - Greater crop losses can result from simultaneous exposure to a combination of drought, heat and salinity in the field. Salicylic acid (SA), a phenolic phytohormone, can affect a range of physiological and biochemical processes in plants and significantly impacts their resistance to these abiotic stresses. Despite numerous reports involving the positive effects of SA by applying each abiotic stress separately, the mechanism of SA-mediated adaptation to combined stresses remains elusive. This study, via a time-course analysis, investigated the role of SA on the roots of hulled and hulless (naked) barley (Hordeum vulgare L. 'Tarm' and 'Ozen', respectively), which differed in salt tolerance, under the combined stress of drought, heat and salt. The combined stress caused marked reductions in root length and increases in proline content in both genotypes; however, Tarm exhibited better adaptation to the triple stress. Under the first 24 h of stress, superoxide dismutase (SOD; EC.1.15.1.1) and peroxidase (POX; EC.1.11.1.7) activity in the Tarm roots increased remarkably, while decreasing in the Ozen roots. Furthermore, the Tarm roots showed higher catalase (CAT; EC 1.11.1.6), ascorbate peroxidase (APX; EC 1.11.1.11) and glutathione reductase (GR; EC 1.6.4.2) activity than the Ozen during the combined stresses. The sensitivity of hulless barley roots may be related to decreasing SOD, POX, CAT and GR activity under stress. Over 72 h of stress, the SA pretreatment improved the APX and GR activity in Tarm and that of POX and CAT in Ozen, demonstrating that exogenously applied SA regulates antioxidant defense enzymes in order to detoxify reactive oxygen species. The results of this study suggest that SA treatment may improve the triple-stress combination tolerance in hulled and hulless barley cultivars by increasing the level of antioxidant enzyme activity and promoting the accumulation of proline. Thus, SA alleviated the damaging effects of the triple stress by improving the antioxidant system, although these effects differed depending on characteristic of the hull of the grain. PMID- 29984431 TI - Is parental oral health literacy a predictor of children's oral health outcomes? Systematic review of the literature. AB - BACKGROUND: The scientific evidence regarding the association between parental oral health literacy (OHL) and children's oral health is unclear. AIM: To evaluate the scientific evidence concerning the association between parental OHL and children's oral health outcomes. DESIGN: Eight databases were searched. Studies that evaluated oral health outcomes among children and measured parental OHL through a validated tool were included. Two independent reviewers selected studies, extracted data and analysed the risk of bias. RESULTS: Eleven studies were included. Most (n = 6) had a high risk of bias. Most studies evaluating dental caries found association between lower parental OHL and higher prevalence/experience of dental caries. Poor oral health-related quality of life was associated with decreased parental OHL (P < 0.05). Studies diverged on the association between OHL and the number of filled, extracted teeth, and dental visits. There was no association between children's tooth brushing frequency, use of toothpaste, oral health claim, oral health expenditures and parental OHL. The literature was inconclusive regarding the association between night bottle feeding, negative parental perception of the child's oral health and OHL. CONCLUSION: Low parental OHL was associated with dental caries among their children. It is too soon to assume an association between OHL and the remaining outcomes. PMID- 29984430 TI - Effects of a responsible retailing mystery shop intervention on age verification by servers and clerks in alcohol outlets: A cluster randomised cross-over trial. AB - INTRODUCTION AND AIMS: Clerks and servers at alcohol establishments often fail to verify age. Using mystery shoppers to provide performance feedback is one approach to improving age verification. Few controlled studies have evaluated mystery shop interventions. This paper reports on a cluster randomised cross-over trial of a mystery shop intervention in 16 communities in four US states. DESIGN AND METHODS: The intervention comprised monthly mystery shops after which clerks and servers received immediate feedback to reinforce age verification. Managers received monthly reports. Communities in each state were matched into pairs and, following a 3-month baseline, were randomly assigned within each pair to receive the intervention beginning after the fourth (Early Intervention) or the tenth (Delayed Intervention) mystery shop. On average, 17 (range = 14-20) randomly selected on-premises and 18 (range = 11-23) off-premises outlets participated in each community (N = 557). RESULTS: Fixed effects multi-level logistic regressions indicated that the intervention led to a two-fold increase in the odds of age verification, odds ratio (OR) = 2.05; P < 0.001; 95% confidence interval (CI) 1.76, 2.39. Overall, ID-checking increased from an average of 80% pre intervention to 94-96% by the end of the program. Significant effects were found for on-premises, OR = 1.79; P < 0.001; 95% CI 1.43, 2.24, and off-premises establishments, OR = 2.29; P < 0.001; 95% CI 1.86, 2.82. DISCUSSION AND CONCLUSIONS: Mystery shop interventions can increase age verification for alcohol purchases and may be an effective supplement to compliance checks and responsible beverage service programs. PMID- 29984432 TI - Advances in Synthesis and Measurement of Charge Transport in DNA-Based Derivatives. AB - Charge transport through molecular structures is interesting both scientifically and technologically. To date, DNA is the only type of polymer that transports significant currents over distances of more than a few nanometers in individual molecules. For molecular electronics, DNA derivatives are by far more promising than native DNA due to their improved charge-transport properties. Here, the synthesis of several unique DNA derivatives along with electrical characterization and theoretical models is surveyed. The derivatives include double stranded poly(G)-poly(C) DNA molecules, four stranded G4-DNA, metal-DNA hybrid molecular wires, and other DNA molecules that are modified either at the bases or at the backbone. The electrical characteristics of these nanostructures, studied experimentally by electrostatic force microscopy, conductive atomic force microscopy, and scanning tunneling microscopy and spectroscopy, are reviewed. PMID- 29984433 TI - Adenosine diphosphate regulates MMP2 and MMP9 activity in malignant mesothelioma cells. AB - Although an association between cancer progression and matrix metalloproteinase (MMP) 2 and MPP9 expression has been known, the expression, nuclear localization, and physiologically controlled activation of these two MMPs have not been investigated in malignant mesothelioma cells. We examined the expression and intracellular localization of MMP2/9 in ZL55 malignant mesothelioma cells, as well as their regulation by ADP. Using real-time PCR, we showed that activation of the P2Y1 receptor by ADP increased the expression of MMP2/9 mRNAs; MMP2/9 collected from conditioned media also showed an increase in activity; and ADP induced the nuclear localization of MMP2/9. The effects of ADP on transcription of the MMPs were due to activation of c-Src, Akt, and NF-kappaB, while ERK1/2 phosphorylation was needed for the increase in enzymatic activity and the regulation of nuclear import. We also showed that the nuclear localization of MMP2/9 induced by ADP causes the cleavage and inactivation of poly-ADP-ribose polymerase-1. These findings may help to elucidate the mechanisms regulating MMP2/9 activation in ZL55 human epithelioid mesothelioma cells, and perhaps other cells. Therapeutic approaches that promote ADP accumulation in a tumor environment may constitute an effective means to induce anticancer activity. PMID- 29984434 TI - Calcium-Ion Batteries: Current State-of-the-Art and Future Perspectives. AB - Recent developments in rechargeable battery technology have seen a shift from the well-established Li-ion technology to new chemistries to achieve the high energy density required for extended range electric vehicles and other portable applications, as well as low-cost alternatives for stationary storage. These chemistries include Li-air, Li-S, and multivalent ion technologies including Mg2+ , Zn2+ , Ca2+ , and Al3+ . While Mg2+ battery systems have been increasingly investigated in the last few years, Ca2+ technology has only recently been recognized as a viable option. In this first comprehensive review of Ca2+ ion technology, the use of Ca metal anodes, alternative alloy anodes, electrolytes suitable for this system, and cathode material development are discussed. The advantages and disadvantages of Ca2+ ion batteries including prospective achievable energy density, cost reduction due to high natural abundance, low ion mobility, the effect of ion size, and the need for elevated temperature operation are reviewed. The use of density functional theory modeling to predict the properties of Ca-ion battery materials is discussed and the extent to which this approach is successful in directing research into areas of promise is evaluated. To conclude, a summary of recent achievements is presented and areas for future research efforts evaluated. PMID- 29984435 TI - A theoretical and experimental study of the temporal reduction in UV protection provided by a facial day cream. AB - OBJECTIVE: To investigate how the UV protection provided by a facial day cream reduces over the course of a day. METHODS: We developed a theoretical model using a Monte Carlo random sampling approach to estimate the variation in local thickness, and hence local effective SPF, at several different sites over the face. The input variables, which are labelled SPF, average application thickness, homogeneity of the product on the skin and the ability of the product to bind to the skin, allow examination of how these different factors affect the delivered photoprotection. We compared the results of our modelling with experimental determination of the binding of an oil-in-water moisturizing day cream with a rated SPF of 15 at various times over the course of a day by means of UV photography and digital image analysis. RESULTS: We demonstrated good agreement between our theoretical predictions of the temporal reduction in product thickness and the experimental observations. We used our modelling approach to show that a substantial reduction in lifetime UV burden on the face could be achieved by a daycare product delivering 3-fold (or greater) protection over the face. CONCLUSION: Comparison with experimental data confirmed the robustness and validity of our model, which predicts that products intended for daily use need to be formulated carefully and applied uniformly, and to have a half-life of binding to the skin of several hours. Products that bind less well to the skin, or are applied non-uniformly, are likely to be providing inadequate protection with regards to influencing the rate of photoaging of the skin. Our data suggest that after a single, realistic application of a day cream rated SPF15, consumers' faces remain protected to at least an average of 5-fold around the middle of the day, especially pertinent to indoor workers who are likely to be exposed to maximum UV levels as they venture outside during their lunch break. PMID- 29984436 TI - The effect of a dysfunctional upper limb on community-dwelling stroke survivors and their carers: An interpretative phenomenological analysis. AB - OBJECTIVES: The poststroke upper limb continues to pose a myriad of physical and psychological challenges for patients and caregivers. To optimize existing services, this study firstly aimed to explore the experiences of both stroke survivors and caregivers and secondly identify their ongoing needs. METHODS: A qualitative approach was utilized for this study. Six participants (three stroke survivors and three caregivers) were purposively sampled from community stroke groups. Semi structured interviews were utilized to collect experiential data, which were analysed using an interpretative phenomenological approach. RESULTS: Three master themes emerged from data analysis: "Finding a way forwards from a poor start," "The battle with the upper-limb," and "Relationships with self and society." All participants, seemingly affected by disappointing services, expressed negative views of rehabilitation. Misplaced or persistent hope, losses in control, and reduced autonomy may have contributed to poor functional outcomes and perceptions of rehabilitation services. The complex physical and psychological impact of the experience of the dysfunctional upper limb was also associated with ongoing and unmet support needs for stroke survivors and carers. CONCLUSIONS: Healthcare professionals may consider the varying impact of the dysfunctional upper limb during decision-making and treatment planning, particularly during acute rehabilitation. Future research could explore therapists' perceptions and experiences of upper-limb rehabilitation during this period. PMID- 29984437 TI - Ultraflexible Near-Infrared Organic Photodetectors for Conformal Photoplethysmogram Sensors. AB - Flexible organic optoelectronic devices simultaneously targeting mechanical conformability and fast responsivity in the near-infrared (IR) region are a prerequisite to expand the capabilities of practical optical science and engineering for on-skin optoelectronic applications. Here, an ultraflexible near IR responsive skin-conformal photoplethysmogram sensor based on a bulk heterojunction photovoltaic active layer containing regioregular polyindacenodithiophene-pyridyl[2,1,3]thiadiazole-cyclopentadithiophene (PIPCP) is reported. The ultrathin (3 um thick) photodetector exhibits unprecedented operational stability under severe mechanical deformation at a bending radius of less than 3 um, even after more than 103 bending cycles. Deliberate optimization of the physical dimensions of the active layer used in the device enables precise on/off switching and high device yield simultaneously. The response frequency over 1 kHz under mechanically deformed conditions facilitates conformal electronic sensors at the machine/human interface. Finally, a mechanically stretchable, flexible, and skin-conformal photoplethysmogram (PPG) device with higher sensitivity than those of rigid devices is demonstrated, through conformal adherence to the flexuous surface of a fingerprint. PMID- 29984438 TI - Glyco-pseudodendrimers on a Polyester Basis: Synthesis and Investigation of Protein-Pseudodendrimer Interaction. AB - Molar mass and end group number of a hyperbranched polyester are significantly increased by its transformation to a pseudodendrimer. Three generations of pseudodendrimers are obtained from hyperbranched aliphatic polyester core by modification with a protected AB*2 monomer. A sequence of protection and deprotection steps leads to OH-terminated pseudodendrimers. NMR studies confirm maximum degree of branching in the first generation, which slightly decreases in the next two generations. Uniform, dense molecular structure formation was confirmed by MD simulation. Further modification to glyco-pseudodendrimers was performed with alpha-D-mannose leading to high molar masses and dense distribution of sugar units. The interaction of these sugar units with a plant lectin concanavalin A (Con A) was investigated using dynamic light scattering and cryogenic transmission electron microscopy. The protein-interaction studies of the glyco-pseudodendrimers confirm a loose network with Con A. The interaction activity depends on the generation number and modification degree. PMID- 29984439 TI - The beta-adrenergic receptor agonist, terbutaline, reduces UVB-induced mechanical sensitization in humans. AB - OBJECTIVES: Previously, we found in cultures of primary neurons and in animals that sensitized primary neurons can be desensitized by treatment with e.g. beta adrenergic receptor agonists. We now tested whether also in human sensitization such as UVB-radiation induced sunburn-like hyperalgesia can be reduced by intradermal injection of the beta-adrenergic receptor agonist terbutaline. METHODS: In our prospective randomized study, 17 participants received an individual UVB dose to cause a defined local sunburn-like erythema at four locations, two on each forearm. Twenty-four hours later, the sensitized four areas were injected intradermally with terbutaline pH 4.3, terbutaline pH 7.0, saline pH 4.3 or saline pH 7.0, respectively. Pain thresholds were examined before and after induction of UVB-sensitization, and 15, 30 and 60 min after injection of the respective solution. Mechanical pain thresholds of the skin and of deeper tissues were determined by pinprick and pressure algometer measurements, respectively. RESULTS: UVB-irradiation decreased mechanical pain thresholds for pinprick and pressure algometer measurements demonstrating a successful sunburn-like sensitization. Intradermal injection of terbutaline pH 7.0 into the sensitized skin reduced the sensitization for all measured timepoints as determined by pinprick measurements. Pinprick measurements of sensitization were not reduced by injection of terbutaline pH 4.3, saline solution pH 7.0 or saline solution pH 4.3. Also, sensitization of deeper tissue nociceptors were not altered by any of the injections as measured with the pressure algometer. CONCLUSIONS: Similar to our cellular observations, also in humans beta-adrenergic agonists such as terbutaline can reduce the sensitization of primary neurons in the skin. SIGNIFICANCE: We previously showed in model systems that beta-adrenergic stimulation can not only sensitize but also desensitize nociceptors. Our study shows that also in humans beta-adrenergic agonists desensitize if injected into UVB-sensitized skin. This indicates an analgesic activity of adrenergic agonists in addition to their vasoconstrictory function. PMID- 29984440 TI - Type-3 von Willebrand disease in India-Clinical spectrum and molecular profile. AB - INTRODUCTION: Type 3 von Willebrand disease (VWD) is the rare and most severe form of VWD which results from a near-complete deficiency of the von Willebrand factor (VWF). This study evaluates in detail the molecular pathology of type-3 VWD in India. One hundred and two patients from 90 families were evaluated. PATIENTS AND METHODS: Phenotypic data, including bleeding scores (BS), were documented using structured questionnaires. Diagnosis of type 3 VWD was based on undetectable VWF antigen levels in the plasma. Genomic DNA from these patients was screened for mutations in VWF gene. Structural modeling and expression studies were carried out for missense mutations. RESULTS: Out of 102 patients, mutations could be identified in 91% (n = 93). Fifty-five different gene variants were identified. Thirty-four (61.8%) were novel. Mutations could be identified in both the alleles in 90 patients, while no causative mutation could be identified in 9 patients; twenty-four (23.5%) patients had mutations clustered in the propeptide region of VWF. Interestingly, five mutations accounted for the defects in 37/93 (39.8%) patients. Structural analysis and in vitro studies on missense mutations imply impaired processes associated with secretion of VWF. CONCLUSION: This study is one of the largest series to define the molecular basis of type-3 VWD. PMID- 29984441 TI - Divalent Anionic Doping in Perovskite Solar Cells for Enhanced Chemical Stability. AB - The chemical stabilities of hybrid perovskite materials demand further improvement toward long-term and large-scale photovoltaic applications. Herein, the enhanced chemical stability of CH3 NH3 PbI3 is reported by doping the divalent anion Se2- in the form of PbSe in precursor solutions to enhance the hydrogen-bonding-like interactions between the organic cations and the inorganic framework. As a result, in 100% humidity at 40 degrees C, the 10% w/w PbSe-doped CH3 NH3 PbI3 films exhibited >140-fold stability improvement over pristine CH3 NH3 PbI3 films. As the PbSe-doped CH3 NH3 PbI3 films maintained the perovskite structure, a top efficiency of 10.4% with 70% retention after 700 h aging in ambient air is achieved with an unencapsulated 10% w/w PbSe:MAPbI3 -based cell. As a bonus, the incorporated Se2- also effectively suppresses iodine diffusion, leading to enhanced chemical stability of the silver electrodes. PMID- 29984442 TI - Chronic graft-versus-host disease: Current management paradigm and future perspectives. AB - INTRODUCTION: The field of allogeneic hematopoietic cell transplantation (allo HCT) began in the 1950s, and despite a seven decade history of remarkable clinical advances, graft-versus-host-disease (GVHD) remains the greatest obstacle in its success due to considerable morbidity and mortality. Graft-versus-host disease is the second leading cause of transplantation-related mortality (TRM) after relapse of primary disease. There are two main types of GVHD-acute and chronic-differing in the pathogenesis, time of onset, and clinical presentation. OBJECTIVE: This review provides a comprehensive overview of chronic GVHD pathophysiology and current management paradigms, as well as consideration of promising novel therapies. CONCLUSION: Chronic GVHD is a serious disease which may be active for years, or even decades, requiring potentially years of immunosuppressive therapies and placing patients at risk for a number of late complications. While the oral cavity has long been recognized to be a prominent target of GVHD, and in particular, chronic GVHD, it must be recognized and appreciated that it is a complex systemic disease with a wide spectrum of clinical manifestations. PMID- 29984443 TI - Effects of napping on cognitive function modulation in elderly adults with a morning chronotype: A nationwide survey. AB - Circadian rhythms and napping habits have been associated with cognitive function; however, little is known about the interaction effects on cognitive function. The present study examined the moderating effects of napping habits on the relationship between chronotypes and cognitive function decline in elderly adults. This cross-sectional study analysed data from the 2009 Taiwan National Health Interview Survey. A total of 1,724 elderly adults (aged >=65 years) were included. Cognitive function was determined by the Mini-Mental State Examination. Participants' chronotypes were assessed using the midpoint of sleep. Napping habits were assessed by self-report questions. Demographic data, health-related factors and sleep characteristics of the participants were also assessed as potential confounding factors. A hierarchical regression will be used to test the moderating role of napping habits in the relationship between chronotype and cognitive function level after adjustment for potential confounders. A significant interaction effect between chronotype and napping habits was observed with the MMSE score (b = -0.29, SE = 0.14, p = 0.03). Morning-type elderly patients with nap durations >60 min exhibited significantly higher MMSE scores than non-nappers (F = 7.48; p = 0.00). This nationwide survey confirms that in morning-type elderly adults, nap durations >60 min are associated with less cognitive decline; however, napping habits are not associated with cognitive function level in evening-type and intermediate-type elderly adults. PMID- 29984444 TI - Modulatory effect of intravenous immunoglobulin on Th17/Treg cell balance in women with unexplained recurrent spontaneous abortion. AB - Recurrent spontaneous abortion (RSA) is a growing problem worldwide. In a majority of cases, the cause remains unknown but there is increasing evidence that immunologic factors play an important role. Intravenous immunoglobulin (IVIg) therapy has been proposed to have immune modulatory effects and therefore been applicable for the treatment of patients with RSA. Although its efficacy is still controversial, several recent studies suggest that IVIg treatment may improve pregnancy outcomes. CD4+ T cells and their related cytokines play an important role in maternal-fetal immune regulation, and an imbalance of Th17/Treg cell ratio has been proposed as a cause for RSA. We review the scientific evidence supporting a modulatory effect of IVIg on Th17/Treg cell balance and discuss the potential mechanisms how IVIg might enhance Treg cells function. We propose that correction of Th17/Treg cell dysregulation could be one of the mechanisms that can explain the positive therapeutic effects of IVIg therapy. Consequently, selecting patients with abnormal Th17/Treg cell ratios could increase the success of IVIg therapy. PMID- 29984445 TI - Anelastic and Electromechanical Properties of Doped and Reduced Ceria. AB - Room-temperature mechanical properties of thin films and ceramics of doped and undoped ceria are reviewed with an emphasis on the anelastic behavior of the material. Notably, the unrelaxed Young's modulus of Gd-doped ceria ceramics measured by ultrasonic pulse-echo techniques is >200 GPa, while the relaxed biaxial modulus, calculated from the stress/strain ratio of thin films, is ~10 times smaller. Oxygen-deficient ceria exhibits a number of anelastic effects, such as hysteresis of the lattice parameter, strain-dependent Poisson's ratio, room-temperature creep, and nonclassical electrostriction. Methods of measuring these properties are discussed, as well as the applicability of Raman spectroscopy for evaluating strain in thin films of Gd-doped ceria. Special attention is paid to detection of the time dependence of anelastic effects. Both the practical advantages and disadvantages of anelasticity on the design and stability of microscopic devices dependent on ceria thin films are discussed, and methods of mitigating the latter are suggested, with the aim of providing a cautionary note for materials scientists and engineers designing devices containing thin films or bulk ceria, as well as providing data-based constraints for theoreticians who are involved in modeling of the unusual electrical and electromechanical properties of undoped and doped ceria. PMID- 29984446 TI - Inhibition of PI3K/AKT/mTOR pathway for the treatment of endometriosis. PMID- 29984448 TI - A Highly Photostable Near-Infrared Labeling Agent Based on a Phospha-rhodamine for Long-Term and Deep Imaging. AB - Various fluorescence microscopy techniques require bright NIR-emitting fluorophores with high chemical and photostability. Now, the significant performance improvement of phosphorus-substituted rhodamine dyes (PORs) upon substitution at the 9-position with a 2,6-dimethoxyphenyl group is reported. The thus obtained dye PREX 710 was used to stain mitochondria in living cells, which allowed long-term and three-color imaging in the vis-NIR range. Moreover, the high fluorescence longevity of PREX 710 allows tracking a dye-labeled biomolecule by single-molecule microscopy under physiological conditions. Deep imaging of blood vessels in mice brain has also been achieved using the bright NIR-emitting PREX 710-dextran conjugate. PMID- 29984447 TI - Glutathione-S-transferase-theta genotypes and the risk of cyclophosphamide toxicity in dogs. AB - The antineoplastic agent cyclophosphamide (CP) has dose-limiting side effects including sterile haemorrhagic cystitis (SHC), bone marrow (BM) suppression and gastrointestinal (GI) toxicity in dogs. The metabolites acrolein and phosphoramide that mediate these toxicities are glutathione-S-transferase (GST) substrates, and low functioning GST alleles are associated with CP toxicity in humans. The aim of this study was to determine whether variants in 2 canine GST genes, GSTT1 and GSTT5, were over-represented in dogs that developed CP toxicity. Dogs undergoing pulse or metronomic CP chemotherapy were recruited (n = 101) and genotyped for 6 GSTT1 polymorphisms and 1 GSTT5 6-bp deletion that leads to non functional enzyme. Median cumulative CP dosages for dogs with SHC (1350 mg/m2 ) were significantly higher than for dogs with GI/BM toxicity (871 mg/m2 ) or no toxicity (991 mg/m2 ; P = .0012). Dogs with SHC were more likely to have had metronomic (84.2%, 16 of 19 SHC cases) vs pulse (15.8%, 3 of 19 SHC cases) CP dosing (P < .0001). All dogs with BM or GI toxicity (n = 30) had pulse chemotherapy. GSTT1 and GSTT5 variant allele frequencies were not significantly different in CP-treated dogs with SHC or GI/BM toxicity compared to dogs without documented adverse effects. Work is underway to identify which canine GSTs detoxify acrolein and phosphoramide, so that better tools are available to predict the risk of CP toxicity in dogs. PMID- 29984449 TI - Stability-indicating spectrofluorimetric method for the assay of riboflavin and photoproducts: Kinetic applications. AB - A stability-indicating spectrofluorimetric method has been developed for the simultaneous assay of riboflavin (RF) and photoproducts, formylmethylflavin (FMF), lumichrome (LC) and lumiflavin (LF) in aqueous solution. The method is based on the extraction of LC formed in acid solution and LC and LF formed in alkaline solution with chloroform at pH 2.0 and their assay by fluorescence measurements at 478 and 530 nm, respectively. The aqueous phase, on readjustment of the pH to 6.5, is used to extract FMF with chloroform and its assay is carried out at 530 nm. The aqueous phase is then used for the assay of RF at 530 nm. The proposed method gives more accurate results for the assay of RF compared to those of the United States Pharmacopeia (USP) spectrofluorimetric method which does not take into account the presence of RF photoproducts having similar fluorescence characteristics. The proposed method along with the USP method has been applied to the study of the kinetics of photolysis of RF, assay of stored commercial vitamin preparations and their radiated samples. The results show that the USP method does not distinguish between the fluorescence of RF and its photoproducts, and, therefore, gives erroneous results with about 11% excess in the quantity of the vitamin compared to that of the proposed method. This is due to the interference of the fluorescence of photoproducts in the assay of RF. The method has been validated for various analytical parameters according to the guideline of the International Council for Harmonization (ICH). PMID- 29984450 TI - The Nuclear RNA-binding Protein RBSR1 Interactome in Trypanosoma cruzi. AB - Trypanosoma cruzi, the etiological agent of Chagas disease, has been widely studied, reflecting both its medical importance and the particular features that make this pathogen an attractive model for basic biological studies. The repression of transcripts by messenger ribonucleoprotein (mRNP) complexes is an important pathway of post-transcriptional regulation in eukaryotes, including T. cruzi. RBSR1 is a serine-arginine (SR)-rich RNA-binding protein (RBP) in T. cruzi that contains one RNA-recognition motif (RRM); this protein has a primarily nuclear localization and is developmentally regulated, not being detected in metacyclic trypomastigotes. RBSR1 interacts with other RBPs, such as UBP1 and UBP2, and the nuclear SR-protein TRRM1. Phylogenetic analysis indicated that RBSR1 is orthologous to the human splicing factor SRSF7, what might indicate its possible involvement in pre-RNA processing. Accordingly, ribonomics data showed the enrichment of snoRNAs and snRNAs in the RBSR1 immunoprecipiatation complex, hence reinforcing the supposition that this protein might be involved in RNA processing in the nucleus. PMID- 29984451 TI - Metal Organic Framework Derived Materials: Progress and Prospects for the Energy Conversion and Storage. AB - Exploring new materials with high efficiency and durability is the major requirement in the field of sustainable energy conversion and storage systems. Numerous techniques have been developed in last three decades to enhance the efficiency of the catalyst systems, control over the composition, structure, surface area, pore size, and moreover morphology of the particles. In this respect, metal organic framework (MOF) derived catalysts are emerged as the finest materials with tunable properties and activities for the energy conversion and storage. Recently, several nano- or microstructures of metal oxides, chalcogenides, phosphides, nitrides, carbides, alloys, carbon materials, or their hybrids are explored for the electrochemical energy conversion like oxygen evolution, hydrogen evolution, oxygen reduction, or battery materials. Interest on the efficient energy storage system is also growing looking at the practical applications. Though, several reviews are available on the synthesis and application of MOF and MOF derived materials, their applications for the electrochemical energy conversion and storage is totally a new field of research and developed recently. This review focuses on the systematic design of the materials from MOF and control over their inherent properties to enhance the electrochemical performances. PMID- 29984452 TI - Antibody-Bactericidal Macrocyclic Peptide Conjugates To Target Gram-Negative Bacteria. AB - To combat antimicrobial infections, new active molecules are needed. Antimicrobial peptides, ever abundant in nature, are a fertile starting point to develop new antimicrobial agents but suffer from low stability, low specificity, and off-target toxicity. These drawbacks have limited their development. To overcome some of these limitations, we developed antibody-bactericidal macrocyclic peptide conjugates (ABCs), in which the antibody directs the bioactive macrocyclic peptide to the targeted Gram-negative bacteria. We used cysteine SN Ar chemistry to synthesize and systematically study a library of large (>30-mer) macrocyclic antimicrobial peptides (mAMPs) to discover variants with extended proteolytic stability in human serum and low hemolytic activity while maintaining bioactivity. We then conjugated, by using sortase A, these bioactive variants onto an Escherichia coli targeted monoclonal antibody. We found that these ABCs had minimized hemolytic activity and were able to kill E. coli at nanomolar concentrations. Our findings suggest macrocyclic peptides if fused to antibodies may facilitate the discovery of new agents to treat bacterial infections. PMID- 29984453 TI - Biosimilars are coming: ready or not. AB - Biosimilars have had a sizeable impact on the availability and use of biologic medicines in Australia, particularly those prescribed for supportive care in oncology or to treat inflammatory diseases. Biosimilars of oncology drugs that modify disease processes are likely to be the next 'wave' of biosimilars to receive regulatory approval, both internationally and in Australia. Given their more tailored development pathway relative to reference biologics, biosimilar versions of these drugs have the potential to reduce substantially the burden on the healthcare system and increase patient access to treatment. However, there is some uncertainty regarding the regulatory approval pathway and expected clinical characteristics of biosimilars among Australian physicians. This review outlines the concept of biosimilarity and details the regulatory pathway leading to the approval of biosimilars. It also highlights the potential benefits to patients and the healthcare system, as well as opportunities stemming from the use of biosimilars in Australia. The Australian regulatory framework and rationale underlying the extrapolation of indications for a biosimilar to others held by the originator biologic, in the absence of a comparative clinical study, is also described. In addition to the benefits biosimilars may bring, Australia's established cooperative clinical trial group programmes afford an opportunity for further innovation by providing a mechanism to expand the use of certain biosimilars to new disease indications. PMID- 29984455 TI - Managing ethical challenges around misattributed parentage within the clinical context: Insights from an African moral theory. AB - This study argues the thesis that a set of guidelines - firmly rooted in a particular interpretation of African moral theory, specifically, Ubuntu - will do a better job than current medical ethics frameworks, in addressing ethical challenges around misattributed parentage within the clinical context. Incidental information such as information with significant personal/health implications raises unique challenges for medical professionals. For example, withholding information of misattributed paternity accidentally discovered in clinical interactions may be seen by a patient as a violation of his/her right-to-know. Contrarily, disclosure where a patient has not requested information - or where establishing paternity is not the purpose of clinical visit/interaction - may be taken by the patient as a violation of his/her right 'not-to-know'. Resolving these challenges remain a herculean task. African moral theory contains an under emphasized value for addressing such ethical challenges around misattributed parentage in the field of transplant. I seek to contribute this knowledge; and enhance clinician-patient relationship. This study builds off three completed systematic reviews, which aimed to answer the following questions: "what are the ethical challenges regarding information health professionals face within the clinical contest?" and "what core aspects (or common themes) of Ubuntu can be identified in existing literature describing the same?" In this present study, I applied the definition of Ubuntu which captures the core aspects of the theory in ethical literature on the same, to address ethical issues around unsought information of misattributed parentage in the field of transplant. PMID- 29984454 TI - Associations between repeated ultrasound measures of fetal growth and biomarkers of maternal oxidative stress and inflammation in pregnancy. AB - PROBLEM: Perturbations in normal fetal growth during pregnancy are associated with poor child and adult health outcomes. Inflammation and oxidative stress are recognized as important mechanisms in preeclampsia and preterm birth but have been examined less in relation to fetal growth. We hypothesized that maternal inflammation and oxidative stress in pregnancy would be associated with reduced fetal growth and sought to identify windows of vulnerability. METHOD OF STUDY: In a secondary analysis of 482 women from the LIFECODES birth cohort study, we measured inflammation (C-reactive protein [CRP] and the cytokines IL-1beta, IL-6, IL-10, and TNF-alpha) and oxidative stress (8-isoprostane and 8 hydroxydeoxyguanosine [8-OHdG]) biomarkers in plasma and urine, respectively, at four time points during pregnancy. We examined associations between repeated measures of each marker and ultrasound (head and abdominal circumference, femur length, and a summary measure of estimated fetal weight) as well as delivery (birthweight) metrics of growth. RESULTS: In adjusted repeated-measures models, an interquartile range (IQR) increase in CRP was associated with a 0.12 standard deviation decrease in fetal weight z-score (95% confidence interval, CI, -0.21, 0.02), which corresponds to approximately 50 g at 40-week gestation. The association was greatest in magnitude (ie, most negative) with CRP measured later in pregnancy. Oxidative stress markers were not associated with fetal weight, although both were inversely associated with head circumference and femur length. CONCLUSION: Inflammation and oxidative stress markers measured later in pregnancy were associated with reduced fetal growth as measured by repeated ultrasound scans. PMID- 29984456 TI - Integrating cell and molecular biology concepts: Comparing learning gains and self-efficacy in corresponding live and virtual undergraduate laboratory experiences. AB - Multiple pedagogical approaches, such as experimental experiences or computer based activities, have been shown to increase student learning and engagement. We have developed a laboratory module that includes both a traditional "live" experimental component and a student-designed "virtual" computer simulation component. This laboratory employs the mating pathway of Saccharomyces cerevisiae (yeast) to demonstrate four fundamental cell and molecular biology concepts: cell signaling, cytoskeleton, cell cycle, and cell cycle checkpoints. In the live laboratory, students add mating pheromone to cultures, then measure changes in cell division and morphology characteristics of the S. cerevisiae mating response. We also developed a "virtual" complement to this laboratory. Using the principles of Design Thinking and Agile methodology, we collaborated with an undergraduate Computer Science course to generate two computer simulations which can support the live laboratory or provide a virtual laboratory experience. We assessed how both the live and virtual laboratories contributed to learning gains in analytical skills and course content. Students who performed the simulation alone or the simulation plus live lab demonstrated learning gains, with greater gains for the live lab, but students who performed neither lab did not. Attitudinal assessment demonstrated increased student engagement and self efficacy after performing the live and virtual labs. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:361-372, 2018. PMID- 29984457 TI - Patients requiring an acute operation: where are the delays in the process? AB - BACKGROUND: Delays to surgery for patients requiring an acute operation are associated with increased morbidity and mortality. A recent study from our institution observed long waiting times for patients booked for an acute operation. The aim of this study was to evaluate the patient's progress from presentation to arrival in the operating theatre and to identify where delays occurred. METHODS: Patients undergoing acute general surgery between July 2016 and May 2017 were studied. Data were obtained for time of presentation, imaging, theatre and booking. A time interval from presentation to booking for theatre of greater than 6 h was defined as a diagnostic delay. A time interval from booking to theatre greater than the category defined time (four-level priority system) was defined as a logistic delay. RESULTS: A total of 683 patients were included. A diagnostic delay was observed in 55.1%. This occurred more frequently in patients who required imaging prior to their operation (82.5 versus 41.1%, P < 0.001). Logistic delay occurred in 31.0% of the patients, and this was most common for patients booked as a category 3 (requiring surgery within 6 h, 41.8%, P < 0.001). Patients who had a diagnostic delay were significantly more likely to have a post-operative complication compared to patients who did not (17.2 versus 10.0%, P = 0.009). CONCLUSION: There are significant delays associated with patients presenting to the acute general surgery service and their transition to theatre. Addressing both the diagnostic and the logistic delays in our institution should result in a significant improvement in patient care. PMID- 29984458 TI - Safety of ultra-rush protocols for hymenoptera venom immunotherapy in systemic mastocytosis. PMID- 29984459 TI - Moving Droplets in 3D Using Light. AB - The emulation of the complex cellular and bacterial vesicles used to transport materials through fluids has the potential to add revolutionary capabilities to fluidic platforms. Although a number of artificial motile vesicles or microdroplets have been demonstrated previously, control over their movement in liquid in 3D has not been achieved. Here it is shown that by adding a chemical "fuel," a photoactive material, to the droplet, it can be moved in any direction (3D) in water using simple light sources without the need for additives in the water. The droplets can be made up of a range of solvents and move with speeds as high as 10.4 mm s-1 toward or away from the irradiation source as a result of a light-induced isothermal change in interfacial tension (Marangoni flow). It is further demonstrated that more complex functions can be accomplished by merging a photoactive droplet with a droplet carrying a "cargo" and moving the new larger droplet to a "reactor" droplet where the cargo undergoes a chemical reaction. The control and versatility of this light-activated, motile droplet system will open up new possibilities for fluidic chemical transport and applications. PMID- 29984461 TI - Editorial Comment to Yonsei nomogram: A predictive model of new-onset chronic kidney disease after on-clamp partial nephrectomy in patients with T1 renal tumors. PMID- 29984460 TI - Cognitive behaviour therapy for anxious paediatric dental patients: a systematic review. AB - BACKGROUND: There is a paucity of evidence about cognitive behaviour therapy in the management of dentally anxious children. AIM: To systematically review evidence of the effectiveness of cognitive behaviour therapy for children with dental anxiety or dental phobia. DESIGN: Clinical trial registries, grey literature, and electronic databases, including The Cochrane Library, EMBASE, PubMed, Scopus, Web of Science, LILACS/BBO, and PsycINFO, were searched (April 2018). The reference lists of relevant studies were hand-searched. Randomised controlled trials that evaluated the effects of cognitive behaviour therapy on dental anxiety or on acceptance of dental treatment in dental patients up to 18 years were included. Two trained and calibrated reviewers performed the study selection and risk of bias assessment. The quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Six studies with a total of 269 patients, aged 41 months to 18 years, were included. Cognitive behaviour therapy decreased level of anxiety compared to control groups and improved cooperation/behaviour, although the quality of the evidence was low. CONCLUSIONS: Cognitive behaviour therapy produces better anxiety reduction than diverse behavioural management techniques but the evidence was of low quality and further studies in children are needed. PMID- 29984463 TI - Clinical biomarkers for assessing neurodevelopmental outcome of infants born preterm. PMID- 29984465 TI - The Effect of Intramolecular Cross-Linking on Polymer Interactions in Solution. AB - The conformation of a polymer in a solvent is typically defined by the solvent quality, which is a consequence of the solvent and macromolecule's chemistry. Yet, additional factors can affect the polymer conformation, such as non-covalent interactions to surfaces or other macromolecules, affecting the amount of polymer solvent interactions. Herein, chemically folded polymers with protein-like architectures are studied and compared to their unfolded linear precursor in good solvents using rheology measurements. The current research reveals that permanent folding by intramolecular chemical cross-linking limits the chain mobility and therefore causes a reduction in polymer-solvent interactions, making a good solvent become theta. This change not only affects the "solvent quality" but also leads to a change in particle-particle interactions as a function of concentration. These findings provide crucial insight into the effects of intramolecular cross-links on macromolecule solubility and self-assembly, which are critical for mimicking structurally similar biological materials. PMID- 29984464 TI - An interactive plan and model evolution method for knowledge-based pelvic VMAT planning. AB - PURPOSE: To test if a RapidPlan DVH estimation model and its training plans can be improved interactively through a closed-loop evolution process. METHODS AND MATERIALS: Eighty-one manual plans (P0 ) that were used to configure an initial rectal RapidPlan model (M0 ) were reoptimized using M0 (closed-loop), yielding 81 P1 plans. The 75 improved P1 (P1+ ) and the remaining 6 P0 were used to configure model M1 . The 81 training plans were reoptimized again using M1 , producing 23 P2 plans that were superior to both their P0 and P1 forms (P2+ ). Hence, the knowledge base of model M2 composed of 6 P0 , 52 P1+ , and 23 P2+ . Models were tested dosimetrically on 30 VMAT validation cases (Pv ) that were not used for training, yielding Pv (M0 ), Pv (M1 ), and Pv (M2 ) respectively. The 30 Pv were also optimized by M2_new as trained by the library of M2 and 30 Pv (M0 ). RESULTS: Based on comparable target dose coverage, the first closed-loop reoptimization significantly (P < 0.01) reduced the 81 training plans' mean dose to femoral head, urinary bladder, and small bowel by 2.65 Gy/15.63%, 2.06 Gy/8.11%, and 1.47 Gy/6.31% respectively, which were further reduced significantly (P < 0.01) in the second closed-loop reoptimization by 0.04 Gy/0.28%, 0.18 Gy/0.77%, 0.22 Gy/1.01% respectively. However, open-loop VMAT validations displayed more complex and intertwined plan quality changes: mean dose to urinary bladder and small bowel decreased monotonically using M1 (by 0.34 Gy/1.47%, 0.25 Gy/1.13%) and M2 (by 0.36 Gy/1.56%, 0.30 Gy/1.36%) than using M0 . However, mean dose to femoral head increased by 0.81 Gy/6.64% (M1 ) and 0.91 Gy/7.46% (M2 ) than using M0 . The overfitting problem was relieved by applying model M2_new . CONCLUSIONS: The RapidPlan model and its constituent plans can improve each other interactively through a closed-loop evolution process. Incorporating new patients into the original training library can improve the RapidPlan model and the upcoming plans interactively. PMID- 29984466 TI - Generality of associations between biological richness and the rates of metabolic processes across microbial communities. AB - Biological richness is positively associated with the rates of some metabolic processes performed by microbial communities. It remains unclear, however, whether these positive associations are a general feature of the metabolic processes performed by microbial communities or whether they are specific to certain types of metabolic processes. For example, it was hypothesized that the strength of any particular positive association depends on how many different genotypes within a microbial community perform the metabolic process of interest (i.e. the 'rarity hypothesis'). We tested the generality of these positive associations by measuring the taxonomic richness, functional gene richness and rate constants for 71 different metabolic processes across 30 independent microbial communities. We found that both taxonomic and functional gene richness do indeed tend to positively associate with the rates of metabolic processes. In addition, we found that positive associations occur across a wide range of different environmental conditions. Counter to the 'rarity hypothesis', however, we did not detect a relationship between the strengths of the positive associations and the rarity of each metabolic process. Together, our data provide empirical evidence that positive associations with biological richness may indeed be a general feature of the metabolic processes performed by microbial communities. PMID- 29984467 TI - Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study. AB - : Essentials Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers. We studied the association of CKD and venous thromboembolism (VTE) in a case-cohort study. Factor VIII, D-dimer and C-reactive protein appeared to explain the association of CKD and VTE. Statin use was protective against VTE in those with and without CKD. SUMMARY: Background Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown. Objectives To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients. Methods Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non-cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged >=45 years with 4.3 years of follow-up. The hazard ratio (HR) of VTE per 10 mL min-1 1.73 m-2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD. Results The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02-1.25), and VTE risk was attenuated by 23% (95% CI 5-100) by D-dimer, by 100% (95% CI 50-100) by factor VIII, and by 15% (95% CI 2-84) by C-reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32-0.70), but not in those with CKD (HR 1.07, 95% CI 0.51-2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups. Conclusions Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients. PMID- 29984468 TI - Phenotypic and genotypic characterization of temporally related nontyphoidal Salmonella strains isolated from humans and food animals in central Ethiopia. AB - Salmonella is one of the common causes of food-borne bacterial illnesses. The primary sources of human nontyphoidal Salmonella (NTS) infection are food animals. This study characterized temporally and spatially related Salmonella isolated during April 2013 to March 2014 from faeces of diarrhoeic human patients in Addis Ababa (n = 68) and food animals (n = 84) in Addis Ababa and surrounding districts (dairy cattle, n = 30; slaughtered cattle, n = 20; poultry, n = 26; swine n = 8). Isolates were serotyped, page typed and tested for antimicrobial susceptibility using Kirby-Bauer disc diffusion method, and genotyped by pulsed field gel electrophoresis (PFGE). The dominant Salmonella serovars isolated from food animals were S. Saintpaul (38.1%), S. Typhimurium (17.9%) and S. Kentucky (9.5%), whereas in humans, S. Typhimurium (39.7%), S. Virchow (30.9%) and S. Kottbus (10.3%) were frequently isolated. Resistance to streptomycin, sulfisoxazole, tetracycline, ampicillin and cephalothin was higher in animal isolates than human isolates, and mean number of antimicrobials to which isolates were resistant was significantly higher in isolates from cattle and poultry compared to those from humans (p < 0.05). All S. Kentucky isolated from animals and humans were multidrug resistant (MDR) with shared resistance phenotype (AmpCfCipTeSuSNa). Although this study involved small sample size and was not able to show clear epidemiological linkage among isolates from various sources, genotyping by PFGE analysis demonstrated circulation of closely related genotypes of S. Virchow, S. Typhimurium and S. Kentucky among humans and food animals. Detection of related Salmonella isolates from humans and animals, the high MDR status of isolates from animals and close proximity of farms and human residential areas in the absence of appropriate biosecurity present major public health problem. Integrated surveillance of Salmonella serovars in humans and animals and implementation of appropriate hazard analysis and pathogen control strategies along critical points of the food chain from farm to table is recommended. PMID- 29984469 TI - Wild and domestic bird faeces likely source of psittacosis transmission-A case control study in Sweden, 2014-2016. AB - Psittacosis is a zoonotic disease transmitted by birds. In Sweden, where psittacosis is notifiable, an average of eight cases per year were reported between 2002 and 2012. In 2013, an unusual increase in cases in southern Sweden was associated with exposure to wild birds. To further explore specific risk factors connected to wild birds and identify other risk factors for sporadic psittacosis, we conducted a case-control study including all domestically acquired psittacosis cases reported between December 2014 and April 2016 in Sweden. Cases were age-, sex- and geo-matched to controls randomly selected from a population register. Cases and controls completed a questionnaire investigating detailed exposures to wild and domestic birds. We compared cases to controls, calculating adjusted matched odds ratios (amOR) using conditional logistic regression. Thirty-one cases were notified: all cases lived in southern Sweden and 26 were ill during winter season. Two risk factors were independently associated with psittacosis infection: cleaning a wild bird feeder (amOR = 18.95; 95% CI: 2.11-170.03) and owning domestic birds (amOR = 5.55, 95% CI: 1.16-26.61). Our results suggest that exposure to bird faeces, for example when cleaning a wild bird feeder, was the main route of transmission. Following this study, the Public Health Agency of Sweden published recommendations on good practices when cleaning surfaces contaminated with bird faeces and recommended use of bird feeders with a design limiting faeces accumulation. PMID- 29984470 TI - Imaging genetics in neurodevelopmental psychopathology. AB - Neurodevelopmental disorders are defined by highly heritable problems during development and brain growth. Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), and intellectual disability (ID) are frequent neurodevelopmental disorders, with common comorbidity among them. Imaging genetics studies on the role of disease-linked genetic variants on brain structure and function have been performed to unravel the etiology of these disorders. Here, we reviewed imaging genetics literature on these disorders attempting to understand the mechanisms of individual disorders and their clinical overlap. For ADHD and ASD, we selected replicated candidate genes implicated through common genetic variants. For ID, which is mainly caused by rare variants, we included genes for relatively frequent forms of ID occurring comorbid with ADHD or ASD. We reviewed case-control studies and studies of risk variants in healthy individuals. Imaging genetics studies for ADHD were retrieved for SLC6A3/DAT1, DRD2, DRD4, NOS1, and SLC6A4/5HTT. For ASD, studies on CNTNAP2, MET, OXTR, and SLC6A4/5HTT were found. For ID, we reviewed the genes FMR1, TSC1 and TSC2, NF1, and MECP2. Alterations in brain volume, activity, and connectivity were observed. Several findings were consistent across studies, implicating, for example, SLC6A4/5HTT in brain activation and functional connectivity related to emotion regulation. However, many studies had small sample sizes, and hypothesis based, brain region-specific studies were common. Results from available studies confirm that imaging genetics can provide insight into the link between genes, disease-related behavior, and the brain. However, the field is still in its early stages, and conclusions about shared mechanisms cannot yet be drawn. PMID- 29984471 TI - Developmental trajectories of children with Down syndrome by socio-economic status: the case of Latin America. AB - BACKGROUND: Several studies show that socio-economic status (SES) is related to the developmental trajectories of children with typical development (TD). However, few studies have analysed this relationship regarding children with neurodevelopmental disorders such as Down syndrome (DS). In this paper, we analyse the impact of SES in the neurodevelopmental trajectories of children with DS in comparison with children with TD. METHOD: Cognitive, language, motor and socio-emotional development were assessed in 31 children with DS between the ages of 15 and 80 months from high to low SES backgrounds. Data from this group were compared with data from a sample of 72 children with TD randomly selected from the Longitudinal Survey of Early Childhood. We analyse and compare these two groups using the developmental trajectories method RESULTS: The results show delayed onsets for the four abilities measured in children with DS compared with children with TD from high to low SES. In the comparison of the developmental trajectories, we found that the differences between the neurodevelopmental trajectories in DS and TD vary according to SES. High SES show differences only in language development, while low SES show significant differences in cognitive, language and socio-emotional development. CONCLUSIONS: The results indicate that SES is a factor that could impact the developmental trajectories of children with DS. Although the differences between children with DS and with TD are similar at the beginning regardless of SES, the developmental trajectories are slower in children with DS of low SES than in children of high SES. We argue that the differences are related to the complex interaction of several biological and cultural factors associated with SES. Some specific hypotheses about nutrition, health care access, quality of education and parenting practices are presented, but more research in this area is needed to fully understand these results. PMID- 29984472 TI - Diverticulum Meckel's and closed loop bowel obstruction: a rare complication. PMID- 29984473 TI - A prospective "test-and-treat" demonstration project among people who inject drugs in Vietnam. AB - INTRODUCTION: Modelling suggests that early diagnosis and immediate antiretroviral therapy (ART) among key populations would have a substantial impact in reducing HIV transmission and mortality in Vietnam. An implementation research project of "test-and-treat" among people who inject drugs (PWID) was developed to inform effective roll-out of such interventions. METHODS: "Test-and treat" was offered to PWID in two high burden provinces, Thai Nguyen and Thanh Hoa. The interventions comprised the offer of biannual HIV testing and immediate ART, irrespective of CD4 count. PWID were enrolled between April 2014 and July 2015 and followed up for 12 months, and retention, HIV viral load (VL) and risk behaviours were assessed. Retention in care of this prospective cohort was compared with the retention among men enrolled in care in the preceding period (April 2012 to March 2013) at the same clinics when ART was initiated at CD4 cell count <=350 cells/mm3 . RESULTS: In total, 287 HIV positive PWID started immediate ART. The majority (98%) were men; median age was 34; and median (interquartile range) CD4 count was 199 (50 to 402) cells/mm3 . After 12 months, 238 participants (83%) were retained on ART, and 205 achieved viral suppression (<1000 copies/mL) (92% among those in whom VL was measured, 71% overall). Baseline CD4 count <=100 cells/mm3 and history of imprisonment were associated with lower retention and viral suppression, while engagement in methadone maintenance was associated with higher retention. Retention in care was higher in the "test-and-treat" cohort (83%) compared with men enrolled in care in the preceding period (78%), primarily because lost-to-follow-up during pre-ART care was eliminated. No decline in consistent condom use and clean needle use was observed. CONCLUSIONS: Early ART initiation resulted in successful treatment outcomes among PWID, with no observed increase in self-reported risk behaviours, suggesting feasibility and potential effectiveness of "test-and-treat" approach. The results also call for differentiated care for PWID, including promoting early diagnosis and engagement in methadone maintenance therapy while enhancing care for those with advanced HIV disease and history of imprisonment. PMID- 29984474 TI - A proposal for a new PhD level curriculum on quantitative methods for drug development. AB - This paper provides an overview of "Improving Design, Evaluation and Analysis of early drug development Studies" (IDEAS), a European Commission-funded network bringing together leading academic institutions and small- to large-sized pharmaceutical companies to train a cohort of graduate-level medical statisticians. The network is composed of a diverse mix of public and private sector partners spread across Europe, which will host 14 early-stage researchers for 36 months. IDEAS training activities are composed of a well-rounded mixture of specialist methodological components and generic transferable skills. Particular attention is paid to fostering collaborations between researchers and supervisors, which span academia and the private sector. Within this paper, we review existing medical statistics programmes (MSc and PhD) and highlight the training they provide on skills relevant to drug development. Motivated by this review and our experiences with the IDEAS project, we propose a concept for a joint, harmonised European PhD programme to train statisticians in quantitative methods for drug development. PMID- 29984476 TI - Predefine resolution of enantiomers in partial filling capillary electrophoresis and two discontinuous function plugs coupling in-capillary. AB - In common partial filling CE (PF-CE), the capillary contains the selectors plug between the injection and detector end to avoid the selector going into the detector zone. To expand this method, we propose a mode of two discontinuous function plugs coupling in-capillary, named as plug-plug PF-CE (ppPF-CE). Initially, we present the method to predefine the effective length of chiral selector to meet the requirement of enantiomers' resolution, which could avoid some experimental procedures. With alpha-CD as a chiral selector, a satisfactory resolution of enantiomers d,l-tryptophan and d,l-tyrosine was obtained with a partial filling alpha-CD plug of optimal length and concentration. Subsequently, a second plug containing hydroxypropyl methylcellulose, organic solvents (acetonitrile and methanol), anionic and cationic surfactants (SDS and CTAB), and different concentrations of sodium phosphate buffer was inserted after the selector plug. Effects of plug-plug filling on enantiomers' migration and resolution are discussed. The ppPF-CE might be a new flexible mode for CE application. PMID- 29984475 TI - Gestational diabetes mellitus is associated with increased CD163 expression and iron storage in the placenta. AB - PROBLEM: GDM has been associated with disturbances in iron homeostasis and exaggerated immune activation. We sought to investigate the extent to which placental iron storage and macrophage accumulations were altered in GDM. METHOD OF STUDY: We conducted a retrospective, case-control study of archived placental tissues obtained from 22 pregnancies complicated by GDM and 22 unaffected controls. Controls were matched to cases based on maternal age, gestational age at birth, and method of delivery. Placental tissues were assessed for altered histology and CD68 and CD163 staining. Tissue iron was assessed using Prussian blue staining. RESULTS: Maternal hematocrit levels were higher in GDM participants compared to controls (P = 0.02). The presence of meconium-laden macrophages was significantly greater within the amnion of GDM cases (adjusted odds ratio (OR) 12.51). Although the total abundance of CD68-expressing macrophages was not significantly different between groups, we detected a significantly greater abundance of CD163 expression within the chorion and decidua of cases. The total area staining positive for iron was 24% (95% confidence intervals of 2%-46%) greater in GDM placentae versus controls. CONCLUSION: GDM is associated with altered placental histology and increases in meconium-laden macrophages. Greater iron stores within the placentae of women with GDM is consistent with reports that iron excess is associated with an increased risk for GDM. The higher level of expression of CD163 on macrophage like cells of the chorion and decidua in GDM suggests an increase in M2-like macrophages. Overall, our results add to growing evidence that GDM has direct effects on placental structure. PMID- 29984478 TI - Peristomal pyoderma gangrenosum: 12-year experience in a single tertiary referral centre. AB - BACKGROUND: Peristomal pyoderma gangrenosum (PPG) is an unusual but potentially devastating condition that is difficult to diagnose and manage. METHODS: This was a single centre, retrospective review of a prospectively collected database. Included were consecutive patients referred to a stoma therapy clinic at a single institution between 2005 and 2016. Main outcomes of interest were management strategies and outcome of patients with PPG including time to healing and recurrence. RESULTS: Of 1295 consecutive patients who underwent stoma formation, 12 patients with PPG were identified. The mean age at the time of diagnosis of PPG was 43.5 years (range 19-72 years). Five cases (41.7%) were associated with Crohn's disease and five cases (41.7%) with ulcerative colitis. The median duration of days between stoma formation and PPG diagnosis was 101.5 days (mean duration was 670 days (range 14-2641 days)). Nearly all patients (91.7%) were referred to a dermatologist. Majority (66.7%) were managed in an outpatient setting. For those requiring inpatient management, the mean length of stay was 13.5 days (range 3-31 days). Five patients had a biopsy and seven patients were diagnosed with PPG by dermatologist without biopsy. A range of oral and topical steroids, steroid injections, dressings, anti-inflammatories, antibiotics, tacrolimus and analgesia was used in the management of PPG. All patients achieved complete healing of PPG, with only one patient developing a recurrence of PPG. The mean duration of time to achieve complete healing of PPG was 282 days (range 28-1751 days). DISCUSSION: Medical management of PPG was effective with complete healing and low recurrence. The average duration to complete healing of PPG was approximately 9 months. PMID- 29984477 TI - A-kinase anchor protein 4 precursor (pro-AKAP4) in human spermatozoa. AB - BACKGROUND: A-kinase anchor protein 4 (AKAP4) and its precursor pro-AKAP4 are two major proteins in spermatozoa of rodents and mammals. Although researchers have characterized the AKAP4 expression in various species, the protein's expression in humans has not been described in detail. OBJECTIVES: The objective of this study was to characterize human pro-AKAP4 more precisely (notably the definition of its localization and expression levels in human spermatozoa and testes). MATERIALS AND METHODS: pro-AKAP4 protein expression levels were assessed by Western blotting. The pro-AKAP4's localization in spermatozoa and testes was determined using immunofluorescence staining and immunogold electron microscopy. Furthermore, pro-AKAP4 protein expression levels were assessed in a series of 77 human semen samples, and associations with semen parameters were evaluated. RESULTS: Western blotting revealed a 100-kDa band in human sperm protein extracts. The pro-AKAP4 was immunolocalized in the fibrous sheath of the flagellum of ejaculated spermatozoa and in elongated spermatids in human testes. A Western blot analysis of 77 normozoospermic semen samples evidenced striking differences in pro-AKAP4 levels from one to another sample (median [interquartile range] integrated optical density = 305 [49-1038]). No correlations were found for pro-AKAP4 levels on one hand and semen volume, sperm concentration, sperm count, sperm motility, or sperm morphology on the other (p > 0.05 for all). However, pro-AKAP4 levels were positively correlated with motility after density gradient centrifugation of the semen (r = 0.224, p = 0.049). DISCUSSION: AKAP4 protein might be activated as an alternative pathway to rescue sperm motility. In human spermatozoa, pro-AKAP4 might therefore be a 'reservoir' of mature AKAP4. CONCLUSION: This study generated new knowledge about pro-AKAP4 in human semen, which may be of interest in the management of male infertility. PMID- 29984479 TI - Uniform Core-Shell Nanoparticles with Thiolated Hyaluronic Acid Coating to Enhance Oral Delivery of Insulin. AB - Oral delivery of protein drugs is an attractive route of administration due to its convenience for repeated dosing and good patient compliance. However, currently oral protein therapeutics show very low bioavailability mainly due to the existence of hostile gastrointestinal (GI) environments, including mucus layers and intestinal epithelial barriers. Herein, using insulin as a model protein therapeutic, the core-shell nanoparticles with thiolated hyaluronic acid (HA-SH) coating (NPHA-SH ) are produced utilizing a two-step flash nanocomplexation process to enhance oral delivery efficiency of insulin. A positively charged nanoparticle core is first generated by electrostatic complexation between insulin and N-(2-hydroxypropyl)-3-trimethyl ammonium chloride modified chitosan (HTCC), followed by surface coating with HA-SH. The optimized NPHA-SH shows an average size of 100 nm with high encapsulation efficiency (91.1%) and loading capacity (38%). In vitro and ex vivo results confirm that NPHA-SH shows high mucus-penetration ability, improved intestinal retention and transepithelial transport property due to its thiolated surface and the ability of HA-SH coating to dissociate from the nanoparticle surface when across the mucosal layer. Oral administration of NPHA-SH to Type 1 diabetic rats yields high efficacy and an average relative bioavailability of 11.3%. These results demonstrate that the HA-SH coated core-shell nanoparticles are a promising oral delivery vehicle for protein therapeutics. PMID- 29984480 TI - Salivary Gland Stem Cells Age Prematurely in Primary Sjogren's syndrome. AB - OBJECTIVE: A major characteristic of the autoimmune disease primary Sjogren's syndrome (pSS) is salivary gland (SG) hypofunction. Resident salivary gland stem cell (SGSC) inability to maintain homeostasis and saliva production has never been explained, and limits our comprehension of mechanisms underpinning pSS. METHODS: SGSCs were isolated from parotid biopsies of controls and patients classified as pSS or incomplete pSS, according to ACR-EULAR criteria. Self renewal and differentiation assays determined SGSC regenerative potential, RNA was extracted for RNASeq analysis, STELA analysis employed to determine telomere length, and frozen tissue used for immunohistochemical analysis. RESULTS: Here we show that SGSCs isolated from pSS parotid gland biopsies are regeneratively inferior to healthy controls. We demonstrate that SGSCs from pSS biopsies are not only lower in number and less able to differentiate, but are likely to be senescent, as revealed by telomere length analysis, RNASeq and immunostaining. We further report that SGSCs exposed to pSS-associated proinflammatory cytokines are induced to proliferate, express senescence associated genes, and subsequently differentiate into intercalated duct cells. We also localize p16+ senescent cells to the intercalated ducts in pSS SG tissue, suggesting a block in SGSC differentiation into acinar cells. CONCLUSION: This study represents the first characterization of SGSCs in pSS, and also the first linkage between an autoimmune disease and a parenchymal premature ageing phenotype. The knowledge garnered in this study argues that disease modifying anti-rheumatic drugs used to treat pSS are not likely to restore saliva production, but should be supplemented with fresh SGSCs to recover saliva production. This article is protected by copyright. All rights reserved. PMID- 29984481 TI - Primary uterine lymphoma: The Yokohama Cooperative Study Group for Hematology (YACHT) study. AB - AIM: Primary malignant lymphomas arising from the female genital tract are very rare, with an incidence rate of 0.5%. Because of its rarity, its clinical characteristics, prognosis and optimal treatment are still unclear. Here, we retrospectively evaluated female patients with uterine lymphoma. METHODS: Between January 2000 and October 2016, 4362 patients were newly diagnosed with malignant lymphoma by the participating institutions of YACHT. Among these 4362 patients, we retrospectively evaluated 14 adult patients with primary uterine lymphoma. RESULTS: The median follow up time was 41 months. The median age at diagnosis was 68 years. Of 14 patients, 10 (72%) were diagnosed with diffuse large B-cell lymphoma. Seven patients presented with vaginal bleeding and three with abdominal pain. Eleven patients (79%) had advanced stages at diagnosis. Three patients (21%) had ovarian involvement and 2 (14%) had vaginal involvement. Induction chemotherapy regimens were R-CHOP in seven patients (50%), CHOP in three (21%) and other regimens in four (29%). Among 14 patients, 12 patients (86%) achieved a complete response and 2 (14%) experienced disease progression. Three patients (21%) showed relapse. Five patients (36%) died because of malignant lymphoma. The 3-year overall survival rate was 57.9%. Soluble interleukin-2 receptor levels > 5000 U/mL, anemia, a bulky mass and the presence of > 1 extranodal sites, B symptom at diagnosis were associated with a poor prognosis. CONCLUSION: Female genital lymphoma is very rare, and further study of more cases is warranted. PMID- 29984482 TI - Large right atrial myxoma presenting with heart failure. PMID- 29984483 TI - Synthesis of Triply Fused Porphyrin-Nanographene Conjugates. AB - Two unprecedented porphyrin fused nanographene molecules, 1 and 2, have been synthesized by the Scholl reaction from tailor-made precursors based on benzo[m]tetraphene-substituted porphyrins. The chemical structures were validated by a combination of high-resolution matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (HR MALDI-TOF MS), IR and Raman spectroscopy, and scanning tunnelling microscopy (STM). The UV-vis-near infrared absorption spectroscopy of 1 and 2 demonstrated broad and largely red-shifted absorption spectra extending up to 1000 and 1400 nm, respectively, marking the significant extension of the pi-conjugated systems. PMID- 29984484 TI - The Regulating Role of Carbon Nanotubes and Graphene in Lithium-Ion and Lithium Sulfur Batteries. AB - The ever-increasing demands for batteries with high energy densities to power the portable electronics with increased power consumption and to advance vehicle electrification and grid energy storage have propelled lithium battery technology to a position of tremendous importance. Carbon nanotubes (CNTs) and graphene, known with many appealing properties, are investigated intensely for improving the performance of lithium-ion (Li-ion) and lithium-sulfur (Li-S) batteries. However, a general and objective understanding of their actual role in Li-ion and Li-S batteries is lacking. It is recognized that CNTs and graphene are not appropriate active lithium storage materials, but are more like a regulator: they do not electrochemically react with lithium ions and electrons, but serve to regulate the lithium storage behavior of a specific electroactive material and increase the range of applications of a lithium battery. First, metrics for the evaluation of lithium batteries are discussed, based on which the regulating role of CNTs and graphene in Li-ion and Li-S batteries is comprehensively considered from fundamental electrochemical reactions to electrode structure and integral cell design. Finally, perspectives on how CNTs and graphene can further contribute to the development of lithium batteries are presented. PMID- 29984485 TI - Clinical utility of surveillance computed tomography scans in infants with cystic fibrosis. AB - BACKGROUND: In cystic fibrosis (CF), irreversible lung disease arises in early life, and is often asymptomatic and unrecognised. Chest computed tomography (CT) scans have been used to detect asymptomatic lung disease in research; however, the clinical utility of chest CT is unknown. This study aimed to determine the effect of surveillance CT in early life on the clinical management of patients with CF. WORKING HYPOTHESIS: Surveillance CT in early life changes the management of patients with CF. METHODS: A medical record review of patients in the AREST-CF cohort who had chest CT at 1 and 3 years of age was performed. Information extracted included CT scan findings and the effect of CT results on clinical management. RESULTS: The chest CT scans and records of 50 subjects with CF were reviewed. The majority of CT scans (n = 75; 75%) were abnormal. N = 31 (31%) of scans overall led to a direct change in management. The number of CT scans needed to be performed to lead to a treatment change was 3.2. The majority (n = 18, 58%) of changes in management were prompted by the finding of bronchiectasis. CONCLUSION: To the authors knowledge, this is the first study to highlight that early life surveillance CT frequently results in changes in clinical management, and hence may have a role beyond research and in routine care. If this can be shown to contribute to improved outcomes (such as reduced rates of bronchiectasis), then, as radiation doses diminish, chest CT could have an important clinical role. PMID- 29984486 TI - Toward Efficient Polymer Solar Cells Processed by a Solution-Processed Layer-By Layer Approach. AB - The solution-processed layer-by-layer (LBL) method has potential to achieve high performance polymer solar cells (PSCs) due to its advantage of enriching donors near the anode and acceptors near the cathode. However, power conversion efficiencies (PCEs) of the LBL-PSCs are still significantly lower than those of conventional one-step-processed PSCs (OS-PSCs). A method to solve the critical problems in LBL-PSCs is reported here. By employing a specific mixed solvent (o dichlorobenzene [o-DCB]/tetrahydrofuran) to spin-coat the small-molecular acceptor IT-4F onto a layer of the newly designed polymer donor (PBDB-TFS1), appropriate interdiffusion between the PBDB-TFS1 and the IT-4F can critically be controlled, and then an ideal phase separation of the active layer and large donor/acceptor interface area can be realized with a certain amount of o-DCB. The PSCs based on the LBL method exhibit PCEs as high as 13.0%, higher than that of the counterpart (11.8%) made by the conventional OS solution method. This preliminary work reveals that the LBL method is a promising approach to the promotion of the photovoltaic performance of polymer solar cells. PMID- 29984487 TI - Impact of Tumor Necrosis Factor Inhibitor Versus Nonsteroidal Antiinflammatory Drug Treatment on Radiographic Progression in Early Ankylosing Spondylitis: Its Relationship to Inflammation Control During Treatment. AB - OBJECTIVE: To investigate the impact of tumor necrosis factor inhibitor (TNFi) treatment and inflammation control on radiographic progression in early ankylosing spondylitis (AS) over 4 years. METHODS: We included a total of 215 patients with early AS (symptom duration <10 years) treated with TNFi (the TNFi group; n = 135) or with nonsteroidal antiinflammatory drugs (NSAIDs) (the control group; n = 80). Two blinded readers assessed radiographic progression using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Inflammation control was inferred from C-reactive protein (CRP) levels time-averaged between 2 radiologic assessments. Linear mixed modeling was used to estimate mSASSS changes over radiographic intervals as well as the impact of clinical factors on outcomes. RESULTS: The TNFi group had longer disease duration, a higher baseline CRP level, and a higher Bath Ankylosing Spondylitis Disease Activity Index than did controls. The time-averaged CRP level over radiographic intervals was lower with TNFi treatment than with NSAID treatment (mean +/- SD 0.27 +/- 0.30 mg/dl versus 0.61 +/- 0.68 mg/dl; P < 0.001). Overall, mean +/- SD mSASSS change over the 2-year interval was 1.30 +/- 2.97 units. In the multivariable model adjusted for age, smoking status, baseline CRP level, and the presence of syndesmophytes at baseline, the TNFi group showed less mSASSS change over the 2-year interval (beta = -0.90 [95% confidence interval {95% CI} -1.51, -0.29]). However, when a time-averaged CRP level was additionally included, it significantly influenced the mSASSS change (beta = 1.02 [95% CI 0.32, 1.71]), decreasing the estimated group difference (beta = -0.52 [95% CI -1.17, 0.14]). NSAID indices of both groups were not associated with either time-averaged CRP levels or mSASSS changes. CONCLUSION: Effective suppression of inflammation by TNFi treatment decreases radiographic progression in early AS. PMID- 29984488 TI - Bayesian basket trial design with exchangeability monitoring. AB - Precision medicine endeavors to conform therapeutic interventions to the individuals being treated. Implicit to the concept of precision medicine is heterogeneity of treatment benefit among patients and patient subpopulations. Thus, precision medicine challenges conventional paradigms of clinical translational which have relied on estimates of population-averaged effects to guide clinical practice. Basket trials comprise a class of experimental designs used to study solid malignancies that are devised to evaluate the effectiveness of a therapeutic strategy among patients defined by the presence of a particular drug target (often a genetic mutation) rather than a particular tumor histology. Acknowledging the potential for differential effectiveness on the basis of traditional criteria for cancer subtyping, evaluations of treatment effectiveness are conducted with respect to the "baskets" which collectively represent a partition of the targeted patient population consisting of discrete subtypes. Yet, designs of early basket trials have been criticized for their reliance on basketwise analysis strategies that suffered from limited power in the presence of imbalanced enrollment as well as failed to convey to the clinical community evidentiary measures for consistent effectiveness among the studied clinical subtypes. This article presents novel methodology for sequential basket trial design formulated with Bayesian monitoring rules. Interim analyses are based a novel hierarchical modeling strategy for sharing information among a collection of discrete potentially nonexchangeable subtypes. The methodology is demonstrated by analysis as well as permutation and simulation studies based on a recent basket trial designed to estimate the effectiveness of vemurafenib in BRAFV600 mutant non-melanoma among six primary disease sites and histologies. PMID- 29984490 TI - Efficacy, acceptability and safety of Internet-delivered psychological therapies for fibromyalgia syndrome: A systematic review and meta-analysis of randomized controlled trials. AB - : This systematic review aimed at evaluating the efficacy, acceptability and safety of Internet-based psychological therapies (IPTs) in fibromyalgia syndrome (FMS). Clinicaltrials.gov, Cochrane Library, MEDLINE, PsycINFO and SCOPUS were searched from inception to January 2018. Randomized controlled trials (RCTs) comparing IPTs with controls were analysed. Primary outcomes were >=50% pain relief, disability, negative mood, acceptability and safety at end of therapy and at 6-month follow up. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD) with 95% confidence intervals (CI). Six RCTs using different types of Internet-based cognitive behavioural therapies [ICBTs] (acceptance-based; exposure-based; traditional) with 493 patients were included. At the end of treatment, ICBTs were superior to controls (waiting list, attention control, treatment as usual) in reducing negative mood (SMD -0.51 [95% CI -0.87 to -0.15]) (moderate quality evidence) and disability (SMD -0.56 [95% CI -1.00 to -0.13]) (moderate quality evidence). There were no statistically significant differences between ICBTs and controls in pain relief of 50% or greater (RD 0.09 [95% CI -0.02 to 0.20] (moderate quality evidence) and acceptability (moderate quality evidence). No data on safety and any outcomes at long-term follow-up compared to controls were found. The data available did not allow statistical comparisons between unguided and guided ICBTs and of ICBTs versus traditional face-to-face therapies. ICBTs provided a clinically relevant benefit over control interventions in reducing negative mood and disability at the end of treatment. SIGNIFICANCE: Internet-delivered cognitive behavioural therapies provided a clinically relevant benefit in reducing negative mood and disability in patients with FMS at the end of treatment if compared to waiting list, treatment as usual and attention controls. PMID- 29984489 TI - Stepwise modifications of genetic parts reinforce the secretory production of nattokinase in Bacillus subtilis. AB - Nattokinase (NK) is an important serine-protease with direct fibrinolytic activity involving the prevention of cardiovascular disease as an antithrombotic agent. Dozens of studies have focused on the characterization of intrinsic novel promoters and signal peptides to the secretory production of recombinant proteins in Bacillus subtilis. However, intrinsic genetic elements have several drawbacks, which cannot mediate the production of NK to the desired level. In this study, the genetic elements, which were used to overproduce the recombinant secretory NK, were rationally modified in B. subtilis in a stepwise manner. The first step was to select a suitable signal peptide for the highly efficient secretion of NK. By comparison of the secretory levels mediated by two different signal peptides, which were encoded by the genes of a minor extracellular protease epr (SPepr ) and cell-wall associated protease wapA (SPwapA ), respectively, SPwapA was verified as the superior secretory element. Second, P04, which was a synthetic promoter screened from an array of mutants based on the promoter cloned from the operon of a quorum-sensing associated gene srfA (PsrfA ), was paired to SPwapA. The secretory level of NK was obviously augmented by the combination of these two genetic elements. Third, the cis-acting element CodY-binding sequence positioned at the 5'UTR was deleted (yielding P08), and thus the secretory level was significantly elevated. The activity of NK, which was defined as fibrinolytic units (FU), reached to a level of 270 FU ml-1 . Finally, the superior genetic element composed of P08 and SPwapA was utilized to overproduce NK in the host B. subtilis WB800, which was able to produce the secretory NK at 292 FU ml-1 . The strategy established in this study can not only be used to overproduce NK in B. subtilis but also might be a promising pipeline to modify the genetic element for the synthetic secretory system. PMID- 29984491 TI - Glucagon-like peptide-1 receptor antagonism impairs basal exercise capacity and vascular adaptation to aerobic exercise training in rats. AB - Cardiorespiratory fitness (CRF) inversely predicts cardiovascular (CV) mortality and CRF is impaired in people with type 2 diabetes (T2D). Aerobic exercise training (ET) improves CRF and is associated with decreased risk of premature death in healthy and diseased populations. Understanding the mechanisms contributing to ET adaptation may identify targets for reducing CV mortality of relevance to people with T2D. The antihyperglycemic hormone glucagon-like peptide 1 (GLP-1) influences many of the same pathways as exercise and may contribute to CV adaptation to ET. We hypothesized that GLP-1 is necessary for adaptation to ET. Twelve-week-old male Wistar rats were randomized (n = 8-12/group) to receive PBS or GLP-1 receptor antagonist (exendin 9-39 (Ex(9-39)) via osmotic pump for 4 weeks +/- ET. CRF was greater with ET (P < 0.01). Ex(9-39) treatment blunted CRF in both sedentary and ET rats (P < 0.001). Ex(9-39) attenuated acetylcholine mediated vasodilation, while this response was maintained with Ex(9-39)+ET (P = 0.04). Aortic stiffness was greater with Ex(9-39) (P = 0.057) and was made worse when Ex(9-39) was combined with ET (P = 0.004). Ex vivo aortic vasoconstriction with potassium and phenylephrine was lower with Ex(9-39) (P < 0.0001). Carotid strain improved with PBS + ET but did not change in the Ex(9-39) rats with ET (P < 0.0001). Left ventricular mitochondrial respiration was elevated with Ex(9-39) (P < 0.02). GLP-1 receptor antagonism impairs CRF with and without ET, attenuates the vascular adaptation to ET, and elevates cardiac mitochondrial respiration. These data suggest that GLP-1 is integral to the adaptive vascular response to ET. PMID- 29984493 TI - Age-dependent determinants of antipsychotic use among newly admitted residents of skilled nursing facilities: A population-based study. AB - OBJECTIVES: To assess factors related to antipsychotic (AP) use in skilled nursing facilities for newly admitted residents aged 18 to 49, 50 to 64, 65 to 84, and 85 years or older. METHODS: Retrospective, population-level, Minimum Data Set (MDS) 2.0 data from the United States during the year of 2009 were used. Over 1 million residents were included. Fourteen clinically relevant variables were identified through a literature search. Antipsychotic use was defined as APs dispensed daily for the prior 7 days. Logistic regression was used to identify clinically relevant variables, which were then ranked based on magnitude of their association with APs. RESULTS: Bipolar disorder and schizophrenia were consistently related to AP use across age groups. For older age groups, off-label indications such as cognitive impairment, dementia, behavioral symptoms, and physical restraint use were more closely related to AP use, while delusions and hallucinations decreased in strength. Higher proportions of APs were found in all diseases and symptoms in nonelderly adults, with the exception of physical restraint use. Concurrent physical restraint and AP use was highest for older adults aged 65 to 84 at 36%. CONCLUSIONS: Correlates of AP use varied by age, with stronger associations between on-label conditions and AP use among younger adults and off-label conditions among older adults. Several less conventional determinants, namely, Parkinson disease, traumatic brain injury, and the use of physical restraints were identified to increase the likelihood of AP use. This study highlights the importance of monitoring for adverse effects for residents of all ages. PMID- 29984492 TI - Increased jejunal permeability in human obesity is revealed by a lipid challenge and is linked to inflammation and type 2 diabetes. AB - Obesity and its metabolic complications are characterized by subclinical systemic and tissue inflammation. In rodent models of obesity, inflammation and metabolic impairments are linked with intestinal barrier damage. However, whether intestinal permeability is altered in human obesity remains to be investigated. In a cohort of 122 severely obese and non-obese patients, we analyzed intestinal barrier function combining in vivo and ex vivo investigations. We found tight junction impairments in the jejunal epithelium of obese patients, evidenced by a reduction of occludin and tricellulin. Serum levels of zonulin and LPS binding protein, two markers usually associated with intestinal barrier alterations, were also increased in obese patients. Intestinal permeability per se was assessed in vivo by quantification of urinary lactitol/mannitol (L/M) and measured directly ex vivo on jejunal samples in Ussing chambers. In the fasting condition, L/M ratio and jejunal permeability were not significantly different between obese and non-obese patients, but high jejunal permeability to small molecules (0.4 kDa) was associated with systemic inflammation within the obese cohort. Altogether, these results suggest that intestinal barrier function is subtly compromised in obese patients. We thus tested whether this barrier impairment could be exacerbated by dietary lipids. To this end, we challenged jejunal samples with lipid micelles and showed that a single exposure increased permeability to macromolecules (4 kDa). Jejunal permeability after the lipid load was two-fold higher in obese patients compared to non-obese controls and correlated with systemic and intestinal inflammation. Moreover, lipid-induced permeability was an explicative variable of type 2 diabetes. In conclusion, intestinal barrier defects are present in human severe obesity and exacerbated by a lipid challenge. This paves the way to the development of novel therapeutic approaches to modulate intestinal barrier function or personalize nutrition therapy to decrease lipid induced jejunal leakage in metabolic diseases. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29984494 TI - Intracellular signaling similarity reveals neural stem cell-like properties of ependymal cells in the adult rat spinal cord. AB - Proliferation of ependymal cells of the adult spinal cord (SCEp cells) in the intact condition has been considered as a quite rare event. To visualize proliferating/proliferated SCEp cells, we used the intensive 5-bromo-2' deoxyuridine (BrdU) administration method to find that about two cells in the ependymal layer incorporated BrdU in a 10-MUm-thick section. Because these two cells were not considered to undergo further proliferation, we analyzed the positioning and motility of two neighboring BrdU-incorporated proliferated cells and elucidated the tendency of the movement of SCEp cells to the outer side inside the ependymal layer. Even if it was rare, one of the proliferated cells in the ependymal layer differentiated into astrocytes. Gene introduction of Notch intracellular domain (NICD), a constitutively active form of Notch1, into SCEp cells demonstrated both increase in proliferation and induction of differentiation into astrocytes. Overexpression of Sox2 promoted proliferation in SCEp cells. The reaction of gene introduction of NICD and Sox2 indicates the similarity of intracellular signaling between SCEp cells and neural stem cells. Also, considering the fact that SCEp cells express these two factors in the intact condition, Notch and Sox2 are important for the cell fate control of SCEp cells in the intact condition. PMID- 29984495 TI - Systematic review with meta-analysis: anxiety and depression in children and adolescents with inflammatory bowel disease. AB - BACKGROUND: The co-existence of psychological problems and paediatric inflammatory bowel disease (IBD) is receiving increasing attention. Most studies investigated anxiety and depression, with prevalence rates varying from 0% to 50%. A systematic review is necessary to provide clear insight into the prevalence of anxiety and depression in paediatric IBD. AIM: To systematically evaluate available data on the prevalence of anxiety and depressive symptoms and disorders in paediatric IBD (aged 6-18 years). METHODS: Comprehensive searches were performed in Embase, Medline Ovid, Web of Science, Cochrane, PubMed, PsychInfo Ovid, and Google scholar for studies published from 1994 to 2017. Pooled prevalence rates were calculated using inverse variance heterogeneity models. Meta-regression was used to study if disease type, disease activity and gender influence prevalence. RESULTS: Twenty-eight studies (N = 8107, mean age: 14.3) were identified. Pooled prevalence estimates were 16.4% (95% confidence interval [CI] 6.8%-27.3%) for anxiety symptoms and 4.2% (95% CI 3.6%-4.8%) for anxiety disorders. Pooled prevalence estimates were 15.0% (95% CI 6.4%-24.8%) for depressive symptoms and 3.4% (95% CI 0%-9.3%) for depressive disorders. Meta regression showed no influence of disease type or gender on these prevalence rates, but studies with a higher percentage of active disease had a higher rate of depressive symptoms. CONCLUSIONS: The described pooled prevalence of anxiety and depressive symptoms is lower than in adult IBD. However, due to varying instruments/cut-offs for measuring symptoms and few studies investigating disorders, the results should be interpreted with caution. Cross-cultural use of the same instruments is needed to gain better insight into prevalence rates. PMID- 29984496 TI - Musculotendon excursion potential, tendon slack and muscle fibre length: the interaction of the canine gastrocnemius muscle and tendon. AB - Although the form-function relation of muscles and tendons has been studied extensively, little in vivo data exist on the musculotendon properties of the gastrocnemius complex in dogs. Using a combination of ultrasound and 3D motion tracking, musculotendon parameters were obtained in vivo from the lateral gastrocnemius muscle and the gastrocnemius tendon in nine healthy Labrador Retrievers. These parameters include musculotendon length and excursion potential, tendon slack length, muscle belly length, muscle fibre length, pennation angle and architectural index. This study also examined the variation of muscle and tendon length contributions to musculotendon length, as well as the relation between musculotendon excursion potential and muscle fibre length or tendon length. To facilitate comparison between dog breeds, the femur length as a potential scaling parameter was examined. In the Labrador gastrocnemius musculotendon complex, the tendon contributes 41% (+/- 9%) of musculotendon length. In longer musculotendon complexes, the contribution of the muscle belly increases while the tendon contribution decreases. Longer muscle belly and musculotendon complexes were, however, associated with shorter muscle fibres. No significant relations were found between musculotendon excursion potential and muscle fibre length or tendon slack length, and femur length did not prove to be a reliable scale factor for the length-related musculotendon parameters examined in this study. Longer musculotendon complexes exhibit relatively longer muscle bellies, which are in turn associated with shorter muscle fibre lengths. This trade-off between gastrocnemius muscle belly length and muscle fibre length might have the advantage that muscle volume stays constant regardless of the length of the limbs. PMID- 29984497 TI - Prescribed sedative and other psychotropic medication use among clients attending alcohol and other drug treatment. AB - INTRODUCTION AND AIMS: Prescribed psychotropic medications contribute to overdose mortality among people with alcohol and other drug (AOD) disorders. We report on prescribed psychotropic medication use among AOD treatment service attendees, focusing on sedative drugs. DESIGN AND METHODS: Prospective multi-site naturalistic outcome study in residential and outpatient AOD treatment facilities in Victoria and Western Australia. A convenience sample of 480 people (57% male; mean age 36.1) entering treatment were surveyed, of whom 313 (65%) were followed up by telephone interview after a median of 377 days. Participants' prescribed psychotropic medication use was ascertained by self-report at baseline and follow up. RESULTS: At baseline, 41% of participants reported prescribed sedative medication (benzodiazepine, zopiclone or zolpidem) use within the past month, including prescriptions to treat withdrawal symptoms. At follow-up, the cohort reported a reduced rate of past month prescribed sedative use (23%; P < 0.001) and this rate did not significantly differ between those who continued to use their primary drug of concern and those who were abstinent at follow-up (P = 0.08). Among those with opioids as their primary drug of concern, one-third were still being prescribed a sedative at follow-up (P > 0.99 for change from baseline). At baseline, 40% of participants were prescribed an antidepressant and 13% an antipsychotic medication, which remained similar at follow-up (45% and 13%, respectively). DISCUSSION AND CONCLUSIONS: The high level of prescribed sedative drug use reported by people receiving AOD treatment is a serious public health concern given the increasing incidence of drug overdose deaths in Australia. PMID- 29984498 TI - Taste sensitivity in anorexia nervosa: A systematic review. AB - OBJECTIVE: There is evidence for altered processing of taste in anorexia nervosa, particularly in the areas of reward processing and hedonic sensitivity. However, research on whether people with anorexia nervosa identify taste stimuli accurately, known as taste sensitivity, has yielded mixed findings. The objective of this study was to synthesize the literature on taste sensitivity in this disorder to provide a basis for future discussion on whether altered taste sensitivity may be also implicated in wider atypical taste processing in anorexia. METHOD: Electronic databases were searched systematically to identify published research examining taste sensitivity in anorexia. Search terms were "anorexia nervosa", or "eating disorder", combined with "taste". 18 studies met inclusion criteria. RESULTS: The review of the findings suggest that individuals with AN may experience reduced taste sensitivity that may improve following recovery. However, there was a significant variability in results across studies, potentially reflecting methodological problems including low sample sizes, experimental designs, and uncontrolled confounding variables. DISCUSSION: This review suggests that altered taste sensitivity could represent a component in the wider altered taste processing observed in anorexia nervosa. However, the heterogeneity of findings highlight the need for future research to consider methodological issues raised by this review. PMID- 29984499 TI - Regression of a metastatic lung mass after receiving whole brain irradiation: Can the abscopal effect cross the blood-brain barrier? AB - An abscopal effect refers to distant tumor regression after localized irradiation. The mechanism is thought to be via local radiotherapy triggering the immune system which then attacks distant tumor sites. Only several cases of solid tumors with an abscopal effect have been reported in the past few decades, and whether an abscopal effect can cross the blood-brain barrier is still unknown. Herein, we present a female patient who was admitted due to unsteady gait and dyspnea. Chest X-ray (CXR) and chest CT showed a huge lung mass with left lung collapse and multiple liver masses. Brain MRI also showed multiple brain metastases. A bronchoscopic biopsy proved metastatic adenocarcinoma from colorectal cancer based on immunohistochemical staining. She therefore received 30 Gy (10 fractions) for the brain metastases; however, she refused to receive any systemic therapy for her lung mass and asked for hospice care. She was therefore transferred to a nursing home and was lost to follow-up. She returned 2 months later due to right pneumonia with fever and productive cough. Surprisingly, her left lung mass had markedly regressed even though she had not received any additional systemic anticancer therapy. This may be the first case of an abscopal effect after receiving whole brain irradiation for brain metastases. PMID- 29984500 TI - Modeling suicide. PMID- 29984502 TI - Erratum. PMID- 29984501 TI - Good syndrome: immunodeficiency associated with thymoma. PMID- 29984503 TI - Making sense of newer treatment options for type 2 diabetes. AB - Over the past decade, several new medications have been developed to treat type 2 diabetes mellitus. Large-scale outcome trials have been performed with patients at high cardiovascular risk to assess the cardiovascular safety of these agents. These trials are changing the landscape of diabetes therapy with evidence beyond safety to cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and some glucagon-like peptide-1 receptor agonists. This review provides an overview of incretin-based therapies and SGLT-2 inhibitors with a particular focus on the results of published cardiovascular outcome trials, which have also provided unique opportunities to evaluate uncommon but potentially serious adverse events of these newer agents. The cardiovascular benefits of SGLT 2 inhibitors and some glucagon-like peptide-1 receptor agonists suggest that they may be the preferred choice, usually as an add-on to metformin, for patients with type 2 diabetes mellitus at high cardiovascular risk. PMID- 29984505 TI - Low accuracy and confidence in chest radiograph interpretation amongst junior doctors and medical students. AB - Accurate chest X-ray (CXR) interpretation is an essential skill in clinical practice. Previous studies have shown poor accuracy and confidence rates (CR) of CXR interpretation by junior doctors and medical students. We presented 10 chest radiographs via an online questionnaire to Australian medical students and junior doctors, who were asked to identify the radiographic abnormality from a list of 15 options and to rate their confidence for each answer. Of 67 complete responses, junior doctors achieved a mean score of 57.6% and medical students 56.1%, with CR of 67 versus 58% respectively. There was a significant positive relationship between accuracy and CR among junior doctors (Pearson's coefficient + 0.798, P = 0.006) and students (Pearson's coefficient + 0.716, P = 0.020). This study identified similarities in strength and weakness in CXR interpretation between medical students and junior doctors. There was a positive association between test scores and self-rated confidence scores. PMID- 29984504 TI - What makes a good doctor? AB - What makes a good doctor probably depends on whom you ask. Patients value interpersonal relations, and being involved in decisions about their care. In contrast, hospital executives place an emphasis on the ability to meet key performance indicators critical to the flow of patients through hospitals. PMID- 29984506 TI - An unusual presentation: breast metastases imitating a gastric primary - first Australian case reported. PMID- 29984507 TI - Perspectives of cancer treatment providers regarding voluntary assisted dying in Victoria. AB - A survey of cancer treatment providers at our institution exploring their perspectives regarding voluntary assisted dying in Victoria and the imminent legislation showed that while almost all were aware of the Bill (92%), reported knowledge and understanding of it was much less (38%). As many clinicians supported the Bill as opposed it (28%); 44% were uncertain of their stance. Most were unwilling to directly provide voluntary assisted dying; if they did, would refer to palliative care services for ongoing support. PMID- 29984508 TI - Waldenstrom macroglobulinaemia manifesting as acquired von Willebrand syndrome. PMID- 29984509 TI - Medical moulages of farm accidents. AB - Although popular for displaying dermatologic conditions before the advent of photography, the medical moulage has also illustrated injuries and accidents. Explored here are three farm accidents and the moulages based on them that occurred in rural Minnesota in the early 20th century. Besides being an object of historical interest, the medical moulage also provides a valuable learning and training opportunity, and can even be thought of as the predecessor of three dimensional printing. PMID- 29984510 TI - Travellers visiting friends and relatives: a high-risk, under-recognised group for imported infectious diseases. PMID- 29984511 TI - Gonococcal aortitis in a patient with fever of unknown origin. PMID- 29984512 TI - Fatal Strongyloides hyperinfection syndrome in an immunocompetent adult with review of the literature. AB - Strongyloides hyperinfection syndrome is rarely described in immunocompetent individuals. We present a case of fatal Strongyloides hyperinfection syndrome, and a literature review identifying nine other cases occurring in immunocompetent individuals, highlighting the challenges of diagnosis and treatment in this setting. While overall mortality is lower compared to immunocompromised patients, fatal outcomes still occur. A high index of suspicion is required for early diagnosis and treatment. PMID- 29984513 TI - Medical Oncology Group of Australia position statement and membership survey on voluntary assisted dying. AB - The controversial topic of voluntary assisted dying (VAD) is receiving significant attention at state government levels and in the community. Acknowledging potential legalisation of VAD, the Medical Oncology Group of Australia (MOGA) undertook a survey of members to inform the development of a position statement on the subject. All MOGA members were invited to complete an anonymous online survey. The survey comprised 12 closed-response categorical questions. Descriptive statistics were used to summarise the survey data. Majority views expressed in the survey would form the basis of a MOGA position statement on VAD. A total of 362 members completed the questionnaire, representing 55% of the membership; 47% of respondents disagreed with VAD; 36% agreed with VAD and the remaining members (17%) were 'neutral'. A clear majority position was not established. Only 14% agreed that physicians involved in VAD should be required personally to administer the lethal medication; 94% supported conscientious objection of physicians to the VAD process; 95% agreed that a palliative care physician consultation should be required and 86% agreed with the need for the involvement of specialist psychiatry medical services before a patient can be deemed as suitable for VAD. The MOGA membership expressed a range of views on the topic of VAD. A clear majority-held view to support a MOGA position that either supports or opposes VAD was not established. The position statement that flows from the survey encourages informed debate on this topic and brings into focus important considerations. PMID- 29984514 TI - Flucloxacillin-warfarin interaction: an under-appreciated phenomenon. AB - Current drug databases do not acknowledge an interaction between warfarin and flucloxacillin although case reports have indicated that flucloxacillin may increase warfarin requirement to maintain therapeutic international normalised ratio (INR). To assess whether flucloxacillin therapy leads to a significant increase in warfarin dose, we conducted a retrospective, observational, cohort study of hospital-in-the-home patients previously stable on warfarin; who were treated with flucloxacillin or other antibiotics for at least 2 weeks between June 2015 and December 2016. The outcome measured was change in average warfarin dose at two time periods: 1 week prior to antibiotic treatment and the final week of antibiotic treatment. Four cases with flucloxacillin and four comparators treated with other antibiotics met inclusion criteria. All cases treated with flucloxacillin had a clinically and statistically significant increase in warfarin dose in the final week of antibiotic treatment compared with pre antibiotics. The warfarin dose increased by a range of 57-130% (P < 0.05). There was no significant change in warfarin dose for patients on vancomycin, benzylpenicillin or piperacillin-tazobactam. One comparator on cephazolin had a statistically significant change in warfarin dose; however, they had a sub therapeutic INR on admission which warranted a dose increase. Due to the high risk of sequelae with sub-therapeutic anticoagulation, close INR monitoring is essential for patients on a prolonged course of flucloxacillin. PMID- 29984515 TI - Metastatic sigmoid colon adenocarcinoma and tumour-related sarcoid reaction. AB - The association between malignancy and tumour-related sarcoid reaction is well documented, characterised by non-caseating granulomatous disease in haematological and solid malignancies. Its occurrence in colon cancer is rare and of unclear clinical significance. Herein, we present a case report of a 32-year old woman diagnosed with concurrent metastatic sigmoid colon adenocarcinoma and pulmonary granulomatous disease suggestive of a tumour-related sarcoid reaction. PMID- 29984516 TI - Resolution of sinus bradycardia, high-grade heart block, and left ventricular systolic dysfunction with rituximab therapy in Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is a rare, typically self-limited, multi-organ vasculitis. Cardiac involvement with HSP carries high morbidity and mortality, thus requiring early aggressive immunosuppressive therapy. We report a case of HSP complicated with acute systolic left ventricular (LV) dysfunction, symptomatic sinus bradycardia and high-grade atrio-ventricular (AV) heart block. Cyclophosphamide, a commonly used agent in HSP, was contraindicated due to the patient's presentation with acute renal failure. Treatment with monoclonal antibody rituximab and corticosteroids was initiated with an improvement in and resolution of LV systolic dysfunction, sinus bradycardia and AV block. We believe this is the first published report on rituximab treatment in HSP with cardiac involvement manifesting with severe LV systolic dysfunction, sinus bradycardia and high-grade AV block. PMID- 29984517 TI - Multifunctional cholinesterase inhibitors for Alzheimer's disease: Synthesis, biological evaluations, and docking studies of o/p-propoxyphenylsubstituted-1H benzimidazole derivatives. AB - This study indicates the synthesis, cholinesterase (ChE) inhibitory activity, and molecular modeling studies of 48 compounds as o- and p-(3 substitutedethoxyphenyl)-1H-benzimidazole derivatives. According to the ChE inhibitor activity results, generally, para series are more active against acetylcholinesterase (AChE) whereas ortho series are more active against butyrylcholinesterase (BuChE). The most active compounds against AChE and BuChE are compounds A12 and B14 with IC50 values of 0.14 and 0.22 MUM, respectively. Additionally, the most active 16 compounds against AChE/BuChE were chosen to investigate the neuroprotective effects, and the results indicated that most of the compounds have free radical scavenging properties and show their effects by reducing free radical production; moreover, some of the compounds significantly increased the viability of SH-SY5Y cells exposed to H2 O2 . Overall, compounds A12 and B14 with potential AChE and BuChE inhibitory activities, high neuroprotection against H2 O2 -induced toxicity, free radical scavenging properties, and metal chelating abilities may be considered as lead molecules for the development of multi-target-directed ligands against Alzheimer's disease. PMID- 29984518 TI - MDS PSP criteria in real-life clinical setting: Motor and cognitive characterization of subtypes. PMID- 29984519 TI - Systematic review with meta-analysis: the prevalence of coeliac disease in patients with osteoporosis. AB - BACKGROUND: Earlier studies have produced highly varying risk estimates for the prevalence of coeliac disease (CD) in osteoporosis. AIMS: To investigate the prevalence of CD among individuals with osteoporosis. METHODS: We conducted a systematic review of articles published in PubMed, Medline or EMBASE through May 2017 to identify studies looking at prevalence of CD in patients with osteoporosis. Search terms included "coeliac disease" combined with "fractures", "bone disease", "bone density", "densitometry", "osteoporos*", "osteomal*", "osteodys" or "dexa" or "dxa" or "skelet". Non-English papers with English language abstracts were included. We used fixed-effects inverse variance-weighted models, and tested heterogeneity through subgroup analysis as well as through meta-regression. RESULTS: We identified eight relevant studies, comprising data from 3188 individuals with osteoporosis. Of these, 59 individuals (1.9%) had CD. A weighted pooled analysis demonstrated biopsy-confirmed CD in 1.6% (95% CI = 1.1%-2.0%) of individuals with osteoporosis. The heterogeneity was moderate (I2 = 40.1%), and influenced by the underlying CD prevalence in the general population. After adding four studies (n = 814) with CD defined as positive tissue transglutaminase or endomysial antibodies, the pooled prevalence was comparable (1.6%; 95% CI = 1.2%-2.0%). CONCLUSIONS: About 1 in 62 individuals with osteoporosis, or 1.6%, have biopsy-verified CD. This prevalence is comparable to that in the general population. These findings argue against routinely screening patients with osteoporosis for CD, which is contrary to current guideline recommendations. Additional studies are needed to determine the true utility of such screening programs. PMID- 29984520 TI - Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN. AB - BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naive but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas. PMID- 29984521 TI - Structures and luminescent sensors of mixed-counterions based salen-type lanthanide coordination polymers. AB - Reactions of N,N'-bis (salicylidene)-1,2-cyclohexanediamine (H2 L) with mixed lanthanide counterions of LnCl3 .6H2 O and Ln (NO3 )3 .6H2 O afford six H2 L lanthanide coordination polymers, e.g. {[Pr(H2 L)2 (NO3 )2 Cl].2CH2 Cl2 }n (1); {[Ln(H2 L)1.5 (NO3 )3 ]2 .5CHCl3 .mCH3 OH}n [Ln = Sm (2), Eu (3), Gd (4), Tb (5) and Yb (6); m = 1 (2-5); m = 0 (6)]. X-ray crystallographic analysis reveals that complex 1 exhibits three-dimensional diamondoid topologic structure and complexes 2-6 are of two-dimensional structure. Luminescent spectra show that complexes 1 and 6 have characteristic near-infrared (NIR) emission of praseodymium (III) and ytterbium (III) ions and complexes 2-5 emit luminescence in the visible region. Complexes 3 and 6 reveal sensitive luminescence responses to formaldehyde. PMID- 29984522 TI - Glottic cancer in patients without complaints of hoarseness. PMID- 29984523 TI - Epidemiology of rubella infection and genotyping of rubella virus in Cote d'Ivoire, 2012-2016. AB - Rubella is a contagious disease caused by the rubella virus (RuV) that can lead to serious birth defects when women are infected in early pregnancy. This study aimed to describe the epidemiology and genetic diversity of rubella viruses in Cote d'Ivoire (CIV). Blood or oral fluid samples collected from suspected measles cases were first tested for the presence of measles specific IgM antibodies by enzyme-linked immunosorbent assay (ELISA). All measles IgM negative or indeterminate samples were tested for rubella IgM antibody using ELISA. Rubella IgM-positive samples were tested by real-time reverse transcription polymerase chain reaction (RT-PCR) for the presence of rubella virus RNA. Real-time RT-PCR positive RNA samples were used as template to amplify the 739 nt region used for rubella genotyping. PCR-positive samples were sequenced and phylogenetic analysis performed. Between 2012 and 2016, 4121 serums and 126 oral fluids were collected through the measles surveillance system. Of these, 3823 and 108 respectively were measles IgM negative or indeterminate. Subsequent testing for rubella found that 690 of 3823 (18%) serum samples and 25 of 108 (23%) oral fluid samples were rubella IgM-positive. The 739 nt segment of the E1 glycoprotein gene was amplified and sequenced for two serums and seven oral fluids samples. Phylogenetic analysis showed that the rubella viruses from CIV belonged to genotypes 1G (eight samples) and 2B (one sample). Rubella virus genotype 2B was found in CIV for the first time. These data contribute to baseline information on rubella virus strains found in CIV before the introduction of rubella vaccine. PMID- 29984524 TI - Design and analysis of a 3-arm noninferiority trial with a prespecified margin for the hazard ratio. AB - A 3-arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3-arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log-rank statistical procedures for evaluating data obtained from 3-arm noninferiority trials to assess assay sensitivity with a prespecified margin Delta. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically. PMID- 29984525 TI - DNA Nanotweezers and Graphene Transistor Enable Label-Free Genotyping. AB - Electronic DNA-biosensor with a single nucleotide resolution capability is highly desirable for personalized medicine. However, existing DNA-biosensors, especially single nucleotide polymorphism (SNP) detection systems, have poor sensitivity and specificity and lack real-time wireless data transmission. DNA-tweezers with graphene field effect transistor (FET) are used for SNP detection and data are transmitted wirelessly for analysis. Picomolar sensitivity of quantitative SNP detection is achieved by observing changes in Dirac point shift and resistance change. The use of DNA-tweezers probe with high-quality graphene FET significantly improves analytical characteristics of SNP detection by enhancing the sensitivity more than 1000-fold in comparison to previous work. The electrical signal resulting from resistance changes triggered by DNA strand displacement and related changes in the DNA geometry is recorded and transmitted remotely to personal electronics. Practical implementation of this enabling technology will provide cheaper, faster, and portable point-of-care molecular health status monitoring and diagnostic devices. PMID- 29984526 TI - Single-Crystal-to-Single-Crystal (SCSC) Linear Polymerization of a Desymmetrized Anthraphane. AB - In this work we present one of the rare cases of single-crystal-to-single-crystal (SCSC) linear polymerizations, resulting in a novel ladder-type polymer. The polymerization is based on the photoinduced [4+4]-cycloaddition reactions between trifunctional anthracene-based monomers. The careful design of the monomer anthraphane-tri(OMe), results in perfectly stacked anthracene pairs in the crystal structure, with Schmidt's distances d=3.505-3.666 A and shift s=1.109 A, allowing a selective linear polymerization in quantitative yields and in a matter of minutes, without compromising the integrity of the single crystals. The obtained polyanthraphane-tri(OMe), reveals moreover a very interesting and unprecedented case of stereoisomerism, which is characteristic for polyanthraphanes. PMID- 29984527 TI - High-throughput Docking and Molecular Dynamics Simulations towards the Identification of Novel Peptidomimetic Inhibitors against CDC7. AB - Inhibition protein-protein interactions (PPIs) using small molecules, that interfere with the formation of these complexes, modulates critical regulatory pathways and has therapeutic significance. DBF4-dependent kinase CDC7 is the S phase checkpoint pathway target, which plays an important role for a proper response to DNA damage and replicative stress in multiple organisms. Overexpression of CDC7 and its protein regulator DBF4 is highly neurotoxic and promotes cancer and neurodegeneration. In the present study, virtual screening of inhibitor scaffolds mimicking DBF4 pharmacophoric properties was carried out and evaluation of their potential inhibitory activity toward CDC7 was performed using high-throughput docking and molecular dynamics simulations. The calculations identified five small molecules exhibiting a high affinity to the active site region of the CDC7 protein. PMID- 29984528 TI - Early discharge of patients with acute pancreatitis to enhanced outpatient care. AB - BACKGROUND: Acute pancreatitis (AP) is a common cause for hospital admission, but some patients have a prolonged stay. The aim of this study was to identify patients with mild AP who had a prolonged hospital stay, who potentially could be discharged at day 2 to enhanced outpatient care. METHODS: Data was retrospectively collected on all patients admitted to the Royal Darwin Hospital between May 2016 and February 2017 with a diagnosis of mild AP to identify factors that may safely predict early discharge to enhanced outpatient care. RESULTS: Of 115 admissions, 62% were male, 50% indigenous and alcohol was causative in 53%. A total of 75 (65%) patients stayed more than 2 days and used 342 bed-days. Factors identified in the first 2 days of admission associated with a length of stay more than 2 days (R2 = 0.56, P < 0.0001) included pain score >5 (P = 0.034), temperature >=38 degrees C (P < 0.0001), white blood cell count >18 (P = 0.036), not tolerating oral diet by day 2 (P = 0.002), severe pancreatitis on imaging (P = 0.008) and readmission in the previous 30 days (P = 0.035). Using these criteria, 57% of all admissions and 87% of admissions greater than 2 days could potentially have been transferred to enhanced outpatient care at day 2 for management. This would have saved 277 inpatient bed-days and an estimated $122 771 over the 9-month study period. CONCLUSIONS: A significant proportion of patients admitted with mild AP, who stay longer than 2 days in hospital, could potentially be identified and discharged early to enhanced outpatient care. PMID- 29984529 TI - Vulvar lichen sclerosus: A single-center retrospective study in China. AB - Vulvar lichen sclerosus (VLS) is an uncommon, chronic inflammatory skin disease lacking clinical data of large sample size in China. This study was intended to provide missing data on this condition through investigating the clinical characteristics of Chinese VLS patients. The medical records of 129 VLS patients from our vulvar outpatient clinic were analyzed with SPSS version 18.0 software. The age of onset followed a normal distribution, with the peak at 25-30 years. Of all cases, the incidence rate during the postmenopausal period was 14.0% with an average duration of 9.22 years. The most frequently involved site was the bilateral labia minora (71.3%). Itching was the principal symptom (94.6%); meanwhile, patients with severe itching more commonly experienced longer duration, flaring at night, hyperkeratotic lesions or rashes on the posterior commissure than those with mild to moderate itching (P < 0.05). Furthermore, 60% of the enrolled patients suffered from sexual dysfunction. The major sign was pallor (92.2%), followed by hyperkeratosis (55.0%) and atrophy (40.3%). The patients with atrophy had a significantly longer duration of the disease, and the older patients presented more frequently with edema in the area of lesions (both P < 0.05). Of our patients, 9.3% suffered concomitantly from autoimmune diseases, mostly thyroid with one case being complicated by vulvar squamous cell carcinoma (SCC). In our study, the severity of pruritus was partly related to clinical manifestations. Moreover, Chinese patients could have developed VLS mostly in the reproductive period, with less complications of autoimmune diseases or SCC. PMID- 29984530 TI - Occurrence and characterization of seven major Shiga toxin-producing Escherichia coli serotypes from healthy cattle on cow-calf operations in South Africa. AB - Cattle are a major reservoir of Shiga toxin-producing Escherichia coli. This study investigated the occurrence of seven major STEC serogroups including O157, O145, O103, O121, O111, O45 and O26 among 578 STEC isolates previously recovered from 559 cattle. The isolates were characterized for serotype and major virulence genes. Polymerase chain reaction revealed that 41.7% (241/578) of isolates belonged to STEC O157, O145, O103, O121, O45 and O26, and 33 distinct serotypes. The 241 isolates corresponded to 16.5% (92/559) of cattle that were STEC positive. The prevalence of cattle that tested positive for at least one of the six serogroups across the five farms was variable ranging from 2.9% to 43.4%. Occurrence rates for individual serogroups were as follows: STEC O26 was found in 10.2% (57/559); O45 in 2.9% (16/559); O145 in 2.5% (14/559); O157 in 1.4% (8/559); O121 in 1.1% (6/559); and O103 in 0.4% (2/559). The following proportions of virulence genes were observed: stx1, 69.3% (167/241); stx2, 96.3% (232/241); eaeA, 7.1% (17/241); ehxA, 92.5% (223/241); and both stx1 and stx2, 62.2% (150/241) of isolates. These findings are evidence that cattle in South Africa carry STEC that belong to six major STEC serogroups commonly incriminated in human disease. However, only a subset of serotypes associated with these serogroups were clinically relevant in human disease. Most STEC isolates carried stx1, stx2 and ehxA but lacked eaeA, a major STEC virulence factor in human disease. PMID- 29984531 TI - Factor VIII activity of BAY 94-9027 is accurately measured with most commonly used assays: Results from an international laboratory study. AB - INTRODUCTION: Discrepancies in the measurement of modified factor VIII (FVIII) products have been recognized, highlighting the need for adjustments in clinical laboratory practices to ensure effective monitoring of patients treated with these products, particularly using the one-stage (activated partial thromboplastin time [aPTT]) assay. AIM: To assess the ability of clinical laboratories to measure the activity of BAY 94-9027, a PEGylated extended half life FVIII product, using routine (predominantly one-stage) assays in clinical laboratories METHODS: Blinded samples of FVIII-deficient plasma spiked with defined levels of BAY 94-9027 and a recombinant FVIII product comparator were provided to 52 clinical laboratories that routinely conduct FVIII testing. Samples were provided at 3 concentrations (low, medium and high), and laboratories analysed the samples using routine in-house one-stage and, when available, chromogenic assays. Acceptable spiked recovery (accuracy) of the local laboratory methods to measure BAY 94-9027 was the primary endpoint of the study. RESULTS: Accurate FVIII measurements were obtained at all concentrations for both products using the chromogenic assay and most of the commonly used one-stage reagents, both ellagic acid and silica based. Two specific silica-based reagents, APTT-SP and PTT-A, underestimated BAY 94-9027 levels at all concentrations, consistent with previous findings. CONCLUSIONS: FVIII activity of BAY 94-9027 was accurately measured with most commonly used one-stage assays used in routine clinical practice. The chromogenic assay was also accurate. It is recommended that clinical laboratories identify and avoid specific inappropriate reagents, such as the APTT-SP and PTT-A, in their one-stage assays for FVIII monitoring. PMID- 29984532 TI - A systematic literature review of the effect of anthocyanins on gut microbiota populations. AB - BACKGROUND: Evidence has shown that anthocyanins, a subclass of polyphenol, are metabolised in the gut, modulate bacterial species and exert bioactive effects through this interaction. METHODS: A systematic literature review was undertaken to determine the level of current evidence for the association between anthocyanin intake and changes in gut microbiota populations. The studies included were also assessed for the different techniques used in microbiota determination. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, scientific databases, including Scopus, PubMed, ScienceDirect, Web of Science and MEDLINE, were searched up to June 2017. Details on population/sample, study design, intervention/control, dosage and method of microbiota determination were extracted. RESULTS: Six studies (three in vitro, two animal and one human trials) were included in the review, which showed that anthocyanins induced a significant proliferative effect on Bifidobacterium spp., known for their wide use in probiotics and for the treatment of irritable bowel syndrome. There was also an observed inhibition of Clostridium histolyticum, which was shown to be pathogenic in humans. The depth of analysis is an important consideration for the choice of microbiota determination technique with respect to a comprehensive, high-resolution microbiota analysis or analysis of the main microbiota taxa. CONCLUSIONS: Very limited research has been carried out in the area of anthocyanins and gut microbiota; beneficial effects have generally been observed, and further clinical trials in humans are needed to confirm changes to gut microbes in relation to dietary anthocyanin intake and potential health benefits. PMID- 29984533 TI - Nursing activities for patients with chronic disease in family medicine groups: A multiple-case study. AB - Family Medicine Groups (FMGs) are the most recently developed primary care organizations in Quebec (Canada). Nurses within FMGs play a central role for patients with chronic diseases (CD). However, this complex role and the nursing activities related to this role vary across FMGs. Inadequate knowledge of nursing activities limits the implementation of exemplary nursing practices. This study aimed to describe FMG nursing activities with patients with CD and to describe the facilitators and barriers to these activities. A multiple-case study was performed with ten nurses practicing among patients with CD in FMGs. Five data sources were used to provide an in-depth description of nursing activities and the facilitators and barriers to the development of these activities. After qualitative data analysis, findings show that nursing activities are clustered into five domains: Global assessment of the patient, Care management, Health promotion, Nurse-physician collaboration, and Planning services for patients with CD. Activities vary depending on contextual factors identified in each case. This multiple-case study provides a clear description of nursing activities with patients with CD. There is a need for improved nursing activities and expertise in domains of activities that are less present in FMGs, such as case management and interprofessional collaboration. PMID- 29984534 TI - Improvement of maternal and fetal outcomes in women with sickle cell disease treated with early prophylactic erythrocytapheresis. AB - BACKGROUND: The desire for pregnancy in sickle cell disease (SCD) women has become a true challenge for hematologists, requiring a multidisciplinary approach. Erythrocytapheresis (ECP) is an important therapeutic tool in SCD, but only limited data on starting time and the effects of ECP during pregnancy are available. STUDY DESIGN AND METHODS: This is a double-center retrospective cross sectional study on a total of 46 single pregnancies in SCD women from January 2008 to June 2017. ECP was started at 10.7 +/- 5.2 weeks of gestation, and prophylactic enoxaparin (4,000 U daily) was introduced due to the reported high prevalence of thromboembolic events in pregnant SCD women. RESULTS: The alloimmunization ratio was 2.1 per 1,000 and the alloimmunization rate was 5.6%. In early ECP-treated SCD women, no severe vaso-occlusive crisis, sepsis or severe infection, or preeclampsia or eclampsia were observed. We found normal umbilical arterial impedance during pregnancy, suggesting an optimal uteroplacental function in early ECP-treated SCD women. This was also supported by the improvement in newborn birthweights compared to previous studies. In our cohort, three SCD women were started later on ECP (20-25 weeks), and gestation ended with late fetal loss. Placenta pathology documented SCD-related damage and erythroblasts in placental vessels, indicating fetal hypoxia. CONCLUSIONS: Collectively, our data generate a rationale to support a larger clinical trial of early ECP program in SCD pregnancy. PMID- 29984535 TI - "Lambda-wave" ST-elevation is associated with severe prognosis in stress (takotsubo) cardiomyopathy. AB - BACKGROUND: Persistent ST-segment elevation in acute coronary syndrome is associated with both short and long-term complications. By contrast, there is limited information about ST-elevation and its evolution during takotsubo (stress) cardiomyopathy (TTC). AIM: To evaluate whether persistent downsloping ST elevation in the early stages of TTC might correlate with short and long-term clinical events. METHODS: One-hundred fifty-eight consecutive subjects with TTC were prospectively enrolled and assessed by electrocardiogram. Patients were classified in two groups according to the presence of downsloping ST-elevation >=5 mm lasting at least 24 hr ("lambda-wave" ST-elevation group vs. without downsloping ST-elevation) in at least one/two contiguous leads. RESULTS: Five (3.2%) patients, all female with a mean left ventricular ejection fraction 32 +/- 5%, were included in the lambda-wave ST-elevation group. These patients were characterized by a higher prevalence of physical stressor (100% vs. 49%, p = 0.04) and higher admission and peak levels of troponin-I levels during hospitalization. Peak of ST-elevation in the lambda-wave ST-elevation group was reached 6 hr after admission and gradually decreased after 24 hr. In-hospital complications were observed in all the patients presenting lambda ST-elevation (100% vs. 23%, p = 0.03, OR: 29.1, p = 0.04); one patient presented endoventricular thrombosis and two died of cardiogenic shock. At long-term follow up (mean 443 days), adverse events were observed in 80% of patients with lambda wave ST-elevation (RR of adverse events at follow-up 32, p < 0.01). CONCLUSION: Persistent downsloping lambda-wave ST-elevation during the acute phase of stress cardiomyopathy may be associated with a higher risk of adverse events at short and long-term follow-up. PMID- 29984536 TI - Alkenyl Magnesium Compounds: Generation and Synthetic Application. AB - Alkenyl magnesium compounds have received much attention in synthetic organic chemistry because of their high reactivity. This review summarizes three types of alkenyl magnesium compounds which contain at least one [Mg-C=C] fragment, for example, (1) alkenyl Grignard reagents prepared by halogen-magnesium exchange reaction; (2) alkenyl magnesium carbenoids prepared by halogen-magnesium exchange reaction or sulfoxide-magnesium exchange reaction; (3) magnesacarbocycles containing at least one alkenyl magnesium bond prepared from Zr- or Ti-catalyzed cyclomagnesation or transmetalation, as well as their further reactions and applications. PMID- 29984537 TI - Developing a conversation: A strategy to engage faculty in pedagogical change. AB - Personal interviews were conducted with biochemistry faculty during which they were presented with student performances on a content survey. From these interviews, four themes that reflect faculty responses to the surveys emerged: awareness of student understanding, self-reflection on teaching practice, planned collaboration with colleagues, and emotional reactions. Here, we discuss these themes and their implications for creating conversation designed to promote reflection on biochemistry teaching. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:382-389, 2018. PMID- 29984539 TI - Reply to 'Comment on 'Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized clinical trials' by Tse et al.' PMID- 29984538 TI - Melt-Centrifuged (Bi,Sb)2 Te3 : Engineering Microstructure toward High Thermoelectric Efficiency. AB - Microstructure engineering is an effective strategy to reduce lattice thermal conductivity (kappal ) and enhance the thermoelectric figure of merit (zT). Through a new process based on melt-centrifugation to squeeze out excess eutectic liquid, microstructure modulation is realized to manipulate the formation of dislocations and clean grain boundaries, resulting in a porous network with a platelet structure. In this way, phonon transport is strongly disrupted by a combination of porosity, pore surfaces/junctions, grain boundaries, and lattice dislocations. These collectively result in a ~60% reduction of kappal compared to zone melted ingot, while the charge carriers remain relatively mobile across the liquid-fused grains. This porous material displays a zT value of 1.2, which is higher than fully dense conventional zone melted ingots and hot pressed (Bi,Sb)2 Te3 alloys. A segmented leg of melt-centrifuged Bi0.5 Sb1.5 Te3 and Bi0.3 Sb1.7 Te3 could produce a high device ZT exceeding 1.0 over the whole temperature range of 323-523 K and an efficiency up to 9%. The present work demonstrates a method for synthesizing high-efficiency porous thermoelectric materials through an unconventional melt-centrifugation technique. PMID- 29984540 TI - Hollow Metal Nanocrystals with Ultrathin, Porous Walls and Well-Controlled Surface Structures. AB - Recent developments of a novel class of catalytic materials built on hollow nanocrystals having ultrathin, porous walls, and well-controlled surface structures are discussed, with a focus on platinum and the oxygen reduction reaction (ORR). An introduction is given to the critical role of platinum in the proton exchange membrane fuel cells, and the pressing need to develop a strategy for achieving cost-effective and sustainable use of this precious metal. How to maximize the mass activity of ORR catalysts based on platinum by rationally engineering the surface structure while increasing the utilization efficiency of atoms is then discussed. After reporting on the synthetic methods involving galvanic replacement and seed-mediated growth followed by etching, respectively, a number of examples to demonstrate the enhancement in activity and durability for this new class of catalytic materials are showcased. The feasibility to have the methodology extended from platinum to other precious metals such as gold and ruthenium is highlighted. In conclusion, some of the remaining issues and emerging solutions are examined. PMID- 29984541 TI - Preventing Wernicke's encephalopathy in anorexia nervosa: A systematic review. AB - Anorexia nervosa (AN) is a common eating disorder that affects 2.9 million people worldwide. Not eating a balanced diet or fasting can cause neurological complications after severe vitamin B1 malnourishment, although the precise signs and symptoms of Wernicke's encephalopathy (WE) are not clear. Our aim was to review the signs and symptoms of WE in patients with AN. We searched MEDLINE, EMBASE, Scopus, and PiCarta on all case descriptions of WE following AN. All case descriptions of WE in AN, irrespective of language, were included. Twelve WE cases were reviewed, suggesting that WE following AN is still a relatively rare neuropsychiatric disorder. WE is characterized by a triad of: mental status change, ocular signs, and ataxia. In alcoholism, this triad is present in 16% of cases, but eight out of 12 AN cases presented themselves with a full triad of symptomatology. Importantly, patients often had a more complex triad than has been previously described, involving vertigo, diplopia, and the consequences of refeeding syndrome. The development of a full triad and additional symptomatology suggests a late recognition of signs and symptoms of WE in AN. A complicating factor is the overlap between symptoms of thiamine deficiency and the symptoms of WE. Specifically, patients who show rapid weight loss are vulnerable for the development of WE. Eating disorders, such as AN, can lead to WE. Prophylactic thiamine checks and treatment in patients with AN are relevant, and in case of suspicion of WE, adequate parenteral thiamine supplementation is necessary. PMID- 29984543 TI - l-Rhamnosylation of wall teichoic acids promotes efficient surface association of Listeria monocytogenes virulence factors InlB and Ami through interaction with GW domains. AB - Wall teichoic acids (WTAs) are important surface glycopolymers involved in various physiological processes occurring in the Gram-positive cell envelope. We previously showed that the decoration of Listeria monocytogenes (Lm) WTAs with l rhamnose conferred resistance against antimicrobial peptides. Here, we show that WTA l-rhamnosylation also contributes to physiological levels of autolysis in Lm through a mechanism that requires efficient association of Ami, a virulence promoting autolysin belonging to the GW protein family, to the bacterial cell surface. Importantly, WTA l-rhamnosylation also controls the surface association of another GW protein, the invasin internalin B (InlB), that promotes Lm invasion of host cells. Whereas WTA N-acetylglucosaminylation is not a prerequisite for GW protein surface association, lipoteichoic acids appear to also play a role in the surface anchoring of InlB. Strikingly, while the GW domains of Ami, InlB and Auto (another autolysin contributing to cell invasion and virulence) are sufficient to mediate surface association, this is not the case for the GW domains of the remaining six uncharacterized Lm GW proteins. Overall, we reveal WTA l rhamnosylation as a bacterial surface modification mechanism that contributes to Lm physiology and pathogenesis by controlling the surface association of GW proteins involved in autolysis and infection. PMID- 29984542 TI - Prevalence and risk factors of hepatitis B virus reactivation in patients with solid tumors with resolved HBV infection. AB - BACKGROUND: Reports of hepatitis B virus (HBV) reactivation in solid tumors are very limited, and their frequencies and risk factors were previously unknown. AIM: To evaluate the prevalence and risk factors of HBV reactivation in patients with solid tumors with resolved HBV infection. METHODS: All 1088 patients with solid tumors were assessed for eligibility; 251 patients had resolved HBV infection (negative for HBs antigen and positive for anti-HBc antibody and/or positive for anti-HBs antibody), and HBV-DNA was assessed for 243 of these patients in whom we analyzed the prevalence of HBV reactivation. Risk factors for HBV reactivation were exploratorily evaluated by analysis of a case-control study. RESULTS: The prevalence of HBV-DNA reactivation was 2.1% (95% confidence interval [CI], 0.3-3.9%). We did not observe any exacerbation of HBV-DNA by early intervention. A low anti-HBs antibody titer (<10.0 mIU/mL) and high average daily dexamethasone dose (>1.0 mg/day) were high risk factors, with odds ratios of 5.94 (95% CI, 1.15-30.6, P = 0.03) and 8.69 (95% CI, 1.27-58.8, P = 0.02), respectively. CONCLUSION: HBV reactivation in solid tumor patients was relatively rare. Therefore, risk factors that can identify targets for HBV screening must be determined in future studies. PMID- 29984544 TI - Aerodigestive dysbiosis in children with chronic cough. AB - : In pediatric patients with chronic cough, respiratory culture techniques commonly yield negative results. Studies using culture-independent methods have found a high relative abundance of oral microbes in the lower airways, suggesting that the topographical continuity, and dynamics of the intraluminal contents of the aerodigestive system likely influence the lower airway microbiota. We hypothesize that in subjects with chronic cough, clinical diagnosis will correlate with distinct microbial signatures detected using culture-independent methods. STUDY DESIGN AND METHODS: We enrolled 36 pediatric subjects with chronic cough in a cross-sectional study. Subjects were categorized into four clinical groups: asthma, bacterial bronchitis, neurologically impaired-orally fed, and neurologically impaired enterally fed. Samples from the aerodigestive tract were obtained through bronchoscopy and upper endoscopy. 16S rRNA gene sequencing compared the microbiota from bronchoalveolar lavage (BAL), tracheal, supraglottic, esophageal, gastric, and duodenal samples. RESULTS: We observed that the lower airway microbiota of asthma subjects had higher alpha diversity as compared with the other groups. beta diversity analysis of BAL samples revealed significant differences between the groups. Among the taxonomic differences found, most differentially enriched taxa were upper airway organisms such as Rothia, Gemellaceae (u.g. or uncharacterized genus), and Granulicatella in asthma, Prevotella in bacterial bronchitis, and Veillonella in neurologically impaired orally fed subjects. Greater dissimilarity between the upper airway and lower airway microbiota was associated with increased neutrophilic airway inflammation. CONCLUSIONS: Distinct dysbiotic signatures can be identified in the lower airway microbiota of pediatric subjects with chronic cough that relates to the degree and type of inflammation. PMID- 29984545 TI - Spontaneous haemothorax caused by collateral intra-pectoralis venous circle rupture: an unusual case. PMID- 29984546 TI - Clinical significance of droplet digital PCR quantitative monitoring of KIT gene mutation levels in core binding factor leukemia. PMID- 29984547 TI - Rectal cancer patients younger than 50 years lack a survival benefit from NCCN guideline-directed treatment for stage II and III disease. AB - BACKGROUND: The incidence of rectal cancer in patients younger than 50 years is increasing. To test the hypothesis that the biology in this younger cohort may differ, this study compared survival patterns, stratifying patients according to National Comprehensive Cancer Network (NCCN) guideline-driven care and age. METHODS: The National Cancer Data Base was queried for patients treated with curative-intent transabdominal resections with negative surgical margins for stage I to III rectal cancer between 2004 and 2014. Outcomes and overall survival for patients younger than 50 years and patients 50 years old or older were compared by subgroups based on NCCN guideline-driven care. RESULTS: A total of 43,106 patients were analyzed. Younger patients were more likely to be female and minorities, to be diagnosed at a higher stage, and to have travelled further to be treated at academic/integrated centers. Short- and long-term outcomes were significantly better for patients younger than 50 years, with age-specific survival rates calculated. Younger patients were more likely to receive radiation treatment outside NCCN guidelines for stage I disease. In younger patients, the administration of neoadjuvant chemoradiation for stage II and III disease was not associated with an overall survival benefit. CONCLUSIONS: Age-specific survival data for patients with rectal cancer treated with curative intent do not support an overall survival benefit from NCCN guideline-driven therapy for stage II and III patients younger than 50 years. These data suggest that early-onset disease may differ biologically and in its response to multimodality therapy. PMID- 29984548 TI - Emergency medicine behind the scenes: Clinical support time. PMID- 29984549 TI - Highly Reactive and Tracelessly Cleavable Cysteine-Specific Modification of Proteins via 4-Substituted Cyclopentenone. AB - A rapid and cysteine-specific modification of proteins using 4-substituted cyclopentenone via a Michael addition tandem elimination reaction was developed. Compared to the classical method, this reaction featured fast kinetics with a stable product. More importantly, this conjugation could be tracelessly removed by exchange with a Michael addition donor. The conjugation and regeneration process not only exhibited little change to the structures or conformations of the proteins but also exhibited little disturbance to their biological functions, such as their enzymatic activities. PMID- 29984550 TI - Does the addition of cognitive therapy to exposure and response prevention for obsessive compulsive disorder enhance clinical efficacy? A randomized controlled trial in a community setting. AB - OBJECTIVES: Exposure and response prevention (ERP) remains the most empirically supported psychological treatment for obsessive compulsive disorder (OCD). Clinical guidelines recommend the addition of cognitive approaches to ERP although the presumed additive benefits have not been directly tested. The aim of this was to compare a treatment that integrated cognitive therapy with ERP (ERP + CT) to traditional, manualized ERP to test the additive benefits. DESIGN: A longitudinal, randomized control trial design was used. METHODS: Participants (N = 127) with OCD were randomly assigned to receive individual outpatient ERP or ERP + CT. Obsessive-compulsive symptom severity measures were completed pre- and post-treatment and at 6-month follow-up. RESULTS: While both conditions led to significant symptom and obsessive belief reduction, ERP + CT led to significantly greater symptom and belief reduction as compared to ERP across all main symptom presentations of OCD. Based on a priori definitions of effectiveness, more patients in ERP + CT compared to the ERP group were also deemed treatment responders. CONCLUSIONS: The results of this study suggest that cognitive therapy can be readily integrated with ERP to improve clinical outcomes beyond ERP alone. PRACTITIONER POINTS: Both ERP and ERP + CT were effective, however a course of ERP + CT was significantly more effective at reducing symptoms of OCD than the ERP treatment condition. Significantly more participants who received ERP + CT experienced clinically significant change in OCD symptoms compared to those who received ERP. OCD symptom dimension did not significantly impact response to either ERP or ERP + CT treatments. PMID- 29984551 TI - A framework for clinical commissioning of 3D-printed patient support or immobilization devices in photon radiotherapy. AB - PURPOSE: The objective of this work is to outline a framework for dosimetric characterization that will comprehensively detail the clinical commissioning steps for 3D-printed materials applied as patient support or immobilization devices in photon radiotherapy. The complex nature of 3D-printed materials with application to patient-specific configurations requires careful consideration. The framework presented is generalizable to any 3D-printed object where the infill and shell combinations are unknown. METHODS: A representative cylinder and wedge were used as test objects to characterize devices that may be printed of unknown, patient-specific dimensions. A case study of a 3D-printed CSI immobilization board was presented as an example of an object of known, but adaptable dimensions and proprietary material composition. A series of measurements were performed to characterize the material's kV radiologic properties, MV attenuation measurements and calculations, energy spectrum water equivalency, and surface dose measurements. These measurements complement the recommendations of the AAPM's TG176 to characterize the additional complexity of 3D-printed materials for use in a clinical radiotherapy environment. RESULTS: The dosimetric characterization of 3D-printed test objects and a case study device informed the development of a step-by-step template that can easily be followed by clinicians to accurately and safely utilize 3D-printed materials as patient specific support or immobilization devices. CONCLUSIONS: A series of steps is outlined to provide a formulaic approach to clinically commission 3D-printed materials that may possess varying material composition, infill patterns, and patient-specific dimensions. PMID- 29984552 TI - Insights into microbial community structure and function from a shallow, simulated CO2 -leakage aquifer demonstrate microbial selection and adaptation. AB - Geological carbon storage is likely to be a part of a comprehensive strategy to minimize the atmospheric release of carbon dioxide (CO2 ), raising concerns that injected CO2 will leak into overlying freshwater aquifers. CO2(aq) leakage may impact the dominant microbial community responsible for important ecosystem functions such as nutrient cycling, metal cycling and carbon conversion. Here, we examined the impact of an experimental in situ CO2 -leakage on a freshwater aquifer microbial community. High-throughput 16S rRNA gene sequencing demonstrated lower microbial diversity in freshwater wells with CO2 concentrations above 1.15 g l-1 . Metagenomic sequencing and population genome binning were used to evaluate the metabolic potential of microbial populations across four CO2 exposed samples and one control sample. Population genome binning resulted in the recovery and annotation of three metagenome assembled genomes (MAGs). Two of the MAGs, most closely related to Curvibacter and Sulfuricurvum, had the functional capacity for CO2 utilization via carbon fixation coupled to sulfur and iron oxidation. The third draft genome was an Archaea, most closely related to Methanoregula, characterized by the metabolic potential for methanogenesis. Together, these findings show that CO2 leakage in a freshwater aquifer poses a strong selection, driving both microbial community structure and metabolic function. PMID- 29984553 TI - Beliefs about back pain and pain management behaviours, and their associations in the general population: A systematic review. AB - : Previous mass media campaigns have aimed to influence how people manage back pain, with mixed success. Campaigns should target beliefs which are related to the behaviours they aim to change. This systematic review brings together research that has measured the prevalence of beliefs about back pain in the general population and factors associated with these beliefs, including future pain-related outcomes. Five databases were searched up until April 2017. Quantitative studies which reported a measure of agreement with a belief about back pain, cross-sectional associations, or associations between beliefs and future outcomes were eligible. Eligibility was assessed and data extracted independently by two authors. Results were tabulated and narratively synthesized. Nineteen studies from 10 countries were eligible (median study n [IQR] = 990.5 [524.75-2387.5]). Beliefs were measured using eight questionnaires and 57 stand alone items. Beliefs about back pain's negative consequences were common across countries and populations, whereas most samples did not hold fear-avoidance beliefs. Beliefs about back pain's consequences were associated with pain and disability, but only one study investigated this specific relationship prospectively. No studies investigated whether beliefs are associated with future pain management behaviours. Agreement with certain beliefs (e.g. about negative consequences) was associated with sociodemographic characteristics (e.g. older age) and poorer self-rated health. Interventions may benefit from targeting beliefs about the perceived negative consequences of back pain in these populations. However, future research should explore how beliefs prospectively influence the management of back pain. SIGNIFICANCE: This review brings together studies which have assessed the prevalence of beliefs about back pain, and factors associated with holding them. It highlights that whether or not these beliefs represent important determinants of how people manage pain remains unknown. PMID- 29984554 TI - Protein ORIGAMI: A program for the creation of 3D paper models of folded peptides. AB - Protein ORIGAMI (http://ibg.kit.edu/protein_origami) is a browser-based web application that allows the user to create straightforward 3D paper models of folded peptides for research, teaching and presentations. An amino acid sequence can be turned into alpha-helices, beta-strands and random coils that can be printed out and folded into properly scaled models, with a color code denoting the biophysical characteristics of each amino acid residue (hydrophobicity, charge, etc.). These models provide an intuitive visual and tactile understanding of peptide interactions with other partners, such as helix-helix assembly, oligomerization, membrane binding, or pore formation. Helices can also be displayed as a helical wheel or helical mesh in 2D graphics, to be used in publications or presentations. The highly versatile programme Protein ORIGAMI is also suited to create less conventional helices with arbitrary pitch (e.g., 310 helix, pi-helix, or left-handed helices). Noncanonical amino acids, labels and different terminal modifications can be defined and displayed at will, and different protonation states can be shown. In addition to the web application, the program source code can be downloaded and installed locally on a PC. The printed paper models can be readily used for daily research and discussions, just as for educational purposes and teaching. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:403-409, 2018. PMID- 29984555 TI - Uremia increases QRS duration after beta-adrenergic stimulation in mice. AB - Chronic kidney disease (CKD) and uremia increase the risk of heart disease and sudden cardiac death. Coronary artery disease can only partly account for this. The remaining mechanistic links between CKD and sudden death are elusive, but may involve cardiac arrhythmias. For the present study, we hypothesized that a thorough electrophysiological study in mice with CKD would provide us valuable information that could aid in the identification of additional underlying causes of sudden cardiac death in patients with kidney disease. Partial (5/6) nephrectomy (NX) in mice induced mild CKD: plasma urea in NX was 24 +/- 1 mmol/L (n = 23) versus 12 +/- 1 mmol/L (n = 22) in sham-operated control mice (P < 0.05). Echocardiography did not identify structural or mechanical remodeling in NX mice. Baseline ECG parameters were comparable in conscious NX and control mice; however, the normal 24-h diurnal rhythm in QRS duration was lost in NX mice. Moreover, beta-adrenergic stimulation (isoprenaline, 200 MUg/kg intraperitoneally) prolonged QRS duration in conscious NX mice (from 12 +/- 1 to 15 +/- 2 msec, P < 0.05), but not in sham-operated controls (from 13 +/- 1 to 13 +/- 2 msec, P > 0.05). No spontaneous arrhythmias were observed in conscious NX mice, and intracardiac pacing in anesthetized mice showed a comparable arrhythmia vulnerability in NX and sham-operated mice. Isoprenaline (2 mg/kg intraperitoneally) changed the duration of the QRS complex from 11.2 +/- 0.4 to 11.9 +/- 0.5 (P = 0.06) in NX mice and from 10.7 +/- 0.6 to 10.6 +/- 0.6 (P = 0.50) in sham-operated mice. Ex vivo measurements of cardiac ventricular conduction velocity were comparable in NX and sham mice. Transcriptional activity of Scn5a, Gja1 and several profibrotic genes was similar in NX and sham mice. We conclude that proper kidney function is necessary to maintain diurnal variation in QRS duration and that sympathetic regulation of the QRS duration is altered in kidney disease. PMID- 29984556 TI - Tailoring MoS2 Valley-Polarized Photoluminescence with Super Chiral Near-Field. AB - Transition metal dichalcogenides with intrinsic spin-valley degrees of freedom hold great potentials for applications in spintronic and valleytronic devices. MoS2 monolayer possesses two inequivalent valleys in the Brillouin zone, with each valley coupling selectively with circularly polarized photons. The degree of valley polarization (DVP) is a parameter to characterize the purity of valley polarized photoluminescence (PL) of MoS2 monolayer. Usually, the detected values of DVP in MoS2 monolayer show achiral property under optical excitation of opposite helicities due to reciprocal phonon-assisted intervalley scattering process. Here, it is reported that valley-polarized PL of MoS2 can be tailored through near-field interaction with plasmonic chiral metasurface. The resonant field of the chiral metasurface couples with valley-polarized excitons, and tailors the measured PL spectra in the far-field, resulting in observation of chiral DVP of MoS2 -metasurface under opposite helicities excitations. Valley contrast PL in the chiral heterostructure is also observed when illuminated by linearly polarized light. The manipulation of valley-polarized PL in 2D materials using chiral metasurface represents a viable route toward valley-polaritonic devices. PMID- 29984557 TI - Performance of resin composite restorations in the primary dentition: a retrospective university-based study. AB - BACKGROUND: Limited data is available on variables influencing the survival of composite restorations in primary teeth. AIM: This retrospective university-based study assessed the survival and risk factors associated with failures of resin composite restorations performed in primary teeth. DESIGN: The sample was composed of 961 restorations from records of 337 patients (178 girls and 159 boys) attended in a university dental clinic. The restorations' longevity up to 48 months of follow-up was assessed using the Kaplan-Meier survival test. Multivariate Cox regression analysis with shared frailty was used to evaluate the factors associated with failures (P < 0.05). RESULTS: Mean survival time was 41.5 months (95% CI: 39.7-43.3), with 70.6% of the restorations surviving after 48 months of evaluation. The overall annual failure rate up to 48 months follow-up was 8.3%. Restorations placed in lower arch had lower survival rate than those in upper arch (HR: 1.82, 95% CI: 1.02-3.28). Restorations involving two or more surfaces had more risk of failure than restorations placed in cavities involving only one surface (HR: 2.55 95% CI: 1.34- 4.83). Girls had less risk of failure in their restorations (HR: 0.43, 95% CI: 0.19-0.96). CONCLUSION: Individual and dental variables such as gender, arch type and number of restored surfaces were associated with failure of composite restorations performed in children under daily life clinical environment. PMID- 29984558 TI - Patient rotation during linac-based photon electron radiotherapy. PMID- 29984559 TI - Nephropathy: New aspects of mechanisms, diagnosis and therapy. PMID- 29984560 TI - From Electron Crystallography to Single Particle CryoEM (Nobel Lecture). AB - Pictures are a key to knowledge: The development of electron microscopy from its beginnings to modern single particle cryo-EM is described by R. Henderson in his Nobel lecture. Shown is the first projection structure at 7 A resolution of the purple membrane from October 1974. PMID- 29984561 TI - A highly selective colorimetric and long-wavelength fluorescent probe for the detection of Hg2. AB - Currently, the fluorescent probe is an important method for detecting heavy metal ions, especially mercury ion (Hg2+ ), which is harmful to the health of humans and the environment due to its toxicity and extensive use. In this paper, we designed and synthesized a colorimetric and long-wavelength fluorescent probe Hg P with high sensitivity and excellent selectivity, which could detect Hg2+ by the changes of visual color, fluorescence and absorption spectroscopy. With the addition of Hg2+ to probe Hg-P solution, its color changed from yellow to pink, and showed a 171 nm red-shifted absorption spectrum. Probe Hg-P was used in real water and soil solution samples to detect Hg2+ , and the result is satisfactory. Therefore, this new probe shows great value and application in detecting Hg2+ in the environment. PMID- 29984562 TI - Optical Coherence Tomography of Small Retinoblastoma. AB - PURPOSE: To investigate hand-held optical coherence tomography (HH-OCT) characteristics of small (<1 mm thickness) retinoblastoma. DESIGN: Retrospective observational case series. METHODS: Patient and tumor data were extracted from the medical record and analyzed along with HH-OCT scans. Determination of tumor layer of origin was performed using a layer-by-layer analysis of HH-OCT data and specific HH-OCT-related features were described. RESULTS: There were 20 sub millimeter retinoblastomas from 16 eyes of 15 patients. Mean largest tumor basal diameter by HH-OCT was 2.2 mm (median, 1.9; range, 0.7-4.1 mm), and mean tumor thickness was 468 MUm (median, 441; range, 151-998 MUm). In all cases, the retinoblastoma caused discontinuity or disruption of the inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL), and external limiting membrane (ELM) layers (20/20, 100%). Tumor origin was in the INL in 19/20 (95%) and equivocal (INL vs ONL) in 1/20 (5%). Intratumoral microcalcification was present in 14/20 tumors (70%). There were 2 characteristic findings (signs) on HH-OCT including the INL "fish tail" sign with splaying of the INL at the tumor margin (19/20, 95%) and the ONL "shark fin" sign with folding of the ONL and OPL, conforming to the lateral tumor margins (15/20, 75%). Both signs were concurrently present in 15 tumors (15/20, 75%). CONCLUSIONS: HH-OCT demonstrated that sub-millimeter retinoblastoma seems to originate from the INL, with tumor base and thickness growth progressing in a linear relationship. Characteristic HH-OCT findings included intratumoral microcalcification, INL "fish tail" sign, and ONL "shark fin" sign. PMID- 29984564 TI - Effects of aquatic training and detraining on women with fibromyalgia: controlled randomized clinical trial. AB - BACKGROUND: Aquatic physical training (APT) promotes improvement of clinical symptoms and aerobic functional capacity in women with fibromyalgia syndrome (FMS). However, there are controversial studies that refer to the maintenance of adaptations obtained from APT after a detraining period. AIM: To evaluate variables oxygen uptake (VO2) relative to lean body mass (LBM) and clinical symptomatology in women with FMS submitted to APT and after 16 weeks of detraining period, and to evaluate the association between the magnitude of VO2 improvement relative to LBM and clinical symptomatology. DESIGN: Blind randomized controlled trial. POPULATION: Fifty-four women with FMS were randomly assigned into trained group (27) and control group (27). METHODS: All women underwent cardiopulmonary exercise test (CPET) and body composition assessment to estimate VO2 and LBM respectively, and clinical symptoms were assessed before and after 16 weeks of training and detraining. trained group was submitted to APT program, performed twice a week for 16 weeks. RESULTS: After APT, trained group presented an increase in VO2 relative to LBM (p = 0.01), in addition to an increase in pressure pain threshold (PPT) (p = 0.02) and visual analogue scale (VAS) pain (p = 0.01), VAS well-being (p <0.01) well-being and lower Fibromyalgia Impact Questionnaire score (FIQ) (p = 0.04). However, these improvements were not maintained after the 16-week detraining period (p > 0.05). In addition, no significant correlations were observed between improvement of clinical manifestations and increased VO2 relative to LBM after APT (p > 0.05). CONCLUSIONS: APT contributed both to increase VO2 at VAT and peak CPET, and improved clinical symptoms, but no association was observed. However, after 16 weeks of detraining, these variables were reduced near baseline. CLINICAL REHABILITATION IMPACT: The results of the present study suggest that APT should be continuously performed in order to improve clinical symptomatology and increase the aerobic functional capacity in women with FMS. PMID- 29984563 TI - Leaving No One Behind: Strengthening Access to Eye Health Programs for People With Disabilities in 6 Low- and Middle-Income Countries. AB - PURPOSE: To assess the impact of inclusive eye health programs for people with disabilities. DESIGN: A synthesis evaluation study. METHODS: A cross-disciplinary team of ophthalmologists, evaluation, and disability-inclusive development advisors purposively selected evaluation reports of CBM-supported inclusive eye health programs in low- and middle-income countries. Employing a change-promoting paradigm, salient achievements and challenges were narratively analyzed and recommendations suggested based on a previously developed framework for strengthening disability inclusion in eye health programs. RESULTS: Evaluations from 10 programs implemented in 6 countries (Cambodia, Egypt, Ethiopia, Indonesia, Pakistan, Vietnam) from 2011 to 2016 were identified. Training of medical staff and government officials resulted in increased awareness about disability rights and improved physical accessibility of eye health facilities. Relevant information about inclusion in eye health was incorporated in national eye health training curricula in some countries. Information, education, and communication material about eye health neglected patients with hearing and learning impairments. An overly narrow focus on disability inclusion confounded intersectoral barriers to eye health services. Collaboration of eye health staff with disability peoples organizations improved significantly but evidence of its impact was elusive. Collection of disability-disaggregated data posed significant challenges and made it difficult to demonstrate increased access to eye health programs by people with disabilities. CONCLUSIONS: Introduction of disability inclusion in eye health systems of countries with limited resources poses significant challenges. Future programs striving to improve access to eye health services for marginalized populations including people with disabilities might consider more flexible and contextualized approaches. PMID- 29984565 TI - Combined aerobic exercise and high-intensity respiratory muscle training in patients surgically treated for non-small cell lung cancer: a pilot randomized clinical trial. AB - BACKGROUND: Lung resection surgery further decreases exercise capacity and negatively affects respiratory muscle function in patients with non-small cell lung cancer (NSCLC). The best design for exercise interventions in these patients has not been determined. AIM: To assess the impact of aerobic exercise and high intensity respiratory muscle training on patient outcomes following lung cancer resection surgery. DESIGN: Prospective, single-blind, pilot randomized controlled trial. SETTING: Outpatient cardiopulmonary rehabilitation unit of two university hospitals. POPULATION: Thirty-seven patients with NSCLC after tumor resection. METHODS: Patients were randomly assigned to exercise training or usual post operative care. The training program consisted of aerobic exercises and high intensity respiratory muscle training (24 supervised sessions, 3 per week, 8 weeks). Primary outcome was exercise capacity assessed with peak oxygen uptake (VO2peak) during cardiopulmonary exercise test. Secondary outcomes included changes in respiratory muscle strength, levels of serum insulin growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3), and quality of life assessed with the European Organization for Research and Treatment of Cancer (EORTC QLQ-C30) questionnaire. RESULTS: The 8-week training program was associated with significant improvement in VO2peak (2.13 mL/Kg/min [95%CI 0.06 to 4.20]), maximal inspiratory and expiratory pressures (18.96 cmH2O [95% CI 2.7 to 24.1] and 18.58 cmH2O [95% CI 4.0 to 33.1], respectively) and IGFBP-3 (0.61 MUg/mL [%95 CI 0.1 to 1.12]). No significant differences were observed in the EORTC QLQ-C30. CONCLUSIONS: An 8-week exercise program consisting of aerobic exercise and high intensity respiratory muscle training improved exercise capacity, respiratory muscle strength, and serum IGFBP-3 levels in NSCLC patients after lung resection. There was no impact on the other outcomes assessed. CLINICAL REHABILITATION IMPACT: A combination of aerobic exercise and respiratory muscle training could be included in the rehabilitation program of deconditioned patients with NSCLC after lung resection surgery. PMID- 29984566 TI - Effect of turning direction on Timed Up and Go test results in stroke patients. AB - BACKGROUND: The Timed Up and Go (TUG) test is an assessment tool for measuring mobility in stroke patients. In stroke patients, the turning direction of the affected and unaffected sides may influence turning time. AIM: To investigate the effects of the turning direction according to the affected and unaffected sides of stroke patients during their Timed Up and Go (TUG) test and to define clinically salient outcomes during TUG tests performed in the clinic. DESIGN: Observational design. SETTING: Department of Physical Therapy in a rehabilitation center. POPULATION: One hundred thirteen hemiparetic stroke patients. METHODS: Stroke patients were asked to perform the TUG test by turning toward their affected and unaffected sides. Patients were divided according to gait speed, with their gait speed from the 10mWT being used. Those with a gait speed <48 m/min were assigned to the severe ambulatory dysfunction (SAD) group, whereas those with a gait speed >=48 m/min were assigned to the moderate ambulatory dysfunction (MAD) group. RESULTS: The TUG test results showed a longer turning time when turning with the unaffected side as the turning axis (17.10+/-5.69 sec) than with the affected side as the turning axis (17.52+/-5.90 sec). When the patients were divided into the MAD and SAD groups based on the 10mWT results, patients in the SAD group exhibited slightly longer times (0.55+/-1.11 sec) than those in the MAD group (0.29+/-1.03 sec); however, this difference was not significant. CONCLUSIONS: The present study found that stroke patients showed differences in the TUG test results based on their turning direction, and less time was required when turning in the direction of the affected side than when turning in the direction of the unaffected side. CLINICAL REHABILITATION IMPACT: Turning direction can affect the results of the TUG test; it should be controlled in the execution of the TUG test in clinical settings. PMID- 29984567 TI - Efficacy of two brief cognitive-behavioural rehabilitation programmes for chronic neck pain: results of a randomized controlled pilot study. AB - BACKGROUND: Current models of pain behaviour suggest that kinesiophobia prevents the reacquisition of normal function, promotes the development of maladaptive coping strategies, and contributes to the disability associated with chronic neck pain (NP). AIM: Comparing two brief cognitive-behavioural programmes aimed at managing kinesiophobia to understand which one induces better short-term improvements in disability, fear of movement, catastrophising, adaptive coping strategies, quality of life (QoL), and pain intensity of chronic NP. DESIGN: Pilot, randomised, controlled trial, 3-months follow-up. SETTING: Outpatients. POPULATION: Subjects with chronic NP. METHODS: The population was randomized into two groups: Group A (n=15) underwent four sessions of cognitive-behavioural therapy (CBT) based on the NeckPix(c) (1-week duration); Group B (n=15) received four sessions of CBT based on the Tampa Scale of Kinesiophobia (TSK) (1-week duration). Afterwards, both groups attended 10 sessions of multimodal exercises (5-week duration). Primary measure: Neck Disability Index (NDI). Secondary measures: NeckPix(c), TSK, Pain Catastrophising Scale, Chronic Pain Coping Inventory, EuroQol-Five Dimensions, and pain intensity Numerical Rating Scale. STATISTICS: Linear mixed model analyses for repeated measures for each outcome measure to evaluate changes over time and between group. RESULTS: A significant effect of time was found for all outcomes, while no outcomes showed group and/or interaction effects. No changes were found in terms of NDI at the end of CBT, while a significant improvement of about 13 points was found for both groups at the end of the motor training (p=0.001). Similarly, in terms of quality of life there was no change after the CBT program, and a significant change at the end of the motor training, with a partial loss at follow-up. From CBT sessions to follow up both groups showed a progressive reduction in kinesiophobia, with each group achieving a bigger change in the specific scale used for the CBT programme. CONCLUSIONS: Two brief cognitive-behavioural rehabilitation programmes based on different methodologies of managing fear-avoidance beliefs induced similar short term improvements in subjects with chronic NP. Clinically significant changes in terms of disability were found in both groups only at the end of a 5-week motor training, regardless of the cognitive-behavioural rehabilitation programme previously administrated. CLINICAL REHABILITATION IMPACT: Treatment of chronic NP requires cognitive modifications closely linked to physical performances in order to achieve mental adjustments and guarantee cognitive-behavioural as well as motor lasting changes. PMID- 29984568 TI - Improvement of exercise capacity in patients with type 2 diabetes mellitus during cardiac rehabilitation. PMID- 29984569 TI - Evidence based position paper on Physical and Rehabilitation Medicine (PRM) professional practice for persons with acute and chronic pain. The European PRM position (UEMS PRM Section). AB - INTRODUCTION: Pain is a frequent complaint from patients undergoing rehabilitation. It can be a major problem and can lead to several activity limitations and participation restrictions. For this reason, when the Professional Practice Committee (PPC) of the Physical and Rehabilitation Medicine (PRM) Section of the European Union of Medical Specialists (UEMS) decided to prepare evidence-based practice position papers (EBPPs) on the most relevant fields of PRM, a paper on the role of the PRM specialist on pain conditions was also included. AIM: The goals of this paper are to provide recommendations on the PRM physician's role in pain management; how to address this major problem and what is the best evidence-based approach for the PRM physician in acute and chronic pain conditions. METHODS: This paper follows the methodology defined by the Professional Practice Committee of the UEMS-PRM Section. A systematic literature search in PubMed was carried out and the results obtained from filtered papers were subjected to four Delphi rounds. RESULTS: Fifteen recommendations were obtained from the Consensus Process and systematic review and were approved by all of the delegates of the UEMS-PRM Section. It is recommended that PRM physicians focus on pain as a primary aim of their interventions, in whatever field they are applying their competencies. It is also recommended that the approach to pain focuses either on reducing the symptoms and improving functioning / reducing disability or recurrences and improving the health condition in the long term avoiding chronicity. CONCLUSIONS: Every PRM specialist encounters the problem of pain and some specialise in this field and their role is greater than that of the regular PRM doctor. Based on the evidence available, it is reasonable to determine the role of the physiatrist in managing pain. PMID- 29984571 TI - In Vivo and in Situ Activated Aggregation-Induced Emission Probes for Sensitive Tumor Imaging Using Tetraphenylethene-Functionalized Trimethincyanines Encapsulated Liposomes. AB - The design and exploration of fluorescent probes with high-sensitivity and low background are essential for noninvasive optical molecular imaging. The in vivo and in situ activated aggregation-induced emission (AIE) probes were found to be ideal for achieving higher signal-to-background ratios for tumor detections. We herein developed novel tetraphenylethene-encapsulated liposomes (TPE-LPs) constructed by loading TPE-trimethincyanine into liposomes for the first time, and the probes were applied to tumor bioimaging in vivo. TPE-functionalized trimethincyanines were synthesized with a new and efficient one-pot reaction. In TPE-LPs, TPE-functionalized bicarboxylic acids benzoindole trimethinecyanine (TPE BICOOH) fluorophores were found to be well dispersed in lipid bilayers (with non restricted rotation) during the blood circulation, and then aggregated (with restriction of intramolecular rotation) upon liposome rupture in the tumor tissue, achieving a low-background and high-target signal for tumor imaging. The in situ activated AIE probes not only had great accumulation at the tumor site after intravenous injection in 4T1 tumor-bearing mice but also demonstrated excellent signal-to-background ratios, as well as low cytotoxicity and excellent biocompatibility. The proposed strategy is believed to be a simple and powerful tool for the sensitive detection of tumors. PMID- 29984570 TI - The Economics of Palliative Care as a Human Right: A Global Action Item. PMID- 29984572 TI - Magnitude and Pathways of Increased Nitrous Oxide Emissions from Uplands Following Permafrost Thaw. AB - Permafrost thawing may release nitrous oxide (N2O) due to large N storage in cold environments. However, N2O emissions from permafrost regions have received little attention to date, particularly with respect to the underlying microbial mechanisms. We examined the magnitude of N2O fluxes following upland thermokarst formation along a 20-year thaw sequence within a thermo-erosion gully in a Tibetan swamp meadow. We also determined the importance of environmental factors and the related microbial functional gene abundance. Our results showed that permafrost thawing led to a mass release of N2O in recently collapsed sites (3 years ago), particularly in exposed soil patches, which presented post-thaw emission rates equivalent to those from agricultural and tropical soils. In addition to abiotic factors, soil microorganisms exerted significant effects on the variability in the N2O emissions along the thaw sequence and between vegetated and exposed patches. Overall, our results demonstrate that upland thermokarst formation can lead to enhanced N2O emissions, and that the global warming potential (GWP) of N2O at the thermokarst sites can reach 60% of the GWP of CH4 (vs ~6% in control sites), highlighting the potentially strong noncarbon (C) feedback to climate warming in permafrost regions. PMID- 29984573 TI - Novel 2D-DNA-Nanoprobe-Mediated Enzyme-Free-Target-Recycling Amplification for the Ultrasensitive Electrochemical Detection of MicroRNA. AB - In this work, on the basis of a new 2D DNA nanoprobe (DNP) and an enzyme-free target-recycling amplification, an electrochemical biosensor is developed for the ultrasensitive detection of microRNA-21 (miRNA-21). Herein, two ferrocene-labeled bipedal DNPs, which show small steric hindrance and strong stability, are prepared on the basis of the mechanism of the proximity-ligation assay (PLA), improving the space utilization. In the presence of the target, miRNA-21, and a hairpin DNA strand, the DNP will collapse, and then two ferrocene-labeled DNA strands and the miRNA-21 will be simultaneously released from the electrode surface through toehold-mediated strand-displacement reactions (TSDRs), leading to a decrease in the electrochemical signal and realization of enzyme-free target recycling. As a result, the one input target, miRNA-21, could release 2 N ferrocene-labeled DNA strands, achieving a dramatic decrease in the electrochemical signal. Combining DNPs and enzyme-free target recycling, this proposed biosensor showed a linear dependence with miRNA-21 concentration, ranging from 1.0 fM to 10 nM with a detection limit of 0.31 fM. In addition, it is worth mentioning that this biosensor can be regenerated through incubating with three assistant-DNA strands, realizing the reuse of raw materials. Surprisingly, the elaborated biosensor provides a novel strategy for building controllable DNA nanoprobes for the sensitive detection of various biomarkers. PMID- 29984574 TI - Multivariate and Multiscale Approaches for Interpreting the Mechanisms of Nitrous Oxide Emission during Pig Manure-Wheat Straw Aerobic Composting. AB - Nitrous oxide (N2O) emission during composting causes nitrogen loss and air pollution. The interpretation of N2O emission mechanisms will help to customize composting strategies that mitigate climate change. At pile and particle scales, this study characterized N2O emission-related variables (gases, ions, and microbes) and their correlations during pig manure-wheat straw aerobic composting. Pile-scale results showed that N2O emission mainly occurred in mesophilic, thermophilic, and cooling phases; the nitrification by ammonia oxidizing bacteria ( AOB) and nitrite-oxidizing bacteria ( NOB) coexisted with the denitrification by denitrificans ( DEN); the major NOB and DEN were Nitrobacter ( NOB_Nba) and Thiobacillus denitrificans ( DEN_Tb), respectively. The mechanisms of nitrification, nitrifier denitrification, and anaerobic denitrification in composting particles were initially visualized by confocal laser scanning microscopy: Betaproteobacteria ( AOB_ Beta) sporadically distributed on the outer area of the particles, NOB_Nba internally attached to AOB_ Beta, and Nitrosomonas europea/ Nitrosomonas eutropha ( AOB_eu) and DEN_Tb concentrated in the interior. Correlation analysis of the variables showed that the distribution area of AOB_eu was proportional to N2O emission ( R2 = 0.84); AOB not only participated in nitrification but also nitrifier denitrification, and N2O formation was mainly from nitrifier denitrification by AOB_eu during the mesophilic-thermophilic phase and from denitrification by AOB_eu and DEN during the cooling phase. PMID- 29984575 TI - Correction to Bronsted-Acid-Promoted Rh-Catalyzed Asymmetric Hydrogenation of N Unprotected Indoles: A Cocatalysis of Transition Metal and Anion Binding. PMID- 29984576 TI - Consumption of Black Legumes Glycine soja and Glycine max Lowers Serum Lipids and Alters the Gut Microbiome Profile in Mice Fed a High-Fat Diet. AB - This study investigated the potential health benefits of two different species of black legume [ Glycine soja Sieb. et Zucc. and Glycine max (L.) Merr.] on diet induced obesity. C57BL/6 mice were fed a high-fat diet (HFD) supplemented with 20% (w/w) black legume for 12 weeks, and the effects on weight gain, serum lipid levels, liver histology, gut fermentation, and microbiome profile were examined. Consumption of black legumes improved the blood lipid profile and increased fecal propionate and butyrate contents; this was accompanied by a reduction in hepatic steatosis and adipocyte size. High-throughput pyrosequencing of 16S rRNA revealed that black legumes prevented the loss of fecal microbiota diversity and richness caused by a HFD and decreased the relative abundance of Verrucomicrobia while increasing that of Bacteroidetes. Collectively, dietary supplementation with black legumes was found to have attenuated many of the adverse health consequences associated with a HFD and modulated gut microbiota in a positive way. PMID- 29984577 TI - Syntheses and Structures of d10 Coinage Metal Complexes of Electron-Accepting Phosphine Ligands Featuring a 3,3,4,4,5,5-Hexafluorocyclopentene Framework. AB - Cu(I), Ag(I), and Au(I) complexes of monophosphine or bisphosphine ligands based on the 3,3,4,4,5,5-hexafluorocyclopentene skeleton were synthesized and structurally characterized by X-ray crystallographic analysis. The electron withdrawing nature of these polyfluorinated phosphines was experimentally revealed via UV/vis absorption studies and crystal structure analysis. Successful catalytic application of the Au(I) complex for alkyne hydration reactions was investigated. PMID- 29984578 TI - Electronic Structure Contributions of Non-Heme Oxo-Iron(V) Complexes to the Reactivity. AB - Oxo-iron(V) species have been implicated in the catalytic cycle of the Rieske dioxygenase. Their synthetic analog, [FeV(O)(OC(O)CH3)(PyNMe3)]2+ (1, PyNMe3 = 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-trimethyl), derived from the O-O bond cleavage of its acetylperoxo iron(III) precursor, has been shown experimentally to perform regio- and stereoselective C-H and C?C bond functionalization. However, its structure-activity relation is poorly understood. Herein we present a detailed electronic-structure and spectroscopic analysis of complex 1 along with well-characterized oxo-iron(V) complexes, [FeV(O)(TAML)]- (2, TAML = tetraamido macrocyclic ligand), [FeV(O)(TMC)(NC(O)CH3)]+ (4, TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), and [FeV(O)(TMC)(NC(OH)CH3)]2+ (4-H+), using wave function-based multireference complete active-space self-consistent field calculations. Our results reveal that the x/ y anisotropy of the 57Fe A-matrix is not a reliable spectroscopic marker to identify oxo-iron(V) species and that the drastically different A x and A y values determined for complexes 1, 4, and 4-H+ have distinctive origins compared to complex 2, a genuine oxo-iron(V) species. Complex 1, in fact, has a dominant character of [FeIV(O...OC(O)CH3)2-*]2+, i.e., an SFe = 1 iron(IV) center antiferromagnetically coupled to an O-O sigma* radical, where the O-O bond has not been completely broken. Complex 4 is best described as a triplet ferryl unit that strongly interacts with the trans acetylimidyl radical in an antiferromagnetic fashion, [FeIV(O)(*N?C(O-)CH3)]+. Complex 4-H+ features a similar electronic structure, [FeIV(O)(*N?C(OH)CH3)]2+. Owing to the remaining approximate half sigma-bond in the O-O moiety, complex 1 can arrange two electron accepting orbitals (alpha sigma*O-O and beta Fe-d xz) in such a way that both orbitals can simultaneously interact with the doubly occupied electron-donating orbitals (sigmaC-H or piC-C). Hence, complex 1 can promote a concerted yet asynchronous two-electron oxidation of the C-H and C?C bonds, which nicely explains the stereospecificity observed for complex 1 and the related species. PMID- 29984579 TI - Multiparametric Study of the Synthesis of ThSiO4 under Hydrothermal Conditions. AB - A multiparametric study of the hydrothermal synthesis of ThSiO4, thorite, was performed with the aim of determining the most efficient conditions to form single-phase samples. Among the experimental parameters examined, significant effects were found for the concentration of reactants in the starting mixture, pH of the reactive media, and temperature of the hydrothermal process. Such parameters affected both the rate of formation of thorite and the morphology of the final products synthesized. Precipitation of pure ThSiO4 was obtained over a wide range of pH on going from CHNO3 = 0.3 mol L-1 to pH 9.1 with a yield of over 95%. Temperatures higher than 160 degrees C favor the formation of thorite. Finally, thorium and silicon concentrations above 2.1 * 10-3 mol L-1 are required to obtain pure thorium silicate. PMID- 29984580 TI - Porphyromonas gingivalis Gingipains Display Transpeptidation Activity. AB - Porphyromonas gingivalis is a keystone periodontal pathogen that has been associated with autoimmune disorders. The cell surface proteases Lys-gingipain (Kgp) and Arg-gingipains (RgpA and RgpB) are major virulence factors, and their proteolytic activity is enhanced by small peptides such as glycylglycine (GlyGly). The reaction kinetics suggested that GlyGly may function as an acceptor molecule for gingipain-catalyzed transpeptidation. Purified gingipains and P. gingivalis whole cells were used to digest selected substrates including human hemoglobin in the presence or absence of peptide acceptors. Mass spectrometric analysis of the substrates digested with gingipains in the presence of GlyGly showed that transpeptidation outcompeted hydrolysis, whereas the trypsin-digested controls exhibited predominantly hydrolysis activity. The transpeptidation levels increased with increasing concentration of GlyGly. Purified gingipains and whole cells exhibited extensive transpeptidation activities on human hemoglobin. All hemoglobin cleavage sites were found to be suitable for GlyGly transpeptidation, and this transpeptidation enhanced hemoglobin digestion. The transpeptidation products were often more abundant than the corresponding hydrolysis products. In the absence of GlyGly, hemoglobin peptides produced during digestion were utilized as acceptors leading to the detection of up to 116 different transpeptidation products in a single reaction. P. gingivalis cells were able to digest hemoglobin faster when acceptor peptides derived from human serum albumin were included in the reaction, suggesting that gingipain-catalyzed transpeptidation may be relevant for substrates encountered in vivo. The transpeptidation of host proteins in vivo may potentially lead to the breakdown of immunological tolerance, culminating in autoimmune reactions. PMID- 29984581 TI - Reactivity of Steroidal 1-Azadienes toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids. AB - The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an initial stereoselective conjugate addition of the in situ generated enamine to the steroidal 1-azadiene. The developed diastereoselective synthetic methodology is a novel approach to a new class of chiral pentacyclic and hexacyclic steroids. PMID- 29984582 TI - Correction to "Structural Insights into the Distinct Binding Mode of Cyclic Di AMP with SaCpaA_RCK". PMID- 29984583 TI - Photocatalytic Reactive Ultrafiltration Membrane for Removal of Antibiotic Resistant Bacteria and Antibiotic Resistance Genes from Wastewater Effluent. AB - Biological wastewater treatment is not effective in removal of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs). In this study, we fabricated a photocatalytic reactive membrane by functionalizing polyvinylidene fluoride (PVDF) ultrafiltration (UF) membrane with titanium oxide (TiO2) nanoparticles for the removal of ARB and ARGs from a secondary wastewater effluent. The TiO2-modified PVDF membrane provided complete retention of ARB and effective photocatalytic degradation of ARGs and integrons. Specifically, the total removal efficiency of ARGs (i.e., plasmid-mediated floR, sul1, and sul2) with TiO2-modified PVDF membrane reached ~98% after exposure to UV irradiation. Photocatalytic degradation of ARGs located in the genome was found to be more efficient than those located in plasmid. Excellent removal of integrons (i.e., intI1, intI2, and intI3) after UV treatment indicated that the horizontal transfer potential of ARGs was effectively controlled by the TiO2 photocatalytic reaction. We also evaluated the antifouling properties of the TiO2-UF membrane to demonstrate its potential application in wastewater treatment. PMID- 29984584 TI - Low Levels of Physical Activity Among Older Persons Living with HIV/AIDS Are Associated with Poor Physical Function. AB - Antiretroviral therapy (ART) has prolonged lives of persons living with HIV/AIDS (PLWHA), resulting in greater incidence of aging-related diseases and disability. Physical activity (PA) is recommended for healthy aging, but little is known about PA in older PLWHA. The purpose of this study was to objectively assess PA levels in older PLWHA and the associations with physical function. Twenty-one PLWHA, >=50 years old, on ART with undetectable HIV-1 viral loads, wore an accelerometer to assess PA, including number of steps, activity intensity, and energy expenditure over 7 days. A physical function performance battery assessing aerobic capacity, strength, and gait speed was also completed. Average age was 66, and 67% were male. An average of 3,442 (interquartile range: 4,613) steps were walked daily, with 254.9 kcals expended. Participants spent most waking hours (75%) sedentary, with minimal hours (24%) in light-intensity activity. Only 5 min per day (35 min per week), on average, were spent in moderate-to-vigorous physical activity (MVPA). Maximal gait speed and 6-min walk test significantly correlated (p < .05) with all PA outcomes. Usual gait speed significantly correlated with all PA outcomes, except for daily kcals and light-intensity activity. Greater PA was associated with better physical performance, while high sedentary time was associated with poorer performance. To our knowledge, this is the first study to objectively measure PA in older PLWHA. Our findings indicate that older PLWHA accumulate substantial sedentary time. Most (86%) do not achieve recommended MVPA levels. This activity profile was associated with poor physical function. Providers should promote PA among PLWHA. PMID- 29984585 TI - Aortic valve replacement with essential thrombocythemia. AB - Cardiac surgery in patients with essential thrombocythemia carries the risks of both thrombotic events and a bleeding tendency. We report the case of a 75-year old man with essential thrombocythemia who underwent successful surgical aortic valve replacement after his platelet count was controlled with plateletpheresis 3 times before surgery. PMID- 29984586 TI - Development of the Broad Learning Adult Questionnaire. AB - Infants and children experience an intense form of intellectual engagement associated with learning a variety of new skills. A recent theory proposes that such broad learning experiences may be the key to maximal cognitive development not just during infancy and childhood but also during adulthood. To begin investigating this possibility, the present questionnaire on broad learning in adulthood builds on prior research on need for cognition, intellectual engagement, personal growth, and leisure activities. After several rounds with preliminary versions of the questionnaire, the final version consists of 28 items. Responses were gathered from two mTurk samples to measure scale reliability and to assess model fit. In the end, we obtained a satisfactory measure of broad learning that consists of six separate reliable scales. Once this questionnaire is validated in future studies, perhaps it could be used as a predictor for cognitive development during adulthood and for interventions inducing broad learning. PMID- 29984588 TI - Facilitating open family communication when a parent has chronic pain: A scoping review. AB - BACKGROUND: When a parent has chronic pain, family communication can become strained. Clinicians are encouraged to identify and support families struggling with open communication. Occupational therapists are commonly involved in the provision of pain management services but their role in facilitating open communication in families affected by this condition has not been clearly articulated. OBJECTIVE: To develop a comprehensive understanding of what is being done and/or thought to be helpful for facilitating open communication in families affected by chronic pain, in order to articulate the role of occupational therapy in this area of care. METHODS: A scoping review was conducted and 24 items analyzed using qualitative content analysis. RESULTS: The facilitation of open communication in families affected by parental chronic pain is dependent on a variety of factors, including the skills that members possess and occupations which they perform individually and together. It can also be prompted by relationship tension or a family accessing professional support. Occupational therapy literature on the matter is currently limited and focused on assertiveness training. CONCLUSION AND SIGNIFICANCE: There is scope for occupational therapist to extend their role beyond assertiveness training and use occupation-centered interventions to facilitate communication within families affected by parental chronic pain. PMID- 29984589 TI - The impact of traditional literacy and education on health literacy in adolescents with asthma. AB - INTRODUCTION: People with low health literacy have poorer self-management of chronic diseases like asthma. Studies of parent health literacy and education level on the management of children's chronic illnesses reveal inconclusive results. We hypothesized a correlation between parent and adolescent health literacy in teens with asthma. METHODS: Sociodemographic data were obtained; health literacy was assessed on adolescents and parents with three instruments: Rapid Estimate of Adolescent/Adult Literacy in Medicine (REALM), Single Item Literacy Screener (SILS) and Newest Vital Sign (NVS). Agreement between scores was examined by calculating weighted kappa statistics and performing Bowkers test of symmetry. RESULTS: In all, 243 adolescents and 203 parents completed health literacy assessments yielding 198 paired observations. 9th-12th graders, 60.6% female, 72.7% African-American (AA), mean age: 15.3 years (+/-0.9). Parent education ranged from < high school (19.1%) to college graduate (24.0%). Agreement between adolescent and parent scores was poor: REALM (kappaw = 0.26), SILS (kappaw = 0.12), and NVS (kappaw = 0.29) and disagreement did not significantly differ by race. Positive correlations of moderate strength (overall and between racial groups) were found between reading scores and both REALM and NVS scores, and between REALM and NVS scores. Due to the inverse relationship of SILS scores with health literacy level, SILS scores (overall and between racial groups) were weakly and negatively correlated with reading scores, REALM and NVS. CONCLUSION: Correlation between education level and traditional literacy suggests that these are contributing factors to the health literacy of adolescents with asthma. Correlation between adolescent and caregiver health literacy was not supported. PMID- 29984587 TI - Structural Insights from HIV-Antibody Coevolution and Related Immunization Studies. AB - Human immunodeficiency virus type 1 (HIV-1) is a rapidly evolving pathogen that causes acquired immunodeficiency syndrome (AIDS) in humans. There are ~30-35 million people infected with HIV around the world, and ~25 million have died since the first reported cases in 1981. In addition, each year 2-3 million people become newly infected, and >1 million die of AIDS. An HIV-1 vaccine would help halt an AIDS pandemic, and efforts to develop a vaccine have focused on targeting the HIV-1 envelope, Env, found on the surface of the virus. A number of chronically infected individuals have been shown to produce antibodies, called broadly neutralizing antibodies (bnAbs), that target many strains of HIV-1 by binding to Env, thus suggesting promise for HIV-1 vaccine development. BnAbs take years to develop, and have a number of traits that inhibit their production; thus, a number of researchers are trying to understand the pathways that result in bnAb production, so that they can be elicited more rapidly by vaccination. This review discusses results and implications from two HIV-1-infected individuals studied longitudinally who produced bnAbs against two different sites on HIV-1 Env, and immunization studies that used Envs derived from those individuals. PMID- 29984590 TI - A Systematic Review of ICU and Non-ICU Clinical Pharmacy Services Using Telepharmacy. AB - OBJECTIVE: To assess the impact of telepharmacy services in the acute care setting. DATA SOURCES: EMBase, MEDLINE, and SCOPUS database searches were performed through April 2018. STUDY SELECTION AND DATA EXTRACTION: PRISMA guidelines were applied for this systematic review. All English-language studies meeting the criteria of the following population, intervention, comparison, and outcome question were included: What impact does the provision of inpatient clinical pharmacy services delivered via telemedicine have on patient outcomes compared with standard of care? DATA SYNTHESIS: A total of 11 studies were identified for the acute care setting, including 3 for critically ill patients. All studies demonstrated a positive impact on patient outcomes, nursing satisfaction, and disease management. Varying modes of telepharmacy technology were used, such as remote access to electronic medical records, faxing or scanning documents, pictures or webcams. For communication purposes, telepharmacists used email or electronic communication, facsimile, video review, or telephone to speak directly with hospital personnel and patients. Relevance to Patient Care and Clinical Practice: Inpatient telepharmacy is feasible and should be leveraged to further enhance patient care by complementing existing service models. CONCLUSIONS: Telepharmacy services enhanced patient outcomes, improved nursing satisfaction, and expanded services within inpatient settings. Similar technologies were leveraged in non-intensive care units (ICUs) and ICUs, but the goals of telepharmacy appeared to differ. ICUs focused on an expansion of services in the ICU and non-ICUs addressed improved patient outreach in rural areas. PMID- 29984591 TI - Does Continuation of Low-Dose Aspirin During Robot-Assisted Radical Prostatectomy Compromise Surgical Outcomes? AB - OBJECTIVE: To evaluate the perioperative outcomes and 90-day complication rates of continuation of low-dose aspirin through surgery in patients undergoing robot assisted radical prostatectomy (RARP). A significant proportion of patients undergoing RARP are on antiplatelet medications for primary or secondary prevention of cardiovascular events. However, there is still a relative lack of data with regard to the advantages and complications of continuing these medications through surgery. MATERIALS AND METHODS: Our usual protocol of RARP entails continuation of low-dose aspirin (75 mg once a day) for patients who are already on antiplatelet agents. We conducted a retrospective audit of a prospectively maintained database of 116 cases of RARP performed by a single surgical team in 1 year. Patients were divided into low-dose aspirin group (AG) (n = 31) and nonaspirin group (NAG) (n = 85). The primary objective was to compare the 90-day complication rates to assess the safety profile. Secondary objective was to compare perioperative parameters such as estimated blood loss, blood transfusion rates, fall in hemoglobin (Hb) level, drain outputs on day 1, days to drain removal, lymph node yield, and margin positivity. Subgroup comparison was performed between patients on aspirin for primary prevention (n = 15) and NAG. RESULTS: Both groups were well matched for preoperative parameters except for significantly higher comorbidities and American Society of Anesthesiologists (ASA) score class in AG. Console time, blood loss, fall in Hb level, drain output, drain and catheter removal days, day of discharge, and lymph node yield were comparable. Margin positivity was significantly higher in NAG. Ninety-day complication rates were not significantly different between the two groups (p = 0.218) with only one major complication (Clavien-Dindo grade 4 hypotension requiring intensive care unit admission) in AG. Subgroup comparison demonstrated similar outcomes. CONCLUSION: Low-dose aspirin can be safely continued perioperatively during RARP, without increasing the bleeding-related complications and overall 90-day complication rates. PMID- 29984592 TI - Targeting the 'right' patients for integrated care: stakeholder perspectives from a qualitative study. AB - Objective To explore the perceptions of relevant stakeholders in terms of targeting the 'right' patients for integrated care. Methods Secondary analysis of qualitative interviews with relevant stakeholders (including programme managers, programme initiators, a representative of the payers, medical and social care professionals and allied health services staff) from two integrated care sites in England. A thematic analysis was conducted of cross-cutting themes. Results Both sites focused on individualized management of 'high-risk' patients through multidisciplinary team case management. The data-driven approach to targeting patients, recommended in the policy literature, did not align with stakeholders' experience of selecting patients in practice. The 'right' patients were at lower risk than those recommended by policy, and their complexities were identified as comprising mostly social rather than medical issues. Conclusions These findings raise timely questions about the individualized management approach. They potentially explain why management of high-risk patients has not been found to be effective using quantitative measures, undermining the assumption that this approach will lead to cost savings. There is a need to expand beyond an individually targeted approach to incorporate prevention and to address social issues. PMID- 29984594 TI - A hospital-based study of socioeconomic status and clinical spectrum of rheumatic heart disease patients of Assam, North-East India. AB - Objective The aim of this study was to assess the impact of socioeconomic factors in increased prevalence of rheumatic heart disease and its clinical spectrum in Assam, North-East India. Method A case-control questionnaire-based study of 100 echocardiography confirmed rheumatic heart disease cases with age- and sex matched healthy controls from Assam medical college and hospital in Dibrugarh, Assam was conducted. Results There was a trend toward increased risk of rheumatic heart disease and its clinical spectrum with respect to low socioeconomic status. Three parameters were found to be statistically significant in posing increased risk towards rheumatic heart disease: rural dwelling location ( p < 0.0001, odds ratio (OR) 4.1, 95% confidence interval (CI = 2.29-7.45), low monthly income ( p < 0.001, OR=9.5, 95% CI = 4.99-18.1) and education status ( p < 0.05, OR=9.5, 95% CI = 1.866). Out of the severe cases of mitral stenosis, mitral regurgitation and aortic regurgitation, 69.6%, 58.3% and 34% patients were of low socioeconomic status. Conclusion Socioeconomic factors can be of significant importance in increased prevalence of rheumatic heart disease and might also influence the clinical spectrum of the disease. Increased awareness and up-gradation of socioeconomic status might ameliorate the prevalence of rheumatic heart disease. PMID- 29984593 TI - Differentiation of Type 1 and Type 2 Myocardial Infarctions Among HIV-Infected Patients Requires Adjudication Due to Overlap in Risk Factors. AB - The Universal Myocardial infarction (MI) definition divides MIs into different types. Type 1 MIs (T1MI) result spontaneously from atherosclerotic plaque instability. Type 2 MIs (T2MI) are due to secondary causes of myocardial oxygen demand/supply mismatch such as occurs with sepsis. T2MI are much more common among those with HIV than in the general population. T1MI and T2MI have different mechanisms, risk factors, and potential treatments suggesting that they should be distinguished to achieve a better scientific understanding of MIs in HIV. We sought to determine whether MI type could be accurately predicted by patient characteristics without adjudication in HIV-infected individuals. We developed a statistical model to predict T2MI versus T1MI using adjudicated events from six sites utilizing demographic characteristics, traditional cardiovascular, and HIV related risk factors. Validation was assessed in a seventh site via mean calibration, and discrimination level was assessed by the area under the curve (AUC). Of 812 MIs, 388 were T2MI. HIV-related factors including hepatitis C infection were predictive of T2MI, whereas traditional cardiovascular risk factors including total cholesterol predicted T1MI. The score predicted 69 T2MI in the validation sample resulting in poor calibration, given that 90 T2MIs were observed. The development sample AUC was 0.75 versus 0.65 in the validation sample, suggesting relatively poor discrimination. The level of discrimination to predict MI type based on patient characteristics is insufficient for individual level prediction. Adjudication is required to distinguish MI types, which is necessary to advance understanding of this important outcome among HIV populations. PMID- 29984595 TI - High Frequencies in QEEG Are Related to the Level of Insight in Patients With Schizophrenia. AB - Lack of insight is a neurocognitive problem commonly encountered in patients with psychotic disorders that negatively affects treatment compliance and prognosis. Measurement of insight is based on self-report scales, which are limited due to subjectivity. This study aimed to determine the correlation between resting state beta and gamma power in 23 patients with schizophrenia and insight. It was observed that as beta and gamma power measured via qualitative electroencephalography (qEEG) increased the level of insight decreased. Negative correlation was found in F3, C3, Cz for gamma activity and in F3 and C3 for beta activity. This finding indicates that resting state qEEG could be used to evaluate the level of insight in patients with schizophrenia. PMID- 29984596 TI - Editorial Comment on: Toward Respiratory-Gated Retrograde Intrarenal Surgery: A Prospective Controlled Randomized Study by Kourmpetis et al. PMID- 29984597 TI - Trifecta Outcomes in Renal Hilar Tumors: A Comparison Between Robotic and Open Partial Nephrectomy. AB - OBJECTIVES: To report a comparative analysis of outcomes in patients who underwent excisions of renal hilar tumors using both open and robotic approaches. MATERIALS AND METHODS: We retrospectively reviewed robotic and open patients who underwent partial nephrectomy of renal hilar tumors between 2011 and 2016. "Trifecta" was defined as negative surgical margins, no complications, and a glomerular filtration rate (GFR) preservation of >=90% at last follow-up. Inverse probability of treatment weighting (IPTW) was applied to equilibrate treatment groups, minimize selection bias, and optimize inference on the basis of each patient's clinicodemographic characteristics. RESULTS: One hundred robotic and 64 open patients had sufficient data for IPTW. After weighting, there were no statistical differences in baseline characteristics between the two groups (p < 0.05). On adjusted analyses, robotic partial nephrectomy (RPN) achieved equivalent rates of trifecta to open surgery (21.1% vs 13.9%, respectively, p = 0.387). There were no differences between robotic and open cohorts for negative margin rates (72.8% vs 90.4%, p = 0.124), absence of complications (68.6% vs 75.2%, p = 0.587), or GFR >=90% (39.4% vs 21.6%, p = 0.111). The robotic cohort had a shorter mean length of stay (3.8 vs 5.0 days, p = 0.012), and no difference in estimated blood loss (253.3 vs 357.1, p = 0.091) or operating time (199.8 vs 200.4, p = 0.961). CONCLUSIONS: In our analysis both open and RPN for hilar tumors were equally likely to achieve a low "trifecta" outcome with a shorter mean length of stay in the robotic cohort. PMID- 29984598 TI - The impact of high-intensity inspiratory muscle training on exercise capacity and inspiratory muscle strength in heart failure with reduced ejection fraction: a systematic review and meta-analysis. AB - OBJECTIVE:: Inspiratory muscle training (IMT) improves prognostic clinical variables in patients with heart failure. However, the optimal intensity for increasing those outcomes remains unclear. Thus, we aimed to determine whether high-intensity inspiratory muscle training (HIIMT) improves exercise capacity and respiratory muscle strength in patients with heart failure with reduced ejection fraction (HFrEF). METHODS:: We searched for randomized controlled clinical trials at MEDLINE, the Cochrane Central Register of Controlled Trials, the Physiotherapy Evidence Database, SciELO and CINAHL from the earliest date available to May 2018. Primary studies on HIIMT against low-intensity IMT or sham-IMT that evaluated exercise capacity and inspiratory muscle strength were included. Two independent reviewers evaluated the eligibility of studies retrieved from the databases. Disagreements were resolved by discussion or by a third reviewer. Weighted mean difference (WMD), standardized mean difference (SMD) and 95% confidence interval (CI) were estimated by random effect models. RESULTS:: Five studies met the eligibility criteria (138 patients). HIIMT improved VO2peak (WMD 2.65 mL kg-1 min-1; 95% CI: 2.2 to 3.1 mL kg-1 min-1), walking tests (SMD 1.71; 95% CI: 0.83 to 2.59) and maximal inspiratory pressure (WMD 16.63 cmH2O; 95% CI: 10.34 to 22.91 cmH2O). The estimate for potential risks of adverse events was not performed because of the low prevalence of reports in primary studies. CONCLUSION:: HIIMT seems to be a useful strategy for improving exercise capacity and inspiratory muscle strength in HFrEF patients. PMID- 29984600 TI - The association between migraine and hospital readmission due to pain after surgery: A hospital registry study. AB - Background Migraine has been identified as a risk factor of 30-day hospital readmission after surgery. We aimed to further characterize this association examining pain as a potentially migraine-associated, preventable reason for readmission. Hypothesis Compared to patients with no migraine, surgical patients with migraine are at increased risk of 30-day hospital readmission with an admitting diagnosis specifying pain. Methods This hospital registry study examined 150,710 patients aged 18 years and above, who underwent surgery with general anesthesia and mechanical ventilation between 2007 and 2015 at a tertiary care center and two affiliated community hospitals in Massachusetts, USA. Results Migraine was associated with an increased risk of 30-day pain-related readmission after surgery (adjusted odds ratio 1.42 [95% confidence interval 1.15-1.75]). The association was stronger for migraine with aura (compared to migraine without aura: Adjusted odds ratio 1.69 [95% confidence interval 1.06-2.70]; compared to no migraine: Adjusted odds ratio 2.20 [95% confidence interval 1.44-3.37]). The predicted adjusted risk of pain-related 30-day readmissions was 9.1 [95% confidence interval 5.3-13.0] in 1000 surgical patients with migraine with aura and 5.4 [95% confidence interval 4.2-6.6] in 1000 patients with migraine without aura, compared to 4.2 [95% confidence interval 3.8-4.5] in 1000 patients with no migraine. Furthermore, migraine was associated with an increased risk of postsurgical 30-day readmission due to a priori defined migraine-related pain (headache or abdominal pain) (adjusted odds ratio 1.55 [95% confidence interval 1.20-2.00]). Conclusion Patients with migraine undergoing surgery are at increased risk of 30-day hospital readmission due to pain. PMID- 29984601 TI - Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study. AB - Background Erenumab was effective and well tolerated in a pivotal clinical trial of chronic migraine. Here, we evaluated efficacy and safety of monthly erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s) (>= 1, >= 2 prior failed medication categories) and in patients who had never failed. Methods Subgroup analyses evaluated change from baseline in monthly migraine days; achievement of >= 50% and >= 75% reduction in monthly migraine days; and change in monthly acute migraine-specific medication days. Adverse events were evaluated for each subgroup. Results Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days (primary endpoint) at Month 3 (treatment difference [95% CI], never failed subgroup: -2.2 [-4.1, -0.3] for 70 mg and -0.5 [-2.4, 1.5] for 140 mg; >= 1 prior failed medication categories subgroup: -2.5 [-3.8, -1.2], for 70 mg and 3.3 [-4.6, -2.1] for 140 mg; >= 2 prior failed medication categories subgroup: 2.7 [-4.2, -1.2], for 70 mg and -4.3 [-5.8, -2.8] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of >= 50% and >= 75% reduction in monthly migraine days. There were no new or unexpected safety issues. Conclusion Erenumab showed consistent efficacy in chronic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups. PMID- 29984602 TI - Editorial Comment on: Successful Diabetic Control as Measured by Hemoglobin A1c Is Associated with Lower Urine Risk Factors for Uric Acid Calculi by Maciolek et al. (From: Maciolek KA, Penniston KL, Jhagroo RA, et al.J Endourol 2018;32:771 776). PMID- 29984603 TI - The Brains Ahead! intervention for children and adolescents with mild traumatic brain injury and their caregivers: rationale and description of the treatment protocol. AB - PURPOSE:: Approximately 20% of the children and adolescents after mild traumatic brain injury will not fully recover. They suffer long-term postconcussive symptoms and may experience limitations in activities and participation. Research suggests that early psychoeducational interventions may prevent long-term postconcussive symptoms. The Brains Ahead! intervention was developed to prevent long-term symptoms and, furthermore, to establish a more successful return to activities and participation after mild traumatic brain injury in children and adolescents. The intervention is currently being evaluated in a multicenter randomized controlled trial. RATIONALE:: Providing individualized information and personal advice in addition to standardized information about the injury and possible consequences early after the injury may enable patients and caregivers to recognize and anticipate on relevant symptoms at an early stage and to prevent problems in activities and participation. THEORY INTO PRACTICE:: The Brains Ahead! intervention is a psychoeducational intervention for children and adolescents who sustained a mild traumatic brain injury and for their caregivers. The patients will receive a partially standardized and partially individualized psychoeducational session and a telephone follow-up within the first two to eight weeks after the injury. PMID- 29984604 TI - An Assessment of Evaluation Instruction Related to the Health Education Specialist Practice Analysis Competencies in Health Education-Related Professional Preparation Programs. AB - BACKGROUND: Conducting evaluation and research is one of the seven areas of responsibility for health education specialists. However, there is little evidence to suggest that professional preparation programs use the competencies as identified by the 2015 Health Education Specialist Practice Analysis (HESPA) as a basis for instruction. AIMS: To determine the degree to which departments with undergraduate health education-related professional preparation programs provide instruction in the HESPA 2015 Model evaluation competencies. METHOD: This was a descriptive, cross-sectional, nonexperimental study design. Data were collected using an online survey from programs that prepare students to sit for the CHES exam. RESULTS: Faculty provide instruction about all evaluation subcompetencies regardless of entry- or advanced-level designation. Developing an evaluation plan, monitoring implementation, and selecting, adapting, and creating instruments to collect data represent the competencies taught most frequently. On average, two to three class periods are spent on each competency. DISCUSSION: Advanced-level competencies, more commonly associated with graduate-level training and degrees, are commonly taught at the undergraduate level. This may be due to a lack of awareness of changes to the designation of competencies and subcompetencies as entry- or advanced-level in the HESPA 2015 Model framework, a lack of awareness or appreciation for the framework in general, competing values in the selection of curriculum content, or lack of professional consensus related to terms and definitions. CONCLUSION: Faculty should consider emphasizing entry level competencies and subcompetencies consistent with process and formative evaluation. The health education profession should also standardize evaluation and research terms and definitions. PMID- 29984605 TI - A general strategy for de novo immunotherapy design: the active treatment of food allergy. AB - INTRODUCTION: IgE-mediated food allergy (FA) has been emerging as a public health priority. It is a potentially life-threatening condition with negative impact on the quality of life of patients and their family and its prevalence is increasing in westernized countries in the recent two decades. The current standard approach to FA consists of the strict avoidance of the triggering food. However, an elimination diet may be difficult and frustrating, above all for those foods (e.g. milk and egg) that are pivotal in the common diet. Oral immunotherapy (OIT) may increase the amount of food that the patient can intake without reaction and reduce the risk of potential life-threatening allergic reactions. It is currently considered the most promising treatment for FA. However, many gaps are still unsolved. Areas covered: The aim of this review is to shed light on the current evidence and the main needs in OIT in order to stimulate the development of longitudinal, prospective, and well-designed studies with the final goal of a 'precision medicine.' Expert commentary: Clinical trials for OIT conducted so far are extremely heterogeneous. The aim in the near future is to identify the most suitable candidates to OIT and algorithms for treatments tailored on well characterized subpopulations of patients. PMID- 29984606 TI - Early Intervention With Adrenocorticotropin for Acute Encephalopathy-Associated Epileptic Spasms: Report of Two Cases. AB - PURPOSE: Acute encephalopathy with biphasic seizures and reduced diffusion (AESD) is a leading cause of childhood-onset encephalopathy in Japan. Children with AESD frequently develop intractable epilepsy, whereas their treatment options remain to be determined. METHOD: We present 2 unrelated girls, who developed AESD at 25 months (case 1) and 12 months of age (case 2). Both cases underwent intensive cares from the first day of illness, whereas severe neurological impairments were left on discharge. They showed repeated signs of epileptic spasms at 2 months (case 1) and 8 months (case 2) after the onset of AESD. Video-monitoring electroencephalograms (EEG) detected the recurrent attacks accompanying slow-wave bursts and transient suppressions of the precedent epileptiform discharges, as typically observed in epileptic spasms. RESULTS: Intramuscular injection of adrenocorticotropic hormone (ACTH, 0.0125 mg/kg/d) was introduced within 1 month from the onset of epileptic spasms and continued for 2 weeks. The ACTH treatment disrupted the paroxysmal activity in EEG, and it has relieved these patients from epileptic seizures for more than 1 year. CONCLUSION: This report illustrates the potential efficacy of ACTH for a group of children with epileptic spasms after AESD. PMID- 29984608 TI - Economic benefits of treating medication-overuse headache - results from the multicenter COMOESTAS project. AB - Background Medication-overuse headache is a costly disease for individuals and society. Objective To estimate the impact of medication-overuse headache treatment on direct and indirect headache-related health care costs. Methods This prospective longitudinal study was part of the COMOESTAS project (COntinuous MOnitoring of Medication Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System). Patients with medication-overuse headache were included from four European and two Latin American headache centers. Costs of acute medication, costs of health care services, and measurements of productivity were calculated at baseline and at 6-month follow-up Treatment consisted of overused drug withdrawal with optional preventive medication. Results A total of 475 patients (71%) completed treatment and were followed up for 6 months. Direct health care costs were on average reduced significantly by 52% ( p < 0.001) for the total study population. Significant reductions were seen in both number of consumed tablets (-71%, p < 0.001) and number of visits to physicians (-43%, p < 0.001). Fifty percent of patients reduced their number of consumed tablets >= 80%. Headache-related productivity loss, calculated either as absence from work or >= 50% reduction of productivity during the workday, were reduced by 21% and 34%, respectively ( p < 0.001). Conclusion Standardized treatment of medication-overuse headache in six countries significantly reduced direct health care costs and increased productivity. This emphasizes the importance of increasing awareness of the value of treating medication-overuse headache. Trial registration The trial was registered at ClinicalTrials.gov (no. NCT02435056). PMID- 29984607 TI - Shock waves increase pulmonary vascular leakage, inflammation, oxidative stress, and apoptosis in a mouse model. AB - Severe lung damage is a major cause of death in blast victims, but the mechanisms of pulmonary blast injury are not well understood. Therefore, it is important to study the injury mechanism of pulmonary blast injury. A model of lung injury induced by blast exposure was established by using a simulation blast device. The effectiveness and reproducibility of the device were investigated. Eighty mice were randomly divided into eight groups: control group and 3 h, 6 h, 12 h, 24 h, 48 h, 7 days and 14 days post blast. The explosive device induced an explosion injury model of a single lung injury in mice. The success rate of the model was as high as 90%, and the degree of lung injury was basically the same under the same pressure. Under the same conditions, the thickness of the aluminum film can be from 0.8 mm to 1.6 mm, and the peak pressure could be from 95.85 +/- 15.61 PSI to 423.32 +/- 11.64 PSI. There is no statistical difference in intragroup comparison. A follow-up lung injury experiment using an aluminum film thickness of 1.4 mm showed a pressure of 337.46 +/- 18.30 PSI induced a mortality rate of approximately 23.2%. Compared with the control group (372 +/- 23 times/min, 85.9 +/- 9.4 mmHg, 4.34 +/- 0.09), blast exposed mice had decreased heart rate (283 +/ 21 times/min) and blood pressure (73.6 +/- 3.6 mmHg), and increased lung wet/dry weight ratio(2.67 +/- 0.11), marked edematous lung tissue, ruptured blood vessels, infiltrating inflammatory cells, increased NF-kappaB (4.13 +/- 0.01), TNF-alpha (4.13 +/- 0.01), IL-1beta (2.43 +/- 0.01) and IL-6 (4.65 +/- 0.01) mRNA and protein, decreased IL-10(0.18 +/- 0.02) mRNA and protein ( P < 0.05). The formation of ROS and the expression of MDA5 (4.46 +/- 0.01) and IREalpha (3.43 +/ 0.00) mRNA and protein were increased and the expression of SOD-1 (0.28 +/- 0.02) mRNA and protein was decreased ( P < 0.05). Increased expression of Bax (3.54 +/- 0.00) and caspase 3 (4.18 +/- 0.01) mRNA and protein inhibited the expression of Bcl-2 (0.39 +/- 0.02) mRNA and protein. The changes of pulmonary edema, inflammatory cell infiltration, and cell damage factor expression increased gradually with time, and reached the peak at 12-24 h after the outbreak, and returned to normal at 7-14 days. Detonation injury can lead to edema of lung tissue, pulmonary hemorrhage, rupture of pulmonary vessels, induction of early inflammatory responses accompanied by increased oxidative stress in lung tissue cells and increased apoptosis in mice experiencing blast injury. The above results are consistent with those reported in other literatures. It is showed that the mouse lung blast injury model is successfully modeled, and the device can be used for the study of pulmonary blast injury. Impact statement The number of patients with explosive injury has increased year by year, but there is no better treatment. However, the research on detonation injury is difficult to carry out. One of the factors is the difficulty in making the model of blast injury. The laboratory successfully developed and produced a simulation device of explosive knocking through a large amount of literature data and preliminary experiments, and verified the preparation of the simulation device through various experimental techniques. The results showed that the device could simulate the shock wave-induced acute lung injury generated, which was similar to the actual knocking injury. The experimental process was controlled. Under the same condition, there was no statistical difference between the groups. It is possible to realize miniaturization and precision of an explosive knocking simulation device, which is a good experimental tool for further research on the mechanism of organ damage caused by detonation and the development of protective drugs. PMID- 29984610 TI - Editorial Comment on: Risk of Radiation-Induced Cataracts: Investigation of Radiation Exposure to the Eye Lens During Endourologic Procedures by Hartmann et al. PMID- 29984609 TI - Physical activity and disability measures in chronic non-specific low back pain: a study of responsiveness. AB - OBJECTIVES:: To compare the responsiveness of disability measures with physical activity measures in patients with chronic low back pain (CLBP) undergoing a course of physical therapy treatment. DESIGN:: This is a prospective cohort study with two-month follow-up. SUBJECTS:: A total of 106 patients presenting with non specific CLBP of more than three months duration were recruited. MAIN MEASURES:: Disability measures investigated were Quebec Back Pain Disability Scale and Roland Morris Disability Questionnaire. Physical activity measures analyzed include the Baecke Habitual Physical Activity Questionnaire and objective measures derived from an accelerometer (i.e. total time spent in moderate-to vigorous and light physical activity, number of steps and counts per minute). Disability and physical activity measures were collected at the baseline and after eight weeks of treatment. For the responsiveness analyses, effect size (ES) and standardized response mean (SRM) were calculated. Correlations between the change in disability and physical activity measures were calculated. RESULTS:: Responsiveness for disability measures was considered to be large with ESs ranging from -1.03 to -1.45 and SRMs ranging from -0.99 to -1.34, whereas all physical activity measures showed values lower than 0.20. Changes in disability measures did not correlate with changes in physical activity measures (correlation coefficients ranged from -0.10 to 0.09). CONCLUSION:: Disability measures were responsive after a course of physical therapy treatment in patients with CLBP. The lack of responsiveness in the physical activity measures might be due to the inability of these measures to detect change over time or the use of an intervention not designed to increase physical activity levels. PMID- 29984611 TI - Diagnostic and Interventional Nephrology in Spain: A snapshot of current situation. AB - BACKGROUND: Diagnostic and Interventional Nephrology has been a rising field in recent years worldwide. Catheter insertion, renal biopsy, renal ultrasound, and peritoneal dialysis catheter or permanent dialysis catheter insertion are vital to our specialty. At present, many of these procedures are delegated to other specialties, generating long waiting lists and limiting diagnosis and treatment. METHODS: An online survey was emailed to all Nephrology departments in Spain. One survey response was allowed per center. RESULTS: Of 195 Nephrology departments, 70 responded (35.8%). Of them, 72.3% (52) had ultrasound equipment, 77.1% insert temporary jugular catheters, and 92.8% femoral. Up to 75.7% (53 centers) perform native renal biopsies, of which 35.8% (19) are real-time ultrasound guided by nephrologists. Transplant kidney biopsies are done in 26 centers, of which 46.1% (12) by nephrologists. Tunneled hemodialysis catheters are inserted in 27 centers (38.5%), peritoneal catheter insertion in 18 (31.6%), and only 2 centers (2.8%) perform arteriovenous fistulae angioplasty. In terms of ultrasound imaging, 20 centers (28.5%) do native renal ultrasound and 16 (22.8%) transplanted kidneys. Of all units 71.4% offer carotid ultrasound to evaluate cardiovascular risk, only in 15 centers (21%) by nephrologists. AVF ultrasound scanning is done in 55.7% (39). CONCLUSION: Diagnostic and Interventional Nephrology is slowly spreading in Spain. It includes basic techniques to our specialty, allowing nephrologists to be more independent, efficient, and reducing waiting times and costs, overall improving patient care. Nowadays, more nephrologists aim to perform them. Therefore, appropriate training on different techniques should be warranted, implementing an official certification and teaching programs. PMID- 29984612 TI - Neoadjuvant chemotherapy followed by interval debulking surgery for unresectable stage IVB Serous endometrial cancer. AB - OBJECTIVE: To test the safety and effectiveness of neoadjuvant chemotherapy followed by interval debulking surgery in unresectable stage IVB serous endometrial cancer. METHODS: Data of consecutive stage IVB serous endometrial cancer are reviewed. Patients undergoing neoadjuvant chemotherapy plus interval debulking surgery were propensity matched with patients undergoing primary surgery followed by adjuvant treatment. RESULTS: Thirty-four patients were diagnosed with a stage IVB endometrial cancer. Fifteen (44.1%) patients had neoadjuvant chemotherapy followed by interval debulking surgery; while 19 (55.8%) patients had primary cytoreduction. Among this latter group, 15 (78.9%) patients were selected, using a propensity-matched algorithm. Results of propensity matching baseline characteristics of patients included were similar between groups. Patients having neoadjuvant chemotherapy plus interval debulking surgery had shorter length of hospital stay (4 [1.40] vs 6 [2.5] days; p=0.011) compared with patients in the control group. Moreover, patients in the neoadjuvant chemotherapy group experienced a trend toward shorter operative time (127 [62] vs 177.6 [84.5] minutes; p=0.072) and lower transfusion rate than patients in the control group (6.6% vs 33.3%; p=0.067). Cytoreduction rate was similar between groups (p=0.962). No difference in postoperative morbidity was recorded. Median disease-free survival was 12.0 vs 15.3 months in the experimental vs control group (p=0.663; log-rank test). Median overall survival was 16.7 vs 18.0 months in the experimental vs control group (p=0.349; log-rank test). CONCLUSIONS: Neoadjuvant chemotherapy might be a valuable treatment modality for patients with unresectable stage IVB serous endometrial cancer. Innovative treatments are warranted in this cluster of patients. PMID- 29984613 TI - Prognostic value of platelet-to-lymphocyte ratio in oncologic outcomes of esophageal cancer: what should we expect from a meta-analysis? PMID- 29984614 TI - Spectral Tuning of White Light Allows for Strong Reduction in Melatonin Suppression without Changing Illumination Level or Color Temperature. AB - Studies with monochromatic light stimuli have shown that the action spectrum for melatonin suppression exhibits its highest sensitivity at short wavelengths, around 460 to 480 nm. Other studies have demonstrated that filtering out the short wavelengths from white light reduces melatonin suppression. However, this filtering of short wavelengths was generally confounded with reduced light intensity and/or changes in color temperature. Moreover, it changed the appearance from white light to yellow/orange, rendering it unusable for many practical applications. Here, we show that selectively tuning a polychromatic white light spectrum, compensating for the reduction in spectral power between 450 and 500 nm by enhancing power at even shorter wavelengths, can produce greatly different effects on melatonin production, without changes in illuminance or color temperature. On different evenings, 15 participants were exposed to 3 h of white light with either low or high power between 450 and 500 nm, and the effects on salivary melatonin levels and alertness were compared with those during a dim light baseline. Exposure to the spectrum with low power between 450 and 500 nm, but high power at even shorter wavelengths, did not suppress melatonin compared with dim light, despite a large difference in illuminance (175 vs. <5 lux). In contrast, exposure to the spectrum with high power between 450 and 500 nm (also 175 lux) resulted in almost 50% melatonin suppression. For alertness, no significant differences between the 3 conditions were observed. These results open up new opportunities for lighting applications that allow for the use of electrical lighting without disturbance of melatonin production. PMID- 29984615 TI - Osteogenic differentiation of mesenchymal stem cells modulated by a chemically modified super-hydrophilic titanium implant surface. AB - This study investigated the osteogenic functionality of multipotent mesenchymal stem cells (MSCs) modulated by a chemically modified super-hydrophilic titanium (Ti) bone implant surface to elucidate the biological mechanism underlying the bone healing capacity of this modified Ti surface. A microstructured Ti surface incorporating bioactive ions (in this study, phosphate (P) ions) was prepared by wet chemical treatment. The results showed that the hydrothermally obtained crystalline P-incorporated Ti surface (P surface) displayed long-term super hydrophilicity (water contact angles <5 degrees ) during a 36-week observation period. The hydrophilic P surface enhanced early cellular functions and osteogenic differentiation of multipotent MSCs derived from mouse bone marrow and human adipose tissue. The expression of critical integrins affecting subsequent osteoblast function and osteoblast phenotype genes was notably upregulated in multipotent MSCs grown on the P surface compared with the commercially available grit-blasted microrough clinical oral implant surface. The P surface supported better cell spreading, focal adhesion and ALP activity of MSCs. These results indicate that a super-hydrophilic P-incorporated Ti surface accelerates implant bone healing by enhancing the early osteogenesis functions of multipotent MSCs. PMID- 29984617 TI - "I Don't Like Being That Hyperaware of My Body": Women Survivors of Sexual Violence and Their Experience of Exercise. AB - The experience of exercise among women survivors of sexual violence is a multifaceted phenomenon. In effort to inform treatment interventions, we used a phenomenological approach to describe the lived experience of exercise among women survivors of sexual violence. Data analysis from a focus group discussion and individual interviews with eight women survivors receiving services at a rape crisis center (RCC) revealed four themes: exercising (and not exercising) fosters safety, exercising is risky, past trauma restricts exercise choices, and exercising is beneficial. Findings indicate that survivors' experience of exercise is related to their connections with self and their social environment. Survivors' choices related to exercise were impacted by their stage of recovery. A variety of social-contextual factors appeared to support or impede motivation to exercise and it was not disinterest in exercise or low confidence in the ability to exercise, but restricted exercise options perceived as safe that influenced exercise motivation. PMID- 29984616 TI - Improving Surgical Methods for Studying Vascular Grafts in Animal Models. AB - While clinical vascular grafting uses an end-to-side surgical method, researchers primarily use end-to-end implant techniques in preclinical models. This may be due in part to the limitations of using small animal models in research. The work presented here provides support and evidence for the improvement of vascular graft implant techniques by demonstrating the successful implantation of experimental grafts into both large and small animal models. Specifically, models of aortoiliac baboon (Papio anubis) bypass and common carotid rabbit (Oryctolagus cuniculus) bypass were used to test vascular grafts for thrombosis and vascular healing after 1 month using an end-to-side anastomosis grafting procedure. Patency was evaluated with ultrasound or histological techniques, and neointimal growth was quantified with histology. In the development of this procedure for small animals, both an end-to-end/end-to-side and an end-to-side/end-to-side configuration were tested in rabbits. One hundred percent of rabbit implants (2/2) with an end-to-end/end-to-side configuration were patent at explant. However, with the end-to-side/end-to-side configuration, 66% (6/9) of rabbit implants and 93% (13/14) of baboon implants remained patent at 1 month, suggesting the importance of replicating the end-to-side method for testing vascular grafts for clinical use. This study describes feasible preclinical surgical procedures, which simulate clinical vascular bypass grafts even in small animals. Widespread implementation of these end-to-side surgical techniques in these or other animals should improve the quality of experimental, preclinical testing and ultimately increase the likelihood of translating new vascular graft technologies into clinical applications. PMID- 29984618 TI - Plasma polyunsaturated fatty acid profile is associated with vascular endothelial function in patients with type 2 diabetes. AB - Decreased plasma n-3 polyunsaturated fatty acid levels or the n-3/n-6 polyunsaturated fatty acid ratios are associated with a risk of cardiovascular events. In this cross-sectional study, we measured plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid and investigated the association between the plasma polyunsaturated fatty acid profile and vascular endothelial function in 396 patients with type 2 diabetes. Endothelium-dependent, flow-mediated dilatation of the brachial artery was measured using ultrasonography. Multiple regression analyses, including age, sex, body mass index, and other cardiovascular risk factors, revealed that plasma eicosapentaenoic acid levels ( beta = 0.140, p = 0.008) and the eicosapentaenoic acid/arachidonic acid ratio ( beta = 0.127, p = 0.019), but not plasma docosahexaenoic acid levels ( beta = 0.067, p = 0.220) or the docosahexaenoic acid/arachidonic acid ratio ( beta = 0.034, p = 0.559), were independently and positively associated with flow-mediated dilatation. In conclusion, plasma eicosapentaenoic acid levels and the eicosapentaenoic acid/arachidonic acid ratio are independently associated with endothelial function in patients with type 2 diabetes. This study indicates a positive association between eicosapentaenoic acid, rather than docosahexaenoic acid, and endothelial function in type 2 diabetes. PMID- 29984619 TI - Mandatory Reporting of Domestic Violence: What Do Abuse Survivors Think and What Variables Influence Those Opinions? AB - For decades, states have passed legislation to mandate reporting of criminal conduct and the abuse of vulnerable persons. Four types of mandatory reporting laws have been enacted, including laws that require reports of injuries associated with crime or due to use of certain weapons, abuse of children, abuse of vulnerable adults, and reporting of domestic violence. While studies have been conducted to evaluate the effectiveness of mandatory reporting laws in domestic violence cases, methodological weaknesses in this body of literature make it difficult to make broad statements about whether mandatory reporting laws advance women's protection or actually place them at additional risk. This study's sample is based on 388 surveys administered in-person to women who had sought services from one of Kentucky's 15 regional domestic violence shelters. In addition to querying women regarding their own experience with mandatory reporting laws, the survey explored the factors that influenced women's views. The study advances research into women's decisions to access shelters, medical, or mental health services and how they are influenced by advance knowledge that their case would be reported if they disclosed abuse. A new and troubling finding was that almost two in five women reported they would have been less likely to contact a domestic violence shelter if they knew in advance that a mandatory report would be made. Future research on mandatory reporting is needed with an eye toward changing state policies and laws to ensure that women feel free to seek the type of assistance they need for themselves and their children. PMID- 29984620 TI - Enhanced Neurogenesis and Collaterogenesis by Sodium Danshensu Treatment After Focal Cerebral Ischemia in Mice. AB - Ischemic stroke remains a serious threat to human life. There are limited effective therapies for the treatment of stroke. We have previously demonstrated that angiogenesis and neurogenesis in the brain play an important role in functional recovery following ischemic stroke. Recent studies indicate that increased arteriogenesis and collateral circulation are determining factors for restoring reperfusion and outcomes of stroke patients. Danshensu, the Salvia miltiorrhiza root extract, is used in treatments of various human ischemic events in traditional Chinese medicine. Its therapeutic mechanism, however, is not well clarified. Due to its proposed effect on angiogenesis and arteriogenesis, we hypothesized that danshensu could benefit stroke recovery through stimulating neurogenesis and collaterogenesis in the post-ischemia brain. Focal ischemic stroke targeting the right sensorimotor cortex was induced in wild-type C57BL6 mice and transgenic mice expressing green fluorescent protein (GFP) to label smooth muscle cells of brain arteries. Sodium danshensu (SDS, 700 mg/kg) was administered intraperitoneally (i.p.) 10 min after stroke and once daily until animals were sacrificed. To label proliferating cells, 5-bromo-2'-deoxyuridine (BrdU; 50 mg/kg, i.p.) was administered, starting on day 3 after ischemia and continued once daily until sacrifice. At 14 days after stroke, SDS significantly increased the expression of vascular endothelial growth factor (VEGF), stromal derived factor-1 (SDF-1), brain-derived neurotrophic factor (BDNF), and endothelial nitric oxide synthase (eNOS) in the peri-infarct region. SDS-treated animals showed increased number of doublecortin (DCX)-positive cells. Greater numbers of proliferating endothelial cells and smooth muscle cells were detected in SDS-treated mice 21 days after stroke in comparison with vehicle controls. The number of newly formed neurons labeled by NeuN and BrdU antibodies increased in SDS-treated mice 28 days after stroke. SDS significantly increased the newly formed arteries and the diameter of collateral arteries, leading to enhanced local cerebral blood flow recovery after stroke. These results suggest that systemic sodium danshensu treatment shows significant regenerative effects in the post-ischemic brain, which may benefit long-term functional recovery from ischemic stroke. PMID- 29984621 TI - Trauma Trainees' Multiple Competing Goals in Opioid Prescription Communication. AB - Prescription opioids and heroin account for more than half of all drug overdose fatalities, costing an estimated 115 American lives every day. The ongoing opioid epidemic devastates communities and represents a tremendous burden to the national economy and health care system. In 2016, the Centers for Disease Control and Prevention and the White House Office of National Drug Control Policy proposed action to train prescribers on the proper dispensing of opioids, which are indispensable pharmacologic resources for treating acute pain resulting from a traumatic injury or surgery. Trauma surgeons who prescribe opioids for severe pain embark on patient consultations with multiple and conflicting goals respective to their roles as a healers of the suffering, regulators of illicit substances, members of a greater medical system working to contain an opioid epidemic, and moral beings with a distinct set of preferences, experiences, social norms, and practice philosophies. Semistructured interviews with 17 trauma and surgical residents and fellows at a southeastern academic medical center in the United States generated descriptive data regarding prescribing practices and patient communication. Guided by the multiple goals framework, the current research presents three prominent themes depicting the problematic convergence of identity, task, and relational goals during opioid-prescribing conversations between trauma trainees and their patients. PMID- 29984622 TI - Doubly robust weighted log-rank tests and Renyi-type tests under non-random treatment assignment and dependent censoring. AB - The log-rank test is widely used to test difference in event time distribution between treatment groups. However, if subjects are not randomly assigned to treatment groups, which is often the case in observation studies, the log-rank test is not asymptotically correct for detecting group survival difference due to the imbalance of confounding variables between groups. We develop a class of modified weighted log-rank tests and Renyi-type tests for two-sample survival comparison under non-random treatment assignment. The new tests can also account for non-random censoring that depends on baseline covariates. The proposed methods involve building working models for treatment assignment, cause-specific hazard of dependent censoring, and the time to event. We prove that, when either the models for treatment assignment and dependent censoring or the model for the event time is true, the new tests are asymptotically correct, i.e. being doubly robust. Numerical experiments demonstrate the tests' double-robustness property in finite samples of realistic sizes, and also show that the doubly robust log rank test is at least as powerful as the regular log-rank test when the treatment assignment is random and there is no dependent censoring. An application to a kidney transplant data set illustrates the utility of the proposed methods. PMID- 29984623 TI - Massive heterotopic ossification after distal femur fracture. AB - Introduction Heterotopic ossification is the formation of lamellar bone in periarticular soft tissue that can be seen in paralysed patients or following trauma. It can cause significant burden to already debilitated patients. Case presentation A 12-year-old boy with paraplegia due to neuromyelitis optica presented with progressive right knee pain and swelling. There was no history of trauma to the knee. Anteroposterior radiograph of femur at the initial presentation showed a supracondylar femur fracture for which casting was performed. Six weeks later, when casting was removed, swelling along with increased rubor in distal thigh region was noted. Radiography of the right femur revealed an unhealed distal femur fracture along with massive ossification extending from lesser trochanter to fracture line along the soft tissue around the femoral shaft. Conclusion This case presented the clinical and imaging findings of a giant heterotopic ossification in the thigh region following an extra-articular fracture. PMID- 29984624 TI - Evaluation of effects of anti-vibration gloves on manual dexterity. AB - The purpose of this study was to evaluate the effects of anti-vibration gloves on manual dexterity and to explore factors affecting the manual dexterity. The manual dexterity of ten different gloves was investigated with 15 adult male subjects via performing two different dexterity tests, namely ASTM F2010 standard test and Two-Hand Turning and Placing Minnesota test. Two-factor repeated measures analysis of variance was conducted to evaluate the main effects of glove type, test method and their interaction effect on manual dexterity. Results suggested that glove type yielded significant effect on manual dexterity (p < .001), while no significant difference was observed between test methods (p = .112). The interaction effect of glove type and test method also revealed a significant difference (p = .009). The manual dexterity decreased nearly linearly with increase in the glove thickness, which further showed a moderately significant difference on the number of drops during the tests. Practitioner Summary: Anti-vibration gloves may adversely affect manual dexterity and work precision, which may discourage their usage. This article presented a study of manual dexterity performance of anti-vibration gloves and the design factors affecting the manual dexterity. The results were discussed in view of a design guidance for improved hand dexterity, which would encourage the use of anti vibration gloves in the workplace. PMID- 29984625 TI - A new survival model with surviving fraction: An application to colorectal cancer data. AB - We propose a new survival model for lifetime data in the presence of surviving fraction and obtain some of its properties. Its genesis is based on extensions of the promotion time cure model, where an extra parameter controls the heterogeneity or dependence of an unobserved number of lifetimes. We construct a regression model to evaluate the effects of covariates in the cured fraction. We discuss inference aspects for the proposed model in a classical approach, where some maximum likelihood tools are explored. Further, an expectation maximization algorithm is developed to calculate the maximum likelihood estimates of the model parameters. We also perform an empirical study of the likelihood ratio test in order to compare the promotion time cure and the proposed models. We illustrate the usefulness of the new model by means of a colorectal cancer data set. PMID- 29984626 TI - The role of the pharmacist in the multidisciplinary approach to the prevention and resolution of drug-related problems in cancer chemotherapy. AB - Background Clinical pharmacists have important roles in implementing scientifically valid knowledge and advice on safe, reasonable use of pharmaceuticals. Clinical pharmacy services were introduced and evaluated in oncology clinic in a tertiary university hospital. Methods A prospective interventional study was conducted from November 2017 to March 2018. Drug-related problems were classified using the Pharmaceutical Care Network Europe drug related problem classification tool v8.01. The main outcome measure is the proposed interventions aimed at identification of the drug-related problems, the role of the pharmacists in the resolution, and the rate of acceptance of these recommendations by physicians. Results A total of 102 patients were included in the study, who were treated with at least two cycles of any cancer type and stage. A total of 55 (53.9%) patients had 251 drug-related problems. Drug-related problems mainly involved antihypertensive (31.6%), antidiabetic (17.8%), and herbal agents (31.6%). Treatment effectiveness was the major type of drug-related problems (50.2%) followed by treatment safety (29.1%). A total of 211 (100%) interventions were accepted and regarded as clinically relevant. Prescriber informed only were the most common types of intervention at the prescriber level. Eighty-six point four percent identified drug-related problems were solved, 9.8% of the problems were partially solved, 2.3% problems were unsolved. Conclusion Clinical pharmacy services may have optimized therapy effectiveness, prevent adverse effects and unclear/compliant problems. The pharmacist interventions were highly acknowledged by oncologists and patients; this may indicate the presence of a great convenience and need to implement Clinical pharmacy services in alternative hospitals in Northern Cyprus. PMID- 29984627 TI - Spontaneous hematoma of the thigh associated with antiproteinase-3 antibody in a patient with metastatic squamous cell carcinoma treated with nivolumab. AB - We report an unusual case of spontaneous intramuscular hematoma associated with antiproteinase 3 antibody in a patient with metastatic squamous cell carcinoma receiving nivolumab and the medical literature is reviewed. PMID- 29984628 TI - Guidewire-induced asystole complicating a right internal jugular catheter placement in a patient with pre-existing left bundle branch block: A case report. AB - Internal jugular venous catheters are widely used for hemodialysis as permanent vascular access in patients with severe peripheral vascular disease or transiently for acute hemodialysis. The Seldinger technique is the most widely used technique in catheter insertion. The guidewire-related complications are rare but sometimes it has significant morbidity and mortality. In this case report, we have a patient who developed asystole during catheter insertion which required transvenous pacemaker insertion. PMID- 29984629 TI - A Bilayered Poly (Lactic-Co-Glycolic Acid) Scaffold Provides Differential Cues for the Differentiation of Dental Pulp Stem Cells. AB - INTRODUCTION: Regenerative endodontics (RE) is a clinical procedure that aims to regenerate the dentin-pulp complex (DPC). Current clinical outcomes of RE are unpredictable, and the regenerated tissue lacks the spatial organization observed in normal DPC. The purpose of this study was to develop and characterize in vitro a bilayered scaffold with distinct porosities on each side that supports directional cell penetration and differential odontoblastic differentiation of cultured human dental pulp stem cells (DPSCs). MATERIALS AND METHODS: Bilayered scaffolds were manufactured from poly (lactic-co-glycolic acid) (PLGA) using diffusion-induced phase separation. The layers were generated separately from 12% and 20% (w/v) PLGA, and combined by lamination. Scaffold morphology was assessed through scanning electron microscopy. Human DPSCs were cultured on either side of the scaffold. Cell proliferation, viability, and penetration into the scaffolds were analyzed biochemically and by confocal imaging. Odontoblastic differentiation of the DPCSs and mineralization were analyzed by quantitative real-time polymerase chain reaction, quantification of Alizarin red staining, energy-dispersive X-ray spectroscopy, and Fourier-transform infrared spectroscopy. RESULTS: The bilayered scaffold (thicknesses 277 +/- 15 MUm) contained continuous channels with gradual taper. Channel diameters ranged from 45 to 10 MUm on the open side (20% side) and 10-5 MUm on the closed side (12% side). While proliferating equally on either scaffold surfaces, DPSCs penetrated into the open side and through the entire thickness of that layer in 14 days. By contrast, the closed side limited cell penetration into the scaffold but significantly promoted dentinogenic differentiation in the absence of any dentinogenic induction medium. CONCLUSIONS: Bilayered scaffolds provide spatial control of differential DPSC penetration and dentinogenic differentiation, thus providing a potential scaffold for DPC regeneration. PMID- 29984630 TI - Experiences of Self-Monitoring in Self-Directed Weight Loss and Weight Loss Maintenance: Systematic Review of Qualitative Studies. AB - The experience and role of self-monitoring in self-directed weight loss attempts may be distinctly different from that within formal interventions, and has yet to be fully explored. We systematically reviewed qualitative studies to examine experiences of self-monitoring as an aid to self-directed weight loss. Thematic synthesis was used to construct descriptive and analytical themes from the available data. In all, 22 studies (681 participants) were included, in which the uses of self-monitoring ranged from an aid to increase adherence to a tool for facilitating analysis. Self-monitoring also influenced and was influenced by self perception and emotions. Feelings of shame were linked with abandonment of efforts. Findings highlight the centrality of interpretation of self-monitored data, the implications this interpretation has on sense of self, and the impact of broader discourses. Explicitly framing self-monitoring as a positive tool with which to aid analysis may encourage helpful use of this technique. PMID- 29984631 TI - Zinc finger and interferon-stimulated genes play a vital role in TB-IRIS following HAART in AIDS. AB - AIM: Co-infection in HIV-1 patients with Mycobacterium tuberculosis poses considerable risk of developing the immune reconstitution inflammatory syndrome (IRIS), especially upon the initiation of antiretroviral therapy (ART). Methodology & results: For transcriptomic analysis, peripheral blood mononuclear cells' whole gene expression was used from three patient groups: HIV+ (H), HIV TB+ (HT), HIV-TB+ with IRIS (HTI). Pathway enrichment and functional analysis was performed before and after highly active ART. Genes in the interferon-stimulating and ZNF families maintained tight functional interaction and tilted the balance in favor of TB-IRIS. DISCUSSION & CONCLUSION: The functional impairment of interaction between ZNF genes and interferon-stimulated genes, along with higher expression of S100A8/S100A9 genes possibly forms the genomic basis of TB-IRIS in a subset of HIV patients while on highly active ART. PMID- 29984632 TI - Closeness Discrepancies and Intimacy Interference: Motivations for HIV Prevention Behavior in Primary Romantic Relationships. AB - Relational closeness has been positively associated with relationship quality and mental health; however, desire for closeness and intimacy in a relationship may also motivate sexual risk-taking, that is, forgoing condom use. This study examined the impact of desiring more closeness with a primary partner (i.e., motivation for reducing closeness discrepancies) on HIV prevention behavior. Using pre-exposure prophylaxis (PrEP) as a case study, we examined the extent to which closeness discrepancies motivate behavioral intentions (Study 1) and actual behavior (Study 2). In both studies, desiring more closeness and believing that condoms interfere with intimacy were independently positively associated with PrEP adoption. Understanding the relational needs for closeness and intimacy in motivating prevention behavior is critical for social psychology, relationship science, and public health efforts to improve sexual health. PMID- 29984633 TI - Bayesian negative-binomial-family-based multistate Markov model for the evaluation of periodic population-based cancer screening considering incomplete information and measurement errors. AB - Population-based cancer screening is often asked but hardly addressed by a question: "How many rounds of screening are required before identifying a cancer of interest staying in the pre-clinical detectable phase (PCDP)?" and also a similar one related to the number of screens required for stopping screening for the low risk group. It can be answered by using longitudinal follow-up data on repeated rounds of screen, namely periodic screen, but such kind of data are rather complicated and fraught with intractable statistical properties including correlated multistate outcomes, unobserved and incomplete (censoring or truncation) information, and imperfect measurements. We therefore developed a negative-binomial-family-based discrete-time stochastic process, taking sensitivity and specificity into account, to accommodate these thorny issues. The estimation of parameters was implemented with Bayesian Markov Chain Monte Carlo method. We demonstrated how to apply this proposed negative-binomial-family-based model to the empirical data similar to the Finnish breast cancer screening program. PMID- 29984634 TI - Hybrid copula mixed models for combining case-control and cohort studies in meta analysis of diagnostic tests. AB - Copula mixed models for trivariate (or bivariate) meta-analysis of diagnostic test accuracy studies accounting (or not) for disease prevalence have been proposed in the biostatistics literature to synthesize information. However, many systematic reviews often include case-control and cohort studies, so one can either focus on the bivariate meta-analysis of the case-control studies or the trivariate meta-analysis of the cohort studies, as only the latter contains information on disease prevalence. In order to remedy this situation of wasting data we propose a hybrid copula mixed model via a combination of the bivariate and trivariate copula mixed model for the data from the case-control studies and cohort studies, respectively. Hence, this hybrid model can account for study design and also due to its generality can deal with dependence in the joint tails. We apply the proposed hybrid copula mixed model to a review of the performance of contemporary diagnostic imaging modalities for detecting metastases in patients with melanoma. PMID- 29984635 TI - Beta-binomial analysis of variance model for network meta-analysis of diagnostic test accuracy data. AB - There are several generalized linear mixed models to combine direct and indirect evidence on several diagnostic tests from related but independent diagnostic studies simultaneously also known as network meta-analysis. The popularity of these models is due to the attractive features of the normal distribution and the availability of statistical software to obtain parameter estimates. However, modeling the latent sensitivity and specificity using the normal distribution after transformation is neither natural nor computationally convenient. In this article, we develop a meta-analytic model based on the bivariate beta distribution, allowing to obtain improved and direct estimates for the global sensitivities and specificities of all tests involved, and taking into account simultaneously the intrinsic correlation between sensitivity and specificity and the overdispersion due to repeated measures. Using the beta distribution in regression has the following advantages, that the probabilities are modeled in their proper scale rather than a monotonic transform of the probabilities. Secondly, the model is flexible as it allows for asymmetry often present in the distribution of bounded variables such as proportions, which is the case with sparse data common in meta-analysis. Thirdly, the model provides parameters with direct meaningful interpretation since further integration is not necessary to obtain the meta-analytic estimates. PMID- 29984636 TI - New expectation-maximization-type algorithms via stochastic representation for the analysis of truncated normal data with applications in biomedicine. AB - To analyze univariate truncated normal data, in this paper, we stochastically represent the normal random variable as a mixture of a truncated normal random variable and its complementary random variable. This stochastic representation is a new idea and it is the first time to appear in literature. According to this stochastic representation, we derive important distributional properties for the truncated normal distribution and develop two new expectation-maximization algorithms to calculate the maximum likelihood estimates of parameters of interest for Type I data (without and with covariates) and Type II/III data. Bootstrap confidence intervals of parameters for small sample sizes are provided. To evaluate the performance of the proposed methods for the truncated normal distribution, in simulation studies, we first focus on the comparison of estimation results between including the unobserved data counts and excluding the unobserved data counts, and we next investigate the impact of the number of unobserved data on the estimation results. The plasma ferritin concentration data collected by Australian Institute of Sport and the blood fat content data are used to illustrate the proposed methods and to compare the truncated normal distribution with the half normal, the folded normal, and the folded normal slash distributions based on Akaike information criterion and Bayesian information criterion. PMID- 29984637 TI - Variable selection in rank regression for analyzing longitudinal data. AB - In this paper, we consider variable selection in rank regression models for longitudinal data. To obtain both robustness and effective selection of important covariates, we propose incorporating shrinkage by adaptive lasso or SCAD in the Wilcoxon dispersion function and establishing the oracle properties of the new method. The new method can be conveniently implemented with the statistical software R. The performance of the proposed method is demonstrated via simulation studies. Finally, two datasets are analyzed for illustration. Some interesting findings are reported and discussed. PMID- 29984638 TI - A Bayesian hierarchical model for demand curve analysis. AB - Drug self-administration experiments are a frequently used approach to assess the abuse liability and reinforcing property of a compound. It has been used to assess the abuse liabilities of various substances such as psychomotor stimulants and hallucinogens, food, nicotine, and alcohol. The demand curve generated from a self-administration study describes how demand of a drug or non-drug reinforcer varies as a function of price. With the approval of the 2009 Family Smoking Prevention and Tobacco Control Act, demand curve analysis provides crucial evidence to inform the US Food and Drug Administration's policy on tobacco regulation because it produces several important quantitative measurements to assess the reinforcing strength of nicotine. The conventional approach popularly used to analyze the demand curve data is individual-specific non-linear least square regression. The non-linear least square approach sets out to minimize the residual sum of squares for each subject in the dataset; however, this one subject-at-a-time approach does not allow for the estimation of between- and within-subject variability in a unified model framework. In this paper, we review the existing approaches to analyze the demand curve data, non-linear least square regression, and the mixed effects regression and propose a new Bayesian hierarchical model. We conduct simulation analyses to compare the performance of these three approaches and illustrate the proposed approaches in a case study of nicotine self-administration in rats. We present simulation results and discuss the benefits of using the proposed approaches. PMID- 29984639 TI - A method to account for covariate-specific treatment effects when estimating biomarker associations in the presence of endogenous medication use. AB - In the modern era, cardiovascular biomarkers are often measured in the presence of medication use, such that the observed biomarker value for the treated participants is different than their underlying natural history value. However, for certain predictors (e.g. age, gender, and genetic exposures) the observed biomarker value is not of primary interest. Rather, we are interested in estimating the association between these predictors and the natural history of the biomarker that would have occurred in the absence of treatment. Nonrandom medication use obscures our ability to estimate this association in cross sectional observational data. Structural equation methodology (e.g. the treatment effects model), while historically used to estimate treatment effects, has been previously shown to be a reasonable way to correct endogeneity bias when estimating natural biomarker associations. However, the assumption that the effects of medication use on the biomarker are uniform across participants on medication is generally not thought to be reasonable. We derive an extension of the treatment effects model to accommodate effect modification. Based on several simulation studies and an application to data from the Multi-Ethnic Study of Atherosclerosis, we show that our extension substantially improves bias in estimating associations of interest, particularly when effect modifiers are associated with the biomarker or with medication use, without a meaningful cost of efficiency. PMID- 29984640 TI - Editorial: Thiazole Heterocycle: A Privileged Scaffold for Drug Design and Discovery. PMID- 29984641 TI - Molecular Aspects of the Dengue Virus Infection Process: A Review. AB - BACKGROUND: At the present time, dengue is one of the most important arboviruses affecting man, becoming a serious global public health problem, especially in subtropical and tropical countries, where environmental conditions favor the development and proliferation of the mosquito Aedes aegypti. Dengue is caused by a type of flavivirus, which is an enveloped virus of spherical geometry. Nowadays, it is one of the diseases with the highest incidence in Brazil, reaching the population of all states, regardless of social class. Several papers address the molecular aspects of infection of human cell by the viruses, which are reviewed in this work. CONCLUSION: Analyzing the three-dimensional structures of the fusion peptide of dengue virus protein E, we observed that the fusion peptide presents a region rich in hydrophobic residues and a "collar" of charged, polar residues. Probably, this hydrophilic collar plays an important role in the fusion process between the dengue virus and the cell membrane. In order for this disease to cease being a serious global public health problem, we must deepen our knowledge about the fusion process between the dengue virus and the cell membrane through further experimental and, especially, computational studies to find ways to inhibit the mechanism of virus infection. PMID- 29984642 TI - Sitosterolemia: diagnosis, metabolic and hematological abnormalities, cardiovascular disease and management. AB - Sitosterolemia is a recessive inherited metabolic disorder of unknown prevalence, characterized by increased levels of plasma plant sterols. It is caused by 28 and 31 variants in ABCG5 and ABCG8 genes, respectively, and is characterized by a predisposition to hyperabsorption and accumulation of toxic levels of plant sterols in plasma. Its clinical picture is extremely heterogeneous. The main clinical features are tendinous and cutaneous xanthomas, arthritis or arthralgia, premature cardiovascular disease and atherosclerosis. These characteristics are shared with familial hypercholesterolemia (FH), making it possible for sitosterolemia to be misdiagnosed as homozygous FH, especially in pediatric patients. In such cases, a specific chromatography-based laboratory method is essential to differentiate sitosterol and cholesterol. Hematological abnormalities (hemolytic anemia and macrothrombocytopenia) may be present in 25 35% of patients, in whom it is usually associated with the main clinical features, as occurs in the 70% of the cases. In this context, the peripheral blood smear is essential and reveals giant platelets and stomatocytes. Only 21 causative variants in ABCG5/ABCG8 are associated with macrothrombocytopenia. Most physicians still do not recognize these hematological abnormalities or relate them to sitosterolemia. Patients may suffer long-term misdiagnosis of immune thrombocytopenia and be at high risk of receiving harmful therapies or of not benefitting from a low-cholesterol diet and/or from the gold standard treatment with ezetimibe. This drug reduces levels of plasma plant sterols, provokes regression of xanthomas, and can alleviate hematological abnormalities. Finally, to identify genetic defects, recent advances in high-throughput sequencing, especially in the use of targeted sequencing of pre-specified genes, have begun to be incorporated into the first-line approach in the field of genetic disorders. PMID- 29984643 TI - The Mechanisms behind the Biological Activity of Flavonoids. AB - Flavonoids are phenolic compounds widely distributed in the human diet. Their intake has been associated with a decreased risk of different diseases such as cancer, immune dysfunction or coronary heart disease. However, the knowledge about the mechanisms behind their in vivo activity is limited and still under discussion. For years, their bioactivity was associated with the direct antioxidant and radical scavenging properties of phenolic compounds, but nowadays this assumption is unlikely to explain their putative health effects, or at least to be the only explanation for them. New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This paper reviews all these topics, from the classical view as antioxidant in the context of the Oxidative Stress theory to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression or interactions with the intestinal microbiota. The use of C. elegans as a model organism for the study of the molecular mechanisms involved in biological activity of flavonoids is also discussed. PMID- 29984644 TI - Epigenetic metalloenzymes. AB - Epigenetics control the expression of genes and is responsible for the cellular phenotypes. The fundamental basis of these mechanisms involves in part the post translational modifications (PTMs) of DNA and proteins, in particular the nuclear histones. DNA can be methylated or demethylated on cytosine. Histones are marked by several modifications including acetylation and/or methylation, and of particular importance are the covalent modifications of lysine. It exists a balance between addition and removal of these PTMs, leading to three groups of enzymes involved in these processes: the writers adding marks, the erasers removing them, and the readers able to detect these marks and participating in the recruitment of transcription factors. The stimulation or the repression in the expression of genes is thus the result of a subtle equilibrium between all the possibilities coming from the combinations of these PTMs. Indeed, these mechanisms can be deregulated and then participate in the appearance, development and maintenance of various human diseases, including cancers, neurological and metabolic disorders. Some of the key players in epigenetics are metalloenzymes, belonging mostly to the group of erasers: the zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji family (JMJ or KDM) and for DNA the iron-dependent ten-eleven-translocation enzymes (TET) responsible for oxidation of methyl cytosine prior demtheylation of DNA. This review presents these metalloenzymes, their importance in human disease and their inhibitors. PMID- 29984645 TI - Porous Inorganic and Hybrid Systems for Drug Delivery: Future Promise in Combatting Drug Resistance and Translation to Botanical Applications. AB - BACKGROUND: Porous micro- and nanoparticles have the capacity to encapsulate a large quantity of therapeutics, making them promising delivery vehicles for a variety of applications. This review aims to highlight the capacity of inorganic and hybrid (inorganic/organic) particles for drug delivery with an additional emphasis on combatting drug resistant cancer. We go one step further and discuss delivery applications beyond medicinal delivery, as there is generally a translation from medicinal delivery to botanic delivery after a short lag time. METHODS: We undertook a search of relevant peer-reviewed. The quality of the relevant papers was appraised using standard tools. The characteristics of the papers are described herein, and the relevant material and therapeutic properties are discussed. RESULTS: We discuss 4 classes of porous particles in terms of drug delivery and theranostics. We specifically focus on silica, calcium carbonate, metal-phenolic network, and metal-organic framework particles. Other relevant biomedically relevant applications are discussed and we highlight outstanding therapeutic results in the relevant literature. CONCLUSION: The findings of this review confirm the importance of studying and utilizing porous particles for therapeutic delivery. Moreover, we show that the properties of porous particles that make them promising for medicinal drug delivery also make them promising candidates for agro-industrial applications. PMID- 29984646 TI - Focusing on the influenza virus polymerase complex: recent progress in drug discovery and assay development. AB - Influenza viruses are severe human pathogens that pose persistent threat to public health. Each year more people die of influenza virus infection than that of breast cancer. Due to the limited efficacy associated with current influenza vaccines, as well as emerging drug resistance from small molecule antiviral drugs, there is a clear need to develop new antivirals with novel mechanisms of action. The influenza virus polymerase complex has become a promising target for the development of the next-generation of antivirals for several reasons. Firstly, the influenza virus polymerase, which forms a heterotrimeric complex that consists of PA, PB1, and PB2 subunits, is highly conserved. Secondly, both individual polymerase subunit (PA, PB1, and PB2) and inter-subunit interactions (PA-PB1, PB1-PB2) represent promising drug targets. Lastly, growing insight into the structure and function of the polymerase complex has spearheaded the structure-guided design of new polymerase inhibitors. In this review, we highlight recent progress in drug discovery and assay development targeting the influenza virus polymerase complex and discuss their therapeutic potentials. PMID- 29984647 TI - The impact of phytosterols on the healthy and diseased brain. AB - The central nervous system (CNS) is the most cholesterol-rich organ in mammals. Cholesterol homeostasis is essential for proper brain functioning and dysregulation of cholesterol metabolism can lead to neurological problems. Multiple sclerosis (MS) and Alzheimer's disease (AD) are examples of neurological diseases that are characterized by a disturbed cholesterol metabolism. Phytosterols (PS) are plant-derived components that structurally and functionally resemble cholesterol. PS are known for their cholesterol-lowering properties. Due to their ability to reach the brain, researchers have started to investigate the physiological role of PS in the CNS. In this review, the metabolism and function of PS in the diseased and healthy CNS are discussed. PMID- 29984648 TI - Recent Drug-Repurposing-Driven Advances in the Discovery of Novel Antibiotics. AB - Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information of potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016-2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, anti-inflammatory, anti malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity into its effective implications for inhibiting MDRBIs by repurposing existing drugs. PMID- 29984649 TI - Use of plant sterol and stanol fortified foods in clinical practice. AB - Plant sterols and stanols (PS) are natural, non-nutritive molecules that play a structural role in plant membranes similar to that of cholesterol in animal membranes and abound in seeds and derived oils. PS exert their physical effect of interference with micellar solubilization of cholesterol within the intestinal lumen and are marginally absorbed by enterocytes, with negiglible increases in circulating levels. The physiological role of PS in plants and their natural origin and non-systemic action, together with their cholesterol-lowering effect, make them an attractive option as non-pharmacological agents for the management of hypercholesterolemia. Recent meta-analyses have summarized the results of >100 controlled clinical trials and have firmly established that consumption of PS supplemented foods in different formats at doses of 2-3 g per day results in LDL cholesterol reductions of 9-12%. PS are both effective and safe cholesterol lowering agents and have many clinical applications: adjuncts to a healthy diet, treatment of common hypercholesterolemia, combination therapy with statins and other lipid-lowering drugs, and treatment of metabolic syndrome and diabetes. The cholesterol-lowering efficacy is similar in all clinical situations. PS are also useful agents for treatment of hypercholesterolemic children who are not yet candidates to statins or are receive low-doses of these agents. In the setting of statin treatment, the average LDL-cholesterol reduction obtained with PS is equivalent to up- titrating twice the statin dose. However, information is still scarce on the efficacy of PS as add-on therapy to ezetimibe, fibrates, omega-3 fatty acids, or bile acid binding resins. The consistent scientific evidence on the cholesterol-lowering efficacy and safety of functional foods supplemented with PS has led several national and international scientific societies to endorse their use for the non-pharmacologic treatment of hypercholesterolemia as adjuncts to a healthy diet. There is, however, a lack of clinical trials of PS with outcomes on cardiovascular events. PMID- 29984650 TI - Recent Progress in the Therapeutic Role of Serelaxin in Vascular Dysfunction. AB - Cardiovascular (CV) diseases are caused by vascular dysfunction. The enhanced sensitivity to vasoconstrictors, reduced endothelium-derived vasodilators nitric oxide (NO) and prostacyclin (PGI2), and endothelium-derived hyperpolarization (EDH) indicate CV dysfunction. In recent years, recombinant human relaxin, known as serelaxin, has emerged as a new vasoactive drug that is useful in acute heart failure. First part of this review article encompasses the role of endogenous relaxin in CV homeostasis. Subsequently, vascular effects of serelaxin and the underlying modes of action in comparison to other vasodilators are discussed. Finally, the usefulness of treatment with serelaxin in vascular dysfunction in different CV diseases, particularly due to oxidative stress, is explained. PMID- 29984651 TI - Current Concepts and Perspectives on Connexin43: A Mini Review. AB - Connexins are a family of gap junction proteins widely distributed in human organs and tissues. Gap junctions are organized systems of intercellular protein channels that allow the exchange of ions, chemical signals, and energy substrates between two adjacent cells. Connexin43 (Cx43) is the most abundant isoform of connexins in the heart which play an important role in myocardium disease. Numerous studies have shown that Cx43 was involved in tumor migration and invasion by mediating gap junctions between tumor cells and normal cells. Changes in the expression and distribution of Cx43 contribute to heart disease and cancer. This review discusses current knowledge on the functional and structural abnormalities in Cx43 associated with heart disease and cancer, aiming to highlight the importance of this connexin as an emerging therapeutic target. Here, the current knowledge on the pharmacology of Gap Junction Channels and Hemichannels were also summarized. Finally, we propose that these knowledges can be exploited to identify new diagnostic and effective therapeutic approaches for ischemic heart disease and cancer. PMID- 29984652 TI - Phenotypic Characterization of a Family With An In-frame Deletion in the DMD Gene and Variable Penetrance. AB - Duchenne muscular dystrophy is a disorder with variable expression caused by framedisrupting mutations in the dystrophin gene. It is characterized by progressive muscle weakness and dilated cardiomyopathy. In-frame dystrophin mutations cause a clinically moderate disorder named Becker muscular dystrophy. Our aim was to study the clinical and genetic characteristics of a family with inherited cardiomyopathy and Becker muscular dystrophy. The index case was diagnosed with psychomotor retardation at 5 years of age. Asymmetric left ventricular hypertrophy and a long QT interval were evidenced at the age of 12. Mild muscular weakness was developed subsequently. Three genetic variants were identified in the index case: p.Arg891Alafs*160 in the MYBPC3 gene, p.Thr263Met in the KCNJ5 gene, and p.Ser2437_Ile2554delinsPhe in the DMD gene. The latter was expected to generate an in-frame deletion of exons 51 and 52 of the dystrophin gene. A family study revealed that the father and 3 uncles were carriers of the MYBPC3 mutation. The mother and a maternal grandfather were carriers of the other 2 variants. The 80-year-old grandfather, who had the dystrophin mutation, showed no sign of cardiomyopathy or muscular weakness. The deletion of exons 51 and 52 in the DMD gene, which has been proposed as one of the therapeutic strategies for Duchenne, is consistent with a normal life expectancy and the absence of myopathic symptoms in hemizygous males. PMID- 29984653 TI - Amyloid and Tau Positron Emission Tomography in Suggested Diabetesrelated Dementia. AB - BACKGROUND: Type 2 diabetes mellitus (DM) has been shown to increase the risk for cognitive decline and dementia, such as Alzheimer disease (AD) and vascular dementia (VaD). In addition to AD and VaD, there may be a dementia subgroup associated with specific DM-related metabolic abnormalities rather than AD pathology or cerebrovascular disease, referred to as diabetes-related dementia (DrD). METHOD: We studied 11C-PiB and 11C-PBB3 positron emission tomography (PET) in 31 subjects with DrD and 5 subjects with AD associated with DM to assess amyloid and tau deposits in the brain. RESULTS: All subjects with AD showed both positive PiB and PBB3. However, only 12 out of 31 subjects (39%) with DrD showed positive PiB, whereas 17 out of 21 subjects (81%) who underwent PBB3 PET showed positive PBB3. Depending on the positivity of PiB and PBB3, we classified 21 subjects into a negative PiB and a positive PBB3 pattern (11 cases, 52%), indicating tauopathy, a positive PiB and a positive PBB3 pattern (6 cases, 29%), indicating AD pathology, or a negative PiB and a negative PBB3 pattern (4 cases, 19%). Among 11 subjects showing a negative PiB and a positive PBB3 pattern, there were 2 PBB3 deposit patterns, including the medial temporal lobe only and extensive neocortex beyond the medial temporal lobe. CONCLUSION: DrD showed variable amyloid and tau accumulation patterns in the brain. DrD may be associated predominantly with tau pathology, in addition to AD pathology and non amyloid/non-tau neuronal damage due to DM-related metabolic abnormalities. PMID- 29984654 TI - Progressive Spatial Memory Impairment, Brain Amyloid Deposition and Changes in Serum Amyloid Levels as a Function of Age in APPswe/PS1dE9 Mice. AB - BACKGROUND: Mice co-expressing human amyloid precursor protein with the Swedish mutation (APPswe) and exon-9-deleted presenilin (PS1dE9) has become one of the most widely used mouse models for studying Alzheimer's disease (AD) pathogenesis and preclinical studies of AD therapeutic approaches. OBJECTIVE: In this study, we systematically investigated cognitive decline, amyloid-beta (Abeta) deposition and cerebral or Abeta serum levels as well as the relationships among these measures in APPswe/PS1dE9 transgenic mice. METHOD: APPswe/PS1dE9 mice were separated into four equal age cohorts (4, 6, 9, and 12 months). We assessed cognitive capacity, deposited plaques, and the levels of Abeta40/Abeta42 in brain tissue and serum of mice at different ages. RESULTS: APPswe/PS1dE9 mice exhibited declined memory beginning at 6 months of age, with cognitive capacity remarkably impaired at 12-months. Coincidently, amyloid deposits began to develop in transgenic mice brain at 6-months and increased with age. In addition, Abeta42 levels in brains of APPswe/ PS1dE9 mice increased with age with no parallel increase in Abeta40. The concentration of serum Abeta42 declined from 4 to 6 months of age, but a similar age-dependent decrease was not observed for Abeta40. CONCLUSION: APPswe/PS1dE9 transgenic mice began to develop amyloid plaques at 6 months of age and exhibited a corresponding impairment of spatial learning capacity. Serum Abeta42 level decreased remarkably from 4 to 6 months, at which stage Abeta42 began to accumulate in the brain and deposit as plaques. PMID- 29984655 TI - Tumor-dependent effects of proteoglycans and various glycosaminoglycan synthesizing enzymes and sulfotransferases on patients' outcome. AB - BACKGROUND: The small leucine-rich proteoglycans (SLRPs) biglycan (BGN) and decorin (DCN) linked with sulfated glycosaminoglycan (GAG) chains exhibit oncogenic or tumor suppressive potentials depending on the cellular context and association with GAGs. OBJECTIVE: We hypothesized that structural alterations and expression levels of BGN, DCN and their associated chondroitin sulfate (CS) polymerizing enzymes, dermatan sulfate (DS) epimerases and various sulfatases might be correlated with the tumor (sub)type and patients' survival. METHODS: We acquired breast cancer (BC) and glioma patients' datasets from cBioPortal and R2 Genomics. Structural alterations and the expression pattern of CS polymerizing enzymes, DS epimerases and carbohydrate sulfotransferases (CHST) were compared to that of BGN and DCN and correlated to their clinical relevance. RESULTS: In BC, no mutations, but amplifications (0.2 - 2.1 %) and deletions (0.05 - 0.4 %) were found in BGN, DCN and CS/DS enzymes. In contrast, missense and/or truncated mutations (0.1 - 0.5 %), but a reduced amplification rate (0 - 1.5 %) were found in glioma. When compared to BC the structural abnormalities caused altered mRNA expression levels of BGN, DCN, GAG synthesizing enzymes and CHST. Mutations in SLPRs, CHSY1, CHST4 and CHSY3 were correlated with a poor prognosis in glioma, while lack of mutations and copy number variations in the SLRPs, CHSY3, CHST15 and DSE displayed an increased survival in BC. CONCLUSIONS: A distinct association of BGN and DCN with CHST, CS polymerizing enzymes and DS epimerases was found in BC and glioma. Thus, a unique pattern of structural alterations and expression, which has clinical relevance, was found for PGs and GAG synthesizing enzymes and CHST in BC and glioma, which might help to identify high risk patients and to develop personalized therapeutics. PMID- 29984656 TI - Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors. AB - Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that makes the identification of a targetable biomarker in platinum and taxane resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxane-resistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease. PMID- 29984657 TI - A Comprehensive review on Ethnomedicinal, Pharmacological and Phytochemical Basis of Anticancer Medicinal Plants of Pakistan. AB - The widespread emergence of cancer and development of resistance to chemotherapeutic agents is increasing the interest of scientists in the use of ethnomedicinal preparations and isolated phytochemicals in the treatment and prevention of disease. Medicinal plants are used in Pakistan for prehistoric times. The present review was designed to identify anticancer plants of ethnomedicinal significance and to summarize the anticancer activities carried out on these medicinal plants to establish the pharmacological and phytochemical basis for their use. Pakistani anticancer medicinal plants of ethnopharmacological significance were reviewed. Conservation status, worldwide distribution and ethno-botanical preparations of these medicinal plants were also tabulated. These medicinal plants and their isolated phytochemicals were also explored for their anticancer activities. It was revealed that there were 108 anticancer medicinal plants used to treat different neoplastic conditions on the folklore basis throughout Pakistan. Among these anticancer plants, 64 plants were found to be investigated previously for anticancer activity through in vivo and in vitro methods. Several ethnomedicinal plants have been validated for their anticancer activities through in vitro and animal models. These medicinal plants and phytochemicals resulted in the inhibition of initiation, progression or metastasis of neoplasm. Some medicinal plants (10) are endangered species. Half of folkloric Pakistani plants have been validated for use against various cancers through in vitro or in vivo methods. It is necessary to carry out further pharmacological and toxicological evaluation of these folkloric anticancer plants of Pakistan. It is also necessary to identify and isolate further potential phytochemicals so as to be evaluated in cancer patients. PMID- 29984658 TI - Conjugation of phthalocyanine photosensitizer with poly(amidoamine) dendrimer: improved solubility, disaggregation and photoactivity against HepG2 cells. AB - Objective:To improve solubility and to reduce aggregation, ZnPcC4 was conjugated to a third-generation polyamidoamine dendrimer with amino end group (G3-PAMAM NH2), which acts as a novel photodynamic therapy (PDT) drug carrier system. Method:The phthalocyanines were synthesized by construction reaction. The nanodrug was obtained from the conjugation of ZnPcC4 to G3-PAMAM-NH2, using EDC and NHS as coupling agents. The ZnPcC4@G3-PAMAM-NH2 conjugation was characterized by UV-Vis and MS. The 1O2 quantum yield of ZnPcC4@G3-PAMAM-NH2 in water was measured by the chemiluminescence method. The in vitro PDT responses of the studied photosensitizers were studied in hepatocellular carcinoma cell line HepG2 by MTT assay. Results: At ZnPcC4/G3-PAMAM-NH2 raw ratio of 100/1, the ZnPcC4 conjugate had improved solubility and reduced aggregation tendency in aqueous solution. At this optimum molar ratio, ZnPcC4-G3-PAMAM-NH2 inhibited HepG2 cells, with a half-maximal inhibitory concentration of 1.67 MUg/mL upon infrared light exposure. The controls, including dark conditions, or media as well as G3-PAMAM NH2 exposure, exhibited no inhibitory response. Conclusion:The conjugation of phthalocyanine photosensitizer ZnPcC4 to polyamidoamine dendrimer G3-PAMAM-NH2 officiously improved the PDT outcomes, in which the optimized binding ratio of ZnPcC4 to G3-PAMAM-NH2 was 6:1. PMID- 29984659 TI - Menopausal hormone therapy and cardiovascular risk. Where are we now? AB - Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding estrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age [<10 years since the final menstrual period (FMP)] or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favourable benefit/risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal estrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone has a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer. PMID- 29984660 TI - Lead optimization studies towards finding NS2B/NS3 protease target-specific inhibitors as potential anti-dengue drug-like compounds. AB - Dengue Fever is a major threatening global health issue caused by a mosquito borne pathogen. Even though some anti-viral drugs are now available to reduce the disease severity. Still, there is a need for better drug compound to combat with dengue fever. The NS2B/NS3 protease is a major therapeutic drug target for Insilco drug discovery. Previously, we have performed a pharmacophore feature based virtual screening studies, which has led to the identification of ZINC92615064 compound as a potent NS2B/NS3 protease inhibitor and demonstrated its potential to act as anti-dengue drug-like compound using computational approaches. In this present study, the identified lead compound ZINC92615064 has been made to undergo scaffold hopping based novel library generation, and the resulted novel library of compounds has been virtually screened on to NS2B/NS3 protease towards identifying novel proprietary scaffold of compound which is acting as a potent inhibitor for the given drug target of NS2B/NS3. A total of 16,847 novels designed compounds library was generated using the scaffold hopping technology based on the structure of the lead compound ZINC92615064. Out of which, compound design no. 3718 has shown the best binding potential with a predicted IC50 value of 417.13 nM along with a permissible range of ADMET properties based on its descriptor values. This NS2B/NS3 protease in complex with compound 3718 was subjected to a rigorous molecular dynamic simulation study to further validate this complex thermodynamic stability, along with the aim to reveal the underlying molecular level interactions and potential mode of action. PMID- 29984661 TI - Role of C1858T polymorphism of Lymphoid Tyrosine Phosphatase in Egyptian children and adolescents with type 1 diabetes. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) is a multifactorial autoimmune disease. The protein tyrosine phosphatase non-receptor 22 (PTPN22) gene is an important negative regulator of signal transduction through the T-cell receptors (TCR). A PTPN22 polymorphism, C1858T, has been found to be a risk determinant for several autoimmune diseases, including T1DM, in different populations. OBJECTIVE: The present study was aimed to analyze a possible association between the C1858T polymorphism in Egyptian children with T1DM. METHODS: This case-control study included 240 children divided evenly between T1DM patients and controls. The PTPN22 C1858T polymorphism was genotyped using polymerase chain reaction with restriction fragment length polymorphism (RFLP). RESULTS: Both the 1858CTau and 1858TauTau genotypes and the 1858T allele were found more frequently in patients (32.5% and 18.7%, respectively) than in controls (10% and 5.0%, respectively), P=0.013 and P=0.007, respectively. Among females, the 1858T allele was more common in patients (18%) than in controls (2.6%), P=0.014. CONCLUSION: These findings suggest that the PTPN22 1858T allele could be a T1DM susceptibility factor in the Egyptian population and that it might play a different role in susceptibility to T1DM according to gender in T1DM patients. PMID- 29984662 TI - Renin-Angiotensin-Aldosterone System Gene Polymorphisms and Type 2 Diabetic Nephropathy in Asian Populations: An Updated Meta-analysis. AB - BACKGROUND: The association of polymorphisms in the renin-angiotensin-aldosterone system candidate genes, namely angiotensin-converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T and angiotensin II receptor type 1 (AGTR1) A1166C with diabetic nephropathy (DN) has been studied for decades. OBJECTIVE: This meta-analysis aimed to assess the updated pooled effects of these polymorphisms with DN among Asian populations with type 2 diabetes mellitus. METHODS: The PubMed electronic database was searched without duration filter until August 2017 and the reference list of eligible studies was screened. The association of each polymorphism with DN was examined using odds ratio and its 95% confidence interval based on dominant, recessive and allele models. Subgroup analyses were conducted based on region, DN definition and DM duration. RESULTS: In the main analysis, the ACE I/D (all models) and AGTR1 A1166C (dominant model) showed a significant association with DN. The main analysis of the AGT M235T polymorphism did not yield significant findings. There were significant subgroup differences and indication of significantly higher odds for DN in terms of DM duration (>=10 years) for ACE I/D (all models), AGT M235T (recessive and allele models) and AGTR1 A1166C (recessive model). Significant subgroup differences were also observed for DN definition (advanced DN group) and region (South Asia) for AGTR1 A1166C (recessive model). CONCLUSION: In the Asian populations, ACE I/D and AGTR1 A1166C may contribute to DN susceptibility in patients with T2DM by different genetic models. However, the role of AGT M235T needs to be further evaluated. PMID- 29984663 TI - Prediction of the Omp16 Epitopes for development of an epitope based Vaccine against Brucellosis. AB - Brucellosis is an infectious disease caused by Brucella bacteria that cause disease in animals and humans. Brucellosis is one of the most common zoonotic diseases transmitted animals -to-human through direct contact with infected animals and also consumption of unpasteurized dairy products. Due to wide incidence of brucellosis in Iran and economical costs in industry animal husbandry, Vaccination is best way to prevent of this disease. All of available commercial vaccines against brucellosis are derived from live attenuated strains of Brucella. But because of disadvantage of live attenuated vaccines, protective subunit vaccine against Brucella may be a good candidate for production of new recombinant vaccines based on Brucella outer membrane protein (OMP) antigens. In the present study, comprehensive bioinformatics analysis has been conducted on prediction software to predict T and B cell epitopes, the secondary and tertiary structures and antigenicity of Omp16 antigen and the validation of used software confirmed by experimental results. The final epitope prediction results have proposed that the three epitopes were predicted for the Omp16 protein with antigenicity ability. We hypothesized that these epitopes likely have protective capacity to stimulate both the B-cell and T-cell mediated immune responses and so may be effective as an immunogenic candidate for the development of an epitope based vaccine against brucellosis. PMID- 29984664 TI - Genistein affects expression of cytochrome P450 (CYP450) genes in hepatocellular carcinoma (HEPG2/C3A) cell line. AB - * Background: Genistein (5,7-Dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is the most abundant isoflavone in soybean, which has been associated with a lower risk of development of cancer and cardiovascular diseases. Of particular interest regarding cancer preventive properties of flavonoids is their interaction with cytochrome P450 enzymes (CYPs). However, contradictory data report the effect of genistein on expression of SYPs enzymes. * Objective: The aim of this study was to investigate the effects of genistein on cytochrome P450 (CYP) gene expression levels in human hepatocellular carcinoma (HepG2/C3A) and colon adenocarcinoma (HT29) cells. * Method: Real-time RT-PCR was used to examine the expression of genes families involved in xenobiotic metabolism, such as CYP1 (CYP1A1, CYP1B1), CYP2 (CYP2E1, CYP2D6), CYP3 (CYP3A4); and of a family involved in the catabolism of the all-trans-retinoic acid (ATRA), CYP26 (CYP26A1, CYP26B1). * Results: RT-qPCR data analysis showed that after 12 h of exposure of HepG2/C3A cells to genistein (5 and 50 uM) there was an upregulation of CYP1A1 and CYP1B1 and downregulation of CYP2D6, CYP26A1 and CYP26B1 mRNA levels. There was no change in the mRNA levels of CYP P450 genes in HT29 cells. * Conclusion: Our results suggest that treatment with genistein in non-toxic concentrations may impact the expression level of CYPs involved in the biotransformation of xenobiotics and drug metabolizing enzymes. Moreover, the downregulation of ATRA metabolism-related genes opens a new research path for the study of genistein as retinoic acid metabolism blocking agent for treating cancer and other pathologies. PMID- 29984665 TI - The Influence of Pre-Analytical Factors on the Analysis of Circulating MicroRNA. AB - BACKGROUND: MicroRNAs (miRNA) are expected as useful biomarkers for various diseases. We studied the pre-analytical factors causing variation in the analysis of miRNA. MATERIAL AND METHODS: Blood samples were collected from 25 healthy subjects. Plasma and serum were obtained from the same samples. The levels of miR 451, -16, -126, and -223 were analyzed using RT-qPCR. Cel-miR-39 was added as a spiked-in control in each sample. RESULTS: With the exception of miR-451, the levels of the miRNAs in plasma were higher than in serum. After high-speed centrifugation, the levels of miRNAs were almost equal between plasma and serum except for miR-451. Membrane filtration with 0.45 um pore size reduced the levels of plasma miRNAs. The coagulation accelerators for serum processing did not affect the analysis of miRNA. The use of fraction containing particles of > 0.45 um in size showed the inhibitory effect on the analysis of plasma miR-451. The RNase inhibitor was effective for protecting against the degradation of miRNAs. CONCLUSION: Plasma contains factors modifying miRNA profiles. The immediate processing of plasma with membrane filtration and RNase inhibitor may be a relevant method for achieving the stable analysis of miRNA. PMID- 29984666 TI - Impact of Electron Beam Irradiation on the Bioactive Principles of Seeds of Coastal Sand Dune Wild Legumes (Canavalia spp.). AB - BACKGROUND: Recent patents reveal that vegetable ingredients have several applications in novel food formulations. Many so-called antinutritional components (e.g. tannins, saponins, lectins and protease inhibitors) have nutraceutical as well as pharmaceutical significance. Seeds of two wild legumes of the genus Canavalia inhabitants of the coastal sand dunes of Southwest India are known for a variety of bioactive principles (e.g. phenolics, tannins, canavanine, concanavalin and phytohemagglutinins). OBJECTIVES: This study evaluates the impact of electron beam (EB) irradiation on the bioactive components of seeds of two coastal sand dune wild legumes Canavalia cathartica and C. maritima. METHODS: The dry seeds of C. cathartica and C. maritima were EB irradiated with different doses (2.5, 5, 10 and 15 kGy) to follow changes in six bioactive principles (total phenolics, orthodihydric phenols, tannins, canavanine, trypsin inhibitors and phytohemagglutinins) in comparison to control seeds. One-way ANOVA was employed to follow the variation in bioactive components of seeds in control and different doses of irradiation. RESULTS: Seeds of both legumes were devoid of orthodihydric phenols and trypsin inhibitors. In C. cathartica, the total phenolics showed significant dose-dependent increase up to 5 kGy and decreased thereafter. Tannin content was not altered up to 10 kGy followed by significant decrease at 15 kGy. There was no significant change in canavanine content and the phytohemagglutinin activity against human erythrocytes was not altered. Seeds of C. maritima did not show significant changes in total phenolics as well as tannin contents. The content of canavanine showed significant dose-dependent increase up to 5 kGy followed by significant decrease. There was no variation in phytohemagglutinin activity against erythrocytes A, B and O, while against AB, the activity decreased at 2.5 kGy and further decrease was constant at higher doses. CONCLUSIONS: The EB irradiation doses employed have selectively altered the bioactive principles of Canavalia seeds and such treatments may facilitate to maneuver desired medicinal, nutritional, functional and cooking properties. Besides selective changes in bioactive components the seeds have extended shelf life. PMID- 29984667 TI - Statins: pharmacokinetics, pharmacodynamics, and cost-effectiveness analysis. AB - Cardiovascular diseases secondary to atherosclerosis are the primary causes of early death and disability worldwide and dyslipidaemia represents one of the most important modifiable risk factors. Among lipid abnormalities that define it, low density lipoprotein cholesterol (LDL-C) is the primary target of therapy, since multiple randomized controlled trials have shown the positive impact of its reduction on atherosclerosis development. For their ability to lower LDL-C levels, statins are the most studied drugs in cardiovascular disease prevention, of proven utility in slowing the progression or even determining regression of atherosclerosis. In addition, they have ancillary proprieties, with positive effects on the mechanisms involved in the development of atherosclerosis and cardiovascular morbidity and mortality, the so called "pleiotropic mechanisms". Although sharing the same mechanism of action, the different chemical and pharmacological characteristics of each kind of statins affect their absorption, bioavailability, plasma protein binding properties, excretion and solubility. In this overview, we analysed pharmacokinetic and pharmacodynamic mechanisms of this class of drugs, specifying the differences among the molecules, along with the economic aspects. Detailed knowledge of characteristics and differences of each kind of available statin could help the physician in the correct choice, based also on patient's clinical profile, of this essential tool with a demonstrated high cost-effectiveness both in primary than in the secondary prevention of cardiovascular disease. PMID- 29984668 TI - High levels of serum uric acid, cystain C and lipids concentration and their clinical significance in primary gouty arthritis patients. AB - OBJECTIVE: To investigate the changes of serum uric acid (sUA), lipids and cystatin C (CysC) in primary gout patients, and to explore the clinical significance in gout patients. METHODS: sUA, CysC, high-sensitivity C-reactive protein (hsCRP) and other biochemical parameters were measured in 326 gout patient and 210 healthy control subjects, blood cell counts were also detected. Clinical data were collected from gout patients. RESULTS: sUA, CysC, hsCRP, Body Mass Index (BMI), white blood cell (WBC) counts, neutrophil granulocyte (GR), monocyte (Mo), triglycerides (TG), plasma total cholesterol (TC), very low density lipoprotein (VLDL), apolipoprotein B100 (apoB100), blood glucose (GLU), serum creatinine (sCr) and urea nitrogen (BUN) were significantly increased in gout patients compared with HC subjects (P<0.01, respectively), while lymphocyte counts and high density lipoprotein-cholesterol (HDL-C) were significantly decreased in gout patients compared with HC subjects (P<0.01, respectively). Positive correlations were observed between concentration of sUA and age, TG, VLDL, sCr and CysC (P<0.05, respectively). While negative correlations were observed between the concentration of sUA and HDL-C(P<0.01). Besides, Positive correlations were observed between concentration of CysC and WBC, GR, Mo, apoA1, GLU, sCr, BUN, sUA, hsCRP (P<0.05, respectively). While negative correlations were observed between the concentration of CysC and TC, LDL-C(P<0.01, respectively). CONCLUSIONS: Blood lipid profile is changed in gout patients. Gout patients who suffer from lipid metabolism disorder and vascular diseases might be associated with hyperuricemia, which leading to endothelial cell damage and vascular smooth muscle cell proliferation. CysC might be as a marker of the renal function damage and inflammation. Hyperuricemia is the risk factor of renal disorder in gout patients. PMID- 29984669 TI - Screening and potential of the incidence of resistance transfer among the multidrug and heavy metal resistant Gram negative isolates from hospital effluents of northern India. AB - BACKGROUND: Hospital wastewater has a high amount of both organic and inorganic matter, as well as high densities of living organisms, including pathogenic, and environmental bacteria. It has been suggested that genes encoding resistance to antibiotic can be located together with heavy metals resistance genes on either the same genetic structure (plasmid), or different genetic structures within the same bacterial strain. Resistance transfer is mainly attributed to conjugation since many antimicrobial resistance genes are situated on mobile elements, such as plasmids and conjugative transposons, whereas renovation and transduction are usually more limited. Our study confirmed the flow of resistance genes between indigenous and foreign organisms and indicated the possibility of resistance transfer from environmental reservoirs to pathogenic strains, which should be underlined in the future. The recent patents on drug resistance (US20030130169, WO/2001/060387, WO/2016/151092) and gene transfer (JP2003189855, JP2010094090), helped in this study. METHODS: Water samples were collected from three different sites of hospital wastewater. Isolation of Gram negative bacteria from hospital wastewater samples was done using standard microbial procedure. The heavy metal resistance was determined by the minimum inhibitory concentration (MIC) against the test bacterial strain by spot plate method. The antibiotic resistance was determined by a standard disc diffusion technique. The bacterial resistance transfer studies were determined between donor and recipient strain in nutrient as well as wastewater. The antibiogram and MIC of the donors and transconjugants were studied by above described methods. RESULTS: A high number of Gram negative bacterial isolates (GNB) exhibited antibiotic and metal resistance transfer into E.coli K-12 and similar GNB isolates in nutrient broth as compared to wastewater. The microbial conjugation experiments showed that a high percentage of multi resistant GNB (75% and 66%) were able to transfer their single or multi drug resistance patterns to E. coli K-12 among antibiotic while 58%, 66% of the multi resistant isolates were able to transfer their single or multi metal resistance patterns to E. coli K-12 among metal in nutrient medium and wastewater, respectively. In the present conjugation study, 97.5% and 70% of the total tested GNB isolates were able to transfer an antibiotic resistant marker to recipient GNB in both the medium (nutrient medium and wastewater), whereas 92.5% and72.5% of the isolates were able to transfer metal resistant marker to recipient GNB in nutrient medium and wastewater from all the site tested. The higher (6.8x10-1 and 5.9x10-1) frequency of transfer was observed among antibiotic and metal while lower frequency of transfer were (7.0x10-3 and 2.0x10-3) exhibited against antibiotic and metal in both the medium from the entire site tested, respectively Conclusion: We can recommend that the hospital water is heavily polluted with several types of antibiotics, toxic metals as well as the potentially hazardous bacterial flora because of their capacity to resist one or the other well known antibiotic and chemotherapeutic agents. These studies provide evidence that a wide variety of clinically important antibiotic and metal resistance genes are mobile within aquatic bacterial communities one step ahead of the above, we can envisage the alarming situation prevailing in our system and surrounding in the light of transmissible nature of R-plasmids. PMID- 29984670 TI - Role of the Immune System in Autism Spectrum Disorders (ASD). AB - BACKGROUND: The evidence based supports that multifactorial and complex immune interactions play a role in autism spectrum disorders (ASD), but contradictory findings are also reported. OBJECTIVE: The aim of this selective review was to identify trends in the research literature on this topic, focusing on immunology and other aberrations with respect to the different ASD subtypes. METHODS: This selective review is based on original and review articles written in English and identified in literature searches of PubMed. RESULTS: Several studies have found that the risk of ASD is greater among children whose mothers suffered from autoimmune diseases while pregnant. Moreover, individuals with ASD show increased levels of antibodies that are specific for several specific proteins. Studies also show that mothers of children with ASD have antibodies against fetal brain proteins. There are also reports on the associations between increased levels of proinflammatory cytokines and ASD. Finally, infections in mothers during pregnancy are linked to an increased risk of ASD. CONCLUSION: We propose that the large inconsistencies in findings among studies in the field are due to differences in subdiagnoses among the included children with ASD. Well-phenotyped ASD samples are needed to understand the biological and immunological mechanisms underpinning ASD and its subdiagnoses. Future research should apply new strategies to scrutinize the link between ASD and changes in immune responsivity. Important new research avenues are to investigate the associations (a) between different ASD phenotypes and aberrations in (auto)immune pathways and (b) between reduced natural regulatory autoimmune responses during pregnancy, which are in turn associated with increased oxidative and nitrosative stress in maternal blood and putative detrimental effects in the offspring. PMID- 29984671 TI - Upregulation of Connexin-43 is Critical for Irradiation-induced Neuroinflammation. AB - BACKGROUND: Radiation therapy is widely used for the treatment of pituitary adenomas. Unfortunately, it might raise the risk of ischemic stroke, with neuroinflammation being a major pathological process. Astrocytes are the most abundant cell type in the central nervous system and have been reported for playing important roles in ischemic stroke. OBJECTIVE: Here we studied how gamma radiation would introduce astrocytes into a detrimental state for neuroinflammation and provide new theory evidence and target for the clinical management of inflammation- related neural damage after radiation-induced ischemic stroke. METHOD: HA-1800 cells were treated with gamma-radiation and then the protein and mRNA levels of Connexin (Cx)-43 were evaluated by western and q PCR. The culture supernatant was collected and the concentrations of the inflammatory factors were determined by ELISA. MiRNA complementary to Cx-43 was designed through the online tools. RESULTS: Cx-43 is upregulated in the treatment of gamma-radiation in astrocytes and gamma-radiation introduced the detrimental function of astrocytes: cell viability was reduced while the apoptotic cells were increased. Inflammatory factors like tumor necrosis factor alpha, interferon gamma, interleukin-6, interleukin 1-beta were dramatically up-regulated by the irradiation. MiR-374a rescued irradiation induced Cx-43 up-regulation of astrocytes and eliminated detrimental function triggered by gamma-radiation. CONCLUSION: Cx-43 expression level may play an important role in the inflammation related neural damage after irradiation-induced ischemic stroke. PMID- 29984672 TI - Overview of the Recent Advances in Pathophysiology and Treatment for Autism. AB - BACKGROUND & OBJECTIVE: Autism is a developmental disorder that manifests itself in early childhood. Autism is characterized by inability to acquire social skills, repetitive behaviors and failure of speech and nonverbal communication development. Recent studies have shown that genetic mutations occur in majority of individuals with autism. These mutations cause a variety of disorders that ultimately lead to brain disorders. It is noteworthy that all mutations do not follow the same pattern. They encompass various kinds of mutations. Autism needs to be treated during childhood as untreated patients usually do not progress to the later stages of development. In this regard, many studies have been performed and numerous treatments have been proposed to improve the outcome of this disease. CONCLUSION: In this review, we have discussed new advancements made in understanding the pathophysiology of autism. Furthermore, we have also discussed new treatments which have been proposed and have successfully translated affected children. Overall, it is concluded that new advances have largely helped these patients. PMID- 29984673 TI - The Efficacy and Safety of Pharmacological Treatments for Post-stroke Aphasia. AB - BACKGROUND: Aphasia is a common complication after stroke, and traditional speech and language therapy (SLT) has a limited effect on post-stroke aphasia (PSA). While there has been an increasing number of controlled clinical trials on the efficacy of drugs in the treatment of PSA, there have been very few systematic reviews on the efficacy and safety of pharmacological treatments in people with PSA. OBJECTIVE: To evaluate the efficacy and safety of pharmacological interventions for PSA. METHODS: The Cochrane Central Register of Controlled Trials (CENTRA), PubMed, Embase, Chinese Journal Full-text Database (CJFD), China Biology Medicine disc (CBMdisc), Wanfang Data and VIP Information System were searched for randomized controlled trials about pharmacological treatments for PSA. Literature screening using the inclusion and exclusion criteria, data extraction and methodological quality assessment of the included studies were completed by two independent reviewers. Methodological quality was considered high for modified Jadad quality scale scores of 4 to 7. RevMan 5.3 software was used to conduct a meta-analysis of high-quality studies. RESULTS: Fifteen studies (578 participants) satisfied the eligibility criteria for this systematic review. Five trials (277 participants) assessed donepezil, four studies (124 participants) assessed memantine, three studies (72 participants) assessed bromocriptine, one trial (45 patients) evaluated galantamine, one study (21 patients) evaluated amphetamine, and one trial (39 patients) evaluated levodopa. The systematic review showed that donepezil achieved remarkable results in terms of the aphasia quotient (AQ) (SMD 0.82, 95% CI 0.48-1.17, P < 0.00001), repetition ability (SMD 0. 81, 95% CI 0.57-1.06, P < 0.00001), naming ability (SMD 0.56, 95% CI 0.29-0. 84, P < 0.00001), auditory comprehension (SMD 0.85, 95% CI 0.58-1. 13, P< 0.00001) and oral expression (SMD 0.90, 95% CI 0.54-1.26, P < 0.00001). Memantine showed no pronounced improvement in auditory comprehension (SMD 0.35, 95% CI -0.05-0.74, P = 0.09) but did improve the AQ (SMD 0.57, 95% CI 0.09-1.06, P = 0. 02), naming ability (SMD 0.81, 95% CI 0.38-1.25, P = 0.0002), spontaneous speech (SMD 0.76, 95% CI 0. 39- 1.13, P < 0.0001), and repetition ability (SMD 0.37, 95% CI 0.01-0.73, P = 0.04). Bromocriptine showed pronounced improvement in naming ability (SMD -0.20, 95% CI- 0.67-0.26, P = 0.39), verbal fluency (SMD 0.02, 95% CI 0.53-0.56, P = 0.95), and repetition ability (SMD 0.29, 95% CI -0.23-0. 81, P = 0.28). There is limited and inconclusive evidence for galantamine, amphetamine and levodopa. CONCLUSION: Current evidence suggests that drugs, such as donepezil and memantine, can improve the prognosis of PSA. Donepezil has a significant effect in improving the ability of auditory comprehension, naming, repetition and oral expression. Memantine has a significant effect in improving the ability of naming, spontaneous speech and repetition. Bromocriptine showed no significant improvements in the treatment of aphasia after stroke. Data regarding galantamine, amphetamine and levodopa in the treatment of aphasia after stroke are limited and inconclusive. PMID- 29984674 TI - Characterization of Polymeric Nanoparticle Dispersions for biomedical applications: Size, Surface Charge and Stability. AB - In the last decades, nanoparticles intended for biomedical applications have gained increased attention due to the advantages they represent among the current diagnostic and therapeutic methods. However, the translation of nanomaterials laboratory results to human therapies is limited, mainly due to incomplete characterization of nanosystem properties, before preclinical studies. In this context, this review aims to summarize the main physicochemical characterization techniques of nanoparticles in a liquid dispersion, required in their design steps; which is of utmost importance for successful applications. One of the key physicochemical parameters of nanomaterials is size. To assess nanoparticles size, a wide revision of light scattering and microscopic techniques is reported here, some of them being also useful for determining nanomaterial morphology. The determination of nanosystem surface charge is also reported, because it is also a key parameter that will influence their interaction with biological components. In addition, determination of nanomaterials stability, which is important in terms of storage and use, is described. In conclusion, this review will be a useful support to find the appropriate techniques for an appropriate nanoparticle physicochemical preclinical characterization. PMID- 29984675 TI - Cheese: Food Perception and Food Choice. AB - In light of the increasing interest in the economic and socio-political impact of the 'traditional food' trend, it is essential to understand the determinant factors that lead to traditional consumer choices. The standardization of sensory quality evaluation methods marks the pressing need for food product certification, particularly foods with specific sensory characteristics, such as those with a Protected Designation of Origin (PDO). Consumer perception of particular foods, especially for foods that are culturally and socially contingent, such as cheese, must be understood as both a psychophysical reflex and a learned social practice. Consumers create their own perceptions based on the overall intrinsic or extrinsic cheese characteristics, mainly sensory characteristics that reflect others' attributes. These characteristics are normally linked to the specific cheese manufacture process. Some patents propose the use of adapted cheesemaking equipment (EP1982582A2), suitable for the manufacture of small-scale cheeses, such as some PDO cheese. Thus, sensory evaluation of any kind of cheese is based, in the initial phase, on knowledge of the sensory methods for cheese evaluation and, in a second phase, on the familiarity of the cheese characteristics and verbalization of desirable and undesirable attributes. This paper presents a case study based on the traditional food product, Evora cheese, assembled with PDO cheeses, whose sensory and physicochemical quality attributes are essential in order to obtain this designation and ensure the genuine properties that characterize them, as well as ascertaining exactly how they are perceived and further accepted by the consumer. PMID- 29984677 TI - Delirium following total joint replacement surgery. AB - Postoperative delirium (POD) is a common complication associated with increased resource utilization, morbidity and mortality. Our institution screens all postsurgical patients for postoperative delirium. The study aim was to perform an automated interrogation of the electronic health records to estimate the incidence of and identify associated risk factors for POD following total joint arthroplasty (TJA). Adult patients who underwent TJA with a multimodal analgesia protocol, including peripheral nerve blockade, from 2008 through 2012, underwent automated chart review. POD was identified by routine nursing assessment and administrative billing codes. Of 11,970 patients, 181 (1.5%) were identified to have POD. Older age (odds ratio, 95% CI 2.20, 1.80-2.71 per decade, p < 0.001), dementia (7.44, 3.54-14.60, p < 0.001), diabetes mellitus (1.70, 1.1.5- 2.47, p = 0.009), renal disease (1.68, 1.03-2.65, p = 0.039), blood transfusions (2.04, 1.14-3.52, p = 0.017), and sedation during anesthesia recovery (1.76, 1.23-2.51, p = 0.002) were associated with POD. Anesthetic management was not associated with POD risk. Patients who developed POD required greater healthcare resources. Dementia is strongly associated with POD. The association between POD and transfusions may reflect higher acuity patients or detrimental effect of blood. Postoperative sedation should be recognized as a warning sign of increased risk. PMID- 29984676 TI - Simple, reliable, and time-efficient colorimetric method for the assessment of mitochondrial function and toxicity. AB - Mitochondria are organelles involved in the production of cellular energy, regulation of Ca2+ and redox signaling, and are critical for normal functioning of eukaryotic cells. The dysfunction of mitochondria has been implicated in a wide range of diseases, including metabolic and neurodegenerative disorders and different types of cancers. To better understand the role of mitochondria in healthy and disease states, the development of efficient and reliable tools for the assessment of mitochondrial function is particularly important. Janus green B (JG-B) is a supravital lipophilic cationic dye which, in its oxidized form, has a green-blue color. As JG-B is taken up and reduced by metabolically active mitochondria, the dye has been used for assessing the purity, integrity and metabolic activity of mitochondria with microscopy-based methods. Here we present a simple, time- and cost-efficient JG-B-based colorimetric assay for assessing mitochondrial function, activity and toxicity. The method is based upon reduction of JG-B by mitochondrial dehydrogenases to diethylsafranine, which is pink colored and has a maximum absorption at 550 nm. In this proof of principle study, using in vitro mitochondrial preparations isolated from rat brain, we provide evidence that monitoring JG-B conversion to diethylsafranine can be used as a reliable and robust indicator of mitochondrial activity and toxicity. Because of its simplicity and efficiency in terms of costs and time, this assay has a wide potential in analytical as well as therapeutic areas of biomedical research. PMID- 29984678 TI - Effects of epinephrine on heart rate variability and cytokines in a rat sepsis model. AB - Catecholamines have both anti-inflammatory and vasoactive properties. A decreased cardiac response to catecholamines has been associated with a high risk of death in sepsis and septic shock. The aim of this study was to investigate the effects of epinephrine (EPI) on heart rate variability and autonomic balance, as well as cytokine levels, in a rat sepsis model. Thirty-six male Sprague-Dawley rats were assigned to 4 experimental groups and 2 control groups of 6 rats each. The rats in the experimental groups were inoculated with a lipopolysaccharide (LPS, endotoxin) to establish a sepsis model. Group A received only LPS; group B received LPS, antecedent EPI and the nonselective beta-blocker propranolol; group C received LPS and antecedent EPI; and group D received LPS, antecedent EPI and the selective beta1-blocker esmolol. One control group received EPI and the other received saline placebo. Heart rate variability was analyzed and tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) levels were measured. Measurements were carried out at baseline and 0, 0.5, 2, and 4 hours after LPS inoculation. There were significant differences in heart rate variability and cytokine levels between the groups, indicating that LPS infusion caused autonomic imbalance. Antecedent EPI significantly decreased the level of TNF-alpha in group C compared with group A in which TNF-alpha level peaked at 2 hours and then declined. Propranolol (group B) but not esmolol (group D) administration resulted in elevated TNF-alpha levels, comparable to those observed in group A. In conclusion, antecedent administration of EPI in a rat sepsis model inhibits the production of TNF-alpha possibly via the beta2 adrenoreceptor. PMID- 29984680 TI - A review of micronutrients in sepsis: the role of thiamine, l-carnitine, vitamin C, selenium and vitamin D. AB - Sepsis is defined as the dysregulated host response to an infection resulting in life-threatening organ dysfunction. The metabolic demand from inefficiencies in anaerobic metabolism, mitochondrial and cellular dysfunction, increased cellular turnover, and free-radical damage result in the increased focus of micronutrients in sepsis as they play a pivotal role in these processes. In the present review, we will evaluate the potential role of micronutrients in sepsis, specifically, thiamine, l-carnitine, vitamin C, Se and vitamin D. Each micronutrient will be reviewed in a similar fashion, discussing its major role in normal physiology, suspected role in sepsis, use as a biomarker, discussion of the major basic science and human studies, and conclusion statement. Based on the current available data, we conclude that thiamine may be considered in all septic patients at risk for thiamine deficiency and l-carnitine and vitamin C to those in septic shock. Clinical trials are currently underway which may provide greater insight into the role of micronutrients in sepsis and validate standard utilisation. PMID- 29984681 TI - Weight loss after pregnancy: challenges and opportunities. AB - It is important to pay attention to weight management before and between pregnancies, as women have an increased risk of weight gain during the reproductive years. Having a baby is a life-changing event for women and the challenge of weight management amidst this period of major physiological, psychological and social change should not be underestimated. However, the postpartum period offers an opportune time for lifestyle interventions, as women may have heightened awareness of their own and their wider families' health. Systematic reviews indicate that interventions including both diet and physical activity along with individualised support and self-monitoring are more likely to be successful in promoting postpartum weight loss. However, high levels of attrition and poor engagement have been an issue in previous trials in this area. Since postpartum women are difficult to reach and retain, future research must consider how to make weight-management interventions an attractive and attainable proposition for women who are juggling multiple, competing demands on their time. Ideally, intervention approaches need to be flexible and allow sustained contact with women, to facilitate a focus on maintenance of weight loss, as well as opportunities for re-engagement after life events that may disrupt weight management progress. Using technology to deliver or support interventions holds promise but trials are needed to generate a range of appealing, effective and scalable options for postpartum women. What works at other life stages may not necessarily work here owing to specific barriers to weight management encountered in the postpartum period. PMID- 29984679 TI - Clinical features and management of oral lichen planus (OLP) with emphasis on the management of hepatitis C virus (HCV)-related OLP. AB - Oral lichen planus (OLP) is a chronic inflammatory disease characterized by the occurrence of multiple, symmetrical lesions in the oral cavity. Hepatitis C virus (HCV) infection has been suggested as an etiological factor in OLP. The purpose of this review was to summarize the current literature regarding the treatment of OLP in patients with HCV infection. An electronic search of the PubMed database was conducted until January 2018, using the following keywords: OLP, HCV, corticosteroids, retinoids, immunomodulatory agents, surgical interventions, photochemotherapy, laser therapy, interferon, ribavirin, and direct-acting antivirals. We selected the articles focusing on the clinical features and treatment management of OLP in patients with/without HCV infection. Topical corticosteroids are considered the first-line treatment in OLP. Calcineurin inhibitors or retinoids can be beneficial for recalcitrant OLP lesions. Systemic therapy should be used in the case of extensive and refractory lesions that involve extraoral sites. Surgical intervention is recommended for isolated lesions. In patients with HCV, monotherapy with interferon (IFN)-alpha may either improve, aggravate or trigger OLP lesions, while combined IFN-alpha and ribavirin therapy does not significantly influence the progression of lesions. Direct acting antiviral (DAA) therapy appears to be a promising approach in patients with HCV-related OLP, as it can improve symptoms of both liver disease and OLP, with fewer side effects. Nevertheless, for clinical utility of DAAs in OLP patients, further studies with larger sample sizes, adequate treatment duration, and long term follow-up are required. PMID- 29984682 TI - Shorter acute care hospital stay, longer stay in post-acute care facilities. PMID- 29984683 TI - Understanding the pathophysiology of hyperglycemia-associated chorea-ballism: a systematic review of positron emission tomography findings. AB - Hyperglycemia-associated chorea-ballism (HCB) is an infrequent neurological syndrome whose pathophysiology remains poorly understood. Positron emission tomography (PET) studies have offered valuable information regarding regional glucose metabolism. The studies included were published between 1980-2017 and reported demographic, clinical, laboratory and imaging data from patients with HCB in whom a PET scan had been performed. Eleven patients were evaluated (women 82%, Asian origin 91%, mean age 71 years). The main findings were an increase in glucose metabolism at the contralateral motor cortex related to recent episodes of hemiballism-hemichorea in 2 patients, and an altered metabolism in the affected basal ganglia in all of them: decreased in 10 patients (91%) and increased in 1 (9%). However during the acute period the patients showed only an increased metabolism, or even no changes. Contrary to what has previously been suggested in a metabolic failure hypothesis, changes in glucose metabolism in the basal ganglia may not be a key factor in the pathogenesis of HCB, and may potentially be a direct result of histological changes such as cellular ischemia and gliosis related to HCB development. PMID- 29984684 TI - A review of 500 patients with acute stroke admitted to the University Hospital of Saudi Arabia. Similarities and differences compared with the published literature. AB - Published studies have shown differences in types and underlying mechanisms of stroke between different regions of the world. There is a lack of published literature describing the characteristics of acute stroke in Saudi Arabia. The aim of this study was to identify different types and associated risk factors among acute stroke patients in Saudi Arabia. In this descriptive study, records of 500 patients with acute stroke were included. Acute stroke was classified as ischemic stroke, intracerebral hemorrhage, cerebral venous sinus thrombosis or subarachnoid hemorrhage. The TOAST classification was used to categorize ischemic stroke. Ischemic stroke was found to be the most common type (86.6%). The patients included comprised 326 (65.2%) males and 174 (34.8%) females. Small vessel occlusive disease was the most common etiology of ischemic stroke. The males had a lower mean age than the females (p=0.00). The results of our study are largely in agreement with published literature, although a few differences emerged which need to be verified through further prospective multicenter studies. PMID- 29984685 TI - Direction-specific cortical response immediately after moving tactile stimuli in female humans. AB - This study looked for a direction-specific cortical response immediately after application of moving tactile stimuli in healthy female humans. Four pairs of stimulus electrodes were placed over the left index finger pulp on the distal proximal axis. Four times, once in every 40 ms interval, an electrical stimulus to the finger pulp was delivered through one of the four pairs of electrodes; each time the stimulus site changed in order to induce a sensation of tactile motion. The slope of the electroencephalographic trace, as recorded from electrodes placed over the CP, P4 and right hMT+/V5 in the period 150-200 ms after the onset of stimuli delivered in sequence from the distal to proximal site, was significantly different from that after stimuli delivered in sequence from the proximal to distal site. The cortical response immediately after the proximally-directed moving tactile stimuli was different from that after the distally-directed moving tactile stimuli in the hemisphere contralateral to the stimulus side. PMID- 29984686 TI - Impact of epilepsy after severe brain injury on safe resumption of driving: two year follow-up. AB - Safe resumption of driving after a severe acquired brain injury (sABI) is a strongly felt need because driving is related to recovery of independence and social-occupational re-integration. The aim of this prospective observational cohort study was to determine whether epilepsy secondary to sABI is a significant factor for being declared fit to drive by the relevant government authorities in Italy. In the period 2006-2015 we recruited 187 patients with sABI, 30 of whom (16.4%) developed secondary epilepsy. The interval between the acute event and the first seizure varied widely (6-96 months), confirming the need for prolonged follow-up. With regard to the aetiology, traumatic brain injury (TBI) was associated with the highest risk of epilepsy: 66.7% of the 30 patients with epilepsy had TBI, as opposed to cerebrovascular disease or anoxic brain damage (33.3%). The percentage of patients who resumed driving was about the same in the epilepsy (80%) and non-epilepsy (81%) groups. PMID- 29984687 TI - Epidemiological and clinical characteristics of 492 patients in a vegetative state in 29 Italian rehabilitation units. What about outcome? AB - Recent studies on recovery of consciousness of subjects in a vegetative state (VS) admitted to rehabilitation units have focused mainly on the identification of prognostic factors, whereas few studies have focused on outcome. The aim of this study was to compare demographic and clinical data and report functional outcome of patients in a VS due to severe acquired brain injury (ABI) of different aetiologies. The study was a retrospective multicentre cohort study and involved 492 patients in a VS due to traumatic (TBI) or non-traumatic (NTBI) severe ABI admitted to 29 Italian rehabilitation units. Demographic and clinical data recorded included age, gender, aetiology, Glasgow Coma Scale score; onset-to admission interval; length of stay in the rehabilitation unit; the department from which they were referred; and the presence of percutaneous endoscopic gastrostomy or tracheostomy. Recovery of consciousness and disability were evaluated using a discharge Disability Rating Scale. At discharge, 53.11% patients had emerged from VS, with TBI subjects significantly more likely to recover consciousness than NTBI ones. Subjects with NTBI had a significantly worse prognosis than those with TBI, and within the NTBI group, subjects with a cerebrovascular aetiology had a better outcome than those with an anoxic aetiology. Among the patients who emerged from VS, 71.30% of TBI and 83.06% of NTBI subjects presented extremely severe disability. Only 37.93% of subjects affected by TBI and 17.44% of those affected by NTBI who presented extremely severe disability returned home after their rehabilitation stay. Even though almost a half of the patients emerged from VS, a large number of these subjects showed severe disability, often making it impossible for them to return home. This situation has a major impact on the healthcare system. PMID- 29984688 TI - Laterality in Parkinson's disease may predict motor and visual imagery abilities. AB - Experimental evidence suggests that motor imagery (MI) engages the same neural substrates supporting actual motor activities and is likely impaired when such substrates are damaged, as in Parkinson's disease (PD). MI intuitively relies on visual imagery (VI), because mental simulations of physical movements depend on the visual retrieval of these movements. Although VI is generally considered a right hemispheric function, the hemispheric dominance of MI is still in dispute. Disparities in sidedness of motor disturbances are a distinctive feature of PD, and recent findings indicate that such disparities may similarly characterize cognition. Specifically, the deficits observed may depend upon which hemisphere is principally involved. Essentially, MI and VI are cognitive tasks subject to differential impairment and reflecting the prevalence of hemispheric impairment in PD. Motor imagery (assessed by the Vividness of Motor Imagery Questionnaire [VMIQ]) and VI (assessed by the Vividness of Visual Imagery Questionnaire [VVIQ] and Test of Visual Imagery Control [TVIC]) were examined in patients with asymmetric PD and in healthy elderly control subjects (HC group). VMIQ scores were similar in PD laterality subsets and the HC group, but VVIQ scores were significantly lower in both PD groups compared with the HC group. TVIC scores were significantly lower in the presence of left motor (right hemispheric) impairment and were predictive of left motor (right hemispheric) impairment. We suspect that MI is strongly reliant on VI and that language may mediate these two functions, to the extent that both are evoked through verbal stimuli. Working memory, both visual and verbal, is also involved in MI and VI tasks. Without due attention to laterality of symptoms, any training incorporating MI and VI may not deliver expected outcomes in the setting of asymmetric PD symptomatology. PMID- 29984689 TI - Development of a patient-centered questionnaire for post-stroke spasticity assessment: a reliability study. AB - In the emerging scenario of patient-centered medicine, it is becoming increasingly important to involve patients in the management of chronic diseases. The rehabilitation field currently has no assessment tool for evaluating the functional impact of post-stroke spasticity on activities of daily living. The aim of this study was to identify a tool to fill this gap. The "Spasticity Questionnaire in Real Life" (SPQR) was administered, twice, to 39 patients with poststroke spasticity. Statistical analysis showed internal consistency and reliability of the questionnaire, with values greater than 0.96 and 0.76, respectively. These results show that the SPQR is a promising tool for evaluating the functional impact of post-stroke spasticity. PMID- 29984690 TI - Musculoskeletal impairment and functional limitations in a patient affected by mutation in the laminin a-5 gene. PMID- 29984692 TI - ? PMID- 29984691 TI - Improving the Quality of Dentistry (IQuaD): a cluster factorial randomised controlled trial comparing the effectiveness and cost-benefit of oral hygiene advice and/or periodontal instrumentation with routine care for the prevention and management of periodontal disease in dentate adults attending dental primary care. AB - BACKGROUND: Periodontal disease is preventable but remains the most common oral disease worldwide, with major health and economic implications. Stakeholders lack reliable evidence of the relative clinical effectiveness and cost-effectiveness of different types of oral hygiene advice (OHA) and the optimal frequency of periodontal instrumentation (PI). OBJECTIVES: To test clinical effectiveness and assess the economic value of the following strategies: personalised OHA versus routine OHA, 12-monthly PI (scale and polish) compared with 6-monthly PI, and no PI compared with 6-monthly PI. DESIGN: Multicentre, pragmatic split-plot, randomised open trial with a cluster factorial design and blinded outcome evaluation with 3 years' follow-up and a within-trial cost-benefit analysis. NHS and participant costs were combined with benefits [willingness to pay (WTP)] estimated from a discrete choice experiment (DCE). SETTING: UK dental practices. PARTICIPANTS: Adult dentate NHS patients, regular attenders, with Basic Periodontal Examination (BPE) scores of 0, 1, 2 or 3. INTERVENTION: Practices were randomised to provide routine or personalised OHA. Within each practice, participants were randomised to the following groups: no PI, 12-monthly PI or 6 monthly PI (current practice). MAIN OUTCOME MEASURES: Clinical - gingival inflammation/bleeding on probing at the gingival margin (3 years). Patient - oral hygiene self-efficacy (3 years). Economic - net benefits (mean WTP minus mean costs). RESULTS: A total of 63 dental practices and 1877 participants were recruited. The mean number of teeth and percentage of bleeding sites was 24 and 33%, respectively. Two-thirds of participants had BPE scores of <= 2. Under intention-to-treat analysis, there was no evidence of a difference in gingival inflammation/bleeding between the 6-monthly PI group and the no-PI group [difference 0.87%, 95% confidence interval (CI) -1.6% to 3.3%; p = 0.481] or between the 6-monthly PI group and the 12-monthly PI group (difference 0.11%, 95% CI -2.3% to 2.5%; p = 0.929). There was also no evidence of a difference between personalised and routine OHA (difference -2.5%, 95% CI -8.3% to 3.3%; p = 0.393). There was no evidence of a difference in self-efficacy between the 6-monthly PI group and the no-PI group (difference -0.028, 95% CI -0.119 to 0.063; p = 0.543) and no evidence of a clinically important difference between the 6-monthly PI group and the 12-monthly PI group (difference -0.097, 95% CI -0.188 to -0.006; p = 0.037). Compared with standard care, no PI with personalised OHA had the greatest cost savings: NHS perspective -L15 (95% CI -L34 to L4) and participant perspective -L64 (95% CI -L112 to -L16). The DCE shows that the general population value these services greatly. Personalised OHA with 6-monthly PI had the greatest incremental net benefit [L48 (95% CI L22 to L74)]. Sensitivity analyses did not change conclusions. LIMITATIONS: Being a pragmatic trial, we did not deny PIs to the no-PI group; there was clear separation in the mean number of PIs between groups. CONCLUSIONS: There was no additional benefit from scheduling 6-monthly or 12-monthly PIs over not providing this treatment unless desired or recommended, and no difference between OHA delivery for gingival inflammation/bleeding and patient-centred outcomes. However, participants valued, and were willing to pay for, both interventions, with greater financial value placed on PI than on OHA. FUTURE WORK: Assess the clinical effectiveness and cost effectiveness of providing multifaceted periodontal care packages in primary dental care for those with periodontitis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN56465715. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 38. See the NIHR Journals Library website for further project information. PMID- 29984693 TI - [Caesarean delivery in a woman with a unicorn uterus and foetal breech presentation]. AB - In this case report a unicorn uterus was diagnosed at a caesarean delivery in a 23-year-old woman with known foetal breech presentation and suspected low foetal weight. She had had a failed attempt of cephalic version two weeks before delivery, and her baby's weight was checked regularly in third term. Unicorn uterus is associated with a higher risk of spontaneous abortions, infertility, preterm labour, foetal malpresentation, low birth weight, caesarean delivery and renal malformations. Although pregnancies in these women can be uneventful, it is advised, that women with unicorn uteri are followed closely during their pregnancies. PMID- 29984694 TI - [Airplane travels can induce headache]. AB - Airplane headache is a common problem with 100 million passengers annually suffering from the condition. It has been suggested that the changes in the cabin pressure during take-off and landing may cause inflammation in sinus tissues. This can lead to elevated levels of prostaglandin E2 and vasodilation of cerebral arteries resulting in airplane headache. Current evidence suggests opportunities to develop a treatment plan by examining future potential drugs for reducing the prostaglandin E2 level or preventing the vasodilation of the cerebral arteries. PMID- 29984695 TI - [Diagnostics, treatment and prognosis in breast cancer during pregnancy]. AB - Breast cancer is the second most common form of cancer diagnosed during pregnancy. The diagnosis and treatment of breast cancer during pregnancy requires multidisciplinary efforts to treat the cancer while protecting the foetus. Pregnancy-related changes in the breast make the diagnosis particularly challenging. Surgery is possible during all three trimesters. Chemotherapy can be administered in the second and third trimesters without increased risk of foetal malformations. Radiation, endocrine and biological therapies however, must be postponed until after delivery. PMID- 29984696 TI - [Muir-Torre syndrome]. AB - Muir-Torre syndrome (MTS) is an autosomal dominant disease with approximately 200 reported cases worldwide, which is characterised by multiple neoplasms of the skin and internal organs. This is a case report of a 57-year-old woman with MTS, who was referred to a plastic surgery department from a gastroenterology department due to a neoplasm of the skin. After treatment, she was referred to a dermatology department for follow-up. MTS is a rare disease, which is now reported in Denmark. Doctors treating any of the composing elements should have basic knowledge of the condition in order to refer patients appropriately. PMID- 29984697 TI - [Vagus and hypoglossus palsy after nasotracheal intubation and throat packing]. AB - Ipsilateral extracranial palsy of the hypoglossus and vagus nerve is a rare complication of intubation. This is a case report of a 50-year-old male with unilateral palsy of the hypoglossus and vagus nerve after reoperation for a mandibular fracture. The patient underwent logopaedic treatment, and ten months after the operation there was significant but not complete remission of symptoms. Videostroboscopy revealed near-normalisation of vocal cord movement. PMID- 29984698 TI - [Postural orthostatic tachycardia syndrome]. AB - Postural orthostatic tachycardia syndrome is a hetero-geneous condition of dysautonomia and suspected autoimmunity characterised by abnormal increments in heart rate upon assumption of the upright posture accompanied by symptoms of cerebral hypoperfusion and sympathoexcitation. An increase in heart rate equal to or greater than 30 bpm or to levels higher than 120 bpm during a head-up tilt test is the main diagnostic criterion. Manage-ment includes both non pharmacological and pharma-cological treatment focusing on stress management, volume expansion and heart rate control. PMID- 29984700 TI - ? PMID- 29984699 TI - ? PMID- 29984701 TI - ? PMID- 29984702 TI - [Life-threatening intrauterine infection with Clostridium perfringens]. AB - In this case report, a 40-year-old woman with a history of a uterine leiomyoma presented with abdominal pain and fever. Initially, her symptoms were associated with a bleeding from an ovarian cyst seen on a CT scan of the abdomen showing free intraperitoneal fluid surrounding the internal genitals. Meanwhile, her blood cultures came out positive for Clostridium perfringens, and her condition deteriorated despite intravenous antibiotics. A new CT scan revealed intrauterine gas development. A laparotomy was performed with removal of the internal genitals, and the patient improved on continuous antibiotics. PMID- 29984703 TI - [Acute liver failure caused by intake of white fly agaric]. AB - This is a case report of a 47-year-old Afghan woman, who was admitted to a Danish emergency department with symptoms initially being interpreted as gastroenteritis, but 18 hours later she had persistent symptoms. A blood test showed raised liver parameters, and the patient told, that the day before onset of the symptoms she had eaten white fly agaric believing that it was mushroom. She was trans-ferred to the Danish National Hospital for liver failure treatment, and she was discharged after eight days. This case shows, that it is important to record a good anamnesis. PMID- 29984704 TI - [Mycotic aorta aneurysm treated with an autologous venous graft]. AB - Systemic side effects, including sepsis, due to bacille Calmette-Guerin treatment for carcinoma in situ in the bladder, are observed in 15% of the patients. In rare cases, patients have developed systemic infections and mycotic aneurysms. In this case report, a 72-year-old man developed a mycotic aortic aneurysm, and the appropriate tuberculostatic drugs had no effect on his systemic infection. He was successfully treated surgically, replacing the affected aortic segment with an autologous venous graft, resulting in complete remission. A follow-up PET-CT three months later showed no sign of ongoing aortic infection. PMID- 29984705 TI - [Diagnostic and treatment of personality disorders]. AB - Patients with personality disorders are common. They often have co-morbid mental and physical illnesses, poor quality of life, and severe social impairment. Yet, these disorders of personality are often undiagnosed. A detailed and carefully taken history and, at best, a structured interview are important for a valid diagnosis, description of dysfunctional traits and for the assessment of severity. An initial psychotherapeutic case formulation is important to enhance alliance and adherence. In case of psychiatric co-morbidities, depending on their severity, they should be treated first. PMID- 29984706 TI - [Information specialists improve the quality of systematic reviews]. AB - Systematic reviews (SR) are a recognised standard for synthesising clinical data in order to support evidence-based clinical decisions. A robust search strategy is the core of an SR, requiring theoretical and methodological considerations in the pre-, intra- and post-search stage. This review discusses the competencies necessary to design a search including the necessary symbiosis between medical knowledge and detailed knowledge of database architecture and corresponding semantics. Information specialists play an important role in high-quality SR. PMID- 29984707 TI - [Overweight and eating disorders in patients with attention deficit hyperactivity disorder]. AB - Recent studies have generally found an increased prevalence of overweight and obesity among children, adolescents and adults with attention deficit hyperactivity disorder (ADHD), and the latest research suggests, that ADHD is also associated with problematic eating behaviour and eating disorders. The pathways of these associations are still up for discussion, but both psychological and biological factors are important aspects. There is further-more a good theoretical basis for the assumption, that active drug treatment of ADHD may minimise the risk of overweight. However, existing research is predominantly based on small, selected cross-sectional studies. PMID- 29984708 TI - Determination of carbonyl compounds in exhaled breath by on-sorbent derivatization coupled with thermal desorption and gas chromatography-tandem mass spectrometry. AB - A reliable method for the determination of carbonyl compounds in exhaled breath based on on-sorbent derivatization coupled with thermal desorption and gas chromatography-tandem mass spectrometry is described. The analytical performances were optimized for a mixture of C2-C9 aldehydes and C3-C9 ketones, particularly interesting for clinical applications, by using an internal standard and applying a 23 full factorial design. A volume of sample (250 ml) was loaded at 50 ml min-1 into a Tenax GR sorbent tube containing 130 nmol of O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine hydrochloride. All compounds showed a limit of detection lower than 200 pptv. The yield of the derivatization procedure was normalized by adding to the sample a known amount of 6D-acetone as an internal standard. This allowed halving the relative standard deviation to 10% and 15% for the mono-and di-carbonyl compounds, respectively, thus improving reliability. The optimized method was applied to the determination of carbonyl compounds in 12 breath samples collected from four patients suffering from heart failure during hospitalization. PMID- 29984709 TI - Sensitive spectroscopic breath analysis by water condensation. AB - Breath analysis has great potential for becoming an important clinical diagnosis method due to its friendly and non-invasive way of sample collection. Hundreds of endogenous trace gases (volatile organic compounds (VOCs)) are present in breath, representing different metabolic processes of the body. They are not only characteristic for a person, their age, sex, habit etc, but also specific to different kinds of diseases. VOCs, related to diseases could serve as biomarkers for clinical diagnostics and disease monitoring. However, due to the large amount of water contained in breath, an identification of specific VOCs is a real challenge. In this work we present a technique of water suppression from breath samples, that enables us to identify several trace gases in breath, e.g., methane, isoprene, acetone, aldehyde, carbon monoxide, etc, using Fourier transform infrared spectroscopy. In the current state, the technique reduces the water concentration by a factor of 2500. Sample preparation and data acquisition take about 25 min, which is clinically relevant. In this article we demonstrate the working principle of the water reduction technique. Further, with specific examples we demonstrate that water elimination from breath samples does not hamper the concentration of trace gases in breath. Preliminary experiments with real breath also indicate that the concentrations of methane, acetone and isoprene remain the same during the sample preparation. PMID- 29984710 TI - Fracture resistance and failure modes of lithium disilicate or composite endocrowns. AB - Purpose: The aim of this study was to determine the fracture strength of endocrowns made of lithium disilicate ceramic and two different indirect resin composites. Materials and Methods: Forty human mandibular molars were randomly separated into four groups (n = 10 in each group) - Group IN: control group, Group IPS: endocrowns made of lithium disilicate ceramic (IPS e.max CAD, IvoclarVivadent, Schaan, Liechtenstein); Group SL: Endocrowns made of Solidex microhybrid composite (Shofu, Ratingen, Germany); and Group GR: Endocrowns made of Grandia microhybrid composite (GC Europa, Leuven, Belgium). In all of the groups, dual-cure resin cement (Relyx Ultimate Clicker, 3M ESPE, St. Paul, MN, USA) was used to cement the endocrowns. All of the teeth were subjected to fracture by means of a universal testing machine (Instron), and compressive force was applied. The failure type and location after fracture were classified. The data were analyzed using one-way ANOVA, Tukey's post hoc test, and Chi-square test (P < 0.05). Results: Group IPS showed significantly higher fracture strength than Groups SL and GR (P < 0.05). There was no significant difference between the SL and GR groups (P > 0.05). In Group SL, 80% of the specimens exhibited favorable fractures; also, 60% of the specimens exhibited favorable fracture in group GR, and only 10% of the specimens exhibited favorable fracture in group IPS. Conclusions: The lithium disilicate ceramic endocrowns exhibited higher fracture resistance than indirect composite groups. Both of the composite endocrowns showed more favorable failure than the lithium disilicate ceramic endocrowns. PMID- 29984711 TI - Phlebitis-related peripheral venous catheterization and the associated risk factors. AB - Background and Aim: Development of phlebitis is a painful and common complication in the application of peripheral intravenous catheter (PIC). This is a prospective observational study performed to identify development rate of phlebitis in application of PIC and the factors that affect the development of phlebitis. Materials and Methods: The study universe comprises of catheters applied on inpatients in the internal diseases clinic of a state hospital, and the sample comprises of catheters eligible to be included in the study. Five hundred and thirty-two PICs applied on a total of 317 patients were reviewed. The patient identification form, information form for peripheral venous catheter and treatment, and visual infusion phlebitis (VIP) assessment scale were used to collect data. Results: 31.8% had phlebitis and a large number of them (79.2%) were Level I phlebitis. There was a significant relationship between having a chronic disease, duration of catheterization and type of fluid used and the development rate of phlebitis. Conclusion: The phlebitis in individuals receiving intravenous (IV) treatment was higher than the rate defined by both the centers for disease control and prevention and IV nurses society. It may be recommended to assess phlebitis by VIP assessment scale and to take preventive measures specifically for development of phlebitis. PMID- 29984712 TI - Cultural perceptions influencing obstetric complications among women in Kaduna, Northwestern Nigeria. AB - Background: Maternal mortality remains a public health challenge despite the global progress made toward its reduction. Cultural beliefs and traditional practices contribute to delays and poor access to maternal health services. This study examined cultural perceptions influencing obstetric complications among women who delivered at Yusuf Dantsoho Memorial Hospital, Tudun-Wada, Kaduna. Methodology: The study was a cross-sectional study conducted at the Obstetrics and Gynecology Department of Yusuf Dantsoho Memorial General Hospital, Tudun Wada, Kaduna, from February to April 2014. Two hundred and six women who delivered during the study period irrespective of their booking status and consented to participate in the study were recruited consecutively. Data were collected using a structured questionnaire. Results: Majority of the participants were Hausas (74.8%), Muslims (94.7%), married (99.0%), unemployed (45.1%), and within the age group of 20-29 years (58.7%). Most had secondary education (44.2%). The most frequent maternal complications encountered were prolonged obstructed labor (27.7%), obstetric hemorrhage (23.4%), severe preeclampsia/eclampsia (18.2%), and sepsis (5.8%). "Feeling embarrassed if delivered in hospital" was significantly associated with prolonged obstructed labor, while "feeling proud if delivered at home" was five times more significantly associated with obstetric hemorrhage. Conclusion and Recommendations: Cultural perceptions and traditional practices are major causes of primary delay in accessing maternal health services. The study emphasizes the importance of maternal health education among women in this region. Cultural perceptions and their influence on maternal mortality and morbidity should be integrated into health education programs. PMID- 29984713 TI - Variations of renal vascular anatomy in a nigerian population: A computerized tomography studys. AB - Background: A broad spectrum of renal vascular variations has been reported by anatomists and radiologists. The prevalence of these variations is extremely divergent in different populations. Therefore, radiologists and surgeons in different climes must be knowledgeable about the type and prevalence of the variants in their area of practice to avoid diagnostic pitfalls and for optimization of surgical techniques. Objective: The objective of this study is to describe the types and prevalence of renal vascular variations among patients undergoing contrast-enhanced computerized tomography (CECT) of the abdomen in a Nigerian population, as well as provide a concise review of literature on the embryological basis and clinical significance of the identified variations. Materials and Methods: This study was a retrospective review of 200 CECT of the abdomen to identify variations of arterial (accessory, early branching, and precaval) and venous (multiple, retroaortic, and circumaortic) anatomy of the kidneys. Results: We studied 200 patients, 102 (51%) females and 98 (49%) males. Age range is 18-90 years (mean = 53.08 +/- 17.01). Prevalence of any renal vascular variations was 50%, arterial variations were 37%, and venous variations were 13%. Variations were significantly more common in males, P = 0.000075. The most common arterial variant was the accessory renal artery (23%) seen in 10% (right) and 13.0% (left); early branching was seen in 4.0% (right) and 0.5% (left) as well as precaval right renal artery seen in 4.5%. Venous variants were late confluence 3.0% (right) and 2.5% (left); multiple veins was seen in 2.5% (right) and 2.5% (left) as well as retroaortic left renal vein seen in 2.0%. The inferior polar accessory artery was the most prevalent accessory artery. Early arterial bifurcation was significantly more common on the right (P = 0.016) while other vascular variants showed no statistically significant association with laterality. Conclusion: Variation of renal vascular anatomy is a frequent finding among Nigerians. Radiologists and surgeons must be aware of these variants for optimization of surgical techniques. PMID- 29984714 TI - Investigating the effects of two different pump heads (Centrifugal vs. Roller Pump) on hematological and immunological mechanisms. AB - Background and Aim: Technological developments and enhancement of knowledge level enable heart surgery with low mortality rates in most centers. On the other hand, increased systemic inflammatory response against cardiopulmonary bypass (CPB) plays a critical role in the development of postoperative complications. We aimed to compare the effects of centrifugal pump where it is claimed that blood is exposed to minimal trauma and roller pump techniques on inflammatory response and oxidant status during CPB. Materials and Methods: : A total of 40 patients, who had coronary artery disease and underwent coronary artery bypass graft (CABG) surgery using either roller or centrifugal pump between June 2012 and June 2013 were enrolled in this study. Patients over 40 years old and without any known immunologic, infectious, or inflammatory incidents and hematological problems for the past 6 months were included in the study. Two study groups (Group R: roller pump group and Group C: centrifugal pump group) were created. During CABG surgery tumor necrosis factor (TNF) alpha, interleukin (IL)-6, IL-8, superoxide dismutase (SOD), catalase (CAT), and nitric oxide levels were measured before and after CPB. Results: TNF alpha, IL-6, and IL-8 levels measured before and after CPB were found to be similar between groups. SOD, CAT and Nitric oxide levels were also similar between groups. After the CPB period, glutathione peroxidase enzyme activities in Group R measured after CPB were significantly lower than those measured in Group C. The platelet-activating factor (PAF) levels before CPB usage period were same in both groups, where PAF levels after CPB were found to be significantly higher in roller pump group than centrifugal pump group. At inter group comparisons, the levels of PAF were same at each group before and after CPB. Conclusion: The study findings indicate that usage of the centrifugal pump does not have a clear superiority in terms of the effects on inflammatory response and oxidant status during CPB when compared to roller pump. Nevertheless, we believe that our results should be supported by further clinical and experimental studies. PMID- 29984715 TI - Comparison of the change in inferior sclera exposure after maxillary protraction with or without skeletal anchorage. AB - Aim: The aim of this retrospective study was to evaluate the change in inferior sclera exposition after maxillary protraction with or without skeletal anchorage in patients with maxillary retrognathia. Materials and Methods: Fifteen patients (Group 1) who applied maxillary protraction with teeth-supported appliance and fifteen patients who applied maxillary protraction with skeletal anchorage (Group 2) were compared in order to investigate the effect of different maxillary protraction methods on the visibility of sclera. The patients in both groups had dental and skeletal Class III malocclusion with maxillary retrusion (ANB <0; SNA <80), increased vertical growth pattern (SnGoGn> 32) (long face), increased sclera exposure, and no congenital anomalies and dentofacial deformities. Pre- and posttreatment records were used to assess the amount of visible sclera on facial photographs using Adobe Photoshop CS6 program and the change in the movement of maxilla on cephalometric film. The pretreatment and after maxillary protraction values were compared statistically by the Wilcoxon signed-rank test (level of significance, P < 0.05). Results: The amount of inferior sclera exposure to eye height decreased in the right and left eyes of the 30 patients with maxillary protraction. The amount of inferior sclera exposure to eye height of the right and left eyes decreased from 3.59 to 3.5 and from 3.44 to 3.39, respectively, in Group I (P = 0.001 and P < 0.001, respectively). The amount of inferior sclera exposure to eye height of the right and left eyes decreased from 4.17 to 3.93 and from 3.86 to 3.68, respectively, in Group II (P = 0.001 and P < 0.001, respectively). Conclusion: There were important results in both of the two methods. Although more improvement was obtained in the skeletal anchorage group, statistically no significant differences were found between the groups. PMID- 29984716 TI - Outcome of management of elevated skull fractures in Enugu, South-East Nigeria. AB - Introduction: Elevated skull fractures, previously thought of as a very rare variety of fractures, are no longer very uncommon. They are expectedly gradually finding a slowly growing list of references in neurosurgical literature. They are mostly posttraumatic compound fractures due to the mechanism of injury. Outcome of operative neurosurgical care is generally rewarding. Materials and Methods: A 4-year retrospective study of case notes, operation registers, and radiology records of patients diagnosed with elevated skull fractures who had neurosurgical care at the University of Nigeria Teaching Hospital, Enugu, Nigeria, between 2012 and 2015, was done. Only patients with evidence of elevated skull fracture on head computed tomography scan were included. The presenting Glasgow Coma Score and Extended Glasgow Outcome Score (GOSE) at the time of discharge from the hospital and 6 months thereafter were analyzed. Results: Out of 209 patients managed with skull fractures over the study period, eight met the inclusion criteria. Seven (87.5%) were males. The latency to presentation was 6 h in one case and> 8 h in the other cases. All the patients had operative care involving debridement, duroplasty, and bone-fragment realignment (cranioplasty) either primarily or on an interval basis. The GOSE at 6 months was at least 7 in 87.5% of the patients. Conclusions: Despite the grotesque appearance at presentation, outcome of properly managed elevated skull fractures is good. PMID- 29984717 TI - Knowledge and perception of episiotomy among women attending antenatal clinic in a secondary health facility in North-West Nigeria. AB - Background: Episiotomy is a common surgical procedure experienced by women worldwide to ease labor and improve its outcome. However, it could influence the use of delivery services because of its associated complications. The study assessed knowledge and perception of episiotomy among antenatal clinic (ANC) attendees. Methods: It was a cross-sectional study conducted among 218 women attending ANC in a secondary health facility in Northwestern Nigeria. Data were collected using a structured, interviewer-administered questionnaire and were analyzed using IBM SPSS Statistics 20. Results: The mean age of women attending ANC was 24.2 +/- 6.6 years, and 31 (14.2%) of them had had an episiotomy in the past. A majority of them were aware of episiotomy (87.6%) and had good knowledge (83.5%) and good perception (77.5%) of it. In addition, a majority (89.0%) were willing to deliver at the facility even if episiotomy would be given during labor. Knowledge of episiotomy showed statistically significant association with only a history of previous delivery while perception did not show statistically significant association with any of the independent variables. Conclusions: Awareness and knowledge of episiotomy among women attending ANC were high and perception of it was generally good. The major factor associated with the knowledge of episiotomy was a history of previous delivery. Effort should be channeled toward improving awareness and knowledge on episiotomy among intending mothers, and health workers should always ensure that women are adequately informed and counseled before an episiotomy is given to them. PMID- 29984718 TI - Train-of-four guard-controlled sugammadex reversal in patients with multiple sclerosis. AB - Objective: Multiple sclerosis (MS) is a chronic inflammatory and demyelinating autoimmune disease of the central nervous system. It is known that the disease, which is manifested by a wide variety of symptoms, may exacerbate after anesthesia and show different responses to muscle relaxants in the normal population. It is planned to measure train-of-four (TOF) values of MS patients to be operated under general anesthesia before sugammadex application. Materials and Methods: With the approval of the local ethics committee of the University of Health Sciences Bagcilar Training and Research Hospital and with written consents of participants, we anesthetized ten patients (from April 2014 to March 2017) with MS and ten American Society of Anesthesiologists I-III patients without MS. Neuromuscular conduction was assessed by the acceleromyometric method using a TOF Guard apparatus (Organon, Holland). The patients were extubated after recovery of TOF higher than 0.9. The primary efficacy variable was the time from the start of administration of sugammadex to recovery of the TOF ratio to 0.9. Results: The demographic characteristics of both groups, the type and duration of surgery and anesthesia applied, and the temperature of the operation room were similar. Similar characteristics of both groups were of concern for postoperative residual paralysis, and therefore we did not notice any difference between time to TOF> 90/s for both groups. Conclusion: Sugammadex and TOF patients will increase patient safety in general anesthesia practice. PMID- 29984719 TI - Levels of burnout and their associated factors among physicians working in Northeast Anatolia. AB - Context: The concept of burnout is a condition seen in occupational groups working face-to-face with people and resulting in emotional exhaustion, depersonalization, and low professional productivity. Aims: The purpose of this study was to determine burnout levels and associated factors in physicians practicing in Erzurum, Northeast Anatolia, Turkey. Settings and Design: This research was designed as a cross-sectional descriptive study. The research sample size was calculated at 663 participants with a 99% confidence interval and a 3% margin of error using Epi Info software. A 10% incomplete or nonresponse rate was added, for a target cohort of 730 individuals. Seven hundred and eleven physicians agreeing to take part were enrolled. Subjects and Methods: A questionnaire consisting of questions concerning sociodemographic characteristics and the Maslach Burnout Inventory (MBI) was used as the data collection tool. The questionnaires were distributed by the authors and completed by the physicians in person. Statistical Analysis: Descriptive data were expressed as percentage, mean, median, and standard deviation. Data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests and binary logistic regression analysis. P < 0.05 was regarded as statistically significant. Statistical analyses were performed on SPSS 15.00 software. Results: The mean age of the physicians in the study was 34.4 +/- 7.7 years. Mean MBI subdimension scores were 15.6 +/- 7.0 for emotional exhaustion, 5.7 +/- 3.9 for depersonalization, and 21.0 +/- 4.4 for personal accomplishment. Mean emotional exhaustion and depersonalization scores were significantly higher and personal accomplishment scores significantly lower in physicians aged under 25, not taking vacations, working in public hospitals, who were working as research assistants. Conclusions: Burnout levels among the participants were low (emotional exhaustion in 75%, depersonalization in 76.2%, and low personal accomplishment in 69.6%). PMID- 29984720 TI - Evaluation of sociodemographic, clinical, and laboratory markers of sickle leg ulcers among young nigerians at a tertiary health institution. AB - Background: Sickle leg ulcer (SLU) is a chronic and debilitating complication of sickle cell disease (SCD) associated with huge physical and psychosocial discomfort. The occurrence of SLU has remained steady despite successful preventive strategies and advances in SCD care. Although multifactorial factors have been implicated in SLU, these are not fully understood, and data on how these relate to young Nigerian SCD patients are scanty. Aims: This study aims to evaluate the sociodemographic, clinical, and laboratory markers of SLU in a young Nigerian SCD cohort. Patients and Methods: This study involved 109 young SCD patients and 67 healthy peers. The sociodemographic and laboratory parameters of the participants were examined in addition to the evaluation of the SCD cohort for SLU. Results: Only the HbSS patients had SLU. This was found in six of them giving a prevalence of 5.9% (6/101). Their median age was 17, range 14-21 years. There was a preceding history of trauma in 4 (66.7%), and this included a case of traditional scarifications for local therapeutic purposes. Two of the three (66.7%) males with SLU also had priapism (P = 0.0132). Patients with SLU were older, had less frequent bone pain crises, and significantly belonged to the low socioeconomic class (P < 0.05). Although patients with SLU had relatively higher lactate dehydrogenase, platelet count, aspartate transaminase, bilirubin, white blood cell, and lower Hb concentration and HbF, these did not attain statistical significance (P > 0.05). Conclusion: This study confirms that SLU is common among young SCD patients with HbSS genotype, low socioeconomic background, and older age. It also suggests that SLU could be more related to hemolysis-associated SCD phenotypes among the patients. PMID- 29984721 TI - Significance and outcome of living-donor liver transplantation in acute mushroom intoxication. AB - Introduction: Mushroom intoxication (MT) can lead to acute liver injury which may result in Mushroom intoxication-related liver failure (M-ALF) requiring liver transplantation (LT). In the present study, we want to share the experience of our institute regarding living-donor LT (LDLT) due to mushroom poisoning. Aim: The aim of this study is to identify the predictors of poor prognosis in patients with ALF secondary to mushroom intoxication requiring LDLT. Materials and Methods: All patients with MT between 2008 and 2016 were evaluated. Demographics, symptoms, interval between symptoms and admission to our institute, laboratory data, model for end-stage liver disease (MELD)/pediatric end-stage liver disease (PELD) scores, clinical course, and outcomes of supportive therapy and LT were evaluated. There were two groups in the study: Group A = responsive to supportive therapy (n = 9) versus Group B = unresponsive to supportive therapy (n = 9). Results: During the study, a total of 18 patients were admitted with M-ALF. Twelve (66.7%) of them were female, and the mean age was 39.9 +/- 18.2 years. All of the nine patients in Group A fully recovered with supportive therapy. In Group B, one patient died during waiting period for LT and 8 patients received LDLT LDLT. Three of the eight patients who were transplanted died in the postoperative early period within postoperative 5 days. The patients in Group B had significantly higher MELD/PELD scores and encephalopathy rate than in Group A (P < 0.05). International normalized ratio (INR), bilirubin, ammonium levels, and platelet count were significantly different between groups (P < 0.05). The patients in Group B had significantly longer interval before admission to our institute (P < 0.05). Conclusion: The presence of encephalopathy, higher MELD/PELD, INR, bilirubin, ammonium levels, and lower platelet count was related to poor prognosis in MT. LDLT provides a good therapeutic option in patients with M-ALF. The time is a crucial factor in successful treatment of MT. Early admission to a tertiary referral center with expertise in LT results in a better prognosis and increased survival following M-ALF. PMID- 29984722 TI - Midkine levels and its relationship with atherosclerotic risk factors in essential hypertensive patients. AB - Background and Objectives: Hypertension (HT) is one of the risk factors associated with atherosclerosis. Midkine (MK) plays a role as a growth factor in various biologic and pathologic events. In some reports, MK expression has been shown to be linked with vascular smooth muscle proliferation and neo-angiogenesis in atherosclerotic vessels. The aim was to research relationship of MK serum levels with some atherosclerotic risk factors in hypertensive patients. Methodology: This study examined 60 patients with essential HT and 30 healthy controls. Serum biochemistry, including lipid profile, MK, Vitamin B12, C reactive protein, zinc and copper levels were obtained. Results: MK levels of the HT patients were significantly higher than the control group (24.8 +/- 6.8 ng/mL vs. 18.39 +/- 5.6 ng/mL, respectively, P < 0.01). Lipid profile parameters such as total cholesterol, triglyceride, low-density lipoprotein (LDL) were also significantly higher in HT patients (P < 0.021, P < 0.01, and P < 0.01, respectively). Zinc levels were 179.13 +/- 34.06 MUg/dL and 172.55 +/- 45.47MUg/dL in the HT and control group, respectively. Serum MK levels were positively correlated with diastolic (r = 0.288, P < 0.05) and systolic blood pressures (r = 0.390, P < 0.002), and also with serum total cholesterol (r = 0.406, P < 0.002) and LDL cholesterol (r = 0.318, P < 0.015) levels. Furthermore MK was also negatively correlated with zinc and Vitamin B12levels (r = -0.298, P < 0.023, r = -0.334, P < 0.027, respectively). Conclusion: This study has demonstrated an important association between increased serum MK levels and risk factors of atherosclerosis such as HT, increased total and LDL cholesterol. PMID- 29984723 TI - Audit of ophthalmology discharge summaries in a Nigerian Teaching Hospital. AB - Background: Discharge summaries are important components of hospital-care transitions in ensuring continuity of care. Aim: We assessed the adequacy and accuracy of discharge summaries written by junior doctors. Methods: An instrument, adapted largely from the current hospital discharge summary template and recommendations regarding content from the Joint Commission International, was used to study 420 discharge summaries written in 2012 from the ophthalmology service of a Rural Teaching Hospital in Nigeria. The simple descriptive analysis was done with Statistical Package for the Social Science version 17. Results: Completeness of entries was relatively high in many traditional areas (biodata of patient, admission/discharge dates, name of supervising consultant, principal diagnosis, surgical procedures done, follow-up instructions, and condition on discharge) of the summaries. The portion of the paper-based template titled "summary" of the admission was most problematic; with information on medication changes and result of tests missing in 368/420 (87.6%) and 334/420 (79.5%), respectively. Conclusion: Educational intervention for doctors in training with the provision of oversight and feedback by their supervisors is required. Standardized discharge summary templates recognizing the peculiarities of specialized patient groups are recommended. Transition to electronic discharge summary system is imperative. PMID- 29984724 TI - Prevalence of Brucella in raw milk: An example from Turkey. AB - Aim: Brucellosis is a highly contagious zoonotic infection affecting livestock and human beings. This study aimed to investigate the prevalence of Brucella in raw milk collected from a provincial center and central villages in the Central Anatolian region. Materials and Methods: This cross-sectional study was completed between March and September of 2016. The sample size for research was calculated as 263 milk samples with the Epi Info 2000 program. Samples were tested with the milk ring test, Rose Bengal test, and standard Brucella tube agglutination test. Suspicious samples according to these tests were seeded on medium for observation. Results: In this study, 202 cow's milk samples collected from 14 central villages were researched for the presence of Brucella abortus, a Brucella species bacterium. According to the medium seeding results, 35 of 202 raw cow's milk samples (17.32%) were identified as suspicious. Conclusion: The research investigated the prevalence of Brucella in milk samples collected from bovine farms used for consumption and production of raw milk products. The most significant infection route in our region is considered to be consumption of milk and milk products such as raw milk and fresh cheese. Especially in rural areas, households consuming their own produced milk are common. In regions with family style milk and milk product production and consumption, interventional studies with the aim of improving knowledge, attitudes, and behavior related to zoonotic diseases should not be neglected. PMID- 29984725 TI - Comparison of time-dependent two-dimensional and three-dimensional stability with micro-computerized tomography and wettability of three impression materials. AB - Objectives: The objective of this study is to explore time-dependent dimensional stability of three different elastomeric impression materials - vinyl polyether silicone (VPES), vinyl polysiloxane (VPS), and polyether (PE) - through micro computerized tomography (MU-CT) imaging, allows three-dimensional (3D) imaging and measurement without sample preparation or chemical fixation. Materials and Methods: Thirty specimens were created using 3 mm high, 30 mm wide Teflon molds (n = 10). Specimens were scanned with MU-CT on the 1st (T1) h and 1st (T2), 7th (T3), and 14th (T4) days. 3D models were created at the above-mentioned times, volumetric measurements were conducted and dimensional changes were calculated. Diameters and heights of each impression material were measured with 2D analyses. Furthermore, contact angle measurements of these elastomeric impression materials were collected using the sessile drop method during and after polymerization at 0, 2, 5, 20, 60, 120, and 240 s These measurements were made on specimens (n = 10) prepared in standard sizes using a 50 MUm deep stainless steel die with dimensions of 62 mm * 20 mm * 3 mm. Results: Evaluation of the dimensional volume changes of the VPES, VPS, and PE measurements showed there to be no statistically significant differences between the T1, T2, T3, and T4 (P > 0.05). Only the decreases in the volume averages of T3 and T4 in the VPES were statistically significant (P < 0.05). As a result of binary comparisons, the evaluation of contact angle measurements of VPES, VPS, and PE materials during and after polymerization were compared. The average contact angle measurements of the VPS group were statistically significantly lower than the averages of the VPES and PE groups (P < 0.01). Conclusions: VPS was found to be the most stable impression material concerning dimensional change and wettability. PMID- 29984726 TI - Risk factors for poor visual outcome in traumatic hyphema: Jakarta eye trauma study. AB - Objective: : To report the risk factors for poor visual outcome in traumatic hyphema. Materials and Methods: A retrospective study was done by collecting data from medical records between January 2011 and December 2015 in Jakarta, Indonesia. Clinical data included initial visual acuity (IVA), final VA at 3 months, slit lamp evaluation with grading of hyphema, intraocular pressure, and fundus findings on direct or indirect ophthalmoscopy. Results: The study included 97 patients, with males showing a preponderance, the ratio being 9:1. Soft gun pellet was the most common cause (27.8%), others being workplace injuries (12.4%), sports injury (14.4%), traffic accident (2.1%), and other injuries (43.3%). Poor visual outcome was due to vitreous hemorrhage, cataract, iridodialysis, and choroidal rupture. On statistical analysis, significant risk factors were causality (P = 0.018), IVA (P = 0.026), onset of injury (0.000), and grade of hyphema (P = 0.000). Conclusion: Grade of hyphema, IVA, causality, and onset of injury were significant risk factors related to poor visual outcome in traumatic hyphema. PMID- 29984727 TI - Color relationships of natural anterior teeth: An In vivo study. AB - Objectives: To investigate the color relationships between the anterior teeth in vivo. Materials and Methods: A total of 640 volunteers (age: 18-22) participated in the study. The color measurements of left maxillary and mandibular central, lateral, and canine were performed using a colorimeter. Color differences were calculated according to the CIE L*a*b* (DeltaE*) and CIEDE2000 (DeltaE00*) system. The National Bureau of Standards (NBS) ratings were also evaluated. Statistical analyses were performed using two-way ANOVA and Fisher's exact test (P < 0.05). Results: Significant differences were found between the L*, a*, b*, and DeltaE* values (P < 0.05), except for mandibular central and lateral. DeltaE* values were found between 1.5 DeltaE* (mandibular central-mandibular lateral) and 8.1 DeltaE* (maxillary central-maxillary canine). While the highest L* (80.5) and the least b* (15.1) values were obtained for mandibular central, the mean L* (73.6) and the mean b* values (21.3) were obtained for the maxillary canine. a* value was found to be highest for the mandibular lateral (1.1) and the least for the maxillary central (-0.2) teeth. NBS values were between 1.3 and 7.4 units, and only mandibular central and mandibular lateral teeth exhibited "almost the same" color values, while the other teeth exhibited "slightly different," "very different," or "remarkably different" color values. Conclusion: Anterior maxillary and mandibular teeth exhibited "different" color values. Only mandibular incisors and mandibular laterals showed "almost the same" color. Canines were more dark/red/yellow for both mandible and maxilla. Centrals were more bright/green/yellow for maxilla and bright/green/blue for mandibular. Clinicians should select the color one by one for each tooth and be aware of their color relations for optimal esthetics. PMID- 29984728 TI - Predictors of autonomic dysfunction among predialysis chronic kidney disease patients in Nigeria. AB - Background: Chronic kidney disease (CKD) is a global public health problem with increasing incidence and mortality in Africa. Autonomic dysfunction (AD) has been implicated as a major contributor to the disease morbidity and mortality, but little is known about the predictors of this dysfunction in African populations. Understanding the predictors of this condition is necessary for early detection and management of CKDs. Objectives: This study was designed to determine the predictors of AD in CKD patients in Nigeria. Materials and Methods: It was a cross-sectional study of CKD patients at University of Nigeria Teaching Hospital, Enugu, Nigeria. The CKD patients with AD were compared with those without AD and a normal control group. Autonomic function was assessed through noninvasive cardiovascular tests: measurement of resting tachycardia, orthostatic hypotension, heart rate response (HRR) to standing, HRR to Valsalva maneuvre, and HRR to respiration. Data on symptoms of CKD and AD were obtained using a validated questionnaire. Results: The mean age of the CKD patients was 41.3 +/- 1.5 (range: 21-69) years. Early hospital presentation is associated with significantly less risk of the development of AD (P < 0.001). Dizziness, nocturnal diarrhea, and impotence are the major markers/predictors of AD in CKD patients (P < 0.05). Conclusion: AD is common among predialysis CKD patients in Nigeria, and best predicted by the presence of postural dizziness, nocturnal diarrhea, and impotence in men. Physicians should, therefore, be on the lookout for these features for prompt and adequate management of cases. PMID- 29984729 TI - Total maxillectomy with prosthetic reconstruction techniqueprosthetic reconstruction technique: A case report of a patient who underwent a total maxillectomy. AB - The prosthetic treatment of patients with total maxillectomies is an enormous reconstruction challenge because of insufficient support and retention from the residual tissues. It is not possible to place the bulb in the presence of unfavorable undercuts throughout the nasal cavity floor and borders. The purpose of this article was to describe a prosthetic reconstruction technique which accomplishes optimum sealing, retention, stabilization, and easy placement of an open-hollow acrylic resin obturator using a spring with a resilient liner for a patient who underwent a total maxillectomy. The springs were placed in the resilient liner to facilitate the placement of the obturator prosthesis because of unfavorable undercuts. It was possible to fit the prosthesis in two stages by means of springs. The objective of this technique is to improve the patient's psychological, functional, and social well-being by producing a stable, retentive, leakproof, comfortable, easy-fitting prosthesis. This technique is appropriate for patients who have undergone total maxillectomies when implant placement is not possible. PMID- 29984730 TI - Acute angle closure following hemodialysis in a 34-year-old Nigerian female. AB - Studies have reported that intraocular pressure (IOP) might change markedly during hemodialysis. We report the case of a 34-year-old Nigerian female with a 3 year history of chronic kidney disease secondary to chronic glomerulonephritis who presented with acute symptomatic elevation of IOPs following hemodialysis. She had no ocular complaints immediately before undergoing hemodialysis. She presented with a history of pain, redness, and mild blurring of vision in the left eye about 15 min after hemodialysis. Examination revealed circumciliary injection, shallow anterior chambers, and closed angles on gonioscopy in both the eyes. She was treated with pilocarpine (4%) four times daily and dorzolamide/timolol (2%/0.5%) twice daily combination eye drops with subsequent relief of symptoms and IOP reduction from an initial 48 and 74 mmHg to 10 and 12 mmHg for the right and left eyes, respectively. This case highlights the need for sensitization and awareness among renal physicians and ophthalmologists of the possibility of extremely high IOP during or immediately following hemodialysis. It also emphasizes the importance of gonioscopy and treatment of at-risk patients with narrow angles before hemodialysis. PMID- 29984731 TI - Cerebral arterial thrombosis in a child with nephrotic syndrome. AB - Nephrotic syndrome (NS) in childhood may be associated with thromboembolic complications, mainly in venous origin. However, arterial thrombosis may also be seen as a very rare and life-threatening complication. Herein, we described a case of steroid-resistant NS who did not respond to full-dose steroid treatment for 8 weeks and was complicated by neurological findings. The renal biopsy was consistent with focal segmental glomerulosclerosis. His cerebral magnetic resonance angiography showed the sudden termination of M3 branch of the left middle cerebral artery which corresponded with subacute infarction in the left frontoparietotemporal area. Thrombosis panel yielded the results of hyperhomocysteinemia (46.1 MUmol/L, range: 5-15 MUmol/L) and heterozygous methylene tetrahydrofolate reductase mutation (C677T, A1298C). After that, the patient was given medical therapy including anticoagulant treatment. Improvement in the neurological outcome was determined on the 1st month of follow-up examinations. PMID- 29984732 TI - Mechanisms of Yangjing Capsule in Leydig Cell Apoptosis and Testosterone Synthesis via Promoting StAR Expression. AB - The present study aims to investigate the roles of steroidogenic acute regulatory protein (StAR) in Yangjing Capsule (YC) induced anti-apoptotic effects on Leydig cells and the related mechanism. Leydig tumor cells (MLTC-1) were cultured and treated with YC, and immunofluorescence assay was performed to examine the expression of StAR; furthermore, luciferase reporter assay was conducted to evaluate the impact of YC on StAR promoter; next, MLTC-1 cells were treated with StAR small interfering RNA (siRNA), and flow cytometry was carried out to examine the effect of StAR siRNA on the apoptosis of the cells; furthermore, quantitative (q)RT-PCR and Western blot methods was used to determine the expression of StAR and apoptosis related molecules Bcl-2, Bax and Caspase-3 on both mRNA and protein levels in different groups; finally the secretion of testosterone in different groups was examined by radioimmunoassay. We observed that the YC can increase the expression of StAR in a dose-dependent manner, and YC can activate the promoter of StAR; moreover, transfection of StAR siRNA can block YC induced anti-apoptotic effects and increased production of testosterone. In conclusion, our results suggested that YC might suppress the apoptosis of MLTC-1 cells and enhance the production of testosterone through regulating the expression of StAR. PMID- 29984733 TI - Proteomic Analysis Reveals the Renoprotective Effect of Tribulus terrestris against Obesity-Related Glomerulopathy in Rats. AB - Tribulus terrestris L. (Zygophyllaceae) (TT) is usually used as a cardiotonic, diuretic, and aphrodisiac, as well as for herbal post-stroke rehabilitation in traditional Chinese medicine. However, little is known about the renoprotective effects of TT on obesity-related glomerulopathy (ORG). In this study, 340 monomeric compounds were identified from TT extracts obtained with ethyl acetate combined with 50% methanol. In vitro, IC50 of TT was 912.01 mg/L, and the appropriate concentration of TT against oxidized-low density lipoprotein (ox-LDL) induced human renal glomerular endothelial cells (HRGECs) was 4 mg/L. TT significantly increased the viability (63.2%) and migration (2.33-fold increase) of HRGECs. ORG model rats were induced by a chronic high-fat diet (45%) for 20 weeks and were then treated with TT extract (2.8 g/kg/d) for 8 weeks. Subsequently, the kidneys were removed and their differentially expressed protein profile was identified using two-dimensional electrophoresis coupled with matrix assisted laser desorption/ionization-time of flight (MALDI-TOF)-TOF MS. Molecular categorization and functional analysis of bioinformatic annotation suggested that excessive energy metabolism, decreased response to stress and low immunity were the potential etiologies of ORG. After TT administration for 8 weeks, body weight, blood pressure, serum cystatin C and cholesterol were decreased. Additionally, TT significantly enhanced the resistance of rats to ORG, decreased energy consumption and the hemorrhagic tendency, and improved the response to acute phase reactants and immunity. In conclusion, TT may play a protective role against ORG in rats. PMID- 29984734 TI - Relationships of plasma insulin-like peptide 3, testosterone, inhibin, and insulin-like growth factor-I concentrations with scrotal circumference and testicular weight in Japanese Black beef bull calves. AB - This study was conducted to clarify the relationships of plasma concentrations of insulin-like peptide 3 (INSL3), testosterone, inhibin, and insulin-like growth factor-I (IGF-I) with scrotal circumference and testicular weight in Japanese Black beef bull calves (n = 20), from birth to pre-puberty. Monthly blood sampling (0 to 7 months) and scrotal circumference measurements (0 to 7 months) were performed. Testicular weight was recorded immediately after castration at 7 months. Plasma INSL3, testosterone, inhibin, and IGF-I concentrations were measured either by enzyme immunoassay or time-resolved fluorescence immunoassay. The correlation coefficients of these hormonal concentrations with scrotal circumference were significant (P < 0.0001) and it was higher for INSL3 (r = 0.647) than for testosterone (r = 0.597), IGF-I (r = 0.400), and inhibin (r = 0.453). Calves with heavier testes (> 60 g) at castration (7 months) had higher (P < 0.05) plasma INSL3 (from 3 to 7 months) and inhibin (from 1 to 4 months) concentrations than those with lighter testes (< 60 g). The calves with heavier testes at castration had larger (P < 0.05) scrotal circumference than those with lighter testes from 3 to 7 months. In conclusion, blood INSL3 concentrations may be the best functional indicator among the hormones analyzed for determining total testicular volume during pre-puberty in bull calves. In addition, inhibin and INSL3 concentrations in early calfhood may be functional predictors for testicular weight at pre-puberty. PMID- 29984735 TI - Histopathological and electron microscopic study in dogs with patellar luxation and skin hyperextensibility. AB - Patellar luxation is abnormal displacement of the patella from the femoral trochlear groove. It is seen primarily in small breed dogs and causes pain and limited mobility of the stifle joint. This study aimed to investigate the relationship among patellar luxation, skin extension, and skin collagen fibril diameter. Nine dogs with patellar luxation and five clinically normal dogs were enrolled in the study. We measured the skin extension and investigated the ultrastructure of the skin and patellofemoral ligament by histopathology and transmission electron microscopy. The mean skin extension in dogs with patellar luxation was 18.5 +/- 5.5% which is greater than the reference value (14.5%). Mean skin extension in controls was 8.8 +/- 1.7% and was within the normal range. In dogs with patellar luxation, histopathology of the skin and patellofemoral ligament showed sparse and unevenly distributed collagen fibers. Transmission electron microscopy identified poorly organized, irregularly shaped, thin collagen fibrils. Collagen fibril thickness in dogs with patellar luxation was significantly less than fibril thickness in controls (P<0.001). There was a significant negative correlation (rho= -0.863; P<0.001) between skin collagen fibril diameter and skin extension. Skin extension was correlated with patellar luxation and disease severity. Dogs with patellar luxation, joint dysplasia, and hyperextensible skin appear to be pathologically related. This might represent a phenotype of the Ehlers-Danlos syndrome, a hereditary connective tissue disorder in humans. PMID- 29984736 TI - Mechanism for Decreased Gene Expression of beta4-Galactosyltransferase 5 upon Differentiation of 3T3-L1 Mouse Preadipocytes to Adipocytes. AB - Upon differentiation of cells, remarkable changes in the structures of glycans linked to lipids on cell surface have been observed. Lactosylceramide (Lac-Cer) serves as a common precursor for a series of glycosphingolipids with diverse structures. In the present study, we examined the underlying mechanism for the biosynthesis of Lac-Cer upon differentiation of 3T3-L1 mouse preadipocytes to adipocytes. TLC analysis showed that the amounts of Lac-Cer decrease in 3T3-L1 adipocytes compared to 3T3-L1 preadipocytes. In accordance with this change, the gene expression level of beta4-galactosyltransferase (beta4GalT) 5, which was identified as Lac-Cer synthase, decreased drastically upon differentiation of 3T3 L1 preadipocytes. The analysis of the transcriptional mechanism of the beta4GalT5 gene demonstrated that the core promoter region is identified between nucleotides -299 and -1 relative to the translational start site. During adipocyte differentiation, the expression levels and promoter activities of the beta4GalT5 gene decreased dramatically. Since the Specificity protein 1 (Sp1)-binding sites in the promoter region were critical for the promoter activity, it is suggested that Sp1 plays an important role for the expression of the beta4GalT5 gene in 3T3 L1 cells. The gene and protein expression of Sp1 decreased significantly upon differentiation of 3T3-L1 preadipocytes. Taken together, the present study suggest that the expression of the beta4GalT5 gene decreases through reduced expression of the Sp1 gene and protein upon differentiation of 3T3-L1 peradipocytes to adipocytes, which may lead to the decreased amounts of Lac-Cer in 3T3-L1 adipocytes. PMID- 29984737 TI - Inter-Regional Differences in Travel Time to the Nearest Nursery for Children with Mild Acute Illness in Japan. AB - Access to day-care services for children with mild acute illness is important for working parents, because infants and toddlers often suddenly become ill, and most Japanese nursery schools do not accept children with even mild illnesses. Actual travel time to nurseries providing such day-care services is one of the indicators for measuring accessibility. However, this variable has not been well analyzed in previous work. To clarify practical access to such nurseries, this study used a car navigation algorithm to calculate the percentage of the population of children in Japan who can access nurseries providing services for children with mild acute illnesses within 15 to 30 minutes and compared this with the proportion of children living within a linear distance of 10 km of such nurseries. Of the 4,987,706 children younger than 5 years in 2015, 51.7% lived in areas from which the nearest nursery for children with mild acute illness was accessible within 0-15 minutes by automobile. In addition, 81.5% lived within 0 30 minutes of such nurseries, and the same percentage (81.5%) lived within a linear distance of 10 km of such nurseries. Both calculation methods (travel time and linear distance) showed inter-regional differences in accessibility, and the proportion of children with access to these nurseries was higher in heavily populated regions (e.g., Kanto and Kinki) than in less populated regions (e.g., Hokkaido and Tohoku). Children and caregivers throughout Japan should have equal access to these nurseries, because the national government subsidizes such services. PMID- 29984738 TI - RNase E/G-dependent degradation of metE mRNA, encoding methionine synthase, in Corynebacterium glutamicum. AB - Corynebacterium glutamicum is used for the industrial production of various metabolites, including L-glutamic acid and L-lysine. With the aim of understanding the post-transcriptional regulation of amino acid biosynthesis in this bacterium, we investigated the role of RNase E/G in the degradation of mRNAs encoding metabolic enzymes. In this study, we found that the cobalamin independent methionine synthase MetE was overexpressed in DeltarneG mutant cells grown on various carbon sources. The level of metE mRNA was also approximately 6- to 10-fold higher in the DeltarneG mutant strain than in the wild-type strain. A rifampicin chase experiment showed that the half-life of metE mRNA was approximately 4.2 times longer in the DeltarneG mutant than in the wild-type strain. These results showed that RNase E/G is involved in the degradation of metE mRNA in C. glutamicum. PMID- 29984739 TI - Management of occupational noise induced hearing loss in the mining sector in South Africa: Where are the audiologists? AB - OBJECTIVE: This study was conducted to explore the scope of practice for occupational audiologists in the mining industry and the audiologists' involvement in hearing conservation programmes in South African mines. Additionally, this study investigated the mining industry's role in the audiologists' involvement, and assessed the audiologists' levels of preparedness for working in occupational audiology. METHODS: In-depth, qualitative telephone and face-to face interviews were conducted with seven occupational audiologists involved in the management of occupational, noise-induced hearing loss (ONIHL) in the South African mining sector. Snowball sampling was utilized to recruit possible participants for this study. Data were analysed using inductive thematic analysis. RESULTS: The following themes were identified: scope-context misalignment, juniorization of the experts, audiologists are important... but for what?, and limited training in occupational audiology. CONCLUSIONS: Our evidence highlights important gaps in HCPs in South Africa. The fact that the audiologists responsible for the management of ONIHL are only minimally and peripherally involved may play a significant role in the lack of progress reported in the management of ONIHL in the South African mining sector. PMID- 29984742 TI - Successful Treatment with a High-dose Rifampin-containing Regimen for Pulmonary Tuberculosis with a Disputed rpoB Mutation. AB - Mutations in the rpoB gene of Mycobacterium tuberculosis can result in resistance to rifampin. Among various mutations in the rpoB gene, some known as disputed rpoB mutations can cause low-level rifampin resistance. It has been suggested that a high-dose rifampin (20 mg/kg)-based regimen might be effective in treating tuberculosis (TB) caused by M. tuberculosis with disputed rpoB mutations exhibiting low-level resistance. We herein report the first two cases of pulmonary TB caused by M. tuberculosis with a disputed rpoB mutation (CTG511CCG) that showed successful treatment outcomes with a high-dose rifampin-based regimen. PMID- 29984740 TI - Occupational Exposure Limits for ethylidene norbornene, ethyleneimine, benomyl, and 2,3-epoxypropyl methacrylate, and classifications on carcinogenicity. PMID- 29984741 TI - Risk of chromosomal aberration in spermatozoa during intracytoplasmic sperm injection. AB - Intracytoplasmic sperm injection (ICSI) has become critical for the treatment of severe male infertility. The principal feature of ICSI is the direct injection of spermatozoon into an oocyte, which facilitates the production of fertilized embryos regardless of semen characteristics, such as sperm concentration and motility. However, the chromosomal integrity of ICSI zygotes is degraded compared to that of zygotes obtained via in vitro fertilization. This chromosomal damage may occur due to the injection of non-capacitated, acrosome-intact spermatozoa, which never enter the oocytes under natural fertilization. Furthermore, it is possible that the in vitro incubation and pre-treatment of spermatozoa during ICSI results in DNA damage. Chromosomal aberrations in embryos induce early pregnancy losses. However, these issues may be overcome by embryo production using gametes with guaranteed chromosomal integrity. Because conventional chromosome analysis requires fixing cells to obtain the chromosome spreads, embryos cannot be produced using the nucleus that has been analyzed. On the other hand, genome cloning using androgenic or gynogenic embryos provides an additional nucleus for chromosome analysis following embryo production. Thus, this review aims to highlight the hazardous nature of chromosomal aberrations in sperm during ICSI and to introduce a method for the prezygotic examination for chromosomal aberrations. PMID- 29984743 TI - Acute Kidney Injury by Renal Hemosiderosis Secondary to Primary Cold Agglutinin Disease Associated with an Excessive Alcohol Intake. AB - Renal hemosiderosis occurs in the context of severe intravascular hemolysis, with the most common cause being paroxysmal nocturnal hematuria. Patients with cold agglutinin disease (CAD) have relatively mild hemolysis, and acute kidney injury (AKI) due to renal hemosiderosis has not been reported. We encountered a patient with CAD caused by lymphoplasmacytic lymphoma who developed AKI secondary to renal hemosiderosis after an excessive alcohol intake. PMID- 29984744 TI - Very Late Relapse of Acute Promyelocytic Leukemia 17 Years after Continuous Remission. AB - The prognosis of acute promyelocytic leukemia (APL) has been improved by the combination of all-trans retinoic acid (ATRA) with chemotherapy. Nonetheless, relapse occurs in a certain proportion of patients, mostly within three to four years after treatment. We herein report a patient treated with ATRA and chemotherapy achieving remission who relapsed approximately 17 years after the treatment. A literature review identified 5 additional reported cases of APL relapse after more than 10 years. None of them presented with generally established risk factors for relapse, such as a high leukocyte count. The potential for late relapse of APL occurring more than 10 years after treatment should be recognized. PMID- 29984745 TI - Systemic Disseminated Angiosarcoma Showing Thin-walled Cystic Nodules in the Lungs. PMID- 29984746 TI - Combined Coagulopathy Can Induce Both Hemorrhagic and Thrombotic Complications in Multiple Myeloma. AB - Coagulation abnormalities are a rare but critical complication associated with plasma cell diseases. We herein present a case of multiple myeloma (MM) with complicated coagulopathy. Initially, the patient showed severe bleeding tendency due to concomitant acquired hemophilia A and acquired von Willebrand syndrome. Interestingly, the patient also exhibited hyperactivation of factor IX. During treatment for MM, the bleeding complications were ameliorated; however, the patient had central retinal vein occlusion. All of the coagulation abnormalities were completely resolved after the complete remission of MM. This case suggests that MM patients may have concomitant risks for both bleeding and thromboembolic complications. PMID- 29984747 TI - Improvement of Alveolar Hemorrhaging in an Elderly and Renally Impaired Patient with Relapsing Anti-neutrophil Cytoplasmic Autoantibody-associated Vasculitis by Single Infusion of Rituximab. AB - Rituximab (RTX) has become a therapeutic option for inducing remission of anti neutrophil cytoplasmic autoantibody-associated vasculitis (AAV). However, the optimum dosage of RTX to induce remission of AAV and reduce adverse events, such as infection, remains unclear. We herein report an elderly and renally impaired patient with alveolar hemorrhaging due to refractory AAV who was successfully treated with single infusion of RTX. Single infusion of RTX may be a therapeutic option in refractory AAV patients who are vulnerable to infections. PMID- 29984748 TI - Hereditary Pancreatitis Showing Numerous Cysts with Pancreatic Cancer. PMID- 29984749 TI - Standard and Novel Additional (Optional) Therapy for Lung Abscess by Drainage Using Bronchoscopic Endobronchial Ultrasonography with a Guide Sheath (EBUS-GS). PMID- 29984750 TI - Stiff-person Syndrome with Waldenstrom Macroglobulinemia. AB - We herein report the case of stiff-person syndrome in a 73-year-old woman. She experienced episodes of painful muscle spasms and was admitted to another hospital. She was diagnosed with Waldenstrom macroglobulinemia. She showed improvement in muscle spasms post-chemotherapy, which was discontinued due to pancytopenia. Six months later, she was admitted to our hospital for repeated whole-body muscle spasms, at which point she was diagnosed with stiff-person syndrome. An anti-glutamic acid decarboxylase antibody text was negative. Her muscle spasms disappeared after the administration of corticosteroids and rituximab. Stiff-person syndrome may develop with Waldenstrom macroglobulinemia. In the present case, corticosteroids and rituximab provided effective treatment. PMID- 29984751 TI - Clival Osteomyelitis with Cavernous Sinus Thrombosis Due to Fusobacterium nucleatum and Campylobacter rectus Induced by Tooth Extraction. AB - A 70-year-old woman who had suffered from aseptic meningitis complained of chronic headache after dental treatment including tooth extraction. She developed a fever and respiratory failure. Based on chest computed tomography and head magnetic resonance imaging (MRI), she was diagnosed with osteomyelitis in the clivus accompanying moderate pituitary involvement, cavernous sinus thrombosis and septic pulmonary embolism. Both of the causal bacteria, Fusobacterium nucleatum and Campylobacter rectus, were isolated from her blood. Dual infection leading to clival osteomyelitis and cavernous sinus thrombosis has not been reported. It is important to perform enhanced MRI and blood culture for patients with chronic headache related to dental treatment. PMID- 29984752 TI - Central Nervous System Lymphoma Harboring the JAK2 V617F Mutation That Developed after a 20-year History of Polycythemia Vera. AB - A 78-year-old man who had a 20-year history of polycythemia vera (PV) with a JAK2 V617F mutation presented with gradually progressive disturbance of consciousness. Hyper-intense lesions in the peri-lateral ventricular area and left cerebellar hemisphere were observed by T2-weighted and fluid-attenuated inversion recovery magnetic resonance imaging. Cytologic and genetic analyses of the lymphoma cells obtained from his cerebrospinal fluid established the diagnosis of B-cell lymphoma. No lesions outside of the brain were recognized. Because of his poor general condition, he was not treated actively. A postmortem analysis revealed a JAK2 V617F mutation in the lymphoma cells, suggesting their origin was a PV clone. PMID- 29984754 TI - A Cardiac Variant of Fabry Disease Diagnosed with Chance Urinary Mulberry Cells. AB - Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A and is classified into two types: classical and variant. The classical type exhibits classic manifestations, but the variant type does not and is therefore difficult to identify sometimes. A 73-year-old woman with a first episode of heart failure was admitted to our hospital. Her left ventricular wall motion was mildly reduced without hypertrophy. Urine sediment revealed mulberry cells, leading to the diagnosis of Fabry disease. In cases without typical clinical findings, urinary mulberry cells may help diagnose Fabry disease. PMID- 29984753 TI - Anti-MDA5 Antibody-positive Dermatomyositis Complicated by Autoimmune-associated Hemophagocytic Syndrome That Was Successfully Treated with Immunosuppressive Therapy and Plasmapheresis. AB - A 56-year-old Japanese woman with muscle weakness, increased creatine kinase and aldolase levels, and characteristic cutaneous lesions was diagnosed with anti melanoma differentiation-associated gene 5 antibody (anti-MDA5 antibody)-positive dermatomyositis. She also had interstitial lung disease (ILD). After corticosteroid and tacrolimus combination therapy was started, bicytopenia and elevated serum ferritin and transaminase emerged. Because the bone marrow tissues were hypoplastic with hemophagocytes, she was diagnosed with concomitant autoimmune-associated hemophagocytic syndrome (HPS). Intravenous cyclophosphamide pulse therapy and plasmapheresis were performed. The laboratory findings indicated improved abnormalities, and the ILD did not progress. Anti-MDA5 antibody-positive dermatomyositis can be complicated by HPS. PMID- 29984755 TI - Falling After Starting Running in a Case of Myoclonus Epilepsy Associated with Ragged-red Fibers with a 8344A>G mtDNA Mutation. AB - Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344A>G mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness. PMID- 29984756 TI - Paroxysmal Atrial Fibrillation in Patients Successfully Treated by Radiofrequency Catheter Ablation with Severely Compression, Lateral Displacement, and Clockwise Rotation of Their Hearts due to Severe Pectus Excavatum. AB - Two cases with severe pectus excavatum and symptomatic atrial fibrillation (AF) underwent radiofrequency catheter ablation (RFCA). Their chest X-ray and computed tomography (CT) findings revealed lateral displacement and clockwise rotation of their hearts, and severe right atrial and mild right ventricular compression against the sternum, but no left atrium compression against the spinal column. The procedure was therefore carefully performed under guidance with CT, intra cardiac echography, atriography, and a three-dimensions mapping system. Finally, the AF was successfully treated by RFCA without any complications. These findings underscore the importance of understanding cases of abnormal anatomy and carefully designing a strategy before performing any procedure. PMID- 29984757 TI - Pharmacokinetics of Isoniazid-induced Rhabdomyolysis in a Girl. PMID- 29984758 TI - The Transbronchial Drainage of a Lung Abscess Using Endobronchial Ultrasonography with a Modified Guide Sheath. AB - Lung abscess is usually treated with long-term antibiotic therapy. Due to the lack of a safe and easy drainage technique, drainage is only applied in refractory cases. We herein describe three cases in which drainage was successfully performed by endobronchial ultrasonography using a modified guide sheath. This procedure may have advantages in the detection of causative pathogens and early infection source control, and may therefore lead to the appropriate selection of antibiotics and reduce the duration of antibiotic therapy. PMID- 29984759 TI - Successful Stenting for Bronchial Stenosis Resulting from Blunt Airway Trauma. AB - Blunt airway trauma is rare but life threatening. Injuries to other vital organs accompany this type of injury in most cases; therefore, conservative treatment may be considered first. In cases of delayed fibrotic airway stenosis after conservative treatment, surgical treatment or bronchoscopic intervention are therapeutic options. We herein report a case of delayed airway stenosis after a blunt traumatic airway injury that was successfully managed by silicone stenting. PMID- 29984760 TI - Hypopituitarism and Central Diabetes Insipidus Caused by Central Nervous System Lymphoma. PMID- 29984761 TI - Irreversible Electroporation for Nonthermal Tumor Ablation in Patients with Locally Advanced Pancreatic Cancer: Initial Clinical Experience in Japan. AB - Objective To evaluate irreversible electroporation (IRE) for locally advanced pancreatic cancer (LAPC). Methods This study was approved by our local review board. Eight patients with histologically proven LAPC <=5 cm were prospectively enrolled to undergo ultrasound-guided IRE. The primary endpoint was complications within 90 days. Secondary outcomes were the overall survival (OS) and time to local progression. Safety was assessed using Common Terminology Criteria for Adverse Events Version 4.0. Results All patients were treated successfully. The median procedure time was 150 min. The median largest tumor diameter was 29.5 mm (20.0-48.0 mm) in the pancreatic head (n=5) and body (n=3). Open (n=4) and percutaneous (n=4) approaches were used. No patients died within 90 days after IRE. There were 5 minor complications in 3 patients and 4 major complications in 3 patients. The incidence rates of major complications did not differ significantly between the approaches. The median time to local progression after IRE was 12.0 months, and the median OS was 17.5 months from IRE and 24.0 months from the diagnosis, with no significant differences between the approaches. Conclusions Percutaneous and open IRE may be acceptable for patients with LAPC (despite some major adverse events) and may represent a useful new therapeutic option. PMID- 29984762 TI - Severe Maxillary Medication-related Osteonecrosis of the Jaw. PMID- 29984763 TI - Trigeminal Root Entry Zone Lesions in Non-multiple Sclerosis. PMID- 29984764 TI - Pulmonary Tuberculosis Complicated with Severe Thrombocytopenia with Diffuse Alveolar Hemorrhaging during Anti-tuberculosis Chemotherapy: An Autopsy Report. AB - Tuberculosis may be accompanied by various hematological abnormalities during treatment, and occasionally thrombocytopenia is also noted. Most cases of thrombocytopenia in tuberculosis are moderate, and there are few reports about thrombocytopenia with diffuse alveolar hemorrhaging (DAH) in pulmonary tuberculosis. We describe the case of an 82-year-old man with pulmonary tuberculosis and tuberculous pleurisy. He underwent anti-tuberculosis chemotherapy; during tuberculosis treatment, he experienced DAH due to fulminant thrombocytopenia. Thrombocytopenia is a common finding in patients with pulmonary tuberculosis, but the laboratory findings should be carefully evaluated. Thrombocytopenia during anti-tuberculosis chemotherapy can cause life-threatening DAH. PMID- 29984765 TI - Perigraft Abscess Subsequent to Aortoesophageal Fistula. AB - A 79-year-old man with appetite loss and nausea for 1 month was admitted to our hospital. His thoracic aortic aneurysm had gradually increased in size due to perigraft endoleak after the previous aneurysm repair surgery. Although he showed no hematemesis, melena, or a fever, gastrointestinal endoscopy and contrast enhanced computed tomography (CT) revealed an aortoesophageal fistula (AEF). He developed septic shock due to a perigraft abscess and eventually died, although aortic graft replacement and esophageal transection were performed. Clinical suspicion is the most important factor for obtaining an accurate diagnosis and improving the prognosis in cases of AEF. PMID- 29984766 TI - Ovarian Metastases from ALK-rearranged Lung Adenocarcinoma: A Case Report and Literature Review. AB - We herein report a 37-year-old woman with lung adenocarcinoma with brain metastases and an asymptomatic ovarian tumor. Immunohistochemistry and a fluorescent in situ hybridization analysis of the biopsied lung tumor revealed anaplastic lymphoma kinase (ALK) gene rearrangement. Although the origin of the ovarian tumor remained unclear, alectinib administration was initiated, and radiological responses were observed in all lesions, which confirmed that the ovarian tumor was a metastasis from lung cancer. Although differentiating the origin of an ovarian tumor is difficult in lung cancer patients due to the rarity of ovarian metastases, alectinib therapy can replace an invasive biopsy, especially in ALK-rearranged lung cancer patients. PMID- 29984767 TI - Imported Tungiasis in a Non-endemic Country. PMID- 29984768 TI - Monocular Oculomotor Nerve Disorder Manifesting as Cranial Neuropathy in Systemic Lupus Erythematosus. AB - We herein report the case of a patient who developed peripheral neuropathy of the bilateral lower legs that later became complicated with isolated oculomotor nerve disorder and was finally diagnosed as systemic lupus erythematosus (SLE). Based on the findings for oculomotor nerve paralysis and contrast-enhanced magnetic resonance imaging findings for the oculomotor nerve in the prepontine cistern, the isolated oculomotor nerve disorder was considered to be a manifestation of peripheral neuropathy. This oculomotor nerve disorder may contribute to the diagnosis of SLE and can be effectively treated with steroid pulse therapy. Reports of SLE manifesting as isolated oculomotor nerve paralysis are rare. PMID- 29984769 TI - Cervical Cord Infarction Caused by Dissection of the Intracranial Segment of the Vertebral Artery. AB - Cervical cord infarction is uncommon but has been increasingly reported as a complication of vertebral artery dissection (VAD). A 54-year-old woman presented with neck pain and neurological deficit following sudden neck movement. Radiological findings suggested cervical cord infarction in the anterior spinal artery territory at the C5-C6 vertebral level and dissection of the intracranial segment of the right vertebral artery. Cervical cord infarction due to VAD is usually caused by dissection of its extracranial segment. The present case indicates that dissection of the intracranial segment of the vertebral artery can also cause cervical cord infarction. PMID- 29984770 TI - Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis. AB - Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60 degrees tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy. PMID- 29984772 TI - Sudden-onset C8 Radiculopathy due to a Plexiform Schwannoma of the Cervical Nerve Root. AB - Plexiform schwannoma is a rare variant of schwannomas and usually presents with chronic symptoms. We herein report a case of cervical nerve plexiform schwannoma that presented with unusually sudden severe left radiculopathy of the eighth cervical nerve after physical exercise. Coronal short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) revealed a multinodular tumor along the eighth cervical nerve. The tumor was partially resected. A pathological analysis revealed that the tumor was a schwannoma, and we diagnosed the case as a plexiform schwannoma. The unusual sudden-onset presentation in this case was considered to be caused by the unusual localization of the tumor involving the nerve root and mechanical stress due to physical exercise. PMID- 29984771 TI - Progressive Encephalomyelitis with Rigidity and Myoclonus Resolving after Thymectomy with Subsequent Anasarca: An Autopsy Case. AB - Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven. PMID- 29984773 TI - Subacute Sensorimotor Neuropathy Accompanied by Anti-ganglioside GM1 Antibody in a Patient with Lung Cancer. AB - A 66-year-old man presented with subacute sensorimotor neuropathy in association with small cell lung cancer. Tests for the anti-ganglioside antibody GM1-IgM were positive. Chemotherapy and intravenous immunoglobulin treatment led to a slight improvement in neurological symptoms. Four additional cases of neuropathy accompanied by anti-ganglioside antibody and lung cancer have been reported. The most commonly reported pattern was subacute sensorimotor neuropathy. Patients died from cancer progression after 5 to 18 months. There is evidence that anti ganglioside antibody inhibits tumor progression, prolonging the patient survival. However, severe neurological disturbance may offset the survival benefit of anti ganglioside antibody in patients with paraneoplastic neurological syndrome. PMID- 29984774 TI - Lung Cancer with a Small Cell Carcinoma Component Diagnosed from Pleural Effusion and a Squamous Cell Carcinoma Component Diagnosed from the Tumor. AB - There have been few reports on the accuracy of the diagnosis of small-cell carcinoma based on a cytological examination of malignant pleural effusion, so whether or not such a diagnosis is possible using this approach alone remains unclear. We herein report a 76-year-old Japanese man in whom small-cell carcinoma was diagnosed cytopathologically from pleural effusion and squamous cell carcinoma was diagnosed histopathologically from a transbronchial biopsy. Tumor shrinkage was achieved by treatment with docetaxel, but the efficacy of carboplatin plus etoposide was inadequate. If small-cell carcinoma is detected on the basis of pleural fluid cytopathology alone, it is extremely important to perform a histopathological examination to rule out the possibility of other malignancies. PMID- 29984775 TI - SIADH with Severe Hyponatremia in an Elderly Man with Herpes Zoster Infection: A Causal or Casual Association? AB - Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is the most common cause of hypotonic hyponatremia in hospitalized patients. An elderly man with severe symptomatic hyponatremia (109 mEq/L) was diagnosed with SIADH that was likely secondary to large cutaneous herpes zoster (HZ) infection. Hypertonic saline and tolvaptan improved the patient's sodium levels and clinical condition. A one month after discharge, tolvaptan was withdrawn, due to inadequate prescription criteria, after which hyponatremia relapsed several times and was properly treated; eventually fever and sopor occurred and the patient died. SIADH secondary to HZ may induce life-threatening and long-lasting hyponatremia, which requires a prompt diagnosis and treatment. PMID- 29984776 TI - Small Cell Lung Cancer with Bizarre Radiographic Findings. PMID- 29984777 TI - Successful Empiric Therapy for Postsplenectomy Sepsis with Campylobacter fetus in an Abattoir Worker with Follicular Lymphoma. AB - Asplenia may yield an increased risk of fulminant sepsis with various pathogens. Human infection with Campylobacter fetus is rare, but it often presents with non gastrointestinal tract infection among immunocompromised individuals. A 55-year old abattoir worker presented with a fever. He had had splenectomy for follicular lymphoma and rituximab maintenance therapy by four months before the presentation. Blood cultures yielded C. fetus, and the administration of meropenem dissolved the bacteremia. Further maintenance therapy was withheld, and no recurrence of infection has been observed for seven years. Asplenia, occupational exposure, and/or rituximab maintenance therapy might have been precipitating factors of this rare infection. PMID- 29984778 TI - Renal Papillary Necrosis with Diabetes and Urinary Tract Infection. PMID- 29984779 TI - The Relationship between the Intrarenal Dopamine System and Intrarenal Renin angiotensin System Depending on the Renal Function. AB - Objective The mechanisms underlying the intrarenal renin-angiotensin system (RAS) activation depend on the conditions of kidney diseases. In angiotensin II (AngII) infusion models, the circulating AngII is filtered into the renal tubular lumens, activating intrarenal RAS. However, in the chronic kidney disease (CKD) models, plasma angiotensinogen (AGT) is filtered into the tubular lumens because of glomerular injury, activating intrarenal RAS. The intrarenal dopamine system activation reduces intrarenal AGT expression and suppresses the intrarenal RAS activity in AngII infusion models. However, the relationship between the intrarenal dopamine system and intrarenal RAS has not been elucidated. Therefore, this study was conducted to determine that relationship in CKD patients. Methods We recruited 46 CKD patients (age: 51.1+/-20.0 years; 16 men; causes of CKD: chronic glomerulonephritis, 34; diabetic nephropathy, 2; nephrosclerosis, 4; and others, 6) not undergoing dialysis or taking RAS blockers. The urinary dopamine (U-DOPA) level, an indicator of intrarenal dopamine activity, and the urinary AGT (U-AGT) level, a surrogate marker of intrarenal RAS activity, were measured. Results As the CKD stages progressed, the U-DOPA levels decreased while the U-AGT levels increased. The U-DOPA levels were significantly and negatively correlated with the U-AGT levels but significantly and positively correlated with the estimated glomerular filtration rate (eGFR). A multiple regression analysis revealed that the U-DOPA levels were associated with the U-AGT levels after adjusting for age, sex, body mass index, and blood pressure (beta=-0.38, p=0.045). However, no correlation was observed when eGFR was also adjusted (beta= 0.17, p=0.29). Conclusion The negative correlation between the intrarenal dopamine system and intrarenal RAS in CKD patients may be affected by the renal function. PMID- 29984780 TI - Detection and Quantification of Bucinnazine Hydrochloride Injection Based on SERS Technology. AB - In this investigation, surface-enhanced Raman spectroscopy (SERS) technology was performed to detect bucinnazine hydrochloride (BH) injection in water and urine. The theoretical Raman spectrum of BH with characteristic peaks was calculated and identified by density functional theory (DFT). Employing an improved silver sol as a SERS active substrate, the SERS spectra of a BH solution with different concentrations were acquired with a 0.5 mol/L KI solution as an aggregation agent. It was determined that the limit of detection (LOD) was low, to 0.01 MUg/mL. A good linear relationship of BH between the Raman intensity and the concentrations was obtained in water at a concentration range from 0.5 to 6 MUg/mL (R2 = 0.9914), which laid a favorable foundation for quantitative analysis. In addition, the recovery rate of spiked samples from 95.13 to 120.54% were calculated. Finally, the detection of BH injection in artificial urine was completed and the detection limit could reach 0.5 MUg/mL, which met the requirements of a rapid on-site detection of drugs in urine. As a result, it indicates that the inspection of BH by the SERS method is with simplicity and high sensitivity, having a great potential for real-time detection. PMID- 29984781 TI - Enzyme-free Gold-silver Core-shell Nanozyme Immunosensor for the Detection of Haptoglobin. AB - Nanoparticles have been widely developed and shown to have intrinsic enzymatic ability, and are used in biosensors. Compared to biological enzymes used in biosensors, which are expensive and tedious to harvest, enzyme-mimic nanoparticles or nanozymes are both more stable and sensitive. An important area in this work is the development of a simple detection principle of immunosensor based on the one-step synthesis of silver nanoparticle seeded onto a gold core. The gold-silver core-shell nanoparticle acts as a peroxidase mimic, which enables them to oxidise 3,3',5,5'-tetramethylbenzidine (TMB) with H2O2, giving a colourimetric response. Herein, the analytical performance of the nanozyme is exploited to detect haptoglobin as a model analyte in a 96-well plate and measured the colourimetric product using spectrophotometer. The sensitivity of the immunosensor was as low as 100 pg mL-1. The viability of our immunosensor was shown to have good selectivity and satisfactory recovery in real serum samples. PMID- 29984782 TI - Isotope-selective Microscale Imaging of Radioactive Cs without Isobaric Interferences Using Sputtered Neutral Mass Spectrometry with Two-step Resonant Ionization Employing Newly-developed Ti:Sapphire Lasers. AB - The characterization of radionuclides in Fukushima is important to determine their origins and current state in the environment. Radionuclides exist as fine particles and are mixed with other constituents. A measurement method with both micro-imaging capability and highly selective element detection is necessary to analyze these particles. We developed such an imaging technique using a time-of flight secondary ion mass spectrometry and wavelength-tunable Ti:Sapphire lasers for the resonance ionization of target elements without mass interference. This is called resonant laser ionization sputtered neutral mass spectrometry. The instrument has a high lateral resolution and a higher ionization selectivity using two-step resonance excitation of Cs with two lasers at different wavelengths. Optimization of the wavelength for resonance ionization using a Cs compound was performed, and a real environmental particle containing radioactive Cs was analyzed. Isotope images of three kinds of Cs were successfully obtained without interfere from Ba isotopes for the first time. PMID- 29984783 TI - The Effect of Varying Slice Thickness and Interslice Gap on T1 and T2 Measured with the Multidynamic Multiecho Sequence. AB - PURPOSE: The purpose of our study was to investigate the effect of different slice thicknesses and/or interslice gaps on longitudinal and transverse relaxation times (T1 and T2) measured by a multi-dynamic, multi-echo (MDME) sequence. MATERIALS AND METHODS: This retrospective study included nine healthy subjects who underwent MDME sequence (at 3T) with four different combinations of slice thicknesses and/or interslice gaps: slice thickness of 4 mm and interslice gap of 0 mm (TH4/G0), TH4/G1, TH5/G0, and TH5/G1. T1 and T2 were measured in various brain regions by a qualified neuroradiologist with 8 years of clinical experience: the frontal white matter (WM), occipital WM, genu, splenium, frontal cortex, thalamus, putamen, caudate head, and cerebrospinal fluid (CSF). The paired samples t-test was used to investigate the effect of different slice thicknesses and interslice gaps (TH4/G0 versus TH4/G1 and TH5/G0 versus TH5/G1). P < 0.013 was considered statistically significant. RESULTS: T2 in all brain regions and T1 in the frontal WM, putamen, and CSF did not significantly change for different slice thicknesses and/or gaps (Ps > 0.013). In addition, T1 in all brain regions of interest did not significantly change between TH4/G0, TH4/G1, TH5/G0 and TH5/G1. However, T1 in some of the brain regions was higher with TH4/G0 than with TH5/G0 (occipital WM, frontal cortex, and caudate head) and with TH4/G1 than with TH5/G1 (occipital WM, genu, splenium and thalamus, all Ps < 0.013). CONCLUSION: T2 estimated using the MDME sequence was stable regardless of slice thickness or gap. Although the sequence seems to provide stable relaxation values, identical slice thicknesses need to be used for follow-up to prevent potential T1 changes. PMID- 29984784 TI - Effect of a coating material containing surface reaction-type pre-reacted glass ionomer filler on prevention of primary enamel demineralization detected by optical coherence tomography. AB - We used optical coherence tomography to examine the effect of a coating material containing surface reaction-type pre-reacted glass-ionomer (S-PRG) filler on primary enamel demineralization in 18 extracted human primary teeth. The pulp was removed, and each tooth was ultrasonically cleaned with distilled water. Six teeth were treated with 0.1-M lactic acid buffer solution (De group). In the second group (n = 6), a thin film of coating material was applied before demineralization (PRG group). A third group (Control group; n = 6) was maintained in artificial saliva. Using optical coherence tomography, we measured peak signal intensity (dB) and width at 1/e2 (um) at predetermined locations on the enamel surface and calculated integrated values. All data were analyzed with ANOVA and the Tukey-Kramer test (alpha = 0.05). Although changes in integrated values differed between groups, there was a small but significant increase in the Control group and a small but significant decrease in the De group. In the PRG group, integrated values were significantly higher at 7 days after the start of the experiment and significantly increased thereafter. Our findings indicate that a coating material containing S-PRG fillers may prevent primary enamel demineralization. PMID- 29984785 TI - Conditioned medium from rat dental pulp reduces the number of osteoclasts via attenuation of adhesiveness in osteoclast precursors. AB - Dental pulp is known to play crucial roles in homeostasis of teeth and periodontal tissue. Although resorption of bone around the roots of nonvital teeth is occasionally observed in clinical practice, little is known about the role of dental pulp in osteoclastogenesis. Here we evaluated the effects of conditioned medium (CM) from rat dental pulp on osteoclastogenesis. It was found that the CM reduced the number of tartrate-resistant acid phosphatase (TRAP) positive multinucleated osteoclasts, but did not alter the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 and TRAP. To further understand the mechanism behind these results, we evaluated the effects of CM on osteoclast precursors and found that the CM removed cell processes, resulting in a significant reduction in the number of attached cells and an increase in the number of freely floating cells. Furthermore, the CM suppressed the mRNA levels of focal adhesion kinase and paxillin, which are involved in cell adhesiveness and spreading. Collectively, the present results show that CM from dental pulp serves as an inhibitor of osteoclastogenesis by reducing the number and adhesiveness of osteoclast precursors, suggesting novel therapeutic applicability for osteoporosis. PMID- 29984786 TI - Periodontal status of buccally and palatally impacted maxillary canines after surgical-orthodontic treatment with open technique. AB - This study investigated differences in periodontal health variables between buccally impacted maxillary canines (BIMC) and palatally impacted maxillary canines (PIMC) after surgical-orthodontic treatment with open technique. Nineteen patients were enrolled: 10 with unilateral BIMC (5 men, 5 women; mean age 18.50 +/- 1.96 years) and 9 with unilateral PIMC (4 men, 5 women; mean age 19.44 +/- 2.40 years). Probing depth and keratinized tissue were recorded 12 months after surgical-orthodontic treatment, and the differences between the 2 sides were analyzed as primary outcomes. In addition, data for BIMC and PIMC were directly compared. In the BIMC group, probing depths were significantly higher for lateral incisors than for the untreated side (P = 0.044), and keratinized tissue values were significantly lower for canines than for the untreated side (P = 0.006). No significant differences were observed in the PIMC group. In BIMC, surgical orthodontic treatment with open technique resulted in loss of periodontal keratinized tissue in the treated tooth and periodontal attachment loss in adjacent lateral incisors. However, the periodontal status of PIMC was not affected by surgical-orthodontic treatment with open technique. PMID- 29984787 TI - Impact of the Coronary Artery Calcium Score on Mid- to Long-Term Cardiovascular Mortality and Morbidity Measured With Coronary Computed Tomography Angiography. AB - BACKGROUND: Although the coronary artery calcium score (CACS) is a prognostic measurement in asymptomatic individuals, it is measured in symptomatic patients using coronary computed tomography angiography (CCTA). We aimed to examine the predictive value of the CACS for mid- to long-term cardiovascular mortality and morbidity in patients who underwent CCTA. Methods and Results: We studied 736 patients with suspected coronary artery disease (CAD) who underwent CCTA. During a median follow-up period of 6.5 years, there were 39 primary outcomes (composite of cardiovascular disease death, non-fatal myocardial infarction, and non-fatal stroke). The estimated 10-year cumulative rates of the primary outcome were significantly increased across CACS classes (3.9%, 9.2%, 11.8%, and 18.2% in CACS of 0, 1-99, 100-399, and >=400, respectively, P<0.001). These rates of cardiovascular disease death and stroke were also significantly increased across CACS classes. Multivariate Cox proportional hazard analysis showed that a CACS >=100 was independently predictive for the primary outcome (hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.40-6.00, P=0.003), as well as the presence of >=50% stenosis on CCTA (HR 2.27, 95% CI 1.13-4.46, P=0.022). CONCLUSIONS: An elevated CACS with the use of CCTA is an independent predictor of mid- to long term cardiovascular mortality and morbidity in patients suspected of having CAD. PMID- 29984788 TI - Renal Dysfunction Affects Anticoagulation Control With Warfarin and Outcomes in Japanese Elderly Patients With Non-Valvular Atrial Fibrillation. AB - BACKGROUND: It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF). Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged >=70 years. Target INR values were 1.6-2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13-1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37-3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41-6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56-18.18, P=0.008 and 1.60, 1.07-2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10-3.76, P=0.024 and 1.58, 1.22-2.04, P=0.001, respectively). CONCLUSIONS: Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death. PMID- 29984789 TI - Baseline Global Longitudinal Strain as a Predictor of Left Ventricular Dysfunction and Hospitalization for Heart Failure of Patients With Malignant Lymphoma After Anthracycline Therapy. AB - BACKGROUND: Our aim was to investigate the baseline clinical and echocardiographic parameters for predicting left ventricular (LV) dysfunction after anthracycline chemotherapy and heart failure (HF) hospitalization in a single cancer disease. Methods and Results: We studied 73 patients with malignant lymphoma and preserved LV ejection fraction (LVEF). Echocardiography was performed before and after anthracycline chemotherapy. Global longitudinal strain (GLS) was determined from 3 standard apical views. LV dysfunction after anthracycline chemotherapy was defined according to the current definition of cancer therapeutics-related cardiac dysfunction. Long-term (50-month) unfavorable outcome was prespecified as hospitalization for HF. A total of 10 patients had LV dysfunction after anthracycline chemotherapy. Multivariate logistic regression analysis showed that baseline GLS was the only independent predictor of this dysfunction. Receiver-operating characteristic curve analysis identified the optimal GLS cutoff for predicting LV dysfunction after anthracycline chemotherapy as <=19% (P=0.008). Furthermore, the Kaplan-Meier curve indicated that fewer patients with GLS >19% were hospitalized for HF than among those with GLS <=19% (log-rank P=0.02). For sequential logistic models, a model based on baseline clinical variables (chi2=2.9) was improved by the addition of baseline LVEF (chi2=9.0; P=0.01), and further improved by the addition of baseline GLS (chi2=13.1, P=0.04). CONCLUSIONS: Watchful observation or early therapeutic intervention with established cardioprotective medications may be necessary for patients with malignant lymphoma and preserved LVEF but with abnormal GLS. PMID- 29984790 TI - Correlation of MACC1/c-Myc Expression in Endometrial Carcinoma with Clinical/Pathological Features or Prognosis. AB - BACKGROUND Endometrial carcinoma (EC) is a type of female reproductive malignant tumor, the incidence of which is generally 20~30%. Multiple factors and genes are involved in the regulation of EC occurrence and progression. This study aimed to measure the expressions of MACC1 and c-Myc in EC patients to analyze their correlation with pathological features of EC. MATERIAL AND METHODS A total of 60 EC patients were recruited in the experimental group, while another cohort of 30 people with endometrial inflammatory hyperplasia was enrolled in the control group. The levels of serum MACC1 and c-Myc were measured by ELISA, and the protein expressions in EC cancer tissues, tumor-adjacent tissues, and controlled endometrial tissues were detected by immunohistochemistry (IHC). The correlation between gene expression and clinical/pathological features was then determined. RESULTS Our data indicate that the level of serum MACC1 and c-Myc in the experimental group was 1.67+/-0.08 ng/ml and 1.78+/-0.07 ng/ml, respectively, both of which were significantly higher than that of the control group (p<0.05). However, no significant difference was found among levels of serum MACC1 or c-Myc at different TNM stages (p>0.05). In cancer tissues, the positive rate of MACC1 or c-Myc was 73.3% and 78.3%, respectively, which were significantly higher than that in adjacent or control tissues (p<0.05). MACC1/c-Myc expression was correlated with TNM stage, primary infiltration grade, lymph node metastasis, and distal metastasis (p<0.05). CONCLUSIONS MACC1 and c-Myc are highly expressed in serum and tumor tissues of EC patients. Both are correlated with TNM stage, primary infiltration, and lymph node or distal metastasis, which provides a scientific basis for the development of new biomarkers for the diagnosis of endometrial carcinoma. PMID- 29984791 TI - From CT scanning to 3D printing technology: a new method for the preoperative planning of a transcutaneous bone-conduction hearing device. AB - SUMMARY: The aim of the present study was to assess the feasibility and utility of 3D printing technology in surgical planning of a transcutaneous bone conduction hearing device (Bonebridge(r)) (BB), focusing on the identification of the proper location and placement of the transducer. 3D printed (3DP) models of three human cadaveric temporal bones, previously submitted to CT scan, were created with the representation of a topographic bone thickness map and the sinus pathway on the outer surface. The 3DP model was used to detect the most suitable location for the BB. A 3DP transparent mask that faithfully reproduced the surface of both the temporal bone and the 3DP model was also developed to correctly transfer the designated BB area. The accuracy of the procedure was verified by CT scan: a radiological marker was used to evaluate the degree of correspondence of the transducer site between the 3DP model and the human temporal bone. The BB positioning was successfully performed on all human temporal bones, with no difficulties in finding the proper location of the transducer. A mean error of 0.13 mm was found when the transducer site of the 3DP model was compared to that of the human temporal bone. The employment of 3D printing technology in surgical planning of BB positioning showed feasible results. Further studies will be required to evaluate its clinical applicability. PMID- 29984792 TI - Tongue carcinoma in young adults: a review of the literature. AB - SUMMARY: A recent reduction in the number of smoke-related tumours has been observed thanks to the diffusion of anti-tobacco campaigns carried out in the majority of developed countries. Nevertheless, as demonstrated by recent global epidemiologic studies, squamous cell carcinoma of the mobile tongue appears to be progressively increasing in incidence, particularly among young adults and especially in females. The driving mechanism responsible for such changes is still to be precisely defined. Several genetic studies have compared the mutational pattern of tongue squamous cell carcinoma in young adults to that of more elderly patients, without identifying significant differences that may help in better characterising this subgroup of subjects. Tongue squamous cell carcinomas in young adults have been historically considered as particularly aggressive clinical entities, with a high risk of loco-regional relapse, survival rates inferior to those of the general head and neck cancer group and need for a more aggressive therapy. However, considering the most recent studies, prognostic results in this patient group are heterogeneous and it is not possible to confirm this tendency. Thus, it is not justified to embrace different therapeutic approaches according to patient age. Eventually, an additional element to consider when examining young subjects affected by tongue cancer is the possibility of genetic predisposition. Alterations affecting pathways involved in DNA repair, surveillance of genetic stability or regulation of cellular growth may determine an increased likelihood of developing head and neck cancers. PMID- 29984793 TI - Electrochemotherapy: a well-accepted palliative treatment by patients with head and neck tumours. AB - SUMMARY: Electrochemotherapy (ECT) is a well established treatment strategy for skin tumuors. The aim of this study was to evaluate the feasibility and efficacy of electrochemotherapy in the palliative setting in patients with head and neck malignancies, in terms of improvement of quality of life and in control of pain and bleeding. Twenty-four patients with a loco-regional M0/M1 relapse not suitable for cure with radical intent by surgery or radiotherapy (RT) and not suitable for systemic therapy and/or already treated with it, were admitted to ECT protocol treatment. Clinical features, treatment response, and adverse effects were evaluated. An overall response of 100% was observed. Overall survival probability at 24 months was 46.5% (median OS: 9 months). The multiple application of ECT was associated with improved survival (p = 0.02). Pain, need for medical assistance or dressing and bleeding events was significantly reduced at 1 month after ECT (p #x003C; 0.001). ECT is effective as palliative treatment of non-resectable head and neck malignancies. Its main advantages are improved quality of life, local tumour control and limited side effects. PMID- 29984794 TI - Clinical utility of an ultrasensitive thyroglobulin assay in the follow-up of patients with differentiated thyroid cancer: can the stimulation test be avoided in patients with an intermediate recurrence risk? AB - SUMMARY: Serum thyroglobulin (Tg) measurement during suppression with levothyroxine (LT4) using an ultrasensitive assay (OnT4-Tg) has been proposed as a replacement of TSH-stimulated Tg measurement (OffT4-Tg) in management of patients with differentiated thyroid cancer (DTC). The aim of this study is to evaluate the capacity of an ultrasensitive Tg assay in predicting an OffT4-Tg > 2.0 ng/mL based on the OnT4-Tg in patients with DTC and an intermediate recurrence risk. We analysed 101 patients with DTC and an intermediate (n = 92) or high risk of recurrence (n = 9) who were treated with total thyroidectomy and ablation with 131I, and followed for an average of 6 years. OnT4-Tg was undetectable in 64 of 101 patients; OffT4-Tg was #x003C; 2.0 ng/mL in 61 of these 64 patients, all with negative imaging results. Furthermore, 37 of 101 patients had detectable OnT4-Tg; 32 of these 37 patients also presented OffT4-Tg > 2.0 ng/mL, and only 3 of these 32 patients had metastases detected by neck ultrasound. Considering a cutoff point of 0.1 ng/mL for OnT4-Tg, the assay had a sensitivity of 91%, specificity of 92%, positive predictive value (PPV) of 86% and the negative predictive value (NPV) of 95% when predicting an OffT4-Tg > 2.0 ng/mL (biochemical disease). The use of an ultrasensitive Tg assay allows prediction of which patients will remain disease-free even if they are at an intermediate risk of recurrence, and to decrease the need for stimulated Tg assays in two-thirds of these patients. PMID- 29984795 TI - Efficacy of microsurgery in Reinke's oedema evaluated by traditional voice assessment integrated with the Vocal Extent Measure (VEM). AB - SUMMARY: There are few data analysing to what specific extent phonomicrosurgery improves vocal function in patients suffering from Reinke's oedema (RE). The recently introduced parameter vocal extent measure (VEM) seems to be suitable to objectively quantify vocal performance. The purpose of this clinical prospective study was to investigate the outcomes of phonomicrosurgery in 60 RE patients (6 male, 54 female; 56 +/- 8 years ([mean +/- SD]) by analysing its effect on subjective and objective vocal parameters with particular regard to VEM. Treatment efficacy was evaluated at three months after surgery by comparing pre- and postoperative videolaryngostroboscopy (VLS), auditory-perceptual assessment (RBH-status), voice range profile (VRP), acoustic-aerodynamic analysis and patient's self-assessment using the voice handicap index (VHI-9i). Phonomicrosurgically, all RE were carefully ablated. VLS revealed removal or substantial reduction of oedema with restored periodic vocal fold vibration. All subjective and most objective acoustic and aerodynamic parameters significantly improved. The VEM increased on average from 64 +/- 37 to 88 +/- 25 (p #x003C; 0.001) and the dysphonia severity index (DSI) from 0.5 +/- 3.4 to 2.9 +/- 1.9. Both parameters correlated significantly with each other (rs = 0.70). RBH-status revealed less roughness, breathiness and overall grade of hoarseness (2.0 +/- 0.7 vs 1.3 +/- 0.7). The VHI-9i-score decreased from 18 +/- 8 to 12 +/- 9 points. The average total vocal range enlarged by 4 +/- 7 semitones, and the mean speaking pitch rose by 2 +/- 4 semitones. These results confirm that: (1) the use of VEM in RE patients objectifies and quantifies their vocal capacity as documented in the VRP, and (2) phonomicrosurgery is an effective, objectively and subjectively satisfactory therapy to improve voice in RE patients. PMID- 29984796 TI - Efficacy of trans-nasal fiberendoscopic injection laryngoplasty with centrifuged autologous fat in the treatment of glottic insufficiency due to unilateral vocal fold paralysis. AB - SUMMARY: The objective of this work is to evaluate the safety, feasibility and efficacy of trans-nasal fiberendoscopic injection laryngoplasty (IL) with centrifuged autologous fat, performed under local anaesthesia, in the treatment of glottic insufficiency due to unilateral vocal fold paralysis (UVFP). It is a within-subject study with follow-up 1 week after phonosurgery and after 6 months. A total of 22 patients with chronic dysphonia caused by glottic insufficiency due to UVFP were enrolled. Each patient underwent trans-nasal IL with centrifuged autologous fat through flexible operative endoscope under local anaesthesia and was evaluated before and twice (1 week and 6 months) after phonosurgery, using a multidimensional set of investigations. The assessment protocol included videolaryngostroboscopy, perceptual evaluation of dysphonia, maximum phonation time and patient's self-assessment on voice-related quality of life (QOL) with the Voice Handicap Index-10 and the comparative self-assessment on vocal fatigue and voice quality pre-post treatment. Trans-nasal IL with centrifuged autologous fat was performed in all 22 patients and there were no complications in any case. Significant improvements in videolaryngostroboscopic findings, perceptual evaluation of dysphonia, maximum phonation time and QoL self-assessment were reported after 1 week and were maintained at 6 months. In one patient, the result after 6 months was not satisfactory and this patient then underwent a medialization laryngoplasty (thyroplasty type I) with satisfactory long-term results. In conclusion, trans-nasal fiberendoscopic IL with centrifuged autologous fat seems to be a safe, feasible and efficacious phonosurgical procedure for treatment of glottic insufficiency due to unilateral vocal fold paralysis. PMID- 29984797 TI - Moderate OSAS and turbinate decongestion: surgical efficacy in improving the quality of life and compliance of CPAP using Epworth score and SNOT-20 score. AB - SUMMARY: Drug-induced sleep endoscopy (DISE) is an important procedure in diagnostic pathway of patients affected by moderate OSAS. However, the Italian National Health System does not provide any compatible Diagnosis-related-group (DRG) code codification for DISE, which makes it impossible to obtain regional reimbursement. In order to overcome this problem, DISE is usually associated with other codified surgical procedures. The aim of our study is to assess the association of turbinate decongestion (TD) and DISE in order to combine in a single operating session diagnostic and therapeutic procedures. The objective of our work is to assess the role of nasal surgery on symptoms of moderate OSA. Recent studies have confirmed that isolated nasal surgery improves quality of life (QOL), but not the apnoea hypopnoea index (AHI) during polygraph registration. We enrolled 30 patients, aged between 29 and 64 years (mean 50.53 +/- 9.20), 26 males and 4 females, with a mean BMI of 26.07 +/- 2.81 kg/m2, who were affected by moderate OSAS. All patients underwent otolaryngologycal pre operative evaluation, home respiratory polygraph and subjective evaluation through Sino-Nasal-Outcome Test (SNOT-20) and Epworth Sleepiness Scale (ESS). During the same surgery session, they underwent DISE and TD. Patients were re evaluated six months later using the same questionnaires. We observed a significant improvement (p #x003C; 0.05) in both the mean ESS index (6.03 +/- 2.75 vs 4.16 +/- 4.63) and total SNOT score (22.53 +/- 12.16 vs 13.23 +/- 10.82). Significant differences (p #x003C; 0.05) were also identified for partial SNOT questions 1-11 (9.1 +/- 5.11 vs 6.13 +/- 4.12) and 11-20 (13.36 +/- 10.20 vs 7.13 +/- 9.644). The results of the present study confirm that TD alone can improve sleepiness, QOL and nasal symptoms. Thus, in absence of a National Health System recognition for DISE, the association of this procedure with TD can be useful for diagnostic and therapeutic management of OSAS, improving CPAP compliance and adherence, reducing sleepiness, ameliorating nasal symptoms and therefore QOL. PMID- 29984798 TI - Implementing strategies for data collection in chronic rhinosinusitis. AB - SUMMARY: Chronic rhinosinusitis (CRS) is a debated topic in the international rhinologic literature because of its high prevalence, heterogeneity of clinical manifestations and unpredictability of disease course. Recently, the focus in CRS research has moved to identify biological subtypes that might explain its aetiology and clinical variability. However, these analyses are still expensive and limited to scientific purposes, so that they cannot be used on a large scale in daily practice. For this reason, we wondered if it was possible to define a risk stratification for CRS patients based only on first level investigations. The heterogeneity of the disease has given us a large amount of data compelling to find an additional storage system. Herein, we present the results of our work, the RhinoBank, as we believe that it is an easy-to-use tool for those professionals dealing with CRS and an effective system to exploit in clinical research. PMID- 29984799 TI - Bromelain's penetration into the blood and sinonasal mucosa in patients with chronic rhinosinusitis. AB - SUMMARY: The aim of this research is to investigate penetration of Bromelain into sinonasal mucosa in patients with chronic rhinosinusitis (CRS) versus a control group. Bromelain is derived from pineapple (Ananas comosus) and has various pharmacological effects. 40 patients (20 patients and 20 controls) were enrolled in the study. Bromelain 500 mg tablet twice daily was administered for 30 days. We scored bromelain presence in turbinate and ethmoid mucosas and in the serum of both the groups. Bromelain has an excellent distribution from blood to rhinosinusal mucosa. Its diffusion ability may allow the use of bromelain as an anti-inflammatory agent in paranasal sinus pathologies. PMID- 29984800 TI - Effect of loading of the central part of the tympanic membrane on pure tone audiometry. AB - SUMMARY: This study was conducted to determine the effects of loading of the central part of the tympanic membrane by different weights on pure tone audiometry of healthy ears. Sixty patients with normal otoscopic view, normal pure tone audiometry and wide external auditory canal to allow direct and endoscopic visualization of TM, but without any history of ear surgeries, were selected and divided equally and randomly into two groups. Loading of the central part of the TM was carried out using weights ranging from [(1 lambda) 13.6 mg] to [(40 lambda) 544 mg]; (lambda) is a symbol for the weight of 1 microliter of mercury. The study was carried out in two steps assisted by direct oto-endoscopy, and pure tone audiometry was used to measure the effects of loading on both air and bone conduction hearing. Air conduction hearing thresholds increased in a statistically significant pattern at low frequencies, 500 Hz, 1000 Hz and 2000 Hz, when the TM was loaded by 340 mg (25 lambda). The maximal effect was recorded at 544 mg (40 lambda), which affected air conduction hearing at all tested frequencies (500 Hz, 1000 Hz, 2000 Hz and 4000 Hz). However, no statistically significant effect was detected on bone conduction hearing thresholds throughout the study. In conclusion, loading of the tympanic membrane by different masses affects the air conduction hearing threshold by only 340 mg (25 lambda), which is very large in comparison to the mass of ossicles, without any significant effects on bone conduction hearing. PMID- 29984801 TI - Transtympanic Hearing Aid: exploratory study on a new device. AB - SUMMARY: In this paper, we present the preliminary results achieved with a transtympanic hearing aid (THA). This is a modified digital, open-fit external hearing aid (HA) designed for acute study only, which allows coupling with a pre implanted ventilation tube. The THA conveys amplified sound directly onto the round window, bypassing the ossicular chain, in contrast with traditional HAs that convey sound onto the second or third portion of the external auditory canal. The THA has been developed as an alternative to standard HAs and active middle ear implants for patients who are unsatisfied with traditional HA outcomes and want to avoid middle-ear implantation. The results achieved using the THA were compared to those obtained with an equivalent device, the Latitude 8 Moxi 13 (Moxi), uncoupled from the ventilation tube, and placed onto the outer ear. For this purpose, 12 patients with conductive (1/12), sensorineural (3/12), or mixed (8/12) hearing loss from moderate to severe, with a pre-implanted ventilation tube, underwent audiological evaluation with both the THA and the Latitude 8 Moxi 13 (Moxi). Our initial results showed that the THA provided significant improvement in the warble tone results in comparison to the Moxi. Moreover, patients with a PTA between 41 and 90 also achieved better results in terms of speech recognition using the THA in comparison to the Moxi. In conclusion, these outcomes provide the first evidence of the potential benefits of the THA over standard open-fit HAs. Nevertheless, these preliminary outcomes require further confirmation. PMID- 29984802 TI - Genes important for otoneurological diagnostic purposes - current status and future prospects. AB - SUMMARY: This review focuses on the current knowledge of the genes responsible for non-syndromic hearing loss that can be useful for otoneurological diagnostic purposes. From among a large number of genes that have been associated with non syndromic hearing impairment, we selected several best-known genes, including the COCH gene, GJB2, GJB6 and SLC26A4, and we describe their role and effects of mutations and prevalence of mutations in various populations. Next, we focus on genes associated with tinnitus. Important areas for further research include assessment of genes potentially involved in pathophysiology of tinnitus and vertigo, which have traditionally been considered as being of otological aetiology, while advances in neuroimaging techniques have increasingly shifted studies toward neurological correlations. PMID- 29984803 TI - Bone-anchored hearing implant surgery: our experience with linear incision and punch techniques. AB - SUMMARY: In recent years, bone-anchored hearing implants (BAHIs) have found wider application in the treatment of conductive and mixed hearing loss. Several surgical techniques have been developed to reduce complications, enhance healing and improve audiological and aesthetic results. We report our experience on the use of three BAHI surgery techniques: Group 1, linear incision with thinning of the subcutaneous tissue; Group 2, linear incision without thinning of the subcutaneous tissue; Group 3, punch technique (Minimally Invasive Ponto Surgery, MIPS). We retrospectively analysed patients undergoing BAHI surgery; results were evaluated on the basis of any intra-operative complication, duration of surgery and occurrence of adverse effects at the implantation site over 1 year of follow up. We collected a total of 30 implantations (12 for Group 1, 8 for Group 2, 10 for Group 3) with an intra-operative complication rate of 25%, 0% and 10%, respectively. The average surgical time was 62.08 minutes, 34.37 minutes and 18.7 minutes respectively. During follow-up, we reported the occurrence of adverse effects in 10.63% of observations in Group 1, 3.12% in Group 2 and 2.5% in Group 3. This study confirms the low rate of intra and postoperative complications during BAHI surgery and documents the simplicity of execution of the novel MIPS technique, with a significant reduction in surgical time compared to the other two techniques, and positive effects in terms of health care costs. PMID- 29984804 TI - The short- and long-term adverse effects of FGF-2 on tympanic membrane perforations. AB - SUMMARY: The objective of this study was to investigate the short- and long-term adverse effects of fibroblast growth factor-2 treatment of tympanic membrane perforations. A total of 134 patients with traumatic tympanic membrane perforations were randomly divided into two groups: an observational group and a fibroblast growth factor-2 treatment group. The closure rate, closure time and principal side-effects were compared between the groups at 6 and 12 months. At 6 months, 131 patients were examined to determine healing outcomes and short-term side-effects. The total closure rate differed significantly between the fibroblast growth factor-2 and observational groups (95.5% vs 73.4, p #x003C; 0.01). The fibroblast growth factor-treated group exhibited a significantly shorter closure time than the observational group (11.9+/-3.1 days vs 52.6 +/- 18.1 days, p = 0.00). Three patients with secondary otitis media with effusion, and three with reperforations, were noted in the fibroblast growth factor-2 group. We additionally performed long-term follow-up on 89.1% of the patients in the observational group and 92.5% of the patients in the fibroblast growth factor 2 group; follow-up was performed 16-42 months after perforation closure. Only a small perforation of the pars flaccida developed in the fibroblast growth factor 2 group. No middle ear cholesteatoma was noted in either group. This study suggests that the topical application of fibroblast growth factor-2 to human traumatic tympanic membranes is safe. Otorrhoea was the most common short-term side-effect; other less common side-effects included otitis media with effusion and reperforation. No serious long-term side-effects were found. PMID- 29984805 TI - Is the team leading surgeon criminally liable for his collaborators' errors? Judges confirm responsibility and condemn an otorhinolaryngologist. AB - SUMMARY: In current healthcare, delivery of medical and surgical treatment takes place in a multidisciplinary manner. This raises the problem of distinguishing the conditions under which the person who has properly carried out his duties, respecting the related leges artis, can be held responsible for damages materially caused by another member of the medical team. Jurisprudence has developed the so-called "principle of trust" for which every member of the team can rely on the fact that other members are acting in compliance with the leges artis of their specialisation. The Supreme Court has limited the application of this principle. The authors examine the jurisprudence on responsibility of the team in otolaryngology and conclude that individual liability should be limited to the specific expertise of the individual specialist. PMID- 29984806 TI - Normalization of data for viability and relative cell function curves. AB - Many types of assays in cell biology, pharmacology and toxicology generate data in which a parameter is measured in a reference system (negative control) and then also under conditions of increasing stress or drug exposure. To make such data easily comparable, they are normalized, i.e., the initial value of the system (e.g., viability or transport function) is set to 100%, and all data are indicated relative to this value. Then, curves are fitted through the data points and summary data of the system behavior are determined. For this, a benchmark response (BMR) is given (e.g., a curve drop by 15 or 50%), and the corresponding benchmark concentration (BMC15 or BMC50) is determined. Especially for low BMRs, this procedure is not very robust and often results in incorrect summary data. It is often neglected that a second normalization (re-normalization) is necessary to make the data suitable for curve fitting. It is also frequently overlooked that this requires knowledge of the system behavior at very low stress conditions. Here, good in vitro practice guidance for the re-normalization procedure is provided so that data of higher fidelity can be generated and presented. PMID- 29984807 TI - The 2017 Impact Factor for Kardiologia Polska. PMID- 29984808 TI - Concomitance of cardiovascular and pulmonary disorders: mutual bystanders or causal interactions? PMID- 29984809 TI - The importance of registries in today's heart failure therapies. PMID- 29984810 TI - Association of cardiac troponin I with prothrombotic alterations in atrial fibrillation. PMID- 29984811 TI - Effective strategy of rescue treatment for acute pump thrombosis after left ventricular assist device implantation in patients with high risk of bleeding complications. PMID- 29984812 TI - Right aortic arch with isolated left subclavian artery: a rare association with coarctation of the left pulmonary artery. AB - We present a case report of rare association of right aortic arch with isolated left subclavian artery with coarctation of the left pulmonary artery. PMID- 29984813 TI - Bland-White-Garland syndrome in a 39-year-old lumberjack. PMID- 29984814 TI - High-density bipolar voltage mapping for substrate-guided ablation of atrial fibrillation. PMID- 29984815 TI - Prosthetic valve endocarditis and acute heart failure in a patient after transcatheter aortic valve implantation procedure. PMID- 29984816 TI - Iatrogenic Gerbode-type defect after surgical correction of double-outlet right ventricle. PMID- 29984817 TI - Hypertrophic obstructive cardiomyopathy with anomalous left circumflex coronary artery. PMID- 29984819 TI - Practice of high fidelity simulation use in baccalaureate nursing programs. PMID- 29984820 TI - Central nervous system plasmablastic lymphoma evolving from polyclonal plasmacytosis. PMID- 29984821 TI - Recognition of Regional Water Table Patterns for Estimating Recharge Rates in Shallow Aquifers. AB - We propose a new method for groundwater recharge rate estimation in regions with stream-aquifer interactions, at a linear scale on the order of 10 km and more. The method is based on visual identification and quantification of classically recognized water table contour patterns. Simple quantitative analysis of these patterns can be done manually from measurements on a map, or from more complex GIS data extraction and curve fitting. Recharge rate is then estimated from the groundwater table contour parameters, streambed gradients, and aquifer transmissivity using an analytical model for groundwater flow between parallel perennial streams. Recharge estimates were obtained in three regions (areas of 1500, 2200, and 3300 km2 ) using available water table maps produced by different methods at different times in the area of High Plains Aquifer in Nebraska. One region is located in the largely undeveloped Nebraska Sand Hills area, while the other two regions are located at a transition zone from Sand Hills to loess covered area and include areas where groundwater is used for irrigation. Obtained recharge rates are consistent with other independent estimates. The approach is useful and robust diagnostic tool for preliminary estimates of recharge rates, evaluation of the quality of groundwater table maps, identification of priority areas for further aquifer characterization and expansion of groundwater monitoring networks prior to using more detailed methods. PMID- 29984822 TI - Single-nucleotide polymorphisms of VEGF-A and VEGFR-2 genes and risk of infantile hemangioma. AB - BACKGROUND: Infantile hemangioma (IH) is the most common vascular tumor of childhood and infancy. It is distinguished by rapid proliferation of endothelial cells during the first year of life followed by spontaneous regression thereafter. One of the possible factors responsible for the IH development is vascular endothelial grow factor (VEGF). The purpose of this study was to evaluate the influence of selected polymorphisms in the genes coding for VEGF-A (+405 G/C, rs2010963; +936 C/T, rs3025039) and its receptor VEGFR-2 (+1416 T/A, rs1870377; -271 G/A, rs7667298) on the susceptibility to infantile hemangioma. METHODS: We performed a case-control study of 99 Polish children hospitalized due to IH and compared them with matched healthy control subjects. The polymorphisms were ascertained through genotyping by PCR-RFLP assay, PCR-HRM, or the allelic discrimination method. RESULTS: The study revealed a lower odds of infantile hemangioma in individuals with GG genotype or G allele for +405 G/C VEGF-A polymorphism (ORdis = 0.52, P = 0.023 and ORdis = 0.63, P = 0.025, respectively). No association was observed for the remaining VEGF and VEGFR-2 polymorphisms and IH risk. CONCLUSIONS: In our study, none of the investigated VEGF-A and VEGFR-2 genes polymorphisms was found to be an independent prognostic marker for infantile hemangioma. However, there is evidence that individuals carrying at least one G allele of +405 G/C VEGF-A polymorphism have significantly lower risk of IH. PMID- 29984824 TI - Novel insight into wound healing properties of methanol extract of Capparis ovata Desf. var. palaestina Zohary fruits. AB - OBJECTIVES: The objective of this study was to investigate the wound healing activity of Capparis ovata var. palaestina fruit extract in mice. For this aim, wound healing, in vitro antimicrobial and antioxidant activities, HPLC, phenolic and flavonoid compounds analyses were performed. METHODS: The wound healing effect was tested by excisional wound model. Wound closure was measured for 14 days and at 14th day wound healing was assessed by levels of TGF-beta, VEGF, COL1A1 and angiogenesis, granulation tissue thickness, epidermal and dermal regeneration. The antioxidant activity was calculated by DPPH and ABTS free radical scavenging assays. Antimicrobial ability was evaluated by minimum inhibitory concentration and agar well diffusion tests. KEY FINDINGS: The extract indicated significant antioxidant activity while it also exhibited antimicrobial activity. Rutin was found in the extract according to HPLC study. Moreover, the extract was found to have rich phenolic and flavonoid contents. Histological evaluation showed that extract group induced significant (P < 0.001) wound healing activity compared to control group. Furthermore, extract group increased wound healing rates by promoting granulation tissue, epidermal regeneration, angiogenesis, collagen, TGF-beta and VEGF. CONCLUSIONS: The results clarified that the extract possesses antioxidant, antimicrobial activity and thus could provide a valuable contribution to the wound healing. PMID- 29984823 TI - Outcome of haematopoietic stem cell transplantation in dyskeratosis congenita. AB - Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event-free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non-myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft-versus-host disease and T-B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged. PMID- 29984825 TI - High-dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL GITMO. AB - The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged >=18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age >=65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy. PMID- 29984826 TI - The use of erythropoiesis-stimulating agents is safe and effective in the management of anaemia in myelofibrosis patients treated with ruxolitinib. AB - Erythropoiesis-stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate-2/high risk; 52.5% transfusion-dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels <125 u/l correlated with a higher AR rate (63% vs. 20%, P = 0.008). No thrombotic events or other toxicities occurred. Overall survival was 62% at 4 years, influenced by DIPSS and transfusion dependency. ESAs seem effective in improving anaemia in ruxruxolitinib-treated myelofibrosis patients. PMID- 29984827 TI - Male-limited secondary sexual trait interacts with environment in determining female fitness. AB - Selection for secondary sexual trait (SST) elaboration may increase intralocus sexual conflict over the optimal values of traits expressed from shared genomes. This conflict can reduce female fitness, and the resulting gender load can be exacerbated by environmental stress, with consequences for a population's ability to adapt to novel environments. However, how the evolution of SSTs interacts with environment in determining female fitness is not well understood. Here, we investigated this question using replicate lines of bulb mites selected for increased or decreased prevalence of a male SST-thickened legs used as weapons. The fitness of females from these lines was measured at a temperature to which the mites were adapted (24 degrees C), as well as at two novel temperatures: 18 degrees C and 28 degrees C. We found the prevalence of the SST interacted with temperature in determining female fecundity. At 28 degrees C, females from populations with high SST prevalence were less fecund than females from populations in which the SST was rare, but the reverse was true at 18 degrees C. Thus, a novel environment does not universally depress female fitness more in populations with a high degree of sexually selected dimorphism. We discuss possible consequences of the interaction we detected for adaptation to novel environments. PMID- 29984828 TI - Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group. AB - We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non-Hodgkin lymphoma (B-NHL) who had refractory or relapsed disease during or after the French-American-British mature lymphoma B (FAB/LMB) 96 multi-agent chemotherapy. Among the 1 111 registered on study, 104 patients (9.4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1- and 2-year overall survival (OS) (95% confidence interval) was 31.5% (23.3-41.0%) and 22.3% (15.3 31.4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase >=2 upper normal limit [hazard ratio (HR) = 2.86 (1.57-5.2), P = 0.0006]; time to failure (>6 months) [HR = 0.59 (0.36-0.97), P = 0.038]; and failure in bone marrow [HR = 2.78 (1.65-4.68), P = 0.0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B-NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy-resistant disease. PMID- 29984829 TI - Impairment of bone marrow endothelial progenitor cells in acute graft-versus-host disease patients after allotransplant. AB - Graft-versus-host disease (GVHD) is a major complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT) that is frequently associated with bone marrow (BM) suppression, and clinical management is challenging. BM endothelial progenitor cells (EPCs) play crucial roles in the regulation of haematopoiesis and thrombopoiesis. However, little is known regarding the functional roles of BM EPCs in acute GVHD (aGVHD) patients. In the current prospective case-control study, reduced and dysfunctional BM EPCs, characterized by decreased migration and angiogenesis capacities and increased levels of reactive oxygen species (ROS) and apoptosis, were found in aGVHD patients compared with those without aGVHD. Moreover, lower frequency and increased levels of ROS, apoptosis and DNA damage, but reduced colony-forming unit-plating efficiency were found in BM CD34+ cells of aGVHD patients compared with those without aGVHD. The severity of aGVHD and GVHD-mediated cytopenia was associated with BM EPC impairment in aGVHD patients. In addition, the EPC impairment positively correlated with ROS level. Taken together, our results suggest that reduced and dysfunctional BM EPCs may be involved in the pathogenesis of aGVHD. Although these findings require validation, our data indicate that improvement of BM EPCs may represent a promising therapeutic approach for aGVHD patients. PMID- 29984830 TI - Quality of life during and following sequential treatment of previously untreated patients with multiple myeloma: findings of the Medical Research Council Myeloma IX randomised study. AB - In the Medical Research Council (MRC) Myeloma IX trial (ISRCTN684564111) patients were randomised to sodium clodronate or zoledronic acid and induction treatment: cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) or cyclophosphamide, thalidomide and dexamethasone (CTD) followed by autologous stem cell transplant (ASCT) in the intensive pathway; attenuated CTD or melphalan and prednisolone (MP) in the non-intensive pathway. Subsequent randomisation allocated patients to either thalidomide or observation. The European Organisation for Research and Treatment of Cancer (EORTC) quality of life (QoL) questionnaires, QLQ-C30 and QLQ-MY24, were administered at baseline, 3, 6 and 12 months and annually thereafter, enabling the effect of sequential treatment on patient-reported health-related QoL (HR-QoL) to be investigated. The protocol specified four subscales of interest: Pain, Fatigue, Global Health Status/Quality of Life and Physical Functioning at 3, 6 and 12 months that were compared using linear models. The intensive pathway showed significant differences in favour of CTD for Fatigue at 3 months and Physical Functioning at 12 months. The non intensive pathway and maintenance phase reported significant differences at 3 months; Pain (improved with attenuated CTD) and Global Health status/Quality of Life (improved with observation). The improved outcomes in MRC Myeloma IX were accompanied by some beneficial and few detrimental effects on HR-QoL. PMID- 29984831 TI - Pore space extraction and characterization of sack paper using MU-CT. AB - : We show that attenuation X-ray microcomputed tomography (MU-CT) offers a route to extract the three-dimensional pore space of paper reliably enough to distinguish samples of the same kind of paper. Here, we consider two sack kraft papers for cement bags with different basis weights and thicknesses. Sample areas of approximately 5 mm2 with a resolution of 1.5 MUm are considered, i.e. sizes that exceed sample areas of 2 mm2 for which the pore structure was previously studied in the literature. The image segmentation is based on indicator kriging as a local method that removes ambiguities in assigning voxels as pore or as fibre. The microstructures of the two samples are statistically compared in terms of descriptors such as sheet thickness, porosity, fractions of externally accessible pores and mean geodesic tortuosity. We demonstrate that a quantitative comparison of samples in terms of porosity and thickness requires a common definition of the sheet surfaces. Finally, the statistical pore space analysis based on the MU-CT scans reliably reveals structural differences between the two paper samples, but only when several descriptors are used. LAY DESCRIPTION: This paper is a seemingly abundant material. Its intrinsic porosity enables a vast number of commercial applications. Particularly packing products, e.g. cement bags, often incorporate sack kraft paper due to its high porosity and its additional mechanical strength. A direct quantification of the porosity of sack kraft papers is, hence, particularly desirable. However, experimental quantification of paper porosity or its pore network properties is difficult and often highly indirect. A nondestructive statistical analysis of the 3D microstructure holds the promise to directly assess the pores. In particular, X ray microcomputed tomography (MU-CT), frequently with sub-MUm resolution, has been established as a method to study the fibre and pore structure of paper. The question arises, whether statistical analysis of the microstructure based on MU CT imaging is sufficient to reliably distinguish between different sack kraft papers. Here, we explore whether the pore structure of paper can be extracted and statistically analysed for larger sample areas despite the fact that a larger sample size directly translates into a lower resolution of the MU-CT scan. We expect that a large sample size increases the region of interest on the basis of which samples can be better distinguished. A lowered resolution poses a severe challenge for the reliable identification of voxel data as pores or as fibres, because the contrast between paper fibres (made of cellulose) and air, which is established due to X-ray absorption, is weak. We show that we can reliably assign each voxel by using an indicator kriging as a two-step method. This method performs an initial voxel identification based on the overall distribution of measured grey values and refines the identification by inspecting the local environment of each voxel. For the pore space extracted in such a way, we can then compute quantities that are related to the geometry and connectivity properties of the pores. Furthermore, we address a paper-born challenge for such an analysis, i.e. we cannot always unambiguously tell whether a pore is located inside the paper sheet or at the surface of the paper. The way the paper surfaces are extracted from the microstructure decisively determines the final specifications of the predicted properties. A significant distinction of the samples is only possible when comparing the properties of the pore network. PMID- 29984832 TI - A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety. AB - Midazolam is one of many bitter drugs where provision of a suitable oral paediatric formulation, particularly in the pre-anaesthetic setting, remains a challenge. To overcome this problem, a novel chocolate-based tablet formulation has been developed with positive pre-clinical results. To further investigate the potential of this formulation, 150 children aged 3-16 years who were prescribed midazolam as a premedication were randomly assigned to receive 0.5 mg.kg-1 either as the novel formulation or an intravenous solution given orally, which is the current standard at our institution. Tolerability was assessed by each child, parent and nurse using a 5-point facial hedonic scale and efficacy was determined as the time to onset of sedation. Blood samples for midazolam and 1 hydroxymidazolam levels were analysed using high-performance liquid chromatography. Population pharmacokinetics were evaluated using non-linear mixed effects modelling. The novel formulation had significantly improved tolerability scores from children, parents and nurses (all p < 0.001). Time to effect was not different between the groups (p = 0.140). The pharmacokinetics of midazolam and 1 hydroxymidazolam were able to be modelled simultaneously. The novel formulation was subject to a higher estimated first-pass metabolism compared with the intravenous solution (8.6% vs. 5.0%) and a significantly lower relative bioavailability of 82.1% (p = 0.013), with no other significant differences. Exposure relative to dose was in the range previously reported for midazolam syrup. We conclude that the novel chocolate-based formulation of midazolam provides improved tolerability while remaining efficacious with suitable pharmacokinetics when used as a premedicant for children. PMID- 29984833 TI - A new prognostic model for myeloma patients relapsing from upfront autologous transplantation based on ISS and PFS1. PMID- 29984834 TI - A clinical audit of combined first trimester screening and non-invasive prenatal testing offered to pregnant women in a regional Australian hospital. AB - The records of women attending a large Australian regional hospital for antenatal care were retrospectively analysed to determine what proportion had undergone or been offered first trimester screening for fetal abnormalities; only 609 (54%) of 1114 women had undergone or been offered screening. Younger women, multiparous women and women living in rural Australia were less likely to be offered screening. Barriers to screening and solutions for overcoming these need to be identified to improve access and equality in antenatal screening for all women. PMID- 29984835 TI - Teaching & Learning Tips 10: Interspecialty teaching through inpatient dermatology consults. AB - Medical students and residents often have little experience in placing or responding to dermatologic consults in the inpatient setting when they first begin training. Trainees often learn what and how to communicate through observation or trial and error. We propose that dermatologists can play an active role in facilitating interspecialty education and improving patient outcomes by teaching in a systematic fashion. PMID- 29984836 TI - Erratum. PMID- 29984837 TI - Automating neurosurgical tumor resection surgery: Volumetric laser ablation of cadaveric porcine brain with integrated surface mapping. AB - OBJECTIVE: Current surgical instruments for soft tissue resection including neurosurgical procedures rely on the accuracy and precision of the human operator and are fundamentally constrained by the human hand. Automated surgical action with the integration of intraoperative data sources can enable highly accurate and fast tissue manipulation using laser ablation. This study presents the first experiments with a prototype designed for automated tumor resection via laser ablation. We demonstrate targeted soft tissue resection in porcine brain with an integrated device that combines 3D scanning capabilities with a steerable surgical laser and discuss implications for future automated robotic neurosurgical procedures. STUDY DESIGN AND METHODS: A device consisting of a two axis galvanometer for steering a cutting laser and a 3D surface profiler is used to perform volumetric removal of tissue of ex vivo porcine brain. Three dimensional surface profiles are gathered between cuts and used to estimate ablation rate. RESULTS: Volumetric ablation of porcine brain tissue is performed and subsequently surface profiled. The average ablation rates across the area cutting areas were 2.6 mm3 /s and 3.7 mm3 /s for the initial and subsequent cuts, respectively. A Kruskal-Wallis and post-hoc Tukey test show statistical significance between the initial and subsequent cuts. Accuracy between cuts when benchmarked against a human surgeon varied from 47 to 88%. CONCLUSION: A feed forward volumetric resection is demonstrated with sensing and cutting housed within a single device, thereby opening the potential for automated soft tissue resection as necessary during the surgical removal of pathologic tissues. High variance around target cut depths motivates future work in developing a closed loop ablation tool as well as characterization of laser-tissue interactions for predictive modelling. Objective Lasers Surg. (c) 2018 Wiley Periodicals, Inc. PMID- 29984838 TI - Corrigendum. PMID- 29984839 TI - Sources of moral injury among war veterans: A qualitative evaluation. AB - OBJECTIVE: Service members deployed to war are at risk for moral injury, but the potential sources of moral injury are poorly understood. The aim of this qualitative study was to explore the types of events that veterans perceive as morally injurious and to use those events to develop a categorization scheme for combat-related morally injurious events. METHOD: Six focus groups with US war veterans were conducted. RESULTS: Analysis based on Grounded Theory yielded two categories (and eight subcategories) of events that putatively cause moral injury. The two categories were defined by the focal attribution of responsibility for the event: Personal Responsibility (veteran's reported distress is related to his own behavior) versus Responsibility of Others (veteran's distress is related to actions taken by others). Examples of each type of morally injurious event are provided. CONCLUSIONS: Implications for the further development of the moral injury construct and treatment are discussed. PMID- 29984840 TI - Laparoscopic transabdominal cerclage in pregnancy: A single centre experience. AB - BACKGROUND: Transabdominal cerclage can reduce the risk of preterm birth in women with cervical insufficiency. AIMS: This study evaluated outcomes following insertion of a laparoscopic transabdominal cerclage in pregnant women. MATERIALS AND METHODS: A retrospective observational study. PATIENTS: pregnant women who underwent laparoscopic transabdominal cerclage from 2011 to 2017. Eligible women had cervical insufficiency and were not suitable for a transvaginal cerclage. INTERVENTION: the insertion of a laparoscopic transabdominal cerclage in the pregnancy. MEASUREMENTS: neonatal survival, delivery of an infant at >=34 weeks gestation and surgical morbidity were evaluated. RESULTS: Of 19 women who underwent laparoscopic transabdominal cerclage in pregnancy, at 6-11 weeks gestation, the perinatal survival rate was 100%. There were no complications. The average gestational age at delivery was 37.1 weeks. Sixteen women delivered after 34 weeks. CONCLUSIONS: Laparoscopic transabdominal cerclage is a safe and effective procedure in women with poor obstetric histories. It requires the correct skill, expertise and patient selection. PMID- 29984841 TI - Crinkled employs wingless pathway for wing development in Tribolium castaneum. AB - Crinkled is associated with embryonic denticle formation and auditory organ development in Drosophila melanogaster. However, the functions of Crinkled have not been fully investigated. Additionally, the genes that participate in the Crinkled pathway are unknown. Phylogenetic analysis indicates that crinkled exhibits a one-to-one orthologous relationship in insects. In Tribolium castaneum, the crinkled gene is 6,498 bp in length and consists of six exons. Crinkled expression peaked during two phases in Tribolium: late embryonic and pupal stages. High levels of crinkled mRNA were detected in the fat body, head, epidermis, ovary, and accessory gland of late adults. Knockdown of crinkled using RNA interference (RNAi) severely affected wing morphogenesis in T. castaneum. We further showed that crinkled silencing reduced forked expression through wingless and shaven-baby, and RNAi of forked phenocopied the effects of crinkled knockdown in T. castaneum. This study investigated the development role of crinkled in postembryonic stages and indicated that forked mediates the functions of crinkled during wing morphogenesis in T. castaneum. PMID- 29984842 TI - The microbial reproductive ecology of white-faced capuchins (Cebus capucinus). AB - Changes in reproductive status influence energy and nutrient requirements in female primates. The gut microbiota may buffer changes in energy demands, with shifts in community composition increasing the energy production potential of the gut during pregnancy and lactation. In this study, we examine changes in the gut microbiome of wild, female white-faced capuchins (Cebus capucinus) across different reproductive states. Fecal samples (n = 39) were collected from five adult females over the course of a year. Gut microbial community composition was assessed using 16S rRNA gene sequences, and PICRUSt was used to make metagenomic functional predictions. We found a significant relationship between reproductive state and both the structure and predicted function of the gut microbiome, neither of which were associated with host diet. For example, the relative abundance of Firmicutes was significantly lower in lactating females compared with cycling females; the relative abundance of Actinobacteria was significantly higher in pregnant females compared with lactating females, and there was a trend toward higher relative abundances of Proteobacteria in pregnant females compared with cycling females. The results of this study suggest that, in addition to behavioral and dietary adaptions, the gut microbiota may play a role in allowing female primates to meet their changing energetic needs during reproduction. Further studies of the "microbial reproductive ecology" of primates will help advance our understanding of gut microbial contributions to primate energetics. PMID- 29984843 TI - High Performance of 3D Symmetric Flowerlike Sb2 S3 Nanostructures in Dye Sensitized Solar Cells. AB - Antimony sulfide (Sb2 S3 ) is an important chalcogenide belonging to Group V-VI that is suitable for application as a photoelectric material in the fields of photocatalysis, photoconductive detectors, ion conductor materials, and solar energy conversion materials. Herein, a facile, one-step hydrothermal method is used to synthesize a 3D, symmetric, flowerlike Sb2 S3 nanostructure. The structure was composed of numerous nanoneedles, which provided a large void fraction and specific surface area. Characteristic mesoporous structures of the samples contribute to excellent performance. If they were used as counter electrode materials in dye-sensitized solar cells, the photoelectric conversion efficiency was as high as 7.12 %, whereas the photoelectric conversion efficiency of platinum was only 6.46 %. Furthermore, according to the results of cyclic voltammetry, electrochemical impedance spectra, and Tafel polarization testing, the obtained Sb2 S3 samples have better electrocatalytic activity and charge transfer ability than that of Pt, and thus, can be regarded as good substitutes for precious metals. PMID- 29984845 TI - Nanosecond pulsed electric field exposure does not induce the unfolded protein response in adult human dermal fibroblasts. AB - Cell-circuit models have suggested that nanosecond pulsed electric fields (nsPEFs) can disrupt intracellular membranes including endoplasmic reticulum (ER), mitochondria, and/or nucleus thereby inducing intrinsic apoptotic pathways. Therefore, we hypothesized that the unfolded protein response (UPR) would be activated, due to the fluctuations of ionic concentrations, upon poration of the ER membrane. Quantitative real-time polymerase chain reaction was utilized to measure changes in messenger RNA (mRNA) expression of specific ER stress genes in adult human dermal fibroblast (HDFa) cells treated with tunicamycin (TM) (known ER stress inducer) and cells exposed to nsPEFs (100, 10-ns pulses at 150 kV/cm delivered at a repetition rate of 1 Hz). For HDFa cells, results showed time dependent UPR activation to TM; however, when HDFa cells were exposed to nsPEFs, no significant changes in mRNA expression of ER stress genes, and/or caspase gene were observed. These results indicate that although cell death can be observed under these exposure parameters, it is most likely not initiated through activation of the UPR. Bioelectromagnetics. 2018;39:491-499, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29984846 TI - Body dysmorphic disorder in pediatric dermatology. AB - Body dysmorphic disorder is an obsessive-compulsive spectrum disorder involving a perceived defect in physical appearance that most commonly develops in early adolescence and causes significant functional impairment and suicidality at much higher rates than in affected adults. Patients may also present with subthreshold body dysmorphic disorder or obsessive concerns over a diagnosable dermatologic condition, both of which can present similarly to body dysmorphic disorder. Pediatric dermatologists can play an important role in detecting body dysmorphic disorder and body dysmorphic disorder-like symptoms, which may occur in as many as 20% of dermatology patients. Greater awareness of the prevalence, clinical presentation, and effect of these symptoms, as well as better screening tools and greater collaboration with our mental health colleagues, may lead to earlier, more effective intervention. PMID- 29984844 TI - New-onset obesity after liver transplantation-outcomes and risk factors: the Swiss Transplant Cohort Study. AB - Weight gain after liver transplantation (LTx) facilitates development of new onset obesity; however, its risk factors and outcomes are poorly understood. We identified the impact of new-onset obesity on cardiovascular events (CVEs) and patient survival, and risk factors for new-onset obesity. Multiple Cox regression models examined risk factors for CVEs, patient survival, and new-onset obesity in 253 adults (mean age 52.2 +/- 11.6 years, male gender 63.6%, mean follow up 5.7 +/- 2.1 years). Cumulative incidence of post-LTx CVE was 28.1%; that of new-onset obesity was 21.3%. Regardless of CVE at LTx, post-LTx CVEs were predicted by new onset obesity [Hazard Ratio (HR), 2.95; P = 0.002] and higher age at LTx (HR, 1.05; P < 0.001). In patients without known pre-LTx CVEs (n = 214), risk factors for post-LTx CVEs were new-onset obesity (HR, 2.59; P = 0.014) and higher age (HR, 1.04; P = 0.001). Survival was not associated with new-onset obesity (P = 0.696). Alcoholic liver disease predicted new-onset obesity (HR, 3.37; P = 0.025), female gender was protective (HR, 0.39; P = 0.034). In 114 patients with available genetic data, alcoholic liver disease (HR, 12.82; P = 0.014) and hepatocellular carcinoma (HR, 10.02; P = 0.048) predicted new-onset obesity, and genetics remained borderline significant (HR, 1.07; P = 0.071). Early introduction of post-LTx weight management programs may suggest a potential pathway to reduce CVE risk. PMID- 29984847 TI - Delayed effects and complex life cycles: How the larval aquatic environment influences terrestrial performance and survival. AB - Species with complex life cycles are susceptible to environmental stressors across life stages, but the carryover and latent effects between stages remain understudied. For species with biphasic life histories, such as pond-breeding amphibians, delayed effects of aquatic conditions can influence terrestrial juveniles and adults directly or indirectly, usually mediated through fitness correlates such as body size. We collected adult southern toads (Anaxyrus terrestris) from 2 source populations-a natural reference wetland and a metal contaminated industrial wetland-and exposed their offspring to 2 aquatic stressors (a metal contaminant, copper [Cu], and a dragonfly predator cue) in outdoor mesocosms (n = 24). We then reared metamorphs in terraria for 5 mo to examine delayed effects of early life stage environmental conditions on juvenile performance, growth, and survival. Larval exposure to Cu, as well as having parents from a contaminated wetland, resulted in smaller size at metamorphosis-a response later negated by compensatory growth. Although Cu exposure and parental source did not affect larval survival, we observed latent effects of these stressors on juvenile survival, with elevated Cu conditions and metal contaminated parents reducing postmetamorphic survival. Parental source and larval Cu exposure affected performance at metamorphosis through carryover effects on body size but, 1 mo later, latent effects of parental source and larval predator exposure directly (i.e., not via body size) influenced performance. The carryover and latent effects of parental source population and aquatic Cu level on postmetamorphic survival and juvenile performance highlight the importance of conducting studies across life stages and generations. Environ Toxicol Chem 2018;37:2660-2669. (c) 2018 SETAC. PMID- 29984848 TI - Assessment of quality of life in Turkish children with psoriasis and their caregivers. AB - BACKGROUND/OBJECTIVES: The effect of pediatric psoriasis on quality of life has been demonstrated, but data regarding its influence on caregiver quality of life are scarce. The objective was to investigate how psoriasis affects quality of life of children and their caregivers. METHODS: This multicenter study included 129 children with psoriasis and their caregivers, who were family members accompanying patients to the clinic. Patient quality of life was measured using the Child Dermatology Life Quality Index. Caregiver quality of life was assessed using Dermatological Family Impact Scale, a 15-item questionnaire validated for use in the Turkish language. RESULTS: Mean Child Dermatology Life Quality Index score was 7.6, indicating a moderate effect on patient quality of life. Symptoms and feelings were the most severely impaired domains of patient quality of life, and emotions was the most severely impaired domain of caregiver quality of life. Dermatological Family Impact Scale score was significantly correlated with Child Dermatology Life Quality Index (correlation coefficient [r] = .554, P < .001) and Psoriasis Area and Severity Index (r = .350, P < .001). Caregivers of patients receiving systemic agents or phototherapy had relative impairment of multiple domains of quality of life compared to caregivers of patients receiving topical treatment only. CONCLUSION: Psychosocial effect of pediatric psoriasis was shown to extend beyond the individual, highlighting the importance of addressing patient and caregiver quality of life concerns in an integrated approach. PMID- 29984849 TI - What's the story? An analysis of children's books about atopic dermatitis. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis is an inflammatory skin condition with significant disease burden. Bibliotherapy, the use of storybooks to understand an illness, has been proven effective in several pediatric disorders but has not been studied in dermatologic disease. The purpose of this study was to assess the availability of storybooks about atopic dermatitis and analyze them based on adherence to American Academy of Dermatology guidelines for the treatment of atopic dermatitis, readability, author qualifications, cost, and availability. METHODS: Selection criteria included that the books were primarily about atopic dermatitis, were illustrated, cost less than $25, and were written in English. Storybooks were identified using an Internet search of the Google, Amazon, and Barnes & Noble websites. Flesch-Kincaid Grade Level was used to calculate reading level. RESULTS: Twenty-three storybooks were identified. The mean cost of the storybooks was $8.2 +/- 7.0. Authors included mothers, professional authors, and medical professionals. Mean reading grade level was 4.1 +/- 1.5. Of American Academy of Dermatology-recommended treatments, most storybooks mentioned moisturizers or bathing. Fewer than half discussed moisturizing after bathing, topical corticosteroids, wet wrap therapy, oral antihistamines, antimicrobials, systemic agents, or phototherapy. None mentioned topical calcineurin inhibitors or bleach baths. CONCLUSION: Storybooks about atopic dermatitis are available. Of those reviewed, none covered all the American Academy of Dermatology treatment guidelines. Studies have shown that bibliotherapy can be useful for education and behavioral modification for pediatric diseases, and future studies are needed to examine whether comprehensive, accurate storybooks about atopic dermatitis improve clinical outcomes or improve the quality of life of individuals with atopic dermatitis and their caregivers. PMID- 29984850 TI - The interphase interval within a bipolar nanosecond electric pulse modulates bipolar cancellation. AB - Nanosecond electric pulse (nsEP) exposure generates an array of physiological effects. The extent of these effects is impacted by whether the nsEP is a unipolar (UP) or bipolar (BP) exposure. A 600 ns pulse can generate 71% more YO PRO-1 uptake compared to a 600 ns + 600 ns pulse exposure. This observation is termed "bipolar cancellation" (BPC) because despite the BP nsEP consisting of an additional 600 ns pulse, it generates reduced membrane perturbation. BPC is achieved by varying pulse amplitudes, and symmetrical and asymmetric pulse widths. The effect appears to reverse by increasing the interphase interval between symmetric BP pulses, suggesting membrane recovery is a BPC factor. To date, the impact of the interphase interval between asymmetrical BP and other BPC inducing symmetrical BP nsEPs has not been fully explored. Additionally, interpulse intervals beyond 50 MUs have not been explored to understand the impact of time between the BP nsEP phases. Here, we surveyed different interphase intervals among symmetrical and asymmetrical BP nsEPs to monitor their impact on BPC of YO-PRO-1 uptake. We identified that a 10 microsecond (ms) interphase interval within a symmetrical 600 ns + 600 ns, and 900 ns + 900 ns pulse can resolve BPC. Furthermore, the interphase interval to resolve asymmetric BPC from a 300 ns + 900 ns pulse versus 600 ns pulse exposure is greater (<10 ms) compared to symmetrical BP nsEPs. From these findings, we extended on our conceptual model that BPC is balanced by localized charging and discharging events across the membrane. Bioelectromagnetics. 39:441-450, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29984851 TI - Random Alloyed versus Intermetallic Nanoparticles: A Comparison of Electrocatalytic Performance. AB - As synthetic methods advance for metal nanoparticles, more rigorous studies of structure-function relationships can be made. Many electrocatalytic processes depend on the size, shape, and composition of the nanocatalysts. Here, the properties and electrocatalytic behavior of random alloyed and intermetallic nanoparticles are compared. Beginning with an introduction of metallic nanoparticles for catalysis and the unique features of bimetallic compositions, the discussion transitions to case studies of nanoscale electrocatalysts where direct comparisons of alloy and intermetallic compositions are undertaken for methanol electrooxidation, formic acid electrooxidation, the oxygen reduction reaction, and the electroreduction of carbon dioxide (CO2 ). Design and synthesis strategies for random alloyed and intermetallic nanoparticles are discussed, with an emphasis on Pt-M and Cu-M compositions as model systems. The differences in catalytic performance between alloys and intermetallic nanoparticles are highlighted in order to provide an outlook for future electrocatalyst design. PMID- 29984852 TI - Response of the mouse sublingual gland to spaceflight. AB - The ultrastructure and immunohistochemistry of secretory proteins of sublingual glands were studied in mice flown on the US space shuttles Discovery [Space Transportation System (STS)-131] and Atlantis (STS-135). No differences in mucous acinar or serous demilune cell structure were observed between sublingual glands of ground (control) and flight mice. In contrast, previous studies showed autophagy and apoptosis of parotid serous acinar cells in flight mice. The expression of parotid secretory protein (PSP) in sublingual demilune cells of STS 131 flight mice was significantly increased compared with ground (control) mice but decreased in STS-135 flight mice. Similarly, expression of mucin (MUC-19) in acinar cells and expression of the type II regulatory subunit of protein kinase A (PKA-RII) in demilune cells were increased in STS-131 flight mice and decreased in STS-135 flight mice, but not significantly. Demilune cell and parotid protein (DCPP) was slightly decreased in mice from both flights, and nuclear PKA-RII was slightly increased. These results indicate that the response of salivary glands to spaceflight conditions varies among the different glands, cell types, and secretory proteins. Additionally, the spaceflight environment, including the effects of microgravity, modifies protein expression. Determining changes in salivary proteins may lead to development of non-invasive methods to assess the physiological status of astronauts. PMID- 29984854 TI - Efficient Vacuum-Processed Light-Emitting Diodes Based on Carbene-Metal-Amides. AB - Efficient vacuum-processed organic light-emitting diodes are fabricated using a carbene-metal-amide material, CMA1. An electroluminescence (EL) external quantum efficiency of 23% is achieved in a host-free emissive layer comprising pure CMA1. Furthermore external quantum efficiencies of up to 26.9% are achieved in host guest emissive layers. EL spectra are found to depend on both the emissive-layer doping concentration and the choice of host material, enabling tuning of emission color from mid-green (Commission Internationale de l'Eclairage co-ordinates [0.24, 0.46]) to sky blue ([0.22 0.35]) without changing dopant. This tuning is achieved without compromising luminescence efficiency (>80%) while maintaining a short radiative lifetime of triplets (<1 MUs). PMID- 29984855 TI - Rapidly growing nodule in an adolescent girl. PMID- 29984853 TI - Infantile hemangioma with minimal or arrested growth as the skin manifestation of PHACE syndrome. AB - BACKGROUND: Infantile hemangiomas with minimal or arrested growth are vascular tumors with a proliferative component involving < 25% of their total surface area. They are commonly described as localized lesions and are mainly located on the lower body. Little has been described about segmental forms on the face and their associations with PHACE syndrome. METHODS: We carried out a multicenter, retrospective, case-series study involving 5 hospitals in Spain. Information was collected on cases of PHACE syndrome featuring infantile hemangiomas with minimal or arrested growth. RESULTS: The frontotemporal and maxillary areas were the most frequently involved sites in our series. The upper eyelid and upper lip were the 2 locations most frequently associated with proliferation and ulceration. Four patients experienced spontaneous resolution, and the rest had a very good cosmetic outcome with oral treatment. Cerebral and cervical arterial anomalies were the most frequent extracutaneous findings associated with PHACE, followed by cerebral and ocular anomalies. Some unique associated disorders were fructose intolerance and retinoblastoma. CONCLUSION: We present the largest case series of segmental facial infantile hemangiomas with minimal or arrested growth in PHACE syndrome and emphasize the importance of recognizing these lesions in early infancy, because they can indicate PHACE syndrome. The data presented suggest that infantile hemangiomas with minimal or arrested growth-associated PHACE syndrome does not seem to differ significantly from PHACE syndrome with classic infantile hemangiomas, and thus the same recommendations for diagnosis, management, and therapy should be followed. Future studies with more patients could contribute to enlighten this specific subset. PMID- 29984856 TI - Erosions and vesicles following the lines of Blaschko in a neonate. PMID- 29984857 TI - Painful callosities in a young boy. PMID- 29984858 TI - An 8-year-old girl with a papule on her cheek. PMID- 29984859 TI - Response to "Case series study of the efficacy of compounded antibacterial, steroid, and moisturizer in atopic dermatitis". PMID- 29984860 TI - Solitary lesion of a newborn's foot. PMID- 29984861 TI - Skin-colored to yellowish subungual flat plaque in a 16-year-old girl. PMID- 29984862 TI - Patient Perspectives: What is mastocytosis? PMID- 29984863 TI - Generalized bullae and erosions in an infant. PMID- 29984864 TI - A facial cutaneous horn. PMID- 29984865 TI - Facial cystic lesions and onychodystrophy. PMID- 29984866 TI - Intracellular calcium chelating agent (BAPTA-AM) aids stallion semen cooling and freezing-thawing. AB - This study aimed to investigate the effects of different concentrations of 1,2 bis-(o-aminophenoxy)-ethane-N,N,N0 N0-tetraacetic acid, tetra-acetoxymethyl ester (BAPTA-AM), an intracellular calcium chelating agent, on stallion semen cooling and freezing-thawing. After collection, semen was extended (1:1 v/v) on a skim milk-based extender, centrifuged and resuspended at 400 million/ml into cooling or freezing extenders containing 0, 5, 25, 50, 100 and 200 MUMU BAPTA-AM. Motility parameters were assessed after cooling in Equitainer at 5 degrees C for 12, 24, 48, 72 and 120 hr and after freezing-thawing. In addition, mitochondrial membrane potential, intracellular ATP, reactive oxygen species and malondialdehyde concentrations were measured in cryopreserved-thawed semen. Cooled stored (48 hr) semen containing 50 MUMU BAPTA-AM and control extender (0 MUMU BAPTA-AM) was used to assess fertility. Inclusion of 50 MUMU BAPTA-AM resulted in superior sperm motility parameters during cooled storage when compared to other groups (p < 0.05). Furthermore, semen cryopreserved in extender containing 50 MUMU BAPTA-AM showed increased intracellular ATP and mitochondrial membrane potential, whereas reactive oxygen species and malondialdehyde were increased after thawing for all groups (p < 0.05). Addition of 50 MUMU BAPTA-AM to cooling extender resulted in similar pregnancy rates to the control group (75% vs. 73.6%, respectively; p > 0.05). In conclusion, the addition of BAPTA-AM to semen extenders aided stallion semen cryopreservation in a dose-dependent manner. Furthermore, the cooling extender supplemented with 50 MUMU BAPTA-AM could be used to prolong the sperm motility during cooling without apparently compromising fertility. Field trials should be conducted to assess fertility of cryopreserved stallion semen with BAPTA-AM. PMID- 29984867 TI - Immunoglobulin heavy chain variable region gene and prediction of time to first treatment in patients with chronic lymphocytic leukemia: Mutational load or mutational status? Analysis of 1003 cases. PMID- 29984868 TI - EBV-positive diffuse large B-cell lymphoma, not otherwise specified: 2018 update on diagnosis, risk-stratification and management. AB - DISEASE OVERVIEW: Epstein Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) is an entity included in the 2016 WHO classification of lymphoid neoplasms. EBV+ DLBCL, NOS, is an aggressive B cell lymphoma associated with chronic EBV infection, and a poor prognosis with standard chemotherapeutic approaches. DIAGNOSIS: The diagnosis is made through a careful pathological evaluation. Detection of EBV-encoded RNA is considered standard for diagnosis; however, a clear cutoff for positivity has not been defined. The differential diagnosis includes plasmablastic lymphoma, DLBCL associated with chronic inflammation, primary effusion lymphoma, HHV8+ DLBCL, NOS, and EBV+ mucocutaneuos ulcer. RISK-STRATIFICATION: The International prognostic index (IPI) and the Oyama score can be used for risk-stratification. The Oyama score includes age >70 years and presence of B symptoms. The expression of CD30 is emerging as a potential adverse, and targetable, prognostic factor. MANAGEMENT: Patients with EBV+ DLBCL, NOS, should be staged and managed following similar guidelines than patients with EBV-negative DLBCL. EBV+ DLBCL, NOS, however, has a worse prognosis than EBV-negative DLBCL in the era of chemoimmunotherapy. There is an opportunity to study and develop targeted therapy in the management of patients with EBV+ DLBCL, NOS. PMID- 29984870 TI - Differences in Internalizing Symptoms Anticipate Adolescent Friendship Dissolution. AB - This study examined the degree to which internalizing symptoms predict adolescent friendship instability. A total of 397 adolescents identified 499 same-sex reciprocated friendships that originated in the seventh grade (M = 13.18 years). Discrete-time survival analyses were conducted with Grade 7 peer, teacher, and self-reports of internalizing symptoms as predictors of friendship dissolution across Grades 8-12. Differences between friends in depressive symptoms, anxiety symptoms, and (for boys only) submissiveness predicted subsequent friendship dissolution. Individual levels of these variables did not predict friendship dissolution, even at extreme or clinical levels. The findings suggest that friendship instability arising from internalizing problems stems from dissimilarity between friends rather than the presence of psychopathological symptoms on the part of one friend. PMID- 29984869 TI - 1H-indazole molecules reduced the activity of human erythrocytes carbonic anhydrase I and II isoenzymes. AB - Carbonic anhydrase (CA) is an important metabolic enzyme family closely related to many physiological and pathological processes. Currently, carbonic anhydrase inhibitors are the target molecules in the treatment and diagnosis of many diseases. In present study, we investigated the inhibitory effects of some indazole molecules on the CA-I and CA-II isoenzymes isolated from human erythrocytes. We showed that human CA-I and CA-II activities were reduced by of some indazoles at low concentrations. IC50 values, Ki constants, and inhibition types for each indazole molecule were determined. The indazoles showed Ki constants in a range of 0.383 +/- 0.021 to 2.317 +/- 0.644 mM, 0.409 +/- 0.083 to 3.030 +/- 0.711 mM against CA-I and CA-II, respectively. Each indazole molecule exhibited a noncompetitive inhibition effect. Bromine- and chlorine-bonded indazoles were found to be more potent inhibitory effects on carbonic anhydrase isoenzymes. In conclusion, we conclude that these results may be useful in the synthesis of carbonic anhydrase inhibitors. PMID- 29984871 TI - Study on the potential way of hepatic cytotoxicity of N,N-dimethylformamide. AB - The intermediate metabolites and redox status imbalance were supported as the two major points for N,N-dimethylformamide (DMF)-induced hepatotoxicity. However, the potential mechanism has not yet been concerned. By applying two inhibitors, this study tried to seek the major role in DMF-induced toxicity on HL7702 cell. We observed that DMF induced cell apoptosis through mitochondrial-dependent and p53 pathway. Inhibition reactive oxygen species by catalase remarkably attenuated the mitochondrial transmembrane potential (MMP), apoptotic proteins, and apoptosis. On the contrary, it reduced the biodegradation rate of DMF by coincubation with CYP2E1 antagonist (DDC) partially reduced late apoptosis. However, the change in MMP, the ratio of Bax to Bcl-xl, and cleaved-caspase 9 was not attenuated by DDC. The pathway in DDC coincubation groups was related to the p53 rather than the mitochondrial pathway. Restoring the redox balance during biodegradation is much more effective than attenuating the metabolite rate of DMF. This study may provide a suitable prevention method to occupational workers. PMID- 29984872 TI - GAL3 receptor knockout mice exhibit an alcohol-preferring phenotype. AB - Galanin is a neuropeptide which mediates its effects via three G-protein coupled receptors (GAL1-3 ). Administration of a GAL3 antagonist reduces alcohol self administration in animal models while allelic variation in the GAL3 gene has been associated with an increased risk of alcohol use disorders in diverse human populations. Based on the association of GAL3 with alcoholism, we sought to characterize drug-seeking behavior in GAL3 -deficient mice for the first time. In the two-bottle free choice paradigm, GAL3 -KO mice consistently showed a significantly increased preference for ethanol over water when compared to wildtype littermates. Furthermore, male GAL3 -KO mice displayed significantly increased responding for ethanol under operant conditions. These differences in alcohol seeking behavior in GAL3 -KO mice did not result from altered ethanol metabolism. In contrast to ethanol, GAL3 -KO mice exhibited similar preference for saccharin and sucrose over water, and a similar preference for a high fat diet over a low fat diet as wildtype littermates. No differences in cognitive and locomotor behaviors were observed in GAL3 -KO mice to account for increased alcohol seeking behavior. Overall, these findings suggest genetic ablation of GAL3 in mice increases alcohol consumption. PMID- 29984873 TI - Characterization and inhibition effects of some metal ions on carbonic anhydrase enzyme from Kangal Akkaraman sheep. AB - In this work, the carbonic anhydrase (CA) enzyme was purified from Kangal Akkaraman sheep in Sivas, Turkey with specific activity value of 6681.57 EU/mg and yield of 14.90% with using affinity column chromatography. For designating the subunit molecular mass and enzyme purity, sodium dodecyl sulfate polyacrylamide gel electrophoresis method was used and single band for this procedure was obtained. The molecular mass of CA enzyme was found as 28.89 kDa. In this study, the optimum temperature and optimum pH were obtained from 30 and 7.5. Vmax and Km values for p-nitrophenylacetate substrate of the CA were determined from Lineweaver-Burk graphs. Additionally, the inhibitory results of diverse heavy metal ions (Hg+ , Fe2+ , Pb2+ , Co2+ , Ag+ , and Cu2+ ) on sheep were studied. Indeed, CA enzyme activities of Kangal sheep were investigated with using esterase procedure under in vitro conditions. The heavy metal concentrations inhibiting 50% of enzyme activity (IC50 ) and Ki values were obtained. PMID- 29984874 TI - Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol-addicted subjects: a functional imaging study. AB - Ghrelin has been shown to be involved in the pathophysiology of alcohol dependence, affecting alcohol self-administration and craving. However, the mechanism of action in alcohol dependence still has to be determined. We thus investigated whether ghrelin is associated with mesolimbic cue reactivity to alcohol cues and alcohol craving in recently detoxified alcohol-addicted subjects. We included 41 recently detoxified alcohol-dependent individuals. Functional magnetic resonance imaging (fMRI) was used to study mesolimbic cue reactivity during the presentation of alcohol-related pictures. Additionally, we assessed patients' alcohol craving using the Alcohol Urge Questionnaire and a visual analogue scale. Plasma concentrations of total and acylated (activated) ghrelin were measured in parallel to the fMRI session. The association between ghrelin plasma concentrations, mesolimbic cue reactivity and alcohol craving was assessed by performing correlation and mediation analyses. Alcohol-induced brain response in a network of brain clusters, including the right and left ventral striatum, showed a significant positive association with acylated ghrelin plasma concentration. Additionally, acylated ghrelin was significantly associated with craving. Mediation analyses showed that the association between acylated ghrelin plasma concentration and alcohol craving is mediated by a cue-induced brain response in the ventral striatum. Based on the finding that ghrelin modulates mesolimbic reactivity to alcohol cues, the following should be considered: If alcohol craving and the appetitive status were interrelated, this has to be taken into account when implementing fMRI studies for addictive disorders. Moreover, appetite regulation seems to represent a valid treatment target for reducing cue reactivity in addictive disorders. PMID- 29984875 TI - Pax6-dependent regulation of the rat Fabp7 promoter activity. AB - Fabp7 gene encodes a brain-specific fatty acid-binding protein that is widely used as a marker for neural stem cells. Here, we report that the activity of rat Fabp7 promoter was regulated directly by a transcription factor, Pax6. Deletion analyses identified an essential region (-837 to -64 from transcription start site) in the rat Fabp7 promoter. This region controls promoter activity in rat embryos and in the mouse cultured cell line MEB5. Over-expressing wild-type Pax6 or a dominant-negative Pax6 mutant enhanced and suppressed, respectively, the promoter activity. Pax6 can bind the region directly, although the region contains no clear binding motif for Pax6. The rat Fabp7 promoter also contains conserved binding sites for Pbx/POU (-384 to -377) and CBF1 (-270 to -262). However, specific deletion of the sites showed no significant reduction in the promoter activity, although a gel mobility shift assay confirmed that CBF1 binds the conserved sequence. Taken together, these results suggest that the rat Fabp7 promoter is mainly regulated by Pax6. The Pax6-dependent regulation of the rat Fabp7 expression might have an evolutionary aspect between rat and mouse; the former may need to efficiently use fatty acids to make the brain bigger than the latter. PMID- 29984876 TI - On the Development of Electron Cryo-Microscopy (Nobel Lecture). AB - An electron microscope must operate under vacuum which means that any observed biological specimen must be dry. When water is removed, however, the molecules stick to each other. J. Dubochet describes in his Nobel lecture the solution to this dilemma that paved the way to electron-cryo microscopy: suspension of the specimen in vitrifying water. PMID- 29984877 TI - The epidemiological magnitude of white-coat hypertension and masked hypertension in Africa. PMID- 29984878 TI - Enantioconvergent Biocatalytic Redox Isomerization. AB - Alcohol dehydrogenases can act as powerful catalysts in the preparation of optically pure gamma-hydroxy-delta-lactones by means of an enantioconvergent dynamic redox isomerization of readily available Achmatowicz-type pyranones. Imitating the traditionally metal-mediated "borrowing hydrogen" approach to shuffle hydrides across molecular architectures and interconvert functional groups, this chemoinspired and purely biocatalytic interpretation effectively expands the enzymatic toolbox and provides new opportunities in the assembly of multienzyme cascades and tailor-made cellular factories. PMID- 29984879 TI - HFIP-Assisted C-H Functionalization by Cp*CoIII : Access to Key Reactive Cobaltacycles and Implication in Catalysis. AB - Described here is a synthetic approach to access two of the most widely invoked cationic cobaltacycles in Cp*CoIII -catalyzed C-H functionalization reactions by C-H activation. The unique stabilizing capability of MeCN was used to surmount the previously proposed reversible nature of the C-H metalation step. Moreover, it is revealed the boosting effect of 1,1,1,3,3,3-hexafluoroisopropanol in the metalation step and in the reaction between N-pyrimidinylindole and diphenylacetylene under catalytic conditions. PMID- 29984880 TI - Access and utilization of mental health services for immigrants and refugees: Perspectives of immigrant service providers. AB - Immigrant and refugee populations experience life stressors due to difficult migration journeys and challenges in leaving one country and adapting to another. These life stressors result in adverse mental health outcomes when coupled with a lack of adequate support-enhancing resources. One area of support is access to and use of mental health services to prevent and address mental health concerns. Immigrant service providers in Canada support the integration and overall well being of newcomers. This study focuses on immigrant service providers' perceptions of access to and use of mental health services for immigrants and refugees in Alberta. A qualitative descriptive design was used to collect and analyse the perspectives of 53 immigrant service providers recruited from nine immigrant serving agencies in Alberta between November 2016 and January 2017. Data were collected using a combination of individual interviews and focus groups, followed by thematic data analysis to identify relevant themes. Barriers to access and use of mental health services include language barriers, cultural interpretations of mental health, stigma around mental illness, and fear of negative repercussions when living with a mental illness. Strategies to improve mental health service delivery include developing community-based services, attending to financial barriers, training immigrant service providers on mental health, enhancing collaboration across sectors in mental health service delivery, and advancing the role of interpreters and cultural brokers. Overall, immigrant service providers present a nuanced view of the complex and inter-related barriers immigrants and refugees experience and identify potential approaches to enhancing mental health service delivery. PMID- 29984881 TI - Tortuous but successful road to achieving the diagnosis of cyclic Cushing's disease. PMID- 29984882 TI - Association between smoking status assessed with plasma-cotinine and inflammatory and endothelial biomarkers in HIV-positive and HIV-negative individuals. AB - OBJECTIVES: Smoking is a major contributor to mortality and morbidity in HIV positive individuals. Our primary objective was to evaluate the association between smoking status determined by plasma cotinine (P-cotinine) concentration and inflammatory and endothelial biomarkers in HIV-positive versus HIV-negative individuals. METHODS: We studied eight inflammatory/endothelial biomarkers [high sensitivity C-reactive protein (hsCRP), E-selectin, soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble intercellular adhesion molecule 1 (sICAM 1), matrix metallopeptidase 9 (MMP-9), myeloperoxidase (MPO), tissue type plasminogen activator inhibitor 1 (tPAI) and endothelin] in 105 HIV-positive individuals and 105 HIV-negative individuals matched on age, sex and self reported smoking status. Smoking status was determined using P-cotinine (a concentration > 14 ng/mL was defined as demonstrating exposure to smoke). We used linear regression models to (1) examine the association between smoking status and inflammatory/endothelial biomarkers in HIV-positive compared with HIV negative individuals, and (2) to determine whether there was evidence to suggest that the impact of smoking status on the biomarkers differed between HIV-positive and HIV-negative individuals. RESULTS: Of the eight biomarkers, smokers had increased hsCRP, sICAM-1 and MMP-9 concentrations irrespective of HIV status and increasing P-cotinine concentration was associated with increasing hsCRP concentration. We found no interaction between smoking and HIV status. HIV infection was associated with increased hsCRP, E-selectin, sVCAM-1, sICAM-1 and MMP-9 concentrations. Self-reported smoking status differed substantially from smoking status assessed with P-cotinine. CONCLUSIONS: Several biomarkers were associated with smoking status and HIV status. However, our data do not indicate that the effects of smoking on the biomarkers differ between HIV-positive and HIV negative individuals. PMID- 29984818 TI - Association between peri-operative angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers and acute kidney injury in major elective non cardiac surgery: a multicentre, prospective cohort study. AB - The peri-operative use of angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri-operative period. This study aimed to investigate if withholding angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers peri-operatively reduces the risk of acute kidney injury following major non-cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi-level models were used to account for centre-level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers withheld during the peri-operative period. One hundred and seventy-five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin-converting enzyme inhibitors or angiotensin-2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin converting enzyme inhibitors or angiotensin-2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58-1.34); p = 0.567). PMID- 29984884 TI - Blood pressure variability predicts adverse events and cardiovascular outcomes in SPRINT. AB - SPRINT (Systolic Blood Pressure Intervention Trial) highlighted the benefits of intensive targeted antihypertensive therapy but resulted in higher rates of treatment-related adverse events. Blood pressure (BP) variability has emerged as a significant predictor of outcomes over and above levels of BP. Using the SPRINT data set, we aimed to determine the relationship of BP variability with cardiovascular outcomes and side effects of antihypertensive therapy. The analyses included all participants randomized in SPRINT who reached the target systolic BP (SBP) for their respective groups (intensive < 120 mm Hg; standard < 140 mm Hg). Coefficients of variation (CV) for SBP, diastolic BP (DBP), and PP for each patient characterized variability. Student t test was used to compare treatment arms for each CV metric. Cox proportional hazards regression was used to identify independent predictors of the SPRINT primary outcome and adverse events. P < .15 on univariate analysis was required to enter the model and P < .05 to remain in it. A total of 8884 patients (4561 standard group; 4323 intensive group) met inclusion criteria. DBP CV differed between the groups (9.12 +/- 3.20 standard group; 9.47 +/- 3.49 intensive group [P < .0001]). DBP CV predicted a greater hazard for the primary outcome (hazard ratio [HR], 1.14) in the overall model as well as separate analyses by treatment arms (standard group HR, 1.15; intensive group HR, 1.19), each P < .0001. DBP CV also independently predicted a greater hazard for acute kidney injury (HR, 1.12) and hypotensive events (HR, 1.12). Visit-to-visit DBP variability independently predicted worse cardiovascular outcomes and hypoperfusion-related adverse events in SPRINT. PMID- 29984885 TI - Visible-Light Photocatalysis of C(sp3 )-H Fluorination by the Uranyl Ion: Mechanistic Insights. AB - The uranyl dication shows photocatalytic activity towards C(sp3 )-H bonds of aliphatic compounds, but not towards those of alkylbenzenes or cyclic ketones. Theoretical insights into the corresponding mechanisms are still limited. Multi configurational ab initio calculations including relativistic effects reveal the inherent electron-transfer mechanism for the uranyl catalyzed C-H fluorination under blue light. Along the reaction path of the triplet state it was found that the hydrogen atom abstraction triggered by the electron-rich oxygen of the uranyl moiety is the rate-limiting step. The subsequent steps, that is, N-F and O-H bond breakage in a manner of concerted asynchronicity, generation of the targeted fluorinated product, and recovery of the photocatalyst are nearly barrierless. Moreover the single electron transfer between the reactive substrates plays a fundamental role during the whole photocatalytic cycle. PMID- 29984883 TI - Enhancement of megavoltage electronic portal images for markerless tumor tracking. AB - PURPOSE: The poor quality of megavoltage (MV) images from electronic portal imaging device (EPID) hinders visual verification of tumor targeting accuracy particularly during markerless tumor tracking. The aim of this study was to investigate the effect of a few representative image processing treatments on visual verification and detection capability of tumors under auto tracking. METHODS: Images of QC-3 quality phantom, a single patient's setup image, and cine images of two-lung cancer patients were acquired. Three image processing methods were individually employed to the same original images. For each deblurring, contrast enhancement, and denoising, a total variation deconvolution, contrast limited adaptive histogram equalization (CLAHE), and median filter were adopted, respectively. To study the effect of image enhancement on tumor auto-detection, a tumor tracking algorithm was adopted in which the tumor position was determined as the minimum point of the mean of the sum of squared pixel differences (MSSD) between two images. The detectability and accuracy were compared. RESULTS: Deblurring of a quality phantom image yielded sharper edges, while the contrast enhanced image was more readable with improved structural differentiation. Meanwhile, the denoising operation resulted in noise reduction, however, at the cost of sharpness. Based on comparison of pixel value profiles, contrast enhancement outperformed others in image perception. During the tracking experiment, only contrast enhancement resulted in tumor detection in all images using our tracking algorithm. Deblurring failed to determine the target position in two frames out of a total of 75 images. For original and denoised set, target location was not determined for the same five images. Meanwhile, deblurred image showed increased detection accuracy compared with the original set. The denoised image resulted in decreased accuracy. In the case of contrast-improved set, the tracking accuracy was nearly maintained as that of the original image. CONCLUSIONS: Considering the effect of each processing on tumor tracking and the visual perception in a limited time, contrast enhancement would be the first consideration to visually verify the tracking accuracy of tumors on MV EPID without sacrificing tumor detectability and detection accuracy. PMID- 29984886 TI - Worthy? Crowdfunding the Canadian Health Care and Education Sectors. AB - Crowdfunding, the practice of asking for money from others using the Internet, is a major private means through which Canadians are funding their health care and education. Crowdfunding has proliferated in Canada during the 2010s and continues to grow, approaching the revenues of Canada's major traditional charities. Proponents describe it as an empowering practice from which anyone can benefit. If its gains are inequitably distributed, however, increasing reliance on this private funding mechanism, especially in core areas of welfare state provision, can further exacerbate inequalities of opportunity and income. This study asks why Canadians turn to health care and education crowdfunding and how equitably funds are raised using this novel method. Based on a mixed methods analysis of 319 campaigns conducted on two prominent crowdfunding platforms between 2012 and 2014, we find that crowdfunding users' needs frequently correspond to known gaps in the contemporary social safety net, including in the area of cancer care, and that campaigns for older and visible minority Canadians face a disadvantage. We argue that health care and education crowdfunding is a response to the shortcomings of Canadian welfare state provision, but one that reproduces offline inequalities with potentially perilous consequences for democratic life and individual suffering. PMID- 29984887 TI - Promoting self-management in older people with arthritis: Preliminary findings of the Northern Ireland Staying Connected Programme. PMID- 29984888 TI - Delays and barriers to the commencement of clozapine in eligible people with a psychotic disorder: A literature review. AB - AIM: While the majority of individuals with a first episode of psychosis (FEP) achieve symptomatic remission with the appropriate treatment, there is a small but significant proportion who do not achieve remission of symptoms despite adequate treatment with at least two antipsychotic medications (termed treatment resistance). Clozapine is indicated in individuals who fulfil the criteria for treatment-resistant schizophrenia, however, despite it being the most effective antipsychotic medication, there can be delays in the commencement of clozapine in eligible patients. METHODS: A systematic search was performed to identify articles reporting either the time taken to commence clozapine (or delays) in eligible individuals or articles reporting barriers to the commencement of clozapine. The initial search generated 5588 articles and of these, 18 were eligible. RESULTS: 13 studies described delays in commencing clozapine and five studies reported on the barriers to the commencement of clozapine. The duration of delay from when an individual was deemed eligible for clozapine treatment to the time of clozapine commencement ranged from 19.3 weeks to 5.5 years. In addition, the duration of illness prior to clozapine initiation ranged from 1.1 to 9.7 years. It was found that some clinicians were more inclined to prescribe antipsychotic polypharmacy or doses higher than recommended than to prescribe clozapine. CONCLUSIONS: Delays in commencing clozapine have been consistently demonstrated. Early intervention for psychosis services are the ideal settings to identify individuals with persistent positive psychotic symptoms and commence clozapine if indicated. PMID- 29984889 TI - Alpha4-overexpressing HL7702 cells can counteract microcystin-LR effects on cytoskeletal structure. AB - Our previous studies indicated that alpha4 was involved in the toxicity of MC-LR on the cytoskeleton via the change of PP2A activity in HEK 293. To explore the role of alpha4 in MC-LR toxicity via PP2A regulation in different cell lines, the HL7702 cell overexpressing alpha4 protein was exposed to MC-LR, and the change of PP2A, cytoskeletal structure, and cytoskeleton-related proteins were investigated. The results showed that PP2A activity was decreased, PP2A/C subunit expression and phosphorylation (Tyr307) increased significantly, but methylation (Leu 309)clearly decreased. The structure of the actin filaments and microtubules (MTs) remained unchanged, and the expression and phosphorylation of the cytoskeleton-related proteins showed different changes. In addition, the main components of the MAPK pathway, JNK, P38, and ERK1/2, were activated together. Our results indicated that elevated alpha4 expression did confer some resistance to MC-LR-induced cytoskeletal changes, but the responses of different cell lines to MC-LR, under the alpha4-overexpression condition, are not exactly the same. PMID- 29984890 TI - Commentary on: Happell, B. & Scholz, B (2018). Doing what we can, but knowing our place: Being an ally to promote consumer leadership in mental health. International Journal of Mental Health Nursing, 27, 440-447 PMID- 29984891 TI - Prevalence of white coat and masked hypertension in Africa: A systematic review and meta-analysis. AB - Data on masked hypertension (MH) and white-coat hypertension (WCH) in African populations are needed to estimate the true prevalence of hypertension in these populations because they have the highest burden of the disease. We conducted the first systematic review and meta-analysis that summarized available data on the prevalence of WCH and MH in Africa. We searched PubMed and Scopus to identify all the articles published on MH and WCH in populations living in Africa from inception to November 30, 2017. We reviewed each study for methodological quality. A random-effects model was used to estimate the prevalence of WCH and MH across studies. Eleven studies were included, all having a low-risk of bias. The prevalence of masked hypertension was 11% (95% CI: 4.7-19.3; 10 studies) in a pooled sample of 7789 individuals. The prevalence of WCH was 14.8% (95% CI: 9.4 21.1; 8 studies) in a pooled sample of 4451 individuals. There was no difference on the prevalence of WCH and MH between studies in which participants were recruited from the community and the hospital. The prevalence of MH was higher in urban areas compared to rural ones; there was no difference for WCH. WHC and MH seem to be frequent in African populations, suggesting the importance of out-of clinic BP measurement in the diagnosis and management of patients with hypertension in Africa, especially in urban areas for MH. PMID- 29984892 TI - Integration of MRI target delineation into rapid workflow cervical cancer brachytherapy: Impact on clinical outcomes. AB - INTRODUCTION: We evaluated the impact of MRI-based target delineation on toxicity and tumour control after implementation of a protocol to incorporate MRI while minimizing impact on overall procedural time. METHODS: We retrospectively reviewed outcomes for a cohort of 96 consecutive patients who received intracavitary brachytherapy for cervical cancer at our institution during 2012 2016. Starting in October 2014, an outpatient MRI was obtained for patients after Smit sleeve placement and first insertion to assess concurrent chemoradiotherapy tumour response. Then, for subsequent fractions, the MRI was co-registered by the Smit sleeve to the planning CT for target volume delineation. The primary and secondary outcomes were toxicity and local control, respectively. RESULTS: Median follow-up for the pre- (n = 50) and post-MRI-based (n = 46) planning groups was 24.6 and 14.7 months, respectively. Median treatment duration for patients before and after MRI implementation was 56 and 58 days (P = 0.052), respectively. Cumulative rectal D2 cc was less for those with MRI-based target delineation (P = 0.005). On multivariable analysis, patients with MRI-based target delineation experienced fewer severe late (CTCAE grade >= 3) toxicities (P = 0.025, hazard ratio = 0.25). Local control was 86% and 91% of the pre- and post-MRI groups, respectively (P = 0.959). CONCLUSIONS: Preliminary findings using this technique, which is applicable to other institutions without in-room MRI availability, are associated with lower radiation prescription doses, lower rectal doses and favourable toxicity rates while maintaining a rapid workflow. Longer follow-up is required to confirm equivalent local control. PMID- 29984893 TI - Feasibility and effectiveness of home-based exercise programs on physical performance and health-related quality of life of the older people dwelling on an isolated, doctor-less island. AB - AIM: To promote preventive care among older individuals dwelling on an isolated, doctor-less island, we investigated the feasibility and the efficacy of a home based exercise program, depending on their functional status and health-related quality of life. METHODS: A total of 23 older (mean age 72.6 years) participants were assigned to a home-based exercise program (intervention group), and 34 older (mean age 74.2 years) participants were assigned to a group without any intervention (control group). The participants of the intervention group attended the exercise program three times a week for 3 months. The exercise program consisted of various exercises involving stretching, muscle strengthening, balance retraining and walking. The physical performance, Functional Independence Measure and Short-Form 36-item health survey were used to assess the physical and the mental wellbeing of the participants. RESULTS: There was no significant difference between the changes in physical performance at baseline and post 3 months in both groups. However, the motor and the cognitive Functional Independence Measure scores significantly improved in the intervention group post 3 months. The domains of the Short-Form 36-item health survey improved post 3 months; particularly, significant improvement was observed in the physical functions, general health, vitality, mental health and mental component summary. CONCLUSIONS: Although an isolated island has several problems to support preventive care services, such as a lack of medical resources and availability of only a few healthcare workers, the present study provides evidence on the feasibility and efficacy of nurse-led home-based exercise programs for improving the physical and mental health of the older people dwelling on an isolated, doctor-less island. Geriatr Gerontol Int 2018; 18: 1313-1317. PMID- 29984894 TI - Natural Triterpenoid- and Oligo(Ethylene Glycol)-Pendant-Containing Block and Random Copolymers: Aggregation and pH-Controlled Release. AB - In this research, a series of random and block amphiphilic copolymers of norbornene derivatives containing biocompatible natural triterpenoid and oligo(ethylene glycol) pendants were synthesized by ring-opening metathesis polymerization. These copolymers were heat and pH responsive, and could self assemble into core-shell spherical micelles in aqueous solution. Their hydrodynamic diameters corresponded to pH values and monomer sequences. By evaluating the loading and release capacity of hydrophobic molecules, it was found that 1) the higher the content of the hydrophobic triterpenoid, the higher the loading capacity; 2) the release speed could be trigged by the pH because of the deprotonation of the carboxyl groups on the triterpenoid. Additionally, the copolymers exhibited low cytotoxicity toward L929 cells, which makes them potential nanocarrier candidates for controlled drug delivery. PMID- 29984895 TI - Blood-brain barrier permeability in a patient with Labrune syndrome due to SNORD118 mutations. PMID- 29984896 TI - Brain comorbidities in normal pressure hydrocephalus and their impact on the cerebrospinal fluid tap test? PMID- 29984897 TI - A novel prion protein gene-truncating mutation causing autonomic neuropathy and diarrhea. PMID- 29984898 TI - Blood-brain barrier permeability in a patient with Labrune syndrome due to SNORD118 mutations: would this be the mechanism for progressive worsening? PMID- 29984899 TI - Functional eyelid opening apraxia: a kinematic study. PMID- 29984900 TI - Brain comorbidities in normal pressure hydrocephalus. PMID- 29984901 TI - Nevertheless They Persisted: Gendered Frameworks and Socialization Advantages in Indian Professional Service Firms. AB - This article uses the Indian case to offer nuance to narratives about the gendered experience of professional work. I find that while gendered constructs certainly infiltrate all workspaces, there remain occupational and organizational differences in the ways in which women experience their environments. Particularly, while Indian women lawyers overall are more disadvantaged than their international counterparts, the experience of women lawyers in very elite law firms is more favorable than both their local and global peers. A confluence of factors might be responsible for this unusual experience of professional work, but this article highlights the importance of one set of supply side dynamics: the variations in socializing experiences and expectations before entry into these firms. In doing so, it adds to the literature that suggests the importance of not just enrollment parity, but also early training and institutional socialization for gender egalitarian professional outcomes. PMID- 29984902 TI - Rifaximin anti-inflammatory activity on bovine endometrium primary cell cultures: a preliminary study. AB - Rifaximin is an unabsorbed oral antibiotic showing anti-inflammatory properties in human pathologies like irritable bowel syndrome and inflammatory bowel disease. In veterinary medicine, rifaximin is primarily used in the treatment of dermatological diseases in all animal species, in therapy and prophylaxis of mastitis in cows and in the treatment of endometritis in cattle and horses. The aim of this preliminary study was to evaluate the anti-inflammatory properties of rifaximin on primary cell cultures from bovine endometrium in which inflammatory response was induced by Lipopolysaccaride (LPS) treatment. Epithelial and stromal cells were isolated from bovine endometrium and separately incubated for 24 h with 1 MUg mL-1 LPS after rifaximin (10, 50 and 100 MUmol L-1 ) or dexamethasone (10 MUmol L-1 ) pre-treatment for 24 h. Supernatants were collected 24 h after LPS treatment and interleukin (IL)-6 and IL-8 accumulation was measured by ELISA. Rifaximin (10, 50 and 100 MUmol L-1 ) dose dependently inhibited the LPS-induced increase in IL-6 and IL-8 in stromal cells, whereas in epithelial cells it was not possible to detect any accumulation of these interleukins. Rifaximin reduced IL-6 and IL-8 production, showing a potential anti-inflammatory effect that opens up to new possibilities for the use of this drug in uterine inflammatory diseases. PMID- 29984903 TI - Cone-beam computed tomographic and histological investigation of regenerative endodontic procedure in an immature mandibular second premolar with chronic apical abscess. AB - AIM: The aim of the present study was to investigate the tissue generated after regenerative endodontic procedure (REP) in the root canal space of an immature mandibular second premolar with pulp necrosis and chronic apical abscess using cone-beam computed tomographic (CBCT) and histological methods. METHODS: REP was performed in an immature mandibular second premolar. At the 3-year follow up, CBCT scans were taken to evaluate the outcome of treatment. As the tooth was not restorable to function, it was extracted and processed for histological examination. RESULTS: CBCT showed a reduction in size of the periradicular radiolucency, with a marginal increase in root length. Apical closure and thickening of the root canal walls were apparent. Histologically, the root canal space was filled with minimally-inflamed fibrous connective tissue. Some cementum like mineralized connective tissue was evident on the internal canal walls. The apical third showed cementum-like deposits at the apex and the outer canal walls, without dentin formation. CONCLUSIONS: The present study of a structurally-failed tooth with prior REP demonstrates that the tissue formed within the root canal space was fibrous connective tissue with cementum-like deposition in the canal space. No evidence of dentin- or pulp-like tissue was found. PMID- 29984904 TI - Recent Progress on Titanium Dioxide Nanomaterials for Photocatalytic Applications. AB - Environmental and energy problems have drawn much attention owing to rapid population growth and accelerated economic development. For instance, photocatalysis, "a green technology", plays an important role in solar-energy conversion owing to its potential to solve energy and environmental problems. Recently, many efforts have been devoted to improving visible-light photocatalytic activity by using titanium dioxide as a photocatalyst as a result of its wide range of applications in the energy and environment fields. However, fast charge recombination and an absorption edge in the UV range limit the photocatalytic efficiency of TiO2 under visible-light irradiation. Many investigations have been undertaken to overcome the limitations of TiO2 and, therefore, to enhance its photocatalytic activity under visible light. The present literature review focuses on different strategies used to promote the separation efficiency of electron-hole pairs and to shift the absorption edge of TiO2 to the visible region. Current synthesis techniques used to elaborate several nanostructures of TiO2 -based materials, recent progress in enhancing visible photocatalytic activity, and different photocatalysis applications will be discussed. On the basis of the studies reported in the literature, we believe that this review will help in the development of new strategies to improve the visible-light photocatalytic performance of TiO2 -based materials further. PMID- 29984905 TI - Seasonal and regional patterns of lower leg cellulitis in Western Australia. AB - INTRODUCTION: Lower leg cellulitis (LLC) is a common infection that is usually caused by Streptococcus pyogenes or other beta-haemolytic streptococci. We hypothesised that in Western Australia (WA), LLC is a summer disease and would be more common in the northern, tropical regions. METHODS: We conducted a state-wide data linkage of adult patients presenting to WA hospitals with a first ever diagnosis of LLC, from January 2002 through December 2013 according to region and season. RESULTS: A total of 36,276 cases presented with a primary episode of LLC. The northern regions of the Kimberley (2.26 [2.13-2.39]; P<0.001) and Midwest (1.13 [1.06-1.20]; P<0.001) had higher incidence rates than the Perth Metropolitan region, whilst the southern regions of Southwest, Great Southern and Goldfields had lower incidence rates (0.89 [0.85-0.93); P<0.001, 0.81 [0.75 0.88); P<0.001 and 0.77 [0.71-0.83); P<0.001, respectively). The total number of primary cases were higher in summer (10,570 [29.1% CI95 28.7-29.6%], P<0.0001) and autumn (9,306 [25.7% CI95 25.2-26.1%], P=0.004). Seasonality of LLC was observed in all WA regions except those in the Kimberley, Pilbara and Great Southern regions. CONCLUSIONS: In most non-tropical regions of WA, LLC is a summer disease, whilst in the warmer tropical regions of WA where year-round temperatures are higher, no seasonality was observed, but overall incidence of LLC presentations were higher. These findings may have important implications for public health messaging and research around prevention of LLC. This article is protected by copyright. All rights reserved. PMID- 29984906 TI - Breast screening participation and retention among immigrants and nonimmigrants in British Columbia: A population-based study. AB - Breast cancer screening programs operate across Canada providing mammography to women in target age groups with the goal of reducing breast cancer mortality through early detection of tumors. Disparities in breast screening participation among socio-demographic groups, including immigrants, have been reported in Canada. Our objectives were to: (1) assess breast screening participation and retention among immigrant and nonimmigrant women in British Columbia (BC), Canada; and (2) to characterize factors associated with screening among screening age recent immigrant women in BC. We examined 2 population-based cohorts of women eligible for breast screening participation (537 783 women) and retention (281 052 women) using linked health and immigration data. Breast screening rates were presented according to socio-demographic and health-related variables stratified by birth country. Factors associated with screening among recent immigrant women were explored using Poisson regression. We observed marked variation in screening participation across birth country cohorts. Eastern European/Central Asian women showed low participation (37.9%) with rates from individual countries ranging from 35.0% to 49.0%. Participation rates for immigrant women from the most common birth countries, such as China/Macau/Hong Kong/Taiwan (45.7%), India (44.5%), the Philippines (45.9%), and South Korea (39.0%), were lower than the nonimmigrant rates (51.2%). Retention rates showed less variation by birth country; however, some disparities between immigrant and nonimmigrant groups persisted. Associations between screening indicators and study factors varied considerably across immigrant groups. Primary care physician visits were consistently positively associated with screening participation; this variable was also the only predictor associated with screening within each of the groups of recent immigrants. Our study provides unique data on both screening participation and retention among Canadian immigrant women compiled by individual country of birth. Our results are further demonstration that screening disparities exist among immigrant populations as well as in comparison with nonimmigrant women. PMID- 29984907 TI - The TERT promoter mutation status and MGMT promoter methylation status, combined with dichotomized MRI-derived and clinical features, predict adult primary glioblastoma survival. AB - PURPOSE: This study aimed to integrate the TERT promoter mutation status, MGMT promoter methylation status, MRI-derived features, and clinical features into a survival analysis model to better understand adult primary glioblastoma prognosis related markers. METHOD: A total of 304 adult glioblastoma samples collected after surgical resection were selected for retrospective analysis, and Sanger sequencing was performed to detect IDH and TERT promoter mutations. The methylation of the MGMT promoter was analyzed by pyrosequencing, and MRI-derived and clinical features were dichotomized into easily acquired variables. Random survival forest analysis, Kaplan-Meier analysis, Cox proportional hazard regression, and LASSO regression were performed for the survival analysis, and ROC analysis and Pearson's chi-squared test were employed for the correlation analysis. RESULTS: Wild-type IDH was present in 89.8% of the adult glioblastoma samples, and TERT promoter mutations and MGMT promoter methylation were observed in 66.42% and 38.49% of all adult primary glioblastomas, respectively. Age and MGMT promoter methylation were identified as independent prognostic biomarkers, and the TERT promoter mutation status and MGMT promoter methylation status, when combined with other tumor-related factors, generated several different survival subgroups. None of the factors investigated in this study predicted the MGMT promoter status, and MRI-detected necrosis was positively associated with TERT promoter mutations. CONCLUSION: MGMT promoter methylation and TERT promoter mutations, combined with MRI-derived and clinical features, revealed different survival subgroups with distinct responses to current treatments, and this information increases the ability to predict the survival of adult primary glioblastoma patients. MRI-detected necrosis often indicates the presence of TERT promoter mutations. PMID- 29984909 TI - A Guide to 'A Guide to....' articles, some thoughts on impact, and why you really should publish with The FEBS Journal. AB - Here, Editor-in-Chief Seamus Martin introduces a new type of article and discusses recent progress at The FEBS Journal, including a marked improvement in the visibility and 'impact' of the journal. PMID- 29984911 TI - Imaging Protein-Protein Interactions by Forster Resonance Energy Transfer (FRET) Microscopy in Live Cells. AB - This updated unit compares three methods to acquire Forster Resonance Energy Transfer (FRET) data in living cells using a confocal microscope: Acceptor photobleaching, Acceptor-sensitized emission FRET, and Donor fluorescence lifetime imaging. Detailed protocols for live cell husbandry, image acquisition, and data analysis are provided. In addition to providing instructions for manufacturer's analysis tool sets, we provide an easy-to-use, MATLAB-based code to calculate FRET efficiency from data obtained using the Acceptor photobleaching or Acceptor-sensitized emission method, which can be freely downloaded. (c) 2018 by John Wiley & Sons, Inc. PMID- 29984910 TI - Primary bone marrow lymphoma: A hematological emergency in adults with fever of unknown origin. AB - Primary bone marrow lymphoma (PBML) represents non-Hodgkin lymphoma (NHL) that primarily arises in the bone marrow (BM) without lymphadenopathy. This condition has various definitions and can be masked by prolonged fever, leading to delayed diagnosis. We aimed to identify clinical features and risk indicators of PBML. We enrolled 269 adults with fever of unknown origin (FUO) who underwent a BM study for potential PBML. Thirty patients were diagnosed with PBML (26 and 4 patients in the training and validation cohort, respectively), and 20 patients (67%) showed initial manifestation of hemophagocytic lymphohistiocytosis (HLH). Among PBML patients in the training cohort, their median overall survival is short (8 days), with pneumonia being the most common direct cause of early mortality, followed by life-threatening HLH. Despite extremely poor prognoses, some B-cell PBML patients who survived 30 days after BM studies achieved long-term survival with rituximab-based treatment. To assist general practitioners in early PBML diagnosis when approaching adults with naive FUO, we identified several risk indicators, including elevated serum alkaline-phosphate levels, lowered serum immunoglobulin-G levels, cytopenia in >=2 lineages, and peripheral blood leukoerythroblastosis. Our recently published scoring system, which can predict hematological BM disease in FUO adults, showed excellent ability in recognizing PBML early, with high sensitivity and specificity. We conclude that PBML is a specific "clinical" phenotype of NHL; moreover, we have identified diagnostic clues for early identification of FUO adults with underlying PBML, which should be considered a hematological emergency once suspected in any adult with FUO. PMID- 29984913 TI - Does gender affect the association between right ventricular strain and arterial hypertension? AB - The importance of right ventricular (RV) structure and function in cardiovascular and total morbidity and mortality has been confirmed previously. The purpose of this study was to evaluate the influence of gender on RV structure and function in untreated hypertensive patients. This cross-sectional study included 243 subjects who underwent 24-hour ambulatory blood pressure (BP) monitoring and comprehensive echocardiographic examination including strain evaluation. There was no difference in RV diameter between hypertensive and normotensive women and men. RV wall thickness, right atrial volume index (RAVI), and tricuspid E/e' ratio were significantly higher in hypertensive women and men than in their normotensive counterparts. RV global longitudinal and RV free wall longitudinal strains were significantly lower in hypertensive women and men than in their normotensive counterparts. Arterial hypertension affected RV wall thickness, RAVI, tricuspid E/e', and RV longitudinal strain. Gender affected RV diameter, RAVI, tricuspid E/e', and RV longitudinal strain, whereas hypertension-gender interaction affected RAVI, E/e', and RV longitudinal strain. The 24-hour systolic BP and LV mass index were independently associated with RV free wall longitudinal strain. RV wall thickness was independently associated with RV free wall longitudinal strain only in women, and tricuspid E/e' was independently associated only in men. In conclusion, RV longitudinal strain was significantly decreased in hypertensive patients in both sexes. Hypertensive men suffered more evident RV mechanical changes than hypertensive women. Gender, arterial hypertension, and their interaction had the important role in RV structural and mechanical remodeling. PMID- 29984912 TI - Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) trial. AB - AIMS: In patients with heart failure and a pathologically prolonged PR interval, left ventricular (LV) filling can be improved by shortening atrioventricular delay using His-bundle pacing. His-bundle pacing delivers physiological ventricular activation and has been shown to improve acute haemodynamic function in this group of patients. In the HOPE-HF (His Optimized Pacing Evaluated for Heart Failure) trial, we are investigating whether these acute haemodynamic improvements translate into improvements in exercise capacity and heart failure symptoms. METHODS AND RESULTS: This multicentre, double-blind, randomized, crossover study aims to randomize 160 patients with PR prolongation (>=200 ms), LV impairment (EF <= 40%), and either narrow QRS (<=140 ms) or right bundle branch block. All patients receive a cardiac device with leads positioned in the right atrium and the His bundle. Eligible patients also receive a defibrillator lead. Those not eligible for implantable cardioverter defibrillator have a backup pacing lead positioned in an LV branch of the coronary sinus. Patients are allocated in random order to 6 months of (i) haemodynamically optimized dual chamber His-bundle pacing and (ii) backup pacing only, using the non-His ventricular lead. The primary endpoint is change in exercise capacity assessed by peak oxygen uptake. Secondary endpoints include change in ejection fraction, quality of life scores, B-type natriuretic peptide, daily patient activity levels, and safety and feasibility assessments of His-bundle pacing. CONCLUSIONS: Hope-HF aims to determine whether correcting PR prolongation in patients with heart failure and narrow QRS or right bundle branch block using haemodynamically optimized dual chamber His-bundle pacing improves exercise capacity and symptoms. We aim to complete recruitment by the end of 2018 and report in 2020. PMID- 29984914 TI - Incidence proportions and prognosis of breast cancer patients with bone metastases at initial diagnosis. AB - INTRODUCTION: Population-based data on the incidence and prognosis of bone metastases at diagnosis of breast cancer are currently limited. Hence, we conducted this study to analyze the incidence proportions and prognostic factors of patients with breast cancer and bone metastases at the time of cancer diagnosis. MATERIALS AND METHODS: Patients with primary invasive breast cancer and bone metastases at initial diagnosis between 2010 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) dataset and Fudan University Shanghai Cancer Center (FUSCC) cohort. Multivariable logistic regression was performed to identify predictors of the presence of bone metastases at diagnosis. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. RESULTS: Of 229, 195 patients from SEER database included in the analysis, 8295 patients had bone metastases at initial diagnosis, reflecting 3.6% of the entire study population, and 65.1% of the subset with metastatic disease to any distant site. Patients with hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative represented the highest incidence proportions among patients with metastatic disease (73.9%). Among entire cohort, multivariable logistic regression identified eight factors as predictors of the presence of bone metastases at diagnosis. Median OS for the patients with bone metastases in SEER and FUSCC cohorts was 30.0 and 68.2 months, respectively. Patients with HR-positive HER2 positive subtype had the longest median OS, and patients with triple-negative subtype showed the shortest median OS. Multivariable Cox model in SEER cohort confirmed age, histology, grade, tumor subtype, extraosseous metastatic sites, history of primary surgery, insurance status, marital status, and income as independent prognostic factors for both OS and BCSS. CONCLUSIONS: The findings of this study provide population-based estimates of the incidence and prognosis for patients with bone metastases at initial diagnosis of breast cancer. PMID- 29984915 TI - Feasibility of optimizing intensity-modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes. AB - We prospectively investigated the feasibility of IMRT treatment plan optimization based on dosimeter measurements of lateral tongue mucosal dose adjacent to the dental fillings and evaluated dose-toxicity relationship and factors affecting oral mucositis (OM) in head and neck cancer patients. Twenty-nine head and neck cancer patients with metallic dental fillings who were scheduled to undergo fractionated external beam radiation therapy (RT) +/- chemotherapy were enrolled. The lateral tongue dose was measured and if the calculated dose for the entire treatment was >=35 Gy, a re-plan was generated to reduce the lateral tongue mucosal dose. OM was graded weekly according to Common Terminology Criteria for Adverse Events version 4.0 and the patients completed the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer. The result showed that it was not feasible to optimize the IMRT plan based on measured tongue dose in most of the patients who needed re-plan as re-planning compromised the target coverage in 60% of these patients. The duration of grade (Gr) 2 OM was correlated with measured lateral tongue dose (P = 0.050). Concurrent cetuximab was significantly associated with faster onset of Gr2 OM than concurrent cisplatin (P = 0.006) and with longer duration of OM (P = 0.041) compared to concurrent cisplatin or IMRT-alone. The pattern of reported pain over time was significantly different for each treatment type (RT and cetuximab, RT and cisplatin and RT-alone) and depending on the dose level (P = 0.006). In conclusion, optimizing the IMRT plan based on measured lateral tongue dose was not feasible. Measured lateral tongue dose was significantly correlated with longer duration of OM >=Gr2, and concurrent cetuximab was associated with earlier onset and longer duration of OM >=Gr2. PMID- 29984916 TI - The need for dedicated advanced heart failure units to optimize heart failure care: impact of optimized advanced heart failure unit care on heart transplant outcome in high-risk patients. AB - AIM: With an increasing prevalence of heart failure (HF), more patients with advanced disease have to be treated in cardiology units by sophisticated medical and interventional strategies. We therefore developed a dedicated advanced heart failure unit (AHFU) to target the specific needs of the many patients with advanced HF. We here present our concept and its impact on outcome in high-risk high-urgency (HU) heart transplant candidates. METHODS AND RESULTS: The eight-bed unit was established as an extension of the cardiologic intensive care and coronary care units in an intermediate care setting. Each bed was equipped with 24 h haemodynamic, respiratory, and arrhythmia monitoring. The unit is served 24/7 by five residents in cardiology, one staff cardiologist specializing in medical and interventional HF care, and 10 intensive care nurses. The cardiology team is supported by colleagues from cardiac surgery, sports medicine, psychosomatics, and the internal medicine departments. As an example of the intensified care on the AHFU, data from the cohorts of patients undergoing heart transplantation from HU status before (pre-AHFU 2008-11) and after establishment of the AHFU (AHFU 2012-15) were analysed. Interestingly, mortality on HU waiting list and post-heart transplant survival was comparable in both cohorts, despite significant increase in morbidity and co-morbidity as assessed by the Index for Mortality Prediction After Cardiac Transplantation model in the AHFU group. CONCLUSIONS: Our AHFU provides a unique and novel setting for the integration of modern pharmacological, interventional, surgical, and supportive HF therapy embedded in an academic heart centre. This may be a major step forward in the care of critical patients with advanced HF. PMID- 29984917 TI - Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21. AB - Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small-molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase-3/7 activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1-CDK1 and cyclin A-CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent-G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1-mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle. PMID- 29984918 TI - Frequency and clinicopathological features of metastasis to liver, lung, bone, and brain from gastric cancer: A SEER-based study. AB - The hematogenous metastatic pattern of gastric cancer (GC) was not fully explored. Here we analyzed the frequency and clinicopathological features of metastasis to liver, lung, bone, and brain from GC patients. Data queried for this analysis included GC patients from the Surveillance, Epidemiology, and End Results Program database from 2010 to 2014. All of statistical analyses were performed using the Intercooled Stata 13.0 (Stata Corporation, College Station, TX). All statistical tests were two-sided. Totally, there were 19 022 eligible patients for analysis. At the time of diagnosis, there were 7792 patients at stage IV, including 3218 (41.30%) patients with liver metastasis, 1126 (14.45%) with lung metastasis, 966 (12.40%) with bone metastasis and 151 (1.94%) with brain metastasis. GC patients with lung or liver metastasis have a higher risk of bone and brain metastasis than those without lung nor liver metastasis. Intestinal subtype had significantly higher rate of liver and lung metastasis, while diffuse type was more likely to have bone metastasis. Proximal stomach had significantly higher risk to develop metastasis than distal stomach. African Americans had the highest risk of liver metastasis and Caucasian had the highest prone to develop lung and brain metastasis. The median survival for patients with liver, lung, bone, and brain metastasis was 4 months, 3 months, 4 months and 3 months, respectively. It is important to evaluate the status of bone and brain metastasis in GC patients with lung or liver metastasis. Knowledge of metastatic patterns is helpful for clinicians to design personalized pretreatment imaging evaluation for GC patients. PMID- 29984919 TI - Comparison of risk factors in newborn hearing screening in a developing country. AB - The aim of this study is to evaluate the results of the newborn-hearing screening program (NHSP) in our institute, investigate the risk factors and their correlation to congenital hearing loss (CHL). Newborns who admitted to our clinic for NHSP from June 2014 to December 2014 were included in the study. After the test parents were asked to fill a questionnaire about the risk factors of CHL. Test results and referral rate were compared with risk factors. One thousand consecutive babies were included in the study. The overall referral rate was 3.5%. Mechanic ventilation, history of familial CHL and familial consanguinity were found to be significantly related to CHL.In the light of our results we can conclude that getting access to every newborn for hearing screening is mandatory and targeting the risk factors and informing the family about the follow-up period is important for diagnosing the delayed hearing impairment. PMID- 29984920 TI - [The modified lip-tooth-ridge classification: a guide for edentulous maxillary arches]. AB - According to the width and height of the maxillary alveolar ridge, the maxillary edentulous jaws can be divided into three categories by using modified lip-tooth ridge (MLTR) classification. Class I is characterized by sufficient bone available for implants in the vertical and horizontal aspects and is suitable for fixed implant-supported prostheses. Class II is characterized by sufficient bone amount available for implants in a horizontal aspect but insufficient for lip support and is suitable for a fixed detachable implant-supported prosthesis. Class III is characterized by inadequate amount of bone for implants (with vertical or horizontal components) and is suitable for the use of zygomatic implants or traditional complete denture. Patients belonging to Class I can be further classified into two sub-categories according to the height of the alveolar ridge. The first subclass is characterized by minimal bone deficiency and is suitable for a conventional implant-supported "crown and bridge" prosthesis. The second subclass is characterized by a larger vertical deficiency than that of the first subclass and is suitable for implant-supported hybrid prosthesis. The MLTR classification system can help the dentist to determine whether the patient is suitable for implanting dentures and whether fixed denture or removable denture is appropriate for the patient, select indications, reduce complications, and achieve long-term results. PMID- 29984921 TI - [Preparation of multifunctional nanoparticles targeting tongue cancer and in vitro study]. AB - OBJECTIVE: This study aims to prepare docetaxel (DOC)-loaded multifunctional nanoparticles containing indocyanine green (ICG) and perfluorohexane (PFH) as targeted drug delivery system, which is supplemented with stromal cellderived factor-1 (SDF-1), and characterize their properties. METHODS: Multifunctional nanoparticles were prepared by using the double emulsion method. SDF-1 was covalently conjugated to the surface of the nanoparticles through thioether bonding. Their particle size, distribution, and surface potential were determined with the Malvern measuring instrument. The conjugation of SDF-1 was evaluated by confocal laser scanning microscope. Encapsulation efficiency (ELC), drug loading capacity (DLC), and release regularity of the nanoparticles were determined by high-performance liquid chromatography (HPLC). In vitro photothermal property was recorded by a thermal imager. The in vitro imaging capacity was observed by a photoacoustic instrument and an ultrasonic diagnostic apparatus. Targeting capability was assessed by flow cytometry. The cell activity on SCC-15 cells was checked by CCK-8 method. RESULTS: The targeted multifunctional nanoparticles showed regularly sphericity. The diameter was (502.88+/-17.92) nm. The zeta potential was (-11.5+/-3.15) mV. ELC was 54.12%+/-1.74%. DLC was 1.08 mg.mL-1. In vitro drug release was initially fast and subsequently slow. The photothermal characteristics were related to the concentration; the higher the concentration, the higher the temperature. Nanoparticles could detect significant photoacoustic and ultrasound signals. The in vitro targeting rate was 89.99%. No significant differences of cell viability in the SINPs groups were observed at each concentration (P>0.05). The inhibition effect of DOC-SINPs was stronger than that of SINPs whether or not in the presence of laser irradiation among the groups of 150 and 200 MUg.mL-1 (P0.05). A positive correlation was found between the expression of SFRP1 and beta-catenin (r=0.657, P<0.01). The expression levels of beta-catenin and SFRP1 were related to periodontal indexes. The correlation between the expression of SFRP1 and probing depth was most significant (r=0.723, P<0.01), as well as that between beta-catenin and bleeding index (r=0.697, P<0.01). CONCLUSIONS: Patients with CP exhibit elevated expression of SFRP1 and beta-catenin in gingival tissues, and this event is related to the degree of periodontal destruction. Abnormal expression of SFRP1 and beta-catenin may promote the development of periodontitis. PMID- 29984925 TI - [Retrospective study of temporomandibular joint dislocation by surgical treatment]. AB - OBJECTIVE: This study aimed to retrospectively analyze temporomandibular joint dislocation by surgical treatment and evaluate the treatment effect. METHODS: From May 2012 to April 2016, a total of 17 cases of temporomandibular joint dislocation were surgically treated, including 8 cases of irreducible dislocation (ID) and 9 cases of recurrent dislocation (RD). Synovial injection of sclerosing agent by arthroscope was performed in 5 cases, 9 sides; augmentation of the articular eminence by titanium plate implantation was performed in 7 cases, 12 sides; iliac bone transplantation was performed in 1 case, 1 side; Medpore implantation was performed in 3 cases, 6 sides; and eminectomy and capsular tightening were performed in 1 case, 2 sides. Follow-up was conducted 1-5 years after the operation, and the success rate statistics was obtained. RESULTS: The cure rate of synovial injection of sclerosing agent by arthroscope was 77.8% (7/9), and the effective rate was 100%. The cure rate of titanium plate implantation was 75% (9/12), and the effective rate was 100%. The cure rates of augmentation of the articular eminence by Medpore implantation (6/6), iliac bone graft (1/1), and eminectomy (2/2) were 100%. CONCLUSIONS: The surgical method of temporomandibular joint dislocation was selected according to the state of the patients. The postoperative recurrent patients were advised to undergo augmentation of the articular eminence by Medpore implantation, which offered a reduced chance of recurrence and relatively less injury, as well as a simple operative method. PMID- 29984926 TI - [Confirmatory factor analysis of the shortened dentine hypersensitivity experience questionnaire]. AB - OBJECTIVE: This review aims to identify the dimensional structure of the shortened dentine hypersensitivity experience questionnaire (DHEQ-15) using confirmatory factor analysis (CFA). METHODS: The Chinese language version of DHEQ 15 was applied to 210 patients with dentine hypersensitivity aged 18-70 years old. The three-dimensional construct was confirmed by CFA. RESULTS: All the questionnaires were fully completed. The item "Because of the sensations, I take longer to finish a meal than others" was the most frequently reported by the parents. The modified three-factor model is suitable for the data. The chi-square fit statistics/degree of freedom was 2.213, the goodness-of-fit index was 0.905, the adjusted goodness-of-fit index was 0.872, the normed fit index was 0.845, the incremental fit index was 0.962, the Tucker-Lewis index was 0.969, the comparative fit index was 0.977, and the root mean square error of approximation was 0.068. CONCLUSIONS: Our findings generally support the three-dimensional construct of the DHEQ-15. Thus, DHEQ-15 can be used as a valid instrument in patients with dentine hypersensitivity in China. PMID- 29984927 TI - [Influencing factors on the quality of life and medical coping style of patients with oral cancer]. AB - OBJECTIVE: To evaluate the influencing factors on the postoperative quality of life and to analyze the coping styles of patients with oral cancer. METHODS: A total of 131 oral cancer cases confirmed through diagnostic criteria were investigated to analyze the influencing factors on the quality of life (QOL) and the relationship between coping style and QOL of these patients by using the fourth edition of the University of Washington Quality of Life Questionnaire (UWQOL) and medical coping modes questionnaires (MCMQ), respectively. RESULTS: Among the 131 questionnaires collected, only 126 were valid with a recovery rate of 96.18% (126/131). Single factor analysis showed that age, marital status, educational level, other systemic diseases, personal income level, tooth loss, operation times, adjuvant radiotherapy, cancer staging, cervical lymph node dissection, recurrence, and jaw resection yielded different UWQOL scale scores (P<0.05). Multiple regression analysis showed that the loss of teeth, cancer staging, recurrence, and jaw resection yielded statistically significant differences in the total score of UWQOL (P<0.05). Among the coping styles, the average scores of "confrontation", "avoidance", and "yielding" were 17.54+/ 4.97, 17.79+/-2.19, and 12.97+/-5.70, respectively. Compared with the norm, the difference was statistically significant (P<0.05). Correlation analysis showed that "confrontation" and "avoidance" were positively correlated, whereas "yielding" was negatively correlated to QOL (P<0.05). CONCLUSIONS: Age, marital status, educational level, other systemic diseases, personal income level, tooth loss, operation times, adjuvant radiotherapy, cancer staging, cervical lymph node dissection, recurrence, and jaw resection have different effects on the quality of QOL. Tooth loss, cancer staging, recurrence, and jaw resection are the main causative factors affecting the patients' perceived QOL. Personalized treatment and nursing care should be strengthened to improve the coping style and quality of life of patients. PMID- 29984928 TI - [Preliminary study on the clinical application of temporary treatment denture in difficult edentulous cases before complete denture restoration]. AB - OBJECTIVE: To explore the clinical effects of treatment denture on difficult edentulous cases before complete denture restoration. METHODS: Thirty-six patients who experienced unsuccessful restoration of conventional complete dentures were included in this study. Treatment dentures were fabricated to solve issues such as abnormal occlusion, tissue surface problems, and neuromuscular dysfunction of the stomatognathic system caused by systemic diseases. The final complete dentures were fabricated by duplicating the treatment dentures. Jaw relation index, stability, and retention were evaluated at different stages. Oral health-related quality of life was measured using the Chinese version of Oral Health Impact Profile for edentulous subjects (OHIP-EDENT). RESULTS: Among the 36 patients, 33 successfully completed the final restoration with positive effects. CONCLUSIONS: Treatment denture is an effective pre-restorative option that can be used to correct abnormal occlusion, improve tissue surface problems, and aid in neuromuscular rehabilitation training. Treatment dentures contribute to the successful restoration of the final complete dentures and is worthy of clinical applications. PMID- 29984929 TI - [CT imaging features of diffuse tenosynovial giant cell tumor of temporomandibular joint]. AB - OBJECTIVE: This study aimed to investigate the characteristic features of CT images of diffuse tenosynovial giant cell tumor (D-TSGCT) from the temporomandibular joint (TMJ) to understand CT imaging diagnosis of the disease. METHODS: CT images and clinical information from 10 patients with D-TSGCT of TMJ were recruited for retrospective analysis from March 2013 to March 2017 in Peking University Hospital of Stomatology. All cases were treated by surgery and confirmed by pathology. RESULTS: CT scan demonstrated hyperdense soft-tissue masses and various kinds of calcification in all of the 10 subjects. Contrast enhanced scan exhibited obvious enhancement in six patients. Bone destruction of the mandibular condyles and skull base was found in seven and six subjects, respectively. CONCLUSIONS: CT appearance of D-TSGCT of the TMJ is characterized by hyperdense soft tissue with calcification, further enhancement in contrast enhanced scan, and bone destruction in the mandibular condyles and skull base in some cases. PMID- 29984930 TI - [Healing of the periimplant mucosal tissue injury after placing retraction cord subgingivally in beagle dogs]. AB - OBJECTIVE: This work aims to observe the healing of periimplant mucosal tissue injury in beagle dogs after subgingival retraction cord placement by examining the gingival index (GI), quantity of gingival crevicular fluid (GCF), and the proinflammatory cytokine in the GCF. METHODS: In eight beagle dogs, the fourth mandibular premolars on the left side were extracted (n=8); after two months of healing, bone-level implants were installed. A plaque control regimen was performed throughout the duration of the experiment. After three months, retraction cords were placed subgingivally for 5 min before the cement-retained implant-supported crowns were cemented. GI, GCF quantity, and levels of tumor necrosis factor-alpha (TNF-alpha) in GCF were assessed before application and on days 1, 3, 7, 14, 28, and 56 after application. RESULTS: GI, quantity of GCF, and TNF-alpha were significantly increased on days 1, 3, and 7 compared with those at the baseline and on days 14, 28, and 56 (P<0.05), and no statistically significant differences were observed among those on days 14, 28, and 56 and the baseline (P>0.05). CONCLUSIONS: Under the circumstances of good oral hygiene, acute injury caused by placing retraction cord subgingivally in periimplant mucosal tissue of bone-level implant is reversible. GI, the quantity of GCF, and TNF-alpha on day 14 return to the baseline levels. PMID- 29984931 TI - [In vivo study of 3D printed porous tantalum implant on osseointegration]. AB - OBJECTIVE: This work aims to investigate the effect of porous tantalum and porous titanium on osseointegration. METHODS: Two kinds of porous materials with same microporous parameters, namely, porous tantalum and porous titanium, were fabricated by computer-aided design (CAD) modeling and 3D printing technology. A defect model was established in 24 New Zealand white rabbits in the bilateral femoral lateral malleolus at the left and right side of each animal. Then, animals were randomly divided into two groups, and bone defects were repaired by porous tantalum and porous titanium (experimental and control groups, respectively). Animals were sacrificed at two, four, and eight weeks after implantation. Gross observation and methylene blue-acid fuchsin staining were used to observe osseointegration of the implant and bone interface, and the osseointegration strength of implant bone interface was tested by push-out test. RESULTS: At two, four, and eight weeks after operation, the new bone tissue in the two groups increased gradually, and new bone trabecula appeared and grew into the pores of the materials. No significant difference (P>0.05) in osteogenesis and the strength of implant bone tissue interface between the two groups was observed. CONCLUSIONS: 3D?printed porous tantalum implants, which exhibit comparable osseointegration capabilities to porous titanium implants, can form an early biological combination with bone tissue. PMID- 29984932 TI - [Relationship between initial archwire materials and pain at the initial stage of orthodontic treatment: a systematic review and network Meta-analysis]. AB - OBJECTIVE: This review aims to assess the relationship between initial archwire materials and pain at the initial stage of orthodontic treatment. METHODS: On October 1, 2017, seven databases were searched electronically for studies oninitial archwire materials and pain at the initial stage of orthodontic treatment. Quality assessment was performed with bias risk assessment tools suggested by Cochrane's handbook. Data extraction of included studies was also carried out. Network Meta-?analysis was conducted using R 3.4.2 (with JAGS 4.3.0), GeMTC 0.14.3, and STATA 11.0. RESULTS: Five studies with 330 participants were included, comparing four different materials: multi-stranded stainless steel, conventional nickel-titanium, super-elastic nickel-titanium, and thermal heat-activated nickel-titanium. Two studies were at low risk of bias, one was at high risk of bias, and the remaining two were at unclear risk of bias. Network Meta-analysis results showed no statistical differences of pain among the four initial archwire materials at day 1 and day 7. However, the most painless material was most likely to be thermal heat-activated nickel-titanium on rank probability. CONCLUSIONS: On statistical probability, thermal heat-activated nickel-titanium initial arch wires is most likely to cause the least pain at the initial stage of orthodontic treatment, compared with other materials. PMID- 29984933 TI - [Effect of calcium sodium phosphosilicate and potassium nitrate on dentin hypersensitivity: a systematic review and Meta-analysis]. AB - OBJECTIVE: This systematic review and Meta-analysis aimed to compare the efficacy of calcium sodium phos-phosilicate (CSPS) and potassium nitrate as desensitizing agents for the treatment of dentin hypersensitivity (DH). METHODS: A thorough search in The Cochrane Library, PubMed, Embase, Chinese WanFang Data, CBM, and CNKI were conducted for studies published up to June 2017. Randomized controlled trials (RCTs) of the treatment of DH with CSPS and potassium nitrate toothpaste were included. Quality assessment and data extraction were performed by two reviewers independently, and Meta-analysis was performed by using RevMan 5.3 software. RESULTS: Eight RCTs involving 411 patients were included. Experimental group comprised 203 and control group had 208 patients. The Meta-analysis indicated the superior effect of CSPS dentifrice on air blast sensitivity at 2, 4, 6, and 8 weeks of follow-up [SMD=-1.85, 95%CI (-2.89, ?-0.81), P=0.000 5, I2=93%], [SMD=-1.61, 95%CI (-1.96, -1.26), P<0.000 01, I2=49%], [SMD=-3.79, 95%CI (-7.18, -0.40), P=0.03, I2=98%], and [SMD=-2.13, 95%CI (-2.69, -1.58), P<0.000 01] , respectively. No significant effects were seen at 12 weeks [SMD=-0.63, 95%CI (-1.47, 0.20), P=0.14, I2=71%]. CSPS dentifrice showed a better desensitizing effect at 2, 4, 6, 8, and 12 weeks of follow-up on cold water sensitivity [SMD=-1.07, 95%CI (-1.48, -0.66), P<0.000 01, I2=69%], [SMD=?-1.29, 95%CI (-1.81, -0.76), P<0.000 01, I2=64%], [SMD=-1.20, 95%CI (-1.57, -0.83), P<0.000 01, I2=86%], [SMD=-1.30, 95%CI (-2.51, -0.08), P=0.04, I2=82%], and [SMD= 0.79, 95%CI (-1.27, -0.31), P=0.001], respectively. No significant effects at 1 week of follow-up [SMD=0.00, 95%CI (-0.62, 0.62), P=1]. The favorable effect of CSPS dentifrice on tactile sensitivity was more obvious than the control group at 2, 4, and 8 weeks of follow-up [SMD=-1.31, 95%CI (-2.00, -0.62), P=0.000 2, I2=67%], [SMD=-1.37, 95%CI (-1.74, -0.99), P<0.000 01, I2=23%], and [SMD=-1.33, 95%CI (-1.82,-0.84), P<0.000 01], respectively. No significant effects at 1 week of follow-up [SMD=-0.32, 95%CI (-0.94, 0.31), P=0.32] were observed. CONCLUSIONS: Current evidence indicated that CSPS was more effective than potassium nitrate at reducing DH. The evidence generated by this review was based on a small number of individuals. High-quality and large sample size as well as ideally-designed clinical trials are required in the future before definitive recommendations can be made. PMID- 29984934 TI - [Prevalence survey of immature permanent tooth trauma about the clinical visiting and prognosis in Xi'an schoolchildren]. AB - OBJECTIVE: This study aims to investigate the clinical visiting and prognosis of schoolchildren in Xi'an after immature permanent tooth trauma and explore the prognostic factors associated with this type of trauma. METHODS: Through cluster and simple random sampling surveys, 4 013 pupils in schools from nine districts and four counties in Xi'an were sampled, respectively. All pupils and their parents were requested to complete a questionnaire, and children who had immature permanent tooth trauma answered a separate questionnaire and underwent oral examinations. The data of the survey were analyzed statistically. RESULTS: The amount of valid questionnaire was 3 641. Clinical visiting rate related to immature permanent tooth trauma of Xi'an schoolchildren was low (38.2%). Gender and trauma type were the factors related to clinical visiting for dental trauma concerns. The incidence of poor prognosis was 29.7%. The incidence of poor prognosis of patients with clinical visiting (35.4%) was higher than that of patients without clinical visiting (20.6%). CONCLUSIONS: Clinical visiting rate related to immature permanent tooth trauma in Xi'an schoolchildren is extremely low, and incidence of poor prognosis is high. PMID- 29984936 TI - [Pharmacokinetics and drug safety of oral infectious disease during pregnancy]. AB - Pregnancy is a time of particular vulnerability in terms of physiologic changes resulting in higher risk of oral infectious diseases. There is emerging evidence showing that irrational dental treatment and drug therapy are associated with adverse pregnancy outcomes, including infant malformation or spontaneous abortion. This article reviews the pharmacokinetics of medications in pregnant women and the fetus and introduces a guideline for drug therapy and common dental drugs used during pregnancy. PMID- 29984935 TI - [Survey and analysis of tooth extraction anxiety of dental patients]. AB - OBJECTIVE: This study aims to understand the current status and analyze the influencing factors of tooth extraction anxiety of dental patients. METHODS: The General Factor Questionnaire and Modified Dental Anxiety Scale (MDAS) were used to survey and analyze tooth extraction anxiety of 800 dental patients. Single factor and multi-factor analyses were used for statistical data analysis. RESULTS: A total of 768 qualified questionnaires were received out of 800, the efficiency was 96%. The mean MDAS score was 10.21+/-3.29. The prevalence percentage of dental anxiety was 14.7%. Significant statistical differences of the incidence of dental anxiety were observed with regard to sex, age, tooth extraction time, accompanying relatives and friends, before tooth extraction, tooth extraction experience for family and friends, pain tolerance, mental health state before tooth extraction, and self-reported oral health status (P<0.05. By contrast, no significant statistical differences in the incidence of dental anxiety were observed with regard to educational level, tooth extraction type, national life experience, profession, and personality (P>0.05). Logistic regression analysis indicated that the risk factors of dental anxiety were sex, accompanying relatives and friends, mental health state before tooth extraction, and self-rated oral health status. CONCLUSIONS: The prevalence percentage of tooth extraction anxiety is high for dental patients. Gender, age, health satisfaction, tooth extraction time, accompanying relatives and friends, before tooth extraction, tooth extraction experience for family and friends, pain tolerance, mental health state before tooth extraction, and self-reported oral health status are the influencing factors of dental anxiety. PMID- 29984937 TI - [Relationship between interleukins in the saliva and oral cavity cancer]. AB - Saliva is being attached great importance for its application in illness diagnosis and have more advantage on the diagnose in oral cavity cancer (OCC). Studies have showed that interleukin (IL) in the saliva could be used as a potential biomarker for OCC diagnosis. Moreover, they have a close connection with tumor genesis, invasion, and metastasis in OCC. Therefore, we reviewed research progress on the relationship between salivary interleukins and OCC. PMID- 29984938 TI - [Research progress on the relationship between oral microbes and digestive system diseases]. AB - The human microbiome project promoted further understanding on human oral microbes. Besides oral diseases such as dental caries, periodontal disease, and oral cancer, oral microbes are closely associated with systematic diseases. They have a close connection with digestive system diseases and even contribute to the origination and progression of colorectal cancer. By reviewing recent studies involving oral microbe-related digestive systemic diseases, we aim to propose the considerable role of oral microbes in relation to digestive systemic diseases and the way of oral microbes to multiple organs of digestive system. PMID- 29984939 TI - [Advances in salivary protein glycosylation and its relationship with systemic and oral diseases]. AB - Protein glycosylation is one of the most important protein post-translational modifications that can affect life activities by endowing the protein with various structural and functional features. Saliva is an easy-to-obtain, noninvasive body fluid that contains components originating from serum, gingival crevicular fluid, and oropharyngeal mucosae. In recent years, understanding of saliva has been constantly updated with the developments in related research. Studies have shown that salivary proteins can be used as diagnostic markers for certain diseases, and changes of protein glycosylation in saliva are generally considered to be related to many diseases. In this review, salivary protein glycosylation and its relationship with systemic and oral diseases were discussed. PMID- 29984940 TI - [Teratomas on the palate and tongue with cleft palate: a case report]. AB - Teratomas is a germ cell tumors, which is rare in the upper palatal and lingual. This article presents a patient with teratomas on the palate and tongue accompanied with cleft palate. The clinical manifestations and histopathological characteristics of teratomas are discussed according to relevant literatures. PMID- 29984941 TI - [Implant prosthesis design scheme for sophisticated congenital partial edentia]. AB - Sophisticated congenital partial edentia are often accompanied by severe shortage of bone height and width due to the absence of permanent teeth; such condition will affect implant placement. This study aimed to display the different typical implant rehabilitation schemes we designed for sophisticated congenital partial edentia cases with severely atrophic alveolar bone. PMID- 29984942 TI - Addressing the Cost, Value, And Student Debt in Nursing Education. AB - The current initiatives to improve the academic preparation of nurses have added emphasis to the presence or prediction of thousands of dollars of debt, which may influence personal decisions about returning to school. In this study, nearly 40% of survey respondents reported less than $25,000 in college debt and 23.5% reported greater than $25,000 of prior college debt. Slightly less than a third of respondents reported no plans to return to school for more education but of those who did have an educational plan, the influence of prior college debt on their plans for academic progression was significant. Debt and the influence of debt on education planning for nurses was confirmed as a concern that will impede achievement of the baccalaureate education benchmark for nurses unless steps are taken to address prior college debt and the cost of further education. Nurse executives should take nurses' debt load into account when planning academic advancement initiatives. PMID- 29984944 TI - [In process]. PMID- 29984943 TI - Program Evaluation of a Nursing Workforce Intervention: The Maryland Nurse Support Program II. AB - A nursing workforce initiative in Maryland sought to graduate additional nursing students to become registered nurses and to increase the number and preparation levels of nursing faculty. Between FY 2006 and FY 2015, nearly $100 million was awarded through 109 competitive institutional grants at 27 nursing programs across the state; 950 faculty received awards through fellowships, scholarships, and grants. Maryland's nursing workforce intervention increased the number of graduates by 27% through this decade-long program. Although Maryland outperformed the nation in the rate of increase of registered nurses, there is still a projected state shortfall of 12,100 nurses by 2025. It is imperative for nurse researchers and nurse leaders to address the future nursing and nurse faculty workforce shortage using effective strategies based on empirical evidence and evaluation of outcomes. This program evaluation informed the decision to continue investments in the nursing and faculty workforce (up to $75 million) for an additional 5 years. PMID- 29984945 TI - Pitolisant for the treatment of narcolepsy with or without cataplexy. AB - Since March 2016, a new treatment option for adult patients with narcolepsy - with or without cataplexy - has been granted marketing authorization in Europe. Pitolisant (Wakix(r)) is an inverse agonst at the histamine-3 (H3) receptor. In clinical studies, tests for measurement of wakefulness and attention, pitolisant showed significantly better results in comparison with placebo and similar results in comparison with modafinil. Pitolisant is well tolerated. Postmarketing analyses have to collect data about the long-term safety of pitolisant when used in a real-life setting. PMID- 29984946 TI - Zika virus infections. AB - The Zika virus is an enveloped RNA virus belonging to the flavivirus family. The virus is transferred to humans primarily through the bite of female Aedes mosquitoes such as A. aegypti, but human-to-human transmission (through sexual contact and from the infected mother to her foetus) also occurs. Until recently, infections with the Zika virus had only little medical significance. For several decades, the virus has sporadically caused benign febrile Dengue-like illnesses in several African and Asian areas. 2007 and 2013/2014, however, two major Zika outbreaks in the Pacific region have been documented. Currently, the biggest Zika virus epidemic ever recorded takes places in several states and territories in South and Central America including the Caribbean islands. During the current outbreak, the virus has been shown to frequently cause severe manifestations, in particular fetal malformations (microcephaly) of the brain, as well as neurological disorders in adults such as Guillain Barre syndrome. Treatment of Zika virus infections is symptomatic and supportive, a specific antiviral therapy does not exist. PMID- 29984947 TI - The Impact of Economic Recession On Registered Nurse Workforce Supply in California. AB - The severe economic recession from December 2007 to December 2010 substantially affected registered nurse (RN) employment. The objective of this study was to determine if the association between RN workforce supply and its potential determinants differed during the period from 2008 to 2012. Older, experienced RNs were more likely to work in 2010, compared to 2008, but less likely to work in 2012 compared to 2010. RNs were less sensitive to financial factors in 2010 than in 2008, but were more sensitive in 2012 than in 2010. These recession-driven changes in employment may have had impacts on the labor market for newly graduating RNs. PMID- 29984948 TI - [In process]. PMID- 29984949 TI - [In process]. PMID- 29984950 TI - A Case Example of a Transitional Education Program for Internationally Educated Nurses from Mexico. AB - Internationally educated nurses migrating for work in other countries help address short and long-term staffing shortage issues. A transitional educational program was designed and implemented to prepare Mexican nurses with the competencies needed to work in any clinical setting in the United States. Through an intensive, full-time, 6-month transitional education program that included a living stipend during program participation, 30 out of 67 Mexican nurse candidates passed the NCLEX-RN, an English-language competency test, and were successfully placed in a hospital setting. Several salient lessons emerged from program implementation that have implications for transitions and capacity building among internationally educated nurses. PMID- 29984951 TI - [In process]. PMID- 29984952 TI - [In process]. PMID- 29984953 TI - [In process]. PMID- 29984954 TI - [In process]. PMID- 29984955 TI - The continuing evolution of endovascular therapy. PMID- 29984956 TI - [In process]. PMID- 29984957 TI - [In process]. PMID- 29984958 TI - American Academy of Ambulatory Care Nursing Position Paper: The Role of the Registered Nurse in Ambulatory Care. PMID- 29984959 TI - [In process]. PMID- 29984960 TI - [In process]. PMID- 29984961 TI - [In process]. PMID- 29984962 TI - Changing of the Guard: What's in Store for Healthcare Policy? AB - Repealing the Affordable Care Act (ACA) was a promise made by President-elect Donald Trump. Altering the ACA is a complex process and it is likely to be at least 2019 before any new program would be in place completely. We can hope there will still be an emphasis on providing high-quality healthcare efficiently, which promotes healthcare institutions to use nurses to their full scope of practice. PMID- 29984963 TI - Editorial. PMID- 29984964 TI - Valid Staffing Models Needed. PMID- 29984965 TI - Editorial. PMID- 29984967 TI - Errata. PMID- 29984966 TI - The Value of Mentorship. PMID- 29984968 TI - Errata. PMID- 29984969 TI - Author's Response. PMID- 29984970 TI - The Medical Reception Station: a new primary care capability for 3 Commando Brigade. AB - 3 Commando Brigade's delivery of pre-hospital (Role 1) care has until now largely been based around junior doctors delivering trauma-based resuscitation and limited primary care from small self-contained Regimental Aid Posts (RAPs). With the drawdown of large scale operations in Iraq and Afghanistan, and the diversity of potential future military operations, the deficiency of General Practitioner(GP)-led care in the deployed setting has become more evident, and this has driven the requirement for a deployable primary care facility in the form of a Medical Reception Station (MRS). This paper describes the evolution of this project, the realities of deploying a new medical capability for the first time, some of the issues faced, and the potential utility of such a medical facility in future. PMID- 29984971 TI - Contemporary French maritime hospital capabilities. AB - The polyvalent nature of the three French BPCs creates flexibility for command, especially if two could be deployed simultaneously on the same operation. They each contain an impressive MTF designed into the ship from the initial concept, with a modular ability to function as anything from Role 2 to 3. It is hoped that as part of Defence Engagement the RNMS will be able to exercise on board a BPC. The level of integration between France and the UK with respect to human resources in the medical environment requires further work to ascertain what is feasible, bearing in mind the language difficulties and differences between the training, working practices and even ranks. PMID- 29984972 TI - Maritime Radiology on Operation GRITROCK. AB - RFA ARGUS deployed on Operation (Op) GRITROCK between Oct 2014 and Apr 2015 to provide support to the United Kingdom (UK) response to the Ebola crisis. This article describes the radiology capability on board ARGUS within the Primary Casualty Receiving Facility (PCRF). PMID- 29984973 TI - Non-Battle Injuries presenting to the Force Medical Rehabilitation Team on Operation GRITROCK. AB - Non-Battle Injuries (NBI) represent a significant attritional threat to personnel deployed on operations. Operation (Op) GRITROCK involved personnel deployed across both land and maritime environments and was the first deployment of the Primary Casualty Receiving Facility (PCRF) on contingency operations of this type. This article outlines the incidence, demographics and functional outcome of individuals assessed for NBI by the embarked rehabilitation team. A total of 138 injured individuals were assessed over the period Oct 2014 - Mar 2015. ARGUS personnel made up 83.3% (n=115) of the injured population. Most common presentations were low back pain (LBP) (21%) and soft tissue lower limb injuries (14.5%), primarily occurring through individual sport (42.8%) or normal duty (34.8%). The Force Medical Rehabilitation Team (FMRT) effectively retained troops in theatre; although 22.5% (n=31) were considered urgent cases, only one individual required medical evacuation. 53.6% of presentations were exacerbations of a previous injury. Future work will examine the long-term outcome of these injuries. PMID- 29984974 TI - An unusual rash for Royal: a case series. AB - Eight patients, whilst on exercise in Albania, presented with a blistering, erythematous and itchy rash, consistent with caustic burns, after living in dense vegetation for a few days. All patients were found to have been living and operating under fig trees and had come into contact with the sap of Ficus carica, which on exposure to ultraviolet A (UVA) radiation, can cause a process of phytophotodermatitis leading to a blistering rash. PMID- 29984975 TI - Acute shoulder injuries: A clinical review of diagnosis and management in the deployed Naval environment. AB - Musculoskeletal injuries of the shoulder are a common presentation in primary care. Injuries to this highly mobile region can have a profound impact on the range of movement, resulting in severe functional limitation. The shoulder can also be one of the more complicated regions to examine due to its high mobility, poor localisation of pain and numerous supporting structures. This article aims to review the anatomy of the shoulder, examination technique and the pathology underlying common acute injuries in order to provide guidance to medical personnel deployed with the Royal Navy and Royal Marines. PMID- 29984976 TI - The management of testicular masses and acute scrotal pain. AB - Within military primary care patients may present with testicular masses or acute scrotal pain. The aim of this article is to examine, by means of case studies, the differential diagnosis, treatment and clinical considerations in managing patients in the military environment. PMID- 29984977 TI - High altitude adaptation and illness: military implications. AB - British military personnel are frequently exposed to high altitude (HA) (>1500m). Operations in Afghanistan have occurred at altitudes of up to 3000m and there remains the possibility of rapid deployment of non-acclimatised troops to HA areas. British military personnel also deploy to HA frequently on Adventurous Training (AT) and there are numerous expeditions every year to the Greater Ranges. As such, there remains a reasonable likelihood of the development of high altitude illness (HAI) with potentially life-threatening consequences. This article aims to provide an overview of the adaptive (acclimatisation) and pathological (acute HAI) responses to HA exposure, with particular reference to military deployments. PMID- 29984979 TI - LA County Hospital and Naval Trauma Training School - The Ian Jenkins Travelling Fellowship 2015. PMID- 29984978 TI - The athletic ECG. AB - The electrocardiogram (ECG) is the most frequently performed basic cardiology investigation. Correct interpretation of the ECG is vital, both to confirm acute diagnoses such as myocardial infarction, and in the elective setting to diagnose previous or underlying cardiac abnormalities. Normal electrocardiographic parameters for the multiple components of the ECG have been identified and are applied to the general population, but it is acknowledged that cardiac conditioning occurs with frequent and sustained aerobic exercise, in turn leading to physiological changes in the ECG. Service personnel may perform exercise at a level that leads to cardiac conditioning with associated ECG changes. This clinical review will briefly address the normal ECG and consider changes associated with aerobic cardiac conditioning. By identifying what constitutes physiological non-pathological changes in the athletic ECG, this clinical review aims to assist those who interpret ECGs in Service personnel. PMID- 29984980 TI - 10 tips for success when undertaking a higher research degree. PMID- 29984981 TI - Micro-Data-Independent Acquisition for High-Throughput Proteomics and Sensitive Peptide Mass Spectrum Identification. AB - State-of-the-art strategies for proteomics are not able to rapidly interrogate complex peptide mixtures in an untargeted manner with sensitive peptide and protein identification rates. We describe a data-independent acquisition (DIA) approach, microDIA (MUDIA), that applies a novel tandem mass spectrometry (MS/MS) mass spectral deconvolution method to increase the specificity of tandem mass spectra acquired during proteomics experiments. Using the MUDIA approach with a 10 min liquid chromatography gradient allowed detection of 3.1-fold more HeLa proteins than the results obtained from data-dependent acquisition (DDA) of the same samples. Additionally, we found the MUDIA MS/MS deconvolution procedure is critical for resolving modified peptides with relatively small precursor mass shifts that cause the same peptide sequence in modified and unmodified forms to theoretically cofragment in the same raw MS/MS spectra. The MUDIA workflow is implemented in the PROTALIZER software tool which fully automates tandem mass spectral deconvolution, queries every peptide with a library-free search algorithm against a user-defined protein database, and confidently identifies multiple peptides in a single tandem mass spectrum. We also benchmarked MUDIA against DDA using a 90 min gradient analysis of HeLa and Escherichia coli peptides that were mixed in predefined quantitative ratios, and our results showed MUDIA provided 24% more true positives at the same false positive rate. PMID- 29984982 TI - Self-Assembled Growth of Ultrastable CH3NH3PbBr3 Perovskite Milliwires for Photodetectors. AB - The unstability of organolead halide perovskite under continuous illumination, moisture, and high temperature has seriously impeded its commercial development for long-period applications. Here, a facile method was developed to grow ultrastable CH3NH3PbBr3 milliwires through the reaction of self-assembled PbBr2 milliwire with CH3NH3Br at room temperature. The initial self-assembled PbBr2 milliwire is that PbBr2 complexed with dimethylformamide (DMF) molecular self assemble into perovskite-type PbBr2. Crystal conversion from PbBr2 to CH3NH3PbBr3 milliwire occurred in the molecular exchange between CH3NH3Br and DMF. The synthesized CH3NH3PbBr3 milliwires present high stability under high humidity ~75%, continuous illumination, heating, and sustain ultrastability in air for more than 255 days. In addition, the CH3NH3PbBr3 milliwire can be dynamically degraded and reconstructed in the presence of water molecules. The milliwires have strong band-edge photoluminescence (PL) with PL lifetime of ~110 ns. On the basis of the mono-milliwire-constructed photodetector, it exhibits high photoresponse and fast response time of 0.407 s. PMID- 29984984 TI - Molecular Effects, Speciation, and Competition of Inorganic and Methyl Mercury in the Aquatic Plant Elodea nuttallii. AB - Mercury (Hg) remains hazardous in aquatic environments because of its biomagnification in food webs. Nonetheless, Hg uptake and impact in primary producers is still poorly understood. Here, we compared the cellular toxicity of inorganic and methyl Hg (IHg and MeHg, respectively) in the aquatic plant Elodea nuttallii. IHg and MeHg regulated contigs involved in similar categories (e.g., energy metabolism, development, transport, secondary metabolism), but MeHg regulated more contigs, supporting a higher molecular impact than IHg. At the organism level, MeHg induced antioxidants, while IHg decreased chlorophyll content. The uptake of Hg and expression of a subset of contigs was subsequently studied in complex media. Measured uptake pointed to a contrasted impact of cell walls and copper (Cu) on IHg and MeHg. Using a speciation modeling, differences in uptake were attributed to the differences in affinities of IHg and MeHg to organic matter in relation to Cu speciation. We also identified a distinct gene expression signature for IHg, MeHg, and Cu, further supporting different molecular toxicity of these trace elements. Our data provided fundamental knowledge on IHg and MeHg uptake in a key aquatic primary producer and confirmed the potential of transcriptomics to assess Hg exposure in environmentally realistic systems. PMID- 29984983 TI - Cation Segregation of A-Site Deficiency Perovskite La0.85FeO3-delta Nanoparticles toward High-Performance Cathode Catalysts for Rechargeable Li-O2 Battery. AB - Cation segregation of perovskite oxide is crucial to develop high-performance catalysts. Herein, we achieved the exsolution of alpha-Fe2O3 from parent La0.85FeO3-delta by a simple heat treatment. Compared to alpha-Fe2O3 and La0.85FeO3-delta, alpha-Fe2O3-LaFeO3- x achieved a significant improvement of lithium-oxygen battery performance in terms of discharge specific capacity and cycling stability. The promotion can be attributed to the interaction between alpha-Fe2O3 and LaFeO3- x. During the cycling test, alpha-Fe2O3-LaFeO3- x can be stably cycled for 108 cycles at a limited discharge capacity of 500 mAh g-1 at a current density of 100 mA g-1, which is remarkably longer than those of La0.85FeO3-delta (51 cycles), alpha-Fe2O3 (21 cycles), and mechanical mixing of LaFeO3 and alpha-Fe2O3 (26 cycles). In general, these results suggest a promising method to develop efficient lithium-oxygen battery catalysts via segregation. PMID- 29984985 TI - Organic Light-Emitting Transistors with Simultaneous Enhancement of Optical Power and External Quantum Efficiency via Conjugated Polar Polymer Interlayers. AB - Organic light-emitting transistors (OLETs) show the fascinating combination of electrical switching characteristics and light generation capability. However, to ensure an effective device operation, an efficient injection of charges into the emissive layer is required. The introduction of solution-processed conjugated polyelectrolyte (CPE) films at the emissive layer/electrode interface represents a promising strategy to improve the electron injection process by dipole formation. However, their use in optoelectronic devices also involves some limitations because of the ionic nature of CPEs. In this context, neutral conjugated polar polymers (CPPs) represent a valid alternative to CPEs because the conjugated backbones of CPPs are functionalized with polar nonionic side groups, thus avoiding ion-dependent drawbacks. By introducing a layer of polyfluorene-containing phosphonate groups underneath the metal electrodes, we here demonstrate a substantial improvement of the electron injection properties into the OLET-emissive layer and, accordingly, a more than 2-fold increased light power and a 5 times higher external quantum efficiency of p-type OLETs in comparison with reference devices without any interlayer. The great benefit of using a transparent glass substrate allowed to selectively investigate the morphological and photoluminescent characteristics of both CPE- and CPP-buried interlayers within complete OLETs by means of an optical scanning probe technique. This, together with a thorough optoelectronic characterization of the figures of merit of working light-emitting devices, allowed to disclose the origin of the improved optical performance of CPP-based devices as well as the operation mechanisms of the investigated interlayer in the corresponding OLETs. PMID- 29984986 TI - Ratiometric Fluorescence Platform Based on Modified Silicon Quantum Dots and Its Logic Gate Performance. AB - A novel optical nanoprobe based on silicon quantum dots (SiQDs) has been assembled through a one-pot low-temperature (40 degrees C) treatment by using 3 (aminopropyl)trimethoxysilane (APTMS) and ascorbic acid (AA) as two precursors. The water-soluble SiQDs demonstrate intense green luminescence in aqueous environment and the excitation-dependent feature has been explored. Meanwhile, the incorporation of salicylaldehyde (SA) serves to suppress the emission of SiQDs effectively via nucleophilic reaction and an "on-off" change is observed. Furthermore, the addition of Zn2+ can lead to evolution of emission peaks, and the green band at 500 nm gradually shifts toward the blue side at 455 nm. The corresponding ratiometric signal changes ( I455/ I500) can accurately determine the Zn2+ concentration and the limit of detection is calculated to be 0.17 MUM in the linear range between 1 and 100 MUM. In this research, a molecular logic gate (AND) system has been well established by using SA and Zn2+ as two inputs. The fluorescence emission changes based on SiQDs will shed new light on the development of functional sensors at the nanoscale level. PMID- 29984987 TI - Electrochemical Deposition: An Advanced Approach for Templated Synthesis of Nanoporous Metal Architectures. AB - Well-constructed porous materials take an essential role in a wide range of applications, including energy conversion and storage systems, electrocatalysis, photocatalysis, and sensing. Although the tailored design of various nanoarchitectures has made substantial progress, simpler preparation methods are compelled to meet large-scale production requirements. Recently, advanced electrochemical deposition techniques have had a significant impact in terms of precise control upon the nanoporous architecture (i.e., pore size, surface area, pore structure, etc.), enabling access to a wide range of compositions. In this Account, we showcase the uniqueness of electrochemical deposition techniques, detail their implementation toward the synthesis of novel nanoporous metals, and finally outline the future research directions. Nanoporous metallic structures are attractive in that they can provide high surface area and large pore volume, easing mass transport of reactants and providing high accessibility to catalytically active metal surface. The great merit of the electrochemical deposition approach does not only lie in its versatility, being applicable to a wide range of compositions, but also in the nanoscale precision it affords when it comes to crystal growth control, which cannot be easily achieved by other bottom-up or top-down approaches. In this Account, we describe the significant progress made in the field of nanoporous metal designed through electrochemical deposition approaches using hard templates (i.e., porous silica, 3D templates of polymer and silica colloids) and soft templates (i.e., lyotropic liquid crystals, polymeric micelles). In addition, we will point out how it accounts for precise control over the crystal growth and describe the unique physical and chemical properties emerging from these novel materials. Up to date, our group has reported the synthesis of several nanoporous metals and alloys (e.g., Cu, Ru, Rh, Pd, Pt, Au, and their corresponding alloys) under various conditions through electrochemical deposition, while investigating their various potential applications. The orientation of the channel structure, the composition, and the nanoporosity can be easily controlled by selecting the appropriate surfactants or block copolymers. The inherent properties of the final product, such as framework crystallinity, catalytic activity, and resistance to oxidation, are depending on both the composition and pore structure, which in turn require suitable electrochemical conditions. This Account is divided into three main sections: (i) a history of electrochemical deposition using hard and soft templates, (ii) a description of the important mechanisms involved in the preparation of nanoporous materials, and (iii) a conclusion and future perspectives. We believe that this Account will promote a deeper understanding of the synthesis of nanoporous metals using electrochemical deposition methods, thus enabling new pathways to control nanoporous architectures and optimize their performance toward promising applications such as catalysis, energy storage, sensors, and so forth. PMID- 29984988 TI - Multigenerational Effects and Demographic Responses of Zebrafish ( Danio rerio) Exposed to Organo-Bromine Compounds. AB - Long-term exposure to toxic chemicals often has deleterious effects on aquatic organisms. In order to support appropriate environmental management of chemicals, a mathematical model was developed to characterize the effects of chemicals on multigenerational population dynamics in aquatic animals. To parametrize the model, we conducted a multigenerational laboratory toxicity test in zebrafish ( Danio rerio) exposed to 2-bromo-4,6-dinitroaniline (BDNA). Long-term exposure to BDNA considerably reduced the fecundity of adult zebrafish (F0 and F1) and caused deformities in the offspring (F2). Life history data, including changes in fecundity and population growth, were then integrated into the model to predict population dynamics of zebrafish exposed to two novel brominated flame retardants, bis(2-ethylhexyl)-2,3,4,5-tetrabromophthalate (TBPH) and 2-ethylhexyl 2,3,4,5-tetrabromobenzoate (TBB). The model predicted that the fecundity of adult zebrafish would be significantly impaired after exposure to 90.36 MUM TBPH and 99.16 MUM TBB. Thus, prolonged exposure to such levels over multiple generations could result in population extinction within 20 years. Our results provide an intensive temporal perspective to investigate a keystone that connects with individual response to chemicals, population dynamics, and ultimately ecosystem influences. PMID- 29984989 TI - Highly Selective and Sensitive Detection of Pb2+ in Aqueous Solution Using Tetra(4-pyridyl)porphyrin-Functionalized Thermosensitive Ionic Microgels. AB - Tetra(4-pyridyl)porphyrin (TPyP)-functionalized thermosensitive ionic microgels (TPyP5-MGs) were synthesized by a two-step quaternization method. The obtained TPyP5-MGs have a hydrodynamic radius of about 189 nm with uniform size distribution and exhibit thermosensitive character. The TPyP5-MG microgel suspensions can optically respond to trace Pb2+ ions in aqueous solution with high sensitivity and selectivity over the interference of other 19 species of metal ions (Yb3+, Gd3+, Ce3+, La3+, Bi3+, Ba2+, Zn2+, Ni2+, Co2+, Mn2+, Cr3+, K+, Na+, Li+, Al3+, Cu2+, Ag+, Cd2+, and Fe3+) by using UV-visible spectroscopy. The sensitivity of TPyP5-MGs toward Pb2+ can be further improved by increasing the solution temperature. The limit of detection for TPyP5-MG microgel suspensions in the detection of Pb2+ in aqueous solution at 50 degrees C is about 25.2 nM, which can be further improved to be 5.9 nM by using the method of higher order derivative spectrophotometry and is much lower than the U. S. EPA standard for the safety limit of Pb2+ ions in drinking water. It is further demonstrated that the TPyP5-MG microgel suspensions have a potential application in the detection of Pb2+ in real world samples, which give consistent results with those obtained by elemental analysis. PMID- 29984991 TI - A Highly Compensated Interferometer for Biochemical Analysis. AB - Here we report an improved interferometric sensing approach that facilitates high sensitivity nanovolume refractive index (RI) measurements and molecular interaction assays without a temperature controller. The compensated backscattering interferometer (CBSI) is based on a helium-neon (He-Ne) laser, a microfluidic chip, and a CCD array. The CBSI enables simultaneous differential RI measurements within nanoliter volumes, at a compensation level of ca. 5 * 10-8 RIU in the presence of large thermal perturbations (8 degrees C). This level of d n/d T compensation is enabled by elongating the laser beam along the central axis of the microfluidic channel and measuring the difference in positional shift of interference patterns from two adjacent regions of the channel. By separating two solutions by an air gap or oil droplet, CBSI can discriminate the difference in RI for the sample and reference at a detection limit of 7 * 10-7 RIU in the absence of electronic filtering. At this level of DeltaRI sensitivity, it is possible to perform label-free, free-solution biochemical assays at the 10s of nM level without the typical high-resolution temperature control needed in conventional interferometers. Here we illustrate the effective use of CBSI by quantifying the binding affinities for mannose-concanavalin A and Ca2+-recoverin interactions. PMID- 29984990 TI - Site-Specific Incorporation of Selenocysteine Using an Expanded Genetic Code and Palladium-Mediated Chemical Deprotection. AB - Selenoproteins containing the 21st amino acid selenocysteine (Sec) exist in all three kingdoms of life and play essential roles in human health and development. The distinct low p Ka, high reactivity, and redox property of Sec also afford unique routes to protein modification and engineering. However, natural Sec incorporation requires idiosyncratic translational machineries that are dedicated to Sec and species-dependent, which makes it challenging to recombinantly prepare selenoproteins with high Sec specificity. As a consequence, the function of half of human selenoproteins remains unclear, and Sec-based protein manipulation has been greatly hampered. Here we report a new general method enabling the site specific incorporation of Sec into proteins in E. coli. An orthogonal tRNAPyl ASecRS was evolved to specifically incorporate Se-allyl selenocysteine (ASec) in response to the amber codon, and the incorporated ASec was converted to Sec in high efficiency through palladium-mediated cleavage under mild conditions compatible with proteins and cells. This approach completely obviates the natural Sec-dedicated factors, thus allowing various selenoproteins, regardless of Sec position and species source, to be prepared with high Sec specificity and enzyme activity, as shown by the preparation of human thioredoxin and glutathione peroxidase 1. Sec-selective labeling in the presence of Cys was also demonstrated on the surface of live E. coli cells. The tRNAPyl-ASecRS pair was further used in mammalian cells to incorporate ASec, which was converted into Sec by palladium catalyst in cellulo. This robust and versatile method should greatly facilitate the study of diverse natural selenoproteins and the engineering of proteins in general via site-specific introduction of Sec. PMID- 29984992 TI - Differentiating Isomeric Deprotonated Glucuronide Drug Metabolites via Ion/Molecule Reactions in Tandem Mass Spectrometry. AB - Isomeric O- and N-glucuronides are common drug metabolites produced in phase II of drug metabolism. Distinguishing these isomers by using common analytical techniques has proven challenging. A tandem mass spectrometric method based on gas-phase ion/molecule reactions of deprotonated glucuronide drug metabolites with trichlorosilane (HSiCl3) in a linear quadrupole ion trap mass spectrometer is reported here to readily enable differentiation of the O- and N-isomers. The major product ion observed upon reactions of HSiCl3 with deprotonated N glucuronides is a diagnostic HSiCl3 adduct that has lost two HCl molecules ([M - H + HSiCl3 - 2HCl]-). This product ion was not observed for deprotonated O glucuronides. Reaction mechanisms were explored with quantum chemical calculations at the M06-2X/6-311++G(d,p) level of theory. PMID- 29984993 TI - Robust Succinonitrile-Based Gel Polymer Electrolyte for Lithium-Ion Batteries Withstanding Mechanical Folding and High Temperature. AB - Fabrication of a gel polymer electrolyte containing succinonitrile (GPE-SN) with high mechanical strength is quite challenging because the SN electrolyte always suppresses the formation of polymer networks during in situ polymerization. In this work, a mechanically robust GPE-SN was successfully prepared by using a solution immersion method. During fabrication, the paste-like SN electrolyte was transformed into a liquid SN electrolyte with low viscosity by heating at 50 degrees C and then infiltrated into the UV-cured highly cross-linked polyurethane acrylate (PUA) skeleton. The resulted GPE-SN film exhibits superior tensile strength (6.5 MPa) compared to the one (0.5 MPa) prepared by in situ polymerization (GPE-SN-IN). The high mechanical strength of the GPE-SN-IM film enables the LiCoO2/Li4Ti5O12 film battery to withstand 100-cycle folding without electrolyte damage and capacity loss. Besides, the GPE-SN presents a high ionic conductivity (1.63 * 10-3 S.cm-1 at 25 degrees C), which is comparable to GPE with a commercial liquid electrolyte (GPE-LE). Because of good thermal stability of the GPE-SN, the LiCoO2/Li cell with this electrolyte shows better charge discharge cycling stability than that with GPE-LE at high temperature (55 degrees C). Thus, the GPE-SN prepared by our method could be a promising polymer electrolyte offering better safety and reliability for lithium-ion batteries. PMID- 29984994 TI - Physical Properties of (Na1- xK x)NbO3 Thin Film Grown at Low Temperature Using Two-Dimensional Ca2Nb3O10 Nanosheet Seed Layer. AB - A monolayer Ca2Nb3O10 (CNO) nanosheet was deposited on a Pt/Ti/SiO2/Si substrate using the Langmuir-Blodgett method. This monolayer CNO nanosheet with a (001) surface termination was used as a seed layer to reduce the growth temperature of the crystalline (Na1- xK x)NbO3 (NKN) film. The crystalline NKN film was preferentially grown along the [001] direction at 400 degrees C. The ferroelectric and piezoelectric properties of this NKN film were influenced by the postannealing atmosphere due to the variations in the amounts of oxygen vacancies in the NKN film. The crystalline NKN film annealed at 300 degrees C under 50 Torr O2 atmosphere showed promising ferroelectric and piezoelectric properties; epsilonr of 303 and tan delta of 2.0% at 100 kHz, Ps of 15.3 MUC/cm2, Pr of 11.7 MUC/cm2, and Ec of 78 kV/cm, and d33 of 139 pm/V. This NKN film showed the lowest leakage current, which can be explained by the Schottky emission mechanism. The Schottky barrier heights of the Pt/NKN and NKN/CNO/Pt interfaces were calculated to be 0.97 and 0.28 eV, respectively. The results of this work suggest a new method to grow crystalline thin films at low temperatures by using metal-oxide nanosheets as the seed layer. PMID- 29984995 TI - Blue-Light Receptors for Optogenetics. AB - Sensory photoreceptors underpin light-dependent adaptations of organismal physiology, development, and behavior in nature. Adapted for optogenetics, sensory photoreceptors become genetically encoded actuators and reporters to enable the noninvasive, spatiotemporally accurate and reversible control by light of cellular processes. Rooted in a mechanistic understanding of natural photoreceptors, artificial photoreceptors with customized light-gated function have been engineered that greatly expand the scope of optogenetics beyond the original application of light-controlled ion flow. As we survey presently, UV/blue-light-sensitive photoreceptors have particularly allowed optogenetics to transcend its initial neuroscience applications by unlocking numerous additional cellular processes and parameters for optogenetic intervention, including gene expression, DNA recombination, subcellular localization, cytoskeleton dynamics, intracellular protein stability, signal transduction cascades, apoptosis, and enzyme activity. The engineering of novel photoreceptors benefits from powerful and reusable design strategies, most importantly light-dependent protein association and (un)folding reactions. Additionally, modified versions of these same sensory photoreceptors serve as fluorescent proteins and generators of singlet oxygen, thereby further enriching the optogenetic toolkit. The available and upcoming UV/blue-light-sensitive actuators and reporters enable the detailed and quantitative interrogation of cellular signal networks and processes in increasingly more precise and illuminating manners. PMID- 29984996 TI - High-Throughput Signal-On Photoelectrochemical Immunoassay of Lysozyme Based on Hole-Trapping Triggered by Disintegrating Bioconjugates of Dopamine-Grafted Silica Nanospheres. AB - A unique split-type photoelectrochemical (PEC) immunoassay has been constructed for detection of low-abundance biocompounds (lysozyme, Lyz, used in this case) via a new trigger strategy by disintegrating bioconjugates of dopamine-grafted silica nanospheres (DA@SiO2NSs) for signal amplification. The preferred electron donor assembly of DA@SiO2NSs is first used as a molecular printboard for positioning anti-Lyz secondary antibody (Ab2) through an amide reaction. With specific immunoreactions in a high-binding microplate, a sandwich immunoassay, the DA@SiO2NSs-based bioconjugate is achieved. By initiating the disintegration of the bioconjugates via acid etching, numerous electron donors of DA are released, thus efficiently triggering hole-trapping with amplified signals obtained. The smart integration of ZnIn2S4-based heterojunctions as photoactive material, a split-type detection mode, and a new trigger strategy by disintegrating the DA@SiO2NSs-based bioconjugate offer an attractive high throughput signal-on PEC immunoassay for detection of Lyz. Such an unusual PEC sensor exhibits an outstanding linear response to the concentration in the range between 0.002 and 500 ng mL-1, and the detection limit is as low as 0.6 ppt ( S/ N = 3). The as-fabricated assay is cost-effective and sensitive. It has been successfully used for measuring Lyz in real samples, which demonstrates great promise for practical applications. PMID- 29984997 TI - Analysis of Fluorescence Spectra of Citrus Polymethoxylated Flavones and Their Incorporation into Mammalian Cells. AB - Citrus polymethoxylated flavones (PMFs) influence biochemical cascades in human diseases, yet little is known about how these compounds interact with cells and how these associations influence the actions of these compounds. An innate attribute of PMFs is their ultraviolet-light-induced fluorescence, and the fluorescence spectra of 14 PMFs and 7 PMF metabolites were measured in methanol. These spectra were shown to be strongly influenced by the compounds' hydroxy and methoxy substituents. For a subset of these compounds, the fluorescence spectra were measured when bound to human carcinoma Huh7.5 cells. Emission-wavelength maxima of PMF metabolites with free hydroxyl substituents exhibited 70-80 nm red shifts when bound to the Huh7.5 cells. Notable solvent effects of water were observed for nearly all these compounds, and these influences likely reflect the effects of localized microenvironments on the resonance structures of these compounds when bound to human cells. PMID- 29984999 TI - Application of the DP4 Probability Method to Flexible Cyclic Peptides with Multiple Independent Stereocenters: The True Structure of Cyclocinamide A. AB - A DP4 protocol has been successfully utilized to establish the true structure of the natural product cyclocinamide A, a flexible cyclic peptide with four isolated stereocenters. Benchmarking the necessary level of theory required to successfully predict the NMR spectra of three previously synthesized isomers of cyclocinamide A led to the prediction of the natural stereochemistry as 4 S, 7 R, 11 R, 14 S, which has been confirmed by total synthesis. PMID- 29984998 TI - Low-Protein Diets Decrease Porcine Nitrogen Excretion but with Restrictive Effects on Amino Acid Utilization. AB - Reducing dietary crude protein (CP) intake effectively decreases nitrogen excretion in growing-finishing pigs but at the expense of poor growth when dietary CP content is reduced by >=3%. In this study, we investigated the main disadvantages of low-protein diets supplemented with lysine, methionine, threonine, and tryptophan in pigs. First, changes in the nitrogen balance in response to differences in dietary CP content (18%, 15%, and 13.5%) were investigated in barrows (40 kg). Then, barrows (40 kg) surgically fitted with catheters in the mesenteric vein, portal vein, hepatic vein, and carotid artery were used to investigate changes in amino acid (AA) metabolism in the portal drained viscera and liver in response to differences in dietary CP content. The results showed that low-protein diets reduced fecal and urinary nitrogen excretion ( P < 0.05) meanwhile resulted in significant decreases in nitrogen retention ( P < 0.05). Moreover, a reduction in the dietary CP content from 18% to 13.5% resulted in decreases in the net portal fluxes of NH3, glycine, and alanine as well as in the urea production in the liver ( P < 0.05), whereas their values as a percentage of nitrogen intake did not decline ( P > 0.05). The net portal fluxes of nonessential AA (NEAA) were reduced in the low-protein diet groups ( P < 0.05), while essential AA consumption in the liver increased ( P < 0.05). Thus, low-protein diets result in reductions in both nitrogen excretion and retention, and NEAA deficiency may be a major disadvantage of low-protein diets. PMID- 29985001 TI - gamma-Iron Phase Stabilized at Room Temperature by Thermally Processed Graphene Oxide. AB - Stabilizing nanoparticles on surfaces, such as graphene, is a growing field of research. Thereby, iron particle stabilization on carbon materials is attractive and finds applications in charge-storage devices, catalysis, and others. In this work, we describe the discovery of iron nanoparticles with the face-centered cubic structure that was postulated not to exist at ambient conditions. In bulk, the gamma-iron phase is formed only above 917 degrees C, and transforms back to the thermodynamically favored alpha-phase upon cooling. Here, with X-ray diffraction and Mossbauer spectroscopy we unambiguously demonstrate the unexpected room-temperature stability of the gamma-phase of iron in the form of the austenitic nanoparticles with low carbon content from 0.60% through 0.93%. The nanoparticles have controllable diameter range from 30 nm through 200 nm. They are stabilized by a layer of Fe/C solid solution on the surface, serving as the buffer controlling carbon content in the core, and by a few-layer graphene as an outermost shell. PMID- 29985000 TI - Coupled Quantum Dots in Bilayer Graphene. AB - Electrostatic confinement of charge carriers in bilayer graphene provides a unique platform for carbon-based spin, charge, or exchange qubits. By exploiting the possibility to induce a band gap with electrostatic gating, we form a versatile and widely tunable multiquantum dot system. We demonstrate the formation of single, double and triple quantum dots that are free of any sign of disorder. In bilayer graphene, we have the possibility to form tunnel barriers using different mechanisms. We can exploit the ambipolar nature of bilayer graphene where pn-junctions form natural tunnel barriers. Alternatively, we can use gates to form tunnel barriers, where we can vary the tunnel coupling by more than 2 orders of magnitude tuning between a deeply Coulomb blockaded system and a Fabry-Perot-like cavity. Demonstrating such tunability is an important step toward graphene-based quantum computation. PMID- 29985002 TI - Bimodal Glycosyl Donors Protected by 2- O-( ortho-Tosylamido)benzyl Group. AB - A glucosyl donor equipped with C2- o-TsNHbenzyl ether was shown to provide both alpha- and beta-glycosides stereoselectivity, by changing the reaction conditions. Namely, beta-glycosides were selectively obtained when the trichloroacetimidate was activated by Tf2NH. On the other hand, activation by TfOH in Et2O provided alpha-glycosides as major products. This "single donor" approach was employed to assemble naturally occurring trisaccharide alpha-d-Glc (1->2)-alpha-d-Glc-(1->6)-d-Glc and its anomers. PMID- 29985003 TI - Copper-Catalyzed Difunctionalization of Allenes with Sulfonyl Iodides Leading to ( E)-alpha-Iodomethyl Vinylsulfones. AB - A highly regioselective iodosulfonylation of allenes in the presence of CuI and 1,10-phenanthroline has been developed for the synthesis of various useful ( E) alpha-iodomethyl vinylsulfones in moderate to excellent yields. This practical reaction is fast, operationally simple, and in particular, proceeds under very mild conditions to afford the target products with high regio- and stereoselectivity. The selectivity was illustrated by a conceptual DFT analysis. PMID- 29985004 TI - Spectral Filtering as a Tool for Two-Dimensional Spectroscopy: A Theoretical Model. AB - Two-dimensional optical spectroscopy is a powerful technique for the probing of coherent quantum superpositions. Recently, the finite width of the laser spectrum has been employed to selectively tune experiments for the study of particular coherences. This involves the exclusion of certain transition frequencies, which results in the elimination of specific Liouville pathways. The rigorous analysis of such experiments requires the use of ever more sophisticated theoretical models for the optical spectroscopy of electronic and vibronic systems. Here we develop a nonimpulsive and non-Markovian model, which combines an explicit definition of the laser spectrum, via the equation of motion-phase matching approach (EOM-PMA), with the hierarchical equations of motion (HEOM). This theoretical framework is capable of simulating the 2D spectroscopy of vibronic systems with low frequency modes, coupled to environments of intermediate and slower time scales. In order to demonstrate the spectral filtering of vibronic coherences, we examine the elimination of lower energy peaks from the 2D spectra of a zinc porphyrin monomer upon blue-shifting the laser spectrum. The filtering of Liouville pathways is revealed through the disappearance of peaks from the amplitude spectra for a coupled vibrational mode. PMID- 29985005 TI - Soybean-Derived Glycine-Arginine Dipeptide Administration Promotes Neurotrophic Factor Expression in the Mouse Brain. AB - Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays an important role in cognitive abilities, including memory and learning. We demonstrated that soybean protein hydrolysate (SPH) diet suppresses age-related cognitive decline via the upregulation of BDNF in a mouse model of senescence. Our purpose was to identify novel bioactive peptides in SPH, which enhance BDNF expression. We treated mouse primary astrocytes with SPH as well as with its positively charged chromatographic fraction. Significant increases in the expression of BDNF were observed in the treatment with positively charged fraction of SPH. Among the synthesized peptides, the dipeptide glycine-arginine (GR) increased BDNF expression in vitro, and LC-TOF-MS analysis showed the presence of GR in the SPH. Furthermore, its administration in vivo increased the expression of BDNF in the cerebral cortex and the number of neurons in hippocampus and cerebral cortex. These data indicate that GR might promote neurogenesis by upregulating BDNF levels. PMID- 29985006 TI - Photoexcited Small Polaron Formation in Goethite (alpha-FeOOH) Nanorods Probed by Transient Extreme Ultraviolet Spectroscopy. AB - Small polaron formation limits the mobility and lifetimes of photoexcited carriers in metal oxides. As the ligand field strength increases, the carrier mobility decreases, but the effect on the photoexcited small polaron formation is still unknown. Extreme ultraviolet transient absorption spectroscopy is employed to measure small polaron formation rates and probabilities in goethite (alpha FeOOH) crystalline nanorods at pump photon energies from 2.2 to 3.1 eV. The measured polaron formation time increases with excitation photon energy from 70 +/- 10 fs at 2.2 eV to 350 +/- 30 fs at 2.6 eV, whereas the polaron formation probability (85 +/- 10%) remains constant. By comparison to hematite (alpha Fe2O3), an oxide analogue, the role of ligand composition and metal center density in small polaron formation time is discussed. This work suggests that incorporating small changes in ligands and crystal structure could enable the control of photoexcited small polaron formation in metal oxides. PMID- 29985008 TI - Inactivation of the cerebellar fastigial nuclei alters social behavior in the rat. AB - Research has implicated the deep cerebellar nuclei in autism. This study questioned whether fastigial nuclei abnormalities account for some of the irregular social behaviors seen in autism. Bilateral cannulation surgery was performed on 13 rats. An ABABAB reversal design was implemented. All animals received a microinfusion of saline during the baseline (A) phases. The experimental animal was placed in an open field with an unfamiliar confederate animal, and social interactions between the two animals were measured for 10 min. Seven animals received microinfusions of bupivacaine during the treatment phases (B), which temporarily inactivated the fastigial nuclei. Six control animals received saline again, and social interaction was retested. This sequence was executed 3 times over 6 days to achieve an ABABAB reversal design. Because the cerebellum is involved in motor behavior, the animals' locomotion was analyzed to ensure results were not because of locomotor deficits. A gait analysis and distance traveled in the open field were used to measure locomotion. No differences were found in locomotor behavior. Results of the social interaction analyses indicate animals with inactivated fastigial nuclei engage in less intense social interactions and engage in more behaviors to prevent social interaction. Knowledge that the fastigial nuclei mediate social interaction can further the understanding of pathology in the autistic brain and lead to breakthrough treatments. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29985007 TI - Noradrenergic receptor modulation influences the acoustic parameters of pro social rat ultrasonic vocalizations. AB - Rats produce high rates of ultrasonic vocalizations (USVs) in social situations; these vocalizations are influenced by multiple neurotransmitter systems. Norepinephrine (NE) plays a significant role in vocalization biology; however, the contribution of NE to normal, prosocial vocal control has not been well established in the rat. To address this, we used NE adrenoceptor agonists (Cirazoline, Clonidine) and antagonists (Prozasin, Atipamezole, Propranolol) to quantify the contribution of specific alpha-1, alpha-2, and beta NE receptors to USV parameters in male Long Evans rats during seminaturalistic calling. We found that multiple USV acoustic variables (intensity, bandwidth, duration, peak frequency, and call profile) are modified by alterations in NE signaling. Very generally, agents that increased NE neurotransmission (Atipamezole) or activated alpha-1 receptors (Cirazoline), led to an increase in intensity and duration, respectively. Agents that decreased NE neurotransmission (Clonidine) or blocked alpha-1 receptors (Prazosin) reduced call rate, intensity, and bandwidth. However, the beta-receptor antagonist, Propranolol, was associated with increased call rate, duration, and intensity. Limb motor behaviors were largely unaffected by any drug, with the exception of Clonidine. Higher doses of Clonidine significantly reduced gross motor, grooming, and feeding behavior. These results confirm the involvement of NE transmission in vocal control in the rat, and suggest that this USV model is useful for studying the neuropharmacology of behavioral measures that may have implications for disease states, such as Parkinson's disease. (PsycINFO Database Record PMID- 29985009 TI - N-acetylcysteine blocks serotonin 1B agonist-induced OCD-related behavior in mice. AB - Glutamate-modulating agents are of increasing interest in obsessive-compulsive disorder (OCD). Current pharmacotherapies for OCD target the serotonin and dopamine systems, and are limited in efficacy. N-acetylcysteine (NAC) is an over the-counter amino acid supplement that inhibits glutamate neurotransmission and has been shown in preliminary studies to reduce symptoms in OCD and related compulsive disorders. Despite growing interest in NAC as a novel psychiatric medication, no studies currently exist examining the effects of NAC in animal models of compulsive disorders. Here, we investigate NAC in a well-validated mouse model of OCD that is predictive of treatment efficacy as well as the time course for therapeutic onset of OCD medications. NAC (60 mg/kg/day or 120 mg/kg/day) was administered via the drinking water of mice for 3 weeks prior to behavioral testing. Mice were tested in the delayed alternation task (DAT) and open field test following acute serotonin 1B receptor (5-HT1B) agonist challenge to induce OCD-related behavior. We found that both doses of NAC blocked 5-HT1B agonist-induced deficits on the DAT. In a separate study, we administered NAC (60 mg/kg/day) for 1 week or 3 weeks in the drinking water of mice prior to examining OCD-related behavior. We found that blockade of 5-HT1B agonist-induced OCD-like behavior is present at 3 weeks, but not 1 week, of NAC treatment. Together, our findings suggest that NAC is a novel OCD treatment with potential utility as monotherapy and therapeutic effects that emerge on a time-course similar to established medications. (PsycINFO Database Record PMID- 29985010 TI - When emotions run high: A critical role for context in the unfolding of dynamic, real-life facial affect. AB - Although positive and negative affect are assumed to be highly distinct, recent work has shown that facial valence of positive and negative situations may be highly confusable, especially when the emotions are intense. However, previous work has relied exclusively on static images, portraying a single peak frame of the emotional display. Dynamic expressions, on the other hand, convey a far broader representation of the emotional reaction, but are they diagnostic of the situational valence? Participants (N = 245) watched videos portraying reactions to real-life highly positive situations and evaluated the affective valence of the target. Video information was controlled by: (a) truncating the movies after 5, 10, or 20 seconds from the start, and by (b) digitally manipulating the videos such that only the face was visible with no context, only the context was visible with no face, or the face appeared in context. Results indicate that during real life intense positive situations, facial expressions alone were rated as negative and failed to convey diagnostic information about the positive situational valence even at the most extended presentation durations. By contrast, when contextual information appeared alone or with the face, participants accurately rated the target as feeling positive, and this positivity increased with extended viewing duration. These findings suggests poor coupling between facial valence and felt emotions, supporting the notion that when emotions run high, the diagnostic power of facial expressions is reduced. Conversely, the findings demonstrate an inherent role for contextual information in the recognition of real-life intense faces. (PsycINFO Database Record PMID- 29985011 TI - Perceived reciprocity and relationship satisfaction: Age and relationship category matter. AB - Past work suggests that perceived reciprocity in social relationships declines with age. Although positive associations between perceived reciprocity and relationship satisfaction have been documented, relationship satisfaction seems to remain relatively stable over the life-span. Addressing this seemingly contradictory pattern of findings, we predicted that perceived reciprocity may become less important to relationship satisfaction with age and that this association differs across various relationship categories (i.e., spousal, communal, and exchange relationships). We tested these predictions applying multilevel models to cross-sectional and longitudinal data of middle-aged and older adults from the Interdisciplinary Longitudinal Study of Aging (ILSE). Consistent with past work, perceived reciprocity was lower in older than middle aged adults and declined over time, while relationship satisfaction did not differ between age groups and increased over time. Inconsistent with our prediction, the association between perceived reciprocity and relationship satisfaction was stronger in older than middle-aged adults in our cross-sectional analyses. By contrast, the longitudinal analyses that were based on only older adults were consistent with our prediction: the association between perceived reciprocity and relationship satisfaction decreased over time. Additionally, the association between perceived reciprocity and relationship satisfaction differed between relationship categories, being particularly strong in spousal relationships and less in communal and exchange relationships. In general, our results suggest that both, age and relationship category, need to be considered when investigating perceived reciprocity and relationship satisfaction from an adult life-span perspective. (PsycINFO Database Record PMID- 29985012 TI - Perceived control and cognition in adulthood: The mediating role of physical activity. AB - The cognitive benefits of a greater sense of control are well-established; however, only recently have the mechanisms involved in this relationship been explored. Because of its well-established cognitive benefits and positive relationship to perceived control, physical activity has been suggested as a potential mediator. However, with age, not only does cognition tend to decline, but so does one's perception of control and their level of physical activity. Therefore, it is important to understand the relationship between these variables from a life span perspective. The goal of the current study was to expand on past work that investigated physical activity as a mediator between perceived control and change in cognition across 4 years to a multi-decade perspective that examines these variables as they change from midlife to older adulthood. To do so, we used longitudinal data across 20 years from the Midlife in the United States Study. Our results show that perceiving more control over one's life predicted less decline in cognition 20 years later, and this relationship was mediated by an increase in physical activity. We consider limitations and future directions to further our understanding of the role of physical activity in the relationship between perceived control and cognitive aging. (PsycINFO Database Record PMID- 29985013 TI - Contrast sensitivity indicates processing level of visual illusions. AB - A nearly linear contrast response function (CRF) is found in the lower level striate cortex whereas a steep, nonlinear increase at lower contrasts that gradually increases toward response saturation for higher contrasts is found in the higher level extrastriate cortex. This change of CRFs along the ventral cortical pathway indicates a shift from stimulus- and energy-dependent coding at lower levels to percept- and information-dependent coding at higher levels. The increase of nonlinearity at higher levels optimizes the extraction of perceptual information by amplifying responses to the ubiquitous low-contrast inputs in the environment. We used this difference of CRFs between lower and higher levels, particularly at lower contrasts (.0 to .30), as a tool to investigate examples of 2 lower level (simultaneous brightness and simultaneous tilt) and 2 higher level (Poggendorff and Ponzo) illusions. As predicted, the Poggendorff and Ponzo illusions yielded strong nonlinear increases in their CRFs compared to the more linear functions found for the simultaneous-brightness and simultaneous-tilt illusions. We conclude that the Poggendorff-Ponzo illusions rely more heavily on high-level, percept-dependent cortical processing than do the simultaneous brightness-simultaneous-tilt illusions and, more generally, that differences between contrast-dependent changes may be a useful tool in determining the relative level of cortical processing of many other visual effects. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29985014 TI - Empowering individuals with psychiatric disabilities to work: Results of a randomized trial. AB - OBJECTIVE: Supported employment has experienced immense growth as an evidence based intervention targeting the disproportionately high rates of unemployment among individuals with psychiatric disabilities who actively want to work. However, employment services are often not available to individuals who are ambivalent about work or lack work self-efficacy. The purpose of this study was to pilot-test the efficacy of a new peer-run photography-based group intervention (Vocational Empowerment Photovoice [VEP]) designed to empower individuals with psychiatric disabilities to consider employment services and pursue work. METHOD: A total of 51 individuals with serious mental illnesses enrolled at a university based recovery center, who were not employed or enrolled in any vocational services, were randomly assigned to the VEP program or to a wait-list control group. Mixed-effects regression models were used to examine the impact of the VEP program on both extrinsic (enrollment in employment services and employment rates) and intrinsic (work hope, motivation and self-efficacy, vocational identity, overall empowerment and internalized stigma) work-related outcomes. RESULTS: Participation in the VEP program was associated with a significantly higher rate of engagement in employment services over the course of the intervention and with significantly higher overall empowerment and decrease of internalized stigma sustained through the 3-month follow-up assessment. Stronger engagement in the VEP program was associated with increased work hope, self efficacy and sense of vocational identity. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The study highlights the malleable nature of defeatist beliefs which prevent many individuals with mental illnesses from pursuing employment services despite their inherent interest in working. (PsycINFO Database Record PMID- 29985015 TI - Subtle ways of stigmatization among professionals: The subjective experience of consumers and their family members. AB - OBJECTIVE: Subtle expressions of stigmata or microaggressions consist of insensitive and demeaning remarks or statements which negate an individual's perception of their reality. They are differentiated from more traditional and overt forms of discrimination in that they are often voiced by well-intentioned individuals who are unaware of the negative underpinnings and potentially harmful effects of their comments. This study aimed to explore the subjective experience of stigma and macroaggression among consumers and their family members during their encounters with mental health care providers. METHOD: Sixteen individuals who were recently diagnosed with schizophrenia spectrum disorders and 15 of their family members were interviewed. The interviews were recorded, transcribed verbatim, and analyzed using grounded theory. RESULTS: Three major forms of subtle stigma expressions or microaggressions were identified: that lived experience is not relevant, people diagnosed with a psychosis have no hope for recovery, and sharing and discussing professional knowledge is not necessary. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Encounters with mental health care providers include subtle conveyance of stigmatizing messages that are well recognized as a barrier to recovery. Psychoeducational interventions for staff that emphasize the importance of lived experience and sharing professional knowledge are recommended, as well as further studying the subtle ways of stigmatization among staff. (PsycINFO Database Record PMID- 29985016 TI - Asymmetrical distractibility of global and focal visuospatial attention during segmental and total compound line bisections. AB - BACKGROUND/OBJECTIVES: Compound horizontal lines are composed of 2 segments of unequal length and width. Line bisection requires that the participants attend to the entire line (global attention). The longer segment often distracts participants, suggesting that attention directed to this segment (focal attention) disrupts the allocation of global attention. This study attempted to learn whether the allocation of focal attention to a line segment is distracted by global attention allocated to the entire line and whether there are right-left distraction asymmetries when allocating focal or global attention. METHOD: Twenty four healthy adults (12 > 65 years old) attempted to bisect horizontal lines composed of 2 segments of unequal length, with the larger segment placed to the right or left. They were also asked to bisect the longer segment of these lines. RESULTS: When allocating focal attention to the larger segment, healthy participants were more distracted when the smaller segment was on the left than on the right. In contrast, when attempting to allocate global attention to the entire line, participants were more distracted when the larger segment was on the right side. There were no significant differences between older and younger participants. CONCLUSIONS: The asymmetrical global distraction during segment bisection might be related to the right hemisphere's dominance in mediating global attention and allocating attention leftward. In contrast, the asymmetrical focal distraction during full-line bisection might be related to the left hemisphere's dominance in mediating focal attention and allocating attention toward the right. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29985017 TI - Occupational cognitive complexity in earlier adulthood is associated with brain structure and cognitive health in midlife: The CARDIA study. AB - OBJECTIVE: In line with cognitive reserve theory, higher occupational cognitive complexity is associated with reduced cognitive decline in older adulthood. How and when occupational cognitive complexity first exerts protective effects during the life span remains unclear. We investigated associations between occupational cognitive complexity during early to midadulthood and brain structure and cognition in midlife. METHOD: Participants were 669 adults from the Coronary Artery Risk Development in Young Adults study (aged 18-30 years at baseline, 52% female, 38% Black). We calculated scores reflecting occupational cognitive complexity using Census Occupation Codes (years 10 and 15) and Occupational Information Network (O*NET) data. At year 25, participants had structural brain magnetic resonance imaging, diffusion tensor imaging, and cognitive testing (Rey Auditory Verbal Learning Test, Digit Symbol Substitution Test, Stroop). In adjusted mixed models, we examined associations between occupational cognitive complexity during early to midadulthood and midlife brain structure, specifically gray matter volume and white matter fractional anisotropy, and cognition in midlife (all outcomes converted to z-scores). RESULTS: Higher occupational cognitive complexity was associated with greater white matter fractional anisotropy (estimate = 0.10, p = .01) but not gray matter volume. Higher occupational cognitive complexity was associated with better Digit Symbol Substitution Test (estimate = 0.13, p < .001) and Stroop (estimate = 0.09, p = .01) performance but not Rey Auditory Verbal Learning Test performance. CONCLUSIONS: Occupational cognitive complexity earlier in adulthood is associated with better white matter integrity, processing speed, and executive function in midlife. These associations may capture how occupational cognitive complexity contributes to cognitive reserve. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29985018 TI - Moderation of alcohol craving reactivity to drinking-related contexts by individual differences in alcohol sensitivity: An ecological investigation. AB - Laboratory cue exposure investigations have demonstrated that, relative to drinkers who report a high sensitivity to the pharmacologic effects of alcohol, low-sensitivity (LS) drinkers show exaggerated neurocognitive and behavioral reactivity to alcohol-related stimuli. The current study extends this line of work by testing whether LS drinkers report stronger cravings for alcohol in daily life. Data were from an ecological momentary assessment study in which participants (N = 403 frequent drinkers) carried a palmtop computer for 21 days and responded to questions regarding drinking behavior, alcohol craving, mood states, and situational context. Initial analyses identified subjective states (positive and negative mood, cigarette craving) and contextual factors (bar restaurant location, weekend, time of day, presence of friend, recent smoking) associated with elevated craving states during nondrinking moments. Effects for nearly all these craving correlates were moderated by individual differences in alcohol sensitivity, such that the associations between situational factors and current alcohol craving were larger among LS individuals (as determined by a questionnaire completed at baseline). Complementary idiographic analyses indicated that self-reported craving increased when the constellation of situational factors more closely resembled individuals' observed drinking situations. Again, this effect was moderated by alcohol sensitivity, with greater craving response increases among LS drinkers. The findings align with predictions generated from theory and laboratory cue exposure investigations and should encourage further study of craving and incentive processes in LS drinkers. (PsycINFO Database Record PMID- 29985021 TI - Memory guides the processing of event changes for older and younger adults. AB - Memory for related past experiences can guide current perceptions. However, memory can lead one astray if situational features have changed. Thus, to adaptively use memory to guide perception, one needs to retrieve relevant memories and also to register differences between remembered and current events. Event Memory Retrieval and Comparison Theory proposes that observers associatively activate memories of related previous episodes, and that this guides their ongoing perception. Conflicts between previous and current event features can hurt immediate performance, but if changes are registered and encoded they can lead to highly effective encoding of the prior event, current event, and their relationship. Disruption of these mechanisms could play a role in older adults' greater susceptibility to event memory interference. Two experiments tested these hypotheses by asking participants to watch movies depicting two fictive days of an actor. Some activities were repeated across days, others were repeated with a changed feature (e.g., waking up to an alarm clock or a phone alarm), and others were performed only on Day 2. One week after watching the Day 2 movie, participants completed a cued-recall test. Changes that participants detected but did not remember led to proactive interference in recall, but changes that were successfully detected and remembered led to facilitation. Younger adults detected and remembered more changes than older adults, which partly explained older adults' differential memory deficit for changed activities. These findings suggest a role for episodic reminding in event perception and a potential source of age differences in event memory. (PsycINFO Database Record PMID- 29985020 TI - Lessons learned: Young children's use of generic-you to make meaning from negative experiences. AB - Learning from negative experiences is an essential challenge of childhood. How do children derive meaning from such events? For adults, one way is to move beyond the specifics of a situation by framing it as exemplifying a more general phenomenon. Here we examine whether children are able to make meaning in this way through their use of generic-you, a linguistic device in which people shift from the here and now to refer to people in general. Participants (N = 89, aged 4-10 years) listened to 2 stories depicting common conflicts and were asked to discuss what lessons the character could learn (Lessons Learned condition) and how the character felt (Relive condition). In the Lessons Learned condition, children were more likely to produce generic-you than in the Relive condition. These findings suggest that young children can make meaning from negative experiences by transcending the immediate context of an event to cast it as normative and general. (PsycINFO Database Record PMID- 29985019 TI - Tension reduction and affect regulation: An examination of mood indices on drinking and non-drinking days among university student drinkers. AB - Several theories posit problematic alcohol use develops through mechanisms of positive and negative reinforcement. However, the literature on these mechanisms remains inconsistent. This may be due to a number of issues including a failure to disaggregate negative mood or a failure to account for mood functioning (i.e., stability in mood). Alternatively, there may be differences in typical postdrinking/evening mood on drinking and nondrinking days, however, this has yet to be fully explored. We examined multiple indices of distinct mood states prior to and after typical drinking onset times on drinking and nondrinking days using ecological momentary assessment. College student drinkers (n = 102) carried personal data devices for 15 days. They reported on mood and alcohol use several times per day. Tonic positive mood was higher on drinking days than nondrinking days prior to typical drinking initiation. After typical drinking times, positive mood was higher on drinking days than nondrinking days. Similarly, negative moods (anxiety, stress, anger, and stress instability) indicated a pattern of lower levels relative to both predrinking mood on drinking days, and matched mood time points on nondrinking days; though, not all of these differences were statistically different. Results suggest positive and negative reinforcing mechanisms may be at play-though the negative reinforcement effects may manifest through subjectively "better" mood on drinking versus nondrinking days. (PsycINFO Database Record PMID- 29985022 TI - Cognitive ability and math computation developmental relations with math problem solving: An integrated, multigroup approach. AB - Individual differences in Cattell-Horn-Carroll (CHC) cognitive abilities are related to individual differences in math problem solving. However, it is less clear whether cognitive abilities are associated with math problem solving directly or indirectly via math component skills and whether these relations differ across grade levels. We used multigroup structural equation models to examine direct and indirect CHC-based cognitive ability relations with math problem solving across six grade-level groups using the Kaufman Assessment Battery for Children, Second Edition and the Kaufman Tests of Educational Achievement, Second Edition co-normed standardization sample data (N = 2,117). After testing factorial invariance of the cognitive constructs across grade levels, we assessed whether the main findings were similar across higher-order and bifactor models. In the higher-order model, the Crystallized Ability, Visual Processing, and Short-Term Memory constucts had direct and indirect relations with math problem solving, whereas the Learning Efficiency and Retrieval Fluency constructs had only indirect relations with math problem solving via math computation. The integrated cognitive ability and math achievement relations were generally consistent across the CHC models of intelligence. In the higher-order model, the g factor operated indirectly on math computation and math problem solving, whereas in the bifactor model, the first-order G factor had direct relations with math computation and math problem solving. In both models, g/G was the most consistent and largest cognitive predictor of math skills. Last, the relation of math computation with math problem solving increased as grade level increased. Theoretical implications for math development and considerations for school psychologists are discussed. (PsycINFO Database Record PMID- 29985023 TI - "Why and when workplace ostracism inhibits organizational citizenship behaviors: An organizational identification perspective: Correction to Wu et al. (2016). AB - Reports an error in "Why and when workplace ostracism inhibits organizational citizenship behaviors: An organizational identification perspective" by Chia-Huei Wu, Jun Liu, Ho Kwong Kwan and Cynthia Lee (Journal of Applied Psychology, 2016[Mar], Vol 101[3], 362-378). In the article, the authors incorrectly reported that they measured job mobility using three items from Tepper (2000) in the Measures section of Study 1. The section for job mobility should read: "We measured job mobility using two items from Tepper (2000) and one item added by the authors. A sample item from Tepper (2000) was: 'I would have no problem finding an acceptable job if I quit.' The added item was: 'If I went out to find a job, many companies would consider giving me offers with a similar or higher salary.' Cronbach's alpha was .80." (The following abstract of the original article appeared in record 2015-49213-001.) Why and when do employees respond to workplace ostracism by withholding their engagement in citizenship behavior? Beyond perspectives proposed in past studies, we offer a new account based on a social identity perspective and propose that workplace ostracism decreases citizenship behavior by undermining employees' identification with the organization. We also theorize that perceived job mobility influences the extent to which employees identify with the organization when being ostracized. These hypotheses were examined in two time-lagged studies conducted in China. The proposed hypotheses were supported by results in Study 1, and findings were generally replicated in Study 2, where effects of other known mediators (i.e., organization-based self-esteem, job engagement, and felt obligation toward the organization) and moderators (i.e., collectivism, power distance, and future orientation) suggested by previous perspectives were controlled. Results of Study 2 provided further support of the hypothesized directional effect of workplace ostracism on citizenship behavior via organizational identification. Our studies support the identification perspective in understanding workplace ostracism and also strengthen the application of this perspective in understanding workplace aggression broadly. (PsycINFO Database Record PMID- 29985024 TI - Issues in solving the problem of effect size heterogeneity in meta-analytic structural equation modeling: A commentary and simulation study on Yu, Downes, Carter, and O'Boyle (2016). AB - Meta-analytic structural equation modeling (MASEM) is becoming increasingly popular for testing theoretical models from a pool of correlation matrices in management and organizational studies. One limitation of the conventional MASEM approaches is that the proposed structural equation models are only tested on the average correlation matrix. It remains unclear how far the proposed models can be generalized to other populations when the correlation matrices are heterogeneous. Recently, Yu, Downes, Carter, and O'Boyle (2016) proposed a full-information MASEM approach to address this limitation by fitting structural equation models from the correlation matrices generated from a parametric bootstrap. However, their approach suffers from several conceptual issues and technical errors. In this study, we reran some of the simulations in Yu et al. by correcting all of the errors in their original studies. The findings showed that bootstrap credible intervals (CVs) work reasonably well, whereas test statistics and goodness-of-fit indices do not. We advise researchers on what they can and cannot achieve by applying the full-information MASEM approach. We recommend fitting MASEM with the two-stage structural equation modeling approach, which works well for the simulation studies. If researchers want to inspect the heterogeneity of the parameters, they may use the bootstrap CVs from the full-information MASEM approach. All of these analyses were implemented in the open-source R statistical platform; researchers can easily apply and verify the findings. This article concludes with several future directions to address the issue of heterogeneity in MASEM. (PsycINFO Database Record PMID- 29985025 TI - The heterogeneity problem in meta-analytic structural equation modeling (MASEM) revisited: A reply to Cheung. AB - Yu, Downes, Carter, and O'Boyle (2016) introduce a new technique to incorporate effect size heterogeneity into meta-analytic structural equation modeling (MASEM) labeled full information meta-analytical structural equation modeling (FIMASEM). Cheung's (2018) commentary raises concerns about the viability of FIMASEM and provides its initial validation. In this reply, we briefly respond to those concerns noting how they relate to Yu et al.'s original conclusions, general MASEM practices, and operational decisions within the FIMASEM procedure. We synthesize Cheung's criticisms and build on his findings to lay out a research agenda for the future of MASEM and the role that our technique might play in it. In doing so, we clarify the conceptual nature of FIMASEM, identity inferential mistakes that current MASEM studies are likely to make, and offer specific and actionable recommendations in terms of the types of research questions FIMASEM is best suited to address and how FIMASEM results can best be interpreted and reported. (PsycINFO Database Record PMID- 29985026 TI - Auditory cues influence the rubber-hand illusion. AB - The perception of one's own body depends on the dynamic integration of signals from different sensory modalities. Earlier studies have shown that visual, tactile, and proprioceptive information contributes to this process. However, little is known about the role of auditory cues in the multisensory integration of bodily signals. To address this issue, we studied the effect of auditory feedback on the rubber-hand illusion and the somatic version of this illusion. In each experiment, we tested 30 healthy participants using four different conditions: synchronous touches without auditory cues (original illusion), asynchronous touches without auditory cues (original control), synchronous touches with synchronous auditory cues (illusion positively modulated by sound), and synchronous touches with asynchronous auditory cues (illusion negatively modulated by sound). For the classic rubber-hand illusion, we found that synchronous auditory cues made the illusion stronger compared with asynchronous auditory cues, as evidenced by both the results of the questionnaires and proprioceptive drift. In both versions of the illusion, proprioceptive drift indicated that the synchronous auditory cues enhanced the illusion compared with the condition without auditory feedback and that the asynchronous auditory cues reduced the illusion compared with the nonauditory condition. Taken together, these results demonstrate that auditory cues modulate the rubber-hand illusion, which suggests that auditory information is used in the formation of the coherent multisensory representation of one's own body. (PsycINFO Database Record PMID- 29985027 TI - In defense of limited-processing-capacity models for encoding into visual short term memory: Comment on Sewell, Lilburn, and Smith (2014). AB - Despite claims to the contrary, experimental results by Sewell, Lilburn, and Smith (2014) appear to be consistent with limited-processing-capacity models for encoding into visual short-term memory. (PsycINFO Database Record PMID- 29985028 TI - Limitations of pure encoding capacity accounts of visual short-term memory phenomena: Reply to Bundesen (2018). AB - In his commentary, Bundesen (2018) argued that limited encoding capacity can account for the near-equivalent set size effects on performance under conditions of simultaneous and sequential presentation reported by Sewell, Lilburn, and Smith (2014). While we agree that limited encoding capacity could, in principle, account for this equivalency, we argue that such an account rests on a number of fortuitous temporal coincidences. In particular, we note that pure encoding capacity limitations appear ill equipped to explain near-equivalent simultaneous sequential performance across a range of stimulus exposure durations, set sizes, and with stimuli with quite different attentional demands. (PsycINFO Database Record PMID- 29985029 TI - Homogeneity of item material boosts the list length effect in recognition memory: A global matching perspective. AB - Kinnell and Dennis (2012) showed that the list length effect in recognition memory is only observed for homogeneous stimulus material. On the basis of the global matching model MINERVA 2 (Hintzman, 1986, 1988), we offer a theoretical explanation for this finding. According to our analysis, homogeneous material immunizes against the disruptive influence of preexperimental items, which might mask the intralist interference predicted by global matching models for familiar heterogeneous material. We tested our approach in three experiments. In Experiment 1, we found list length effects for homogeneous photographs of flowers and landscapes. In Experiment 2 and 3, we presented heterogeneous photographs of scenes (Experiment 2) and faces (Experiment 3). List length effects were only found if these photographs were homogenized by the use of image-processing filters. We further show that our explanation is also in line with the results of Dennis and Chapman (2010) who found an inverse list length effect. Overall, our results provide evidence for a global matching account of familiarity. (PsycINFO Database Record PMID- 29985030 TI - Systematic distortions in clinicians' memories for client cases: Increasing causal coherence. AB - In accord with classic schema theory, people are susceptible to forming false memories that align with stored schema representations (Brewer & Treyens, 1981). Furthermore, clinicians schematize mental disorders as causal networks of features (de Kwaadsteniet, Hagmayer, Krol, & Witteman, 2010; Kim & Ahn, 2002). We asked whether one important consequence of this representation is that clinicians tend to misremember client cases as being more causally coherent than they actually are. We tested this hypothesis by manipulating the causal coherence of case descriptions via a well-documented cue-to-causality, the proportionality between features (Einhorn & Hogarth, 1986). Clinicians read hypothetical cases describing three pieces of clinically relevant client information presented in causal order: recent life events, the clients' emotional reactions to those events, and their behaviors following those reactions. Each piece of information (event, reaction, behaviors) was manipulated to either be severely or mildly negative, rendering it proportionate or disproportionate to the other pieces of information. The clinicians offered diagnoses for these client cases, and then completed an unexpected recognition task. Clinicians were significantly more likely to misremember causally incoherent cases (i.e., in which the severity of the client's emotional reaction did not match the severity of the life event or behaviors) as having been coherent, compared to their likelihood of misremembering coherent cases as having been incoherent. They also incorrectly recognized false reaction lures more frequently overall than false event lures or false behavior lures. We discuss potential implications for the proportionate response effect, schema theory, inference, causal coherence, and expert judgments. (PsycINFO Database Record PMID- 29985032 TI - Winners and losers: Reward and punishment produce biases in temporal selection. AB - Studies of visual search demonstrate that the 'learned value' of stimuli (the extent to which they signal valued events, such as rewards and punishments) influences whether they will be prioritized by spatial attention. Recent work suggests that learned value also modulates attentional prioritization even when all stimuli are presented in the same location, suggesting an influence on temporal selection wherein value-related stimuli become more capable of disrupting central mechanisms of perceptual awareness. However, it remains unclear whether temporal selection is influenced specifically by learning about the relationship of stimuli with reward, or with punishment, or both. This question motivated the current experiments. Participants saw a stream of pictures in a central location, and had to identify the orientation of a rotated target picture. In Experiment 1, response accuracy was reduced if the target was preceded by a 'valued' distractor picture that signaled that a correct response to the target would be rewarded, relative to a distractor picture that did not signal reward. In Experiment 2, accuracy was reduced if the valued distractor picture signaled that an incorrect response would be punished, relative to a distractor that did not signal punishment. Experiment 3 replicated these findings, and demonstrated that the influence of rewards/punishments persisted into an extinction phase in which valued distractors were entirely task irrelevant. These findings suggest that it is the motivational significance of the outcome, rather than its valence, that is the crucial determinant of the influence of learned value on temporal selection. (PsycINFO Database Record PMID- 29985031 TI - Learning-dependent evolution of spatial representations in large-scale virtual environments. AB - An important question regards how we use environmental boundaries to anchor spatial representations during navigation. Behavioral and neurophysiological models appear to provide conflicting predictions, and this question has been difficult to answer because of technical challenges with testing navigation in novel, large-scale, realistic spatial environments. We conducted an experiment in which participants freely ambulated on an omnidirectional treadmill while viewing novel, town-sized environments in virtual reality on a head-mounted display. Participants performed interspersed judgments of relative direction (JRD) to assay their spatial knowledge and to determine when during learning they employed environmental boundaries to anchor their spatial representations. We designed JRD questions that assayed directions aligned and misaligned with the axes of the surrounding rectangular boundaries and employed structural equation modeling to better understand the learning-dependent dynamics for aligned versus misaligned pointing. Pointing accuracy showed no initial directional bias to boundaries, although such "alignment effects" did emerge after the fourth block of learning. Preexposure to a map in Experiment 2 led to similar overall findings. A control experiment in which participants studied a map but did not navigate the environment, however, demonstrated alignment effects after a brief, initial learning experience. Our results help to bridge the gap between neurophysiological models of location-specific firing in rodents and human behavioral models of spatial navigation by emphasizing the experience-dependent accumulation of route-specific knowledge. In particular, our results suggest that the use of spatial boundaries as an organizing schema during navigation of large scale space occurs in an experience-dependent fashion. (PsycINFO Database Record PMID- 29985033 TI - The dynamic adjustment of saccades during Chinese reading: Evidence from eye movements and simulations. AB - This article reports an eye-movement experiment in which participants scanned continuous sequences of Landolt-Cs for target circles to examine the visual and oculomotor constraints that might jointly determine where the eyes move in a task that engages many of the perceptual and motor processes involved in Chinese reading but without lexical or linguistic processing. The lengths of the saccades entering the Landolt-C clusters were modulated by the processing difficulty (i.e., gap sizes) of those clusters. Simulations using implemented versions of default-targeting (Yan, Kliegl, Richter, Nuthmann, & Shu, 2010) versus dynamic adjustment (Liu, Reichle, & Li, 2016) models of saccadic targeting indicated that the latter provided a better account of our participants' eye movements, further supporting the hypothesis that Chinese readers "decide" where to move their eyes by adjusting saccade length in response to processing difficulty rather than by selecting default saccade targets. We discuss this hypothesis in relation to both what is known about saccadic targeting during the reading of English versus Chinese and current models of eye-movement control in reading. (PsycINFO Database Record PMID- 29985034 TI - The graded effect of valence on word recognition in Spanish. AB - The influence of emotional content on language processing remains unclear. Previous research conducted in English has obtained contradictory results regarding the effects of valence on word recognition. Whereas some studies indicate that valence predicts recognition latencies such that negative words are processed more slowly than positive words, other studies indicate facilitation of responses to emotional (both positive and negative) compared to neutral words. The authors examined the influence of valence and arousal on word recognition reaction time (RT) using large-scale word naming and lexical decision data-sets in Spanish. They found that linear mixed-effects model estimates revealed a valence but not an arousal effect on reading latencies. The influence of valence was better captured by a graded (RTs to positive words < neutral < negative) than by a categorical (positive < negative) valence effect. A categorical emotional versus neutral effect was not reliably observed. In an advance on previous research, the authors' analyses showed that the valence effect is substantially more prominent in lexical decision than in pronunciation. These results mirror some of those reported previously in English, adding evidence to support their validity, and demonstrating important parallels in word recognition processes in orthographically shallow as well as deep languages. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29985035 TI - Morphological processing in single-word and sentence reading. AB - Research on morphological processing has been mainly conducted in the single-word reading domain using the lexical-decision task. Similar research in the sentence reading domain has been conducted using eye-tracking techniques, yet the experimental paradigms used in each domain are not directly comparable. In the present study, we investigated morphological processing in single-word reading using the masked priming paradigm (Experiments 1a, 1b, 3), and in sentence reading using the fast priming paradigm in eye tracking (Experiment 2). The study was conducted in German using the same prefixed and suffixed items in both tasks. All experiments yielded an identical pattern of results, indicating early processing of the embedded stems, independently of whether these stems were combined with a prefix, a suffix, or a nonmorphological letter sequence. We interpret our findings in relation to previous results in the literature and discuss their implications for reading research both in the single-word and sentence-reading domains. (PsycINFO Database Record PMID- 29985036 TI - Does early active bilingualism enhance inhibitory control and monitoring? A propensity-matching analysis. AB - Prior research suggesting that longer bilingual experience benefits inhibitory control and monitoring has been criticized for a lack of control over confounding variables. We addressed this issue by using a propensity-score matching procedure that enabled us to match early and late bilinguals on 18 confounding variables for example, demographic characteristics, immigration status, fitness, extracurricular training, motivation, and emotionality-that have been shown to influence cognitive control. Before early and late bilinguals were matched (N = 196), we found early active bilingual advantages in flanker effects (in accuracy), global accuracy, and sensitivity (d') on the Attention Network Test for Interaction and Vigilance and global accuracy on the saccade task. After matching (n = 113), many of the early active bilingual advantages that had been identified before matching were either attenuated or disappeared. However, we observed that early active bilingual advantages in flanker effects (in response time) were strengthened after matching. These results stress robust early active bilingual advantages in inhibitory control and highlight the importance of matching language groups on nonlinguistic covariates. (PsycINFO Database Record PMID- 29985037 TI - A semantic mismatch effect on serial recall: Evidence for interlexical processing of irrelevant speech. AB - Short-term memory (STM) for serially presented visual items is disrupted by task irrelevant, to-be-ignored speech. Five experiments investigated the extent to which irrelevant speech is processed semantically by contrasting the following two hypotheses: (1) semantic processing of irrelevant speech is limited and does not interfere with serial STM or (2) irrelevant speech is routinely processed semantically at an interlexical level to allow for the detection of stimuli that are of potential relevance for the individual. We tested these hypotheses by comparing the disruption of serial recall by distractor sentences with semantically expected endings to that of sentences with semantically unexpected endings. Sentences with unexpected endings consistently produced more disruption than sentences with expected endings. Phonologically expected, but semantically unexpected endings had the same effect, demonstrating that a semantic and not a phonological mismatch is responsible for the increased disruption. In all five experiments, the semantic mismatch effect was not reduced after repeated exposure to sentences with unexpected endings. The results suggest that (1) semantic processing occurs at the interlexical level of irrelevant speech, which requires the integration of words into the sentence context and (2) the semantic content of a distractor interferes with the maintenance of serial information in short term-memory if it is unexpected. (PsycINFO Database Record PMID- 29985038 TI - Eye-movement evidence for the mental representation of strokes in Chinese characters. AB - Although strokes are the smallest identifiable units in Chinese words, the fact that they are often embedded within larger units (i.e., radicals and/or characters that comprise Chinese words) raises questions about how and even if strokes are separately represented in lexical memory. The present experiment examined these questions using a gaze-contingent boundary paradigm (Rayner, 1975) to manipulate the parafoveal preview of the first of two-character target words. Relative to a normal preview, the removal of whole strokes was more disruptive (i.e., resulting in longer looking times on targets) than the removal of an equivalent amount of visual information (i.e., number of pixels) from strokes located either in similar locations or throughout the entire character. These findings suggest that strokes are represented as discrete functional units rather than visual features or integral parts of the radicals/characters in which they are embedded. We discuss the theoretical implications of this conclusion for models of Chinese word identification. (PsycINFO Database Record PMID- 29985039 TI - Individual differences in mixing costs relate to general executive functioning. AB - The ability to enact cognitive control under changing environmental demands is commonly studied using set-shifting paradigms. While the control processes required for task set reconfiguration (switch costs) have been studied extensively, less research has focused on the control required during task repetition in blocks containing multiple tasks as compared to those containing a single task (mixing costs). We investigated how individual differences in mixing costs related to other executive functions (EFs) in a large sample (N = 749) of young adults. Individual differences in mixing costs across three different set shifting paradigms loaded significantly onto a mixing cost latent variable. This Mixing Cost factor moderately correlated with a Common EF factor capturing variance shared across nine EF tasks designed to tap response inhibition, working memory updating, and mental set-shifting. It did not correlate with Updating Specific and Shifting-Specific factors. Results indicate that the additional cognitive control required during mixed-task block repeat trials relies on general executive processes, as well as unique abilities distinct from both set shifting and working memory updating. (PsycINFO Database Record PMID- 29985040 TI - Sample size weighting follows a curvilinear function. AB - Previous research is mixed regarding whether laypeople are sensitive to sample size. Here the author argues that this is in part because sample size sensitivity follows a curvilinear function with decreasing sensitivity as sample size become larger. This functional form reconciles apparent discrepancies in the literature, accounting for results where sample size is greatly attended to or nearly overlooked. The curvilinear form is found across confidence and estimation tasks that have square-root and linear normative standards. Thus, although people intuitively know that larger samples provide more reliable information, they do not modulate how they weight sample size in different circumstances. Further, individuals higher in numeracy show greater sensitivity to sample size than those lower numeracy (i.e., have a steeper curvilinear slope), but still underweight it relative to normative standards. Providing raw data can boost sample size use for individuals who are lower in numerical ability. (PsycINFO Database Record PMID- 29985041 TI - The impact of one's own voice and production skills on word recognition in a second language. AB - Second language (L2) learners often speak with a strong accent, which can make them difficult to understand. However, familiarity with an accent enhances intelligibility. We propose that L2 learners are even more familiar with their own accented speech patterns and may thus understand self-produced L2 words better than others' accented productions, presumably because of adaptation. This hypothesis was tested by asking German learners of English to identify English words from minimal pairs that are distinguished by difficult L2 sound contrasts. Words had been spoken by the learners themselves or other learners who produced the contrasts equally well. Self-produced words were identified significantly better than others' productions. A second experiment revealed that better producers can exploit acoustic cues in perception more than poor producers, especially when the produced acoustic cues to the minimal pairs were clearly differentiated. The self-benefit, however, did not depend on production skills. We conclude that L2 learners adapt not only to their L1 accent in general but also to their own specific speech patterns. Speculating about L2 acquisition more generally, these results may raise the question whether adaptation to own, accented productions may be one reason why learners have difficulties to improve their pronunciation, since they may not notice a need to improve. (PsycINFO Database Record PMID- 29985042 TI - Voluntary switching in an invertebrate: The effect of cue and reward change. AB - When faced with multiple competing goals, individuals must decide which goal to attend to. Voluntary task switching is an important paradigm for testing cognitive flexibility and spontaneous decision-making when competing tasks are present. Of particular importance is the study of how reward affects task switching, as reward is perhaps the most commonly used tool for shaping both human and animal behavior. Recently, Frober and Dreisbach (2016) demonstrated that it is not reward level per se, but reward change, which most strongly affects switching behavior in humans: Task switching was lowest when reward remained high and highest when reward is changed (increase or decrease), while the repetition of low reward showed intermediate switching levels. Here we replicate their experiment on individual foragers of the ant species Lasius niger. Using an adapted spontaneous alternation task, we find that ants' switching response in light of their immediate reward history is qualitatively identical to that of humans. In a second experiment, we show that some of this behavior can be explained by the cue change, rather than the rewards. However, patterns exist in the data which cue change cannot explain. The striking parallel in behavior between humans and insects raises questions about how reward shapes behavioral flexibility and stability in humans. (PsycINFO Database Record PMID- 29985043 TI - An associability decay model of paradoxical choice. AB - Paradoxical choices in human and nonhuman animals represent substantial deviations from rational models of behavior; such deviations often demand models that incorporate multiple perspectives, including psychology, biology, and economics. The past couple of decades have seen an increased interest in the paradoxical choice of pigeons in 2-armed bandit tasks (2ABT) developed by Zentall and colleagues. In these 2ABTs, pigeons, but not rats, systematically choose an alternative that yields less reward over multiple trials but provides more information on events within a trial, over an alternative that yields more reward over trials but provides less information on events within a trial. Although current computational models account for much of the extant data generated in studies on 2ABT choice, they do not explain, in a trial-by-trial basis, how pigeons learn to ignore some stimuli and not others in 2ABTs. To address the provenance of this differential allocation of attention, a simple model composed of Bush-Mosteller linear operators and a Pearce-Hall-like associability mechanism is proposed. This model, referred to as the Associability Decay Model (ADM) of paradoxical choice, adequately accounts for the performance of pigeons and rats in 2ABTs. The ADM yields an untested prediction that is inconsistent with other computational models of 2ABT performance, and offers potential explanations for why differences in motivation, social enrichment, and impulsivity alter the degree to which pigeons systematically choose information despite earning fewer rewards. The success of the ADM shows that a relatively simple dynamic trial-by trial model can account for much of the extant paradoxical-choice data while identifying opportunities for further study and refinement of models of 2ABT performance. (PsycINFO Database Record PMID- 29985044 TI - Midsession reversal task with pigeons: Parallel processing of alternatives explains choices. AB - Most models of choice assume a "tug of war" (ToW) between options present at the time of the choice, arguing that preferences are built on this process, and implying that adding options increases delay to act. In contrast, the sequential choice model (SCM) proposes that choices are driven by parallel expression of the mechanisms that control action in sequential encounters, without comparative deliberation at choice time. Only the SCM predicts choice preferences based on latencies to respond in single-option encounters. SCM further predicts that latencies to choose should either be the same or shorter than those in sequential encounters. We contrasted these models using a midsession reversal task with pigeons. Responses to one alternative (S1) were rewarded in the first half of each session and those to the other (S2) in the second half. Single-option (sequential) and two-option (choice) trials were intermingled. In choice trials subjects strongly preferred S1 early in the session, showed intermediate preferences toward the midsession, and preferred S2 late. These preferences were all predicted by changes in latency toward the presently negative alternative (S2 early and S1 late) in single-option trials. Latency toward presently positive stimuli were minimal throughout, in both single and two option trials, with no evidence of an evaluation time cost of choice. The ability to predict choice preference from latencies in sequential encounters and the absence of a choice delay support the SCM against ToW models, consistently with results from other protocols and species. (PsycINFO Database Record PMID- 29985045 TI - Extinguishing cue-controlled reward choice: Effects of Pavlovian extinction on outcome-selective Pavlovian-instrumental transfer. AB - Outcome-selective Pavlovian-instrumental transfer (PIT) refers to the finding that presenting Pavlovian predictors of outcomes can enhance the vigor of instrumental responding for those same outcomes. Three experiments examined the sensitivity of outcome-selective PIT to Pavlovian (stimulus-outcome) extinction. In Experiment 1, participants first learnt to perform different instrumental responses to earn different outcomes. In a separate Pavlovian training phase, certain stimuli were established as Pavlovian signals of the different outcomes. Some of these Pavlovian stimuli were then extinguished (they were presented alone, without any outcome), while others were not. A final transfer test measured the extent to which these Pavlovian cues biased instrumental response choice. Consistent with previous work, the observed PIT effects were immune to Pavlovian extinction; the non-extinguished and extinguished cues produced PIT effects that did not significantly differ in size. In Experiment 2, response choice was tested in the presence of compound stimuli that included both extinguished and non-extinguished cues. Response choice was highly sensitive to the extinction manipulation under these circumstances. Experiment 3 tested whether this sensitivity to Pavlovian extinction was a direct effect of the associative strength of the Pavlovian cues present, or an indirect effect of cue salience. The results provide unique evidence to suggest that PIT is a direct consequence of the strength of the Pavlovian associations. (PsycINFO Database Record PMID- 29985046 TI - Human performance on random interval schedules. AB - Four experiments explored the factors controlling human responding on random interval (RI) schedules of reinforcement. All experiments identified 2 types of responding: "bout-initiation" and "within-bout" responding. Responding on RI schedules was related to the interval value rates, being higher on an RI-30s than on an RI-60s or RI-120s schedule, which impacted bout-initiation responding to the greater degree (Experiments 1 and 3). Experiment 2 found similar overall response rates on random ratio (RR) and random interval with a linear feedback loop (RI+) schedules, with both higher than on an RI schedule. Bout-initiation rates were similar across all schedules, but within-bout responding differed. Experiments 3 and 4 examined the impact of a response cost and noted greater bout initiation responding but not greater within-bout rates with low costs. Overall, these experiments suggest that bout-initiation responding may be subject to control by factors that increase the strength of conditioning to the context, whereas within-bout responding is less sensitive to these influences. (PsycINFO Database Record PMID- 29985047 TI - Firm, Indurated Plaques After Therapeutic Hypothermia. PMID- 29985048 TI - Factors Associated With Child Restraint Use in Motor Vehicle Crashes. AB - Motor vehicle crashes (MVCs) are a leading cause of death among children. Multivariable analyses of age-appropriate child restraint system (CRS) use in the "booster-aged" population are needed. The current study identified factors associated with age-appropriate CRS use in fatal MVCs for children 4 to 7 years old, using 2011 to 2015 data from the Fatality Analysis Reporting System. Of 929 MVC fatalities, 32% of fatally injured children were in an age-appropriate restraint. While age-appropriate CRS use was higher for 4-, 5-, and 6-year-olds relative to 7-year-olds (adjusted relative risk [aRR] = 2.57, 2.51, and 2.18, respectively; p < .01 for each comparison), black children (aRR = 0.62; p < .01) relative to white children, and drivers who had not used a lap-shoulder belt (aRR = 0.40; p < .01) relative to belted drivers were associated with lower levels of age-appropriate CRS use. Our findings underscore the continued importance of communicating best practice guidelines on CRSs to caregivers of young children. PMID- 29985049 TI - Intestinal homeostasis is restored in mice following a period of intestinal growth induced by orally administered Emu Oil. AB - Previously, we reported that orally administered Emu Oil (EO) increases mucosal thickness in the small intestine and colon in rodent models of chemotherapy induced mucositis and colitis. However, it remains unclear whether mucosal thickening (crypt and villus lengthening) represents a process of normal or aberrant growth. We sought to determine if villus height (VH) and crypt depth (CD) measurements returned to normal in EO-treated rats following withdrawal of EO therapy. Dark agouti rats ( n = 8/group) were gavaged daily for 10 days with water, olive oil (OO), or EO (0.5 mL or 1 mL). Groups of rats were euthanized on days 10 and 17. Intestinal weights, lengths, VH, and CD were quantified. P < 0.05 was considered significant. On day 10, jejuno-ileum weight was increased by OO (26%) and EO (0.5 mL: 15%; 1 mL: 29%) compared to water controls ( P < 0.01), which was normalized by day 17. On days 10 and 17, jejuno-ileum length was greater in OO- (12%) and EO-treated rats (0.5 mL: 8%; 1 mL: 12%; P < 0.05), relative to water controls. On day 10, OO and EO increased ileal VH (OO: 32%; 0.5 EO: 22%; EO: 35%; P < 0.01) and CD (OO: 17%; 0.5 EO: 13%; EO: 22%) compared to water controls. Importantly, however, after withdrawal of all oils, VH and CD measurements returned to normal control values. Moreover, the VH:CD ratio (potential indicator of dysplasia) remained unchanged in all experimental groups on days 10 and 17. The restoration of normal intestinal architecture following cessation of Emu Oil therapy supports its safety for application in intestinal disorders. Impact statement Uncontrolled inflammation and intestinal proliferation can predispose to the development of colorectal cancer. In previous pre-clinical studies, we demonstrated that oral administration of Emu Oil promotes intestinal repair via stimulation of the mucosa in response to tissue injury and inflammation. Therefore, it was important to determine if Emu Oil administration did not promote the precocious development of colorectal cancer. The current study revealed that Emu Oil returned indicators of intestinal proliferation back to normal values after a period of seven days. These data strongly support the safety of Emu Oil for further studies in the context of bowel inflammation. PMID- 29985050 TI - Outcomes of Total Ankle Arthroplasty in Moderate and Severe Valgus Deformity. AB - INTRODUCTION: Failure to correct coronal deformity at the time of total ankle arthroplasty (TAA) can lead to early implant failure. We aimed to determine clinical, radiographic, and patient-reported outcomes of patients with moderate to severe valgus deformity who underwent TAA for end-stage ankle arthritis. METHODS: Patients with a valgus deformity of at least 10 degrees who underwent TAA were retrospectively reviewed. The coronal tibiotalar angle was assessed on radiographs preoperatively, at 1 year, and at final follow-up. The visual analog scale (VAS) for pain, Short Form-36 (SF-36), American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot-ankle scale, and Short Musculoskeletal Function Assessment (SMFA) scores were assessed preoperatively and at final follow-up. RESULTS: Mean preoperative valgus deformity was 15.5 +/- 5.0 degrees , and was corrected to a mean of 1.2 +/- 2.6 degrees of valgus postoperatively. VAS, SF 36, AOFAS, and SMFA scores improved significantly ( P < .001 for all). There was no significant change in tibiotalar angle between 1 year and final follow-up in either group. Reoperation and revision rates did not differ between groups. CONCLUSION: Correction of coronal alignment was achieved and maintained in patients with both moderate and severe preoperative valgus malalignment. Outcome scores significantly improved for all patients. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 29985051 TI - The Incidence of Glenohumeral Bone and Cartilage Lesions at the Time of Anterior Shoulder Stabilization Surgery: A Comparison of Patients Undergoing Primary and Revision Surgery. AB - BACKGROUND: Intra-articular glenohumeral joint changes frequently occur after shoulder instability events. PURPOSE: (1) To compare demographic characteristics, baseline patient-reported outcomes, and intraoperative findings for patients undergoing primary or revision shoulder stabilization surgery and (2) to determine the incidence of glenohumeral bone and cartilage lesions in this population while identifying factors independently associated with these lesions. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The Multicenter Orthopaedic Outcomes Network (MOON) Shoulder Group shoulder instability database was used to identify all prospectively enrolled patients undergoing shoulder stabilization surgery for anterior instability between October 2012 and September 2016. Any patient who underwent surgery for posterior or multidirectional shoulder instability or concomitant rotator cuff repair surgery was excluded. Patient demographic characteristics, preoperative patient reported outcomes, and intraoperative findings, including glenohumeral bone and cartilage lesions, were compared for patients undergoing primary and revision shoulder stabilization surgery. Additionally, patients with and without glenohumeral bone and cartilage lesions were compared and independent associations determined using multivariate analysis. RESULTS: There were 545 patients available for analysis (461/545 [84.6%] primary; 84/545 [15.4%] revision). Patients undergoing revision surgery were older ( P = .001), were more frequently smokers ( P = .022), had a greater number of instability events before surgery ( P = .047), more frequently required reduction assistance ( P < .001), and had lower Short Form-36 (SF-36) Mental Component Summary ( P = .020) and Western Ontario Shoulder Instability Index (WOSI) ( P = .026) scores preoperatively. Additionally, patients undergoing revision surgery had a higher frequency of bone and cartilage lesions than those undergoing primary surgery (47.6% vs 18.4%, respectively; P < .001). Male sex, revision surgery, black race, increasing body mass index, increasing patient age, and lower preoperative SF-36 Physical Component Summary score were independently associated with the presence of glenohumeral bone and cartilage lesions at the time of shoulder stabilization surgery. Revision surgery was strongly associated with the presence of glenohumeral bone and cartilage lesions (odds ratio [OR], 4.381 [95% CI, 2.591 7.406]) and glenoid bone loss greater than 10% (OR, 9.643 [95% CI, 5.128-18.134]) or 20% (OR, 13.076 [95% CI, 5.113-33.438]) of the glenoid width. CONCLUSION: Glenohumeral bone and cartilage lesions are common at the time of shoulder stabilization surgery, occurring more frequently in patients undergoing revision surgery as compared with primary surgery. On the basis of these findings, future prospective studies should aim to compare the clinical outcomes in these 2 groups. PMID- 29985053 TI - Influence of Work-Related Factors on Work Ability Among Young Cambodian Migrant Workers in Thailand. AB - This cross-sectional study was conducted to evaluate the effects of work-related factors on work ability among young Cambodian migrant workers in Thailand. The participants consisted of 258 Cambodian migrant workers working in farms in the northeast region of Thailand. Work-related factors consisted of a general work environment and a psychosocial factor. General work environment was assessed by perception of subjects on biological, chemical, physical, and ergonomic factors. The psychosocial factor was assessed by the Job Content Questionnaire. The Work Ability Index was used to evaluate their work ability. Logistic regression analysis was applied to test the association between work-related factors and work ability. The results indicate that a chemical work environment and psychosocial factor associated with Work Ability Index among young Cambodian migrant workers, after adjusting for sociodemographic factors. These findings suggest that improving the work environment would be the most effective way to increase the work ability of Cambodian migrant workers in Thailand. PMID- 29985054 TI - Content analysis of Spanish judgements addressing the sexual transmission of HIV: 1996-2016. AB - This study performed a content analysis of the language of the Spanish judgements addressing the sexual transmission of HIV in order to determine its possible interrelationship with HIV-related stigma. All judgements and writs dictated by Spanish penal and civil jurisdictions between 1981 and December 2016 were obtained through a systematic search of the Spanish legal databases. The inclusion criterion was that the possible transmission of HIV was judged as an individual infraction, regardless of whether other infractions were involved. Twenty judgements were selected and analysed through direct content analysis assisted by the software MAXQDA 12. The majority of the cases (85%) were brought before the penal jurisdiction. Most of the judgements applied the crimes of bodily harm or grievous bodily harm (75%). Aspects closely related to the determinants of HIV-related stigma, such as the perception of HIV as a severe and easily transmitted infection, and attributions of responsibility and blame to people with HIV, were found in the judgements' reasoning. They were associated with outdated scientific and technical knowledge. Furthermore, some arguments found are repeated literally and successively in several judgments from different years, ignoring medical advances. Most plaintiffs were unaware of their sexual partner's HIV status. The scarce results found regarding the concealment of HIV status suggested that fear of stigma could be the reason thereof. The results suggested that training legal professionals in the epidemiological, clinical, and social aspects of HIV could influence stigma reduction, leading to a more objective consideration of the characteristics of this infection. PMID- 29985055 TI - Economic strengthening for HIV testing and linkage to care: a review of the evidence. AB - Delayed HIV diagnosis and enrollment in HIV care can lead to negative health outcomes for individuals and pose major barriers to achieving the UNAIDS 90-90-90 treatment targets. Household economic strengthening (HES) initiatives are increasingly used to alleviate the direct and indirect costs of HIV testing and linkage to care for those who are diagnosed. The evidence linking HES with a range of HIV outcomes is growing, and this evidence review aimed to comprehensively synthesize the research linking 15 types of HES interventions with a range of HIV prevention and treatment outcomes. The review was conducted between November 2015 and October 2016 and consisted of an academic database search, citation tracking of relevant articles, examination of secondary references, expert consultation, and a gray literature search. Given the volume of evidence, the results are presented and discussed in three papers. This is the second paper in the series and focuses on the 20 studies on HIV testing, diagnosis, and enrollment in care. The results indicate that financial incentives are consistently and independently linked with higher testing uptake and yield among adults. Limited evidence indicates they may also be beneficial for enrollment in care. Evidence for other HES interventions is too sparse to identify clear trends. PMID- 29985056 TI - Assessment of Cell Viability of Fresh Osteochondral Allografts in N Acetylcysteine-Enriched Medium. AB - Objective The purpose of this study was to evaluate the effect of N acetylcysteine (NAC)-enriched storage medium on fresh osteochondral viability at 4 degrees C. Our hypothesis was that the cell viability of chondrocytes obtained from human osteochondral tissue and stored at 4 degrees C significantly improves in the presence of NAC. Design Controlled laboratory study. For this study, 8 samples of femoral condyle osteochondral tissue were obtained from patients undergoing total knee replacement. The samples were stored at either 4 degrees C in phosphate-buffered saline (PBS) or at 3 different concentrations of NAC (NAC 1, 2, and 5 mM). Cell viability was analyzed at time 0 and 4 weeks by flow cytometry. The results of cell viability (median) were analyzed statistically using analysis of variance and Tukey's post hoc test. P values <0.05 were considered statistically significant. Results The viability at time 0 was 95.5% +/- 3.7%. At 4 weeks, the cell viability was 56.8% +/- 20.1% in the control group (PBS), 83.8% +/- 11.9% in the group stored with NAC 1 mM, 73.4% +/- 13.6% in the group stored with NAC 2 mM, and 66.4% +/- 27.7% in the group stored with NAC 5 mM. A statistically significant difference from the baseline viability (time 0) was observed in the PBS control group ( P = 0.0018) but not in the other groups. A statistically significant difference was observed in the NAC 1 mM group compared with the PBS group ( P = 0.0255). Conclusion The use of NAC at 1 mM concentration improves cell viability after 4 weeks of storage in chondrocytes obtained from human osteochondral tissue. PMID- 29985057 TI - Influence of opponent standard on activity profile and fatigue development during preseasonal friendly soccer matches: a team study. AB - We examined the influence of competitive standard of the opponent on activity profile and fatigue during preseason friendly soccer matches. Time motion analysis was performed in a male professional soccer team (N = 14) during six friendly games played against professional, semi-professional and amateur-level opponents (PL, SPL and AL). The reference team covered higher acceleration distance, acceleration and deceleration > 2 m. s-2 distance against PL than AL (ES = 0.77 to 0.91). Acceleration and deceleration distance > 2 m. s-2 was also higher (ES = 0.66 to 0.84) against SPL than AL. Greater decreases in total distance, distance> 16 km. h-1 and > 22 km. h-1, total acceleration and deceleration, acceleration and deceleration distance > 2 m. s-2 (ES = 0.84 to 2.20) were also observed during PL compared to AL opponent. Playing against a stronger opponent seems to be more physically demanding, with special emphasis on events related with change of velocity (accelerations and decelerations). Declines in physical performance appear more evident against a higher opponent. PMID- 29985058 TI - Ocular toxicity due to colours used during holi celebration in India: correlation of clinical findings with the anterior segment OCT. AB - PURPOSE: To correlate the anatomical extent of ocular surface toxicity due to colours using anterior segment optical coherence tomography (ASOCT) with the clinical findings. METHODS: Patients presenting to our emergency department with ocular colour toxicity during the Holi festival celebrations from March 2 2018 to March 5 2018 were assessed for any adnexal, conjunctival, corneal, and anterior chamber findings, as well as findings on anterior segment optical coherence tomography. RESULTS: A total of 21 patients were observed. The average age was 23 years with 16 patients being male (76.19%). Bilateral ocular involvement was more common (13 patients, 61.90%). Clinically, the corneal changes included localized punctate epitheliopathy (type I) in 12 patients (57.14%) and diffuse punctate epitheliopathy admixed with a variable sized epithelial defect (type II) in the other 9 patients (42.85%). The visual acuity among the former group varied from 6/6 to 6/9, whereas for the latter, it ranged from 6/12 to 6/24. On ASOCT in both the types, the superficial stromal involvement was noted up to 60 microns. Interestingly in two patients with type II corneal involvement, anterior segment involvement was noted in the form of staining of the lens capsule and dense anterior chamber inflammation. CONCLUSIONS: Ocular toxicity due to colours used during Holi mainly involves the surface epithelium and the superficial stroma. This was observed clinically and also confirmed on ASOCT. The colour can rarely diffuse into the anterior chamber causing an inflammatory reaction and staining of the lens capsule. However, if managed appropriately, vision-threatening complications can be averted. PMID- 29985059 TI - Epidemiology of patients with anterior cruciate ligament injuries undergoing reconstruction surgery in a multi-ethnic Asian population. AB - We conducted an epidemiological study to identify the demographics and pre operative characteristics of patients undergoing primary anterior cruciate ligament (ACL) reconstruction in a multi-ethnic Asian population. A retrospective study was performed on 696 patients who registered in our ACL reconstruction registry from January 2013 to August 2016. Important inter-ethnic differences were found. Indian patients were significantly older compared to Malay and Chinese patients. Malay and Indian patients were more likely to be male, overweight, and obese compared to Chinese patients. Soccer was the predominant sport involved, although ethnic predominance in specific sports exists. Novel findings from this study include increased prevalence of concomitant chondral injuries in the Chinese population compared to Malays and Indians, and significantly higher rates of concomitant intra-articular injuries in soccer and basketball compared to netball. Identification of these high-risk subgroups would serve useful in guiding the formulation of prevention strategies within our multi ethnic community. PMID- 29985060 TI - PF-00547659 for the treatment of Crohn's disease and ulcerative colitis. AB - INTRODUCTION: Gut-specific homing is mainly mediated by the expression of MAdCAM 1 on endothelial cells. An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD). Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the alpha4beta7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD. Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naive and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn's disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD. PMID- 29985061 TI - Patient impact and economic burden of mild-to-moderate atopic dermatitis. AB - OBJECTIVE: To present a systematic review of studies conducted to evaluate patient impact and economic burden of mild-to-moderate atopic dermatitis. METHODS: A MEDLINE (via PubMed), Excerpta Medica database (Embase), and Cochrane Library search for English-language articles published January 1, 1996-December 31, 2016 was performed. Abstracts were manually reviewed from 2015-2016 from 10 leading conferences and congresses associated with atopic dermatitis. Manuscripts were reviewed for inclusion in two main categories within the review: patient impact of mild-to-moderate atopic dermatitis and economic burden of atopic dermatitis. Excluded from this dataset were any patients in these studies who had severe atopic dermatitis, moderate-to-severe atopic dermatitis, or atopic dermatitis of unspecified severity. RESULTS: In total, 222 studies qualified for inclusion in the analysis; this report focuses on the 76 studies that reported results stratified by disease severity. Measured by general and specific instruments, even mild-to-moderate atopic dermatitis reduces the overall quality of-life of patients and their caregivers/families. Disease severity assessed by validated severity instruments directly correlated with quality-of-life. Treatment of atopic dermatitis can improve the quality-of-life of patients and their caregivers/families by alleviation of symptoms and reduction in severity. In general, total costs increased as disease severity increased; even mild atopic dermatitis imposed substantial costs. CONCLUSIONS: The results emphasize the impact of atopic dermatitis, especially mild atopic dermatitis, on patient lives and finances, including education of clinicians, payers, and patients regarding benefits associated with treatment adherence. PMID- 29985062 TI - Extract of the Medicinal Plant Pao Pereira Inhibits Pancreatic Cancer Stem-Like Cell In Vitro and In Vivo. AB - Pancreatic cancers are enriched with cancer stem-like cells (CSCs), which are resistant to chemotherapies, and responsible for tumor metastasis and recurrence. Here, we investigated the extract of a medicinal plant Pao Pereira (Pao) for its activity against pancreatic CSCs. Pao inhibited overall proliferation of human pancreatic cancer cell lines with IC50 ranging from 125 to 325 MUg/mL and had limited cytotoxicity to normal epithelial cells. Pancreatic CSC population, identified using surface markers CD24+ CD44+ EpCam+ or tumor spheroid formation assay, was significantly reduced, with IC50s of ~100 MUg/mL for 48 hours treatment, and ~27 MUg/mL for long-term treatment. Nuclear beta-catenin levels were decreased, suggesting suppression of Wnt/beta-catenin signaling pathway. In vivo, Pao at 20 mg/kg, 5 times/week gavage, significantly reduced tumorigenicity of PANC-1 cells in immunocompromised mice, indicating inhibition of CSCs in vivo. Further investigation is warranted in using Pao as a novel treatment targeting pancreatic CSCs. PMID- 29985063 TI - Training Child Care Inspectors to Deliver Health Messaging: A Quality Improvement Pilot Project. AB - Early childhood obesity is at epidemic proportions. Early child care providers have a unique opportunity to instill healthy eating and active living behaviors in children that can foster lifelong health. Academic-community partnerships that involve collaborations between child care centers, local public health departments, and universities provide one avenue to strengthening healthy eating and active living-related knowledge and skills among early child care providers. This quality improvement pilot intervention, titled Healthy Child Care Makes a Healthy Start, is one example of this type of collaboration. This quality improvement pilot project consisted of two complementary intervention components. Inspectors were trained to cofacilitate a strategic planning process with university researchers to help providers implement healthy eating and active living-related policy, system, and environment changes in their child care homes and centers. An average of five changes were implemented in participating child care locations. Inspectors also received training on health-related best practices and delivered 1-minute health messages to child care providers during routine inspection visits. This type of innovative partnership has the potential to leverage a currently existing relationship between child care providers and licensing and regulation inspectors and shift the relationship to include dissemination and implementation of health messaging in child care center and home settings. PMID- 29985064 TI - Challenges with chromone as a privileged scaffold in drug discovery. PMID- 29985065 TI - Bilateral adrenal hemorrhage revealed antiphospholipid syndrome in a male patient: benefit from comprehensive treatment. AB - BACKGROUND: Adrenal hemorrhage caused by antiphospholipid syndrome (APS) secondary to systemic lupus erythematosus (SLE) is very rare, especially in males. REPORT: This study reports a 45-year-old male patient who presented with fatigue, loss of appetite, nausea, and vomiting for 2 months with a history of recurring epilepsy. On examination, he had low blood pressure (95/53 mmHg) and hyponatremia (117.9 mmol/L). His abdominal computed tomography (CT) scan showed bilateral diffusely enlarged adrenal hemorrhage. Laboratory studies revealed evidence of APS secondary to SLE. He remains well with adrenal lesions shrunken under the treatment of steroid, cyclophosphamide, hydroxychloroquine, warfarin, oxcarbazepine and entecavir. CONCLUSION: This case is presented as a warning that the correct diagnosis of adrenal hemorrhage and appropriate treatment is needed, especially when complications set in. PMID- 29985066 TI - Salmonella enterica Serotype Javiana Infections Linked to a Seafood Restaurant in Maricopa County, Arizona, 2016. AB - On 10 August 2016, the Maricopa County Department of Public Health identified culture-confirmed Salmonella enterica serotype Javiana isolates from two persons who reported eating at a seafood restaurant; seven additional cases were reported by 15 August. We investigated to identify a source and prevent further illness. We interviewed persons with laboratory-reported Salmonella Javiana infection. Pulsed-field gel electrophoresis (PFGE) and whole genome sequencing of isolates were performed. A case was defined as diarrheal illness in a person during July to September 2016; confirmed cases had Salmonella Javiana isolate yielding outbreak-related PFGE patterns; probable cases had diarrheal illness and an epidemiologic link to a confirmed case. Case finding was performed (passive surveillance and identification of ill meal companions). A case-control study assessed risk factors for Salmonella Javiana infection among restaurant diners; control subjects were chosen among meal companions. No restaurant workers reported illness. Foods were reportedly cooked according to the Food Code. Food and environmental samples were collected and cultured; Salmonella Javiana with an indistinguishable PFGE pattern was isolated from portioned repackaged raw shrimp, halibut, and a freezer door handle. We identified 50 Salmonella Javiana cases (40 confirmed and 10 probable); illness onset range was from 22 July to 17 September 2016. Isolates from 40 patients had highly related PFGE patterns. Thirty-three (73%) of 45 patients interviewed reported eating at the restaurant. Among 21 case patients and 31 control subjects, unfried cooked shrimp was associated with illness (odds ratio, 6.7; 95% confidence interval, 1.8 to 24.9; P = 0.004). Among restaurant diners, laboratory and case-control evidence indicated shrimp as the possible outbreak source; poor thermal inactivation of Salmonella on shrimp is theorized as a possible cause. Cross-contamination might have prolonged this outbreak; however, the source was not identified and highlights limitations that can arise during these types of investigations. PMID- 29985067 TI - Biogenic Amine Production by and Phylogenetic Analysis of 23 Photobacterium Species. AB - Photobacterium species are members of the bacterial communities typically associated with scombrotoxin-forming fish. Reclassification and discovery of new Photobacterium species has caused confusion as to which species are capable of biogenic amine production. We analyzed histamine, cadaverine, and putrescine production by 104 Photobacterium strains representing 23 species. The presence of the genes for histidine decarboxylase ( hdc), lysine decarboxylase ( ldc), and ornithine decarboxylase ( odc) was determined by real-time or conventional PCR and whole genome sequencing. Significant histamine production (>200 ppm) was detected in five Photobacterium species: P. angustum, P. aquimaris, P. kishitanii, P. damselae, and P. phosphoreum. The hdc gene was detected in all of these histamine-producing species except P. phosphoreum. Cadaverine was produced by eight Photobacterium species: P. angustum, P. aquimaris, P. damselae, P. iliopiscarium, P. kishitanii, P. leiognathi, P. mandapamensis, and P. phosphoreum. Putrescine was produced by six Photobacterium species: P. angustum, P. aquimaris, P. kishitanii, P. leiognathi, P. mandapamensis, and Photobacterium sp. Cadaverine production correlated closely with the presence of the ldc gene, but putrescine production did not correlate closely with the presence of the odc gene. Characterization of the biogenic amine production by Photobacterium species will allow identification of these marine bacteria and help ensure that current guidelines account for mitigation of these bacteria. PMID- 29985069 TI - (+/-) Cochlearoids N-P: three pairs of phenolic meroterpenoids from the fungus Ganoderma cochlear and their bioactivities. AB - Three pairs of meroterpenoids (+/-) cochlearoids N-P (1-3) were isolated from the fruiting bodies of Ganoderma cochlear. Their structures including absolute configurations were assigned by spectroscopic techniques. All the isolated compounds were tested for their inhibitory activities toward BRD4, human cancer cells, and micro-organisms. The results show that the enantiomers of (+/-)-1 are BRD4 inhibitors, (-)-1 and (+)-3 are cytotoxic against human cancer cells (K562) with IC50 values of 7.68 and 6.68 MUM, respectively. Besides compounds (+/-)-2 and (+/-)-3 exhibit potent inhibitory activity against Staphylococcus aureus with IC50 values in the range of 5.43-17.99 MUM. PMID- 29985068 TI - Interlaboratory Evaluation of the U.S. Food and Drug Administration Escherichia coli Identification Microarray for Profiling Shiga Toxin-Producing Escherichia coli. AB - The U.S. Food and Drug Administration Escherichia coli Identification (FDA-ECID) microarray provides rapid molecular characterization of E. coli. The effectiveness of the FDA-ECID for characterizing Shiga toxin-producing E. coli (STEC) was evaluated by three federal laboratories and one reference laboratory with a panel of 54 reference E. coli strains from the External Quality Assurance program. Strains were tested by FDA-ECID for molecular serotyping (O and H antigens), Shiga toxin subtyping, and the presence of the ehxA and eae genes for enterohemolysin and intimin, respectively. The FDA-ECID O typing was 96% reproducible among the four laboratories and 94% accurate compared with the reference External Quality Assurance data. Discrepancies were due to the absence of O41 target loci on the array and to two pairs of O types with identical target sequences. H typing was 96% reproducible and 100% accurate, with discrepancies due to two strains from one laboratory that were identified as mixed by FDA-ECID. Shiga toxin (Stx) type 1 subtyping was 100% reproducible and accurate, and Stx2 subtyping was 100% reproducible but only 64% accurate. FDA-ECID identified most Stx2 subtypes but had difficulty distinguishing among stx2a, stx2c, and stx2d genes because of close similarities of these sequences. FDA-ECID was 100% effective for detecting ehxA and eae and accurately subtyped the eae alleles. This interlaboratory study revealed that FDA-ECID for STEC characterization was highly reproducible for molecular serotyping, stx and eae subtyping, and ehxA detection. However, the array was less useful for distinguishing among the highly homologous O antigen genes and the stx2a, stx2c, and stx2d subtypes. PMID- 29985070 TI - Aging-related increase in store-operated Ca2+ influx in human ventricular fibroblasts. AB - Senescence-related fibrosis contributes to cardiac dysfunction. Profibrotic processes are Ca2+ dependent. The effect of aging on the Ca2+ mobilization processes of human ventricular fibroblasts (hVFs) is unclear. Therefore, we tested whether aging altered intracellular Ca2+ release and store-operated Ca2+ entry (SOCE). Disease-free hVFs from 2- to 63-yr-old trauma victims were assessed for cytosolic Ca2+ dynamics with fluo 3/confocal imaging. Angiotensin II or thapsigargin was used to release endoplasmic reticulum Ca2+ in Ca2+-free solution; CaCl2 (2 mM) was then added to assess SOCE, which was normalized to ionomycin-induced maximal Ca2+. The angiotensin II experiments were repeated after phosphoenolpyruvate pretreatment to determine the role of energy status. The expression of genes encoding SOCE-related ion channel subunits was assessed by quantitative PCR, and protein expression was assessed by immunoblot analysis. Age groups of <50 and >=50 yr were compared using unpaired t-test or regression analysis. Ca2+ release by angiotensin II or thapsigargin was not different between the groups, but SOCE was significantly elevated in the >=50-yr group. Regression analysis showed an age-dependent phosphoenolpyruvate-sensitive increase in SOCE of hVFs. Aging did not alter the mRNA expression of SOCE-related genes. The profibrotic phenotype of hVFs was evident by sprouty1 downregulation with age. Thus, an age-associated increase in angiotensin II- and thapsigargin induced SOCE occurs in hVFs, independent of receptor mechanisms or alterations of mRNA expression level of SOCE-related ion channel subunits but related to the cellular bioenergetics status. Elucidation of mechanisms underlying enhanced hVF SOCE with aging may refine SOCE targets to limit aging-related progression of Ca2+-dependent cardiac fibrosis. NEW & NOTEWORTHY Human ventricular fibroblasts exhibit an age-related increase in store-operated Ca2+ influx induced by angiotensin II, an endogenous vasoactive hormone, or thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase, independent of receptor mechanisms or genes encoding store-operated Ca2+ entry-related ion channel subunits. Selective inhibition of this augmented store-operated Ca2+ entry could therapeutically limit aging-related cardiac fibrosis. PMID- 29985071 TI - The pharmacokinetics, pharmacodynamics, and clinical role of fixed dose combination of tenofovir disoproxil fumarate, lamivudine and reduced dose efavirenz (TLE-400) in treating HIV-1 infection. AB - INTRODUCTION: Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection. Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018. Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection. Due to the lower dose of EFV, TLE-400 has a lower rate of toxicity and higher tolerability compared to its predecessor, the TLE 600, which contained a higher 600 mg dose of EFV. Given its low cost and ease of administration, TLE-400 is a promising alternative first line FDC in the management of HIV-1. PMID- 29985072 TI - Reference curves for the normal fetal small bowel and colon diameters; their usefulness in fetuses with suspected dilated bowel. AB - OBJECTIVES: To establish reference curves of normal fetal small bowel and colon diameters and to assess the clinical applicability. METHOD: Serial longitudinal ultrasound examinations at four-weekly intervals between 20 to 41 weeks of gestation in 39 low-risk fetuses. The largest loop of the small bowel and colon was identified. The bowel lumen short axis was measured. Linear mixed modeling was used to determine individual developmental trajectories. Twenty-eight fetuses with suspected bowel dilatation were analyzed relative to the reference curves. RESULTS: Development of the small bowel and colon diameters was best described by a linear and cubic model, respectively. The intraobserver and inter observer concordance were > 0.94. In cases with suspected bowel dilatation, normal fetal outcome occurred if the bowel dilatation was transient. Progressive increase of fetal bowel diameter was associated with pathology after birth. Cases with small bowel pathology had a Z-score > 8 after 25 weeks of gestation. CONCLUSION: We provided the first ultrasound reference curves for normal fetal small bowel and colon diameters. Progressive increase of the fetal bowel diameter Z-score was highly predictive of intestinal abnormalities after birth. Longitudinal follow-up of dilated fetal bowel is important to distinguish normality from disease. PMID- 29985073 TI - Maternal age potentiates the impact of operative birth on serious neonatal outcomes. AB - BACKGROUND: Pregnancies at the extremes of maternal age (<20 and >35) are associated with adverse obstetric and perinatal outcomes. There is limited evidence regarding the influence of maternal age on serious neonatal outcomes by mode of delivery. The aim of this study thus was to assess the relationship between maternal age and mode of delivery and its impact on a composite of serious neonatal outcomes. METHODS: This was a retrospective cohort study of low risk women birthing at term in Australia's largest maternity hospital over a 7 year period. Intrapartum and perinatal outcomes were collated and a composite of severe adverse neonatal outcomes (SANO) was generated. Multiple regression was applied to adjust for confounders and generate adjusted odds ratios for the risk of SANO according to mode of delivery and maternal age. RESULTS: A total of 84,698 women were included in this study of which 1572 (1.9%) were aged <20 years, 7471 (8.8%) were aged 20-24 years, 20,125 (23.8%) were aged 25-29 years, 31,594 (37.3%) were aged 30-34 years, 19,371 (22.9%) were aged 35-40 years, 4280 (5.1%) were aged 40-44 years and 285 (0.3%) were aged >=45 years. The incidence of SANO was significantly greater among adolescents compared to all other age groups. Overall, SANO was most likely to occur following Emergency Caesarean Section (EmCS) for severe intrapartum hemorrhage/uterine rupture compared to all other indications. Instrumental delivery was associated with the greatest odds of SANO (adjusted odds ratios (aOR) 3.31, 95% CI 3.08-3.55, p < .001) while spontaneous vaginal delivery (SVD) was associated with the lowest odds (aOR 0.46, 95% CI 0.43-0.48, p < .001). The adjusted odds for SANO was lowest in women aged 30-34 years (aOR 0.92, 95% CI 0.87-0.97, p < .001). The odds of SANO following an SVD increased with maternal age, with women aged 40-44 years having the highest odds. Similarly, the odds of SANO following an instrumental delivery increased with maternal age (age <20 years: aOR 2.21, 95% CI 1.38-3.54, p < .001 versus age 35-39 years: aOR 3.76, 95% CI 3.16-4.48, p < .001). CONCLUSION: This large retrospective cohort study has demonstrated that maternal age not only affects the mode of delivery and the incidence of adverse neonatal outcomes but that the effect of mode of delivery upon the risk of SANO is not independent of maternal age. PMID- 29985074 TI - VEGF-R2 and TNF-R1 expression and cytokine production by samples of mammary adenocarcinomas and correlations with histopathological parameters of these malignant tumors. AB - Currently, the role of cytokines in the tumor progression, including breast cancer, is universally recognized. At the same time, there are still many questions concerning the role of individual cytokines and receptors for cytokines in various morphogenetic processes underlying the tumor progression. The objective of this work was to study cytokine production and vascular endothelial growth factor (VEGF)-R2 and VEGF-R1 expression by mammary adenocarcinoma (MAC) and the correlations with histopathological parameters of malignant tumors. The object of the study was cultured tumor biopsy samples from 47 women aged 43-75 years with invasive ductal carcinoma, which was classified as grade II-III adenocarcinoma. It was shown that the cytokine profiles of the supernatants of MAC samples from patients differ greatly. A correlation between the levels of VEGF-R2 and tumor necrosis factor (TNF)-R1 expression was observed. Correlations were also revealed during analysis of the relations of histopathological MAC indicators with KVEGF-R2/VEGF-A and KTNF-R1/TNF-alpha coefficients, which are equal, respectively, to the ratio of expression values of receptors VEGF-R2 and TNF-R1 to the concentrations of the relevant cytokines (VEGF-A and TNF-alpha) in the culture supernatants of the same MAC samples. A direct correlation was identified between KVEGF-R/VEGF-A and some histopathological MAC characteristics: proportion of cells undergoing mitosis or pathological mitosis in MAC and poorly differentiated cells. KVEGF-R2/VEGF-A directly correlated with the concentration in supernatant interleukin (IL)-18 and interferon (IFN)-gamma. KTNF-R1/TNF-alpha was inversely correlated with the concentration in supernatant of IL-1Ra, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF). The data obtained show that the high-level production of IL-18 and IL-1beta by MAC, overexpression of VEGF-R2 in tumor (at relatively low VEGF-A production), and the high level of IFN-gamma production are attributed factors contributing to the formation of a population of low-grade cells in the tumor. The factors regulating the population of moderately differentiated cells in the tumor are referred to as IL-1Ra, IL-8, and GM-CSF. PMID- 29985075 TI - Association between blood loss at delivery and fatigue in the puerperium: a prospective longitudinal study. AB - OBJECTIVE: The objective was to investigate the association between blood loss at delivery and physical and mental fatigue during the first 12 weeks postpartum. We also investigated the association between hemoglobin and postpartum fatigue. METHODS: We performed a single center prospective longitudinal study of healthy women with a singleton delivery. Women completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale at 3 and 7 d, 3, 8 and 12 weeks postpartum. The hemoglobin level was measured at inclusion (baseline). RESULTS: A total of 196 women with blood loss at delivery ranging from 100 to 2800 mL were included in the study. At 12 weeks follow-up the response rate was 92% (n = 181). We found a significant association between blood loss and scores of physical and mental fatigue within the first week postpartum. When adjusted for bleeding, hemoglobin measured at inclusion was not associated with fatigue at any given time point. CONCLUSIONS: The amount of measured blood loss was significantly associated with increased physical and mental fatigue in the first week postpartum. When adjusted for bleeding, baseline hemoglobin was no longer associated with physical and mental fatigue. PMID- 29985076 TI - Complications associated with cardiac resynchronization therapy upgrades versus de novo implantations. AB - INTRODUCTION: A significant number of patients undergo upgrade to cardiac resynchronization therapy (CRT). These patients tend to differ from individuals undergoing de novo CRT implantations both in terms of their baseline demographics and the etiology underlying their heart failure. Areas covered: There are several factors that need to be considered when upgrading patients to CRT, such as, venous patency. Potentially, these conditions can cause issues which may result in procedures being more difficult than de novo implantations. This article discusses these issues and compares the rates of procedural-related complications for CRT upgrades and de novo implantations. It discusses the proportion of patients that are likely to respond to CRT with each intervention. Expert commentary: Understanding the relative risks of CRT upgrades versus de novo implantations is important to help operators select the correct initial device and counsel patients accordingly. Growing experience with image-guided implantations and endocardial pacing may prove to be particularly relevant to patients undergoing CRT upgrades. PMID- 29985077 TI - Dioscorea bulbifera L. delays the excretion of doxorubicin and aggravates doxorubicin-induced cardiotoxicity and nephrotoxicity by inhibiting the expression of P-glycoprotein in mice liver and kidney. AB - 1. We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. 2. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys, and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues. 3. Our results demonstrated that, after co administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone. 4. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys. PMID- 29985078 TI - Wrist arthroplasty using prosthesis as an alternative to arthrodesis: design, outcomes and future. AB - We developed an uncemented screw-shaped ball-and-socket wrist prosthesis and modified it during a decade of trails from 1996 to 2005. The final Motec(r) wrist prosthesis was launched in 2006. Since then we have used this prosthesis in 110 wrists (110 patients) from 2006 to 2018. This article reviews the design, functional outcomes, complications, clinical usefulness and possible future modifications of the Motec(r) wrist prosthesis. PMID- 29985079 TI - One-step versus two-step diagnostic testing for gestational diabetes: a randomized controlled trial. AB - OBJECTIVE: To evaluate the incidence of gestational diabetes mellitus (GDM) using the one-step as compared with the two-step approach. STUDY DESIGN: This was a parallel group nonblinded randomized trial conducted at Thomas Jefferson University Hospital (TJUH) in Philadelphia, Pennsylvania from June 2016 to December 2016. The primary outcome was GDM incidence in the one-step compared to the two-approach. Pregnant women without a history of pregestational diabetes were offered screening for GDM at gestational age 24-28 weeks. Obese women, defined as having a BMI >=30 kg/m2, as well as those with a history of a pregnancy complicated by GDM, a history of a macrosomic baby (>4000 g), or with polycystic ovarian syndrome (PCOS), were offered early screening at their initial prenatal visit, and screening was repeated at 24-28 weeks if initially normal. Women were excluded if they had pre-existing diabetes or had a history of bariatric surgery. Women who were eligible were randomized in a 1:1 ratio to either the one-step or two-step approaches. A sample size of 142 women was planned per group. Women randomized to the one-step approach, after an overnight fast, were given a 2-h glucose tolerance test, which consisted of a 75-g glucose load. Blood glucose levels were measured fasting, at 1 h and 2 h after the glucose load. Diagnostic cutoffs for GDM diagnosis were one value of either fasting >=92 mg/dL, 1 h >=180 mg/dL, or 2 h >=153 mg/dL, respectively. Women randomized to the two-step approach were given a nonfasting 50-g glucose load, and the blood glucose level was measured an hour after the glucose load. If that value was >=135 mg/dL, the patient had a 3-h glucose tolerance test consisting of a 100-g glucose load. Diagnostic cutoffs for GDM diagnosis for this 3-h test were >=2 abnormal values of fasting >=95 mg/dL, 1 h >=180 mg/dL, 2 h >=155 mg/dL and 3 h >=140 mg/dL, respectively. All analyses were done using an intention-to-treat approach, evaluating women according to the treatment group to which they were randomly allocated. RESULTS: Two hundred eighty-four women agreed to take part in the study and underwent randomization from June 2015 to December 2015. Of them, 249 completed the screening and were followed up for the primary endpoint. Out of the 249 women who completed the screening, 123 were assigned to the one-step group and 126 to the two-step group. GDM occurred in 10 women (8.1%) in the one step group, and 7 women (5.6%) in the two-step group (p = .42). Preeclampsia, preterm birth (PTB), induction of labor, mode of delivery and incidence of gestational age (OASIS) were not significantly different. Perinatal outcomes were similar as well. CONCLUSIONS: Screening for GDM with one-step, compared with the two-step approach, resulted in a similar incidence of GDM. PMID- 29985080 TI - Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post-hoc study of the OPERA trial. AB - OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial. METHOD: Treatment-naive RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (?TSS >= 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year. RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (<= 44) (p = 0.003). CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (<= 44) had a clinical value by predicting very low risk of radiographic progression at 12 months. PMID- 29985081 TI - 16S metagenomics for diagnosis of bloodstream infections: opportunities and pitfalls. AB - INTRODUCTION: Bacterial bloodstream infections (BSI) form a large public health threat worldwide. Current routine diagnosis is based on blood culture (BC) but this technique suffers from limited sensitivity. Molecular diagnostic tools have been developed for identification of bacteria in the blood of BSI patients. 16S metagenomics is an open-ended technique that can detect simultaneously all bacteria in a given sample based on PCR amplification of the 16S ribosomal RNA gene (rDNA) followed by sequencing of the PCR amplicons and taxonomic labeling of the sequence reads at genus or species level. Areas covered: Here we review the studies that have used 16S metagenomics for the identification of bacteria in human blood samples. We also discuss the potential added value of 16S metagenomics in the diagnosis of BSI, challenges as well as future directions for implementation in clinical settings. Expert commentary: 16S metagenomics has the potential to complement conventional BC; however, the technique currently suffers from several technical limitations jeopardizing implementation in routine clinical microbiology laboratories. Further studies are required to assess the cost-efficiency and clinical impact of 16S metagenomics in comparison to BC which remains the gold standard diagnostic method for BSI. PMID- 29985082 TI - Enhanced pause correlates with airway neutrophils and airway-epithelial injury in asthmatic mice treated with dexamethasone. AB - OBJECTIVE: To investigate the correlations among airway inflammation, airway epithelial injury and airway hyperresponsiveness (AHR) in asthmatic mice treated with dexamethasone. METHODS: Female BALB/c mice were sensitized with intraperitoneal and hypodermic injections of ovalbumin (OVA) and aluminum on days 0, 7 and 14, challenged with OVA starting on day 21 for 10 days, and treated with dexamethasone via intraperitoneal injection starting on day 28 for 3 days. Female C57BL/6 mice were treated intranasally with house dust mite (HDM) on days 1 and 14, challenged intranasally with HDM on days 21, 23, 25, 27 and 29, and treated with sivelestat (a selective neutrophil elastase inhibitor) via intraperitoneal injection after each challenge. Following the final challenge, enhanced pause (Penh) and differential cell counts in the broncho-alveolar lavage fluid were measured and the correlations were analyzed. RESULTS: Compared with OVA challenged BALB/c mice, the counterpart mice treated with dexamethasone showed reduced Penh and shedding of airway epithelial cells. In addition, we found that Penh 50 (an indicator of AHR) had positive correlations with airway neutrophils and shedding of airway epithelial cells, but no correlation with eosinophils, lymphocytes or macrophages. Moreover, shedding of airway epithelial cells had positive correlations with airway neutrophils, but no correlation with eosinophils, lymphocytes or macrophages. Further, sivelestat decreased Penh 50 and shed airway-epithelial cells in HDM-challenged C57BL/6 mice. CONCLUSIONS: Collectively, our findings suggest that airway neutrophils and excessive shedding of airway epithelial cells, but not eosinophils, lymphocytes or macrophages, may be involved in AHR in asthmatic mice treated with dexamethasone. PMID- 29985083 TI - Primary optic neuropathy in Behcet's syndrome. AB - BACKGROUND: Primary optic neuropathy in Behcet's syndrome (PONBS) is limited to a few case reports. OBJECTIVE: To investigate the clinical features, magnetic resonance imaging (MRI) changes, and visual prognosis of PONBS. METHODS: Sixty one patients who presented with first onset of optic neuritis and fulfilled the International Criteria for Behcet's Disease (ICBD) were evaluated. RESULTS: The female-to-male ratio was 1.7:1. No patient had other central nervous system (CNS) disease. In 67 eyes with optic nerve abnormalities on MRI scan, perineural enhancement around the orbital optic nerve (46 eyes, 68.7%) was significantly more frequent than was increased signal in the optic nerve itself (31 eyes, 46.3%; p = 0.000), typically with sunflower-like appearance on coronal view (33 eyes, 71.7%). Two patients (3.6%) relapsed during follow-up (median 12 months). Kaplan-Meier survival analysis estimated the cumulative risk of severe visual loss (?0.1) at 24 months was 14.7% in females versus 62.5% in males (hazard ratio (HR), 0.16; 95% confidence interval, 0.05-0.54). CONCLUSION: PONBS frequently presents with isolated optic neuropathy in females. The sunflower-like sign might be a distinctive MRI feature. Short-term recurrence is very rare. Males have a higher cumulative risk of severe visual loss. PMID- 29985084 TI - Drug-associated progressive multifocal leukoencephalopathy in multiple sclerosis patients. AB - OBJECTIVE: To investigate characteristics of multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients associated with drugs other than natalizumab since our experience in other disease-modifying drugs (DMD) is still limited. METHODS: This is a descriptive observational study within the FAERS database, registered between July 2015 and June 2017. RESULTS: The primary cohort for the analysis consisted of 100,921 MS patients (mean (standard deviation (sd)) age, 48.9 (12.8) years, 20.9% male). Among them 786 (0.78%) developed PML. The adjusted odds ratio of PML for each drug was as follows; natalizumab 115.72 (95% CI; 83.83, 159.74), fingolimod 4.98 (3.64, 6.81) followed by dimethyl fumarate 1.77 (1.2, 2.62) and rituximab 3.22 (1.07, 9.72). The median time from the start of suspected drugs to the onset of PML for natalizumab and other agents were 1463 and 178 days, respectively. The proportion of PML appeared higher in Japan (2.4%) compared to that in the United States (0.24%). CONCLUSION: The reporting proportion of PML was relatively higher in natalizumab followed by fingolimod, dimethyl fumarate and rituximab. Other characteristics of PML associated with DMDs, including the time to onset and differences in reporting among countries, are described. PMID- 29985085 TI - Professionals' Perceptions of Female Child Sexual Offenders. AB - The aims of the current study were to (a) obtain an in-depth understanding about professionals' perceptions of female child sexual offenders and (b) identify where system efforts should be focused to better address and acknowledge female child sexual offenders. In-depth semistructured interviews were conducted one-on one with a diverse group of professionals (police officers, social workers, counselors, case managers, child and family support workers, and a legal professional; N = 21) involved in the community response and justice sector, which allowed for unique views across diverse vantage points. Four core themes were identified through thematic analysis: (a) female child sexual offenders are a heterogeneous group, (b) negative impact of female-perpetrated sexual abuse, (c) gender of perpetrator is predominantly insignificant in case dealings, and (d) the need for a more open discourse on female child sexual offenders. Professionals in the current study acknowledged that female child sexual offenders can inflict serious and persistent negative impacts on victims and that the gender of the offender is insignificant in their individual professional dealings of child sexual abuse cases. While these findings appear to be a positive step forward, away from earlier perceptions identified in the literature, it was evident that the gender of the perpetrator may still play a significant role in some dealings across professions and among colleagues. Two areas identified by professionals as requiring system efforts were (a) professional development along with the dissemination of appropriate research to better inform professionals and (b) the need for a more open discussion in society concerning female-perpetrated sexual abuse. The findings of the current study may assist with appropriate recognition, protection, and intervention for victims of female-perpetrated sexual abuse. PMID- 29985086 TI - The potential utility of PFKFB3 as a therapeutic target. AB - INTRODUCTION: It has been known for over half a century that tumors exhibit an increased demand for nutrients to fuel their rapid proliferation. Interest in targeting cancer metabolism to treat the disease has been renewed in recent years with the discovery that many cancer-related pathways have a profound effect on metabolism. Considering the recent increase in our understanding of cancer metabolism and the enzymes and pathways involved, the question arises as to whether metabolism is cancer's Achilles heel. Areas covered: This review summarizes the role of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in glycolysis, cell proliferation, and tumor growth, discussing PFKFB3 gene and isoenzyme regulation and the changes that occur in cancer and inflammatory diseases. Pharmacological options currently available for selective PFKFB3 inhibition are also reviewed. Expert opinion: PFKFB3 plays an important role in sustaining the development and progression of cancer and might represent an attractive target for therapeutic strategies. Nevertheless, clinical trials are needed to follow up on the promising results from preclinical studies with PFKFB3 inhibitors. Combination therapies with PFKFB3 inhibitors, chemotherapeutic drugs, or radiotherapy might improve the efficacy of cancer treatments targeting PFKFB3. PMID- 29985087 TI - Improbable, but plausible, research study: a randomised controlled trial of premature cord clamping vs. neonatal venesection to achieve routine prophylactic neonatal red cell reduction. PMID- 29985088 TI - Misuse of Coauthorship in Medical Theses in Sweden. AB - The aim of this study was to explore experiences of authorship issues among persons who have recently received their doctoral degree in medicine in Sweden. A survey was mailed to all who received their PhD at a medical faculty at a Swedish university the first half of 2016. Questions concerned experiences of violations of the first three authorship criteria in the Vancouver rules and of misuse of authorship order in the articles of their thesis, and the respondents' attitudes to these matters. The questionnaire was returned by 285 respondents (68%). According to the majority (53%), the Vancouver rules were not fully respected in the articles of their thesis. A vast majority (97%) found it important that authorship issues are handled correctly, but only 19% responded that their department has a clear and consistently applied policy. We conclude that authorship guidelines are frequently disrespected at medical faculties in Sweden. The universities seem to provide limited support on authorship issues. PMID- 29985089 TI - The efficacy of repetitive transcranial magnetic stimulation for Parkinson disease patients with depression. AB - Objective To evaluate the efficacy of repetitive transcranial magnetic stimulation for Parkinson disease (PD) patients with depression. Methods A meta analysis was performed using relevant randomized controlled trials (RCTs) from online databases such as PubMed, Embase, Cochrane Online Library, and Clinicaltrials.gov. Studies were selected according to pre-defined inclusion and exclusion criteria, and the quality of the studies was evaluated using the Jadad Scale. All data were pooled by RevMan 5.2 software for meta-analysis. Results The review covered 528 articles, and 7 articles with Jadad score >= 4 were included in the analysis. The meta-analysis showed that, compared to sham repetitive transcranial magnetic stimulation (sham-rTMS), repetitive transcranial magnetic stimulation (rTMS) over dorsolateral prefrontal cortex (DLPFC) improved depression, but that there was no significant difference in depression improvement between rTMS and selective serotonin reuptake inhibitor (SSRI) treatment. In contrast, rTMS over DLPFC did not improve motor function compared to sham-rTMS or SSRI, and the studies that included neurocognitive measures showed no significant difference between rTMS and sham-rTMS. Conclusion This meta analysis provides evidence that rTMS over DLPFC can improve depression similar to SSRI treatment, has no effect on the motor function and cognition of PD patients with depression. PMID- 29985090 TI - Parental Stress and Parental Self-Efficacy as Mediators of the Association Between Children's ADHD and Marital Satisfaction. AB - : Parents of children with ADHD often experience low marital satisfaction, since the child's increased susceptibility to maladjustment can affect family dynamics as a whole. OBJECTIVES: To explore this association by examining parental stress and parental self-efficacy as two possible mediators. METHOD: Totally, 182 Israeli parents of children in the first to ninth grades (63 parents of children with ADHD and 119 without) completed parental self-efficacy, marital satisfaction, and parental stress questionnaires. RESULTS: As expected, parents of children with ADHD reported higher parental stress, and lower self-efficacy and marital satisfaction than non-ADHD parents. The association between ADHD parents and marital satisfaction was fully explained by parental stress and self efficacy, suggesting that personal characteristics and situation appraisal are tapped when facing strain and hardship. CONCLUSION: These findings provide a window of hope for an otherwise deterministic view of the ADHD-marital dissolution relationship and propose individual and familial interventions that may minimize these damaging effects. PMID- 29985092 TI - Cerebrospinal fluid mitochondrial DNA levels in patients with multiple sclerosis. AB - The role of cerebrospinal fluid (CSF) mitochondrial DNA (mtDNA) levels as biomarker in multiple sclerosis (MS) is unknown. We determined CSF mtDNA levels in a cohort of 237 individuals, including patients with MS and clinically isolated syndrome (CIS), inflammatory and non-inflammatory neurological controls, and cognitively healthy controls (HC). mtDNA concentration was measured by droplet digital polymerase chain reaction. CSF mtDNA levels were increased in all pathological conditions compared with HC, though no differences were observed between relapse-onset and progressive MS clinical forms, CIS patients and neurological controls. These findings do not support the determination of CSF mtDNA levels as a useful biomarker in MS clinical practice. PMID- 29985091 TI - Effects of AANAT overexpression on the inflammatory responses and autophagy activity in the cellular and transgenic animal levels. AB - To explore the anti-inflammatory activity of endogenous produced melatonin, a melatonin-enriched animal model (goat) with AANAT transfer was successfully generated with somatic cell nuclear transfer (SCNT) technology. Basically, a pIRES2-EGFP-AANAT expression vector was constructed and was transferred into the female fetal fibroblast cells (FFCs) via electrotransfection and then the nuclear of the transgenic FFC was transferred to the eggs of the donor goats. The peripheral blood mononuclear cells (PBMCs) of the transgenic offspring expressed significantly higher levels of AANAT and melatonin synthetic function than those PBMCs from the wild-type (WT) animals. After challenge with lipopolysaccharide (LPS), the transgenic PBMCs had increased autophagosomes and LC3B expression while they exhibited suppressed production of the proinflammatory cytokines, IL1B and IL12 (IL12A-IL12B/p70), compared to their WT. The mechanistic analysis indicated that the anti-inflammatory activity of endogenous melatonin was mediated by MTNR1B (melatonin receptor 1B). MTNR1B stimulation activated the MAPK14 signaling pathway to promote cellular macroautophagy/autophagy, thus, suppressing the excessive inflammatory response of cellular. However, when the intact animals challenged with LPS, the serum proinflammatory cytokines were significantly higher in the transgenic goats than that in the WT. The results indicated that endogenous melatonin inhibited the MAPK1/3 signaling pathway and ROS production, subsequently downregulated gene expression of BECN1, ATG5 in PMBCs and then suppressed the autophagy activity of PBMCs and finally elevated levels of serum proinflammatory cytokines in transgenic animals, Herein we provided a novel melatonin-enriched animal model to study the potential effects of endogenously produced melatonin on inflammatory responses and autophagy activity. PMID- 29985093 TI - Purkinje Cell Representations of Behavior: Diary of a Busy Neuron. AB - Fundamental for understanding cerebellar function is determining the representations in Purkinje cell activity, the sole output of the cerebellar cortex. Up to the present, the most accurate descriptions of the information encoded by Purkinje cells were obtained in the context of motor behavior and reveal a high degree of heterogeneity of kinematic and performance error signals encoded. The most productive framework for organizing Purkinje cell firing representations is provided by the forward internal model hypothesis. Direct tests of this hypothesis show that individual Purkinje cells encode two different forward models simultaneously, one for effector kinematics and one for task performance. Newer results demonstrate that the timing of simple spike encoding of motor parameters spans an extend interval of up to +/-2 seconds. Furthermore, complex spike discharge is not limited to signaling errors, can be predictive, and dynamically controls the information in the simple spike firing to meet the demands of upcoming behavior. These rich, diverse, and changing representations highlight the integrative aspects of cerebellar function and offer the opportunity to generalize the cerebellar computational framework over both motor and non-motor domains. PMID- 29985095 TI - Impact of mindfulness-based stress reduction for people with multiple sclerosis at 8 weeks and 12 months: A randomized clinical trial. AB - BACKGROUND: Mindfulness training is often used as a therapeutic intervention to manage stress and enhance emotional well-being, yet trials for multiple sclerosis (MS) are limited and few have used an active control. OBJECTIVE: Assess the feasibility of mindfulness-based stress reduction (MBSR) for people with MS and evaluate the efficacy of MBSR compared to an education control. METHODS: We conducted a single-blind, randomized trial of MBSR versus education control among 62 adults with MS. Primary outcomes were measures of feasibility. Secondary outcomes included perceived stress, anxiety, depression, fatigue, pain, resilience, and the Paced Auditory Serial Addition Test, assessed at baseline, 8 weeks, and 12 months. Mean scores for secondary outcome measures were compared between groups at each time point and within groups across time by analyses of covariance or paired t-tests, respectively. RESULTS: Successful recruitment and retention demonstrated feasibility. Improvements in several secondary outcomes were observed among both MBSR and control groups. However, differences between the groups were not statistically significant at either 8 weeks or 12 months. CONCLUSION: Emotional well-being improved with both MBSR and education. Spontaneous improvement cannot be ruled out as an explanation for findings and additional studies that evaluate the impact of mindfulness training to improve emotional health are warranted. PMID- 29985096 TI - Single inhaler triple therapy with extrafine beclomethasone, formoterol, and glycopyrronium for the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) management focuses on the alleviation of symptoms and prevention of exacerbations. Inhaled long acting bronchodilators and inhaled corticosteroids (ICS) are the main classes of treatment for COPD. Triple therapy with a long acting beta2-agonist (LABA), long acting muscarinic antagonist (LAMA), and ICS is commonly prescribed for symptomatic COPD patients experiencing regular exacerbations. Triple therapy is usually administered using separate inhalers; there is little clinical trial evidence of an effect on exacerbation prevention with this approach. Areas covered: This evaluation reviews the single inhaler extrafine combination containing beclometasone diproprionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) which has been developed as a simplified triple regime. BDP/FF/GB significantly reduced exacerbation rates in three clinical trials (1-year duration) compared against LAMA monotherapy (20% exacerbation reduction), ICS/LABA combination (23% exacerbation reduction), and LAMA/LABA combination (15% exacerbation reduction). Expert opinion: The practical benefits of single inhaler triple therapy in the real world have not been studied. However, the robust clinical trial evidence that BDP/FF/GB reduces exacerbations compared to double combination treatments and LAMA monotherapy cements triple therapy positioning as an escalation step in COPD management pathways. PMID- 29985097 TI - Impacts of Low Self-Control and Delinquent Peer Associations on Bullying Growth Trajectories Among Korean Youth: A Latent Growth Mixture Modeling Approach. AB - The emergence of studies applying Gottfredson and Hirschi's (1990) self-control theory to offending behaviors has produced empirical support confirming the position that individuals with low self-control are more likely to engage in deviant behaviors. However, few have examined its effects with opportunity factors. The present study examines the time-invariant effect of low self control, as well as the time-concurrent and lagged effects of opportunity factors (parental attachment and delinquent peer associations), on bullying growth trajectories. The findings in the latent growth curve analysis demonstrate that low self-control is significantly related to both the initial levels and change in bullying over time, even after controlling for delinquent peer associations in homogeneous populations. The new approach described within the latent class growth modeling framework (i.e., growth mixture) incorporates a categorical latent trajectory variable representing latent classes (i.e., distinct subgroups), having similar patterns of bullying growth trajectories. Three groups of students emerged from the student-reported data at five time points from ages 11 to 15, decreasers (90%), moderate late peakers (7%), and high late peakers(3%), defined by different predictors and sequelae. Low self-control was rendered insignificant for both moderate late peakers and high late peakers relative to decreasers; delinquent peer associations had a time-concurrent effect for moderate late peakers than decreasers; and high late peakers had a time lagged effect relative to moderate late peakers. PMID- 29985098 TI - A Cross-Modal Working Memory Binding Span Deficit in Reading Disability. AB - Successful reading demands the ability to combine visual-phonological information into a single representation and is associated with an efficient short-term memory. Reading disability may consequently involve an impaired working memory binding of visual and phonological information. The present study proposes two span tasks for assessing visual-phonological working memory binding. The tasks involved memorizing cross-modal associations between nonsense figures and nonwords, and they were administered, with other working memory measures, to children with and without a reading disability. The tasks required recognizing which figure was associated with a given nonword and recalling which nonword was associated with a given figure. Children with a reading disability had a similar significant deficit in both cross-modal binding tasks when compared with the control children, and the difference remained significant even after controlling for other verbal and nonverbal working memory measures. The cross-modal binding tasks described here seem to capture a core aspect of working memory associated with reading and may be a useful procedure for assessing reading disabilities. PMID- 29985099 TI - Reducing reward responsivity and daily food desires in female dieters through domain-specific training. AB - According to the strength model, self-regulation relies on a domain-general capacity that may be strengthened by training. From this perspective, training self-regulation in one domain may transfer to other domains. Here we used two inhibitory training paradigms, a domain-general and domain-specific stop-signal training task and compared their effects on brain reward activity as well as daily food desires in female dieters. Before and after the training, functional magnetic resonance imaging was used to assess food cue-reactivity, coupled with one week of smart-phone ecological momentary assessments to examine eating urges. Whereas the food-specific inhibitory training was successful in reducing both food cue-reactivity and food desires, the domain-general (sound-cue) training showed no transfer effects. These findings suggest that domain-specific training may be a more effective method for supporting self-regulation than domain-general approaches aimed at strengthening self-regulation across domains. PMID- 29985094 TI - Influence of transcriptional variants on metastasis. AB - Cancer metastasis is defined as the dissemination of malignant cells from the primary tumor site, leading to colonization of distant organs and the establishment of a secondary tumor. Metastasis is frequently associated with chemoresistance and is the major cause of cancer-related mortality. Metastatic cells need to acquire the ability to resist to stresses provided by different environments, such as reactive oxygen species, shear stress, hemodynamic forces, stromal composition, and immune responses, to colonize other tissues. Hence, only a small population of cells has a metastasis-initiating potential. Several studies have revealed the misregulation of transcriptional variants during cancer progression, and many splice events can be used to distinguish between normal and tumoral tissue. These variants, which are abnormally expressed in malignant cells, contribute to an adaptive response of tumor cells and the success of the metastatic cascade, promoting an anomalous cell cycle, cellular adhesion, resistance to death, cell survival, migration and invasion. Understanding the different aspects of splicing regulation and the influence of transcriptional variants that control metastatic cells is critical for the development of therapeutic strategies. In this review, we describe how transcriptional variants contribute to metastatic competence and discuss how targeting specific isoforms may be a promising therapeutic strategy. PMID- 29985100 TI - Incidence and risk factors of chronic thromboembolic pulmonary hypertension following venous thromboembolism, a population-based cohort study in England. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of unresolved organised pulmonary emboli/thrombi obstructing the major pulmonary arteries. The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE). This was a population based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012. CTEPH was assessed using a rigorous case-ascertainment algorithm. Risk factors for CTEPH were studied using a nested case-control approach by matching CTEPH cases to VTE patients without CTEPH. Adjusted odds ratios (OR) of comorbidities were estimated from conditional logistic regression. During 81,413 person-years of follow-up among 23,329 patients with first VTE (mean follow-up 3.5 years; maximum 11.0 years) 283 patients were diagnosed with CTEPH (incidence rate 3.5 per 1000 person-years); cumulative incidence was 1.3% and 3.3% at 2 and 10 years after pulmonary embolism, and 0.3% and 1.3% following deep vein thrombosis (DVT), respectively. Risk factors for CTEPH included age over 70, OR 2.04 (95% CI 1.23 to 3.38), female gender, 1.44 (1.06 to 1.94), pulmonary embolism at first VTE, 3.11 (2.23 to 4.35), subsequent pulmonary embolism and DVT, 3.17 (2.02 to 4.96) and 2.46 (1.34 to 4.51) respectively, chronic obstructive pulmonary disease 3.17 (2.13 to 4.73), heart failure 2.52 (1.76 to 3.63) and atrial fibrillation, 2.42 (1.71 to 3.42). CTEPH develops most commonly after pulmonary embolism and less frequently after DVT. Awareness of risk factors may increase referrals to specialised centres for confirmation of CTEPH and initiation of specific treatment. PMID- 29985101 TI - Aged care staff's experiences of 'Better Oral Health in Residential Care Training': a qualitative study. AB - BACKGROUND: The The Better Oral Health in Residential Care (BOHRC) Training was rolled out to Residential Aged Care Facilities (RACF) across Australia in 2010. AIM: To examine aged care staff's views on the implementation of the BOHRC Training at their facilities; challenges that they faced in the provision of oral health care to residents and their training needs. METHODS: A qualitative study using semi-structured interviews was conducted with 20 staff across Tasmania. Interview data was thematically analysed. RESULTS: Major barriers reported were a lack of time, competing priorities, workload and staffing issues. The majority of participants did not receive the BOHRC training directly. Participants preferred to have practical, 'hands-on' training delivered on site at least every 12 months. CONCLUSIONS: Oral hygiene training should be provided regularly to equip staff with knowledge and skills to overcome some of the challenges they face and to improve oral hygiene care provision to residents. PMID- 29985102 TI - Enhanced adsorption of Cd(II) using a composite of poly(acrylamide-co-sodium acrylate) incorporated LDH@[Formula: see text]. AB - The Mg/Al layered double hydroxide (Mg/Al-LDH) intercalated with the [Formula: see text] (MoS4-LDH) impregnated into poly(acrylamide-co-sodium acrylate) (PP) was synthesized as layered double hydroxides-PP (LDHS-PP), whose characterization, adsorption properties and mechanisms were investigated. The maximum adsorption capacity (qm) for Cd(II) was ~2789.58 mg/g by 1% LDHS-PP, while it was ~1893.09 mg/g by PP, which indicated that the MoS4-LDH greatly improved the Cd(II) uptake for PP in aqueous solution. In strongly acidic conditions (~pH 3.0), there was still a good removal efficiency of about 45.65% by the 1% LDHS-PP, while that of PP was almost zero. At pH 5.0 the removal efficiency increased to 85.17% by the 1% LDHS-PP. The sorption kinetics for the 1% LDHS-PP was described well by a pseudo-second-order kinetic model. X-ray photoelectron spectrometry (XPS) and elemental distribution maps further confirmed the presence of MoS4-LDH in the PP and most of the Cd(II) chemisorption based on the Cd-S bonding. Due to its high removal efficiency and acid resistance, LDHS-PP is a promising in-situ fixation agent for the remediation of agricultural soil polluted with Cd(II) at low pH. PMID- 29985103 TI - KrCl and XeCl excilamps and LP-Hg lamp for UV and UV/H2O2 decolourization of dyes in water. AB - In the present study, the decolourization efficiencies of LP-Hg lamp, XeCl and KrCl excilamps at the same power density were compared for the decolourization of dyes in water by UV and UV/H2O2 processes in a batch reactor. Laboratory prototypes of XeCl and KrCl excilamps and a commercial LP-Hg lamp were studied as UV sources. Methylene Blue and Eliamine Blue dyes were used as model pollutants. The effect of the initial concentrations of dye and H2O2 in the TOC removal and kinetic parameters were also studied. The ratio of dye decolourization to the electric power consumption of the KrCl excilamp and LP-Hg lamp for the decolourization of Methylene Blue and Eliamine Blue were evaluated. As a result, the KrCl excilamp showed significantly higher decolourization efficiencies than LP-Hg lamp and XeCl excilamp, but the dye removal rate was significantly slower for Methylene Blue than for Eliamine Blue with this lamp. The KrCl lamp can be an alternative to conventional LP-Hg lamp for the decolourization of dyes by photodegradation, but it depends on the type of dye treated. The addition of H2O2 in a concentration between 0.05 and 0.09%v/v increases significantly the efficiency of the decolourization of Methylene Blue, and further increase does not lead to a higher increase in conversion. The experimental data were fitted to the one phase decay kinetic model with good agreement and the kinetic parameters were reported. PMID- 29985104 TI - Clock Drawing Test in acute stroke and its relationship with long-term functional and cognitive outcomes. AB - OBJECTIVE: The Clock Drawing Test (CDT) is commonly used as a screening tool for the assessment of dementia. The association between the CDT in acute stroke and long-term functional and cognitive outcomes in this population is unknown. The present prospective study is the first to examine if CDT scores in the acute stage after stroke are related to long-term outcomes and to compare the predictive ability of two scoring systems in a large sample of stroke patients. METHOD: A total of 340 patients admitted to an acute stroke unit were included in the present study. Separate stepwise multiple linear regression analyses were performed with eight independent variables (demographic/pre-stroke variables - age, sex, premorbid functioning; stroke-related variables - stroke severity, localization; cognitive variables - Orientation Test, CDT [2 scoring systems]), and four dependent variables administered one year post-stroke (Barthel Index, modified Rankin Scale, Reintegration to Normal Living index, Global Deterioration Scale). RESULTS: Although both CDT scoring methods were related to all long-term outcome measures, the more comprehensive scoring system was the only baseline variable that significantly explained the variance in outcome measures in all four multiple regression models. CONCLUSION: Performance on the CDT in acute stroke is related to long-term outcomes including patients' degree of independence in performing activities of daily living, the degree to which they achieved reintegration into daily occupations, and the degree of cognitive decline observed one-year post-stroke. Future studies are needed to clarify the nature of the relationship between different CDT scoring systems and post-stroke outcomes. PMID- 29985105 TI - Characterization and abolishment of the cyclopiazonic acids produced by Aspergillus oryzae HMP-F28. AB - Extracellular alkalinization and H2O2 production are important early events during induced resistance establishment in plants. In a screen for metabolites as plant resistance activators from 98 fungal isolates associated with marine sponge Hymeniacidon perleve, the cyclopiazonic acids (CPAs) produced by Aspergillus oryzae HMP-F28 induced significant extracellular alkalinization coupled with augmented H2O2 production in tobacco cell suspensions. Bioassay-guided fractionation led to the isolation and structural elucidation of a new CPA congener (4, 3-hydroxysperadine A) and three known ones (1-3). To construct a mutasynthetic strain to generate unnatural CPA analogues, a hybrid pks-nrps gene (cpaS) was disrupted to abolish the production of the critical precursor of cyclo acetoacetyl-L-tryptophan (cAATrp) and all the downstream CPA products. Elimination of cAATrp will allow cAATrp mimics being processed by the CPA biosynthetic machinery to produce CPA derivatives with designed structural features. PMID- 29985106 TI - The processing of task-irrelevant emotion and colour in the Approach-Avoidance Task. AB - When processing information about human faces, we have to integrate different sources of information like skin colour and emotional expression. In 3 experiments, we investigated how these features are processed in a top-down manner when task instructions determine the relevance of features, and in a bottom-up manner when the stimulus features themselves determine process priority. In Experiment 1, participants learned to respond with approach avoidance movements to faces that presented both emotion and colour features (e.g. happy faces printed in greyscale). For each participant, only one of these two features was task-relevant while the other one could be ignored. In contrast to our predictions, we found better learning of task-irrelevant colour when emotion was task-relevant than vice versa. Experiment 2 showed that the learning of task-irrelevant emotional information was improved in general when participants' awareness was increased by adding NoGo-trials. Experiment 3 replicated these results for faces and emotional words. We conclude that during the processing of faces, both bottom-up and top-down processes are involved, such that task instructions and feature characteristics play a role. Ecologically significant features like emotions are not necessarily processed with high priority. The findings are discussed in the light of theories of attention and cognitive biases. PMID- 29985107 TI - Cognitive Reflection and the 2016 U.S. Presidential Election. AB - We present a large exploratory study ( N = 15,001) investigating the relationship between cognitive reflection and political affiliation, ideology, and voting in the 2016 Presidential Election. We find that Trump voters are less reflective than Clinton voters or third-party voters. However, much (although not all) of this difference was driven by Democrats who chose Trump. Among Republicans, conversely, Clinton and Trump voters were similar, whereas third-party voters were more reflective. Furthermore, although Democrats/liberals were somewhat more reflective than Republicans/conservatives overall, political moderates and nonvoters were least reflective, whereas libertarians were most reflective. Thus, beyond the previously theorized correlation between analytic thinking and liberalism, these data suggest three additional consequences of reflectiveness (or lack thereof) for political cognition: (a) facilitating political apathy versus engagement, (b) supporting the adoption of orthodoxy versus heterodoxy, and PMID- 29985108 TI - Evaluating an intervention to increase meaningful activity after severe traumatic brain injury: A single-case experimental design with direct inter-subject and systematic replications. AB - Severe traumatic brain injury (sTBI) often results in significant morbidity, with fewer than 50% returning to work and only a minority resuming leisure and social activity. Yet few effective interventions are available for non-vocational activity. The aim of the study was to develop a new goal-directed intervention, the Programme for Engagement, Participation and Activities (PEPA), and evaluate its effect. The research design was a multiple-baseline design across behaviours, with direct inter-subject and systematic replications. Seven participants with sTBI, neurobehavioural impairment including apathy, inability to work, and limited leisure/social activities were categorised into two groups. Group 1 (n = 4) had cognitive impairments but were functionally independent. Systematic replication was conducted in a further three participants (group 2) with major neurobehavioural impairments and functional disability. Generalisation measures evaluated other life domains in group 1 participants (e.g., mood, community participation). Results of the weighted average Tau-U across the tiers was significant for six out of seven participants, with large effect sizes (>=.64) for five participants. Generalisation effects extended to other domains of life. The PEPA thus shows promise as an effective intervention to increase non vocational activity and improve mental health outcomes in people with neurobehavioural disability after sTBI. These results add to the evidence for the effectiveness of goal-directed interventions. PMID- 29985109 TI - Cognitive sex differences and hemispheric asymmetry: A critical review of 40 years of research. AB - According to a longstanding view, sex differences in cognitive abilities such as mental rotation or verbal memory arise from sex differences in hemispheric asymmetry: males are thought to be more lateralized than females which boosts their spatial but hampers their verbal skills. This idea sparked great interest and, even though it lost support in the 1990s, it is still put forward in contemporary (popular) scientific papers and textbooks. We aimed to provide a comprehensive review that summarizes the last 40 years of research. First, we confirm previous findings that the stronger hemispheric asymmetry in males is very small but robust. Second, we conclude that stronger hemispheric asymmetry, in general, does not enhance spatial and reduce verbal performance. Crucially, we carried out a systematic literature review showing that cognitive sex differences often emerge in the absence of sex differences in hemispheric asymmetry (and vice versa), implying the two phenomena are at least partly independent of each other. At present, there is insufficient data to conclude that sex differences in hemispheric asymmetry and cognitive performance are uncorrelated. However, we can conclude that sex differences in hemispheric asymmetry are certainly not the driving force behind sex differences in cognitive functioning. PMID- 29985110 TI - A cautionary note on electronic cigarettes and vascular health. PMID- 29985111 TI - Associations between liveweight, body condition score and previous reproductive outcomes, and the risk of ewes bred at 18-months of age being dry at docking. AB - AIMS Firstly, to investigate associations between liveweight and body condition score (BCS) of two-tooth ewes (18-months-old at breeding) at breeding, pregnancy diagnosis (PD) and pre-lambing and the risk of being dry at docking, on commercial New Zealand sheep farms. Secondly, to investigate the association between previous reproductive outcomes as ewe lambs, and risk of being dry at docking as two-tooth ewes. METHODS Two-tooth ewes (n=9,006) were enrolled in four cohorts from three commercial sheep farms between 2010-14. Ewes were weighed and BCS assessed immediately pre-breeding, at PD (mid-pregnancy) and pre-lambing. At PD, ewes were identified as either non-pregnant, or having single or multiple fetuses. Palpation and examination of udders at docking was used to classify each ewe as either lactating or dry at docking. RESULTS Overall, 437/8,025 (5.4%) of ewes that were diagnosed pregnant at PD were dry at docking. The risk of being dry at docking decreased with increasing pre-lambing conceptus adjusted liveweight (CALW) on all farms (p<=0.002); for 2010-born ewes from Farm A the OR=0.87 (95% CI=0.81-0.92); for Farm B the OR=0.88 (95% CI=0.83-0.92) and for Farm C the OR=0.86 (95% CI=0.79-0.95). The risk of being dry at docking also decreased with increasing CALW gain from PD to pre-lambing for all farms (p<=0.003); for 2010-born ewes from Farm A the OR=0.89 (95% CI=0.84-0.94); for Farm B the OR=0.85 (95% CI=0.81-0.89) and for Farm C the OR=0.88 (95% CI=0.80 0.96). There was no association between BCS at breeding, PD or pre-lambing and the risk of being dry at docking for 2010-born ewes from Farm A, Farm B or Farm C (p>0.05). For 2010-born ewes on Farm A, the risk of being dry at docking was greater for two-tooth ewes that were previously dry at docking as ewe lambs than those that were lactating at docking as ewe lambs (OR=1.7 (95% CI=1.1-2.8); p=0.018), but this difference was not observed for ewes on Farm B or Farm C (p>0.5). CONCLUSIONS There were negative associations between ewe CALW pre lambing, and CALW gain between PD and pre-lambing, and risk of being dry at docking. For all cohorts, heavier ewes and those that gained CALW were less likely to be dry at docking than lighter ewes or those that lost CALW, however these relationships varied between cohorts. PMID- 29985112 TI - Maternal Caregiving Practices and Child Abuse Experiences as Developmental Antecedents to Insecure Attachments: Differential Pathways Between Adolescents Who Commit Sexual and Non-Sexual Crimes. AB - Grady, Levenson, and Bolder's etiological framework contextualizes sexual offending behaviors through a trauma and attachment lens to suggest child abuse experiences (CAE) are associated with attachment problems that contribute to sexual offending. To empirically test a portion of this theory, this cross sectional study employed a structural equation mediated-moderated model on a sample of juvenile justice-involved youth ( N = 505) who committed sexual ( n = 355) and non-sexual ( n = 150) offenses. Results revealed a good model fit and statistically significant direct effects between maternal harsh and indifferent caregiving styles and insecure attachment. However, CEAs did not mediate the relationship between caregiving styles and insecure attachment. Results also revealed a moderation effect whereby youth who commit sexual crimes who report harsher and more indifferent maternal caregiving styles were more likely to have higher CAEs relative to youth who commit non-sexual crimes. Implications are discussed using a public health perspective of prevention. PMID- 29985113 TI - E-cigarettes and cigarettes worsen peripheral and central hemodynamics as well as arterial stiffness: A randomized, double-blinded pilot study. AB - The introduction of electronic cigarettes has led to widespread discussion on the cardiovascular risks compared to conventional smoking. We therefore conducted a randomized cross-over study of the acute use of three tobacco products, including a control group using a nicotine-free liquid. Fifteen active smokers were studied during and after smoking either a cigarette or an electronic cigarette with or without nicotine (eGo-T CE4 vaporizer). Subjects were blinded to the nicotine content of the electronic cigarette and were followed up for 2 hours after smoking a cigarette or vaping an electronic cigarette. Peripheral and central blood pressures as well as parameters of arterial stiffness were measured by a Mobil-O-Graph(r) device. The peripheral systolic blood pressure rose significantly for approximately 45 minutes after vaping nicotine-containing liquid ( p<0.05) and for approximately 15 minutes after smoking a conventional cigarette ( p<0.01), whereas nicotine-free liquids did not lead to significant changes during the first hour of follow-up. Likewise, heart rate remained elevated approximately 45 minutes after vaping an electronic cigarette with nicotine-containing liquid and over the first 30 minutes after smoking a cigarette in contrast to controls. Elevation of pulse wave velocity was independent from mean arterial pressure as well as heart rate in the electronic cigarette and cigarette groups. In this first of its kind trial, we observed changes in peripheral and central blood pressure and also in pulse wave velocity after smoking a cigarette as well as after vaping a nicotine-containing electronic cigarette. These findings may be associated with an increased long term cardiovascular risk. PMID- 29985114 TI - The promise of functional near-infrared spectroscopy in autism research: What do we know and where do we go? AB - Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that has been gaining increasing interest as a method to investigate the brain function of individuals on the autism spectrum. It is a non-invasive, portable and relatively motion-tolerant method of measuring haemodynamic activity in the brain. fNIRS can be particularly effective for quantifying brain function in challenging clinical populations. In light of this, there is a growing body of fNIRS literature focusing on individuals on the autism spectrum. The aim of this review is to evaluate and summarise key studies from the literature and discuss their implications for the field. Potential limitations of the fNIRS approach and resolution of these issues based on emerging fNIRS research are also discussed. PMID- 29985115 TI - Enhanced solar water disinfection using ZnO supported photocatalysts. AB - Nano-structured ZnO photocatalysts on cellulose and polyester supports were developed for enhancing solar water disinfection (SODIS). The photocatalysts were fabricated by a two-step hydrothermal method, in which ZnO nanoparticles were synthesized and deposited on a cellulose or polyester support as a seed layer, followed by the growth of one-dimensional ZnO nanorods on the seed layer in a liquid bath containing zinc nitrate and hexamethylenetetramine as sources of precursors. The morphologies and phase compositions of the synthesized ZnO nanorods from different growth conditions were investigated with field emission scanning electron microscope and X-ray diffraction (XRD), respectively. The crystallinity size of the ZnO nanorods was in the range of 17-30 nm and increased with the precursor concentration. The XRD patterns also revealed that higher growth solution concentrations led to higher intensity of XRD peaks, indicating higher crystallinity. Additionally, to test for SODIS enhancement, experiments using 200-mL transparent polyethylene bags as SODIS reactors, with ZnO photocatalysts inside, and water samples containing 106 CFU of Escherichia Coli were conducted in a laboratory UVA setup. The photocatalyst with a polyester support resulted in a 15% higher disinfection efficiency than that of the one with a cellulose support. Moreover, a field test of enhanced SODIS was conducted in actual sunlight, using specially designed SODIS reactors containing ZnO photocatalysts with a polyester support. Nearly total disinfection (97-98% efficiency) was achieved within the first 15 min of every test. The treated water was also tested for zinc contents, which could be released from the photocatalysts, by ICP-OES. The results were lower than 2 mg/L. PMID- 29985116 TI - Influences of continuous sitting and psychosocial stress on low back kinematics, kinetics, discomfort, and localized muscle fatigue during unsupported sitting activities. AB - Continuous seated postures may increase the risk of adverse health outcomes such as low-back pain, and this risk may be influenced by several modifying factors. In the present study, we aimed to quantify the effects of continuous sitting and psychosocial stress under an unsupported sitting condition. Fourteen participants completed continuous, 40 min. periods of computer-based tasks, involving both low and higher levels of psychosocial stress, while using a laptop computer without a desk. Continuous sitting significantly increased perceived discomfort (particularly in the upper and lower back), trunk flexion and metrics of localized muscle fatigue. A higher level of psychosocial stress increased estimated lumbosacral compression forces (by ~12%). Only weak correlations were found between subjective and objective measures, while various fatigue metrics showed a good level of correspondence with each other. These results could support the future evaluation or design of diverse seated work configurations. Practitioner Summary: Continuous, 40 min. periods of unsupported sitting had broad impacts on subjective and objective outcomes, including discomfort, postures, spine loads and localized muscle fatigue, while psychosocial stress only had a substantial influence on lumbosacral compression. These results extend our understanding of sitting behaviors and provide information for designing future sitting environments. PMID- 29985117 TI - Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review. AB - BACKGROUND: The clinical and preclinical exploration of the therapeutic properties of vitamin D have significantly increased in the past decade, owing to the growing associative evidence suggesting vitamin D is neuroprotective. However, whether depletion of vitamin D contributes to the onset of neurological disorders or is a symptom of neurological disease has yet to be defined. Much remains unclear about the causal role of vitamin D and the method of use and forms of vitamin D. OBJECTIVES: We sought to quantitatively assess if neuroprotective benefits from vitamin D in neurodegenerative diseases are dependent on route of administration: comparing the effect of endogenously sourced vitamin D from UV exposure to exogenously derived vitamin D through synthetic supplementation. DESIGN: We systematically searched PubMed, Embase and PsycInfo databases which included both pre-clinical and clinical studies investigating vitamin D in neurodegenerative diseases. Articles were subject to strict inclusion criteria and objectively assessed for quality. Additionally, Medline data was analysed to identify trends in topic publications and linguistic characteristics of papers. RESULTS: From a total of 231 screened articles, we identified 73 appropriate for review based on inclusion criteria: original studies that investigated vitamin D levels or levels of vitamin D supplementation in neurodegenerative diseases or investigated past/present sun exposure in disease cohorts. Results indicate there is insufficient evidence to comprehensively reflect on a potential neuroprotective role for vitamin D and if this was dependent on route of administration. The majority of current data supporting neuroprotective benefits from vitamin D are based on pre-clinical and observational studies. Solid evidence is lacking to support the current hypothesis that the beneficial effect of UV exposure results from the synthesis of vitamin D. Sun exposure, independent of vitamin D production, may be protective against multiple Sclerosis, Parkinson's disease and Alzheimer's disease. Yet, further research is required to elucidate the beneficial mechanism of actions of UV exposure. The literature of vitamin D and amyotrophic lateral sclerosis was limited, and no conclusions were drawn. Therefore, in cases where UV-derived vitamin D was hypothesized to be the beneficial mediator in the neuroprotective effects of sun exposure, we propose results are based only on associative evidence. CONCLUSION: On the basis of this systematic review, strong recommendations regarding therapeutic benefits of vitamin D in neurodegenerative disease cannot be made. It is unclear if vitamin D mediates a protective benefit in neurodegenerative disease or whether it is an associative marker of UV exposure, which may contribute to as of yet unidentified neuroprotective factors. PMID- 29985118 TI - Bone marrow cell therapy and cardiac reparability: better cell characterization will enhance clinical success. AB - Nearly two decades of experimental and clinical research with bone marrow cells have paved the way for Phase III pivotal trials in larger groups of heart patients. Despite immense advancements, a multitude of factors are hampering the acceptance of bone marrow cell-based therapy for routine clinical use. These include uncertainties regarding purification and characterization of the cell preparation, delivery protocols, mechanistic understanding and study end points and their methods of assessment. Clinical data show mediocre outcomes in terms of sustained cardiac pump function. This review reasons that the modest outcomes observed in trials thus far are based on quality of the cell preparation with a focus on the chronological aging of cells when autologous cells are used for transplantation in elderly patients. PMID- 29985119 TI - Freezing of gait in Parkinson's disease: functional neuroimaging studies of the frontal lobe. AB - OBJECTIVE: The objective of the study is to study a group of patients with Parkinson's disease (PD) with and without freezing of gait (FOG) and analyze neuropsychological differences, especially regarding executive functions, according to their performance in a set of tests, and potential anomalies in functional positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-d glucose integrated with computed tomography (18F-FDG PET/CT) neuroimaging results of the frontal lobe. METHODS: The study recruited 23 patients. We performed an 18F-FDG PET/CT scan for 17 patients (9 with FOG and 8 without FOG) and 6 controls. Frontal functions were evaluated in all the patients during their 'on' situation. RESULTS: In FDG PET studies, PD patients differed from controls in that they presented hypometabolic areas in the parietal and bilateral occipital regions, as well as in the bilateral frontal region, especially on the right side. Compared to patients without FOG, patients with FOG displayed more pronounced frontal and predominantly right-sided hypometabolism. Both groups of patients displayed a poorer performance than the control population in the frontal cognitive tests. A greater executive disfunction was found in patients with FOG. CONCLUSIONS: Our study revealed greater hypometabolism in FDG PET studies, predominantly in right-sided-specific motor regions of the frontal lobe in FOG patients and greater frontal disfunction in neuropsychological tests in PD patients with FOG. These data suggest that FOG may be related to functional impairment of the circuits connecting the frontal lobe and the basal ganglia. PMID- 29985120 TI - Emotions and the Right Hemisphere: Can New Data Clarify Old Models? AB - Models advanced to explain hemispheric asymmetries in representation of emotions will be discussed following their historical progression. First, the clinical observations that have suggested a general dominance of the right hemisphere for all kinds of emotions will be reviewed. Then the experimental investigations that have led to proposal of a different hemispheric specialization for positive versus negative emotions (valence hypothesis) or, alternatively, for approach versus avoidance tendencies (motivational hypothesis) will be surveyed. The discussion of these general models will be followed by a review of recent studies which have documented laterality effects within specific brain structures, known to play a critical role in different components of emotions, namely the amygdata in the computation of emotionally laden stimuli, the ventromedial prefrontal cortex in the integration between cognition and emotion and in the control of impulsive reactions and the anterior insula in the conscious experience of emotion. Results of these recent investigations support and provide an updated integrated version of early models assuming a general right hemisphere dominance for all kinds of emotions. PMID- 29985121 TI - Endovascular repair of an extracranial carotid artery aneurysm complicated by late stent thrombosis. AB - Extracranial carotid artery aneurysms (ECAA) are extremely rare, accounting for less than 1% of all peripheral artery aneurysms. The most common presentation is central neurologic dysfunction, typically due to embolization of thrombus from the aneurysm. Historically open surgical intervention is the treatment of choice for symptomatic ECAA. Recent data suggest that endovascular repair is a valuable alternative, with a high procedural success rate and relatively low complication rate. We present a case of an ECAA with symptoms of vision loss, successfully treated by endovascular covered stenting but complicated by late in stent thrombosis and cerebral infarction. The patient was subsequently treated with IV thrombolysis and life-long warfarin. The patient had discrete residual symptoms at follow-up 3 months later. PMID- 29985122 TI - Glycomyces xiaoerkulensis sp. nov., isolated from Xiaoerkule lake in Xinjiang, China. AB - A novel actinomycete, strain TRM 41368T, was isolated from a silt sample from Xiaoerkule lake in Xinjiang province, China, and was examined using a polyphasic approach. Strain TRM 41368T was aerobic, Gram-stain-positive, with an optimum NaCl concentration for growth of 5 % (w/v), and an optimum temperature for growth of 35-37 degrees C. On the basis of 16S rRNA gene sequence analysis, strain TRM 41368T was most closely related to Glycomycesfuscus TRM 49117T (98.46 % similarity). However, it had a relatively low DNA-DNA relatedness value with G. fuscus TRM 49117T (ANI=70.59 %). The organism had chemical and morphological features typical of the genus Glycomyces. The cell wall of TRM 41368T contained meso-diaminopimelic acid; xylose, ribose and glucose were the major whole-cell sugars. The diagnostic polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylinositolmannosides. The predominant menaquinone was MK-9(H6). The major fatty acids were C18 : 1omega9c, C16 : 0, iso C16 : 0, anteiso-C17 : 0 and anteiso-C15 : 0. The G+C content of the DNA was 69.9 mol%. On the basis of the polyphasic evidence, strain TRM 41368T should be designated as a novel species of the genus Glycomyces, for which the name Glycomyces xiaoerkulensis sp. nov. is proposed. The type strain is TRM 41368T (=CCTCC AA 2017005T=KCTC 39932T). PMID- 29985124 TI - Extending the ecological distribution of Desmonostoc genus: proposal of Desmonostoc salinum sp. nov., a novel Cyanobacteria from a saline-alkaline lake. AB - Cyanobacteria is an ancient phylum of oxygenic photosynthetic microorganisms found in almost all environments of Earth. In recent years, the taxonomic placement of some cyanobacterial strains, including those belonging to the genus Nostocsensu lato, have been reevaluated by means of a polyphasic approach. Thus, 16S rRNA gene phylogeny and 16S-23S internal transcribed spacer (ITS) secondary structures coupled with morphological, ecological and physiological data are considered powerful tools for a better taxonomic and systematics resolution, leading to the description of novel genera and species. Additionally, underexplored and harsh environments, such as saline-alkaline lakes, have received special attention given they can be a source of novel cyanobacterial taxa. Here, a filamentous heterocytous strain, Nostocaceae CCM-UFV059, isolated from Laguna Amarga, Chile, was characterized applying the polyphasic approach; its fatty acid profile and physiological responses to salt (NaCl) were also determined. Morphologically, this strain was related to morphotypes of the Nostocsensu lato group, being phylogenetically placed into the typical cluster of the genus Desmonostoc. CCM-UFV059 showed identity of the 16S rRNA gene as well as 16S-23S secondary structures that did not match those from known described species of the genus Desmonostoc, as well as distinct ecological and physiological traits. Taken together, these data allowed the description of the first strain of a member of the genus Desmonostoc from a saline-alkaline lake, named Desmonostoc salinum sp. nov., under the provisions of the International Code of Nomenclature for algae, fungi and plants. This finding extends the ecological coverage of the genus Desmonostoc, contributing to a better understanding of cyanobacterial diversity and systematics. PMID- 29985123 TI - Accuracy of a commercial multiplex PCR for the diagnosis of bacterial vaginosis. AB - PURPOSE: Bacterial vaginosis (BV) is a common clinical condition characterized by odorous vaginal discharge, vaginal itching and/or burning. BV can occur when vaginal lactobacilli are depleted and replaced by diverse anaerobic bacteria. We evaluated a commercial multiplex PCR (ATRiDA) for the diagnosis of BV. METHODS: Cervicovaginal samples were included from women reporting urogenital symptoms and from women notified for sexually transmitted infections (STI) - who were not (necessarily) symptomatic. Clinical BV diagnoses were obtained from electronic patient files. The ATRiDA test measures the loads of Gardnerella vaginalis, Atopobium vaginae and Lactobacillus species in relation to overall bacterial load. The ATRiDA test outcome was compared to the clinical BV diagnosis and to vaginal microbiota composition, determined by 16SrRNA gene sequencing. RESULTS: We included samples from 185 women reporting urogenital symptoms, of whom 81 had BV and 93 women who were notified for an STI, of whom 16 had BV. Overall, compared to the clinical BV diagnosis, the ATRiDA test demonstrated high sensitivity (96.9 %) and moderate specificity (70.2 %). The negative predictive value was high (>97.3). The positive predictive value differed by study group and was highest in women reporting urogenital symptoms (78.2 %). Sequencing showed that 54 % of women who had an ATRiDA BV-positive test outcome, but who were not clinically diagnosed with BV, had diverse anaerobic vaginal microbiota (asymptomatic vaginal dysbiosis). CONCLUSION: The ATRiDA test is a sensitive method for the detection of BV but, given the high occurrence of asymptomatic vaginal dysbiosis, a positive test outcome should be interpreted together with clinical symptoms. PMID- 29985125 TI - Genetic diversity, mobilisation and spread of the yersiniabactin-encoding mobile element ICEKp in Klebsiella pneumoniae populations. AB - Mobile genetic elements (MGEs) that frequently transfer within and between bacterial species play a critical role in bacterial evolution, and often carry key accessory genes that associate with a bacteria's ability to cause disease. MGEs carrying antimicrobial resistance (AMR) and/or virulence determinants are common in the opportunistic pathogen Klebsiella pneumoniae, which is a leading cause of highly drug-resistant infections in hospitals. Well-characterised virulence determinants in K. pneumoniae include the polyketide synthesis loci ybt and clb (also known as pks), encoding the iron-scavenging siderophore yersiniabactin and genotoxin colibactin, respectively. These loci are located within an MGE called ICEKp, which is the most common virulence-associated MGE of K. pneumoniae, providing a mechanism for these virulence factors to spread within the population. Here we apply population genomics to investigate the prevalence, evolution and mobility of ybt and clb in K. pneumoniae populations through comparative analysis of 2498 whole-genome sequences. The ybt locus was detected in 40 % of K. pneumoniae genomes, particularly amongst those associated with invasive infections. We identified 17 distinct ybt lineages and 3 clb lineages, each associated with one of 14 different structural variants of ICEKp. Comparison with the wider population of the family Enterobacteriaceae revealed occasional ICEKp acquisition by other members. The clb locus was present in 14 % of all K. pneumoniae and 38.4 % of ybt+ genomes. Hundreds of independent ICEKp integration events were detected affecting hundreds of phylogenetically distinct K. pneumoniae lineages, including at least 19 in the globally-disseminated carbapenem-resistant clone CG258. A novel plasmid-encoded form of ybt was also identified, representing a new mechanism for ybt dispersal in K. pneumoniae populations. These data indicate that MGEs carrying ybt and clb circulate freely in the K. pneumoniae population, including among multidrug-resistant strains, and should be considered a target for genomic surveillance along with AMR determinants. PMID- 29985126 TI - NSF-mediated disassembly of on- and off-pathway SNARE complexes and inhibition by complexin. AB - SNARE complex disassembly by the ATPase NSF is essential for neurotransmitter release and other membrane trafficking processes. We developed a single-molecule FRET assay to monitor repeated rounds of NSF-mediated disassembly and reassembly of individual SNARE complexes. For ternary neuronal SNARE complexes, disassembly proceeds in a single step within 100 msec. We observed short- (<0.32 s) and long lived (>=0.32 s) disassembled states. The long-lived states represent fully disassembled SNARE complex, while the short-lived states correspond to failed disassembly or immediate reassembly. Either high ionic strength or decreased alphaSNAP concentration reduces the disassembly rate while increasing the frequency of short-lived states. NSF is also capable of disassembling anti parallel ternary SNARE complexes, implicating it in quality control. Finally, complexin-1 competes with alphaSNAP binding to the SNARE complex; addition of complexin-1 has an effect similar to that of decreasing the alphaSNAP concentration, possibly differentially regulating cis and trans SNARE complexes disassembly. PMID- 29985127 TI - Removing physiological motion from intravital and clinical functional imaging data. AB - Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data. PMID- 29985129 TI - Engineering ER-stress dependent non-conventional mRNA splicing. AB - The endoplasmic reticulum (ER) protein folding capacity is balanced with the protein folding burden to prevent accumulation of un- or misfolded proteins. The ER membrane-resident kinase/RNase Ire1 maintains ER protein homeostasis through two fundamentally distinct processes. First, Ire1 can initiate a transcriptional response through a non-conventional mRNA splicing reaction to increase the ER folding capacity. Second, Ire1 can decrease the ER folding burden through selective mRNA decay. In Saccharomyces cerevisiae and Schizosaccharomyces pombe, the two Ire1 functions have been evolutionarily separated. Here, we show that the respective Ire1 orthologs have become specialized for their functional outputs by divergence of their RNase specificities. In addition, RNA structural features separate the splicing substrates from the decay substrates. Using these insights, we engineered an S. pombe Ire1 cleavage substrate into a splicing substrate, which confers S. pombe with both Ire1 functional outputs. PMID- 29985128 TI - Rad52-Rad51 association is essential to protect Rad51 filaments against Srs2, but facultative for filament formation. AB - Homology search and strand exchange mediated by Rad51 nucleoprotein filaments are key steps of the homologous recombination process. In budding yeast, Rad52 is the main mediator of Rad51 filament formation, thereby playing an essential role. The current model assumes that Rad51 filament formation requires the interaction between Rad52 and Rad51. However, we report here that Rad52 mutations that disrupt this interaction do not affect gamma-ray- or HO endonuclease-induced gene conversion frequencies. In vivo and in vitro studies confirmed that Rad51 filaments formation is not affected by these mutations. Instead, we found that Rad52-Rad51 association makes Rad51 filaments toxic in Srs2-deficient cells after exposure to DNA damaging agents, independently of Rad52 role in Rad51 filament assembly. Importantly, we also demonstrated that Rad52 is essential for protecting Rad51 filaments against dissociation by the Srs2 DNA translocase. Our findings open new perspectives in the understanding of the role of Rad52 in eukaryotes. PMID- 29985130 TI - JNK signaling triggers spermatogonial dedifferentiation during chronic stress to maintain the germline stem cell pool in the Drosophila testis. AB - Exhaustion of stem cells is a hallmark of aging. In the Drosophila testis, dedifferentiated germline stem cells (GSCs) derived from spermatogonia increase during lifespan, leading to the model that dedifferentiation counteracts the decline of GSCs in aged males. To test this, we blocked dedifferentiation by mis expressing the differentiation factor bag of marbles (bam) in spermatogonia while lineage-labeling these cells. Strikingly, blocking bam-lineage dedifferentiation under normal conditions in virgin males has no impact on the GSC pool. However, in mated males or challenging conditions, inhibiting bam-lineage dedifferentiation markedly reduces the number of GSCs and their ability to proliferate and differentiate. We find that bam-lineage derived GSCs have significantly higher proliferation rates than sibling GSCs in the same testis. We determined that Jun N-terminal kinase (JNK) activity is autonomously required for bam-lineage dedifferentiation. Overall, we show that dedifferentiation provides a mechanism to maintain the germline and ensure fertility under chronically stressful conditions. PMID- 29985133 TI - Evaluation of a Three-Hydrophone Method for 2-D Cavitation Localization. AB - Cavitation is a critical parameter in various therapeutic applications involving ultrasound (US) such as histotripsy, lithotripsy, drug delivery, and cavitation enhanced hyperthermia. A cavitation exposure outside the region of interest may lead to suboptimal treatment efficacy or in a worse case, to safety issues. Current methods of localizing cavitation are based on imaging approaches, such as beamforming the cavitation signals received passively by a US imager. These methods, although efficient, require expensive equipment, which may discourage potential future developments. We propose a three-hydrophone method to localize the cavitation cloud source. First, the delays between the three receptors are measured by detecting the maximum of their intercorrelations. Then, the position of the source is calculated by either minimizing a cost function or solving hyperbolic equations. After a numerical validation, the method was assessed experimentally. This method was able to track a source displacement with accuracy similar to the size of the cavitation cloud (2-4 mm). This light and versatile method provides interesting perspectives since localization can be executed in real time, and the extension to 3-D localization seems straightforward. PMID- 29985132 TI - Inferring circuit mechanisms from sparse neural recording and global perturbation in grid cells. AB - A goal of systems neuroscience is to discover the circuit mechanisms underlying brain function. Despite experimental advances that enable circuit-wide neural recording, the problem remains open in part because solving the 'inverse problem' of inferring circuity and mechanism by merely observing activity is hard. In the grid cell system, we show through modeling that a technique based on global circuit perturbation and examination of a novel theoretical object called the distribution of relative phase shifts (DRPS) could reveal the mechanisms of a cortical circuit at unprecedented detail using extremely sparse neural recordings. We establish feasibility, showing that the method can discriminate between recurrent versus feedforward mechanisms and amongst various recurrent mechanisms using recordings from a handful of cells. The proposed strategy demonstrates that sparse recording coupled with simple perturbation can reveal more about circuit mechanism than can full knowledge of network activity or the synaptic connectivity matrix. PMID- 29985134 TI - Sequential Video VLAD: Training the Aggregation Locally and Temporally. AB - As characterizing videos simultaneously from spatial and temporal cues has been shown crucial for the video analysis, the combination of convolutional neural networks and recurrent neural networks, i.e., recurrent convolution networks (RCNs), should be a native framework for learning the spatio-temporal video features. In this paper, we develop a novel sequential vector of locally aggregated descriptor (VLAD) layer, named SeqVLAD, to combine a trainable VLAD encoding process and the RCNs architecture into a whole framework. In particular, sequential convolutional feature maps extracted from successive video frames are fed into the RCNs to learn soft spatio-temporal assignment parameters, so as to aggregate not only detailed spatial information in separate video frames but also fine motion information in successive video frames. Moreover, we improve the gated recurrent unit (GRU) of RCNs by sharing the input-to-hidden parameters and propose an improved GRU-RCN architecture named shared GRU-RCN (SGRU-RCN). Thus, our SGRU-RCN has a fewer parameters and a less possibility of overfitting. In experiments, we evaluate SeqVLAD with the tasks of video captioning and video action recognition. Experimental results on Microsoft Research Video Description Corpus, Montreal Video Annotation Dataset, UCF101, and HMDB51 demonstrate the effectiveness and good performance of our method. PMID- 29985131 TI - PARP1-dependent recruitment of the FBXL10-RNF68-RNF2 ubiquitin ligase to sites of DNA damage controls H2A.Z loading. AB - The mammalian FBXL10-RNF68-RNF2 ubiquitin ligase complex (FRRUC) mono ubiquitylates H2A at Lys119 to repress transcription in unstressed cells. We found that the FRRUC is rapidly and transiently recruited to sites of DNA damage in a PARP1- and TIMELESS-dependent manner to promote mono-ubiquitylation of H2A at Lys119, a local decrease of H2A levels, and an increase of H2A.Z incorporation. Both the FRRUC and H2A.Z promote transcriptional repression, double strand break signaling, and homologous recombination repair (HRR). All these events require both the presence and activity of the FRRUC. Moreover, the FRRUC and its activity are required for the proper recruitment of BMI1-RNF2 and MEL18-RNF2, two other ubiquitin ligases that mono-ubiquitylate Lys119 in H2A upon genotoxic stress. Notably, whereas H2A.Z is not required for H2A mono ubiquitylation, impairment of the latter results in the inhibition of H2A.Z incorporation. We propose that the recruitment of the FRRUC represents an early and critical regulatory step in HRR. PMID- 29985135 TI - Retrieval Oriented Deep Feature Learning With Complementary Supervision Mining. AB - Deep convolutional neural networks (CNNs) have been widely and successfully applied in many computer vision tasks, such as classification, detection, semantic segmentation, and so on. As for image retrieval, while off-the-shelf CNN features from models trained for classification task are demonstrated promising, it remains a challenge to learn specific features oriented for instance retrieval. Witnessing the great success of low-level SIFT feature in image retrieval and its complementary nature to the semantic-aware CNN feature, in this paper, we propose to embed the SIFT feature into the CNN feature with a Siamese structure in a learning-based paradigm. The learning objective consists of two kinds of loss, i.e., similarity loss and fidelity loss. The first loss embeds the image-level nearest neighborhood structure with the SIFT feature into CNN feature learning, while the second loss imposes that the CNN feature with the updated CNN model preserves the fidelity of that from the original CNN model solely trained for classification. After the learning, the generated CNN feature inherits the property of the SIFT feature, which is well oriented for image retrieval. We evaluate our approach on the public data sets, and comprehensive experiments demonstrate the effectiveness of the proposed method. PMID- 29985136 TI - Robust Object Tracking via Local Sparse Appearance Model. AB - In this paper, we propose a novel local sparse representation-based tracking framework for visual tracking. To deeply mine the appearance characteristics of different local patches, the proposed method divides all local patches of a candidate target into three categories, which are stable patches, valid patches, and invalid patches. All these patches are assigned different weights to consider the different importance of the local patches. For stable patches, we introduce a local sparse score to identify them, and discriminative local sparse coding is developed to decrease the weights of background patches among the stable patches. For valid patches and invalid patches, we adopt local linear regression to distinguish the former from the latter. Furthermore, we propose a weight shrinkage method to determine weights for different valid patches to make our patch weight computation more reasonable. Experimental results on public tracking benchmarks with challenging sequences demonstrate that the proposed method performs favorably against other state-of-the-art tracking methods. PMID- 29985137 TI - Robust Multi-Frame Super-Resolution Based on Spatially Weighted Half-Quadratic Estimation and Adaptive BTV Regularization. AB - Multi-frame image super-resolution focuses on reconstructing a high-resolution image from a set of low-resolution images with high similarity. Combining image prior knowledge with fidelity model, the Bayesian-based methods have been considered as an effective technique in super-resolution. The minimization function derived from maximum a posteriori probability (MAP) is composed of a fidelity term and a regularization term. In this paper, based on the MAP estimation, we propose a novel initialization method for super-resolution imaging. For the fidelity term in our proposed method, the half-quadratic estimation is used to choose error norm adaptively instead of using fixed and norms. Besides, a spatial weight matrix is used as a confidence map to scale the estimation result. For the regularization term, we propose a novel regularization method based on adaptive bilateral total variation (ABTV). Both the fidelity term and the ABTV regularization guarantee the robustness of our framework. The fidelity term is mainly responsible for dealing with misregistration, blur, and other kinds of large errors, while the ABTV regularization aims at edge preservation and noise removal. The proposed scheme is tested on both synthetic data and real data. The experimental results illustrate the superiority of our proposed method in terms of edge preservation and noise removal over the state-of the-art algorithms. PMID- 29985138 TI - Hybrid All Zero Soft Quantized Block Detection for HEVC. AB - Transform and quantization account for a considerable amount of computation time in video encoding process. However, there are a large number of discrete cosine transform coefficients which are finally quantized into zeros. In essence, blocks with all zero quantized coefficients do not transmit any information, but still occupy substantial unnecessary computational resources. As such, detecting all zero block (AZB) before transform and quantization has been recognized to be an efficient approach to speed up the encoding process. Instead of considering the hard-decision quantization (HDQ) only, in this paper, we incorporate the properties of soft-decision quantization into the AZB detection. In particular, we categorize the AZB blocks into genuine AZBs (G-AZB) and pseudo AZBs (P-AZBs) to distinguish their origins. For G-AZBs directly generated from HDQ, the sum of absolute transformed difference-based approach is adopted for early termination. Regarding the classification of P-AZBs which are generated in the sense of rate distortion optimization, the rate-distortion models established based on transform coefficients together with the adaptive searching of the maximum transform coefficient are jointly employed for the discrimination. Experimental results show that our algorithm can achieve up to 24.16% transform and quantization time-savings with less than 0.06% RD performance loss. The total encoder time saving is about 5.18% on average with the maximum value up to 9.12%. Moreover, the detection accuracy of larger TU sizes, such as and can reach to 95% on average. PMID- 29985139 TI - Video Salient Object Detection Using Spatiotemporal Deep Features. AB - This paper presents a method for detecting salient objects in videos, where temporal information in addition to spatial information is fully taken into account. Following recent reports on the advantage of deep features over conventional handcrafted features, we propose a new set of spatiotemporal deep (STD) features that utilize local and global contexts over frames. We also propose new spatiotemporal conditional random field (STCRF) to compute saliency from STD features. STCRF is our extension of CRF to the temporal domain and describes the relationships among neighboring regions both in a frame and over frames. STCRF leads to temporally consistent saliency maps over frames, contributing to accurate detection of salient objects' boundaries and noise reduction during detection. Our proposed method first segments an input video into multiple scales and then computes a saliency map at each scale level using STD features with STCRF. The final saliency map is computed by fusing saliency maps at different scale levels. Our experiments, using publicly available benchmark datasets, confirm that the proposed method significantly outperforms the state-of-the-art methods. We also applied our saliency computation to the video object segmentation task, showing that our method outperforms existing video object segmentation methods. PMID- 29985140 TI - LATE: A Level-Set Method Based on Local Approximation of Taylor Expansion for Segmenting Intensity Inhomogeneous Images. AB - Intensity inhomogeneity is common in real-world images and inevitably leads to many difficulties for accurate image segmentation. Numerous level-set methods have been proposed to segment images with intensity inhomogeneity. However, most of these methods are based on linear approximation, such as locally weighted mean, which may cause problems when handling images with severe intensity inhomogeneities. In this paper, we view segmentation of such images as a nonconvex optimization problem, since the intensity variation in such an image follows a nonlinear distribution. Then, we propose a novel level-set method named local approximation of Taylor expansion (LATE), which is a nonlinear approximation method to solve the nonconvex optimization problem. In LATE, we use the statistical information of the local region as a fidelity term and the differentials of intensity inhomogeneity as an adjusting term to model the approximation function. In particular, since the first-order differential is represented by the variation degree of intensity inhomogeneity, LATE can improve the approximation quality and enhance the local intensity contrast of images with severe intensity inhomogeneity. Moreover, LATE solves the optimization of function fitting by relaxing the constraint condition. In addition, LATE can be viewed as a constraint relaxation of classical methods, such as the region scalable fitting model and the local intensity clustering model. Finally, the level-set energy functional is constructed based on the Taylor expansion approximation. To validate the effectiveness of our method, we conduct thorough experiments on synthetic and real images. Experimental results show that the proposed method clearly outperforms other solutions in comparison. PMID- 29985141 TI - Two-Stage Frequency Recognition Method Based on Correlated Component Analysis for SSVEP-Based BCI. AB - A canonical correlation analysis (CCA) is a state-of-the-art method for frequency recognition in steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) systems. Various extended methods have been developed, and among such methods, a combination method of CCA and individual-template-based CCA has achieved the best performance. However, the CCA requires the canonical vectors to be orthogonal, which may not be a reasonable assumption for the EEG analysis. In this paper, we propose using the correlated component analysis (CORRCA) rather than CCA to implement frequency recognition. CORRCA can relax the constraint of canonical vectors in CCA and generate the same projection vector for two multichannel EEG signals. Furthermore, we propose a two-stage method based on the basic CORRCA method (termed TSCORRCA). Evaluated on a benchmark data set of 35 subjects, the experimental results demonstrate that CORRCA significantly outperformed CCA, and TSCORRCA obtained the best performance among the compared methods. This paper demonstrates that CORRCA-based methods have a great potential for implementing high-performance SSVEP-based BCI systems. PMID- 29985142 TI - Intersession Instability in fNIRS-Based Emotion Recognition. AB - Emotion recognition based on neural signals is a promising technique for the detection of patients' emotions for enhancing healthcare. However, emotion related neural signals, such as from functional near infrared spectroscopy (fNIRS), can be affected by various psychophysiological and environmental factors. There is a paucity of literature regarding data instability and classification instability in fNIRS-based emotion recognition systems, phenomenon which may lead to user dissatisfaction and abandonment. We collected data in an fNIRS-based 2-class emotion recognition test-retest experiment (3 week interval) with visual stimuli emotion induction to examine data instability and its impact on classification accuracy. We found a 22.2% average deterioration of emotion classification accuracy between the two sessions, suggesting that classification instability is a serious problem. We found that the changes in the distributions of the selected neural signal features, as evaluated by Kullback-Leibler (KL) divergence, were a likely cause of the accuracy decline. We analyzed the data instability and our results showed that instability of spatial activation patterns and instability of the hemodynamic response in the most activated region are correlated with accuracy decline. Finally, we propose a method for mitigating classification instability in fNIRS-based emotion recognition based on feature selection for stable features, the first such method to our knowledge. This new feature selection criterion considers not only the separability of features (evaluated by Fisher Score) but also their stability over time (evaluated by KL divergence between feature distributions at different time points). Testing showed that this method led to an approximately 5% improvement in cross-session generalization accuracy. PMID- 29985143 TI - Effects of Virtual Reality and Augmented Reality on Induced Anxiety. AB - To explore the effects of virtual reality (VR) and augmented reality (AR) in the treatment of claustrophobia, the potential effects of VR and AR on induced anxiety were investigated in this paper. During the experiment, 34 subjects were randomly selected and distributed in AR and VR scenes in a sequence. The skin conductance and heart rates of the subjects were measured throughout the entire process, and the anxiety scale was used to assess the subjective anxiety when the task in each scene was completed. The results showed the following: (1) AR and VR scenes led to feelings of discomfort, but the subjective anxiety scores obtained in the two scenes were not significantly different; (2) the skin conductance level of the subjects significantly increased from the baseline when the subjects entered the experimental scene but remained active in the two scenes without showing significant difference between the scenes; and (3) the heart rate index significantly increased from the baseline after the subjects entered the scene and then gradually decreased. The heart rates of the subjects significantly increased again when the anxiety-induced event was triggered. However, no significant difference was observed between AR and VR scenes. AR and VR have induced obvious anxiety, which was reflected in the subjective and objective physiological indicators. However, no significant difference was found in the effects of AR and VR on the induced anxiety. Considering the cost of building two scenes and other factors, AR was more suitable for the treatment of claustrophobia than VR. PMID- 29985144 TI - A Novel Technique for Selecting EMG-Contaminated EEG Channels in Self-Paced Brain Computer Interface Task Onset. AB - Electromyography artifacts are a well-known problem in electroencephalography studies [brain-computer interfaces (BCIs), brain mapping, and clinical areas]. Blind source separation (BSS) techniques are commonly used to handle artifacts. However, these may remove not only the EMG artifacts but also some useful electroencephalography (EEG) sources. To reduce this useful information loss, we propose a new technique for statistically selecting EEG channels that are contaminated with class-dependent EMG (henceforth called EMG-CCh). The EMG-CCh is selected based on the correlation between EEG and facial EMG channels. They were compared (using a Wilcoxon test) to determine whether the artifacts played a significant role in class separation. To ensure that the promising results are not due to the weak EMG removal, reliability tests were done In our data set, the comparison results between BSS artifact removal applied in two ways, to all channels and only to EMG-CCh showed that ICA, PCA, and BSS-CCA can yield significantly better ( ) class separation with the proposed method (79% of the cases for ICA, 53% for PCA, and 11% for BSS-CCA). With BCI competition data, we saw improvement in 60% of the cases for ICA and BSS-CCA. The simple method proposed in this paper showed improvement in class separation with both our data and the BCI competition data. There are no existing methods for removing EMG artifacts based on the correlation between the EEG and EMG channels. Also, the EMG-CCh selection can be used on its own or it can be combined with pre-existing artifact handling methods. For these reasons, we believe that this method can be useful for other EEG studies. PMID- 29985145 TI - Reduced Effort Does Not Imply Slacking: Responsiveness to Error Increases With Robotic Assistance. AB - In both neurorehabilitation and functional augmentation, the patient or the user's muscular effort diminishes when the movement of their limb is supported by a robot. Is this relaxation a result of "slacking" by letting the robot take-over the movement, resulting in less responsiveness in the task? To address this question, we tested subjects who controlled a virtual cursor isometrically to track a moving target without and with different assistants. We measured the force applied by the subject as a metric for effort and estimated their control gain as the metric for responsiveness in the task. Although subjects applied less force with position assistance, the norm of the control gain increased with all assistants, i.e., they applied proportionately larger forces for the same difference between the cursor and the target states. Furthermore, assisting velocity errors improved baseline performance without reducing effort. Though all assistants improved task performance, the control gain adapted differently to position and velocity assistance. Position assistance was exploited to accurately track the target, whereas velocity assistance was treated as a disturbance, and was effectively nullified as it prevented submovements that minimized positional error. Our results show that robotic assistance increases task responsiveness in healthy individuals and that assisting velocity errors could boost patient performance without reducing their motor effort. PMID- 29985147 TI - Tactile Sensor-Based Steering as a Substitute of the Attendant Joystick in Powered Wheelchairs. AB - Attendant joysticks of powered wheelchairs are devices oriented to help caregivers. Diseases and disabilities such as dementia, spinal cord injuries or blindness make the user unable to drive the chair by his or her own. However, this device is not intuitive to use, especially for old people. Proper processing of the information provided by two tactile sensors in the handlebar achieves control signals that allow an easy and intuitive driving. This is done in this paper, where the performance of this approach is evaluated in comparison with that of the joystick by means of objective measurements as well as questionnaires to obtain the subjective perception of the participants in the experiments. The results show a better performance of the handlebar in terms of error in following a trajectory, collisions with the surrounding furniture, and user feeling related to ease of use, comfort, required training, usefulness, safety, and fatigue. PMID- 29985146 TI - A Model to Estimate the Optimal Layout for Assistive Communication Touchscreen Devices in Children With Dyskinetic Cerebral Palsy. AB - Excess involuntary movements and slowness of movement in children with dyskinetic cerebral palsy often result in the inability to properly interact with augmentative and alternative communication (AAC) devices. This significantly limits communication. It is, therefore, essential to know how to adjust the device layout in order to maximize each child's rate of communication. The aim of this paper was to develop a mathematical model to estimate the information rate in children with dyskinetic cerebral palsy and to determine the optimal AAC layout for a touchscreen tablet that results in enhanced speed of communication. The model predicts information rate based on button size, number, spacing between buttons, and the probability of making an error or missing target buttons. Estimation of the information rate confirmed our hypothesis of lower channel capacity in children with dyskinetic cerebral palsy compared with age-matched healthy children. Information rate increased when the AAC layout was customized based on the optimal parameters predicted by the model. In conclusion, this paper quantifies the effect of motor impairments on communication with assistive communication devices and shows that communication performance can be improved by optimally matching the parameters of the AAC touchscreen device to the abilities of the child. PMID- 29985148 TI - Design and Functional Evaluation of a Dexterous Myoelectric Hand Prosthesis With Biomimetic Tactile Sensor. AB - This paper presents the design, tactile sensor, characterization, and control system of a new dexterous myoelectric hand prosthesis to overcome the limitations of state-of-the-art myoelectric prostheses (e.g., limited functionality, controllability, and sensory feedback). Our dexterous myoelectric hand allows independent finger movement and thumb abduction/adduction, with a motor for each finger and an additional motor for the thumb (i.e., six total motors). Each fingertip has a biomimetic tactile sensor with 13 tactile units, each of which can detect normal and tangential forces. The hand controller uses an electromyography pattern recognition controller and a tactile sensor feedback based grasping controller to automatically and dynamically adjust the finger grasp force to prevent objects from slipping. This closed-loop controller structure will allow users to safely and effectively grasp complex objects with varying densities and shapes. In addition, the electronic hardware is integrated into the hand, and the pattern recognition controller can be implemented in the hand embedded system. PMID- 29985149 TI - Validity of the Nintendo Wii Balance Board for the Assessment of Balance Measures in the Functional Reach Test. AB - The functional reach test (FRT) is widely used for assessing dynamic balance stability in elderly and pathological subjects. Force platforms (FPs) represent a fundamental part of the instrumented FRT experimental setup due to the central role of center-of-pressure (COP) displacement in FRT analysis. Recently, the nintendo wii balance board (NBB) has been suggested as a low-cost and reliable device for ground reaction force and COP measurement in poorly dynamic motor tasks. Therefore, this paper aimed to compare NBB-COP data with those obtained from a laboratory-grade platform during FRT. Data from 48 healthy subjects were simultaneously acquired from both devices. FP-COP and NBB-COP trajectories showed a remarkable correlation in both directions ( ) and low root-mean-square error values (1.14 +/- 0.88 mm and 0.55 +/- 0.28 mm for anterior-posterior and medial lateral direction). Fixed biases between COP-based parameters did not exceed 2% of the FP outcomes with high consistency throughout the present measurement range (ICC consistency always >0.950). Only the COP mean velocity exhibited a tendency toward proportional errors, which can be adjusted by a calibration of NBB data. Findings of this paper confirmed the NBB validity for COP measurement in a widely used motor task as the functional reach, supporting the feasibility of NBB in research scenarios. PMID- 29985150 TI - Compliant Prosthetic Wrists Entail More Natural Use Than Stiff Wrists During Reaching, Not (Necessarily) During Manipulation. AB - Developing an artificial arm with functions equivalent to those of the human arm is one of the challenging goals of bioengineering. State-of-the-artprostheses lack several degrees of freedom and force the individuals to compensate for them by means of compensatory movements, which often result in residual limb pain and overuse syndromes. Passive wristsmay reduce such compensatory actions, nonethelessto date their actual efficacy, associated to conventional myoelectric hands is a matter of debate. We hypothesized that a transradial prosthesiswould allow a simpler operation if its wrist behaved compliant during the reaching and grasping phase, and stiff during the holding andmanipulation phase. To assess this, we compared a stiff and a compliant wrist and evaluating the extent of compensatory movements in the trunk and shoulder, with unimpaired subjects wearing orthoses, while performing nine activities of daily living taken from the southampton hand assessment procedure. Our findings show indeed that the optimal compliance for a prosthetic wrist is specific to the phase of the motor task: the compliant wrist outperforms the stiff wrist during the reaching phase, whereas the stiff wrist exhibits more natural movements during the manipulation phase of heavy objects. Hence, this paper invites rehabilitation engineers to develop wrists with switchable compliance. PMID- 29985151 TI - Objective Assessment of Spasticity With a Method Based on a Human Upper Limb Model. AB - This paper presents a method based on a human upper limb model that assesses the severity of spasticity in patients with stroke objectively. The kinematic model consists of four moving segments connected by four joints. The joint torques are computed using inverse dynamics with measurements from three inertial measurement units (IMUs) attached to the participant's upper limb. The muscle activations are estimated using the joint torques via a musculoskeletal model which consists of 22 muscles. The severity of spasticity is then quantified by measuring the tonic stretch reflex threshold (TSRT) of the participant. 15 patient participants participated in the experiments where they were assessed by two qualified therapists using modified Ashworth scale (MAS), and their motions and EMG signals were captured at the same time. Using the upper limb model, the TSRT of each patient was measured and ranked. The estimated muscle activation profiles have a high correlation (0.707) to the EMG signal profiles. The null hypothesis that the rankings of the severity using the model and the MAS assessment have no correlation has been tested, and was rejected convincingly ( ). These findings suggest that the model has the potential to complement the existing practices by providing an alternative evaluation method. PMID- 29985152 TI - Spasticity Measurement Based on the HHT Marginal Spectrum Entropy of sEMG Using a Portable System: A Preliminary Study. AB - To facilitate stretch reflex onset (SRO) detection and improve accuracy and reliability of spasticity assessment in clinical settings, a new method to measure dynamic stretch reflex threshold (DSRT) based on Hilbert-Huang transform marginal spectrum entropy (HMSEN) of surface electromyography (sEMG) signals and a portable system to quantify modified Ashworth scale (MAS) for spasticity assessment were developed. The sEMG signals were divided into frames using a fixed-length sliding window, and the HMSEN of each frame was calculated. An adaptive threshold was set to measure the DSRT. The HMSEN based method can quantify muscle activity through time-frequency and nonlinear dynamics analysis, therefore providing deeper insight about the spastic muscle mechanisms during stretching and a reliable SRO detection method. Experimental results revealed that the HMSEN based method could reliably detect the SRO and measure the DSRT (recognition rate: 95.45%), and could achieve improved performance over the time domain based method. There was a strong correlation ( to -0.900) between the MAS scores and the DSRT index, and the test-retest reliability was high. Additionally, limitations of the MAS were analyzed. This paper indicates that the presented framework can provide a promising tool to measure DSRT and a clinical quantitative approach for spasticity assessment. PMID- 29985153 TI - Myoelectric Control Based on a Generic Musculoskeletal Model: Toward a Multi-User Neural-Machine Interface. AB - This paper aimed to develop a novel electromyography (EMG)-based neural-machine interface (NMI) that is user-generic for continuously predicting coordinated motion betweenmuscle contractionmetacarpophalangeal (MCP) and wrist flexion/extension. The NMI requires a minimum calibration procedure that only involves capturing maximal voluntary muscle contraction for themonitoredmuscles for individual users. At the center of the NMI is a user-generic musculoskeletal model based on the experimental data collected from six able-bodied (AB) subjects and nine different upper limb postures. The generic model was evaluated on-line on both AB subjects and a transradial amputee. The subjectswere instructed to performa virtual hand/wrist posture matching task with different upper limb postures. The on-line performanceof the genericmodelwas also compared with that of the musculoskeletal model customized to each individual user (called "specific model"). All subjects accomplished the assigned virtual tasks while using the user-generic NMI, although the AB subjects produced better performance than the amputee subject. Interestingly, compared with the specific model, the generic model produced comparable completion time, a reduced number of overshoots, and improved path efficiency in the virtual hand/wrist posture matching task. The results suggested that it is possible to design an EMG-driven NMI based on a musculoskeletalmodelthat could fit multiple users, including upper limb amputees, for predicting coordinated MCP and wrist motion. The present new method might address the challenges of existing advanced EMG-based NMI that require frequent and lengthy customization and calibration. Our future research will focus on evaluating the developed NMI for powered prosthetic arms. PMID- 29985154 TI - A High Performance Spelling System based on EEG-EOG Signals With Visual Feedback. AB - In this paper, we propose a highly accurate and fast spelling system that employs multi-modal electroencephalography-electrooculography (EEG-EOG) signals and visual feedback technology. Over the last 20 years, various types of speller systems have been developed in brain-computer interface and EOG/eye-tracking research; however, these conventional systems have a tradeoff between the spelling accuracy (or decoding) and typing speed. Healthy users and physically challenged participants, in particular, may become exhausted quickly; thus, there is a need for a speller system with fast typing speed while retaining a high level of spelling accuracy. In this paper, we propose the first hybrid speller system that combines EEG and EOG signals with visual feedback technology so that the user and the speller system can act cooperatively for optimal decision making. The proposed spelling system consists of a classic row-column event related potential (ERP) speller, an EOG command detector, and visual feedback modules. First, the online ERP speller calculates classification probabilities for all candidate characters from the EEG epochs. Second, characters are sorted by their probability, and the characters with the highest probabilities are highlighted as visual feedback within the row-column spelling layout. Finally, the user can actively select the character as the target by generating an EOG command. The proposed system shows 97.6% spelling accuracy and an information transfer rate of 39.6 (+/-13.2) [bits/min] across 20 participants. In our extended experiment, we redesigned the visual feedback and minimized the number of channels (four channels) in order to enhance the speller performance and increase usability. Most importantly, a new weighted strategy resulted in 100% accuracy and a 57.8 (+/-23.6) [bits/min] information transfer rate across six participants. This paper demonstrates that the proposed system can provide a reliable communication channel for practical speller applications and may be used to supplement existing systems. PMID- 29985155 TI - Towards Real-Time, Continuous Decoding of Gripping Force From Deep Brain Local Field Potentials. AB - Lack of force information and longevity issues are impediments to the successful translation of brain-computer interface systems for prosthetic control from experimental settings to widespread clinical application. The ability to decode force using deep brain stimulation electrodes in the subthalamic nucleus (STN) of the basal ganglia provides an opportunity to address these limitations. This paper explores the use of various classes of algorithms (Wiener filter, Wiener Cascade model, Kalman filter, and dynamic neural networks) and recommends the use of a Wiener-Cascade model for decoding force from STN. This recommendation is influenced by a combination of accuracy and practical considerations to enable real-time, continuous operation. This paper demonstrates an ability to decode a continuous signal (force) from the STN in real time, allowing the possibility of decoding more than two states from the brain at low latency. PMID- 29985156 TI - Wearable Haptics and Immersive Virtual Reality Rehabilitation Training in Children With Neuromotor Impairments. AB - The past decade has seen the emergence of rehabilitation treatments using virtual reality (VR) environments although translation into clinical practice has been limited so far. In this paper, an immersive VR rehabilitation training system endowed with wearable haptics is proposed for children with neuromotor impairments: it aims to enhance involvement and engagement of patients, to provide congruent multi-sensory afferent feedback during motor exercises and to benefit from the flexibility of VR in adapting exercises to the patient's need. An experimental rehabilitation session conducted with children with cerebral palsy (CP) and developmental dyspraxia (DD) has been performed to evaluate the usability of the system and proof of concept trial of the proposed approach. We compared CP/DD performance with both typically developing children and adult control group. Results show the system was compliant with different levels of motor skills and allowed patients to complete the experimental rehabilitation session, with performance varying according to the expected motor abilities of different groups. Moreover, a kinematic assessmentbased on the presented system has been designed. Obtained results reflected different motor abilities of patients and participants, suggesting suitability of the proposed kinematic assessment as a motor function outcome. PMID- 29985157 TI - Lift and power in fruitflies in vertically-ascending flight. AB - We measured the wing kinematics of fruitflies in both vertically-ascending and hovering flights and studied the aerodynamic forces and power in the two flight modes. The average ascending velocity is 0.45 m s-1; the stroke plane angle and the stroke frequency are the same as that in hovering flight, whilst the stroke amplitude is increased by 12% and the wing angle of attack in the latter half of a down- and upstroke both increased by 10%. Flow analysis shows that during ascending, the flies experience a downward inflow which reduces the effective angle of attack considerably. This problem is overcome by the increases in the stroke amplitude and the angle of attack, which result in a larger wing drag. As a result, the power at ascending is increased by 36% over that at hovering. Two very interesting observations were made. (1) Using the same power, level-forward flight can be about four times as fast as ascending flight. (2) Power for ascending flight is the same as that for carrying a load about 27% of the insect's weight at hovering. PMID- 29985158 TI - Electronic energy spectroscopy of monochromatic edge magnetoplasmons in the quantum Hall regime. AB - We investigate electronic excitation in a quantum Hall edge channel when a monochromatic plasmon wave is excited by applying a radio-frequency voltage to a long surface gate on an AlGaAs/GaAs heterostructure. A quantum-dot energy spectrometer is employed to evaluate the amplitude of the potential wave and possible electronic heating. The potential wave is analyzed with a capacitance model. Non-monotonic frequency dependence observed under specific conditions can be explained by destructive plasmon interference in the gated region. The observed small heating effect suggests that the single plasmon mode is dominantly excited with this scheme. PMID- 29985159 TI - Photophysical characterization of interchromophoric interactions between rhodamine dyes conjugated to proteins. AB - Rhodamine dyes in aqueous solution form non-fluorescent dimers with a plane-to plane stacking geometry (H-dimers). The self-quenching properties of these dimers have been exploited to probe the conformation and dynamics of proteins using a variety of fluorescence approaches that require the interpretation of fluorescence intensities, lifetimes and fluctuations. Here, we report on a systematic study of the photophysical properties of three rhodamine dyes (tetramethylrhodamine, Alexa 488 and Alexa 546) covalently bound to the E. coli sliding clamp (beta clamp) with emphasis on the properties of the H-dimers that form when the dimeric protein is labeled with one dye at each side of the dimer interface. Overall, results are consistent with an equilibrium between non emissive dimers and unstacked monomers that experience efficient dynamic quenching Protein constructs labeled with tetramethylrhodamine show the characteristic features of H-dimers in their absorption spectra and a c.a. 40 fold quenching of fluorescence intensity. The degree of quenching decreases when samples are labeled with a tetramethylrhodamine derivative bearing a six-carbon linker. H-dimers do not form in samples labeled with Alexa 488 and A546, but fluorescence is still quenched in these samples through a dynamic mechanism. These results should help researchers design and interpret fluorescence experiments that take advantage of the properties of rhodamine dimers in protein research. PMID- 29985160 TI - Growth mode evolution during (100)-oriented beta-Ga2O3 homoepitaxy. AB - This work focuses on homoepitaxial growth of beta-Ga2O3 on (100)-oriented substrates during molecular beam epitaxy. It provides a comprehensive study on the growth mode by combining in situ with ex situ tools. In situ reflection high energy electron diffraction (RHEED) indicates 2D layer-by-layer mode accompanied by (1 * 1) surface reconstruction. The homoepitaxial layers are grown pseudomorphic with the substrate without in-plane strain as probed by in-plane azimuthal RHEED and out-of-plane synchrotron-based high resolution x-ray diffraction. In contrast to the substrate, stacking faults and twin domains are present in the layer. PMID- 29985161 TI - Transport theory for electrical detection of the spin-momentum locking of topological surface states. AB - We provide a general transport theory for spin-polarized scanning tunneling microscopy (STM) through a doped topological insulator (TI) surface. It is found that different from the conventional magnetic substrate, the tunneling conductance through the tip-TI surface acquires an extra component determined by the in-plane spin texture, exclusively associated with the spin momentum locking. Importantly, this extra conductance unconventionally depends on the spatial azimuthal angle of the magnetized STM tip. By introducing a magnetic impurity to break the symmetry of rotation and local time reversal of the TI surface, we find that the measurement of the spatial resolved conductance can reconstruct the helical structure of spin texture, from which the spin-momentum locking angle can be extracted if the in-plane magnetization is induced purely by the spin-orbit coupling of surface Dirac electrons. Our theory offers an alternative way, differing from existing in-plane-current polarization probed in a multi-terminal setup or angle resolved photoemission spectroscopy, to electrically identify the helical spin texture on TI surfaces. PMID- 29985162 TI - Electronic structure of single layer 1T-NbSe2: interplay of lattice distortions, non-local exchange, and Mott-Hubbard correlations. AB - Using ab initio calculations we reveal the nature of the insulating phase recently found experimentally in monolayer 1T-NbSe2. We find soft phonon modes in a large part of the Brillouin zone indicating the strong-coupling nature of a charge-density-wave instability. Structural relaxation of a [Formula: see text] supercell reveals a Star-of-David reconstruction with an energy gain of 60 meV per primitive unit cell. The band structure of the distorted phase exhibits a half-filled flat band which is associated with orbitals that are delocalized over several atoms in each Star of David. By including many-body corrections through a combined GW, hybrid-functional, and DMFT treatment, we find the flat band to split into narrow Hubbard bands. The lowest energy excitation across the gap turns out to be between itinerant Se-p states and the upper Hubbard band, determining the system to be a charge-transfer insulator. Combined hybrid functional and GW calculations show that long-range interactions shift the Se-p states to lower energies. Thus, a delicate interplay of local and long-range correlations determines the gap nature and its size in this distorted phase of the monolayer 1T-NbSe2. PMID- 29985163 TI - Intense yellow luminescence from Dy3+-doped TeO2-WO3-GeO2 glasses: structural and optical characterization. AB - Different concentrations of Dy3+-doped oxyfluoride tellurite (TWGDy) glasses of composition (85 - x) TeO2 + 5 WO3 + 10 GeO2 + x DyF3, where x = 0, 0.1, 0.5, 1.0 and 2.0 mol% were prepared by melt quenching method. The Judd-Ofelt theory was applied to study the luminescence properties. Three phenomenological Judd-Ofelt (Omega lambda=2,4,6) intensity parameters were obtained as Omega2 = 4.90 * 10-20 cm2, Omega4 = 1.73 * 10-20 cm2 and Omega6 = 1.48 * 10-20 cm2 for 0.5 mol% of Dy3+-doped TWGDy glass. When excited at different wavelengths, the TWGDy glasses exhibit three emission bands due to 4F9/2 -> 6H15/2 (blue), 4F9/2 -> 6H13/2 (yellow) and 4F9/2 -> 6H11/2 (red) transitions. The excitation wavelength was optimized as 453 nm for strong and proficient luminescence from TWGDy glasses. Beyond 0.5 mol% of Dy3+ concentration, the TWGDy glasses show luminescence quenching. The laser characteristic parameters such as effective bandwidth, stimulated emission cross section, gain bandwidth and optical gain were determined using the emission spectra and radiative parameters. The 0.5 mol% of Dy3+-doped TWGDy glass could be potential to design a new class of yellow laser material. PMID- 29985164 TI - Valence charge distribution in homogenous silicon-aluminium thin-films. AB - Homogenous aSi1-x Al x H y alloyed thin films, made by magnetron sputtering, has been found to exhibit tunable band gap and dielectric constant depending on their composition. The optical properties of alloys are largely defined by their electronic structure, which is is strongly influenced by interatomic charge transfer. In this work we have quantified interatomic charge transfer between Si, Al and H in aSi1-x Al x H y thin-films, with [Formula: see text] and [Formula: see text]. Charge transfer was found experimentally using x-ray photoelectron spectroscopy, by incorporating Auger parameter data into the Thomas and Weightman model. Both the perfect and imperfect screening models were tested, and the results were compared to models calculated using density functional theory based molecular dynamics. Using imperfect screening properties of Si and Al resulted in an excellent agreement between the experimental and computational results. Alloying aSi with Al is associated with donation of electrons from Al to Si for y = 0. For y > 0 electrons are transferred away from both Al and Si. The change in Si valence charge increases linearly with increasing band gap and decreasing dielectric constant. These relationships can be used as a quick guide for the evaluation of the Si valence charge and subsequently optoelectronic properties, at specific Al/Si ratios. PMID- 29985165 TI - Vaginal epidermal dendritic cells: defense against HIV-1 or a safe haven? AB - Langerhans cells (LCs) are likely among the first targets of HIV-1 infection due to their localization in mucosal tissues. In their recent work, Pena-Cruz and colleagues were able to study HIV-1 infection in vaginal epithelial DCs (VEDCs), termed CD1a+ VEDCs. They show that VEDCs are distinct from other blood- and tissue-derived DCs or LCs because they express the protein langerin but not the lectin receptor DC-SIGN, and they do not have Birbeck granules. The results from this study indicate that HIV-1 using CXCR4 replicates poorly in VEDCs but that a higher replication for HIV-1 using CCR5 strains is supported by VDECs. Furthermore, Pena-Cruz and colleagues demonstrate that VDECs can represent a viral reservoir in HIV-1-infected virologically suppressed women. As such, VDECs may represent another sanctuary of viral persistence and can be an additional obstacle to viral eradication. PMID- 29985166 TI - CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. AB - Podocyte malfunction occurs in autoimmune and nonautoimmune kidney disease. Calcium signaling is essential for podocyte injury, but the role of Ca2+/calmodulin-dependent kinase (CaMK) signaling in podocytes has not been fully explored. We report that podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and lupus-prone and lipopolysaccharide- or adriamycin-treated mice display increased expression of CaMK IV (CaMK4), but not CaMK2. Mechanistically, CaMK4 modulated podocyte motility by altering the expression of the GTPases Rac1 and RhoA and suppressed the expression of nephrin, synaptopodin, and actin fibers in podocytes. In addition, it phosphorylated the scaffold protein 14-3-3beta, which resulted in the release and degradation of synaptopodin. Targeted delivery of a CaMK4 inhibitor to podocytes preserved their ultrastructure, averted immune complex deposition and crescent formation, and suppressed proteinuria in lupus-prone mice and proteinuria in mice exposed to lipopolysaccharide-induced podocyte injury by preserving nephrin/synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of a CaMK4 inhibitor prevented and reversed podocyte injury and renal disease. We conclude that CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis. PMID- 29985167 TI - The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. AB - Myocardial infarction (MI) arising from obstruction of the coronary circulation engenders massive cardiomyocyte loss and replacement by non-contractile scar tissue, leading to pathological remodeling, dysfunction, and ultimately heart failure. This is presently a global health problem for which there is no effective cure. Following MI, the innate immune system directs the phagocytosis of dead cell debris in an effort to stimulate cell repopulation and tissue renewal. In the mammalian adult heart, however, the persistent influx of immune cells, coupled with the lack of an inherent regenerative capacity, results in cardiac fibrosis. Here, we reveal that stimulation of cardiac lymphangiogenesis with VEGF-C improves clearance of the acute inflammatory response after MI by trafficking immune cells to draining mediastinal lymph nodes (MLNs) in a process dependent on lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). Deletion of Lyve1 in mice, preventing docking and transit of leukocytes through the lymphatic endothelium, results in exacerbation of chronic inflammation and long-term deterioration of cardiac function. Our findings support targeting of the lymphatic/immune cell axis as a therapeutic paradigm to promote immune modulation and heart repair. PMID- 29985168 TI - Bowman's capsule provides a protective niche for podocytes from cytotoxic CD8+ T cells. AB - T cells play a key role in immune-mediated glomerulonephritis, but how cytotoxic T cells interact with podocytes remains unclear. To address this, we injected EGFP-specific CD8+ T cells from just EGFP death inducing (Jedi) mice into transgenic mice with podocyte-specific expression of EGFP. In healthy mice, Jedi T cells could not access EGFP+ podocytes. Conversely, when we induced nephrotoxic serum nephritis (NTSN) and injected Jedi T cells, EGFP+ podocyte transgenic mice showed enhanced proteinuria and higher blood urea levels. Morphometric analysis showed greater loss of EGFP+ podocytes, which was associated with severe crescentic and necrotizing glomerulonephritis. Notably, only glomeruli with disrupted Bowman's capsule displayed massive CD8+ T cell infiltrates that were in direct contact with EGFP+ podocytes, causing their apoptosis. Thus, under control conditions with intact Bowman's capsule, podocytes are not accessible to CD8+ T cells. However, breaches in Bowman's capsule, as also noted in human crescentic glomerulonephritis, allow access of CD8+ T cells to the glomerular tuft and podocytes, resulting in their destruction. Through these mechanisms, a potentially reversible glomerulonephritis undergoes an augmentation process to a rapidly progressive glomerulonephritis, leading to end-stage kidney disease. Translating these mechanistic insights to human crescentic nephritis should direct future therapeutic interventions at blocking CD8+ T cells, especially in progressive stages of rapidly progressive glomerulonephritis. PMID- 29985169 TI - CD8+ cells and glomerular crescent formation: outside-in as well as inside-out. AB - Crescentic glomerulonephritis, a complication of severe immune glomerular injury, is the pathological correlate of rapidly progressive glomerulonephritis, mediated by both humoral and cellular effectors. In the current issue of the JCI, Chen et al. have implicated Bowman's capsule in functionally isolating potentially immune effectors, specifically antigen-specific CD8+ T lymphocytes, from podocytes. They suggest that, in crescentic glomerulonephritis, immune-mediated glomerular endothelial injury results in inside-out injury to the glomerulus, with subsequent leukocyte migration through a weakened or ruptured Bowman's capsule, resulting in outside-in injury. Effector T cells then recognize nephritogenic antigens presented by podocytes or other cells within the urinary space, enhancing injury and crescent formation. PMID- 29985170 TI - Two breakthrough gene-targeted treatments for spinal muscular atrophy: challenges remain. AB - The motor neuron disease spinal muscular atrophy (SMA) is caused by recessive, loss-of-function mutations of the survival motor neuron 1 gene (SMN1). Alone, such mutations are embryonically lethal, but SMA patients retain a paralog gene, SMN2, that undergoes alternative pre-mRNA splicing, producing low levels of SMN protein. By mechanisms that are not well understood, reduced expression of the ubiquitously expressed SMN protein causes an early-onset motor neuron disease that often results in infantile or childhood mortality. Recently, striking clinical improvements have resulted from two novel treatment strategies to increase SMN protein by (a) modulating the splicing of existing SMN2 pre-mRNAs using antisense oligonucleotides, and (b) transducing motor neurons with self complementary adeno-associated virus 9 (scAAV9) expressing exogenous SMN1 cDNA. We review the recently published clinical trial results and discuss the differing administration, tissue targeting, and potential toxicities of these two therapies. We also focus on the challenges that remain, emphasizing the many clinical and biologic questions that remain open. Answers to these questions will enable further optimization of these remarkable SMA treatments as well as provide insights that may well be useful in application of these therapeutic platforms to other diseases. PMID- 29985172 TI - Managing Menopause by Combining Evidence With Clinical Judgment. AB - Menopause occurring before the age of 40 harbors unique challenges as well as lifetime burden resulting from premature deprivation from ovarian hormones, primarily estrogen. Cessation of ovarian function before age 40 is considered premature (ovarian insufficiency), whereas if occurring before age 45, it is deemed "early." Early/premature menopause may be idiopathic, medically, or surgically induced. Regardless of the cause, for such women, menopausal hormone therapy is truly replacement and should continue until at least the average age of menopause. Hormone therapy offers the benefit of symptom control, and prevention of health consequences associated with premature loss of ovarian hormones. PMID- 29985173 TI - Megakaryocyte modification of platelets in thrombocytopenia. AB - PURPOSE OF REVIEW: Platelets are small, anucleate cells that circulate within the blood and play essential roles in preserving vascular integrity. However, abnormalities in either platelet production or destruction can result in thrombocytopenia, clinically defined by a platelet count lower than 150 000/MUL of whole blood. Thrombocytopenia is frequently associated with impaired hemostatic responses to vascular injury and can be life-threatening because of bleeding complications. Megakaryocytes are the precursor cells responsible for platelet production, a process commonly referred to as thrombopoiesis. This review specifically discusses how perturbation of molecular mechanisms governing megakaryocyte differentiation and development manifest in various forms of thrombocytopenia. RECENT FINDINGS: This review highlights the identification of novel transcriptional regulators of megakaryocyte maturation and platelet production. We also provide an update into the essential role of cytoskeletal regulation in thrombopoiesis, and how both megakaryopoiesis and platelet production are altered by anticancer therapeutics. Lastly, we focus on recent investigative approaches to treat thrombocytopenia and discuss future prospects in the field of megakaryocyte research. SUMMARY: In patients where thrombocytopenia is not due to heightened platelet destruction or clearance, defects in megakaryocyte development should be considered. PMID- 29985171 TI - Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome. AB - Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1ex4-/-) and postnatal hair cell-specific conditional (Clrn1ex4fl/fl Myo15-Cre+/-) knockout mice. Clrn1ex4-/- mice were profoundly deaf, whereas Clrn1ex4fl/fl Myo15-Cre+/- mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F actin and CaV1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein interaction assays revealed interactions between clarin-1 and the synaptic CaV1.3 Ca2+ channel complex via the Cavbeta2 auxiliary subunit and the PDZ domain-containing protein harmonin (defective in Usher syndrome type IC). Cochlear gene therapy in vivo, through adeno-associated virus-mediated Clrn1 transfer into hair cells, prevented the synaptic defects and durably improved hearing in Clrn1ex4fl/fl Myo15-Cre+/- mice. Our results identify clarin-1 as a key organizer of IHC ribbon synapses, and suggest new treatment possibilities for USH3A patients. PMID- 29985174 TI - Facial profile and additional features in fetuses with trisomy 21. AB - Aneuploidies occur in about 5% of clinically recognized pregnancies. Facial gestalt is a vital tool for the clinical diagnosis of trisomy 21. Facial anomalies are subtle in fetal life and challenging for a clinician not familiar with perinatal dysmorphology. Here, we present the facial profile and additional features in six fetuses with Down syndrome as a visual aid. We present the facial photographs of six fetuses with genetically confirmed trisomy 21. These photographs will serve as a diagnostic aid for trisomy 21 in perinatal dysmorphology. We noted punctate calcifications in two fetuses with trisomy 21. PMID- 29985176 TI - Controversies in periocular reconstruction for facial nerve palsy. AB - PURPOSE OF REVIEW: Periocular rehabilitation of the patient with a facial nerve palsy has evolved over time. Although protection of the ocular surface is paramount, application of disfiguring tarsorrhaphies should be utilized only in special situations. The purpose of this review is to discuss current surgical and medical strategies in treatment of the periocular area in patients with facial nerve palsy to give maximal functional and cosmetic results. RECENT FINDINGS: Upper lid lagophthalmos is preferentially treated with upper eyelid weights. Platinum has distinct advantages over gold. A supratarsal position of the upper lid weight is preferred over a pretarsal location. Lower lid malposition should be treated as a retraction, rather than an ectropion. Recalcitrant ocular surface disease can be effectively managed with a scleral lens. Tearing in the patient with a facial nerve palsy is often multifactorial; small lumen Jones tubes and botulinum toxin injection to the lacrimal gland should be considered to treat epiphora in these patients. SUMMARY: A facial nerve palsy can be devastating for patients from both a functional and cosmetic perspective. Although seismic shifts in treatment of the periocular subunit have not occurred, there are a number of small, yet significant, changes in treatment that should be adopted in taking care of these patients. PMID- 29985175 TI - Current review of sebaceous cell carcinoma. AB - PURPOSE OF REVIEW: Periocular sebaceous cell carcinoma is a rare malignancy that is often misdiagnosed leading to increased morbidity and mortality. This review aims to describe current knowledge on the disease to aid clinicians in timely diagnosis and treatment. RECENT FINDINGS: New research has shown that the diagnosis of sebaceous cell carcinoma can be aided with immunohistochemical stains. A revision in the American Joint Committee on Cancer staging system incorporates new tumor size classifications in the staging of eyelid carcinomas. Wide local excision and Mohs micrographic surgery continue to represent the standard of care for initial treatment of localized disease. SUMMARY: The current review highlights diagnostic and treatment modalities to allow clinicians to make timely diagnosis and tailor treatment plans for individual patient presentations. PMID- 29985177 TI - Psychological interventions in palliative care. AB - PURPOSE OF REVIEW: To provide an update on recent studies about psychological interventions in palliative (mainly cancer) care with a focus on physical, psychological, spiritual, and social aspects. RECENT FINDINGS: Some promising psychological interventions for physical challenges, such as fatigue, pain, dyspnea, and insomnia do exist, but further research is needed. Regarding psychological aspects, current reviews showed small to large effects in the reduction of depression and anxiety symptoms through cognitive behavioral-based interventions, mindfulness-based interventions, and meaning-based interventions. Meaning-based or dignity-based approaches were also used for targeting spiritual aspects or existential distress. Social aspects that play a crucial role in palliative care are addressed by social support interventions, end-of-life discussions, and advanced careplanning. All of these psychological interventions must meet the specific requirements of palliative care, namely abbreviated session time and flexibility concerning locality of interventions, a minimized questionnaire burden and a high attrition rate caused by patients' poor physical conditions or deaths. SUMMARY: There is substantial research on psychological interventions in palliative care that shows promising results, but sample sizes were often small. Due to its high relevance for this growing patient group, there is a strong need for ongoing/further research. PMID- 29985178 TI - Clozapine pharmacogenomics: a review of efficacy, pharmacokinetics, and agranulocytosis. AB - PURPOSE OF REVIEW: To examine recent literature regarding the pharmacogenomics of clozapine (CLZ) efficacy, pharmacokinetics, and agranulocytosis. RECENT FINDINGS: Several genetic loci (FKBP5, NR3C1, BDNF, NTRK2) along the hypothalamic pituitary adrenal axis have been investigated as targets for CLZ response. Homozygous FKBP5 rs1360780, homozygous NTRK2-rs1778929, and homozygous NTRK2-rs10465180 conferred significant risks for CLZ nonresponse - 2.11x risk [95% confidence interval (CI) 1.22-3.64], 1.7x risk (95% CI 1.13-2.59), and 2.15x risk (95% CI 1.3-3.55), respectively. BDNF and NR3C1 had no significant associations with CLZ response. Candidate genes within neurotransmitter pathways continue to be explored including dopaminergic (DRD1-4, COMT) and glutamatergic pathways (GRIN2B, SLC1A2, SLC6A9, GRIA1, GAD1). Despite promising trending data, no significant associations between CLZ response and glutamatergic system variants have been found. Synergistic effect of catecholamine O-methyltransferase (COMT) Met and dopamine receptor-4 (DRD4) single 120 bp duplicate associated with improved CLZ response odds ratio (OR) 0.15 (95% CI 0.03-0.62) while COMT Val/Val confer a risk of CLZ nonresponse OR 4.34 (95% CI 0.98-23.9). Diagnostic performance testing continues through human leukocyte antigen (HLA) and other genetic loci but have yet to find statistically or clinically meaningful results. SUMMARY: Current landscape of pharmacogenomic research in CLZ continues to be limited by small sample sizes and low power. However, many promising candidate genes have been discovered and should be further investigated with larger cohorts. PMID- 29985179 TI - Recent developments in the use of smartphone interventions for mental health. AB - PURPOSE OF REVIEW: The purpose of this update is to provide an overview of the breadth of research studies published from April 2017 to April 2018 on mobile based interventions for mental health, with a special emphasis on smartphone based interventions. RECENT FINDINGS: Several studies during the review period have described the process of applying user-centred design in the development of mental health apps and novel approaches to enhance user-engagement. Studies on consumer perspectives indicate largely positive findings about open-ness to utilize mental health apps. There is a scarcity of similar studies on health providers. Efficacy studies have provided evidence for apps for a variety of psychiatric disorders. There are fewer studies on preventive and promotive interventions. Although a plethora of mental health apps is available for public, most have not undergone scientific evaluation. Many well researched apps are not accessible to public. The potential of smartphone technology in enhancing healthcare service delivery in low-resource settings has also been examined in a few studies. SUMMARY: Evidence for acceptability, feasibility and efficacy of mobile-based mental health interventions for facilitating recovery is on the rise. More research is needed on implementation and integration of these interventions in diverse real-world clinical and community contexts. PMID- 29985180 TI - Role of imbalance between Th17 and regulatory T-cells in sarcoidosis. AB - PURPOSE OF REVIEW: A relatively new class of CD4 expressing T cells that also express and release interleukin-17 (Th17 cells) is gaining attention based on their capacity to regulate inflammatory responses in a spectrum of chronic autoimmune diseases. The purpose of this review is to consider recent studies relating to the critical role played by Th17 cells in the pathogenesis of sarcoidosis. RECENT FINDINGS: Th17 cells are unique in their capacity to adapt to local molecular cues to variably promote or suppress inflammation. On the basis of knowledge established originally in the context of autoimmune disorders, recent investigations indicate that Th17 cells are instrumental in all stages of granuloma evolution, including granuloma formation, maintenance and resolution. Recent research shed light on the mechanisms regulating Th17 cell plasticity and the implications for sarcoidosis disease progression, such as the mechanisms by which regulatory T cells (Tregs) promote resolution of Th17-mediated inflammation. SUMMARY: The balance between Th17 cells and Tregs in sarcoidosis patients has important implications for clinicians and clinical researchers seeking more reliable prognostic markers and more targeted therapeutic agents. PMID- 29985181 TI - Sarcoidosis and autoimmune diseases: differences, similarities and overlaps. AB - PURPOSE OF REVIEW: Sarcoidosis is a rare, multisystem granulomatous disease of incompletely understood pathogenesis. Clinically, it shares common features with several systemic and organ-specific autoimmune diseases, although known autoantibodies or useful serologic markers for diagnosis and monitoring of disease activity are lacking. Sarcoidosis can both coexist with or mimic connective tissue diseases or vasculitis. Here, we review possible common etiologic factors between sarcoidosis and autoimmune disease, comparing clinical, laboratory and imaging features. RECENT FINDINGS: Autoimmune diseases may precede or follow the diagnosis of sarcoidosis. Overall, the prevalence of both co existing is unknown because of limited evidence. The presence of autoantibodies in sarcoidosis should raise suspicion of an underlying autoimmune disease that mimics or co-occurs with sarcoidosis. Silica dust exposure has been associated with an increased prevalence of both sarcoidosis and rheumatoid arthritis. In another study, autoimmune thyroid disease, Sjogren's syndrome and ankylosing spondylitis have been reported to be more frequent in sarcoidosis compared with healthy controls. SUMMARY: A systematic diagnostic work-up is necessary to detect overlapping disease features in patients with sarcoidosis. Immune-modulating therapies need to be taken into account as these can induce paradoxical reactions. PMID- 29985182 TI - Pediatric neuroanesthesia. AB - PURPOSE OF REVIEW: Pediatric neuroanesthesia is a fascinating, yet challenging branch of anesthesia. This review highlights some of the recent insights into pediatric neuroanesthesia from the past 18 months. RECENT FINDINGS: Although there are incontrovertible evidences in animals suggesting that prolonged exposure to general anesthesia causes long-term neurological impairment, the translational relevance of these findings in humans is debatable. Early surgery for pediatric drug-refractory epilepsy is supported by emerging literature, but poses unique perioperative problems for the treating neuroanesthesiologist. Similarly, minimizing intraoperative blood loss and blood transfusion concerns every anesthesiologist managing small children. The usefulness of tranexamic acid in children is further enhanced by some studies in spine surgeries. Some pertinent issues related to intraoperative neuromonitoring are also discussed in the text. SUMMARY: There are several logistical and ethical problems of carrying out high-quality prospective studies in children but important findings on prevention of anesthetic neurotoxicity; minimizing intraoperative blood loss, intraoperative neurophysiological monitoring, examining optimal doses and choices of anesthetic agents in epilepsy surgery have been published recently. PMID- 29985183 TI - Pulmonary manifestations of systemic lupus erythematosus and Sjogren's syndrome. AB - PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) and Sjogren syndrome are chronic autoimmune inflammatory disorders that can present with multiorgan involvement including the lungs. This review will focus on recent literature pertaining to the epidemiology, pathogenesis, clinical presentation and diagnosis and management of SLE and Sjogren syndrome-associated pulmonary conditions. RECENT FINDINGS: Pulmonary manifestations of both disease entities have been well characterized and lung involvement can be observed during the course of the disease in most cases. Pulmonary manifestations of SLE and Sjogren syndrome can be classified based on anatomical site of involvement; and the large and small airways, lung parenchyma, lung vasculature, pleura and respiratory muscles can be involved. The pleura is most commonly involved in SLE, whereas the airways are most commonly involved in primary Sjogren's syndrome (pSS). Sleep disturbances have also been described in both entities. SUMMARY: Although further research into treatment strategies for the pulmonary complications seen in SLE and pSS is needed, the clinician should be aware of the risk factors and clinical presentation of the various pulmonary complications in SLE and pSS in order to identify patients who should be screened and/or have modifications in treatment strategies to mitigate the morbidity and mortality associated with these complications. PMID- 29985184 TI - Correspondence. PMID- 29985185 TI - Glutamate concentration in the anterior cingulate cortex in alcohol dependence: association with alcohol withdrawal and exploration of contribution from glutamatergic candidate genes. PMID- 29985186 TI - Waiting List Mortality and Transplant Rates for NASH Cirrhosis When Compared to Cryptogenic, Alcoholic or AIH Cirrhosis. AB - BACKGROUND: Patients with NASH cirrhosis have excellent post liver transplant (LT) survival despite having many co-morbidities. We hypothesized that this could be due to a selection bias. METHODS: We analyzed the UNOS data from 2002 to 2016 and compared post-LT survival of NASH (n=7,935) patients with cryptogenic (CC, n= 6,087), alcoholic AC, n=16,810) and autoimmune hepatitis (AIH, n= 2,734) cirrhosis. RESULTS: By 3 years of listing, the cumulative incidence (CI) of death or deterioration was 29% for NASH, 28% for CC and AC, and 24% for AIH, but when adjusted for risk factors, the CI was similar for NASH and AIH. The factors that increased the risk of waiting list removal due to death/deterioration were poor performance status, encephalopathy, diabetes, high MELD, Hispanic race, older age and a low serum albumin. Most patients were transplanted within the first year [median 2 months (1-7 IQR] of listing and by 5 years, the unadjusted CI of transplantation was 54% for NASH, 52% for CC, 51% for AIH and 48% for AC. The adjusted CI of transplantation within 2 months of listing was higher for AC (SHR 1.17), AIH (SHR 1.17) and CC (SHR 1.13) when compared to NASH, but after 2 months adjusted transplantation rates decreased in AC (SHR =0.6), AIH (0.78) and CC (SHR 0.95). The negative predictors of receiving a transplant were dialysis, female gender, non-White race, high albumin and creatinine. CONCLUSIONS: Patients with NASH cirrhosis are not disadvantaged by higher waitlist removal or lower transplantation rates. PMID- 29985187 TI - Effects of dexamethasone on autophagy and apoptosis in acute spinal cord injury. AB - Previous studies have indicated that spinal cord injury can induce autophagy. To a certain extent, increased autophagy has a protective effect on neurons. Early hormone therapy is well recognized as a treatment for spinal cord injury. However, whether the protective effect of autophagy is important in recovery from spinal cord injury remains unclear. In this study, we established an in-vitro model of spinal cord injury to study the effects of dexamethasone on mechanical injury, autophagy, and apoptosis in spinal cord neurons. The results showed that dexamethasone inhibited the level of autophagy in the injured nerve cells in a dose-dependent manner. High doses of dexamethasone protected the damaged spinal cord neurons by inhibiting apoptosis, but a protective effect from low hormone concentrations was not obvious. When autophagy was inhibited in damaged spinal cord neurons, apoptosis decreased significantly; in contrast, impairment of autophagy-induced activation of spinal cord neurons and apoptosis levels were significantly increased. PMID- 29985188 TI - Aucubin alleviates glial cell activation and preserves dopaminergic neurons in 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian mice. AB - Aucubin (AUC) is a major bioactive ingredient in Eucommia ulmoides, Plantain asiatica, and Aucuba japonica, and has been shown to exert anti-inflammatory, antioxidative, and neuroprotective effects. We explore the neuroprotective effects of AUC in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Mice were administered MPTP (30 mg/kg) daily for 5 days, followed by treatment with AUC for 7 days. Measurement of dopamine levels was performed by high-performance liquid chromatography and tyrosine hydroxylase expression was assessed by western blot. Our results showed that AUC treatment improved mobility in the pole descent test and the traction test, and reduced the loss of dopaminergic neurons in MPTP-induced parkinsonian mice. AUC treatment rescued the decreased dopamine and tyrosine hydroxylase levels in the striatum of parkinsonian mice. Furthermore, AUC treatment reduced both microglia and astrocyte activation in the substantia nigra of parkinsonian mice. These findings suggest that AUC exerts neuroprotective effects, in part by reducing inflammation and preserving dopaminergic neurons. Possible protection mechanisms involved in MPTP-induced parkinsonian mice need to be clarified further. PMID- 29985189 TI - Outcomes after chronic total occlusion percutaneous coronary interventions: an observational study of 5496 patients from the Pan-London CTO Cohort. AB - BACKGROUND: Chronic total occlusions (CTO) are commonly encountered in patients undergoing coronary angiography; however, percutaneous coronary intervention (PCI) is infrequently performed owing to technical difficulty, the perceived risk of complications and a lack of randomized data. The aim of this study was to analyse the frequency and outcomes of CTO-PCI procedures in a large contemporary cohort of successive patients. PATIENTS AND METHODS: We undertook an observational cohort study of 48 234 patients with stable angina of which 5496 (11.4%) procedures were performed for CTOs between 2005 and 2015 at nine tertiary cardiac centres across London, UK. Outcome was assessed by in-hospital major adverse cardiac events and all-cause mortality at a median follow-up of 4.8 years (interquartile range: 2.2-6.4 years). RESULTS: Over time, there was an increase in the proportion of elective PCI procedures performed for CTOs, but no increase in the absolute number. Overall success rates increased over time (74.3% in 2005 to 81.5% in 2015; P=0.0003) despite an increase in case complexity (previous myocardial infarction, diabetes, renal failure, previous coronary artery bypass grafting, peripheral vascular disease and left ventricular impairment) that correlated with procedural advancements. Successful CTO PCI was associated with lower mortality [9.5%, 95% confidence interval (CI): 8.1-11.6 vs. 15.3%, 95% CI: 13.7-20.6, P<0.0001] that persisted after multivariate cox analysis (hazard ratio: 0.37, 95% CI: 0.25-0.62) and propensity matching (hazard ratio=0.36, 95% CI: 0.18-0.73, P=0.0005). CONCLUSION: Successful procedures were associated with lower mortality suggesting that the greater uptake of CTO PCI may improve clinical outcomes in a wider population than are currently being offered therapy. PMID- 29985190 TI - Developing a High-Fidelity Simulation Program in a Nursing Educational Setting. AB - This change project was developed in response to the lack of a high-fidelity simulation program at a midwestern university in the United States. The use of clinical simulation as a teaching-and-learning strategy has significantly increased within nursing education. Unlike some colleges, this university had a dedicated simulation laboratory with two high-fidelity simulators; however, there was no clinical simulation program to use this equipment. The expensive simulation equipment sat unused because of the lack of funding for dedicated faculty, lack of a champion to implement, shortage of faculty time, minimal knowledge of the use of high-fidelity simulators, and a lack of curriculum integration. The purpose of the project was to create a simulation program, including faculty development and curriculum integration of simulation-based experiences. The framework of the program was based on the International Nurses Association of Clinical Simulation and Learning "Standards of Best Practice: Simulation." The high-fidelity simulation program grew from 0 simulation encounter per year to greater than 250 per year from the onset of the project. Faculty accepted high-fidelity simulation as a new teaching strategy and incorporated a minimum of at least one simulation-based experience within their courses. Simulation has been integrated successfully into the current curriculum. Students and faculty have positively evaluated simulation as an effective teaching/learning strategy. Each semester has seen an increase in the number of simulations, types of simulations, and acuity of simulations offered in clinical courses for students. PMID- 29985191 TI - "Paying it forward": The link between providers' civility climate, civility toward patients and patient experience outcomes. AB - BACKGROUND: Interpersonal relationships are increasingly recognized as an important determinant for care performance and quality in the health care context. An unresolved issue in health care research is whether and to which extent providers' perceptions of their work relationships are associated with their interactions with patients and, in turn, patient experience outcomes. PURPOSE: The aim of this study was to investigate the extent to which nurses' experiences of their work relationship climate (i.e., civility climate) affect their interactions with patients (i.e., civility towards patients), which in turn contribute to patient experience outcomes (i.e., overall hospital rating, willingness to return, intent to recommend). Furthermore, we analyze the mediating role of civility toward patients in the relation between civility climate and patient experience outcomes. METHODOLOGY: The 2011 study sample comprised responses from 6,019 nurses and 38,619 patients at 123 Veterans Health Administration acute care inpatient hospitals located in the United States. We developed and empirically tested a theoretical model using multilevel regression modeling and assessing multilevel mediation. RESULTS: The results indicate a positive association between civility climate and civility toward patients. With regard to patient experience outcomes, the analyses reveal a direct effect of civility climate on overall hospital rating, intent to recommend, and willingness to return and an indirect effect mediated by civility toward patients. CONCLUSION AND PRACTICE IMPLICATIONS: This is one of the first studies theorizing and testing the extent to which relationship climate among providers affect their interactions with patients. The findings provide support that providers who experience a positive civility climate are more likely to pay forward this relationship experience and engage in civility toward patients. The results point to the importance of a civility climate for ensuring and potentially improving patient experience of care. PMID- 29985192 TI - B-cell lymphoma 2 ovarian killer suppresses testicular cancer cell malignant behavior, but plays a role in platinum resistance. AB - Testicular cancer (TC) is the most common malignancy in men. Although the 5-year survival rate of TC patients exceeds 95%, the prognosis of patients with platinum resistant tumors remains poor because of limited therapeutic options. Overcoming chemoresistance is the key to improving survival in poor-prognosis patients. However, the mechanism remains poorly understood. B-cell lymphoma 2 ovarian killer (BOK) is a proapoptotic protein and functions as a tumor suppressor in malignancy tumors. In this study, we found that BOK was frequently downregulated in TC tissues compared with paratumor tissues. BOK overexpression inhibited TC cell proliferation and invasion. In contrast, BOK knockdown promoted TC cell proliferation and invasion. Surprisingly, either BOK overexpression or knockdown rendered TC cells resistant to Cisplatin (DDP). In conclusion, BOK downregulation may be associated with tumorigenesis of TC. BOK had the potency to suppress TC cell proliferation and invasion, and may function as a tumor suppressor in TC. However, BOK also contributes to Cisplatin resistance. These data may provide a wider perspective on TC research and treatment. PMID- 29985193 TI - Thromboelastometric prediction of mortality using the kinetics of clot growth in critically ill septic patients. AB - : Sepsis induces alterations in blood coagulation which are associated with mortality. Using rotational thromboelastometry (ROTEM), these states are often characterized by changes in parameters representing terminal clot lysis. However, the ROTEM changes are often subtle, making them difficult to recognize and interpret. The objective of this study is to evaluate a new ROTEM clot velocity parameter representing clot formation kinetics in septic ICU patients. We hypothesized that this time-based parameter was significantly different in critically ill septic survivors vs. nonsurvivors. This retrospective observational study included severe sepsis and septic shock patients having a minimum of two organ dysfunctions by Sequential Organ Failure Assessment criteria (study group), and a control group of healthy adults without infection . ROTEM with EXTEM activation was performed in all groups. The time from maximal clot formation velocity to zero velocity, representing the latter portion of time during active clot formation prior to achieving maximal clot firmness (t-AUCi) was calculated along with other ROTEM parameters and compared between septic survivors, nonsurvivors and healthy controls. A total of 76 septic patients, of which 26.3%, survived, were included in the study group, and 26 healthy control individuals were included in the control group. t-AUCi correlated with terminal clot lysis (P < 0.001), and was significantly prolonged in septic nonsurvivors compared with survivors and healthy controls (P < 0.001). t-AUCi also differentiated nonsurvivors vs. survivors among those patients having similar ROTEM lysis indices. t-AUCi was useful to differentiate critically ill septic patients, and could be useful to identify septic patients with high-risk of ICU mortality. PMID- 29985194 TI - Successful treatment of massive pulmonary embolism with low-dose tissue plasminogen activator after meniscus surgery. AB - : Pulmonary embolism is a life-threatening disease which represents with high mortality and morbidity. Systemic fibrinolysis is the first-line recommended therapy in hemodynamically instable patients with massive pulmonary embolism. Systemic fibrinolytic treatment remains controversial for pulmonary embolism after surgery due to high risk of hemorrhage. Herein, we report a 49-year-old man with massive pulmonary embolism after meniscus surgery, successfully treated with low-dose prolonged infusion of tissue type plasminogen activator. PMID- 29985195 TI - Educational Analytics: A New Frontier for Gamification? AB - To determine the effects of gamification on student education, researchers implemented "Kaizen," a software-based knowledge competition, among a first-year class of undergraduate nursing students. Multiple-choice questions were released weekly or biweekly during two rounds of play. Participation was voluntary, and students could play the game using any Web-enabled device. Analyses of data generated from the game included (1) descriptive, (2) logistic regression modeling of factors associated with user attrition, (3) generalized linear mixed model for retention of knowledge, and (4) analysis of variance of final examination performance by play styles. Researchers found a statistically significant increase in the odds of a correct response (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) for a round 1 question repeated in round 2, suggesting retention of knowledge. They also found statistically significant differences in final examination performance among different play styles.To maximize the benefits of gamification, researchers must use the resulting data both to power educational analytics and to inform nurse educators how to enhance student engagement, knowledge retention, and academic performance. PMID- 29985196 TI - Evaluating a Blended Online Learning Model Among Undergraduate Nursing Students: A Quantitative Study. AB - In Australia, the emerging use of technology in higher education has brought about significant change in the delivery of undergraduate nursing programs. Universities are now tasked with delivering a blend of online and face-to-face education, while students face new and sometimes challenging online learning environments with little technical support. This article explores the attitudes held by Bachelor of Nursing students toward the blended educational mode at a rural university in Victoria, Australia. A total of 109 participants constituted a convenience sample from a Bachelor of Nursing program across all 3-year levels. Responses provided by participants who completed an online self-report questionnaire were analyzed via descriptive and inferential statistics. The results indicated that participants struggled with inaccurate expectations of workload and the technical difficulties presented by online modules. Although this area requires further research, to an extent autonomy and flexibility were identified as two prominent traits exhibited by students who flourished in the blended modes. All in all, the results of this study strongly reflect the challenges faced by undergraduate nursing students navigating newly introduced online systems in a blended mode of study. PMID- 29985197 TI - Managing sexually transmitted infections: Beyond the 2015 guidelines. AB - Guidelines for the prevention and management of sexually transmitted infections (STIs) are updated periodically while new science is continuously developed. Advanced practice registered nurses implement clinical decisions based on current guidelines and evidence. This article provides recent updates on managing STIs. PMID- 29985198 TI - Classic Papers Revisited: An Early Study of Cardioprotection by Volatile Anesthetics: A Behind-the-scenes Look. AB - Recovery of Contractile Function of Stunned Myocardium in Chronically Instrumented Dogs Is Enhanced by Halothane or Isoflurane. By Warltier DC, al Wathiqui MH, Kampine JP, and Schmeling WT. ANESTHESIOLOGY 1988; 69:552-65. Reprinted with permission.Following brief periods (5-15 min) of total coronary artery occlusion and subsequent reperfusion, despite an absence of tissue necrosis, a decrement in contractile function of the postischemic myocardium may nevertheless be present for prolonged periods. This has been termed "stunned" myocardium to differentiate the condition from ischemia or infarction. Because the influence of volatile anesthetics on the recovery of postischemic, reperfused myocardium has yet to be studied, the purpose of this investigation was to compare the effects of halothane and isoflurane on systemic and regional hemodynamics following a brief coronary artery occlusion and reperfusion. Nine groups comprising 79 experiments were completed in 42 chronically instrumented dogs. In awake, unsedated dogs a 15-min coronary artery occlusion resulted in paradoxical systolic lengthening in the ischemic zone. Following reperfusion active systolic shortening slowly returned toward control levels but remained approximately 50% depressed from control at 5 h. In contrast, dogs anesthetized with halothane or isoflurane (2% inspired concentration) demonstrated complete recovery of function 3-5 h following reperfusion. Because the anesthetics directly depressed contractile function, additional experiments were conducted in which a 15-minute coronary artery occlusion was produced during volatile anesthesia; however, each animal was allowed to emerge from the anesthetized state at the onset of reperfusion. Similar results were obtained in these experiments, demonstrating total recovery of contractile function within 3-5 h following reperfusion. Thus, despite comparable degrees of contractile dysfunction during coronary artery occlusion in awake and anesthetized dogs, the present results demonstrate that halothane and isoflurane produce marked improvement in the recovery of segment function following a transient ischemic episode. Therefore, volatile anesthetics may attenuate postischemic left ventricular dysfunction occurring intraoperatively and enhance recovery of regional wall motion abnormalities during reperfusion. PMID- 29985199 TI - Colorectal Cancer Stratification in the Routine Clinical Pathway: A District General Hospital Experience. AB - Colorectal cancer (CRC) has many subtypes with different prognoses and response to treatment. Patients must be characterized to access the most appropriate treatment and improve outcomes. An increasing number of biomarkers are required for characterization but are not in routine use. We investigated whether CRC can be stratified routinely within a small district general hospital to inform clinical decision making at local multidisciplinary team meeting/tumor board level. We evaluated mismatch repair (MMR) and EGFR signaling pathways using predominantly in-house immunohistochemical (IHC) tests (MSH2, MSH6, MLH1, PMS2, BRAF-V600E, Her2, PTEN, cMET) as well as send away PCR/NGS tests (NRAS, KRAS, and BRAF). We demonstrated that many of the tests required for personalized treatment of CRC can be done locally and timely. Send away tests need to be requested shortly after cut-up and this needs to be firmly established in the tissue pathways for the results to be considered at multidisciplinary team meeting/tumor board. We have shown that MMR IHC combined with BRAFV600E IHC is practical and easy to perform in a small district general hospital, has full concordance with DNA-based tests and satisfies the latest NICE requirements for the identification of potential Lynch syndrome patients. We provide a framework for the interpretation and presentation of test results. It is a practical classification that clinical pathologists can use to communicate effectively with the clinical team. It is broadly based on molecular subtyping, firmly focused on treatment decisions and dependent on the panel of molecular tests currently available.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 29985200 TI - A novel predictor of radial spasm: arterial stiffness. AB - OBJECTIVE: In this study, we aimed to assess the relationship between radial artery spasm (RAS) and arterial stiffness (AS) measured by the oscillometric method. MATERIALS AND METHODS: A total of 123 consecutive patients scheduled for elective coronary angiography in a single default radial center were enrolled for the study. AS [namely, augmentation pressure; augmentation index (AIx); and pulse wave velocity] was assessed using a validated oscillometric device (Mobil-O-Graph NG 24 h PWA). Central arterial pressures were also recorded. In the cath lab, the number of puncture attempts, total procedural time (TPT), and largest catheter size were noted. If greater than two catheters were required to complete imaging, it was additionally specified. RAS was considered to exist if two or more of predefined clinical features were present. RESULTS: RAS was observed in 20 (16.3%) patients. Patients were divided into two distinct groups in terms of the occurence of RAS. In the RAS(+) group, the proportion of hypertensive individuals was significantly higher, whereas there were fewer smokers. With respect to operational data, TPT (24.3+/-9.8 vs. 29.3+/-9.1 mins; P=0.038) and procedures carried out with more than one puncture attempts were significantly higher in the RAS(+) group. Among all oscillometric parameters, augmentation pressure, AIx, and PR were found to be higher in the RAS(+) group. According to multivariate analysis, TPT (P=0.029) and AIx (odds ratio: 1.044, 95% confidence interval=0.977 1.117; P=0.009) were found to be independent predictors of RAS. CONCLUSION: Along with conventional risk factors, AS assessment, as a practical, noninvasive method, may help to predict RAS in angiographic procedures. PMID- 29985201 TI - Association of systolic blood pressure with cardiovascular outcomes in elderly patients with hypertension in Northern China. AB - OBJECTIVE: The aim of this study was to investigate the association of systolic blood pressure (SBP) with cardiovascular disease and all-cause mortality among elderly hypertensive patients in northern China. PARTICIPANTS AND METHODS: In this prospective cohort study, 9655 elderly hypertensive patients from Kailuan study were followed up with the incidence of primary outcomes (composite outcomes including myocardial infarction, stroke, and all-cause death) and the incidence of secondary outcomes (stroke, myocardial infarction, and all-cause death). Patients were categorized into five groups on the basis of SBP levels: Q1 (SBP<130 mmHg), Q2 (130<=SBP<140 mmHg), Q3 (140<=SBP<150 mmHg), Q4 (150<=SBP<160 mmHg), and Q5 (SBP>=160 mmHg). RESULTS: During an average of 7.2+/-1.6 years of follow-up, patients in the group Q2 had the lowest incidence rates of composite outcomes. Q1 was not associated with a decreased risk of composite outcomes. Interestingly, compared with reference group Q2, the risk of composite outcomes [hazard ratio (HR): 1.36; 95% confidence interval (CI): 1.06-1.75] was significantly increased in the Q3 subgroup with high risk+very high risk for the incidence of ischemic cardiovascular disease (ICVD). Similarly, the risk of composite outcomes (HR: 1.25; 95% CI: 1.01-1.53 and HR: 1.35; 95% CI: 1.04-1.75) was significantly increased in Q4 subgroups, with both intermediate risk and high risk+very high risk for 10-year ICVD. CONCLUSION: Elderly hypertensive patients with a high risk of 10-year ICVD were still at a higher risk of developing adverse outcomes even with 140<=SBP<150 mmHg. SBP of less than 130 mmHg was not associated significantly with a reduced risk of developing adverse outcomes. PMID- 29985202 TI - Women's health: making cardiovascular disease real. AB - PURPOSE OF REVIEW: When patients are seen for persistent chest pain in the absence of obstructive coronary artery disease, the physician must decide if the symptoms are due to myocardial ischemia in order to guide treatment. RECENT FINDINGS: Recent findings indicate that ischemia due to coronary microvascular dysfunction (CMD) is associated with subclinical coronary atherosclerosis and an adverse prognosis. Therapeutic probe trials suggest that antiatherosclerotic and anti-ischemic therapeutic strategies may be useful. A large randomized clinical trial of high-intensity statin, maximally tolerated angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker and low-dose aspirin (WARRIOR NCT#03417388) is in progress. SUMMARY: The diagnosis of CMD should be considered in patients with persistent angina, evidence of myocardial ischemia and normal coronary angiogram. Because of the associated adverse prognosis of CMD , conservative empiric treatment or further diagnostic evaluation of the coronary microvasculature can be performed. Diagnosis involves the measurement of coronary blood blow in response to a vasodilator agent invasively or noninvasively. Treatment of CMD can include the use of traditional antianginal and antiatherosclerotic medications. Clinical trials are needed to assess therapeutic strategies on the outcomes of cardiovascular disease and quality of life, in order to develop evidence-based guidelines. PMID- 29985203 TI - Treatment of Addiction to Kratom With Buprenorphine-naloxone. AB - : In this article, we describe a middle-aged woman with a history of addiction to opioid medications who eventually became dependent on kratom. Her kratom-related withdrawal symptoms responded to a trial of buprenorphine-naloxone. Subsequently, she was maintained on this medication. PMID- 29985204 TI - Multimodal Imaging Study of Gadolinium Presence in Rat Cerebellum: Differences Between Gd Chelates, Presence in the Virchow-Robin Space, Association With Lipofuscin, and Hypotheses About Distribution Pathway. AB - PURPOSE: The aim of this study was to investigate, based on in-depth multimodal imaging, the presence of Gd deposits, their ultrastructure, location, and co location with endogenous elements, in the cerebellum, after repeated administrations of gadolinium-based contrast agents (GBCAs). METHODS: Rats sensitized by subtotal nephrectomy received 20 daily intravenous injections of 0.6 mmol Gd/kg for 5 weeks of commercial forms of either gadoterate, gadobenate or gadodiamide, or saline (n = 2/group). The study was randomized and blinded. Magnetic resonance imaging examination was performed weekly. One month after the last injection, electron microscopy analysis of the deep cerebellar nuclei, the granular layer of cerebellar cortex, and the choroid plexus was performed. Elemental analysis of deposits was carried out by electron energy loss spectroscopy. Secondary ion mass spectroscopy was used for complementary chemical mapping. RESULTS: A T1 hypersignal was evidenced in the deep cerebellar nuclei of rats treated with linear GBCAs, and Gd deposits were identified in all the studied cerebellar structures with gadobenate and gadodiamide (except in the granular layer in gadobenate-treated rats). No such effect was found with the macrocyclic GBCA gadoterate. Most of the Gd deposits revealed a characteristic spheroid "sea urchin-like" morphology, rich in phosphorus, and were localized in the basal lamina of microvessels, in the perivascular Virchow-Robin space, and in the interstitium. Gd was also identified in the glial cells, associated with lipofuscin pigments, for these same groups. CONCLUSIONS: Transmission electron microscopy analysis of cerebellums of renally impaired rats repeatedly injected with gadobenate and gadodiamide revealed the presence of Gd. Spheroid Gd depositions consisting of a filamentous meshwork were observed in the wall of microvessels, in perivascular Virchow-Robin space, and in the interstitium. Gd was also found in choroid plexus and was associated with pigments (likely lipofuscin) in glial cells. This is consistent with the involvement of the glymphatic distribution pathway for GBCAs. No insoluble Gd deposits were detected in rats injected with the macrocyclic GBCA gadoterate and controls. PMID- 29985205 TI - Dose-response relationship between thyroid stimulating hormone and hypertension risk in euthyroid individuals. AB - BACKGROUND: The adverse impact of thyroid dysfunction on cardiovascular system is well established, but the relationship between the level of thyroid stimulating hormone (TSH) and the risk of hypertension in euthyroid individuals is still inconclusive. METHODS: We carried out a population-based, cross-sectional study to evaluate the relationship between TSH and hypertension risk in euthyroid individuals, and logistic regression analysis was utilized. In addition, a dose response meta-analysis of relevant cohort or cross-sectional studies was carried out to further assess the impact of TSH on hypertension risk among euthyroid individuals. RESULTS: A total of 2289 euthyroid individuals without thyroid diseases were recruited in our cross-sectional study. Serum TSH level within the upper reference range was associated with higher risk of hypertension [odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.04-1.61, P = 0.023], and the OR for hypertension was still statistically significant after adjustment for confounding factors (OR = 1.32, 95% CI 1.01-1.72, P = 0.041). Moreover, meta-analysis suggested an obvious dose-response relationship between TSH and hypertension risk in euthyroid individuals, and the OR for hypertension associated with per 1 mIU/l increase in TSH level was 1.09 (95% CI 1.04-1.14, P < 0.001). Meta-analysis also showed that the beta-coefficients of SBP and DBP associated with per 1 mIU/l increase in TSH level were 0.78 (95% CI 0.37-1.18, P < 0.001) and 0.45 (95% CI 0.15-0.76, P = 0.004), respectively. CONCLUSION: The current study provides strong evidence for the dose-response relationship between serum TSH level and hypertension risk in euthyroid individuals. Euthyroid individuals with higher normal TSH level are at higher risk of developing hypertension than those with lower normal TSH level. PMID- 29985206 TI - Pregnancy outcome after first trimester exposure to bisoprolol: an observational cohort study. AB - OBJECTIVES: Beta-blockers are frequently used during pregnancy, with labetalol and metoprolol being considered as drugs of choice. As there are no prospective pregnancy studies for bisoprolol yet, our aim was to analyze pregnancy outcomes after bisoprolol exposure. METHODS: Pregnancies exposed to bisoprolol during the first trimester were retrieved from the German Embryotox pharmacovigilance database. Pregnancy outcomes of prospectively ascertained pregnancies were compared with women neither exposed to beta-blockers nor other antihypertensives. In addition, retrospective reports on adverse drug reactions were screened for patterns of birth defects. RESULTS: Inclusion criteria for the prospective study were met by 339 bisoprolol-treated women and 678 patients in the comparison cohort. Neither the risk for spontaneous abortions [adjusted hazard ratio (HRadj.) 1.06; 95% confidence interval (CI) 0.66-1.70] nor for major congenital malformations [adjusted odds ratio (ORadj.) 0.77; 95% CI 0.34-1.75] was increased after first trimester bisoprolol treatment. However, higher rates of preterm births [ORadj. 1.90; 95% CI 1.17-3.11] and reduced birthweights in singleton pregnancies (adjusted standard deviation score difference -0.48; 95% CI -0.62 to 0.34) were noted. Continued treatment with beta-blockers until birth was found to be associated with a higher risk for growth restriction than first trimester exposure only. A sensitivity analysis did not suggest higher rates of adverse pregnancy outcomes in hypertensive women on bisoprolol compared with nonhypertensive bisoprolol-exposed women. CONCLUSION: Our study supports the hypothesis that first trimester bisoprolol treatment does not increase the risk for spontaneous abortions or major birth defects. However, an influence of prolonged bisoprolol exposure on fetal growth cannot be ruled out. PMID- 29985207 TI - Intra-arterial Versus Intravenous Adoptive Cell Therapy in a Mouse Tumor Model. AB - Adoptive cell transfer therapy for cancer has existed for decades and is experiencing a resurgence in popularity that has been facilitated by improved methods of production, techniques for genetic modification, and host preconditioning. The trafficking of adoptively transferred lymphocytes and infiltration into the tumor microenvironment is sine qua non for successful tumor eradication; however, the paradox of extremely poor trafficking of lymphocytes into the tumor microenvironment raises the issue of how best to deliver these cells to optimize entry into tumor tissue. We examined the route of administration as a potential modifier of both trafficking and antitumor efficacy. Femoral artery cannulation and tail vein injection for the intra arterial (IA) and IV delivery, respectively, were utilized in the B16-OVA/OT-I mouse model system. Both IV and IA infusions showed decreased tumor growth and prolonged survival. However, although significantly increased T-cell tumor infiltration was observed in IA mice, tumor growth and survival were not improved as compared with IV mice. These studies suggest that IA administration produces increased early lymphocyte trafficking, but a discernable survival benefit was not seen in the murine model examined. PMID- 29985208 TI - Change of treatment modalities over the last 10 years in pediatric patients with inflammatory bowel disease in Switzerland. AB - BACKGROUND AND AIM: During the past decade, several new drugs were approved for the treatment of pediatric inflammatory bowel disease (IBD). We aimed to evaluate if and how pharmacologic treatment options for pediatric IBD in Switzerland have changed over time. PATIENTS AND METHODS: Data from the pediatric Swiss IBD Cohort Study, a national prospective cohort study initiated in 2006, were analyzed. Patients were divided into two groups: patients with IBD diagnosis until 2009 (168 patients) and patients with IBD diagnosis in 2010 and after (210 patients). Both groups were analyzed regarding the past and the current therapies as well as need for surgery. RESULTS: Overall, 378 pediatric patients with IBD were analyzed, of which 51.9% had Crohn's disease (CD) and 48.1% had ulcerative colitis/indeterminate colitis. Median age at diagnosis was 12 years. The majority (65.4%) of the patients with ulcerative colitis experienced pancolitis, whereas 45.4% of patients with CD presented with ileocolonic disease at diagnosis. A decreased use of corticosteroids in pediatric patients with CD can be found after 2010 (P=0.041). Use of 5-aminosalicylic acid for patients with CD was dramatically reduced after the year 2010 (33.5 vs. 67.7% after 6 years of disease). A significant shift toward earlier use of biologicals could be shown after 2010 (P<0.001). However, there was no significant decrease of surgery rate after 5 years of disease. CONCLUSION: In the past decade, a significant earlier use of anti-tumor necrosis factor-alpha agents in pediatric patients with IBD was observed with steroid-sparing effect in patients with CD. However, this change was not associated with reduction of surgery. PMID- 29985209 TI - A review article on gastric varices with focus on the emerging role of endoscopic ultrasound-guided angiotherapy. AB - BACKGROUND: Gastric varices (GV) manifest in almost one-fifth of the patients with portal hypertension. Although primary pharmacological prevention of esophageal varices has been identified, there are limited therapeutic options that are optimal for GV bleeding. Recently, the use of endoscopic ultrasound (EUS)-guided angiotherapy [cyanoacrylate (CA) and coils] was introduced for the treatment of GV. Although CA injection is the recommended first-line therapeutic modality, it is associated with systemic, life-threatening embolization as well as technical instrumental challenges. Recently, EUS-guided coiling for GV was used with high safety profile. METHODS: This is a review of the current literature on the treatment of GV, focusing on the role of EUS-guided angiotherapy in the treatment of GV. We performed a Medline/PubMed search, and 37 relevant studies were extracted and examined. RESULTS: EUS-guided angiotherapy has shown a consistent favorable result among the several reports throughout the literature, with better safety and efficacy profile toward EUS-guided coiling; however, a combination treatment with EUS-guided coiling followed by glue injection has shown as well to reduce the embolization adverse events associated with glue injection. CONCLUSION: EUS-guided angiotherapy and specifically EUS guided coiling is an emerging promising technique and should be considered as a first-line therapeutic option for bleeding GV. PMID- 29985212 TI - The Impact of Early Adequate Treatment on Extubation and Discharge Alive of Patients With Pseudomonas aeruginosa-Related Ventilator-Associated Pneumonia. AB - OBJECTIVES: We aim to examine the effect of early adequate treatment in comparison with inadequate or delayed treatment on being extubated or discharged alive over time, in patients with Pseudomonas aeruginosa-related ventilator associated pneumonia. DESIGN: Retrospective analyses of a prospective observational multicenter cohort study. SETTING: ICU. PATIENTS: Patients of the French prospective database (OUTCOMEREA) were included if they acquired a ventilator-associated pneumonia due to P. aeruginosa between 1997 and 2014 and were mechanically ventilated for more than 48 hours. INTERVENTIONS: Early adequate treatment in comparison with inadequate or delayed adequate treatment. MEASUREMENTS AND MAIN RESULTS: Multistate models were applied to estimate the time-dependent probability of being extubated or discharged alive, and separate Cox regression analyses were used to assess the treatment effect on all important events that influence the outcome of interest. A propensity score-adjusted innovative regression technique was used for a combined and comprehensive patient relevant summary effect measure. No evidence was found for a difference between adequate and inadequate or delayed treatment on being extubated or discharged alive. However, for all patients, the probability of being extubated or discharged alive remains low and does not exceed 50% even 40 days after a P. aeruginosa-related ventilator-associated pneumonia. CONCLUSIONS: Early adequate treatment does not seem to be associated with an improved prognosis. Its potential benefit requires further investigation in larger observational studies. PMID- 29985210 TI - Features of Adult Hyperammonemia Not Due to Liver Failure in the ICU. AB - OBJECTIVES: To evaluate the epidemiology of hyperammonemia unrelated to liver failure in the critical care setting. DESIGN: Retrospective case series. SETTING: Critically ill patients admitted to ICUs at Mayo Clinic, Rochester, MN (medical ICU, two mixed medical-surgical ICUs, coronary care unit, or the cardiosurgical ICU) between July 1, 2004, and October 31, 2015. PATIENTS: Adult critically ill patients with hyperammonemia not related to acute or chronic liver failure. We excluded patients with diagnosis of moderate or severe liver disease, hyperbilirubinemia, and patients who denied the use of their medical records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 3,908 ICU patients with hyperammonemia, 167 (4.5%) had no evidence of acute or chronic liver failure. One hundred one patients (60.5%) were male with median age of 65.7 years (interquartile range, 50-74.5 yr) and median serum ammonia level of 68 ug/dL (interquartile range, 58-87 ug/dL). Acute encephalopathy was present in 119 patients (71%). Predisposing conditions included malnutrition 27 (16%), gastric bypass six (3.6%), total parenteral nutrition four (2.4%); exposure to valproic acid 17 (10%); status epilepticus 11 (6.6%), high tumour burden 19 (11.3%), and renal failure 82 (49.1%). Urea cycle defects were diagnosed in seven patients (4.1%). Hospital mortality was high (30%), and median ammonia level was higher among the nonsurvivors (74 vs 67 ug/dL; p = 0.05). Deaths were more likely in hyperammonemic patients who were older (p = 0.016), had greater illness severity (higher Acute Physiology and Chronic Health Evaluation III score, p < 0.01), malignancy (p < 0.01), and solid organ transplantation (p = 0.04), whereas seizure disorder was more common in survivors (p = 0.02). After adjustment, serum ammonia level was not associated with increased mortality. CONCLUSIONS: Hyperammonemia occurs in a substantial minority of critically ill patients without liver failure. These patients have a poor prognosis, although ammonia level per se is not independently associated with mortality. Serum ammonia should be measured when risk factors are present, such as nutritional deficiencies and protein refeeding, treatment with valproic acid, high tumour burden, and known or suspected urea cycle abnormalities. PMID- 29985213 TI - Outcomes in Patients With Severe West Nile Neuroinvasive Disease. AB - OBJECTIVE: To assess the long-term outcomes of patients hospitalized with severe West Nile neuroinvasive disease. DESIGN: Retrospective cohort. SETTING: Patients admitted to a referral center (Saint Mary's Hospital, Mayo Clinic). PARTICIPANTS: Twenty-six patients with West Nile neuroinvasive disease were identified by retrospective search of electronic database of Saint Mary's Hospital from January 1999 to November 2016. INTERVENTIONS: Retrospective electronic medical records review and prospective telephone follow-up. MEASUREMENTS AND MAIN RESULTS: Functional disability and cognitive outcomes were evaluated with the modified Rankin Scale and the Telephone Interview for Cognitive Status scores. Data on the time that the patient returned home after the hospitalization for West Nile neuroinvasive disease and the time of return to work were also collected. We identified 26 patients (81% males), 59 +/- 17 years old. After a median hospital stay of 14.5 days (3-126), four patients died and 90% of survivors had a modified Rankin Scale of 3-5. Two additional patients died, and 80% of survivors had a modified Rankin Scale of 0-2 after a median follow-up of 73 months (1-144). Seven patients had cognitive impairment, which was severe in two of them. The combination of encephalitis and acute flaccid paralysis at presentation was associated with lower likelihood of returning home within 1 month after discharge (p < 0.01). Patients who required mechanical ventilation were more likely to have a modified Rankin Scale of 3-5 at last follow-up (p = 0.03), less likely to return home within 1 month of discharge (p < 0.01), less likely to return to their jobs (p < 0.01), and showed a trend toward having cognitive impairment (p = 0.05). CONCLUSIONS: Despite having poor outcomes at discharge, most West Nile neuroinvasive disease survivors with severe early disability can recover functional independence in the long term, justifying aggressive support during the acute phase and extensive rehabilitation efforts. PMID- 29985211 TI - Double Cycling During Mechanical Ventilation: Frequency, Mechanisms, and Physiologic Implications. AB - OBJECTIVES: Double cycling generates larger than expected tidal volumes that contribute to lung injury. We analyzed the incidence, mechanisms, and physiologic implications of double cycling during volume- and pressure-targeted mechanical ventilation in critically ill patients. DESIGN: Prospective, observational study. SETTING: Three general ICUs in Spain. PATIENTS: Sixty-seven continuously monitored adult patients undergoing volume control-continuous mandatory ventilation with constant flow, volume control-continuous mandatory ventilation with decelerated flow, or pressure control-continuous mandatory mechanical ventilation for longer than 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 9,251 hours of mechanical ventilation corresponding to 9,694,573 breaths. Double cycling occurred in 0.6%. All patients had double cycling; however, the distribution of double cycling varied over time. The mean percentage (95% CI) of double cycling was higher in pressure control-continuous mandatory ventilation 0.54 (0.34-0.87) than in volume control-continuous mandatory ventilation with constant flow 0.27 (0.19-0.38) or volume control continuous mandatory ventilation with decelerated flow 0.11 (0.06-0.20). Tidal volume in double-cycled breaths was higher in volume control-continuous mandatory ventilation with constant flow and volume control-continuous mandatory ventilation with decelerated flow than in pressure control-continuous mandatory ventilation. Double-cycled breaths were patient triggered in 65.4% and reverse triggered (diaphragmatic contraction stimulated by a previous passive ventilator breath) in 34.6% of cases; the difference was largest in volume control continuous mandatory ventilation with decelerated flow (80.7% patient triggered and 19.3% reverse triggered). Peak pressure of the second stacked breath was highest in volume control-continuous mandatory ventilation with constant flow regardless of trigger type. Various physiologic factors, none mutually exclusive, were associated with double cycling. CONCLUSIONS: Double cycling is uncommon but occurs in all patients. Periods without double cycling alternate with periods with clusters of double cycling. The volume of the stacked breaths can double the set tidal volume in volume control-continuous mandatory ventilation with constant flow. Gas delivery must be tailored to neuroventilatory demand because interdependent ventilator setting-related physiologic factors can contribute to double cycling. One third of double-cycled breaths were reverse triggered, suggesting that repeated respiratory muscle activation after time-initiated ventilator breaths occurs more often than expected. PMID- 29985215 TI - Benzodiazepine Use and Neuropsychiatric Outcomes in the ICU: A Systematic Review. AB - OBJECTIVES: A systematic assessment of the role of benzodiazepine use during ICU stay as a risk factor for neuropsychiatric outcomes during and after ICU admission. DATA SOURCES: PubMed/Medline, EMBASE, The Cochrane Library, CINAHL, and PsychINFO. STUDY SELECTION: Databases were searched independently by two reviewers for studies in adult (former) ICU patients, reporting benzodiazepine use, and neuropsychiatric outcomes of delirium, posttraumatic stress disorder, depression, anxiety, and cognitive dysfunction. DATA EXTRACTION: Data were extracted using a piloted extraction form; methodological quality of eligible studies was assessed by applying the Quality Index checklist. DATA SYNTHESIS: Forty-nine of 3,066 unique studies identified were included. Thirty-five studies reported on neuropsychiatric outcome during hospitalization, 12 after discharge, and two at both time points. Twenty-four studies identified benzodiazepine use as a risk factor for delirium, whereas seven studies on delirium or related outcomes did not; six studies reported mixed findings. Studies with high methodological quality generally found benzodiazepine use to be a risk factor for the development of delirium. Five studies reported an association between benzodiazepine use and symptoms of posttraumatic stress disorder, depression, anxiety, and cognitive dysfunction after ICU admission; five studies reported mixed findings, and in four studies, no association was found. No association was found with methodological quality and sample size for these findings. Meta analysis was not feasible due to major differences in study methods. CONCLUSIONS: The majority of included studies indicated that benzodiazepine use in the ICU is associated with delirium, symptoms of posttraumatic stress disorder, anxiety, depression, and cognitive dysfunction. Future well-designed studies and randomized controlled trials are necessary to rule out confounding by indication. PMID- 29985214 TI - Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness. AB - OBJECTIVES: To characterize current practice in fluid administration and deresuscitation (removal of fluid using diuretics or renal replacement therapy), the relationship between fluid balance, deresuscitative measures, and outcomes and to identify risk factors for positive fluid balance in critical illness. DESIGN: Retrospective cohort study. SETTING: Ten ICUs in the United Kingdom and Canada. PATIENTS: Adults receiving invasive mechanical ventilation for a minimum of 24 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four-hundred patients were included. Positive cumulative fluid balance (fluid input greater than output) occurred in 87.3%: the largest contributions to fluid input were from medications and maintenance fluids rather than resuscitative IV fluids. In a multivariate logistic regression model, fluid balance on day 3 was an independent risk factor for 30-day mortality (odds ratio 1.26/L [95% CI, 1.07-1.46]), whereas negative fluid balance achieved in the context of deresuscitative measures was associated with lower mortality. Independent predictors of greater fluid balance included treatment in a Canadian site. CONCLUSIONS: Fluid balance is a practice dependent and potentially modifiable risk factor for adverse outcomes in critical illness. Negative fluid balance achieved with deresuscitation on day 3 of ICU stay is associated with improved patient outcomes. Minimization of day 3 fluid balance by limiting maintenance fluid intake and drug diluents, and using deresuscitative measures, represents a potentially beneficial therapeutic strategy which merits investigation in randomized trials. PMID- 29985216 TI - Running Intensities in Elite Youth Soccer by Age and Position. AB - Duthie, GM, Thornton, HR, Delaney, JA, Connolly, DR, and Serpiello, FR. Running intensities in elite youth soccer by age and position. J Strength Cond Res 32(10): 2918-2924, 2018-The purpose of this investigation was to examine differences between the peak running speed, acceleration, and metabolic power of elite youth soccer across a range of age levels by position. Ninety-six elite junior soccer players were assessed between 2015 and 2017. Ninety-six elite junior soccer players (at time of match: age, 15.8 +/- 0.9 years; body mass, 69.1 +/- 8.0 kg) were assessed during 61 games within the 2015, 2016, and 2017 season, for a total of 441 individual match observations (4.8 +/- 3.3 matches per player, range 1-13). Participants were classified by age group: under 15 (U15, n = 121, 14.7 +/- 0.3 years), under 16 (U16, n = 176, 15.8 +/- 0.3 years), or under 17 (U17, n = 144, 16.7 +/- 0.4 years), and according to their playing position: Attacker (ATT), Defender (DEF), Mid-Fielder (MID), or Wide (WIDE). Participants wore global positioning system units during each match, where speed (m.min), acceleration/deceleration (m.s), and metabolic power (Pmet) were established. A 1 to 10-minute moving average was applied to establish the intercept (c) and slope (n) of running intensity variables as a power law y = cx relationship. Linear mixed models were used to examine differences in the intercept and slope between age group and player position. There were no substantial differences in peak (intercept) or decline (slope) in running intensity between playing levels. Several differences were observed in the peak running speeds (m.min), particularly peak running speeds of ATT and DEF being substantially lower than the MID. Despite variability between positions, we suggest that the magnitude of these differences would not warrant the prescription of different running intensities across positions at the elite junior level. These findings describe the peak running intensities of elite junior soccer, useful in the monitoring and prescription of training to ensure that players are prepared for the most demanding periods of competition. PMID- 29985217 TI - Strength Training in Long-Distance Triathletes: Barriers and Characteristics. AB - Luckin, KM, Badenhorst, CE, Cripps, AJ, Landers, GJ, Merrells, RJ, Bulsara, MK, and Hoyne, GF. Strength training in long-distance triathletes: Barriers and characteristics. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this investigation was to identify perceived and physical barriers toward the completion of concurrent strength training and endurance training in long distance triathletes. Three hundred ninety long-distance triathletes (224 women, 166 men; age [y]: 39 +/- 10) completed a 68-question self-administered, semiquantitative survey that assessed endurance and strength training characteristics, experience in triathlon, and perceived barriers regarding the completion of strength training. Mean training hours per week was 14.92 +/- 5.25, with 54.6% reporting participation in strength training. Heavy strength training was the most commonly reported (39.4%), with significantly more men completing this form of strength training (p < 0.001). Results from participants who did not complete strength training indicated that perceived time constraints (53.1%) in addition to lack of knowledge on exercise progression and form (52.5%) are prominent perceived barriers to strength training completion. Identification of the barriers perceived by long-distance triathletes that prevent them from completing concurrent strength training and endurance training may be useful for coaches, athletes, and sports scientists who seek to incorporate strength training for injury prevention and performance improvement. PMID- 29985218 TI - Methods of Monitoring Training Load and Their Association With Changes Across Fitness Measures in Hurling Players. AB - Malone, S, Hughes, B, Collins, K, and Akubat, I. Methods of monitoring training load and their association with changes across fitness measures in hurling players. J Strength Cond Res XX(X): 000-000, 2018-The aim of the current investigation was to assess the dose-response relationship for various methods of monitoring training load (TL) and changes in aerobic and anaerobic fitness in hurling players. Training and match load measures were collected from 30 hurling players (speed at different blood lactate [vLT, vOBLA], maximal oxygen uptake [V[Combining Dot Above]O2max], speed at V[Combining Dot Above]O2max [vV[Combining Dot Above]O2max], peak treadmill velocity [PTV] running economy [RE] Yo-Yo intermittent recovery test (Yo-YoIR1, Yo-YoIR2), speed at 5, 10 , 20 m, and repeated sprint ability [6 * 35 m]) before and after during a 12-week in-season period. Mean weekly training and match loads as determined by s-RPE, bTRIMP, luTRIMP, eTRIMP, iTRIMP, and gTRIMP were correlated with each other, percentage change in V[Combining Dot Above]O2max, vV[Combining Dot Above]O2max, RE, PTV, the speed at blood lactate concentrations of 2 mmol.L (vLT) and 4 mmol.L (vOBLA), and YoYoIR1, Yo-YoIR2 performance. iTRIMP showed a trivial association with s-RPE and a small to moderate association with other heart rate-based methods. Small to large changes (effect size: 0.38-1.12) were observed in aerobic and anaerobic fitness measures were observed across the 12-week period. Trivial to very large associations (r = 0.11-0.78) were observed between TL variables and changes in fitness depending on the variable analyzed. iTRIMP was shown to have large to very large associations with changes in vOBLA {r = 0.78 (95% confidence interval [CI]: 0.71-0.88)}, V[Combining Dot Above]O2max (r = 0.77 [95% CI: 0.68-0.82]), RE (r = 0.77 [95% CI: 0.67-0.82]), Yo-YoIR1 (r = 0.69 [95% CI: 0.51-0.72]), and RSAb (r = 0.66 [95% CI: 0.60-0.72]) with moderate associations reported between iTRIMP and other variables. All other measures of TL showed trivial to moderate associations (r = 0.11-0.66). The current investigation shows that fully individualized training load (iTRIMP) measures may potentially offer a better understanding of dose-response relationships when compared with subjective and nonindividualized measures of TL to changes in aerobic and anaerobic fitness in team sports athletes; as such, it may be suggested that practitioners should use individualized measures of TL assessment within their day-to-day practices. PMID- 29985219 TI - Baseline Assessments of Strength and Balance Performance and Bilateral Asymmetries in Collegiate Athletes. AB - Dai, B, Layer, J, Vertz, C, Hinshaw, T, Cook, R, Li, Y, and Sha, Z. Baseline assessments of strength and balance performance and bilateral asymmetries in collegiate athletes. J Strength Cond Res XX(X): 000-000, 2018-Injuries to upper and lower extremities comprise more than 70% of the total injuries in collegiate athletes. Establishing normative data of upper and lower extremity strength and balance may help guide postinjury rehabilitation and return-to-play decisions. The purposes of the current study were to develop the normative data of performance and bilateral asymmetries during 4 upper and lower extremity strength and balance tests in collegiate athletes and to quantify the correlations between strength and balance performance and bilateral asymmetries. A total of 304 male and 195 female Division I athletes from 14 sports performed a maximum push-up test to assess upper extremity strength, a countermovement jump test to assess lower extremity strength, an upper extremity reaching test to assess upper extremity balance, and a lower extremity reaching test to assess lower extremity balance. Bilateral ground reaction forces were collected for the push-up and jump tests. Reaching distances were measured for the 2 balance tests. Bilateral asymmetries were generally less than 10%. Significant sports effects were observed for all 5 performance variables (p < 0.001) but not for asymmetry variables (p >= 0.36). Weak correlations were found between strength and balance performance and asymmetries (r < 0.3). Normative data are sex and sports specific in collegiate athletes. Increased asymmetries could be more individualized rather than sex and sports specific. When return-to-play decisions are made, athletes following injuries need to demonstrate less than 10% of asymmetries to be consistent with the normative data. Strength and balance should be evaluated and improved with specific focuses. PMID- 29985220 TI - Isometric Midthigh Pull Characteristics in Elite Youth Male Soccer Players: Comparisons by Age and Maturity Offset. AB - Morris, RO, Jones, B, Myers, T, Lake, J, Emmonds, S, Clarke, ND, Singleton, D, Ellis, M, and Till, K. Isometric midthigh pull characteristics in elite youth male soccer players: Comparisons by age and maturity offset. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to (a) provide comparative isometric midthigh pull (IMTP) force-time characteristics for elite youth soccer players and (b) determine the effect of age and maturation on IMTP force-time characteristics. Elite male youth soccer players (U12 n = 51; U13 n = 54; U14 n = 56; U15 n = 45; U16 n = 39; and U18 n = 48) across 3 maturity offset groups (Pre n = 117; circa n = 84; and Post-peak height velocity n = 92) performed 2 maximal IMTP trials on a portable force platform (1,000 Hz). Absolute and relative values for peak force (PF) and impulse over 100 and 300 ms were analyzed. A full Bayesian regression model was used to provide probable differences similar to that of a frequentist p value. Advanced age and maturation resulted in superior IMTP force-time characteristics. Peak force demonstrated high probabilities of a difference between all consecutive age groups (p > 0.95). For absolute and relative impulse (100 and 300 ms), only 2 consecutive age groups (U14-15's and U16-18's) demonstrated high probabilities of a difference (p > 0.95) with large effects (d = 0.59-0.93). There were high probable differences between all maturity offset groups for PF and impulse with medium to large effects (d = 0.56 3.80). These were also reduced when expressed relative to body mass (relative PF and relative impulse). This study provides comparative IMTP force-time characteristics of elite male youth soccer players. Practitioners should consider individual maturation status when comparing players given the impact this has on force expression. PMID- 29985222 TI - Influence of Situational Variables, Team Formation, and Playing Position on Match Running Performance and Social Network Analysis in Brazilian Professional Soccer Players. AB - Aquino, R, Carling, C, Palucci Vieira, LH, Martins, G, Jabor, G, Machado, J, Santiago, P, Garganta, J, and Puggina, E. Influence of situational variables, team formation, and playing position on match running performance and social network analysis of brazilian professional soccer players. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to investigate the independent and interactive effects of situational variables, opposition team formation, and playing position on running performance and network analysis in Brazilian professional soccer players (n = 22). Global positioning system technology was used to determine total distance covered, mean speed, maximum running speed, and distance covered in 6 speed ranges. Social network analysis was used to assess interpersonal coordination (team interactions characterized as successful passes [n = 3,033] between teammates). Observations of match running performance (n = 129) and network analysis (n = 108) were obtained. The main results were: (a) no interactive effects between team formation and playing position were observed for running and network variables (unclear to possibly); (b) matches played at home or against "weaker" opponents presented greater running demands and individual/global metrics of network analysis (likely to almost certain); (c) match outcome demonstrated influence only for running performance; matches in which the reference team won resulted in higher values than in matches lost; (d) when the reference team competed in 1-4-4-2 formation, this resulted in greater running demands than 1-4-2-3-1 formation (likely to almost certain); (e) reduced values of running performance variables were reported in central defenders compared with other positions. Central/external midfielders reported greater closeness/betweenness centrality, outdegree, and eigenvector compared with central/external defenders and forwards (likely to almost certain). The results from this study provide practical information to potentially impact on physical, tactical, and technical training. PMID- 29985221 TI - Recent Advancements in Our Understanding of the Ergogenic Effect of Respiratory Muscle Training in Healthy Humans: A Systematic Review. AB - Shei, R-J. Recent advancements in our understanding of the ergogenic effect of respiratory muscle training in healthy humans: a systematic review. J Strength Cond Res 32(9): 2674-2685, 2018-Respiratory muscle training (RMT) has been shown to be an effective ergogenic aid for sport performance. Respiratory muscle training has been documented to improve performance in a wide range of exercise modalities including running, cycling, swimming, and rowing. The physiological effects of RMT that may explain the improvements in performance have been proposed to include diaphragm hypertrophy, muscle fiber-type switching, improved neural control of the respiratory muscles, increased respiratory muscle economy, attenuation of the respiratory muscle metaboreflex, and decreases in perceived breathlessness and exertion. This review summarizes recent studies on the ergogenicity and mechanisms of RMT since 2013 when the topic was last systematically reviewed. Recent evidence confirms the ergogenic effects of RMT and explores different loading protocols, such as concurrent exercise and RMT (i.e., "functional" RMT). These studies suggest that adapting new training protocols may have an additive improvement effect, but evidence of the efficacy of such an approach is conflicting thus far. Other recent investigations have furthered our understanding of the mechanisms underpinning RMT-associated improvements in performance. Importantly, changes in ventilatory efficiency, oxygen delivery, cytokine release, motor recruitment patterns, and respiratory muscle fatigue resistance are highlighted as potential mechanistic factors linking RMT with performance improvements. It is suggested that future investigations focus on development of sport-specific RMT loading protocols, and that further work be undertaken to better understand the mechanistic basis of RMT induced performance improvements. PMID- 29985223 TI - Jump Training in Rugby Union Players: Barbell or Hexagonal Bar? AB - Weakley, JJS, Till, K, Read, DB, Leduc, C, Roe, GAB, Phibbs, PJ, Darrall-Jones, J, and Jones, B. Jump training in rugby union players: barbell or hexagonal bar?. J Strength Cond Res XX(X): 000-000, 2018-The countermovement jump (CMJ) is an exercise that can develop athletic performance. Using the conventional barbell (BAR) and hexagonal barbell (HEX) while jumping, the intensity can be increased. However, the bar that provides greater adaptations is unknown. Therefore, this study aimed to assess changes in loaded and unloaded CMJ with either a BAR or HEX across a 4-week mesocycle in rugby union players. Twenty-nine subjects were strength-matched and randomized into 2 groups. Subjects completed 3 sets of CMJ at 20% of 1 repetition maximum back squat, 3 times per week for 4 weeks, using either a BAR or HEX. Subjects completed an unloaded CMJ on a force plate before and after, whereas the highest peak concentric velocity during the jump squat was recorded in the first and last training sessions using a linear position transducer. Magnitude-based inferences assessed meaningful changes within- and between-groups. Possibly greater improvements in unloaded CMJ were found in the HEX group in jump height (effect size +/- 90% confidence intervals: 0.27 +/- 0.27), relative peak (0.21 +/- 0.23), and mean power (0.32 +/- 0.36). In addition, likely to very likely greater improvements were observed in the HEX group in peak velocity (0.33 +/- 0.27), relative mean power (0.53 +/- 0.30), mean force (0.47 +/- 0.27), and 100-ms impulse (0.60 +/- 0.48). Similar raw changes in jump squat peak velocity occurred (0.20-0.25 m.s), despite the likely greater ES occurring with the BAR (0.32 +/- 0.26). These results indicate that training with the HEX leads to superior unloaded CMJ adaptations. In addition, practitioners should use either the HEX or BAR when aiming to enhance loaded jump ability. PMID- 29985224 TI - Reliability and Usefulness of Time-Motion and Physiological Responses in Simulated Judo Matches. AB - Franchini, E, Dunn, E, and Takito, MY. Reliability and usefulness of time-motion and physiological responses in simulated judo matches. J Strength Cond Res XX(X): 000-000, 2018-Match simulations have been used to investigate different interventions in judo. However, no study has assessed the reliability of actions performed and the physiological responses to the match and its usefulness. Thus, 2 studies were conducted to verify the reliability of time-motion and physiological responses to judo matches. In the first study, 25 judo athletes performed one 5-minute judo match simulation twice, 1 week apart, and had their heart rate and blood lactate measured. In the second, 12 judo athletes performed one 5-minute judo simulation 4 times, 72 hours apart, and had their primary actions and match temporal structure analyzed. Comparisons between conditions, reliability (using intraclass correlation coefficient, ICC), typical error (TE), smallest worthwhile change (SWC), and minimal detectable change were determined. The main findings indicated that: (a) there were no differences between matches for any variable; (b) ICCs were significant (except for blood lactate before matches in both studies) with 6 variables presenting large (number of attacks plus defensive actions, number of scoring actions, efficiency, number of sutemi waza, time per combat sequence, and time per interval phase time), and the remaining 15 variables presenting very large reliability; (c) TE was higher than SWC for all variables when small differences were considered. Moderate changes in peak blood lactate and the change in blood lactate (in both studies), and time in tachi-waza could be properly detected; however, only large changes could be detected for all other variables, suggesting that investigations using match simulation as an outcome variable may only detect large changes. PMID- 29985225 TI - Measurement of Cortisol and Testosterone in Athletes: Accuracy of Liquid Chromatography-Tandem Mass Spectrometry Assays for Cortisol and Testosterone Measurement in Whole-Blood Microspecimens. AB - Fragala, MS, Goldman, SM, Goldman, MM, Bi, C, Colletti, JD, Arent, SM, Walker, AJ, and Clarke, NJ. Measurement of cortisol and testosterone in athletes: Accuracy of LC-MS/MS assays for cortisol and testosterone measurement in whole blood microspecimens. J Strength Cond Res 32(9): 2425-2434, 2018-Biomarker monitoring provides insight into athletes' training tolerance but is limited by the need for office-based specimen collection. To facilitate self-collection during training, we developed liquid chromatography-tandem mass spectrometry based tests that measure circulating total cortisol and testosterone using a finger stick volumetric absorptive microsampler. Here, we describe the analytical validation of these tests. Forty-six Division I athletes (18-22 years, 30 women, 16 men) provided a 20-uL finger stick microspecimen and a 5-ml venous blood specimen from the forearm; the venous blood sample was analyzed using both normal volume serum analysis and analysis of dried whole blood (from the microsampler). Liquid chromatography-tandem mass spectrometry on standard serum specimens obtained by venipuncture yielded total cortisol levels of 26.2 +/- 11.6 ug.dl (women and men), and total testosterone levels of 37 +/- 17 ng.dl in women and 564 +/- 171 ng.dl in men. Analytical measurement ranges of the microspecimen assay were 0.3-440 ug.dl (CV <9%) for cortisol and 15 to 20,000 ng.dl (CV <9%) for testosterone. Deming regression and Pearson correlation indicated good test accuracy for the microspecimen tests compared with venipuncture tests for cortisol (y = 0.98x + 1.34, 95% CI of slope = 0.83-1.14; r = 0.92, p < 0.0001) and testosterone (y = 1.06x - 0.01, 95% CI of slope = 0.99-1.14; r = 0.99, p < 0.0001). Similarly, high agreement was observed between finger stick and venous microspecimens for cortisol (y = 1.00x + 0.65, 95% CI of slope = 0.9-1.11; r = 0.96, p < 0.001) and testosterone (y = 0.97x + 2.75, 95% CI of slope = 0.9-1.03; r = 0.99, p < 0.001). These findings suggest the viability of finger stick collection whole-blood microspecimens for assessment of total cortisol and testosterone in athletes. PMID- 29985226 TI - Improving Power Output in Older Adults Using Plyometrics in a Body Mass-Supported Treadmill. AB - Dobbs, TJ, Simonson, SR, and Conger, SA. Improving power output in older adults using plyometrics in a body mass-supported treadmill. J Strength Cond Res 32(9): 2458-2465, 2018-The purpose of this study was to determine if performing plyometrics in a body mass-supported treadmill would lead to greater increases in power output and functional strength in older adults compared with traditional strength training. Twenty-three participants were randomized to strength (SG, n = 8), plyometric (PG, n = 8), or control (CG, n = 7) groups. The SG and PG exercised 3 times per week for 8 weeks, whereas the CG performed no exercise. Timed sit-to-stand and stair climb, estimated maximal muscular isotonic strength, and isokinetic strength were assessed pre- and posttraining. Significant improvements occurred in the PG vs. CG in the timed chair sit-to-stand (22.11 +/- 8.48%; p = 0.013), timed stair climb (14.68 +/- 6.28%; p = 0.002), and stair climb power (16.59 +/- 9.07%; p < 0.001). PG and SG significantly increased their estimated 1 repetition maximum in the leg extension and single leg lunge (p < 0.05), and PG was significantly more powerful at all 3 velocities in both flexion and extension compared with SG and CG ranging from 24.54 to 61.85% (p < 0.001) except for 60 degrees .s extension during isokinetic testing. Eight weeks of plyometrics in a body mass-supported treadmill can significantly improve functional strength and power in older adults. In this study, the PG increased muscular strength at the same rate or better than the SG without performing any resistance training. The PG also outperformed SG during the functional tests. These results suggest that plyometrics, if modified and performed in a safe environment, can increase muscular strength and power and improve functional abilities in older adults. PMID- 29985227 TI - Partial Compared with Full Range of Motion Resistance Training for Muscle Hypertrophy: A Brief Review and an Identification of Potential Mechanisms. AB - Newmire, DE and Willoughby, DS. Partial compared to full range of motion resistance training for muscle hypertrophy: A brief review and an identification of potential mechanisms. J Strength Cond Res 32(9): 2661-2673, 2018-Resistance training promotes skeletal muscle hypertrophy; there are specific recommendations of intensity, volume, and duration that appear to facilitate hypertrophy the greatest. However, currently, there is not a definitive consensus on optimal range of motion. It appears that the partial range of motion (pROM) mode of exercise may have some similar benefit on muscle hypertrophy as the conventional full range of motion (fROM). Because of the dynamic and multiplanar movement pattern of a multijoint resistance exercise, there may be variation in human force-length and strength-curve theories, which may influence optimal muscle force production at differing portions of a fROM. This suggests specific muscle groups may potentially be optimally recruited during a specific portion of the exercise. The majority of previous research has primarily focused on strength outcomes opposed to muscle hypertrophy. The purpose of this brief review is to highlight the limited and relative pROM literature on muscle hypertrophy and some potential pROM mechanisms that require investigation to assess any plausible relationships. Some potential mechanisms and outcomes of interest are muscle time under tension, muscle activation, and nonuniform hypertrophy. This mode of resistance exercise requires further evaluation on hypertrophic responses; if proven efficacious, it may be employed to those in rehabilitative environments and those that seek more specific regional, local hypertrophic responses such as physique competitors. PMID- 29985228 TI - Pilates Method Training: Functional and Blood Glucose Responses of Older Women With Type 2 Diabetes. AB - Melo, KCB, Araujo, FdS, Cordeiro Junior, CCM, de Andrade, KTP, and Moreira, SR. Pilates method training: Functional and blood glucose responses of older women with type 2 diabetes. J Strength Cond Res XX(X): 000-000, 2018-The objective of the study was to investigate the effects of 12 weeks (wk) of Pilates method on the functional capacity (FC) and glycemic control of older women with type 2 diabetes (T2D). Twenty-two women with T2D were randomized into the control (CONTROL: 67.5 +/- 6.3 years; 154.7 +/- 6.1 cm; 73.5 +/- 6.1 kg) and Pilates groups (PILATES: 65.5 +/- 5.5 years; 155.0 +/- 4.5 cm; 66.2 +/- 5.4 kg), which held sessions of 60 minutes 3* per week during 12 weeks. Blood glucose was measured before and after sessions in PILATES, as well as in moments of pre, rest, 4 weeks, 8 weeks, and 12 weeks of the PILATES and CONTROL interventions. The glycated hemoglobin (HbA1c) before and after 12 weeks of intervention was evaluated. The general index of FC (GIFC) was obtained through battery of tests for the older. Analysis of variance detected differences in GIFC for PILATES vs. CONTROL, respectively, in the 4 weeks (30.3 +/- 4.6 seconds vs. 34.8 +/- 4.9 seconds; p < 0.05), 8 weeks (29.2 +/- 4.5 seconds vs. 34.6 +/- 4.9 seconds; p < 0.05), and 12 weeks (27.2 +/- 4.0 seconds vs. 35.3 +/- 4.6 seconds; p < 0.05). PILATES presented difference in postprandial glycemia pre vs. 4 weeks and 12 weeks (246.1 +/- 58.5 mg.dl vs. 219.9 +/- 59.9 mg.dl and 207.6 +/- 49.1 mg.dl, respectively; p < 0.05), as well as in the HbA1c pre vs. 12 weeks (7.8 +/- 1.0% vs. 6.7 +/- 0.6%, respectively; p < 0.05). Differences in postprandial glycemia (p < 0.05) were found in the PILATES before vs. after session, respectively, of the 1st-12th (217.1 +/- 49.1 mg.dl vs. 157.9 +/- 55.7 mg.dl), 13th-24th (204.5 +/ 44.7 mg.dl vs. 146.3 +/- 44.5 mg.dl), and 25th-36th (214.3 +/- 40.4 mg.dl vs. 152.7 +/- 52.0 mg.dl). Correlation between postprandial glycemia and GIFC after 12 weeks was detected (r = 0.37; p = 0.04). It is concluded that 12 weeks of PILATES method induce improvement and relationship in the FC and glycemic control in older women with T2D. PMID- 29985229 TI - Inability to predict subprophylactic anti-factor Xa levels in trauma patients receiving early low-molecular-weight heparin. AB - BACKGROUND: Standard low-molecular-weight heparin dosing may be suboptimal for venous thromboembolism prophylaxis. We aimed to identify independent predictors of subprophylactic Xa (subXa) levels in trauma patients treated under a novel early chemoprophylaxis algorithm. METHODS: A retrospective analysis of trauma patients from July 2016 to June 2017 who received enoxaparin 40 mg twice daily and had peak Xa levels drawn was performed. Patients were divided into cohorts based on having a subXa (<0.2 IU/mL) or prophylactic (>=0.2 IU/mL) Xa level. RESULTS: In all, 124 patients were included, of which 38 (31%) had subXa levels, and 17 (14%) had Xa levels greater than 0.4 IU/mL. Of the subXa cohort, 35 (92%) had their dosage increased, and the repeat Xa testing that was done in 32 revealed that only 75% reached prophylactic levels. The median time to the initiation of chemoprophylaxis was 21.9 hours (interquartile range [IQR], 11.45 35.07 hours). Patients who were defined as having lower risk of having a complication as a result of bleeding had a shorter time to starting prophylaxis than those at higher risk (18.39 hours [IQR 5.76-26.51 hours] vs. 29.5 hours [IQR 16.23-63.07 hours], p < 0.01).There was no difference in demographics, weight, body mass index, creatinine, creatinine clearance, injury severity score, type of injury, weight-based dose, time to chemoprophylaxis, or bleeding complications between the cohorts. No independent predictors of subXa level were identified on multivariable logistic regression. CONCLUSIONS: A significant number of trauma patients fail to achieve prophylactic Xa levels. Intrinsic factors may prevent adequate prophylaxis even with earlier administration and higher dosing of low molecular-weight heparin. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 29985230 TI - Severely injured trauma patients with admission hyperfibrinolysis: Is there a role of tranexamic acid? Findings from the PROPPR trial. AB - INTRODUCTION: Administration of tranexamic acid (TXA) in coagulopathy of trauma gained popularity after the CRASH-2 trial. The aim of our analysis was to analyze the role of TXA in severely injured trauma patients with admission hyperfibrinolysis. METHODS: We reviewed the prospectively collected Pragmatic, Randomized Optimal Platelet and Plasma Ratios database. We included patients with admission hyperfibrinolysis (Ly30 >3%) on thromboelastography. Patients were stratified into two groups (TXA and No-TXA) and were matched in 1:2 ratio using propensity score matching for demographics, admission vitals, and injury severity. Primary outcome measures were 6-, 12-, and 24-hour and 30-day mortality; 24-hour transfusion requirements; time to achieve hemostasis; and rebleeding after hemostasis requiring intervention. Secondary outcome measures were thrombotic complications. RESULTS: We analyzed 680 patients. Of those, 118 had admission hyperfibrinolysis, and 93 patients (TXA: 31 patients; No-TXA: 62 patients) were matched. Matched groups were similar in age (p = 0.33), gender (p = 0.84), race (p = 0.81), emergency department (ED) Glasgow Coma Scale (p = 0.34), ED systolic blood pressure (p = 0.28), ED heart rate (p = 0.43), mechanism of injury (p = 0.45), head Abbreviated Injury Scale score (p = 0.68), injury severity score (p = 0.56), and blood products ratio (p = 0.44). Patients who received TXA had a lower 6-hour mortality rate (34% vs. 13%, p = 0.04) and higher 24-hour transfusion of plasma (15 vs. 10 units, p = 0.03) compared with the No TXA group. However, there was no difference in 12-hour (p = 0.24), 24-hour (p = 0.25), and 30-day mortality (p = 0.82). Similarly, there was no difference in 24 hour transfusion of RBC (p = 0.11) or platelets (p = 0.13), time to achieve hemostasis (p = 0.65), rebleeding requiring intervention (p = 0.13), and thrombotic complications (p = 0.98). CONCLUSION: Tranexamic acid was associated with increased 6-hour survival but does not improve long-term outcomes in severely injured trauma patients with hemorrhage who develop hyperfibrinolysis. Moreover, TXA administration was not associated with thrombotic complications. Further randomized clinical trials will identify the subset of trauma patients who may benefit from TXA. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 29985232 TI - Use of diaphragm pacing in the management of acute cervical spinal cord injury. AB - BACKGROUND: Cervical spinal cord injury (CSCI) is devastating. Respiratory failure, ventilator-associated pneumonia (VAP), sepsis, and death frequently occur. Case reports of diaphragm pacing system (DPS) have suggested earlier liberation from mechanical ventilation in acute CSCI patients. We hypothesized DPS implantation would decrease VAP and facilitate liberation from ventilation. METHODS: We performed a retrospective review of patients with acute CSCI managed at a single Level 1 trauma center between January 2005 and May 2017. Routine demographics were collected. Patients underwent propensity matching based on age, injury severity score, ventilator days, hospital length of stay, and need for tracheostomy. Outcome measures included hospital length of stay, intensive care unit length of stay, ventilator days (vent days), incidence of VAP, and mortality. Bivariate and multivariate logistic and linear regression statistics were performed using STATA Version 10. RESULTS: Between July 2011 and May 2017, all patients with acute CSCI were evaluated for DPS implantation. Forty patients who had laparoscopic DPS implantation (DPS) were matched to 61 who did not (NO DPS). Median time to liberation after DPS implantation was 7 days. Hospital length of stay and mortality were significantly lower on bivariate analysis in DPS patients. Diaphragm pacing system placement was not found to be associated with statistically significant differences in these outcomes on risk-adjusted multivariate models that included admission year. CONCLUSIONS: Diaphragm pacing system implantation in patients with acute CSCI can be one part of a comprehensive critical care program to improve outcomes. However, the association of DPS with the marked improved mortality seen on bivariate analysis may be due solely to improvements in critical care throughout the study period. Further studies to define the benefits of DPS implantation are needed. LEVEL OF EVIDENCE: Therapeutic, level IV. PMID- 29985231 TI - Perhaps it's not the platelet: Ristocetin uncovers the potential role of von Willebrand factor in impaired platelet aggregation following traumatic brain injury. AB - BACKGROUND: Injury to the blood-brain barrier exposes endothelium rich in von Willebrand factor (vWF), which may play a role in altered platelet aggregation following traumatic brain injury (TBI). Ristocetin is an antimicrobial substance that induces vWF-mediated aggregation of platelets. We examined these mechanisms in injured patients by measuring the aggregation response of platelets to stimulating agonists (including ristocetin) via whole-blood multiple-electrode platelet aggregometry. We hypothesized that patients with TBI have an altered platelet aggregation response to ristocetin stimulation compared with patients without TBI. METHODS: Blood was collected from 233 trauma patients without thrombocytopenia. Platelet aggregation was assessed using multiple-electrode platelet aggregometry (Multiplate). Platelet aggregation response to stimulating agonists collagen, thrombin receptor-activating peptide 6, adenosine diphosphate, arachidonic acid, and ristocetin was measured. Factor activity was measured. RESULTS: Of the 233 patients, 23% had TBI. There were no differences in platelet aggregation responses to any agonists between TBI and non-TBI patients except ristocetin. Platelet aggregation response to ristocetin stimulation was significantly lower in TBI patients (p = 0.03). Patients with TBI also had higher factor VIII activity (215% vs. 156%, p = 0.01). In multivariate analysis, there was a significant independent association of impaired platelet aggregation response to ristocetin stimulation with TBI (odds ratio, 3.05; p = 0.04). CONCLUSIONS: Given the importance of platelets in hemostasis, understanding the mechanisms of impaired platelet aggregation following injury is critical. The impaired platelet aggregation response to ristocetin stimulation and corresponding increase in factor VIII activity in TBI patients may be secondary to a TBI-induced effect on vWF quantity (due to injury-driven consumption of vWF) or vWF function with resultant increase in circulating factor VIII activity (due to impaired carrying capacity of vWF). Given there are multiple known therapies for vWF deficits including desmopressin, purified and recombinant vWF, and estrogens, these lines of investigation are particularly compelling in patients with TBI and hemorrhage. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 29985233 TI - Abdominal Aortic and Junctional Tourniquet release after 240 minutes is survivable and associated with small intestine and liver ischemia after porcine class II hemorrhage. AB - BACKGROUND: Uncontrolled hemorrhage is a leading cause of tactical trauma-related deaths. Hemorrhage from the pelvis and junctional regions are particularly difficult to control due to the inability of focal compression. The Abdominal Aortic and Junctional Tourniquet (AAJT) occludes aortic blood flow by compression of the abdomen. The survivability of tourniquet release beyond 120 minutes is unknown and fluid requirements to maintain sufficient blood pressure during prolonged application are undetermined. We therefore compared 60-minute and 240 minute applications and release of the AAJT for 30 minutes, with crystalloid fluid therapy, after a Class II hemorrhage. METHODS: Sixty-kilogram anesthetized pigs were subjected to 900-mL hemorrhage and AAJT application for 60 minutes (n = 5), 240 minutes (n = 5), and fluid therapy only for 240 minutes (n = 5) and reperfusion for 30 minutes. RESULTS: The AAJT application was hemodynamically and respiratory tolerable for 60 minutes and 240 minutes. Cumulative fluid requirements decreased by 64%, comparable to 3000 mL of crystalloids. Mechanical ventilation was impaired. AAJT increased the core temperature by 0.9 degrees C compared with fluid therapy. Reperfusion consequences were reversible after 60 minutes but not after 240 minutes. A 240-minute application resulted in small intestine and liver ischemia, persisting hyperkalemia, metabolic acidosis, and myoglobinemia, suggesting rhabdomyolysis. CONCLUSION: The AAJT application for 240 minutes with reperfusion was survivable in an intensive care setting and associated with abdominal organ damage. Long time consequences and spinal cord effects was not assessed. We propose an application time limit within 60 minutes to 240 minutes, though further studies are needed to increase the temporal resolution. The AAJT application may be considered as a rescue option to maintain central blood pressure and core temperature in cases of hemorrhagic shock from extremity bleedings, if fluid therapy is unavailable or if the supply is limited. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 29985234 TI - Implementation is not enough: Graduated drivers licensing benefits from a comprehensive enforcement, education, and awareness campaigns. AB - BACKGROUND: Graduated drivers license (GDLs) are required in most states. Graduated drivers licenses are intermediate licenses requiring a supervisory period prior to full licensure. Surveys suggests poor acceptance of GDL restrictions high variability in GDL compliance. New Jersey initiated GDLs in 2002 and introduced a comprehensive public health campaign in 2010. This study analyzed the effect of GDL and the campaign on teen driver-related fatalities and hypothesized that implementation alone was insufficient to decrease deaths. METHODS: Data were analyzed from 1998 to 2016 from New Jersey's Fatal Accident Investigation Unit. In 2005, collaboration with state police added total crash fatalities and teen passenger deaths to the data set. Patterns in data before and after GDL implementation in 2002 and a comprehensive campaign in 2010 were evaluated to determine effects in New Jersey. Paired t tests, analysis of variance, and regression analyses were performed, with p value less than 0.05 considered significant. RESULTS: Little effect was seen after initiation of GDL, with no change in number of dead teen drivers (44 vs. 49, p > 0.05) or fatal accidents (117 vs.115, p > 0.05) in the 4 years before and after implementation. However, after the comprehensive campaign, decreases are seen in dead teenaged drivers (42 vs. 22, p < 0.005) and total fatal accidents involving teens (107 vs. 61, p < 0.005). Comparing 4 years before and 6 years after the campaign demonstrates decreases in total crash fatalities involving teen drivers (112 vs. 66, p < 0.05) and in the number of dead teenaged passengers in a vehicle operated by another teen (19 vs. 11 p < 0.05). CONCLUSIONS: Implementation of GDLs alone may not be an effective strategy in decreasing the number of teen fatalities. A multipronged approach combining comprehensive, public-health based campaign with targeted enforcement is necessary to decrease the number of teen driver-related deaths. Additional studies are needed to assess the relationship between decreased death and compliance with GDLs. LEVEL OF EVIDENCE: Retrospective comparative study, level III. PMID- 29985235 TI - HYPOBARIA DURING LONG RANGE FLIGHT RESULTED IN SIGNIFICANTLY INCREASED HISTOPATHOLOGICAL EVIDENCE OF LUNG AND BRAIN DAMAGE IN A SWINE MODEL. AB - BACKGROUND: Aeromedical evacuation to definitive care is standard in current military conflicts. However, there is minimal knowledge on the effects of hypobaria on either the flight crew or patients. The effects of hypobaria was investigated using healthy swine. METHODS: Anesthetized Yorkshire swine underwent a simulated 4 h "transport" to an altitude of 2,441 m (8,000 ft.; HYPO, N = 6) or at normobaric conditions (NORMO, N = 6). Physiological and biochemical data were collected. Organ damage was assessed for hemorrhage, inflammation, edema, necrosis and, for lungs only, microatelectasis. RESULTS: All parameters were similar prior to and after "transport" with no significant effects of hypobaria on hemodynamic, neurologic, or oxygen transport parameters, nor on blood gas, chemistry, or complete blood count data. However, the overall Lung Injury Score was significantly worse in the HYPO than the NORMO group (10.78 +/-1.22 vs. 2.31 +/- 0.71, respectively) with more edema/fibrin/hemorrhage in the subpleural, interlobular and alveolar space, more congestion in alveolar septa, and evidence of microatelectasis (vs. no microatelectasis in the NORMO group). There was also increased severity of pulmonary neutrophilic (1.69 +/-0.20 vs. 0.19 +/-0.13) and histiocytic inflammation (1.83 +/-0.23 vs. 0.47 +/-0.17) for HYPO vs. NORMO, respectively. On the other hand, there was increased renal inflammation in NORMO compared to HYPO (1.00 +/-0.13 vs. 0.33 +/-0.17, respectively). There were no histopathological differences in brain (whole or individual regions), liver, pancreas or adrenals. CONCLUSION: Hypobaria, itself, may have an adverse effect on the respiratory system, even in healthy individuals and this may be superimposed on combat casualties where there may be pre-existing lung injury. The additional effects of anesthesia and controlled ventilation on these results are unknown and further studies are indicated using awake models to better characterize the mechanisms for this pathology and the factors that influence its severity.Level II, Therapeutic/Care Management. PMID- 29985236 TI - A comparison of resuscitation intensity and critical administration threshold in predicting early mortality among bleeding patients: A multicenter validation in 680 major transfusion patients. AB - BACKGROUND: To address deficiencies associated with the classic definition of massive transfusion (MT), critical administration threshold (CAT) and resuscitation intensity (RI) were developed to better quantify the overall severity of illness and predict the need for transfusions and early mortality. We sought to evaluate these as more appropriate replacements for MT in defining mortality risk in patients undergoing major transfusions. METHODS: Patients predicted to receive MT at 12 Level I trauma centers were randomized in the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial. MT of 10 U or greater red blood cell (RBC) in 24 hours; CAT+, 3 U or greater RBC in the first hour; and RI, total products in the first 30 minutes (1 U RBC, 1 U plasma, 1000 mL crystalloid, 500 mL colloid each valued at 1 U). Resuscitation intensity was evaluated as a continuous variable and dichotomized as RI4+, where RI is 4 U or greater. Each metric was evaluated for its ability to predict mortality at 3 hours, 6 hours, and 24 hours, and at 30 days. RESULTS: Of the 680 patients, 301 patients met MT definition, 521 were CAT+, and 445 were RI4+. Of those that died, 23% never reached MT threshold, but all were captured by CAT+ and RI4+. The 3 hour (9% vs. 9%), 6-hour (14% vs. 14%), 24-hour (17% vs. 18%), and 30-day mortality rates (28% vs. 29%) were similar between CAT+ and RI4+ patients. When RI was evaluated as a continuous variable, each unit increase was associated with a 20% increase in hemorrhage-related mortality (odds ratio, 1.20; 95% confidence interval, 1.15-1.29; p < 0.05). CONCLUSION: Both RI and CAT are valid surrogates for early mortality in patients undergoing major transfusion, capturing patients omitted by the MT definition. The CAT+ showed the best sensitivity; RI4+ demonstrated better specificity and good positive predictive values and negative predictive values. While CAT+ may be suited for patients receiving an RBC dominant resuscitation, RI4+ is more comprehensive. RI can also be used as a continuous variable to provide quantitative as well as qualitative risk of death. LEVEL OF EVIDENCE: Prognostic, level III. PMID- 29985238 TI - AAST Statement on Firearm Injury. PMID- 29985237 TI - Emergent chest wall reconstruction for an incarcerated pulmonary hernia. PMID- 29985239 TI - Quetiapine protects the blood-brain barrier in traumatic brain injury. AB - BACKGROUND: The integrity of the blood-brain barrier (BBB) is paramount in limiting vasogenic edema following traumatic brain injury (TBI). The purpose of this study was to ascertain if quetiapine, an atypical antipsychotic commonly used in trauma/critical care for delirium, protects the BBB and attenuates hyperpermeability in TBI. METHODS: The effect of quetiapine on hyperpermeability was examined through molecular modeling, cellular models in vitro and small animal models in vivo. Molecular docking was performed with AutoDock Vina to matrix metalloproteinase-9. Rat brain microvascular endothelial cells (BMECs) were pretreated with quetiapine (20 MUM; 1 hour) followed by an inflammatory activator (20 MUg/mL chitosan; 2 hours) and compared to controls. Immunofluorescence localization for tight junction proteins zonula occludens-1 and adherens junction protein beta-catenin was performed. Human BMECs were grown as a monolayer and pretreated with quetiapine (20 MUM; 1 hour) followed by chitosan (20 MUg/mL; 2 hours), and transendothelial electrical resistance was measured. C57BL/6 mice (n = 5/group) underwent mild to moderate TBI (controlled cortical impactor) or sham craniotomy. The treatment group was given 10 mg/kg quetiapine intravenously 10 minutes after TBI. The difference in fluorescence intensity between intravascular and interstitium (DeltaI) represented BBB hyperpermeability. A matrix metalloproteinase-9 activity assay was performed in brain tissue from animals in the experimental groups ex vivo. RESULTS: In silico studies showed quetiapine thermodynamically favorable binding to MMP-9. Junctional localization of zonula occludens-1 and beta-catenin showed retained integrity in quetiapine-treated cells as compared with the chitosan group in rat BMECs. Quetiapine attenuated monolayer permeability compared with chitosan group (p < 0.05) in human BMECs. In the animal studies, there was a significant decrease in BBB hyperpermeability and MMP-9 activity when compared between the TBI and TBI plus quetiapine groups (p < 0.05). CONCLUSION: Quetiapine treatment may have novel anti-inflammatory properties to provide protection to the BBB by preserving tight junction integrity. LEVEL OF EVIDENCE: level IV. PMID- 29985240 TI - Facing the facts on prophylactic antibiotics for facial fractures: 1 day or less. AB - BACKGROUND: To evaluate the role of initial prophylactic antibiotics on facial fractures, outcomes were compared between a short course (<=24 hours) of antibiotics to those who received an extended course (>24 hours). METHODS: Adults admitted (2010-2015) to a Level I trauma center intensive care unit with at least one facial bone fracture and major injuries isolated to the head and neck were included. Our primary analysis compared infectious complications of the head or neck (H/N infection) between patients given short or extended courses of antibiotic prophylaxis. Multivariate logistic regression and analysis of propensity score matched pairs were performed. RESULTS: A total of 403 patients were included, 85.6% had blunt injuries and 72.7% had their facial fracture managed nonoperatively. The H/N infection rate was 11.2%. Two hundred eighty patients received a short course of antibiotics and 123 patients received an extended course. Median Injury Severity Score was 14 in both groups (p = 0.78). Patients receiving an extended course of antibiotics had higher rates of H/N infection (20.3% vs. 7.1%, p < 0.001). Factors associated with development of H/N infection included younger age, penetrating injury, open fracture, upper face or mandible fracture, fractures in multiple facial thirds, vascular injury, hypertension, and extended antibiotic course. Multivariate logistic regression identified younger age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96 1.00; p = 0.02), multiple facial third fractures (OR, 4.9; 95% CI, 2.4-10.2; p < 0.001), and penetrating mechanism (OR, 3.1; 95% CI, 1.5-6.4; p = 0.003) as independent predictors of H/N infection, but not antibiotic duration. Propensity score-matched analysis found no differences in H/N infection between short and extended antibiotic courses (11.4% vs. 12.5%; p = 1.0). Subgroup analyses demonstrated no differences in H/N infection between short or extended antibiotic courses by injury pattern, mechanism, or treatment (operative or nonoperative). CONCLUSION: These results lead us to believe that we should limit antibiotics to 24 hours or less upon admission for facial fractures. LEVEL OF EVIDENCE: Therapeutic/care management, level IV. PMID- 29985241 TI - Risk of infectious complications in pelvic fracture urethral injury patients managed with internal fixation and suprapubic catheter placement. AB - BACKGROUND: There exists significant controversy regarding the use of suprapubic tubes (SPT) in pelvic fracture urethral injury (PFUI) patients undergoing internal fixation (IF) as to the potential risk of infection. Using the National Trauma Data Bank, we sought to examine if placement of SPT in patients with traumatic urethral injuries undergoing IF of pelvic fractures increases the risks of infectious complications during the index hospitalization. PATIENTS AND METHODS: Using International Classification of Disease, version 9 and Abbreviated Injury Scale codes, patients with PFUI were identified in the National Trauma Data Bank between 2002 and 2014. International Classification of Disease, version 9 codes were used to identify patients who underwent IF of pelvic fractures, as well as those who underwent SPT placement. Covariates analyzed included age, Injury Severity Score (ISS), diabetes, hypertension, coronary artery disease, obesity, smoking status, associated colorectal injuries, and pelvic angioembolization. Demographics, management and infectious complications were compared between IF patients who did or did not undergo SPT placement using chi and t tests. Poisson regression analysis was performed to identify independent predictors of infectious complications. RESULTS: Six hundred ninety-six PFUI patients were identified. Two hundred four (29.3%) patients underwent IF during the index hospitalization, of which 35 underwent concomitant SPT placement during that same admission. There was no difference in likelihood of undergoing IF in patients with or without SPT (p = 0.36). Multivariate analysis revealed that only ISS (Relative risk [RR], 4.00; 95% confidence interval, 1.25-12.77) and smoking status (RR, 2.45; 95% confidence interval, 1.11-5.43) were significant predictors of infectious complications, while SPT placement was not. CONCLUSION: Among patients with PFUI undergoing IF, SPT placement does not appear to increase the risk for acute infectious complications during the index hospitalization, while higher ISS and smoking are significantly associated. Further longitudinal studies are required to provide definitive recommendations regarding the long-term safety of SPT placement in this patient population. LEVEL OF EVIDENCE: Prognostic, level IV. PMID- 29985242 TI - The pulseless supracondylar humeral fracture: Our experience and a 1-year follow up. AB - BACKGROUND: Although the pulseless supracondylar humeral fracture (SHF) in children is well known in the bibliography, controversy still exists regarding the treatment strategy. The purpose of this study was: (a) to describe our policy with pulseless hands following SHF and (b) evaluate the functional outcome in a 1 year follow-up. METHODS: During the years 2013 to 2018 in our department, 23 of 210 children with type III SHF presented with a pulseless hand (20 with a PPH and 3 with a cold, pulseless hand). Fracture reduction was attempted in all patients followed by reevaluation of the vascular clinical status (including a Doppler ultrasound). RESULTS: In PPH, a palpable radial pulse was present in all patients in less than 48 hours after surgery. Closed reduction was able to improve the vascular status in 1 patient with pale pulseless hand but surgical exploration of the brachial artery was performed in the other two patients. A palpable radial pulse was present 24 hours after surgery in these 3 patients. All patients had good/excellent outcomes at 1-year follow-up. CONCLUSION: With our study, we want to enhance the traditional dogma of "watchful waiting" in pink pulseless hands following SHF, and we believe that it should not be revisited. In pale pulseless hands following SHF, at least one attempt of reduction and fixation of the fracture is recommended. If the pulse does not return or the vascular status does not improve, immediate surgical exploration of the artery is strongly indicated. LEVEL OF EVIDENCE: Case series prognostic study, level IV. PMID- 29985244 TI - Intra-articular Gentamicin-loaded PLA Microparticle Injection for the Treatment of Septic Arthritis in Rabbits. AB - BACKGROUND: Because local delivery of drugs induces high concentrations, it could be helpful to apply these delivery systems to the treatment of septic arthritis by antibiotics. Thus, a gentamicin-loaded polymer was tested in a rabbit model of Staphylococcus aureus septic arthritis. METHODS: Thirty New Zealand rabbits were split into five groups: A: infection only; B: infection and systemic gentamicin treatment; C: infection and unloaded polymer and systemic gentamicin treatment; D: infection and gentamicin-loaded polymer only; and E: no infection and unloaded polymer. After inducing nonlethal septic arthritis in the knee joint by injecting 10 colony-forming units (CFUs) of a strain of methicillin-sensitive S aureus in groups A, B, C, and D, rabbits were housed for 15 days, and then the joint capsules were removed and the remaining bacteria were counted. Bacterial load was expressed in CFUs per gram of synovial tissue. In group E, capsules were removed, and a pathologic examination was done. RESULTS: At day 15, the bacterial load was 6 * 10, 2 * 10, 1.8 * 10, and 7 * 10 CFU/g of tissue for groups A, B, C, and D, respectively. Compared with the mean of groups A, B, and C, the bacterial load of group D was 4.94 units of log10 CFU/g lower than that of these groups. The bacterial load of group D was statistically significantly lower than that of the other three groups. Noticeably, two animals of group D had a nil bacterial count. In group E animals, a minimal foreign body reaction was observed around the polymer. DISCUSSION: Gentamicin-containing microparticles were more efficient in reducing bacterial load than systemic injections of gentamicin and thus have an interesting role to play in the treatment of human arthritis. However, inserting microparticles in joints is not easy, and hydrogels might be a good alternative approach. PMID- 29985245 TI - Letter to the Editor: Compliance With the AAOS Guidelines for Treatment of Osteoarthritis of the Knee: A Survey of the American Association of Hip and Knee Surgeons. PMID- 29985246 TI - Regenerative Rehabilitation of the Musculoskeletal System. PMID- 29985247 TI - Reply to the Letter to the Editor: Compliance With the AAOS Guidelines for Treatment of Osteoarthritis of the Knee: A Survey of the American Association of Hip and Knee Surgeons. PMID- 29985249 TI - Diana L. Smalley, RN, FACHE, Regional President, Mercy/Oklahoma. PMID- 29985248 TI - EDITORIAL. PMID- 29985250 TI - Promoting Stellar Team Performance to Achieve Stellar Results at MetroHealth. PMID- 29985251 TI - Improving Quality and Lowering Cost Through Community Care Teams. AB - EXECUTIVE SUMMARY: The U.S. healthcare industry has seen a sharpened focus on delivering value-based care. To accomplish this, providers have turned their attention toward high-risk patients who are in frequent contact with the healthcare system. Specific attention has been given to Medicaid patients, who make up a majority of the high-risk population. Providers are implementing new approaches and strategies to improve the quality of healthcare and lower the cost for high-risk Medicaid patients. This essay highlights how the implementation of community care teams (CCTs) can improve quality and lower costs for these patients. Through discussion of the success at Community Care North Carolina, other states can understand the impact CCTs have on high-risk Medicaid patients by delivering value-based care, improving quality, and lowering costs. PMID- 29985252 TI - Delivering Value-Based Care With E-Health Services. AB - EXECUTIVE SUMMARY: The emergence of value-based healthcare requires new approaches for physicians and their organizations in serving their patients. Traditional medical practices have centered on physicians detecting and responding to patients' needs, but with new payment models and technologies, practitioners will be required to prevent health issues from developing. Transitions of care and service coordination among providers and specialists need to be seamless as patients are educated about their health issues and better connected to their medical information. A key enabler of this change will be how well patients can collaborate with their care teams, and several e-health disciplines catalyze this process. In fact, there is an e-health imperative to affect outcomes and patient experiences while lowering costs.The Triple Aim objectives of the Institute for Healthcare Improvement are more achievable with the integration of e-health tools and services with clinical care. The mobile revolution and improvements in data management practices now make improved care coordination possible throughout a patient's journey. Telehealth services facilitate connected care and inform physicians with data that flow into a patient portal, which improves risk monitoring and enables proactive treatment. The growing use of social media fosters community development, which enables patients to share experiences with others, further empowering consumerism in healthcare delivery. Finally, e-health tools enable customization of care for large populations as we stratify patient groups. Clinical data scientists and informaticists partner with physicians to establish and operationalize programs that identify new best practices and drive behavior change-especially for those patients with costly chronic conditions and comorbidities. E-health disciplines are the lifeblood of a system that engages patients in new ways to help them and their physicians adhere to practices that support value-based care. PMID- 29985254 TI - Practitioner Application: Engaging More Nurses in Cancer Preventive Care: Challenges and Opportunities. PMID- 29985253 TI - Engaging More Nurses in Cancer Preventive Care: Challenges and Opportunities. AB - EXECUTIVE SUMMARY: Nurse-led care is crucial to improving the effectiveness of cancer prevention, as demonstrated by research. However, barriers to nurse-led cancer preventive care are still prevalent. What are the challenges that impede nurses from providing effective preventive care? How can hospital leaders address these challenges to better engage nurses in preventive care? What should be the focal areas in terms of policy changes and training programs? This article explores those questions. We examine the difficulties nurses have encountered. We identify the barriers yet to be examined extensively. Finally, we propose that many barriers can be addressed through carefully designed nurses' training programs and substantial policy changes. Our data were collected from a Nurse Oncology Education Program survey that included questions on perceived oncology knowledge, current cancer-related preventive practices, and barriers to preventive practices. We identified the barriers for the nurse population studied and opportunities to overcome these barriers. PMID- 29985255 TI - Developing Data to Support Effective Coordination of Nonprofit Hospital Community Benefit Investments. AB - EXECUTIVE SUMMARY: Nonprofit hospitals achieve tax exemption through community benefit investments. The objective of this study was to characterize urban and suburban nonprofit hospitals' community benefit expenditures and to estimate regional per capita community benefit spending relative to community need. Community benefit expenditures, both overall and by subtype, were compared for urban versus suburban nonprofit hospitals in a large metropolitan area, the greater Philadelphia region. Estimated zip code-level per capita expenditures were mapped in the urban core area. We found that urban hospitals report higher overall community benefit expenditures than suburban hospitals yet invest less in community health improvement services, both proportionally and absolutely, despite spending similar proportions on charity care. There is an overlap in hospital-identified community benefit service areas in the urban core, but the degree of overlap is not related to community poverty levels. There is significant variation in zip code-level per capita community benefit expenditures, which does not correlate with community need. Community benefit investments offer the potential to improve community health, yet without regional coordination, the ability to maximize the potential of these investments is limited. This study's findings highlight the need to implement policies that increase transparency, accountability, and regional coordination of community benefit spending. PMID- 29985256 TI - PRACTITIONER APPLICATION: Developing Data to Support Effective Coordination of Nonprofit Hospital Community Benefit Investments. PMID- 29985257 TI - The Impact of Hospitalists on Value-Based Purchasing Program Scores. AB - EXECUTIVE SUMMARY: As part of the provisions of the 2010 Affordable Care Act, the Centers for Medicare & Medicaid Services adjusts payments made to hospitals through its Hospital Value-Based Purchasing (HVBP) program. In light of the increasing aim to improve efficiency, healthcare organizations are exploring innovative strategies for care delivery, including the use of hospitalists. Supporters of the hospitalist model suggest use of these specialists offers several advantages over the traditional model of physician care in the inpatient setting, including improved coordination, reduced costs, and improved quality indicator scores. This study explores the effect of hospitalists on hospitals' scores in the four domains of the fiscal year 2016 HVBP program: clinical process of care, patient experience of care (PEOC), outcome, and efficiency. Data from the 2015 HVBP database, the 2015 Medicare Final Rule Standardizing File, and the 2015 American Hospital Association database were used for the analysis. The study used multivariate regression analysis in Stata 12. Results from this study suggest that hospitals employing a higher percentage of hospitalists see related improvement in their overall total performance score. In light of improvements within the PEOC, outcome, and efficiency scores, it would appear that hospitalists are primarily providing linking services, which helps provide better coordination of care that is otherwise lacking in more traditionally fragmented approaches to care. PMID- 29985258 TI - Practitioner Application: The Impact of Hospitalists on Value-Based Purchasing Program Scores. PMID- 29985259 TI - The Association of Out-of-Pocket Spending and Health Status With Consumer Directed Health Plan Choice. AB - EXECUTIVE SUMMARY: This study examines how health status and experiences with cost sharing affect consumers' choices between managed care and consumer-directed health plan (CDHP) options. Human resources and claims system information were obtained from a single, large multistate employer through a third-party firm that extracted, merged, and deidentified the data for a final sample of 9,616 insured households. Multinomial logistic regression was used to estimate plan choice between a managed care preferred provider organization and two forms of CDHP. Andersen's Behavioral Model guided the cross-sectional, nonexperimental ex post facto design.Results indicate that cost sharing and health status have minimal effect on CDHP choice when operationalized as a continuous measure. However, a nonlinear association is suggested when examining the lowest and lower cost sharing and health status groups. Enrollees in the lowest cost-sharing and best health status groups are most likely to choose a CDHP option offering a health savings account, while those in the lower cost-sharing and better health status groups are most likely to opt for a CDHP that includes a health reimbursement arrangement.This study supports the assessment that CDHPs benefit from favorable selection. Results also suggest that previously experienced cost sharing is a greater factor than health status when choosing a CDHP, particularly for those who are less healthy and who have experienced greater out-of-pocket spending. Employers should consider enrollees' experiences with healthcare plans, as these may influence plan choice and suggest features most important to employees, which can also influence healthcare-related behaviors. PMID- 29985260 TI - PRACTITIONER APPLICATION: The Association of Out-of-Pocket Spending and Health Status With Consumer-Directed Health Plan Choice. PMID- 29985261 TI - Using Time-Driven Activity-Based Costing to Model the Costs of Various Process Improvement Strategies in Acute Pain Management. AB - EXECUTIVE SUMMARY: Pain control for patients undergoing thoracic surgery is essential for their comfort and for improving their ability to function after surgery, but it can significantly increase costs. Here, we demonstrate how time driven activity-based costing (TDABC) can be used to assess personnel costs and create process-improvement strategies.We used TDABC to evaluate the cost of providing pain control to patients undergoing thoracic surgery and to estimate the impact of specific process improvements on cost. Retrospective healthcare utilization data, with a focus on personnel costs, were used to assess cost across the entire cycle of acute pain medicine delivery for these patients. TDABC was used to identify possible improvements in personnel allocation, workflow changes, and epidural placement location and to model the cost savings of those improvements.We found that the cost of placing epidurals in the preoperative holding room was less than that of placing epidurals in the operating room. Personnel reallocation and workflow changes resulted in mean cost reductions of 14% with epidurals in the holding room and 7% cost reductions with epidurals in the operating room. Most cost savings were due to redeploying anesthesiologists to duties that are more appropriate and reducing their unnecessary duties by 30%. Furthermore, the change in epidural placement location alone in 80% of cases reduced costs by 18%. These changes did not compromise quality of care.TDABC can model personnel costs and process improvements in delivering specific healthcare services and justify further investigation of process improvements. PMID- 29985262 TI - Practitioner Application: Using Time-Driven Activity-Based Costing to Model the Costs of Various Process Improvement Strategies in Acute Pain Management. PMID- 29985263 TI - Trends Over Time for Adolescents Enrolling in HIV Care in Kenya, Tanzania, and Uganda From 2001-2014. AB - BACKGROUND: The data needed to understand the characteristics and outcomes, over time, of adolescents enrolling in HIV care in East Africa are limited. SETTING: Six HIV care programs in Kenya, Tanzania, and Uganda. METHODS: This retrospective cohort study included individuals enrolling in HIV care as younger adolescents (10-14 years) and older adolescents (15-19 years) from 2001-2014. Descriptive statistics were used to compare groups at enrollment and antiretroviral therapy (ART) initiation over time. The proportion of adolescents was compared with the total number of individuals aged 10 years and older enrolling over time. Competing-risk analysis was used to estimate 12-month attrition after enrollment/pre-ART initiation; post-ART attrition was estimated by Kaplan-Meier method. RESULTS: A total of 6344 adolescents enrolled between 2001 and 2014. The proportion of adolescents enrolling among all individuals increased from 2.5% (2001-2004) to 3.9% (2013-2014, P < 0.0001). At enrollment, median CD4 counts in 2001-2004 compared with 2013-2014 increased for younger (188 vs. 379 cells/mm, P < 0.0001) and older (225 vs. 427 cells/mm, P < 0.0001) adolescents. At ART initiation, CD4 counts increased for younger (140 vs. 233 cells/mm, P < 0.0001) and older (64 vs. 323 cells/mm, P < 0.0001) adolescents. Twelve-month attrition also increased for all adolescents both after enrollment/pre-ART initiation (4.7% vs. 12.0%, P < 0.001) and post-ART initiation (18.7% vs. 31.2%, P < 0.001). CONCLUSIONS: Expanding HIV services and ART coverage was likely associated with earlier adolescent enrollment and ART initiation but also with higher attrition rates before and after ART initiation. Interventions are needed to promote retention in care among adolescents. PMID- 29985264 TI - Brief Report: Prevalence of Peripheral Artery Disease Is Higher in Persons Living With HIV Compared With Uninfected Controls. AB - OBJECTIVE: Ankle-brachial index is an excellent tool for diagnosing peripheral artery disease (PAD). We aimed to determine the prevalence and risk factors for PAD in people living with HIV (PLWH) compared with uninfected controls. We hypothesized that prevalence of PAD would be higher among PLWH than among controls independent of traditional cardiovascular disease (CVD) risk factors. METHODS: PLWH aged 40 years and older were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study. Sex- and age-matched uninfected controls were recruited from the Copenhagen General Population Study. We defined PAD as ankle-brachial index <=0.9 and assessed risk factors for PAD using logistic regression adjusting for age, sex, smoking status, dyslipidemia, diabetes, hypertension, and high-sensitivity C-reactive protein. RESULTS: Among 908 PLWH and 11,106 controls, PAD was detected in 112 [12% confidence interval: (95% 10 to 14)] and 623 [6% (95% 5 to 6)], respectively (P < 0.001), odds ratio = 2.4 (95% 1.9 to 2.9), and adjusted odds ratio = 1.8 (95% 1.3 to 2.3, P < 0.001). Traditional CVD risk factors, but not HIV-related variables, were associated with PAD. The strength of the association between PAD and HIV tended to be higher with older age (P = 0.052, adjusted test for interaction). CONCLUSIONS: Prevalence of PAD is higher among PLWH compared with uninfected controls, especially among older persons, and remains so after adjusting for traditional CVD risk factors. Our findings expand the evidence base that PLWH have excess arterial disease to also include PAD. The exact biological mechanisms causing this excess risk remain to be elucidated. Until then, focus on management of modifiable traditional risk factors is important. PMID- 29985266 TI - Availability of HIV and HCV On-Site Testing and Treatment at Syringe Service Programs in the United States. PMID- 29985265 TI - Antiretroviral Drug Use and HIV Drug Resistance Among Young Women in Rural South Africa: HPTN 068. AB - BACKGROUND: Antiretroviral (ARV) drugs are used for HIV treatment and prevention. We analyzed ARV drug use and HIV drug resistance in a cohort of young women in rural South Africa enrolled in the HIV Prevention Trials Network (HPTN) 068 study, which evaluated the use of a cash transfer conditional on school attendance to reduce HIV incidence. METHODS: ARV drug testing was performed using plasma samples from 2526 young women. This included 2526 enrollment samples (80 HIV-infected and 2446 HIV-uninfected) and 162 seroconversion samples (first HIV positive study visit). Testing was performed using a qualitative assay that detects 20 ARV drugs from 5 drug classes. HIV drug resistance testing was performed with the ViroSeq HIV-1 Genotyping System for samples that had HIV viral loads >=400 copies per milliliter. RESULTS: At enrollment, ARV drugs were detected in 10 (12.5%) of 80 HIV-infected young women. None of 2446 HIV uninfected young women had ARV drugs detected at enrollment. ARV drugs were also detected in 16 (9.9%) of 162 seroconverters. At enrollment, 9 (13.4%) of 67 young women with genotyping results had HIV drug resistance; resistance was also detected in 9 (6.9%) of 131 seroconverters with genotyping results. CONCLUSIONS: Most of the HIV-infected young women in this cohort from rural South Africa were not taking ARV drugs, suggesting they were unaware of their HIV status or were not in care. HIV drug resistance was detected in young women with both prevalent and new HIV infection. PMID- 29985267 TI - Contraception and PrEP in South African Hair Salons: Owner, Stylist, and Client Views. PMID- 29985268 TI - Translating Research Findings Into Practice: The Importance of Updating Knowledge. PMID- 29985269 TI - The Challenges of Manpower in Long-Term Care: Intergenerational Learning Approach From Ageism to Caregiving. PMID- 29985270 TI - Plain Language is Preferred (PLiP). PMID- 29985271 TI - The Hand-eye Coordination of Professional Baseball Players: The Relationship to Batting. AB - SIGNIFICANCE: A visuomotor skill (eye-hand visual-motor reaction time [EH-VMRT]) important for baseball performance is described. Eye-hand visual-motor reaction time represents the integration of visual information, perceptually based decisions, and motor movements to accomplish a specific task. The speed at which this occurs depends on many factors, some visual, some perceptual, and some motor related. PURPOSE: The purpose of this study was to describe the EH-VMRT ability and evaluate its relationship to the baseball batting performance of professional baseball players. METHODS: A commercially available EH-VMRT system was used on 450 professional baseball players. Results were retrospectively compared with standard, career, plate discipline metrics. RESULTS: Statistically significant correlations were found between the EH-VMRT metrics and plate discipline batting metrics. Better EH-VMRT ability also correlated with longer service in, and likelihood to achieve, the major-league level. The better (top 20%) EH-VMRT group had three fewer at bats before gaining a walk (22% decrease), as well as swinging 10 to 12% less often at pitches outside the strike zone and 6 to 7% less often at pitches in the strike zone as compared with the bottom 20% group. In addition, EH VMRT displays a threshold-like relationship with the ability to gain a walk. CONCLUSIONS: These results describe the EH-VMRT ability of professional baseball players and show a significant relationship between the EH-VMRT ability and batting performance. These results may suggest a possible role in player selection, indicating that batters with better EH-VMRT may be more likely to reach the major-league level and be more productive for their team. Further studies will be needed to demonstrate whether training better EH-VMRT results in improved batting performance. PMID- 29985272 TI - Words Matter. PMID- 29985274 TI - Secondary Brain Injury: A Concept Analysis. AB - BACKGROUND: Traumatic brain injury and cerebrovascular disease may lead to motor, behavioral, and/or cognitive disabilities. The associated neurologic and vascular damage triggers a chain of events that lead to a secondary brain injury (SBI), a preventable cause of adverse neurological outcomes. Proper prevention of these factors may limit undesirable outcomes. This article presents a concept analysis that aims to form a single definition of the term secondary brain injury for nursing personnel. METHODOLOGY: Concept analysis was used to clarify the concept of SBI. An electronic search was performed on existing nursing literature dating from 1995 to 2016 on PubMed, MEDLINE, Ovid Journal, Wiley, and ProQuest. RESULTS: A clear definition and description of the attributes, antecedents, and consequences of SBI increases the knowledge and level of recognition of the secondary injuries. This may lead to strategies that reduce the risk of long-term effects (disability) and poor clinical outcomes. CONCLUSIONS: This concept analysis contributes to the endeavor of identifying phenomena that are pertinent for nursing; it also provides a basis for future research that leads to improving nursing interventions and creating educational programs and healthcare policies that prevent or eliminate the consequences of SBI. PMID- 29985273 TI - Complications Associated With Nasogastric Tube Placement in the Acute Phase of Stroke: A Systematic Review. AB - This systematic review explores the frequency of complications associated with nasogastric tube (NGT) placement in patients with acute stroke. The unique condition of the dysphasic, immobile, confused immunosuppressed patient who has had an acute stroke hampers any consistent inference from other neurological or nonneurological condition in which NGT placement is used. Twelve studies including 921 patients fed by NGT in the acute phase (first 4 weeks) were included in the analysis. The overall quality of the included studies was good. The main limitation was the heterogeneity and small size of most studies. The occurrence of NGT placement failure and malposition, hypoxemia, and regurgitation was addressed in the selected studies. Recurrent NGT dislodgement and a combination of tube dislodgement and blockage of the tube were the main reasons for NGT placement failure. In the absence of chronic hypoxemic pulmonary or cardiac disorders, NGT feeding was not associated with clinically significant hypoxemia in patients who have had an acute stroke. Data are scarce on the topic. Research about the frequency of local and systemic NGT complications and strategies for prevention will certainly contribute to enhance evidence-based management of dysphagia in acute stroke. PMID- 29985276 TI - Vasopressor Infusion After Subarachnoid Hemorrhage Does Not Increase Regional Cerebral Tissue Oxygenation. PMID- 29985275 TI - Vasopressor Infusion After Subarachnoid Hemorrhage Does Not Increase Regional Cerebral Tissue Oxygenation. AB - INTRODUCTION: Vasopressors are commonly used after aneurysmal subarachnoid hemorrhage (aSAH) to sustain cerebral pressure gradients. Yet, the relationship between vasopressors and the degree of cerebral microcirculatory support achieved remains unclear. This study aimed to explore the changes in cerebral and peripheral regional tissue oxygen saturation (rSO2) as well as blood pressure (BP) before and after vasopressor infusion in patients with aSAH. METHODS: Continuous noninvasive cerebral and peripheral rSO2 was obtained using near infrared spectroscopy for up to 14 days after aSAH. Within-subject differences in rSO2 before and after the commencement of vasopressor infusion were analyzed controlling for Hunt and Hess grade and vasospasm. RESULTS: Of 45 patients with continuous rSO2 monitoring, 19 (42%) received vasopressor infusion (all 19 on norepinephrine, plus epinephrine in 2 patients, phenylephrine in 4 patients, and vasopressin in 2 patients). In these 19 patients, their vasopressor infusion times were associated with higher BP (systolic [b = 15.1], diastolic [b = 7.3], and mean [b = 10.1]; P = .001) but lower cerebral rSO2 (left cerebral rSO2 decreased by 4.4% [b = -4.4, P < .0001]; right cerebral rSO2 decreased by 5.5% [b = -5.5, P = .0002]). CONCLUSIONS: Despite elevation in systemic BP during vasopressor infusion times, cerebral rSO2 was concurrently diminished. These findings warrant further investigation for the effect of induced hypertension on cerebral microcirculation. PMID- 29985277 TI - Stroke Education Video Does Not Affect Patient Satisfaction Scores: A System Analysis. AB - With limited time and resources in the acute care hospital, the most effective methods of stroke education are crucial. A combination of methods of one-on-one counseling or teaching, print, and video has been shown to have the greatest effect. Video education is a component of a combination educational approach. This evaluation from a large integrated system comprising 21 medical facilities compared patient satisfaction data with stroke education from 5 facilities that have video educational services and print materials and 17 facilities that provide print materials only. All 21 facilities provided additional teaching by the nurse. From this evaluation, it seems that there may be no relationship between video or kiosk equipment on patient satisfaction scores for this integrated system. PMID- 29985278 TI - Effects of Different Head-of-Bed Elevations and Body Positions on Intracranial Pressure and Cerebral Perfusion Pressure in Neurosurgical Patients. AB - PURPOSE: The aim of this study was to evaluate the effects of different head of bed (HOB) elevations and body positions on intracranial pressure (ICP) and cerebral perfusion pressure (CPP) and to identify safe positions for neurosurgical patients with different Glasgow Coma Scale (GCS) scores. METHODS: This study with a quasi-experimental, prospective repeated measures is designed with control over the intervention consisted of 30 patients hospitalized in the neurocritical care units (NCU). Patients' HOB was elevated (degree of 15,30,45) and the patients were at supine, left lateral and right lateral positions. ICP and CPP were recorded for each patient. RESULTS: It was found that ICP increased and CPP decreased at supine, left and right lateral positions with different HOB elevations, which, however, did not reach statistical significance. When patients with a GCS score of 3-8 were at degree of 15 right and left lateral positions and 45 right lateral position; and when patients with a GCS score of 13-15 were positioned at degree of 15 left lateral, ICP and CPP changed significantly. CONCLUSION: The results of this study showed that different positions the patients' HOB (degree of 15,30,45) led to slight insignificant changes in ICP and CPP; and these values were maintained within the ranges established by recent guidelines. PMID- 29985279 TI - Posttraumatic Growth of Stroke Survivors and Its Correlation With Rumination and Social Support. AB - OBJECTIVE: This study focused on gaining insight into the positive changes of stroke survivors. This study aimed to describe the level of posttraumatic growth (PTG) and explore its correlation with rumination and social support in stroke survivors. The impacts of individual characteristics on PTG were also discussed. METHODS: A descriptive correlation design was used in this study. Stroke survivors from a tertiary hospital in Guangzhou City were investigated. The Posttraumatic Growth Inventory, Chinese version of Event Related Rumination Inventory, and Perceived Social Support Scale were used to assess the level of PTG, rumination, and social support. RESULTS: The mean (SD) score of the Posttraumatic Growth Inventory was 61.12 (25.41). There were moderate positive correlations between PTG with rumination and social support among stroke survivors (r1 = 0.392, r2 = 0.336, P < .01). The level of education, support from family, and deliberate rumination accounted for 34.6% of the total variance in PTG (F = 11.554, P < .001). CONCLUSIONS: The phenomenon of PTG of stroke patients in hospital existed, but it was at a low level. Stroke survivors with a higher level of rumination, social support, and a university level education had a higher level of PTG. PMID- 29985280 TI - Cerebral Amyloid Angiopathy: A Different Kind of Stroke. PMID- 29985281 TI - Simvastatin Treatment Protects Myocardium in Noncoronary Artery Cardiac Surgery by Inhibiting Apoptosis Through miR-15a-5p Targeting. AB - Simvastatin treatment is cardioprotective in patients undergoing noncoronary artery cardiac surgery. However, the mechanisms by which simvastatin treatment protects the myocardium under these conditions are not fully understood. Seventy patients undergoing noncoronary cardiac surgery, 35 from a simvastatin treatment group and 35 from a control treatment group, were enrolled in our clinical study. Simvastatin (20 mg/d) was administered preoperatively for 5-7 days. Myocardial tissue biopsies were taken before and after surgery. Apoptosis was detected by TUNEL staining. The expressions of Bcl-2 and Bak in myocardial tissue were detected by immunoblotting. The expressions of miRNA and Bcl-2 mRNA were detected by quantitative real-time polymerase chain reaction assays. Cardiomyocytes were isolated from rat and cultured cells. MiR-15a-5p mimic was transfected into cardiomyocytes, and the Bcl-2 was detected by immunoblotting. TUNEL staining showed significantly less myocardial apoptosis in the simvastatin treatment group when compared with the control treatment group. Protein expression of Bcl-2 was increased in the simvastatin treatment group before surgery, and Bak expression was increased in the control treatment group after surgery. Further comparisons showed that Bcl-2/Bak ratios were reduced in the control treatment group but were not significantly changed in the simvastatin treatment group after surgery. Furthermore, microarray assays revealed that miR-15a-5p was significantly decreased by simvastatin treatment. This was validated by quantitative real-time polymerase chain reaction analysis. MiR-15a-5p was predicted to target Bcl-2 mRNA at nucleotide positions 2529-2536. This was validated by luciferase binding assays. Coincident with the change in miR-15a-5p, the mRNA expression of Bcl-2 was increased in the simvastatin treatment group. MiR-15a-5p mimic significantly inhibited Bcl-2 expression in cardiomyocytes. Our findings strongly suggest that simvastatin treatment preoperatively protected the myocardium in patients undergoing noncoronary artery cardiac surgery, at least in part, by inhibiting apoptosis via suppressing miR-15a-5p expression, leading to increasing expression of Bcl-2 and decreasing expression of Bak. PMID- 29985282 TI - Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Atrial Fibrillation and Thrombocytopenia. AB - AIMS: Thrombocytopenia was one of the exclusion criteria in randomized trials in which non-vitamin K antagonist oral anticoagulants (NOACs) were tested. The safety of NOACs in patients with atrial fibrillation (AF) and thrombocytopenia remains unclear. METHODS: We studied 62 patients with AF aged from 53 to 85 (mean 70.5) years with platelet count from 50 to 100 * 109/L who were treated with rivaroxaban 15 mg once daily (33.9%), dabigatran 110 mg twice daily (bid) (54.8%), or apixaban 2.5 mg bid (11.3%). Age- and sex-matched AF patients with normal platelet count and similar CHA2DS2-VASc scores who were treated with the recommended doses of NOACs served as a reference group. RESULTS: Patients were followed for a mean of 55 months (range, 23-64 months). In the thrombocytopenia group bleeding risk was higher (mean HAS-BLED score 2.0, vs. 1.0, P < 0.0001). During follow-up in thrombocytopenic and normocytopenic patients, we observed similar rates of major bleeding (1.8%/year vs. 2.7%/year, P = 0.49), clinically relevant nonmajor bleeding (CRNMB) (1.5%/year vs. 1.1%/year, P = 0.74), ischemic stroke and transient ischemic attacks (1.8%/year vs. 1.5%/year, P = 0.8), and death (1.06%/year vs. 1.11%/year, P = 0.96). The risk of bleeding and stroke was unaffected by the type of the NOAC used in both groups. Major bleedings and clinically relevant nonmajor bleeding in thrombocytopenic patients on NOACs were predicted only by age (hazard ratio 1.1, 95% confidence interval 1.0-1.3, P = 0.04). CONCLUSIONS: Our findings indicate that in AF patients with mild thrombocytopenia, anticoagulation with NOAC at reduced doses seems to be safe and effective. PMID- 29985283 TI - Dofetilide-Associated QT Prolongation: Total Body Weight Versus Adjusted or Ideal Body Weight for Dosing. AB - Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW. PMID- 29985284 TI - Safety and Efficacy in Prasugrel- Versus Ticagrelor-Treated Patients With ST Elevation Myocardial Infarction. AB - Prasugrel and ticagrelor are recommended over clopidogrel in patients with ST elevation myocardial infarction (STEMI). In this registry analysis, we compared efficacy and safety of ticagrelor and prasugrel P2Y12 inhibition in patients with STEMI. We included 318 patients in this single-center analysis. Twelve-month follow-up was conducted during ambulatory care at our department. Patients were on dual antiplatelet therapy with aspirin and ticagrelor or prasugrel during the follow-up period. Prescription of prasugrel or ticagrelor, respectively, was according to the preference of the treating physician. Major adverse cardiac and cerebrovascular events (MACCE) [death, myocardial infarction (MI), stroke, and unplanned reintervention] and thrombolysis in myocardial infarction (TIMI) bleeding (major/minor) were registered during hospitalization and follow-up. TIMI bleeding events were more frequent in ticagrelor-treated patients [17 vs. 5 patients, hazard ratio (HR) 2.85, 95% confidence interval (CI) 1.2-6.6; log-rank P value = 0.01]. Prasugrel-treated patients were significantly younger (ticagrelor 63 +/- 12 years vs. prasugrel 57 +/- 10; P < 0.0001). Besides that, patients' characteristics were similar in both groups. Multivariate analysis revealed that ticagrelor medication was independently associated with bleeding risk after adjustment for age, percutaneous coronary intervention approach (femoral vs. radial), diabetes mellitus, and kidney function (HR 3.01; 95% CI 1.0 7.4; P = 0.043). In patients treated with ticagrelor, 35 MACCE were detected. There was no difference as compared to prasugrel-treated patients (24 events, HR 1.24, 95% CI 0.79-2.09; log-rank P value = 0.41). TIMI bleeding events were more frequent in ticagrelor-treated patients with STEMI during 12-month follow-up. There were no differences in MACCE between groups in this registry analysis. PMID- 29985285 TI - Striking the Right Balance-Applying Machine Learning to Pediatric Critical Care Data. PMID- 29985286 TI - New Drugs for Old Problems: Which Inotropes for Critically Ill Children? PMID- 29985287 TI - The Man in the Shadows Has Something to Say. PMID- 29985288 TI - Do-Not-Resuscitate Orders and Overall Goals of Care in Critically Ill Newborns: Are We Always on the Same Page? PMID- 29985289 TI - Is "See One, Do One, Teach One" Still Relevant in the 21st Century? PMID- 29985290 TI - How to Push the Limit: Developing Informed Research and Implementation Programs in Resource-Limited Settings. PMID- 29985291 TI - Variability Reduction-An Essential Aspect of Quality. PMID- 29985292 TI - Mortality Is Passe: The Importance of Morbidity as an Outcome. PMID- 29985293 TI - Navigating Between Scylla and Charybdis; Sevoflurane for Difficult Sedation at the PICU. PMID- 29985294 TI - Acute Liver Failure: How Intensive Should Be the Care? PMID- 29985295 TI - Multistakeholder Qualitative Research Methods to Impact Culture of Care Practices in the ICU. PMID- 29985296 TI - Parents' Soothing of Critically Ill Children: Does One Size Fit All? PMID- 29985297 TI - Hyperferritinemia in Sepsis in Children: Ironing Out the Global Details. PMID- 29985299 TI - The author replies. PMID- 29985298 TI - Virus or Bacteria: Is It the Only Cause of Sepsis-Induced Rhabdomyolysis? PMID- 29985300 TI - Why Bedside Clinical Neurologic Assessments in PICUs Are Not Good Enough? PMID- 29985301 TI - The authors reply. PMID- 29985302 TI - Reply. PMID- 29985303 TI - Systematic Review and Meta-Analysis of Selected Cancers in Petroleum Refinery Workers. AB - OBJECTIVE: We studied the risk of 11 cancers of a priori interest in petroleum refinery workers. METHODS: Iterative searches identified 36 studies for the 11 cancer sites. Statistical heterogeneity and publication bias were assessed to enhance interpretation of meta-relative risks. RESULTS: Statistical heterogeneity was marked for mesothelioma, but was largely due to study quality. Higher quality studies showed a meta-relative risk (RR) of 3.22, (95% prediction interval 1.45 to 7.23). Melanoma (meta-RR = 1.23) and acute lymphoid leukemia (meta-RR = 1.51), showed results consistent with higher risk, but both were driven by one or two studies. Eight other cancer outcomes showed summary meta-RR's consistent with unity. CONCLUSIONS: Most cancer outcomes are consistent with background risk in refinery workers. This work has clarified an excess mesothelioma risk, conditional on study quality stratification. Continued surveillance is warranted for melanoma and ALL. PMID- 29985304 TI - Testing for Metacognitive Responding Using an Odor-based Delayed Match-to-Sample Test in Rats. AB - Metamemory involves the cognitive ability to assess the strength of one's memories. To explore the possibility of metamemory in non-human animals, numerous behavioral tasks have been created, many of which utilize an option to decline memory tests. To assess metamemory in rats, we utilized this decline-test option paradigm by adapting previous visual delayed-match-to-sample tests (DMTS)1,2 developed for primate species to an odor-based test suitable for rodents. First, rats are given a sample to remember by digging in a cup of scented sand. After a delay, the rat is presented with four distinctly scented cups, one of which contains the identical scent experienced during the sample; if this matching cup is selected, then the rat obtains a preferred, larger reward. Selection of any of the other three non-matching sand-filled scented cups results in no reward. Retention intervals are individually titrated such that subjects perform between 40 and 70% correct, therefore ensuring rats sometimes remember and sometimes forget the sample. Here, the operational definition of metamemory is the ability to distinguish between the presence and absence of memory through behavioral responding. Towards this end, on two-thirds of trials, a decline option is presented in addition to the four choice cups (choice trials). If the decline test option- an unscented colored sand cup, is selected, the subject receives a smaller less-preferred reward and avoids the memory test. On the remaining third of trials, the decline-test option is not available (forced trials), causing subjects to guess the correct cup when the sample is forgotten. On choice tests, subjects that know when they remember should select the decline option when memory is weak rather than take the test and choose incorrectly. Therefore, significantly higher performance on chosen tests as compared to forced memory tests is indicative of the adaptive use of the decline-test response and metacognitive responding. PMID- 29985305 TI - Protocol for MicroRNA Transfer into Adult Bone Marrow-derived Hematopoietic Stem Cells to Enable Cell Engineering Combined with Magnetic Targeting. AB - While CD133+ hematopoietic stem cells (SCs) have been proven to provide high potential in the field of regenerative medicine, their low retention rates after injection into injured tissues as well as the observed massive cell death rates lead to very restricted therapeutic effects. To overcome these limitations, we sought to establish a non-viral based protocol for suitable cell engineering prior to their administration. The modification of human CD133+ expressing SCs using microRNA (miR) loaded magnetic polyplexes was addressed with respect to uptake efficiency and safety as well as the targeting potential of the cells. Relying on our protocol, we can achieve high miR uptake rates of 80-90% while the CD133+ stem cell properties remain unaffected. Moreover, these modified cells offer the option of magnetic targeting. We describe here a safe and highly efficient procedure for the modification of CD133+ SCs. We expect this approach to provide a standard technology for optimization of therapeutic stem cell effects and for monitoring of the administered cell product via magnetic resonance imaging (MRI). PMID- 29985306 TI - Microstate and Omega Complexity Analyses of the Resting-state Electroencephalography. AB - Microstate and omega complexity are two reference-free electroencephalography (EEG) measures that can represent the temporal and spatial complexities of EEG data and have been widely used to investigate the neural mechanisms in some brain disorders. The goal of this article is to describe the protocol underlying EEG microstate and omega complexity analyses step by step. The main advantage of these two measures is that they could eliminate the reference-dependent problem inherent to traditional spectrum analysis. In addition, microstate analysis makes good use of high time resolution of resting-state EEG, and the four obtained microstate classes could match the corresponding resting-state networks respectively. The omega complexity characterizes the spatial complexity of the whole brain or specific brain regions, which has obvious advantage compared with traditional complexity measures focusing on the signal complexity in a single channel. These two EEG measures could complement each other to investigate the brain complexity from the temporal and spatial domain respectively. PMID- 29985307 TI - A Protein Microarray Assay for Serological Determination of Antigen-specific Antibody Responses Following Clostridium difficile Infection. AB - We provide a detailed overview of a novel high-throughput protein microarray assay for the determination of anti-Clostridium difficile antibody levels in human sera and in separate preparations of polyclonal intravenous immunoglobulin (IVIg). The protocol describes the methodological steps involved in sample preparation, printing of arrays, assay procedure, and data analysis. In addition, this protocol could be further developed to incorporate diverse clinical samples including plasma and cell culture supernatants. We show how protein microarray can be used to determine a combination of isotype (IgG, IgA, IgM), subclass (IgG1, IgG2, IgG3, IgG4, IgA1, IgA2), and strain-specific antibodies to highly purified whole C. difficile toxins A and B (toxinotype 0, strain VPI 10463, ribotype 087), toxin B from a C. difficile toxin-B-only expressing strain (CCUG 20309), a precursor form of a B fragment of binary toxin, pCDTb, ribotype specific whole surface layer proteins (SLPs; 001, 002, 027), and control proteins (tetanus toxoid and Candida albicans). During the experiment, microarrays are probed with sera from individuals with C. difficile infection (CDI), individuals with cystic fibrosis (CF) without diarrhea, healthy controls (HC), and from individuals pre- and post-IVIg therapy for the treatment of CDI, combined immunodeficiency disorder, and chronic inflammatory demyelinating polyradiculopathy. We encounter significant differences in toxin neutralization efficacies and multi-isotype specific antibody levels between patient groups, commercial preparations of IVIg, and sera before and following IVIg administration. Also, there is a significant correlation between microarray and enzyme-linked immunosorbent assay (ELISA) for antitoxin IgG levels in serum samples. These results suggest that microarray could become a promising tool for profiling antibody responses to C.difficile antigens in vaccinated or infected humans. With further refinement of antigen panels and a reduction in production costs, we anticipate that microarray technology may help optimize and select the most clinically useful immunotherapies for C. difficile infection in a patient specific manner. PMID- 29985308 TI - Pentylenetetrazole-Induced Kindling Mouse Model. AB - Pentylenetetrazole (PTZ) is a GABA-A receptor antagonist. An intraperitoneal injection of PTZ into an animal induces an acute, severe seizure at a high dose, whereas sequential injections of a subconvulsive dose have been used for the development of chemical kindling, an epilepsy model. A single low-dose injection of PTZ induces a mild seizure without convulsion. However, repetitive low-dose injections of PTZ decrease the threshold to evoke a convulsive seizure. Finally, continuous low-dose administration of PTZ induces a severe tonic-clonic seizure. This method is simple and widely applicable to investigate the pathophysiology of epilepsy, which is defined as a chronic disease that involves repetitive seizures. This chemical kindling protocol causes repetitive seizures in animals. With this method, vulnerability to PTZ-mediated seizures or the degree of aggravation of epileptic seizures was estimated. These advantages have led to the use of this method for screening anti-epileptic drugs and epilepsy-related genes. In addition, this method has been used to investigate neuronal damage after epileptic seizures because the histological changes observed in the brains of epileptic patients also appear in the brains of chemical-kindled animals. Thus, this protocol is useful for conveniently producing animal models of epilepsy. PMID- 29985309 TI - Evaluating Vascular Hyperpermeability-inducing Agents in the Skin with the Miles Assay. AB - The primary function of the vascular endothelium in vertebrate organisms is to serve as a barrier between the blood and each tissue of the body, whereby the permeability of the endothelium to blood cells, plasma macromolecules, and water can be adapted according to the physiological need. In certain diseases, cytokines and growth factors are released that target the endothelial barrier to transiently increase vascular permeability; however, their prolonged presence may cause chronic vascular hyperpermeability and thereby tissue-damaging edema. The Miles assay is an in vivo technique that allows researchers to study vascular hyperpermeability through the proxy measurement of vascular leakage. Here, we provide a detailed protocol on how to perform this procedure in the mouse, which is the most widely used model organism to study mammalian physiology and pathology. The procedure involves the intravenous injection of Evans blue dye to label the circulating albumin followed by multiple intradermal injections of permeability-inducing agents and vehicle control solutions into opposing flanks of the mouse. Consequently, Evans blue dye gradually leaks into the dermis, where it accumulates and can be extracted for quantification as leakage induced by the permeability-inducing agent relative to the vehicle. The Miles assay can be performed in wild type or genetically modified mouse models and may be combined with drug administration to study molecular mechanisms that regulate vascular permeability and identify agents/targets capable of inducing or blocking hyperpermeability. PMID- 29985310 TI - Rapid In Vivo Assessment of Adjuvant's Cytotoxic T Lymphocytes Generation Capabilities for Vaccine Development. AB - The assessment of modern sub-unit vaccines reveals that the generation of neutralizing antibodies is important but not sufficient for adjuvant selection. Therefore, adjuvants with both humoral and cellular immuno-stimulatory capabilities that are able to promote cytotoxic T lymphocytes (CTL) responses are urgently needed. Thus, faithful monitoring of adjuvant candidates that induce cross-priming and subsequently enhance CTL generation represents a crucial step in vaccine development. In here we present an application for a method that uses SIINFEKL-specific (OT-I) T cells to monitor the cross-presentation of the model antigen ovalbumin (OVA) in vivo in the presence of different adjuvant candidates. This method represents a rapid test to select adjuvants with the best cross priming capabilities. The proliferation of CD8+ T cells is the most valuable indication of cross-priming and it is also regarded as a correlate of adjuvant induced cross-presentation. This feature can be evaluated in different immune organs like lymph nodes and spleen. The extent of the CTL generation can also be monitored, thereby giving insights on the nature of a local (draining lymph node mainly) or a systemic response (distant lymph nodes and/or spleen). This technique further allows multiple modifications for testing drugs that can inhibit specific cross-presentation pathways and also offers the possibility to be used in different strains of conventional and genetically modified mice. In summary, the application that we present here will be useful for vaccine laboratories in industry or academia that develop or modify chemical adjuvants for vaccine research and development. PMID- 29985311 TI - PET Imaging of Neuroinflammation Using [11C]DPA-713 in a Mouse Model of Ischemic Stroke. AB - Neuroinflammation is central to the pathological cascade following ischemic stroke. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and role of certain neuroimmune interactions in stroke. Specifically, Positron Emission Tomography (PET) imaging of translocator protein 18 kDa (TSPO), a marker of activated microglia and peripheral myeloid-lineage cells, provides a means to detect and track neuroinflammation in vivo. Here, we present a method to accurately quantify neuroinflammation using [11C]N,N-Diethyl-2-[2-(4-methoxyphenyl)-5,7 dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide ([11C]DPA-713), a promising second generation TSPO-PET radiotracer, in distal middle cerebral artery occlusion (dMCAO) compared to sham-operated mice. MRI was performed 2 days post dMCAO surgery to confirm stroke and define the infarct location and volume. PET/Computed Tomography (CT) imaging was carried out 6 days post-dMCAO to capture the peak increase in TSPO levels following stroke. Quantitation of PET images was conducted to assess the uptake of [11C]DPA-713 in the brain and spleen of dMCAO and sham mice to assess central and peripheral levels of inflammation. In vivo [11C]DPA-713 brain uptake was confirmed using ex vivo autoradiography. PMID- 29985312 TI - Culturing Mammalian Cells in Three-dimensional Peptide Scaffolds. AB - A useful technique for culturing cells in a self-assembling nanofiber three dimensional (3D) scaffold is described. This culture system recreates an environment that closely mimics the structural features of non-polarized tissue. Furthermore, the particular intrinsic nanofiber structure of the scaffold makes it transparent to visual light, which allows for easy visualization of the sample under microscopy. This advantage was largely used to study cell migration, organization, proliferation, and differentiation and thus any development of their particular cellular function by staining with specific dyes or probes. Furthermore, in this work, we describe the good performance of this system to easily study the redifferentiation of expanded human articular chondrocytes into cartilaginous tissue. Cells were encapsulated into self-assembling peptide scaffolds and cultured under specific conditions to promote chondrogenesis. Three dimensional cultures showed good viability during the 4 weeks of the experiment. As expected, samples cultured with chondrogenic inducers (compared to non-induced controls) stained strongly positive for toluidine blue (which stains glycosaminoglycans (GAGs) that are highly present in cartilage extracellular matrix) and expressed specific molecular markers, including collagen type I, II and X, according to Western Blot analysis. This protocol is easy to perform and can be used at research laboratories, industries and for educational purposes in laboratory courses. PMID- 29985313 TI - Large-area Scanning Probe Nanolithography Facilitated by Automated Alignment and Its Application to Substrate Fabrication for Cell Culture Studies. AB - Scanning probe microscopy has enabled the creation of a variety of methods for the constructive ('additive') top-down fabrication of nanometer-scale features. Historically, a major drawback of scanning probe lithography has been the intrinsically low throughput of single probe systems. This has been tackled by the use of arrays of multiple probes to enable increased nanolithography throughput. In order to implement such parallelized nanolithography, the accurate alignment of probe arrays with the substrate surface is vital, so that all probes make contact with the surface simultaneously when lithographic patterning begins. This protocol describes the utilization of polymer pen lithography to produce nanometer-scale features over centimeter-sized areas, facilitated by the use of an algorithm for the rapid, accurate, and automated alignment of probe arrays. Here, nanolithography of thiols on gold substrates demonstrates the generation of features with high uniformity. These patterns are then functionalized with fibronectin for use in the context of surface-directed cell morphology studies. PMID- 29985314 TI - Surface Engineering of Pancreatic Islets with a Heparinized StarPEG Nanocoating. AB - Cell surface engineering can protect implanted cells from host immune attack. It can also reshape cellular landscape to improve graft function and survival post transplantation. This protocol aims to achieve surface engineering of pancreatic islets using an ultrathin heparin-incorporated starPEG (Hep-PEG) nanocoating. To generate the Hep-PEG nanocoating for pancreatic islet surface engineering, heparin succinimidyl succinate (Heparin-NHS) was first synthesized by modification of its carboxylate groups using N-(3-dimethylamino propyl)-N'-ethyl carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS). The Hep-PEG mixture was then formed by crosslinking of the amino end-functionalized eight armed starPEG (starPEG-(NH2)8) and Heparin-NHS. For islet surface coating, mouse islets were isolated via collagenase digestion and gradient purification using Histopaque. Isolated islets were then treated with ice cold Hep-PEG solution for 10 min to allow covalent binding between NHS and the amine groups of islet cell membrane. Nanocoating with the Hep-PEG incurs minimal alteration to islet size and volume and heparinization of the islets with Hep-PEG may also reduce instant blood-mediated inflammatory reaction during islet transplantation. This "easy-to adopt" approach is mild enough for surface engineering of living cells without compromising cell viability. Considering that heparin has shown binding affinity to multiple cytokines, the Hep-PEG nanocoating also provides an open platform that enables incorporation of unlimited functional biological mediators and multi layered surfaces for living cell surface bioengineering. PMID- 29985315 TI - Two-step Approach to Explore Early- and Late-stages of Organ Formation in the Avian Model: The Thymus and Parathyroid Glands Organogenesis Paradigm. AB - The avian embryo, as an experimental model, has been of utmost importance for seminal discoveries in developmental biology. Among several approaches, the formation of quail-chicken chimeras and the use of the chorioallantoic membrane (CAM) to sustain the development of ectopic tissues date back to the last century. Nowadays, the combination of these classical techniques with recent in vitro methodologies offers novel prospects to further explore organ formation. Here we describe a two-step approach to study early- and late-stages of organogenesis. Briefly, the embryonic region containing the presumptive territory of the organ is isolated from quail embryos and grown in vitro in an organotypic system (up to 48 h). Cultured tissues are subsequently grafted onto the CAM of a chicken embryo. After 10 days of in ovo development, fully formed organs are obtained from grafted tissues. This method also allows the modulation of signaling pathways by the regular administration of pharmacological agents and tissue genetic manipulation throughout in vitro and in ovo developmental steps. Additionally, developing tissues can be collected at any time-window to analyze their gene-expression profile (using quantitative PCR (qPCR), microarrays, etc.) and morphology (assessed with conventional histology and immunochemistry). The described experimental procedure can be used as a tool to follow organ formation outside the avian embryo, from the early stages of organogenesis to fully formed and functional organs. PMID- 29985316 TI - Adherence of Bacteria to Plant Surfaces Measured in the Laboratory. AB - This manuscript describes a method to measure bacterial binding to axenic plant surfaces in the light microscope and through the use of viable cell counts. Plant materials used include roots, sprouts, leaves, and cut fruits. The methods described are inexpensive, easy, and suitable for small sample sizes. Binding is measured in the laboratory and a variety of incubation media and conditions can be used. The effect of inhibitors can be determined. Situations that promote and inhibit binding can also be assessed. In some cases it is possible to distinguish whether various conditions alter binding primarily due to their effects on the plant or on the bacteria. PMID- 29985317 TI - Single Sensillum Recordings for Locust Palp Sensilla Basiconica. AB - The palps of locust mouthparts are considered to be conventional gustatory organs that play an important role in a locust's food selection, especially for the detection of non-volatile chemical cues through sensilla chaetica (previously named terminal sensilla or crested sensilla). There is now increasing evidence that these palps also have an olfactory function. An odorant receptor (LmigOR2) and an odorant-binding protein (LmigOBP1) have been localized in the neurons and accessory cells, respectively, in the sensilla basiconica of the palps. Single sensillum recording (SSR) is used for recording the responses of odorant receptor neurons, which is an effective method for screening active ligands on specific odorant receptors. SSR is used in functional studies of odorant receptors in palp sensilla. The structure of the sensilla basiconica located on the dome of the palps differs somewhat from the structure of those on the antennae. Therefore, when performing an SSR elicited by odorants, some specific advice may be helpful for obtaining optimum results. In this paper, a detailed and highly effective protocol for an SSR from insect palp sensilla basiconica is introduced. PMID- 29985318 TI - Single Cell Multiplex Reverse Transcription Polymerase Chain Reaction After Patch clamp. AB - The cerebral cortex is composed of numerous cell types exhibiting various morphological, physiological, and molecular features. This diversity hampers easy identification and characterization of these cell types, prerequisites to study their specific functions. This article describes the multiplex single cell reverse transcription polymerase chain reaction (RT-PCR) protocol, which allows, after patch-clamp recording in slices, to detect simultaneously the expression of tens of genes in a single cell. This simple method can be implemented with morphological characterization and is widely applicable to determine the phenotypic traits of various cell types and their particular cellular environment, such as in the vicinity of blood vessels. The principle of this protocol is to record a cell with the patch-clamp technique, to harvest and reverse transcribe its cytoplasmic content, and to detect qualitatively the expression of a predefined set of genes by multiplex PCR. It requires a careful design of PCR primers and intracellular patch-clamp solution compatible with RT PCR. To ensure a selective and reliable transcript detection, this technique also requires appropriate controls from cytoplasm harvesting to amplification steps. Although precautions discussed here must be strictly followed, virtually any electrophysiological laboratory can use the multiplex single cell RT-PCR technique. PMID- 29985319 TI - High-throughput, Microscale Protocol for the Analysis of Processing Parameters and Nutritional Qualities in Maize (Zea mays L.). AB - Maize is an important grain crop in the United States and worldwide. However, maize grain must be processed prior to human consumption. Furthermore, whole grain composition and processing characteristics vary among maize hybrids and can impact the quality of the final processed product. Therefore, in order to produce healthier processed food products from maize, it is necessary to know how to optimize processing parameters for particular sets of germplasm to account for these differences in grain composition and processing characteristics. This includes a better understanding of how current processing techniques impact the nutritional quality of the final processed food product. Here, we describe a microscale protocol that both simulates the processing pipeline to produce cornflakes from large flaking grits and allows for the processing of multiple grain samples simultaneously. The flaking grits, the intermediate processed products, or final processed product, as well as the corn grain itself, can be analyzed for nutritional content as part of a high-throughput analytical pipeline. This procedure was developed specifically for incorporation into a maize breeding research program, and it can be modified for other grain crops. We provide an example of the analysis of insoluble-bound ferulic acid and p-coumaric acid content in maize. Samples were taken at five different processing stages. We demonstrate that sampling can take place at multiple stages during microscale processing, that the processing technique can be utilized in the context of a specialized maize breeding program, and that, in our example, most of the nutritional content was lost during food product processing. PMID- 29985320 TI - Proofreading and DNA Repair Assay Using Single Nucleotide Extension and MALDI-TOF Mass Spectrometry Analysis. AB - The maintenance of the genome and its faithful replication is paramount for conserving genetic information. To assess high fidelity replication, we have developed a simple non-labeled and non-radio-isotopic method using a matrix assisted laser desorption ionization with time-of-flight (MALDI-TOF) mass spectrometry (MS) analysis for a proofreading study. Here, a DNA polymerase [e.g., the Klenow fragment (KF) of Escherichia coli DNA polymerase I (pol I) in this study] in the presence of all four dideoxyribonucleotide triphosphates is used to process a mismatched primer-template duplex. The mismatched primer is then proofread/extended and subjected to MALDI-TOF MS. The products are distinguished by the mass change of the primer down to single nucleotide variations. Importantly, a proofreading can also be determined for internal single mismatches, albeit at different efficiencies. Mismatches located at 2-4 nucleotides (nt) from the 3' end were efficiently proofread by pol I, and a mismatch at 5 nt from the primer terminus showed only a partial correction. No proofreading occurred for internal mismatches located at 6 - 9 nt from the primer 3' end. This method can also be applied to DNA repair assays (e.g., assessing a base-lesion repair of substrates for the endo V repair pathway). Primers containing 3' penultimate deoxyinosine (dI) lesions could be corrected by pol I. Indeed, penultimate T-I, G-I, and A-I substrates had their last 2 dI-containing nucleotides excised by pol I before adding a correct ddN 5'-monophosphate (ddNMP) while penultimate C-I mismatches were tolerated by pol I, allowing the primer to be extended without repair, demonstrating the sensitivity and resolution of the MS assay to measure DNA repair. PMID- 29985321 TI - Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry. AB - Complex diseases are often underpinned by multiple common genetic variants that contribute to disease susceptibility. Here, we describe a cost-effective tag single nucleotide polymorphism (SNP) approach using a multiplexed genotyping assay with mass spectrometry, to investigate gene pathway associations in clinical cohorts. We investigate the food allergy candidate locus Interleukin13 (IL13) as an example. This method efficiently maximizes the coverage by taking advantage of shared linkage disequilibrium (LD) within a region. Selected LD SNPs are then designed into a multiplexed assay, enabling up to 40 different SNPs to be analyzed simultaneously, boosting cost-effectiveness. Polymerase chain reaction (PCR) is used to amplify the target loci, followed by single nucleotide extension, and the amplicons are then measured using matrix-assisted laser desorption/ionization-time of flight(MALDI-TOF) mass spectrometry. The raw output is analyzed with the genotype calling software, using stringent quality control definitions and cut-offs, and high probability genotypes are determined and output for data analysis. PMID- 29985322 TI - Ovarian Tissue Culture to Visualize Phenomena in Mouse Ovary. AB - Mammalian females periodically ovulate an almost constant number of oocytes during each estrus cycle. To sustain such regularity and periodicity, regulation occurs at the hypothalamic-pituitary-gonadal axis level and on developing follicles in the ovary. Despite active studies, follicle development mechanisms are not clear because of the several steps involved from the dormant primordial follicle activation to ovulation, and because of the regulation complexity that differs at each follicular stage. To investigate the mechanisms of follicle development, and the dynamics of follicles throughout the estrus cycle, we developed a mouse ovarian tissue culture model that can be used to observe follicle development using a microscope. Systematic follicle development, periodical ovulation, and follicle atresia can all be reproduced in the cultured ovary model, and the culture conditions can be experimentally modulated. Here, we demonstrate the usefulness of this method in the study of the regulatory mechanisms of follicle development and other ovarian phenomena. PMID- 29985323 TI - A Rapid Synthesis Method for Au, Pd, and Pt Aerogels Via Direct Solution-Based Reduction. AB - Here, a method to synthesize gold, palladium, and platinum aerogels via a rapid, direct solution-based reduction is presented. The combination of various precursor noble metal ions with reducing agents in a 1:1 (v/v) ratio results in the formation of metal gels within seconds to minutes compared to much longer synthesis times for other techniques such as sol-gel. Conducting the reduction step in a microcentrifuge tube or small volume conical tube facilitates a proposed nucleation, growth, densification, fusion, equilibration model for gel formation, with final gel geometry smaller than the initial reaction volume. This method takes advantage of the vigorous hydrogen gas evolution as a by-product of the reduction step, and as a consequence of reagent concentrations. The solvent accessible specific surface area is determined with both electrochemical impedance spectroscopy and cyclic voltammetry. After rinsing and freeze drying, the resulting aerogel structure is examined with scanning electron microscopy, X ray diffractometry, and nitrogen gas adsorption. The synthesis method and characterization techniques result in a close correspondence of aerogel ligament sizes. This synthesis method for noble metal aerogels demonstrates that high specific surface area monoliths may be achieved with a rapid and direct reduction approach. PMID- 29985324 TI - Oral Biofilm Formation on Different Materials for Dental Implants. AB - Dental implants and their prosthetic components are prone to bacterial colonization and biofilm formation. The use of materials that provides low microbial adhesion may reduce the prevalence and progression of peri-implant diseases. In view of the oral environment complexity and oral biofilm heterogeneity, microscopy techniques are needed that can enable a biofilm analysis of the surfaces of teeth and dental materials. This article describes a series of protocols implemented for comparing oral biofilm formation on titanium and ceramic materials for prosthetic abutments, as well as the methods involved in oral biofilms analyses at the morphological and cellular levels. The in situ model to evaluate oral biofilm formation on titanium and zirconia materials for dental prosthesis abutments as described in this study provides a satisfactory preservation of the 48 h biofilm, thereby demonstrating methodological adequacy. Multiphoton microscopy allows the analysis of an area representative of the biofilm formed on the test materials. In addition, the use of fluorophores and the processing of the images using multiphoton microscopy allows the analysis of the bacterial viability in a very heterogeneous population of microorganisms. The preparation of biological specimens for electron microscopy promotes the structural preservation of biofilm, images with good resolution, and no artifacts. PMID- 29985325 TI - Methods for the Study of Regeneration in Stentor. AB - Cells need to be able to regenerate their parts to recover from external perturbations. The unicellular ciliate Stentor coeruleus is an excellent model organism to study wound healing and subsequent cell regeneration. The Stentor genome became available recently, along with modern molecular biology methods, such as RNAi. These tools make it possible to study single-cell regeneration at the molecular level. The first section of the protocol covers establishing Stentor cell cultures from single cells or cell fragments, along with general guidelines for maintaining Stentor cultures. Culturing Stentor in large quantities allows for the use of valuable tools like biochemistry, sequencing, and mass spectrometry. Subsequent sections of the protocol cover different approaches to inducing regeneration in Stentor. Manually cutting cells with a glass needle allows studying the regeneration of large cell parts, while treating cells with either sucrose or urea allows studying the regeneration of specific structures located at the anterior end of the cell. A method for imaging individual regenerating cells is provided, along with a rubric for staging and analyzing the dynamics of regeneration. The entire process of regeneration is divided in three stages. By visualizing the dynamics of the progression of a population of cells through the stages, the heterogeneity in regeneration timing is demonstrated. PMID- 29985326 TI - Generation of First Heart Field-like Cardiac Progenitors and Ventricular-like Cardiomyocytes from Human Pluripotent Stem Cells. AB - The generation of large amounts of functional human pluripotent stem cells derived cardiac progenitors and cardiomyocytes of defined heart field origin is a pre-requisite for cell-based cardiac therapies and disease modeling. We have recently shown that Id genes are both necessary and sufficient to specify first heart field progenitors during vertebrate development. This differentiation protocol leverages these findings and uses Id1 overexpression in combination with Activin A as potent specifying cues to produce first heart field-like (FHF-L) progenitors. Importantly, resulting progenitors efficiently differentiate (~70 90%) into ventricular-like cardiomyocytes. Here we describe a detailed method to 1) generate Id1-overexpressing hPSCs and 2) differentiate scalable quantities of cryopreservable FHF-L progenitors and ventricular-like cardiomyocytes. PMID- 29985327 TI - Protrusion Force Microscopy: A Method to Quantify Forces Developed by Cell Protrusions. AB - In numerous biological contexts, animal cells need to interact physically with their environment by developing mechanical forces. Among these, traction forces have been well-characterized, but there is a lack of techniques allowing the measurement of the protrusion forces exerted by cells orthogonally to their substrate. We designed an experimental setup to measure the protrusion forces exerted by adherent cells on their substrate. Cells plated on a compliant Formvar sheet deform this substrate and the resulting topography is mapped by atomic force microscopy (AFM) at the nanometer scale. Force values are then extracted from an analysis of the deformation profile based on the geometry of the protrusive cellular structures. Hence, the forces exerted by the individual protruding units of a living cell can be measured over time. This technique will enable the study of force generation and its regulation in the many cellular processes involving protrusion. Here, we describe its application to measure the protrusive forces generated by podosomes formed by human macrophages. PMID- 29985328 TI - In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration. AB - Assessing the functionality of the nerve axon provides detailed information on the progression of neuromuscular disorders. Electrophysiological recordings provide a sensitive approach to measure nerve conduction in humans and rodent models. To broaden the technical possibilities for electromyography in mice, the measurement of compound muscle action potentials (CMAPs) from the brachial plexus nerve in the forelimb using needle electrodes is described here. CMAP recordings after stimulating the sciatic nerve in hindlimbs have been previously described. The newly introduced method here allows for the evaluation of the nerve conductivity at an additional site, and thus provides a more profound overview of the neuromuscular functionality. The technique provides information on both the relative number of functional axons and the myelination level. Thereby, this method can be applied to assess both axonal diseases as well as demyelinating conditions. This minimally invasive method does not require extraction of the nerve and therefore it is suitable for repeated measurements for longitudinal follow-up in the same animal. Similar recordings are performed in clinical setups to emphasize the translational relevance of the method. PMID- 29985330 TI - Diagonal Method to Measure Synergy Among Any Number of Drugs. AB - A synergistic drug combination has a higher efficacy compared to the effects of individual drugs. Checkerboard assays, where drugs are combined in many doses, allow sensitive measurement of drug interactions. However, these assays are costly and do not scale well for measuring interaction among many drugs. Several recent studies have reported drug interaction measurements using a diagonal sampling of the traditional checkerboard assay. This alternative methodology greatly decreases the cost of drug interaction experiments and allows interaction measurement for combinations with many drugs. Here, we describe a protocol to measure the three pairwise interactions and one three-way interaction among three antibiotics in duplicate, in five days, using only three 96-well microplates and standard laboratory equipment. We present representative results showing that the three-antibiotic combination of Levofloxacin + Nalidixic Acid + Penicillin G is synergistic. Our protocol scales up to measure interactions among many drugs and in other biological contexts, allowing for efficient screens for multi-drug synergies against pathogens and tumors. PMID- 29985329 TI - A Protocol for Measuring Cue Reactivity in a Rat Model of Cocaine Use Disorder. AB - Cocaine use disorder (CUD) follows a trajectory of repetitive self-administration during which previously neutral stimuli gain incentive value. Cue reactivity, the sensitivity to cues previously linked with the drug-taking experience, plays a prominent role in human craving during abstinence. Cue reactivity can be assessed as the attentional orientation toward drug-associated cues that is measurable as appetitive approach behavior in both preclinical and human studies. Herein describes an assessment of cue reactivity in rats trained to self-administer cocaine. Cocaine self-administration is paired with the presentation of discrete cues that act as conditioned reinforcers (i.e., house light, stimulus light, infusion pump sounds). Following a period of abstinence, lever presses in the cocaine self-administration context accompanied by the discrete cues previously paired with cocaine infusion are measured as cue reactivity. This model is useful to explore neurobiological mechanisms underlying cue reactivity processes as well as to assess pharmacotherapies to suppress cue reactivity and therefore, modify relapse vulnerability. Advantages of the model include its translational relevance, and its face and predictive validities. The primary limitation of the model is that the cue reactivity task can only be performed infrequently and must only be used in short duration (e.g., 1 hour), otherwise rats will begin to extinguish the pairing of the discrete cues with the cocaine stimulus. The model is extendable to any positively reinforcing stimulus paired with discrete cues; though particularly applicable to drugs of abuse, this model may hold future applications in fields such as obesity, where palatable food rewards can act as positively reinforcing stimuli. PMID- 29985331 TI - A Temperature Gradient Assay to Determine Thermal Preferences of Drosophila Larvae. AB - Many animals, including the fruit fly, Drosophila melanogaster, are capable of discriminating minute differences in environmental temperature, which enables them to seek out their preferred thermal landscape. To define the temperature preferences of larvae over a defined linear range, we developed an assay using a temperature gradient. To establish a single-directional gradient, two aluminum blocks are connected to independent water baths, each of which controls the temperature of individual blocks. The two blocks set the lower and upper limits of the gradient. The temperature gradient is established by placing an agarose coated aluminum plate over the two water-controlled blocks so that the plate spans the distance between them. The ends of the aluminum plate that is set on the top of the water blocks defines the minimum and maximum temperatures, and the regions in-between the two blocks form a linear temperature gradient. The gradient assay can be applied to larvae of different ages and can be used to identify mutants that exhibit phenotypes, such as those with mutations affecting genes encoding TRP channels and opsins, which are required for temperature discrimination. PMID- 29985332 TI - Leaf Spray Mass Spectrometry: A Rapid Ambient Ionization Technique to Directly Assess Metabolites from Plant Tissues. AB - Plants produce thousands of small molecules that are diverse in their chemical properties. Mass spectrometry (MS) is a powerful technique for analyzing plant metabolites because it provides molecular weights with high sensitivity and specificity. Leaf spray MS is an ambient ionization technique where plant tissue is used for direct chemical analysis via electrospray, eliminating chromatography from the process. This approach to sampling metabolites allows for a wide range of chemical classes to be detected simultaneously from intact plant tissues, minimizing the amount of sample preparation needed. When used with a high resolution, accurate mass MS, leaf spray MS facilitates the rapid detection of metabolites of interest. It is also possible to collect tandem mass fragmentation data with this technique to facilitate a compound identification. The combination of accurate mass measurements and fragmentation is beneficial in confirming compound identities. The leaf spray MS technique requires only minor modifications to a nanospray ionization source and is a useful tool to further expand the capabilities of a mass spectrometer. Here, fresh leaf tissue from Sceletium tortuosum (Aizoaceae), a traditional medicinal plant from South Africa, is analyzed; numerous mesembrine alkaloids are detected with leaf spray MS. PMID- 29985333 TI - High-sensitivity Detection of Micrometastases Generated by GFP Lentivirus transduced Organoids Cultured from a Patient-derived Colon Tumor. AB - Despite current advances in human colorectal cancer (CRC) treatment, few radical therapies are effective for the late stages of CRC. To overcome this clinical challenge, tumor xenograft mouse models using long-established human carcinoma cell lines and many transgenic mouse models with tumors have been developed as preclinical models. They partially mimic the features of human carcinomas, but often fail to recapitulate the key aspects of human malignancies including invasion and metastasis. Thus, alternative models that better represent the malignant progression in human CRC have long been awaited. We herein show generation of patient-derived tumor xenografts (PDXs) by subcutaneous implantation of small CRC fragments surgically dissected from a patient. The colon PDXs develop and histopathologically resemble the CRC in the patient. However, few spontaneous micrometastases are detectable in conventional cross sections of affected distant organs in the PDX model. To facilitate the detection of metastatic dissemination into distant organs, we extracted the tumor organoid cells from the colon PDXs in culture and infected them with GFP lentivirus prior to injection into highly immunodeficient NOD/Shi-scid IL2Rgammanull (NOG) mice. Orthotopically injected PDX-derived CRC organoid cells consistently form primary tumors positive for GFP in recipient mice. Moreover, spontaneously developing micrometastatic colonies expressing GFP are notably detected in the lungs of these mice by fluorescence microscopy. Moreover, intrasplenic injection of CRC organoids frequently produces hepatic colonization. Taken together, these findings indicate GFP-labelled PDX-derived CRC organoid cells to be visually detectable during a multistep process termed the invasion-metastasis cascade. The described protocols include the establishment of PDXs of human CRC and 3D culture of the corresponding CRC organoid cells transduced by GFP lentiviral particles. PMID- 29985334 TI - Fabrication of Flexible Image Sensor Based on Lateral NIPIN Phototransistors. AB - Flexible photodetectors have been intensely studied for the use of curved image sensors, which are a crucial component in bio-inspired imaging systems, but several challenging points remain, such as a low absorption efficiency due to a thin active layer and low flexibility. We present an advanced method to fabricate a flexible phototransistor array with an improved electrical performance. The outstanding electrical performance is driven by a low dark current owing to deep impurity doping. Stretchable and flexible metal interconnectors simultaneously offer electrical and mechanical stabilities in a highly deformed state. The protocol explicitly describes the fabrication process of the phototransistor using a thin silicon membrane. By measuring I-V characteristics of the completed device in deformed states, we demonstrate that this approach improves the mechanical and electrical stabilities of the phototransistor array. We expect that this approach to a flexible phototransistor can be widely used for the applications of not only next-generation imaging systems/optoelectronics but also wearable devices such as tactile/pressure/temperature sensors and health monitors. PMID- 29985335 TI - Evaluation of the Impact of Protein Aggregation on Cellular Oxidative Stress in Yeast. AB - Protein misfolding and aggregation into amyloid conformations have been related to the onset and progression of several neurodegenerative diseases. However, there is still little information about how insoluble protein aggregates exert their toxic effects in vivo. Simple prokaryotic and eukaryotic model organisms, such as bacteria and yeast, have contributed significantly to our present understanding of the mechanisms behind the intracellular amyloid formation, aggregates propagation, and toxicity. In this protocol, the use of yeast is described as a model to dissect the relationship between the formation of protein aggregates and their impact on cellular oxidative stress. The method combines the detection of the intracellular soluble/aggregated state of an amyloidogenic protein with the quantification of the cellular oxidative damage resulting from its expression using flow cytometry (FC). This approach is simple, fast, and quantitative. The study illustrates the technique by correlating the cellular oxidative stress caused by a large set of amyloid-beta peptide variants with their respective intrinsic aggregation propensities. PMID- 29985336 TI - Simple and Effective Administration and Visualization of Microparticles in the Circulatory System of Small Fishes Using Kidney Injection. AB - The systemic administration of micro-size particles into a living organism can be applied for vasculature visualization, drug and vaccine delivery, implantation of transgenic cells and tiny optical sensors. However, intravenous microinjections into small animals, which are mostly used in biological and veterinary laboratories, are very difficult and require trained personnel. Herein, we demonstrate a robust and efficient method for the introduction of microparticles into the circulatory system of adult zebrafish (Danio rerio) by injection into the fish kidney. To visualize the introduced microparticles in the vasculature, we propose a simple intravital imaging technique in fish gills. In vivo monitoring of the zebrafish blood pH was accomplished using an injected microencapsulated fluorescent probe, SNARF-1, to demonstrate one of the possible applications of the described technique. This article provides a detailed description of the encapsulation of pH-sensitive dye and demonstrates the principles of the quick injection and visualization of the obtained microcapsules for in vivo recording of the fluorescent signal. The proposed method of injection is characterized by a low mortality rate (0-20%) and high efficiency (70-90% success), and it is easy to institute using commonly available equipment. All described procedures can be performed on other small fish species, such as guppies and medaka. PMID- 29985337 TI - Analysis of N-glycans from Raphanus sativus Cultivars Using PNGase H. AB - In recent years, the carbohydrate moieties of plants have received considerable attention, as they are a potential source of cross-reactive, allergy-provoking immune responses. In addition, carbohydrate structures also play a critical role in plant metabolism. Here, we present a simple and rapid method for preparing and analyzing N-glycans from different cultivars of radish (Raphanus sativus) using an N-glycanase specific for the release of plant-derived carbohydrate structures. To achieve this, crude trichloroacetic acid precipitates of radish homogenates were treated with PNGase H+, and labeled using 2-aminobenzamide as a fluorescent tag. The labeled N-glycan samples were subsequently analyzed by ultra performance liquid chromatography (UPLC) separation and matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry for a detailed structural evaluation and to quantify relative abundancies of the radish-derived N-glycan structures. This protocol can also be used for the analysis of N-glycans from various other plant species, and may be useful for further investigation of the function and effects of N-glycans on human health. PMID- 29985338 TI - Evaluation of Commercial-Off-The-Shelf Wrist Wearables to Estimate Stress on Students. AB - Wearable commercial-off-the-shelf (COTS) devices have become popular during the last years to monitor sports activities, primarily among young people. These devices include sensors to gather data on physiological signals such as heart rate, skin temperature or galvanic skin response. By applying data analytics techniques to these kinds of signals, it is possible to obtain estimations of higher-level aspects of human behavior. In the literature, there are several works describing the use of physiological data collected using clinical devices to obtain information on sleep patterns or stress. However, it is still an open question whether data captured using COTS wrist wearables is sufficient to characterize the learners' psychological state in educational settings. This paper discusses a protocol to evaluate stress estimation from data obtained using COTS wrist wearables. The protocol is carried out in two phases. The first stage consists of a controlled laboratory experiment, where a mobile app is used to induce different stress levels in a student by means of a relaxing video, a Stroop Color and Word test, a Paced Auditory Serial Addition test, and a hyperventilation test. The second phase is carried out in the classroom, where stress is analyzed while performing several academic activities, namely attending to theoretical lectures, doing exercises and other individual activities, and taking short tests and exams. In both cases, both quantitative data obtained from COTS wrist wearables and qualitative data gathered by means of questionnaires are considered. This protocol involves a simple and consistent method with a stress induction app and questionnaires, requiring a limited participation of support staff. PMID- 29985339 TI - Analyzing the Photo-oxidation of 2-propanol at Indoor Air Level Concentrations Using Field Asymmetric Ion Mobility Spectrometry. AB - We demonstrate a versatile protocol to be used for determining the effectiveness of photocatalysts in degrading indoor air concentration (ppb) volatile organic carbons (VOCs), illustrating this with a titanium dioxide based catalyst, and the VOC 2-propanol. The protocol takes advantage of field asymmetric ion mobility spectroscopy (FAIMS), an analysis tool that is capable of continuously identifying and monitoring the concentration of VOCs such as 2-propanol and acetone at the ppb level. The continuous nature of FAIMS allows detailed kinetic analysis, and long-term reactions, offering a significant advantage over gas chromatography, a batch process traditionally used in air purification characterization. The use of FAIMS in photocatalytic air purification has only recently been used for the first time, and with the protocol illustrated here, the flexibility in allowing alternative VOCs and photocatalysts to be tested using comparable protocols offers a unique system to elucidate photocatalytic air purification reactions at low concentrations. PMID- 29985340 TI - A Quantitative Dot Blot Assay for AAV Titration and Its Use for Functional Assessment of the Adeno-associated Virus Assembly-activating Proteins. AB - While adeno-associated virus (AAV) is widely accepted as an attractive vector for gene therapy, it also serves as a model virus for understanding virus biology. In the latter respect, the recent discovery of a non-structural AAV protein, termed assembly-activating protein (AAP), has shed new light on the processes involved in assembly of the viral capsid VP proteins into a capsid. Although many AAV serotypes require AAP for assembly, we have recently reported that AAV4, 5, and 11 are exceptions to this rule. Furthermore, we demonstrated that AAPs and assembled capsids of different serotypes localize to different subcellular compartments. This unexpected heterogeneity in the biological properties and functional roles of AAPs among different AAV serotypes underscores the importance of studies on AAPs derived from diverse serotypes. This manuscript details a straightforward dot blot assay for AAV quantitation and its application to assess AAP dependency and serotype specificity in capsid assembly. To demonstrate the utility of this dot blot assay, we set out to characterize capsid assembly and AAP dependency of Snake AAV, a previously uncharacterized reptile AAV, as well as AAV5 and AAV9, which have previously been shown to be AAP-independent and AAP dependent serotypes, respectively. The assay revealed that Snake AAV capsid assembly requires Snake AAP and cannot be promoted by AAPs from AAV5 and AAV9. The assay also showed that, unlike many of the common serotype AAPs that promote heterologous capsid assembly by cross-complementation, Snake AAP does not promote assembly of AAV9 capsids. In addition, we show that the choice of nuclease significantly affects the readout of the dot blot assay, and thus, choosing an optimal enzyme is critical for successful assessment of AAV titers. PMID- 29985341 TI - Biotin-based Pulldown Assay to Validate mRNA Targets of Cellular miRNAs. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that post transcriptionally regulate cellular gene expression. MiRNAs bind to the 3' untranslated region (UTR) of target mRNA to inhibit protein translation or in some instances cause mRNA degradation. The binding of the miRNA to the 3' UTR of the target mRNA is mediated by a 2-8 nucleotide seed sequence at the 5' end of miRNA. While the role of miRNAs as cellular regulatory molecules is well established, identification of the target mRNAs with functional relevance remains a challenge. Bioinformatic tools have been employed to predict sequences within the 3' UTR of mRNAs as potential targets for miRNA binding. These tools have also been utilized to determine the evolutionary conservation of such sequences among related species in an attempt to predict functional role. However, these computational methods often generate false positive results and are limited to predicting canonical interaction between miRNA and mRNA. Therefore, experimental procedures that measure direct binding of miRNA to its mRNA target are necessary to establish functional interaction. In this report, we describe a sensitive method for validating direct interaction between the cellular miRNA miR-125b and the 3' UTR of PARP-1 mRNA. We elaborate a protocol in which synthetic biotinylated-miRNA mimics were transfected into mammalian cells and the miRNA mRNA complex in the cellular lysate was pulled down with streptavidin-coated magnetic beads. Finally, the target mRNA in the pulled-down nucleic acid complex was quantified using a qPCR-based strategy. PMID- 29985343 TI - Synchrotron X-ray Microdiffraction and Fluorescence Imaging of Mineral and Rock Samples. AB - In this report, we describe a detailed procedure for acquiring and processing x ray microfluorescence (MUXRF), and Laue and powder microdiffraction two dimensional (2D) maps at beamline 12.3.2 of the Advanced Light Source (ALS), Lawrence Berkeley National Laboratory. Measurements can be performed on any sample that is less than 10 cm x 10 cm x 5 cm, with a flat exposed surface. The experimental geometry is calibrated using standard materials (elemental standards for XRF, and crystalline samples such as Si, quartz, or Al2O3 for diffraction). Samples are aligned to the focal point of the x-ray microbeam, and raster scans are performed, where each pixel of a map corresponds to one measurement, e.g., one XRF spectrum or one diffraction pattern. The data are then processed using the in-house developed software XMAS, which outputs text files, where each row corresponds to a pixel position. Representative data from moissanite and an olive snail shell are presented to demonstrate data quality, collection, and analysis strategies. PMID- 29985342 TI - Imaging FITC-dextran as a Reporter for Regulated Exocytosis. AB - Regulated exocytosis is a process by which cargo, which is stored in secretory granules (SGs), is released in response to a secretory trigger. Regulated exocytosis is fundamental for intercellular communication and is a key mechanism for the secretion of neurotransmitters, hormones, inflammatory mediators, and other compounds, by a variety of cells. At least three distinct mechanisms are known for regulated exocytosis: full exocytosis, where a single SG fully fuses with the plasma membrane, kiss-and-run exocytosis, where a single SG transiently fuses with the plasma membrane, and compound exocytosis, where several SGs fuse with each other, prior to or after SG fusion with the plasma membrane. The type of regulated exocytosis undertaken by a cell is often dictated by the type of secretory trigger. However, in many cells, a single secretory trigger can activate multiple modes of regulated exocytosis simultaneously. Despite their abundance and importance across cell types and species, the mechanisms that determine the different modes of secretion are largely unresolved. One of the main challenges in investigating the different modes of regulated exocytosis, is the difficulty in distinguishing between them as well as exploring them separately. Here we describe the use of fluorescein isothiocyanate (FITC)-dextran as an exocytosis reporter, and live cell imaging, to differentiate between the different pathways of regulated exocytosis, focusing on compound exocytosis, based on the robustness and duration of the exocytic events. PMID- 29985345 TI - Fabrication of Tongue Extracellular Matrix and Reconstitution of Tongue Squamous Cell Carcinoma In Vitro. AB - In order to construct an effective and realistic model for tongue squamous cell carcinoma (TSCC) in vitro, the methods were created to produce decellularized tongue extracellular matrix (TEM) which provides functional scaffolds for TSCC construction. TEM provides an in vitro niche for cell growth, differentiation, and cell migration. The microstructures of native extracellular matrix (ECM) and biochemical compositions retained in the decellularized matrix provide tissue specific niches for anchoring cells. The fabrication of TEM can be realized by deoxyribonuclease (DNase) digestion accompanied with a serious of organic or inorganic pretreatment. This protocol is easy to operate and ensures high efficiency for the decellularization. The TEM showed favorable cytocompatibility for TSCC cells under static or stirred culture conditions, which enables the construction of the TSCC model. A self-made bioreactor was also used for the persistent stirred condition for cell culture. Reconstructed TSCC using TEM showed the characteristics and properties resembling clinical TSCC histopathology, suggesting the potential in TSCC research. PMID- 29985346 TI - High Throughput SiRNA Screening for Chloropicrin and Hydrogen Fluoride-Induced Cornea Epithelial Cell Injury. AB - Toxicant-induced ocular injury is a true ocular emergency because chemicals have the potential to rapidly inflict significant tissue damage. Treatments for toxicant-induced corneal injury are generally supportive as no specific therapeutics exist to treat these injuries. In the efforts to develop treatments and therapeutics to care for exposure, it can be important to understand the molecular and cellular mechanisms of these injuries. We propose that utilization of high throughput small inhibitory RNA (siRNA) screening can be an important tool that could help to more rapidly elucidate the molecular mechanisms of chemical cornea epithelial injury. siRNA are double stranded RNA molecules that are 19-25 nucleotides long and utilize the post-transcriptional gene silencing pathway to degrade mRNA which have homology to the siRNA. The resulting reduction of expression of the specific gene can then be studied in toxicant exposed cells to ascertain the function of that gene in the cellular response to the toxicant. The development and validation of in vitro exposure models and methods for the high throughput screening (HTS) of hydrogen fluoride- (HF) and chloropicrin- (CP) induced ocular injury are presented in this article. Although we selected these two toxicants, our methods are applicable to the study of other toxicants with minor modifications to the toxicant exposure protocol. The SV40 large T antigen immortalized human corneal epithelial cell line SV40-HCEC was selected for study. Cell viability and IL-8 production were selected as endpoints in the screening protocol. Several challenges associated with the development of toxicant exposure and cell culture methods suitable for HTS studies are presented. The establishment of HTS models for these toxicants allows for further studies to better understand the mechanism of injury and to screen for potential therapeutics for chemical ocular injury. PMID- 29985344 TI - The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues. AB - Metastasis is the major cause of cancer death. The role of circulating tumor cells (CTCs) in promoting cancer metastasis, in which lung colonization by CTCs critically contributes to early lung metastatic processes, has been vigorously investigated. As such, animal models are the only approach that captures the full systemic process of metastasis. Given that problems occur in previous experimental designs for examining the contributions of CTCs to blood vessel extravasation, we established an in vivo lung colonization assay in which a long term-fluorescence cell-tracer, carboxyfluorescein succinimidyl ester (CFSE), was used to label suspended tumor cells and lung perfusion was performed to clear non specifically trapped CTCs prior to lung removal, confocal imaging, and quantification. Polymeric fibronectin (polyFN) assembled on CTC surfaces has been found to mediate lung colonization in the final establishment of metastatic tumor tissues. Here, to specifically test the requirement of polyFN assembly on CTCs for lung colonization and extravasation, we performed short term lung colonization assays in which suspended Lewis lung carcinoma cells (LLCs) stably expressing FN-shRNA (shFN) or scramble-shRNA (shScr) and pre-labeled with 20 MUM of CFSE were intravenously inoculated into C57BL/6 mice. We successfully demonstrated that the abilities of shFN LLC cells to colonize the mouse lungs were significantly diminished in comparison to shScr LLC cells. Therefore, this short-term methodology may be widely applied to specifically demonstrate the ability of CTCs within the circulation to colonize the lungs. PMID- 29985347 TI - Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-alpha. AB - The main aim of this protocol is to describe the development and validation of an interferon (IFN)-alpha single molecule array digital Enzyme-Linked ImmunoSorbent Assay (ELISA) assay. This system enables the quantification of human IFN-alpha protein with unprecedented sensitivity, and with no cross-reactivity for other species of IFN. The first key step of the protocol is the choice of the antibody pair, followed by the conjugation of the capture antibody to paramagnetic beads, and biotinylation of the detection antibody. Following this step, different parameters such as assay configuration, detector antibody concentration, and buffer composition can be modified until optimum sensitivity is achieved. Finally, specificity and reproducibility of the method are assessed to ensure confidence in the results. Here, we developed an IFN-alpha single molecule array assay with a limit of detection of 0.69 fg/mL using high-affinity autoantibodies isolated from patients with biallelic mutations in the autoimmune regulator (AIRE) protein causing autoimmune polyendocrinopathy syndrome type 1/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1/APECED). Importantly, these antibodies enabled detection of all 13 IFN-alpha subtypes. This new methodology allows the detection and quantification of IFN-alpha protein in human biological samples at attomolar concentrations for the first time. Such a tool will be highly useful in monitoring the levels of this cytokine in human health and disease states, most particularly infection, autoimmunity, and autoinflammation. PMID- 29985348 TI - Fluorescence Live-cell Imaging of the Complete Vegetative Cell Cycle of the Slow growing Social Bacterium Myxococcus xanthus. AB - Fluorescence live-cell imaging of bacterial cells is a key method in the analysis of the spatial and temporal dynamics of proteins and chromosomes underlying central cell cycle events. However, imaging of these molecules in slow-growing bacteria represents a challenge due to photobleaching of fluorophores and phototoxicity during image acquisition. Here, we describe a simple protocol to circumvent these limitations in the case of Myxococcus xanthus (which has a generation time of 4 - 6 h). To this end, M. xanthus cells are grown on a thick nutrient-containing agar pad in a temperature-controlled humid environment. Under these conditions, we determine the doubling time of individual cells by following the growth of single cells. Moreover, key cellular processes such as chromosome segregation and cell division can be imaged by fluorescence live-cell imaging of cells containing relevant fluorescently labeled marker proteins such as ParB-YFP, FtsZ-GFP, and mCherry-PomX over multiple cell cycles. Subsequently, the acquired images are processed to generate montages and/or movies. PMID- 29985349 TI - Modeling Osteosarcoma Using Li-Fraumeni Syndrome Patient-derived Induced Pluripotent Stem Cells. AB - Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer disorder. Patients with LFS are predisposed to a various type of tumors, including osteosarcoma--one of the most frequent primary non-hematologic malignancies in the childhood and adolescence. Therefore, LFS provides an ideal model to study this malignancy. Taking advantage of iPSC methodologies, LFS-associated osteosarcoma can be successfully modeled by differentiating LFS patient iPSCs to mesenchymal stem cells (MSCs), and then to osteoblasts--the cells of origin for osteosarcomas. These LFS osteoblasts recapitulate oncogenic properties of osteosarcoma, providing an attractive model system for delineating the pathogenesis of osteosarcoma. This manuscript demonstrates a protocol for the generation of iPSCs from LFS patient fibroblasts, differentiation of iPSCs to MSCs, differentiation of MSCs to osteoblasts, and in vivo tumorigenesis using LFS osteoblasts. This iPSC disease model can be extended to identify potential biomarkers or therapeutic targets for LFS-associated osteosarcoma. PMID- 29985350 TI - Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification (BiCAP). AB - The assembly of protein complexes is a central mechanism underlying the regulation of many cell signaling pathways. A major focus of biomedical research is deciphering how these dynamic protein complexes act to integrate signals from multiple sources in order to direct a specific biological response, and how this becomes deregulated in many disease settings. Despite the importance of this key biochemical mechanism, there is a lack of experimental techniques that can facilitate the specific and sensitive deconvolution of these multi-molecular signaling complexes. Here this shortcoming is addressed through the combination of a protein complementation assay with a conformation-specific nanobody, which we have termed Bimolecular Complementation Affinity Purification (BiCAP). This novel technique facilitates the specific isolation and downstream proteomic characterization of any pair of interacting proteins, to the exclusion of un complexed individual proteins and complexes formed with competing binding partners. The BiCAP technique is adaptable to a wide array of downstream experimental assays, and the high degree of specificity afforded by this technique allows more nuanced investigations into the mechanics of protein complex assembly than is currently possible using standard affinity purification techniques. PMID- 29985351 TI - Long-term In Vivo Tracking of Inflammatory Cell Dynamics Within Drosophila Pupae. AB - During the rapid inflammatory response to tissue damage, cells of the innate immune system are quickly recruited to the injury site. Once at the wound, innate immune cells perform a number of essential functions, such as fighting infection, clearing necrotic debris, and stimulating matrix deposition. In order to fully understand the diverse signaling events that regulate this immune response, it is crucial to observe the complex behaviors of (and interactions that occur between) multiple cell lineages in vivo, and in real-time, with the high spatio-temporal resolution. The optical translucency and the genetic tractability of Drosophila embryos have established Drosophila as an invaluable model to live-image and dissect fundamental aspects of inflammatory cell behavior, including mechanisms of developmental dispersal, clearance of apoptotic corpses and/or microbial pathogens, and recruitment to wounds. However, more recent work has now demonstrated that employing a much later stage in the Drosophila lifecycle - the Drosophila pupa - offers a number of distinct advantages, including improved RNAi efficiency, longer imaging periods, and significantly greater immune cell numbers. Here we describe a protocol for imaging wound repair and the associated inflammatory response at the high spatio-temporal resolution in live Drosophila pupae. To follow the dynamics of both re-epithelialization and inflammation, we use a number of specific in vivo fluorescent markers for both the epithelium and innate immune cells. We also demonstrate the effectiveness of photo-convertible fluorophores, such as Kaede, for following the specific immune cell subsets, to track their behavior as they migrate to, and resolve from, the injury site. PMID- 29985352 TI - Deep Dermal Injection As a Model of Candida albicans Skin Infection for Histological Analyses. AB - The skin is an extremely extended organ of the body and, due to this large surface, it is continuously exposed to microorganisms. Skin damage can easily lead to infections in the dermis which can, in turn, result in the dissemination of pathogens into the bloodstream. Understanding how the immune system fights infections at the very early stage and how the host can eliminate the pathogens is an important step to set the base for future therapeutic interventions. Here we describe a model of Candida albicans infection that can visualize the processes that occur early during an infection, including when the pathogen has passed the epithelial barrier, as well as the immune response elicited by the C. albicans invasion. We used this infection model to perform histological analyses that show the immune cells that infiltrate the skin as well as the presence and localization of the pathogen. Samples collected after the infection can be processed for RNA extraction. PMID- 29985353 TI - Zygotic Fluorescence Recovery After Photo-bleaching Analysis for Chromatin Looseness That Allows Full-term Development. AB - Live imaging is a powerful tool that allows for the analysis of molecular events during ontogenesis. Recently, chromatin looseness or openness has been shown to be involved in the cellular differentiation potential of pluripotent embryonic stem cells. It was previously reported that compared with embryonic stem cells, zygotes harbor an extremely loosened chromatin structure, suggesting its association with their totipotency. However, until now, it has not been addressed whether this extremely loosened/open chromatin structure is important for embryonic developmental potential. In the present study, to examine this hypothesis, an experimental system in which zygotes that were analyzed by fluorescence recovery after photo-bleaching can develop to term without any significant damage was developed. Importantly, this experimental system needs only a thermos-plate heater in addition to a confocal laser scanning microscope. The findings of this study suggest that fluorescence recovery after photo bleaching analysis (FRAP) analysis can be used to investigate whether the molecular events in zygotic chromatin are important for full-term development. PMID- 29985354 TI - A Murine Pancreatic Islet Cell-based Screening for Diabetogenic Environmental Chemicals. AB - Exposure to certain environmental chemicals in human and animals has been found to cause cellular damage of the pancreatic beta cells which will lead to the development of type 2 diabetes mellitus (T2DM). Although the mechanisms for the chemical-induced beta cell damage were unclear and likely to be complex, one recurring finding is that these chemicals induce oxidative stress leading to the generation of excessive reactive oxygen species (ROS) which induce damage to the beta cell. To identify potential diabetogenic environmental chemicals, we isolated pancreatic islet cells from C57BL/6 mice and cultured islet cells in 96 well cell culture plates; then, the islet cells were dosed with chemicals and the ROS generation was detected by 2',7'-dichlorofluorescein (DCFH-DA) fluorescent dye. Using this method, we found that bisphenol A (BPA), Benzo[a]pyrene (BaP), and polychlorinated biphenyls (PCBs), could induce high levels of ROS, suggesting that they may potentially induce damage in islet cells. This method should be useful for screening diabetogenic xenobiotics. In addition, the cultured islet cells may also be adapted for in vitro analysis of chemical-induced toxicity in pancreatic cells. PMID- 29985355 TI - Determination of Plasma Membrane Partitioning for Peripherally-associated Proteins. AB - This method provides a fast approach for the determination of plasma membrane partitioning of any fluorescently-tagged peripherally-associated protein using the profiles of fluorescence intensity across the plasma membrane. Measured fluorescence profiles are fitted by a model for membrane and cytoplasm fluorescence distribution along a line applied perpendicularly to the cell periphery. This model is constructed from the fluorescence intensity values in reference cells expressing a fluorescently-tagged marker for cytoplasm and with FM 4-64-labeled plasma membrane. The method can be applied to various cell types and organisms; however, only plasma membranes of non-neighboring cells can be evaluated. This fast microscopy-based method is suitable for experiments, where subtle and dynamic changes of plasma membrane-associated markers are expected and need to be quantified, e.g., in the analysis of mutant versions of proteins, inhibitor treatments, and signal transduction observations. The method is implemented in a multi-platform R package that is coupled with an ImageJ macro that serves as a user-friendly interface. PMID- 29985356 TI - Analysis of Minerals Produced by hFOB 1.19 and Saos-2 Cells Using Transmission Electron Microscopy with Energy Dispersive X-ray Microanalysis. AB - This video presents the use of transmission electron microscopy with energy dispersive X-ray microanalysis (TEM-EDX) to compare the state of minerals in vesicles released by two human bone cell lines: hFOB 1.19 and Saos-2. These cell lines, after treatment with ascorbic acid (AA) and beta-glycerophosphate (beta GP), undergo complete osteogenic transdifferentiation from proliferation to mineralization and produce matrix vesicles (MVs) that trigger apatite nucleation in the extracellular matrix (ECM). Based on Alizarin Red-S (AR-S) staining and analysis of the composition of minerals in cell lysates using ultraviolet (UV) light or in vesicles using TEM imaging followed by EDX quantitation and ion mapping, we can infer that osteosarcoma Saos-2 and osteoblastic hFOB 1.19 cells reveal distinct mineralization profiles. Saos-2 cells mineralize more efficiently than hFOB 1.19 cells and produce larger mineral deposits that are not visible under UV light but are similar to hydroxyapatite (HA) in that they have more Ca and F substitutions. The results obtained using these techniques allow us to conclude that the process of mineralization differs depending on the cell type. We propose that, at the cellular level, the origin and properties of vesicles predetermine the type of minerals. PMID- 29985357 TI - Solvothermal Synthesis of MIL-96 and UiO-66-NH2 on Atomic Layer Deposited Metal Oxide Coatings on Fiber Mats. AB - Metal-organic frameworks (MOFs), which contain reactive metal clusters and organic ligands allowing for large porosities and surface areas, have proven effective in gas adsorption, separations, and catalysis. MOFs are most commonly synthesized as bulk powder, requiring additional processes to adhere them to functional devices and fabrics that risk decreasing the powder porosity and adsorption capacity. Here, we demonstrate a method of first coating fabrics with metal oxide films using atomic layer deposition (ALD). This process creates conformal films of controllable thickness on each fiber, while providing a more reactive surface for MOF nucleation. By submerging the ALD coated fabric in solution during solvothermal MOF synthesis, the MOFs create a conformal, well adhered coating on the fibers, resulting in a MOF-functionalized fabric, without additional adhesion materials that may block MOF pores and functional sites. Here we demonstrate two solvothermal synthesis methods. First, we form a MIL-96(Al) layer on polypropylene fibers using synthetic conditions that convert the metal oxide to MOF. Using initial inorganic films of varying thicknesses, diffusion of the organic linker into the inorganic allows us to control the extent of MOF loading on the fabric. Second, we perform a solvothermal synthesis of UiO-66-NH2 in which the MOF nucleates on the conformal metal oxide coating on polyamide-6 (PA-6) fibers, thereby producing a uniform and conformal thin film of MOF on the fabric. The resulting materials can be directly incorporated into filter devices or protective clothing and eliminate the maladroit qualities of loose powder. PMID- 29985358 TI - Isolation, Characterization, And High Throughput Extracellular Flux Analysis of Mouse Primary Renal Tubular Epithelial Cells. AB - Mitochondrial dysfunction in the renal tubular epithelial cells (TECs) can lead to renal fibrosis, a major cause of chronic kidney disease (CKD). Therefore, assessing mitochondrial function in primary TECs may provide valuable insight into the bioenergetic status of the cells, providing insight into the pathophysiology of CKD. While there are a number of complex protocols available for the isolation and purification of proximal tubules in different species, the field lacks a cost-effective method optimized for tubular cell isolation without the need for purification. Here, we provide an isolation protocol that allows for studies focusing on both primary mouse proximal and distal renal TECs. In addition to cost-effective reagents and minimal animal procedures required in this protocol, the isolated cells maintain high energy levels after isolation and can be sub-cultured up to four passages, allowing for continuous studies. Furthermore, using a high throughput extracellular flux analyzer, we assess the mitochondrial respiration directly in the isolated TECs in a 96-well plate for which we provide recommendations for the optimization of cell density and compound concentration. These observations suggest that this protocol can be used for renal tubular ex vivo studies with a consistent, well-standardized production of renal TECs. This protocol may have broader future applications to study mitochondrial dysfunction associated with renal disorders for drug discovery or drug characterization purposes. PMID- 29985359 TI - Mapping Metabolism: Monitoring Lactate Dehydrogenase Activity Directly in Tissue. AB - Mapping enzymatic activity in space and time is critical for understanding the molecular basis of cell behavior in normal tissue and disease. In situ metabolic activity assays can provide information about the spatial distribution of metabolic activity within a tissue. We provide here a detailed protocol for monitoring the activity of the enzyme lactate dehydrogenase directly in tissue samples. Lactate dehydrogenase is an important determinant of whether consumed glucose will be converted to energy via aerobic or anaerobic glycolysis. A solution containing lactate and NAD is provided to a frozen tissue section. Cells with high lactate dehydrogenase activity will convert the provided lactate to pyruvate, while simultaneously converting provided nicotinamide adenine dinucleotide (NAD) to NADH and a proton, which can be detected based on the reduction of nitrotetrazolium blue to formazan, which is visualized as a blue precipitate. We describe a detailed protocol for monitoring lactate dehydrogenase activity in mouse skin. Applying this protocol, we found that lactate dehydrogenase activity is high in the quiescent hair follicle stem cells within the skin. Applying the protocol to cultured mouse embryonic stem cells revealed higher staining in cultured embryonic stem cells than mouse embryonic fibroblasts. Analysis of freshly isolated mouse aorta revealed staining in smooth muscle cells perpendicular to the aorta. The methodology provided can be used to spatially map the activity of enzymes that generate a proton in frozen or fresh tissue. PMID- 29985360 TI - Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration. AB - Motor behavior tests are commonly used to determine the functional relevance of a rodent model and to test newly developed treatments in these animals. Specifically, gait analysis allows recapturing disease relevant phenotypes that are observed in human patients, especially in neurodegenerative diseases that affect motor abilities such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and others. In early studies along this line, the measurement of gait parameters was laborious and depended on factors that were hard to control (e.g., running speed, continuous running). The development of ventral plane imaging (VPI) systems made it feasible to perform gait analysis at a large scale, making this method a useful tool for the assessment of motor behavior in rodents. Here, we present an in-depth protocol of how to use kinematic gait analysis to examine the age-dependent progression of motor deficits in mouse models of neurodegeneration; mouse lines with decreased levels of endophilin, in which neurodegenerative damage progressively increases with age, are used as an example. PMID- 29985361 TI - Facile Protocol for the Synthesis of Self-assembling Polyamine-based Peptide Amphiphiles (PPAs) and Related Biomaterials. AB - Polyamine-based Peptide Amphiphiles (PPAs) are a new class of self-assembling amphiphilic biomaterials-related to the peptide amphiphiles (PAs). Traditional PAs possess charged amino acids as solubilizing groups (lysine, arginine), which are directly connected to a lipid segment or can contain a linker region made of neutral amino acids. Tuning the peptide sequence of PAs can yield diverse morphologies. Similarly, PPAs possess a hydrophobic segment and neutral amino acids, but also contain polyamine molecules as water solubilizing (hydrophilic) groups. As is the case with PAs, PPAs can also self-assemble into diverse morphologies, including small rods, twisted nano-ribbons, and fused nano-sheets, when dissolved in water. However, the presence of both primary and secondary amines on a single polyamine molecule poses a significant challenge when synthesizing PPAs. In this paper, we show a simple protocol, based on literature precedents, to achieve a facile synthesis of PPAs using solid phase peptide synthesis (SPPS). This protocol can be extended to the synthesis of PAs and other similar systems. We also illustrate the steps that are needed for cleavage from the resin, identification, and purification. PMID- 29985362 TI - Light-sheet Microscopy for Three-dimensional Visualization of Human Immune Cells. AB - In vivo, activation, proliferation, and function of immune cells all occur in a three-dimensional (3D) environment, for instance in lymph nodes or tissues. Up to date, most in vitro systems rely on two-dimensional (2D) surfaces, such as cell culture plates or coverslips. To optimally mimic physiological conditions in vitro, we utilize a simple 3D collagen matrix. Collagen is one of the major components of extracellular matrix (ECM) and has been widely used to constitute 3D matrices. For 3D imaging, the recently developed light-sheet microscopy technology (also referred to as single plane illumination microscopy) is featured with high acquisition speed, large penetration depth, low bleaching, and photocytotoxicity. Furthermore, light-sheet microscopy is particularly advantageous for long-term measurement. Here we describe an optimized protocol how to set up and handle human immune cells, e.g. primary human cytotoxic T lymphocytes (CTL) and natural killer (NK) cells in the 3D collagen matrix for usage with the light-sheet microscopy for live cell imaging and fixed samples. The procedure for image acquisition and analysis of cell migration are presented. A particular focus is given to highlight critical steps and factors for sample preparation and data analysis. This protocol can be employed for other types of suspension cells in a 3D collagen matrix and is not limited to immune cells. PMID- 29985364 TI - Laparoscopic Pancreatoduodenectomy With Modified Blumgart Pancreaticojejunostomy. AB - Minimally invasive pancreatic resections are technically demanding but rapidly increasing in popularity. In contrast to laparoscopic distal pancreatectomy, laparoscopic pancreatoduodenectomy (LPD) has not yet obtained wide acceptance, probably due to technical challenges, especially regarding the pancreatic anastomosis. The study describes and demonstrates all steps of LPD, including the modified Blumgart pancreaticojejunostomy. Indications for LPD are all pancreatic and peri-ampullary tumors without vascular involvement. Relative contra indications are body mass index >35 kg/m2, chronic pancreatitis, mid cholangiocarcinomas and large duodenal cancers. The patient is in French position, 6 trocars are placed, and dissection is performed using an (articulating) sealing device. A modified Blumgart end-to-side pancreaticojejunostomy is performed with 4 large needles (3/0) barbed trans pancreatic sutures and 4 to 6 duct-to-mucosa sutures using 5/0 absorbable multifilament combined with a 12 cm, 6 or 8 Fr internal stent using 3D laparoscopy. Two surgical drains are placed alongside the pancreaticojejunostomy. The described technique for LPD including a modified Blumgart pancreatico jejunostomy is well standardized, and its merits are currently studied in the randomized controlled multicenter trial. This complex operation should be performed at high-volume centers where surgeons have extensive experience in both open pancreatic surgery and advanced laparoscopic gastro-intestinal surgery. PMID- 29985363 TI - Induction and Validation of Cellular Senescence in Primary Human Cells. AB - Cellular senescence is a state of permanent cell cycle arrest activated in response to different damaging stimuli. Activation of cellular senescence is a hallmark of various pathophysiological conditions including tumor suppression, tissue remodeling and aging. The inducers of cellular senescence in vivo are still poorly characterized. However, a number of stimuli can be used to promote cellular senescence ex vivo. Among them, most common senescence-inducers are replicative exhaustion, ionizing and non-ionizing radiation, genotoxic drugs, oxidative stress, and demethylating and acetylating agents. Here, we will provide detailed instructions on how to use these stimuli to induce fibroblasts into senescence. This protocol can easily be adapted for different types of primary cells and cell lines, including cancer cells. We also describe different methods for the validation of senescence induction. In particular, we focus on measuring the activity of the lysosomal enzyme Senescence-Associated beta-galactosidase (SA beta-gal), the rate of DNA synthesis using 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay, the levels of expression of the cell cycle inhibitors p16 and p21, and the expression and secretion of members of the Senescence-Associated Secretory Phenotype (SASP). Finally, we provide example results and discuss further applications of these protocols. PMID- 29985365 TI - Deposition of Porous Sorbents on Fabric Supports. AB - A microwave deposition technique for silanes, previously described for production of oleophobic fabrics, is adapted to provide a fabric support material that can be subsequently treated by dip coating. Dip coating with a sol preparation provides a supported porous layer on the fabric. In this case, the porous layer is a porphyrin functionalized sorbent system based on a powdered material that has been demonstrated previously for the capture and conversion of phosgene. A representative coating is applied to cotton fabric at a loading level of 10 mg/g. This coating has minimal impact on water vapor transport through the fabric (93% of the support fabric rate) while significantly reducing transport of 2 chloroethyl ethyl sulfide (CEES) through the material (7% of support fabric rate). The described approaches are suitable for use with other fabrics providing amine and hydroxyl groups for modification and can be used in combination with other sol preparations to produce varying functionality. PMID- 29985366 TI - Semi-quantitative Detection of RNA-dependent RNA Polymerase Activity of Human Telomerase Reverse Transcriptase Protein. AB - Human telomerase reverse transcriptase (TERT) is the catalytic subunit of telomerase, and it elongates telomere through RNA-dependent DNA polymerase activity. Although TERT is named as a reverse transcriptase, structural and phylogenetic analyses of TERT demonstrate that TERT is a member of right-handed polymerases, and relates to viral RNA-dependent RNA polymerases (RdRPs) as well as viral reverse transcriptase. We firstly identified RdRP activity of human TERT that generates complementary RNA stand to a template non-coding RNA and contributes to RNA silencing in cancer cells. To analyze this non-canonical enzymatic activity, we developed RdRP assay with recombinant TERT in 2009, thereafter established in vitro RdRP assay for endogenous TERT. In this manuscript, we describe the latter method. Briefly, TERT immune complexes are isolated from cells, and incubated with template RNA and rNTPs including radioactive rNTP for RdRP reaction. To eliminate single-stranded RNA, reaction products are treated with RNase I, and the final products are analyzed with polyacrylamide gel electrophoresis. Radiolabeled RdRP products can be detected by autoradiography after overnight exposure. PMID- 29985367 TI - Ligand-Mediated Nucleation and Growth of Palladium Metal Nanoparticles. AB - The size, size distribution and stability of colloidal nanoparticles are greatly affected by the presence of capping ligands. Despite the key contribution of capping ligands during the synthesis reaction, their role in regulating the nucleation and growth rates of colloidal nanoparticles is not well understood. In this work, we demonstrate a mechanistic investigation of the role of trioctylphosphine (TOP) in Pd nanoparticles in different solvents (toluene and pyridine) using in situ SAXS and ligand-based kinetic modeling. Our results under different synthetic conditions reveal the overlap of nucleation and growth of Pd nanoparticles during the reaction, which contradicts the LaMer-type nucleation and growth model. The model accounts for the kinetics of Pd-TOP binding for both, the precursor and the particle surface, which is essential to capture the size evolution as well as the concentration of particles in situ. In addition, we illustrate the predictive power of our ligand-based model through designing the synthetic conditions to obtain nanoparticles with desired sizes. The proposed methodology can be applied to other synthesis systems and therefore serves as an effective strategy for predictive synthesis of colloidal nanoparticles. PMID- 29985368 TI - Cochlear Implantation in the Guinea Pig. AB - Cochlear implants are highly efficient devices that can restore hearing in subjects with profound hearing loss. Due to improved speech perception outcomes, candidacy criteria have been expanded over the last few decades. This includes patients with substantial residual hearing that benefit from electrical and acoustical stimulation of the same ear, which makes hearing preservation during cochlear implantation an important issue. Electrode impedances and the related issue of energy consumption is another major research field, as progress in this area could pave the way for fully implantable auditory prostheses. To address these issues in a systematic way, adequate animal models are essential. Therefore, the goal of this protocol is to provide an animal model of cochlear implantation, which can be used to address various research questions. Due to its large tympanic bulla, which allows easy surgical access to the inner ear, as well as its hearing range which is relatively similar to the hearing range of humans, the guinea pig is a commonly used species in auditory research. Cochlear implantation in the guinea pig is performed via a retroauricular approach. Through the bullostomy a cochleostomy is drilled and the cochlear implant electrode is inserted into the scala tympani. This electrode can then be used for electrical stimulation, determination of electrode impedances and the measurement of compound action potentials of the auditory nerve. In addition to these applications, cochlear implant electrodes can also be used as drug delivery devices, if a topical delivery of pharmaceutical agents to the cells or fluids of the inner ear is intended. PMID- 29985369 TI - Generation of Knock-out Primary and Expanded Human NK Cells Using Cas9 Ribonucleoproteins. AB - CRISPR/Cas9 technology is accelerating genome engineering in many cell types, but so far, gene delivery and stable gene modification have been challenging in primary NK cells. For example, transgene delivery using lentiviral or retroviral transduction resulted in a limited yield of genetically-engineered NK cells due to substantial procedure-associated NK cell apoptosis. We describe here a DNA free method for genome editing of human primary and expanded NK cells using Cas9 ribonucleoprotein complexes (Cas9/RNPs). This method allowed efficient knockout of the TGFBR2 and HPRT1 genes in NK cells. RT-PCR data showed a significant decrease in gene expression level, and a cytotoxicity assay of a representative cell product suggested that the RNP-modified NK cells became less sensitive to TGFbeta. Genetically modified cells could be expanded post-electroporation by stimulation with irradiated mbIL21-expressing feeder cells. PMID- 29985370 TI - Optimization of Laser-Capture Microdissection for the Isolation of Enteric Ganglia from Fresh-Frozen Human Tissue. AB - The purpose of this method is to obtain high-integrity RNA samples from enteric ganglia collected from unfixed, freshly-resected human intestinal tissue using laser capture microdissection (LCM). We have identified five steps in the workflow that are crucial for obtaining RNA isolates from enteric ganglia with sufficiently high quality and quantity for RNA-seq. First, when preparing intestinal tissue, each sample must have all excess liquid removed by blotting prior to flattening the serosa as much as possible across the bottom of large base molds. Samples are then quickly frozen atop a slurry of dry ice and 2 methylbutane. Second, when sectioning the tissue, it is important to position cryomolds so that intestinal sections parallel the full plane of the myenteric plexus, thereby yielding the greatest surface area of enteric ganglia per slide. Third, during LCM, polyethylene napthalate (PEN)-membrane slides offer the greatest speed and flexibility in outlining the non-uniform shapes of enteric ganglia when collecting enteric ganglia. Fourth, for distinct visualization of enteric ganglia within sections, ethanol-compatible dyes, like Cresyl Violet, offer excellent preservation of RNA integrity relative to aqueous dyes. Finally, for the extraction of RNA from captured ganglia, we observed differences between commercial RNA extraction kits that yielded superior RNA quantity and quality, while eliminating DNA contamination. Optimization of these factors in the current protocol greatly accelerates the workflow and yields enteric ganglia samples with exceptional RNA quality and quantity. PMID- 29985372 TI - Preparing Developing Peripheral Olfactory Tissue for Molecular and Immunohistochemical Analysis in Drosophila. AB - The olfactory system of Drosophila is a widely used system in developmental neurobiology, systems neuroscience, as well as neurophysiology, behavior, and behavioral evolution. Drosophila olfactory tissues house the olfactory receptor neurons (ORNs) that detect volatile chemical cues in addition to hydro- and thermo-sensory neurons. In this protocol, we describe the dissection of developing peripheral olfactory tissue of the adult Drosophila species. We first describe how to stage and age Drosophila larvae, followed by the dissection of the antennal disc from early pupal stages, followed by the dissection of the antennae from mid-pupal stages and adults. We also show methods where preparations can be utilized in molecular techniques, such as the RNA extraction for qRT-PCR, RNAseq, or immunohistochemistry. These methods can also be applied to other Drosophila species after species-specific pupal development times are determined, and respective stages are calculated for appropriate aging. PMID- 29985371 TI - Endoscopic Septoplasty with Limited Two-line Resection: Minimally Invasive Surgery for Septal Deviation. AB - Endoscopic septoplasty is a surgical procedure in otolaryngology that is commonly performed to treat nasal airway obstruction caused by nasal septal deviation. It has a long history with multiple variations. In this article, a modified endoscopic septoplasty procedure using the limited two-line resection (2LoRs) technique at the posterior and inferior junction of the cartilaginous and bony septum is presented based on embryologic and anatomic knowledge of the nasal septum and the biomechanics of cartilaginous behavior. With this procedure, the quadrangular cartilage can be preserved as much as possible, which is helpful in retaining the supporting framework and rigidness of the septum. 2LoRs has been proven effective and sound for the correction of nasal septal deviation with rare complications. This modified procedure can be applied to correct the deviated nasal septum in the absence of any external nasal deformity to improve nasal patency or to improve access to the middle meatus or to the axillary region of the middle turbinate. It may also be used to expand the indications of septoplasty to children and adolescents because of its minimally invasive approach. PMID- 29985373 TI - In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge. AB - MicroRNA (miRNA) is small non-coding RNA which inhibits post-transcriptional messenger RNA (mRNA) expression. Human diseases, such as cancer and cardiovascular disease, have been shown to activate tissue and/or cell-specific miRNA expression associated with disease progression. The inhibition of miRNA expression offers the potential for a therapeutic intervention. However, traditional approaches to inhibit miRNAs, employing antagomir oligonucleotides, affect specific miRNA functions upon global delivery. Herein, we present a protocol for the in vivo cardio-specific inhibition of the miR-181 family in a rat model. A miRNA-sponge construct is designed to include 10 repeated anti-miR 181 binding sequences. The cardio-specific alpha-MHC promoter is cloned into the pEGFP backbone to drive the cardio-specific miR-181 miRNA-sponge expression. To create a stable cell line expressing the miR-181-sponge, myoblast H9c2 cells are transfected with the alpha-MHC-EGFP-miR-181-sponge construct and sorted by fluorescence-activated cell sorting (FACs) into GFP positive H9c2 cells which are cultured with neomycin (G418). Following stable growth in neomycin, monoclonal cell populations are established by additional FACs and single cell cloning. The resulting myoblast H9c2-miR-181-sponge-GFP cells exhibit a loss of function of miR-181 family members as assessed through the increased expression of miR-181 target proteins and compared to H9c2 cells expressing a scramble non-functional sponge. In addition, we develop a nanovector for the systemic delivery of the miR 181-sponge construct by complexing positively charged liposomal nanoparticles and negatively charged miR-181-sponge plasmids. In vivo imaging of GFP reveals that multiple tail vein injections of a nanovector over a three-week period are able to promote a significant expression of the miR-181-sponge in a cardio-specific manner. Importantly, a loss of miR-181 function is observed in the heart tissue but not in the kidney or the liver. The miRNA-sponge is a powerful method to inhibit tissue-specific miRNA expression. Driving the miRNA-sponge expression from a tissue-specific promoter provides specificity for the miRNA inhibition, which can be confined to a targeted organ or tissue. Furthermore, combining nanovector and miRNA-sponge technologies permits an effective delivery and tissue specific miRNA inhibition in vivo. PMID- 29985374 TI - [The influence of trans-cranial electrical stimulation on the cells of the macrophagal system of the women presenting with the climacteric syndrome]. AB - BACKGROUND: The search for the harmless and effective methods for the drug-free correction of various vegetovascular manifestations associated with the climacteric syndrome (CS) is currently a serious challenge facing modern medicine. Dysfunction of the ovaries during the perimenopause is characterized by the impaired production of sex steroids. The estrogens and progesterone, in their turn, are able to interact with macrophages via the specific receptors of steroid hormones localized on the surface of these cells. In this context, the trans cranial electrical stimulation (TES) technique is of great interest due to its strong influence on the functional state of the central nervous system, subcortical brain structures, the vegetative and hormonal balance. The immunotropic effects of TES therapy described in the literature provide a basis for anticipating its beneficial action on the functional activity of monocytes/macrophages in the women presenting with the climacteric syndrome. AIM: The objective of the present study was to evaluate the influence of trans-cranial electrical stimulation on the state and stability of lysosomal membranes of blood monocytes and peritoneal macrophages, the secretory and synthetic activity of these cells in the women exhibiting the vegetovascular manifestations of the climacteric syndrome. MATERIAL AND METHODS: The influence of the transcranial electrical stimulation (TES) technique on the stability of lysosomal membranes of blood monocytes and peritoneal macrophages, the secretory and synthetic activity of these cells was studied in 23 women at the age from 45 to 52 years presenting with vegetovascular manifestations of the climacteric syndrome. The control group was comprised of 16 healthy women of the same age. The state of blood monocytes and peritoneal macrophages was evaluated before and after the course of TES therapy. To determine stability of lysosomal membranes of blood monocytes and peritoneal macrophages and calculate the stability index (PSI), the isolated cells were cultured in a medium 199 supplemented by sterile 0.5% L-glutamine and 2.5% mixed human serum previously heated at 560 degrees C for 30 min and at 37 degrees C for 12-15 hours. The micro-method was employed to determine secreted lysozyme (Lsec) as well as total lysozyme (L total=L secreted plus L intracellular) following 4-6-fold freeze-thawing of the cultured cells. The data obtained on the levels of secreted and total lysozymes were used to calculate PSI by the formula: PSI=Lsec/Ltotal'100%. The increase in PSI above the optimal value (53- 58%) was regarded as giving evidence of labilization of the lysosomal membranes and the decrease of this parameter as the indicator of membrane stabilization. Based on the difference between the total lysozyme levels before and after cultivation, the amount of newly synthesized lysozyme (L int) was determined. RESULTS: The results of the present study give evidence that the women with climacteric syndrome experience labilization of the blood monocytes and peritoneal macrophages; their lysozyme secretion increases while its synthesis decreases. In other words, the therapeutic application of the transcranial electrical stimulation technique contributed to the disappearance or reduction of 'hot flashes' and the change of these features to the level characteristic of the healthy women. CONCLUSIONS: The data obtained extend our knowledge about the mechanisms underlying the action of TES therapy on the macrophagic cells; moreover, they allow to draw the conclusion that the course of medication with the application this technique not only decreases the intensity of manifestations of the climacteric syndrome but also corrects the function of the immune system during the perimenopause. PMID- 29985375 TI - [The effectiveness of autogenic training in the psycho-corrective treatment of the patients presenting with chronic somatic diseases]. AB - BACKGROUND: The autogenic training (AT) is one of the most widely used methods for psychotherapy of patients suffering from chronic somatic diseases (CSD). A number of studies have demonstrated the improvement of the psychological status in the patients under the influence of autogenic training. However, up to the present time, both the mechanisms underlying the therapeutic effectiveness and the predictors of the AT effectiveness have remained to be poorly studied which hampers the development of differentiated indications for the application of this technique. AIM: The objective of the present study was to estimate the effectiveness of AT and to identify the predictors of the outcomes of the treatment of patients presenting with chronic somatic diseases. MATERIAL AND METHODS: The study included 325 patients with CSD who were examined with the use of the shortened multifactorial personality inventory (SMPI), the Spielberger State-Trait Anxiety Inventory (STAI), and the Beck depression inventory (BDI) scales. The patients were randomized into two groups. Group 1 (main) was comprised of 163 patients who underwent AT-based psychotherapy, group 2 (control) consisted of 162 patients who did not receive the psychotherapy. In order to identify the predictors of AT effectiveness, the patients of the main group were subdivided into two subgroups at the end of the study period: (a) including 128 patients whose psychologic status was normalized under psychotherapy and (b) containing 35 patients showing the improvement of their health status. The comparative analysis of the baseline characteristics of the patients belonging to each group was performed. RESULTS: The study has demonstrated that by the end of the observation period the patients of the main group showed a significantly more pronounced (compared with controls) decrease of scales 1, 2, and 7 indicators, an increase of the SMPI scale 9 indicators, and a decrease of STAI and BDI indicators. The positive impact of autogenic training on the psychological status of the patients was mostly attributable to the reduction of anxiety, tension, fixation on negative sensations, and sensitivity to the stress factors as well as to the increased activity and the improved mood. The study of AT predictors revealed that the increase of scales 4 and 6 of SMPI and BDI indicators fairly well predicts the lack of the effectiveness of the method under consideration. CONCLUSIONS: The beneficial influence of the autogenic training on the psychological status of the patients presenting with chronic somatic diseases is mainly mediated through the decrease of anxiety, tension, fixation on negative feelings, sensitivity to stressful influences, increased activity, and improved mood of the patients. A study of AT effectiveness predictors revealed that an increased level of rigidity reduces the effectiveness of this method because of the tendency of the patients toward making excessive efforts to achieve the state of relaxation. The predictors of the high effectiveness of AT the development of which requires regular training proved to be a moderate decrease of the psychological adaptation level together with such characteristics as the ability of the patients to control their behavior, purposefulness, and perseverance in achieving the goal. PMID- 29985376 TI - [The treatment of the patients suffering from acute bacterial external otitis with the use of intravenous blood illumination by low-intensity laser radiation at a wavelength of 445 nm]. AB - BACKGROUND: The prevalence of allergic reactions to the pharmaceutical products and the development of antibiotic resistance limit the provision of the high quality medical care to the patients presenting with acute bacterial external otitis media (ABEO). AIM: The objective of the present study was to evaluate the effectiveness of the treatment of the patients suffering from ABEO with the application of the new technique based on intravenous blood illumination by low intensity laser radiation at a wavelength of 445 nm (ILBI-445). MATERIAL AND METHODS: This open comparative clinical study was carried out from April 2017 till June 2017 and included the patients with ABEO who were divided into two groups. The patients of the main group underwent the standard treatment in the combination with low-intensity laser radiation at a wavelength of 445 nm. Those comprising the control group were given the conventional treatment alone. The end point of the study was the complete disappearance of local inflammatory signs in the region of the external auditory canal (EAC) and auricle, the restoration of the volume of the EAC, the absence of complaints estimated based on the visual analogue scale (VAS), and the complete disappearance of symptoms of intoxication. The local signs of inflammation in the region of the EAC and auricle were assessed from the otoscopic picture. The measurement of the volume of the external auditory canal were carried out by filling it with a furacilin solution at a temperature of 360C using a 2 ml syringe. The character of the inflammatory changes in the external auditory canal, the intensity of pain and itching, as well as the degree of hearing loss were estimated at 10 points based on the 10 point visual analogue scale (with 0 points standing for the absence of complaints and 10 points denoting the maximum severity of the complaints). The symptoms of intoxication were determined from the measurements of body temperature. RESULTS: The combined treatment of the patients with ABEO using ILBI-445 resulted in their earlier recovery in comparison with that achieved by means of the standard therapy. The differences were especially pronounced on the 5th day of treatment. Complaints of pain and the loss of hearing were documented only in the patients of the control group. Itching was a significantly less serious trouble in the patients of the main group than it was in those comprising the control group. The volume of the external auditory canal in the patients of the main group on the 5th day after the onset of the treatment was more than 16.7% greater than in the control one. CONCLUSIONS: The high therapeutic effectiveness and simplicity of the approach employed in the present study taken together with a minimum of contraindications for its application give reason to recommend intravenous blood illumination by low-intensity laser radiation at a wavelength of 445 nm for the treatment of the patients suffering from acute bacterial external otitis. PMID- 29985377 TI - [On the history of the problem of the rehabilitative treatment of the subjects suffering wounds in the maxillofacial region with the concomitant disorders of the speech function]. AB - The authors made an attempt to highlight the issues of rehabilitation of the patients suffering wounds in the maxillofacial region with the concomitant disorders in the function of the organs of speech. The secondary objective of the study was to prove that rehabilitation of such patients is possible only by means of the joint efforts and close cooperation of dentists, physiotherapists, and speech therapists. The results of the clinical observations of the most severe cases of the impaired speech function obtained in the evacuation hospitals have been considered, with the special emphasis placed on the leading role of the speech therapist in the rehabilitation of such patients. A scheme of therapeutic physical exercises and speech therapy is presented that includes the correction and development of respiration. The guidelines are proposed for the breathing exercises and exercises for the muscles of the shoulder girdle, neck, pharynx, tongue, and the soft palate, chewing-articular muscles and mimic-articular muscles as well as for the correction of open and closed rhinolalia. Special attention is given to the implementation of socio-psychological rehabilitation for the restoration of the stable, clear and comprehensible speech function. The rehabilitation teams have been organized for the first time comprised of the maxillofacial surgeon, the orthopedic dentist, the physiotherapist, the speech therapist, and the physiotherapist. The classification of the disorders of interest have been developed based on the available data concerning the anatomical-physiological and sound-producing disturbances. The methods for the restoration of the speech function in the patients presenting with the injuries to the maxillofacial region with the concomitant disorders of the speech function are described together with the newly developed modalities of physical therapy and speech therapy. PMID- 29985379 TI - [Genetic polymorphism of cytogenetic effects of radon bath therapy in the patients presenting with gonosteoarthritis of different etiology based at the Belokurikha health resort]. AB - BACKGROUND: Borrelia infection is known to develop as a result of the bites of the ixodid ticks while the extremely difficult working conditions and low temperatures contribute to the development of chronic gonosteoarthritis (CGA) associated with ixodid tick-borne borreliosis (ITB) in the residents of the northern part of Siberia. AIM: The objective of the present study was to elucidate the frequency of occurrence of the synovial cells in the knee joints exhibiting the cytogenetic abnormalities with special reference to trisomy of chromosome 7 and the glutathione-S-transferase (GSTM1) gene polymorphism in the residents of the northern part of Siberia presenting with Lyme borreliosis (LB) whose genotype contains some alleles of the GSTM1 gene before and after the treatment of LB-associated CGA with the use of the radon bath therapy. The secondary objective was to compare the respective characteristics and the results of the treatment with those in the patients with post-traumatic gonosteoarthritis (PTGA) and to evaluate the influence of the above abnormalities on the severity of CGA. MATERIAL AND METHODS: The study included 69 patients having gonosteoarthritis associated with ixodid tick-borne borreliosis and residing in the northern areas of Siberia; in addition, 52 other individuals presenting with post-traumatic CGA made up the control group. The synovial cells of the knee joints were obtained from all the participants of the study for their culturing, making preparations, and analyzing chromosomal aberrations. The polymorphism of the GSTM1 gene was investigated with the use of the real-time polymerase chain reaction. RESULTS: The frequency of cytogenetic abnormalities in the synovial cells obtained from the group of patients presenting with LB-associated CGA who were the carriers of the homozygous mutant genotype GSTM1(0/0) was significantly higher than that in the patients having the normal genotype GSTM1(+) before the course of radon bath therapy. This treatment resulted in a significant decrease of the severity of pain syndrome and the improvement of the locomotor function of the affected joints in all groups of the patients involved in the study. The correlation analysis has demonstrated the significant positive correlation between the decrease in the frequency of occurrence of the synovial cells with trisomy of chromosome 7 and the severity of the pain syndrome. CONCLUSIONS: The results of the present study give evidence of the significant association between the genetic polymorphism of the glutathione-S-transferase gene and the frequency of cytogenetic abnormalities in the synovial cells of the knee joints of the patients suffering from CGA associated with LB. The treatment based on radon bath therapy caused a considerable decrease in the frequency of synovial cells with trisomy of chromosome 7 which correlated with the reduction of the intensity of the pain syndrome in these patients. PMID- 29985378 TI - [The restoration of the shoulder joint function in the patients presenting with hemiparesis during the acute phase of hemispheric stroke]. AB - : The impaired function of the shoulder joint resulting from cerebral stroke is a common disorder involving permanent total disability as well as impaired capability of self-care. The functional pathological changes in the shoulder joint and the dynamics of the patients' health status during the acute period of cerebral stroke remain virtually unexplored. AIM: The objective of the present study was to obtain a deeper insight into the process of recovery of the movements in the shoulder joint of the patients presenting with hemiparesis during the acute period of hemispheric stroke based on the results of the analysis of the biomechanical data and the targeted training with biofeedback (BFB). MATERIAL AND METHODS: The study included three groups comprised of 25 subjects each. One (control) group included the subjects having neither neurological nor orthopedic pathology. The second group consisted of the patients receiving the conventional treatment in the combination with therapeutic physical exercises (TPE). Group 3 was composed of the patients given the standard course of conventional and physical (TPE) therapy complemented by biofeedback training (the TPE/BFB group). The study included clinical investigations and biomechanical registration of the movements of the shoulder joints and trunk. RESULTS: The results of the study gave evidence that the patients presenting with hemiparesis during the acute period of hemispheric ischemic stroke including those treated with the application of the active means and methods of rehabilitation, such as BFB training, showed no appreciable dynamics of the parameters being evaluated with the use of the relevant clinical scales. The biomechanical study has demonstrated that the movements in the shoulder joints (in a single plain) of the patients comprising the control group are characterized by the presence of the main component with a maximum amplitude in the plane of this movement and additional components (in other planes with a significantly lower amplitude); they are accompanied by the ancillary movements of the trunk. Functionally, the condition of paresis at the level of the shoulder joint is characterized by a decrease in the amplitude of the primary movement and the increase of one of the additional amplitudes, with the growing amplitude of the auxiliary movements of the trunk. The biomechanical methods for the objective assessment have revealed the following functional changes in the shoulder joints: the 6% improvement of flexion in the group of the patients treated with the use of therapeutic physical exercises and the 10% improvement in those treated with the combination of TPE and BFB. Moreover, abduction in the patients of these two groups improved by 4% and 9% respectively. CONCLUSIONS: The method for the study of kinematics of the movements in the shoulder joints appears to be most sensitive and informative for the purpose of diagnostics of disorders of the motor function and assessment of the process of its restoration in the patients presenting with hemiparesis during the acute period of hemispheric stroke. PMID- 29985380 TI - [The use of the functional state of the joints for the estimation of the effectiveness of the application of oxygen/ozone therapy for the rehabilitative treatment of the patients suffering from knee arthritis]. AB - BACKGROUND: In the recent years, the ever increasing tendency toward the growth in the prevalence of degenerative-dystrophic articular diseases has been observed especially among the young subjects and the middle-aged people. The enhanced economic burden of treating the patients with this condition on the public health care system frequently comes not only from chronic pathology of the joints but also from the development of concomitant disorders which dictates the necessity of the search for the new methods for the management of such patients. AIM: The objective of the present study was the optimization of the treatment of the patients presenting with stage I-II gonarthrosis by the para-articular application of oxygen/ozone therapy at the early stages of knee arthritis and the evaluation of the clinical effectiveness of this approach. MATERIAL AND METHODS: A total of 89 patients suffering from I-II sg gonarthrosis were recruited for the participation in the study. They included 67.2% of men and 32.8% of women. The age of the patients varied from 33 to 54 (mean 42+/-5) years, the duration of the disease averaged 4+/-1.2 years. All the patients were randomly divided into two groups: matched for the age, gender, the duration and severity of the disease, and the methods of its treatment. The main group was comprised of 45 patients whereas the group of comparison consisted of 44 patients. The generally accepted therapeutic modalities were used to treat the patients of both groups. Those included in the main group (n=45) additionally received para-articular oxygen/ozone therapy applied to the affected knee at a permanent ozone concentration of 8 gr/l (the injection area 15-20 sq.cm), main group n=45). The results of the treatment were evaluated within 1 and 6 months after the onset of therapy. RESULTS: The application of the up-to-date methods of oxygen/ozone therapy in the combination with the universally-accepted drug-based treatments for the patients of the main group resulted in the significant (p<0.01) improvement of the indicators of the biomechanical activity of the knee joints in comparison with that achieved by means of the generic drug-based treatment alone. DISCUSSION: The results of the present study give evidence of the feasibility of application of oxygen/ozone therapy for the treatment of degenerative-dystrophic articular diseases of the knees. The positive dynamics of the indicators of the functional activity of the knee joints, intensity and duration of the pain syndrome as well as the reduction of the period of the temporary incapacity for work associated with exacerbation of knee arthrosis suggests the high clinical and economic effectiveness of the para-articular application of oxygen/ozone therapy. CONCLUSIONS: The present study has demonstrated the expediency and effectiveness of the application of oxygen/ozone therapy during exacerbation of stage I-II knee arthritis as evaluated based on the WOMAC index, VAS, and Lyshom scale within one and six months after the onset of the treatment. The resulting reduction in the number of days of temporary incapacity for work in the patients suffering from knee arthritis gives evidence of the clinical and economic validity of the proposed method of the combined treatment of this condition based on the application of oxygen/ozone therapy. PMID- 29985381 TI - [The rationale for the application of magnetophoresis for the treatment of intra articular pathology]. AB - The present study was designed to elucidate the influence of the magnetic field on the spectroscopic characteristics of nimesulide and glucosamine sulfate preparations. The secondary objective of the study was to evaluate the clinical effectiveness of the combined application of magnetotherapy and transdermal forms containing a non-steroidal anti-inflammatory preparation and a chondroprotector with the use of magnetophoresis. For this purpose, we analyzed the samples exposed to the running magnetic field in an infrared spectrometer to elucidate the changes in the optical characteristics of the preparations of interest. The clinical effectiveness of the combined application of magnetophoresis was estimated in 83 patients presenting with knee osteoarthritis. The use of the infrared spectroscopic technique in the combination with the Fourier analysis made it possible to visualize the absence of coarse optical defects and structural changes in the test samples under the influence of the physical factors which provides the basis for their physiophoretic administration. The clinical studies conducted with the application of the combined physio pharmacological treatment have demonstrated the feasibility and high effectiveness of this approach for the management of the patients presenting with articular pathology. The rehabilitative measures accelerated the earlier appearance of the pronounced analgesic effect and promoted the restoration of the joint function. Moreover, they reduced the drug load and improved the quality of life of the patients. PMID- 29985382 TI - [Dynamics of the emotional state and physiological parameters of the organism during long-term aqua-thermal impact]. AB - : The data presented in this article illustrate the dynamics of the affective sphere of the mental processes associated with the higher nervous activity and the characteristics of the neuroendocrine system (including the vegetative index of Kerdo, cortisol and serotonin levels) in the participants of the marathon swimming competition covering the distance of 101.4 km. We investigated the relationship between the levels of the above hormones and the functional activity of the vegetative nervous system. AIM: The objectives of the present study were (1) to determine the dynamics of the changes in the psychophysiological characteristics of the participants in the marathon swimming competition during which the world record for the covering of the 101,4 km distance in the ice water was set and (2) to follow up the development of the stress response at different levels of the life support system. MATERIAL AND METHODS: A total of 22 participants in the competition were available for the examination designed to evaluate their psychological status and hemodynamic parameters as well as to determine the cortisol and serotonin levels in the blood sera of these subjects. RESULTS: The data obtained in this study give evidence that before the start and during the marathon distance swimming, only positive emotions prevailed among the participants whereas the setting of the world record was followed by the progressive development of the state of indifference. The dynamics of the Kerdo vegetative index suggests the balance between the functioning of the sympathetic and parasympathetic parts of the autonomous nervous system at the start of the competition and the prevalence of sympathetic activity in the autonomic nervous system at its finish. The dynamics of the level of cortisol in the serum indicates the presence of a stress. CONCLUSIONS: Despite the lack of the proper sports training, the participants in the marathon distance swimming competition proved capable of overcoming a variety of physical and psychological workloads which made it possible to set the world record. On the one hand, this confirms that the experience with winter swimming gained during a few years is sufficient to enable the swimmers to participate in such events. On the other hand, the results of the study give the idea of the 'price' to be paid by the physiological and psychological components of the life support system of the participants in the marathon distance swimming competitions seeking to set a world record. PMID- 29985383 TI - [The pilot studies for the development of the combined methods of rehabilitation of the patients as exemplified by the application of phyto- and physiotherapeutic modalities]. AB - Under the modern market conditions, the process of development of the methods for the combined rehabilitation of the patients is becoming increasingly more complicated. For the reduction of potential risks and leveling the factors responsible for the uncertain market situation influencing the creation of new methods, it is necessary to carry out the full-scale pilot studies with the use of the marketing analysis methods. The objective of the present work was to create and elaborate the rationale for the graphological structure (the scheme) of the process of exploratory research with a view to the development of the combined rehabilitation methods as exemplified by phyto- and physiotherapeutic modalities. The work is based on the application of the existing approaches to the structural, comparative, systemic, and situational analyses. The proposed graphological structure (scheme) of the exploratory research process consists of 6 stages. Its distinctive features are as follows: a fractional stage by stage evaluation of a variety of issues including the study of physical factors, characteristic of the means of herbal medicine with special reference to the mechanisms of their production and application under the current market conditions, monitoring the marketing environment with the constant focus on the trends and behavior of the target market, the parallel pursuing of serial studies with the application of the iterative procedures; the use of the previously created data bank to expand medical services at the stages of development and maturation of the life cycle, the evaluation of the possibility of establishment of the industry of parapharmaceutical products. PMID- 29985384 TI - [The medicinal mineral waters in the southern part of the Tyumen region]. AB - This article presents data concerning the natural medicinal resources in the southern part of the Tyumen region with special reference to the mineral water resources. The relevance of the work is determined by the presence of the huge deposits of medicinal sodium chloride and iodine-bromine thermal waters with the composition highly enriched in the trace elements suitable for the internal and external use and by the necessity of the assessment of their therapeutic value. The characteristics of the mineral waters of special interest are presented with the major emphasis placed on the chemical composition of sodium chloride waters used by the authors in the routine medical practice. The concrete results of the studiesdesigned to determine content of anions, cations, and trace elements in the water are reported. Taken together the high levels of iodine, bromine, and silica in mineral waters and their naturally high temperature provide a basis for their extensive and efficient application as a balneotherapeutic factor to be used for the purpose of the spa and health resort-based treatment and prophylaxis. Also, it opens up the prospects for the extension of the medical indications for the use of mineral waters the basis for further detailed study with a view to increasing medical evidence and taking into account regional particularities of natural iodine deficiency. Study of the action of trace elements of natural mineral waters taking into consideration the specific regional features of the territory in question, such as natural iodine deficiency. The study of the action of the microelements on the human organism in the cases of their combined application as well as the evaluation of their use for the prophylactic purposes constitutes an important scientific and practical problem. PMID- 29985385 TI - [The Kiran health resort in the Republic of Buryatia: the past and the present]. AB - This article presents the overview of the history of the Kiran health resort located in the Kyakhta district of the Republic of Buryatia at the shore of Lake Kiran. The Kiran health resort which has the 167-year history is one of the oldest resorts in Siberia and the Far East. The foundation of the resort dates back to 1850 when the first clinic for the soldiers and Cossacks of the Siberian Linear Battalion was set up on the lake shore. It existed till 1862. In 1885, the industrial use of the lake waters began for the extraction of table salt and caustic soda. This practice lasted for more than forty years and ceased only in 1928 when the further production of these substances was considered to be unprofitable and the resources of raw materials became depleted. During the Soviet period, the Kiran health resort has been functioning on the lake shore since 1924 until 1949 when the mud baths were constructed and opened. At present, the resort is going through bad times, and its modernization is urgently needed if its valuable curative factors are to be preserved. It will require the adequate governmental and private investments. To evaluate the prospects for the functioning of the health resort in the future, it is necessary to carry out a series of comprehensive investigations aimed at the assessment of its present-day potential. The Kiran health resort has the promising prospects for the further development, taking into consideration the demands for the treatment and rehabilitation of the population of Siberia and the Far East based on the available experience with the management of various pathological conditions. PMID- 29985386 TI - Evolutionary and expression analysis of CAMTA gene family in Nicotiana tabacum yielded insights into their origin, expansion and stress responses. AB - Calmodulin-binding transcription activators (CAMTAs) represent the novel gene family of transcriptional regulators, which play important biological functions. Though, the first ever plant CAMTA gene was evidenced in Nicotiana tabacum in 2002. But, the systematic identification, origin and function of this gene family has not been performed due to the lack of reference genome information until now. Here, we identified 29 CAMTA genes in four Nicotiana species, including thirteen NtabCAMTAs, six NsylCAMTAs, and five NtomCAMTAs and NbenCAMTAs. These CAMTA families were classified into five phylogenetic groups (I-V), among which, the group-IV CAMTAs probably emerged the earliest. The NtabCAMTA family genes have diverse structures, and are randomly localized on five chromosomes and scaffolds. N. tabacum acquired 11 copies of homolog CAMATA genes from the parental genomes of N. tomentosiformis and N. sylvestris, followed by expansion through polyploidization and duplication. The NtabCAMTA genes were differentially expressed in different plant parts, and showed sensitivity towards different abiotic and biotic stresses. Co-expression network analysis revealed that some NtabCAMTA subunits interact with each other, and co-expressed. The current study is the first report presenting a comprehensive overview of Nicotiana CAMTA families, and opens a new avenue for the improvement of the cultivated tobacco. PMID- 29985387 TI - The impact of stimulus size and orientation on individual face coding in monkey face-selective cortex. AB - Face-selective neurons in the monkey temporal cortex discharge at different rates in response to pictures of different individual faces. Here we tested whether this pattern of response across single neurons in the face-selective area ML (located in the middle Superior Temporal Sulcus) tolerates two affine transformations; picture-plane inversion, known to decrease the average response of face-selective neurons and the other, stimulus size. We recorded the response of 57 ML neurons in two awake and fixating monkeys. Face stimuli were presented at two sizes (10 and 5 degrees of visual angle) and two orientations (upright and inverted). Different faces elicited distinct patterns of activity across ML neurons that were reliable (i.e., predictable with a classifier) within a specific size and orientation condition. Despite observing a reduction in the average response magnitude of face-selective neurons to inverted faces, compared to upright faces, classifier performance was above chance for both upright and inverted faces. While decoding was largely preserved across changes in stimulus size, a classifier trained with one orientation condition and tested on the other did not lead to performance above chance level. We conclude that different individual faces can be decoded from patterns of responses in the monkey area ML regardless of orientation or size, but with qualitatively different patterns of responses for upright and inverted faces. PMID- 29985388 TI - Targeting TRPV1 to relieve motion sickness symptoms in mice by electroacupuncture and gene deletion. AB - Motion sickness (MS) is an acute disorder that occurs in healthy individuals worldwide regardless of gender, age, or ethnicity. Our study used a mouse model to rule out the effects of any psychological factors related to MS and EA. Subjects were randomly separated into four groups, namely the control group (Con), motion sickness inducing group (MS), mentioning sickness inducing with electroacupuncture treatment group (EA) and motion sickness inducing only in TRPV1 knockout mice group (TRPV1-/-). The consumption of kaolin, a non-nutrient substance, was measured as a behavior observed response of an emetic reflex in a murine model. This behavior is referred to as pica behavior. Our results showed that pica behavior was observed in the MS group. Moreover, kaolin consumption in the EA group decreased to the average baseline of the control group. A similar result was observed in TRPV1 null mice. We also observed an increase of TRPV1 and related molecules in the thalamus, hypothalamic and brain stem after MS stimulation and a significant decrease in the EA and TRPV1 null groups. This is the first study to demonstrate that TRPV1 pathways are possibly associated with mechanisms of MS, and can be attended through EA or TRPV1 genetic manipulation. PMID- 29985389 TI - Publisher Correction: Computational identification of specific genes for glioblastoma stem-like cells identity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29985390 TI - Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates. AB - Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of murine leukemia virus-driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel statistical approaches for identifying selected mutations and yields a high-resolution, genome-wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening of two BCL2 transgenic models confirmed known drivers of human non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features independently of local variance in mutation density also provides support for weakly evidenced cancer genes. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset. PMID- 29985391 TI - Assembly and activation of the Hippo signalome by FAT1 tumor suppressor. AB - Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes. PMID- 29985392 TI - Priming of dendritic cells by DNA-containing extracellular vesicles from activated T cells through antigen-driven contacts. AB - Interaction of T cell with antigen-bearing dendritic cells (DC) results in T cell activation, but whether this interaction has physiological consequences on DC function is largely unexplored. Here we show that when antigen-bearing DCs contact T cells, DCs initiate anti-pathogenic programs. Signals of this interaction are transmitted from the T cell to the DC, through extracellular vesicles (EV) that contain genomic and mitochondrial DNA, to induce antiviral responses via the cGAS/STING cytosolic DNA-sensing pathway and expression of IRF3 dependent interferon regulated genes. Moreover, EV-treated DCs are more resistant to subsequent viral infections. In summary, our results show that T cells prime DCs through the transfer of exosomal DNA, supporting a specific role for antigen dependent contacts in conferring protection to DCs against pathogen infection. The reciprocal communication between innate and adaptive immune cells thus allow efficacious responses to unknown threats. PMID- 29985393 TI - TCR signal strength controls thymic differentiation of iNKT cell subsets. AB - During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells. PMID- 29985394 TI - Heterogeneity in tumor chromatin-doxorubicin binding revealed by in vivo fluorescence lifetime imaging confocal endomicroscopy. AB - We present an approach to quantify drug-target engagement using in vivo fluorescence endomicroscopy, validated with in vitro measurements. Doxorubicin binding to chromatin changes the fluorescence lifetime of histone-GFP fusions that we measure in vivo at single-cell resolution using a confocal laparo/endomicroscope. We measure both intra- and inter-tumor heterogeneity in doxorubicin chromatin engagement in a model of peritoneal metastasis of ovarian cancer, revealing striking variation in the efficacy of doxorubicin-chromatin binding depending on intra-peritoneal or intravenous delivery. Further, we observe significant variations in doxorubicin-chromatin binding between different metastases in the same mouse and between different regions of the same metastasis. The quantitative nature of fluorescence lifetime imaging enables direct comparison of drug-target engagement for different drug delivery routes and between in vitro and in vivo experiments. This uncovers different rates of cell killing for the same level of doxorubicin binding in vitro and in vivo. PMID- 29985395 TI - Voltage-Controlled Magnetic Anisotropy in Fe1-xCox/Pd/MgO system. AB - Voltage-controlled magnetic anisotropy (VCMA) in an epitaxially grown Fe/Fe1 xCox/Pd/MgO system was investigated using spin-wave spectroscopy. The spin-wave resonant frequency linearly depended on the bias-voltage. The resonant-frequency shift increased with the Co fraction in Fe1-xCox/Pd. We achieved a VCMA of approximately 250 fJ/Vm at the Co/Pd/MgO region. PMID- 29985396 TI - Prolonged phloem ingestion by Diaphorina citri nymphs compared to adults is correlated with increased acquisition of citrus greening pathogen. AB - Citrus greening disease (huanglongbing), currently the most destructive citrus disease worldwide, is putatively caused by Candidatus Liberibacter asiaticus (CLas), a phloem-limited bacterium transmitted by the Asian citrus psyllid Diaphorina citri. Electrical penetration graph (EPG) recordings over 42 h were performed to compare the feeding behavior of D. citri adults and 4th or 5th instar nymphs feeding on CLas-infected or healthy citron plants. Nymphs performed more individual bouts of phloem ingestion (E2) and recorded longer phloem ingestion total time compared with adults, whereas adults performed more bouts of xylem ingestion (G) and recorded greater total time of xylem ingestion compared with nymphs. Quantitative polymerase chain reaction tests indicated that 58% of nymphs and 6% of adults acquired CLas during the 42 h EPG-recorded feeding on infected plants. In a histological study, a greater proportion of salivary sheaths produced by nymphs were branched compared to those of the adults. Our results strongly suggest that more bouts and longer feeding time in the phloem by nymphs may explain their more efficient CLas acquisition from infected plants compared to adults. This is the first EPG study comparing nymphs and adults of D. citri on healthy and infected citrus plants in relation to CLas acquisition. PMID- 29985397 TI - Annexins induce curvature on free-edge membranes displaying distinct morphologies. AB - Annexins are a family of proteins characterized by their ability to bind anionic membranes in response to Ca2+-activation. They are involved in a multitude of cellular functions including vesiculation and membrane repair. Here, we investigate the effect of nine annexins (ANXA1-ANXA7, ANXA11, ANXA13) on negatively charged double supported membrane patches with free edges. We find that annexin members can be classified according to the membrane morphology they induce and matching a dendrogam of the annexin family based on full amino acid sequences. ANXA1 and ANXA2 induce membrane folding and blebbing initiated from membrane structural defects inside patches while ANXA6 induces membrane folding originating both from defects and from the membrane edges. ANXA4 and ANXA5 induce cooperative roll-up of the membrane starting from free edges, producing large rolls. In contrast, ANXA3 and ANXA13 roll the membrane in a fragmented manner producing multiple thin rolls. In addition to rolling, ANXA7 and ANXA11 are characterized by their ability to form fluid lenses localized between the membrane leaflets. A shared feature necessary for generating these morphologies is the ability to induce membrane curvature on free edged anionic membranes. Consequently, induction of membrane curvature may be a significant property of the annexin protein family that is important for their function. PMID- 29985398 TI - Mass Cytometry Reveals Distinct Platelet Subtypes in Healthy Subjects and Novel Alterations in Surface Glycoproteins in Glanzmann Thrombasthenia. AB - Mass cytometry (MC) uses mass spectrometry to simultaneously detect multiple metal-conjugated antibodies on single cells, thereby enabling the detailed study of cellular function. Here, for the first time, we applied MC to the analysis of platelets. We developed a panel of 14 platelet-specific metal-tagged antibodies (targeting cluster of differentiation [CD] 9, CD29, CD31, CD36, CD41, CD42a, CD42b, CD61, CD62P, CD63, CD107a, CD154, glycoprotein [GP] VI and activated integrin alphaIIbbeta3) and compared this panel with two fluorescence flow cytometry (FFC) panels (CD41, CD42b, and CD61; or CD42b, CD62P, and activated integrin alphaIIbbeta3) in the evaluation of activation-dependent changes in glycoprotein expression on healthy subject and Glanzmann thrombasthenia (GT) platelets. High-dimensional analysis of surface markers detected by MC identified previously unappreciated subpopulations of platelets in healthy donors. As expected, MC and FFC revealed that GT platelets had significantly reduced CD41, CD61, and activated integrin alphaIIbbeta3 surface expression. MC also revealed that surface expression of CD9, CD42a and CD63 were elevated, CD31, CD154 and GPVI were reduced and CD29, CD36, CD42b, CD62P and CD107a were similar on GT platelets compared to healthy donor platelets. In summary, MC revealed distinct platelet subtypes in healthy subjects and novel alterations in surface glycoproteins on GT platelets. PMID- 29985399 TI - N-mixture models reliably estimate the abundance of small vertebrates. AB - Accurate measures of species abundance are essential to identify conservation strategies. N-mixture models are increasingly used to estimate abundance on the basis of species counts. In this study we tested whether abundance estimates obtained using N-mixture models provide consistent results with more traditional approaches requiring capture (capture-mark recapture and removal sampling). We focused on endemic, threatened species of amphibians and reptiles in Italy, for which accurate abundance data are needed for conservation assessments: the Lanza's Alpine salamander Salamandra lanzai, the Ambrosi's cave salamander Hydromantes ambrosii and the Aeolian wall lizard Podarcis raffonei. In visual counts, detection probability was variable among species, ranging between 0.14 (Alpine salamanders) and 0.60 (cave salamanders). For all the species, abundance estimates obtained using N-mixture models showed limited differences with the ones obtained through capture-mark-recapture or removal sampling. The match was particularly accurate for cave salamanders in sites with limited abundance and for lizards, nevertheless non-incorporating heterogeneity of detection probability increased bias. N-mixture models provide reliable abundance estimates that are comparable with the ones of more traditional approaches, and offer additional advantages such as a smaller sampling effort and no need of manipulating individuals, which in turn reduces the risk of harming animals and spreading diseases. PMID- 29985400 TI - The effectiveness of virtual reality based interventions for symptoms of anxiety and depression: A meta-analysis. AB - We report a meta-analysis of virtual reality (VR) interventions for anxiety and depression outcomes, as well as treatment attrition. We included randomized controlled trials comparing VR interventions, alone or in combination, to control conditions or other active psychological interventions. Effects sizes (Hedges' g) for anxiety and depression outcomes, as post-test and follow-up, were pooled with a random-effects model. Drop-outs were compared using odds ratio (OR) with a Mantel-Haenszel model. We included 39 trials (52 comparisons). Trial risk of bias was unclear for most domains, and high for incomplete outcome data. VR-based therapies were more effective than control at post-test for anxiety, g = 0.79, 95% CI 0.57 to 1.02, and depression, g = 0.73, 95% CI 0.25 to 1.21, but not for treatment attrition, OR = 1.34, 95% CI 0.95 to 1.89. Heterogeneity was high and there was consistent evidence of small study effects. There were no significant differences between VR-based and other active interventions. VR interventions outperformed control conditions for anxiety and depression but did not improve treatment drop-out. High heterogeneity, potential publication bias, predominant use of waitlist controls, and high or uncertain risk of bias of most trials question the reliability of these effects. PMID- 29985401 TI - Gut microbiota associations with common diseases and prescription medications in a population-based cohort. AB - The human gut microbiome has been associated with many health factors but variability between studies limits exploration of effects between them. Gut microbiota profiles are available for >2700 members of the deeply phenotyped TwinsUK cohort, providing a uniform platform for such comparisons. Here, we present gut microbiota association analyses for 38 common diseases and 51 medications within the cohort. We describe several novel associations, highlight associations common across multiple diseases, and determine which diseases and medications have the greatest association with the gut microbiota. These results provide a reference for future studies of the gut microbiome and its role in human health. PMID- 29985402 TI - Detecting intermittent switching leadership in coupled dynamical systems. AB - Leader-follower relationships are commonly hypothesized as a fundamental mechanism underlying collective behaviour in many biological and physical systems. Understanding the emergence of such behaviour is relevant in science and engineering to control the dynamics of complex systems toward a desired state. In prior works, due in part to the limitations of existing methods for dissecting intermittent causal relationships, leadership is assumed to be consistent in time and space. This assumption has been contradicted by recent progress in the study of animal behaviour. In this work, we leverage information theory and time series analysis to propose a novel and simple method for dissecting changes in causal influence. Our approach computes the cumulative influence function of a given individual on the rest of the group in consecutive time intervals and identify change in the monotonicity of the function as a change in its leadership status. We demonstrate the effectiveness of our approach to dissect potential changes in leadership on self-propelled particles where the emergence of leader-follower relationship can be controlled and on tandem flights of birds recorded in their natural environment. Our method is expected to provide a novel methodological tool to further our understanding of collective behaviour. PMID- 29985403 TI - Genome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development. AB - Genome-wide analysis of transcription in the malaria parasite Plasmodium falciparum has revealed robust variation in steady-state mRNA abundance throughout the 48-h intraerythrocytic developmental cycle (IDC), suggesting that this process is highly dynamic and tightly regulated. Here, we utilize rapid 4 thiouracil (4-TU) incorporation via pyrimidine salvage to specifically label, capture, and quantify newly-synthesized RNA transcripts at every hour throughout the IDC. This high-resolution global analysis of the transcriptome captures the timing and rate of transcription for each newly synthesized mRNA in vivo, revealing active transcription throughout all IDC stages. Using a statistical model to predict the mRNA dynamics contributing to the total mRNA abundance at each timepoint, we find varying degrees of transcription and stabilization for each mRNA corresponding to developmental transitions. Finally, our results provide new insight into co-regulation of mRNAs throughout the IDC through regulatory DNA sequence motifs, thereby expanding our understanding of P. falciparum mRNA dynamics. PMID- 29985404 TI - Microtubule minus-end aster organization is driven by processive HSET-tubulin clusters. AB - Higher-order structures of the microtubule (MT) cytoskeleton are comprised of two architectures: bundles and asters. Although both architectures are critical for cellular function, the molecular pathways that drive aster formation are poorly understood. Here, we study aster formation by human minus-end-directed kinesin-14 (HSET/KIFC1). We show that HSET is incapable of forming asters from preformed, nongrowing MTs, but rapidly forms MT asters in the presence of soluble (non-MT) tubulin. HSET binds soluble (non-MT) tubulin via its N-terminal tail domain to form heterogeneous HSET-tubulin clusters containing multiple motors. Cluster formation induces motor processivity and rescues the formation of asters from nongrowing MTs. We then show that excess soluble (non-MT) tubulin stimulates aster formation in HeLa cells overexpressing HSET during mitosis. We propose a model where HSET can toggle between MT bundle and aster formation in a manner governed by the availability of soluble (non-MT) tubulin. PMID- 29985405 TI - An InP-based vortex beam emitter with monolithically integrated laser. AB - Semiconductor devices capable of generating a vortex beam with a specific orbital angular momentum (OAM) order are highly attractive for applications ranging from nanoparticle manipulation, imaging and microscopy to fiber and quantum communications. In this work, an electrically pumped integrated OAM emitter operating at telecom wavelengths is fabricated by monolithically integrating an optical vortex emitter with a distributed feedback laser on the same InGaAsP/InP epitaxial wafer. A single-step dry-etching process is adopted to complete the OAM emitter, equipped with specially designed top gratings. The vortex beam emitted by the integrated device is captured and its OAM mode purity characterized. The integrated OAM emitter eliminates the external laser required by silicon- or silicon-on-insulator-based OAM emitters, thus demonstrating great potential for applications in communication systems and the quantum domain. PMID- 29985407 TI - Crystal and melt inclusion timescales reveal the evolution of magma migration before eruption. AB - Volatile element concentrations measured in melt inclusions are a key tool used to understand magma migration and degassing, although their original values may be affected by different re-equilibration processes. Additionally, the inclusion bearing crystals can have a wide range of origins and ages, further complicating the interpretation of magmatic processes. To clarify some of these issues, here we combined olivine diffusion chronometry and melt inclusion data from the 2008 eruption of Llaima volcano (Chile). We found that magma intrusion occurred about 4 years before the eruption at a minimum depth of approximately 8 km. Magma migration and reaction became shallower with time, and about 6 months before the eruption magma reached 3-4 km depth. This can be linked to reported seismicity and ash emissions. Although some ambiguities of interpretation still remain, crystal zoning and melt inclusion studies allow a more complete understanding of magma ascent, degassing, and volcano monitoring data. PMID- 29985406 TI - AAVvector-mediated in vivo reprogramming into pluripotency. AB - In vivo reprogramming of somatic cells into induced pluripotent stem cells (iPSC) holds vast potential for basic research and regenerative medicine. However, it remains hampered by a need for vectors to express reprogramming factors (Oct-3/4, Klf4, Sox2, c-Myc; OKSM) in selected organs. Here, we report OKSM delivery vectors based on pseudotyped Adeno-associated virus (AAV). Using the AAV-DJ capsid, we could robustly reprogram mouse embryonic fibroblasts with low vector doses. Swapping to AAV8 permitted to efficiently reprogram somatic cells in adult mice by intravenous vector delivery, evidenced by hepatic or extra-hepatic teratomas and iPSC in the blood. Notably, we accomplished full in vivo reprogramming without c-Myc. Most iPSC generated in vitro or in vivo showed transcriptionally silent, intronic or intergenic vector integration, likely reflecting the increased host genome accessibility during reprogramming. Our approach crucially advances in vivo reprogramming technology, and concurrently facilitates investigations into the mechanisms and consequences of AAV persistence. PMID- 29985408 TI - Thermally assisted self-healing behavior of anhydride modified polybenzoxazines based on transesterification. AB - A self-healing polybenzoxazine is synthesized solely based on dynamic ester bonds. For this purpose, an anhydride (succinic anhydride) was added into bisphenol F derived benzoxazine monomer before thermocuring. Owing to the transesterification of newly formed ester bonds, the thermoset network behaves as a thermoplastic at 140 degrees C in the presence of Zn (Ac)2, and shows self healing properties even after multiple damage-healing cycles. Furthermore, kinetics study indicates that the transesterification is a first-order reaction and the activation energy is about 135.4 kJ/mol. This study proposes a facile and economical way to prepare self-healing polybenzoxazine. It has promising applications in coating, adhesive, and other smart materials that rely on structurally dynamic polymers. PMID- 29985409 TI - LtpA, a CdnL-type CarD regulator, is important for the enzootic cycle of the Lyme disease pathogen. AB - Little is known about how Borrelia burgdorferi, the Lyme disease pathogen, adapts and survives in the tick vector. We previously identified a bacterial CarD N terminal-like (CdnL) protein, LtpA (BB0355), in B. burgdorferi that is preferably expressed at lower temperatures, which is a surrogate condition mimicking the tick portion of the enzootic cycle of B. burgdorferi. CdnL-family proteins, an emerging class of bacterial RNAP-interacting transcription factors, are essential for the viability of Mycobacterium tuberculosis and Myxococcus xanthus. Previous attempts to inactivate ltpA in B. burgdorferi have not been successful. In this study, we report the construction of a ltpA mutant in the infectious strain of B. burgdorferi, strain B31-5A4NP1. Unlike CdnL in M. tuberculosis and M. xanthus, LtpA is dispensable for the viability of B. burgdorferi. However, the ltpA mutant exhibits a reduced growth rate and a cold-sensitive phenotype. We demonstrate that LtpA positively regulates 16S rRNA expression, which contributes to the growth defects in the ltpA mutant. The ltpA mutant remains capable of infecting mice, albeit with delayed infection. Additionally, the ltpA mutant produces markedly reduced spirochetal loads in ticks and was not able to infect mice via tick infection. Overall, LtpA represents a novel regulator in the CdnL family that has an important role in the enzootic cycle of B. burgdorferi. PMID- 29985410 TI - Optimization of a MT1-MMP-targeting Peptide and Its Application in Near-infrared Fluorescence Tumor Imaging. AB - Membrane type 1 metalloproteinase (MT1-MMP) is an important regulator of cancer invasion, growth and angiogenesis, thus making it an attractive target for cancer imaging and therapy. A non-substrate peptide (MT1-AF7p) that bonded to the "MT Loop" region of MT1-MMP was identified by using a phage-displayed peptide library and was used to image the MT1-MMP expression in vivo through optical imaging. However, the substrate in the screening did not have a 3D structure, thus resulting in a loose bonding of MT1-AF7p. To simulate the real conformation of the "MT-Loop" and improve the performance of MT1-AF7p, molecular simulations were performed, because this strategy provides multiple methods for predicting the conformation and interaction of proteinase in 3D. In view of the binding site of the receptor-ligand interactions, histidine 4 was selected for mutation to achieve an increased affinity effect. The optimized peptides were further identified and conformed by atomic force microscopy, isothermal titration calorimetry, cell fluorescence imaging in vitro, and near-infrared fluorescence tumor optical imaging in vivo. The results revealed that the optimized peptide with a mutation of histidine 4 to arginine has the highest affinity and specificity, and exhibited an increased fluorescence intensity in the tumor site in optical imaging. PMID- 29985411 TI - Attentional fluctuations induce shared variability in macaque primary visual cortex. AB - Variability in neuronal responses to identical stimuli is frequently correlated across a population. Attention is thought to reduce these correlations by suppressing noisy inputs shared by the population. However, even with precise control of the visual stimulus, the subject's attentional state varies across trials. While these state fluctuations are bound to induce some degree of correlated variability, it is currently unknown how strong their effect is, as previous studies generally do not dissociate changes in attentional strength from changes in attentional state variability. We designed a novel paradigm that does so and find both a pronounced effect of attentional fluctuations on correlated variability at long timescales and attention-dependent reductions in correlations at short timescales. These effects predominate in layers 2/3, as expected from a feedback signal such as attention. Thus, significant portions of correlated variability can be attributed to fluctuations in internally generated signals, like attention, rather than noise. PMID- 29985412 TI - Evolution of tigecycline- and colistin-resistant CRKP (carbapenem-resistant Klebsiella pneumoniae) in vivo and its persistence in the GI tract. AB - Emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the blaKPC-2 and tet(A) variant genes readily evolve into tigecycline- and colistin-resistant CRKP upon treatment with these two antibiotics and persist in the human GI tract. PMID- 29985414 TI - Lateral optical confinement of GaN-based VCSEL using an atomically smooth monolithic curved mirror. AB - We demonstrate the lateral optical confinement of GaN-based vertical-cavity surface-emitting lasers (GaN-VCSELs) with a cavity containing a curved mirror that is formed monolithically on a GaN wafer. The output wavelength of the devices is 441-455 nm. The threshold current is 40 mA (Jth = 141 kA/cm2) under pulsed current injection (Wp = 100 ns; duty = 0.2%) at room temperature. We confirm the lateral optical confinement by recording near-field images and investigating the dependence of threshold current on aperture size. The beam profile can be fitted with a Gaussian having a theoretical standard deviation of sigma = 0.723 um, which is significantly smaller than previously reported values for GaN-VCSELs with plane mirrors. Lateral optical confinement with this structure theoretically allows aperture miniaturization to the diffraction limit, resulting in threshold currents far lower than sub-milliamperes. The proposed structure enabled GaN-based VCSELs to be constructed with cavities as long as 28.3 um, which greatly simplifies the fabrication process owing to longitudinal mode spacings of less than a few nanometers and should help the implementation of these devices in practice. PMID- 29985413 TI - Collective molecular switching in hybrid superlattices for light-modulated two dimensional electronics. AB - Molecular switches enable the fabrication of multifunctional devices in which an electrical output can be modulated by external stimuli. The working mechanism of these devices is often hard to prove, since the molecular switching events are only indirectly confirmed through electrical characterization, without real-space visualization. Here, we show how photochromic molecules self-assembled on graphene and MoS2 generate atomically precise superlattices in which a light induced structural reorganization enables precise control over local charge carrier density in high-performance devices. By combining different experimental and theoretical approaches, we achieve exquisite control over events taking place from the molecular level to the device scale. Unique device functionalities are demonstrated, including the use of spatially confined light irradiation to define reversible lateral heterojunctions between areas possessing different doping levels. Molecular assembly and light-induced doping are analogous for graphene and MoS2, demonstrating the generality of our approach to optically manipulate the electrical output of multi-responsive hybrid devices. PMID- 29985415 TI - A power law distribution of metabolite abundance levels in mice regardless of the time and spatial scale of analysis. AB - Biomolecule abundance levels change with the environment and enable a living system to adapt to the new conditions. Although, the living system maintains at least some characteristics, e.g. homeostasis. One of the characteristics maintained by a living system is a power law distribution of biomolecule abundance levels. Previous studies have pointed to a universal characteristic of biochemical reaction networks, with data obtained from lysates of multiple cells. As a result, the spatial scale of the data related to the power law distribution of biomolecule abundance levels is not clear. In this study, we researched the scaling law of metabolites in mouse tissue with a spatial scale of quantification that was changed stepwise between a whole-tissue section and a single-point analysis (25 MUm). As a result, metabolites in mouse tissues were found to follow the power law distribution independently of the spatial scale of analysis. Additionally, we tested the temporal changes by comparing data from younger and older mice. Both followed similar power law distributions, indicating that metabolite composition is not diversified by aging to disrupt the power law distribution. The power law distribution of metabolite abundance is thus a robust characteristic of a living system regardless of time and space. PMID- 29985416 TI - Glucose and glutamine handling in the Sertoli cells of transgenic rats overexpressing regucalcin: plasticity towards lactate production. AB - Sertoli cells (SCs) possess the unparalleled ability to provide the germ line with growth factors and nutrients. Although SCs can oxidize amino acids, e.g., glutamine, they mostly metabolize glucose, producing high amounts of lactate, the germ cells preferential substrate. Regucalcin (RGN) is a calcium-binding protein that has been indicated as a regulator of cell metabolism. In this study, we investigated glucose and glutamine handling in the SCs of transgenic rats overexpressing RGN (Tg-RGN) comparatively with wild-type (Wt) littermates. Primary SCs isolated from adult Tg-RGN animals and maintained in culture for 24 hours, produced and exported more lactate, despite consuming less glucose. These observations were underpinned by increased expression of alanine transaminase, and augmented glutamine consumption, suggesting that alternative routes are contributing to the enhanced lactate production in the SCs of Tg-RGN rats. Moreover, lactate seems to be used by germ cells, with diminished apoptosis being detected in the seminiferous tubules of Tg-RGN animals cultured ex vivo. The obtained results showed a distinct metabolism in the SCs of Wt and Tg-RGN rats widening the roles assigned to RGN in spermatogenesis. These findings also highlighted the plasticity of SCs metabolism, a feature that would be exploited in the context of male infertility. PMID- 29985417 TI - The inducible chemical-genetic fluorescent marker FAST outperforms classical fluorescent proteins in the quantitative reporting of bacterial biofilm dynamics. AB - To increase our understanding of bacterial biofilm complexity, real- time quantitative analyses of the living community functions are required. To reach this goal, accurate fluorescent reporters are needed. In this paper, we used the classical fluorescent genetic reporters of the GFP family and demonstrated their limits in the context of a living biofilm. We showed that fluorescence signal saturated after only a few hours of growth and related this saturation to the reduction of oxygen concentration induced by bacterial consumption. This behaviour prevents the use of GFP-like fluorescent proteins for quantitative measurement in living biofilms. To overcome this limitation, we propose the use of a recently introduced small protein tag, FAST, which is fluorescent in the presence of an exogenously applied fluorogenic dye, enabling to avoid the oxygen sensitivity issue. We compared the ability of FAST to report on biofilm growth with that of GFP and mCherry, and demonstrated the superiority of the FAST:fluorogen probes for investigating dynamics in the complex environment of a living biofilm. PMID- 29985418 TI - Propagule size and structure, life history, and environmental conditions affect establishment success of an invasive species. AB - Population dynamics of species that are recently introduced into a new area, e.g., invasive species and species of conservation concern that are translocated to support global populations, are likely to be dominated by short-term, transient effects. Wild pigs (Sus scrofa, or wild boar) are pulsed-resource consumers of mast nuts that are commonly introduced into new areas. We used vital rate data (i.e., survival and fecundity) for wild pigs in Germany under varying forage conditions to simulate transient population dynamics in the 10-years following introduction into a new environment. In a low forage environment (i.e., conditions similar to their native range), simulated wild pig populations maintained a stable population size with low probability of establishment, while in environments with better quality forage (i.e., conditions similar to parts of their invasive range), high juvenile fecundity and survival facilitated rapid population growth and establishment probability was high. We identified a strategy for simulating population dynamics of species whose reproduction and survival depend on environmental conditions that fluctuate and for predicting establishment success of species introduced into a new environment. Our approach can also be useful in projecting near-term transient population dynamics for many conservation and management applications. PMID- 29985419 TI - Interleukin 10 mutant zebrafish have an enhanced interferon gamma response and improved survival against a Mycobacterium marinum infection. AB - Tuberculosis ranks as one of the world's deadliest infectious diseases causing more than a million casualties annually. IL10 inhibits the function of Th1 type cells, and IL10 deficiency has been associated with an improved resistance against Mycobacterium tuberculosis infection in a mouse model. Here, we utilized M. marinum infection in the zebrafish (Danio rerio) as a model for studying Il10 in the host response against mycobacteria. Unchallenged, nonsense il10e46/e46 mutant zebrafish were fertile and phenotypically normal. Following a chronic mycobacterial infection, il10e46/e46 mutants showed enhanced survival compared to the controls. This was associated with an increased expression of the Th cell marker cd4-1 and a shift towards a Th1 type immune response, which was demonstrated by the upregulated expression of tbx21 and ifng1, as well as the down-regulation of gata3. In addition, at 8 weeks post infection il10e46/e46 mutant zebrafish had reduced expression levels of proinflammatory cytokines tnfb and il1b, presumably indicating slower progress of the infection. Altogether, our data show that Il10 can weaken the immune defense against M. marinum infection in zebrafish by restricting ifng1 response. Importantly, our findings support the relevance of M. marinum infection in zebrafish as a model for tuberculosis. PMID- 29985420 TI - beta-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-beta Aggregates. AB - Oligomers populated during the early amyloid aggregation process are more toxic than mature fibrils, but pinpointing the exact toxic species among highly dynamic and heterogeneous aggregation intermediates remains a major challenge. beta barrel oligomers, structurally-determined recently for a slow-aggregating peptide derived from alphaB crystallin, are attractive candidates for exerting amyloid toxicity due to their well-defined structures as therapeutic targets and compatibility to the "amyloid-pore" hypothesis of toxicity. To assess whether beta-barrel oligomers are common intermediates to amyloid peptides - a necessary step toward associating beta-barrel oligomers with general amyloid cytotoxicity, we computationally studied the oligomerization and fibrillization dynamics of seven well-studied fragments of amyloidogenic proteins with different experimentally-determined aggregation morphologies and cytotoxicity. In our molecular dynamics simulations, beta-barrel oligomers were only observed in five peptides self-assembling into the characteristic cross-beta aggregates, but not the other two that formed polymorphic beta-rich aggregates as reported experimentally. Interestingly, the latter two peptides were previously found nontoxic. Hence, the observed correlation between beta-barrel oligomers formation and cytotoxicity supports the hypothesis of beta-barrel oligomers as the common toxic intermediates of amyloid aggregation. PMID- 29985421 TI - Repurposing drugs to target the malaria parasite unfolding protein response. AB - Drug resistant Plasmodium falciparum parasites represent a major obstacle in our efforts to control malaria, a deadly vector borne infectious disease. This situation creates an urgent need to find and validate new drug targets to contain the spread of the disease. Several genes associated with the unfolded protein response (UPR) including Glucose-regulated Protein 78 kDa (GRP78, also known as BiP) have been deemed potential drug targets. We explored the drug target potential of GRP78, a molecular chaperone that is a regulator of the UPR, for the treatment of P. falciparum parasite infection. By screening repurposed chaperone inhibitors that are anticancer agents, we showed that GRP78 inhibition is lethal to drug-sensitive and -resistant P. falciparum parasite strains in vitro. We correlated the antiplasmodial activity of the inhibitors with their ability to bind the malaria chaperone, by characterizing their binding to recombinant parasite GRP78. Furthermore, we determined the crystal structure of the ATP binding domain of P. falciparum GRP78 with ADP and identified structural features unique to the parasite. These data suggest that P. falciparum GRP78 can be a valid drug target and that its structural differences to human GRP78 emphasize potential to generate parasite specific compounds. PMID- 29985422 TI - The active site residues Gln55 and Arg73 play a key role in DNA damage bypass by S. cerevisiae Pol eta. AB - Eukaryotic DNA polymerase eta (Pol eta) plays a key role in the efficient and accurate DNA translesion synthesis (TLS) opposite UV-induced thymine dimers. Pol eta is also involved in bypass of many other DNA lesions but possesses low fidelity on undamaged DNA templates. To better understand the mechanism of DNA synthesis by Pol eta we investigated substitutions of evolutionary conserved active site residues Gln55 and Arg73 in Saccharomyces cerevisiae Pol eta. We analyzed the efficiency and fidelity of DNA synthesis by the mutant Pol eta variants opposite thymine dimers, abasic site, thymine glycol, 8-oxoguanine and on undamaged DNA. Substitutions Q55A and R73A decreased the catalytic activity and significantly affected DNA damage bypass by Pol eta. In particular, the Q55A substitution reduced the efficiency of thymine dimers bypass, R73A had a stronger effect on the TLS-activity opposite abasic site, while both substitutions impaired replication opposite thymine glycol. Importantly, the R73A substitution also increased the fidelity of Pol eta. Altogether, these results reveal a key role of residues Gln55 and Arg73 in DNA synthesis opposite various types of DNA lesions and highlight the evolutionary importance of the Pol eta TLS function at the cost of DNA replication accuracy. PMID- 29985423 TI - Role of the Renin Angiotensin System in Blood Pressure Allostasis-induced by Severe Food Restriction in Female Fischer rats. AB - Severe food restriction (FR) is associated with blood pressure (BP) and cardiovascular dysfunction. The renin-angiotensin system (RAS) regulates BP and its dysregulation contributes to impaired cardiovascular function. Female Fischer rats were maintained on a control (CT) or severe FR (40% of CT) diet for 14 days. In response to severe FR, BP allostasis was achieved by up-regulating circulating Ang-[1-8] by 1.3-fold through increased angiotensin converting enzyme (ACE) activity and by increasing the expression of AT1Rs 1.7-fold in mesenteric vessels. Activation of the RAS countered the depressor effect of the severe plasma volume reduction (>=30%). The RAS, however, still underperformed as evidenced by reduced pressor responses to Ang-[1-8] even though AT1Rs were still responsive to the depressor effects of an AT1R antagonist. The aldosterone (ALDO) response was also inadequate as no changes in plasma ALDO were observed after the large fall in plasma volume. These findings have implications for individuals who have experienced a period(s) of severe FR (e.g., anorexia nervosa, dieters, natural disasters) and suggests increased activity of the RAS in order to achieve allostasis contributes to the cardiovascular dysfunction associated with inadequate food intake. PMID- 29985424 TI - Soluble interleukin-27 receptor alpha is a valuable prognostic biomarker for acute graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. AB - Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic haematopoietic stem cell transplantation. Interleukin-27 receptor alpha (IL-27Ralpha) is a co-receptor of IL-27, an inflammatory cytokine that possesses extensive immunological functions. It has been reported that IL 27Ralpha can exist in its soluble form (sIL-27Ralpha) in human serum and can function as a natural IL-27 antagonist. In this study, we examined serum sIL 27Ralpha levels and evaluated their prognostic value in aGVHD. A total of 152 subjects were prospectively recruited and separated into the training group (n = 72) and the validation group (n = 80). Serum sIL-27Ralpha at neutrophil engraftment was measured by ELISA. In the training set, a cut-off value of sIL 27Ralpha = 59.40 ng/ml was identified to predict grade II-IV aGVHD (AUC = 0.735, 95% CI 0.618-0.853, P = 0.001). Cumulative incidences of grade II-IV aGVHD (P = 0.004), relapse rate (P = 0.008), and non-relapse mortality (P = 0.008) in patients with low serum sIL-27Ralpha (>=59.40 ng/ml) were significantly higher than those of patients with high serum sIL-27Ralpha (<59.40 ng/ml). Multivariate analysis confirmed that low sIL-27Ralpha level (HR = 2.83 95% CI 1.29-6.19, P < 0.01) was an independent risk factor for predicting grade II-IV aGVHD. In addition, serum sIL-27Ralpha was positively correlated with IL-27 (R = 0.27, P = 0.029), IL-10 (R = 0.37, P = 0.0015) and HGF (R = 0.27, P = 0.0208), but was negatively correlated with TNFR1 (R = -0.365, P = 0.0022) and ST2 (R = -0.334, P = 0.0041), elafin (R = -0.29, P = 0.0117), and REG3alpha (R = -0.417, P = 0.0003). More importantly, the threshold value of sIL-27Ralpha was then validated in an independent cohort of 80 patients (AUC = 0.790, 95% CI 0.688-0.892, P < 0.001). Taken together, our findings suggested that serum sIL-27Ralpha at neutrophil engraftment maybe a valuable prognostic biomarker in predicting the incidence of moderate-to-severe aGVHD. PMID- 29985425 TI - Structural and functional characterization of suramin-bound MjTX-I from Bothrops moojeni suggests a particular myotoxic mechanism. AB - Local myonecrosis is the main event resulting from snakebite envenomation by the Bothrops genus and, frequently, it is not efficiently neutralized by antivenom administration. Proteases, phospholipases A2 (PLA2) and PLA2-like toxins are found in venom related to muscle damage. Functional sites responsible for PLA2 like toxins activity have been proposed recently; they consist of a membrane docking-site and a membrane rupture-site. Herein, a combination of functional, biophysical and crystallographic techniques was used to characterize the interaction between suramin and MjTX-I (a PLA2-like toxin from Bothrops moojeni venom). Functional in vitro neuromuscular assays were performed to study the biological effects of the protein-ligand interaction, demonstrating that suramin neutralizes the myotoxic effect of MjTX-I. Calorimetric assays showed two different binding events: (i) inhibitor-protein interactions and (ii) toxin oligomerization processes. These hypotheses were also corroborated with dynamic light and small angle X-ray scattering assays. The crystal structure of the MjTX I/suramin showed a totally different interaction mode compared to other PLA2 like/suramin complexes. Thus, we suggested a novel myotoxic mechanism for MjTX-I that may be inhibited by suramin. These results can further contribute to the search for inhibitors that will efficiently counteract local myonecrosis in order to be used as an adjuvant of conventional serum therapy. PMID- 29985426 TI - Thyroid cancer cells in space during the TEXUS-53 sounding rocket mission - The THYROID Project. AB - Human follicular thyroid cancer cells (FTC-133) were sent to space via a sounding rocket during the TEXUS-53 mission to determine the impact of short-term microgravity on these cells. To enable cell culture and fixation in real microgravity, an automated experiment container (EC) was constructed. In order to ensure safe cell culture, cell-chambers consisting of polycarbonate (PC) material were used. They were highly biocompatible as proved by measuring cell survival using Annexin V flow cytometry. In the follow-up experiment, FTC-133 cells were sent to space via a sounding rocket and were fixed before and after the microgravity (ug) phase with RNAlater. In addition, cells were tested for reactions on hypergravity (hyper-g) as much as 18 g to determine whether worst case acceleration during launch can have an influence on the cells. We investigated genes belonging to biological processes such as cytoskeleton, cell adhesion, tumor growth, angiogenesis and apoptosis. Pathway analyses revealed central functions of VEGFA and EGF. EGF upregulates aspartate beta-hydroxylase (ASPH) which is influencing CASP3. Hyper-g induced a significant up-regulation of TUBB1, VIM, RDX, CAV1, VEGFA and BCL2. FTC-133 cells grown in an automated EC exposed to ug revealed moderate gene expression changes indicating their survival in orbit. PMID- 29985428 TI - Dynamic behavior of DNA topoisomerase IIbeta in response to DNA double-strand breaks. AB - DNA topoisomerase II (Topo II) is crucial for resolving topological problems of DNA and plays important roles in various cellular processes, such as replication, transcription, and chromosome segregation. Although DNA topology problems may also occur during DNA repair, the possible involvement of Topo II in this process remains to be fully investigated. Here, we show the dynamic behavior of human Topo IIbeta in response to DNA double-strand breaks (DSBs), which is the most harmful form of DNA damage. Live cell imaging coupled with site-directed DSB induction by laser microirradiation demonstrated rapid recruitment of EGFP-tagged Topo IIbeta to the DSB site. Detergent extraction followed by immunofluorescence showed the tight association of endogenous Topo IIbeta with DSB sites. Photobleaching analysis revealed that Topo IIbeta is highly mobile in the nucleus. The Topo II catalytic inhibitors ICRF-187 and ICRF-193 reduced the Topo IIbeta mobility and thereby prevented Topo IIbeta recruitment to DSBs. Furthermore, Topo IIbeta knockout cells exhibited increased sensitivity to bleomycin and decreased DSB repair mediated by homologous recombination (HR), implicating the role of Topo IIbeta in HR-mediated DSB repair. Taken together, these results highlight a novel aspect of Topo IIbeta functions in the cellular response to DSBs. PMID- 29985429 TI - Integer-dimensional fractals of nonlinear dynamics, control mechanisms, and physical implications. AB - Fractal dimensionality is accepted as a measure of complexity for systems that cannot be described by integer dimensions. However, fractal control mechanisms, physical implications, and relations to nonlinear dynamics have not yet been fully clarified. Herein we explore these issues in a spacetime using a nonlinear integrated model derived by applying Newton's second law into self-regulating systems. We discover that (i) a stochastic stable fixed point exhibits self similarity and long-term memory, while a deterministic stable fixed point usually only exhibits self-similarity, if our observation scale is large enough; (ii) stochastic/deterministic period cycles and chaos only exhibit long-term memory, but also self-similarity for even restorative delays; (iii) fractal level of a stable fixed point is controlled primarily by the wave indicators that reflect the relative strength of extrinsic to intrinsic forces: a larger absolute slope (smaller amplitude) indicator leads to higher positive dependence (self similarity), and a relatively large amplitude indicator or an even restorative delay could make the dependence oscillate; and (iv) fractal levels of period cycles and chaos rely on the intrinsic resistance, restoration, and regulative delays. Our findings suggest that fractals of self-regulating systems can be measured by integer dimensions. PMID- 29985427 TI - Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics. AB - Asthma is a chronic inflammatory disease process involving the conductive airways of the human lung. The dysregulated inflammatory response in this disease process may involve multiple cell-cell interactions mediated by signaling molecules, including lipid mediators. Extracellular vesicles (EVs) are lipid membrane particles that are now recognized as critical mediators of cell-cell communication. Here, we compared the lipid composition and presence of specific lipid mediators in airway EVs purified from the bronchoalveolar lavage (BAL) fluid of healthy controls and asthmatic subjects with and without second-hand smoke (SHS) exposure. Airway exosome concentrations were increased in asthmatics, and correlated with blood eosinophilia and serum IgE levels. Frequencies of HLA DR+ and CD54+ exosomes were also significantly higher in asthmatics. Lipidomics analysis revealed that phosphatidylglycerol, ceramide-phosphates, and ceramides were significantly reduced in exosomes from asthmatics compared to the non exposed control groups. Sphingomyelin 34:1 was more abundant in exosomes of SHS exposed asthmatics compared to healthy controls. Our results suggest that chronic airway inflammation may be driven by alterations in the composition of lipid mediators within airway EVs of human subjects with asthma. PMID- 29985430 TI - Fatty liver is associated with blood pathways of inflammatory response, immune system activation and prothrombotic state in Young Finns Study. AB - Fatty liver (FL) disease is the most common type of chronic liver disease. We hypothesized that liver's response to the process where large droplets of triglyceride fat accumulate in liver cells is reflected also in gene pathway expression in blood. Peripheral blood genome wide gene expression analysis and ultrasonic imaging of liver were performed for 1,650 participants (316 individuals with FL and 1,334 controls) of the Young Finns Study. Gene set enrichment analysis (GSEA) was performed for the expression data. Fourteen gene sets were upregulated (false discovery rate, FDR < 0.05) in subjects with FL. These pathways related to extracellular matrix (ECM) turnover, immune response regulation, prothrombotic state and neural tissues. After adjustment for known risk factors and biomarkers of FL, we found i) integrin A4B1 signaling, ii) leukocyte transendothelial migration, iii) CD40/CD40L and iv) netrin-1 signaling pathways to be upregulated in individuals with FL (nominal p < 0.05). From these all but not ii) remained significantly upregulated when analyzing only subjects without history of heavy alcohol use. In conclusion, FL was associated with blood gene sets of ECM turnover, inflammatory response, immune system activation and prothrombotic state. These may form a systemic link between FL and the development of cardiovascular diseases. PMID- 29985432 TI - A tRNS investigation of the sensory representation of time. AB - The understanding of the mechanisms underlying the representation of temporal intervals in the range of milliseconds/seconds remains a complex issue. Different brain areas have been identified as critical in temporal processing. The activation of specific areas is depending on temporal range involved in the tasks and on the modalities used for marking time. Here, for the first time, transcranial random noise stimulation (tRNS) was applied over the right posterior parietal (P4) and right frontal (F4) cortex to investigate their role in intra- and intermodal temporal processing involving brief temporal intervals (<1 sec). Eighty University students performed a time bisection task involving standard durations lasting 300 ms (short) and 900 ms (long). Each empty interval to be judged was marked by two successive brief visual (V) or auditory (A) signals defining four conditions: VV, VA, AV or AA. Participants were assigned to one of these four conditions. Half of the participants received tRNS over P4 and half over F4. No effect of stimulation was observed on temporal variability (Weber ratio). However, participants that were stimulated over P4 overestimated temporal intervals in the random condition compared to the sham condition. In addition to showing an effect of tRNS on perceived duration rather than on temporal variability, the results of the present study confirm that the right posterior parietal cortex is involved in the processing of time intervals and extend this finding to several sensory modality conditions. PMID- 29985431 TI - Physiological costs of infection: herpesvirus replication is linked to blood oxidative stress in equids. AB - Viruses may have a dramatic impact on the health of their animal hosts. The patho physiological mechanisms underlying viral infections in animals are, however, not well understood. It is increasingly recognized that oxidative stress may be a major physiological cost of viral infections. Here we compare three blood-based markers of oxidative status in herpes positive and negative individuals of the domestic horse (Equus ferus caballus) and of both captive and free-ranging Mongolian khulan (Equus hemionus hemionus) and plains zebra (Equus quagga). Herpes positive free-ranging animals had significantly more protein oxidative damage and lower glutathione peroxidase (antioxidant enzyme) than negative ones, providing correlative support for a link between oxidative stress and herpesvirus infection in free-living equids. Conversely, we found weak evidence for oxidative stress in herpes positive captive animals. Hence our work indicates that environment (captive versus free living) might affect the physiological response of equids to herpesvirus infection. The Mongolian khulan and the plains zebra are currently classified as near threatened by the International Union for Conservation of Nature. Thus, understanding health impacts of pathogens on these species is critical to maintaining viable captive and wild populations. PMID- 29985433 TI - Comparison of Systematic Ticagrelor-Based Dual Antiplatelet Therapy to Selective Triple Antithrombotic Therapy for Left Ventricle Dysfunction Following Anterior STEMI. AB - Antithrombotic management of STEMI patients with apical dysfunction, but without demonstrable thrombus, is controversial. Triple antithrombotic therapy (TATT, defined as the addition of oral anticoagulation to dual antiplatelet therapy, or DAPT) may be associated with increased bleeding, while DAPT alone may not adequately protect against cardio-embolic events. We undertook a dual-center study of anterior STEMI patients treated with primary PCI (pPCI) from 2013 to 2015 and presenting presumed new apical dysfunction. The Centre hospitalier de l'Universite de Montreal (CHUM) uses a strategy of selective TATT, whereas the Centre hospitalier universitaire de Sherbrooke (CHUS) has favored ticagrelor based DAPT for all patients since 2013. The primary composite outcome consisted of death, MI, stroke, revascularization, and BARC 3 to 5 bleeding up to 4-months follow-up. We identified 177 cases (69 CHUM; 108 CHUS). Baseline characteristics were similar and procedural success was high (97%). There was no difference in post-procedure LVEF (39 +/- 9% vs 37 +/- 9%) or the extent of apical dysfunction. The primary composite outcome occurred in 27% with the selective TATT strategy compared to 19% with ticagrelor-DAPT (p = 0.342). Thus, this retrospective dual center analysis does not support a strategy of conventional TATT over ticagrelor based DAPT for patients with apical dysfunction following anterior STEMI treated with pPCI. A pragmatic randomized trial is needed to provide a definitive answer to this clinical conundrum. PMID- 29985434 TI - Bacillus amyloliquefaciens strain MBI600 induces salicylic acid dependent resistance in tomato plants against Tomato spotted wilt virus and Potato virus Y. AB - Plant growth promoting rhizobacteria have been proposed as effective biocontrol agents against several fungal and bacterial plant pathogens. However, there is limited knowledge regarding their effect against viruses. In this study, Bacillus amyloliquefaciens strain MBI600 (MBI600), active ingredient of the biological fungicide Serifel(r) (BASF SE), was tested for its antiviral action in tomato plants. Drench, foliar or soil amendment applications of MBI600 reduced up to 80% the incidence of Tomato spotted wilt virus under two different sets of environmental conditions. In addition, drench application of MBI600 delayed Potato virus Y systemic accumulation. Transcriptional analysis of a range of genes associated with salicylic acid (SA)- or jasmonic acid - related defense, priming or basal defense against viruses, revealed the induction of the SA signaling pathway in tomato after MBI600 treatment, and discrete gene expression patterns in plant response to TSWV and PVY infection. PMID- 29985436 TI - Preservation of explicit learning of visuomotor sequences during Parkinson's disease progression. AB - While motor learning approaches are effective in rehabilitating Parkinson's disease (PD) patients, many studies reported deficits in sequential motor learning in these patients. We hypothesised that preserved explicit learning of visuomotor sequences in PD patients contributed to the effectiveness of motor learning approaches. However, there are very few studies analysing explicit learning of visuomotor sequences during the progression of PD. We investigated this phenomenon in 23 patients with moderate to severe PD (Hoehn-Yahr stages II IV) and 17 age-matched controls using sequential button-press tasks (2 * 5 task). We found (1) no significant differences in numbers of errors in the 2 * 5 task among control and PD groups. (2) There was a significant difference in response times while exploring correct sequences (ERT) among control and PD groups; ERTs in stage-IV patients tended to be longer than those of control and stage-II groups. (3) All four groups significantly improved their performance (i.e., reduced ERTs in the 2 * 5 task) with sequence repetition, although stage-III:IV patients were slower. Thus, even patients with severe PD can learn visual sequences and can translate them into visuomotor sequences (explicit visuomotor sequence learning), albeit slower than controls, providing evidence for effective motor learning approaches during rehabilitation of patients with advanced PD. PMID- 29985435 TI - Shifts of Faecal Microbiota During Sporadic Colorectal Carcinogenesis. AB - Gut microbiota has been implicated in the etiopathogenesis of colorectal cancer. The development of colorectal cancer is a multistep process by which healthy epithelium slowly develops into preneoplastic lesions, which in turn progress into malignant carcinomas over time. In particular, sporadic colorectal cancers can arise from adenomas (about 85% of cases) or serrated polyps through the "adenoma-carcinoma" or the "serrated polyp-carcinoma" sequences, respectively. In this study, we performed 16 S rRNA gene sequencing of bacterial DNA extracted from faecal samples to compare the microbiota of healthy subjects and patients with different preneoplastic and neoplastic lesions. We identified putative microbial biomarkers associated with stage-specific progression of colorectal cancer. In particular, bacteria belonging to the Firmicutes and Actinobacteria phyla, as well as members of the Lachnospiraceae family, proved to be specific of the faecal microbiota of patients with preneoplastic lesions, including adenomas and hyperplastic polyps. On the other hand, two families of the Proteobacteria phylum, Alcaligeneaceae and Enterobacteriaceae, with Sutterella and Escherichia/Shigella being the most representative genera, appeared to be associated with malignancy. These findings, once confirmed on larger cohorts of patients, can represent an important step towards the development of more effective diagnostic strategies. PMID- 29985437 TI - Hotspots within a global biodiversity hotspot - areas of endemism are associated with high mountain ranges. AB - Conservation biology aims at identifying areas of rich biodiversity. Currently recognized global biodiversity hotspots are spatially too coarse for conservation management and identification of hotspots at a finer scale is needed. This might be achieved by identification of areas of endemism. Here, we identify areas of endemism in Iran, a major component of the Irano-Anatolian biodiversity hotspot, and address their ecological correlates. Using the extremely diverse sunflower family (Asteraceae) as our model system, five consensus areas of endemism were identified using the approach of endemicity analysis. Both endemic richness and degree of endemicity were positively related to topographic complexity and elevational range. The proportion of endemic taxa at a certain elevation (percent endemism) was not congruent with the proportion of total surface area at this elevation, but was higher in mountain ranges. While the distribution of endemic richness (i.e., number of endemic taxa) along an elevational gradient was hump shaped peaking at mid-elevations, the percentage of endemism gradually increased with elevation. Patterns of endemic richness as well as areas of endemism identify mountain ranges as main centres of endemism, which is likely due to high environmental heterogeneity and strong geographic isolation among and within mountain ranges. The herein identified areas can form the basis for defining areas with conservation priority in this global biodiversity hotspot. PMID- 29985438 TI - AMPA receptor trafficking and its role in heterosynaptic plasticity. AB - Historically, long-term potentiation (LTP) and long-term depression (LTD), the best-characterized forms of long-term synaptic plasticity, are viewed as experience-dependent and input-specific processes. However, cumulative experimental and theoretical data have demonstrated that LTP and LTD can promote compensatory alterations in non-stimulated synapses. In this work, we have developed a computational model of a tridimensional spiny dendritic segment to investigate the role of AMPA receptor (AMPAR) trafficking during synaptic plasticity at specific synapses and its consequences for the populations of AMPAR at nearby synapses. Our results demonstrated that the mechanisms of AMPAR trafficking involved with LTP and LTD can promote heterosynaptic plasticity at non-stimulated synapses. These alterations are compensatory and arise from molecular competition. Moreover, the heterosynaptic changes observed in our model can modulate further activity-driven inductions of synaptic plasticity. PMID- 29985439 TI - Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment. AB - Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected by projections from neurons in the lateral parabrachial nucleus. Collectively, we provide a rapid and unbiased analytical framework for LSFM data which enables quantification and exploration based on data from AIBS to support basic and translational discovery. PMID- 29985440 TI - Cancer mortality does not differ by antiarrhythmic drug use: A population-based cohort of Finnish men. AB - In-vitro studies have suggested that the antiarrhythmic drug digoxin might restrain the growth of cancer cells by inhibiting Na+/K+-ATPase. We evaluated the association between cancer mortality and digoxin, sotalol and general antiarrhythmic drug use in a retrospective cohort study. The study population consists of 78,615 men originally identified for the Finnish Randomized Study of Screening for Prostate Cancer. Information on antiarrhythmic drug purchases was collected from the national prescription database. We used the Cox regression method to analyze separately overall cancer mortality and mortality from the most common types of cancer. During the median follow-up of 17.0 years after the baseline 28,936 (36.8%) men died, of these 8,889 due to cancer. 9,023 men (11.5%) had used antiarrhythmic drugs. Overall cancer mortality was elevated among antiarrhythmic drug users compared to non-users (HR 1.43, 95% CI 1.34-1.53). Similar results were observed separately for digoxin and for sotalol. However, the risk associations disappeared in long-term use and were modified by background co-morbidities. All in all, cancer mortality was elevated among antiarrhythmic drug users. This association is probably non-causal as it was related to short-term use and disappeared in long-term use. Our results do not support the anticancer effects of digoxin or any other antiarrhythmic drug. PMID- 29985441 TI - Coordinated autophagy modulation overcomes glioblastoma chemoresistance through disruption of mitochondrial bioenergetics. AB - Glioblastoma Multiforme (GBM) is known to be one of the most malignant and aggressive forms of brain cancer due to its resistance to chemotherapy. Recently, GBM was found to not only utilise both oxidative phosphorylation (OXPHOS) and aerobic glycolysis, but also depend on the bulk protein degradation system known as macroautophagy to uphold proliferation. Although autophagy modulators hold great potential as adjuvants to chemotherapy, the degree of upregulation or inhibition necessary to achieve cell death sensitisation remains unknown. Therefore, this study aimed to determine the degree of autophagy modulation necessary to impair mitochondrial bioenergetics to the extent of promoting cell death onset. It was shown that coordinated upregulation of autophagy followed by its inhibition prior to chemotherapy decreased electron transfer system (ETS) and oxidative phosphorylation (OXPHOS) capacity, impaired mitochondrial fission and fusion dynamics and enhanced apoptotic cell death onset in terms of cleaved caspase 3 and cleaved PARP expression. Therefore, coordinated autophagy modulation may present a favourable avenue for improved chemotherapeutic intervention in the future. PMID- 29985443 TI - Correction: Association between interleukin family gene polymorphisms and recurrent aphthous stomatitis risk. AB - The original version of this article omitted the corresponding author Mingfang Sun and the author Ying Zhou from the Division of Rheumatology, Research Institute of Surgery, Daping Hospital, the Army Medical University, Chongqing 400042, China. This has now been corrected in the PDF and HTML versions of the article. PMID- 29985442 TI - MifM-instructed translation arrest involves nascent chain interactions with the exterior as well as the interior of the ribosome. AB - Bacillus subtilis MifM is a monitoring substrate of the YidC pathways of protein integration into the membrane and controls the expression of the YidC2 (YqjG) homolog by undergoing regulated translational elongation arrest. The elongation arrest requires interactions between the MifM nascent polypeptide and the ribosomal components near the peptidyl transferase center (PTC) as well as at the constriction site of the ribosomal exit tunnel. Here, we addressed the roles played by more N-terminal regions of MifM and found that, in addition to the previously-identified arrest-provoking elements, the MifM residues 41-60 likely located at the tunnel exit and outside the ribosome contribute to the full induction of elongation arrest. Mutational effects of the cytosolically exposed part of the ribosomal protein uL23 suggested its involvement in the elongation arrest, presumably by interacting with the extra-ribosomal portion of MifM. In vitro translation with reconstituted translation components recapitulated the effects of the mutations at the 41-60 segment, reinforcing the importance of direct molecular interactions between the nascent chain and the ribosome. These results indicate that the nascent MifM polypeptide interacts extensively with the ribosome both from within and without to direct the elongation halt and consequent up-regulation of YidC2. PMID- 29985444 TI - Methyl quantum tunneling in ionic liquid [DMIm][TFSI] facilitated by Bis(trifluoromethane)sulfonimide lithium salt. AB - We probe, for the first time, quantum tunneling in the methyl groups of the ionic liquid [DMIm][TFSI] facilitated by the presence of Bis(trifluoromethane)sulfonimide lithium salt. The observation of tunneling is made possible by crystallization, rather than vitrification, of [DMIm][TFSI] at low temperature. Neutron scattering measurements detect quantum tunneling excitations at ~27 MUeV at temperatures below 30 K in the presence of LiTFSI at a concentration of 1 mol/kg, but not in salt-free [DMIm][TFSI]. This indicates that the methyl rotational potential barrier is reduced by the presence of LiTFSI, thus bringing the tunneling excitations into the measurable range. The salt induced reduction of the rotational barrier is corroborated by quasi-elastic scattering data associated with stochastic re-orientation of methyl groups measured between 40 and 60 K. PMID- 29985446 TI - Correction: MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences. AB - In the original version of this Article, the affiliation details for Giovanni Martinelli were incorrectly given as 'Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy' and it should have been given as 'Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy and not Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, 40138, Bologna, Italy.'Furthermore, the original version of this Article contained an error in the spelling of the authors Alberto L'Abbate and Pietro D'Addabbo, an acute accent was used instead of an apostrophe for these authors names.These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29985445 TI - Enhanced GABAergic actions resulting from the coapplication of the steroid 3alpha hydroxy-5alpha-pregnane-11,20-dione (alfaxalone) with propofol or diazepam. AB - Many GABAergic drugs are in clinical use as anesthetics, sedatives, or anxiolytics. We have investigated the actions of the combinations of the neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-11,20-dione (alfaxalone) with the intravenous anesthetic propofol or the benzodiazepine diazepam. The goal of the study was to determine whether coapplication of alfaxalone reduces the effective doses and concentrations of propofol and diazepam. Behavioral effects of alfaxalone, propofol, diazepam, and the combinations of the drugs were evaluated during a 30-min activity test in mice. Functional effects of the individual drugs and drug combinations were tested by measuring the decay times of spontaneous inhibitory postsynaptic currents in rat hippocampal neurons, and peak current responses from heterologously expressed concatemeric alpha1beta2gamma2L GABAA receptors. Co-administration of alfaxalone increased the sedative actions of propofol and diazepam in mice. The combination of alfaxalone with propofol or diazepam increased the decay times of sIPSCs and shifted the concentration-response relationships for GABA-activated receptors to lower transmitter concentrations. We infer that alfaxalone acts as a co-agonist to enhance the GABAergic effects of propofol and diazepam. We propose that co administration of alfaxalone, and possibly other neuroactive steroids, can be employed to reduce dosage requirements for propofol and diazepam. PMID- 29985447 TI - Adapted Taekwondo Training for Prepubertal Children with Developmental Coordination Disorder: A Randomized, Controlled Trial. AB - This study evaluated the effectiveness of adapted Taekwondo (TKD) training on skeletal development and motor performance in children with developmental coordination disorder (DCD). One hundred forty-five prepubertal children with DCD were allocated to either the TKD or control groups. Children in the TKD group participated in a weekly 1-hour adapted TKD intervention and daily TKD home exercises for 12 weeks. The primary outcome (delay in skeletal development) and secondary outcomes (Movement Assessment Battery for Children (MABC) total impairment score, eye-hand coordination (EHC) scores, and a standing balance score) were measured at baseline, after the intervention and 3 months after the intervention. Skeletal development improved in both groups over time (p < 0.017). The TKD group had a significant delay in skeletal development at baseline compared to the control group (p = 0.003) but caught up with the controls at 3 months (p = 0.041). Improvements in the MABC scores were also seen in both groups across time (p < 0.017). Only the TKD group had a significant improvement in the EHC movement time at 3 (p = 0.009) and 6 months (p = 0.016). The adapted TKD intervention may be effective in improving the skeletal development and EHC movement time of children with DCD. For motor performance, the effect of maturation might be more profound. PMID- 29985448 TI - Simultaneous GLP-1 receptor activation and angiotensin receptor blockade increase natriuresis independent of altered arterial pressure in obese OLETF rats. AB - Obesity is associated with an inappropriately activated renin-angiotensin aldosterone system, suppressed glucagon-like peptide-1 (GLP-1), increased renal Na+ reabsorption, and hypertension. To assess the link between GLP-1 and angiotensin receptor type 1 (AT1) signaling on obesity-associated impairment of urinary Na+ excretion (UNaV) and elevated arterial pressure, we measured mean arterial pressure (MAP) and heart rate by radiotelemetry and metabolic parameters for 40 days. We tested the hypothesis that stimulation of GLP-1 signaling provides added benefit to blockade of AT1 by increasing UNaV and further reducing arterial pressure in the following groups: (1) untreated Long-Evans Tokushima Otsuka (LETO) rats (n = 7); (2) untreated Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 9); (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 9); (4) OLETF + GLP-1 receptor agonist (EXE; 10 ug exenatide/kg/day; n = 7); and (5) OLETF + ARB + EXE (Combo; n = 6). On day 2, UNaV was 60% and 62% reduced in the EXE and Combo groups, respectively, compared with that in the OLETF rats. On day 40, UNaV was increased 69% in the Combo group compared with that in the OLETF group. On day 40, urinary angiotensinogen was 4.5-fold greater in the OLETF than in the LETO group and was 56%, 62%, and 58% lower in the ARB, EXE, and Combo groups, respectively, than in the OLETF group. From day 2 to the end of the study, MAP was lower in the ARB and Combo groups than in the OLETF rats. These results suggest that GLP-1 receptor activation may reduce intrarenal angiotensin II activity, and that simultaneous blockade of AT1 increases UNaV in obesity; however, these beneficial effects do not translate to a further reduction in MAP. PMID- 29985449 TI - Live imaging analysis of the growth plate in a murine long bone explanted culture system. AB - Skeletal growth in mammals, which owes the growth of an individual, occurs at the growth plate and to observe and analyze its dynamic growth is of high interest. Here we performed live imaging analysis of the growth plate of a fetal murine long bone organ culture using two-photon excitation microscopy. We could observe a dynamic growth of the growth plate of explanted fetal murine ulna, as well as the resultant linear elongation of the explants. As for the factors contributing to the elongation of the growth plate, the displacement length of each chondrocyte was larger in the prehypertrophic or hypertrophic zone than in the proliferative zone. The segmented area and its extracellular component were increased in both the proliferative and prehypertrophic-hypertrophic zones, whereas an increase in cellular components was only seen in the prehypertrophic hypertrophic zone. C-type natriuretic peptide, a known positive stimulator of endochondral bone growth mainly targeting prehypertrophic-hypertrophic zone, augmented all of the factors affecting growth plate elongation, whereas it had little effect on the proliferation of chondrocytes. Collectively, the axial trajectory of each chondrocyte mainly owes cellular or extracellular expansion especially in prehypertrophic-hypertrophic zone and results in growth plate elongation, which might finally result in endochondral bone elongation. PMID- 29985450 TI - Radio-frequency current drive for thermonuclear fusion reactors. AB - Principal research on energy from thermonuclear fusion uses Deuterium-Tritium plasmas magnetically trapped in toroidal devices. As major scientific problem for an economic (i.e., really feasible) reactor, we must understand how to lead strongly heated plasmas to sustain a high fusion gain while large fraction of current is self-produced via the presence of strong pressure gradient. To suppress turbulent eddies that impair thermal insulation and pressure tight of the plasma, current drive (CD) is necessary. However, tools envisaged so far in ITER (International Thermonuclear Experiment Rector) are unable accomplishing this task that requires efficiently and flexibly matching the natural current profiles of plasma. Consequently, viability of a thermonuclear reactor should be problematic. Multi-megawatt radio-frequency (RF) power coupled to plasma would produce the necessary CD, but modelling results based on previous understanding found difficult the extrapolation of this CD concept to reactor conditions of high temperature plasma, and greater flexibility of method would also be required. Here we present new model results based on standard quasilinear (QL) theory that allow establish conditions to drive efficiently and flexibly the RF driven current at large radii of the plasma column, as necessary for the goal of a reactor. PMID- 29985452 TI - Balance of stresses guides metastasis. PMID- 29985451 TI - Data analysis and uncertainty estimation in supercontinuum laser absorption spectroscopy. AB - A set of algorithms is presented that facilitates the evaluation of super continuum laser absorption spectroscopy (SCLAS) measurements with respect to temperature, pressure and species concentration without the need for simultaneous background intensity measurements. For this purpose a non-linear model fitting approach is employed. A detailed discussion of the influences on the instrument function of the spectrometer and a method for the in-situ determination of the instrument function without additional hardware are given. The evaluation procedure is supplemented by a detailed measurement precision assessment by applying an error propagation through the non-linear model fitting approach. While the algorithms are tailored to SCLAS, they can be transferred to other spectroscopic methods, that similarly require an instrument function. The presented methods are validated using gas cell measurements of methane in the near infrared region at pressures up to 8.7 bar. PMID- 29985453 TI - Detection of atrial fibrillation using a smartwatch. PMID- 29985454 TI - PAX7 expression in sarcomas bearing the EWSR1-NFATC2 translocation. PMID- 29985455 TI - Neuroimaging results suggest the role of prediction in cross-domain priming. AB - The repetition of a stimulus leads to shorter reaction times as well as to the reduction of neural activity. Previous encounters with closely related stimuli (primes) also lead to faster and often to more accurate processing of subsequent stimuli (targets). For instance, if the prime is a name, and the target is a face, the recognition of a persons' face is facilitated by prior presentation of his/her name. A possible explanation for this phenomenon is that the prime allows predicting the occurrence of the target. To the best of our knowledge, so far, no study tested the neural correlates of such cross-domain priming with fMRI. To fill this gap, here we used names of famous persons as primes, and congruent or incongruent faces as targets. We found that congruent primes not only reduced RT, but also lowered the BOLD signal in bilateral fusiform (FFA) and occipital (OFA) face areas. This suggests that semantic information affects not only behavioral performance, but also neural responses in relatively early processing stages of the occipito-temporal cortex. We interpret our results in the framework of predictive coding theories. PMID- 29985456 TI - Normalization of disrupted clock gene expression in males with tetraplegia: a crossover randomized placebo-controlled trial of melatonin supplementation. AB - STUDY DESIGN: Crossover double blind, randomized placebo-controlled trial. OBJECTIVES: Circadian oscillators are located both in the brain and in peripheral organs. Melatonin, the main brain-derived hormone governing circadian variations, is highly associated with daylight patterns. However, in subjects with tetraplegia the melatonin levels are blunted. Here we studied peripheral oscillators in peripheral blood mononuclear cells (PBMCs) in males with tetraplegia by examining how exogenous melatonin may influence the expression of clock gene mRNAs. SETTING: Sunnaas Rehabilitation Hospital, Nesoddtangen, Norway. METHODS: Six males with tetraplegia received 2 mg of melatonin or placebo 4 days before the study period. We also included six able-bodied men sleeping or kept awake during the night. Plasma samples were collected four times during a 24-h period. The mRNA expression levels of the clock genes PER1, PER2, BMAL1, and REV ERBalpha were quantified in PBMCs using quantitative RT-PCR. RESULTS: The mRNA expression levels of PER-1 and -2 and REV-ERBalpha were increased at 04:00 h compared with the able-bodied controls (p < 0.05). Melatonin supplementation changed mRNA peak-time toward the time of supplementation. CONCLUSIONS: Several peripheral clock genes displayed distorted expression levels in tetraplegia. Supplementation with melatonin changed the mRNA expression levels of these genes toward those observed among able-bodied. SPONSORSHIP: Financial support was provided from the Throne Holst Foundation, Sunnaas Rehabilitation hospital and the University of Ferrara (FAR2016). PMID- 29985457 TI - Predictors of falls in persons with spinal cord injury-a prospective study using the Downton fall risk index and a single question of previous falls. AB - STUDY DESIGN: Prediction study. OBJECTIVES: To investigate the prediction accuracy of the Downton fall risk index (DFRI) and a question of falls the previous year; further to examine the association between time to first fall and risk indicators for falls in wheelchair users and ambulatory persons with Spinal Cord Injury (SCI). SETTING: Two SCI centres in Norway and Sweden (Sunnaas Rehabilitation Hospital, Rehab Station Stockholm /Spinalis). METHODS: Two hundred and twenty-four persons with traumatic SCI, >=1 year post-injury, >=18 years participated. Prospective falls were reported by text messages every second week for one year. Sensitivity, specificity and time to first fall (Kaplan Meier) were investigated for DFRI and the question of falls in the previous year. DFRI >=3 was defined as a high risk of falls. Cox survival analysis was used to calculate hazard ratios for functional independence, gait speed and fear of falling. RESULTS: The sensitivity was 36-57% for DFRI and 82-89% for the question of falls, while specificity was 74-83%, and 34-49%. For DFRI, time to first fall was shorter in the high-risk group, for both wheelchair users (p = 0.005) and ambulatory persons (p = 0.006). Falls previous year increased the hazard ratio of falls for wheelchair users (HR = 3.35, 95% CI = 1.86 to 6.02) but not for ambulatory persons. CONCLUSIONS: Falls in the previous year showed a better predictive accuracy than DFRI due to the low sensitivity of DFRI. As previous falls had low specificity, it still remains difficult to predict falls in those who have not fallen yet. PMID- 29985458 TI - Inactivation of group 2 sigma factors upregulates production of transcription and translation machineries in the cyanobacterium Synechocystis sp. PCC 6803. AB - We show that the formation of the RNAP holoenzyme with the primary sigma factor SigA increases in the DeltasigBCDE strain of the cyanobacterium Synechocystis sp. PCC 6803 lacking all group 2 sigma factors. The high RNAP-SigA holoenzyme content directly induces transcription of a particular set of housekeeping genes, including ones encoding transcription and translation machineries. In accordance with upregulated transcripts, DeltasigBCDE contain more RNAPs and ribosomal subunits than the control strain. Extra RNAPs are fully active, and the RNA content of DeltasigBCDE cells is almost tripled compared to that in the control strain. Although DeltasigBCDE cells produce extra rRNAs and ribosomal proteins, functional extra ribosomes are not formed, and translation activity and protein content remained similar in DeltasigBCDE as in the control strain. The arrangement of the RNA polymerase core genes together with the ribosomal protein genes might play a role in the co-regulation of transcription and translation machineries. Sequence logos were constructed to compare promoters of those housekeeping genes that directly react to the RNAP-SigA holoenzyme content and those ones that do not. Cyanobacterial strains with engineered transcription and translation machineries might provide solutions for construction of highly efficient production platforms for biotechnical applications in the future. PMID- 29985459 TI - Nurse-led hypertension management was well accepted and non-inferior to physician consultation in a Chinese population: a randomized controlled trial. AB - The objective of this study is to evaluate if nurse-led repeated prescription (NRP) could ensure non-inferior disease control and would be accepted in Chinese patients with controlled hypertension (HT) in primary care clinics. A 12-month follow-up non-inferiority randomized trial was conducted. The non-inferior margins for systolic and diastolic blood pressure were 6.6 mmHg and 3.7 mmHg, respectively. Eligible patients (>18 years of age) with HT were randomized to the NRP and usual care (UC) groups for their regular clinical follow-up. We used ANCOVA to study the difference-of-difference of the blood pressures between the two groups. The levels of patient acceptance and experience of NRP were assessed by the observed opt-out rate and a qualitative analysis. We found no statistically significant differences in BP blood pressure between the NRP (N = 194) and UC (N = 199) groups. Only 4 of the participants in the NRP group opted out due to a preference for assessment by a physician. The interviewed participants (N = 12) felt positive about NRP, because they experienced more relaxed communication with the nurse and believed that the eligibility to join the NRP program was an indication of optimal BP control. We observed no adverse events. The findings show that NRP was well accepted and found to be non-inferior to physician consultation for HT management. PMID- 29985460 TI - A Novel Forming Method of Traditional Chinese Medicine Dispersible Tablets to Achieve Rapid Disintegration Based on the Powder Modification Principle. AB - Slow disintegration and poor solubility are common problems facing the dispersible tablets of Traditional Chinese Medicine (TCM). In an early study, the research group found that co-grinding of extracts and silica could achieve a rapid disintegration effect, though the mechanism of this effect was not thoroughly elucidated. In this study, Yuanhu Zhitong dispersible tablets (YZDT) were selected as a model drug to explore the mechanism of rapid disintegration and dissolution. First, eight types of silica were used to prepare modified YZDT, and their disintegration time and amount of dissolution within 5 min were measured. Next, the powder properties of eight types of silica were investigated. By correlation analysis, it was found that the average pore size and density of silica were closely related to the effect of promoting disintegration. It was determined that the co-grinding of silica and extracts provided high porosity for the raw material drug, and its abundant narrow channels provided a strong static pressure for water penetration to achieve a rapid disintegration effect. Meanwhile, it was found that the addition of silica had a certain effect on promoting dissolution. Our results provide a highly operational approach for improving the disintegration and dissolution of TCM dispersible tablets. Meanwhile, this approach is also beneficial for establishing a high-quality evaluation index for silica. PMID- 29985461 TI - Cobra Venom Factor-induced complement depletion protects against lung ischemia reperfusion injury through alleviating blood-air barrier damage. AB - The purpose of this study was to study whether complement depletion induced by pretreatment with Cobra Venom Factor (CVF) could protect against lung ischemia reperfusion injury (LIRI) in a rat model and explore its molecular mechanisms. Adult Sprague-Dawley rats were randomly assigned to five groups (n = 6): Control group, Sham-operated group, I/R group, CVF group, I/R + CVF group. CVF (50 MUg/kg) was injected through the tail vein 24 h before anesthesia. Lung ischemia reperfusion (I/R) was induced by clamping the left hilus pulmonis for 60 minutes followed by 4 hours of reperfusion. Measurement of complement activity, pathohistological lung injury score, inflammatory mediators, pulmonary permeability, pulmonary edema, integrity of tight junction and blood-air barrier were performed. The results showed that pretreatment with CVF significantly reduced complement activity in plasma and BALF. Evaluation in histomorphology showed that complement depletion induced by CVF significantly alleviated the damage of lung tissues and inhibited inflammatory response in lung tissues and BALF. Furthermore, CVF pretreatment had the function of ameliorating pulmonary permeability and preserving integrity of tight junctions in IR condition. In conclusion, our results indicated that complement depletion induced by CVF could inhibit I/R-induced inflammatory response and alleviate lung I/R injury. The mechanisms of its protective effects might be ameliorated blood-air barrier damage. PMID- 29985463 TI - HLA in transplantation. AB - The human major histocompatibility complex is a family of genes that encodes HLAs, which have a crucial role in defence against foreign pathogens and immune surveillance of tumours. In the context of transplantation, HLA molecules are polymorphic antigens that comprise an immunodominant alloreactive trigger for the immune response, resulting in rejection. Remarkable advances in knowledge and technology in the field of immunogenetics have considerably enhanced the safety of transplantation. However, access to transplantation among individuals who have become sensitized as a result of previous exposure to alloantigens is reduced proportional to the breadth of their sensitization. New approaches for crossing the HLA barrier in transplantation using plasmapheresis, intravenous immunoglobulin and kidney paired donation have been made possible by the relative ease with which even low levels of anti-HLA antibodies can now be detected and tracked. The development of novel protocols for the induction of tolerance and new approaches to immunomodulation was also facilitated by advances in HLA technology. Here, we review the progress made in understanding HLAs that has enabled organ transplantation to become a life-saving endeavour that is accessible even for sensitized patients. We also discuss novel approaches to desensitization, immunomodulation and tolerance induction that have the potential to further improve transplantation access and outcomes. PMID- 29985462 TI - Arsenic-silicon priming of rice (Oryza sativa L.) seeds influence mineral nutrient uptake and biochemical responses through modulation of Lsi-1, Lsi-2, Lsi 6 and nutrient transporter genes. AB - Silicon (Si) has attracted substantial attention because of its beneficial effect on plants during abiotic stress, including stress due to arsenic (As). We here report that priming rice seeds with As and Si together, helped the plant to sustain As stress for longer period. We examined Si induced tolerance against As in rice seedlings at short (7 d) and long (15 d) exposure periods under As(III) and Si treatments since their germinating stage. Results showed that the expression of As(III) transporter genes OsLsi1, OsLsi2 and OsLsi6 was more in As(III) + Si treatment as compared to control and Si treatment, but lower than As(III) alone treatments. The gene expression was maximum in shoot and root at 15 d over 7 d under both As(III) and As(III) + Si treatment, which ultimately leads to decreased accumulation of As in the presence of Si. Morphological characters, antioxidant capacity, oxidative stress marker (MDA), stress modulators (cysteine, proline), and enzymes related with ascorbate-glutathione cycle significantly altered during As(III) + Si treatment at both exposure periods. Further, macro and micronutrient contents also improved with Si, and differentially regulated 12 key genes (NR, NiR, AMT, NR, GS, GOGAT, PT, PHT1, PHT2, APase, KAT1 and HAK10) related with NPK transport and utilization. Results highlight that Si priming of seeds along with As(III) influences growth positively of As-stressed rice. PMID- 29985465 TI - Publisher Correction: Symmetry and magnetism allied. AB - In the version of this News & Views originally published, the placement of the white circle in Fig. 1 was in the wrong position; it should have been over the six-domain vortex. This has now been corrected; see the correction notice for details. PMID- 29985464 TI - Helix alpha-3 inter-molecular salt bridges and conformational changes are essential for toxicity of Bacillus thuringiensis 3D-Cry toxin family. AB - Bacillus thuringiensis insecticidal Cry toxins break down larval midgut-cells after forming pores. The 3D-structures of Cry4Ba and Cry5Ba revealed a trimeric oligomer after cleavage of helices alpha-1 and alpha-2a, where helix alpha-3 is extended and made contacts with adjacent monomers. Molecular dynamic simulations of Cry1Ab-oligomer model based on Cry4Ba-coordinates showed that E101 forms a salt-bridge with R99 from neighbor monomer. An additional salt bridge was identified in the trimeric-Cry5Ba, located at the extended helix alpha-3 in the region corresponding to the alpha-2b and alpha-3 loop. Both salt-bridges were analyzed by site directed mutagenesis. Single-point mutations in the Lepidoptera specific Cry1Ab and Cry1Fa toxins were affected in toxicity, while reversed double-point mutant partially recovered the phenotype, consistent with a critical role of these salt-bridges. The single-point mutations in the salt-bridge at the extended helix alpha-3 of the nematicidal Cry5Ba were also non-toxic. The incorporation of this additional salt bridge into the nontoxic Cry1Ab-R99E mutant partially restored oligomerization and toxicity, supporting that the loop between alpha-2b and alpha-3 forms part of an extended helix alpha-3 upon oligomerization of Cry1 toxins. Overall, these results highlight the role in toxicity of salt bridge formation between helices alpha-3 of adjacent monomers supporting a conformational change in helix alpha-3. PMID- 29985466 TI - Stability of Circulating Exosomal miRNAs in Healthy Subjects. AB - Exosomes are nano-vesicles present in the circulation that are involved in cell to-cell communication and regulation of different biological processes. MicroRNAs (miRNAs) are part of their cargo and are potential biomarkers. Methods of exosome isolation and the inter-individual and intra-individual variations in circulating miRNA exosomal cargo have been poorly investigated. This study aims for comparing two exosome isolation methods and to assess the stability of eleven plasma exosomal miRNAs over time. In addition to evaluate miRNA variability of both kits, the effect of freezing plasma before exosome isolation or freezing isolated exosomes on miRNA stability was also evaluated. MiRNA levels were tested in 7 healthy subjects who underwent four different blood extractions obtained in 4 consecutive weeks. One of the isolation kits displayed generally better amplification signals, and miRNAs from exosomes isolated after freezing the plasma had the highest levels. Intra-subject and inter-subject coefficients of variance were lower for the same isolation kit after freezing plasma. Finally, miRNAs that showed an acceptable expression level were stable across the consecutive extractions. This study shows for the first time the stability over time of miRNAs isolated from circulating plasma exosomes, establishing a key step in the use of exosomal miRNAs as biomarkers. PMID- 29985468 TI - Redefining KRAS activation. PMID- 29985467 TI - Reconciling differences in natural tags to infer demographic and genetic connectivity in marine fish populations. AB - Processes regulating population connectivity are complex, ranging from extrinsic environmental factors to intrinsic individual based features, and are a major force shaping the persistence of fish species and population responses to harvesting and environmental change. Here we developed an integrated assessment of demographic and genetic connectivity of European flounder Platichthys flesus in the northeast Atlantic (from the Norwegian to the Portuguese coast) and Baltic Sea. Specifically, we used a Bayesian infinite mixture model to infer the most likely number of natal sources of individuals based on otolith near core chemical composition. Simultaneously, we characterised genetic connectivity via microsatellite DNA markers, and evaluated how the combined use of natural tags informed individual movement and long-term population exchange rates. Individual markers provided different insights on movement, with otolith chemistry delineating Norwegian and Baltic Sea sources, whilst genetic markers showed a latitudinal pattern which distinguished southern peripheral populations along the Iberian coast. Overall, the integrated use of natural tags resulted in outcomes that were not readily anticipated by individual movement or gene flow markers alone. Our ecological and evolutionary approach provided a synergistic view on connectivity, which will be paramount to align biological and management units and safeguard species' biocomplexity. PMID- 29985469 TI - Sequencing cells of the immune TME. PMID- 29985470 TI - Knockdown Indian Hedgehog (Ihh) does not delay Fibular Fracture Healing in genetic deleted Ihh mice and pharmaceutical inhibited Ihh Mice. AB - The objective of this study was to determine if Ihh is required for fracture healing. Fibular fracture was created in adult Col2a1-CreERT2; Ihhfl/fl mice. Ihhfl/fl mice received Tamoxifen (TM) to delete Ihh. WT mice received Cyclopamine to inhibit Hh pathway. Callus tissue properties and Ihh pathway were analyzed at 1, 2, and 3 weeks post-fracture by X-ray, micro-CT, mechanical test, RT-PCR and immunohistochemistry. Deleted Ihh was evidenced by the occurrence of growth plate closure in the Ihhfl/fl mice by X-ray 3 weeks after TM treatment. All mice showed fracture healing at 3 weeks post-operation. Histology analysis indicated that, compared to the control, cartilage area was less in fracture sites from Ihh deficient animals by either genetic deletion or drug inhibition at 1 and 2 weeks post-fracture. Ihh immunostaining and its mRNA level were diminished in the fracture callus in Ihh reduced mice. There was no significant difference in BV/TV, BMD and mechanical test. Interruption to Ihh pathway by either genetic or pharmaceutical approach didn't affect fibular fracture healing in these mice. This surprised finding implicates that the deleted Ihh does not affect fracture healing in this model. PMID- 29985471 TI - Phosphate Removal in Relation to Structural Development of Humic Acid-Iron Coprecipitates. AB - Precipitation of Fe-hydroxide (FH) critically influences the sequestration of PO4 and organic matter (OM). While coatings of pre-sorbed OM block FH surfaces and decrease the PO4 adsorption capacity, little is known about how OM/Fe coprecipitation influences the PO4 adsorption. We aimed to determine the PO4 adsorption behaviors on humic acid (HA)-Fe coprecipitates in relation to surface and structural characteristics as affected by HA types and C/(C + Fe) ratios using the Fe and P X-ray absorption spectroscopy. With increasing C/(C + Fe) ratios, the indiscernible changes in the proportion of near-surface C for coprecipitates containing HA enriched in polar functional groups implied a relatively homogeneous distribution between C and Fe domains. Wherein PO4 adsorbed on FH dominated the P inventory on coprecipitates, yielding PO4 sorption properties nearly equivalent to that of pure FH. Structural disruptions of FH caused by highly associations with polar functional groups of HA enhanced the C solubilisation. While polar functional groups were limited, coprecipitates consisted of core FH with surface outgrowth of HA. Although surface-attached HA that was vulnerable to solubilisation provided alternatively sites for PO4 via ternary complex formation with Fe bridges, it also blocked FH surfaces, leading to a decrease in PO4 adsorption. PMID- 29985472 TI - Hidden hearing loss in patients with Charcot-Marie-Tooth disease type 1A. AB - The aim of this study was to investigate hidden hearing loss in patients with Charcot-Marie-Tooth disease type 1 A (CMT1A), a common inherited demyelinating neuropathy. By using pure-tone audiometry, 43 patients with CMT1A and 60 healthy controls with normal sound detection abilities were enrolled. Speech perception in quiet and noisy backgrounds, spectral ripple discrimination (SRD), and temporal modulation detection (TMD) were measured. Although CMT1A patients and healthy controls had similar pure-tone thresholds and speech perception scores in a quiet background, CMT1A patients had significantly (p < 0.05) decreased speech perception ability in a noisy background compared to controls. CMT1A patients showed significantly decreased temporal and spectral resolution (both p < 0.05). Also, auditory temporal processing of CMT1A patients was correlated with speech perception in a noisy background (r = 0.447, p < 0.01) and median motor conduction velocity (r = 0.335, p < 0.05). Therefore, we assumed that demyelination of auditory nerve in CMT1A causes defective cochlear neurotransmission, which reduces temporal resolution and speech perception in a noisy background. Because the temporal resolution test was well correlated with the degree of demyelination in auditory and peripheral motor nerves, temporal resolution testing could be performed as an additional marker for CMT1A. PMID- 29985473 TI - Data-driven analysis of motor activity implicates 5-HT2A neurons in backward locomotion of larval Drosophila. AB - Rhythmic animal behaviors are regulated in part by neural circuits called the central pattern generators (CPGs). Classifying neural population activities correlated with body movements and identifying the associated component neurons are critical steps in understanding CPGs. Previous methods that classify neural dynamics obtained by dimension reduction algorithms often require manual optimization which could be laborious and preparation-specific. Here, we present a simpler and more flexible method that is based on the pre-trained convolutional neural network model VGG-16 and unsupervised learning, and successfully classifies the fictive motor patterns in Drosophila larvae under various imaging conditions. We also used voxel-wise correlation mapping to identify neurons associated with motor patterns. By applying these methods to neurons targeted by 5-HT2A-GAL4, which we generated by the CRISPR/Cas9-system, we identified two classes of interneurons, termed Seta and Leta, which are specifically active during backward but not forward fictive locomotion. Optogenetic activation of Seta and Leta neurons increased backward locomotion. Conversely, thermogenetic inhibition of 5-HT2A-GAL4 neurons or application of a 5-HT2 antagonist decreased backward locomotion induced by noxious light stimuli. This study establishes an accelerated pipeline for activity profiling and cell identification in larval Drosophila and implicates the serotonergic system in the modulation of backward locomotion. PMID- 29985474 TI - Sex differences in Alzheimer disease - the gateway to precision medicine. AB - Alzheimer disease (AD) is characterized by wide heterogeneity in cognitive and behavioural syndromes, risk factors and pathophysiological mechanisms. Addressing this phenotypic variation will be crucial for the development of precise and effective therapeutics in AD. Sex-related differences in neural anatomy and function are starting to emerge, and sex might constitute an important factor for AD patient stratification and personalized treatment. Although the effects of sex on AD epidemiology are currently the subject of intense investigation, the notion of sex-specific clinicopathological AD phenotypes is largely unexplored. In this Review, we critically discuss the evidence for sex-related differences in AD symptomatology, progression, biomarkers, risk factor profiles and treatment. The cumulative evidence reviewed indicates sex-specific patterns of disease manifestation as well as sex differences in the rates of cognitive decline and brain atrophy, suggesting that sex is a crucial variable in disease heterogeneity. We discuss critical challenges and knowledge gaps in our current understanding. Elucidating sex differences in disease phenotypes will be instrumental in the development of a 'precision medicine' approach in AD, encompassing individual, multimodal, biomarker-driven and sex-sensitive strategies for prevention, detection, drug development and treatment. PMID- 29985475 TI - Multidimensional communication in the microenvirons of glioblastoma. AB - Glioblastomas are heterogeneous and invariably lethal tumours. They are characterized by genetic and epigenetic variations among tumour cells, which makes the development of therapies that eradicate all tumour cells challenging and currently impossible. An important component of glioblastoma growth is communication with and manipulation of other cells in the brain environs, which supports tumour progression and resistance to therapy. Glioblastoma cells recruit innate immune cells and change their phenotype to support tumour growth. Tumour cells also suppress adaptive immune responses, and our increasing understanding of how T cells access the brain and how the tumour thwarts the immune response offers new strategies for mobilizing an antitumour response. Tumours also subvert normal brain cells - including endothelial cells, neurons and astrocytes - to create a microenviron that favours tumour success. Overall, after glioblastoma induced phenotypic modifications, normal cells cooperate with tumour cells to promote tumour proliferation, invasion of the brain, immune suppression and angiogenesis. This glioblastoma takeover of the brain involves multiple modes of communication, including soluble factors such as chemokines and cytokines, direct cell-cell contact, extracellular vesicles (including exosomes and microvesicles) and connecting nanotubes and microtubes. Understanding these multidimensional communications between the tumour and the cells in its environs could open new avenues for therapy. PMID- 29985476 TI - Visual discrimination of polymorphic nestlings in a cuckoo-host system. AB - Mimicry by avian brood parasites favours uniformity over variation within a breeding attempt as host defence against parasitism. In a cuckoo-host system from New Caledonia, the arms race resulted in both host (Gerygone flavolateralis) and parasite (Chalcites lucidus) having nestlings of two discrete skin colour phenotypes, bright and dark. In our study sites, host nestlings occurred in monomorphic and polymorphic broods, whereas cuckoo nestlings only occurred in the bright morph. Irrespective of their brood colour, host parents recognised and ejected parasite nestlings but never ejected their own. We investigated whether host parents visually recognised their own nestlings by using colour, luminance and pattern of multiple body regions. We found that the parasite mimicked multiple visual features of both host morphs and that the visual difference between host morphs was larger than the difference between the parasite and the mimicked host morph. Visual discrimination alone may result in higher chances of recognition errors in polymorphic than in monomorphic host broods. Host parents may rely on additional sensorial cues, not only visual, to assess nestling identity. Nestling polymorphism may be a trace of evolutionary past and may only have a marginal role in true-recognition of nestlings in the arms race in New Caledonia. PMID- 29985477 TI - A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies. AB - The neurotransmitter acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body. Despite its importance, cholinergic transmission in the majority of tissues and organs remains poorly understood owing primarily to the limitations of available ACh-monitoring techniques. We developed a family of ACh sensors (GACh) based on G-protein-coupled receptors that has the sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo. GACh sensors were validated with transfection, viral and/or transgenic expression in a dozen types of neuronal and non-neuronal cells prepared from multiple animal species. In all preparations, GACh sensors selectively responded to exogenous and/or endogenous ACh with robust fluorescence signals that were captured by epifluorescence, confocal, and/or two-photon microscopy. Moreover, analysis of endogenous ACh release revealed firing-pattern-dependent release and restricted volume transmission, resolving two long-standing questions about central cholinergic transmission. Thus, GACh sensors provide a user-friendly, broadly applicable tool for monitoring cholinergic transmission underlying diverse biological processes. PMID- 29985478 TI - Meganuclease targeting of PCSK9 in macaque liver leads to stable reduction in serum cholesterol. AB - Clinical translation of in vivo genome editing to treat human genetic diseases requires thorough preclinical studies in relevant animal models to assess safety and efficacy. A promising approach to treat hypercholesterolemia is inactivating the secreted protein PCSK9, an antagonist of the LDL receptor. Here we show that single infusions in six non-human primates of adeno-associated virus vector expressing an engineered meganuclease targeting PCSK9 results in dose-dependent disruption of PCSK9 in liver, as well as a stable reduction in circulating PCSK9 and serum cholesterol. Animals experienced transient, asymptomatic elevations of serum transaminases owing to the formation of T cells against the transgene product. Vector DNA and meganuclease expression declined rapidly, leaving stable populations of genome-edited hepatocytes. A second-generation PCSK9-specific meganuclease showed reduced off-target cleavage. These studies demonstrate efficient, physiologically relevant in vivo editing in non-human primates, and highlight safety considerations for clinical translation. PMID- 29985479 TI - Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. AB - Adoptive cell therapy (ACT) with antigen-specific T cells has shown remarkable clinical success; however, approaches to safely and effectively augment T cell function, especially in solid tumors, remain of great interest. Here we describe a strategy to 'backpack' large quantities of supporting protein drugs on T cells by using protein nanogels (NGs) that selectively release these cargos in response to T cell receptor activation. We designed cell surface-conjugated NGs that responded to an increase in T cell surface reduction potential after antigen recognition and limited drug release to sites of antigen encounter, such as the tumor microenvironment. By using NGs that carried an interleukin-15 super-agonist complex, we demonstrated that, relative to systemic administration of free cytokines, NG delivery selectively expanded T cells 16-fold in tumors and allowed at least eightfold higher doses of cytokine to be administered without toxicity. The improved therapeutic window enabled substantially increased tumor clearance by mouse T cell and human chimeric antigen receptor (CAR)-T cell therapy in vivo. PMID- 29985480 TI - PIM2-mediated phosphorylation of hexokinase 2 is critical for tumor growth and paclitaxel resistance in breast cancer. AB - Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer. Furthermore, phosphorylation of HK2 on Thr473 increased HK2 enzyme activity and glycolysis, and enhanced glucose starvation induced autophagy. As a result, phosphorylated HK2 Thr473 promoted breast cancer cell growth in vitro and in vivo. Interestingly, PIM2 kinase inhibitor SMI-4a could abrogate the effects of phosphorylated HK2 Thr473 on paclitaxel resistance in vitro and in vivo. Taken together, our findings indicated that PIM2 was a novel regulator of HK2, and suggested a new strategy to treat breast cancer. PMID- 29985481 TI - ZFPM2-AS1, a novel lncRNA, attenuates the p53 pathway and promotes gastric carcinogenesis by stabilizing MIF. AB - Long non-coding RNAs (lncRNAs) are implicated to be involved in the pathogenesis of many cancers. Herein we report on our discovery of a novel lncRNA, ZFPM2 antisense RNA 1 (ZFPM2-AS1), and its critical role in gastric carcinogenesis. ZFPM2-AS1 expression in gastric cancer specimens was analyzed using Gene Expression Omnibus data set and validated in 73 paired gastric tumor and normal adjacent gastric tissue specimens using qRT-PCR. The effect of ZFPM2-AS1 expression on proliferation and apoptosis in gastric cancer cells was assessed by altering its expression in vitro and in vivo. Mechanistic investigation was carried out using cell and molecular biological approaches. ZFPM2-AS1 expression was higher in gastric tumors than in normal gastric tissue. Also, increased ZFPM2 AS1 expression in gastric cancer specimens was associated with tumor size, depth of tumor invasion, differentiation grade, and TNM stage. High ZFPM2-AS1 expression predicted markedly reduced overall and disease-free survival in gastric cancer patients. Functional experiments demonstrated that ZFPM2-AS1 expression promoted proliferation and suppressed apoptosis of gastric cancer cells in vitro and promoted tumor growth in vivo. This effect is associated with attenuated nuclear translocation of p53. Mechanistic experiments demonstrated that tumor-activated ZFPM2-AS1 could bind to and protect the degradation of macrophage migration inhibitory factor (MIF), a potent destabilizer of p53. Knockdown of MIF expression diminished ZFPM2-AS1's impact on p53 expression in gastric cancer cells. Our findings demonstrated that ZFPM2-AS1 regulates gastric cancer progression and revealed a novel ZFPM2-AS1/MIF/p53 signaling axis, shedding light on the molecular mechanisms underlying the tumorigenicity of certain malignant gastric cells. PMID- 29985482 TI - The Rac1 splice form Rac1b favors mouse colonic mucosa regeneration and contributes to intestinal cancer progression. AB - We previously have identified the ectopic expression of Rac1b, an activated and novel splice variant of Rac1, in a subset of human colorectal adenocarcinomas, as well as in inflammatory bowel diseases and in colitis mouse model. Rac1b overexpression has been further evidenced in breast, pancreatic, thyroid, ovarian, and lung cancers. In this context, the aim of our study was to investigate the physiopathological implications of Rac1b in intestinal inflammation and carcinogenesis in vivo. The ectopic expression of Rac1b was induced in mouse intestinal epithelial cells after crossing Rosa26-LSL-Rac1b and villin-Cre mice. These animals were let to age or were challenged with dextran sulfate sodium (DSS) to induce experimental colitis, or either received azoxymethane (AOM)/DSS treatment, or were bred with ApcMin/+ or Il10-/- mice to trigger intestinal tumors. Rac1b ectopic expression increased the intestinal epithelial cell proliferation and migration, enhanced the production of reactive oxygen species, and promoted the Paneth cell lineage. Although Rac1b overexpression alone was not sufficient to drive intestinal neoplasia, it enhanced Apc-dependent intestinal tumorigenesis. In the context of Il10 knockout, the Rac1b transgene strengthened colonic inflammation due to induced intestinal mucosa permeability and promoted cecum and proximal colon carcinogenesis. In contrast, Rac1b alleviated carcinogen/acute inflammation-associated colon carcinogenesis (AOM/DSS). This resulted at least partly from the early mucosal repair after resolution of inflammation. Our data highlight the critical role of Rac1b in driving wound-healing after resolution of intestinal inflammation, and in cooperating with Wnt pathway dysregulation and chronic inflammation to promote intestinal carcinogenesis. PMID- 29985485 TI - Tumour decides immune cell ins and outs. PMID- 29985486 TI - Author Correction: What models eat. AB - In the version of this article originally published, there was an error in the sentence "That quest, which started in the 1980s, continues through until today: For a paper published online in 2017, a group of researchers based at Brazil's Federal University of Rio Grande do Sul tested Sprague Dawley rats on either a high-fat diet, a cafeteria diet or what they called a 'Western diet', formulated to match up more closely with eating patterns in developed nations (it had 42.5% of its calories from fat and added salt and carbohydrates)." Wistar rats were used in the experiment, not Sprague Dawley rats. Also, in ref. 7, the first author's last name was listed as Bortoloin. The correct spelling is Bortolin. The errors have been corrected in the HTML and PDF versions of this article. PMID- 29985483 TI - Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization. AB - Influenza virus continues to be a major health problem due to the continually changing immunodominant head regions of the major surface glycoprotein, hemagglutinin (HA). However, some emerging vaccine platforms designed by biotechnology efforts, such as recombinant influenza virus-like particles (VLPs) have been shown to elicit protective antibodies to antigenically different influenza viruses. Here, using biochemical analyses and cryo-electron microscopy methods coupled to image analysis, we report the composition and 3D structural organization of influenza VLPs of the 1918 pandemic influenza virus. HA molecules were uniformly distributed on the VLP surfaces and the conformation of HA was in a prefusion state. Moreover, HA could be bound by antibody targeting conserved epitopes in the stem region of HA. Taken together, our analysis suggests structural parameters that may be important for VLP biotechnology such as a multi component organization with (i) an outer component consisting of prefusion HA spikes on the surfaces, (ii) a VLP membrane with HA distribution permitting stem epitope display, and (iii) internal structural components. PMID- 29985484 TI - High-density Genotyping reveals Genomic Characterization, Population Structure and Genetic Diversity of Indian Mithun (Bos frontalis). AB - The current study aimed at genomic characterization and improved understanding of genetic diversity of two Indian mithun populations (both farm, 48 animals and field, 24 animals) using genome wide genotype data generated with Illumina BovineHD BeadChip. Eight additional populations of taurine cattle (Holstein and NDama), indicine cattle (Gir) and other evolutionarily closely related species (Bali cattle, Yak, Bison, Gaur and wild buffalo) were also included in this analysis (N = 137) for comparative purposes. Our results show that the genetic background of mithun populations was uniform with few possible signs of indicine admixture. In general, observed and expected heterozygosities were quite similar in these two populations. We also observed increased frequencies of small-sized runs of homozygosity (ROH) in the farm population compared to field mithuns. On the other hand, longer ROH were more frequent in field mithuns, which suggests recent founder effects and subsequent genetic drift due to close breeding in farmer herds. This represents the first study providing genetic evidence about the population structure and genomic diversity of Indian mithun. The information generated will be utilized for devising suitable breeding and conservation programme for mithun, an endangered bovine species in India. PMID- 29985487 TI - Subacute sclerosing panencephalitis - current perspectives. AB - Subacute sclerosing panencephalitis is a progressive neurodegenerative disease. It usually occurs 7-10 years after measles infection. The clinical course is characterized by progressive cognitive decline and behavior changes followed by focal or generalized seizures as well as myoclonus, ataxia, visual disturbance, and later vegetative state, eventually leading to death. It is diagnosed on the basis of Dyken's criteria. There is no known cure for subacute sclerosing panencephalitis to date, but it is preventable by ensuring that an effective vaccine program for measles is made compulsory for all children younger than 5 years in endemic countries. PMID- 29985488 TI - Detecting Local Zika Virus Transmission in the Continental United States: A Comparison of Surveillance Strategies. AB - Introduction: The 2015-2017 Zika virus (ZIKV) epidemic in the Americas has driven efforts to strengthen surveillance systems and to develop interventions, testing, and travel recommendations. In the continental U.S. and Hawaii, where limited transmission has been observed, detecting local transmission is a key public health objective. We assessed the effectiveness of three general surveillance strategies for this situation: testing all pregnant women twice during pregnancy, testing blood donations, and testing symptomatic people who seek medical care in an emergency department (ED). Methods: We developed a simulation model for each surveillance strategy and simulated different transmission scenarios with varying population sizes and infection rates. We then calculated the probability of detecting transmission, the number of tests needed, and the number of false positive test results. Results: The probability of detecting ZIKV transmission was highest for testing ED patients with Zika symptoms, followed by pregnant women and blood donors, in that order. The magnitude of the difference in probability of detection between strategies depended on the incidence of infection. Testing ED patients required fewer tests and resulted in fewer false positives than surveillance among pregnant women. The optimal strategy identified was to test ED patients with at least two Zika virus disease symptoms. This case definition resulted in a high probability of detection with relatively few tests and false positives. Discussion: In the continental U.S. and Hawaii, where local ZIKV transmission is rare, optimizing the probability of detecting infections while minimizing resource usage is particularly important. Local surveillance strategies will be influenced by existing public health system infrastructure, but should also consider the effectiveness of different approaches. This analysis demonstrated differences across strategies and indicated that testing symptomatic ED patients is generally a more efficient strategy for detecting transmission than routine testing of pregnant women or blood donors. PMID- 29985495 TI - Transfer of cells with uptaken nanocomposite, magnetite-nanoparticle functionalized capsules with electromagnetic tweezers. AB - Targeted cell delivery via magnetically sensitive microcapsules of an applied magnetic field would advance localized cell transplantation therapy, by which healthy cells can be introduced into tissues to repair damaged or diseased organs. In the present research, we implement magnetically sensitive cells via an uptake of microcapsules containing magnetic nanoparticles in their walls. As is shown in an example of the MA-104 cell line, the magnetic polyelectrolyte multilayer capsules have no toxicity effect on the cells after internalization. Microscopy methods have been used to evaluate the uptake of capsules by the cells. Magnetically sensitive cells are retained in the capillary flow when the magnetic gradient field is applied (<200 T m-1), but they proliferate at the site of retention for several days after the magnet is removed. As an example of cell manipulation, we have demonstrated a novel methodology for cell sheet isolation and transfer using cells impregnated with magnetic microcapsules. A weak enzyme treatment is used to facilitate tissue engineering assemblies by cell monolayer deposition. This type of cell monolayer assembly has provided a 3D tissue engineering construction using an externally applied magnetic field, which is modelled in this study. The approach presented in this work opens perspectives for preclinical studies of tissue and organ repair. PMID- 29985496 TI - A new strategy for hydrophobic drug delivery using a hydrophilic polymer equipped with stacking units. AB - A highly hydrophilic polymer equipped with guanidinium groups was used to load aromatic ring-containing hydrophobic agent doxorubicin (DOX) via pi-pi interaction. The results have shown that the delivery system exhibited enhanced cellular uptake and antitumor efficiency compared with free drugs. This study opens new avenues for the application of hydrophilic polymers in drug delivery. PMID- 29985499 TI - Measuring a frequency spectrum for single-molecule interactions with a confined nanopore. AB - Nanopore analysis is a powerful technique for single molecule analysis by virtue of its electrochemically confined effects. As a single molecule translocates through the nanopore, the featured ionic current pattern on the time scale contains single molecule characteristics including volume, charge, and conformational properties. Although the characteristics of a single molecule in a nanopore have been written to the featured ionic current, extracting the dynamic information from a complex current trace is still a big challenge. Here, we present an applicable nanopore analysis method employing the Hilbert-Huang Transform (HHT) to study the vibrational features and interactions of a single molecule during the dynamic translocation process through the confined space of a nanopore. The HHT method is specially developed for analyzing nonlinear and non stationary data that is highly compatible with nanopore data with a high frequency resolution. To provide proof-of-concept, we applied HHT to measure the frequency response for the wild-type (WT) aerolysin and mutant K238E aerolysin nanopores with and without the presence of poly(dA)4, respectively. The energy frequency-time distribution spectra demonstrate that the biological nanopore contributes greatly to the characteristics of the high frequency component (>2 kHz) in the current recording. Our results suggest that poly(dA)4 undergoes relatively more consistent and confined interactions with K238E than WT, leading to a prolonging of the duration time. Therefore, the characteristics in frequency analysis could be regarded as an "single-molecule ionic spectrum" inside the nanopore, which encodes the detailed behaviours of single-molecule weak interactions. PMID- 29985500 TI - CsPbBr3 perovskite quantum dots/ZnO inverse opal electrodes: photoelectrochemical sensing for dihydronicotinamide adenine dinucleotide under visible irradiation. AB - All-inorganic perovskite quantum dots (PQDs) have attracted tremendous attention due to their extraordinary optical properties, especially CsPbBr3 QDs with their high stability and photoluminescence efficiency. However, studies investigating the biosensing capabilities of PQDs are still limited. In this work, we designed a visible -light-triggered photoelectrochemical (PEC) sensor based on CsPbBr3 QDs for the first time. The immobilized three-dimensional (3D) ZnO inverse opal photonic crystals (IOPCs) were applied to dihydronicotinamide adenine dinucleotide (NADH) sensing. It was found that the CsPbBr3 QDs, as a photoactive material in a PEC sensor, can expand the photocurrent response of the PEC sensor to the visible region, as well as boost its conductivity. This PEC sensor based on a ZnO/CsPbBr3 electrode demonstrates sensitive detection of NADH in phosphate buffer saline solution and serum, with a good linear range from 0.1 MUM to 250 MUM and a low detection limit of 0.010 MUM. Our strategy offers a new approach to perovskite QD-based PEC sensing, which could be more sensitive and convenient for clinical analysis. PMID- 29985501 TI - Floatable superhydrophobic Ag2O photocatalyst without a modifier and its controllable wettability by particle size adjustment. AB - In this research, a controlling mechanism of particle size on the wettability of Ag2O particles is reported, and an interesting floatable Ag2O photocatalyst with superhydrophobicity and superoleophilicity is prepared based on this mechanism. Stable superhydrophobic and superhydrophilic Ag2O without a low-surface-energy modifier can be obtained only by adjusting its particle size, and its wettability can switch mutually by changing the particle size. The wettability of Ag2O converts from superhydrophilic to hydrophobic when the average particle size is more than 1.08 MUm. The operation parameters of the Ag2O crystallization process significantly influence the wettability of the Ag2O particles. The obtained superhydrophobic Ag2O floated on the water surface, and exhibited excellent photodegradation performance with various floating oils. This attractive superhydrophobic Ag2O photocatalyst is promising for practical applications, and provides a strategy for the development of functional photocatalysts and superhydrophobic materials. PMID- 29985502 TI - Na2C monolayer: a novel 2p Dirac half-metal with multiple symmetry-protected Dirac cones. AB - A Dirac half-metal material, which has a gapped band structure in one spin channel but Dirac cones in the other, combines two intriguing properties of 100% spin polarization and massless Dirac fermions and has recently started to attract increasing attention. In this work, using first-principles calculations we predict that the disodium carbide (Na2C) monolayer is an intrinsic 2p Dirac half metal material with 12 fully spin-polarized and symmetry-protected Dirac cones, and a slightly gapped (53 meV) spin-polarized nodal line coexisting in one spin channel, leaving the other spin channel insulated with a gap of 1.9 eV. There are two kinds of Dirac cones in Na2C, protected by different crystalline symmetries, both of which are robust against biaxial strains (+/-5%) and spin-orbit coupling effects, with Fermi velocities of up to 5.2 * 105 m s-1. Ferromagnetism is mainly contributed to by the unpaired 2p electrons in the carbon, with a Curie temperature estimated to be 382 K, and the origin of the 2p magnetism could be explained by the superexchange mechanism between C2- anions with the Na+ cation as a bridge. Our results not only indicate a promising candidate for high-speed spintronic devices, but also reveal the hidden mechanism of the origin of symmetric protection and ferromagnetic exchange interactions in a Dirac semi metal, which would provide a feasible strategy for the design of Dirac materials. PMID- 29985503 TI - Engineering copper nanoparticles synthesized on the surface of carbon nanotubes for anti-microbial and anti-biofilm applications. AB - Biofilms adhere to surfaces to produce extracellular polymeric substances (EPSs). EPSs grow and protect themselves from external stresses. Their formation causes a foul odor and may lead to chronic infectious diseases in animals and people. Biofilms also inhibit the contact between bacteria and antibiotics, thereby reducing their antibacterial activity. Thus, we describe novel nanostructures, a fusion of copper and multi-walled carbon nanotubes (MWCNTs), which increase antimicrobial activity against biofilms without being toxic to human cells. Simulations based on the stochastic response were performed to predict the efficiency of synthesizing nanostructures. The synthesized Cu/MWCNTs inhibit the growth of Methylobacterium spp., which forms biofilms; antimicrobial testing and cytotoxicity assessments showed that the Cu/MWCNTs were not cytotoxic to human cells. The Cu/MWCNTs come in direct contact with the bacterial cell surface, damage the cell wall, and cause secondary oxidation of reactive oxygen species. Furthermore, the Cu/MWCNTs release copper ions, which inhibit the quorum sensing in Methylobacterium spp., thereby inhibiting the expression of the genes that form biofilms. Additionally, we confirmed excellent electrical and thermal conductivity of Cu/MWCNTs as well as biofilm removal efficiency in the microfluidic channel. PMID- 29985507 TI - Charge regulating macro-ions in salt solutions: screening properties and electrostatic interactions. AB - We revisit the charge-regulation mechanism of macro-ions and apply it to mobile macro-ions in a bathing salt solution. In particular, we examine the effects of correlation between various adsorption/desorption sites and analyze the collective behavior in terms of the solution effective screening properties. We show that such a behavior can be quantified in terms of the charge asymmetry of the macro-ions, defined by their preference for a non-zero effective charge, and their donor/acceptor propensity for exchanging salt ions with the bathing solution. Asymmetric macro-ions tend to increase the screening, while symmetric macro-ions can in some cases decrease it. Macro-ions that are classified as donors display a rather regular behavior, while those that behave as acceptors exhibit an anomalous non-monotonic Debye length. The screening properties, in their turn, engender important modifications to the disjoining pressure between two charged surfaces. Our findings are in particular relevant for solutions of proteins, whose exposed amino acids can undergo charge dissociation/association processes to/from the bathing solution, and can be considered as a solution of charged regulated macro-ions, as analyzed here. PMID- 29985509 TI - Rapid cationic defect and anion dual-regulated layered double hydroxides for efficient water oxidation. AB - Defect engineering and anionic regulation are effective approaches to improve the intrinsic activity of oxygen evolution reaction (OER) catalysts, particularly for highly efficient and low-cost cobalt-based electrocatalysts. Layered double hydroxides (LDHs) are considered as promising electrocatalysts toward OER. However, their electronic properties and active sites need to be optimized for their large-scale application. Herein, rapidly cationic defect and anion dual regulated CoAl LDHs (PS-CoAl LDHs) were in situ synthesized in a few minutes via a modified water DBD plasma treatment. Abundant Al3+ vacancies and a relatively rough surface for S2- regulation were formed by the etching effect of the plasma. Consequently, the as-obtained PS-LDHs possess improved intrinsic conductivity and an optimal electronic structure. Simultaneously, the synergistic effect of the Al3+ vacancies and S2- regulation promote the exposure of active Co sites, resulting in an amorphous and porous surface for improving the OER performance. PMID- 29985510 TI - Novel antimonene tunneling field-effect transistors using an abrupt transition from semiconductor to metal in monolayer and multilayer antimonene heterostructures. AB - Recently, a mono-elemental two-dimensional (2-D) material, namely antimonene, with a large band gap, decent mobility and ambient stability has been extensively researched. Interestingly, although antimonene is a semiconductor with a sizable band gap in the monolayer, it is transformed to a metal in the multilayer. Inspired by this thickness dependent semiconductor to metal transition, we propose novel antimonene tunneling field-effect transistors (TFETs) based on the lateral monolayer (semiconducting)/multilayer (metallic)/monolayer (semiconducting) heterostructure. Our antimonene TFETs consist of a semiconducting monolayer source, channel and a drain and a small metallic multilayer region between the source and the channel. The local multilayer region introduces gapless metallic states which dramatically enhance the tunneling probability and hence result in a large current. To investigate the effect of a metallic multilayer on device performances, we carried out ab-initio electronic structure and quantum transport calculations for several antimonene TFETs based on different monolayer/multilayer/monolayer heterostructures. Simulation shows that even ~1 nm scale nanostructured multilayer significantly boosts the current and enables abrupt device switching. More extensive evaluation is performed through benchmarking with phosphorene TFETs which have been identified as the best 2-D material based TFETs so far. In terms of the main figures of merit for FETs such as the intrinsic delay time and the power delay product, antimonene heterostructure TFETs outperform phosphorene TFETs, primarily due to the elimination of the tunneling barrier by the locally constructed multilayer antimonene. PMID- 29985512 TI - Technical Steps and Tips for Linear-Stapled Gastric Bypass Based on Personal Experience and the Classification of Intraoperative Complexity. AB - The most commonly performed Roux-en-Y gastric bypass (RYGB) procedure is difficult and has many technical variations. The individual patient's anatomic characteristics, like an exceptionally large left liver lobe, fatty mesentery with limited mobile Roux limb, difficulty in positioning a stapler, etc., can greatly increase the technical difficulty of this procedure. Challenging situations in laparoscopic gastric bypass surgery can be classified according to the intraoperative complexity. According to this classification scheme, all patients in laparoscopic linear-stapled gastric bypass can be classified into one of four types: Type I - ideal. Surgery is straightforward, and every operative technique is relatively routine. Type II - less-than-ideal. Some minor technical difficulties may occur; some operative techniques can be more difficult than others. Type III - problematic. Difficult, with some operative techniques considerably more difficult than others. Type IV - very difficult. Every operative step is very difficult. The goal of this article is to analyze the steps of laparoscopic linear-stapled RYGB with regard to personal experience and the classification of intraoperative complexity. PMID- 29985513 TI - Special Use of Intraoperative Endoscopy in Sleeve Gastrectomy: A Case Report. AB - Sleeve gastrectomy is the most frequently performed operation for the treatment of morbid obesity. Even though sleeve gastrectomy is now widely standardized, it may still benefit from the use of certain devices and procedures such as intraoperative endoscopy. The use of an endoscope offers numerous advantages that can considerably reduce the morbidity and mortality of patients who undergo laparoscopic sleeve gastrectomy. This paper describes our experience with a case in which the information obtained by endoscopy allowed us to perform a real-time assessment of the location of two large gastric polyps to control the staple line. PMID- 29985514 TI - Three Techniques of Contained Morcellation for the Minimally Invasive Gynecologic Surgeon. AB - Since 1993 (and prior, WISAP(r) [WISAP Medical Technology GmbH, Brunnthal, Germany] hand morcellators), laparoscopic power morcellation has been an indispensably employed technique for minimally invasive gynecologic surgery, contributing both to laparoscopic myomectomies and hysterectomies. However, the technique was highlighted with concern by the FDA for the given potential to disseminate neoplastic and non-neoplastic cells by morcellating an unexpected uterine sarcoma (Fig. 1). Given this concern, many gynecologists are either resorting to performing traditional laparotomies or risking dissemination with uncontained power morcellation techniques. The purpose of this article is to address these concerns by illustrating three techniques to perform contained power morcellation, thereby reaping the benefits of the technique without the disadvantage of possible dissemination of neoplastic cells. The techniques outlined in this article include the use of trans-abdominal mini-laparotomy manual contained morcellation, trans-vaginal manual contained morcellation, and the new Contained Tissue Extraction (CTE) System (Olympus America, Inc., Center Valley, Pennsylvania) for power morcellation. PMID- 29985515 TI - The Association Between Hospital Surgical Volume and the Uptake of Minimally Invasive Surgical Approach and Outpatient Setting for Hysterectomy. AB - BACKGROUND: There are large variations in the use of minimally invasive surgery (MIS), and outpatient hysterectomy (OP) among Medicare patients according to hospital surgical volume and geographical distribution. OBJECTIVE: To explore the changing trend in OP and MIS hysterectomy in the United States. STUDY DESIGN: We used all Medicare fee-for-service claims data for 2012 and 2014 to determine the incidence of OP and MIS hysterectomy according to hospital surgical volume and geographical distribution. MIS included both laparoscopy and robotic surgery. OP procedures included only same-day discharge hysterectomies. RESULTS: A total of 55,562 and 53,054 hysterectomies were performed in the years 2012 and 2014, respectively. OP rate in 2014 in high-volume centers (16,828 [47.1%]) exceeded low-volume centers (136 [16%]) by 31.1% (p<0.001). Time trends between 2014 and 2012 show that a rise in OP rate was 17.7% and 7% for high- and low-volume hospitals (p<0.001), respectively. High-volume hospitals showed an increase of 3.1% (p=0.003) in MIS hysterectomy rate in 2014 (69%) as compared to 2012 (65.9%). There was no change in MIS rate among low-volume hospitals. CONCLUSION: In the Medicare population, the rate of OP and MIS hysterectomy for high-volume centers is significantly different form low-volume centers. Over the years, outpatient hysterectomy is being practiced widely but an increase in MIS rate is limited to high-volume centers. PMID- 29985516 TI - Outcomes of Revision Joint Arthroplasty Due to Metal Allergy and Hypersensitivity: A Systematic Review. AB - BACKGROUND: Lower extremity total joint arthroplasty (TJA) is one of the most successful orthopaedic procedures. However, it is estimated that as many as 10% to 20% of TJAs could fail due to various well-known causes. Furthermore, metal allergy-related complications have recently gained attention as one of the potential causes of failure when the common reasons have been excluded. Reported symptoms from metal allergy can include chronic eczema, joint effusions, joint pain, and limited range of motion. Few studies have explored the outcomes of patients undergoing revisions due to allergic complications. The aim of our study is to quantitatively evaluate the outcomes of revision joint arthroplasty due to metal allergy and hypersensitivity. PMID- 29985517 TI - Anterolateral Ligament of the Knee: What we Know About its Anatomy, Histology, Biomechanical Properties and Function. AB - To better control anterolateral rotational instability (ALRI) after anterior cruciate ligament reconstruction (ACLR), many recent studies have examined the anterolateral ligament (ALL). Although some inconsistencies have been reported, anatomic studies demonstrated that the ALL runs on the lateral side of the knee from the femoral lateral epicondyle area to the proximal tibia, between Gerdy's tubercle and the fibula head. Histologic research has characterized the ALL structure, which is more than a simple capsular thickening; it shows a dense collagen core, typical bony insertions and mechanoreceptor function. An analysis of biomechanical properties suggests that the ALL is weaker than other knee ligaments. While its contributions to tibial anterior translation control and to a high grade on the Pivot-Shift test are still unclear, there is a consensus that the ALL controls tibial internal rotation. Further research will be needed to clarify the significance of ALL injuries and to gauge the value of combined ACL and ALL reconstructions. PMID- 29985518 TI - Management of Staple Line Leaks Following Laparoscopic Sleeve Gastrectomy for Morbid Obesity. AB - PURPOSES: Management of staple-line leaks following laparoscopic sleeve gastrectomy (LSG) is challenging and controversial. Guidelines for leak treatment are not standardized and often involve multidisciplinary management by surgical, medical and radiological methods. Herein we present our experience and proposed strategy for handling leaks after LSG. PATIENTS AND METHODS: Retrospective data regarding LSG performed from April 2012 to October 2017 at the Surgical Oncology Division, Department of Human Pathology in Adulthood and Childhood ''G. Barresi'', University Hospital "G. Martino", University of Messina, Italy, were reviewed. The management approaches and the surgical, endoscopic, and percutaneous procedures used were examined. Outcomes measured included the prevalence of gastric leaks, radiological features, related morbidities and mortalities, hospital stay and management. RESULTS: LSG was performed in 310 patients. Eight patients were managed for gastric leak within the 5-year period: 5 (1.6% overall prevalence) from our division, 3 referred from another hospital. All cases were successfully treated conservatively with combined CT/US-guided drainage using a locking pigtail catheter and endoscopic gastric stent positioning. Endoscopic therapy included the use of fully covered self-expanding esophageal metal stents (Hanarostent(r) 24 cm; M.I. Tech, Seoul, Korea) in addition to pigtail drains (Drainage Catheter Locking Pigtail 8F/21cm; Tru-Set(r) Ure-Sil, Skokie, IL, USA). Complete closure of the leak was achieved in all patients. The mean time from presentation to healing was 74 days +/- 37.76 (SD). None of the patients underwent remedial surgery. CONCLUSION: This study presents our management strategy for leak resolution in LSG patients. Based on our results, we strongly recommend the conservative and combined management of gastric leaks following LSG by endoscopic stenting and percutaneous drainage. PMID- 29985519 TI - Mechanical Reinforced Terminolateral Ileo-Transverse Anastomosis: An Option After Right Hemicolectomy-A 452 Patients Study. AB - INTRODUCTION: Bowel reconstruction techniques after right hemicolectomy has currently been objective of review, due to the high rate of anastomotic leak. The aim of this study is to analyse our results of the mechanical reinforced terminolateral ileo-transverse anastomosis. MATERIALS AND METHODS: A prospective and descriptive study of a consecutive series of right colonic cancer cases that underwent right hemicolectomy. Mechanical reinforced terminolateral ileo transverse anastomosis technique was carried out in all patients. Demographics, emergency or elective surgery, surgical management, postoperative complications, rate of anastomotic leak, need for surgical procedure after complication, average stay, and mortality were analysed. RESULTS: A total of 452 patients underwent surgery between 2010 and 2017. Of those, 40.6% were female and 59.4% were male. The average age and body mass index (BMI) was 72+/-11.3 years old, and 26+/-7.1, respectively. Elective surgery was carried out in 405 (89.6%) patients. Laparoscopic approach was used in 250 patients (61.7%) and 6% needed conversion. Only 41 patients (10.6%) had major complications (Clavien-Dindo III-IV). The rate of postoperative paralytic ileus reach was up to 13.9%. Reintervention was needed in five patients (1.1%) due to anastomotic leak and three (0.7%) of them from the elective surgery subgroup. There were 10 patients (2.2%) with postoperative gastrointestinal bleeding. The average stay was 8.2+/-2.8 days and late postoperative mortality in the first 30 days was 2%. CONCLUSIONS: Mechanical reinforced terminolateral ileo-colic anastomosis is a safe technique with a low anastomotic leak rate. Although our results using this approach seem promising, postoperative paralytic ileus is still a high-rate complication. PMID- 29985520 TI - Influence of Soft Tissue Preservation in Total Hip Arthroplasty: A 16-Year Experience. AB - BACKGROUND: Surgical technique in total hip arthroplasty (THA) has been a topic of debate over the last 50 years. Evidence-based studies are needed to compare one technique to another. This study investigated the outcome of the direct superior approach in primary THA as measured by patient perception of pain and recovery over a 16-year period. MATERIALS AND METHODS: We retrospectively reviewed a series of 3,357 consecutive patients who underwent primary THA by a single surgeon using the direct superior approach between 2001 and 2017. The surgical technique was modified twice during this 16-year period. The first modification (2007) consisted of piriformis tendon preservation. The second modification (2012) consisted of iliotibial band (ITB) preservation. These two modifications of the surgical technique created three different patient groups. A telephone interview regarding patient pain and recovery after each THA was conducted with 147 patients who had staged bilateral THA procedures wherein the surgical technique was modified between the first and second (contralateral) THA. RESULTS: Results show the addition of ITB preservation to capsular repair, with or without piriformis preservation, greatly improves the patient's perception of pain and recovery, causing the majority of patients to prefer their ITB preserving surgery over their ITB-sacrificing surgery. In addition, the dislocation rate over this 16-year period is 0.17%. CONCLUSION: The direct superior approach to the hip results in excellent stability with a dislocation rate of 0.17%. The patient's perception of pain and recovery is dramatically improved with preservation of the iliotibial band. PMID- 29985521 TI - The multilayered structure of the human corpus spongiosum. AB - PURPOSE: Urethral reconstruction is performed in patients with urethral strictures or for correction of congenital disorders. In the case of shortage of tissue, engineered tissue may enhance urethral reconstruction. As the corpus spongiosum (CS) is important in supporting the function of the urethra, tissue engineering of the urethra should be combined with reconstruction of a CS. For that purpose, detailed knowledge of the composition of the CS, more specifically its extracellular matrix (ECM) and vascularization is needed for scaffold design. The objective of this study is to analyze the microarchitecture of the CS through (immuno) histology and scanning electron microscopy (SEM). METHODS: The CS including the urethra of patients undergoing male-to-female genital confirming surgery was harvested. This CS was fixed and processed for either (immuno) histology or for SEM. RESULTS: Four layers could be distinguished in the CS; first a transition zone from urethra epithelium to a collagen rich layer, which was highly vascularized, followed by a second, elastin rich layer. The third layer was formed by veins, arteries and vascular spaces and the last layer showed the transition from this vascular rich region to the collagen rich tunica albuginea. In this layer collagen bundles intertwined with elastic fibres. In the CS different components of the ECM were visible and distinguishable. CONCLUSION: This study provides novel and detailed information on the microarchitecture of the CS and the distribution of vascularization, which is important for scaffold design in tissue engineering. PMID- 29985522 TI - Digest: Untangling the influence of soft and hard selection in experimental populations-from environment to genomics. AB - Gallet et al. (2018) studied the effect of two selection regimes on the maintenance of polymorphism in experimental populations. They took two strains of Escherichia coli, each resistant to a different antibiotic, evolved them in culture conditions representing "soft" or "hard" selective regimes, and measured polymorphism levels for three to five transfers. Their results supported theoretical predictions that only "soft" selection maintains polymorphism, highlighting the importance of experimental studies to understand maintenance of variation in nature. PMID- 29985523 TI - Digest: Ancestry mosaics hint at selection and may provide an alternative to differentiation scans. AB - We now have a flood of genomic sequencing data available to study reproductive isolation and selection in action, but how are these data best analyzed? Usually, genetic differentiation is compared between two groups, scanning along genomes. This approach has several drawbacks, and has been criticized repeatedly. An alternative, truly genetic approach, based on blocks of common ancestry in a hybrid zone setting, is presented by Hvala et al. (2018) in this issue. PMID- 29985524 TI - Comparison of the effectiveness of various rotary and reciprocating systems with different surface treatments to remove gutta-percha and an epoxy resin-based sealer from straight root canals. AB - AIM: To compare the Reciproc Blue, Reciproc and ProTaper Universal Retreatment systems with regard to the effective removal of epoxy resin-based sealer and gutta-percha during the retreatment of oval, straight root canals. METHODOLOGY: Forty-five extracted, human mandibular first premolars with single straight oval canals were selected on the basis of cone beam computed tomography evaluations. The root canals were instrumented with the ProTaper Next system up to the X2 file, and filled with gutta-percha and epoxy resin-based sealer using the cold lateral condensation technique. After 1 month, the samples were randomly divided into three groups (n = 15) according to the retreatment system used: Reciproc Blue R40, Reciproc R40 and ProTaper Universal. The specimens were scanned at the resolution of 1.2 MUm by a microcomputed tomography device after the root filling and retreatment procedures, and the decrease in the volume of filling material after each retreatment protocol was measured. The results were analysed using the Kruskal-Wallis test and additional box-and-whisker plots. RESULTS: Although the volume of the filling material decreased significantly in all three groups (P < 0.05), none of the systems removed the material completely. The Reciproc system removed significantly more material than the ProTaper Universal (P < 0.001) and Reciproc Blue (P = 0.005) systems, with the latter two exhibiting equal volumes of remaining material (P = 0.068). CONCLUSION: The Reciproc system was more effective than the Reciproc Blue and ProTaper Universal Retreatment systems during the removal of filling material from oval, straight canals, although none of the systems completely removed the filling material. PMID- 29985525 TI - Mouth dimorphism in scale-eating cichlid fish from Lake Tanganyika advances individual fitness. AB - Random asymmetry, that is the coexistence of left- and right-sided (or -handed) individuals within a population, is a particular case of natural variation; what triggers and maintains such dimorphisms remains unknown in most cases. Here, we report a field-based cage experiment in the scale-eating Tanganyikan cichlid Perissodus microlepis, which occurs in two morphs in nature: left-skewed and right-skewed individuals with respect to mouth orientation. Using underwater cages stocked with scale-eaters and natural prey fish, we first confirm that, under semi-natural conditions, left-skewed scale-eaters preferentially attack the right flank of their prey, whereas right-skewed individuals feed predominantly from the left side. We then demonstrate that scale-eaters have a higher probability for successful attacks when kept in dimorphic experimental populations (left- and right-skewed morphs together) as compared to monomorphic populations (left- or right-skewed morphs), most likely because prey fishes fail to accustom to strikes from both sides. The significantly increased probability for attacks appears to be the selective agent responsible for the evolution and maintenance of mouth dimorphism in P. microlepis, lending further support to the hypothesis that negative frequency-dependent selection is the stabilizing force balancing the mouth dimorphism at quasi-equal ratios in scale-eating cichlids. PMID- 29985526 TI - Opioid Therapy in Acute and Chronic Pain. AB - This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical procedures or anesthesia is not discussed. Basic pharmacokinetic and pharmacodynamic properties of opioids are reviewed. The safe and effective use of opioids, including clinical assessment and treatment plan, equianalgesic dosing, opioid rotation, opioid risks and side effects, and clinical adherence monitoring are discussed. Individualized opioid use can be a safe and effective component of a patient-specific multimodal treatment plan for acute or chronic pain. Adverse effects and risks can be prevented or effectively managed when anticipated and recognized. The article is followed by 4 clinical vignettes with discussions. PMID- 29985527 TI - Directional selection reduces developmental canalization against genetic and environmental perturbations in Drosophila wings. AB - Natural selection may enhance or weaken the robustness of phenotypes against genetic or environmental perturbations. However, important aspects of the relationship between adaptive evolution and canalization remain unclear. Recent work showed that the evolution of larger wing size in a high altitude natural population of Drosophila melanogaster was accompanied by decanalized wing development--specifically a loss of robustness to genetic perturbation. But this study did not address environmental robustness, and it compared populations that may have numerous biological differences. Here, we perform artificial selection on this same trait in D. melanogaster (larger wing length) and directly test whether this directional selection resulted in decanalization. We find that in general, size-selected replicates show greater frequencies of wing defects than control replicates both after mutagenesis (genetic perturbation) and when subjected to high temperature stress (environmental perturbation), although the increase in defect frequency varies importantly among replicates. These results support the hypothesis that directional selection may result in the loss of both genetic and environmental robustness-offering a rare window into the relationship between adaptation and canalization. PMID- 29985528 TI - Fracture incidence of instruments from a single-file reciprocating system by students in an endodontic graduate programme: a cross-sectional retrospective study. AB - AIM: To assess the fracture incidence of instruments from single-file reciprocating systems when used by students in an endodontic graduate programme. METHODOLOGY: Dental records and periapical radiographs of patients treated by students on an endodontic graduate programme using reciprocating systems were assessed. Data on tooth type, number of treated root canals, number of fractured instruments, fragment size, angle, radius, arc length and position of root canal curvature where fractures occurred were tabulated for analysis. The risk of fracture was calculated for each group of teeth, root canal and root thirds, whilst the incidence of fractures reported for the reciprocating systems was compared using the chi-squared test at 5% significance level. RESULTS: Overall, 2056 root canals (826 teeth) from 810 patients were included. The incidence of fractured files from single-file reciprocating systems in relation to a number of instrumented canals was 0.92%. Fracture rates of 0.84% and 0.93% were found in 830 and 1226 root canals instrumented with WaveOne and Reciproc systems, respectively. No significant differences were observed between the systems. The highest fracture rate was 52.6% in the mesiobuccal root of mandibular molars. The central angle, radius and arc length of the curvature of root canals where the instruments fractured ranged from 58 degrees to 84 degrees , from 1.7 to 7.2 mm and from 2.4 to 7.6 mm, respectively. CONCLUSION: The use of WaveOne and Reciproc single-file reciprocating systems in an endodontic graduate programme was associated with a low incidence of instrument fractures. PMID- 29985530 TI - Evaluation of Aromaticity for Open-Shell Singlet Dicyclopenta-Fused Acenes and Polyacenes Based on a Magnetically Induced Current. AB - The aromaticity of dicyclopenta-fused acenes (DPAs) and polyacenes (PAs) of increasing size has been studied by evaluation with the GIMIC method at the DFT level of the magnetically-induced currents (MICs), and by analyzing their spatial distributions. For these open-shell singlet molecules, spin-restricted and unrestricted treatments provide very different MICs, the latter ones providing the most reliable solution. These MICs and the differences between spin restricted and -unrestricted treatments are interpreted in terms of the bond current strengths and the current gradients, which indicate the bond aromaticity and enable the spatial distributions of the diatropic and paratropic currents to be analyzed, respectively. In particular, they allow the rationalization of the MICs in correlation with the odd-electron density distributions and their diradical characters. These calculations demonstrate that 1) in increasingly large PAs the bond current strengths get smaller and smaller than in benzene and get almost similar in the central and terminal rings, 2) for DPAs the MICs increase from dominant paratropic currents and antiaromaticity in the small compounds to diatropic currents and aromaticity in the larger ones, and 3) in the largest DPAs, the central rings are characterized by large diatropic currents and the terminal five-membered rings, for which the odd-electron densities are localized by weak ones. PMID- 29985529 TI - Gr1-/low CD11b-/low MHCII+ myeloid cells boost T cell anti-tumor efficacy. AB - Conventional APCs that express MHC class II (MHCII) and co-stimulatory molecules include dendritic cells (DCs) and macrophages. Beyond these conventional APCs, immune stimulatory cells have been more recently shown to extend to a class of atypical APCs, composed of mast cells, basophils, and eosinophils. Here, we describe a unique type of APC, Gr1-/low CD11b-/low cells with a granularity and size characteristic of myeloid cells and with the ability to present Ag for crosspresentation. These cells constitutively express MHCII and the costimulatory molecules, CD80, CD86, and CD40. They do not express pan markers of myeloid DCs (CD11c), plasmacytoid DCs (Ly6C), or macrophages (F4/80), and their frequency is inversely correlated with myeloid-derived suppressor cells (MDSCs) in tumor bearing mice. Among splenocytes, they are more abundant than DCs and macrophages, and they exhibit antitumor immune stimulatory function at a steady state without further activation, ex vivo. They are also found within the tumor bed where they retain their immune stimulatory function. Our findings suggest the use of these novel APCs in additional preclinical studies to further investigate their utility in APC-based cancer immunotherapies. PMID- 29985531 TI - Mechanical reduction in intracanal Enterococcus faecalis when using three different single-file systems: an ex vivo comparative study. AB - AIM: To evaluate the bacterial reduction achieved by WaveOne Gold (Dentsply Sirona Endodontics, Ballaigues, Switzerland), Hyflex EDM (Coltene-Whaledent, Altstatten, Switzerland), and XP-endo Shaper (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland) in canals infected with Enterococcus faecalis. The null hypothesis (H0 ) was that there would be no difference amongst the NiTi systems in reducing the root canal bacterial load. METHODOLOGY: Seventy-four mandibular premolar teeth with straight and round root canals were selected. Sixty-two root canals were contaminated with E. faecalis for 4 weeks and subjected to mechanical preparation with one of three single-file NiTi rotary systems (WaveOne Gold, Hyflex EDM, and XP Endo Shaper). Twelve non-contaminated root canals were used as negative controls. Bacterial samples were collected with sterile paper points (Dentsply Sirona Endodontics) before and after rotary instrumentation to quantify the bacterial load. Five roots from each instrumentation group were evaluated topographically from the coronal, middle and apical thirds by SEM. The bacterial reduction was calculated and analysed statistically by the Kruskal-Wallis and Dunn post hoc tests, all at 5% significance. RESULTS: The samples taken before instrumentation showed approximately 9.64 log CFU bacterial load. Instrumentation with the Hyflex EDM and XP-endo Shaper resulted in significantly greater bacterial reduction than those with WaveOne Gold (P = 0.00). All specimens had bacterial growth. SEM images supported the CFU/mL data. Thick and dense debris was observed in WaveOne Gold samples. Instrumentation resulted in the disruption of the biofilm-like structure, and both areas of clean and open dentinal tubules and areas with thick debris were observed in Hyflex EDM and XP-endo Shaper samples. CONCLUSIONS: Instrumentation in straight and round canals of premolar teeth with the Hyflex EDM and XP-endo Shaper resulted in significantly greater bacterial reduction than WaveOne Gold. No instrumentation system rendered root canals completely free from bacteria. PMID- 29985532 TI - Elliptical localization with pulsed second-order fields (ECLIPSE) for robust lipid suppression in proton MRSI. AB - Proton MRSI has great clinical potential for metabolic mapping of the healthy and pathological human brain. Unfortunately, the promise has not yet been fully achieved due to numerous technical challenges related to insufficient spectral quality caused by magnetic field inhomogeneity, insufficient RF transmit power and incomplete lipid suppression. Here a robust, novel method for lipid suppression in 1 H MRSI is presented. The method is based on 2D spatial localization of an elliptical region of interest using pulsed second-order spherical harmonic (SH) magnetic fields. A dedicated, high-amplitude second-order SH gradient setup was designed and constructed, containing coils to generate Z2, X2Y2 and XY magnetic fields. Simulations and phantom MRI results are used to demonstrate the principles of the method and illustrate the manifestation of chemical shift displacement. 1 H MRSI on human brain in vivo demonstrates high quality, robust suppression of extracranial lipids. The method allows a wide range of inner or outer volume selection or suppression and should find application in MRSI, reduced-field-of-view MRI and single-volume MRS. PMID- 29985534 TI - Solvatomorphism-Induced 45 K Hysteresis Width in a Spin-Crossover Mononuclear Compound. AB - Spin-transition compounds are coordination complexes that can present two stable or metastable high-spin and low-spin states at a given temperature (thermal hysteresis). The width of the thermal hysteresis (difference between the maximum and minimum temperature between which the compound exhibits bi-stability) depends on the interactions between the coordination complexes within the compound, and which may be modulated by the absence or presence of solvent within the structure. The new compound [Fe(3-bpp)2 ][Au(CN)2 ]2 (1, 3-bpp=2,6-di-(1H-pyrazol 3-yl)pyridine) was synthesized and its properties were compared with those of the solvated compound [Fe(3-bpp)2 ][Au(CN)2 ]2 ?2 H2 O (1.H2 O) already described. 1 has a two-steps thermal hysteresis of 45 K, in contrast to the compound 1.H2 O which exhibits a gradual conversion without hysteresis. This hysteretic transition is accompanied by a reversible reconstructive structural transition and twinning. This stepped behaviour is also observed in the photomagnetic properties despite the low efficiency of photoswitching. Single-crystal photocrystallographic investigations confirm this low conversion, which we attributed to the high energy cost to form the high-spin structure, whose symmetry differs from that of the low-spin phase. PMID- 29985533 TI - Activation of alphaSMA expressing perivascular cells during reactionary dentinogenesis. AB - AIM: To examine the contribution of perivascular cells expressing alphaSMA to reactionary dentinogenesis. METHODOLOGY: An inducible, Cre-loxP in vivo fate mapping approach was used to examine the contribution of the descendants of cells expressing the alphaSMA-CreERT2 transgene to reactionary dentinogenesis in mice molars. Reactionary dentinogenesis was induced by experimental mild injury to dentine without pulp exposure. The Student's t test was used to determine statistical significance at *P <= 0.05. RESULTS: The lineage tracing experiments revealed that mild injury to dentine first led to activation of alphaSMA tdTomato+ cells in the entire pulp chamber. The percentage of areas occupied by alphaSMA-tdTomato+ in injured (7.5 +/- 0.7%) teeth were significantly higher than in teeth without injury (2 +/- 0.5%). After their activation, alphaSMA-tdTomato+ cells migrated towards the site of injury, gave rise to pulp cells and a few odontoblasts that became integrated into the existing odontoblast layer expressing Col2.3-GFP and Dspp. CONCLUSION: Mild insult to dentine activated perivascular alphaSMA-tdTomato+ cells giving rise to pulp cells as well as a few odontoblasts that were integrated into the pre-existing odontoblast layer. PMID- 29985535 TI - Interpretation of HbA1c in primary care and potential influence of anaemia and chronic kidney disease: an analysis from the Copenhagen Primary Care Laboratory (CopLab) Database. AB - AIMS: To investigate, in a large population in primary care, the relationship between fasting plasma glucose and HbA1c measurements, as well as the clinical implications of anaemia or chronic kidney disease for the interpretation of HbA1c values. METHODS: From a primary care resource, we examined HbA1c and fasting plasma glucose as well as haemoglobin and estimated GFR. We stratified observations by chronic kidney disease stage and anaemia level. The estimation of the mean fasting plasma glucose level from HbA1c alone, and from HbA1c , haemoglobin and estimated GFR, respectively, was evaluated. RESULTS: In 198 346 individuals, the fasting plasma glucose-HbA1c relationship mimicked the regression described in the A1c-Derived Average Glucose (ADAG) study, which was based on average capillary and interstitial glucose. The fasting plasma glucose HbA1c relationship was unaffected in mild to moderate chronic kidney disease and in mild to moderate anaemia. The correlation changed only in severe hyperglycaemia and concurrent severe anaemia or when estimated GFR was <45 ml/min/1.73m2, so that glucose concentration was underestimated by HbA1c in anaemia and overestimated in chronic kidney disease. The prevalence of estimated GFR <30 ml/min/1.73m2 was 0.82%, while the prevalence of haemoglobin <81 g/l (5.0 mmol/l) was 0.11%. CONCLUSIONS: The relationship between fasting plasma glucose and HbA1c mimics that of the people with diabetes included in the ADAG study. Mild to moderate anaemia and CKD do not have a significant impact on the interpretation of HbA1c as a marker of retrograde glycaemia. Hence, it seems justified to use HbA1c without adjustment in primary care. PMID- 29985536 TI - TERT promoter mutations in solitary fibrous tumour. AB - AIMS: TERT promoter mutations have been reported in 22% of solitary fibrous tumours (SFT) and have been associated with poor outcomes. We performed testing for TERT hot-spot mutations in a large series of SFT in order to confirm this finding and explore clinicopathological correlates of mutation status. METHODS AND RESULTS: PCR for TERT hot-spot mutations C250T and C228T was performed on DNA extracted from 216 SFT and mutation status correlated with clinicopathological factors, including predicted risk for metastasis using a previously published model. Testing was successful in 189 tumours from 172 patients, and mutations were present in 29%. The presence of TERT promoter mutation was associated with larger primary tumour size, necrosis and older patient age. TERT promoter mutations were most common in high-risk tumours (nine of 20, 45%), and were present in 11 of 26 (42%) moderate-risk tumours and 14 of 67 (21%) low-risk tumours (P = 0.004). Overall, TERT mutations were associated with shorter time to first metastasis (P = 0.04), but had no impact on overall survival. TERT promoter mutation status was found not to provide additional prognostic information in low and high-risk SFT, but did identify a group of patients with intermediate risk SFT who had an increased risk of metastasis. CONCLUSIONS: TERT promoter mutations were more frequent in SFT with higher risk of metastasis, but TERT promoter mutation status was not a reliable predictor of clinical outcome by itself. However, mutations in the TERT promoter may be useful in further stratifying patients with intermediate risk tumours. PMID- 29985537 TI - Secukinumab decreases serum Krebs von den Lungen 6 (KL-6) level in patients with psoriasis with elevated serum KL-6 level. PMID- 29985538 TI - Segmental allopolyploidy in action: Increasing diversity through polyploid hybridization and homoeologous recombination. AB - PREMISE OF THE STUDY: The genetic bottleneck of polyploid formation can be mitigated by multiple origins, gene flow, and recombination among different lineages. In crop plants with limited origins, efforts to increase genetic diversity have limitations. Here we used lineage recombination to increase genetic diversity in peanut, an allotetraploid likely of single origin, by crossing with a novel allopolyploid genotype and selecting improved lines. METHODS: Single backcross progeny from cultivated peanut * wild species-derived allotetraploid cross were studied over successive generations. Using genetic assumptions that encompass segmental allotetraploidy, we used single nucleotide polymorphisms and whole-genome sequence data to infer genome structures. KEY RESULTS: Selected lines, despite a high proportion of wild alleles, are agronomically adapted, productive, and with improved disease resistances. Wild alleles mostly substituted homologous segments of the peanut genome. Regions of dispersed wild alleles, characteristic of gene conversion, also occurred. However, wild chromosome segments sometimes replaced cultivated peanut's homeologous subgenome; A. ipaensis B sometimes replaced A. hypogaea A subgenome (~0.6%), and A. duranensis replaced A. hypogaea B subgenome segments (~2%). Furthermore, some subgenome regions historically lost in cultivated peanut were "recovered" by wild chromosome segments (effectively reversing the "polyploid ratchet"). These processes resulted in lines with new genome structure variations. CONCLUSIONS: Genetic diversity was introduced by wild allele introgression, and by introducing new genome structure variations. These results highlight the special possibilities of segmental allotetraploidy and of using lineage recombination to increase genetic diversity in peanut, likely mirroring what occurs in natural segmental allopolyploids with multiple origins. PMID- 29985539 TI - Adaptive differentiation among populations of the Mediterranean dry grassland species Brachypodium retusum: The role of soil conditions, grazing, and humidity. AB - PREMISE OF THE STUDY: Genetic differentiation in plant species may result from adaptation to environmental conditions, but also from stochastic processes. The drivers selecting for local adaptation and the contribution of adaptation to genetic differentiation are often unknown. Restoration and succession studies have revealed different colonization patterns for Brachypodium retusum, a common Mediterranean grass. In order to understand these patterns, we tested population differentiation and adaptation to different environmental factors. METHODS: Structured sampling of 12 populations from six sites and two soil types within site was used to analyze the spatial and environmental structure of population differentiation. Sampling sites differ in grazing intensity and climate. We tested germination and growth in a common garden. In subsets, we analyzed the differential response to stone cover, grazing and soil moisture. KEY RESULTS: We found significant differences among populations. The site explained population differentiation better than soil, suggesting a dominant influence of climate and/or genetic drift. Stone cover had a positive influence on seedling establishment, and populations showed a differential response. However, this response was not related to environmental differences between collection sites. Regrowth after clipping was higher in populations from the more intensively grazed Red Mediterranean soils suggesting an adaptation to grazing. Final germination was generally high even under drought, but germination response to differences in soil moisture was similar across populations. CONCLUSIONS: Adaptive population differentiation in germination and early growth may have contributed to different colonization patterns. Thus, the provenance of B. retusum needs to be carefully considered in ecological restoration. PMID- 29985540 TI - Drug-induced thrombotic microangiopathy: An updated systematic review, 2014-2018. PMID- 29985542 TI - Repurposing Cyanine NIR-I Dyes Accelerates Clinical Translation of Near-Infrared II (NIR-II) Bioimaging. AB - The significantly reduced tissue autofluorescence and scattering in the NIR-II region (1000-1700 nm) opens many exciting avenues for detailed investigation of biological processes in vivo. However, the existing NIR-II fluorescent agents, including many molecular dyes and inorganic nanomaterials, are primarily focused on complicated synthesis routes and unknown immunogenic responses with limited potential for clinical translation. Herein, the >1000 nm tail emission of conventional biocompatible NIR cyanine dyes with emission peaks at 700-900 nm is systematically investigated, and a type of bright dye for NIR-II imaging with high potential for accelerating clinical translation is identified. The asymmetry of the pi domain in the S1 state of NIR cyanine dyes is proven to result in a twisted intramolecular charge-transfer process and NIR-II emission, establishing a general rule to guide future NIR-I/II fluorophore synthesis. The screened NIR dyes are identified to possess a bright emission tail in the NIR-II region along with high quantum yield, high molar-extinction coefficient, rapid fecal excretion, and functional groups amenable for bioconjugation. As a result, NIR cyanine dyes can be used for NIR-II imaging to afford superior contrast and real time imaging of several biological models, facilitating the translation of NIR-II bioimaging to clinical theranostic applications. PMID- 29985541 TI - Intraoperative use of low volume ventilation to decrease postoperative mortality, mechanical ventilation, lengths of stay and lung injury in adults without acute lung injury. AB - BACKGROUND: Since the 2000s, there has been a trend towards decreasing tidal volumes for positive pressure ventilation during surgery. This an update of a review first published in 2015, trying to determine if lower tidal volumes are beneficial or harmful for patients. OBJECTIVES: To assess the benefit of intraoperative use of low tidal volume ventilation (less than 10 mL/kg of predicted body weight) compared with high tidal volumes (10 mL/kg or greater) to decrease postoperative complications in adults without acute lung injury. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (OvidSP) (from 1946 to 19 May 2017), Embase (OvidSP) (from 1974 to 19 May 2017) and six trial registries. We screened the reference lists of all studies retained and of recent meta-analysis related to the topic during data extraction. We also screened conference proceedings of anaesthesiology societies, published in two major anaesthesiology journals. The search was rerun 3 January 2018. SELECTION CRITERIA: We included all parallel randomized controlled trials (RCTs) that evaluated the effect of low tidal volumes (defined as less than 10 mL/kg) on any of our selected outcomes in adults undergoing any type of surgery. We did not retain studies with participants requiring one-lung ventilation. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the quality of the retained studies with the Cochrane 'Risk of bias' tool. We analysed data with both fixed-effect (I2 statistic less than 25%) or random-effects (I2 statistic greater than 25%) models based on the degree of heterogeneity. When there was an effect, we calculated a number needed to treat for an additional beneficial outcome (NNTB) using the odds ratio. When there was no effect, we calculated the optimum information size. MAIN RESULTS: We included seven new RCTs (536 participants) in the update.In total, we included 19 studies in the review (776 participants in the low tidal volume group and 772 in the high volume group). There are four studies awaiting classification and three are ongoing. All included studies were at some risk of bias. Participants were scheduled for abdominal surgery, heart surgery, pulmonary thromboendarterectomy, spinal surgery and knee surgery. Low tidal volumes used in the studies varied from 6 mL/kg to 8.1 mL/kg while high tidal volumes varied from 10 mL/kg to 12 mL/kg.Based on 12 studies including 1207 participants, the effects of low volume ventilation on 0- to 30-day mortality were uncertain (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.42 to 1.53; I2 = 0%; low-quality evidence). Based on seven studies including 778 participants, lower tidal volumes probably reduced postoperative pneumonia (RR 0.45, 95% CI 0.25 to 0.82; I2 = 0%; moderate-quality evidence; NNTB 24, 95% CI 16 to 160), and it probably reduced the need for non invasive postoperative ventilatory support based on three studies including 506 participants (RR 0.31, 95% CI 0.15 to 0.64; moderate-quality evidence; NNTB 13, 95% CI 11 to 24). Based on 11 studies including 957 participants, low tidal volumes during surgery probably decreased the need for postoperative invasive ventilatory support (RR 0.33, 95% CI 0.14 to 0.77; I2 = 0%; NNTB 39, 95% CI 30 to 166; moderate-quality evidence). Based on five studies including 898 participants, there may be little or no difference in the intensive care unit length of stay (standardized mean difference (SMD) -0.06, 95% CI -0.22 to 0.10; I2 = 33%; low-quality evidence). Based on 14 studies including 1297 participants, low tidal volumes may have reduced hospital length of stay by about 0.8 days (SMD -0.15, 95% CI -0.29 to 0.00; I2 = 27%; low-quality evidence). Based on five studies including 708 participants, the effects of low volume ventilation on barotrauma (pneumothorax) were uncertain (RR 1.77, 95% CI 0.52 to 5.99; I2 = 0%; very low-quality evidence). AUTHORS' CONCLUSIONS: We found moderate-quality evidence that low tidal volumes (defined as less than 10 mL/kg) decreases pneumonia and the need for postoperative ventilatory support (invasive and non invasive). We found no difference in the risk of barotrauma (pneumothorax), but the number of participants included does not allow us to make definitive statement on this. The four studies in 'Studies awaiting classification' may alter the conclusions of the review once assessed. PMID- 29985543 TI - Spores potentially dispersed to longer distances are more tolerant to ultraviolet radiation: A case study in the moss genus Orthotrichum. AB - PREMISE OF THE STUDY: Ultraviolet (UV) radiation influences the viability of algal spores and seed-plant pollen depending on the species, the dose, and the wavelength. In bryophytes, one of the dominant groups of plants in many habitats, UV radiation could determine their spore dispersal strategy, and such data are critical for reconstructing the ancestral state in plants and for determining the distribution range and persistence of bryophyte species. METHODS: Spores of four bryophyte species of the moss genus Orthotrichum that were either hygrochastic or xerochastic (spores dispersed under wet or dry conditions, respectively) were exposed to realistic doses of UV radiation under laboratory conditions. Spore viability was evaluated through germination experiments and, for the first time in bryophytes, ultrastructural observations. Given that the UV-B doses used were relatively higher than the UV-A doses, the UV effect was probably due more to UV B than UV-A wavelengths. KEY RESULTS: All four species reduced their spore germination capacity in a UV dose-dependent manner, concomitantly increasing spore ultrastructural damage (cytoplasmic and plastid alterations). Most spores eventually died when exposed to the highest UV dose. Interestingly, spores of hygrochastic species were much more UV-sensitive than those of xerochastic species. CONCLUSIONS: UV tolerance determines moss spore viability, as indicated by germination capacity and ultrastructural damage, and differs between spores of species with different dispersal strategies. Specifically, the higher UV tolerance of xerochastic spores may enable them to be dispersed to longer distances than hygrochastic spores, thus extending more efficiently the distribution range of the corresponding species. PMID- 29985544 TI - Update on infection control practices in cancer hospitals. AB - Therapies in oncology have evolved rapidly over the last years. At the same pace, supportive care for patients receiving cancer therapy has also evolved, allowing patients to safely receive the newest advances in treatment in both an inpatient and outpatient basis. The recognition of the role of infection control and prevention (ICP) in the outcomes of patients living with cancer has been such that it is now a requirement for hospitals and involves multidisciplinary groups. Some unique aspects of ICP for patients with cancer that have gained momentum over the past few decades include catheter-related infections, multidrug resistant organisms, community-acquired viral infections, and the impact of the health care environment on the horizontal transmission of organisms. Furthermore, as the potential for infections to cross international borders has increased, alertness for outbreaks or new infections that occur outside the area have become constant. As the future approaches, ICP in immunocompromised hosts will continue to integrate emerging disciplines, such as antibiotic stewardship and the microbiome, and new techniques for environmental cleaning and for controlling the spread of infections, such as whole-genome sequencing. CA Cancer J Clin 2018;000:000-000. (c) 2018 American Cancer Society. PMID- 29985546 TI - Considerations on human Herpesvirus 6 reactivation after cord blood transplantation. PMID- 29985545 TI - Interventions for recurrent corneal erosions. AB - BACKGROUND: Recurrent corneal erosion is a common cause of disabling ocular symptoms and predisposes the cornea to infection. It may follow corneal trauma. Measures to prevent the development of recurrent corneal erosion following corneal trauma have not been firmly established. Once recurrent corneal erosion develops, simple medical therapy (standard treatment) may lead to resolution of the episode. However, some people continue to suffer when such therapy fails and repeated episodes of erosion develop. A number of treatment and prophylactic options are then available but there is no agreement as to the best option. This review version is an update to the original version published in 2007 and a previous update published in 2012. OBJECTIVES: To assess the effectiveness and adverse effects of regimens for the prophylaxis of further recurrent corneal erosion episodes, the treatment of recurrent corneal erosion and prophylaxis of the development of recurrent corneal erosion following trauma. SEARCH METHODS: We searched CENTRAL, which contains the Cochrane Eyes and Vision Trials Register; MEDLINE; Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov and the ICTRP. The date of the search was 14 December 2017. SELECTION CRITERIA: We included randomised and quasi-randomised trials that compared a prophylactic or treatment regimen with another prophylaxis/treatment or no prophylaxis/treatment for people with recurrent corneal erosion. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Two authors independently screened search results, extracted data and assessed risk of bias in the included studies using the Cochrane tool for assessing risk of bias. We considered the following outcome measures: resolution of symptoms after treatment; recurrence after complete or partial resolution; symptoms (pain); adverse effects (corneal haze, astigmatism). We graded the certainty of the evidence using GRADE for the three most clinically relevant comparisons. MAIN RESULTS: We included eight randomised and two quasi randomised controlled trials in the review, encompassing 505 participants. Seven studies were from Europe (Germany, Sweden and the UK), two from East Asia (Hong Kong and Japan) and one from Australia. Nine of the studies examined treatments for episodes of recurrent corneal erosions and one study considered prophylaxis to prevent development of recurrent corneal erosions after injury. Two of the nine treatment studies also enrolled participants in a study of prophylaxis to prevent further episodes of recurrent corneal erosions. The studies were poorly reported; we judged only one study low risk of bias on all domains.Two studies compared therapeutic contact lens with topical lubrication but one of these studies was published over 30 years ago and used a therapeutic contact lens that is no longer in common use. The more recent study was a two-centre UK study with 29 participants. It provided low-certainty evidence on resolution of symptoms after treatment with similar number of participants in both groups experiencing resolution of symptoms at four months (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.62 to 1.53). There was very low-certainty evidence on recurrence after partial or total resolution at seven months' follow-up (RR 1.07, 95% CI 0.07 to 15.54). There was no evidence of an important difference in pain score (score of 3 in the contact lens group and score of 2 in the topical lubrication group, low-certainty evidence) and no adverse effects were reported. The older study, using a contact lens no longer in common use, found an increased risk of pain and complications with the contact lens compared with hypromellose drops and paraffin ointment at night.A single-centre, Australian study, with 33 participants, provided low-certainty evidence of an increased risk of recurrence with phototherapeutic keratectomy compared with alcohol delamination but with wide confidence intervals, compatible with increased or decreased risk (RR 1.27, 95% CI 0.48 to 3.37). Time to recurrence was similar in both groups (6.5 and 6 months, low-certainty evidence). On average people receiving phototherapeutic keratectomy reported less pain but confidence intervals included no difference or greater pain (mean difference (MD) -0.70, 95% CI -2.23 to 0.83, low-certainty evidence). No adverse effects were reported.A 48-participant study in Hong Kong found recurrences were less common in people given diamond burr superficial keratectomy after epithelial debridement compared with sham diamond burr treatment after epithelial debridement (RR 0.07, 95% CI 0.01 to 0.50, moderate certainty evidence). The study did not report pain scores but adverse effects such as corneal haze (RR 0.92, 95% CI 0.06 to 13.87, low-certainty evidence) and astigmatism (0.88 versus 0.44 dioptres, moderate-certainty evidence) were similar between the groups.A study comparing transepithelial versus subepithelial excimer laser ablation in 100 people found low-certainty evidence of a small increased risk of recurrence of corneal erosion at one-year follow-up in people given the transepithelial compared with subepithelial technique, however, the confidence intervals were wide and compatible with increased or decreased risk (RR 1.20, 95% CI 0.58 to 2.48, low-certainty evidence). Other outcomes were not reported.Other treatment comparisons included in this review were only addressed by studies published two decades or more ago. The results of these studies were inconclusive: excimer laser ablation (after epithelial debridement) versus no excimer laser ablation (after epithelial debridement), epithelial debridement versus anterior stromal puncture, anterior stromal puncture versus therapeutic contact lens, oral oxytetracycline and topical prednisolone (in addition to 'standard therapy') versus oral oxytetracycline (in addition to 'standard therapy') versus 'standard therapy'. AUTHORS' CONCLUSIONS: Well-designed, masked, randomised controlled trials using standardised methods are needed to establish the benefits of new and existing prophylactic and treatment regimes for recurrent corneal erosion. Studies included in this review have been of insufficient size and quality to provide firm evidence to inform the development of management guidelines. International consensus is also needed to progress research efforts towards evaluation of the major effective treatments for recurrent corneal erosions. PMID- 29985548 TI - Are we correctly assessing transplant outcomes by using deprivation indices? PMID- 29985547 TI - Persistent involvement of anterior mesorectal fascia in carcinoma rectum - extended resection of rectum vs total pelvic exenteration: results from a single centre retrospective study. AB - AIM: Involvement of the anterior mesorectal fascia (iAMRF) after neoadjuvant treatment leads to either resection of the involved organ alone [extended resection of the rectum (ERR)] or total pelvic exenteration (TPE). The purpose of this study was to compare the rate of recurrence and survival of patients undergoing ERR or TPE for iAMRF after neoadjuvant treatment. The outcome of patients who underwent total mesorectal excision after downstaging was also compared. METHOD: This was a retrospective study of primary rectal cancer patients. RESULTS: Of 237 patients, 61 (21.5%) patients with nonmetastatic carcinoma rectum had iAMRF at baseline. Ten patients defaulted before completion of neoadjuvant chemoradiotherapy. After neoadjuvant chemoradiotherapy, 22 patients (43.1%) developed systemic metastases, seven patients (13.8%) were downstaged to free anterior mesorectal fascia and underwent total mesorectal excision (anterior resection/abdominoperineal resection) and the remaining 22 patients (43.1%) had persistent iAMRF. Thirteen patients with persistent iAMRF underwent ERR, whereas nine patients underwent TPE. The median duration of hospital stay in the TPE group was 13 days (10-26), whereas it was 7 days (5-21) in the ERR group. A clear circumferential resection margin, R0 resection, was achieved in all patients with TPE and ERR. After a median follow-up of 31.6 months, five patients with TPE (55.6%), four patients with ERR (30.7%) and three patients in the downstaged group (42.9%) developed systemic recurrence. None of the patients with TPE and the downstaged group developed local recurrence, whereas three patients with ERR (23.1%) developed local recurrence. Median disease-free survival was 12.3 months in the TPE group, 18.9 months in the ERR group and 10.6 months in the downstaged group, whereas mean overall survival was 36.2, 32.8 and 27.9 months, respectively. CONCLUSION: Although there is no significant difference in the overall survival and disease-free survival, ERR is associated with a high risk of local recurrence compared to TPE and the downstaged group. PMID- 29985549 TI - Visible-Light-Mediated Metal-Free Synthesis of Trifluoromethylselenolated Arenes. AB - The first visible-light-mediated synthesis of trifluoromethylselenolated arenes under metal-free conditions is reported. The use of an organic photocatalyst enables the trifluoromethylselenolation of arene diazonium salts using the shelf stable reagent trifluoromethyl tolueneselenosulfonate at room temperature. The reaction does not require the presence of any additives and shows high functional group tolerance, covering a very broad range of starting materials. Mechanistic investigations, including EPR spectroscopy, luminescence investigations, and cyclic voltammetry allow rationalization of the reaction mechanism. PMID- 29985550 TI - Electrocatalytic Oxidation of 5-(Hydroxymethyl)furfural Using High-Surface-Area Nickel Boride. AB - The electrochemical oxidation of the biorefinery product 5 (hydroxymethyl)furfural (HMF) to 2,5-furandicarboxylic acid (FDCA), an important platform chemical for the polymer industry, is receiving increasing interest. FDCA-based polymers such as polyethylene 2,5-furandicarboxylate (PEF) are sustainable candidates for replacing polyethylene terephthalate (PET). Herein, we report the highly efficient electrocatalytic oxidation of HMF to FDCA, using Ni foam modified with high-surface-area nickel boride (Nix B) as the electrode. Constant potential electrolysis in combination with HPLC revealed a high faradaic efficiency of close to 100 % towards the production of FDCA with a yield of 98.5 %. Operando electrochemistry coupled to ATR-IR spectroscopy indicated that HMF is oxidized preferentially via 5-hydroxymethyl-2-furancarboxylic acid rather than via 2,5-diformylfuran, which is in agreement with HPLC results. This study not only reports a low-cost active electrocatalyst material for the electrochemical oxidation of HMF to FDCA, but additionally provides insight into the reaction pathway. PMID- 29985551 TI - Arene-Limited Nondirected C-H Activation of Arenes. AB - The nondirected C(sp2 )-H activation of simple arenes has advanced significantly in recent years through the discovery of new catalyst systems that are able to perform transformations with the arene as the limiting reagent. Important developments in catalyst and ligand design that have improved reactivity and selectivity are reviewed. PMID- 29985552 TI - Measuring metagenome diversity and similarity with Hill numbers. AB - The first step of any metagenome sequencing project is to get the inventory of OTU abundances (operational taxonomic units) and/or metagenomic gene abundances. The former is generated with 16S-rRNA-tagged amplicon sequencing technology, and the latter can be generated from either gene-targeted or whole-sample shotgun metagenomics technologies. With 16S-rRNA data sets, measuring community diversity with diversity indexes such as species richness and Shannon's index has been a de facto standard analysis; nevertheless, similarly comprehensive approaches to metagenomic gene abundances are still largely missing, despite that both OTU and gene abundances are DNA reads. Here, we adapt the Hill numbers, which were reintroduced to macrocommunity ecology recently and are now widely regarded as a most appropriate measure system for ecological diversity, for measuring metagenome alpha-, beta- and gamma-diversities, and similarity. Our proposal includes the following: (a) Metagenomic gene (MG) diversity measures the single gene-level metagenome diversity; (b) Type-I metagenome functional gene cluster (MFGC) diversity measures the diversity of functional gene clusters but ignoring within-cluster gene abundance information; (c) Type-II MFGC diversity considers within-cluster gene abundances information and integrates gene-cluster-level metagenome diversity and functional gene redundancy information; and (d) Four classes of Hill-numbers-based similarity metrics, including local gene overlap, regional gene overlap, gene homogeneity measure and gene turnover complement, were introduced in terms of MG and MFGC, respectively. We demonstrate the proposal with the gut metagenomes from healthy and IBD (inflammatory bowel disease) cohorts. The Hill numbers offer a unified approach to cohesively and comprehensively measuring the ecological and metagenome diversities of microbiomes. PMID- 29985553 TI - Flexible Assembly of an Enzyme Cascade on a DNA Triangle Prism Nanostructure for the Controlled Biomimetic Generation of Nitric Oxide. AB - Spatial organization of multiple enzymes at specific positions for a controlled reaction cascade has attracted wide attention in recent years. Here, we report the construction of a biomimetic enzyme cascade organized on DNA triangle prism (TP) nanostructures to enable the efficient catalytic production of nitric oxide (NO) on a single microbead. Two enzymes, glucose oxidase (GOx) and horseradish peroxidase (HRP), were assembled at adjacent locations on a DNA TP nanostructure by using DNA-binding protein adaptors with small interenzyme distances. In the cascade, the first enzyme, GOx, converts glucose into gluconic acid in the presence of oxygen. The produced H2 O2 intermediate is rapidly transported to the second enzyme, HRP, which oxides hydroxyurea into NO and other nitroxyl species. The pH near the surface of the negatively charged DNA nanostructures is believed to be lower than that in the bulk solution; this creates an optimal pH environment for the anchored enzymes, which results in higher yields of the NO product. Furthermore, the multienzyme system was immobilized on a microbead mediated by a DNA adaptor, and this enabled the efficient catalytic generation of gas molecules in the microreactor. Therefore, this work provides an alternative route for the biomimetic generation of NO through enzyme cascades. In particular, the dynamic binding capability of the DNA sequence enabled the positions of the protein enzyme and the DNA nanostructure to be reversed, which allowed the cascade catalysis to be modulated. PMID- 29985554 TI - A Supramolecular [10]CPP Junction Enables Efficient Electron Transfer in Modular Porphyrin-[10]CPP?Fullerene Complexes. AB - Efficient photoinduced electron transfer was observed across a [10]cycloparaphenylene ([10]CPP) moiety that serves as a rigid non-covalent bridge between a zinc porphyrin and a range of fullerenes. The preparation of iodo-[10]CPP is the key to the synthesis of a porphyrin-[10]CPP conjugate, which binds C60 , C70 , (C60 )2 , and other fullerenes (KA >105 m-1 ). Fluorescence and pump-probe spectroscopy revealed intramolecular energy transfer between CPP and porphyrin and also efficient charge separation between porphyrin and fullerenes, affording up to 0.5 MUs lifetime charge-separated states. The advantage of this approach towards electron donor-acceptor dyads is evident in the case of dumbbell-shaped (C60 )2 , which gave intricate charge-transfer behavior in 1:1 and 2:1 complexes. These results suggest that [10]CPP and its cross-coupled derivatives could act as supramolecular mediators of charge transport in organic electronic devices. PMID- 29985555 TI - What is peripersonal space? An examination of unresolved empirical issues and emerging findings. AB - Findings from diverse fields of study, including neuroscience, psychology, zoology, and sociology, demonstrate that human and non-human primates maintain a representation of the space immediately surrounding the body, known as peripersonal space (PPS). However, progress in this field has been hampered by the lack of an agreed upon definition of PPS. Since the beginning of its formal study, scientists have argued that PPS plays a crucial role in both defensive and non-defensive actions. Yet consensus is lacking about the cognitive and neural instantiation of these functions. In particular, researchers have begun to ask whether a single, unified system of spatial-attentional resources supports both the defensive and non-defensive functions of PPS or, rather, whether there are multiple, independent systems. Moreover, there are open questions about the specificity of PPS. For example: Does PPS dissociate from other well-known phenomena such as personal space and the body schema? Finally, emerging research has brought attention to important questions about individual differences in the flexibility of PPS and the distribution of PPS in front compared to behind the body. In this advanced review, we shed light on questions about the nature of PPS, offering answers when the research permits or providing recommendations for achieving answers in future research. In so doing, we lay the groundwork for a comprehensive definition of PPS. This article is categorized under: Cognitive Biology > Evolutionary Roots of Cognition Psychology > Attention Psychology > Perception and Psychophysics Neuroscience > Plasticity. PMID- 29985557 TI - Mixed-Valent Molecular Triple Deckers. AB - Two phenothiazine (PTZ) moieties were connected via naphthalene spacers to a central arene to result in stacked PTZ-arene-PTZ structure elements. Benzene and tetramethoxybenzene units served as central arenes mediating electronic communication between the two PTZ units. Based on cyclic voltammetry, UV/Vis-NIR absorption, EPR spectroscopy, and computational studies, the one-electron oxidized forms of the resulting compounds behave as class II organic mixed valence species in which the unpaired electron is partially delocalized over both PTZ units. The barrier for intramolecular electron transfer depends on the nature of the central arene sandwiched between the two PTZ moieties. These are the first examples of rigid organic mixed-valent triple-decker compounds with possible electron-transfer pathways directly across a stacked structure, and they illustrate the potential of oligo-naphthalene building blocks for long-range electron transfer and a future molecular electronics technology. PMID- 29985556 TI - X-ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan McDermid Syndrome. AB - CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan-McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X-ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high-resolution X-ray structures of all CLKs, including the first CLK4 X-ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX-4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan-CLK inhibition in PMDS. PMID- 29985558 TI - Effects of everolimus and HLA-G on cellular proliferation and neutrophil adhesion in an in vitro model of cardiac allograft vasculopathy. AB - Human leukocyte antigen-G (HLA-G) expression is modulated by immunosuppressant use and is associated with lower incidence of graft rejection and cardiac allograft vasculopathy (CAV). We examined whether everolimus induces HLA-G expression and inhibits human coronary artery smooth muscle cell (HCASMC) proliferation, a critical event in CAV. Also, we examined whether TNFalpha stimulated neutrophil adhesion is inhibited by HLA-G on human coronary artery endothelial cells (HCAECs). HLA-G expression in HCASMCs following everolimus treatment was determined by western-blot densitometric analysis. HCASMCs proliferation following incubation with recombinant HLA-G was determined by automated cell counter detecting 2-10 um particles. Assessment of recombinant HLA G on neutrophil adhesion to HCAECs in response to TNF-alpha induced-injury was determined by nonstatic adhesion assays. HLA-G expression was upregulated in HCASMCs following everolimus exposure (1000 ng/ml; P < .05). HLA-G (500, 1000 ng/ml; both P < .05) reduced HCASMC proliferation and inhibited TNFalpha stimulated neutrophil adhesion to endothelial cells at all concentrations (0.1-1 ng/ml; all P < .001). Our study reveals novel regulation of HLA-G by everolimus, by demonstrating HLA-G upregulation and subsequent inhibition of HCASMC proliferation. HLA-G is a potent inhibitor of neutrophil adhesion to HCAECs. Findings support HLA-G's importance and potential use in heart transplantation for preventative therapy or as a marker to identify patients at high risk for developing CAV. PMID- 29985560 TI - Need for a better characterization of HHV-6 infections and associated clinical impacts. PMID- 29985559 TI - Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant. AB - Noninvasive biomarkers are needed to monitor stable patients after kidney transplant (KT), because subclinical acute rejection (subAR), currently detectable only with surveillance biopsies, can lead to chronic rejection and graft loss. We conducted a multicenter study to develop a blood-based molecular biomarker for subAR using peripheral blood paired with surveillance biopsies and strict clinical phenotyping algorithms for discovery and validation. At a predefined threshold, 72% to 75% of KT recipients achieved a negative biomarker test correlating with the absence of subAR (negative predictive value: 78%-88%), while a positive test was obtained in 25% to 28% correlating with the presence of subAR (positive predictive value: 47%-61%). The clinical phenotype and biomarker independently and statistically correlated with a composite clinical endpoint (renal function, biopsy-proved acute rejection, >=grade 2 interstitial fibrosis, and tubular atrophy), as well as with de novo donor-specific antibodies. We also found that <50% showed histologic improvement of subAR on follow-up biopsies despite treatment and that the biomarker could predict this outcome. Our data suggest that a blood-based biomarker that reduces the need for the indiscriminate use of invasive surveillance biopsies and that correlates with transplant outcomes could be used to monitor KT recipients with stable renal function, including after treatment for subAR, potentially improving KT outcomes. PMID- 29985561 TI - Regiodivergent Synthesis of 1,3- and 1,4-Enynes through Kinetically Favored Hydropalladation and Ligand-Enforced Carbopalladation. AB - Pd-catalyzed hydroalkynylations were developed that involve ligand-enabled regiodivergent addition of an alkyne to an allenamide, giving branched and linear products stereoselectively and facilitated by the neighboring amide group. Regioselectivity was achieved with the use of (o-OMePh)3 P and BrettPhos, which allowed the functionalization of various alkynes, including steroids, carbohydrates, alkaloids, chiral ligands, and vitamins. Based on the experimental results, it was proposed that hydro- and carbopalladation processes operated during the formations of the branched and linear products, respectively. PMID- 29985562 TI - Graft dysfunction in simultaneous pancreas kidney transplantation (SPK): Results of concurrent kidney and pancreas allograft biopsies. AB - Simultaneous pancreas and kidney transplants offer significant therapeutic advantages but present a diagnostic approach dilemma in the diagnosis of rejection. Because both organs are from the same donor, the kidney has been treated traditionally as the "sentinel" organ to biopsy, presumably representing the status of both allografts. Truly concurrent biopsy studies, however, are needed to confirm this hypothesis. We examined 101 concurrent biopsies from 70 patients with dysfunction in either or both organs. Results showed concurrent rejection in 23 of 57 (40%) of cases with rejection; 19 of 57 (33.5%) and 15 of 57 (26.5%) showed kidney or pancreas only rejection, respectively. The degree and type of rejection differed in the majority (13 of 23, 56.5%) of cases with concurrent rejection, with the pancreas more often showing higher rejection grade. Taking into account pancreas dysfunction, a positive kidney biopsy should correctly predict pancreas rejection in 86% of the instances. However, the lack of complete concordance between the 2 organs, the discrepancies in grade and type of rejection, and the tendency for higher rejection grades in concurrent or pancreas only rejections, all support the rationale for pancreas biopsies. The latter provide additional data on the overall status of the organ, as well as information on nonrejection-related pathologies. PMID- 29985563 TI - To Scan or Not to Scan: Horses and Zebras. PMID- 29985564 TI - Psychiatric Disorders and Comorbid Cannabis Use: How Common Is It and What Is the Clinical Impact? PMID- 29985565 TI - Prescribing Trends in US Active Duty Service Members With Posttraumatic Stress Disorder: A Population-Based Study From 2007-2013. AB - OBJECTIVE: The US Veterans Affairs (VA)/Department of Defense (DoD) Posttraumatic Stress Disorder (PTSD) Clinical Practice Guidelines provide evidence-based pharmacologic treatment recommendations. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are considered first-line medications. Benzodiazepines are relatively contraindicated with a warning that they may cause harm. This population-based study is the first to describe prescribing patterns for active duty service members (ADSMs) diagnosed with PTSD. METHODS: Health-care-related administrative DoD data from federal fiscal years 2007 through 2013 identified ADSMs with PTSD using ICD-9 codes. Prescription frequencies for antidepressants, benzodiazepines, antipsychotics, anticonvulsants, and other psychotropic medications were calculated for each year. RESULTS: Between 2007 and 2013, ADSMs with a PTSD diagnosis increased from 16,931 to 70,942. SSRI or SNRI prescribing decreased from 55.4% in 2007 to 41.8% in 2010 before increasing to 54.9% in 2013. Benzodiazepine prescribing was stable between 20.9% and 22.3% through 2010 before increasing to 24.7% by 2013. Antipsychotic prescribing declined from 22.6% in 2007 to 14.6% in 2013, driven by a decrease in low-dose quetiapine (<= 300 mg/d) prescribing, which declined from 19.1% in 2007 to 8.2% in 2013. CONCLUSIONS: The increase in SSRI or SNRI prescribing after 2010 and the overall increase in prazosin and decrease in low dose quetiapine prescribing all suggest increased concordance with the VA/DoD PTSD Clinical Practice Guidelines. The decline in SSRI prescribing up to 2010 is not concordant. The increase in benzodiazepine prescribing, a trend opposite that observed in the VA, is concerning. PMID- 29985566 TI - A Double-Blind Placebo-Controlled Trial of Omega-3 Fatty Acids as a Monotherapy for Adolescent Depression. AB - OBJECTIVE: Reports are mixed on the efficacy of omega-3 fatty acids (O3FA) for the treatment of major depressive disorder (MDD), with only limited data in adolescents. The present trial aimed to investigate systematically the efficacy of O3FA as a monotherapy, compared to a placebo, in adolescents with MDD. Secondarily, we explored O3FA effects on anhedonia, irritability, and suicidality all key features of adolescent MDD. METHODS: Fifty-one psychotropic medication free adolescents with DSM-IV-TR diagnoses of MDD (aged 12-19 years; 57% female) were randomized to receive O3FA or a placebo for 10 weeks. Data were collected between January 2006 and June 2013. O3FA and a placebo were administered on a fixed-flexible dose titration schedule based on clinical response and side effects. The initial dose of 1.2 g/d was increased 0.6 g/d every 2 weeks, up to a maximum of 3.6 g/d. Clinician-rated and self-rated depression severity, along with treatment response, served as primary outcome measures. Additionally, we examined O3FA effects on depression-related symptoms, including anhedonia, irritability, and suicidality. Treatment differences were analyzed via intent-to treat analyses. RESULTS: O3FA were not superior to a placebo on any clinical feature, including depression severity and levels of anhedonia, irritability, or suicidality. Additionally, response rates were comparable between treatment groups. Within-treatment analyses indicated that both treatments were associated with significant improvement in depression severity on self- (O3FA: t = -4.38, P < .001; placebo: t = -3.52, P = .002) and clinician (O3FA: t = -6.47, P < .001; placebo: t = -8.10, P < .001) ratings. CONCLUSIONS: In adolescents with MDD, O3FA do not appear to be superior to placebo. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00962598. PMID- 29985567 TI - Efficacy of Dextromethorphan/Quinidine for Patients With Psychosis-Related Aggression: A Retrospective Case Series. AB - Background: Treatment-resistant aggressive behavior is a complex psychoneurological phenomenon with high health care and societal costs commonly observed in mental illnesses involving psychosis. Here, we report a preliminary evaluation of treatment with dextromethorphan/quinidine in 4 adult patients with significant history of psychosis-related aggression and impulsive behaviors. Methods: The files of 4 inpatients with DSM-5-defined psychotic disorder and treatment-resistant aggression treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were retrospectively analyzed. The patients (age: mean +/- SD = 59.8 +/- 7.6) received open-label treatment with dextromethorphan/quinidine (final dose 20 mg/10 mg twice daily) for at least 12 weeks. Outcome was measured on the basis of patient self-report, treatment team evaluation, and physical examination by psychiatrists and primary care physicians. Results: Three of the 4 patients were considered responders to dextromethorphan/quinidine based on clinical impressions of reduction in aggression and impulsive behavior. The nonresponder, who had a history of multiple traumatic brain injuries, showed mild improvement in agitation but continued to display impulsive self-harm behavior despite treatment. Dextromethorphan/quinidine was generally well-tolerated. No metabolic, gastrointestinal, or cardiovascular side effects were observed. Conclusions: These preliminary findings support dextromethorphan/quinidine as a potential alternative to conventional regimens for treating aggression and impulsive behavior in patients with psychotic disorder. These results should be interpreted cautiously, as extended, double-blinded, placebo-controlled studies with a larger sample size are needed to validate findings from this retrospective case series. PMID- 29985568 TI - Speaking Truth to Power: Implications for Nursing's Values And Voice. PMID- 29985569 TI - Does Contracting with Managed Care Organizations Remain A Barrier for Nurse Practitioners? AB - Upon implementation of the Affordable Care Act (ACA), many managed care organizations (MCOs) initially increased their nurse practitioner (NP) contracting. This trend has not continued, potentially frustrating ACA efforts to expand primary care provider capacity. In this study, about 25% of the responding MCOs did not contract with NPs as primary care providers. only 62.5% of respondent MCOs offering Medicaid products reported contracting with NPs as primary care providers, suggesting this will place a disproportionate burden on low-income patients seeking to access care. Findings from this study also have important geographic implications, suggesting the decision to contract with NPs is made individually, not necessarily influenced by the numbers of newly insured or available primary care physicians. PMID- 29985570 TI - Succession Planning: Creating A Case for Hiring New Graduates. AB - With an aging nursing workforce and rising patient acuity levels, healthcare institutions are challenged to meet the demand for competent nursing care Swedish Medical Center (SMC) adopted an aggressive approach for building a new graduate residency program to promote new graduates' opportunity to tap into the valuable expert knowledge and wisdom of retiring nurses. Nursing leadership chose to take an unorthodox approach by identifying new graduates as their hires of choice, citing the ability to create and influence the values and professional practice of the novice nurse as a desired advantage. The program's success focused on adding three key elements to the traditional 1:1 preceptor support model: cohort hiring, monitoring progression to competence, and simulation. SMC is confident this strategy for workforce succession planning will continue to be successful both financially and with regard to patient care quality. PMID- 29985571 TI - Policies that Restrict Full Utilization of Nurse Practitioners In Primary Care. AB - The nation is struggling with the challenges and inefficiencies in the current healthcare environment, the increased demand for primary care services, and growing shortage of primary care providers to meet that demand. Although nurse practitioners (NPs) are highly educated, licensed, and certified healthcare professionals who are qualified to provide primary care services, the restrictive policies for physician oversight that exist in many states impede full utilization of the skills possessed by NPs in primary care provider roles. NPs are a crucial part of the solution to the growing demands for primary care in the United States and the transformation of the healthcare system to one in which accessible, patient-centered, essential health services are provided while improving the quality of care and controlling healthcare costs. PMID- 29985572 TI - A Partnership for Patients Initiative: Redesigning a Medical-Surgical Unit's Discharge Process to Reduce Readmissions. AB - Each year millions of people are readmitted to hospitals across the nation; many of these readmissions are preventable. Successful care coordination and transition management strategies are critical steps needed to meet Partnership for Patients goals of reducing harm and improving the quality and safety of health care. Decreasing variance in healthcare delivery can improve quality, safety, and improve patient outcomes. Project Re-Engineered Discharge shows promise as an evidence-based, standardized approach to address preventable hospital readmissions. PMID- 29985573 TI - Enhanced RN Role in Behavioral Health Care: An Untapped Resource. AB - Globally, an estimated 25% of individuals suffer from mental disorders. Approximately 50% of Americans will experience mental disorders in their lifetime. The cost of this U.S. mental health crisis is estimated at $444 billion per year when lost economic productivity is included, with only about one-third of the total dollars going to care itself. The generalist RN workforce is an untapped resource and invaluable health provider choice, uniquely suited to make an economic difference to the U.S. healthcare system by improving access, lowering costs, and improving quality of behavioral health care. PMID- 29985574 TI - Leveraging National Reports to Transform Ambulatory Care Practice. AB - Multiple national reports identify actionable recommendations to transform education and practice to meet the needs of health care and healthcare delivery beyond the hospital walls. The Josiah Macy Jr. Conference (2016) focused on transforming primary care and changing healthcare culture to support expansion of roles for registered nurses (RNs). Partnerships between academia and clinical practice are critical to expanding learning opportunities beyond traditional acute care settings. Development of primary care expertise in nursing faculty and adjunct faculty, in collaboration with primary care and ambulatory care nursing leaders, is essential. Academic-practice partnerships must advocate for removing regulatory and practice barriers to allow RNs to practice to the full scope of education and training. Recommendations from national reports extend beyond enhanced roles in primary care practice and have global implications for all RNs practicing in ambulatory care. PMID- 29985575 TI - From Single-Payer to All-Payer: Why Vermont's Reform Efforts Matter to U.S. Nurses and Their Patients. AB - In October 2016, the State of Vermont signed an unprecedented agreement (The All Payer Accountable Care Model) with the Federal Government to completely reform how health care is delivered and paid for in Vermont. This innovative agreement builds on sweeping 2011 legislation that set Vermont on a course towards payment reform designed to eliminate the fragmentation, overtreatment, and high costs associated with fee-for-service reimbursement. The strong emphasis on care coordination, preventative care, the patient experience, and population health ensures a crucial and growing role for nurses in this innovative environment and provides a model to inform the nation. Such state-led reform may have particular importance during the Trump administration, given the expected emphasis on state's rights and state leadership. PMID- 29985576 TI - Synaptic Plasticity and Metaplasticity of Biological Synapse Realized in a KNbO3 Memristor for Application to Artificial Synapse. AB - Amorphous KNbO3 (KN) films were grown on a TiN/SiO2/Si substrate to synthesize a KN memristor as a potential artificial synapse. The Pt/KN/TiN memristor exhibited typical and reliable bipolar switching behavior with multiple resistance levels. It also showed the transmission properties of a biological synapse, with a good conductance modulation linearity. Moreover, the KN memristor can emulate various biological synaptic plasticity characteristics including short-term plasticity, long-term plasticity, spike-rate dependent plasticity, paired-pulse facilitation, and post-tetanic potentiation by controlling the number and rate of the potentiation spike. Spike-timing-dependent plasticity (STDP), which is an essential property of biological synapses, is also realized in the KN memristor. The synaptic plasticity of the KN memristor can be explained by oxygen vacancy movement and oxygen vacancy filaments. The metaplasticity of biological synapses was also implemented in the KN memristor, including the metaplasticity of long term potentiation and depression, and of STDP. Therefore, the KN memristor could be used as an artificial synapse in neuromorphic computing systems. PMID- 29985577 TI - Reversibly Stabilized Polycation Nanoparticles for Combination Treatment of Early and Late-Stage Metastatic Breast Cancer. AB - Metastatic breast cancer is a major cause of cancer-related female mortality worldwide. The signal transducer and activator of transcription 3 (STAT3) and the chemokine receptor CXCR4 are involved in the metastatic spread of breast cancer. The goal of this study was to develop nanomedicine treatment based on combined inhibition of STAT3 and CXCR4. We synthesized a library of CXCR4-inhibiting polymers with a combination of beneficial features that included PEGylation, fluorination, and bioreducibility to achieve systemic delivery of siRNA to silence STAT3 expression in the tumors. An in vivo structure-activity relationship study in an experimental lung metastasis model revealed superior antimetastatic activity of bioreducible fluorinated polyplexes when compared with nonreducible controls despite similar CXCR4 antagonism and the ability to inhibit in vitro cancer cell invasion. When compared with nonreducible and nonfluorinated polyplexes, improved siRNA delivery was observed with the bioreducible fluorinated polyplexes. The improvement was ascribed to a combination of enhanced physical stability, decreased serum destabilization, and improved intracellular trafficking. Pharmacokinetic analysis showed that fluorination decreased the rate of renal clearance of the polyplexes and contributed to enhanced accumulation in the tumors. Therapeutic efficacy of the polyplexes with STAT3 siRNA was assessed in early stage breast cancer and late-stage metastatic breast cancer with primary tumor resection. Strong inhibition of the primary tumor growth and pronounced antimetastatic effects were observed in both models of metastatic breast cancer. Mechanistic studies revealed multifaceted mechanism of action of the combined STAT3 and CXCR4 inhibition by the developed polyplexes relying both on local and systemic effects. PMID- 29985578 TI - Electric-Field-Driven Translocation of ssDNA through Hydrophobic Nanopores. AB - The accurate sequencing of DNA using nanopores requires control over the speed of DNA translocation through the pores and also of the DNA conformation. Our studies show that ssDNA translocates through hourglass-shaped pores with hydrophobic constriction regions when an electric field is applied. The constriction provides a barrier to translocation and thereby slows down DNA movement through the pore compared with pores without the constriction. We show that ssDNA moves through these hydrophobic pores in an extended conformation and therefore does not form undesirable secondary structures that may affect the accuracy of partial current blockages for DNA sequencing. PMID- 29985579 TI - Label-Free Graphene Oxide-Based Surface Plasmon Resonance Immunosensor for the Quantification of Galectin-3, a Novel Cardiac Biomarker. AB - We report the first optical biosensor for the novel and important cardiac biomarker, galectin-3 (Gal3), using the anti-Gal3 antibody as a biorecognition element and surface plasmon resonance (SPR) for transducing the bioaffinity event. The immunosensing platform was built at a thiolated Au surface modified by self-assembling four bilayers of poly(diallyldimethylammonium chloride) and graphene oxide (GO), followed by the covalent attachment of 3-aminephenylboronic acid (3ABA). The importance of GO, both as the anchoring point of the antibody and as a field enhancer for improving the biosensor sensitivity, was critically discussed. The advantages of using 3ABA to orientate the anti-Gal3 antibody through the selective link to the Fc region were also demonstrated. The new platform represents an interesting alternative for the label-free biosensing of Gal3 in the whole range of clinically relevant concentrations (linear range between 10.0 and 50.0 ng mL-1, detection limit of 2.0 ng mL-1) with successful application for Gal3 biosensing in enriched human serum samples. PMID- 29985580 TI - Cross-Linking Hollow Carbon Sheet Encapsulated CuP2 Nanocomposites for High Energy Density Sodium-Ion Batteries. AB - Sodium-ion batteries (SIB) are regarded as the most promising competitors to lithium-ion batteries in spite of expected electrochemical disadvantages. Here a "cross-linking" strategy is proposed to mitigate the typical SIB problems. We present a SIB full battery that exhibits a working potential of 3.3 V and an energy density of 180 Wh kg-1 with good cycle life. The anode is composed of cross-linking hollow carbon sheet encapsulated CuP2 nanoparticles (CHCS-CuP2) and a cathode of carbon coated Na3V2(PO4)2F3 (C-NVPF). For the preparation of the CHCS-CuP2 nanocomposites, we develop an in situ phosphorization approach, which is superior to mechanical mixing. Such CHCS-CuP2 nanocomposites deliver a high reversible capacity of 451 mAh g-1 at 80 mA g-1, showing an excellent capacity retention ratio of 91% in 200 cycles together with good rate capability and stable cycling performance. Post mortem analysis reveals that the cross-linking hollow carbon sheet structure as well as the initially formed SEI layers are well preserved. Moreover, the inner electrochemical resistances do not significantly change. We believe that the presented battery system provides significant progress regarding practical application of SIB. PMID- 29985581 TI - Molecular Beam Epitaxy of Highly Crystalline MoSe2 on Hexagonal Boron Nitride. AB - Molybdenum diselenide (MoSe2) is a promising two-dimensional material for next generation electronics and optoelectronics. However, its application has been hindered by a lack of large-scale synthesis. Although chemical vapor deposition (CVD) using laboratory furnaces has been applied to grow two-dimensional (2D) MoSe2 cystals, no continuous film over macroscopically large area has been produced due to the lack of uniform control in these systems. Here, we investigate the molecular beam epitaxy (MBE) of 2D MoSe2 on hexagonal boron nitride (hBN) substrate, where highly crystalline MoSe2 film can be grown with electron mobility ~15 cm2/(V s). Scanning transmission electron microscopy (STEM) shows that MoSe2 grains grown at an optimum temperature of 500 degrees C are highly oriented and coalesced to form continuous film with predominantly mirror twin boundaries. Our work suggests that van der Waals epitaxy of 2D materials is tolerant of lattice mismatch but is facilitated by substrates with similar symmetry. PMID- 29985582 TI - Quantitative Analysis of Microstructures and Reaction Interfaces on Composite Cathodes in All-Solid-State Batteries Using a Three-Dimensional Reconstruction Technique. AB - The composite cathode of an all-solid-state battery composed of various solid state components requires a dense microstructure and a highly percolated solid state interface different from that of a conventional liquid-electrolyte-based Li ion battery. Indeed, the preparation of such a system is particularly challenging. In this study, quantitative analyses of composite cathodes by three dimensional reconstruction analysis were performed beyond the existing qualitative analysis, and their microstructures and reaction interfaces were successfully analyzed. Interestingly, various quantitative values of structure properties (such as the volume ratio, connectivity, tortuosity, and pore formation) associated with material optimization and process development were predicted, and they were found to result in limited electrochemical charge/discharge performances. We also verified that the effective two-phase boundaries were significantly suppressed to ~23% of the total volume because of component dispersion and packing issues. PMID- 29985583 TI - Thermal Imaging with Plasmon Resonance Enhanced HgTe Colloidal Quantum Dot Photovoltaic Devices. AB - Thermal imaging in the midwave infrared plays an important role for numerous applications. The key functionality is imaging devices in the atmospheric window between 3 and 5 MUm, where disturbance from fog, dust, and other atmospheric influence could be avoided. Here, we demonstrate sensitive thermal imaging with HgTe colloidal quantum dot (CQD) photovoltaic detectors by integrating the HgTe CQDs with plasmonic structures. The responsivity at 5 MUm is enhanced 2- to 3 fold over a wide range of operating temperatures from 295 to 85 K. A detectivity of 4 * 1011 Jones is achieved at cryogenic temperature. The noise equivalent temperature difference is 14 mK at an acquisition rate of 1 kHz for a 200 MUm pixel. Thermal images are captured with a single-pixel scanning imaging system. PMID- 29985584 TI - Control of Polar Orientation and Lattice Strain in Epitaxial BaTiO3 Films on Silicon. AB - Conventional strain engineering of epitaxial ferroelectric oxide thin films is based on the selection of substrates with a suitable lattice parameter. Here, we show that the variation of oxygen pressure during pulsed laser deposition is a flexible strain engineering method for epitaxial ferroelectric BaTiO3 films either on perovskite substrates or on Si(001) wafers. This unconventional growth strategy permits continuous tuning of strain up to high levels (epsilon > 0.8%) in films greater than one hundred nanometers thick, as well as selecting the polar axis orientation to be either parallel or perpendicular to the substrate surface plane. PMID- 29985585 TI - China's Fight for Clean Air and Human Health. PMID- 29985586 TI - Kirigami-Inspired Conducting Polymer Thermoelectrics from Electrostatic Recognition Driven Assembly. AB - Two-dimensional (2D) conducting polymers are expected to offer emergent topological, structural, and physical properties, which has become the "holy grail" for the development of plastic electronics. Here, we report the assembly of a free-floating metallic polymer layer, consisting of poly(3,4 ethylenedioxythiophene) complexed with poly(styrenesulfonate) anions, directed by electrostatic recognition, amphiphilicity, and aromatic interactions. The obtained large-area crystalline nanosheets exhibit excellent environmental stability and mechanical robustness, meanwhile showing an electrical conductivity of 1216 S.cm-1, the highest among the nanometer-thick conducting polymers. The kirigami-inspired freestanding polymer thermoelectrics, repeatedly stretching up to 200% strain, is demonstrated with high Seebeck coefficient with an optimized power factor of 95 MUW m-1 K-2. The large-scale assembly and aqueous compatibility of 2D conducting polymers provide an exciting platform for integrating thermoelectricity into free-floating polymer nanostructures. PMID- 29985587 TI - Injectable Hemostat Composed of a Polyphosphate-Conjugated Hyaluronan Hydrogel. AB - We have developed a new hydrogel hemostat composed of hyaluronan (HA) conjugated with inorganic polyphosphate (PolyP). A hemostatic hydrogel, HAX-PolyP, was formed rapidly by mixing aldehyde-modified HA and hydrazide-modified HA conjugated with PolyP (HA-PolyP). Although the gelation rate decreased with increasing PolyP content, the gelation time was below 5 min. In addition, the hydrogel swelling volume decreased with increasing PolyP content, but the degradation rate did not depend on PolyP content and the hydrogel underwent complete degradation through hydrolysis over 3 weeks in phosphate buffered saline. HAX-PolyP showed similar biocompatibility with the HA hydrogel without PolyP conjugation in vitro and in vivo. Intraperitoneal administration of HAX PolyP did not induce any adhesion in the peritoneum and clot formation in the lungs. Finally, HA-PolyP accelerated the coagulation rate of human plasma ex vivo, and HAX-PolyP showed as strong a hemostatic effect as fibrin glue in a mouse liver bleeding model in vivo. PMID- 29985588 TI - Effects of Transplanted Islets Nano-Encapsulated with Hyperbranched Polyethylene Glycol and Heparin on Microenvironment Reconstruction and Glucose Control. AB - The microenvironment of pancreatic islets gets disrupted during enzyme digestion and causes islets to remain in a vulnerable state, leading to poor outcome in the initial days of transplantation. To avoid immune invasion while allowing the reconstruction of the microenvironment of the transplanted site, we propose immunoisolation polymers, which can nanoencapsulate islets quickly without cytotoxicity. Here, nonhuman primate (NHP) islets were nanoencapsulated with hyperbranched polyethylene glycol (hb-PEG) and heparin by layer-by-layer technology and transplanted into the kidney subcapsular space of diabetic C57BL/6 mice. An immunosuppressive drug protocol was applied to increase the survival time until the animals were sacrificed. The recipients of NHP islets exhibited high nonfasting blood glucose level (BGL) for 2-3 weeks, which was normalized afterward. Immunohistochemical (IHC) analysis revealed an immature vascular basement membrane and cell surface integrins directly associated with poor initial insulin production. The transplanted grafts regained their own microenvironment within a month without any outside stimuli. No lymphocyte infiltration was observed in the grafts at any time. Humoral and cell-mediated immune responses were prominently diminished by the hb-PEG/Heparin nanoencapsulated islets. Immunoisolation accompanied by an immunosuppressive drug protocol protects islets by helping them avoid immunogenesis while at the same time allowing them to reconstruct their microenvironment. PMID- 29985589 TI - Formation and Evolution of aqSOA from Aqueous-Phase Reactions of Phenolic Carbonyls: Comparison between Ammonium Sulfate and Ammonium Nitrate Solutions. AB - We investigate the effects of sulfate and nitrate on the formation and evolution of secondary organic aerosol formed in the aqueous phase (aqSOA) from photooxidation of two phenolic carbonyls emitted from wood burning. AqSOA was formed efficiently from the photooxidation of both syringaldehyde (C9H10O4) and acetosyringone (C10H12O4) in ammonium sulfate and ammonium nitrate solutions, with mass yields ranging from 30% to 120%. Positive matrix factorization on the organic mass spectra acquired by an Aerosol Mass Spectrometer revealed a combination of functionalization, oligomerization, and fragmentation processes in the chemical evolution of aqSOA. Functionalization and oligomerization dominated in the first 4 h of reaction, with phenolic oligomers and their derivatives significantly contributing to aqSOA formation; and oxidation of the first generation products led to an abundance of oxygenated ring-opening products. Degradation rates of syringaldehyde and acetosyringone in nitrate solutions were 1.5 and 3.5 times faster than rates in sulfate solutions, and aqSOA yields in nitrate experiments are twice as high as in sulfate experiments. Nitrate likely promoted the reactions because it is a photolytic source of OH radicals, while sulfate is not, highlighting the importance of aerosol-phase nitrate in the formation of aqSOA by facilitating the photooxidation of organic precursors. PMID- 29985590 TI - In Vivo Photopharmacology. AB - Synthetic photoswitches have been known for many years, but their usefulness in biology, pharmacology, and medicine has only recently been systematically explored. Over the past decade photopharmacology has grown into a vibrant field. As the photophysical, pharmacodynamic, and pharmacokinetic properties of photoswitches, such as azobenzenes, have become established, they have been applied to a wide range of biological targets. These include transmembrane proteins (ion channels, transporters, G protein-coupled receptors, receptor linked enzymes), soluble proteins (kinases, proteases, factors involved in epigenetic regulation), lipid membranes, and nucleic acids. In this review, we provide an overview of photopharmacology using synthetic switches that have been applied in vivo, i.e., in living cells and organisms. We discuss the scope and limitations of this approach to study biological function and the challenges it faces in translational medicine. The relationships between synthetic photoswitches, natural chromophores used in optogenetics, and caged ligands are addressed. PMID- 29985592 TI - Dried-Blood-Spot Technique to Monitor Direct Oral Anticoagulants: Clinical Validation of a UPLC-MS/MS-Based Assay. AB - Plasma concentrations of direct oral anticoagulants (DOACs) vary largely between individuals, and they correlate well with desired and adverse outcomes. Although regular concentration monitoring of DOACs is not recommended, information on DOAC exposure could be useful in situations when multiple DOAC-clearance pathways are impaired or nonadherence is suspected. Self-sampling techniques, like the use of dried-blood spots (DBSs), would be particularly useful because they enable the collection of information in ambulatory patients at relevant points in time of the dosing interval (e.g., trough). We developed and validated a DBS-based assay to quantify all currently marketed DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) in a single ultraperformance-liquid-chromatography-tandem-mass spectrometry assay. It fulfilled all validation standards within a hematocrit range of 0.33-0.65 and was linear over the calibration ranges of 2.5-750 ng/mL (apixaban and rivaroxaban), 4.4-750 ng/mL (dabigatran), and 9.3-750 ng/mL (edoxaban). Only minor ion suppression (matrix effect <=13%) was present, inter- and intra-assay precision was <=13%, and inter- and intra-assay accuracies ranged between 88 and 110%. All DOACs were stable in DBSs up to 52 days at room temperature, if the DBSs were protected from light and humidity. The correlation between (whole blood) DBS and plasma concentrations was assessed in 33 patients under regular DOAC therapy. Deming-regression coefficients between simultaneously collected capillary DBSs and plasma samples were used to predict plasma concentrations from DBSs. Bland-Altman plots revealed a strong agreement between predicted and observed plasma concentrations, thus confirming the suitability of DBSs for DOAC monitoring as an important step toward the important aim of self sampling at home. PMID- 29985591 TI - Personal Ozone Exposure and Respiratory Inflammatory Response: The Role of DNA Methylation in the Arginase-Nitric Oxide Synthase Pathway. AB - Little is known regarding the molecular mechanisms behind respiratory inflammatory response induced by ozone. We performed a longitudinal panel study with four repeated measurements among 43 young adults in Shanghai, China from May to October in 2016. We collected buccal samples and measured the fractional exhaled nitric oxide (FeNO) after 3-day personal ozone monitoring. In buccal samples, we measured concentrations of inducible nitric oxide synthase (iNOS) and arginase (ARG), and DNA methylation of NOS2A and ARG2. We used linear mixed effect models to analyze the effects of ozone on FeNO, two enzymes and their DNA methylation. A 10 ppb increase in ozone (lag 0-8 h) was significantly associated with a 3.89% increase in FeNO, a 36.33% increase in iNOS, and a decrease of 0.36 in the average methylation (%5mC) of NOS2A. Ozone was associated with decreased ARG and elevated ARG2 methylation, but the associations were not significant. These effects were more pronounced among allergic subjects than healthy subjects. The effects were much stronger when using personal exposure monitoring than fixed site measurements. Our study demonstrated that personal short-term exposure to ozone may result in acute respiratory inflammation, which may be mainly modulated by NOS2A hypomethylation in the arginase-nitric oxide synthase pathway. PMID- 29985593 TI - Selective Cation Incorporation into Copper Sulfide Based Nanoheterostructures. AB - Heterogeneous copper sulfide based nanostructures have attracted intense attention based on their potential to combine the plasmonic properties of copper deficient copper sulfides with properties of other semiconductors and metals. In general, copper sulfides are versatile platforms for production of other materials by cation incorporation and exchange processes. However, the outcomes of subsequent cation exchange (CE) or incorporation processes involving nanoheterostructure (NH) templates have not been explored. In this work, we incorporate indium and tin into Cu1.81S-ZnS NHs. We demonstrate that the outcomes of cation incorporation are strongly influenced by heterocation identity and valence and by the presence of a Cu-extracting agent. The selectivity of cation incorporation depends upon both the cation itself and the heterodomains in which CE reactions take place. The final nanocrystals (NCs) emerge in many forms including homogeneous NCs, heterodimers, core@shell NHs and NHs with three different domains. This selective cation incorporation not only facilitates the preparation of previously unavailable metal sulfide NHs but also provides insight into mechanisms of CE reactions. PMID- 29985594 TI - Simple Polydisperse Droplet Emulsion Polymerase Chain Reaction with Statistical Volumetric Correction Compared with Microfluidic Droplet Digital Polymerase Chain Reaction. AB - Nucleic acid amplification technology, such as polymerase chain reaction (PCR), has enabled highly sensitive and specific disease detection and quantification, leading to more accurate diagnosis and treatment regimens. Lab-on-a-chip applications have developed methods to partition single biomolecules, such as DNA and RNA, into picoliter-sized droplets. These individual reaction vessels lead to digitization of PCR enabling improved time to detection and direct quantification of nucleic acids without a standard curve, therefore simplifying assay analysis. Though impactful, these improvements have generally been restricted to centralized laboratories with trained personnel and expensive equipment. To address these limitations and make this technology more applicable for a variety of settings, we have developed a statistical framework to apply to droplet PCR performed in polydisperse droplets prepared without any specialized equipment. The polydisperse droplet system allows for accurate quantification of droplet digital PCR (ddPCR) and reverse transcriptase droplet digital PCR (RT-ddPCR) that is comparable to commercially available systems such as BioRad's ddPCR. Additionally, this approach is compatible with a range of input sample volumes, extending the assay dynamic range beyond that of commercial ddPCR systems. In this work, we show that these ddPCR assays can reduce overall assay time while still providing quantitative results. We also report a multiplexed ddPCR assay and demonstrate proof-of-concept methods for rapid droplet preparation in multiple samples simultaneously. Our simple polydisperse droplet preparation and statistical framework can be extended to a variety of settings for the quantification of nucleic acids in complex samples. PMID- 29985596 TI - Synthesis, Structural, Spectral, and Electrochemical Studies of Selenabenziporphyrin and Its Pd(II) Complex. AB - A new nonaromatic selenabenziporphyrin was synthesized by (3 + 1) condensation of m-benzitripyrrane and 2,5-bis[( p-tolyl)hydroxymethyl] selenophene under mild trifluoroacetic acid-catalyzed reaction conditions. The selenabenziporphyrin was characterized by high-resolution mass spectrometry, one- and two-dimensional NMR spectroscopy, and X-ray crystallography. The crystal structure revealed that the macrocycle was planar with moderately tilted m-phenylene ring and that the phenylene ring completely blocks the macrocyclic pi-delocalization. The selenabenziporphyrin exhibits one broad absorption band at 645 nm along with one sharp band at 415 nm, and electrochemical studies revealed that the macrocycle was electron-deficient. The selenabenziporphyrin readily forms organometallic Pd(II) complex when treated with PdCl2 in CH3CN/CHCl3 at reflux followed by recrystallization. The X-ray structure revealed that the Pd(II) ion was coordinated with two pyrrole "N"s, selenophene "Se", and m-phenylene ring "C" in square-planar fashion, and the complex retained its nonaromatic nature. The Pd(II) complex exhibits ill-defined absorption bands, and it was more electron deficient than free-base selenabenziporphyrin macrocycle. Time-dependent density functional theory studies supported the experimental observations. PMID- 29985595 TI - Synthesis and Characterization of Silylated Phosphonium [P(OSiMe3)4]+ and Phosphate [O2P(OSiMe3)2]- Salts. AB - Starting from an optimized synthesis of silylated phosphoric acid, OP(OSiMe3)3, a borate salt bearing the [P(OSiMe3)4]+ cation was generated in the reaction of OP(OSiMe3)3 with [Me3Si-H-SiMe3][B(C6F5)4], isolated, and fully characterized. Analogously to the protonated species, phosphoric acid (H3PO4) reaction of OP(OSiMe3)3 with a base led to the formation of the unknown [O2P(OSiMe3)2]- anion, which could be crystallized as potassium salt and structurally characterized, too. Both [P(OSiMe3)4]+ and [O2P(OSiMe3)2]- can be regarded as the formal autoprotolysis products of OP(OSiMe3)3. PMID- 29985598 TI - Biodiversity Recovery and Transformation Impacts for Wetland Biodiversity. AB - Life Cycle Assessment (LCA) methods for land use take both occupation and transformation impacts into account. However, for wetlands and impacts from water consumption, it is so far not possible to account for transformation impacts. It is our goal to close this research gap, by determining wetland recovery times and developing characterization factors for transformation. To do this, we conducted a meta-analysis of 59 studies analyzing biodiversity recovery in wetlands subject to passive and active restoration. Generalized linear models were fitted to the biodiversity data and age, along with other wetland characteristics (such as elevation, latitude, or climate class), and were used as predictor variables. The results indicate that elevation, latitude, type of wetland, and restoration method have the strongest effect on recovery speed. Recovery times vary from less than one year to a maximum of 107 years with passive restoration and 105 years with active restoration. Corresponding transformation characterization factors vary between 10-14 and 10-2 species-eq.year2/m3. Finally, recognizing the relevance of this work to real-world policy issues beyond LCA, we discuss the implications of our estimated restoration times on the feasibility of "biodiversity offsetting". Offsetting utilizes restoration to replace biodiversity value lost due to development impacts. Our work can help stakeholders make informed decisions on whether offsetting represents a legitimate policy option in a particular context. PMID- 29985597 TI - Crowd on a Chip: Label-Free Human Monoclonal Antibody Arrays for Serotyping Influenza. AB - Rapid changes in influenza A virus (IAV) antigenicity create challenges in surveillance, disease diagnosis, and vaccine development. Further, serological methods for studying antigenic properties of influenza viruses often rely on animal models and therefore may not fully reflect the dynamics of human immunity. We hypothesized that arrays of human monoclonal antibodies (hmAbs) to influenza could be employed in a pattern-recognition approach to expedite IAV serology and to study the antigenic evolution of newly emerging viruses. Using the multiplex, label-free Arrayed Imaging Reflectometry (AIR) platform, we have demonstrated that such arrays readily discriminated among various subtypes of IAVs, including H1, H3 seasonal strains, and avian-sourced human H7 viruses. Array responses also allowed the first determination of antigenic relationships among IAV strains directly from hmAb responses. Finally, correlation analysis of antibody binding to all tested IAV subtypes allowed efficient identification of broadly reactive clones. In addition to specific applications in the context of understanding influenza biology with potential utility in "universal" flu vaccine development, these studies validate AIR as a platform technology for studying antigenic properties of viruses and also antibody properties in a high-throughput manner. We further anticipate that this approach will facilitate advances in the study of other viral pathogens. PMID- 29985599 TI - Dual-Modal Split-Type Immunosensor for Sensitive Detection of Microcystin-LR: Enzyme-Induced Photoelectrochemistry and Colorimetry. AB - Microcystins, the lethal cyanotoxins from Microcystis aeruginosa, can inhibit the activity of protein phosphatase and promote liver tumors. Herein, a dual-modal split-type immunosensor was constructed to detect microcystin-LR (MC-LR), based on the photocurrent change of CdS/ZnO hollow nanorod arrays (HNRs) and the blue shift of the surface plasmon resonance peak from Au nanobipyramids@Ag. By using mesoporous silica nanospheres as the carrier to immobilize secondary antibody and DNA primer, a hybridization chain reaction was adopted to capture alkaline phosphatase, while its catalytic reaction product, ascorbic acid, exhibited dual functions. The detailed mechanism was investigated, showing that ascorbic acid can not only act as the electron donor to capture the holes in CdS/ZnO-HNRs, leading to the increase photocurrent, but also as the reductant to form silver shells on Au nanobipyramids, generating multiply vivid color variations and blue shifts. Compared with the traditional photoelectrochemical immunosensor or colorimetric method for MC-LR, a more accurate and reliable result can be obtained, due to different mechanisms and independent signal transduction. Therefore, this work can not only propose a new dual-modal immunosensor for MC-LR detection but also provide innovative inspiration for constructing sensitive, accurate, and visual analysis for toxins. PMID- 29985600 TI - In Situ Observation of Resistive Switching in an Asymmetric Graphene Oxide Bilayer Structure. AB - Graphene oxide decorated with oxygen functional groups is a promising candidate as an active layer in resistive switching devices due to its controllable physical-chemical properties, high flexibility, and transparency. However, the origin of conductive channels and their growth dynamics remain a major challenge. We use in situ transmission electron microscopy techniques to demonstrate that nanoscale graphene oxide sheets bonded with oxygen dynamically change their physical and chemical structures upon an applied electric field. Artificially engineered bilayer reduced graphene oxide films with asymmetric oxygen content exhibit nonvolatile write-once-read-many memory behaviors without experiencing the bubble destruction due to the efficient migration of oxygen ions. We clearly observe that a conductive graphitic channel with a conical shape evolves from the upper oxygen-rich region to the lower oxygen-poor region. These findings provide fundamental guidance for understanding the oxygen motions of oxygen-containing carbon materials for future carbon-based nanoelectronics. PMID- 29985601 TI - Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) Inhibitors as Potential Therapeutics. AB - Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a member of an evolutionarily conserved family of protein kinases that belongs to the CMGC group of kinases. DYRK1A, encoded by a gene located in the human chromosome 21q22.2 region, has attracted attention due to its association with both neuropathological phenotypes and cancer susceptibility in patients with Down syndrome (DS). Inhibition of DYRK1A attenuates cognitive dysfunctions in animal models for both DS and Alzheimer's disease (AD). Furthermore, DYRK1A has been studied as a potential cancer therapeutic target because of its role in the regulation of cell cycle progression by affecting both tumor suppressors and oncogenes. Consequently, selective synthetic inhibitors have been developed to determine the role of DYRK1A in various human diseases. Our perspective includes a comprehensive review of potent and selective DYRK1A inhibitors and their forthcoming therapeutic applications. PMID- 29985602 TI - Development and Interlaboratories Validation of Event-Specific Quantitative Real Time PCR Method for Genetically Modified Rice G6H1 Event. AB - The transgenic rice G6H1 was a new event with the traits of herbicide-tolerance and insect-resistant. Herein, we developed one event-specific real-time PCR method with high specificity and sensitivity for G6H1 event quantitative analysis, and validated its performance on practical samples quantification through a collaborative ring trial. A total of eight laboratories participated in this validation and quantified three blind G6H1 powder samples including DNA extraction and real-time PCR analysis. The statistically analyzed results from returned data confirmed its high PCR efficiency and good linearity, trueness, and precision, indicating that the developed G6H1 real-time PCR assay was accurate, reliable, and comparable for G6H1 identification and quantification. PMID- 29985603 TI - Avenanthramide Aglycones and Glucosides in Oat Bran: Chemical Profile, Levels in Commercial Oat Products, and Cytotoxicity to Human Colon Cancer Cells. AB - Avenanthramides (AVAs), unique phytochemicals in oat, have attracted an increasing amount of attention due to their outstanding health benefits. However, the chemical profile and the levels of AVAs in commercial oat products as well as their health benefits have not been examined in detail. In the present study, a total of 29 AVA aglycones and AVA glucosides were identified and characterized from oat bran using NMR (1D and 2D NMR) and LC-MS techniques. Among them, 17 novel AVA glucosides were reported in oat bran for the first time. The most abundant AVA glucoside, 2c-3'- O-glc, had a similar growth inhibitory activity with the major AVA, 2c, against HCT-116 and HT-29 human colon cancer cells, indicating glucosylation does not affect the growth inhibitory effects of AVAs. Furthermore, the levels of all individual AVAs in 13 commercial oat products were analyzed using HPLC-MS/MS. The total AVAs contents in various oat products ranged from 9.22 to 61.77 mg/kg (fresh weight). PMID- 29985604 TI - Aniline-Tetramic Acids from the Deep-Sea-Derived Fungus Cladosporium sphaerospermum L3P3 Cultured with the HDAC Inhibitor SAHA. AB - Four new tetramic acids, cladosins H-K (1-4), and a related known compound, cladodionen (5), were isolated from the culture of the Mariana Trench (depth 6562 m) sediment-derived fungus Cladosporium sphaerospermum L3P3 treated with the histone deacetylase inhibitor SAHA (suberanilohydroxamic acid). Interestingly, compounds 1-5 existed as equilibrium E/ Z mixtures and 1-4 were the first cases of tetramic acids containing aniline moieties. Their structures including absolute configurations were elucidated through a combination of NMR, MS, and Mosher's method, together with the consideration of biogenetic origins. Incubation experiments of exogenous aniline and N-phenyloctanamide revealed that the aniline moiety in cladosins H-K (1-4) is probably derived from the degradation of SAHA, indicating that the well-known histone deacetylase inhibitor SAHA could be metabolized by L3P3 and provide aniline as a precursor for biotransformation of chemically reactive polyketides. The cytotoxicity of 1-5 was evaluated against the PC-3, MGC-803, SH-SY5Y, HCT-116, K562, and HL-60 cell lines, and compound 2 showed promising cytotoxicity against the HL-60 cell line with an IC50 value of 2.8 MUM. PMID- 29985606 TI - Effect of Emulsifier Concentration and Physical State on the In Vitro Digestion Behavior of Oil-in-Water Emulsions. AB - The influence of emulsifier physical state and concentration on the in vitro digestion of oil-in-water (O/W) emulsions was investigated. Two citrated monoacylglycerols, glyceryl stearate citrate (GSC, bulk mp of 55-65 degrees C) and glyceryl oleate citrate (GOC, bulk mp of 0-10 degrees C), were used at 0.5 or 5 wt % of the emulsions to generate 20 wt % soybean oil O/W emulsions. Oil droplet lipolysis was slower in emulsions with 0.5 wt % emulsifier versus in those with 5 wt % emulsifier, resulting from the reduced surface-to-volume ratio in emulsions at 0.5 wt % emulsifier and the increased concentration of hydrolyzable groups at 5 wt % emulsifier. When excluding gastric digestion, all emulsions were similarly digested, confirming that emulsion intestinal digestion was highly dependent on gastric preprocessing. Finally, at a given emulsifier concentration, GSC-based emulsions with an interfacial crystalline shell experienced a decreased rate of intestinal lipid digestion compared with their GOC-based counterparts, confirming that emulsifier physical state played a role in lipid digestion. PMID- 29985607 TI - Exhaustively Trichlorosilylated C1 and C2 Building Blocks: Beyond the Muller Rochow Direct Process. AB - The Cl--induced heterolysis of the Si-Si bond in Si2Cl6 generates an [SiCl3]- ion as reactive intermediate. When carried out in the presence of CCl4 or Cl2C?CCl2 (CH2Cl2 solutions, room temperature or below), the reaction furnishes the monocarbanion [C(SiCl3)3]- ([A]-; 92%) or the vicinal dianion [(Cl3Si)2C C(SiCl3)2]2- ([B]2-; 85%) in excellent yields. Starting from [B]2-, the tetrasilylethane (Cl3Si)2(H)C-C(H)(SiCl3)2 (H2B) and the tetrasilylethene (Cl3Si)2C?C(SiCl3)2 (B; 96%) are readily available through protonation (CF3SO3H) or oxidation (CuCl2), respectively. Equimolar mixtures of H2B/[B]2- or B/[B]2- quantitatively produce 2 equiv of the monoanion [HB]- or the blue radical anion [B*]-, respectively. Treatment of B with Cl- ions in the presence of CuCl2 furnishes the disilylethyne Cl3SiC=CSiCl3 (C; 80%); in the presence of [HMe3N]Cl, the trisilylethene (Cl3Si)2C?C(H)SiCl3 (D; 72%) is obtained. Alkyne C undergoes a [4+2]-cycloaddition reaction with 2,3-dimethyl-1,3-butadiene (CH2Cl2, 50 degrees C, 3d) and thus provides access to 1,2-bis(trichlorosilyl)-4,5-dimethylbenzene (E1; 80%) after oxidation with DDQ. The corresponding 1,2-bis(trichlorosilyl) 3,4,5,6-tetraphenylbenzene (E2; 83%) was prepared from C and 2,3,4,5-tetraphenyl 2,4-cyclopentadien-1-one under CO extrusion at elevated temperatures (CH2Cl2, 180 degrees C, 4 d). All closed-shell products were characterized by 1H, 13C{1H}, and 29Si NMR spectroscopy; an EPR spectrum of [ nBu4N][B*] was recorded. The molecular structures of [ nBu4N][A], [ nBu4N]2[B], B, E1, and E2 were further confirmed by single-crystal X-ray diffraction. On the basis of detailed experimental investigations, augmented by quantum-chemical calculations, plausible reaction mechanisms for the formation of [A]-, [B]2-, C, and D are postulated. PMID- 29985608 TI - Predicting Cotranscriptional Folding Kinetics For Riboswitch. AB - On the basis of a helix-based transition rate model, we developed a new method for sampling cotranscriptional RNA conformational ensemble and the prediction of cotranscriptional folding kinetics. Applications to E. coli. SRP RNA and pbuE riboswitch indicate that the model may provide reliable predictions for the cotranscriptional folding pathways and population kinetics. For E. coli. SRP RNA, the predicted population kinetics and the folding pathway are consistent with the SHAPE profiles in the recent cotranscriptional SHAPE-seq experiments. For the pbuE riboswitch, the model predicts the transcriptional termination efficiency as a function of the force. The theoretical results show (a) a force-induced transition from the aptamer (antiterminator) to the terminator structure and (b) the different folding pathways for the riboswitch with and without the ligand (adenine). More specifically, without adenine, the aptamer structure emerges as a short-lived kinetic transient state instead of a thermodynamically stable intermediate state. Furthermore, from the predicted extension-time curves, the model identifies a series of conformational switches in the pulling process, where the predicted relative residence times for the different structures are in accordance with the experimental data. The model may provide a new tool for quantitative predictions of cotranscriptional folding kinetics, and results can offer useful insights into cotranscriptional folding-related RNA functions such as regulation of gene expression with riboswitches. PMID- 29985609 TI - Water Dynamics in Polyacrylamide Hydrogels. AB - Polymeric hydrogels have wide applications including electrophoresis, biocompatible materials, water superadsorbents, and contact lenses. The properties of hydrogels involve the poorly characterized molecular dynamics of water and solutes trapped within the three-dimensional cross-linked polymer networks. Here we apply ultrafast two-dimensional infrared (2D IR) vibrational echo and polarization-selective pump-probe (PSPP) spectroscopies to investigate the ultrafast molecular dynamics of water and a small molecular anion solute, selenocyanate (SeCN-), in polyacrylamide hydrogels. For all mass concentrations of polymer studied (5% and above), the hydrogen-bonding network reorganization (spectral diffusion) dynamics and reorientation dynamics reported by both water and SeCN- solvated by water are significantly slower than in bulk water. As the polymer mass concentration increases, molecular dynamics in the hydrogels slow further. The magnitudes of the slowing, measured with both water and SeCN-, are similar. However, the entire hydrogen-bonding network of water molecules appears to slow down as a single ensemble, without a difference between the core water population and the interface water population at the polymer-water surface. In contrast, the dissolved SeCN- do exhibit two-component dynamics, where the major component is assigned to the anions fully solvated in the confined water nanopools. The slower component has a small amplitude which is correlated with the polymer mass concentration and is assigned to adsorbed anions strongly interacting with the polymer fiber networks. PMID- 29985610 TI - Glyphosate Resistance in Tridax procumbens via a Novel EPSPS Thr-102-Ser Substitution. AB - This study confirmed the first case of glyphosate resistance in Tridax procumbens and investigated the glyphosate-resistance mechanisms. Sequencing and cloning of the full 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) coding sequences revealed a point mutation (ACC to TCC) at amino acid position 102, resulting in a novel Thr-102-Ser substitution. Other possible resistance mechanisms (i.e., target-site EPSPS-gene overexpression, nontarget-site differential glyphosate uptake and translocation) were also examined and were unlikely to be involved in resistance in this population. Structural modeling of the wild-type and mutant EPSPS in complex with glyphosate and phosphoenolpyruvate (PEP) revealed that the Thr-102-Ser substitution weakly decreased EPSPS affinity to glyphosate, but sharply increased EPSPS affinity to the natural substrate, PEP. Therefore, this novel mutation is very likely responsible for the observed glyphosate resistance in this tetraploid weed species via dual mechanisms of reducing glyphosate binding and favoring PEP binding to EPSPS. PMID- 29985611 TI - Making the Coupled Cluster Correlation Energy Machine-Learnable. AB - Calculating the electronic structure of molecules and solids has become an important pillar of modern research in diverse fields of research from biology and materials science to chemistry and physics. Unfortunately, increasingly accurate and thus reliable approximate solution schemes to the underlying Schrodinger equation scale steeply in computational cost, rendering most accurate approaches like "gold standard" coupled cluster theory, CC, quickly intractable for larger systems of interest. Here we show that this scaling can be significantly reduced by applying machine-learning to the CC correlation energy. We introduce a vector-based representation of CC wave functions and use potential energy surfaces of a small molecule test set to learn the correlation energy from this representation. Our results show that the CC correlation energy can be efficiently learned, even when the representation is constructed from approximate amplitudes provided by computationally less demanding Moller-Plesset (MP2) perturbation theory. Exploiting existing linear scaling MP2 implementations, this potentially opens the door to CC-quality molecular dynamics simulations. PMID- 29985612 TI - Eu2+ Site Preferences in the Mixed Cation K2BaCa(PO4)2 and Thermally Stable Luminescence. AB - Site preferences of dopant Eu2+ on the locations of K+, Ba2+, and Ca2+ in the mixed cation phosphate K2BaCa(PO4)2 (KBCP) are quantitatively analyzed via a combined experimental and theoretical method to develop a blue-emitting phosphor with thermally stable luminescence. Eu2+ ions are located at K2 (M2) and K3 (M3) sites of KBCP, with the latter occupation relatively more stable than the former, corresponding to emissions at 438 and 465 nm, respectively. KBCP:Eu2+ phosphor exhibits highly thermal stable luminescence even up to 200 degrees C, which is interpreted as due to a balance between thermal ionization and recombination of Eu2+ 5d excited-state centers with the involvement of electrons trapped at crystal defect levels. Our results can initiate more exploration of activator site engineering in phosphors and therefore allow predictive control of photoluminescence tuning and thermally stable luminescence for emerging applications in white LEDs. PMID- 29985613 TI - Cyanine-Mediated DNA Nanofiber Growth with Controlled Dimensionality. AB - Supramolecular one-dimensional (1D) architectures are of high interest in drug delivery and templation of complex linear arrays due to their high aspect ratio and rigidity. A particular desire is the access of 1D nanostructures with high functionality and biorelevance, which opens the door to their applications in materials science and nanomedicine. Here we report the discovery that the site specific introduction of a cyanine (Cy3) dye unit in sequence-defined DNA amphiphiles causes a complete shift of the overall structure from spheres to 1D DNA nanofibers in aqueous media. We show that the generation of DNA nanofibers is dependent on the presence of cyanine units and their position within the DNA polymer hybrid. We further demonstrate an example of stimuli-responsive shape shifting DNA nanofibers to highlight the role of the dye in the overall assembly. Notably, we show the preparation of fibers with controlled length by seeded growth mechanism. Additionally, the DNA nanofibers exhibit a change in Cy3 dye optical properties upon assembly, typical of cyanine dye aggregation, which can be used to monitor the fiber growth process. To demonstrate the functionality of these structures, we show the templation of gold nanoparticles (AuNP) along the fiber length and demonstrate the directional templation of DNA nanofibers on rectangular DNA origami. Our findings provide a method for generating functional nanomaterials and hierarchical complex architectures and show promise as a platform for biosensing and targeted drug delivery. PMID- 29985614 TI - Hierarchical Assembly of a {Co24} Cluster from Two Vertex-Fused {Co13} Clusters and Their Single-Molecule Magnetism. AB - We present the synthesis, structural characterization, and magnetic properties of two high-nuclearity cobalt clusters formulated as [Co13(MU3-OH)3(MU3 Cl)(dpbt)5(ptd)Cl10][Co(H2O)2Cl2].(CH3)2CHOH (1) and [Co24(MU3-OH)6(MU3 Cl)2(dpbt)10(ptd)2Cl16].2CH3CH2OH (2), respectively (H2dpbt = 5,5'-bis(pyridin-2 yl)-3,3'-bis(1,2,4-triazole) and H2ptd = 3-(pyridin-2-yl)-1,2,4-triazine-5,6 diol). Compound 1 is composed of an inner [Co4(MU3-OH)3(MU3-Cl)] cubane and an outer [Co9(dpbt)5(ptd)Cl10] defective adamantane. Compound 2 reveals a giant {Co24} cluster possessing a dual-[Co12] skeleton from 1. The hierarchical assembly from 1 to 2 has been established and tracked through high-resolution electrospray ionization (HRESI-MS) analyses from the solvothermal reaction mother solution. Magnetic studies of 1 and 2 revealed the highly correlated spins, a glasslike magnetic phase transition at ca. 8 K, and slow relaxation behavior of SMM nature in the lower-temperature region (below 4 K). PMID- 29985615 TI - Improved Nonenzymatic Glucose Sensing Properties of Pd/MnO2 Nanosheets: Synthesis by Facile Microwave-Assisted Route and Theoretical Insight from Quantum Simulations. AB - The electrocatalytic properties of manganese oxide (MnO2) can be improved significantly by making hybrids/composites with noble metals (Au, Pd). Here, efforts have been made to synthesize the MnO2/Au and MnO2/Pd nanocomposites by a facile, rapid microwave irradiation method. The products characterized by X-ray diffraction and transmission electron microscopy exhibited their tetragonal phase and nanosheet morphology. The efficiency of the prepared composite materials as glucose sensor was tested by cyclic voltammetry and chronoamperometry measurements, and the results are discussed. The study revealed that successful modification of MnO2 by Pd led to excellent sensing performance by the reduction of size and the synergistic effect between MnO2 and PdO, which expedites the electron transfer. Besides, the wide detection range, good selectivity, and stability demonstrate its robustness in the design of electrochemical sensor platform. To get theoretical insight into the excellent sensing performance of MnO2/Pd, we have performed detailed density functional theory simulations to explore the charge transfer and bonding mechanism of glucose on MnO2 and Pd/Au doped MnO2 surface. Pd is bonded strongly on MnO2 and makes MnO2/Pd more conducting due to the enhancement of density of states near Fermi level. The higher binding energy of glucose and enhanced charge transfer from glucose to Pd doped MnO2 compared to bare MnO2 infer that Pd-doped MnO2 possess superior charge transfer kinetics, resulting in higher glucose sensing performance, which supports our experimental observations. PMID- 29985616 TI - Targeted Screening Approach to Systematically Identify the Absorbed Effect Substances of Poria cocos in Vivo Using Ultrahigh Performance Liquid Chromatography Tandem Mass Spectrometry. AB - Poria cocos are extensively used as nutritious food, dietary supplements, and oriental medicine in Asia. However, the effect substances are still not very clear. In this study, a targeted screening approach was developed to systematically identify absorbed constituents of Poria cocos in vivo using ultrahigh performance liquid chromatography tandem mass spectrometry combined with UNIFI software. First, incubation reactions in vitro with rat intestinal microflora and rat liver microsomes were conducted to sum up metabolic rules of main constituents. Second, the absorbed constituents in vivo were picked out and identified based on the results of metabolic study in vitro. Finally, the absorbed active constituents in the treatment of Alzheimer's disease were screened by targeted network pharmacology analysis. A total of 62 absorbed prototypes and 59 metabolites were identified and characterized in dosed plasma. Thirty potential active constituents were screened, and 86 drug-targets shared by absorbed constituents and Alzheimer's disease were discovered by targeted network pharmacology analysis. In general, this proposed targeted strategy comprehensively provides new insight for active ingredients of Poria cocos. PMID- 29985617 TI - Role of Lipid Coating in the Transport of Nanodroplets across the Pulmonary Surfactant Layer Revealed by Molecular Dynamics Simulations. AB - Hydrophilic drugs can be delivered into lungs via nebulization for both local and systemic therapies. Once inhaled, ultrafine nanodroplets preferentially deposit in the alveolar region, where they first interact with the pulmonary surfactant (PS) layer, with nature of the interaction determining both efficiency of the pulmonary drug delivery and extent of the PS perturbation. Here, we demonstrate by molecular dynamics simulations the transport of nanodroplets across the PS layer being improved by lipid coating. In the absence of lipids, bare nanodroplets deposit at the PS layer to release drugs that can be directly translocated across the PS layer. The translocation is quicker under higher surface tensions but at the cost of opening pores that disrupt the ultrastructure of the PS layer. When the PS layer is compressed to lower surface tensions, the nanodroplet prompts collapse of the PS layer to induce severe PS perturbation. By coating the nanodroplet with lipids, the disturbance of the nanodroplet on the PS layer can be reduced. Moreover, the lipid-coated nanodroplet can be readily wrapped by the PS layer to form vesicular structures, which are expected to fuse with the cell membrane to release drugs into secondary organs. Properties of drug bioavailability, controlled drug release, and enzymatic tolerance in real systems could be improved by lipid coating on nanodroplets. Our results provide useful guidelines for the molecular design of nanodroplets as carriers for the pulmonary drug delivery. PMID- 29985618 TI - Visible-Light-Promoted Cascade Alkene Trifluoromethylation and Dearomatization of Indole Derivatives via Intermolecular Charge Transfer. AB - An intramolecular dearomatization of indole derivatives has been developed via an electron donor-acceptor complex formed between indole derivatives and Umemoto's reagent. Without the requirement of any catalyst and additive, diverse trifluoromethyl-substituted spiroindolenines bearing a quaternary stereogenic center were obtained in good yields (up to 90%) merely upon the illumination of two starting materials in 1,2-dichloroethane solution at room temperature. This work provides facile access to spiroindolenines bearing a trifluoromethyl group enabled by visible light. PMID- 29985619 TI - Effect of Mutations on the Global and Site-Specific Stability and Folding of an Elementary Protein Structural Motif. AB - Understanding the folding mechanism of proteins requires detailed knowledge of the roles of individual amino acid residues in stabilization of specific elements and local segments of the native structure. Recently, we have utilized the combination of circular dichroism (CD) and site-specific 13C isotopically edited infrared spectroscopy (IR) coupled with the Ising-like model for protein folding to map the thermal unfolding at the residue level of a de novo designed helix turn-helix motif alphatalpha. Here we use the same methodology to study how the sequence of local thermal unfolding is affected by selected mutations introduced into the most and least stable parts of the motif. Seven different mutants of alphatalpha are screened to find substitutions with the most pronounced effects on the overall stability. Subsequently, thermal unfolding of two mutated alphatalpha sequences is studied with site-specific resolution, using four distinct 13C isotopologues of each. The data are analyzed with the Ising-like model, which builds on a previous parametrization for the original alphatalpha sequence and tests different ways of incorporating the amino acid substitution. We show that for both more and less stable mutants only the adjustment of all interaction parameters of the model can yield a satisfactory fit to the experimental data. The stabilizing and destabilizing mutations result, respectively, in a similar increase and decrease of the stability of all probed local segments, irrespective of their position with respect to the mutation site. Consequently, the relative order of their unfolding remains essentially unchanged. These results underline the importance of the interconnectivity of the stabilizing interaction network and cooperativity of the protein structure, which is evident even in a small motif with apparently noncooperative, heterogeneous unfolding. Overall, our findings are consistent with the native structure being the dominant factor in determining the folding mechanism, regardless of the details of its overall or local thermodynamic stabilization. PMID- 29985620 TI - Novel 99mTc-Labeled Glucose Derivative for Single Photon Emission Computed Tomography: A Promising Tumor Imaging Agent. AB - In this study, a d-glucosamine derivative with an isonitrile group (CN5DG) was synthesized and it was chosen to coordinate with 99mTc for preparing 99mTc-CN5DG. 99mTc-CN5DG could be readily obtained with high radiochemical purity (>95%) and had great in vitro stability and metabolic stability in urine. The radiotracer demonstrated a positive response to the administration of glucose and insulin in S180 and A549 tumor cells in vitro, suggesting the mechanism of 99mTc-CN5DG into tumor cells was related to glucose transporters. Biodistribution studies in mice bearing A549 xenografts showed 99mTc-CN5DG had a high tumor uptake and high tumor to-background ratios. SPECT/CT images further supported its ability for tumor imaging. As a cheap, conveniently made and widely available probe, 99mTc-CN5DG would become a potential "working horse" and be a breakthrough in 99mTc-labeled radiopharmaceuticals for tumor detection. PMID- 29985621 TI - Static and Dynamic Near-Field Measurements of High-Order Plasmon Modes Induced in a Gold Triangular Nanoplate. AB - Precise understanding of the spatiotemporal characteristics of plasmons is essential for the development of applications of plasmonic nanoparticles. In this study, we investigated the spatiotemporal properties of high-order plasmon modes induced in a gold triangular nanoplate by static and dynamic near-field measurements. The near-field transmission measurements revealed that in-plane and out-of-plane polarized plasmon modes were simultaneously excited and these modes spectroscopically and spatially overlapped. The superposition of these modes was visualized in the near-field two-photon excitation image of the nanoplate. We performed time-resolved autocorrelation measurements on the nanoplate and found that the correlation width was broader than the excitation pulse due to the plasmon dephasing process. From the correlation width map of the nanoplate, we experimentally demonstrated that the out-of-plane plasmon mode exhibits a longer dephasing time than the in-plane plasmon mode. These findings indicate that the out-of-plane mode is desirable for improving the performance of plasmons in various applications. PMID- 29985622 TI - Charge Carrier Dynamics in Photocatalytic Hybrid Semiconductor-Metal Nanorods: Crossover from Auger Recombination to Charge Transfer. AB - Hybrid semiconductor-metal nanoparticles (HNPs) manifest unique, synergistic electronic and optical properties as a result of combining semiconductor and metal physics via a controlled interface. These structures can exhibit spatial charge separation across the semiconductor-metal junction upon light absorption, enabling their use as photocatalysts. The combination of the photocatalytic activity of the metal domain with the ability to generate and accommodate multiple excitons in the semiconducting domain can lead to improved photocatalytic performance because injecting multiple charge carriers into the active catalytic sites can increase the quantum yield. Herein, we show a significant metal domain size dependence of the charge carrier dynamics as well as the photocatalytic hydrogen generation efficiencies under nonlinear excitation conditions. An understanding of this size dependence allows one to control the charge carrier dynamics following the absorption of light. Using a model hybrid semiconductor-metal CdS-Au nanorod system and combining transient absorption and hydrogen evolution kinetics, we reveal faster and more efficient charge separation and transfer under multiexciton excitation conditions for large metal domains compared to small ones. Theoretical modeling uncovers a competition between the kinetics of Auger recombination and charge separation. A crossover in the dominant process from Auger recombination to charge separation as the metal domain size increases allows for effective multiexciton dissociation and harvesting in large metal domain HNPs. This was also found to lead to relative improvement of their photocatalytic activity under nonlinear excitation conditions. PMID- 29985623 TI - Hydrogen Sulfide: A Reagent for pH-Driven Bioinspired 1,2-Diol Mono-deoxygenation and Carbonyl Reduction in Water. AB - Hydrogen sulfide (H2S) was evaluated for its peculiar sulfur radical species generated at different pHs and was used under photolytical conditions in aqueous medium for the reduction of 1,2-diols to alcohols. The conversion steps of 1,2 cyclopentanediol to cyclopentanol via cyclopentanone were analyzed, and it was proven that the reaction proceeds via a dual catalytic/radical chain mechanism. This approach was successfully adapted to the reduction of a variety of carbonyl compounds using H2S at pH 9 in water. This work opens up the field of environmental friendly synthetic processes using the pH-driven modulation of reactivity of this simple reagent in water. PMID- 29985624 TI - Geometric Effects of Colloidal Particles on Stochastic Interface Adsorption. AB - The stochastic interface adsorption behaviors of ellipsoid particles were investigated using optical laser tweezers. The particles were brought close to the oil-water interface, attempting to attach forcefully to the interface. Multiple attempts of the particle attachments statistically quantified the dependence of the adsorption probability on the particle aspect ratio. It was found that the adsorption probability proportionally increased with the aspect ratio because of the decrease in electrostatic interactions between the charged particles and the charged interface for higher aspect ratio particles. In addition, the adsorption holding time required for the interface attachments was found to increase as the aspect ratio decreased. Notably, the probabilistic adsorption behaviors of the ellipsoid particles and the holding time dependence revealed that the particle adsorption to the interface occurred stochastically, not deterministically. We also demonstrated that the adsorption behaviors measured on a single-particle scale were consistent with the gravity-induced spontaneous adsorption properties performed on a large scale with regard to the nondeterministic adsorption behaviors and the aspect ratio dependence on the adsorption probability. PMID- 29985625 TI - Small-Size-Induced Plasticity and Dislocation Activities on Non-Charge-Balanced Slip System of Ionic MgO Pillars. AB - We observed the small-size-induced hardening and plasticity of brittle ionic MgO as a result of abnormally triggered dislocation gliding on a non-charge-balanced slip system. The indentation tests of ?111? MgO pillars revealed an increased hardness with decreasing pillar size, and the tips of the pillars that were <=200 nm were plastically deformed. The in situ compression tests of ?111? MgO nanopillars in transmission electron microscopy verified aligned dislocation mediated plasticity on the {111}?110? and {100}?110? systems rather than the charge-balanced {110}?110? slip system. PMID- 29985626 TI - Electrically Conductive Copper Core-Shell Nanowires through Benzenethiol-Directed Assembly. AB - Ultrathin nanowires with <3 nm diameter have long been sought for novel properties that emerge from dimensional constraint as well as for continued size reduction and performance improvement of nanoelectronic devices. Here, we report on a facile and large-scale synthesis of a new class of electrically conductive ultrathin core-shell nanowires using benzenethiols. Core-shell nanowires are atomically precise and have inorganic five-atom copper-sulfur cross-sectional cores encapsulated by organic shells encompassing aromatic substituents with ring planes oriented parallel. The exact nanowire atomic structures were revealed via a two-pronged approach combining computational methods coupled with experimental synthesis and advanced characterizations. Core-shell nanowires were determined to be indirect bandgap materials with a predicted room-temperature resistivity of ~120 Omega.m. Nanowire morphology was found to be tunable by changing the interwire interactions imparted by the functional group on the benzenethiol molecular precursors, and the nanowire core diameter was determined by the steric bulkiness of the ligand. These discoveries help define our understanding of the fundamental constituents of atomically well-defined and electrically conductive core-shell nanowires, representing significant advances toward nanowire building blocks for smaller, faster, and more powerful nanoelectronics. PMID- 29985627 TI - Supersaturation Potential of Ordered Mesoporous Silica Delivery Systems. Part 1: Dissolution Performance and Drug Membrane Transport Rates. AB - Ordered mesoporous silica materials have shown great potential as oral drug delivery systems for poorly soluble drugs. However, the ability of these delivery systems to generate drug supersaturation has not been widely investigated, and the recently noted phenomenon of incomplete drug release is not well understood. Therefore, the aim of this study was to comprehensively evaluate the release of hydrophobic drug molecules into solution from ordered mesoporous silica, focusing on the extent and duration of drug supersaturation. The dissolution and supersaturation behavior of ritonavir, following loading into mesoporous SBA-15 silica particles, was investigated by undertaking simple in vitro dissolution studies in phosphate buffer pH 6.8 and fasted state simulated intestinal fluid, as well as membrane flux studies using a side-by-side diffusion cell apparatus. It was found that supersaturated ritonavir solutions were generated from ritonavir-loaded mesoporous SBA-15 particles; however, drug release was always incomplete, even under sink conditions. In addition, the percentage drug release was observed to decrease significantly as the theoretical supersaturation ratio and dose of ritonavir-loaded SBA-15 formulation increased. The data obtained suggest an equilibrium exists between drug adsorbed to the SBA-15 silica surface and free drug present in solution. The findings described herein are highly significant in aiding our understanding of ordered mesoporous silica as a supersaturating drug delivery system for bioavailability enhancement. PMID- 29985628 TI - Protein Folding Cooperativity and Thermodynamic Barriers of the Simplest beta Sheet Fold: A Survey of WW Domains. AB - Theory and experiments have shown that microsecond folding proteins exhibit characteristic thermodynamic properties that reflect the limited cooperativity of folding over marginal barriers (downhill folding). Those studies have mostly focused on proteins with large alpha-helical contents and small size, which tend to be the fastest folders. A key open question is whether such properties are also present in the fastest all-beta proteins. We address this issue by investigating the unfolding thermodynamics of a collection of WW domains as representatives of the simplest beta-sheet fold. WW domains are small microsecond folders, although they do not fold as fast as their alpha-helical counterparts. In previous work on the NEDD4-WW4 domain, we reported deviations from two-state thermodynamics that were less apparent and thus suggestive of an incipient downhill scenario. Here we investigate the unfolding thermodynamics of four other WW domains (NEDD4-WW3, YAP65-WW1(L30K), FBP11-WW1, and FBP11-WW2) by performing all of the thermodynamic tests for downhill folding that have been previously developed on alpha-helical proteins. This set of five WW domains shares low sequence identity and include examples from two specificity classes, thus providing a comprehensive survey. Thermodynamic analysis of the four new WW domains consistently reveals all of the properties of downhill folding equilibria, which are in all cases more marked than what we found before in NEDD4 WW4. Our results show that fast-folding all-beta proteins do share limited cooperativity and gradual unfolding thermodynamics with fast alpha-helical proteins and suggest that the free energy barrier to folding of natural proteins is mostly determined by size and fold topology and much less by the specific amino acid sequence. PMID- 29985629 TI - Anisotropic Photoluminescence from Isotropic Optical Transition Dipoles in Semiconductor Nanoplatelets. AB - Many important light-matter coupling and energy-transfer processes depend critically on the dimensionality and orientation of optical transition dipoles in emitters. We investigate individual quasi-two-dimensional nanoplatelets (NPLs) using higher-order laser scanning microscopy and find that absorption dipoles in NPLs are isotropic in three dimensions at the excitation wavelength. Correlated polarization studies of the NPLs reveal that their emission polarization is strongly dependent on the aspect ratio of the lateral dimensions. Our simulations reveal that this emission anisotropy can be readily explained by the electric field renormalization effect caused by the dielectric contrast between the NPLs and the surrounding medium, and we conclude that emission dipoles in NPLs are isotropic in the plane of the NPLs. Our study presents an approach for disentangling the effects of dipole degeneracy and electric field renormalization on emission anisotropy and can be adapted for studying the intrinsic optical transition dipoles of various nanostructures. PMID- 29985630 TI - Molecular Actuators in Action: Electron-Transfer-Induced Conformation Transformation in Cofacially Arrayed Polyfluorenes. AB - There is much current interest in the design of molecular actuators, which undergo reversible, controlled motion in response to an external stimulus (light, heat, oxidation, etc.). Here we describe the design and synthesis of a series of cofacially arrayed polyfluorenes (MeF nH m) with varied end-capping groups, which undergo redox-controlled electromechanical actuation. Such cofacially arrayed polyfluorenes are a model molecular scaffold to investigate fundamental processes of charge and energy transfer across a pi-stacked assembly, and we show with the aid of NMR and optical spectroscopies, X-ray crystallography and DFT calculations that in the neutral state the conformation of MeF nH1 and MeF nH2 is open rather than cofacial, with a conformational dependence that is highly influenced by the local environment. Upon (electro)chemical oxidation, these systems undergo a reversible transformation into a closed fully pi-stacked conformation, driven by charge-resonance stabilization of the cationic charge. These findings are expected to aid the design of novel wire-like cofacially arrayed systems capable of undergo redox-controlled actuation. PMID- 29985631 TI - PET Imaging of 18F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients. AB - Sustaining the growth of tumor cells requires extra energy and metabolic building blocks. In addition to consuming glucose, glutamine may play the role as an alternative source of nutrient for growth and survival. We aim to characterize a glutamine analog, 18F-(2 S,4 R)4-fluoroglutamine (18F-(2 S,4 R)4-FGln), as an imaging agent for interrogating the role of glutamine from the in vitro study of tumor cells to clinical manifestation in breast cancer patients. Purity was measured by radio-high-performance liquid chromatography (radio-HPLC), and the stability after production was evaluated in phosphate buffer saline (PBS), saline, and mouse and human serum buffers. The presence of Myc expression in MCF 7 and U87 cells was conducted using qPCR. In vitro cell uptake of 18F-(2 S,4 R)4 FGln in MCF-7 and U87 cells was directly compared with 18F-fluorodeoxyglucose (18F-FDG). In vivo biodistribution and micro-PET imaging of 18F-(2 S,4 R)4-FGln in MCF-7 bearing BALB/c nude mice were performed. PET/CT imaging of 18F-(2 S,4 R)4-FGln was compared with 18F-FDG in the same group of breast cancer patients ( n = 10). We successfully synthesized 18F-(2 S,4 R)4-FGln with a high radiochemical purity (>98%), and the radiochemical purity was unchanged in PBS and saline buffers during a 2 h incubation. In vitro cell uptake studies of 18F (2 S,4 R)4-FGln displayed a rapid and higher uptake in MCF-7 and U87 cells as compared with 18F-FDG. Biodistribution and micro-PET images showed excellent tumor accumulation of 18F-(2 S,4 R)4-FGln in the MCF-7-implanted mice tumor model. In a preliminary clinical study, 18F-(2 S,4 R)4-FGln/PET detected more lesions in breast cancer patients than 18F-FDG/PET (90% vs 80%). Additionally, in one patient with breast lobular carcinoma, there was a lesion mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) for 18F-(2 S,4 R)4-FGln higher than those obtained by 18F-FDG, as determined by PET imaging. 18F-(2 S,4 R)4-FGln may be a useful glutamine-targeting metabolic probe for noninvasive imaging of breast cancer. PMID- 29985632 TI - Dichotomous Disorder versus Excitonic Splitting of the B800 Band of Allochromatium vinosum. AB - The LH2 antenna complex of the purple bacterium Allochromatium vinosum has a distinct double peak structure of the 800 nm band (B800). Several hypotheses were proposed to explain its origin. Recent 77 K two-dimensional electronic spectroscopy data suggested that excitonic coupling of dimerized bacteriochlorophylls (BChls) within the B800 ring is largely responsible for the B800 split [M. Schroter et al., J. Phys. Chem. Lett. 2018, 9, 1340]. Here we argue that the excitonic interactions between BChls in the B800 ring, though present, are weak and cannot explain the B800 band split. This conclusion is based on hole-burning data and modeling studies using an exciton model with dichotomous protein conformation disorder. Therefore, we uphold our earlier interpretation, first reported by Kell et al. [ J. Phys. Chem. B 2017, 121, 9999], that the two B800 sub-bands are due to different site-energies (most likely due to weakly and strongly hydrogen-bonded B800 BChls). PMID- 29985633 TI - Atomic-Scale 3D Local Hydration Structures Influenced by Water-Restricting Dimensions. AB - Hydration structures at solid-liquid interfaces mediate between the atomic-level surface structures and macroscopic functionalities in various physical, chemical, and biological processes. Atomic-scale local hydration measurements have been enabled by ultralow noise three-dimensional (3D) frequency-modulation atomic force microscopy. However, for their application to complicated surface structures, e.g., biomolecular devices, understanding the relationship between the hydration and surface structures is necessary. Herein, we present a systematic study based on the concept of the structural dimensionality, which is crucial in various scientific fields. We performed 3D measurements and molecular dynamics simulations with silicate surfaces that allow for 0, 1, and 2 degrees of freedom to water molecules. Consequently, we found that the 3D hydration structures reflect the structural dimensions and the hydration contrasts decrease with increasing dimension due to the enlarged water self-diffusion coefficient and increased embedded hydration layers. Our results provide guidelines for the analysis of complicated hydration structures, which will be exploited in extensive fields. PMID- 29985634 TI - Interference Potential of Tannins and Chlorophylls in Zebrafish Phenotypic-Based Assays. AB - Natural products are prolific producers of diverse chemical scaffolds, which have yielded several clinically useful drugs. However, the complex features of natural products present challenges for identifying bioactive molecules using high throughput screens. For most assays, measured endpoints are either colorimetric or luminescence based. Thus, the presence of the major metabolites, tannins, and chlorophylls, in natural products could potentially interfere with these measurements to give either false-positive or false-negative hits. In this context, zebrafish phenotypic assays provide an alternative approach to bioprospect naturally occurring bioactive compounds. Whether tannins and/or chlorophylls interfere in zebrafish phenotypic assays, is unclear. In this study, we evaluated the interference potential of tannins and chlorophylls against efficacy of known small-molecule inhibitors that are known to cause phenotypic abnormalities in developing zebrafish embryos. First, we fractionated tannin enriched fraction (TEF) and chlorophyll-enriched fraction (CEF) from Camellia sinensis and cotreated them with PD0325901 [mitogen-activated protein kinase kinase (MEK) inhibitor] and sunitinib malate (SM; anti-[lymph]angiogenic drug). While TEF and CEF did not interfere with phenotypic or molecular endpoints of PD0325901, TEF at 100 MUg/mL partially masked the antiangiogenic effect of SM. On the other hand, CEF (100 MUg/mL) was toxic when treated up to 6 dpf. Furthermore, CEF at 100 MUg/mL potentially enhanced the activity of gamma-secretase inhibitors, resulting in toxicity of treated embryos. Our study provides evidence that the presence of tannin and/or chlorophyll in natural products do interfere with zebrafish phenotype assays used for identifying potential hits. However, this may be target/assay dependent and thus requiring additional optimization steps to assess interference potential of tannins and chlorophylls before performing any screening assay. PMID- 29985635 TI - Prenatal Exposure to Stressful Life Events and Infant Breastfeeding. AB - BACKGROUND: Of the various barriers to breastfeeding, limited information is available on the relationship between prenatal stress and breastfeeding. This study investigates the association between prenatal stressful life event (SLE) exposure and breastfeeding initiation postpartum. MATERIALS AND METHODS: Using Rhode Island Pregnancy Risk Assessment Monitoring System data from 2012 to 2014, SLE was defined as self-report of prenatal exposure to 14 predefined life events such as job loss or illness. Exposure to SLE was categorized by number and type of events. Multivariable logistic regression was performed to assess the relationship between SLE and breastfeeding initiation. Results accounted for complex survey design and were adjusted for maternal and infant characteristics (age, race, ethnicity, insurance, delivery type, parity, gestational age, birth weight for gestational age, and neonatal intensive care unit admission). RESULTS: Among 3,353 respondents, 86% reported breastfeeding initiation, 74% reported exposure to >=1 SLE, and 17% reported exposure to >=4 SLE. Decreased odds of breastfeeding initiation were associated with prenatal exposure to >=4 SLE (adjusted odds ratio [aOR] 0.67; 95% confidence interval [CI]: 0.48-0.95), emotional stressors (aOR 0.77; 95% CI: 0.61-0.98), and traumatic stressors (aOR 0.68; 95% CI: 0.50-0.91). CONCLUSION: This study underscores the impact of exposure to prenatal SLE on breastfeeding initiation among postpartum women. Findings may assist providers in identifying at-risk women for anticipatory guidance to improve breastfeeding rates. PMID- 29985636 TI - Designing Effective Testimonial Pictorial Warning Labels for Tobacco Products. AB - Warning labels on tobacco products sometimes feature images and stories of real people whose health has been affected by smoking. We examined effects of some of the design elements that may contribute to the effectiveness of these testimonial pictorial warning labels (PWLs). Beginning with a testimonial PWL that contained an image of a person and a basic warning statement (e.g., "Smoking can kill you"), we examined the impact of adding: (a) text detailing the person's name, age and health status (identifiers); and (b) explanatory statements that elaborated on the basic warning using a testimonial or non-testimonial message. In an online experiment, 1255 adult smokers in the United States were randomly assigned to one of six experimental conditions (2 [identifier: none/identifier] * 3 [explanatory statement: none/non-testimonial/testimonial]), or a control condition (text only warning labels that currently appear on packs in the United States). In each condition, participants were exposed to multiple labels each focused on a different health effect. Effectiveness was assessed using emotional responses, engagement and behavioral intentions measured immediately post exposure, and quit attempts measured at five-week follow up. Testimonial PWLs were more effective than the text only labels. However, there was little evidence that adding identifiers or the explanatory statements enhanced effectiveness; rather, there was some evidence that testimonial explanatory statements reduced effectiveness. These findings suggest that the most effective design for testimonial PWLs may be to combine a basic warning statement with an image of a real person, without any additional textual components. PMID- 29985637 TI - Microbiological quality of organic chicken meat during refrigerated storage in air and modified atmospheres. AB - 1. The aim of this study was to assess the incidence of pathogens and the development of spoilage microflora in organic chicken meat originating from a small poultry slaughterhouse and stored for 14 days at 2 degrees C aerobically (control) or in one of two modified atmosphere packaging systems (MAP1: 80% O2, 20% CO2 and MAP2: 70% N2, 30% CO2). 2. Campylobacter jejuni survived well during storage; and was found on the skin in 95% of samples (262/276). 3. In general, both the skin and meat samples showed a good initial microbiological quality with total viable counts of less than 3 log cfu/g in meat and approximately 5 log cfu/g on skin. 4. No difference was found between breast and thigh samples during the experiment. 5. Shelf life was limited mainly by the development of mesophilic and psychrotrophic microflora on skin which were found at 7-day storage for the control and MAP1 and 10 days for MAP2. PMID- 29985638 TI - Desired, Expected, and Received Support: How Support Gaps Impact Affect Improvement and Perceived Stigma in the Context of Unintended Pregnancy. AB - Unintended pregnancies constitute potentially stigmatizing moments that mobilize desires for several types of support from multiple members of people's networks. This study examines gaps among the support people desire, expect, and receive when coping with an unintended pregnancy. The support gaps people experience can influence their feelings about the pregnancy and their perceptions of stigma surrounding it. People (N = 203) who recently experienced an unintended pregnancy reported in an online survey the supportive communication they experienced from their romantic partner, mother/maternal figure, and close friend at the time of the unintended pregnancy. People experienced gaps among the amounts of support they desired, expected, and received, and the nature of gaps varied by the provider and type of support under consideration. Males and females perceived different gaps that varied according to their roles associated with an unintended pregnancy. The gaps people experienced contributed to their perceptions of stigma and affect improvement surrounding the pregnancy. PMID- 29985639 TI - Current dietary intake and eating habits in connection with socio-demographic characteristics of students of Nangui Abrogoua University of Cote d'Ivoire. AB - The socio-demographic features and eating pattern were assessed on 156 Ivorian students (18-34 years) from Nangui Abrogoua University. The study population was made of randomly selected students who were willing to participate to the survey. The semi-structured questionnaire was used to collect information on breakfast, lunch, and dinner consumption pattern and 24-h dietary recall to document the dietary intake. Results showed that 88% of the respondents were not used to having breakfast, while 87.70% and 94.80% would have lunch and dinner, respectively. 33.30% of the respondents claimed financial problems as a reason for skipping meals. 82% of the respondents do daily physical activity for a minimum of 30 min three times a week. 25.69% of the students with bad nutritional status including 17.95% being underweight and 7.74% overweight to the extent of obesity. Rice and "Attieke" (cassava semolina) were the favorite foods during the three daily meals. PMID- 29985641 TI - Comparing fracture patterns of younger versus older riders involved in nonfatal motorcycle accidents. AB - OBJECTIVE: The motorcyclist demographic is shifting to a larger proportion of riders over the age of 40. We sought to identify differences in orthopedic injury distribution and severity between 3 age cohorts and identify independent factors that contribute to fractures following a motorcycle collision (MCC). METHODS: A trauma registry at a level 1 trauma center was queried for motorcycle-related orthopedic injuries between January 1, 2008, and December 31, 2014. Subjects were stratified into 3 age groups: Young (<40 years), middle-aged (40-59 years), and elderly (>=60 years). Age groups were compared with respect to gender, weight, mechanism of collision, helmet use, Glascow Coma Scale (GCS), fracture type and location, Injury Severity Score (ISS), and hospital length of stay (LOS). A logistic regression model was constructed to identify independent factors that contribute to fractures following MCCs. RESULTS: Five hundred sixty-seven patients received care for motorcycle-related injuries (219 young, 264 middle aged, and 84 elderly). Patients were predominantly male (88.7%), were wearing a helmet at the time of collision (58.0%), and sustained a mean of 1.48 fractures per patient. The primary mechanism of collision was noncollision transport accidents (41.4%). Elderly riders weighed significantly more than middle-aged and young riders (P < .0001). There was a significant difference in mean GCS between age groups (P = .02), with elderly patients demonstrating the highest mean GCS (14.0 +/- 3.3). Young patients sustained no fractures most frequently when compared with middle-aged and elderly riders (P = .002). There was a significant difference in the percentage of patients sustaining right-sided, lower body fractures between age groups (P = .02) for elderly, middle-aged, and young patients, respectively. There was also a significant difference between age groups in the percentage of riders sustaining fractures other than those of the extremities, pelvis, or spine (P = .0005). Only age was identified as an independent predictor of sustaining a fracture (P = .008). CONCLUSIONS: Elderly patients sustained fractures more frequently. There was no difference between age groups with respect to injury severity. Mechanism of collision may have more influence than age with respect to fracture type and location. Further research is warranted to develop a more widely generalizable characterization of motorcycle collision injury patterns, risk factors, and patient characteristics. PMID- 29985642 TI - Evaluation of 'The Father Effect' Media Campaign to Increase Awareness of, and Participation in, an Online Father-Inclusive Parenting Program. AB - There is substantial evidence that parenting programs are effective in improving parenting and child mental health outcomes. While there is increasing focus on delivering parenting interventions online to increase their reach and dissemination, fathers are underrepresented in all formats of parenting programs. However, research suggests that father participation is important for intervention effectiveness. This study evaluated the effectiveness of a media campaign for increasing awareness of, and participation in, an online father inclusive parenting program called 'ParentWorks'. An 8-week campaign was conducted in Australia via social media channels, digital display advertising, digital television, and radio. To assess the impact of the campaign, data were obtained from caregivers registering for ParentWorks during the campaign period (n = 848) and an 8-week comparison period that occurred 3 months later (n = 254). Additionally, a nationally representative sample of 2021 caregivers of children aged 2-16 years completed an online survey. Survey questions asked about exposure to the campaign, registration for participation in ParentWorks, and knowledge of the importance of father participation in parenting programs. Three times as many caregivers registered during the 8-week media campaign compared to the comparison period, and a significantly greater proportion of male caregivers registered in the campaign versus the comparison period. The online survey found that 11% of caregivers reported exposure to the campaign, and significantly more fathers than mothers reported exposure. Results showed that those who were exposed to the campaign were significantly more likely to endorse the importance of father participation in parenting programs, than those not exposed to the campaign. The findings indicate that media campaigns appear to be an effective method of increasing awareness of online parenting programs and enhancing rates of father involvement. PMID- 29985640 TI - Highly pathogenic avian influenza A/H5N1 Clade 2.3.2.1c virus in poultry in Cameroon, 2016-2017. AB - In May 2016, highly pathogenic avian influenza virus of the subtype A/H5N1 was detected in Cameroon in an industrial poultry farm at Mvog-Betsi, Yaounde (Centre region), with a recorded sudden increase of deaths among chickens, and an overall mortality rate of 75%. The virus spread further and caused new outbreaks in some parts of the country. In total, 21 outbreaks were confirmed from May 2016 to March 2017 (six in the Centre, six in the West, eight in the South and one in the Adamaoua regions). This resulted in an estimated total loss of 138,252 birds (44,451 deaths due to infection and 93,801 stamped out). Only domestic birds (chickens, ducks and geese) were affected in farms as well as in poultry markets. The outbreaks occurred in three waves, the first from May to June 2016, the second in September 2016 and the last wave in March 2017. The topology of the phylogeny based on the haemagglutinin gene segment indicated that the causative H5N1 viruses fall within the genetic clade 2.3.2.1c, within the same group as the A/H5N1 viruses collected in Niger in 2015 and 2016. More importantly, the gene constellation of four representative viruses showed evidence of H5N1/H9N2 intra clade reassortment. Additional epidemiological and genetic data from affected countries in West Africa are needed to better trace the origin, spread and evolution of A/H5N1 in Cameroon. RESEARCH HIGHLIGHTS HPAI A/H5N1 was detected in May 2016 in domestic chickens in Yaounde-Cameroon. Twenty-one outbreaks in total were confirmed from May 2016 to March 2017. The causative H5N1 viruses fall within the genetic clade 2.3.2.1c. The viral gene constellation showed evidence of H5N1/H9N2 intra-clade reassortment. PMID- 29985643 TI - Analysis of the Genetic Diversity in Methicillin-Resistant Staphylococcus aureus Isolates from Bovine Subclinical Mastitis Case in Xinjiang, China. AB - BACKGROUND: Diseases caused by livestock-associated methicillin-resistant Staphylococcus aureus (MRSA) are an important global public health concern, and MRSA is increasingly being isolated in bovine milk. However, information on the genotype and antimicrobial resistance of MRSA in bovine milk in Xinjiang is limited. The objective of this study was to determine the antimicrobial susceptible phenotypes and genotypes of the circulating MRSA clone isolated in bovine mastits milk samples in Xinjiang, China. METHODS: Fifty six MRSA isolates collected from milk of bovine mastitis were investigated by multilocus sequence typing (MLST), staphylococcal protein A (spa) typing, and a minimum inhibitory concentration test with 21 antimicrobial agents. RESULTS: Antibiotic resistance results showed that 47.4% of the isolates were resistant to 16 or more antibiotics. Twelve MLST types were defined in this study, and ST398 (n = 7) and ST2393 (n = 2) were found to be the most prevalent types. Seven spa types (t034, t269, t4030, t114, t35, t189, and t7589) were identified, of which t034 (n = 7), t189 (n = 3), and t4030 (n = 3) were predominant. Here, 3 MRSA ST188 is reported among human MRSA isolates in China, and this is the first time that it is reported in bovine MRSA strains. CONCLUSIONS: The antimicrobial susceptibility of MRSA in this area exhibited multidrug resistance, and clonal complexes CC398 and CC188, which have been reported among human MRSA isolates, do occur in Xinjiang dairy cows. This study provides a foundation for further MRSA monitoring. PMID- 29985644 TI - High-depth transcriptomic profiling reveals the temporal gene signature of human mesenchymal stem cells during chondrogenesis. AB - Mesenchymal stem/stromal cells (MSCs) provide an attractive cell source for cartilage repair and cell therapy; however, the underlying molecular pathways that drive chondrogenesis of these populations of adult stem cells remain poorly understood. We generated a rich data set of high-throughput RNA sequencing of human MSCs throughout chondrogenesis at 6 different time points. Our data consisted of 18 libraries with 3 individual donors as biologic replicates, with each library possessing a sequencing depth of 100 million reads. Computational analyses with differential gene expression, gene ontology, and weighted gene correlation network analysis identified dynamic changes in multiple biologic pathways and, most importantly, a chondrogenic gene subset, whose functional characterization promises to further harness the potential of MSCs for cartilage tissue engineering. Furthermore, we created a graphic user interface encyclopedia built with the goal of producing an open resource of transcriptomic regulation for additional data mining and pathway analysis of the process of MSC chondrogenesis.-Huynh, N. P. T., Zhang, B., Guilak, F. High-depth transcriptomic profiling reveals the temporal gene signature of human mesenchymal stem cells during chondrogenesis. PMID- 29985645 TI - Aquatic caddisworm silk is solidified by environmental metal ions during the natural fiber spinning process. AB - Aquatic caddisfly larvae (caddisworms) wet spin fibers to construct composite cases of silk and stone. The silk emerges from labial ducts as a nanofibrous fluid gel, flowing over the stone substrate and making intimate interfacial adhesive contacts before being drawn into tough fibers that rapidly solidify underwater to span gaps in the construction. Divalent metal ions are responsible for the unique mechanical properties of naturally spun silk fibers; however, when and where divalent metal ions are incorporated into the metallofibers and other aspects of the fiber solidification mechanism are poorly understood. To investigate, the elemental composition and secondary structure of silk precursors stored in the silk gland lumen were compared with naturally spun fibers by inductively coupled plasma optical emission spectroscopy and attenuated total reflection Fourier transform infrared spectroscopy. Naturally spun fibers contained near equimolar ratios of Ca2+ to P. In contrast, silk precursors stored in the silk gland lumen contained only traces of Ca2+ and other multivalent metal ions. Ca2+ was also undetectable in anterior lumenal silk using the histochemical Ca2+ indicator, alizarin S red. Addition of Ca2+ to isolated lumenal silk resulted in Ca2+ complexation by H-fibroin phosphoserines (pSs) and a shift in secondary structure from random coils to beta-structures, creating infrared spectra in the phosphate and amide I regions nearly equivalent to those found in naturally spun Ca2+-containing silk fibers. Light and electron microscopy within distinct regions of the silk gland suggested that posterior gland silk colloidal complexes transition into a nanofibrous morphology as they pass into the chitin lined anterior lumen. Altogether, the results suggest that environmental Ca2+ absorbed from natural water triggers silk fiber solidification postdraw by complexing H-fibroin pSs, creating Ca2+-stabilized crystalline beta-nanodomains that cross-link and toughen the freshly drawn silk fibers.-Ashton, N. N., Stewart, R. J. Aquatic caddisworm silk is solidified by environmental metal ions during the natural fiber spinning process. PMID- 29985646 TI - Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer. AB - Helicobacter pylori infection is a major risk factor for the development of gastric cancer. Aberrant expression of microRNAs is strongly implicated in gastric tumorigenesis; however, their contribution in response to H. pylori infection has not been fully elucidated. In this study, we evaluated the expression of miR-135b-5p and its role in gastric cancer. We describe the overexpression of miR-135b-5p in human gastric cancer tissue samples compared with normal tissue samples. Furthermore, we found that miR-135b-5p is also up regulated in gastric tumors from the trefoil factor 1-knockout mouse model. Infection with H. pylori induced the expression of miR-135b-5p in the in vitro and in vivo models. miR-135b-5p induction was mediated by NF-kappaB. Treatment of gastric cancer cells with TNF-alpha induced miR-135b-5p in a NF-kappaB-dependent manner. Mechanistically, we found that miR-135b-5p targets Kruppel-like factor 4 (KLF4) and binds to its 3' UTR, leading to reduced KLF4 expression. Functionally, high levels of miR-135b-5p suppress apoptosis and induce cisplatin resistance. Our results uncovered a mechanistic link between H. pylori infection and miR-135b 5p-KLF4, suggesting that targeting miR-135b-5p could be a potential therapeutic approach to circumvent resistance to cisplatin.-Shao, L., Chen, Z., Soutto, M., Zhu, S., Lu, H., Romero-Gallo, J., Peek, R., Zhang, S., El-Rifai, W. Helicobacter pylori-induced miR-135b-5p promotes cisplatin resistance in gastric cancer. PMID- 29985648 TI - The Ryan White HIV/AIDS Program: Supplementary Service Provision Post-Affordable Care Act. AB - The Ryan White HIV/AIDS program (RWHAP) provides essential primary and supplementary health services to people living with HIV (PLWH). We examined the relationship between supplementary RWHAP services (Part B) and two outcomes: viral suppression (VS) and two separate measures of retention in care (RiC) based on kept- and missed-visits. We used purposive sampling to identify adult patients who received primary medical care at an academically-affiliated HIV/AIDS clinic in the southeastern United States (N = 1159) and who attended at least one scheduled HIV primary care appointment at the study site during 2015. Unadjusted and adjusted logistic regression models were fit, in which RWHAP supplementary services were the primary independent variables of interest. Age, race, gender, education level, and income were control variables. Among 1159 PLWH, 45.3% received RWHAP supplementary services in addition to public insurance, private insurance, or primary RWHAP. Among participants, 91.4% were virally suppressed, 87.4% were retained in care using the Institute of Medicine (IOM) kept-visits measure, and 60% were retained in care using the missed-visits measure. In multivariable models, patients with RWHAP supplementary services had significantly higher odds of (1) VS [adjusted odds ratio (AOR) = 1.91], (2) RiC using the IOM kept-visits measure (AOR = 2.56), and (3) RiC using the missed visits measure (AOR = 1.58). Receipt of supplementary RWHAP services is associated with increased odds of VS and two measures of RiC when adjusting for key sociodemographic variables. Policymakers should consider the vital role of RWHAP as continued funding is uncertain. PMID- 29985647 TI - Increasing Prevalence of HIV Pretreatment Drug Resistance in Women But Not Men in Rural Uganda During 2005-2013. AB - The prevalence of HIV pretreatment drug resistance (PDR) is increasing in sub Saharan Africa. We sought to describe correlates of PDR and evaluate effects of PDR on clinical outcomes in rural Uganda. We analyzed data from the Uganda AIDS Rural Treatment Outcomes study, a cohort of antiretroviral therapy (ART)-naive adults with HIV (2005-2015). We performed resistance testing on pre-ART specimens. We defined PDR as any World Health Organization (WHO) 2009 surveillance drug resistance mutation and classified PDR level using the Stanford algorithm. We fit unadjusted and sex-stratified log binomial regression and Cox proportional hazard models to identify correlates of PDR and the impact of PDR on viral suppression, loss to follow-up (LTFU), and death. We analyzed data from 738 participants (median age 33 years, 69% female). Overall, prevalence of PDR was 3.5% (n = 26), owing mostly to resistance to non-nucleoside reverse transcriptase inhibitors. PDR increased over time in women (1.8% in those enrolling in clinic in 2001-2006, vs. 7.0% in 2007-2013; p = 0.006), but not in men (1.15% vs. 0.72%, p = 0.737). Lower pre-ART log10 HIV RNA was also associated with higher prevalence of PDR. We identified longer time to viral suppression among those with PDR compared with without PDR (0.5 and 0.3 years, respectively, p = 0.023), but there was no significant relationship with mortality or LTFU (p = 0.139). We observed increasing rates of PDR in women in southwestern Uganda. Implications of this trend, particularly to prevention of mother-to-child transmission programs in the region, require attention due to delayed viral suppression among those with PDR. PMID- 29985649 TI - What's on YouTube? A Case Study on Food and Beverage Advertising in Videos Targeted at Children on Social Media. AB - BACKGROUND: Unhealthy food marketing to children is a key risk factor for childhood obesity. Online video platforms have surpassed television as the primary choice for screen viewing among children but the extent of food marketing through such media is relatively unknown. We aimed to examine food and beverage advertisements (ads) encountered in YouTube videos targeting children in Malaysia. METHODS: The social media analytics site SocialBlade.com was used to identify the most popular YouTube videos (n = 250) targeting children. Ads encountered while viewing these videos were recorded and analyzed for type of product promoted and ad format (video vs. overlay). Food and beverage ads were further coded based on food category and persuasive marketing techniques used. RESULTS: In total 187 ads were encountered in sampled videos. Food and beverage ads were the most common at 38% (n=71), among which 56.3% (n = 40) promoted noncore foods. Ads for noncore foods were more commonly delivered as video rather than overlay ads. Among ads promoting noncore foods, the most commonly employed persuasive marketing techniques found were taste appeal (42.3%), uniqueness/novelty (32.4%), the use of animation (22.5%), fun appeal (22.5%), use of promotional characters (15.5%), price (12.7%), and health and nutrition benefits (8.5%). CONCLUSIONS: Similar to television, unhealthy food ads predominate in content aimed toward children on YouTube. Policies regulating food marketing to children need to be extended to cover online content in line with a rapidly-evolving digital media environment. Service providers of social media can play a part in limiting unhealthy food advertising to children. PMID- 29985650 TI - Large-Scale Simulations of Bacterial Populations Over Complex Networks. AB - The understanding of bacterial population genetics and evolution is crucial in epidemic outbreak studies and pathogen surveillance. However, all epidemiological studies are limited to their sampling capacities which, by being usually biased or limited due to economic constraints, can hamper the real knowledge of the bacterial population structure of a given species. To this end, mathematical models and large-scale simulations can provide a quantitative analytical framework that can be used to assess how or if limited sampling can infer the true population structure. In this article, we address the large-scale simulation of genetic evolution of bacterial populations, using Wright-Fisher model, in the presence of complex host contact networks. We present an efficient approach for large-scale simulations over complex host contact networks, using MapReduce on top of Apache Spark and GraphX API. We evaluate the relation between cluster computing power and simulations speedup and include insights on how bacterial population diversity can be affected by mutation and recombination rates, and network topology. PMID- 29985651 TI - High-Dose Methotrexate Treatment in a Breastfeeding Mother with Placenta Accreta: A Case Report. AB - BACKGROUND: Morbidly placenta accreta as a cause of postpartum morbidity is increasing in incidence. One conservative option is use of methotrexate as an adjuvant therapy for the management of placenta accreta. There is concern that use of methotrexate in a lactating mother could potentially expose her neonate to harmful effects of this medication. CASE REPORT: Here we report a 29-year-old woman subjected to methotrexate treatment for placenta accreta. Her child was delivered at 32 weeks weighing 3 lbs. On postpartum day 5, this patient was diagnosed with placenta accreta and treated with intramuscular methotrexate for 3 consecutive days. She received 92 mg methotrexate intramuscularly daily, and was advised not to breastfeed. She collected milk samples on day 2, the 0 hour before the second dose and at 1, 2, 4, 8, 12, and 24 hours after taking the dose. A high performance liquid chromatography mass spectrometry method was developed to measure methotrexate and its metabolite 7-hydroxymethotrexate levels in milk samples. DISCUSSION: Very low levels were found for both methotrexate and 7 hydroxymethotrexate in the milk samples obtained. The results indicate that methotrexate or its metabolite receded to minimum concentration over a period of 24 hours. CONCLUSION: This case report found the relative infant dose of methotrexate to be 0.11%. Methotrexate does transfer into breast milk, although the levels detected were very low. However, caution should still be used in counseling mothers regarding breastfeeding with this toxic drug. PMID- 29985652 TI - Comparison between paraffin and mineral oil covering on early human embryo culture: a prospective randomized study. AB - : The oil overlay in microdrop culture systems prevents medium evaporation, helps to maintain appropriate pH and osmotic conditions and protects from microbial contamination. In the present study, we prospectively compared covering by OvoilTM, a paraffin oil, and LiteOil(r), a mineral oil, on the in vitro development of human embryos and their suitability for transfer/freezing at day 3 and live birth rate. One hundred and one patients undergoing in vitro fertilization (IVF) treatment by intracytoplasmic sperm injection (ICSI) were enrolled in our study. After ICSI, 1237 oocytes were 1:1 randomly allocated into 2 groups according to the type of overlaying oil: OvoilTM (616 oocytes) or LiteOil(r) (621 oocytes). Fertilization rate was assessed around 18 hours post insemination (hpi) and embryos were checked for early cleavage at 25 hpi. Embryo morphology was recorded on days 2 and 3. A total of 437 (OvoilTM) and 438 day 3 embryos (LiteOil(r)) were analyzed. There were no differences between the two groups in terms of fertilization rate and occurrence of early cleavage. The proportion of top quality embryos (41.7% vs. 41.2%) and the final utilization rates (92.2% vs. 92.0%) were similar in Ovoil and LiteOil groups, respectively, at day 3. Live birth rate per transfer was essentially the same with OvoilTM overlay (26.9%) when compared to LiteOil(r) (26.2%). Live birth rate in patients who simultaneously received embryos from both overlay types was 17.2%. Despite the different characteristics of these two oils regarding hydrocarbon saturation, packing and temperature storage, OvoilTM and LiteOil(r) can be used in parallel in the same IVF protocol. ABBREVIATIONS: ART: assisted reproductive technologies; hpi: hours post-insemination; hSA: human serum albumin; HTF: human tubal fluid; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MII: metaphase II; MEA: mouse embryo assay; RT: room temperature. PMID- 29985653 TI - Do postconcussive symptoms from traumatic brain injury in combat veterans predict risk for receiving opioid therapy for chronic pain? AB - OBJECTIVES: Opioid therapy is contraindicated in patients with traumatic brain injury (TBI) with neuropsychological impairment, yet guidelines do not consistently predict practice. We evaluated independent risk for initiation of opioid therapy among combat veterans with chronic pain diagnoses and persistent postconcussive symptoms. METHODS: We assembled a retrospective cohort of 53 124 Iraq and Afghanistan veterans in Veterans Affairs (VA) healthcare between October 2007 and March 2015 who received chronic pain diagnoses, completed a Comprehensive TBI Evaluation (CTBIE) and had not received opioid therapy in the prior year. Primary exposure variables were self-reported severe or very severe Emotional, Vestibular, Cognitive and Somatic/Sensory symptoms measured using the Neurobehavioral Symptom Inventory. Outcome measures were initiation of short-term and long-term opioid therapy within the year following CTBIE. RESULTS: Self reported severe and very severe postconcussive symptoms predicted initiation of long-term and short-term opioid use for chronic pain in both unadjusted and adjusted analyses. In adjusted analyses, all four postconcussive symptom domains significantly predicted initiation of long-term opioid therapy, with Emotional symptoms being the strongest predictor [ARR = 1.68 (1.52, 1.86)]. CONCLUSIONS: Increased opioid prescribing in veterans with self-reported severe persistent postconcussive symptoms indicates a need to educate prescribers and make non opioid pain management options available for veterans with TBI and neuropsychological sequelae. PMID- 29985654 TI - Cognitive behavioural therapy for aggression among individuals with moderate to severe acquired brain injury: a systematic review and meta-analysis. AB - BACKGROUND: Aggression is common after an acquired brain injury (ABI). Cognitive behavioural therapy (CBT) is a form of psychotherapy, in which therapists help patients to identify their maladaptive behaviours. OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the effectiveness of CBT interventions in treating aggression in an ABI population. METHODS: A systematic literature search was conducted using: PubMed/MEDLINE, CINAHL, EMBASE and PsycINFO from database inception to August 2016. English articles were included if: at least 50% of the study sample had a moderate to severe ABI, there were at least three adult human participants, and use of a CBT intervention for the treatment of aggression. RESULTS: Seven articles met inclusion criteria: one RCT, an RCT crossover and five pre-post trials. Of these, four articles were included in a pre-post meta-analysis for treatment efficacy on subscales of the State Trait Anger Expression Inventory (STAXI) and STAXI-2 outcome measures. The meta analysis found CBT was effective in moderating the external behaviours of aggression, but not internal anger. CONCLUSION: The differences in outcomes may be related to the differential management of anger expression and anger suppression. CBT shows promise, but further studies with comparator groups are needed before conclusions about its efficacy can be made. PMID- 29985655 TI - Trimethylamine-N-oxide (TMAO) increased aquaporin-2 expression in spontaneously hypertensive rats. AB - Recent evidence suggests that elevated plasma levels of Trimethylamine-N-oxide (TMAO) can prolong the duration of elevated blood pressure in rats. The purpose of this study was to investigate the plasma TMAO level in Spontaneously Hypertensive Rats (SHR) and to explore the possible relationship between TMAO and aquaporin-2 (AQP-2) in the formation of hypertension. Twelve-week-old, male Spontaneously Hypertensive rats (SHR, n = 40) and Wistar-Kyoto rats (WKY, n = 40) were accordingly grouped into SHR group and WKY group. Each group was divided randomly into four subgroups: Untreated group, TMAO group, TMAO+Tolvaptan (TMAO+TVP) group, and TVP group, respectively. Systolic blood pressure (SBP), plasma TMAO, plasma osmolality (POsm), plasma vasopressin (PAVP), and plasma AQP 2 (PAQP-2) concentration were measured, and the expression of AQP-2 in kidney medulla was detected by RT-PCR and Western blot. At 14 weeks, rats in SHR TMAO group were shown the increased plasma TMAO, POsm, PAVP, and PAQP-2 levels, while those rats in SHR TMAO+TVP group were shown the decreased plasma TMAO, POsm, and PAQP-2 levels, but an even higher PAVP (due to the blockage of TVP to V2 receptor). These findings indicate that an increase of plasma TMAO levels in SHR leads to a higher plasma osmotic pressure, triggers the regulation of the TMAO AVP-AQP-2 axis in SHR, elicits the greater water reabsorption, and eventually leads to hypertension. PMID- 29985656 TI - Corrigendum. PMID- 29985657 TI - Introducing WCM-SE: The word complexity measure phonetically justified and adapted to Swedish. AB - This paper presents the Word Complexity Measure for Swedish (WCM-SE), an adaptation of the original WCM developed for English by Stoel-Gammon. These measures are used to calculate the phonological complexity of words or vocalizations, based on a number of phonological complexity parameters. Each production receives a complexity score based on how many of the parameters are present in the production. Using phonological complexity scores to measure expressive phonology is suitable for assessing very young children, children with early phonology and children with phonological deficits. It is useful for both relational and independent analyses and enables comparisons between children and across development. The original WCM uses eight phonological complexity parameters in three domains: word patterns, syllable structures and sound classes. The parameters selected are phonological characteristics that are acquired late in development among English-speaking children. In the WCM-SE, complexity parameters in the domain sound classes were modified or added according to Swedish or universal patterns of phonology development. The parameters' complexity is accounted for in terms of language-general phonetic characteristics. PMID- 29985658 TI - Longitudinal evaluation of ventricular volume changes associated with mild traumatic brain injury in military service members. AB - PRIMARY OBJECTIVE: To investigate differences in longitudinal trajectories of ventricle-brain ratio (VBR), a general measure of brain atrophy, between Veterans with and without history of mild traumatic brain injury (mTBI). RESEARCH DESIGN: Structural magnetic resonance imaging (MRI) was used to calculate VBR in 70 Veterans with a history of mTBI and 34 Veterans without such history at two time points approximately 3 and 8 years after a combat deployment. MAIN OUTCOMES AND RESULTS: Both groups demonstrated a quadratic relationship between VBR and age that is consistent with normal developmental trajectories. Veterans with history of mTBI had larger total brain volume, but no interaction between mTBI and age was observed for brain volume, ventricular volume, or VBR. CONCLUSIONS: In our longitudinal sample of deployed Veterans, mTBI was not associated with gross brain atrophy as reflected by abnormally high VBR or abnormal increases in VBR over time. PMID- 29985659 TI - Hospitalization-induced exacerbation of the ill effects of chemotherapy on rest activity rhythm and quality of life of breast cancer patients: a prospective and comparative cross-sectional follow-up study. AB - Chemotherapy administration may result in the disruption of circadian rhythms and impairment of quality of life (QoL) of cancer patients. Nevertheless, we have little knowledge on the long-term consequences of chemotherapy and the effects of hospitalization. In the present study, we employed the two-factor repeated measure cross-sectional design to determine the effects of chemotherapy and hospitalization on rest-activity (RA) rhythm and QoL of breast cancer patients. Initially, we randomly selected 39 inpatients and 42 outpatients, scheduled to receive six cycles of chemotherapy, from the Regional Cancer Center (RCC), Raipur, India. Finally, 30 patients in each group were included in the current study. We monitored circadian RA rhythm and QoL using wrist actigraphy and QLQ C30 and QLQ-BR23, respectively, during the 1st (C1), 3rd (C3) and 6th (C6) chemotherapy cycles. Results revealed that with the progression of chemotherapy cycles (from C1 to C6), all rhythm parameters, namely mesor, amplitude, acrophase, rhythm quotient (RQ), circadian quotient (CQ), peak activity (PA), dichotomy index and autocorrelation coefficient, significantly decreased in both cancer in- and outpatients. In both groups of patients and during C1-C6, all functional and global QoL measures of QLQ-C30 and QLQ-BR23 significantly decreased and the symptoms significantly increased, except constipation, body image, sexual functioning and future perspectives in outpatients. The hospitalization exacerbated the problems associated with the RA rhythm and the QoL of the patients. In conclusion, the current study highlighted the negative consequences of hospitalization among inpatients, irrespective of the stage of cancer. We, therefore, recommend that cancer patients should be administered with chemotherapy as outpatients. The proposed protocol might have a covert bearing on the expression of better physiological state leading to satisfactory treatment outcomes. PMID- 29985660 TI - Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye. AB - INTRODUCTION: Considering that the number of patients afflicted by posterior eye diseases is increasing, effective drug delivery is currently in high clinical demand. Topical administration has been identified as the preferred option, while sufferingfrom multiple barriers. The development of nanoparticle-based drug delivery system provides an option, which would enhance the drug permeability across the barriers and achieve the desired drug level in the targeted tissue. Areas covered: This review highlights the barrier to the posterior segment of the eye via topical administration. The up-to-date development of lipid nanoparticles, liposomes, emulsions, spanlastics, micelles, polymeric nanoparticles, layered double hydroxides (LDH), dendrimers, cyclodextrins(CDs), and prodrugs are summarized. Moreover, nanocarriers currently in clinical trials for posterior segment diseases have been discussed. Expert opinion: Topical nanoparticle-based drug delivery systems have demonstrated significant progress. An ideal formulation should prolong retention time on the surface, enhance drug permeability through the ocular tissues, and efficiently deliver drugs to the targeted site. To design the rational targeting nanoparticle-based drug delivery system, a better understanding of the distribution of transporters and receptors on the eye is required. Ultimately, there is an urgent need to develop targeting hybrid drug delivery systems with the combination of the advantages of several nanocarriers. PMID- 29985661 TI - Introduction for the Fifth International Symposium on Thymosins in Health and Disease. PMID- 29985662 TI - Voluntary exercise stabilizes photic entrainment of djungarian hamsters (Phodopus sungorus) with a delayed activity onset. AB - The Djungarian hamsters of our breeding colony show unstable daily activity patterns when kept under standard laboratory conditions. Moreover, part of them develops a delayed activity onset (DAO) or an arrhythmic phenotype. In former studies, we have shown that the system of photic entrainment works at its limits. If the period length (tau) increases, which is the case in DAO hamsters, the light-induced phase advances are too small to compensate the daily delay of the activity rhythm caused by tau being longer than 24 h. Accordingly, under natural conditions, there must be further (environmental) factors to enable a stable entrainment. One of these may be the higher level of motor activity. Animals must cover long distances to search for food, sexual partners and others. In the laboratory, hamsters are kept singly in small cages. This does restrict animals' options for motor activity. Also, there is less need for moving around as the hamsters are fed ad libitum. In the present study, a series of experiments was performed to investigate the putative effect of the activity level. To begin with, wild type (WT) and DAO animals were given access to running wheels. 50% of DAO hamsters developed a WT activity pattern. As the main reason for the DAO phenomenon is their long tau together with a too weak photic phase response, the effect of wheel running on these parameters was investigated in further experiments. With higher activity level, tau decreased in WT hamsters but increased in DAO animals even though the increase for the activity onset was only close to significance. Moreover, the photic phase responses were weaker though significant only for the activity offset of DAO hamsters. Based on the assumptions that running wheel activity will affect the phase response and/or the free running period, the results of the present paper do not provide an explanation for why part of DAO hamsters developed a WT phenotype when they had access to running wheels. Obviously, mechanisms downstream from the suprachiasmatic nuclei must be taken into account when investigating the stabilizing, improving circadian entrainment effect of motor activity. PMID- 29985663 TI - Pro-netupitant/palonosetron (IV) for the treatment of radio-and-chemotherapy induced nausea and vomiting. AB - INTRODUCTION: Prevention of nausea and vomiting is of paramount importance for ensuring that patients undergoing anticancer treatments have optimal quality of life. The oral fixed-dose combination of netupitant/palonosetron (NEPA) was developed to improve dual-targeted anti-emetic prophylaxis administration. Areas covered: This article summarizes the available evidence for the pharmacology, safety, and efficacy of the new intravenous formulation of NEPA (IV NEPA). The clinical role of NEPA and future perspectives for anti-emetic research are also discussed. Expert opinion: Each patient undergoing emetogenic anticancer treatments should receive guideline-consistent prophylaxis from the beginning of therapy. However, physicians may be nonadherent to guidelines in prescribing prophylaxis, while patients may be nonadherent in taking their medication as prescribed. Therefore, simplification of anti-emetic regimens with agents that are administered once per treatment cycle may contribute to improve guideline adherence by physicians and compliance with regimens by patients. IV NEPA may also help overcome potential logistical issues surrounding the oral administration of NEPA. While short-term olanzapine can improve control of nausea, it also causes transient but significantly increased sedation. This side effect as well as new evidence support further efforts to explore the overall potential of NEPA against nausea caused by either chemotherapy or concurrent chemo-radiotherapy. PMID- 29985664 TI - Linaclotide for the treatment of chronic constipation. AB - INTRODUCTION: Chronic constipation (CC) is a common gastrointestinal disorder with limited treatment options. Linaclotide is a potent peptide agonist of the guanylate cyclase-C receptor. This action activates intracellular conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate resulting in the stimulation of intestinal fluid secretion. Linaclotide is a promising new agent for refractory constipation. Areas covered: All published articles regarding the development, clinical efficacy, and safety of linaclotide in treating CC were reviewed. Pharmacodynamics, pharmacokinetics, and metabolism of this secretagogue agent were examined. Clinical studies showed that linaclotide increases the number of spontaneous bowel movements and stool consistency scores. Overall, patients reported relief from abdominal discomfort and severity of constipation. Finally, linaclotide has a good safety profile, with diarrhea being the main side effect. Expert opinion: Linaclotide appears to be a well-tolerated and effective agent for patients with CC, and could be effectively combined with other drugs in patients with refractory constipation. However, data on the efficacy and safety of linaclotide in pediatric patients and in opioid-induced constipation are currently limited and more studies need to be undertaken. PMID- 29985665 TI - Improvement of cerebral blood perfusion in certain cerebral regions after cranioplasty could be monitored via tympanic membrane temperature changes. AB - OBJECTIVE: Delayed neurological deficit was often observed in patients underwent craniectomy, which could be improved by cranioplasty. Little is known about hemodynamic improvement before and after cranioplasty. METHODS: Cerebral blood perfusion, tympanic membrane temperature (TMT), neuropsychological and cognitive function were assessed in eleven craniectomy patients before and after cranioplasty. RESULTS: Before cranioplasty, the cerebral blood volume (CBV) on the decompressed side was significantly lower than that of the contralateral side. The cranioplasty led to instant improvement (7 days after cranioplasty) of cerebral perfusion at the cranioplasty side in the frontal lobe, parietal lobe, temporal lobe, mesencephalon, basal ganglia and thalamus, but not the occipital lobe and epencephalon. Interestingly, CBV of the thalamus and basal ganglia gradually decreased to pre-surgical status 6 months later while the frontal lobe, parietal lobe, temporal lobe, mesencephalon remained well perfused. Meanwhile, the TMT changes acquired positive correlation with the perfusion of temporal lobe and mesencephalon as well as the GCS and MMSE score. CONCLUSION: The cranioplasty remarkably improves neurological and cognitive function by ameliorating cerebral perfusion in certain regions. The TMT could be used as a non-invasive method to monitor the cerebral perfusion improvement after the cranioplasty. PMID- 29985666 TI - Public perceptions of traumatic brain injury: predictors of knowledge and the effects of education. AB - AIM: Existing research suggests that the public demonstrates inadequate knowledge about traumatic brain injury (TBI), indicating a need for public education initiatives; however, limited research exists on the effectiveness of these initiatives. The purposes of this study were to (1) identify whether any demographic/personal variables (e.g. gender, age, experience with TBI) predicted TBI knowledge and (2) determine whether presenting an educational video to members of the general public would improve knowledge about TBI. METHODS: Participants included 392 adults recruited from a state fair. Participants were divided into two groups, one of which viewed a 6-min video about TBI, and one which viewed an unrelated video. Participants completed measures relating to their backgrounds and knowledge about TBI. RESULTS: Greater educational attainment and professional experience with TBI were predictive of better TBI knowledge (F(1, 336) = 13.76 and 6.92, respectively, p < 0.01); no other demographic or personal variables predicted knowledge. Participants who viewed the TBI video demonstrated significantly better knowledge than participants who did not (F(1, 336) = 52.41, p < 0.0001). CONCLUSION: These results indicate that public education can result in immediate gains in public knowledge about TBI. Further research should include randomized controlled trials to determine long term effectiveness of public education campaigns. PMID- 29985667 TI - The effect of hypertension on cardiac structure and function in different types of hypertrophic cardiomyopathy: A single-center retrospective study. AB - OBJECTIVES: To determine whether hypertension (HTN) affects cardiac structure and function in different types of hypertrophic cardiomyopathy (HCM). DESIGN: Patients with obstructive HCM (n = 40), septal HCM (n = 88), and apical HCM (n = 42) were separated into hypertensive and non-hypertensive subgroups, and echocardiographic parameters at baseline and at follow-up were compared between the subgroups. RESULTS: At follow-up, hypertensive obstructive HCM patients showed a decrease in end-diastolic volume (from 93.87 +/- 26.08 mL to 79.06 +/- 20.07 mL; p= 0.045) and in left ventricular end-diastolic diameter (from 45.00 +/ 5.32 mm to 41.83 +/- 4.58 mm; p =0.042). Non-hypertensive obstructive HCM patients showed a decrease in maximum aortic velocity (from 2.01 +/- 0.53 m/s to 1.28 +/- 0.25 m/s; p= 0.011) and in aortic maximum pressure gradient (from 17.22 +/- 9.57 mm Hg to 6.79 +/- 2.44 mm Hg; p= 0.03). Hypertensive apical HCM patients showed an increase in end-diastolic volume (from 95.28 +/- 16.54 mL to 119.74 +/- 25.19 mL; p= 0.016) and in left ventricular end-diastolic diameter (from 45.28 +/ 3.36 mm to 50.20 +/- 4.56 mm; p= 0.007). CONCLUSIONS: HTN can affect left ventricular capacity in obstructive HCM and apical HCM, causing a decrease in ventricular capacity in the former and increase in the latter; it has no significant effect on the size of the left ventricular cavity in septal HCM. HTN can lead to a poor therapeutic effect on aortic flow rate and pressure gradient in obstructive HCM patients. PMID- 29985668 TI - Normative nasalance scores for Estonian children. AB - Normative nasalance scores are essential for the treatment and assessment purposes for clinicians. Till date, no studies have been done on nasalance in Estonia. This research was conducted to develop Estonia-specific optimized speech stimuli for Nasometer II and establish the normative nasalance scores. Ninety-two randomly selected healthy and 14 cleft palate Estonian monolingual children, aged four to seven years, were included as participants. Estonian language-specific test material was developed. The Estonian test material consisted of 24 speech stimuli. Based on the phoneme content, the stimuli were divided into three groups: (1) sentences that included oral and nasal phonemes and targeted the same phoneme distribution as in spontaneous speech, (2) sentences that included only oral phonemes and (3) sentences that were loaded with nasal phonemes. Nasometer II software was used to calculate the nasalance scores for each child and each sentence. Results indicated that there were significant differences in nasalance scores for oronasal and oral stimuli scores, and no significant differences were found in nasal stimuli scores between the study and control group. The threshold for oronasal stimuli was 42.1-18.9, oral stimuli was 27.9-3.9 and nasal stimuli was 69.4-46.2. In conclusion, Estonia-specific optimized speech stimuli were developed and normative nasalance scores were established. These normative scores can be used for the diagnosis and follow-up treatment of patients with resonance disorders, especially for patients with cleft palate. PMID- 29985669 TI - A brief pre-exercise nap may alleviate physical performance impairments induced by short-term sustained operations with partial sleep deprivation - A field-based study. AB - The purpose of the study was to evaluate the recuperative efficacy of pre exercise napping on physical capacity after military sustained operations (SUSOPS) with partial sleep deprivation. Before and after a 2-day SUSOPS, 61 cadets completed a battery of questionnaires, and performed a 2-min lunges trial and a 3,000-m running time-trial. After the completion of SUSOPS, subjects were randomized to either a control [without pre-exercise nap (CON); n = 32] or a nap [with a 30-min pre-exercise nap (NAP); n = 29] group. SUSOPS enhanced perceived sleepiness and degraded mood in both groups. Following SUSOPS, the repetitions of lunges, in the CON group, were reduced by ~ 2.3%, albeit the difference was not statistically significant (p = 0.62). In the NAP group, however, the repetitions of lunges were increased by ~ 7.1% (p = 0.01). SUSOPS impaired the 3,000-m running performance in the CON group (~ 2.3%; p = 0.02), but not in the NAP group (0.3%; p = 0.71). Present results indicate, therefore, that a relatively brief pre-exercise nap may mitigate physical performance impairments ensued by short term SUSOPS. PMID- 29985670 TI - Three-Level Longitudinal Mediation with Nested Units: How does an Upper-Level Predictor Influence a Lower-Level Outcome via an Upper-Level Mediator Over Time? AB - In the study, extending from the cross-lagged panel model (CLPM) and the 2-2-1 cross-sectional multilevel mediation model, we proposed a three-level longitudinal mediation model to evaluate the causal process among variables at different levels over time. Given the complexity of the proposed model, Bayesian estimation was used. A simulation study was conducted to examine the estimation accuracy of Bayesian estimation for the proposed model. Factors considered in the simulation study included average sample sizes of the lower-level units within each upper-level unit (or cluster size; [Formula: see text]), numbers of upper level units (or clusters; J), numbers of time points (T), fixed direct and indirect effect sizes, and variances and covariances of upper-level random effects. Results indicated that the fixed effect estimates for the indirect effect components (a and b), fixed direct effect (c), and the average mediation effect estimate were reasonably accurate when [Formula: see text], J > 20, and T ? 4. Comparing the proposed model against the CLPMs coupled with aggregation or disaggregation techniques, we found that the CLPMs yielded misleading fixed effects estimates and low coverage rates when variation existed between upper level units. The proposed model was illustrated using a study on early childhood education. We compared estimates and inferences from the proposed three-level longitudinal mediation model, the CLPMs with aggregation and disaggregation, and the traditional 2-2-1 mediation model. Limitations and extensions of the current study were discussed. PMID- 29985671 TI - The effects of 12-week progressive strength training on strength, functional capacity, metabolic biomarkers, and serum hormone concentrations in healthy older women: morning versus evening training. AB - Previous findings suggest that performing strength training (ST) in the evening may provide greater benefit for young individuals. However, this may not be optimal for the older population. The purpose of this study was to compare the effects of a 12-week ST program performed in the morning vs. evening on strength, functional capacity, metabolic biomarker and basal hormone concentrations in older women. Thirty-one healthy older women (66 +/- 4 years, 162 +/- 4 cm, 75 +/- 13 kg) completed the study. Participants trained in the morning (M) (07:30, n = 10), in the evening (E) (18:00, n = 10), or acted as a non-training control group (C) (n = 11). Both intervention groups performed whole-body strength training with 3 sets of 10-12 repetitions with 2-3 minutes rest between sets. All groups were measured before and after the 12-week period with; dynamic leg press and seated-row 6-repetition maximum (6-RM) and functional capacity tests (30-second chair stands and arm curl test, Timed Up and Go), as well as whole-body skeletal muscle mass (SMM) (kg) and fat mass (FM-kg, FM%) assessed by bioelectrical impedance (BIA). Basal blood samples (in the intervention groups only) taken before and after the intervention assessed low-density lipoprotein (LDL-C), high density lipoprotein (HDL-C), blood glucose (GLU), triglycerides (TG), high sensitive C-reactive protein (hsCRP) concentrations and total antioxidant status (TAS) after a 12 h fast. Hormone analysis included prolactin (PRL), progesterone (P) estradiol (ESTR), testosterone (T), follicle stimulating hormone (FSH), and luteinizing hormone (LH). While C showed no changes in any variable, both M and E significantly improved leg press (+ 46 +/- 22% and + 21 +/- 12%, respectively; p < 0.001) and seated-row (+ 48 +/- 21% and + 42 +/- 18%, respectively; p < 0.001) 6-RM, as well as all functional capacity outcomes (p < 0.01) due to training. M were the only group to increase muscle mass (+ 3 +/- 2%, p < 0.01). Both M and E group significantly (p < 0.05) decreased GLU (-4 +/- 6% and -8 +/- 10%, respectively), whereas significantly greater decrease was observed in the E compared to the M group (p < 0.05). Only E group significantly decreased TG (-17 +/- 25%, p < 0.01), whereas M group increased (+ 15%, p < 0.01). The difference in TG between the groups favored E compared to M group (p < 0.01). These results suggest that short-term "hypertrophic" ST alone mainly improves strength and functional capacity performance, but it influences metabolic and hormonal profile of healthy older women to a lesser extent. In this group of previously untrained older women, time-of-day did not have a major effect on outcome variables, but some evidence suggests that training in the morning may be more beneficial for muscle hypertrophy (i.e. only M significantly increased muscle mass and had larger effect size (M: g = 2 vs. E: g = 0.5). PMID- 29985672 TI - Parent and child ratings of child behaviour following mild traumatic brain injury. AB - BACKGROUND: Mild traumatic brain injury (mTBI) in children is most commonly associated with parent-reported child behaviour problems. The extent to which parent and child ratings align is unknown. OBJECTIVES: To examine differences in child behaviour and patterns of recovery over the first 12 months following mTBI based on parent and child self-report. METHODS: Ninety-nine children (8-15 years) with mTBI and one of their parents completed the Behavioural Assessment Scale for Children - version 2 to assess child hyperactivity, anxiety and depression at baseline, 1, 6 and 12 months post-injury. Differences between ratings from parents and children were evaluated using Bland-Altman limits of agreement analyses. Child recovery over time was examined using mixed models repeated measures analyses. RESULTS: Parent and child ratings for child hyperactivity, anxiety and depression differed significantly at baseline and these differences remained constant at each follow-up. Parents tended to report more child hyperactivity, anxiety and depression. Over time, parents and children reported fewer child hyperactivity and anxiety problems. CONCLUSIONS: Parents and children have poor agreement in ratings of child behaviour yet there is general agreement in patterns of recovery in the year following mTBI. Findings show the importance of considering both parent and self-report of child behaviour. PMID- 29985673 TI - Longitudinal changes in neuroimaging and neuropsychiatric status of post deployment veterans: a CENC pilot study. AB - PRIMARY OBJECTIVE: The purpose of this study was to evaluate preliminary data on longitudinal changes in psychiatric, neurobehavioural, and neuroimaging findings in Iraq and Afghanistan combat veterans following blast exposure. RESEARCH DESIGN: Longitudinal observational analysis. METHODS AND PROCEDURES: Participants were invited to participate in two research projects approximately 7 years apart. For each project, veterans completed the Structured Clinical Interview for DSM-IV Disorders and/or the Clinician-Administered PTSD Scale, Neurobehavioral Symptom Inventory, and magnetic resonance imaging (MRI). MAIN OUTCOMES AND RESULTS: Chi squared tests indicated no significant changes in current psychiatric diagnoses, traumatic brain injury (TBI) history, or blast exposure history between assessment visits. Wilcoxon signed-rank tests indicated significant increases in median neurobehavioural symptoms, total number of white matter hyperintensities (WMH), and total WMH volume between assessment visits. Spearman rank correlations indicated no significant associations between change in psychiatric diagnoses, TBI history, blast exposure history, or neurobehavioural symptoms and change in WMH. CONCLUSION: MRI WMH changes were not associated with changes in psychiatric diagnoses or symptom burden, but were associated with severity of blast exposure. Future, larger studies might further evaluate presence and aetiology of long-term neuropsychiatric symptoms and MRI findings in blast-exposed populations. PMID- 29985674 TI - Is the endovascular embolization of tributaries of the internal iliac veins essential in the treatment of isolated pelvic-perineal reflux? AB - AIM: The aim of study was to investigate the opportunities of local phlebectomy in the elimination of isolated pelvic-perineal reflux (PPR), as well as to determine the feasibility of endovascular embolization of the tributaries of internal iliac veins in PPR. Clinical trial no. NCT01598051. MATERIALS AND METHODS: The work is based on the results of examination and treatment of 43 female patients with varicose veins of the pelvis, perineum, and lower extremities. Patients had no signs of pelvic congestion syndrome (PCS). All patients underwent duplex ultrasound scanning (DUS) and ovariography with pelvic phlebography (OPP). For the elimination of PPR, local phlebectomy was performed in the major labia and perineal area, with maximal possible mobilization of the vessel within the operative wound (33 patients). In 10 patients with isolated varicose transformation of the superficial veins on the posterior thigh, mini phlebectomy was performed using the Varady phlebectomy extractors. RESULTS AND DISCUSSION: The varicose syndrome of the external genitalia, perineum, and posterior thigh was successfully treated in 100% of patients. Findings suggest that thorough mobilization and excision of the veins of the pudendal labia, perineum, and subcutaneous veins of the thigh is a reliable method for eliminating the pathological reflux from the intrapelvic veins to the superficial veins of the perineum and lower extremities. No recurrences of vulvar, perineal varices or dilation of the veins of the lower extremities were observed in 100% of patients over the 3-year follow-up period. CONCLUSION: Local phlebectomy is an effective technique for eliminating the isolated PPR in patients with varicose transformation of intrapelvic, vulvar, or perineal veins. Endovascular embolization of the tributaries of the internal iliac veins is not an essential component in the treatment of PPR. The present study has a limitation due to the absence of patients with PCS. The effectiveness of phlebectomy in the treatment of isolated PPR was studied. PMID- 29985675 TI - IRF5-mediated immune responses and its implications in immunological disorders. AB - Transcription factors are gene regulators that activate or repress target genes. One family of the transcription factors that have been extensively studied for their crucial role in regulating gene network in the immune system is the interferon regulatory factors (IRFs). IRFs possess a novel turn-helix turn motif that recognizes a specific DNA consensus found in the promoters of many genes that are involved in immune responses. IRF5, a member of IRFs has recently gained much attention for its role in regulating inflammatory responses and autoimmune diseases. Here, we discuss the role of IRF5 in regulating immune cells functions and how the dysregulation of IRF5 contributes to the pathogenesis of immune disorders. We also review the latest findings of potential IRF5 inhibitors that modulate IRF5 activity in the effort of developing therapeutic approaches for treating inflammatory disorders. PMID- 29985676 TI - Exploring the factor structure of a battery of neuropsychological assessments among the CENC cohort. AB - OBJECTIVE: The goal of the Chronic Effects of Neurotrauma Consortium (CENC) study is to explore the effects of concussions among Service Members and Veterans. A factor model was fit to selected neuropsychological measures to identify potentially useful relationships between assessments collected on CENC-enrolled participants. METHOD: 492 post-9/11 participants with combat exposure were enrolled across four VA study sites. Participants completed assessments including concussion history, neurocognitive functioning, and self-report questionnaires. Exploratory factor analyses (EFA) using four different methods with varimax and promax rotations were used to analyse the cognitive variables. Final model selection was based on factor loadings towards simple structure. RESULTS: The scree plot suggested the number of factors to be extracted was between 4 and 5. EFA produced a 5-factor MINRES model with promax rotation that resulted in a factor loading with variables loading on only one factor with a predefined threshold (0.40). Variables loaded on five cognition domains: list learning, working memory/executive skills, cognitive control, fluency, and memory. CONCLUSION: These results provide reasonable evidence that data collected from the CENC neuropsychological battery can be reduced to five clinically useful factors. This will enable us to use the factors for further study of the impact of concussion on neurodegeneration. PMID- 29985677 TI - Recruiting for a multicentre DoD and VA longitudinal study: lessons learned. AB - PRIMARY OBJECTIVE: The primary objective of the study is to identify and delineate effective recruitment practises in a large, multi-site, longitudinal, observational study employing both military service members and Veterans. SETTING: Four Chronic Effects of Neurotrauma Consortium sites. DESIGN: A descriptive study. RESULTS: Overall and cohort-specific recruitment increased with the addition of focused recruitment strategies and a military/Veteran centric recruitment director. CONCLUSION: Use of site-specific strategies aligned with local Institutional Review Board procedures and emphasizing awareness of service member organizational allegiances was the key to effective recruiting. Adding a recruitment director with background similar to study participants coincided with significantly improved overall participant numbers and specific subpopulations of research subjects, thus adding to the value of the study. PMID- 29985678 TI - Lichen Planus in Ocular Surface: Major Presentations and Treatments. AB - Ocular lichen planus (LP) is a rare disease which has been increasingly reported in the literature in the last two decades involving conjunctiva, cornea, and lacrimal drainage system. Most reported cases of ocular LP are cicatricial conjunctivitis with subepithelial fibrosis, fornix shortening, and symblepharon formation. It is not clear whether corneal involvement is a primary event or secondary to these changes. Topical cyclosporine and corticosteroid can be considered as first-line therapy in ocular surface involvement, while treatment regimen in more aggravated disease should be boosted with systemic immunosuppressives. After resolving acute inflammation, the patient should be treated with long-term maintenance therapy to halt the chronic progression of the disease. Lacrimal drainage system could also be involved, usually in a bilateral bicanalicular pattern with severe punctal/canalicular stenosis. Because of severity, the surgical outcomes are not favorable but successive treatments with dacryocystorhinostomy + mitomycin C (MMC), Jones tube implantation, and systemic cyclosporine are reported. PMID- 29985679 TI - The Effects of Sodium Phosphate Supplementation on Physiological Responses to Submaximal Exercise and 20 km Cycling Time-Trial Performance. AB - The aim of this study was to examine the effects of sodium phosphate (SP) supplementation on physiological responses to submaximal exercise and 20 km cycling time-trial performance. Using a randomized, double-blind, crossover design, 20 endurance-trained male cyclists (age: 31 +/- 6 years; height: 1.82 +/- 0.07 m; body mass: 76.3 +/- 7.0 kg; maximal oxygen uptake [VO2max]: 57.9 +/- 5.5 mL.kg-1.min-1) completed two supplementation trials separated by a 14-day washout period. The trials consisted of 10 minutes of cycling at 65% VO2max followed by a 20 km time trial. Expired air was monitored throughout each trial for the evaluation of VO2, minute ventilation (VE), and respiratory exchange ratio (RER). Heart rate was monitored during each trial along with ratings of perceived exertion (RPE) and blood lactate concentration. For four days before each trial, participants ingested 50 mg.kg fat-free mass-1.day-1 of either SP or placebo. There were no effects (p >= .05) of supplementation on physiological responses during cycling at 65% VO2max. There were also no effects of supplementation on time-trial performance (placebo: 32.8 +/- 2.2 min; SP: 32.8 +/- 2.3 min). Nevertheless, relative to placebo, SP increased VE (mean difference: 3.81 L.min 1; 95% confidence interval: [0.16, 7.46 L.min-1]), RER (mean difference: 0.020; 95% confidence interval: [0.004, 0.036]), and RPE (mean difference: 0.39; 95% confidence interval: [0.04, 0.73]) during time trials, as well as post time-trial blood lactate concentration (mean difference: 1.06 mmol.L-1; 95% confidence interval: [0.31, 1.80 mmol.L-1]). In conclusion, SP supplementation has no significant effects on submaximal physiological responses or 20 km time-trial performance. PMID- 29985680 TI - Changes in metabolic parameters and body weight in brexpiprazole-treated patients with acute schizophrenia: pooled analyses of phase 3 clinical studies. AB - OBJECTIVE: To analyze the effect of brexpiprazole on metabolic parameters and body weight in adults with schizophrenia, including clinically relevant sub groups of patients, based on data from two pivotal phase 3 studies (NCT01393613; NCT01396421) and a long-term extension study (NCT01397786). METHODS: The short term studies were randomized, double-blind, placebo-controlled, fixed-dose (2 and 4 mg/day), 6-week phase 3 studies. The long-term study was an open-label 52-week study, recruiting de novo patients and those completing either short-term study. Maximum exposure to brexpiprazole was 58 weeks. Fasting metabolic parameters and weight were measured throughout the studies. Metabolic values were characterized as normal, borderline, or high (cholesterol, triglycerides, and glucose) and low or normal (HDL), using commonly reported thresholds. The incidences of all possible shifts in metabolic parameters were measured from baseline to any time post-baseline during the first 6 weeks, first 6 months, and last 6 months of treatment. RESULTS: In short-term studies, the proportion of brexpiprazole treated patients with unfavorable shifts in metabolic parameters was low and like that of placebo-treated patients; the incidence of these shifts was not dose dependent. During both short- and long-term treatment, the incidence of unfavorable shifts with brexpiprazole was lower than that of favorable shifts. During short-term studies, the mean increase in body weight was 1.2 kg with brexpiprazole treatment and 0.2 kg with placebo. The mean increase in body weight during long-term treatment was 3.2 kg at week 58. CONCLUSIONS: Brexpiprazole treatment was associated with moderate weight gain and small changes in metabolic parameters during both short- and long-term treatment. PMID- 29985682 TI - Bilateral angle closure glaucoma in a 28-year-old Cohen syndrome patient. PMID- 29985681 TI - No increase in readmissions or adverse events after implementation of fast-track program in total hip and knee replacement at 8 Swedish hospitals: An observational before-and-after study of 14,148 total joint replacements 2011 2015. AB - Background and purpose - Fast-track care programs in elective total hip and knee replacement (THR/TKR) have been introduced in several countries during the last decade resulting in a significant reduction of hospital stay without any rise in readmissions or early adverse events (AE). We evaluated the risk of readmissions and AE within 30 and 90 days after surgery when a fast-track program was introduced in routine care of joint replacement at 8 Swedish hospitals. Patients and methods - Fast-track care programs were introduced at 8 public hospitals in Vastra Gotaland region from 2012 to 2014. We obtained data from the Swedish Hip and Knee Arthroplasty Registers for patients operated with THR and TKR in 2011 2015. All readmissions and new contacts with the health care system within 3 months with a possible connection to the surgical intervention were requested from the regional patient register. We compared patients operated before and after the introduction of the fast-track program. Results - Implementation of the fast-track program resulted in a decrease in median hospital length of stay (LOS) from 5 to 3 days in both THR and TKR. The total readmission rate <90 days for THR was 7.2% with fast-track compared with 6.7% in the previous program, and for TKR 8.4% in both groups. Almost half of the readmissions occurred without any AE identified. There was no statistically significant difference concerning readmissions or AE when comparing the programs. Interpretation - Implementation of a fast-track care program in routine care of elective hip and knee replacement is effective in reducing hospital stay without increasing the risk of readmissions or adverse events within 90 days after surgery. PMID- 29985683 TI - Pembrolizumab and epacadostat induced fatal myocarditis and myositis presenting as a case of ptosis and ophthalmoplegia. AB - We report the first case of fatal myocarditis presenting as bilateral ptosis in a patient on combination therapy with pembrolizumab and epacadostat. An 83 year-old man with stage III high-grade urothelial carcinoma presented with acute onset droopy eyelids one month after starting pembrolizumab and epacadostat. Exam showed myogenic ptosis and ophthalmoplegia. He was later found to have acute myocarditis with complete heart block and subsequently passed away. Pembrolizumab in combination with epacadostat can induce a potentially fatal myocarditis. Although immune mediated myocarditis is a rare established side effect, more reported fatalities are needed in the literature to highlight the urgency for standardized cardiac monitoring of even asymptomatic patients to prevent fatal outcomes, as well as a consensus on treatment protocols. Cancer immunotherapy complications are not well known to ophthalmologists. This case is unique in that the presenting sign was ptosis, which prompted the patient to call his ophthalmologist first. PMID- 29985684 TI - Tolerance to exposure to essential oils exposure in patients with allergic asthma. AB - BACKGROUND: Essential oils are volatile compounds of plant origin increasingly used by allergic and/or asthmatic subjects to purify indoor air. The active compounds of essential oils belong to terpenes, the most widespread biogenic volatile organic compounds (VOC). Although there is substantial literature showing associations between exposure to chemical VOCs and asthmatic symptoms and impaired respiratory function, the impact of essential oils in patients with asthma has never been studied. OBJECTIVES: To evaluate the safety of a purifying air spray containing 41 essential oils (PPAS) in patients with mild or moderate allergic asthma. METHODS: This was a prospective open study in which 25 mild (19) and moderate (6) asthmatics were exposed to PPAS, one spray twice a day at 8 am and 8 pm in two different corners of a given subjects bedroom for 4 weeks. Before and after 4 weeks of exposure, fractional exhaled nitric oxide (FeNO), lung function and methacholine challenge (PD20) were performed and asthma control was assessed by the 5 questions of the Asthma Control Test (ACT). The spray was weighed after the 4-week exposure to assess compliance. RESULTS: FeNO was the primary endpoint and was thus analyzed in all (N = 25) subjects irrespective of the level of airflow obstruction. The results apply to all (N = 25) subjects in which FeNO could be measured at D1 and D30 (17 subjects). Mean (SD) FeNO amounted to 37.4 (16.6) and to 33.1 (18.7) ppm before and after PPAS exposure, respectively (p = 0.09). No significant change in lung function and methacholine responsiveness was noted after PPAS exposure, the mean PD20 amounting to 1179 (1124.42) MUg (range 100-3200) before and to 1226 (1189.8) MUg (p = 0.06) after. The mean ACT before and after PPAS exposure amounted to 20.9 (4.2) and 21 (5.15), respectively (p = 0.80). The mean weight of the PPAS bottles was 211.4 g (DS:0) before the first use and 171.41 g (DS: 29.8) at the end of the study. The average amount of PPAS used was 40.0 g (29.8). In the subgroup of subjects who used the highest quantities of essential oils (>40 g), as assessed by the mean weight of the bottle at the end of the study, FeNO after 30 days of exposure decreased more than in the entire group: 7.9 ppm vs 4.2 ppm (p = 0.07). CONCLUSION: No difference was noted on airway inflammation, lung function or asthma control in mild and moderate allergic asthmatics after exposure twice a day for one month, to a spray containing a mixture of 41 essential oils. PMID- 29985685 TI - Impact Of Risk Adjustment For Socioeconomic Status On Medicare Advantage Plan Quality Rankings. AB - Sociodemographically disadvantaged patients have worse outcomes on some quality measures that inform Medicare Advantage plan ratings. Performance measurement that does not adjust for sociodemographic factors may penalize plans that disproportionately serve disadvantaged populations. We assessed the impact of adjusting for socioeconomic and demographic factors (sex, race/ethnicity, dual eligibility, disability, rurality, and neighborhood disadvantage) on Medicare Advantage plan rankings for blood pressure, diabetes, and cholesterol control. After adjustment, 20.3 percent, 19.5 percent, and 11.4 percent of Medicare Advantage plans improved by one or more quintiles in rank on the diabetes, cholesterol, and blood pressure measures, respectively. Plans that improved in ranking after adjustment enrolled higher proportions of disadvantaged enrollees. Adjusting quality measures for socioeconomic factors is important for equitable payment and quality reporting. Our study suggests that plans serving disadvantaged populations would have improved relative rankings for three important outcome measures if socioeconomic factors were included in risk adjustment models. PMID- 29985686 TI - Behavioral Health Coverage In The Individual Market Increased After ACA Parity Requirements. AB - As of January 1, 2014, the Affordable Care Act designated mental health and substance use services as an essential health benefit in Marketplace plans and extended parity protections to the individual and small-group markets. We analyzed documents for seventy-eight individual and small-group plans in 2014 (after parity provisions took effect) and sixty comparison plans in 2013 (the year before parity provisions took effect) to understand the degree to which coverage for mental health and substance use care improved relative to medical/surgical benefits. The results suggest that plan issuers did what the provisions required them to do. Although in 2013 a lower proportion of plans covered mental health or substance use care, compared to medical/surgical care, in 2014 the proportions were the same. If essential health benefit requirements were to be removed and mental health and substance use coverage becomes similar to that in 2013, as many as 20 percent of the plans in our sample would not cover these conditions. To determine whether increases in behavioral health coverage will result in improved access to behavioral health services requires complementary data on the size of provider networks and use of services. PMID- 29985687 TI - Electronic Health Records Associated With Lower Hospital Mortality After Systems Have Time To Mature. AB - Evidence linking electronic health record (EHR) adoption to better care is mixed. More nuanced measures of adoption, particularly those that capture the common incremental approach of adding functions over time in US hospitals, could help elucidate the relationship between adoption and outcomes. We used data for the period 2008-13 to assess the relationship between EHR adoption and thirty-day mortality rates. We found that baseline adoption was associated with a 0.11 percentage-point higher rate per function. Over time, maturation of the baseline functions was associated with a 0.09-percentage-point reduction in mortality rate per year per function. Each new function adopted in the study period was associated with a 0.21-percentage-point reduction in mortality rate per year per function. We observed effect modification based on size and teaching status, with small and nonteaching hospitals realizing greater gains. These findings suggest that national investment in hospital EHRs should yield improvements in mortality rates, but achieving them will take time. PMID- 29985689 TI - Per Visit Emergency Department Expenditures By Insurance Type, 1996-2015. AB - Between 1996 and 2015, mean annual increases in per visit emergency department (ED) expenditures were significantly greater for private insurance than Medicare, Medicaid, and no insurance, with no corresponding difference in ED charges. Expenditures as a proportion of charges decreased for all insurers over time. Private insurance had the highest expenditure-to-charge ratio in each year. PMID- 29985688 TI - Is Inpatient Volume Or Emergency Department Crowding A Greater Driver Of Ambulance Diversion? AB - Inpatient volume has long been believed to be a contributing factor to ambulance diversion, which can lead to delayed treatment and poorer outcomes. We examined the extent to which both daily inpatient and emergency department (ED) volumes at specified hospitals, and diversion levels (that is, the number of hours ambulances were diverted on a given day) at their nearest neighboring hospitals, were associated with diversion levels in the period 2005-12. We found that a 10 percent increase in patient volume was associated with a sevenfold greater increase in diversion hours when the volume increase occurred among inpatients (5 percent) versus ED visitors (0.7 percent). When the next-closest ED experienced mild, moderate, or severe diversion, the study hospital's diversion hours increased by 8 percent, 23 percent, and 44 percent, respectively. These findings suggest that efforts focused on managing inpatient volume and flow might reduce diversion more effectively than interventions focused only on ED dynamics. PMID- 29985690 TI - Value-Based Insurance Design Improves Medication Adherence Without An Increase In Total Health Care Spending. AB - Value-based insurance design (VBID) is a strategy that reduces cost sharing for high-value services and increases consumers' out-of-pocket spending for low-value care. VBID has increasingly been implemented by private and public payers and has inspired demonstration programs in Medicare Advantage and TRICARE. Given the recent publication of several studies, we performed an updated systematic review that evaluated the effects of reducing consumer cost sharing on medication adherence and other relevant outcomes. Searches were conducted in key online databases, and the screening of citations yielded twenty-one unique studies, of which eight had not been included in previous reviews. Using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, we found moderate-quality evidence showing improvement (range: 0.1-14.3 percent) in medication adherence with VBID. This increase in adherence was associated with no effect on total health care spending, which suggests that the incremental drug spending was offset by decreases in spending for other health care services. PMID- 29985691 TI - No Association Found Between The Medicaid Primary Care Fee Bump And Physician Reported Participation In Medicaid. AB - On average, state Medicaid programs paid 59 percent of what Medicare paid for primary care services in 2012. The Affordable Care Act required states in 2013 and 2014 to raise Medicaid payment rates to primary care physicians for certain services to the level of Medicare rates. The result was an average 73 percent increase in primary care Medicaid payments for qualifying physicians. This study used nationally representative data to examine the association between this Medicaid "fee bump" and physician-reported measures of participation in Medicaid. No such association was found. For example, about 65 percent of primary care physicians reported accepting new Medicaid patients in both 2012 and 2013, whereas about 67 percent reported doing so in 2014-a difference that is not significant. Multivariate results were similar. The lack of a sizable change in measures of physician participation in Medicaid may have been due to the temporary nature of the fee bump. PMID- 29985692 TI - Why Did Employer Coverage Fall In Massachusetts After The ACA? Potential Consequences Of A Changing Employer Mandate. AB - The Affordable Care Act (ACA) attempted to minimize disruptions to employer sponsored insurance in part by implementing an employer mandate. Research has shown that employer coverage rates have been stable nationally under the ACA. Massachusetts enacted its own employer mandate in 2006 before eliminating it in 2014, in anticipation of the federal mandate. But the ACA's employer mandate was delayed until 2015 and exempted smaller firms that had been covered by the Massachusetts' mandate. In this unique policy environment, we found that the employer-sponsored insurance rate in Massachusetts fell by 2.3 percentage points after the ACA's coverage expansion took effect (2014-16), compared to the rest of the US. Coverage dropped more for middle-income workers than for lower-income workers, which suggests that crowd-out by Medicaid was not the primary factor. Employer surveys show that employer coverage offer rates declined significantly at small firms in Massachusetts beginning in 2014, but not at large firms. Our findings suggest that eliminating Massachusetts's employer mandate may have contributed to falling employer coverage rates in the state, although other policy and economic factors cannot be ruled out. These results may have implications for understanding the effects of the ACA's employer mandate and its potential repeal. PMID- 29985693 TI - Membership In Seguro Popular In Mexico Linked To A Small Reduction In Catastrophic Health Expenditure. AB - In 2004 the government of Mexico initiated an ambitious program, Seguro Popular, to extend health insurance coverage to poor and informal-sector workers. While the program had a protective effect during its early stages, its impact on out-of pocket health spending over time is unclear. This study used two waves of the Encuesta Nacional de Salud y Nutricion (from 2006 and 2012) to analyze the protective effects of Seguro Popular and social security programs on out-of pocket and catastrophic health spending. While, given the endogeneity of Seguro Popular enrollment, we found no link between membership and out-of-pocket health care spending in the study period, we did find a robust, albeit small, link between membership and a reduction in catastrophic health spending. A significant part of overall out-of-pocket health spending goes to purchase medications. Policy decisions are necessary to address gaps in coverage and access to medicines. Improving the quality of care as well as including more clinically effective and cost-effective medicines in the Seguro Popular package could significantly reduce out-of-pocket health care spending in Mexico. PMID- 29985694 TI - Hospital-Physician Consolidation Accelerated In The Past Decade In Cardiology, Oncology. AB - Consolidation of physician practices by hospitals, or vertical integration, increased across all practice types in 2007-17. Rates of growth were highest among medical and surgical specialty practices and lowest among primary care practices. There was substantial variation within the specialties, ranging from 4 percentage points in dermatology to 34 percentage points in cardiology and oncology. PMID- 29985696 TI - Chronic Care, Prescription Drugs, And More. PMID- 29985695 TI - Specialty Drug Coverage Varies Across Commercial Health Plans In The US. AB - We analyzed specialty drug coverage decisions issued by the largest US commercial health plans to examine variation in coverage and the consistency of those decisions with indications approved by the Food and Drug Administration (FDA). Across 3,417 decisions, 16 percent of the 302 drug-indication pairs were covered the same way by all of the health plans, and 48 percent were covered the same way by 75 percent of the plans. Specifically, 52 percent of the decisions were consistent with the FDA label, 9 percent less restrictive, 2 percent mixed (less restrictive in some ways but more restrictive in others), and 33 percent more restrictive, while 5 percent of the pairs were not covered. Health plans restricted coverage of drugs indicated for cancer less often than they did coverage of drugs indicated for other diseases. Using multivariate regression, we found that several drug-related factors were associated with less restrictive coverage, including indications for orphan diseases or pediatric populations, absence of safety warnings, time on the market, lack of alternatives, and expedited FDA review. Variations in coverage have implications for patients' access to treatment and health system costs. PMID- 29985697 TI - Physician Perspectives In Year 1 Of MACRA And Its Merit-Based Payment System: A National Survey. AB - We surveyed a national sample of internal medicine physicians in March-May 2017 to explore their beliefs about the newly implemented Merit-based Incentive Payment System (MIPS). Respondents believed that their efforts in the four focus areas identified in the survey would ultimately improve the value of care. When informed that those areas represented the four MIPS domains, the majority remained positive about the likely impact on value. However, expectations varied by physicians' characteristics and sense of control over the desired outcomes, and many respondents believed that unintended consequences could occur. Moreover, respondents generally reported low familiarity with the policy and disagreed with program guidelines for weighting domains in the composite score. These findings indicate the need to educate physicians about MIPS and suggest potentially fruitful approaches. Moving forward, policy makers should monitor for unintended consequences and explore ways to better align program guidelines with physicians' perspectives. PMID- 29985698 TI - Transgender And Cisgender US Veterans Have Few Health Differences. AB - Transgender people have been able to serve openly in the military since June 2016. However, the administration of President Donald Trump has signaled its interest in reinstating a ban on transgender military service. In March 2018 President Trump issued a revised memorandum that stated, in part, that people with a "history or diagnosis of gender dysphoria" who "may require substantial medical treatment, including medications and surgery-are disqualified from military service except under certain limited circumstances." Whether and how the health of transgender service members differs from that of cisgender service members (that is, those who identify with their sex assigned at birth) is largely unknown. This study used population-level data for 2014-16 from the Behavioral Risk Factor Surveillance System to compare the health of transgender and cisgender veterans and civilians. An estimated 0.5 percent of veterans in the sample identified themselves as transgender. While transgender civilians had worse health than cisgender civilians across most indicators, very few differences existed among veterans. However, transgender veterans had higher odds of having at least one disability compared to cisgender veterans, despite similar levels of access to health care. These findings largely suggest that transgender veterans do not have worse health than cisgender veterans. PMID- 29985700 TI - Complicated: Medical Missteps Are Not Inevitable. AB - Much of the time, care teams react to complications instead of preventing them. A doctor calls on the medical system to take responsibility. PMID- 29985701 TI - Population Health And Economic Impacts Of Reaching Chronic Hepatitis B Diagnosis And Treatment Targets In The US. AB - The National Academies of Sciences, Engineering, and Medicine have concluded that eliminating the public health problem of chronic hepatitis B is feasible. We examined the economic and public health impact of reaching the World Health Organization targets of having 90 percent of chronic hepatitis B cases diagnosed and 80 percent being treated by 2030 in the United States with an annual incremental increase in screening and treatment rates. To reach the targets by 2030 would require screening approximately 14.5 million adults in at-risk populations to diagnose an estimated 870,000 undiagnosed cases and would result in substantial health gains: an increase of 16.5 million quality-adjusted life years (QALYs), and reductions in liver-related deaths of 37 percent and in cases of compensated cirrhosis of 24 percent, decompensated liver cirrhosis of 51 percent, and liver cancer of 35 percent. Achieving the targets by 2030 would be highly cost-effective at $103 per QALY and would be cost-saving if the antiviral drug price were no more than $114 per month. Achieving them by 2025 would be cost saving and would reduce liver-related deaths by 47 percent. PMID- 29985702 TI - Physicians' Participation In Medicaid Increased Only Slightly Following Expansion. AB - While most primary care physicians treated at least one Medicaid patient in 2013, Medicaid represented a small share of their payer mix. Following Medicaid eligibility expansion in 2014, most physicians maintained or slightly increased their Medicaid participation, with greater increases observed in states that expanded eligibility. Nevertheless, Medicaid patients remained concentrated among relatively few physicians after expansion. PMID- 29985699 TI - Factors Contributing To Geographic Variation In End-Of-Life Expenditures For Cancer Patients. AB - Health care spending in the months before death varies across geographic areas but is not associated with outcomes. Using data from the prospective multiregional Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study, we assessed the extent to which such variation is explained by differences in patients' sociodemographic factors, clinical factors, and beliefs; physicians' beliefs; and the availability of services. Among 1,132 patients ages sixty-five and older who were diagnosed with lung or colorectal cancer in 2003-05, had advanced-stage cancer, died before 2013, and were enrolled in fee-for-service Medicare, mean expenditures in the last month of life were $13,663. Physicians in higher-spending areas reported less knowledge about and comfort with treating dying patients and less positive attitudes about hospice, compared to those in lower-spending areas. Higher-spending areas also had more physicians and fewer primary care providers and hospices in proportion to their total population than lower-spending areas did. Availability of services and physicians' beliefs, but not patients' beliefs, were important in explaining geographic variations in end of-life spending. Enhanced training to better equip physicians to care for patients at the end of life and strategic resource allocation may have potential for decreasing unwarranted variation in care. PMID- 29985703 TI - Financing Medicare Into The Future: Premium Support Fails The Risk-Bearing Test. AB - One often-discussed option for controlling Medicare spending is to switch to a premium-support design. This would shift part of the risk of future health care cost increases from the federal treasury to Medicare beneficiaries. The economics of risk bearing suggests that this would be a mistake for three reasons. First, political decisions, not beneficiary choices, are the critical determinants of future health care costs. Second, only Congress can take into account the consequences of cost-containment decisions for both current and future generations. Third, the federal government is best able to diversify against the risk of future cost growth. Tying Medicare spending to the government's budget so that Congress sees the benefits of tough cost containment choices is the only way to force the program to make those politically difficult decisions. Economic efficiency is served by retaining the program's current structure instead of shifting risk to beneficiaries. PMID- 29985704 TI - Funders Support The Health Care Safety Net. PMID- 29985705 TI - Interruptions In Private Health Insurance And Outcomes In Adults With Type 1 Diabetes: A Longitudinal Study. AB - Type 1 diabetes mellitus, which often originates during childhood, is a lifelong disease that requires intensive daily medical management. Because health care services are critical to patients with this disease, we investigated the frequency of interruptions in private health insurance, and the outcomes associated with them, for working-age adults with type 1 diabetes in the United States in the period 2001-15. We designed a longitudinal study with a nested self controlled case series, using the Clinformatics Data Mart Database. The study sample consisted of 168,612 adults ages 19-64 with type 1 diabetes who had 2.6 mean years of insurance coverage overall. Of these adults, 24.3 percent experienced an interruption in coverage. For each interruption, there was a 3.6 percent relative increase in glycated hemoglobin. The use of acute care services was fivefold greater after an interruption in health insurance compared to before the interruption and remained elevated when stratified by age, sex, or diabetic complications. An interruption was associated with lower perceived health status and lower satisfaction with life. We conclude that interruptions in private health insurance are common among adults with type 1 diabetes and have serious consequences for their well-being. PMID- 29985706 TI - Growing Number Of Unsubsidized Part D Beneficiaries With Catastrophic Spending Suggests Need For An Out-Of-Pocket Cap. AB - Medicare Part D has no cap on beneficiaries' out-of-pocket spending for outpatient prescription drugs, and, unlike Medicare Parts A and B, beneficiaries are prohibited from purchasing supplemental insurance that could provide such a cap. Historically, most beneficiaries whose annual Part D spending reached the catastrophic level were protected from unlimited personal liability by the Low Income Subsidy (LIS). However, we found that the proportion of beneficiaries whose spending reached that level but did not qualify for the subsidy-and therefore remained liable for coinsurance-increased rapidly, from 18 percent in 2007 to 28 percent in 2015. Moreover, average total per person per year spending grew much more rapidly for those who did not qualify for the LIS than for those who did, primarily because of differences in price and utilization trends for the drugs that represented disproportionately large shares of their spending. We estimated that a cap for all Part D enrollees in 2015 would have raised monthly premiums by only $0.40-$1.31 per member. PMID- 29985707 TI - Surgical management of obturator neuropathy with a concomitant acetabular labral tear - a case report. PMID- 29985708 TI - Non-Occlusive Retinal Vascular Inflammation and Role of Red Blood Cell Deformability in Birdshot Chorioretinopathy. AB - PURPOSE: To investigate differences in red blood cell (RBC) deformability between birdshot chorioretinopathy (BCR) subjects and matched controls, and to postulate its relationship with lack of vascular occlusion in BCR. METHODS: In a single center, prospective, non-randomized mechanistic study, blood samples were collected from eight healthy controls and nine BCR patients, and subjected to biochemical and hematological tests, as well as RBC indices assessment using dual beam optical tweezers. RESULTS: The mean age of the controls was 52.37 +/- 10.70 years and BCR patients was 53.44 +/- 12.39 years. Initial cell size (Io) for the controls was 8.48 +/- 0.25 MUm and 8.87 +/- 0.31 MUm for BCR RBCs (p = 0.014). The deformability index (DI) for the controls was 0.066 +/- 0.02 and that for BCR RBCs was 0.063 +/- 0.03 (p = 0.441). CONCLUSION: There was no statistically significant difference in DI between RBCs from BCR and healthy controls. This may explain the rare occurrence of retinal vascular occlusion despite the underlying vasculitic pathophysiology of BCR. PMID- 29985709 TI - Five cases of orbital extramedullary plasmacytoma: diagnosis and management of an aggressive malignancy. AB - PURPOSE: Multiple myeloma is an insidious haematological malignancy characterised by monoclonal proliferation of plasma cells in the bone marrow. Extramedullary plasmacytoma is a rare manifestation of multiple myeloma and usually occurs in the upper respiratory tract. Orbital involvement is particularly uncommon, but may be associated with devastating visual impairment and poor clinical outcomes. Therefore, this article aims to highlight the need for multidisciplinary management of orbital extramedullary plasmacytoma. METHODS: This is a retrospective observational case series of five patients. All presented to the authors for management of orbital extramedullary plasmacytomas from 2004 to 2015 at Prince of Wales and Mater Hospitals in Sydney, Australia. Medical records were reviewed for pertinent information including demographics, disease features, management strategy, and clinical progress. The study met Medical Ethics Board standards and is in accordance with the Helsinki Agreements. RESULTS: This case series of five patients underscores the poor prognosis of orbital extramedullary plasmacytoma. Despite aggressive multidisciplinary management, four of these five patients succumbed to their illness during the study period. However, multidisciplinary management did manage to minimise symptoms and preserve quality of life. CONCLUSIONS: On a case-by-case basis, patients may derive palliative benefit from orbital surgery in conjunction with radiotherapy and chemotherapy. Orbital surgeons are encouraged to work within a multidisciplinary framework of medical specialists, including haematologists and radiation oncologists, when determining the optimal management plan in cases of orbital extramedullary plasmacytoma. PMID- 29985710 TI - Association of IL17 and IL23R gene polymorphisms with rheumatic heart disease in South Indian population. AB - BACKGROUND: IL-23/Th17 signaling pathway plays a crucial role in the cell mediated immune response against bacterial infections and also in the pathogenesis of inflammatory and autoimmune diseases. Recent studies indicate that Th17 cell-associated cytokines are involved in the progression and maintenance of valvular lesions in rheumatic heart disease (RHD). Variants in the genes of cytokines that are potentially involved in Th17 response may influence interindividual differences in their expression levels, thereby contributing to the pathogenesis of immune-mediated diseases such as RHD. OBJECTIVE: The aim of the study is to investigate the association of IL17A, IL17F, and IL23R gene variants with the risk perception of RHD. METHODS: A total of 225 individuals (99 RHD patients and 126 healthy siblings) were recruited for the study. The IL17A (rs2275913), IL17F (rs763780), and IL23R (rs10889677) polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphisms and amplification-refractory mutation system-polymerase chain reaction methods, respectively. RESULTS: The frequency of IL17A (rs2275913) A/A genotype was significantly high in pooled RHD patients (odds ratio [OR] = 2.76; pc = 0.021), rheumatic fever (RF) patients (OR = 14.5; pc = 0.0001), and mitral valvular lesions patients (OR = 2.74; pc = 0.039) when compared to healthy siblings. However, the IL17F (rs763780) and IL23R (rs10889677) polymorphisms did not show any association with RHD. CONCLUSIONS: The results suggest that IL17A (rs2275913) polymorphism is associated with the development of RF/RHD in South Indian population. Further studies are required to substantiate the association of these genes with the disease risk. PMID- 29985711 TI - Effects of Resveratrol and Mangiferin on PPARgamma and FALDH Gene Expressions in Adipose Tissue of Streptozotocin-Nicotinamide-Induced Diabetes in Rats. AB - Type 2 diabetes (T2D) is characterized by insufficient insulin secretion by the pancreatic beta cells and insulin resistance in liver, skeletal muscle, and white adipose tissue. Adipose tissue plays a major role in glucose homeostasis and lipid metabolism. Dietary antioxidants such as resveratrol and mangiferin may offer some protection against the early stage of diabetes mellitus. Therefore, an attempt has been made to investigate the effects of resveratrol and mangiferin on biochemical parameters and molecular mechanism of PPARgamma and FALDH gene expression in adipose tissue of streptozotocin- (STZ-) nicotinamide- (NA-) induced diabetic rats. Albino Wister rats were randomly divided into five groups: control rats (Group 1), diabetic control rats (Group 2), diabetic rats given resveratrol (40 mg/kg body weight per day; Group 3), diabetic rats given mangiferin (40 mg/kg body weight per day; Group 4), diabetic rats given glibenclamide (0.6 mg/kg body weight per day; Group 5). Serum biochemical parameters-total cholesterol (TC), total triglyceride (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, glycosylated hemoglobin (HbA1c), urea, and uric acid were analyzed. We found that the oral administration of resveratrol and mangiferin to STZ-NA-induced diabetic rats for 30 days showed the significant protective effect on all the biochemical parameters. A significant reduction in blood glucose and HbA1c levels was observed in rats treated with 40 mg/kg body weight per day of resveratrol or mangiferin. Moreover, both these antioxidants showed significant enhancement of PPARgamma and FALDH gene expression in rat adipose tissue compared to control rats. PMID- 29985712 TI - Neural dysfunction and retinopathy in persons with type 1 diabetes. AB - OBJECTIVE: To determine associations of microvascular and neuropathic complications of diabetes cross-sectionally and longitudinally in persons with long-term type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: Persons receiving care for T1D in South Central Wisconsin were identified in 1979-1980 and examined approximately every 5 years. Associations between neuropathic and microvascular complications were examined at most prior visits, when information on several neuropathic complications was collected. Temporal relationships were examined by modeling incidence between examinations across the visits. RESULTS: Adjusting for duration of diabetes, glycated hemoglobin, and systolic blood pressure, the following were cross-sectionally associated with prevalent PDR (proliferative diabetic retinopathy): the presence of sensory neuropathy (SN) as reported at each Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) examination (odds ratio (OR) = 2.76, confidence interval (CI) = 1.71, 4.48) and the heartrate variability measures RMSD (square root of the mean of squared differences of successive RR intervals) (OR = 0.24, CI = 0.16, 0.37) and SDNN (standard deviation of successive RR intervals) (OR = 0.26, CI = 0.17, 0.39). Findings were similar for prevalent ME (macular edema) as assessed from spectral-domain optical coherence tomography (SD-OCT). The presence of PDR (OR = 2.13, CI = 1.63, 2.78) and ME (OR = 2.36, CI = 1.66, 3.34) were both significantly associated with incident WESDR SN. WESDR SN was associated with incident PDR (OR = 1.53, CI = 1.09, 2.15) but not incident ME (OR = 1.31, CI = 0.92, 1.87). CONCLUSIONS: Sensory neuropathy and heartrate variability were significantly associated with prevalent PDR and ME in people with long-term T1D. PDR and ME were significantly associated with incident sensory neuropathy, and sensory neuropathy was significantly associated with incident PDR. Studies using earliest detectable markers of microvascular and neurologic abnormalities are needed to determine which of the two systems 'fails' first. Such information might suggest a temporal sequence of diabetes complications. PMID- 29985713 TI - Effects of Glutamine and Alanine Supplementation on Adiposity, Plasma Lipid Profile, and Adipokines of Rats Submitted to Resistance Training. AB - Glutamine and alanine are lipogenic and could prevent the effects of resistance training (RT) in reducing adiposity and modulating lipid profile. Thus, we aimed to investigate the effects of RT and glutamine and alanine supplementation, in their free or conjugated form, on relative epididymal adipose tissue (EAT) and brown adipose tissue (BAT) weight, plasma lipid profile, and adipokines in EAT. Thirty Wistar rats, aged two months, were distributed into five groups: control (CTRL), trained (TRN), trained and supplemented with alanine (ALA), glutamine and alanine in their free form (GLN+ALA), or L-alanyl-L-glutamine (DIP). Trained groups underwent a ladder-climbing exercise for eight weeks, with progressive load increase. Supplementations were offered in a solution with a concentration of 4% in the last 21 days of training. Food consumption and body weight gain were decreased in the TRN group compared with CTRL. RT also reduced relative EAT and BAT weight, while supplementations, especially with ALA, increased adipose tissue mass. RT reduced total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) (TRN vs. CTRL), whereas glutamine and alanine supplementation increased TC and LDL-c, impairing lipid profile modulation by physical exercise. RT did not affect the concentrations of adipokines in EAT, but DIP supplementation increased interleukin- (IL-) 6 and IL-10. In conclusion, RT reduced adiposity and modulated lipid profile, whereas glutamine and alanine supplementation increased adiposity and impaired lipid profile but increased the concentration of the anti-inflammatory cytokines IL-6 and IL-10 in EAT. PMID- 29985714 TI - Corrigendum. PMID- 29985715 TI - The Prevention and Therapy of Osteoporosis: A Review on Emerging Trends from Hormonal Therapy to Synthetic Drugs to Plant-Based Bioactives. AB - Osteoporosis is one of the major health problems worldwide. It is characterized by increased bone fragility and loss of bone matter due to the action of osteoclast cells, which are associated with modified hormone levels and factors such as aging. Bisphosphonates are the primary treatment for osteoporosis. Apart from bisphosphonates, hormone therapy, calcitonin treatment, selective estrogen receptor modulators (SERMs), and strontium ranelate (SR) are some of the other treatments available for osteoporosis. However, these treatments have some side effects, such as oily skin, fluid retention, nausea, long-term toxicity, and even prostate cancer in males, and thus natural therapies that incur fewer side effects are sought. Phytochemicals, antioxidants, and other plant-based bioactives are important in the human diet. They are abundant in fruits and help against various chronic diseases, including bone disorders. Other providers of these important compounds are the medicinal plant parts. In this article, we highlight the various species of plants and herbs that are useful for the treatment of osteoporosis. The prospect of using these plant-based bioactives in amelioration of osteoporosis as an alternative to hormonal and synthetic drug based therapy is also discussed. PMID- 29985716 TI - Platelet aggregation measured by single-platelet counting and using PFA-100 devices. AB - Platelets play a crucial role in haemostasis and thrombosis and evaluation of platelet function in vitro, in particular platelet aggregation responses, has been one of the most common and useful ways of evaluating the risk of bleeding and thrombotic events and assessing the effects of various compounds and conditions on platelets. Traditional approaches to assessing platelet aggregation require specialised equipment and trained laboratory personnel and have other limitations. Studying platelet aggregation in whole blood offers a more physiologically relevant measurement. Additionally, certain approaches could be more widely available than in specialised laboratories. Here we summarise the application of the platelet function analyser (PFA-100), an accessible first point-of-care test for platelet function in whole blood, and the less established, but promising approach of assessing platelet aggregation by single platelet counting that can also be performed in whole blood. The possibilities of a wider and more accessible application of the latter methodology are also discussed. PMID- 29985717 TI - Defective Treg response in acute kidney injury was caused by a reduction in TIM 3+ Treg cells. AB - BACKGROUND: Despite years of research, the treatment of acute kidney injury (AKI) remains a significant challenge. Animal studies presented causal links between elevated regulatory T cell (Treg) response and better prognosis in AKI. Previous studies in mice and humans showed that TIM-3+ Treg cells were more potent than TIM-3- Treg cells. In this study, we investigated the role of TIM-3 in Treg in AKI patients. METHODS: Peripheral blood from AKI patients and healthy controls were gathered, and TIM-3+ Treg subset was examined. RESULTS: Compared to healthy controls, the AKI patients presented a significant upregulation in the frequency of circulating CD4+CD25+ T cells; however, the majority of this increase was from the CD4+CD25+TIM-3- subset, and the frequency of CD4+CD25+TIM-3+ T cells was downregulated in AKI patients. In both healthy controls and AKI patients, the CD4+CD25+TIM-3+ T cells expressed higher levels of Foxp3, and were more potent at expressing LFA-1, LAG-3, CTLA-4, IL-10 and TGF-beta. In addition, the CD4+CD25+TIM-3+ T cells from both healthy controls and AKI patients presented higher capacity to suppress CD4+CD25- T cell proliferation than the CD4+CD25+TIM 3- T cells. Interestingly, the total CD4+CD25+ T cells from AKI patients presented significantly lower inhibitory capacity than those from healthy controls, indicating that the low frequency of CD4+CD25+TIM-3+ T cells was restricting the efficacy of the Treg responses in AKI patients. CONCLUSIONS: We demonstrated that TIM-3 downregulation impaired the function of Treg cells in AKI. The therapeutic potential of CD4+CD25+TIM-3+ T cells in AKI should be investigated in future studies. PMID- 29985718 TI - Self-management behaviors in World Trade Center rescue and recovery workers with asthma. AB - BACKGROUND: Asthma is a major source of morbidity among World Trade Center (WTC) rescue and recovery workers. While physical and mental health comorbidities have been associated with poor asthma control, the potential role and determinants of adherence to self-management behaviors (SMB) among WTC rescue and recovery workers is unknown. OBJECTIVES: To identify modifiable determinants of adherence to asthma self-management behaviors in WTC rescue and recovery worker that could be potential targets for future interventions. METHODS: We enrolled a cohort of 381 WTC rescue and recovery workers with asthma. Sociodemographic data and asthma history were collected during in-person interviews. Based on the framework of the Model of Self-regulation, we measured beliefs about asthma and controller medications. Outcomes included medication adherence, inhaler technique, use of action plans, and trigger avoidance. RESULTS: Medication adherence, adequate inhaler technique, use of action plans, and trigger avoidance were reported by 44%, 78%, 83%, and 47% of participants, respectively. Adjusted analyses showed that WTC rescue and recovery workers who believe that they had asthma all the time (odds ratio [OR]: 2.37; 95% confidence interval [CI]: 1.38-4.08), that WTC related asthma is more severe (OR: 1.73; 95% CI: 1.02-2.93), that medications are important (OR: 12.76; 95% CI: 5.51-29.53), and that present health depends on medications (OR: 2.39; 95% CI: 1.39-4.13) were more likely to be adherent to their asthma medications. Illness beliefs were also associated with higher adherence to other SMB. CONCLUSIONS: Low adherence to SMB likely contributes to uncontrolled asthma in WTC rescue and recovery workers. Specific modifiable beliefs about asthma chronicity, the importance of controller medications, and the severity of WTC-related asthma are independent predictors of SMB in this population. Cognitive behavioral interventions targeting these beliefs may improve asthma self-management and outcomes in WTC rescue and recovery workers. Key message: This study identified modifiable beliefs associated with low adherence to self-management behaviors among World Trade Center rescue and recovery rescue and recovery workers with asthma which could be the target for future interventions. CAPSULE SUMMARY: Improving World Trade Center-related asthma outcomes will require multifactorial approaches such as supporting adherence to controller medications and other self-management behaviors. This study identified several modifiable beliefs that may be the target of future efforts to support self-management in this patient population. PMID- 29985719 TI - Bio-Electro-Magnetic-Energy-Regulation (BEMER) for the treatment of type I complex regional pain syndrome: A pilot study. AB - OBJECTIVE: The study aimed to evaluate the efficacy of Bio-Electro-Magnetic Energy-Regulation (BEMER) magneto-therapy on pain and functional outcome in complex regional pain syndrome type I (CRPS-I). We hypothesized that BEMER therapy, based on its declared effects on microcirculation, could be beneficial in the treatment of this condition. METHODS: This was a randomized controlled double-blind pilot study that included 30 patients with CRPS-I. Patients were divided into two groups: a study group, in which the rehabilitation program was combined with BEMER therapy for 10 consecutive days, and a control group, in which the rehabilitation program was combined with a sham BEMER treatment. Outcome measures (Visual Analogic Scale pain; Hand Grip Strength; Disabilities of the Arm, Shoulder, and Hand ; Maryland Foot Score) were taken at the beginning and end of treatment, and at 1 month follow-up. RESULTS: The study demonstrated that the group treated with BEMER combined with rehabilitation yielded better results in the short term, in terms of pain reduction and functional improvement both at the upper and lower limbs. CONCLUSIONS: Data from the present pilot study suggest that BEMER therapy can be indicated, in combination with traditional rehabilitation programs, for the treatment of CRPS-I. PMID- 29985720 TI - "On Your Own": Adolescent and Young Adult Cancer Survivors' Experience of Managing Return to Secondary or Higher Education in Denmark. AB - PURPOSE: As a consequence of cancer treatment, many adolescents and young adults (AYA) patients are required to take leave or face setbacks from their education. While most AYA cancer survivors and survivors of childhood cancer are capable of successfully returning to the educational system, unsuccessful returns place AYA at an increased risk of social isolation, stigmatization, and financial burden. The perspective of AYA cancer survivors who have returned to education is valuable to understand the challenges faced and resources available throughout this transition. The purpose of this study was to explore AYA cancer survivors' management of returning to secondary or higher education. METHODS: Semistructured interviews were conducted with AYA cancer survivors between the ages of 15 and 25 at diagnosis pursuing secondary or higher education (n = 9). Interviews were transcribed verbatim and analyzed using Malterud's Systemic Text Condensation. RESULTS: Five themes were found: (Theme 1) Symptoms and Late Effects, (Theme 2) Navigating the System, (Theme 3) Lack of Understanding from Peers, (Theme 4) Unofficial Support, and (Theme 5) Changed Perspectives. AYA cancer survivors described facing challenges from the physical late effects of cancer treatment, as well as misunderstanding from municipal systems and peer groups. However, they stated that assistance was provided from unofficial sources of support, such as teachers and parents. CONCLUSIONS: AYA cancer survivors face social and systemic challenges throughout the return to education. The findings of this study support previous research suggesting that late effects and misunderstanding from peers and academic and municipal institutions may play a role in impacting social outcomes and academic performance. PMID- 29985721 TI - Novel symptom questionnaire for the differential diagnosis of detrusor underactivity and bladder outlet obstruction in men. AB - OBJECTIVE: To develop a questionnaire for the differential diagnosis of detrusor underactivity (DUA) and bladder outlet obstruction (BOO) without performing invasive pressure flow studies. STUDY DESIGN AND METHODS: Symptoms of men with DUA were analyzed and compared with those of men with BOO using eight questions from the developing questionnaire. Patients with DUA have a bladder contractility index (PdetQmax+5xQmax) less than 100, whereas those with BOO have a BOO index (PdetQmax-2xQmax) greater than 40 in urodynamic studies (UDS). Men with detrusor overactivity in UDS and neurogenic issues were excluded from the analysis. One urologist reviewed patients' medical records, and responded to eight questions without using information from UDS. Scores in the developing questionnaire were then compared to make a differential diagnosis between DUA and BOO. RESULTS: Overall, 318 men who underwent UDS were included. Symptoms were compared in patients diagnosed with DUA without BOO (n = 165) and BOO without DUA (n = 153). Questions 1, 2, 4, 5, 6, and 7 were significantly different between groups. The sensitivity and specificity of the questionnaire were 95.8% and 95.4%, respectively, for predicting DUA in patients with scores greater than 45 points (cutoff value). CONCLUSIONS: Men with DUA and BOO may be distinguished using a developing questionnaire without invasive evaluation. Men with scores greater than 45 points would be expected to have DUA but not BOO. PMID- 29985722 TI - Periorbital desmoplastic squamous cell carcinoma. AB - Desmoplasia is the formation of a dense collagenous stroma around a neoplasm. It occurs in a variety of malignancies including squamous cell carcinoma (SCC). While desmoplasia is uncommonly seen in cutaneous SCC, it is an independent risk factor for recurrence and metastasis. We report a case series of desmoplastic SCC in the periorbital region. Seven cases were identified: the median age was 68, four were men. The mean follow-up was 48 months. Two patients (29%) had aggressive local recurrence: one required salvage surgery including orbital exenteration, parotidectomy, and neck dissection to excise involved parotid and cervical lymph nodes; the other required repeat excision and adjuvant radiotherapy. Desmoplastic SCC is an uncommon but highly aggressive subtype. In the periorbital region, due to the high risk of orbital invasion, it is potentially sight and life-threatening. PMID- 29985724 TI - Effects of kinesio taping on neuromuscular performance and pain of individuals affected by patellofemoral pain: A randomized controlled trial. AB - Patellofemoral pain (PFP) is one of the most frequent musculoskeletal dysfunctions in the knee and its treatment is controversial. This study analyzed the effects of Kinesio Taping (KT) immediately and 72 hours after its application on the electromyographic (EMG) activity of the vastus medialis oblique (VMO) muscle, on the isokinetic performance of the quadriceps femoris and on the pain of subjects with PFP. Fifty-four participants were divided into three groups and performed one of the following protocols: (1) control group (CG)-remained at rest; (2) KT tension group (TG)-KT application with tension in the VMO region; and (3) KT without tension group (WTG)-KT application without tension in the same region. VMO and vastus lateralis (VL) EMG activity (RMS and onset), isokinetic performance and pain intensity were evaluated at three moments: before KT application, immediately after and 72 hours after. A mixed model ANOVA was used for statistical analysis with a significance level of 5% (p <= 0.05). No differences between the evaluated groups were found in relation to EMG variables and isokinetic performance. A reduction in pain intensity was found in the WTG in comparison to CG, after 72 hours. KT does not alter EMG parameters nor the isokinetic performance of subjects with PFP. However, we noticed reduced pain in the group submitted to the technique without tension 72 hours after its application. PMID- 29985723 TI - Characterization of Epidermal Lipoxygenase Expression in Normal Human Skin and Tissue-Engineered Skin Substitutes. AB - Lipoxygenases (LOXs) are enzymes likely to be involved in corneocyte lipid envelope formation and skin barrier function. In humans, mutations in epidermis type lipoxygenase 3 ( eLOX-3) and 12R-lipoxygenase ( 12R-LOX) genes are associated with autosomal recessive congenital ichthyosis (ARCI), whereas deletion of these genes in mice causes epidermal defects. LOXs also represent a matter of interest in psoriasis as well as in cancer research. However, their expression as well as the exact role of these enzymes in normal human skin have not been fully described. Our goal was to characterize the expression of epidermal LOXs in both normal human skin and Tissue-Engineered Skin Substitutes (TESS) and to consider TESS as a potential model for LOX functional studies. Staining for epidermal differentiation markers and LOXs was performed, in parallel, on normal human skin and TESS. Our results showed similar expression profiles in TESS when compared with native skin for e-LOX3, 12R-LOX, 12S lipoxygenase (12S-LOX), and 15-lipoxygenase 2 (15-LOX-2) but not for 15 lipoxygenase 1 (15-LOX-1). Because of their appropriate epidermal differentiation and LOX expression, TESS represent an alternative model for future studies on LOX function. PMID- 29985726 TI - Interleukin-4 and Interleukin-4 Receptor Alpha Gene Polymorphisms in Recurrent Aphthous Stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is a common oral condition with a major impact on the quality of life. The condition is thought to be due to the overexpression of T helper-1(Th1)-related cytokines. Since interleukin-4 (IL-4) and its receptor (IL-4Ralpha) are antagonistic to Th-1 pathways, polymorphisms in their genes may also be involved in the pathogenesis of aphthous stomatitis. METHODS: Sixty-four patients diagnosed with minor RAS and 141 (age- and sex matched) healthy controls were assessed for 3 single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-4 gene (-1098G/T, -590C/T, and 33C/T), and 1 SNP in IL-4Ralpha gene (+1902 A/G). RESULTS: No significant differences were detected between the patient and the control group regarding IL 4 allele frequencies. However, the patient group demonstrated a higher frequency of IL-4 -590 CC genotype and a lower rate of IL-4 -590 TC genotype. The TCT, GTT, GCT, and GTC haplotypes of the IL-4 gene (-1098, -590, -33) were significantly more frequent in the patients and the GCC, and TTT haplotypes were more common in healthy controls. No significant differences were found in IL-4Ralpha gene polymorphism between the 2 groups. CONCLUSIONS: Certain polymorphisms of IL4 gene could predispose individuals to RAS. PMID- 29985725 TI - Sucroferric oxyhydroxide for the treatment of hyperphosphatemia. AB - INTRODUCTION: Sucroferric oxyhydroxide is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. Areas covered: Herein, the preclinical development and clinical data for sucroferric oxyhydroxide are reviewed, including the key data from the Phase III registration study and the latest evidence from the real-world clinical setting. Expert opinion: Sucroferric oxyhydroxide displays potent phosphate-binding capacity and clinical studies demonstrate its effectiveness for the long-term reduction of serum phosphorus levels in dialysis patients. Observational study data also show that sucroferric oxyhydroxide provides effective serum phosphorus control for hyperphosphatemic patients in the real-world clinical setting. The serum phosphorus reductions with sucroferric oxyhydroxide can be achieved with a relatively low pill burden in comparison with other phosphate binders, which may translate into better treatment adherence in clinical practice. The Phase III data also indicate that sucroferric oxyhydroxide has a favorable impact on other chronic kidney disease related mineral bone disease parameters, including a fibroblast growth factor-23 lowering effect. Sucroferric oxyhydroxide is well tolerated and associated with low systemic iron absorption, minimizing the potential for iron accumulation or overload. These attributes render sucroferric oxyhydroxide an attractive non calcium-containing phosphate binder for the treatment of hyperphosphatemia. PMID- 29985727 TI - Letter to the Editor. Posterior pseudocapsule in macroadenomas. PMID- 29985728 TI - Associations of circulating cell-free microRNA with vasculopathy and vascular events in systemic lupus erythematosus patients. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a high risk of atherosclerosis and cardiovascular disease (CVD). MicroRNAs (miRNAs) are small non-coding RNAs that modulate protein translation, and dysregulation is seen in autoimmunity, atherosclerosis, and CVD. We investigate associations between circulating miRNAs and markers of atherosclerosis in SLE patients. METHOD: A group (n = 121) of well-characterized SLE patients were screened for atherosclerosis by cardiac computed tomography and carotid ultrasound. RNA was purified from plasma and 46 specific miRNAs were determined using quantitative real-time polymerase chain reaction. RESULTS: Forty-one miRNAs were consistently detected. Fifty out of 118 available SLE patients had atherosclerosis. A profile consisting of three miRNAs (decreased miR-125b, miR 101, miR-375) was indicative of atherosclerosis. Multivariate logistic regression identified eight clinical manifestations associated with atherosclerotic outcome. The full classification profile showed a specificity of 88% and a sensitivity of 86%. Hierarchical clustering identified an eight-miRNA profile that differentiated a subgroup of SLE patients (n = 16) who had significantly increased venous thrombotic events (p = 0.045), a higher prevalence of beta2 glycoprotein I antibodies (p = 0.029), and an increased prevalence of thrombocytopenia (p = 0.028). CONCLUSION: In this cross-sectional study, the circulating miRNA profile distinguished SLE patients with atherosclerosis from those without. Furthermore, an eight-miRNA signature was associated with thrombocytopenia, venous thrombotic events, and beta2-glycoprotein I antibodies in SLE patients. Prospective studies are needed to confirm the findings and to establish the precise role of circulating miRNA profiling in the evaluation of atherosclerosis in SLE. PMID- 29985729 TI - Platelet reactivity in overweight and obese patients undergoing cardiac surgery. AB - Body mass index (BMI) and specifically overweight and obesity have been associated with an increased platelet reactivity in different series of patients. This information is derived by different laboratory platelet function tests (PFTs) like mean platelet volume (MPV), platelet microparticles, thromboxane B2 metabolites, and others. Point-of-care PFT, which are often used in cardiac surgery, are rarely addressed. The present study aims to verify platelet reactivity using multiple-electrode aggregometry (MEA) as a function of BMI in cardiac surgery patients. One-hundred ninety-eight cardiac surgery patients free from the effects of drugs acting on the P2Y12 receptor and undergoing cardiac surgery received MEA-PFT immediately before surgery. Platelet reactivity was compared between normal weight and overweight-obese subjects. There were 99 underweight/normal (BMI < 25), 60 overweight (BMI >= 25) and 39 obese (BMI >= 30) patients. Overweight-obese patients did not show higher platelet counts nor a clear platelet hyper-reactivity, when tested with MPV and MEA ADP test. At TRAPtest, the overweight/obese patients had a significantly (P = 0.011) higher platelet reactivity (median 118, interquartile range 106-136) than controls (median 112, interquartile range 101-123) and a higher rate of platelet hyper reactivity (odds ratio 2.19, 95% confidence interval 1.15-4.16, P = 0.016) in a multivariable model. A minor association was found between the BMI and platelet reactivity at TRAPtest, with a higher degree of activity for increasing BMI. The BMI determines an increased thrombin-dependent platelet reactivity in cardiac surgery patients. Thrombin is extensively formed during cardiac surgery, and this may explain the lower postoperative bleeding observed in obese patients in previous studies. PMID- 29985730 TI - Physiotherapy assessment of individuals with multiple sclerosis prior to a group intervention - A qualitative observational and interview study. AB - Assessment prior to both individual and group interventions is fundamental to neurological physiotherapy practice. However, knowledge is limited regarding how assessments are carried out, particularly assessments conducted prior to group interventions, which have recently gained increasing attention in clinical research. In this qualitative study, we investigated how physiotherapy assessments of patients with multiple sclerosis prior to a group exercise intervention were carried out and what physiotherapists considered vital elements in the assessment process. Data were gathered through 12 qualitative non participatory video observations followed by in-depth interviews of physiotherapists. Systematic text condensation analysis was conducted within an enactive theoretical framework of participatory sense making. In the assessments, patients' bodily perceptions of movement changes appeared to be vital in establishing patient expectations for the forthcoming intervention. The extent of patient participation and an embodied approach to communication influenced both the physiotherapists' and patients' insights into the patients' movement problems, which were further utilized in the initial intervention planning. Significant differences in context from the assessment to the intervention require a systematic completion of the assessments in the course of the first clinical meeting, which should be considered in the further development of research and clinical practices. PMID- 29985731 TI - Content Validity of a Conceptual Model of a Palliative Approach. AB - BACKGROUND: The term "palliative approach" has emerged to connote healthcare activities provided consistent with the philosophy of palliative care, but not limited to specialized care providers or settings. A rigorous understanding of the palliative approach requires a conceptual model, which links the philosophy of palliative care to specific actions of practitioners, and is applicable to patients with any life-threatening illness, at any point on the disease trajectory, and provided by any care provider in any setting. This article proposes a conceptual model asserting that a palliative approach exists when care simultaneously addresses whole-person needs, enhances quality of life, and acknowledges mortality. OBJECTIVE: To test the content validity of the proposed model against definitions of palliative care in existing literature. DESIGN: Electronic and manual literature searches identified definitions of palliative care and palliative approach. Two authors independently conducted thematic analysis to assess congruence with the domains of the proposed conceptual model. RESULTS: Nineteen definitions were identified. The three domains were represented in the majority: whole-person care (17/19), quality-of-life focus (17/19), and mortality acknowledgement (15/19). Published definitions also included other concepts, but only one of these (family within the unit of care) appeared in more than a few definitions. CONCLUSIONS: The content validity of the proposed conceptual model is supported by the consistent presence of the three domains in published definitions. This conceptual model bridges philosophical definitions and clinician behavior and has potential to inform broad implementation of a palliative approach, at both clinic and system levels. PMID- 29985732 TI - Management of pregnancy for a patient with the new syndromic macrothrombocytopenia, DIAPH1-related disease. AB - The number of genes involved in the identification of macrothrombocytopenia (MTP) is growing but the clinical consequences for the affected patients are not well determined. Here, we report the management of the bleeding risk for a patient with the newly reported and rare DIAPH1-related disease during surgery for infertility and then during her subsequent pregnancy. The R1213* DIAPH1 variant responsible for a mild bleeding syndrome in six families was considered a potential risk factor for our patient. Preliminary laparoscopic surgery was followed by neosalpingostomy to open the obstructed fallopian tube that was followed by an ectopic pregnancy requiring further surgery, tranexamic acid was used on each occasion and no bleeding complications were observed. A second pregnancy proceeded to term; the mother's platelet count was controlled throughout the gestation period and remained close to her basal values. No bleeding occurred at delivery or during the postpartum period. In conclusion, with strict repeated assessments of blood parameters and maintenance of the platelet count, the bleeding risk in pregnancy in DIAPH1-related disease can be successfully controlled. PMID- 29985733 TI - Evaluation of combined effect of hyperthermia and ionizing radiation on cytotoxic damages induced by IUdR-loaded PCL-PEG-coated magnetic nanoparticles in spheroid culture of U87MG glioblastoma cell line. AB - PURPOSE: Glioblastoma multiform (GBM) is the most prevalent and aggressive type of primary brain tumor. None of the current conventional treatment methods has improved treatment considerably. Therefore, in this study the effect of magnetic nanoparticles coated with poly (caprolactone)-poly (ethylene glycol) (PCL-PEG) as a 5-iodo 2'deoxyuridine (IUdR) carrier in the presence of hyperthermia and 6 MV (megavoltage) X-ray radiation, were investigated in a spheroid model of U87MG glioblastoma cell line using colony formation assay. MATERIALS AND METHODS: First, the human glioblastoma cell line U87MG was cultured as a spheroid using the liquid overlay technique. Spheroids on day 10 with 100 mm diameters were treated with 1 uM IUdR or nanoparticles as IUdR carriers for one volume doubling time (VDT) of spheroids (67 h) and hyperthermia at 43 degrees C for 1 h, and then irradiated with 2 Gy of 6 MV X-ray in different groups. Finally, the effect of treatment on colony-forming ability was obtained by colony formation and alkaline assay. RESULTS: Our results revealed that hyperthermia in combination with radiation could significantly reduce the colony number of glioblastoma spheroid cells treated with IUdR or nanoparticles as IUdR carriers. However, the extent of reduction in colony number following treatment with IUdR-loaded nanoparticles in combination with hyperthermia and then X-ray radiation was significantly more than free IUdR. CONCLUSION: According to this study, PCL-PEG coated magnetic nanoparticles are effective delivery vehicles for IUdR into cells. Moreover, they can act as a radiosensitizer and thermosensitizer in the treatment of the glioblastoma cell line. PMID- 29985734 TI - Measuring the Impact of an Adolescent and Young Adult Program on Addressing Patient Care Needs. AB - PURPOSE: We aimed to evaluate the effectiveness of an adult-based adolescent and young adult (AYA) cancer program by assessing patient satisfaction and whether programming offers added incremental benefit beyond primary oncology providers (POP) to address their needs. METHODS: A modified validated survey was used to ask two questions: (1) rate on a 10-point Likert scale their level of satisfaction with the information provided to them by their POP and (2) did the AYA consult provide added value on top of their POP. Young people at PM were recruited over two separate time points spaced 1 year apart. Descriptive statistics was used to report demographics and survey responses. Differences in demographics between cohorts 1 and 2 were compared using Student's t-tests. RESULTS: Participants were an average of 31 years (range 15-39) of age; (Cohort 1 = 137; Cohort 2 = 130) and were dominated by diagnoses of leukemia, lymphoma, and breast cancer. More patients had a consultation with the AYA program in 2016 (Cohort 2 = 55/130, 42%) compared to 2015 (Cohort 1 = 34/137, 25%, p = 0.026). Mean satisfaction scores (+/-SD) with information provided by POP in AYA domains in both cohorts combined were highest among (1) cancer information (8.09 +/- 2.22), (2) social supports (7.45 +/- 2.52), and (3) school/work (7.42 +/- 2.88). When evaluating the incremental benefit of the AYA-dedicated team, statistically significant added value was perceived in 5/10 domains, including school/work (p < 0.001), social supports (p < 0.001), physical appearance (p = 0.009), sexual health (p = 0.01), and fertility (p < 0.001). CONCLUSIONS: Participants were satisfied with the information provided by their POP and still declared incremental added benefit of the AYA program. Cancer centers should continue to advocate for AYA focused programming with ongoing evaluation. PMID- 29985735 TI - Comparison of nine platelet function tests used to determine responses to different aspirin dosages in people with type 2 diabetes. AB - The antiplatelet efficacy of aspirin (ASA) is reduced in type 2 diabetes (T2D). As the best ex vivo method of measuring ASA efficacy remains uncertain, we compared nine platelet function tests to assess responsiveness to three ASA dosing regimens in 24 T2D patients randomized in a three-treatment crossover design to ASA 100 mg/day, 200 mg/day, or 100 mg twice daily for 2-week treatment periods. Platelet function tests compared were as follows: light transmission aggregometry (LTA)-0.5 mg/mL of arachidonic acid (AA) and 10 uM adenosine diphosphate (ADP); multiplate whole blood aggregometry (WBA)-0.5 mM AA and 6.5 uM ADP; platelet function analyzer (PFA)-100TM-collagen and ADP (CADP) and collagen and epinephrine (CEPI); VerifyNowTM-ASA; and urinary 11-dehydro-thromboxane B2 (TxB2) and serum TxB2. All cyclo-oxygenase (COX-1)-dependent tests and some COX-1 independent tests (PFA-CEPI, LTA-ADP) demonstrated significant reductions in platelet reactivity with all ASA doses. Two COX-1-independent tests (WBA-ADP and PFA-CADP) showed no overall reduction in platelet reactivity. Overall classifications for detecting all ASA doses, compared to baseline, were as follows: very good-LTA-AA (k = 0.95) and VerifyNowTM-ASA (k = 0.85); good-serum TxB2 (k = 0.79); moderate-LTA-ADP (k = 0.59), PFA-100TM-CEPI (k = 0.56), urinary TxB2 (k = 0.55), WBA-AA (k = 0.47); and poor-PFA-100TM-CADP (k = -0.02) and WBA ADP (k = -0.07). No significant kappa statistic differences were seen for each test for each ASA dose. Correlations for each test with serum TxB2 measurements were as follows: very good-VerifyNowTM-ASA (k = 0.81, R2 = 0.56) and LTA-AA (k = 0.85, R2 = 0.65); good-PFA-100TM-CEPI (k = 0.62, R2 = 0.30); moderate-urinary TxB2 (k = 0.57, R2 = 0.51) and LTA-ADP (k = 0.47, R2 = 0.56); fair-WBA-AA (k = 0.31, R2 = 0.31); and poor-PFA-100TM-CADP (k = 0.04, R2 = 0.003) and WBA-ADP (k = -0.04, R2 = 0.0005). The platelet function tests we assessed were not equally effective in measuring the antiplatelet effect of ASA and correlated poorly amongst themselves, but COX-1-dependent tests performed better than non-COX-1 dependent tests. PMID- 29985736 TI - Immunotherapy of systemic sclerosis. AB - Systemic sclerosis (SSc) is a chronic systemic disease characterized by microvasculopathy, immune activation, and extensive collagen deposition. Microvasculopathy and immune activation occur very early in the disease process. Evidence from animal models and in vitro studies indicate that T-cells and B cells activate fibroblasts to produce collagen. Traditional immunosuppressants, cyclophosphamide(CyP), methotrexate(MTX), and more recently mycophenolate mofetil(MMF), may prove more effective if used very early in the disease course. These drugs showed some benefit in skin (MTX, CyP, MMF) and lung function (CyP, MMF). Biologicals, such as intravenous immunoglobulin (IVIg), belimumab(Beli), tocilizumab(TCZ), abatacept(Aba), rituximab(RTX) and fresolimumab(Fresu) appear promising as they exhibited some benefit in skin (IVIg, Beli, TCZ, Aba, RTX, Fresu), hand function (IVIg), and joints (IVIg, TCZ, Aba). Autologous stem cell transplantation showed the best therapeutic efficacy on skin and internal organs, and looks very promising, as modification of transplantation immunosuppression is decreasing the early high mortality. PMID- 29985737 TI - Slow gait as a motor marker of mild cognitive impairment? the relationships between functional mobility and mild cognitive impairment. AB - The purpose of this study was to evaluate the association between functional mobility and mild cognitive impairment in older adults. A total of 800 older adults were recruited (653 controls and 147 subjects with MCI [88 subjects with aMCI and 59 subjects with naMCI]). Motor performance was measured with the Timed Up and Go test (TUG). The demographic factors associated with MCI were: age (OR = 1.05; 95% CI: 1.01-1.09) and the level of education (OR = 0.73; 95% CI: 0.68 0.79). An independent clinical factor associated with MCI was the TUG (OR = 1.14; 95% CI: 1.03-1.27). In the aMCI group, the relation between the TUG and cognitive status occurred (OR = 1.15; 95% CI: 1.02-1.31), whereas in the naMCI group this relationship was not observed. There is an association between cognitive dysfunction and impaired motor performance in older adults with MCI. PMID- 29985738 TI - Association between changes in function among patients with lumbar impairments classified according to the STarT Back Screening Tool and managed by McKenzie credentialed physiotherapists. AB - PURPOSE: To examine the association between functional status (FS) scores using a Patient Reported Outcome Measure (PROM) for patients with non-specific low back pain classified according to psychosocial risk using the STarT Back Screening Tool and managed by physiotherapists credentialed in McKenzie methods. METHODS: Participants (n = 705) completed FS and STarT surveys at intake and discharge. Prevalence of STarT risk classifications and change in STarT risk was calculated. Regression models were developed to examine associations between baseline and change in STarT risk categories, and FS outcomes at discharge from rehabilitation services. RESULTS: FS outcomes at discharge was not significantly different (p values > 0.10) across baseline STarT risk subgroups after controlling for model covariates. Seventy-eight and 91.5% of medium and high-risk patients respectively decreased STarT risk. When compared with subjects whose STarT risk decreased, there was no significant difference in subjects whose STarT risk remained low. For subjects whose risk remained medium/high, or whose risk worsened, FS outcome scores were statistically significant (p < 0.001) and clinically relevant (-15.76 and -23.42 points respectively) compared to patients whose STarT risk decreased. CONCLUSIONS: Baseline STarT psychosocial risk stratifications should be interpreted cautiously to estimate the likelihood of good or poor FS outcomes at discharge from physiotherapy practice in the US when patients are managed by clinicians credentialed in McKenzie methods. Decreased STarT risk was associated with clinically important improvements in FS outcomes scores at discharge from McKenzie directed physiotherapy care. PMID- 29985739 TI - Treatment effect on ordinal functional outcome using piecewise multistate Markov model with unobservable baseline: an application to the modified Rankin scale. AB - In clinical trials, longitudinally assessed ordinal outcomes are commonly dichotomized and only the final measure is used for primary analysis, partly for ease of clinical interpretation. Dichotomization of the ordinal scale and failure to utilize the repeated measures can reduce statistical power. Additionally, in certain emergent settings, the same measure cannot be assessed at baseline prior to treatment. For such a data set, a piecewise-constant multistate Markov model that incorporates a latent model for the unobserved baseline measure is proposed. These models can be useful in analyzing disease history data and are advantageous in clinical applications where a disease process naturally moves through increasing stages of severity. Two examples are provided using acute stroke clinical trials data. Conclusions drawn in this article are consistent with those from the primary analysis for treatment effect in both of the motivating examples. Use of these models allows for a more refined examination of treatment effect and describes the movement between health states from baseline to follow up visits which may provide more clinical insight into the treatment effect. PMID- 29985740 TI - Evolving Soft Locomotion in Aquatic and Terrestrial Environments: Effects of Material Properties and Environmental Transitions. AB - Designing soft robots poses considerable challenges; automated design approaches may be particularly appealing in this field, as they promise to optimize complex multimaterial machines with very little or no human intervention. Evolutionary soft robotics is concerned with the application of optimization algorithms inspired by natural evolution to let soft robots (both their morphologies and controllers) spontaneously evolve within physically realistic simulated environments, figuring out how to satisfy a set of objectives defined by human designers. In this article, a powerful evolutionary system is put in place to perform a broad investigation on the free-form evolution of simulated walking and swimming soft robots in different environments. Three sets of experiments are reported, tackling different aspects of the evolution of soft locomotion. The first two explore the effects of different material properties on the evolution of terrestrial and aquatic soft locomotion: particularly, we show how different materials lead to the evolution of different morphologies, behaviors, and energy performance trade-offs. It is found that within our simplified physics world, stiffer robots evolve more sophisticated and effective gaits and morphologies on land, while softer ones tend to perform better in water. The third set of experiments starts investigating the effect and potential benefits of major environmental transitions (land<->water) during evolution. Results provide interesting morphological exaptation phenomena and point out a potential asymmetry between land->water and water->land transitions: while the first type of transition appears to be detrimental, the second one seems to have some beneficial effects. PMID- 29985741 TI - Non-glaucoma periocular allergic, atopic, and irritant dermatitis at an academic institution: A retrospective review. AB - PURPOSE: To better understand the nature of periocular dermatitis (PD) patient presentation, treatment, time-to-cure, and referral pattern for allergy testing in an ophthalmic academic center. METHODS: A retrospective chart review of 344 patients diagnosed with PD between January 1, 2000 and November 30, 2016 at the Edward S. Harkness Eye Institute was performed. Eighty patients were eligible for the study. The primary endpoint was the time-to-cure. Cox proportional hazards regression was performed to assess if there was a significant difference between time-to-cure in patients treated with: 1) combination topical steroid/antibiotic (n = 6) vs. topical steroid alone (n = 40) and 2) combination topical steroid and oral antihistamine (n = 5) vs. topical steroid alone (n = 40). RESULTS: The median age of eligible patients was 57.69 years old, 66.25% of patients were female, and 41.25% had a history of atopy. Seven patients in total were referred for allergy testing. A significant difference was found in likelihood of cure when comparing combination topical steroid and oral antihistamine versus topical steroid alone, adjusting for age and gender (aHR = 3.97, 95% CI: 1.40-11.25). No significance was found when comparing combination topical steroid/antibiotic versus topical steroid alone (aHR = 1.96, 95% CI: 0.72-5.27). CONCLUSION: Patients treated with topical steroid and oral antihistamine were approximately 4 times more likely to experience cure in comparison to patients treated with topical steroids alone. While the majority of patients were not referred for formal allergy testing, this would likely be of benefit. PMID- 29985742 TI - How Do Experienced Professors Teach Palliative Medicine in European Universities? A Cross-Case Analysis of Eight Undergraduate Educational Programs. AB - BACKGROUND: In Europe in recent decades, university teaching of palliative medicine (PM) has evolved. In some countries it has been introduced as a compulsory subject in all medical schools, but in a majority of countries it remains an isolated subject at few universities. OBJECTIVE: To explore how PM has been introduced into the curricula and how it is currently being taught at different European universities. METHOD: Case study method using face-to-face semistructured interviews with experienced PM professors, comparing how they have developed PM undergraduate programs at their universities. RESULTS: An intentional sample of eight university professors from Spain, France, UK, Italy, Hungary, Sweden, Germany, and Poland was chosen. The introduction of PM in the universities depends on the existence of a favorable social and political context in relation to palliative care and the initiative of pioneers, trusted by students, to push this education forward. A PM curriculum frequently starts as an optional subject and becomes mandatory in a short period. In the reported universities, PM uses a wide variety of teaching methods, such as lectures, workshops, role-plays, and discussions. PM assessment included tests, discussions, reflections, portfolios, and research works. According to respondents' opinions, lack of recognition, funding, and accredited teachers, along with competition from other curricula, are the main barriers for palliative medicine teaching development at universities. CONCLUSION: Diverse paths and tools have been identified for PM teaching in Europe. The described cases may shed light on other medical schools to develop PM curricula. PMID- 29985743 TI - A modified vertical muscle transposition for the treatment of large-angle esotropia due to sixth nerve palsy. AB - INTRODUCTION: Multiple different procedures have been proposed to address complete sixth nerve palsy with severe abduction limitation. In this study, we report a modification of the Hummelsheim's procedure. It is in fact muscle pulley transposition that obviates the need for tenotomy or muscle splitting. For the first time, Muraki and Nishida proposed this technique. MATERIALS AND METHODS: Patients with large angle esotropia and abduction limitation of minus four or greater were enrolled. The surgery involved insertion of a polyester monofilament fiber suture through the temporal muscular margin of each vertical rectus muscle at approximately one-third of the width from the edge at 10 mm behind the muscle insertion. We tried to insert sutures away from the vessels of vertical muscles. Then, the vertical muscles were transposed without any tenotomy or splitting and the sutures were secured to the sclera 16 mm from the limbus in supratemporal and infratemporal quadrants. In all of the patients, this transposition was combined with medial rectus recession. RESULTS: A total of 10 patients were included; all of them had an esotropia with profound abduction deficit (-4 or more). The mean age of patients was 44.2 +/- 9.2 years (mean +/- standard deviation) (range: 28 57). The mean preoperative deviation was 49.5 +/- 9 PD prism diopters (PD) (range: 40-65 PD). The mean preoperative abduction limitation was -4.8 +/- 0.8. The patients were followed for at least 6 months. Postoperative deviation ranged from orthotropia to 12 PD of esotropia and all the patients obtained abduction at least beyond the midline. No vertical ductional disturbances or deviations were developed. The adduction was not compromised in any patient. Anterior segment ischemia did not occur in any patients. CONCLUSION: This procedure is comparable to traditional procedures with the advantages of no need to tenotomy or splitting and can be a good alternative to conventional Hummelsheim's procedure. PMID- 29985744 TI - Incorporating a companion test into the noninferiority design of medical device trials. AB - Noninferiority trials are commonly utilized to evaluate the safety and effectiveness of medical devices. It could happen that the noninferiority hypothesis is rejected while the performance of the active control is clinically not satisfactory. This may pose a great challenge when making a regulatory decision. To avoid such a difficult situation, we propose to conduct a companion test to assess the performance of the active control when testing the main noninferiority hypothesis and to incorporate such a test into the study design. Under our proposal, the noninferiority of the investigational device to the active control can only be claimed when both hypotheses are rejected. The operating characteristics of the proposed study design based on these two tests can be fully evaluated at the design stage. This proposed approach is aimed to facilitate regulatory decision making in a more transparent manner. PMID- 29985745 TI - Ten cold clubfeet. AB - Background and purpose - Idiopathic clubfeet are commonly treated with serial manipulation and casting, known as the Ponseti method. The use of Plaster of Paris as casting material causes both exothermic and endothermic reactions. The resulting temperature changes can create discomfort for patients. Patients and methods - In 10 patients, we used a digital thermometer with a data logger to measure below-cast temperatures to create a thermal profile of the treatment process. Results - After the anticipated temperature peak, a surprisingly large dip was observed (Tmin = 26 degrees C) that lasted 12 hours. Interpretation - Evaporation of excess water from a cast might be a cause for discomfort for clubfoot patients and subsequently, their caregivers. PMID- 29985746 TI - Randomized Trials of Proton Therapy: Why They Are at Risk, Proposed Solutions, and Implications for Evaluating Advanced Technologies to Diagnose and Treat Cancer. PMID- 29985747 TI - Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. AB - Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets. PMID- 29985749 TI - Extracellular vesicles derived from mesenchymal cells: perspective treatment for cutaneous wound healing in pediatrics. AB - AIM: We evaluated the effects of the intradermal injection of extracellular vesicles (EVs) derived from adipose stem cells (ASC-EVs) and bone marrow cells (BM-EVs) in an experimental cutaneous wound repair model. METHODS: Mesenchymal stem cells (MSCs) were in vitro expanded from adipose (ASC) or BM tissues (BM MSC) of rabbits. EVs were separated from the supernatants of confluent ASC and BM MSCs. Two skin wounds were induced in each animal and treated with MSC or EV injections. Histological examination was performed postinoculation. RESULTS: EV treated wounds exhibited a better restoration compared with the counterpart MSC treatment. ASC-EV-treated wounds were significantly better than BM-EVs (p = 0.036). CONCLUSION: EV topical inoculation provides restored architecture during cutaneous wound healing and represents a promising solution for regenerative medicine in children. PMID- 29985748 TI - Do Patients With Advanced Cancer Have the Ability to Make Informed Decisions for Participation in Phase I Clinical Trials? AB - Purpose Patients with advanced cancer (ACPs) participating in phase I clinical trials inadequately understand many elements of informed consent (IC); however, the prevalence and impact of cognitive impairment has not been described. Patients and Methods ACPs enrolled onto phase I trials underwent neuropsychological assessment to evaluate cognitive functioning (CF) covering the following domains: memory (Hopkins Verbal Learning Test), executive functioning (Trail Making Test B), language (Boston Naming Test-Short Version and Controlled Oral Word Association Test), attention (Trail Making Test A and Wechsler Adult Intelligenence Scale-IV Digit Span), comprehension (Wechsler Adult Intelligence Scale-IV), and quality of life (Functional Assessment of Cancer Therapy-Cognitive Function). Structured interviews evaluated IC and decisional capacity. Psychological measures included distress (Hospital Anxiety Depression Scale) and depression (Beck Depression Inventory-II). Results One hundred eighteen ACPs on phase I trials were evaluated, with CF ranging from mild impairment to superior performance. Only 45% of ACPs recalled physician disclosure of the phase I trial purpose. The 50% of ACPs who correctly identified the phase I research purpose had greater CF compared with ACPs who did not, as revealed by the mean T scores for memory (37.2 +/- 5.6 v 32.5 +/- 5.1, respectively; P = .001), attention (29 +/- 2.7 v 26.9 +/- 2.4, respectively; P < .001), visual attention (35.2 +/- 6.6 v 31.5 +/- 6.2, respectively; P = .001), and executive function (38.9 +/- 7.5 v 34 +/- 7.1, respectively; P < .001). Older ACPs (>= 60 years) were less likely to recall physician disclosure of phase I purpose than younger ACPs (30% v 70%, respectively; P = .02) and had measurable deficits in total memory (34.2 +/- 5.0 v 37.3 +/- 5.6, respectively; P = .002), attention (24.5 +/- 2.6 v 28 +/- 2.8, respectively; P < .001), and executive function (32.8 +/- 7.3 v 36.4 +/- 7.6, respectively; P = .01). Older ACPs, compared with younger ACPs, also had greater depression scores (10.6 +/- 9.2 v 8.1 +/- 5.2, respectively; P = .03) and lower quality-of-life scores (152 +/- 29.6 v 167 +/- 20, respectively; P = .03). After adjustment by age, no psychological or neuropsychological variable was further significantly associated with likelihood of purpose identification. Conclusion CF seems to play a role in ACP recall and comprehension of IC for early-phase clinical trials, especially among older ACPs. PMID- 29985750 TI - Aspirin, platelet inhibition and cancer prevention. AB - Several lines of evidence are consistent with the hypothesis that activated platelets contribute to colorectal tumorigenesis and metastatization through direct cell-cell interactions and the release of different lipid and protein mediators, and microvesicles. This review examines the clinical pharmacology of low-dose aspirin as a basis for discussing the mechanisms underlying the contribution of platelets to neoplastic transformation and progression of cancer via the development of metastases. PMID- 29985751 TI - Immunogenicity of sequential inactivated and oral poliovirus vaccines (OPV) versus inactivated poliovirus vaccine (IPV) alone in healthy infants: A systematic review and meta-analysis. AB - BACKGROUND: The emergence of vaccine-associated paralytic poliomyelitis has become an ongoing burden of poliomyelitis. During this special period from OPV to IPV-only immunization schedule, we did a meta-analysis to compare the immunogenicity of sequential IPV and OPV versus IPV alone in healthy infants. METHODS: This systematic review and meta-analysis was registered at international prospective register of systematic reviews (PROSPERO), and the number was CRD42017054889. We performed it as described. RESULTS: Finally, 6 articles were qualified for our review. The results showed that seroconversion rates against all 3 serotype polioviruses were non-inferior and Geometric mean antibody titers (GMTs) were superior in sequential schedules compared with IPV-only schedule. Thus, the sequential vaccination schedules could induce a stronger immunogenicity. CONCLUSIONS: To decrease vaccine-associated and vaccine-derived poliomyelitis, it is a reasonable option to select sequential schedules during this special transition from OPV to IPV-only immunization schedule, which coincides with the current WHO recommendations. PMID- 29985752 TI - Methods for the analysis of multiple endpoints in small populations: A review. AB - While current guidelines generally recommend single endpoints for primary analyses of confirmatory clinical trials, it is recognized that certain settings require inference on multiple endpoints for comprehensive conclusions on treatment effects. Furthermore, combining treatment effect estimates from several outcome measures can increase the statistical power of tests. Such an efficient use of resources is of special relevance for trials in small populations. This paper reviews approaches based on a combination of test statistics or measurements across endpoints as well as multiple testing procedures that allow for confirmatory conclusions on individual endpoints. We especially focus on feasibility in trials with small sample sizes and do not solely rely on asymptotic considerations. A systematic literature search in the Scopus database, supplemented by a manual search, was performed to identify research papers on analysis methods for multiple endpoints with relevance to small populations. The identified methods were grouped into approaches that combine endpoints into a single measure to increase the power of statistical tests and methods to investigate differential treatment effects in several individual endpoints by multiple testing. PMID- 29985753 TI - Comprehensive study of domain rearrangements of single-chain bispecific antibodies to determine the best combination of configurations and microbial host cells. AB - Small bispecific antibodies (bsAbs) are important therapeutic molecules and represent the first bsAb format approved by the United States Food and Drug Administration. Diabody (Db), a small bsAb format, has four possible domain orders; we previously reported the differences in the expression levels and cancer growth inhibition effects upon rearranging the domain order of this format. However, there have been no comprehensive reports on domain rearrangements of bispecific single-chain Db (scDb) and tandem single-chain Fv (taFv), which are widely used bsAb formats. In this study, we designed all possible domain orders for scDb and taFv (each with eight variants) with identical Fv pairs and individually expressed all 16 variants using Escherichia coli, Pichia pastoris, and Brevibacillus choshinensis. Comprehensive investigations showed that the intrinsic functions of the variants were similar to each other, regardless of the expression host system, but expression levels varied depending on the format as well as on the host cell. Among the 16 variants, we found a promising candidate that exhibited high activity and productivity. Furthermore, we determined that B. choshinensis is an attractive expression host because of its secretory production of recombinant proteins. PMID- 29985754 TI - Assessment of Douro and Ave River (Portugal) lower basin water quality focusing on physicochemical and trace element spatiotemporal changes. AB - Water quality of Douro and Ave lower basin was evaluated regarding physicochemical parameters (pH, conductivity, dissolved oxygen and temperature), nutrient compounds (nitrates, nitrites, ammonium and orthophosphates), chlorophyll a and occurrence of trace elements (Li, Be, Al, Ti, V, Cr, Co, Ni, Cu, Zn, Se, Mo, Ag, Cd, Sb, Ba, Tl, Pb, Th and U). To study spatiotemporal variations and possible anthropogenic sources, estuarine samples were collected at nine sampling sites in Douro and five in Ave distributed along the estuaries at four sampling campaigns (spring, summer, fall and winter). According to the water quality standards for aquatic life and recreation, Douro and Ave river water quality was found out of safe limits regarding several parameters. Nitrate levels were systematically high (> 50 mg L-1 in a significant number of samples) and mean levels of trace elements were higher than the established values of Canadian Environmental Quality Guidelines for aquatic life protection for Al, Cu, Se, Ag, Cd and Pb in Douro and Ave, and also Zn in Ave. Significant spatial differences were found in Ave river estuary for trace elements with a clear trend for higher values from upstream to downstream found. Seasonal differences were also observed particularly in Douro river estuary with higher levels in spring for most elements. PMID- 29985755 TI - Pure platelet-rich plasma and supernatant of calcium-activated P-PRP induce different phenotypes of human macrophages. AB - AIM: This study aimed to evaluate the effect of two platelet preparations used in the clinic, pure platelet-rich plasma (P-PRP) and the supernatant of calcium activated P-PRP (S-PRP), on the phenotype of human macrophages. MATERIALS & METHODS: Surface markers and cytokine production of human monocyte-derived macrophages were analyzed after 24 h stimulation with P-PRP or S-PRP. RESULTS: P PRP and S-PRP present no difference in the expression of CD206, a M2 tissue repair macrophage-related marker. However, these same macrophages presented different levels of CD163, CD86 as well as different IL-10 secretion capacities after 24 h incubation. CONCLUSION: These platelet preparations do not have an equivalent biological effect over macrophages, which suggest that they may present different clinical regenerative potentials. PMID- 29985756 TI - Passive immunization with influenza haemagglutinin specific monoclonal antibodies. AB - The isolation of broadly neutralising antibodies against the influenza haemagglutinin has spurred investigation into their clinical potential, and has led to advances in influenza virus biology and universal influenza vaccine development. Studies in animal models have been invaluable for demonstrating the prophylactic and therapeutic efficacy of broadly neutralising antibodies, for comparisons with antiviral drugs used as the standard of care, and for defining their mechanism of action and potential role in providing protection from airborne infection. PMID- 29985757 TI - Selling stem cell 'treatments' as research: prospective customer perspectives from crowdfunding campaigns. AB - AIM: To better understand how prospective customers interpret claims of businesses marketing unproven stem cell products that they are engaging in research activities. MATERIALS & METHODS: The authors examined 408 crowdfunding campaigns for unproven stem cell interventions for references to research activities. RESULTS: The authors identified three overarching themes: research as a signifier of scientific credibility; the experimental nature of stem cells as a rationale for noncoverage by insurers; and contributing to the advancement of science by engaging in research. CONCLUSION: The NIH, US FDA and others should be concerned about being co-opted to misrepresent the nature of these businesses' activities. Efforts are also needed to better inform those considering purchasing unproven stem cell interventions about their relationship to legitimate research. PMID- 29985759 TI - An unexpected world population variation of MCT1 polymorphism 1470T > A involved in lactate transport. AB - A common missense mutation (1470T > A) in gene SLC16A1 responsible for an amino acid substitution in protein MCT1 has been associated with differential lactate transport and hence, differences in physical performance and muscle injuries in relation to physical exercise. This study describes, for the first time, the worldwide variation of MCT1 variant 1470T > A at an intra- and inter-continental level. Two thousand five hundred and four individual genotypes of 26 populations clustered in 5 population groups have been analysed with data downloaded from the public database 1000 Genomes Phase 3 Browser. Several parameters of population differentiation and structure have been explored as well as selection signatures in the whole gene. Allele T, the common variant, shows extremely high values in Sub-Saharan African groups (frequencies 86-91%) as compared with the remaining world regions (69-49%). TT genotype also predominates in African groups, showing significant differences with the rest of world populations. In view of the evidence that the TT genotype is associated with clinical implications and a better predisposition to sprint/power performances, we suggest that the high presence of the TT genotype in African populations should be taken into account in future association studies at both medical and sports fields. PMID- 29985758 TI - Simple and practical on-site treatment of high microcystin levels in water using polypropylene plastic. AB - Microcystin (MC) is a hepatotoxin produced by various cyanobacteria during harmful algal blooms (HAB's) in freshwater environments. Advanced treatment methods can remove MC from drinking water, but are costly and do not address recreational water exposure and ecosystem health concerns. Here we investigate the feasibility of utilizing plastics as a MC-adsorbing material, for use in water resources used for recreation, agriculture, aquaculture and drinking water. Water containing 20 ug/L MC-LR was exposed to polypropylene (PP) plastic for a six-day period at varying temperatures (22, 37, 65 degrees C). Water samples were then collected at 0, 1, 2, and 6 hour-intervals to examine short term treatment feasibility. Samples were also taken at 24 hours, 3 days, and 6 days to determine long-term treatment effectiveness. MC concentrations were analyzed using ELISA. Results showed a maximal reduction of nearly 70% of MC-LR after a 6-day treatment with PP at 65 degrees C. Temperature enhanced MC-LR reduction over a 6-day period: 70% reduction at 65 degrees C; 50% at 37 degrees C; 38% at 22 degrees C. We propose an inexpensive intervention strategy which can be deployed rapidly on site in various source waters, including in resource-limited settings. During the high peak of HAB season, the strategy can be applied in source waters, alleviating water treatment burden for treatment plants, lowering treatment costs and reducing chemical usage. PMID- 29985760 TI - Chlamydia caviae Causing Community-Acquired Pneumonia: An Emerging Zoonosis. AB - We describe a case of community-acquired pneumonia due to Chlamydia caviae in a patient with no direct animal exposure, raising questions about the zoonotic reservoirs and potential transmission routes. Genotyping of Chamydia isolates that cause pneumonia should be performed for a precise diagnosis and to initiate adequate infection control measures. PMID- 29985761 TI - Rejoinder to Mr. Peter J. Laud. PMID- 29985762 TI - A comparison of respirable crystalline silica concentration measurements using a direct-on-filter Fourier transform infrared (FT-IR) transmission method vs. a traditional laboratory X-ray diffraction method. AB - Evaluation and control of respirable crystalline silica (RCS) exposures are critical components of an effective mine industrial hygiene program. To provide more timely exposure data in the field, an end-of-shift Fourier transform infrared (FT-IR) spectrometry method has been developed for evaluation of direct on-filter RCS. The present study aimed to apply this FT-IR method using field samples collected in three Northwestern U.S. metal/nonmetal mines and compare the results to traditional laboratory X-ray diffraction analysis (XRD). Seventy-five dust samples were analyzed using both methods. Samples for each mine were split in half by random assignment, with half used to create a calibration factor for the FT-IR analysis and half used to apply the calibration. Nonparametric correlational and two-sample comparative tests were used to assess the strength of association and the level of agreement between the two methods. Strong, positive correlations were observed between FT-IR and XRD RCS concentrations, with Spearman rank correlation coefficients ranging between 0.84 and 0.97. The mean RCS concentrations determined through FT-IR analysis were lower than through XRD analysis, with mean differences ranging from -4 to -133 ug/m3 and mean percent errors ranging from 12% to 28%. There was a statistically significant improvement in the level of agreement between log FT-IR and log XRD RCS concentrations following calibration at two of the three mines, with mean differences of -0.03 (p = 0.002) and -0.02 (p = 0.044) in the log scale. The reduction in mean difference following calibration at the other mine was not statistically significant (mean log scale difference = -0.05, p = 0.215), but the differences between FT-IR and XRD were not significantly different without calibration (mean log scale difference = -0.07, p = 0.534). The results indicate that mine-specific calibration factors can improve the level of agreement between RCS concentrations determined via a field-based, end-of-shift FT-IR method in metal/non-metal mines as compared to traditional XRD analysis. PMID- 29985763 TI - Advances in addressing full-thickness skin defects: a review of dermal and epidermal substitutes. AB - full-thickness skin defects remain a reconstructive challenge. Novel regenerative modalities can aid in addressing these defects. A literature review of currently available dermal and epidermal regenerates was performed. The mechanism and application for each skin substitute was analyzed to provide a guide for these modalities. Available epidermal substitutes include autografts and allografts and may be cultured or noncultured. Dermal regenerate templates exist in biologic and synthetic varieties that differ in the source animal and processing. Epidermal and dermal skin substitutes are promising adjunctive tools for addressing certain soft tissue defects and have improved outcomes in reconstructive procedures. The following article provides a comprehensive review of the biologic materials available and the types of complex wounds amenable to their use. PMID- 29985764 TI - Feasibility of a computer application to develop social workers knowledge of integrated healthcare concepts. AB - Disseminating evidence-based knowledge and strengthening the education program of the healthcare workforce is an essential step toward achieving transformation of the U.S. healthcare delivery system to integrated healthcare. Computer applications may be an effective approach for social workers to learn integrated concepts. A feasibility study using an experimental research design was used to compare instructional approaches among MSW students (N = 15) composed of experimental (N = 7) and control (N = 8) group participants. Students completed a pre-test on integrated healthcare concepts and screening measures along with a post-test on screening measures. While ANCOVA results suggest no significant differences on post-test scores between the two groups, dependent sample t-test revealed a significant increase for both groups. Results suggest training on an integrated healthcare topic using a computer application is feasible. Future research should be conducted to determine if the computer application is comparable to other instructional methods. PMID- 29985765 TI - A modified sandwich ELISA for accurate measurement of HbF in alpha-thalassemia carriers containing Hb Bart's and Hb Portland 1. AB - Hemoglobin F (HbF) in blood lysate can be accurately measured by various methods, including immunoassay. In this study, we have produced polyclonal antibody (pAb) against HbF and established a modified sandwich-type ELISA for HbF quantification in blood lysates. The modified sandwich ELISA utilized anti-gamma-globin monoclonal antibody clones Thal N/B as the capture antibody (Ab) coated on solid phase, fluorescein isothiocyanate (FITC)-labeled pAb as the detecting Ab, and HPR labeled anti-FITC Ab as the signal-generating Ab. By using an optimized blood lysate dilution, the HbF could be measured with no interference from hemoglobin Bart's (Hb Bart's) and hemoglobin Portland (Hb Portland 1) presented in alpha thalassemia carriers. HbF levels measured by the modified sandwich ELISA were comparable to those quantified by the standard cation-exchange high performance liquid chromatography. We suggested that this modified sandwich ELISA was able to accurately measure HbF levels even in alpha-thalassemia carriers containing Hb Bart's and Hb Portland 1 and be an alternative method for HbF measurement. PMID- 29985766 TI - Molecular Characterization and Phylogenetic Analysis of Theileria spp. and Babesia spp. Isolated from Various Ticks in Southeastern and Northwestern Regions of Iran. AB - INTRODUCTION: Piroplasms are hemoprotozoa comprising heterogeneous tick-borne parasites, which are differentiated into three genera, namely Babesia, Theileria, and Cytauxzoon. The aim of this study was to determine the prevalence, molecular identification, and phylogenetic relationship of both Theileria spp. and Babesia spp. in tick species isolated from different domestic animals from two different geographical locations of Iran. MATERIALS AND METHODS: A total of 930 ticks collected from goats, sheep, and cattle were examined for the presence of Theileria spp. and Babesia spp. using PCR targeting 18S rRNA gene followed by sequencing. Sequence analysis was performed based on the data published in the GenBank on Theileria spp. and Babesia spp. isolates using bioinformatic tools, such as the standard nucleotide BLAST. RESULTS: A 390 or 430 base pair fragment of 18S rRNA gene of Theileria and Babesia species was successfully amplified in 17.2% of the examined ticks (16of 93). Genome of Theileria or Babesia species was detected in 4 ticks collected in Heris, including 3 Dermacentor marginatus and 1 Rhipicephalus sanguineus, and also in 12 ticks collected in Chabahar, including 10 R. sanguineus and 2 D. marginatus. Partial analysis of 18S rRNA gene sequence of the four D. marginatus, collected from goats and sheep in Heris, showed that they were infected with Theileria spp. that were 95-97% identical to Iranian Theileria ovis present in the GenBank database (GenBank acc. no. KP019206.1). While the five R. sanguineus, collected from sheep and goats in Chabahar, were infected with Babesia spp. that were 91-97% identical to Iranian Babesia ovis present in the GenBank database (GenBank acc. no. AY362829.1: KT587794.1). CONCLUSION: The prevalence of Babesia and Theileria is different in southeastern and northwestern parts of Iran, with higher prevalence of babesiosis in the southeastern region and that of theileriosis in the northwestern region. Sequence analysis of 18S rRNA gene revealed that T. ovis and B. ovis are genetically polymorphic in these regions. PMID- 29985767 TI - Destructive psoriatic arthritis of the temporomandibular joint: a clinical case, an overview of the pathophysiology and its differential diagnoses. AB - Background Clinical assessments and uniplanar images in temporomandibular disorders are not always entirely reliable. This predicament is especially important when clinicians need to determine the nature of temporomandibular joint disease, particularly when clinical features are not helpful in determining the diagnosis. Clinical presentation A 63-year-old female patient presented with mild pain in her right TMJ. During routine imaging exams, a destructive monoarticular arthritis was noticed, producing multiple erosions of the mandibular and temporal condyles. In addition, attrition of the ceiling of the glenoid fossa was observed, generating a communication with the endocranium. Only the presumptive biological behavior revealed on TMJ imaging and the appearance of the psoriatic plaques later during follow-up helped the authors to narrow the differential diagnosis. Conclusion The clinical case presented illustrates the difficulties in diagnosing an erosive, seronegative TMJ destruction, suggestive of a systemic arthritis. PMID- 29985768 TI - Role of myeloperoxidase in early diagnosis of acute myocardial infarction in patients admitted with chest pain. AB - Myeloperoxidase (MPO) is an inflammatory marker, elevated in acute coronary syndromes (ACSs), especially in acute myocardial infarction (AMI) cases. This study aimed to evaluate the diagnostic power of MPO in AMI patients. MPO, creatine kinase (CK) MB, and Troponin I (cTn I) were performed for all study patients. Area under the curves (AUCs) and 95% confidence intervals (CI); P values of baseline levels of MPO for discriminating AMI patients from noncoronary chest pain (NCCP) patients, stable angina (SA) patients, and unstable angina (UA) patients were 0.91, 95% CI: 0.82-0.99; P < 0.0001, 0.87, 95% CI: 0.77-0.98; P < 0.0001, and 0.72, 95% CI: 0.58-0.85; P = 0.002, respectively. For diagnosing AMI from ACS patients, MPO was the most efficient marker than others markers with efficiency 82.5% within 0-6 hr after the onset time of chest pain. A predictive score that depends on a combination of baseline levels of three markers (MPO, CK MB, and TnI) was correctly discriminated 91% of the AMI patients with high specificity 76%. In conclusion, the use of baseline levels of three biomarkers in combination could confer the information that is required for best available early diagnosis of AMI. PMID- 29985769 TI - Developing a process for assessing equivalency of wheelchair cushion pressure redistribution performance. AB - For wheelchair users who are at risk for developing pressure ulcers, cushion prescription seeks to address tissue integrity. Because many designs of wheelchair cushions exist, a need exists to estimate their performance in supporting the body. The objective of this research was to develop an approach to assess the equivalency of cushions with respect to their pressure redistribution performance. Two instrumented compliant buttock models, differing in form, were used in the evaluation. Stress and strain parameters were used to characterize load-bearing performance. A cohort of 8 wheelchair cushions was compared to a standard reference material, HR45 foam. Each cushion was measured using both models under two loading conditions. The use of compliant buttock models that are capable of measuring both stress and strain parameters offer greater capability in measuring load-bearing performance compared to previously described methods. The proposed approach was able to evaluate cushion performance and use a logic based approach to define whether or not a cushion was equivalent to the HR45 material. Additional study is needed to further validate the approach and to define the thresholds and criteria used to define cushion equivalency. PMID- 29985770 TI - Stakeholder Perspectives on Using and Developing the MYPLAN Suicide Prevention Mobile Phone Application: A Focus Group Study. AB - The objective of this study was to explore different stakeholder perspectives on the MYPLAN app for suicide prevention safety planning. The study was a comparative analysis of 4 focus groups with Danish MYPLAN stakeholders, young users, adult users, relatives, and clinicians. The focus groups were audio recorded, transcribed, and subjected to a thematic analysis. The analysis contextualized the participants' experiences of the benefits and limitations of MYPLAN. While participants believed that MYPLAN could potentially interrupt early stages of a suicidal process, clinicians' involvement in safety planning was considered important. MYPLAN could potentially give users a sense of increased personal control but learning how to effectively safety plan was not perceived to be simple and additional support should be considered for MYPLAN users. PMID- 29985771 TI - Self-Narrative Profiles of Elite Athletes and Comparisons on Psychological Well Being. AB - : Further research is needed on factors related to the emotional health of elite athletes. Previous research has linked self-narratives of people or their narrative identities to their psychological well-being. However, no study has yet examined self-narratives among elite athletes. PURPOSE: This study examined whether specific profiles or narrative identities of athletes emerge through multiple self-narrative indicators; these profiles were compared on measures of psychological well-being (e.g., depression, anxiety, postfailure shame levels, and life satisfaction). METHOD: Self-report data were collected from a sample of elite athletes (n = 99, Mdn age = 22 years, 52% male, 53% individual sports) competing at a National Collegiate Athletic Association Division 1, professional, or Olympic level. RESULTS: Latent profile analysis revealed 3 profile types that significantly differed on measures of psychological well-being. Athletes with a performance-based narrative identity (high perfectionism, fear of failure, and contingent self-worth) demonstrated the highest levels of psychological disruptions (highest levels of depression, anxiety, and shame; lowest levels of life satisfaction), whereas a purpose-based narrative identity (high purpose, global self-worth, positive view of self after sport) was associated with the highest level of psychological well-being (lowest levels of depression, anxiety, and shame; highest levels of life satisfaction). Athletes in the mixed-type profile class reported better psychological well-being compared with the performance-based profile class but not the purpose-based profile class. CONCLUSIONS: Our findings provide initial evidence that particular self-narrative profiles of elite athletes contribute to their own psychological well-being in a significant way. Possible implications for practitioners are also discussed. PMID- 29985772 TI - Females With Visual Impairments in Physical Education: Exploring the Intersection Between Disability and Gender Identities. AB - PURPOSE: The purpose of this study was to use an explicitly intersectional approach to examine the embodied experiences of individuals identifying as female and as having a visual impairment in school-based physical education. METHOD: An interpretative phenomenological analysis (IPA) research approach was used, and 8 adult women (ages 21-30 years) with visual impairments acted as participants for this study. The primary sources of data were semistructured audiotaped telephone interviews and reflected field notes. Data were analyzed thematically using a 3 step analytical process inspired by IPA. RESULTS: Based on the data analysis, 3 interrelated themes were constructed from the participant transcripts. The first theme, "Girls don't like gym anyway": limited participation from the female perspective, described the participants' experiences with limited participation and the influence of gender and visual impairment on these limitations. The second theme, "She can't do what other kids can do": teachers' expectations and unable bodies, described how the participants' unable or flawed bodies influenced their teachers' expectations of their abilities in physical education. The final theme, "It was really awkward": feelings about negative peer interactions, demonstrated participants' embodied perspectives toward bullying and other negative peer interactions. CONCLUSIONS: Utilizing an IPA approach, the researchers constructed 3 themes that exposed central experiences and reflections that were informed by the participants' identified gender and disability. Through the lens of intersectionality, these themes contribute to our understanding of how multiple identities (femaleness, visual impairment) contributed to disadvantages in physical education contexts. PMID- 29985773 TI - Symptoms of temporomandibular disorder, self-reported bruxism, and the risk of implant failure: A retrospective analysis. AB - Objective To investigate the association between symptoms of temporomandibular disorder and self-reported bruxism with the risk of implant failure. Methods This retrospective study is based on 2127 records of patients who had 4519 implants placed and restored at the University of Minnesota School of Dentistry. Patient and implant level information were retrieved from each dental record: age, gender, implant location, as well as history of clicking, pain, difficulty opening, difficulty chewing, and clenching or grinding. Results A total of 51 implant failures were identified in the sample. This corresponded to a failure rate of 1.1% at the implant level and 1.7% at the patient level. Among all the patient and implant level variables, the binary logistic regression showed that none of them were significantly associated with implant failure (p > 0.05). Discussion The identification of risk indicators for implant loss can foster long term implant survival, peri-implant health, and ultimately, implant prosthesis survival. PMID- 29985774 TI - Improving Functional Movement Proficiency in Middle School Physical Education. AB - PURPOSE: The purpose of this study was to examine whether functional movement proficiency could be improved as measured via the Functional Movement Screen using a standardized warm-up protocol in middle school physical education. A secondary purpose was to determine whether such improvement, if it occurred, would positively influence the technical performance of 4 fundamental motor skills: overhand throw, vertical jump, kicking, and running. METHOD: Participants were 120 7th- and 8th-grade physical education student volunteers. Two classes from each grade level were assigned to the functional group (N = 54) while the remaining 2 classes of each grade were assigned to the control group (N = 66). Baseline measures were obtained using the Functional Movement Screen and the Get Skilled: Get Active (2000) process-oriented motor skill assessment. For 6 weeks, the functional group warmed up by performing functional stretching, stability, and mobility exercises while the control group completed a traditional dynamic warm-up. RESULTS: According to gain score analysis, those in the functional group significantly reduced dysfunctional movements (scores of 1) compared with those in the control group. Further, boys in the functional group significantly improved their Functional Movement Screen composite score as compared with their male counterparts in the control group whose scores declined. No differences were found for fundamental motor skill performance. CONCLUSION: Replacing the traditional dynamic warm-up with one that emphasizes functional movement in preparation for activity in physical education appears effective for correcting movement dysfunctions in young adolescents. PMID- 29985775 TI - Adding omega-3 fatty acids to a protein-based supplement during pre-season training results in reduced muscle soreness and the better maintenance of explosive power in professional Rugby Union players. AB - Evidence suggests that omega-3 fatty acid supplementation could reduce muscle soreness and maintain muscle function following eccentric exercise-induced muscle damage. The aim of this applied field study was to investigate the effectiveness of consuming a protein-based supplement containing 1546 mg of omega-3 polyunsaturated fatty acid (PUFA) (551 mg eicosapentaenoic acid (EPA) and 551 mg docosahexaenoic acid (DHA)) twice daily (FO) compared to a protein-based placebo (P) on muscle soreness, countermovement jump (CMJ) performance and psychological well-being in 20 professional Rugby Union players during 5 weeks of pre-season training. Players completed a 5-point-Likert soreness scale with 5 indicating "no soreness" and a questionnaire assessing fatigue, sleep, stress and mood each morning of training, plus they performed CMJ tests once or twice per week. Data were analysed using magnitude-based inferential statistics and are presented as percent beneficial/trivial/harmful. On day 35, there was a likely (% beneficial/trivial/harmful: 94/5/1) moderate (0.75, standardized mean difference (SMD)) beneficial effect of FO vs. P on the change in lower body muscle soreness compared with day 0 (FO: -3.8 +/- 21.7%; P: -19.4 +/- 11.2%). There was a likely (92/7/0) moderate (SMD: 0.60) beneficial effect of FO vs. P on CMJ performance (change from baseline to day 35, FO: +4.6 +/- 5.9%; P: -3.4 +/- 8.6%). From day 20, a moderate beneficial effect of FO on fatigue was observed. In terms of practical relevance, the moderate beneficial effect of adding fish oil to a protein-based supplement on muscle soreness translated into the better maintenance of explosive power in elite Rugby Union players during pre-season training. PMID- 29985777 TI - Standardizing industrial hygiene data collection forms used by workers' compensation insurers. AB - Workers' compensation (WC) insurers collect large amounts of industrial hygiene (IH) data in the United States. The data collected is not easily accessible for research or surveillance purposes. Individual WC insurers are using computerized systems to standardize and store the IH data, leaving a gap in standardization among the different WC insurers. This study sought to standardize IH data collection among WC insurers and to determine the feasibility of pooling collected IH data. IH air and noise survey forms were collected from WC insurers. Data fields on the forms were evaluated for importance and a study list of core fields was developed. The core study list was presented to an IH review panel for review before finalization. The final core study list was compared to recommendations published by the American Conference of Governmental Industrial Hygienists (ACGIH) and the American Industrial Hygiene Association (AIHA). Fifty nine forms from 10 organizations were collected. Industrial hygienists from research organizations, state-based WC insurers, and private WC insurers participated in the data field evaluation and on the review panel. For both air and noise survey forms, more than half the data fields (55% and 54%, respectively) were ranked as "essential." Three of the four fields in the worker and control observations category ranked "essential" were found less than half of the time on both types of survey forms. The study list of core data elements consisted of more than half of the data fields from both the air and noise survey forms. Three additional fields were added based on the comparison to the ACGIH AIHA recommendations. Data fields essential to standardizing IH data collection were identified and verified. The "essential" data fields will be made available and have the potential to be incorporated into WC insurers electronic IH data management systems. Future research should focus on other IH survey forms, such as those used in ergonomic assessments and specific chemical exposures, and methods to transfer data fields to electronic platforms. PMID- 29985776 TI - Development of a Target cell-Biologics-Effector cell (TBE) complex-based cell killing model to characterize target cell depletion by T cell redirecting bispecific agents. AB - T-cell redirecting bispecific antibodies (bsAbs) or antibody-derived agents that combine tumor antigen recognition with CD3-mediated T cell recruitment are highly potent tumor-killing molecules. Despite the tremendous progress achieved in the last decade, development of such bsAbs still faces many challenges. This work aimed to develop a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that can be used to assist the development of T-cell redirecting bsAbs. A Target cell-Biologics-Effector cell (TBE) complex-based cell killing model was developed using in vitro and in vivo data, which incorporates information on binding affinities of bsAbs to CD3 and target receptors, expression levels of CD3 and target receptors, concentrations of effector and target cells, as well as respective physiological parameters. This TBE model can simultaneously evaluate the effect of multiple system-specific and drug-specific factors on the T-cell redirecting bsAb exposure-response relationship on a physiological basis; it reasonably captured multiple reported in vitro cytotoxicity data, and successfully predicted the effect of some key factors on in vitro cytotoxicity assays and the efficacious dose of blinatumomab in humans. The mechanistic nature of this model uniquely positions it as a knowledge-based platform that can be readily expanded to guide target selection, drug design, candidate selection and clinical dosing regimen projection, and thus support the overall discovery and development of T-cell redirecting bsAbs. PMID- 29985778 TI - Situational Factors Related to Childhood Sexual Abuse in the Orthodox Jewish Community Among Adult and Juvenile Offenders. AB - In recent years, increasing attention has been paid to situational factors associated with childhood sexual abuse (CSA) to explain incidence of CSA, as well as to provide potential targets for prevention efforts. However, very few studies have examined situational factors associated with juvenile perpetration, despite juveniles composing a substantial proportion of offenders. In addition, no studies to our knowledge have applied a situational framework to CSA research in the Orthodox Jewish community (OJC). In the present study, we obtained data from therapists regarding 80 victims of CSA in the OJC from both the United States and Israel. We hypothesized that (a) more abusers' first perpetration would be between ages 12 and 17 than between any other age range, which corresponds to increased sexual urges, as well as increased unsupervised access to minors; (b) among juvenile offenders, the time of day of the abuse would depend on the relationship of the offender to the victim; and (c) age of the victim and grooming strategies would be associated with the frequency of abuse. Our first two hypotheses were confirmed, and our third hypothesis was partially confirmed, as younger victims tended to have higher frequency of abuse. Additionally, we discuss possible implications of significant correlations found during exploratory analyses. Our results generally support the importance of considering culturally specific situational factors when studying or developing prevention efforts for CSA. PMID- 29985779 TI - Regenerative medicine in lower limb reconstruction. AB - Bone is a highly specialized connective tissue and has a rare quality as one of the few tissues that can repair without a scar to regain pre-injury structure and function. Despite the excellent healing capacity of bone, tumor, infection, trauma and surgery can lead to significant bone loss requiring skeletal augmentation. Bone loss in the lower limb poses a complex clinical problem, requiring reconstructive techniques to restore form and function. In the past, amputation may have been the only option; however, there is now an array of reconstructive possibilities and cellular therapies available to salvage a limb. In this review, we will evaluate current applications of bone tissue engineering techniques in limb reconstruction and identify potential strategies for future work. PMID- 29985780 TI - Detection of West Nile Virus Infection in Viral Encephalitis Cases, China. AB - This study detected West Nile virus (WNV) infection in serum samples of patients clinically diagnosed with viral encephalitis in the Japanese encephalitis virus (JEV) endemic area (seven provinces) and JEV nonendemic area (Xinjiang province) in China from 2011 to 2012. In JEV endemic areas, there were 22 positive cases of WNV immunoglobulin M (IgM) antibody in serum specimens of 65 JEV patients (JEV IgM antibody positive) in the acute phase, whereas WNV IgM antibodies were not detected in serum specimens of 63 non-JEV patients (JEV IgM antibody negative). However, the titer of JEV-neutralizing antibody was four times higher than that of WNV-neutralizing antibody in WNV-IgM-positive serum specimens. Detection was also conducted in serum specimens collected from 12 patients clinically diagnosed as viral encephalitis in Xinjiang; five serum specimens were WNV IgM antibody positive, and there were fourfold differences in WNV-neutralizing antibody titers between convalescent and acute serum. Meanwhile JEV-neutralizing antibody titer was negative or significantly lower than that of WNV-neutralizing antibody in the same specimens. WNV IgM antibodies positive were detected in acute serum specimens of patients clinically diagnosed with JEV infection in JEV-endemic areas, but no WNV neutralization antibodies were detected fourfold greater than that of the corresponding JEV antibodies. Clinical cases of WNV infection were detected in patients clinically diagnosed with viral encephalitis in Xinjiang. PMID- 29985781 TI - Design and Development of a Topology-Optimized Three-Dimensional Printed Soft Gripper. AB - In the past decade, a rich repertoire of soft robots, designed from biomimetic and intuitive approaches, has been developed to overcome challenges faced by their rigid-bodied counterparts. However, these design approaches are greatly limited by the designers' experience and inspiration. In this article, the structural design problem is mathematically modeled under the framework of topology optimization, and solved by a new implementation tool that combines Abaqus/CAE and Matlab coding. Herein, a pneumatic soft gripper with two identical fingers was developed as a practical application. To fulfill the grasping task, each gripper finger is optimized to achieve its maximal bending deformation. The optimized gripper fingers are in high consistence with human fingers as indicated by pseudo-joints. Thereafter, the optimized gripper fingers are directly fabricated by three-dimensional printing technique with unprecedented fidelity regardless of high geometric complexity. Experimental results show that the gripper can grasp an elastic balloon, and each gripper finger is able to undergo a [Formula: see text] free travel bending and exert 0.23 N grasping force upon 0.06 MPa actuation pressure. The proposed approach is freely extendable to develop other types of soft robots and this represents an important step toward the goal of designing and fabricating soft robots automatically. PMID- 29985782 TI - Reading or Listening to a Gain- or Loss-Framed Health Message: Effects of Message Framing and Communication Mode in the Context of Fruit and Vegetable Intake. AB - Gain-framed health messages are found to be more effective when targeting prevention behaviors. However, framing research has only minimally investigated the role of communication mode, another important factor in health communication. This study explored the role of communication mode in interaction with message framing, and the influence of two individual differences related to involvement as conditions under which gain framing can lead to health behavior change. Participants (N = 258) were exposed to either an auditory or written health message concerning fruit and vegetable intake, with either gain- or loss-framed arguments. In addition, the online experiment consisted of baseline and posttest measures, among which intention to consume sufficient fruit and vegetables. Moderating effects of perceived baseline fruit and vegetable consumption and baseline intention were assessed. A significant interaction between message framing and communication mode was observed: In case of a gain-framed message, an auditory message resulted in a higher intention than a written message. This pattern was most explicitly found among those with a lower perceived fruit and vegetable intake at baseline. Although further research is warranted in health persuasion research, the findings can possibly be used to target health interventions better at specific groups of people who behave less healthy. PMID- 29985783 TI - Long-term prescribing of nitrofurantoin for urinary tract infections (UTI) in veterans with spinal cord injury (SCI). AB - CONTEXT/OBJECTIVE: To evaluate the impact of long-term nitrofurantoin for UTI prophylaxis in veterans with SCI. DESIGN: Matched pairs study. SETTING: Veterans cared for at VA facilities from 10/1/2012-9/30/2013. PARTICIPANTS: Veterans. INTERVENTIONS: n/a. OUTCOMES MEASURES: UTI, positive urine cultures, resistant cultures. METHODS: Cases receiving long-term nitrofurantoin (>=90 days supply) were matched to controls by facility. Controls were patients who did not receive long-term nitrofurantoin with a history of >=3 positive urine cultures and at least one diagnosis of UTI or asymptomatic bacteriuria in the previous year. RESULTS: 122 SCI cases were identified and matched to 196 controls. After adjusting for differences in baseline demographic characteristics, UTIs were less frequent in cases (OR = 0.60 [95% CI 0.44-0.72]). Cases had a greater mean number of days between positive urine cultures as compared to controls (<0.0001). Cases were more likely to have isolates resistant to nitrofurantoin (P <= 0.0001); however, the frequency of multi-drug resistant organisms isolated from the urine was not significantly different. CONCLUSIONS: Long-term prescription of nitrofurantoin may reduce UTIs in veterans with SCI and there is no evidence that it promotes multi-drug resistance. Future prospective studies should be conducted prior to incorporating routine use of long-term nitrofurantoin into clinical care. PMID- 29985784 TI - Integrating site-specific dispersion modeling into life cycle assessment, with a focus on inhalation risks in chemical production. AB - It has become increasingly important for environmental managers to evaluate the human health (HH) impact of chemicals in their supply chain. Current life cycle assessment (LCA) methods are limited because they often only address the HH impact at large geographical scales. This paper aims to develop a method that derives a regionalized life cycle inventory data set and site-specific air dispersion modeling to evaluate the HH impact of chemicals along the life cycle phases at finer geographical scales to improve decision-making, with focus on inhalation pathway. More specifically, cancer risk and noncancer hazard index (HI) are quantified at the county level to identify high-risk regions and at the census tract level to reveal the geographical pattern of health impacts. The results showed that along the cradle-to-gate life cycle stages of a widely used chemical, methylene diphenyl diisocyanate (MDI), the accumulative inhalation risk was 3 orders of magnitude below the U.S. Environmental Protection Agency (EPA) risk management thresholds for both cancer risk (2.16 * 10-9) and noncancer HI (1.53 * 10-3). However, the absolute value of inhalation risks caused by the case study chemicals varied significantly in different geographical areas, up to 4 orders of magnitude. This paper demonstrates a feasible approach to improve human health impact assessment (HHIA) by combining site-specific air dispersion modeling and LCA using publicly available inventory data. This proposed method complements existing life cycle impact assessment (LCIA) models to improve HHIA by employing both HH risk assessment and LCA techniques. One potential outcome is to prioritize pollution prevention and risk reduction measures based on the risk maps derived from this method. Implications: It has become increasingly important for environmental managers to evaluate the human health impacts of chemicals in their supply chain. Regionalized life cycle inventory data sets should be developed using publically available databases such as EPA's toxic release inventory. The combination of site-specific dispersion modeling and life cycle assessment modeling can improve human health impact assessment of chemicals by providing more regionalized results along their supply chain. PMID- 29985785 TI - Evaluating the use of a field-based silica monitoring approach with dust from copper mines. AB - Monitoring worker exposure to respirable crystalline silica in dusty environments is an important part of a proactive health and safety program. This is the case for surface copper mines in Arizona and New Mexico. The spatial and temporal variability of respirable dust and crystalline silica concentrations in those mines, coupled with the time lapse in obtaining crystalline silica analysis results from accredited laboratories, present a challenge for an effective exposure monitoring approach and the resulting intervention strategies. The National Institute for Occupational Safety and Health (NIOSH) is developing a novel approach to be used at a mine site for the quantification of crystalline silica in respirable dust samples collected with traditional sampling techniques. The non-destructive analysis is carried out using a portable Fourier transform infrared spectroscopy (FTIR) unit. In this study, respirable dust samples were collected over two visits to each of five copper mines, for a total of 10 datasets. The silica in each respirable dust sample was estimated by analyzing the sample with the portable FTIR unit. The quality of the estimation was assessed using the results of the NIOSH 7500 method on the same samples. The confounding effect of other minerals present in the respirable dust in the mines was also assessed, and two quantification approaches were investigated to address it: a sector-specific and a mine-specific approach. The results showed that the sector-specific approach is not effective due to the high variability of relative composition of the minerals among mines. For this approach the combined average relative difference was -13% (-17.6%, -8.9% CI). When using the mine-specific quantification approach, the average relative difference was as low as 2.8% ( 3.7%, 9.3% CI); however, this approach was still affected by the variable relative composition of the minerals in the dust in each mine. The use of a multivariate approach on the analysis of each sample was proposed as the next step to achieve consistent low relative differences. This study demonstrates the potential of using a portable FTIR for estimation of crystalline silica in respirable dust samples for in-field exposure monitoring. PMID- 29985786 TI - A review of dietary and microbial connections to depression, anxiety, and stress. AB - OBJECTIVE: Pre-clinical evidence suggests that the gastrointestinal microbiota contributes to mood and behavior disorders. Among humans, diet quality and patterns, which also impact the gastrointestinal microbiota, have been linked to depression, anxiety, and stress. This review summarizes findings from clinical studies using dietary intervention to improve depression, anxiety, or stress and the role the gastrointestinal microbiota may have in these disorders. METHODS: A literature search was conducted using the keywords microbiome, microbiota, depression, anxiety, stress, diet, dietary pattern, diet quality, fiber, prebiotics, probiotics, and mood. RESULTS: Mood was improved by enhancing diet quality. Fructooligosaccharide and galactooligosaccharide improved anxiety and depression in participants consuming >= 5 g/day. Additionally, bifidobacteria were enriched in subjects consuming >= 5 g/day. Probiotic consumption improved psychological or biological measures of depression, anxiety, or stress in individuals predisposed to a mood disorder. Probiotics suppressed biological markers of stress in healthy individuals in a strain-dependent manner. DISCUSSION: High-quality diets, prebiotics, and probiotics may beneficially affect mood. Habitual diets rich in dietary fiber and omega-3-polyunsaturated fatty acids may be linked to reduced risk of developing symptoms of depression, anxiety, and stress; however, additional studies are necessary. Certain probiotics may enhance mood, but their influence on the gastrointestinal microbiota requires further investigation. PMID- 29985787 TI - Toxicity and occupational exposure assessment for Fischer-Tropsch synthetic paraffinic kerosene. AB - Fischer-Tropsch (FT) Synthetic Paraffinic Kerosene (SPK) jet fuel is a synthetic organic mixture intended to augment petroleum-derived JP-8 jet fuel use by the U.S. armed forces. The FT SPK testing program goal was to develop a comparative toxicity database with petroleum-derived jet fuels that may be used to calculate an occupational exposure limit (OEL). Toxicity investigations included the dermal irritation test (FT vs. JP-8 vs. 50:50 blend), 2 in vitro genotoxicity tests, acute inhalation study, short-term (2-week) inhalation range finder study with measurement of bone marrow micronuclei, 90-day inhalation toxicity, and sensory irritation assay. Dermal irritation was slight to moderate. All genotoxicity studies were negative. An acute inhalation study with F344 rats exposed at 2000 mg/m3 for 4 hr resulted in no abnormal clinical observations. Based on a 2-week range-finder, F344 rats were exposed for 6 hr per day, 5 days per week, for 90 days to an aerosol-vapor mixture of FT SPK jet fuel (0, 200, 700 or 2000 mg/m3). Effects on the nasal cavities were minimal (700 mg/m3) to mild (2000 mg/m3); only high exposure produced multifocal inflammatory cell infiltration in rat lungs (both genders). The RD50 (50% respiratory rate depression) value for the sensory irritation assay, calculated to be 10,939 mg/m3, indicated the FT SPK fuel is less irritating than JP-8. Based upon the proposed use as a 50:50 blend with JP 8, a FT SPK jet fuel OEL is recommended at 200 mg/m3 vapor and 5 mg/m3 aerosol, in concurrence with the current JP-8 OEL. PMID- 29985788 TI - Case of Microcephaly after Congenital Infection with Asian Lineage Zika Virus, Thailand. AB - We sequenced the virus genomes from 3 pregnant women in Thailand with Zika virus diagnoses. All had infections with the Asian lineage. The woman infected at gestational week 9, and not those infected at weeks 20 and 24, had a fetus with microcephaly. Asian lineage Zika viruses can cause microcephaly. PMID- 29985790 TI - Erratum: "Prenatal Organophosphate Pesticide Exposure and Traits Related to Autism Spectrum Disorders in a Population Living in Proximity to Agriculture". AB - [This corrects the article DOI: 10.1289/EHP2580.]. PMID- 29985789 TI - Vertex sliding drives intercalation by radial coupling of adhesion and actomyosin networks during Drosophila germband extension. AB - Oriented cell intercalation is an essential developmental process that shapes tissue morphologies through the directional insertion of cells between their neighbors. Previous research has focused on properties of cell-cell interfaces, while the function of tricellular vertices has remained unaddressed. Here, we identify a highly novel mechanism in which vertices demonstrate independent sliding behaviors along cell peripheries to produce the topological deformations responsible for intercalation. Through systematic analysis, we find that the motion of vertices connected by contracting interfaces is not physically coupled, but instead possess strong radial coupling. E-cadherin and Myosin II exist in previously unstudied populations at cell vertices and undergo oscillatory cycles of accumulation and dispersion that are coordinated with changes in cell area. Additionally, peak enrichment of vertex E-cadherin/Myosin II coincides with interface length stabilization. Our results suggest a model in which asymmetric radial force balance directs the progressive, ratcheted motion of individual vertices to drive intercalation. PMID- 29985791 TI - Vonoprazan versus proton-pump inhibitors for gastric endoscopic submucosal dissection-induced ulcers: a systematic review and meta-analysis. AB - Acid secretion inhibitors are usually prescribed to promote the healing of artificial ulcers caused by endoscopic submucosal dissection (ESD) to reduce the risk of gastric perforation and delayed bleeding. Vonoprazan is a newer agent that has been shown to be more potent than a proton-pump inhibitor (PPI). However, it remains unclear whether vonoprazan is more effective than PPI in promoting healing of ulcers caused by ESD. Medline and Embase databases were searched through January 2018 for studies that compared the rate of complete healing of ulcers caused by ESD and post-ESD delayed bleeding in patients who received vonoprazan versus those who received PPI after ESD. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random-effect model, generic inverse variance method. The between-study heterogeneity was quantified using the Q-statistic and I. A total of six studies consisting of 461 patients were identified. The likelihood that ulcers caused by ESD were completely healed at 4-8 weeks after the procedure was significantly higher among patients who received vonoprazan compared with those who received PPI, with a pooled OR of 2.27 (95% CI=1.38-3.73; I=0%). The risk of developing post-ESD delayed bleeding was also numerically lower among those who received vonoprazan, with a pooled OR of 0.79, although the result did not reach statistical significance (95% CI=0.18-3.49; I=29%). This study found that patients who received vonoprazan after ESD had a significantly higher rate of completely healed ulcers compared with those who received PPI. PMID- 29985792 TI - Quantitative Apparent Diffusion Coefficient Derived From Diffusion-Weighted Imaging Has the Potential to Avoid Unnecessary MRI-Guided Biopsies of mpMRI Detected PI-RADS 4 and 5 Lesions. AB - OBJECTIVE: The aim of this study was to evaluate the potential of diffusion weighted imaging-derived apparent diffusion coefficient (ADC) measurements to obviate unnecessary biopsies in multiparametric MRI-detected PI-RADS 4 and 5 lesions. MATERIALS AND METHODS: This retrospective, institutional review board approved study investigated 101 PI-RADS 4 and 5 prostate lesions (52 malignant, 49 benign) verified by in-bore MRI-guided biopsy in 101 men (mean age, 62.8 years). Two readers, who were not aware of the biopsy results independently and repeatedly measured minimum, mean, and maximum ADC from diffusion-weighted imaging measurements (in line with PI-RADS v2 recommendations) using a 2 dimensional region of interest drawn around the biopsied lesions. Diagnostic performance was evaluated using receiver operating characteristic statistics and reproducibility statistics were calculated. RESULTS: The best diagnostic performance (overall area under the receiver operating characteristic curve [AUC] R1: 0.801; R2: 0.796 peripheral zone AUC R1:0.814, R2: 0.805; transitional zone AUC R1:0.786, R2:0.779) and the tightest limits of interreader agreement (-8.6% to 9.9%) were found in minimum ADC values. Rule-in and rule-out thresholds for diagnosis of prostate cancer were identified, demonstrating a potential to avoid unnecessary biopsies in 32.7% (16/49). CONCLUSIONS: Quantitative ADC measurement in multiparametric MRI-detected PI-RADS 4 and 5 lesions has the potential to avoid unnecessary MRI-guided biopsies in up to 33%. PMID- 29985793 TI - Lisinopril-Induced Acute Pancreatitis. PMID- 29985794 TI - High-Resolution Anterior Segment Optical Coherence Tomography in Intraepithelial Versus Invasive Ocular Surface Squamous Neoplasia. AB - PURPOSE: To evaluate the imaging characteristics of intraepithelial and invasive ocular surface squamous neoplasia (OSSN) on high-resolution anterior segment optical coherence tomography (ASOCT). METHODS: In this prospective cross sectional study, 17 consecutive patients (10 intraepithelial and 7 invasive) with histopathologically proven OSSN were included. All patients underwent slit-lamp imaging and time-domain ASOCT at premarked sites. Management included standard complete surgical excision with margin clearance and cryotherapy for all cases. The correlation between imaging characteristics and histopathology sections at the premarked sites was analyzed to determine surrogate markers that may help differentiate intraepithelial from invasive OSSN. In addition, 3 patients with presumed OSSN underwent serial ASOCT for surveillance. RESULTS: All tumors were staged as T3N0M0 except 2 that were staged as T1N0M0 by the eighth edition of the American Joint Committee on Cancer (AJCC). Mean age was comparable between the 2 groups (56 years vs. 54 years for intraepithelial and invasive groups, respectively, P = 0.79). ASOCT characteristics included all cases (100%) showing a hyperreflective thickened epithelium and abrupt transition between normal and abnormal epithelium. Nine of 10 (90%) intraepithelial OSSN showed a clear plane of separation. A hyperreflective basal membrane was seen in 60% of intraepithelial OSSN, and hyporeflective zones were seen in 57% of invasive OSSN. Mean thickness was 924 and 1662 um in intraepithelial and invasive OSSN, respectively (P = 0.02, Mann-Whitney test). CONCLUSIONS: A visible clear plane of separation and increased thickness on ASOCT may serve as surrogate markers of intraepithelial OSSN and help differentiate it from invasive OSSN. PMID- 29985795 TI - Survival Analysis of Corneal Densitometry After Collagen Cross-Linking for Progressive Keratoconus. AB - PURPOSE: To evaluate the history of densitometric data in patients with keratoconus undergoing corneal cross-linking. METHODS: Twenty-two eyes of 22 patients with keratoconus were included. Corneal tomography and densitometry measurements were performed before and after accelerated corneal cross-linking. The duration of corneal haze was defined as the time between cross-linking and densitometry measurements returning to the preoperative value. Survival analysis of corneal haze after cross-linking was performed. Preoperative and postoperative corneal densitometry, maximum keratometry (Kmax), and central corneal thickness were compared. RESULTS: The duration of corneal haze was 18.2 +/- 3.8 months at the first zone of 0 to 2 mm and 10.9 +/- 2.5 months at the second zone of 2 to 6 mm. There was no change in Kmax between the preoperative period and the time at which corneal haze resolved (P = 0.394 at the first zone; P = 0.658 at the second zone). Compared with the measurement taken at resolution of corneal haze, Kmax at 1 year after haze resolution was lower (62.0 +/- 9.9 D to 61.2 +/- 9.9 D, P = 0.008 at the first zone; 63.6 +/- 10.9 D to 62.5 +/- 10.1 D, P = 0.016 at the second zone). There was a decrease of central corneal thickness between the preoperative period and the time at which corneal haze resolved (470.8 +/- 34.1 MUm to 464.8 +/- 34.5 MUm, P = 0.047 at the first zone; 465.0 +/- 35.3 MUm to 454.7 +/- 37.2 MUm, P = 0.001 at the second zone), but it remained unchanged after haze resolution (P = 0.146 at the first zone; P = 0.067 at the second zone). CONCLUSIONS: Corneal cross-linking halted keratoconus progression when detectable haze was present. There was continuous corneal flattening measured at 1 year after haze resolution. Thinning of the cornea was seen only when haze was detectable after cross-linking. PMID- 29985796 TI - Comparative Image Atlas of Current and New Technologies in Corneal Donor Tissue Evaluation: Erratum. PMID- 29985797 TI - Topical Tacrolimus as Adjuvant Therapy to Corticosteroids in Acute Endothelial Graft Rejection After Penetrating Keratoplasty: A Randomized Controlled Trial: Erratum. PMID- 29985798 TI - Transcatheter leadless pacemaker implantation in a patient with failing transvenous pacemaker and total occlusion of superior vena cava. PMID- 29985800 TI - The Visual Snow Conference: May 5, 2018, University of California San Francisco. PMID- 29985799 TI - Metabolic Concepts in Idiopathic Intracranial Hypertension and Their Potential for Therapeutic Intervention. AB - BACKGROUND: Traditional risk factors associated with idiopathic intracranial hypertension (IIH) include obesity, weight gain, and female sex. The incidence of IIH is increasing and yet the underlying trigger and the fueling pathological mechanisms are still poorly understood. EVIDENCE ACQUISITION: Review of ophthalmology, neurology, general surgery, obesity, endocrinology, nutrition, and neurosurgery literature was made. RESULTS: The facts that implicate sex and obesity in IIH and headache are examined. The role of fat distribution in IIH is questioned, and the concept of adipose tissue functioning as an endocrine organ driving IIH is discussed. The impact of androgen metabolism in IIH is reviewed as is the emerging role of glucagon-like-peptide-1 analogues in modulating intracranial pressure. This introduces the concept of developing targeted disease modifying therapeutic strategies for IIH. CONCLUSIONS: This review will discuss the possible role of the adipose/gut/brain metabolism axis in IIH and speculate how this may impact the pathogenesis of IIH and therapeutic opportunities. PMID- 29985801 TI - Population-based Risk Factors for the Development of Degenerative Disk Disease. AB - STUDY DESIGN: This is a retrospective case control study. OBJECTIVE: Identify risk factors and assess their relative impact on the development of degenerative disk disease (DDD). SUMMARY OF BACKGROUND DATA: DDD is responsible for widespread disability in the civilian and military population. Despite the impact of low back pain and DDD, its multifactorial etiology is not entirely understood. MATERIALS AND METHODS: The Defense Medical Surveillance System was searched for military members with the diagnosis of DDD as identified with the use of International Classification of Disease, 9th Revision (ICD-9) codes. These patients were compared with an age-matched and sex-matched control of military members without DDD from the Defense Medical Surveillance System. The prevalence of risk factors (obesity, hip, and knee osteoarthritis, tobacco dependence, diabetes, and type of employment) was then determined for both groups. In total, 160,911 patients with DDD were identified compared with 315,225 controls. Multivariate conditional logistical regression analysis was utilized to determine odds ratio (OR) for these groups based on data matched by age and sex and were adjusted for military rank and race/ethnicity. RESULTS: Diabetes showed an OR of 1.469 [confidence interval (CI), 1.350-1.598]. Hip and knee arthritis produced an OR of 2.925 (CI, 2.685-3.187) and tobacco dependency showed an OR of 1.799 (CI, 1.762-1.836). The comparison of overweight to normal body mass index produced an OR of 1.334 (CI, 1.307-1.361) and the analysis of obese to normal body mass index had an OR of 1.556 (CI, 1.497-1.618). There failed to be a clinically significant association between military duty assignments and the presence of DDD. CONCLUSIONS: Our research failed to show a clinical significance association between military duty assignment and DDD. However, we were able to identify a significant association between concomitant hip and knee osteoarthritis, obesity, diabetes, and tobacco dependency with the development of DDD. LEVEL OF EVIDENCE: Level IV. PMID- 29985802 TI - Pseudoparalysis of the Right Arm in a 6-Week- Old Infant. AB - Neonatal pyogenic liver abscess is rare and potentially lethal. We present a six week-old infant with pseudoparalysis of the right arm. PMID- 29985803 TI - Impact of Protease Inhibitors on HIV-Associated Kaposi Sarcoma Incidence: A Systematic Review. AB - BACKGROUND: Protease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type. METHODS: We searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence. RESULTS: We identified 3 unique retrospective cohort studies, and supplemented one of the studies with results from 6 previous subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4 adjusted KS incidence decreased by ~50%, with either non-nucleoside reverse transcriptase inhibitor- or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only. CONCLUSIONS: The risk of incident KS was significantly reduced, regardless of ART class even after adjusting for CD4 count. The quality of evidence (ie, most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data are indicated. PMID- 29985804 TI - Smoking and Accelerated Lung Function Decline in HIV-Positive Individuals: A Secondary Analysis of the START Pulmonary Substudy. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability globally. Both cigarette smoking and HIV have been identified as independent risk factors for COPD. We used data from the strategic timing of antiretroviral treatment (START) Pulmonary Substudy to quantify the impact of smoking on rate of lung function decline in HIV. METHODS: We included START Pulmonary Substudy participants who contributed at least 2 good quality spirometry measures during the study. Slope of forced expiratory volume in 1 second (FEV1) was estimated using a repeated-measures model adjusted for the treatment group (immediate vs deferred treatment arm of START), age, sex, race, baseline COPD, and region. RESULTS: Of 1026 START Pulmonary Substudy participants, 915 (89%) were included in this analysis. Median follow-up time was 3.9 years. Smokers and nonsmokers were similar in baseline age (median 36 years), but smokers were more likely to be white, male, and from Europe/Israel/Australia. Smokers had faster average FEV1 decline compared with nonsmokers [-38.3 mL/yr vs 25.1 mL/yr; difference of -13.2 mL/yr (95% confidence interval: -23.6 to -2.7); P = 0.013], were more likely to meet criteria for rapid FEV1 decline [7.2%-11.7% more likely (P = 0.09-P = 0.002), depending on the definition of rapid decline], and had borderline, but not statistically significant, higher incident COPD during follow-up (9.7% vs 5.8%, P = 0.06). CONCLUSIONS: Compared to nonsmokers, HIV-positive smokers experience faster decline in lung function. These results underscore the need for a better understanding of how to best support smoking cessation among HIV-positive populations. PMID- 29985805 TI - Electrocochleographic Responses Before and After Short-Term Suprathreshold Electrical Stimulation in Human Cochlear Implant Recipients. AB - OBJECTIVE: To assess changes in electrocochleographic (ECoG) responses following short-term suprathreshold electrical stimulation during cochlear implant (CI) telemetry in CI recipients. METHODS: Extracochlear ECoG recordings were conducted before and after intraoperative short-term suprathreshold electrical stimulation. Tone bursts at 500, 750, and 1000 Hz as well as clicks were used as acoustic stimuli. Changes of ECoG responses were correlated to calculated maximum electrical charge levels. RESULTS: Fourteen subjects were included. On average, no significant changes of ECoG responses occurred in the earliest postoperative phase; therefore, also following short-term suprathreshold electrical stimulation. However, one subject (S7) showed a decrease of ECoG responses. Neural as well as hair cell components of the ECoG signal were affected. On average, the maximum electrical charge level was 22 nC (range, 15-37 nC). In S7, the maximum electrical charge level was 17 nC. No correlations were found between maximum electrical charge levels and changes of ECoG signals. CONCLUSION: In a majority of cases, electrophysiological responses to acoustic stimuli remain unchanged in the earliest postoperative phase. However, deterioration of cochlear function occurs in this phase. Neural as well as hair cell components of the ECoG signal are affected. Such deterioration is not associated with unusually high electrical charge levels during CI telemetry. Overall, our results support the notion that an electrical charge applied at levels used in the clinical routine does not have an acute deleterious effect on cochlear function. PMID- 29985806 TI - An Academic-Practice Partnership: Fostering Collaboration and Improving Care Across Settings. AB - BACKGROUND: Through the Veterans Affairs Nursing Academic Partnership (VANAP), baccalaureate nursing students and faculty participated in practice innovations in a Veterans Affairs Health Care System. Nationally, VANAP has attempted to bridge gaps between theory and practice and across care settings. APPROACH: In a population health course, nursing students were placed in both inpatient and outpatient settings. Through activities such as postconferences and population based projects, students joined forces with Veterans Affairs staff on issues that affected veterans' health care. OUTCOMES: Two student groups worked on amputation prevention from opposite ends of the spectrum. Their projects, with the continuation of these by faculty and staff, resulted in 47% decrease in vascular related hospital readmissions. CONCLUSIONS: Student placements in settings across the care continuum improved communication between the settings. The enhanced partnership between the 2 organizations addressed a relevant, meaningful patient care issue. PMID- 29985807 TI - Methodologic Innovation in Creating Clinical Practice Guidelines: Insights From the 2018 Society of Critical Care Medicine Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption Guideline Effort. AB - OBJECTIVES: To describe novel guideline development strategies created and implemented as part of the Society of Critical Care Medicine's 2018 clinical practice guidelines for pain, agitation (sedation), delirium, immobility (rehabilitation/mobility), and sleep (disruption) in critically ill adults. DESIGN: We involved critical illness survivors from start to finish, used and expanded upon Grading of Recommendations, Assessment, Development and Evaluation methodology for making recommendations, identified evidence gaps, and developed communication strategies to mitigate challenges. SETTING/SUBJECTS: Thirty-two experts from five countries, across five topic-specific sections; four methodologists, two medical librarians, four critical illness survivors, and two Society of Critical Care Medicine support staff. INTERVENTIONS: Unique approaches included the following: 1) critical illness survivor involvement to help ensure patient-centered questions and recommendations; 2) qualitative and semiquantitative approaches for developing descriptive statements; 3) operationalizing a three-step approach to generating final recommendations; and 4) systematic identification of evidence gaps. MEASUREMENTS AND MAIN RESULTS: Critical illness survivors contributed to prioritizing topics, questions, and outcomes, evidence interpretation, recommendation formulation, and article review to ensure that their values and preferences were considered in the guidelines. Qualitative and semiquantitative approaches supported formulating descriptive statements using comprehensive literature reviews, summaries, and large-group discussion. Experts (including the methodologists and guideline chairs) developed and refined guideline recommendations through monthly topic-specific section conference calls. Recommendations were precirculated to all members, presented to, and vetted by, most members at a live meeting. Final electronic voting provided links to all forest plots, evidence summaries, and "evidence to decision" frameworks. Written comments during voting captured dissenting views and were integrated into evidence to decision frameworks and the guideline article. Evidence gaps, reflecting clinical uncertainty in the literature, were identified during the evidence to decision process, live meeting, and voting and formally incorporated into all written recommendation rationales. Frequent scheduled "check-ins" mitigated communication gaps. CONCLUSIONS: Our multifaceted, interdisciplinary approach and novel methodologic strategies can help inform the development of future critical care clinical practice guidelines. PMID- 29985809 TI - World Gastroenterology Organisation (WGO) News and Events. PMID- 29985808 TI - Low Interleukin-7 Receptor Messenger RNA Expression Is Independently Associated With Day 28 Mortality in Septic Shock Patients. AB - OBJECTIVES: Septic shock is the primary cause of death in ICUs. A better comprehension of its pathophysiology, in particular, the immune alteration mechanisms, opened new therapeutic perspectives such as the recombinant interleukin-7. The use of biomarkers could improve the identification of eligible patients for this therapy. The soluble form of the interleukin-7 appears as a promising candidate in this regard since an association between its high plasmatic level and mortality in critically ill patients has been demonstrated. Because there are no data available on the transcriptional regulation of the interleukin-7 receptor in such patients, this study aimed to explore the expression level of different interleukin-7 receptor transcripts after septic shock and evaluate their association with mortality. DESIGN: Retrospective discovery cohort (30 patients) and validation cohort (177 patients). SETTING: Two French ICUs (discovery study) and six French ICUs (validation study). PATIENTS: Adult septic shock patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The quantification of several interleukin-7 receptor transcripts using specific reverse transcription quantitative polymerase chain reaction designs allowed for global evaluation of interleukin-7 receptor gene expression in whole blood. In the discovery cohort, all interleukin-7 receptor transcripts studied were expressed at lower levels in septic shock patients than in healthy volunteers. Interleukin-7 receptor gene expression at day 3 after septic shock diagnosis was associated with day 28 mortality. Patients at a lower risk of death showed higher expression levels. These results were confirmed in the independent validation cohort. Interestingly, using a threshold obtained on the discovery cohort, we observed in the validation cohort a high negative predictive value for day 28 mortality for the transcript encoding the membrane form of interleukin-7 receptor (0.86; 95% CI, 0.79-0.93). CONCLUSIONS: Interleukin-7 receptor transcripts appear as biomarkers of impaired adaptive immune response in septic shock patients and as a promising tool for patient stratification in clinical trials evaluating immunoadjuvant therapies. PMID- 29985810 TI - Ability of a New Smartphone Pulse Pressure Variation and Cardiac Output Application to Predict Fluid Responsiveness in Patients Undergoing Cardiac Surgery. AB - BACKGROUND: Pulse pressure variation (PPV) can be used to predict fluid responsiveness in anesthetized patients receiving controlled mechanical ventilation but usually requires dedicated advanced monitoring. Capstesia (Galenic App, Vitoria-Gasteiz, Spain) is a novel smartphone application that calculates PPV and cardiac output (CO) from a picture of the invasive arterial pressure waveform obtained from any monitor screen. The primary objective was to compare the ability of PPV obtained using the Capstesia (PPVCAP) and PPV obtained using a pulse contour analysis monitor (PPVPC) to predict fluid responsiveness. A secondary objective was to assess the agreement and the trending of CO values obtained with the Capstesia (COCAP) against those obtained with the transpulmonary bolus thermodilution method (COTD). METHODS: We studied 57 mechanically ventilated patients (tidal volume 8 mL/kg, positive end-expiratory pressure 5 mm Hg, respiratory rate adjusted to keep end tidal carbon dioxide [32 36] mm Hg) undergoing elective coronary artery bypass grafting. COTD, COCAP, PPVCAP, and PPVPC were measured before and after infusion of 5 mL/kg of a colloid solution. Fluid responsiveness was defined as an increase in COTD of >10% from baseline. The ability of PPVCAP and PPVPC to predict fluid responsiveness was analyzed using the area under the receiver-operating characteristic curve (AUROC), the agreement between COCAP and COTD using a Bland-Altman analysis and the trending ability of COCAP compared to COTD after volume expansion using a 4 quadrant plot analysis. RESULTS: Twenty-eight patients were studied before surgical incision and 29 after sternal closure. There was no significant difference in the ability of PPVCAP and PPVPC to predict fluid responsiveness (AUROC 0.74 [95% CI, 0.60-0.84] vs 0.68 [0.54-0.80]; P = .30). A PPVCAP >8.6% predicted fluid responsiveness with a sensitivity of 73% (95% CI, 0.54-0.92) and a specificity of 74% (95% CI, 0.55-0.90), whereas a PPVPC >9.5% predicted fluid responsiveness with a sensitivity of 62% (95% CI, 0.42-0.88) and a specificity of 74% (95% CI, 0.48-0.90). When measured before surgery, PPV predicted fluid responsiveness (AUROC PPVCAP= 0.818 [P = .0001]; PPVPC= 0.794 [P = .0007]) but not when measured after surgery (AUROC PPVCAP= 0.645 [P = .19]; PPVPC= 0.552 [P = .63]). A Bland-Altman analysis of COCAP and COTD showed a mean bias of 0.3 L/min (limits of agreement: -2.8 to 3.3 L/min) and a percentage error of 60%. The concordance rate, corresponding to the proportion of CO values that changed in the same direction with the 2 methods, was poor (71%, 95% CI, 66-77). CONCLUSIONS: In patients undergoing cardiac surgery, PPVCAP and PPVPC both weakly predict fluid responsiveness. However, COCAP is not a good substitute for COTD and cannot be used to assess fluid responsiveness. PMID- 29985811 TI - Comparison of GlideScope Video Laryngoscopy and Direct Laryngoscopy for Tracheal Intubation in Neonates. AB - BACKGROUND: GlideScope video laryngoscope (GS) has been widely used to facilitate tracheal intubation in adults and pediatric patients because it can improve glottic view. Several investigations performed in pediatric patients have shown that GS provides a better view of the glottis than direct laryngoscope (DL). However, to date, there are no studies assessing the use of GS in neonates. Therefore, we conducted a prospective study to compare time to intubate (TTI) when either GS or DL was used for endotracheal intubation in neonates. METHODS: Seventy neonates (American Society of Anesthesiologists physical status I and II, scheduled to undergo elective surgery under general anesthesia) were randomized to GS group (n = 35) and DL group (n = 35). The primary outcome variable of the study was TTI. As secondary outcomes, success rate of first intubation attempt of all neonates, intubation attempts, and adverse events were also evaluated. The glottic views (depicted by Cormack and Lehane [C&L] grades) obtained with GS and DL were compared. RESULTS: There were no significant differences in TTIs of neonates with all C&L grades (95% CI, -7.36 to 4.44). There was also no difference in the subgroups of neonates with C&L grades I and II (n = 30 each; 95% CI, -0.51 to 5.04). However, GS significantly shortened the TTIs of neonates with C&L grades III and IV compared to DL (n = 5 each group; 95% CI, 4.94-46.67). GS improved the glottic view as compared to DL. Although the total tracheal intubation attempts in the GS group was fewer than that in the DL group (36 vs 41), there was no significant difference (P = .19). CONCLUSIONS: GS use did not decrease the TTI of all neonates and neonates with C&L grades I and II as compared to DL use; however, GS significantly decreased the TTI of neonates with C&L grades III and IV. Additionally, GS use provided improved glottic views. PMID- 29985812 TI - Response to: "Follow-up of the STOMAMESH Cohort". PMID- 29985813 TI - Response to: "Sweet Versus Ivor-Lewis: Is It Time To Draw a Conclusion?" PMID- 29985814 TI - In the Next Issue. PMID- 29985815 TI - Applying Machine-Learning Techniques to Build Self-reported Depression Prediction Models. PMID- 29985817 TI - Erratum to: Usage and Usability of a Web-based Program for Family Caregivers of Older People in Three European Countries: A Mixed-Methods Evaluation. PMID- 29985816 TI - ANI Steering Committee Welcomes New Members. PMID- 29985818 TI - Impact of Adoption of a Comprehensive Electronic Health Record on Nursing Work and Caring Efficacy. PMID- 29985819 TI - Association of Admission Functional Status and Assistive Device Provision for Veterans Poststroke: A Retrospective Study. AB - OBJECTIVES: The aims of the study were (a) to provide knowledge about the provision of assistive devices in practice and (b) to describe the challenges of standardizing device provision. DESIGN: This is a retrospective study using Department of Veteran Affairs National Prosthetic Patient Database and other administrative databases. The cohort included all veterans treated by the Veterans Health Administration for stroke during fiscal years 2007-2008. Descriptive methods were used to analyze data with emphasis on inspecting relationships between device provision and motor and cognitive function using Functional Independence Measure scores. RESULTS: A total of 8374 veterans treated for stroke and receiving at least one assistive device are included. Individuals who received standard or caregiver controlled wheelchairs tended to be older, and those who received ultralight or caregiver controlled wheelchairs had a higher proportion of Hispanics than the overall cohort. Veterans who received any type of wheelchair had lower motor, cognitive, and total functioning scores than the cohort as a whole. Veterans who received canes had the highest functioning. Veteran patients who received patient lifts and beds had lower cognitive scores compared with the overall cohort. CONCLUSIONS: Functional status can provide some objectivity to the largely subjective assistive device provision decision-making process; however, many other factors must be considered simultaneously, complicating efforts to standardize provision. PMID- 29985820 TI - Effectiveness of a Tailored Lifestyle Management Program for Middle-Aged Women With Coronary Artery Disease: A Preliminary Study. AB - BACKGROUND: Coronary artery disease (CAD) is a leading cause of death in women. Many of the risk factors for CAD relate to lifestyle and thus may be influenced by lifestyle modification. However, middle-aged women often find it difficult to adjust their lifestyle behaviors. Thus, providing individualized treatment is crucial to reducing the risk and incidence of CAD in this population. PURPOSE: The aim of this study was to explore the effectiveness of a tailored lifestyle management program (TLMP) for middle-aged women with CAD. METHODS: An experimental design was employed. Thirty-five middle-aged women with CAD (with stenosis [> 50%] of at least one main artery as determined by cardiac catheterization examination results) were recruited. The 35 women were randomly assigned to the experimental group (n = 17) or the control group (n = 18). Both groups received regular health education during their hospitalization. After discharge, the experimental group received the 12-week, home-based TLMP. A generalized estimating equation was used to examine the effects of the TLMP on metabolic and biomarker indicators for CAD. RESULTS: The average age of participants was 56.1 +/- 5.6 years. No significant demographic differences were identified between the two groups. Compared with the control group, the experimental group had a significantly higher high-density lipoprotein level (B = 7.83, p < .001), a lower level of total cholesterol (B = -49.21, p = .04), and a lower waist circumference (B = -6.42, p < .001). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study suggests that using tailored interventions is an effective approach to improving high-density lipoprotein, total cholesterol, and waist circumference in middle-aged women with CAD. This result is expected to have important implications for women's healthcare, particularly in terms of preventing the incidence of CAD. PMID- 29985821 TI - The Cognitive Impact of Chronic Diseases on Functional Capacity in Community Dwelling Adults. AB - BACKGROUND: People with chronic diseases may experience poor cognitive functioning associated with advanced age, progression of disease, or other comorbid chronic conditions. Empirical evidence of this phenomenon is limited despite the clinical relevance of cognitive decline and associated adverse outcomes such as poor physical functioning. PURPOSE: The purpose of this study was to examine cognitive functioning in the domains of memory, attention, and executive function and its association with functional capacity in a sample of community-dwelling adults with a spectrum of chronic diseases. METHODS: An exploratory cross-sectional study was conducted in a sample of community-dwelling adults with chronic diseases, including hypertension (58.9%), diabetes mellitus (DM; 20.0%), and dyslipidemia (14.4%). Participants' mean age was 64.1 +/- 11.2 years, and 48.9% were male. Ninety persons completed the face-to-face interviews, which evaluated cognitive functioning in the domains of memory, attention, and executive function using neuropsychological tests and the physical well-being test, which measured functional capacity using the Duke Activity Status Index. RESULTS: Compared with those with other chronic diseases, our sample with hypertension and DM had significantly more memory loss and poorer executive function. These significant differences were nullified when adjusting for age, gender, and education. Approximately one third had functional limitations (n = 29, 32.2%), using a cutoff point of 35 or less (Duke Activity Status Index). Memory loss (delayed recall, b = 1.5, p = .016) and poor executive function (Trail Making Test Part A, b = -0.2, p < .001) were predicting factors of functional decline, independent of age, gender, education, and comorbidity. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Cognitive function, particularly memory and executive function, was poorer among chronically ill Korean adults in the community with hypertension or DM than their counterparts. Functional decline was worse in the presence of memory loss and poor executive function. Studies examining the mechanism by which overall functioning is impacted by cognitive decline and its relevance to functional declines in a larger representative sample are warranted. PMID- 29985822 TI - Psychometric Properties of an Arabic Version of the Patient Satisfaction With Nursing Care Quality Questionnaire. AB - BACKGROUND: Quality measurements are crucial to healthcare quality improvement, and patient satisfaction with nursing care is widely adopted as a key outcome indicator of the overall quality of healthcare. There is a lack of instruments to measure patient satisfaction with nursing care in an Arabic context. PURPOSE: The purpose of this study was to develop and validate an Arabic version of the Patient Satisfaction with Nursing Care Quality Questionnaire and to explore patient satisfaction with nursing care across hospital units. METHODS: This was a cross-sectional, methodological research study. A forward-backward translation process and face and content validation using a panel of experts and a pilot test were used to produce an Arabic version of the Patient Satisfaction with Nursing Care Quality Questionnaire. A convenience sampling technique was employed to recruit 292 adult patients who were hospitalized for more than 48 hours. Data were collected over the first quarter of 2016 using a secure electronic survey method. RESULTS: The item-level content validity index ranged from .83 to 1, and the scale-level content validity index was .94. Evidence of construct validity was obtained. Exploratory factor analysis revealed a two-factor model that explained 69.3% of the total variance. Confirmatory factor analysis showed that the two-factor model fits the observed data. Internal consistency was satisfactory and similar across different hospital units. Cronbach's alpha estimates for Factors 1 and 2 were .83 and .96, respectively, with an overall Cronbach's alpha estimate of .96. Level of patient satisfaction with nursing care was quite high (mean = 4.30/5, SD = 0.74). CONCLUSIONS: This study provides a 17 item, Likert-scaled, self-reporting instrument, which is psychometrically sound for its content, comprehension, readability, and practicality, to measure patient satisfaction with nursing care quality in an Arabic context. PMID- 29985823 TI - Clozapine-Associated Pulmonary Embolism: A High-Mortality, Dose-Independent and Early-Onset Adverse Effect. AB - BACKGROUND: Recent epidemiological studies have identified an excess of pulmonary embolism (PE) cases in patients treated with antipsychotic drugs. The findings are particularly relevant for patients treated with clozapine, which has many potentially life-threatening adverse drug effects. Among these adverse drug effects are myocarditis and agranulocytosis that have early onset and are dose independent, but also seizures and myocardial repolarization delay, which are dose dependent and may occur at any time. Together with death rates, these variables have important implications for clinical practice. AREAS OF UNCERTAINTY: Study Question: What are the time of onset, dose relationship, and mortality of clozapine-associated PE? DATA SOURCES: The published case reports of clozapine-associated PE were identified in a MEDLINE search. Cases occurring within 6 months of starting clozapine were considered to have early onset. Dosages of clozapine at the time of PE were defined as low (200 mg/d or less) or high (300 mg/d or greater). Patient outcome was divided into survival of the PE event and death. RESULTS: The search identified 23 cases of clozapine-associated PE. The PE had early onset (6.4 +/- 7.0 weeks) in 20 patients (87%, 95% confidence interval 67.9%-95.5%). PE occurred in 9 patients treated with low doses (152.8 +/- 50.7 mg/d) and in 11 patients on high doses (372.7 +/- 127.2 mg/d) of clozapine. Six patients (26.1%, 95% confidence interval 12.6%-46.5%) died. CONCLUSIONS: A systematic review of the published case reports of clozapine associated PE indicates that this adverse effect is highly lethal, has early onset and is dose independent. The findings should prompt careful monitoring and consideration of prophylactic treatment for venous thromboembolism for 6 months after starting treatment with clozapine. PMID- 29985824 TI - The Vulnerable Phase of Heart Failure. PMID- 29985827 TI - Medicinal Plants Usage in Our Days. PMID- 29985828 TI - Effect of Ofloxacin and Norfloxacin on Rifampicin Pharmacokinetics in Man: Erratum. PMID- 29985826 TI - Improving Postdischarge Outcomes in Acute Heart Failure. PMID- 29985825 TI - Optimal Endpoints of Acute Heart Failure Therapy. PMID- 29985829 TI - Electronic Charting During Simulation: A Descriptive Study. AB - Informatics is a core competency for nursing students recognized by several national organizations in healthcare and nursing education. Nurses must be able to use information and technology to communicate and manage knowledge in support of clinical decisions. Many hospitals either limit or deny nursing students' access to the electronic health record during traditional clinical learning. Simulation-based learning experiences are an alternative to traditional clinical experiences. What remains unclear is how nursing programs are incorporating electronic health record platforms within simulation. This study used a descriptive design to survey nursing programs exploring electronic health record use within simulation-based learning experiences in the classroom, skills laboratory, or simulation laboratory settings. Findings of the survey show that 56.2% of participants used an electronic health record in the classroom, skills laboratory, or simulation laboratory for simulation. Electronic health record use is gaining momentum via simulation-based learning experiences and students are not only documenting but also gathering data and appraising patient data for meaningful use to inform patient care decisions and promote clinical readiness. PMID- 29985831 TI - Low-molecular-weight chondroitin sulfate attenuated injury by inhibiting oxidative stress in amyloid beta-treated SH-SY5Y cells. AB - The neurotoxicity of aggregated amyloid beta (Abeta) has been implicated as a critical cause in the pathogenesis of Alzheimer's disease. In a previous work, we have shown that low-molecular-weight chondroitin sulfate (LMWCS), a derivative of chondroitin sulfate, protected the SH-SY5Y neuroblastoma cells from Abeta25-35 induced neurotoxicity, decreased intracellular reactive oxygen species level and inhibited the cell apoptosis. However, the underlying mechanism of the antioxidative effect of LMWCS in the SH-SY5Y cells has not been well explored. In the present study, the SH-SY5Y cells were cultured and exposed to 30 MUM Abeta25 35 in the absence or presence of LMWCS (50, 100 and 200 MUg/ml). Results indicate that incubation of cells with LMWCS before Abeta25-35 exposure increased superoxide dismutase, glutathione peroxidase and Na/K-ATPase activities and decreased the malondialdehyde content. In addition, LMWCS inhibited the imbalance of Bcl-2 and Bax and decreased caspase-3 and caspase-9 expressions. LMWCS antagonizes Abeta25-35-induced neurotoxicity by attenuating oxidative stress, and our results suggest that LMWCS might be used as a potential compound for Alzheimer's disease prevention. PMID- 29985830 TI - Physical Activity, Cardiorespiratory Fitness, and Incident Glaucoma. AB - PURPOSE: This study aimed to examine the associations of physical activity and cardiorespiratory fitness (hereafter fitness) with incident glaucoma in a prospective observational study. METHODS: Physical activity was measured by self reported leisure-time activities, and fitness was measured by maximal treadmill test. Incident glaucoma was defined based on physician diagnosis. Participants were 9519 men and women between the ages of 40 and 81 yr old (mean age 50 yr) who were enrolled in the Aerobics Center Longitudinal Study. Hazard ratios (HR) were estimated using Cox proportional hazard regression after adjusting for age, sex, race, examination year, smoking status, heavy alcohol drinking, hypertension, hypercholesterolemia, abnormal ECG, diabetes, cardiovascular disease, and cancer. RESULTS: A total of 128 cases of incident glaucoma were reported during a mean follow-up of 5.7 yr. A significantly lower risk of incident glaucoma (HR = 0.53, 95% confidence interval [95% CI] = 0.35-0.79) was found in individuals who met the physical activity guidelines of >=500 MET.min.wk compared with inactive individuals (0 MET.min.wk). Compared with low fitness (lower third), individuals with high fitness (upper third) also had a significantly lower risk of incident glaucoma (HR = 0.60, 95% CI = 0.38-0.95). A joint analysis of physical activity and fitness showed that meeting physical activity guidelines and being in the high fitness category was associated with the lowest risk for developing glaucoma (HR = 0.49, 95% CI = 0.31-0.79). CONCLUSION: These data provide epidemiological evidence that meeting physical activity guidelines or being fit reduces the risk of developing glaucoma. PMID- 29985832 TI - Validation of scatter limitation correction to eliminate scatter correction error in oxygen-15 gas-inhalation positron emission tomography images. AB - OBJECTIVE: High levels of radioactivity inside a facemask cause scatter correction (SC) errors that appear as photopenic artifacts on quantitative oxygen 15 (O) gas-inhalation positron emission tomography (PET) images. The present study aimed to validate the ability of scatter limitation correction (SLC) to eliminate SC errors in O gas-inhalation PET images acquired from patients and a phantom. MATERIALS AND METHODS: We analyzed the SC errors in phantom images and calculated parametric images of the cerebral blood flow (CBF), cerebral blood volume, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2). Phantoms comprised a cylinder and paper with radioactivity to simulate a facemask during (O)O2 gas inhalation. Parametric images were calculated from O gas-inhalation PET images of ten participants. All PET data were reconstructed using conventional SC as model-based SC and SLC. Images acquired from the phantoms and parametric images were assessed visually and quantitatively in the presence and absence of SC error. RESULTS: SC error was evident in images derived from the paper phantom and at the slice level of the cerebellum in CBF, OEF, and CMRO2 images. The radioactivity concentration in the cylindrical phantom with the paper phantom significantly improved with SLC. The SLC also increased the quantitative indices of CBF, OEF, and CMRO2 by 23.8, 42.2, and 44.4%, respectively. CONCLUSION: SLC visually eliminated the SC error and increased the quantitative parameters on O gas-inhalation images derived from a phantom and from patients. PMID- 29985833 TI - Severe skin toxicity with organ damage under the combination of targeted therapy following immunotherapy in metastatic melanoma. AB - Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade >=3) are described with first-line TTC (17% for vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC. PMID- 29985835 TI - Program Summary of the 4th ITEDS International Symposium, London, 23-25 June, 2016. PMID- 29985834 TI - Fourth International Thyroid Eye Disease Symposium: Introduction. PMID- 29985836 TI - Pediatric Thyroid Eye Disease: Clinical Characteristics and Orbital Decompression Outcomes. AB - PURPOSE: To review the clinical presentation, disease severity, and surgical interventions of children with thyroid eye disease (TED) at a single institution over a 7-year period. METHODS: Retrospective cohort study of children 0 to 18 years of age with a diagnosis of TED, seen at the Children's Hospital of Philadelphia from 2009 to 2016. Ophthalmic examination findings, neuroimaging study results, and ophthalmological management were recorded. t-Tests were used to test for statistical significance. Institutional Review Board approval was obtained for the study. RESULTS: Sixty-seven subjects with pediatric TED were studied: 59 female and 8 male. The mean age at diagnosis was 11.6 years (SD 4.2, range 2.3-17.9). All subjects had proptosis (67, 100%). Other clinical findings were eyelid retraction in 46 (69%), chemosis in 7 (10%), punctate epithelial erosions in 8 (12%), and strabismus in 1 (1.5%). No subjects had evidence of optic neuropathy. Five subjects with static-phase TED received orbital decompression surgery for exposure keratopathy and disfigurement. All had significant cosmetic improvement and resolution of exposure keratopathy. DISCUSSION: In this series, children with TED generally exhibit mild ocular signs, which is in agreement with past studies. Our study presented a high incidence of proptosis compared with other studies; however, this may represent a referral bias to our quaternary care center. CONCLUSION: Pediatric TED patients exhibit mild symptoms, such as proptosis and eyelid retraction without strabismus, vision loss, or optic neuropathy. Some children with TED have severe disfigurement and corneal exposure due to the disease and benefit from orbital decompression. PMID- 29985837 TI - Epoprostenol Therapy for a Pediatric Patient With Subacute Heparin-Induced Thrombocytopenia and a Ventricular Assist Device Undergoing Heart Transplant: A Case Report. AB - Concerns remain regarding the use of direct thrombin inhibitors for cardiopulmonary bypass anticoagulation in pediatric patients with heparin-induced thrombocytopenia undergoing complex cardiac surgery. We describe the safe and effective use of epoprostenol sodium as an alternative therapy before heparin exposure for a pediatric patient with subacute heparin-induced thrombocytopenia and a ventricular assist device undergoing heart transplant. PMID- 29985838 TI - Collaborative Establishment of Difficult Vascular Access for General Anesthetic Management of an Adult With Tetra-Amelia: A Case Report. AB - Tetra-amelia is a rare congenital disorder characterized by the absence of limbs. We describe the anesthetic management of a 29-year-old woman with tetra-amelia who underwent general anesthesia for tympanomastoidectomy with meatoplasty for an extensive right ear cholesteatoma. Anesthetic challenges related to tetra-amelia include difficult intravenous access, lack of sites for blood pressure monitoring, and possible difficult airway management due to craniofacial anomalies. Our case report focuses on the complex establishment of iliac artery access for invasive blood pressure monitoring by initially cannulating the carotid artery. PMID- 29985839 TI - Airway Fire During Left Internal Mammary Dissection in Cardiac Surgery: A Case Report. AB - Previous case reports describing fire during left internal mammary artery dissection involved patients with pulmonary blebs and did not involve the airway. We present a case of an airway fire, diagnosed by the sound of a pop, the appearance of a spark, and the development of an airway circuit leak in a patient with a 4-year-old tracheostomy scar who presented for coronary artery bypass with a left internal mammary artery. The case description is followed by a brief discussion of operating room fires and their management. PMID- 29985840 TI - Ultrasonographic Diagnosis for Dysfunction of the Diaphragm After Iatrogenic Tension Pneumoperitoneum by a Gastrointestinal Endoscopic Procedure: A Case Report. AB - There are various causes of dysfunction of the diaphragm. We present a case of diaphragm dysfunction caused by an excessive pneumoperitoneum in a 65-year-old woman. Her abdomen became distended during endoscopic investigation and circulatory failure occurred. A computed tomography scan revealed excessive pneumoperitoneum. Urgent laparotomy was performed to repair gastric perforation. Tracheal extubation was successfully performed in the intensive care unit. After extubation, a paradoxical breathing pattern appeared in addition to tachypnea. A diagnosis of dysfunction of the bilateral diaphragm was made by ultrasonography. Although nasal high-flow cannula therapy was required for several days, she was discharged from our hospital 2 weeks after surgery without any further complications. We should keep in mind that diaphragm dysfunction after excessive abdominal extension can be a cause of respiratory failure. PMID- 29985842 TI - Exchange Autotransfusion for Rapid Correction of Hyperkalemia During Liver Transplantation: A Case Report. AB - A 46-year-old woman with alcoholic cirrhosis and hepatorenal syndrome requiring hemodialysis presented with hyperkalemia (5.5 mEq/L) immediately before liver transplantation. For correction of hyperkalemia, an exchange transfusion began by removing her blood into an autotransfusion system to wash out noncellular components while maintaining normovolemia. Additionally, she received washed homologous red blood cells, insulin, and glucose to minimize or reduce the degree of hyperkalemia. Serum potassium level decreased to 4.0 mEq/L within 3 hours and was 5.0 mEq/L 30 seconds after reperfusion of the grafted liver. Postreperfusion syndrome was not observed. In summary, exchange transfusion was used successfully for rapid correction of hyperkalemia, showing the value of its application in liver transplantation. PMID- 29985841 TI - Postoperative Airway Obstruction in a Low Resource Setting: A Case Report. AB - A 2-month-old girl with abnormal facial features and malnutrition presented for placement of a gastrostomy tube. The surgery was performed under general anesthesia using a laryngeal mask airway (LMA); however, after removal of the LMA, the patient had recurrent airway collapse, requiring repeated insertion of the LMA. The authors describe the management of this problem with the use of a tongue suture and anterior traction in the postoperative period in a resource limited setting. PMID- 29985843 TI - Cesarean Hysterectomy in a Parturient With Morbidly Adherent Placenta Complicated by Postoperative Ischemic Stroke Secondary to Vertebral Artery Dissection: A Case Report. AB - We report a case of cesarean hysterectomy in a parturient with morbidly adherent placenta that was complicated by an estimated blood loss of 25 L, with the usage of massive transfusion protocols. On the third postoperative day, symptomatology suggestive of a stroke was elicited. Imaging showed a right vertebral artery dissection with cerebellar, midbrain, and pontine infarcts. She showed gradual recovery in the following months with almost complete return to baseline function. We present this case to highlight vertebral artery dissection as a potential complication after peripartum massive blood transfusion and to consider the management decisions this scenario presents. PMID- 29985844 TI - Ultrasound Assessment of Gastric Volume After Bariatric Surgery: A Case Report. AB - Gastric ultrasound is emerging as a tool that can be used to assess gastric content and volume in patients with an unknown fasting history. This information can impact the choice of anesthetic technique or the timing of surgery due to the presumed risk of aspiration. Currently, no data are available regarding the use of gastric ultrasound for patients who have had prior gastric operations, despite the increasing number of patients undergoing bariatric surgery. Our experience suggests that a patient with a prior Roux-en-Y gastric bypass may present with altered anatomy, rendering gastric ultrasound an ineffective technique to assess the volume of ingested food or liquid. PMID- 29985845 TI - Initial Evaluation for Low-Pressure Cardiac Tamponade Using Focused Cardiac Ultrasound. PMID- 29985846 TI - The Significant Value of Preoperative Prognostic Nutritional Index for Survival in Pancreatic Cancers: A Meta-analysis. AB - Nutritional status plays a significant value in the incidence of postoperative complications and survival rate after resection of cancers. The preoperative prognostic nutritional index (PNI) has recently been reported to be a simple, sensitive, and effective prognostic parameter in various cancers. We conducted a meta-analysis to explore the significant value of PNI in pancreatic cancers. We systematically searched electronic databases of PubMed, Embase, Cochrane Library, Web of Science, Wanfang Data, and Chinese National Knowledge Infrastructure. Then, relevant studies were selected to perform this meta-analysis. Eleven studies with a total of 2123 patients met the inclusion criteria of this meta analysis. The pooled results revealed that a lower PNI was significantly correlated with poorer overall survival (hazard ratio, 1.57; 95% confidence interval, 1.40-1.77; P < 0.001). Preoperative PNI might be an efficient predictor of survival with pancreatic cancers. PMID- 29985847 TI - Acute Pancreatitis History Carries Higher Risk in Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Lesions. PMID- 29985848 TI - Disease Course Differences in Acute Pancreatitis Based on Etiology Using the Pancreatitis Activity Scoring System. PMID- 29985849 TI - Five Cases of Interstitial Pneumonitis Due to Gemcitabine and Nab-Paclitaxel Combination Treatment in Pancreatic Cancer Patients. PMID- 29985850 TI - Clinical Features and Prognosis of Patients With the Bone Metastasis of Pancreatic Cancer: A Single-Institutional Cohort Study. PMID- 29985852 TI - Oh, the Places You'll Go! PMID- 29985851 TI - Comparison Between Modified Extracellular-Type Trehalose-Containing Kyoto Solution and University of Wisconsin Solution in 18-Hour Pancreas Preservation for Islet Transplantation. PMID- 29985853 TI - Use of Plasma-Based Trauma Transfusion Protocols at Level IV Trauma Centers. AB - Early initiation of a high ratio massive transfusion can lower trauma patient mortality by 80%. Long transport times from rural Level IV trauma centers therefore require that damage control resuscitation begin before patient transfer. This study evaluates the current use of fresh frozen plasma (FFP) at Level IV trauma centers and the feasibility of implementing trauma transfusion protocols at these centers. Demographic and clinical data were collected for trauma patients at all state Level IV trauma centers who would have met criteria for massive transfusion protocol (MTP) activation based on the Assessment of Blood Consumption (ABC) score. All state Level IV trauma centers were also surveyed to determine availability of blood bank plasma resources. A total of 760 adult trauma patients presented to a Level IV trauma center during the study period. Three hundred sixty-eight patients (48.4%) were transferred to a higher level of care. Because FAST (Focused Assessment with Sonography for Trauma) results were not available in the state registry data, we included all blunt trauma patients with an ABC score of 1 as "potential ABC-positive patients." Forty-two (5.5%) patients were potentially ABC positive. Fifteen of 22 Level IV centers responded to our survey. Seventy-three percent of respondents have FFP available. Mean time to FFP availability was 63.1 min. Median total length of stay from registration to emergency department discharge for potentially ABC positive patients was 2 hr. Because most Level IV trauma centers have FFP and thaw times are such that administration would not delay transport to a higher level of care, we recommend implementation of MTPs at Level IV trauma centers to reduce hemorrhage-associated mortality. PMID- 29985854 TI - Geriatric Trauma Protocol. AB - Study design for a quality improvement project. Objective was to implement a geriatric trauma protocol (GTP) based on American College of Surgeons recommendations to improve patient outcomes. Geriatric trauma patients comprise a vulnerable and high-risk trauma population, and must be treated with specific protocols that take into account physiological, psychosocial, environmental, and pharmacological needs. A growing body of research and organizations such as the American College of Surgeons and the Eastern Association for the Surgery of Trauma recommend that a specific trauma protocol for geriatric adults must be utilized in hospitals and trauma centers. A retrospective chart review was conducted to assess geriatric patient outcomes prior to GTP implementation. Surgical residents then received training on the GTP, including performing additional diagnostics, referrals, and discussing goals of care early in treatment. The GTP was then implemented for 8 weeks and monitored to determine its effects on patient outcomes. The training for surgical residents in the GTP yielded a 9.2% increase in provider knowledge. The results of the GTP showed a reduced length of stay and increased geriatric consultations. More patients received a full evaluation by the trauma team, contributing the reduced length of stay. The use of a GTP shows promise in being able to improve patient outcomes, including morbidity and mortality. The principles of the GTP can be applied in all clinical settings, especially emergency rooms, which are on the frontlines of initial evaluations. In order to improve health care delivery to an aging population, organizations and clinicians should adopt a specialized GTP into their practices. PMID- 29985855 TI - Scratching Below the Surface: Screening for Posttraumatic Stress Symptoms Following Hospitalization With the Pediatric Trauma Service. AB - : Significant progress has occurred medically for children who have experienced traumatic injuries; however, attention to their psychological adjustment has only more recently been a focus in research and clinical practice. These needs do not cease at discharge but, instead, require monitoring to determine whether further assessment and/or intervention are required. Our team, inclusive of the Psychology Service and the Trauma Service, identified 2 established screening measures (based on age) that were completed by patients during their outpatient follow-up visits postdischarge. Should a patient screen positive, the Trauma Service referred them to the Psychology Service for further evaluation and possible treatment (i.e., trauma-focused cognitive-behavioral therapy). Of 881 trauma activations, 31 (4%) patients were screened at an outpatient follow-up appointment through pediatric surgery/trauma clinic. Of these completed screening tools, 29% screened positive and warranted a referral to Psychology. Intervention was recommended for the majority of the patients evaluated; however, half of these did not return for this intervention. A collaboration between the Psychology Service and the Trauma Service is a vital step toward providing stepped care for patients after unintentional injuries. This allows for evaluation of patient needs and then a referral source to meet these identified needs. Future directions include increasing the number of screened patients, perhaps with use of technological supports (i.e., REDCap) or expansion into other clinics and consideration of ways to increase family's use of psychological intervention. LEVEL OF EVIDENCE: Therapeutic/Care management Level IV. PMID- 29985856 TI - Scratching Below the Surface: Screening for Posttraumatic Stress Symptoms Following Hospitalization With the Pediatric Trauma Service. PMID- 29985857 TI - Patients' Experiences of Their Recovery Process After Minor Physical Trauma. AB - Injuries due to trauma are the leading cause of death in Sweden among people younger than 45 years, and more than 120,000 patients were admitted to hospitals in 2014 as a result of trauma. Patients suffering from less serious physical trauma are often discharged directly from the trauma unit, commonly without any follow-up plans. There is a lack of knowledge about how these patients experience their recovery process.Eight women and 6 men were interviewed 3 months after being directly discharged from a trauma unit. Data were analyzed using the constructive grounded theory approach.The main finding was the core category of social support, the key to recovery. Patients' roads to recapturing their health and to recovery had several barriers, which can be clustered together to either physical or psychological symptoms that enhanced their feelings of ill health and delayed their recovery. Participants described different strategies that they used to deal with these barriers. Most important was the support of others, that is, family, social life, work, and health care (primary health care).The participants in this study described managing the recovery process by themselves as troublesome. This is partly because they do not view themselves as healthy, as the health care providers do, and many are in need of further health care after discharge. Health care providers should give better information on the expected process of recovery and the importance of social support, as it might enable patients to better overcome physical and psychological barriers in their recovery. PMID- 29985858 TI - The FRAIL Questionnaire: A Useful Tool for Bedside Screening of Geriatric Trauma Patients. AB - Frailty screening is a priority in acute care. Using secondary data from our prior study, we derived a 5-item FRAIL Questionnaire (instrument) score for 188 geriatric trauma patients and aimed to examine the influence of preinjury physical frailty (as measured by FRAIL) on 1-year outcomes. The study used a secondary data analysis design. Patients were 65 years and older admitted through the emergency department (ED) between October 2013 and March 2014. The 5 items of the FRAIL instrument were identified within data sources of our prior study, and a preinjury FRAIL score was created for each patient. For data analysis, frequencies, measures of central tendency, and linear and logistic regression models were used. Median age of the patients was 77 years (interquartile range [IQR] = 69-86), and median Injury Severity Score = 10 (IQR = 9-17). Upon admission to the ED, 63 patients (34%) were screened as frail (FRAIL score >=3), 71 (38%) as prefrail (score = 1-2), and 54 (29%) as nonfrail (score = 0). Frequencies for components of the FRAIL score were as follows: fatigue (N = 123; 65%), resistance (N = 61; 32%), ambulation (N = 76; 40%), illnesses (N = 51; 27%), and loss of weight (N = 11; 6%). After controlling for age, comorbidities, injury severity, and cognitive status, preinjury FRAIL scores explained 13% of the variability in function as measured by the Barthel Index (N = 129, beta = .36, p < .001). Forty-seven patients died (26%) within 1 year. Logistic regression analysis revealed that the higher the preinjury FRAIL score, the greater the likelihood of mortality within 1 year (OR = 1.74, p = .001; 95% CI [1.27, 2.39)]. The FRAIL Questionnaire predicts 1-year functional status and mortality and is a useful tool for bedside screening. PMID- 29985859 TI - The FRAIL Questionnaire: A Useful Tool for Bedside Screening of Geriatric Trauma Patients. PMID- 29985860 TI - The Effect of Telenursing on Referral Rates of Patients With Head Trauma and Their Family's Satisfaction After Discharge. AB - We aimed to assess the effect of telenursing on referral rates of patients with head trauma and their family's satisfaction after discharge. Seventy-two patients with head trauma were randomly allocated to equal intervention and control groups. The caregivers in both groups were provided with 1-hr face-to-face training on patients' home care and educational booklets, 2 days before discharge. The cell phone numbers of the telenurse was given to the caregivers of the intervention group. Then, the patients in the intervention group were followed up every week through phone calls by the telenurse for 12 weeks and the patient status checklists were completed. Caregivers in the intervention group could call the telenurse any time they desired. The health status of the control group was followed once by a phone call after 12 weeks. Data were analyzed using SPSS software, version 19. Ultimately, 33 patients with a mean +/- SD age of 31.12 +/- 10.83 years were studied in the control group and 35 patients with a mean +/- SD age of 34.11 +/- 12.34 years were studied in the intervention group (p = .098). The 2 groups differed significantly with respect to referral rates; 39.4% of the participants in the control group referred to physicians whereas only 25.7% of the patients in the intervention group needed to refer to physicians (p = .017). Also, the mean times of referring to a physician differed significantly in both groups. In general, 53.8% of the caregivers were satisfied with the telenursing program. Follow-up programs using telephone calls were effective and would lead to higher caregiver satisfaction. PMID- 29985861 TI - Resuscitative Strategies in the Trauma Patient: The Past, the Present, and the Future. AB - Over the last decade, trends in fluid resuscitation have changed dramatically as have our practices. Research is driving trauma centers across the globe to initiate modifications in fluid resuscitation of the hemorrhagic trauma patients both in the prehospital and intrahospital arena. This is being done by combining the theory of permissive hypotension and damage control surgery with hemostatic resuscitation as the preferred methods of resuscitation in patients with hemorrhagic shock. The literature illustrates that previous strategies we considered to be beneficial are actually detrimental to the outcomes of these severely injured patients. This complex and continuously changing adaptation in practice must be made without losing our strategic focus of improvement of outcomes and recognition of the morbidity associated with bleeding of the trauma patient. Designating limits on large-volume crystalloid resuscitation will prevent cellular injury. These wiser resuscitation strategies are key in the efforts to reduce mortality and to improve outcomes. This article is to serve as a review of each of the resuscitative fluid strategies as well as new methods of trauma resuscitation. PMID- 29985862 TI - Public Perception of Ethical Issues in Dermatology: Evidenced by New York Times Commenters. AB - BACKGROUND: A 2017 New York Times (NYT) article questioning the appropriateness of skin cancer treatment modality by dermatology providers stimulated discussion among the public pertaining to ethics in the current state of dermatologic practice. OBJECTIVE: The purpose of this study is to characterize issues raised by the comments on the NYT article, discuss strategies to address these concerns, and encourage reflection on ethics in dermatologic care. MATERIALS AND METHODS: A qualitative analysis was performed on the 309 comments on the NYT article. General themes were identified, resulting in the inclusion of 222 comments. These comments were reviewed and characterized by the type of commenter, his or her stance on health care, and what issues they raised. RESULTS: Providers interested in "profit over patient" was the most common theme, followed by mistrust of APPs, health care system interested in "profit over patient," inadequate supervision by advanced practice providers (APPs), finding the "right" provider, support for coordinated APP and physician care, support for APP credentials, and finally inappropriate elderly care. CONCLUSION: The NYT article raises the concern of identifying quality care and choosing the "right provider"-one who successfully balances the various incentives affecting skin cancer management including appropriate usage of APPs. PMID- 29985863 TI - Responses to Topical Diphenylcyclopropenone as an Adjunct Treatment for In Transit Melanoma: A Tertiary Referral Center Experience. AB - BACKGROUND: In-transit cutaneous metastases occur in 5% to 10% of patients with melanoma. Recently, topical diphenylcyclopropenone (DPCP) has been described as a treatment option. OBJECTIVE: To evaluate efficacy of DPCP in treatment of in transit cutaneous melanoma. METHODS: The authors retrospectively reviewed the records of 13 consecutive patients with in-transit metastases treated with topical DPCP between March 1, 2013, and January 31, 2017. The authors recorded the response of in-transit cutaneous melanoma lesions treated with DPCP measured by clinical examination. RESULTS: Among the 13 patients, 9 patients completed at least a 1-month course of DPCP treatment. Of these 9 patients, 6 (66.7%) maintained either stable disease or had a partial or complete regression, and 3 (33.3%) had progressive disease. Patients with less burden of disease (e.g., <15 lesions) responded more favorably than those with a greater burden of disease (e.g., >25 lesions or plaques). Both patients who received DPCP alone had progression of their cutaneous lesions. One patient who did not become sensitized to DPCP died within 2 months, and his anergy likely reflecting immense burden of disease. CONCLUSION: Topical DPCP is a low-cost, patient-applied treatment option for in-transit melanoma, most effective for patients with relatively low tumor burden and localized disease. PMID- 29985864 TI - Successful Hair Transplantation for Scarring Alopecia Associated With Incontinentia Pigmenti. PMID- 29985865 TI - Systematic Review of Surgical Treatment and Outcomes After Local Surgery of Primary Cutaneous Melanomas of the Penis and Scrotum. AB - BACKGROUND: Few data exist to guide surgical management and counseling about local recurrence after surgery of primary male genital melanoma. OBJECTIVE: To compile all available data on local recurrence rates after surgery of primary cutaneous melanoma of the penis and scrotum. MATERIALS AND METHODS: A systematic review of PubMed, Literatura Latino-Americana e do Caribe em Ciencias da Saude (LILACS), Excerpta Medica database (EMBASE), and Web of Science identified all surgically treated penile and scrotal melanomas that reported local recurrence status and follow-up time. RESULTS: One hundred twenty-seven melanomas from 74 manuscripts were included. Eighty-six percent of melanomas were located on the penis, and 14% were located on the scrotum. Average follow-up time was 35.7 months. Scrotal melanomas were predominantly treated with organ-sparing surgeries (16/18, 88.9%), whereas penile melanomas were treated more often with amputation (61/109, 56.0%). Overall, local recurrence rate was 15.7% (20/127). Local recurrence rates for penile cases were 18.8% (9/48) after organ-sparing surgery versus 13.1% (8/61) for amputative surgery. Local recurrence rates were 66.7% (4/6) after positive surgical margins versus 10.2% (5/49) after negative surgical margins. CONCLUSION: Local recurrence rates are high after both organ-sparing and amputative surgery of primary cutaneous melanoma of the penis and scrotum. There is a need to standardize reporting for this rare tumor, as more complete data are necessary to develop consensus guidelines for surgical management of male genital melanoma. PMID- 29985866 TI - 0.01% Hypochlorous Acid as an Alternative Skin Antiseptic: An In Vitro Comparison. AB - OBJECTIVE: Compare the in vitro efficacy of hypochlorous acid 0.01% (HA), povidone iodine 5% (PI), chlorhexidine gluconate 4% (CHG), and isopropyl alcohol 70% (IPA) against common skin microorganisms. MATERIALS AND METHODS: Time-kill studies were conducted against methicillin-susceptible Staphylococcus aureus (MSSA) and Staphylococcus epidermidis (MSSE), methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE), Candida albicans, Corynebacterium species (striatum and amycolatum), Propionibacterium acnes, Pseudomonas aeruginosa, Streptococcus pyogenes, Staphylococcus capitis, and Staphylococcus xylosus. RESULTS: Methicillin-resistant S. aureus: Bactericidal effect was immediate for HA and IPA. For PI and CHG, the effect occurred at 1 and 10 minutes, respectively. Methicillin-resistant S. epidermidis: Hypochlorous acid, IPA, and PI had immediate bactericidal effects, whereas CHG required 1 minute. Methicillin susceptible Staphylococcus aureus: All agents had bactericidal effects at 1 minute. C. species, S. pyogenes, P. aeruginosa, and P. acnes: All antiseptics demonstrated immediate bactericidal effects. Methicillin-susceptible Staphylococcus epidermidis and S. capitis: Hypochlorous acid and IPA had immediate effect, whereas PI and CHG required 1 minute. C. albicans: Hypochlorous acid, IPA, and PI were immediately bactericidal, whereas CHG required 1 minute. S. xylosus: Hypochlorous acid and CHG were immediately bactericidal, whereas IPA and PI required 1 and 2 minutes, respectively. CONCLUSION: In vitro studies of HA 0.01% were observed to have equal or more efficacious antiseptic properties compared with IPA, CHG, and PI. Future studies will be needed to investigate its role in periocular use. PMID- 29985867 TI - Hip Power and "Stiff Knee" Gait: A Tool for Identifying Appropriate Candidates for Rectus Transfer. AB - BACKGROUND: Rectus femoris transfer (RFT) is performed in children with cerebral palsy to treat stiff-knee gait. However, the results are variable in part because there is no gold standard to identify appropriate candidates. Hip flexion kinematics and kinetics are important factors in the determination of peak knee flexion during gait. This study aimed to evaluate whether a kinetic preoperative analysis of hip power can be a predictor of RFT outcomes and determine its usability for identifying appropriate candidates for the procedure. METHODS: Sixteen children with spastic cerebral palsy (20 limbs) GMFCS I/II who underwent RFT for a stiff-knee gait and had preoperative and postoperative 3D gait analyses were retrospectively evaluated. Patient outcomes were classified as "good" or "poor" according to postoperative results. The outcomes were evaluated as a function of (a) 1-parameter criteria-peak hip power (PHP) with a cut-off magnitude>=0.60 W/kg; (b) 2-parameter criteria-PHP (cut-off magnitude>=0.60 W/kg) and the time the PHP occurred during the gait cycle (tPHP), with a cut-off <=68% of the gait cycle. RESULTS: When the 1-parameter criterion was used, 13 limbs met the criterion; of them, 11 had good outcomes. Seven limbs did not meet the criterion; of them, 6 had poor results (P=0.0049). When the 2-parameter criterion was used, 11 limbs met the criteria; all had good results. Nine limbs did not meet the criterion; of them, 8 had poor results (P=0.0002). PHP+tPHP had the same sensitivity as PHP alone (91%) but with higher specificity (100%) for predicting outcomes. The positive predictive value of magnitude PHP+tPHP was 100%, whereas the accuracy index was 95%. CONCLUSIONS: Preoperative kinetic evaluation of the hip power characteristics from 3D gait analysis appears to be a very important predictor for RFT outcomes and identifying appropriate candidates for the procedure. LEVEL OF EVIDENCE: Level III-therapeutic retrospective study. PMID- 29985868 TI - Range of Motion Improvement Following Surgical Management of Knee Arthrofibrosis in Children and Adolescents. AB - BACKGROUND: Arthrofibrosis of the knee is well-described in adults as a potentially debilitating postoperative complication following anterior cruciate ligament reconstruction, total knee arthroplasty, or fracture fixation. Knee arthrofibrosis in children and adolescents, however, has received little attention. The primary purpose of this study was to report improvements in range of motion (ROM) following lysis of adhesions and manipulation under anesthesia (LOA/MUA) in children and adolescents with knee arthrofibrosis, and, secondarily, to evaluate for any effect of preoperative dynamic splinting on ROM outcomes. METHODS: Ninety patients aged 18 years and below (mean, 14.4+/-3.5) and 31% male who underwent LOA/MUA at an urban tertiary care hospital following prior knee surgery were evaluated. Demographic, clinical, ROM, and revision data were compiled. Primary outcome was absolute ROM. Secondarily, ROM was analyzed as a categorical variable with "Full ROM" defined to be -5 to 130 degrees or better, "functional" ROM was defined as unable to obtain -5 to 130 degrees but not requiring revision, and "failure" defined as resulting in revision arthrofibrosis surgery. t tests and chi analyses were used to compare ROM and count variables between dynamic splinting subgroups. RESULTS: Mean time from index surgery to LOA/MUA was 6.0+/-4.4 months, and follow-up was 42+/-56 months. Index procedures included anterior cruciate ligament reconstruction (N=33), tibial spine arthroscopic reduction and internal fixation (N=18), fracture fixation (N=17), soft tissue repair (N=17), and multiligament reconstruction (N=5). In total, 68 subjects (76%) had any flexion loss, 57 subjects (63%) had any extension loss, and 40 subjects (44%) had both flexion and extension loss.Fifty-six subjects (62%) had full ROM at final follow-up, 25 subjects (28%) had functional ROM, and 9 subjects (10%) required revision. No demographic, clinical, or surgical variable was predictive of treatment failure. Patients who underwent dynamic splinting preoperatively (N=46; 51%) had greater preoperative flexion (99+/-16 vs.77+/-34 degrees; P=0.001), but no difference in flexion at final follow-up (121+/-20 vs.128+/-11 degrees; P=0.08). Failure was not associated with time from index procedure to LOA/MUA, and the proportion who regained full ROM postoperatively was equivalent between those who had dynamic splinting and those who did not (65% vs. 59%; P=0.70). CONCLUSIONS: LOA/MUA for children with arthrofibrotic knees results in significant improvements in ROM with 90% revision free success. Preoperative dynamic or static progressive splinting improves preoperative flexion but does not affect postoperative range of motion or failure rate. LEVEL OF EVIDENCE: Level II. PMID- 29985870 TI - Early Systemic Alterations in Severe Spinal Cord Injury: An Experimental Study on the Impact of Injury Level on Renal Function. AB - STUDY DESIGN: An experimental model of spinal cord injury (SCI) intended to characterize changes in renal function. OBJECTIVE: The aim of this study was to evaluate the possible influence of SCI level on renal function during spinal shock. SUMMARY OF BACKGROUND DATA: SCI triggers multiple systemic and metabolic alterations. Among them, renal dysfunction stands out. Although several variables have been related to its extent, the impact of the cord injury level on renal function has not been clearly stated, particularly during the spinal shock. METHODS: Anesthetized adult Sprague-Dawley rats were subjected to severe spinal cord contusion at low (T8) and high (T1) thoracic levels using the weight-drop method. Glomerular filtration rate (GFR) and tubular secretion (TS) were estimated 24 hours after injury, using a validated method based on the determination of plasma concentrations of iopamidol and p-aminohippuric acid by high-performance liquid chromatography. RESULTS: GFR, fell to 33% (95% CI [24%, 43%]) and 10% (8%, 13%) of the sham-injured controls, whereas TS, decreased to 59% (95% CI [47%, 71%]), and 25% (18%, 32%) of the sham-injured controls, in T8 and T1 injury levels, respectively. Comparisons between cords injured and control rats, as well as between low and high-injured levels, were statistically significant (P < 0.01). CONCLUSION: Renal dysfunction occurs early after severe SCI. The damage is greater in high compared to low injuries. These findings could have important implications in the acute management of patients with high thoracic and cervical injuries, especially in pharmacotherapy using drugs eliminated by the kidney. LEVEL OF EVIDENCE: N/A. PMID- 29985869 TI - Expansion Thoracoplasty in Rabbit Model: Effect of Timing on Preserving Pulmonary Growth and Correcting Spine Deformity. AB - STUDY DESIGN: In a treatment-control animal study expansion thoracoplasty (ET) was performed in a juvenile rabbit model of thoracic insufficiency syndrome (TIS) and benefits to thoracic development and respiratory function quantified. Rabbits treated early versus late were compared to age-matched normal and disease control rabbits through to skeletal maturity. OBJECTIVE: Evaluate (1) how ET changes the natural TIS disease trajectory and (2) how timing of ET affects changes in spine growth, lung growth, and respiratory mechanics. SUMMARY OF BACKGROUND DATA: Pulmonary growth potential is thought to diminish with age; thus, early therapeutic intervention may increase pulmonary growth in children with TIS. However, no direct empirical evidence exists to support this treatment paradigm. METHODS: Convex left scoliosis and resultant TIS was induced in 3-week-old rabbits via surgical rib tethering. We compare the efficacy of ET performed at 7 weeks and expanded at 11 weeks (early, n = 7) versus only at 11 weeks of age (late, n = 7) in preserving lung growth and respiratory function relative to normal (n = 8) and disease (n = 10) rabbits. Sequential computed tomography images and pulmonary function testing was performed to quantify spine curvature, lung growth, and respiratory volumes. At 28 weeks of age chest wall elastance was measured in vivo then acinar complexity analyzed histologically via radial alveolar counts. RESULTS: ET performed early or late altered the predicted trajectory of spine deformity, pulmonary growth inhibition, and respiratory dysfunction seen in disease rabbits. Growth was not significantly different between early and late rabbits and post-treatment gains remained below those of age-matched normal rabbits. Chest wall elastance was impaired by ET and more so in early rabbits, there were no differences in pulmonary elastance. CONCLUSION: ET interrupted the natural progression of deformity and pulmonary hypoplasia associated with spine curvature in disease rabbits. However, growth benefits are only seen in cases of the most severe initial deformity and must be balanced against the further impairment to chest wall function associated with repetitive surgery. LEVEL OF EVIDENCE: N/A. PMID- 29985871 TI - Cognitive Impairment Level and Elderly Hip Fracture: Implications in Rehabilitation Nursing. AB - PURPOSE: The aim of the study was to determine the cognitive impairment level influence in descriptive characteristics, comorbidities, complications, and pharmacological features of older adults with hip fracture. DESIGN: Cross sectional study. METHOD: Five hundred fifty-seven older adults with hip fracture were recruited and divided into cognitive impairment levels (severe/moderate, mild, no impairment). Descriptive characteristics, comorbidities, complications, and pharmacological data were collected. FINDINGS: Significant differences (p < .05, R = .012-.475) between cognitive impairment levels were shown. Shorter presurgery hospital length of stay and lower depression and Parkinson comorbidities; delirium complication; and antidepressants, antiparkinsonians, and neuroleptics use were shown for the no-impairment group. With regard to the cognitive impairment groups, lower presence of cardiopathy and hypertension; higher presence of dementia; antihypertensives, antiplatelets, and antidementia medication; infection/respiratory insufficiency complications; and lower constipation complications were shown. CONCLUSION: Cognitive impairment levels may determine the characteristics, comorbidities, pharmacology, and complications of older adults with hip fracture. CLINICAL RELEVANCE: Cognitive impairment level may impact rehabilitation nursing practice, education, and care coordination. PMID- 29985872 TI - Newborn Exposure to Polycyclic Aromatic Hydrocarbons Through Parenteral Nutrition. AB - BACKGROUND AND OBJECTIVES: Parenteral nutrition (PN) administered to newborns (NB) may be contaminated with polycyclic aromatic hydrocarbons (PAHs) and may therefore increase the contact with these toxicants in very early life stages. The aim of the study is to determine to what extent, if any, commercial products for PN are contaminated with PAHs and to determine whether these contaminants, when present in the bag content, are delivered to NB and whether 1-hydroxypyrene (1-HP), the pyrene metabolite, can be detected in the urine of exposed NB. METHODS: Commercial products and the bags administered to 10 NB during their period in the NICU were analyzed for the 16 priority US Environmental Protection Agency PAHs. Urine samples were collected and analyzed for their 1-HP content. Urine samples of a control group composed of 8 breastfed NB were also analyzed for the determination of 1-HP. RESULTS: From 9 different commercial products used to compound PN bags, 6 were contaminated with PAHs, with total concentrations varying from 0.02 to 10.56 mg/L. In the bags administered to the NB, this sum varied from 0.01 to 6.30 mg/L with a mean of 2.62 mg/L. Therefore, for each 100 mL PN, an average load of 0.26 mg PAHs was observed. The majority of the urine samples taken from NB in the study group (80%) contained 1-HP, but it was not detected in the urine of any baby in the control group. CONCLUSIONS: The contamination of PN with PAHs poses a critical toxicological risk. The elevated contaminant concentrations and the parenteral way of administration make this source of PAHs considerably worse than any other, including maternal exposure to environmental pollution or tobacco. PMID- 29985873 TI - Piecemeal Deglutition and the Implications for Pressure Impedance Dysphagia Assessment in Pediatrics. AB - OBJECTIVES: High-resolution impedance manometry (HRIM) enables biomechanical swallow assessment. Piecemeal deglutition (PD) defines swallowing of a single bolus in 2 or more portions. We investigated PD sequences on HRIM recordings to ascertain appropriate swallow selection for analysis and to determine the impact of PD on swallow function measures. METHODS: Pharyngo-esophageal motility and bolus flow were assessed in 27 children (19 M, mean age 15 months) with repaired esophageal atresia and trachea-esophageal fistula, but who were asymptomatic of oropharyngeal dysphagia. A consistent volume of between 2 and 5 mL saline boluses was given to each patient. Retrospectively, PD sequences were defined based on the number of swallows required to clear the bolus from the oral cavity: pattern A = 1-2 swallows; pattern B = 3 swallows; and pattern C = 4+ swallows. The largest bolus volume swallowed was noted as the dominant swallow in each pattern. Pressure Flow Analysis defined contractility, distension and flow timing metrics. Data were averaged for each PD pattern, and compared with dominant swallows from each pattern. RESULTS: PD pattern B (43.7%) was the most prevalent across the cohort. PD patterns were similarly distributed across age groups (G1: <1 years, G2: 1-4 years). Differences in upper esophageal sphincter distension and pharyngeal flow timing measures were, however, seen in relation to both age and PD pattern, whereby a larger pharynx in older children elicited greater distension for a longer latency, and for larger volumes. CONCLUSIONS: PD reduces bolus volume, and biomechanical swallow measures are impacted. PD is a necessary consideration for accurate HRIM analysis of swallow function. Selection of dominant swallows from a PD sequence provides a swallow profile which best represents a child's swallow function, and should always be reported and interpreted in context of the PD sequence observed. PMID- 29985874 TI - Erythromycin and Reflux Events in Premature Neonates: A Randomized Clinical Trial. AB - OBJECTIVE: Gastroesophageal reflux disease (GERD) in premature neonates may manifest as apnea, bradycardia, growth failure, aspiration, or feeding intolerance. Erythromycin ethylsuccinate (EES), is often used as a pro-kinetic in the management of GERD, despite lack of evidence or safety from randomized controlled trials. We sought to study the efficacy of enteral EES at a dose of 50 mg . kg . day in decreasing the frequency of gastroesophageal reflux events as determined by pH-multichannel intraluminal impedance (pH-MII) monitoring. METHODS: In a randomized, double-blind, placebo-controlled trial, eligible premature neonates with clinical signs of GERD underwent 24-hour pH-MII monitoring. If >5 reflux events were identified on pH-MII, then subjects were randomized to receive either EES or placebo. Repeat 24-hour pH-MII was performed on day 7 of study treatment and compared to initial pH-MII. RESULTS: Forty-three premature neonates were enrolled. Of those, 31 neonates were randomized, 15 to EES and 16 to placebo with a median (IQR) pretreatment total reflux events per 24 hours of 23 (16-40) and 29 (12-40), respectively. Day 7 total events per 24 hours decreased by 4 events in the EES group to 19 (15-33) and by 10 events in the placebo group to 19 (11-26) (P = 0.09). There were no differences in pretreatment and day 7 acidic and nonacidic reflux, proximal reflux, total or percent reflux time, median or longest bolus clearance time, or nurse-reported apnea events between groups. CONCLUSIONS: Enteral EES did not decrease reflux events on 24 hour pH-MII at the dose studied. Therefore, it may be ineffective in the treatment of GERD in premature neonates. PMID- 29985875 TI - Genetic Diversity of Norovirus Infections, Coinfections, and Undernutrition in Children From Brazilian Semiarid Region. AB - BACKGROUND AND OBJECTIVE: Norovirus (NoV) infections are known to have high morbidity and mortality rates and are a major health problem globally. The impact of NoV on child development is, however, poorly understood. We evaluated the distribution of NoV genotypes in children from a low-income Brazilian semiarid region, in relation with their clinical symptoms, nutritional status, and co pathogens. METHODS: The test population included children aged 2 to 36 months from 6 cities of the Brazilian semiarid region. Fecal samples were collected from each child, along with the information regarding their socioeconomic/clinical conditions using a standardized questionnaire. Detection and quantification of NoV were performed by reverse-transcription quantitative polymerase chain reaction, followed by molecular and phylogenetic analyses. RESULTS: The NoV detection rate was 45.2%. Presence of NoV was associated with lower z scores for weight-for-age (P = 0.03), weight-for-height (P = 0.03), and body mass index-for age (P = 0.03). NoV infection was associated with more frequent respiratory illnesses (P < 0.01). GII.P7 (polymerase) and GII.3 (capsid) were the most frequent NoV genotypes. Analysis of the open reading frame (ORF)1-2 junction identified recombinant NoV strains in 80% of the sequenced samples. Enteroaggregative Escherichia coli coinfection was the major predictor for diarrhea in NoV-positive samples (P < 0.02). Moreover, Shigella spp was also associated with NoV-positive diagnosis (P = 0.02). CONCLUSIONS: This study highlights the genetic variability of NoV and, associated co-infections and undernutrition in infants from low-income Brazilian semiarid region. PMID- 29985876 TI - A Rare Case Of a 2 year old Boy With Alagille Syndrome & Type 3 Hereditary Hemochromatosis With TFR2 Mutation. PMID- 29985877 TI - Switching From Originator to Biosimilar Infliximab in Paediatric Inflammatory Bowel Disease Is Feasible and Uneventful. AB - The safety, clinical efficacy, and cost-effectiveness of biosimilar infliximab in adult inflammatory bowel disease (IBD) have now been extensively shown. Limited data have been collected in the paediatric setting. We report nationwide, prospective, clinical safety and effectiveness data for patients from all 3 Scottish paediatric inflammatory bowel disease networks switching from originator to biosimilar infliximab. Prospective clinical data were collected for 33 patients. Information was collected from electronic patient records, laboratory reports, and patient case notes. There were no clinically significant changes to disease activity, biomarkers, antidrug antibodies, or trough drug levels (P > 0.1) within a 12-month follow-up period; in addition, there were no significant adverse events reported. No infusion reactions were seen in the 264 infusions delivered. Switching from originator infliximab to the biosimilar (CT-P13) appears to be associated with neither an increase in infusion reactions nor significant loss of effectiveness in the short term. PMID- 29985878 TI - Efficacy of Reslizumab for Eosinophilic Esophagitis. PMID- 29985879 TI - Response to Letter to the Editor. PMID- 29985880 TI - Re: Phenylephrine Test Protocol. PMID- 29985881 TI - Reply re: "The Phenylephrine Test Revisited". PMID- 29985882 TI - Bleeding in the Post-operative Oculoplastic Patient on Novel Anticoagulants. PMID- 29985883 TI - Effect of Sibutramine on Upper Eyelid Position. PMID- 29985884 TI - Three-Dimensional Surgery in Oculoplastics. PMID- 29985885 TI - Changes in Patient Safety Culture in Palestinian Public Hospitals: Impact of Quality and Patient Safety Initiatives and Programs. AB - OBJECTIVES: To assess the changes in the patient safety culture between 2011 and 2016 after the implementation of patient safety initiative in Palestinian public hospitals. METHODS: A cross-sectional quantitative design employed using the Hospital Survey on Patient Safety Culture to collect data. Participants were 1,229 clinical and nonclinical employees from all public hospitals in the West Bank. RESULTS: Significant improvements were observed in patient safety culture with positive responses to 10 (83.3%) composite categories and 36 (86.0%) items of the Hospital Survey on Patient Safety Culture since the baseline survey in 2011 (P < 0.05). The increase in the percent of positive responses to the survey composites ranged from 9.1% (P < 0.001) to "Frequency of events reported" to 3.8% for "Teamwork across hospital units" (P < 0.001). Significant decrease in positive responses to "Staffing" (11.4%) was observed (P < 0.05); no significant change was observed in "Organizational learning-continuous improvement" (P > 0.05). Most participants (70.5%) rated patient safety level in their units/hospital as 'Excellent/Very good', with an increase of 6.3% from the baseline (P < 0.001); no significant increase in the number of reported events in the past 12 months was observed (P < 0.05). CONCLUSIONS: Compared with the baseline survey results, patients' safety initiatives and quality improvement programs had positive effect on the safety culture in public Palestinian hospitals. PMID- 29985886 TI - Pressure Ulcer Rate in Multidisciplinary Hospital Units After Multifactorial Intervention: A Stepped-Wedge, Cluster Randomized Controlled Trial. AB - OBJECTIVES: This study was conducted to measure the effectiveness of interventions in decreasing the rates of pressure ulcer in a general hospital setting. METHODS: Sixteen units in a general hospitals in Iran participated in this stepped-wedge, cluster randomized controlled trial during a 45-week study period. This trial has a one-sided crossover design from control to intervention. The units were randomly assigned fulfilling entry criteria. After the approval by the governing board of hospital, the manipulative intervention, in addition to usual care, was implemented on patients with a Braden criterion of 14 or less. The primary outcome was ulcer specification (grade and location of ulcer), and the secondary outcome was the length of hospital stay. RESULTS: A total of 18,900 patients were admitted during the 45-week study period in the study units, of whom approximately 20% (3846 patients) were identified as high risk according to the items of Braden scale criteria during the admission assessment by nurses. The highest rate of PUs (80%) was in grade 2, and 16% of patients had grade 3 and 4 PUs. The ulcers of the skin overlying the sacrum and hip areas were the most common sites in the patients under study. The rates of PU in the control, training, and intervention phases were 5.49 (4.72-6.34), 5.68 (3.82-8.15), and 4.62 (3.87-5.47), respectively, per 1000 patient-days. CONCLUSIONS: The multifaceted intervention proposed by the present study has succeeded in reducing rate of pressure ulcer. Multifaceted programs based on training are appropriate ways to provide essential information to patients and their caregivers, which result in improvement of their participation in therapeutic process. We recommend hospitals to use these findings as a quality improvement plan for decreasing the rate of pressure ulcer. PMID- 29985887 TI - Criticality of Maternal Complications During Childbirths. AB - BACKGROUND: The incidence of severe maternal morbidity is increasing in the United Sates. To improve maternal outcomes, three maternal complications have been selected for priority intervention based on their proportionate mortality and preventability: obstetric hemorrhage, severe hypertension, and venous thromboembolism. This approach excludes complications that are not associated with high mortality but significantly contribute to maternal morbidity. The aim of this study was to provide an alternative ranking of maternal complications requiring interventions using cost-based criticality analysis. METHODS: Discharge records indicating delivery hospitalizations, and 17 maternal complications were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in the 2012 National Inpatient Sample, a 20% national representative sample of hospital discharge records from community hospitals. For each complication, criticality was calculated as the product of its incidence and severity. Severity was estimated using excess cost, the difference between the mean costs of discharges with and without the complication. Costs were calculated as the product of hospital charges and a cost-to-charge ratio and adjusted with a linear regression model. Complications were ranked based on criticality. RESULTS: The study sample included 734,865 delivery hospitalizations. At least one complication was recorded in 80,657 discharges (11.0%, 95% confidence interval = 10.9-11.1). The four highest-ranked critical complications were pre eclampsia/eclampsia (criticality: $93), postpartum hemorrhage ($47), gestational hypertension ($34), and anesthesia-related complications ($5). CONCLUSIONS: In addition to postpartum hemorrhage and severe hypertension, anesthesia-related complications and gestational hypertension may be new priority targets for interventions during delivery hospitalizations. Criticality analysis seems to be an alternative or complimentary approach for planning healthcare quality improvement programs. PMID- 29985888 TI - Introduction. PMID- 29985889 TI - Distal Clavicle Fractures: Open Reduction and Internal Fixation With a Hook Plate. AB - Displaced distal clavicle fractures pose unique challenges because of their propensity for instability. In particular, type II fracture patterns are associated with high rates of nonunion with nonoperative management; therefore, surgical fixation is often recommended. Hook plate fixation has demonstrated reliably high rates of osseous union with good functional outcomes. We present our surgical technique and rationale for using a hook plate in the setting of an unstable distal clavicle fracture. PMID- 29985890 TI - Shoulder Arthrodesis. AB - PURPOSE: The purpose of this video is to demonstrate the surgical technique of a shoulder arthrodesis for a patient with multidirectional instability and multiple failed previous surgeries. METHODS: A 25-year-old woman with a long history of left shoulder multidirectional instability in the setting of Ehlers-Danlos syndrome is shown undergoing a shoulder arthrodesis. The video demonstrates intraoperative patient positioning, approach, shoulder osseous and articular preparation, implant placement (narrow 4.5 dynamic compression plate), and wound closure. The video includes a brief case history with preoperative radiographic imaging, indications, and patient outcome with postoperative radiographic imaging. RESULTS: The video is 11 minutes, 34 seconds in time. CONCLUSION: This video demonstrates a left shoulder arthrodesis with successful glenohumeral positioning of 30 degrees/30 degrees/30 degrees flexion, abduction, and internal rotation, respectively, and functional ability to reach the mouth and top of the head. PMID- 29985891 TI - Surgical Technique: Anterolateral Approach to the Humerus. AB - INTRODUCTION: Although most humeral shaft fractures can be treated nonoperatively, many patients do benefit significantly from surgical treatment. The anterolateral approach to the humerus provides excellent exposure to the humeral shaft, especially to more proximal aspects. In addition, the approach can be extended both proximally and distally, providing the surgeon a dynamic exposure to the humerus for the treatment of fractures and other pathologies. METHODS: This video highlights a clinical case where a mid-shaft humerus fracture was diagnosed and treated with open reduction internal fixation using an 8-hole 4.5-mm limited contact dynamic compression plate through an anterolateral approach. RESULTS: We present indications, anatomic considerations, and surgical techniques used to surgically treat a transverse, mid-shaft humerus fracture through an anterolateral approach. In addition, we demonstrate the use of a push pull screw to aid in achieving appropriate compression across a fracture site. Using this technique, an anatomic reduction and satisfactory clinical outcome were achieved. CONCLUSIONS: The anterolateral approach to the humerus offers excellent exposure to some humeral shaft fractures, particularly those that lie more proximally. However, its use must be weighed carefully against several other approach options, and the surgeon must account for the specific fracture pattern, as well as their own comfort and familiarity with the approach. PMID- 29985892 TI - Fixation of a Proximal Humerus Fracture Using a Polyaxial Locking Plate and Endosteal Fibular Strut. AB - Proximal humerus fractures have a bimodal distribution and are most commonly seen in the elderly and are the third most common fracture pattern seen in the elderly. There is also a subset of these fractures that occur in younger patients secondary to higher energy mechanisms. Nonoperative management is often advocated for a majority of patients, but surgical fixation is often pursued for younger patients or active, older patients with significantly displaced and reconstructable fractures. The most common options for fixation include open reduction and internal fixation with locking plates and intramedullary nailing. Percutaneous pinning and non-locking plate fixation have lost favor with the advent of improved fixation techniques. Recently developed polyaxial locking plates and the use of endosteal fibular strut grafts offer an excellent option for the fixation of these injuries. In this video, we discuss the case of a 47 year-old man with a four-part proximal humerus fracture. PMID- 29985893 TI - Posterior Scapula Approaches: Extensile and Modified Judet. AB - The Extensile Judet has been widely used in the management of scapula fractures. An enhanced understanding of these injuries, however, has allowed for the strategic development of alternative methods in which soft tissues may be better spared. The purpose of this video is to highlight the indications and techniques for 2 posterior approaches to the scapula: The Extensile Judet and the Modified Judet. Case 1 demonstrates the Modified Judet approach. The "boomerang" incision follows the curve of the scapula spine and vertebral border, and fixation occurs through an intermuscular window. Case 2 illustrates the Extensile Judet. The incision is identical to that of the Modified Judet, but differs in that posterior musculature is elevated in 1 periosteocutaneous flap. The utility of 2 different posterior approaches to the scapula are described. Both include the same incision, but differ with regards to management of the musculature overlying the fracture. The Modified Judet lacks the exposure of the Extensile approach, but significant soft-tissue trauma is avoided. Regarding the Extensile Judet, substantial tissue trauma is incurred to gain the exposure necessary for complex fracture patterns. Reduction goals, wound closure, and postoperative care remain the same for both approaches. Both approaches are valuable in terms of operative management of scapula fractures, although certain populations may benefit from tissue-sparing procedures. PMID- 29985894 TI - Ilioinguinal Approach: Indication and Technique. AB - This video on the ilioinguinal approach presents its indications and techniques for the operative treatment of acetabular fractures. The principle of the ilioinguinal approach is to work through 3 different windows. The lateral window gives access to the pelvic bone from the sacroiliac joint to the lateral border of the iliopsoas muscle, the middle window accesses the medial border of the iliopsoas muscle to the femoral artery, and the medial window allows for control of the anterior pelvic ring medially from the femoral vein to the symphysis pubis. In this video, we demonstrate anatomical reconstruction of the acetabulum in a patient with an associated both-column fracture using the ilioinguinal approach. Indications are all acetabular fracture types, where in addition to anterior column fracture, a fractured posterior column is reducible through the middle window, that is, there is no involvement of the posterior column or wall that would necessitate a direct posterior approach. The ilioinguinal approach is a standard anatomical approach that gives an excellent visual and palpatory exposure of the anterior column up to the symphysis pubis and of the quadrilateral plate. Indications and techniques, how to develop this approach for the anatomical reduction and fixation of appropriate acetabular fractures, are demonstrated in this video. PMID- 29985895 TI - Supra-acetabular Pelvic External Fixator, Percutaneous With Fluoroscopic Guidance. AB - Unstable pelvic fractures are associated with high-energy trauma and can lead to increased morbidity and mortality if not managed properly in the acute setting. Early recognition and intervention is crucial for optimal patient outcomes. This article, in addition to the video footage, outlines a safe and effective method for stabilizing unstable pelvic fractures by applying a supra-acetabular pelvic external fixator using fluoroscopic guidance. PMID- 29985896 TI - Open Reduction and Internal Fixation of the Femoral Head via the Smith-Petersen Approach. AB - Pipkin described femoral head fractures in the 1950s, but controversy still exists regarding indications for surgery and approaches for operative treatment of femoral head fractures. Clear indications for operative intervention include inability to reduce the hip with closed methods, a nonconcentric reduction, fracture fragments within the articulating surface of the hip, and associated injuries (acetabulum and femoral neck fractures) with their own indications for surgery. The anterior approach described by Smith-Petersen has been modified (using only the distal portion) and used to visualize, clean, reduce, and fix these fractures with and without anterior dislocation of the hip. PMID- 29985897 TI - Posttraumatic Heterotopic Ossification of the Hip. AB - INTRODUCTION: Posttraumatic heterotopic ossification (HO) of the hip frequently follows acetabular fracture and hip surgery and can become symptomatic, with significant pain and limited range of motion (ROM). Definitive treatment may require surgical excision, which can result in serious complications if not planned and executed appropriately. METHODS: Surgical excision of posttraumatic hip HO requires appropriate indications, preoperative planning, and intraoperative guidance using fluoroscopy to maximize excision of HO and minimize complications. This video presents a case of severe posttraumatic hip HO, indications and technique of surgical excision using fluoroscopic guidance, postoperative protocol, and the patient's clinical follow-up. RESULTS: Surgical excision along with appropriate postoperative HO prophylaxis and immediate mobilization resulted in significant improvement in hip ROM and return to activities of daily living without complications or recurrence. Intraoperative blood loss can be significant and should be appropriately planned for preoperatively. CONCLUSIONS: Posttraumatic hip HO can cause significantly limited hip ROM and pain with resulting disability. Surgical excision of posttraumatic hip HO in a preserved hip joint can be successful in restoring hip ROM and function. Appropriate postoperative HO prophylaxis can prevent recurrence. PMID- 29985899 TI - Preoperative Planning for Percutaneous Transsacral, Transiliac Screws. AB - Percutaneous transsacral, transiliac screw placement is a well-described, well established management option for unstable posterior pelvic ring injuries. Safe and effective placement of these screws relies on extensive preoperative planning and scrutiny of the preoperative images. Malpositioning of the implants risks injury to the surrounding neurovascular structures. We present our methods for preoperative templating for safe placement of transsacral, transiliac screws. PMID- 29985898 TI - Autologous Bone Graft Harvest Using the Reamer-Irrigator-Aspirator. AB - Initially developed to reduce intramedullary pressures during long bone intramedullary nail placement, the reamer-irrigator-aspirator (RIA) can be used to harvest large volume autologous bone graft from the intramedullary canal of a long bone. This case-based surgical technique video demonstrates the appropriate techniques that should be applied while using the RIA to obtain autologous bone graft from the femur. A large volume of bone graft, generally between 30 and 90 cm, can be obtained using a single RIA procedure. The bone graft harvested from the intramedullary canal is excellent regarding its biochemical properties, with several studies reporting higher levels of growth factors and stem cells when compared with iliac crest bone graft. Surgical technique is key to maximize bone graft harvest, as well as to avoid complications including iatrogenic fracture, intraarticular penetration, and fragmentation of either the reamer head from the drive shaft or the guide wire. Pearls and pitfalls regarding sizing of the reamer head, determination of starting point, guide wire placement, reamer advancement, and diligent use of fluoroscopic imaging are highlighted during this video. Finally, outcomes regarding healing of long bone defects when using RIA-derived autologous bone graft and reduction in postoperative pain at the graft donor site are briefly reviewed. PMID- 29985900 TI - Intraoperative CT and Surgical Navigation for Iliosacral Screws: Technique for Patients With Sacral Dysmorphism. AB - Percutaneous iliosacral screw (IS) fixation for pelvic ring injuries with the use of an O-arm imaging system has been associated with decreased procedure time and improved accuracy of IS screw placement compared with the use of fluoroscopic guidance. Specifically, patients with sacral dysmorphism require identification of safe bony sacral corridors, using specific anatomical measurements, to decrease the likelihood of complications such as screw perforation. Intraoperative computed tomography imaging and navigation can aid in safe and accurate IS screw fixation in patients with difficult anatomy. PMID- 29985901 TI - Use of the 95-degree Angled Blade Plate to Treat a Proximal Femur Fracture. AB - There are a variety of ways to treat high-energy proximal femur fractures, including intramedullary nails and laterally based plates. Although each have distinct advantages and disadvantages, fracture reduction and avoiding varus alignment are critical. For some fractures, the blade plate is a reliable, straightforward implant to treat these injuries. This article and the accompanying video describe the surgical technique of using a 95-degree angled blade plate to treat an acute high-energy proximal femur fracture. PMID- 29985902 TI - ORIF With Submuscular Plating of an Intercondylar/Supracondylar Distal Femur Fracture. AB - Fractures of the distal femur with intercondylar extension and comminution are challenging cases and demand a thorough preoperative evaluation and execution of proper surgical technique. Identification of the intra-articular fractures, including coronal fractures of the lateral condyle, is important in planning surgery and emphasizes the need for computerized tomography scans. Recent advances with anatomic, locking plates have made minimally invasive surgery easier, but joint reduction needs to be performed meticulously in an open manner, and restoration of the mechanical alignment through plate fixation is essential for a good clinical outcome. Stable fixation that allows for early range of motion and mobilization are essential for the patient's recovery. This video demonstrates open reduction and internal fixation of a high-energy supracondylar/intercondylar distal femur fracture and emphasizes minimally invasive, biologically friendly techniques. PMID- 29985903 TI - Lateral Distal Femur Plate for Periprosthetic Fracture. AB - In this case, a lateral locking plate is used for fixation of a periprosthetic distal femur fracture in a 68-year-old woman. Modern implants with locking screw options and soft-tissue-sparing surgical techniques have improved the care of periprosthetic distal femur fractures. Although much debate about the working length and technical variables of plating exists, it is generally accepted that longer (>10 hole) plates with adequate working length and careful soft-tissue handling are preferred. This case outlines a stepwise approach to distal femur fractures to achieve appropriate plate position and restoration of alignment while avoiding excessive surgical exposure or soft-tissue dissection. In this case, retrograde intramedullary nail was not considered because of the distal nature of the fracture, but this option may be favorable for cruciate-retaining total knee arthroplasty or open box designs that will accommodate nail insertion. Although weight bearing was protected for 6 weeks, plate fixation allows early rehabilitation and knee range of motion. This patient went on to successful union and excellent clinical outcome with return to baseline function. PMID- 29985904 TI - Surgical Technique: Achieving Reduction With Temporizing, Knee-Spanning External Fixation. AB - INTRODUCTION: Peri- and intra-articular fractures about the knee are frequently managed with joint-spanning external fixation before definitive treatment. With a systematic approach, a near-anatomic reduction with respect to length, alignment, and rotation can be obtained. METHODS: This video highlights 2 clinical cases: a bicondylar tibial plateau fracture-dislocation and a distal femur fracture, both of which were treated with temporizing, knee-spanning external fixation. RESULTS: The indications, principles, and biomechanics of knee-spanning external fixation are presented. In addition, we demonstrate a systematic approach to applying knee spanning external fixation. CONCLUSIONS: Temporizing, joint-spanning external fixation is a critical treatment modality in the orthopaedic armamentarium for managing fractures about the knee. With a systematic approach, it is possible to obtain a near-anatomic reduction with respect to length, alignment, and rotation. PMID- 29985905 TI - Distal Tibial Intramedullary Nailing Using an Extraarticular, Lateral Parapatellar Approach in the Semiextended Position. AB - Semiextended positioning can improve the surgeon's ability to obtain, maintain, and fluoroscopically evaluate a fracture reduction when performing fixation with an intramedullary nail, especially in fractures at the proximal and distal ends. Furthermore, this position allows for evaluation of instrument placement, including the start point, without moving the fluoroscopic unit into extremes of angulation or compromising the quality of the beam orientation. The intraarticular suprapatellar approach has been described as a soft tissue approach to maintain the leg in a position that would not complicate management of these fractures, especially those in the proximal third of the tibia. A semiextended extraarticular soft tissue approach to the start point was described by Kubiak et al, and the lateral parapatellar version has become commonly used on the Orthopaedic Trauma Service at Washington University in Saint Louis. This video demonstrates advantages of semiextended positioning while performing reduction and intramedullary nail fixation for distal tibia fractures. This lateral parapatellar approach can be performed without specialized instrumentation, results in precise establishment of the start point and completion of the fixation without injury to the knee. PMID- 29985906 TI - ORIF Pilon via Posteromedial and Anterolateral Approaches. AB - Tibial pilon fractures are complex injuries of soft tissue and bone that challenge patients and surgeons. Outcomes following this injury are guarded, and complications are frequently reported. Soft-tissue compromise at the time of injury is potentially amplified with surgical trauma, necessitating thorough evaluation, preoperative planning, and expertise to minimize complications and maximize outcomes. Understanding angiosome anatomy and typical fracture patterns (and their variations) allows for design of surgical tactics that accomplish these goals. PMID- 29985907 TI - Surgical Technique: Achieving Anatomic Alignment With Temporizing, Ankle-Spanning External Fixation. AB - INTRODUCTION: Severe injuries to the ankle frequently result in soft tissue trauma too severe to proceed with immediate definitive fixation. Additionally, patients with multiple or vascular injuries may need a temporizing measure before undergoing definitive treatment. Temporizing, ankle-spanning external fixation offers a management strategy that allows for soft tissue rest and prioritized treatment of patients with polytrauma. METHODS: The video demonstrates 2 clinical cases managed with temporizing, ankle-spanning external fixation: a pilon fracture and a bimalleolar ankle fracture-dislocation. RESULTS: The indications, advantages, and a systematic operative approach to applying ankle-spanning external fixation are presented. Specific attention is paid to restoring an anatomic alignment of the ankle. CONCLUSIONS: Temporizing, ankle-spanning external fixation is an important modality in the management of fractures about the ankle, especially in patients with dislocation and/or severe soft tissue injury. A systematic approach that initially addresses length, followed by sagittal and coronal plane correction, can be used to restore anatomic alignment of the ankle. PMID- 29985908 TI - Ankle Spanning External Fixator Application. AB - A 2-stage approach to treatment of tibia pilon fractures was reported in the 1990s and popularized over the ensuing decade to help avoid catastrophic soft tissue complications experienced with one-stage open reduction and internal fixation. This approach can be expanded to the treatment of other high-energy injuries of the hind foot, with variation in external fixator application as needed. Key factors to maximize the utility and decrease complications of the external fixation stage include the following: (1) anatomic reduction of the talus under the long axis of the tibia in the coronal and sagittal planes, (2) strategic application of Schantz pins to resist deforming forces resulting from the injury, and (3) external fixation outside the zone of injury and definitive surgical treatment. This video demonstrates concepts and tactics to obtain and maintain fracture reduction with an external fixator with examples of a complex combined plafond and talus injury, as well as a more typical Orthopaedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen C-type pilon fracture. PMID- 29985909 TI - Open Reduction Internal Fixation of the Lisfranc Complex. AB - Lisfranc injuries are uncommon; however, if left untreated, it can have a detrimental effect causing deformity, chronic pain, and mid-foot arthrosis. Injury can include disruption of the first through fifth tarsometatarsal joints as well as variant patterns that include the involvement of the metatarsals, the naviculocuneiform articulation, and the cuboid. There is controversy regarding the benefits of open reduction internal fixation versus arthrodesis. Regardless, anatomical reduction is paramount to obtaining a good functional outcome. This video details the surgical approach and the reduction and fixation strategy of a high-energy Lisfranc complex fracture dislocation. PMID- 29985910 TI - Does Timing of Surgery Affect Treatment of the Terrible Triad of the Elbow? AB - BACKGROUND This study investigated the influence of surgical timing on the treatment of terrible triad of the elbow (TTE). MATERIAL AND METHODS After exclusion, 63 patients were enrolled in this study: 20 patients were classified into the emergency group (group A, within 24 h after injury), 26 into the early surgery group (group B, from 4 to 14 days after injury), and 17 into the delayed surgery group (group C, more than 14 days after injury). All patients underwent the same approach, and elbow motion and complication rates were recorded and compared. RESULTS Fifty-eight patients were followed up (mean 20.5+/-1.9 months), and 5 patients had lost partial final data. At 1 month after the operation, elbow motion in group A was higher than in group B and group C (P<0.01); however, 3 or more months later, there was no distinct difference between group A and group B (P>0.05), while both group A and group B showed better outcomes than group C at all time points (P<0.05). Moreover, group A and group B had better higher elbow motion, MEPS, excellent and good rate than group C at the final clinical visit (all P<0.05). No postoperative pain or complication rate differences were found among the 3 groups except for elbow stiffness (2 in group A, 3 in group B, and 7 in group C) (P<0.05) which required reoperation to enhance elbow function. CONCLUSIONS Emergency or early operation for TTE patients were more effective than delayed operation. PMID- 29985911 TI - Correction: A mechanistic pan-cancer pathway model informed by multi-omics data interprets stochastic cell fate responses to drugs and mitogens. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005985.]. PMID- 29985912 TI - CTEN induces epithelial-mesenchymal transition (EMT) and metastasis in non small cell lung cancer cells. AB - To explore the effects and mechanism of CTEN (COOH-terminus tensin-like molecule) on EMT, cell migration and invasion of Human lung adenocarcinoma cells. The pCMV vector, pCMV-CTEN, Control-shRNA, and CTEN-shRNA were transfected into A549 and NCI-H1299 cells by Lipofectamine 2000. Transforming growth factor-beta1(TGF beta1)and epithelial-mesenchymal transition (EMT) -related biomarkers were detected by eliseand western blot. The migration and invasion ability of A549 cells and NCI-H1299 were examined by scratch-wound assay and transwell assay respectively. We found compare with control group, the expression of TGF-beta and mesenchymal markers in CTEN overexpression group were increased, and the epithelial marker was decreased, which induced the EMT process. Meanwhile, scratch-woundassay showed that the migration efficiency of A549 and NCI-H1299 cells in CTEN overexpression group were higher than that in control group.Transwell assay demonstrated that the number of cells that migrated and invaded through the membrane were obviously more than those in control group.Furthermore, Knockdown of CTEN partially reversed transforming growth factor-beta1(TGF-beta1)-induced changes in EMT markers. In conclusion, CTEN activated the expression of TGF-beta1, thereby prompting EMT in lung adenocareinma cancer cells. PMID- 29985913 TI - Diagnostic performance of urinary IgG antibody detection: A novel approach for population screening of strongyloidiasis. AB - The diagnosis of strongyloidiasis by coprological methods has a low sensitivity, underestimating the prevalence of Strongyloides stercoralis in endemic areas. Serodiagnostic tests for strongyloidiasis have shown robust diagnostic properties. However, these methods require a blood draw, an invasive and labor intensive sample collection method, especially in the resource-limited settings where S. stercoralis is endemic. Our study examines a urine-based assay for strongyloidiasis and compares its diagnostic accuracy with coprological and serological methods. Receiver operating characteristic (ROC) curve analyses determined the diagnostic sensitivity (D-Sn) and specificity (D-Sp) of the urine ELISA, as well as estimates its positive predictive value and diagnostic risk. The likelihood ratios of obtaining a positive test result (LR+) or a negative test result (LR-) were calculated for each diagnostic positivity threshold. The urine ELISA assay correlated significantly with the serological ELISA assay for strongyloidiasis, with a D-Sn of 92.7% and a D-Sp of 40.7%, when compared to coprological methods. Moreover, the urine ELISA IgG test had a detection rate of 69%, which far exceeds the coprological method (28%). The likelihood of a positive diagnosis of strongyloidiasis by the urine ELISA IgG test increased significantly with increasing units of IgG detected in urine. The urine ELISA IgG assay for strongyloidiasis assay has a diagnostic accuracy comparable to serological assay, both of which are more sensitive than coprological methods. Since the collection of urine is easy and non-invasive, the urine ELISA IgG assay for strongyloidiasis could be used to screen populations at risk for strongyloidiasis in S. stercoralis endemic areas. PMID- 29985914 TI - Cholinergic-mediated coordination of rhythmic sympathetic and motor activities in the newborn rat spinal cord. AB - Here, we investigated intrinsic spinal cord mechanisms underlying the physiological requirement for autonomic and somatic motor system coupling. Using an in vitro spinal cord preparation from newborn rat, we demonstrate that the specific activation of muscarinic cholinergic receptors (mAchRs) (with oxotremorine) triggers a slow burst rhythm in thoracic spinal segments, thereby revealing a rhythmogenic capability in this cord region. Whereas axial motoneurons (MNs) were rhythmically activated during both locomotor activity and oxotremorine-induced bursting, intermediolateral sympathetic preganglionic neurons (IML SPNs) exhibited rhythmicity solely in the presence of oxotremorine. This somato-sympathetic synaptic drive shared by MNs and IML SPNs could both merge with and modulate the locomotor synaptic drive produced by the lumbar motor networks. This study thus sheds new light on the coupling between somatic and sympathetic systems and suggests that an intraspinal network that may be conditionally activated under propriospinal cholinergic control constitutes at least part of the synchronizing mechanism. PMID- 29985915 TI - The importance of mechanical constraints for proper polarization and psuedo cleavage furrow generation in the early Caenorhabditis elegans embryo. AB - Intracellular polarization, where a cell specifies a spatial axis by segregation of specific factors, is a fundamental biological process. In the early embryo of the nematode worm Caenorhabditis elegans (C. elegans), polarization is often accompanied by deformations of the cortex, a highly contractile structure consisting of actin filaments cross-linked by the motor protein myosin (actomyosin). It has been suggested that the eggshell surrounding the early embryo plays a role in polarization although its function is not understood. Here we develop a mathematical model which couples a reaction-diffusion model of actomyosin dynamics with a phase field model of the cell cortex to implicitly track cell shape changes in the early C. elegans embryo. We investigate the potential rigidity effect of the geometric constraint imposed by the presence and size of the eggshell on polarization dynamics. Our model suggests that the geometric constraint of the eggshell is essential for proper polarization and the size of the eggshell also affects the dynamics of polarization. Therefore, we conclude that geometric constraint on a cell might affect the dynamics of a biochemical process. PMID- 29985916 TI - The actin remodeling protein cofilin is crucial for thymic alphabeta but not gammadelta T-cell development. AB - Cofilin is an essential actin remodeling protein promoting depolymerization and severing of actin filaments. To address the relevance of cofilin for the development and function of T cells in vivo, we generated knock-in mice in which T-cell-specific nonfunctional (nf) cofilin was expressed instead of wild-type (WT) cofilin. Nf cofilin mice lacked peripheral alphabeta T cells and showed a severe thymus atrophy. This was caused by an early developmental arrest of thymocytes at the double negative (DN) stage. Importantly, even though DN thymocytes expressed the TCRbeta chain intracellularly, they completely lacked TCRbeta surface expression. In contrast, nf cofilin mice possessed normal numbers of gammadelta T cells. Their functionality was confirmed in the gammadelta T-cell driven, imiquimod (IMQ)-induced, psoriasis-like murine model. Overall, this study not only highlights the importance of cofilin for early alphabeta T-cell development but also shows for the first time that an actin-binding protein is differentially involved in alphabeta versus gammadelta T-cell development. PMID- 29985917 TI - Gain control with A-type potassium current: IA as a switch between divisive and subtractive inhibition. AB - Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two "modes" of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can "self-regulate" the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract. PMID- 29985918 TI - General Component Analysis (GCA): A new approach to identify Chinese corporate bond market structures. AB - PCA has been widely used in many fields to detect dominant principle components, but it ignores the information embedded in the remaining components. As a supplement to PCA, we propose the General Component Analysis (GCA). The inverse participation ratios (IPRs) are used to identify the global components (GCs) and localized components (LCs). The mean values of the IPRs derived from the shuffled data are taken as the natural threshold, which is exquisite and novel. In this paper, the Chinese corporate bond market is analyzed as an example. We propose a novel network method to divide time periods based on micro data, which performs better in capturing the time points when the market state switches. As a result, two periods have been obtained. There are two GCs in both periods, which are influenced by terms to maturity and ratings. Besides, there are 382 LCs in Period 1 and 166 LCs in Period 2. In the LC portfolios there are two interesting bond collections which are helpful to understand the thoughts of the investors. One is the supper AAA bond collection which is believed to have implicit governmental guarantees by the investors, and the other is the overcapacity industrial bond collection which is influenced by the supply-side reform led by the Chinese government. GCA is expected to be applied to other complex systems. PMID- 29985920 TI - Words by the tail: Assessing lexical diversity in scholarly titles using frequency-rank distribution tail fits. AB - This research assesses the evolution of lexical diversity in scholarly titles using a new indicator based on zipfian frequency-rank distribution tail fits. At the operational level, while both head and tail fits of zipfian word distributions are more independent of corpus size than other lexical diversity indicators, the latter however neatly outperforms the former in that regard. This benchmark-setting performance of zipfian distribution tails proves extremely handy in distinguishing actual patterns in lexical diversity from the statistical noise generated by other indicators due to corpus size fluctuations. From an empirical perspective, analysis of Web of Science (WoS) article titles from 1975 to 2014 shows that the lexical concentration of scholarly titles in Natural Sciences & Engineering (NSE) and Social Sciences & Humanities (SSH) articles increases by a little less than 8% over the whole period. With the exception of the lexically concentrated Mathematics, Earth & Space, and Physics, NSE article titles all increased in lexical concentration, suggesting a probable convergence of concentration levels in the near future. As regards to SSH disciplines, aggregation effects observed at the disciplinary group level suggests that, behind the stable concentration levels of SSH disciplines, a cross-disciplinary homogenization of the highest word frequency ranks may be at work. Overall, these trends suggest a progressive standardization of title wording in scientific article titles, as article titles get written using an increasingly restricted and cross-disciplinary set of words. PMID- 29985919 TI - Snakebite incidence in two townships in Mandalay Division, Myanmar. AB - INTRODUCTION: The global incidence of snakebite is estimated at more than 2.5 million cases annually, with greater than 100,000 deaths. Historically, Myanmar has one of the highest incidences of venomous snakebites. In order to improve the health outcomes of snakebite patients in Myanmar, access to accurate snakebite incidence data is crucial. The last population-based study in Myanmar was conducted more than a decade ago. In 2014, the Ministry of Health and Sports data from health facilities indicated an incidence of about 29.5 bites/ 100,000 population/year (a total of 15,079 bites). Since data from health facilities lack information about those who do not seek health care from government health services, a new population-based survey was conducted in 2 rural areas of Mandalay region. The survey data were compared to those obtained from healthcare services. METHOD: 4,276 rural respondents in Kyaukse and Madaya townships in Mandalay Division were recruited using cluster sampling that involved random selection of 150 villages and random sampling of 30 households from each village. One adult member of each household was interviewed using a structured questionnaire. RESULTS: One respondent from each of 4,276 households represented 19,877 residents from 144 villages. 24 people in these households had suffered snakebite during the last one year giving an annual incidence of 116/100,000. During the last ten years, 252 people suffered snakebites. 44.1% of the victims were women. 14% of the villages reported 4 or more bites during the last ten years, whereas 27% villages reported no snakebites. 92.4% of the victims recovered fully, 5.4% died, and 2% suffered long term health issues. One victim was reported to have died from causes unrelated to the snakebite. While there was no statistically significant difference between outcomes for children and adults, 4 of 38 of those under 18 years of age died compared to 7 of 133 adults between 19 to 40 years of age. CONCLUSION: This incidence reported by the community members points to substantially more snakebites than the number of snakebite patients attending health facilities. This higher incidence points to the need for a nation-wide population-based survey, community education about gaining access to care where antivenom is available, and to the potential need for a larger supply of antivenom and expansion of medical care in rural areas. PMID- 29985921 TI - Quantitative MRI evaluation of glaucomatous changes in the visual pathway. AB - BACKGROUND: The aims of this study were to investigate glaucomatous morphological changes quantitatively in the visual cortex of the brain with voxel-based morphometry (VBM), a normalizing MRI technique, and to clarify the relationship between glaucomatous damage and regional changes in the visual cortex of patients with open-angle glaucoma (OAG). METHODS: Thirty-one patients with OAG (age: 55.9 +/- 10.7, male: female = 9: 22) and 20 age-matched controls (age: 54.9 +/- 9.8, male: female = 10: 10) were included in this study. The cross-sectional area (CSA) of the optic nerve was manually measured with T2-weighed MRI. Images of the visual cortex were acquired with T1-weighed 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequencing, and the normalized regional visual cortex volume, i.e., gray matter density (GMD), in Brodmann areas (BA) 17, 18, and 19, was calculated with a normalizing technique based on statistic parametric mapping 8 (SPM8) analysis. We compared the regional GMD of the visual cortex in the control subjects and OAG patients. Spearman's rank correlation analysis was used to determine the relationship between optic nerve CSA and GMD in BA 17, 18, and 19. RESULTS: We found that the normal and OAG patients differed significantly in optic nerve CSA (p < 0.001) and visual cortex GMD in BA 17 (p = 0.030), BA 18 (p = 0.003), and BA 19 (p = 0.005). In addition, we found a significant correlation between optic nerve CSA and visual cortex GMD in BA 19 (r = 0.33, p = 0.023), but not in BA 17 (r = 0.17, p = 0.237) or BA 18 (r = 0.24, p = 0.099). CONCLUSION: Quantitative MRI parametric evaluation of GMD can detect glaucoma-associated anatomical atrophy of the visual cortex in BA 17, 18, and 19. Furthermore, GMD in BA 19 was significantly correlated to the damage level of the optic nerve, as well as the retina, in patients with OAG. This is the first demonstration of an association between the cortex of the brain responsible for higher-order visual function and glaucoma severity. Evaluation of the visual cortex with MRI is thus a very promising potential method for objective examination in OAG. PMID- 29985923 TI - Dynamical selection of Nash equilibria using reinforcement learning: Emergence of heterogeneous mixed equilibria. AB - We study the distribution of strategies in a large game that models how agents choose among different double auction markets. We classify the possible mean field Nash equilibria, which include potentially segregated states where an agent population can split into subpopulations adopting different strategies. As the game is aggregative, the actual equilibrium strategy distributions remain undetermined, however. We therefore compare with the results of a reinforcement learning dynamics inspired by Experience-Weighted Attraction (EWA) learning, which at long times leads to Nash equilibria in the appropriate limits of large intensity of choice, low noise (long agent memory) and perfect imputation of missing scores (fictitious play). The learning dynamics breaks the indeterminacy of the Nash equilibria. Non-trivially, depending on how the relevant limits are taken, more than one type of equilibrium can be selected. These include the standard homogeneous mixed and heterogeneous pure states, but also heterogeneous mixed states where different agents play different strategies that are not all pure. The analysis of the reinforcement learning involves Fokker-Planck modeling combined with large deviation methods. The theoretical results are confirmed by multi-agent simulations. PMID- 29985922 TI - Genome-wide identification and characterization of mRNAs and lncRNAs involved in cold stress in the wild banana (Musa itinerans). AB - Cold stress seriously affects banana growth, yield and fruit quality. Long noncoding RNAs (lncRNAs) have been demonstrated as key regulators of biotic and abiotic stress in plants, but the identification and prediction of cold responsive mRNAs and lncRNAs in wild banana remains unexplored. In present study, a cold resistant wild banana line from China was used to profile the cold responsive mRNAs and lncRNAs by RNA-seq under cold stress conditions, i.e. 13 degrees C (critical growth temperature), 4 degrees C (chilling temperature), 0 degrees C (freezing temperature) and normal growing condition, i.e. 28 degrees C (control group). A total of 12,462 lncRNAs were identified in cold-stressed wild banana. In mRNA, much more alternative splicing events occurred in wild banana under the cold stress conditions compared with that in the normal growing condition. The GO analysis of differential expression genes (DEGs) showed the biochemical processes and membrane related genes responded positively to the cold stress. The KEGG pathway enrichment analysis of the DEGs showed that the pathways of photosynthesis, photosynthesis-antenna proteins, circadian rhythm-plant, glutathione metabolism, starch and sucrose metabolism, cutin/suberine/biosynthesis were altered or affected by the cold stress conditions. Our analyses of the generated transcriptome and lncRNAs provide new insights into regulating expression of genes and lncRNAs that respond to cold stress in the wild banana. PMID- 29985925 TI - A knowledge, attitude, and practice survey on mediation among clinicians in a tertiary-care hospital in Singapore. AB - Healthcare delivery is a highly complex, deeply personal and costly endeavour that involves multiple specialties and services. There is an imbalance in knowledge between the healthcare provider and consumer that may contribute to doubts and uncertainty over treatment and outcomes. It is unsurprising that conflict and dispute can develop between healthcare providers and patients and their next-of-kin. The use of mediation in the healthcare setting has recently been promoted in many developed countries, including Singapore. We administered a detailed 32-item survey in a large tertiary-care teaching hospital to improve our understanding of the knowledge, attitude and practice of dispute resolution among clinicians to pave the way for better strategies to improve the adoption of mediation in healthcare setting. Ninety-seven respondents had an average of 62% (SD: 12%) knowledge score. The most common misconceptions held by the respondents about mediation were: (1) mediation was about fact-finding, (2) mediation is limited to only certain types of dispute, (3) mediation proceeds by both parties giving their account of the dispute, then a third party decides a settlement, (4) the average time it takes to resolve a dispute through mediation, (5) the cost of mediation, (5) the venue of mediation, (6) the person determining the outcome of mediation, (7) confidentiality of mediation. In general, the respondents were positive about the use of mediation as a dispute resolution tool. When asked to indicate the relative importance of different outcomes of dispute resolution, financial compensation and waiver of hospital bill attracted mixed responses while understanding facts of dispute, assurance that the same error would not recur, and offering corrective treatment were rated as being important. By contrast, seeking an apology from the complainant was considered neutral to somewhat important and the respondents were least concerned with the publicity of the dispute. Direct negotiation with the complainant was considered the most time and cost-efficient means of resolving a dispute while the opposite was true for litigation. Mediation was considered the approach where the clinicians are most likely to achieve their desired outcome while litigation was considered least likely to produce a favourable outcome. Approximately half of the respondents reported having personal experience or known of a colleague who had been involved in a medico-legal dispute. A quarter of these cases were resolved by direct negotiations with the complainant while lawyers, the judge and mediation, resolved approximately 15% each, respectively. The knowledge base of the clinicians in this study about mediation was moderate and probably reflected the general lack of direct experience in the resolution of a dispute or training in mediation. This further corroborated with the general response that the uptake of mediation in the healthcare setting is currently poor in Singapore due to the lack of awareness and perceived lack of avenue among the surveyed clinicians. Any further work to be done with clinicians may be in the direction of (1) increasing general understanding of mediation, (2) increasing awareness of avenues for mediation, and (3) becoming better aware of when to propose mediation. PMID- 29985924 TI - Insect diversity in the Saharo-Arabian region: Revealing a little-studied fauna by DNA barcoding. AB - Although insects dominate the terrestrial fauna, sampling constraints and the poor taxonomic knowledge of many groups have limited assessments of their diversity. Passive sampling techniques and DNA-based species assignments now make it possible to overcome these barriers. For example, Malaise traps collect specimens with minimal intervention while the Barcode Index Number (BIN) system automates taxonomic assignments. The present study employs Malaise traps and DNA barcoding to extend understanding of insect diversity in one of the least known zoogeographic regions, the Saharo-Arabian. Insects were collected at four sites in three countries (Egypt, Pakistan, Saudi Arabia) by deploying Malaise traps. The collected specimens were analyzed by sequencing 658 bp of cytochrome oxidase I (DNA barcode) and assigning BINs on the Barcode of Life Data Systems. The year long deployment of a Malaise trap in Pakistan and briefer placements at two Egyptian sites and at one in Saudi Arabia collected 53,092 specimens. They belonged to 17 insect orders with Diptera and Hymenoptera dominating the catch. Barcode sequences were recovered from 44,432 (84%) of the specimens, revealing the occurrence of 3,682 BINs belonging to 254 families. Many of these taxa were uncommon as 25% of the families and 50% of the BINs from Pakistan were only present in one sample. Family and BIN counts varied significantly through the year, but diversity indices did not. Although more than 10,000 specimens were analyzed from each nation, just 2% of BINs were shared by Pakistan and Saudi Arabia, 4% by Egypt and Pakistan, and 7% by Egypt and Saudi Arabia. The present study demonstrates how the BIN system can circumvent the barriers imposed by limited access to taxonomic specialists and by the fact that many insect species in the Saharo-Arabian region are undescribed. PMID- 29985926 TI - Global methylation in relation to methotrexate-induced oral mucositis in children with acute lymphoblastic leukemia. AB - BACKGROUND: Children with acute lymphoblastic leukemia (ALL) often suffer from toxicity of chemotherapeutic drugs such as Methotrexate (MTX). Previously, we reported that 20% of patients receiving high-dose MTX developed oral mucositis. MTX inhibits folate metabolism, which is essential for DNA methylation. We hypothesize that MTX inhibits DNA methylation, which results into adverse effects. We studied DNA methylation markers during high-dose methotrexate treatment in pediatric acute lymphoblastic leukemia (ALL) in relation to developing oral mucositis. MATERIALS & METHODS: S-Adenosyl-Methionine (SAM) and S Adenosyl-Homocysteine (SAH) levels and LINE1 DNA methylation were measured prospectively before and after high-dose methotrexate (HD-MTX 4 x 5g/m2) therapy in 82 children with ALL. Methotrexate-induced oral mucositis was registered prospectively. Oral mucositis (grade >= 3 National Cancer Institute Criteria) was used as clinical endpoint. RESULTS: SAM levels decreased significantly during methotrexate therapy (-16.1 nmol/L (-144.0 -+46.0), p<0.001), while SAH levels and the SAM:SAH ratio did not change significantly. LINE1 DNA methylation (+1.4% (-1.1 -+6.5), p<0.001) increased during therapy. SAM and SAH levels were not correlated to LINE1 DNA methylation status. No association was found between DNA methylation markers and developing oral mucositis. CONCLUSIONS: This was the first study that assessed DNA methylation in relation to MTX-induced oral mucositis in children with ALL. Although global methylation markers did change during methotrexate therapy, methylation status was not associated with developing oral mucositis. PMID- 29985928 TI - Computed tomography and histopathological findings after embolization with inherently radiopaque 40MUm-microspheres, standard 40MUm-microspheres and iodized oil in a porcine liver model. AB - PURPOSE: The present study compared standard computed tomography (CT) and histopathological findings after endovascular embolization using a prototype of inherently radiopaque 40MUm-microspheres with both standard 40MUm-microspheres and iodized oil in a porcine liver model. MATERIALS AND METHODS: Twelve pigs were divided into six study groups, of two pigs each. Four pigs were embolized with iodized oil alone and four with radiopaque microspheres; two animals in each group were sacrificed at 2 hours and two at 7 days. Two pigs were embolized with radiopaque microspheres and heparin and sacrificed at 7 days. Two pigs were embolized with standard microspheres and sacrificed at 2 hours. CT was performed before and after segmental embolization and before sacrifice at 7 days. The distribution of embolic agent, inflammatory response and tissue necrosis were assessed histopathologically. RESULTS: Radiopaque microspheres and iodized oil were visible on standard CT 2 hours and 7 days after embolization, showing qualitatively comparable arterial and parenchymal enhancement. Quantitatively, the enhancement was more intense for iodized oil. Standard microspheres, delivered without contrast, were not visible by imaging. Radiopaque and standard microspheres similarly occluded subsegmental and interlobular arteries and, to a lesser extent, sinusoids. Iodized oil resulted in the deepest penetration into sinusoids. Necrosis was always observed after embolization with microspheres, but never after embolization with iodized oil. The inflammatory response was mild to moderate for microspheres and moderate to severe for iodized oil. CONCLUSION: Radiopaque 40MUm-microspheres are visible on standard CT with qualitatively similar but quantitatively less intense enhancement compared to iodized oil, and with a tendency towards less of an inflammatory reaction than iodized oil. These microspheres also result in tissue necrosis, which was not observed after embolization with iodized oil. Both radiopaque and standard 40MUm-microspheres are found within subsegmental and interlobar arteries, as well as in hepatic sinusoids. PMID- 29985927 TI - Regulation of the opposing (p)ppGpp synthetase and hydrolase activities in a bifunctional RelA/SpoT homologue from Staphylococcus aureus. AB - The stringent response is characterized by (p)ppGpp synthesis resulting in repression of translation and reprogramming of the transcriptome. In Staphylococcus aureus, (p)ppGpp is synthesized by the long RSH (RelA/SpoT homolog) enzyme, RelSau or by one of the two short synthetases (RelP, RelQ). RSH enzymes are characterized by an N-terminal enzymatic domain bearing distinct motifs for (p)ppGpp synthetase or hydrolase activity and a C-terminal regulatory domain (CTD) containing conserved motifs (TGS, DC and ACT). The intramolecular switch between synthetase and hydrolase activity of RelSau is crucial for the adaption of S. aureus to stress (stringent) or non-stress (relaxed) conditions. We elucidated the role of the CTD in the enzymatic activities of RelSau. Growth pattern, transcriptional analyses and in vitro assays yielded the following results: i) in vivo, under relaxed conditions, as well as in vitro, the CTD inhibits synthetase activity but is not required for hydrolase activity; ii) under stringent conditions, the CTD is essential for (p)ppGpp synthesis; iii) RelSau lacking the CTD exhibits net hydrolase activity when expressed in S. aureus but net (p)ppGpp synthetase activity when expressed in E. coli; iv) the TGS and DC motifs within the CTD are required for correct stringent response, whereas the ACT motif is dispensable, v) Co-immunoprecipitation indicated that the CTD interacts with the ribosome, which is largely dependent on the TGS motif. In conclusion, RelSau primarily exists in a synthetase-OFF/hydrolase-ON state, the TGS motif within the CTD is required to activate (p)ppGpp synthesis under stringent conditions. PMID- 29985929 TI - Epitope-mapping of the glycoprotein from Crimean-Congo hemorrhagic fever virus using a microarray approach. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) causes severe acute human disease with lethal outcome. The knowledge about the immune response for this human health threat is highly limited. In this study, we have screened the glycoprotein of CCHFV for novel linear B-cell epitopic regions using a microarray approach. The peptide library consisted of 168 synthesized 20mer peptides with 10 amino acid overlap covering the entire glycoprotein. Using both pooled and individual human sera from survivors of CCHF disease in Turkey five peptide epitopes situated in the mucin-like region and GP 38 (G15-515) and GN G516-1037 region of the glycoprotein were identified as epitopes for a CCHF immune response. An epitope walk of the five peptides revealed a peptide sequence located in the GN region with high specificity and sensitivity. This peptide sequence, and a sequence downstream, reacted also against sera from survivors of CCHF disease in South Africa. The cross reactivity of these peptides with samples from a geographically distinct region where genetically diverse strains of the virus circulate, enabled the identification of unique peptide epitopes from the CCHF glycoprotein that could have application in development of diagnostic tools. In this study clinical samples from geographically distinct regions were used to identify conserved linear epitopic regions of the glycoprotein of CCHF. PMID- 29985930 TI - Socioeconomic risk markers of leprosy in high-burden countries: A systematic review and meta-analysis. AB - Over 200,000 new cases of leprosy are detected each year, of which approximately 7% are associated with grade-2 disabilities (G2Ds). For achieving leprosy elimination, one of the main challenges will be targeting higher risk groups within endemic communities. Nevertheless, the socioeconomic risk markers of leprosy remain poorly understood. To address this gap we systematically reviewed MEDLINE/PubMed, Embase, LILACS and Web of Science for original articles investigating the social determinants of leprosy in countries with > 1000 cases/year in at least five years between 2006 and 2016. Cohort, case-control, cross-sectional, and ecological studies were eligible for inclusion; qualitative studies, case reports, and reviews were excluded. Out of 1,534 non-duplicate records, 96 full-text articles were reviewed, and 39 met inclusion criteria. 17 were included in random-effects meta-analyses for sex, occupation, food shortage, household contact, crowding, and lack of clean (i.e., treated) water. The majority of studies were conducted in Brazil, India, or Bangladesh while none were undertaken in low-income countries. Descriptive synthesis indicated that increased age, poor sanitary and socioeconomic conditions, lower level of education, and food-insecurity are risk markers for leprosy. Additionally, in pooled estimates, leprosy was associated with being male (RR = 1.33, 95% CI = 1.06-1.67), performing manual labor (RR = 2.15, 95% CI = 0.97-4.74), suffering from food shortage in the past (RR = 1.39, 95% CI = 1.05-1.85), being a household contact of a leprosy patient (RR = 3.40, 95% CI = 2.24-5.18), and living in a crowded household (>=5 per household) (RR = 1.38, 95% CI = 1.14-1.67). Lack of clean water did not appear to be a risk marker of leprosy (RR = 0.94, 95% CI = 0.65-1.35). Additionally, ecological studies provided evidence that lower inequality, better human development, increased healthcare coverage, and cash transfer programs are linked with lower leprosy risks. These findings point to a consistent relationship between leprosy and unfavorable economic circumstances and, thereby, underscore the pressing need of leprosy control policies to target socially vulnerable groups in high-burden countries. PMID- 29985931 TI - Identifying influential nodes based on network representation learning in complex networks. AB - Identifying influential nodes is an important topic in many diverse applications, such as accelerating information propagation, controlling rumors and diseases. Many methods have been put forward to identify influential nodes in complex networks, ranging from node centrality to diffusion-based processes. However, most of the previous studies do not take into account overlapping communities in networks. In this paper, we propose an effective method based on network representation learning. The method considers not only the overlapping communities in networks, but also the network structure. Experiments on real world networks show that the proposed method outperforms many benchmark algorithms and can be used in large-scale networks. PMID- 29985932 TI - African and Asian strains of Zika virus differ in their ability to infect and lyse primitive human placental trophoblast. AB - Zika virus (ZIKV) drew worldwide attention when a recent epidemic was linked to fetal microcephaly. Here we used human embryonic stem cell derived trophoblasts as a model for primitive placental trophoblast to test the hypothesis that there are differences in how the two genetically distinct ZIKV lineages, African (AF) and Asian (AS), target the human placenta. Upon infection with three AF (ib H30656, SEN/1984/41525-DAK, and MR-766) and three AS (FSS13025, MexI-44, and PANcdc259249) ZIKV strains, we observed that severe placental cell lysis was only induced after infection with AF strains, while viral replication rates remained similar between both lineages. Differences in cytopathic effects (CPE) were not observed in Vero cells, indicating that the AF strains were not inherently superior at cell lysis. Taken together, we propose that infection with AF strains of ZIKV early in pregnancy would likely result in pregnancy loss, rather than allow further fetal development with accompanying brain damage. Our results also suggest that the long term laboratory-adapted MR-766 strain does not behave aberrantly in cell culture relative to other AF lineage strains. PMID- 29985933 TI - Combining H-FABP and GFAP increases the capacity to differentiate between CT positive and CT-negative patients with mild traumatic brain injury. AB - Mild traumatic brain injury (mTBI) patients may have trauma-induced brain lesions detectable using CT scans. However, most patients will be CT-negative. There is thus a need for an additional tool to detect patients at risk. Single blood biomarkers, such as S100B and GFAP, have been widely studied in mTBI patients, but to date, none seems to perform well enough. In many different diseases, combining several biomarkers into panels has become increasingly interesting for diagnoses and to enhance classification performance. The present study evaluated 13 proteins individually-H-FABP, MMP-1, MMP-3, MMP-9, VCAM, ICAM, SAA, CRP, GSTP, NKDA, PRDX1, DJ-1 and IL-10-for their capacity to differentiate between patients with and without a brain lesion according to CT results. The best performing proteins were then compared and combined with the S100B and GFAP proteins into a CT-scan triage panel. Patients diagnosed with mTBI, with a Glasgow Coma Scale score of 15 and one additional clinical symptom were enrolled at three different European sites. A blood sample was collected at hospital admission, and a CT scan was performed. Patients were divided into two two-centre cohorts and further dichotomised into CT-positive and CT-negative groups for statistical analysis. Single markers and panels were evaluated using Cohort 1. Four proteins-H-FABP, IL 10, S100B and GFAP-showed significantly higher levels in CT-positive patients. The best-performing biomarker was H-FABP, with a specificity of 32% (95% CI 23 40) and sensitivity reaching 100%. The best-performing two-marker panel for Cohort 1, subsequently validated in Cohort 2, was a combination of H-FABP and GFAP, enhancing specificity to 46% (95% CI 36-55). When adding IL-10 to this panel, specificity reached 52% (95% CI 43-61) with 100% sensitivity. These results showed that proteins combined into panels could be used to efficiently classify CT-positive and CT-negative mTBI patients. PMID- 29985934 TI - Care workers, the unacknowledged persons in person-centred care: A secondary qualitative analysis of UK care home staff interviews. AB - Personhood discourses in dementia care have gained prominence and current care home standards mandate that care should be "person-centred". However, it is unclear how the personhood of staff is construed within the care relationship. This paper aims to explore how the personhood of paid carers of people with dementia can be understood by focussing on the views and experiences of care home staff. We undertook a secondary qualitative analysis of interviews with 25 paid care staff in England, conducted as part of the MARQUE (Managing Agitation and Raising QUality of lifE) study. The authors inductively developed themes around the topic of personhood for staff, contrasting management and care staff perspectives. We found that many care staff are not identified as persons in their own right by their employing institutions, and that there is a general lack of acknowledgment of the moral work of caring that occurs within formal care work. This oversight can reduce the complex relationships of care work to a series of care tasks, challenges care workers' self-worth and self-efficacy, and impede their efforts to deliver person-centred care. We conclude that care staff status as persons in their own right should be explicitly considered in quality standards and supported by employers' policies and practices, not simply for their role in preserving the personhood of people with dementia but for their own sense of valued personhood. Enhancing staff personhood may also result in improved care. PMID- 29985935 TI - Fractal-structured multifocal intraocular lens. AB - In this work, we present a new concept of IOL design inspired by the demonstrated properties of reduced chromatic aberration and extended depth of focus of Fractal zone plates. A detailed description of a proof of concept IOL is provided. The result was numerically characterized, and fabricated by lathe turning. The prototype was tested in vitro using dedicated optical system and software. The theoretical Point Spread Function along the optical axis, computed for several wavelengths, showed that for each wavelength, the IOL produces two main foci surrounded by numerous secondary foci that partially overlap each other for different wavelengths. The result is that both, the near focus and the far focus, have an extended depth of focus under polychromatic illumination. This theoretical prediction was confirmed experimentally by means of the Through-Focus Modulation Transfer Function, measured for different wavelengths. PMID- 29985936 TI - Largely different carotenogenesis in two pummelo fruits with different flesh colors. AB - Carotenoids in citrus fruits have health benefits and make the fruits visually attractive. Red-fleshed 'Chuhong' ('CH') and pale green-fleshed 'Feicui' ('FC') pummelo (Citrus maxima (Burm) Merr.) fruits are interesting materials for studying the mechanisms of carotenoid accumulation. In this study, particularly high contents of linear carotenes were observed in the albedo tissue, segment membranes and juice sacs of 'CH'. However, carotenoids, especially beta-carotene and xanthophylls, accumulated more in the flavedo tissue of 'FC' than in that of 'CH'. Additionally, the contents of other terpenoids such as limonin, nomilin and abscisic acid significantly differed in the juice sacs at 150 days postanthesis. A dramatic increase in carotenoid production was observed at 45 to 75 days postanthesis in the segment membranes and juice sacs of 'CH'. Different expression levels of carotenogenesis genes, especially the zeta-carotene desaturase (CmZDS), beta-carotenoid hydroxylase (CmBCH) and zeaxanthin epoxidase (CmZEP) genes, in combination are directly responsible for the largely different carotenoid profiles between these two pummelo fruits. The sequences of eleven genes involved in carotenoid synthesis were investigated; different alleles of seven of eleven genes might also explain the largely different carotenogenesis observed between 'CH' and 'FC'. These results enhance our understanding of carotenogenesis in pummelo fruits. PMID- 29985937 TI - The prevalence of endoscopic gastric mucosal damage in patients with rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) patients often take non-steroidal anti inflammatory drugs (NSAIDs) and corticosteroids as supportive drugs. In this study, we investigated the prevalence of endoscopic gastric damage and their prescribed medications under an actual clinical condition. METHODS: We collected the data of 1704 RA patients who underwent upper gastrointestinal fiberscopy. Gastric mucosal erosion and ulcer were classified using modified LANZA score. We analyzed these data with a multiple regression analysis. RESULTS: The prevalence of endoscopic gastric mucosal damage in these RA patients was 16.7% (285 cases). A multiple regression analysis indicated that prednisolone (PSL), NSAIDs and proton pump inhibitors (PPIs) were independent risk factors associated with the modified LANZA score. PSL and NSAIDs were positively correlated with the score, while the administration of PPIs was inversely correlated with the score. The modified LANZA score in RA patients treated with both PSL and NSAIDs was significantly higher than that in those treated with PSL alone (no NSAIDs use). CONCLUSIONS: Our findings suggest that PSL and NSAIDs were exacerbating factors for gastric mucosal damage, while PPIs usage was a protective factor. And, the combined usage of corticosteroids and NSAIDs may induce the development of gastric ulcers. PMID- 29985938 TI - Gender-specific associations between fat mass, metabolic syndrome and musculoskeletal pain in community residents: A three-year longitudinal study. AB - Increase in fat mass is correlated with musculoskeletal pain. The aim of this study was to examine the relationship between fat mass and the musculoskeletal pain prospectively in Korean community residents. In the Korean Health and Genome Study, participants (mean age 60.2 years, 56.2% women) completed pain questionnaires and underwent dual x-ray absorptiometry to calculate body composition. Three-year follow-up data on pain was available for 1,325 participants. Pain was categorized according to number of pain regions. At three years of follow-up, participants were classified as follows: 1) no pain both at baseline and at three years (no pain), 2) any pain (one, two or more, or widespread regions) at baseline and no pain at three years (transient pain), 3) no pain at baseline and any pain at three years (new pain) 4) any pain both at baseline and at 3 years (persistent pain). 1) and 2) were grouped as no/transient pain group (no pain) and 3) and 4) as new/persistent pain group (pain). Female gender and obesity were two significant factors associated with the persistence or development of pain. Total fat mass and fat:muscle mass ratio were associated with pain among female participants only, and the odds ratios for pain were significantly increased in female participants in the highest quartile of total fat mass and fat muscle ratio after adjustment. In conclusion, both female gender and obesity were two significant factors associated with pain. Fat mass parameters and pain were significantly associated only among females. PMID- 29985939 TI - Creating longitudinal datasets and cleaning existing data identifiers in a cystic fibrosis registry using a novel Bayesian probabilistic approach from astronomy. AB - Patient registry data are commonly collected as annual snapshots that need to be amalgamated to understand the longitudinal progress of each patient. However, patient identifiers can either change or may not be available for legal reasons when longitudinal data are collated from patients living in different countries. Here, we apply astronomical statistical matching techniques to link individual patient records that can be used where identifiers are absent or to validate uncertain identifiers. We adopt a Bayesian model framework used for probabilistically linking records in astronomy. We adapt this and validate it across blinded, annually collected data. This is a high-quality (Danish) sub-set of data held in the European Cystic Fibrosis Society Patient Registry (ECFSPR). Our initial experiments achieved a precision of 0.990 at a recall value of 0.987. However, detailed investigation of the discrepancies uncovered typing errors in 27 of the identifiers in the original Danish sub-set. After fixing these errors to create a new gold standard our algorithm correctly linked individual records across years achieving a precision of 0.997 at a recall value of 0.987 without recourse to identifiers. Our Bayesian framework provides the probability of whether a pair of records belong to the same patient. Unlike other record linkage approaches, our algorithm can also use physical models, such as body mass index curves, as prior information for record linkage. We have shown our framework can create longitudinal samples where none existed and validate pre-existing patient identifiers. We have demonstrated that in this specific case this automated approach is better than the existing identifiers. PMID- 29985940 TI - The Relative Age Effect in under-18 basketball: Effects on performance according to playing position. AB - The Relative Age Effect (RAE) in sport is defined as the age difference in the same sport group. This chronological difference implies a different level of sport experience and performance due to developmental and maturational processes. The aim of the present study was to analyze the relative age effect in elite u-18 basketball according to playing positions. The variables analyzed were: date of birth, playing position and technical-tactical performance indicators in basketball (TTPI). A descriptive analysis was carried out to characterize the sample, a lineal regression was used to analyze the influence of the date of birth on basketball performance and finally an ANOVA and discriminant analysis were performed to identify the differences among different playing positions. The results show the existence of the RAE in the top European Under-18 basketball competition (S1 = 67%; S2 = 33%). Performance indicators which are predictors of the birth quarter (p< .05) were only found in the small forwards (defensive rebounds (beta: -.463) and fouls received (beta: -.140)) and in the centers (three point throws scored (beta: -.321) and tried (beta: .342)). These results may be of use for coaches and clubs when recruiting players for each playing position. Older forwards and centers are capable of performing at a higher level. Therefore, clubs have to sign up those players born at the beginning of the year. PMID- 29985941 TI - No unexpected CRISPR-Cas9 off-target activity revealed by trio sequencing of gene edited mice. AB - CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole genome sequencing (WGS) of gene-edited embryos or animals to search for de novo mutations (DNMs), which may represent candidate changes introduced by poor editing fidelity. Critically, these studies used strain-matched, but not pedigree matched controls and thus were unable to reliably distinguish generational or colony-related differences from true DNMs. Here we used a trio design and whole genome sequenced 8 parents and 19 embryos, where 10 of the embryos were mutagenised with well-characterised gRNAs targeting the coat colour Tyrosinase (Tyr) locus. Detailed analyses of these whole genome data allowed us to conclude that if CRISPR mutagenesis were causing SNV or indel off-target mutations in treated embryos, then the number of these mutations is not statistically distinguishable from the background rate of DNMs occurring due to other processes. PMID- 29985942 TI - Ex vivo HIV entry into blood CD4+ T cells does not predict heterosexual HIV acquisition in women. AB - BACKGROUND: A blood-based assay that could quantify HIV susceptibility would be very valuable for HIV prevention research. Previously, we developed and validated an ex vivo, flow-based, HIV entry assay to assess genital HIV susceptibility in endocervical CD4+ T cells. METHODS: Here we assessed whether this tool could be used to predict HIV risk using blood-derived CD4+ T cells in a rigorously blinded, nested case-control study using blood samples collected from high-risk, HIV-uninfected South African women enrolled in the CAPRISA 004 clinical trial. Cases, subsequently acquiring HIV were sampled prior to HIV infection and compared with controls, who remained HIV-uninfected. The primary endpoint was ex vivo entry of a CCR5-tropic HIV founder virus into blood CD4+ T cells. Secondary endpoints included HIV entry into CD4+ central (TCM) and effector (TEM) memory T cells, and into CD4+ T cell subsets expressing CCR5, CD69, CCR6, alpha4beta1 or alpha4beta7. RESULTS: Compared to bulk CD4+ T cells (4.9% virus entry), CD4+ T cells expressing CCR5, CCR6 or alpha4beta1 and TEM were highly susceptible (15.5%, 8.8%, 8.2% and 10.8% entry, respectively, all p<0.0001), while TCM, CD69+ or alpha4beta7+ CD4+ cells were moderately susceptible (6.4%, 6.0% and 5.8% respectively, p <= 0.003). While the proportion of the aforementioned highly susceptible cells correlated with overall virus entry into CD4+ T cells within an individual (r = 0.68, 0.47, 0.67, and 0.60 respectively, p<0.0001), blood virus entry did not predict subsequent mucosal HIV acquisition after controlling for sexual behaviour and condom use (OR 0.92, 95% CI 0.77-1.11, p = 0.40). CONCLUSIONS: Although virus entry identified several previously known highly susceptible cellular HIV targets, blood HIV entry did not predict subsequent heterosexual HIV acquisition. Assessment of mucosal HIV susceptibility may require sampling at the site of HIV exposure. PMID- 29985943 TI - Development of a scoring method to visually score cortical interruptions on high resolution peripheral quantitative computed tomography in rheumatoid arthritis and healthy controls. AB - OBJECTIVES: To develop a scoring method to visually score cortical interruptions in finger joints on High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT), determine its intra- and inter-reader reliability and test its feasibility. METHODS: The scoring method was developed by integrating results from in-depth discussions with experts, consensus meetings, multiple reading experiments and the literature. Cortical interruptions were scored by two independent readers in an imaging dataset with finger joints from patients with rheumatoid arthritis (RA) and healthy controls and assessed for adjacent trabecular distortion. Reliability for the total number of cortical interruptions per joint and per quadrant was calculated using intraclass correlation coefficient (ICC). Feasibility was tested by recording the time to analyze one joint. RESULTS: In 98 joints we identified 252 cortical interruptions, 17% had trabecular distortion. Mean diameter of the interruptions was significantly larger in patients with RA compared with healthy controls (0.88 vs 0.47 mm, p = 0.03). Intra-reader reliability was ICC 0.88 (95% CI 0.83;0.92) per joint and ICC 0.69 (95% CI 0.65;0.73) per quadrant. Inter-reader reliability was ICC 0.48 (95% CI 0.20;0.67) per joint and ICC 0.56 (95% CI 0.49;0.62) per quadrant. The time to score one joint was mean 9.2 (SD 4.9) min. CONCLUSIONS: This scoring method allows detection of small cortical interruptions on HR-pQCT imaging of finger joints, which is promising for use in clinical studies. PMID- 29985944 TI - Germination ecology of Chloris truncata and its implication for weed management. AB - Chloris truncata is a significant weed in summer crops in the subtropical region of Australia. A study was conducted to evaluate the effect of environmental factors on germination and emergence of two populations of C. truncata. Overall, germination was not affected by the populations. Seeds germinated at a wide range of alternating day/night temperatures, suggesting that seeds can germinate throughout the spring, winter and autumn seasons. Seed germination was stimulated by the presence of light; however, 51 to 71% of these seeds still germinated in the dark. The sodium chloride concentration and osmotic potential required to inhibit germination of 50% of the population were 179 mM and -0.52 MPa, respectively. A high proportion of seeds germinated over a wide pH range (4 to 10). Seeds placed on the soil surface had greatest germination (67%) and a burial depth of 3 cm resulted in complete inhibition of emergence. The sorghum residue amount required to reduce emergence by 50% was 1.8 t ha-1. The results suggest that, although this weed will be favored in no-till systems, residue retention on the soil surface will help in reducing its infestation. Seed bank buildup can be managed by burying seeds below the depth of emergence. PMID- 29985945 TI - Inhibition of ferrochelatase impairs vascular eNOS/NO and sGC/cGMP signaling. AB - Ferrochelatase (FECH) is an enzyme necessary for heme synthesis, which is essential for maintaining normal functions of endothelial nitric oxide synthase (eNOS) and soluble guanylyl cyclase (sGC). We tested the hypothesis that inhibition of vascular FECH to attenuate heme synthesis downregulates eNOS and sGC expression, resulting in impaired NO/cGMP-dependent relaxation. To this end, isolated bovine coronary arteries (BCAs) were in vitro incubated without (as controls) or with N-methyl protoporphyrin (NMPP; 10-5-10-7M; a selective FECH antagonist) for 24 and 72 hours respectively. Tissue FECH activity, heme, nitrite/NO and superoxide levels were sequentially measured. Protein expression of FECH, eNOS and sGC was detected by western blot analysis. Vascular responses to various vasoactive agents were evaluated via isometric tension studies. Treatment of BCAs with NMPP initiated a time- and dose-dependent attenuation of FECH activity without changes in its protein expression, followed by significant reduction in the heme level. Moreover, ACh-induced relaxation and ACh-stimulated release of NO were significant reduced, associated with suppression of eNOS protein expression in NMPP-treated groups. Decreased relaxation to NO donor spermine-NONOate reached the statistical significance in BCAs incubated with NMPP for 72 hours, concomitantly with downregulation of sGCbeta1 expression that was independent of heat shock protein 90 (HSP90), nor did it significantly affect BCA relaxation caused by BAY 58-2667 that activates sGC in the heme-deficiency. Neither vascular responses to non-NO/sGC-mediators nor production of superoxide was affected by NMPP-treatment. In conclusion, deletion of vascular heme production via inhibiting FECH elicits downregulation of eNOS and sGC expression, leading to an impaired NO-mediated relaxation in an oxidative stress-independent manner. PMID- 29985946 TI - Knowledge, attitude and practice on diet and physical activity among mothers with young children in the Jhaukhel-Duwakot Health Demographic Surveillance Site, Nepal. AB - The prevalence of cardiovascular diseases is increasing in low and middle-income countries; Nepal's population shows a high prevalence of behavioral risk factors. Our cross-sectional study in the Jhaukhel-Duwakot Health Demographic Surveillance Site (JD-HDSS), located near the capital Kathmandu, explored knowledge, attitude, and practice (KAP) of mothers with young children regarding diet and physical activity and mothers' perception of their children's attitude and behavior toward the same issues. The purpose of our study was to assess needs of the mothers concerning cardiovascular health in general and more specifically regarding diet and physical activity, and to establish a baseline for future intervention in the community by comparing two villages of JD-HDSS. In August-November 2014, nine trained enumerators interviewed all mothers of children aged 1-7 years (N = 962). We scored responses on dietary and physical activity KAP, then categorized the scores based on the percentage obtained out of the maximum possible scores into "poor," "fair," and "good." More highly educated mothers scored higher for KAP (all p<0.001); the children's behavior score reflected their mother's education level (p = 0.007). Most respondents were unfamiliar with the concept of healthy and unhealthy food. Overall, 57% of respondents in JD-HDSS had "good" knowledge, 44.6% had "good" attitude, and most (90%) had "poor" practice. We observed no significant differences between the villages regarding mothers' knowledge and attitude or children's behavior. Practice score of mothers in Jhaukhel was higher than those in Duwakot regarding diet and physical activity (p<0.001). Mothers' perceived barriers for improving lifestyle were high cost of healthy food, taste preference of other family members, and lack of knowledge regarding healthy food. Barriers for physical activity were lack of leisure time, absence of parks and playgrounds, busy caring for children and old people, feeling lazy, and embarrassed to be physically active in front of others. Our findings suggest that a health education intervention promoting a healthy lifestyle for mothers and children might improve KAP and also improve cardiovascular health. To address mothers' gap between knowledge and practice, a future intervention should consider perceived barriers. PMID- 29985947 TI - Correction: Metabolic and taxonomic insights into the Gram-negative natural rubber degrading bacterium Steroidobacter cummioxidans sp. nov., strain 35Y. AB - [This corrects the article DOI: 10.1371/journal.pone.0197448.]. PMID- 29985949 TI - Improving the impact of HIV pre-exposure prophylaxis implementation in small urban centers among men who have sex with men: An agent-based modelling study. AB - OBJECTIVES: Identifying prescribing strategies that improve the efficiency of PrEP should increase its impact at the population level. This study identifies PrEP allocation criteria that most effectively reduce 10-year HIV incidence by 25%, in accordance with the US National HIV/AIDS Strategy's goal for the proportionate reduction in new diagnoses. METHODS: We used a discrete-time stochastic agent-based model to simulate several PrEP engagement strategies. The model represented MSM aged 15-74 in Rhode Island and was calibrated to statewide prevalence from 2009-2014. We simulated HIV transmission in the absence of PrEP and compared the following PrEP engagement scenarios: 1) allocation to the current patient population; 2) random allocation; 3) allocation to MSM with greater than 5 sexual partners in one year; 4) allocation to MSM with greater than 10 sexual partners in one year. For each scenario and coverage level we estimated the number and proportion of infections averted and the person-years on PrEP per averted infection. RESULTS: In 2014, HIV prevalence before PrEP implementation was between 4% and 5%. In the No PrEP scenario 826 new infections (95% simulation limits [SL]: 711, 955) occurred over 10 years, with an incidence rate of 3.51 per 1000 person-years (95% SL: 3.00, 4.08). Prevalence rose to 7.4% (95% SL: 6.7, 8.1). None of the PrEP scenarios reduced new HIV infections by 25% while covering less than 15% of the HIV-uninfected population. At 15% coverage, allocating PrEP to the current patient population, MSM with greater than 5 sexual partners in a year, and MSM with greater than 10 partners reduced new infections by at least 25%, requiring 161 (95% SL: 115, 289), 150 (95% SL: 107, 252), and 128 (95% SL: 100, 184) person-years on PrEP per averted infection, respectively. CONCLUSIONS: Engaging MSM with high numbers of sexual partners would improve the population-level impact and efficiency of PrEP in settings where PrEP coverage remains low. However, the sustained population-level PrEP coverage needed to reduce new infections by 25% is substantially higher than current levels of PrEP uptake. PMID- 29985948 TI - Are electronic nicotine delivery systems helping cigarette smokers quit? Evidence from a prospective cohort study of U.S. adult smokers, 2015-2016. AB - BACKGROUND: The potential of electronic nicotine delivery systems (ENDS) to reduce the cardiovascular and other disease risks of smoking is of great interest. While many smokers report using ENDS for cessation, their impact under real-world use patterns and conditions on adult smokers' quitting behavior is uncertain. The objective of this study was to generate more recent and comprehensive evidence on the effect of "real world" ENDS use on the population quit rates of adult smokers while taking account of frequency and duration of use, device type, e-liquid flavor, and reasons for use. METHODS AND FINDINGS: We conducted a population-based, prospective cohort study of a random probability sample of 1284 U.S. adult smokers recruited in August/September 2015 and re contacted one-year later (September 2016) from GfK's KnowledgePanel, a national, probability-based web-panel designed to be representative of non institutionalized U.S. adults. Among the 1081 baseline smokers who remained members of KnowledgePanel, 858 completed the follow-up survey. The primary outcome was smoking abstinence for at least 30 days prior to follow-up. Secondary outcomes were making a quit attempt during the 12-month study period and number of cigarettes smoked per day at follow-up. The adjusted odds of quitting smoking were lower for those that used ENDS at baseline (9.4%, 95% CI = 5.22%-16.38%; AOR = 0.30, 95% CI = 0.13-0.72) compared to smokers who did not use at ENDS (18.9%, 95% CI = 14.24%-24.68%). Smokers who used ENDS daily at some point during the study period were also less likely to quit smoking than nonusers (AOR = 0.17; 95% CI = 0.04-0.82). Limited ability to draw causal inferences from the observational design and a lack of biochemical verification of quitting smoking or ENDS use are limitations of this study. CONCLUSIONS: We found no evidence that ENDS use, within context of the 2015-2016 US regulatory and tobacco/vaping market landscape, helped adult smokers quit at rates higher than smokers who did not use these products. Absent any meaningful changes, ENDS use among adult smokers is unlikely to be a sufficient solution to obtaining a meaningful increase in population quit rates. Additional research is needed to reconcile the divergent literature and monitor the impact of ENDS in an environment of rapidly evolving markets and regulatory policies. PMID- 29985950 TI - Gene expression profile of a selection of Polycomb Group genes during zebrafish embryonic and germ line development. AB - Polycomb Group (PcG) genes are transcriptional repressors that are described to be important during development and differentiation. There is significant interest in PcGs proteins because of their role in stem cell biology and tumorigenesis. In this study we characterize the expression of a selection of PcG genes in the adult germline of zebrafish and during embryogenesis. In adults, expression of selected PcG genes is found to be enriched in germ line over somatic tissues. Therefore, the germ line of adult zebrafish was analyzed for the expression pattern of a selection of PcG genes by whole mount in situ hybridization. We detected presence of the tested PcG gene transcripts at early stages of both oogenesis and spermatogenesis. This enriched expression for early stages of gametogenesis is also observed in developing gonads at 4 and 5 weeks post fertilization. Additionally, zebrafish embryos were used to study the spatio temporal expression patterns of a selection of PcG genes during development. The PcG genes that we tested are maternally loaded and ubiquitously expressed at early developmental stages, except of ezh1. The expression of the PcG genes that were assessed becomes enriched anteriorly and is more defined during tissue specification. The data shown here is an important resource for functional PcG gene studies in vivo. PMID- 29985952 TI - Pattern of radiation-induced thyroid gland changes in nasopharyngeal carcinoma patients in 48 months after radiotherapy. AB - OBJECTIVES: Radiation-induced hypothyroidism is the most common thyroid disorder after radiotherapy in nasopharyngeal carcinoma (NPC) patients. This study evaluated the pattern of radiation-induced thyroid gland changes in 48 months after radiotherapy in NPC patients and the association of hypothyroidism incidence with thyroid dose. METHODS: Fifty-six NPC patients treated by intensity modulated radiotherapy in 2013 were recruited. All patients received baseline thyroid hormones (fT3, fT4 and TSH) tests and CT scan before radiotherapy. Repeated measures of the thyroid hormones and gland volume were performed at 3, 6, 12, 18, 24, 30, 36 and 48 months after treatment. Trend lines of the thyroid volume and hormone level changes against time were plotted. The incidence of hypothyroidism patients and its relationship with the dose were also evaluated. RESULTS: The mean thyroid volume followed a decreasing trend after radiotherapy, reaching a minimum (-39.8%) at 30 months and slightly increased afterward. The fT4 level followed a similar pattern with its mean value dropped by 21.5% at 30 months and became steady after 36 months. TSH level showed gradual rise from just after radiotherapy, reaching a peak at 24 months and became relatively steady after 36 months. The incidence of hypothyroidism increased to a maximum at 24 months (28.6%) and dropped afterwards. Thyroid Dmean and D50 were significantly correlated with hypothyroidism incidence in 12 to 30 months (rho > 0.40, p < 0.05). CONCLUSION: The patterns of radiation induced thyroid volume shrinkage and fT4 level reduction were similar, with both of them showed decreasing trend from 0 to 30 months. The thyroid volume and function reached a relatively steady state after 36 months. The incidence of hypothyroidism increased up to 24 months and its frequency was associated with the thyroid dose. PMID- 29985951 TI - Runs of homozygosity in a selected cattle population with extremely inbred bulls: Descriptive and functional analyses revealed highly variable patterns. AB - The analysis of runs of homozygosity (ROH), using high throughput genomic data, has become a valuable and frequently used methodology to characterize the genomic and inbreeding variation of livestock and wildlife animal populations. However, this methodology has been scarcely used in highly inbred domestic animals. Here, we analyzed and characterized the occurrence of ROH fragments in highly inbred (HI; average pedigree-based inbreeding coefficient FPED = 0.164; 0.103 to 0.306) and outbred Retinta bulls (LI; average FPED = 0.008; 0 to 0.025). We studied the length of the fragments, their abundance, and genome distribution using high density microarray data. The number of ROH was significantly higher in the HI group, especially for long fragments (>8Mb). In the LI group, the number of ROH continuously decreased with fragment length. Genome-wide distribution of ROH was highly variable between samples. Some chromosomes presented a larger number of fragments (BTA1, BTA19, BTA29), others had longer fragments (BTA4, BTA12, BTA17), while other ones showed an increased ROH accumulation over specific loci (BTA2, BTA7, BTA23, BTA29). Similar differences were observed in the analysis of 12 individuals produced by a similar inbred event (FPED3 = 0.125). The correlation between the fraction of the genome covered by ROH (FROH) and FPED was high (0.79), suggesting that ROH-based estimations are indicative of inbreeding levels. On the other hand, the correlation between FPED and the microsatellite based inbreeding coefficient (FMIC) was only moderate (r = 0.44), suggesting that STR-based inbreeding estimations should be avoided. Similarly, we found a very low correlation (r = -0.0132) between recombination rate and ROH abundance across the genome. Finally, we performed functional annotation analyses of genome regions with significantly enriched ROH abundance. Results revealed gene clusters related to pregnancy-associated proteins and immune reaction. The same analysis performed for regions enriched with recently formed ROH (> 8 Mb) showed gene clusters related to flagellum assembly. In both cases, the processes were related to male and female reproductive functions, which may partially explain the reduced fertility associated with inbred populations. PMID- 29985954 TI - Correction: The economic burden of human papillomavirus-related precancers and cancers in Sweden. AB - [This corrects the article DOI: 10.1371/journal.pone.0179520.]. PMID- 29985953 TI - The myodural bridges' existence in the sperm whale. AB - Recent studies have identified that the myodural bridge (MDB) is located between the suboccipital muscles and cervical dura mater in the posterior atlanto occipital interspace within humans. The myodural bridge has been considered to have a significant role in physiological functions. However, there is little information about the myodural bridge in marine mammals; we conducted this study to investigate and examine the morphology of the myodural bridge in a sperm whale. We also aim to discuss the physiological functions of the myodural bridge. In this study, a 15.1-meter long sperm whale carcass was examined. Multiple methods were conducted to examine the bridges of the sperm whale which included dissection, P45 plastination and histological analysis. This study confirmed the existence of the myodural bridge in the sperm whale and shows there are two types of the bridge in the sperm whale: one type was the occipital-dural bridge (ODB), the other type was the MDB. A large venous plexus was found within the epidural space and this venous plexus is thought to contain a great amount of blood when in deep water and thus the movements of suboccipital muscles could be a unique power source that drives cerebrospinal fluid circulation. PMID- 29985955 TI - Purification and identification of two novel antioxidant peptides from perilla (Perilla frutescens L. Britton) seed protein hydrolysates. AB - Proteins were extracted from perilla (Perilla frutescens L. Britton) seed by products and hydrolyzed with an alkaline protease. Antioxidant peptides were purified from the hydrolysate by size-exclusion chromatography and RP-HPLC. Two peptides with strong antioxidant activity were identified as Tyr-Leu (YL) and Phe Tyr (FY) with the molecular mass of 294.33 Da and 328.33 Da, respectively. Synthesized YL and FY efficiently quenched free radicals (DPPH, ABTS and hydroxyl radicals) and showed high oxygen radical absorbance capacity. The two peptides also inhibited lipid peroxidation in the rat liver. Furthermore, YL and FY could protect HepG-2 cells against hydrogen peroxide-induced oxidative damage without cytotoxicity. Based on the structure-activity analysis, the Tyr residue was crucial for the antioxidant activity of YL and FY. The results indicate that the protein hydrolysate from perilla seed by-products possessed potent biological activity and can be utilized to develop health-related nutraceutical ingredients. PMID- 29985956 TI - Correction: Community structure informs species geographic distributions. AB - [This corrects the article DOI: 10.1371/journal.pone.0197877.]. PMID- 29985957 TI - Comparison of spinal curvature parameters as determined by the ZEBRIS spine examination method and the Cobb method in children with scoliosis. AB - BACKGROUND AND PURPOSE: The most common and gold standard method to diagnose and follow-up on scoliosis treatment is to capture biplanar X-ray images and then use these to determine the sagittal frontal spinal curvature angles by the Cobb method. Reducing exposure to radiation is an important aspect for consideration, especially regarding children. The ZEBRIS spinal examination method is an external, non-invasive measurement method that uses an ultrasound-based motion analysis system. The aim of this study is to compare angle values of patients with adolescent idiopathic scoliosis (AIS) determined by the ZEBRIS spine examination method with the angle values defined by the gold standard Cobb method on biplanar X-ray images. METHODS: Subjects included 19 children with AIS (mean age 14.5+/-2.1 years, range 8-16 years, frontal plane thoracic Cobb angle 19.95+/ 10.23 degrees , thoracolumbar/lumbar angle 16.57+/-10.23 degrees ). The thoracic kyphosis and lumbar lordosis in the sagittal plane and the thoracic and lumbar scoliosis values were calculated by the Cobb method on biplanar X-ray images. The sagittal frontal spinal curvature angles were calculated from the position of the processus spinosus of 19 vertebrae, as determined by the ZEBRIS spine examination method. The validity of the ZEBRIS spine examination method was evaluated with Bland-Altman analyses between the sagittal and frontal spinal curvature parameters calculated from data determined by the ZEBRIS spine examination method and data obtained by the Cobb method on the X-ray images. RESULTS AND DISCUSSION: Thoracic spinal curvature angles in sagittal and in frontal planes can be measured with sufficient accuracy. The slopes of the linear regression lines for thoracic kyphosis (TK) and thoracic scoliosis (TSC) are close to one (1.00 and 0.79 respectively), and the intercept values are below 5 degrees. The correlation between the TK and TSC values determined by the two methods is significant (p = 0.000) and excellent (rTK = 0.95, rTSC = 0.85). The differences are in the limit of agreement. The lumbar lordosis (LL) in the sagittal plane shows a very good correlation (rLL = 0.76); however the differences between the angles determined by the two methods are out of the limit of agreement in patients with major lumbar lordosis (LL>=50 degrees ). The thoracolumbar/lumbar spinal curvature angles in the frontal plane determined by ZEBRIS spine examination were underestimated at curvatures larger than 15 degrees , mainly due to the rotational and pathological deformities of the scoliotic vertebrae. However, the correlation between lumbar scoliosis (LSC) values determined by the two methods is significant (p = 0.000) and excellent (rLSC = 0.84), the slopes are below one (0.71), the intercept values are below 5 degrees, and the differences between the angles determined by the two methods are within the limits of agreement. We could conclude that ZEBRIS spinal examination is a valid and reliable method for determination of sagittal and frontal curvatures during the treatment of patients with scoliosis. However, it cannot replace the biplanar X-ray examination for the visualization of spinal curvatures in the sagittal and frontal planes and the rotation of vertebral bodies during the diagnosis and annual evaluation of the progression. PMID- 29985958 TI - KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi's sarcomagenesis. AB - Kaposi's sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth. PMID- 29985959 TI - Causes and predictors of mortality in Asian Indians with and without diabetes-10 year follow-up of the Chennai Urban Rural Epidemiology Study (CURES - 150). AB - BACKGROUND: The incidence and prevalence of diabetes is increasing worldwide and it is the fifth leading cause of mortality accounting for over 3.8 million deaths annually. Despite the enormity of the diabetes-related health burdens, very few studies have evaluated the factors associated with mortality among people with diabetes in India. We sought to study the causes and predictors of mortality among urban Asian Indians with and without diabetes. METHODS AND FINDINGS: Of 2273 adults (27,850 person-years of follow-up) from the 10-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES), the cause of death could be ascertained in 552 individuals out of the 671 who had died (response rate 82.3%). Verbal autopsy was obtained from the family members of the deceased and this was adjudicated by trained physicians. The age-standardized mortality rate was 28.2 (95%CI 25.9-30.6) per 100,000 population. Mortality rates were significantly higher in individuals with diabetes compared to those without [27.9(95% CI 25.5 30.6) vs. 8.0 (6.6-9.9) per 1000 person years]. Compared to individuals of normal body mass index, underweight individuals had higher risk of mortality (Hazard ratio 1.49; 95% CI 1.11-2.0), whereas overweight and obese individuals did not show a higher risk. The population-attributable risk for all-cause mortality in the entire study cohort was highest for ischemic heart disease and diabetes. The excess mortality attributable to diabetes was highest in the age group of 51 to 70 years, and was mostly accounted for by renal disease (Rate ratio 5.68, 95%CI 2.43-6.23), ischemic heart disease (4.23,2.78-6.67), and cerebrovascular disease (4.00,1.87-9.81). CONCLUSION: Underweight (but not overweight or obesity) was strongly associated with mortality in this Asian Indian population. Ischemic heart disease and diabetes contributed the most to risk for all cause mortality. Excess mortality due to diabetes was higher in relatively younger individuals and was mostly accounted for by renal disease. PMID- 29985960 TI - Validation of quantitative real-time PCR reference genes for the determination of seasonal and labor-specific gene expression profiles in the head of Western honey bee, Apis mellifera. AB - Honey bee is not only considered an important pollinator in agriculture, but is also widely used as a model insect in biological sciences, thanks to its highly evolved sociality, specialization of labor division, and flexibility of colony management. For an intensive investigation of the seasonal and labor-dependent expression patterns of its genes, accurate quantification of the target gene transcription level is a fundamental step. To date, quantitative real-time PCR (qRT-PCR) has been widely used for rapid quantification of gene transcripts, with reliable reference gene(s) for normalization. To this end, in an attempt to search for reliable reference genes, the amplification efficiencies of six candidate reference genes (rp49, rpL32, rpS18, tbp, tub, and gapdh) were determined. Subsequently, four genes (rpL32, rpS18, tbp, and gapdh) with PCR efficiencies of 90% to 110% were evaluated for their expression stabilities with three programs (geNorm, NormFinder, and BestKeeper) and used for normalization of seasonal expression patterns of target genes in the forager and nurse heads. Although the three programs revealed slightly different results, two genes, rpS18 and gapdh, were suggested to be the optimal reference genes for qRT-PCR-based determination of seasonal and labor-specific gene expression profiles. Furthermore, the combined use of these two genes yielded a more accurate normalization, compared with the use of a single gene in the head of honey bee. The validated reference genes can be widely used for quantification of target gene expression in honey bee head although it is still remained to be elucidated the expression levels of the selected reference genes in specific tissues in head. PMID- 29985962 TI - The twenty most charismatic species. AB - Charisma is a term commonly used in conservation biology to describe species. However, as the term "charismatic species" has never been properly defined, it needs to be better characterized to fully meet its potential in conservation biology. To provide a more complete depiction, we collected information from four different sources to define the species currently considered to be the most charismatic and to understand what they represent to the Western public. First, we asked respondents of two separate surveys to identify the 10 animal species that they considered to be the most charismatic and associate them with one to six traits: Rare, Endangered, Beautiful, Cute, Impressive, and Dangerous. We then identified the wild animals featured on the website homepages of the zoos situated in the world's 100 largest cities as well as on the film posters of all Disney and Pixar films, assuming in both cases that the most charismatic species were generally chosen to attract viewers. By combining the four approaches, we set up a ranked list of the 20 most charismatic animals. The majority are large exotic, terrestrial mammals. These species were deemed charismatic, mainly because they were regarded as beautiful, impressive, or endangered, although no particular trait was discriminated, and species were heterogeneously associated with most of the traits. The main social characteristics of respondents did not have a significant effect on their choices. These results provide a concrete list of the most charismatic species and offer insights into the Western public's perception of charismatic species, both of which could be helpful to target new species for conservation campaigns. PMID- 29985961 TI - GROWTH-REGULATING FACTOR 9 negatively regulates arabidopsis leaf growth by controlling ORG3 and restricting cell proliferation in leaf primordia. AB - Leaf growth is a complex process that involves the action of diverse transcription factors (TFs) and their downstream gene regulatory networks. In this study, we focus on the functional characterization of the Arabidopsis thaliana TF GROWTH-REGULATING FACTOR9 (GRF9) and demonstrate that it exerts its negative effect on leaf growth by activating expression of the bZIP TF OBP3 RESPONSIVE GENE 3 (ORG3). While grf9 knockout mutants produce bigger incipient leaf primordia at the shoot apex, rosette leaves and petals than the wild type, the sizes of those organs are reduced in plants overexpressing GRF9 (GRF9ox). Cell measurements demonstrate that changes in leaf size result from alterations in cell numbers rather than cell sizes. Kinematic analysis and 5-ethynyl-2' deoxyuridine (EdU) incorporation assay revealed that GRF9 restricts cell proliferation in the early developing leaf. Performing in vitro binding site selection, we identified the 6-base motif 5'-CTGACA-3' as the core binding site of GRF9. By global transcriptome profiling, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) we identified ORG3 as a direct downstream, and positively regulated target of GRF9. Genetic analysis of grf9 org3 and GRF9ox org3 double mutants reveals that both transcription factors act in a regulatory cascade to control the final leaf dimensions by restricting cell number in the developing leaf. PMID- 29985964 TI - Effect of dexamethasone exposure on the neonatal unit on the school age lung function of children born very prematurely. AB - The objective of this study was to determine the impact of postnatal dexamethasone treatment on the neonatal unit on the school age lung function of very prematurely born children. Children born prior to 29 weeks of gestational age had been entered into a randomised trial of two methods of neonatal ventilation (United Kingdom Oscillation Study). They had comprehensive lung function measurements at 11 to 14 years of age. One hundred and seventy-nine children born at a mean gestational age of 26.9 (range 23-28) weeks were assessed at 11 to 14 years; 50 had received postnatal dexamethasone. Forced expiratory flow at 75% (FEF75), 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes including total lung capacity and residual volume were assessed. Lung function outcomes were compared between children who had and had not been exposed to dexamethasone after adjustment for neonatal factors using linear mixed effects regression. After adjustment for confounders all the mean spirometry results were between 0.38 and 0.87 standard deviations lower in those exposed to dexamethasone compared to the unexposed. For example, the mean FEF75 z-score was 0.53 lower (95% CI 0.21 to 0.85). The mean lung function was lower as the number of courses of dexamethasone increased. In conclusion, postnatal dexamethasone exposure was associated with lower mean lung function at school age in children born extremely prematurely. Our results suggest the larger the cumulative dose the greater the adverse effect on lung function at follow-up. PMID- 29985963 TI - PIK3CA mutations are specifically localized to lymphatic endothelial cells of lymphatic malformations. AB - Lymphatic malformations (LM) are characterized by the overgrowth of lymphatic vessels during pre- and postnatal development. Macrocystic, microcystic and combined forms of LM are known. The cysts are lined by lymphatic endothelial cells (LECs). Resection and sclerotherapy are the most common treatment methods. Recent studies performed on LM specimens in the United States of America have identified activating mutations in the phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit alpha (PIK3CA) gene in LM. However, whole tissue but not isolated cell types were studied. Here, we studied LM tissues resected at the University Hospitals Freiburg and Regensburg, Germany. We isolated LECs and fibroblasts separately, and sequenced the commonly affected exons 8, 10, and 21 of the PIK3CA gene. We confirm typical monoallelic mutations in 4 out of 6 LM derived LEC lines, and describe two new mutations i.) in exon 10 (c.1636C>A; p.Gln546Lys), and ii.) a 3bp in-frame deletion of GAA (Glu109del). LM-derived fibroblasts did not possess such mutations, showing cell-type specificity of the gene defect. High activity of the PIK3CA-AKT- mTOR pathway was demonstrated by hyperphosphorylation of AKT-Ser473 in all LM-derived LECs (including the ones with newly identified mutations), as compared to normal LECs. Additionally, hyperphosphorylation of ERK was seen in all LM-derived LECs, except for the one with Glu109del. In vitro, the small molecule kinase inhibitors Buparlisib/BKM 120, Wortmannin, and Ly294002, (all inhibitors of PIK3CA), CAL-101 (inhibitor of PIK3CD), MK-2206 (AKT inhibitor), Sorafenib (multiple kinases inhibitor), and rapamycin (mTOR inhibitor) significantly blocked proliferation of LM-derived LECs in a concentration-dependent manner, but also blocked proliferation of normal LECs. However, MK-2206 appeared to be more specific for mutated LECs, except in case of Glu109 deletion. In sum, children that are, or will be, treated with kinase inhibitors must be monitored closely. PMID- 29985965 TI - Morphology and fine organization of the midgut of Gampsocleis gratiosa (Orthoptera: Tettigoniidae). AB - The morphology and ultrastructure of the midgut of Gampsocleis gratiosa (Orthoptera: Tettigoniidae) was examined by light and electron microscopy. The midgut consists of two bulbous gastric caeca and a tubular ventriculus. The general organization of the gastric caeca is similar to that of the ventriculus. They are composed of a peritrophic membrane, an epithelium, a basal lamina and muscle layer from the inside to outside. Three types of cells were identified: regenerative, principal, and endocrine. Regenerative cells occur in groups (called nidi) at the base of principal cells. Principal cells grow from regenerative cells. Rare endocrine cells are scattered throughout the epithelium. Principal cells exhibit intense secretory activity, and regional differences in their ultrastructure were observed along the entire midgut. The microvilli are longer than those in any other region in the posterior region of the midgut. Lysosomes, multivesicular bodies (MVBs), autophagosomes, abundant Golgi apparatuses and lipid droplets primarily occur in the gastric caeca. Three pathways of secretion (merocrine, apocrine and holocrine) occur within the midgut epithelium, and a distinctive type of apocrine bleb was found in the gastric caeca. Therefore, these gastric caeca may be evolving toward a special type of gland. PMID- 29985967 TI - Rosuvastatin calcium nanoparticles: Improving bioavailability by formulation and stabilization codesign. AB - PURPOSE: Rosuvastatin calcium (ROSCa) is a poorly soluble drug with bioavailability not exceeding 20%. Decreasing the particle size may enhance its solubility, dissolution rate and bioavailability. Therefore, the aim of the current study is to prepare ROSCa nanoparticles by wet milling technique using planetary ball mill. The codesign between formulation and stabilization of nanoparticles was studied to achieve both high dissolution as well as bioavailability. METHODOLOGY: ROSCa nanosuspensions was prepared by wet milling technique using planetary ball mill, by applying milling ball size of 0.1 mm at speed of 800 rpm for 3 cycles each cycle composed of 10 minutes. HPMC, PVP k-30, pluronic F-127, Tween 80 and PEG 6000 were used as stabilizers. The nanosuspensions were then freeze-dried, and the dried nanoparticles were evaluated for particle size, zeta potential, in-vitro dissolution test, XRPD and in-vivo study. RESULTS: ROSCa nanoparticles stabilized with 10% PVP (P3) had a good stability with smallest particle size, which in turn enhanced the dissolution rate. The particle size of the leading formula was 461.8 +/- 16.68 nm with zeta potential of -31.8 +/- 7.22 mV compared to untreated drug that has a particle size of 618MUm. The percent of ROSCa dissolved after 1 hour enhanced significantly which reached 72% and 58.25% for leading nanoparticle formula and untreated ROSCa, respectively (P < 0.05). The in-vivo study of ROSCa from the leading nanoparticle formula showed a significant enhancement in the Cmax after 2 h (82.35 ng/ml) compared to 9.2 ng/ml for untreated drug. CONCLUSION: Wet milling technique is a successful method to prepare ROSCa nanoparticles. From different stabilizer used, PVP (10%) was able to produce stable nanoparticle with small particle size which significantly enhance the dissolution rate and pharmacokinetics parameters of ROSCa. PMID- 29985968 TI - Intervention Effects of "Girls on the Move" on Increasing Physical Activity: A Group Randomized Trial. AB - Background: Limited intervention success in increasing and sustaining girls' moderate-to-vigorous physical activity (MVPA) underscores a need for continued research. Purpose: The aim of this study was to evaluate the effect of a 17-week Girls on the Move (GOTM) intervention on increasing MVPA among fifth- to eighth grade girls. Methods: This study is a group (cluster) randomized trial, including 24 schools, pair matched and assigned to intervention (n = 12) or control (n = 12) conditions. Participants included 1,519 girls in racially diverse public schools in urban, underserved areas of the Midwestern USA. The intervention included three components: (i) 90-min after-school physical activity (PA) club offered 3 days/week; (ii) two motivational, individually tailored counseling sessions; and (iii) an interactive Internet-based session at the midpoint of the intervention. Main outcome measures were weighted mean minutes of MVPA per week post-intervention and at 9-month follow-up measured via accelerometer. Results: No between-group differences occurred for weighted mean minutes of MVPA per week at post-intervention (B = -0.08, p = .207) or 9-month follow-up (B = -0.09, p = .118) while controlling for baseline MVPA. Conclusions: Research is needed to identify interventions that assist girls in attaining and maintaining adequate PA. ClinicalTrials.gov Identifier: NCT01503333. PMID- 29985966 TI - Differential roles of sleep spindles and sleep slow oscillations in memory consolidation. AB - Sleep plays an important role in the consolidation of recent memories. However, the cellular and synaptic mechanisms of consolidation during sleep remain poorly understood. In this study, using a realistic computational model of the thalamocortical network, we tested the role of Non-Rapid Eye Movement (NREM) sleep in memory consolidation. We found that sleep spindles (the hallmark of N2 stage sleep) and slow oscillations (the hallmark of N3 stage sleep) both promote replay of the spike sequences learned in the awake state and replay was localized at the trained network locations. Memory performance improved after a period of NREM sleep but not after the same time period in awake. When multiple memories were trained, the local nature of the spike sequence replay during spindles allowed replay of the distinct memory traces independently, while slow oscillations promoted competition that could prevent replay of the weak memories in a presence of the stronger memory traces. This could lead to extinction of the weak memories unless when sleep spindles (N2 sleep) preceded slow oscillations (N3 sleep), as observed during the natural sleep cycle. Our study presents a mechanistic explanation for the role of sleep rhythms in memory consolidation and proposes a testable hypothesis how the natural structure of sleep stages provides an optimal environment to consolidate memories. PMID- 29985969 TI - Effects of Mental Fatigue on Exercise Intentions and Behavior. AB - Background: Exerting cognitive control results in mental fatigue, which is associated with impaired performance during physical endurance tasks. However, there has been little research on the effects of mental fatigue on people's perceptions or behaviors involving lifestyle or recreational exercise. Purpose: The purpose of this study was to examine the effect of mental fatigue on intended physical exertion and exercise performance reflective of current physical activity guidelines. Methods: Using a counterbalanced design, participants completed two 50-min experimental manipulations (high vs. low cognitive control exertion) before exercising at a self-selected intensity for 30 min. At visit 1, participants performed a graded exercise task to gain familiarity with a range of exercise intensities and rating of perceived exertion (RPE) while exercising. At visits 2 and 3, participants rated their intended RPE for the exercise session, performed the experimental manipulations, re-rated their intended RPE, and then completed 30-min of exercise on a cycle ergometer. Total work performed while exercising was recorded for each session. Results: Compared with the low cognitive control condition, the high cognitive control manipulation resulted in significantly greater mental fatigue (d = .73), significantly greater reductions in intended RPE (mean difference = -0.62), and significantly less total work ( 12.7 kJ) performed during the exercise session. Conclusions: Mental fatigue alters the amount of physical effort people are willing to invest in an exercise workout and follow through with those intentions by doing less work. These are the first results showing people may deliberately adjust their physical effort to cope with mental fatigue. PMID- 29985970 TI - BrainEXP: a database featuring with spatiotemporal expression variations and co expression organizations in human brains. AB - Motivation: Gene expression changes over the lifespan and varies among different tissues or cell types. Gene co-expression also changes by sex, age, different tissues or cell types. However, gene expression under the normal state and gene co-expression in the human brain has not been fully defined and quantified. Here we present a database named Brain EXPression Database (BrainEXP) which provides spatiotemporal expression of individual genes and co-expression in normal human brains. BrainEXP consists of 4,567 samples from 2,863 healthy individuals gathered from existing public databases and our own data, in either microarray or RNA-Seq library types. We mainly provide two analysis results based on the large dataset: (i) basic gene expression across specific brain regions, age ranges, and sexes; (ii) co-expression analysis from different platforms. Availability: http://www.brainexp.org/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29985971 TI - Computational Analysis of Kinase Inhibitor Selectivity using Structural Knowledge. AB - Motivation: Kinases play a significant role in diverse disease signaling pathways and understanding kinase inhibitor selectivity, the tendency of drugs to bind to off-targets, remains a top priority for kinase inhibitor design and clinical safety assessment. Traditional approaches for kinase selectivity analysis using biochemical activity and binding assays are useful but can be costly and are often limited by the kinases that are available. On the other hand, current computational kinase selectivity prediction methods are computational intensive and can rarely achieve sufficient accuracy for large-scale kinome wide inhibitor selectivity profiling. Results: Here, we present a KinomeFEATURE database for kinase binding site similarity search by comparing protein microenvironments characterized using diverse physiochemical descriptors. Initial selectivity prediction of 15 known kinase inhibitors achieved an > 90% accuracy and demonstrated improved performance in comparison to commonly used kinase inhibitor selectivity prediction methods. Additional kinase ATP binding site similarity assessment (120 binding sites) identified 55 kinases with significant promiscuity and revealed unexpected inhibitor cross-activities between PKR and FGFR2 kinases. Kinome-wide selectivity profiling of 11 kinase drug candidates predicted novel as well as experimentally validated off-targets and suggested structural mechanisms of kinase cross-activities. Our study demonstrated potential utilities of our approach for large-scale kinase inhibitor selectivity profiling that could contribute to kinase drug development and safety assessment. Availability: The KinomeFEATURE database are available at https://simtk.org/projects/kdb. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29985972 TI - Mitochondrial function in thoracic aortic aneurysms. PMID- 29985974 TI - Noise peak filtering in multi-dimensional NMR spectra using convolutional neural networks. AB - Motivation: Multi-dimensional NMR spectra are generally used for NMR signal assignment and structure analysis. There are several programs that can achieve highly automated NMR signal assignments and structure analysis. On the other hand, NMR spectra tend to have a large number of noise peaks even for data acquired with good sample and machine conditions, and it is still difficult to eliminate these noise peaks. Results: We have developed a method to eliminate noise peaks using convolutional neural networks, implemented in the program package Filt_Robot. The filtering accuracy of Filt_Robot was around 90-95% when applied to 2D and 3D NMR spectra, and the numbers of resulting non-noise peaks were close to those in corresponding manually prepared peaks lists. The filtering can strongly enhance automated NMR spectra analysis. Availability: The full package of the program, documents and example data are available from http://bmrbdep.pdbj.org/en/nmr_tool_box/Filt_Robot.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29985973 TI - TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice. AB - Glyceryl trinitrate is administered as a provocative test for migraine pain. Glyceryl trinitrate causes prolonged mechanical allodynia in rodents, which temporally correlates with delayed glyceryl trinitrate-evoked migraine attacks in patients. However, the underlying mechanism of the allodynia evoked by glyceryl trinitrate is unknown. The proalgesic transient receptor potential ankyrin 1 (TRPA1) channel, expressed by trigeminal nociceptors, is sensitive to oxidative stress and is targeted by nitric oxide or its by-products. Herein, we explored the role of TRPA1 in glyceryl trinitrate-evoked allodynia. Systemic administration of glyceryl trinitrate elicited in the mouse periorbital area an early and transient vasodilatation and a delayed and prolonged mechanical allodynia. The systemic, intrathecal or local administration of selective enzyme inhibitors revealed that nitric oxide, liberated from the parent drug by aldehyde dehydrogenase 2 (ALDH2), initiates but does not maintain allodynia. The central and the final phases of allodynia were respectively associated with generation of reactive oxygen and carbonyl species within the trigeminal ganglion. Allodynia was absent in TRPA1-deficient mice and was reversed by TRPA1 antagonists. Knockdown of neuronal TRPA1 by intrathecally administered antisense oligonucleotide and selective deletion of TRPA1 from sensory neurons in Advillin Cre; Trpa1fl/fl mice revealed that nitric oxide-dependent oxidative and carbonylic stress generation is due to TRPA1 stimulation, and resultant NADPH oxidase 1 (NOX1) and NOX2 activation in the soma of trigeminal ganglion neurons. Early periorbital vasodilatation evoked by glyceryl trinitrate was attenuated by ALDH2 inhibition but was unaffected by TRPA1 blockade. Antagonists of the calcitonin gene-related peptide receptor did not affect the vasodilatation but partially inhibited allodynia. Thus, although both periorbital allodynia and vasodilatation evoked by glyceryl trinitrate are initiated by nitric oxide, they are temporally and mechanistically distinct. While vasodilatation is due to a direct nitric oxide action in the vascular smooth muscle, allodynia is a neuronal phenomenon mediated by TRPA1 activation and ensuing oxidative stress. The autocrine pathway, sustained by TRPA1 and NOX1/2 within neuronal cell bodies of trigeminal ganglia, may sensitize meningeal nociceptors and second order trigeminal neurons to elicit periorbital allodynia, and could be of relevance for migraine-like headaches evoked by glyceryl trinitrate in humans. PMID- 29985975 TI - Mammalian prion propagation in PrP transgenic Drosophila. AB - Mammalian prions propagate by template-directed misfolding and aggregation of normal cellular prion related protein PrPC as it converts into disease-associated conformers collectively referred to as PrPSc. Mammalian species may be permissive for prion disease because these hosts have co-evolved specific co-factors that assist PrPC conformational change and prion propagation. We have tested this hypothesis by examining whether faithful prion propagation occurs in the normally PrPC-null invertebrate host Drosophila melanogaster. Ovine PrP transgenic Drosophila exposed at the larval stage to ovine scrapie showed a progressive accumulation of transmissible prions in adult flies. Strikingly, the biological properties of distinct ovine prion strains were maintained during their propagation in Drosophila. Our observations show that the co-factors necessary for strain-specific prion propagation are not unique to mammalian species. Our studies establish Drosophila as a novel host for the study of transmissible mammalian prions. PMID- 29985977 TI - Relevance of Medical Big Data Analysis depends on Clinical Accuracy: The Q fever paradigm. PMID- 29985976 TI - Sampling and Analysis of Bitumen Fumes: Comparison of German and French Methods to Determine a Conversion Formula. AB - Bitumen is classed as possibly carcinogenic to humans according to the International Agency for Research on Cancer. Data on individual exposure to bitumen fumes is therefore required to highlight the exposing situations and develop methods to prevent them. The Institute for Occupational Safety and Health of the German Social Accident Insurance (IFA) and the French National Research and Safety Institute for the Prevention of Occupational Accidents and Diseases (INRS) have both developed methods to measure individual exposure. The objective of this study was to determine a conversion factor to allow interconversion of data acquired by the two methods. To develop this conversion factor, comparative laboratory and workplace tests were performed according to both the IFA method (No. 6305) and the INRS method (MetroPol M-2). The amounts of organic material collected on the filters and XAD-2 beds were compared. The results revealed differences between the sampling and analytical methods that could be linked to sampler design, extraction solvent, and the detection method used. The total quantification returned by the two methods-the sum of the masses quantified on filter and XAD-2 bed for each sampler-were correlated in both controlled and real life tests. A conversion equation was therefore determined, based on field tests: CIFA = 1.76 CINRS +/- 0.39 (R2 = 0.99) that is applicable to total quantification data. This formula can be applied to data acquired by the two institutes to increase the number of data points available on exposure to bitumen fumes in various conditions, and thus increase the statistical power of studies into occupational prevention. PMID- 29985978 TI - Randomised trial of community treatment with azithromycin and ivermectin mass drug administration for control of scabies and impetigo. AB - Background: Scabies is a public health problem in many countries, with impetigo and its complications important consequences. Ivermectin based mass drug administration (MDA) reduces the prevalence of scabies and, to a lesser extent, impetigo. We studied the impact of co-administering azithromycin on the prevalence of impetigo and antimicrobial resistance. Methods: Six communities were randomised to receive either ivermectin-based MDA or ivermectin-based MDA co administered with azithromycin. We measured scabies and impetigo prevalence at baseline and twelve months. We collected impetigo lesions swabs at baseline, three and twelve months to detect antimicrobial resistance. Results: At baseline, scabies and impetigo prevalences were 11.8% and 10.1% in the ivermectin-only arm and 9.2% and 12.1% in the combined treatment arm. At twelve months, the prevalences had fallen to 1.0% and 2.5% in the ivermectin-only arm and 0.7% and 3.3% in the combined treatment arm. The proportion of impetigo lesions containing Staphylococcus aureus detected did not change (80% at baseline vs 86% at twelve months; no significant difference between arms) but the proportion containing pyogenic streptococci fell significantly (63% vs 23%, p < 0.01). At three months, 53% (8/15) of S. aureus isolates were macrolide-resistant in the combined treatment arm, but no resistant strains (0/13) were detected at twelve months. Conclusions: Co-administration of azithromycin with ivermectin led to similar decreases in scabies and impetigo prevalence compared to ivermectin alone. The proportion of impetigo lesions containing pyogenic streptococci declined following MDA. There was a transient increase in the proportion of macrolide resistant S. aureus strains following azithromycin MDA. Registered on clinicaltrials.gov (NCT02775617). PMID- 29985979 TI - RNAvista: a webserver to assess RNA secondary structures with non-canonical base pairs. AB - Motivation: In the study of 3D RNA structure, information about non-canonical interactions between nucleobases is increasingly important. Specialized databases support investigation of this issue based on experimental data, and several programs can annotate non-canonical base pairs in the RNA 3D structure. However, predicting the extended RNA secondary structure which describes both canonical and non-canonical interactions remains difficult. Results: Here, we present RNAvista that allows predicting an extended RNA secondary structure from sequence or from the list enumerating canonical base pairs only. RNAvista is implemented as a publicly available webserver with user-friendly interface. It runs on all major web browsers. Availability: http://rnavista.cs.put.poznan.pl. PMID- 29985981 TI - PingPongPro: a tool for the detection of piRNA-mediated transposon silencing in small RNA-Seq data. AB - Summary: Piwi-interacting RNAs (piRNAs) are a class of small non-coding RNAs which guide endonucleases to mRNAs of actively transcribed transposons in order to prevent their translation. The resulting mRNA fragments induce a positive feedback loop (the "ping-pong cycle"), which reinforces piRNA production and hence the transposon-silencing effect. PingPongPro is a command-line tool to scan small RNA-Seq data for signs of ping-pong cycle activity. It implements a novel algorithm that combines empirical probabilities in a multi-factor model to accurately identify transposons which are suppressed through the ping-pong cycle. Availability: Source code, a user manual, and binaries for Microsoft Windows and Linux are available at https://github.com/suhrig/pingpongpro under the GPLv3 license. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29985980 TI - Automated analysis of breathing waveforms using BreathMetrics: a respiratory signal processing toolbox. AB - Nasal inhalation is the basis of olfactory perception and drives neural activity in olfactory and limbic brain regions. Therefore, our ability to investigate the neural underpinnings of olfaction and respiration can only be as good as our ability to characterize features of respiratory behavior. However, recordings of natural breathing are inherently nonstationary, nonsinusoidal, and idiosyncratic making feature extraction difficult to automate. The absence of a freely available computational tool for characterizing respiratory behavior is a hindrance to many facets of olfactory and respiratory neuroscience. To solve this problem, we developed BreathMetrics, an open-source tool that automatically extracts the full set of features embedded in human nasal airflow recordings. Here, we rigorously validate BreathMetrics' feature estimation accuracy on multiple nasal airflow datasets, intracranial electrophysiological recordings of human olfactory cortex, and computational simulations of breathing signals. We hope this tool will allow researchers to ask new questions about how respiration relates to body, brain, and behavior. PMID- 29985982 TI - Joint modeling of recurrent events and survival: a Bayesian non-parametric approach. AB - Heart failure (HF) is one of the main causes of morbidity, hospitalization, and death in the western world, and the economic burden associated with HF management is relevant and expected to increase in the future. We consider hospitalization data for HF in the most populated Italian Region, Lombardia. Data were extracted from the administrative data warehouse of the regional healthcare system. The main clinical outcome of interest is time to death and research focus is on investigating how recurrent hospitalizations affect the time to event. The main contribution of the article is to develop a joint model for gap times between consecutive rehospitalizations and survival time. The probability models for the gap times and for the survival outcome share a common patient specific frailty term. Using a flexible Dirichlet process model for %Bayesian nonparametric prior as the random-effects distribution accounts for patient heterogeneity in recurrent event trajectories. Moreover, the joint model allows for dependent censoring of gap times by death or administrative reasons and for the correlations between different gap times for the same individual. It is straightforward to include covariates in the survival and/or recurrence process through the specification of appropriate regression terms. The main advantages of the proposed methodology are wide applicability, ease of interpretation, and efficient computations. Posterior inference is implemented through Markov chain Monte Carlo methods. PMID- 29985983 TI - A Gray Matter Volume Covariance Network Associated with the Motoric Cognitive Risk Syndrome: A Multi-Cohort MRI Study. AB - Background: Motoric Cognitive Risk (MCR) syndrome is a pre-dementia syndrome characterized by slow gait and cognitive complaint that predicts both Alzheimer's disease and vascular dementia. Yet, we know very little about the brain structures and brain pathologies associated with MCR. The aim of this study was to identify gray matter networks associated with MCR. Methods: We used voxel based morphometry and multivariate covariance-based statistics to identify gray matter networks associated with MCR in a pooled sample of 267 older adults without dementia from three different cohorts - two North American cohorts and one French cohort. Results: The mean age of participants was 75.63 years, 50.56 % identified as female, 57.68 % had >= 13 years of education, and 5.99% had a prior history of stroke. A total of 14.23 % participants met criteria for MCR. We identified a significant gray matter volume covariance pattern that was associated with MCR - even after adjusting for age, sex, education, mild cognitive impairment, stroke, total intracranial volume, and cohort status. This gray matter volume covariance network was primarily composed of supplementary motor, insular, and prefrontal cortex regions. Conclusions: These findings suggest that MCR is primarily associated with gray matter atrophy in brain regions previously linked to the control aspects of gait such as motor planning and modulation, rather than the motor aspects of gait such as gait initiation and maintenance. PMID- 29985984 TI - Empirical Bayes shrinkage and false discovery rate estimation, allowing for unwanted variation. AB - We combine two important ideas in the analysis of large-scale genomics experiments (e.g. experiments that aim to identify genes that are differentially expressed between two conditions). The first is use of Empirical Bayes (EB) methods to handle the large number of potentially-sparse effects, and estimate false discovery rates and related quantities. The second is use of factor analysis methods to deal with sources of unwanted variation such as batch effects and unmeasured confounders. We describe a simple modular fitting procedure that combines key ideas from both these lines of research. This yields new, powerful EB methods for analyzing genomics experiments that account for both sparse effects and unwanted variation. In realistic simulations, these new methods provide significant gains in power and calibration over competing methods. In real data analysis, we find that different methods, while often conceptually similar, can vary widely in their assessments of statistical significance. This highlights the need for care in both choice of methods and interpretation of results. PMID- 29985985 TI - Syphilis testing among sexually active men who have sex with men and who are receiving medical care for HIV in the United States-Medical Monitoring Project, 2013-2014. AB - Background: Guidelines recommend that sexually active men who have sex with men (MSM) including HIV-positive MSM be tested at least annually for syphilis; with testing every 3-6 months for MSM at elevated risk. We examined the proportion of HIV-positive MSM tested for syphilis in the past 3, 6, and 12 months by their HIV care provider during 2013-2014. Methods: Using medical record and interview data from the Medical Monitoring Project, a population-based HIV surveillance system, we evaluated the proportion of MSM who had documentation of being tested for syphilis by their HIV care provider in the past 3, 6, and 12 months. Results: During 2013-2014, 71% (95% CI: 69%-73%) of sexually active HIV-positive MSM were tested for syphilis in the past year. This proportion was higher among MSM at elevated risk: 75% (95% CI: 72%-78%) among men reporting condomless sex, and 77% (95% CI: 74%-79%) among men reporting >= 2 sex partners, in the past 12 months. Among MSM reporting condomless sex, 49% (95% CI: 45%-53%) were tested in the past 6 months and 26% (95% CI: 22%-30%) in the past 3 months. Among MSM reporting >= 2 sex partners, 49% (95% CI: 44%-54%) were tested in the past 6 months and 26% (95% CI: 22%-29%) in the past 3 months. Conclusions: Nearly one-third of sexually active HIV-positive MSM were not tested annually and many at increased risk were not tested at recommended frequencies. Efforts to improve compliance with screening guidelines for high risk HIV-positive MSM are warranted. PMID- 29985986 TI - Serum Potassium and Cardiovascular Events in Heart Failure With Preserved Left Ventricular Ejection Fraction Patients. AB - BACKGROUND: Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS: This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 <= sK < 4.4 mEq/l, Q3: 4.4 <= sK < 4.7 mEq/l, and Q4: sK >= 4.7 mEq/l). RESULTS: No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin aldosterone system inhibitors, calcium channel blockers, beta-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan-Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS: sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. Clinical Trials Registration: UMIN-CTR (http://www.umin.ac.jp/ctr/). Identifier: UMIN000029600. Public Access Information: Opt-out materials are available at the website: http://www.kumadai junnai.com/home/wp-content/uploads/houkatsu.pdf. PMID- 29985987 TI - Age-Related Adverse Inflammatory and Metabolic Changes Begin Early in Adulthood. AB - Aging is characterized by deleterious immune and metabolic changes, but the onset of these changes is unknown. We measured immune and metabolic biomarkers in adults beginning at age 30. To our knowledge, this is the first study to evaluate these biomarkers in adults aged 30 to over 80. Biomarkers were quantified in 961 adults. Tumor necrosis factor alpha (TNF-alpha), tumor necrosis factor receptor I (TNFR-I), tumor necrosis factor receptor II (TNFR-II), interleukin (IL)-2, IL-6, VCAM-I, D-Dimer, G-CSF, regulated on activation, normal T cell expressed and secreted (RANTES), matrix metalloproteinase-3 (MMP-3), adiponectin, and paraoxonase activity were measured by ELISA. Acylcarnitines and amino acids (AAs) were measured by mass spectrometry and reduced to a single factor using principal components analysis (PCA). Glycine was analyzed separately. The relationship between age and biomarkers was analyzed by linear regression with sex, race, and body mass index (BMI) as covariates. Age was positively correlated with TNF alpha, TNFR-I, TNFR-II, IL-6, IL-2, VCAM-1, D-Dimer, MMP-3, adiponectin, acylcarnitines, and AAs. Age was negative correlated with G-CSF, RANTES, and paraoxonase activity. BMI was significant for all biomarkers except IL-2, VCAM-1, RANTES, paraoxonase activity, and the AA factor. Excluding MMP-3, greater BMI was associated with potentially adverse changes in biomarker concentrations. Age related changes in immune and metabolic biomarkers, known to be associated with poor outcomes in older adults, begin as early as the thirties. PMID- 29985988 TI - The Efficacy of the Quadrivalent Human Papillomavirus Vaccine in Girls and Women Living with HIV. AB - Background: Human papillomavirus (HPV) vaccination is safe and efficacious in women without HIV. While good immunogenicity has been observed in women living with HIV (WLWH), efficacy data in this population are needed. Methods: We enrolled 420 females aged >=9 years (range: 9-65) living with HIV. Participants were to receive 3 doses of qHPV vaccine (0/2/6 months). The main endpoint was vaccine failure (i.e., incident persistent qHPV infection, cervical intraepithelial neoplasia of grade 2 or higher (CIN2+), or genital warts). We compared these rates to published rates in vaccinated and unvaccinated women without HIV as well as unvaccinated WLWH. Results: Among 279 eligible women, median follow-up was 2 years. In the intention-to-treat population, the incidence rate (IR) of persistent qHPV (HPV6/11/16/18) was 2.3 per 100 person-years (/100PY) (95% confidence interval [CI]=1.1-4.1) and IR of genital warts was 2.3/100PY (95% CI=1.2-4.1). In the per-protocol efficacy population, IR of persistent qHPV was 1.0/100PY (95% CI=0.3-2.6) and of genital warts was 1.0/100PY (95% CI=0.3-2.5). No cases of CIN2+ occurred. Reported rates of qHPV-related infection and disease within the vaccinated women without HIV, unvaccinated women without HIV, and the vaccinated WLWH: 0.1 (95% CI=0.02-0.03), 1.5 (95% CI=1.1 2.0), and 1.2 (95% CI=0.2-3.4) /100PY, respectively. The rate of persistent qHPV among vaccinated WLWH was lower than among unvaccinated WLWH (2.3 vs. 6.0/100PY). Conclusions: Vaccinated WLWH may be at higher risk for vaccine failure than vaccinated women without HIV. However, overall rates of vaccine failure were low and rates of persistent qHPV were lower than in unvaccinated WLWH. PMID- 29985989 TI - Androgens downregulate anti-Mullerian hormone promoter activity in the Sertoli cell through the androgen receptor and intact SF1 sites. AB - Testicular anti-Mullerian hormone (AMH) production is inhibited by androgens around pubertal onset, as observed under normal physiological conditions and in patients with precocious puberty. In agreement, AMH downregulation is absent in patients with androgen insensitivity. The molecular mechanisms underlying the negative regulation of AMH by androgens remain unknown. Our aim was to elucidate the mechanisms through which androgens downregulate AMH expression in the testis. A direct negative effect of androgens on the transcriptional activity of the AMH promoter was found using luciferase reporter assays in the mouse prepubertal Sertoli cell line SMAT1. A strong inhibition of AMH promoter activity was seen in the presence of both testosterone and DHT and of the androgen receptor. By site directed mutagenesis and chromatin immunoprecipitation assays, we showed that androgen-mediated inhibition involved the binding sites for steroidogenic factor 1 (SF1) present in the proximal promoter of the AMH gene. In this study we describe for the first time the mechanism behind AMH inhibition by androgens, as seen in physiological and pathological conditions in males. Inhibition of AMH promoter activity by androgens could be due to protein-protein interactions between the ligand-bound androgen receptor and SF1 or by blockage of SF1 binding to its sites on the AMH promoter. PMID- 29985990 TI - Reply to Million and Raoult. PMID- 29985991 TI - MicroRNA-498 promotes proliferation and migration by targeting the tumor suppressor PTEN in breast cancer cells. AB - Triple negative breast cancer (TNBC) is a subtype of breast cancer with a poor prognosis and high mortality rate. The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) plays an important role in cell proliferation and cell migration by negatively regulating the PI3K/Akt pathway. PTEN is downregulated by microRNAs in multiple cancers. However, few microRNAs have been reported to directly target PTEN in TNBC. In this study, microRNAs predicted to target PTEN were screened by immunoblotting and luciferase reporter assays. Expression levels of microRNA-498 (miR-498) were measured by TaqMan microRNA assays. We performed clonogenic, cell cycle and scratch wound assays to examine the oncogenic role of miR-498. We demonstrated that miR-498 directly targeted the 3'untranslated region of PTEN mRNA and reduced PTEN protein levels in TNBC cells. Compared with the non-tumorigenic breast epithelial cell line MCF 10A, TNBC cell lines overexpressed miR-498. Moreover, miR-498 promoted cell proliferation and cell cycle progression in TNBC cells in a PTEN-dependent manner. Suppressing miR-498 overexpression impaired the oncogenic effects of miR 498 on cell proliferation and cell migration. This study identified a novel microRNA (miR-498) overexpressed in TNBC cells and its oncogenic role in suppressing PTEN. These results provide new insight into the downregulation of PTEN and indicate a potential therapeutic target for treating TNBC. PMID- 29985993 TI - Frailty, Hospitalization, and Mortality in Residential Aged Care. AB - Background: Frailty predicts mortality in residential aged care, but the relationship with hospitalization is inconsistent. The purpose of this study was to investigate and compare whether frailty is associated with hospitalization and mortality among residents of aged care services. Methods: A prospective cohort study of 383 residents aged 65 years and older was conducted in six Australian residential aged care services. Frailty was assessed using the FRAIL-NH scale and a 66-item frailty index. Results: Overall, 125 residents were hospitalized on 192 occasions and 85 died over the 12-month follow-up. Over this period, less than 3% of the nonfrail/vulnerable residents but more than 20% of the most frail residents died at the facility without hospitalization. Using the FRAIL-NH, residents with mild/moderate frailty had higher numbers of hospitalizations (adjusted incidence rate ratio 1.57, 95% confidence interval [CI] 1.11-2.20) and hospital days (incidence rate ratio 1.48, 95% CI 1.32-1.66) than nonfrail residents. Residents who were most frail had lower numbers of hospitalizations (incidence rate ratio 0.65, 95% CI 0.42-0.99) and hospital days (incidence rate ratio 0.39, 95% CI 0.33-0.46) than nonfrail residents. Similar patterns of associations with number of hospital days were observed for the frailty index. Most frail residents had a higher risk of death than nonfrail residents (for FRAIL-NH, adjusted hazard ratio 2.96, 95% CI 1.50-5.83; for frailty index, hazard ratio 5.28, 95% CI 2.05-13.59). Conclusions: Residents with mild/moderate frailty had higher risk of hospitalization and death than nonfrail residents. Residents who were most frail had higher risk of death but lower risk of hospitalization than nonfrail residents. PMID- 29985994 TI - Longitudinal Changes in Muscle Mass and Strength, and Bone Mass in Older Adults: Gender-Specific Associations Between Muscle and Bone Losses. AB - Background: The aims of this study were to investigate the longitudinal changes in muscle and bone with aging, and to clarify the muscle-bone relationships. Methods: In a community-based prospective study, a total of 172 men and 165 women aged >= 65 years who had performed body composition analysis and bone mineral density (BMD) by dual-energy x-ray absorptiometry at baseline and 5-year follow up evaluations were included. Results: The rate of BMD loss in total hip was significantly associated with baseline legs lean mass and loss rate of leg strength, but not with the rate of muscle mass losses in men (r = .205 in leg lean mass, r = .170 in loss rate of leg muscle strength, p < .05 respectively). However, in women, it was significantly correlated with the rate of leg lean mass loss, but not with baseline values, and the rate of loss in leg muscle strength (r = .169 in the rate of loss in leg lean mass, r = .246 in the rate of loss in leg muscle strength, p < .05 respectively). In multivariate analyses, the rates of decrease in leg muscle strength showed independent positive associations with loss in total hip BMD in both men and women (beta = 0.023 for men and beta = 0.045 for women, both p < .05 respectively). Conclusion: There was a gender difference in muscle and bone mass changes with aging, and muscle-bone interactions as well. However, a longitudinal change in muscle strength was the most significant independent factor associated with bone loss for both genders. PMID- 29985995 TI - Predicting influenza vaccine effectiveness with hemagglutinin sequences is not sufficient enough. PMID- 29985996 TI - A ROADMAP plan to address research needs for gonococcal antimicrobial resistance in China. AB - Gonococcal antimicrobial resistance (AMR) has become a global threat significantly hampering the control of gonorrhea. Many socio-economic, biological, behavioral, and programmatic factors have played an important role in driving the emergence, transmission and spread of gonococcal AMR. However, research to address these scientific and programmatic questions is limited in China. Here we propose a ROADMAP (resistance surveillance, outcomes due to AMR, antibiotic stewardship and application, diagnostic tools, mechanisms of AMR, antimicrobial assessment, and population pharmacokinetics and pharmacodynamics) plan for expanding interdisciplinary collaborations to address the research needs in China. PMID- 29985997 TI - The influence of hospital volume upon clinical management and outcomes of esophageal achalasia: an English national population-based cohort study. AB - Management of achalasia is potentially complex. Previous studies have identified equivalence between pneumatic dilatation and surgical cardiomyotomy in terms of clinical outcomes. However, previous research has not investigated whether a management strategies and outcomes are different in high-volume achalasia centers. This national population-based cohort study aimed to identify the treatment modalities utilized in centers, which regularly manage achalasia and those which manage it infrequently. This study also assessed rates of re intervention and complications to establish if a volume-outcome relationship exists for the management of achalasia in England. In this study, the Hospitals Episode Statistics database was used to identify all patients treated for achalasia in England from 2002 to 2012. Primary treatment was defined as surgical cardiomyotomy, sequential pneumatic dilatation, or botulinum toxin therapy. Primary outcome measure was reintervention. Centers were divided into regular achalasia centers (>=5.7 cases per annum) and infrequent achalasia centers (<5.7 cases per annum), and were analyzed according to tertiary cancer center status. In total, there were 7,487 patients treated for achalasia. Out of 1,947 cases (26%) were treated in regular achalasia centers, with 5,540 (74%) treated in infrequent centers. In binary logistic regression modeling regular centers treated a similar proportion of patients with primary surgical cardiomyotomy (OR: 1.11 (95% CI 0.98-1.27)) and had similar rates of re-intervention to infrequent achalasia centers (HR: 1.03 (0.94-1.12)). RA-CUSUM analysis demonstrated no relationship between total hospital volume and reintervention rates. Tertiary cancer centers treated more achalasia patients with primary surgical cardiomyotomy (OR: 1.51 (95% CI 1.31-1.73)) but there was no significant difference in reintervention rates (OR: 1.05 (95% CI 0.95-1.16)). In conclusion, this analysis failed to demonstrate a volume-outcome relationship in the management of achalasia in England. This study highlights that achalasia is treated infrequently by the majority of centers. PMID- 29985992 TI - BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells. AB - The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes. PMID- 29985998 TI - High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans. AB - Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy. PMID- 29985999 TI - Accuracy of Diffusion-weighted Magnetic Resonance Imaging in Detecting Mucosal Healing and Treatment Response, and in Predicting Surgery, in Crohn's Disease. AB - Background and Aims: The Nancy score is a luminal Crohn's disease [CD] activity index applied in diffusion-weighted magnetic resonance imaging [DW-MRI]. We assessed the accuracy of the Nancy score in detecting mucosal healing and treatment response, and in predicting surgery. Methods: This was a retrospective, single-centre study of all patients with active CD and serial DW-MRI before and after treatment initiation with a biologic drug, between January 2010 and September 2016. The gold standard was endoscopy. The association between the Nancy score and the cumulative probability of intestinal resection during follow up was tested combining Kaplan-Meier curves and log-rank testing. Results: A total of 96 patients were included; 20 had concomitantly undergone endoscopy. The Nancy score correlated well with the Crohn's Disease Endoscopic Index of Severity [r = 0.60 for the total score and r = 0.63 for the segmental score]. A total Nancy score <6 and a segmental Nancy score <2 detected mucosal healing with an area under the receiver operating characteristic curve [AUROC] of 0.82 (95% confidence interval [CI] 0.69-0.94, p <0.0001) and 0.80 [95% CI 0.73-0.87, p <0.0001], respectively. The Nancy score was highly sensitive to changes [Guyatt's responsiveness indices: 1.18 for the total score and 0.85 for the segmental score]. Mucosal healing on DW-MRI after treatment initiation was associated with a lower cumulative probability of intestinal surgery (p = 0.0251, median [interquartile range: IQR] follow-up 2.2 [1.6-3.7] years). Conclusions: In CD, the Nancy score accurately detects mucosal healing and treatment response, the latter associated with a lower likelihood of intestinal resection. PMID- 29986000 TI - Gene-by-Gene or Localized Dosage Compensation on the Neo-X Chromosome in Drosophila miranda. AB - Many organisms have a global mechanism for dosage compensation (DC) operating along the entire male X chromosome, which equalizes gene expression on the male X with that on the two Xs in females and/or on autosomes. At the initial stage of sex chromosome evolution, however, gene-by-gene (or localized) DC may also be necessary because the degeneration of Y-linked genes occurs independently at different times. We therefore tested whether the up-regulation of X-linked genes depends on the status of their Y-linked homologs, using the young sex chromosomes, neo-X and neo-Y, in Drosophila miranda. In support of the presence of gene-by-gene DC, the extent of up-regulation in males was indeed higher for neo-X-linked genes with pseudogenized neo-Y-linked homologs than for neo-X-linked genes with functional neo-Y-linked homologs. Further molecular evolutionary analysis also supports the idea that many individual neo-X-linked genes first acquired the potential for up-regulation, which then enabled the pseudogenization of neo-Y-linked homologs, without serious deleterious effects on male fitness. PMID- 29986001 TI - Stroke and bleeding risk scores in patients with atrial fibrillation and valvular heart disease: evaluating 'valvular heart disease' in a nationwide cohort study. AB - Aims: Substantial interest has been directed towards stroke risk stratification in patients with atrial fibrillation (AF) but prior studies have focused on AF without significant valvular heart disease (VHD), so-called 'non-valvular AF'. A formal validation exercise addressing stroke risks in relation to the CHA2DS2 VASc risk factor(s) in AF patients with VHD is lacking. Also, the use of the HAS BLED score in anticoagulated patients with VHD has not been previously studied. The aim of this study was to investigate stroke and bleeding rates in AF patients with VHD in relation to the CHA2DS2-VASc and HAS-BLED scores. Methods and results: We conducted a nationwide cohort study. VHD were categorized based on the 2017 joint European consensus document definition, i.e. Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA)', thus including severe native mitral stenosis and prosthetic mechanical heart valves and (ii) EHRA Type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a non-VKA oral anticoagulant (NOAC)', thus including all other forms of VHD. We identified 25 818 AF patients with VHD with EHRA Type 2 in 90% (n = 23 253). Thromboembolism and bleeding events increased with increasing CHA2DS2-VASc and HAS-BLED scores, whether with 1 or 2.5 years follow-up. EHRA Type 1 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.62 (0.55-0.70) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. EHRA Type 2 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.63 (0.60-0.65) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. Conclusion: This is the first validation of CHA2DS2-VASc and HAS-BLED scores in AF patients with VHD (so-called 'valvular AF') using the new EHRA classification. Both scores are modestly predictive of thromboembolism and bleeding events in VHD, respectively. Event rates increased with increasing risk factors as evident by increasing CHA2DS2-VASc and HAS-BLED score points, consistent with performance of these clinical scores in 'non-valvular AF' patients. PMID- 29986002 TI - In vitro genomic and proteomic evidence of a type IV pili-like structure in the fish pathogen Piscirickettsia salmonis. AB - Piscirickettsia salmonis is an intracellular gamma-proteobacteria and the etiological agent of piscirickettsiosis, which causes massive economic losses in the Chilean salmon industry. The type IV pili (T4P) play an important role in adherence to host cell surfaces and bacterial pathogenicity. T4P contains a variable number of components, as predicted in P. salmonis genomes. However, no studies have determined if P. salmonis possesses T4P. The aims of this investigation were to identify T4P components in the P. salmonis type strain LF 89T, evaluate respective transcript expressions, and analyze the main putative T4P proteins using bioinformatics and proteomic approaches. Two main clusters of P. salmonis T4P genes were found. Expression of the pilA gene was upregulated at 4 h post-infection (hpi), while pilQ was upregulated 4 days post-infection. At 16 hpi, pilB and pilD were strongly upregulated. The PilA amino acid sequence analysis showed a conserved N-terminal domain and sequence motifs critical for T4P biosynthesis. MudPIT analysis revealed PilA in the P. salmonis LF-89T proteome, and TEM showed pili-like filamentous structures on the P. salmonis surface. These results strongly suggest the presence of a T4P-like structure in P. salmonis. PMID- 29986003 TI - Fuscumol and Geranylacetone as Pheromone Components of Californian Longhorn Beetles (Coleoptera: Cerambycidae) in the Subfamily Spondylidinae. AB - In field trials testing attraction of cerambycid beetles to a blend of known pheromone components plus host plant volatiles, several species in the subfamily Spondylidinae were attracted to baited traps, suggesting that one or more components of the blend might constitute their pheromones. Here, we describe laboratory and field experiments aimed at identifying the actual pheromone components produced by these species. Analysis of headspace odors collected from male Tetropium abietis (Fall) (Coleoptera: Cerambycidae) contained (S)-fuscumol as a single component, whereas Asemum nitidum (LeConte) (Coleoptera: Cerambycidae) males produced both (S)-fuscumol and geranylacetone, and Asemum caseyi (Linsley) (Coleoptera: Cerambycidae) produced only geranylacetone. In field trials testing fuscumol, fuscumol acetate, and geranylacetone as individual components or in blends, in combination with host plant volatiles, A. nitidum were attracted to blends of fuscumol and geranylacetone, T. abietis were attracted to fuscumol alone, and A. caseyi were attracted to geranylacetone alone. Fuscumol acetate did not appear to be either attractive or inhibitory. These results, along with previous catches of spondylidine species in traps baited with fuscumol, provide evidence that fuscumol and geranylacetone are likely to be relatively common pheromone structures for species in the subfamily Spondylidinae. PMID- 29986004 TI - Impact of flat chest on cadaveric lung transplantation: postoperative pulmonary function and survival. AB - OBJECTIVES: Thoracic cage flatness, the so-called flat chest, is a chest wall deformity associated with end-stage lung disease requiring lung transplantation. There is little information on the impact of flat chest on lung transplantation. The purpose of this study was to investigate whether flat chest directly influences respiratory function and survival after cadaveric lung transplantation. METHODS: Data from 68 patients who underwent cadaveric lung transplantation between August 2010 and September 2017, excluding patients with chronic obstructive pulmonary disease and lymphangioleiomyomatosis, were retrospectively collected and divided into 2 groups: a flat chest group (n = 30) and a non-flat chest group (n = 38). Flat chest was diagnosed when the ratio of the thoracic anteroposterior diameter to the transverse diameter was 1/3 or less. Preoperative characteristics, postoperative pulmonary function, exercise capacity and survival were compared between the 2 groups. RESULTS: Preoperative forced vital capacity (FVC) and %FVC were significantly lower in the flat chest group. A downsizing of lobar transplantation to overcome size disparity was more frequent in the flat chest group (P = 0.04). However, there were no significant differences in the ratio of postoperative FVC to the preoperatively estimated FVC and postoperative 6-min walk distances between the 2 groups. The 5-year overall survival rate of patients in the flat chest group and the non-flat chest group was 64.3% and 66.5%, respectively (P = 0.87). CONCLUSIONS: Although tailoring of the donor lung was occasionally needed for flat chest patients, postoperative function and survival of flat chest patients were satisfactory compared with those of non-flat chest patients after cadaveric lung transplantation. PMID- 29986005 TI - Spatiotemporal immunofluorescent evaluation of porcine reproductive and respiratory syndrome virus transmission across the maternal-fetal interface. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection causes severe reproductive failure characterized by high fetal morbidity and mortality leading to substantial economic losses to the swine industry. Evaluation of spatiotemporal transmission of PRRSV at the maternal-fetal interface (MFI) is critical for understanding fetal infection. Localization of PRRSV-2 strain NVSL 97-7895 at different regions of the MFI in 20 pregnant gilts at 2, 5, 8, 12 and 14 days post inoculation (dpi) were analyzed by immunofluorescence (IF). Samples of MFI were collected from 15 inoculated and 5 control gilts and transplacental PRRSV transmission assessed in randomly selected fetuses from each litter. Localization of NVSL 97-7895 antigen immunoreactivity in the MFI was focused in three major areas: endometrial connective tissues (ENDO), the feto-maternal junction (FMJ) and fetal placenta (PLC). NVSL 97-7895 was detected at the FMJ by 2 dpi. At 2, 5 and 8 dpi, NVSL 97-7895 was localized within the ENDO and FMJ, whereas at 12 and 14 dpi, it was mainly localized in the PLC. Using a novel IF strategy for counting and size sorting NVSL 97-7895 viral antigen in situ, results of this study indicate that non-cell associated mechanisms are involved in PRRSV transmission across the MFI. PMID- 29986006 TI - Chronic Opioid Use Among Youth With Inflammatory Bowel Disease: A New Approach Is Needed. PMID- 29986007 TI - Success of a National Intervention in Controlling Carbapenem-Resistant Enterobacteriaceae in Israel's Long-Term Care Facilities. AB - Background: Long-term care facilities (LTCFs) are a major reservoir of carbapenem resistant Enterobacteriaceae (CRE) in healthcare facilities, contributing to rapid regional dissemination of CRE. Methods: In 2008, The Israeli National Center for Infection Control (NCIC) initiated a coordinated, comprehensive intervention in Israel's LTCFs, encompassing approximately 25,000 beds in over 300 institutions. The intervention included implementation of population-tailored contact precautions and early detection of carriers. The NCIC established a real time repository of all CRE carriers and events of acquisition, supervised information exchange between healthcare facilities and directed intervention at the institutional level during local outbreaks. CRE incidence was determined based on detection of CRE, either during LTFC stay or on admission to another facility. Prevalence was determined by a series of 5 cross-sectional surveys commenced between 2008 and 2015. Results: From January 2009 through December 2015, 5265 patients acquired CRE in LTCFs. During the study period, incidence of acquisition declined in all facility types, to approximately 50% of the baseline (p<0.001). The number of skilled nursing facilities and nursing homes experiencing > 5 CRE acquisitions annually decreased from 35 to 11 during this period. The point prevalence of newly detected CRE carriage in post-acute care hospitals decreased from 12.3% in the survey commenced in 2008 to 0.8% in that begun in 2015 (P<0.001). Conclusions: A national, coordinated intervention resulted in a sustained decrease in CRE incidence and prevalence in LTCFs. These results support the assumption that centrally coordinated intervention is an essential public health tool in reducing CRE in healthcare facilities. PMID- 29986008 TI - Monocenter Investigation Micra(r) MRI study (MIMICRY): feasibility study of the magnetic resonance imaging compatibility of a leadless pacemaker system. AB - Aims: As in vivo real-life data are still scarce, we conducted a study to assess the safety and feasibility of cardiac magnetic resonance imaging (MRI) in patients with a leadless pacemaker system. Methods and results: In this prospective non-randomized interventional trial, we enrolled 15 patients with an MRI conditional Micra(r) leadless pacemaker system to undergo either a 1.5 T or 3.0 T cardiac MRI scan. Clinical adverse events as well as device parameters such as pacing threshold, sensing, impedance, and battery life were assessed at baseline as well as 1 and 3 months after the scan. Device parameter changes between different time points were tested for statistical significance and compared with pre-set cut-off values. Fourteen patients underwent the cardiac MRI scan according to the protocol as well as the scheduled follow-up visits. One participant was excluded from analysis, as the MRI scan was not possible because of severe claustrophobia. Other clinical events did not occur during the scan and the follow-up period. Device parameters stayed stable and changes during the observational period were statistically not significant (changes vs. baseline: pacing threshold: 0.01 +/- 0.05 V, P = 0.308, 0.01 +/- 0.07 V, P = 0.419, sensing: -0.15 +/- 1.11 mV, P = 0.658, -0.19 +/- 1.17 mV, P = 0.800, impedance: 7.86 +/- 30.7 Ohm, P = 0.447, -7.86 +/- 25.77 Ohm, P = 0.183, at 1 and 3 months follow-up, respectively). Parameter changes were not statistically different between patients who underwent imaging at 1.5 T (n = 7) or 3.0 T (n = 7). Conclusion: In our set of patients with a Micra(r) leadless pacemaker, cardiac magnetic resonance imaging at either 1.5 T or 3.0 T proved feasible and safe with no relevant changes in device parameters within 3 months of follow-up. PMID- 29986011 TI - Reply to Xu and Ye. PMID- 29986012 TI - Good practice criteria for childhood obesity prevention in kindergartens and schools-elaboration, content and use. AB - Background: In accordance with the policy actions that address childhood overweight and obesity at European level and as a contribution to the EU Action Plan on Childhood Obesity 2014-20, a Joint Action on Nutrition and Physical Activity (JANPA) was established. As part of JANPA work package 6, an evaluation framework to identify good practices, targeting childhood obesity prevention in kindergartens and schools, was developed. This article describes the WP 6 JANPA framework of good practice criteria and its development, compares it to other frameworks and discusses its potential for future use. Methods: Based on the analysis of scientific literature, a set of 47 potential good practice criteria was drafted, that was then revised and complemented through a series of online Delphi consultations. Results: A final list of 48 good practice criteria (9 of which were rated as core criteria) was developed and grouped into three categories: intervention characteristics (n = 17), implementation (n = 17) and monitoring and evaluation (n = 14). Conclusion: The identified JANPA framework of good practice criteria complements the existing frameworks by focussing on kindergarten- and school-based initiatives and provides guidance for evaluators, programme planners and decision makers bearing in mind that a one-size-fits-all approach is inadequate. To ensure the effectiveness of future practices, programme planners should endeavour to meet at least the nine JANPA core criteria. PMID- 29986009 TI - A Revised Spiralian Homeobox Gene Classification Incorporating New Polychaete Transcriptomes Reveals a Diverse TALE Class and a Divergent Hox Gene. AB - The diversity of mechanisms and capacity for regeneration across the Metazoa present an intriguing challenge in evolutionary biology, impacting on the burgeoning field of regenerative medicine. Broad taxonomic sampling is essential to improve our understanding of regeneration, and studies outside of the traditional model organisms have proved extremely informative. Within the historically understudied Spiralia, the Annelida have an impressive variety of tractable regenerative systems. The biomeralizing, blastema-less regeneration of the head appendage (operculum) of the serpulid polychaete keelworm Spirobranchus (formerly Pomatoceros) lamarcki is one such system. To profile potential regulatory mechanisms, we classified the homeobox gene content of opercular regeneration transcriptomes. As a result of retrieving several difficult-to classify homeobox sequences, we performed an extensive search and phylogenetic analysis of the TALE and PRD-class homeobox gene content of a broad selection of lophotrochozoan genomes. These analyses contribute to our increasing understanding of the diversity, taxonomic extent, rapid evolution, and radical flexibility of these recently discovered homeobox gene radiations. Our expansion and integration of previous nomenclature systems helps to clarify their cryptic orthology. We also describe an unusual divergent S. lamarcki Antp gene, a previously unclassified lophotrochozoan orphan gene family (Lopx), and a number of novel Nk class orphan genes. The expression and potential involvement of many of these lineage- and clade-restricted homeobox genes in S. lamarcki operculum regeneration provides an example of diversity in regenerative mechanisms, as well as significantly improving our understanding of homeobox gene evolution. PMID- 29986013 TI - Corrigendum. REPLY: The 'Big Freeze': freeze-all should not be used for everyone. PMID- 29986014 TI - Epicardial atrial mapping during minimally invasive cardiothoracic surgery. AB - Mapping of the unorganized activation patterns of atrial fibrillation requires a high-resolution mapping approach to diagnose substrate-mediated pathophysiological mechanisms. At present, epicardial mapping is the only approach that is able to acquire electrograms of >200 high-density sites simultaneously. This study introduces a technique to perform high-resolution mapping in minimally invasive surgery. In 3 patients with mitral valve disease, epicardial mapping of the right atrium, Bachmann's bundle and parts of the left atrium was safely performed via minimal right thoracotomy. PMID- 29986015 TI - Starting Young: Trends in Opioid Therapy Among US Adolescents and Young Adults With Inflammatory Bowel Disease in the Truven MarketScan Database Between 2007 and 2015. AB - Background: Opioids are commonly prescribed for relief in inflammatory bowel disease (IBD). Emerging evidence suggests that adolescents and young adults are a vulnerable population at particular risk of becoming chronic opioid users and experiencing adverse effects. Objectives: This study evaluates trends in the prevalence and persistence of chronic opioid therapy in adolescents and young adults with IBD in the United States. Method: A longitudinal retrospective cohort analysis was conducted with the Truven MarketScan Database from 2007 to 2015. Study subjects were 15-29 years old with >=2 IBD diagnoses (Crohn's: 555/K50; ulcerative colitis: 556/K51). Opioid therapy was identified with prescription claims within the Truven therapeutic class 60: opioid agonists. Persistence of opioid use was evaluated by survival analysis for patients who remained in the database for at least 3 years following index chronic opioid therapy use. Results: In a cohort containing 93,668 patients, 18.2% received chronic opioid therapy. The annual prevalence of chronic opioid therapy increased from 9.3% in 2007 to 10.8% in 2015 (P < 0.01), peaking at 12.2% in 2011. Opioid prescriptions per patient per year were stable (approximately 5). Post hoc Poisson regression analyses demonstrated that the number of opioid pills dispensed per year increased with age and was higher among males. Among the 2503 patients receiving chronic opioid therapy and followed longitudinally, 30.5% were maintained on chronic opioid therapy for 2 years, and 5.3% for all 4 years. Conclusion: Sustained chronic opioid use in adolescents and young adults with IBD is increasingly common, underscoring the need for screening and intervention for this vulnerable population. PMID- 29986016 TI - Dialysis Catheter-Related Bloodstream Infections in Patients Receiving Hemodialysis on an Emergency-Only Basis: A Retrospective Cohort Analysis. AB - Background: An estimated 6500 undocumented immigrants with end-stage renal disease (ESRD) live in the United States. Those living in states that do not provide undocumented immigrants scheduled hemodialysis receive intermittent hemodialysis only when life-threatening conditions arise. Little is known about catheter-related bloodstream infections (CRBSIs) in this population. Methods: We conducted a retrospective cohort study of emergency-only hemodialysis patients in the Harris Health System in Houston, Texas between January 2012 and December 2015. We assessed CRBSI risk factors including demographics, comorbidities, and duration and frequency of hemodialysis. We investigated the microbiologic etiology of these infections, rates of recurrent CRBSI, and associated morbidity and mortality. Results: The cohort included 329 patients; 90% were Hispanic, 60% had diabetes, and the average age was 51 years. A total 101 CRBSIs occurred, with a rate of 0.84 infections per 1000 catheter days. Cirrhosis and duration of hemodialysis during the study period were associated with increased risk of CRBSI. Seventeen CRBSIs were recurrent; infection with gram-positive bacteria predicted recurrence. Adherence to catheter-related infection guidelines was improved by Infectious Diseases consultation and associated with fewer recurrent infections. CRBSI was associated with prolonged hospitalization (mean 15 days), composite complication rate of 8%, and a 4% mortality rate. Conclusions: Patients receiving emergency-only hemodialysis via tunneled catheters have a high CRBSI rate compared to infection rates previously reported in patients receiving scheduled maintenance hemodialysis. Increased CRSBI risk likely contributes to the increased morbidity and mortality seen in ESRD patients receiving emergency only hemodialysis. PMID- 29986018 TI - First-degree atrioventricular block on basal electrocardiogram predicts future arrhythmic events in patients with Brugada syndrome: a long-term follow-up study from the Veneto region of Northeastern Italy. AB - Aims: This study was designed to assess the prognostic value of clinical and electrocardiographic parameters in Brugada syndrome (BrS). Methods and results: The study population included 272 consecutive patients (82% males; mean age 43 +/ 12 years), with either a spontaneous (n = 137, 50%) or drug-induced (n = 135, 50%) Type 1 Brugada electrocardiogram (ECG) pattern. The study combined endpoint included sudden cardiac death (SCD), cardiac arrest, and appropriate intervention of implantable cardioverter-defibrillator (ICD). A first-degree atrioventricular (AV) block (PR = 219 +/- 17 ms) was documented at basal ECG in 45 patients (16.5%); 27 of these underwent an electrophysiological study with recording in 21 (78%) of an HV interval >=55 ms (mean 61 +/- 3 ms). Patients with first-degree AV block had a wider QRS complex (median 110 ms vs. 95 ms; P = 0.04) and more often showed a left anterior hemiblock pattern (n = 13, 29% vs. n = 35, 16%; P = 0.056). During a mean follow-up of 85 +/- 55 months, 17 patients (6.3%) experienced >=1 major arrhythmic events (appropriate ICD intervention, n = 13 and SCD, n = 4). At univariate analysis, the occurrence of major arrhythmic events was significantly associated with a history of syncope or cardiac arrest (P < 0.001), Type 1 ECG pattern (P = 0.04), and first-degree AV block (P < 0.001). Univariate and multivariable predictors of events included a history of syncope or cardiac arrest [hazard ratio (HR) 5.8, 95% confidence interval (95% CI) 2.04 16.5; P < 0.001; and HR 6.68, 95% CI 2.34-19.1; P < 0.001; respectively], a spontaneous Type 1 ECG pattern (HR 1.56, 95% CI 1.03-4.24; P = 0.033; and HR 1.84, 95% CI 1.01-4.29; P = 0.044; respectively) and a first-degree AV block at baseline ECG (HR 3.84, 95% CI 1.47-9.99; P = 0.006; and HR 4.65, 95% CI 2.34 19.1; P = 0.002; respectively). Conclusion: Besides a history of cardiac arrest or syncope, first-degree AV block on basal ECG is an independent predictor of malignant arrhythmic events and a stronger marker of arrhythmic risk than a spontaneous 'coved-type' ECG pattern in patients with BrS. PMID- 29986019 TI - Is a Reported Penicillin Allergy Sufficient Grounds to Forgo the Multidimensional Antimicrobial Benefits of beta-Lactam Antibiotics? AB - The majority of patients with reported penicillin allergy are not allergic when tested or challenged. Penicillin allergy testing has been shown to significantly reduce future annual healthcare expenditures. Data have emerged showing beta lactams to be multi-dimensional antibacterial effects in vivo, far beyond what is appreciated in standard bacteriological susceptibility testing media. These include enhancing bacterial killing by the innate immune system. Supporting the clinical relevance of these secondary underappreciated effects are recent clinical and pharmaco-economic analyses that show worse outcomes in patients with reported penicillin allergies who receive non-beta lactam antibiotics when compared to their non-penicillin allergic counterparts. This is particularly relevant in the treatment of Staphylococcus aureus bacteremia.This article reviews the tremendous advantages offered by beta-lactam therapy and makes a strong case that the debunking of false penicillin allergies through a detailed allergy history and penicillin allergy testing should be a vital component of antimicrobial stewardship practices. PMID- 29986017 TI - Genome-Wide Changes in Protein Translation Efficiency Are Associated with Autism. AB - We previously proposed that changes in the efficiency of protein translation are associated with autism spectrum disorders (ASDs). This hypothesis connects environmental factors and genetic factors because each can alter translation efficiency. For genetic factors, we previously tested our hypothesis using a small set of ASD-associated genes, a small set of ASD-associated variants, and a statistic to quantify by how much a single nucleotide variant (SNV) in a protein coding region changes translation speed. In this study, we confirm and extend our hypothesis using a published set of 1,800 autism quartets (parents, one affected child and one unaffected child) and genome-wide variants. Then, we extend the test statistic to combine translation efficiency with other possibly relevant variables: ribosome profiling data, presence/absence of CpG dinucleotides, and phylogenetic conservation. The inclusion of ribosome profiling abundances strengthens our results for male-male sibling pairs. The inclusion of CpG information strengthens our results for female-female pairs, giving an insight into the significant gender differences in autism incidence. By combining the single-variant test statistic for all variants in a gene, we obtain a single gene score to evaluate how well a gene distinguishes between affected and unaffected siblings. Using statistical methods, we compute gene sets that have some power to distinguish between affected and unaffected siblings by translation efficiency of gene variants. Pathway and enrichment analysis of those gene sets suggest the importance of Wnt signaling pathways, some other pathways related to cancer, ATP binding, and ATP-ase pathways in the etiology of ASDs. PMID- 29986020 TI - Implementation and applications of EMOD, an individual-based multi-disease modeling platform. AB - Individual-based models provide modularity and structural flexibility necessary for modeling of infectious diseases at the within-host and population levels, but are challenging to implement. Levels of complexity can exceed the capacity and timescales for students and trainees in most academic institutions. Here we describe the process and advantages of a multi-disease framework approach developed with formal software support. The epidemiological modeling software, EMOD, has undergone a decade of software development. It is structured so that a majority of code is shared across disease modeling including malaria, HIV, tuberculosis, dengue, polio, and typhoid. In additional to implementation efficiency, the sharing increases code usage and testing. The freely available codebase also includes hundreds of regression tests, scientific feature tests, and component tests to help verify functionality and avoid inadvertent changes to functionality during future development. Here we describe the levels of detail, flexible configurability, and modularity enabled by EMOD and the role of software development principles and processes in its development. PMID- 29986021 TI - Increased Burden of Psychiatric Disorders in Inflammatory Bowel Disease. AB - Background: Psychiatric comorbidity in inflammatory bowel disease (IBD) is well known; however, data from a truly representative sample are sparse. We aimed to estimate the incidence and prevalence of psychiatric disorders in an IBD cohort compared with a matched cohort without IBD. Methods: Using population-based administrative health data from Manitoba, Canada, we identified all persons with incident IBD from 1989 to 2012 and a general population matched cohort (5:1). We applied validated algorithms for IBD, depression, anxiety disorders, bipolar disorder, and schizophrenia to determine the annual incidence of these conditions post-IBD diagnosis and their lifetime and current prevalence. Results: There were 6119 incident cases of IBD and 30,573 matched individuals. After adjustment for age, sex, socioeconomic status, region of residence, and year, there was a higher incidence in the IBD cohort compared with controls for depression (incidence rate ratio [IRR], 1.58; 95% confidence interval [CI], 1.41-1.76), anxiety disorder (IRR, 1.39; 95% CI, 1.26-1.53), bipolar disorder (IRR, 1.82; 95% CI, 1.44-2.30), and schizophrenia (IRR, 1.64; 95% CI, 0.95-2.84). Incidence rate ratios were similar for Crohn's disease and ulcerative colitis between males and females and were stable over time. However, within the IBD cohort, the incidence rates of depression, anxiety, and bipolar disorders were higher among females, those aged 18-24 years vs those older than 44 years, urbanites, and those of lower socioeconomic status. The lifetime and current prevalence rates of psychiatric disorders were also higher in the IBD than the matched cohort. Conclusions: The incidence and prevalence of psychiatric disorders are elevated in the IBD population. PMID- 29986022 TI - Osteomyelitis complicating sacral pressure ulcers: whether or not to treat with antibiotic therapy. AB - The treatment of osteomyelitis in patients with stage IV sacral pressure ulcers is controversial. We conducted a systematic literature review and did not find evidence of benefit of antibacterial therapy in this setting without concomitant surgical debridement and wound coverage. Furthermore, many patients with chronically exposed bone do not have evidence of osteomyelitis when biopsied, and MRI may not accurately distinguish osteomyelitis from bone remodeling. The goal of therapy should be local wound care and assessment for the potential of wound closure. If the wound can be closed and osteomyelitis is present on bone biopsy, appropriate antibiotic therapy is reasonable. We find no data to support antibiotic durations of greater than 6 weeks in this setting, and some authors recommend 2 weeks of therapy if the osteomyelitis is limited to cortical bone. If the wound will not be closed, we find no clear evidence supporting a role for antibiotic therapy. PMID- 29986023 TI - Microenvironment of saphenous vein graft preservation prior to coronary artery bypass grafting. AB - OBJECTIVES: The best preservation solution for a free vascular graft prior to coronary artery bypass grafting (CABG) remains controversial. The aim of this investigation was to evaluate the microenvironment of the human saphenous vein graft when preserved in normal saline (NS) solution or autologous heparinized whole blood (AWB). METHODS: Between January 2014 and December 2014, 21 patients who underwent CABG were enrolled and a total of 162 saphenous vein graft rings were collected. NS and AWB were used to investigate the influence of the microenvironment. The hypoxia, oxidative stress and vascular apoptosis were assayed by western blot, and endothelial integrity was assessed by immunohistochemical analysis. RESULTS: The level of PaO2 in AWB was lower than that in NS (median: 100.5 mmHg vs 185.8 mmHg, P = 0.004). This hypoxic condition led to the production of more hypoxia-inducible factor-1 (median: 60.1% vs 15.1%, P = 0.008) and endothelial nitric oxide synthase (median: 52.6% vs 25%, P = 0.046) within 30 min of preservation time. The fact that higher levels of glutathione peroxidase resulted in the preservation of AWB suggests that it is beneficial to boost the vascular antioxidant defense with lower levels of NOX2. AWB led to increased Bcl-2, reduced cytochrome c and cleaved 85 kDa poly ADP ribose polymerase apoptotic fragments. CONCLUSIONS: We concluded that AWB possesses a microenvironment that is superior to that of NS for saphenous vein graft preservation prior to CABG. PMID- 29986024 TI - Delineating the origins, developmental programs and homeostatic functions of tissue-resident macrophages. AB - A literature covering 150 years of research indicates that macrophages are a diverse family of professional phagocytes that continuously explore their environment, recognize and scavenge pathogens, unfit cells, cell debris as well as metabolites, and produce a large range of bioactive molecules and growth factors. A new paradigm suggests that most tissue-resident macrophages originate from fetal precursors that colonize developing organs and self-maintain independently of bone marrow-derived cells throughout life. The differentiation of these precursors is driven by a core macrophage transcriptional program and immediately followed by their specification through expression of tissue-specific transcriptional regulators early during embryogenesis. Despite our increasing understanding of ontogeny and genetic programs that shape differentiation processes and functions of macrophages, the precise developmental trajectories of tissue-resident macrophages remain undefined. Here, I review current models of fetal hematopoietic waves, possible routes of macrophage development and their roles during homeostasis. Further, transgenic mouse models are discussed providing a toolset to study the developmentally and functionally distinct arms of the phagocyte system in vivo. PMID- 29986025 TI - VIM/IMP carbapenemase-producing Enterobacteriaceae in Poland: epidemic Enterobacter hormaechei and Klebsiella oxytoca lineages. AB - Objectives: To analyse VIM/IMP-type MBL-producing Enterobacteriaceae isolates identified in Poland during 2006-12. Methods: Isolates were typed by PFGE, followed by MLST. blaVIM/IMP genes were amplified and sequenced within class 1 integrons. Their plasmidic versus chromosomal location was assessed by nuclease S1 and I-CeuI plus hybridization experiments. Plasmids were characterized by transfer assays and PCR-based replicon typing. Results: One hundred and nineteen VIM/IMP-positive Enterobacteriaceae cases were reported in Poland from the first case in 2006 until 2012. The patients were in 54 hospitals and were infected or colonized by 121 organisms, including Enterobacter cloacae complex (n = 64), Klebsiella oxytoca (n = 23), Serratia marcescens (n = 20) and Klebsiella pneumoniae (n = 11). The isolates represented numerous pulsotypes and mainly original STs, and carried eight integrons with blaVIM-1-like genes (blaVIM-1/-4/ 28/-37/-40; n = 101), three with blaVIM-2 variants (blaVIM-2/-20; n = 17) and one with blaIMP-19 (n = 3). Six integrons were new, and five and two formed prevalent families of In238-like (n = 96) and In1008-like (n = 16) elements, respectively. In238 (aacA4-blaVIM-4rpt) and In1008 (blaVIM-2-aacA4) had been originally observed in Polish Pseudomonas aeruginosa, suggestive of their transfer to enterobacteria, followed by spread and diversification. Four organisms have disseminated inter-regionally, i.e. Enterobacter hormaechei ST90 with plasmidic In238/In238a integrons (n = 36), K. oxytoca ST145 with a chromosomal In237-like element (n = 18) and two subclones of E. hormaechei ST89 with In1008- or In238 type variants (n = 8 and n = 7, respectively). Conclusions: The epidemiology of VIM/IMP-producing Enterobacteriaceae in Poland has revealed a remarkable number of specific or novel characteristics of the organisms, with some possible links to other mid-southern European countries. PMID- 29986026 TI - Using Photovoice to examine adolescents' experiences receiving mental health services in the United States. AB - In the U.S., fewer than half of children and adolescents who report mental disorders receive care and the needs of those who receive care have yet to be explored. There is a scarcity of studies examining the needs of adolescents with mental conditions and at risk for suicide. Learning directly from the adolescents can fill in this gap by providing insight that clinicians and researchers lack about adolescents' experience. This study uses Photovoice, a Community-Based Participatory Research method that involves focus groups and the use of cameras by participants to visually capture their reality and express their ideas through photographs. By using Photovoice, this study aims to provide an opportunity for adolescents to voice their own perspectives and for researchers and clinicians to gain an understanding of adolescents' life experience away from the treatment setting, as well as their experience as consumers of mental health services. Four participants, including two 15 year olds and two 17 year olds, were recruited from a mental health clinic in New York City. Parental consent and adolescent assent were collected per Institutional Review Board requirements. Thematic analysis was used to identify and report response patterns. Four themes emerged: (i) sense of self, (ii) family, (iii) suicidal ideation and (iv) treatment. Findings suggest that Photovoice is valued by adolescents and leads to critical thinking, self-reflection, discovering strengths and social support. Adolescents reported feeling empowered, which is the ultimate goal of Photovoice. Photovoice presents a powerful opportunity to be used as therapeutic strategy with adolescents that demands further research. PMID- 29986027 TI - RNA stability and metabolism in regulated cell death, aging and diseases. AB - The stability of RNAs represents a crucial point for cell life in that these molecules code for proteins and also play structural and regulatory functions. In this review, we will mainly focus on RNA stability and its connection with cell death and aging. In addition, we will consider the interaction of RNAs with ribonucleoprotein complexes, such as P-bodies and stress granules, as well as the role of non-coding RNAs. Finally, we will mention some correlations between RNA and diseases, considering yeast as a simple model system for the study of human cancer and neurodegenerative disorders. PMID- 29986028 TI - Mortality Time Trends of Three Subterranean Termite Species When Exposed to 20 Hydroxyecdysone, Alone and in Combination With Noviflumuron. AB - Workers of three termite species, Coptotermes formosanus Shiraki (Blattodea: Rhinotermitidae), Coptotermes gestroi (Wasmann) (Blattodea: Rhinotermitidae), and Reticulitermes flavipes (Kollar) (Blattodea: Rhinotermitidae), were force-fed with cellulose media pads treated with 20-hydroxyecdysone (20E) alone and in combination with noviflumuron for 3 d to examine their mortality time trends up to 14 d (including 3-d exposure time). Termites exhibited symptoms of hyperecdysonism before the onset of death. The times required for 20E to fully express its effects were 10-13 d for C. formosanus, 13-14 d for C. gestroi, and 11-13 d for R. flavipes. Higher 20E concentrations resulted in higher mortalities at 14 d, and the addition of noviflumuron generally yielded higher mortalities. The lethal time of 20E was similar to chitin synthesis inhibitors such as noviflumuron than metabolic inhibitors, and the 10-14 d lethal time may be sufficient for 20E-affected termites to return to the central nest before the onset of hyperecdysonism and ultimate death. As an active ingredient in baiting systems, 20E has shown potential to reduce the colony elimination time. PMID- 29986029 TI - Consumption of Coffee but Not of Other Caffeine-Containing Beverages Reduces the Risk of End-Stage Renal Disease in the Singapore Chinese Health Study. AB - Background: Cross-sectional studies suggest that coffee drinking is associated with better renal function. However, to our knowledge, no prospective study has examined its relation with the risk of end-stage renal disease (ESRD). Objective: We examined the relations between coffee, tea, soda, and total caffeine consumption and the risk of ESRD among middle-aged and older Chinese in Singapore. Methods: We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women aged 45-74 y at recruitment from 1993 to 1998. Baseline information on the consumption of caffeinated coffee and other caffeinated beverages (tea and sodas), habitual diet, medical history, and lifestyle factors was obtained via in-person interviews. The standard serving size of 1 cup was assigned as 237 mL in the questionnaire. Incident ESRD cases were identified via linkage with the nationwide registry. We used multivariable Cox regression models to estimate HRs and 95% CIs of ESRD risk associated with the consumption of caffeinated beverages, with adjustment for potential confounders. Results: After a mean follow-up of 16.8 y, 1143 cohort subjects developed ESRD. Compared with those who drank coffee less than daily, the HR (95% CI) was 0.91 (0.79, 1.05) for those who drank 1 cup of coffee/d and 0.82 (0.71, 0.96) for those who drank >=2 cups/d (P-trend = 0.012). When stratified by sex, this association was observed in men but not in women. Compared with those who drank less than daily, the HR (95% CI) for drinking >=2 cups/d was 0.71 (0.57, 0.87) among men and 0.97 (0.78, 1.19) among women (P-interaction = 0.03). Conversely, intakes of tea, soda, or total caffeine were not associated with the risk of ESRD in multivariable models. Conclusion: The consumption of >=2 cups of coffee/d may reduce the risk of ESRD in the general population, especially among men. This study was registered at http://www.clinicaltrials.gov as NCT03356340. PMID- 29986031 TI - Tetracycline and fluoroquinolone resistance in clinical Ureaplasma spp. and Mycoplasma hominis isolates in France between 2010 and 2015. AB - Objectives: As information on Ureaplasma spp. and Mycoplasma hominis resistance is currently limited, the aim of this study was to investigate the susceptibility of Ureaplasma spp. and M. hominis to tetracyclines and fluoroquinolones in France. Methods: The susceptibility of 1014 clinical isolates obtained in Bordeaux University Hospital (Bordeaux, France) between 2010 and 2015 was evaluated using two commercial kits, S.I.R. Mycoplasma (Bio-Rad) from 1 January 2010 to 5 October 2012 and MYCOFAST RevolutioN kit (ELITech Group) from 6 October 2012 to 31 December 2015. The MICs of isolates designated as resistant were determined using the broth microdilution assay. Additionally, the tet(M) gene and fluoroquinolone resistance-associated mutations were identified. Results: Among 831 Ureaplasma spp. isolates, the tetracycline, levofloxacin and moxifloxacin resistance rates were 7.5%, 1.2% and 0.1%, respectively. Among 183 M. hominis isolates, the resistance rates were 14.8%, 2.7% and 1.6% for tetracycline, levofloxacin and moxifloxacin, respectively. Over the 6 year period, no significant change in resistance to tetracycline or fluoroquinolones was observed. The tet(M) gene was found in all tetracycline-resistant isolates. All levofloxacin-resistant isolates harboured a mutation in the parC or parE genes. Isolates that were also resistant to moxifloxacin harboured an additional mutation in the gyrA gene. The MYCOFAST RevolutioN kit significantly overestimated levofloxacin and moxifloxacin resistance in Ureaplasma spp. isolates. Conclusions: Resistance to tetracycline and fluoroquinolones is limited in France in mycoplasmas but compared with a previous report in 1999-2002, a significant increase in tetracycline resistance among Ureaplasma spp. was observed. Ongoing monitoring of the antibiotic susceptibility of these urogenital mycoplasmas remains necessary. PMID- 29986030 TI - Effectiveness of Market-Level Biosecurity at Reducing Exposure of Poultry and Humans to Avian Influenza: A Systematic Review and Meta-Analysis. AB - Background: In this study, we aimed to identify the effect of market-level risk factors on avian influenza (AI) infection in poultry and humans and generate evidence that will inform AI prevention and control programs at live bird markets (LBMs). Methods: We performed a systematic literature review in both English and Chinese search engines. We estimated the pooled odds ratios of biosecurity indicators relating to AI infections at market level using a quality effects (QE) meta-analysis model. Results: Biosecurity measures effective at reducing AI market contamination and poultry infection at LBMs include smaller market size, selling single poultry species and separating different species, performing cleaning and disinfection and market closures, ban on overnight storage, and sourcing poultry from local areas. Our meta-analysis indicates that higher risk of exposure to AI infection occurs in workers at retail LBMs, female workers, and those who contact ducks, conduct cleaning, slaughtering, defeathering, or evisceration. Conclusions: The most effective strategies to reduce AI market contamination identified in this study should target larger LBMs that are located at noncentral city areas and sell and slaughter multispecies of live poultry. Live bird market workers directly involved in cleaning and poultry processing tasks should participate in occupational health and safety programs. PMID- 29986032 TI - Genome-Wide Assessment of Diversity and Divergence Among Extant Galapagos Giant Tortoise Species. AB - Genome-wide assessments allow for fuller characterization of genetic diversity, finer-scale population delineation, and better detection of demographically significant units to guide conservation compared with those based on "traditional" markers. Galapagos giant tortoises (Chelonoidis spp.) have long provided a case study for how evolutionary genetics may be applied to advance species conservation. Ongoing efforts to bolster tortoise populations, which have declined by 90%, have been informed by analyses of mitochondrial DNA sequence and microsatellite genotypic data, but could benefit from genome-wide markers. Taking this next step, we used double-digest restriction-site associated DNA sequencing to collect genotypic data at >26000 single nucleotide polymorphisms (SNPs) for 117 individuals representing all recognized extant Galapagos giant tortoise species. We then quantified genetic diversity, population structure, and compared results to estimates from mitochondrial DNA and microsatellite loci. Our analyses detected 12 genetic lineages concordant with the 11 named species as well as previously described structure within one species, C. becki. Furthermore, the SNPs provided increased resolution, detecting admixture in 4 individuals. SNP based estimates of diversity and differentiation were significantly correlated with those derived from nuclear microsatellite loci and mitochondrial DNA sequences. The SNP toolkit presented here will serve as a resource for advancing efforts to understand tortoise evolution, species radiations, and aid conservation of the Galapagos tortoise species complex. PMID- 29986033 TI - RE: Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. PMID- 29986034 TI - Effects of Bt Corn on the Development and Fecundity of Corn Earworm (Lepidoptera: Noctuidae). AB - The corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), is only moderately susceptible to most toxins from the bacterium Bacillus thuringiensis (Bt) expressed in transgenic corn. To better understand the impact of Bt corn on the life cycle of H. zea, we collected pupae of H. zea during 2014-2016 in North Carolina, South Carolina, and Mississippi from corn hybrids expressing Cry1Ab, Cry1F, Cry1F + Cry1Ab, Cry1F + Cry1Ab + Vip3Aa20, Cry1A.105 + Cry2Ab2, and Cry1A.105 + Cry2Ab2 + Cry1F, as well as from non-Bt near-isolines. We investigated the effect of Bt corn on pupal weight, fecundity, and egg viability of H. zea. Pupal weights were significantly reduced for males and females from all Bt hybrids compared with non-Bt near-isolines. Female pupae from the hybrid expressing Cry1F + Cry1Ab were also significantly lighter relative to those from the near-isolines expressing only Cry1F. Reductions in pupal weight did not result in any detectable effects on fecundity or egg viability. The reduction in pupal weight in the hybrids expressing Cry1F and Cry1F + Cry1Ab significantly declined over time in South Carolina, possibly indicating developing resistance to these Bt toxins. These data can be incorporated into insect resistance management models used to improve risk management decisions regarding H. zea in Bt crops in the complex landscapes of the southern United States. PMID- 29986035 TI - T-Cell Receptor Diversity and the Control of T-Cell Homeostasis Mark Ebola Virus Disease Survival in Humans. AB - Differences in T-cell phenotype, particularly the expression of markers of T-cell homeostasis, have been observed in fatal and nonfatal Ebola virus disease (EVD). However, the relationship between these markers with T-cell function and virus clearance during EVD is poorly understood. To gain biological insight into the role of T cells during EVD, combined transcriptomics and T-cell receptor sequencing was used to profile blood samples from fatal and nonfatal EVD patients from the recent West African EVD epidemic. Fatal EVD was characterized by strong T-cell activation and increased abundance of T-cell inhibitory molecules. However, the early T-cell response was oligoclonal and did not result in viral clearance. In contrast, survivors mounted highly diverse T-cell responses, maintained low levels of T-cell inhibitors, and cleared Ebola virus. Our findings highlight the importance of T-cell immunity in surviving EVD and strengthen the foundation for further research on targeting of the dendritic cell-T cell interface for postexposure immunotherapy. PMID- 29986036 TI - WGS analysis of ST9-MRSA-XII isolates from live pigs in China provides insights into transmission among porcine, human and bovine hosts. AB - Objectives: To elucidate the phylogenetic relationships among ST9-MRSA-XII isolates from different sources and their genetic features in colonization of different hosts. Methods: We obtained whole-genome sequences of two ST9-MRSA-XII isolates from nasal swabs associated with live pigs in China, and compared them with 135 previously sequenced genomes of 78 human-associated, 39 bovine and 18 porcine Staphylococcus aureus consisting of 11 MRSA of SCCmecXII, 62 MRSA of other SCCmec types and 62 MSSA. The distribution of diverse mobile genetic elements (MGEs), resistance genes and virulence determinants was investigated in relation to isolate phylogeny. Comparisons of SNPs and small insertion/deletions (indels) were conducted to examine genome-level variation between porcine and bovine ST9-MRSA-XII. Results: Phylogenetic analysis revealed that both of our porcine ST9-MRSA-XII isolates clustered with porcine, bovine and human-associated ST9-MRSA-XII. All of these isolates possessed a novel type V pathogenicity island, nuSaalpha, carrying the von Willebrand-binding protein gene vwb, the immune evasion complex gene scn, the aminoglycoside resistance gene aadE, staphylococcal superantigen-like genes (ssl1-ssl11) and lpl tandem genes. Compared with bovine ST9-MRSA-XII BA01611, our porcine isolates contain non synonymous nucleotide substitutions in genes encoding adhesins and an indel located in a phosphonate ABC transporter pseudogene. Conclusions: The data suggest transmission of ST9-MRSA-XII among swine, cattle and humans. The extraordinary success of the ST9-MRSA-XII group in colonization of various hosts is likely due to acquisition of many MGEs harbouring functional antimicrobial resistance and virulence genes. Transmission of ST9-MRSA-XII between porcine and bovine hosts was accompanied by changes in binding profile and function in genes involved in metabolism. PMID- 29986037 TI - Association of Perfluoroalkyl and Polyfluoroalkyl Substances With Premature Ovarian Insufficiency in Chinese Women. AB - Context: Perfluoroalkyl and polyfluoroalkyl substances (PFASs), a group of ubiquitous environmental chemicals with properties of endocrine disruption, are often detectable in humans. Objective: The current study investigated the association between exposure to PFAS and primary ovarian insufficiency (POI). Design, Patients, Interventions, and Main Outcome Measures: Levels of plasma PFAS were measured in 120 Chinese women with overt POI and 120 healthy control subjects from 2013 to 2016. Associations between PFAS levels and odds of POI, as well as hormonal profiles, were evaluated using multiple logistic regression and multiple linear regression models. Results: Levels of perfluorooctanate (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexanesulfonate (PFHxS) were positively associated with the risks of POI (highest vs. lowest tertile, PFOA: OR, 3.80; 95% CI, 1.92-7.49; PFOS: OR, 2.81; 95% CI, 1.46-5.41; PFHxS: OR, 6.63; 95% CI, 3.22-13.65). In patients with POI, levels of PFOS and PFHxS exposure were positively associated with FSH (PFOS: adjusted beta, 0.26; 95% CI, 0.15 to 0.38; PFHxS: adjusted beta, 0.16; 95% CI, 0.04 to 0.28) and negatively associated with estradiol (PFOS: adjusted beta, -0.30; 95% CI, -0.47 to -0.12; PFHxS: adjusted beta, -0.19; 95% CI, -0.37 to -0.02). Exposure to PFOS and PFOA was associated with elevation of prolactin (PFOS: adjusted beta, 0.17; 95% CI, 0.06 to 0.29; PFOA: adjusted beta, 0.16; 95% CI, 0.01 to 0.30) or with a decrease of free triiodothyronine (PFOS: adjusted beta, -0.88; 95% CI, -1.64 to -0.09; PFOA: adjusted beta, -0.90; 95% CI, -1.88 to 0.09) and thyroxine (PFOS: adjusted beta, 2.99; 95% CI, -4.52 to -1.46; PFOA: adjusted beta, -3.42; 95% CI, -5.39 to 1.46). Conclusion: High exposure to PFOA, PFOS, and PFHxS is associated with increased risk of POI in humans. PMID- 29986038 TI - Evidence of Reduced Agmatine Concentrations in the Cerebral Cortex of Suicides. AB - Background: The polyamines are a group of ubiquitous low-molecular-weight aliphatic molecules that play an essential role in various physiological functions of the mammalian CNS. Previous literature has indicated alterations in the expression of polyamine-related genes in the brains of individuals who died by suicide, including downregulation of spermidine/spermine N1-acetyltransferase, a key enzyme involved in polyamine catabolism. One such polyamine, agmatine, has been shown to act as an antidepressant in animal models of depressive-like behavior. However, agmatine concentrations have not been explored in postmortem human brain of individuals who died by suicide. Methods: To measure agmatine in postmortem human brain tissue, we employed our previously published high resolution capillary gas chromatography in combination with mass spectrometry method. Using this method, we analyzed agmatine levels in a total of 120 tissue samples from Brodmann areas 4, 11, and 44 of 40 male subjects comprising controls (n=13), individuals who died by suicide and met criteria for major depressive disorder (n=14), and subjects who died by suicide and did not meet criteria for major depressive disorder (n=13). Results: Agmatine fell within the expected nanomolar range and was significantly reduced in the cortex of suicides, irrespective of meeting criteria for major depressive disorder compared with controls. Conclusions: This is the first gas chromatography-mass spectrometry study to analyze agmatine concentrations in human postmortem brain of individuals who died by suicide. These results add to our mechanistic understanding of the role that the polyamine stress response pathway may play in the neurobiology of major depression and/or suicide. PMID- 29986039 TI - Personality Traits, Self-Efficacy, and Cochlear Implant Use Among Deaf Young Adults. AB - A variety of studies have examined ways in which cognitive and social-emotional factors may be linked to and affected by hearing loss, use of cochlear implants (CIs), and sign language. A related domain that largely has been overlooked, however, is personality. This paper reports a study of personality traits and self-efficacy among deaf and hard-of-hearing (DHH; n = 223) college students, with and without CIs, as compared to hearing peers (n = 106). All participants completed (HEXACO) personality trait and self-efficacy inventories; DHH participants also completed a communication questionnaire. Hearing participants scored higher on the personality trait Conscientiousness than both DHH CI users and non-CI users, as well as higher on Openness to Experience compared to DHH CI users. Hearing participants also scored higher on self-efficacy compared to DHH non-CI users. Among DHH non-CI users, greater self-rated sign language skills were associated with higher Extraversion and Agreeableness scores. Among the DHH CI users, earlier sign language acquisition was associated with higher Openness to Experience scores, and earlier cochlear implantation was associated with greater Emotionality scores. Self-efficacy was associated with both better self rated spoken language skills and a stronger preference for spoken language over sign language use among DHH CI users. PMID- 29986040 TI - Plasma Betaine Is Positively Associated with Developmental Outcomes in Healthy Toddlers at Age 2 Years Who Are Not Meeting the Recommended Adequate Intake for Dietary Choline. AB - Background: Choline is an important nutrient during development. However, there are limited data on dietary choline intake and status in toddlers and the relation to neurodevelopmental outcomes. Objective: This study assessed dietary choline intake and status in healthy toddlers at ages 1 and 2 y and determined the relation to neurodevelopmental outcomes. Methods: This is a secondary analysis of data from healthy toddlers enrolled in a double-blind, randomized controlled trial of long-chain polyunsaturated fatty acid supplementation between ages 1 and 2 y. Dietary intakes of betaine and choline were estimated by 3-d food records; plasma free choline, betaine, and dimethylglycine were quantified by liquid chromatography-tandem mass spectrometry. Developmental outcomes were assessed at age 2 y with the use of the Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III), Cognitive and Language composites, and the Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery-VMI). Results: The mean +/- SD daily intake for total choline at age 1 y was 174 +/- 56.2 mg/d and increased (P < 0.001) to 205 +/- 67.5 mg/d at age 2 y. At ages 1 and 2 y, 71.8% and 55.8%, respectively, of toddlers did not meet the recommended 200-mg/d Adequate Intake (AI) for dietary choline. At age 1 y, mean +/- SD plasma free choline, betaine, and dimethylglycine concentrations were 10.4 +/- 3.3, 41.1 +/- 15.4, and 4.1 +/- 1.9 umol/L, respectively. Plasma free choline (8.5 +/- 2.3 umol/L) and dimethylglycine (3.2 +/- 1.3 umol/L) concentrations were lower (P < 0.001) at age 2 y. Plasma betaine concentrations were positively associated with the Beery-VMI (beta = 0.270; 95% CI: 0.026, 0.513; P = 0.03) at age 2 y. Conclusions: These findings suggest that most toddlers are not meeting the recommended AI for dietary choline and that higher plasma betaine concentrations are associated with better visual-motor development at age 2 y. Further work is required to investigate choline metabolism and its role in neurodevelopment in toddlers. The trial is registered at clinicaltrials.gov as NCT01263912. PMID- 29986041 TI - Evidence of negative relationship between female fertility and feed efficiency in Nellore cattle. AB - The objective of this study was to evaluate phenotypic and genetic relationships between fertility traits and feed efficiency in male and female Nellore cattle. Data from 320 females born between 2004 and 2011 were used for phenotypic evaluation. These animals were evaluated for postweaning residual feed intake (RFI) and classified as negative (RFI < 0, mean = -0.294 +/- 0.017 kg DM/d) or positive RFI (RFI > 0, mean = 0.305 +/- 0.0189 kg DM/d). Of these, 118 prepuberal heifers were submitted to ultrasonography of the uterus and ovaries for monitoring the presence (or absence) of a corpus luteum and for the measurement of endometrial thickness. The following fertility traits were evaluated in all females: age at first calving, days to calving, first calving interval, calving success, stayability, and longevity. The variance components were estimated by the average information restricted maximum likelihood method under an animal model in 5-trait analysis of backfat and rump fat thickness, scrotal circumference, days to calving, and RFI. The total number of animals with records was 6,718, including 927 males with records of scrotal circumference and RFI and 264 females with records of days to calving and RFI. Negative RFI females consumed 12.5% less DM daily than positive RFI females and had a lower rump fat thickness when evaluated postweaning. Among the fertility traits studied, only first calving interval differed (P = 0.0858) between RFI classes, with the interval of negative RFI females being 45 d shorter than that of positive RFI animals. The heritability estimates were 0.29, 0.34, 0.50, 0.12, and 0.16 for backfat and rump fat thickness, scrotal circumference, days to calving, and RFI, respectively. The genetic correlations between RFI and the other traits studied were unfavorable for selection and were of moderate magnitude with backfat thickness, rump fat thickness, and days to calving (0.53, 0.37, and -0.49, respectively) and close to zero with scrotal circumference (0.07). Scrotal circumference (0.17 and 0.15) and days to calving (-0.10 and -0.22) were weakly and favorably correlated with backfat and rump fat thickness. There is evidence of moderate genetic antagonism between female fertility and feed efficiency, but with no evidence of a genetic correlation between male fertility and feed efficiency. There is also evidence of low genetic synergism between fat thickness and fertility. PMID- 29986043 TI - No Effect of Human Presence at Night on Disease, Body Mass, or Metabolism in Rural and Urban House Finches (Haemorhous mexicanus). AB - Global urban development continues to accelerate and have diverse effects on wildlife. Although most studies of anthropogenic impacts on animals have focused on indirect effects (e.g., environmental modifications like habitat change or pollution), there may also be direct effects of physical human presence and actions on wildlife stress, behavior, and persistence in cities. Most studies on how humans physically interact with wildlife have focused on the active, daytime phase of diurnal animals, rarely considering effects of our night-time activities. We hypothesized that, if night-time human presence is a stressor for wildlife that are not commonly exposed to humans, night-disturbed rural animals would show stronger physiological signs of elevated stress than would urban individuals. Specifically, we experimentally investigated the effects of human presence at night (HPAN) on disease, body mass, and mass-specific metabolic rates in urban- and rural-caught house finches (Haemorhous mexicanus) in captivity. Our HPAN treatment consisted of a human entering the housing room of the birds and briefly jostling the home cages of each finch as the person walked around the room for a 3-min period on five randomly selected nights per week. Compared with a control (night-undisturbed) group, we found that HPAN greatly increased the odds finches were awake for ca. 33 min post-disturbance, but that chronic treatment did not alter body mass, parasitic infection by coccidian endoparasites, or mass-specific basal metabolic rates. Additionally, finches caught from urban and rural sites did not differ in their response to the treatment. Overall, our results are consistent with those showing that brief but regular human disturbances can have acute negative effects on wildlife, but carry few if any long-term metabolic or disease-related costs in fast-lived birds. However, these findings contrast with the broad, chronic physiological effects of other anthropogenic changes, such as artificial light at night, and highlight the differential impacts that various human activities (which differ in sensory stimulus type, perceived threat, duration and intensity, etc.) can have on wildlife health and behavior. PMID- 29986042 TI - Risk of Neuropsychiatric Adverse Effects of Lipid-Lowering Drugs: A Mendelian Randomization Study. AB - Background: Recent studies have highlighted the possible risk of neuropsychiatric adverse effects during treatment with lipid-lowering medications. However, there are still controversies that require a novel genetic-based approach to verify whether the impact of lipid-lowering drug treatment results in neuropsychiatric troubles including insomnia, depression, and neuroticism. Thus, we applied Mendelian randomization to assess any potential neuropsychiatric adverse effects of conventional lipid-lowering drugs such as statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and ezetimibe. Methods: A 2-sample Mendelian randomization study was conducted based on summary statistics from genome-wide association studies for lipids, insomnia, depression, and neuroticism. Single-nucleotide polymorphisms located in or near drug target genes of HMGCR, PCSK9, and NPC1L1 were used as proxies for statins, PCSK9 inhibitors, and ezetimibe therapy, respectively. To assess the validity of the genetic risk score, their associations with coronary artery disease were used as a positive control. Results: The Mendelian randomization analysis showed a statistically significant (P <.004) increased risk of depression after correcting for multiple testing with both statins (odds ratio=1.15, 95% CI: 1.04-1.19) and PCSK9 inhibitor treatment (odds ratio =1.19, 95%CI: 1.1-1.29). The risk of neuroticism was slightly reduced with statin therapy (odds ratio=0.9, 95%CI: 0.83-0.97). No significant adverse effects were associated with ezetimibe treatment. As expected, the 3 medications significantly reduced the risk of coronary artery disease. Conclusion: Using a genetic-based approach, this study showed an increased risk of depression during statin and PCSK9 inhibitor therapy while their association with insomnia risk was not significant. PMID- 29986044 TI - The Beta-Arrestin-Biased Dopamine D2 Receptor Ligand, UNC9994, Is a Partial Agonist at G-Protein-Mediated Potassium Channel Activation. AB - Background: Previous evidence suggests that UNC9994 is a beta-arrestin2-selective agonist at the dopamine D2 receptor, lacking ability both to activate and antagonize G protein-dependent signaling. However, this has only been reported by one laboratory using a single assay. Methods: We used G protein-coupled inward rectifier potassium channel activation in Xenopus oocytes to investigate UNC9994 induced modulation of G protein-dependent signaling at dopamine D2 receptor and dopamine D3 receptor. Results: At dopamine D2 receptor, UNC9994 induced G protein coupled inward rectifier potassium channel currents that were 15% of the maximal response to dopamine, with an EC50 of 185 nM. At dopamine D3 receptor, the ligand elicited 89% of the maximal dopamine response with an EC50 of 62 nM. Pertussis toxin abolished G protein-coupled inward rectifier potassium channel activation. Furthermore, UNC9994 antagonized dopamine-induced G protein-coupled inward rectifier potassium channel activation at dopamine D2 receptor. Conclusions: UNC9994 modulates G protein-coupled inward rectifier potassium channel channel activation via pertussis toxin-sensitive G proteins at dopamine D2 receptor and dopamine D3 receptor. These findings may have implications for the interpretation of data obtained with this ligand. PMID- 29986046 TI - Evidence for Geographic Variation in Life-Cycle Processes Affecting Phenology of the Lyme Disease Vector Ixodes scapularis (Acari: Ixodidae) in the United States. AB - The seasonal activity pattern of immature Ixodes scapularis Say (Acari: Ixodidae) varies geographically in the United States, which may affect the efficiency of transmission cycles of pathogens transmitted by this species. To study the factors that determine seasonality, a multiyear study at seven sites across the geographic range of I. scapularis systematically collected questing ticks by flagging/dragging, and feeding ticks by capture of their hosts. The observed phenology patterns were consistent with previous studies reporting geographic variation in seasonal tick activity. Predictions of seasonal activity for each site were obtained from an I. scapularis simulation model calibrated using contemporaneous weather data. A range of scenarios for life-cycle processes including different regimes of temperature-independent behavioral and developmental diapause, variations in temperature-development rate relationships, and temperature-dependent tick activity-were used in model formulations. These formulations produced a range of simulations of seasonal activity for each site and were compared against the field observed tick data using negative binomial regression models. Best fit scenarios were chosen for each site on the basis of Akaike's information criterion and regression model parameters. This analysis suggests that temperature-independent diapause mechanisms explain some key observed variations in I. scapularis seasonality, and are responsible in part for geographic variations in I. scapularis seasonality in the United States. However, diapause appears to operate in idiosyncratic ways in different regions of the United States, so further studies on populations in different regions will be needed to enable predictive modeling of climatic and climate change effects on I. scapularis seasonal activity and pathogen transmission. PMID- 29986045 TI - A Pilot Radio Telemetry Field Study of Triatomine Vectors (Hemiptera: Reduviidae) of the Chagas Disease Parasite. AB - We conducted the first pilot radio telemetry study of hematophagous arthropods by placing transmitters on wild-caught triatomine insects ('kissing bugs'), vectors of the Chagas disease parasite. In Texas-a recognized hotspot for triatomine diversity and locally-acquired human and animal Chagas disease-we tagged five female and four male Triatoma gerstaeckeri (Stal) (Hemiptera: Reduviidae), as well as one female and one male Triatoma sanguisuga (Leconte) (Hemiptera: Reduviidae) in three counties from 2015 to 2017. In comparative trials, placement of the transmitter on the dorsal side of the abdomen underneath the hemelytra wings, with the transmitter antenna shortened to 3 cm, yielded the best results. We tracked the movements of the 11 tagged bugs over an average of 4.8 d (range of 1 to 12 d) and detected 18 movement events with an average distance of 3.8 m (range of 1 to 20 m). This pilot study demonstrates the potential utility for using telemetry as a tool for studying fine-scale non-flight movement of triatomines and the discovery of cryptic resting habitats. Future studies using this or similar technologies to study movement and behavior of triatomines could test for site-fidelity of resting habitats and provide novel insight into aspects of vector biology that could be targeted in disease risk reduction efforts. PMID- 29986047 TI - Hyperthermia enhances methyl methanesulfonate-induced adaptive response in meiotic cells of grasshopper Poecilocerus pictus. AB - To understand the role of hyperthermia (HT) in adaptive response, methyl methanesulfonate (MMS) adapted meiotic cells of Poecilocerus pictus were used. Poecilocerus pictus were treated with conditioning (L) or challenging (H) dose of MMS and 2-h time lag (TL) between these doses (L-2h-H) (combined) was employed. Different treatment schedules were used to analyse the influence of HT on MMS induced adaptive response namely pre; inter; post-treatment and cross-adaptation. After each treatment schedules, chromosomal anomalies were analysed. The frequencies of chromosomal anomalies induced by conditioning and challenging doses of MMS were significantly higher (P < 0.0001) compared to that of the control or HT groups. The combined treatments resulted in significant reduction of chromosomal anomalies compared to additive effect of MMS (P < 0.0001). The pre, inter, post and cross-adaptation treatments with HT reduced the frequencies of chromosomal anomalies compared to the challenge and combined treatments with MMS. There is a protection against MMS-induced chromosomal anomalies by HT in in vivo P.pictus. This is the first report to demonstrate that HT enhances the MMS induced adaptive response in in vivo meiotic cells. PMID- 29986049 TI - Response to H Chen, Y Liu, P Li, and D Zhu. PMID- 29986048 TI - Accurate detection of convergent amino-acid evolution with PCOC. AB - In the history of life, some phenotypes have been acquired several times independently, through convergent evolution. Recently, lots of genome-scale studies have been devoted to identify nucleotides or amino acids that changed in a convergent manner when the convergent phenotypes evolved. These efforts have had mixed results, probably because of differences in the detection methods, and because of conceptual differences about the definition of a convergent substitution. Some methods contend that substitutions are convergent only if they occur on all branches where the phenotype changed towards the exact same state at a given nucleotide or amino acid position. Others are much looser in their requirements and define a convergent substitution as one that leads the site at which they occur to prefer a phylogeny in which species with the convergent phenotype group together. Here we suggest to look for convergent shifts in amino acid preferences instead of convergent substitutions to the exact same amino acid. We define as convergent shifts substitutions that occur on all branches where the phenotype changed and such that they correspond to a change in the type of amino acid preferred at this position. We implement the corresponding model into a method named PCOC. We show on simulations that PCOC better recovers convergent shifts than existing methods in terms of sensitivity and specificity. We test it on a plant protein alignment where convergent evolution has been studied in detail and find that our method recovers several previously identified convergent substitutions and proposes credible new candidates. PMID- 29986050 TI - AptaBlocks: Designing RNA complexes and accelerating RNA-based drug delivery systems. AB - RNA-based therapeutics, i.e. the utilization of synthetic RNA molecules to alter cellular functions, have the potential to address targets which are currently out of scope for traditional drug design pipelines. This potential however hinges on the ability to selectively deliver and internalize therapeutic RNAs into cells of interest. Cell internalizing RNA aptamers selected against surface receptors and discriminatively expressed on target cells hold particular promise as suitable candidates for such delivery agents. Specifically, these aptamers can be combined with a therapeutic cargo and facilitate internalization of the cargo into the cell of interest. A recently proposed method to obtain such aptamer-cargo constructs employs a double-stranded "sticky bridge" where the complementary strands constituting the bridge are conjugated with the aptamer and the cargo respectively. The design of appropriate sticky bridge sequences however has proven highly challenging given the structural and functional constraints imposed on them during synthesis and administration. These include, but are not limited to, guaranteed formation and stability of the complex, non-interference with the aptamer or the cargo, as well as the prevention of spurious aggregation of the molecules during incubation. In order to address these issues, we have developed AptaBlocks - a computational method to design RNA complexes that hybridize via sticky bridges. The effectiveness of our approach has been verified computationally, and experimentally in the context of drug delivery to pancreatic cancer cells. Importantly, AptaBlocks is a general method for the assembly of nucleic acid systems that, in addition to designing of RNA-based drug delivery systems, can be used in other applications of RNA nanotechnology. AptaBlocks is available at https://github.com/wyjhxq/AptaBlocks. PMID- 29986051 TI - Initiation of homologous recombination at DNA nicks. AB - Discontinuities in only a single strand of the DNA duplex occur frequently, as a result of DNA damage or as intermediates in essential nuclear processes and DNA repair. Nicks are the simplest of these lesions: they carry clean ends bearing 3' hydroxyl groups that can undergo ligation or prime new DNA synthesis. In contrast, single-strand breaks also interrupt only one DNA strand, but they carry damaged ends that require clean-up before subsequent steps in repair. Despite their apparent simplicity, nicks can have significant consequences for genome stability. The availability of enzymes that can introduce a nick almost anywhere in a large genome now makes it possible to systematically analyze repair of nicks. Recent experiments demonstrate that nicks can initiate recombination via pathways distinct from those active at double-strand breaks (DSBs). Recombination at targeted DNA nicks can be very efficient, and because nicks are intrinsically less mutagenic than DSBs, nick-initiated gene correction is useful for genome engineering and gene therapy. This review revisits some physiological examples of recombination at nicks, and outlines experiments that have demonstrated that nicks initiate homology-directed repair by distinctive pathways, emphasizing research that has contributed to our current mechanistic understanding of recombination at nicks in mammalian cells. PMID- 29986052 TI - MetClo: methylase-assisted hierarchical DNA assembly using a single type IIS restriction enzyme. AB - Efficient DNA assembly is of great value in biological research and biotechnology. Type IIS restriction enzyme-based assembly systems allow assembly of multiple DNA fragments in a one-pot reaction. However, large DNA fragments can only be assembled by alternating use of two or more type IIS restriction enzymes in a multi-step approach. Here, we present MetClo, a DNA assembly method that uses only a single type IIS restriction enzyme for hierarchical DNA assembly. The method is based on in vivo methylation-mediated on/off switching of type IIS restriction enzyme recognition sites that overlap with site-specific methylase recognition sequences. We have developed practical MetClo systems for the type IIS enzymes BsaI, BpiI and LguI, and demonstrated hierarchical assembly of large DNA fragments up to 218 kb. The MetClo approach substantially reduces the need to remove internal restriction sites from components to be assembled. The use of a single type IIS enzyme throughout the different stages of DNA assembly allows novel and powerful design schemes for rapid large-scale hierarchical DNA assembly. The BsaI-based MetClo system is backward-compatible with component libraries of most of the existing type IIS restriction enzyme-based assembly systems, and has potential to become a standard for modular DNA assembly. PMID- 29986053 TI - Identification of transcribed protein coding sequence remnants within lincRNAs. AB - Long intergenic non-coding RNAs (lincRNAs) are non-coding transcripts >200 nucleotides long that do not overlap protein-coding sequences. Importantly, such elements are known to be tissue-specifically expressed and to play a widespread role in gene regulation across thousands of genomic loci. However, very little is known of the mechanisms for the evolutionary biogenesis of these RNA elements, especially given their poor conservation across species. It has been proposed that lincRNAs might arise from pseudogenes. To test this systematically, we developed a novel method that searches for remnants of protein-coding sequences within lincRNA transcripts; the hypothesis is that we can trace back their biogenesis from protein-coding genes or posterior transposon/retrotransposon insertions. Applying this method, we found 203 human lincRNA genes with regions significantly similar to protein-coding sequences. Our method provides a visualization tool to trace the evolutionary biogenesis of lincRNAs with respect to protein-coding genes by sequence divergence. Subsequently, we show the expression correlation between lincRNAs and their identified parental protein coding genes using public RNA-seq repositories, hinting at novel gene regulatory relationships. In summary, we developed a novel computational methodology to study non-coding gene sequences, which can be applied to identify the evolutionary biogenesis and function of lincRNAs. PMID- 29986054 TI - Acute kidney injury following coronary revascularization procedures in patients with advanced CKD. AB - Background: Previous studies reported that compared with percutaneous coronary interventions (PCIs), coronary artery bypass grafting (CABG) is associated with a reduced risk of mortality and repeat revascularization in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Information about outcomes associated with CABG versus PCI in patients with advanced stages of CKD is limited. We evaluated the incidence and relative risk of acute kidney injury (AKI) associated with CABG versus PCI in patients with advanced CKD. Methods: We examined 730 US veterans with incident ESRD who underwent a first CABG or PCI up to 5 years prior to dialysis initiation. The association of CABG versus PCI with AKI was examined in multivariable adjusted logistic regression analyses. Results: A total of 466 patients underwent CABG and 264 patients underwent PCI. The mean age was 64 +/- 8 years, 99% were male, 20% were African American and 84% were diabetic. The incidence of AKI in the CABG versus PCI group was 67% versus 31%, respectively (P < 0.001). The incidence of all stages of AKI were higher after CABG compared with PCI. CABG was associated with a 4.5-fold higher crude risk of AKI {odds ratio [OR] 4.53 [95% confidence interval (CI) 3.28-6.27]; P < 0.001}, which remained significant after multivariable adjustments [OR 3.50 (95% CI 2.03-6.02); P < 0.001]. Conclusion: CABG was associated with a 4.5-fold higher risk of AKI compared with PCI in patients with advanced CKD. Despite other benefits of CABG over PCI, the extremely high risk of AKI associated with CABG should be considered in this vulnerable population when deciding on the optimal revascularization strategy. PMID- 29986056 TI - Intrinsically disordered domain of tumor suppressor p53 facilitates target search by ultrafast transfer between different DNA strands. AB - Intersegmental transfer (IST) is an important strategy in the target search used by sequence-specific DNA-binding proteins (DBPs), enabling DBPs to search for targets between multiple DNA strands without dissociation. We examined the IST of the tumor suppressor p53 using ensemble stopped-flow and single-molecule fluorescence measurements. The ensemble measurements demonstrated that p53 exhibits very fast IST, whose rate constant was ~108 M-1 s-1. To determine the domains of p53 responsible for IST, two mutants with deletions of one of its two DNA binding domains were generated. The mutant lacking the disordered C-terminal (CT) domain (the CoreTet mutant) abolished IST, whereas the mutant lacking the structured core domain (the TetCT mutant) maintained IST, clearly demonstrating the importance of the CT domain. Single-molecule fluorescence measurements further demonstrated the transfer of p53 between two tethered DNA strands. The pseudo-wild-type p53 and the TetCT mutant showed significant transfer efficiencies, whereas the transfer efficiency for the CoreTet mutant was zero. These results suggest that ultrafast IST might be promoted by four copies of the CT domain, by binding to two DNA strands simultaneously. Such ultrafast IST might be important to avoid nearby-bound DBPs during the target search process of p53 in nucleus. PMID- 29986055 TI - Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response. AB - A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation. PMID- 29986057 TI - Nucleoporin 54 contributes to homologous recombination repair and post replicative DNA integrity. AB - The nuclear pore complex (NPC) machinery is emerging as an important determinant in the maintenance of genome integrity and sensitivity to DNA double-strand break (DSB)-inducing agents, such as ionising radiation (IR). In this study, using a high-throughput siRNA screen, we identified the central channel NPC protein Nup54, and concomitantly its molecular partners Nup62 and Nup58, as novel factors implicated in radiosensitivity. Nup54 depletion caused an increase in cell death by mitotic catastrophe after IR, and specifically enhanced both the duration of the G2 arrest and the radiosensitivity of cells that contained replicated DNA at the time of IR exposure. Nup54-depleted cells also exhibited increased formation of chromosome aberrations arisen from replicated DNA. Interestingly, we found that Nup54 is epistatic with the homologous recombination (HR) factor Rad51. Moreover, using specific DNA damage repair reporters, we observed a decreased HR repair activity upon Nup54 knockdown. In agreement with a role in HR repair, we also demonstrated a decreased formation of HR-linked DNA synthesis foci and sister chromatid exchanges after IR in cells depleted of Nup54. Our study reveals a novel role for Nup54 in the response to IR and the maintenance of HR-mediated genome integrity. PMID- 29986058 TI - More is not always better: finding the right trade-off between affinity and selectivity of a G-quadruplex ligand. AB - Guanine-rich nucleic acid sequences can fold into four-stranded G-quadruplex (G4) structures. Despite growing evidence for their biological significance, considerable work still needs to be done to detail their cellular occurrence and functions. Herein, we describe an optimized core-extended naphthalene diimide (cex-NDI) to be exploited as a G4 light-up sensor. The sensing mechanism relies on the shift of the aggregate-monomer equilibrium towards the bright monomeric state upon G4 binding. In contrast with the majority of other ligands, this novel cex-NDI is able to discriminate among G4s with different topologies, with a remarkable fluorescent response for the parallel ones. We investigate this sensing by means of biophysical methods, comparing the lead compound to a non selective analogue. We demonstrate that mitigating the affinity of the binding core for G4s results in an increased selectivity and sensitivity of the fluorescent response. This is achieved by replacing positively charged substituents with diethylene glycol (DEG) side chains. Remarkably, the limit of detection values obtained for parallel G4s are more than one order of magnitude lower than those of the parallel-selective ligand N-methyl mesoporphyrin IX (NMM). Interestingly, the classical fluorescent intercalator displacement (FID) assay failed to reveal binding of cex-NDI to G4 because of the presence a ternary complex (G4-TO-cex-NDI) revealed by electrospray-MS. Our study thus provides a rational basis to design or modify existent scaffolds to redirect the binding preference of G4 ligands. PMID- 29986059 TI - Evaluating Facility Infrastructure for Prevention of Mother-to-Child Transmission of HIV-A 2015 Assessment of Major Delivery Hospitals in Atlanta, Georgia. AB - Objective: Our goal was to evaluate the infrastructure of programs for the prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) in major delivery units in the Atlanta, Georgia, metropolitan statistical area and to assess the knowledge, attitude, and practice of providers in these facilities around PMTCT. Methods: Hospital assessments and individual knowledge and practices were surveyed among 71 healthcare providers from March 2015 to March 2016 in 11 hospitals that deliver 40000 infants annually, which represents 70% of all deliveries in the Atlanta metropolitan statistical area. Included were questions about HIV testing for mother-infant pairs, test result turnaround times, policies and procedures for PMTCT, opt-out versus opt-in testing, availability of rapid point-of-care testing on labor and delivery units, and postnatal prophylaxis. Results: Seventy-three percent (8 of 11) of the hospitals had limitations in their PMTCT infrastructure, and 36% (4 of 11) reported no standardized policies for care of HIV-infected women. Three labor and delivery units used opt-in HIV testing of women. Only 27% (3 of 11) of the hospitals reported nucleic acid testing of HIV-exposed infants. Oral zidovudine for infant prophylaxis was available in all the hospitals, but 64% (7 of 11) of them did not stock nevirapine. Fifty-nine percent (24 of 44) of the obstetricians did not routinely offer rapid testing at delivery without a third-trimester HIV test, and 78% (n = 32 of 41) of them did not offer testing at delivery if the woman declined antenatal testing. The facility with the most annual births in Georgia did not offer rapid testing at delivery for women with an unknown HIV status. Conclusion: We identified several limitations in PMTCT infrastructure that might have contributed to perinatal HIV transmissions. The need to address these healthcare gaps to eliminate mother-to-child transmission of HIV in the United States is urgent. PMID- 29986061 TI - Engineering orthogonal synthetic timer circuits based on extracytoplasmic function sigma factors. AB - The rational design of synthetic regulatory circuits critically hinges on the availability of orthogonal and well-characterized building blocks. Here, we focus on extracytoplasmic function (ECF) sigma factors, which are the largest group of alternative sigma factors and hold extensive potential as synthetic orthogonal regulators. By assembling multiple ECF sigma factors into regulatory cascades of varying length, we benchmark the scalability of the approach, showing that these 'autonomous timer circuits' feature a tuneable time delay between inducer addition and target gene activation. The implementation of similar timers in Escherichia coli and Bacillus subtilis shows strikingly convergent circuit behavior, which can be rationalized by a computational model. These findings not only reveal ECF sigma factors as powerful building blocks for a rational, multi layered circuit design, but also suggest that ECF sigma factors are universally applicable as orthogonal regulators in a variety of bacterial species. PMID- 29986060 TI - The conserved regulatory RNA RsaE down-regulates the arginine degradation pathway in Staphylococcus aureus. AB - RsaE is a regulatory RNA highly conserved amongst Firmicutes that lowers the amount of mRNAs associated with the TCA cycle and folate metabolism. A search for new RsaE targets in Staphylococcus aureus revealed that in addition to previously described substrates, RsaE down-regulates several genes associated with arginine catabolism. In particular, RsaE targets the arginase rocF mRNA via direct interactions involving G-rich motifs. Two duplicated C-rich motifs of RsaE can independently downregulate rocF expression. The faster growth rate of DeltarsaE compared to its parental strain in media containing amino acids as sole carbon source points to an underlying role for RsaE in amino acid catabolism. Collectively, the data support a model in which RsaE acts as a global regulator of functions associated with metabolic adaptation. PMID- 29986063 TI - An Epistemic Argument for Research-Practice Integration in Medicine. AB - Arguments in favor of greater research-practice integration in medicine have tended to be ethical, political, or pragmatic. There are good epistemic reasons to pursue greater integration, and it is important to think through these reasons in order to avoid inadvertently designing new systems in ways that replicate the epistemic elitism common within current systems. Meaningful transformation within health care is possible with close attention to all reasons in favor of greater research-practice integration, including epistemic reasons. PMID- 29986064 TI - A Practice-Oriented Review of Health Concepts. AB - Whereas theories on health generally argue in favor of one specific concept, we argue that, given the variety of health practices, we need different concepts of health. We thus approach health concepts as a Wittgensteinian family of thick concepts. By discussing five concepts of health offered by (philosophical) theory, we argue that all capture something that seems relevant when we talk and think about health. Classifying these concepts reveals their family resemblances: each of these concepts differs from the others in at least one respect and resembles the others in several respects. Moreover, our classification shows that "health" always both describes a condition and evaluates that condition at the same time. Having both descriptive and evaluative dimensions, we can see health concepts as "thick concepts." It is because of this evaluative dimension that it is important to reflect on the question of what understanding of health guides specific practices. We show that the distinctions revealed by our classification can serve as a conceptual toolbox for reflection on the assumptions and purposes of particular health practices. Finally, we illustrate how such reflection could work out by briefly exploring three specific health practices. PMID- 29986062 TI - Small but large enough: structural properties of armless mitochondrial tRNAs from the nematode Romanomermis culicivorax. AB - As adapter molecules to convert the nucleic acid information into the amino acid sequence, tRNAs play a central role in protein synthesis. To fulfill this function in a reliable way, tRNAs exhibit highly conserved structural features common in all organisms and in all cellular compartments active in translation. However, in mitochondria of metazoans, certain dramatic deviations from the consensus tRNA structure are described, where some tRNAs lack the D- or T-arm without losing their function. In Enoplea, this miniaturization comes to an extreme, and functional mitochondrial tRNAs can lack both arms, leading to a considerable size reduction. Here, we investigate the secondary and tertiary structure of two such armless tRNAs from Romanomermis culicivorax. Despite their high AU content, the transcripts fold into a single and surprisingly stable hairpin structure, deviating from standard tRNAs. The three-dimensional form is boomerang-like and diverges from the standard L-shape. These results indicate that such unconventional miniaturized tRNAs can still fold into a tRNA-like shape, although their length and secondary structure are very unusual. They highlight the remarkable flexibility of the protein synthesis apparatus and suggest that the translational machinery of Enoplea mitochondria may show compensatory adaptations to accommodate these armless tRNAs for efficient translation. PMID- 29986065 TI - A New Approach to Defining Disease. AB - In this paper, we examine recent critiques of the debate about defining disease, which claim that its use of conceptual analysis embeds the problematic assumption that the concept is classically structured. These critiques suggest, instead, developing plural stipulative definitions. Although we substantially agree with these critiques, we resist their implication that no general definition of "disease" is possible. We offer an alternative, inductive argument that disease cannot be classically defined and that the best explanation for this is that the concept is structured as a cluster. We further argue that we do not need to reject the possibility of defining the general concept "disease" to legitimate developing stipulative definitions of disease that are relative to particular purposes. A cluster definition of disease is compatible with contextually motivated definitions, which may be considered precisifications of the more general cluster concept. PMID- 29986066 TI - Boorse's Theory of Disease: (Why) Do Values Matter? AB - There has been much debate about whether the concept of disease articulated in Boorse's biostatistical theory is value-neutral or value-laden. Here, I want to examine whether this debate matters. I suggest that there are two basic respects in which value-ladenness might be important: it could threaten either scientific legitimacy or moral permissibility. I argue that value-ladenness does not threaten the scientific legitimacy of our disease-concept because the concept makes little difference to the formulation and testing of scientific hypotheses. Likewise, even if our disease-concept is value-laden, this does not show it is morally impermissible. To determine its permissibility, we must regard it as a tool to structure social institutions. Seen in that way, whether our disease concept is morally permissible is a consequentialist matter and depends exquisitely on unanswered empirical questions. PMID- 29986068 TI - Corrigendum. PMID- 29986067 TI - Michel Foucault and the Problematics of Power: Theorizing DTCA and Medicalized Subjectivity. AB - This article explores Foucault's two different notions of power: one where the subject is constituted by power-knowledge relations and another that emphasizes how power is a central feature of human action. By drawing out these two conceptualizations of power, Foucault's work contributes three critical points to the formation of medicalized subjectivities: (1) the issue of medicalization needs to be discussed both in terms of both specific practices and holistically (within the carceral archipelago); (2) we need to think how we as human beings are "disciplined" and "subjectivated" through medicalization, as discourses, practices, and institutions are all crystallizations of power relations; and (3) we need to reflect on how we can "resist" this process of subjectification, since "power comes from below" and patients shape themselves through "technologies of the self." Ultimately, Foucault's work does not merely assist us in refining our analysis; rather, it is essential for conceptualizing medicalization in contemporary society. PMID- 29986069 TI - Mechanisms of template handling and pseudoknot folding in human telomerase and their manipulation to expand the sequence repertoire of processive repeat synthesis. AB - Telomerase adds telomeric repeats to chromosome ends by processive copying of a template within the telomerase RNA bound to telomerase reverse transcriptase. Telomerase RNAs have single-stranded regions that separate the template from a 5' stem and 3' pseudoknot, and mammals gained additional stem P2a.1 separating the template from the pseudoknot. Using human telomerase, we show that the length of template 3'-flanking single-stranded RNA is a determinant of repeat addition processivity whereas template 5'-flanking single-stranded RNA and P2a.1 are critical for activity but not processivity. In comparison, requirements for the template sequence itself are confounding: different substitutions of the same position have strikingly different consequences, from improved processivity and activity to complete inactivation. We discovered that some altered-template sequences stabilize an alternative RNA conformation that precludes the pseudoknot by base-pairing of one pseudoknot strand to the template 3' end. Using mutations to reduce over-stability of the alternative conformation, we restore high activity and processivity to otherwise inactive altered-template telomerase ribonucleoproteins. In cells, over-stabilization or destabilization of the alternative state severely inhibited biogenesis of active telomerase. Our findings delineate roles for human telomerase RNA template-flanking regions, establish a biologically relevant pseudoknot-alternative RNA conformation, and expand the repertoire of human telomerase repeat synthesis. PMID- 29986070 TI - Prevalence and Correlates of Snuff Use, and its Association With Tuberculosis, Among Women Living With HIV in South Africa. AB - Introduction: A higher proportion of people living with HIV (PLWH) smoke compared to the general population, but little information exists about the prevalence and correlates of smokeless tobacco use among PLWH. In South Africa, dry powdered tobacco is inhaled nasally as snuff. Methods: A cross-sectional survey among PLWH attending three HIV clinics was conducted. Snuff use was assessed via self-report and urine cotinine. Results: Given the low (3%) prevalence of snuff use among men, analysis was restricted to n = 606 nonsmoking women living with HIV. Half (n = 298, 49%) were snuff users, the majority of whom (n = 244, 84%) had a positive urine cotinine test. In adjusted analysis, snuff use was negatively associated with higher education (relative risk [RR] 0.55; 95% confidence interval [CI]: 0.39, 0.77) and mobile phone ownership (RR 0.83; 95% CI: 0.71, 0.98), and positively associated with ever having tuberculosis (TB) (RR 1.22; 95% CI: 1.03, 1.45). In adjusted analysis, with current TB as the outcome, snuff use was marginally statistically significantly associated with a twofold increase in odds of a current TB diagnosis (odds ratio [OR] 1.99; 95% CI: 0.98, 4.15). Discussion: A high proportion of nonsmoking South African women living with HIV use snuff, which was a risk factor for TB. Additional research is needed to understand the relationship between snuff, TB, and other potential health risks. Implications: PLWH have a higher prevalence of smoking than their seronegative peers, but there is a paucity of research on smokeless tobacco use in this population, especially in low-resource settings. TB is the leading cause of death among PLWH, and with improvements to HIV treatment and care, PLWH are at greater risk of tobacco related diseases. We report an extremely high prevalence of snuff use among women living with HIV in South Africa. Further, in this population snuff use is positively associated with ever having a TB diagnosis, as well as currently having TB. PMID- 29986072 TI - Brain Metabolites and Peripheral Biomarkers Associated with Neuroinflammation in Complex Regional Pain Syndrome Using [11C]-(R)-PK11195 Positron Emission Tomography and Magnetic Resonance Spectroscopy: A Pilot Study. AB - Objective: The aim of this study was to find peripheral biomarkers and central metabolites affecting neuroinflammation in complex regional pain syndrome (CRPS) patients using [11C]-(R)-PK11195 positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). Methods: Using MRS and PET, we measured associations between neurometabolites and neuroinflammation in 12 CRPS patients and 11 healthy controls. Also, we investigated various peripheral parameters that may affect neuroinflammation in CRPS. Results: We found positive correlations of Lipid (Lip)13a/total creatine (tCr) and Lip09/tCr with neuroinflammation, the distribution volume ratio (DVR) of [11C]-(R)-PK11195 in the right and left insula in CRPS patients. However, these correlations were not found in controls. High hemoglobin levels correlated with decreased neuroinflammation (the DVR of [11C] (R)-PK11195) in the right thalamus and left insula in healthy controls. We found that high levels of glucose and pH correlated with increased neuroinflammation, but high levels of CO2, basophil, and creatinine were associated with decreased neuroinflammation in the left thalamus and the right and left insula in CRPS patients. Conclusions: This is the first report indicating that elevated neuroinflammation levels are associated primarily with lipids in the brain and pH, glucose, CO2, basophil, and creatinine in the peripheral parameters in CRPS patients. Our results suggest that characterizing the peripheral biomarkers and central metabolites affecting neuroinflammation is essential to understanding the pathophysiology of CRPS. PMID- 29986071 TI - IL-10 Receptor or TGF-beta Neutralization Abrogates the Protective Effect of a Specific Nondigestible Oligosaccharide Mixture in Cow-Milk-Allergic Mice. AB - Background: Dietary nondigestible, short-chain galacto-, long-chain fructo-, and pectin-derived acidic oligosaccharides (GFAs) lower the effector response in cow milk-allergic (CMA) mice; and forkhead box P3 (Foxp3)-positive regulatory T cells (Tregs) were shown to contribute to this. Objective: The aim of this study was to assess the contribution of interleukin 10 (IL-10) and transforming growth factor beta (TGF-beta) to the protective effect of the GFA diet in CMA mice. Methods: Female C3H/HeOuJ mice, 3-4 wk old, were orally sensitized with cholera toxin (Sham) or whey and cholera toxin (Whey) 1 time/wk for 5 consecutive weeks and challenged with whey 1 wk later. The mice were fed a control or 1% GFA (9:2:1) (Whey+GFA) diet starting 2 wk before the first sensitization. In a second experiment, the mice were also injected with alphaIL-10 receptor (alphaIL-10r), alphaTGF-beta, or isotype control antibodies 24 h before each sensitization. The acute allergic skin response, anaphylaxis score, whey-specific IgE, mucosal mast cell protease 1 (mMCP-1), and Treg frequency in the mesenteric lymph nodes (MLNs) and intestinal Foxp3, Il10, and Tgfb mRNA expression were determined. Results: In Whey+GFA mice, intestinal Il10, Tgfb, or Foxp3 mRNA expression was 2-10 times higher (P < 0.05) and the MLN Treg frequency was 25% higher compared with Whey mice (P < 0.05). The acute allergic skin response was 50% lower in Whey+GFA mice compared with Whey mice (P < 0.01), and IL-10 receptor (IL-10r) or TGF-beta neutralizing antibodies prevented this protective effect (P < 0.001). The Whey mice had higher serum mMCP-1 concentrations and whey-immunoglobulin E (-IgE) levels than Sham mice (P < 0.01), whereas these were not higher in Whey+GFA mice, and neutralizing antibodies partially interfered with these responses. Conclusions: Dietary GFAs enhance the Treg frequency in the MLNs and mucosal IL 10 and TGF-beta transcription while suppressing the allergic effector response. Neutralizing antibodies showed that the allergy-protective effect of the GFA diet was mediated by IL-10 and TGF-beta in CMA mice. PMID- 29986073 TI - Rapid high-resolution measurement of DNA replication timing by droplet digital PCR. AB - Genomes are replicated in a reproducible temporal pattern. Current methods for assaying allele replication timing are time consuming and/or expensive. These include high-throughput sequencing which can be used to measure DNA copy number as a proxy for allele replication timing. Here, we use droplet digital PCR to study DNA replication timing at multiple loci in budding yeast and human cells. We establish that the method has temporal and spatial resolutions comparable to the high-throughput sequencing approaches, while being faster than alternative locus-specific methods. Furthermore, the approach is capable of allele discrimination. We apply this method to determine relative replication timing across timing transition zones in cultured human cells. Finally, multiple samples can be analysed in parallel, allowing us to rapidly screen kinetochore mutants for perturbation to centromere replication timing. Therefore, this approach is well suited to the study of locus-specific replication and the screening of cis- and trans-acting mutants to identify mechanisms that regulate local genome replication timing. PMID- 29986074 TI - Kmer-db: instant evolutionary distance estimation. AB - Summary: Kmer-db is a new tool for estimating evolutionary relationship on the basis of k-mers extracted from genomes or sequencing reads. Thanks to an efficient data structure and parallel implementation, our software estimates distances between 40,715 pathogens in less than 7 minutes (on a modern workstation), 26 times faster than Mash, its main competitor. Availability and Implementation: https://github.com/refresh-bio/kmer-db and http://sun.aei.polsl.pl/REFRESH/kmer-db. Supplementary information: Supplementary data are available at publisher's Web site. PMID- 29986075 TI - The pursuit of social acceptance: aberrant conformity in social anxiety disorder. AB - The defining pathological features of social anxiety disorder primarily concern the social landscape, yet few empirical studies have examined the potentially aberrant behavioral and neural patterns in this population using socially interactive paradigms. We addressed this issue by investigating the behavioral and neural patterns associated with social conformity in patients with social anxiety disorder. We recorded event-related potentials when healthy subjects (n = 19), and patients with social anxiety disorder (n = 20) made attractiveness judgements of unfamiliar others, while at the same time, being exposed to congruent/incongruent peer ratings. Afterwards, participants were asked to rerate the same faces without the presence of peer ratings. When compared with healthy controls, social anxiety disorder patients exhibited more positive attitudes to unfamiliar others and conformed more with peers-higher feedback. These behavioral effects were in parallel with neural responses associated with social conflict in the N400 signal, showing higher conformity to peers-higher feedback compared with peers-lower or peers-agree feedback among social anxiety disorder patients. Our findings provide evidence on the behavioral and neural patterns of social anxiety disorder during social interactions, and support the hypothesis that individuals with social anxiety disorder are more motivated to pursue social acceptance and possibly avoid social rejection. PMID- 29986077 TI - Neurocognitive and behavioral significance of periodic limb movements during sleep in adolescents with attention-deficit/hyperactivity disorder. AB - Study Objectives: The purpose of this study is to examine the association of abnormal periodic limb movements during sleep (PLMS) with neurocognitive and behavioral outcomes in adolescents with attention-deficit/hyperactivity disorder (ADHD) from the general population. Methods: Four hundred twenty-one adolescents (17.0 +/- 2.3 years, 53.9% male) from the Penn State Child Cohort, a random general population sample, underwent 9 hr polysomnography, clinical history, physical examination, neurocognitive evaluation, and completed the Child or Adult Behavioral Checklist (C/ABCL). The presence of ADHD was ascertained by parent- or self-report of receiving a diagnosis of ADHD. PLMS were defined as a PLM index (PLMI) of >=5 events per hour of sleep. Results: Adolescents with ADHD (n = 98) had a significantly higher PLMI (5.4 +/- 7.3) and prevalence of PLMS (35%) when compared with controls (3.4 +/- 5.6, p = 0.006 and 21%, p = 0.004). Significant interactions between ADHD and PLMS showed that adolescents with both disorders (n = 35) were characterized by deficits in control interference, as measured by Stroop test, and elevated internalizing behaviors, as measured by C/ABCL. ADHD severity and externalizing behaviors were elevated in a dose-response manner across ADHD-alone (n = 63) and ADHD + PLMS groups. The association of ADHD with other neurocognitive functions did not vary as a function of PLMS. Conclusions: PLMS are significantly more frequent in adolescents with ADHD. Importantly, adolescents with both disorders not only have worse neurobehavioral functioning than adolescents with ADHD-alone but specifically presented with executive deficits and anxiety symptoms. These data suggest that PLMS may be a marker of more severe underlying neurobiological deficits in adolescents with ADHD and comorbid internalizing problems. PMID- 29986076 TI - Modulation of the HIV nucleocapsid dynamics finely tunes its RNA-binding properties during virion genesis. AB - During HIV-1 assembly and budding, Gag protein, in particular the C-terminal domain containing the nucleocapsid domain (NCd), p1 and p6, is the site of numerous interactions with viral and cellular factors. Most in vitro studies of Gag have used constructs lacking p1 and p6. Here, using NMR spectroscopy, we show that the p1-p6 region of Gag (NCp15) is largely disordered, but interacts transiently with the NCd. These interactions modify the dynamic properties of the NCd. Indeed, using isothermal titration calorimetry (ITC), we have measured a higher entropic penalty to RNA-binding for the NCd precursor, NCp15, than for the mature form, NCp7, which lacks p1 and p6. We propose that during assembly and budding of virions, concomitant with Gag oligomerization, transient interactions between NCd and p1-p6 become salient and responsible for (i) a higher level of structuration of p6, which favours recruitment of budding partners; and (ii) a higher entropic penalty to RNA-binding at specific sites that favours non specific binding of NCd at multiple sites on the genomic RNA (gRNA). The contributions of p6 and p1 are sequentially removed via proteolysis during Gag maturation such that the RNA-binding specificity of the mature protein is governed by the properties of NCd. PMID- 29986078 TI - Small Molecule Probes of ABA Biosynthesis and Signaling. AB - The phytohormone ABA mediates many physiological and developmental responses, and its key role in plant water relations has fueled efforts to improve crop water productivity by manipulating ABA responses. ABA's core signaling components are encoded by large gene families, which has hampered functional studies using classical genetic approaches due to redundancy. Chemical approaches can complement genetic approaches and have the advantage of delivering both biological probes and potential agrochemical leads; these benefits have spawned the discovery and design of new chemical modulators of ABA signaling and biosynthesis, which have contributed to the identification of ABA receptors and helped to define PYR1 and related subfamily III receptors as key cellular targets for chemically manipulating water productivity. In this review, we provide an overview of small molecules that have helped dissect both ABA signaling and metabolic pathways. We further discuss how the insights gleaned using ABA probe molecules might be translated to improvements in crop water productivity and future opportunities for development of small molecules that affect ABA metabolism and signaling. PMID- 29986079 TI - Identification and Characterization of Novel Nemophila menziesii Flavone Glucosyltransferases that Catalyze Biosynthesis of Flavone 7,4'-O-Diglucoside, a Key Component of Blue Metalloanthocyanins. AB - The brilliant blue color of the Nemophila menziesii flower is derived from metalloanthocyanin, which consists of anthocyanin {petunidin 3-O-[6-O-(trans-p coumaroyl)-beta-glucoside]-5-O-[6-O-(malonyl)-beta-glucoside]}, flavone [apigenin 7-O-beta-glucoside-4'-O-(6-O-malonyl)-O-beta-glucoside] and metal ions (Mg2+, Fe3+). Although the two glucosyl moieties at the apigenin 7-O and 4'-O positions are essential for metalloanthocyanin formation, the mechanism of glucosylation has not yet been clarified. In this study, we used crude protein extract prepared from N. menziesii petals to determine that apigenin is sequentially glucosylated by the catalysis of UDP-glucose:flavone 4'-O-glucosyltrasferase (F4'GT) and UDP glucose:flavone 4'-O-glucoside 7-O-glucosyltransferase (F4'G7GT). We identified 150 contigs exhibiting homology with a UDP-glucose-dependent GT in the N. menziesii petal transcriptome and isolated 24 putative full-length GT cDNAs which were then subjected to functional analysis. Two GT cDNAs, NmF4'GT and NmF4'G7GT, which are highly expressed during the early stages of petal development and rarely in leaves, were shown to encode F4'GT and F4'G7GT activities, respectively. Biochemical characterization of the recombinant enzymes revealed that NmF4'GT specifically catalyzed 4'-glucosylation of flavonoids and that NmF4'G7GT specifically catalyzed 7-glucosylation of flavone 4'-O-glucosides and flavones. Apigenin 7,4'-O-diglucoside was efficiently synthesized from apigenin in the presence of recombinant NmF4'GT and NmF4'G7GT. Transgenic tobacco BY-2 cells expressing NmF4'GT and NmF4'G7GT converted apigenin into apigenin 7,4'-O diglucoside, confirming their activities in vivo. Based on these results, we conclude that these two GTs act co-ordinately to catalyze apigenin 7,4'-O diglucoside biosynthesis in N. menziesii. PMID- 29986080 TI - The crystal structure of the RsbN-sigmaBldN complex from Streptomyces venezuelae defines a new structural class of anti-sigma factor. PMID- 29986081 TI - Screening Germplasm and Quantification of Components Contributing to Thrips Resistance in Cotton. AB - Three hundred and ninety-one Gossypium hirsutum and 34 Gossypium barbadense accessions were screened for thrips resistance under field conditions at the Upper Coastal Plain Research Station in Rocky Mount, North Carolina in years 2014 and 2015. Visual damage ratings, thrips counts, and seedling dry weights were recorded at 2.5, 3.5, and 4.5 wk after planting, respectively. Population density and thrips arrival times varied between years. Data from the three separate damage scoring dates provided a better estimate of resistance or susceptibility to thrips than ratings from the individual dates over the season. Tobacco thrips [Frankliniella fusca (Hinds) (Thysanoptera: Thripidae)], followed by western flower thrips [Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae)], were the dominant thrips species observed in the study. Five resistant G. barbadense accessions and five moderately resistant upland cotton accessions were identified from field evaluations. Greenhouse experiments were conducted in Fall 2015 and Spring 2016 to determine if plant height, growth rate, leaf pubescence, and leaf area were significantly different in resistant and susceptible groups of G. hirsutum and G. barbadense accessions identified from the field screenings. Leaf pubescence and relative growth rate were significantly higher in resistant accessions compared with susceptible accessions in absence of thrips. There was no difference for plant height and leaf area between resistant and susceptible groups. Results suggest thrips-resistant plants have a possible competitive advantage through faster growth and higher trichome density, which limits thrips movement. PMID- 29986082 TI - beta-Lactam Antibiotics Modify Root Architecture and Indole Glucosinolate Metabolism in Arabidopsis thaliana. AB - The presence of antibiotics in soils could be due to natural production by soil microorganisms or to the effect of anthropogenic activities. However, the impact of these compounds on plant physiology has not been thoroughly investigated. To evaluate the effect of beta-lactam antibiotics (carbenicillin and penicillin) on the growth and development of Arabidopsis thaliana roots, plants were grown in the presence of different amounts and we found a reduction in root size, an increase in the size of root hairs as well as an abnormal position closer to the tip of the roots. Those phenomena were dependent on the accumulation of both antibiotics inside root tissues and also correlated with a decrease in size of the root apical meristem not related to an alteration in cell division but to a decrease in cell expansion. Using an RNA sequencing analysis, we detected an increase in the expression of genes related to the response to oxidative stress, which would explain the increase in the levels of endogenous reactive oxygen species found in the presence of those antibiotics. Moreover, some auxin responsive genes were misregulated, especially an induction of CYP79B3, possibly explaining the increase in auxin levels in the presence of carbenicillin and the decrease in the amount of indole glucosinolates, involved in the control of fungal infections. Accordingly, penicillin-treated plants were hypersensitive to the endophyte fungus Colletotrichum tofieldiae. These results underscore the risks for plant growth of beta-lactam antibiotics in agricultural soils, and suggest a possible function for these compounds as fungus-produced signaling molecules to modify plant behavior. PMID- 29986083 TI - Ophthalmic manifestations of giant cell arteritis. AB - GCA, the most common systemic arteritis, affects medium-sized and larger extradural arteries that have the internal elastic lamina. Involvement of the ophthalmic artery and its branches results in visual loss, which is often complete but is usually painless. Visual loss may be monocular or binocular developing simultaneously or sequentially. Rarely, it stems from occipital lobe infarct that result in homonymous hemianopia, a visual field defect involving the two identical halves (right or left) of the visual fields of both eyes. Visual hallucinations and diplopia are less common. All visual symptoms, including those that are transient, require urgent ophthalmological evaluation and treatment with high-dose glucocorticoids to avoid permanent visual loss. PMID- 29986084 TI - Gorham-Stout syndrome. PMID- 29986085 TI - Long-term compliance, safety, and tolerability of sodium oxybate treatment in patients with narcolepsy type 1: a postauthorization, noninterventional surveillance study. AB - Study Objectives: To evaluate adherence to sodium oxybate prescribing information for indication and dosage, patients' compliance with instructions for use, safety/tolerability in routine clinical practice, and abuse potential. Methods: A postauthorization, noninterventional surveillance study (NCT00244465) in patients who were prescribed sodium oxybate according to current practice by sleep disorders specialists. Patients were monitored for <=18 months. Results: Overall, 749 patients were enrolled; 730 included in the intent-to-treat population (narcolepsy type 1 n = 670, other indications n = 60). We report on patients with narcolepsy type 1 (female 47.9%, mean age 39.4 years); 495/670 (73.9%) completed the study. Median dose: at start of study 4.5 g per night, 6 g per night throughout study, in two equal doses. According to the treatment compliance checklist, 35.5 per cent of patients consumed alcohol, 19.3 per cent took the medication <2 hr after food, and 27.1 per cent did not adhere to recommended time schedule, with few associated treatment-emergent adverse events (TEAEs). Incidences of higher-than-recommended doses, difficulty in preparing doses, and abuse were low. TEAEs were reported by 67.3 per cent, most frequently headache (11.6%) and nasopharyngitis (6.4%). Discontinuation due to TEAEs: 8.8 per cent. Serious TEAEs: 6.4 per cent. There were no reports of respiratory depression. No particular safety concerns were identified in pediatric or elderly patients, or those with underlying sleep apnea. Conclusions: In this large postauthorization safety study of sodium oxybate use, indication and dosage prescribing recommendations were generally followed, and most patients complied with instructions, with deviations around alcohol consumption, eating before dosing and timing. The overall safety profile was consistent with previous observations; incidence of abuse was low. Section: Neurological disorders. Clinical Trial: Postauthorization, noninterventional, surveillance, pharmacoepidemiology study to evaluate long-term safety, tolerability, and compliance in administration of Xyrem (sodium oxybate) oral solution in patients who receive treatment with this medication in regular clinical practice. https://clinicaltrials.gov/ct2/show/NCT00244465, ClinicalTrials.gov: NCT00244465. PMID- 29986086 TI - Eradication of Hepatitis C Virus (HCV) Reduces Immune Activation, Microbial Translocation, and the HIV DNA Level in HIV/HCV-Coinfected Patients. AB - Background: There are contradictory data about the influence that hepatitis C virus (HCV) has on immune activation and inflammation in patients coinfected with human immunodeficiency virus (HIV) and HCV. Methods: HIV/HCV-coinfected patients receiving antiretroviral treatment who achieved a sustained virological response with interferon-free regimens were consecutively enrolled in a prospective study. The following factors were assessed before, immediately after the end of, and 1 month after the end of therapy: expression of HLA-DR/CD38, PD-1, and CD57 on CD4+ and CD8+ T-cells; measurement of the total HIV DNA load in peripheral blood mononuclear cells; and determination of plasma levels of soluble CD14 (sCD14), lipopolysaccharide (LPS), 16S ribosomal DNA (rDNA), interleukin 6 (IL-6), D dimers, and high-sensitivity C-reactive protein (hsCRP). Results: Ninety-seven patients were consecutively included. At the end of therapy and 1 month later, there were significant reductions in the expression of HLA-DR and CD38 in CD4+ and CD8+ T cells, as well as levels of proviral HIV DNA, sCD14, LPS, 16S rDNA, and D-dimer (P < .001). By contrast, the expression of PD-1 and CD57 in CD4+ and CD8+ T cells and levels of IL-6 and hsCRP did not change. The improvement in levels of immune activation markers, proviral HIV DNA, and microbial translocation markers did not translate into an increased CD4+ T-cell count or increased ratio of the CD4+ T-cell count to the CD8+ T-cell count. Conclusions: HCV eradication in HIV/HCV-coinfected patients results in significant decreases in levels of immune activation markers, proviral HIV DNA load, microbial translocation markers, and D-dimers. These findings support the use of HCV treatment for all HIV/HCV-coinfected patients, even those with low-grade fibrosis. PMID- 29986087 TI - Patient reported symptoms, body temperature and hospital mortality: an observational study in a low resource healthcare environment. AB - Background: Fever is a common presenting complaint of patients, especially in sub Saharan Africa. Although most medical authorities consider fever to be synonymous with an elevated body temperature the relationship of the complaint of fever made by patients to temperature has not been well defined. Aim: This study examined the relationship of the complaint of fever to temperature on and after admission and in-hospital mortality. Method: Observational study in a low-resource Ugandan mission hospital. Results: Out of 2122 alert patients admitted between 9 August 2016 and 5 January 2018, 349 (16.4%) complained of fever: these patients were no more likely to have an abnormal temperature or die in-hospital than those not complaining of fever. Of the 707 alert patients admitted after 1 July 2017, 422 were interviewed in detail about their symptoms: only rigors, feeling intermittently hot and cold, and anorexia were statistically related to the complaint of fever, and only rigors to an admission temperature >38 degrees C. No symptom or sign was associated with a temperature <=36 degrees C: cold and clammy skin was the only finding associated with in-hospital death. On logistic regression the only independent predictors of mortality were: the National Early Warning Score, impaired mobility on presentation and cold and clammy skin. Conclusion: In this study, the term fever used by patients and raised body temperature were not synonymous. Although fever and related symptoms reported by patients are common presenting complaints only the finding of cold and clammy skin was associated with in-hospital mortality. PMID- 29986088 TI - A deep recurrent neural network discovers complex biological rules to decipher RNA protein-coding potential. AB - The current deluge of newly identified RNA transcripts presents a singular opportunity for improved assessment of coding potential, a cornerstone of genome annotation, and for machine-driven discovery of biological knowledge. While traditional, feature-based methods for RNA classification are limited by current scientific knowledge, deep learning methods can independently discover complex biological rules in the data de novo. We trained a gated recurrent neural network (RNN) on human messenger RNA (mRNA) and long noncoding RNA (lncRNA) sequences. Our model, mRNA RNN (mRNN), surpasses state-of-the-art methods at predicting protein-coding potential despite being trained with less data and with no prior concept of what features define mRNAs. To understand what mRNN learned, we probed the network and uncovered several context-sensitive codons highly predictive of coding potential. Our results suggest that gated RNNs can learn complex and long range patterns in full-length human transcripts, making them ideal for performing a wide range of difficult classification tasks and, most importantly, for harvesting new biological insights from the rising flood of sequencing data. PMID- 29986089 TI - Impact of public smoking bans on social inequalities in children's exposure to tobacco smoke at home: an equity-focused systematic review. AB - Introduction: A systematic review was conducted to evaluate the impact of public smoking bans on social inequalities in children's secondhand smoke (SHS) exposure at home. Methods: Five databases were electronically searched for articles on children's SHS exposure at home related to public smoking bans. Additionally, grey literature and German public health journals were considered. Search was restricted to English and German publications. Of 3037 records screened, 25 studies fulfilled the inclusion criteria by either measuring SHS exposure before and after public smoking ban introduction or by comparing exposure between regions with and without smoke-free legislation. Studies were further examined whether they additionally reported on impacts on social inequalities in SHS exposure. Information on children's SHS exposure at home in relation to smoke free legislation were extracted by one reviewer and checked for accuracy by a second reviewer. According to PRISMA-E guidelines for equity-focused systematic reviews, the PROGRESS-Plus framework was applied to data extraction and analysis with focus on social inequalities in SHS exposure. Results were visualised by a Harvest Plot. Results: Eight studies gave results on the impact of public smoking bans on social inequalities in children's SHS exposure. Whereas only one study indicated widening of the social gap in exposure, seven studies showed no impact or a reduction of social inequalities in exposure. Conclusions: First evidence on short-term impact of public smoking bans does not support the assumption of intervention-generated inequalities in children's SHS exposure at home. Future studies should focus on long-term equity impacts of smoke-free legislation. Implications: There are substantial social inequalities in children's secondhand smoke (SHS) exposure in many countries. Both hypotheses on the effect of smoke free legislation on children's SHS exposure at home, the displacement hypothesis and the social diffusion hypothesis, did not take social inequalities into account. Up to now, only few studies analysed the effects of smoke-free legislation on social inequalities in children's SHS exposure at home. Public smoking bans had overall no negative impact on social inequalities in children's SHS exposure at home. More consistent reporting of absolute and relative inequalities is needed to comprehensively assess equity impact of smoke-free legislation. PMID- 29986090 TI - Late-life depressive symptoms are associated with functional impairment cross sectionally and over time: Results of the AgeMooDe study. AB - Objectives: This study examines the relationship between late-life depressive symptoms, cognitive and functional impairment in a cohort of very old community based participants. Methods: A sample of 1226 primary care patients was assessed at baseline (Mage = 80.6 years). Statistical analyses were conducted using baseline and 12 month follow-up data. Results: At baseline, depressed participants showed minor cognitive deficits compared to non-depressed participants, whereas functional deficits were pronounced. Depressive symptoms and global cognition were not associated longitudinally. In contrast, follow-up functional impairment was predicted by baseline level and increase of depressive symptoms between baseline and follow-up. Reversely, follow-up depressive symptoms were predicted by functional decline between baseline and follow-up, whereas baseline functional status was not predictive. Discussion: Depressive symptoms and global cognitive function were not associated longitudinally, but level and increase of depressive symptoms over time predicted functional impairment after one year. Interventions to reduce depressive symptoms, or to encourage coping strategies might be promising to reduce functional impairment. Elevated follow-up depressive symptoms were only predicted by functional decline, supposedly emphasizing that incident functional impairment might be associated with an acute increase of depressive symptoms. Psychological adjustment processes were not examined, but might be targeted in future. PMID- 29986091 TI - Performance of treponemal tests for the diagnosis of syphilis. AB - Background: Treponemal immunoassays are increasingly used for syphilis screening with the reverse sequence algorithm. There are little data describing performance of treponemal immunoassays compared to traditional treponemal tests in patients with and without syphilis. Methods: We calculated sensitivity and specificity of seven treponemal assays: 1) ADVIA Centaur (chemiluminescence immunoassay-CIA), 2) Bioplex 2200 (microbead immunoassay-MBIA), 3) fluorescent treponemal antibody absorption test (FTA-ABS), 4) INNO-LIA (line immunoassay), 5) LIAISON CIA, 6) TP PA (Treponema pallidum particle agglutination assay), and 7) Trep-Sure (enzyme immunoassay-EIA), using a reference standard combining clinical diagnosis and serology results. Sera were collected between May 2012-January 2013. Cases were characterized as: 1) current clinical diagnosis of syphilis: primary, secondary, early latent, late latent 2) prior treated syphilis only, 3) no evidence of current syphilis, no prior history of syphilis and at least 4/7 treponemal tests negative. Results: Among 959 participants, 262 had current syphilis, 294 had prior syphilis, and 403 did not have syphilis. FTA-ABS was less sensitive for primary syphilis [78.2% (65.0-88.2%)], than the immunoassays or TP-PA (94.5 96.4%) (all p<=0.01). All immunoassays were 100% sensitive for secondary syphilis, 95.2-100% sensitive for early latent disease, and 86.8-98.5% sensitive in late latent disease. TP-PA had 100% specificity (99.0-100%). Conclusion: Treponemal immunoassays demonstrated excellent sensitivity for secondary, early latent, and seropositive primary syphilis. Sensitivity of FTA-ABS in primary syphilis was poor compared to the immunoassays and TP-PA. Given its high specificity and superior sensitivity, TP-PA is a better test to adjudicate discordant results with the reverse sequence algorithm than the FTA-ABS. PMID- 29986094 TI - Pulmonary artery rupture during right heart catheterization: successful endovascular treatment with Amplatzer Vascular Plug. PMID- 29986092 TI - Germline DNA replication timing shapes mammalian genome composition. AB - Mammalian DNA replication is a highly organized and regulated process. Large, Mb sized regions are replicated at defined times along S-phase. Replication Timing (RT) is thought to play a role in shaping the mammalian genome by affecting mutation rates. Previous analyses relied on somatic RT profiles. However, only germline mutations are passed on to offspring and affect genomic composition. Therefore, germ cell RT information is necessary to evaluate the influences of RT on the mammalian genome. We adapted the RT mapping technique for limited amounts of cells, and measured RT from two stages in the mouse germline - primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). RT in germline cells exhibited stronger correlations to both mutation rate and recombination hotspots density than those of RT in somatic tissues, emphasizing the importance of using correct tissues-of-origin for RT profiling. Germline RT maps exhibited stronger correlations to additional genetic features including GC-content, transposable elements (SINEs and LINEs), and gene density. GC content stratification and multiple regression analysis revealed independent contributions of RT to SINE, gene, mutation, and recombination hotspot densities. Together, our results establish a central role for RT in shaping multiple levels of mammalian genome composition. PMID- 29986095 TI - Leaf phenology and water-use patterns of canopy trees in Northern Argentinean subtropical forests. AB - Tree physiological processes are affected not only by environmental conditions, but also by phenological leaf stages. During foliar expansion, rapid changes occur, such as the activation of metabolic processes that encompass a hydraulic link between xylem and phloem pathways at a whole-tree level. Daily and seasonal changes in stem diameter may reveal different temporal dynamics of water use and recharge in tree reservoirs. Foliar phenological patterns were studied in relation to stem dimensional changes in 10 canopy tree species with different phenological patterns (three deciduous, three brevideciduous and four evergreen species). Additionally, we assessed (i) daily sap flow fluctuations in branch and main stem, (ii) diurnal changes in sapwood volumetric water content and (iii) stem radius variations during leafless, expanding and mature leaves periods in three of the 10 tree species (two deciduous and one brevideciduous). During the leaf expansion phase, the diameter of trees decreased in all 10 species, with a larger impact on deciduous and brevideciduous species. For the subset of deciduous and brevideciduous species, the movement of long-distance water transport occurred first near the branches and then in the main stem during the leafless stage. Changes in stored water use and a decrease in the volumetric water content and the radius of the main stem during this period suggest that there is a contribution of water from internal stem reservoirs toward the construction of new leaves. PMID- 29986093 TI - High Viral Diversity and Mixed Infections in Cerebral Spinal Fluid From Cases of Varicella Zoster Virus Encephalitis. AB - Background: Varicella zoster virus (VZV) may cause encephalitis, both with and without rash. Here we investigate whether viruses recovered from the central nervous system (CNS; encephalitis or meningitis) differ genetically from those recovered from non-CNS samples. Methods: Enrichment-based deep sequencing of 45 VZV genomes from cerebral spinal fluid (CSF), plasma, bronchoalveolar lavage (BAL), and vesicles was carried out with samples collected from 34 patients with and without VZV infection of the CNS. Results: Viral sequences from multiple sites in the same patient were identical at the consensus level. Virus from vesicle fluid and CSF in cases of meningitis showed low-level diversity. By contrast, plasma, BAL, and encephalitis had higher numbers of variant alleles. Two CSF-encephalitis samples had high genetic diversity, with variant frequency patterns typical of mixed infections with different clades. Conclusions: Low viral genetic diversity in vesicle fluid is compatible with previous observations that VZV skin lesions arise from single or low numbers of virions. A similar result was observed in VZV from cases of VZV meningitis, a generally self limiting infection. CSF from cases of encephalitis had higher diversity with evidence for mixed clade infections in 2 cases. We hypothesize that reactivation from multiple neurons may contribute to the pathogenesis of VZV encephalitis. PMID- 29986097 TI - Colorectal Adenomas and Cancers After Childhood Cancer Treatment: A DCOG-LATER Record Linkage Study. AB - Background: Although colorectal adenomas serve as prime target for colorectal cancer (CRC) surveillance in other high-risk groups, data on adenoma risk after childhood cancer are lacking. We evaluated the risk of histologically confirmed colorectal adenomas among childhood cancer survivors. A secondary aim was to assess CRC risk. Methods: The DCOG-LATER cohort study includes five-year Dutch childhood cancer survivors and a sibling comparison group (n = 883). Colorectal tumors were identified from the population-based Dutch Pathology Registry (PALGA). We calculated cumulative incidences of adenomas/CRCs for survivors and siblings. For adenomas, multivariable Cox regression models were used to evaluate potential risk factors. All statistical tests were two-sided. Results: Among 5843 five-year survivors (median follow-up = 24.9 years), 78 individuals developed an adenoma. Cumulative incidence by age 45 years was 3.6% (95% confidence interval [CI] = 2.2% to 5.6%) after abdominopelvic radiotherapy (AP-RT; 49 cases) vs 2.0% (95% CI = 1.3% to 2.8%) among survivors without AP-RT (28 cases; Pdifference = .07) and vs 1.0% (95% CI = 0.3% to 2.6%) among siblings (6 cases) (Pdifference = .03). Factors associated with adenoma risk were AP-RT (hazard ratio [HR] = 2.12, 95% CI = 1.24 to 3.60), total body irradiation (TBI; HR = 10.55, 95% CI = 5.20 to 21.42), cisplatin (HR = 2.13; 95% CI = 0.74 to 6.07 for <480 mg/m2; HR = 3.85, 95% CI = 1.45 to 10.26 for >=480 mg/m2; Ptrend = .62), a hepatoblastoma diagnosis (HR = 27.12, 95% CI = 8.80 to 83.58), and family history of early-onset CRC (HR = 20.46, 95% CI = 8.10 to 51.70). Procarbazine was statistically significantly associated among survivors without AP-RT/TBI (HR = 2.71, 95% CI = 1.28 to 5.74). Thirteen CRCs occurred. Conclusion: We provide evidence for excess risk of colorectal adenomas and CRCs among childhood cancer survivors. Adenoma risk factors include AP-RT, TBI, cisplatin, and procarbazine. Hepatoblastoma (familial adenomatous polyposis-associated) and family history of early-onset CRC were confirmed as strong risk factors. A full benefit-vs-harm evaluation of CRC screening among high-risk childhood cancer survivors warrants consideration. PMID- 29986098 TI - Solid phase chemistry to covalently and reversibly capture thiolated RNA. AB - Here, we describe an approach to enrich newly transcribed RNAs from primary mouse neurons using 4-thiouridine (s4U) metabolic labeling and solid phase chemistry. This one-step enrichment procedure captures s4U-RNA by using highly efficient methane thiosulfonate (MTS) chemistry in an immobilized format. Like solution based methods, this solid-phase enrichment can distinguish mature RNAs (mRNA) with differential stability, and can be used to reveal transient RNAs such as enhancer RNAs (eRNAs) and primary microRNAs (pri-miRNAs) from short metabolic labeling. Most importantly, the efficiency of this solid-phase chemistry made possible the first large scale measurements of RNA polymerase II (RNAPII) elongation rates in mouse cortical neurons. Thus, our approach provides the means to study regulation of RNA metabolism in specific tissue contexts as a means to better understand gene expression in vivo. PMID- 29986096 TI - A coding and non-coding transcriptomic perspective on the genomics of human metabolic disease. AB - Genome-wide association studies (GWAS), relying on hundreds of thousands of individuals, have revealed >200 genomic loci linked to metabolic disease (MD). Loss of insulin sensitivity (IS) is a key component of MD and we hypothesized that discovery of a robust IS transcriptome would help reveal the underlying genomic structure of MD. Using 1,012 human skeletal muscle samples, detailed physiology and a tissue-optimized approach for the quantification of coding (>18,000) and non-coding (>15,000) RNA (ncRNA), we identified 332 fasting IS related genes (CORE-IS). Over 200 had a proven role in the biochemistry of insulin and/or metabolism or were located at GWAS MD loci. Over 50% of the CORE IS genes responded to clinical treatment; 16 quantitatively tracking changes in IS across four independent studies (P = 0.0000053: negatively: AGL, G0S2, KPNA2, PGM2, RND3 and TSPAN9 and positively: ALDH6A1, DHTKD1, ECHDC3, MCCC1, OARD1, PCYT2, PRRX1, SGCG, SLC43A1 and SMIM8). A network of ncRNA positively related to IS and interacted with RNA coding for viral response proteins (P < 1 * 10-48), while reduced amino acid catabolic gene expression occurred without a change in expression of oxidative-phosphorylation genes. We illustrate that combining in depth physiological phenotyping with robust RNA profiling methods, identifies molecular networks which are highly consistent with the genetics and biochemistry of human metabolic disease. PMID- 29986099 TI - DMRcaller: a versatile R/Bioconductor package for detection and visualization of differentially methylated regions in CpG and non-CpG contexts. AB - DNA methylation has been associated with transcriptional repression and detection of differential methylation is important in understanding the underlying causes of differential gene expression. Bisulfite-converted genomic DNA sequencing is the current gold standard in the field for building genome-wide maps at a base pair resolution of DNA methylation. Here we systematically investigate the underlying features of detecting differential DNA methylation in CpG and non-CpG contexts, considering both the case of mammalian systems and plants. In particular, we introduce DMRcaller, a highly efficient R/Bioconductor package, which implements several methods to detect differentially methylated regions (DMRs) between two samples. Most importantly, we show that different algorithms are required to compute DMRs and the most appropriate algorithm in each case depends on the sequence context and levels of methylation. Furthermore, we show that DMRcaller outperforms other available packages and we propose a new method to select the parameters for this tool and for other available tools. DMRcaller is a comprehensive tool for differential methylation analysis which displays high sensitivity and specificity for the detection of DMRs and performs entire genome wide analysis within a few hours. PMID- 29986100 TI - Influence of age at first calving in a continuous calving season on productive, functional, and economic performance in a Blonde d'Aquitaine beef population. AB - The lifetime production of 7,655 cows with known age at first calving and a total of 27,118 parity records from 301 purebred Blonde d'Aquitaine herds were used to demonstrate the economic benefits of 2 yr of age at first calving. Ages at first calving ranged from 20 to 48 mo, and cows were divided into 5 calving groups, starting with early calving from age 20 to 27 mo up to late calving from age 40 to 48 mo. The information was gathered into 2 data sets, one for only primiparous cows and the second for all cows. The traits analyzed in this study were grouped as functional, linear type, and production traits. Functional traits were calving interval, calving ease, and number of calvings. Skeletal, muscle, and functional appraisal were included as linear type traits. The production traits studied were BW and weaning weight, carcass growth, and conformation of the offspring. The only significant traits found in primiparous cows were late age at first calving, which resulted in heavier BW calves, and early age at first calving, which resulted in calves with greater carcass conformation scores. Age at first calving was found to be significant only in its effect on BW and the number of calvings over a cow's lifetime, with lighter calves for early age at first calving. Heritability for age at first calving was 0.17. Genetic correlation of age at first calving with direct calving ease was positive (0.27) and that with maternal calving ease was negative (-0.39). Age at first calving showed a negative genetic correlation with lifetime number of calvings (-0.29) and a positive correlation with calving interval (0.14). Correlations with production and type traits were low, except for skeletal development (-0.29). Based on phenotypic and genetic analysis, there is a tendency for early-calving cows to produce a greater lifetime number of calves with less muscle but good carcass growth. Age at first calving affected the number of heifers in the herd, replacement rate, and number of animals slaughtered each year. Shortening the age at first calving from 3 to 2 yr led to a reduction of heifer feeding cost of US$21.24 (17.7?), a reduction of production cost of $26.52 (22.1?), and a profit increase of $25.80 (21.50?) per slaughtered animal per year over lifetime cow production. PMID- 29986101 TI - Melanonychia. PMID- 29986102 TI - An overview of the case fatality of inpatient severe acute malnutrition in Ethiopia and its association with human immunodeficiency virus/tuberculosis comorbidity-a systematic review and meta-analysis. AB - Background: Mortality of children with severe acute malnutrition (SAM) is a devastating problem in Ethiopia. This study estimated the pooled case fatality ratio of SAM among children <5 y of age and its association with comorbidity. Methods: An electronic search was carried out using the database of MEDLINE/PubMed through the HINARI Programme, Google Scholar and Google for grey literature. A random effects model was used to estimate the pooled case fatality ratio of SAM and the hazard ratio (HR) of human immunodeficiency virus (HIV)/tuberculosis (TB) comorbidity using Stata/SE version 14. Results: A total of 13 studies were included in the meta-analysis. The overall case fatality ratio of SAM among children <5 y of age in Ethiopia was 11.3% (95% confidence interval [CI] 8.8-13.7) with the I2 heterogeneity test (I2=89.5%). Furthermore, the HR of SAM children was 3.4 (95% CI 1.91-6.06) in HIV and 2.08 (95% CI 1.2-3.61) in TB comorbidity as compared with their counterparts without comorbidity. Conclusions: In the aggregate, the pooled case fatality ratio was unacceptably high in Ethiopia. The case fatality ratio of SAM children is higher in HIV and TB comorbidity. Therefore, escalation of the existing nutritional strategies and early case detection of comorbidity are strongly recommended to mitigate the case fatality ratio of SAM. PMID- 29986104 TI - E-cigarette Use Among US Adults: Population Assessment of Tobacco and Health (PATH) Study. AB - Introduction: In 2011 the US Food and Drug Administration launched the Population Assessment of Tobacco and Health (PATH) Study to gather information for regulatory activities authorized by the Family Smoking Prevention and Tobacco Control Act (TCA). Methods: Data were drawn from the first wave of the PATH survey, involving interviews of 32 320 civilian and non-institutionalized adults. In addition to conventional classifications for current, former and never smoking and e-cigarette use, we used PATH questions to classify former and current triers of these products. Descriptive statistics were used to describe the prevalence, patterns of, and reasons for e-cigarette use, and the perceptions of nicotine and e-cigarettes among user groups, according to smoking status. Results: The prevalence of current smoking was 18%; an additional 3.1% of participants were current triers. The prevalence of current e-cigarette use was 2.4% (1.0% every day, 1.4% some days), with another 3.2% as current triers. The majority of nonsmokers who were current e-cigarette users were already current (56%) or former (34%) cigarette triers. Reasons for e-cigarette use were similar across subgroups, but patterns of use were different. Majorities of participants believed that nicotine is the main substance driving tobacco use, that nicotine causes most cancers, and that e-cigarettes were less harmful than cigarettes. Conclusions: E-cigarettes were used primarily by current smokers and recent former smokers. The main reasons for use center around perceptions that e cigarettes are less harmful than cigarettes to users and others. Implications: This study reports detailed information about the prevalence, patterns of, and reasons for e-cigarette use in the first (baseline) wave of the PATH Study in 2014. In addition to conventional categories for current, former and never smoking and e-cigarette use, the PATH questionnaire facilitated classification of new usage groups consisting of current and former triers of these products, which may impact prevalence estimates. PMID- 29986103 TI - Associations Between Early Onset of E-cigarette Use and Cigarette Smoking and Other Substance Use Among US Adolescents: A National Study. AB - Introduction: This study examines the associations between early onset of e cigarette use and cigarette smoking and other substance use behaviors among US adolescents. Methods: Data were collected via self-administered questionnaires from a nationally representative sample of 2299 US high school seniors attending public and private high schools during the spring of their senior year in 2015 as part of the Monitoring the Future study. Results: A higher percentage of adolescents who began using e-cigarettes in ninth grade or earlier (early onset) were found to report current and lifetime cigarette smoking and other substance use relative to those individuals who never used e-cigarettes or those who began using e-cigarettes later in the 12th grade. Multivariate logistic regression analyses indicated that the adjusted odds of alcohol use, cigarette smoking, marijuana use, nonmedical prescription drug use, and other illicit drug use among early onset e-cigarette users were significantly greater than those for individuals never having used e-cigarettes (adjusted odds ratios [AORs] ranged 9.5-70.6, p < .001). While these associations were significant for both experimental and frequent e-cigarette users, the effects of early onset were stronger among frequent e-cigarette users. Similarly, the odds of these substance use behaviors (except alcohol) among early onset e-cigarette users were also significantly greater than the odds for later onset e-cigarette users (AORs ranged 2.8-4.1, p < .05). Conclusions: Early onset of e-cigarette use was significantly associated with increased odds of cigarette smoking and other substance use behaviors. E-cigarette use is often preceded by alcohol use, cigarette smoking, and marijuana use, suggesting that more long-term prospective studies are warranted. Implications: To date, no studies have examined the probability of cigarette smoking and other substance use behaviors as a function of age at onset of e-cigarette use. In the present study, early onset of e cigarette use was significantly associated with increased odds of cigarette smoking and other substance use behaviors. The findings reinforce the importance of addressing a wide range of substances including alcohol, traditional cigarettes, and marijuana when developing early primary prevention efforts to reduce e-cigarette use among youth. PMID- 29986105 TI - Level of Alcohol Consumption and Successful Smoking Cessation. AB - Introduction: The negative association between heavy alcohol use and likelihood of successful smoking cessation is well established. However, evidence on the effects of moderate alcohol consumption on smoking cessation is sparse. This analysis evaluated the association between alcohol use and smoking and the interaction of alcohol use and use of pharmacotherapy interventions in relation to smoking cessation. Methods: Data from adults (n=923) recruited through a smoking cessation website between November 2011 and March 2012 were analyzed. Data on past-year alcohol use, tobacco use, and demographics were collected at baseline. Self-reported smoking abstinence and current alcohol use data were collected at 1 and 7 months post-treatment. Chi-square and multivariate logistic regression analyses were conducted. Results: At 1 month, adjusted odds of continued smoking were 1.54 times greater (95% CI: 1.05, 2.23) for moderate drinkers and 2.59 times greater (95% CI: 1.33, 4.28) for heavy drinkers than non drinkers. At 7 months, adjusted odds of continued smoking were not greater for moderate drinkers than non-drinkers, and were 2.32 times greater (95% CI: 1.35, 3.96) among heavy alcohol drinkers than non-drinkers. At 1 month, adjusted odds of smoking cessation were 2.33 times greater (95% CI: 1.04, 3.09) for alcohol users assigned to nicotine replacement therapy (NRT) than for those not assigned to NRT. This relationship was not observed at 7 months. Conclusions: Moderate and heavy drinking might impact smoking cessation efforts. Recent moderate drinking may be associated with short-term continued smoking and heavy drinking associated with relapse in the short and long term. Implications: (1) This study suggests that moderate drinking may influence the quit smoking process. Further study is needed to better understand the implications of moderate drinking for smoking cessation. (2) Providing information alone may not be effective in helping people abstain from drinking during smoking cessation, especially if moderate drinkers do not perceive their behavior as reducing their chance for a successful quit attempt. Tailoring smoking cessation interventions to include strategies to reduce moderate-to-heavy alcohol consumption may improve smoking cessation outcomes among alcohol users attempting to quit smoking. PMID- 29986106 TI - A genome-wide scan for correlated mutations detects macromolecular and chromatin interactions in Arabidopsis thaliana. AB - The concept of exploiting correlated mutations has been introduced and applied successfully to identify interactions within and between biological macromolecules. Its rationale lies in the preservation of physical interactions via compensatory mutations. With the massive increase of available sequence information, approaches based on correlated mutations have regained considerable attention. We analyzed a set of 10 707 430 single nucleotide polymorphisms detected in 1135 accessions of the plant Arabidopsis thaliana. To measure their covariance and to reveal the global genome-wide sequence correlation structure of the Arabidopsis genome, the adjusted mutual information has been estimated for each possible pair of polymorphic sites. We developed a series of filtering steps to account for genetic linkage and lineage relations between Arabidopsis accessions, as well as transitive covariance as possible confounding factors. We show that upon appropriate filtering, correlated mutations prove indeed informative with regard to molecular interactions, and furthermore, appear to reflect on chromosomal interactions. Our study demonstrates that the concept of correlated mutations can also be applied successfully to within-species sequence variation and establishes a promising approach to help unravel the complex molecular interactions in A. thaliana and other species with broad sequence information. PMID- 29986107 TI - Research use of electronic health records: patients' perspectives on contact by researchers. AB - Objective: The use of electronic health records (EHRs) for research has the potential to improve the diagnosis and treatment of disease, yet contact with patients based on results of EHR phenotyping has received little attention. Researchers will almost certainly discover discrepancies in EHRs that call for resolution and, in some cases, raise the ethical dilemma of whether to contact patients about a potentially undiagnosed or untreated health concern. The objective of this study was to explore patients' attitudes and opinions about potential contact by researchers who have had access to their EHRs. Materials and methods: We conducted 15 focus groups in four diverse counties in the southeastern United States. We designed vignettes to describe different situations in which researchers conducting a hypothetical study might have reason to consider contact with patients. Results: Many patients believed it was important for researchers to take action if they discovered information suggesting a current serious health concern. Relaying the information through patients' physicians was considered the most appropriate course of action. Across vignettes, there were significant differences between urban and rural sites. Discussion and conclusions: Researchers may increasingly encounter situations involving contact with patients following EHR phenotyping. They should carefully consider the possibility of such contact when planning their studies, including the time and expertise needed to adjudicate potentially serious discrepancies. Our focus group results are one source of input for the development of ethical approaches to the research use of EHRs. PMID- 29986108 TI - Biologic prescribing decisions following serious infection: results from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis. AB - Objectives: To establish whether the decision to stop, continue or switch TNF inhibitor (TNFi) therapy to a biologic drug with an alternative mode of action following a serious infection (SI) impacts upon the risk of recurrent SI in patients with RA. Methods: Patients recruited to the British Society for Rheumatology Biologics Register-RA with at least one episode of SI while on TNFi were included. The biologic treatment decision following SI was considered. A multivariable adjusted Cox proportional hazards model was used to identify predictors of recurrent SI and whether biologic treatment choices influenced future SI risk. Results: In total, 1583 patients suffered at least one SI while on TNFi. Most patients (73%) were recorded as continuing TNFi 60 days after an index SI. The rate of recurrent SI was 25.6% per annum (95% CI: 22.5, 29.2%). The rate of recurrent SI was highest in patients who stopped their TNFi (42.6% per annum, 95% CI: 32.5, 55.7%) and lowest in those who switched biologic drug class (12.1% per annum, 95% CI: 3.9, 37.4%). Compared with patients stopping biologic therapy, patients who continued or switched drug class had significantly lower risk of recurrent SI (drug continuation hazard ratio = 0.54, 95% CI: 0.40, 0.74; drug switch hazard ratio = 0.29, 95% CI: 0.09, 0.95). Conclusions: Patients who continued or switched their TNFi post-index SI had a lower risk of recurrent SI infection compared with those who stopped the drug. This may be explained by better control of disease activity with reintroduction of biologic therapy, a driving factor for SI or alternatively channelling fitter patients to restart biologic therapy. PMID- 29986109 TI - Socio-economic and racial/ethnic differences in e-cigarette uptake among cigarette smokers: Longitudinal analysis of the Population Assessment of Tobacco and Health (PATH) study. AB - Introduction: Socio-demographic differences in electronic cigarette use among cigarette smokers have not been previously characterized in the US adult population. Methods: We analyzed longitudinal data from Waves 1 and 2 of the nationally representative Population Assessment of Tobacco and Health (PATH) study. Differences by income (based on federal poverty level (FPL)) and race/ethnicity in e-cigarette uptake at Wave 2 among cigarette smokers who were e cigarette non-users at Wave 1 were assessed using binomial and multinomial logistic regression. We differentiated e-cigarette users who quit cigarettes (exclusive users) from those who did not quit cigarettes (dual users). E cigarette-related attitudes/beliefs were evaluated to understand potential contributions to socio-demographic differences in e-cigarette uptake and use patterns. Results: Among 6,592 smokers who were e-cigarette non-users at Wave 1, 13.5% began using e-cigarettes at Wave 2, of whom 91.3% were dual users. Compared to non-Hispanic Whites, non-Hispanic Black and Hispanics were less likely to become exclusive e-cigarette users (OR [Blacks] =0.27, 95% CI 0.09-0.77; OR [Hispanics] =0.26, 95% CI 0.09-0.70). Low-income smokers were less likely than higher-income smokers to become exclusive e-cigarette users (OR [<100% FPL vs. >=200% FPL] =0.48, 95% CI 0.27-0.89). Black, Hispanic, and low-income smokers were more likely to believe e-cigarettes are more harmful than cigarettes and to have positive tobacco-related social norms. Conclusions: Black, Hispanic, and low income smokers were less likely than White and higher-income smokers to begin using e-cigarettes in the context of quitting cigarettes. Differences in e cigarette uptake may be partly explained by perceived harm or social norms of e cigarettes. Implications: Results of this study show that the exclusive use of e cigarettes is more prevalent in higher-income and White smokers. Our data suggest higher-income and White smokers may be more likely to use e-cigarettes as a means to quit combustible cigarettes compared to low-income and racial/ethnic minority smokers. These findings suggest that socio-demographic differences in e-cigarette uptake and use patterns may contribute to widening disparities in cigarette smoking. PMID- 29986110 TI - Will Machine Learning Enable Us to Finally Cut the Gordian Knot of Schizophrenia. PMID- 29986112 TI - "Maybe He Was in Love With You?": How to Talk With People in Psychosis. PMID- 29986111 TI - Snapshots of an evolved DNA polymerase pre- and post-incorporation of an unnatural nucleotide. AB - The next challenge in synthetic biology is to be able to replicate synthetic nucleic acid sequences efficiently. The synthetic pair, 2-amino-8-(1-beta-d-2'- deoxyribofuranosyl) imidazo [1,2-a]-1,3,5-triazin-[8H]-4-one (trivially designated P) with 6-amino-3-(2'-deoxyribofuranosyl)-5-nitro-1H-pyridin-2-one (trivially designated Z), is replicated by certain Family A polymerases, albeit with lower efficiency. Through directed evolution, we identified a variant KlenTaq polymerase (M444V, P527A, D551E, E832V) that incorporates dZTP opposite P more efficiently than the wild-type enzyme. Here, we report two crystal structures of this variant KlenTaq, a post-incorporation complex that includes a template-primer with P:Z trapped in the active site (binary complex) and a pre incorporation complex with dZTP paired to template P in the active site (ternary complex). In forming the ternary complex, the fingers domain exhibits a larger closure angle than in natural complexes but engages the template-primer and incoming dNTP through similar interactions. In the binary complex, although many of the interactions found in the natural complexes are retained, there is increased relative motion of the thumb domain. Collectively, our analyses suggest that it is the post-incorporation complex for unnatural substrates that presents a challenge to the natural enzyme and that more efficient replication of P:Z pairs requires a more flexible polymerase. PMID- 29986113 TI - National survey of intracavitary brachytherapy for intact uterine cervical cancer in Japan. AB - To review the current status of, and labor expended for (in terms of time required), intracavitary brachytherapy (ICBT) in definitive radiotherapy/chemoradiotherapy for cervical cancer patients, two national surveys were performed. The first survey was conducted between July and August 2016 and consisted of a questionnaire of 12 items regarding ICBT procedures for cervical cancer, which was sent to 173 centers installed with high-dose-rate remote after loading brachytherapy systems. Between November and December 2016, another survey was performed in 79 centers to evaluate labor required for ICBT procedures in terms of time spent and number of staff involved. In the first survey, the response rate was 77% of the 173 centers. ICBT was performed for cervical cancer in 118 (89%) centers. Imaging modalities used after applicator insertion were X ray alone in 46 (40%), computed tomography in 69 (60%) and magnetic resonance imaging in 5 (4%) centers. Three-dimensional (3D) planning was performed in 55 centers (48%). Fifty-five (70%) centers responded to the second survey regarding ICBT-mandated labor. The median cumulative duration of the entire ICBT procedure was 330 min (the sum of the times spent by each staff member) and was longer in the 3D image-guided brachytherapy (3D-IGBT) (405 min) than in the X-ray group (230 min). This trend was significant for the specific processes of image acquisition and treatment planning, especially for radiation oncologists. In definitive radiotherapy/chemoradiotherapy for cervical cancer patients, 3D-IGBT use has been gradually spreading in Japan. The present survey revealed that ICBT, especially 3D-IGBT, requires substantial labor and time from staff. PMID- 29986114 TI - A Super Strong Engineered Auxin-TIR1 Pair. AB - Auxin regulates diverse aspects of plant growth and development through induction of the interaction between TRANSPORT INHIBITOR RESPONSE 1/AUXIN SIGNALING F-BOX proteins (TIR1/AFBs) and AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) co-receptor proteins and the subsequent transcriptional regulation. The artificial control of endogenous auxin signaling should enable the precise delineation of auxin mediated biological events as well as the agricultural application of auxin. To this end, we previously developed a synthetic auxin-receptor pair that consists of 5-(3-methoxyphenyl)-IAA (convexIAA, cvxIAA) and the engineered TIR1 whose phenylalanine at position 79 in the auxin-binding pocket is substituted to glycine (TIR1F79G) (concaveTIR1, ccvTIR1). This synthetic auxin-receptor pair works orthogonally to natural auxin signaling in transgenic plants harboring the engineered TIR1 by exogenous application of 5-(3-methoxyphenyl)-IAA, and has potential to be utilized as novel agricultural/horticultural tools. In the present study, we report an improved version of the synthetic cvxIAA-ccvTIR1 pair such that synthetic IAA can act at lower concentrations. Using a yeast two-hybrid system, we screened various 5-substituted IAAs and identified 5-adamantyl-IAA, named pico_cvxIAA, which mediates interaction of TIR1F79G and IAA3 proteins at a 1,000-fold lower concentration than the original version, 5-(3-methoxyphenyl) IAA. Furthermore, we found that TIR1F79A interacts with IAA3 protein in the presence of picomolar concentrations of 5-adamantyl-IAA, 10,000-fold lower than our prototype version of the cvxIAA-ccvTIR1 pair. In addition, pull-down assays confirmed that 5-adamantyl-IAA mediates in vitro interaction of TIR1F79A and IAA7 DII peptides at lower concentrations. The improved synthetic IAA-TIR1 pair with high affinity would be beneficial for basic science as well as for practical use in agriculture/horticulture. PMID- 29986116 TI - Characteristics of sleep-active neurons in the medullary parafacial zone in rats. AB - Growing evidence supports a role for the medullary parafacial zone in non-rapid eye movement (non-REM) sleep regulation. Cell-body specific lesions of the parafacial zone or disruption of its GABAergic/glycinergic transmission causes suppression of non-REM sleep, whereas, targeted activation of parafacial GABAergic/glycinergic neurons reduce sleep latency and increase non-REM sleep amount, bout duration, and cortical electroencephalogram (EEG) slow-wave activity. Parafacial GABAergic/glycinergic neurons also express sleep-associated c-fos immunoreactivity. Currently, it is not clear if parafacial neurons are non REM sleep-active and/or REM sleep-active or play a role in the initiation or maintenance of non-REM sleep. We recorded extracellular discharge activity of parafacial neurons across the spontaneous sleep-waking cycle using microwire technique in freely behaving rats. Waking-, non-REM sleep-, and REM sleep-active neuronal groups were segregated by the ratios of their discharge rate changes during non-REM and REM sleep versus waking and non-REM sleep versus REM sleep. Parafacial neurons exhibited heterogeneity in sleep-waking discharge patterns, but 34 of 86 (40%) recorded neurons exhibited increased discharge rate during non REM sleep compared to waking. These neurons also exhibited increased discharge prior to non-REM sleep onset, similar to median preoptic nucleus (MnPO) and ventrolateral preoptic area (VLPO) sleep-active neurons. However, unlike MnPO and VLPO sleep-active neurons, parafacial neurons were weakly-moderately sleep-active and exhibited a stable rather than decreasing discharge across sustained non-REM sleep episode. We show for the first time that the medullary parafacial zone contains non-REM sleep-active neurons. These neurons are likely functionally important brainstem compliments to the preoptic-hypothalamic sleep-promoting neuronal networks that underlie sleep onset and maintenance. PMID- 29986115 TI - The primary transcriptome, small RNAs and regulation of antimicrobial resistance in Acinetobacter baumannii ATCC 17978. AB - We present the first high-resolution determination of transcriptome architecture in the priority pathogen Acinetobacter baumannii. Pooled RNA from 16 laboratory conditions was used for differential RNA-seq (dRNA-seq) to identify 3731 transcriptional start sites (TSS) and 110 small RNAs, including the first identification in A. baumannii of sRNAs encoded at the 3' end of coding genes. Most sRNAs were conserved among sequenced A. baumannii genomes, but were only weakly conserved or absent in other Acinetobacter species. Single nucleotide mapping of TSS enabled prediction of -10 and -35 RNA polymerase binding sites and revealed an unprecedented base preference at position +2 that hints at an unrecognized transcriptional regulatory mechanism. To apply functional genomics to the problem of antimicrobial resistance, we dissected the transcriptional regulation of the drug efflux pump responsible for chloramphenicol resistance, craA. The two craA promoters were both down-regulated >1000-fold when cells were shifted to nutrient limited medium. This conditional down-regulation of craA expression renders cells sensitive to chloramphenicol, a highly effective antibiotic for the treatment of multidrug resistant infections. An online interface that facilitates open data access and visualization is provided as 'AcinetoCom' (http://bioinf.gen.tcd.ie/acinetocom/). PMID- 29986117 TI - Systematic reviews and meta-analyses on smokeless tobacco products should include Shammah. PMID- 29986120 TI - Feasibility of a Smartphone-based pilot intervention for Hispanic breast cancer survivors: a brief report. AB - Hispanic breast cancer survivors (BCS) are at high risk for experiencing poor health-related quality of life (HRQoL) after completion of active breast cancer treatment. Therefore, there is a need to develop culturally tailored interventions for Hispanic BCS. To date, there have been limited interventions that have demonstrated that increasing cancer-related knowledge, self-efficacy in communication, and self-management skills can improve HRQoL among Hispanic BCS. These interventions have been delivered in person or by phone, which may be burdensome for Hispanic BCS. To facilitate intervention delivery, we developed My Guide, a Smartphone application aimed at improving HRQoL among Hispanic BCS. The purpose of the current study is to describe the feasibility results of a 4-week pilot trial testing My Guide among Hispanic BCS. Twenty-five women enrolled in the study (75% recruitment rate) and 22 women were retained (91.6% retention rate). Mean time spent using My Guide across the 4 weeks was 9.25 hr, and mean score on the satisfaction survey was 65.91 (range 42-70), in which higher scores reflect greater satisfaction. Participants' scores on the Breast Cancer Knowledge Questionnaire significantly improved from study baseline (M = 9.50, SD = 2.92) to the postintervention assessment (M = 11.14, SD = 2.66), d = 0.59. Participants' HRQoL scores improved over the course of 4 weeks, but these improvements were not statistically significant. Overall, My Guide was feasible and acceptable. Future studies will assess the preliminary efficacy of My Guide in improving HRQoL in a larger, randomized trial of Hispanic BCS. PMID- 29986118 TI - Identification of receptors for UNCG and GNRA Z-turns and their occurrence in rRNA. AB - In contrast to GNRA tetraloop receptors that are common in RNA, receptors for the more thermostable UNCG loops have remained elusive for almost three decades. An analysis of all RNA structures with resolution <=3.0 A from the PDB allowed us to identify three previously unnoticed receptors for UNCG and GNRA tetraloops that adopt a common UNCG fold, named 'Z-turn' in agreement with our previously published nomenclature. These receptors recognize the solvent accessible second Z turn nucleotide in different but specific ways. Two receptors participating in a complex network of tertiary interactions are associated with the rRNA UUCG and GAAA Z-turns capping helices H62 and H35a in rRNA large subunits. Structural comparison of fully assembled ribosomes and comparative sequence analysis of >6500 rRNA sequences helped us recognize that these motifs are almost universally conserved in rRNA, where they may contribute to organize the large subunit around the subdomain-IV four-way junction. The third UCCG receptor was identified in a rRNA/protein construct crystallized at acidic pH. These three non-redundant Z turn receptors are relevant for our understanding of the assembly of rRNA and other long-non-coding RNAs, as well as for the design of novel folding motifs for synthetic biology. PMID- 29986119 TI - Transcriptome-Wide Analysis Reveals the Origin of Peloria in Chinese Cymbidium (Cymbidium sinense). AB - An orchid flower exhibits a zygomorphic corolla with a well-differentiated labellum. In Cymbidium sinense, many varieties with peloric or pseudopeloric flowers have been bred during centuries of domestication. However, little is known about the molecular basis controlling orchid floral zygomorphy and the origin of these varieties. Here, we studied the floral morphogenesis of C. sinense and transcriptome-wide enriched differentially expressed genes among different varieties. The floral zygomorphy of C. sinense is established in the early developmental process. Out of 27 MIKCC-MADS factors, we found two homeotic MADS genes whose expression was down-regulated in peloric varieties but up regulated in pseudopeloric varieties. CsAP3-2 expressed in the inner floral organs co-operates with a labellum-specific factor CsAGL6-2, asymmetrically promoting the differentiation of inner tepals. Interestingly, we detected exon deletions on CsAP3-2 in peloric varieties, indicating that loss of B-function results in the origin of peloria. Additional petaloid structures developed when we ectopically expressed these genes in Arabidopsis, suggesting their roles in floral morphogenesis. These findings indicate that the interplay among MADS factors would be crucial for orchid floral zygomorphy, and mutations in these factors may have maintained during artificial selection. PMID- 29986121 TI - Application of Compound Action Potential of Facial Muscles Evoked by Transcranial Stimulation as a Reference Waveform of Motor-evoked Potential in Spinal Surgery. AB - Transcranial electrical stimulation motor-evoked potential (TES-MEP) has been widely used to monitor major motor pathways in cranial and spinal surgeries. However, the results of TES-MEP might be strongly influenced by anesthetic agents and muscle relaxants. To compensate for this effect, a technique using compound muscle action potentials of the abductor pollicis brevis (APB-CMAP) evoked by median nerve stimulation has recently been reported. In this article, we adopted the transcranial electrical stimulation motor-evoked potential of facial muscles (TES-FMEP) instead of APB-CMAP as a reference waveform for compensation. Intraoperative monitoring in spinal surgeries using TES-MEP, TES-FMEP and APB CMAP was performed in 64 patients. We compared with and without compensation methods using TES-FMEP and APB-CMAP to evaluate TES-MEP. The cases which demonstrated postoperative motor disturbance, including transient symptoms, were judged to be positive cases. Postoperative transient paraplegia was shown in one intramedullary tumor case among those 64 cases. Compensation by TES-FMEP exhibited the highest specificity (90.5%) and lowest false-positive rate (9.5%) among the three compensation modalities when evaluated at 80% amplitude decrease. TES-FMEP, being derived from motor cortex stimulation, is not influenced by the original spinal lesion or surgical manipulation of the spine. Therefore, compensation using TES-FMEP is suitable for intraoperative monitoring during spinal surgery. The authors advocate TES-FMEP as a reference waveform for the compensation of intraoperative TES-MEP. PMID- 29986122 TI - A Case of Holocord Leptomeningeal Dissemination from Cerebellar Hemangioblastoma without von Hippel-Lindau Disease. AB - Hemangioblastoma disseminated along leptomeninges from the solitary cranial lesion without von Hippel-Lindau (VHL) disease is a quite rare instance with 23 cases reported in 40 years. We add a new case and discuss these rare instances. A 55-year-old female underwent surgery for total removal of cerebellar hemangioblastoma. Twenty months later, magnetic resonance (MR) images of the spinal cord revealed a tumor compressing the thoracic cord at T3-4 level which was removed en bloc by emergent spinal surgery. However, paraplegia and bowel bladder dysfunction recurred 5 months after the spinal surgery. Spine MR images showed diffuse enhancement of subarachnoid space. Exploratory surgery disclosed that the enhanced lesion was disseminated hemangioblastoma. After whole spinal irradiation, she was transferred to a palliative care hospital. Even after complete removal, possibility of leptomeningeal dissemination demands continuous follow-up. The mechanism of seeding of hemangioblastoma remains unclear, but attention must be paid to avoid spreading tumor cells during surgery because all the disseminated cases had precedent cranial surgery. PMID- 29986123 TI - Hybrid Surgery for Portosystemic Encephalopathy in a Patient with Liver Cirrhosis: a case report. AB - Regarding the treatment for a portosystemic shunt, surgical or interventional radiological closure of the shunt was established. Interventional radiology including balloon-occluded retrograde transvenous obliteration can worsen portal hypertension and create a large thrombus close to the major venous system in the case of a huge portosystemic shunt. In contrast, it is also difficult to treat some cases through surgery alone when huge complicated shunts exist very deep in the body. Herein, we report a successful case of surgical shunt ligation for portosystemic encephalopathy in a hybrid operation room that enabled intraoperative angiography and computed tomography. A 62-year-old woman with chronic hepatitis C was referred to our hospital due to high levels of serum ammonia and hepatic encephalopathy. She had a massive, complicated portosystemic shunt from the inferior mesenteric vein to the left renal vein but did not have esophageal or gastric varices. It was difficult to occlude the portosystemic shunt by interventional radiologic techniques because the shunt had an extremely large amount of blood flow and many collateral routes. We performed the shunt ligation in the hybrid operation room. Intraoperative angiography provided detailed information about the portosystemic shunt, such as direction or volume of blood flow and collateral routes in real time. Her encephalopathy disappeared completely and she remains healthy with improved liver functional reserve to date. In conclusion, this is a successful case of a hybrid operation for an extremely large and complicated portosystemic shunt, providing for intraoperative angiography as a safe and reliable surgical treatment for portosystemic encephalopathy in patients with liver cirrhosis. PMID- 29986125 TI - Spontaneous Celiac and Splenic Artery Dissection. AB - Dissection of the splanchnic artery unrelated to an aortic lesion is extremely rare. We describe a patient with dissection of the celiac and splenic arteries causing splenic circulatory impairment. A 55-year-old Japanese man was referred to our hospital for left back pain that suddenly occurred 3 days previously and spread to the left flank. He had complicated sleep apnea syndrome well controlled with continuous positive airway pressure, and had been prophylactically taking aspirin (100 mg/day) because of asymptomatic cerebral lacunar infarcts. Contrast enhanced computed tomography (CT) in the arterial phase revealed dissection from the celiac root extending to the entire splenic artery, the caliber of which was irregularly narrowed, causing malperfusion in the spleen. Because of hemodynamic stability and lack of impending sequelae, the patient was carefully observed with rest, strict blood pressure control, and aspirin administration. One month later, CT revealed restoration of the caliber of the dissected arteries and regression of the organizing false lumen, which confirmed the patient's recovery. Despite the extreme rarity or nonspecific symptoms, splanchnic artery dissection should be considered a potentially life-threatening emergency. This case supports the possible benefit of starting antithrombotic treatment early to prevent thrombotic sequelae such as organ infarction and aneurysmal formation. PMID- 29986124 TI - Portosystemic Encephalopathy without Liver Disease Masquerading as Dementia. AB - An 84-year-old woman was hospitalized due to consciousness disorder as hyperammonemia. She had no etiology of liver disease. Twelve months before the current admission, she had been diagnosed with dementia based on her low level of daily perception and physical activity. Abdominal computed tomography revealed a large portosystemic shunt between the medial branch of the portal vein and middle hepatic vein. After the improvement of her consciousness disturbance by medical treatment, percutaneous shunt embolization was electively performed. The patient showed a remarkable clinical improvement. Consciousness disturbance caused by hyper-ammonemia might be underlying in dementia patients. Increase of hepatopetal portal blood flow might have contributed to the improvement of her consciousness disturbance. Embolization of the portosystemic shunt might be more effective for patients without liver disease as in the present case. PMID- 29986126 TI - Hydrogel Cross-Linked with Dynamic Covalent Bonding and Micellization for Promoting Burn Wound Healing. AB - A novel hydrogel (HA-az-F127 hydrogel) formed by reacting hydrazide modified hyaluronic acid (HAAD) and benzaldehyde terminated F127 triblock copolymers (BAF127) was developed in this work. The hydrogel with dynamic covalent chemically and micellar physically double-cross-linked networks exhibited rapid gelation and shear thinning properties. Besides, the hydrogel possessed functions, such as adaptable mechanical strength, self-healability, liquid absorption, or drainage and tissue adhesion, which are important for wound treatment. Studies on cytocompatibility and histopathology by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide tests, live/death staining, and cell counting kit 8 assay demonstrated excellent biocompatibility of the hydrogels. After it was applied in the deep partial-thickness burn model, the hydrogel contributed effectively in promoting burn wound repair. Therefore, the HA-az-F127 hydrogel combined multiple functions in one system, demonstrating potential application in promoting burn wound healing. PMID- 29986127 TI - Renewable Cr2O3 Nanolayer on Cr(W)N Surface for Seizure Prevention at Elevated Temperatures. AB - Chromium nitride coating is now the norm for improving the wear resistance of high-performance mechanical components. Even so, to prevent the seizure issue between the contacting interfaces, the prerequisites are oil or solid lubricants which would however lose the lubricating functionality at elevated temperatures due to breakdown or degradation. In this research, we utilize a Cr2O3 nanolayer formed on modified Cr(W)N coating to prevent the adhesive seizure for steel-based components. X-ray photoelectron spectroscopy (XPS) analyses show that the chromium oxide can be generated at 200-400 degrees C. At 400 degrees C, the Cr2O3 nanolayer is in situ formed and maintains a consistent thickness of 2.2 nm due to the oxide renewal during the heating-sliding operation. The in situ, renewable oxide nanolayer provides a novel approach to the technically unsolved seizure problem occurring in high-performance machines operated at elevated temperatures. PMID- 29986128 TI - Necessary Experimental Conditions for Single-Shot Diffraction Imaging of DNA Based Structures with X-ray Free-Electron Lasers. AB - It has been proposed that the radiation damage to biological particles and soft condensed matter can be overcome by ultrafast and ultraintense X-ray free electron lasers (FELs) with short pulse durations. The successful demonstration of the "diffraction-before-destruction" concept has made single-shot diffraction imaging a promising tool to achieve high resolutions under the native states of samples. However, the resolution is still limited because of the low signal-to noise ratio, especially for biological specimens such as cells, viruses, and macromolecular particles. Here, we present a demonstration single-shot diffraction imaging experiment of DNA-based structures at SPring-8 Angstrom Compact Free Electron Laser (SACLA), Japan. Through quantitative analysis of the reconstructed images, the scattering abilities of gold and DNA were demonstrated. Suggestions for extracting valid DNA signals from noisy diffraction patterns were also explained and outlined. To sketch out the necessary experimental conditions for the 3D imaging of DNA origami or DNA macromolecular particles, we carried out numerical simulations with practical detector noise and experimental geometry using the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory, USA. The simulated results demonstrate that it is possible to capture images of DNA-based structures at high resolutions with the technique development of current and next-generation X-ray FEL facilities. PMID- 29986129 TI - Generation and Alkylation of alpha-Carbamyl Radicals via Organic Photoredox Catalysis. AB - Strategies for the direct C-H functionalization of amines are valuable as these compounds comprise a number of pharmaceuticals, agrochemicals and natural products. This work describes a novel method for the C-H functionalization of carbamate-protected secondary amines via alpha-carbamyl radicals generated using photoredox catalysis. The use of the highly oxidizing, organic acridinium photoredox catalyst allows for direct oxidation of carbamate-protected amines with high redox potentials to give the corresponding carbamyl cation radical. Following deprotonation, the resultant open-shell species can be intercepted by a variety of Michael acceptors to give elaborate alpha-functionalized secondary amines. The reaction proceeds under mild conditions without the requirement of exogenous redox mediators or substrate prefunctionalization. Additionally, we were able to showcase the utility of this methodology through the enantioselective synthesis of the indolizidine alkaloid, (+)-monomorine I. PMID- 29986131 TI - On the Question of the Total Energy in the Fermi-Lowdin Orbital Self-Interaction Correction Method. AB - The Fermi-Lowdin orbital self-interaction correction (FLOSIC) formalism is a novel method for implementing the Perdew-Zunger self-interaction correction (PZ SIC) in density functional theory calculations. In this paper we consider how the use of Fermi orbitals affects total energies and other calculated properties compared to a standard approach to PZ-SIC that utilizes the localization equation conditions. We directly compare the results of the two methods using identical basis sets and numerical techniques in calculations for isolated atoms up to Kr and for a large test set of molecules. We find differences in total energies that increase with increasing atomic number and show that these differences can be traced to a less negative SIC correction for the 1s orbital in FLOSIC. Importantly, energies for highest occupied orbitals and molecular atomization energies are nearly identical in the two methods. PMID- 29986132 TI - Thiol-Epoxy "Click" Chemistry to Engineer Cytocompatible PEG-Based Hydrogel for siRNA-Mediated Osteogenesis of hMSCs. AB - Thiol-epoxy "click" chemistry is employed for the first time to engineer a new cytocompatible PEG-based hydrogel system in aqueous media with the ability to encapsulate human mesenchymal stem cells (hMSCs) and control their fate for tissue regeneration. Cells were easily encapsulated into the hydrogels and exhibited high cell viability over 4 weeks of culture regardless of the presence of siRNA, complexed with polyethylenimine (PEI) in the form of siRNA/PEI nanocomplexes, indicating the biocompatibility of the developed hydrogel. Loading pro-osteogenic siNoggin in the hydrogel significantly enhanced the osteogenesis of encapsulated hMSCs, demonstrating the potential application of this system in tissue engineering. PMID- 29986130 TI - Synthesis of Functionalized N-Acetyl Muramic Acids To Probe Bacterial Cell Wall Recycling and Biosynthesis. AB - Uridine diphosphate N-acetyl muramic acid (UDP NAM) is a critical intermediate in bacterial peptidoglycan (PG) biosynthesis. As the primary source of muramic acid that shapes the PG backbone, modifications installed at the UDP NAM intermediate can be used to selectively tag and manipulate this polymer via metabolic incorporation. However, synthetic and purification strategies to access large quantities of these PG building blocks, as well as their derivatives, are challenging. A robust chemoenzymatic synthesis was developed using an expanded NAM library to produce a variety of 2 -N-functionalized UDP NAMs. In addition, a synthetic strategy to access bio-orthogonal 3-lactic acid NAM derivatives was developed. The chemoenzymatic UDP synthesis revealed that the bacterial cell wall recycling enzymes MurNAc/GlcNAc anomeric kinase (AmgK) and NAM alpha-1 phosphate uridylyl transferase (MurU) were permissive to permutations at the two and three positions of the sugar donor. We further explored the utility of these derivatives in the fluorescent labeling of both Gram (-) and Gram (+) PG in whole cells using a variety of bio-orthogonal chemistries including the tetrazine ligation. This report allows for rapid and scalable access to a variety of functionalized NAMs and UDP NAMs, which now can be used in tandem with other complementary bio-orthogonal labeling strategies to address fundamental questions surrounding PG's role in immunology and microbiology. PMID- 29986133 TI - Evaluation of Amphiphilic Star/Linear-Dendritic Polymer Reverse Micelles for Transdermal Drug Delivery: Directing Carrier Properties by Tailoring Core versus Peripheral Branching. AB - The reverse micelle self-assembly of lipophile-functionalized poly(ethylene glycol) (PEG) dendrimer hybrids is probed for applications in carrier-mediated transdermal drug delivery. Under investigation are topologically diverse amphiphiles featuring controlled branching motifs at either the polymer core (one , two-, and four-arm PEG) and the polar/nonpolar interface (peripheral dendritic generations 0-2). Thus, a systematic investigation of the effect of branching location (core vs peripheral) on carrier properties is described. Dye encapsulation experiments verify these materials are capable of forming well defined aggregates and solubilizing polar compounds. Further quantification of reverse micelle critical micelle concentration and dye loading capacity for the branched amphiphile library was obtained through spectroscopy characterization. Both core and peripheral branching are shown to significantly influence dynamic encapsulation behavior, with evidence of location-based contributions extending beyond multiplicity of branching alone. Finally, the in vitro transdermal diffusion of the reverse micelle carriers was investigated through Franz diffusion cell experiments using physiologically relevant juvenile porcine dermis. The permeation results, combined with previously reported aggregate size trends, show the complex relationship between polymer branching and transdermal transport, with the lowest core- and highest peripherally-branched amphiphilic analogs exhibiting optimal transdermal permeation characteristics for this set of branched carriers. PMID- 29986134 TI - Novel ALD Chemistry Enabled Low-Temperature Synthesis of Lithium Fluoride Coatings for Durable Lithium Anodes. AB - Lithium metal anodes can largely enhance the energy density of rechargeable batteries because of the high theoretical capacity and the high negative potential. However, the problem of lithium dendrite formation and low Coulombic efficiency (CE) during electrochemical cycling must be solved before lithium anodes can be widely deployed. Herein, a new atomic layer deposition (ALD) chemistry to realize the low-temperature synthesis of homogeneous and stoichiometric lithium fluoride (LiF) is reported, which then for the first time, as far as we know, is deposited directly onto lithium metal. The LiF preparation is performed at 150 degrees C yielding 0.8 A/cycle. The LiF films are found to be crystalline, highly conformal, and stoichiometric with purity levels >99%. Nanoindentation measurements demonstrate the LiF achieving a shear modulus of 58 GPa, 7 times higher than the sufficient value to resist lithium dendrites. When used as the protective coating on lithium, it enables a stable Coulombic efficiency as high as 99.5% for over 170 cycles, about 4 times longer than that of bare lithium anodes. The remarkable battery performance is attributed to the nanosized LiF that serves two critical functions simultaneously: (1) the high dielectric value creates a uniform current distribution for excellent lithium stripping/plating and ultrahigh mechanical strength to suppress lithium dendrites; (2) the great stability and electrolyte isolation by the pure LiF on lithium prevents parasitic reactions for a much improved CE. This new ALD chemistry for conformal LiF not only offers a promising avenue to implement lithium metal anodes for high-capacity batteries but also paves the way for future studies to investigate failure and evolution mechanisms of solid electrolyte interphase (SEI) using our LiF on anodes such as graphite, silicon, and lithium. PMID- 29986135 TI - Revealing the Effects of Electrode Crystallographic Orientation on Battery Electrochemistry via the Anisotropic Lithiation and Sodiation of ReS2. AB - The crystallographic orientation of battery electrode materials can significantly impact electrochemical performance, such as rate capability and cycling stability. Among the layered transition metal dichalcogenides, rhenium disulfide (ReS2) has the largest anisotropic ratio between the two main axes in addition to exceptionally weak interlayer coupling, which serves as an ideal system to observe and analyze anisotropy of electrochemical phenomena. Here, we report anisotropic lithiation and sodiation of exfoliated ReS2 at atomic resolution using in situ transmission electron microscopy. These results reveal the role of crystallographic orientation and anisotropy on battery electrode electrochemistry. Complemented with density functional theory calculations, the lithiation of ReS2 is found to begin with intercalation of Li-ions, followed by a conversion reaction that results in Re nanoparticles and Li2S nanocrystals. The reaction speed is highly anisotropic, occurring faster along the in-plane ReS2 layer than along the out-of-plane direction. Sodiation of ReS2 is found to proceed similarly to lithiation, although the intercalation step is relatively quicker. Furthermore, the microstructure and morphology of the reaction products after lithiation/sodiation show clear anisotropy along the in-plane and out-of plane directions. These results suggest that crystallographic orientation in highly anisotropic electrode materials can be exploited as a design parameter to improve battery electrochemical performance. PMID- 29986136 TI - Multiplexed Biomolecular Arrays Generated via Parallel Dip-Pen Nanolithography. AB - The capability of transferring target materials especially functionality-reliable biomolecules, into specific locations and with arbitrarily designed patterns are of critical importance for high-throughput disease diagnosis, multiplexing, and drug screening. Herein, we report the simultaneous patterning of two types of biomolecules using the parallel dip-pen nanolithography technology where an array of the atomic force microscope (AFM) tips can be selectively and alternately coated with target biomolecules via a specially designed inkwell array. Moreover, mixing target biomolecules at a proper volumetric ratio with polyethylene glycol dissolved in PBS buffer solution that works as an ink carrier can not only facilitate the smooth transfer of ink materials from the AFM tip to the substrate, it can also help to adjust the ink diffusion constant of different biomolecules to be highly similar so that the multiplexed biofunctional dot and/or line arrays at similar sizes can be reliably generated. PMID- 29986137 TI - Bias-Dependent Normal and Inverted J- V Hysteresis in Perovskite Solar Cells. AB - Perovskite solar cells (PSCs) typically exhibit hysteresis in current density voltage ( J- V) measurements. The most common type of J- V hysteresis in PSCs is normal hysteresis, in which the performance in the reverse scan is better than that in the forward scan. However, inverted hysteresis also exists, in which the reverse scan performance is worse than in the forward scan; this hysteresis, however, is significantly less well studied. In this work, we show that the hysteresis decreases when the sweep rate is decreased only in cases involving a small bias range, and it does not decrease with a large bias range. Under large forward bias and slowing sweep rate, we observe enhanced normal hysteresis or inverted hysteresis in PSCs. Moreover, the degree of normal and inverted hysteresis can be adjusted by varying the bias. Here, we hypothesize that the tunable hysteresis is derived from the different distribution of ionic defects (VI and VMA) at the electron (hole) transport layer/perovskite interface due to ionic movement in the perovskite layer under the different bias scanning conditions. This conclusion is confirmed using Kelvin probe force microscopy with different bias voltages and scanning rates, which shows surface potential hysteresis based on ionic-migration-related Fermi level shifting in perovskite films and agrees with the tunable J- V hysteresis hypothesis. Moreover, the increased time response in the milliseconds region in open-circuit voltage decay after J- V scanning further corroborates the mechanism of ionic migration under bias. Our work provides new insights into the ionic movement hypothesis for the J V hysteresis in PSCs. PMID- 29986138 TI - Scavenging Ability of Homogentisic Acid and Ergosterol toward Free Radicals Derived from Ethanol Consumption. AB - Acute, or chronic, ethanol consumption leads to the formation of free radicals in the liver, which is related to hepatic damage. Among these radicals 1 hydroxyethyl, *CH(OH)CH3, is the most abundant one. Thus, efficient *CH(OH)CH3 scavengers are likely candidates to offer liver protection after ethanol consumption. In the present work ergosterol and homogentisic acid (HGA), which are found in edible mushrooms, were investigated as potential candidates to that purpose. The investigation was carried out following the QM-ORSA protocol, and using the density functional theory (DFT). The overall rate constants calculated for the *CH(OH)CH3 radical scavenging activity of ergosterol in lipid and ethanol media are 1.34 * 107 and 1.86 * 107 M-1 s-1, respectively. For homogentisic acid the overall rate constant in lipid, ethanol and aqueous media are 4.33 * 108, 2.74 * 106, and 3.62 * 107 M-1 s-1, respectively. Accordingly, both compounds are predicted to efficiently scavenge the *CH(OH)CH3 radical. Thus, the results from this investigation support the antioxidant capability of edible mushrooms, their potential beneficial effects against ethanol hepatotoxicity, and the nutraceuticals properties of ergosterol and homogentisic acid. PMID- 29986139 TI - Dietary Fiber Increases Butyrate-Producing Bacteria and Improves the Growth Performance of Weaned Piglets. AB - The study investigated the impact of dietary fibers on the performance, fecal short-chain fatty acids, nutrient digestibility, and bacterial community in weaned piglets with the control group (CON) and dietary supplementation of 5% corn bran (CB), 5% wheat bran (WB), or 5% soybean hulls (SB). The piglets in CB and WB groups showed greater weight gain and feed efficiency ( p < 0.05) in comparison to piglets in CON and SB groups. Fecal samples from piglets in CB, SB, and WB groups contained greater ( p < 0.05) butyrate levels than fecal samples from piglets in the CON group. The fecal samples from piglets in CB or WB groups contained greater ( p < 0.05) abundances of Actinobacteria and Firmicutes or Fibrobacteres than the fecal sample from piglets in the CON group, which could promote fiber degradation and the production of butyrate. In summary, dietary CB or WB may enhance the growth performance of weaned piglets via altering gut microbiota and improving butyrate production, which shed light on the mechanism of dietary fiber in improving gut health. PMID- 29986140 TI - Template-Guided Programmable Janus Heteronanostructure Arrays for Efficient Plasmonic Photocatalysis. AB - Janus heteronanostructures (HNs), as an important class of anisotropic nanomaterials, could facilitate synergistic coupling of diverse functions inherited by their comprised nanocomponents. Nowadays, synthesizing deterministically targeted Janus HNs remains a challenge. Here, a general yet scalable technique is utilized to fabricate an array of programmable Janus HNs based on anodic aluminum oxide binary-pore templates. By designing and employing an overetching process to partially expose four-edges of one set of nanocomponents in a binary-pore template, selective deposition and interfacing of the other set of nanocomponents is successfully achieved along the exposed four edges to form a densely packed array of Janus HNs on a large scale. In combination with an upgraded two-step anodization, the synthesis provides high degrees of freedom for both nanocomponents of the Janus HNs, including morphologies, compositions, dimensions, and interfacial junctions. Arrays of TiO2 Au and TiO2/Pt NPs-Au Janus HNs are designed, fabricated, and demonstrated about 2.2 times photocurrent density and 4.6 times H2 evolution rate of that obtained from their TiO2 counterparts. The enhancement was mainly determined as a result of localized surface plasmon resonance induced direct hot electron injection and strong plasmon resonance energy transfer near the interfaces of TiO2 nanotubes and Au nanorods. This study may represent a promising step forward to pursue customized Janus HNs, leading to novel physicochemical effects and device applications. PMID- 29986141 TI - Collagen Prolyl 4-Hydroxylase as a Therapeutic Target. AB - Collagen is the dominant protein of the extracellular matrix. Its distinguishing feature is a three-stranded helix of great tensile strength. (2 S,4 R)-4 Hydroxyproline residues are essential for the stability of this triple helix. These residues arise from the post-translational modification of (2 S)-proline residues by collagen prolyl 4-hydroxylases (CP4Hs), which are members of the Fe(II)- and alpha-ketoglutarate (AKG)-dependent dioxygenase family. Here, we provide a framework for the inhibition of CP4Hs as the basis for treating fibrotic diseases and cancer metastasis. We begin with a summary of the structure and enzymatic reaction mechanism of CP4Hs. Then, we review the metal ions, metal chelators, mimetics of AKG and collagen strands, and natural products that are known to inhibit CP4Hs. Our focus is on inhibitors with potential utility in the clinic. We conclude with a prospectus for more effective inhibitors. PMID- 29986142 TI - Monoacylglycerol Acyltransferase 2 (MGAT2) Inhibitors for the Treatment of Metabolic Diseases and Nonalcoholic Steatohepatitis (NASH). AB - Monoacylglycerol transferase 2 (MGAT2) is a pivotal enzyme in the monoacylglycerol pathway for triacylglycerol synthesis. The pathway for triacylglycerol synthesis has provided several attractive targets for drug discovery in the treatment of metabolic diseases. Marketed drugs that inhibit enzymes in this pathway include orlistat (pancreatic lipase inhibitor), lomitapide (mitochondrial transfer protein inhibitor), and mipomersen (apolipoprotein B synthesis inhibitor), but poor gastrointestinal (GI) tolerability or safety considerations have limited their use and indications. In addition, several inhibitors of diacylglycerol transferase 1 (DGAT1) have advanced to the clinic but were withdrawn due to poor GI tolerability. This report first discusses the biological rationale in support of inhibition of MGAT2 as a therapeutic approach that may offer a distinct and superior efficacy versus GI tolerability profile and then reviews advances in the discovery of small molecule MGAT2 inhibitors for the treatment of metabolic diseases and nonalcoholic steatohepatitis (NASH). PMID- 29986143 TI - Simulating Electron Dynamics of Complex Molecules with Time-Dependent Complete Active Space Configuration Interaction. AB - Time-dependent electronic structure methods are growing in popularity as tools for modeling ultrafast and/or nonlinear processes, for computing spectra, and as the electronic structure component of mean-field molecular dynamics simulations. Time-dependent configuration interaction (TD-CI) offers several advantages over the widely used real-time time-dependent density functional theory: namely, that it correctly models Rabi oscillations; it offers a spin-pure description of open shell systems; and a hierarchy of TD-CI methods can be defined that systematically approach the exact solution of the time-dependent Schrodinger equation (TDSE). In this work, we present a novel TD-CI approach that extends TD CI to large complete active-space configuration expansions. Such extension is enabled by use of a direct configuration interaction approach that eliminates the need to explicitly build, store, or diagonalize the Hamiltonian matrix. Graphics processing unit (GPU) acceleration enables fast solution of the TDSE even for large active spaces-up to 12 electrons in 12 orbitals (853776 determinants) in this work. A symplectic split operator propagator yields long-time norm conservation. We demonstrate the applicability of our approach by computing the response of a large molecule with a strongly correlated ground state, decacene (C42H24), to various pulses (delta-function, transform limited, chirped). Our simulations predict that chirped pulses can be used to induce dipole-forbidden transitions. Simulations of decacene using the 6-31G(d) basis set and a 12 electrons/12 orbitals active space took 20.1 h to propagate for 100 fs with a 1 attosecond time step on a single NVIDIA K40 GPU. Convergence with respect to time step is found to depend on the property being computed and the chosen active space. PMID- 29986144 TI - Synthesis and Self-Assembly of Amphiphilic Star/Linear-Dendritic Polymers: Effect of Core versus Peripheral Branching on Reverse Micelle Aggregation. AB - A series of branched polymers, consisting of a poly(ethylene glycol) (PEG) core and lipophilic peripheral dendrons, were synthesized and their self-assembly into reverse micelles studied toward the ultimate goal of carrier-mediated transdermal drug delivery. More specifically, this investigation systematically explores the structure-property contributions arising from location and extent of branching by varying the number of branch points at the core and the generation of dendrons at the polar/nonpolar interface. For branching at the core, PEGs were selected with one, two or four arms, with one terminal functionality per arm. For peripheral branching, end groups were modified with polyester dendrons (of dendritic generations 0, 1, and 2) for each of the three cores. Finally, lauric acid (LA) was used to esterify the periphery, yielding a library of branched, amphiphilic polymers. Characterization of these materials via MALDI-TOF MS, GPC and NMR confirmed their exceptionally well-defined structure. Furthermore, atomic force microscopy (AFM) and dynamic light scattering (DLS) confirmed these polymers' abilities to make discrete aggregates. As expected, increased multiplicity of branching resulted in more compact aggregates; however, the location of branching (core vs periphery) did not seem as important in defining aggregate size as the extent of branching. Finally, computational modeling of the branched amphiphile series was explored to elucidate the macromolecular interactions governing self assembly in these systems. PMID- 29986145 TI - High-Throughput Screening Approach for Nanoporous Materials Genome Using Topological Data Analysis: Application to Zeolites. AB - The materials genome initiative has led to the creation of a large (over a million) database of different classes of nanoporous materials. As the number of hypothetical materials that can, in principle, be experimentally synthesized is infinite, a bottleneck in the use of these databases for the discovery of novel materials is the lack of efficient computational tools to analyze them. Current approaches use brute-force molecular simulations to generate thermodynamic data needed to predict the performance of these materials in different applications, but this approach is limited to the analysis of tens of thousands of structures due to computational intractability. As such, it is conceivable and even likely that the best nanoporous materials for any given application have yet to be discovered both experimentally and theoretically. In this article, we seek a computational approach to tackle this issue by transitioning away from brute force characterization to high-throughput screening methods based on big-data analysis, using the zeolite database as an example. For identifying and comparing zeolites, we used a topological data analysis-based descriptor (TD) recognizing pore shapes. For methane storage and carbon capture applications, our analyses seeking pairs of highly similar zeolites discovered good correlations between performance properties of a seed zeolite and the corresponding pair, which demonstrates the capability of TD to predict performance properties. It was also shown that when some top zeolites are known, TD can be used to detect other high performing materials as their neighbors with high probability. Finally, we performed high-throughput screening of zeolites based on TD. For methane storage (or carbon capture) applications, the promising sets from our screenings contained high-percentages of top-performing zeolites: 45% (or 23%) of the top 1% zeolites in the entire set. This result shows that our screening approach using TD is highly efficient in finding high-performing materials. We expect that this approach could easily be extended to other applications by simply adjusting one parameter, the size of the target gas molecule. PMID- 29986146 TI - Effect of beetroot juice supplementation on 10-km performance in recreational runners. AB - The purpose of this study was to investigate the effects of chronic beetroot juice (BRJ) supplementation on 10-km running performance in recreational runners. In a double-blind, placebo-controlled, crossover-designed study, fourteen male recreational runners (age: 27.8 +/- 3.4 y) performed three 10-km running tests at baseline, under the conditions of BRJ supplementation and placebo (PLA). Supplementation was administered for three days, and on the day of the assessments, the ingestion occurred two hours before each test and consisted of a dose of 420 mL of BRJ in natura (8.4 mmol NO3-/day) or PLA with depleted NO3- (0.01 mmol NO3-/day). The mean velocity (MV) was calculated and the following variables were determined: maximum heart rate (HRmax), maximal rating of perceived exertion (RPEmax), and determined at pre and post test glucose concentrations (Glycpre, Glycpost), and lactate peak. There was no main effect between conditions regarding to 10-km running time performance (BRJ: 50.1 +/- 5.3; PLA: 51.0 +/- 5.1 min, p = 0.391) and total MV (BRJ: 12.1 +/- 1.3; PLA: 11.9 +/- 1.2 km.h-1, p = 0.321), as well as in the other analyzed variables. The time to complete the first half of the test (5 km) was statistically lower in the BRJ compared to that in the PLA (P = 0.027). In conclusion, chronic supplementation with BRJ increasing MV in the first half of the test and improves the final test time of ten of the fourteen runners, although we did not find a statistically significant difference in the performance of 10-km. PMID- 29986147 TI - Nasometric Comparison Between Spanish-English Bilingual and English Monolingual Children. AB - OBJECTIVE: It is well established in the literature that English diagnostic tests should not be directly applied to speakers whose primary language is Spanish. Normative nasalance data across word and sentence-level stimuli among Spanish English bilingual children living in the United States have not been provided. The present study aims to (1) compare differences in nasalance between typically developing Spanish-English bilingual children and English-speaking monolingual children and (2) determine whether within-speaker nasalance differences exist in Spanish-English bilingual children when presented with English and Spanish speech stimuli. DESIGN: Thirty-four typically developing children including 17 monolingual English speakers and 17 Spanish-English bilingual speakers with normal velopharyngeal anatomy between 5 and 7 years of age participated in the study. Speakers were recorded using a nasometer producing sets of stimulus items at the word and sentence level in English (English monolinguals) and in both Spanish and English for bilingual children. RESULTS: Results indicated no statistically significant difference between nasalance values across the different stimuli between monolingual and bilingual participants. However, within subject effects showed statistical significance between English and Spanish word stimuli among the bilingual group. CONCLUSIONS: These findings emphasize the importance of using language-specific diagnostic materials for nasalance testing, which would be of importance in the treatment of individuals with cleft palate. PMID- 29986148 TI - Floseal only versus in combination in spine surgery: a comparative, retrospective hospital database evaluation of clinical and healthcare resource outcomes. AB - OBJECTIVE: Flowable agents such as Floseal(r) (F) are often reserved as adjuncts to non-flowable agents (i.e. gelatin (G) sponges and thrombin (T)) when bleeding is not sufficiently controlled. Based on their perceived positive impact, it is postulated that flowable agents alone may result in better clinical and resource utilization outcomes. Clinical and health-care utilization outcomes were compared in this retrospective analysis of spine surgery cases with charges for Floseal only (FO) and F + G/T. METHODS: The United States Premier Hospital Database was searched for adult spine surgeries performed between October 2010 and September 2015 with FO or F and G/T charges. To obtain an unbiased treatment estimate, 1:1 propensity-score matching was used to identify FO and F + G/T cohorts. The cohorts were compared for rates of intraoperative, perioperative, postoperative and transfusion; blood loss-related, serious and other complications; hospital length-of-stay (LOS), surgical time, and volume of hemostat charged. RESULTS: Among 40,335 spine surgeries, 15,105 FO and F + G/T matched pairs were compared. Significantly (p < 0.0001) lower percentages of FO than F + G/T cases received intraoperative (1.4% vs. 2.5%), perioperative (1.6% vs. 2.8%), postoperative (1.6% vs 3.0%), and any transfusion (2.3% vs. 4.3%). FO cases had significantly less blood loss complications than F + G/T cases (0.5% vs. 0.8%, p = 0.0022) and significantly (p < 0.0001) shorter hospital LOS (-0.45 days), surgical time ( 39.0 min), and used less hemostat (-12.5 mL). CONCLUSIONS: Results from this observational hospital database analyses indicate that FO use in spine surgery is associated with lower blood transfusion use and blood loss complications compared to its use with adjunct non-flowable hemostatic agents. The shorter hospital stay, reduced surgical time, and less hemostat volume health-care utilization outcomes that favored FO versus combination use may translate to health system cost savings. Further validation of these findings using controlled clinical trials and cost-consequence studies is warranted. CLINICAL RELEVANCE: The use of flowable hemostatic agents alone may result in better clinical and possibly economic outcomes in spine surgery. PMID- 29986149 TI - Nothing but a Number? Age and Precision Treatment in Pulmonary Arterial Hypertension. PMID- 29986150 TI - A short-term intervention combining aerobic exercise with medium-chain triglyceride (MCT) is more ketogenic than either MCT or aerobic exercise alone: A comparison of normoglycemic and pre-diabetic older women. AB - OBJECTIVES: Determine whether - (1) a five-day aerobic exercise (AE) program combined with a medium-chain triglyceride (MCT) supplement would increase the plasma ketone response in older women more than either intervention alone, and (2) ketonemia after these combined or separate treatments was alike in normoglycemic (NG) versus pre-diabetic (PD) women. DESIGN: Older women (NG=10; PD=9) underwent a 4 h metabolic study after each of four different treatments: (i) no treatment control, (ii) five days of MCT alone (30 g/day), (iii) one session of 30 min of AE alone, and (iv) five days of MCT and AE combined (MCT+AE). Blood was sampled every 30 minutes over 4 h for analysis. RESULTS: In NG, MCT+AE induced the highest AUC for plasma ketones (835 +/- 341 umol h/L), values that were 69% higher than MCT alone (P<0.05). AUCs were not different between MCT alone and MCT+AE in PD, but both treatments induced a significantly higher AUC than the control or AE alone (P<0.05). Except for a trend towards a higher ketone AUC in NG vs. PD on AE alone (P=0.091), there was no significant difference between the ketone AUCs in PD and NG. CONCLUSION: Combination of MCT+AE was more ketogenic in older women than MCT or AE alone. MCT+AE had a synergistic effect on ketonemia in NG but not in PD. Whether by improving insulin sensitivity with a longer term AE intervention can improve the ketogenic effect of MCT in PD and thereby increase brain ketone uptake in older people merits further investigation. PMID- 29986151 TI - Neuromuscular adaptations to healthy aging. AB - Even in the absence of disease or disability, aging is associated with marked physiological adaptations within the neuromuscular system. An ability to perform activities of daily living and maintain independence with advanced age is reliant on the health of the neuromuscular system. Hence, it is critical to elucidate the age-related adaptations that occur within the central nervous system and the associated muscles to design interventions to maintain or improve neuromuscular function in the elderly. This brief review focuses on the neural alterations observed at both spinal and supraspinal levels in healthy humans in their seventh decade and beyond. The topics addressed are motor unit loss and remodelling, neural drive, and responses to transcranial magnetic stimulation of the motor cortex. PMID- 29986153 TI - ADAM9: A DAMaging Player in COPD. PMID- 29986152 TI - Test Performance Characteristics of the AIR, GAD-7 and HADS-Anxiety Screening Questionnaires for Anxiety in Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Anxiety is a common co-morbidity of Chronic Obstructive Pulmonary Disease (COPD) that is associated with higher morbidity and mortality. We evaluated three anxiety screening questionnaires, the Generalized Anxiety Disorder (GAD-7) questionnaire, the Hospital Anxiety and Depression Scale (HADS A), and the Anxiety Inventory for Respiratory Disease (AIR). OBJECTIVES: Evaluate and compare thet test performance characteristics of 3 anxiety screening questionnaires using the Mini International Neuropsychiatric Interview (MINI) version 7.0 as the gold standard. METHODS: Individuals with COPD were recruited at 16 centers. The MINI interview and questionnaires were administered by trained research coordinators at an in-person visit and re-administered by telephone 2 to 4 weeks later. A composite score for the presence of any DSM-V anxiety disorder was computed based on the MINI as the gold standard compared to a participant screening positive on self report measures for these analyses. RESULTS: 220 eligible individuals with COPD were enrolled; 219 completed the study. 11% were identified as having a DSM-V anxiety disorder based upon the MINI. Elevated anxiety symptoms based on questionnaires were 38% for the AIR, 30% for the GAD-7, and 20% for the HADS-A. Area under the receiver operating curve (AUC) was highest for the GAD-7 (0.78, 95%CI 0.69-0.87), followed by the HADS-A (0.74, 95%CI 0.64 0.84) and the AIR (0.66, 95%CI 0.56-0.76). AUC for the GAD-7 was significantly greater than for the AIR (P=0.014). Sensitivity was not statistically different among the questionnaires: 77% for the GAD-7; 63% for the HADS-A; and 66% for the AIR. The HADS-A had the highest specificity, 85%, which was significantly higher than the GAD-7 (77%, P<0.001) and the AIR (65%, P<0.001); the GAD-7 specificity was higher than the AIR (P<0.001). CONCLUSION: Symptoms of anxiety among COPD patients as identified by screening questionnaires were common and significantly higher than the prevalence of anxiety disorder meeting by DSM-V criteria. The GAD 7, the HADS and the AIR questionnaires had fair to moderate psychometric properties as screening tools for anxiety in individuals with COPD, indicating the need for improved measures for this patient population. PMID- 29986154 TI - Computed Tomographic Biomarkers in Idiopathic Pulmonary Fibrosis: The Future of Quantitative Analysis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with great variability in disease severity and rate of progression. The need for a reliable, sensitive, and objective biomarker to track disease progression and response to therapy remains a great challenge in IPF clinical trials. Over the past decade, quantitative computed tomography (QCT) has emerged as an area of intensive research to address this need. We have gathered a group of pulmonologists, radiologists and scientists with expertise in this area to define the current status and future promise of this imaging technique in the evaluation and management of IPF. In this Pulmonary Perspective, we review the development and validation of six computer-based QCT methods and offer insight into the optimal use of an imaging-based biomarker as a tool for prognostication, prediction of response to therapy, and potential surrogate endpoint in future therapeutic trials. PMID- 29986155 TI - Hacking the Human: The Prevalence Paradox in Cybersecurity. AB - OBJECTIVE: This work assesses the efficacy of the "prevalence effect" as a form of cyberattack in human-automation teaming, using an email task. BACKGROUND: Under the prevalence effect, rare signals are more difficult to detect, even when taking into account their proportionally low occurrence. This decline represents diminished human capability to both detect and respond. As signal probability (SP) approaches zero, accuracy exhibits logarithmic decay. Cybersecurity, a context in which the environment is entirely artificial, provides an opportunity to manufacture conditions enhancing or degrading human performance, such as prevalence effects. Email cybersecurity prevalence effects have not previously been demonstrated, nor intentionally manipulated. METHOD: The Email Testbed (ET) provides a simulation of a clerical email work involving messages containing sensitive personal information. Using the ET, participants were presented with 300 email interactions and received cyberattacks at rates of either 1%, 5%, or 20%. RESULTS: Results demonstrated the existence and power of prevalence effects in email cybersecurity. Attacks delivered at a rate of 1% were significantly more likely to succeed, and the overall pattern of accuracy across declining SP exhibited logarithmic decay. APPLICATION: These findings suggest a "prevalence paradox" within human-machine teams. As automation reduces attack SP, the human operator becomes increasingly likely to fail in detecting and reporting attacks that remain. In the cyber realm, the potential to artificially inflict this state on adversaries, hacking the human operator rather than algorithmic defense, is considered. Specific and general information security design countermeasures are offered. PMID- 29986156 TI - Identification and Functional Studies of MYO1H for Mandibular Prognathism. AB - Mandibular prognathism (MP) is regarded as a craniofacial deformity resulting from the combined effects of environmental and genetic factors, while the genetically predetermined component is considered to play an important role to develop MP. Although linkage and association studies for MP have identified multiple strongly associated regions and genes, the causal genes and variants responsible for the deformity remain largely undetermined. To address this, we performed targeted sequencing of 396 genes selected from previous studies as well as genes and pathways related with craniofacial development as primary candidates in 199 MP cases and 197 controls and carried out a series of statistical and functional analyses. A nonsynonymous common variant of MYO1H rs3825393, C>T, p.Pro1001Leu, was identified to be significantly associated with MP. During zebrafish embryologic development, expression of MYO1H orthologous genes were detected at mandibular jaw. Furthermore, jaw cartilage defects were observed in zebrafish knockdown models. Collectively, these data demonstrate that MYO1H is required for proper jaw growth and contributes to MP pathogenesis, expanding our knowledge of the genetic basis of MP. PMID- 29986158 TI - Role of Rats ( Rattus norvegicus) in the Epidemiology of Toxoplasma gondii Infection in Grenada, West Indies. AB - Rodents are known to be reservoir hosts of Toxoplasma gondii infection for other animals, such as cats and pigs. From February to July 2017, 167 rats ( Rattus norvegicus) were trapped in Grenada, and serum, heart, skeletal muscle, and brain were examined for T. gondii infection by serological examination (modified agglutination test, 1:25) for T. gondii antibodies and for viable parasites by bioassay in mice. Samples of heart, skeletal muscle, and brain of all rats were bioassayed in Swiss Webster (SW) outbred albino mice and interferon gamma gene knockout (KO) mice. Toxoplasma gondii was isolated from heart and brain from 1 rat; this was the only seropositive rat. The T. gondii strain was avirulent for SW mice but killed KO mice. Tissue cysts were detected in the brains of SW mice, and tachyzoites were detected in the lungs of KO mice that died of acute toxoplasmosis. The strain was propagated in cell culture, and DNA derived from cell-cultured tachyzoites was genotyped using the 10 PCR restriction fragment length polymorphisms (SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico). The strain was a clonal Type III (ToxoDB genotype no. 2) strain. Although the prevalence of T. gondii in humans and animals in Grenada is high, rats seem to have little importance in the transmission of T. gondii on this island. PMID- 29986157 TI - Protein Arginine Methyltransferase PRMT1 Is Essential for Palatogenesis. AB - Cleft palate is among the most common birth defects. Currently, only 30% of cases have identified genetic causes, whereas the etiology of the majority remains to be discovered. We identified a new regulator of palate development, protein arginine methyltransferase 1 (PRMT1), and demonstrated that disruption of PRMT1 function in neural crest cells caused complete cleft palate and craniofacial malformations. PRMT1 is the most highly expressed of the protein arginine methyltransferases, enzymes responsible for methylation of arginine motifs on histone and nonhistone proteins. PRMT1 regulates signal transduction and transcriptional activity that affect multiple signal pathways crucial in craniofacial development, such as the BMP, TGFbeta, and WNT pathways. We demonstrated that Wnt1-Cre;Prmt1 fl/fl mice displayed a decrease in palatal mesenchymal cell proliferation and failure of palatal shelves to reach the midline. Further analysis in signal pathways revealed that loss of Prmt1 in mutant mice decreased BMP signaling activation and reduced the deposition of H4R3me2a mark. Collectively, our study demonstrates that Prmt1 is crucial in palate development. Our study may facilitate the development of a better strategy to interrupt the formation of cleft palate through manipulation of PRMT1 activity. PMID- 29986159 TI - Epidural Analgesia to Facilitate Breastfeeding in a Grand Multipara. PMID- 29986161 TI - Cortical Coding of Auditory Features. AB - How the cerebral cortex encodes auditory features of biologically important sounds, including speech and music, is one of the most important questions in auditory neuroscience. The pursuit to understand related neural coding mechanisms in the mammalian auditory cortex can be traced back several decades to the early exploration of the cerebral cortex. Significant progress in this field has been made in the past two decades with new technical and conceptual advances. This article reviews the progress and challenges in this area of research. PMID- 29986162 TI - Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions. AB - Understanding the biological basis for human-specific cognitive traits presents both immense challenges and unique opportunities. Although the question of what makes us human has been investigated with several different methods, the rise of comparative genomics, epigenomics, and medical genetics has provided tools to help narrow down and functionally assess the regions of the genome that seem evolutionarily relevant along the human lineage. In this review, we focus on how medical genetic cases have provided compelling functional evidence for genes and loci that appear to have interesting evolutionary signatures in humans. Furthermore, we examine a special class of noncoding regions, human accelerated regions (HARs), that have been suggested to show human-lineage-specific divergence, and how the use of clinical and population data has started to provide functional information to examine these regions. Finally, we outline methods that provide new insights into functional noncoding sequences in evolution. PMID- 29986160 TI - Computational Principles of Supervised Learning in the Cerebellum. AB - Supervised learning plays a key role in the operation of many biological and artificial neural networks. Analysis of the computations underlying supervised learning is facilitated by the relatively simple and uniform architecture of the cerebellum, a brain area that supports numerous motor, sensory, and cognitive functions. We highlight recent discoveries indicating that the cerebellum implements supervised learning using the following organizational principles: ( a) extensive preprocessing of input representations (i.e., feature engineering), ( b) massively recurrent circuit architecture, ( c) linear input-output computations, ( d) sophisticated instructive signals that can be regulated and are predictive, ( e) adaptive mechanisms of plasticity with multiple timescales, and ( f) task-specific hardware specializations. The principles emerging from studies of the cerebellum have striking parallels with those in other brain areas and in artificial neural networks, as well as some notable differences, which can inform future research on supervised learning and inspire next-generation machine based algorithms. PMID- 29986163 TI - Myelin Plasticity and Nervous System Function. AB - Structural plasticity in the myelinated infrastructure of the nervous system has come to light. Although an innate program of myelin development proceeds independent of nervous system activity, a second mode of myelination exists in which activity-dependent, plastic changes in myelin-forming cells influence myelin structure and neurological function. These complementary and possibly temporally overlapping activity-independent and activity-dependent modes of myelination crystallize in a model of experience-modulated myelin development and plasticity with broad implications for neurological function. In this article, I consider the contributions of myelin to neural circuit function, the dynamic influences of experience on myelin microstructure, and the role that plasticity of myelin may play in cognition. PMID- 29986165 TI - What Happens with the Circuit in Alzheimer's Disease in Mice and Humans? AB - A major mystery of many types of neurological and psychiatric disorders, such as Alzheimer's disease (AD), remains the underlying, disease-specific neuronal damage. Because of the strong interconnectivity of neurons in the brain, neuronal dysfunction necessarily disrupts neuronal circuits. In this article, we review evidence for the disruption of large-scale networks from imaging studies of humans and relate it to studies of cellular dysfunction in mouse models of AD. The emerging picture is that some forms of early network dysfunctions can be explained by excessively increased levels of neuronal activity. The notion of such neuronal hyperactivity receives strong support from in vivo and in vitro cellular imaging and electrophysiological recordings in the mouse, which provide mechanistic insights underlying the change in neuronal excitability. Overall, some key aspects of AD-related neuronal dysfunctions in humans and mice are strikingly similar and support the continuation of such a translational strategy. PMID- 29986166 TI - Student perceptions of self-efficacy and teacher support for learning in fostering youth competencies: Roles of affective and cognitive engagement. AB - INTRODUCTION: This exploratory study extends research on student engagement by examining the relationships between its different facets, students' perception of teacher support for learning and self-efficacy, and adaptive youth competencies. Guided by Reschly and Christenson's (2012) student engagement framework, affective and cognitive engagement were posited to mediate the relationships between students' perceived beliefs, adaptive competencies and behavior engagement. METHOD: 3776 Singapore Grade 7 and 8 students completed a self report survey questionnaire. RESULTS: Self-efficacy and teacher support demonstrated different indirect relationships with student competencies and via different engagement pathways. Cognitive engagement mediated the effects of teacher support and self-efficacy on the four student competencies, while affective engagement's mediated effects was only evident on academic buoyancy. CONCLUSION: This study holds important implications for educational and psychological research on student engagement, demonstrating that the construct, though theorized in a western context, has empirical utility and relevance in an East Asian context. PMID- 29986164 TI - How Movement Modulates Hearing. AB - Hearing is often viewed as a passive process: Sound enters the ear, triggers a cascade of activity through the auditory system, and culminates in an auditory percept. In contrast to a passive process, motor-related signals strongly modulate the auditory system from the eardrum to the cortex. The motor modulation of auditory activity is most well documented during speech and other vocalizations but also can be detected during a wide variety of other sound generating behaviors. An influential idea is that these motor-related signals suppress neural responses to predictable movement-generated sounds, thereby enhancing sensitivity to environmental sounds during movement while helping to detect errors in learned acoustic behaviors, including speech and musicianship. Findings in humans, monkeys, songbirds, and mice provide new insights into the circuits that convey motor-related signals to the auditory system, while lending support to the idea that these signals function predictively to facilitate hearing and vocal learning. PMID- 29986167 TI - A sulfated heterorhamnan with novel structure isolated from the green alga Monostroma angicava. AB - A sulfated polysaccharide, designated MAP2, was isolated from Monostroma angicava by water extraction, anion-exchange and size-exclusion chromatography. The structural characteristics of MAP2 were investigated by chemical and spectroscopic methods, including methylation analysis, one- and two-dimensional nuclear magnetic resonance and electrospray mass spectrometry with collision induced dissociation spectroscopic analyses. The results showed that MAP2 was primarily composed of rhamnose with small amounts of xylose, glucuronic acid and glucose. The molecular weight of MAP2 was estimated to be about 671 kDa. The backbone of MAP2 was mainly constituted by 3-linked, 2-linked-a-l-rhamnose residues. Sulfate substitutions were at C-2/C-4 of 3-linked-a-l-rhamnose and C 3/C-4 of 2-linked-a-l-rhamnose residues. The branches consisted of 3-linked and 2 linked-a-l-rhamnose with monosulfate/unsulfate, as well as small amounts of beta d-GlcA-(1-> and beta-d-GlcA (2SO4)-(1 -> . Minor amounts of ->4)-d-Glcp-(1-> and beta-d-Xylp (4SO4)-(1-> might also be existent in MAP2. The investigation demonstrated that MAP2 was a novel sulfated rhamnan distinguishing from other algal sulfated rhamnans. PMID- 29986168 TI - Listening beyond seeing: Event-related potentials to audiovisual processing in visual narrative. AB - Every day we integrate meaningful information coming from different sensory modalities, and previous work has debated whether conceptual knowledge is represented in modality-specific neural stores specialized for specific types of information, and/or in an amodal, shared system. In the current study, we investigated semantic processing through a cross-modal paradigm which asked whether auditory semantic processing could be modulated by the constraints of context built up across a meaningful visual narrative sequence. We recorded event related brain potentials (ERPs) to auditory words and sounds associated to events in visual narratives-i.e., seeing images of someone spitting while hearing either a word (Spitting!) or a sound (the sound of spitting)-which were either semantically congruent or incongruent with the climactic visual event. Our results showed that both incongruent sounds and words evoked an N400 effect, however, the distribution of the N400 effect to words (centro-parietal) differed from that of sounds (frontal). In addition, words had an earlier latency N400 than sounds. Despite these differences, a sustained late frontal negativity followed the N400s and did not differ between modalities. These results support the idea that semantic memory balances a distributed cortical network accessible from multiple modalities, yet also engages amodal processing insensitive to specific modalities. PMID- 29986169 TI - Differentially expressed genes in response to amitraz treatment suggests a proposed model of resistance to amitraz in R. decoloratus ticks. AB - The widespread geographical distribution of Rhipicephalus decoloratus in southern Africa and its ability to transmit the pathogens causing redwater, gallsickness and spirochaetosis in cattle makes this hematophagous ectoparasite of economic importance. In South Africa, the most commonly used chemical acaricides to control tick populations are pyrethroids and amitraz. The current amitraz resistance mechanism described in R. microplus, from South Africa and Australia, involves mutations in the octopamine receptor, but it is unlikely that this will be the only contributing factor to mediate resistance. Therefore, in this study we aimed to gain insight into the more complex mechanism(s) underlying amitraz resistance in R. decoloratus using RNA-sequencing. Differentially expressed genes (DEGs) were identified when comparing amitraz susceptible and resistant ticks in the presence of amitraz while fed on bovine hosts. The most significant DEGs were further analysed using several annotation tools. The predicted annotations from these genes, as well as KEGG pathways potentially point towards a relationship between the alpha-adrenergic-like octopamine receptor and ionotropic glutamate receptors in establishing amitraz resistance. All genes with KEGG pathway annotations were further validated using RT-qPCR across all life stages of the tick. In susceptible ticks, the proposed model is that in the presence of amitraz, there is inhibition of Ca2+ entry into cells and subsequent membrane hyperpolarization which prevents the release of neurotransmitters. In resistant ticks, we hypothesize that this is overcome by ionotropic glutamate receptors (NMDA and AMPA) to enhance synaptic transmission and plasticity in the presence of neurosteroids. Activation of NMDA receptors initiates long term potentiation (LTP) which may allow the ticks to respond more rapidly and with less stimulus when exposed to amitraz in future. Overactivation of the NMDA receptor and excitotoxicity is attenuated by the estrone, NAD+ and ATP hydrolysing enzymes. This proposed pathway paves the way to future studies on understanding amitraz resistance and should be validated using in vivo activity assays (through the use of inhibitors or antagonists) in combination with metabolome analyses. PMID- 29986170 TI - When a word is worth more than a picture: Words lower the threshold for object identification in 3-year-old children. AB - A large literature shows strong developmental links between early language abilities and later cognitive abilities. We present evidence for one pathway by which language may influence cognition and development: by influencing how visual information is momentarily processed. Children were asked to identify a target in clutter and either saw a visual preview of the target or heard the basic-level name of the target. We hypothesized that the name of the target should activate category-relevant information and, thus, facilitate more rapid detection of the target amid distractors. Children who heard the name of the target before search were more likely to correctly identify the target at faster speeds of response, a result that supports the idea that words lower the threshold for target identification. This finding has significant implication for understanding the source of vocabulary-mediated individual differences in cognitive achievement and, more generally, for the relation between language and thought. PMID- 29986171 TI - Correlates of neurocognitive functions in individuals at ultra-high risk for psychosis - A 6-month follow-up study. AB - Cognitive deficits are evident at the prodromal phase of psychosis. It has been noted that brain-derived neurotrophic factor (BDNF) is correlated with cognition in both preclinical and clinical studies. However, to our knowledge, no study has evaluated blood BDNF levels and their association with cognitive impairment in individuals at ultra-high risk for psychosis (UHR). We included 13 individuals at UHR and 30 healthy controls (HC) matched by sex, age, and educational level. Plasma BDNF levels were measured at baseline and 6 months. Neurocognitive functions (executive functions, speed of processing, verbal learning and memory, working memory) were examined at 6 months. Regression analyses were conducted to examine the relationship between BDNF levels and cognitive performance. BDNF levels were lower in UHR group than in HC group both at baseline and at 6 months (P = 0.001, and P = 0.007, respectively). There were no associations between plasma BDNF levels and all of the cognitive domains in both groups. Our findings showed that peripheral BDNF levels were not related to cognitive deficits in UHR and HC groups while the lower BDNF level in the former persisted up to 6 months. Further research is needed in a large sample. PMID- 29986172 TI - How and when does mental illness stigma impact treatment seeking? Longitudinal examination of relationships between anticipated and internalized stigma, symptom severity, and mental health service use. AB - Although mental illness stigma has been identified as an important barrier to mental health treatment, there is little consensus regarding how and when mental illness stigma negatively impacts treatment seeking. The relationship between mental illness stigma and treatment seeking may depend on the particular stigma mechanism under investigation, as well as an individual's symptom severity. In the present study, we examined relationships between anticipated and internalized stigma, depressive symptom severity, and mental health service use using data from a two-wave longitudinal survey study of U.S. post-9/11 veterans. Mediated and moderated relationships were tested using PROCESS. Mediation analyses revealed that higher anticipated stigma led to higher levels of internalized stigma, which was associated with decreased treatment seeking. Moderation analyses revealed that anticipated stigma was only associated with treatment seeking when depressive symptoms were severe. The central role observed for internalized stigma highlights the value of stigma reduction efforts that focus on this stigma mechanism, whereas the finding that only those individuals with more severe symptoms are vulnerable to the negative effects of anticipated stigma underscores the importance of more targeted anti-stigma interventions. PMID- 29986173 TI - The relationship between negative symptoms and cognitive functioning in patients at clinical high risk for psychosis. AB - Negative symptoms and neurocognitive performance have been reported to be negatively associated in patients with emerging psychosis. However, most previous studies focused on patients with frank psychosis and did not differentiate between subdomains of negative symptoms. Hence, we aimed to elucidate the specific relationship between negative symptoms and cognitive functioning in patients at clinical high risk (CHR) for psychosis. Data from 154 CHR patients collected within the prospective Fruherkennung von Psychosen (FePsy) study were analyzed. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and cognitive functioning with an extensive neuropsychological test battery. Regression analyses revealed significant negative associations between negative symptoms and cognitive functioning, particularly in the domains of nonverbal intelligence and verbal fluency. When analyzing each negative symptom domain separately, alogia and asociality/anhedonia were significantly negatively associated with nonverbal intelligence and alogia additionally with verbal fluency. Overall, our results in CHR patients are similar to those reported in patients with frank psychosis. The strong negative association between verbal fluency and negative symptoms may be indicative of an overlap between these constructs. Verbal fluency might have a strong influence on the clinical impression of negative symptoms (particularly alogia) and vice versa. PMID- 29986174 TI - Factors related to metabolic parameters in medicated patients with major depressive disorder--a naturalistic study. AB - The aim of this study was to examine the metabolic parameters, including body mass index (BMI), homeostasis model assessment-estimated insulin resistance (HOMA IR), homeostasis model assessment-estimated pancreatic beta-cell function (HOMA beta), and lipid plasma level, in medicated patients with major depressive disorder (MDD) and to assess factors related to metabolic parameters in patients with MDD. 121 patients with MDD and 63 controls were recruited. The Hamilton Depression Rating Scale (HDRS), Wisconsin Card Sorting Test (WCST), Continuous Performance Test (CPT), and Finger-Tapping Test (FTT), were administered. BMI, HOMA-IR, and HOMA-beta were calculated as modifiable metabolic parameters. The FTT results and BMI in depressed patients were significantly poorer and lower, respectively, than those of the controls. However, no significant differences were noted between MDD patients and controls included metabolic parameters and other neuropsychological tests. Among depressed patients, higher BMI is significantly related with lower education, no tobacco use, and male. The result demonstrated metabolic parameters could be neutral among medicated patients with MDD, particularly in non-elderly Asian individuals. The deficits of psychomotor speed could be more prominent than other cognitive alterations in patient with MDD. PMID- 29986175 TI - Interrelations among negative core beliefs, attachment anxiety and low self directedness, putative central constructs of depression vulnerabilities in cognitive, attachment and psychobiological personality theories. AB - The present study examined the interrelations among negative core beliefs, attachment anxiety and low self-directedness, to test if the central constructs of depression vulnerabilities in cognitive, attachment and psychobiological personality theories are integrated into negative self-image. The subjects were 410 healthy Japanese medical students and staff. Negative core beliefs, attachment anxiety and self-directedness were evaluated by the Brief Core Schema Scales, Experiences in Close Relationships and Temperament and Character Inventory, respectively. There were strong interrelations among the three factors. The present study suggests that the central constructs of depression vulnerabilities in the three theories are integrated into negative self-image. PMID- 29986176 TI - Tell about yourself to improve your autobiographical memory: A study of Korsakoff's syndrome. AB - Korsakoff's syndrome (KS) has been associated with a difficulty to retrieve specific autobiographical memories. We investigated whether this difficulty can be alleviated after the retrieval of statements describing self-images. KS patients and control participants were recruited and asked to retrieve autobiographical memories after providing statements to the question "Who am I?" and after a control condition consisting of verbal fluency. Analysis showed higher autobiographical specificity in the "Who am I?" than in verbal fluency condition in both patients with KS and control participants. At a theoretical level, our findings demonstrate how retrieval of information related to conceptual self may influence autobiographical memory in KS. At a clinical level, our procedures are important as they demonstrate how a simple task (i.e., "Who am I?" statements) may serve as a tool to cue specific autobiographical memories in patients with KS. PMID- 29986177 TI - Prevalence and factors associated with Premenstrual Dysphoric Disorder: A community sample of young adult women. AB - Premenstrual Dysphoric Disorder (PMDD) was recently included in DSM-5 as a full diagnostic category. Few studies have investigated PMDD in a community sample of young adults, especially in Brazil. Thus, the objective of this study was to evaluate the prevalence and the factors associated with PMDD in a community sample of 727 young adult women between the 18 and 24 years of age in southern Brazil. This was a cross-sectional population-based study. The data were collected from 2012 to 2014. PMDD was assessed using the Mini International Neuropsychiatry Interview (M.I.N.I. - Plus). The prevalence of PMDD was 17.6%. PMDD was significantly higher among older women, and in women from lower socio economic status. A trend towards significance was found for women without a current occupation (study or work). The comorbidities significantly associated with PMDD were current major depression disorder, agoraphobia, bipolar disorder, current suicide risk, generalized anxiety disorder, social phobia, and specific phobia. The high prevalence found in the present study should be interpreted considering a retrospective report. However, our data showed that clinicians should be alert for PMDD symptoms, especially among young adult women. PMID- 29986178 TI - Non-monotonic temporal variation in fearlessness about death: A latent class growth analysis. AB - According to the Interpersonal-Psychological Theory of Suicide, fearlessness about death is proposed to increase monotonically (i.e., either increasing or remaining stable) and thus, not be amenable to intervention; however, this assumption has not been explicitly tested. We utilized latent class growth modeling to examine the trajectory of this construct over a brief interval (i.e., data collected every three days over a 15-day time period) among college students (N = 716), and found evidence that fearlessness does not monotonically increase. Specifically, our analyses revealed three classes, each with distinct trajectories over time: a High/Increasing class (i.e., high intercept, significantly increasing slope), Average/Stable class (i.e., average intercept, flat and non-significant slope), and Low/Decreasing class (i.e., low intercept, significantly decreasing slope). The emergence of a Low/Decreasing group is in contrast to the assertion that fearlessness cannot decrease over time. Exploratory results also indicated that lifetime exposure to certain events (e.g., abuse, injury) was associated with membership in the Low/Decreasing class, suggesting that some individuals may be responding differently to painful and/or fear-inducing stimuli than the IPTS predicts. Our findings contradict the current conceptualization of fearlessness about death, and suggest instead that this construct fluctuates upward and downward over a brief interval. PMID- 29986179 TI - Spanish translation and analysis of the metric properties of inpatient satisfaction scale in psychiatry: The Satispsy-22-E. AB - The Satispsy-22 scale is an instrument created for the specific evaluation of psychiatric inpatient satisfaction. Therefore, the study aims to carry out the Satispsy-22 scientific translation to Spanish and to learn its psychometric properties. The Satipsy-22-E was administered to discharged patients from four units of acute psychiatric admission, a unit of dual pathology and two units of subacute psychiatric admission (N = 268). Cronbach's alpha was 0.886, which can be interpreted as good internal reliability. All the dimensions showed a good internal consistency with scores from 0.722 to 0.919. Test-retest offered scores of 0.752-0.951 showing good stability. Confirmatory factor analysis showed that all elements load in the estimated dimensions of the original scale and these were significant and the adjustment measures showed, in general, a rather good adjustment, Root Mean Square Error (RMSE) showed that the error between observations and actual data is small and acceptable. Satispsy-22-E is a specific scale in Spanish language for the assessment of psychiatric inpatient satisfaction. It is an easy to use tool that offers good psychometric properties. The availability of a validated survey in Spanish may help to improve the care provided by psychiatric wards in Spanish-speaking countries. PMID- 29986180 TI - Enhancement in anti-tubercular activity of indole based thiosemicarbazones on complexation with copper(I) and silver(I) halides: Structure elucidation, evaluation and molecular modelling. AB - A series of monomeric tetrahedral complexes of stoichiometry, [MX(HL)(Ph3P)2] (In case of M = Cu, H1L, X = I, 1; Br, 2; Cl, 3; H3L, X = I, 4; Br, 5; Cl, 6; H4L, X = I, 7; Br, 8; Cl, 9 and in case of M = Ag, H1L, X = Cl, 13; Br, 14; H2L, X = Cl, 15, Br 16; H3L, X = Cl, 17, Br, 18) were synthesized by the reaction of copper (I) or silver (I) halides with indole-3-thiosemicarbazone (H1L) or 5-methoxy indole-3-thiosemicarbazone (H2L) or 5-methoxy indole-N1-methyl-3 thiosemicarbazone (H3L), whereas dimers of stoichiometry, [Cu2(MU-X)2(eta1-S H2L)2(Ph3P)2] (X = I, 10; Br, 11; Cl, 12) were obtained by the reaction of copper (I) halides with indole-N1-methyl-3-thiosemicarbazone (HIntsc-N1-Me, H2L). The synthesized complexes were characterized using NMR (1H and 13C) and single crystal X-ray diffraction (H2L, 3, 7, 8, 10, 11 and 13) as well as elemental analysis. Anti- M. tuberculosis activity of ligands (H1L-H4L) and their metal complexes (1-18) were evaluated against M. tuberculosis H37RV strain ATCC 27294. It has been observed that there is unusual enhancement in anti TB activity of these ligands on complexation with copper (I) and silver (I). Molecular modelling studies in the active binding site are also giving complementary theoretical support for the experimental biological data acquired. PMID- 29986181 TI - Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents. AB - Tuberculosis is an infectious disease that affects millions of population every year. Mtb-DHFR is a validated target that is vital for nucleic acids biosynthesis and therefore DNA formation and cell replication. This paper report identification and synthesis of novel compounds for selective inhibition of Mtb DHFR and unleash the selective structural features necessary to inhibit the same. Virtual screening of databases was carried out to identify novel compounds on the basis of difference between the binding pockets of the two proteins. Consensus docking was performed to improve upon the results and best ten hits were selected. Hit 1 was subjected to analogues design and the analogues were docked against Mtb-DHFR. From the docking results 11 compounds were selected for synthesis and biological assay against H37Rv. Most potent compound (IND-07) was tested for selectivity using enzymatic assay against Mtb-DHFR and h-DHFR. The compounds were found to have good inhibitory activity (25-200 uM) against H37Rv and in enzyme assay against Mtb-DHFR and h-DHFR the compound was found selective towards Mtb-DHFR with selectivity index of 6.53. This work helped to identify indole moiety as novel scaffold for development of novel selective Mtb-DHFR inhibitors as antimycobacterial agents. PMID- 29986182 TI - Synthesis of spherical Fe3O4 nanoparticles from the thermal decomposition of iron (III) nano-structure complex: DFT studies and evaluation of the biological activity. AB - A novel Fe(III) Schiff base complex of the [FeL2(NO3)2]NO3 type where L = 2 ((pyridin-4-yl)methyleneamino)-3-aminomaleonitrile was synthesized using the reflux and sonochemical methods and their antibacterial and antifungal activity were evaluated. The nanoparticles of iron oxide (Fe2O3) were obtained from the iron nano-structure complex as a precursor after calcination at 600 C for 3 h. All the synthesized compounds were characterized by various spectroscopic techniques. The results of SEM showed that the morphology of iron nano-structure complex was rod-like while the morphology of the Fe2O3 nano powder was spherical. The results of the biological studies indicated that the iron nano-structure complex showed a stronger antibacterial and antifungal efficiency than its bulk complex. Finally, the empirical geometrical parameters of complexes revealed a good agreement with calculated ones at DFT-B3LYP level. PMID- 29986183 TI - Studies on the lipid-regulating mechanism of alisol-based compounds on lipoprotein lipase. AB - Studies on the lipid-regulating effects of alisol compounds are reported that include alisol B, alisol A 24-acetate (24A), alisol A and an alisol B - 24A - alisol A mixture (content ratio = 1:1:1). The effects on the activity of lipoprotein lipase (LPL), a key lipid-modulating enzyme, were studied to investigate the molecular mechanism of lipid-regulating activity of alisols. The effects of alisols on regulating blood lipids and the activities of LPL were determined using a reagent kit method. The structure of LPL was obtained by homology modeling and the interactive mechanism of alisol monomers and the mixture with LPL was investigated by molecular simulation. The alisol monomer and mixture were shown to regulate blood lipids, suggesting that alisols may decrease the level of triglyceride (TG) by improving the activity of LPL. The order of intensity was: mixture > alisol A > alisol B > 24A, indicating that alisols of alismatis rhizoma feature a synergistic effect on LPL. The N- and C-terminus of LPL both represented the catalytic active domains of this lipid-regulating effect. Cys306, Gln129 and Ser166 were the key amino acid residues resulting in the lipid-regulating effect of the alisol monomer while Ser166 and Arg18 were found to be responsible for the lipid-regulating effect of the mixture. The C terminus of LPL was indirectly involved in the enzymatic process. A folded side chain of alisols or the parent ring was found to bind somewhat weaker to LPL than an open side chain or parent ring. The hydroxyl groups on the C14-, C22-, C28-, C30- and C31-terminus in the side chain, the ring ether structure in C23 position, and the acetyl group in C29-position represented the key sites for the lipid-regulating action of alisols. Meanwhile, the C30-site hydroxyl group played an important role in the synergistic effect of the alisol mixture. PMID- 29986184 TI - 3-Aryl/Heteroaryl-5-amino-1-(3',4',5'-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization. AB - Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3',4',5' trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50 < 1 MUM) against selected cancer cells. Among them, several molecules preferentially inhibited the proliferation of leukemic cell lines, showing IC50 values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC50 value of 0.66 MUM, half that obtained in simultaneous experiments with CA-4 (IC50 = 1.3 MUM). PMID- 29986185 TI - Design, synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers. AB - In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4 d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFRWT. Compounds 15b, 15j, and 18d potently inhibited EGFRWT at sub-micro molar IC50 values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC50 values against EGFRWT were tested in vitro for their inhibitory activities against mutant EGFRT790M. Compounds 17d and 17f exhibited potent inhibitory activities towards EGFRT790M comparable to osimertinib. Compounds that showed promising IC50 values against EGFRWT were further tested for their anti proliferative activities against three cancer cell lines bearing EGFRWT (MCF-7, HepG2, A549), and two cancer cell lines bearing EGFRT790M (H1975 and HCC827). Compounds 15g, 15j, 15n, 18d and 18e were the most potent anticancer agents against the EGFRWT containing cells, while compounds 15e, 17d and 17f showed promising anti-proliferative activities against EGFRT790M containing cells. Furthermore, the most active compound 18d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G0/G1and G2/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFRWT (PDB: 4HJO) and EGFRT790M (PDB: 3W2O). PMID- 29986186 TI - Lipid reducing activity of novel cholic acid (CA) analogs: Design, synthesis and preliminary mechanism study. AB - Bile acids, initially discovered as endogenous ligands of farnesoid X receptor (FXR), play a central role in the regulation of triglyceride and cholesterol metabolism and have recently emerged as a privileged structure for interacting with nuclear receptors relevant to a large array of metabolic processes. In this paper, phenoxy containing cholic acid derivatives with excellent drug-likeness have been designed, synthesized, and assayed as agents against cholesterol accumulation in Raw264.7 macrophages. The most active compound 14b reduced total cholesterol accumulation in Raw264.7 cells up to 30.5% at non-toxic 10 MUM and dosage-dependently attenuated oxLDL-induced foam cell formation. Western blotting and qPCR results demonstrate that 14b reduced both cholesterol and lipid in Raw264.7 cells through (1) increasing the expression of cholesterol transporters ABCA1 and ABCG1, (2) accelerating ApoA1-mediated cholesterol efflux. Through a cell-based luciferase reporter assay and molecular docking analysis, LXR was identified as the potential target for 14b. Interestingly, unlike conventional LXR agonist, 14b did not increase lipogenesis gene SREBP-1c expression. Overall, these diverse properties disclosed herein highlight the potential of 14b as a promising lead for further development of multifunctional agents in the therapy of cardiovascular disease. PMID- 29986187 TI - Synthesis, in vitro and in silico evaluation of diaryl heptanones as potential 5LOX enzyme inhibitors. AB - A new series of diaryl heptanones (12a-q) were synthesized and their structures were confirmed by its 1H, 13C NMR and Mass spectral data. These analogs were evaluated for their anti-oxidant activity and potential to inhibit 5 lipoxygenase. Compounds 12k and 12o showed potent in vitro 5-lipoxygenase enzyme inhibitory activity with IC50 values of 22.2, 21.5 MUM, which are comparable to curcumin (24.4 MUM). Further they also have shown significant antioxidant activity. Molecular docking studies clearly showed correlation between binding energy and potency of these compounds. PMID- 29986188 TI - Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety. AB - A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 MUg/mL) and curative activity against potato virus Y (EC50 = 350.5 MUg/mL), which were better than those of ningnanmycin (357.7 MUg/mL and 493.7 MUg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity. PMID- 29986189 TI - Design and Amberlyst-15 mediated synthesis of novel thienyl-pyrazole carboxamides that potently inhibit Phospholipase A2 by binding to an allosteric site on the enzyme. AB - Inflammation-mediated disorders are on the rise and hence, there is an urgent need for the design and synthesis of new anti-inflammatory drugs with higher affinity and specificity for their potential targets. The current study presents an effective and new protocol for the synthesis of thienyl-pyrazoles through 3 + 2 annulations using a recyclable heterogeneous catalyst Amberlyst-15. Chalcones 3(a-g) prepared from 3-methylthiophene-2-carbaldehyde and acetophenones by Claisen-Schmidt approach reacted with semicarbazide hydrochloride 4 in the presence of Amberlyst-15 in acetonitrile at room temperature producing thienyl pyrazole carboxamides 5(a-h) in good yields. Alternatively, the compounds 5(a-h) were prepared by conventional method using acetic acid (30%) medium. Structures of synthesized new pyrazoles were confirmed by spectral and crystallographic studies. All the new compounds were evaluated for their in vitro inhibition of Phospholipase A2 from Vipera russelli and preliminary studies revealed that, amongst the designed series, compounds 5b, 5c and 5h showed promising inhibition. Further, the compounds exhibited linear mixed-type inhibition behavior for the sPLA2 enzyme indicating that they bind to an allosteric site distinct from either the calcium or substrate binding site on the enzyme. These kinetic conclusions were further validated by macromolecular rigid-body docking whereby compounds 5c and 5h showed binding to distinct pockets on the protein. These findings present a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorders. PMID- 29986191 TI - Synthesis, biological evaluation and docking study of 1,3,4-thiadiazole thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. AB - Selective inhibition of both cyclooxygenase-2 (COX-2) and 15-lipooxygenase (15 LOX) may provide good strategy for alleviation of inflammatory disorders while minimizing side effects associated with current anti-inflammatory drugs. The present study describes the synthesis, full characterization and biological evaluation of a series of thiadiazole-thiazolidinone hybrids bearing 5 alk/arylidene as dual inhibitors of these enzymes. Our design was based on merging pharmacophores that exhibit portent anti-inflammatory activities in one molecular frame. 5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-amine (3) was efficiently synthesized, chloroacetylated and cyclized to give the key 4-thiazolidinone (5). Knovenagel condensation of 5 with different aldehydes afforded the final compounds 6a-m, 7, 8 and 9. These compounds were subjected to in vitro COX-1/COX 2, 15-LOX inhibition assays. Compounds (6a, 6f, 6i, 6l, 6m and 9) with promising potency (IC50 = 70-100 nM) and selectivity index (SI = 220-55) were further tested for in vivo anti-inflammatory activity and effect on gastric mucosa. The most promising compound (6l) inhibits COX-2 enzyme at a nanomolar concentration (IC50 = 70 nM, SI = 220) with simultaneous inhibition of 15-LOX (IC50 = 11 uM). These results are comparable to the potency and selectivity of the standard drugs of both enzymes; celecoxib (COX-2 IC50 = 49 nM, SI = 308) and zileuton (15-LOX IC50 = 15 uM) in one construct. Interestingly three compounds (6a, 6l and 9) exhibited equivalent to or even higher than that of celecoxib in vivo anti inflammatory activity at 3 h interval with good GIT safety profile. Molecular docking study conferred binding sites of these compounds on COX-2 and 15-LOX. Such type of compounds would represent valuable leads for further investigation and derivatization. PMID- 29986190 TI - QM/MM study of the reaction mechanism of Cl-cis,cis-muconate with muconate lactonizing enzyme. AB - The lactonization process of Cl-cis,cis-muconate catalyzed by anti-muconate lactonizing enzyme (anti-MLE) was studied theoretically with the aid of a combined quantum mechanics/molecular mechanics (QM/MM) approach. Two elementary processes steps involved in the lactanization process were investigated. The calculated energy barriers agree well with the experimental values. The present work provided the explicit structures of the enolate anion intermediates. The electrostatic influence analysis highlighted residues Arg51, Gln294 and TIP383 for the MLE-Cl-2 system and the residue Asn193 for the MLE-Cl-4 system as the possible mutation targets for rational design of anti-MLE in future enzyme modification. PMID- 29986192 TI - Femoral nerve excursion with knee and neck movements in supine, sitting and side lying slump: An in vivo study using ultrasound imaging. AB - BACKGROUND: Neurodynamic assessment and management are advocated for femoral nerve pathology. Contrary to neurodynamic techniques for other nerves, there is limited research that quantifies femoral nerve biomechanics. OBJECTIVES: To quantify longitudinal and transverse excursion of the femoral nerve during knee and neck movements. DESIGN: Single-group, experimental study, with within participant comparisons. METHODS: High-resolution ultrasound recordings of the femoral nerve were made in the proximal thigh/groin region in 30 asymptomatic participants. Scans were made during knee flexion in supine and a semi-seated position, and during neck flexion in side-lying slump (Slump FEMORAL). Healthy participants were assessed to reveal normal nerve biomechanics, not influenced by pathology. Data were analysed with one-sample and paired t-tests. Reliability was assessed with intraclass correlation coefficients (ICC). RESULTS: Longitudinal and transverse excursion measurements were reliable (ICC>=0.87). With knee flexion, longitudinal femoral nerve excursion was significant and larger in supine than in sitting (supine (mean (SD)): 3.6 (2.0) mm; p < 0.001; sitting: 1.1 (1.6) mm; p = 0.001; comparison: p = 0.001). There was also excursion in a medial direction (supine: 1.4 (0.3) mm; p < 0.001; sitting: 0.7 (0.6) mm; p < 0.001) and anterior direction (supine: 0.2 (0.2) mm; p < 0.001; sitting: 0.1 (0.2) mm; p = 0.06). Neck flexion in Slump FEMORAL did not result in longitudinal (0.0 (0.3) mm; p = 0.55) or anteroposterior (0.0 (0.1) mm; p = 0.10) excursion, but resulted in medial excursion (1.1 (0.5) mm; p < 0.001). CONCLUSION: Although the femoral nerve terminates proximal to the knee, femoral nerve excursion in the proximal thigh occurred with knee flexion; Neck flexion in Slump FEMORAL resulted in medial excursion. PMID- 29986193 TI - Does muscle guarding play a role in range of motion loss in patients with frozen shoulder? AB - STUDY DESIGN: Observational: cross-sectional study. BACKGROUND: Idiopathic frozen shoulder is a common cause of severe and prolonged disability characterised by spontaneous onset of pain with progressive shoulder movement restriction. Although spontaneous recovery can be expected the average length of symptoms is 30 months. Chronic inflammation and various patterns of fibrosis and contracture of capsuloligamentous structures around the glenohumeral joint are considered to be responsible for the signs and symptoms associated with frozen shoulder, however, the pathoanatomy of this debilitating condition is not fully understood. OBJECTIVES: To investigate the feasibility of a muscle guarding component to movement restriction in patients with idiopathic frozen shoulder. METHODS: Passive shoulder abduction and external rotation range of motion (ROM) were measured in patients scheduled for capsular release surgery for frozen shoulder before and after the administration of general anaesthesia. RESULTS: Five patients with painful, global restriction of passive shoulder movement volunteered for this study. Passive abduction ROM increased following anaesthesia in all participants, with increases ranging from approximately 55 degrees -110 degrees of pre-anaesthetic ROM. Three of these participants also demonstrated substantial increases in passive external rotation ROM following anaesthesia ranging from approximately 15 degrees -40 degrees of pre-anaesthetic ROM. CONCLUSION: This case series of five patients with frozen shoulder demonstrates that active muscle guarding, and not capsular contracture, may be a major contributing factor to movement restriction in some patients who exhibit the classical clinical features of idiopathic frozen shoulder. These findings highlight the need to reconsider our understanding of the pathoanatomy of frozen shoulder. LEVEL OF EVIDENCE: Level 4. PMID- 29986194 TI - Defining diagnostic approaches and outcomes in patients with inflammatory CSF: A retrospective cohort study. AB - OBJECTIVE: Define the etiologies, clinical features, time to diagnosis, and outcomes of patients that present with cerebral spinal fluid (CSF) pleocytosis. PATIENTS AND METHODS: This is retrospective cohort study of patients with CSF pleocytosis, defined as WBC count >5 cells/mm3 in the CSF, from July 2015 to June 2016 at a large tertiary care hospital. The proportion of patients within specific diagnostic categories were analyzed for differences in diagnostic testing and outcomes. RESULTS: 53% of patients had CSF pleocytosis due to an unknown etiology. The leading known cause of neuroinflammation was CNS infection (n = 43/244, 18%), followed by malignancy (n = 28/244, 11%). Mean time to diagnosis was 125 days in patients with autoimmune neuroinflammation and was 16 days in patients with an infection or malignancy. CSF parameters and peripheral white blood cell counts did not distinguish between categories of disease. The presence of CSF oligoclonal bands or a positive biopsy result most commonly supported a diagnosis of an autoimmune disease or malignancy, respectively. Neuroimaging changes were present in only 44% of infections but were found in 80 90% of other categories of neuroinflammation. Patients presenting with a severe neurologic deficit had 22.29 higher odds of a severe deficit at the last neurologic assessment, and mortality was highest (29%) in patients with malignancy-associated neuroinflammation. CONCLUSIONS: This study to defines general diagnostic categories of neuroinflammatory disease in patients and provides new insight on the value of specific diagnostic testing, time to diagnosis, and outcomes in these patient populations. PMID- 29986195 TI - Loss of MycBP may be associated with the improved survival in 1P co-deletion of lower grade glioma patients. AB - OBJECTIVES: The chromosome 1p/19q co-deletion is a favorable prognostic factor in patients with low grade glioma. In the current analysis, we examined MycBP expression in low grade glioma. MycBP lies on chromosome 1p. PATIENTS AND METHODS: We evaluated the association between MycBP and overall survival in the TCGA Lower Grade Glioma (LGG) dataset in TCGA (The Cancer Genome Atlas). RESULTS: Loss of MycBP copy number segment expression coincides with co-deletion of 1 P. The deleterious effect of MycBP on survival is significant (p = 0.00006306, hazard ratio 2.02, 95% CI 1.4-2.9). Patients with astrocytoma have the poorest survival of low grade glioma patients. MycBP mRNA is significantly overexpressed in astrocytomas when compared to normal brain (2.156 fold change, p = 0.0000488). CONCLUSION: Our report that Chromosome 1 P co-deletion may confer better survival in patients with lower grade glioma in part because of loss of MycBP corroborates other studies of the importance of MycBP in glioma development. Further work with microRNAs may lead to new treatments. PMID- 29986196 TI - Epilepsy video animation: Impact on knowledge and drug adherence in pediatric epilepsy patients and caregivers. AB - OBJECTIVES: Insufficient of knowledge of epilepsy causes poor drug adherence and seizure control. Leading us to create video animation to educate epilepsy patients and caregivers and evaluate the benefit of this video. PATIENTS AND METHODS: The 8.52-min video animation was created to provide fundamental information regarding diagnosis, treatment and drug usage for pediatric epilepsy patients. The impact of this video animation was evaluated in a randomized controlled trial (RCT) study during June- September 2016. One month to 15 year old epilepsy patients and caregivers were recruited and randomized into 2 groups; group A: receiving advice from the clinician and watching the video animation, group B: only receiving advice from the clinician. A ten-item questionnaires and drug adherence (Morisky Medication Adherence Scales (MMAS-8)) were used to evaluate before/after watching video/receiving advice and at 3 month-follow up. RESULTS: Two hundreds and fourteen epilepsy patients (126 in group A and 88 in group B) were recruited in the study. Before watching video/receiving advice, the mean scores of questionnaires in group A was lower compare with the group B (group A (6.74) and group B (7.38)) but after the video intervention the score of group A significantly rose to 7.42 (immediate after watching video) and to 7.47 scores at 3 month-follow up, while in group B, no significant differences were observed. The comparison of the MMAS-8 in group A showed a significant improvement of drug adherence than the cases in group B. CONCLUSION: Video animation as a new method of education for epilepsy patients and caregivers, can improve both their knowledge and the drug adherence. PMID- 29986197 TI - Assessment of preoperative anxiety in neurosurgical patients: Comparison of widely used measures and recommendations for clinic and research. AB - OBJECTIVE: Preoperative anxiety is frequent in neurosurgical patients and of high clinical relevance (e. g., associated with anestesiological requirements and surgery outcome). Little however is known about the quality of instruments for assessment of preoperative anxiety in this specific patient group and setting. This paper therefore focused on the psychometric properties of widely used questionnaires. Aim of this study was thus to enable both the clinician and the researcher to select appropriate instruments for assessment of surgery-related anxiety. PATIENTS AND METHODS: The following instruments for assessment of preoperative anxiety were administered in a pseudo-randomized order one day prior to surgery in sample of 158 neurosurgical patients: The State Trait Operation Anxiety Inventory (STOA) - state scale, the Amsterdam Preoperative Anxiety and Information Scale (APAIS), and the one-item visual analogue scale (VAS). The questionnaires were psychometrically tested according to classical test theory (validity, reliability, diagnostic accuracy). RESULTS: Construct validity was supported in all applied measures (convergent and divergent validity, known-group comparisons). For the STOA state, we found a one factor scale structure and thus no support for the proposed subscales covering cognitive and affective anxiety. The proposed scale structure of the APAIS, measuring anxiety and information requirement, was replicated. Internal consistency as indicator for reliability of the STOA and the APAIS was excellent (Cronbach's alpha = 0.937/0.868). All instruments showed adequate diagnostic accuracy with the most favourable results of the STOA. CONCLUSIONS: All instruments included in this study can be recommended for assessment of surgery-related anxiety in neurosurgical patients with regard to their psychometric properties. Each instrument offers distinct advantages. Thus, clinicians and researchers can base their individual choice on specific aims and available resources. PMID- 29986198 TI - Clinical characteristics of AChRAb and MuSKAb double seropositive myasthenia gravis patients. AB - OBJECTIVES: To explore the characteristics of double seropositive myasthenia gravis (DSP-MG). PATIENTS AND METHODS: A literature review of twenty-four cases of DSP-MG including 2 novel cases presented in the current study, was performed. RESULTS: Among 24 reported patients, 7 were male (29.17%) and 17 were female (70.83%). Among 20 patients with known age, the mean age of onset was 37.30 +/- 19.50 years, among which the average onset age of the 6 male patients was 53.17 +/- 8.98 years, while the average onset age of the remaining 14 female patients was 30.50 +/- 18.94 years. Three patients had simple ocular muscle-type MG (14.28%), while 18 (85.71%) had non-ocular muscle-type MG. After administration of penicillide, 1 patient developed DSP-MG. In 9 cases, patients developed DSP-MG after thymectomy, while 5 patients naturally developed DSP-MG. CONCLUSION: Women more frequently developed DSP-MG than men and men were diagnosed at an older age. MG is typically found in the ocular muscles, bulbar and limb muscles. PMID- 29986199 TI - Comparative effectiveness and safety of posterior lumbar interbody fusion, Coflex, Wallis, and X-stop for lumbar degenerative diseases: A systematic review and network meta-analysis. AB - Posterior lumbar interbody fusion and lumbar interspinous non-fusion technique are common surgical procedures for lumbar degenerative diseases, but the effectiveness and safety of these two techniques are still unclear. We performed this network meta-analysis to evaluate the comparative effectiveness and safety of posterior lumbar interbody fusion and the three commonly used interspinous devices including Coflex, Wallis, and X-stop for lumbar degenerative diseases. Randomized controlled trials and cohort studies comparing among posterior lumbar interbody fusion, Coflex, Wallis, and X-stop for lumbar degenerative diseases were identified using the databases including PubMed, the Cochrane Library, Web of Science, the China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and Wanfang data. A network meta-analysis was performed using R 3.4.3 software. 27 studies with 2241 patients were included. The results of network meta-analysis revealed that no significant differences in Oswestry Disability Index, Visual Analogue Scale, Japanese Orthopedic Association Scores, and posterior disc height were found among posterior lumbar interbody fusion group, Coflex, Wallis, or X-stop. However, compared with posterior lumbar interbody fusion, the three interspinous process devices presented with significantly more range of motion in surgical segment, but no significant difference was found among these three interspinous process devices. Node splitting analysis showed no significant inconsistency in our network meta analysis. We concluded that compared with posterior lumbar interbody fusion, Coflex, Wallis and X-stop had the same effectiveness in relieving pain, improving quality of life, recovering disc space height and lumbar function, but may lower incidence of adjacent segment degeneration. PMID- 29986200 TI - Red blood cell distribution width is an independent predictor of mortality in patients with aneurysmal subarachnoid hemorrhage. AB - OBJECTIVES: This study was performed to evaluate the association between red blood cell distribution width (RDW) and 3-month mortality in patients with aneurysmal subarachnoid hemorrhage. PATIENTS AND METHODS: This observational study was performed from March 2007 to May 2017 in an emergency department. The baseline characteristics and clinical and laboratory data were collected prospectively and analyzed. Clinical outcomes included 3-month mortality and poor functional outcome referred to as modified Rankin scale 3-6. RESULTS: A total 364 patients were included, and the overall 3-month mortality was 8.5%. The median RDW increased with disease severity classified according to the Hunt and Hess scale. RDW was significantly higher in patients with poor functional outcome than in patients with good functional outcome. The optimal RDW cutoff for predicting 3 month mortality was 13.9%. Cox regression analysis showed that higher RDW was independently associated with 3-month mortality (hazard ration 17.187, 95% CI 4.474-66.022). The area under the receiver-operating curve for RDW was 0.917 (95% CI 0.883-0.943). CONCLUSION: An elevated RDW is associated with poor functional outcome and 3-month mortality in patients with aneurysmal subarachnoid hemorrhage. PMID- 29986201 TI - Solitary subdural osteoma: A case report and literature review. AB - BACKGROUND: Subdural osteomas are benign neoplasms that are rarely encountered. We report the case of a 64-year-old female patient with a left temporal subdural osteoma. CASE DESCRIPTION: The patient presented with intermittent dizziness that first began two years earlier. Non-contrast computed tomography revealed a densely calcified left temporal extra-axial mass. Magnetic resonance imaging of the lesion revealed signal loss on T1-weighted and T2-weighted images and non enhancement on Gadolinium enhanced T1-weighted images, and diffusion-weighted and ADC images demonstrated reduced values attributed to calcium-induced signal loss. Histologically, the lesion predominantly consisted of lamellar bone without bone marrow elements. The patient underwent stereotactic magnetic resonance imaging guided neurosurgical resection and recovered without complication. CONCLUSIONS: Subdural osteomas may not be enhanced on magnetic resonance imaging. Surgical tumourectomy can be considered for symptomatic patients with subdural osteomas. PMID- 29986202 TI - Anti-neutral glycolipids antibody-positive combined central and peripheral demyelination mimicking encephalomyeloradiculoneuropathy phenotype. AB - We herein report the first combined central and peripheral demyelination (CCPD) case originally diagnosed as multifocal acquired demyelinating sensory and motor neuropathy followed by CNS impairments with a long lag time (160 days after first attack). The anti-neutral glycolipids antibodies, especially anti lactosylceramide antibodies but not anti-NF155 antibodies typical for CCPD were detected in the acute phase of sera and cerebrospinal fluid (CSF) and disappeared in the recovery phase. This case strongly illustrated the significance of examining anti-neutral glycolipids antibodies in future anti-NF 155 antibodies negative CCPD cases. PMID- 29986203 TI - Voriconazole as mono-therapy in orbitofrontal erosive aspergillosis without gross total resection: A case report and review of literature. AB - In this case report we present an immunocompetent 64-year-old patient presenting with an orbitofrontal invasive aspergillosis treated successfully with voriconazole monotherapy following biopsy and orbital decompression. PMID- 29986204 TI - Functional magnetic resonance imaging under anaesthesia of a patient with severe chronic disorders of consciousness. AB - CLINICAL CASE: We report on a 19-year old male patient who is recovering from near-drowning. The patient was admitted for re-evaluation in a Minimally Conscious State. METHOD: A regular functional Magnetic Resonance Imaging was not possible due to complex motor tics of the patient with sudden flexion and extension movements of arms and legs as well as opisthotonic retroflexion of the head and trunk. Thus, the patient was anaesthetised and functional Magnetic Resonance Imaging was performed under general anaesthesia which was introduced and maintained with Sevoflorane and Fentanyl provided analgesia. Four functional runs were performed and the patient's responses were recorded. During each one of these runs one extremity (dorsum manus or pedis) was stimulated with a brush with an operator-paced frequency of about 2 Hz. RESULTS AND CONCLUSION: Clear responses were found in the somatosensory cortex contra lateral within the post central gyrus during stimulation of the left hand. Considering the other three extremities no significant responses were found. Nevertheless, we conclude that a functional Magnetic Resonance Imaging under anaesthesia is possible for patients with severe chronic disorders of consciousness and brain areas responding to stimuli can be detected. PMID- 29986205 TI - Tentorial alignment and its relationship to cisternal dimensions of the pineal region: MRI anatomical study with surgical implications using the new clivotentorial method. AB - OBJECTIVES: Tentorial alignment and dimensions of posterior fossa cisterns are measurements whose variability can decrease surgical freedom if not taken into account when choosing the approach to the pineal region. The aim is to provide quantitative anatomical information regarding these dimensions, and to discuss their relevance in two most commonly used approaches to this region: the occipital transtentorial and supracerebellar-infratentorial approach. PATIENTS AND METHODS: A retrospective study of midsagittal T1-weighted MRI images of 410 randomly selected healthy subjects was performed. The clivus-tentorium (C-T) angle was measured to assess tentorial alignment. The following distances were used as craniocaudal cisternal measurements: quadrigeminal cistern = superior colliculi - inferior part of the splenium of corpus callosum (SC-ISCC), and superior cerebellar cistern = vermis - inferior part of the splenium of corpus callosum (VER-ISCC). RESULTS: Median C-T angle value was 19 +/- 7 degrees , the quadrigeminal cistern height 6.7 +/- 1.6 cm, and the superior cerebellar cistern height 10.4 +/- 2.6 cm. The C-T angle was negatively correlated with the SC-ISCC distance (r = -0.271; p < 0.001) and the VER-ISCC distance (r = -0.052, p > 0.001). The SC-ISCC distance was positively correlated with the VER-ISCC distance (r = 0.282; p < 0.001). CONCLUSION: Our new method of measuring tentorial alignment provides a simple and effective aid in preoperative planning. For the first time, we present data on craniocaudal dimensions of posterior fossa cisterns, their relationship with tentorial alignment, and discuss their relevance in SCIT and OT approaches. PMID- 29986206 TI - Auditory temporal processing, reading, and phonological awareness among aging adults. AB - Auditory temporal processing (ATP) has been related in the literature to both speech perception as well as reading and phonological awareness. In aging adults, it is known to be related to difficulties in speech perception. In the present study, we aimed to test whether an age-related deficit in ATP would also be accompanied by poor reading and phonological awareness. Thirty-eight aging adults were compared to 55 readers with dyslexia and 42 young normal readers on temporal order judgment (TOJ), speech perception, reading, and phonological awareness tests. Aging adults had longer TOJ thresholds than young normal readers, but shorter than readers with dyslexia; however, they had lower speech perception accuracy than both groups. Phonological awareness of the aging adults was better than readers with dyslexia, but poorer than young normal readers, although their reading accuracy was similar to that of the young controls. This is the first report on poor phonological awareness among aging adults. Suprisingly, it was not accompanied by difficulties in reading ability, and might instead be related to aging adults' difficulties in speech perception. This newly discovered relationship between ATP and phonological awareness among aging adults appears to extend the existing understanding of this relationship, and suggests it should be explored in other groups with ATP deficits. PMID- 29986207 TI - Functional fixedness in tool use: Learning modality, limitations and individual differences. AB - Functional fixedness is a cognitive bias that describes how previous knowledge of a tool's function can negatively impact the use of this tool in novel contexts. As such, functional fixedness disturbs the use of tools during mechanical problem solving. Little is known about whether this bias emerges from different experiences with tools, whether it occurs regardless of problem difficulty, or whether there are protective factors against it. To resolve the first issue, we created five experimental groups: Reading (R), Video (V), Manual (M), No Functional Fixedness (NFF), and No Training (NT). The R group learned to use tools by reading a description of their use, the V group by watching an instructional video, and the M group through direct instruction and active manipulation of the tools. To resolve the remaining two issues, we created mechanical puzzles of distinct difficulty and used tests of intuitive physics, fine motor skills, and creativity. Results showed that misleading functional knowledge is at the core of functional fixedness, and that this bias generates cognitive impasses in simple puzzles, but it does not play a role in higher difficulty problems. Additionally, intuitive physics and motor skills were protective factors against its emergence, but creativity did not influence it. Although functional fixedness leads to inaccurate problem solving, our results suggest that its effects are more limited than previously assumed. PMID- 29986208 TI - Attentional competition across saccadic eye movements. AB - Human behavior is guided by visual object recognition. For being recognized, objects compete for limited attentional processing resources. The more objects compete, the lower is performance in recognizing each individual object. Here, we ask whether this competition is confined to eye fixations, periods of relatively stable gaze, or whether it extends from one fixation to the next, across saccadic eye movements. Participants made saccades to a peripheral saccade target. After the saccade, a letter was briefly presented within the saccade target and terminated by a mask. Object recognition of the letter was assessed as participants' report. Critically, either no, two, or four additional non-target objects appeared before the saccade. In Experiment 1, presaccadic non-targets were task-irrelevant and had no effects on postsaccadic object recognition. In Experiment 2, presaccadic non-targets were task-relevant and, here, postsaccadic object recognition deteriorated with increasing number of presaccadic non targets. As suggested by Experiment 3 and a mathematical model, this effect was due to a slowing down but also a delayed start of visual processing after the saccade. Together, our findings show that objects compete for recognition across saccades, but only if they are task-relevant. This reveals an attentional mechanism of task-driven object recognition that is interlaced with active saccade-mediated vision. PMID- 29986210 TI - ROS-mediated lysosomal membrane permeabilization is involved in bupivacaine induced death of rabbit intervertebral disc cells. AB - Bupivacaine is frequently administered for diagnosing and controlling spine related pain in interventional spine procedures. However, the potential cytotoxic effects of bupivacaine on intervertebral disc (IVD) cells and the underlying molecular mechanisms have not yet been fully established. Here, we showed that bupivacaine decreased the viability of rabbit IVD cells in a dose- and time dependent manner. Moreover, the short-term cytotoxicity of bupivacaine in IVD cells was primarily due to cell necrosis, as assessed by Annexin V-propidium iodide staining and live/dead cell staining. Necrosis was verified by observations of swollen organelles, plasma membrane rupture, and cellular lysis under transmission electronic microscopy. Interestingly, our data indicated that bupivacaine-induced primary necrosis might involve the necroptosis pathway. The key finding of this study was that bupivacaine was able to induce lysosomal membrane permeabilization (LMP) with the release of cathepsins into the cytosol, as evidenced by LysoTracker Red staining, acridine orange staining, and cathepsin D immunofluorescence staining. Consistently, inhibitors of lysosomal cathepsins, CA074-Me and pepstatin A, significantly reduced bupivacaine-induced cell death. Finally, we found that bupivacaine resulted in an increase in intracellular reactive oxygen species (ROS) and that inhibition of ROS by N-acetyl-L-cysteine effectively blocked bupivacaine-induced LMP and cell death. In summary, the results of this in vitro study reveal a novel mechanism underlying bupivacaine induced cell death involving ROS-mediated LMP. Our findings establish a basis for the further investigation of bupivacaine cytotoxicity in an in vivo system. PMID- 29986209 TI - Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. AB - Chronic inflammation involving both innate and adaptive immune cells is implicated in the pathogenesis of asthma. Intercellular communication is essential for driving and resolving inflammatory responses in asthma. Emerging studies suggest that extracellular vesicles (EVs) including exosomes facilitate this process. In this report, we have used a range of approaches to show that EVs contain markers of mitochondria derived from donor cells which are capable of sustaining a membrane potential. Further, we propose that these participate in intercellular communication within the airways of human subjects with asthma. Bronchoalveolar lavage fluid of both healthy volunteers and asthmatics contain EVs with encapsulated mitochondria; however, the % HLA-DR+ EVs containing mitochondria and the levels of mitochondrial DNA within EVs were significantly higher in asthmatics. Furthermore, mitochondria are present in exosomes derived from the pro-inflammatory HLA-DR+ subsets of airway myeloid-derived regulatory cells (MDRCs), which are known regulators of T cell responses in asthma. Exosomes tagged with MitoTracker Green, or derived from MDRCs transduced with CellLight Mitochondrial GFP were found in recipient peripheral T cells using a co-culture system, supporting direct exosome-mediated cell-cell transfer. Importantly, exosomally transferred mitochondria co-localize with the mitochondrial network and generate reactive oxygen species within recipient T cells. These findings support a potential novel mechanism of cell-cell communication involving exosomal transfer of mitochondria and the bioenergetic and/or redox regulation of target cells. PMID- 29986211 TI - MicroRNAs mediate the senescence-associated decline of NRF2 in endothelial cells. AB - Oxidative stress predisposes to several aging-associated diseases, such as cardiovascular diseases and cancer. In aging, increase in the production of reactive oxygen species is typically accompanied with a decline in adaptive stress responses to oxidative stress. The decline is primarily due to a decrease in antioxidant production. Nuclear factor E2-Related Factor 2 (NRF2) is a key transcription factor regulating oxidative and electrophilic stress responses, but it has also been shown to play a role in the regulation of cell metabolism. NRF2 expression declines in aging, but the mechanisms remain unclear. In this study, we show that microRNAs (miRNAs) that are abundant in old endothelial cells decrease NRF2 expression by direct targeting of NRF2 mRNA. The effect is reversed by miRNA inhibition. The senescence-associated downregulation of NRF2 decreases endothelial glycolytic activity and stress tolerance both of which are restored after reinstating NRF2. Manipulation of the senescence-associated miRNA levels affects the glycolytic activity and stress tolerance consistently with the NRF2 results. We conclude that senescence-associated miRNAs are involved in the decline of NRF2 expression, thus contributing to the repression of adaptive responses during cell senescence. PMID- 29986214 TI - Gene flow prevents mitonuclear co-adaptation: A comparative portrait of sympatric wild types and cybrids in the fish Chrosomus eos. AB - Allospecific mtDNA can occasionally be beneficial for the fitness of populations. It is, however, difficult to assess the effect of mtDNA in natural conditions due to genetic and/or environmental interactions. In the fish Chrosomus eos, the transfer of C. neogaeus mitochondria occurs in a single generation and results in natural cybrids. For a few lakes in Quebec, C. eos can harbor either a C. eos mtDNA (wild types) or a C. neogaeus mtDNA (cybrids). Moreover, mtDNA of cybrids originated either from Mississippian or Atlantic glacial refuges. Such diversity provides a useful system for in situ assessment of allospecific mtDNA effects. We determined genetic, epigenetic and transcriptomic variation as well as mitochondrial enzymatic activity (complex IV) changes among wild types and cybrids either in sympatry or allopatry. Wild types and cybrids did not segregate spatially within a lake. Moreover, no significant genetic differentiation was detected among wild types and cybrids indicating sustained gene flow. Mitochondrial complex IV activity was higher for cybrids in both sympatry and allopatry while no difference was detected among cybrid haplotypes. Epigenetic and transcriptomic analyses revealed only subtle differences between sympatric wild types and cybrids compared to differences between sites. Altogether, these results indicate a limited influence of allospecific mtDNA in nuclear gene expression when controlling for genetic and environmental effects. The absence of a reproductive barrier between wild types and cybrids results in random association of either C. eos or C. neogaeus mtDNA with C. eos nDNA at each generation, and prevents mitonuclear co-adaptation in sympatry. PMID- 29986212 TI - Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis. AB - Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity. Enoxacin treatment down-regulated miR-34-5p and did not further extend lifespan of long lived mir-34 mutants. Moreover, N-acetyl-cysteine abrogated mir-34(gk437)-induced longevity. Evidence also points to double-stranded RNA-specific adenosine deaminases (ADARs) as new targets of enoxacin since ADAR loss-of-function abrogates enoxacin-induced lifespan extension. Thus, enoxacin increases lifespan by reducing miR-34-5p levels, interfering with the redox balance and promoting healthspan. PMID- 29986213 TI - Structure-kinetic relationships that control the residence time of drug-target complexes: insights from molecular structure and dynamics. AB - Time-dependent target occupancy is a function of both the thermodynamics and kinetics of drug-target interactions. However, while the optimization of thermodynamic affinity through approaches such as structure-based drug design is now relatively straight forward, less is understood about the molecular interactions that control the kinetics of drug complex formation and breakdown since this depends on both the ground and transition state energies on the binding reaction coordinate. In this opinion we highlight several recent examples that shed light on current approaches that are elucidating the factors that control the life-time of the drug-target complex. PMID- 29986215 TI - Modeling and optimizing Acid Orange 142 degradation in aqueous solution by non thermal plasma. AB - The effects of the high voltage electrode material, initial pH of the solution, initial concentration of Fe2+, and time of plasma treatment on the efficiency of Acid Orange 142 (AO142) degradation were studied and evaluated. Furthermore, based on the Box-Behnken response surface methodology (BBD-RSM), a model between response (decolorization efficiency %) and influencing factors was proposed to estimate the interactive effects and optimize the process conditions. The proposed model was adequate with an R2 of 0.8005 which is in reasonable agreement with the R2adj of 0.9307. According to the model, the optimum conditions were steel as a high voltage electrode, an initial pH 3.0, an initial Fe2+ concentration 0.9 mM, and 20 min time of treatment to obtain a decolorization efficiency of 95.05%. In addition, the analytical results of UV-Vis, FT-IR, TOC and GC-MS indicated the degradation of the dye molecule. PMID- 29986216 TI - Herbicides diuron and fluazifop-p-butyl affect avoidance response and multixenobiotic resistance activity in earthworm Eisenia andrei. AB - The usage of pesticides has been steadily increasing over the last decades, and among them herbicides are the most commonly used ones. Despite their main mode of action targeting plant organisms, they can also have adverse effects on non target animal organisms. In soil ecosystems, earthworms play an important role due to their positive impacts on the soil functioning and they represent good model organisms in soil ecotoxicology. The aim of the present study was to assess the effects of two herbicides on several endpoints at different levels of biological organization in the earthworm Eisenia andrei. Diuron and fluazifop-p butyl were selected for the investigation and their lethal concentrations were determined: LC50 48 h: 89.087 MUg/cm2 for diuron and 6.167 MUg/cm2 for fluazifop p-butyl. Furthermore, measurements of enzymatic biomarkers (catalase (CAT), acetylcholinesterase (AChE), carboxylesterase (CES) and glutathione S-transferase (GST)), multixenobiotic resistance (MXR) activity and gene expression of antioxidative enzymes (only for fluazifop-p-butyl) were conducted. Enzymatic biomarker responses showed no significant differences compared to the control after the exposure to the investigated herbicides, whereas the MXR activity was significantly inhibited. The gene expression level of superoxide dismutase (sod) and glutathione S-transferase (gst) after fluazifop-p-butyl exposure showed a significant increase. Finally, avoidance behavior in soil was assessed and it was determined that both herbicides caused significant avoidance response. The obtained results show that both investigated herbicides significantly affect earthworms on different levels of biological organization. This emphasizes the importance of comprehensive ecotoxicological assessment of herbicide effects on non-target organisms at all organizational levels. PMID- 29986217 TI - Enhanced heterogeneous activation of peroxydisulfate by S, N co-doped graphene via controlling S, N functionalization for the catalytic decolorization of dyes in water. AB - 3D porous sulfur and nitrogen co-doped graphene aerogel has been fabricated by a facile one-pot process. Both experimental and theoretical studies have demonstrated that sulfur and nitrogen co-doping could synergistically enhance the catalytic performance for activating peroxydisulfate (PDS) compared to the original and N doped graphene aerogels. The ratio of sulfur/nitrogen in the aerogel can be controlled by regulating the additions of thiourea and urea sources, and the aerogel with the S/N ratio of about 1:2.5 shows a better catalytic effect due to more significant changes in the electrostatic potential and the surface charge distribution, as revealed by the theoretical simulations. The radical quenching tests indicated that both SO4.- and .OH radicals could be formed in the SN-rGO aerogel + PDS system and contribute most to RhB degradation. PMID- 29986218 TI - Behavior responses of zebrafish (Danio rerio) to aquatic environmental stresses in the characteristic of circadian rhythms. AB - As behavior shows a distinct circadian rhythm, it is hypothesized that circadian rhythms based on zebrafish (Danio rerio) behavior responses could be affected by contaminants in this study, and then the behavior strength of zebrafish exposed to 0.005 mg/L Cadmium chloride (CdCl2), 0.01 mg/L Dibasic Sodium Phosphate (Na2HPO4), 0.002 mg/L deltamethrin, and 0.003 mg/L atrazine for 6 days is used to illustrate the possibility of behavior circadian rhythms as an indicator in the environmental stress assessment. Statistical analysis with p < 0.01 shows that a clear difference between average values of BS during dark period (AVD) and those during light period (AVL) could be observed, and 24 h circadian rhythms do exist in zebrafish behavior responses. Both BS values and circadian rhythms of zebrafish can be affected in the aspect of periodicity with clear time delay, which were 1 h delay in CdCl2, 4 h delay in Na2HPO4, 4 h delay in deltamethrin, and 1 h delay in atrazine. Behavior circadian rhythms were disturbed according to the repetitive cycles after autocorrelation analysis, and the toxic effects of different chemicals could be reflected by the profiles of the Self-Organizing Map (SOM), which indicated the circadian rhythm disorder in different degrees. These results deduced from the statistical analysis, autocorrelation and SOM strongly supported that circadian rhythms based on zebrafish BS could be used as an indicator in the environmental stress assessment. PMID- 29986219 TI - Chronic exposure to diclofenac induces delayed mandibular defects in medaka (Oryzias latipes) in a sex-dependent manner. AB - Diclofenac is widely distributed in freshwater environments. To support a robust aquatic risk assessment, medaka (Oryzias latipes) were exposed to diclofenac at sublethal concentrations of 0.608, 2.15, 7.29, 26.5, and 94.8 MUg/L (as mean measured concentrations) from fertilized eggs to 90-day posthatch. Except for the induction of mandibular defects, no deleterious effects were observed on hatching success and time to hatching at the embryonic stage, or on posthatch mortality, growth in hatched larvae and juveniles, and no abnormal behavior was observed. After 40-day posthatch, mandibular defects in the fish were observed at a concentration of 7.29 MUg/L and above. Cumulatively, a morphological examination showed that 4% of the fish in the 7.29 MUg/L treatment, 20% in the 26.5 MUg/L treatment, and 38% in the 94.8 MUg/L treatment exhibited mandibular defects, and the sex ratio of fish with mandibular defects was skewed toward males. These results suggest that diclofenac affects bone remodeling in the lower jaw of medaka after puberty in a sex-dependent manner. The lowest observed-effect concentration and no observed-effect concentration of diclofenac for mandibular dysmorphism through the partial life cycle exposure of the medaka were 26.5 and 7.29 MUg/L, respectively. PMID- 29986220 TI - Combining partial nitrification and post endogenous denitrification in an EBPR system for deep-level nutrient removal from low carbon/nitrogen (C/N) domestic wastewater. AB - In this study, partial nitrification and post endogenous denitrification (PED) were combined with enhancing bacterial phosphorus removal (EBPR) in an anaerobic/aerobic/anoxic operated sequencing batch reactor (SBR) for deep-level nutrient removal from low carbon/nitrogen (C/N, chemical oxygen demand (COD)/total nitrogen (TN)) domestic wastewater. At anaerobic stage, abundant organic matters (96.6% of COD consumption) in raw wastewater were stored as poly hydroxyalkanoates (PHAs) by phosphorus and glycogen accumulating organisms with enhanced activities, which provided sufficient intracellular carbons for subsequent aerobic phosphorus uptake and anoxic PED. By controlling suitable aeration rate and duration, high nitrite accumulation rate (97.2%) was obtained at aerobic stage, which saved intracellular carbons consumption of PED. Moreover, the subsequent utilization of glycogen after PHAs via PED ensured the deep-level TN removal (94.9%) without external carbon addition. After 160-day operation, the average effluent PO43--P and TN concentrations were 0.4 and 3.0 mg/L, respectively, at C/N of 3.1. PMID- 29986221 TI - Stabilized landfill leachate treatment using heterogeneous Fenton and electro Fenton processes. AB - In the present study, stabilized landfill leachate treatment by heterogeneous Fenton and electro-Fenton (EF) was carried out. Iron-manganese binary oxide loaded zeolite (IMZ) was used as a catalyst for generating hydroxyl radicals in the acidic medium. Heterogeneous Fenton process was capable of removing 88.6% COD from landfill leachate at the optimal conditions, while 87.5% COD removal was observed at optimal EF treatment conditions. Biodegradability of landfill leachate was increased significantly from 0.03 to 0.52 after Fenton treatment. The prepared heterogeneous catalyst was found reusable with a reduction in COD removal rate. Even though, both the processes are efficient for leachate treatment, the low catalyst dosage requirement in case of EF process justifies that it is more feasible than Fenton process. PMID- 29986222 TI - Treatment of industrial wastewater produced by desulfurization process in a coal fired power plant via FO-MD hybrid process. AB - In this study, the feasibility of forward osmosis (FO) hybridized with membrane distillation (MD) was systematically investigated for treating flue gas desulfurization (FGD) wastewater. FO experiments were conducted using raw FGD wastewater obtained from a coal-fired power plant in Korea. Severe membrane fouling in FO was observed since FGD wastewater contained various components (i.e., particles, colloids, organics, and ions). The combined fouling layer by particulates and scales was identified via scanning electron microscope (SEM), energy dispersive X-ray (EDX) and X-ray diffraction (XRD). Therefore, fouling control strategies were suggested and evaluated. Microfiltration (MF) pre treatment was effective in removing particulates and mitigating the initial fouling. Antiscalant-blended draw solution (DS) could inhibit the formation of membrane scaling. With such fouling control schemes, FO achieved the highest recovery rate compared to other desalting processes (i.e., RO and MD), suggesting that FO is suitable for treating wastewater with high fouling potential and high TDS. Finally, the diluted DS was recovered by MD. MD could re-concentrate the diluted DS up to 50% recovery rate with no significant flux decline. Rapid flux decline was then observed due to membrane scaling. Thus, appropriate antiscalants in DS should be considered to inhibit scaling formation in FO and MD simultaneously. PMID- 29986223 TI - CORAL: Predictive models for cytotoxicity of functionalized nanozeolites based on quasi-SMILES. AB - Unlike the well-known simplified molecular input-line entry system (SMILES), the so-called quasi-SMILES contains information related to physicochemical and biochemical conditions by a special additional symbols (codes), each standing for different conditions (time exposure, concentration, type of cell, etc.). Thus, quasi-SMILES can be used to build up models for cytotoxicity of functionalized nanozeolites using a mathematical function of eclectic information. These calculations were done with the Monte Carlo CORAL software. The statistical quality of models based on quasi-SMILES was usually considerably better than the statistical quality of models based on traditional SMILES. PMID- 29986224 TI - Stability of organochlorine pesticides during storage in water and loaded SPE disks containing sediment. AB - With regard to the Water Framework Directive (WFD) and the required investigation of the whole water sample including suspended particulate matter (SPM), a storage stability study was conducted to determine the suitable storage time and conditions of 21 organochlorine pesticides (OCPs) spiked in water samples and pre concentrated on solid-phase extraction disks (SPE disks). Furthermore, this work demonstrates the behaviour of three different certified sediment reference materials (CRMs) contaminated with OCPs in water samples as well as loaded on SPE disks under different temperature conditions and storage time periods. Extracts collected on SPE disks were stored for 3, 14 and 30 days at both 4 degrees C and -18 degrees C in darkness covered in (a) freezer bags and (b) aluminum foil. With few exceptions the results of these tests demonstrate stability of OCPs up to 30 days at -18 degrees C. The recoveries for most substances range between 84% and 133%. Furthermore, the stability of OCPs in water samples additionally spiked with CRM up to 500 mg and stored at a temperature of 4 degrees C in darkness up to 56 days was investigated. The addition of sodium azide enhanced the stability of some substances during storage, especially the endosulfans (I, II) but most substances were stable regardless of sodium azide addition over the entire storage period. An important conclusion of this study is that the storage of loaded SPE disks is an appropriate alternative to storing water samples. PMID- 29986225 TI - A contribution of nanoscale particles of road-deposited sediments to the pollution of urban runoff by heavy metals. AB - Road-deposited sediments (RDS) present a sink for traffic-related pollutants including heavy metals (HMs). HMs associated with RDS particles enter the urban aquatic environment during rainfall events and have adverse effects for biota. RDS nanoscale particles (NSPs) require special consideration due to their specific properties, extremely high mobility in the environment, and ability to penetrate into living organisms. In the present work, the contribution of NSPs of RDS to the pollution of urban runoff by HMs has been evaluated for the first time. It has been shown that bulk RDS samples are polluted by HMs as compared to background urban soils (geo-accumulation indexes of Cu and Zn may attain 2-3). Meanwhile, NSPs of RDS are enriched by HMs as compared to bulk samples; concentration factor for Ni, Cu, Zn, Cd, Sn, and Pb in NSPs being varied from 2 to 10. The water-soluble fractions of RDS samples were also analyzed. Results have shown that the content of water-soluble HMs in RDS is insignificant and rarely exceeds 0.5% of the total contents of HMs in the bulk samples; the highest contents are identified for Cu and Pb. It should be noted that the water-soluble fraction is nearly free from Zn and this element is almost entirely present as particulate matter (NSPs). In general, the overall contribution of NSPs and water soluble fraction of HMs to the pollution of urban runoff is comparable. PMID- 29986226 TI - Oxidative stress-induced skeletal muscle injury involves in NF-kappaB/p53 activated immunosuppression and apoptosis response in copper (II) or/and arsenite exposed chicken. AB - The adverse effects of environmental toxicants such as copper and arsenic occur due to the generation of reactive oxygen species. Recent study also reported that both copper (Cu) and arsenic (As) may alter muscle regeneration. In order to assess the toxic effects of copper and arsenic on chicken skeletal muscle, chickens were subjected by different toxicologically relevant concentrations of copper or arsenic and their combination in diets for 12 weeks. Upon comparative analysis, a significantly higher malondialdehyde (MDA) and hydroxy radical content were observed in Cu or/and As exposed chicken skeletal muscle, which confirmed the strong lipid peroxidation nature of these two heavy metals. In addition, the depleted activity of catalase and glutathione peroxidase suggested the strong association of copper and arsenic with oxidative stress. Moreover, the higher elevation of pro-inflammatory mediators (NF-kappaB et al.) and Th1 bias immune system, suggested that exposure to Cu or/and As induces inflammation via NF-kappaB mediated response pathway. These results further coincided with inflammatory infiltration and nuclear condensation. Further, the execution of apoptosis machinery were characterized by a considerably elevated pro-apoptotic response and apoptotic index. In conclusion, the increased p53 levels detected in Cu or/and As treated chickens suggest the possibility that the NF-kB/p53 axis might lead to the impairment of immune-apoptosis cross talk in the present model. PMID- 29986227 TI - Impact of Lebanese practices in industry, agriculture and urbanization on soil toxicity. Evaluation of the Polycyclic Aromatic Hydrocarbons (PAHs) levels in soil. AB - This study was carried out in order to investigate the toxicity on Lebanese soil and to show the impact of the anthropogenic activities, industrialization and urbanization, on the release of Polycyclic Aromatic Hydrocarbons (PAHs) in Lebanese soils. Hundred soil samples of different land use were screened for 17 PAHs using a UAE/GC-MS method. Detection frequency varied between 76 and 100% for most of the PAHs, where the SigmaPAHs ranged from 33.5 to 4062.9 ng g-1. Moreover, BaPeq values varied between 0.93 and 332.4 ng g-1. BaPeq values in industrial and urban soils were 777 and 256 times higher than those in rural soil, respectively. None of the soil samples showed concentrations above the safe BaPeq value of 600 ng g-1. Significant decrease in concentration levels of SigmaPAHs was obtained in the following order: Industrial, urban, traffic and agricultural. Furthermore, the relative high contribution of Chrysene, Benzo(a)Anthracene and Benzo(k)Fluoranthene in agricultural soils indicates that open burning remains an adopted way in Lebanon for disposal of agricultural residues, while the predominance of Benzo(ghi)Perylene and Benzo(b)Fluoranthene in industrial soils suggests the broad use of diesel powered engines in the Lebanese industrial sector. The ratios of Low Molecular Weight/High Molecular Weight and fluoranthene/fluoranthene+pyrene (Fln/Fln+Pyr) showed that PAHs in soil samples are mainly pyrogenic and created during combustion of petrol, coal, wood and other biomasses. PMID- 29986229 TI - Prediction of biogeographical ancestry in admixed individuals. AB - Estimation of ancestral affiliation for human genotypes is now possible for major geographic populations and has been employed for forensic casework. Prediction algorithms, such as the Snipper Bayesian classifier, have the ability to classify non-admixed BGA in African (AFR), European (EUR), East Asian (EAS), and most Amerindian (NAM) individuals, but are not always appropriate for admixed individuals. Artificial admixture was simulated for all possible admixture ratios (1:1, 3:1, 2:1:1, and 1:1:1:1) from four grandparents. The simulated genotypes were used to test the accuracy of various prediction algorithms, most successful of which were the population genetics program, STRUCTURE, and a novel genetic distance algorithm (GDA). STRUCTURE was ideal for admixed individuals with 1:1 and 3:1 ratios from AFR, EUR, EAS, and NAM reference populations. Individuals with 1:1:1:1 BGA proportions were more accurately predicted by GDA. The use of hypothetical root genotypes improved the accuracy of GDA predictions for 1:1 and 3:1 admixtures and STRUCTURE classification of 1:1:1:1 admixture. The GDA requires only allele or genotype frequency values from each reference population, which offers a simpler sampling and input formatting procedure than is required by STRUCTURE. It can also be implemented in a spreadsheet without the need for long run times. PMID- 29986228 TI - Effects of triclocarban on oxidative stress and innate immune response in zebrafish embryos. AB - Triclocarban (TCC) is used in many household and personal hygiene products. TCC has been widely detected in wastewater around the world. The present study reveals that TCC can activate oxidative stress, induce total antioxidant capacity expression and lipid peroxidation, and increase the activities of superoxide dismutase and other antioxidant enzymes to resist oxidative damage. A significant induction of concentrations of proinflammatory mediator and nitric oxide (NO), accompanied by an upregulated expression of inducible NO synthase gene, was detected in zebrafish embryos exposed to TCC. The transcription of immune response-related genes, including tnf-alpha, il-1beta, il-4, il-8, and cxcl-clc, was significantly upregulated on exposure to TCC. Furthermore, we found that the exposure of zebrafish embryos to TCC decreased immune cell recruiting in the head. Expressions of nf-kappab, trif, myd88, irak4, and traf6 were altered on exposure to TCC. These results demonstrated that exposure to TCC at environmental concentrations significantly affects the expression of immune-response-related genes in zebrafish embryos following oxidative stress and the release of proinflammatory mediators through Toll-like receptor signaling pathway. Thus, we assumed that the ecological risk of TCC on aquatic organisms could not be ignored. PMID- 29986230 TI - Introducing novel type of human DNA markers for forensic tissue identification: DNA copy number variation allows the detection of blood and semen. AB - Establishing the cellular or tissue-type origin of human biological traces found at crimes scenes is forensically relevant, as it allows evaluating the crime relevance of such traces and enables reconstructing the sequence of crime events. Messenger RNA and micro RNA markers are useful for forensic tissue identification, but provide challenges for linking RNA-identified cell/tissue types with DNA-identified trace donors, especially in mixed traces. DNA methylation markers overcome this problem, but provide technical challenges due to the DNA treatment required by most analysis methods. Here we introduce a novel type of DNA markers for forensic tissue identification analysed without prior DNA treatment, namely copy number variation (CNV). Using genome-wide CNV screening followed-up by targeted qPCR confirmation, and using qPCR analysis of additional CNV-like candidate DNA markers, in samples of several individuals from all commonly encountered forensically-relevant tissue types, we identified DNA markers specific for blood and semen, respectively. Preliminary forensic validation testing demonstrates that the developed qPCR assays are highly sensitive - delivering positive results down to picogram level of input DNA, specific, and can cope well with degraded DNA, providing suitable prerequisites for forensic applications. Moreover, we exemplified that using the CNV qPCR products as input material for subsequent forensic STR analysis delivered full STR profiles, opening-up new avenues of using the same DNA aliquot for both forensic purposes, tissue and individual identification. Provided additional forensic validation studies, we envision the application of these novel DNA markers for forensic tissue identification in future forensic casework. Such CNV markers are particularly useful for tissue identification in old/cold cases, where aged/old DNA extracts are available that contain no RNA and are not suitable for DNA methylation analysis due to limited DNA quantity and quality. PMID- 29986231 TI - Systematic evaluation of the early access applied biosystems precision ID Globalfiler mixture ID and Globalfiler NGS STR panels for the ion S5 system. PMID- 29986232 TI - In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis. AB - Tumour models mimicking in vivo three-dimensional (3D) microenvironments are of increasing interest in drug discovery because of the limitations inherent to current models. For example, preclinical assays that rely on monolayer or spheroid cell cultures cannot easily predict 3D cancer behaviours because they have no vasculature. Furthermore, there are major differences in cancer behaviour between human and animal experiments. Here, we show the construction of 3D blood/lymph-vascularized human stromal tissues that can be combined with cancer cells to mimic dynamic metastasis for real-time throughput screening of secreted proteinases. We validated this tool using three human carcinoma cell types that are known to invade blood/lymph vessels and promote angiogenesis. These cell types exhibited characteristic haematogenous/lymphogenous metastasis and tumour angiogenesis properties. Importantly, these carcinoma cells selectively secreted different matrix metalloproteinases depending on their metastasis stage and target vasculature, suggesting the possibility of developing drugs that can target each secreted proteinase. We conclude that the 3D tissue tool will be a powerful throughput system for predicting cancer cell responses and time dependent secretion of molecules in preclinical assays. PMID- 29986233 TI - Tissue-engineered submillimeter-diameter vascular grafts for free flap survival in rat model. AB - Vascular grafts for free flap transfers should be of very small diameter and remain patent for approximately three weeks to supply blood until the revascularization from the surrounding tissue is established, with the autologous vein grafts acting as the gold standard. Artificial submillimeter-diameter vascular grafts with clinically useful size of 0.6 mm inner diameter and 5 cm length were prepared and evaluated by replacing the axial artery of free flap in rats. The rat tail artery, selected as a novel bioscaffold material, was decellularized using ultrahigh-hydrostatic pressure (UHP) method and compared with the detergent-based conventional method. To induce rapid endothelialization, the graft lumen was modified with synthesized peptides, having high affinity to the endothelial progenitor cells. The UHP method and peptide modification at 37 degrees C were found to preserve the extracellular matrix structure well, leading to the stable immobilization of the peptide at the luminal surface. These grafts showed the neointima formation, even at the center position far from the native vessels, remained patent for three weeks, and resulted in the flap survival in the rat free-flap model. The tissue-engineered vascular grafts with functionalized lumen have great future potential as an alternative to autologous vein grafts in free flap transfers. PMID- 29986234 TI - Near-infrared light-triggered drug delivery system based on black phosphorus for in vivo bone regeneration. AB - A near-infrared (NIR) light-triggered drug delivery platform is produced by incorporating SrCl2 and BP nanosheets (BPs) into poly(lactic-co-glycolic acid) (PLGA) for bone regeneration. The fabricated BP-SrCl2/PLGA microspheres show efficient NIR absorption and photothermal effects due to the BPs. The NIR triggered release behavior of Sr2+ by flawing the PLGA shells is investigated and the microspheres exhibit excellent cell viability and biodegradability. Implantation of the BP-SrCl2/PLGA microspheres into a rat femoral defect demonstrates good tissue compatibility and excellent bone regeneration capacity under NIR light irradiation. Our study indicates that local release of Sr2+ at optimal time periods controlled by NIR irradiation improves bone regeneration significantly and this NIR-triggered drug delivery system composed of BPs is suitable for therapies requiring precise control at specific time. PMID- 29986235 TI - Domperidone use and risk of primary liver cancer in the Clinical Practice Research Datalink. AB - BACKGROUND: Pronounced sex-disparity in liver cancer suggests a role for hormones, one of which could be prolactin. Stimulation of prolactin production in mice via domperidone has been reported to decrease hepatocarcinogenesis, thus may have chemopreventive potential. To study the effect of domperidone in humans, a large medical records study was conducted. METHODS: Based in the Clinical Practice Research Datalink, 1921 liver cancer cases and 7681 controls were identified. Conditional logistic regression was employed to estimate odds ratios (OR) and 95% confidence intervals (CI). Domperidone use was analyzed overall, and by number of prescriptions and cumulative dose. RESULTS: Comparing ever- versus never-use, there was no association between domperidone and liver cancer among men (OR = 1.06, 95% CI: 0.76-1.48) or women (OR = 1.21, 95% CI: 0.82-1.76). Among men, there was no association with dose or number of prescriptions, while among women who received the highest doses (OR2700 mg vs. 0 mg = 2.52, 95% CI: 1.18 5.41, p-trend = 0.02) and greatest number of prescriptions (OR>=11 Rx vs. 0 Rx = 3.17, 95% CI: 1.07-9.40, p-trend = 0.02) there was a significantly increased risk, although there was no evidence of heterogeneity in the results by gender. CONCLUSION: Domperidone use was not associated with decreased liver cancer risk among all study participants. Among women, an increased risk at highest levels of exposure warrants further study. PMID- 29986236 TI - A novel environmental fate of graphene oxide: Biodegradation by a bacterium Labrys sp. WJW to support growth. AB - Graphene oxide (GO) is a new type of nanomaterial with unique physicochemical properties and diverse applications, whereas it poses potential risk to human and environment. By screening from natural soil exposed to GO in the laboratory, we successfully obtained a novel bacterium, Labrys sp. WJW, which was able to use GO as the sole carbon source for growth. Within 8 days, cell numbers increased 16.76 +/- 3.21 folds using 100 mg/L GO as the carbon source by qPCR analysis. The bacterial biodegradation which resulted in formation of holes and functional group changes of GO was proved by Raman spectroscopy, atomic force microscopy, transmission electron microscopy and X-ray photoelectron spectroscopy analyses. Aromatic intermediates with structures of benzoic acid and phenol were identified using gas chromatograph-mass spectrometry and liquid chromatography/time-of flight/mass spectrometry. Combination of genomic and proteomic analyses were performed to explore the proteins associated with GO degradation. A total of 644 proteins were significantly shifted. Bioinformatics analysis indicated that part of the up-regulated proteins were related to oxidation, ring cleavage and intermediates transmembrane processes, and GO was supposed to be degraded to benzoate and further degraded for downstream processes. This study enriches our understanding and provides new insights into the environmental fate of GO. PMID- 29986238 TI - Inter-basin water transfers and the expansion of aquatic invasive species. AB - Inter-basin Water Transfers (IBWT) are recognized as one of the major pathways of freshwater invasion. They provide a direct link between previously isolated catchments and may modify the habitat conditions of the receiving waters such that they become more favourable for the establishment of invasive species. Combined, IBWT and invasive species will intensify the stress upon native species and ecosystems. Using the Severn and Thames Rivers -two of the largest river systems in Great Britain-as a case study, here we assess the potential influence of IBWT on the expansion of invasive species and thus their impact on biodiversity conservation. The Thames Valley is subject to extensive water abstraction, and an increasing population means that supplemented flow from the River Severn is being considered. Multi-scale Suitability Models, based on climate and water chemistry respectively, provided novel evidence that there is serious risk for further spread of invasive species in the focus area, particularly of the quagga mussel, a recent invader of the Thames River. Native freshwater mussels are particularly vulnerable to changing environmental conditions, and may suffer the decrease in alkalinity and increase in sedimentation associated with an IBWT from the lower Severn to the upper Thames. Regional models suggest considerable overlap between the areas suitable for three vulnerable native freshwater mussels and the expansion of invasive species that negatively impact upon the native mussels. This study illustrates the use of novel spatially-explicit techniques to help managers make informed decisions about the risks associated with introducing aquatic invasive species under different engineering scenarios. Such information may be especially important under new legislation (e.g. EU Invasive Species Regulation No 1143/2014) which increases the responsibility of water managers to contain and not transfer invasive species into new locations. PMID- 29986237 TI - Supernatant organics from anaerobic digestion after thermal hydrolysis cause direct and/or diffusional activity loss for nitritation and anammox. AB - Treatment of sewage sludge with a thermal hydrolysis process (THP) followed by anaerobic digestion (AD) enables to boost biogas production and minimize residual sludge volumes. However, the reject water can cause inhibition to aerobic and anoxic ammonium-oxidizing bacteria (AerAOB & AnAOB), the two key microbial groups involved in the deammonification process. Firstly, a detailed investigation elucidated the impact of different organic fractions present in THP-AD return liquor on AerAOB and AnAOB activity. For AnAOB, soluble compounds linked to THP conditions and AD performance caused the main inhibition. Direct inhibition by dissolved organics was also observed for AerAOB, but could be overcome by treating the filtrate with extended aerobic or anaerobic incubation or with activated carbon. AerAOB additionally suffered from particulate and colloidal organics limiting the diffusion of substrates. This was resolved by improving the dewatering process through an optimized flocculant polymer dose and/or addition of coagulant polymer to better capture the large colloidal fraction, especially in case of unstable AD performance. Secondly, a new inhibition model for AerAOB included diffusion-limiting compounds based on the porter-equation, and achieved the best fit with the experimental data, highlighting that AerAOB were highly sensitive to large colloids. Overall, this paper for the first time provides separate identification of organic fractions within THP-AD filtrate causing differential types of inhibition. Moreover, it highlights the combined effect of the performance of THP, AD and dewatering on the downstream autotrophic nitrogen removal kinetics. PMID- 29986239 TI - Synergy of MS2 disinfection by sequential exposure to tailored UV wavelengths. AB - The advantages of polychromatic ultraviolet (UV) light for viral disinfection can be optimized for disinfection using emerging tailored wavelength sources including KrCl excimer lamps and light emitting diodes (LEDs). Disinfection of the common viral surrogate MS2 bacteriophage was measured after exposure to these emerging sources and conventional low pressure (LP) mercury UV lamps in individual or sequential exposures. The first dose response for any virus (MS2) exposed to a KrCl excimer lamp is reported, showing the high efficiency of fluence-based disinfection because of increased viral susceptibility at the low wavelengths emitted by the excilamp. Sequential exposure dose responses indicated synergy from sequential exposures of LP and excimer lamps, which were competitive on an electrical basis at worst-and best-case scenarios of wall plug efficiency with current medium pressure (MP) disinfection. Best-case scenarios for electrical efficiency also showed all sequential exposures to be competitive with MP UV disinfection. Predictive models for sequential exposure dose responses were assessed to support the current feasibility of incorporating sequential UV exposures to optimize tailored wavelength viral disinfection. PMID- 29986240 TI - On the implementation of reliable early warning systems at European bathing waters using multivariate Bayesian regression modelling. AB - For ensuring microbial safety, the current European bathing water directive (BWD) (76/160/EEC 2006) demands the implementation of reliable early warning systems for bathing waters, which are known to be subject to short-term pollution. However, the BWD does not provide clearly defined threshold levels above which an early warning system should start warning or informing the population. Statistical regression modelling is a commonly used method for predicting concentrations of fecal indicator bacteria. The present study proposes a methodology for implementing early warning systems based on multivariate regression modelling, which takes into account the probabilistic character of European bathing water legislation for both alert levels and model validation criteria. Our study derives the methodology, demonstrates its implementation based on information and data collected at a river bathing site in Berlin, Germany, and evaluates health impacts as well as methodological aspects in comparison to the current way of long-term classification as outlined in the BWD. PMID- 29986241 TI - Insights into the variability of microbial community composition and micropollutant degradation in diverse biological wastewater treatment systems. AB - The biological potential of conventional wastewater treatment plants to remove micropollutants mainly depends on process conditions and the predominant microbial community. To explore this dependence and to connect the occurrence of genera with operating conditions, five pilot-scale reactors with different process conditions were combined into two reactor cascades and fed with the effluent of the primary clarifier of a municipal WWTP. All reactors and the WWTP were analyzed for the removal of 33 micropollutants by LC-MS/MS and the presence of the microbial community using 16S rRNA gene sequencing. The overall removal of the micropollutants was slightly improved (ca. 20%) by the reactor cascades in comparison to the WWTP while certain compounds such as diatrizoate, venlafaxine or diclofenac showed an enhanced removal (ca. 70% in one or both cascades). To explore the diverse bacteria in more detail, the general community was divided into a core and a specialized community. Despite their profoundly different operating parameters (especially redox conditions), the different treatments share a core community consisted of 143 genera (9% of the overall community). Furthermore, the alpha- and beta-biodiversity as well as the occurrence of several genera belonging to the specialized microbial community could be linked to the prevalent process conditions of the individual treatments. Members of the specialized community also correlated with the removal of certain groups of micropollutants. Hence, the comparison of the specialized community with micropollutant removal and operating conditions via correlation analysis is a valuable tool for an extended evaluation of prevalent process conditions. Based on an extended data set this approach could also be used to identify organisms as indicators for operating conditions which are beneficial for an improved removal of specific micropollutants. PMID- 29986242 TI - Rapid degradation of brominated and iodinated haloacetamides with sulfite in drinking water: Degradation kinetics and mechanisms. AB - The effective removal of haloacetamides (HAMs) as a group of emerging disinfection by-products is essential for drinking water safety. This study investigated the degradation of 10 HAMs, including chlorinated, brominated, and iodinated analogues, by sodium sulfite (S(IV)) and the mechanism behind it. The results indicated that all HAMs, excluding chlorinated HAMs, decomposed immediately when exposed to S(IV). The reductive dehalogenation kinetics were well described by a second-order kinetics model, first-order in S(IV) and first order in HAMs. The degradation rates of HAMs increased with the increase of pH and they were positively correlated with sulfite concentration, indicating that the reaction of S(IV) with HAMs mainly depends on sulfite. The rank order and relative activity of the reaction of sulfite with HAMs depends on bimolecular nucleophilic substitution reaction reactivity. The order of the reductive dehalogenation rates of HAMs versus the substitution of halogen atoms was iodo- > bromo- >> chloro-. During reductive dehalogenation of HAMs by sulfite, the alpha carbon bound to the amide group underwent nucleophilic attack at 180 degrees to the leaving group (halide). As a consequence, the halide was pushed off the opposite side, generating a transition state pentacoordinate. The breaking of the C-X bond and the formation of the new C-S bond occurred simultaneously and HAM sulfonate formed as the immediate product. Results suggest that S(IV) can be used to degrade brominated and iodinated HAMs in drinking water and therefore should not be added as a quenching agent before HAM analysis to accurately determine the HAM concentrations produced during water disinfection. PMID- 29986243 TI - Solar photo-Fenton disinfection of 11 antibiotic-resistant bacteria (ARB) and elimination of representative AR genes. Evidence that antibiotic resistance does not imply resistance to oxidative treatment. AB - The emergence of antibiotic resistance represents a major threat to human health. In this work we investigated the elimination of antibiotic resistant bacteria (ARB) by solar light and solar photo-Fenton processes. As such, we have designed an experimental plan in which several bacterial strains (Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae) possessing different drug-susceptible and -resistant patterns and structures (Gram-positive and Gram-negative) were subjected to solar light and the photo-Fenton oxidative treatment in water. We showed that both solar light and solar photo-Fenton processes were effective in the elimination of ARB in water and that the time necessary for solar light disinfection and solar photo-Fenton disinfection were similar for antibiotic susceptible and antibiotic-resistant strains (mostly 180-240 and 90-120 min, respectively). Moreover, the bacterial structure did not significantly affect the effectiveness of the treatment. Similar regrowth pattern was observed (compared to the susceptible strain) and no development of bacteria with higher drug resistance values was found in waters after any treatment. Finally, both processes were effective to reduce AR genes (ARGs), although solar photo-Fenton was more rapid than solar light. In conclusion, the solar photo-Fenton process ensured effective disinfection of ARB and elimination of ARGs in water (or wastewater) and is a potential mean to ensure limitation of ARB and ARG spread in nature. PMID- 29986244 TI - Effect of crystallization of settled aluminum hydroxide precipitate on "dissolved Al". AB - When aluminum salts are added to water at around neutral pH, a precipitate of Al hydroxide is formed very rapidly. Initially the precipitate is in the form of nano-scale primary particles, which then aggregate to form flocs. The nature of the flocs depends greatly on the solution composition, for instance on the presence of humic acid (HA), which not only increases the size of the primary nanoparticles, but also decreases the connection points between them. The nanoparticles become smaller with aging, both with and without HA, as a result of crystallization. The aggregated amorphous nanoparticles (settled flocs) undergo a room temperature structural modification best characterized as a disorder-to order transition, following elimination of water. During this process, the apparent Al concentration in the supernatant of water increases with age. The "dissolved Al" concentration in the supernatant becomes higher with increasing pH and, to some extent, in the presence of HA. However, it can be shown that the "dissolved Al" in the supernatant exists in the form of crystalline nano particles or larger clusters, which are detached from the settled flocs. TEM results confirmed that HA only adsorbed on the surface of nano-particles during the coagulation process, which shows precipitate nanoparticles formed firstly during sweep coagulation before the adsorption of HA or complexed Al3+-HA. However, the adsorbed outer layer of HA does not change the crystallization process for the inner part of nano-particles. This laboratory study may have implications for the release of Al from sediments into lake water, following addition of coagulants to lower phosphorus concentrations. PMID- 29986245 TI - Interactions of functional bacteria and their contributions to the performance in integrated autotrophic and heterotrophic denitrification. AB - Compared to autotrophic and heterotrophic denitrification process, the Integrated autotrophic and heterotrophic denitrification (IAHD) has wider foreground of applications in the condition where the organic carbon, nitrate and inorganic sulfur compounds usually co-exist in the actual wastewaters. As the most well known IAHD process, the denitrifying sulfide removal (DSR) could simultaneously convert sulfide, nitrate and organic carbon into sulfur, dinitrogen gas and carbon dioxide, respectively. Thus, systematical metabolic functions and contributions of autotrophic and heterotrophic denitrifiers to the IAHD-DSR performance became an problem demanding to be promptly studied. In this work, three upflow anaerobic sludge bioreactors (UASBs) were individually started up in autotrophic (a-DSR), heterotrophic (h-DSR) and mixotrophic conditions (m-DSR). Then, the operating conditions of each bioreactor were switched to different trophic conditions with low and high sulfide concentrations in the influent (200 and 400 mg/L). The removal efficiencies of sulfide, nitrate and acetate all reached 100% in all three bioreactors throughout the operational stages. However, the sulfur transformation ratio ranged from 34.5% to 39.9% at the low sulfide concentration and from 76.8% to 86.7% at the high sulfide concentration in the mixotrophic conditions. Microbial community structure analyzed by the Illumina sequencing indicated that Thiobacillus, which are autotrophic sulfide-oxidizing, nitrate-reducing bacteria (a-soNRB), was the dominant genus (81.3%) in the a-DSR bioreactor. With respect to the mixotrophic conditions, at low sulfide concentration in the m-DSR bioreactor, Thiobacillus (a-soNRB) and Thauera, which are heterotrophic nitrate-reducing bacteria (hNRB), were the dominant genera, with percentages of 48.8% and 14.9%, respectively. When the sulfide concentration in the influent was doubled, the percentage of Thiobacillus decreased by approximately 9-fold (from 48.8% to 5.4%), and the total percentage of Azoarcus and Pseudomonas, which are heterotrophic sulfide-oxidizing, nitrate-reducing bacteria (h-soNRB), increased by approximately 6-fold (from 10.1% to 59.4%). Therefore, the following interactions between functional groups and their functional mechanisms in the DSR process were proposed: (1) a-soNRB (Thiobacillus) and hNRB (Thauera) worked together to maintain the performance under the low sulfide concentration; (2) h-soNRB (Azoarcus and Pseudomonas) took the place of a-soNRB and worked together with hNRB (Thauera and Allidiomarina) under the high sulfide concentration; and (3) a-soNRB (such as Thiobacillus) were possibly the key bacteria and may have contributed to the low sulfur transformation, and h-soNRB may be responsible for the high sulfur transformation in the DSR process. PMID- 29986246 TI - Energy consumption in capacitive deionization - Constant current versus constant voltage operation. AB - In the field of Capacitive Deionization (CDI), it has become a common notion that constant current (CC) operation consumes significantly less energy than constant voltage operation (CV). Arguments in support of this claim are that in CC operation the endpoint voltage is reached only at the end of the charging step, and thus the average cell voltage during charging is lower than the endpoint voltage, and that in CC operation we can recover part of the invested energy during discharge. Though these arguments are correct, in the present work based on experiments and theory, we conclude that in operation of a well-defined CDI cycle, this does not lead, for the case we analyze, to the general conclusion that CC operation is more energy efficient. Instead, we find that without energy recovery there is no difference in energy consumption between CC and CV operation. Including 50% energy recovery, we find that indeed CC is more energy efficient, but also in CV much energy can be recovered. Important in the analysis is to precisely define the desalination objective function, such as that per unit total operational time -including both the charge and discharge steps- a certain desalination quantity and water recovery must be achieved. Another point is that also in CV operation energy recovery is possible by discharge at a non-zero cell voltage. To aid the analysis we present a new method of data representation where energy consumption is plotted against desalination. In addition, we propose that one must analyze the full range of combinations of cycle times, voltages and currents, and only compare the best cycles, to be able to conclude which operational mode is optimal for a given desalination objective. We discuss three methods to make this analysis in a rigorous way, two experimental and one combining experiments and theory. We use the last method and present results of this analysis. PMID- 29986247 TI - Topological attributes of network resilience: A study in water distribution systems. AB - Resilience has been increasingly pursued in the management of water distribution systems (WDSs) such that a system can adapt to and rapidly recover from potential failures in face of a deep uncertain and unpredictable future. Topology has been assumed to have a great impact on resilience of WDSs, and is the basis of many studies on assessing and building resilience. However, this fundamental assumption has not been justified and requires investigation. To address this, a novel framework for mapping between resilience performance and network topological attributes is proposed. It is applied to WDSs here but can be adaptable to other network systems. In the framework, resilience is comprehensively assessed using stress-strain tests which measure system performance on six metrics corresponding to system resistance, absorption and restoration capacities. Six key topological attributes of WDSs (connectivity, efficiency, centrality, diversity, robustness and modularity) are studied by mathematical abstraction of WDSs as graphs and measured by eight statistical metrics in graph theory. The interplay between resilience and topological attributes is revealed by the correlations between their corresponding metrics, based on 85 WDSs with different sizes and topological features. Further, network variants from a single WDS are generated to uncover the value of topological attribute metrics in guiding the extension/rehabilitation design of WDSs towards resilience. Results show that only certain aspects of resilience performance, i.e. spatial and temporal scales of failure impacts, are strongly influenced by some (not all) topological attributes, i.e. network connectivity, efficiency, modularity and centrality. Metrics for describing the topological attributes of WDSs need to be carefully selected; for example, clustering coefficient is found to be weakly correlated with resilience performance compared to other metrics of network connectivity (due to the grid-like structures of WDSs). Topological attribute metrics alone are not sufficient to guide the design of resilient WDSs and key details such as the location of water sources also need to be considered. PMID- 29986248 TI - A metabolomic view of how low nitrogen strength favors anammox biomass yield and nitrogen removal capability. AB - The low yield of anaerobic ammonium oxidation (anammox) biomass has attracted great attention because of its difficulty to be abundantly enriched. Patterns of substrate supply greatly influence microbial metabolism and behavior. The present study proposed that low nitrogen strength was beneficial to anammox biomass yield and nitrogen removal when comparing a membrane bioreactor (MBR) operated at low nitrogen strength with short hydraulic retention time (HRT) (R-low; influent: fixed at 100 mg-N L-1) and one operated at high nitrogen strength with long HRT (R-stepwise; influent: 100-700 mg-N L-1). Different nitrite concentrations in the two MBRs would indicate discrepant environments, and inevitably resulted in the discrepant microbial responses for anammox community. In particular, we found that at low nitrogen strength, increased activities of purine and pyrimidine metabolism pathways provided more abundant nucleic acids for bacterial proliferation. More active reaction of lipid and protein synthesis favored the synthesis of cellular structure. Importantly, the metabolism of cheaper amino acids was more active under low nitrogen strength, which was coupled with higher metabolic flux and potentially more active exchange of costly amino acids as public goods. In this way, more energy could be saved and applied to biomass yield. Higher active bacterial diversity and more positive interactions among bacterial species in R-low further favored biomass yield and nitrogen removal. The present study highlighted the significant effect of substrate supply patterns on anammox, which is meaningful to overcome the current bottleneck of deficient anammox biomass for application in wastewater treatment. PMID- 29986249 TI - Biological sulfur oxidation in wastewater treatment: A review of emerging opportunities. AB - Sulfide prevails in both industrial and municipal waste streams and is one of the most troublesome issues with waste handling. Various technologies and strategies have been developed and used to deal with sulfide for decades, among which biological means make up a considerable portion due to their low operation requirements and flexibility. Sulfur bacteria play a vital role in these biotechnologies. In this article, conventional biological approaches dealing with sulfide and functional microorganisms are systematically reviewed. Linking the sulfur cycle with other nutrient cycles such as nitrogen or phosphorous, and with continued focus of waste remediation by sulfur bacteria, has led to emerging biotechnologies. Furthermore, opportunities for energy harvest and resource recovery based on sulfur bacteria are also discussed. The electroactivity of sulfur bacteria indicates a broad perspective of sulfur-based bioelectrochemical systems in terms of bioelectricity production and bioelectrochemical synthesis. The considerable PHA accumulation, high yield and anoxygenic growth conditions in certain phototrophic sulfur bacteria could provide an interesting alternative for bioplastic production. In this review, new merits of biological sulfide oxidation from a traditional environmental management perspective as well as a waste to resource perspective are presented along with their potential applications. PMID- 29986250 TI - Freshwater plastic pollution: Recognizing research biases and identifying knowledge gaps. AB - The overwhelming majority of research conducted to date on plastic pollution (all size fractions) has focused on marine ecosystems. In comparison, only a few studies provide evidence for the presence of plastic debris in freshwater environments. However, owing to the numerous differences between freshwater studies (including studied species and habitats, geographical locations, social and economic contexts, the type of data obtained and also the broad range of purposes), they show only fragments of the overall picture of freshwater plastic pollution. This highlights the lack of a holistic vision and evidences several knowledge gaps and data biases. Through a bibliometric analysis we identified such knowledge gaps, inconsistencies and survey trends of plastic pollution research within freshwater ecosystems. We conclude that there is a continued need to increase the field-data bases about plastics (all size fractions) in freshwater environments. This is particularly important to estimate river plastic emissions to the world's oceans. Accordingly, data about macroplastics from most polluted and larger rivers are very scarce, although macroplastics represent a huge input in terms of plastics weight. In addition, submerged macroplastics may play an important role in transporting mismanaged plastic waste, however almost no studies exist. Although many of the most plastic polluted rivers are in Asia, only 14% of the reviewed studies were carried out in this continent (even though the major inland fisheries of the world are located in Asia's rivers). The potential damage caused by macroplastics on a wide range of freshwater fauna is as yet undetermined, even though negative impacts have been well documented in similar marine species. We also noted a clear supremacy of microplastic studies over macroplastic ones, even though there is no reason to assume that freshwater ecosystems remain unaffected by macro-debris. Finally, we recommend focusing monitoring efforts in most polluted rivers worldwide, but particularly in countries with rapid economic development and poor waste management. PMID- 29986251 TI - Different electrically charged proteins result in diverse bacterial transport behaviors in porous media. AB - The influence of proteins on bacterial transport and deposition behaviors in quartz sand was examined in both NaCl (10 and 25 mM) and CaCl2 solutions (1.2 and 5 mM). Bovine Serum Albumin (BSA) and bovine trypsin were used to represent negatively and positively charged proteins in natural aquatic systems, respectively. The presence of negatively charged BSA in suspensions increased the transport and decreased bacterial deposition in quartz sand, regardless of the ionic strength and ion types. Whereas, positively charged trypsin inhibited the transport and enhanced bacterial deposition under all experimental conditions. The potential mechanisms controlling the changes of bacterial transport behaviors varied for different charged proteins. The steric repulsion resulting from BSA adsorption onto both bacteria and quartz sand was found to play a dominant role in the transport and deposition of bacteria in porous media with BSA copresent in suspension. BSA adsorption onto bacterial surfaces and competition for deposition sites onto sand surfaces (adsorption of quartz sand surfaces) contributed to the increased cell transport with BSA in suspension. In contrast, the attractive patch-charged interaction induced by the adsorption of trypsin onto both bacteria and quartz sand had great contribution to the decreased bacterial transport in porous media with trypsin copresent in suspension. The increase in bacteria size, and the adsorption of trypsin onto cell surfaces (resulting in less negative cell surface charge) and quartz sand surfaces (providing extra deposition sites) were found to be the main contributors to the decreased transport and increased deposition of bacteria in quartz sand with trypsin in suspension. PMID- 29986253 TI - Evaluation of three turbulence models in predicting the steady state hydrodynamics of a secondary sedimentation tank. AB - The secondary sedimentation tank (SST) is a sensitive and complicated process in an activated sludge process. Due to the importance of its performance, computational fluid dynamics (CFD) methods have been employed to study the underflow hydrodynamics and solids distribution. Unlike most of the previous numerical studies, in the present investigation, the performance of three different types of turbulence models, standard k-epsilon, RNG k-epsilon and Realizable k-epsilon, are evaluated. Firstly, two-dimensional axisymmetric CFD models of two circular SSTs are validated with the field observations. Next, comprehensive comparisons are presented of the model predictions of the key physical quantities, such as the concentration of effluent suspended solids (ESS), and returned activated sludge (RAS), sludge blanket height (SBH), turbulent properties and flow and concentration patterns. A surprising result shows that the prediction of the ESS concentration is not sensitive to the change of turbulence models; while remarkable prediction difference can be observed in the inlet zone and near-field of sludge hopper and SBH. The results suggest that more observations inside the inlet zone are needed to achieve better model calibration and correct application of the turbulence model, which can be crucial to optimizing the geometry of inlet structure and sludge hopper as well as changing return solids concentration for the operation. PMID- 29986252 TI - Effect of aromatic repolymerization of humic acid-like fraction on digestate phytotoxicity reduction during high-solid anaerobic digestion for stabilization treatment of sewage sludge. AB - Humification plays an important role in the sewage sludge stabilization treatment and probably influences the end-product ecotoxicity, which are not fully understood for high-solid anaerobic digestion (AD) process. This study monitored the aromaticity degree of humic acid-like fraction (HA) and detected digestate phytotoxicity during a 48-d high-solid AD. Significant repolymerization of aromatic structures in HA. Electrical conductivity (EC) of digestate changed negatively with the aromaticity degree in HA, and the digestate with high EC had low seed germination index (SGI). A positive correlation between SGI and the aromaticity degree of HA was found. Aromatic repolymerization of HA supplies more aromatic electron-rich sites to form neo-humic polymers and to determine the distribution of organic and/or inorganic phytotoxic compounds; thus, aromatic repolymerization of HA may control the digestate phytotoxicity by reducing excessive salinity. The results showed the effect of HA repolymerization on digestate stabilization and phytotoxicity reduction during the high-solid AD process. The inadequate phytotoxicity reduction efficiency (SGI <= 17%) may be ascribed to unaccomplished HA repolymerization, creating a demand for humification intensification studies. PMID- 29986254 TI - Enhanced triclosan and nutrient removal performance in vertical up-flow constructed wetlands with manganese oxides. AB - Limited concentrations of oxygen in constructed wetlands (CWs) have inhibited their ability to remove emerging organic contaminants (EOCs) at MUg/L or ng/L levels. Manganese (Mn) oxides were proposed as a solution, as they are powerful oxidants with strong adsorptive capabilities. In the present study, triclosan (TCS) was selected as a typical EOC, and CW microcosms with Mn oxides (birnessite) coated sand (B-CWs) and without (C-CWs) were developed to test the removal capacities of TCS and common nutrients. We found that the addition of Mn oxides coated sand significantly improved removal efficiencies of TCS, NH4-N, COD, NO3-N and TP (P < 0.05). The average concentration of Mn(II) effluent was 0.036 mg L-1, mostly lower than the drinking water limit. To gain insight into the mechanisms of pollution removal, Mn transformation, dissolved oxygen (DO) distribution, bacterial abundance, and microbial community composition were also investigated. Maximum Mn(II) was detected at 20 cm height of the B-CWs in anoxic zone. Although Mn-oxidizing bacteria existed in the layer of 30-50 cm with 103 104 CFU g-1 dry substate, Mn oxides were only detected at height from 40 to 50 cm with rich oxygen in B-CW. The quantities of bacterial 16S rRNA, amoA, narG and nosZ were not significantly different between two systems (P > 0.05), while Illumina high-throughput sequencing analysis revealed that the abundance of denitrifying bacteria was significant higher in B-CWs, and the abundance of Gammaproteobacteria that have a recognized role in Mn transformation were significantly increased. The results indicated that Mn oxides could enhance TCS and common pollutants removal in both anoxic and aerobic areas through the recycling of Mn between Mn(II) and biogenic Mn oxides. PMID- 29986255 TI - Evaluation of revolving algae biofilm reactors for nutrients and metals removal from sludge thickening supernatant in a municipal wastewater treatment facility. AB - This work is to evaluate pilot-scale Revolving Algal Biofilm (RAB) reactors of two heights (0.9-m and 1.8-m tall) to treat supernatant from sludge sedimentation at Metropolitan Water Reclamation District of Greater Chicago (MWRD) for removing nutrients (N and P) as well as various metals. The RAB reactors demonstrated a superior performance in N and P removal as compared to control raceway ponds. Taller 1.8-m RAB reactors performed better than 0.9-m RAB reactors in terms of total nutrient removal and algal biomass productivity. At 7-day HRT, total P (TP) and Total Kjeldahl N (TKN) removal efficiency reached to 80% and 87%, respectively, while ortho-P and ammonia removal efficiency reached to 100%. Decreasing HRT led to an enhanced TP and TKN removal rate and nutrient removal capacity. At HRT of 1.3-day, the TP removal per footprint of 1.8-m tall RAB reactors was around 7-times higher than the open pond system. The RAB reactors also showed certain capabilities of removing metals from wastewater. The study demonstrated that RAB-based treatment process is an effective method to recover nutrients from municipal wastewater. PMID- 29986256 TI - Model-based design of a software sensor for real-time diagnosis of the stability conditions in high-rate anaerobic reactors - Full-scale application to Internal Circulation technology. AB - Internal Circulation (IC) anaerobic systems are especially suitable when plant designs that involve both small footprints and high organic loading rates (>25 kg COD m-3 d-1) are required. However, given that operating anaerobic processes at high organic loads increases their vulnerability to external disturbances, real time indicators of the stability conditions become particularly pertinent for IC reactors. This paper addresses the design and full-scale validation of a software sensor that uses only feeding flow-rate and biogas flow-rate measurements to classify the operating conditions of the reactor as "strongly", "moderately" or "weakly" stable. A simulation-based procedure was used to design the software sensor and configure its parameters. Then, the performance of the software sensor was tested under real conditions in a full-scale IC reactor of 1679 m3 installed in a recycled paper mill (RPM). PMID- 29986257 TI - Formation of brominated trihalomethanes during chlorination or ozonation of natural organic matter extracts and model compounds in saline water. AB - Oxidation experiments (chlorine, ozone and bromine) were carried out with synthetic saline waters containing natural organic matter (NOM) extracts and model compounds to evaluate the potential of these surrogates to mimic the formation of brominated trihalomethanes (Br-THMs) in natural saline waters. Synthetic saline water with Pony Lake fulvic acid (PLFA) showed comparable results to natural brackish and sea water for Br-THMs formation during chlorination and ozonation for typical ballast water treatment conditions ([Cl2]0 >= 5 mg/L or [O3]0 >= 3 mg/L). The molar CHBr3 yield in synthetic saline waters is higher for chlorination than for ozonation, since ozone reacts slower with bromide and faster with THM precursors. For bromination, the molar yields of CHBr3 for the NOM model compounds phenol, resorcinol, 3-oxopentanedioic acid and hydroquinone are 28, 62, 91 and 11%, respectively. CHBr3 formation is low during chlorination or ozonation of resorcinol-containing synthetic saline waters due to the faster reaction of resorcinol with these oxidants compared to the bromine formation from bromide. Oxidation experiments with mixtures of hydroquinone and phenol (or resorcinol) were conducted to mimic various functional groups of NOM reacting with Cl2 (or O3) in saline water. With increasing hydroquinone concentrations, the CHBr3 formation increases during both chlorination and ozonation of the mixtures, except for chlorination of the mixture of hydroquinone and resorcinol. The formation of THMs during chlorination of the mixture of hydroquinone and resorcinol is similar to that of resorcinol alone due to the much faster reaction of HOX with resorcinol compared to hydroquinone. In general, PLFA seems to be a reasonable DOM surrogate to simulate CHBr3 formation for realistic ballast water treatment. During chlorination, CHBr3 formations from phenol- and PLFA-containing synthetic brackish waters are comparable, for similar phenol contents. PMID- 29986258 TI - Finding the ideal polyethylenimine-plasmid DNA system for co-delivery of payloads in cancer therapy. AB - Researchers still hold for the development of a safety and advanced delivery system able of efficient therapeutic action. The co-delivery of different payloads is part of this strategy and has already demonstrated to be a valuable tool against the most severe diseases. In the pursuit of an "ideal" drug/gene co delivery vector for cancer therapy, we present a complete comparison study of different morphology and molecular weight polyethylenimine (PEI)/p53 encoding plasmid DNA (pDNA) polyplexes. Besides pDNA, also methotrexate (MTX) has been loaded into PEI/pDNA nanoparticles. The polyplexes have been characterized in terms of morphology, size, surface charges, loading/encapsulation efficiencies and toxicity. Although the nature of PEI can influence these properties, they deeply vary with the polymer nitrogen to pDNA phosphate (N/P) ratio. The transfection of HeLa cells mediated by PEI/pDNA/MTX vectors leads to both the release of MTX and the p53 protein expression. Modelling of MTX release kinetics brings valuable information concerning drug delivery mechanism. Moreover, the success of transfection is dependent on the nature of PEI and, mainly, on the N/P ratio used in the formulation of polyplexes. This work represents a great contribution for the design and development of innovative PEI based carriers for the most challenging biomedical applications. PMID- 29986259 TI - Armamentarium of nanoscaled lipid drug delivery systems customized for oral administration: In silico docking patronage, absorption phenomenon, preclinical status, clinical status and future prospects. AB - Poor drug solubility and bioavailability remain a significant and frequently encountered concern for pharmaceutical scientists. Nanoscaled lipid drug delivery systems (NSLDDS) have exhibited great potentials in oral delivery of poorly water soluble drugs, primarily for lipophilic drugs, with several successful clinical products. In the past few years, we have find out that optimized composition of drug in lipid, surfactant, or mixture of lipid and surfactant omits the solubility, permeability and bioavailability issues, which are potential limitations for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. Therefore, in current critical review, a comprehensive overview of the different lipid based nanostructured drug delivery systems intended for oral administration has been presented. In addition, implication of in silico docking in designing of NSLDDS as well as mechanism of absorption of different lipid based nanoformulations through intestinal absorption window has also been offered. Moreover, attention has also been paid to NSLDDS that are currently undergoing preclinical or clinical analysis. PMID- 29986260 TI - Encapsulation of green tea polyphenol by pH responsive, antibacterial, alginate microgels used for minimally invasive treatment of bone infection. AB - The treatment of bone infection requires drug carriers take large number of cargo, be antibacterial, promote proliferation and differentiation of osteoblasts. Herein, we proposed a strategy of preparing pH responsive, antibacterial, multistage structured microspheres encapsulated with green tea polyphenol used for minimally invasive treatment of bone infection. Tea polyphenol (TP) were encapsulated by porous silica nanospheres (SiO2 NSs). Then, sodium alginate (SA) microgel spheres (MSs) were prepared to encapsulate a lot of TP loaded SiO2 NSs. The outer layer of obtained TP@SiO2@SA microgel spheres were further wrapped by pH sensitive CaCO3. Mineral out-layer of the composite microspheres is used to neutralize the acidic environment caused by bacterial infection. At the same time, encapsulated TP is released pH sensitively to resist oxidative stress. Our results exhibited excellent drug delivery properties including drug loading efficiency (DLE) of 92.96% and drug loading content (DLC) of 19.62%. Besides, results demonstrated that TP@SiO2@SA@CaCO3 MSs can effectively kill Staphylococcus aureus and promote proliferation and differentiation of osteoblasts under stimulation of H2O2 at pH = 5.5. PMID- 29986261 TI - Photoluminescence modulation of silicon nanoparticles via highly ordered arrangement with phospholipid membranes. AB - Highly ordered self-assembly of nanoparticles (NPs) in a large scale promises attractive potential in optical modulation of the NPs for illuminating, imaging and sensing applications. In this work, a type of multi-lamellar nanocomposite membranes composed of phospholipid multilayers and Si NPs sandwiched between each adjacent lipid layers was fabricated via a facile co-assembly method. X-ray reflectivity (XRR), grazing incident X-ray diffraction (GIXRD) and TEM measurements verified the highly ordered arrangement of NPs within the multilayers with a controlled in-plane inter-particle separation from ~7 nm to ~14 nm. Due to such an arrangement, the photoluminescence (PL) properties of the Si NPs were effectively modulated. Compared to the NPs in suspension or its pure film, the PL of the NPs in the membranes blue-shifted and remarkably narrowed, with the full-width-at-half-maximum (FWHM) value reduced from >110 nm of the pure Si NP film to below 43 nm. The radiative lifetime of the NPs was also significantly reduced from ~16.7 ns to ~3.3 ns depending on the inter-particle distance in the membrane. Meanwhile, the Si NPs within membranes maintained robust photostability under UV irradiation. PMID- 29986262 TI - Corrigendum to "Multifunctional organically modified silica nanoparticles for chemotherapy, adjuvant hyperthermia and near infrared imaging" [Colloids Surf. B: Biointerfaces 147 (2016) 492-500]. PMID- 29986263 TI - Conformational changes of adsorbed and free proteins on magnetic nanoclusters. AB - Conformational changes of proteins have an influence on their biological activity, so as to affect their use efficiency. However, the conformation of proteins is typically measured in a mixture containing the adsorbed protein, free protein and adsorbing material, which does not truly reflect the influence of the material on protein conformation. In this study, Fe3O4/carboxymethylated chitosan (Fe3O4/CMCS) nanoclusters with unique superparamagnetism were utilized as the separation carrier to study the conformational changes of the adsorbed and the free proteins. Four representative proteins with different molecular weights and isoelectric points, lysozyme (LYZ, 13.4 kDa; pI 10.8), bovine hemoglobin (BHB, 64.5 kDa; pI 6.9), apo-transferrin (TRT, 80 kDa; pI 5.9) and bovine serum albumin (BSA, 68 kDa; pI 4.8), were selected as model proteins to investigate the influences of material coating with/without metal ions and environmental factors including pH and ion strength, on the conformational behaviors of the adsorbed or free proteins. This study was aimed at providing a platform for an improved reflection of the conformational changes of proteins and has a potential to guide immobilization and separation of proteins. PMID- 29986264 TI - Colloidal stability as a determinant of nanoparticle behavior in the brain. AB - Drug delivery to the brain is challenging due to a highly regulated blood-brain barrier (BBB) and a complex brain microenvironment. Nanoparticles, due to their tailorability, provide promising platforms to enhance therapeutic delivery and achieve controlled release and disease-specific localization in the brain. However, we have yet to fully understand the complex interactions between nanoparticles and the biological environments in which they operate. It is important to perform a systematic study to characterize nanoparticle behavior as a function of ion composition, concentration, and pH in cerebrospinal fluid (CSF). These could alter nanoparticle biological identity and influence diffusive capability and cellular uptake. In this study, poly(ethylene glycol) (PEG)-coated and carboxyl-coated polystyrene (PS-PEG and PS-COOH respectively) nanoparticles (NPs) were used to evaluate the aggregation kinetics, colloidal stability, and diffusive capability of nanoparticles in conditions relevant to the brain microenvironment. Size, surface charge, and surface coating were varied in a range of CSF ion concentrations and compositions, pH conditions, and temperatures. Small changes in calcium concentration and pH destabilize nanoparticles in CSF. However, PS-PEG NPs remain stable over a wider variety of conditions than PS-COOH NPs, and have higher diffusion capabilities in both agarose gels, an in vitro model of the brain microenvironment, and an organotypic brain tissue slice model. These results demonstrate the need for steric stabilization to maintain nanoparticle colloidal stability in a wide range of conditions. Importantly, colloidal stabilization allows for increased diffusive capability and can be used to predict diffusive behavior in the brain microenvironment. PMID- 29986265 TI - Bioadhesive polymeric film-based integrative platform for the unidirectional carbamazepine release from a volatile microemulsion. AB - Carbamazepine (CBZ) shows inconsistent absorption primarily due to its poor dissolution rate. In this study, we describe a bioadhesive polymeric film, embedded with microemulsion (ME), as a tool to enable improved CBZ dissolution and achieve sustained release. The ME was formulated using pseudo-ternary components; water, oil (n-butyl acetate), surfactant (tocopheryl polyethylene glycol 1000 succinate, TPGS) and cosurfactant (1,4-butanediol). The region at surfactant to co-surfactant ratio of 1:1 was characterized using dynamic light scattering, small angle neutron scattering and differential scanning calorimetry. Scattering studies showed that size distribution did not change upon water addition and temperature. Optimized ME composition containing CBZ was embedded into bioadhesive films composed with a backing layer. We successfully demonstrate the confinement of CBZ-ME into the film matrix and thereupon, the achievement of unidirectional sustained drug release up to 8 h. Our further investigations are directed over testing the system for localized drug delivery applications. PMID- 29986266 TI - Construction, stability, and enhanced antioxidant activity of pectin-decorated selenium nanoparticles. AB - Selenium nanoparticles (SeNPs) as a new replacement source of other Se forms applied in nutritional supplements have been associated with health-related issues. Pectin (PEC) as a well-known food-grade polysaccharide has been considered as a potential soft template for the preparation and stabilization of SeNPs in aqueous medium. In this study, therefore, PEC was used as a stabilizer and dispersing agent to form well-dispersed and stable SeNPs under a simple redox system of selenite and ascorbic acid. Se/PEC ratios significantly affected the color of the suspension, particle size, and surface morphology of the as-prepared SeNPs in the presence of PEC. PEC-SeNPs with a Se/PEC ratio of 1:2 appeared amorphous and exhibited a well-dispersed and stable spherical structure with an average size of ~41 nm, which corresponds to the strong hydrogen bonding between the hydroxyl groups of PEC and SeNPs. The PEC-SeNPs (Se/PEC = 1:2) remained highly stable in different acidic solutions for at least 1 month. Small and highly stable PEC-SeNPs (Se/PEC = 1:2) possessed the strongest DPPH radical scavenging ability and antioxidant capacity among the evaluated PEC-SeNPs. They also possessed a low cytotoxic activity against cancer cells (SPCA-1 and HeLa) and normal cells (RWPE-1) in vitro. These findings suggested that pectin as a surface decorator could be effectively used to improve the stability and antioxidant capacity of SeNPs remarkably. PMID- 29986267 TI - Ru nanoparticles coated with gamma-Fe2O3 promoting and monitoring the differentiation of human mesenchymal stem cells via MRI tracking. AB - Human mesenchymal stem cells (MSCs) can be successively passaged and can differentiate into multiple lineages. These attributes are important in tissue engineering, which has a great deal of attention in stem cell therapy. However, the effective labelling and tracking of MSCs in vivo remain major unresolved issues. Based on the use of iron oxides to label stem cells for magnetic resonance imaging (MRI), we synthesized nanoparticle (NPs) containing ruthenium (RuNPs), gamma-Fe2O3@Ru (Fe2O3@Ru), and gamma-Fe2O3@selenium (Fe2O3@Se) to label MSCs and promote osteogenic differentiation. Fe2O3@Ru and Fe2O3@Se could be used as T2-weighted MRI contrast agents. Fe2O3@Ru more effectively diffused in the cytoplasm and localized in the nuclei of MSCs, compared with Fe2O3@Se. RuNPs, Fe2O3@Ru, and Fe2O3@Se induced MSCs to differentiate into osteoblasts. Fe2O3@Ru, in particular, was a potent osteoinductive agent. Fe2O3@Ru also inhibited adipocytic differentiation. Promotion of the osteogenic differentiation of MSCs may be regulated by a Smad-dependent bone morphogenetic protein signaling pathway with reduced expression of CD44, CD73, and CD105. MSCs treated with Fe2O3@Ru NPs expressing osteoblast surface markers. PMID- 29986269 TI - Grievable lives? Death by opioid overdose in Australian newspaper coverage. AB - Opioid overdose deaths are increasing in Australia and around the world. Despite this, measures aimed at reducing these deaths such as safe injecting facilities and take-home naloxone continue to face obstacles to uptake. The reasons for this are manifold, but a key contributor is public discourse on opioid consumption and overdose. In this article we explore this public discourse using Judith Butler's work on 'grievable lives'. The article analyses mainstream newspaper coverage of opioid overdose in Australia to map key articulations of overdose and to consider how public understandings of overdose are shaped. It then goes on to consider ways these understandings might be reshaped, looking at what have been called overdose 'anti-memorials' and a new website Livesofsubstance.org. In concluding we argue that until the lives of opioid consumers come to be considered grievable, the measures known to reduce overdose deaths may struggle to find public support. PMID- 29986268 TI - Predicting smoking abstinence with biological and self-report measures of adherence to varenicline: Impact on pharmacogenetic trial outcomes. AB - INTRODUCTION: Adherence to pharmacotherapies for tobacco dependence, such as varenicline, is necessary for effective treatment. The relationship between varenicline adherence, determined by commonly used indirect (i.e., self-reported pill counts) and infrequently used direct (i.e., varenicline levels) methods, and abstinence outcomes have not been previously examined, nor has their impact on the outcomes of a genetically randomized clinical trial been assessed. METHODS: At Week 1 following target quit date, self-reported pill count and salivary varenicline levels were obtained from participants (N = 376) in a smoking cessation clinical trial (NCT01314001). Point-prevalence abstinence was biochemically-verified by salivary cotinine at Week 1 and by exhaled carbon monoxide at Week 1, end-of-treatment, 6 and 12 months following treatment. Blood nicotine metabolite ratio (NMR) was obtained at baseline. RESULTS: Adherent individuals based on varenicline levels were significantly more likely to be abstinent than non-adherent individuals at Week 1 (odds ratios [ORs] 1.92-3.16, p's<=0.006), end-of-treatment (OR = 2.53, p = .004), and six months following treatment (OR = 2.30, p = .03). In contrast, pill counts did not consistently predict abstinence. Including direct measures of adherence enhanced the association between rate of nicotine metabolism (NMR) and end-of-treatment abstinence; normal metabolizers (NMR >= 0.31) were significantly more likely than slow metabolizers (NMR < 0.31) to be abstinent at end-of-treatment (OR = 2.00, p = .005). CONCLUSION: Adherence based on salivary varenicline, rather than on pill counts, is predictive of Week 1 abstinence, irrespective of the biomarker of abstinence assessed, and of long-term abstinence. Direct measures of adherence enhance the ability to assess the impact of a biomarker or genetic marker on abstinence outcomes. PMID- 29986271 TI - Stigma and the public health agenda for the opioid crisis in America. AB - The current opioid crisis in the U.S. is unprecedented and calling for a nationwide reorganization of the public health prevention program. Stigma is a persistent barrier to this agenda, unfortunately with a limited body of research on substance use disorder (SUD) available to inform it. We review the broader research literature on the stigma of behavioral health (i.e., mental illness and SUD) to identify strategies to address the opioid crisis and harmful stigma. A major difference between mental illness and SUD stigma is that the latter is legally and socially sanctioned. In making sense of the behavioral strategies for stigma change, we consider three agendas for stigma prevention (prevention, rights, and self-worth). We suggest that incorporating the rights and the self worth agendas with an in vivo focused contact model, might be most effective for an integrative strategy aimed at targeting opioid stigma. Involving people in recovery as key drivers of this agenda and evaluating the detrimental impact of using stigma as a health tool (social sanction), will bring new horizons to solving this deadly epidemic. PMID- 29986270 TI - Transitions in income generation among marginalized people who use drugs: A qualitative study on recycling and vulnerability to violence. AB - BACKGROUND: Income is an important determinant of health among people who use drugs (PWUD). However, understanding transitions between differing types of income generation within the formal and informal economy and how they can be shaped by vulnerability to risk and harm remain poorly understood. This study examines how transitions in income-generating activities are shaped by and influence exposure to violence among marginalised PWUD, in Vancouver, Canada's, Downtown Eastside (DTES) neighbourhood. METHODS: Qualitative interviews were conducted with twenty-six individuals engaged in informal and illegal income generating activities in the DTES. Interview transcripts were analyzed thematically, focusing on relationships between income generation and violence during the study period between January 2014 to April 2015 and drew upon concepts of social violence when interpreting these themes. RESULTS: Participants' engagement in informal and illegal income-generating activities represented a means to negotiate survival given multiple barriers to formal employment and inadequate economic supports. Our findings highlight how informal and illegal income-generating activities in the DTES are characterized by structural, symbolic and everyday violence, while transitions from 'high risk' (e.g., sex work, drug dealing) to perceived 'low risk' (e.g., recycling) activities represent attempts to reduce exposure to violence. However, participants emphasized how informal income generation was nonetheless shaped by structural violence (e.g., gendered hierarchies and police harassment), experienced as everyday violence, and introduced exposure to alternate risks. CONCLUSION: Our findings underscore the critical role of income generation in shaping exposure to violence, highlighting the need for low-threshold employment interventions targeting PWUD as a central component of harm reduction strategies. PMID- 29986272 TI - Treatment with direct-acting antivirals in a multicenter cohort of HCV-infected inmates in Italy. AB - BACKGROUND: People who are incarcerated have a significantly higher prevalence of HCV infection than the general population. Given their high-risk behavior, they represent a reservoir of HCV infection for the whole community. METHODS: We evaluated all HCV-infected people who were incarcerated in 25 Italian prisons starting direct-acting antivirals (DAAs) treatment between May 2015 and October 2016. We collected information on demographic characteristics, liver disease, HCV related aspects, anti-HCV treatment, HIV or HBV co-infection. RESULTS: We enrolled 142 incarcerated people treated with DAAs. They were mostly Italians (93.7%) and males (98.6%). Median age was 50 years and 108/142 (76.1%) were cirrhotic patients. Prevalent genotypes were 1a (35.9%) and 3 (35.9%). Two patients were HBV co-infected, twenty-one patients (14.8%) were HIV co-infected and almost all (95.2%) received antiretroviral therapy. 118/142 (83.1%) DAAs based regimens included sofosbuvir. Treatment completion rate was 94.4%. There were eight (5.6%) discontinuations, one (0.7%) due to an adverse reaction, one due to death (0.7%) and six (5.6%) due to release from prison. SVR12 was achieved in 90.8%. Four patients relapsed but no breakthrough occurred. CONCLUSIONS: Our study shows that in Italian penitentiary settings DAAs treatment is feasible and effective. This intervention is crucial for reducing HCV circulation with possible benefits to the general population. PMID- 29986273 TI - Efficacy of the Head Up collar in facilitating functional head movements in patients with Amyotrophic Lateral Sclerosis. AB - BACKGROUND: The Head Up collar is a cervical orthosis designed to be adaptable to a patient's needs using adjustable removable supports. The aim of this study was to characterise the ability of this orthosis to provide head support and facilitate the control of head movements in people living with Amyotrophic Lateral Sclerosis. METHODS: Thirteen patients (6 females, age range: 45-74 years old, Amyotrophic Lateral Sclerosis Functional Rating Scale range: 13-44) with neck muscle weakness due to Amyotrophic Lateral Sclerosis were enrolled in the study. An additional inclusion criterion was the presence of enough residual muscle strength to enable the performance of the test procedure. Participants were asked to perform a series of head movements with and without wearing the collar. Two parameters (mean angular velocity and ratio of movement coupling) were extracted from recorded angular velocities, to quantify changes in the execution of the movement between the two conditions. FINDINGS: Participants exhibited different levels of impairment in performing different movements. When wearing the collar self-selected movement velocity was preserved and significant improvement in the control of lateral flexion movement was observed (median ratio of movement coupling value reduced from 1.1 to 0.84, P = 0.013). A lower ratio of movement coupling was also observed in 4 out of 7 individuals that were fitted with anterior supports. INTERPRETATION: The heterogeneity observed in the level of impairment and residual function highlights the need for personalized interventions. The Head Up was effective in enabling more controlled movements and maintaining the natural velocity of head movement. PMID- 29986274 TI - The effect of cup medialization and lateralization on hip range of motion in total hip arthroplasty. AB - BACKGROUND: There is little description of the effect of cup position on the hip range of motion in total hip arthroplasty. The purpose is to evaluate the effect of cup medialization/lateralization with a compensatory increase/decrease in femoral offset on the hip range of motion, and whether the bone morphology of the anterior inferior iliac spine affects hip range of motion in total hip arthroplasty. METHODS: Using the CT data of 100 patients (male; 30, female; 70), 3D-dynamic motion analysis was performed in four scenarios with cup medialization/lateralization with the same/decreased global offset. We calculated the range of motion before component impingement and bony impingement in flexion, internal rotation and external rotation using the software. Furthermore, we measured bony morphological features of anterior inferior iliac spine, and we analyzed the correlations among them. FINDINGS: We found that the cup medialization with the same stem offset had negative effects on hip range of motion in flexion and internal rotation due to bony impingement, whereas cup medialization caused external rotation to significantly decrease with the same global offset. On the other hand, cup lateralization with the same global offset had negative effects on flexion and internal rotation, whereas external rotation increased. Furthermore, there were negative correlations among flexion and laterally large and steep anterior inferior iliac spine. INTERPRETATION: Our results demonstrated that the advantage of cup medialization can depend on the individual anatomy such as bony morphology of anterior inferior iliac spine in flexion. PMID- 29986275 TI - A hierarchy in functional muscle roles at the knee is influenced by sex and anterior cruciate ligament deficiency. AB - BACKGROUND: Sex-related neuromuscular differences have been linked to greater risk of anterior cruciate ligament injuries in females. Despite this, it remains unclear if sex-related differences are present after injury. This study sought to determine if sex differences are present in the functional roles of knee joint muscles in an anterior cruciate ligament deficient population. METHODS: An isometric, weight-bearing, force-generation protocol required injured and healthy males and females to modulate ground reaction forces. Electromyography was used to classify the functional role of 10 lower limb muscles in their contribution to knee joint stability during various loading directions. These roles were compared between the four groups at 12 loading directions using a directional analysis. FINDINGS: Functional muscle roles were different between groups, except for injured males and healthy females. Healthy males had either joint actuators or specific joint stabilisers, but no general stabilisers; the vastus medialis and lateralis of injured males and healthy females were classified as general stabilisers while injured females added the gluteus medialis and medial gastrocnemius as general stabilisers. INTERPRETATION: A population-based hierarchy in functional muscle roles was discovered. Healthy males demonstrated the most specific muscle roles, which can be viewed as more adaptive to variable loading conditions. The more generalised stabilisation strategies seen in injured males and females would alter joint loading which may be detrimental to the knee joint health over time. In summary, (1) these injuries alter muscle roles; (2) these alterations are sex-specific; (3) rehabilitation might be optimised if sex differences are considered. PMID- 29986276 TI - Quantitative assessment of upper limb functional impairments in people with Parkinson's disease. AB - BACKGROUND: In clinical routine, upper limb motor disorders of people with Parkinson's disease are commonly assessed using scale- or timed tests, but such tools are not fully suitable for providing detailed information about their type and magnitude. To partly overcome these limitations, the present study aims to quantitatively investigate upper limb functional impairments through quantitative analysis of the "hand-to-mouth" task. METHODS: Twenty-five individuals with Parkinson's disease and 20 age-matched healthy individuals underwent a kinematic analysis of the hand-to-mouth task from which spatio-temporal and kinematic measures, including summary measures (Arm Variable Score and Arm Profile Score), were calculated and correlated with clinical scores (Hoehn & Yahr, H&Y and the Unified Parkinson Disease Rating Scale, UPDRS). FINDINGS: The "hand-to-mouth" movement is significantly altered in individuals with Parkinson's disease, especially in terms of reduced velocity, reduced range of motion of elbow flexion extension and deviation from a physiologic pattern (Arm Profile Score 12.8 degrees vs. 10.1 degrees of unaffected, P = 0.002). Significant moderate correlations were found between movement duration and UPDRS-III (rho = 0.478, P = 0.001) and between the Arm Profile Score and H&Y (rho = 0.481, P = 0.024) and UPDRS-III (rho = 0.326, P = 0.001). INTERPRETATION: On the basis of such findings, we can state that the kinematic analysis of "hand-to-mouth" movement, and in particular the summary indexes, are suitable for easily representing upper limb movement alterations in people with Parkinson's disease, thus allowing the monitoring either of disease progression or effectiveness of pharmacologic and rehabilitative treatments. PMID- 29986277 TI - Extensibility of the supraspinatus muscle can be predicted by combining shear wave elastography and magnetic resonance imaging-measured quantitative metrics of stiffness and volumetric fat infiltration: A cadaveric study. AB - BACKGROUND: A torn rotator cuff tendon will retract over time causing changes in muscle properties and decreasing its extensibility, or deformation. During surgery, large tensile loads are applied to bring the torn tendon to the footprint. Poor muscle extensibility and large tensile stresses at the repair might lead to gap formation or re-tear of the repair. A quantitative evaluation of muscle properties could be used to predict the extensibility of the supraspinatus (SSP) muscle. METHOD: Magnetic resonance imaging (MRI)-measured volumetric fat fraction and shear wave elastography (SWE)-measured elastic modulus of the SSP muscle were obtained on seventeen cadaveric shoulders. Experimental extensibility and stiffness were then measured by axially pulling the tendon up-to 60 N. Univariate and multivariate analyses were used to determine the correlation and contribution of fat fraction and elastic modulus to experimental outcomes. FINDINGS: SWE moduli negatively correlated with SSP muscle extensibility (r = 0.54-0.58, P <= 0.0259); fat fraction resulted in a positive correlation (r = 0.69, P = 0.0021). SWE measurements, solely, explained up to 34% and 33% of the variability in measured extensibility and stiffness, respectively. Fat Fraction, solely, explained 48% of the variability in extensibility and 36% of the variability in stiffness. These methods combined predicted up to 62% of the musculotendinous extensibility. INTERPRETATION: This study showed a comprehensive quantitative assessment of SSP muscle properties using SWE to estimate stiffness and MRI to measure fatty infiltration. The extensibility of the detached muscle/tendon unit was highly correlated to material properties of the muscle when these methods were used in combination. PMID- 29986278 TI - Toxicity of environmentally-relevant concentrations of arsenic on developing T lymphocyte. AB - Arsenic is a ubiquitous environmental contaminant that exists in many inorganic and organic forms. In particular, arsenite is known to induce immunotoxicity in humans and animals. There are still major gaps in our understanding of the mechanism(s) of the immunotoxicity induced by arsenic at environmentally-relevant concentrations. T cells are an essential part of the immune system required for host resistance to infections and protection from cancer. Developing T cells in the thymus have been shown to be particularly prone to arsenite-induced toxicity at low concentrations. Suppression of DNA repair proteins and oxidative stress have been identified as a mechanism of genotoxicity that occurs at low to moderate concentrations. Inhibition of the IL-7 signaling pathway was thought to be responsible for the non-genotoxicity induced by low to moderate doses of arsenic. Interestingly, T cells at different stages of their development had distinct sensitivities to arsenite, which was regulated by arsenite exporters. The current evidence strongly suggests that low to moderate doses of arsenic induces toxic effects in the developing T cells and accumulates to highest levels in the early cells that are least capable to pump out arsenic, which may be the mechanism of the high arsenic sensitivity. Therefore, quantification of the exposure levels should be encouraged in future arsenic toxicity studies. PMID- 29986279 TI - Joint toxicity on hepatic detoxication enzymes in goldfish (Carassius auratus) exposed to binary mixtures of lead and paraquat. AB - Compared to single exposure, chemical mixtures might induce joint toxicity including additive, synergistic and antagonistic effects on both organisms and environment. Owing to the specific toxicity of oxidative stress and binding to proteins, lead (Pb) is generally recognized a non-essential and threatening heavy metal to animals and human. Paraquat (PQ) is a widely used herbicide in agriculture and can trigger oxidative stress as well as Pb. Little information was available about joint effects of the two chemicals on toxicological responses in organisms, especially in fish. In our present study, goldfish (Carassius auratus) were randomly exposed to single and combined experiments with different concentrations of Pb and PQ for 28 days. Activities of four enzyme biomarkers in liver, ethoxyresorufin-O-deethylase (EROD), 7-benzyloxy-4-trifluoromethyl coumarin-O-debenzyloxylase (BFCOD), glutathione-S-transferase (GST) and UDP glucuronosyltransferase (UGT) were evaluated in each experimental group on day 14 and 28. The results showed four enzyme levels were markedly reduced with the increase of concentrations in mixtures and prolonged exposure. The inhibitory EROD and BFCOD activities were not significantly changed in goldfish following PQ treated groups with or without 0.5 mg/L Pb, which indicated PQ has more inhibitory toxicity on CYP450 enzymes than Pb in co-exposure groups. However, the reduced values of GST were observed only in the combinations containing high doses of Pb or PQ during experimental periods. Although the responses of UGT activity were similar to GST on 14th day, all combinations of Pb and PQ generated stronger inhibitions on UGT activities compared to individual Pb and PQ-treated group. These results suggested that combined exposure of Pb and PQ have more inhibitory toxicity on phase I enzymes than phase II enzymes. PMID- 29986281 TI - The PKCdelta-Nrf2-ARE signalling pathway may be involved in oxidative stress in arsenic-induced liver damage in rats. AB - Arsenic poisoning is a worldwide endemic disease that affects thousands of people. Growing evidence from animal, cell, and human studies indicates that arsenic has deleterious effects on the liver. Oxidative stress is considered the primary mechanism for arsenic toxicity in liver damage. However, the mechanisms remain unclear. In light of this fact, the main objective of this study was to investigate the effects of the protein kinase C delta-nuclear factor E2-related factor 2-antioxidant response element (PKCdelta-Nrf2-ARE) signalling pathway on oxidative stress in liver damage. In the present study, we used a model of liver damage induced by coal-burning arsenic in rats, which was set up by our research group. The oxidative stress index and the transcription and protein expression levels of PKCdelta, Nrf2, Keap1, SOD1, and GPx1 were detected, and then their correlation analyses were carried out. The results demonstrated that coal-burning arsenic can cause oxidative stress liver damage in rats, which may be related to the PKCdelta-Nrf2-ARE signalling pathway. This study may provide a new pathway for studies of the mechanisms of arsenism. PMID- 29986282 TI - Effect of salinity on the bioaccumulation and depuration of cadmium in the pacific cupped oyster, Crassostrea gigas. AB - As a euryhaline species, the oyster Crassostrea gigas can adapt rapid and dramatic salinity fluctuations, and show physiological mechanisms of adaption to tolerant salinity changes. They are continuously exposed to Cd because they are filter feeders and their mobility is poor. In order to understand the influence of salinity on the molecular responses of C. gigas exposed to Cd, oysters were acclimatized to different salinities (13, 20, 27, and 34) for 14 days and then exposed to 10 MUg/L Cd for 28 d, followed by a depuration period of 35 d. Control groups were kept at the same salinities without Cd. Oysters were sampled for chemical analysis by inductively coupled plasma mass spectrometry (ICP-MS) and for mRNA quantification by qPCR. The rank order of the mean concentrations of Cd in oyster tissues was digestive gland > mantle > adductor muscle. Use of a two compartment model showed that in the three tissues, Cd uptake rates (k1) in digestive gland (13.525-35.430 d-1) also increased as salinity decreased. However, no difference was observed in Cd uptake rates of C.gigas in the three higher salinities in mantle (11.703-17.250 d-1). Cd depuration rates (k2) (0.0139 - 0.0127 d-1 in mantle and 0.0111-0.0134 d-1 in digestive gland) followed a reverse trend. There was not a relationship between k2 and salinity in adductor muscle. In response to Cd contamination, MT was significantly up-regulated by Cd at all salinities, and P-gp was significantly up-regulated in mantle, while down regulated in digestive gland, which means a disruption of the protein synthesis at high concentration. At depuration phase, MT level was higher in digestive gland and mantle, and its expression was higher at S13 than that at S34. No relationship was found between the P-gp gene expression level and concentrations of cadmium in tissues in either accumulation phase or depuration phase. In accumulation phase, the MT gene expression level was positively correlated with the concentration of cadmium in both the digestive gland and the mantle, while the relationship was weakened in depuration phase, suggesting an effort to create a detoxification mechanism. PMID- 29986280 TI - Hydroxylated and sulfated metabolites of commonly observed airborne polychlorinated biphenyls display selective uptake and toxicity in N27, SH-SY5Y, and HepG2 cells. AB - Although neurotoxicity and hepatotoxicity have long been associated with exposure to polychlorinated biphenyls (PCBs), less is known about the selective toxicity of those hydroxylated PCBs (OH-PCBs) and PCB sulfates that are metabolites derived from exposure to PCBs found in indoor air. We have examined the toxicity of OH-PCBs and PCB sulfates derived from PCBs 3, 8, 11, and 52 in two neural cell lines (N27 and SH-SY5Y) and an hepatic cell line (HepG2). With the exception of a similar toxicity seen for N27 cells exposed to either OH-PCB 52 or PCB 52 sulfate, these OH-PCBs were more toxic to all three cell-types than their corresponding PCB or PCB sulfate congeners. Differences in the distribution of individual OH-PCB and PCB sulfate congeners between the cells and media, and the ability of cells to interconvert PCB sulfates and OH-PCBs, were important components of cellular sensitivity to these toxicants. PMID- 29986284 TI - 'A smile is most important.' Why chains are not currently the answer to quality concerns in the Indian retail pharmacy sector. AB - Chain pharmacies are expanding in many low and middle-income countries (LMICs). Historically practices of independent pharmacies in these settings have been poor, and there is a need to understand how these new organisational arrangements are affecting the functioning of pharmacies, and the implications for public health. Drawing on economics literature, we develop a set of hypotheses as to how chains could address the quality failures that typify LMIC retail pharmacy markets, and explore these hypotheses using a set of 38 in-depth interviews, conducted in Bengaluru, India between 2014 and 2015. We look specifically at how being organised in a chain affects several key behaviours: employment of qualified staff; the ability of government authorities to focus regulation on central management structures; the propensity for firms to self-regulate; and the impact of the potentially lower-powered incentives faced by chain employees compared to independent owners. In practice, few differences were identified between chain and independent organisations in these areas. Not all chains were operating with a qualified pharmacist (akin to independent shops). Drug control authorities did not take advantage of the existing chain architecture to enforce regulation. Chains did heavily self-regulate but their focus was on customer service, rather than aspects of quality relevant to health outcomes. Additionally, widespread bribery in the sector was a barrier to effective drug control. Finally, the incentives faced by chain employees were not low-powered due to rewarding sales targets and pressure to increase sales. We observed that chains exerted strong influence over their staff but the potential to exploit this to improve quality of care is not currently being realised. A shift in focus from customer satisfaction to outcomes of public health concern is unlikely without either financial incentives or strengthened external regulation. PMID- 29986283 TI - Effects of the food additives sodium acid pyrophosphate, sodium acetate, and citric acid on hemato-immunological pathological biomarkers in rats: Relation to PPAR-alpha, PPAR-gamma and tnfalpha signaling pathway. AB - The food additives sodium acid pyrophosphate (SAPP), sodium acetate (SA), and citric acid (CA) were evaluated for their hemato-immunotoxic effects. Forty adult Sprague-Dawley rats were distributed into four groups and were orally administered water, SAPP (12.6 mg/kg), CA (180 mg/kg), or SA (13.5 mg /kg) daily for 90 days. Erythrogram and leukogram profiles were evaluated. The levels of lysozyme, nitric oxide, immunoglobulin, and phagocytic activity were measured. Histologic and immunohistochemical evaluations of splenic tissues were performed. Changes in the mRNA expression levels of peroxisome proliferator-activated receptor alpha and gamma (PPAR-alpha and PPAR-gamma), and tumor necrosis factor alpha (TNF-alpha) genes were assessed. A significant leukopenic condition was observed with SAPP, while CA induced marked leukocytosis, and SA showed a lymphocytosis condition. Both the innate and humoral parameters were significantly depressed. Various pathological lesions were observed, including diffuse hyperplasia of the red pulp, depletion of the white pulp, and capsular and parenchymal fibrosis. A marked decrease in CD3 T-lymphocyte and CD20 B lymphocyte immunolabeling in rats treated with SAPP and SA was evident. Marked downregulation of PPAR-alpha and PPAR-gamma together with upregulation of TNF alpha was recorded. These results indicate that high doses of SAPP, SA and CA exert hematotoxic and immunotoxic effects with long-term exposure. PMID- 29986285 TI - Mechanical elasticity of proline-rich and hydroxyproline-rich collagen-like triple-helices studied using steered molecular dynamics. AB - Identity of the amino acids in Gly-X-Y repetitive motives governs biomechanical features of collagen such as elasticity in the extracellular matrix. Proline and hydroxyproline are the most abundant residues at the X and Y sites of collagen repetitive motives, respectively. However, their effects on the elasticity of collagen have not been identified. Here, we investigated the molecular mechanics of five different proline-rich collagens with Gly-Pro-Y repetitive motives, four hydroxyproline-rich collagens with Gly-X-Hyp repetitive motives as well as a collagen with Gly-Pro-Hyp repetitive motif, focusing on molecular stiffness and elasticity. The proteins were virtually built and stiffness, Young's modulus, cross-sectional radius, intermolecular and protein-solvent hydrogen bonds of the collagens were investigated using steered molecular dynamic simulation. Results showed a higher stiffness and Young's moduli of the proline-rich collagens compared to the hydroxyproline-rich collagens. Young's modulus of the proline rich collagens was negatively correlated with the cross-sectional radius. There was no significant difference between the proline-rich and the hydroxyproline rich collagen from the point of view of intermolecular and protein-water hydrogen bonds. However, a decreased and an increased number of protein-water hydrogen bonds in response to stretching was found for the proline-rich and the hydroxyproline-rich collagens respectively. Interestingly, the collagen with Gly Pro-Hyp repetitive motif showed an intermediate stiffness, Young's moduli and cross-sectional radius. The collagen also had a lower number of intermolecular and protein -water hydrogen bonds when compared to the proline-rich and hydroxproline-rich collagens. These results suggest that the presence of proline in the structure of collagen reduces elasticity and increases stiffness, whereas presence of hydroxyproline increases elasticity of the collagen. We conclude that any codon substitution in the collagen genes causing alteration of proline and/or hydroxyproline residues may result in drastic collagen deficiency. PMID- 29986286 TI - Processing-property relationships of biaxially stretched poly(L-lactic acid) sheet for application in coronary stents. AB - The development of coronary stents from poly(L-lactic acid) requires knowledge of its mechanical properties and the effects of manufacturing processes on those properties. The effects of the biaxial stretching procedure on the mechanical and microstructural properties of poly(L-lactic acid) are hereby investigated. The mechanical properties were evaluated before and after biaxial stretching, with a Design of Experiments methodology employed to identify processing parameters that had the most significant effect on the elastic modulus and yield strength of the biaxially stretched sheets. Microstructural characterisation was performed using differential scanning calorimetry to evaluate crystallinity and thermal transitions of the biaxially stretched sheets. The results show that the mechanical properties of the stretched sheets are highly dependent on the extent of stretch ratio applied during processing; however, neither the elastic modulus nor yield strength are directly attributable to crystallinity, but are affected by the degree of amorphous orientation. The results of this study have the potential to be applied in the design of high stiffness, thin-strut polymeric expandable scaffolds for the application of coronary stents. PMID- 29986287 TI - Effect of grinding on subsurface modifications of pre-sintered zirconia under different cooling and lubrication conditions. AB - Pre-sintered zirconia is preferred as a restoration material in dental applications due to its excellent strength and fracture toughness. When abrasive processes were used to obtain the required shape of (Y-TZP) yttria-stabilized tetragonal pre-sintered zirconia, it resulted in material strength degradation in the presence of coolant. Therefore, experiments were carried out on pre-sintered zirconia with diamond grinding wheel to evaluate the performance of cooling conditions such as dry, wet and minimum quantity lubrication (MQL). The effects of different environments on the grinding performance were studied based on the temperature distribution, phase transformation, flexural strength, microhardness and edge chipping damage. The Raman spectroscopy and X-ray diffraction analysis were used to estimate the quantity of monoclinic phase in pre-sintered zirconia. The temperature rise of the workpiece material during the grinding experiment was not higher and insufficient to cause the thermal stresses. The microstructural changes induced by grinding under different cooling strategies were associated with the quantitative assessment of monoclinic phase. The flexural strength of ground components was improved in the dry condition compared to the other process due to the absence of the defective layer and the occurrence of Y3+ ions segregation. After grinding, there was a slight decrease in the hardness value by (1-8 HV), which was due to the formation of microcracks in the subsurface layer of the ground surface. In addition, to ensure the presence of microcracks, the edge chipping depth was measured. The damage depth obtained from the wet condition showed a higher value of 30 um compared to the dry and MQL conditions. PMID- 29986288 TI - Impact of annular and supra-annular CoreValve deployment locations on aortic and coronary artery hemodynamics. AB - CoreValve is widely used in transcatheter aortic valve replacement, but the impact of its deployment location on hemodynamics is unexplored despite a potential role in subsequent aortic and coronary artery pathologies. The objectives of this investigation were to perform fluid-structure interaction (FSI) simulations for a 29 mm CoreValve deployed in annular vs supra-annular locations, and characterize resulting hemodynamics including velocity and wall shear stress (WSS). Patient-specific geometry was reconstructed from computed tomography scans and CoreValve was deployed using a finite element approach. FSI simulations were then performed using a boundary conforming method and realistic boundary conditions. Results showed that CoreValve deployment location impacts hemodynamics in the ascending aorta and flow patterns in the coronary arteries. During peak-systole, annularly deployed CoreValve produced a jet-like flow structure impinging on the outer-curvature of the ascending aorta. Supra annularly deployed CoreValve having a lateral tilt of 10 degrees led to a more centered jet impinging further downstream. At mid-systole, valve leaflets of the annularly deployed CoreValve closed asymmetrically leading to disorganized flow patterns in the ascending aorta vs those from the supra-annular position. Supra annularly deployed CoreValve also led to high-velocity para-valvular flow supplying the coronary arteries. CoreValve in the supra-annular position significantly (P < 0.05) elevated WSS within the first few diameters of both coronary arteries as compared to the annular position for many time points quantified. These results afforded by the advanced simulation methods may have important clinical implications given the role of aortic hemodynamics in dilation and the pro-atherogenic nature of WSS alterations in the coronary arteries. PMID- 29986289 TI - Mechano-tribological properties and in vitro bioactivity of biphasic calcium phosphate coating on Ti-6Al-4V. AB - Biphasic calcium phosphate (BCP) consists of hydroxyapatite (HA) and beta tricalcium phosphate (beta-TCP). BCP is mainly used in artificial tooth and bone implants due to higher protein adsorption and osteoinductivity compared to HA alone. Although, many studies have been investigated on radio frequency (RF) magnetron sputtering of HA on Ti and its alloy, however, limited studies are available on BCP coating by this process and its bioactivity and adhesion behavior. Thus, in order to obtain a better understanding and applications of BCP films, RF magnetron sputtering is used to deposit BCP films on Ti-6Al-4V in the present study. The effect of film thickness on wettability, mechanical properties and in vitro bioactivity at a particular set of sputtering parameters are investigated. BCP film thickness of 400 nm, 700 nm and 1000 nm are obtained when sputtered for 4 h, 6 h and 8 h, respectively. Although the phase compositions are almost same for all films, the surface roughness values varies around 112-153 nm with rise in film thickness. This in turn enhances hydrophilicity in accordance to Wenzel relation as the contact angle decreases from 89.6 +/- 2 degrees to 61.2 +/- 2 degrees . It is found that the 1000 nm film possess highest micro hardness and surface scratch resistance. No cracking of film up to scratch load of 2.3 N and no significant delamination up to load of 7.8 N are observed, indicating very good adhesion between BCP films and Ti-6Al-4V substrate. There is a great improvement in wt% apatite layer formation on all films when dipped in simulated body fluid (SBF) for 14 days. Among these, 1000 nm sputtered film results the highest increase in wt% apatite layer from 44.87% to 86.7%. The apatite layer possess small globular as well as elliptical structure are nucleated and grew on all the BCP films. Thus, sputtering of BCP films improves wettability, mechanical properties as well as bioactivity of Ti-6Al-4V, which can be applied for orthopedic implants. PMID- 29986290 TI - Electromyography activity of triceps surae and tibialis anterior muscles related to various sports shoes. AB - Triceps surae (TS) and tibialis anterior (TA) activation patterns have not yet been studied under different types of sport shoes. We hypothesized that sports shoes may reduce the activity patterns of these muscles in relation to barefoot condition. Thus, our main aim was to evaluate the activity patterns of TS and TA muscles in healthy people during all gait phases using five types of sport shoes with respect to barefoot condition. A total sample of thirty healthy participants, mean age 36.20 +/- 8.50, was recruited in a podiatry laboratory following an observational research design. During walking and running, electromyography signals were recorded from TS and TA muscles using surface electrodes in the following experimental situations: 1.) barefoot, 2.) minimalist, 3.) pronated control, 4.) air chamber, 5.) ethyl-vinyl-acetate and 6.) boost. The TS and TA showed significant reductions (P < 0.05) in the peak amplitude of different sport shoes types with respect to the barefoot condition in different phases of the gait cycle during walking and running. Nevertheless, the boost sport shoe produced statistically significant increases in the peak amplitude of the gastrocnemius medialis muscle in comparison with the barefoot condition in the midstance phase of the gait cycle during running (P = 0.047). In addition, the pronation control and air chamber sport shoes produced statistically significant increases in the peak amplitude of the TA muscle with respect to the barefoot condition in the contact phase of the gait cycle (P = 0.021; P = 0.013), respectively, during running. Despite TS and TA muscles activity patterns seem to be reduced using different sport shoes types with respect to the barefoot condition in different phases of the gait cycle during walking and running, some sport shoes may increase this muscular activity in specific phases of the gait cycle during running. PMID- 29986291 TI - Validation of finite element models of the mouse tibia using digital volume correlation. AB - The mouse tibia is a common site to investigate bone adaptation. Micro-Finite Element (microFE) models based on micro-Computed Tomography (microCT) images can estimate bone mechanical properties non-invasively but their outputs need to be validated with experiments. Digital Volume Correlation (DVC) can provide experimental measurements of displacements over the whole bone volume. In this study we applied DVC to validate the local predictions of microFE models of the mouse tibia in compression. Six mouse tibiae were stepwise compressed within a microCT system. MicroCT images were acquired in four configurations with applied compression of 0.5 N (preload), 6.5 N, 13.0 N and 19.5 N. Failure load was measured after the last scan. A global DVC algorithm was applied to the microCT images in order to obtain the displacement field over the bone volume. Homogeneous, isotropic linear hexahedral microFE models were generated from the images collected in the preload configuration with boundary conditions interpolated from the DVC displacements at the extremities of the tibia. Experimental displacements from DVC and numerical predictions were compared at corresponding locations in the middle of the bone. Stiffness and strength were also estimated from each model and compared with the experimental measurements. The magnitude of the displacement vectors predicted by microFE models was highly correlated with experimental measurements (R2 >0.82). Higher but still reasonable errors were found for the Cartesian components. The models tended to overestimate local displacements in the longitudinal direction (R2 = 0.69-0.90, slope of the regression line=0.50-0.97). Errors in the prediction of structural mechanical properties were 14% +/- 11% for stiffness and 9% +/- 9% for strength. In conclusion, the DVC approach has been applied to the validation of microFE models of the mouse tibia. The predictions of the models for both structural and local properties have been found reasonable for most preclinical applications. PMID- 29986292 TI - Reliability of wear measurements of CAD-CAM restorative materials after artificial aging in a mastication simulator. AB - OBJECTIVES: The purpose of this in vitro study was to assess the 2-body wear behavior of computer-aided design and computer-aided manufacturing (CAD-CAM) restorative materials and additionally to validate an automatic approach to wear quantification as provided by newly developed software. MATERIALS AND METHODS: Two composite resins (Experimental Composite, Shofu Block HC), 1 polymethyl methacrylate- (PMMA)-based material (Telio CAD), and 1 dual-network material (VITA Enamic) were tested (n = 12). The materials were stored in distilled water at 37 degrees C for 14 days, then aged in a mastication simulator (cycles: 400 000, 50 N, 1.2 Hz, 5/55 degrees C) for 2-body wear testing with human molars as antagonists. Software was developed as a freely available function in R for automatic wear quantification and was applied to 2 (vertical and horizontal) images obtained by an optical laser scanner (SDM). Wear measurements were validated with a reference confocal laser scanning microscope (LSM) system. The Kruskal-Wallis with Tukey-Kramer post hoc test (alpha = 0.05), coefficient of variation, Bland-Altman method, and intraclass correlation were applied. RESULTS: Shofu Block HC showed the greatest wear, and no differences were found among other materials. The automatic wear measurements agreed well with the reference LSM system. The reliability of the SDM scans was 98.5%. CONCLUSIONS: The wear resistance caused by two-body wear differed among the restorative materials tested, with the mean wear resistance of the 2 composite resin materials differing significantly. Wear quantification with R software based on SDM scans showed satisfactory agreement with the reference LSM system. PMID- 29986293 TI - The effect of artificial aging on Martens hardness and indentation modulus of different dental CAD/CAM restorative materials. AB - OBJECTIVES: To determine the Martens hardness parameters for five different classes of CAD/CAM restorative materials after storage in water and thermo cycling. MATERIALS AND METHODS: Lithium disilicate ceramic IPS e.max CAD (EX), silicate ceramic IPS Empress CAD (EC), a polymer infiltrated interpenetrating network material (hybrid material) VITA Enamic (VE), two compact filled composites Lava Ultimate (LU), experimental material (EM), two low filled resin composites Katana Avencia (KA), Ambarino High-Class (AH) and ultra-low/unfilled acrylic polymers CAD-Temp (CT), Telio CAD (TC), breCAM.HIPC (BC) were tested. Specimens were stored in water at 37 degrees C for 30, 60, 90, 120 days and afterwards thermo-cycled (30,000*, 5 degrees C/55 degrees C). Martens hardness (HM) and indentation modulus (EIT) were longitudinally investigated after each storage time. For structural analysis, each material was analyzed by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). RESULTS: The groups of unfilled polymers/ultra-low filled composite (CT, TC, BC) followed by low (KA, AH) and compact filled resin composites (LU, EM) showed the lowest HM and EIT values (p < 0.001). The highest values presented ceramics (EX, EC) followed by hybrid material (VE) (p < 0.001). High influence on the Martens hardness parameters was exerted by the aging duration (HM: etaP2 = 0.108, p < 0.001; EIT: etaP2 = 0.074, p < 0.001). Structural analyses of resin composites revealed big differences in shape, size and distribution of filler particles. CONCLUSIONS: The tested CAD/CAM materials showed differences in Martens hardness and indentation modulus pursuant to the material class. Ceramics showed highest values, followed by the hybrid material. For resin composites the Martens hardness and indentation modulus increased with the filler content. Artificial aging affected CAD/CAM materials differently. Some materials tested are prone to aging, the Martens hardness and indentation modulus decreased after thermo cycling. PMID- 29986294 TI - An investigation on the correlation between the mechanical property change and the alterations in composition and microstructure of a porcine vascular tissue underwent trypsin-based decellularization treatment. AB - PURPOSE: The nonlinear pseudoelastic behavior of a native/decellularized vascular tissue is closely related to the detailed composition and microstructure of the extracellular matrix and is important in maintaining the patency of a small caliber vascular graft. A commonly used enzyme-detergent based decellularization protocol is effective in cell component removal but it also changes the microstructure and composition of the decellularized tissues. Previous studies provide limited information to correlate the mechanical property change with the alterations in composition and microstructure in a decellularization process. In this study, the correlations were studied by implementing a previously established fiber-progressive-engagement model to describe the nonlinear pseudoelastic behavior of a vascular tissue and to evaluate the effects of trypsin concentration and exposure duration on porcine coronary artery decellularization RESULTS: Results showed that tissue length and width increased and thickness and wet weight decreased with the exposure of trypsin. The effects of trypsin exposure times on the four mechanical parameters, i.e. initial strain, turning strain, initial modulus and stiffness modulus, in the longitudinal and circumferential directions were similar, but stronger in the circumferential direction. Major components of the extracellular matrix were vulnerable to the trypsin-based decellularization process. The decreases in initial and turning strain and the increase in initial modulus in circumferential direction were correlated with the significant decrease of collagen and glycosaminoglycans in the media layer. CONCLUSIONS: Although trypsin-based decellularization achieved cell component removal and preservation of ultimate tensile stress, the microstructure and composition changed with alterations in the pseudoelastic behavior of the porcine coronary artery. Taken together, the current observations suggested less waviness, early engagement, or re-alignment of insoluble collagen fibers in the media layer, which resulted in turning from anisotropic into isotropic uniaxial mechanical property of porcine vascular tissue. Selecting the proper trypsin concentration (< 0.03-0.5%) and duration (< 12 h) of trypsin exposure in combination with other methods will achieve optimal porcine coronary artery decellularization. PMID- 29986296 TI - Tailoring the mechanical property and cell-biological response of beta-tricalcium phosphate composite bioceramics by SrO-P2O5-Na2O based additive. AB - beta-tricalcium phosphate (beta-TCP) bioceramic, which is a prevalent bone graft, is deficient in mechanical strength and mediating the biological functions. In the present study, beta-tricalcium phosphate composite bioceramics (TCP/SPNs) were prepared by introducing SrO-P2O5-Na2O based (SPN) sintering additive. With increasing mole ratio of SrO to P2O5, the SPN tended to crystallize. In the liquid-phase sintering process, beta-TCP reacted with SPN, producing new compounds. The difference in characteristic of SPN additive affected the compressive strength and cell-biological response of the fabricated TCP/SPNs. By selecting SPN with appropriate formulation, the TCP/SPNs not only could more than double their compressive strength, but also improved the cell viability, promoted osteogenic differentiation and inhibited osteoclastic activities. Taken together, this work establishes a beneficial strategy to improve the overall performance of calcium phosphate bioceramic for application in bone regeneration. PMID- 29986295 TI - Anti-corrosion performance of chemically bonded phosphate ceramic coatings reinforced by nano-TiO2. AB - To promote anti-corrosion property of chemically bonded phosphate ceramic coatings (CBPCs), the nano-TiO2 is selected as the reinforcement. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), Scanning electron microscope (SEM), Energy Dispersive Spectrometer (EDS) and the electrochemical analysis are carried out to clarify the role of nano-TiO2 on the improvement of anti-corrosion performance. The experiments show that with the addition of nano-TiO2, the curing temperature and the activation energy of the curing process increase, which allows longest reaction and positively drives curing reactions at elevated conversions. The enhancement of anti-corrosion performance of CBPCs reinforced by nano-TiO2 particles is based on three main mechanisms. Firstly, more bonded phase (AlPO4) can be formed with the addition of nano-TiO2, which can help CBPCs to get more compact microstructure. Additionally, AlPO4 particles possess the low density and good corrosion resistance, which leads to the increase in the corrosion resistance of CBPCs. Secondly, increasing content of nano-TiO2 can also strengthen the compactness of CBPCs to protect the substrates from the penetration of aggressive electrolyte and prolong electrolyte diffusion path. Thirdly, through the analysis of microstructure of CBPCs, it is found that most of the hydrophobic nano-TiO2 particles homogeneously distribute on the surface of CBPCs. Therefore, CBPCs show well hydrophobic performance, which can further improve the anti-corrosion property of themselves. PMID- 29986297 TI - Microstructure and elastic modulus evolution of TiTaNb alloys. AB - In order to develop Ti based alloys with promising biocompatibility and matching mechanical response with human bone, TiTaNb alloys with 15, 23 and 30 mass% Ta are designed and systematically examined in terms of microstructural evolution and mechanical response. The Ti-30mass%Ta-10mass%Nb is demonstrated to be satisfactory with an elastic modulus ~60 GPa, hardness ~3.1 GPa, and strength ~1250 MPa. The evolution trend of the resulting microstructure and phases as a function of Ta content and annealing temperature are established. The relationship between the various phase amounts and alloy moduli is explored. PMID- 29986298 TI - Stented valve dynamic behavior induced by polyester fiber leaflet material in transcatheter aortic valve devices. AB - OBJECTIVE: This study aims at assessing the global dynamic behavior, elastic deformability, closing energy and turbulence of rigid versus deformable stented (RS vs DS) valve systems with deformable and rigid textile materials (DT vs RT) through studying the stent-valve interaction compared to a bioprosthetic material in transcatheter aortic valves (TAV). METHODS: Three 19 mm stented textile TAV designs (RS-DT, RS-RT and DS-RT) with different stent and leaflet properties were tested and compared with a control bioprosthetic TAV (RS-DB) in a left heart simulator flow loop under physiological pressure and flow. Particle Image Velocimetry and high speed imaging were performed. Pressure gradients (PG), leakage fractions (LF), Pinwheeling indices (PI), closing energy (E) and Reynolds shear stresses (RSS) were calculated. RESULTS: (a) PGs and LFs were 11.86 +/- 0.51 mmHg, 11.70 +/- 0.34%; 8.84 +/- 0.40 mmHg, 29.80 +/- 0.76%; 11.59 +/- 0.12 mmHg, 14.23 +/- 1.64%; and 7.05 +/- 0.09 mmHg, 12.08 +/- 0.45% % for RS-DB, RS DT, RS-RT and DS-RT respectively. (b) PIs were 15.79 +/- 2.34%, 4.36 +/- 0.84%, 2.47 +/- 0.51% and 2.03 +/- 0.33% for RS-DB, RS-DT, RS-RT and DS-RT respectively. (c) E is lowest for DS-RT (0.0010 +/- 0.0002 J) followed by RS-RT (0.0017 +/- 0.0002 J), RS-DB (0.0023 +/- 0.0004 J) and highest with RS-DT (0.0036 +/- 0.0007 J). (d) At peak systole lowest RSS was obtained with RS-DT (87.82 +/- 0.58 Pa) and highest with DS-RT (122.98 +/- 1.87 Pa). CONCLUSION: PGs, LFs, PIs and E were improved with DS-RT compared to other textile TAVs and RS-DB. Despite achieving more RSS than the rest of TAVs, DS-RT still falls within the same range of RSS produced by the other 2 valves and control exceeding the threshold for platelet activation. PMID- 29986299 TI - Mechanical, degradation and drug-release behavior of nano-grained Fe-Ag composites for biomedical applications. AB - An original fabrication route of high-strength bulk Fe-5Ag and Fe-10Ag nanocomposites with enhanced degradation rate is reported. Near fully dense materials with fine nanostructures and uniform distribution of Ag nanoparticles were obtained employing high energy attrition milling of Fe-Ag2O powder blends followed by cold sintering - high pressure consolidation at ambient temperature that allowed the retention of the nanoscale structure. Annealing in hydrogen flow at 550 degrees C resulted in enhanced ductility without coarsening the nanostructure. The strength in compression of Fe5Ag and Fe10Ag nanocomposites was several-fold higher than the values reported for similar composites with micrometer grain size. The galvanic action of finely dispersed Ag nanoparticles greatly increased the corrosion rate and degradation kinetics of iron. Following four weeks immersion of Fe-Ag nanocomposites in saline solution, a more than 10% weight loss accompanied by less than 25% decrease in bending strength were measured. The interconnected nanoporosity of cold sintered Fe-Ag nanocomposites was utilized for incorporation of vancomycin that was gradually released upon immersion. In cell culture experiments, the Fe-Ag nanocomposites supported the attachment of osteoblast cells and exhibited no signs of cytotoxicity. The results suggest that the proposed Fe-Ag nanocomposites could be developed into attractive biodegradable load-bearing implant materials with drug delivery capability. PMID- 29986300 TI - Design of a remote-control drug delivery implantable chip for cancer local on demand therapy using ionic polymer metal composite actuator. AB - Since the local, on demand, cancer therapy is a challenging clinical issue today, this paper presents the design, fabrication and characterization of a remotely controlled single reservoir drug delivery chip using Ionic Polymer Metal Composite (IPMC) actuator. Here, Drug release was externally programmed and controlled wirelessly on demand by a communication circuit. The transmitter and receiver circuits were designed to control the release/sealed status remotely even from 7 cm distance while the transmitter and receiver were coupled magnetically. IPMC here was used as the moving cap of the reservoir, that in release mode, lets the drug out on demand with a low received power of 20 mW. The novel simple design could release the whole content of the drug which is remarkable in comparison with the designs which need complicated optimizations of diffuser, nuzzle and IPMC diaphragm pump, leading to an incomplete release. To make sure that there is no leakage in the sealed mode, IPMC was attached to a polydimethylsiloxane (PDMS) support film. Biocompatibility of all the components of the chip were tested by 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay. PMID- 29986302 TI - Targeting IgE in allergic disease. AB - Immunoglobulin E (IgE) represents the least abundant antibody isotype in human serum. Nevertheless, it has the ability to induce potent allergic reactions. As a key component in the development and manifestation of hypersensitivity responses against usually non-hazardous foreign substances, IgE has become a major target of investigation and the subject of multiple therapeutic approaches for the treatment of allergies. Recent advances in the understanding of pathophysiologic mechanisms underlying IgE-associated allergic disorders have led to the generation of new drug candidates that are currently in development or under clinical evaluation. In this review, we highlight molecular and structural mechanisms underlying the different anti-IgE molecules and suggest a concept of multi-level targeting using a new class of disruptive IgE inhibitors to potentially optimize treatment efficacy. PMID- 29986301 TI - The hygiene hypothesis: immunological mechanisms of airway tolerance. AB - The hygiene hypothesis was initially proposed as an explanation for the alarming rise in allergy prevalence in the last century. The immunological idea behind this hypothesis was a lack of infections associated with a Western lifestyle and a consequential reduction in type 1 immune responses. It is now understood that the development of tolerance to allergens depends on microbial colonization and immunostimulatory environmental signals during early-life or passed on by the mother. These environmental cues are sensed and integrated by barrier epithelial cells of the lungs and possibly skin, which in turn instruct dendritic cells to regulate or impede adaptive T cell responses. Recent reports also implicate immunoregulatory macrophages as powerful suppressors of allergy by the microbiome. We propose that loss of adequate microbial stimulation due to a Western lifestyle may result in hypersensitive barrier tissues and the observed rise in type 2 allergic disease. PMID- 29986304 TI - Can the dietary fat type facilitate memory impairments in adulthood? A comparative study between Mediterranean and Western-based diet in rats. AB - A balanced intake of fatty acids (FA) of both omega-6 (n-6) and -3 (n-3) series is essential for memory. The Mediterranean diet (MD), rich in n-3 polyunsaturated FA (PUFA) and low n-6/n-3 PUFA ratio, has shown beneficial influences on health. Inversely, the Western diet contains saturated fats, including hydrogenated vegetable fat (HVF, rich in trans fat) and interesterified fat (IF), making the n 6/n-3 PUFA ratio high. Due to the health impairments caused by HVF, it has been replaced by IF in processed foods. We compared an MD (balanced n-6/n-3 PUFA ratio) with Western diets 1 (WD1, rich in trans fat) and 2 (WD2, rich in IF) on memory process per se and following scopolamine (SCO) administration, which induces amnesia in rats. While MD exerted protective effects, WD1 and WD2 showed declined memory per se, showing higher susceptibility to SCO-induced memory deficits. In addition, WD1 and WD2 showed increased proinflammatory cytokines [tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6] and decreased anti inflammatory cytokines (IL-10) in plasma. IL-1beta was higher in the hippocampus of WD1, which was reflected on histological assessments. Significant correlations between cognitive decline and inflammatory markers reinforce our hypothesis: MD like fats may act preventively on cognitive loss, while WD-like fats may facilitate this. PMID- 29986305 TI - Paracellular calcium flux across Caco-2 cell monolayers: Effects of individual amino acids. AB - High-protein diets are generally considered beneficial for calcium (Ca) economy and bone health. Improved intestinal Ca absorption efficiency may be one mechanism by which higher-protein diets affect Ca homeostasis and bone health. The signaling pathways and individual amino acids (AA) responsible for this effect have not been fully elucidated and may involve the transcellular pathway, paracellular pathway or a combination. The primary aim of this study was to investigate whether a mixture of AA and/or functionally distinct individual AA directly affect paracellular Ca absorption across an intestinal epithelial cell model (Caco-2 Bbe). Using Ussing chambers, we examined the effect of six treatments - vehicle (Veh), 80 mM raffinose (Raf; positive control), 2* mixed AA(2*AA, twice the concentration in standard growth media), the branched-chain amino acid leucine (2-10 mM Leu), the aromatic amino acid phenylalanine (2-10 mM Phe) and the dibasic amino acid lysine (2-10 mM Lys) - on Ca flux. Leu (5 mM) increased Ca flux by 38% (+122 nmol Ca/cm2/h, P<.001) as compared to Veh, while 10 mM Phe reduced Ca flux. No other differences were observed. Leu increased Ca flux through cellular redistribution of the Ca permissive channel Cldn-2 to the tight junction membrane (P<.05). Inhibition of mTORC1 signaling did not abrogate the effect of Leu on Cldn-2 localization, indicating a non-mTORC1-dependent signaling pathway is involved. These data indicate that Leu may improve Ca absorption in a cell model, potentially contributing to the observed benefits of higher-protein diets on bone health in humans. PMID- 29986303 TI - Partners in anti-crime: how interferon-inducible GTPases and autophagy proteins team up in cell-intrinsic host defense. AB - Once pathogens have breached the mechanical barriers to infection, survived extracellular immunity and successfully invaded host cells, cell-intrinsic immunity becomes the last line of defense to protect the mammalian host against viruses, bacteria, fungi and protozoa. Many cell-intrinsic defense programs act as high-precision weapons that specifically target intracellular microbes or cytoplasmic sites of microbial replication while leaving endogenous organelles unharmed. Critical executioners of cell-autonomous immunity include interferon inducible dynamin-like GTPases and autophagy proteins, which often act cooperatively in locating and antagonizing intracellular pathogens. Here, we discuss possible mechanistic models to account for the functional interactions that occur between these two distinct classes of host defense proteins. PMID- 29986307 TI - Betaine or folate can equally furnish remethylation to methionine and increase transmethylation in methionine-restricted neonates. AB - Methionine partitioning between protein turnover and a considerable pool of transmethylation precursors is a critical process in the neonate. Transmethylation yields homocysteine, which is either oxidized to cysteine (i.e., transsulfuration), or is remethylated to methionine by folate- or betaine- (from choline) mediated remethylation pathways. The present investigation quantifies the individual and synergistic importance of folate and betaine for methionine partitioning in neonates. To minimize whole body remethylation, 4-8-d-old piglets were orally fed an otherwise complete diet without remethylation precursors folate, betaine and choline (i.e. methyl-deplete, MD-) (n=18). Dietary methionine was reduced from 0.3 to 0.2 g/(kg?d) on day-5 to limit methionine availability, and methionine kinetics were assessed during a gastric infusion of [13C1]methionine and [2H3-methyl]methionine. Methionine kinetics were reevaluated 2 d after pigs were rescued with either dietary folate (38 MUg/(kg?d)) (MD + F) (n=6), betaine (235 mg/(kg?d)) (MD + B) (n=6) or folate and betaine (MD + FB) (n=6). Plasma choline, betaine, dimethylglycine (DMG), folate and cysteine were all diminished or undetectable after 7 d of methyl restriction (P<.05). Post rescue, plasma betaine and folate concentrations responded to their provision, and homocysteine and glycine concentrations were lower (P<.05). Post-rescue, remethylation and transmethylation rates were~70-80% higher (P<.05), and protein breakdown was spared by 27% (P<.05). However, rescue did not affect transsulfuration (oxidation), plasma methionine, protein synthesis or protein deposition (P>.05). There were no differences among rescue treatments; thus betaine was as effective as folate at furnishing remethylation. Supplemental betaine or folate can furnish the transmethylation requirement during acute protein restriction in the neonate. PMID- 29986306 TI - A diet defined by its content of bovine milk exosomes and their RNA cargos has moderate effects on gene expression, amino acid profiles and grip strength in skeletal muscle in C57BL/6 mice. AB - Exosomes are nanoparticles that transfer cargos from donor cells to recipient cells where they elicit changes in gene expression and metabolism. Evidence suggests that exosomes and their cargos are also absorbed from dietary sources such as bovine milk, and bovine exosomes promote the growth of myofibers in murine C2C12 myotube cell cultures. The aim of the current study was to determine whether the dietary intake of bovine milk exosomes alters strength, gene expression and amino acid profiles in murine skeletal muscles. Male and female C57BL/6 mice, age three weeks, were fed an AIN93G-based, exosome and RNA-depleted (ERD) diet for six weeks; controls were fed an exosome and RNA-sufficient (ERS) diet. Variables of feeding behavior, metabolism, grip strength, liver and kidney function, amino acid profiles, and gene expression patterns were analyzed by using metabolic cages, grip strength analyzers, clinical chemistry analyzers, targeted LC/MS-MS, and RNA sequencing analysis. The diets had no effect on food and water intake, respiratory exchange rate, physical activity, grip strength, markers of liver and kidney dysfunction, and amino acid profiles in muscle. Only twelve and nine mRNAs were differentially expressed in skeletal muscle from female and male mice, respectively, fed ERD and ERS diets. The modest effect of the ERD diet on gene expression and levels of free amino acids in skeletal muscle is consistent with observations that bovine milk exosomes and their cargos accumulate in tissues other than skeletal muscle. PMID- 29986308 TI - Down-regulation of placental folate transporters in intrauterine growth restriction. AB - Folate deficiency in pregnancy is associated with neural tube defects, restricted fetal growth and fetal programming of diseases later in life. Fetal folate availability is dependent on maternal folate levels and placental folate transport capacity, mediated by two key transporters, Folate Receptor-alpha and Reduced Folate Carrier (RFC). We tested the hypothesis that intrauterine growth restriction (IUGR) is associated with decreased folate transporter expression and activity in isolated syncytiotrophoblast microvillous plasma membranes (MVM). Women with pregnancies complicated by IUGR (birth weight <3rd percentile, mean birth weight 1804+/-110 g, gestational age 35.7+/-0.61 weeks, n=25) and women delivering an appropriately-for gestational age infant (control group, birth weight 25th-75th centile, mean birth weight 2493+/-216 g, gestational age 33.9+/ 0.95 weeks, n=19) were recruited and placentas were collected at delivery. MVM was isolated and folate transporter protein expression was measured using Western blot and transporter activity was determined using radiolabelled methyltetrahydrofolic acid and rapid filtration. Whereas the expression of FR alpha was unaffected, MVM RFC protein expression was significantly decreased in the IUGR group (-34%, P<.05). IUGR MVM had a significantly lower folate uptake compared to the control group (-38%, P<.05). In conclusion, placental folate transport capacity is decreased in IUGR, which may contribute to the restricted fetal growth and intrauterine programming of childhood and adult disease. These findings suggest that continuation of folate supplementation in the second and third trimester is of particular importance in pregnancies complicated by IUGR. PMID- 29986309 TI - Mechanisms of DHA-enriched phospholipids in improving cognitive deficits in aged SAMP8 mice with high-fat diet. AB - Recent studies have shown that a high-fat diet (HFD) is involved in both metabolic dysfunction and cognitive deficiency and that docosahexaenoic-acid enriched phospholipids (DHA-PLs) have beneficial effects on obesity and cognitive impairment. However, there are only a few studies comparing differences between DHA-PC and DHA-PS in HFD-induced Alzheimer's disease (AD) models. After 8 weeks feeding with HFD, 10-month-old SAMP8 mice were fed with 1% (w/w) DHA-PC or 1% DHA PS (biosynthesized from DHA-PC) for 8 weeks; we then tested the behavioral performances in the Barnes maze test and Morris maze test. The changes of the generation and accumulation of Abeta, oxidative stress, apoptosis, neuroinflammation and neurotrophic factors were also measured. The results indicated that both DHA-PC and DHA-PS significantly improved the metabolic disorders and cognitive deficits. Both DHA-PC and DHA-PS could ameliorate oxidative stress, and DHA-PS presented more notable benefits than DHA-PC on Abeta pathology, mitochondrial damage, neuroinflammation and neurotrophic factors; DHA PS was for the first time found to increase the production of insoluble Abeta (less pathogenic) in this AD model. These data suggest that DHA-PLs can significantly improve cognitive deficiency, and the molecular mechanisms for this closely relate to the phospholipid polar groups. PMID- 29986310 TI - Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice. AB - Folic acid (FA) supplementation may protect from obesity and insulin resistance, the effects and mechanism of FA on chronic high-fat-diet-induced obesity-related metabolic disorders are not well elucidated. We adopted a genome-wide approach to directly examine whether FA supplementation affects the DNA methylation profile of mouse adipose tissue and identify the functional consequences of these changes. Mice were fed a high-fat diet (HFD), normal diet (ND) or an HFD supplemented with folic acid (20 MUg/ml in drinking water) for 10 weeks, epididymal fat was harvested, and genome-wide DNA methylation analyses were performed using methylated DNA immunoprecipitation sequencing (MeDIP-seq). Mice exposed to the HFD expanded their adipose mass, which was accompanied by a significant increase in circulating glucose and insulin levels. FA supplementation reduced the fat mass and serum glucose levels and improved insulin resistance in HFD-fed mice. MeDIP-seq revealed distribution of differentially methylated regions (DMRs) throughout the adipocyte genome, with more hypermethylated regions in HFD mice. Methylome profiling identified DMRs associated with 3787 annotated genes from HFD mice in response to FA supplementation. Pathway analyses showed novel DNA methylation changes in adipose genes associated with insulin secretion, pancreatic secretion and type 2 diabetes. The differential DNA methylation corresponded to changes in the adipose tissue gene expression of Adcy3 and Rapgef4 in mice exposed to a diet containing FA. FA supplementation improved insulin resistance, decreased the fat mass, and induced DNA methylation and gene expression changes in genes associated with obesity and insulin secretion in obese mice fed a HFD. PMID- 29986311 TI - Chlorogenic acid improves intestinal barrier functions by suppressing mucosa inflammation and improving antioxidant capacity in weaned pigs. AB - Intestinal barrier plays key roles in maintaining intestinal homeostasis. Inflammation and oxidative damage can severely destroy the intestinal integrity of mammals. Chlorogenic acid (CGA) is a natural polyphenol present in human diet and plants, possessing potent antioxidant and anti-inflammatory activities. This study was conducted to investigate the protective effects of CGA and its molecular mechanisms on intestinal barrier function in a porcine model. Twenty four weaned pigs were allotted to two groups and fed with a basal diet or a basal diet containing 1000 mg/kg CGA. The results showed that CGA decreased serum D lactate and diamine oxidase levels, and enhanced the expression and localization of claudin-1 protein in apical intercellular region of small intestinal epithelium. Interestingly, CGA significantly decreased the mucosa histamine and tryptase contents, as well as the tryptase-positive mast cell counts. Moreover, the expression levels of critical inflammation molecules (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, and nuclear factor-kappaB) were down regulated by CGA in jejunal and ileal mucosa. However, the expression levels of inflammation repressors (suppressor of cytokine signaling 1 and toll-interacting protein) were up-regulated by CGA. Importantly, CGA decreased the malondialdehyde content but elevated glutathione peroxidase and catalase content in duodenal and jejunal mucosa. The expression levels of critical molecules in antioxidant signaling (nuclear factor erythroid-derived 2-related factor 2 and heme oxygenase 1) were elevated by CGA in duodenal and jejunal mucosa. These results suggested that CGA could ameliorate intestinal barrier disruption in weaned pigs, which might be mediated by suppressing the TLR4/NF-kappaB signaling pathway and activating the Nrf2/HO-1 signaling pathway. PMID- 29986312 TI - High-fat diet disrupts bone remodeling by inducing local and systemic alterations. AB - A high-fat (HF) diet leads to detrimental effects on alveolar bone (AB); however, the mechanisms linking adiposity to bone loss are poorly understood. This study investigated if AB resorption induced by an HF diet is associated with the regulation of inflammatory gene expression and if adipocytes can directly interfere with osteoclastogenesis. We also evaluated the effects of diet restriction (DR) on bone phenotype. C57BL6/J mice were fed normal chow or an HF diet for 12 weeks. Samples of maxillae, femur, blood and white adipose tissue were analyzed. In vitro co-culture of bone marrow-derived osteoclasts and mature adipocytes was carried out. The results revealed an increased number of osteoclasts and fewer osteoblasts in animals fed the HF diet, which led to the disruption of trabecular bone and horizontal AB loss. Similar effects were observed in the femur. The metabolic parameters and the deleterious effects of the HF diet on AB and the femur were reversed after DR. The HF diet modulated the expression of 30 inflammatory genes in AB such as Fam3c, InhBa, Tnfs11, Ackr2, Pxmp2 and Chil3, which are related to the inflammatory response and bone remodeling. In vitro, mature adipocytes produced increased levels of adipokines, and co-culture with osteoclasts resulted in augmented osteoclastogenesis. The results indicate that the mechanisms by which an HF diet affects bone involve induction of osteoclastogenesis and inflammatory gene expression. Adipokines apparently are key molecules in this process. Strategies to control diet-induced bone loss might be beneficial in patients with preexisting bone inflammatory conditions. PMID- 29986313 TI - Web-based education about vulvodynia and its care among student healthcare staff: A quasi-experimental study. AB - Student healthcare providers are the type of primary healthcare professionals who usually have first contact with young women who have problems with intimacy, such as vulvar pain - known as vulvodynia. However, a need to increase healthcare professionals' level of knowledge of vulvodynia and its care has been identified. This study aimed to assess the awareness and knowledge of vulvodynia and its care among student healthcare providers, before and after Web-based education. The study design was national, descriptive and quasi-experimental, and was conducted across Finland. A total of 79 participants completed baseline measurements, 58 completed web-based education and 30 took part in a follow-up survey. A survey instrument called 'Awareness and knowledge of vulvodynia and its care' was developed for this study, and the data were collected using a web-based questionnaire. Descriptive statistical methods were used to evaluate the participants' awareness and knowledge of vulvodynia and its care before and after web-based education. The primary results indicated that the participants' awareness and knowledge of vulvodynia and its care was statistically significantly improved following web-based education. PMID- 29986314 TI - Concentrations and biological half-life of radioactive cesium in epigeic earthworms after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - To understand the long-term behavior of radiocesium in the biological processes of a forest ecosystem, its concentration in Japanese epigeic earthworms (Megascolecidae), litter, and soil, and the ambient dose equivalent rates, were investigated after the Fukushima Dai-ichi Nuclear Power Plant accident. The metabolism of radiocesium in the earthworms was also investigated in the laboratory, and its biological half-life (Tb) was estimated. The concentration of 137Cs in the habitat soil and litter changed from 2014 to 2016, with levels in the litter going from 44.9 Bq/g dw (in 2014) to 45.3 Bq/g dw (2015) and 10.7 Bq/g dw (2016); in soil, these values were 9.79 Bq/g dw, 7.14 Bq/g dw and 18.0 Bq/g dw, respectively. By contrast, no significant changes were observed in the concentrations in the earthworms, which were 4.87 Bq/g fw, 5.30 Bq/g fw and 4.67 Bq/g fw in 2014, 2015, and 2016, respectively. The ambient dose equivalent rates at the sampling site declined significantly over these three years, going from 2.15 MUSv/h to 1.68 MUSv/h and 1.35 MUSv/h, mostly corresponding to physical decay of radiocesium. The majority (95%) of the 137Cs in the earthworms, observed via autoradiography, was concentrated primarily in the intestine. The clearance of 137Cs from the earthworms was described by dual exponential functions: the half-life in the rapid loss due to gut clearance was 0.10 days and a second slower loss due to physiological clearance was 27.4 days. PMID- 29986315 TI - Review of Russian language studies on radionuclide behaviour in agricultural animals: Transfer to animal tissues. AB - Data on radionuclide transfer to animals from research performed in the former Soviet Union were reviewed to collate transfer coefficient values (Ff) to animal tissues such as liver, kidney and bone, but not muscle which has previously been reported. The derived values were compared with selected data published in the English language literature. The new data are mainly for 90Sr and 137Cs, although some data were also provided for 3H, 54Mn, 59Fe, 60Co, 22Na 65Zn, 131I and U. The Russian language data may provide a basis for better informed evaluation of radiation dose from the consumption of such animal products, which can form important components of the diet in some countries. PMID- 29986316 TI - A study of the influence of brevetoxin exposure on trace element bioaccumulation in the blue mussel Mytilus edulis. AB - Marine organisms are exposed to and affected by a multitude of chemicals present in seawater and can accumulate in their tissues a wide range of contaminants as well as natural biotoxins associated with harmful algal blooms (HABs). Trace elements and biotoxins may modify physiological functions in exposed organisms, and studies have been conducted to better understand their respective kinetics and effects in marine species. Despite the increasing concern of concurrent toxic HABs and pollution events due to anthropogenic pressures and global change, very little information is available on their combined effects. Chemical interactions between biotoxins and trace elements have been reported, and exposure to certain biotoxins is known to modify ion transport pathways, suggesting that biotoxins have the potential to alter trace element uptake. Using specific and sensitive radiotracer techniques (radioligand receptor binding assay and gamma spectrometry), this laboratory study examined the influence of pre-exposure to the brevetoxins (PbTxs)-producing microalgae Karenia brevis on the bioaccumulation of selected non-essential (Cd) and essential (Co, Mn and Zn) trace elements in the blue mussel Mytilus edulis. PbTxs are a group of neurotoxins known to accumulate in bivalves but also to have lethal effects on a number of marine organisms including fish and mammals. We found that, over 23 days exposure to the radiotracers, the bioaccumulation of the dissolved essential trace elements Co, Mn and Zn in M. edulis was not significantly affected by pre exposure to toxic K. brevis. In contrast, the uptake rate constant ku of Cd was significantly higher in the pre-exposed group (p < 0.05), likely caused by a decrease in mussel clearance rates after K. brevis exposure. These results suggest that the effects of algal toxin exposure on bioaccumulation of trace elements in mussels may be trace element-dependent. PMID- 29986318 TI - The theoretical and experimental vibrational studies of thiourea and silver nitrate (2:1) complex. AB - The theoretical and experimental vibrational studies for poly thiourea silver nitrate (2:1) complex using DFT method are performed on the basis of experimental data. During the geometry optimization process one equilibrium structure was found. The Mulliken charges, harmonic vibrational frequencies, Infrared and Raman intensities were calculated on the basis of quantum chemical density functional calculations using firefly (PC GAMESS) Version 7.1G. The clear - cut assignments of observed bands are performed on the basis of potential energy distribution (PED) analysis. Highest Occupied Molecular Orbital (HOMO) and the Lowest Occupied Molecular Orbital (LUMO) are obtained and graphically illustrated with minimum energy. The energy difference between HOMO and LUMO is analyzed. The other molecular properties like molecular electrostatic potential, Mulliken charges and thermodynamic properties of the title compound have also been calculated. PMID- 29986317 TI - Evaluation of groundwater discharge into surface water by using Radon-222 in the Source Area of the Yellow River, Qinghai-Tibet Plateau. AB - Understanding hydrological processes in the Source Area of the Yellow River (SAYR), Qinghai-Tibet Plateau, is vital for protection and management of groundwater and surface water resources in the region. In situ water measurements of exchange rates between surface water and groundwater are, however, hard to conduct because of the harsh natural conditions of the SAYR. We here present an indirect method using in situ 222Rn measurements to estimate groundwater discharge into rivers and lakes in the SAYR. 222Rn was measured in rivers, lakes, groundwater and springs during three sampling periods (2014-2016), and the results indicate large variability in the concentration of the isotope. The data also indicate decreasing 222Rn trends in groundwater in the cold season (the Feb 2015 sampling period) which may be linked to frequency of capturing 222Rn in the frozen ground caused by geocryogenic processes. In addition, permafrost spatial extent and freeze-thaw processes have strongly affected the hydrological conditions in the region. PMID- 29986320 TI - Impacts of the water framework directive on learning and knowledge practices in a Swedish catchment. AB - Catchments are complex social-ecological systems involving multiple, and often competing, interests. Water governance and management regimes are increasingly embracing pluralistic, participatory, and holistic norms as a means to engage with issues of complexity, uncertainty, and value-conflicts. Integrated, participatory approaches are theoretically linked to improved learning amongst stakeholders across sectors and decision-making that is grounded in shared knowledge, experiences and scientific evidence. However, few studies have empirically examined the impacts of an integrated approach to learning and knowledge practices related to water resources. Here, a Swedish sub-catchment that has adopted such an approach in association with implementation of the European Water Framework Directive (WFD) is examined. Interview-based analyses show that WFD implementation has both helped and hindered learning and knowledge practices surrounding both water planning and spatial planning. Whilst communities of practice have developed in the study area, a number of important challenges remain. These include the rigid goal-orientation of the WFD, the fragmentation of knowledge caused by an over-reliance on external consultants, as well as a lack of resources to synthesise information from multiple sources. Present results raise questions regarding the efficacy of the WFD to sufficiently enable the development of learning and knowledge practices capable of handling the complexity, uncertainties and value-conflicts facing catchments in Sweden and elsewhere. PMID- 29986319 TI - A simple flow injection spectrophotometric procedure for iron(III) determination using Phyllanthus emblica Linn. as a natural reagent. AB - The use of natural reagents from plant extracts for chemical analysis is one approach in the development of green analytical chemistry methodology. In this work, a natural reagent extracted from Phyllanthus emblica Linn. has been applied for the determination of iron(III) using a simple flow injection spectrophotometric method. The method was based on the measurement of a dark purple complex formed by the reaction between iron(III) and the extracted solution in an acetate buffer (pH 5.6) at 570 nm. Under the optimum conditions, a linear calibration graph in the range of 0.50-20.0 mg L-1 iron(III) was obtained with a correlation coefficient (r2) of 0.9996. The limit of detection and limit of quantification were 0.31 and 0.50 mg L-1, respectively. The relative standard deviation was less than 2.50%. The proposed method was successfully applied for quantitative analysis of iron(III) in pharmaceutical preparations and water samples with a sampling rate of 90 samples h-1. The results are in good agreement with those obtained by the official ICP-OES technique at the 95% confidence level. The presented method provides a simple, cost-effective and environmentally friendly approach which is suitable and useful for determining iron(III). Therefore, it can be considered as an alternative analytical technique in green chemistry. PMID- 29986321 TI - Long-term influence of trace element deficiency on anaerobic mono-digestion of chicken manure. AB - Recent findings showed that some trace elements essential for anaerobic digestion might be deficient in chicken (laying hens) manure. In this study, the long-term influence of trace element deficiency on anaerobic mono-digestion of chicken manure was investigated. Three bench-scale anaerobic reactors were operated with or without trace element supplementation. As trace element, only Se or a mix containing Co, Mo, Ni, Se, and W was added to the reactors. The results revealed that in anaerobic digestion of chicken manure at total ammonium nitrogen concentrations over 6000 mg L-1, Se supplementation was critical but not sufficient alone for long-term stable CH4 production. Addition of a mix consisting of Co, Mo, Ni, Se and W resulted in a more stable digestion performance. Daily trace element mix supplementation promoted the hydrogenotrophic Methanoculleus bourgensis, which is an ammonia tolerant methanogen. The decrease in the relative abundance of Methanoculleus detected after termination of trace element addition and resulted in accumulation of acetate and propionate that followed by a significant decrease in CH4 production. PMID- 29986322 TI - Predicting the effectiveness of oil recovery strategies in the marine polluted environment. AB - Many recent studies have focused their attention on the physiological stress experienced by marine organisms in measuring ecotoxicological responses. Here we suggest a new approach for investigating the effects of an anthropogenic pollutant on Life-History (LH) traits of marine organisms, to provide stakeholders and policy makers an effective tool to evaluate the best environmental recovery strategies and plans. A Dynamic Energy Budget (DEB), coupled with a biophysical model was used to predict the effects of a six-month oil spill on Mytilus galloprovincialis' LH traits and to test two potential recovery strategies in the central Mediterranean Sea. Oxygen consumption rates were used to check for increasing energetic maintenance costs [pM] respectively in oil-polluted system treatments (~76.2%) and polluted systems with physical (nano-bubbles ~32.6%) or chemical treatment (dispersant ~18.4%). Our model outputs highlighted a higher growth reduction of intertidal compared to subtidal populations and contextually an effect on the reproductive output and on the maturation time of this latter. The models also enabled an estimation of the timing of the disturbance affecting both the intertidal and subtidal populations' growth and reproduction. Interestingly, results led to the identification of the chemical dispersant as being the best remediation technique in contexts of oil spill contamination. PMID- 29986323 TI - Optimal reservoir operation using multi-objective evolutionary algorithms for potential estuarine eutrophication control. AB - Increased nutrient loads and changed nutrient ratios in estuarine waters have enhanced the occurrence of eutrophication and harmful algae blooms. Most of these consequences are caused by the new proliferation of toxin-producing non-siliceous algae. In this study, we propose a multi-objective reservoir operation model based on 10-day time scale for estuarine eutrophication control to reduce the potential non-siliceous algae outbreak. This model takes the hydropower generation and social economy water requirement in reservoir into consideration, minimizing the ICEP (indicator of estuarine eutrophication potential) as an ecological objective. Three modern multi-objective evolutionary algorithms (MOEAs) are applied to solve the proposed reservoir operation model. The Three Gorges Reservoir and its operation effects on the Yangtze Estuary were chosen as a case study. The performances of these three algorithms were evaluated through a diagnostic assessment framework of modern MOEAs' abilities. The results showed that the multi-objective evolutionary algorithm based on decomposition with differential evolution operator (MOEA/D-DE) achieved the best performance for the operation model. It indicates that single implementation of hydrological management cannot make effective control of potential estuarine eutrophication, while combined in-estuary TP concentration control and reservoir optimal operation is a more realistic, crucial and effective strategy for controlling eutrophication potential of non-siliceous algae proliferation. Under optimized operation with controlled TP concentration and estuarine water withdrawal of 1470 m3/s, ecological satiety rate for estuarine drinking water source increased to 77.78%, 88.89% and 83.33% for wet, normal and dry years, the corresponding values in practical operation were only 72.22%, 58.33% and 55.56%, respectively. The results suggest that these operations will not negatively affect the economic and social interests. Therefore, the proposed integrated management approaches can provide guidance for water managers to reach a stable trophic control of estuarine waters. PMID- 29986324 TI - Efficacy of spent black tea for the removal of nitrobenzene from aqueous media. AB - Nitrobenzene (NB) is a kind of persistent organic pollutant. A ubiquitous and cost-effective substance spent black tea (SBT) was investigated for the removal of nitrobenzene from aqueous media. The maximum uptake potential of dried biomass (SBT) for NB was found to be 14.86 mg per gram (qmax) in a batch experimental set up. Equilibration time for NB sorption was about 50 min, and optimal removal efficiency was achieved at a dosage of 2 g/L with an initial concentration of 100 mg/L of NB. Findings revealed that NB uptake increased with an increase in the temperature from 273 K to 353 K. Sorption was also found to be pH sensitive, sorption improved as the pH value changes from alkaline to acidic (from 10 to 2). Different isotherm (Langmuir, Freundlich, Temkin and Dubinin Radushkevich) and kinetic models (pseudo-1st order, pseudo-2nd order and Elovich models) were applied to experimental results; the sorption mechanism was well described by the Freundlich and pseudo-2nd order models. Moreover, Scanning electron micrographs, ATR-FTIR spectra and the results of elemental analysis also supported the efficacy of SBT as an efficient bio-sorbent for the elimination of NB from water. PMID- 29986325 TI - Enhanced CO2 capturing over ultra-microporous carbon with nitrogen-active species prepared using one-step carbonization of polybenzoxazine for a sustainable environment. AB - Nitrogen-enriched porous carbon has been a promising material for CO2 capture in the recent decades. To enhance the performance of CO2 adsorption, both an N active site and the textural properties are crucial determinants. Herein, ultra microporous carbon with N-active species was prepared using two synthesis procedures: 1) one-step carbonization of a polybenzoxazine (PBZ) precursor at 800 degrees C, and 2) the CO2 activation process at 900 degrees C. The activated porous carbon had the higher specific surface area (943 m2/g) and a total pore volume (0.51 cm3/g) compared to un-activated porous carbon (335 m2/g and 0.19 cm3/g, respectively). In addition, the presence of N-active species such as pyridine-N, secondary-N, pyridone-N, and oxide-N in the carbon structures could be clearly observed in the high-resolution XPS spectra. The CO2 adsorption measurement was performed at 30 and 50 degrees C under a wide range of pressures (1-7 bar). The maximum amount of CO2 uptake was ca. 3.59 mmol/g for the activated porous carbon operated at 30 degrees C and a CO2 pressure of 7 bar, which was due to the high specific surface area and the large micropore volume. Specifically, carbon with a 3D interconnected pore structure, derived from the sol-gel process of the PBZ precursor, exhibited good structural stability and consequently led to better absorption capability under the high atmospheric pressure of CO2. The enhanced CO2 adsorption capability for the as-prepared porous carbon was based on two mechanisms: physisorption as a result of textural properties and chemisorption as a result of the acid-base interaction between the basic N functionality and the acidic CO2 gas. All results suggested that ultra microporous carbon with N-active species prepared from polybenzoxazine is a promising adsorbent for CO2 capture and storage, which can be used at a wide range of pressures and in many applications e.g. flue gas adsorption and natural gas production. PMID- 29986326 TI - Screening of potential bioremediation enzymes from hot spring bacteria using conventional plate assays and liquid chromatography - Tandem mass spectrometry (Lc-Ms/Ms). AB - The search for an eco-friendly, non-toxic, economical and efficient means of cleaning water through bioremediation is not only more favourable but critical to maintaining water quality globally especially in water-scarce countries. Thermophilic bacteria including Bacillus species are an important source of novel enzymes for biotechnology applications. In this study, 56 bacterial isolates which were cultured from five hot springs in South Africa were identified predominantly as Bacillus sp. or Bacillus-related spp by 16S rDNA gene sequencing. These isolates were screened for potentially useful enzymes for water bioremediation. Using conventional agar plate assays, 56% (n = 43), 68% (n = 38) and 16% (n = 31) were positive for amylase, protease and bromothymol blue decolorisation respectively. In liquid starch culture, three amylase-positive isolates differentially degraded starch by 34% (isolate 20S) to 98% (isolate 9T). Phenol degradation revealed that five out of thirty reduced phenol up to 42% by colorimetric assay. A thermophilic strain of Anoxybacillus rupiensis 19S (optimal growth temperature of 50 degrees C), which degraded starch, protein and phenol, was selected for further analysis by tandem LC-MS/MS. This newer technique identified potential enzymes for water bioremediation relating to pollutants from the food industry (amylase, proteases), polyaromatic hydrocarbons and dye pollutants (catalase peroxidase, superoxide dismutase, azoreductase, quinone oxidoreductase), antibiotic residues (ribonucleases), solubilisation of phosphates (inorganic pyrophosphatase) and reduction of chromate and lead. In addition, potential enzymes for biomonitoring of environmental pollutants were also identified. Specifically, dehydrogenases were found to decrease as the level of inorganic heavy metals and petroleum increased in soil samples. This study concludes that bacteria found in South African hot springs are a potential source of novel enzymes with tandem LC-MS/MS revealing substantially more information compared with conventional assays, which can be used for various applications of water bioremediation. PMID- 29986327 TI - Recent developments and prospects of dioxins and furans remediation. AB - Rapid urbanization and industrialization of anthropogenic activities have exerted immense pressure on the environment. Polyhalogenated organic compounds, especially dioxins and furans are regarded as ubiquitously persistent environmental pollutants in the ecosystem. The recalcitrant nature of dioxins and furans induce toxicity in both humans and wildlife. Dioxins and furans are generated by defective technological chemical processes that occur during the manufacture of herbicides and pesticides, use of fertilizers, bleaching of paper and wood pulp and incomplete combustion process. However, incineration and incomplete combustion of solid waste are the main cause for the discharge of dioxins and furans to the environment. During incineration and incomplete combustion, noxious flue gas and ashes are released into the atmosphere and contaminate the soil and water systems; thereby affecting the ecology. According to World Health Organization fact sheet 2016, more than 90% of human exposure to dioxins is through the food chain, especially from dairy products, seafood and meat. These pollutants are mutagenic, carcinogenic, immunotoxic and teratogenic for lower and higher forms of life i.e. microorganisms to humans. This review describes the sources of dioxins and furans pollution, hazardous effects on the ecosystem and recent techniques to minimize and treat dioxins and furans contaminants in the environment. This paper also previews the significance of conventional and latest remediation techniques prevailing around the globe for treating dioxins and furans entry into the ecosystem. PMID- 29986329 TI - A system dynamics model for supporting decision-makers in irrigation water management. AB - Water management is a controversial environmental policy issue, due to the heterogeneity of interests associated with a shared resource and the increasing level of conflict among water uses and users. Nowadays, there is a cumulative interest in enhancing multi-stakeholder decision-making processes, overtaking binding mercantile business, in water management domain. This requires the development of dynamic decision-aiding tools able to integrate the different problem frames held by the decision makers, to clarify the differences, to support the creation of collaborative decision-making processes and to provide shared platforms of interactions. In literature, these issues are faced by concepts such as Ostrom's action arena and Ostanello-Tsoukias' interaction space (IS). The analysis of the interactions structure and of the different problem framing involved are fundamental premises for a successful debate for the management of a common-pool resource. Specifically, the present paper suggests a dynamic evolution of the IS, highlighting its criticalities. It develops an alternative perspective on the problem, using a System Dynamics Model (SDM), exploring how different actions can influence the decision-making processes of various stakeholders involved in the IS. The SDM has been implemented in a multi stakeholders decision-making situation in order to support water management and groundwater protection in the agricultural systems in the Capitanata area (Apulia region, Southern Italy). PMID- 29986328 TI - Statistical monitoring of a wastewater treatment plant: A case study. AB - The efficient operation of wastewater treatment plants (WWTPs) is key to ensuring a sustainable and friendly green environment. Monitoring wastewater processes is helpful not only for evaluating the process operating conditions but also for inspecting product quality. This paper presents a flexible and efficient fault detection approach based on unsupervised deep learning to monitor the operating conditions of WWTPs. Specifically, this approach integrates a deep belief networks (DBN) model and a one-class support vector machine (OCSVM) to separate normal from abnormal features by simultaneously taking advantage of the feature extraction capability of DBNs and the superior predicting capacity of OCSVM. Here, the DBN model, which is a powerful tool with greedy learning features, accounts for the nonlinear aspects of WWTPs, while OCSVM is used to reliably detect the faults. The developed DBN-OCSVM approach is tested through a practical application on data from a decentralized WWTP in Golden, CO, USA. The results from the DBN-OCSVM are compared with two other detectors: DBN-based K-nearest neighbor and K-means algorithms. The results show the capability of the developed strategy to monitor the WWTP, suggesting that it can raise an early alert to the abnormal conditions. PMID- 29986330 TI - Wet peroxidation of resorcinol catalyzed by copper impregnated granular activated carbon. AB - The present article reports the treatment of resorcinol using a catalytic wet peroxidation (CWPO) process in the presence of copper impregnated granular activated carbon (Cu/GAC) with a bench-scale batch reactor. The typical physico chemical properties of synthesized catalyst were characterized with different equipment and methods. 90% resorcinol removal and 81% of TOC removal was achieved at optimum conditions (pH = 6, the stoichiometric ratio of H2O2/resorcinol = 1.2, catalyst dose = 0.5 g/L, initial concentration of resorcinol = 100 mg/L, temperature = 70 degrees C and time t = 4 h). Fourier-transform infrared spectroscopy (FTIR) measurements revealed that GAC posses various conjugated hydrocarbon groups including aromatic hydrocarbons, carboxylic groups, carboxyl and carbonate. Cu/GAC catalyst has a surface smoother than that of pristine GAC. At neutral or natural pH (~6.4) of resorcinol, CWPO of resorcinol is favorable by Cu/GAC catalyst. Catalyst stability study revealed that Cu/GAC sustain its catalytic reactivity to over 76% in the five cycles without any regeneration. The thermogravimetric analysis confirmed that 350 degrees C temperature found to be optimum for calcination of Cu/GAC without any major losses. The mineralization mechanism was proposed based on intermediates identified during CWPO reaction. PMID- 29986331 TI - Evaluation of biomethane potential from by-products and agricultural residues co digestion in southern Italy. AB - The suitability of the co-digestion of feedstock-mixtures (by-products and agricultural residues) depends on their ability to produce biogas. In this study, the effects of mixing five feedstocks (citrus pulp, olive pomace, poultry manure, Italian sainfoin silage and opuntia fresh cladodes) on anaerobic digestion for biogas production have been investigated by carrying out biomethane potential (BMP) tests on six different mixing ratios of the selected five biomasses. The BMP test results demonstrated that all the six studied feedstock-mixtures could be potentially used for renewable energy generation by biogas plants. More in detail, two mixing ratios of the studied feedstock-mixtures showed the best biomethane potential of 249.9 and 260.1 Nm3CH4/tVS, respectively. Since this research study made it possible to screen the suitability and technical feasibility of the feedstock-mixtures analysed, the results provide the basis for subsequent pilot scale evaluation of anaerobic digestion in Mediterranean area, where by-products and agricultural residues are profuse and necessary to produce advanced biofuels. PMID- 29986333 TI - A brief overview of trends in groundwater research: Progress towards sustainability? PMID- 29986332 TI - Entangled stakeholder roles and perceptions of sustainable consumption: An evaluation of sustainable consumption practices in Tianjin, China. AB - Sustainable consumption and production are considered to be fundamental ways to solve problems with environmental resources that human beings are facing. There is a broad consensus that promoting sustainable consumption requires the joint efforts of different social actors. This paper aims to define the roles of different stakeholders and the relationships between them, and then establish a modeling framework to analyze those relationships between stakeholders, which include members of government, business, consumer, mass media, environmental non government organizations, education and research institutions, financial markets, etc. The research found that members of government, business, and consumers make up the core stakeholder network. The modeling framework could be used to evaluate sustainable consumption practices and identify deficiencies that would assist in defining better trajectories. This paper describes the evaluation of sustainable consumption practice in Tianjin, China from a stakeholder perspective to show how the modeling framework can function. According to this analysis, the following six actions may promote sustainable consumption practices in areas like Tianjin: 1) the cultivation of a consciousness of sustainable consumption, 2) the exemplary role of government, 3) a series of laws, regulations, and policies, 4) a thorough sustainable consumption action plan, 5) an insistence on sustainable production and consumption by businesses and consumers, and 6) the concerted efforts of various stakeholders. PMID- 29986334 TI - Electrochemical effect on bioleaching of arsenic and manganese from tungsten mine wastes using Acidithiobacillus spp. AB - Mine wastes from tungsten mine which contain a high concentration of arsenic (As) may expose many environmental problems because As is very toxic. This study aimed to evaluate bioleaching efficiency of As and manganese (Mn) from tungsten mine wastes using the pure and mixed culture of Acidithiobacillus ferrooxidans and A. thiooxidans. The electrochemical effect of the electrode through externally applied voltage on bacterial growth and bioleaching efficiency was also clarified. The obtained results indicated that both the highest As extraction efficiency (96.7%) and the highest Mn extraction efficiency (100%) were obtained in the mixed culture. A. ferrooxidans played a more important role than A. thiooxidans in the extraction of As whereas A. thiooxidans was more significant than A. ferrooxidans in the extraction of Mn. Unexpectedly, the external voltage applied to the bioleaching did not enhance metal extraction rate but inhibited bacterial growth, resulting in a reverse effect on bioleaching efficiency. This could be due to the low electrical tolerance of bioleaching bacteria. However, this study asserted that As and Mn could be successfully removed from tungsten mine waste by the normal bioleaching using the mixed culture of A. ferrooxidans and A. thiooxidans. PMID- 29986335 TI - Facile microwave synthesis of pine cone derived C-doped TiO2 for the photodegradation of tetracycline hydrochloride under visible-LED light. AB - Pine cone derived carbon was doped into TiO2 via a facile microwave procedure at different powers, different from other conventional synthesis methods. The materials were adequately characterized and applied in the photodegradation of 5 mg/L tetracycline hydrochloride (TA) under visible-LED light. The XRD results showed that all materials exist as both anatase and rutile phase. However, both the microwave power and the carbon content of the composite material inhibited the conversion of anatase into rutile. The composite material synthesized at a microwave power of 800 W (CT800), displayed the highest band gap energy (3.14 eV) but showed the least electron-hole recombination rate. Hence, CT800 exhibited the highest apparent rate constant of 9.9 * 10-3 min-1 and a half-life of 70 min. An inverse relationship between OH* radical scavenger (isopropanol) and the percentage degradation by CT800 suggests that OH* is majorly responsible for the degradation of TA. Recyclability studies revealed that after 4 cycles of photocatalytic degradation reactions, CT800 retained approximately 83% performance confirming its stability and reusability. PMID- 29986336 TI - Valuing visitor access to forested areas and exploring willingness to pay for forest conservation and restoration finance: The case of small island developing state of Mauritius. AB - Small island developing states share as common constraints their small size, geographical dispersion, greater vulnerability to rapid and drastic environmental change, and limited administrative and technical resources. Within these, they have to cater for urban and agricultural areas, as well as enough natural landscape for ecosystem services. Funding for conservation of forest ecosystems on these islands has received relatively less attention and national park systems are chronically underfunded. We used Mauritius as a case study to investigate the willingness to pay for conservation of state and privately owned forests. It is part of a biodiversity hotspot with highly threatened forest ecosystems, but has known some conservation successes. We designed and administered survey based contingent valuation approach to estimate the willingness to pay entry fees to visit forest areas across the island. Study results suggest international and domestic tourists have a mean willingness to pay of USD 7.73 and USD 3.74 respectively, for conservation. These values represent amounts visitors are willing to pay every time they visit a public or private forested site. Results show that mid-level supervisory roles positively influence willingness to pay values. Results also show that people aged 50 and above, not having any supervisory role, married with one child or less, tend to have lower willingness to pay for conservation. PMID- 29986338 TI - An Aberrant Subclavius Posticus Muscle - A Case Report. AB - OBJECTIVE: An aberrant subclavius posticus muscle was found during routine dissection of the left infraclavicular fossa of a 60-year-old male cadaver. PRESENTATION: This aberrant muscle arises antero-medially, from the costoclavicular ligament, runs postero-laterally, over the trunks of the brachial plexus, and postero-lateral has a common insertion with the omohyoid muscle. CONCLUSION: The presence of such an aberrant muscle may cause a dynamic compression of the subclavian artery and brachial plexus. PMID- 29986337 TI - Aripiprazole-Triggered Alice in Wonderland Syndrome Episodes Studied with 99mTc HMPAO Brain SPECT. PMID- 29986339 TI - T2-FLAIR Mismatch Sign as an Imaging Biomarker in Lower-Grade Gliomas. PMID- 29986340 TI - Association of Autonomic Nervous System Abnormalities on Head-Up Tilt Table Test with Joint Hypermobility. AB - AIM: The aim of this study was to investigate the association of autonomic nervous system abnormalities on head-up tilt table test (HUTT) with generalized joint hypermobility, expressed by Beighton score (BS). METHODS: This was a prospective study that included 115 consecutive patients (91 females; mean age 34.35 +/- 14.11) referred either for the HUTT or testing of the cardiovascular autonomic reflexes together with HUTT. Generalized joint hypermobility was evaluated according to the BS system after which HUTT was performed. Clinically significant BS was considered if >=4. RESULTS: Fifteen patients (15.1%) had BS >=4. Results of the HUTT were normal in 58 (50.4%) patients and in 57 (49.6%) patient HUTT was abnormal. Fifteen (13.0%) patients fulfilled criteria for orthostatic hypotension, 30 (26.1%) for reflex syncope and 21 (18.3%) for postural orthostatic tachycardia syndrome. Patients with pathological findings on HUTT had significantly higher BS compared to patients with normal HUTT (median 1 vs. 0, p = 0.001). There was a significant association between participants with BS >=4 and pathological HUTT (chi[1] = 6.392, p = 0.011). Results of the multivariate regression analysis revealed that increase in the BS is associated with the increased likelihood of HUTT pathology (Exp[B] 1.44, 95% CI 1.084-1.922, p = 0.012), while increase in age is associated with lower risk of HUTT pathology (Exp[B] 0.968, 95% CI 0.939-0.998, p = 0.036). CONCLUSION: There is an association between autonomic nervous system abnormalities on HUTT test and generalized joint hypermobility. PMID- 29986341 TI - In Hyperacute Recanalization Therapy, Early Hospital Arrival Improves Outcome in Patients with Large Artery Occlusion. AB - BACKGROUND: It is unknown whether the effect of onset---to-door (OTD) time on clinical outcomes differs between -patients with and without large artery occlusion (LAO) who undergo hyperacute recanalization therapy. METHODS: Hyperacute recanalization therapy includes intravenous thrombolysis tissue plasminogen activator (tPA), and endovascular therapy (EVT). Favorable clinical outcome was defined as modified Rankin Scale of <=2 at discharge. RESULTS: Among 164 patients, 117 (71%) patients received tPA, 86 (52%) received EVT, and 39 (24%) received tPA and EVT. One hundred and fifteen patients (70%) were classified into the LAO group and 49 (30%) into the non-LAO group. In the total cohort, multivariate regression analysis showed OTD time (OR 0.809 [95% CI 0.693 0.944], p = 0.007) was an independent factor related to the favorable outcome. Similarly, among patients with LAO, OTD was an independent negative factor for the favorable outcome (0.779 [0.646-0.940], p = 0.009). On the contrary, OTD was not associated with the favorable outcome (1.5 [0.7-2.5] vs. 1.7 [1.1-3.2], p = 0.155) in patients without LAO. This was confirmed with multivariate regression analysis, which did not show OTD to be an independent factor for the favorable outcome (0.900 [0.656-1.236], p = 0.516). CONCLUSION: The effect of early hospital arrival on clinical outcome differed between patients with and without LAO. PMID- 29986342 TI - Early Predictors of Drug-Resistant Epilepsy Development after Convulsive Status Epilepticus. AB - BACKGROUND: Drug-resistant epilepsy (DRE) is a common and serious consequence of convulsive status epilepticus (CSE). Little is known on the early prediction of DRE development after CSE. Our aim was to identify independent DRE predictors in patients with CSE. METHODS: One hundred and forty consecutive patients identified with CSE in a tertiary academic hospital between March 2008 and January 2015 were reviewed. Demographics, clinical features, serum albumin neuroimaging, and electroencephalogram characteristics were collected and analyzed. Independent predictors of DRE were identified using multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to quantify the predictive validity of all the risk factors. RESULTS: After a median 62-month observation period, 91 patients were enrolled into this study. Thirty-seven (40.7%) patients did not have DRE, 22 (24.2%) developed DRE, and 32 (35.2%) were dead. History of epilepsy (OR 9.17, 95% CI 1.77-49.22, p = 0.010), status epilepticus duration >=24 h (OR 4.82, 95% CI 1.04-22.37, p = 0.044), and cortical or hippocampal abnormalities on neuroimaging (OR 9.49, 95% CI 1.90-47.50, p = 0.006) were independent predictors of DRE after CSE. A combination of these 3 variables yielded an area under the ROC curve of 0.77 (0.65-0.89). CONCLUSIONS: History of epilepsy, longer SE duration, and cortical or hippocampal abnormalities on neuroimaging are early predictors for the development of DRE after CSE. Further studies are needed to assess whether a more aggressive treatment will reduce the likelihood of DRE development in these high-risk patients. PMID- 29986344 TI - Chronic Hypertension in Pregnancy: New Concepts for Classification and Management. AB - Chronic hypertension in pregnancy is traditionally classified according to degree of blood pressure (BP) elevation. Alternatively, stratifying women as high or low risk based on the etiology of hypertension, baseline work-up, and comorbid medical conditions will better inform clinicians about thresholds to initiate antihypertensive therapy, target BPs, frequency of antepartum visits, and timing of delivery. Women classified as high-risk chronic hypertension as described here require stricter BP management and more frequent follow-up visits as their associated rates of adverse maternal and/or fetal/neonatal outcomes appear higher than women classified as low-risk chronic hypertension. The latter group can in most cases be managed similarly to the general obstetric population. PMID- 29986343 TI - Risk Factors of Cage Subsidence in Patients with Ossification of Posterior Longitudinal Ligament (OPLL) After Anterior Cervical Discectomy and Fusion. AB - BACKGROUND There are numerous reports on cage subsidence after ACDF; however, few studies have identified its risk factors. The current study aimed to identify risk factors for cage subsidence after ACDF using the PEEK cage packed with local autobone implant with plate and provides evidence for surgical decision-making. MATERIAL AND METHODS We retrospectively reviewed 77 patients with OPLL who underwent 1/2-level ACDF using the PEEK cage packed with local autobone implant with plate from March 2013 to December 2015. Implant subsidence was defined as the decrease in interbody height at the final follow-up compared to that measured on the first postoperative day >=2 mm. Intervertebral fusion was evaluated on the basis of no motion across the fusion site and the presence of trabeculae between bone and implant in the X-rays. Multivariate logistic regression analysis was used to identify the risk factors for cage subsidence. RESULTS In comparing the end-plate removal group with the end-plate preservation group, we found that the fusion rate (removal group, 35.90%; preservation group, 10.50%) and the change of IH (P=0.011) were significantly different during the first 6 weeks after surgery. Advanced age (OR=1.34, 95% CI=1.04-1.24, P=0.004), end-plate removal (OR=11.84, 95% CI=2.91-48.28, P=0.001), and nonunion within 6 weeks after surgery (OR=22.67, 95% CI=2.36-217.67, P=0.007) played an important role in predicting cage subsidence. CONCLUSIONS These findings suggest that advanced age, end-plate removal, and nonunion within 6 weeks after surgery are risk factors for the cage subsidence after ACDF using the PEEK cage packed with local autobone implant with plate in patients with OPLL. PMID- 29986345 TI - Outcomes of a Negative Rapid Influenza Diagnostic Test in Pregnant Women. AB - OBJECTIVE: The objective of this study was to evaluate the negative predictive value (NPV) of a rapid influenza diagnostic test (RIDT) compared with polymerase chain reaction (PCR) in pregnant women. STUDY DESIGN: Retrospective cohort study of pregnant women with a negative RIDT followed by confirmatory PCR for influenza A, H1N1, and B during the influenza seasons from 2012 to 2015. RESULTS: The NPV of the RIDT was 85.4% (211 of 247), 93.5% (231 of 247), and 97.9% (242 of 247) for influenza A, H1N1, and B, respectively. Antiviral treatment was administered to 47.2% (17 of 36) of women with a false-negative RIDT for influenza A compared with 9.0% (19 of 211) of women with a true-negative RIDT (p< 0.001). Patients were more likely to receive antiviral treatment if they were feverish (adjusted odds ratio [aOR]: 6.05, 95% confidence interval [CI]: 1.83-20.03), had cough (aOR: 6.43, 95% CI: 1.06-39.26), dyspnea (aOR: 6.41, 95% CI: 1.63-25.29), or had a subsequently positive PCR (aOR: 9.41, 95% CI: 3.13-28.31). CONCLUSION: Up to 14.5% of women with a negative RIDT in pregnancy had positive influenza A by PCR of whom more than half did not receive antiviral treatment. PMID- 29986346 TI - Accelerometry-Derived Relative Exercise Intensities in Elite Women's Basketball. AB - This study assessed accelerometry-derived relative exercise intensity during elite women's basketball match play. The influence of player position/role and match period on relative exercise intensities was evaluated. Ten basketballers wore accelerometers during a Yo-Yo intermittent recovery test (Yo-Yo-IR1) and 18 competitive matches. Relative exercise intensity was quantified using predicted oxygen consumption reserve determined using correlations from Yo-Yo-IR1. Total time, bout frequency and bout duration were calculated in seven intensity zones and compared between quarters, positions (back-court vs. front-court) and roles (starters vs. bench). Back-court players spent 6.0+/-1.9% more match time performing supramaximal activity when compared to front-court players (p<0.045). Back-court players experienced more supramaximal bouts (125+/-37 vs. 52+/-36; p=0.031) of greater average duration (2.1+/-0.4 vs. 1.4+/-0.2 s; p=0.021) and maximum duration (7+/-2 vs. 3+/-1 s; p=0.020). More sedentary to very light activity was observed in the 2nd and 4th quarters compared to the 1st and 3rd quarters (p<0.05). Despite reduced playing time, bench players performed similar amounts of maximal and supramaximal exercise when compared to starters (p>=0.279). Player position, role and match periods influence the demands of women's basketball; these factors should be considered when designing match specific conditioning programs. PMID- 29986347 TI - [Telephone-Based Psychological Counselling of Accident Victims: Initial Evaluation of a Pilot Project of the German Statutory Accident Insurance in the Healthcare and Welfare Services]. AB - A telephone-based psychological counselling service was implemented and evaluated in four regional offices of the German statutory accident insurance in healthcare and welfare services (BGW). Insurance employees/caseworkers, psychotherapists, and insured persons were asked to rate the counselling service in terms of their experiences and satisfaction. 15.5% of all insured persons initially contacted made use of the counselling service. Those using the service reported a slightly higher level of psychological distress, were less likely to be able to work 3 months after using the service and were more likely to attend a subsequent psychotherapy session. Telephone-based counselling by psychotherapists was rated as helpful by most insured persons. Caseworkers and psychotherapists also rated the concept favorably. All in all, the implementation can be regarded as successful. In a next step, the approach should be evaluated regarding its efficacy in a randomized, controlled trial. PMID- 29986348 TI - [Topic Check Medicine: Patient and Consumer Orientation in Topic Collection and Selection for HTA Reports]. AB - INTRODUCTION: The involvement of the public in the collection and selection of topics for health technology assessments (HTAs) is an important prerequisite for producing HTA reports on questions actually relevant to patients. In S139b (5) Social Code Book (SGB V), the legislator established the requirements for health insurance members and other interested individuals to propose topics for HTA reports to the Institute for Quality and Efficiency in Health Care (IQWiG). OBJECTIVES: How is the legal remit implemented with regard to the involvement of patients and consumers in topic collection and selection for HTA reports in IQWiG's Topic Check Medicine? TOPIC COLLECTION AND SELECTION: Topic proposals for HTA reports can be submitted by any interested individual via a simple submission form on the "ThemenCheck Medizin" website. If the HTA question is unclear, IQWiG consults the person submitting the proposal. On the basis of topic processing, a Selection Committee comprising members of the public and patient representatives nominates 15 patient-relevant topics suitable for the production of an HTA report. IQWiG then chooses 4-6 topics from which HTA reports are produced. EXPERIENCE WITH TOPIC COLLECTION AND SELECTION: In the first 2 selection cycles (July 2016 to July 2017), 57 topic proposals for HTA reports were submitted from a wide range of topics. At the end of 2016 and 2017, the Selection Committee nominated 15 patient-relevant topics suitable for HTA reports. At the beginning of 2017, IQWiG selected 5, at the beginning of 2018 4 topics for HTA reports. The processing of topics and the selection process were largely judged positively by the Selection Committee. CONCLUSION: A high degree of involvement in topic collection for "ThemenCheck Medizin" is achieved through the simple submission form and the nomination of topics by the Selection Committee. Furthermore, important factors for successful implementation were political support from the legislator, choice of suitable members for the Selection Committee, and support of topic selection by this Committee. How the demand for greater involvement of patients and public can be implemented needs investigation in the future. PMID- 29986350 TI - Comparison of Postoperative Pain and Recovery between Single-Port and Two-Port Thoracoscopic Lobectomy for Lung Cancer. AB - OBJECTIVE: To investigate whether the single-port (SP) technique had more favorable postoperative outcomes than had the two-port (TP) technique. METHODS: One hundred sixty-six single-port video-assisted thoracoscopic surgery (SP-VATS) lobectomy and 162 two-port video-assisted thoracoscopic surgery (TP-VATS) lobectomy had been successfully completed between August 2015 and September 2016. A single incision of ~3 cm was made in an intercostal space along the anterior axillary line. Perioperative outcomes and the safety between SP-VATS and TP-VATS lobectomy for NSCLC was compared. RESULTS: In the SP-VATS group, incision size was kept to a minimum, with a median of 3 cm; mediastinal lymph node dissection was performed in all patients with malignancy. Overall, median operative time was 89 minutes, and median chest tube duration was 3.1 days. The VAS on postoperative days 3, 7, and 14 was less in the SP-VATS group than that in the TP-VATS group. The VAS on days 1, 30, 60, 90, 180, and 360 did not differ significantly between the two groups. The number of days of use of analgesic agents after surgery was less in the SP-VATS group. The pathological symptoms of wound pain were significantly less in the SP-VATS group. CONCLUSIONS: Compared with the multiport approach, SP VATS lobectomy might reduce postoperative pain and lead to faster recovery. PMID- 29986351 TI - Fine-needle Aspiration Cytology to Identify a Rare Mimicker of Breast Cancer: Plasma Cell Mastitis. AB - There are rare benign diseases that can mimic malignant breast neoplasms in the clinical exam and in mammography. We evaluated the contribution of an accessible procedure to most clinicians, the fine-needle aspiration cytology, to identify a rare mimicker of malignant breast neoplasms. A type 2 diabetic 85-year-old female presented with a 6-month history of a left breast lump. The physical exam and mammography were compatible with breast cancer. Nevertheless, after fine-needle aspiration cytology, the diagnosis was plasma cell mastitis. Once this rare diagnosis was established, the tumor was extirpated, and the final histologic diagnosis corroborated chronic plasma cell mastitis. The patient's postoperative evolution was uneventful, and no other treatment was needed. Fine-needle aspiration cytology could be a valuable tool to identify rare mimickers of malignant breast neoplasms. PMID- 29986352 TI - New Hirsutinolide-Type Sesquiterpenoids from Vernonia cinerea Inhibit Nitric Oxide Production in LPS-Stimulated RAW264.7 Cells. AB - Phytochemical investigation of ethanol extracts from two Taiwanese collections of Vernonia cinerea resulted in the isolation of eighteen hirsutinolide-type sesquiterpenoids, including seven new ones designated as vernolides E - K (1: -7: ). All structures were determined by a combination of detailed spectroscopic analyses (NMR and MS) and comparison with reported data. In an in vitro anti inflammatory assay, compounds 3, 7, 9, 11: , and 14: exhibited strong inhibitory activities toward NO production by LPS-induced RAW264.7 macrophages, with IC50 values of 1.18, 0.85, 0.66, 0.71 and 0.45 uM, respectively, without affecting cellular viability at 40 uM. Preliminary structure-activity relationships indicate that the ester groups at C-8 and C-13 may enhance inhibition of NO production. PMID- 29986354 TI - [Why Certification of Colorectal Cancer Centres Does Not Improve Surgical Quality]. AB - BACKGROUND: To improve treatment results, certification of colorectal cancer centres in Germany assures interdisciplinary treatment according to official treatment guidelines. The treatment results of certified colorectal cancer centres are published annually. Despite certification, the surgical quality indicators of anastomotic leakage, wound infection, and revision surgery have not improved between 2009 and 2015. PATIENTS AND METHODS: Patients with anastomotic leakage (AL) after colorectal resection of an adenocarcinoma were analyzed in a Morbidity and Mortality (M+M) conference structured according to the London Protocol. The results were compared to structure and process parameters that are part of the data entry form (DEF) of the Deutsche Krebsgesellschaft (DKG) used for the certification of colorectal cancer centres. RESULTS: Between 2015 and 2017, 387 colorectal resections were performed. Of these, 158 resections were performed due to the diagnosis of a colorectal carcinoma. For 13/149 resections with anastomosis, a leak was diagnosed (8.7%). All patients suffering from an AL were analysed in an M+M conference structured according to the London Protocol. For 10/13 patients, abnormalities in structural and procedural quality were found. As regards procedural quality, this included the application of standards (n = 6/10), communication (n = 3/10) and missing but needed results from examinations (n = 1/10). As regards structural quality, insufficient physical resources were predominant (n = 3/10). Only one of these abnormalities was identified using the DEF. CONCLUSION: For processes and structures to improve surgical quality, it is required that they have relevant influence on surgical quality. We found that only 1/13 abnormalities detected in the M+M conference structured according to the London Protocol was represented in the DEF. To improve the influence on surgical quality, extensions to the DEF of the Deutsche Krebsgesellschaft should be discussed. PMID- 29986353 TI - The Micro-Elimination Approach to Eliminating Hepatitis C: Strategic and Operational Considerations. AB - The introduction of efficacious new hepatitis C virus (HCV) treatments galvanized the World Health Organization to define ambitious targets for eliminating HCV as a public health threat by 2030. Formidable obstacles to reaching this goal can best be overcome through a micro-elimination approach, which entails pursuing elimination goals in discrete populations through multi-stakeholder initiatives that tailor interventions to the needs of these populations. Micro-elimination is less daunting, less complex, and less costly than full-scale, country-level initiatives to eliminate HCV, and it can build momentum by producing small victories that inspire more ambitious efforts. The micro-elimination approach encourages stakeholders who are most knowledgeable about specific populations to engage with each other and also promotes the uptake of new models of care. Examples of micro-elimination target populations include medical patients, people who inject drugs, migrants, and prisoners, although candidate populations can be expected to vary greatly in different countries and subnational areas. PMID- 29986355 TI - [Traumatic Birth: Recognition and Prevention]. AB - A history of sexual as well as physical or emotional abuse may represent a high risk factor for difficult pregnancies and birth processes, potentially yielding the development of postpartum posttraumatic stress disorder as well as impaired mother-child attachment. However, birth itself may also be experienced as primarily traumatic, i. e., without having had prior trauma experiences. Difficult and traumatic births may affect midwives and obstetricians, too. This article provides an overview of the prevalence and risk factors of traumatic childbirth as well as the course, consequences, and intervention possibilities. PMID- 29986356 TI - [Acute Gout in Emergency Admissions - Patient Characteristics and Adherence of Care Processes to Current Guidelines]. AB - BACKGROUND: Gout or hyperuricemia are both well known and common diseases. The prevalence of gout is increasing worldwide. Thus, patients with gout are becoming more common. Although there are several published guidelines for the management of gout, actual treatment of gout is inconsistent with these guidelines in many respects. Gout is usually treated by general practitioners (GP) in Germany. The aim of our study was to show which patients present to the emergency department and to record how treatment and clinical diagnostic testing of gout patients is performed in the emergency department of a university hospital in Germany. No such data have been published for Germany. METHOD: Retrospective analysis of data of patients with ICD Code M10.xx from the emergency department at a university hospital from 05/2013 until 04/2016. RESULTS: 65 patients were treated with acute gout during the study period at the emergency department (age ? 53.45 y, 76.9% male, 23.07% female). 42 patients (65%) came outside normal office hours of GPs. In 31 patients, hyperuricemia or gout was known in their medical history, in 22 of these acute gout was known. 48 (73%) of patients came with monoarthritis and therefrom 40 with "classic" gout, such as podagra. 57 (86%) patients were subjected to diagnostic blood analysis and 31 (48%) diagnostic X-ray of the affected joint. We defined the appropriate indications for X-ray in diagnosis of acute gout as: signs of superinfection, prior surgical intervention or uncertain trauma in case history. According to this definition, 67% of the X-rays were performed without the correct indication. Four Patients were given punction of the affected joint to demonstrate monosodium urate monohydrate (MSU) crystals. Twelve patients were admitted as inpatients for surgery and/or antibiotic treatment. 51 (78%) patients received NSAIDs, 7 in combination with steroids and 4 patients received colchicine. Of those patients who received NSAID, 17 had an unknown or impaired renal function. Seven patients received neither pharmacological treatment nor recommendations for further treatment. Ten patients (15%) received a urate-lowering therapy or an existing therapy was increased during acute gout. In 10 patients, a urate-lowering therapy was recommended as further therapy. 63% were given further treatment recommendations such as cryotherapy or diet. CONCLUSIONS: Acute gout is seldom presented in the emergency room (< 10/00). This confirms the impression that gout is mainly a disease treated in the outpatient setting. As shown in our study, the pharmacological treatment of acute gout was largely consistent with the guideline recommendations; nevertheless observance of renal function before treatment with NSAIDs should be emphasised. Furthermore, we identified overuse of diagnostic procedures. Current guidelines recommend diagnosing acute gout with clinical scores. In conclusion, our study shows that those clinical diagnostic scores should be implemented in clinical practice, in order to avoid unnecessary diagnostic procedures. PMID- 29986357 TI - ? PMID- 29986358 TI - [Adjuvant chemotherapy with Capecitabine as new standard for resected cholangiocarcinomas - a look at the BILCAP trial]. PMID- 29986359 TI - [Editor's Comment]. PMID- 29986360 TI - ? PMID- 29986361 TI - ? PMID- 29986362 TI - ? PMID- 29986365 TI - ? PMID- 29986366 TI - [Pregnancy Rhinitis - an Update]. AB - Pregnancy rhinitis (PR), a common condition in pregnant women, is defined as long lasting nasal congestion due to mucosal swelling and increased secretion without any signs of infection, allergy or tumor, starting at any time during pregnancy and disappearing within 2 weeks of delivery. Smoking and a sensitization to house dust mites are known risk factors. While a definitive pathophysiological concept for PR does not exist, hormonal influences are discussed. We present a stepwise therapeutic strategy for PR and an overview to the latest literature. PMID- 29986367 TI - [From the expert's Office: Objective diagnostic by means of chirp stimulation used for auditory steady state responses (ASSR) in the assessment of hearing impairment]. PMID- 29986368 TI - [Otitis media: definition, pathogenesis, clinical presentation, diagnosis and therapy]. AB - A number of diseases of the middle ear are summed up under the term otitis media: acute otitis media, recurrent acute otitis media, otitis media with effusion, chronic suppurative otitis media and chronic otitis media epitympanalis (= cholesteatoma). Acute otitis media belongs to the most common pediatric diseases and is often caused by bacterial infection. Since the advent of pneumococcal vaccines the quantity of AOM caused by pneumococci has declined; vaccination against NTHi and Moraxella catarrhalis are being developed. Main pillar of conservative treatment of AOM is symptomatic therapy of otalgia and fever as well as restoring the Eustachian tubal function. When indicated, amoxicillin represents antibiotic medication of choice. Acute mastoiditis, facial nerve paresis, labyrinthitis, Gradenigo syndrome, sinus vein thrombosis, meningitis and brain abscess belong to the complications of AOM among others. Both innate and adaptive immune system are involved in recovery of OM with innate immunity playing a critical role. Dysfunction of the Eustachian tube often underlies OM. Manometric measurement of Eustachian tube function may be useful for indication of balloon Eustachian tuboplasty. Several theories explain pathogenesis of cholesteatoma and multiple pro-inflammatory processes promote its progress in the course of the disease. PMID- 29986369 TI - ? PMID- 29986370 TI - ? PMID- 29986372 TI - Algorithms For Treatment of Major Depressive Disorder: Efficacy and Cost Effectiveness. AB - In spite of multiple new treatment options, chronic and treatment refractory courses still are a major challenge in the treatment of depression. Providing algorithm-guided antidepressant treatments is considered an important strategy to optimize treatment delivery and avoid or overcome treatment-resistant courses of major depressive disorder (MDD). The clinical benefits of algorithms in the treatment of inpatients with MDD have been investigated in large-scale, randomized controlled trials. Results showed that a stepwise treatment regimen (algorithm) with critical decision points at the end of each treatment step based on standardized and systematic measurements of response and an algorithm-guided decision-making process increases the chances of achieving remission and optimizes prescription behaviors for antidepressants. In conclusion, research in MDD revealed that systematic and structured treatment procedures, the diligent assessment of response at critical decision points, and timely dose and treatment type adjustments make the substantial difference in treatment outcomes between algorithm-guided treatment and treatment as usual. PMID- 29986373 TI - Hemostasis at Extremes of Body Weight. AB - Extremes of body weight are not uncommon in the modern world and include anorexia nervosa (AN) and obesity. Both conditions are associated with increased morbidity and mortality: AN has the highest mortality rate of all mental illnesses and unfortunately obesity has reached epidemic proportions and is a well-recognized risk factor for cardiovascular disease including venous thromboembolism (VTE). This article summarizes the current understanding of hemostatic changes of these extremes of body weight. The hemostatic changes of AN have not been well described. Severe AN is associated with pancytopenia with decreased bone marrow cellularity, which causes a mild thrombocytopenia. Platelet hyperaggregability has been recognized in AN and has been attributed at least in part to increased adrenoceptor density. Obesity and the metabolic syndrome are associated with prothrombotic changes, which have been well characterized and related to complex adipocyte-induced inflammatory changes, including increased levels of plasminogen activator inhibitor type 1, von Willebrand factor, fibrinogen, and other evidence of increased coagulation and platelet activation. Accumulating evidence suggests a significant role for increased tissue factor expression and signaling in this relationship, with increased tissue factor expression present in adipose and possibly systemic tissues, induced by adipose-generated cytokines. Intriguingly, the hemostatic changes do not seem to increase with increasing BMI, although the risk of VTE increases with BMI, suggesting that decreased venous flow due to venous enlargement may play the most important role in increased VTE risk with obesity. PMID- 29986374 TI - Correction. PMID- 29986375 TI - Correction. PMID- 29986376 TI - Viral Recombination: Ecology, Evolution, and Pathogenesis. AB - Recombination between and within virus genomes is being increasingly recognized as a majordriver of virus evolution. PMID- 29986377 TI - Interaction between Insects, Toxins, and Bacteria: Have We Been Wrong So Far? AB - Toxins are a major virulence factor produced by many pathogenic bacteria. In vertebrates, the response of hosts to the bacteria is inseparable from the response to the toxins, allowing a comprehensive understanding of this tripartite host-pathogen-toxin interaction. However, in invertebrates, this interaction has been investigated by two complementary but historically distinct fields of research: toxinology and immunology. In this article, I highlight how such dichotomy between these two fields led to a biased, or even erroneous view of the ecology and evolution of the interaction between insects, toxins, and bacteria. I focus on the reason behind such a dichotomy, on how to bridge the fields together, and on confounding effects that could bias the outcome of the experiments. Finally, I raise four questions at the border of the two fields on the cross-effects between toxins, bacteria, and spores that have been largely underexplored to promote a more comprehensive view of this interaction. PMID- 29986378 TI - Videoscope-Assisted Minimally Invasive Surgery (VMIS) for Bone Regeneration around Teeth and Implants: A Literature Review and Technique Update. AB - Background—The literature related to minimally invasive periodontal surgery is reviewed. This includes the original minimally invasive surgery (MIS) procedure for bone regeneration, the modification of MIS for the minimally invasive surgery technique (MIST) and modified MIST (M-MIST) procedures, and the introduction of the videoscope for oral surgical procedures and the ability to perform videoscope-assisted minimally invasive surgery (VMIS). The evolution from MIS through MIST to the current VMIS is reviewed. The results from studies of each of these methods are reported. Conclusion—The use of small incisions that produce minimal trauma and preserve most of the blood supply to the periodontal and peri-implant tissues results in improved regenerative outcomes, minimal to absent negative esthetic outcomes, and little or no patient discomfort. Minimally invasive procedures are a reliable method to regenerate periodontal tissues. PMID- 29986379 TI - miR-196a Is Able to Restore the Aggressive Phenotype of Annexin A1 Knock-Out in Pancreatic Cancer Cells by CRISPR/Cas9 Genome Editing. AB - Annexin A1 (ANXA1) is a Ca2+-binding protein that is involved in pancreatic cancer (PC) progression. It is able to mediate cytoskeletal organization maintaining a malignant phenotype. Our previous studies showed that ANXA1 Knock Out (KO) MIA PaCa-2 cells partially lost their migratory and invasive capabilities and also the metastatization process appeared affected in vivo. Here, we investigated the microRNA (miRNA) profile in ANXA1 KO cells finding that the modification in miRNA expression suggests the significant involvement of ANXA1 in PC development. In this study, we focused on miR-196a which appeared down modulated in absence of ANXA1. This miRNA is a well known oncogenic factor in several tumour models and it is able to trigger the agents of the epithelial to mesenchymal transition (EMT), like ANXA1. Our results show that the reintroduction in ANXA1 KO cells of miR-196a through the mimic sequence restored the early aggressive phenotype of MIA PaCa-2. Then, ANXA1 seems to support the expression of miR-196a and its role. On the other hand, this miRNA is able to mediate cytoskeletal dynamics and other protein functions promoting PC cell migration and invasion. This work describes the correlation between ANXA1 and specific miRNA sequences, particularly miR-196a. These results could lead to further information on ANXA1 intracellular role in PC, explaining other aspects that are apart from its tumorigenic behaviour. PMID- 29986382 TI - Highly Ductile and Ultra-Thick P-Doped FeSiB Amorphous Alloys with Excellent Soft Magnetic Properties. AB - Herein, we demonstrate the successful synthesis of novel Fe80Si9B(11−x)Px (x = 0, 1, 3, 5, 7) ultra-thick amorphous ribbons by planar flow casting. The influence of P alloying on glass forming ability (GFA), microstructure, thermal stability, soft magnetic properties, and ductility has been systematically investigated. The results reveal that introduction of P into Fe80Si9B11 alloy can remarkably enhance the GFA and increase critical thickness (tc) of the alloy from 45 to 89 um. Furthermore, the annealed FeSiBP amorphous alloys exhibited excellent soft magnetic properties, including high saturation magnetic flux density of 1.54 T, the low coercivity of 1.5 A/m, and low core losses of 0.15 W/kg. In addition, the representative Fe80Si9B8P3 ultra-thick amorphous alloy demonstrate excellent ductility even after annealing at 400 °C for 10 min, which indicates the superior performance of P-doped FeSiB alloys as compared to the commercial Fe78Si9B13 (Metglas 2605 S2) alloy. The combination of high GFA, excellent ductility, and low core losses of newly developed FeSiBP amorphous soft magnetic alloys makes them attractive candidates for magnetic applications in the high-frequency and high-speed electric devices. PMID- 29986380 TI - Applications of Yeast Synthetic Biology Geared towards the Production of Biopharmaceuticals. AB - Engineered yeast are an important production platform for the biosynthesis of high-value compounds with medical applications. Recent years have witnessed several new developments in this area, largely spurred by advances in the field of synthetic biology and the elucidation of natural metabolic pathways. This minireview presents an overview of synthetic biology applications for the heterologous biosynthesis of biopharmaceuticals in yeast and demonstrates the power and potential of yeast cell factories by highlighting several recent examples. In addition, an outline of emerging trends in this rapidly-developing area is discussed, hinting upon the potential state-of-the-art in the years ahead. PMID- 29986381 TI - Exercise Training Has Contrasting Effects in Myocardial Infarction and Pressure Overload Due to Divergent Endothelial Nitric Oxide Synthase Regulation. AB - The beneficial effects of exercise training (EX) on cardiac pathology are well recognized. Previously, we found that the effects of EX on cardiac dysfunction in mice critically depend on the underlying etiology. EX exerted beneficial effects after myocardial infarction (MI); however, cardiac pathology following pressure overload produced by transverse aortic constriction (TAC) was aggravated by EX. In the presented study, we investigated whether the contrasting effects of EX on cardiac dysfunction can be explained by an etiology-specific response of endothelial nitric oxide (NO) synthase (eNOS) to EX, which divergently affects the balance between nitric oxide and superoxide. For this purpose, mice were exposed to eight weeks of voluntary wheel running or sedentary housing (SED), immediately after sham, MI, or TAC surgery. Left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements. EX ameliorated LV dysfunction and remodeling after MI, but not following TAC, in which EX even aggravated fibrosis. Strikingly, EX attenuated superoxide levels after MI, but exacerbated NOS-dependent superoxide levels following TAC. Similarly, elevated eNOS S-glutathionylation and eNOS monomerization, which were observed in both MI and TAC, were corrected by EX in MI, but aggravated by EX after TAC. Additionally, EX reduced antioxidant activity in TAC, while it was maintained following EX in MI. In conclusion, the present study shows that EX mitigates cardiac dysfunction after MI, likely by attenuating eNOS uncoupling-mediated oxidative stress, whereas EX tends to aggravate cardiac dysfunction following TAC, likely due to exacerbating eNOS-mediated oxidative stress. PMID- 29986383 TI - Photocatalytic Oxidation of VOCs in Gas Phase Using Capillary Microreactors with Commercial TiO2 (P25) Fillings. AB - The elimination of volatile organic compounds (VOCs) at low concentration is a subject of great interest because these compounds are very harmful for the environment and human health. In this work, we have developed an easy methodology to immobilize a benchmark photocatalyst (P25) inside a capillary microreactor (Fused silica capillary with UV transparent coating) without any previous treatment. For this purpose, a dispersion of the sample (P25) in EtOH was used obtaining a packed bed configuration. We have improved the immobilization of the benchmark photocatalyst (P25) inside the capillary incorporating a surfactant (F 127) to generate porosity inside the microreactor to avoid severe pressure drops (?P < 0.5 bar). The resulting capillaries were characterized by Scanning Electron Microscopy (SEM). These microreactors show a good performance in the abatement of propene (VOC) under flow conditions per mol of active phase (P25) due to an improved mass transfer when the photocatalyst is inside the capillary. Moreover, the prepared microreactors present a higher CO2 production rate (mole CO2/(mole P25·s)) with respect to the same TiO2 operating in a conventional reactor. The microreactor with low pressure drop is very interesting for the abatement of the VOCs since it improves the photoactivity of P25 per mol of TiO2 operating at near atmospheric pressure. PMID- 29986384 TI - S-allylmercaptoglutathione Is a Substrate for Glutathione Reductase (E.C. 1.8.1.7) from Yeast (Saccharomyces cerevisiae). AB - Allicin (diallylthiosulfinate) is a potent thiol reagent and natural defense substance produced by garlic (Allium sativum) tissues when damaged. Allicin acts as a redox toxin and oxidizes the cellular glutathione (GSH) pool producing S allylmercaptoglutathione (GSSA). The cellular enzyme glutathione reductase (GR) uses NADPH to reduce glutathione disulfide (GSSG) back to GSH and replenishes the GSH pool. It was not known whether GR could accept GSSA as a substrate. Here, we report that GR from yeast (Saccharomyces cerevisiae) shows Michaelis-Menten kinetics with GSSA as substrate in vitro (Km = 0.50 mM), but that GSSA is not as good a substrate as GSSG (Km = 0.07 mM). Furthermore, cells unable to synthesize GSH because the γ-glutamylcysteine synthetase (GSH1) gene is deleted, cannot grow without GSH supplementation and we show that the auxotrophic requirement for GSH in Δgsh1 mutants can be met by GSSA in the growth medium, suggesting that GSSA can be reduced to GSH in vivo. PMID- 29986385 TI - Occurrence and Toxicological Risk Assessment of Polycyclic Aromatic Hydrocarbons and Heavy Metals in Drinking Water Resources of Southern China. AB - Polycyclic aromatic hydrocarbons (PAHs) and heavy metals exposure is related to a variety of diseases and cancer development, posing a great health risk to humans. In this study, water samples were collected from nine important water sources in Guangdong, Guangxi and Hainan provinces to determine the degree of PAHs and heavy metals contamination. Overall, the total contents of 16 PAHs and heavy metals were found within the permissible levels. In human health risk assessment, the benzo(a)pyrene equivalent concentration (BaPeq) presented a much lower level than the guideline values announced by Chinese Environmental Protection Agency (CEPA) and United States Environmental Protection Agency (US EPA), demonstrating that the PAHs contamination level in drinking water was mostly acceptable. For heavy metals, the Chronic daily intake (CDI), hazard quotient (HQ) or hazard index (HI) suggested that the water quality in nine water sources was desirable and did not present a risk to human health. PMID- 29986386 TI - FUS Negatively Regulates Kaposi's Sarcoma-Associated Herpesvirus Gene Expression. AB - Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi’s sarcoma. KSHV is also causally associated with the development of lymphoproliferative diseases, including primary effusion lymphoma (PEL). KSHV reactivation from latency plays an integral role in the progression to KSHV-associated disease as several lytic proteins have angiogenic and anti-apoptotic functions essential to the tumor microenvironment. Thus, restriction of KSHV reactivation represents an attractive therapeutic target. Here, we demonstrate that the cellular protein Fused-in-sarcoma (FUS) restricts KSHV lytic reactivation in PEL and in an epithelial cell-based model. Depletion of FUS significantly enhances viral mRNA and protein expression, resulting in increased viral replication and production of infectious virions. Chromatin immunoprecipitation analyses demonstrate that FUS is present at several KSHV lytic cycle genes during the latent stage of infection. We further demonstrate that FUS interacts with RNA polymerase II and negatively affects Serine-2 phosphorylation of its C-terminal domain at the KSHV RTA gene, decreasing nascent RNA synthesis. Knockdown of FUS increases transcription of RTA, thus driving enhanced expression of KSHV lytic genes. Collectively, these data reveal a novel role for FUS in regulating viral gene expression and are the first to demonstrate its role as a viral restriction factor. PMID- 29986387 TI - Synthesis of a Novel Fluorescent Ruthenium Complex with an Appended Ac4GlcNAc Moiety by Click Reaction. AB - The O-linked β-N-acetylglucosamine (O-GlcNAc) modification is an abundant post-translational modification in eukaryotic cells, which plays a fundamental role in the activity of many cells and is associated with pathologies like type II diabetes, Alzheimer’s disease or some cancers. However, the precise connexion between O-GlcNAc-modified proteins and their function in cells is largely undefined for most cases. Confocal microscopy is a powerful and effective tool for in-cell elucidation of the function of biological molecules. Chemical labeling of non-ultraviolet or non-fluorescent carbohydrates with fluorescent tag is an essential step that makes intra-cellular microscopic inspection possible. Here we report a strategy based on the 1,3-dipolar cycloaddition, called click chemistry, between unnatural N-acetylglucosamine (GlcNAc) analogues Ac4GlcNAc (substituted with an azido group) and the corresponding fluorescent tag Ru(bpy)2(Phen-alkyne)Cl2 (4) to synthesize the fluorescent dye Ru(bpy)2(Phen Ac4GlcNAc)Cl2 (5) under mild and neutral reaction conditions. Moreover, 5 showed good stability, desirable fluorescence characteristics, and exhibited rather low levels of cytotoxicity against sensitive MCF-7 cells. Additionally, we have achieved successful fluorescent imaging of 5 transported in living MCF-7 cells. Cell images displayed that proteins are potentially labelled with 5 in the cytoplasm. PMID- 29986388 TI - Valproic Acid Downregulates Cytokine Expression in Human Macrophages Infected with Dengue Virus. AB - Natural infection with dengue virus (DENV) induces an increase in the production of cytokines that play an important role in disease pathogenesis. Despite numerous scientific studies, there are still no commercially available disease specific therapeutics. Previous evidence shows that inhibiting histone deacetylase enzymes (HDACs) regulates the immune response in several inflammatory disease models. The aim of the current study was to evaluate the effect of HDAC inhibition in the production of inflammatory cytokines in human monocyte-derived macrophages infected with DENV serotype 2 (DENV-2). To this end, human monocyte derived macrophages (MDMs) were treated with valproic acid (VPA) before or after infection and the inflammatory cytokine concentration was quantified by flow cytometry. We found that infected MDMs secreted IL-8, IL-1b, IL-6, TNF-alpha, and IL-10, but not IL-12. Strikingly, treatment of infected cells with VPA had a differential and concentration-dependent effect on the production of specific cytokines without eliciting significant changes in cell viability. Using the highest concentration of VPA, a significant reduction in the production of all cytokines was observed. These results suggest that HDAC inhibition during DENV-2 infection could exert an important regulatory effect in the production of inflammatory cytokines, representing a significant advance in the design of novel therapeutic dengue treatments. PMID- 29986390 TI - Trait Emotional Empathy and Resting State Functional Connectivity in Default Mode, Salience, and Central Executive Networks. AB - Emotional empathy is the ability to experience and/or share another person’s emotional states and responses. Although some research has examined the neural correlates of emotional empathy, there has been little research investigating whether this component of empathy is related to the functional connectivity of resting state networks in the brain. In the current study, 32 participants answered a trait emotional empathy questionnaire in a session previous to their functional magnetic resonance imaging scan. Results indicate that emotional empathy scores were correlated with different patterns of functional connectivity in the default mode network (DMN), salience network (SN), and left and right central executive networks. For example, within the DMN, emotional empathy scores positively correlated with connectivity in the premotor cortex. Within the SN, empathy scores were positively correlated with the fusiform gyrus and cuneus. These findings demonstrate that emotional empathy is associated with unique patterns of functional connectivity in four of the brain’s resting state networks. PMID- 29986389 TI - Geriatric Assessment in Older Patients with Acute Myeloid Leukemia. AB - The incidence of acute myeloid leukemia (AML) increases with age, but the outcomes for older adults with AML are poor due to underlying tumor biology, poor tolerance to aggressive treatment, and the physiologic changes of aging. Because of the underlying heterogeneity in health status, treatment decisions are difficult in this population. A geriatric assessment (GA) refers to the use of various validated tools to assess domains that are important in older adults including physical function, cognition, comorbidities, polypharmacy, social support, and nutritional status. In older patients with cancer, a GA can guide treatment decision-making, predict treatment toxicity, and guide supportive care interventions. Compared to solids tumors, there is a relative lack of studies evaluating the use of a GA in older patients with AML. In this review, we will discuss the principles, common domains, feasibility, and benefits of GA, with a focus on older patients with AML that includes practical applications for clinical management. PMID- 29986391 TI - Hair Testosterone and Cortisol Concentrations in Pre- and Post-Rut Roe Deer Bucks: Correlations with Blood Levels and Testicular Morphometric Parameters. AB - The roe deer is a seasonally breeding species with a reproductive cycle regulated by endogenous rhythms and photoperiod-sensitivity. Sexually mature bucks show hormonal and testicular activation during the reproductive season, with a peak in the rut period, and following gradual involution. Hair is a good matrix for non invasive endocrinological analyses that provide long-term information without being influenced by the hormones’ pulsating release patterns in blood. The aim of the work was to quantify hair concentrations of testosterone and cortisol in wild roe deer bucks hunted during the pre- and post-rut period, using a radioimmunoassay methodology, and to look for differences between the two periods. The secondary objective was the evaluation of possible correlations of such hair concentrations with blood and morphometric parameters of the testes. Both hormones showed statistical differences, with opposing trends, when comparing the two periods: testosterone increased while cortisol decreased. The correlation analysis was in agreement with existing literature regarding metabolism/actions of these hormones and testicular morphometric parameters. This study represents the first report of the use of radioimmunoassay techniques to quantify testosterone and cortisol in roe deer hair, and may provide interesting insights into their reproductive physiology. PMID- 29986393 TI - Modification of Eutectic Si in Al-Si-(Ba) Alloy by Inducing a Novel 9R Structure in Twins. AB - The change of twinning morphology plays an important role in the modification of Al-Si alloys, which are widely used in industrial applications. However, the interpretation of this change is still insufficient. In this work, the microstructure of twins was investigated in two kinds of Al-Si alloys with different additions of Ba using high-resolution transmission electron microscopy (HRTEM). Unlike the normal {111} twin that exists in Ba-free alloy, discontinuous twins and multiple twins were observed in the Ba-containing alloy. In addition, the 9R structure formed by the dissociation of twins was firstly observed at the turning of discontinuous twins and the intersection of multiple twins in Al-Si alloys. PMID- 29986392 TI - Torsional Behavior of WaveOne Gold Endodontic File with the Dedicated Motor of the Original WaveOne File. AB - This study compares the safety limits and torsional resistances of WaveOne Gold (WOG) and WaveOne (WO) endodontic files while using the original motor. The safety limits for reciprocating angles were tested by measuring the torsional limit before plastic deformation (TLP) after repetitive torsional loading at gradually increasing load, and after single continuous rotation. Statistical analysis was performed by independent t-test at 95% confidence level. The tested specimens were observed under a scanning electron microscope (SEM). Regardless of the test mode, the distortion angle at the TLP was higher for WOG than WO (p < 0.05), and all were greater than the 150-degree rotation of the original motor. The mean values of the distortion angle and torque from the single continuous rotation loading were significantly lower than those with repetitive loading movements. Comparing the two systems under SEM, WO showed a catastrophic change in comparison with WOG. Evaluation of the lateral aspects showed longitudinal micro-cracks after 270-degree repetitive movements. After 150-degree repetitive movements, no distorted machining grooves were found in either group, but WO showed evidence of longitudinal micro-cracks. Under the conditions of this study, the torsional loading from the pre-set mode of the dedicated motor for WO was safe for WOG as well. PMID- 29986394 TI - Comprehensive Metabolomics Analysis of Xueshuan Xinmaining Tablet in Blood Stasis Model Rats Using UPLC-Q/TOF-MS. AB - Blood stasis syndrome (BSS) is one of the most common Chinese medicine patterns in coronary heart disease. Our previous work proved that Xueshuan Xinmaining Tablet (XXT) could treat blood stasis through regulating the expression of F13a1, Car1 and Tbxa2r. In the current study, the effect and mechanism of XXT on BSS was comprehensively and holistically investigated based on a metabolomics approach. Urine and plasma samples of 10 BBS rats treated with XXT (XT), 9 BSS model rats (BM) and 11 normal control (NC) rats were collected and then determined by UPLC Q/TOP-MS. Multivariate analyses were applied to distinguish differentiate urinary and plasma metabolite patterns between three groups. Results showed that a clear separation of three groups was achieved. XT group was located between BM group and NC group, and showing a tendency of recovering to NC group, which was consistent with the results of hemorheological studies. Some significantly changed metabolites like cortexolone, 3alpha,21-dihydroxy-5beta-pregnane-11,20 dione and 19S-hete and leukotriene A4, chiefly involved in steroid hormone biosynthesis, arachidonic acid metabolism and lipid metabolism, were found and identified to explain the mechanism. These potential markers and their corresponding pathways will help explain the mechanism of BSS and XXT treatment. This work also proves that metabolomics is effective in traditional Chinese medicinal research. PMID- 29986395 TI - Professor Barry V.L. Potter: Winner of the 2018 Tu Youyou Award in Honor of the Co-Recipient of the 2015 Nobel Prize in Physiology or Medicine for Her Discoveries Concerning a Novel Therapy against Malaria. PMID- 29986396 TI - Lost in Translation: Transforming Behaviour Change Techniques into Engaging Digital Content and Design for the StopApp. AB - Frameworks to support the application of behaviour change theory to the choice of behaviour change techniques (BCTs) in designing digital behaviour change interventions (DBCIs) are becoming well established, and have been employed by the authors in the development of StopApp. However, guidance on the next stage—effective operationalisation (translation) of these BCTs to a digital context, including the precise delivery and design of “behavioural intervention technology” (BIT) elements, is still in its infancy. This is despite growing recognition of the need to optimise engagement and usability, alongside a theoretical basis, for intervention effectiveness. The aim of this study was to explore methods to translate BCTs into digital content in an accurate and systematic manner. We describe the process of using co-creation (user-led) rather than expert-driven methods in the development of user-facing features and design in StopApp, including the iterative “bottom-up” and “top-down processes” necessary for accurate BCT translation. We found a small disparity between the intended and actual BCT content, reflecting the difficulties of translating BCTs into digital intervention content and the need for better guidance and methodical approaches to enhance this under researched process. The involvement of our Patient and Public Involvement (PPI) group throughout these processes is described. PMID- 29986397 TI - Cytotoxicity-Guided Isolation of Two New Phenolic Derivatives from Dryopteris fragrans (L.) Schott. AB - Dryopteris fragrans is a valuable medicinal plant resource with extensive biological activities including anti-cancer, anti-oxidation, and anti inflammation activities. This work aims to study further the cytotoxic constituents from Dryopteris fragrans. In this work, two new phenolic derivatives known as dryofragone (1) and dryofracoumarin B (2) with six known compounds (3-8) were isolated from the petroleum ether fraction of the methanol extract of the aerial parts of Dryopteris fragrans (L.) Schott by two round cytotoxicity-guided tracking with the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and cell counting kit-8 (CCK-8) assay. Their structures were elucidated by the extensive spectroscopic analysis (1H-NMR, 13C-NMR, and two dimensions NMR), chemical derivatization, and comparison with data reported in the literature. All the isolates were evaluated for their cytotoxicity against nine cancer cell lines as well as their in vitro immunomodulatory activity. The results showed that compounds have a modest cytotoxicity toward human HeLa cell line with IC50 value below 30 μM and compounds 4 and 5 may modulate immunity to affect the growth of tumor cells. PMID- 29986398 TI - Recruitment Strategies for a Randomised Controlled Trial Comparing Fast Versus Slow Weight Loss in Postmenopausal Women with Obesity-The TEMPO Diet Trial. AB - Current research around effective recruitment strategies for clinical trials of dietary obesity treatments have largely focused on younger adults, and thus may not be applicable to older populations. The TEMPO Diet Trial (Type of Energy Manipulation for Promoting optimal metabolic health and body composition in Obesity) is a randomised controlled trial comparing the long-term effects of fast versus slow weight loss on body composition and cardio-metabolic health in postmenopausal women with obesity. This paper addresses the recruitment strategies used to enrol participants into this trial and evaluates their relative effectiveness. 101 post-menopausal women aged 45-65 years, with a body mass index of 30-40 kg/m2 were recruited and randomised to either fast or slow weight loss. Multiple strategies were used to recruit participants. The total time cost (labour) and monetary cost per randomised participant from each recruitment strategy was estimated, with lower values indicating greater cost effectiveness and higher values indicating poorer cost-effectiveness. The most cost-effective recruitment strategy was word of mouth, followed (at equal second place) by free publicity on TV and radio, and printed advertorials, albeit these avenues only yielded 26/101 participants. Intermediate cost-effective recruitment strategies were flyer distribution at community events, hospitals and a local tertiary education campus, internet-based strategies, and clinical trial databases and intranets, which recruited a further 40/101 participants. The least cost-effective recruitment strategy was flyer distribution to local health service centres and residential mailboxes, and referrals from healthcare professionals were not effective. Recruiting for clinical trials involving postmenopausal women could benefit from a combination of recruitment strategies, with an emphasis on word of mouth and free publicity via radio, TV, and print media, as well as strategic placement of flyers, supplemented with internet-based strategies, databases and intranets if a greater yield of participants is needed. PMID- 29986399 TI - Anti-Infectivity against Herpes Simplex Virus and Selected Microbes and Anti Inflammatory Activities of Compounds Isolated from Eucalyptus globulus Labill. AB - Herpes simplex virus (HSV) causes numerous mild-to-serious human diseases, including mucocutaneous herpes infections and life-threatening herpes encephalitis. Moreover, herpes viral lesions can be complicated by inflammation and secondary bacterial infections. The development of resistance to antiviral drugs along with the undesirable side effects of these drugs are relevant argue for the development of new anti-HSV drugs with diverse mechanisms of action. Eucalyptus extracts have been used for decades to combat various infectious diseases. We isolated and studied 12 pure compounds and one mixture of two constitutional isomers from the leaves and twigs of E. globulus. The structures were identified by spectroscopic methods (NMR, HR-MS, IR) and all of them were tested for antiherpetic activity against the replication of antigen types HSV-1 and HSV-2. Tereticornate A (12) (IC50: 0.96 μg/mL; selectivity index CC50/IC50: 218.8) showed the strongest activity in the anti-HSV-1 assay, even greater than acyclovir (IC50: 1.92 μg/mL; selectivity index CC50/IC50: 109.4), a standard antiviral drug. Cypellocarpin C (5) (EC50: 0.73 μg/mL; selectivity index CC50/EC50: 287.7) showed the most potent anti-HSV-2 activity, also more intensive than acyclovir (EC50: 1.75 μg/mL; selectivity index CC50/EC50: 120.0). The antimicrobial activity of the isolated compounds was also evaluated against the bacteria Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and the yeast Candida albicans. The anti-inflammatory potential was examined using LPS-stimulated THP-1-XBlue™-MD2-CD14 and THP-1 macrophages and focusing on the influences of the NF-κB/AP-1 activity and the secretion of pro-inflammatory cytokines IL-1β and TNF-α. PMID- 29986400 TI - The Limited Benefit of Fish Consumption on Risk of Hip Fracture among Men in the Community-Based Hordaland Health Study. AB - Hip fractures have a high prevalence worldwide. Few studies have investigated whether fish consumption is associated with risk of hip fractures. The objective of the present study was to investigate the effect of fish intake on the subsequent risk of a hip fracture because of the low number of studies on this topic. A community-based prospective cohort study of 2865 men and women from Hordaland county in Norway, born between 1925-1927 and enrolled in the study in 1997-1999. Information on hip fracture cases was extracted from hospital records until 31 December 2009. Baseline information on the intake of fish was obtained from a semi-quantitative food frequency questionnaire. Cox proportional hazard regression models with death as a competing risk were used to evaluate the association of fish intake with risk of hip fracture. During a mean (SD) follow up time of 9.6 (2.7) years, 226 hip fractures (72 in men, 154 in women) were observed. The mean (SD) fish intake was 48 (25) g/1000 kcal. The association between fish intake and risk of hip fracture was not linear and displayed a threshold, with low intake of fish being associated with an increased risk of hip fracture in men (HR (Hazard Ratio) = 1.84, 95% CI 1.10, 3.08). In this community based prospective study of men and women, a low intake of fish was associated with the risk of a hip fracture in men. PMID- 29986401 TI - General Method for the Synthesis of (-)-Conduritol C and Analogs from Chiral Cyclohexadienediol Scaffolds. AB - An efficient and facile general method for the synthesis of conduritol C analogs, taking advantage of an enantioselective biocatalysis process of monosubstituted benzenes, is described. The absolute stereochemical patterns of the target molecules (−)-conduritol C, (−)-bromo-conduritol C, and (−) methyl-conduritol C were achieved by means of chemoenzymatic methods. The stereochemistry present at the homochiral cyclohexadiene-cis-1,2-diols derived from the arene biotransformation and the enantioselective ring opening of a non isolated vinylepoxide derivative permitted the absolute configuration of the carbon bearing the hydroxyl groups at the target molecules to be established. All three conduritols and two intermediates were crystallized, and their structures were confirmed by X-ray diffraction. The three conduritols and intermediates were isostructural. The versatility of our methodology is noteworthy to expand the preparation of conduritol C analogs starting from toluene dioxygenase (TDO) monosubstituted arene substrates. PMID- 29986402 TI - Verbal and Non-Verbal Aggression in a Swiss University Emergency Room: A Descriptive Study. AB - Workplace violence (WPV) by patients and visitors is a hazard in many emergency departments (ED), with serious consequences for both staff and patients. Patients with a migratory background seem to be prone to being involved in WPV. We therefore reviewed all reports of ED staff who experienced WPV over a 4-year period (2013-2016). We analyzed data on the reasons for the incident, the time of day, the manner of violence, the consequences, and the migratory background of the aggressor. In total, 83 cases of WPV were reported over a four-year period. The average age of the violent person was 33.1 years; in 35 cases (42.0%), aggressors were younger than 30 years old, 53 (63.8%) were male, 49 (59%) were of Swiss nationality, and 35-40% had a migratory background. The odds ratio of people originating from a low- to middle-income country versus those originating from a high-income country was 1.8. Furthermore, 45.8% of the patients arrived by ambulance (n = 38) and 19 patients (22.9%) were self-presenting. Most cases (92.8%) involved verbal aggression, but in more than half of the cases, physical assault (56.6%) was also reported. In addition, 43 (51.8%) of the events occurred during the night. Results also showed that 42 (50.6%) of patients who were involved in WPV were under the influence of alcohol and 29 (34.9%) suffered from psychiatric disorders. Security personnel and police were involved in 53 (63.9%) and 47 (56.6%) cases, respectively. Twenty patients (24.1%) were sedated and 16 (19.3%) were restrained. In 18 cases (21.7%), the psychiatrist ordered compulsory hospitalization in a psychiatric institution. Taken together, WPV is a relatively common event in our ED and persons with a migratory background are involved more often relative to their frequency of ED visits. PMID- 29986403 TI - A Novel Desloratadine-Benzoic Acid Co-Amorphous Solid: Preparation, Characterization, and Stability Evaluation. AB - Low physical stability is the limitation of the widespread use of amorphous drugs. The co-amorphous drug system is a new and emerging method for preparing a stable amorphous form. Co-amorphous is a single-phase amorphous multicomponent system consisting of two or more small molecules that are a combination of drugs or drugs and excipients. The co-amorphous system that uses benzoic acid (BA) as an excipient was studied to improve the physical stability, dissolution, and solubility of desloratadine (DES). In this study, the co-amorphous formation of DES and BA (DES-BA) was prepared by melt-quenching method and characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and polarized light microscopy (PLM). Dissolution, solubility, and physical stability profiles of DES-BA were determined. The DES crystals were converted into DES-BA co-amorphous form to reveal the molecular interactions between DES and BA. Solid-state analysis proved that the co-amorphous DES-BA system (1:1) is amorphous and homogeneous. The DSC experiment showed that the glass transition temperature (Tg) of tested DES-BA co amorphous had a higher single Tg compared to the amorphous DES. FTIR revealed strong interactions, especially salt formation. The dissolution rate and solubility of co-amorphous DES-BA (1:1) obtained were larger than the DES in crystalline form. The PXRD technique was used to assess physical stability for three months at 40 °C with 75% RH. The DES-BA co-amorphous system demonstrated better physical stability than a single form of amorphous DES. Co amorphous DES-BA has demonstrated the potential for improving solid-state stability, as the formation of DES-BA co-amorphous salt increased solubility and dissolution when compared to pure crystalline DES. This study also demonstrated the possibility for developing a DES-BA co-amorphous system toward oral formulations to improve DES solubility and bioavailability. PMID- 29986404 TI - Asymptomatic Host Plant Infection by the Widespread Pathogen Botrytis cinerea Alters the Life Histories, Behaviors, and Interactions of an Aphid and Its Natural Enemies. AB - Plant pathogens can profoundly affect host plant quality as perceived by their insect herbivores, with potentially far-reaching implications for the ecology and structure of insect communities. Changes in host plants may have direct effects on the life-histories of their insect herbivores, which can then influence their value as prey to their natural enemies. While there have been many studies that have explored the effects of infection when plants show symptoms of disease, little is understood about how unexpressed infection may affect interactions at higher trophic levels. We examined how systemic, asymptomatic, and seed-borne infection by the ubiquitous plant pathogen Botrytis cinerea, infecting two varieties of the lettuce Lactuca sativa, affected aphids (the green peach aphid, Myzus persicae) and two widely used biocontrol agents (the parasitoid Aphidius colemani and the ladybird predator Adalia bipunctata). Lettuce varieties differed in host plant quality. Asymptomatic infection reduced chlorophyll content and dry weight of host plants, irrespective of plant variety. Aphids reared on asymptomatic plants were smaller, had reduced off-plant survival time and were less fecund than aphids reared on uninfected plants. Parasitoids showed reduced attack rates on asymptomatically infected plants, and wasps emerging from hosts reared on such plants were smaller and showed reduced starvation resistance. When given a choice in an olfactometer, aphids preferentially chose uninfected plants of one variety (Tom Thumb) but showed no preference with the second (Little Gem) variety. Parasitoids preferentially chose aphids on uninfected plants, irrespective of host plant variety, but ladybirds did not show any such preference. These results suggest that the reduced quality of plants asymptomatically infected by Botrytis cinerea negatively affects the life history of aphids and their parasitoids, and alters the behaviors of aphids and parasitoids, but not of ladybirds. Fungal pathogens are ubiquitous in nature, and this work shows that even when host plants are yet to show symptoms, pathogens can affect interactions between insect herbivores and their natural enemies. This is likely to have important implications for the success of biological control programs. PMID- 29986405 TI - ENABLE 2017, the First European PhD and Post-Doc Symposium. Session 1: Building the Foundations of Biology: Synthetic and Cellular Research. AB - The European Academy for Biomedical Science (ENABLE) is an initiative funded by the European Union Horizon 2020 program involving four renowned European Research Institutes (Institute for Research in Biomedicine—IRB Barcelona, Spain; Radboud Institute for Molecular Life Sciences—RIMLS, the Netherlands; Novo Nordisk Foundation Center for Protein Research—NNF CPR, Denmark; European School of Molecular Medicine—SEMM, Italy) and an innovative science communication agency (Scienseed). With the aim of promoting biomedical science of excellence in Europe, ENABLE organizes an annual three-day international event. This gathering includes a top-level scientific symposium bringing together leading scientists, PhD students, and post-doctoral fellows; career development activities supporting the progression of young researchers and fostering discussion about opportunities beyond the bench; and outreach activities stimulating the interaction between science and society. The first European PhD and Postdoc Symposium, entitled “Breaking Down Complexity: Innovative Models and Techniques in Biomedicine”, was hosted by the vibrant city of Barcelona. The scientific program of the conference was focused on the most recent advances and applications of modern techniques and models in biomedical research and covered a wide range of topics, from synthetic biology to translational medicine. Overall, the event was a great success, with more than 200 attendees from all over Europe actively participating in the symposium by presenting their research and exchanging ideas with their peers and world renowned scientists. PMID- 29986406 TI - Thermal Imaging Metrology with a Smartphone Sensor. AB - Thermal imaging cameras are expensive, particularly those designed for measuring high temperature objects with low measurement uncertainty. A wide range of research and industrial applications would benefit from lower cost temperature imaging sensors with improved metrology. To address this problem, we present the first ever quantification methodology for the temperature measurement performance of an ultra-low cost thermal imaging system based on a smartphone sensor. The camera was formed from a back illuminated silicon Complementary Metal Oxide Semiconductor (CMOS) sensor, developed for the smartphone camera market. It was packaged for use with a Raspberry Pi computer. We designed and fitted a custom made triplet lens assembly. The system performance was characterised with a range of state-of-the-art techniques and metrics: establishing a temperature resolution of below 10 °C in the range 600-1000 °C. Furthermore, the scene dependent aspects of combined uncertainty were considered. The minimum angular subtense for which an accurate thermal measurement could be made was determined to be 1.35°, which corresponds to a 23 mm bar at a distance of 1 m, or 45:1 field of-view in radiation thermometer nomenclature. PMID- 29986407 TI - Systematic Experimental Assessment of a 2D-Motion Sensor to Detect Relative Movement between Residual Limb and Prosthetic Socket. AB - A sensor system for measuring the relative movement between prosthetic socket and residual limb based on a 2D-motion sensor is introduced and thoroughly tested experimentally. The quantitative analysis of test rig evaluation is used to identify advantageous sensor settings and liner configurations. Considering these favorable settings, sensor functionality is quantified to errrel=0.52+/-1.78%. Advancing to convex measurement surfaces, the sensor shows absolute errors of errabs≤1 mm in an observable measurement scenario. The feasibility of measuring gait-induced relative movement with the proposed 2D-motion sensor is shown via a biomechanical plausibility study. Overall, the findings suggest that the proposed sensor system is suitable for investigating the relative movement between residual limb and prosthetic socket in dynamic gait situations. PMID- 29986409 TI - Identification and Functional Analysis of the psaD Promoter of Chlorella vulgaris Using Heterologous Model Strains. AB - Chlorella has great potential as a bio-factory for production of value-added compounds. To produce the desired chemicals more efficiently in Chlorella, genetic tools for modification of Chlorella need to be developed, especially an endogenous promoter. In this study, the promoter of photosystem I protein D (psaD) from Chlorella vulgaris UTEX395 was identified. Computational analysis revealed the presence of several putative cis-acting elements, including a potential core element, and light-responsive or stress-responsive elements. Gene expression analysis in heterologous expression system in Chlamydomonasreinhardtii and Nicotianabenthamiana showed that CvpsaD promoter can be used to drive the expression of genes. Functional analysis of this promoter suggested that the initiator element (Inr) is important for its function (i.e., TATA-less promoter) and that an additional factor (e.g., downstream of the transcriptional start site) might be needed for light response. We have shown that the CvpsaD promoter is functional, but not sufficiently strong, both in microalgae and higher plant. PMID- 29986410 TI - Damage Detection of L-Shaped Concrete Filled Steel Tube (L-CFST) Columns under Cyclic Loading Using Embedded Piezoceramic Transducers. AB - L-shaped concrete filled steel tube (L-CFST) columns are used frequently in civil engineering, and the concrete damage inside the L-CFST column is difficult to monitor. This research aims to develop a new method to monitor the internal concrete damage in the L-CFST column by using embedded piezoceramic smart aggregates (SAs) under low frequency cyclic loading. The SA enabled active method is used to monitor the concrete damages near the bottom of the L-CFST columns, and the wavelet packet analysis is used to establish a damage index, which is used to analyze the acquired data. During the experiment, three L-CFST columns with different wall thickness of the steel tube were tested. The experimental results find that the structural damage indices under the low-frequency cyclic loading are basically consistent with the results of the hysteretic curves and the skeleton curve of the specimens, and are in good agreement with the experimental phenomena. We conclude that the use of smart aggregate can directly and clearly reflect the damage process of the concrete core, demonstrating the feasibility of using piezoceramic smart aggregates to monitor the internal concrete damage of the L-CFST column. PMID- 29986408 TI - Schisandra chinensis Fructus and Its Active Ingredients as Promising Resources for the Treatment of Neurological Diseases. AB - Neurological diseases (NDs) are a leading cause of death worldwide and tend to mainly affect people under the age of 50. High rates of premature death and disability caused by NDs undoubtedly constrain societal development. However, effective therapeutic drugs and methods are very limited. Schisandra chinensis Fructus (SCF) is the dry ripe fruit of Schisandra chinensis (Turcz.) Baill, which has been used in traditional Chinese medicine for thousands of years. Recent research has indicated that SCF and its active ingredients show a protective role in NDs, including cerebrovascular diseases, neurodegenerative diseases, or depression. The key neuroprotective mechanisms of SCF and its active ingredients have been demonstrated to include antioxidation, suppression of apoptosis, anti inflammation, regulation of neurotransmitters, and modulation of brain-derived neurotrophic factor (BDNF) related pathways. This paper summarizes studies of the role of SCF and its active ingredients in protecting against NDs, and highlights them as promising resources for future treatment. Furthermore, novel insights on the future challenges of SCF and its active ingredients are offered. PMID- 29986411 TI - Transcranial Magnetic Stimulation in Tourette Syndrome: A Historical Perspective, Its Current Use and the Influence of Comorbidities in Treatment Response. AB - BACKGROUND: Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder consisting of impairing motor and vocal tics which often persists adolescent and adult years. In this older refractory group, standard treatments such as pharmacotherapy and psychotherapeutic interventions may only have limited effects. Based on electrical cortical dysregulation in individuals with TS, a novel approach has employed brain stimulation strategies to modulate the putative aberrant neural electrical activity in pathways that may underlie tics, such as insula-supplementary motor area (SMA) connectivity. METHODS: This review will examine all published clinical trials employing transcranial magnetic stimulation (TMS) to ameliorate tics, and discuss a framework for the pathophysiology of TS in relation to electrical brain activity. A framework for future research in tic disorders using TMS and imaging targeting neuroplasticity will be discussed. RESULTS: Therapeutic electrical brain activity modulation with TMS has been carried out in stroke neuro-rehabilitation and neuropsychiatry, including trials in TS. Eleven trials document the use of TMS in TS targeting several brain areas, a positive effect is seen for those trials targeting the SMA. In particular, it appears that younger individuals with concurrent attention-deficit hyperactivity disorder (ADHD) benefit the most. CONCLUSIONS: TMS can be used as an effective tool to explore the psychophysiology of TS and potentially provide a therapeutic option. Ultimately, translational research using TMS in TS needs to explore connectivity differences pre- and post-treatment in individuals with TS that are linked to improvement in tic symptoms, with an emphasis on approaches using functional neuroimaging as well as other probes of neuroplasticity. PMID- 29986412 TI - Iodine Status and Consumption of Key Iodine Sources in the U.S. Population with Special Attention to Reproductive Age Women. AB - We estimated iodine status (median urinary iodine concentration (mUIC (µg/L))) for the US population (6 years and over; n = 4613) and women of reproductive age (WRA) (15-44 years; n = 901). We estimated mean intake of key iodine sources by race and Hispanic origin. We present the first national estimates of mUIC for non-Hispanic Asian persons and examine the intake of soy products, a potential source of goitrogens. One-third of National Health and Nutrition Examination Survey (NHANES) participants in 2011-2014 provided casual urine samples; UIC was measured in these samples. We assessed dietary intake with one 24-h recall and created food groups using the USDA’s food/beverage coding scheme. For WRA, mUIC was 110 µg/L. For both non-Hispanic white (106 µg/L) and non-Hispanic Asian (81 µg/L) WRA mUIC was significantly lower than mUIC among Hispanic WRA (133 µg/L). Non-Hispanic black WRA had a mUIC of 124 µg/L. Dairy consumption was significantly higher among non Hispanic white (162 g) compared to non-Hispanic black WRA (113 g). Soy consumption was also higher among non-Hispanic Asian WRA (18 g compared to non Hispanic black WRA (1 g). Differences in the consumption pattern of key sources of iodine and goitrogens may put subgroups of individuals at risk of mild iodine deficiency. Continued monitoring of iodine status and variations in consumption patterns is needed. PMID- 29986414 TI - Abnormal Hippocampal Melatoninergic System: A Potential Link between Absence Epilepsy and Depression-Like Behavior in WAG/Rij Rats? AB - Absence epilepsy and depression are comorbid disorders, but the molecular link between the two disorders is unknown. Here, we examined the role of the melatoninergic system in the pathophysiology of spike and wave discharges (SWDs) and depression-like behaviour in the Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. In WAG/Rij rats, SWD incidence was higher during the dark period of the light-dark cycle, in agreement with previous findings. However, neither pinealectomy nor melatonin administration had any effect on SWD incidence, suggesting that the melatoninergic system was not involved in the pathophysiology of absence-like seizures. Endogenous melatonin levels were lower in the hippocampus of WAG/Rij rats as compared to non-epileptic control rats, and this was associated with higher levels of melatonin receptors in the hippocampus, but not in the thalamus. In line with the reduced melatonin levels, cell density was lower in the hippocampus of WAG/Rij rats and was further reduced by pinealectomy. As expected, WAG/Rij rats showed an increased depression-like behaviour in the sucrose preference and forced swim tests, as compared to non epileptic controls. Pinealectomy abolished the difference between the two strains of rats by enhancing depression-like behaviour in non-epileptic controls. Melatonin replacement displayed a significant antidepressant-like effect in both WAG/Rij and control rats. These findings suggest that a defect of hippocampal melatoninergic system may be one of the mechanisms underlying the depression-like phenotype in WAG/Rij rats and that activation of melatonin receptors might represent a valuable strategy in the treatment of depression associated with absence epilepsy. PMID- 29986415 TI - The Production of Human beta-Glucocerebrosidase in Nicotiana benthamiana Root Culture. AB - Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase (GCase). Currently, enzyme-replacement therapy using recombinant GCase produced in mammalian cells is considered the most effective treatment. Plants are an attractive alternative host for recombinant protein production due to the low cost of large-scale production and lack of risk of contamination by human pathogens. Compared to whole plants, root cultures can grow faster. Therefore, this study aimed to produce recombinant GCase in a Nicotiana benthamiana root culture. Root culture of a GCase-producing transgenic plant was induced by indole 3-acetic acid at the concentration of 1 mg/L. Recombinant GCase was successfully produced in roots as a functional protein with an enzyme activity equal to 81.40 +/- 17.99 units/mg total protein. Crude proteins were extracted from the roots. Recombinant GCase could be purified by concanavalin A and phenyl 650C chromatography. The productivity of GCase was approximately 1 µg/g of the root. A N-glycan analysis of purified GCase was performed using nano LC/MS. The Man3XylFucGlcNAc2 structure was predominant in purified GCase with two plant specific glycan residues. This study presents evidence for a new, safe and efficient system of recombinant GCase production that might be applied to other recombinant proteins. PMID- 29986416 TI - Study of the Grape Cryo-Maceration Process at Different Temperatures. AB - This research aimed to determine the effects of cryo-maceration at different temperatures on polyphenol content during the winemaking process of Chardonnay wine. Samples of Chardonnay grapes were subjected to rapid cooling processes by direct injection of liquid CO2 to obtain final temperatures of 10.0, 8.0, 6.0 and 4.0 °C and yield different batches of grape mash. Subsequently, each batch underwent the winemaking process to produce four different wines. The wines obtained were characterized by chemical analyses. We observed higher extraction of polyphenolic compounds with low-temperature cold maceration, particularly when the temperature was reduced from 10.0 to 6.0 °C. Conversely, when the temperature was reduced below 6.0 °C, the increase in polyphenol content in wine was negligible, whereas CO2 consumption increased. Furthermore, a numerical simulation was performed to determine the pipe length, L0, after which the temperature was constant. This condition is very important because it guarantees that after the length L0, the thermodynamic exchange between liquid CO2 and is complete, eliminating the possibility of liquid CO2 pockets in the cyclone. PMID- 29986418 TI - Expression of Genes Involved in Stress, Toxicity, Inflammation, and Autoimmunity in Relation to Cadmium, Mercury, and Lead in Human Blood: A Pilot Study. AB - There is growing evidence of immunotoxicity related to exposure to toxic trace metals, and an examination of gene expression patterns in peripheral blood samples may provide insights into the potential development of these outcomes. This pilot study aimed to correlate the blood levels of three heavy metals (mercury, cadmium, and lead) with differences in gene expression in 24 participants from the Long Island Study of Seafood Consumption. We measured the peripheral blood mRNA expression of 98 genes that are implicated in stress, toxicity, inflammation, and autoimmunity. We fit multiple linear regression models with multiple testing correction to correlate exposure biomarkers with mRNA abundance. The mean blood Hg in this cohort was 16.1 µg/L, which was nearly three times the Environmental Protection Agency (EPA) reference dose (5.8 µg/L). The levels of the other metals were consistent with those in the general population: the mean Pb was 26.8 µg/L, and the mean Cd was 0.43 µg/L. The expression of three genes was associated with mercury, four were associated with cadmium, and five were associated with lead, although none were significant after multiple testing correction. Little evidence was found to associate metal exposure with mRNA abundance for the tested genes that were associated with stress, toxicity, inflammation, or autoimmunity. Future work should provide a more complete picture of physiological reactions to heavy metal exposure. PMID- 29986413 TI - Unravelling HDL-Looking beyond the Cholesterol Surface to the Quality Within. AB - High-density lipoprotein (HDL) particles have experienced a turbulent decade of falling from grace with widespread demotion from the most-sought-after therapeutic target to reverse cardiovascular disease (CVD), to mere biomarker status. HDL is slowly emerging from these dark times due to the HDL flux hypothesis wherein measures of HDL cholesterol efflux capacity (CEC) are better predictors of reduced CVD risk than static HDL-cholesterol (HDL-C) levels. HDL particles are emulsions of metabolites, lipids, protein, and microRNA (miR) built on the backbone of Apolipoprotein A1 (ApoA1) that are growing in their complexity due to the higher sensitivity of the respective “omic” technologies. Our understanding of particle composition has increased dramatically within this era and has exposed how our understanding of these particles to date has been oversimplified. Elucidation of the HDL proteome coupled with the identification of specific miRs on HDL have highlighted the “hormonal” characteristics of HDL in that it carries and delivers messages systemically. HDL can dock to most peripheral cells via its receptors, including SR-B1, ABCA1, and ABCG1, which may be a critical step for facilitating HDL-to-cell communication. The composition of HDL particles is, in turn, altered in numerous disease states including diabetes, auto-immune disease, and CVD. The consequence of changes in composition, however, on subsequent biological activities of HDL is currently poorly understood and this is an important avenue for the field to explore in the future. Improving HDL particle quality as opposed to HDL quantity may, in turn, prove a more beneficial investment to reduce CVD risk. PMID- 29986419 TI - Elasto-Plastic Mechanical Properties and Failure Mechanism of Innovative Ti (SiCf/Al3Ti) Laminated Composites for Sphere-Plane Contact at the Early Stage of Penetration Process. AB - A novel silicon carbide (SiC) continuous ceramic fiber-reinforced (CCFR) Ti/Al3Ti Metal-Intermetallic-Laminate (MIL) composite was fabricated. A high-efficiency semi-analytical model was proposed based on the numerical equivalent inclusion method (NEIM) for analyzing the small-strain elasto-plastic contact in the early stage of the penetration process. The microstructure and interface features were characterized by the scanning electron microscopy (SEM). Quasi-static compression tests were performed to determine the contact response and validate the proposed model. A group of in-depth parametric studies were carried out to quantify the influence of the microstructure. The comparison between results under the sphere plane and plane-plane contact load indicates that, under the first sphere-plane, the compressive strength and failure strain are both lower and the SiC reinforcement effect on strength is very clear while the effect on ductility is not clear. The maximum plastic strain concentration (MPSC) in the Al3Ti layer is closest to the upper boundary of the central SiC fiber and then extends along the depth direction as the load increases, which are also the locations where cracks may initiate and extend. Moreover, the CCFR-MIL composite shows better mechanical properties when the center distance between adjacent SiC fibers is four times the fiber diameter and the volume fraction of Ti is 40%. PMID- 29986417 TI - Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes. AB - The cytochromes P450 are drug metabolizing enzymes in the body that typically react with substrates through a monoxygenation reaction. During the catalytic cycle two reduction and protonation steps generate a high-valent iron (IV)-oxo heme cation radical species called Compound I. However, with sufficient reduction equivalents present, the catalytic cycle should be able to continue to the reduced species of Compound I, called Compound II, rather than a reaction of Compound I with substrate. In particular, since electron transfer is usually on faster timescales than atom transfer, we considered this process feasible and decided to investigate the reaction computationally. In this work we present a computational study using density functional theory methods on active site model complexes alongside quantum mechanics/molecular mechanics calculations on full enzyme structures of cytochrome P450 enzymes. Specifically, we focus on the relative reactivity of Compound I and II with a model substrate for O-H bond activation. We show that generally the barrier heights for hydrogen atom abstraction are higher in energy for Compound II than Compound I for O-H bond activation. Nevertheless, for the activation of such bonds, Compound II should still be an active oxidant under enzymatic conditions. As such, our computational modelling predicts that under high-reduction environments the cytochromes P450 can react with substrates via Compound II but the rates will be much slower. PMID- 29986421 TI - A New Vegetation Index Based on Multitemporal Sentinel-2 Images for Discriminating Heavy Metal Stress Levels in Rice. AB - Heavy metal stress in crops is a worldwide problem that requires accurate and timely monitoring. This study aimed to improve the accuracy of monitoring heavy metal stress levels in rice by using multiple Sentinel-2 images. The selected study areas are in Zhuzhou City, Hunan Province, China. Six Sentinel-2 images were acquired in 2017, and heavy metal concentrations in soil were measured. A novel vegetation index called heavy metal stress sensitive index (HMSSI) was proposed. HMSSI is the ratio between two red-edge spectral indices, namely the red-edge chlorophyll index (CIred-edge) and the plant senescence reflectance index (PSRI). To demonstrate the capability of HMSSI, the performances of CIred edge and PSRI in discriminating heavy metal stress levels were compared with that of HMSSI at different growth stages. Random forest (RF) was used to establish a multitemporal monitoring model to detect heavy metal stress levels in rice based on HMSSI at different growth stages. Results show that HMSSI is more sensitive to heavy metal stress than CIred-edge and PSRI at different growth stages. The performance of a multitemporal monitoring model combining the whole growth stage images was better than any other single growth stage in distinguishing heavy metal stress levels. Therefore, HMSSI can be regarded as an indicator for monitoring heavy metal stress levels with a multitemporal monitoring model. PMID- 29986420 TI - Food Insecurity and Mental Health among Females in High-Income Countries. AB - Food insecurity is a persistent concern in high-income countries, and has been associated with poor mental health, particularly among females. We conducted a scoping review to characterize the state of the evidence on food insecurity and mental health among women in high-income countries. The research databases PubMed, EMBASE, and psycINFO were searched using keywords capturing food insecurity, mental health, and women. Thirty-nine articles (representing 31 unique studies/surveys) were identified. Three-quarters of the articles drew upon data from a version of the United States Department of Agriculture Household Food Security Survey Module. A range of mental health measures were used, most commonly to measure depression and depressive symptoms, but also anxiety and stress. Most research was cross-sectional and showed associations between depression and food insecurity; longitudinal analyses suggested bidirectional relationships (with food insecurity increasing the risk of depressive symptoms or diagnosis, or depression predicting food insecurity). Several articles focused on vulnerable subgroups, such as pregnant women and mothers, women at risk of homelessness, refugees, and those who had been exposed to violence or substance abuse. Overall, this review supports a link between food insecurity and mental health (and other factors, such as housing circumstances and exposure to violence) among women in high-income countries and underscores the need for comprehensive policies and programs that recognize complex links among public health challenges. PMID- 29986422 TI - Effect of Silicon Fertilization on Crop Yield Quantity and Quality-A Literature Review in Europe. AB - This paper presents a research review of the effect of silicon fertilization on the yield quantity and quality in the last 15 years. The study focuses on plant species grown in Europe: cereals, soybean, rapeseed, sugar beet, potato, meadows, berries and vegetables, and orchard and ornamental plants. The use of silicon is most common in the production of vegetables in greenhouses. However, the use of this element for the fertilization of agricultural plants is rare. Positive prospects of silicon fertilization are associated with foliar application, which is much cheaper and more convenient to use than soil fertilization. Foliar application of silicon has a biostimulative effect, and the best results are observed in stressful conditions for plants such as salinity, deficiency or excess of water, high and low temperature, and the strong pressure of diseases and pests, etc. Based on the results of previous studies, it can be concluded that foliar nutrition should be introduced into production as a standard treatment in the crop management of many species of agricultural plants. It can help farmers to increase the yield of crops. It is also important that it is safe for the environment, which is particularly important in Europe. PMID- 29986425 TI - Microscale and Nanoscale Biosensors. AB - The emerge of nanotechnology along with the success of the microelectronics industry has motivated the miniaturization of biosensors into the nano/microscale. This Special Issue highlights recent advances in microscale and nanoscale biosensors, including self-propelled micromotors: their materials, fabrication, and applications. A total of seven papers (five research and two review papers) are included. Different but related topics are covered, from biosensor design (paper strips and digital microfluidic chips) to integrated configurations that monitor metabolites in cellular environments. The reviews are devoted to protein-based biosensors and moving biosensors based on self-propelled micromotors. PMID- 29986423 TI - Psychiatric Comorbidity in Children and Adults with Gluten-Related Disorders: A Narrative Review. AB - Gluten-related disorders are characterized by both intestinal and extraintestinal manifestations. Previous studies have suggested an association between gluten related disorder and psychiatric comorbidities. The objective of our current review is to provide a comprehensive review of this association in children and adults. A systematic literature search using MEDLINE, Embase and PsycINFO from inception to 2018 using terms of ‘celiac disease’ or ‘gluten sensitivity-related disorders’ combined with terms of ‘mental disorders’ was conducted. A total of 47 articles were included in our review, of which 28 studies were conducted in adults, 11 studies in children and eight studies included both children and adults. The majority of studies were conducted in celiac disease, two studies in non-celiac gluten sensitivity and none in wheat allergy. Enough evidence is currently available supporting the association of celiac disease with depression and, to a lesser extent, with eating disorders. Further investigation is warranted to evaluate the association suggested with other psychiatric disorders. In conclusion, routine surveillance of potential psychiatric manifestations in children and adults with gluten related disorders should be carried out by the attending physician. PMID- 29986424 TI - Lithocholic Acid Is a Vitamin D Receptor Ligand That Acts Preferentially in the Ileum. AB - The vitamin D receptor (VDR) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and regulates calcium and bone metabolism. Lithocholic acid (LCA), which is a secondary bile acid produced by intestinal bacteria, acts as an additional physiological VDR ligand. Despite recent progress, however, the physiological function of the LCA−VDR axis remains unclear. In this study, in order to elucidate the differences in VDR action induced by 1,25(OH)2D3 and LCA, we compared their effect on the VDR target gene induction in the intestine of mice. While the oral administration of 1,25(OH)2D3 induced the Cyp24a1 expression effectively in the duodenum and jejunum, the LCA increased target gene expression in the ileum as effectively as 1,25(OH)2D3. 1,25(OH)2D3, but not LCA, increased the expression of the calcium transporter gene Trpv6 in the upper intestine, and increased the plasma calcium levels. Although LCA could induce an ileal Cyp24a1 expression as well as 1,25(OH)2D3, the oral LCA administration was not effective in the VDR target gene induction in the kidney. No effect of LCA on the ileal Cyp24a1 expression was observed in the VDR-null mice. Thus, the results indicate that LCA is a selective VDR ligand acting in the lower intestine, particularly the ileum. LCA may be a signaling molecule, which links intestinal bacteria and host VDR function. PMID- 29986426 TI - Deformation Behavior of Foam Laser Targets Fabricated by Two-Photon Polymerization. AB - Two-photon polymerization (2PP), which is a three-dimensional micro/nano-scale additive manufacturing process, is used to fabricate component for small custom experimental packages (“targets”) to support laser-driven, high energy-density physics research. Of particular interest is the use of 2PP to deterministically print millimeter-scale, low-density, and low atomic number (CHO) polymer matrices (“foams”). Deformation during development and drying of the foam structures remains a challenge when using certain commercial acrylic photo-resins. Acrylic resins were chosen in order to meet the low atomic number requirement for the foam; that requirement precludes the use of low shrinkage organic/inorganic hybrid resins. Here, we compare the use of acrylic resins IP-S and IP-Dip. Infrared and Raman spectroscopy are used to quantify the extent of the polymerization during 2PP vs. UV curing. The mechanical strength of beam and foam structures is examined, particularly the degree of deformation that occurs during the development and drying processes. The magnitude of the shrinkage is quantified, and finite element analysis is used in order to simulate the resulting deformation. Capillary drying forces during development are shown to be small and are likely below the elastic limit of the foam log-pile structures. In contrast, the substantial shrinkage in IP-Dip (~5-10%) causes large shear stresses and associated plastic deformation, particularly near constrained boundaries and locations with sharp density transitions. Use of IP-S with an improved writing procedure results in a marked reduction in deformation with a minor loss of resolution. PMID- 29986427 TI - Distribution of Tetrodotoxin in the New Zealand Clam, Paphies australis, Established Using Immunohistochemistry and Liquid Chromatography-Tandem Quadrupole Mass Spectrometry. AB - Tetrodotoxin (TTX) is one of the most potent neurotoxins known. It was originally thought to only occur in puffer fish but has now been identified in twelve different classes of freshwater and marine organisms, including bivalves. Despite being one of the world’s most studied biotoxins, its origin remains uncertain. There is contradictory evidence regarding the source of TTX and its pathway through food webs. To date, the distribution of TTX has not been examined in bivalves. In the present study, 48 Paphies australis, a TTX-containing clam species endemic to New Zealand, were collected. Thirty clams were dissected, and organs and tissues pooled into five categories (siphons, digestive gland, adductor muscles, and the ‘rest’) and analyzed for TTX using liquid chromatography-mass spectrometry (LC-MS). The micro-distribution of TTX was visualized in the remaining 18 individuals using an immunohistological technique incorporating a TTX-specific monoclonal antibody. The LC-MS analysis revealed that siphons contained the highest concentrations of TTX (mean 403.8 µg/kg). Immunohistochemistry analysis showed TTX in the outer cells of the siphons, but also in the digestive system, foot, and gill tissue. Observing TTX in organs involved in feeding provides initial evidence to support the hypothesis of an exogenous source in P. australis. PMID- 29986429 TI - Electro-Superplastic Solid State Welding of 40Cr/QCr0.5. AB - Hot-squeezed chrome bronze QCr0.5 and ultra-fine treated 40Cr steel have been successfully welded using an electro-superplastic solid-state welding technique. Results have shown that the tensile strength of a 40Cr/QCr0.5 weld joint can be greatly increased, up to or exceeding that of QCr0.5 base metal. The weld interface between 40Cr and QCr0.5 has achieved metallurgical bonding and there are less micro-gaps, thicker transition regions and more copper convexes and dimples on the fracture surface of the 40Cr side when applying an external electrical field of E = 3 kV/cm, as well as with other welding parameters, including no vacuum, no shield gas, a pre-pressure of 56.6 MPa, an initial strain rate of 1.5 × 10−4 s−1, a pressure welding temperature of 710 800 °C, and a pressure welding time of 0-8 min. PMID- 29986428 TI - Emerging Opportunities for Synthetic Biology in Agriculture. AB - Rapid expansion in the emerging field of synthetic biology has to date mainly focused on the microbial sciences and human health. However, the zeitgeist is that synthetic biology will also shortly deliver major outcomes for agriculture. The primary industries of agriculture, fisheries and forestry, face significant and global challenges; addressing them will be assisted by the sector’s strong history of early adoption of transformative innovation, such as the genetic technologies that underlie synthetic biology. The implementation of synthetic biology within agriculture may, however, be hampered given the industry is dominated by higher plants and mammals, where large and often polyploid genomes and the lack of adequate tools challenge the ability to deliver outcomes in the short term. However, synthetic biology is a rapidly growing field, new techniques in genome design and synthesis, and more efficient molecular tools such as CRISPR/Cas9 may harbor opportunities more broadly than the development of new cultivars and breeds. In particular, the ability to use synthetic biology to engineer biosensors, synthetic speciation, microbial metabolic engineering, mammalian multiplexed CRISPR, novel anti microbials, and projects such as Yeast 2.0 all have significant potential to deliver transformative changes to agriculture in the short, medium and longer term. Specifically, synthetic biology promises to deliver benefits that increase productivity and sustainability across primary industries, underpinning the industry’s prosperity in the face of global challenges. PMID- 29986430 TI - Anti-Agglomeration Behavior and Sensing Assay of Chlorsulfuron Based on Acetamiprid-Gold Nanoparticles. AB - Monitoring of low levels of chlorsulfuron in environmental water samples is important. Although several detection methods have been developed, they all have some drawbacks, such as being time-consuming, requiring expensive instruments and experienced operators, and consuming large volumes of organic solvents. There is an urgent need for a simple, rapid, and inexpensive detection method for chlorsulfuron. Herein, such a method was developed using anti-aggregation of gold nanoparticles (AuNPs) in the presence of acetamiprid in agricultural irrigation water samples. Aggregation of the AuNPs was induced by acetamiprid, and this produced a distinct color change from Bordeaux red to blue. However, the strong hydrogen bonding interaction between chlorsulfuron and acetamiprid could inhibit AuNP aggregation. The effect of chlorsulfuron on the anti-agglomeration behavior of AuNPs was monitored by ultraviolet-visiblespectroscopy (UV-Vis) and the naked eye over a concentration range 0.1-100 mg/L. The detection limit for chlorsulfuron was 0.025 mg/L (signal-to-noise ratio of three). This colorimetric method was successfully applied to the determination of chlorsulfuron in spiked tap water and agricultural irrigation water with satisfactory recoveries (76.3% 94.2%). PMID- 29986431 TI - Inverse Finite Element Method for Reconstruction of Deformation in the Gantry Structure of Heavy-Duty Machine Tool Using FBG Sensors. AB - The deformation of the gantry structure in heavy-duty machine tools is an important factor that affects machining accuracy. In order to realize real-time monitoring of the deformation of the gantry structure, which is statically indeterminate and complex in shape, the reconstruction algorithm based on inverse Finite Element Method (iFEM) is proposed and fiber Bragg grating (FBG) sensors are used to measure strain data. The elements of the gantry structure are divided and the displacement functions of each element are determined. The shape function is obtained by substituting degree of freedoms (DOF) of element nodes into displacement functions. Through a differential method, the relation between strain and DOF of element nodes is established by the strain matrices. Subsequently, the DOF of element nodes are obtained by minimizing an error functional defined as the least-squares error between the analytic strain data and the corresponding experimental strains. Considering coordinate transformation and problem-specific displacement boundary conditions, the total deformation of the gantry structure is obtained. Following this, the experiment was carried out. The deformation simulated by ANSYS was used to replace the experimentally measured deformation and then compared with the deformation reconstructed by iFEM under the same loading condition. The accuracy of iFEM for reconstructing deformation of the gantry structure in heavy-duty machine tools is verified. It provides a new view for improving the machining precision of heavy-duty machine tools. PMID- 29986433 TI - Cost-Benefit Optimization of Structural Health Monitoring Sensor Networks. AB - Structural health monitoring (SHM) allows the acquisition of information on the structural integrity of any mechanical system by processing data, measured through a set of sensors, in order to estimate relevant mechanical parameters and indicators of performance. Herein we present a method to perform the cost-benefit optimization of a sensor network by defining the density, type, and positioning of the sensors to be deployed. The effectiveness (benefit) of an SHM system may be quantified by means of information theory, namely through the expected Shannon information gain provided by the measured data, which allows the inherent uncertainties of the experimental process (i.e., those associated with the prediction error and the parameters to be estimated) to be accounted for. In order to evaluate the computationally expensive Monte Carlo estimator of the objective function, a framework comprising surrogate models (polynomial chaos expansion), model order reduction methods (principal component analysis), and stochastic optimization methods is introduced. Two optimization strategies are proposed: the maximization of the information provided by the measured data, given the technological, identifiability, and budgetary constraints; and the maximization of the information-cost ratio. The application of the framework to a large-scale structural problem, the Pirelli tower in Milan, is presented, and the two comprehensive optimization methods are compared. PMID- 29986432 TI - Effect of Endoplasmic Reticular Stress on Free Hemoglobin Metabolism and Liver Injury. AB - Elevated soluble (s) CD163 and free hemoglobin (Hb) levels predict fatty liver progression; however, the molecular mechanisms underlying Hb metabolism and liver injury remain undefined. We investigated the effects of endoplasmic reticular (ER) stress on red blood cell (RBC) rheology and free Hb recycling pathways. ER stress was induced in Sprague-Dawley rats by an intraperitoneal injection of tunicamycin (TM) (50, 100, and 200 μg/100 g body weight (BW)) or an intravenous injection of Hb (5 mg/100 g BW). A TM injection increased sCD163 levels, attenuated free Hb uptake, and maintained RBC aggregability. An Hb injection increased serum LVV-hemorphin-7 and total bilirubin levels, but this effect was suppressed by TM. A Western blot analysis showed that ER stress suppressed Hb degradation in the liver through downregulation of globin degradation proteins cathepsin D and glyoxalase-1, as well as heme degradation protein heme oxyganase-1 and keap-1 expression. An ER stress activator also increased the translocation of nuclear factor (NF)-κB (p65) and nuclear factor-erythroid 2-related factor 2 (Nrf2) to nuclei. In conclusion, ER stress triggers ineffective Hb metabolism via altering globin and heme iron degradation pathways. Inability to recycle and metabolize free Hb may underlie the association between iron dysfunction and liver injury. PMID- 29986434 TI - A Child with a c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 Mutation Associated with a Severe Early Infantile Epileptic Encephalopathy. AB - Early infantile epileptic encephalopathies (EIEEs) are a group of neurological disorders characterized by early-onset refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. Recently, genetic studies have indicated that a significant portion of previously cryptogenic EIEEs are single-gene disorders. SPTAN1 is among the genes whose mutations are associated with EIEE development (OMIM# 613477). Here, a case of the c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe EIEE is reported. This case shows that mutations in the α20 repeat in the C-terminal of αII spectrin can be associated with EIEE. Duplication seems essential to cause EIEE. This causation is not demonstrated for amino acid deletions in the same spectrin residues. Reportedly, children with p.(Asp2303_Leu2305del) and p.(Gln2304_Gly2306del) deletions have childhood-onset epilepsy and no or marginal magnetic resonance imaging abnormalities, suggesting that not only the location but also the type of mutation plays a role in conditioning nervous system damage. Further studies are needed for a better understanding of the phenotype/genotype correlation in SPTAN1-related encephalopathies. PMID- 29986435 TI - Environmentally-Friendly Green Approach for the Production of Zinc Oxide Nanoparticles and Their Anti-Fungal, Ovicidal, and Larvicidal Properties. AB - Green synthesis of nanoparticles can be an important alternative compared to conventional physio-chemical synthesis. We utilized Scadoxus multiflorus leaf powder aqueous extract as a capping and stabilizing agent for the synthesis of pure zinc oxide nanoparticles (ZnO NPs). Further, the synthesized ZnO NPs were subjected to various characterization techniques. Transmission electron microscope (TEM) analysis showed an irregular spherical shape, with an average particle size of 31 +/- 2 nm. Furthermore, the synthesized ZnO NPs were tested against Aedes aegypti larvae and eggs, giving significant LC50 value of 34.04 ppm. Ovicidal activity resulted in a higher percentage mortality rate of 96.4 +/- 0.24 at 120 ppm with LC50 value of 32.73 ppm. Anti-fungal studies were also conducted for ZnO NPs against Aspergillus niger and Aspergillus flavus, which demonstrated a higher inhibition rate for Aspergillus flavus compared to Aspergillus niger. PMID- 29986437 TI - Effects of Filler-Bitumen Ratio and Mineral Filler Characteristics on the Low Temperature Performance of Bitumen Mastics. AB - This study analyzed the effects of the filler-bitumen interaction of the content and the meso powder characteristics of the mineral filler on the low-temperature performance of bitumen mastics. Control strategies for the mineral filler content (filler-bitumen ratio (RFB)) were also determined. Panjin #90 bitumen and styrene butadiene-styrene polymer-modified bitumen were used in the experiment. Four kinds of limestone powder were used, all of which satisfy the Chinese standard for powder particle size but exhibit different meso characteristics. Each kind of limestone powder was used to prepare bitumen mastic samples under five different RFBs. The meso voids in the unit mass (Vg) of the four kinds of mineral filler were tested on the basis of the principle of the Rigden void ratio. The fixed bitumen-free bitumen ratio in the bitumen mastic samples was determined using Vg, bitumen density, and RFB. The low-temperature cohesive strength of the bitumen mastics was used as the control index for critical failure, whereas variation rates of bending creep stiffness at low temperature were used as the control index for fatigue failure. Results showed that the effects of the filler-bitumen interaction of the content and the meso characteristics of the mineral filler are significant and such effects are determined by the fixed bitumen-free bitumen ratio. The optimal fixed bitumen-free bitumen ratio in the bitumen mastics under two low-temperature conditions (−30 °C and −10 °C) can be determined on the basis of the influence of the fixed bitumen-free bitumen ratio on the critical and the failure control indices. Moreover, RFB can be obtained through reverse calculation. The mineral filler content can therefore be precisely controlled, which is crucial for the rational use of mineral filler and for the improvement of the pavement performance of bitumen mastics at low temperatures. PMID- 29986436 TI - Surface Modifications of Nanoparticles for Stability in Biological Fluids. AB - Due to the high surface: volume ratio and the extraordinary properties arising from the nanoscale (optical, electric, magnetic, etc.), nanoparticles (NPs) are excellent candidates for multiple applications. In this context, nanoscience is opening a wide range of modern technologies in biological and biomedical fields, among others. However, one of the main drawbacks that still delays its fast evolution and effectiveness is related to the behavior of nanomaterials in the presence of biological fluids. Unfortunately, biological fluids are characterized by high ionic strengths which usually induce NP aggregation. Besides this problem, the high content in biomacromolecules—such as lipids, sugars, nucleic acids and, especially, proteins—also affects NP stability and its viability for some applications due to, for example, the formation of the protein corona around the NPs. Here, we will review the most common strategies to achieve stable NPs dispersions in high ionic strength fluids and, also, antifouling strategies to avoid the protein adsorption. PMID- 29986438 TI - UV-Vis Spectroscopy: A New Approach for Assessing the Color Index of Transformer Insulating Oil. AB - Monitoring the condition of transformer oil is considered to be one of the preventive maintenance measures and it is very critical in ensuring the safety as well as optimal performance of the equipment. Various oil properties and contents in oil can be monitored such as acidity, furanic compounds and color. The current method is used to determine the color index (CI) of transformer oil produces an error of 0.5 in measurement, has high risk of human handling error, additional expense such as sampling and transportations, and limited samples can be measured per day due to safety and health reasons. Therefore, this work proposes the determination of CI of transformer oil using ultraviolet-to-visible (UV-Vis) spectroscopy. Results show a good correlation between the CI of transformer oil and the absorbance spectral responses of oils from 300 nm to 700 nm. Modeled equations were developed to relate the CI of the oil with the cutoff wavelength and absorbance, and with the area under the curve from 360 nm to 600 nm. These equations were verified with another set of oil samples. The equation that describes the relationship between cutoff wavelength, absorbance and CI of the oil shows higher accuracy with root mean square error (RMSE) of 0.1961. PMID- 29986439 TI - Temperature Compensation of Elasto-Magneto-Electric (EME) Sensors in Cable Force Monitoring Using BP Neural Network. AB - Techniques based on the elasto-magnetic (EM) effect have been receiving increasing attention for their significant advantages in cable stress/force monitoring of in-service structures. Variations in ambient temperature affect the magnetic behaviors of steel components, causing errors in the sensor and measurement system results. Therefore, temperature compensation is essential. In this paper, the effect of temperature on the force monitoring of steel cables using smart elasto-magneto-electric (EME) sensors was investigated experimentally. A back propagation (BP) neural network method is proposed to obtain a direct readout of the applied force in the engineering environment, involving less computational complexity. On the basis of the data measured in the experiment, an improved BP neural network model was established. The test result shows that, over a temperature range of approximately −10 °C to 60 °C, the maximum relative error in the force measurement is within +/-0.9%. A polynomial fitting method was also implemented for comparison. It is concluded that the method based on a BP neural network can be more reliable, effective and robust, and can be extended to temperature compensation of other similar sensors. PMID- 29986440 TI - Protective Cancer Vaccine Using Genetically Modified Hematopoietic Stem Cells. AB - Hematopoietic stem cells (HSCs) yield both the myeloid and lymphoid lineages of blood cells and can be reprogrammed into tumor antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) to prevent tumor growth. However, the optimal approach for differentiating tumor Ag-specific CTLs from HSCs, such as HSC-CTLs, remains elusive. In the current study, we showed that a combination of genetic modification of HSCs and in vivo T cell development facilitates the generation of Ag-specific CTLs that suppressed tumor growth. Murine HSCs, which were genetically modified with chicken ovalbumin (OVA)-specific T cell receptor, were adoptively transferred into recipient mice. In the following week, mice were administered with intraperitoneal injections of an agonist α-Notch 2 antibody and cytokines (rFlt3L and rIL-7) three times. After another two weeks, mice received a subcutaneous inoculation of B16-OVA melanoma cells that express OVA as a surrogate tumor Ag, before the anti-tumor activity of HSC-derived T cells was assessed. OVA-specific CTLs developed in vivo and greatly responded to OVA Ag stimulation ex vivo. In addition, mice receiving genetically modified HSCs and in vivo priming established anti-tumor immunity, resulting in the suppression of tumor growth. These results reported in this present study provide an alternative strategy to develop protective cancer vaccines by using genetically modified HSCs. PMID- 29986442 TI - Fabrication and Mechanical Properties of Tungsten Inert Gas Welding Ring Welded Joint of 7A05-T6/5A06-O Dissimilar Aluminum Alloy. AB - In this paper, Tungsten Inert Gas Welding (TIG) and single-sided welding and double-sided forming have been used to weld the 7A05-T6/5A06-O dissimilar aluminum alloy circular welded joint of a ring-stiffened closed cylindrical sandwich shell. Microstructural characterization and mechanical properties of welded joints were investigated by use of scanning electron microscopy (SEM), backscatter electron diffraction (EBSD) and transmission electron microscopy (TEM), respectively. Hardness distribution and tensile properties of the welded joints were examined. The results showed the failure of the welded joints produced in the fusion zone (FZ). The tensile strength and yield strength of the welded joints were, respectively, 78.87% and 97.24% of the 5A06-O base metal (BM), and the elongation reached 84.29% of 7A05-T6 base metal. Welding high heat input led to the coarse grain size in the fusion zone, and the long-term similar quenching effect can lead to the full dissolution of the strengthening zone of the fusion zone resulting in the reductions of strength and hardness. Around 7A05 heat-affected zone (HAZ), there is an obvious hardening zone and softening zone, the solid solution precipitates into the Rayleigh brilliant η′ (MgZn2) phase, which results in natural aging strengthening, thus obtaining high hardness. η′ (MgZn2) enhanced phase dissolved fully and the dislocation density decreased rapidly in the HAZ region resulted in a softening zone with a lower hardness at about (10-18) mm from the center of the weld center. PMID- 29986441 TI - Roles of Oral Infections in the Pathomechanism of Atherosclerosis. AB - Oral infections occur frequently in humans and often lead to chronic inflammations affecting the teeth (i.e., caries), the gingival tissues surrounding the teeth (i.e., gingivitis and endodontic lesions), and the tooth supporting structures (i.e., periodontitis). At least four basic pathogenic mechanisms have been proposed that involve oral inflammations in the pathogenesis of atherosclerosis: (1) low level bacteremia by which oral bacteria enter the blood stream and invade the arterial wall; (2) systemic inflammation induced by inflammatory mediators released from the sites of the oral inflammation into the blood stream; (3) autoimmunity to host proteins caused by the host immune response to specific components of oral pathogens; (4) pro-atherogenic effects resulting from specific bacterial toxins that are produced by oral pathogenic bacteria. In this narrative review, we summarize published experimental evidence related to these four mechanisms and discuss their impact on the pathogenesis of atherosclerosis. PMID- 29986443 TI - The I-CAM-FR: A French Translation and Cross-Cultural Adaptation of the I-CAM-Q. AB - Background: The use of complementary and alternative medicine (CAM) is growing every year. The extent of its use is still not clear, and it is difficult to undertake comparative studies due to the variety of data collection tools used. Therefore, a standardized International Complementary and Alternative Medicine Questionnaire (I-CAM-Q) has been recommended to determine data about its usage. The purpose of the present study is to present a controlled translation of the questionnaire into French which is also properly adapted to a French audience. Methods: The English-written questionnaire, the I-CAM-Q, was submitted to three independent translators. Each translator produced a separate French translation (FT.1.1, FT.1.2, FT.1.3) that was then synthesized into a unique new version (FT.2.0). Version FT.2.0 was then submitted to three new translators, who translated them back to three distinct English versions (BT.1.1, BT.1.2, BT.1.3). These versions were once again synthesized in a unique questionnaire (BT.2.0). The version BT.2.0 was then submitted to an expert committee that compared it to the original I-CAM-Q in order to review the process and adapt FT.2.0 according to differences between the I-CAM-Q and BT.2.0. This led to a revised French version, PT.0.0. Version PT.0.0 was then tested with the use of cognitive interviews. These interviews allowed a final adjustment of the translations to produce a definitive version in French: the I-CAM-FR. Results: Four French translations and four versions in English of the I-CAM-Q questionnaire were produced. This allowed us to present a consolidated French translation to an expert committee. Their adjustments were taken into account before testing the final French-translated questionnaire on a group of people (n = 10) representing a diverse sample of the French population. The expert committee then suggested changes according to the errors due to the translation process sought out by the pre-tests, and recommendations based on the errors that were not due to the translation process. Conclusions: Through a rigorous methodology, we produced a French translation and a cross-cultural adaptation of the I-CAM-Q questionnaire. This work has led to the creation of an equivalent questionnaire available for use in France, the I CAM-FR. PMID- 29986444 TI - Is It Possible to "Find Space for Mental Health" in Young People? Effectiveness of a School-Based Mental Health Literacy Promotion Program. AB - Lack of knowledge regarding, and the stigma associated with, mental disorders have been identified as major obstacles for the promotion of mental health and early intervention. The present study aimed to evaluate the effectiveness of a school-based intervention program focused on the promotion of mental health literacy (MHL) in young people (“Finding Space for Mental Health”). A sample of 543 students (22 classes), aged between 12 and 14 years old, participated in the study. Each class of students was randomly assigned to the control group (CG; n = 284; 11 classes) or the experimental group (EG; n = 259; 11 classes). MHL was assessed using the Mental Health Literacy questionnaire (MHLq), which is comprised of three dimensions—Knowledge/Stereotypes, First Aid Skills and Help Seeking, and Self-Help Strategies. The scores on these dimensions can also be combined to give an overall or total score. Participants from the EG attended the MHL promotion program (two sessions, 90 min each) delivered at one-week intervals. Sessions followed an interactive methodology, using group dynamics, music, and videos adapted to the target group. All participants responded to the MHLq at three points in time: pre-intervention assessment (one week prior to the intervention), post-intervention assessment (one week after the intervention) and follow-up assessment (six months after the intervention). The intervention effectiveness and the differential impact of sociodemographic variables on the effectiveness of the program were studied using a Generalized Estimation Equation (GEE). Results revealed that participants from the EG demonstrated, on average, significantly higher improvement in MHL from pre intervention to follow-up when compared to participants from the CG. Different sociodemographic variables affected the effectiveness of the program on distinct dimensions of the MHLq. Overall, “Finding Space for Mental Health” showed efficacy as a short-term promotion program for improving MHL in schools. PMID- 29986445 TI - Genetics of Lipodystrophy: Can It Help in Understanding the Pathophysiology of Metabolic Syndrome? AB - Understanding phenotypes and their genetic determinants for metabolic syndrome (MetS) has been quite challenging. With the advent of systems genomic approaches, there is a need to decipher methods for identification and evaluating the functional role of phenotypic traits associated with complex diseases, such as MetS. The monogenic syndromes of lipodystrophy are well understood, but the molecular pathophysiology of insulin resistance (IR) underpinning the obesity, diabetes mellitus, and dyslipidemia is not well deciphered. In this commentary, we argue the role of pathophysiology of MetS, and its effects into possible understanding of genetic determinants associated with lipodystrophy-mediated diabetes mellitus. PMID- 29986447 TI - Vitamin D Content of Australian Native Food Plants and Australian-Grown Edible Seaweed. AB - Vitamin D has previously been quantified in some plants and algae, particularly in leaves of the Solanaceae family. We measured the vitamin D content of Australian native food plants and Australian-grown edible seaweed. Using liquid chromatography with triple quadrupole mass spectrometry, 13 samples (including leaf, fruit, and seed) were analyzed in duplicate for vitamin D2, vitamin D3, 25 hydroxyvitamin D2, and 25-hydroxyvitamin D3. Five samples contained vitamin D2: raw wattleseed (Acacia victoriae) (0.03 µg/100 g dry weight (DW)); fresh and dried lemon myrtle (Backhousia citriodora) leaves (0.03 and 0.24 µg/100 g DW, respectively); and dried leaves and berries of Tasmanian mountain pepper (Tasmannia lanceolata) (0.67 and 0.05 µg/100 g DW, respectively). Fresh kombu (Lessonia corrugata) contained vitamin D3 (0.01 µg/100 g DW). Detected amounts were low; however, it is possible that exposure to ultraviolet radiation may increase the vitamin D content of plants and algae if vitamin D precursors are present. PMID- 29986446 TI - Epidemiology of Suicide and the Psychiatric Perspective. AB - Suicide is a worldwide phenomenon. This review is based on a literature search of the World Health Organization (WHO) databases and PubMed. According to the WHO, in 2015, about 800,000 suicides were documented worldwide, and globally 78% of all completed suicides occur in low- and middle-income countries. Overall, suicides account for 1.4% of premature deaths worldwide. Differences arise between regions and countries with respect to the age, gender, and socioeconomic status of the individual and the respective country, method of suicide, and access to health care. During the second and third decades of life, suicide is the second leading cause of death. Completed suicides are three times more common in males than females; for suicide attempts, an inverse ratio can be found. Suicide attempts are up to 30 times more common compared to suicides; they are however important predictors of repeated attempts as well as completed suicides. Overall, suicide rates vary among the sexes and across lifetimes, whereas methods differ according to countries. The most commonly used methods are hanging, self poisoning with pesticides, and use of firearms. The majority of suicides worldwide are related to psychiatric diseases. Among those, depression, substance use, and psychosis constitute the most relevant risk factors, but also anxiety, personality-, eating- and trauma-related disorders as well as organic mental disorders significantly add to unnatural causes of death compared to the general population. Overall, the matter at hand is relatively complex and a significant amount of underreporting is likely to be present. Nevertheless, suicides can, at least partially, be prevented by restricting access to means of suicide, by training primary care physicians and health workers to identify people at risk as well as to assess and manage respective crises, provide adequate follow-up care and address the way this is reported by the media. Suicidality represents a major societal and health care problem; it thus should be given a high priority in many realms. PMID- 29986448 TI - Is There a Relationship between Lead Exposure and Aggressive Behavior in Shooters? AB - Lead exposure has been associated with psycho-neurological disorders. Elevated blood lead levels have been found in shooters. This study assesses the association between the blood lead levels of shooters and their levels of aggression. An analytical cross-sectional study was conducted in Gauteng, South Africa. Participants were recruited from four randomly selected shooting ranges with three randomly selected archery ranges used as a comparison group. A total of 118 (87 shooters and 31 archers) participants were included in the analysis. Aggressiveness was measured using the Buss-Perry Aggression Questionnaire. Shooters had significantly higher blood lead levels (BLL) compared to archers with 79.8% of shooters versus 22.6% of archers found to have a BLL ≥ 5 μg/dL (p < 0.001). Aggression scores were significantly higher in shooters (p < 0.05) except for verbal aggression. In the bivariate and regression analyses, shooters with BLLs ≥ 10 μg/dL were significantly associated with the hostility sub-scale (p = 0.03, adjusted odds ratio (OR) 2.83, 95% confidence interval (CI) 1.103-7.261). Shooters have a significantly higher BLL and aggressiveness compared to archers. However, elevated blood lead levels were significantly associated with hostility only. Interventions need to be put in place to prevent continued exposure and routine screening of populations at risk should be implemented. PMID- 29986451 TI - Indoor Motion Detection Using Wi-Fi Channel State Information in Flat Floor Environments Versus in Staircase Environments. AB - Recently, Wi-Fi channel state information (CSI) motion detection systems have been widely researched for applications in human health care and security in flat floor environments. However, these systems disregard the indoor context, which is often complex and consists of unique features, such as staircases. Motion detection on a staircase is also meaningful and important for various applications, such as fall detection and intruder detection. In this paper, we present the difference in CSI motion detection in flat floor and staircase environments through analysing the radio propagation model and experiments in real settings. For comparison in the two environments, an indoor CSI motion detection system is proposed with several novel methods including correlation based fusion, moving variance segmentation (MVS), Doppler spread spectrum to improve the system performance, and a correlation check to reduce the implementation cost. Compared with existing systems, our system is validated to have a better performance in both flat floor and staircase environments, and further utilized to verify the superior CSI motion detection performance in staircase environments versus flat floor environments. PMID- 29986449 TI - Effect of Dibutyltin Dilaurate on Triglyceride Metabolism through the Inhibition of the mTOR Pathway in Human HL7702 Liver Cells. AB - Dibutyltin dilaurate (DBTD) has multiple applications in daily life. However, DBTD is easily deposited in the liver and affects liver functions. This study was designed to explore the effects of DBTD on triglyceride metabolism in human normal hepatocyte HL7702 cells. Our results showed that the intracellular fat contents were dose-dependently decreased by DBTD. The expression of lipolysis genes and proteins were elevated while the lipogenesis genes and proteins were diminished by DBTD. The phosphorylation levels of ribosomal S6 kinase 1 were reduced by both rapamycin and DBTD, indicating that the mTOR pathway was suppressed possibly. The decreased sterol regulatory element-binding protein 1C (SREBP1C) transcription levels, as well as the increased peroxisome proliferator activated receptor alpha (PPARα) transcription levels, caused by rapamycin and DBTD corresponded to the inactive mTOR pathway. In conclusion, it was possible that DBTD reduced the intracellular triglyceride through depressing the mTOR pathway and affecting its downstream transcription factors. PMID- 29986450 TI - Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer. AB - The application of nanotechnology for the treatment of cancer is mostly based on early tumor detection and diagnosis by nanodevices capable of selective targeting and delivery of chemotherapeutic drugs to the specific tumor site. Due to the remarkable properties of gold nanoparticles, they have long been considered as a potential tool for diagnosis of various cancers and for drug delivery applications. These properties include high surface area to volume ratio, surface plasmon resonance, surface chemistry and multi-functionalization, facile synthesis, and stable nature. Moreover, the non-toxic and non-immunogenic nature of gold nanoparticles and the high permeability and retention effect provide additional benefits by enabling easy penetration and accumulation of drugs at the tumor sites. Various innovative approaches with gold nanoparticles are under development. In this review, we provide an overview of recent progress made in the application of gold nanoparticles in the treatment of cancer by tumor detection, drug delivery, imaging, photothermal and photodynamic therapy and their current limitations in terms of bioavailability and the fate of the nanoparticles. PMID- 29986452 TI - Design, Synthesis and Characterization of Novel Co-Polymers Decorated with Peptides for the Selective Nanoparticle Transport across the Cerebral Endothelium. AB - The development of new strategies for enhancing drug delivery to the brain represents a major challenge in treating cerebral diseases. In this paper, we report on the synthesis and structural characterization of a biocompatible nanoparticle (NP) made up of poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) co-polymer (namely PELGA) functionalized with the membranotropic peptide gH625 (gH) and the iron-mimicking peptide CRTIGPSVC (CRT) for transport across the blood-brain barrier (BBB). gH possesses a high translocation potency of the cell membrane. Conversely, CRT selectively recognizes the brain endothelium, which interacts with transferrin (Tf) and its receptor (TfR) through a non-canonical ligand-directed mechanism. We hypothesize that the delivery across the BBB of PELGA NPs should be efficiently enhanced by the NP functionalization with both gH and CRT. Synthesis of peptides and their conjugation to the PLGA as well as NP physical-chemical characterization are performed. Moreover, NP uptake, co-localization, adhesion under dynamic conditions, and permeation across in vitro BBB model are evaluated as a function of gH/CRT functionalization ratio. Results establish that the cooperative effect of CRT and gH may change the intra-cellular distribution of NPs and strengthen NP delivery across the BBB at the functionalization ratio 33% gH-66% CRT. PMID- 29986453 TI - Perinatal Mortality in South Asia: Systematic Review of Observational Studies. AB - BACKGROUND: This study aimed to systematically review observational studies on perinatal mortality in South Asia. METHODS: This review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Five computerized bibliographic databases: MEDLINE, CINAHL, Embase, PsycINFO, and Scopus were searched for published studies which reported factors associated with perinatal mortality in South Asia from 1 January 2000 to 20 March 2018. All relevant observational studies (cohort, cross-sectional and case-control) were reviewed. RESULTS: Fourteen studies met the selection criteria. The most common factors associated with perinatal mortality were: low socioeconomic status, lack of quality health-care services, pregnancy/obstetric complications and lack of antenatal care. CONCLUSIONS: Interventions to reduce perinatal mortality in the South Asia should focus on the provision of adequate antenatal care and quality healthcare services which are accessible to women of low socioeconomic status. PMID- 29986454 TI - On the Mechanism of Magnesium Storage in Micro- and Nano-Particulate Tin Battery Electrodes. AB - This study reports on the electrochemical alloying-dealloying properties of Mg2Sn intermetallic compounds. 119Sn Mössbauer spectra of β-Sn powder, thermally alloyed cubic-Mg2Sn, and an intermediate MgSn nominal composition are used as references. The discharge of a Mg/micro-Sn half-cell led to significant changes in the spectra line shape, which is explained by a multiphase mechanism involving the coexistence of c-Mg2Sn, distorted Mg2−δSn, and Mg-doped β-Sn. Capacities and capacity retention were improved by using nanoparticulate tin electrodes. This material reduces significantly the diffusion lengths for magnesium and contains surface SnO and SnO2, which are partially electroactive. The half-cell potentials were suitable to be combined versus the MgMn2O4 cathodes. Energy density and cycling properties of the resulting full Mg ion cells are also scrutinized. PMID- 29986456 TI - Tensile Properties and Corrosion Behavior of Extruded Low-Alloyed Mg-1Sn-1Al-1Zn Alloy: The Influence of Microstructural Characteristics. AB - A low-alloyed Mg-Sn-Al-Zn system was developed and successfully fabricated through the extrusion process. The dependence of tensile properties and corrosion behavior on microstructural characteristics of the studied alloy has been investigated. After extrusion, the alloy consists of fine dynamically recrystallized (DRXed) grains of ~2.65 μm and strongly textured coarse unDRXed grains. As a consequence, the extruded alloy showed a high-tensile yield strength (YS) of 259 MPa, ultimate tensile strength (UTS) of 297 MPa and elongation (EL) of 19.0%. The strengthening response was discussed in terms of grain size, texture and solutes. The as-extruded alloy presented severe pitting corrosion and the dependence of corrosion properties on the crystallographic orientation and the formation of corrosion products was analyzed. PMID- 29986455 TI - Glycine Relieves Intestinal Injury by Maintaining mTOR Signaling and Suppressing AMPK, TLR4, and NOD Signaling in Weaned Piglets after Lipopolysaccharide Challenge. AB - This study was conducted to envaluate whether glycine could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury by regulating intestinal epithelial energy status, protein synthesis, and inflammatory response via AMPK, mTOR, TLR4, and NOD signaling pathways. A total of 24 weanling piglets were randomly allotted to 1 of 4 treatments: (1) non-challenged control; (2) LPS challenged control; (3) LPS + 1% glycine; (4) LPS + 2% glycine. After 28 days feeding, piglets were injected intraperitoneally with saline or LPS. The pigs were slaughtered and intestinal samples were collected at 4 h postinjection. The mRNA expression of key genes in these signaling pathways was measured by real time PCR. The protein abundance was measured by Western blot analysis. Supplementation with glycine increased jejunal villus height/crypt depth ratio. Glycine also increased the jejunal and ileal protein content, RNA/DNA ratio, and jejunal protein/DNA ratio. The activities of citroyl synthetase in ileum, and α-ketoglutarate dehydrogenase complex in jejunum, were increased in the piglets fed diets supplemented with glycine. In addition, glycine decreased the jejunal and ileal phosphorylation of AMPKα, and increased ileal phosphorylation of mTOR. Furthermore, glycine downregulated the mRNA expression of key genes in inflammatory signaling. Meanwhile, glycine increased the mRNA expression of negative regulators of inflammatory signaling. These results indicate that glycine supplementation could improve energy status and protein synthesis by regulating AMPK and mTOR signaling pathways, and relieve inflammation by inhibiting of TLR4 and NOD signaling pathways to alleviate intestinal injury in LPS-challenged piglets. PMID- 29986457 TI - Morphology, Optical Properties and Photocatalytic Activity of Photo- and Plasma Deposited Au and Au/Ag Core/Shell Nanoparticles on Titania Layers. AB - Titania is a promising material for numerous photocatalytic reactions such as water splitting and the degradation of organic compounds (e.g., methanol, phenol). Its catalytic performance can be significantly increased by the addition of co-catalysts. In this study, Au and Au/Ag nanoparticles were deposited onto mesoporous titania thin films using photo-deposition (Au) and magnetron sputtering (Au and Au/Ag). All samples underwent comprehensive structural characterization by grazing incidence X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Nanoparticle distributions and nanoparticle size distributions were correlated to the deposition methods. Light absorption measurements showed features related to diffuse scattering, the band gap of titania and the local surface plasmon resonance of the noble metal nanoparticles. Further, the photocatalytic activities were measured using methanol as a hole scavenger. All nanoparticle decorated thin films showed significant performance increases in hydrogen evolution under UV illumination compared to pure titania, with an evolution rate of up to 372 μL H2 h−1 cm−2 representing a promising approximately 12-fold increase compared to pure titania. PMID- 29986458 TI - Association of Sensory Liking for Fat with Dietary Intake and Metabolic Syndrome in Korean Adults. AB - Individual sensory liking is perceived as a major determinant of dietary intake and may influence chronic disease. This study aimed to assess the odds of metabolic syndrome in Korean adults based on their liking for fat. Data from 7731 adults aged 40-69, included in the Korean Genome and Epidemiology Study, were collected. Fat liking scores were obtained from self-report questionnaires. In both genders, sensory liking for fat was positively associated with consumption of red meat and added fat. Subjects with a stronger liking for fat showed a higher intake of energy and fat and a lower intake of vitamin C and fiber as compared to subjects with a lower liking for fat. There were increasing trends in the odds of metabolic syndrome with stronger liking for fat (odds ratios (ORs) for the Like group compared to the Dislike group, men: ORs = 1.29 (95% confidence interval 1.06-1.50) p-trend = 0.01; women: ORs = 1.28 (1.04-1.58) p-trend = 0.018) after adjustment for age, alcohol intake, smoking, exercise, education level, and income status. Our results suggested that the liking for fat-rich food might partially contribute to the increased odds of metabolic syndrome. PMID- 29986459 TI - Family-Based Mindful Eating Intervention in Adolescents with Obesity: A Pilot Randomized Clinical Trial. AB - Mindfulness has gained attention in the treatment of obesity. However, there is a paucity of data on family-based training in mindful eating in children. The objective of this pilot randomized clinical trial was to evaluate the feasibility and acceptability of a family-based mindful eating intervention (MEI) in adolescents with obesity, and to compare the efficacy of the MEI versus standard dietary counseling (SDC) for decreasing weight and improving cardiometabolic risk markers. Twenty-two adolescents (age 14.5-17.9 years) and parent pairs were randomized to the MEI or SDC. The MEI was administered in four 90-min sessions over 10 weeks and SDC was provided at baseline, 12 weeks, and 24 weeks. Despite the requirement of more frequent visits with the MEI, adolescents and parents attended 100% of the sessions and there were no dropouts in that group. High density lipoprotein (HDL) cholesterol increased in the SDC group, but not in the MEI group. Adolescents receiving the MEI demonstrated an increase in awareness at 24 weeks (p = 0.01) and a decrease in distraction during eating at 12 weeks (p = 0.04), when compared with the SDC group. The family-based MEI showed feasibility and acceptability in adolescents with obesity. Future studies with more intense therapy and larger sample sizes are warranted to examine the role of mindful eating in treating pediatric obesity. PMID- 29986460 TI - Polyketides and Alkaloids from the Marine-Derived Fungus Dichotomomyces cejpii F31-1 and the Antiviral Activity of Scequinadoline A against Dengue Virus. AB - In our continuous chemical investigation on the marine-derived fungus Dichotomomyces cejpii F31-1, two new polyketides dichocetides B-C (1, 2), two new alkaloids dichotomocejs E-F (3, 4), and three known fumiquinozalines: scequinadoline A (5), quinadoline A (6), and scequinadoline E (7) were discovered from the culture broth and the mycelium in the culture medium, by the addition of l-tryptophan and l-phenylalanine. Their chemical structures were established by one dimensional (1D), two dimensional (2D) nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HR-MS) data. Among them, scequinadoline A (5) exhibited significant inhibitory activity against dengue virus serotype 2 production by standard plaque assay, equivalent to the positive control andrographlide. Scequinadoline A (5) possesses the potential for further development as a dengue virus inhibitor. PMID- 29986461 TI - Role of Carboxyl and Amine Termination on a Boron-Doped Diamond Solution Gate Field Effect Transistor (SGFET) for pH Sensing. AB - In this paper, we report on the effect of carboxyl- and amine terminations on a boron-doped diamond surface (BDD) in relation to pH sensitivity. Carboxyl termination was achieved by anodization oxidation in Carmody buffer solution (pH 7). The carboxyl-terminated diamond surface was exposed to nitrogen radicals to generate an amine-terminated surface. The pH sensitivity of the carboxyl- and amine-terminated surfaces was measured from pH 2 to pH 12. The pH sensitivities of the carboxyl-terminated surface at low and high pH are 45 and 3 mV/pH, respectively. The pH sensitivity after amine termination is significantly higher—the pH sensitivities at low and high pH are 65 and 24 mV/pH, respectively. We find that the negatively-charged surface properties of the carboxyl-terminated surface due to ionization of -COOH causes very low pH detection in the high pH region (pH 7-12). In the case of the amine-terminated surface, the surface properties are interchangeable in both acidic and basic solutions; therefore, we observed pH detection at both low and high pH regions. The results presented here may provide molecular-level understanding of surface properties with charged ions in pH solutions. The understanding of these surface terminations on BDD substrate may be useful to design diamond-based biosensors. PMID- 29986462 TI - A Non-Label and Enzyme-Free Sensitive Detection Method for Thrombin Based on Simulation-Assisted DNA Assembly. AB - Taking advantage of the high selectivity of aptamers and enzyme-free catalyzed hairpin assembly (CHA) amplification strategy, we herein describe a label-free and enzyme-free sensitive fluorescent and colorimetric strategy for thrombin detection in this paper. In the presence of target, the corresponding aptamer of the partial dsDNA probes will bind to the target and liberate the initiation strand, which is artfully designed as the “on” switch for hairpin assembly. Moreover, the displaced initiation strand partakes in a multi-cycle process and produces numerous G-quadruplexes, which have a remarkable enhancement in fluorescent/colorimetric signal from NMM (N-methyl-mesoporphyrin IX) and TMB (3,3′,5,5′-tetramethylbenzidine), respectively. The proposed amplification strategy for thrombin detection is of high sensitivity, down to 2.4 pM, and also achieves colorimetric signals that are able to be distinguished by naked eye. More importantly, the thermodynamics of interacting DNA strands used in our work, and the process of toehold strand displacement-driven assembly are simulated before biological testing, verifying the feasibility theoretically, and simplifying the subsequent actual experiments. Therefore, our approach and simulation have a certain potential application in biomarker detection and quantitatively monitor for disease diagnosis. PMID- 29986464 TI - A Multi-Stakeholder Perspective on the Integration of Safety in University Nursing, Education, and Engineering Curricula. AB - Improvement in workplace safety is dependent upon the active engagement of workforce leaders and designers. The university sector plays a key role in the education of these future leaders, and there is an expectation that safety education in universities will encompass more than just a safe learning environment—that is the nurturing of broader safety attitudes and awareness. However, with the exception of dedicated safety training programs, safety education is often delivered and assessed on an ad-hoc basis and at academic discretion. This is partly due to the absence of a simple tool with which curricula can be evaluated from a safety perspective. In a qualitative approach, semi-structured interviews were undertaken with multiple stakeholders (academics, professional organizations, and students) to determine their views on existing safety content in university curricula and on the level of preparedness, from a safety perspective, for workforce entry. University participants came from nursing, mechanical engineering, and education schools at three universities. A simple curriculum evaluative tool was also validated. Results indicated there were divergent views on the level of preparedness for workforce entry both between schools and stakeholder groups. However, the limitations of university curricula were acknowledged. The evaluation tool was shown to provide positive feedback on existing, but previously unacknowledged, safety content and also highlighted areas for future improvement and integration. However, voluntary utilization of the tool was a challenge for busy academics. PMID- 29986463 TI - The 125th Lys and 145th Thr Amino Acids in the GTPase Domain of Goose Mx Confer Its Antiviral Activity against the Tembusu Virus. AB - The Tembusu virus (TMUV) is an avian pathogenic flavivirus that causes a highly contagious disease and catastrophic losses to the poultry industry. The myxovirus resistance protein (Mx) of innate immune effectors is a key antiviral “workhorse” of the interferon (IFN) system. Although mammalian Mx resistance against myxovirus and retrovirus was witnessed for decades, whether or not bird Mx has anti-flavivirus activity remains unknown. In this study, we found that the transcription of goose Mx (goMx) was obviously driven by TMUV infection, both in vivo and in vitro, and that the titers and copies of TMUV were significantly reduced by goMx overexpression. In both primary (goose embryo fibroblasts, GEFs) and passaged cells (baby hamster kidney cells, BHK21, and human fetal kidney cells, HEK 293T), it was shown that goMx was mainly located in the cytoplasm, and sporadically distributed in the nucleus. The intracellular localization of this protein is attributed to the predicted bipartite nuclear localization signal (NLS; 30 residues: the 441st-471st amino acids of goMx). Intuitively, it seems that the cells with a higher level of goMx expression tend to have lower TMUV loads in the cytoplasm, as determined by an immunofluorescence assay. To further explore the antiviral determinants, a panel of variants was constructed. Two amino acids at the 125th (Lys) and 145th (Thr) positions in GTP binding elements, not in the L4 loop (40 residues: the 532nd-572nd amino acids of goMx), were vital for the antiviral function of goMx against TMUV in vitro. These findings will contribute to our understanding of the functional significance of the antiviral system in aquatic birds, and the development of goMx could be a valuable therapeutic agent against TMUV. PMID- 29986465 TI - An Electronic Nose Based Method for the Discrimination of Weathered Petroleum Derived Products. AB - In recent years pollution due to hydrocarbon spills has increased markedly as a result of the numerous advances in technologies and industrial processes. Anthropogenic activities (accidental or illegal) are responsible for most of these incidents. In some cases, the spills are not detected at the moment they occur and the contaminants are subjected to different degradation phenomena that may change the chemical composition of the hydrocarbon over time. An incorrect or ineffective identification of the spill could lead to significant consequences, bearing in mind that most spills are hazardous to the environment. In the present work the capacity of the analytical technique based on the Electronic Nose (eNose) combined with chemometrics in the identification and discrimination of different weathered petroleum-derived products (PDPs) was studied. Different volumes (40 μL and 80 μL) of PDPs (gasoline, diesel, and paraffin) were poured onto different supports (wood, cork, paper, and cotton sheet) and subjected to a natural weathering process by evaporation for one month. The porosity of the support was also studied. The application of linear discriminant analysis allowed the full discrimination of the samples according to the presence/absence of PDP and a 97.7% of correct discrimination of the different PDPs regardless of the weathering time, support or volume used. The results show that the system is capable of detecting and discriminating the presence of petroleum-derived products in any of the situations studied. PMID- 29986466 TI - Label-Free Quantitative Proteomics Combined with Biological Validation Reveals Activation of Wnt/beta-Catenin Pathway Contributing to Trastuzumab Resistance in Gastric Cancer. AB - Resistance to trastuzumab, which specifically target HER2-positive breast and gastric cancer, can develop ultimately in cancer patients. However, the underlying mechanisms of resistance in gastric cancer have not been fully elucidated. Here, we established trastuzumab-resistant MKN45 and NCI N87 gastric cancer sublines from their parental cells. The resistant cells exhibited characteristics of epithelial-mesenchymal transition (EMT) and acquired higher migratory and invasive capacities. To exploit the activated pathways and develop new strategies to overcome trastuzumab resistance, we investigated MKN45 and MKN45/R cells via label-free quantitative proteomics, and found pathways that were altered significantly in MKN45/R cells, with the Wnt/β-catenin pathway being the most significant. We further confirmed the activation of this pathway by detecting its key molecules in MKN45/R and NCI N87/R cells via Western blot, in which Wnt3A, FZD6, and CTNNB1 increased, whereas GSK-3β decreased, manifesting the activation of the Wnt/β-catenin pathway. Correspondingly, inhibition of Wnt/β-catenin pathway by ICG-001, a specific Wnt/β catenin inhibitor, preferentially reduced proliferation and invasion of trastuzumab-resistant cells and reversed EMT. Concurringly, CTNNB1 knockdown in stable cell lines potently sensitized cells to trastuzumab and induced more apoptosis. Taken together, our study demonstrates that the Wnt/β-catenin pathway mediates trastuzumab resistance, and the combination of Wnt/β catenin inhibitors with trastuzumab may be an effective treatment option. PMID- 29986468 TI - Spectral Imaging Analysis for Ultrasensitive Biomolecular Detection Using Gold Capped Nanowire Arrays. AB - A spectral integration combined with a threshold method for the analysis of spectral scanning surface plasmon resonance (SPR) images can significantly increase signal recognition at low concentration of antibody solution. The 12 well SPR sensing plates consisted of gold-capped nanowire arrays with 500-nm period, 80-nm linewidth and 50-nm gold thickness which were used for generating multiple SPR images. A threshold method is introduced to eliminate background noises in spectral scanning images. Combining spectral integration and the threshold method, the detection limit of antibody concentration was 1.23 ng/mL. Using multiple-well SPR sensing plates and the proposed analytical method, multiple kinetic responses with spectral and spatial information on different sensing areas can be sensitively measured. PMID- 29986469 TI - Dynamic Deflection of a Railroad Sleeper from the Coupled Measurements of Acceleration and Strain. AB - Dynamic deflection of a railroad sleeper works as an indicator of ballast stiffness, reflecting the health conditions of a ballast track. However, difficulty exists in measuring dynamic deflection of a railroad sleeper by conventional deflection transducers such as a linear variable differential transformer (LVDT) or a potentiometer. This is because a fixed reference point is unattainable due to ground vibrations during train passage. In this paper, a patented signal processing technique for evaluation of pseudo-deflection is presented to recover dynamic deflection of a railroad sleeper using a coupled measurement of acceleration and strain at the concrete sleeper. The presented technique combines high-frequency deflections calculated from double integration of acceleration and low-frequency deflections determined from strains. Validity of the combined deflections was shown by the deflections measured with a camera target on a concrete sleeper, captured by a high-resolution DSLR camera with superb video capturing features and processed by computer vision techniques, such as Canny edge detection and Blob analysis. PMID- 29986467 TI - An Insight into the Difficulties in the Discovery of Specific Biomarkers of Limbal Stem Cells. AB - Keeping the integrity and transparency of the cornea is the most important issue to ensure normal vision. There are more than 10 million patients going blind due to the cornea diseases worldwide. One of the effective ways to cure corneal diseases is corneal transplantation. Currently, donations are the main source of corneas for transplantation, but immune rejection and a shortage of donor corneas are still serious problems. Graft rejection could cause transplanted cornea opacity to fail. Therefore, bioengineer-based corneas become a new source for corneal transplantation. Limbal stem cells (LSCs) are located at the basal layer in the epithelial palisades of Vogt, which serve a homeostatic function for the cornea epithelium and repair the damaged cornea. LSC-based transplantation is one of the hot topics currently. Clinical data showed that the ratio of LSCs to total candidate cells for a transplantation has a significant impact on the effectiveness of the transplantation. It indicates that it is very important to accurately identify the LSCs. To date, several putative biomarkers of LSCs have been widely reported, whereas their specificity is controversial. As reported, the identification of LSCs is based on the characteristics of stem cells, such as a nuclear-to-cytoplasm ratio (N/C) ≥ 0.7, label-retaining, and side population (SP) phenotype. Here, we review recently published data to provide an insight into the circumstances in the study of LSC biomarkers. The particularities of limbus anatomy and histochemistry, the limits of the current technology level for LSC isolation, the heterogeneity of LSCs and the influence of enzyme digestion are discussed. Practical approaches are proposed in order to overcome the difficulties in basic and applied research for LSC-specific biomarkers. PMID- 29986470 TI - Internet-Of-Things in Motion: A UAV Coalition Model for Remote Sensing in Smart Cities. AB - Unmanned aerial vehicles (UAVs) or drones are increasingly used in cities to provide service tasks that are too dangerous, expensive or difficult for human beings. Drones are also used in cases where a task can be performed more economically and or more efficiently than if done by humans. These include remote sensing tasks where drones can be required to form coalitions by pooling their resources to meet the service requirements at different locations of interest in a city. During such coalition formation, finding the shortest path from a source to a location of interest is key to efficient service delivery. For fixed-wing UAVs, Dubins curves can be applied to find the shortest flight path. When a UAV flies to a location of interest, the angle or orientation of the UAV upon its arrival is often not important. In such a case, a simplified version of the Dubins curve consisting of two instead of three parts can be used. This paper proposes a novel model for UAV coalition and an algorithm derived from basic geometry that generates a path derived from the original Dubins curve for application in remote sensing missions of fixed-wing UAVs. The algorithm is tested by incorporating it into three cooperative coalition formation algorithms. The performance of the model is evaluated by varying the number of types of resources and the sensor ranges of the UAVs to reveal the relevance and practicality of the proposed model. PMID- 29986471 TI - Risk Factor for Incident Functional Disability and the Effect of a Preventive Exercise Program: A 4-Year Prospective Cohort Study of Older Survivors from the Great East Japan Earthquake and Nuclear Disaster. AB - OBJECTIVE: The aim of this study is to assess the risk factors for incident functional disability among long-term evacuees of Iitate village after Great East Japan Earthquake and nuclear disaster (GEJE). We also investigated the effectiveness of exercise classes as an intervention measure in this situation. METHODS: 1159 subjects (75.2 +/- 5.8 years, 57.5% female) were included at baseline, and followed-up for four years. Cox proportional hazard regression analysis was used to estimate the hazard ratio (HR) of incident functional disability according to the presence of risk factors evaluated by the municipality’s self-assessment Basic Checklist (BCL). Evacuees from Iitate who participated in the exercise classes and those who did not were matched using the propensity scores, which were then used to obtain the HR of incident functional disability. RESULTS: New functional disability occurred in 280 (24.2%) participants during the follow-up. Participants who scored negative for the “Physical function” domain in the BCL had a HR of 2.04 (95% CI: 1.54 2.69) for incident functional disability when compared to those who scored positive for this domain. Similarly, the HR for “Cognitive function” was 1.37 (CI: 1.06-1.77), and 1.60 (CI: 1.24-2.08) for “Depression”. Using a Cox proportional hazard regression model, both the group with low participation in the exercise program and the group with high-participation in the exercise program had a significantly lower rate of incident functional disability compared to those who did not participate at all (HR = 0.27, CI: 0.16 0.46; HR = 0.30, CI: 0.12-0.74, respectively). CONCLUSIONS: Pre-disaster BCL domains were useful to identify individuals at risk of functional disability after a major socio-technical disaster. Therefore, this instrument can be used to identify at-risk older adults who would benefit from early exercise programs to prevent incident functional disability. PMID- 29986472 TI - Gene Regulatory Networks Reconstruction Using the Flooding-Pruning Hill-Climbing Algorithm. AB - The explosion of genomic data provides new opportunities to improve the task of gene regulatory network reconstruction. Because of its inherent probability character, the Bayesian network is one of the most promising methods. However, excessive computation time and the requirements of a large number of biological samples reduce its effectiveness and application to gene regulatory network reconstruction. In this paper, Flooding-Pruning Hill-Climbing algorithm (FPHC) is proposed as a novel hybrid method based on Bayesian networks for gene regulatory networks reconstruction. On the basis of our previous work, we propose the concept of DPI Level based on data processing inequality (DPI) to better identify neighbors of each gene on the lack of enough biological samples. Then, we use the search-and-score approach to learn the final network structure in the restricted search space. We first analyze and validate the effectiveness of FPHC in theory. Then, extensive comparison experiments are carried out on known Bayesian networks and biological networks from the DREAM (Dialogue on Reverse Engineering Assessment and Methods) challenge. The results show that the FPHC algorithm, under recommended parameters, outperforms, on average, the original hill climbing and Max-Min Hill-Climbing (MMHC) methods with respect to the network structure and running time. In addition, our results show that FPHC is more suitable for gene regulatory network reconstruction with limited data. PMID- 29986473 TI - A Personalized Healthcare Monitoring System for Diabetic Patients by Utilizing BLE-Based Sensors and Real-Time Data Processing. AB - Current technology provides an efficient way of monitoring the personal health of individuals. Bluetooth Low Energy (BLE)-based sensors can be considered as a solution for monitoring personal vital signs data. In this study, we propose a personalized healthcare monitoring system by utilizing a BLE-based sensor device, real-time data processing, and machine learning-based algorithms to help diabetic patients to better self-manage their chronic condition. BLEs were used to gather users’ vital signs data such as blood pressure, heart rate, weight, and blood glucose (BG) from sensor nodes to smartphones, while real-time data processing was utilized to manage the large amount of continuously generated sensor data. The proposed real-time data processing utilized Apache Kafka as a streaming platform and MongoDB to store the sensor data from the patient. The results show that commercial versions of the BLE-based sensors and the proposed real-time data processing are sufficiently efficient to monitor the vital signs data of diabetic patients. Furthermore, machine learning-based classification methods were tested on a diabetes dataset and showed that a Multilayer Perceptron can provide early prediction of diabetes given the user’s sensor data as input. The results also reveal that Long Short-Term Memory can accurately predict the future BG level based on the current sensor data. In addition, the proposed diabetes classification and BG prediction could be combined with personalized diet and physical activity suggestions in order to improve the health quality of patients and to avoid critical conditions in the future. PMID- 29986474 TI - To Buy or Not to Buy? Consumer Attitudes and Purchase Intentions for Suboptimal Food. AB - Food system and food safety have drawn spontaneous global attention due to the effect of substantial environmental concerns. Three billion tons of food are wasted every year, estimated as being a third of all produced food. The production of much of this waste is directly linked to the unwillingness to sell, purchase, and consume suboptimal food that have deviated from regular products in terms of appearance standards, date labeling, or damaged packaging. Yet empirical research on this issue is scarce. This study aims to develop an extended Theory of Planned Behavior (TPB) research model, which includes environmental concern and sensory appeal to predict consumers' purchase intention to suboptimal foods. A total of 539 respondents collected in Taiwan as data input. The empirical results of structural equation modeling (SEM) indicate that consumers' attitude was the main predictor of their intention to purchase suboptimal foods. Interestingly, this research showed that both perceived behavioral control and subjective norms were not significant predictors of intention. Furthermore, adding environmental concern and sensory appeal as the additional constructs to the TPB significantly increased the explanatory power of the standard model. These findings provide important insights for suboptimal food and useful recommendations for marketing channels, suggesting that promotion of suboptimal food may be the key to potential business. PMID- 29986475 TI - Epistatic Interactions in NS5A of Hepatitis C Virus Suggest Drug Resistance Mechanisms. AB - Hepatitis C virus (HCV) causes a major health burden and can be effectively treated by direct-acting antivirals (DAAs). The non-structural protein 5A (NS5A), which plays a role in the viral genome replication, is one of the DAAs’ targets. Resistance-associated viruses (RAVs) harbouring NS5A resistance associated mutations (RAMs) have been described at baseline and after therapy failure. A mutation from glutamine to arginine at position 30 (Q30R) is a characteristic RAM for the HCV sub/genotype (GT) 1a, but arginine corresponds to the wild type in the GT-1b; still, GT-1b strains are susceptible to NS5A inhibitors. In this study, we show that GT-1b strains with R30Q often display other specific NS5A substitutions, particularly in positions 24 and 34. We demonstrate that in GT-1b secondary substitutions usually happen after initial R30Q development in the phylogeny, and that the chemical properties of the corresponding amino acids serve to restore the positive charge in this region, acting as compensatory mutations. These findings may have implications for RAVs treatment. PMID- 29986476 TI - A Self-Powered Six-Axis Tactile Sensor by Using Triboelectric Mechanism. AB - Triboelectric nanogenerators (TENGs) are highly promising because they can scavenge energy from their working environment to sustainably power wearable/mobile electronics. In this work, we propose a novel and straightforward strategy for six-axis force detection and object controlling by using a self powered sensor based on TENG. The self-powered sensor can be used in diversified tactile sensing and energy saving applications, which has been demonstrated to be able to detect normal force in the range of 0-18 N. Using the vector properties of external force, six-axis directions in three-dimensional (3D) space is detected. Additionally, it is fabricated with environmental friendly materials, i.e., galinstan and polydimethylsiloxane (PDMS), promoting its applications in more diversified situations. Because of the available and high output voltage as well as the low internal impedance, the self-powered sensor is readily compatible with commercial signal processing and management circuits. The device presented in this work shows robust structure and stable output performance, enabling itself as an ideal human machine interface in self-powered, batteryless, and electric energy saving applications. PMID- 29986478 TI - Toward a More Complete, Flexible, and Safer Speed Planning for Autonomous Driving via Convex Optimization. AB - In this paper, we present a complete, flexible and safe convex-optimization-based method to solve speed planning problems over a fixed path for autonomous driving in both static and dynamic environments. Our contributions are five fold. First, we summarize the most common constraints raised in various autonomous driving scenarios as the requirements for speed planner developments and metrics to measure the capacity of existing speed planners roughly for autonomous driving. Second, we introduce a more general, flexible and complete speed planning mathematical model including all the summarized constraints compared to the state of-the-art speed planners, which addresses limitations of existing methods and is able to provide smooth, safety-guaranteed, dynamic-feasible, and time-efficient speed profiles. Third, we emphasize comfort while guaranteeing fundamental motion safety without sacrificing the mobility of cars by treating the comfort box constraint as a semi-hard constraint in optimization via slack variables and penalty functions, which distinguishes our method from existing ones. Fourth, we demonstrate that our problem preserves convexity with the added constraints, thus global optimality of solutions is guaranteed. Fifth, we showcase how our formulation can be used in various autonomous driving scenarios by providing several challenging case studies in both static and dynamic environments. A range of numerical experiments and challenging realistic speed planning case studies have depicted that the proposed method outperforms existing speed planners for autonomous driving in terms of constraint type covered, optimality, safety, mobility and flexibility. PMID- 29986477 TI - Centrosome Remodelling in Evolution. AB - The centrosome is the major microtubule organizing centre (MTOC) in animal cells. The canonical centrosome is composed of two centrioles surrounded by a pericentriolar matrix (PCM). In contrast, yeasts and amoebozoa have lost centrioles and possess acentriolar centrosomes—called the spindle pole body (SPB) and the nucleus-associated body (NAB), respectively. Despite the difference in their structures, centriolar centrosomes and SPBs not only share components but also common biogenesis regulators. In this review, we focus on the SPB and speculate how its structures evolved from the ancestral centrosome. Phylogenetic distribution of molecular components suggests that yeasts gained specific SPB components upon loss of centrioles but maintained PCM components associated with the structure. It is possible that the PCM structure remained even after centrosome remodelling due to its indispensable function to nucleate microtubules. We propose that the yeast SPB has been formed by a step-wise process; (1) an SPB-like precursor structure appeared on the ancestral centriolar centrosome; (2) it interacted with the PCM and the nuclear envelope; and (3) it replaced the roles of centrioles. Acentriolar centrosomes should continue to be a great model to understand how centrosomes evolved and how centrosome biogenesis is regulated. PMID- 29986479 TI - New Insights about How to Make an Intervention in Children and Adolescents with Metabolic Syndrome: Diet, Exercise vs. Changes in Body Composition. A Systematic Review of RCT. AB - OBJECTIVE: To record which interventions produce the greatest variations in body composition in patients ≤19 years old with metabolic syndrome (MS). METHOD: search dates between 2005 and 2017 in peer reviewed journals, following the PRISMA method (Preferred Reporting Items for Systematic reviews and Meta Analyses). The selection criteria were: diagnostic for MS or at least a criterion for diagnosis; randomized clinical trials, ≤19 years of age; intervention programs that use diet and/or exercise as a tool (interventions showing an interest in body composition). RESULTS: 1781 clinical trials were identified under these criteria but only 0.51% were included. The most frequent characteristics of the selected clinical trials were that they used multidisciplinary interventions and were carried out in America. The most utilized parameters were BMI (body mass index) in kg/m2 and BW (body weight) in kg. CONCLUSIONS: Most of the clinical trials included had been diagnosed through at least 2 diagnostic criteria for MS. Multidisciplinary interventions obtained greater changes in body composition in patients with MS. This change was especially prevalent in the combinations of dietary interventions and physical exercise. It is proposed to follow the guidelines proposed for patients who are overweight, obese, or have diabetes type 2, and extrapolate these strategies as recommendations for future clinical trials designed for patients with MS. PMID- 29986480 TI - Grape Pomace: Antioxidant Activity, Potential Effect Against Hypertension and Metabolites Characterization after Intake. AB - Observational studies indicate that the intake of polyphenol-rich foods improves vascular health, thereby significantly reducing the risk of hypertension and cardiovascular disease (CVD). Therefore, the aim of this study was to analyse the remained potential of grape by-products from important Rhône Valley red wine cultivars: Grenache, Syrah, Carignan, Mourvèdre and Alicante. For that, six different extracts from grape pomaces, selected by their antioxidant activity, were studied in vivo during six weeks with spontaneously hypertensive rats (SHR). Extracts used in SHR1, SHR2 and SHR6 groups presented a « rebound effect » on systolic blood pressure, whereas the other extracts do not change it significantly. The bioavailability of Grenache (GRE1) (EA70) seed pomace extract (SHR1 group), Mouvendre (MOU) (EA70) skin pomace extract (SHR5 group) and Alicante (ALI) (EA70) skin pomace extract (SHR6 group) was studied by High Performance Liquid Chromatography with Photodiode Array detector and Electrospray Ionization Mass Spectrometer (HPLC-PDA-ESI-MSn) in urine, plasma and tissues to search differences on the metabolism of the different extracts intake. PMID- 29986481 TI - In Search of Factors Negatively Affecting Vaccine Immunity to Pertussis in Preschool Children Before the Administration of the First Booster. AB - INTRODUCTION: The top priority for active immunoprophylaxis of pertussis is the immunisation of infants as they can sometimes develop severe multiple-organ complications. OBJECTIVES: The aim of the work is the identification of factors negatively affecting vaccine immunity to pertussis in preschool children prior to the administration of the first booster. PATIENTS AND METHODS: The research was conducted on 352 children from 4.5 to 5.9 years of age who were hospitalised in the University Children's Hospital in Lublin (Poland) from 1 January 2012 to 31 December 2015. The children taking part in the study had been administered all the mandatory vaccines from their birth to the age of 2 or 2.5 years old according to the Polish Immunisation Program 2008-2009. The immunoenzymatic method ELISA (enzyme-linked immunosorbent assay) was applied to assess vaccine immunity to tetanus, diphtheria, pertussis, Haemophilus influenzae type b (Hib), poliomyelitis (IPV), mumps, rubella and measles. The level of vaccine antibodies to hepatitis type B was determined chemilumiscently. RESULTS: The protective antibody titre was not found in 41 (11.65%) children before the administration of the booster. To verify the collective impact of parameters analysed on antibody titre to pertussis, the Generalized Linear Model (GLZ) was used. Gender, type of vaccine, asthma, Hib and mumps antibody titres have been shown to be predictors of vaccine immunity to pertussis. CONCLUSIONS: Immunomodulation considered on the example of titre of IgG antibody to pertussis can serve as a useful model of the assessment of development of acquired immunity after mandatory vaccinations. PMID- 29986482 TI - Using a Chemical Genetic Screen to Enhance Our Understanding of the Antibacterial Properties of Silver. AB - It is essential to understand the mechanisms by which a toxicant is capable of poisoning the bacterial cell. The mechanism of action of many biocides and toxins, including numerous ubiquitous compounds, is not fully understood. For example, despite the widespread clinical and commercial use of silver (Ag), the mechanisms describing how this metal poisons bacterial cells remains incomplete. To advance our understanding surrounding the antimicrobial action of Ag, we performed a chemical genetic screen of a mutant library of Escherichia coli—the Keio collection, in order to identify Ag sensitive or resistant deletion strains. Indeed, our findings corroborate many previously established mechanisms that describe the antibacterial effects of Ag, such as the disruption of iron-sulfur clusters containing proteins and certain cellular redox enzymes. However, the data presented here demonstrates that the activity of Ag within the bacterial cell is more extensive, encompassing genes involved in cell wall maintenance, quinone metabolism and sulfur assimilation. Altogether, this study provides further insight into the antimicrobial mechanism of Ag and the physiological adaption of E. coli to this metal. PMID- 29986483 TI - Tick-Virus-Host Interactions at the Cutaneous Interface: The Nidus of Flavivirus Transmission. AB - Tick-borne viral diseases continue to emerge in the United States, as clearly evident from the increase in Powassan encephalitis virus, Heartland virus, and Bourbon virus infections. Tick-borne flaviviruses (TBFVs) are transmitted to the mammalian host along with the infected tick saliva during blood-feeding. Successful tick feeding is facilitated by a complex repertoire of pharmacologically active salivary proteins/factors in tick saliva. These salivary factors create an immunologically privileged micro-environment in the host’s skin that influences virus transmission and pathogenesis. In this review, we will highlight tick determinants of TBFV transmission with a special emphasis on tick-virus-host interactions at the cutaneous interface. PMID- 29986484 TI - Awareness, Risk Perception, and Protective Behaviors for Extreme Heat and Climate Change in New York City. AB - Preventing heat-related illness and death requires an understanding of who is at risk and why, and options for intervention. We sought to understand the drivers of socioeconomic disparities in heat-related vulnerability in New York City (NYC), the perceived risk of heat exposure and climate change, and barriers to protective behaviors. A random digit dial telephone survey of 801 NYC adults aged 18 and older was conducted from 22 September-1 October, 2015. Thirteen percent of the population did not possess an air conditioner (AC), and another 15% used AC never/infrequently. In adjusted models, odds of not possessing AC were greater for non-Hispanic blacks compared with other races/ethnicities, odds ratio (OR) = 2.0 (95% CI: 1.1, 3.5), and for those with low annual household income, OR = 3.1 (95% CI: 1.8, 5.5). Only 12% reported going to a public place with AC if they could not keep cool at home. While low-income individuals were less likely to be aware of heat warnings, they were more likely to be concerned that heat could make them ill and that climate change would affect their health than participants with a higher household income, OR = 1.6 (95% CI: 1.0, 2.3). In NYC, lack of access to AC partially explains disparities in heat-related health outcomes. Our results point to opportunities for knowledge building and engagement on heat health awareness and climate change adaptation that can be applied in NYC and other metropolitan areas to improve and target public health prevention efforts. PMID- 29986485 TI - Chemokine CCL4 Induced in Mouse Brain Has a Protective Role against Methylmercury Toxicity. AB - Methylmercury (MeHg) is selectively toxic to the central nervous system, but mechanisms related to its toxicity are poorly understood. In the present study, we identified the chemokine, C-C motif Chemokine Ligand 4 (CCL4), to be selectively upregulated in the brain of MeHg-administered mice. We then investigated the relationship between CCL4 expression and MeHg toxicity using in vivo and in vitro approaches. We confirmed that in C17.2 cells (a mouse neural stem cell line) and the mouse brain, induction of CCL4 expression occurs prior to cytotoxicity caused by MeHg. We also show that the addition of recombinant CCL4 to the culture medium of mouse xprimary neurons attenuated MeHg toxicity, while knockdown of CCL4 in C17.2 cells resulted in higher MeHg sensitivity compared with control cells. These results suggest that CCL4 is a protective factor against MeHg toxicity and that induction of CCL4 expression is not a result of cytotoxicity by MeHg but is a protective response against MeHg exposure. PMID- 29986487 TI - Residents' Disaster Preparedness after the Meinong Taiwan Earthquake: A Test of Protection Motivation Theory. AB - Because effective preparations are required to mitigate disaster impacts before implementing effective interventions, it is important to understand why people do or do not act on disaster preparedness. This study explores factors influencing residents’ intentions and actual behaviors following the 2016 Kaohsiung Meinong earthquake in southern Taiwan. Protection Motivation Theory was used to develop a hypothesized model to test hypotheses regarding residents’ disaster preparedness, and structural equation modeling (SEM) was used to test the model. Data were comprised of 286 valid responses from seven major administration areas in Tainan, Taiwan. Self-efficacy, response-efficacy, and obstacles were significantly correlated with behavioral intentions and actual disaster preparedness behaviors. SEM results revealed that (a) the model fit the data well, (b) the relationship between risk perception and response-efficacy was fully mediated by behavioral intention, and (c) self-efficacy and obstacles were partially mediated by behavioral intention. Behavioral intent and actual disaster preparedness behavior are related but not equal. The main factors affecting actual disaster preparedness behavior are self-efficacy and obstacles. Therefore, strategies like drills or workshops can improve disaster-preparedness knowledge and capabilities and reduce difficulties of implementing disaster preparedness. To improve health and well-being, healthcare providers should promote disaster preparedness by interventions to increase self-efficacy during disasters. PMID- 29986486 TI - Comparison of the Active Compositions between Raw and Processed Epimedium from Different Species. AB - Epimedium herb is one of the most vital traditional Chinese medicines (TCMs), which is used for “nourishing the kidney and reinforcing the Yang”. In the guidance of TCM theory, Epimedium herb is usually processed with lamb oil to increase its efficacy. The contents of active ingredients in different Epimedium are significantly varied, which may derive from their different species, regions and processing methods. In this research, 13 batches of raw Epimedium collected from 6 provinces were identified. After optimization of the processing method of Epimedium, a liquid chromatography-mass spectrometry (LC MS/MS) method for simultaneous determination of 16 compounds was established to evaluate the quality of raw and processed. Then the multivariate statistical technique was applied to compare different batches of Epimedium based on the LC MS/MS data. As a conclusion, the herbs collected from 6 areas were ascribed to 5 species by microscopic and appearance features. Meanwhile, all of the raw and processed samples were classified by partial least squares discriminant analysis (PLS-DA) based on the 16 analyzed compounds. The comparison results indicate that processing and species both have important influences on Epimedium compositions contents. PMID- 29986488 TI - Radical Scavenging and Antioxidant Activity of Anthyllis Vulneraria Leaves and Flowers. AB - The main targets of this work were to determine the phenolic content of Anthyllis vulneraria (A. vulneraria) leaves and flowers and to evaluate their antioxidant activity. Total polyphenols and flavonoid content (TPC and TFC, respectively) were determined. Antioxidant capacity was evaluated by the Ferric Reducing Antioxidant Power (FRAP), the Oxygen Radical Absorbance Capacity (ORAC), the Trolox Equivalent Antioxidant Capacity (TEAC) and the diphenyl picrylhydrazyl (DPPH) assays, and by the analysis of primary and secondary oxidation products in oil-in-water emulsions and in raw beef patties during storage. The results revealed that the flowers of the A. vulneraria contained the highest content of total polyphenols and flavonoids and extracts from these tissues exhibited the strongest antioxidant activity, as they were more effective at retarding lipid oxidation in oil-in-water emulsions and raw beef patties than extracts from the leaves which had a potent antioxidant effect only at the beginning of the oxidation process. The results of this study allowed us to obtain a deep knowledge about the properties of A. vulneraria and confirmed the possibility of using its biologically active extracts in the food, cosmetic and pharmaceutical industries. PMID- 29986489 TI - Evolution of Elevated-Temperature Strength and Creep Resistance during Multi-Step Heat Treatments in Al-Mn-Mg Alloy. AB - The present work has systematically investigated the evolution of dispersoids and elevated-temperature properties including strength and creep resistance during various multi-step heat treatments in Al-Mn-Mg 3004 alloys. Results show that only the α-Al(MnFe)Si dispersoid is observed in the studied temperature range (up to 625 °C), and that it coarsens with increasing temperature to 500 °C, but dissolves at 625 °C. The evolution of elevated-temperature strength and creep resistance is greatly related to the temperature of each step during the multi-step heat treatments. Generally, lower temperature at the first step heat treatment leads to higher properties, while the properties decrease with increasing temperature of last-step heat treatment. Suitable models have been introduced to explain the evolution of strength and the creep threshold stress at elevated-temperatures during the various heat treatments. PMID- 29986490 TI - Failure Characteristics and Mechanism of Nano-Modified Oil-Impregnated Paper Subjected to Repeated Impulse Voltage. AB - Nano-modification is a prospective method for improving the electrical properties of transformer oil. In most situations, transformer oil combined with cellulose paper is used to construct an insulation system for power equipment, such as power transformers. However, the influence of nanoparticles on the electrical performance of oil-impregnated paper is still unclear. Therefore, in this paper, we identify the failure characteristics of both fresh and nano-modified oil/paper. Specifically, the accumulative failure characteristics of nano-oil impregnated paper (NOIP) are experimentally determined. The space charge distribution and trap characteristics of fresh paper and NOIP were measured, and the effect of nanoparticles on the space charge behavior are then analyzed. Finally, we measure the microstructure of fresh paper and NOIP subjected to repeated impulses. The test results indicate that nano-titanium oxide (TiO2) particles have a limited effect on the breakdown voltage of NOIP. However, the particles can dramatically improve the resistant ability of NOIP against repeated impulses. For the NOIP with a nano-concentration of 0.25 g/L, the improvement reaches 62.5% compared with fresh paper. Under repeated applications of impulse voltages, the space charge density of NOIP is much lower than that of fresh paper. The deep trap density of NOIP is much higher than that of fresh OIP, whereas shallow trap density is relatively lower. Micropores are generated in paper insulation subjected to repeated impulses. The amount of the generated micropores in NOIP is lower than that in fresh paper. Nano-TiO2 particles suppress the accumulation of space charge in the oil paper insulation, which weakens the electric field distortion in the dielectric. However, nanoparticles reduce the accumulative damage caused by repeated impulses. The above two points are considered the main reasons to improve the resistant ability against repeated impulses. PMID- 29986491 TI - An Outlier Detection Method Based on Mahalanobis Distance for Source Localization. AB - This paper addresses the problem of localization accuracy degradation caused by outliers of the angle of arrival (AOA). The problem of outlier detection of the AOA is converted into the detection of the estimated source position sets, which are obtained by the proposed division and greedy replacement method. The Mahalanobis distance based on robust mean and covariance matrix estimation method is then introduced to identify the outliers from the position sets. Finally, the weighted least squares method based on the reliable probabilities and distances is proposed for source localization. The simulation and experimental results show that the proposed method outperforms representative methods when unreliable AOAs are present. PMID- 29986492 TI - Effect of Nutritional Interventions on Micronutrient Status in Pregnant Malawian Women with Moderate Malnutrition: A Randomized, Controlled Trial. AB - Micronutrient deficiencies during pregnancy are common in Africa and can cause adverse outcomes. The objective was to measure micronutrient status and change in moderately malnourished pregnant Malawian women randomized to one of three nutritional interventions. Serum vitamin B12, 25-hydroxyvitamin D, folate, retinol, ferritin, zinc, albumin and C-reactive protein were measured in pregnant women with MUAC ≥20.6 cm and ≤23.0 cm at enrollment (n = 343) and after 10 weeks (n = 229) of receiving: (1) ready-to-use supplementary food (RUSF); (2) fortified corn-soy blend (CSB+) with multiple-micronutrient supplement (CSB+UNIMMAP); or (3) CSB+ with iron and folic acid (CSB+IFA). Each provided 100 300% Recommended Dietary Allowance of most micronutrients and 900 kcal/day. Birth length was measured in 272 infants. Enrollment measurements indicated deficiencies in vitamin B12 (20.9%) and zinc (22.3%), low values of ferritin (25.1%) and albumin (33.7%), and elevated CRP (46.0%). Vitamin B12 is known to decrease in the third trimester; the RUSF group had the smallest decrease from enrollment to week 10 (3%), compared to 20% decrease in the CSB+IFA group and 8% decrease in the CSB+UNIMMAP group (p = 0.001). Mean serum 25-hydroxyvitamin D increased most in the RUSF group (+6.4 ng/mL), compared to CSB+IFA (+1.7 ng/mL) and CSB+UNIMMAP (+2.7 ng/mL) (p < 0.001). Micronutrient deficiencies and inflammation are common among moderately malnourished pregnant women and had little improvement despite supplementation above the RDA, with the exception of vitamins B12 and D. PMID- 29986494 TI - Environmentally-Friendly Extraction of Cellulose Nanofibers from Steam-Explosion Pretreated Sugar Beet Pulp. AB - Cellulose nanofibers (CNFs) with an average diameter of 22 nm were prepared from sugar beet pulp (SBP) via an environmentally-friendly method. Steam-explosion pretreated SBP was treated with hydrogen peroxide (H2O2) bleaching, high-speed blending, and ultrasonic treatment. Thermogravimetric analysis showed that hemicellulose was partially hydrolyzed in the steam-cooking stage, pectin was removed in the explosion stage, and lignin was removed by H2O2 bleaching. The removal of non-cellulosic components was confirmed by Fourier-transform infrared (FT-IR) spectroscopy. Morphological analysis showed that steam-explosion pretreatment largely extracted the binder materials of hemicellulose and pectin. This exposed the microfibrillated cellulosic fibers, which promoted subsequent nanofibrillation. X-ray diffraction showed that the CNFs had a crystallinity index of 62.3%. The CNFs had good thermal stability, and thus have potential for use as fillers in polymer matrices. The only chemical reagent used in this green method was H2O2. Combining H2O2 bleaching with steam explosion, high-speed blending, and ultrasonic treatment reduced the overall energy consumption and increased the efficiency of the CNFs extraction. The method, therefore, has potential application in industrial processes. PMID- 29986495 TI - Determination of Intensity-Based Stochastic Models for Terrestrial Laser Scanners Utilising 3D-Point Clouds. AB - Recent advances in stochastic modelling of reflectorless rangefinders revealed an inherent relationship among raw intensity values and the corresponding precision of observed distances. In order to derive the stochastic properties of a terrestrial laser scanner’s (TLS) rangefinder, distances have to be observed repeatedly. For this, the TLS of interest has to be operated in the so called 1D-mode—a functionality which is offered only by a few manufacturers due to laser safety regulations. The article at hand proposes two methodologies to compute intensity-based stochastic models based on capturing geometric primitives in form of planar shapes utilising 3D-point clouds. At first the procedures are applied to a phase-based Zoller + Fröhlich IMAGER 5006h. The generated results are then evaluated by comparing the outcome to the parameters of a stochastic model which has been derived by means of measurements captured in 1D-mode. Another open research question is if intensity-based stochastic models are applicable for other rangefinder types. Therefore, one of the suggested procedures is applied to a Riegl VZ-400i impulse scanner, as well as a Leica ScanStation P40 TLS that deploys a hybrid rangefinder technology. The generated results successfully demonstrate alternative methods for the computation of intensity-based stochastic models as well as their transferability to other rangefinder technologies. PMID- 29986493 TI - The INHERIT Model: A Tool to Jointly Improve Health, Environmental Sustainability and Health Equity through Behavior and Lifestyle Change. AB - The need for analysis and action across the interrelated domains of human behaviors and lifestyles, environmental sustainability, health and inequality is increasingly apparent. Currently, these areas are often not considered in conjunction when developing policies or interventions, introducing the potential for suboptimal or conflicting outcomes. The INHERIT model has been developed within the EU-funded project INHERIT as a tool to guide thinking and intersectoral action towards changing the behaviors and lifestyles that play such an important role in today’s multidisciplinary challenges. The model integrates ecological public health and behavioral change models, emphasizing inequalities and those parts of the causal process that are influenced by human behaviors and lifestyles. The model was developed through web-based and live discussions with experts and policy stakeholders. To test the model’s usability, the model was applied to aspects of food consumption. This paper shows that the INHERIT model can serve as a tool to identify opportunities for change in important −food-related behaviors and lifestyles and to examine how they impact on health, health inequalities, and the environment in Europe and beyond. The INHERIT model helps clarify these interrelated domains, creating new opportunities to improve environmental health and health inequality, while taking our planetary boundaries into consideration. PMID- 29986496 TI - Myrianthus arboreus P. Beauv (Cecropiaceae) Extracts Accelerates Sexual Maturation, and Increases Fertility Index and Gestational Rate in Female Wistar Rats. AB - Background: Despite the wide use of leaves of Myrianthus arboreus (Cecropiaceae) in several African countries including Cameroon as food and against amenorrhea and female infertility, it has never been tested for this purpose. Methods: Using immature female Wistar rats, the impact of M. arboreus on the sexual maturation parameters (vaginal opening, ovarian relative weight and follicle maturation, gonadotropins and ovarian hormones serum levels) and fertility index has been evaluated through a 30-day oral administration of aqueous and methanol extracts of leaves at the doses of 20, 110 and 200 g/kg/day. Results: Aqueous extract increased the ovarian relative weight (p < 0.001), progesterone (p < 0.001) and gonadotropins (p < 0.001) serum levels, and induced the maturation of ovarian follicles. The methanol extract additionally induced an early vaginal opening (p < 0.001), uterine growth (p < 0.01) and increased estradiol (p < 0.001) serum levels. The fertility index generally increased following treatments, while the gestation rate remained almost unaffected except at the highest tested dose of M. arboreus extracts where lowest values were observed. Conclusion: Globally, M. arboreus induced an early puberty onset and an increased fertility rate validating at least in part its traditional use for female infertility. PMID- 29986498 TI - Proposal of Characterization Procedure of Metal-Graphite Interface Strength in Compacted Graphite Iron. AB - Compacted graphite iron is the material of choice for engine cylinder heads of heavy-duty trucks. Compacted graphite iron provides the best possible compromise between optimum mechanical properties, compared to flake graphite iron, and optimum thermal conductivity, compared to spheroidal graphite iron. The vermicular-shaped graphite particles, however, act as stress concentrators, and, as a result of delamination from the metal matrix, they are responsible for crack initiation during the thermomechanical fatigue cycles occurring through engine startup and shutdown cycles. Scratch tests driven over the matrix and into the graphite particles were performed in order to characterize the strength of the metal-graphite interface. Samples extracted from a cylinder head in as-cast condition were compared to samples subjected to a heat-treatment at 700 °C for 60 h. The former samples were composed of a primarily pearlitic matrix and graphite particles (~11.5 vol %), whereas, after annealing, a certain pearlite fraction decomposed into Fe and C, producing a microstructure with graphite ferrite interfaces, exhibiting a partially spiky morphology. The scratch test revealed that the ferrite-graphite interfaces with spiky nature exhibited a stronger resistance to delamination compared to the ferrite-graphite interfaces with smooth morphology. One reason for the high interface strength is the mechanical interlocking between graphite spikes and ferrite, increasing the contact area between the two phases. PMID- 29986497 TI - Influence of Iodine Feeding on Microbiological and Physico-Chemical Characteristics and Biogenic Amines Content in a Raw Ewes' Milk Cheese. AB - Iodine is an essential trace element involved in the regulation of thyroid metabolism and antioxidant status in humans and animals. The aim of this study was to evaluate the effect of ewes’ dietary iodine supplementation on biogenic amines content as well as microbiological and physico-chemical characteristics in a raw milk cheese at different ripening times (milk, curd, and 2, 7, 15, 30, 60, and 90 days). Two cheese-making trials were carried out using milk from ewes fed with unifeed (Cheese A) or with the same concentrate enriched with iodine (Cheese B). The results indicated that the counts of principal microbial groups and physico-chemical characteristics were quite similar in both cheeses at day 90. Cheese B was characterized by a higher content of biogenic amines and propionic acid. Propionic bacteria were found in both cheeses mainly in Trial B in agreement with the higher content of propionic acid detected. PMID- 29986499 TI - Real-Time Vehicle Roll Angle Estimation Based on Neural Networks in IoT Low-Cost Devices. AB - The high rate of vehicle-crash victims has a fatal economic and social impact in today’s societies. In particular, road crashes where heavy vehicles are involved cause more severe damage because they are prone to rollover. For this reason, many researches are focused on developing RSC Roll Stability Control (RSC) systems. Concerning the design of RSC systems with an adequate performance, it is mandatory to know the dynamics of the vehicle. The main problem arises from the lack of ability to directly capture several required dynamic vehicle variables, such as roll angle, from low-cost sensors. Previous studies demonstrate that low-cost sensors can provide data in real-time with the required precision and reliability. Even more, other research works indicate that neural networks are efficient mechanisms to estimate roll angle. Nevertheless, it is necessary to assess that the fusion of data coming from low-cost devices and estimations provided by neural networks can fulfill hard real-time processing constraints, achieving high level of accuracy during circulation of a vehicle in real situations. In order to address this issue, this study has two main goals: (1) Design and develop an IoT based architecture, integrating ANN in low cost kits with different hardware architectures in order to estimate under real-time constraints the vehicle roll angle. This architecture is able to work under high dynamic conditions, by following specific best practices and considerations during its design; (2) assess that the IoT architecture deployed in low-cost experimental kits achieve the hard real-time performance constraints estimating the roll angle with the required calculation accuracy. To fulfil these objectives, an experimental environment was set up, composed of a van with two set of low-cost kits, one including a Raspberry Pi 3 Model Band the other having an Intel Edison System on Chip linked to a SparkFun 9 Degrees of Freedom module. This experimental environment be tested in different maneuvers for comparison purposes. Neural networks embedded in low-cost sensor kits provide roll angle estimations highly approximated to real values. Even more, Intel Edison and Raspberry Pi 3 Model B have enough computing capabilities to successfully run roll angle estimation based on neural networks to determine rollover risk situations, fulfilling real-time operation restrictions stated for this problem. PMID- 29986500 TI - Greatly Enhanced Photovoltaic Performance of Crystalline Silicon Solar Cells via Metal Oxide. AB - Band-gap alignment engineering has now been extensively studied due to its high potential for application. Here we demonstrate a simple route to synthesize two metal oxide layers and align them together according to their bandgaps on the surface of crystalline silicon (c-Si) solar cells. The metal oxide layers not only extend absorption spectrum to generate extra carriers but also more efficiently separate electron-hole pairs. As a consequence, the photovoltaic performance of SnO2/CdO/Si double-layer solar cell (DLSC) is highly improved compared to the controlled Si solar cell, CdO/Si and SnO2/Si single-layer solar cells (SLSCs). Via alignment engineering, the SnO2/CdO/Si DLSC produces a short circuit photocurrent (Jsc) of 38.20 mA/cm2, an open circuit photovoltage (Voc) of 0.575 V and a fill factor (FF) of 68.7%, a conversion efficiency (η) of 15.09% under AM1.5 illumination. PMID- 29986501 TI - Pterostilbene Suppresses Ovarian Cancer Growth via Induction of Apoptosis and Blockade of Cell Cycle Progression Involving Inhibition of the STAT3 Pathway. AB - A growing body of evidence has demonstrated the promising anti-tumor effects of resveratrol in ovarian cancer cells, including its inhibitory effects on STAT3 activation. Nonetheless, the low bioavailability of resveratrol has reduced its attractiveness as a potential anti-cancer treatment. In contrast, pterostilbene, a stilbenoid and resveratrol analog, has demonstrated superior bioavailability, while possessing significant antitumor activity in multiple solid tumors. In this study, the therapeutic potential of pterostilbene was evaluated in ovarian cancer cells. Pterostilbene reduces cell viability in several different ovarian cancer cell lines by suppressing cell cycle progression and inducing apoptosis. Further molecular study has shown that pterostilbene effectively suppressed phosphorylation of STAT3, as well as STAT3 downstream genes that regulate cell cycle and apoptosis, indicating that inhibition of STAT3 pathway may be involved in its anti-tumor activity. The addition of pterostilbene to the commonly used chemotherapy cisplatin demonstrated synergistic antiproliferative activity in several ovarian cancer cell lines. Pterostilbene additionally inhibited cell migration in multiple ovarian cancer cell lines. The above results suggest that pterostilbene facilitates significant anti-tumor activity in ovarian cancer via anti-proliferative and pro-apoptotic mechanisms, possibly via downregulation of JAK/STAT3 pathway. Pterostilbene thus presents as an attractive non-toxic alternative for potential adjuvant or maintenance chemotherapy in ovarian cancer. PMID- 29986502 TI - Glycomimetics: Design, Synthesis, and Therapeutic Applications. PMID- 29986503 TI - Benefits and Limitations of the Record and Replay Approach for GNSS Receiver Performance Assessment in Harsh Scenarios. AB - Global navigation satellite systems play a significant role in the development of intelligent transport systems, where the estimation of the vehicle’s position is a key element. However, in strongly constrained environments such as city centers, the definition of quality metrics and the assessment of positioning performances are challenges to be addressed. Due to the variability of different urban scenarios, the modeling of the dynamics as well as the architecture of the positioning platform, which might embed other sensors and aiding means to the GNSS unit, make it hard to define unambiguous positioning metrics. Performance assessment through analytical models and simulators can be ineffective in terms of cost, complexity, and general validity and scalability of the results. This paper shows how a record and replay approach can be an efficient solution to grant fidelity to a realistic scenario. This work discusses advantages and disadvantages with emphasis on the case study of harsh scenarios. Such an approach requires proper data collections that allow the replay phase to test the GNSS-based positioning terminals. This paper presents the results obtained on a set of field tests related to different scenarios, selected as representative for the key performance indicators assessment. PMID- 29986504 TI - Code-VEP vs. Eye Tracking: A Comparison Study. AB - Even with state-of-the-art techniques there are individuals whose paralysis prevents them from communicating with others. Brain-Computer-Interfaces (BCI) aim to utilize brain waves to construct a voice for those whose needs remain unmet. In this paper we compare the efficacy of a BCI input signal, code-VEP via Electroencephalography, against eye gaze tracking, among the most popular modalities used. These results, on healthy individuals without paralysis, suggest that while eye tracking works well for some, it does not work well or at all for others; the latter group includes individuals with corrected vision or those who squint their eyes unintentionally while focusing on a task. It is also evident that the performance of the interface is more sensitive to head/body movements when eye tracking is used as the input modality, compared to using c-VEP. Sensitivity to head/body movement could be better in eye tracking systems which are tracking the head or mounted on the face and are designed specifically as assistive devices. The sample interface developed for this assessment has the same reaction time when driven with c-VEP or with eye tracking; approximately 0.5 1 second is needed to make a selection among the four options simultaneously presented. Factors, such as system reaction time and robustness play a crucial role in participant preferences. PMID- 29986506 TI - A Normal Distribution-Based Methodology for Analysis of Fatal Accidents in Land Hazardous Material Transportation. AB - The deaths of accident occurring in land hazardous material transport (rail and road) is a scale standard for judging accident severity in safety programmes. The f-N curve is a common practice to express the results from past scattered accident data through curve fitting method, which only estimate the overall trend. For this reason, this paper proposed a simple methodology by combination of normal distribution and f-N curve. To verify the method, the following three sets of statistical data were selected and analysed in this study: 1932 accidents in over 95 countries (1931-2004) and 322 accidents in China (2000-2008) available in the literature, and 2046 accidents investigated in China (2013-2017). It was found that the mean value curve is almost identical or even better than the best fitted curve, while the predicted upper and lower limits with 96% reliability (+/ 2σ) covering nearly all the statistical data are beyond the scope of common curve fitting. The result explains the inherent relation between accumulated frequency and deaths in different transport mode, in different country and at different period. This study also provides insights on the evolution of accident severity with the development of social economy and the requirement of safety. PMID- 29986505 TI - The Impact of Heat Waves on Emergency Department Admissions in Charlottesville, Virginia, U.S.A. AB - Heat waves have been linked to increases in emergency-related morbidity, but more research is needed on the demographic and disease-specific aspects of these morbidities. Using a case-crossover approach, over 700,000 daily emergency department hospital admissions in Charlottesville, Virginia, U.S.A. from 2005 2016 are compared between warm season heat wave and non-heat wave periods. Heat waves are defined based on the exceedance, for at least three consecutive days, of two apparent temperature thresholds (35 °C and 37 °C) that account for 3 and 6% of the period of record. Total admissions and admissions for whites, blacks, males, females, and 20-49 years old are significantly elevated during heat waves, as are admissions related to a variety of diagnostic categories, including diabetes, pregnancy complications, and injuries and poisoning. Evidence that heat waves raise emergency department admissions across numerous demographic and disease categories suggests that heat exerts comorbidity influences that extend beyond the more well-studied direct relationships such as heat strokes and cardiac arrest. PMID- 29986507 TI - A Dynamic Estimation of Service Level Based on Fuzzy Logic for Robustness in the Internet of Things. AB - The Internet of things (IoT) technology is developing rapidly, and the IoT services are penetrating broadly into every aspect of people’s lives. As the large amount of services grows dramatically, how to discover and select the best services dynamically to satisfy the actual needs of users in the IoT service set, the elements of which have the same function, is an unavoidable issue. Therefore, for the robustness of the IoT system, evaluating the quality level of the IoT service to provide a reference for the users choosing the most appropriate service has become a hot topic. Most of the current methods just use some static data to evaluate the quality of the service and ignore the dynamic changing trend of the service performance. In this paper, an estimation mechanism for the quality level of the IoT service based on fuzzy logic is conducted to grade the quality of the service. Specifically, the comprehensive factors are taken into account according to the defined level changing rules and the effect of the service in the previous execution process, so that it can provide users with an effective reference. Experiments are carried out by using a simulated service set. It is shown that the proposed algorithm can estimate the quality level of the service more comprehensively and reasonably, which is evidently superior to the other two common methods, i.e., the estimating method by a Randomization Test (RT) and the estimating method by a Single Test in Steps (STS). PMID- 29986509 TI - Colloidal Synthesis of CsX Nanocrystals (X = Cl, Br, I). AB - A facile colloidal synthesis of highly ionic cesium halide nanocrystals is reported. Colloidal nanocrystals of CsI, CsCl and CsBr with unprecedentedly small dimensions are obtained using oleylammonium halides and cesium oleate as precursors. The ease and adaptability of our method enables its universalization for the formation of other highly ionic nanocrystals. PMID- 29986508 TI - Mycophenolic Acid Derivatives with Immunosuppressive Activity from the Coral Derived Fungus Penicillium bialowiezense. AB - Mycophenolic acid (MPA) is a potent inosine-5′-monophosphate dehydrogenase (IMPDH) inhibitor for immunosuppressive chemotherapy. Most importantly, as the 2 morpholinoethyl ester prodrug of MPA, mycophenolate mofetil (MMF) is a well-known immunosuppressant used to prevent rejection in organ transplantations. Nevertheless, due to its frequently occurred side effects, searching for new therapeutic agents is ongoing. In our current work, by virtue of efficient bioassay-guided fractionation and purification, eleven mycophenolic acid derivatives, including five previously unreported metabolites (3-7) and six known compounds (1, 2, and 8-11), were obtained from the coral-derived fungus Penicillium bialowiezense. Their structures were elucidated by means of extensive spectroscopic analyses (including 1D and 2D NMR and HRESIMS data) and comparison of the NMR and other physical data with those reported in the literature in the case of the known compounds. All the isolates 1-11 were evaluated for the immunosuppressive activity, and 1-3 showed potent IMPDH2 inhibitory potency with IC50 values of 0.84-0.95 μM, which were comparable to that of MPA (the positive control), while 4-10 showed significant inhibitory potency with IC50 values of 3.27-24.68 μM. All the MPA derivatives showed promising immunosuppressive activity, endowing them as potential drug leads for organ transplantations and autoimmune related diseases. PMID- 29986510 TI - Research on a Fast-Response Thermal Conductivity Sensor Based on Carbon Nanotube Modification. AB - Aiming at solving the slow-response problem of traditional bead-type thermal conductivity gas sensors, a fast-response thermal conductivity gas sensor can be made by using multiwalled carbon nanotubes (MWNTs), combined with the technology of carrier modification, to modify the performance of the sensor carrier. The carrier material, granular nanoscale γ-Al2O3/ZrO2, was synthesized by chemical precipitation, and its particle size was found to be 50-70 nm through SEM. After the carrier material was wet-incorporated into carbon nanotubes, the composite carrier γ-Al2O3/ZrO2/MWNTs was obtained. The results show that the designed thermal conductivity sensor has a fast response to methane gas, with a 90% response time of 7 s and a recovery time of 16 s. There is a good linear relationship between the sensor output and CH4 gas concentration, with an average sensitivity of 1.15 mV/1% CH4. Thus, the response speed of a thermal conductivity sensor can be enhanced by doping carbon nanotubes into γ-Al2O3/ZrO2. PMID- 29986511 TI - PD-L1 Nanobody Competitively Inhibits the Formation of the PD-1/PD-L1 Complex: Comparative Molecular Dynamics Simulations. AB - The anti-PD-L1 monoclonal antibody (mAb) targeting PD-1/PD-L1 immune checkpoint has achieved outstanding results in clinical application and has become one of the most popular anti-cancer drugs. The mechanism of molecular recognition and inhibition of PD-L1 mAbs is not yet clear, which hinders the subsequent antibody design and modification. In this work, the trajectories of PD-1/PD-L1 and nanobody/PD-L1 complexes were obtained via comparative molecular dynamics simulations. Then, a series of physicochemical parameters including hydrogen bond, dihedral angle distribution, pKa value and binding free energy, and so forth, were all comparatively analyzed to investigate the recognition difference between PD-L1 and PD-1 and nanobody. Both LR113 (the amino acid residues in PD-L1 are represented by the lower left sign of L) and LR125 residues of PD-L1 undergo significant conformational change after association with mAbs, which dominates a strong electrostatic interaction. Solvation effect analysis revealed that solvent water enhanced molecular recognition between PD-L1 and nanobody. By combining the analyses of the time-dependent root mean squared fluctuation (RMSF), free energy landscape, clustering and energy decomposition, the potential inhibition mechanism was proposed that the nanobody competitively and specifically bound to the β-sheet groups of PD-L1, reduced the PD-L1’s flexibility and finally blocked the formation of PD-1/PD-L1 complex. Based on the simulation results, site-directed mutagenesis of ND99 (the amino acid residues in Nano are displayed by the lower left sign of N) and NQ116 in the nanobody may be beneficial for improving antibody activity. This work offers some structural guidance for the design and modification of anticancer mAbs based on the structure of the PD-1/PD-L1 complex. PMID- 29986512 TI - Simultaneous Determination of the Traditional Herbal Formula Ukgansan and the In Vitro Antioxidant Activity of Ferulic Acid as an Active Compound. AB - Ukgansan (UGS), a traditional herbal formula composing seven medicinal herbal plants, has been applied in Asian countries for treating neurosis, insomnia, and irritability. Here, the current study performed a simultaneous determination of the seven marker compounds (liquiritin apioside, liquiritin, ferulic acid, glycyrrhizin, decursin, decursinol angelate, and atractylenolide I) using high performance liquid chromatography (HPLC), to establish quality control of UGS. A 70% ethanol extract of UGS and a mixture of the seven compounds were separated using a C-18 analytical column on a gradient solvent system of 1.0% (v/v) aqueous acetic acid and acetonitrile. Data were recorded at a UV wavelength of 250 nm for glycyrrhizin; 276 nm for liquiritin apioside, liquiritin, and atractylenolide I; and 325 nm for ferulic acid, decursin, and decursinol angelate. The results exhibited high linearity (correlation coefficient (r2) ≥ 0.9998) and proper precision (0.38-3.36%), accuracy (95.12-105.12%), and recovery (95.99-104.94%) for the seven marker compounds. The amount of the seven marker compounds at the concentrations from 0.190 to 16.431 mg/g. In addition, the current study evaluated the antioxidant effects of UGS by measuring their scavenging activities against the 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2′-diphenyl-1-picrylhydrazyl (DPPH) radicals using in vitro cell-free systems and observed its antioxidant activity. Among the seven components of the UGS extract, ferulic acid dramatically enhanced the scavenging of ABTS and DPPH radicals compared with other compounds. The concentrations of ferulic acid required for a 50% reduction (RC50) in ABTS and DPPH radicals were 16.22 μM and 41.21 μM, respectively. Furthermore, UGS extract exerted the neuroprotective effect and blocked the inflammatory response in neuronal hippocampal cells and microglia, respectively. Overall, the established method of HPLC will be valuable for improving the quality control of UGS extract, and ferulic acid may be useful as a potential antioxidant agent. PMID- 29986513 TI - Investigation of A Slow-Light Enhanced Near-Infrared Absorption Spectroscopic Gas Sensor, Based on Hollow-Core Photonic Band-Gap Fiber. AB - Generic modeling and analysis of a slow-light enhanced absorption spectroscopic gas sensor was proposed, using a mode-tuned, hollow-core, photonic band-gap fiber (HC-PBF) as an absorption gas cell. Mode characteristics of the un-infiltrated and infiltrated HC-PBF and gas absorption enhancement of the infiltrated HC-PBF were analyzed. A general rule of microfluidic parameters for targeting different gas species in the near-infrared was obtained. Ammonia (NH3) was used as an example to explore the effects of slow light on gas detection. The second harmonic (2f) signal and Allan deviation were theoretically investigated based on the derived formulations. PMID- 29986515 TI - Integration of Low-Cost GNSS and Monocular Cameras for Simultaneous Localization and Mapping. AB - Low-cost Global Navigation Satellite System (GNSS) receivers and monocular cameras are widely used in daily activities. The complementary nature of these two devices is ideal for outdoor navigation. In this paper, we investigate the integration of GNSS and monocular camera measurements in a simultaneous localization and mapping system. The proposed system first aligns the coordinates between two sensors. Subsequently, the measurements are fused by an optimization based scheme. Our system can function in real-time and obtain the absolute position, scale, and attitude of the vehicle. It achieves a high accuracy without a preset map and also has the capability to work with a preset map. The system can easily be extended to create other forms of maps or for other types of cameras. Experimental results on a popular public dataset are presented to validate the performance of the proposed system. PMID- 29986514 TI - Theoretical Studies on Catalysis Mechanisms of Serum Paraoxonase 1 and Phosphotriesterase Diisopropyl Fluorophosphatase Suggest the Alteration of Substrate Preference from Paraoxonase to DFP. AB - The calcium-dependent β-propeller proteins mammalian serum paraoxonase 1 (PON1) and phosphotriesterase diisopropyl fluorophosphatase (DFPase) catalyze the hydrolysis of organophosphorus compounds and enhance hydrolysis of various nerve agents. In the present work, the phosphotriesterase activity development between PON1 and DFPase was investigated by using the hybrid density functional theory method B3LYP. Based on the active-site difference between PON1 and DFPase, both the wild type and the mutant (a water molecule replacing Asn270 in PON1) models were designed. The results indicated that the substitution of a water molecule for Asn270 in PON1 had little effect on the enzyme activity in kinetics, while being more efficient in thermodynamics, which is essential for DFP hydrolysis. Structure comparisons of evolutionarily related enzymes show that the mutation of Asn270 leads to the catalytic Ca2+ ion indirectly connecting the buried structural Ca2+ ion via hydrogen bonds in DFPase. It can reduce the plasticity of enzymatic structure, and possibly change the substrate preference from paraoxon to DFP, which implies an evolutionary transition from mono- to dinuclear catalytic centers. Our studies shed light on the investigation of enzyme catalysis mechanism from an evolutionary perspective. PMID- 29986516 TI - Detection of the Mitochondrial Membrane Potential by the Cationic Dye JC-1 in L1210 Cells with Massive Overexpression of the Plasma Membrane ABCB1 Drug Transporter. AB - JC-1, a cationic fluorescent dye when added to living cells, is known to be localized exclusively in mitochondria, particularly in good physiological conditions characterized by sufficient mitochondrial membrane potential (ΔΨ). The accumulation of JC-1 in these organelles leads to the formation J-aggregates (with a specific red fluorescence emission maximum at 590 nm), which is in addition to the typical green fluorescence of J-monomers (emission maximum of ∼529 nm). The lack of mitochondrial ΔΨ leads to the depression of JC-1 mitochondrial accumulation and a decrease in J aggregate formation. Therefore, the ratio between the red and green fluorescence of cells loaded with JC-1 is often used for the detection of the mitochondrial membrane potential. However, JC-1 represents a suitable substrate of the multidrug transporter P-glycoprotein (P-gp). Therefore, the depression of the JC 1 content in intracellular space and particularly in the mitochondria to a level that is inefficient for J-aggregate formation could be expected in P-gp-positive cells. In the current paper, we proved this behavior on parental P-gp-negative L1210 (S) cells and their P-gp-positive variants obtained by either selection with vincristine (R) or transfection with the human gene encoding P-gp (T). P glycoprotein inhibitors cyclosporine A and verapamil fail to restore JC-1 loading of the R and T cells to an extent similar to that observed in S cells. In contrast, the noncompetitive high affinity P-gp inhibitor tariquidar fully restored JC-1 accumulation and the presence of the typical red fluorescence of J aggregates. In the presence of tariquidar, measurement of the JC-1 fluorescence revealed similar levels of mitochondrial membrane potential in P-gp-negative (S) and P-gp-positive cells (R and T). PMID- 29986517 TI - Review of Three-Dimensional Human-Computer Interaction with Focus on the Leap Motion Controller. AB - Modern hardware and software development has led to an evolution of user interfaces from command-line to natural user interfaces for virtual immersive environments. Gestures imitating real-world interaction tasks increasingly replace classical two-dimensional interfaces based on Windows/Icons/Menus/Pointers (WIMP) or touch metaphors. Thus, the purpose of this paper is to survey the state-of-the-art Human-Computer Interaction (HCI) techniques with a focus on the special field of three-dimensional interaction. This includes an overview of currently available interaction devices, their applications of usage and underlying methods for gesture design and recognition. Focus is on interfaces based on the Leap Motion Controller (LMC) and corresponding methods of gesture design and recognition. Further, a review of evaluation methods for the proposed natural user interfaces is given. PMID- 29986518 TI - Date Palm Trees Root-Derived Endophytes as Fungal Cell Factories for Diverse Bioactive Metabolites. AB - Endophytic fungi of healthy and brittle leaf diseased (BLD) date palm trees (Phoenix dactylifera L.) represent a promising source of bioactive compounds with biomedical, industrial, and pharmaceutical applications. The fungal endophytes Penicillium citrinum isolate TDPEF34, and Geotrichum candidum isolate TDPEF20 from healthy and BLD date palm trees, respectively, proved very effective in confrontation assays against three pathogenic bacteria, including two Gram positive bacteria Bacillus thuringiensis (Bt) and Enterococcus faecalis (Ef), and one Gram-negative bacterium Salmonella enterica (St). They also inhibited the growth of three fungi Trichoderma sp. (Ti), Fusarium sporotrichioides (Fs), Trichoderma sp. (Ts). Additionally, their volatile organic compounds (VOCs) were shown to be in part responsible for the inhibition of Ti and Ts and could account for the full inhibition of Fs. Therefore, we have explored their potential as fungal cell factories for bioactive metabolites production. Four extracts of each endophyte were prepared using different solvent polarities, ethanol (EtOH), ethyl acetate (EtOAc), hexane (Hex), and methanol (MetOH). Both endophyte species showed varying degrees of inhibition of the bacterial and fungal pathogens according to the solvent used. These results suggest a good relationship between fungal bioactivities and their produced secondary metabolites. Targeting the discovery of potential anti-diabetic, anti-hemolysis, anti-inflammatory, anti obesity, and cytotoxic activities, endophytic extracts showed promising results. The EtOAc extract of G. candidum displayed IC50 value comparable to the positive control diclofenac sodium in the anti-inflammatory assays. Antioxidant activity was evaluated using α,α-diphenyl-β-picrylhydrazyl (DPPH), β carotene bleaching, reducing power (RP), and 2,2-azino-bis(3-ethylbenzothiazoline 6-sulphonique) (ABTS) radical scavenging assays. The findings revealed strong anti-oxidant power with an IC50 of 177.55 µg/mL for G. candidum EtOAc extract using DPPH assay, probably due to high polyphenol and flavonoid content in both fungal extracts. Finally, LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry) and GC-MS (Gas Chromatography-Mass Spectrometry) analysis of G. candidum and P. citrinum extracts revealed an impressive arsenal of compounds with previously reported biological activities, partly explaining the obtained results. Finally, LC-HRMS analysis indicated the presence of new fungal metabolites that have never been reported, which represent good candidates to follow for the discovery of new bioactive molecules. PMID- 29986519 TI - Radiation Sensitivity of Adipose-Derived Stem Cells Isolated from Breast Tissue. AB - Within their niche, adipose-derived stem cells (ADSCs) are essential for homeostasis as well as for regeneration. Therefore, the interest of physicians is to use ADSCs as a tool for radiation oncology and regenerative medicine. To investigate related risks, this study analyses the radiation response of adult stem cells isolated from the adipose tissue of the female breast. To avoid donor specific effects, ADSCs isolated from breast reduction mammoplasties of 10 donors were pooled and used for the radiobiological analysis. The clonogenic survival fraction assay was used to classify the radiation sensitivity in comparison to a more radiation-sensitive (ZR-75-1), moderately sensitive (MCF-7), and resistant (MCF10A) cell lines. Afterwards, cytotoxicity and genotoxicity of irradiation on ADSCs were investigated. On the basis of clonogenic cell survival rates of ADSCs after irradiation, we assign ADSCs an intermediate radiation sensitivity. Furthermore, a high repair capacity of double-strand breaks is related to an altered cell cycle arrest and increased expression of cyclin-dependent kinase (CDK) inhibitor p21. ADSCs isolated from breast tissue exhibit intermediate radiation sensitivity, caused by functional repair mechanisms. Therefore, we propose ADSCs to be a promising tool in radiation oncology. PMID- 29986520 TI - Regenerative and Protective Actions of the GHK-Cu Peptide in the Light of the New Gene Data. AB - The human peptide GHK (glycyl-l-histidyl-l-lysine) has multiple biological actions, all of which, according to our current knowledge, appear to be health positive. It stimulates blood vessel and nerve outgrowth, increases collagen, elastin, and glycosaminoglycan synthesis, as well as supports the function of dermal fibroblasts. GHK’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK has also been found to possess powerful cell protective actions, such as multiple anti-cancer activities and anti-inflammatory actions, lung protection and restoration of chronic obstructive pulmonary disease (COPD) fibroblasts, suppression of molecules thought to accelerate the diseases of aging such as NFκB, anti-anxiety, anti-pain and anti-aggression activities, DNA repair, and activation of cell cleansing via the proteasome system. Recent genetic data may explain such diverse protective and healing actions of one molecule, revealing multiple biochemical pathways regulated by GHK. PMID- 29986521 TI - HPLC Separation of 2-Ethyl-5(6)-methylpyrazine and Its Electroantennogram and Alarm Activities on Fire Ants (Solenopsis invicta Buren). AB - 2-Ethyl-3,6-dimethylpyrazine (EDMP) was an alarm pheromone component isolated from the mandibular gland of the red imported fire ant, Solenopsis invicta Buren. Several pyrazine analogues have been previously found to elicit significant alarm responses in S. invicta workers. This study aimed to separate the commercially available 2-ethyl-5(6)-methylpyrazine (EMP), i.e., a mixture of 2-ethyl-6 methylpyrazine (2E6MP) and 2-ethyl-5-methylpyrazine (2E5MP), and to examine both electroantennogram (EAG) and behavioral responses of S. invicta workers to EMP and the purified isomers. HPLC separations were achieved using a polysaccharide chiral stationary phase (Chiralpak AD-H) column with both mobile phases: Cyclohexane/isopropanol, and hexane/isopropanol. A ratio of 99:1 was selected for the separation of EMP at semipreparative level. The structures of the isomers obtained through the cyclohexane/isopropanol mobile phase were confirmed by detailed analyses of 2D-HSQC- and -HMBC-NMR data. The two isomers showed differential methine C-H correlations evidenced by 2D-HMBC-NMR spectra. The two concentrated fractions obtained through hexane/isopropanol mobile phase were subjected to EAG test and behavioral bioassay on S. invicta workers. The two HPLC−purified isomers, 2E6MP and 2E5MP, and their mixture (1:1) at same dose elicited similar EAG and alarm responses, indicating that these two isomers are equally active. The 2D-NMR−spectroscopic characterization, and electrophysiological and alarm activities of 2E6MP and 2E5MP were reported here for the first time. PMID- 29986522 TI - Habitat Structure, Quality and Landscape Predict Species Richness and Communities of Collembola in Dry Grasslands in Austria. AB - We assessed the relationships between site size, habitat quality, landscape factors (fragmentation, landscape diversity) and species richness in communities of Collembola in 50 small dry grassland habitat patches in an agricultural landscape of eastern Austria. Grasslands in that region were once widespread and extensive, but have become increasingly fragmented and isolated. We hypothesized that dry grassland springtails species richness is significantly correlated with site variables (soil properties, habitat quality) and that the size of grassland sites is positively correlated with species richness. We used pitfall traps in 50 dry grasslands in differently structured agricultural landscapes and tested total abundance and three species richness measures: (1) the number of dry grassland specialist species, (2) total number of dry grassland species and (3) overall species richness. In the multivariate correlation models, we found that all species richness measures were significantly related to the plant species richness, a shape parameter of the sites, soil properties such as humus, temperature, sand and gravel content and the landscape variable reflecting isolation (distance to the nearest large dry grassland area). This landscape variable indicates that neighbouring grasslands are influencing the species richness of the sites. This may be a result of passive wind dispersal across the landscape or historic connection of the small sites with much larger dry grasslands. The size of the site did not show any significant correlation with total, dry grassland specialist, dry grassland generalist or generalist species richness. The small size of Collembola might explain these findings, because they have high population densities even in small patches. PMID- 29986524 TI - A Compact Impact Rotary Motor Based on a Piezoelectric Tube Actuator with Helical Interdigitated Electrodes. AB - This paper presents a novel impact rotary motor based on a piezoelectric tube actuator with helical interdigitated electrodes which has a compact structure and high resolution. The assembled prototype motor has a maximum diameter of 15 mm and a length of 65 mm and works under a saw-shaped driving voltage. The LuGre friction model is adopted to analyze the rotary motion process of the motor in the dynamic simulations. From the experimental tests, the first torsional resonant frequency of the piezoelectric tube is 59.289 kHz with a free boundary condition. A series of experiments about the stepping characteristics of different driving voltages, duty cycles, and working frequencies are carried out by a laser Doppler vibrometer based on a fabricated prototype motor. The experimental results show that the prototype rotary motor can produce a maximum torsional angle of about 0.03° using a driving voltage of 480 Vp-p (peak-to peak driving voltage) with a duty ratio of 0% under a small friction force of about 0.1 N. The motor can produce a maximum average angle of about 2.55 rad/s and a stall torque of 0.4 mN?m at 8 kHz using a driving voltage of 640 Vp-p with a duty ratio of 0% under a large friction force of about 3.6 N. The prototype can be driven in forward and backward motion and is working in stick-slip mode at low frequencies and slip-slip mode at high frequencies. PMID- 29986525 TI - Correction: Sugiyama, K.; et al. Management of Dyslipidemia in Type 2 Diabetes: Recent Advances in Nonstatin Treatment. Diseases 2018, 6, 44. PMID- 29986523 TI - Impact of Drosophila Models in the Study and Treatment of Friedreich's Ataxia. AB - Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models. PMID- 29986528 TI - Green Preparation of Ag-Au Bimetallic Nanoparticles Supported on Graphene with Alginate for Non-Enzymatic Hydrogen Peroxide Detection. AB - In this work, a facile, environmentally friendly method was demonstrated for the synthesis of Ag-Au bimetallic nanoparticles (Ag-AuNPs) supported on reduced graphene oxide (RGO) with alginate as reductant and stabilizer. The prepared Ag AuNPs/RGO was characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The results indicated that uniform, spherical Ag-AuNPs was evenly dispersed on graphene surface and the average particle size is about 15 nm. Further, a non-enzymatic sensor was subsequently constructed through the modified electrode with the synthesized Ag-AuNPs/RGO. The sensor showed excellent performance toward H2O2 with a sensitivity of 112.05 μA·cm−2·mM−1, a linear range of 0.1-10 mM, and a low detection limit of 0.57 μM (S/N = 3). Additionally, the sensor displayed high sensitivity, selectivity, and stability for the detection of H2O2. The results demonstrated that Ag-AuNPs/RGO has potential applications as sensing material for quantitative determination of H2O2. PMID- 29986526 TI - TRPV1-Like Immunoreactivity in the Human Locus K, a Distinct Subregion of the Cuneate Nucleus. AB - The presence of transient receptor potential vanilloid type-1 receptor (TRPV1) like immunoreactivity (LI), in the form of nerve fibres and terminals, is shown in a set of discrete gray matter subregions placed in the territory of the human cuneate nucleus. We showed previously that those subregions share neurochemical and structural features with the protopathic nuclei and, after the ancient name of our town, collectively call them Locus Karalis, and briefly Locus K. TRPV1-LI in the Locus K is codistributed, though not perfectly overlapped, with that of the neuropeptides calcitonin gene-related peptide and substance P, the topography of the elements immunoreactive to the three markers, in relation to each other, reflecting that previously described in the caudal spinal trigeminal nucleus. Myelin stainings show that myelinated fibres, abundant in the cuneate, gracile and trigeminal magnocellular nuclei, are scarce in the Locus K as in the trigeminal substantia gelatinosa. Morphometric analysis shows that cell size and density of Locus K neurons are consistent with those of the trigeminal substantia gelatinosa and significantly different from those of the magnocellular trigeminal, solitary and dorsal column nuclei. We propose that Locus K is a special component of the human dorsal column nuclei. Its functional role remains to be determined, but TRPV1 appears to play a part in it. PMID- 29986527 TI - Molecular Cloning and Expression Analysis of Lactate Dehydrogenase from the Oriental River Prawn Macrobrachium nipponense in Response to Hypoxia. AB - Metabolic adaption to hypoxic stress in crustaceans implies a shift from aerobic to anaerobic metabolism. Lactate dehydrogenase (LDH) is a key enzyme in glycolysis in prawns. However, very little is known about the role of LDH in hypoxia inducible factor (HIF) pathways of prawns. In this study, full-length cDNA of LDH (MnLDH) was obtained from the oriental river prawn Macrobrachium nipponense, and was characterized. The full-length cDNA is 2267-bp with an open reading frame of 999 bp coding for a protein of 333 amino acids with conserved domains important for function and regulation. Phylogenetic analysis showed that MnLDH is close to LDHs from other invertebrates. Quantitative real-time PCR revealed that MnLDH is expressed in various tissues with the highest expression level in muscle. MnLDH mRNA transcript and protein abundance in muscle, but not in hepatopancreas, were induced by hypoxia. Silencing of hypoxia-inducible factor 1 (HIF-1) α or HIF-1β subunits blocked the hypoxia-dependent increase of LDH expression and enzyme activity in muscle. A series of MnLDH promoter sequences, especially the full-length promoter, generated an increase in luciferase expression relative to promoterless vector; furthermore, the expression of luciferase was induced by hypoxia. These results demonstrate that MnLDH is probably involved a HIF-1-dependent pathway during hypoxia in the highly active metabolism of muscle. PMID- 29986529 TI - The Effect of Food Unit Sizes and Meal Serving Occasions on Eating Behaviour Characteristics: Within Person Randomised Crossover Studies on Healthy Women. AB - Manipulating food properties and serving environment during a meal can significantly change food intake at group level. However, the evaluation of the usefulness of such manipulations requires an understanding of individual behavioural changes. Three studies were conducted to explore the effect of unit size and meal occasion on eating behaviour characteristics (food intake, meal duration, number of bites and chews). All studies used a randomised crossover design, with a one-week wash-out period, starting with a familiarisation meal, with the participation of healthy, normal weight females between the ages of 18 35 years. In Study 1 (n = 19) three cube sizes (0.5, 1.0 and 1.5 cm3) of vegetable hash and chicken were compared. In Study 2 (n = 18) mashed potatoes and mincemeat were compared to whole potatoes and meatballs. In Study 3 (n = 29) meals served at lunch time (11:00-13:00) were compared to identical meals served at dinner time (17:00-19:00). The largest food unit size lead to significantly increased meal duration in Study 2 (mean difference 0.9 min, 95% confidence interval (CI) 0.0-1.8), but not in Study 1 (mean difference 1 min, 95% CI 0.1 2.0). There was a significant increase in number of chews in the large unit size condition of both Study 1 (mean difference 88, 95% CI 12-158) and Study 2 (mean difference 95, 95% CI 12-179). Different serving occasions did not significantly change any of the eating behaviours measured. Except for number of bites in Study 2 (R2 = 0.60), most individuals maintained their eating behaviour relative to the group across unit sizes and serving occasions conditions (R2 > 0.75), which suggests single meal testing can provide information about the behavioural characteristics of individual eating styles under different conditions. PMID- 29986531 TI - Monitoring and Biosurveillance Tools for the Brown Marmorated Stink Bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae). AB - Halyomorpha halys (Stål) (Hemiptera: Pentatomidae) is an invasive pest of numerous agricultural crops with an increasing global distribution. Finding simple and reliable monitoring tools for H. halys agricultural and surveillance programs is imperative. In 2016, we compared standard pyramid traps to clear sticky cards attached atop wooden stakes and evaluated two commercially formulated lures (Trécé and AgBio) with low and high rates of the H. halys aggregation pheromone (PHER) and pheromone synergist (MDT) at 12 sites (low: 5 mg PHER + 50 mg MDT; high: 20 mg PHER + 200 mg MDT). In 2017, we reevaluated lure efficacy using only the clear sticky traps at six locations. Sites were classified as having low, moderate, or high relative population densities of H. halys in 2016, and as very low or low densities of H. halys in 2017. Although clear sticky traps captured fewer adults and nymphs than pyramid traps, their captures were generally correlated at all population levels indicating that clear sticky traps can reliably monitor H. halys presence and relative abundance regardless of relative population density. During both years, adult and nymphal captures were significantly greater in traps baited with Trécé lures than with AgBio lures. Captures were greater in traps baited with high loading rate lures for each lure type, and with the exception of traps baited with AgBio lures at high relative density sites in 2016, H. halys captures in traps with low and high loading rates of each lure type were correlated for both years. Comparison of yellow and clear sticky cards indicated they performed equally, but yellow cards captured more nontargets. In summary, clear sticky traps attached atop wooden posts and baited with H. halys pheromone and pheromone synergist lures are an effective option for this pest monitoring and detection. PMID- 29986532 TI - Effect of Cold Rolling Process on Microstructure, Texture and Properties of Strip Cast Fe-2.6%Si Steel. AB - The use of twin-roll strip casting for the preparation of non-oriented silicon steel has attracted widespread attention in recent years, but related reports are limited. In this study, both one- and two-stage cold rolling with three intermediate annealing temperatures were employed to produce strip cast non oriented silicon steel. The evolution of the microstructure and texture through the processing routes and its effect on magnetic properties were studied. Compared with one-stage rolling, two-stage rolling increased the in-grain shear bands and the retention of Cube texture in the cold rolled sheets, thereby promoting the nucleation of favorable Goss and Cube grains and restraining the nucleation of harmful {111}<112> grains. With the increase in intermediate annealing temperature, the η-fiber texture in annealed sheets was gradually enhanced, and the average grain size was increased, leading to significant improvement of magnetic properties. PMID- 29986530 TI - Gold Nanoparticles: A Powerful Tool to Visualize Proteins on Ordered Mesoporous Silica and for the Realization of Theranostic Nanobioconjugates. AB - Ordered mesoporous silica (OMS) is a very interesting nanostructured material for the design and engineering of new target and controlled drug-delivery systems. Particularly relevant is the interaction between OMS and proteins. Large pores (6 9 nm) micrometric particles can be used for the realization of a drug depot system where therapeutic proteins are adsorbed either inside the mesopores or on the external surface. Small pores (1-2 nm) mesoporous silica nanoparticles (MSNs), can be injected in the blood stream. In the latter case, therapeutic proteins are mainly adsorbed on the MSNs’ external surface. Whenever a protein-OMS conjugate is prepared, a diagnostic method to locate the protein either on the internal or the external silica surface is of utmost importance. To visualize the fine localization of proteins adsorbed in mesoporous silica micro- and nanoparticles, we have employed specific transmission electron microscopy (TEM) analytical strategies based on the use of gold nanoparticles (GNPs) conjugates. GNPs are gaining in popularity, representing a fundamental tool to design future applications of MSNs in nanomedicine by realizing theranostic nanobioconjugates. It may be pointed out that we are at the very beginning of a new age of the nanomaterial science: the “mesoporous golden age”. PMID- 29986533 TI - In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-Psychoactive Cannabinoid. AB - Inflammation and oxidative stress play main roles in neurodegeneration. Interestingly, different natural compounds may be able to exert neuroprotective actions against inflammation and oxidative stress, protecting from neuronal cell loss. Among these natural sources, Cannabis sativa represents a reservoir of compounds exerting beneficial properties, including cannabigerol (CBG), whose antioxidant properties have already been demonstrated in macrophages. Here, we aimed to evaluate the ability of CBG to protect NSC-34 motor neurons against the toxicity induced from the medium of LPS-stimulated RAW 264.7 macrophages. Using MTT assay, we observed that CBG pre-treatment was able to reduce the loss of cell viability induced by the medium of LPS-stimulated macrophages in NSC-34 cells. Indeed, CBG pre-treatment inhibited apoptosis, as shown by the reduction of caspase 3 activation and Bax expression, while Bcl-2 levels increased. Furthermore, CBG pre-treatment counteracted not only inflammation, as demonstrated by the reduction of IL-1β, TNF-α, IFN-γ and PPARγ protein levels assessed by immunocytochemistry, but also oxidative stress in NSC-34 cells treated with the medium of LPS-stimulated RAW 264.7. Indeed, immunocytochemistry showed that CBG pre-treatment reduced nitrotyrosine, SOD1 and iNOS protein levels and restored Nrf-2 levels. All together, these results indicated the neuroprotective effects of CBG, that may be a potential treatment against neuroinflammation and oxidative stress. PMID- 29986534 TI - Selective Monitoring of Oxyanion Mixtures by a Flow System with Raman Detection. AB - Raman spectroscopy is a selective detection system scarcely applied for the flow analysis of solutions with the aim of detecting several compounds at once without a previous separation step. This work explores the potential of a portable Raman system in a flow system for the selective detection of a mixture of seven oxyanions (carbonate, sulphate, nitrate, phosphate, chlorate, perchlorate, and thiosulphate). The specific bands of these compounds (symmetric stretching Raman active vibrations of carbonate at 1068 cm−1, nitrate at 1049 cm−1, thiosulphate at 998 cm−1, phosphate at 989 cm−1, sulphate at 982 cm−1, perchlorate at 935 cm−1, and chlorate at 932 cm−1) enabled their simultaneous detection in mixtures. Although the oxyanions’ limit of detection (LOD) was rather poor (in the millimolar range), this extremely simple system is very useful for the single-measurement detection of most of the oxyanions in mixtures, without requiring a previous separation step. In addition, quantitative determination of the desired oxyanion can be performed by means of the corresponding calibration line. These are important advantages for controlling in-line processes in industries like those manufacturing fertilizers, pharmaceuticals, chemicals, or food, among others. PMID- 29986535 TI - Glass Ionomer Cements for the Restoration of Non-Carious Cervical Lesions in the Geriatric Patient. AB - BACKGROUND: The restoration of non-carious cervical lesions in geriatric patients is a demanding process. Glass ionomer cements can be promising materials for the management of these lesions in older adults. The aim of this literature review is to present the benefits of glass ionomers and how they can be used for the restoration of non-carious cervical lesions of older adults depending on the geriatric patient's profile. DATA SOURCES: All available in vitro and in vivo studies from Google Scholar, PubMed and Scopus search engines corresponding to glass ionomer cements, geriatric dentistry, elderly patients, and non-carious lesions as key words were reviewed. DATA SYNTHESIS: The advantages of glass ionomer cements, such as good retention and fluoride release, make them suitable for the restoration of non-carious cervical lesions. However, several factors related to the geriatric patient's profile determine the most suitable material type. CONCLUSION: In general, the resin modified glass ionomer cements (RMGICs) appear to be preferred, but under certain circumstances the use of the conventional product is more appropriate, despite its poorer mechanical features. Further studies are required for more reliable data analysis and clinical interpretation of the relevant results. PMID- 29986536 TI - Cryochemically Processed Li1+yMn1.95Ni0.025Co0.025O4 (y = 0, 0.1) Cathode Materials for Li-Ion Batteries. AB - A new route for the preparation of nickel and cobalt substituted spinel cathode materials (LiMn1.95Co0.025Ni0.025O4 and Li1.1Mn1.95Co0.025Ni0.025O4) by freeze drying of acetate precursors followed by heat treatment was suggested in the present work. The experimental conditions for the preparation single-phase material with small particle size were optimized. Single-phase spinel was formed by low-temperature annealing at 700 °C. For discharge rate 0.2 C, the reversible capacities 109 and 112 mAh g−1 were obtained for LiMn1.95Co0.025Ni0.025O4 and Li1.1Mn1.95Co0.025Ni0.025O4, respectively. A good cycle performance and capacity retention about 90% after 30 cycles at discharge rate 0.2-4 C were observed for the materials cycled from 3 to 4.6 V vs. Li/Li+. Under the same conditions pure LiMn2O4 cathode materials represent a reversible capacity 94 mAh g−1 and a capacity retention about 80%. Two independent experimental techniques (cyclic voltammetry at different scan rates and electrochemical impedance spectroscopy) were used in order to investigate the diffusion kinetics of lithium. This study shows that the partial substitution of Mn in LiMn2O4 with small amounts of Ni and Co allows the cyclability and the performance of LiMn2O4-based cathode materials to be improved. PMID- 29986537 TI - Decimeter-Level Geolocation Accuracy Updated by a Parametric Tropospheric Model with GF-3. AB - GaoFen-3 (GF-3) is a multi-polarization C-band synthetic aperture radar (SAR) satellite in China with a resolution of up to 1 m. Up to now, the geolocation accuracy of GF-3 could be improved to 3 m. According to the current study, there still exist meter-level geolocation residuals caused by atmospheric path delay after compensating with a static tropospheric model. In this paper, we compensate the residuals with the sophisticated tropospheric model based on real meteorological data. The experimental results show that the tropospheric model has an accuracy on the millimeter level, which can increase GF-3’s geolocation accuracy to several decimeters compared with the static tropospheric model. PMID- 29986539 TI - Flexible and Stretchable Bio-Integrated Electronics Based on Carbon Nanotube and Graphene. AB - Scientific and engineering progress associated with increased interest in healthcare monitoring, therapy, and human-machine interfaces has rapidly accelerated the development of bio-integrated multifunctional devices. Recently, compensation for the cons of existing materials on electronics for health care systems has been provided by carbon-based nanomaterials. Due to their excellent mechanical and electrical properties, these materials provide benefits such as improved flexibility and stretchability for conformal integration with the soft, curvilinear surfaces of human tissues or organs, while maintaining their own unique functions. This review summarizes the most recent advanced biomedical devices and technologies based on two most popular carbon based materials, carbon nanotubes (CNTs) and graphene. In the beginning, we discuss the biocompatibility of CNTs and graphene by examining their cytotoxicity and/or detrimental effects on the human body for application to bioelectronics. Then, we scrutinize the various types of flexible and/or stretchable substrates that are integrated with CNTs and graphene for the construction of high-quality active electrode arrays and sensors. The convergence of these carbon-based materials and bioelectronics ensures scalability and cooperativity in various fields. Finally, future works with challenges are presented in bio-integrated electronic applications with these carbon-based materials. PMID- 29986540 TI - A Cost-Effective IoT System for Monitoring Indoor Radon Gas Concentration. AB - Radon is a noble gas originating from the radioactive decay chain of uranium or thorium. Most radon emanates naturally from the soil and from some building materials, so it can be found in many places around the world, in particular in regions with soils containing granite or slate. It is almost impossible for a person to detect radon gas without proper tools, since it is invisible, odorless, tasteless and colorless. The problem is that a correlation has been established between the presence of high radon gas concentrations and the incidence of lung cancer. In fact, the World Health Organization (WHO) has stated that the exposure to radon is the second most common cause of lung cancer after smoking, and it is the primary cause of lung cancer among people who have never smoked. Although there are commercial radon detectors, most of them are either expensive or provide very limited monitoring capabilities. To tackle such an issue, this article presents a cost-effective IoT radon gas remote monitoring system able to obtain accurate concentration measurements. It can also trigger events to prevent dangerous situations and to warn users about them. Moreover, the proposed solution can activate mitigation devices (e.g., forced ventilation) to decrease radon gas concentration. In order to show its performance, the system was evaluated in three different scenarios corresponding to representative buildings in Galicia (Spain), a region where high radon gas concentrations are common due to the composition of the soil. In addition, the influence of using external hardware (i.e., WiFi transceivers and an embedded System-on-Chip (SoC)) next to the radon gas sensor is studied, concluding that, in the tested scenarios, they do not interfere with the measurements. PMID- 29986538 TI - Recent Development of Genetic Code Expansion for Posttranslational Modification Studies. AB - Nowadays advanced mass spectrometry techniques make the identification of protein posttranslational modifications (PTMs) much easier than ever before. A series of proteomic studies have demonstrated that large numbers of proteins in cells are modified by phosphorylation, acetylation and many other types of PTMs. However, only limited studies have been performed to validate or characterize those identified modification targets, mostly because PTMs are very dynamic, undergoing large changes in different growth stages or conditions. To overcome this issue, the genetic code expansion strategy has been introduced into PTM studies to genetically incorporate modified amino acids directly into desired positions of target proteins. Without using modifying enzymes, the genetic code expansion strategy could generate homogeneously modified proteins, thus providing powerful tools for PTM studies. In this review, we summarized recent development of genetic code expansion in PTM studies for research groups in this field. PMID- 29986541 TI - A Novel Probability Model for LncRNA-Disease Association Prediction Based on the Naive Bayesian Classifier. AB - An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play crucial roles in biological processes, complex disease diagnoses, prognoses, and treatments. However, experimentally validated associations between lncRNAs and diseases are still very limited. Recently, computational models have been developed to discover potential associations between lncRNAs and diseases by integrating multiple heterogeneous biological data; this has become a hot topic in biological research. In this article, we constructed a global tripartite network by integrating a variety of biological information including miRNA disease, miRNA-lncRNA, and lncRNA-disease associations and interactions. Then, we constructed a global quadruple network by appending gene-lncRNA interaction, gene disease association, and gene-miRNA interaction networks to the global tripartite network. Subsequently, based on these two global networks, a novel approach was proposed based on the naïve Bayesian classifier to predict potential lncRNA disease associations (NBCLDA). Comparing with the state-of-the-art methods, our new method does not entirely rely on known lncRNA-disease associations, and can achieve a reliable performance with effective area under ROC curve (AUCs)in leave one-out cross validation. Moreover, in order to further estimate the performance of NBCLDA, case studies of colorectal cancer, prostate cancer, and glioma were implemented in this paper, and the simulation results demonstrated that NBCLDA can be an excellent tool for biomedical research in the future. PMID- 29986542 TI - Thermal Energy Storage of R1234yf, R1234ze, R134a and R32/MOF-74 Nanofluids: A Molecular Simulation Study. AB - Thermal energy storage can be carried out by working fluid adsorbing and desorbing in porous materials. In this paper, the energy storage properties of four refrigerants, R1234yf, R1234ze, R134a and R32, with M-metal organic framework (MOF)-74 (M = Zn, Ni, Mg, Co) nanoparticles are investigated using molecular dynamics simulations and grand canonical Monte Carlo simulations. The results show that M-MOF-74 can adsorb more R32 and R134a than R1234yf and R1234ze, as the molecular structures of R32 and R134a are smaller than those of R1234yf and R1234ze. Mg-MOF-74 owns a higher adsorbability than the other MOFs. The energy storage properties of the studied refrigerants can be enhanced when the sum of thermodynamic energy change of MOF particles and the desorption heat of fluid in MOFs is larger than the enthalpy change of pure organic fluid. The R1234yf/M-MOF-74 (M = Co, Mg, Ni) nanofluid can store more energy than other refrigerants/M-MOF-74 (M = Co, Mg, Ni) nanofluid. The energy storage enhancement ratios of R1234yf, R1234ze and R134a with Mg-MOF-74 nanoparticles are higher than those of other M-MOF-74 (M = Co, Ni, Zn) materials. PMID- 29986544 TI - A Novel Damage Indicator Based on the Electromechanical Impedance Principle for Structural Damage Identification. AB - This paper presents a novel structural damage detection indicator, i.e., fourth order voltage statistical moment (FVSM) based on the electromechanical impedance (EMI) principle, and then proposes a two-step damage detection method based on the novel indicator and a differential evolution algorithm (DEA). In this study, several lead zirconate titanate (PZT) sensors bonded to an experimental steel beam were utilized to acquire the time-domain voltage responses. On this basis, the fourth-order voltage statistical moments (FVSMs) of the voltage responses are computed to locate the damage element in the detected structure, and the proposed damage detection method is utilized to quantify the damage. In addition, theoretical PZT voltage responses are also calculated based on the piezoelectric theory and the spectral element method (SEM). Experimental results verify the accuracy of the theoretical voltage values and the effectiveness of the proposed damage indicator. Results indicate that the FVSM is effective in locating the damage element. Integrated with DEA, the proposed technique is capable of quantifying damage. PMID- 29986545 TI - CMOS Capacitive Fingerprint Sensor Based on Differential Sensing Circuit with Noise Cancellation. AB - In this paper, we introduce a differential sensing technique for CMOS capacitive fingerprint detection. It employs a new capacitive-sensing cell structure with charge sharing detection and readout circuit. The proposed technique also can eliminate the effect of parasitic capacitances by employing parasitic insensitive switched-capacitor structure and so increases the sensitivity even under severe noisy conditions. It can also overcome the performance degradation caused by various conditions of finger surface by using a differential integrator and adjusting its number of integrations. In addition, the proposed architecture allows parallel detection of all sensing channels. It can, therefore, substantially speed up the detection process compared with conventional architectures. We implemented a prototype fingerprint sensor chip with an array of 20 * 16 sensor cells using a 130 nm CMOS process. Simulation experiments demonstrated that the proposed architecture provided an SNR gain of 54 dB, whereas a conventional single line sensing gives an SNR gain of only 13 dB. PMID- 29986543 TI - Bioavailability Enhancement of Poorly Water-Soluble Drugs via Nanocomposites: Formulation-Processing Aspects and Challenges. AB - Drug nanoparticles embedded in a dispersant matrix as a secondary phase, i.e., drug-laden nanocomposites, offer a versatile delivery platform for enhancing the dissolution rate and bioavailability of poorly water-soluble drugs. Drug nanoparticles are prepared by top-down, bottom-up, or combinative approaches in the form of nanosuspensions, which are subsequently dried to prepare drug-laden nanocomposites. In this comprehensive review paper, the term “nanocomposites” is used in a broad context to cover drug nanoparticle-laden intermediate products in the form of powders, cakes, and extrudates, which can be incorporated into final oral solid dosages via standard pharmaceutical unit operations, as well as drug nanoparticle-laden strip films. The objective of this paper is to review studies from 2012-2017 in the field of drug-laden nanocomposites. After a brief overview of the various approaches used for preparing drug nanoparticles, the review covers drying processes and dispersant formulations used for the production of drug-laden nanocomposites, as well as various characterization methods including quiescent and agitated redispersion tests. Traditional dispersants such as soluble polymers, surfactants, other water-soluble dispersants, and water-insoluble dispersants, as well as novel dispersants such as wet-milled superdisintegrants, are covered. They exhibit various functionalities such as drug nanoparticle stabilization, mitigation of aggregation, formation of nanocomposite matrix-film, wettability enhancement, and matrix erosion/disintegration. Major challenges such as nanoparticle aggregation and poor redispersibility that cause inferior dissolution performance of the drug-laden nanocomposites are highlighted. Literature data are analyzed in terms of usage frequency of various drying processes and dispersant classes. We provide some engineering considerations in comparing drying processes, which could account for some of the diverging trends in academia vs. industrial practice. Overall, this review provides rationale and guidance for drying process selection and robust nanocomposite formulation development, with insights into the roles of various classes of dispersants. PMID- 29986546 TI - Human 3D Cultures as Models for Evaluating Magnetic Nanoparticle CNS Cytotoxicity after Short- and Repeated Long-Term Exposure. AB - Since nanoparticles (NPs) can translocate to the brain and impact the highly vulnerable central nervous system (CNS), novel in vitro tools for the assessment of NP-induced neurotoxicity are advocated. In this study, two types of CNS spheroids have been developed from human D384 astrocyte- and SH-SY5Y neuronal like cells, and optimized in combination with standard assays (viability readout and cell morphology) to test neurotoxic effects caused by Fe3O4NPs, as NP-model, after short- (24-48 h; 1-100µg/ml) and long-term repeated exposure (30days; 0.1-25µg/ml). Short-term exposure of 3D-spheroids to Fe3O4NP induced cytotoxicity at 10 µg/mL in astrocytes and 25 µg/mL neurons. After long-term repeated dose regimen, spheroids showed concentration- and time dependent cell mortality at 10 µg/mL for D384 and 0.5 µg/mL for SH SY5Y, indicating a higher susceptibility of neurons than astrocytes. Both spheroid types displayed cell disaggregation after the first week of treatment at ≥0.1 µg/mL and becoming considerably evident at higher concentrations and over time. Recreating the 3D-spatial environment of the CNS allows cells to behave in vitro more closely to the in vivo situations, therefore providing a model that can be used as a stand-alone test or as a part of integrated testing strategies. These models could drive an improvement in the species-relevant predictivity of toxicity testing. PMID- 29986549 TI - An OWA Distance-Based, Single-Valued Neutrosophic Linguistic TOPSIS Approach for Green Supplier Evaluation and Selection in Low-Carbon Supply Chains. AB - This paper presents a technique based on the ordered weighted averaging (OWA) distance for the single-valued neutrosophic linguistic (SVNL) technique for order preference by similarity to an ideal solution (TOPSIS). First, the inadequacies of the existing SVNL TOPSIS are analyzed in detail. Second, a SVNL OWA distance (SVNLOWAD) measure is presented, and based on this, a modified TOPSIS, termed the SVNLOWAD-TOPSIS, is developed for multiple attribute decision-making problems with SVNL information. Third, a revised relative coefficient is proposed to rank potential alternatives. Finally, a numerical example concerning green supplier selection in low-carbon supply chains is introduced to demonstrate the effectiveness of the model. PMID- 29986548 TI - Repetition-to-Repetition Differences Using Cluster and Accentuated Eccentric Loading in the Back Squat. AB - The current investigation was an examination of the repetition-to-repetition magnitudes and changes in kinetic and kinematic characteristics of the back squat using accentuated eccentric loading (AEL) and cluster sets. Trained male subjects (age = 26.1 +/- 4.1 years, height = 183.5 +/- 4.3 cm, body mass = 92.5 +/- 10.5 kg, back squat to body mass ratio = 1.8 +/- 0.3) completed four load condition sessions, each consisting of three sets of five repetitions of either traditionally loaded straight sets (TL), traditionally loaded cluster sets (TLC), AEL cluster sets (AEC), and AEL straight sets where only the initial repetition had eccentric overload (AEL1). Eccentric overload was applied using weight releasers, creating a total eccentric load equivalent to 105% of concentric one repetition maximum (1RM). Concentric load was 80% 1RM for all load conditions. Using straight sets (TL and AEL1) tended to decrease peak power (PP) (d = −1.90 to −0.76), concentric rate of force development (RFDCON) (d = −1.59 to −0.27), and average velocity (MV) (d = −3.91 to −1.29), with moderate decreases in MV using cluster sets (d = −0.81 to −0.62). Greater magnitude eccentric rate of force development (RFDECC) was observed using AEC at repetition three (R3) and five (R5) compared to all load conditions (d = 0.21-0.65). Large within-condition changes in RFDECC from repetition one to repetition three (?REP1-3) were present using AEL1 (d = 1.51), demonstrating that RFDECC remained elevated for at least three repetitions despite overload only present on the initial repetition. Overall, cluster sets appear to permit higher magnitude and improved maintenance of concentric outputs throughout a set. Eccentric overload with the loading protocol used in the current study does not appear to potentiate concentric output regardless of set configuration but may cause greater RFDECC compared to traditional loading. PMID- 29986547 TI - Suicide Risk among Immigrants and Ethnic Minorities: A Literature Overview. AB - Recent studies have demonstrated that immigrants and ethnic minorities may be at higher risk of suicidal behaviour as compared to the general population. We conducted a literature search to identify studies in English from 1980 to 2017 related to suicide risk among immigrants and ethnic minorities. Six hundred and seventy-eight reports were screened, and 43 articles were included in the qualitative synthesis of the review. Some studies reported lower rates of suicide attempts, while other findings suggested higher rates of suicidal behaviour and deaths among immigrants as compared to the native population. Also, a positive correlation was found between suicidal behaviour and specific countries of origin. Non-European immigrant women were at the highest risk for suicide attempts, a group which included young women of South Asian and black African origin. Risk factors among migrants and ethnic minorities were found to be: language barriers, worrying about family back home, and separation from family. The lack of information on health care system, loss of status, loss of social network, and acculturation were identified as possible triggers for suicidal behaviour. Overall, results suggest that specific migrant populations and ethnic minorities present a higher risk of suicidal behaviour than native populations, as well as a higher risk of death by suicide. PMID- 29986550 TI - Simulated Microgravity Reduces Focal Adhesions and Alters Cytoskeleton and Nuclear Positioning Leading to Enhanced Apoptosis via Suppressing FAK/RhoA Mediated mTORC1/NF-kappaB and ERK1/2 Pathways. AB - Simulated-microgravity (SMG) promotes cell-apoptosis. We demonstrated that SMG inhibited cell proliferation/metastasis via FAK/RhoA-regulated mTORC1 pathway. Since mTORC1, NF-κB, and ERK1/2 signaling are important in cell apoptosis, we examined whether SMG-enhanced apoptosis is regulated via these signals controlled by FAK/RhoA in BL6-10 melanoma cells under clinostat-modelled SMG condition. We show that SMG promotes cell-apoptosis, alters cytoskeleton, reduces focal adhesions (FAs), and suppresses FAK/RhoA signaling. SMG down-regulates expression of mTORC1-related Raptor, pS6K, pEIF4E, pNF-κB, and pNF-κB regulated Bcl2, and induces relocalization of pNF-κB from the nucleus to the cytoplasm. In addition, SMG also inhibits expression of nuclear envelope proteins (NEPs) lamin-A, emerin, sun1, and nesprin-3, which control nuclear positioning, and suppresses nuclear positioning-regulated pERK1/2 signaling. Moreover, rapamycin, the mTORC1 inhibitor, also enhances apoptosis in cells under 1 g condition via suppressing the mTORC1/NF-κB pathway. Furthermore, the FAK/RhoA activator, toxin cytotoxic necrotizing factor-1 (CNF1), reduces cell apoptosis, restores the cytoskeleton, FAs, NEPs, and nuclear positioning, and converts all of the above SMG-induced changes in molecular signaling in cells under SMG. Therefore, our data demonstrate that SMG reduces FAs and alters the cytoskeleton and nuclear positioning, leading to enhanced cell apoptosis via suppressing the FAK/RhoA-regulated mTORC1/NF-κB and ERK1/2 pathways. The FAK/RhoA regulatory network may, thus, become a new target for the development of novel therapeutics for humans under spaceflight conditions with stressed physiological challenges, and for other human diseases. PMID- 29986552 TI - Concentration and Temperature Effects on Water and Salt Permeabilities in Osmosis and Implications in Pressure-Retarded Osmosis. AB - Osmotic power extracted from the mixing of freshwater with seawater is a renewable energy resource that has gained increasing attention during recent years. The estimated energy can significantly contribute to the production of power worldwide. However, this power production will be subject to variation due to both local conditions and seasonal variation. The present paper explores the effect of concentration and temperature on water and salt fluxes in osmosis at zero transmembrane pressure for five different membranes. Further, the measured fluxes have been utilized to model water and salt permeabilities (A and B), and the structure parameter (S). The observed flux variations at different combinations of concentration and temperature have been ascribed to skin properties, i.e., changes in A and B of each membrane, whereas S was assumed constant within the range of concentrations and temperatures that were tested. Simplified equations for the variation in A and B with temperature and concentration have been developed, which enable A and B to be calculated at any concentration and temperature based on permeabilities determined from osmotic experiments at standard test conditions. The equations can be used to predict fluxes and specific power production with respect to geographical and seasonal variations in concentration and temperature for river water/seawater pressure retarded osmosis. The obtained results are also useful for forward osmosis processes using seawater as draw solution. PMID- 29986551 TI - The Anti-Wrinkle Mechanism of Melatonin in UVB Treated HaCaT Keratinocytes and Hairless Mice via Inhibition of ROS and Sonic Hedgehog Mediated Inflammatory Proteins. AB - Though melatonin is known to improve ultraviolet B (UVB)-induced oxidative damage and inflammatory conditions via the blockade of the nuclear factor (NF)-κB, interleukin (IL)-6, there is no report on the anti-wrinkle effect of melatonin to date. Hence in the present study, the anti-wrinkle mechanism of melatonin was elucidated in UVB treated HaCaT keratinocytes and hairless mice. Herein melatonin protected against a radical initiator tert-Butyl hydroperoxide (t-BOOH) induced reactive oxygen species (ROS) production, matrix metalloprotease 1 (MMP-1), pro collagen and cytotoxicity in HaCaT keratinocytes. Additionally, melatonin suppressed the expression of sonic hedgehog (SHH) and GLI1 for hedgehog signaling and p-NF-κB, cyclooxygenase (COX-2), phospho-extracellular signal-regulated kinase-1 (p-ERK) for inflammatory responses in UVB treated HaCaT keratinocytes. Furthermore, melatonin protected skin from wrinkle formation, transdermal water loss in hairless mice irradiated by UVB for 8 weeks. Notably, melatonin prevented against epidermal thickness and dermal collagen degradation in UVB irradiated hairless mice by Hematoxylin and Eosin and Masson’s trichrome staining. Taken together, these findings suggest that melatonin reduces wrinkle formation via inhibition of ROS/SHH and inflammatory proteins such as NF-κB/COX 2/ERK/MMP1. PMID- 29986553 TI - A Survey of the Common Mutations and IVS8-Tn Polymorphism of Cystic Fibrosis Transmembrane Conductance Regulator Gene in Infertile Men with Nonobstructive Azoospermia and CBAVD in Iranian Population AB - Background: Studies have revealed a strong association between mutations of CFTR gene and the congenital bilateral absence of the vas deferens (CBAVD), but the role of this gene in other types of male infertility is still unclear. The purpose of the this study was to investigate the frequency of the most common mutations of the CFTR gene (DF508, G542X, N1303K, G551D, and W1282X) in a population of infertile men with nonobstructive azoospermia (NOA) and CBAVD in Iran. Methods: Blood samples were obtained from 50 NOA, 50 CBAVD, and 100 normal males (control). Genomic DNA was isolated from whole blood leukocytes, and the presence of common mutations of the CFTR gene was assessed by an amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Restriction fragment length polymorphism (PCR-RFLP) was also used to analyze IVS8-Tn polymorphism. Results: It was found that 16%, 8%, and 8% of patients with CBAVD were heterozygote for DF508, G542X, and N1303K, respectively. The frequency of the 5T allele was 34% and higher than the normal group (p < 0.001). None of the common CFTR gene mutations were detected in NOA patients, and no significant difference was found in the distribution of the 5T allele between the NOA patients and the control group (5 vs. 3 p = 0.721). Conclusion: Based on the present case-control study, the CFTR gene mutations and IVS8-Tn polymorphisms are correlated with CBAVD; however, extensive investigations are necessary to determine the exact relationship between the gene mutations and other forms of male infertility. PMID- 29986554 TI - [Synthesis of cell penetrating peptide decorated magnetic nanoparticles loading cisplatin for nasopharyngeal cancer therapy]. AB - Objective:To synthesize cisplatin loaded and cell penetrating peptide TAT decorated magnetic nanoparticles and to observe the inhibiting effect in vitro on nasopharyngeal cancer therapy.Method:The aldehyde sodium alginate coated magnetic nanoparticles (ASA-MNPs) was prepared as the drug delivery system, which was covalently attached by PEGylation TAT (TAT-ASA-MNPs) via condensation of aldehyde with amino group and then coordinated with cisplatin (TAT-ASA-MNPs@CDDP). The complex was characterized by H-NMR and FT-IR. The cell penetrating ability and biocompatibility were observed by means of fluorescent tags. The inhibited effect on nasopharyngeal cancer CNE-2 cells was measured by cellular toxicity research and flow cytometry.Result:The H NMR and FT-IR of TAT-ASA-MNPs exhibited the characteristic peaks of TAT, PEG as well as ASA. The dynamic light scattering showed the hydrodynamic diameter of the complex was(145.9+/-1.5)nm. Zeta potential was(-21.66+/-1.24)mV and the drug loading rate was(25.03+/-3.05)%. Fluorescent labeling assay revealed that FITC marked TAT?ASA?MNPs was quickly taken up by CNE-2 cells. Cytotoxicity experiment on 293T cells displayed high survival rate (>70%) after cultured for 72h. Negative hemagglutination reflected decent biocompatibility. In vitro cytotoxicity test and cell apoptosis assay exhibited obvious inhibition on CNE-2 cell with TAT?ASA?MNPs@CDDP at low concentration of cisplatin compared to ASA-MNPs@CDDP (P<0.05).Conclusion:TAT-ASA MNPs showed decent biocompatibility while distinctly inhibit CNE-2 cells in vitro study. PMID- 29986555 TI - [Significance of the reverse phase nystagmus for the diagnosis of benign paroxysmal positional vertigo]. AB - Objective:To investigate the significance of the reverse phase nystagmus for the diagnosis of benign paroxysmal positional vertigo when going on the positioning test. Method:During the positioning test,there are 26 cases with reverse phase nystagmus in the 118 BPPV patients,note and analyse their nystagmus characteristics,then combine their disease history,to diagnose the affected side of the BPPV,and following with the corresponding treat of canalith repositioning procedure(CRP). Result:All the 26 cases with reverse phase nystagmus are the BPPV patients of horizontal semicircular postal?canalithasis,in which,RHSC-pCan for 15 cases,LHSC-pCan for 11 cases,with the treat of CRP,the significant effectivities are 4 cases,effectivities 15,uneffectivities 7,after single factor chi-square test,chi2=7.46,P< 0.05.Conclusion:For the BPPV cases with reverse phase nystagmus during the positioning test,their efficacy difference of the CRP is significant statistically,that is the CRP treat is effective, the therapeutic diagnosis is established, which contributes to the analysis and judgment for the affected side of the semi-circular canals. PMID- 29986556 TI - [Application of transoral endoscopic thyroidectomy for benign thyroid nodule]. AB - Objective:To evaluate the feasibility and application value of transoral endoscopic thyroidectomy for benign thyroid nodule.Method:Thirty-one patients with benign thyroid tumors underwent transoral endoscopic thyroidectomy via oral vestibular approach at our hospital between July 2016 and December 2017. Forty five patients were enrolled as control group by conventional approach.Two groups were compared with regards to tumor size,types of operation, operation time, bleeding, volume of drainage, complication and postoperative hospital stay.Result:Pathology examinations proved benign in both groups.Two groups were matched by age, sex, tumor size and types of operation. No statistical significance was found in volume of drainage, postoperative hospital stay and complication. Endoscopic group:no permanent glottic paralysis;one patient had transient hoarseness and recovered after 3 months. In one case,subcutaneous seroma was noted.One patient suffered from cervical subcutaneous emphysema. One patient had a epidermal damage of the ala nasi on the side of the nasal intubation, and recovered after one week. no permanent glottic paralysis;One patient had transient hoarseness and recovered after 3 months. No local infection at the incision site or within the cervical spaces occurred. No mental nerve palsy was observed. Control group: one patients occurred transient hoarseness and recovered after 3 months. No permanent recurrent nerve paralysis occurred; one patient suffered from local infection; one patient had subcutaneous seroma; one cases of postoperative hematoma occurred after 8 hours later. The average blood loss of endoscopic surgery was (20+/-4) ml, and the mean of operation time was (107+/-11) min. The difference was statistically significant between the endoscopic surgery and the conventional surgery.Conclusion:The novel transoral endoscopic thyroidectomy is feasible and safe,and it may be a good choice for patients with beauty needs. PMID- 29986557 TI - [Analysis of risk factors for recurrent sudden sensorineural hearing loss]. AB - Objective:To analyze the factors that may affect the recurrence of sudden sensorineural hearing loss (SSNHL).Method:We retrospectively analyzed the data of 665 SSNHL patients admitted to our hospital from January 2006 to December 2016, among which 12 patients were recurrent. The possible factors that may affect the recurrence of SSNHL were analyzed by Logistic regression analysis.Result: Hyperlipidemia might be one of the factors that caused the recurrence of SSNHL (Odds ratio 54.943,P=0.000). History of radiotherapy might be another factor that caused the recurrence of SSNHL (Odds ratio 64.100,P=0.000).Conclusion:Hyperlipidemia and the history of radiotherapy of head and neck might be risk factors for the recurrence of SSNHL. PMID- 29986558 TI - [Analysis of clinical audiology and etiology in 72 twins aged 0-4 years]. AB - Objective:To investigate the clinical audiological characteristics of twins and analyze the risk factors for hearing loss. Method:The subjects were 72 cases,selected from our hospital otological outpatient of 0 to 4 years old twins. All subjects underwent universal newborn hearing screening and had definite results. At the same time, acoustic immittance,auditory brainstem response, auditory steady-state response, pediatric behavior audiometry and other audiological tests were carried out. Subjects were divided into two groups according to whether with high risk factors for hearing loss: 42 patients(58.33%) in group A(risk factor group) and 30 patients(41.67%) in group B (no risk factor group).The results of universal newborn hearing screening(UNHS),hearing diagnosis, degree of hearing loss, type of hearing curve and risk factors categories of hearing loss were analyzed for both groups of subjects.Result:In 72 cases,41 were males and 31 were females. Thirty-one were the first born and 41 were the second born. Age distribution of first visit:3 to 40 months, median age: 4-6 months.Forty-seven(65.27%) failed in the UNHS. The failing rate was higher in group A(76.19%) than in group B(50.00%).Fifty(69.44%) were diagnosed with hearing loss.78.57% of hearing loss was diagnosed in group A, which was higher than that in group B(56.67%).The degree of hearing loss in group A was mainly profound(43.55%) and group B was moderate(48.00%).The differences above all was statistically significant.For the hearing curve type, group A(35.48%) and group B(40.00%) were both mainly flat-type, the difference was not statistically significant. In 72 cases, there were 42 cases(58.33%) with risk factors for hearing loss, of which 38.1% had two or more kinds of risk factors and 61.9% had one kind of risk factor.Hyperbilirubinemia was the major risk factor(34.92%).Conclusion:69.44% of twins had a confirmed hearing loss. Those with risk factors had higher failing rate of UNHS and more serious hearing loss.58.33% of twins had risk factors for hearing loss, and individuals with two or more kinds of risk factors were much more. Hyperbilirubinemia takes the first place and should be paid enough attention by clinicians. PMID- 29986559 TI - [The anatomic characteristics and surgical treatment of congenital pyriform sinus fistula]. AB - Objective:To discuss the clinical anatomic characteristics of congenital pyriform sinus fistula and summarize the experiences of open neck surgery. Method:The clinical data of 12 patients with congenital pyriform sinus fistula were retrospectively analyzed.Result:During the operation, all lesions were located below of superior laryngeal nerve. All fistulas were closely related with the supperior part of thyroid gland and laterally passed over the left recurrent laryngeal nerve just before merging into the apex of piriform sinus or beginning of aesophagus. Follow-up periods were ranging between 8 to 65 months. Two months after surgery,one patient showed lateral neck abscess again. After open drainage procedures and antibiotics treatment, there was no recurrence signs during 3 years of follow-up.Conclusion:We found that the congenital pyriform sinus fistula was closely related to the superior thyroid gland and recurrent laryngeal nerve,which was different from the popular theory.We had not encountered types descending into mediastinum and thoracic cavity or ascending along common carotid artery sheath. All fistulas passed over the left recurrent laryngeal nerve,and then merged into the apex of pyriform sinus or beginning of aesophagus.The key point for successful resection of fistulas in block was to remove the superior involvement part of the thyroid gland and exposure the recurrent laryngeal nerve. Based on our practical findings, the neck dissection procedure should not be taken in some patients that the anatomical structure is not clear for repeated infections. PMID- 29986560 TI - [Comparison of lymphatic staining methods based on whole organ sections of laryngeal carcinoma]. AB - Objective:To compare the diagnostic potential of HE staining, enzymatic histochemistry and immunohistochemistry in displaying lymphatic vessel of laryngeal carcinoma.Method:We recruited 3 patients who were pathologically diagnozed as laryngeal squamous cell carcinoma and were performed total laryngectomy in the First Affiliated Hospital of Shanxi Medical University from April to December 2016. According to the improved Kawamoto's Film Method, frozen specimens of whole laryngeal squamous cell carcinoma were made. Immunohistochemistry, using lymphatic endothelial cell specific marker D2-40, enzymatic histochemistry (5-nucleotidase) and HE staining were used to stain the frozen sections of laryngeal carcinoma. Then the staining results of lymphatic vessels in the specimens of laryngeal carcinoma were compared by the optical microscope. Result:The background of HE and D2-40 immunohistochemical staining were clear.5-Nase staining had a deeper background and more nonspecific staining. By immunohistochemistry,102(97.1%,102/105)blood vessels were identified, and 3(2.9%) were partly positive. While using 5-Nase,56(53,3%,56/105)blood vessels were identified. In 105 lumen structures that could not be clearly judged,95(90,5%)were positive by D2-40,while by 5-Nase staining,89(84.8%)were positive including a large number of glands.In addition, positive cells scattered in dots or clusters were observed in 5-Nase and D2-40 staining sections, but these cells or structures could not be identified by HE staining. Conclusion:D2 40 immunohistochemistry may have certain applied value in the study of lymphatic vessels associated with laryngeal carcinoma. PMID- 29986561 TI - [The surgical treatments and clinical characteristics of snoring with epiglottis collapse]. AB - Objective:The aim of this study is to summary the characteristics of sleep breath disorder patients with epiglottis collapse and find out the way to treat them with surgery.Method:This is a retrospective study. There were eighteen patients who complained of snoring and somnolence, as well as had undergone DISE. Eight of them were diagnosed as epiglottis collapse. We analysis the clinical features, surgical treatments and prognosis of these eight patents, and compare their BMI, shape of epiglottis and AHI with the patients without epiglottis collapse. Result: Patients with epiglottis collapse usually complained of breathless during sleeping. The shape of their epiglottis was mainly flat and wide, as the cure of the upper margin of their epiglottises shows significant difference with those who are without epiglottis collapse(P=0.03,0.04).DISE is the diagnosis examination. The primary surgical treatment is Epiglottoplasty. Conclusion: It's not uncommon to see epiglottis collapse clinically. Whenever we meet the particular clinical manifestation,the diagnose of epiglottis collapse should be taken into consideration. DISE is the diagnosis examination. Epiglottoplasty can treat them to some degree. PMID- 29986562 TI - [The study of the rational use of antibiotics after nasal surgery]. AB - Objective:To study whether the antibiotics should be used in the patients with or without chronic nasal sinusitis after the nasal surgery,and how to rationally use it.Method:Study design:prospective stratified randomized controlled study.Patients with sinusitis were divided into three groups.A group was without antibiotics,B group was with standard antibiotics using ,and C group was with prolonged antibiotics using.Patients without sinusitis were divided into D group without antibiotics,E group with standard antibiotics using,and F group with prolonged antibiotics using. Observe the postoperative infection rate in each group and compare them.Result:The infection rates were 3.53%,2.67%,0.00% in A,B and C group, and there was no significant differences between three groups. The infection rates were 1.22%,0.00%,1.39% in D,E and F group,and there was no significant differences between them.Conclusion: There was no influence in patients with or without using antibiotics,standard or prolonged using antibiotics after nasal surgery. Recommend not to use antibiotics after nasal surgery,and appropriately use antibioctics within 48 hours.Prolonged using is not recommended. PMID- 29986563 TI - [Clinical application of folded free radial forearm flaps for reconstruction of full-tickness cheek defects after resection of buccal carcinoma]. AB - Objective:To investigate the therapeutic effect of folded free radial forearm flaps (RFF) for reconstruction of full-tickness cheek defects after the resection of buccal carcinoma.Method:Seventeen cases of buccal carcinoma received radical neck dissection with cheekectomy and mandibulectomy, and the folded RFF to reconstruct full-tickness cheek defects simultaneously. Preoperative Allen test, ultrasonic doppler blood flow meter examination or computed tomography angiography confirmed good vascular condition of the forearm. Result: RFF were obtained from all patients, and completely survived. During the follow-up period of 6-36 months, the lateral morphology of the cheek was restored well and the mouth opening is normal. Language and swallowing function recovered well, without salivation or cheek biting. There were no obvious complications in the donor site. One case(T3N1M0)died of pulmonary metastatic carcinoma a year later. Conclusion:The success rate is high and the morphology and function recovered well of the folded RFF for reconstruction of full-tickness cheek defects, so it is a reliable method to reconstruct full-tickness cheek defects after the resection of buccal carcinoma. PMID- 29986564 TI - [Individualized treatment of chronic pharyngitis and its clinical significance]. AB - Objective:Analysis of the etiology of chronic pharyngitis. Study on the individualized therapeutic effect of chronic pharyngitis caused by different causes and its clinical significance.Method:One hundred and sixty-eight cases of chronic pharyngitis in our department from October 2016 to December 2017.It was divided into the experimental group and the control group,2 groups of patients were evaluated by questionnaire.According to clinical manifestations and etiologies,the experimental group was divided into chronic naso pharyngitis,32 cases, pharyngology and reflux related chronic pharyngitis,36 cases,OSAHS related chronic pharyngitis,30 cases, and allergic chronic pharyngitis,30 cases.Individualized treatment in each group,40 cases in control group were given symptomatic treatment. The effect of two groups was compared.Result:There was no significant difference in the total score of the groups before the treatment(P> 0.05).After treatment,the total score of the 2 groups was reduced(P< 0.05).The reduction of the experimental groups were significantly higher than that of the control group(P< 0.05).The total effective rate and effective rate of the experimental groups were significantly higher than that of the control group(P< 0.05).Conclusion:The individualized treatment of chronic pharyngitis is better than the traditional treatment of chronic pharyngitis.It has important guiding significance in clinical treatment. PMID- 29986565 TI - [Short-term outcomes of Li's repositioning maneuver of different age groups patients of horizontal semicircular canal canalithiasis benign paroxysmal positional vertigo]. AB - Objective:To analyse whether there is statistical difference between different age group short-term outcomes of horizontal semicircular canal canalithiasis benign paroxysmal positional vertigo (HC-BPPV) patients treated by Li's repositioning maneuver.Method:Since October 2009 to July 2017, we included 169 unilateral HC-BPPV patients treated by Li's repositioning maneuver. Then we recorded and analyse 3-day and 1-week outcomes.Result:Three-day efficacy rates of youth, middle aged, young elderly and elderly patients were 97.9%,93.9%,90.9% and 90.% (P=0.136), respectively. Rates of 1-week efficacy were 100.0%,98.5%,97.7%and 100.0% (P=0.799),respectively. There was no statistical difference.Conclusion:Treated by Li's repositioning maneuver,HC-BPPV patients of different age groups can both get good short-term outcomes without statistical difference. PMID- 29986566 TI - [Diagnosis and treatment of labyrinthine fistula caused by chronic otitis media]. AB - Objective:To evaluate the clinical features diagnostic experience and the surgical management of labyrinthine fistula in chronic suppurative otitismedia.Method:Twenty-four cases(24 ears)of labyrinthine fistula caused by chronic suppurative otitis media that were treated from 2006 to 2013 were reviewed.The fistula test and temporal bone CT scan were performed before the operation, then compare the positive rates between them.In all of these cases, the lesion tissue of fistula is cleaned. Then the fistula was repair of through fascia sealing by temporal myofascial or mastoid periosteum in type I and II fistula.Semicircular canal occlusion was used in type III fistula.Comparison of the effect of fistula typing on preoperative and postoperative hearing.Result:The fistulae were located at the lateral semicircular canal in 23 ears, at the lateral semicircular canal in 1 ears.Temporal bones was positive in 10 cases(41.66%) while fistula test was positive in 9 cases(37.5%). There was no statistically significant difference between the diagnosis of the labyrinthine fistula(P=0.50).The effect of fistula typing on postoperative auditory changes was not statistically significant (P=0.73).Conclusion:In the preoperative diagnosis of the fistula,the use of fistula test and CT scan simultaneously may increase the accuracy of the diagnostic. However the test results are not reliable when is negative results,intraoperative exploration is the most important method for the diagnosis of labyrinth fistula.Surgery should be based on the type of fistula,size,hearing levels and operation experience. PMID- 29986567 TI - [Study on the characteristics of benign paroxysmal positional vertigo and the influencing factors of short-term residual symptoms after reposition treatment]. AB - Objective:The objective of this article is to study the characteristics of benign paroxysmal positional vertigo (BPPV) and the influencing factors of residual symptoms after otolith repositioning therapy, so as to provide references for clinical diagnosis and treatment.Method:From June to November in 2017,568 patients with BPPV were diagnosed and treated in otolaryngology out-patient clinics. All of these patients were followed up after 1 month, and we summarized the amount of residual symptoms.The age,sex,type of disease, etiological factor and the condition of internal medicine were compared between residual symptom ones and no residual symptom ones. All data were statistically analyzed by SPPS 22.0 software.Result: The age range was 12-92 years, and the average age of onset was (54.89+/-13.06) years. The proportion of men and women was 1.00?2.74, and the number of middle aged and elderly women at the age of 45-65 was the highest, up to 74.4%. The posterior semicircular canal accounted for about 55.6%, the horizontal semicircular canal accounted for about 22.6%, and the two kinds of semicircular canals were involved in about 21.8%. Primary BPPV accounted for about 90.67% and secondary BPPV accounted for about 9.33%. Secondary BPPV patients had more trauma and middle ear surgery. After reposition, there were 98 remnants of dizziness and balance disorder. There was no significant difference of residual symptoms (P>0.05) between the different sex,the cause and the incidence of the disease. Whether more than 65 years old, whether or not accumulative semicircular canals,whether the combination of related internal medical diseases were compared (P<0.05), and the difference was statistically significant.Conclusion:The residual symptoms such as dizziness and balance disorder were easy to occur after otolith reduction in patients with older, multi?semi?conventional tube and associated internal medical diseases. Correct guidance and education should be carried out for the patients, and the training of the vestibule rehabilitation should be instructed. PMID- 29986568 TI - [The curative effect analysis of 164 tinnitus patients with different types of hearing curve]. AB - Objective:To investigate the difference of therapeutic effect of tinnitus patients with different types of hearing curve.Method:Patients with the inclusion and exclusion criteria for the treatment were studied retrospectively.Use the SPSS 20.0 Chinese version of the software to collect data and analysis.The difference was statistically significant when P<0.05.Result:A total of 164 patients were collected, and the most of the hearing curve types was high frequency hearing loss; according to the TEQ scoring and grading method, most tinnitus patients were in the middle severity; The chi-square test showed that there was no significant difference among the patients with different hearing curve types when the first visit,the severity among the groups was evenly distributed. After treatment,there was no significant difference in the effect of last visit and the follow-up between the patients with different hearing curve types.Conclusion:Unlike the sudden deafness, there was no statistically significant difference in the prognosis of tinnitus patients with different types of hearing curve. We can not choose the treatment program or even predict the curative effect according to the hearing curve type. PMID- 29986570 TI - [The bacterial flora and drug sensitivity of chronic tonsillitis in different age groups]. AB - Objective:To investigate the pathogenic bacteria and drug sensitivity tests in patients with chronic tonsillitis.Method:We chose a group of patients who were diagnosed chronic tonsillitis as the research object. According to age, they were divided into the children group, the adolescents group and the adults group. Collect secretions of tonsil in the operation, then summarize and analyze the secretions.Result: The detection rate of gram-negative bacteria in adult group was significantly higher than that of children and adolescents groups.Conclusion: Broad-spectrum antibiotics should be preferred in adult patients. While others should choose the antibiotic that is sensitive to gram positive bacterium first, before the pathogenic bacteria and drug sensitivity tests. The multi-drug resistant bacterium infection can not be neglected. PMID- 29986569 TI - [Treatment of patients with probable benign paroxysmal positional vertigot]. AB - Objective:To study the treatment and outcome of the patients with probable BPPV who lacked typical nystagmus.Method: Nine hundred and twenty-two patients with posterior canal BPPV or lateral canal BPPV were selected from the database of our department. There were 801 patients with typical nystagmus during positional testing and 121 patients lacked of typical nystagmus. Manual reposition (Eply,modified Semount,Barbecue and Li manuve) were used and the follow-up was(3.7+/-2.5)days.Result:In the patients with probable BPPV,there were 44 patients affected by posterior canal and 77 patients had been affected by lateral canal.In the patients with definite BPPV,there were 489 patients affected by posterior canal and 312 by horizontal canal.There was no statistic difference in the result of the treatment (cure,relief and no response) between the probable BPPV and definite BPPV (P>0.05).However,the rate of 'cure' and 'relief' in the probable BPPV was higher than the definite BPPV in lateral canal (P=0.023).Conclusion:A few patients with probable BPPV may develop to definite BPPV or other disease with dizziness.Maneuver of reposition is meaningful for probable BPPV,especially for patients with lateral canal probable BPPV. PMID- 29986571 TI - [Analysis of the clinical diagnosis and treatment of extranodal NK-T cell lymphoma nasal type]. PMID- 29986572 TI - [Small cell carcinoma of external auditory canal:one case report]. AB - The aim of the study was to present a case of small cell carcinoma of external auditory canal and associated facial nerve paralysis. Extrapulmonary small cell carcinoma from the head and neck is rarely described and carries a poor prognosis. To our knowledge, this is the first case report describing small cell carcinoma of the EAC in our nationality. This study includes a case report and review of the literature. PMID- 29986573 TI - [Advances in peripheral vestibular diseases with downbeat nystagmus]. AB - Downbeat nystagmus is not rare and usually considered as a central nervous system disease. However, there are a lot of diseases that present with downbeat nystagmus only or downbeat component in nystagmus, including peripheral and central vestibular diseases and Chiari malformations. This review will briefly summarize the vestibulo ocular reflexes and the mechanisms of the downbeat nystagmus with a peripheral origin, and then common vestibular disease such as the anterior semicircular canal benign paroxysmal positional vertigo,posterior semicircular canal benign paroxysmal positional vertigo, posterior semicircular canal light cupula, Meniere's disease and inferior vestibular neuritis are reviewed. PMID- 29986574 TI - [The research progress of CPEB4 in tumor]. AB - Cytoplasmic polyadenylation element binding protein 4 (Cytoplasmic polyadenylation element binding protein 4, CPEB4) ,a newly discovered member of the cytoplasmic polyadenylation element binding proteins, is a kind of RNA binding proteins with mediator of mRNA cytoplasmic polyadenylation and translation. CPEB4 plays an important role in the proliferation, migration, invasion and interstitial transformation of many tumors. In recent years, studies have shown that CPEB4 has abnormal expression in a variety of human tumors, and the abnormal expression of cancer patients has a significant correlation with the prognosis. Based on the current research progress, the purpose of this article is to further understand the relationship between CPEB4 and malignant tumor and its molecular mechanism of regulating tumorigenesis and to provide a new direction and means for the molecular diagnosis and targeted therapy of malignant tumor. PMID- 29986575 TI - Radiation Therapy Outcome and Clinical Features of Duodenal-Type Follicular Lymphoma. AB - Purpose: Duodenal-type follicular lymphoma (FL) is a rare variant of FL. There is still no consensus on the initial treatment, and clinical features including endoscopic findings are not familiar to most physicians. The objective of this study was to evaluate the outcome of patients who were initially treated with radiation therapy for duodenal-type FL. Materials and Methods: We retrospectively analyzed 20 patients who were consecutively diagnosed with duodenal-type FL between 2008 and 2017. All patients received radiation therapy with curative intent. Results: The median age of the patients was 52 years (range, 26 to 66 years), and females were predominant. Most patients (n = 18, 90%) had stage I disease, and were diagnosed by a regular health examination in an asymptomatic state. The histological grade was 1 in 19 patients (95%), and the endoscopic findings were diffuse nodular (n = 8), whitish granular (n = 8), and mixed pattern (n = 4). Radiation therapy was delivered to 17 patients with 24 Gy in 12 fractions, and to three patients with 30.6-36 Gy in 18 fractions. All patients were evaluated with endoscopy for response to radiation therapy, and complete response was achieved in 19 patients (95%). At the time of analysis, all patients survived without any evidence of late toxicities related with radiation therapy. Conclusion: Taken together, radiation therapy alone could be effective in controlling duodenal lesion. A further study with longer follow-up duration is warranted to confirm our findings. PMID- 29986576 TI - Diabetes Medication Use in Association with Survival among Patients of Breast, Colorectal, Lung, or Gastric Cancer. AB - Purpose: Studies suggest that regular use of metformin may decrease cancer mortality. We investigated the association between diabetes medication use and cancer survival. Materials and Methods: The current study includes 633 breast, 890 colorectal, 824 lung, and 543 gastric cancer cases identified from participants of two population-based cohort studies in Shanghai. Information on diabetes medication use was obtained by linking to electronic medical records. The associations between diabetes medication use (metformin, sulfonylureas, and insulin) and overall and cancer-specific survival were evaluated using time dependent Cox proportional hazards models. Results: After adjustment for clinical characteristics and treatment factors, use of metformin was associated with better overall survival among colorectal cancer patients (hazards ratio [HR], 0.55, 95% confidence interval [CI], 0.34 to 0.88) and for all four types of cancer combined (HR, 0.75; 95% CI, 0.57 to 0.98). Ever use of insulin was associated with worse survival for all cancer types combined (HR, 1.89; 95% CI, 1.57 to 2.29) and for the four cancer types individually. Similar associations were seen for diabetic patients. Sulfonylureas use was associated with worse overall survival for breast or gastric cancer (HR, 2.87; 95% CI, 1.22 to 6.80 and HR, 2.05; 95% CI, 1.09 to 3.84, respectively) among diabetic patients. Similar association patterns were observed between diabetes medication use and cancer specific survival. Conclusion: Metformin was associated with improved survival among colorectal cancer cases, while insulin use was associated with worse survival among patients of four major cancers. Further investigation on the topic is needed given the potential translational impact of these findings. PMID- 29986577 TI - Increased Risk of Osteoporosis in Gastric Cancer Survivors Compared to General Population Control: A Study with Representative Korean Population. AB - Purpose: Although several studies have suggested that osteoporosis is common in survivors of gastric cancer (GC), no study to date has directly assessed the risk for osteoporosis in GC survivors compared to matched controls. Thus, we aimed to investigate the relative risk for osteoporosis in survivors of GC compared to general population. Materials and Methods: We used the Korea National Health and Nutrition Examination Survey data (2008-2011). Patients with a history of GC (n=94) were defined as case among 8,142 individuals over 50 years old who were evaluated by dual-energy X-ray absorptiometry. Controls (n=470) were matched to cases by age and sex in a 1:5 ratio. Osteopenia (-2.5 < T-score < -1.0) and osteoporosis (T-score <= -2.5) were defined. Results: The prevalence of osteoporosis in GC survivors was 30.2%, which was significantly greater than that of controls (19.7%). In total, GC survivors had a 3.7-fold increased risk for osteoporosis compared to controls (p=0.021). In addition, the risk for osteoporosis of the total proximal femur total (TF) and femur neck (FN) was significantly increased among GC survivors compared to controls (adjusted relative risk, 4.64; 95% confidence interval, 1.16 to 18.6 in TF and adjusted relative risk, 3.58; 95% confidence interval, 1.19 to 10.8 in FN). Furthermore, we found sub-optimal daily calcium intake and mean serum levels of 25-hydroxy vitamin D in both groups. Conclusion: GC survivors are at significantly increased risk for osteoporosis, especially in the femur. Clinically, our finding supports the importance of screening bone health and adequate nutrient supplementation in survivors of GC. PMID- 29986578 TI - Zero-Dimensional Carbon Dots Enhance Bone Regeneration, Osteosarcoma Ablation, and Clinical Bacterial Eradication. AB - Zero-dimensional carbon dots (CD) and their effects on osteogenesis have been rarely studied in bone repair scaffolds. Here, we fabricate a novel CD doped chitosan/nanohydroxyapatite (CS/nHA/CD) scaffold with full potential to promote bone regeneration by a facile freeze-drying method. The CS/nHA/CD scaffolds enhanced cell adhesion and osteoinductivity in rat bone mesenchymal stem cells by up-regulating genes involved in focal adhesion and osteogenesis in vitro, which significantly improved the formation of vascularized new bone tissue at 4 weeks compared to pure CS/nHA scaffolds in vivo. Inspired by the excellent photothermal effect of CD, the scaffolds were applied in tumor photothermal therapy (PTT) under near-infrared (NIR) irradiation (808 nm, 1 W/cm2). The scaffolds significantly inhibited osteosarcoma cell proliferation in vitro and effectively suppressed tumor growth in vivo. Moreover, the CS/nHA/CD scaffolds possessed distinct antibacterial properties toward clinically collected S. aureus and E. coli, and their antibacterial activity was further enhanced under NIR irradiation. This work demonstrates that zero-dimensional CD can enhance the osteogenesis-inducing property of bone repair scaffolds and that CD doped scaffolds have potential for use in PTT for tumors and infections. PMID- 29986579 TI - The Inhibitory Effect of Hydroxylated Carbon Nanotubes on the Aggregation of Human Islet Amyloid Polypeptide Revealed by a Combined Computational and Experimental Study. AB - Fibrillar deposits formed by the aggregation of the human islet amyloid polypeptide (hIAPP) are the major pathological hallmark of type 2 diabetes mellitus (T2DM). Inhibiting the aggregation of hIAPP is considered the primary therapeutic strategy for the treatment of T2DM. Hydroxylated carbon nanoparticles have received great attention in impeding amyloid protein fibrillation owing to their reduced cytotoxicity compared to the pristine ones. In this study, we investigated the influence of hydroxylated single-walled carbon nanotubes (SWCNT OHs) on the first step of hIAPP aggregation: dimerization by performing explicit solvent replica exchange molecular dynamics (REMD) simulations. Extensive REMD simulations demonstrate that SWCNT-OHs can dramatically inhibit interpeptide beta sheet formation and completely suppress the previously reported beta-hairpin amyloidogenic precursor of hIAPP. On the basis of our simulation results, we proposed that SWCNT-OH can hinder hIAPP fibrillation. This was further confirmed by our systematic turbidity measurements, thioflavin T fluorescence, circular dichroism (CD), transmission electron microscope (TEM), and atomic force microscopy (AFM) experiments. Detailed analyses of hIAPP-SWCNT-OH interactions reveal that hydrogen bonding, van der Waals, and pi-stacking interactions between hIAPP and SWCNT-OH significantly weaken the inter- and intrapeptide interactions that are crucial for beta-sheet formation. Our collective computational and experimental data reveal not only the inhibitory effect but also the inhibitory mechanism of SWCNT-OH against hIAPP aggregation, thus providing new clues for the development of future drug candidates against T2DM. PMID- 29986580 TI - Multivalent Binding of Precision Glycooligomers on Soft Glycocalyx Mimicking Hydrogels. AB - We present a synthetic approach toward soft, glycooligomer-functionalized microgel particles mimicking carbohydrate presenting cell surfaces and analyze their specific binding to a model lectin (Concanavalin A, ConA). Focusing on multivalent presentation, a series of sequence-controlled glycooligomers with varying spacing and number of mannose units was synthesized and analyzed for the resulting glycooligomer-ConA affinity. Both direct binding and inhibition studies show a higher affinity with increasing the number of sugar moieties, but they level off for higher valent systems, indicating steric hindrance. Furthermore, the results suggest that increasing the scaffold length tends to decrease binding due to entropic repulsion, which could be compensated by larger scaffolds able to address multiple ConA binding sites. These findings were consistent in all assays (adhesion, fluorescence, and ITC) regardless of binding partner immobilization, demonstrating that flexible ligands exert similar binding modes in solution and when attached to polymer networks, which is relevant for designing glyco functionalized materials. PMID- 29986581 TI - Advances in Decarboxylative Oxidative Coupling Reaction. AB - Since carboxylic acid derivatives are commercially available, nontoxic, cheap, and normally stable to air and moisture, carboxylic acid derivatives are ideal reactants for synthetic strategy. In recent years, decarboxylative oxidative coupling reactions, which normally involve direct C-H bond activation, have attracted more and more interest from the synthetic community. Compared with conventional methods, this strategy is more environmentally friendly and step economic. This review mainly focuses on recent advances of the decarboxylative oxidative coupling reaction. PMID- 29986582 TI - Colloidal Binary Supracrystals with Tunable Structural Lattices. AB - Colloidal binary supracrystals (SCs) possessing tunable and ordered assembly of two different types of functional nanoparticles (NPs) represent a unique class of artificial materials for both fundamental study and technological applications, but related study has been limited due to substantial challenges in materials growth. Here we report the controlled growth of colloidal binary SCs consisting of Au and Fe3O4 NPs via an oil-in-water emulsion process. The size, stoichiometry, and lattice structure of the SCs can be broadly tuned by the growth parameters. Furthermore, our growth method is general and applicable to other NP building blocks to achieve various functional binary SCs. These as-grown free-standing binary SCs should therefore enable new test beds for exploring different nanoscale interactions ranging from the formation and stability of nanoscale binary phase to the emerging magneto-plasmonic coupling physics. PMID- 29986583 TI - Stabilization and Characterization of Cytotoxic Abeta40 Oligomers Isolated from an Aggregation Reaction in the Presence of Zinc Ions. AB - Small oligomers formed during the aggregation of certain peptides and proteins are highly cytotoxic in numerous neurodegenerative disorders. Because of their transient nature and conformational heterogeneity, however, the structural and biological features of these oligomers are still poorly understood. Here, we describe a method of generating stable oligomers formed by the Alzheimer's Abeta40 peptide by carrying out an aggregation reaction in the presence of zinc ions. The resulting oligomers are amenable to detailed biophysical and biological characterization, which reveals a homogeneous population with small size, high cross-beta sheet structure content, and extended hydrophobic surface patches. We also show that these oligomers decrease the viability of neuroblastoma cells and impair the motility of C. elegans. The availability of these oligomers offers novel opportunities for studying the mechanisms of Abeta40 toxicity in vitro and in cellular and animal models of Alzheimer's disease. PMID- 29986584 TI - Water Vapor-Assisted "Universal" Nonmatrix-Matched Analytical Method for the in Situ U-Pb Dating of Zircon, Monazite, Titanite, and Xenotime by Laser Ablation Inductively Coupled Plasma Mass Spectrometry. AB - The U-Pb geochronologic analysis of accessory minerals has played an important role in Earth and solar system science in constraining the ages of a wide variety of rocks and minerals. Laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) is one of the most popular techniques for U-Pb geochronologic analysis. Currently, the significant matrix effects observed between different accessory minerals and the lack of high-quality standards for many minerals of interest are the major limitations of its geochronological applications. In this study, we investigated the effects of the addition of oxygen, nitrogen, and water vapor before and after the ablation cell on the accuracy of the U-Pb dating of different minerals (e.g., zircon, monazite, titanite, and xenotime) by LA-ICP-MS. We found that the addition of water vapor, unlike that of oxygen and nitrogen, before the ablation cell can significantly suppress the matrix effects on U-Pb dating. The deviations of the measured 206Pb/238U ratios in these accessory minerals were significantly reduced from 10 to 24% to less than 1-2% when using NIST 610 glass as an external standard. This can be attributed to the suppression of elemental fractionation in both the laser ablation and ICP ionization processes by the presence of water vapor. The developed water vapor-assisted LA-ICPMS U-Pb dating method has been successfully applied to the analysis of zircon, monazite, xenotime, and titanite with NIST 610 glass as a reference material in both the 193 nm excimer laser and 213 nm Nd:YAG laser ablation systems. PMID- 29986585 TI - The Penetration Depth for Hanatoxin Partitioning into the Membrane Hydrocarbon Core Measured with Neutron Reflectivity. AB - Hanatoxin (HaTx) from spider venom works as an inhibitor of Kv2.1 channels, most likely by interacting with the voltage sensor (VS). However, the way in which this water-soluble peptide modifies the gating remains poorly understood as the VS is deeply embedded within the bilayer, although it would change its position depending on the membrane potential. To determine whether HaTx can indeed bind to the VS, the depth at which HaTx penetrates into the POPC membranes was measured with neutron reflectivity. Our results successfully demonstrate that HaTx penetrates into the membrane hydrocarbon core (~9 A from the membrane surface), not lying on the membrane-water interface as reported for another voltage sensor toxin (VSTx). This difference in penetration depth suggests that the two toxins fix the voltage sensors at different positions with respect to the membrane normal, thereby explaining their different inhibitory effects on the channels. In particular, results from MD simulations constrained by our penetration data clearly demonstrate an appropriate orientation for HaTx to interact with the membranes, which is in line with the biochemical information derived from stopped flow analysis through delineation of the toxin-VS binding interface. PMID- 29986586 TI - Zearalenone-Promoted Follicle Growth through Modulation of Wnt-1/beta-Catenin Signaling Pathway and Expression of Estrogen Receptor Genes in Ovaries of Postweaning Piglets. AB - Feedstuffs are severely contaminated by zearalenone (ZEA) worldwide. A specific dietary level of ZEA could cause malformations of the reproductive organs of sows, false estrus, decreased litter size, and abortion. However, the underlying mechanisms are still not clear. The objectives of the present study were to assess the effects of ZEA on morphology, distribution, and expression of estrogen receptors (ERalpha and ERbeta) in the ovaries of postweaning piglets. Furthermore, the relationship between ERs/glycogen synthase kinase (GSK)-3beta dependent pathways mediated by ZEA and the Wnt-1/beta-catenin signaling pathway was examined. Forty healthy weaning piglets were allocated to the following four treatment groups: piglets fed with basal diet only (control), and ZEA0.5, ZEA1.0, and ZEA1.5, which were fed basal diets supplemented with ZEA at 0.5, 1.0, and 1.5 mg.kg-1, respectively. Then, the expression of GSK-3beta, ERalpha, ERbeta, and Wnt-1/beta-catenin were examined histomorphologically and immunohistochemically. Results showed that the proportion of primordial follicles (PrF's) decreased ( p < 0.001) but that of atretic primordial follicles (APFs) increased ( p < 0.001) with increasing dietary ZEA levels. More interestingly, the immunopositivity of ERbeta in the ovaries was stronger than that of ERalpha with the same treatment. The relative mRNA and protein expression levels of ERalpha, ERbeta, Wnt-1, beta catenin, and GSK-3beta in the ovaries of postweaning gilts increased linearly ( p < 0.05) as dietary ZEA concentrations increased. Moreover, the accumulation of Wnt-1 and beta-catenin in the ovaries indicated that ZEA activated the Wnt-1/beta catenin pathway, mediated by ERs/GSK-3beta. Our results strongly suggested that ovarian follicles in the ZEA (0.5-1.5 mg.kg-1)-treated groups were highly proliferative state, indicating that ZEA promoted ovarian development. The results also suggested that ZEA activates the ERs/GSK-3beta-dependent Wnt-1/beta catenin signaling pathway, indicating its important role in accelerating development of the ovaries. PMID- 29986588 TI - Shape-Anisotropic Colloids at Interfaces. AB - Research in the 1980s demonstrated the formation of monolayers of particles achieved by interfacial particle trapping as a model system for investigating colloids in two dimensions. Since then, microscopy visualization of two dimensional particle monolayers and quantification of the microstructure have led to significant fundamental understanding of a number of phenomena such as crystallization, freezing and melting transitions, dislocation dynamics, aggregation kinetics, and others. On the application front, particles at curved interfaces, as often the case in particle-stabilized emulsions and foams, have received considerable attention in the last few decades. The growing interest in the search for novel particles and new strategies to effect emulsion stabilization stems from their application in several disciplines. Moreover, particle-stabilized Pickering emulsions and foams can also be used to derive a number of advanced functional materials. Compared to several accounts of research on spherical colloids at fluid-fluid interfaces, investigations of the behavior of shape-anisotropic particles at interfaces, albeit receiving considerable attention in recent years, are still in a nascent stage. The objective of this feature article is to highlight our recent work in this area. In particular, the adsorption of shape-anisotropic particles to interfaces, wetting behavior, interfacial self-assembly, the response of nonspherical-particle-coated interfaces to compression and shear, and their ability to stabilize emulsions are discussed. PMID- 29986587 TI - Transition Metal-Free Trans Hydroboration of Alkynoic Acid Derivatives: Experimental and Theoretical Studies. AB - We report a phosphine-catalyzed trans hydroboration of alkynoate esters and amides. The reaction proceeds under mild conditions with exclusive ( E) selectivity to afford ( E)-beta-boryl acrylates and ( E)-beta-boryl acrylamides in good to excellent yields. The reaction is tolerant of a variety of functional groups and allows efficient access to novel oxaboroles as well as a pargyline derivative (MAO inhibitor). Theoretical calculations suggest an internal hydride generates a phosphonium allenoxyborane followed by the formation of a key phosphonocyclobutene intermediate that collapses in a stereoselective, rate limiting step. PMID- 29986589 TI - Nanoparticle Induced Conformational Switch Between alpha-Helix and beta-Sheet Attenuates Immunogenic Response of MPT63. AB - Although significant efforts have been devoted to develop nanoparticle-based biopharmaceuticals, it is not understood how protein conformation and nanoparticle surface modulate each other in optimizing the activity and/or toxicity of the biological molecules. This is particularly important for a protein, which can adopt different conformational states separated by a relatively small energy barrier. In this paper, we have studied nanoparticle binding-induced conformational switch from beta-sheet to alpha-helix of MPT63, a small major secreted protein from Mycobacterium tuberculosis and a drug target against Tuberculosis. The binding of magnetite nanoparticles to MPT63 results in a beta-sheet to alpha-helix switch near the sequence stretch between the 19th and 30th amino acids. As a consequence, the immunogenic response of the protein becomes compromised, which could be restored by protein engineering. This study emphasizes that conformational stability toward NP surface binding may require optimization involving genetic engineering for development of a nanoparticle conjugated pharmaceutical. PMID- 29986590 TI - Instability of Emulsions Made with Surfactant-Oil-Water Systems at Optimum Formulation with Ultralow Interfacial Tension. AB - We have studied emulsions made with two- and three-phase oil-water-surfactant systems in which one of the phases is a microemulsion, the other phases being water or/and oil excess phases. Such systems have been extensively studied in the 1970-1980s for applications in enhanced oil recovery. It was found at that time that the emulsions became very unstable in the three-phase systems, but so far few explanations have been proposed. In the most complete one, Kabalnov and colleagues related the emulsion stability to the probability of hole nucleation in the liquid film separating two nearby emulsion drops and associated this probability to the curvature elastic energy of the surfactant layer covering drop surfaces. We propose a different explanation, linked to another type of interfacial elastic energy, associated with compression of the surfactant layers. As found long ago, the three-phase systems are found near optimum formulation (hydrophile lipophile difference, HLD = 0), where the interfacial tension exhibits a deep minimum. The determination of interfacial elastic properties in low interfacial tension systems is not straightforward. In our present work, we used a spinning drop tensiometer with an oscillating rotation velocity. We show that the interfacial compression elastic modulus and viscosity also exhibit a minimum at optimum formulation. We propose that this minimum is related to the acceleration of the surfactant exchanges between the interface, oil and water, near the optimum formulation. Furthermore, we find that the surfactant partitions close to equally between oil and water at the optimum, as in earlier studies. The interfacial tension gradients that slow the thinning of liquid films between drops are reduced by surfactant exchanges between drops and the interface, which are fast whatever the type of drop, oil or water; film thinning is therefore very rapid, and emulsions are almost as unstable as in the absence of surfactant. PMID- 29986591 TI - A Molecular Window into the Brain: Special Issue on Molecules and the Brain. PMID- 29986593 TI - A Few Good Men: It's Not Easy Recruiting Male Hospice Palliative Care Volunteers. AB - Two studies were conducted to explore how to engage male volunteers in hospice palliative care. Four male hospice palliative care volunteers were interviewed in study 1. The men agreed that a direct approach is best when it comes to recruiting male volunteers, especially a personal story or testimonial. Two different volunteer position descriptions were created for study 2: one description was similar to what might appear on a community-based hospice palliative care program's web site or in a newspaper ad looking for visiting hospice palliative care volunteers; the other description was in the form of a personal testimonial ostensibly written by a male hospice palliative care volunteer describing his role through examples of interactions he has had with patients and patients' family members. Twenty-five males responded to each description. Both of the descriptions generated low and nonsignificantly different levels of interest in becoming a hospice palliative care volunteer. Believing this work to be too emotionally demanding and not having enough time for volunteering were the two most commonly given reasons for not wanting to become a hospice palliative care volunteer. Suggestions for future recruitment efforts are discussed. PMID- 29986592 TI - Enrollment Strategies, Barriers to Participation, and Reach of a Workplace Intervention Targeting Sedentary Behavior. AB - PURPOSE: To review enrollment strategies, participation barriers, and program reach of a large, 2-year workplace intervention targeting sedentary behavior. APPROACH: Cross-sectional, retrospective review. SETTING: Twenty-four worksites balanced across academic, industry, and government sectors in Minneapolis/Saint Paul (Minnesota) and Phoenix (Arizona) regions. PARTICIPANTS: Full-time (>=30+ h/wk), sedentary office workers. METHODS: Reach was calculated as the proportion of eligible employees who enrolled in the intervention ([N enrolled/(proportion of eligible employees * N total employees)] * 100). Mean (1 standard deviation) and median worksite sizes were calculated at each enrollment step. Participation barriers and modifications were recorded by the research team. A survey was sent to a subset of nonparticipants (N = 57), and thematic analyses were conducted to examine reasons for nonparticipation, positive impacts, and negative experiences. RESULTS: Employer reach was 65% (56 worksites invited to participate; 66% eligible of 56 responses; 24 enrolled). Employee reach was 58% (1317 invited to participate, 83% eligible of 906 responses; 632 enrolled). Postrandomization, on average, 59% (15%) of the worksites participated. Eighteen modifications were developed to overcome participant-, context-, and research-related participation barriers. CONCLUSION: A high proportion of worksites and employees approached to participate in a sedentary behavior reduction intervention engaged in the study. Interventions that provide flexible enrollment, graded participant engagement options, and adopt a participant-centered approach may facilitate workplace intervention success. PMID- 29986594 TI - Sociodemographic Characteristics and Lengths of Stay Associated With Acute Palliative Care: A 10-Year National Perspective. AB - Patient demographics and characteristics are essential components associated with length of stay in hospice. Race, age, gender, health insurance status, income level, and location of hospice care services are indicators that are associated with differing lengths of stay. Hospice care demand is on the rise, and with 70 million boomers retiring in the next few decades, demand is expected to increase. It is because of demand that exploring the factors that affect a patient's length of stay is essential for understanding beneficiary care and family experience. These insights are key for medical and clinical practitioners in providing hospice patients and their families with the intended benefits and care of the Medicare Hospice Program. This study uses Medicare hospice services data from 2006 to 2014 to examine how race, age, gender, health insurance status, income level, and location before entering acute care are associated with acute care lengths of stay. Overall, this study found that race, age, gender, health insurance status, and income level have a statistically significant association with whether a patient was from home-based or from facility-based hospice. These findings suggest that racial disparities remain a relevant matter in access to hospice, palliative care, and length of stay and can assist future research in moving knowledge forward about the association between length of stay and patient characteristics. PMID- 29986595 TI - Application of Traditional Chinese Medicines as Personalized Therapy in Human Cancers. AB - Although lots of great achievements have been gained in the battle against cancer during the past decades, cancer is still the leading cause of death in the world including in developing countries such as China. Traditional Chinese medicine (TCM) is popular in Chinese and East Asian societies as well as some other Western countries and plays an active role in the modern healthcare system including patients with cancer, which may act as a potential effective strategy in treating human cancers. In this review, we aimed to introduce the mechanisms of TCM compound, as an option of individualized therapy, in treating cancer patients from the perspective of both Chinese and Western medicine. In the view of traditional Chinese medicine theory, individualized treatment for human cancers based on syndrome type benefits the cancer patients with personalized conditions. Balancing Qi, Xue, Yin and Yang, eliminating phlegm and removing dampness is how TCM compound functions on cancer patients. While in the view of Western medicine, inhibiting cancer cell growth and metastasis as well as improving immune status is how herbal compounds act on cancer patients. We also summarized the applications of TCM compound in human cancers, which will shed light on the clinical application of TCM compound on patients with cancer. TCM compound could be used as a complementary and alternative medicine (CAM) in human cancers. It could be applied in cancer patients with cancer-related fatigue (CRF). In addition, it is a good method for alleviating the side effects of both radiotherapy and chemotherapy. Therefore, TCM compound plays a critical role in treating patients with cancer, which has a promising strategy in the field of cancer management. PMID- 29986596 TI - Dendropanax morbifera Prevents Cardiomyocyte Hypertrophy by Inhibiting the Sp1/GATA4 Pathway. AB - An extract of Dendropanax morbifera branch exerts antioxidant, anti-inflammatory, antithrombotic, and anticancer activities. The purpose of this study was to investigate the effect of the extract in isoproterenol-induced cardiac hypertrophy. Phalloidin staining showed that treatment with the extract dramatically prevents isoproterenol-induced H9c2 cell enlargement and the expression of cardiac hypertrophic marker genes, including atrial natriuretic peptide (ANP) and B-type brain natriuretic peptide (BNP). Further, pretreatment with the extract decreased isoproterenol-induced GATA4 and Sp1 expression in H9c2 cells. Overexpression of Sp1 induced the expression of GATA4. The forced expression of Sp1 or its downstream target GATA4, as well as the co-transfection of Sp1 and GATA4 increased the expression of ANP, which was decreased by treatment with the extract. To further elucidate the regulation of the Sp1/GATA4 mediated expression of ANP, knockdown experiments were performed. Transfection with small interfering RNAs (siRNAs) for Sp1 or GATA4 decreased ANP expression. The extract did not further inhibit the expression of ANP reduced by the transfection of GATA4 siRNA. Sp1 knockdown did not affect the expression of ANP that was induced by the overexpression of GATA4; however, GATA4 knockdown abolished the expression of ANP that had been induced by Sp1 overexpression. The extract treatment also attenuated the isoproterenol-induced activation of p38 MAPK, ERK1/2, and JNK1. Hesperidin, catechin, 2,5-dihydroxybenzoic acid, and salicylic acid are the main phenolic compounds present in the extract as observed by high performance liquid chromatography. Hesperidin and 2,5-dihydroxybenzoic acid attenuated isoproterenol-induced cardiac hypertrophy. These findings suggest that the D. morbifera branch extract prevents cardiac hypertrophy by downregulating the activation of Sp1/GATA4 and MAPK signaling pathways. PMID- 29986597 TI - Presessions to the National Diabetes Prevention Program May be a Promising Strategy to Improve Attendance and Weight Loss Outcomes. AB - PURPOSE: The National Diabetes Prevention Program (NDPP) is a widely disseminated lifestyle intervention. Attendance is problematic, leading to suboptimal weight loss, especially among racial/ethnic minority participants. We conducted a novel "presession" protocol to improve engagement of diverse NDPP candidates, comparing NDPP participants who attended a presession to those who did not on attendance and weight loss outcomes. DESIGN: Longitudinal cohort study. SETTING: A safety net health-care system. PARTICIPANTS: A total of 1140 patients with diabetes risks (58.9% Hispanic, 19.8% non-Hispanic black, 61.8% low income). INTERVENTION: The NDPP has been delivered in a Denver, Colorado health-care system since 2013. The program included 22 to 25 sessions over 1 year. Beginning September 2016, individuals were required to attend a presession before enrollment that focused on (1) increasing risk awareness, (2) motivational interviewing to participate in the NDPP, and (3) problem-solving around engagement barriers. MEASURES: Duration and intensity of NDPP attendance and weight loss. ANALYSIS: Outcomes of 75 presession participants who enrolled in the NDPP were compared to 1065 prior participants using analysis of covariance and multivariable logistic regression. RESULTS: Presession participants stayed in the NDPP 99.8 days longer ( P < .001) and attended 14.3% more sessions ( P < .001) on average than those without a presession. Presession participants lost 2.0% more weight ( P < .001) and were 3.5 times more likely to achieve the 5% weight loss target ( P < .001). CONCLUSION: Presessions may improve NDPP outcomes for individuals from diverse backgrounds. A full-scale trial is needed to determine whether presessions reliably improve NDPP effectiveness. PMID- 29986598 TI - Gain of function of sporadic/familial hemiplegic migraine-causing SCN1A mutations: Use of an optimized cDNA. AB - Introduction Familial hemiplegic migraine 3 is an autosomal dominant headache disorder associated with aura and transient hemiparesis, caused by mutations of the neuronal voltage-gated sodium channel Nav1.1. While a gain-of function phenotype is generally assumed to underlie familial hemiplegic migraine, this has not been fully explored. Indeed, a major obstacle in studying in vitro neuronal sodium channels is the difficulty in propagating and mutagenizing expression plasmids containing their cDNAs. The aim of this work was to study the functional effect of two previously uncharacterized hemiplegic migraine causing mutations, Leu1670Trp (L1670W) and Phe1774Ser (F1774S). Methods A novel SCN1A containing plasmid was designed in silico and synthesized, and migraine mutations were inserted in this background. Whole-cell patch clamp was performed to investigate the functional properties of mutant Nav1.1 transiently expressed in Human Embryonic Kidney 293 cells. Results and conclusions We generated an optimized Nav1.1 expression plasmid that was extremely simple to handle and used the novel plasmid to study the functional effects of two migraine mutations. We observed that L1670W, but not F1774S, reduced current density and that both mutations led to a dramatic increase in persistent sodium currents, a depolarizing shift of the steady state-inactivation voltage-dependence, and a faster recovery from inactivation. The results are consistent with a major gain-of function effect underlying familial hemiplegic migraine 3. Our optimization strategy will help to characterize in an efficient manner the effect in vitro of mutations of neuronal voltage-gated sodium channels. PMID- 29986600 TI - Corrigendum. PMID- 29986599 TI - Type II aortopulmonary window with tetralogy of Fallot: successful repair. AB - Aortopulmonary window associated with tetralogy of Fallot is a rare cardiac anomaly. An 8-month-old boy presented with failure to thrive and recurrent chest infections. Echocardiography and imaging studies revealed a type II aortopulmonary window with tetralogy of Fallot. Corrective surgery in the form of patch closure of the aortopulmonary window and intracardiac repair of tetralogy of Fallot was carried out successfully. PMID- 29986601 TI - An Exploration of Barriers Facing Physicians in Diagnosing and Treating Obesity. AB - PURPOSE: To determine whether primary care physicians can accurately assess body mass index (BMI) by visual inspection and to assess barriers related to the diagnosis and management of obesity. DESIGN: Prospective Survey Study. SETTING: Hospitals and Clinics. SUBJECTS: Primary care providers in the fields of Internal Medicine, Family Medicine and Obstetrics/Gynecology. MEASURES: Measures investigated included providers visual assessment of BMI, BMI knowledge, diagnosis and management of obese patients, and perceived barriers to treatment. ANALYSIS: Top and bottom quartiles and total scores were determined for responses regarding the reported management of obesity, reported comfort with care, and reported barriers to care and used as the cut point. Statistical analyses were utilized to examine relations and compare groups. RESULTS: 206 (74%) of the 280 eligible providers completed the survey. The accuracy of visual assessment of BMI was 52%. Physicians were more likely to underestimate BMI than overestimate (36% +/- 4% vs 12% +/- 6%, respectively, P < .001). Although 91% of providers report routinely calculating BMI, only 61% routinely discuss BMI. Providers feel comfortable providing exercise (72%) and dietary counseling (61%). However, fewer are comfortable prescribing medical (16.4%) and surgical options (36%). CONCLUSION: Visual assessment of BMI is not reliable. Primary care physicians in our study population do not consistently discuss obesity with their patients and many report insufficient knowledge with regard to treatment options. Further studies are needed to determine whether these results are valid for other physicians in various practice settings and to mid-level providers. In addition, research is needed that investigate how collaboration with providers outside the medical field could reduce the burden on physicians in treating patients with overweight or obesity. PMID- 29986602 TI - Evaluation of Mental Health First Aid USA Using the Mental Health Beliefs and Literacy Scale. AB - PURPOSE: This study assessed the impact of Mental Health First Aid (MHFA) in the United States with a theoretically based and psychometrically sound measure, the Mental Health Beliefs and Literacy Scale (MBLS). DESIGN: Online MBLS surveys were administered pre-MHFA training, 3-weeks post-training, and 6-months posttraining. SETTING: Mental Health First Aid trainings carried out across the United States. PARTICIPANTS: Six hundred sixty-two trainees were contacted, and 273 (41%) completed the presurvey. Of those, 63% filled out the postsurvey and 35% completed the 6-month survey. Seventy-six individuals completed all 3 surveys. INTERVENTION: Mental Health First Aid is an 8-hour education program to help the general public identify, understand, and respond to signs of mental illness and substance abuse; to date, almost 1 million people have been trained. MEASURE: The MLBS, based on the Unified Theory of Behavior Change framework, consists of attitudinal, social-, and skill-based constructs affecting the intention to perform and achievement of MHFA actions and reports of their actual completion. ANALYSIS: Change across time points was assessed using multivariate repeated measures analysis of variance. RESULTS: Significant short- and longer term changes were found in internally consistent constructs tapping positive beliefs about MHFA actions, the confidence and intention to perform them as well as mental health literacy. CONCLUSION: The MBLS documented strong positive effects of MHFA training that were greater in individuals without prior mental health training, the intended targets of MHFA efforts. PMID- 29986603 TI - Eating-Related and Psychological Outcomes of Health at Every Size Intervention in Health and Social Services Centers Across the Province of Quebec. AB - PURPOSE: To report the outcomes of a Health at Every Size (HAES) intervention in a real-world setting. DESIGN: Quasi-experimental design evaluating eating behaviors and psychological factors. SETTING: The HAES intervention is offered in Health and Social Services Centers in Quebec (Canada). PARTICIPANTS: For this study, 216 women (body mass index [BMI]: 35.76 [6.80] kg/m2) who participated to the HAES intervention were compared to 110 women (BMI: 34.56 [7.30] kg/m2) from a comparison group. INTERVENTION: The HAES intervention is composed of 14 weekly meetings provided by health professionals. It focuses on healthy lifestyle, self acceptance, and intuitive eating. MEASURES: Eating behaviors (ie, flexible restraint, rigid restraint, disinhibition, susceptibility to hunger, intuitive eating, and obsessive-compulsive eating) and psychological correlates (ie, body esteem, self-esteem, and depression) were assessed using validated questionnaires at baseline, postintervention, and 1-year follow-up. ANALYSIS: Group, time, and interaction effects analyzed with mixed models. RESULTS: Significant group by time interactions were found for flexible restraint ( P = .0400), disinhibition ( P < .0001), susceptibility to hunger ( P < .0001), intuitive eating ( P < .0001), obsessive-compulsive eating ( P < .0001), body-esteem ( P < .0001), depression ( P = .0057), and self-esteem ( P < .0001), where women in the HAES group showed greater improvements than women in the comparison group at short and/or long term. CONCLUSION: The evaluation of this HAES intervention in a real-life context showed its effectiveness in improving eating-, weight-, and psychological-related variables among women struggling with weight and body image. PMID- 29986604 TI - Effects of Anti-Inflammatory Agents on Expression of Early Responsive Inflammatory and Catabolic Genes in Ex Vivo Porcine Model of Acute Knee Cartilage Injury. AB - Objective Early intervention therapies targeting inflammation and cell death during the acute phase of cartilage injury have the potential to prevent posttraumatic osteoarthritis. The objective of this study was to investigate the effects of interleukin receptor antagonist protein (IRAP), hyaluronan (HA), dexamethasone (DEX), and mesenchymal stem cell (MSC) treatment on the expression of established genetic markers for matrix degradation, apoptosis, and inflammation in articular cartilage during the acute phase of injury. Design A custom impact device was used to create replicable injury ex vivo to intact porcine knee joint. One hour after impact, IRAP, HA, DEX, or MSCs was intra articularly injected. At 8 hours postinjury, cartilage and meniscus samples were harvested for genetic expression analysis. Expression of miR-27b, miR-140, miR 125b, miR-16, miR-34a, miR-146a, miR-22, ADAMTS-4, ADAMTS-5, MMP-3, IL-1beta, and TNF-alpha was analyzed by real-time polymerase chain reaction. Results At 8 hours postinjury, expression of ADAMTS-4, ADAMTS-5, MMP-3, IL-1beta, and TNF-alpha in cartilage was significantly decreased in IRAP- and DEX-treated joints as compared to nontreated injured joints, whereas only IRAP upregulated expression of miR 140, miR-125b, miR-27b, miR-146a, and miR-22 in cartilage. HA and MSC treatments had no significant effects on catabolic and inflammatory gene expression in cartilage. However, HA treatment significantly upregulated expression of all miRNAs except miR-16. In addition, the treatments tested also exhibited significant influences on meniscus. Conclusions This study provides a valuable starting point for further research into potential targets for and efficacy of various early intervention strategies that may delay or prevent the progression of posttraumatic osteoarthritis after acute cartilage injury. PMID- 29986605 TI - A precise, sensitive and stable LC-MSMS method for detection of picomolar levels of serum aldosterone. AB - BACKGROUND: Accurate quantification of aldosterone is essential in the diagnosis of primary aldosteronism. Liquid chromatography-tandem mass spectrometry (LC MSMS) analysis is increasingly being used to improve analytical sensitivity and specificity, since this technology reduces most of the interferences observed with immunological methods. METHODS: Serum samples with d7-aldosterone as internal standard were extracted with methyl tert-butyl ether, using liquid liquid extraction (LLE). Chromatographic separation was performed on a C18 reverse phase column with a methanol-water gradient containing ammonium fluoride. Aldosterone detection was performed on an Agilent 6490 triple quadrupole using electro spray ionisation in positive mode. RESULTS: Multiple reaction monitoring transitions were m/z 361.2-315.1 for aldosterone, and 368.5-323.3 for d7 aldosterone. Chromatographic retention time was 2.7 min. The method's total CVs at aldosterone concentrations of 45.4 and 1080 pmol/L were 7.0% and 4.8%, respectively. The intra-assay CVs at concentrations of 60.0 and 637 pmol/L were 4.0% and 2.6%, respectively. The method's LOQ and LOD were 10 and 5 pmol/L, respectively, demonstrating an excellent analytical sensitivity. The upper limit of quantification was set to 5000 pmol/L, corresponding to the highest calibrator concentration. The long-term stability of the method was evident from repeated measurements of external control pools from UKNEQAS over a period of about 3 years, showing CVs between 2.0 and 7.0%. CONCLUSIONS: We have described a precise, sensitive and stable LC-MSMS method for the measurement of serum aldosterone. In addition, due to the use of LLE and a short LC-column, the method is simple to perform, with a short chromatographic run time. PMID- 29986607 TI - Effectiveness of psychosocial treatments on symptoms and functional domains in schizophrenia spectrum disorders: a prospective study in a real-world setting. AB - PURPOSE: Data of investigations suggested that psychosocial interventions are required to provide a more complete and effective treatment of schizophrenia spectrum disorders. In particular, art therapy was found an effective psychosocial intervention in SSD. Moreover, some authors reported that Befriending was as effective as cognitive behavior therapy in the treatment of schizophrenic patients. The aim of this study is to test Befriending in comparison with Group Art Therapy in patients with SSD, in order to identify differences of effects between treatments. MATERIALS AND METHODS: All subjects were evaluated at baseline and after six months with the Clinical Global Impression-Severity Scale; the 18-item Italian version of the Brief Psychiatric Rating Scale; the Coping Inventory for Stressful Situations; the Rosenberg Self Esteem Scale; the Global Assessment of Functioning scale; and the Personal and Social Performance scale. Statistical analysis was performed with chi-square tests for categorical variables and analyses of variance for continuous variables to compare the two groups at baseline. A two-way analysis of variance for repeated measures was performed for clinical and psychosocial variables. RESULTS: A significant improvement over trial duration (within-group effect) was observed for both treatments in psychosocial functioning, self-esteem, and thought disturbance. Befriending was found superior to Art therapy (between-group effect) in improving psychosocial functioning. Both interventions were found efficacious in improving emotion-oriented coping strategies (within group effect), with a significant difference (between group effect) favoring Befriending. CONCLUSIONS: Both interventions, in spite of some differences of efficacy, can be considered an important contribution to improve the patients' real-world functioning. Implications for rehabilitation Our study confirmed the need to include a set of psychosocial interventions for patients with schizophrenia spectrum disorders among usual treatment modalities. Techniques such as Befriending and Art therapy can be considered an important contribution to the treatment instruments required by the new community model for mental health. Befriending was found superior to Art therapy (between group effect) in improving psychosocial functioning. Both interventions were found efficacious in improving emotion-oriented coping strategies (within group effect), with a significant difference (between group effect) favoring Befriending. PMID- 29986606 TI - Therapeutic Effect of Camel Milk and Its Exosomes on MCF7 Cells In Vitro and In Vivo. AB - BACKGROUND/OBJECTIVES: In the Middle East, people consume camel milk regularly as it is believed to improve immunity against diseases and decrease the risk for cancer. Recently, it was noted that most of the beneficial effects of milk come from their nanoparticles, especially exosomes. Herein, we evaluated the anticancer potential of camel milk and its exosomes on MCF7 breast cancer cells (in vitro and in vivo) and investigated the possible underlying molecular mechanism of action. METHODS/RESULTS: Administration of camel milk (orally) and its exosomes (orally and by local injection) decreased breast tumor progression as evident by ( a) higher apoptosis (indicated by higher DNA fragmentation, caspase-3 activity, Bax gene expression, and lower Bcl2 gene expression), ( b) remarkable inhibition of oxidative stress (decrease in MDA levels and iNOS gene expression); ( c) induction of antioxidant status (increased activities of SOD, CAT, and GPX), ( d) notable reduction in expression of inflammation-( IL1b, NFkappaB), angiogenesis-( VEGF) and metastasis-( MMP9, ICAM1) related genes; and ( e) higher immune response (high number of CD+4, CD+8, NK1.1 T cells in spleen). CONCLUSIONS: Overall, administration of camel milk-derived exosomes showed better anticancer effect, but less immune response, than treatment by camel milk. Moreover, local injection of exosomes led to better improvement than oral administration. These findings suggest that camel milk and its exosomes have anticancer effect possibly through induction of apoptosis and inhibition of oxidative stress, inflammation, angiogenesis and metastasis in the tumor microenvironment. Thus, camel milk and its exosomes could be used as an anticancer agent for cancer treatment. PMID- 29986608 TI - Self-Care Behavior Profiles With Arteriovenous Fistula in Hemodialysis Patients. AB - Patients with end-stage renal disease should be educated and trained to take care of their own arteriovenous fistula (AVF) with the purpose of developing self-care behaviors concerning vascular access. This was a prospective and observational study. We designed this research to identify clinically meaningful self-care behavior profiles in hemodialysis (HD) patients, and it was carried out in a private dialysis unit in the Lisbon region, Portugal, involving 101 patients. The proportion of male patients was 66.3%, the mean age was 60.9 years, and the frequency of self-care behaviors was 71%. Cluster analysis based on the subscale scores grouped patients in two clusters named "moderate self-care" and "high self care." Those profiles exhibit significant differences concerning gender, education, employment, dialysis vintage, AVF duration, and information on care with the AVF. Identification of self-care-behavior profiles in HD patients with AVF enables one to adjust education programs to the patients' characteristics. PMID- 29986609 TI - The putative lithium-mimetic ebselen reduces impulsivity in rodent models. AB - BACKGROUND: Deficits in impulse control feature in many psychiatric conditions including bipolar disorder, suicidality and addictions. Lithium lowers impulsivity in clinical populations and decreases pathological gambling in experimental medicine studies, but suffers from adverse effects, poor compliance and a low therapeutic index. AIMS: Recently we identified that the neuroprotective agent ebselen, which is reportedly safe in humans, inhibited inositol monophosphatase (IMPase), a candidate lithium mechanism. Ebselen also reduced 5-HT receptor (5-HT2A) function which predicts impulsivity lowering properties. Here we investigated the effect of ebselen in rat models of impulsive behaviour. METHODS: Ebselen was tested in two models of impulsivity with human analogues: the five-choice serial reaction time task (5-CSRTT) and rodent gambling task (rGT). The main outcome measures were premature responses (5-CSRTT and rGT) and choice behaviour (rGT), which model motor impulsivity and choice impulsivity, respectively. RESULTS: At doses that decreased 5-HT2A receptor function (DOI-induced wet dog shakes), ebselen decreased premature responding in the 5-CSRTT both in the absence and presence of cocaine. The 5-HT2A receptor antagonist MDL 100,907 also reduced premature responding in the 5-CSRTT although not in the presence of cocaine. In the rGT ebselen showed a tendency to reduce premature responding but had no effect on choice behaviour. CONCLUSIONS: These findings suggest that ebselen preferentially reduces motor impulsivity over choice impulsivity, and that inhibition of 5-HT2A receptor function is a contributing mechanism. Collectively, these data support the repurposing of ebselen as an anti-impulsive treatment and fast-tracking to clinical trials in patient groups characterised by poor impulse control. PMID- 29986610 TI - Drug-Coated Balloon Angioplasty in Atherosclerosis Patients With Popliteal Artery Involvement. AB - PURPOSE: To investigate outcomes of drug-coated balloon (DCB) angioplasty in endovascular interventions including or restricted to the popliteal artery. METHODS: A retrospective analysis was conducted of 266 patients [median age 72 years, interquartile range (IQR) 62, 78; 166 men] treated with DCB angioplasty in 281 de novo lesions including the popliteal artery between December 2011 and January 2015 at a single center. The median lesion length was 270 mm (IQR 150, 373). The study outcomes were primary patency and predictors of restenosis [reported as the hazard ratio (HR) with 95% confidence interval (CI)]. RESULTS: The primary patency was 77.4% at a median 12.2 months (IQR 5.7, 18.8). Independent variables associated with restenosis included baseline Rutherford category (HR 1.36, 95% CI 1.05 to 1.77, p=0.02), reference vessel diameter (HR 0.77, 95% CI 0.63 to 0.95, p=0.02), dissection (HR 1.69, 95% CI 1.022.79, p=0.04), and standard nitinol stent use (HR 2.08, 95% CI 1.14 to 3.79, p=0.02). CONCLUSION: Outcomes after DCB angioplasty in lesions including the popliteal artery were acceptable compared with previous studies. Further investigation with long-term follow-up is needed to confirm these results. PMID- 29986611 TI - A randomized, double-blind, placebo-controlled study of once weekly elcatonin in primary postmenopausal osteoporosis. AB - OBJECTIVE: Very few reports have described changes in bone mineral density (BMD) with long-term, once weekly administration of elcatonin, and its effects in reducing incident fractures remain unverified. Therefore, the efficacy and safety of once weekly elcatonin were examined over a 3 year period. METHODS: This was a multicenter, double-blinded, randomized, placebo-controlled study. Postmenopausal women with primary osteoporosis received either 20 units of elcatonin (EL group, n = 433) or placebo (P group, n = 436) once a week for 144 weeks (3 years) intramuscularly. The primary endpoint was the incidence of new vertebral fractures at 24, 48, 72, 96, 120, and 144 weeks after the start. Secondary endpoints were the incidence of non-vertebral fractures, changes in lumbar, hip total and femoral neck BMD, and the incidence of adverse drug reactions (ADRs). RESULTS: No significant reduction in the incidence of new vertebral fractures was found in the EL group. The percentage increase in lumbar BMD was significantly higher in the EL group from 24 weeks to the last administration. Although the EL group showed tendencies toward smaller decreased hip total and femoral neck BMD, no significant differences were observed between groups. The incidence of ADRs was significantly greater in the EL group, although these have all been previously reported and no new safety concerns were identified. CONCLUSIONS: Once weekly injection of 20 units of elcatonin significantly increased lumbar BMD over a 3 year period and did not cause any safety problems, but no significant reduction in the incidence of vertebral or non-vertebral fractures was demonstrated. PMID- 29986612 TI - Nimbandiolactone-21 and nimbandioloxyfuran, two new 28-norlimonoids from the leaves of Azadirachta indica (Meliaceae). AB - From an EtOAc-soluble fraction of the leaves of Azadirachta indica, two new 28 norlimonoids named nimbandiolactone-21 (1) and nimbandioloxyfuran (2), together with nimbandiolactone-23 (3), were isolated. Their relative structures were elucidated based on NMR spectroscopic interpretation and biosynthetic consideration. Nimbandioloxyfuran (2) and nimbandiolactone-23 (3) showed potent alpha-glucosidase inhibitory activity, with the IC50 values of 46.2 and 38.7 MUM, respectively. PMID- 29986614 TI - Co-occurrence of Health Risk Behaviors Among Brazilian Adolescent Victims of Family Violence. AB - Although recent studies have related the occurrence of violence in childhood and adolescence with the adoption of health risk behaviors, there are no studies that quantify this co-occurrence among adolescent victims of family violence. Our objective was, therefore, to investigate the co-occurrence of health risk behaviors in these adolescent victims. Data from the National School Health Survey, collected in 2015, were used. Co-occurrence of risk behaviors-involvement in fights, substance use (alcohol, drugs, and tobacco), not wearing seat belts and helmets, inadequate food consumption-was analyzed using Venn diagrams, according to the victim's status and sex. The association between the four risk behaviors and victimization was investigated using multiple logistic regression. All the analyses were performed using Stata(r)13. We found an excess of risk behaviors among victims of family violence in both sexes. The co-occurrence of the four risk behaviors analyzed was higher among male and female adolescents, who were victims of family violence than in nonvictims. Family violence was associated with the adoption of risk behaviors, regardless of sex. This association was stronger as the number of risk behaviors adopted increased. The chance of engaging in one risk behavior was 1.32 (95% confidence interval (CI) = [0.88, 1.98]) and 1.24 (95% CI = [0.90, 1.72]) higher for boys and girls, respectively, who had suffered family violence. This increased to 7.76 (95% CI = [5.33, 11.29]) and 7.28 (95% CI = [5.20, 10.20]) when considering engagement in four risk behaviors. Identifying the prevalence of co-occurrence of health risk behaviors in vulnerable subgroups (such as victims of domestic violence) could help target broader interventions focusing on multiple risk behaviors. PMID- 29986613 TI - Continuous oxytocin versus intermittent oxytocin for induction of labor: a randomized study. AB - OBJECTIVE: To assess whether intermittent usage of oxytocin infusion increases the duration of the active phase of labor and reduces maternal and neonatal complications or not. MATERIALS AND METHODS: A prospective randomized controlled study was conducted of 200 consenting women with singleton pregnancy in the vertex position undergoing labor induction or augmentation at the Zeynep Kamil Maternity and Children's Training and Research Hospital. Participants with cervical dilation of 3 cm were randomized to either continued or intermittent oxytocin infusion when cervical dilation reached 5 cm. The primary outcome measures were the duration of the active phase of labor, defined as the period of labor from 5 cm of cervical dilation to vaginal delivery. Secondary outcomes were the duration of oxytocin infusion, mode of delivery, hyperstimulation, abnormalities in fetal heart rate, perineal tears, and neonatal outcomes. RESULTS: The median duration of the active phase for the women with a vaginal delivery was longer in the intermittent oxytocin group than the continued oxytocin group, but it was not statistically significant (median, 6.91 vs. 7.58 h, p = .37). There was a significant difference in the duration of oxytocin infusion (median, 12.38 h in the intermittent group vs. 15.79 h in the continued group, p = .005). The incidence of uterine hyperstimulation was significantly greater in the continued group (21.1%) than the intermittent oxytocin group (3.8%) (p=.001). CONCLUSIONS: Intermittent usage of oxytocin infusion seems to make labor less complicated without lengthening duration of labor. PMID- 29986615 TI - A Call for Research on Sex Offender Treatment Programs. AB - The effects of sex offender treatment programs have been addressed in the literature, but there are opportunities to expand research and potentially improve existing sex offender treatment programs. The Federal Bureau of Prison's Sex Offender Treatment Program gives offenders the opportunity to change their behavior by reducing criminality and recidivism, and receive transition services as offenders exit the prison system and reenter society. This program is evidence based and utilizes landmark research in sex offender treatment, however there are a few details that may present limitations to the effectiveness of the treatment program within the Federal Bureau of Prisons. Entry requirements, such as literacy, cognitive, and remaining sentence requirements, as well as the treatment program environment, present opportunities for research to evaluate the effects of these variables on the convicted sex offender population. PMID- 29986616 TI - Translation, cross-cultural adaptation, reliability, and validity of the Identification of Functional Ankle Instability questionnaire in Persian speaking participants with a history of ankle sprain. AB - PURPOSE: To cross-culturally translate the Identification of Functional Ankle Instability (IdFAI) questionnaire into Persian and to assess its psychometric properties and factor structure. METHODS: The Persian version of IdFAI questionnaire was prepared after a forward-backward translation and cultural adaptation process. One hundred and twenty patients with a history of lateral ankle sprain completed the Persian version of this questionnaire and the Cumberland Ankle Instability Tool (CAIT), Foot and Ankle Ability Measure, Foot and Ankle Outcome Score, Fear Avoidance Belief questionnaire and the Tampa Scale of Kinesiophobia in the first test session. Afterwards, 60 randomly selected patients completed the questionnaires in the second session. Psychometric testing which included test-retest reliability, internal consistency, standard error of measurement (SEM) and minimal metric detectable change (MMDC), weighted kappa coefficient and construct validity were performed using Spearman's correlation coefficient and confirmatory factor analysis of the three-factor structure of the IdFAI. RESULTS: The interclass correlation coefficient, Cronbach's alpha, SEM and MMDC were 0.91, 0.95, 2.43, and 6.73 (95% confidence interval, 0.86-0.95) for the IdFAI, respectively. The repeatability of all the questions after one week was rated good to excellent (kappa = 0.60-0.93, p < 0.001). The IdFAI total score had strong correlation with CAIT measure, but had moderate correlation with other questionnaires. The results of factor analysis showed an adequate fit of the model to the data and goodness-of-various fit indices. CONCLUSIONS: The Persian version of IdFAI is a reliable and valid tool to identify patients with functional ankle instability which have a history of ankle sprain. Its original three-factor structure was replicated in this study. Implications for Rehabilitation The Persian version of the Identification of Functional Ankle Instability (IdFAI) questionnaire is a reliable and valid instrument in order to identify Iranian patients with functional ankle instability in both clinical practice and research. The Persian IdFAI questionnaire may be considered as a standardized clinical instrument that can be used to classify degree of ankle instability in Iranian Persian-speaking people with a history of lateral ankle sprain. People with a history of ankle sprain can be assessed using IdFAI questionnaire before and after rehabilitative interventions in an attempt to determine any change in their degree of ankle instability over time. PMID- 29986617 TI - Heart Failure Patients' Perceptions of Received and Wanted Information: A Cross Sectional Study. AB - This study aimed to investigate heart failure patients' perceptions of received and wanted information and to identify differences regarding received and wanted information in relation to sociodemographic variables. A cross-sectional descriptive design was used. Patients with heart failure ( n = 192) were recruited from six primary health care centers in Sweden. Data were collected by a postal questionnaire. A majority of the respondents had received information about the condition and the medication. Within primary health care, most respondents had been informed about medication. The respondents wanted more information about continued care and treatment, medication, and the condition. There were significant differences between sociodemographic groups concerning what information they wanted. Clinical nurses can support patients with heart failure by using evidence-based methods that strengthen the patients' self efficacy and by individualized information that increases patients' knowledge and improves their self-care behaviors. Future studies are needed to identify informational needs of particular fragile groups of patients. PMID- 29986618 TI - Disease Progression in a Patient With Indolent T-Cell Lymphoproliferative Disease of the Gastrointestinal Tract. AB - Indolent T-cell lymphoproliferative disorder (T-LPD) of the gastrointestinal (GI) tract is a new provisional entity in the 2016 revision of the World Health Organization classification. The disease has an indolent course and progression to aggressive T-cell lymphoma has rarely been reported. We describe a case of a 37-year-old male with indolent T-LPD of the GI tract who 3 years later developed aggressive T-cell lymphoma and died of progressive disease. An infiltrate of indolent T-LPD in the GI tract and aggressive lymphoma diagnosed from the liver biopsy had similar immunophenotype, but cellular infiltrate in the liver showed more atypia compared with the GI biopsies of indolent T-LPD. Moreover, T-cell gene rearrangement studies showed an identical clonal rearrangement in indolent T LPD and aggressive lymphoma. Patients with indolent T-LPD of the GI tract need a long-term follow-up, as some of them may develop more aggressive lymphoma. PMID- 29986619 TI - Fluid Management in Sepsis. AB - Among critically ill adults, sepsis remains both common and lethal. In addition to antibiotics and source control, fluid resuscitation is a fundamental sepsis therapy. The physiology of fluid resuscitation for sepsis, however, is complex. A landmark trial found early goal-directed sepsis resuscitation reduced mortality, but 3 recent multicenter trials did not confirm this benefit. Multiple trials in resource-limited settings have found increased mortality with early fluid bolus administration in sepsis, and the optimal approach to early sepsis resuscitation across settings remains unknown. After initial resuscitation, excessive fluid administration may contribute to edema and organ dysfunction. Using dynamic variables such as passive leg raise testing can predict a patient's hemodynamic response to fluid administration better than static variables such as central venous pressure. Whether using measures of "fluid responsiveness" to guide fluid administration improves patient outcomes, however, remains unknown. New evidence suggests improved patient outcomes with the use of balanced crystalloids compared to saline in sepsis. Albumin may be beneficial in septic shock, but other colloids such as starches, dextrans, and gelatins appear to increase the risk of death and acute kidney injury. For the clinician caring for patients with sepsis today, the initial administration of 20 mL/kg of intravenous balanced crystalloid, followed by consideration of the risks and benefits of subsequent fluid administration represents a reasonable approach. Additional research is urgently needed to define the optimal dose, rate, and composition of intravenous fluid during the management of patients with sepsis and septic shock. PMID- 29986620 TI - Effects of antenatal indomethacin on ductus arteriosus early closure and on adverse outcomes in preterm neonates. AB - INTRODUCTION: Premature birth is a leading cause of neonatal morbidity and mortality. Since gestational age at birth is the most important predictive factor of adverse neonatal outcomes, strategies to postpone premature labor are of major importance. Studies on tocolytic drugs show that COX inhibitors such as indomethacin are superior to others in terms of efficiency in delaying birth, but results concerning neonatal outcomes associated with prenatal exposure to these drugs show controversial results. Indomethacin is also used in the postnatal age for pharmacologic treatment of patent ductus arteriosus (PDA), but no data concerning the effects of antenatal exposure on postnatal ductal patency are available. METHODS: In this study, we focused primarily on the association between antenatal indomethacin (AI) and postnatal patency of ductus arteriosus while our secondary aim was to highlight any possible influence of AI exposure on adverse neonatal outcomes. We performed a retrospective analysis of 241 medical records of newborns born before 33 weeks' gestation and exposed to antenatal tocolysis. Obstetrical data and neonatal outcomes of newborns exposed to AI were compared to those of neonates exposed to other tocolytic drugs. Early ductal closure (EDC) was defined when functional echocardiography performed within 24 hours of life showed a closed duct. Occurrence of intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), respiratory distress syndrome (RDS), chronic lung disease (CLD), necrotizing enterocolitis (NEC), sepsis, and PDA were compared between the groups and the diagnosis of at least one of III-IV grade IVH, PVL, CLD, sepsis, surgical NEC, or death was defined as a severe outcome. RESULTS: The univariate analysis showed that infants in the AI group were at a higher risk of IVH, CLD, RDS, sepsis, and PDA. The incidence of severe outcomes also appeared to be higher in this group, while no effect of AI on PDA was observed. Since we noticed that infants exposed to AI had a lower gestational age and worse clinical conditions at birth when compared to the controls, we considered this as a confounding factor. To overcome this bias, we performed a multivariate analysis that evidenced no significant role of AI on the occurrence of severe outcomes. On the other hand, a possible association was confirmed for all degrees of IVH (OR: 3.16, 95% CI : [1.41; 7.05]) and sepsis (OR: 2.81, 95% CI: [1.24; 6,28]). CONCLUSIONS: The unexpected result shown by the multivariate analysis was the association between AI exposure and EDC (OR: 2.52, 95% CI: [1.02; 6.21]). This result, which has never been evidenced in previous studies, has great clinical importance. It is well known that PDA is more frequent at lower gestational ages, thus reducing the incidence of PDA could lead to an improvement of overall outcomes in extremely preterm newborns. PMID- 29986621 TI - An Empirical Examination of Nursing Units in China Based on Nurse Experience. AB - OBJECTIVES: To create opportunities to increase nursing staff's satisfaction and operational efficiency and eventually improve nurses' experiences through better design in unit layout. BACKGROUND: The majority of research performed on nursing units in China only focused on the spatial design itself, and few studies examined the nursing unit empirically based on nurses' experience. Nursing units need to be designed with understanding nurses' behavior and experience in China. METHOD: A mixed-method approach was conducted in four double-corridor nursing units in China. Observation and interview data were collected to explore how physical environments for managing administrative duties, medications, and caring patient were used in nursing units. RESULTS: The most frequent activities were communication, medication, and patient-care activities. The places in which nurses spent the most of theirs working times were the nurse station (NS), patient room, workstation on wheels (WoW), and medication room. The important clinical work spaces were the patient room, NS, WoW, medication room, doctor's office, disposal room, examining room, and back corridor. The important traffic linkages were between NS and medication room, patient room and WoW, and medication room and patient room. CONCLUSIONS: This article revealed the frequency of nurse activities; how they spent their time; how they use the clinical spaces; identified important clinical spaces, linkages, and driver of inefficiency in nursing work and nursing unit design; and finally generated recommendations for double-corridor nursing unit design in China which can be used by medical planner, hospital administrator. PMID- 29986622 TI - Endoscopic vs Microscopic Overlay Tympanoplasty for Correcting Large Tympanic Membrane Perforations: A Randomized Clinical Trial. AB - OBJECTIVE: Although overlay grafting for complicated tympanic perforations offers a high success rate, potential complications may outweigh its advantages. This study aimed to assess endoscopic overlay tympanoplasty (EOT), compared with microscopic overlay tympanoplasty (MOT), to optimize outcomes while minimizing complications associated with large tympanic perforations. STUDY DESIGN: Nonmasked, randomized. SETTING: Tertiary care university hospital. SUBJECTS AND METHODS: Altogether, 70 patients with large tympanic perforations were randomized to undergo overlay tympanoplasty between June 2014 and July 2016. Primary outcome was the visual analog scale (VAS) of pain. Secondary outcomes were anatomic closure, hearing results, middle ear findings, and postoperative complications. RESULTS: Overall, 34 EOT patients and 30 MOT patients completed the follow-up. VAS scores at 4, 24, and 48 hours in EOT and MOT groups were, respectively, 3 and 8, 1.7 and 6.0, and 0.6 and 4.1. Postoperative pain was less in the EOT group ( P < .001), and canalplasty was not required ( P = .003). Graft "take" rates for EOT and MOT were 97.1% and 93.3%, respectively ( P = .60). Postoperative air-bone gap was lower with EOT (5.0 vs 10.3 dB) ( P = .01). Various middle ear structures were more visible after EOT than after MOT ( P < .001). Ear protrusion ( P = .008) and postauricular numbness ( P < .001) occurred after 50 MOTs. CONCLUSION: EOT for repairing large tympanic perforations provides more favorable anatomical and audiometric outcomes. It also offers superior visibility of middle ear structures without lifting the annulus, with fewer complications and less invasiveness than MOT. PMID- 29986623 TI - Facilitating Interviews in Qualitative Research With Visual Tools: A Typology. AB - Visual methods are gaining traction in qualitative research to support data generation, data analysis, and research dissemination. In this article, I propose a preliminary typology that categorizes five identified purposes of applying visual methods in qualitative interviews: to (a) enable communication, (b) represent the data, (c) enhance data quality and validity, (d) facilitate the relationship, and (e) effect change. Examples of visual tools are presented to demonstrate their utility in addressing these five aims. An existing ethical framework for visual tool use in qualitative research is then presented to structure a discussion on ethical considerations related to confidentiality, consent, representations and audiences, fuzzy boundaries between researchers and participants, authorship and ownership, and minimizing harm. Future directions include testing and extending the typology with respect to other visual methods and qualitative research processes, and research to evaluate the effectiveness of various visual tools at achieving the aims represented in the typology. PMID- 29986624 TI - CD105+ Porcine Endometrial Stromal Mesenchymal Stem Cells Possess Differentiation Potential Toward Cardiomyocyte-Like Cells and Insulin-Producing beta Cell-Like Cells In Vitro. AB - Porcine mesenchymal stem cells (MSCs) are similar to human MSCs, hence considered a valuable model for assessing potential for cell therapy. Porcine adipose derived MSCs (AD-MSCs) and endometrial stromal MSCs (EMSCs) displayed fibroblast like morphology and were positive for MSC markers CD73, CD90, and CD105 and negative for hematopoietic markers CD34 and CD45. The EMSCs had similar or slightly higher growth rate compared to AD-MSCs, and similar percentage of cells of both EMSCs and AD-MSCs were at G0/G1 and G2/M phases; however, EMSCs had significantly ( P < .05) higher percentage of cells at S phase of cell cycle than AD-MSCs. Transdifferentiation ability to cardiomyocyte-like cells was confirmed in differentiated cells by the expression of lineage-specific marker genes such as DES, ACTA2, cTnT, and ACTC1 by real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, cardiomyocyte-specific protein markers cTnT and ACTC1 were expressed in completely differentiated cells. Endodermal differentiation capacity of EMSCs to pancreatic beta cell-like cells was evident with the changes in morphology and the expression of beta-cell-specific marker genes such as PDX1, GLUT2, SST, NKX6.1, PAX4, and NGN3 as analyzed by RT-qPCR. The differentiated cells secreted insulin and C-peptide upon glucose challenge and also they expressed insulin, PDX1, PAX4, NGN3, and GLUT2 at protein level as assessed by immunostaining confirming the successful differentiation to beta cell like cells. Porcine EMSCs possess all the characteristics of MSCs and are suitable model for studying molecular mechanisms of cellular differentiation. PMID- 29986625 TI - Retraction notice. AB - At the request of the Editors, SAGE Publishing and the Authors, the following article has been retracted. Cost-utility analysis of trastuzumab combined with Docetaxel for patients with HER-2 positive metastatic breast cancer - real world claim data, Henry WC Leung, Agnes LF Chan, Shyh-Yau Wang, Journal of Oncology Pharmacy Practice, first published online January 31st 2018 DOI: 10.1177/1078155218755548 The authors notified the Editor and SAGE that some of the data included in this paper is incorrect and therefore results may be unreliable. For this reason, the article has been retracted. The authors of this paper are currently reviewing their data and the journal welcomes the authors to submit a new paper with revised, corrected data for consideration. PMID- 29986626 TI - Negativity bias in false memory: moderation by neuroticism after a delay. AB - The negativity bias is the tendency for individuals to give greater weight, and often exhibit more rapid and extreme responses, to negative than positive information. Using the Deese-Roediger-McDermott illusory memory paradigm, the current study sought to examine how the negativity bias might affect both correct recognition for negative and positive words and false recognition for associated critical lures, as well as how trait neuroticism might moderate these effects. In two experiments, participants studied lists of words composed of semantic associates of an unpresented word (the critical lure). Half of the lists were comprised of positive words and half were comprised of negative words. As expected, individuals remembered negative list words better than positive list words, consistent with a negativity bias in correct recognition. When tested immediately (Experiment 1), individuals also exhibited greater false memory for negative versus positive critical lures. When tested after a 24-hr delay (Experiment 2), individuals higher in neuroticism maintained greater false memory for negative versus positive critical lures, but those lower in neuroticism showed no difference in false memory between negative and positive critical lures. Possible mechanisms and implications for mental health disorders are discussed. PMID- 29986627 TI - School Safety. PMID- 29986628 TI - Tribute to Janice Denehy, PhD, RN, FNASN. PMID- 29986629 TI - Epidemiology and Management of Pediatric Epistaxis. AB - Objectives The purpose of this study is to describe the demographics of children undergoing inpatient management of epistaxis and recognize the clinical circumstances that may necessitate embolization or ligation for epistaxis management. Study Design and Setting Cross-sectional analysis of a national database. Subjects and Methods A review of data reported by hospitals in the United States to the Healthcare Cost and Utilization Project Kids' Inpatient Database with a diagnosis of epistaxis was conducted ( International Classification of Diseases, Ninth Revision [ ICD-9] code 784.7). The database provides new data every 3 years. The most recent databases, 2006, 2009, and 2012, were reviewed. Results A total of 11,366 patients with a diagnosis of epistaxis were identified. The average age was 12 years, and most patients were male (60%). Of the patients who underwent intervention for epistaxis, 704 underwent packing, 119 underwent ligation, and 98 underwent embolization. Transfusion of blood or platelets was highest in the patients undergoing packing only (38%, P < .0001). The lowest average length of stay was for the ligation group with a mean (SD) of 6.95 (14.02) days. Embolization and ligation most frequently occurred in the setting of an urban teaching hospital (95.63% and 73.28%, respectively). For patients who underwent embolization with epistaxis as a secondary diagnosis, benign neoplasm of nasopharynx (58.3%) was the most common primary diagnosis. In those patients who underwent ligation, nasal bone fracture (28.5%) was the most common primary diagnosis. Conclusion This study highlights that 11,366 patients were treated for epistaxis during 2006, 2009, and 2012, and most patients were treated conservatively. PMID- 29986630 TI - An Exploratory Study of a Nurse-Led HIV Postexposure Prophylaxis Program. AB - The provision of HIV medications to HIV-negative persons after exposure to HIV is known as postexposure prophylaxis (PEP). Because this prevention strategy is primarily only available in emergency rooms, we piloted a nurse-led community based PEP program in Ottawa from September 2013 through August 2015. As part of evaluating this program, we conducted qualitative interviews with persons who initiated PEP. Twelve men who had engaged in condomless anal sex with other males participated. Thematic analysis of the interview transcripts highlighted that PEP was considered unmentionable because the participants' saw it as proof of past behavior that was perceived negatively. Our results thus revealed that PEP was stigmatized, which made our participants reluctant to answer health care professionals' "questions" about why they needed PEP. To do so was to be exposed to stigma. The use of PEP for our participants was a balance between wanting to minimize the risks of HIV acquisition against the risks of disclosing the unmentionable. We take these findings to mean that clinicians and health service policy workers should move PEP into community clinics (decentralizing it from hospitals, and increase the involvement of nurses); aim to provide all required PEP services in community settings (consolidate PEP provision in these clinics); and ensure PEP services are streamlined to remove extraneous data collection (meaning history and exam tools should be standardized to minimize needless questions that may impede PEP access). Together, these recommendations may increase patients' access to PEP, and maximize its HIV prevention effects. PMID- 29986631 TI - Child Maltreatment 2017 Best Article Award. PMID- 29986633 TI - Ultrasound-guided vacuum-assisted breast biopsy with a small-caliber device: A multicenter consecutive study of 162 biopsied lesions. AB - OBJECTIVE: In this study, we aimed to analyze technical and diagnostic potential, and safety of the small-caliber vacuum-assisted biopsy (SCVAB) device in a multicenter consecutive study taking into consideration the type and location of breast lesion. METHODS: We collected data from 5 breast imaging centers where radiologists used the SCVAB device for biopsies in 162 patients. We analyzed the conditions for using the SCVAB device according to the characteristics of the lesions, the volume of excision, and the analyzability obtained by biopsy samples. RESULTS: The biopsies of 80 circumscribed masses, 61 complex lesions, and 24 microcalcification foci were included in the study. The reasons for choosing SCVAB as an initial technique were identified. A total of 47 lesions were removed with SCVAB; among them, 24 lesions were initially chosen for total excision. SCVAB was used as a second-choice biopsy method after core-needle biopsy failure in 20 cases. If SCVAB had not been available, vacuum-assisted biopsy would have been the most frequently used technique (106 under ultrasound, and 18 under stereotactical guidance). CONCLUSIONS: The SCVAB system is an alternative to classical vacuum biopsy, enabling representative samples to be obtained from lesions that are difficult to access, complex, small, or in cases of unsuccessful previous biopsy. The SCVAB system was determined as the chosen technique by the radiologists in this study due to feasibility, ergonomics and absence of side effects detected in this study. PMID- 29986632 TI - Electrochemotherapy as a New Modality in Interventional Oncology: A Review. AB - Electroporation is a well-known phenomenon that occurs at the cell membrane when cells are exposed to high-intensity electric pulses. Depending on electric pulse amplitude and number of pulses, applied electroporation can be reversible with membrane permeability recovery or irreversible. Reversible electroporation is used to introduce drugs or genetic material into the cell without affecting cell viability. Electrochemotherapy refers to a combined treatment: electroporation and drug injection to enhance its cytotoxic effect up to 1000-fold for bleomycin. Since several years, electrochemotherapy is gaining popularity as minimally invasive oncologic treatment. The adoption of electrochemotherapy procedure in interventional oncology poses several unsolved questions, since suitable tumor histology and size as well as therapeutic efficacy still needs to be deepen. Electrochemotherapy is usually applied in palliative settings for the treatment of patients with unresectable tumors to relieve pain and ameliorate quality of life. In most cases, it is used in the treatment of advanced stages of neoplasia when radical surgical treatment is not possible (eg, due to lesion location, size, and/or number). Further, electrochemotherapy allows treating tumor nodules in the proximity of important structures like vessels and nerves as the treatment does not involve tissue heating. Overall, the safety profile of electrochemotherapy is favorable. Most of the observed adverse events are local and transient, moderate local pain, erythema, edema, and muscle contractions during electroporation. The aim of this article is to review the recent published clinical experiences of electrochemotherapy use in deep-seated tumors with particular focus on liver cases. The principle of electrochemotherapy as well as the application to cutaneous metastases is briefly described. A short insight in the treatment of bone metastases, unresectable pancreas cancer, and soft tissue sarcoma will be given. Preclinical and clinical studies on treatment efficacy with electrochemotherapy of hepatic lesions and safety of the procedure adopted are discussed. PMID- 29986634 TI - The Power of Peers: Applying User-Generated Content to Health Behaviors "Off Line". AB - Many patients seek and share information online regarding health, especially those diagnosed with chronic disease. The social cognitive theory is used as the theoretical framework for analyzing how members learn within online health communities. This study conducted in-depth interviews with members from online health communities related to arthritis to understand their motivation for participating in the community and how the content exchanged therein is applied to managing their disease. Four themes were identified: processing disease diagnosis, collaborating to solve problem, recognizing personal limitations, and appreciating that health is variable. Topical communication within the online communities was often tailored to members' situational needs with the ultimate goal being better self-management. The findings demonstrate the online health community is an environment that invites members who share common characteristics to engage with one another and with the shared content for the purpose of learning arthritis self-management strategies. Theoretical and practical implications are discussed. PMID- 29986635 TI - Silencing of ENO1 by shRNA Inhibits the Proliferation of Gastric Cancer Cells. AB - alpha-Enolase is a significant subunit of enolase and acts as a glycolytic enzyme responsible for catalyzing the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the anaerobic glycolysis pathway. The research about their role is known little in tumor invasion and metastasis. This research analyzed the effect of alpha-enolase in proliferation and progression of human gastric cancer. The constructed PLKO.1-ENO1 shRNA vector was transfected into 293 T cells and used to infect gastric cancer cells, MKN45, by using lentivirus method. Negative controls were generated by infection with viruses containing empty vector PLKO.1 scramble-shRNA by the same protocol and using wild-type MKN45 cells as blank control. The silencing effect was confirmed by reverse transcription polymerase chain reaction and Western blotting at messenger RNA and protein levels, respectively. Cell proliferation and chemosensitivity were tested by methyl thiazolyl-tetrazolium assay. Cell apoptosis was tested by flow cytometry. The cell line alpha-enolase short hairpin RNA stabling silence alpha-enolase was successfully constructed. In the alpha-enolase short hairpin RNA cell lines, messenger RNA and protein expression of alpha-enolase were significantly lower than those in negative control and blank control groups. The proliferation and clone formation ability were significantly inhibited, cell apoptosis was increased significantly, and the inhibition rate of chemotherapy drugs was increased ( P < .05). Our data provide strong evidence that alpha-enolase short hairpin RNA interference vector can effectively suppress the proliferation and increase chemosensitivity of MKN45 cells, which may provide a novel gene therapy for gastric cancer. PMID- 29986636 TI - Long-term Trends in Head and Neck Surgery Outcomes. AB - OBJECTIVE: The aim of the present study is to address the paucity of data on long term trends in postoperative complication rates in head and neck surgery. Specifically, this study assesses trends in morbidity and mortality following head and neck surgery over a 20-year period from 1995 to 2015 and identifies risk factors for the development of complications. STUDY DESIGN: Retrospective cross sectional analysis of Veterans Affairs Surgical Quality Improvement Program database from 1995 to 2015. SETTING: Veterans Affairs medical centers across the United States. SUBJECTS AND METHODS: Using the Veterans Affairs Surgical Quality Improvement Program database, we selected 44,161 patients undergoing head and neck procedures from 1995 to 2015. Trends in 30-day morbidity and mortality were assessed, and univariate and multivariate analyses of risk factors for complications were performed. RESULTS: From 1995-2000 to 2011-2015, overall complication rates decreased >45% (from 10.9% to 5.9%), and 30-day postsurgical mortality decreased nearly 70% (from 1.3% to 0.4%). Postoperative hospital stays also significantly declined. Major procedures, such as free flap cases and total laryngectomies, had less change in complication rate as compared with less invasive procedures. CONCLUSION: Substantial improvement in postoperative morbidity and mortality has taken place in head and neck surgery over the past decades. Static complication rates in some procedures may reflect that the improvement of surgical techniques allow for the treatment of sicker patients. The trends seen in this study speak to the importance of probing further why high rates of complications are still seen in certain procedures and ensuring that effective treatment is balanced with limiting morbidity and mortality. PMID- 29986637 TI - Equipment, staffing, and provision of radiotherapy in Lombardy, Italy: Results of three surveys performed between 2012 and 2016. AB - INTRODUCTION:: Several efforts are being implemented at the European level to measure provision of up-to-date radiation treatments across the continent. METHODS:: A snapshot survey involving all radiation oncology centers within Lombardy, Italy, was performed in 2012 and repeated in 2014 and 2016, in cooperation with regional governmental officers. Centers were asked to provide detailed information concerning all individual patients being treated on the index day, and to report data on available local resources. RESULTS:: We observed an increase in the number of centers and of megavoltage units (MVU) (from 76 to 87, i.e., 8.7 MVU per million inhabitants in 2016). Mean number of MVU per center was 2.5. Average age of MVU increased from 5.3 to 7.5 years and patients on the waiting list also increased. Conformal 3D radiotherapy (RT) treatments decreased from 56% to 42% and were progressively replaced by intensity-modulated RT treatments (from 39% to 49%). Waiting times were overall satisfactory. Radiation oncologists treated on average 152 and radiation therapists 100 RT courses per year. Average reimbursement per course was ?4,879 (range ?2,476-?8,014). CONCLUSIONS:: The methodology of snapshot survey proved feasible and provided valuable information about radiation oncology provision and accessibility in Lombardy. PMID- 29986638 TI - Converting Treatment Plans From Helical Tomotherapy to L-Shape Linac: Clinical Workflow and Dosimetric Evaluation. AB - This work evaluated a commercial fallback planning workflow designed to provide cross-platform treatment planning and delivery. A total of 27 helical tomotherapy intensity-modulated radiotherapy plans covering 4 anatomical sites were selected, including 7 brain, 5 unilateral head and neck, 5 bilateral head and neck, 5 pelvis, and 5 prostate cases. All helical tomotherapy plans were converted to 7 field/9-field intensity-modulated radiotherapy and volumetric-modulated radiotherapy plans through fallback dose-mimicking algorithm using a 6-MV beam model. The planning target volume (PTV) coverage ( D1, D99, and homogeneity index) and organs at risk dose constraints were evaluated and compared. Overall, all 3 techniques resulted in relatively inferior target dose coverage compared to helical tomotherapy plans, with higher homogeneity index and maximum dose. The organs at risk dose ratio of fallback to helical tomotherapy plans covered a wide spectrum, from 0.87 to 1.11 on average for all sites, with fallback plans being superior for brain, pelvis, and prostate sites. The quality of fallback plans depends on the delivery technique, field numbers, and angles, as well as user selection of structures for organs at risk. In actual clinical scenario, fallback plans would typically be needed for 1 to 5 fractions of a treatment course in the event of machine breakdown. Our results suggested that <1% dose variance can be introduced in target coverage and/or organs at risk from fallback plans. The presented clinical workflow showed that the fallback plan generation typically takes 10 to 20 minutes per case. Fallback planning provides an expeditious and effective strategy for transferring patients cross platforms, and minimizing the untold risk of a patient missing treatment(s). PMID- 29986639 TI - Value of SPECT/CT for Sentinel Lymph Node Localization in the Parotid and External Jugular Chain. AB - OBJECTIVE: Preoperative single-photon emission computed tomography/computed tomography (SPECT/CT) imaging may aid in the localization of sentinel lymph nodes (SLNs) in cutaneous head and neck malignancy and has been rigorously evaluated for deep cervical lymph nodes. The purpose of this study was to assess the sensitivity, specificity, and positive predictive value (PPV) of SPECT/CT for preoperative localization of nodal basins superficial to the sternocleidomastoid muscle, with comparison to deep nodal basins of the neck. STUDY DESIGN: Retrospective review. SETTING: Tertiary care center. SUBJECTS AND METHODS: SPECT/CT images obtained preoperatively for patients undergoing SLN biopsy for cutaneous head and neck malignancy between June 2015 and June 2016 were reviewed by a blinded nuclear medicine physician and head and neck surgeon. SPECT/CT imaging was compared to intraoperatively determined SLN location via gamma probe. Sensitivity, specificity, and positive and negative predictive values were determined and compared for superficial (external jugular [EJ] and parotid) nodes vs level II nodes. RESULTS: Fifty-three patients were included in the study. Most had cutaneous melanoma (69.8%). The PPV of EJ/parotid node identification by SPECT/CT imaging was 85.7%, specificity was 88.9%, and sensitivity was 69.2%. Comparatively, the PPV for level II nodes was 76.9%, specificity was 50%, and sensitivity was 85.7%. No significant difference in SPECT/CT predictive value was identified between EJ/parotid and level II node identification ( P > .05). CONCLUSION: SPECT/CT imaging has strong specificity and positive predictability for preoperative localization of SLN superficial to the sternocleidomastoid muscle in cutaneous head and neck malignancy. SPECT/CT imaging may be a useful radiographic aid for preoperative SLN mapping in this patient population. PMID- 29986640 TI - Prospective evaluation of first and last memory reports following moderate to severe traumatic brain injury. AB - Prospective monitoring of posttraumatic amnesia (PTA) status is recommended following traumatic brain injury (TBI). Use of patients' subjective reports is, however, still common and necessary in some circumstances. It is therefore important to understand how patients' self-reported first memories relate to prospective measures and how reliable these reports remain over time. In the present study, patients with moderate-severe TBI in PTA were asked about their first and last memories surrounding the injury daily and were administered the Westmead Post-Traumatic Amnesia Scale (WPTAS). Following PTA emergence, a semistructured interview was used to ascertain participants' reports of return of continuous memory after the injury, as well as their last preinjury memory. This interview was repeated six months later, along with the Community Integration Questionnaire to measure functional outcome and the Rey Auditory Verbal Learning Test to measure anterograde memory. The temporal order of recovery of WPTAS variables and subjective reports was determined, and consistency of subjective reports over time was examined using bivariate correlation and intraclass correlation coefficients (ICCs). Findings suggested that patients' reports of return of continuous memory aligned most closely with return of consistent orientation, and occurred significantly earlier than attainment of criterion on the WPTAS. Reported first memories were significantly later at follow-up (i.e., greater days post injury) and the ICC was not suggestive of adequate clinical reliability. Last memory reports were slightly more reliable, with 71% of cases remaining in the same band at follow-up. Demographic and injury-related variables were not significantly associated with the discrepancy between reports. The variability in patients' reports over time highlights the importance and value of prospective PTA monitoring. PMID- 29986641 TI - Tiredness, Fatigue, and Exhaustion as Perceived by Recreational Marathon Runners. AB - In this article, we report the results of a study that was part of a five-study concept development project. Our goal was to learn about the nature of illness by exploring variations in the manifestations of fatigue, a symptom that is prevalent in both ill (cancer, depression, chronic fatigue syndrome) and selected nonill (recreational marathon runners, shift workers) populations. In this article, we report results of our study of recreational marathon runners, obtained from unstructured interviews with 13 runners between the ages 19 and 49 years using ethnoscience as the design. Key findings with implications for practice are the importance of planning recovery periods following large energy expenditures, the value of using dissociative strategies to manage tiredness, and the usefulness of associative strategies and support systems to manage fatigue. Future studies could explore whether these strategies would be useful for management of tiredness and fatigue in other populations. PMID- 29986643 TI - Analysis of coastal cod (Gadus morhua L.) sampled on spawning sites reveals a genetic gradient throughout Norway's coastline. AB - BACKGROUND: Atlantic cod (Gadus morhua L.) has formed the basis of many economically significant fisheries in the North Atlantic, and is one of the best studied marine fishes, but a legacy of overexploitation has depleted populations and collapsed fisheries in several regions. Previous studies have identified considerable population genetic structure for Atlantic cod. However, within Norway, which is the country with the largest remaining catch in the Atlantic, the population genetic structure of coastal cod (NCC) along the entire coastline has not yet been investigated. We sampled > 4000 cod from 55 spawning sites. All fish were genotyped with 6 microsatellite markers and Pan I (Dataset 1). A sub set of the samples (1295 fish from 17 locations) were also genotyped with an additional 9 microsatellites (Dataset 2). Otoliths were read in order to exclude North East Arctic Cod (NEAC) from the analyses, as and where appropriate. RESULTS: We found no difference in genetic diversity, measured as number of alleles, allelic richness, heterozygosity nor effective population sizes, in the north-south gradient. In both data sets, weak but significant population genetic structure was revealed (Dataset 1: global FST = 0.008, P < 0.0001. Dataset 2: global FST = 0.004, P < 0.0001). While no clear genetic groups were identified, genetic differentiation increased among geographically-distinct samples. Although the locus Gmo132 was identified as a candidate for positive selection, possibly through linkage with a genomic region under selection, overall trends remained when this locus was excluded from the analyses. The most common allele in loci Gmo132 and Gmo34 showed a marked frequency change in the north-south gradient, increasing towards the frequency observed in NEAC in the north. CONCLUSION: We conclude that Norwegian coastal cod displays significant population genetic structure throughout its entire range, that follows a trend of isolation by distance. Furthermore, we suggest that a gradient of genetic introgression between NEAC and NCC contributes to the observed population genetic structure. The current management regime for coastal cod in Norway, dividing it into two stocks at 62 degrees N, represents a simplification of the level of genetic connectivity among coastal cod in Norway, and needs revision. PMID- 29986642 TI - Population genetic structure and evolutionary history of Bale monkeys (Chlorocebus djamdjamensis) in the southern Ethiopian Highlands. AB - BACKGROUND: Species with a restricted geographic distribution, and highly specialized habitat and dietary requirements, are particularly vulnerable to extinction. The Bale monkey (Chlorocebus djamdjamensis) is a little-known arboreal, bamboo-specialist primate endemic to the southern Ethiopian Highlands. While most Bale monkeys inhabit montane forests dominated by bamboo, some occupy forest fragments where bamboo is much less abundant. We used mitochondrial DNA (mtDNA) sequences to analyse the genetic structure and evolutionary history of Bale monkeys covering the majority of their remaining distribution range. We analysed 119 faecal samples from their two main habitats, continuous forest (CF) and fragmented forests (FF), and sequenced 735 bp of the hypervariable region I (HVI) of the control region. We added 12 orthologous sequences from congeneric vervets (C. pygerythrus) and grivets (C. aethiops) as well as animals identified as hybrids, previously collected in southern Ethiopia. RESULTS: We found strong genetic differentiation (with no shared mtDNA haplotypes) between Bale monkey populations from CF and FF. Phylogenetic analyses revealed two distinct and highly diverged clades: a Bale monkey clade containing only Bale monkeys from CF and a green monkey clade where Bale monkeys from FF cluster with grivets and vervets. Analyses of demographic history revealed that Bale monkey populations (CF and FF) have had stable population sizes over an extended period, but have all recently experienced population declines. CONCLUSIONS: The pronounced genetic structure and deep mtDNA divergence between Bale monkey populations inhabiting CF and FF are likely to be the results of hybridization and introgression of the FF population with parapatric Chlorocebus species, in contrast to the CF population, which was most likely not impacted by hybridization. Hybridization in the FF population was probably enhanced by an alteration of the bamboo forest habitat towards a more open woodland habitat, which enabled the parapatric Chlorocebus species to invade the Bale monkey's range and introgress the FF population. We therefore propose that the CF and FF Bale monkey populations should be managed as separate units when developing conservation strategies for this threatened species. PMID- 29986644 TI - Stepwise approach to SNP-set analysis illustrated with the Metabochip and colorectal cancer in Japanese Americans of the Multiethnic Cohort. AB - BACKGROUND: Common variants have explained less than the amount of heritability expected for complex diseases, which has led to interest in less-common variants and more powerful approaches to the analysis of whole-genome scans. Because of low frequency (low statistical power), less-common variants are best analyzed using SNP-set methods such as gene-set or pathway-based analyses. However, there is as yet no clear consensus regarding how to focus in on potential risk variants following set-based analyses. We used a stepwise, telescoping approach to analyze common- and rare-variant data from the Illumina Metabochip array to assess genomic association with colorectal cancer (CRC) in the Japanese sub-population of the Multiethnic Cohort (676 cases, 7180 controls). We started with pathway analysis of SNPs that are in genes and pathways having known mechanistic roles in colorectal cancer, then focused on genes within the pathways that evidenced association with CRC, and finally assessed individual SNPs within the genes that evidenced association. Pathway SNPs downloaded from the dbSNP database were cross matched with Metabochip SNPs and analyzed using the logistic kernel machine regression approach (logistic SNP-set kernel-machine association test, or sequence kernel association test; SKAT) and related methods. RESULTS: The TGF beta and WNT pathways were associated with all CRC, and the WNT pathway was associated with colon cancer. Individual genes demonstrating the strongest associations were TGFBR2 in the TGF-beta pathway and SMAD7 (which is involved in both the TGF-beta and WNT pathways). As partial validation of our approach, a known CRC risk variant in SMAD7 (in both the TGF-beta and WNT pathways: rs11874392) was associated with CRC risk in our data. We also detected two novel candidate CRC risk variants (rs13075948 and rs17025857) in TGFBR2, a gene known to be associated with CRC risk. CONCLUSIONS: A stepwise, telescoping approach identified some potentially novel risk variants associated with colorectal cancer, so it may be a useful method for following up on results of set-based SNP analyses. Further work is required to assess the statistical characteristics of the approach, and additional applications should aid in better clarifying its utility. PMID- 29986645 TI - Highly focused transcriptional response of Anopheles coluzzii to O'nyong nyong arbovirus during the primary midgut infection. AB - BACKGROUND: Anopheles mosquitoes are efficient vectors of human malaria, but it is unknown why they do not transmit viruses as well as Aedes and Culex mosquitoes. The only arbovirus known to be consistently transmitted by Anopheles mosquitoes is O'nyong nyong virus (ONNV, genus Alphavirus, family Togaviridae). The interaction of Anopheles mosquitoes with RNA viruses has been relatively unexamined. RESULTS: We transcriptionally profiled the African malaria vector, Anopheles coluzzii, infected with ONNV. Mosquitoes were fed on an infectious bloodmeal and were analyzed by Illumina RNAseq at 3 days post-bloodmeal during the primary virus infection of the midgut epithelium, before systemic dissemination. Virus infection triggers transcriptional regulation of just 30 host candidate genes. Most of the regulated candidate genes are novel, without known function. Of the known genes, a significant cluster includes candidates with predicted involvement in carbohydrate metabolism. Two candidate genes encoding leucine-rich repeat immune (LRIM) factors point to possible involvement of immune protein complexes in the mosquito antiviral response. The primary ONNV infection by bloodmeal shares little transcriptional response in common with ONNV infection by intrathoracic injection, nor with midgut infection by the malaria parasites, Plasmodium falciparum or P. berghei. Profiling of A. coluzzii microRNA (miRNA) identified 118 known miRNAs and 182 potential novel miRNA candidates, with just one miRNA regulated by ONNV infection. This miRNA was not regulated by other previously reported treatments, and may be virus specific. Coexpression analysis of miRNA abundance and messenger RNA expression revealed discrete clusters of genes regulated by Imd and JAK/STAT, immune signaling pathways that are protective against ONNV in the primary infection. CONCLUSIONS: ONNV infection of the A. coluzzii midgut triggers a remarkably limited gene regulation program of mostly novel candidate genes, which likely includes host genes deployed for antiviral defense, as well as genes manipulated by the virus to facilitate infection. Functional dissection of the ONNV-response candidate genes is expected to generate novel insight into the mechanisms of virus-vector interaction. PMID- 29986646 TI - Variation and asymmetry in host-symbiont dependence in a microbial symbiosis. AB - BACKGROUND: Symbiosis is a major source of evolutionary innovation and, by allowing species to exploit new ecological niches, underpins the functioning of ecosystems. The transition from free-living to obligate symbiosis requires the alignment of the partners' fitness interests and the evolution of mutual dependence. While symbiotic taxa are known to vary widely in the extent of host symbiont dependence, rather less is known about variation within symbiotic associations. RESULTS: Using experiments with the microbial symbiosis between the protist Paramecium bursaria and the alga Chlorella, we show variation between pairings in host-symbiont dependence, encompassing facultative associations, mutual dependence and host dependence upon the symbiont. Facultative associations, that is where both the host and the symbiont were capable of free living growth, displayed higher symbiotic growth rates and higher per host symbiont loads than those with greater degrees of dependence. CONCLUSIONS: These data show that the Paramecium-Chlorella interaction exists at the boundary between facultative and obligate symbiosis, and further suggest that the host is more likely to evolve dependence than the algal symbiont. PMID- 29986647 TI - Novel long-range regulatory mechanisms controlling PKD2 gene expression. AB - BACKGROUND: Cis-regulatory elements control gene expression over large distances through the formation of chromatin loops, which allow contact between enhancers and gene promoters. Alterations in cis-acting regulatory systems could be linked to human genetic diseases. Here, we analyse the spatial organization of a large region spanning the polycystic kidney disease 2 (PKD2) gene, one of the genes responsible of autosomal dominant polycystic kidney disease (ADPKD). RESULTS: By using chromosome conformation capture carbon copy (5C) technology in primary human renal cyst epithelial cells, we identify novel contacts of the PKD2 promoter with chromatin regions, which display characteristics of regulatory elements. In parallel, by using functional analysis with a reporter assay, we demonstrate that three DNAse I hypersensitive sites regions are involved in the regulation of PKD2 gene expression. CONCLUSIONS: Finally, through alignment of CCCTC-binding factor (CTCF) sites, we suggest that these novel enhancer elements are brought to the PKD2 promoter by chromatin looping via the recruitment of CTCF. PMID- 29986648 TI - Generation of Mycoplasma hominis gene-targeted mutants by targeting-induced local lesions in genomes (TILLING). AB - BACKGROUND: Mycoplasma hominis is a human urogenital pathogen involved in gynaecological, neonatal and extra-genital infections. However, no versatile genetic tools are currently available to study the pathogenicity of this bacterium. Targeting-Induced Local Lesions IN Genomes (TILLING) is a reverse genetic method that combines point mutations induced by chemical mutagenesis with a DNA screening technique. We used ethyl methanesulfonate (EMS) that introduces C G to T-A transition mutations to generate a library of M. hominis mutants. As a proof of concept, mutagenized organisms were screened for mutations in two target genes previously associated with the mycoplasma pathogenicity, the vaa gene encoding an adhesin lipoprotein and the oppA gene encoding the main ectoATPase of the bacterium. The resulting mutants were evaluated using functional assays, an adhesion to HeLa cell assay for vaa-mutants and an ATPase activity test for oppA mutants. RESULTS: A 1200-clone library was generated by exposing M. hominis PG21 to 9 mg/mL EMS for 3 h. To identify mutants of interest, targeted gene fragments were amplified, heat-denatured, slowly reannealed and digested with the mismatch specific endonuclease ENDO1. If multiple alleles were present in the PCR amplicons, these alleles formed heteroduplexes during reannealing that were specifically cleaved by ENDO1 at mismatching positions. A total of four vaa mutants and two oppA-mutants harbouring missense mutations were obtained and fully sequenced. Zero to eight additional mutations were identified in the genomes of each mutant. The vaa-mutants were tested for adhesion to immobilized HeLa cells but their adhesion was not significantly different from the adhesion of M. hominis PG21. One of the two oppA-mutants that were tested for ATPase activity presented a higher affinity for its ATP substrate than the parental strain. CONCLUSION: For the first time, we demonstrated that M. hominis gene targeted mutants could be successfully obtained using this TILLING strategy. In the absence of robust genetic tools for studying M. hominis, the TILLING strategy that can target any gene of the genome could help to elucidate gene functions and to better understand the pathogenesis of this human pathogenic species. PMID- 29986649 TI - An acute gastroenteritis outbreak associated with person-to-person transmission in a primary school in Shanghai: first report of a GI.5 norovirus outbreak in China. AB - BACKGROUND: GII noroviruses are a common cause of acute gastroenteritis (AGE) outbreaks in institutional settings globally. However, AGE outbreaks caused by GI norovirus, especially the GI.5 genotype, are relatively uncommon. METHODS: In February 2017, an AGE outbreak occurred in a primary school in Shanghai, China. An outbreak investigation was undertaken, and fecal specimens, rectal swabs, and environmental swabs were collected. Pathogen detection was performed and the positive specimens were characterized by gene sequencing. RESULTS: The descriptive epidemiological analysis suggested that this outbreak, involving 19 cases in two classes (designated classes A and B), was a small-scale propagated epidemic and person-to-person transmission was the most plausible transmission mode. The outbreak comprised two peaks, with 15 cases occurring in class A during the main peak and four cases occurring in class B in the subsequent minor peak. The primary attack rate was 38% and the secondary attack rate was 10%. Univariable logistic regression indicated that contacting a suspect case was a risk factor for norovirus infection, with an unadjusted OR of 5.6 (95% CI: 1.6 20.1). Six fecal specimens were positive for GI norovirus, with a single genotype, GI.5 norovirus, being involved, as characterized by genotyping. This outbreak was the first reported outbreak of GI.5 norovirus in China. CONCLUSIONS: This study implies that GI.5 norovirus is a potential agent of outbreaks spread by person-to-person transmission in institutional settings. The investigation highlights the importance of sensitive surveillance, timely isolation of individuals who are ill, adequate hand hygiene, and proper environmental disinfection for prevention and control of AGE outbreaks caused by norovirus. PMID- 29986650 TI - Genome-wide identification and characterization of InDels and SNPs in Glycine max and Glycine soja for contrasting seed permeability traits. AB - BACKGROUND: Water permeability governed by seed coat is a major facet of seed crops, especially soybean, whose seeds lack physiological dormancy and experience rapid deterioration in seed viability under prolonged storage. Moreover, the physiological and chemical characteristics of soybean seeds are known to vary with seed coat color. Thus, to underpin the genes controlling water permeability in soybean seeds, we carried out an in-depth characterization of the associated genomic variation. RESULTS: In the present study, we have analyzed genomic variation between cultivated soybean and its wild progenitor with implications on seed permeability, a trait related to seed storability. Whole genome resequencing of G.max and G. soja, identified SNPs and InDels which were further characterized on the basis of their genomic location and impact on gene expression. Chromosomal density distribution of the variation was assessed across the genome and genes carrying SNPs and InDels were characterized into different metabolic pathways. Seed hardiness is a complex trait that is affected by the allelic constitution of a genetic locus as well as by a tricky web of plant hormone interactions. Seven genes that hold a probable role in the determination of seed permeability were selected and their expression differences at different stages of water imbibition were analyzed. Variant interaction network derived 205 downstream interacting partners of 7 genes confirmed their role in seed related traits. Interestingly, genes encoding for Type I- Inositol polyphosphate 5 phosphatase1 and E3 Ubiquitin ligase could differentiate parental genotypes, revealed protein conformational deformations and were found to segregate among RILs in coherence with their permeability scores. The 2 identified genes, thus showed a preliminary association with the desirable permeability characteristics. CONCLUSION: In the light of above outcomes, 2 genes were identified that revealed preliminary, but a relevant association with soybean seed permeability trait and hence could serve as a primary material for understanding the molecular pathways controlling seed permeability traits in soybean. PMID- 29986652 TI - Complete atrioventricular block as an initial manifestation of recurred oral cavity cancer: a case report. AB - BACKGROUND: Intracardiac invasion of head and neck cancer is extremely rare. Here, we report a case of recurred oral cavity cancer presenting with complete atrioventricular (AV) block caused by cardiac metastasis. CASE PRESENTATION: A 70 year-old male presented with dizziness for 2 days. He had a history of oral cavity cancer a year ago, and the tumor was treated by surgical excision after induction chemotherapy and concurrent chemoradiation therapy. Electrocardiography showed complete AV block with ventricular escape rate of 43 beats per minute. Cardiac imaging revealed about 4.0 * 2.0 cm-sized mass invading interventricular septum and AV nodes and protruding into the right ventricle. Magenetic resonance imaging of head and neck demonstrated recurred mass in oral cavity and maxillary sinus. Fluorodeoxyglucose-positron emission tomography showed hypermetabolic lesion in both oral cavity and the heart around interventricular septum and atrioventricular node indicating recurred oral cavity cancer with cardiac metastasis. Permament pacemaker of DDD type was implanted for the symptomatic complete AV block, and palliative chemotherapy was initiated. CONCLUSION: The present case demonstrated that oral cavity cancer can metastasize to the heart, and complete AV block may be an initial manifestation of the recurrence of extracardiac cancer with intracardiac invasion. PMID- 29986651 TI - Patients' experiences of motivation, change, and challenges in group treatment for insomnia in primary care: a focus group study. AB - BACKGROUND: The majority of patients who seek help for insomnia do so in primary health care. Nurse-led group treatment in primary care based on cognitive behavioral therapy for insomnia (CBT-I) can lead to improvements in both day- and nighttime symptoms. This study aimed to explore patients' experiences of nurse led group treatment for insomnia in primary health care. METHODS: Seventeen patients who had participated in the group treatment program were interviewed in five focus groups. Interview transcriptions were analyzed with qualitative content analysis. RESULTS: Four themes emerged that described patients' experiences of the group treatment program. Involvement and trust open the door for change: Motivation to engage in treatment arose from patients' own desire for change, from being together with others who shared or understood their struggles, and from feeling emotionally affirmed and trustful. Competence arising from deeper understanding: Patients obtained knowledge and made it their own, which enabled them to develop functional sleep habits and let go of sleep performance and worry. The ability to impact their insomnia increased patients' trust in their own efficacy and helped them persist in behavioral change. Struggling with vulnerability and failure: Treatment was tough, and patients could feel challenged by external circumstances. Moreover, they could distrust their own efficacy. Tailoring treatment to individual needs: Patients experienced different life circumstances and adapted the techniques to their needs and abilities by focusing on what felt right for them. CONCLUSIONS: Patients went through a process of motivation, change, and challenges. They experienced certain aspects of treatment as essential to changing behavior and achieving improvements. Examples included being in a group with others who shared similar experiences, gaining knowledge about sleep, keeping a sleep diary, and practicing the sleep restriction technique. The study provides insights into patients' struggles during treatment, both those related to external circumstances and those related to feelings of vulnerability and failure. It also highlights the importance of adapting treatment to patients' differing needs, underscoring the value of person centered care. PMID- 29986653 TI - Study of patterns of inheritance of premature ovarian failure syndrome carrying maternal and paternal premutations. AB - BACKGROUND: Premature ovarian failure / primary ovarian insufficiency (POF/POI) associated with the mutations of the FMR1 (Fragile-X Mental Retardation 1) gene belongs to the group of the so-called trinucleotide expansion diseases. Our aim was to analyse the relationship between the paternally inherited premutation (PIP) and the maternally inherited premutation (MIP) by the examination of the family members of women with POF, carrying the premutation allele confirmed by molecular genetic testing. METHODS: Molecular genetic testing was performed in the patients of the 1st Department of Obstetrics and Gynecology with suspected premature ovarian failure. First we performed the southern blot analyses and for the certified premutation cases we used the Repeat Primed PCR. RESULTS: Due to POF/POI, a total of 125 patients underwent genetic testing. The FMR1 gene trinucleotide repeat number was examined in the DNA samples of the patients, and in 15 cases (12%) deviations (CGG repeat number corresponding to premutation or gray zone) were detected. In 6 cases out of the 15 cases the CGG repeat number fell within the range of the so-called gray zone (41-54 CGG repeat) (4.8%, 6/125), and the FMR1 premutation (55-200 CGG repeat) ratio was 7.2% (9/125). In 4 out of the 15 cases we found differences in both alleles, one was a premutation allele, and the other allele showed a repeat number belonging to the gray zone. Out of 15 cases, only maternal inheritance (MIP) was detected in 2 cases, in one case the premutation allele (91 CGG repeat number), while in the other case an allele belonging to the gray zone (41 CGG repeat number) were inherited from their mothers. In 10 out of 15 cases, the patient inherited the premutation allele only from the father (PIP). In 5 out of the 10 cases (50%) the premutation allele was inherited from the father, and the repeat number ranged from 55 to 133. Out of 125 cases, 9 patients had detectable cytogenetic abnormalities (7.2%). CONCLUSIONS: The RP-PCR method can be used to define the smaller premutations and the exact CGG number. Due to the quantitative nature of the RP PCR, it is possible to detect the mosaicism as well. PMID- 29986654 TI - Creation of a new clinical framework - why women choose mastectomy versus breast conserving therapy. AB - BACKGROUND: Clinical medicine has lagged behind other fields in understanding and utilizing frameworks to guide research. In this article, we introduce a new framework to examine why women choose mastectomy versus breast conserving therapy in early stage breast cancer, and highlight the importance of utilizing a conceptual framework to guide clinical research. METHODS: The framework we present was developed through integrating previous literature, frameworks, theories, models, and the author's past research. RESULTS: We present a conceptual framework that illustrates the central domains that influence women's choice between mastectomy versus breast conserving therapy. These have been organized into three broad constructs: clinicopathological factors, physician factors, and individual factors with subgroups of sociodemographic, geographic, and individual belief factors. The aim of this framework is to provide a comprehensive basis to describe, examine, and explain the factors that influence women's choice of mastectomy versus breast conserving therapy at the individual level. CONCLUSION: We have developed a framework with the purpose of helping health care workers and policy makers better understand the multitude of factors that influence a patient's choice of therapy at an individual level. We hope this framework is useful for future scholars to utilize, challenge, and build upon in their own work on decision-making in the setting of breast cancer. For clinician researchers who have limited experience with frameworks, this paper will highlight the importance of utilizing a conceptual framework to guide future research and provide an example. PMID- 29986656 TI - Correction to: Functional outcomes in Hirschsprung disease patients after transabdominal Soave and Duhamel procedures. AB - After publication of the original article [1], the authors reported that the Acknowledgments section was incomplete. The full section is the following. PMID- 29986655 TI - Whole genome sequencing and identification of Bacillus endophyticus and B. anthracis isolated from anthrax outbreaks in South Africa. AB - BACKGROUND: Bacillus endophyticus is a soil plant-endophytic bacterium, while B. anthracis is the causative agent of anthrax. The virulence factors of B. anthracis are the plasmid encoded tripartite toxins (pXO1) and poly-gamma glutamic acid (PGA) capsule (pXO2). B. endophyticus isolated alongside B. anthracis from animals that died of anthrax in Northern Cape Province (NCP), South Africa, harbored polyglutamate genes. The study compared the characteristics of B. anthracis and B. endophyticus with other Bacillus species with a focus on the presence of the PGA capsule or/and unbound PGA. The morphology and whole genome sequence analysis of B. endophyticus strains and B. anthracis were compared. RESULTS: In conventional microbiology, B. endophyticus showed gram-positive round-shaped rods in single/short chains, which were endospore-forming, non-motile, non-haemolytic with white and dry colonies, and gamma-phage resistant. B. anthracis was differentiated from B. endophyticus based on the latter's box-shaped rods in pairs/long chains, white-grey and slimy colonies, encapsulated and gamma-phage susceptible. The study identified a PGA polyglutamate synthase operon that consisted of pgsBCA, gamma glutamyltranspeptidase (ggt) and pgsE in B. endophyticus genomes. CONCLUSIONS: PGA regions of B. anthracis contain capBCADE genes located in the pXO2 required for capsulation formation, while B. endophyticus contain the pgsBCAE genes in the chromosome. Whole genome and microbiology analysis identified B. endophyticus, as a non-capsuled endospore-forming bacterium that consists of PGA required for biosynthesis. B. endophyticus strains do not synthesize surface associated PGA, therefore capsule visualization of B. anthracis is a key diagnostic characteristic. The study highlights the significance of using whole genome shotgun sequencing to identify virulence and other important genes that might be present amongst unknown samples from natural outbreaks. None of the B. anthracis related plasmids or virulence genes were found in the B. endophyticus genomes. PMID- 29986657 TI - Successful renal transplantation to a recipient with type II cryoglobulinemia: a case report. AB - BACKGROUND: Recurrence of glomerulonephritis is an important risk factor for renal graft dysfunction. Cryoglobulinemia is known as a relatively rare cause of renal failure, and doctors are usually hesitant to perform transplantation on a recipient with cryoglobulinemia because of the risk for graft loss. We present a case of renal transplantation on a patient with organ manifestations of type II cryoglobulinemia. CASE PRESENTATION: At the age of 44 years, the patient developed acute kidney injury and purpura on the lower extremities with type II cryoglobulinemia after interferon therapy for hepatitis C virus. Cryoglobulinemic glomerulonephritis was suspected; however, despite immunosuppressive therapy combined with plasmapheresis, she eventually needed hemodialysis treatment. She was referred to us at the age of 49 years for renal transplantation. Cryocrit was 14% and the organ manifestations persisted, including the lower extremity purpura and neurologic symptoms. After monitoring and confirming sufficient suppression of cryoglobulin concentration by immunosuppressive treatment with prednisolone, cyclophosphamide, and rituximab combined with plasmapheresis, the operation was performed. After transplantation, the cryoglobulin concentration was continuously monitored, and plasmapheresis and rituximab infusion were performed as appropriate. Her graft function has remained stable for 2 years and 6 months. CONCLUSION: Our case suggested that a patient with cryoglobulinemia and persistent organ manifestations can receive a renal graft if the cryoglobulin concentration is sufficiently controlled by pretransplant treatment. PMID- 29986658 TI - Prevalence and associated knowledge of hepatitis B infection among healthcare workers in Freetown, Sierra Leone. AB - BACKGROUND: Hepatitis B virus (HBV) is considered highly prevalent in West Africa. However, major gaps in surveillance exist in Sierra Leone. Although healthcare workers (HCWs) are at high risk for HBV infection, little is known about the prevalence and knowledge of hepatitis B among HCWs in Sierra Leone. METHODS: A cross-sectional study of all HCWs at the No. 34 Military Hospital located in Freetown, Sierra Leone, was conducted from March 20 to April 10, 2017. Whole blood was collected and screened for HBV markers using a one-step rapid immunochromatographic test with positive samples tested for HBV DNA. Additionally, questionnaires assessing self-reported knowledge of HBV infections were administered to all participants. Data were processed and analyzed using SPSS (version 17.0) software. RESULTS: A total of 211 HCWs were included in this study with a median age of 39.0 years (range: 18-59). Of the participating HCWs, 172 (81.5%) participants were susceptible (all markers negative), 21(10.0%) were current HBV (HBsAg positive) and nine (4.3%) were considered immune because of past infection (HBsAg negative and anti-HBc positive; anti-HBs positive). Additionally, nine (4.3%) participants displayed immunity to the virus as a result of prior hepatitis B vaccination (only anti-HBs positive). Of the 21 HCWs with positive HBsAg, 13 (61.9%) had detectable HBV DNA. There was a significantly lower risk for current HBV infection among HCWs older than 39 years (OR 0.337, p = 0.046). In addition, only 14 (6.6%), 73 (34.6%) and 82 (38.9%) participants in this survey had adequate knowledge about the clinical outcome, routes of transmission, and correct preventive measures of HBV infection, respectively. CONCLUSIONS: HCWs in Sierra Leone lacked adequate knowledge of the hepatitis B virus. Additionally, the low coverage rate of hepatitis B vaccination among HCWs fails to meet WHO recommendations, leaving many of the sampled HCWs susceptible to infection. This study reaffirms the need for more intensive training for HCWs in addition to strengthening vaccination programmes to protect HCWs against HBV in Sierra Leone. PMID- 29986659 TI - Compassionate and respectful maternity care during facility based child birth and women's intent to use maternity service in Bahir Dar, Ethiopia. AB - BACKGROUND: Compassionate and respectful maternity care is one of the most important facilitating factors to increase access to skilled maternity care. Disrespect and abuse is a violation of human rights and is the main hindering factor preventing skilled birth utilization versus other more commonly recognized deterrents such as financial and geographical obstacles. METHODS: Institution based cross-sectional study design was conducted. A structured and pre-tested interviewer administered questionnaire was used to collect the data from 284 study participants. Study participant were selected using a systematic random sampling technique by allocating a proportion to each health facility. The data were entered with Epi data version 3.1statistical software and exported to Statistical Package for Social Sciences version 22.0 for further analysis. Both bivariate and multivariate logistic regression analysis were performed to identify associated factors. P values < 0.05 with 95% confidence level were used to declare statistical significance. RESULT: A total of 284 respondents participated in the study with a response rate of 100%.The overall prevalence of respectful maternity care experienced was 57%.The multivariable analysis indicated that respondents who live in a rural area [AOR = 6.49(95%CI; 2.59, 16.21)], experience a caesarian birth [AOR = 4.52(95%CI; 1.64, 12.42)], have complications during delivery [AOR = 2.38(95%CI; 1.28, 4.45)] and future intention to use health facility [AOR = 3.57(95%CI; 1.81, 7.07)] were some of the factors associated with experiencing disrespect and abuse. CONCLUSION: This study showed a high prevalence of disrespect and abuse during facility child birth in Bahir Dar town, Ethiopia as compared to previous literature. Being from rural area, having complications during delivery and mothers who gave birth through caesarian section were more likely to be exposed to disrespect and abuse than other women. Mistreatment of mothers during facility child birth is a health facility failure, a violation of women's rights and a notable barrier for institutional delivery. PMID- 29986661 TI - Dynamics of macrophage populations of the liver after subtotal hepatectomy in rats. AB - BACKGROUND: In many clinical cases of extensive liver resection (e.g. due to malignancy), the residual portion is too small to maintain the body homeostasis. The resulting acute liver failure is associated with the compensatory growth inhibition, which is a typical manifestation of the 'small for size' liver syndrome. The study investigates possible causes of the delayed onset of hepatocyte proliferation after subtotal hepatectomy (80% liver resection) in rats. RESULTS: The data indicate that the growth inhibition correlates with delayed upregulation of the Tnf gene expression and low content of the corresponding Tnfalpha protein within the residual hepatic tissue. Considering the involvement of Tnf/Tnfalpha, the observed growth inhibition may be related to particular properties of liver macrophages - the resident Kupffer cells with CD68+CX1CR3-CD11b- phenotype. CONCLUSIONS: The delayed onset of hepatocyte proliferation correlates with low levels of Tnfalpha in the residual hepatic tissue. The observed growth inhibition possibly reflects specific composition of macrophage population of the liver. It is entirely composed of embryonically derived Kupffer cells, which express the 'proregeneratory' M2 macrophage-specific marker CD206 in the course of regeneration. PMID- 29986660 TI - Temporal transcriptome profiling of developing seeds reveals a concerted gene regulation in relation to oil accumulation in Pongamia (Millettia pinnata). AB - BACKGROUND: Pongamia (Millettia pinnata syn. Pongamia pinnata), an oilseed legume species, is emerging as potential feedstock for sustainable biodiesel production. Breeding Pongamia for favorable traits in commercial application will rely on a comprehensive understanding of molecular mechanism regulating oil accumulation during its seed development. To date, only limited genomic or transcript sequences are available for Pongamia, while a temporal transcriptome profiling of developing seeds is still lacking in this species. RESULTS: In this work, we conducted a time-series analysis of morphological and physiological characters, oil contents and compositions, as well as global gene expression profiles in developing Pongamia seeds. Firstly, three major developmental phases were characterized based on the combined evidences from embryonic shape, seed weight, seed moisture content, and seed color. Then, the gene expression levels at these three phases were quantified by RNA-Seq analyses with three biological replicates from each phase. Nearly 94% of unigenes were expressed at all three phases, whereas only less than 2% of unigenes were exclusively expressed at one of these phases. A total of 8881 differentially expressed genes (DEGs) were identified between phases. Furthermore, the qRT-PCR analyses for 10 DEGs involved in lipid metabolism demonstrated a good reliability of our RNA-Seq data in temporal gene expression profiling. We observed a dramatic increase in seed oil content from the embryogenesis phase to the early seed-filling phase, followed by a steady and moderate increase towards the maximum at the desiccation phase. We proposed that a highly active expression of most genes related to fatty acid (FA) and triacylglycerol (TAG) biosynthesis at the embryogenesis phase might trigger both the substantial oil accumulation and the membrane lipid synthesis for rapid cell proliferation at this phase, while a concerted reactivation of TAG synthesis related genes at the desiccation phase might further promote storage lipid synthesis to achieve the maximum content of seed oils. CONCLUSIONS: This study not only built a bridge between gene expression profiles and oil accumulation in developing seeds, but also laid a foundation for future attempts on genetic engineering of Pongamia varieties to acquire higher oil yield or improved oil properties for biofuel applications. PMID- 29986662 TI - Facilitating HIV/AIDS and HIV testing literacy for emergency department patients: a randomized, controlled, trial. AB - BACKGROUND: Although this has not been fully studied, videos and pictorial brochures might be equivalent methods of delivering HIV/AIDS and HIV testing information to emergency departments (ED) patients. It also is not known how well or for how long such knowledge is retained, if this information should be tailored according to patient health literacy, and if retention of this knowledge impacts future HIV testing behavior. METHODS: We will conduct a multi-site, randomized, controlled, longitudinal trial among 600 English- and 600 Spanish speaking 18-64-year-old ED patients to investigate these questions. We will stratify our sample within language (English vs. Spanish) by health literacy level (lower vs. higher) and randomly assign patients to receive HIV/AIDS and HIV testing information by video or pictorial brochure. All patients will be tested for HIV in the ED. At 12-months post-enrollment, we will invite participants to be tested again for HIV. As primary aims, we will compare the efficacy of pictorial brochures and videos in improving short-term (in ED) HIV/AIDS and HIV testing knowledge and retaining this knowledge over 12 months. We will determine if and how short-term improvement and longer-term retention of knowledge interacts with information delivery mode (pictorial brochure or video), patient health literacy level (lower or higher), and language (English or Spanish). As secondary aims, using the Information-Motivation-Behavioral Skills (IMB) model as a heuristic framework, we will measure constructs from the IMB model relevant to our study, and assess their impact on HIV re-testing behavior; we will also examine the moderating influences of information delivery mode, language, and health literacy level. In addition, we will explore simplified screening strategies to identify ED patients with lower health literacy as ways to implement a tailored approach to HIV/AIDS and HIV testing information delivery in EDs. DISCUSSION: Study findings will guide ED-based delivery of HIV/AIDS and HIV testing information; that is, whether delivery modes (video or pictorial brochure) should be selected for patients by language and/or health literacy level. The results also will inform EDs when, how, and for whom information needs to be provided for those undergoing testing again for HIV within a one-year period. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02284451 . Posted November 6, 2014. PMID- 29986663 TI - Efficiency and nutritional parameters in an elderly high risk population on hemodialysis and hemodiafiltration in Italy and France: different treatments with similar names? AB - BACKGROUND: Choice of dialysis is context sensitive, explored for PD and extracorporeal dialysis, but less studied for haemodialysis (HD) and hemodiafiltration (HDF), both widely employed in Italy and France; reasons of choice and differences in prescriptions may impact on dialysis-related variables, particularly relevant in elderly, high-comorbidity patients. METHODS: The study involved two high-comorbidity in-hospital cohorts, treated in Centers with similar characteristics, in Italy (Cagliari) and France (Le Mans). All patients (204) agreed to participate. Stable cases on thrice-weekly dialysis, with at least 2 months follow-up were selected (180 patients, Males 59.4%, median age 71 years, vintage 4.3 years, Charlson index 9). Univariate and multivariate correlations between baseline data, HD-HDF, dialysis efficiency and nutritional markers were assessed. RESULTS: In Le Mans HDF was mainly chosen to increase efficiency (large surface dialysers, high convective volume; 76.3% of the patients), in Cagliari to improve tolerance (smaller surfaces, lower convective volume; 59% of patients). Kt/V was similar in HD and HDF, and in both settings(median Kt/V Daugirdas 2: 1.6); in the setting of high efficiency no correlation was found between Kt/V, BMI, urea, creatinine, n-PCR and phosphate. The relationship between Kt/V and albumin was divergent: a weak consensual increase was present in Cagliari, a decrease in Le Mans, suggesting a role of albumin losses with high convective volumes. In the multivariate analysis, after adjustment for other covariates (including comorbidity and type of treatment) low albumin level < 3.5 g/dl was highly correlated with setting of study: Le Mans (OR: 7.155 (2.955-17.324)). The multivariate analysis confirmed a role of type of treatment, with higher risk of low albumin levels in HDF (OR: 3.592 (1.466 8.801)), and of comorbidity (Charlson index> = 7 (OR: 3.153 (1.311-7.582)), MIS index> = 7 (OR: 5.916 (2.457-14.241)). CONCLUSIONS: The different prescriptions of HD and HDF may have similar effects on dialysis efficiency, but diverging effects on crucial nutritional markers, such as albumin levels, probably more evident in high-comorbidity populations. PMID- 29986664 TI - A deep learning approach to bilingual lexicon induction in the biomedical domain. AB - BACKGROUND: Bilingual lexicon induction (BLI) is an important task in the biomedical domain as translation resources are usually available for general language usage, but are often lacking in domain-specific settings. In this article we consider BLI as a classification problem and train a neural network composed of a combination of recurrent long short-term memory and deep feed forward networks in order to obtain word-level and character-level representations. RESULTS: The results show that the word-level and character level representations each improve state-of-the-art results for BLI and biomedical translation mining. The best results are obtained by exploiting the synergy between these word-level and character-level representations in the classification model. We evaluate the models both quantitatively and qualitatively. CONCLUSIONS: Translation of domain-specific biomedical terminology benefits from the character-level representations compared to relying solely on word-level representations. It is beneficial to take a deep learning approach and learn character-level representations rather than relying on handcrafted representations that are typically used. Our combined model captures the semantics at the word level while also taking into account that specialized terminology often originates from a common root form (e.g., from Greek or Latin). PMID- 29986665 TI - The role of community-based health services in influencing postnatal care visits in the Builsa and the West Mamprusi districts in rural Ghana. AB - BACKGROUND: Globally, maternal mortality is still a challenge. In Ghana, maternal morbidity and mortality rates remain high, particularly in rural areas. Postnatal Care (PNC) is one of the key strategies for improving maternal health. This study examined determinants of at least three PNC visits in rural Ghana. METHODS: We conducted a cross-sectional study at the Community-Based Health Planning and Services (CHPS) Zones in the Builsa and West Mamprusi Districts between April and June 2016. We selected 650 women who delivered within 5 years preceding the survey (325 from each of the two sites) using the two-stage random sampling technique. RESULTS: Of the 650 respondents, 62% reported attending postnatal care at least three times. In the Builsa district, the percentage of women who made at least three PNC visits were 90% compared with 35% in the West Mamprusi district. Older women and those who attended antenatal clinics at least four times (AOR: 5.23; 95% CI: 2.49-11.0) and women who had partners with some secondary education (AOR: 3.31; 95% CI: 1.17-9.39) were associated with at least three PNC visits. CONCLUSIONS: Men engagement in maternal health services and the introduction of home-based PNC services in rural communities could help health workers reach out to many mothers and children promptly and improve PNC visits in those communities. PMID- 29986666 TI - Determinants of hyperuricemia in non-dialysed chronic kidney disease patients in three hospitals in Cameroon. AB - BACKGROUND: Chronic kidney disease (CKD) poses a substantial health burden in sub Saharan Africa, with risk factors ranging from communicable to non-communicable diseases. Hyperuricemia has been recently identified as a factor of progression of CKD. Identifying factors associated with hyperuricemia in CKD patients would help determine interventions to reduce CKD mortality, particularly in resources limited countries. We sought to determine the prevalence and factors associated with hyperuricemia in non-dialysed CKD adult patients in Cameroon. METHODS: This was a cross-sectional study of non-dialysed CKD patients, conducted in 3 referral nephrology units in Cameroon. Relevant clinical and laboratory data were collected using interviewer-administered questionnaires. Serum uric acid, spot urine protein and spot urine creatinine were assessed. Associations between variables were assessed using multivariate analysis. Level of statistical significance was set at alpha < 0.05. RESULTS: A sample of 103 participants was included. Mean age of study participants was 55.78 +/- 12.58 years, and 59.3% were men. Sixty-nine (67%) had hyperuricemia. Patient's age (OR: 1.08, 95% CI: 1.03-1.13), estimated glomerular filtration rate (OR: 0.94, 95% CI: 0.90-0.98), spot urine protein-creatinine ratio (OR: 1.83, 95% CI: 1.07-3.12), no hypertension (OR: 0.09, 95% CI: 0.02-0.46), urate lowering therapy (OR: 4.99, 95% CI: 1.54-16.16), loop diuretics (OR: 3.39, 95% CI: 1.01-11.42), obesity (OR: 6.12, 95% CI: 1.15-32.55) and no anaemia (OR: 0.04, 95% CI: 0.00-0.29) were independently significantly associated with hyperuricemia. CONCLUSIONS: In this sample of non-dialysed CKD patients in Cameroon, about 7 out of 10 had hyperuricemia. Hyperuricemia was independently associated with patient's age, estimated glomerular filtration rate, spot urine protein-creatinine ratio, hypertension, urate lowering therapy, loop diuretics, obesity and anaemia. More studies are required to establish causal relationships between these associations. PMID- 29986667 TI - Genomic prediction accuracy for switchgrass traits related to bioenergy within differentiated populations. AB - BACKGROUND: Switchgrass breeders need to improve the rates of genetic gain in many bioenergy-related traits in order to create improved cultivars that are higher yielding and have optimal biomass composition. One way to achieve this is through genomic selection. However, the heritability of traits needs to be determined as well as the accuracy of prediction in order to determine if efficient selection is possible. RESULTS: Using five distinct switchgrass populations comprised of three lowland, one upland and one hybrid accession, the accuracy of genomic predictions under different cross-validation strategies and prediction methods was investigated. Individual genotypes were collected using GBS while kin-BLUP, partial least squares, sparse partial least squares, and BayesB methods were employed to predict yield, morphological, and NIRS-based compositional data collected in 2012-2013 from a replicated Nebraska field trial. Population structure was assessed by F statistics which ranged from 0.3952 between lowland and upland accessions to 0.0131 among the lowland accessions. Prediction accuracy ranged from 0.57-0.52 for cell wall soluble glucose and fructose respectively, to insignificant for traits with low repeatability. Ratios of heritability across to within-population ranged from 15 to 0.6. CONCLUSIONS: Accuracy was significantly affected by both cross-validation strategy and trait. Accounting for population structure with a cross-validation strategy constrained by accession resulted in accuracies that were 69% lower than apparent accuracies using unconstrained cross-validation. Less accurate genomic selection is anticipated when most of the phenotypic variation exists between populations such as with spring regreening and yield phenotypes. PMID- 29986668 TI - Reduction of inappropriate medication in older populations by electronic decision support (the PRIMA-eDS study): a qualitative study of practical implementation in primary care. AB - BACKGROUND: Within the EU-funded project PRIMA-eDS (Polypharmacy in chronic diseases: Reduction of Inappropriate Medication and Adverse drug events in older populations by electronic Decision Support) an electronic decision support tool (the "PRIMA-eDS-tool") was developed for general practitioners (GPs) to reduce inappropriate medication in their older polypharmacy patients. After entering patient data relevant to prescribing in an electronic case report form the physician received a comprehensive medication review (CMR) on his/her screen displaying recommendations regarding missing indications, necessary laboratory tests, evidence-base of current medication, dose adjustments for renal malfunction, potentially harmful drug-drug interactions, contra-indications, and possible adverse drug events. We set out to explore the usage of the PRIMA-eDS tool and the adoption of the recommendations provided by the CMR to optimise the tool and prepare it for its future implementation. METHODS: In a qualitative study carried out in North Rhine-Westphalia, Germany, 21 GPs using the PRIMA-eDS tool within the PRIMA-eDS study were interviewed. Interviews encompassed the GPs' attitudes regarding use of the electronic case report form and the CMR, their response to the recommendations, and the implementation of the tool into daily practice routine. The collected data were analysed applying thematic qualitative text analysis. RESULTS: GPs found the patient data entry into the electronic case report form to be inconvenient and time-consuming. The CMR was conducted often outside practice hours and without the patient present. GPs found that the PRIMA eDS CMR provided relevant information for and had several positive effects on the caring process. However, they encountered several barriers when wanting to change medication. CONCLUSIONS: It is unlikely that the PRIMA-eDS CMR will be used in the future as it is now as patient data entry is too time-consuming. Several barriers towards deprescribing medications were found which are common in deprescribing studies. Given the positive attitude towards the CMR, a new way of entering patient data into the PRIMA-eDS tool to create the CMR needs to be developed. PMID- 29986669 TI - Factors associated with quality of life in patients with Alzheimer's disease. AB - BACKGROUND: Evaluation of health-related quality of life (HRQoL) in patients with Alzheimer's disease (AD) is necessary to ensure optimal management. Several scales for assessing HRQoL of patients with AD exist, in particular the Quality of Life in Alzheimer's Disease (QoL-AD), which includes an evaluation by the caregiver of the patient's HRQoL. The aim of this study was to identify factors associated with patient, caregiver and overall HRQoL as assessed by the QoL-AD. METHODS: Cross-sectional multicenter study in subjects aged 65 years and older, with mild to moderate AD. HRQoL scores from the QoL-AD were recorded (3 scores, corresponding to patient, caregiver and overall), as well as sociodemographic variables for the patient and the caregiver, and data from the geriatric cognitive assessment (cognitive, psycho-behavioral, functional evaluations). Caregiver burden was evaluated using the Zarit caregiver burden scale. Factors associated with each QoL-AD score were identified by multivariate linear regression using t-tests and beta estimations. Study was registered in Clinical Trial.gov (NCT02814773). RESULTS: In total, 123 patients with AD were included. For the patient QoL-AD evaluation, depression was significantly associated with lower HRQoL (beta = - 2.56 +/- 1.28, p = 0.04), while polypharmacy (beta = - 1.80 +/- 0.99, p = 0.07) and anxiety (beta = - 1.70 +/- 1.01, p = 0.09) tended to be associated with lower HRQoL scores. In terms of caregiver evaluations, depression (beta = - 3.46 +/- 1.09, p = 0.002), polypharmacy (beta = - 1.91 +/- 0.92, p = 0.04) and the presence of caregiver burden (beta = - 3.50 +/- 0.91, p = 0.0002) were associated with lower HRQoL. For the overall evaluation, depression (beta = 3.26 +/- 1.02, p = 0.002) and polypharmacy (beta = - 1.85 +/- 0.81, p = 0.03) were significantly related to lower HRQoL. CONCLUSIONS: Depression and polypharmacy were two factors influencing HRQoL in patients with AD, both by patient self-report and on the caregiver report. Thus, despite the discrepancies between HRQoL as assessed by patients with AD and HRQoL as assessed by their caregiver, the caregiver's assessment may be used to guide patient management when the patient can no longer complete QoL evaluations. Moreover, the association between caregiver burden and the caregiver's QoL-AD score underlines the need to take caregivers into consideration in the overall management of the AD patient. PMID- 29986670 TI - Correlation between circulating tumour DNA and metabolic tumour burden in metastatic melanoma patients. AB - BACKGROUND: Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB). METHODS: Thirty-two treatment naive metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR). RESULTS: CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of <=10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR. CONCLUSIONS: We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naive metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden. PMID- 29986671 TI - Influence of pterygium size on corneal higher-order aberration evaluated using anterior-segment optical coherence tomography. AB - BACKGROUND: The prospective observation study aimed to evaluate changes in corneal higher-order aberrations induced by advancement of pterygium using an anterior-segment optical coherence tomography (AS-OCT) and Zernike aberration analysis. METHODS: The corneal topography of 284 eyes with primary pterygia originating from the nasal region was measured using an AS-OCT (SS-1000, Tomey). With anterior corneal elevation data, Zernike polynomial coefficients were calculated in diameters of 1.0, 3.0, and 5.0 mm, and the coma, spherical, coma like, spherical-like, and total higher-order aberrations were obtained. Pterygium size was also measured as a ratio of positions of the pterygium end with respect to the corneal diameter and categorized in eight classes: less than 15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45, and 45% or larger. Increases in the aberrations were analyzed with reference to those in eyes with pterygium size < 15%. RESULTS: The mean age of the participants was 69.3 years, and the pterygium size ranged from 2 to 57% (mean: 28.8%). The coma aberration significantly increased when the pterygium size was 45% or larger in 1.0 and 3.0 mm diameters and over 25-30% in 5.0 mm diameter. Similar increases were found in the pterygium sizes exceeding 45, 40, and 25%, respectively, in the coma-like, spherical-like, and total higher-order aberrations. On contrast, there was no increase in the spherical aberration. CONCLUSION: Increases in higher-order aberrations reflected the pterygium size, and significant aberrations were induced in 5.0 mm diameter when the end exceeded 25% of corneal diameter. The use of AS-OCT and Zernike analysis could enable objective grading of pterygium advancement based on changes in corneal optics. PMID- 29986672 TI - Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: study protocol of a randomised controlled trial to evaluate the effect of short message service (SMS) reminder. AB - BACKGROUND: Medication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy. METHODS/DESIGN: In this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the chi2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (< 18.4 pmol/L versus >=18.4 pmol/L) will be compared using the chi2 test, and the logistic regression. Further, the assessment of knowledge, attitude, behaviour, and barriers and facilitating factors of medication adherence will be made via logistic regression. DISCUSSION: This will be the first study to evaluate short-term clinical outcomes from SMS reminder for breast cancer patients on aromatase inhibitor therapy. Random allocation to SMS reminder or control arm ensures that patients in both arms will be comparable with respect to demographic and clinical characteristics, and any difference in outcomes can be attributed to the intervention. Participants are not blinded to the assignment of intervention, thus there may be potential for bias in outcome assessments. TRIAL REGISTRATION: NCT02524548 . Retrospectively registered on 17 August 2015. PMID- 29986674 TI - Phacoemulsification with hydrodelineation and OVD-assisted hydrodissection in posterior polar cataract. AB - BACKGROUND: To evaluate the results and complications of phacoemulsification with hydrodelineation and ophthalmic viscosurgical device (OVD)-assisted hydrodissection for posterior polar cataract (PPC). METHODS: Medical records of 24 eyes from 17 patients with clinical diagnosis of PPC, who underwent phacoemulsification with hydrodelineation and OVD-assisted hydrodissection, were retrospectively reviewed. RESULTS: The incidence of posterior capsule rupture (PCR) was 16.67% (4/24): 2 cases occurred during epinucleus removal, and 2 cases occurred during OVD removal after the implantation of the intraocular lens into the bag. No nucleus piece or lens materials dropped into the vitreous during cataract surgery, and no obvious postoperative complications were found during follow-up. All patients had improved best-corrected visual acuity (BCVA) 1 month postoperatively. CONCLUSION: OVD-assisted hydrodissection could be an effective technique in phacoemulsification to reduce the incidence of PCR and achieve satisfactory postoperative outcomes. PMID- 29986675 TI - Intimate partner violence and abuse against Nigerian women resident in England, UK: a cross- sectional qualitative study. AB - BACKGROUND: Intimate partner violence and abuse is a public health problem affecting more than one third of all women globally. It usually takes place between individuals in intimate relationships and/or within the family. In the United Kingdom (UK), while theoretical and policy interventions have led to an increase in intimate partner violence and abuse service provision for women, there is paucity of research on the disclosure and help-seeking practices of women from ethnic minority populations. METHODS: A cross-sectional qualitative research design was utilised. This included individual, in-depth semi-structured interviews with Nigerian women (n = 16) resident in England with lived experience of intimate partner violence and abuse. The interviews were conducted between May 2012 and May 2013, and data were analysed using thematic analysis technique. RESULTS: Three main themes were identified as factors influencing the disclosure and help-seeking practices of Nigerian (ethnic minority population) women in England, UK. These are socialisation from country of birth, immigration status, and acculturation in the country of immigration. CONCLUSIONS: Nigerian (ethnic minority populations) women resident in England with lived experience of abuse are likely to seek help from leaders and members of their ethnic community groups and faith-based organisations. There is need for collaborative working with ethnic community groups and faith-based organisations to enhance access and facilitate the utilisation of existing intimate partner violence services. PMID- 29986673 TI - The BabySeq project: implementing genomic sequencing in newborns. AB - BACKGROUND: The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. The "BabySeq Project" is a randomized trial that explores the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. METHODS: Families of newborns are enrolled from Boston Children's Hospital and Brigham and Women's Hospital nurseries, and half are randomized to receive genomic sequencing and a report that includes monogenic disease variants, recessive carrier variants for childhood onset or actionable disorders, and pharmacogenomic variants. All families participate in a disclosure session, which includes the return of results for those in the sequencing arm. Outcomes are collected through review of medical records and surveys of parents and health care providers and include the rationale for choice of genes and variants to report; what genomic data adds to the medical management of sick and healthy babies; and the medical, behavioral, and economic impacts of integrating genomic sequencing into the care of healthy and sick newborns. DISCUSSION: The BabySeq Project will provide empirical data about the risks, benefits and costs of newborn genomic sequencing and will inform policy decisions related to universal genomic screening of newborns. TRIAL REGISTRATION: The study is registered in ClinicalTrials.gov Identifier: NCT02422511 . Registration date: 10 April 2015. PMID- 29986676 TI - Protocol for a cluster randomized controlled trial to study the effectiveness of an obesity and diabetes intervention (PASOS) in an immigrant farmworker population. AB - BACKGROUND: Studies have shown that the prevalence of overweight, obesity and diabetes are higher in the largely Hispanic, immigrant farmworker population in California. Though to date, few interventional studies have focused on these issues in this at-risk population. The objective of this paper is to describe the study design of a cluster randomized controlled trial aimed at evaluating the effectiveness of an obesity and diabetes work place intervention in an immigrant farm worker population. METHODS: PASOS is an obesity and diabetes intervention program that will be implemented on ranches where immigrant farmworkers spend a considerable amount of time each day. This cluster randomized controlled study will enroll approximately 600 farmworkers. Using a uniform distribution for random number generation, ranches are randomized using a 1:1 ratio as either control or intervention. Baseline data will be taken from eligible participants and analyzed against data collected at the post-intervention, 6-month, 1-year, and 1.5-year follow-ups. The enrollment period is 1.5 years. DISCUSSION: Few studies have been conducted that aim to evaluate the effectiveness of a worksite intervention for obesity and diabetes prevention in a largely Hispanic, farmworker population. This study has been tailored to this population in order to enhance the feasibility of implementation and retention. If successful in reducing obesity and increasing healthy lifestyle choices to reduce diabetes, this study design can be implemented on a larger scale. TRIAL REGISTRATION: NCT02480244 . Registered 24 June 2015. PMID- 29986677 TI - Comparison of two bone markers with growth evolution in 74 girls with central precocious puberty. AB - BACKGROUND: The bone markers bone alkaline phosphatase (BAP) and C-terminal telopeptide of type I collagen crosslinks (CTX) are correlated with growth rate during normal puberty. The objective of this study was to evaluate the relationship between the serum concentrations of BAP and CTX and growth evolution in girls with idiopathic central precocious puberty (CPP) to help predict adult height. METHODS: A retrospective single-center study was conducted in 74 girls with CPP for whom a serum sample at initial evaluation was available to retrospectively measure BAP and CTX concentrations; 66.2% of them were untreated. RESULTS: The serum BAP concentrations showed significant positive correlations with height in standard deviations (SDS) at the initial evaluation (n = 62; r = 0.31; p = 0.015) and with the difference between bone and chronological ages (n = 61; r = 0.39; p = 0.002). BAP was also positively correlated with adult height as measured in both cm and SDS in untreated patients (n = 19; r = 0.58; p = 0.009). The serum CTX concentrations showed significant positive correlations with growth rate the year before the initial evaluation as measured in both cm and SDS (n = 65; r = 0.34; p = 0.006). CONCLUSIONS: This study revealed significant correlations of serum BAP and CTX concentrations with growth evolution in girls with CPP. The high positive correlation between serum BAP and adult height in untreated girls suggests that BAP can possibly be used to optimize models of adult height prediction in girls with CPP. PMID- 29986679 TI - Controlled before-after intervention study of suburb-wide street changes to increase walking and cycling: Te Ara Mua-Future Streets study design. AB - BACKGROUND: Achieving a shift from car use to walking, cycling and public transport in cities is a crucial part of healthier, more environmentally sustainable human habitats. Creating supportive active travel environments is an important precursor to this shift. The longevity of urban infrastructure necessitates retrofitting existing suburban neighbourhoods. Previous studies of the effects of street changes have generally relied on natural experiments, have included few outcomes, and have seldom attempted to understand the equity impacts of such interventions. METHODS: In this paper we describe the design of Te Ara Mua - Future Streets, a mixed-methods, controlled before-after intervention study to assess the effect of retrofitting street changes at the suburb scale on multiple health, social and environmental outcomes. The study has a particular focus on identifying factors that improve walking and cycling to local destinations in low-income neighbourhoods and on reducing social and health inequities experienced by Maori (Indigenous New Zealanders) and Pacific people. Qualitative system dynamics modelling was used to develop a causal theory for the relationships between active travel, and walking and cycling infrastructure. On this basis we selected outcomes of interest. Together with the transport funder, we triangulated best evidence from the literature, transport policy makers, urban design professionals and community knowledge to develop interventions that were contextually and culturally appropriate. Using a combination of direct observation and random sample face to face surveys, we are measuring outcomes in these domains of wellbeing: road-user behaviour, changes to travel mode for short trips, physical activity, air quality, road traffic injuries, greenhouse gas emissions, and perceptions of neighbourhood social connection, safety, and walking and cycling infrastructure . DISCUSSION: While building on previous natural experiments, Te Ara Mua - Future Streets is unique in testing an intervention designed by the research team, community and transport investors together; including a wide range of objective outcome measures; and having an equity focus. When undertaking integrated intervention studies of this kind, a careful balance is needed between epidemiological imperatives, the constraints of transport funding and implementation and community priorities, while retaining the ability to contribute new evidence for healthy, equitable transport policy. The study was retrospectively registered as a clinical trial on 21 June 2018 in the ISCRTN registry: ISRCTN89845334 http://www.isrctn.com/ISRCTN89845334. PMID- 29986678 TI - NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD. AB - BACKGROUND: Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH. METHODS: In this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs. RESULTS: Results demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-beta), which in turn led pulmonary arteriolar remodeling in COPD lungs. CONCLUSION: These results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling. PMID- 29986680 TI - Resveratrol prevents nanoparticles-induced inflammation and oxidative stress via downregulation of PKC-alpha and NADPH oxidase in lung epithelial A549 cells. AB - BACKGROUND: Exposure to carbon black nanoparticles (CBNPs), a well-known industrial production, promotes pulmonary toxicity through inflammation and oxidative stress. Recent studies show that some polyphenols exert their antioxidant properties through regulation of protein kinase C-alpha (PKC-alpha) and NADPH oxidase (Nox) signaling. Resveratrol, a dietary polyphenol in fruits, possesses various health beneficial effects including anti-inflammatory and antioxidative properties. In this study, we aimed to elucidate the involvement of PKC-alpha and Nox in CBNPs-induced inflammation and oxidative stress, and to investigate the protective effects of resveratrol on CBNP-induced inflammation and oxidative stress in human lung epithelial A549 cells. METHODS: The production of reactive oxygen species (ROS) and the change of mitochondrial membrane potential (DeltaPsim) were measured by flow cytometry. Nitric oxide (NO) was measured using the Griess reagent, and prostaglandin E2 (PGE2) production was detected by ELISA, while protein expressions were measured by Western blotting analysis. RESULTS: In lung epithelial A549 cells, CBNPs significantly enhanced oxidative stress by upregulation of Nox2 and membrane expression of p67phox accompanied with increase of ROS production. CBNPs also increased inflammatory factors, including iNOS, COX-2, NO and PGE2. However, resveratrol attenuated the above effects induced by CBNPs in A549 cells; additionally, CBNPs-induced activation of PKC-alpha was observed. We found that PKC-alpha inhibitor (Go6976) could attenuate CBNPs-induced inflammation by down-regulation of ROS, NO and PGE2 production in A549 cells, suggesting PKC-alpha might be involved in CBNPs-induced oxidative stress and inflammation. Our results also found resveratrol was able to inhibit protein expression of PKC-alpha induced by CBNPs. Moreover, ROS scavenger (NAC) and Nox inhibitor (DPI) attenuated CBNPs-induced expressions of iNOS and COX-2. DPI could also attenuate CBNPs-induced ROS, NO and PGE2 production. CONCLUSIONS: Resveratrol attenuated CBNPs-induced oxidative and inflammatory factors in lung epithelial A549 cells, at least in part via inhibiting PKC-alpha- and Nox-related signaling. PMID- 29986681 TI - The relationship between objectively-measured attributes of the built environment and selected cardiovascular risk factors in a South African urban setting. AB - BACKGROUND: Evidence concerning the relationship between objectively-measured attributes of the built environment with cardio-metabolic risk in populations from lower- and middle-income countries is lacking. In this paper, we describe the association between the objectively-measured built environment with body mass index, blood pressure and physical activity in adult South Africans. METHODS: This cross-sectional study included 341 adults aged >=35 years drawn from the Cape Town arm of the Prospective Urban Rural Epidemiology (PURE) cohort study. All Cape Town PURE participants were invited to take part in the study. Actigraph GT3X accelerometer and Geographic Information Systems were used to measure physical activity and built environment attributes (community center, shopping center and taxi rank). RESULTS: In age and sex adjusted models (reference 500 m), access to community centers (1000 m) was positively related to body mass index [beta 4.70 (95%CI: 2.06 to 7.34)] and diastolic blood pressure [4.97 (0.00 to 9.95)]. Distance from a community center (1600 m) was positively related to diastolic blood pressure [6.58 (1.57 to 11.58)] and inversely with moderate-to vigorous physical activity [- 69.30 (- 134.92 to - 3.70)]. Distance to a shopping center (1600 m) was positively related to body mass index [4.78 (1.11 to 8.45)] and shopping center (1000 m) was positively related to systolic blood pressure respectively [76.99 (0.03 to 83.95)]. CONCLUSION: Distance to community and shopping centers were significantly associated with BMI, systolic, diastolic blood pressure and moderate-to-vigorous physical activity. Future research should include multiple aspects of built environment variables in order to provide for a broader understanding of their effect on cardiovascular risk profile of African populations. PMID- 29986682 TI - Coronal and sagittal balance in Lenke 5 AIS patients following posterior fusion: important role of the lowest instrument vertebrae selection. AB - BACKGROUND: Lenke 5 AIS is a kind of three-dimensional deformity and literature reported it usually accompany with coronal or/and sagittal imbalance. However, the postoperative coronal and sagittal balance in these patients has rarely be analyzed previously and the predict factors for postoperative trunk balance are still unclear. To synthetically analysis coronal and sagittal balance of Lenke 5 AIS patients simultaneously and found out predict factors for postoperative coronal or/and sagittal imbalance. METHODS: Fifty-six Lenke 5 AIS patients who underwent posterior surgery and be followed up more than 2 years were included in this study. Coronal parameters included main curve Cobb angle, lumbosacral hemi curve Cobb angle, preoperative LEV/LIV tilt and translation and C7-CSVL distance; While sagittal parameters included pelvic incidence(PI), sacral slope(SS), pelvic tilt(PT), lumbar lordosis(LL), thoracic kyphosis(TK), and sagittal vertical axis(SVA). Coronal imbalance was defined as C7-CSVL> 20 mm, and sagittal imbalance defined as (1) SVA > 40 mm or (2) PT < 20% PI/2 or PT > 20 degrees or (3) PI-LL > 10 degrees . And relative parameters were compared between balance and imbalance group to find out predict factors. RESULTS: All seven final coronal imbalance patients occurred in LIV = L5 group. Preoperative LIV tilt(11.4 degrees ) and translation(5.2 mm) in coronal imbalance group were abnormally lower than balance group (21.7 degrees and 15.7 mm respectively). Eighteen patients performed final sagittal imbalance. The PI in these patients (37.7 degrees ) was significantly lower than balance group (48.0 degrees ). And most of finial sagittal imbalance patients also occurred in LIV = L5 group. CONCLUSIONS: LIV = L5 as a threshold point, represents higher risk of postoperative coronal and/or sagittal imbalance. Besides, large LEV-S1 curve in reduce-bending film and small PI is directly related to final coronal imbalance and sagittal imbalance respectively. PMID- 29986683 TI - Effectiveness of early intervention programs for parents of preterm infants: a meta-review of systematic reviews. AB - BACKGROUND: Various intervention programs exist for parents of preterm babies and some systematic reviews (SRs) have synthesised the evidence of their effectiveness. These reviews are, however, limited to specific interventions, components, or outcomes, and a comprehensive evidence base is lacking. The aim of this meta-review was to appraise and meta-synthesise the evidence from existing SRs to provide a comprehensive evidence base on the effectiveness of interventions for parents of preterm infants on parental and infant outcomes. METHODS: We conducted a comprehensive search of the following databases to identify relevant SRs: Cochrane library, Web of science, EMBASE, CINAHL, British Nursing Index, PsycINFO, Medline, ScienceDirect, Scopus, IBSS, DOAJ, ERIC, EPPI Centre, PROSPERO, WHO Library. Additional searches were conducted using authors' institutional libraries, Google Scholar, and the reference lists of identified reviews. Identified articles were screened in two stages against an inclusion criteria with titles and abstracts screened first followed by full-text screening. Selected SRs were appraised using the AMSTAR tool. Extracted data using a predesigned tool were synthesised narratively examining the direction of impact on outcomes. RESULTS: We found 11 SRs eligible for inclusion that synthesised a total of 343 quantitative primary studies. The average quality of the SRs was 'medium'. Thirty four interventions were reported across the SRs with considerable heterogeneity in the structural framework and the targeted outcomes that included maternal-infant dyadic, maternal/parental, and infant outcomes. Among all interventions, Kangaroo Care (KC) showed the most frequent positive impact across outcomes (n = 19) followed by Mother Infant Transaction Program (MITP) (n = 14). Other interventions with most consistent positive impact on infant outcomes were Modified-Mother Infant Transaction Program (M-MITP) (n = 6), Infant Health and Development Program (IHDP) (n = 5) and Creating Opportunities for Parent Empowerment (COPE) (n = 5). Overall, interventions with both home and facility based components showed the most frequent positive impact across outcomes. CONCLUSIONS: Neonatal care policy and planning for preterm babies should consider the implementation of interventions with most positive impact on outcomes. The heterogeneity in interventions and outcomes calls for the development and implementation of an integrated program for parents of preterm infants with a clearly defined global set of parental and infant outcomes. PMID- 29986684 TI - Smart medical beds in patient-care environments of the twenty-first century: a state-of-art survey. AB - BACKGROUND: Recent scientific achievements and technological advances have brought forward a massive display of new or updated medical devices, enabled with highly-developed embedded-control functions and interactivity. From the final decade of the twentieth century, medical beds have particularly been affected by this surge, taking on new forms and functions, while accommodating to established properties that have become well-known for these devices. The past fifteen years have also brought forward changes to conceptual frameworks, concerning the product design and manufacturing processes (standards), as well as the patient (perspectives on patient-care environments and accessibility). This work presents a state-of-art survey on electric medical beds, representing what is defined as the time of "smart beds", as part of an increasingly comprehensive patient-care environment. METHODS: A survey and assessment of market trends, research efforts and standards related to smart medical beds was performed, covering a wide range of public records of intellectual property, models and related healthcare solutions, as well as relevant research efforts in the field between 2000 and 2016. Contextual topics, necessary for the understanding of this subject, on novel technologies, disability and the reach of healthcare systems, were also researched and interpreted. RESULTS: The new generation of electric medical beds is defined, with the final stage of the proposed timeline for these devices being covered. Functional, aesthetic and interactive features are presented, and the current global market for medical beds and related standards are also assessed. Finally, discussions concerning rising challenges and opportunities for these systems are explored, with the potential for adding further monitoring and assistive implementations into medical devices and environments being highlighted. CONCLUSIONS: Smart medical beds are integrated solutions for patient care, assistance and monitoring, based on a comprehensive, multidisciplinary design approach. Research in this field is critical in a context of global ageing, and powered by a surge in opportunities for accessibility solutions. Smart beds, seamlessly integrated into the healthcare system, have a unique opportunity in enabling more efficient efforts for caregivers, and more responsive environments for patients. PMID- 29986685 TI - Protective effects of Liuweiwuling tablets on carbon tetrachloride-induced hepatic fibrosis in rats. AB - BACKGROUND: Liuweiwuling tablets (LWWL) are an herbal product that exerts remarkable effects on liver protection and aminotransferase levels, and they have been approved by the Chinese State Food and Drug Administration (CFDA). Clinical studies have found that LWWL can inhibit collagen production and reduce the levels of liver fibrosis markers in the serum. Thus, LWWL is expected to have beneficial effects in the treatment of liver fibrosis. The purpose of this study was to evaluate the pharmacological effects of LWWL. METHODS: Hepatic fibrosis was induced in rats via carbon tetrachloride (CCl4) treatment. The rats were treated twice weekly for 8 weeks with either 2 mL.kg- 1 body weight of a 50% solution of CCl4 in olive oil or olive oil alone by oral gavage. A subset of rats received daily intraperitoneal injections of either colchicine (0.2 mg/kg per day), LWWL (0.4, 1.6, or 6.4 g/kg per day), or vehicle (N = 12 for all groups) during weeks 9-12. The rats were sacrificed after 12 weeks. Pathological changes in hepatic tissue were examined using hematoxylin and eosin (H&E) and Sirius Red staining. Immunohistochemistry was performed to observe alpha-smooth muscle actin (alpha-SMA) and collagen type I (collagen I) protein expression. Western blotting was also used to detect alpha-SMA protein expression. Real-time quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to detect transforming growth factor-1 (TGF-beta1), platelet-derived growth factor (PDGF), tissue inhibitor of metalloproteinase-1 (TIMP1), and tissue inhibitor of metalloproteinase-2 (TIMP2) mRNA expression. RESULTS: LWWL significantly reversed histological fibrosis and liver injury, reduced the hydroxyproline content in liver tissue, and decreased alpha-SMA and collagen I expression. LWWL also suppressed hepatic stellate cell (HSC) activation by reducing the expression of the profibrogenic factors TGF-beta1 and PDGF. The expression levels of TIMP1 and TIMP2, which regulate extracellular matrix (ECM) degradation, were decreased after CCl4 injury in LWWL-treated rats. CONCLUSIONS: These data suggest that LWWL may serve as a promising therapeutic agent to reduce fibrogenesis. PMID- 29986686 TI - CogChamps: impact of a project to educate nurses about delirium and improve the quality of care for hospitalized patients with cognitive impairment. AB - BACKGROUND: Achieving sustainable practice changes to ensure best-practice nursing care in acute hospital environments can be challenging and is not well understood. A multi-faceted practice change intervention was implemented in a large Australian hospital to enhance the capacity of the nursing workforce to provide quality care for older patients with cognitive impairment (CI). METHODS: Thirty-four experienced Registered Nurses (RNs) became Cognition Champions (CogChamps), and led practice-change initiatives to improve nursing care for older patients (>=65 years) on six wards in one hospital. The CogChamps received comprehensive education about dementia and the identification, prevention, and management of delirium. Over five months, they were supported to develop and implement ward-specific Action Plans designed to change care practices. Nurse patient interactions were observed and patient charts were audited prior to the implementation of the plans and regularly throughout, using a purpose built Audit/ Observational tool. Data were also collected at a comparable hospital where there were no CogChamps. Data were analyzed for evidence of practice change. RESULTS: Observational and audit data were collected for 181 patients (average age = 82.5 years) across the two hospitals. All patients had CI and both cohorts had similar behavioral characteristics requiring a high level of care assistance [e.g. 38% displayed evidence of confusion/disorientation and a majority experienced meal-time difficulty (62-70%)]. While nursing practices were generally the same at both hospitals, some differences were evident (e.g. analgesia use was higher at the control hospital). Following implementation of Action Plans, significant increases in nurses' assessments of patients' cognitive functioning (35 to 69%), and administration of analgesia (27 to 48%) were observed at the intervention hospital, although only the improvement in cognitive assessments was maintained at three months follow-up. No other changes in nursing processes were evident. CONCLUSION: The CogChamps project demonstrates how RN champions were empowered to educate their colleagues about dementia and delirium resulting in a sustained increase in cognitive assessments by ward nurses. Practice improvements were mostly associated with clearly defined Action Plan tasks and goals and where responsibility for task completion was clearly assigned. These elements appear to be important when implementing practice changes. TRIAL REGISTRATION: Australian Clinical Trials Registration Number: ACTRN 12617000563369 . Retrospectively registered. PMID- 29986687 TI - Cross-national aspects of cyberbullying victimization among 14-17-year-old adolescents across seven European countries. AB - BACKGROUND: The increasing use of the Internet and social network sites (SNS) has created a new domain of socio-emotional development for adolescents. The aim of this cross-sectional study was to explore cybervictimization across seven European countries, in relation to socio-demographic, Internet use and psychosocial variables. METHODS: A cross-sectional school-based study was conducted in the participating countries: Germany, Greece, Iceland the Netherlands, Poland, Romania and Spain. Anonymous self-completed questionnaires included sociodemographic data, internet usage characteristics, school achievement, parental control, the Internet Addiction Test and Achenbach's Youth Self-Report. RESULTS: The highest rate of cyber victimization was found in Romania (37.3%) and the lowest in Spain (13.3%). Multiple logistic regression analyses gave differing results between countries. In Romania, Poland and Germany cyberbullying victimization was associated with SNS use, whereas Internet use was associated with increased odds of cybervictimization only in Romania. Cybervictimization was associated with greater internalizing behavior problems in all countries analysed, and with externalizing problems in all except Romania. CONCLUSIONS: Cyberbullying victimization is an on-going problem, which is subject to country-specific socio-demographic factors and diverse patterns of current Internet use and its development. Preventive measures should emphasize the integration of Internet communication technology education in educational contexts, and focus on the consistent association between cybervictimization and internalizing and externalizing difficulties. PMID- 29986688 TI - Evaluating the effectiveness of a multi-component intervention on early childhood development in paediatric HIV care and treatment programmes: a randomised controlled trial. AB - BACKGROUND: HIV infection in a family may affect optimum child development. Our hypothesis is that child development outcomes among HIV-exposed infants will be improved through a complex early childhood stimulation (ECS) programme, and income and loans saving programme for HIV positive parents. METHODS: The study was a cluster-randomized controlled trial in 30 clinic sites in two districts in Zimbabwe. Clinics were randomised in a 1:1 allocation ratio to the Child Health Intervention for Development Outcomes (CHIDO) intervention or Ministry of Health standard care. The CHIDO intervention comprises three elements: a group ECS parenting programme, an internal savings and lending scheme (ISALS) and case management home visits by village health workers. The intervention was aimed at caregiver-child dyads (child aged 0-24 months) where the infant was HIV exposed or infected. The primary outcomes were cognitive development (assessed by the Mullen Scales of Early Learning) and retention of the child in HIV care, at 12 months after enrolment. A comprehensive process evaluation was conducted. DISCUSSION: The results of this cluster-randomised trial will provide important information regarding the effects of multi-component interventions in mitigating developmental delays in HIV-exposed infants living in resource-limited environments. TRIAL REGISTRATION: This trial is registered with the Pan African Clinical Trials Registry ( www.pactr.org ), registration number PACTR201701001387209; the trial was registered on 16th January 2017 (retrospectively registered). PMID- 29986690 TI - Cost-effectiveness of Family Group Conferencing in child welfare: a controlled study. AB - BACKGROUND: This study aimed to examine the short- and long term (cost-) effectiveness of Family Group Conferencing (FGC) compared to care as usual (CAU) in terms of improved child safety, empowerment and social support. METHODS: A subgroup of a larger randomized controlled trial, comprising 69 families in child welfare (experimental group: n = 46; control group: n = 23), was included. RESULTS: No additional effects of FGC on child safety, social support and only short-term positive effects on empowerment were found. There were no differences in costs between FGC and CAU. The chance for FGC to be cost-effective was small. For families who refused FGC, the FGC approach was more cost-effective than CAU, whereas it was less cost-effective for families that prepared or completed FGC. CONCLUSIONS: Overall, FGC is not (cost-)effective in improving child safety, empowerment and social support, but cost-effectiveness varies at different levels of FGC-completion. TRIAL REGISTRATION: Dutch Trial Register number NTR4320 . Registered 17 December 2013. PMID- 29986689 TI - Standards of practice in empirical bioethics research: towards a consensus. AB - BACKGROUND: This paper reports the process and outcome of a consensus finding project, which began with a meeting at the Brocher Foundation in May 2015. The project sought to generate and reach consensus on standards of practice for Empirical Bioethics research. The project involved 16 academics from 5 different European Countries, with a range of disciplinary backgrounds. METHODS: The consensus process used a modified Delphi approach. RESULTS: Consensus was reached on 15 standards of practice, organised into 6 domains of research practice (Aims, Questions, Integration, Conduct of Empirical Work, Conduct of Normative Work; Training & Expertise). CONCLUSIONS: Through articulating these standards we outline a position that encourages responses, and through those responses we will be able to identify points of agreement and contestation that will drive the conversation forward. In that vein, we would encourage researchers, funders and journals to engage with what we have proposed, and respond to us, so that our community of practice of empirical bioethics research can develop and evolve further. PMID- 29986691 TI - Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL). AB - BACKGROUND: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. METHODS: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. RESULTS: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four compartment model with first-order elimination of drug from central plasma and CSF compartments. CONCLUSIONS: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03392714 ; retrospectively registered January 8, 2018. PMID- 29986692 TI - Assessment of facility readiness for implementing the WHO/UNICEF standards for improving quality of maternal and newborn care in health facilities - experiences from UNICEF's implementation in three countries of South Asia and sub-Saharan Africa. AB - BACKGROUND: There is a global drive to promote facility deliveries but unless coupled with concurrent improvement in care quality, it might not translate into mortality reduction for mothers and babies. The World Health Organization published the new "Standards for improving quality of care for mothers and newborns in health facilities" but these have not been tested in low- and middle income settings. UNICEF and its partners are taking the advantage provided by the Mother and Baby Friendly Hospital Initiative in Bangladesh, Ghana and Tanzania to test these standards to inform country adaptation. This manuscript presents a framework used for assessment of facility quality of care to inform the effect of quality improvement interventions. METHODS: This assessment employed a quasi experimental design with pre-post assessments in "implementation" and "comparison" facilities-the latter will have no quality improvement interventions implemented. UNICEF and assessment partners developed an assessment framework, developed uniform data collection tools and manuals for harmonised training and implementation across countries. The framework involves six modules assessing: facility structures, equipment, drugs and supplies; policies and guidelines supporting care-giving, staff recruitment and training; care-providers competencies; previous medical records; provider-client interactions (direct observation); and client perspectives on care quality; using semi-structured questionnaires and data collectors with requisite training. In Bangladesh, the assessment was conducted in 3 districts. In one "intervention" district, the district hospital and five upazilla health complexes were assessed. similar number of facilities were assessed each two adjoining comparison districts. In Ghana it was in three hospitals and five health centres and in Tanzania, two hospitals and four health centres. In the latter countries, same number of facilities were selected in the same number of districts to serve for comparison. Outcomes were structured to examine whether facilities currently provide services commensurate with their designation (basic or comprehensive emergency obstetric and newborn care). These outcomes were stratified so that they inform intervention implementation in the short-, medium- and long-term. CONCLUSION: This strategy and framework provides a very useful model for supporting country implementation of the new WHO standards. It will serve as a template around which countries can build quality of care assessment strategies and metrics to inform their health systems on the effect of QI interventions on care processes and outcomes. PMID- 29986693 TI - Detecting change in comparison to peers in NHS prescribing data: a novel application of cumulative sum methodology. AB - BACKGROUND: The widely used OpenPrescribing.net service provides standard measures which compare prescribing of Clinical Commissioning Groups (CCGs) and English General Practices against that of their peers. Detecting changes in prescribing behaviour compared with peers can help identify missed opportunities for medicines optimisation. Automating the process of detecting these changes is necessary due to the volume of data, but challenging due to variation in prescribing volume for different measures and locations. We set out to develop and implement a method of detecting change on all individual prescribing measures, in order to notify CCGs and practices of such changes in a timely manner. METHODS: We used the statistical process control method CUSUM to detect prescribing behaviour changes in relation to population trends for the individual standard measures on OpenPrescribing. Increases and decreases in percentile were detected separately, using a multiple of standard deviation as the threshold for detecting change. The algorithm was modified to continue re-triggering when trajectory persists. It was deployed, user-tested, and summary statistics generated on the number of alerts by CCG and practice. RESULTS: The algorithm detected changes in prescribing for 32 prespecified measures, across a wide range of CCG and practice sizes. Across the 209 English CCGs, a mean of 2.5 increase and 2.4 decrease alerts were triggered per CCG, per month. For the 7578 practices, a mean of 1.3 increase and 1.4 decrease alerts were triggered per practice, per month. CONCLUSIONS: The CUSUM method appears to effectively discriminate between random noise and sustained change in prescribing behaviour. This method aims to allow practices and CCGs to be informed of important changes quickly, with a view to improve their prescribing behaviour. The number of alerts triggered for CCGs and practices appears to be appropriate. Prescribing behaviour after users are alerted to changes will be monitored in order to assess the impact of these alerts. PMID- 29986694 TI - Childhood diabetes: a myth or reality?- perception of the public from a low income country: a cross-sectional study. AB - BACKGROUND: The diagnosis of Type 1 diabetes is commonly missed in most health facilities in Nigeria. Adequate knowledge of childhood diabetes is necessary for the recognition and possible intervention for the control of the disease. However, research to assess knowledge deficiencies and their relationship to attitude is lacking in most developing countries including Nigeria. This study intends to survey the beliefs and perceptions of caregivers of children towards diabetes in childhood. It also aims at determining the caregivers' depth of knowledge of diabetes in children, the relationship between knowledge and practices as well as the association between level of education and gender with practices and knowledge. The study outcome will help in the formulation of policy and education of the communities with regards to the preconceived myths and realities of childhood diabetes. METHODS: A descriptive study involving 500 respondents, population groups were selected by multi-staged sampling from different areas in Enugu metropolis, south-East of Nigeria. A validated structured interviewer-administered questionnaire was used. Ethical approval was obtained, and only consenting subjects were interviewed. Data was analyzed with Statistical Package for the Social Sciences (SPSS) version 20. RESULT: Almost all the respondents (99.8%) had heard of diabetes in adults. However, a lower proportion of respondents 43.2% knew about diabetes in childhood. Only 24.8% had good knowledge of the different aspects of diabetes. Although females were more knowledgeable about the effects of healthy life style modifications on diabetes, there was no gender predisposition in knowledge about diabetes in childhood. A positive association existed between knowledge and education [p < 0.001] concerning childhood diabetes. Irrespective of this association 82.6% of the respondents with good knowledge of the disease still had a poor attitude towards healthy life style practices. CONCLUSION: This study has shown that beliefs and perceptions of childhood diabetes among the adult caregivers in Enugu, south - East Nigeria is mostly erroneous and their knowledge deficient. Literacy did not improve both knowledge and attitude to healthy lifestyle practices. PMID- 29986695 TI - Proactive expert system intervention to prevent or quit at-risk alcohol use (PRINT): study protocol of a randomized controlled trial. AB - BACKGROUND: The population impact of alcohol screening and brief intervention might be increased by approaching an entire population rather than individuals at high risk only. The aim is to present the protocol of the study "Testing a proactive expert system intervention to prevent and to quit at-risk alcohol use" (PRINT) which tests the efficacy of a computer-based brief intervention (i) to elicit drinking reductions among persons with at-risk alcohol use and (ii) to prevent at-risk alcohol use among current low-risk drinkers. METHODS/DESIGN: The PRINT study is a two-arm randomized controlled trial with a 12-month follow-up. A total of 1648 participants will be proactively recruited in the waiting area of a municipal registry office. All 18- to 64-year-old persons with past year alcohol use will be randomized to either the intervention group or the control group. Participants in the intervention group will receive computer-generated individualized feedback letters at baseline, month 3, and month 6. Participants in the control group will receive assessment only. The primary outcome is the change in the number of drinks per day from baseline to month 12. DISCUSSION: We expect to provide a computer-based brief alcohol intervention that is appropriate for a wide range of people with alcohol use regardless of their initial alcohol risk level. The intervention might have the potential to decrease alcohol use and alcohol-related problems on a population level at low costs. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00014274 (date of registration: 2018/03/12). PMID- 29986696 TI - Correction to: decision-making at the limit of viability: differing perceptions and opinions between neonatal physicians and nurses. AB - After publication of the original article [1], the corresponding author noticed the given names and family names of the members included in the Swiss Neonatal End-of-Life Study Group were incorrectly reverted. PMID- 29986697 TI - Interleukin 8 is a biomarker of telomerase inhibition in cancer cells. AB - BACKGROUND: Telomerase activity is required for both initiation and maintenance of tumorigenesis and over 90% cancers overexpress telomerase. Therefore, telomerase targeting has emerged as a potential strategy for cancer treatment. In agreement with this, several telomerase inhibitors are being tested for cancer treatment and have shown some promise. However, because of the variability in response between the cancer patients, it is important to identify biomarkers that allow for distinguishing cancers that are responsive to telomerase inhibition from the cancers that are not. Therefore, in this study we performed experiments to identify a biomarker that can be used to predict telomerase inhibition induced tumor growth inhibition. METHODS: In our study, we have performed transcriptome wide gene expression analysis on multiple ovarian and colon cancer cell lines that were treated with telomerase inhibitor imetelstat and were responsive to telomerase inhibition-induced tumor growth attenuation. RESULTS: We demonstrate that telomerase inhibition by telomerase inhibitor imetelstat results in decreased expression of interleukin 8 (IL8) in all telomerase responsive cancer cell lines. This phenomenon is of general occurrence because we find that multiple ovarian and colon cell lines show decrease in IL8 mRNA and protein levels after telomerase inhibition. Additionally, we find loss of IL8 phenocopy Telomerase inhibition mediated growth inhibitory effect in cancer cells. CONCLUSION: Taken together, our results show that IL8 is a biomarker that predict telomerase inhibition mediated growth attenuation of cancer cells and its loss phenocopy telomerase inhibition. Therefore, IL8 expression can be utilized as a biomarker for telomerase targeted cancer therapies to potentially predict therapeutic response. PMID- 29986698 TI - Associations between post-operative rehabilitation of hip fracture and outcomes: national database analysis (90 characters). AB - BACKGROUND: Rehabilitation programmes are used to improve hip fracture outcomes. There is little published trial clinical trial or population-based data on the effects of the type or provider of rehabilitation treatments on hip fracture outcomes. We evaluated the associations of rehabilitation interventions with post operative hip fracture outcomes. METHODS: Cross-sectional (2013-2015) analysis of data from the English National Hip Fracture Database (NHFD) from all 191 English hospitals treating hip fractures. Of 62,844 NHFD patients, we included 17,708 patients with rehabilitation treatment and 30-day mobility data, and 34,142 patients with rehabilitation treatment and discharge destination data. The intervention was early mobilisation rehabilitation treatments delivered by a physiotherapist (PT, physical therapist in North America) or other clinical staff as identifiable in NHFD. We used ordinal logistic and propensity scoring regression models to adjust for confounding variables including age, sex, pre fracture mobility, operative delay, and cognitive function and peri-operative risk scores. RESULTS: In both the adjusted multivariate and propensity-weighted analyses, mobilisation on the day or the day following surgery is associated with better mobility function 30 days after discharge. However patients mobilised by a PT did not have better mobility compared to mobilisation by other professionals. Patients who received a PT assessment were not protected from poorer mobility 30 days after discharge, compared with those who did not receive an assessment. The discharge destination outcome is also better in mobilised than unmobilised patients, whether done by a PT or another health professional, and the difference persists, slightly attenuated, after propensity weighting. CONCLUSIONS: In addition to the type of health professional initiating mobilisation, data on rehabilitation treatment activity and post-operative gait speed is needed to determine optimum rehabilitation dosage and functional outcome. After adjustment patients mobilised by non-PTs did as well as patients mobilised by PTs, suggesting that PTs' current roles in very early rehabilitation should be reconsidered, with a view to redeploying them to more specialised later rehabilitation activity. PMID- 29986699 TI - Evaluation of anaesthesia and analgesia quality during disbudding of goat kids by certified Swiss farmers. AB - BACKGROUND: Certified Swiss farmers are allowed to disbud their goat kids using a standard intramuscularly administered anaesthetic mixture. This mixture, containing xylazine and ketamine, is officially distributed with the goal to provide a painless disbudding. This study aimed to evaluate the quality of analgesia and anaesthesia achieved during disbudding, when performed by Swiss farmers. To assess this, 174 goat kids at 31 different farms were observed and filmed during cautery disbudding. RESULTS: The standard anaesthetic mixture (0.05 mg/kg xylazine and 20 mg/kg ketamine) was used only in 71 goat kids. Fifty-eight goat kids were anaesthetised with different dosages of xylazine (median 0.18 mg/kg) and ketamine (median 10 mg/kg), 22 with xylazine only (median 0.61 mg/kg), 20 with xylazine (median 1.84 mg/kg) and perineural lidocaine (median 1.23 mg/kg), three with acepromazine (dosage unknown) and ketamine (10 mg/kg). Based on vocalisation, limb movement and head lifting during disbudding, a general reaction score was attributed to 168 goat kids (six were excluded due to firm restraint): 56.5% were scored zero (no limb movement, no vocalisation), 7.7% one, 17.3% two and 18.5% three (strong movements, vocalisation). Significant risk factors for higher reaction scores were the type of anaesthetic protocol and manipulation by the farmer during induction. Significant risk factors for longer recoveries were use of xylazine alone or xylazine in combination with perineural lidocaine, breed, younger age and recovery underneath heat lamp. CONCLUSIONS: The present study indicates that anaesthesia and analgesia of goat kids disbudded by Swiss farmers is inadequate, as 35.8% of the animals showed moderate to strong behavioural reactions during the procedure. Unexpectedly, only 40.8% of the goat kids were anaesthetised with the standard anaesthetic mixture and several other protocols were used. A refinement of the recommended protocol is urgently needed to guarantee animal welfare. PMID- 29986701 TI - Quality of life and owner attitude to dog overweight and obesity in Thailand and the Netherlands. AB - BACKGROUND: This study investigated whether the body condition score (BCS) and/or culture influences the quality of life (QoL) of dogs, as evaluated by the owner, and whether the BCS is influenced by feeding and exercise and its owner's culture. To this end, a questionnaire was administered to 355 selected dog owners (Thai and Dutch). Their dogs had a BCS of 3 (normal weight), 4 (overweight) or 5 (obese) but no other physical problems. Instead of using Likert scales, continuous scales were used. Further, data for the questionnaire items were transformed using an integrated z-score methodology. RESULTS: The magnitude of factor loadings was similar to that reported in a previous study, indicating that the questionnaire is not culture specific. QoL scores for general sickness were significantly higher (worse) in dogs with a higher BCS. Thus even though the dogs were apparently healthy, the BCS influenced the perceived QoL of the dog. Immobility was seen more often in dogs with a higher (poorer) BCS than in dogs with a lower (better) BCS; however, there was no clear relationship between immobility and total activity. The higher the BCS, the less owners felt in control of feeding and exercise. The BCS was higher in the dogs of owners who did not like to exercise. The Thai dogs showed more separation-related behaviour problems when their owner left home than did the Dutch dogs. CONCLUSIONS: The QoL of overweight and obese dogs is mainly influenced by the dog's physical status. The owners of dogs with a high BCS have less perceived control over feeding and exercise. Our findings indicate that owner attitudes and beliefs essentially cause obesity as a result of a lack of knowledge and perceived control. PMID- 29986700 TI - Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. AB - BACKGROUND: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. METHODS: An open-label, non inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. RESULTS: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%. CONCLUSIONS: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008. PMID- 29986702 TI - Characterization of primary normal and malignant breast cancer cell and their response to chemotherapy and immunostimulatory agents. AB - BACKGROUND: The phenomenon of chemotherapy-resistant cancers has necessitated the development of new therapeutics as well as the identification of specific prognostic markers to predict the response to novel drugs. Primary cancer cells provide a model to study the multiplicity of tumourigenic transformation, to investigate alterations of the cellular response to various molecular stimuli, and to test therapeutics for cancer treatment. METHODS: Here, we developed primary cultures of human breast tissue - normal cells (BN1), cancer cells (BC5), and cells from a chemotherapy-treated tumour (BrCCh1) to compare their response to conventional chemotherapeutics and to innate immunity stimulators with that of the immortalized breast cells MCF7, MDA-MB-231, and MCF10A. Expression of the progesterone receptor (PGR), oestrogen receptor (ER) alpha and beta, human epidermal growth factor receptor (HER) 2 and 3 and aromatase CYP19, as well as expression of interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) mRNA in human breast cells were characterized. RESULTS: We revealed that BC5 carcinoma cells were PGRlow/ERbhigh/ERa-/Cyp19+, the BrCCh1 cells that originated from the recurrent tumour were PGR-/ERb+/ERa-/Cyp19+, and normal BN cells were PGR-/ERb+/ERa-/Cyp19high. The treatment of primary culture cells with antitumour therapeutics revealed that BrCCh1 cells were doxorubicine-resistant and sensitive to cisplatin. BC5 cells exhibited low sensitivity to tamoxifen and cisplatin. The innate immunity activators interferon-alpha and an artificial small nucleolar RNA analogue increased expression of IFIT3 at different levels in primary cells and in the immortalized breast cells MCF7, MDA-MB-231, and MCF10A. The relative level of activation of IFIT3 expression was inversely correlated with the baseline level of IFIT3 mRNA expression in breast cell lines. CONCLUSION: Our data demonstrated that primary cancer cells are a useful model for the development of novel cancer treatments. Our findings suggest that expression of IFIT3 mRNA can be used as a prognostic marker of breast cancer cell sensitivity to immunostimulating therapeutics. PMID- 29986703 TI - Effects of sodium bicarbonate on cell growth, lipid accumulation, and morphology of Chlorella vulgaris. AB - BACKGROUND: Low concentration NaHCO3 (ca. 12 mM) had been demonstrated to be an excellent carbon source for industrially important green alga Chlorella vulgaris and high concentration NaHCO3 (e.g. 160 mM) had been shown to be capable of controlling protozoa and stimulating lipid accumulation of another green alga, i.e., Neochloris oleoabundans. Furthermore, little was known about the mechanisms of the effects of NaHCO3 on microalgae. Thorough studies on the effects of high NaHCO3 on C. vulgaris and their mechanisms were therefore warranted. METHODS: We systematically compared the cell growth, lipid production, and cell morphology of the industrially important C. vulgaris in 160 mM NaHCO3 or 160 mM NaCl media at different pH levels. These data allowed us to analyze the effects of total dissolved inorganic carbon (DIC) and individual DIC species on C. vulgaris. Cell growth of C. vulgaris at a range of concentrations at 160 mM or lower was also studied. RESULTS: Cellular lipid cell content of 494 mg g-1 and lipid productivity of 44.5 mg L-1 day-1 were obtained at 160 mM NaHCO3 and pH 9.5. High concentration NaHCO3 (e.g. 160 mM) was inhibitive to cell growth but stimulating to lipid accumulation and caused unicellular C. vulgaris to transfer to colonial cells. Increasing pH in the range of 7.5-9.5 caused increasing inhibition to cell growth in 160 mM NaCl. Whereas the optimal pH for cell growth was 8.5 for 160 mM NaHCO3 cultures. Comparative experiments with 0-160 mM NaHCO3 indicate that 10 mM was the optimal concentration and increasing NaHCO3 from 10 to 160 mM caused increasing inhibition to cell growth. CONCLUSIONS: High concentration DIC was inhibitor to cell growth but stimulator to lipid accumulation of C. vulgaris. It caused unicellular C. vulgaris to transform to colonial cells. Results suggest that high concentration of a particular DIC species, i.e., dCO2, was the primary stress responsible for cell growth inhibition. Where CO32- was likely the DIC species responsible for lipid stimulation of C. vulgaris. Furthermore, we propose that the colony formation at high DIC conditions was employed by C. vulgaris to mitigate the stress by minimizing cell exposure to unfavorable environment. PMID- 29986704 TI - Species-habitat associations in an old-growth temperate forest in northeastern China. AB - BACKGROUND: Species coexistence mechanisms and maintenance of biodiversity have long been considered important components of community ecology research. As one of the important mechanisms, species coexistence theory based on niche differentiation has received attention in past years. Thus, topography, through the formation of habitat heterogeneity, affects species distributions and coexistence. A 30-ha dynamic plot of mixed broadleaved-Korean pine (Pinus koraiensis) forest is located in the Heilongjiang Fenglin National Nature Reserve. We examined species-habitat associations using the torus-translation method. We aim to understand the habitat associations of different species, life forms (shrubs, trees), and shade tolerance (light-demanding, midtolerant, shade tolerant) across life stages (sapling, juvenile and mature), providing further evidence for the role of niche theory in temperate forests. RESULTS: Of the 33 species we tested, 28 species (84.8%) were at least significantly associated with one habitat type. Positive associations were more frequent in the valley and slope (shady and sunny) and less frequent on the ridge. Thirty-four significant positive associations with the five habitats were detected at three life stages (11, 11 and 12 at the sapling stage, juvenile stage, and mature stage, respectively). The trees were positively associated with the valley, and the shrubs were positively associated with sunny and ridge. The majority of species' habitat preferences shifted among different life stages; the exceptions were Corylus mandshurica, Maackia amurensis, Quercus mongolica, Picea jezoensis and Acer ukurunduense, which had consistent associations with the same habitat at all stages. The midtolerant trees and midtolerant shrubs were positively correlated with sunny across the three life stages. CONCLUSIONS: Most species show habitat preferences in the plot. These results indicate that niche theory plays an important role in species coexistence. Most species have no consistent association with habitat at different life stages. PMID- 29986706 TI - Facilitating evidence uptake: development and user testing of a systematic review summary format to inform public health decision-making in German-speaking countries. AB - BACKGROUND: Systematic reviews are an important source of evidence for public health decision-making, but length and technical jargon tend to hinder their use. In non-English speaking countries, inaccessibility of information in the native language often represents an additional barrier. In line with our vision to strengthen evidence-based public health in the German-speaking world, we developed a German language summary format for systematic reviews of public health interventions and undertook user-testing with public health decision makers in Germany, Austria and Switzerland. METHODS: We used several guiding principles and core elements identified from the literature to produce a prototype summary format and applied it to a Cochrane review on the impacts of changing portion and package sizes on selection and consumption of food, alcohol and tobacco. Following a pre-test in each of the three countries, we carried out 18 user tests with public health decision-makers in Germany, Austria and Switzerland using the 'think-aloud' method. We analysed participants' comments according to the facets credibility, usability, understandability, usefulness, desirability, findability, identification and accessibility. We also identified elements that hindered the facile and satisfying use of the summary format, and revised it based on participants' feedback. RESULTS: The summary format was well received; participants particularly appreciated receiving information in their own language. They generally found the summary format useful and a credible source of information, but also signalled several barriers to a positive user experience such as an information-dense structure and difficulties with understanding statistical terms. Many of the identified challenges were addressed through modifications of the summary format, in particular by allowing for flexible length, placing more emphasis on key messages and relevance for public health practice, expanding the interpretation aid for statistical findings, providing a glossary of technical terms, and only including graphical GRADE ratings. Some barriers to uptake, notably the participants' wish for actionable recommendations and contextual information, could not be addressed. CONCLUSIONS: Participants welcomed the initiative, but user tests also revealed their problems with understanding and interpreting the findings summarised in our prototype format. The revised summary format will be used to communicate the results of Cochrane reviews of public health interventions. PMID- 29986705 TI - Comprehensive genomic diagnosis of non-syndromic and syndromic hereditary hearing loss in Spanish patients. AB - BACKGROUND: Sensorineural hearing loss (SNHL) is the most common sensory impairment. Comprehensive next-generation sequencing (NGS) has become the standard for the etiological diagnosis of early-onset SNHL. However, accurate selection of target genomic regions (gene panel/exome/genome), analytical performance and variant interpretation remain relevant difficulties for its clinical implementation. METHODS: We developed a novel NGS panel with 199 genes associated with non-syndromic and/or syndromic SNHL. We evaluated the analytical sensitivity and specificity of the panel on 1624 known single nucleotide variants (SNVs) and indels on a mixture of genomic DNA from 10 previously characterized lymphoblastoid cell lines, and analyzed 50 Spanish patients with presumed hereditary SNHL not caused by GJB2/GJB6, OTOF nor MT-RNR1 mutations. RESULTS: The analytical sensitivity of the test to detect SNVs and indels on the DNA mixture from the cell lines was > 99.5%, with a specificity > 99.9%. The diagnostic yield on the SNHL patients was 42% (21/50): 47.6% (10/21) with autosomal recessive inheritance pattern (BSND, CDH23, MYO15A, STRC [n = 2], USH2A [n = 3], RDX, SLC26A4); 38.1% (8/21) autosomal dominant (ACTG1 [n = 3; 2 de novo], CHD7, GATA3 [de novo], MITF, P2RX2, SOX10), and 14.3% (3/21) X-linked (COL4A5 [de novo], POU3F4, PRPS1). 46.9% of causative variants (15/32) were not in the databases. 28.6% of genetically diagnosed cases (6/21) had previously undetected syndromes (Barakat, Usher type 2A [n = 3] and Waardenburg [n = 2]). 19% of genetic diagnoses (4/21) were attributable to large deletions/duplications (STRC deletion [n = 2]; partial CDH23 duplication; RDX exon 2 deletion). CONCLUSIONS: In the era of precision medicine, obtaining an etiologic diagnosis of SNHL is imperative. Here, we contribute to show that, with the right methodology, NGS can be transferred to the clinical practice, boosting the yield of SNHL genetic diagnosis to 50-60% (including GJB2/GJB6 alterations), improving diagnostic/prognostic accuracy, refining genetic and reproductive counseling and revealing clinically relevant undiagnosed syndromes. PMID- 29986707 TI - Changes in the fucoxanthin production and protein profiles in Cylindrotheca closterium in response to blue light-emitting diode light. AB - BACKGROUND: Marine diatoms have a higher fucoxanthin content in comparison to macroalgae. Fucoxanthin features many potent bioactive properties, particularly anti-obesity properties. Despite the great potential for harvesting larger amounts of fucoxanthin, the impacts of light quality (light source, intensity, and photoperiod) on fucoxanthin production and the essential proteins involved in fucoxanthin biosynthesis in marine diatoms remain unclear. RESULTS: In the present study, Cylindrotheca closterium was selected from four different species of diatoms based on its high fucoxanthin content and productivity. Optimal light conditions (light source, intensity, and regime) were determined by a "Design of Experiment" approach (software MODDE Pro 11 was used). The model indicated that an 18/6 light/darkness regime increased fucoxanthin productivity remarkably as opposed to a 12/12 or 24/0 regime. Eventually, blue light-emitting diode light, as an alternative to fluorescent light, at 100 MUmol/m2/s and 18/6 light/darkness regime yielded maximum fucoxanthin productivity and minimal energy consumption. The fucoxanthin production of C. closterium under the predicted optimal light conditions was assessed both in bottle and bag photobioreactors (PBRs). The high fucoxanthin content (25.5 mg/g) obtained from bag PBRs demonstrated the feasibility of large-scale production. The proteomes of C. closterium under the most favorable and unfavorable fucoxanthin biosynthesis light/darkness regimes (18/6 and 24/0, respectively) were compared to identify the essential proteins associated with fucoxanthin accumulation by matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Six proteins that were up regulated in the 18/6 regime but down-regulated in the 24/0 were identified as important chloroplastic proteins involved in photosynthesis, energy metabolism, and cellular processes. CONCLUSIONS: Blue light-emitting diode light at 100 MUmol/m2/s and 18/6 light/darkness regime induced maximum fucoxanthin productivity in C. closterium and minimized energy consumption. The high fucoxanthin production in the bag photobioreactor under optimal light conditions demonstrated the possibility of commercialization. Proteomics suggests that fucoxanthin biosynthesis is intimately associated with the photosynthetic efficiency of the diatom, providing another technical and bioengineering outlook on fucoxanthin enhancement. PMID- 29986708 TI - A role for telomere length and chromosomal damage in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a fatal lung disease characterized by a progressive formation of fibroblastic foci in the interstitium. This disease is strongly associated with telomere dysfunction but the extent of telomere shortening and consequent chromosomal damage within IPF lungs and with regional disease severity remains unknown. METHODS: Explanted IPF lungs (n = 10) were collected from transplant surgeries with six samples per lung analysed to capture the regional heterogeneity ranging from mild to severe disease. Non-used donor lungs (n = 6) were collected as "healthy" controls. Structural changes related to disease severity (microCT surface density), relative telomere length (real-time qPCR), and quantitative histology of chromosomal damage (gamma-H2A.X) and extracellular matrix (elastin, total collagen, collagen 1, and collagen 3) were measured. A multivariate linear mixed-effects model controlling for subject was used to identify association of disease severity or fibrotic markers with telomere length and chromosomal damage. RESULTS: We observed shorter telomere length (p = 0.001) and increased chromosomal damage (p = 0.018) in IPF lungs compared to controls. In IPF lungs, telomere length was associated with total collagen (p < 0.001) but not with structural changes of disease severity. Chromosomal damage was positively associated with increased elastin (p = 0.006) and negatively with structural disease severity (p = 0.046). Extensive gamma H2A.X staining was also present in airway epithelial cells. CONCLUSIONS: Telomere length and chromosomal damage are involved in IPF with regional variation in telomere length and chromosomal damage associated with pathological changes in tissue structure and the extracellular matrix. PMID- 29986709 TI - Indirect and direct routes to C-glycosylated flavones in Saccharomyces cerevisiae. AB - BACKGROUND: C-glycosylated flavones have recently attracted increased attention due to their possible benefits in human health. These biologically active compounds are part of the human diet, and the C-linkage makes them more resistant to hydrolysis and degradation than O-glycosides. In contrast to O glycosyltransferases, few C-glycosyltransferases (CGTs) have so far been characterized. Two different biosynthetic routes for C-glycosylated flavones have been identified in plants. Depending on the type of C-glycosyltransferase, flavones can be glycosylated either directly or indirectly via C-glycosylation of a 2-hydroxyflavanone intermediate formed by a flavanone 2-hydroxylase (F2H). RESULTS: In this study, we reconstructed the pathways in the yeast Saccharomyces cerevisiae, to produce some relevant CGT substrates, either the flavanones naringenin and eriodictyol or the flavones apigenin and luteolin. We then demonstrated two-step indirect glycosylation using combinations of F2H and CGT, to convert 2-hydroxyflavanone intermediates into the 6C-glucoside flavones isovitexin and isoorientin, and the 8C-glucoside flavones vitexin and orientin. Furthermore, we established direct glycosylation of flavones using the recently identified GtUF6CGT1 from Gentiana triflora. The ratio between 6C and 8C glycosylation depended on the CGT used. The indirect route resulted in mixtures, similar to what has been reported for in vitro experiments. In this case, hydroxylation at the flavonoid 3'-position shifted the ratio towards the 8C glucosylated orientin. The direct flavone glycosylation by GtUF6CGT1, on the other hand, resulted exclusively in 6C-glucosides. CONCLUSIONS: The current study features yeast as a promising host for production of flavone C-glycosides, and it provides a set of tools and strains for identifying and studying CGTs and their mechanisms of C-glycosylation. PMID- 29986710 TI - Prospective evaluation of the Quality of Life after Brain Injury (QOLIBRI) score: minor differences in patients with major versus no or mild traumatic brain injury at one-year follow up. AB - BACKGROUND: The Quality of Life after Brain Injury (QOLIBRI) score was developed to assess disease-specific health-related quality of life (HRQoL) after traumatic brain injury (TBI). So far, validation studies on the QOLIBRI were only conducted in cohorts with traumatic brain injury. This study investigated the longer-term residuals in severely injured patients, focusing specifically on the possible impact of major TBI. METHODS: In a prospective questionnaire investigation, 199 survivors with an injury severity score (ISS) > 15 participated in one-year follow-up. Patients who had sustained major TBI (abbreviated injury scale, AIS head > 2) were compared with patients who had no or only mild TBI (AIS head <= 2). Univariate analysis (ANOVA, Cohen's kappa, Pearson's r) and stepwise linear regression analysis (B with 95% CI, R, R2) were used. RESULTS: The total QOLIBRI revealed no differences in one-year outcomes between patients with versus without major TBI (75 and 76, resp.; p = 0.68). With regard to the cognitive subscore, the group with major TBI demonstrated significantly more limitations than the one with no or mild TBI (p < 0.05). The AIS head correlated significantly with the cognitive dimension of the QOLIBRI (r = - 0.16; p < 0.05), but not with the mental components of the SF-36 or the TOP. In multivariate analysis, the influence of the severity of head injury (AIS head) on total QOLIBRI was weaker than that of injured extremities (R2 = 0.02; p < 0.05 vs. R2 = 0.04; p = 0.001) and equal to the QOLIBRI cognitive subscore (R2 = 0.03, p < 0.01 each). CONCLUSIONS: Given the unexpected result of similar mean QOLIBRI total score values and only minor differences in cognitive deficits following major trauma independently of whether patients sustained major brain injury or not, further studies should investigate whether the QOLIBRI actually has the discriminative capacity to detect specific residuals of major TBI. In effect, the score appears to indicate mental deficits following different types of severe trauma, which should be evaluated in more detail. TRIAL REGISTRATION: NCT02165137 ; retrospectively registered 11 June 2014. PMID- 29986711 TI - Planning and implementation of a countrywide campaign to deliver over 16 million long-lasting insecticidal nets in Mozambique. AB - BACKGROUND: In 2016/2017, Mozambique conducted a countrywide long-lasting insecticidal nets (LLINs) universal coverage campaign (UCC). This paper aims to describe the planning and implementation process of the campaign in Mozambique. METHODS: A cross-sectional and descriptive design was used for reporting the planning and implementation process of the UCC. The UCC used a collaborative approach, involving institutional and non-institutional actors, namely: National Malaria Control Programme (NMCP), provincial and district health authorities, community members and civil society partners. A new household registration strategy based on coupons, stickers, and one LLIN per two persons as allocation criterion was implemented. The campaign was implemented in phases, allowing for continuous improvement of implementation quality by applying lessons learnt from each phase. RESULTS: A total of 7,049,894 households were registered corresponding to a total of 31,972,626 registered persons. A total of 16,557,818 LLINs were distributed between November 2016 and December 2017, corresponding to 97% of LLINs needs based on household registration, and covering 95% of the registered households (6,708,585 households), resulting in an estimated 85% of the total Mozambican population with LLIN access. CONCLUSIONS: The collaborative planning process and strong coordination of campaign actors allowed Mozambique's NMCP and partners to successfully carry out the first countrywide LLINs UCC in the country. The increased access to LLINs in households will likely result in increased LLIN use and a reduction of the malaria burden in the country, therefore contributing to the achievement of the 2016-2030 Global Technical Strategy for Malaria goals. PMID- 29986712 TI - Priming food intake with weight control cues: systematic review with a meta analysis. AB - BACKGROUND: A growing number of studies suggest that exposure to cues which are associated with weight control can prime or prompt controlled food intake in tempting food environments. However, findings are mixed and understanding which types of cues and for whom such cues may be most effective is needed to inform subsequent research and societal applications. A systematic review and meta analysis were conducted to evaluate the effects of exposure to weight control cues compared with control cues on food intake. METHODS: PsycINFO, Medline, Embase and Web of Science were searched using key terms. Hedge's g was used to calculate effect sizes based on mean food intake, standard deviations and sample sizes extracted from relevant publications and, a random effects model was used for the meta-analysis. RESULTS: Twenty-five articles consisting of 26 studies were eligible. Data from 25 studies (31 effect sizes) were available for the meta analysis. Overall, weight control cues reduced food intake, albeit to a trivial effect (ES: -0.149, 95% CI: -0.271 to - 0.027). Subgroup analyses when studies which induced negative affect were removed showed that for individuals with strong weight control goals the effect was small-to-moderate (ES: -0.440, 95% CI: -0.718 to - 0.163), whereas for individuals with weak weight control goals this effect was trivial and non-significant (ES: 0.014, 95% CI: -0.249 to 0.278). Cue type and level of engagement did not significantly moderate the effect; however, specific cues (low-calorie foods and thin models) and attended engagement yielded significant effects. Caution is needed interpreting these findings as most studies were rated with high risk of bias and a number of studies could not be included in the subgroup analyses. CONCLUSIONS: Based on the data available, weight control cues reduce food intake in individuals with strong weight control goals. Further research is needed to explore longer term effects of cue exposure and confirm underlying mechanisms. PROSPERO registry#CRD42016052396. PMID- 29986713 TI - A comparison of the operative outcomes of D1 and D2 gastrectomy performed at a single Western center with multiple surgeons: a retrospective analysis with propensity score matching. AB - BACKGROUND: There has been worldwide debate on lymphadenectomy for gastric cancer, with increasing consensus on performing an extended (D2) resection. There is a paucity of data in Australia. Our aim is to compare overall outcomes between a D1 and D2 lymphadenectomy for gastric cancer in a single specialist unit. METHODS: We performed a retrospective analysis on patients who underwent a curative primary gastric resection for gastric adenocarcinoma between January 1996 and April 2016, primary outcomes included overall survival (OS) and disease free survival (DFS). Propensity score matching (PSM) analysis was used to balance covariates between D1/D1+ and D2 groups. Kaplan-Meier survival curves of D1/D1+ versus D2 were constructed and evaluated using the log-rank test with subgroup analyses for pathological node (pN) status. Multiple Cox proportional hazards model was used to determine predictors of overall survival. RESULTS: Two hundred four patients underwent a gastrectomy, 54 had D1/D1+, and 150 had a D2 lymphadenectomy. After PSM, there were 39 patients in each group, the 10-year OS for D1/D1+ was 52.1 and 76.2% for D2 (p = 0.008), and 10-year DFS was 35% for D1 and 58.1% for D2 (p = 0.058). Subgroup analysis showed that node-negative (N0) patients had improved 5-year OS for D2 (90.9%), compared to D1/D1+ (76.4%) (p = 0.028). There was no difference in operative mortality between the groups (D1 vs D2: 2 vs 0%, p = 0.314), nor in post-operative complications (p = 0.227). Multiple Cox analysis showed advanced tumor stage (stages III and IV), and lymphadenectomy type (D1) and the presence of postoperative complications were independent predictors of poor overall survival. CONCLUSIONS: D2 lymphadenectomy with spleen and pancreas preservation can be performed safely on patients with gastric adenocarcinoma. Significant improvement in overall survival is observed in patients with N0 disease who underwent D2 lymphadenectomy without increasing operative morbidity or mortality. This paper supports the notion of a global consensus for a D2 lymphadenectomy, particularly in the Western context. PMID- 29986714 TI - The TGFbeta-signaling pathway and colorectal cancer: associations between dysregulated genes and miRNAs. AB - BACKGROUND: The TGFbeta-signaling pathway plays an important role in the pathogenesis of colorectal cancer (CRC). Loss of function of several genes within this pathway, such as bone morphogenetic proteins (BMPs) have been seen as key events in CRC progression. METHODS: In this study we comprehensively evaluate differential gene expression (RNASeq) of 81 genes in the TGFbeta-signaling pathway and evaluate how dysregulated genes are associated with miRNA expression (Agilent Human miRNA Microarray V19.0). We utilize paired carcinoma and normal tissue from 217 CRC cases. We evaluate the associations between differentially expressed genes and miRNAs and sex, age, disease stage, and survival months. RESULTS: Thirteen genes were significantly downregulated and 14 were significantly upregulated after considering fold change (FC) of > 1.50 or < 0.67 and multiple comparison adjustment. Bone morphogenetic protein genes BMP5, BMP6, and BMP2 and growth differentiation factor GDF7 were downregulated. BMP4, BMP7, INHBA (Inhibin beta A), TGFBR1, TGFB2, TGIF1, TGIF2, and TFDP1 were upregulated. In general, genes with the greatest dysregulation, such as BMP5 (FC 0.17, BMP6 (FC 0.25), BMP2 (FC 0.32), CDKN2B (FC 0.32), MYC (FC 3.70), BMP7 (FC 4.17), and INHBA (FC 9.34) showed dysregulation in the majority of the population (84.3, 77.4, 81.1, 80.2, 82.0, 51.2, and 75.1% respectively). Four genes, TGFBR2, ID4, ID1, and PITX2, were un-associated or slightly upregulated in microsatellite stable (MSS) tumors while downregulated in microsatellite-unstable (MSI) tumors. Eight dysregulated genes were associated with miRNA differential expression. E2F5 and THBS1 were associated with one or two miRNAs; RBL1, TGFBR1, TGIF2, and INHBA were associated with seven or more miRNAs with multiple seed-region matches. Evaluation of the joint effects of mRNA:miRNA identified interactions that were stronger in more advanced disease stages and varied by survival months. CONCLUSION: These data support an interaction between miRNAs and genes in the TGFbeta-signaling pathway in association with CRC risk. These interactions are associated with unique clinical characteristics that may provide targets for further investigations. PMID- 29986715 TI - Setting the agenda for nurse leadership in India: what is missing. AB - BACKGROUND: Current policy priorities to strengthen the nursing sector in India have focused on increasing the number of nurses in the health system. However, the nursing sector is afflicted by other, significant problems including the low status of nurses in the hierarchy of health care professionals, low salaries, and out-dated systems of professional governance, all affecting nurses' leadership potential and ability to perform. Stronger nurse leadership has the potential to support the achievement of health system goals, especially for strengthening of primary health care, which has been recognised and addressed in several other country contexts. This research study explores the process of policy agenda setting for nurse leadership in India, and aims to identify the structural and systemic constraints in setting the agenda for policy reforms on the issue. METHODS: Our methods included policy document review and expert interviews. We identified policy reforms proposed by different government appointed committees on issues concerning nurses' leadership and its progress. Experts' accounts were used to understand lack of progress in several nursing reform proposals and analysed using deductive thematic analysis for 'legitimacy', 'feasibility' and 'support', in line with Hall's agenda setting model. RESULTS: The absence of quantifiable evidence on the nurse leadership crisis and treatment of nursing reforms as a 'second class' issue were found to negatively influence perceptions of the legitimacy of nurse leadership reform. Feasibility is affected by the lack of representation of nurses in key positions and the absence of a nurse-specific institution, which is seen as essential for creating visibility of the issues facing the profession, their processing and planning for policy solutions. Finally, participants noted the lack of strong support from nurses themselves for these policy reforms, which they attributed to social disempowerment, and lack of professional autonomy. CONCLUSIONS: The study emphasises that the nursing empowerment needs institutional reforms to facilitate nurse's distributed leadership across the health system and to enable their collective advocacy that questions the status quo and the structures that uphold it. PMID- 29986716 TI - Elucidation of auxotrophic deficiencies of Bacillus pumilus DSM 18097 to develop a defined minimal medium. AB - BACKGROUND: Culture media containing complex compounds like yeast extract or peptone show numerous disadvantages. The chemical composition of the complex compounds is prone to significant variations from batch to batch and quality control is difficult. Therefore, the use of chemically defined media receives more and more attention in commercial fermentations. This concept results in better reproducibility, it simplifies downstream processing of secreted products and enable rapid scale-up. Culturing bacteria with unknown auxotrophies in chemically defined media is challenging and often not possible without an extensive trial-and-error approach. In this study, a respiration activity monitoring system for shake flasks and its recent version for microtiter plates were used to clarify unknown auxotrophic deficiencies in the model organism Bacillus pumilus DSM 18097. RESULTS: Bacillus pumilus DSM 18097 was unable to grow in a mineral medium without the addition of complex compounds. Therefore, a rich chemically defined minimal medium was tested containing basically all vitamins, amino acids and nucleobases, which are essential ingredients of complex components. The strain was successfully cultivated in this medium. By monitoring of the respiration activity, nutrients were supplemented to and omitted from the rich chemically defined medium in a rational way, thus enabling a systematic and fast determination of the auxotrophic deficiencies. Experiments have shown that the investigated strain requires amino acids, especially cysteine or histidine and the vitamin biotin for growth. CONCLUSIONS: The introduced method allows an efficient and rapid identification of unknown auxotrophic deficiencies and can be used to develop a simple chemically defined tailor-made medium. B. pumilus DSM 18097 was chosen as a model organism to demonstrate the method. However, the method is generally suitable for a wide range of microorganisms. By combining a systematic combinatorial approach based on monitoring the respiration activity with cultivation in microtiter plates, high throughput experiments with high information content can be conducted. This approach facilitates media development, strain characterization and cultivation of fastidious microorganisms in chemically defined minimal media while simultaneously reducing the experimental effort. PMID- 29986717 TI - Evaluation of loop-mediated isothermal amplification as a surveillance tool for malaria in reactive case detection moving towards elimination. AB - BACKGROUND: As malaria transmission decreases, the proportion of infections that are asymptomatic at any given time increases. This poses a challenge for diagnosis as routinely used rapid diagnostic tests (RDTs) miss asymptomatic malaria cases with low parasite densities due to poor sensitivity. Yet, asymptomatic infections can contribute to onward transmission of malaria and therefore act as infectious reservoirs and perpetuate malaria transmission. This study compared the performance of RDTs to loop-mediated isothermal amplification (LAMP) in the diagnosis of malaria during reactive active case detection surveillance. METHODS: All reported malaria cases in the Engela Health District of Namibia were traced back to their place of residence and persons living within the four closest neighbouring houses to the index case (neighbourhood) were tested for malaria infection with RDTs and dried blood spots (DBS) were collected. LAMP and nested PCR (nPCR) were carried out on all RDTs and DBS. The same procedure was followed in randomly selected control neighbourhoods. RESULTS: Some 3151 individuals were tested by RDT, LAMP and nPCR. Sensitivity of RDTs and LAMP were 9.30 and 95.50%, respectively, and specificities were 99.27 and 99.92%, respectively, compared to nPCR. LAMP carried out on collected RDTs showed a sensitivity and specificity of 95.35 and 99.85% compared to nPCR carried out on DBS. There were 2 RDT samples that were negative by LAMP but the corresponding DBS samples were positive by PCR. CONCLUSION: The study showed that LAMP had the equivalent performance as nPCR for the identification of Plasmodium falciparum infection. Given its relative simplicity to implement over more complex and time consuming methods, such as PCR, LAMP is particularly useful in elimination settings where high sensitivity and ease of operation are important. PMID- 29986718 TI - Is objectively measured light-intensity physical activity associated with health outcomes after adjustment for moderate-to-vigorous physical activity in adults? A systematic review. AB - BACKGROUND: An increasing number of studies have demonstrated that light intensity physical activity (LPA) confers health benefits after adjustment for moderate-to-vigorous physical activity (MVPA). The purpose of this systematic review was to summarize existing epidemiological evidence on associations of objectively measured LPA with health outcomes in adults. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched on PubMed, Web of Science, CINAL, and Cochrane Library for articles analyzing the association between objectively determined LPA and health outcomes that were published up to January 2017. Data were extracted regarding authors, publication year, country of survey, study setting, number of participants, study design, physical activity (PA) assessment (type of accelerometer and intensity), health outcomes, confounders, and results (summary measures and association). A coding system was used to summarize the results. RESULTS: Of the 3254 studies identified, 24 cross-sectional and 6 longitudinal studies were included in this review. Most of the studies targeted the Western population. LPA was inversely associated with all-cause mortality risk and associated favorably with some cardiometabolic risk factors including waist circumference, triglyceride levels, insulin, and presence of metabolic syndrome. Only a small amount of data were available on mental health and cognitive function. CONCLUSIONS: LPA appears to be beneficially associated with important health outcomes after adjustment for MVPA in the adult population. Although current global PA guidelines recommend only MVPA, promoting LPA may confer additional health benefits. PMID- 29986719 TI - CO-dependent hydrogen production by the facultative anaerobe Parageobacillus thermoglucosidasius. AB - BACKGROUND: The overreliance on dwindling fossil fuel reserves and the negative climatic effects of using such fuels are driving the development of new clean energy sources. One such alternative source is hydrogen (H2), which can be generated from renewable sources. Parageobacillus thermoglucosidasius is a facultative anaerobic thermophilic bacterium which is frequently isolated from high temperature environments including hot springs and compost. RESULTS: Comparative genomics performed in the present study showed that P. thermoglucosidasius encodes two evolutionary distinct H2-uptake [Ni-Fe] hydrogenases and one H2-evolving hydrogenases. In addition, genes encoding an anaerobic CO dehydrogenase (CODH) are co-localized with genes encoding a putative H2-evolving hydrogenase. The co-localized of CODH and uptake hydrogenase form an enzyme complex that might potentially be involved in catalyzing the water-gas shift reaction (CO + H2O -> CO2 + H2) in P. thermoglucosidasius. Cultivation of P. thermoglucosidasius DSM 2542T with an initial gas atmosphere of 50% CO and 50% air showed it to be capable of growth at elevated CO concentrations (50%). Furthermore, GC analyses showed that it was capable of producing hydrogen at an equimolar conversion with a final yield of 1.08 H2/CO. CONCLUSIONS: This study highlights the potential of the facultative anaerobic P. thermoglucosidasius DSM 2542T for developing new strategies for the biohydrogen production. PMID- 29986720 TI - Efficacy of ketogenic diet on body composition during resistance training in trained men: a randomized controlled trial. AB - BACKGROUND: Ketogenic diets (KD) have become a popular method of promoting weight loss. More recently, some have recommended that athletes adhere to ketogenic diets in order to optimize changes in body composition during training. This study evaluated the efficacy of an 8-week ketogenic diet (KD) during energy surplus and resistance training (RT) protocol on body composition in trained men. METHODS: Twenty-four healthy men (age 30 +/- 4.7 years; weight 76.7 +/- 8.2 kg; height 174.3 +/- 19.7 cm) performed an 8-week RT program. Participants were randomly assigned to a KD group (n = 9), non-KD group (n = 10, NKD), and control group (n = 5, CG) in hyperenergetic condition. Body composition changes were measured by dual energy X-ray absorptiometry (DXA). Compliance with the ketosis state was monitored by measuring urinary ketones weekly. Data were analyzed using a univariate, multivariate and repeated measures general linear model (GLM) statistics. RESULTS: There was a significant reduction in fat mass (mean change, 95% CI; p-value; Cohen's d effect size [ES]; - 0.8 [- 1.6, - 0.1] kg; p < 0.05; ES = - 0.46) and visceral adipose tissue (- 96.5 [- 159.0, - 34.0] g; p < 0.05; ES = - 0.84), while no significant changes were observed in the NKD and CG in fat mass (- 0,5 [- 1.2, 0.3] kg; p > 0.05; ES = - 0.17 and - 0,5 [- 2.4, 1.3] kg; p > 0.05; ES = - 0.12, respectively) or visceral adipose tissue (- 33.8 [- 90.4, 22.8]; p > 0.5; ES = - 0.17 and 1.7 [- 133.3, 136.7]; p > 0.05; ES = 0.01, respectively). No significant increases were observed in total body weight (- 0.9 [- 2.3, 0.6]; p > 0.05; ES = [- 0.18]) and muscle mass (- 0.1 [- 1.1,1.0]; p > 0,05; ES = - 0.04) in the KD group, but the NKD group showed increases in these parameters (0.9 [0.3, 1.5] kg; p < 0.05; ES = 0.18 and (1.3[0.5, 2.2] kg; p < 0,05; ES = 0.31, respectively). There were no changes neither in total body weight nor lean body mass (0.3 [- 1.2, 1.9]; p > 0.05; ES = 0.05 and 0.8 [- 0.4, 2.1]; p > 0.05; ES = 0.26, respectively) in the CG. CONCLUSION: Our results suggest that a KD might be an alternative dietary approach to decrease fat mass and visceral adipose tissue without decreasing lean body mass; however, it might not be useful to increase muscle mass during positive energy balance in men undergoing RT for 8 weeks. PMID- 29986721 TI - INSIGHT responsive parenting intervention and infant feeding practices: randomized clinical trial. AB - BACKGROUND: What, when, how, how much, and how often infants are fed have been associated with childhood obesity risk. The objective of this secondary analysis was to examine the effect of a responsive parenting (RP) intervention designed for obesity prevention on parents' infant feeding practices in the first year after birth. METHODS: Primiparous mother-newborn dyads were randomized to the Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) Study RP intervention or child safety control. Research nurses delivered intervention content at home at infant age 3-4, 16, 28, and 40 weeks, and at a research center at 1 year. RP feeding guidance advised feeding that was contingent (i.e., feed in response to hunger and satiety signs, alternatives to using food to soothe), and developmentally appropriate (i.e., delaying introduction of solids, age appropriate portion sizes). Infant feeding practices (i.e., bottle use, introduction of solids, food to soothe) were assessed by phone interviews and online surveys and dietary intake was assessed using a food frequency questionnaire. RESULTS: RP mothers were more likely to use of structure-based feeding practices including limit-setting (p < 0.05) and consistent feeding routines (p < 0.01) at age 1 year. RP group mothers were less likely to use non responsive feeding practices such as pressuring their infant to finish the bottle/food (p < 0.001), and using food to soothe (p < 0.01), propping the bottle (p < 0.05) assessed between 4 and 8 months, and putting baby to bed with a bottle at age 1 year (p < 0.05). Few differences were seen between groups in what specific foods or food groups infants were fed. CONCLUSIONS: Anticipatory guidance on RP in feeding can prevent the use of food to soothe and promote use of more sensitive, structure-based feeding which could reduce obesity risk by affecting how and when infants are fed during the first year. TRIAL REGISTRATION: The Intervention Nurses Start Infants Growing on Healthy Trajectories (INSIGHT) Study. www.clinicaltrials.gov . NCT01167270. Registered 21 July 2010. PMID- 29986723 TI - Evolution of host preference in anthropophilic mosquitoes. AB - BACKGROUND: Insecticide-treated bed nets (ITNs) have played a large role in reducing the burden of malaria. There is concern however regarding the potential of the mass distributions and use of ITNs to select for insecticide and behavioural resistance in mosquito populations. A key feature of the vectorial capacity of the major sub-Saharan African malaria vector Anopheles gambiae sensu stricto (s.s.) is its tendency to feed almost exclusively on humans. Here, an evolutionary model is used to investigate the potential for ITNs to select for increased zoophily in this highly anthropophilic species and how this is influenced by ecological and operational conditions. RESULTS: The evolution of a single trait, namely the tendency to accept cattle as hosts, is modelled in mosquito populations which initially only bite humans. Thus, the conditions under which a resource specialist would broaden its diet and become a generalist are investigated. The results indicate that in the absence of insecticide-treated nets, host specialization in mosquitoes is either driven toward human specialization (when humans are more abundant than alternative hosts), or displays evolutionary bistability. The latter implies that the evolutionary endpoint relies on the initial trait value of the population. Bed nets select for increased zoophily while in use. When ITNs are removed, whether or not the population reverts to anthropophagic or zoophagic behaviour depends on whether the intervention had been maintained sufficiently long to drive the population past the evolutionarily unstable point. CONCLUSIONS: The use of ITNs is likely to select for an increase in the biting preference for cattle. Bed nets may thus alter the population composition of major vector species in a manner that has positive epidemiological ramifications. Whether populations are set on a trajectory toward increased zoophily following the cessation of intense bed net usage in an area depends on the composition of host communities as well as operational conditions. This has potential implications for bed net campaigns, particularly with an eye toward scaling down interventions following interruption of transmission. Further research on malaria mosquito feeding behaviour is warranted to explore the conditions under which such adaptive shifts may actually occur in the field. PMID- 29986722 TI - "It's better to have three brains working instead of one": a qualitative study of building therapeutic alliance with family members of critically ill patients. AB - BACKGROUND: Studies in the intensive care unit (ICU) suggest that better communication between families of critically ill patients and healthcare providers is needed; however, most randomized trials targeting interventions to improve communication have failed to achieve family-centered outcomes. We aim to offer a novel analysis of the complexities involved in building positive family provider relationships in the ICU through the consideration of not only communication but other important aspects of family-provider interactions, including family integration, collaboration, and empowerment. Our goal is to explore family members' perspectives on the enablers and challenges to establishing therapeutic alliance with ICU physicians and nurses. METHODS: We used the concept of therapeutic alliance as an organizational and analytic tool to conduct an interview-based qualitative study in a 20-bed adult medical surgical ICU in an academic hospital in Toronto, Canada. Nineteen family members of critically ill patients who acted as substitute decision-makers and/or regularly interacted with ICU providers were interviewed. Participants were sampled purposefully to ensure maximum variation along predetermined criteria. A hybrid inductive-deductive approach to analysis was used. RESULTS: Participating family members highlighted the complementary roles and practices of ICU nurses and physicians in building therapeutic alliance. They reported how both provider groups had profession specific and shared contributions to foster family communication, integration, and collaboration, while physicians played a key role in family empowerment. Families' lack of familiarity with ICU personnel and processes, physicians' sporadic availability and use of medical jargon during rounds, however, reinforced long established power differences between lay families and expert physicians and challenged family integration. Family members also identified informal interactions as missed opportunities for relationship building with physicians. While informal interactions with nurses at the bedside facilitated therapeutic alliance, inconsistent and ad-hoc interactions related to routine decision-making hindered family empowerment. CONCLUSIONS: Multiple opportunities exist to improve family-provider relationships in the ICU. The four dimensions of therapeutic alliance prove analytically useful to highlight those aspects that work well and need improvement, such as in the areas of family integration and empowerment. PMID- 29986724 TI - Unveiling anti-oxidative and anti-inflammatory effects of docosahexaenoic acid and its lipid peroxidation product on lipopolysaccharide-stimulated BV-2 microglial cells. AB - BACKGROUND: Phospholipids in the central nervous system are enriched in n-3 and n 6 polyunsaturated fatty acids (PUFA), especially docosahexaenoic acid (DHA) and arachidonic acid (ARA). These PUFA can undergo enzymatic reactions to produce lipid mediators, as well as reaction with oxygen free radicals to produce 4 hydroxyhexenal (4-HHE) from DHA and 4-hydroxynonenal (4-HNE) from ARA. Recent studies demonstrated pleiotropic properties of these peroxidation products through interaction with oxidative and anti-oxidant response pathways. In this study, BV-2 microglial cells were used to investigate ability for DHA, 4-HHE, and 4-HNE to stimulate the anti-oxidant stress responses involving the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and synthesis of heme oxygenase (HO 1), as well as to mitigate lipopolysaccharide (LPS)-induced nitric oxide (NO), reactive oxygen species (ROS), and cytosolic phospholipase A2 (cPLA2). In addition, LC-MS/MS analysis was carried out to examine effects of exogenous DHA and LPS stimulation on endogenous 4-HHE and 4-HNE levels in BV-2 microglial cells. METHODS: Effects of DHA, 4-HHE, and 4-HNE on LPS-induced NO production was determined using the Griess reagent. LPS-induced ROS production was measured using CM-H2DCFDA. Western blots were used to analyze expression of p-cPLA2, Nrf2, and HO-1. Cell viability and cytotoxicity were measured using the WST-1 assay, and cell protein concentrations were measured using the BCA protein assay kit. An ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was used to determine levels of free 4-HHE and 4-HNE in cells. RESULTS: DHA (12.5-100 MUM), 4-HHE (1.25-10 MUM), and 4-HNE (1.25-10 MUM) dose dependently suppressed LPS-induced production of NO, ROS, and as p-cPLA2 in BV-2 microglial cells. With the same concentrations, these compounds could enhance Nrf2 and HO-1 expression in these cells. Based on the estimated IC50 values, 4-HHE and 4-HNE were five- to tenfold more potent than DHA in inhibiting LPS-induced NO, ROS, and p-cPLA2. LC-MS/MS analysis indicated ability for DHA (10-50 MUM) to increase levels of 4-HHE and attenuate levels of 4-HNE in BV-2 microglial cells. Stimulation of cells with LPS caused an increase in 4-HNE which could be abrogated by cPLA2 inhibitor. In contrast, bromoenol lactone (BEL), a specific inhibitor for the Ca2+-independent phospholipase A2 (iPLA2), could only partially suppress levels of 4-HHE induced by DHA or DHA + LPS. CONCLUSIONS: This study demonstrated the ability of DHA and its lipid peroxidation products, namely, 4 HHE and 4-HNE at 1.25-10 MUM, to enhance Nrf2/HO-1 and mitigate LPS-induced NO, ROS, and p-cPLA2 in BV-2 microglial cells. In addition, LC-MS/MS analysis of the levels of 4-HHE and 4-HNE in microglial cells demonstrates that increases in production of 4-HHE from DHA and 4-HNE from LPS are mediated by different mechanisms. PMID- 29986725 TI - Evidence for histidine-rich protein 2 immune complex formation in symptomatic patients in Southern Zambia. AB - BACKGROUND: Rapid diagnostic tests based on histidine-rich protein 2 (HRP2) detection are the primary tools used to detect Plasmodium falciparum malaria infections. Recent conflicting reports call into question whether alpha-HRP2 antibodies are present in human host circulation and if resulting immune complexes could interfere with HRP2 detection on malaria RDTs. This study sought to determine the prevalence of immune-complexed HRP2 in a low-transmission region of Southern Zambia. METHODS: An ELISA was used to quantify HRP2 in patient sample DBS extracts before and after heat-based immune complex dissociation. A pull-down assay reliant on proteins A, G, and L was developed and applied for IgG and IgM capture and subsequent immunoprecipitation of any HRP2 present in immune complexed form. A total of 104 patient samples were evaluated using both methods. RESULTS: Immune-complexed HRP2 was detectable in 17% (18/104) of all samples evaluated and 70% (16/23) of HRP2-positive samples. A majority of the patients with samples containing immune-complexed HRP2 had P. falciparum infections (11/18) and were also positive for free HRP2 (16/18). For 72% (13/18) of patients with immune-complexed HRP2, less than 10% of the total HRP2 present was in immune complexed form. For the remaining samples, a large proportion (>= 20%) of total HRP2 was complexed with alpha-HRP2 antibodies. CONCLUSIONS: Endogenous alpha-HRP2 antibodies form immune complexes with HRP2 in the symptomatic patient population of a low-transmission area in rural Southern Zambia. For the majority of patients, the percentage of HRP2 in immune complexes is low and does not affect HRP2-based malaria diagnosis. However, for some patients, a significant portion of the total HRP2 was in immune-complexed form. Future studies investigating the prevalence and proportion of immune-complexed HRP2 in asymptomatic individuals with low HRP2 levels will be required to assess whether alpha-HRP2 antibodies affect HRP2 detection for this portion of the transmission reservoir. PMID- 29986726 TI - Inhibition of endoplasmic-reticulum-stress-mediated autophagy enhances the effectiveness of chemotherapeutics on pancreatic cancer. AB - BACKGROUND: Endoplasmic reticulum (ER) stress and its consequent unfolded protein response (UPR) are believed to be associated with progression, survival and chemoresistance of a variety of tumor cells through multiple cellular processes, including autophagy. Therefore, the ER stress-autophagy pathway presents a potential molecular target for therapeutic intervention. The objective of this study was to evaluate the therapeutic efficacy of ER stress and autophagy modulators in the context of pancreatic ductal adenocarcinoma (PDAC). METHODS: We first targeted IRE1alpha, an important regulator of the UPR, through STF-083010 treatment in PDAC cell lines in vitro. Chloroquine was then used to target autophagy and an optimal combination treatment was developed using chloroquine, sunitinib and gemcitabine. Apoptosis was analyzed using TUNEL assay, autophagy was estimated using lysotracker staining and electron microscopy, and UPR was analyzed using anti-GRP78 immunostaining and XBP1 splicing. Transplantation of PDAC derived KPCP1 and Panc02 cells in mouse pancreas were performed to study treatment efficacy in vivo. RESULTS: Suppression of the IRE1alpha by STF-083010 alone resulted in increased lysosomes and reduced viability of PDAC cells. Chloroquine treatment alone inhibited downstream autophagy but was insufficient in reducing PDAC cell growth. However, combining STF-083010 and chloroquine had additive anti-tumor efficacy when used with gemcitabine. Sunitinib alone caused abnormal maturation of the autolysosomes with increased intracellular multivesicular bodies and increased apoptosis evident in PDAC cells. Sunitinib showed a synergistic effect with chloroquine in reducing in vitro PDAC cell viability and significantly increased the efficacy of gemcitabine in human and murine PDAC cell lines. The anti-proliferative effect of gemcitabine was significantly increased when used in combination with sunitinib and/or chloroquine in both in vitro and in vivo PDAC models. The addition of sunitinib and/or chloroquine to gemcitabine, resulted in a significantly increased survival of the animals without noticeably increased toxicity. Sunitinib, gemcitabine and chloroquine treated mice showed a significant reduction of GRP78 expression, reduced cell proliferation and increased apoptosis in pancreas, compatible with a tumor response. CONCLUSIONS: Sunitinib combined with chloroquine reduces tumor growth through suppression of autophagy and increased apoptosis. Co administration of modulators of ER stress-mediated autophagy with chemotherapy presents a novel therapeutic approach in PDAC. PMID- 29986727 TI - Streptococcus pyogenes-purpura fulminans as an invasive form of group A streptococcal infection. AB - BACKGROUND: Streptococcus pyogenes is an uncommon pathogen of purpura fulminans, and the pathogenesis of S. pyogenes-purpura fulminans remains unclear because of paucity of cases. We reported a pediatric case of S. pyogenes-purpura fulminans with literature review of the disease. CASE PRESENTATION: A 3-year-old boy showed limping, lethargy and acral gangrene within 24 h. A diagnosis of S. pyogenes purpura fulminans was made for bacterial isolation from throat and peripheral blood. Intensive therapy led to a survival with amputation of the left distal metatarsal bone, and normal development. The isolated M12 carried no mutation of csrS/R or rgg. Thrombophilia or immunodeficiency was excluded. DISCUSSION: Twelve reported cases (9 pediatric and 3 elderly) of S. pyogenes-purpura fulminans started with shock and coagulopathy. Five patients age < 8 years had no underlying disease and survived. One youngest and two immunocompromised patients died. CONCLUSION: Streptococcus pyogenes-acute infectious purpura fulminans is a distinctive rare form of aggressive GAS infections. PMID- 29986728 TI - Characterizing the effect of expression of an acetyl-CoA synthetase insensitive to acetylation on co-utilization of glucose and acetate in batch and continuous cultures of E. coli W. AB - BACKGROUND: Due to its high stress tolerance and low acetate secretion, Escherichia coli W is reported to be a good production host for several metabolites and recombinant proteins. However, simultaneous co-utilization of glucose and other substrates such as acetate remains a challenge. The activity of acetyl-CoA-synthetase, one of the key enzymes involved in acetate assimilation is tightly regulated on a transcriptional and post-translational level. The aim of this study was to engineer E. coli W for overexpression of an acetylation insensitive acetyl-CoA-synthetase and to characterize this strain in batch and continuous cultures using glucose, acetate and during co-utilization of both substrates. RESULTS: Escherichia coli W engineered to overexpress an acetylation insensitive acetyl-CoA synthetase showed a 2.7-fold increase in acetate uptake in a batch process containing glucose and high concentrations of acetate compared to a control strain, indicating more efficient co-consumption of glucose and acetate. When acetate was used as the carbon source, batch duration could significantly be decreased in the overexpression strain, possibly due to alleviation of acetate toxicity. Chemostat cultivations with different dilution rates using glucose revealed only minor differences between the overexpression and control strain. Accelerostat cultivations using dilution rates between 0.20 and 0.70 h-1 indicated that E. coli W is naturally capable of efficiently co utilizing glucose and acetate over a broad range of specific growth rates. Expression of acetyl-CoA synthetase resulted in acetate and glucose accumulation at lower dilution rates compared to the control strain. This observation can possibly be attributed to a higher ratio between acs and pta-ackA in the overexpression strain as revealed by gene expression analysis. This would result in enhanced energy dissipation caused by an imbalance in the Pta-AckA-Acs cycle. Furthermore, yjcH and actP, genes co-transcribed with acetyl-CoA synthetase showed significant down-regulation at elevated dilution rates. CONCLUSIONS: Escherichia coli W expressing an acetylation-insensitive acetyl-CoA synthetase was shown to be a promising candidate for mixed feed processes using glucose and acetate. Comparison between batch and continuous cultures revealed distinct differences in glucose-acetate co-utilization behavior, requiring additional investigations such as multi-omics analysis and further engineering towards even more efficient co-utilization strains of E. coli W. PMID- 29986729 TI - Private retail drug shops: what they are, how they operate, and implications for health care delivery in rural Uganda. AB - BACKGROUND: Retail drug shops play a significant role in managing pediatric fevers in rural areas in Uganda. Targeted interventions to improve drug seller practices require understanding of the retail drug shop market and motivations that influence practices. This study aimed at describing the operational environment in relation to the Uganda National Drug Authority guidelines for setup of drug shops; characteristics, and dispensing practices of private retail drug shops in managing febrile conditions among under-five children in rural western Uganda. METHODS: Cross sectional survey of 74 registered drug shops, observation checklist, and 428 exit interviews using a semi-structured questionnaire with care-seekers of children under five years of age, who sought care at drug shops during the survey period. The survey was conducted in Mbarara and Bushenyi districts, South Western Uganda, in May 2013. RESULTS: Up to 90 and 79% of surveyed drug shops in Mbarara and Bushenyi, largely operate in premises that meet National Drug Authority requirements for operational suitability and ensuring medicines safety and quality. Drug shop attendants had some health or medical related training with 60% in Mbarara and 59% in Bushenyi being nurses or midwives. The rest were clinical officers, pharmacists. The most commonly stocked medicines at drug shops were Paracetamol, Quinine, Cough syrup, ORS/Zinc, Amoxicillin syrup, Septrin(r) syrup, Artemisinin-based combination therapies, and multivitamins, among others. Decisions on what medicines to stock were influenced by among others: recommended medicines from Ministry of Health, consumer demand, most profitable medicines, and seasonal disease patterns. Dispensing decisions were influenced by: prescriptions presented by client, patients' finances, and patient preferences, among others. Most drug shops surveyed had clinical guidelines, iCCM guidelines, malaria and diarrhea treatment algorithms and charts as recommended by the Ministry of Health. Some drug shops offered additional services such as immunization and sold non-medical goods, as a mechanism for diversification. CONCLUSION: Most drug shops premises adhered to the recommended guidelines. Market factors, including client demand and preferences, pricing and profitability, and seasonality largely influenced dispensing and stocking practices. Improving retail drug shop practices and quality of services, requires designing and implementing both supply-side and demand side strategies. PMID- 29986730 TI - The diagnostic ureteroscopy before radical nephroureterectomy in upper urinary tract urothelial carcinoma is not associated with higher intravesical recurrence. AB - BACKGROUND: To clarify if diagnostic ureteroscopy (URS) before radical nephroureterectomy for patients with upper tract urothelial carcinoma (UTUC) will increase the risk of intravesical recurrence. METHODS: From retrospective review of cohort at our institution, 502 patients with UTUC who underwent radical nephroureterectomy with bladder cuff excision were enrolled from 1990 to 2013. Cox proportional hazards model was used to analyze the overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and intravesical recurrence-free survival (IVRFS). The log-rank test was used for comparing survival curves. All potential risk factors were included in the multivariate Cox proportional hazards model to recognize independent predictors. From NHI database, we included patients of UTUC without bladder cancer history using population-based database in Taiwan from 1996 to 2013. In total, 3079 URS and 2634 non-URS patients with UTUC were identified. Univariate and multivariate Cox proportional hazards regressions were performed to measure the risk of IVRFS and all-cause mortality. RESULTS: From our database, the comparison of clinicopathological characteristics in UTUC patients between with URS biopsy group (URS+) (n = 206, 41%) and without URS biopsy group (URS-) (n = 296, 59%) was insignificantly different excluding surgical method. URS biopsy is not associated with worse OS (p = 0.720), DFS (p = 0.294), MFS (p = 0.808), and IVRFS (p = 0.560) by multivariate analysis. Only bladder cancer history is an independent significant factor to predict IVR (p < 0.001). The same result from NHI database, URS before radical surgery will not increase the risk of IVRFS [adjusted HR 1.136, 95% CI 1.00-1.30; P = 0.059] and OS [adjusted HR 0.919, 95% CI 0.82-1.04; P = 0.164]. CONCLUSIONS: Preoperative URS manipulation is not associated with higher risk of IVRFS even in patients without bladder cancer history. Diagnostic URS is feasible to compensate the insufficient information of image in patients with UTUC. PMID- 29986731 TI - Are three-dimensional patient-specific cutting guides for open wedge high tibial osteotomy accurate? An in vitro study. AB - BACKGROUND: The aim of this in vitro study was to assess the accuracy of three dimensional patient-specific cutting guides for open wedge high tibial osteotomy (OWHTO) to provide the planned correction in both frontal and sagittal planes. METHODS: Ten cadaveric tibias underwent OWHTO performed using a patient-specific cutting guide based on 3D preoperative planning. An initial CT scan of the tibias was performed, and after segmentation, 3D geometrical models of the pre-OWHTO tibias were obtained. Reference planes were defined, and OWHTO virtually planned to then design patient-specific cutting guides. OWHTO were performed using the patient-specific cutting guides. The patient-specific cutting guide controls the cut and the correction of the OWHTO in both planes. 3D models of post-OWHTO tibias were created after a postoperative CT scan. Geometrical post-OWHTO 3D models were superimposed on pre-OWHTO 3D models. Mechanical medial proximal tibial angle (mMPTA) in the frontal plane and posterior tibial slope (PTS) in the sagittal plane were compared between planned-OWHTO and post-OWHTO 3D reconstructions relative to the pre-OWHTO reference planes and axis. Pearson's and Lin's correlation tests were performed to assess precision and accuracy of patient-specific cutting guides. RESULTS: The mean difference between post-OWHTO and planned-OWHTO was 0.2 degrees (max 0.5 degrees , SD 0.3 degrees ) in the frontal plane and - 0.1 degrees (max 0.8 degrees , SD 0.5 degrees ) in the sagittal plane. Statistically significant correlations were found between the planned-OWHTO and post-OWHTO configurations for the mMPTA (p < 0.0001) and PTS (p < 0.0001) measurements, and the bias correction factor was 0.99 in both planes. CONCLUSIONS: 3D patient-specific cutting guides for OWHTO-based 3D virtual planning is a reliable and accurate method of achieving multiplanar correction in both frontal and sagittal planes. PMID- 29986732 TI - Can pelvic tilt be restored by spinal osteotomy in ankylosing spondylitis patients with thoracolumbar kyphosis? A minimum follow-up of 2 years. AB - BACKGROUND: Defining the postoperative pelvic tilt (PT) individually can help to reconstruct sagittal balance. However, the postoperative actual PT is hardly restored to theoretical value. Some cases with theoretical postoperative PT was overcorrected and still did not have normal horizontal visual field after surgery. The objective of this study is to describe the pelvic tilt change after spinal osteotomy in ankylosing spondylitis (AS) kyphotic deformity and evaluate the effect on clinical outcomes. METHODS: Twenty-three AS patients including 21 men and two women with thoracolumbar kyphosis, who underwent spinal osteotomy from 2013 to 2015 in our center, were retrospectively reviewed. A series of parameters including sacral slop (SS), pelvic incidence (PI), PT, and sagittal vertical axis (SVA) measured on preoperative and postoperative standing radiographs were analyzed. The theoretical postoperative PT (tPT) was calculated by the formula tPT = 0.37 * PI - 7. The radiographic measurements were compared before surgery, 2 weeks and at least 2 years postoperatively. Clinical outcomes were performed with the Oswestry disability index and Scoliosis Research Society 22 surveys. RESULTS: Mean age of the patients (2 women, 21 men) was 39.8 +/- 9.1 years. Mean follow-up was 27.4 +/- 3.8 months, at least 24 months. After spinal osteotomy, SS and SVA were corrected from 11.9 degrees +/- 11.2 degrees and 18.0 +/- 7.6 mm preoperatively to 25.8 degrees +/- 8.1 degrees and 9.6 +/- 6.3 mm postoperatively, respectively (p < 0.001). PT reduced from 37.6 degrees +/- 12.1 degrees to 21.8 degrees +/- 9.8 degrees postoperatively (p < 0.001). The tPT was different from postoperative actual PT significantly (p < 0.001). The clinical evaluations were not correlated with postoperative PT. CONCLUSION: The abnormal PT is corrected by spinal osteotomy but is hard to restore to theoretical normal value. PT is a helpful parameter in making surgery plan. But pursuing postoperative PT being totally equal to tPT is undesirable and even may cause for overcorrection. PMID- 29986733 TI - How can mobile phones be used to improve nutrition service delivery in rural Bangladesh? AB - BACKGROUND: Nutrition has been integrated within the health services in Bangladesh as it is an important issue for health and development. High penetration of mobile phones in the community and favourable policy and political commitment of the Government of Bangladesh has created possibilities of using Information Communication Technology such as mobile phones for nutrition programs. In this paper the implementation of nutrition services with a specific focus on infant and young child feeding was explored and the potential for using mobile phones to improve the quality and coverage of nutrition services was assessed. METHODS: A qualitative study was conducted in Mirzapur and Chakaria sub districts, Bangladesh from February-April 2014. We conducted 24 in-depth interviews (mothers of young children), 8 focus group discussions (fathers and grandmothers); and 13 key informant interviews (community health workers or CHWs). We also observed 4 facilities and followed 2 CHWs during their work day. The data was analyzed manually using pre-existing themes. RESULTS: In this community, mothers demonstrated gaps in knowledge about IYCF. They depended on their social network and media for IYCF information. Although CHWs were trusted in the community, mothers and their family members did not consider them a good source of nutrition information as they did not talk about nutrition. In terms of ICTs, mobile phones were the most available and used by both CHWs and mothers. CHWs showed willingness to incorporate nutrition counselling through mobile phone as this can enhance their productivity, reduce travel time and improve service quality. Mothers were willing to receive voice calls from CHWs as long as the decision makers in the households were informed. CONCLUSIONS: Our study indicated that there are gaps in IYCF related service delivery and there is a potential for using mobile phones to both strengthen the quality of service delivery as well as reaching out to the mothers in the community. It is important however, to consider the community readiness to accept the technology during the design and delivery of the intervention. PMID- 29986734 TI - Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia. AB - Stem cell memory T (TSCM) and central memory T (TCM) cells can rapidly differentiate into effector memory (TEM) and terminal effector (TEF) T cells, and have the most potential for immunotherapy. In this study, we found that the frequency of TSCM and TCM cells in the CD8+ population dramatically decreased together with increases in TEM and TEF cells, particularly in younger patients with acute myeloid leukemia (AML) (< 60 years). These alterations persisted in patients who achieved complete remission after chemotherapy. The decrease in TSCM and TCM together with the increase in differentiated TEM and TEF subsets in CD8+ T cells may explain the reduced T cell response and subdued anti-leukemia capacity in AML patients. PMID- 29986735 TI - Current practice patterns of preoperative bowel preparation in colorectal surgery: a nation-wide survey by the Chinese Society of Colorectal Cancer. AB - BACKGROUND: The optimal preoperative bowel preparation for colorectal surgery remains controversial. However, recent studies have established that bowel preparation varies significantly among countries and even surgeons at the same institution. This survey aimed to obtain information on the current practice patterns of bowel preparation for colorectal surgery in China. METHODS: A paper based survey was circulated to the members of the Chinese Society of Colorectal Cancer (CSCC). The survey responses were collected and analyzed. Statistical analysis was performed for all the categorical variables according to the responses to individual questions. RESULTS: Three hundred forty-one members completed the questionnaire. Regarding surgical practice, 203 (59.5%) performed > 50% of the colorectal operations laparoscopically or robotically; the use of mechanical bowel preparation (MBP) alone was significantly higher (63.5 vs 31.9%; P < 0.001). The respondents who performed > 200 colonic or rectal resections provided significantly more MBP alone (79.6 vs 39.1%, P < 0.001; 76.6 vs 43.2%, P < 0.001; respectively). Among hospitals with fewer than 500 beds, 52.4% of the respondents used MBP + oral antibiotics preparation (OAP) + enema, a significantly higher percentage than the respondents of hospitals with more than 500 beds (P < 0.001). Nearly 40% of the respondents prescribed OAP in regimens; meanwhile, 74.8% prescribed preoperative intravenous antibiotics. CONCLUSIONS: The study demonstrates considerable variation among members from the CSCC. These findings should be considered when developing multicenter trials and to provide more definitive answers. PMID- 29986736 TI - miR-182 suppresses invadopodia formation and metastasis in non-small cell lung cancer by targeting cortactin gene. AB - BACKGROUND: Metastasis is the leading cause of cancer mortality and is a major hurdle for lung cancer treatment. Invadopodia, which are cancer-specific protrusive structures, play a crucial role in the metastatic cascade through degradation of the basement membrane and surrounding stroma. Cortactin, a critical component of invadopodia, frequently used as an invadopodia marker, a universally important player in invadopodia function, and is frequently overexpressed in cancer, but the exact mechanism of regulation is not yet fully understood. METHODS: The expression level of CTTN in human non-small cell lung cancer (NSCLC) tissues was detected by qRT-PCR. Cell migration, invasion and invadopodia formation were assessed in vitro by wound-healing, transwell assay and immunofluorescence, respectively. The dual-luciferase reporter assay was used to identify the direct target of miR-182. RESULTS: Hepatocyte growth factor (HGF) and phorbol 12,13-dibutyrate (PDBu) can induce CTTN expression, motility, and invasion ability, as well as invadopodia formation in non-small cell lung cancer (NSCLC). Moreover, miR-182 suppressed metastasis and invadopodia formation by targeting CTTN in NSCLC. Our qRT-PCR results showed that CTTN expression was inversely correlated with miR-182 expression that suppressed invadopodia formation via suppression of the Cdc42/N-WASP pathway. Furthermore, miR-182 negatively regulated invadopodia function, and suppressed extracellular matrix(ECM) degradation in lung cancer cells by inhibiting cortactin. CONCLUSION: Collectively, our results demonstrated that miR-182 targeted CTTN gene in NSCLC and suppressed lung cancer invadopodia formation, and thus suppressed lung cancer metastasis. This suggests a therapeutic application of miR-182 in NSCLC. PMID- 29986737 TI - Thoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer. AB - BACKGROUND: Combined resection of a phrenic nerve is occasionally required in T3 primary lung carcinomas invading the phrenic nerve to completely remove a malignant tumour, resulting in diaphragmatic paralysis. We describe the first case of thoracoscopic lobectomy and diaphragmatic plication as a one-stage surgery for lung cancer invading the phrenic nerve. CASE PRESENTATION: A 56-year old woman with a T3N0M0 primary adenosquamous carcinoma in the left upper lobe presented with suspicious invasion to the anterior mediastinal fat tissue and left phrenic nerve and underwent left upper lobectomy, node dissection, and partial resection of the anterior mediastinal fat tissue with the left phrenic nerve. Furthermore, thoracoscopic diaphragmatic plication was performed as a concomitant procedure. The patient's postoperative course was favourable, without any complications, and respiratory function was preserved for 1 year postoperatively. CONCLUSIONS: Thoracoscopic one-stage lobectomy and diaphragmatic plication for T3 lung cancer invading the phrenic nerve is effective for preservation of postoperative pulmonary function. PMID- 29986738 TI - Challenges of palliative care in children with inborn metabolic diseases. AB - BACKGROUND: Our objective was to evaluate children with metabolic diseases in paediatric palliative home care (PPC) and the process of decision-making. This study was conducted as single-centre retrospective cohort study of patients in the care of a large specialized PPC team. RESULTS: Between 01/2013 and 09/2016, 198 children, adolescents and young adults were in the care of our PPC team. Twenty-nine (14.6%) of these patients had metabolic conditions. Median age at referral was 2.6 years (0-24), median duration of care 352 days (3-2248) and median number of home visits 13 (1-80). Most patients are still alive (16; 55.2%). Median number of drugs administered was 5 (range 0-12), antiepileptics were given most frequently. Symptom burden was high in all children with metabolic disorders at referral and remained high throughout care. Predominant symptoms were gastrointestinal, respiratory and neurologic symptoms. Children with metabolic conditions, who were referred to PPC younger than 1 year of age had a shorter period of care and died earlier compared to those children, who were referred to PPC later in their lives (older than 10 years of age). Eleven (37.9%) of the children initially had no resuscitation restrictions and 7 (53.8%) of those who died, did so on ICU. CONCLUSIONS: About 15% of children with life limiting conditions in PPC present with metabolic diseases. Symptom burden is high with neurologic, respiratory and gastrointestinal symptoms being the most frequent and most of those being difficult to treat. In these children, particular attention needs to be addressed to advance care planning. PMID- 29986739 TI - Correction to: The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells. AB - After the publication of this work [1], an error was noticed in Fig. 2b, Fig. 3a and Fig. 5b. The Skp1 loading control was accidentally duplicated. We apologize for this error, which did not affect any of the interpretations or conclusions of the article. PMID- 29986740 TI - Determinants of low birth weight among neonates born in Amhara Regional State Referral Hospitals of Ethiopia: unmatched case control study. AB - OBJECTIVE: This study was conducted to identify the determinants of low birth weight among infants born in Amhara Regional State Referral Hospitals of Ethiopia. RESULTS: This study found that mothers who delivered female infants (AOR: 1.7, 95% CI 1.1, 2.6), occurrence of health problems during current pregnancy (AOR: 2.8, 95% CI 1.7,4.5), absence of antenatal care (AOR: 2.3,95% CI 1.3,4.0), lack of iron supplementation (AOR: 2.8, 95% CI 1.6,4.9), maternal MUAC below 23 cm (AOR: 1.7, 95% CI 1.0,2.7), and gestational age below 37 completed weeks (AOR: 3.3; 95% CI 1.9, 5.7) were found to be determinants of low birth weight. PMID- 29986742 TI - Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. AB - BACKGROUND: Progressive supranuclear palsy (PSP) is a parkinsonian neurodegenerative tauopathy affecting brain regions involved in motor function, including the basal ganglia, diencephalon and brainstem. While PSP is largely considered to be a sporadic disorder, cases with suspected familial inheritance have been identified and the common MAPT H1haplotype is a major genetic risk factor. Due to the relatively low prevalence of PSP, large sample sizes can be difficult to achieve, and this has limited the ability to detect true genetic risk factors at the genome-wide statistical threshold for significance in GWAS data. With this in mind, in this study we genotyped the genetic variants that displayed the strongest degree of association with PSP (P<1E-4) in the previous GWAS in a new cohort of 533 pathologically-confirmed PSP cases and 1172 controls, and performed a combined analysis with the previous GWAS data. RESULTS: Our findings validate the known association of loci at MAPT, MOBP, EIF2AK3 and STX6 with risk of PSP, and uncover novel associations with SLCO1A2 (rs11568563) and DUSP10 (rs6687758) variants, both of which were classified as non-significant in the original GWAS. CONCLUSIONS: Resolving the genetic architecture of PSP will provide mechanistic insights and nominate candidate genes and pathways for future therapeutic intervention strategies. PMID- 29986743 TI - Morphological plasticity in Myxobolus Butschli, 1882: a taxonomic dilemma case and renaming of a parasite species of the common carp. AB - BACKGROUND: Myxozoans are a group of cnidarian parasites, the present taxonomy of which favors a more comprehensive characterization strategy combining spore morphology, biological traits (host/organ specificity, tissue tropism), and DNA data over the classical morphology-based taxonomy. However, a systematist might again run into a taxonomic dilemma if more than two of the following exceptional cases were encountered at the same time: extensive intraspecific polymorphism, interspecific morphological similarity, identical interspecific biological traits and blurred small-subunit (SSU) rDNA-based species boundaries. In the present study, spores of a species of Myxobolus Butschli, 1882 with two morphotypes (wide type and narrow type) were collected from the gills of common carp Cyprinus carpio Linnaeus. Confusingly, the wide type was found to be identical to Myxobolus paratoyamai Kato, Kasai, Tomochi, Li & Sato, 2017 in spore morphology and SSU rDNA sequence, which confidently suggested their conspecificity; while the narrow type, was highly similar to Myxobolus toyamai Kudo, 1917 based on spore morphology and SSU rDNA sequence and thus could not be easily classified. This discordance between wide type and narrow type has caused a taxonomic dilemma. To address this problem, a hypothesis about the conspecificity of the narrow type and M. toyamai was addressed. RESULTS: It was found that if the narrow type is conspecific with M. toyamai, it would be paradoxical for the SSU rDNA sequence of the narrow type to be more similar to M. paratoyamai (99.3%), Myxobolus acinosus Nie & Li, 1973 (98.6%) and Myxobolus longisporus Nie & Li, 1992 (98.7%) than to M. toyamai (97.6%). According to the results of the above what-if analysis, the narrow type and M. toyamai were considered to be different species. All in all, the present dual-morphotype species is estimated to be conspecific with M. paratoyamai Kato, Kasai, Tomochi, Li & Sato, 2017. Considering that this species name was preoccupied by Myxobolus paratoyamai Nie & Li, 1992, the replacement name Myxobolus pseudoacinosus nom. nov. is proposed. CONCLUSIONS: This work addresses the taxonomic dilemma in polymorphic myxozoans and demonstrates that M. pseudoacinosus is a distinct species with two morphotypes. The present study may serve as a baseline for future studies that encounter similar classification complexities. PMID- 29986744 TI - Protein phosphatase 2A activation mechanism contributes to JS-K induced caspase dependent apoptosis in human hepatocellular carcinoma cells. AB - BACKGROUND: JS-K is a nitric oxide (NO) donor and could generate intracellularly high levels of NO. The study explores PP2A as a tumor suppressor is a major determinant mediating JS-K-caused apoptosis in human hepatocellular carcinoma (HCC) cells. METHODS: The human HCC cell lines (PLC5, Huh-7, Bel-7402, SMMC-7721 and HepG2) were used to assess effects of JS-K on cell viability, apoptosis induction and PP2A activation. Effects of JS-K on cell morphology, mitochondrial membrane potential, apoptosis and NO levels were determined in HCC cells expressing PP2A. Simultaneously, the expression of PP2A family including PP2A A(alpha/beta), PP2A-B55, PP2A-C(alpha/beta) and the substrates of PP2A, such as beta-catenin, c-Myc and p-Bcl-2 (Ser70) were detected in sensitive HCC cells. Furthermore, the role of NO in mediating the expression of PP2A was further validated with Z-VAD-FMK (a caspase inhibitor), Carboxy-PTIO (a NO scavenger), okadaic acid (OA, a PP2A inhibitor) and FTY720 (a PP2A agonist) in JS-K treated cells. In addition, the genetic manuplation of PP2A including overexpression and knockdown have been also performed in JS-K treated cells. Moreover, the rat model of primary hepatic carcinoma was established with diethylnitrosamine for 16 weeks to verify the anti-tumor effects of JS-K in vivo. Immunohistochemical and Western blot analysis were used to determine the expression of proteins in rat primary hepatic carcinoma tissues. RESULTS: JS-K significantly inhibited cell proliferation, increased apoptosis rate and activated PP2A activity in five HCC cells viability, especially SMMC7721 and HepG2 cells. It was characterized by loss of mitochondrial membrane potential, significant externalization of phosphatidylserine, nuclear morphological changes. Moreover, JS-K enhanced Bax-to Bcl-2 ratio, released cytochrome c (Cyt c) from mitochondria, activated cleaved caspase-9/3 and the cleavage of PARP, and decreased the expression of X-linked inhibitor of apoptosis protein (XIAP). Both Z-VAD-FMK and Carboxy-PTIO suppressed the activation of cleaved-caspase-9/3 and of cleaved-PARP in JS-K-treated sensitive HCC cells. Simultaneously, JS-K treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C) but not PP2A-A and PP2A-B55, which subsequently inactivated and dephosphorylated the PP2A substrates including beta catenin, c-Myc, and p-Bcl-2 (Ser70). However, silencing PP2A-C could abolish both the activation of PP2A-C and down-regulation of beta-catenin, c-Myc and p-Bcl-2 (Ser70) in sensitive HCC cells. Conversely, PP2A overexpression could enhance the effects of JS-K on activation of PP2A and down-regulation of beta-catenin, c-Myc and p-Bcl-2 (Ser70). In addition, adding okadaic acid (OA), a PP2A inhibitor, abolished the effects of JS-K on apoptosis induction, PP2A activation and the substrates of PP2A dephosphorylation; FTY720, a PP2A agonist, enhanced the effects of JS-K including apoptosis induction, PP2A activation and the substrates of PP2A dephosphorylation. The mice exhibited a lower number and smaller tumor nodules in response to JS-K-treated group. A marked increase in the number of hepatocytes with PCNA-positive nuclei (proliferating cells) was evident in DEN group and tended to decrease with JS-K treatment. Furthermore, JS-K treatment could induce PP2A activation and the substrates of PP2A inactivation such as beta catenin, c-Myc and p-Bcl-2(Ser70) in DEN-induced hepatocarcinogenesis. CONCLUSIONS: High levels of NO released from JS-K induces a caspase-dependent apoptosis through PP2A activation. PMID- 29986741 TI - Splicing heterogeneity: separating signal from noise. AB - Single-cell analyses have revealed a tremendous variety among cells in the abundance and chemical composition of RNA. Much of this heterogeneity is due to alternative splicing by the spliceosome. Little is known about how many of the resulting isoforms are biologically functional or just provide noise with little to no impact. The dynamic nature of the spliceosome provides numerous opportunities for regulation but is also the source of stochastic fluctuations. We discuss possible origins of splicing stochasticity, the experimental approaches for studying heterogeneity in isoforms, and the potential biological significance of noisy splicing in development and disease. PMID- 29986745 TI - Aerobic exercise-based cardiac rehabilitation in Chinese patients with coronary heart disease: study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in the world, including China. Cardiac rehabilitation (CR) has been demonstrated to be beneficial in reducing cardiovascular mortality, myocardial infarction, and cerebrovascular events. This pilot study seeks to assess the feasibility of aerobic-exercise-based CR in Chinese patients with coronary heart disease (CHD) and outcomes of aerobic metabolism capacity and molecular biomarkers. METHODS/DESIGN: This study is a single-center, pilot, randomized, controlled study that is currently being carried out at a regional hospital in Shanghai. Forty patients with CHD who underwent percutaneous coronary intervention will be randomly allocated into either the intervention group or control group. Participants in the intervention group will undergo 8 weeks of aerobic exercise with targeted intensity and participants in the control group will undergo 8 weeks of leisure exercise. The primary measurement is the feasibility of the trial; the secondary measurement is the capacity of aerobic metabolism and the exploratory measurement includes additional molecular biomarkers underlying cardiovascular function. DISCUSSION: This is the first prospective randomized and controlled clinical study in China that assesses the parameters of aerobic metabolism and comprehensively screens for substantial blood biomarkers to reveal the molecular mechanisms underlying changes in cardiovascular function after aerobic exercise with targeted intensity in participants with CHD. The success of this study will contribute to guide the design of future CR studies in patients with CHD in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-17010556 . Registered on 1 June 2016. PMID- 29986746 TI - Deterioration of alveolar development in mice with both HIF-3alpha knockout and HIF-2alpha knockdown. AB - OBJECTIVE: Earlier studies from our group using hypoxia-inducible factor 3alpha knockout mice showed impairments in lung remodeling and lung endothelial cells. Another research from our group demonstrated that impaired expression of hypoxia inducible factor 2alpha induced compensatory expression of hypoxia-inducible factor 1alpha in hypoxia-inducible factor 2alpha knockdown mice. The present study uncovers more insights by extending the investigation, utilizing mice with both hypoxia-inducible factor 3alpha knockout and hypoxia-inducible factor 2alpha knockdown. RESULTS: No mice with both hypoxia-inducible factor 3alpha knockout and hypoxia-inducible factor 2alpha knockdown died immediately after birth. The mice with both hypoxia-inducible factor 3alpha knockout and hypoxia-inducible factor 2alpha knockdown exhibited impaired alveolar sacs and lung alveolar structure and decreased endothelial cell numbers. Analysis of relative mRNA expression revealed depressed expressions of hypoxia-inducible factor 1alpha, vascular cell adhesion molecule 1, vascular endothelial cadherin, angiopoietin 2, Tie-2, and vascular endothelial growth factor in the lungs of mice with both hypoxia-inducible factor 3alpha knockout and hypoxia-inducible factor 2alpha knockdown compared to that in wild-type mice. Further analysis is needed to elucidate the impaired development occurred in the lung endothelial cells. PMID- 29986748 TI - Prevalence and risk factors of gastro-esophageal reflux disease among undergraduate medical students from a southern Indian medical school: a cross sectional study. AB - OBJECTIVE: Gastro-esophageal reflux disease (GERD) affects all age groups, and various lifestyle as well as psychological factors are recognized as risk factors for GERD. Undergraduate medical students are exposed to lifestyle changes and psychological stressors. We aimed to study the prevalence of GERD among undergraduate students of a medical school in southern India in a cross-sectional survey using a validated symptom score. RESULTS: A total of 358 undergraduate medical students participated in the study. There were 188 (52.5%) males and 170 (47.4%) females; the mean (SD) age of the participants was 20.3 (1.5) years. A total of 115 (31.2%) participants had at least one episode of heartburn per week, while 108 (30.1%) participants had at least one episode of regurgitation per week. Heartburn or regurgitation of at least mild severity was present in 115 (32.1%) and 108 (30.16%) of participants respectively. Based on the symptom score, a diagnosis of GERD was made in 18 (5.02%) students. Frequent consumption of carbonated drinks (OR = 3.63 [95% CI 1.39-9.5]; P = 0.008) and frequent consumption of tea or coffee (OR = 4.65 [95% CI 1.2-17.96]; P = 0.026) were significantly associated with a diagnosis of GERD. PMID- 29986747 TI - Establishment and molecular characterization of a human ovarian clear cell carcinoma cell line (FDOV1). AB - BACKGROUND: Ovarian clear cell carcinoma is a distinct histologic subtype with grave survival. The underlying molecular mechanism is not fully elucidated. However, we don't have many cell lines, which are useful experimental tools for research. We describe the establishment and characterization of a new ovarian clear cell carcinoma cell line from a Chinese patient. RESULTS: FDOV1 has been subcultured for more than 80 generations. Monolayer cultured cells are polygonal in shape, showing a transparent cytoplasm full of vacuoles. The number of chromosomes ranges from 45 to 90. FDOV1 cells produces CA-125, but not CA-199. The cells could be transplanted and produced tumors mimicking the donor tumor morphologically and immunohistochemically. Whole exome sequence showed both FDOV1 and tissue block harbored PIK3CA H1047R mutation and ARID1A frameshift mutations (p.L2106 fs, p.N201 fs). More interestingly, we observed SPOP mutation (p.D82H) and ZNF217 (chromosome 20q13) amplification in FDOV1, which are quite novel. CONCLUSIONS: Only a few patient-derived ovarian clear cell carcinoma cell lines have been reported in the literature. FDOV1 is the very first one, to the best of our knowledge, from a Mainland Chinese patient. It showed infinite multiplication until now and tumorigenicity in vivo. FDOV1 has co-existing PIK3CA and ARID1A mutations. It also harbored SPOP mutation and ZNF217 amplification, which would probably be a good model for exploring the molecular mechanism of ovarian clear cell carcinoma. PMID- 29986749 TI - Dichotomous associations of liver pathology with hepatocellular carcinoma morphology in Middle Africa: the situation in Cameroon. AB - OBJECTIVE: This study evaluates the occurrence of the various morphological subtypes of hepatocellular carcinoma (HCC) and their connections with some risk factors in Cameroonian patients. The database of the 360 liver biopsies received and associated medical records were reviewed for histological and demographic analysis. Archival formalin-fixed and paraffin embedded liver biopsy specimens or slide were re-evaluated in malignancies patients. HCC classification was determined according to the World Health Organization criteria. RESULTS: Malignancies were confirmed in 24.7% (89/360) of liver biopsies. Primary liver tumors consisted in 80 cases of HCC and one case of hepatoblastoma. The distribution of the morphological variants of HCC was trabecular pattern (n = 45/80, 56.25%), acinar/pseudoglandular (32.5%) or scirrhous (11.2%). Remarkably, liver steatosis was present in 60.0% (48/80) of patients with HCC, most of them infected with hepatitis C virus (75.8%). Well-differentiated trabecular tumors were significantly associated with important fibrotic and necro-inflammatory activities in livers (P = 0.008) whereas acinar pattern was more frequent on fatty livers (P = 0.02). Our finding indicates that in Middle Africa the morphology of HCC subtypes correlates with changes affecting non-tumor liver tissue. Trabecular subtype is installed by strong liver injury whereas acinar pattern is more often associated with lipid metabolism defects. PMID- 29986750 TI - Intra-operative spectroscopic assessment of surgical margins during breast conserving surgery. AB - BACKGROUND: In over 20% of breast conserving operations, postoperative pathological assessment of the excised tissue reveals positive margins, requiring additional surgery. Current techniques for intra-operative assessment of tumor margins are insufficient in accuracy or resolution to reliably detect small tumors. There is a distinct need for a fast technique to accurately identify tumors smaller than 1 mm2 in large tissue surfaces within 30 min. METHODS: Multi modal spectral histopathology (MSH), a multimodal imaging technique combining tissue auto-fluorescence and Raman spectroscopy was used to detect microscopic residual tumor at the surface of the excised breast tissue. New algorithms were developed to optimally utilize auto-fluorescence images to guide Raman measurements and achieve the required detection accuracy over large tissue surfaces (up to 4 * 6.5 cm2). Algorithms were trained on 91 breast tissue samples from 65 patients. RESULTS: Independent tests on 121 samples from 107 patients - including 51 fresh, whole excision specimens - detected breast carcinoma on the tissue surface with 95% sensitivity and 82% specificity. One surface of each uncut excision specimen was measured in 12-24 min. The combination of high spatial-resolution auto-fluorescence with specific diagnosis by Raman spectroscopy allows reliable detection even for invasive carcinoma or ductal carcinoma in situ smaller than 1 mm2. CONCLUSIONS: This study provides evidence that this multimodal approach could provide an objective tool for intra-operative assessment of breast conserving surgery margins, reducing the risk for unnecessary second operations. PMID- 29986752 TI - Interleukin-18 as a diagnostic marker of adult-onset Still's disease in older patients: a case report and review of the literature. AB - BACKGROUND: Adult onset Still's disease is a systemic auto-inflammatory condition of unknown etiology characterized by intermittent spiking high fever, an evanescent salmon-pink or erythematous maculopapular skin rash, arthralgia or arthritis, and leukocytosis. Recently, a high level of interleukin-18 has been reported as a new characteristic marker. On the other hand no reports have been published on high interleukin-18 as a marker in older patients. We report a case of adult onset Still's disease in an older patient successfully treated with steroids in which interleukin-18 was a useful marker of disease activity. CASE PRESENTATION: A 66-year-old Asian woman presented to our hospital with fever and arthralgia. We diagnosed adult onset Still's disease based on Yamaguchi criteria and a history of a high spiking fever, salmon-colored rash, and bilateral pain to shoulders, knees, and wrists. In this case, a high serum level of interleukin-18 was a diagnostic parameter. Administration of 40 mg of prednisolone followed by subcutaneous administration of 200 mg cyclosporine daily resulted in a dramatic resolution of our patient's febrile episodes 2 months after admission. Prednisolone was tapered to 5 mg/day every 2 weeks and cyclosporine 200 mg/day was continued. Her serum interleukin-18 level was prominently decreased, and she was discharged 3 months after treatment. CONCLUSIONS: Serum interleukin-18 level may be a good diagnostic biomarker to monitor adult onset Still's disease activity in older patients, measuring levels in both the acute and convalescent phases. PMID- 29986751 TI - Maize Genomes to Fields: 2014 and 2015 field season genotype, phenotype, environment, and inbred ear image datasets. AB - OBJECTIVES: Crop improvement relies on analysis of phenotypic, genotypic, and environmental data. Given large, well-integrated, multi-year datasets, diverse queries can be made: Which lines perform best in hot, dry environments? Which alleles of specific genes are required for optimal performance in each environment? Such datasets also can be leveraged to predict cultivar performance, even in uncharacterized environments. The maize Genomes to Fields (G2F) Initiative is a multi-institutional organization of scientists working to generate and analyze such datasets from existing, publicly available inbred lines and hybrids. G2F's genotype by environment project has released 2014 and 2015 datasets to the public, with 2016 and 2017 collected and soon to be made available. DATA DESCRIPTION: Datasets include DNA sequences; traditional phenotype descriptions, as well as detailed ear, cob, and kernel phenotypes quantified by image analysis; weather station measurements; and soil characterizations by site. Data are released as comma separated value spreadsheets accompanied by extensive README text descriptions. For genotypic and phenotypic data, both raw data and a version with outliers removed are reported. For weather data, two versions are reported: a full dataset calibrated against nearby National Weather Service sites and a second calibrated set with outliers and apparent artifacts removed. PMID- 29986753 TI - Co-morbidity of malnutrition with falciparum malaria parasitaemia among children under the aged 6-59 months in Somalia: a geostatistical analysis. AB - BACKGROUND: Malnutrition and malaria are both significant causes of morbidity and mortality in African children. However, the extent of their spatial comorbidity remains unexplored and an understanding of their spatial correlation structure would inform improvement of integrated interventions. We aimed to determine the spatial correlation between both wasting and low mid upper arm circumference (MUAC) and falciparum malaria among Somalian children aged 6-59 months. METHODS: Data were from 49 227 children living in 888 villages between 2007 to 2010. We developed a Bayesian geostatistical shared component model in order to determine the common spatial distributions of wasting and falciparum malaria; and low-MUAC and falciparum malaria at 1 * 1 km spatial resolution. RESULTS: The empirical correlations with malaria were 0.16 and 0.23 for wasting and low-MUAC respectively. Shared spatial residual effects were statistically significant for both wasting and low-MUAC. The posterior spatial relative risk was highest for low-MUAC and malaria (range: 0.19 to 5.40) and relatively lower between wasting and malaria (range: 0.11 to 3.55). Hotspots for both wasting and low-MUAC with malaria occurred in the South Central region in Somalia. CONCLUSIONS: The findings demonstrate a relationship between nutritional status and falciparum malaria parasitaemia, and support the use of the relatively simpler MUAC measurement in surveys. Shared spatial distribution and distinct hotspots present opportunities for targeted seasonal chemoprophylaxis and other forms of malaria prevention integrated within nutrition programmes. PMID- 29986754 TI - Determinants of burnout syndrome among nursing students in Cameroon: cross sectional study. AB - OBJECTIVES: Burnout syndrome defined as a state of emotional exhaustion and disengagement; which could reduce optimal healthcare delivery, is relatively common amongst healthcare trainees. We sought to assess the determinants of burnout syndrome amongst nursing students in Cameroon. A cross-sectional study which included 447 nursing students recruited after written informed consent by convenience sampling, was carried out from January to April 2018. A printed self administered questionnaire assessing burnout using the OLdenburg Burnout Inventory was used. Multivariable linear regression was used to identify independent determinants of burnout syndrome. RESULTS: Most (81.17%) of the students were female with the average for disengagement items being 17.10 +/- 3.09 (minimum = 8, maximum = 26) and 20.94 +/- 3.04 (minimum = 13, maximum = 31) for exhaustion items. After multivariable linear regression analysis, satisfaction with results (RC: - 1.42, 95% CI - 2.52, - 0.32, p value: 0.012) and regret of choice of nursing studies (RC: 2.13, 95% CI 0.58, 3.68, p value = 0.007) were found to be independent predictors of burnout in these students. Early identification of these determinants is required to prevent progression to burnout. PMID- 29986756 TI - Experiences of antenatal care among pregnant adolescents at Kanyama and Matero clinics in Lusaka district, Zambia. AB - BACKGROUND: Adolescent pregnancy is among the many public health concerns not only in Zambia but also in other parts of the world. Exploring pregnant adolescents' experiences of antenatal care may help to identify specific problems and the contextual relevant strategies to improve the access to antenatal care. The purpose of this study was to explore and describe the lived experiences of antenatal care among pregnant adolescents aged between 12 to 19 years old at Kanyama and Matero Referral Clinics in Lusaka district of Zambia. METHODS: This was a qualitative study which used in-depth interviews to collect data. Maximum variation sampling technique was used to select 12 pregnant adolescents of 12 to 19 years age range that attended antenatal care. Data were analysed thematically with the help of Nvivo software version 10. RESULTS: The study revealed that the adolescents experienced positive and negative antenatal care. While there were some reported cases of caring and friendly health care providers and older pregnant women, there were also reported cases of poor attitudes and behaviours by the older pregnant women and health care providers towards the adolescents. In addition, other issues that were reported by the adolescents were the opening hours for the health facilities which was not favourable to all adolescents and the lack of specific spaces for adolescents as well as inadequate privacy and confidentiality. Some solutions were suggested to overcome some of the problems such as reducing the waiting hours or time for consultations at the clinic and to have specific rooms or spaces for pregnant adolescents at the clinic. CONCLUSION: Appropriate interventions targeting pregnant adolescents with emphasis on making antenatal care services more adolescent friendly may improve the quality of and accessibility of antenatal services. The adolescent friendly antenatal services should integrate health promotion activities aimed at sensitising elderly women within the health facilities on the importance of supporting pregnant adolescents. PMID- 29986755 TI - Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. AB - BACKGROUND: Mounting evidence suggests that RAF-mediated MEK activation plays a crucial role in paradox MAPK (re)activation, leading to resistance and therapeutic failure with agents hitting a single step along the MAPK cascade. METHODS: We examined the molecular and functional effects of single and combined BRAF (dabrafenib), pan-RAF (RAF265), MEK (trametinib) and EGFR/HER2 (lapatinib) inhibition, using Western Blot and conservative isobologram analysis to assess functional synergism, and explored genetic determinants of synergistic interactions. Immunoprecipitation based assays were used to detect the interaction between BRAF and CRAF. The Mann-Whitney U test was used for comparing quantitative variables. RESULTS: Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro. This results in growth inhibitory synergism, both in vitro and in vivo, in the majority (65%) of the cellular models analyzed, encompassing cell lines and patient-derived cancer stem cells and organoids. However, RAS mutational status is not the sole determinant of functional synergism between RAF and MEK inhibitors, as demonstrated in KRAS isogenic tumor cell line models. Moreover, in EGFR-driven contexts, paradoxical MAPK (re)activation in response to selective BRAF inhibition was dependent on EGFR family signaling and could be offset by simultaneous EGFR/HER-2 blockade. CONCLUSIONS: Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting. PMID- 29986758 TI - Features of randomised trials designed by the NPEU Perinatal Trials Service during Adrian Grant's directorship. AB - Adrian Grant pioneered methodological innovations in the randomised trials organised by the Perinatal Trials Service established at the national Perinatal Epidemiology Unit in Oxford, UK. This Commentary discusses these innovations, and shows the wide range of trials designed under his directorship. PMID- 29986757 TI - Modelling the association between fibrinogen concentration on admission and mortality in patients with massive transfusion after severe trauma: an analysis of a large regional database. AB - BACKGROUND: The relationship between fibrinogen concentration and traumatic death has been poorly explored after severe trauma. Existing studies analysed this relationship in unselected trauma population, often considering fibrinogen concentration as a categorical variable. The aim of our study was to model the relationship between fibrinogen concentration and in-hospital mortality in severe trauma patients requiring massive transfusion using fibrinogen on admission as a continuous variable. METHODS: We designed a retrospective observational study based on prospectively collected data from 2009 to 2015 in seven French level-I trauma centres. All consecutive patients requiring a transfusion of at least 10 packed red blood cells (RBC) within 24 h were included. To assess the relationship between in-hospital death and fibrinogen concentration on admission, we performed generalized linear and additive models with death as a dependent variable. We also assessed the relationship between fibrinogen concentration below 1.5 g.L- 1 and potential predictors. RESULTS: Within the study period, 366 patients were included. A non-linear relationship was found between fibrinogen concentration and death. Graphical modelling of this relationship depicted a negative association between fibrinogen levels and death below a fibrinogen concentration of 1.5 g.L- 1. Predictors of low fibrinogen concentration (< 1.5 g.L- 1) were systolic blood pressure, Glasgow coma scale and haemoglobin concentration on admission. CONCLUSIONS: A complex and robust approach for modelling the relationship between fibrinogen and mortality revealed a critical fibrinogen threshold of 1.5 g.L- 1 for severe trauma patients requiring massive transfusion. This trigger may guide the administration of procoagulant therapies in this context. PMID- 29986759 TI - M1-like tumor-associated macrophages activated by exosome-transferred THBS1 promote malignant migration in oral squamous cell carcinoma. AB - BACKGROUND: Treatment strategies targeting tumor-associated macrophages (TAMs) have been proposed in cancer areas. The functional alterations of macrophages in the microenvironment during the tumorigenesis of human epithelial cancer remain poorly understood. Here, we explored phenotypic alteration of macrophages during the development of oral squamous cell carcinoma (OSCC). METHODS: Conditioned media (CM) and exosome supernatants were harvested from normal oral epithelium, oral leukoplakia cells and OSCC cells. We measured phenotypic alteration of macrophages using flow cytometry, luminex assays, and quantitative real-time PCR assay. Intracellular signaling pathway analysis, mass spectrometry proteomics, western blotting, enzyme-linked immunosorbent assay, immunohistochemical staining, and bioinformatics analysis were performed to uncover the underlying mechanisms. RESULTS: THP-1-derived and PBMCs derived macrophages exhibited an M1 like phenotype but not M2-like phenotype, when treated with CM from OSCC cells but not with the CM from normal epithelium or leukoplakia cells. Further investigations revealed that macrophages were activated by taking up exosomes released from OSCC cells through p38, Akt, and SAPK/JNK signaling at the early phase. We further provided evidences that THBS1 derived from OSCC exosomes participated in the polarization of macrophages to an M1-like phenotype. Reciprocally, CM from exosomes induced M1-like TAMs and significantly promoted migration of OSCC cells. CONCLUSIONS: We proposed a novel paracrine loop between cancer cells and macrophages based on exosomes from OSCC. Therefore, target management of M1-like TAMs polarized by exosomes shows great potential as a therapeutic target for the control of cancerous migration in OSCC. PMID- 29986760 TI - Biological compatibility between two temperate lineages of brown dog ticks, Rhipicephalus sanguineus (sensu lato). AB - BACKGROUND: The brown dog tick Rhipicephalus sanguineus (sensu stricto) is reputed to be the most widespread tick of domestic dogs worldwide and has also been implicated in the transmission of many pathogens to dogs and humans. For more than two centuries, Rh. sanguineus (s.s.) was regarded as a single taxon, even considering its poor original description and the inexistence of a type specimen. However, genetic and crossbreeding experiments have indicated the existence of at least two distinct taxa within this name: the so-called "temperate" and "tropical" lineages of Rh. sanguineus (sensu lato). Recent genetic studies have also demonstrated the existence of additional lineages of Rh. sanguineus (s.l.) in Europe and Asia. Herein, we assessed the biological compatibility between two lineages of Rh. sanguineus (s.l.) found in southern Europe, namely Rhipicephalus sp. I (from Italy) and Rhipicephalus sp. II (from Portugal). METHODS: Ticks morphologically identified as Rh. sanguineus (s.l.) were collected in southern Portugal and southern Italy. Tick colonies were established and crossbreeding experiments conducted. Morphological, biological and genetic analyses were conducted. RESULTS: Crossbreeding experiments confirmed that ticks from the two studied lineages were able to mate and generate fertile hybrids. Hybrid adult ticks always presented the same genotype of the mother, confirming maternal inheritance of mtDNA. However, larvae and nymphs originated from Rhipicephalus sp. I females presented mtDNA genotype of either Rhipicephalus sp. I or Rhipicephalus sp. II, suggesting the occurrence of paternal inheritance or mitochondrial heteroplasmy. While biologically compatible, these lineages are distinct genetically and phenotypically. CONCLUSIONS: The temperate lineages of Rh. sanguineus (s.l.) studied herein are biologically compatible and genetic data obtained from both pure and hybrid lines indicate the occurrence of paternal inheritance or mitochondrial heteroplasmy. This study opens new research avenues and raises question regarding the usefulness of genetic data and crossbreeding experiments as criteria for the definition of cryptic species in ticks. PMID- 29986761 TI - The impact of an exercise training intervention on cortisol levels and post traumatic stress disorder in juveniles from an Ugandan refugee settlement: study protocol for a randomized control trial. AB - BACKGROUND: Latest research demonstrates a significant improvement in stress related symptoms in psychological disorders as a result of exercise training (ET). Controlled clinical trials further validate the significance of ET by demonstrating lower salivary cortisol levels in patients with post-traumatic stress disorder (PTSD) after intervention. A significant change in cortisol and dehydroepiandrosterone (DHEA) levels can already be found after an 8-12-week ET program. The proposed study aims to investigate the impact of an 8-week ET on PTSD symptoms and changes in cortisol levels in a juvenile refugee sample from the Democratic Republic of the Congo (DRC) at an Ugandan refugee settlement. It is the first to implement an ET intervention in a resource-poor, post-conflict setting. METHODS/DESIGN: In a randomized controlled trial, 198 adolescent participants aged 13-16 years from the DRC who, suffer from PTSD, will be investigated. The participants are based at the Nakivale refugee settlement, an official refugee camp in Uganda, Africa, which is among the largest in the world. The participants will be randomized into an Exercise Training (ET) group with a maximum heart rate (HRmax) of > 60%, an Alternative Intervention (AI) group with low-level exercises, and a Waiting-list Control (WC) group. After the 8-week interventional phase, changes in cortisol awakening response (CAR) and DHEA in the ET group that correspond to an improvement in PTSD symptoms are expected that remain at follow-up after 3 months. DISCUSSION: To date, there is no controlled and reliable longitudinal study examining the effects of an ET program on symptom severity in individuals with PTSD that can be explained with a harmonization of cortisol secretion. The presented study design introduces an intervention that can be implemented with little expenditure. It aims to provide a promising low threshold and cost-effective treatment approach for the application in resource poor settings. TRIAL REGISTRATION: German Trials Register, ID: DRKS00014280 . Registered prospectively on 15 March 2018. PMID- 29986762 TI - Temperature-dependent development and freezing survival of protostrongylid nematodes of Arctic ungulates: implications for transmission. AB - BACKGROUND: Umingmakstrongylus pallikuukensis and Varestrongylus eleguneniensis are two potentially pathogenic lungworms of caribou and muskoxen in the Canadian Arctic. These parasites are currently undergoing northward range expansion at differential rates. It is hypothesized that their invasion and spread to the Canadian Arctic Archipelago are in part driven by climate warming. However, very little is known regarding their physiological ecology, limiting our ability to parameterize ecological models to test these hypotheses and make meaningful predictions. In this study, the developmental parameters of V. eleguneniensis inside a gastropod intermediate host were determined and freezing survival of U. pallikuukensis and V. eleguneniensis were compared. METHODS: Slug intermediate hosts, Deroceras laeve, were collected from their natural habitat and experimentally infected with first-stage larvae (L1) of V. eleguneniensis. Development of L1 to third-stage larvae (L3) in D. laeve was studied at constant temperature treatments from 8.5 to 24 degrees C. To determine freezing survival, freshly collected L1 of both parasite species were held in water at subzero temperatures from -10 to -80 degrees C, and the number of L1 surviving were counted at 2, 7, 30, 90 and 180 days. RESULTS: The lower threshold temperature (T0) below which the larvae of V. eleguneniensis did not develop into L3 was 9.54 degrees C and the degree-days required for development (DD) was 171.25. Both U. pallikuukensis and V. eleguneniensis showed remarkable freeze tolerance: more than 80% of L1 survived across all temperatures and durations. Larval survival decreased with freezing duration but did not differ between the two species. CONCLUSION: Both U. pallikuukensis and V. eleguneniensis have high freezing survival that allows them to survive severe Arctic winters. The higher T0 and DD of V. eleguneniensis compared to U. pallikuukensis may contribute to the comparatively slower range expansion of the former. Our study advances knowledge of Arctic parasitology and provides ecological and physiological data that can be useful for parameterizing ecological models. PMID- 29986763 TI - Efficacy of praziquantel treatment regimens in pre-school and school aged children infected with schistosomiasis in sub-Saharan Africa: a systematic review. AB - BACKGROUND: Schistosomiasis is a serious public health burden in sub-Saharan Africa. Praziquantel is the only drug recommended by the World Health Organization to treat both urogenital and intestinal schistosomiasis. The reliance on a single drug to treat a disease with such a huge burden has raised concerns of possible drug resistance mainly in endemic areas. This systematic review was conducted to identify gaps and recent progress on the efficacy of different regimens of praziquantel in treating schistosomiasis among children in sub-Saharan Africa where Schistosoma mansoni and S. haematobium are endemic. MAIN TEXT: A literature search of peer-reviewed journals was done on Google Scholar, MEDLINE (under EBSCOhost) and PubMed databases using pre-defined search terms and Boolean operators. The search included studies published from 2008 to 2017 (August) with emphasis on the efficacy of praziquantel on S. haematobium and S. mansoni infections among preschool and school children. Nineteen publications satisfied the inclusion criteria for the review. The studies reviewed were from 10 sub-Saharan African countries and 7/19 of the studies (37%) were conducted in Uganda. Seven studies (37%) focused on Schistosoma mansoni, 6/19 (31.5%) on S. haematobium and another 6 on mixed infection. A single standard dose of 40 mg/kg body weight was the most used regimen (9) followed by the repeated single standard dose assessed for efficacy at 3-4 weeks post-treatment. CONCLUSIONS: A repeated standard dose of 40 mg/kg achieved satisfactory efficacy compared to a single dose against both parasite species. However, findings on efficacy of repeated doses in co-infection of S. mansoni and S. haematobium were not conclusive. Praziquantel administrated at 60 mg/kg was slightly more efficacious than the 40 mg/kg standard dose. Minor and transitory side-effects were reported for both regimens. The review indicates that further investigations are necessary to conclusively determine efficacy of praziquantel on coinfection of S. haematobium and S. mansoni to formulate concrete guidelines on the use of repeated doses at 40 or 60 mg/kg for treating schistosomiasis. We recommend the use of the egg reduction rate (ERR) formula recommended by the WHO for assessing praziquantel efficacy in order for the results to be comparable for different regions. PMID- 29986764 TI - Correction to: Metagenomics of urban sewage identifies an extensively shared antibiotic resistome in China. AB - Unfortunately, after publication of this article [1], it was noticed that the accession numbers for the study were missing. The correct numbers are PRJNA438554, SRP148953. PMID- 29986765 TI - Organizational culture and climate as moderators of enhanced outreach for persons with serious mental illness: results from a cluster-randomized trial of adaptive implementation strategies. AB - BACKGROUND: Organizational culture and climate are considered key factors in implementation efforts but have not been examined as moderators of implementation strategy comparative effectiveness. We investigated organizational culture and climate as moderators of comparative effectiveness of two sequences of implementation strategies (Immediate vs. Delayed Enhanced Replicating Effective Programs [REP]) combining Standard REP and REP enhanced with facilitation on implementation of an outreach program for Veterans with serious mental illness lost to care at Veterans Health Administration (VA) facilities nationwide. METHODS: This study is a secondary analysis of the cluster-randomized Re-Engage implementation trial that assigned 3075 patients at 89 VA facilities to either the Immediate or Delayed Enhanced REP sequences. We hypothesized that sites with stronger entrepreneurial culture, task, or relational climate would benefit more from Enhanced REP than Standard REP. Veteran- and site-level data from the Re Engage trial were combined with site-aggregated measures of entrepreneurial culture and task and relational climate from the 2012 VA All Employee Survey. Longitudinal mixed-effects logistic models examined whether the comparative effectiveness of the Immediate vs. Delayed Enhanced REP sequences were moderated by culture or climate measures at 6 and 12 months post-randomization. Three Veteran-level outcomes related to the engagement with the VA system were assessed: updated documentation, attempted contact by coordinator, and completed contact. RESULTS: For updated documentation and attempted contact, Veterans at sites with higher entrepreneurial culture and task climate scores benefitted more from Enhanced REP compared to Standard REP than Veterans at sites with lower scores. Few culture or climate moderation effects were detected for the comparative effectiveness of the full sequences of implementation strategies. CONCLUSIONS: Implementation strategy effectiveness is highly intertwined with contextual factors, and implementation practitioners may use knowledge of contextual moderation to tailor strategy deployment. We found that facilitation strategies provided with Enhanced REP were more effective at improving uptake of a mental health outreach program at sites with stronger entrepreneurial culture and task climate; Veterans at sites with lower levels of these measures saw more similar improvement under Standard and Enhanced REP. Within resource-constrained systems, practitioners may choose to target more intensive implementation strategies to sites that will most benefit from them. TRIAL REGISTRATION: ISRCTN: ISRCTN21059161 . Date registered: April 11, 2013. PMID- 29986766 TI - Community knowledge, attitudes and practices related to schistosomiasis and associated healthcare-seeking behaviours in northern Cote d'Ivoire and southern Mauritania. AB - BACKGROUND: Among parasitic infections, schistosomiasis ranks second after malaria in terms of worldwide morbidity. Despite efforts to contain transmission, more than 230 million people are infected, of which 85% live in Sub-Saharan Africa. While the epidemiologic characteristics of schistosomiasis have been extensively studied across endemic settings, social factors have been paid less attention. The current study assesses community knowledge of schistosomiasis causes, transmission, signs, symptoms and prevention, as well as healthcare seeking behaviours in two West African settings, with the aim of strengthening schistosomiasis control interventions. METHODS: From August 2014 to June 2015, we conducted two cross-sectional surveys in Korhogo, Cote d'Ivoire and Kaedi, Mauritania. We applied a questionnaire to collect quantitative data at the household level in Korhogo (n = 1456) and Kaedi (n = 1453). Focus group discussions (Korhogo: n = 32, Kaedi: n = 32) and participatory photography (photovoice) (Korhogo: n = 16, Kaedi: n = 16) were conducted within the communities to gather qualitative data. In addition, semi-structured interviews were used to discuss with key informants from control programmes, non governmental organizations and health districts (Korhogo: n = 8, Kaedi: n = 7). RESULTS: The study demonstrated that schistosomiasis is not well known by the communities; 64.1% claimed to know the causes of the disease, but the reality is different. This knowledge is more from cultural than biomedical source. It was observed that social construction of the disease is different from the biomedical definition. In Korhogo, schistosomiasis was often associated with several other diseases, notably stomach ulcer and gonorrhoea. The populations believe that schistosomiasis is caused by exposure to goat or dog urine in the environment. In Kaedi, schistosomiasis is considered as a disease transmitted by environmenal elements such as sunshine and dirty water. In both settings, the care-seeking pathways were found to be strongly influenced by local customs and self medication acquired from the informal sector. CONCLUSIONS: This study revealed that knowledge about the aetiology, transmission, symptoms, prevention and treatment of schistosomiasis among the populations in Korhogo and Kaedi is based on their local culture. Deep-rooted habits could therefore pose a significant obstacle to the elimination of schistosomiasis. PMID- 29986767 TI - Sporadic Parkinson's disease derived neuronal cells show disease-specific mRNA and small RNA signatures with abundant deregulation of piRNAs. AB - Differentiated neurons established via iPSCs from patients that suffer from familial Parkinson's disease (PD) have allowed insights into the mechanisms of neurodegeneration. In the larger cohort of patients with sporadic PD, iPSC based information on disease specific cellular phenotypes is rare. We asked whether differences may be present on genomic and epigenomic levels and performed a comprehensive transcriptomic and epigenomic analysis of fibroblasts, iPSCs and differentiated neuronal cells of sporadic PD-patients and controls. We found that on mRNA level, although fibroblasts and iPSCs are largely indistinguishable, differentiated neuronal cells of sporadic PD patients show significant alterations enriched in pathways known to be involved in disease aetiology, like the CREB-pathway and the pathway regulating PGC1alpha. Moreover, miRNAs and piRNAs/piRNA-like molecules are largely differentially regulated in cells and post-mortem tissue samples between control- and PD-patients. The most striking differences can be found in piRNAs/piRNA-like molecules, with SINE- and LINE derived piRNAs highly downregulated in a disease specific manner. We conclude that neuronal cells derived from sporadic PD-patients help to elucidate novel disease mechanisms and provide relevant insight into the epigenetic landscape of sporadic Parkinson's disease as particularly regulated by small RNAs. PMID- 29986768 TI - A team effort: natural killer cells on the first leg of the tumor immunity relay race. AB - Recent work by Bottcher and colleagues defines a new role for Natural Killer cells in the anti-tumor immune response, arriving early into the tumor microenvironment before passing the baton to DC1 dendritic cells. DC1 dendritic cells subsequently activate CD8+ T cells resulting in effective anti-tumor immunity. This work highlights the cooperative nature of anti-tumor immunity set in motion by Natural Killer cells, and immune evasion by tumors through their exclusion. PMID- 29986769 TI - Complete response to ipilimumab and nivolumab therapy in a patient with extensive extrapulmonary high-grade small cell carcinoma of the pancreas and HIV infection. AB - BACKGROUND: Immune checkpoint inhibitors (CPIs) have shown promising results in many solid tumors. There are limited data on the safety and efficacy of these drugs in HIV infected patients as they have traditionally been excluded from CPIs clinical trials. CASE PRESENTATION: We present a case of an HIV-positive patient with extensive extrapulmonary high-grade small cell carcinoma who was treated with dual CPIs (nivolumab and ipilimumab) with a complete response to therapy and with a manageable safety profile. We performed a comprehensive literature review identifying 62 total HIV positive cases treated with CPIs showing this to be a potentially safe option in HIV-positive patients. CONCLUSION: HIV infection is not an absolute contraindication to CPI therapy. Our case and others provide justification for ongoing trials of CPI therapy in patients with HIV infection, a group that has traditionally been excluded from clinical trials. PMID- 29986770 TI - HEALTH TECHNOLOGY ASSESSMENT UNIT PROCESSES FOR THE VALIDATION OF AN INFORMATION TOOL TO INVOLVE PATIENTS IN THE SAFETY OF THEIR CARE. AB - INTRODUCTION: Patients and families play an important role in preventing adverse events. The quality council at our hospital produced a communication tool in considering the main causes of adverse events and requested the health technology assessment (HTA) unit to validate it. OBJECTIVES: Assess the validity of the content of a tablemat sticker as an information tool for hospitalized patients. METHODS: A qualitative validation was first performed with individual interviews and focus groups to evaluate the understanding of the content. The tool was modified and as a second step, a survey was conducted on patients and their families from a surgical care unit to validate their understanding and relevance of the content. RESULTS: From the survey, patients and families found the tablemat attractive and stimulating (97 percent). It encouraged them to communicate with staff about the safety of their care (84 percent). They understood well the objective (79 percent) and text (90 percent), but less for the pictograms (30 percent to 62 percent). The communication and recommendations to avoid falling were good and 99 percent were wearing the medical identification. However, it was not clear that these indicators represented the real concerns of the patients and healthcare staff because no user evaluation was done when developing the tool. CONCLUSIONS: The tool was well understood, but some improvements are needed considering that pictograms were not always well understood and so need careful consideration from patient perspective. The HTA unit recommended conducting an unbiased survey to assess the concerns of patients and professionals to identify the most relevant indicators. PMID- 29986771 TI - Integrating spirituality into the care of older adults. AB - ABSTRACTWe examine how to sensibly integrate spirituality into the care of older adult medical and psychiatric patients from a multi-cultural perspective. First, definitions of spirituality and spiritual integration are provided. Second, we examine the logic that justifies spiritual integration, including research that demonstrates an association between religious/spiritual (R/S) involvement and health in older adults and research that indicates widespread spiritual needs in later life and the consequences of addressing or ignoring them. Third, we describe how and when to integrate spirituality into the care of older adults, i.e. taking a spiritual history to identify spiritual needs and then mobilizing resources to meet those needs. Fourth, we examine the consequences of integrating spirituality on the well-being of patients and on the doctor-patient relationship. Finally, we describe boundaries in addressing R/S issues that clinicians should be cautious about violating. Resources will be provided to assist with all of the above. PMID- 29986772 TI - Absence of cerebrospinal fluid antineuronal antibodies in schizophrenia spectrum disorders - CORRIGENDUM. AB - SummaryThis notice describes a correction to the above mentioned paper. PMID- 29986773 TI - Potential confounding in a study of dietary inflammatory index and cognitive function. PMID- 29986774 TI - Thiamine status, metabolism and application in dairy cows: a review. AB - As the co-enzyme of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, thiamine plays a critical role in carbohydrate metabolism in dairy cows. Apart from feedstuff, microbial thiamine synthesis in the rumen is the main source for dairy cows. However, the amount of ruminal thiamine synthesis, which is influenced by dietary N levels and forage to concentrate ratio, varies greatly. Notably, when dairy cows are overfed high-grain diets, subacute ruminal acidosis (SARA) occurs and results in thiamine deficiency. Thiamine deficiency is characterised by decreased ruminal and blood thiamine concentrations and an increased blood thiamine pyrophosphate effect to >45 %. Thiamine deficiency caused by SARA is mainly related to the increased thiamine requirement during high grain feeding, decreased bacterial thiamine synthesis in the rumen, increased thiamine degradation by thiaminase, and decreased thiamine absorption by transporters. Interestingly, thiamine deficiency can be reversed by exogenous thiamine supplementation in the diet. Besides, thiamine supplementation has beneficial effects in dairy cows, such as increased milk and component production and attenuated SARA by improving rumen fermentation, balancing bacterial community and alleviating inflammatory response in the ruminal epithelium. However, there is no conclusive dietary thiamine recommendation for dairy cows, and the impacts of thiamine supplementation on protozoa, solid-attached bacteria, rumen wall-adherent bacteria and nutrient metabolism in dairy cows are still unclear. This knowledge is critical to understand thiamine status and function in dairy cows. Overall, the present review described the current state of knowledge on thiamine nutrition in dairy cows and the major problems that must be addressed in future research. PMID- 29986775 TI - Molecular epidemiology of Cryptosporidium spp. in dairy cattle in Guangdong Province, South China. AB - To determine the prevalence of Cryptosporidium in dairy cattle in Guangdong Province, South China, 1440 fecal samples were collected from 10 farms and screened for Cryptosporidium with PCR. The overall prevalence of Cryptosporidium was 4.38% (63/1440), and the infection rates in preweaned calves, postweaned calves, heifers and adults were 6.4% (19/297), 6.19% (33/533), 1.48% (4/271) and 2.06% (7/339), respectively. Three Cryptosporidium species, Cryptosporidium andersoni (n = 33), Cryptosporidium bovis (n = 22) and Cryptosporidium ryanae (n = 8) were detected by DNA sequence analysis of the 63 positive samples, and C. andersoni was identified as the most common species on the dairy cattle farms. In preweaned calves, C. bovis was the most prevalent species (9/19, 47.4%). In contrast, C. andersoni was the predominant species (19/33, 57.6%) in postweaned calves and the only species found in heifers and adults. The zoonotic species Cryptosporidium parvum was not detected in this study. Twenty-four C. andersoni isolates were successfully classified into three multilocus sequence typing (MLST) subtypes. MLST subtype A4,A4,A4,A1 was the predominant subtype, and MLST subtype A2,A5,A2,A1, previously found in sheep, was detected in cattle for the first time. A linkage disequilibrium analysis showed that the C. andersoni isolates had a clonal genetic population structure. However, further molecular studies are required to better understand the epidemiology of Cryptosporidium in Guangdong. PMID- 29986776 TI - Molecular evidence linking the larval and adult stages of Mexiconema cichlasomae (Dracunculoidea: Daniconematidae) from Mexico, with notes on its phylogenetic position among Dracunculoidea. AB - We describe the larval developmental stages and life cycle of the dracunculid nematode Mexiconema cichlasomae in both the intermediate, Argulus yucatanus (Crustacea: Branchiura), and definitive hosts, Cichlasoma urophthalmus (Perciformes: Cichlidae), from the Celestun tropical coastal lagoon, Yucatan, Mexico. The morphological analyses showed significant differences between the total length of L1 found in M. cichlasomae gravid female and L2-L3 in A. yucatanus. This result indicates that the M. cichlasomae larval development occurs in the intermediate host. We obtained sequences from the small subunit (SSU) ribosomal marker from larval stages of M. cichlasomae in A. yucatanus and adult nematodes in C. urophthalmus. Our morphological and molecular results support conspecificity between M. cichlasomae larvae in A. yucatanus and the adult stages in C. urophthalmus. We briefly discuss the phylogenetic position of M. cichlasomae among the Daniconematidae, and provide evidence of the monophyly of the daniconematids associated with branchiurid intermediate hosts. Based on the phylogenetic results, we support the transfer of the Mexiconema genus to the family Skrjabillanidae and do not support the lowering of family Daniconematidae to subfamily. PMID- 29986777 TI - Post-Campylobacter Guillain Barre Syndrome in the USA: secondary analysis of surveillance data collected during the 2009-2010 novel Influenza A (H1N1) vaccination campaign. AB - Guillain Barre syndrome (GBS), which is triggered by autoantibodies produced in response to antigenic stimuli such as certain infections and vaccinations, is the most common cause of acute flaccid paralysis worldwide. Campylobacter, the most common bacterial enteric infection in the USA, is reported to be the most commonly diagnosed antecedent of GBS, yet little information is available about the risk of post-Campylobacter GBS. Data collected through active, population based surveillance in the Emerging Infections Program during the 2009-2010 novel Influenza A (H1N1) vaccination campaign allowed us to compare confirmed and probable GBS cases to non-cases to determine whether antecedent Campylobacter infection (or a diarrhoeal illness consistent with campylobacteriosis) was more common among cases and to assess the risk of GBS following Campylobacter infection. We estimate that 8-12% of GBS cases in the USA are attributable to Campylobacter infection (or a diarrhoeal illness consistent with campylobacteriosis), with 434-650 cases of post-diarrhoeal GBS annually and about 49 cases of GBS per 100 000 Campylobacter infections. These results provide updated estimates for post-Campylobacter GBS incidence in the USA and highlight an important benefit of effective measures to prevent Campylobacter infections. PMID- 29986778 TI - Co-circulation of Chikungunya and Dengue viruses in Dengue endemic region of New Delhi, India during 2016. AB - Co-circulation of Chikungunya and Dengue viral infections (CHIKV and DENV) have been reported mainly due to transmission by common Aedes vector. The purpose of the study was to identify and characterise the circulating strains of CHIKV and DENV in DENV endemic region of New Delhi during 2016. CHIKV and DENV were identified in the blood samples (n = 130) collected from suspected patients by RT PCR. CHIKV was identified in 26 of 65 samples (40%). Similarly, DENV was detected in 48 of 120 samples (40%). Co-infection with both the viruses was identified in five (9%) of the samples. Interestingly, concurrent infection with DENV, CHIKV and Plasmodium vivax was detected in two samples. CHIKV strains (n = 11) belonged to the ECSA genotype whereas DENV-3 sequences (n = eight) clustered in Genotype III by phylogenetic analysis. Selection pressure of E1 protein of CHIKV and CprM protein of DENV-3 revealed purifying selection with four and two positive sites, respectively. Four amino acids of the CHIKV were positively selected and had high entropy suggesting probable variations. Co-circulation of both viruses in DENV endemic regions warrants effective monitoring of these emerging pathogens via comprehensive surveillance for implementation of effective control measures. PMID- 29986779 TI - Morphological and molecular confirmation of the validity of Trichuris rhinopiptheroxella in the endangered golden snub-nosed monkey (Rhinopithecus roxellana). AB - The golden snub-nosed monkey (Rhinopithecus roxellana) is an endangered species endemic to China. Relatively little is known about the taxonomic status of soil transmitted helminths (STH) in these monkeys. Trichuris spp. (syn. Trichocephalus) are among the most important STHs, causing significant socio economic losses and public health concerns. To date, five Trichuris species have been reported in golden monkeys, including a novel species, T. rhinopiptheroxella, based on morphology. In the present study, molecular and morphological analysis was conducted on adult Trichuris worms obtained from a dead golden snub-nosed monkey, to better understand their taxonomic status. Morphology indicated that the adult Trichuris worms were similar to T. rhinopiptheroxella. To further ascertain their phylogenetic position, the complete mitochondrial (mt) genome of these worms was sequenced and characterized. The mt genome of T. rhinopiptheroxella is 14,186 bp, encoding 37 genes. Phylogenetic analysis based on the concatenated amino acids of 12 protein coding genes (with the exception of atp8) indicated that T. rhinopiptheroxella was genetically distinct and exhibited 27.5-27.8% genetic distance between T. rhinopiptheroxella and other Trichuris spp. Our results support T. rhinopiptheroxella as a valid Trichuris species and suggest that mt DNA could serve as a marker for future studies on the classification, evolution and molecular epidemiology of Trichuris spp. from golden snub-nosed monkeys. PMID- 29986780 TI - Clinical impact of a novel ambulatory rhythm monitor in children. AB - Traditional ambulatory rhythm monitoring in children can have limitations, including cumbersome leads and limited monitoring duration. The ZioTM patch ambulatory monitor is a small, adhesive, single-channel rhythm monitor that can be worn up to 2 weeks. In this study, we present a retrospective cross-sectional analysis of the ZioTM monitor's impact in clinical practice. Patients aged 0-18 years were included in the study. A total of 373 studies were reviewed in 332 patients. In all, 28.4% had structural heart disease, and 16.9% had a prior surgical, catheterisation, or electrophysiology procedure. The most common indication for monitoring was tachypalpitations (41%); 93.5% of these patients had their symptoms captured during the study window. The median duration of monitoring was 5 days. Overall, 5.1% of ZioTM monitoring identified arrhythmias requiring new intervention or increased medical management; 4.0% identified arrhythmias requiring increased clinical surveillance. The remainder had either normal-variant rhythm or minor rhythm findings requiring no change in management. For patients with tachypalpitations and no structural heart disease, 13.2% had pathological arrhythmias, but 72.9% had normal-variant rhythm during symptoms, allowing discharge from cardiology care. Notably, for patients with findings requiring intervention or increased surveillance, 56% had findings first identified beyond 24 hours, and only 62% were patient-triggered findings. Seven studies (1.9%) were associated with complications or patient intolerance. The ZioTM is a well-tolerated device that may improve what traditional Holter and event monitoring would detect in paediatric cardiology patients. This study shows a positive clinical impact on the management of patients within a paediatric cardiology practice. PMID- 29986781 TI - Iron deficiency anaemia: experiences and challenges. AB - Iron deficiency remains the largest nutritional deficiency worldwide and the main cause of anaemia. Severe iron deficiency leads to anaemia known as iron deficiency anaemia (IDA), which affects a total of 1.24 billion people, the majority of whom are children and women from resource-poor countries. In sub Saharan Africa, iron deficiency is frequently exacerbated by concomitant parasitic and bacterial infections and contributes to over 120 000 maternal deaths a year, while it irreparably limits the cognitive development of children and leads to poor outcomes in pregnancy.Currently available iron compounds are cheap and readily available, but constitute a non-physiological approach to providing iron that leads to significant side effects. Consequently, iron deficiency and IDA remain without an effective treatment, particularly in populations with high burden of infectious diseases. So far, despite considerable investment in the past 25 years in nutrition interventions with iron supplementation and fortification, we have been unable to significantly decrease the burden of this disease in resource-poor countries.If we are to eliminate this condition in the future, it is imperative to look beyond the strategies used until now and we should make an effort to combine community engagement and social science approaches to optimise supplementation and fortification programmes. PMID- 29986782 TI - OVERCOMING THE BARRIERS TO ACHIEVING UNIVERSAL HEALTH CARE IN THE ASIAN REGION. AB - OBJECTIVES: The Health Technology Assessment International (HTAi) Asia Policy Forum (HAPF) met to discuss the challenges of achieving universal health care (UHC) in Asia. METHODS: Group discussions and presentations at the 2017 HAPF, informed by a background paper, including a literature review and the results of pre-meeting surveys of health technology assessment (HTA) agencies and industry, formed the basis of this article. RESULTS: Affordability was identified as the greatest barrier to establishing UHC; however, other impediments include the lack of political will to implement UHC, and the cultural issue of deference to expert opinion instead of evidence-based assessments. Although HTA was identified as an important prioritization tool when adding new technologies to benefit packages, it is used inconsistently in the region, resulting in a less transparent decision making process for stakeholders. Although regional challenges exist around real world data (RWD), including a lack of capacity to enable information and data sharing, most policy or funding decision makers in the region have access to data. However, there appears to be a disconnect with the experience of industry, whose representatives identify the lack of RWD as their primary issue. To overcome these issues, both HTA agencies and industry agree that collaboration and transparency should be fostered to support the development of robust evidence generation in the region. CONCLUSIONS: There is a willingness for HTA agencies and industry to collaborate to develop HTA methodology for the prioritization of technologies in the Asia region that support healthcare systems to achieve the ultimate outcome of UHC. PMID- 29986783 TI - Patients with Acute Stroke Presenting Like Conversion Disorder. AB - Conversion disorder is a form of somatoform disorders which has a high prevalence among women, individuals with lower socioeconomic status, under-educated populations, and in developing countries. However, up to one-half of patients who had been initially diagnosed with conversion disorder were eventually shown to have an underlying organic pathology-mostly neurological or non-psychiatric conditions. In this article, two patients are presented who accessed the emergency department (ED) with an initial diagnosis of conversion disorder in the ambulance that turned out to be stroke.Serinken M, Karcioglu O. Patients with acute stroke presenting like conversion disorder. Prehosp Disaster Med. 2018;33(4):451-453. PMID- 29986784 TI - Pertussis surveillance by small serosurveys of blood donors. AB - Serosurveys have established data about the distribution of immunoglobulin G (IgG)-antibodies to pertussis toxin (PT) in various populations. We tried to detect whether small serosurveys in blood donors could serve as a simple and inexpensive means to collect information about the circulation of Bordetella pertussis. We screened every donation in 307 adult blood donors aged 19-69 years for IgG-anti-PT by standardised enzyme-linked immunosorbent assays (ELISA), and the donors were followed between 2014 and 2016 for a total of 426 person-years. When we used a vertical survey with cut-offs of 100, 62.5 and 40 IU/ml, respectively, as an indicator for recent contacts with B. pertussis, nine (2.9%), 22 (7.2%) and 54 (17.6%) of donors had IgG-anti-PT titres above the respective levels. During the horizontal observation period of 426 person years, six significant increases and two conversions were found, which lead to an estimate of 1878 contacts/100.000 person-years (1.9% per year). Median and mean IgG-anti PT concentrations remained relatively stable from year to year during the observation period. Our findings show that small serosurveys of blood donors offer a simple and cheap method for the surveillance of B. pertussis. PMID- 29986785 TI - Preconception Hb concentration and risk of preterm birth in over 2.7 million Chinese women aged 20-49 years: a population-based cohort study. AB - Evidence on the association between maternal Hb concentration and preterm birth (PTB) risk is inconclusive. This paper aimed to explore whether women with anaemia or high Hb level before pregnancy would be at higher risk of PTB. We conducted a population-based cohort study with 2 722 274 women aged 20-49 years, who participated in National Free Pre-Pregnancy Checkups Project between 2013 and 2015 and delivered a singleton before 2016 in rural China. Logistic models were used to estimate OR and 95 % CI after adjusting for confounding variables. Restricted cubic spline models were applied to evaluate the dose-response relationships. A total of 192 819 (7.08 %) women had preterm deliveries. Compared with women with Hb of 110-149 g/l, the multivariable-adjusted OR for PTB was 1.19 (95 % CI 0.98, 1.44) for women with Hb<70 g/l, 1.01 (95 % CI 0.97, 1.03) for 70 99 g/l, 0.96 (95 % CI 0.95, 0.98) for 100-109 g/l, 1.04 (95 % CI 1.01, 1.06) for 150-159 g/l, 1.11 (95 % CI 1.05, 1.17) for 160-169 g/l and 1.19 (95 % CI 1.11, 1.27) for >=170 g/l, respectively. The multivariable-adjusted OR for very PTB (VPTB) was 1.07 (95 % CI 1.03, 1.12) and 1.06 (95 % CI 1.01, 1.12) for women with Hb <110 and >=150 g/l, compared with those with Hb of 110-149 g/l, respectively. Our study identified a U-shaped relationship between maternal preconception Hb concentration and PTB risk. Both preconception anaemia and high Hb level can significantly increase VPTB risk. Appropriate intervention for women with abnormal Hb levels before pregnancy is very necessary. PMID- 29986786 TI - A pre-post pilot study of electronic cigarettes to reduce smoking in people with severe mental illness. AB - BACKGROUND: Smoking is the largest single contributor to poor physical health and increased mortality in people with serious mental illnesses. The aim of the study was to investigate the utility of electronic cigarettes (e-cigarettes) as a harm reduction intervention in this population. METHOD: Fifty tobacco smokers with a psychotic disorder were enrolled onto a 24-week pilot study (ClinicalTrials.gov: NCT02212041) investigating the efficacy of a 6-week free e-cigarette intervention to reduce smoking. Cigarette and e-cigarette use was self-reported at weekly visits, and verified using carbon monoxide tests. Psychopathology, e-cigarette acceptability and adverse effects were assessed using standardised scales. RESULTS: There was a significant (?50%) reduction in cigarettes consumed per day between baseline and week 6 [F(2.596,116.800) = 25.878, p < 0.001], and e cigarette use was stable during this period [F(2.932,46.504) = 2.023, p = 0.115]. These changes were verified by significant carbon monoxide reductions between these time points [F(3.335,126.633) = 5.063, p = 0.002]. CONCLUSIONS: The provision of e-cigarettes is a potentially useful harm reduction intervention in smokers with a psychotic disorder. PMID- 29986787 TI - Morphological evidence of biofilm in chronic obstructive sialadenitis. AB - OBJECTIVE: Bacterial infection is a common finding in acute sialadenitis and may play a role in the chronicity of the condition. This study investigated if bacterial biofilm is present in submandibular chronic obstructive sialadenitis. METHODS: A descriptive case-control study was conducted that compared 10 histological sections of submandibular glands with chronic obstructive sialadenitis, to 10 histological sections of the healthy part of submandibular glands with pleomorphic adenoma. Fluorescence in situ hybridisation and confocal laser scanning microscopy visualised evidence of bacterial biofilm. RESULTS: In the chronic obstructive sialadenitis group, 5 out of 10 histological sections showed morphological evidence of bacterial biofilm. In the control group, there was no sign of bacterial biofilm formation. CONCLUSION: Morphological evidence of bacterial biofilm was found in the submandibular gland sections from patients with chronic sialadenitis and suggests a role in the chronicity of submandibular chronic obstructive sialadenitis. PMID- 29986789 TI - Postnatal differential expression of chemoreceptors of free fatty acids along the gastrointestinal tract of supplemental feeding v. grazing kid goats. AB - The gastrointestinal tract (GIT) of animals is capable of sensing various kinds of nutrients via G-protein coupled receptor-mediated signaling transduction pathways, and the process is known as 'gut nutrient chemosensing'. GPR40, GPR41, GPR43 and GPR119 are chemoreceptors for free fatty acids (FFAs) and lipid derivatives, but they are not well studied in small ruminants. The objective of this study is to determine the expression of GPR40, GPR41, GPR43 and GPR119 along the GIT of kid goats under supplemental feeding (S) v. grazing (G) during early development. In total, 44 kid goats (initial weight 1.35+/-0.12 kg) were slaughtered for sampling (rumen, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum) between days 0 and 70. The expression of GPR41 and GPR43 were measured at both mRNA and protein levels, whereas GPR40 and GPR119 were assayed at protein level only. The effects of age and feeding system on their expression were variable depending upon GIT segments, chemoreceptors and expression level (mRNA or protein), and sometimes feeding system * age interactions (P0.05) on GPR43 expression; and there were no feeding system*age interactions (P>0.05) on GPR41 and GPR43 protein expression. The expression of GPR41 and GPR43 in rumen and abomasum linearly (P<0.01) increased with increasing age (from days 0 to 70). Meanwhile, age was the main factor affecting GPR40 expression throughout the GIT. These outcomes indicate that age and feeding system are the two factors affecting chemoreceptors for FFAs and lipid derivatives expression in the GIT of kids goats, and S enhanced the expression of chemoreceptors for FFAs, whereas G gave rise to greater expression of chemoreceptors for lipid derivatives. Our results suggest that enhanced expression of chemoreceptors for FFAs might be one of the benefits of early supplemental feeding offered to young ruminants during early development. PMID- 29986788 TI - A new landscape of host-protozoa interactions involving the extracellular vesicles world. AB - Extracellular vesicles (EVs) are released by a wide number of cells including blood cells, immune system cells, tumour cells, adult and embryonic stem cells. EVs are a heterogeneous group of vesicles (~30-1000 nm) including microvesicles and exosomes. The physiological release of EVs represents a normal state of the cell, raising a metabolic equilibrium between catabolic and anabolic processes. Moreover, when the cells are submitted to stress with different inducers or in pathological situations (malignancies, chronic diseases, infectious diseases.), they respond with an intense and dynamic release of EVs. The EVs released from stimulated cells vs those that are released constitutively may themselves differ, both physically and in their cargo. EVs contain protein, lipids, nucleic acids and biomolecules that can alter cell phenotypes or modulate neighbouring cells. In this review, we have summarized findings involving EVs in certain protozoan diseases. We have commented on strategies to study the communicative roles of EVs during host-pathogen interaction and hypothesized on the use of EVs for diagnostic, preventative and therapeutic purposes in infectious diseases. This kind of communication could modulate the innate immune system and reformulate concepts in parasitism. Moreover, the information provided within EVs could produce alternatives in translational medicine. PMID- 29986790 TI - Nurse sow strategies in the domestic pig: I. Consequences for selected measures of sow welfare. AB - Management strategies are needed to optimise the number of piglets weaned from hyper-prolific sows. Nurse sow strategies involve transferring supernumerary new born piglets onto a sow whose own piglets are either weaned or fostered onto another sow. Such 'nurse sows' have extended lactations spent in farrowing crates, which could have negative implications for their welfare. This study used 47 sows, 20 of which farrowed large litters and had their biggest piglets fostered onto nurse sows which were either 1 week (2STEP7, n=9) or 3 weeks into lactation (1STEP21, n=10). Sows from which piglets were removed (R) were either left with the remainder of the litter intact (I) (remain intact (RI) sows, n=10), or had their litters equalised (E) for birth weight using piglets of the same age from non-experimental sows (remain equalised (RE) sows, n=9). Piglets from 2STEP7 were fostered onto another nurse sow which was 3 weeks into lactation (2STEP21, n=9). Back-fat thickness was measured at entry to the farrowing house, at fostering (nurse sows only) and weaning. Sows were scored for ease of locomotion and skin and claw lesions at entry to the farrowing house and weaning. Salivary cortisol samples were collected and tear staining was scored at 0900 h weekly from entry until weaning. Saliva samples were also taken at fostering. Data were analysed using GLMs with appropriate random and repeated factors, or non parametric tests were applied where appropriate. Back-fat thickness decreased between entry and weaning for all sows (F 1,42=26.59, P<0.001) and tended to differ between treatments (F 4,16=2.91; P=0.06). At weaning RI sows had lower limb lesion scores than 2STEP7 and RE sows (chi 2 4=10.8, P0.05) and all nurse sows had a higher salivary cortisol concentration at fostering, compared with the other days (F 10,426=3.47; P<0.05). Acute effects of fostering differed between nurse sow treatments (F 2,113=3.45, P0.05). In conclusion, no difference was detected between nurse sows and non-nurse sows in body condition or severity of lesions. Although some nurse sows experienced stress at fostering, no long-term effect of the nurse sow strategies was detected on stress levels compared with sows that raised their own litter. PMID- 29986791 TI - Unexpected source of fever: Liver abscess on point-of-care ultrasound. PMID- 29986795 TI - Standard Method Performance RequirementsSM. PMID- 29986792 TI - The dilemma of knowledge use in political decision-making: National Guidelines in a Swedish priority-setting context. AB - There is a growing recognition of the importance of evidence to support allocative policy decisions in health care. This study is based on interviews with politicians in four regional health authorities in Sweden. Drawing on theories of strategic use of knowledge, the article analyses how politicians perceive and make use of expert knowledge represented by the National Guidelines, embracing both a scientific and a political rationale. As health care is an organisation with a dual basis for legitimacy - at the same time a political and an action organisation - it affects knowledge use. We investigate how the context of health care priority setting influences the conditions for knowledge use among regional politicians. Our findings illustrate the dilemma of political decision makers and how they prefer to use expert knowledge. The politicians use this policy instrument in a legitimising fashion, as it will fit into the current political debate on more equal care. As an instrument for resource allocation the politicians noted that 'facts' per se could not provide them with a sufficient basis for legitimising their governing of health care. The dualistic organisational context makes knowledge important as a political weapon in negotiations with the medical profession. PMID- 29986796 TI - Standard Method Performance Requirements (SMPRs(r)) 2017.020: Quantitation of Chicken Egg by ELISA-Based Methods. PMID- 29986798 TI - HPLC Determination of Total Tryptophan in Infant Formula and Adult/Pediatric Nutritional Formula Following Enzymatic Hydrolysis: Single-Laboratory Validation, First Action 2017.03. PMID- 29986799 TI - Determination of Carotenoids in Infant, Pediatric, and Adult Nutritionals by HPLC with UV-Visible Detection: Single-Laboratory Validation, First Action 2017.04. PMID- 29986797 TI - Standard Method Performance Requirements (SMPRs(r)) 2017.021: Quantitation of Wheat, Rye, and Barley Gluten in Oats. PMID- 29986800 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.004: Determination of trans Resveratrol in Dietary Supplements and Dietary Ingredients. PMID- 29986801 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.005: Determination of Kavalactones and/or Flavokavains from Kava (Piper methysticum). PMID- 29986802 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.006: Determination of Select Flavonoids from Skullcap. PMID- 29986803 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.007: Identification of Skullcap in Raw Materials, Skullcap-Based Dietary Ingredients, and Dietary Supplements. PMID- 29986804 TI - Standard Method Performance Requirements (SMPRs(r)) 2014.003: Revised: Determinional of GOS in Infant Formula and Adult/Pediatric Nutritional Formula. PMID- 29986805 TI - Standard Method Performance Requirements (SMPRs(r)) 2014.016: Revised: Determination of Fluoride in Infant and Adult/Pediatric Nutritional Formula. PMID- 29986806 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.003: Quantitation of Milk by ELISA-Based Methods. PMID- 29986809 TI - Effects of eHealth on hospital practice: synthesis of the current literature. AB - Objective The transition to digital hospitals is fast-moving. Although US hospitals are further ahead than some others in implementing eHealth technologies, their early experiences are not necessarily generalisable to contemporary healthcare because both the systems and technologies have been rapidly evolving. It is important to provide up-to-date assessments of the evidence available. The aim of this paper is to provide an assessment of the current literature on the effects to be expected from hospital implementations of eHealth technologies.Methods A narrative review was conducted of systematic reviews investigating the effects of eHealth technologies (clinical decision support systems (CDSS), computerised provider order entry (CPOE), ePrescribing, electronic medical records (EMRs)) published between November 2015 and August 2017 and compared the findings with those of a previous narrative review that examined studies published between January 2010 and October 2015. The same search strategy and selection criteria were used in both studies.Results Of the seven relevant articles, three (42.9%) examined the effects of more than one eHealth system: only two (28.6%) studies were high quality, three (42.9%) were of intermediate quality and two (28.6%) were of low quality. We identified that EMRs are largely associated with conflicting findings. Previous reviews suggested that CPOE are associated with significant positive results of cost savings, organisational efficiency gains, less resource utilisation and improved individual performance. However, these effects were not investigated in the more recent reviews, and only mixed findings for communication between clinicians were reported. Similarly, for ePrescribing, later reviews reported limited evidence of benefits, although when coupled with CDSS, more consistent positive findings were reported.Conclusion This overview can help inform other hospitals in Australia and elsewhere of the likely effects resulting from eHealth technologies. The findings suggest that the effects of these systems are largely mixed, but there are positive findings, which encourage ongoing digital transformation of hospital practice.What is known about the topic? Governments are increasingly devoting substantial resources towards implementing eHealth technologies in hospital practice with the goals of improving clinical and financial outcomes. Yet, these outcomes are yet to be fully realised in practice and conflicting findings are often reported in the literature.What does this paper add? This paper extends a previous narrative review of systematic reviews and categorises the effects of eHealth technologies into a typology of outcomes to enable overall findings to be reported and comparisons to be made. In doings so, we synthesise 7 years of eHealth effects. Mixed results are largely reported for EMRs, with many benefits being compromised by practices stemming from resistance to EMRs. Limited evidence of effectiveness exists for CPOE and ePrescribing. CDSS are associated with the most consistent positive findings for clinician- and hospital-level effects. We observed renewed interest in the literature for the effect of eHealth technologies on communication both between clinicians and with patients. Other new insights have emerged relating to effects on clinical judgement, changing practice and staff retention.What are the implications for practitioners? eHealth technologies have the potential to positively affect clinical and financial outcomes. However, these benefits are not guaranteed, and mixed results are often reported. This highlights the need for hospitals and decision makers to clearly identify and act on the drivers of successful implementations if eHealth technologies are to facilitate the creation of new, more effective models of patient care in an increasingly complex healthcare environment. PMID- 29986810 TI - Familial hypercholesterolemia in pediatric patients. The success begins here. PMID- 29986807 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.001: Sugars in Animal Feed, Pet Food, and Human Food. PMID- 29986811 TI - Post-graduate year two transitions of care pharmacy residencies no longer accredited. AB - INTRODUCTION: Literature supports pharmacist integration within transitions of care. A total of eight health-system pharmacies and colleges of pharmacy developed focused post-graduate year two (PGY2) training in this specialty. However, in fall 2016, ongoing accreditation of these PGY2 transitions of care programs was discontinued by the American Society of Health-System Pharmacists Commission on Credentialing. PERSPECTIVE: Healthcare relies on interprofessional collaborations and corresponding programs in order to improve patient care. Pharmacists who have completed specialized training in transitions of care are not only leaders in this realm but also ambassadors for interprofessional medicine. IMPLICATIONS: Rebranding transitions of care PGY2 programs fails to capture all the opportunities available to train and mentor new transitions of care pharmacists. Lack of consensual accreditation introduces variability within training. There may be opportunities to revisit transitions of care PGY2 accreditation in the future. PMID- 29986808 TI - Standard Method Performance Requirements (SMPRs(r)) 2018.002: Fructans in Animal Food (Animal Feed, Pet Food, and Ingredients). PMID- 29986812 TI - Connecting non-pharmacist faculty to pharmacy practice. AB - United States (US) colleges and schools of pharmacy employ faculty from various disciplines. Many of these are basic scientists who do not have professional degrees in pharmacy. Nevertheless, all faculty members in colleges/schools of pharmacy, irrespective of discipline, are expected to possess a conceptual understanding of contemporary pharmacy practice and of the pharmacist's role in the healthcare system. Therefore, an essential element of a non-pharmacist faculty development is to gain and maintain a basic understanding of pharmacy practice. The purpose of this short commentary is to describe a mechanism used at our college that connects basic scientists to pharmacy practice through participation as facilitators in an introductory first-year course focused on foundations of pharmacy and the US healthcare system. Through sharing personal experience with this mechanism, the author aims to inspire non-pharmacist faculty to seek out formal and informal avenues available at their institutions to interface with pharmacy practice. PMID- 29986813 TI - Development of valid and reliable tools for student evaluation of teaching. AB - INTRODUCTION: The objective of this project was to develop valid and reliable course and instructor student evaluation tools (SETs) of teaching for utilization by a college of pharmacy. METHODS: A collection of 119 course and instructor evaluation items was compiled from a review of the primary literature and grouped into six different themes (subscales): organization, communication, motivation, rapport, fairness, and learning. Input was sought from the college of pharmacy faculty to reduce the list of items to a more manageable pilot tool (27 for course evaluations; 29 for instructor evaluations) for developing pilot SETs. The results were analyzed for internal consistency and reliability using Cronbach's alpha, and whether factor structures aligned with the content structure using Confirmatory Factor Analysis (CFA). RESULTS: The Cronbach's alpha for all six subscales in the designed instructor evaluation and for three of the six subscales in the designed course evaluation were above 0.9, indicating high internal consistency and reliability. The CFA results indicated a moderate model fit with factor loadings for all items above 0.6. The correlation coefficients between each dimension were about 0.8, indicating high correlations among dimensions. Those data items found to be valid were then used to construct new course and instructor evaluation instruments, both consisting of three validated items in each of the six themes (subscales). CONCLUSION: This report describes the process that one college of pharmacy employed to develop a valid and reliable SET. The methodology can inform other colleges and schools of pharmacy who wish to design, revise, or develop their own SETs. PMID- 29986814 TI - Confidence in skills applied to patient care among PharmD students in telehealth medication management programs versus other settings. AB - INTRODUCTION: Exposure to medication therapy management (MTM) courses has demonstrated to increase student pharmacist's confidence in the application of patient care skills. The purpose of this study was to evaluate the effects of student pharmacists' work experience in a telehealth MTM program, versus hospital or community settings, on their confidence in skills applied in patient care. METHODS: This was a cross-sectional multicenter survey. Confidence in patient care among student pharmacists was assessed between those who worked in a telehealth MTM program versus other settings. The data was evaluated using Chi Square, Fisher exact, unpaired-t, Kruskal-Wallis, and Mann-Whitney U tests. RESULTS: 282 surveys were completed. First-year student pharmacists who worked in the telehealth MTM programs, versus other settings, were more confident in the provision of a comprehensive medication review (CMR) (p < .001), interviewing patients (p < .001), identifying medication errors (p < .001), and making therapeutic recommendations to patients (p = .04) and prescribers (p = .04). Second and third-year student pharmacists who worked in telehealth MTM programs, versus other settings, were more confident in the provision of a CMR (p <= .005). Fourth-year student pharmacists who worked in the telehealth MTM programs, versus other settings, were more confident in the provision of a CMR (p = .003), interviewing patients (p = .02), and identifying medication errors (p = .04). CONCLUSION: Student pharmacists' participation in a telehealth MTM program may markedly increase their confidence in skills applied in patient care. MTM work experience should be offered to student pharmacists during their PharmD programs to enhance their confidence in the provision of patient care. PMID- 29986815 TI - Trends in electronic health record usage among US colleges of pharmacy. AB - INTRODUCTION: Electronic health records (EHRs) are used extensively throughout health systems; this indicates a need for pharmacy student competencies prior to pharmacy practice experiences. The objective was to determine current utility, perceived benefit, and future plans for EHR use in the didactic curriculum of doctor of pharmacy programs in the United States. METHODS: An electronic survey was distributed to members of two special interest groups through the American Association of Colleges of Pharmacy. Content areas in the 14-question survey included current utilization of EHRs in the didactic curriculum, perceived benefit for preparing students for pharmacy practice experiences, and future plans for implementing or improving EHR use. RESULTS: A total of 59 (7.7%) individuals responded to the survey, representing 43 out of 133 schools (32%). Of the respondents currently using EHRs (37%), more than 60% have been using an EHR in the classroom for two years or less while 18.2% reported five or more years of experience. The most common application of EHRs was for clinical cases (77%) followed by pharmaceutical care lab courses (59%), other uses in pharmacotherapeutics (27%), and interprofessional education (23%). Of those not currently using EHRs (63%), the vast majority (84%) plan to integrate EHRs into didactic coursework within the next two years. CONCLUSIONS: EHRs appear to be used by many colleges of pharmacy in courses where clinical cases are being discussed. Further research into the value of EHR usage at earlier stages of professional programs, including within skills labs, objective structured clinical examinations, and other pharmacy coursework, may be helpful given increasing EHR use in healthcare settings. PMID- 29986816 TI - Implementation and assessment of a pulmonary diseases elective course for third year pharmacy students. AB - BACKGROUND: Given the significant public health burden of pulmonary diseases and the vital role pharmacists play in management across the continuum of care (and within transitions in care), an elective course for pharmacy students focused on pulmonary diseases was developed. EDUCATIONAL ACTIVITY: A month-long elective course for third-year pharmacy students consisting of 12 class sessions delivered in two-hour periods three times per week, was implemented. The course was delivered using the team-based learning (TBL) format in addition to hands-on skills and simulation sessions. Knowledge and skills assessments were administered before and after completion of the course. Student perceptions of self-confidence and ability regarding management of pulmonary diseases pre- and post-course and their perceptions of the course and TBL as a teaching strategy for this course were evaluated upon course completion. CRITICAL ANALYSIS: Nine students completed the course. Mean scores on knowledge and skills assessment significantly improved after completion of the course (54.5% pre-course vs. 79.3% post-course; p < 0.05% and 60.3% pre-course vs. 93.2% post-course; p < 0.05, respectively). Student perceptions of their ability to care for patients with pulmonary diseases significantly increased, compared to pre-assessments, in all areas taught in the course (p< 0.05). Additionally, students' confidence in managing specific disease states significantly improved in all areas (p < 0.05) except for spirometry (p = 0.06). Students' knowledge, skills, and confidence regarding management of common pulmonary disease states improved following this month-long elective course delivered using a combination of TBL activities and hands-on skills sessions. PMID- 29986817 TI - Survey of faculty workload and operational characteristics for academic drug information centers. AB - INTRODUCTION: A survey of drug information specialists from academic drug information centers in the United States was conducted to identify faculty workload, operational characteristics of the center, and contribution of those faculty and centers to pharmacy education. METHODS: A 32-item survey was administered to drug information specialists and pharmacy college/school deans. Faculty workload items included age, credentials, training, and responsibilities. Center operational items identified clients, number of requests, staffing structure, and funding source. Pharmacy education items included number and type of students training at the center as well as drug information's role in the curriculum. Participants were also asked to identify recent and anticipated changes as well as predict future challenges for academic drug information centers. RESULTS: The survey achieved a response rate of 81% from eligible institutions. The typical drug information specialist is between 31 and 50 years old, in a clinical track faculty position, and has an average of 13 years of drug information experience. Academic drug information centers are generally funded by the institution, open five days a week, and serve a variety of clients including the lay public. The average drug information specialist teaches one didactic course and is a preceptor for 17 advanced practice experience students, and 15 introductory practice experience students. CONCLUSIONS: Drug information specialists and centers play an important role in pharmacy education. Results of this survey could assist in the creation of benchmarks for academic drug information faculty and centers in terms of workload, resource allocation, and promotion. PMID- 29986818 TI - The IPE performance report: A tool for preceptor development. AB - INTRODUCTION: In order to promote interprofessional education (IPE) within the advanced experiential curriculum, the Office of Experiential Affairs (OEA) at Western New England University (WNE) created a process by which information regarding IPE at the practice sites is collected, verified, quantified, and used for preceptor development. METHODS: An interprofessional education preceptor survey (IPEPS), consisting of 43 standardized questions designed to assess IPE opportunities available at practice sites, was administered to 55 preceptors in spring 2016 using QualtricsTM. Throughout the 2016-2017 academic year, students were required to document two interprofessional interactions that occurred during each of their four required APPE rotations. Results from the IPEPS were used to determine a perceived level of IPE occurring at each site and compared to student field encounter logs, then used to inform preceptor development through a customized IPE Performance Report. RESULTS AND DISCUSSION: Response rates for both the IPEPS and student field encounter logs were 100%. Data relating to preceptors' perception of IPE opportunities afforded by their sites were collected and compared to data logged by students regarding IPE encounters at the sites. The data were compiled through a customized IPE Performance Report and communicated to preceptors as a form of professional development around IPE. PMID- 29986819 TI - The future of weight management in pharmacy education - Perspectives of new generation pharmacists. AB - INTRODUCTION: Over recent years, the profession of pharmacy has transitioned towards providing more individualised patient care services. In this context, community pharmacy has proven to be an excellent facilitator for weight management programs. However, education on weight management in pharmacy undergraduate curricula is often lacking. The perspectives of early career pharmacists on their perceived role in weight management services and their associated educational needs can inform curricula review. METHODS: In-depth, semi structured interviews were conducted with 20 final year pharmacy students of The University of Sydney and five early career pharmacists from the greater Sydney, Australia area. Interviews were recorded, transcribed, and analysed for themes emerging. RESULTS: Participants were positive about their perceived role in providing weight management services. They regarded a program not based on commercial products as most suitable for pharmacy-delivered weight management services. However, some barriers were identified, such as lack of training and communication skills related to weight management. Participants requested more educational resources to ensure the delivery of high quality weight management services. DISCUSSION: Methods to enhance (future) pharmacists' knowledge of weight management services could include case-based learning, enhancement of communication skills, and the development of suitable guidelines. CONCLUSIONS: Participants perceived a clear role for themselves in providing weight management services in community pharmacies. However, the current educational system does not meet their requirements to prepare them for this role. A hands-on approach in education on weight management and appropriate communication skills should be introduced in pharmacy curricula to ensure future pharmacists are well prepared to deliver weight management services. PMID- 29986820 TI - Teaching and assessing clinical ethics through group reading experience and student-led discussion. AB - BACKGROUND AND PURPOSE: Ethical decision-making is one of the foundational elements of responsible patient care, yet traditional didactic coursework often misses the nuances of specific situational aspects of ethics as well as the impact of individual patient experiences on their perspective related to health care. The purpose of this study was to assess the impact of a clinical research ethics elective course involving a group reading experience and facilitated discussion on student decision-making and perspective on questions related to ethics. EDUCATIONAL ACTIVITY AND SETTING: The elective was offered to second-year pharmacy students and was designed to teach ethical concepts within the framework of a group reading experience employing active learning through facilitated student-led group discussion. The book chosen was The Immortal Life of Henrietta Lacks by Rebecca Skloot. Students were assessed pre- and post-course using ethical scenarios (framed as "yes/no" questions) covering a wide range of topics, as well as over their familiarity with and confidence in making decisions related to ethical topics using a five-point Likert scale. FINDINGS: Sixteen students were enrolled in the course, with 14 (87.5%) completing all pre- and post-course assessments. There were no statistically significant changes in the proportion of students answering "yes" or "no" to the scenarios from pre- to post-course, though there were several items in which responses "shifted," meaning students switched answers from pre- to post-course. Overall, students showed significantly more familiarity with the topics covered after the course versus before (p < 0.05), also reporting improved confidence (p < 0.05) in making decisions related to the topics. The per-student analysis also showed significant changes in overall confidence and familiarity (p < 0.05). SUMMARY: Through the course, students showed increased familiarity with the history of clinical research and ethical topics discussed as well as improved confidence in making decisions related to clinical ethics. This type of course design provided a strong environment for discussion and group learning. PMID- 29986821 TI - Qualitative Analysis of Student Pharmacists' Reflections of Harvard's Race Implicit Association Test. AB - BACKGROUND AND PURPOSE: Identify and analyze pharmacy students' perceptions about their own implicit racial biases. EDUCATIONAL ACTIVITY AND SETTING: First year pharmacy students (n = 97) enrolled in a Pharmacy Practice course completed a test, Harvard Race Implicit Association Test (IAT), for homework to uncover their unconscious black-white racial bias. All students then wrote at least one paragraph reflecting on if they agreed or disagreed with their results and why. At the beginning of class, students were given a brief survey to capture their IAT results and demographic information. Retrospectively and following Institutional Review Board approval, pharmacy students' reflections were subjected to thematic analysis with the assistance of NVivo 10 and descriptive analyses were completed of their demographic info. FINDINGS: Out of the 97 students enrolled in this course, all completed the self-reflection. But only 90 completed the survey. From those that completed the survey, 54% (N = 49) self identified as women. The average age was 22.6 years old. Most of the students (77%) identified themselves as White Non-Hispanic. Six percent (N = 5) identified as Black. Most students (66%) reported that their results from the Race IAT indicated some level of preference for European Americans; 13% of the students reported some level of preference for African-Americans. All students' reflections were categorized by their agreement or lack of agreement with their implicit association test results. Those that agreed with their results cited family, friends, and community contributing to their implicit biases. Students who did not agree with their results were subcategorized as denying their results, believing that their implicit association did not affect their behavior, or believing that the Race IAT was invalid. DISCUSSION/SUMMARY: Many pharmacy students were found to be unaware of their implicit biases and some do not believe that these biases will negatively affect the treatment of others. Pharmacy curricula should be developed to provide adequate self-awareness training and space in the curriculum so students can challenge these unconscious beliefs. PMID- 29986822 TI - Design of a 15-month interprofessional workplace learning program to expand the added value of clinical pharmacists in primary care. AB - BACKGROUND AND PURPOSE: Clinical pharmacists who work in the general practice settings bring an improvement to patient care and outcomes. Postgraduate training for an independent clinical role does not often occur in the primary health care setting. When it does, the design of the curriculum is infrequently based on interprofessional workplace learning principles and it does not always integrate practical experience with classroom-based learning activities. This could lead to situations where clinical pharmacists are insufficiently trained to apply clinical reasoning skills and direct patient care in the general practice setting. EDUCATIONAL ACTIVITY AND SETTING: A program was designed, including competencies and learning objectives, based on results from focus group interviews with stakeholders and the literature on interprofessional workplace learning. Ten participants were selected for a pilot run of the program and were asked several times for their opinion about the program. FINDINGS: A 15-month training program was offered to pharmacists who became clinical pharmacists with the responsibility to perform patient consultations in general practice. The program was based on interprofessional workplace learning principles and facilitated the participants' skill in connecting the evidence, the patients' perspective and their own professional perspective. The 10 participating pharmacists were satisfied with the program. DISCUSSION AND SUMMARY: The training program provided increased opportunities to clinical pharmacists to add value in general practice. The training program enabled pharmacists to advance their skills in direct patient care and to improve the alignment between different professionals in the primary care domain. PMID- 29986824 TI - Evaluation of first year student pharmacists' perceptions of the pharmaceutical industry. AB - BACKGROUND AND PURPOSE: There are a limited number of pedagogical studies evaluating student pharmacists' perceptions of the pharmaceutical industry. The objective of this two year prospective study was to evaluate changes in student pharmacists' perceptions of the pharmaceutical industry during the first year of enrollment in the doctor of pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: An online survey was developed and offered to all first-year student pharmacists during the 2014 and 2015 Fall semesters prior to didactic instruction on the pharmaceutical industry and then again at the end of the respective academic years. Descriptive and inferential statistics were used to analyze the data. FINDINGS: A majority of students had a positive impression of the pharmaceutical industry in both the fall (75%) and spring semesters (78%). Over the course of the year, significantly greater numbers of student pharmacists reported favorable impressions of the pharmaceutical industry with respect to research innovation, drug safety, and the provision of drug information. On the other hand, findings suggest that many students remain skeptical regarding the benefits of prescription medications relative to cost and there were significant increases in the number of students who perceived pharmaceutical industry-based marketing practices to have a negative impact on patients and society. DISCUSSION AND SUMMARY: Didactic education may influence student pharmacists' perceptions of the pharmaceutical industry. Further research is warranted to evaluate the role of pharmacy curricula and extra-curricular activities in influencing changes in student pharmacists' perceptions and the potential implications of these changes to pharmacy practice. PMID- 29986823 TI - Description of a pediatric degree option program in a doctorate of pharmacy curriculum and its impact on pediatric-focused advanced pharmacy practice experience rotations and faculty scholarly productivity. AB - PURPOSE: To describe the development of a Pediatric Degree Option program and its impact on pediatric-focused advanced pharmacy practice experiences (APPEs) and faculty scholarly productivity. EDUCATIONAL ACTIVITY: The Pediatric Degree Option program was established in 2011 and requires 16 h of didactic coursework and APPEs. The number of pediatric-focused APPEs and mean number of APPEs per pediatric faculty per year was compared pre- (2005-2010) and post-implementation (2011-2016). In addition, the median number of scholarship activities per student pre- and post-implementation was compared. The initial position obtained by graduates completing the degree option was collected. FINDINGS: Thirty students have completed the program. There were 146 pediatric-focused APPEs for the pre implementation period and 259 post-implementation. However, there was an increase in pediatric faculty during the post-implementation, so there was no difference in the mean number of pediatric-focused APPEs per pediatric faculty in the pre- versus post-implementation period, 8.4 + 2.7 versus 6.9 +1.0, p = .224. A significant increase in the median number of pediatric-focused scholarly activities per student was observed pre-versus post-implementation, 3 (2-5) versus 5 (3-7), p = .005. Twenty-six (86.7%) students in the post-implementation period participated as a research assistant or coauthor in an original research or manuscript writing project. Students accepted a variety of positions after graduation including twelve (40%) accepting a PGY1 residency and eight (36.7%) as community pharmacists. SUMMARY: Although the number of pediatric-focused APPEs increased in the post-implementation, this did not result in an increase in the mean number of mean pediatric-focused APPEs per pediatric faculty member. However, it did allow a unique opportunity for 30 students with interest in pediatrics and allowed for content and skill development. The Pediatric Degree Option program allowed students to gain experience with pediatric-focused scholarly activities that also enhanced faculty productivity in scholarship and research. PMID- 29986825 TI - Assessing pharmacy student confidence to answer patient questions regarding herbal medicines and natural product drugs. AB - BACKGROUND AND PURPOSE: To assess the change in confidence answering questions about herbal medicines and natural product drugs (HMNPD) in third year professional pharmacy students in an HMNPD course. EDUCATIONAL ACTIVITY AND SETTING: A questionnaire was developed to query confidence in responding to patient questions, recommending specific products, and ability to retrieve resources regarding HMNPD. It was administered the first and last week of the semester; responses were evaluated using a Chi-squared test. FINDINGS: At baseline, 46 students (84%) were "very hesitant", "hesitant", or "neither hesitant nor confident" in responding to HMNPD questions; after the course, most students were "confident" or "very confident" (n=30, 54%) (p < .001). Confidence in finding reliable resources increased from the first week (29 students [40%] were "confident" or "very confident") to the last week (51 students [91%] were "confident" or "very confident" [p < .001]). At baseline, five students (9%) were "confident" or "very confident" in ability to recommend a specific product; after the course, 26 students (46%) were "confident" or "very confident" (p < .001). Nine students (16%) felt "very confident" or "confident" in HMNPD safety/effectiveness at baseline; the same proportion felt this way at conclusion (p = .93). Four students (7%) were confident in HMNPD efficacy at baseline and nine (16%) felt the same way at the end (p = .12). DISCUSSION: Significant increases in student confidence answering patient questions, responding to disease-specific queries, and using appropriate resources were found. There was no difference in confidence in HMNPD safety/efficacy. SUMMARY: This study supported continued HMNPD education in the pharmacy program. PMID- 29986826 TI - Effects of Ebola Virus Disease education on student health professionals. AB - BACKGROUND AND PURPOSE: Ebola Virus Disease (EVD) is a severe, often fatal illness. Studies have shown that healthcare professionals lack an in-depth knowledge of EVD. Countries in Europe, Asia, and Africa are beginning to emphasize the need to train healthcare professionals about EVD, but the United States still lacks formal training for healthcare students. There is little research about the effectiveness of EVD training to support this study. The purpose of this study was to examine the knowledge-base and attitudes of healthcare students concerning EVD. EDUCATIONAL ACTIVITY AND SETTING: Two-hundred sixty-nine participants (including pharmacy students, physician assistant students, and nursing students) completed a pre- and post-survey. The survey measured both knowledge and perceptions. The post-survey was administered after the intervention to measure change. The intervention was comprised of a pre recorded lecture about EVD transmission, prevention, and treatment. FINDINGS: All groups displayed significant changes in knowledge and perception, specifically in the areas of EVD transmission, prevention, and treatment. Pharmacy students' attitudes increased significantly over their baseline score for all three attitude questions, whereas there were no significant changes in attitude to EVD among nurses. Physician assistant students' attitudes changed regarding the topic of isolation. DISCUSSION: Education on EVD in pharmacy schools may provide beneficial results for students' knowledge, and it may also help schools provide evidence to meet current standards for accreditation. SUMMARY: This educational intervention represents an effective format that could be a useful tool to help enhance or augment knowledge for healthcare workers. This could lead to better care for patients. PMID- 29986827 TI - Role and impact of student pharmacists and a pharmacist on an international interprofessional medical brigade. AB - BACKGROUND AND PURPOSE: Colleges of pharmacy will be seeking new opportunities to provide student pharmacists with interprofessional and global experiences. The objectives of this paper are to describe an international experience to expand interprofessional and global pharmacy education and to evaluate the roles and impact of fourth-year pharmacy students and a pharmacist integrated into an interprofessional team on a medical brigade to Guatemala. EDUCATIONAL ACTIVITY AND SETTING: In August 2014, two fourth-year student pharmacists and one pharmacist/professor joined a group of 26 pre-medical students from Boston College (BC), six medical doctors and a nursing assistant as part of a one-week medical brigade to Quetzaltenango, Guatemala. An electronic survey was administered to all brigade members upon completion of travel. The survey assessed the most useful services provided by the pharmacist and pharmacy students on the brigade and changes in perspective towards the role of pharmacy on an interprofessional healthcare team. The survey also collected information describing satisfaction with communication, efficiency, professionalism and knowledge of the pharmacy staff. FINDINGS AND DISCUSSION: Pharmacy staff was utilized for knowledge of drug products, therapeutic substitution, counseling and drug dosing/calculations. The brigade directly resulted in an increased likelihood for physicians and students to refer a question to a pharmacist. After this brigade, all non-pharmacy members viewed pharmacists as important members of the medical team and felt better prepared to work as part of a team. SUMMARY: The experience was effective in fostering interprofessional relationships amongst healthcare students and professionals. PMID- 29986828 TI - Successes, challenges, and impact of a large-cohort preclinical interprofessional curriculum: A four-year reflection. AB - BACKGROUND: Accreditation Council for Pharmacy Education (ACPE) Standards 2016 established a new standard on interprofessional education (IPE) to place specific emphasis on developing interprofessional competence among pharmacy graduates. INTERPROFESSIONAL EDUCATION ACTIVITY: Interprofessional Collaboration And Team Skills (iCATS) serves as the core interprofessional curriculum for nearly 700 first-year students in seven participating health professional programs. The curriculum was developed around the four Interprofessional Education Collaborative (IPEC) Competencies to develop foundational interprofessional knowledge, skills, and attitudes. Pharmacy students build preliminary competence in interprofessional roles and responsibilities, team dynamics, values and ethics, communication, and conflict resolution (ACPE Standard 11.1) and have an opportunity to learn about, from, and with other interprofessional students (ACPE Standard 11.2). DISCUSSION: Refinement of the iCATS curriculum has been an iterative process over the past four years. For iCATS 2016-2017, all Interprofessional Collaborative Competency Attainment Scale (ICCAS) evaluation items indicated significant changes in pre- and posttest indicating targeted IPEC Competencies were addressed through the iCATS curriculum. IMPLICATIONS: The 2016 2017 revision of iCATS resulted in the most effective iteration of this core interprofessional curriculum to date. Clearer course objectives, a compressed schedule, employment of a variety of teaching/learning methods, and greater schedule cooperation among the colleges have contributed to the success and delivery of an IPE curriculum. Additionally, iCATS provides a unique opportunity for pharmacy students to interact with health professions students from six other programs while making significant progress toward competence in ACPE Standards 11.1 and 11.2 on interprofessional education (IPE). PMID- 29986829 TI - The concentration and probabilistic health risk assessment of pesticide residues in commercially available olive oils in Iran. AB - This study was undertaken to analyze 29 pesticides residues in 37 commercially olive oil collected samples from Iran's markets using Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) approach along with acetonitrile for the extraction, surface adsorbents for clean-up procedure, following with a gas chromatography-mass spectroscopy (GC-MS). In order to eliminate the matrix effect, the calibration curves were drawn using spiked samples with the Area under curve (AUC) portion calculation of pesticide residue to AUC internal standard (Triphenyl Methane (TPM)). Moreover, the probabilistic health risk assessment includes non-carcinogenic and carcinogenic risk were estimated by target hazard quotient (THQ), total target hazard quotient (TTHQ) and cancer risk (CR) using the Monte Carlo Simulation (MCS) method. The calibration curves were linear in the range of 10-1500 ng/g, and R2 was higher than 0.994. All pesticides recoveries as average were in the range of 77.97-112.65%. The respective numbers attributed to LOD and LOQ were 3-5 ng/g and 8-15 ng/g. Results showed that 29.7% of samples were contaminated by pesticides which according to Iranian regulation, while in 7 cases banned pesticides were detected. Only 4 samples are noncompliant with EU regulation. The rank order of pesticides based on THQ was Heptachlor > DDT > Pretilachlor. Also, TTHQ for adults was 0.139; and children 0.467. The rank order of pesticides based on CR was Heptachlor > DDT. Consumers (adults and children) are not at non-carcinogenic risk due to ingestion of oil olive content (THQ and TTHQ < 1 value) but are at considerable carcinogenic (CR > 1E-6). According to the observed profile of pesticide in olive oil samples, which are mostly banned according to Iranian regulation, further improvements in agriculture procedures of cultivated olive in Iran, as well as required assessments of imported olive oil, was recommended. PMID- 29986830 TI - Sulfanilic acid increases intracellular free-calcium concentration, induces reactive oxygen species production and impairs trypsin secretion in pancreatic AR42J cells. AB - We studied the effects of the tartrazine-metabolite sulfanilic acid on the physiology of pancreatic AR42J cells. Sulfanilic acid (1 MUM-1 mM) induced a slow and progressive increase in intracellular free-calcium concentration that reached a plateau. The effect of sulfanilic acid was not concentration-dependent. Stimulation of cells with thapsigargin (1 MUM) after treatment with sulfanilic acid (1 mM) induced a smaller Ca2+ response compared with that obtained with thapsigargin alone. Sulfanilic acid induced a concentration-dependent production of reactive oxygen species; however, this effect was not Ca2+-dependent. Depolarization of mitochondrial membrane potential was observed at the concentration of 1 mM sulfanilic acid. In the presence of the compound a decrease in the GSH/GSSG ratio was observed. A decrease in the expression of superoxide dismutase 2 was noted. Finally, stimulation of cells with CCK-8 led to a concentration-dependent increase of trypsin secretion that was impaired by pretreatment of cells with sulfanilic acid. Preincubation of cells with the antioxidant melatonin (100 MUM) reduced the effect of sulfanilic acid on trypsin secretion. We conclude that sulfanilic acid might induce oxidative stress, which could alter Ca2+ signaling and enzyme secretion in pancreatic AR42J cells. This creates a situation potentially leading to damage of the exocrine pancreas. PMID- 29986831 TI - Flavocoxid attenuates airway inflammation in ovalbumin-induced mouse asthma model. AB - Asthma is a common airways inflammatory disease. This study provides evidence on the efficacy of flavocoxid against ovalbumin (OVA)-induced allergic airways inflammation in a mouse model of asthma. Airway inflammation was induced by intraperitoneal injection of 10 mg ovalbumin (OVA) on day zero and day 7 followed by OVA challenge starting from 14th day to 16th day. Beclomethasone; a standard anti-inflammatory agent was selected as a drug in asthma. Flavocoxid (20 mg/kg, i. p.) was administered on day zero till 16th day followed by OVA challenge. At the end of the study, lung weight index, bronchoalveolar lavage fluid (BALF) content of total and differential WBCs, interleukin-13(IL-13), in addition to lung tissue nitrate/nitrite (NO) and oxidative stress biomarkers were measured. Also, histological and immunohistochemical analysis were conducted. Daily i. p. injection of flavocoxid (20 mg/kg) significantly improved airway inflammation. Inflammatory cells in BALF, malondialdehyde (MDA), NO and IL-13 significantly declined with concomitant increase in superoxide dismutase (SOD) activity. Histopathological examination and immunohistochemical staining of mast cells were correlated with observed biochemical improvements. Collectively, these results demonstrate that flavocoxid mitigates the allergic airway inflammation induced by ovalbumin through attenuation of IL-13, NO expressions and oxidative stress. PMID- 29986832 TI - PPARs are mediators of anti-cancer properties of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with conjugated linoleic acid. AB - Breast cancer chemotherapy can cause side effects due to nonspecific drug delivery, low solubility and fast metabolism of drugs used in conventional therapy. Moreover, the therapeutic effect of the drugs is often reduced by the strengthening of chemoresistance, which occurs via a variety of mechanisms. Different strategies have been developed to reduce multidrug resistance (MDR) associated gene expressions including the use of surfactants and polymers. In this study superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with conjugated linoleic acid (CLA) reduced the number and viability of cells in comparison with both untreated cells or cells treated with SPIONs alone. This cytostatic effect correlated with the increase of peroxisome proliferator activated receptors gamma (PPARgamma). The necrotic cell death induced, as a consequence, an inflammatory process, as evidenced by the decrease of the anti inflammatory PPARalpha and increase of pro-inflammatory TNFalpha and IL-1beta. PPARs were examined because CLA is one of their natural ligands. The antitumor effect observed was accompanied by a down-regulation of p-glycoprotein (P-gp), which was the first important discovered efflux transporter belonging to MDR, and of ALDH3A1, an enzyme able to metabolize some drugs, reducing their effects. The down-regulation of P-gp correlated with the increase of cytokines. The ALDH3A1 decrease correlated with the increase of PPARgamma. Based on these results, PPARs are molecular mediators of anti-cancer effect of SPIONs functionalized with CLA, being changes in these nuclear receptors correlated with induction of cytotoxicity and inflammation, and decreased ability of cancer cells in blocking anti-cancer drug effect. PMID- 29986833 TI - Neural circuits for long-range color filling-in. AB - Surface color appearance depends on both local surface chromaticity and global context. How are these inter-dependencies supported by cortical networks? Combining functional imaging and psychophysics, we examined if color from long range filling-in engages distinct pathways from responses caused by a field of uniform chromaticity. We find that color from filling-in is best classified and best correlated with appearance by two dorsal areas, V3A and V3B/KO. In contrast, a field of uniform chromaticity is best classified by ventral areas hV4 and LO. Dynamic causal modeling revealed feedback modulation from area V3A to areas V1 and LO for filling-in, contrasting with feedback from LO modulating areas V1 and V3A for a matched uniform chromaticity. These results indicate a dorsal stream role in color filling-in via feedback modulation of area V1 coupled with a cross stream modulation of ventral areas suggesting that local and contextual influences on color appearance engage distinct neural networks. PMID- 29986835 TI - Heat shock factor 1 regulates heat shock proteins and immune-related genes in Penaeus monodon under thermal stress. AB - Heat shock factors (HSFs) participate in the response to environmental stressors and regulate heat shock protein (Hsp) expression. This study describes the molecular characterization and expression of PmHSF1 in black tiger shrimp Penaeus monodon under heat stress. PmHSF1 expression was detected in several shrimp tissues: the highest in the lymphoid organ and the lowest in the eyestalk. Significant up-regulation of PmHSF1 expression was observed in hemocytes (p < 0.05) following thermal stress. The expression of several PmHsps was rapidly induced following heat stress. Endogenous PmHSF1 protein was expressed in all three types of shrimp hemocyte and strongly induced under heat stress. The suppression of PmHSF1 expression by dsRNA-mediated gene silencing altered the expression of PmHsps, several antimicrobial genes, genes involved in the melanization process, and an antioxidant gene (PmSOD). PmHSF1 plays an important role in the thermal stress response, regulating the expression of Hsps and immune related genes in P. monodon. PMID- 29986836 TI - Transcriptional response to a prime/boost vaccination of chickens with three vaccine variants based on HA DNA and Pichia-produced HA protein. AB - Highly pathogenic avian influenza causes severe economic losses and is a potential threat to public health. Better knowledge of the mechanisms of chicken response to the novel types of vaccines against avian influenza might be helpful in their successful implementation into poultry vaccination programs in different countries. This work presents a comprehensive analysis of gene expression response elicited in chicken spleens by a combined DNA/recombinant protein prime/boost vaccination compared to DNA/DNA and protein/protein regimens. All groups of vaccinated chickens displayed changes in spleen transcriptomes in comparison to the control group with 423, 375 and 212 identified differentially expressed genes in protein/protein, DNA/DNA and DNA/protein group, respectively. Genes with most significantly changed expression belong to immune-related categories. Depending on a group, a fraction of 15-34% of up-regulated and a fraction of 15-42% of down-regulated immune-related genes are shared by all groups. Interestingly, the most upregulated genes encode beta-defensins, short peptides with antimicrobial activity and immunomodulatory functions. Microarray results were validated with RT-qPCR method, which confirmed differential regulation of the selected immune-related genes. Immune-related differentially expressed genes and metabolic pathways identified in this work are compared to the available literature data on gene expression changes in vaccinated and non vaccinated chickens after influenza infection. PMID- 29986834 TI - Tracking and validation techniques for topographically organized tractography. AB - Topographic regularity of axonal connections is commonly understood as the preservation of spatial relationships between nearby neurons and is a fundamental structural property of the brain. In particular the retinotopic mapping of the visual pathway can even be quantitatively computed. Inspired from this previously untapped anatomical knowledge, we propose a novel tractography method that preserves both topographic and geometric regularity. We make use of parameterized curves with Frenet-Serret frame and introduce a highly flexible mechanism for controlling geometric regularity. At the same time, we incorporate a novel local data support term in order to account for topographic organization. Unifying geometry with topographic regularity, we develop a Bayesian framework for generating highly organized streamlines that accurately follow neuroanatomy. We additionally propose two novel validation techniques to quantify topographic regularity. In our experiments, we studied the results of our approach with respect to connectivity, reproducibility and topographic regularity aspects. We present both qualitative and quantitative comparisons of our technique against three algorithms from MRtrix3. We show that our method successfully generates highly organized fiber tracks while capturing bundle anatomy that are geometrically challenging for other approaches. PMID- 29986837 TI - Enhanced squalene biosynthesis in Yarrowia lipolytica based on metabolically engineered acetyl-CoA metabolism. AB - As a bioactive triterpenoid, squalene is widely used in the food industry, cosmetics, and pharmacology. Squalene's major commercial sources are the liver oil of deep-sea sharks and plant oils. In this study, we focused on the enhancement of squalene biosynthesis in Yarrowia lipolytica, with particular attention to the engineering of acetyl-CoA metabolism based on genome-scale metabolic reaction network analysis. Although the overexpression of the rate limiting endogenous ylHMG1 (3-hydroxy-3-methylglutaryl-CoA reductase gene) could improve squalene synthesis by 3.2-fold over that by the control strain, the availability of the key intracellular precursor, acetyl-CoA, was found to play a more significant role in elevating squalene production. Analysis of metabolic networks with the newly constructed genome-scale metabolic model of Y. lipolytica iYL_2.0 showed that the acetyl-CoA pool size could be increased by redirecting carbon flux of pyruvate dehydrogenation towards the ligation of acetate and CoA or the cleavage of citrate to form oxaloacetate and acetyl-CoA. The overexpression of either acetyl-CoA synthetase gene from Salmonella enterica (acs*) or the endogenous ATP citrate lyase gene (ylACL1) resulted in a more than 50% increase in the cytosolic acetyl-CoA level. Moreover, iterative chromosomal integration of the ylHMG1, asc*, and ylACL1 genes resulted in a significant improvement in squalene production (16.4-fold increase in squalene content over that in the control strain). We also found that supplementation with 10 mM citrate in a flask culture further enhanced squalene production to 10 mg/g DCW. The information obtained in this study demonstrates that rationally engineering acetyl-CoA metabolism to ensure the supply of this key metabolic precursor is an efficient strategy for the enhancement of squalene biosynthesis. PMID- 29986838 TI - An update on the NLRP3 inflammasome and influenza: the road to redemption or perdition? AB - Inflammation is an integral aspect of influenza A virus (IAV) infection. It is critical to induce an antiviral environment to reduce viral replication and dissemination, while also being essential to the development and maturation of adaptive immunity, which ultimately resolves infection. Conversely, excessive pulmonary inflammation and cellular influx are characteristic of lethal IAV infections. It has become increasingly apparent that the innate immune inflammasome complex is a crucial moderator in IAV disease pathogenesis. It is responsible for the maturation and secretion of prototypic inflammatory cytokines, Interleukin (IL)-1beta and IL-18, and the induction of pyroptotic cell death. This short review will examine recent work on the regulation and targeting of the NLRP3 inflammasome as a means of intrinsic and extrinsic modulation of inflammasome-mediated inflammation. It is encouraging that recent studies suggest 'starving' the inflammasome of substrate, or directly inhibiting activity, may be the means to reducing host inflammatory responses to IAV infection and to directing a positive disease outcome. PMID- 29986840 TI - Clinico-hematological and oxidative stress status in Nili Ravi buffaloes infected with Trypanosoma evansi. AB - Hemoparasitic diseases like trypanosomiasis have an adverse influence on the health and working capability of infected animals. Monitoring and identification of blood born parasitic infections in dairy animals are of vital importance to get the optimum production. In this study blood samples were collected from Nili Ravi buffaloes (n = 390) kept at different villages of district Lodhran, Punjab province of Pakistan. Blood samples were evaluated for red blood cell counts, total and differential leukocyte counts, hematocrit, hemoglobin, total proteins and different serum parameters such as alanine aminotransferase, aspartate aminotransferase, malondialdehyde, alkaline phosphatase, lactate dehydrogenase, phosphorous, copper, calcium and magnesium. Overall prevalence of Trypanosoma evansi was 4.61% based on microscopic smear examination, 11.02% with Formol Gel Test and 16.15% with PCR. Infected buffaloes showed different clinical signs, including high fever (105 +/- 1.0 degrees F), edema of face and legs, hyperemic mucosa of eyes, lachrymation, bulging eyes, pale mucus membranes and frequent urination. Microscopic examination of blood films showed morphologically different parasites. Statistical analysis did not indicate an association of infection based on age and sex of buffaloes. Results revealed significantly (p < 0.05) lower values of red blood cell counts, hemoglobin, hematocrit, mean corpuscular hemoglobin concentration and total proteins, while increased values of mean corpuscular volume, total white blood cells, monocyte, neutrophils, basophils and eosinophils in infected animals. Infected buffaloes were suffering from macrocytic hypochromic anemia. A significant (p < 0.05) increase in serum lipid per oxidation product (malondialdehyde) level and serum enzymes while a decrease in macrominerals and trace mineral (copper) in trypanosomiasis positive buffaloes were recorded. It was concluded that Trypanosoma evansi is prevalent in Pakistan under tropical and subtropical climatic conditions. It causes clinical disease with macrocytic hypochromic anemia and oxidative stress in infected buffaloes. PMID- 29986839 TI - FV3-like ranavirus infection outbreak in black-spotted pond frogs (Rana nigromaculata) in China. AB - In April 2016, an outbreak emerged in a cultured population of black-spotted pond frog tadpoles in Shuangliu County, China, whereas tadpoles were suffering from substantial mortality (90%). Principal clinical signs of diseased tadpoles were comprised haemorrhage on their body surface, swollen abdomen with yellow ascites, congestion and swelling of the liver. The diseased tadpole's homogenates tissue were inoculated into epithelioma papulosum cyprini (EPC) cells at 25 degrees C for 4 days which caused typical cytopathic effect, and the viral titer TCID50 reached 107/0.1 mL. In pathogenicity tests, tadpoles were immersed in 20/00 virus fluid for 8 h, the clinical signs were observed similar to those recognized in naturally infected tadpoles and mortality rate were reached up to 80%, which affirms that the virus was the main cause for this disease. In addition, transmission electron microscopy of EPC cells infected with isolated virus reflected that the virus was in a regular hexagon way (shape) with capsule like structure. The diagonal diameter was recorded 135 +/- 8 nm, wherever virus particles were arrayed in crystalline manner in the cytoplasm. The electrophoresis of MCP gene PCR-product showed that the samples of diseased tadpoles, aquaculture water source and isolated virus were all positive. The sequence of the isolate revealed more than 99% similarities to ranavirus based on homology and genetic evolution analysis of the whole MCP gene, and the isolate belongs to FV3-like virus group. This study confirmed that ranavirus was the causative agent of this outbreak, and named the virus as Rana nigromaculata ranavirus (RNRV). PMID- 29986841 TI - Sleep disordered breathing and fibroblast growth factor 23 in the Hispanic Community Health Study/Study of Latinos. AB - Preclinical data suggest that hypoxia stimulates fibroblast growth factor 23 (FGF23) transcription and cleavage in osteocytes, resulting in elevated circulating c-terminal (cFGF23) levels but normal intact FGF23 (iFGF23) levels. We conducted a case-control study within the Hispanic Community Health Study/Study of Latinos to investigate whether sleep disordered breathing, as a model of hypoxemia, is independently associated with elevated cFGF23 levels in the general population and with elevated cFGF23 and iFGF23 levels in patients with chronic kidney disease (CKD), in whom FGF23 cleavage may be impaired. Cases (n = 602) had severe sleep disordered breathing defined as an apnea/hypopnea index (AHI) of >=30. Controls without severe sleep disordered breathing (n = 602) were matched for sex and CKD stage. The median AHI in the cases was 45.8 (IQR 35.5-62.5) compared to 2.6 (IQR 0.6-8.2) in the controls. Cases had higher cFGF23 levels than controls (66.2 RU/mL, IQR 52.8-98.4 vs. 61.2 RU/mL, IQR 49.5-80.1, p value <0.001). There were no differences in iFGF23 levels between cases and controls. In adjusted linear regression and multinomial regression analyses, body mass index attenuated the relationship between severe sleep disordered breathing and cFGF23 levels. No significant relationships were seen in analyses of severe sleep disordered breathing and iFGF23 levels or in analyses of iFGF23 and cFGF23 stratified by CKD status. Additional studies using other models of intermittent and chronic hypoxia are needed to confirm whether hypoxia stimulates FGF23 transcription in humans and to determine the impact on iFGF23 levels in CKD. PMID- 29986842 TI - Interaction between two aggregation chemical signals in Triatoma infestans (Hemiptera: Reduviidae). AB - The nymphs and adults of Triatoma infestans spend much of their time aggregated among themselves within narrow and dark shelters. The search for a suitable shelter depends in part on the recognition of chemical signals coming from the feces and the cuticle of the other individuals who use the refuge. The aim of this study was determine the possible interaction between the chemical signals associated to the feces and to the cuticle of T. infestans. The results showed that the insects remained significantly more time on the feces that had contact with legs and the feces plus footprints than feces or footprints alone, demonstrating the interaction between evaluated signals. These results demonstrates also that feces extracted a chemical stimulus from the legs. Understanding the interaction feces-legs as an interaction feces-cuticle of legs, the results suggest that the feces could extract some cuticular compound with activity on the behavior of the insects. This is the first report of the interaction between the two aggregation signals recognized in T. infestans and of the increase in the behavioral response of insects exposed to feces that had contact with a cuticular structure. PMID- 29986843 TI - Public Perception Analysis of Tweets During the 2015 Measles Outbreak: Comparative Study Using Convolutional Neural Network Models. AB - BACKGROUND: Timely understanding of public perceptions allows public health agencies to provide up-to-date responses to health crises such as infectious diseases outbreaks. Social media such as Twitter provide an unprecedented way for the prompt assessment of the large-scale public response. OBJECTIVE: The aims of this study were to develop a scheme for a comprehensive public perception analysis of a measles outbreak based on Twitter data and demonstrate the superiority of the convolutional neural network (CNN) models (compared with conventional machine learning methods) on measles outbreak-related tweets classification tasks with a relatively small and highly unbalanced gold standard training set. METHODS: We first designed a comprehensive scheme for the analysis of public perception of measles based on tweets, including 3 dimensions: discussion themes, emotions expressed, and attitude toward vaccination. All 1,154,156 tweets containing the word "measles" posted between December 1, 2014, and April 30, 2015, were purchased and downloaded from DiscoverText.com. Two expert annotators curated a gold standard of 1151 tweets (approximately 0.1% of all tweets) based on the 3-dimensional scheme. Next, a tweet classification system based on the CNN framework was developed. We compared the performance of the CNN models to those of 4 conventional machine learning models and another neural network model. We also compared the impact of different word embeddings configurations for the CNN models: (1) Stanford GloVe embedding trained on billions of tweets in the general domain, (2) measles-specific embedding trained on our 1 million measles related tweets, and (3) a combination of the 2 embeddings. RESULTS: Cohen kappa intercoder reliability values for the annotation were: 0.78, 0.72, and 0.80 on the 3 dimensions, respectively. Class distributions within the gold standard were highly unbalanced for all dimensions. The CNN models performed better on all classification tasks than k-nearest neighbors, naive Bayes, support vector machines, or random forest. Detailed comparison between support vector machines and the CNN models showed that the major contributor to the overall superiority of the CNN models is the improvement on recall, especially for classes with low occurrence. The CNN model with the 2 embedding combination led to better performance on discussion themes and emotions expressed (microaveraging F1 scores of 0.7811 and 0.8592, respectively), while the CNN model with Stanford embedding achieved best performance on attitude toward vaccination (microaveraging F1 score of 0.8642). CONCLUSIONS: The proposed scheme can successfully classify the public's opinions and emotions in multiple dimensions, which would facilitate the timely understanding of public perceptions during the outbreak of an infectious disease. Compared with conventional machine learning methods, our CNN models showed superiority on measles-related tweet classification tasks with a relatively small and highly unbalanced gold standard. With the success of these tasks, our proposed scheme and CNN-based tweets classification system is expected to be useful for the analysis of tweets about other infectious diseases such as influenza and Ebola. PMID- 29986844 TI - Task-Data Taxonomy for Health Data Visualizations: Web-Based Survey With Experts and Older Adults. AB - BACKGROUND: Increasingly, eHealth involves health data visualizations to enable users to better understand their health situation. Selecting efficient and ergonomic visualizations requires knowledge about the task that the user wants to carry out and the type of data to be displayed. Taxonomies of abstract tasks and data types bundle this knowledge in a general manner. Task-data taxonomies exist for visualization tasks and data. They also exist for eHealth tasks. However, there is currently no joint task taxonomy available for health data visualizations incorporating the perspective of the prospective users. One of the most prominent prospective user groups of eHealth are older adults, but their perspective is rarely considered when constructing tasks lists. OBJECTIVE: The aim of this study was to construct a task-data taxonomy for health data visualizations based on the opinion of older adults as prospective users of eHealth systems. eHealth experts served as a control group against the bias of lacking background knowledge. The resulting taxonomy would then be used as an orientation in system requirement analysis and empirical evaluation and to facilitate a common understanding and language in eHealth data visualization. METHODS: Answers from 98 participants (51 older adults and 47 eHealth experts) given in an online survey were quantitatively analyzed, compared between groups, and synthesized into a task-data taxonomy for health data visualizations. RESULTS: Consultation, diagnosis, mentoring, and monitoring were confirmed as relevant abstract tasks in eHealth. Experts and older adults disagreed on the importance of mentoring (chi24=14.1, P=.002) and monitoring (chi24=22.1, P<.001). The answers to the open questions validated the findings from the closed questions and added therapy, communication, cooperation, and quality management to the aforementioned tasks. Here, group differences in normalized code counts were identified for "monitoring" between the expert group (mean 0.18, SD 0.23) and the group of older adults (mean 0.08, SD 0.15; t96=2431, P=.02). Time dependent data was most relevant across all eHealth tasks. Finally, visualization tasks and data types were assigned to eHealth tasks by both experimental groups. CONCLUSIONS: We empirically developed a task-data taxonomy for health data visualizations with prospective users. This provides a general framework for theoretical concession and for the prioritization of user-centered system design and evaluation. At the same time, the functionality dimension of the taxonomy for telemedicine-chosen as the basis for the construction of present taxonomy-was confirmed. PMID- 29986845 TI - Health Care Provider Utilization and Cost of an mHealth Intervention in Vulnerable People Living With HIV in Vancouver, Canada: Prospective Study. AB - BACKGROUND: Improving adherence to combined antiretroviral therapy (cART) can be challenging, especially among vulnerable populations living with HIV. Even where cART is available free of charge, social determinants of health act as barriers to optimal adherence rates. Patient-centered approaches exploiting mobile phone communications (mHealth) have been shown to improve adherence to cART and promote achievement of suppressed HIV plasma viral loads. However, data are scarce on the health care provider (HCP) time commitments and health care costs associated with such interventions. This knowledge is needed to inform policy and programmatic implementation. OBJECTIVE: The purpose of this study was to approximate the resources required and to provide an estimate of the costs associated with running an mHealth intervention program to improve medication adherence in people living with HIV (PLWH). METHODS: This prospective study of HCP utilization and costs was embedded within a repeated measures effectiveness study of the WelTel short-message service (SMS) mHealth program. The study included 85 vulnerable, nonadherent PLWH in Vancouver, Canada, and resulted in improved medication adherence and HIV plasma viral load among participants. Study participants were provided mobile phones with unlimited texting (where required) and received weekly bidirectional text messages to inquire on their status for one year. A clinic nurse triaged and managed participants' responses, immediately logging all patient interactions by topic, HCP involvement, and time dedicated to addressing issues raised by participants. Interaction costs were determined in Canadian dollars based on HCP type, median salary within our health authority, and their time utilized as part of the intervention. RESULTS: Participant-identified problems within text responses included health-related, social, and logistical issues. Taken together, management of problems required a median of 43 minutes (interquartile range, IQR 17-99) of HCP time per participant per year, for a median yearly cost of Can $36.72 (IQR 15.50-81.60) per participant who responded with at least one problem. The clinic nurse who monitored the texts solved or managed 65% of these issues, and the remaining were referred to a variety of other HCPs. The total intervention costs, including mobile phones, plans, and staffing were a median Can $347.74/highly vulnerable participant per year for all participants or Can $383.18/highly vulnerable participant per year for those who responded with at least one problem. CONCLUSIONS: Bidirectional mHealth programs improve HIV care and treatment outcomes for PLWH. Knowledge about the HCP cost associated, here less than Can $50/year, provides stakeholders and decision makers with information relevant to determining the feasibility and sustainability of mHealth programs in a real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02603536; https://clinicaltrials.gov/ct2/show/NCT02603536 (Archived by WebCite at http://www.webcitation.org/70IYqKUjV). PMID- 29986846 TI - An Assessment Framework for e-Mental Health Apps in Canada: Results of a Modified Delphi Process. AB - BACKGROUND: The number of e-mental health apps is increasing rapidly. Studies have shown that the use of some apps is beneficial, whereas others are ineffective or do not meet users' privacy expectations. Individuals and organizations that curate, recommend, host, use, or pay for apps have an interest in categorizing apps according to the consensus criteria of usability and effectiveness. Others have previously published recommendations for assessing health-related apps; however, the extent to which these recommendations can be generalized across different population groups (eg, culture, gender, and language) remains unclear. This study describes an attempt by Canadian stakeholders to develop an e-mental health assessment framework that responds to the unique needs of people living in Canada in an evidence-based manner. OBJECTIVE: The objective of our study was to achieve consensus from a broad group of Canadian stakeholders on guiding principles and criteria for a framework to assess e-mental health apps in Canada. METHODS: We developed an initial set of guiding principles and criteria from a rapid review and environmental scan of pre existing app assessment frameworks. The initial list was refined through a two round modified Delphi process. Participants (N=25) included app developers and users, health care providers, mental health advocates, people with lived experience of a mental health problem or mental illness, policy makers, and researchers. Consensus on each guideline or criterion was defined a priori as at least 70% agreement. The first round of voting was conducted electronically. Prior to Round 2 voting, in-person presentations from experts and a persona empathy mapping process were used to explore the perspectives of diverse stakeholders. RESULTS: Of all respondents, 68% (17/25) in Round 1 and 100% (13/13) in Round 2 agreed that a framework for evaluating health apps is needed to help Canadian consumers identify high-quality apps. Consensus was reached on 9 guiding principles: evidence based, gender responsive, culturally appropriate, user centered, risk based, internationally aligned, enabling innovation, transparent and fair, and based on ethical norms. In addition, 15 informative and evaluative criteria were defined to assess the effectiveness, functionality, clinical applicability, interoperability, usability, transparency regarding security and privacy, security or privacy standards, supported platforms, targeted users, developers' transparency, funding transparency, price, user desirability, user inclusion, and meaningful inclusion of a diverse range of communities. CONCLUSIONS: Canadian mental health stakeholders reached the consensus on a framework of 9 guiding principles and 15 criteria important in assessing e-mental health apps. What differentiates the Canadian framework from other scales is explicit attention to user inclusion at all stages of the development, gender responsiveness, and cultural appropriateness. Furthermore, an empathy mapping process markedly influenced the development of the framework. This framework may be used to inform future mental health policies and programs. PMID- 29986847 TI - Effects of Deep Versus Moderate Neuromuscular Blockade in Laparoscopic Gynecologic Surgery on Postoperative Pain and Surgical Conditions: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Postoperative pain, especially shoulder pain, is commonly reported after laparoscopic gynecologic procedures. Some studies suggest that a lower insufflation pressure may reduce the risk of postoperative pain; however, there is no agreement on the optimal pneumoperitoneum pressure during gynecologic laparoscopic surgery or whether lower pressure would lead to clinically significant improvements without increasing operative complications. Questions remain regarding the clinical significance of improvements, safety, and cost effectiveness of deep neuromuscular blockade with low-pressure pneumoperitoneum. OBJECTIVE: The primary objective of this study was to assess the superiority of anesthesia with deep neuromuscular blockade with pneumoperitoneum 8 mm Hg over moderate blockade with pneumoperitoneum 12 mm Hg in terms of overall pain 24 hours after surgery in adult women undergoing pelvic surgery for hysterectomy or benign adnexal diseases. Effects on the intensity and timing of postoperative pain in specific locations, surgeon satisfaction, respiratory and hemodynamic stability, operating times, and direct and indirect costs will be assessed. METHODS: In this multicenter, randomized controlled trial with a superiority design, 300 patients will be randomly allocated in the ratio 1:1 to moderate neuromuscular blockade with a target insufflation pressure of 12 mm Hg or deep neuromuscular blockade with a target insufflation pressure of 8 mm Hg, with stratification by type of surgery and clinical center. The patient, the statistician, and the nurse who will assess the primary endpoint will be blinded to the allocation. RESULTS: Recruitment to this trial is expected to open in June 2018 and is expected to close in June 2019. CONCLUSIONS: This study is designed to confirm the reported benefits of postoperative pain and provide additional data needed to address questions regarding the effects of this intervention on operating theater management and direct and indirect costs. Strengths of this protocol include the large sample size distributed among diverse institutions across the Italian territory and the collection and analysis of data on numerous secondary objectives. Limitations include the possible introduction of bias because the surgeon and anesthesiologist are not blinded to the intervention. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9277. PMID- 29986848 TI - Electronic Health Literacy Across the Lifespan: Measurement Invariance Study. AB - BACKGROUND: Electronic health (eHealth) information is ingrained in the healthcare experience to engage patients across the lifespan. Both eHealth accessibility and optimization are influenced by lifespan development, as older adults experience greater challenges accessing and using eHealth tools as compared to their younger counterparts. The eHealth Literacy Scale (eHEALS) is the most popular measure used to assess patient confidence locating, understanding, evaluating, and acting upon online health information. Currently, however, the factor structure of the eHEALS across discrete age groups is not well understood, which limits its usefulness as a measure of eHealth literacy across the lifespan. OBJECTIVE: The purpose of this study was to examine the structure of eHEALS scores and the degree of measurement invariance among US adults representing the following generations: Millennials (18-35-year-olds), Generation X (36-51-year-olds), Baby Boomers (52-70-year-olds), and the Silent Generation (71-84-year-olds). METHODS: Millennials (N=281, mean 26.64 years, SD 5.14), Generation X (N=164, mean 42.97 years, SD 5.01), and Baby Boomers/Silent Generation (N=384, mean 62.80 years, SD 6.66) members completed the eHEALS. The 3 factor (root mean square error of approximation, RMSEA=.06, comparative fit index, CFI=.99, Tucker-Lewis index, TLI=.98) and 4-factor (RMSEA=.06, CFI=.99, TLI=.98) models showed the best global fit, as compared to the 1- and 2-factor models. However, the 4-factor model did not have statistically significant factor loadings on the 4th factor, which led to the acceptance of the 3-factor eHEALS model. The 3-factor model included eHealth Information Awareness, Search, and Engagement. Pattern invariance for this 3-factor structure was supported with acceptable model fit (RMSEA=.07, Deltachi2=P>.05, DeltaCFI=0). Compared to Millennials and members of Generation X, those in the Baby Boomer and Silent Generations reported less confidence in their awareness of eHealth resources (P<.001), information seeking skills (P=.003), and ability to evaluate and act on health information found on the Internet (P<.001). RESULTS: Young (18-48-year olds, N=411) and old (49-84-year olds, N=419) adults completed the survey. A 3 factor model had the best fit (RMSEA=.06, CFI=.99, TLI=.98), as compared to the 1 factor, 2-factor, and 4-factor models. These 3-factors included eHealth Information Awareness (2 items), Information Seeking (2 items), and Information and Evaluation (4 items). Pattern invariance was supported with the acceptable model fit (RMSEA=.06, Deltachi2=P>.05, DeltaCFI=0). Compared with younger adults, older adults had less confidence in eHealth resource awareness (P<.001), information seeking skills (P<.01), and ability to evaluate and act upon online health information (P<.001). CONCLUSIONS: The eHEALS can be used to assess, monitor uniquely, and evaluate Internet users' awareness of eHealth resources, information seeking skills, and engagement abilities. Configural and pattern invariance was observed across all generation groups in the 3-factor eHEALS model. To meet gold the standards for factor interpretation (ie, 3 items or indicators per factor), future research is needed to create and assess additional eHEALS items. Future research is also necessary to identify and test items for a fourth factor, one that captures the social nature of eHealth. PMID- 29986849 TI - Unsupervised Machine Learning to Identify High Likelihood of Dementia in Population-Based Surveys: Development and Validation Study. AB - BACKGROUND: Dementia is increasing in prevalence worldwide, yet frequently remains undiagnosed, especially in low- and middle-income countries. Population based surveys represent an underinvestigated source to identify individuals at risk of dementia. OBJECTIVE: The aim is to identify participants with high likelihood of dementia in population-based surveys without the need of the clinical diagnosis of dementia in a subsample. METHODS: Unsupervised machine learning classification (hierarchical clustering on principal components) was developed in the Health and Retirement Study (HRS; 2002-2003, N=18,165 individuals) and validated in the Survey of Health, Ageing and Retirement in Europe (SHARE; 2010-2012, N=58,202 individuals). RESULTS: Unsupervised machine learning classification identified three clusters in HRS: cluster 1 (n=12,231) without any functional or motor limitations, cluster 2 (N=4841) with walking/climbing limitations, and cluster 3 (N=1093) with both functional and walking/climbing limitations. Comparison of cluster 3 with previously published predicted probabilities of dementia in HRS showed that it identified high likelihood of dementia (probability of dementia >0.95; area under the curve [AUC]=0.91). Removing either cognitive or both cognitive and behavioral measures did not impede accurate classification (AUC=0.91 and AUC=0.90, respectively). Three clusters with similar profiles were identified in SHARE (cluster 1: n=40,223; cluster 2: n=15,644; cluster 3: n=2335). Survival rate of participants from cluster 3 reached 39.2% (n=665 deceased) in HRS and 62.2% (n=811 deceased) in SHARE after a 3.9-year follow-up. Surviving participants from cluster 3 in both cohorts worsened their functional and mobility performance over the same period. CONCLUSIONS: Unsupervised machine learning identifies high likelihood of dementia in population-based surveys, even without cognitive and behavioral measures and without the need of clinical diagnosis of dementia in a subsample of the population. This method could be used to tackle the global challenge of dementia. PMID- 29986851 TI - Quizartinib Bests Chemo for FLT3-Mutant AML. AB - The FLT3 inhibitor quizartinib provided a survival benefit over chemotherapy in a phase III trial of patients with relapsed or refractory FLT3-mutant acute myeloid leukemia. The drug, along with other FLT3 inhibitors, could become a first-line treatment based on results from ongoing studies. PMID- 29986850 TI - Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins. AB - The oncogenesis-promoting role of chromosomal rearrangements for several hematologic and solid malignancies is well recognized. However, identifying targetable, actionable, and druggable chromosomal rearrangements remains a challenge. Targeting gene fusions and chromosomal rearrangements is an effective strategy in treating gene rearrangement-driven tumors. The NTRK (Neurotrophic Tyrosine Receptor Kinase) gene family encodes three tropomyosin-related kinase (TRK) receptors that preserve central and peripheral nervous system development and function. NTRK genes, similar to other genes, are subject to alterations, including fusions. Preclinical studies have demonstrated that TRK fusion proteins promote oncogenesis by mediating constitutive cell proliferation and survival. Several clinical trials have estimated the safety and efficacy of TRK fusion kinase receptor inhibitors and have demonstrated encouraging antitumor activity in patients with NTRK-rearranged malignancies. Specifically, larotrectinib and entrectinib have emerged as potent, safe, and promising TRK inhibitors. Herein, we discuss the potential oncogenic characteristics of TRK fusion proteins in various malignancies and highlight ongoing clinical trials of kinase inhibitors targeting them. PMID- 29986853 TI - Impact of post-ASCT maintenance therapy on outcomes in patients with newly diagnosed multiple myeloma in Connect MM. AB - Autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). Clinical trials show progression-free survival (PFS) benefits, with some studies (Cancer and Leukemia Group [CALGB] trial and meta-analysis) also showing overall survival (OS) benefits, but applicability to real-world clinical settings is unclear. Using data from Connect MM, the largest US-based observational registry of NDMM patients, we analyzed effects of maintenance therapy on long-term outcomes in 1450 treated patients enrolled from 2009 to 2011. Patients who received induction therapy and ASCT (n = 432) were analyzed from 100 days post-ASCT (data cut 7 January 2016): 267 received maintenance (80% lenalidomide-based [of whom 88% received lenalidomide monotherapy]); 165 did not. Lenalidomide maintenance improved median PFS and 3 year PFS rate vs no maintenance (50.3 vs 30.8 months [hazard ratio (HR), 0.62; 95% confidence interval (CI), 0.46-0.82; P < .001] and 56% vs 42%, respectively). Improvements in median OS and 3-year OS rate were associated with lenalidomide maintenance vs no maintenance (not reached in either group [HR, 0.54; 95% CI, 0.36-0.83; P = .005] and 85% vs 70%, respectively). Five hematologic serious adverse events were reported with lenalidomide maintenance (pancytopenia [n = 2], febrile neutropenia, anemia, and thrombocytopenia [n = 1 each]) and 1 with no maintenance (thrombocytopenia). Second primary malignancies occurred at rates of 1.38 and 2.19 events per patient-year in lenalidomide maintenance and no maintenance groups, respectively. Survival benefits associated with lenalidomide maintenance previously demonstrated in clinical trials were observed in this community-based Connect MM Registry. PMID- 29986852 TI - Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. AB - There is an unmet need for effective biological therapies for relapsed central nervous system (CNS) lymphoma. Lenalidomide is active in activated B-cell type diffuse large B-cell lymphoma and rituximab is effective in CNS lymphoma. These observations are the basis for this first trial of an immunomodulatory drug as monotherapy in CNS lymphoma, and, in patients with inadequate responses to lenalidomide, with rituximab. In an independent cohort, we evaluated lenalidomide maintenance after salvage with high-dose methotrexate or focal irradiation in relapsed primary CNS lymphoma (PCNSL). We determined safety, efficacy, and cerebrospinal fluid (CSF) penetration of lenalidomide at 10-, 15-, and 20-mg dose levels in 14 patients with refractory CD20+ CNS lymphoma. Nine subjects with relapsed, refractory CNS lymphoma achieved better than partial response with lenalidomide monotherapy, 6 maintained response >=9 months, and 4 maintained response >=18 months. Median progression-free survival for lenalidomide/rituximab was 6 months. In the independent cohort, response duration with lenalidomide maintenance after complete responses 2 through 5 were significantly longer than response durations after standard therapy. The CSF/plasma partition coefficient of lenalidomide was >=20% at 15- and 20-mg dose levels. Change in CSF interleukin 10 at 1 month correlated with clinical response and response duration to lenalidomide. Metabolomic profiling of CSF identified novel biomarkers, including lactate, and implicated indoleamine-2,3 dioxygenase activity with CNS lymphoma progression on lenalidomide. We conclude that lenalidomide penetrates ventricular CSF and is active as monotherapy in relapsed CNS lymphomas. We provide evidence that maintenance lenalidomide potentiates response duration after salvage in relapsed PCNSL and delays whole brain radiotherapy (WBRT). This trial was registered at www.clinicaltrials.gov as #NCT01542918. PMID- 29986855 TI - Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin. PMID- 29986854 TI - Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models. AB - JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3A572V knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8+ T cells in the periphery before colonization of the bone marrow. This phenotype is dependent on the gammac chain of cytokine receptors and presents several features of the human leukemic form of cutaneous T-cell lymphoma (L-CTCL), including skin involvements. We also showed that the JAK3A572V-positive malignant cells are transplantable and phenotypically heterogeneous in bone marrow transplantation assays. Interestingly, we revealed that activated JAK3 functionally cooperates with partial trisomy 21 in vivo to enhance the L-CTCL phenotype, ultimately leading to a lethal and fully penetrant disorder. Finally, we assessed the efficacy of JAK3 inhibition and showed that CTCL JAK3A572V positive T cells are sensitive to tofacitinib, which provides additional preclinical insights into the use of JAK3 inhibitors in these disorders. Altogether, this JAK3A572V knockin model is a relevant new tool for testing the efficacy of JAK inhibitors in JAK3-related hematopoietic malignancies. PMID- 29986856 TI - Maternal peanut consumption and risk of peanut allergy in childhood. PMID- 29986857 TI - Validation and refinement of a clinical decision rule for the use of computed tomography in children with minor head injury in the emergency department. AB - BACKGROUND: There is uncertainty about which children with minor head injury need to undergo computed tomography (CT). We sought to prospectively validate the accuracy and potential for refinement of a previously derived decision rule, Canadian Assessment of Tomography for Childhood Head injury (CATCH), to guide CT use in children with minor head injury. METHODS: This multicentre cohort study in 9 Canadian pediatric emergency departments prospectively enrolled children with blunt head trauma presenting with a Glasgow Coma Scale score of 13-15 and loss of consciousness, amnesia, disorientation, persistent vomiting or irritability. Phys icians completed standardized assessment forms before CT, including clinical predictors of the rule. The primary outcome was neurosurgical intervention and the secondary outcome was brain injury on CT. We calculated test characteristics of the rule and used recursive partitioning to further refine the rule. RESULTS: Of 4060 enrolled patients, 23 (0.6%) underwent neurosurgical intervention, and 197 (4.9%) had brain injury on CT. The original 7-item rule (CATCH) had sensitivities of 91.3% (95% confidence interval [CI] 72.0%-98.9%) for neurosurgical intervention and 97.5% (95% CI 94.2%-99.2%) for predicting brain injury. Adding ">= 4 episodes of vomiting" resulted in a refined 8-item rule (CATCH2) with 100% (95% CI 85.2%-100%) sensitivity for neurosurgical intervention and 99.5% (95% CI 97.2%-100%) sensitivity for brain injury. INTERPRETATION: Among children presenting to the emergency department with minor head injury, the CATCH2 rule was highly sensitive for identifying those children requiring neurosurgical intervention and those with any brain injury on CT. The CATCH2 rule should be further validated in an implementation study designed to assess its clinical impact. PMID- 29986858 TI - Recommendations on screening for asymptomatic bacteriuria in pregnancy. PMID- 29986859 TI - A 63-year-old returned traveller with fever, rash, hepatitis and eosinophilia. PMID- 29986860 TI - Healthy-vaccinated effect. PMID- 29986861 TI - The collaborative chronic care model for mental health should be implemented in Canada. PMID- 29986862 TI - Access to new drugs for rare disorders in Canada. PMID- 29986864 TI - Sexual harassment rampant in science and worst in medicine, says report. PMID- 29986863 TI - Trump administration shutters clinical guidelines database. PMID- 29986865 TI - Medical students risk disappointment when applying to both Canada and US for residency. PMID- 29986866 TI - Employers must tackle high level of burnout among trainees, says GMC. PMID- 29986867 TI - Women's prepregnancy lipid levels and number of children: a Norwegian prospective population-based cohort study. AB - OBJECTIVE: To study prepregnancy serum lipid levels and the association with the number of children. DESIGN: Prospective, population-based cohort. SETTING: Linked data from the Cohort of Norway and the Medical Birth Registry of Norway. PARTICIPANTS: 2645 women giving birth to their first child during 1994-2003 (488 one-child mothers and 2157 women with >=2 births) and 1677 nulliparous women. MAIN OUTCOME MEASURES: ORs for no and one lifetime pregnancy (relative to >=2 pregnancies) obtained by multinomial logistic regression, adjusted for age at examination, education, body mass index (BMI), smoking, time since last meal and oral contraceptive use. RESULTS: Assessed in quintiles, higher prepregnant triglyceride (TG) and TG to high-density lipoprotein (TG:HDL-c) ratio levels were associated with increased risk of one lifetime pregnancy compared with having >=2 children. Compared with the highest quintile, women in the lowest quintile of HDL cholesterol levels had an increased risk of one lifetime pregnancy (OR 1.7, 95% CI 1.2 to 2.4), as were women with the highest low-density lipoprotein (LDL) cholesterol, TG and TG:HDL-c ratio quintiles (compared with the lowest) (OR 1.2, 95% CI 0.8 to 1.7; OR 2.2, 95% CI 1.5 to 3.2; and OR 2.2, 95% CI 1.5 to 3.2, respectively). Similar effects were found in women with BMI>=25 and the highest LDL and total cholesterol levels in risk of lifetime nulliparity. CONCLUSION: Women with unfavourable prepregnant lipid profile had higher risk of having no or only one child. These findings substantiate an association between prepregnant serum lipid levels and number of children. Previously observed associations between low parity and increased cardiovascular mortality may in part be due to pre-existing cardiovascular disease lipid risk factors. PMID- 29986868 TI - Pax6 regulation of Sox9 in the mouse retinal pigmented epithelium controls its timely differentiation and choroid vasculature development. AB - The synchronized differentiation of neuronal and vascular tissues is crucial for normal organ development and function, although there is limited information about the mechanisms regulating the coordinated development of these tissues. The choroid vasculature of the eye serves as the main blood supply to the metabolically active photoreceptors, and develops together with the retinal pigmented epithelium (RPE). Here, we describe a novel regulatory relationship between the RPE transcription factors Pax6 and Sox9 that controls the timing of RPE differentiation and the adjacent choroid maturation. We used a novel machine learning algorithm tool to analyze high resolution imaging of the choroid in Pax6 and Sox9 conditional mutant mice. Additional unbiased transcriptomic analyses in mutant mice and RPE cells generated from human embryonic stem cells, as well as chromatin immunoprecipitation and high-throughput analyses, revealed secreted factors that are regulated by Pax6 and Sox9. These factors might be involved in choroid development and in the pathogenesis of the common blinding disease: age related macular degeneration (AMD). PMID- 29986871 TI - Donald Seldin: A Transformative Leader in Medicine and Nephrology. PMID- 29986870 TI - The MAPK Erk5 is necessary for proper skeletogenesis involving a Smurf-Smad-Sox9 molecular axis. AB - Erk5 belongs to the mitogen-activated protein kinase (MAPK) family. Following its phosphorylation by Mek5, Erk5 modulates several signaling pathways in a number of cell types. In this study, we demonstrated that Erk5 inactivation in mesenchymal cells causes abnormalities in skeletal development by inducing Sox9, an important transcription factor of skeletogenesis. We further demonstrate that Erk5 directly phosphorylates and activates Smurf2 (a ubiquitin E3 ligase) at Thr249, which promotes the proteasomal degradation of Smad proteins and phosphorylates Smad1 at Ser206 in the linker region known to trigger its proteasomal degradation by Smurf1. Smads transcriptionally activated the expression of Sox9 in mesenchymal cells. Accordingly, removal of one Sox9 allele in mesenchymal cells from Erk5 deficient mice rescued some abnormalities of skeletogenesis. These findings highlight the importance of the Mek5-Erk5-Smurf-Smad-Sox9 axis in mammalian skeletogenesis. PMID- 29986872 TI - Life in the flow: unique adaptations for feeding on drifting zooplankton in garden eels. AB - A major challenge faced by sessile animals that feed in the flow is to maintain effective feeding postures while enduring hydrodynamic forces. Garden eels exhibit an exceptional lifestyle: feeding on drifting zooplankton while being 'anchored' in a burrow they dig in the sand. Using underwater observations, sampling and three-dimensional video recording, we measured the feeding rates and characterized feeding postures of garden eels under a wide range of current speeds. We show that the eels behaviorally resolve the trade-off between adverse biomechanical forces and beneficial fluxes of food by modulating their body postures according to current speeds. In doing so, the eels substantially reduce drag forces when currents are strong, yet keep their head well above bottom in order to effectively feed under conditions of high prey fluxes. These abilities have allowed garden eels to become one of the rare oceanic fishes that live in sandy, predation-rich habitats and feed on zooplankton while being attached to the bottom. PMID- 29986869 TI - RDH10-mediated retinol metabolism and RARalpha-mediated retinoic acid signaling are required for submandibular salivary gland initiation. AB - In mammals, the epithelial tissues of major salivary glands generate saliva and drain it into the oral cavity. For submandibular salivary glands (SMGs), the epithelial tissues arise during embryogenesis from naive oral ectoderm adjacent to the base of the tongue, which begins to thicken, express SOX9 and invaginate into underlying mesenchyme. The developmental mechanisms initiating salivary gland development remain unexplored. In this study, we show that retinoic acid (RA) signaling activity at the site of gland initiation is colocalized with expression of retinol metabolic genes Rdh10 and Aldh1a2 in the underlying SMG mesenchyme. Utilizing a novel ex vivo assay for SMG initiation developed for this study, we show that RDH10 and RA are required for salivary gland initiation. Moreover, we show that the requirement for RA in gland initiation involves canonical signaling through retinoic acid receptors (RAR). Finally, we show that RA signaling essential for gland initiation is transduced specifically through RARalpha, with no contribution from other RAR isoforms. This is the first study to identify a molecular signal regulating mammalian salivary gland initiation. PMID- 29986873 TI - Early medical abortion: best practice now lawful in Scotland and Wales but not available to women in England. PMID- 29986874 TI - Detention is still harming children at the US border. PMID- 29986876 TI - Adult Neurogenesis Conserves Hippocampal Memory Capacity. AB - The hippocampus is crucial for declarative memories in humans and encodes episodic and spatial memories in animals. Memory coding strengthens synaptic efficacy via a long-term potentiation (LTP)-like mechanism. Given that animals store memories of everyday experiences, the hippocampal circuit must have a mechanism that prevents saturation of overall synaptic weight for the preservation of learning capacity. Long-term depression (LTD) works to balance plasticity and prevent saturation. In addition, adult neurogenesis in the hippocampus is proposed to be involved in the down-scaling of synaptic efficacy. Here, we show that adult neurogenesis in male rats plays a crucial role in the maintenance of hippocampal capacity for memory (learning and/or memory formation). Neurogenesis regulated the maintenance of LTP, with decreases and increases in neurogenesis prolonging or shortening LTP persistence, respectively. Artificial saturation of hippocampal LTP impaired memory capacity in contextual fear conditioning, which completely recovered after 14 days, which was the time required for LTP to decay to the basal level. Memory capacity gradually recovered in parallel with neurogenesis-mediated gradual decay of LTP. Ablation of neurogenesis by X-ray irradiation delayed the recovery of memory capacity, while enhancement of neurogenesis using a running wheel sped up recovery. Thus, one benefit of ongoing adult neurogenesis is the maintenance of hippocampal memory capacity through homeostatic renewing of hippocampal memory circuits. Decreased neurogenesis in aged animals may be responsible for the decline in cognitive function with age.SIGNIFICANCE STATEMENTLearning many events each day increases synaptic efficacy via long-term potentiation (LTP), which can prevent the storage of new memories in the hippocampal circuit. In this study, we demonstrate that hippocampal capacity for the storage of new memories is maintained by ongoing adult neurogenesis through homoeostatic renewing of hippocampal circuits in rats. A decrease or an increase in neurogenesis, respectively, delayed or sped up the recovery of memory capacity, suggesting that hippocampal adult neurogenesis plays a critical role in reducing LTP saturation and keeps the gate open for new memories by clearing out the old memories from the hippocampal memory circuit. PMID- 29986875 TI - Associative prediction of visual shape in the hippocampus. AB - Perception can be cast as a process of inference, in which bottom-up signals are combined with top-down predictions in sensory systems. In line with this, neural activity in sensory cortex is strongly modulated by prior expectations. Such top down predictions often arise from cross-modal associations, such as when a sound (e.g., bell or bark) leads to an expectation of the visual appearance of the corresponding object (e.g., bicycle or dog). We hypothesised that the hippocampus - which rapidly learns arbitrary relations between stimuli over space and time - may be involved in forming such associative predictions. We exposed male and female human participants to auditory cues predicting visual shapes, while measuring high-resolution fMRI signals in visual cortex and the hippocampus. Using multivariate reconstruction methods, we discovered a dissociation between these regions: representations in visual cortex were dominated by whichever shape was presented, whereas representations in the hippocampus reflected only which shape was predicted by the cue. The strength of hippocampal predictions correlated across participants with the amount of expectation-related facilitation in visual cortex. These findings help bridge the gap between memory and sensory systems in the human brain.SIGNIFICANCE STATEMENTThe way we perceive the world is to a great extent determined by our prior knowledge. Despite this intimate link between perception and memory, these two aspects of cognition have mostly been studied in isolation. Here we investigate their interaction by asking how memory systems that encode and retrieve associations can inform perception. We find that upon hearing a familiar auditory cue, the hippocampus represents visual information that had previously co-occurred with the cue, even when this expectation differs from what is currently visible. Furthermore, the strength of this hippocampal expectation correlates with facilitation of perceptual processing in visual cortex. These findings help bridge the gap between memory and sensory systems in the human brain. PMID- 29986877 TI - The aging heart. AB - As the elderly segment of the world population increases, it is critical to understand the changes in cardiac structure and function during the normal aging process. In this review, we outline the key molecular pathways and cellular processes that underlie the phenotypic changes in the heart and vasculature that accompany aging. Reduced autophagy, increased mitochondrial oxidative stress, telomere attrition, altered signaling in insulin-like growth factor, growth differentiation factor 11, and 5'- AMP-activated protein kinase pathways are among the key molecular mechanisms underlying cardiac aging. Aging promotes structural and functional changes in the atria, ventricles, valves, myocardium, pericardium, the cardiac conduction system, and the vasculature. We highlight the factors known to accelerate and attenuate the intrinsic aging of the heart and vessels in addition to potential preventive and therapeutic avenues. A greater understanding of the processes involved in cardiac aging may facilitate our ability to mitigate the escalating burden of CVD in older individuals and promote healthy cardiac aging. PMID- 29986879 TI - Improving the career prospects of international medical graduates. PMID- 29986878 TI - Intratubular and intracellular renin-angiotensin system in the kidney: a unifying perspective in blood pressure control. AB - The renin-angiotensin system (RAS) is widely recognized as one of the most important vasoactive hormonal systems in the physiological regulation of blood pressure and the development of hypertension. This recognition is derived from, and supported by, extensive molecular, cellular, genetic, and pharmacological studies on the circulating (tissue-to-tissue), paracrine (cell-to-cell), and intracrine (intracellular, mitochondrial, nuclear) RAS during last several decades. Now, it is widely accepted that circulating and local RAS may act independently or interactively, to regulate sympathetic activity, systemic and renal hemodynamics, body salt and fluid balance, and blood pressure homeostasis. However, there remains continuous debate with respect to the specific sources of intratubular and intracellular RAS in the kidney and other tissues, the relative contributions of the circulating RAS to intratubular and intracellular RAS, and the roles of intratubular compared with intracellular RAS to the normal control of blood pressure or the development of angiotensin II (ANG II)-dependent hypertension. Based on a lecture given at the recent XI International Symposium on Vasoactive Peptides held in Horizonte, Brazil, this article reviews recent studies using mouse models with global, kidney- or proximal tubule-specific overexpression (knockin) or deletion (knockout) of components of the RAS or its receptors. Although much knowledge has been gained from cell- and tissue-specific transgenic or knockout models, a unifying and integrative approach is now required to better understand how the circulating and local intratubular/intracellular RAS act independently, or with other vasoactive systems, to regulate blood pressure, cardiovascular and kidney function. PMID- 29986881 TI - Conserved motifs on the cytoplasmic face of the protein translocation channel are critical for the transition between resting and active conformations. AB - The Sec61 complex is the primary cotranslational protein translocation channel in yeast (Saccharomyces cerevisiae). The structural transition between the closed inactive conformation of the Sec61 complex and its open and active conformation is thought to be promoted by binding of the ribosome nascent-chain complex to the cytoplasmic surface of the Sec61 complex. Here, we have analyzed new yeast Sec61 mutants that selectively interfere with cotranslational translocation across the endoplasmic reticulum. We found that a single substitution at the junction between transmembrane segment TM7 and the L6/7 loop interferes with cotranslational translocation by uncoupling ribosome binding to the L6/7 loop from the separation of the lateral gate transmembrane spans. Substitutions replacing basic residues with acidic residues in the C-terminal tail of Sec61 had an unanticipated impact upon binding of ribosomes to the Sec61 complex. We found that similar charge-reversal mutations in the N-terminal tail and in cytoplasmic loop L2/3 did not alter ribosome binding but interfered with translocation channel gating. These findings indicated that these segments are important for the structural transition between the inactive and active conformations of the Sec61 complex. In summary our results have identified additional cytosolic segments of the Sec61 complex important for promoting the structural transition between the closed and open conformations of the complex. We conclude that positively charged residues in multiple cytosolic segments, as well as bulky hydrophobic residues in the L6/7-TM7 junction, are required for cotranslational translocation or integration of membrane proteins by the Sec61 complex. PMID- 29986880 TI - Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation. AB - Cancer stem cells (CSCs) are unique populations of cells that can self-renew and generate different cancer cell lineages. Although CSCs are believed to be a promising target for novel therapies, the specific mechanisms by which these putative therapeutics could intervene are less clear. Nitric oxide (NO) is a biological mediator frequently up-regulated in tumors and has been linked to cancer aggressiveness. Here, we search for targets of NO that could explain its activity. We find that it directly affects the stability and function of octamer binding transcription factor 4 (Oct4), known to drive the stemness of lung cancer cells. We demonstrated that NO promotes the CSC-regulatory activity of Oct4 through a mechanism that involves complex formation between Oct4 and the scaffolding protein caveolin-1 (Cav-1). In the absence of NO, Oct4 forms a molecular complex with Cav-1, which promotes the ubiquitin-mediated proteasomal degradation of Oct4. NO promotes Akt-dependent phosphorylation of Cav-1 at tyrosine 14, disrupting the Cav-1:Oct4 complex. Site-directed mutagenesis and computational modeling studies revealed that the hydroxyl moiety at tyrosine 14 of Cav-1 is crucial for its interaction with Oct4. Both removal of the hydroxyl via mutation to phenylalanine and phosphorylation lead to an increase in binding free energy (DeltaGbind) between Oct4 and Cav-1, destabilizing the complex. Together, these results unveiled a novel mechanism of CSC regulation through NO mediated stabilization of Oct4, a key stem cell transcription factor, and point to new opportunities to design CSC-related therapeutics. PMID- 29986882 TI - Targeting the MMP-14/MMP-2/integrin alphavbeta3 axis with multispecific N-TIMP2 based antagonists for cancer therapy. AB - The pathophysiological functions of the signaling molecules matrix metalloproteinase-14 (MMP-14) and integrin alphavbeta3 in various types of cancer are believed to derive from their collaborative activity in promoting invasion, metastasis, and angiogenesis, as shown in vitro and in vivo The two effectors act in concert in a cell-specific manner through the localization of pro-MMP-2 to the cell surface, where it is processed to intermediate and matured MMP-2. The matured MMP-2 product is localized to the cell surface via its binding to integrin alphavbeta3 The MMP-14/MMP-2/integrin alphavbeta3 axis thus constitutes an attractive putative target for therapeutic interventions, but the development of inhibitors that target this axis remains an unfulfilled task. To address the lack of such multitarget inhibitors, we have established a combinatorial approach that is based on flow cytometry screening of a yeast-displayed N-TIMP2 (N terminal domain variant of tissue inhibitor of metalloproteinase-2) mutant library. On the basis of this screening, we generated protein monomers and a heterodimer that contain monovalent and bivalent binding epitopes to MMP-14 and integrin alphavbeta3 Among these proteins, the bi-specific heterodimer, which bound strongly to both MMP-14 and integrin alphavbeta3, exhibited superior ability to inhibit MMP-2 activation and displayed the highest inhibitory activity in cell-based models of a MMP-14-, MMP-2-, and integrin alphavbeta3-dependent glioblastoma and of endothelial cell invasiveness and endothelial capillary tube formation. These assays enabled us to show the superiority of the combined target effects of the inhibitors and to investigate separately the role each of the three signaling molecules in various malignant processes. PMID- 29986883 TI - Biochemical characterization and chemical inhibition of PfATP4-associated Na+ ATPase activity in Plasmodium falciparum membranes. AB - The antimalarial activity of chemically diverse compounds, including the clinical candidate cipargamin, has been linked to the ATPase PfATP4 in the malaria-causing parasite Plasmodium falciparum The characterization of PfATP4 has been hampered by the inability thus far to achieve its functional expression in a heterologous system. Here, we optimized a membrane ATPase assay to probe the function of PfATP4 and its chemical sensitivity. We found that cipargamin inhibited the Na+ dependent ATPase activity present in P. falciparum membranes from WT parasites and that its potency was reduced in cipargamin-resistant PfATP4-mutant parasites. The cipargamin-sensitive fraction of membrane ATPase activity was inhibited by all 28 of the compounds in the "Malaria Box" shown previously to disrupt ion regulation in P. falciparum in a cipargamin-like manner. This is consistent with PfATP4 being the direct target of these compounds. Characterization of the cipargamin-sensitive ATPase activity yielded data consistent with PfATP4 being a Na+ transporter that is sensitive to physiologically relevant perturbations of pH, but not of [K+] or [Ca2+]. With an apparent Km for ATP of 0.2 mm and an apparent Km for Na+ of 16-17 mm, the protein is predicted to operate at below its half-maximal rate under normal physiological conditions, allowing the rate of Na+ efflux to increase in response to an increase in cytosolic [Na+]. In membranes from a cipargamin-resistant PfATP4-mutant line, the apparent Km for Na+ is slightly elevated. Our study provides new insights into the biochemical properties and chemical sensitivity of an important new antimalarial drug target. PMID- 29986884 TI - Silencing of the Hsp70-specific nucleotide-exchange factor BAG3 corrects the F508del-CFTR variant by restoring autophagy. AB - The protein chaperones heat shock protein 70 (Hsp70) and Hsp90 are required for de novo folding of proteins and protect against misfolding-related cellular stresses by directing misfolded or slowly folding proteins to the ubiquitin/proteasome system (UPS) or autophagy/lysosomal degradation pathways. Here, we examined the role of the Bcl2-associated athanogene (BAG) family of Hsp70-specific nucleotide-exchange factors in the biogenesis and functional correction of genetic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) whose mutations cause cystic fibrosis (CF). We show that siRNA mediated silencing of BAG1 and -3, two BAG members linked to the clearance of misfolded proteins via the UPS and autophagy pathways, respectively, leads to functional correction of F508del-CFTR and other disease-associated CFTR variants. BAG3 silencing was the most effective, leading to improved F508del-CFTR stability, trafficking, and restoration of cell-surface function, both alone and in combination with the FDA-approved CFTR corrector, VX-809. We also found that the BAG3 silencing-mediated correction of F508del-CFTR restores the autophagy pathway, which is defective in F508del-CFTR-expressing cells, likely because of the maladaptive stress response in CF pathophysiology. These results highlight the potential therapeutic benefits of targeting the cellular chaperone system to improve the functional folding of CFTR variants contributing to CF and possibly other protein-misfolding-associated diseases. PMID- 29986885 TI - The cardiac ryanodine receptor, but not sarcoplasmic reticulum Ca2+-ATPase, is a major determinant of Ca2+ alternans in intact mouse hearts. AB - Sarcoplasmic reticulum (SR) Ca2+ cycling is governed by the cardiac ryanodine receptor (RyR2) and SR Ca2+-ATPase (SERCA2a). Abnormal SR Ca2+ cycling is thought to be the primary cause of Ca2+ alternans that can elicit ventricular arrhythmias and sudden cardiac arrest. Although alterations in either RyR2 or SERCA2a function are expected to affect SR Ca2+ cycling, whether and to what extent altered RyR2 or SERCA2a function affects Ca2+ alternans is unclear. Here, we employed a gain-of-function RyR2 variant (R4496C) and the phospholamban-knockout (PLB-KO) mouse model to assess the effect of genetically enhanced RyR2 or SERCA2a function on Ca2+ alternans. Confocal Ca2+ imaging revealed that RyR2-R4496C shortened SR Ca2+ release refractoriness and markedly suppressed rapid pacing induced Ca2+ alternans. Interestingly, despite enhancing RyR2 function, intact RyR2-R4496C hearts exhibited no detectable spontaneous SR Ca2+ release events during pacing. Unlike for RyR2, enhancing SERCA2a function by ablating PLB exerted a relatively minor effect on Ca2+ alternans in intact hearts expressing RyR2 WT or a loss-of-function RyR2 variant, E4872Q, that promotes Ca2+ alternans. Furthermore, partial SERCA2a inhibition with 3 MUm 2,5-di-tert-butylhydroquinone (tBHQ) also had little impact on Ca2+ alternans, whereas strong SERCA2a inhibition with 10 MUm tBHQ markedly reduced the amplitude of Ca2+ transients and suppressed Ca2+ alternans in intact hearts. Our results demonstrate that enhanced RyR2 function suppresses Ca2+ alternans in the absence of spontaneous Ca2+ release and that RyR2, but not SERCA2a, is a key determinant of Ca2+ alternans in intact working hearts, making RyR2 an important therapeutic target for cardiac alternans. PMID- 29986886 TI - Cell surface expression of homomeric GABAA receptors depends on single residues in subunit transmembrane domains. AB - Cell surface expression of type A GABA receptors (GABAARs) is a critical determinant of the efficacy of inhibitory neurotransmission. Pentameric GABAARs are assembled from a large pool of subunits according to precise co-assembly rules that limit the extent of receptor structural diversity. These rules ensure that particular subunits, such as rho1 and beta3, form functional cell surface ion channels when expressed alone in heterologous systems, whereas other brain abundant subunits, such as alpha and gamma, are retained within intracellular compartments. Why some of the most abundant GABAAR subunits fail to form homomeric ion channels is unknown. Normally, surface expression of alpha and gamma subunits requires co-assembly with beta subunits via interactions between their N-terminal sequences in the endoplasmic reticulum. Here, using molecular biology, imaging, and electrophysiology with GABAAR chimeras, we have identified two critical residues in the transmembrane domains of alpha and gamma subunits, which, when substituted for their rho1 counterparts, permit cell surface expression as homomers. Consistent with this, substitution of the rho1 transmembrane residues for the alpha subunit equivalents reduced surface expression and altered channel gating, highlighting their importance for GABAAR trafficking and signaling. Although not ligand-gated, the formation of alpha and gamma homomeric ion channels at the cell surface was revealed by incorporating a mutation that imparts the functional signature of spontaneous channel activity. Our study identifies two single transmembrane residues that enable homomeric GABAAR subunit cell surface trafficking and demonstrates that alpha and gamma subunits can form functional ion channels. PMID- 29986887 TI - PBRM1 bromodomains variably influence nucleosome interactions and cellular function. AB - Chromatin remodelers use bromodomains (BDs) to recognize histones. Polybromo 1 (PBRM1 or BAF180) is hypothesized to function as the nucleosome-recognition subunit of the PBAF chromatin-remodeling complex and is frequently mutated in clear cell renal cell carcinoma (ccRCC). Previous studies have applied in vitro methods to explore the binding specificities of the six individual PBRM1 BDs. However, BD targeting to histones and the influence of neighboring BD on nucleosome recognition have not been well characterized. Here, using histone microarrays and intact nucleosomes to investigate the histone-binding characteristics of the six PBRM1 BDs individually and combined, we demonstrate that BD2 and BD4 of PBRM1 mediate binding to acetylated histone peptides and to modified recombinant and cellular nucleosomes. Moreover, we show that neighboring BDs variably modulate these chromatin interactions, with BD1 and BD5 enhancing nucleosome interactions of BD2 and BD4, respectively, whereas BD3 attenuated these interactions. We also found that binding pocket missense mutations in BD4 observed in ccRCC disrupt PBRM1-chromatin interactions and that these mutations in BD4, but not similar mutations in BD2, in the context of full-length PBRM1, accelerate ccRCC cell proliferation. Taken together, our biochemical and mutational analyses have identified BD4 as being critically important for maintaining proper PBRM1 function and demonstrate that BD4 mutations increase ccRCC cell growth. Because of the link between PBRM1 status and sensitivity to immune checkpoint inhibitor treatment, these data also suggest the relevance of BD4 as a potential clinical target. PMID- 29986889 TI - Association of Antibodies to VAR2CSA and Merozoite Antigens with Pregnancy Outcomes in Women Living in Yaounde, Cameroon. AB - Plasmodium falciparum infections are serious in pregnant women, because VAR2CSA allows parasitized erythrocytes to sequester in the placenta, causing placental malaria (PM). In areas of endemicity, women have substantial malarial immunity prior to pregnancy, including antibodies to merozoite antigens, but produce antibodies to VAR2CSA only during pregnancy. The current study sought to determine the importance of antibodies to VAR2CSA and merozoite antigens in pregnant women in Yaounde, Cameroon, where malaria transmission was relatively low. A total of 1,377 archival plasma samples collected at delivery were selected (at a 1:3 ratio of PM-positive [PM+] to PM-negative [PM-] women) and screened for antibodies to full-length VAR2CSA and 7 merozoite antigens. Results showed that many PM+ women and most PM- women lacked antibodies to VAR2CSA at delivery. Among PM+ women, antibodies to VAR2CSA were associated with a reduced risk of having high placental parasitemia (odds ratio [OR], 0.432; confidence interval [CI], 0.272, 0.687; P = 0.0004) and low-birth-weight (LBW) babies (OR = 0.444; CI, 0.247, 0.799; P = 0.0068), even during first pregnancies. Among antibodies to the 7 merozoite antigens, i.e., AMA1, EBA-175, MSP142, MSP2, MSP3, MSP11, and Pf41, only antibodies to MSP3, EBA-175, and Pf41 were associated with reduced risk for high placental parasitemias (P = 0.0389, 0.0291, and 0.0211, respectively) and antibodies to EBA-175 were associated with reduced risk of premature deliveries (P = 0.0211). However, after adjusting for multiple comparisons significance declined. Thus, in PM+ women, antibodies to VAR2CSA were associated with lower placental parasitemias and reduced prevalence of LBW babies in this low transmission setting. PMID- 29986888 TI - Interleukin-17A Exacerbates Disease Severity in BALB/c Mice Susceptible to Lung Infection with Mycoplasma pulmonis. AB - Mycoplasmas are atypical bacteria that disrupt the immune response to promote respiratory tract infections and secondary complications. However, not every immunologic response that protects or damages the host during mycoplasma infection is known. Interleukin-17A (IL-17A) is elevated in individuals infected with mycoplasmas, but how IL-17A and its cellular sources dictate disease outcome remains unclear. Here, IL-17A is hypothesized to worsen disease in individuals susceptible to mycoplasma infection. Thus, monoclonal anti-IL-17A antibodies were given to disease-susceptible BALB/c mice and disease-resistant C57BL/6 mice infected with Mycoplasma pulmonis Neutralizing the function of IL-17A using anti IL-17A antibodies reduced disease severity during M. pulmonis infection in BALB/c, but not C57BL/6, mice. Neutralizing IL-17A also reduced the incidence of neutrophilic lung lesions during infection in BALB/c mice. Reduced pathology occurred without impacting the bacterial burden, demonstrating that IL-17A is not required for mycoplasma clearance. The main source of IL-17A throughout infection in BALB/c mice was CD4+ T cells, and neutralizing IL-17A after infiltration of the lungs by T cells reduced disease severity, identifying the Th17 response as a herald of late mycoplasma pathology in susceptible mice. Neutralizing IL-17A did not further reduce disease during M. pulmonis infection in BALB/c mice depleted of neutrophils, suggesting that IL-17A requires the presence of pulmonary neutrophils to worsen respiratory pathology. IL-17A is a pathological element of murine respiratory mycoplasma infection. Using monoclonal antibodies to neutralize IL-17A could reduce disease severity during mycoplasma infection in humans and domesticated animals. PMID- 29986890 TI - Edwardsiella piscicida Type III Secretion System Effector EseK Inhibits Mitogen Activated Protein Kinase Phosphorylation and Promotes Bacterial Colonization in Zebrafish Larvae. AB - Bacteria utilize type III secretion systems (T3SS) to deliver effectors directly into host cells. Hence, it is very important to identify the functions of bacterial (T3SS) effectors to understand host-pathogen interactions. Edwardsiella piscicida encodes a functional T3SS effector, EseK, which can be translocated into host cells and affect bacterial loads. Here, it was demonstrated that an eseK mutant (the DeltaeseK mutant) significantly increased the phosphorylation levels of p38alpha, c-Jun NH2-terminal kinases (JNK), and extracellular signal regulated protein kinases 1/2 (ERK1/2) in HeLa cells. Overexpression of EseK directly inhibited mitogen-activated protein kinase (MAPK) signaling pathways in HEK293T cells. The DeltaeseK mutant consistently promoted the phosphorylation of MAPKs in zebrafish larva infection models. Further, it was shown that the DeltaeseK mutant increased the expression of tumor necrosis factor alpha (TNF alpha) in an MAPK-dependent manner. Importantly, the EseK-mediated inhibition of MAPKs in vivo attenuated bacterial clearance in larvae. Taken together, this work reveals that the E. piscicida T3SS effector EseK promotes bacterial infection by inhibiting MAPK activation, which provides insights into the molecular pathogenesis of E. piscicida in fish. PMID- 29986891 TI - In Vivo Intradermal Delivery of Bacteria by Using Microneedle Arrays. AB - Infectious diseases propagated by arthropod vectors, such as tularemia, are commonly initiated via dermal infection of the skin. However, due to the technical difficulties in achieving accurate and reproducible dermal deposition, intradermal models are less commonly used. To overcome these limitations, we used microneedle arrays (MNAs), which are micron-scale polymeric structures, to temporarily disrupt the barrier function of the skin and deliver a bacterial inoculum directly to the dermis of an animal. MNAs increase reliability by eliminating leakage of the inoculum or blood from the injection site, thereby providing a biologically relevant model for arthropod-initiated disease. Here, we validate the use of MNAs as a means to induce intradermal infection using a murine model of tularemia initiated by Francisella novicida We demonstrate targeted delivery of the MNA bolus to the dermal layer of the skin, which subsequently led to innate immune cell infiltration. Additionally, F. novicida coated MNAs were used to achieve lethality in a dose-dependent manner in C57BL/6 mice. The immune profile of infected mice mirrored that of established F. novicida infection models, consisting of markedly increased serum levels of interleukin-6 and keratinocyte chemoattractant, splenic T-cell depletion, and an increase in splenic granulocytes, together confirming that MNAs can be used to reproducibly induce tularemia-like pathogenesis in mice. When MNAs were used to immunize mice using an attenuated F. novicida mutant (F. novicida DeltalpxD1), all immunized mice survived a lethal subcutaneous challenge. Thus, MNAs can be used to effectively deliver viable bacteria in vivo and provide a novel avenue to study intradermally induced microbial diseases in animal models. PMID- 29986892 TI - Malaria parasite-mediated alteration of macrophage function and increased iron availability predispose to disseminated non-typhoidal Salmonella infection. AB - Disseminated infections with non-typhoidal Salmonella (NTS) are a significant cause of child mortality in sub-Saharan Africa. NTS infection in children is clinically associated with malaria, suggesting that malaria compromises control of disseminated NTS infection. To study the mechanistic basis for increased NTS susceptibility, we utilized a model of concurrent infection with Salmonella enterica serotype Typhimurium and Plasmodium yoelii Underlying malaria blunted monocyte expression of Ly6C, a marker for inflammatory activation, and impaired recruitment of inflammatory cells to the liver. Hepatic mononuclear phagocytes expressed lower levels of iNOS, TNFalpha and GM-CSF and increased production of IL-10 and heme oxygenase-1, indicating that that underlying malaria modifies the activation state and inflammatory response of mononuclear phagocytes to NTS. P. yoelii infection also increased intracellular iron levels in liver mononuclear cells, as evidenced by elevated levels of ferritin and by rescue of a S. Typhimurium tonBfeoB mutant defective for iron uptake. In addition, concurrent P. yoelii infection partially rescued the systemic colonization defect of a S Typhimurium spiB mutant defective for type III secretion system-2 (T3SS-2), indicating that the ability of phagocytic cells to limit spread of S. Typhimurium is impaired during concurrent P. yoelii infection. These results show that concurrent malaria increases susceptibility to disseminated NTS infection by blunting macrophage bactericidal mechanisms and providing an essential nutrient that enhances bacterial growth. PMID- 29986893 TI - ATG Genes Influence the Virulence of Cryptococcus neoformans through Contributions beyond Core Autophagy Functions. AB - The process of autophagy is conserved among all eukaryotes from yeast to humans and is mainly responsible for bulk degradation of cellular contents and nutrient recycling during starvation. Autophagy has been suggested to play a role in the pathogenesis of the opportunistic human fungal pathogen Cryptococcus neoformans, potentially through a contribution to the export of virulence factors. In this study, we showed that deletion of each of the ATG1, ATG7, ATG8, and ATG9 genes in C. neoformans leads to autophagy-related phenotypes, including impaired amino acid homeostasis under nitrogen starvation. In addition, the atgDelta mutants were hypersensitive to inhibition of the ubiquitin-proteasome system, a finding consistent with a role in amino acid homeostasis. Although each atgDelta mutant was not markedly impaired in virulence factor production in vitro, we found that all four ATG genes contribute to C. neoformans virulence in a murine inhalation model of cryptococcosis. Interestingly, these mutants displayed significant differences in their ability to promote disease development. A more detailed investigation of virulence for the atg1Delta and atg8Delta mutants revealed that both strains stimulated an exaggerated host immune response, which, in turn, contributed to disease severity. Overall, our results suggest that different ATG genes are involved in nonautophagic functions and contribute to C. neoformans virulence beyond their core functions in autophagy. PMID- 29986894 TI - Tailoring a Plasmodium vivax Vaccine To Enhance Efficacy through a Combination of a CSP Virus-Like Particle and TRAP Viral Vectors. AB - Vivax malaria remains one of the most serious and neglected tropical diseases, with 132 to 391 million clinical cases per year and 2.5 billion people at risk of infection. A vaccine against Plasmodium vivax could have more impact than any other intervention, and the use of a vaccine targeting multiple antigens may result in higher efficacy against sporozoite infection than targeting a single antigen. Here, two leading P. vivax preerythrocytic vaccine candidate antigens, the P. vivax circumsporozoite protein (PvCSP) and the thrombospondin-related adhesion protein (PvTRAP) were delivered as a combined vaccine. This strategy provided a dose-sparing effect, with 100% sterile protection in mice using doses that individually conferred low or no protection, as with the unadjuvanted antigens PvTRAP (0%) and PvCSP (50%), and reached protection similar to that of adjuvanted components. Efficacy against malaria infection was assessed using a new mouse challenge model consisting of a double-transgenic Plasmodium berghei parasite simultaneously expressing PvCSP and PvTRAP used in mice immunized with the virus-like particle (VLP) Rv21 previously reported to induce high efficacy in mice using Matrix-M adjuvant, while PvTRAP was concomitantly administered in chimpanzee adenovirus and modified vaccinia virus Ankara (MVA) vectors (viral vectored TRAP, or vvTRAP) to support effective induction of T cells. We examined immunity elicited by these vaccines in the context of two adjuvants approved for human use (AddaVax and Matrix-M). Matrix-M supported the highest anti-PvCSP antibody titers when combined with Rv21, and, interestingly, mixing PvCSP Rv21 and PvTRAP viral vectors enhanced immunity to malaria over levels provided by single vaccines. PMID- 29986895 TI - Delineating the Physiological Roles of the PE and Catalytic Domains of LipY in Lipid Consumption in Mycobacterium-Infected Foamy Macrophages. AB - Within tuberculous granulomas, a subpopulation of Mycobacterium tuberculosis resides inside foamy macrophages (FM) that contain abundant cytoplasmic lipid bodies (LB) filled with triacylglycerol (TAG). Upon fusion of LB with M. tuberculosis-containing phagosomes, TAG is hydrolyzed and reprocessed by the bacteria into their own lipids, which accumulate as intracytosolic lipid inclusions (ILI). This phenomenon is driven by many mycobacterial lipases, among which LipY participates in the hydrolysis of host and bacterial TAG. However, the functional contribution of LipY's PE domain to TAG hydrolysis remains unclear. Here, enzymatic studies were performed to compare the lipolytic activities of recombinant LipY and its truncated variant lacking the N-terminal PE domain, LipY(DeltaPE). Complementarily, an FM model was used where bone marrow-derived mouse macrophages were infected with M. bovis BCG strains either overexpressing LipY or LipY(DeltaPE) or carrying a lipY deletion mutation prior to being exposed to TAG-rich very-low-density lipoprotein (VLDL). Results indicate that truncation of the PE domain correlates with increased TAG hydrolase activity. Quantitative electron microscopy analyses showed that (i) in the presence of lipase inhibitors, large ILI (ILI+3) were not formed because of an absence of LB due to inhibition of VLDL-TAG hydrolysis or inhibition of LB-neutral lipid hydrolysis by mycobacterial lipases, (ii) ILI+3 profiles in the strain overexpressing LipY(DeltaPE) were reduced, and (iii) the number of ILI+3 profiles in the DeltalipY mutant was reduced by 50%. Overall, these results delineate the role of LipY and its PE domain in host and mycobacterial lipid consumption and show that additional mycobacterial lipases take part in these processes. PMID- 29986896 TI - Standardizing pneumococcal biofilm release to PncO expression, a predictive measurement of virulence. AB - A critical component in clinical trials for vaccines against pneumococcal disease is the establishment of robust preclinical models and clinical correlates of protection, which in the case of the causative bacterial agent Streptococcus pneumoniae, include standard sepsis/pneumonia mouse models and opsonophagocytic activity (OPA), respectively. Despite broad usage, these gold standard measures are ill-equipped to evaluate non-traditional antigens that target virulence factors beyond capsular polysaccharides and/or proteins not associated with colonization or routine growth. These assays are further complicated by observed inconsistencies in expression of target protein antigens as well as the quantity of usable bacteria provided from respective growth processes. To overcome these issues, we performed an extensive optimization study of the critical steps in a bacterial biofilm-dispersion model (termed the biofilm model) to identify conditions that yield the greatest quantity of released pneumococci displaying a consistent virulence phenotype. Using this knowledge, we developed a secondary immune-absorbance assay to provide immediate insight into the phenotypic state of bacteria conditioned using the biofilm model. Specifically, positive correlations between PncO (a key virulent-associated protein antigen) expression and immune absorbance (R2=0.96) were translated into a predictive readout of virulence in sepsis and pneumonia challenge models, capsule-shedding, and OPA assay titer. These results present a methodology to generate consistent lots of virulent bacteria to standardize inputs in preclinical and clinical models against biofilm associated bacteria. PMID- 29986897 TI - Micronuclei Formation Is Prevented by Aurora B-Mediated Exclusion of HP1a from Late-Segregating Chromatin in Drosophila. AB - While it is known that micronuclei pose a serious risk to genomic integrity by undergoing chromothripsis, mechanisms preventing micronucleus formation remain poorly understood. Here, we investigate how late-segregating acentric chromosomes that would otherwise form micronuclei instead reintegrate into daughter nuclei by passing through Aurora B kinase-dependent channels in the nuclear envelope of Drosophila melanogaster neuroblasts. We find that localized concentrations of Aurora B preferentially phosphorylate H3(S10) on acentrics and their associated DNA tethers. This phosphorylation event prevents HP1a from associating with heterochromatin and results in localized inhibition of nuclear envelope reassembly on endonuclease- and X-irradiation-induced acentrics, promoting channel formation. Finally, we find that HP1a also specifies initiation sites of nuclear envelope reassembly on undamaged chromatin. Taken together, these results demonstrate that Aurora B-mediated regulation of HP1a-chromatin interaction plays a key role in maintaining genome integrity by locally preventing nuclear envelope assembly and facilitating the incorporation of late-segregating acentrics into daughter nuclei. PMID- 29986899 TI - Single-cell biology: resolving biological complexity, one cell at a time. AB - In March 2018, over 250 researchers came together at the Wellcome Genome Campus in Hinxton, Cambridge, UK, to present their latest research in the area of single cell biology. A highly interdisciplinary meeting, the Single Cell Biology conference covered a variety of topics, ranging from cutting-edge technological innovation, developmental biology and stem cell research to evolution and cancer. This meeting report summarises the key findings presented and the major research themes that emerged during the conference. PMID- 29986900 TI - Auricular acupuncture for treatment of preoperative anxiety in patients scheduled for ambulatory gynaecological surgery: a prospective controlled investigation with a non-randomised arm. AB - OBJECTIVE: Auricular acupuncture (AA) is a promising alternative treatment for situational anxiety. The aim of this pilot investigation was to test the acceptability and feasibility of AA as a treatment for preoperative anxiety (PA) in preparation for a subsequent randomised controlled trial. METHODS: AA was offered for treatment of PA to female patients who were scheduled for ambulatory gynaecological surgery. In patients who agreed, indwelling fixed needles were applied bilaterally at the points MA-IC1, MA-TF1, MA-SC, MA-AH7 and MA-T the day before surgery. Patients who declined AA but agreed to be examined constituted the control group (no intervention). State anxiety (primary outcome) was measured using the State-Trait-Anxiety Inventory (STAI) before AA (time I), the evening before surgery (time II) and immediately before surgery (time III). Anxiety was measured with a 100 mm visual analogue scale (VAS-100); heart rate, blood pressure and serum cortisol were also quantified. RESULTS: Data from 62 patients (32 with AA and 30 with no intervention) were analysed. Whereas preoperative anxiety was reduced after AA the evening before surgery (P<0.01), anxiety levels in the control group increased from the first to the last measurement (P<0.001). Secondary outcomes were comparable between the patients from both groups. CONCLUSIONS: AA was acceptable and feasible as a treatment for preoperative anxiety. The results were used for the sample size calculation of a subsequent randomised controlled clinical trial. TRIAL REGISTRATION NUMBER: NCT02656966; Results. PMID- 29986898 TI - TOR signaling in plants: conservation and innovation. AB - Target of rapamycin (TOR) is an evolutionarily conserved protein kinase that plays a central role in both plants and animals, despite their distinct developmental programs and survival strategies. Indeed, TOR integrates nutrient, energy, hormone, growth factor and environmental inputs to control proliferation, growth and metabolism in diverse multicellular organisms. Here, we compare the molecular composition, upstream regulators and downstream signaling relays of TOR complexes in plants and animals. We also explore and discuss the pivotal functions of TOR signaling in basic cellular processes, such as translation, cell division and stem/progenitor cell regulation during plant development. PMID- 29986901 TI - Warm needle acupuncture in primary osteoporosis management: a systematic review and meta-analysis. AB - BACKGROUND: Warm needle acupuncture (WNA) is commonly used in primary osteoporosis (OP) management in China. The evidence of its effectiveness needs to be systematically reviewed. OBJECTIVE: The aim of the meta-analysis was to evaluate whether using WNA alone or combined with conventional medicine benefits primary OP. METHODS: PubMed, Embase, the Cochrane Central Register, Medline, China National Knowledge Infrastructure, Wanfang and VIP databases were searched from their inception through 30 June 2016. RCTs applying WNA independently or as an adjunct to conventional medicine, compared with conventional medicine alone, were included. Primary outcomes were bone mineral density (BMD) of the lumbar vertebrae, femoral neck, Ward's triangle and greater trochanter. The secondary outcome was chronic pain measured by VAS score. Meta-analysis was conducted using RevMan V.5.3 software. RESULTS: Nine RCTs involving 572 participants were included. When WNA was used as an adjunct to conventional medicine, meta-analysis revealed a statistical difference in favour of increasing BMD of the lumbar vertebrae (mean difference (MD)=0.06, 95% CI 0.03 to 0.08, P<0.001). WNA increased BMD of the femoral neck (MD 0.14, 95% CI 0.08 to 0.21, P<0.001) and greater trochanter (MD 0.09, 95% CI 0.04 to 0.15, P<0.001) when used alone, and additionally decreased VAS scores (MD=-1.10, 95% CI -1.14 to -1.06, P<0.001) when used as an adjunct to conventional medicine. However, the safety of WNA was not specifically reported. CONCLUSIONS: WNA may have beneficial effects on BMD and VAS scores of patients with primary OP. However, all included trials were at high risk of bias and of low quality. Further rigorous studies are needed to determine the effectiveness of WNA for primary OP treatment. PMID- 29986902 TI - Effects of dry needling on post-stroke spasticity, motor function and stability limits: a randomised clinical trial. AB - OBJECTIVE: To determine the effects of inclusion of deep dry needling into a treatment session following the Bobath concept on spasticity, motor function and postural control after a stroke. METHODS: 26 patients who had suffered a stroke were randomly assigned to one of two treatment groups: Bobath only, or Bobath plus dry needling. Both groups received a session including strengthening, stretching and reconditioning exercises following the principles of the Bobath concept. Patients in the Bobath plus dry needling group also received a single session of ultrasound-guided dry needling of the tibialis posterior. Spasticity (Modified Modified Ashworth Scale), function (Fugl-Meyer Scale) and stability limits (computerised dynamic posturography using the SMART EquiTest System) were collected before and 10 min after treatment by a blinded assessor. The parameters of the stability limits included movement velocity (MVL), maximum excursion (MXE), end-point excursion (EPE) and directional control (DCL). RESULTS: A greater number of individuals receiving Bobath plus dry needling exhibited a decrease in spasticity after treatment (P<0.001). Analysis of covariance (ANCOVA) showed that patients receiving Bobath plus dry needling exhibited greater improvements in the balance (0.8, 95% CI 0.2 to 1.4), sensory (1.7, 95% CI 0.7 to 2.7) and range of motion (3.2, 95% CI 2.0 to 4.4) domains of the Fugl-Meyer Scale than those receiving Bobath only. ANCOVA also found that subjects receiving dry needling showed a greater increase in MVL non-affected forward direction, EPE non affected direction, MXE backward and MXE affected/non-affected, DCL backward and DCL affected backward direction, than those who did not receive it. CONCLUSIONS: The inclusion of deep dry needling into a treatment session following the Bobath concept was effective at decreasing spasticity and improving balance, range of motion and the accuracy of maintaining stability in patients who had experienced a stroke. TRIAL REGISTRATION NUMBER: NCT02579291. PMID- 29986903 TI - Relationship between consciousness and injury of ascending reticular activating system in patients with hypoxic ischaemic brain injury. PMID- 29986904 TI - Unilateral pallidal stimulation for disabling dystonia due to Rasmussen's disease. AB - OBJECTIVE: To describe an adult patient with Rasmussen's disease with focal dystonia as the most disabling symptom and the good response to unilateral globus pallidus internus (GPi) deep brain stimulation (DBS). METHODS: Retrospective review of clinical records and diagnostic tests. RESULTS: The patient had displayedmild focal seizures with sensory and motor symptoms on the left arm and hemiface since the age of 22. Ten years later she experienced abrupt onset of focal left dystonia involving mainly the leg. Brain MRI showed progressive right hemisphere atrophy, and 18 fluorodeoxyglucose-positron emission tomography (18FDG PET) showed right hypometabolism mainly over the frontal and insular regions. Brain biopsy confirmed chronic encephalitis. The dystonia became very severe and made walking extremely difficult. Different treatments including dopaminergic, anticholinergic, immunomodulatory drugs and botulinum toxin were ineffective. Finally the patient was treated with unilateral GPi DBS. Shortly after the onset of the stimulation, the dystonia started to improve. Parameters have been adjusted, and 18 months after surgery the patient is able to walk and run unaided, although a mild left leg dystonia persists. CONCLUSION: Rasmussen's disease may be difficult to diagnose in adult patients. Associated movement disorders may be more disabling than seizures. Focal dystonia may be treated successfully with DBS. PMID- 29986906 TI - Margaret McCartney: If screening is worth doing, it's worth doing well. PMID- 29986905 TI - Advance decisions in dementia: when the past conflicts with the present. AB - As the prevalence of dementia increases across the Western world, there is a growing interest in advance care planning, by which patients may make decisions on behalf of their future selves. Under which ethical principles is this practice justified? I assess the justification for advance care planning put forward by the philosopher Ronald Dworkin, which he rationalises through an integrity-based conception of autonomy. I suggest his judgement is misguided by arguing in favour of two claims. First, that patients with dementia qualify for some right to contemporary autonomy conceptualised under the 'sense of liberty' it provides. Second, that respecting precedent autonomy, such as an advance care plan, is not essential to Dworkin's integrity-based account of autonomy. Together, my claims problematise the practice of using advance decisions in the context of dementia. PMID- 29986908 TI - Novel agents for primary central nervous system lymphoma: evidence and perspectives. AB - Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal non- Hodgkin lymphoma. Although high remission rates can be achieved with high dose methotrexate-based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives. The body of evidence for novel agents is still limited to noncomparative studies, but the most promising approaches include Bruton kinase inhibition with ibrutinib and immunomodulatory treatment (eg, with lenalidomide). Targeting the mammalian target of rapamycin pathway does not seem to have a meaningful clinical benefit, and evidence of checkpoint inhibition with nivolumab is limited to anecdotal evidence. Future studies should embrace the concept of induction and maintenance therapy as well as the combination of drugs with different mechanisms of action. Selection of patients based on molecular profiling and relapse patterns should be another aspect informing future comparative trials, which are urgently needed to improve prognosis for patients with PCNSL. PMID- 29986907 TI - Modulation of TORC2 Signaling by a Conserved Lkb1 Signaling Axis in Budding Yeast. AB - Nutrient availability, growth rate, and cell size are closely linked. For example, in budding yeast, the rate of cell growth is proportional to nutrient availability, cell size is proportional to growth rate, and growth rate is proportional to cell size. Thus, cells grow slowly in poor nutrients and are nearly half the size of cells growing in rich nutrients. Moreover, large cells grow faster than small cells. A signaling network that surrounds TOR kinase complex 2 (TORC2) plays an important role in enforcing these proportional relationships. Cells that lack components of the TORC2 network fail to modulate their growth rate or size in response to changes in nutrient availability. Here, we show that budding yeast homologs of the Lkb1 tumor suppressor kinase are required for normal modulation of TORC2 signaling in response to changes in carbon source. Lkb1 kinases activate Snf1/AMPK to initiate transcription of genes required for utilization of poor carbon sources. However, Lkb1 influences TORC2 signaling via a novel pathway that is independent of Snf1/AMPK. Of the three Lkb1 homologs in budding yeast, Elm1 plays the most important role in modulating TORC2. Elm1 activates a pair of related kinases called Gin4 and Hsl1. Previous work found that loss of Gin4 and Hsl1 causes cells to undergo unrestrained growth during a prolonged mitotic arrest, which suggests that they play a role in linking cell cycle progression to cell growth. We found that Gin4 and Hsl1 also control the TORC2 network. In addition, Gin4 and Hsl1 are themselves influenced by signals from the TORC2 network, consistent with previous work showing that the TORC2 network constitutes a feedback loop. Together, the data suggest a model in which the TORC2 network sets growth rate in response to carbon source, while also relaying signals via Gin4 and Hsl1 that set the critical amount of growth required for cell cycle progression. This kind of close linkage between control of cell growth and size would suggest a simple mechanistic explanation for the proportional relationship between cell size and growth rate. PMID- 29986909 TI - TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma. AB - Immune-based therapies hold promise for the treatment of multiple myeloma (MM), but so far, immune checkpoint blockade targeting programmed cell death protein 1 has not proven effective as single agent in this disease. T-cell immunoglobulin and ITIM domains (TIGIT) is another immune checkpoint receptor known to negatively regulate T-cell functions. In this study, we investigated the therapeutic potential of TIGIT blockade to unleash immune responses against MM. We observed that, in both mice and humans, MM progression was associated with high levels of TIGIT expression on CD8+ T cells. TIGIT+ CD8+ T cells from MM patients exhibited a dysfunctional phenotype characterized by decreased proliferation and inability to produce cytokines in response to anti-CD3/CD28/CD2 or myeloma antigen stimulation. Moreover, when challenged with Vk*MYC mouse MM cells, TIGIT-deficient mice showed decreased serum monoclonal immunoglobulin protein levels associated with reduced tumor burden and prolonged survival, indicating that TIGIT limits antimyeloma immune responses. Importantly, blocking TIGIT using monoclonal antibodies increased the effector function of MM patient CD8+ T cells and suppressed MM development. Altogether our data provide evidence for an immune-inhibitory role of TIGIT in MM and support the development of TIGIT blocking strategies for the treatment of MM patients. PMID- 29986910 TI - California's carbon market and energy prices: a wavelet analysis. AB - Carbon price is a key variable in management and risk decisions in activities related to the burning of fossil fuels. Different major players in this market, such as polluters, regulators and financial actors, have different time horizons. We use innovative multivariate wavelet analysis tools, including partial wavelet coherence and partial wavelet gain, to study the link between carbon prices and final energy prices in the time and frequency dimensions in California's carbon market, officially known as the California cap-and-trade programme. We find that gasoline prices lead an anti-phase relation with carbon prices. This result is very stable at lower frequencies (close to 1-year period cycles), and it is also present before mid-2015 in the 20-34 weeks frequency band. Regarding electricity, we find that at about a 1-year period, a rise in carbon prices is reflected in higher electricity prices. We conclude that the first 5 years of compliance of the California cap-and-trade programme show that emissions trading is a significant measure for climate change mitigation, with visible rising carbon prices. The quantitative financial analytics we present supports the recent decision to extend the current market to 2030 without the need for complementary carbon pricing schemes.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986911 TI - Nonlinear analysis of natural folds using wavelet transforms and recurrence plots. AB - Three-dimensional models of natural geological fold systems established by photogrammetry are quantified in order to constrain the processes responsible for their formation. The folds are treated as nonlinear dynamical systems and the quantification is based on the two features that characterize such systems, namely their multifractal geometry and recurrence quantification. The multifractal spectrum is established using wavelet transforms and the wavelet transform modulus maxima method, the generalized fractal or Renyi dimensions and the Hurst exponents for longitudinal and orthogonal sections of the folds. Recurrence is established through recurrence quantification analysis (RQA). We not only examine natural folds but also compare their signals with synthetic signals comprising periodic patterns with superimposed noise, and quasi-periodic and chaotic signals. These results indicate that the natural fold systems analysed resemble periodic signals with superimposed chaotic signals consistent with the nonlinear dynamical theory of folding. Prediction based on nonlinear dynamics, in this case through RQA, takes into account the full mechanics of the formation of the geological system.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986912 TI - Introduction to redundancy rules: the continuous wavelet transform comes of age. AB - Redundancy: it is a word heavy with connotations of lacking usefulness. I often hear that the rationale for not using the continuous wavelet transform (CWT)-even when it appears most appropriate for the problem at hand-is that it is 'redundant'. Sometimes the conversation ends there, as if self-explanatory. However, in the context of the CWT, 'redundant' is not a pejorative term, it simply refers to a less compact form used to represent the information within the signal. The benefit of this new form-the CWT-is that it allows for intricate structural characteristics of the signal information to be made manifest within the transform space, where it can be more amenable to study: resolution over redundancy. Once the signal information is in CWT form, a range of powerful analysis methods can then be employed for its extraction, interpretation and/or manipulation. This theme issue is intended to provide the reader with an overview of the current state of the art of CWT analysis methods from across a wide range of numerate disciplines, including fluid dynamics, structural mechanics, geophysics, medicine, astronomy and finance.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986913 TI - A review of Morlet wavelet analysis of radial profiles of Saturn's rings. AB - Spiral waves propagating in Saturn's rings have wavelengths that vary with radial position within the disc. The best-quality observations of these waves have the form of radial profiles centred on a particular azimuth. In that context, the wavelength of a given spiral wave is seen to change substantially with position along the one-dimensional profile. In this paper, we review the use of Morlet wavelet analysis to understand these waves. When signal to noise is high and the cause of the wave is well understood, wavelet analysis has been used to solve for wave parameters that are diagnostic of local disc properties. Waves that are not readily perceptible in the spatial domain signal can be clearly identified. Furthermore, filtering in wavelet space, followed by the reverse wavelet transform, has been used to isolate the part of the signal that is of interest. When the cause of the wave is not known, comparing the phases of the complex valued wavelet transforms from many profiles has been used to determine wave parameters that cannot be determined from any single profile. When signal to noise is low, co-adding wavelet transforms while manipulating the phase has been used to boost a wave's signal above detection limits.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986914 TI - Wavelet analysis techniques in cavitating flows. AB - Cavitating and bubbly flows involve a host of physical phenomena and processes ranging from nucleation, surface and interfacial effects, mass transfer via diffusion and phase change to macroscopic flow physics involving bubble dynamics, turbulent flow interactions and two-phase compressible effects. The complex physics that result from these phenomena and their interactions make for flows that are difficult to investigate and analyse. From an experimental perspective, evolving sensing technology and data processing provide opportunities for gaining new insight and understanding of these complex flows, and the continuous wavelet transform (CWT) is a powerful tool to aid in their elucidation. Five case studies are presented involving many of these phenomena in which the CWT was key to data analysis and interpretation. A diverse set of experiments are presented involving a range of physical and temporal scales and experimental techniques. Bubble turbulent break-up is investigated using hydroacoustics, bubble dynamics and high speed imaging; microbubbles are sized using light scattering and ultrasonic sensing, and large-scale coherent shedding driven by various mechanisms are analysed using simultaneous high-speed imaging and physical measurement techniques. The experimental set-up, aspect of cavitation being addressed, how the wavelets were applied, their advantages over other techniques and key findings are presented for each case study.This paper is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986915 TI - Branch/mode competition in the flow-induced vibration of a square cylinder. AB - The flow-induced vibration response of a square cross-sectional cylinder with low mass and damping ratio is analysed using continuous wavelet transforms (CWT) for three representative angles of attack of the cylinder to the incoming flow. The amplitude and frequency responses over a range of flow velocities map out multiple regimes (branches) of oscillation. Analysis of the time-frequency domain for boundary regions between branches using CWT reveals intermittency at the synchronization region boundaries as well as mode competition at branch boundaries. Complementary recurrence analysis shows that periodic dynamical states are interrupted by chaotic bursts in the transition regions around the higher branch at an angle of attack of alpha = 20 degrees (a new branch first observed by Nemes et al. (2012 J. Fluid Mech.710, 102-130 (doi:10.1017/jfm.2012.353))), supporting the CWT-based frequency-time analysis.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986916 TI - Wavelet-based analysis of time-variant adaptive structures. AB - Wavelet analysis is applied to identify the time-variant dynamics of adaptive structures. The wavelet-based power spectrum of the structural response, wavelet based frequency response function (FRF) and wavelet-based coherence are used to identify continuously and abruptly varying natural frequencies. A cantilever plate with surface-bonded macro fibre composite-which alters the structural stiffness-is used to demonstrate the application of the methods. The results show that the wavelet-based input-output characteristics-i.e. the FRF and coherence can identify correctly the dynamics of the analysed time-variant system and reveal the varying natural frequency. The wavelet-based coherence can be used not only for the assessment of the quality of the wavelet-based FRF but also for the identification.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986917 TI - A wavelet neural control scheme for a quadrotor unmanned aerial vehicle. AB - Wavelets are designed to have compact support in both time and frequency, giving them the ability to represent a signal in the two-dimensional time-frequency plane. The Gaussian, the Mexican hat and the Morlet wavelets are crude wavelets that can be used only in continuous decomposition. The Morlet wavelet is complex valued and suitable for feature extraction using the continuous wavelet transform. Continuous wavelets are favoured when high temporal and spectral resolution is required at all scales. In this paper, considering the properties from the Morlet wavelet and based on the structure of a recurrent high-order neural network model, a novel wavelet neural network structure, here called a recurrent Morlet wavelet neural network, is proposed in order to achieve a better identification of the behaviour of dynamic systems. The effectiveness of our proposal is explored through the design of a decentralized neural backstepping control scheme for a quadrotor unmanned aerial vehicle. The performance of the overall neural identification and control scheme is verified via simulation and real-time results.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986918 TI - Continuous wavelet transform and higher-order spectrum: combinatory potentialities in breath sound analysis and electroencephalogram-based pain characterization. AB - The combination of the continuous wavelet transform (CWT) with a higher-order spectrum (HOS) merges two worlds into one that conveys information regarding the non-stationarity, non-Gaussianity and nonlinearity of the systems and/or signals under examination. In the current work, the third-order spectrum (TOS), which is used to detect the nonlinearity and deviation from Gaussianity of two types of biomedical signals, that is, wheezes and electroencephalogram (EEG), is combined with the CWT to offer a time-scale representation of the examined signals. As a result, a CWT/TOS field is formed and a time axis is introduced, creating a time bifrequency domain, which provides a new means for wheeze nonlinear analysis and dynamic EEG-based pain characterization. A detailed description and examples are provided and discussed to showcase the combinatory potential of CWT/TOS in the field of advanced signal processing.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986919 TI - Quantitative feature analysis of continuous analytic wavelet transforms of electrocardiography and electromyography. AB - Theoretical and practical advances in time-frequency analysis, in general, and the continuous wavelet transform (CWT), in particular, have increased over the last two decades. Although the Morlet wavelet has been the default choice for wavelet analysis, a new family of analytic wavelets, known as generalized Morse wavelets, which subsume several other analytic wavelet families, have been increasingly employed due to their time and frequency localization benefits and their utility in isolating and extracting quantifiable features in the time frequency domain. The current paper describes two practical applications of analysing the features obtained from the generalized Morse CWT: (i) electromyography, for isolating important features in muscle bursts during skating, and (ii) electrocardiography, for assessing heart rate variability, which is represented as the ridge of the main transform frequency band. These features are subsequently quantified to facilitate exploration of the underlying physiological processes from which the signals were generated.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986920 TI - Continuous wavelet transform in the study of the time-scale properties of intracranial pressure in hydrocephalus. AB - Normal pressure hydrocephalus (NPH) encompasses a heterogeneous group of disorders generally characterized by clinical symptoms, ventriculomegaly and anomalous cerebrospinal fluid (CSF) dynamics. Lumbar infusion tests (ITs) are frequently performed in the preoperatory evaluation of patients who show NPH features. The analysis of intracranial pressure (ICP) signals recorded during ITs could be useful to better understand the pathophysiology underlying NPH and to assist treatment decisions. In this study, 131 ICP signals recorded during ITs were analysed using two continuous wavelet transform (CWT)-derived parameters: Jensen divergence (JD) and spectral flux (SF). These parameters were studied in two frequency bands, associated with different components of the signal: B1(0.15 0.3 Hz), related to respiratory blood pressure oscillations; and B2 (0.67-2.5 Hz), related to ICP pulse waves. Statistically significant differences (p < 1.70 * 10-3, Bonferroni-corrected Wilcoxon signed-rank tests) in pairwise comparisons between phases of ITs were found using the mean and standard deviation of JD and SF. These differences were mainly found in B2, where a lower irregularity and variability, together with less prominent time-frequency fluctuations, were found in the hypertension phase of ITs. Our results suggest that wavelet analysis could be useful for understanding CSF dynamics in NPH.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986921 TI - On the use of wavelets to reveal oscillatory patterns in stellar flare emission. AB - Wavelet analysis is a powerful tool to investigate non-stationary signals such as amplitude modulated sinusoids or single events lasting for a small percentage of the observing time. Wavelet analysis can be used, for example, to reveal oscillations in the light curve of stars during coronal flares. A careful treatment of the background in the wavelet scalogram is necessary to determine robust confidence levels required to distinguish between patterns caused by actual oscillations and noise. This work describes the method using synthetic light curves and investigates the effect of background noise when determining confidence levels in the scalogram. The result of this analysis shows that the wavelet transform is able to reveal oscillatory patterns even when frequency dependent noise is dominant. However, their significance in the wavelet scalogram may be reduced, depending on the assumed background spectrum. To show the power of wavelet analysis, the light curve of a well-known flaring star is analysed. It shows two oscillations overlapped. The lower-frequency oscillation is not mentioned in previous works in the literature. This result demonstrates the need for correctly characterizing the background noise of the signal.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986922 TI - Analysis of time-varying signals using continuous wavelet and synchrosqueezed transforms. AB - The continuous wavelet transform (CWT) has played a key role in the analysis of time-frequency information in many different fields of science and engineering. It builds on the classical short-time Fourier transform but allows for variable time-frequency resolution. Yet, interpretation of the resulting spectral decomposition is often hindered by smearing and leakage of individual frequency components. Computation of instantaneous frequencies, combined by frequency reassignment, may then be applied by highly localized techniques, such as the synchrosqueezing transform and ConceFT, in order to reduce these effects. In this paper, we present the synchrosqueezing transform together with the CWT and illustrate their relative performances using four signals from different fields, namely the LIGO signal showing gravitational waves, a 'FanQuake' signal displaying observed vibrations during an American football game, a seismic recording of the Mw 8.2 Chiapas earthquake, Mexico, of 8 September 2017, followed by the Irma hurricane, and a volcano-seismic signal recorded at the Popocatepetl volcano showing a tremor followed by harmonic resonances. These examples illustrate how high-localization techniques improve analysis of the time frequency information of time-varying signals.This article is part of the theme issue 'Redundancy rules: the continuous wavelet transform comes of age'. PMID- 29986923 TI - Criminalised abortion in UK obstructs reflective choice and best care. PMID- 29986924 TI - 65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents. AB - As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today 'precision medicine': genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes, GNAS and RET, both identified in the late 1980s, contributed greatly in the understanding of cancer and its progression. The use of RET mutation testing for the management of medullary thyroid cancer was among the first and one of most successful applications of genetics in informing clinical decisions in an individualised manner, in this case by preventing cancer or guiding the choice of tyrosine kinase inhibitors in cancer treatment. New information emerges every day in the genetics or system biology of endocrine disorders. This review goes over most of these discoveries and the known endocrine tumour syndromes. We cover key genetic developments for each disease and provide information that can be used by the clinician in daily practice. PMID- 29986925 TI - Coordination Among Lipid Droplets, Peroxisomes, and Mitochondria Regulates Energy Expenditure Through the CIDE-ATGL-PPARalpha Pathway in Adipocytes. AB - Metabolic homeostasis is maintained by an interplay among tissues, organs, intracellular organelles, and molecules. Cidea and Cidec are lipid droplet (LD) associated proteins that promote lipid storage in brown adipose tissue (BAT) and white adipose tissue (WAT). Using ob/ob/Cidea-/- , ob/ob/Cidec-/- , and ob/ob/Cidea-/-/Cidec-/- mouse models and CIDE-deficient cells, we studied metabolic regulation during severe obesity to identify ways to maintain metabolic homeostasis and promote antiobesity effects. The phenotype of ob/ob/Cidea-/- mice was similar to that of ob/ob mice in terms of serum parameters, adipose tissues, lipid storage, and gene expression. Typical lipodystrophy accompanied by insulin resistance occurred in ob/ob/Cidec-/- mice, with ectopic storage of lipids in the BAT and liver. Interestingly, double deficiency of Cidea and Cidec activated both WAT and BAT to consume more energy and to increase insulin sensitivity compared with their behavior in the other three mouse models. Increased lipolysis, which occurred on the LD surfaces and released fatty acids, led to activated beta oxidation and oxidative phosphorylation in peroxisomes and mitochondria in CIDE deficient adipocytes. The coordination among LDs, peroxisomes, and mitochondria was regulated by adipocyte triglyceride lipase (ATGL)-peroxisome proliferator activated receptor alpha (PPARalpha). Double deficiency of Cidea and Cidec activated energy consumption in both WAT and BAT, which provided new insights into therapeutic approaches for obesity and diabetes. PMID- 29986927 TI - Fourteen new specialist treatments get routine NHS funding. PMID- 29986926 TI - Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. AB - Glucose metabolism stimulates cell division control protein 42 homolog (Cdc42) p21-activated kinase (Pak1) activity and initiates filamentous actin (F-actin) cytoskeleton remodeling in pancreatic beta-cells so that cytoplasmic secretory granules can translocate to the plasma membrane where insulin exocytosis occurs. Since glucose metabolism also generates cAMP in beta-cells, the cross talk of cAMP signaling with Cdc42-Pak1 activation might be of fundamental importance to glucose-stimulated insulin secretion (GSIS). Previously, the type-2 isoform of cAMP-regulated guanine nucleotide exchange factor 2 (Epac2) was established to mediate a potentiation of GSIS by cAMP-elevating agents. Here we report that nondiabetic human islets and INS-1 832/13 beta-cells treated with the selective Epac activator 8-pCPT-2'-O-Me-cAMP-AM exhibited Cdc42-Pak1 activation at 1 mmol/L glucose and that the magnitude of this effect was equivalent to that which was measured during stimulation with 20 mmol/L glucose in the absence of 8-pCPT-2'-O Me-cAMP-AM. Conversely, the cAMP antagonist Rp-8-Br-cAMPS-pAB prevented glucose stimulated Cdc42-Pak1 activation, thereby blocking GSIS while also increasing cellular F-actin content. Although islets from donors with type 2 diabetes had profound defects in glucose-stimulated Cdc42-Pak1 activation and insulin secretion, these defects were rescued by the Epac activator so that GSIS was restored. Collectively, these findings indicate an unexpected role for cAMP as a permissive or direct metabolic coupling factor in support of GSIS that is Epac2 and Cdc42-Pak1 regulated. PMID- 29986928 TI - Absence of a Transcranial Magnetic Stimulation-Induced Lower Limb Corticomotor Response Does Not Affect Walking Speed in Chronic Stroke Survivors. AB - Background and Purpose- Transcranial magnetic stimulation is used to measure the functional integrity of the corticomotor system via motor evoked potentials (MEPs) in stroke. The association between corticomotor mechanisms and walking recovery is still not completely understood. This study determined the association between transcranial magnetic stimulation-induced MEPs and walking outcomes and examined the contribution of the contralesional hemisphere to walking recovery. Methods- Contralateral and ipsilateral transcranial magnetic stimulation responses from the contralesional and ipsilesional hemispheres were collected from 61 chronic stroke survivors. Clinical assessments included gait speeds, 6-minute walk distance, Timed Up and Go test, Fugl Meyer lower extremity scale, and strength measurements. Results- Stroke participants were classified based on the presence (MEP+ [n=28]) or absence (MEP- [n=33]) of MEPs in the paretic tibialis anterior and rectus femoris muscles. A between-group analyses showed no significant differences for any gait variable. MEP+ group showed significantly higher Fugl Meyer lower extremity and ankle dorsiflexor strength. Ipsilateral conductivity was not significantly different between groups. Finally, in the MEP+ group, MEP parameters did not predict gait recovery. Conclusions- Our study investigated the association between walking outcomes and neurophysiological parameters of lower limb function in a large cohort of stroke survivors. We did not find an associations between transcranial magnetic stimulation-induced tibialis anterior and rectus femoris MEPs and walking speeds. Further work is required to develop more comprehensive models in stroke for predicting walking recovery. PMID- 29986929 TI - Magnetic Resonance Imaging-Based Cerebrovascular Reactivity and Hemodynamic Reserve. PMID- 29986930 TI - Association of Low Lysosomal Enzymes Activity With Brain Arterial Dilatation. AB - Background and Purpose- Absent or diminished alpha-galactosidase A (GLA) and acid alpha-glucosidase (GAA) enzyme activity are core features of Fabry and Pompe disease, respectively. Patients with Fabry or Pompe disease may have dilated intracranial arteries but whether lower GLA or GAA enzyme activity relates to brain arterial dilatation in other populations is unknown. Methods- Participants included Parkinson disease patients and nonblood-related controls, whose GLA and GAA enzymatic activities were measured in dried blood spots. Independent readers measured the axial arterial diameter of the ascending portion of the cavernous internal carotid arteries and the most proximal segment of the basilar artery in T2 black voids. Linear regression models were built to investigate the relationship between brain arterial diameters and lysosomal enzymatic activities. Results- The cohort included 107 participants (mean age, 66.5+/-10.3; 67% men). In an adjusted linear regression model, lower GLA activity was associated with larger brain arterial diameters (B=0.50+/-0.23, P=0.03). The strength of association was the greatest for the basilar artery diameter (B=0.80+/-0.33, P=0.02). Similarly, lower GAA activity was associated with an increased basilar arterial diameter (B=0.73+/-0.35, P=0.04). Conclusions- Lower GLA and GAA enzymatic activities were associated with larger brain arterial diameters, particularly the basilar artery diameter. Lower lysosomal enzymatic function in patients without Fabry or Pompe disease may play a role in brain arterial dilatation. PMID- 29986931 TI - Cortical Microinfarcts on 3T Magnetic Resonance Imaging in Cerebral Amyloid Angiopathy. AB - Background and Purpose- Cerebral microinfarcts are small ischemic lesions that are found in cerebral amyloid angiopathy (CAA) patients at autopsy. The current study aimed to detect cortical microinfarcts (CMI) on in vivo 3 Tesla (3T) magnetic resonance imaging (MRI) in CAA patients, to study the progression of CMI over a 1-year period, and to correlate CMI with markers of CAA-related vascular brain injury and cognitive functioning. Methods- Thirty-five CAA patients (mean age, 74.2+/-7.6 years), 13 Alzheimer disease (AD) patients (67.0+/-5.8 years), and 26 healthy controls (67.2+/-9.5 years) participated in the study. All participants underwent a standardized clinical and neuropsychological assessment as well as 3T MRI. CMI were rated according to standardized criteria. Results- CMI were present in significantly more CAA patients (57.1%; median number: 1, range 1-9) than in Alzheimer disease (7.7%) or in healthy controls (11.5%; P<0.001). Incident CMI were observed after a 1-year follow-up. CMI did not correlate with any other MRI marker of CAA nor with cognitive function. Conclusions- In vivo CMI are a frequent finding on 3T MRI in CAA patients, and incident CMI are observable after 1-year follow-up. CMI can be regarded as a new MRI marker of CAA, potentially distinct from other well-established markers. Future larger cohort studies with longitudinal follow-up are needed to elucidate the relationship between CMI and possible causes and clinical outcomes in CAA. PMID- 29986932 TI - Rates and Quality of Preinterventional Reperfusion in Patients With Direct Access to Endovascular Treatment. AB - Background and Purpose- Preinterventional reperfusion before endovascular treatment (ET) is a benefit of bridging with intravenous tPA (tissue-type plasminogen activator). However, detailed data on reperfusion quality and rates of obviating ET in a cohort of patients with immediate access to ET is lacking. Purpose of this analysis was to evaluate prevalence and quality of preinterventional reperfusion in mothership patients. Methods- All mothership patients (n=627) from a prospective registry subjected to angiography with an intention to perform ET were reviewed. Preinterventional change of occlusion site (COS) was categorized into COS with Thrombolysis in Cerebral Infarction (TICI) 0/1, COS with TICI >=2a, COS with TICI >=2b, and COS with perfusion worsening. Predictors and clinical relevance were evaluated using multivariable logistic regression and results are displayed as adjusted odds ratios (aOR) and corresponding 95% confidence intervals (95% CI). Results- Prevalence of COS in all patients was 10.7% (95% CI, 8.3%-13.1%), subdividing into 2.7% COS with TICI 0/1, 6.2% COS with >=TICI 2a (including 2.9% with TICI >=2b), and 1.8% COS with perfusion worsening. Factors related to COS with >=TICI 2a were intravenous tPA (aOR, 11.98; 95% CI, 4.5-31.6), cardiogenic thrombus origin (aOR, 2.3; 95% CI, 1.1-4.6), and thrombus length (aOR per 1 mm increase 0.926; 95% CI, 0.87-0.99). Additional ET was performed despite COS with >=TICI 2a in 51.3%. COS with >=TICI 2a showed a tendency for favorable outcomes (modified Rankin Scale, <=2; aOR, 2.65; 95% CI, 0.98-7.17). Rates of COS with >=TICI 2a were particularly low in internal carotid artery and proximal M1 occlusions (2.2%; 95% CI, 0.9%-5%), where intravenous tPA was associated with perfusion worsening (aOR, 4.33; 95% CI, 1.12 16.80). Conclusions- Prevalence of preinterventional reperfusion is non negligible in patients with direct access to ET and is clearly favored by intravenous tPA treatment. However, it is often incomplete and often requires additional ET. Preinterventional reperfusion of internal carotid artery and proximal M1 occlusions is rare and usually of low quality, where intravenous tPA may also promote perfusion worsening. PMID- 29986933 TI - Why Are Only Some Subcortical Ischemic Lesions on Diffusion Magnetic Resonance Imaging Associated With Stroke Symptoms in Small Vessel Disease? AB - Background and Purpose- In cerebral small vessel diseases, small subcortical ischemic lesions (SSIL) on diffusion imaging are responsible for stroke manifestations but can also be occasionally observed in the absence of overt neurological symptoms. We aimed to determine, in a large cohort of young patients with CADASIL (Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy), a severe monogenic condition leading to SSIL in young patients, the characteristics of SSIL and of surrounding cerebral tissue associated with the presence of stroke symptoms. Methods- Among a cohort of 323 genetically confirmed CADASIL patients who were systematically evaluated every 18 months clinically and with magnetic resonance imaging, we studied all visible SSIL and documented ischemic stroke events with available magnetic resonance imaging data. We used mixed-effect logistic regression models to determine whether the presence of stroke symptoms was associated with age, sex, the volume of SSIL, their location with respect to preexisting white matter hyperintensities and with the load of the different magnetic resonance imaging markers of small vessel disease. Results- We identified 73 SSIL (30 with stroke symptoms and 43 without) in 55 patients. In multivariable models, stroke symptoms were more frequent in male patients (estimate=1.94; SE=0.82; P=0.03) and less frequent when SSIL appeared in contact to preexisting white matter hyperintensities (estimate= 2.12; SE=0.83; P=0.01). Within pyramidal tracts, stroke symptoms were more frequent in patients with extensive white matter hyperintensities (estimate=3.8*10-5; SE=9.3*10-6; P<10-4). Conclusions- Altogether, our results suggest that when SSIL occur, the presence of stroke symptoms may depend on sex and alterations of the surrounding brain tissue rather than on the characteristics of the SSIL itself. PMID- 29986934 TI - Ultraearly Intravenous Thrombolysis for Acute Ischemic Stroke in Mobile Stroke Unit and Hospital Settings. AB - Background and Purpose- Mobile stroke units (MSUs) are known to increase the proportion of acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) in the first golden hour (GH) after onset compared with hospital settings (HS). However, because of the low number of AIS patients treated with intravenous thrombolysis within this ultraearly time window in conventional care, characteristics, and outcome of this subgroup of AIS patients have not been compared between MSU and HS. Methods- MSU-GH patients were selected from the Berlin-based MSU (STEMO [Stroke Emergency Mobile]), whereas HS-GH patients were selected from the SITS-EAST (Safe Implementation of Treatments in Stroke-East) registry. The outcome events of interest included the rates of favorable functional outcome (modified Rankin Scale scores of 0 or 1), distribution of the modified Rankin Scale scores, and mortality after 3 months between MSU-GH and HS-GH groups. Results- We identified 117 MSU-GH (38.4% of 305 MSU-treated patients) and 136 HS-GH (0.9% of 15 591 HS-treated patients) eligible patients without prestroke disability. No significant differences were documented in the rates of favorable functional outcome (51.3% versus 46.2%, P=0.487) and mortality (7.7% versus 9.9%, P=0.576) at 3 months, or in the distribution of 3 month modified Rankin Scale scores between the 2 groups ( P=0.196). In multivariable logistic regression analyses, adjusting for potential confounders, MSU treatment was not associated with a significantly different likelihood of favorable functional outcome (odds ratio, 1.84 for MSU patients; 95% CI, 0.86 3.96) or mortality (odds ratio, 0.95; 95% CI, 0.28-3.20) at 3 months. Conclusions There is no evidence that safety and efficacy of ultraearly intravenous thrombolysis for AIS differs when used in MSUs or in HS. PMID- 29986935 TI - Endovascular Treatment in the DEFUSE 3 Study. AB - Background and Purpose- Endovascular therapy in an extended time window has been shown to be beneficial in selected patients. This study correlated angiographic outcomes of patients randomized to endovascular therapy with clinical and imaging outcomes in the DEFUSE 3 study (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3). Methods- Angiograms were assessed for the primary arterial occlusive lesion and the modified Thrombolysis in Cerebral Infarction (TICI) score at baseline and the final modified TICI score. Clinical outcomes were assessed using an ordinal analysis of 90-day modified Rankin Scale and a dichotomous analysis for functional independence (modified Rankin Scale score of 0-2). TICI scores were correlated with outcome, types of device used for thrombectomy, and 24-hour follow-up imaging. Results- TICI 2B-3 reperfusion was achieved in 70 of 92 patients (76%). TICI 2B-3 reperfusion showed a more favorable distribution of Rankin scores compared with TICI 0-2A; odds ratio, 2.77; 95% confidence interval, 1.17-6.56; P=0.019. Good functional outcome (90 day modified Rankin Scale score of 0-2) increased with better TICI scores ( P=0.0028). There was less disability comparing TICI 3 patients to TICI 2B patients ( P=0.037). Successful reperfusion (TICI 2B-3) was independent of the device used, the site of occlusion (internal carotid artery or M1) or adjunctive use of carotid angioplasty and stenting. Significantly less infarct growth at 24 hours was seen in TICI 3 patients compared with TICI 0-2A ( P=0.0015) and TICI 2B ( P=0.0002) patients. Conclusions- Thrombectomy in an extended time window demonstrates similar rates of TICI 2B-3 reperfusion to earlier time window studies. Successful reperfusion was independent of the device used, the site of occlusion or adjunctive use of carotid angioplasty and stenting. TICI 3 reperfusion was more likely to result in low rates of infarct growth at 24 hours and good functional outcome at 90 days. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02586415. PMID- 29986936 TI - Treatment and Long-Term Outcomes of Primary Central Nervous System Vasculitis. AB - Background and Purpose- We aimed to analyze the long-term outcomes of patients with primary central nervous system vasculitis according to the different therapeutic strategies used to induce remission. Methods- We assessed the rate of prolonged remission (defined by the absence of relapse at >=12 months after diagnosis) and the functional status at last follow-up in patients with primary central nervous system vasculitis included in the French cohort, who achieved a first remission according to the 3 main groups of treatments administered: glucocorticoids only (group 1); induction treatment with glucocorticoids and an immunosuppressant, but no maintenance (group 2); and combined treatment with glucocorticoids and an immunosuppressant for induction followed by maintenance therapy (group 3). Good functional status was defined as a modified Rankin Scale score <=2 at the last follow-up. Results- Remission was achieved with the initial induction treatment in 106 (95%) of the 112. Prolonged remission without relapse was observed in 70 (66%) patients after 57 (12-198) months of follow-up. A good functional status at last follow-up (ie, modified Rankin Scale score <=2) was observed in 63 (56%) patients. Overall mortality was 8%. The initial severity and the radiological presentations were comparable in the 3 treatment groups. More prolonged remissions ( P=0.003) and a better functional status at the last follow up ( P=0.0004) were observed in group 3. In multivariate analysis, the use of maintenance therapy was associated with prolonged remission (odds ratio, 4.32 [1.67-12.19]; P=0.002) and better functional status (odds ratio, 8.09 [3.24 22.38]; P<0.0001). Conclusions- This study suggests that maintenance therapy with an immunosuppressant combined with glucocorticoids lead to the best long-term clinical and functional outcomes in patients with primary central nervous system vasculitis after having achieved remission with either glucocorticoids alone or in combination with another immunosuppressant. PMID- 29986937 TI - Specialized ribosomes and the control of translation. AB - The control of translation is increasingly recognized as a major factor in determining protein levels in the cell. The ribosome - the cellular machine that mediates protein synthesis - is typically seen as a key, but invariant, player in this process. This is because translational control is thought to be mediated by other auxiliary factors while ribosome recruitment is seen as the end-point of regulation. However, recent developments have made it clear that heterogeneous ribosome types can exist in different tissues, and more importantly, that these ribosomes can preferentially translate different subsets of mRNAs. In so doing, heterogeneous ribosomes could be key regulatory players in differentiation and development. Here, we examine current evidence for the existence of different ribosome types and how they might arise. In particular, we will take a close look at the mechanisms through which these ribosomes might mediate selective mRNA translation. We also summarize recently developed techniques/approaches that will aid in our understanding of the functions of such specialized ribosomes. PMID- 29986938 TI - Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention. AB - Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Abeta, tau, alpha-synuclein and TDP-43 leads to a toxin gain- or loss-of function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin-proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies. PMID- 29986940 TI - Expression of Adhesive Pili and the Collagen-Binding Adhesin Ace Is Activated by ArgR Family Transcription Factors in Enterococcus faecalis. AB - It was shown previously that the disruption of the ahrC gene encoding a predicted ArgR family transcription factor results in a severe defect in biofilm formation in vitro, as well as a significant attenuation of virulence of Enterococcus faecalis strain OG1RF in multiple experimental infection models. Using transcriptome sequencing (RNA-seq), we observed ahrC-dependent changes in the expression of more than 20 genes. AhrC-repressed genes included predicted determinants of arginine catabolism and several other metabolic genes and predicted transporters, while AhrC-activated genes included determinants involved in the production of surface protein adhesins. Most notably, the structural and regulatory genes of the ebp locus encoding adhesive pili were positively regulated, as well as the ace gene, encoding a collagen-binding adhesin. Using lacZ transcription reporter fusions, we determined that ahrC and a second argR transcription factor gene, argR2, both function to activate the expression of ebpR, which directly activates the transcription of the pilus structural genes. Our data suggest that in the wild-type E. faecalis, the low levels of EbpR limit the expression of pili and that biofilm biomass is also limited by the amount of pili expressed by the bacteria. The expression of ace is similarly enhanced by AhrC and ArgR2, but ace expression is not dependent on EbpR. Our results demonstrate the existence of novel regulatory cascades controlled by a pair of ArgR family transcription factors that might function as a heteromeric protein complex.IMPORTANCE Cell surface adhesins play critical roles in the formation of biofilms, host colonization, and the pathogenesis of opportunistic infections by Enterococcus faecalis Here, we present new results showing that the expression of two major enterococcal surface adhesins, ebp pili, and the collagen-binding protein Ace is positively regulated at the transcription level by two argR family transcription factors, AhrC and ArgR2. In the case of pili, the direct target of regulation is the ebpR gene, previously shown to activate the transcription of the pilus structural genes, while the activation of ace transcription appears to be directly impacted by the two ArgR proteins. These transcription factors may represent new targets for blocking enterococcal infections. PMID- 29986939 TI - MSC exosome works through a protein-based mechanism of action. AB - Mesenchymal stem cell (MSC) exosome specifically defines the 50-200 nm vesicles that are secreted into the extracellular space when multivesicular bodies in the MSC fuse with the plasma membrane. However, the exosome is just one of several 50 200 nm extracellular vesicles (EVs) known to be secreted by cells. Nevertheless, the term 'MSC exosome' is often used to describe populations of 50-200 nm EVs that are prepared from culture medium conditioned by MSCs on the basis that these populations collectively exhibited typical exosome-associated proteins such as endosomal proteins, TSG101 and Alix, and tetraspanin proteins, CD9, CD63 and CD81. They also carry a rich diverse RNA cargo. MSC exosomes are increasingly implicated as the mediator of many of the MSC-associated therapeutic potencies. They elicit therapeutic activity by delivering their cargo of potentially therapeutic proteins and RNAs to the recipient cells. The therapeutic potency of MSC exosomes is usually rationalized on the presence of a biologically relevant protein or RNA in the MSC exosome. In the present paper, we expanded this rationale beyond a physical presence to include biologically relevant concentration, biochemical functionality and the potential to elicit an appropriate timely biochemical response. Based on these, we propose that MSC exosomes most probably work through the protein rather than the RNA. PMID- 29986941 TI - Characteristics of the Conjugative Transfer System of the IncM Plasmid pCTX-M3 and Identification of Its Putative Regulators. AB - Plasmid conjugative transfer systems comprise type IV secretion systems (T4SS) coupled to DNA processing and replication. The T4SSs are divided into two phylogenetic subfamilies, namely, IVA and IVB, or on the basis of the phylogeny of the VirB4 ATPase, into eight groups. The conjugation system of the IncM group plasmid pCTX-M3, from Citrobacter freundii, is classified in the IVB subfamily and in the MPFI group, as are the conjugation systems of IncI1 group plasmids. Although the majority of the conjugative genes of the IncM and IncI1 plasmids display conserved synteny, there are several differences. Here, we present a deletion analysis of 27 genes in the conjugative transfer regions of pCTX-M3. Notably, the deletion of either of two genes dispensable for conjugative transfer, namely, orf35 and orf36, resulted in an increased plasmid mobilization efficiency. Transcriptional analysis of the orf35 and orf36 deletion mutants suggested an involvement of these genes in regulating the expression of conjugative transfer genes. We also revised the host range of the pCTX-M3 replicon by finding that this replicon is unable to support replication in Agrobacterium tumefaciens, Ralstonia eutropha, and Pseudomonas putida, though its conjugation system is capable of introducing plasmids bearing oriTpCTX-M3 into these bacteria, which are representatives of Alpha-, Beta-, and Gammaproteobacteria, respectively. Thus, the conjugative transfer system of pCTX M3 has a much broader host range than its replicon.IMPORTANCE Horizontal gene transfer is responsible for rapid changes in bacterial genomes, and the conjugative transfer of plasmids has a great impact on the plasticity of bacteria. Here, we present a deletion analysis of the conjugative transfer system genes of the pCTX-M3 plasmid of the IncM group, which is responsible for the dissemination of antibiotic resistance genes in Enterobacteriaceae We found that the deletion of either of the orf35 and orf36 genes, which are dispensable for conjugative transfer, increased the plasmid mobilization efficiency. Real-time quantitative PCR (RT-qPCR) analysis suggested the involvement of orf35 and orf36 in regulating the expression of transfer genes. We also revised the host range of pCTX-M3 by showing that its conjugative transfer system has a much broader host range than its replicon. PMID- 29986942 TI - The Treponema denticola PAS Domain-Containing Histidine Kinase Hpk2 Is a Heme Binding Sensor of Oxygen Levels. AB - Periodontal disease (PD) results from a shift in the composition of the microbial community of the subgingival crevice. As the bacterial population transitions from Gram-positive bacteria to predominantly Gram-negative anaerobes and spirochetes, dramatic changes occur in the physiological and immunological environment at diseased sites. Treponema denticola thrives in periodontal pockets, indicating that it has a unique ability to adapt to changing environmental conditions. Hpk2 (tde1970), a Per-Arnt-Sim motif (PAS) domain containing histidine kinase (HK), is part of the T. denticola Hpk2-Rrp2 (tde1969) two-component regulatory (TCR) system. This TCR system is growth phase regulated and has been postulated to play a key role in adaptive responses. In this study, we employ predictive structural analyses and site-directed mutagenesis to investigate the functional role of specific amino acid residues located within the Hpk2 PAS domain. Specific substitutions impacted autophosphorylation (AP), phosphotransfer (PT), oligomerization, and hemin binding. The AP, PT, hemin binding, and oligomerization potential of some mutated Hpk2 proteins differed under aerobic versus anaerobic reaction conditions. The data presented here suggest that the regulatory activity of Hpk2 is linked to diatomic gas levels. In a broader sense, this study highlights the importance of studying proteins produced by anaerobes under conditions that approximate the environment in which they thrive.IMPORTANCE Periodontal disease affects nearly 60% of the global adult population. Its costs to individuals, and to society as a whole, are enormous. As periodontal disease develops, there is a shift in the composition of the oral microbial community. The bacteria that become dominant are able to cause significant damage to the tissues that support the teeth, leading to tooth loss. Treponema denticola is one of the keystone pathogens associated with periodontal disease. An earlier study demonstrated that the Hpk2 and Rrp2 proteins play an important role in adaptive responses. Here, we explore the role of specific Hpk2 amino acids in environmental sensing and function, using structural analyses and site-directed mutagenesis. PMID- 29986943 TI - The Mla Pathway Plays an Essential Role in the Intrinsic Resistance of Burkholderia cepacia Complex Species to Antimicrobials and Host Innate Components. AB - Antibiotic resistance is a threat to our modern society, and new strategies leading to the identification of new molecules or targets to combat multidrug resistant pathogens are needed. Species of the genus Burkholderia, including the Burkholderia cepacia complex (Bcc), Burkholderia pseudomallei, and Burkholderia mallei, can be highly pathogenic and are intrinsically resistant to multiple classes of antibiotics. Bcc species are nonetheless sensitive to extracellular products released by Pseudomonas aeruginosa in interspecies competition. We screened for Burkholderia transposon mutants with increased sensitivity to P. aeruginosa spent medium and identified multiple mutants in genes sharing homology with the Mla pathway. Insertional mutants in representative genes of the Bcc Mla pathway had a compromised cell membrane and were more sensitive to various extracellular stresses, including antibiotics and human serum. More precisely, mla mutants in the Bcc species Burkholderia cenocepacia and Burkholderia dolosa were more susceptible to Gram-positive antibiotics (i.e., macrolides and rifampin), fluoroquinolones, tetracyclines, and chloramphenicol. Genetic complementation of mlaC insertional mutants restored cell permeability and resistance to Gram-positive antibiotics. Importantly, Bcc mla mutants were not universally weaker strains since their susceptibilities to other classes of antibiotics were unaffected. Although cell permeability of homologous mla mutants in Escherichia coli or P. aeruginosa was also impaired, they were not more sensitive to Gram-positive antibiotics or other antimicrobials as was observed in Bcc mla mutants. Together, the data suggest that the Mla pathway in Burkholderia may play a different biological role, which could potentially represent a Burkholderia-specific drug target in combination therapy with antibiotic adjuvants.IMPORTANCE The outer membrane of Gram-negative bacteria acts as an effective barrier against toxic compounds, and therefore compromising this structure could increase sensitivity to currently available antibiotics. In this study, we show that the Mla pathway, a system involved in maintaining the integrity of the outer membrane, is genetically and functionally different in Burkholderia cepacia complex species compared to that in other proteobacteria. Mutants in mla genes of Burkholderia cenocepacia or Burkholderia dolosa were sensitive to Gram-positive antibiotics, while this effect was not observed in Escherichia coli or Pseudomonas aeruginosa The Mla pathway in Burkholderia species may represent an ideal genus-specific target to address their intrinsic antimicrobial resistances. PMID- 29986944 TI - A Defective Undecaprenyl Pyrophosphate Synthase Induces Growth and Morphological Defects That Are Suppressed by Mutations in the Isoprenoid Pathway of Escherichia coli. AB - The peptidoglycan exoskeleton shapes bacteria and protects them against osmotic forces, making its synthesis the target of many current antibiotics. Peptidoglycan precursors are attached to a lipid carrier and flipped from the cytoplasm into the periplasm to be incorporated into the cell wall. In Escherichia coli, this carrier is undecaprenyl phosphate (Und-P), which is synthesized as a diphosphate by the enzyme undecaprenyl pyrophosphate synthase (UppS). E. coli MG1655 exhibits wild-type morphology at all temperatures, but one of our laboratory strains (CS109) was highly aberrant when grown at 42 degrees C. This strain contained mutations affecting the Und-P synthetic pathway genes uppS, ispH, and idi Normal morphology was restored by overexpressing uppS or by replacing the mutant (uppS31) with the wild-type allele. Importantly, moving uppS31 into MG1655 was lethal even at 30 degrees C, indicating that the altered enzyme was highly deleterious, but growth was restored by adding the CS109 versions of ispH and idi Purified UppSW31R was enzymatically defective at all temperatures, suggesting that it could not supply enough Und-P during rapid growth unless suppressor mutations were present. We conclude that cell wall synthesis is profoundly sensitive to changes in the pool of polyisoprenoids and that isoprenoid homeostasis exerts a particularly strong evolutionary pressure.IMPORTANCE Bacterial morphology is determined primarily by the overall structure of the semirigid macromolecule peptidoglycan. Not only does peptidoglycan contribute to cell shape, but it also protects cells against lysis caused by excess osmotic pressure. Because it is critical for bacterial survival, it is no surprise that many antibiotics target peptidoglycan biosynthesis. However, important gaps remain in our understanding about how this process is affected by peptidoglycan precursor availability. Here, we report that a mutation altering the enzyme that synthesizes Und-P prevents cells from growing at high temperatures and that compensatory mutations in enzymes functioning upstream of uppS can reverse this phenotype. The results highlight the importance of Und-P metabolism for maintaining normal cell wall synthesis and shape. PMID- 29986945 TI - Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells. AB - RATIONALE: Human-induced pluripotent stem cell-derived endothelial cells (iPSC ECs) have risen as a useful tool in cardiovascular research, offering a wide gamut of translational and clinical applications. However, inefficiency of the currently available iPSC-EC differentiation protocol and underlying heterogeneity of derived iPSC-ECs remain as major limitations of iPSC-EC technology. OBJECTIVE: Here, we performed droplet-based single-cell RNA sequencing (scRNA-seq) of the human iPSCs after iPSC-EC differentiation. Droplet-based scRNA-seq enables analysis of thousands of cells in parallel, allowing comprehensive analysis of transcriptional heterogeneity. METHODS AND RESULTS: Bona fide iPSC-EC cluster was identified by scRNA-seq, which expressed high levels of endothelial-specific genes. iPSC-ECs, sorted by CD144 antibody-conjugated magnetic sorting, exhibited standard endothelial morphology and function including tube formation, response to inflammatory signals, and production of NO. Nonendothelial cell populations resulting from the differentiation protocol were identified, which included immature cardiomyocytes, hepatic-like cells, and vascular smooth muscle cells. Furthermore, scRNA-seq analysis of purified iPSC-ECs revealed transcriptional heterogeneity with 4 major subpopulations, marked by robust enrichment of CLDN5, APLNR, GJA5, and ESM1 genes, respectively. CONCLUSIONS: Massively parallel, droplet-based scRNA-seq allowed meticulous analysis of thousands of human iPSCs subjected to iPSC-EC differentiation. Results showed inefficiency of the differentiation technique, which can be improved with further studies based on identification of molecular signatures that inhibit expansion of nonendothelial cell types. Subtypes of bona fide human iPSC-ECs were also identified, allowing us to sort for iPSC-ECs with specific biological function and identity. PMID- 29986946 TI - Compared performance of Spot and SW800 photoscreeners on Chinese children. AB - PURPOSE: To evaluate the effectiveness of Spot photoscreener and SW800 vision screener in detecting amblyopia risk factors in Chinese children between 4 and 6 years of age. METHODS: One hundred and thirteen children (226 eyes) underwent complete ophthalmologic examination, cycloplegic retinoscopy refraction, prism cover tests and photoscreen using both Spot (v2.1.4) and SW800 (v1.0.1.0) photoscreeners. The agreement of results obtained from photoscreener and retinoscopy was evaluated by paired t-test as well as Pearson correlation test. The sensitivity and specificity of detecting amblyopia risk factors were calculated based on the American Association of Pediatric Ophthalmology and Strabismus 2013 guidelines. The overall effectiveness of detecting amblyopia risk factors by using either photoscreener was analysed by receiver operating characteristic (ROC) curves. RESULTS: A strong linear agreement was observed between Spot and retinoscopy (p<0.01) in aspects of spherical equivalent (SE, Pearson's r=0.95), dioptre sphere (DS, r=0.97), dioptre cylinder (DC, r=0.84) and horizontal deviation (Hdev, r=0.91), with overall -0.17 D myopic shift of SE. Significant correlation was also shown between SW800 and retinoscopy (p<0.01) in aspects of SE (r=0.90), DS (r=0.93), DC (r=0.82) and Hdev (r=0.80), with overall 0.12 D myopic shift of SE. The overall sensitivity and specificity in detecting amblyopia risk factors were 94.0% and 80.0% for Spot and 88.8% and 81.1% for SW800. CONCLUSION: The measurements of Spot and SW800 photoscreener showed a strong agreement with cycloplegic retinoscopy refraction and prism cover tests. The performance of both screeners in detecting individual amblyopia risk factors is satisfactory. ROC analysis indicates that the Spot and SW800 performed very similarly in detecting amblyopia risk factors. PMID- 29986947 TI - Electrophysiological Characteristics of Bundle Branch Reentry Ventricular Tachycardia in Patients Without Structural Heart Disease. AB - BACKGROUND: The distinct electrophysiological features of bundle branch reentry ventricular tachycardia (VT) in patients without structural heart disease have not been systemically characterized. METHODS: Nine patients (mean age, 29.6 years) with normal left ventricular function were enrolled. Bundle branch reentry VT with right and left bundle branch block (BBB) patterns was induced in 1 and 9 patients, respectively. The right bundle was attempted to record by a 6F decapolar or quadripolar catheter. Electroanatomic mapping of the left ventricle was performed in 6 patients. In all left BBB pattern VT, the mean VT cycle length was 329.3+/-89.1 ms, and the median HV interval during tachycardia was longer than that of baseline (78 [73-100] versus 71 [64.5-88] ms; P=0.11). RESULTS: The H-RB interval during VT was slightly shorter (P=0.14); however, the median RB-V interval was markedly longer than that during sinus rhythm (50 [29.5-83] versus 30 [8-51] ms; P=0.043]. In 6 patients with 3-dimensional mapping of the left ventricle, a slow anterograde or retrograde conduction over left HIS-Purkinje system with normal myocardial voltage was identified. In addition, Purkinje related VTs (1.0+/-1.3 types) were also induced in 5 patients. Ablation was applied in distal left BB in patients with baseline left BBB and in one narrow QRS patient with sustained Purkinje-related VT, whereas right BB was targeted in other patients. During a mean follow-up of 31.4 months, frequent premature ventricular contractions occurred in one patient, and new VT developed in the other patient. CONCLUSIONS: Bundle branch reentry VT can occur in young patients with extensive conduction disturbances within HIS-Purkinje system. Ablation targeting at the distal left BB which bifurcates into left posterior and anterior fascicle can preserve the residual atrioventricular conduction, but intensive follow-up is needed. PMID- 29986948 TI - Letter by Schuster Regarding Article, "Outcomes and Management of Patients With Severe Pulmonary Vein Stenosis From Prior Atrial Fibrillation Ablation". PMID- 29986949 TI - Slow and Unsteady in the Fast Lane. PMID- 29986950 TI - Efavirenz and Lopinavir Levels in HIV-Infected Women and Their Nursing Infants, in Mali. AB - Limited data are currently available on antiretroviral pharmacokinetics in breast milk (BM) and in breastfed infants' blood. To explore these parameters in patients in Mali, we measured plasma antiretroviral levels in human immunodeficiency virus (HIV)-infected mothers and their breastfed infants over 6 months. We specifically analyzed the concentrations of efavirenz (EFV) and lopinavir (LPV) in the plasma of mothers living with HIV and their breastfed infants. Blood samples were collected at delivery and at month 1, 3, and 6 postpartum. EFV and LPV concentrations were measured by liquid chromatography tandem mass spectrometry. HIV-1 RNA load was measured by Abbott M2000RT RealTime System at delivery and 6 months postpartum for mothers, and at 3 and 6 months postbirth for infants. The median duration of antiretroviral therapy at study inclusion was 57 months [interquartile range (IQR), 0-168 months]. The median EFV ratios of infant plasma/maternal plasma (MP) were 0.057 at month 1, 0.072 at month 3, and 0.048 at month 6. During the study period, the median BM/MP ratio of EFV was 1.16 (IQR, 0.96-20.62), which corresponds to a relative infant dose of 2.46% of the recommended weight-adjusted pediatric EFV dose at month 6. The apparent infant clearance of EFV was 0.146 l/h per kilogram at month 6. The LPV concentrations in the plasma of all infants were undetectable. No drug-related adverse reaction or toxicity was observed in any of the infants. The two women who presented a viral load of >50 copies/ml at month 6 had undetectable plasma drug concentrations at the same period. This study showed that breastfed infants received a low level of EFV but not LPV from their treated mothers. PMID- 29986951 TI - NYX-2925 Is a Novel N-Methyl-d-Aspartate Receptor Modulator that Induces Rapid and Long-Lasting Analgesia in Rat Models of Neuropathic Pain. AB - NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2 yl)butanamide] is a novel N-methyl-d-aspartate (NMDA) receptor modulator that is currently being investigated in phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies demonstrated that NYX-2925 is a member of a novel class of NMDA receptor-specific modulators that affect synaptic plasticity processes associated with learning and memory. Studies here examined NYX-2925 administration in rat peripheral chronic constriction nerve injury (CCI) and streptozotocin-induced diabetic mechanical hypersensitivity. Additionally, NYX-2925 was examined in formalin-induced persistent pain model and the tail flick test of acute nociception. Oral administration of NYX-2925 resulted in rapid and long-lasting analgesia in both of the neuropathic pain models and formalin-induced persistent pain, but was ineffective in the tail flick model. The analgesic effects of NYX-2925 were blocked by the systemic administration of NMDA receptor antagonist 3-(2 carboxypiperazin-4-yl)propyl-1-phosphonic acid. Microinjection of NYX-2925 into the medial prefrontal cortex of CCI rats resulted in analgesic effects similar to those observed following systemic administration, whereas intrathecal administration of NYX-2925 was ineffective. In CCI animals, NYX-2925 administration reversed deficits seen in a rat model of rough-and-tumble play. Thus, it appears that NYX-2925 may have therapeutic potential for the treatment of neuropathic pain, and the data presented here support the idea that NYX-2925 may act centrally to ameliorate pain and modulate negative affective states associated with chronic neuropathic pain. PMID- 29986952 TI - Salivary cotinine concentration and carbon monoxide levels in young adults smoking midwakh in comparison with cigarette smokers. AB - OBJECTIVES: To estimate and compare the salivary cotinine levels using a semiquantitative method, called NicAlert, between three groups: non-smokers, daily smokers of cigarettes and daily smokers of midwakh, and to compare the carbon monoxide (CO) levels among these groups. MATERIALS AND METHODS: A total of 159 adult male volunteers aged 20 and above were included, with 54 current cigarette smokers, 52 current midwakh smokers and 53 non-smokers. Estimate of breath carbon monoxide and salivary cotinine were collected, as well as sociodemographic characteristics and details of smoking habits and second-hand smoke exposure among participants. Institutional review board approval was obtained and data were analysed using SPSS V.21 with the Kruskal-Wallis test used to obtain differences in the distribution. RESULTS: There was no significant difference in the median breath CO and salivary cotinine levels between cigarette and midwakh smokers. Levels of breath CO were significantly higher in cigarette and midwakh smokers as compared with non-smokers (19.5, 17.5 and 6.0, respectively, p<0.05); the same relationship was observed for cotinine levels among cigarette and midwakh smokers as compared with non-smokers (4.0, 3.0 and 0.0, respectively, p<=0.05). Additionally, the values of both salivary cotinine and breath CO increased with the frequency of tobacco use. CONCLUSION: These are the first data that we are aware of that demonstrate that in terms of at least two key biomarkers of tobacco use, there are comparable levels of exposure between cigarettes and midwakh users, demonstrating a need for intensified attention to the use of midwakh. PMID- 29986953 TI - Aggressive and malignant pituitary tumours: state-of-the-art. AB - Pituitary adenomas are unique in multiple ways. They are rarely malignant in terms of metastases, yet they may be aggressive. Their cancerous potential is defined in a classic oncological way by the ability to metastasise, and therefore it has been crucial to differentiate this process from aggressive behaviour, characterised as a particularly invasive and/or recurrent behaviour and resistance to common modalities of therapy. Recently, however, important changes have been introduced to the diagnosis and management of aggressive and malignant pituitary tumours including the 4th edition of the WHO classification for endocrine tumours (2017) as well as ESE Clinical Guidelines (2018), although an attempt to establish predictive and/or prognostic markers of clinical aggressiveness remains difficult. In this review, we focus on a group of pituitary tumours causing significant problems in clinical practice and requiring multidisciplinary input. We summarise updates in definitions of tumour invasiveness, aggressiveness and malignant transformation, as well as histological classification, and emphasise the new considerations regarding aggressive and malignant potential and its relationship to therapeutic strategies. PMID- 29986954 TI - Clusters of fatty acids in the serum triacylglyceride fraction associate with the disorders of type 2 diabetes. AB - Our aim was to examine longitudinal associations of triacylglyceride fatty acid (TGFA) composition with insulin sensitivity (IS) and beta-cell function. Adults at risk for T2D (n = 477) had glucose and insulin measured from a glucose challenge at three time points over 6 years. The outcome variables Matsuda insulin sensitivity index, homeostatic model of assessment 2-percent sensitivity (HOMA2-%S), Insulinogenic Index over HOMA-IR (IGI/IR), and Insulin Secretion Sensitivity Index-2 were computed from the glucose challenge. Gas chromatography quantified TGFA composition from the baseline. We used adjusted generalized estimating equation (GEE) models and partial least squares (PLS) regression for the analysis. In adjusted GEE models, four TGFAs (14:0, 16:0, 14:1n-7, and 16:1n 7 as mol%) had strong negative associations with IS, whereas others (e.g., 18:1n 7, 18:1n-9, 20:2n-6, and 20:5n-3) had strong positive associations. Few associations were seen for beta-cell function, except for 16:0, 18:1n-7, and 20:2n-6. PLS analysis indicated four TGFAs (14:0, 16:0, 14:1n-7, and 16:1n-7) that clustered together and strongly related with lower IS. These four TGFAs also correlated highly (r > 0.4) with clinically measured triacylglyceride. We found that higher proportions of a cluster of four TGFAs strongly related with lower IS as well as hypertriglyceridemia, suggesting that only a few FAs within the TGFA composition may primarily explain lipids' role in glucose dysregulation. PMID- 29986956 TI - Argument for Prophylactic, Catheter-Based Repair of Mitral Regurgitation. PMID- 29986957 TI - Age, Blood Pressure Targets, and Guidelines: Rift Between Those Who Preach, Those Who Teach, and Those Who Treat? PMID- 29986955 TI - Novel bisretinoids of human retina are lyso alkyl ether glycerophosphoethanolamine-bearing A2PE species. AB - Bisretinoids are a family of fluorophores that form in photoreceptor cells' outer segments by nonenzymatic reaction of two vitamin A aldehydes (A2) with phosphatidylethanolamine (PE). Bisretinoid fluorophores are the major constituents of the lipofuscin of retinal pigment epithelium (RPE) that accumulate with age and contribute to some retinal diseases. Here, we report the identification of a previously unknown fluorescent bisretinoid. By ultra performance LC (UPLC) coupled to photodiode array detection, fluorescence (FLR), and ESI-MS, we determined that this novel bisretinoid is 1-octadecyl-2-lyso-sn glycero A2PE (alkyl ether lysoA2PE). This structural assignment was based on molecular mass (m/z 998), UV-visible absorbance maxima (340 and 440 nm), and retention time (73 min) and was corroborated by biomimetic synthesis using all trans-retinal and glycerophosphoethanolamine analogs as starting materials. UPLC profiles of ocular extracts acquired from human donor eyes revealed that alkyl ether lysoA2PE was detectable in RPE, but not neural retina. LysoA2PE FLR spectra exhibited a significant hyperchromic shift in hydrophobic environments. The propensity for lysoA2PE to undergo photooxidation/degradation was less pronounced than A2E. In mechanistic studies, A2PE was hydrolyzed by phospholipase A2 and plasmalogen lysoA2PE was cleaved under acidic conditions. The characterization of these additional members of the bisretinoid family advances our understanding of the mechanisms underlying bisretinoid biogenesis. PMID- 29986958 TI - Low-Grade Inflammation Modifies Cardiovascular Risk Even at Very Low LDL-C Levels: Are We Aiming for a Dual Target Concept? PMID- 29986960 TI - Learning From Diversity. PMID- 29986959 TI - How Do Resuscitation Teams at Top-Performing Hospitals for In-Hospital Cardiac Arrest Succeed? A Qualitative Study. AB - BACKGROUND: In-hospital cardiac arrest (IHCA) is common, and outcomes vary substantially across US hospitals, but reasons for these differences are largely unknown. We set out to better understand how top-performing hospitals organize their resuscitation teams to achieve high survival rates for IHCA. METHODS: We calculated risk-standardized IHCA survival to discharge rates across American Heart Association Get With The Guidelines-Resuscitation registry hospitals between 2012 and 2014. We identified geographically and academically diverse hospitals in the top, middle, and bottom quartiles of survival for IHCA and performed a qualitative study that included site visits with in-depth interviews of clinical and administrative staff at 9 hospitals. With the use of thematic analysis, data were analyzed to identify salient themes of perceived performance by informants. RESULTS: Across 9 hospitals, we interviewed 158 individuals from multiple disciplines including physicians (17.1%), nurses (45.6%), other clinical staff (17.1%), and administration (20.3%). We identified 4 broad themes related to resuscitation teams: (1) team design, (2) team composition and roles, (3) communication and leadership during IHCA, and (4) training and education. Resuscitation teams at top-performing hospitals demonstrated the following features: dedicated or designated resuscitation teams; participation of diverse disciplines as team members during IHCA; clear roles and responsibilities of team members; better communication and leadership during IHCA; and in-depth mock codes. CONCLUSIONS: Resuscitation teams at hospitals with high IHCA survival differ from non-top-performing hospitals. Our findings suggest core elements of successful resuscitation teams that are associated with better outcomes and form the basis for future work to improve IHCA. PMID- 29986961 TI - Sex Differences in Cardiovascular Pathophysiology: Why Women Are Overrepresented in Heart Failure With Preserved Ejection Fraction. AB - Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex specific diagnostic criteria, improved risk stratification models, and targeted therapies. PMID- 29986962 TI - From the American College of Cardiology 67th Annual Scientific Sessions. PMID- 29986963 TI - Trends in Apolipoprotein B, Non-High-Density Lipoprotein, and Low-Density Lipoprotein for Adults 60 Years and Older by Use of Lipid-Lowering Medications: United States, 2005 to 2006 Through 2013 to 2014. PMID- 29986964 TI - Letter by Lei Wang and Yun-Tao Zhao Regarding Article, "Young Male With Incessantly Wide Complex Tachycardia: What Is the Substrate of the Arrhythmia?" PMID- 29986965 TI - Response by Miranda-Arboleda et al to Letter Regarding Article, "Young Male With Incessantly Wide Complex Tachycardia: What Is the Substrate of the Arrhythmia?" PMID- 29986966 TI - Letter by Kikkert et al Regarding Article, "Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl)". PMID- 29986967 TI - Response by Ibrahim et al to Letter Regarding Article, "Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl)". PMID- 29986968 TI - Letter by Calabro et al Regarding Article, "Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)". PMID- 29986969 TI - Letter by Alkhalil Regarding Article, "Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)". PMID- 29986970 TI - Response by Bonaca and Sabatine to Letters Regarding Article, "Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)". PMID- 29986971 TI - Celebrating 35 Years of the AJNR: July 1983 edition. PMID- 29986972 TI - The Potpourri of Family Medicine, in Sickness and in Health. AB - Some aspects of the health of Americans are declining, and family medicine is addressing these ailments. Obesity is one factor, and family physicians provide nutrition counseling. Despite new models such as direct primary care, we have not found an ideal method for providing primary care to everyone in our health system. Not all family physicians report burnout: what is their secret? Scribes: some positives and negatives from one group. Rural America is in need of more family physicians who provide prenatal and natal care, and the proof is in the infant mortality rate. We also have 2 articles on improving pediatric care, and research on the relationship of thrush to mode of infant delivery. We have reviews of new cancer and cholesterol drugs, raising awareness of important knowledge for the primary care clinicians seeing the patients who take these drugs. In addition: tick bites and delayed anaphylaxis-when and how, culture related skin findings, and helping male perpetrators of domestic violence. PMID- 29986973 TI - Is the National Health Service Corps the Answer? (for Placing Family Doctors in Underserved Areas). PMID- 29986974 TI - 30% of Recent Family Medicine Graduates Report Participation in Loan Repayment Programs. AB - Rising educational debt may discourage entry into primary care and practice in safety net settings, but little is known about participation in loan repayment programs that are thought to be part of the solution. A survey of 2052 recent family physician residency graduates found that 30% pursued loan repayment, only a portion of which is tied to service obligations, suggesting opportunities for research and areas for the attention of policymakers. PMID- 29986975 TI - Multimorbidity Trends in United States Adults, 1988-2014. AB - IMPORTANCE: The simultaneous presence of multiple conditions in one patient (multi-morbidity) is a key challenge facing primary care. OBJECTIVE: The purpose of this study was to determine the prevalence of multi-morbidity and to document changes in prevalence during the last 25 years. DESIGN/SETTING: Cross-sectional study using multiple years (1988-2014) of the National Health and Nutrition Examination Survey (NHANES) were analyzed. SETTING: Multiple years (1988 to 2014) of the National Health and Nutrition Examination Survey (NHANES) from the United States were analyzed. PARTICIPANTS: Noninstitutionalized adults. MAIN OUTCOMES AND MEASURES: Number of chronic conditions per individual analyzed by age, race, gender, and socioeconomic factors. RESULTS: A total of 57,303 individuals were surveyed regarding the presence of multi-morbidity in separate surveys spanning 1988-2014. The overall current prevalence in 2013-2014 of >2 morbidities was 59.6% (95% CI 58.1%-61.1%), 38.5% had 3 or more, and 22.7% had 4 or more morbidities, which was significantly higher than in 1988 (45.7%, 95% CI 43.5% 47.8%, with >2 morbidities). Among individuals with 2 or more morbidities, 54.1% have obesity compared to 41.9% in 1988. Among adults age >65, prevalence was 91.8% for 2 or more morbidities. Whites and Blacks had significantly higher prevalence (59.2% and 60.1%) than Hispanic or "other" race (45.0%, P < .0001). Women (58.4%) had more current multi-morbidities (>2) than men (55.9%, P = .01). CONCLUSIONS AND RELEVANCE: Multimorbidity is common and has been increasing over the last 25 years. This finding has implications for public health policy and anticipated health costs for the coming years. PMID- 29986976 TI - Socioeconomic Status and Other Factors Associated with Childhood Obesity. AB - BACKGROUND: Childhood obesity in the United States is a critical public health issue. Although multiple child and parental factors are associated with childhood obesity, few models evaluate how socioeconomic status influences these risk factors. We aimed to create a model to examine how socioeconomic status modifies risk factors for child obesity. METHODS: We conducted a secondary data analysis of the Early Childhood Longitudinal Birth Cohort. Using logistic regression, we modeled childhood obesity status from known parental and child risk factors for childhood obesity and tested interactions with socioeconomic status. RESULTS: Compared with healthy-weight children, socioeconomic status, race, birth weight, parental smoking, and not eating dinner as a family were associated with kindergarten-aged children being overweight or obese. Parental smoking increased the odds of a child being overweight or obese by 40%, and eating dinner as a family reduced the odds of a child being overweight or obese by 4%. In addition, black or Hispanic children had a 60% increased odds of being overweight or obese when compared with their white counterparts. Native American children had almost double the odds of being overweight or obese compared with white children. Socioeconomic status did not modify any of these associations. CONCLUSION: Parental smoking, birth weight, and not eating dinner as a family were two modifiable factors associated with overweight and obesity in kindergarten-age children, regardless of socioeconomic status. Changing these life-style factors could reduce the child's risk for obesity. PMID- 29986977 TI - Family Physicians' Perspectives on Their Weight Loss Nutrition Counseling in a High Obesity Prevalence Area. AB - BACKGROUND: Obesity is a serious and highly prevalent health problem. Behavioral modification for weight loss is effective, and physician nutrition counseling is encouraged. Nevertheless, several studies have reported that physicians provide nutrition counseling infrequently. Time constraints and lack of patient compliance are among frequently reported barriers. AIM: In this pilot study, we aimed to examine physician weight loss nutrition counseling among family physicians in Huntington, West Virginia, an area with the highest obesity prevalence in the United States. METHODS: We administered an anonymous 13 question online survey designed for this study to all area family physicians in continuity ambulatory practice, asking about how often they provided nutrition counseling to their comorbidly obese patients, their nutrition education background, the counseling resources used, and the barriers they faced. RESULTS: Thirty-eight of the 47 invited physicians completed surveys. The 35 to 55 age group comprised 55% of the respondents. Men comprised 53% of our sample. Two thirds of the physicians reported that they counseled at a high frequency. Twenty six of the 38 physicians reported that their nutrition education in medical school was none to minimal. Of the rest, 47.2% viewed their education as clinically relevant. The most frequently-used specific patient education sources were those embedded in electronic health records, the US Department of Agriculture's MyPlate tool, and a variety of smartphone-based apps. Time constraints and lack of patient interest in nutrition topics were the leading barriers cited. CONCLUSION: Family physicians practicing in the most obese population in the United States tend to be high-frequency obesity nutrition counselors who frequently use specific tools, consider their education lacking and face oft-cited barriers. Studies in other highly endemic areas are needed to confirm these findings. PMID- 29986978 TI - Correlates of Burnout in Small Independent Primary Care Practices in an Urban Setting. AB - BACKGROUND: Little is known about the prevalence and correlates of burnout among providers who work in small independent primary care practices (<5 providers). METHODS: We conducted a cross-sectional analysis by using data collected from 235 providers practicing in 174 small independent primary care practices in New York City. RESULTS: The rate of provider-reported burnout was 13.5%. Using bivariate logistic regression, we found higher adaptive reserve scores were associated with lower odds of burnout (odds ratio, 0.12; 95% CI, 0.02-0.85; P = .034). CONCLUSION: The burnout rate was relatively low among our sample of providers compared with previous surveys that focused primarily on larger practices. The independence and autonomy providers have in these small practices may provide some protection against symptoms of burnout. In addition, the relationship between adaptive reserve and lower rates of burnout point toward potential interventions for reducing burnout that include strengthening primary care practices' learning and development capacity. PMID- 29986979 TI - Neonatal Thrush Is Not Associated with Mode of Delivery. AB - PURPOSE: Thrush is an opportunistic infection of the buccal cavity by the organism Candida albicans. It is most commonly seen in infants and becomes relatively uncommon between 6 to 9 months of age implying the infection is possibly dictated by risk factors present at or around the time of birth. The objective of this study is to determine if there is an association between the development of thrush and cesarean delivery, as we hypothesize. METHODS: Neonatal records were obtained through retrospective chart review of the past 10 years from an outpatient clinic and hospital records in Sandusky Ohio. ICD 9 and 10 codes for thrush and well child visit were used to identify patients. Statistical analysis performed on the data included: multivariable logistic regression, chi2 test of association, and nonparametric chi2 test of goodness-of-fit. RESULTS: A total of 636 patient records were reviewed, with 127 having a diagnosis of thrush and 509 without the diagnosis. A multivariable logistic regression indicated that during the first year of life, children born by cesarean section were no more likely to develop thrush compared with those born by vaginal delivery, controlling for age and sex of the neonate as well as parity and group B streptococcus status of the mother. CONCLUSION: This study demonstrated that there is no significant correlation between the mode of delivery and the development of thrush. It is reasonable to conclude that of the many factors associated with neonatal thrush development, mode of delivery is likely not one of them. PMID- 29986980 TI - Obstetric Care by Family Physicians and Infant Mortality in Rural Alabama. AB - BACKGROUND: The closure of obstetrics (OB) units at rural hospitals is thought to have implications for access to prenatal care (PNC) and infant mortality rate (IMR). The objective of this study was to determine whether local availability of PNC and OB services, specifically as provided by family physicians (FPs), would be associated with a lower IMR in 1 rural Alabama county. METHODS: Data from 1986 to 2013 from Pickens County was compared with data from 2 sets of control counties: Clarke/Monroe (full OB care) and Coosa/Conecuh (no local OB care). RESULTS: From 1986 to 1991 (no local OB services; period 1), Pickens County's IMR was 17.9, which fell to 7.2 from 1993 to 2001 (with local services; period 2). After the county's OB unit closed, IMR rose to 16.0 from 2005 to 2013 (period 3). In Clarke/Monroe (continuous OB service), the IMR fell from 14.5 to 9.9 from period 1 to period 3. Coosa/Conecuh (no OB service) exhibited a consistent IMR ranging from 10.9 to 14.4. CONCLUSION: OB services provided by FPs in Pickens County resulted in improvement of the county's IMR. Local PNC was associated with a lower IMR. PMID- 29986981 TI - Decreasing Low Acuity Pediatric Emergency Room Visits with Increased Clinic Access and Improved Parent Education. AB - BACKGROUND AND OBJECTIVE: The goal of this study was to decrease avoidable, low acuity emergency department (ED) use among pediatric patients at Coastal Family Medicine. The rationale behind this focus was to improve continuity for our patients while decreasing the cost burden for low-acuity ED visits. The family medicine residency clinic pediatric panel has grown by 35% over the past 3 years, bringing this issue of same-day acute access in our clinic to the forefront. METHODS: A survey was created to better understand the needs of our high users of the ED. The survey identified that patients believed the ED provided better same day access than our clinic during the daytime hours, 8 am-5 pm, Monday-Friday. By using this data, along with a literature review and a community practice review, a business-hour walk-in clinic for ages 0 years to 18 years was started to improve access. Clinic posters, revised scripting for office staff, phone room staff, and our after-hour triage line as well as bookmarks advertising the walk in clinic given during well-child checks were created to address parent education. Pediatric ED data generated through our electronic medical record as well as through Medicaid reimbursement data framed the scope of this issue as significant. This was used to monitor pediatric ED visits following interventions as well. RESULTS: Over the initial 3 months of interventions, pediatric ED use decreased by 62 visits compared with the prior year. The low-acuity diagnoses of upper respiratory infections decreased by 43.7% (71 to 40 visits) and fever decreased by 50.0% (14 to 7 visits) from the same 3 months the year prior. This decrease was sustained when examined during year 3. Over the next 12 months, there were 284 (29.8%) less visits to the ED with low-acuity diagnoses. This calculates to approximately $300,000 saved to the Medicaid system. During this time frame, our pediatric panel increased by 200 patients. DISCUSSION: Increasing access and improving patient education decreased low-acuity pediatric ED visits in our clinic. This combination of interventions worked well in our community and has been shown to help optimize the setting in which pediatric patients are seen. PMID- 29986982 TI - Screenings during Well-Child Visits in Primary Care: A Quality Improvement Study. AB - BACKGROUND: Early Periodic Screening, Diagnosis, and Treatment visits are designed to address physical, mental, and developmental health of children enrolled in Medicaid. METHODS: We conducted a mixed methods intervention by using a quality improvement theory. We assessed preintervention and postintervention screening rates of development, anemia, lead, oral health, vision and hearing, interventions for improvement, and barriers for the well-child visits at an academic family medicine clinic. For quantitative analysis, we assessed the preintervention baseline for 183 children and postintervention outcome for 151 children. For qualitative analysis, we used group interviews and key informant interviews to develop interventions in the preintervention stage and to explore potential barriers for further improvement in the postintervention stage. RESULTS: Interventions based on baseline results included user-friendly materials, checklists, posters, education, and order sets. After the intervention, there were significant statistical improvements (P < .05) for the anemia test ordered rate, serum lead test ordered rate, oral health screening and referral rates, and ordered and confirmed test rates for both vision and hearing. Despite these improvements, 3 qualitative findings indicated barriers for further improvement, including difficulties in venipuncture, medical assistant aversion to vision screening, and poor fit of equipment for hearing assessment. The procedures prompted further continuous quality improvement activities using fingerstick hemoglobin testing, a child-friendly vision screener, and manual audiometer with headphones. CONCLUSIONS: The trial findings demonstrated potential benefits of improving screenings in an office-based intervention by using a quality improvement process. Postintervention qualitative findings illustrate additional factors that could be addressed for further improvements. PMID- 29986983 TI - What Patients with Mild-to-Moderate Kidney Disease Know, Think, and Feel about Their Disease: An In-Depth Interview Study. AB - INTRODUCTION: It is unknown what patients in primary care with mild-to-moderate chronic kidney disease (CKD) know, think, and feel about their diagnoses and how they value the information provided. The aim of the study was to explore their knowledge, thoughts, and experiences concerning their CKD and the information given to them. METHOD: Qualitative interview study with patients with mild-to moderate CKD who know their diagnoses and are treated mainly by family physicians. RESULTS: Four themes arose: CKD literacy, coping with anxiety, prerequisites for self-management, and reciprocity in information provision. The participants filled deficiencies in their CKD knowledge with misconceptions and half-truth about causes, symptoms, and treatment. The anxiety about CKD at the time of diagnosis versus the feeling of irrelevance later on was due to the absence of CKD symptoms and their physicians' minimization of the seriousness of CKD. Participants failed to connect lifestyle and cardiovascular disease with CKD. Not all participants were well informed about the consequences that CKD might have. CKD literacy and willingness to change were both necessary to accept lifestyle changes. Further, the participants felt that it would be helpful when information comes with empathy and is tailored to patients' personal needs. CONCLUSIONS: Patients have various perceptions about their CKD. Exploring these perceptions could help match their needs with better-tailored information. Doctors should be aware that they can deliver inaccurate signals about CKD severity, so that patients fail to realize the potential impact of CKD. This makes them less open to lifestyle changes and improving their self-management. PMID- 29986984 TI - Doctor-Patient Trust Among Chronic Pain Patients on Chronic Opioid Therapy after Opioid Risk Reduction Initiatives: A Survey. AB - OBJECTIVE: This analysis examined patients' perceptions about trust within the doctor-patient relationship related to managing opioid pain medications. We compared perceptions among chronic opioid therapy (COT) patients who were and were not exposed to opioid risk reduction initiatives. METHODS: Between 2014 and 2016, we surveyed 1588 adults with chronic pain receiving COT about their trust in their prescribing doctor, their perceptions of their doctor's trust in them, their concerns about opioid prescribing, and their knowledge of opioid safety concerns. The population included adults receiving care in intervention settings that implemented opioid risk reduction initiatives and control settings with similar COT patients that did not. RESULTS: Overall, 82.2% of COT patients said they trusted their doctor's judgment, with more agreement among patients in the control clinics (86.3%; n = 653) than in the intervention clinics (77.9%; n = 935; P = .002). Similarly, slightly more patients in the control clinics believed their physician trusted how they managed their opioid pain medicines (91.1%) compared with the intervention clinics (86.2%; P = .002). The percent who worried that their doctor would stop prescribing opioid pain medicine was 29.3% in intervention clinics and 21.8% in control clinics (P = .007). CONCLUSIONS: Although COT patients typically reported favorable perceptions of doctor-patient trust in managing opioid pain medicines, implementation of opioid risk reduction initiatives may have reduced levels of trust for a minority of COT patients. This suggests that it may be possible to implement opioid risk-reduction initiatives while sustaining high levels of doctor-patient trust for most COT patients. PMID- 29986986 TI - Direct Primary Care: Applying Theory to Potential Changes in Delivery and Outcomes. AB - Direct Primary Care (DPC), where patients pay a fee to a primary care provider to obtain access to services, is a delivery model that has received notable attention and enthusiasm from some providers. Proponents of DPC believe that the model increases accessibility, reduces overhead, and ultimately improves care for patients; however, there is little evidence in the peer-reviewed literature to support these claims. The objective of this analysis was to apply Starfield's adaptation of Donabedian's Structure-Process-Outcome conceptual model to evaluate primary care to formally display the links between potential changes in clinical structure and processes from DPC adoption. Based on existing literature on the constructs in Starfield's model, expectations of DPC's impact at the patient, clinic, and system levels were defined. DPC uses changes to financing and the population eligible to trigger potential gains in continuity and accessibility to subsequently improve care processes. There is evidence to support DPC as a theoretically sound approach to improve attributes of primary care, such as first contact care and longitudinality at the clinic level for participating patients. At the health system level, DPC has low-construct validity that would suggest a positive impact on the potentially eligible population's health due to membership fees that exclude patients who are more likely to be vulnerable and complex than patients who are willing and able to stay in the practice. Descriptive and comparative research of included and excluded patients is needed to inform providers, patients, and policy makers of the DPC's ability to attain the attributes of primary care and ultimately achieve better outcomes over alternative primary care delivery and financing models. Meanwhile, theoretic application informed by years of research on primary care provide insight as to what changes to expect and to monitor as practices consider DPC adoption. PMID- 29986985 TI - How Evolving United States Payment Models Influence Primary Care and Its Impact on the Quadruple Aim. AB - INTRODUCTION: Prior research has demonstrated the associations between a strong primary care foundation with improved Quadruple Aim outcomes. The prevailing fee for-service payment system in the United States reinforces the volume of services over value-based care, thereby devaluing primary care, and obstructing the health care system from attaining the Quadruple Aim. By supporting a shift from volume based to value-based payment models, the Medicare Access and Children's Health Insurance Program Reauthorization Act may help fortify the role of primary care. This narrative review proposes a taxonomy of the major health care payment models, reviewing their ability to uphold the functions of primary care, and their impacts across the Quadruple Aim. METHODS: An Ovid MEDLINE search and expert opinion from members of the Family Medicine for America's Health payment and research tactic teams were used. Titles and abstracts were reviewed for relevance to the topic, and expert opinion further narrowed the literature for inclusion to timely and relevant articles. FINDINGS: No payment model demonstrates consistent benefits across the Quadruple Aim across a limited evidence base. Several cross-cutting lessons from available payment models several recommendations for primary care payment models, including the following: implementing per member per month-based models, validating risk-adjustment tools, increasing investments in integrated behavioral health and social services, and connecting payments to patient-oriented and primary care-oriented metrics. Along with ongoing research in emerging payment models, data systems integrated across health care and social services settings using metrics that can capture the ideal functions of primary care will be critical to the development of future payment models that most optimally enhance the role of primary care in the United States. CONCLUSIONS: Although the ideal payment model for primary care remains to be determined, lessons learned from existing payment models can help guide the shift from volume-based to value-based care. To most effectively pay for primary care, future payment models should invest in a primary care infrastructure, one that supports team-based, community-oriented care, and measures the delivery of the functions of primary care. PMID- 29986987 TI - Impact of Medical Scribes in Primary Care on Productivity, Face-to-Face Time, and Patient Comfort. AB - BACKGROUND: Medical scribes are a clinical innovation increasingly being used in primary care. The impact of scribes in primary care remain unclear. We aimed to examine the impact of medical scribes on productivity, time spent facing the patient during the visit, and patient comfort with scribes in primary care. METHODS: We conducted a prospective observational pre-post study of 5 family and internal medicine-pediatrics physicians and their patients at an urban safety net health clinic. Medical scribes accompanied providers in the examination room and documented the clinical encounter. After an initial phase-in period, we added an additional 20-minute patient slot per 200-minute session. We examined productivity by using electronic medical record data on the number of patients seen and work relative value units (work RVUs) per hour. We directly observed clinical encounters to measure the amount of time providers spent facing patients and other visit components. We queried patient comfort with scribes by using surveys administered after the visit. RESULTS: Work RVUs per hour increased by 10.5% from 2.59 prescribe to 2.86 post-scribe (P < .001). Patients seen per hour increased by 8.8% from 1.82 to 1.98 (P < .001). Work RVUs per patient did not change. After scribe implementation, time spent facing the patient increased by 57% (P < .001) and time spent facing the computer decreased by 27% (P = .003). The proportion of the visit time that was spent face-to-face increased by 39% (P < .001). Most (69%) patients reported feeling very comfortable with the scribe in the room, while the proportion feeling very comfortable with the number of people in the room decreased from 93% to 66% (P < .001). CONCLUSIONS: Although the full implications of medical scribe implementation remain to be seen, this initial study highlights the promising opportunity of medical scribe implementation in primary care. PMID- 29986988 TI - New Immunotherapies in Oncology Treatment and Their Side Effect Profiles. AB - BACKGROUND: Immunotherapies in cancer treatment have a long history going all the way back to the very beginning of the field, and recent advances are extremely promising. These therapies are becoming a larger part in many patients' oncology treatment as the number of approaches, individual medicines, and indications increase. Furthermore, these novel therapies have different side effect profiles from those traditional chemotherapies which have, until recently, typified the oncologist's approach to treatment together with surgery and radiation. METHODS: An electronic literature search was conducted in May and June 2017 and March 2018 with the PubMed and Ebscohost databases. Articles were chosen for their relevance to the drugs in question, cancer physiology, or historic significance. CONCLUSIONS: Checkpoint inhibitors are becoming very common and possess autoimmune side effects such as pneumonitis, hypothyroidism, and colitis. These may present at any time the patient is on the medications but are more common several weeks to several months from beginning therapy. Chimeric antigen receptor T-cell therapies are powerful but have strong side effects such as cytokine release syndrome. Neoantigens are currently in the early stages of clinical trials and may become an exciting avenue for personalized cancer treatment but are not yet typical. PMID- 29986989 TI - Hyperlipidemia: Management with Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors. AB - Coronary artery disease is the leading cause of death in United States. Hyperlipidemia is an independent and potentially reversible risk factor for coronary artery disease. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, collectively known as statins, have been the mainstay of pharmacologic therapy. Their availability, ease of administration, low cost, and strong evidence behind safety and efficacy makes them one of the most widely prescribed lipid-lowering agents. However, some patients may be intolerant to statins, and few others suffer from very high serum levels of cholesterol in which statin therapy alone or in combination with other cholesterol-lowering agents is insufficient in reducing serum lipid levels to achieve desired levels. In 2015, the Food and Drug Administration approved a new family of lipid-lowering agents, collectively known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.PCSK9 inhibitors are biologically active molecules that decrease serum low-density lipoprotein cholesterol compared with statin therapy alone. They serve as an alternative to statins for patients who are intolerant to statin or as supplemental therapy in those patients for whom lower levels in serum low-density lipoprotein cholesterol are not achieved by statins alone. This article discusses PCSK9 inhibitors, their mechanism of action, indications, efficacy, safety, costs and limitations. PMID- 29986990 TI - The Role of the Physician When a Patient Discloses Intimate Partner Violence Perpetration: A Literature Review. AB - Intimate partner violence (IPV) is prevalent and has lasting impacts on the health and well-being of the entire family involved. Primary care physicians often interact with male patients who perpetrate IPV and are in a role potentially to intervene, but there is very little research and guidance about how to address perpetration of IPV in the health care setting. We reviewed the existing literature research related to physicians' interactions with male perpetrators of IPV and summarize the recommendations. If a male patient discloses IPV perpetration, physicians should assess for lethality, readiness to change, and comorbid medical conditions that could impact treatment, such as substance abuse and mental illness. Experts agree that referrals to a Batterer Intervention Program should be the primary intervention. If there are no locally available Batterer Intervention Programs or the patient is unwilling to go, then a physician should refer the abuser to a therapist who has been trained specifically to work with perpetrators of IPV. In addition, physicians should be prepared to offer education about the negative impact of IPV on the victim, on any children, and on the abuser himself. Physicians should address any untreated substance abuse or mental health issues. Referral to couples therapy should generally be avoided. Physicians should continue to have regular follow-up with their male patients to support them in changing their behavior. Further research is needed to assess the role the health care system can have in preventing IPV perpetration. PMID- 29986991 TI - Physicians' Understanding of Clinical Trial Data in Professional Prescription Drug Promotion. AB - BACKGROUND: Prescription drug marketing to physicians often includes clinical trial data. Prior research has shown that physicians may not have the necessary knowledge to understand all clinical trial results and they can be influenced by how these results are reported. This study focused on physicians' reactions to and evaluations of clinical trial data presented in professional prescription drug promotion. METHODS: We conducted 60-minute interviews with practicing physicians across the United States (50 primary care physicians and 22 endocrinologists). Physicians viewed prescription drug promotional materials that contained clinical trial data and answered follow-up questions. RESULTS: Physicians demonstrated low to moderate knowledge about clinical trial-related terms found in promotional prescription drug materials. DISCUSSION: Results from this qualitative analysis underscore a need to determine how clinical trial data in prescription drug promotional materials affect physicians' attitudes and decision making. PMID- 29986992 TI - Diagnosing Meat Allergy After Tick Bite Without Delay. AB - Galactose-alpha-1, 3 galactose (alpha-gal) is a carbohydrate found in mammalian meat. In 2007, it was implicated as a cause of severe hypersensitivity reactions when a study found elevated levels of antibodies directed against this oligosaccharide among patients treated with cetuximab, a monoclonal antibody that contained an alpha -gal epitope. The majority of these cases were reported in the Southeast United States in a distribution similar to that of Rocky Mountain spotted fever and ehrlichiosis, and that geographic association led researchers to the conclusion that a bite from the Lone Star tick can induce this antibody. Here, we present a case of delayed urticarial angioedema due to a mammalian meat allergy caused by alpha-gal immunoglobulin E acquired after tick exposures, and the knowledge and patient education required to prevent recurrences. It is estimated that approximately 0.5% to 1.0% of the general population will experience an episode of angioedema in their lifetime, and this case demonstrates why clinicians in areas that are inhabited by ticks, particularly the Lone Star species, should include this cause in their differential. PMID- 29986993 TI - Recognizing Culturally Related Findings on Refugee Physical Examinations. AB - On physical examination, refugees from countries in Africa, Asia, and the Middle East often present with findings that are unfamiliar to primary health care providers in the West. Previous traditional practices that may have left their mark include scarification and burning of the skin, excision of body parts, and subcutaneous insertion of foreign material. The descriptions detailed here introduce providers to some of the signs that result from body modification practices commonly encountered on physical examination of refugees. PMID- 29986994 TI - Prostate-Specific Antigen Testing Initiation and Shared Decision-Making: Findings from the 2000 and 2015 National Health Interview Surveys. AB - PURPOSES: Despite recommendations against prostate cancer screening with prostate specific antigen (PSA) tests, about one-fourth of men age >=40 years received PSA tests in 2015. This study aimed to answer 3 questions for men who had a PSA test in the past year: (1) What percentage of these men received the test first suggested by physicians? (2) What factors were associated with physician initiated PSA testing (PIPT) versus patient/someone else-initiated testing? (3) What percentage of patients ever had shared decision-making when tests were initiated by physicians? METHODS: We analyzed the 2000 and 2015 National Health Interview Survey data. We calculated age-standardized prevalence of PIPT for both years. For 2015, we used logistic regression to calculate adjusted prevalence ratios for PIPT. We also calculated the prevalence of ever discussing both advantages and disadvantages. RESULTS: The age-standardized prevalence of PIPT was significantly higher in 2015 (84.9%) than in 2000 (72.3%). In 2015, nearly 90% of PSA screenings for men aged >=70 years were suggested by physicians. PIPT was positively associated with 2 or more comorbid conditions and number of patient visits to the doctor. Less than one-third of men reported they had ever participated in a discussion of advantages and disadvantages of PSA testing. CONCLUSIONS: The majority of men who had PSA testing in the past year reported that their physicians were the first to suggest testing, including men aged >=70 years. Our study also points to the challenges and needs in conducting shared decision-making before PSA testing in clinical practice. PMID- 29986995 TI - Re: Burnout in Young Family Physicians: Variation Across States. PMID- 29986997 TI - Therapeutic Targeting of the Premetastatic Stage in Human Lung-to-Brain Metastasis. AB - Brain metastases (BM) result from the spread of primary tumors to the brain and are a leading cause of cancer mortality in adults. Secondary tissue colonization remains the main bottleneck in metastatic development, yet this "premetastatic" stage of the metastatic cascade, when primary tumor cells cross the blood-brain barrier and seed the brain before initiating a secondary tumor, remains poorly characterized. Current studies rely on specimens from fully developed macrometastases to identify therapeutic options in cancer treatment, overlooking the potentially more treatable "premetastatic" phase when colonizing cancer cells could be targeted before they initiate the secondary brain tumor. Here we use our established brain metastasis initiating cell (BMIC) models and gene expression analyses to characterize premetastasis in human lung-to-BM. Premetastatic BMIC engaged invasive and epithelial developmental mechanisms while simultaneously impeding proliferation and apoptosis. We identified the dopamine agonist apomorphine to be a potential premetastasis-targeting drug. In vivo treatment with apomorphine prevented BM formation, potentially by targeting premetastasis associated genes KIF16B, SEPW1, and TESK2 Low expression of these genes was associated with poor survival of patients with lung adenocarcinoma. These results illuminate the cellular and molecular dynamics of premetastasis, which is subclinical and currently impossible to identify or interrogate in human patients with BM. These data present several novel therapeutic targets and associated pathways to prevent BM initiation.Significance: These findings unveil molecular features of the premetastatic stage of lung-to-brain metastases and offer a potential therapeutic strategy to prevent brain metastases. Cancer Res; 78(17); 5124-34. (c)2018 AACR. PMID- 29986996 TI - SMAD4 Suppresses WNT-Driven Dedifferentiation and Oncogenesis in the Differentiated Gut Epithelium. AB - The cell of origin of colon cancer is typically thought to be the resident somatic stem cells, which are immortal and escape the continual cellular turnover characteristic of the intestinal epithelium. However, recent studies have identified certain conditions in which differentiated cells can acquire stem-like properties and give rise to tumors. Defining the origins of tumors will inform cancer prevention efforts as well as cancer therapies, as cancers with distinct origins often respond differently to treatments. We report here a new condition in which tumors arise from the differentiated intestinal epithelium. Inactivation of the differentiation-promoting transcription factor SMAD4 in the intestinal epithelium was surprisingly well tolerated in the short term. However, after several months, adenomas developed with characteristics of activated WNT signaling. Simultaneous loss of SMAD4 and activation of the WNT pathway led to dedifferentiation and rapid adenoma formation in differentiated tissue. Transcriptional profiling revealed acquisition of stem cell characteristics, and colabeling indicated that cells expressing differentiated enterocyte markers entered the cell cycle and reexpressed stem cell genes upon simultaneous loss of SMAD4 and activation of the WNT pathway. These results indicate that SMAD4 functions to maintain differentiated enterocytes in the presence of oncogenic WNT signaling, thus preventing dedifferentiation and tumor formation in the differentiated intestinal epithelium.Significance: This work identifies a mechanism through which differentiated cells prevent tumor formation by suppressing oncogenic plasticity. Cancer Res; 78(17); 4878-90. (c)2018 AACR. PMID- 29986998 TI - Differential composition of DHA and very-long-chain PUFAs in rod and cone photoreceptors. AB - Long-chain PUFAs (LC-PUFAs; C20-C22; e.g., DHA and arachidonic acid) are highly enriched in vertebrate retina, where they are elongated to very-long-chain PUFAs (VLC-PUFAs; C ?28) by the elongation of very-long-chain fatty acids-4 (ELOVL4) enzyme. These fatty acids play essential roles in modulating neuronal function and health. The relevance of different lipid requirements in rods and cones to disease processes, such as age-related macular degeneration, however, remains unclear. To better understand the role of LC-PUFAs and VLC-PUFAs in the retina, we investigated the lipid compositions of whole retinas or photoreceptor outer segment (OS) membranes in rodents with rod- or cone-dominant retinas. We analyzed fatty acid methyl esters and the molecular species of glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine) by GC MS/GC-flame ionization detection and ESI-MS/MS, respectively. We found that whole retinas and OS membranes in rod-dominant animals compared with cone-dominant animals had higher amounts of LC-PUFAs and VLC-PUFAs. Compared with those of rod dominant animals, retinas and OS membranes from cone-dominant animals also had about 2-fold lower levels of di-DHA (22:6/22:6) molecular species of glycerophospholipids. Because PUFAs are necessary for optimal G protein-coupled receptor signaling in rods, these findings suggest that cones may not have the same lipid requirements as rods. PMID- 29986999 TI - Omega-6 oxylipins generated by soluble epoxide hydrolase are associated with knee osteoarthritis. AB - Omega-6 FAs are inflammatory mediators that are increased in joints with osteoarthritis (OA), but their association with OA progression is not yet well defined. To investigate the relationship between omega-6 FAs and knee OA, we measured with LC-MS the levels of 22 omega-6 lipids (arachidonic acid, linoleic acid, and 20 oxylipins) in synovial fluid (SF) from 112 knees of 102 individuals (58 with knee OA; 44 controls). We hypothesized that oxylipin metabolites would increase in OA knee SF and with radiographically progressive disease. We validated results by comparing samples from affected and unaffected knees in 10 individuals with unilateral OA. In adjusted analysis, SF levels of three omega-6 oxylipins [prostaglandin D2, 11,12-dihydroxyeicosatrienoic acid (DHET), and 14,15 DHET] were associated with OA. Of these, 11,12-DHET and 14,15-DHET were higher in affected versus unaffected knees of people with unilateral disease (P < 0.014 and P < 0.003, respectively). Levels of these and 8,9-DHET were also associated with radiographic progression over 3.3 years in 87 individuals. Circulating levels of all three were associated with gene variants at the soluble epoxide hydrolase enzyme. Lipidomic profiling in SF identified an additional inflammatory pathway associated with knee OA and radiographic progression. PMID- 29987001 TI - Immune Cells at the Fetomaternal Interface: How the Microenvironment Modulates Immune Cells To Foster Fetal Development. AB - Immune cells adapt their phenotypic and functional characteristics in response to the tissue microenvironment within which they traffic and reside. The fetomaternal interface, consisting of placental trophoblasts and the maternal decidua, is a highly specialized tissue with a unique and time-limited function: to nourish and support development of the semiallogeneic fetus and protect it from inflammatory or immune-mediated injury. It is therefore important to understand how immune cells within these tissues are educated and adapt to fulfill their biological functions. This review article focuses on the local regulatory mechanisms ensuring that both innate and adaptive immune cells appropriately support the early events of implantation and placental development through direct involvement in promoting immune tolerance of fetal alloantigens, suppressing inflammation, and remodeling of maternal uterine vessels to facilitate optimal placental function and fetal growth. PMID- 29987000 TI - FGF21 gene therapy as treatment for obesity and insulin resistance. AB - Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno-associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long-term high-fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D. PMID- 29987002 TI - An ETHYLENE RESPONSE FACTOR-MYB Transcription Complex Regulates Furaneol Biosynthesis by Activating QUINONE OXIDOREDUCTASE Expression in Strawberry. AB - 4-Hydroxy-2,5-dimethyl-3(2H)-furanone is a major contributor to the aroma of strawberry (Fragaria * ananassa) fruit, and the last step in its biosynthesis is catalyzed by strawberry quinone oxidoreductase (FaQR). Here, an ethylene response factor (FaERF#9) was characterized as a positive regulator of the FaQR promoter. Linear regression analysis indicated that FaERF#9 transcript levels were correlated significantly with both FaQR transcripts and furanone content in different strawberry cultivars. Transient overexpression of FaERF#9 in strawberry fruit significantly increased FaQR expression and furaneol production. Yeast one hybrid assays, however, indicated that FaERF#9 by itself did not bind to the FaQR promoter. An MYB transcription factor (FaMYB98) identified in yeast one-hybrid screening of the strawberry cDNA library was capable of both binding to the promoter and activating the transcription of FaQR by ~5.6-fold. Yeast two-hybrid assay and bimolecular fluorescence complementation confirmed a direct protein protein interaction between FaERF#9 and FaMYB98, and in combination, they activated the FaQR promoter 14-fold in transactivation assays. These results indicate that an ERF-MYB complex containing FaERF#9 and FaMYB98 activates the FaQR promoter and up-regulates 4-hydroxy-2,5-dimethyl-3(2H)-furanone biosynthesis in strawberry. PMID- 29987004 TI - Digital GP providers that register out-of-area patients could receive less funding under contract revamp. PMID- 29987003 TI - Towards Identification of the Substrates of ATP-Binding Cassette Transporters. AB - Most ATP-binding cassette (ABC) proteins function in transmembrane transport, and plant genomes encode a large number of ABC transporters compared with animal or fungal genomes. These transporters have been classified into eight subfamilies according to their topology and phylogenetic relationships. Transgenic plants and mutants with altered ABC transporter expression or function have contributed to deciphering the physiological roles of these proteins, such as in plant development, responses to biotic and abiotic stress, or detoxification activities within the cell. In agreement with the diversity of these functions, a large range of substrates (e.g. hormones and primary and secondary metabolites) have been identified. We review in detail transporters for which substrates have been unambiguously identified. However, some cases are far from clear, because some ABC transporters have the ability to transport several structurally unrelated substrates or because the identification of their substrates was performed indirectly without any flux measurement. Various heterologous or homologous expression systems have been used to better characterize the transport activity and other biochemical properties of ABC transporters, opening the way to addressing new issues such as the particular structural features of plant ABC transporters, the bidirectionality of transport, or the role of posttranslational modifications. PMID- 29987006 TI - Dual-process theory of racial isolation, legal cynicism, and reported crime. AB - Why is neighborhood racial composition linked so strongly to police-reported crime? Common explanations include over-policing and negative interactions with police, but police reports of crime are heavily dependent on resident 911 calls. Using Sampson's concept of legal cynicism and Vaisey's dual-process theory, we theorize that racial concentration and isolation consciously and nonconsciously influence neighborhood variation in 911 calls for protection and prevention. The data we analyze are consistent with this thesis. Independent of police reports of crime, we find that neighborhood racial segregation in 1990 and the legal cynicism about crime prevention and protection it engenders have lasting effects on 911 calls more than a decade later, in 2006-2008. Our theory explains this persistent predictive influence through continuity and change in intervening factors. A source of cumulative continuity, the intensification of neighborhood racial concentration and isolation between 1990 and 2000, predicts 911 calls. Likewise, sources of change-heightened neighborhood incarceration and home foreclosures during the financial crisis in 2006-2008-also predict these calls. Our findings are consistent with legal cynicism theory's focus on neighborhood disadvantage, racial isolation, and concerns about police protection and crime prevention; they correspond less with the emphasis of procedural justice theory on police legitimacy. PMID- 29987005 TI - N6-Furfuryladenine is protective in Huntington's disease models by signaling huntingtin phosphorylation. AB - The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington's disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems. PMID- 29987008 TI - Picture perception reveals mental geometry of 3D scene inferences. AB - Pose estimation of objects in real scenes is critically important for biological and machine visual systems, but little is known of how humans infer 3D poses from 2D retinal images. We show unexpectedly remarkable agreement in the 3D poses different observers estimate from pictures. We further show that all observers apply the same inferential rule from all viewpoints, utilizing the geometrically derived back-transform from retinal images to actual 3D scenes. Pose estimations are altered by a fronto-parallel bias, and by image distortions that appear to tilt the ground plane. We used pictures of single sticks or pairs of joined sticks taken from different camera angles. Observers viewed these from five directions, and matched the perceived pose of each stick by rotating an arrow on a horizontal touchscreen. The projection of each 3D stick to the 2D picture, and then onto the retina, is described by an invertible trigonometric expression. The inverted expression yields the back-projection for each object pose, camera elevation, and observer viewpoint. We show that a model that uses the back projection, modulated by just two free parameters, explains 560 pose estimates per observer. By considering changes in retinal image orientations due to position and elevation of limbs, the model also explains perceived limb poses in a complex scene of two bodies lying on the ground. The inferential rules simply explain both perceptual invariance and dramatic distortions in poses of real and pictured objects, and show the benefits of incorporating projective geometry of light into mental inferences about 3D scenes. PMID- 29987007 TI - Systems genetic analysis of inversion polymorphisms in the malaria mosquito Anopheles gambiae. AB - Inversion polymorphisms in the African malaria vector Anopheles gambiae segregate along climatic gradients of aridity. Despite indirect evidence of their adaptive significance, little is known of the phenotypic targets of selection or the underlying genetic mechanisms. Here we adopt a systems genetics approach to explore the interaction of two inversions on opposite arms of chromosome 2 with gender, climatic conditions, and one another. We measure organismal traits and transcriptional profiles in 8-d-old adults of both sexes and four alternative homokaryotypic classes reared under two alternative climatic regimes. We show that karyotype strongly influences both organismal traits and transcriptional profiles but that the strength and direction of the effects depend upon complex interactions with gender and environmental conditions and between inversions on independent arms. Our data support the suppressed recombination model for the role of inversions in local adaptation, and-supported by transcriptional and physiological measurements following perturbation with the drug rapamycin-suggest that one mechanism underlying their adaptive role may be the maintenance of energy homeostasis. PMID- 29987009 TI - River-discharge effects on United States Atlantic and Gulf coast sea-level changes. AB - Identifying physical processes responsible for historical coastal sea-level changes is important for anticipating future impacts. Recent studies sought to understand the drivers of interannual to multidecadal sea-level changes on the United States Atlantic and Gulf coasts. Ocean dynamics, terrestrial water storage, vertical land motion, and melting of land ice were highlighted as important mechanisms of sea-level change along this densely populated coast on these time scales. While known to exert an important control on coastal ocean circulation, variable river discharge has been absent from recent discussions of drivers of sea-level change. We update calculations from the 1970s, comparing annual river-discharge and coastal sea-level data along the Gulf of Maine, Mid Atlantic Bight, South Atlantic Bight, and Gulf of Mexico during 1910-2017. We show that river-discharge and sea-level changes are significantly correlated ([Formula: see text]), such that sea level rises between 0.01 and 0.08 cm for a 1 [Formula: see text] annual river-discharge increase, depending on region. We formulate a theory that describes the relation between river-discharge and halosteric sea-level changes (i.e., changes in sea level related to salinity) as a function of river discharge, Earth's rotation, and density stratification. This theory correctly predicts the order of observed increment sea-level change per unit river-discharge anomaly, suggesting a causal relation. Our results have implications for remote sensing, climate modeling, interpreting Common Era proxy sea-level reconstructions, and projecting coastal flood risk. PMID- 29987010 TI - Transient surface ocean oxygenation recorded in the ~2.66-Ga Jeerinah Formation, Australia. AB - Many paleoredox proxies indicate low-level and dynamic incipient oxygenation of Earth's surface environments during the Neoarchean (2.8-2.5 Ga) before the Great Oxidation Event (GOE) at ~2.4 Ga. The mode, tempo, and scale of these redox changes are poorly understood, because data from various locations and ages suggest both protracted and transient oxygenation. Here, we present bulk rock and kerogen-bound nitrogen isotope ratios as well as bulk rock selenium abundances and isotope ratios from drill cores sampled at high stratigraphic resolution through the Jeerinah Formation (~2.66 Ga; Fortescue Group, Western Australia) to test for changes in the redox state of the surface environment. We find that both shallow and deep depositional facies in the Jeerinah Formation display episodes of positive primary delta15N values ranging from +4 to +60/00, recording aerobic nitrogen cycling that requires free O2 in the upper water column. Moderate selenium enrichments up to 5.4 ppm in the near-shore core may indicate coincident oxidative weathering of sulfide minerals on land, although not to the extent seen in the younger Mt. McRae Shale that records a well-documented "whiff" of atmospheric oxygen at 2.5 Ga. Unlike the Mt. McRae Shale, Jeerinah selenium isotopes do not show a significant excursion concurrent with the positive delta15N values. Our data are thus most parsimoniously interpreted as evidence for transient surface ocean oxygenation lasting less than 50 My, extending over hundreds of kilometers, and occurring well before the GOE. The nitrogen isotope data clearly record nitrification and denitrification, providing the oldest firm evidence for these microbial metabolisms. PMID- 29987011 TI - Observing carbon cycle-climate feedbacks from space. AB - The impact of human emissions of carbon dioxide and methane on climate is an accepted central concern for current society. It is increasingly evident that atmospheric concentrations of carbon dioxide and methane are not simply a function of emissions but that there are myriad feedbacks forced by changes in climate that affect atmospheric concentrations. If these feedbacks change with changing climate, which is likely, then the effect of the human enterprise on climate will change. Quantifying, understanding, and articulating the feedbacks within the carbon-climate system at the process level are crucial if we are to employ Earth system models to inform effective mitigation regimes that would lead to a stable climate. Recent advances using space-based, more highly resolved measurements of carbon exchange and its component processes-photosynthesis, respiration, and biomass burning-suggest that remote sensing can add key spatial and process resolution to the existing in situ systems needed to provide enhanced understanding and advancements in Earth system models. Information about emissions and feedbacks from a long-term carbon-climate observing system is essential to better stewardship of the planet. PMID- 29987012 TI - Virion structure and genome delivery mechanism of sacbrood honeybee virus. AB - Infection by sacbrood virus (SBV) from the family Iflaviridae is lethal to honey bee larvae but only rarely causes the collapse of honey bee colonies. Despite the negative effect of SBV on honey bees, the structure of its particles and mechanism of its genome delivery are unknown. Here we present the crystal structure of SBV virion and show that it contains 60 copies of a minor capsid protein (MiCP) attached to the virion surface. No similar MiCPs have been previously reported in any of the related viruses from the order Picornavirales. The location of the MiCP coding sequence within the SBV genome indicates that the MiCP evolved from a C-terminal extension of a major capsid protein by the introduction of a cleavage site for a virus protease. The exposure of SBV to acidic pH, which the virus likely encounters during cell entry, induces the formation of pores at threefold and fivefold axes of the capsid that are 7 A and 12 A in diameter, respectively. This is in contrast to vertebrate picornaviruses, in which the pores along twofold icosahedral symmetry axes are currently considered the most likely sites for genome release. SBV virions lack VP4 subunits that facilitate the genome delivery of many related dicistroviruses and picornaviruses. MiCP subunits induce liposome disruption in vitro, indicating that they are functional analogs of VP4 subunits and enable the virus genome to escape across the endosome membrane into the cell cytoplasm. PMID- 29987013 TI - Genetic analysis of social-class mobility in five longitudinal studies. AB - A summary genetic measure, called a "polygenic score," derived from a genome-wide association study (GWAS) of education can modestly predict a person's educational and economic success. This prediction could signal a biological mechanism: Education-linked genetics could encode characteristics that help people get ahead in life. Alternatively, prediction could reflect social history: People from well off families might stay well-off for social reasons, and these families might also look alike genetically. A key test to distinguish biological mechanism from social history is if people with higher education polygenic scores tend to climb the social ladder beyond their parents' position. Upward mobility would indicate education-linked genetics encodes characteristics that foster success. We tested if education-linked polygenic scores predicted social mobility in >20,000 individuals in five longitudinal studies in the United States, Britain, and New Zealand. Participants with higher polygenic scores achieved more education and career success and accumulated more wealth. However, they also tended to come from better-off families. In the key test, participants with higher polygenic scores tended to be upwardly mobile compared with their parents. Moreover, in sibling-difference analysis, the sibling with the higher polygenic score was more upwardly mobile. Thus, education GWAS discoveries are not mere correlates of privilege; they influence social mobility within a life. Additional analyses revealed that a mother's polygenic score predicted her child's attainment over and above the child's own polygenic score, suggesting parents' genetics can also affect their children's attainment through environmental pathways. Education GWAS discoveries affect socioeconomic attainment through influence on individuals' family-of-origin environments and their social mobility. PMID- 29987014 TI - Hsp70-Bag3 complex is a hub for proteotoxicity-induced signaling that controls protein aggregation. AB - Protein abnormalities in cells are the cause of major pathologies, and a number of adaptive responses have evolved to relieve the toxicity of misfolded polypeptides. To trigger these responses, cells must detect the buildup of aberrant proteins which often associate with proteasome failure, but the sensing mechanism is poorly understood. Here we demonstrate that this mechanism involves the heat shock protein 70-Bcl-2-associated athanogene 3 (Hsp70-Bag3) complex, which upon proteasome suppression responds to the accumulation of defective ribosomal products, preferentially recognizing the stalled polypeptides. Components of the ribosome quality control system LTN1 and VCP and the ribosome associated chaperone NAC are necessary for the interaction of these species with the Hsp70-Bag3 complex. This complex regulates important signaling pathways, including the Hippo pathway effectors LATS1/2 and the p38 and JNK stress kinases. Furthermore, under proteotoxic stress Hsp70-Bag3-LATS1/2 signaling regulates protein aggregation. We established that the regulated step was the emergence and growth of abnormal protein oligomers containing only a few molecules, indicating that aggregation is regulated at very early stages. The Hsp70-Bag3 complex therefore functions as an important signaling node that senses proteotoxicity and triggers multiple pathways that control cell physiology, including activation of protein aggregation. PMID- 29987015 TI - Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants. AB - Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients' lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients' LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients' LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA-RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect. PMID- 29987016 TI - Subsistence practices, past biodiversity, and anthropogenic impacts revealed by New Zealand-wide ancient DNA survey. AB - New Zealand's geographic isolation, lack of native terrestrial mammals, and Gondwanan origins make it an ideal location to study evolutionary processes. However, since the archipelago was first settled by humans 750 y ago, its unique biodiversity has been under pressure, and today an estimated 49% of the terrestrial avifauna is extinct. Current efforts to conserve the remaining fauna rely on a better understanding of the composition of past ecosystems, as well as the causes and timing of past extinctions. The exact temporal and spatial dynamics of New Zealand's extinct fauna, however, can be difficult to interpret, as only a small proportion of animals are preserved as morphologically identifiable fossils. Here, we conduct a large-scale genetic survey of subfossil bone assemblages to elucidate the impact of humans on the environment in New Zealand. By genetically identifying more than 5,000 nondiagnostic bone fragments from archaeological and paleontological sites, we reconstruct a rich faunal record of 110 species of birds, fish, reptiles, amphibians, and marine mammals. We report evidence of five whale species rarely reported from New Zealand archaeological middens and characterize extinct lineages of leiopelmatid frog (Leiopelma sp.) and kakapo (Strigops habroptilus) haplotypes lost from the gene pool. Taken together, this molecular audit of New Zealand's subfossil record not only contributes to our understanding of past biodiversity and precontact Maori subsistence practices but also provides a more nuanced snapshot of anthropogenic impacts on native fauna after first human arrival. PMID- 29987017 TI - Anomalous diffusion, spatial coherence, and viscoelasticity from the energy landscape of human chromosomes. AB - The nucleus of a eukaryotic cell is a nonequilibrium system where chromatin is subjected to active processes that continuously rearrange it over the cell's life cycle. Tracking the motion of chromosomal loci provides information about the organization of the genome and the physical processes shaping that organization. Optical experiments report that loci move with subdiffusive dynamics and that there is spatially coherent motion of the chromatin. We recently showed that it is possible to predict the 3D architecture of genomes through a physical model for chromosomes that accounts for the biochemical interactions mediated by proteins and regulated by epigenetic markers through a transferable energy landscape. Here, we study the temporal dynamics generated by this quasi equilibrium energy landscape assuming Langevin dynamics at an effective temperature. Using molecular dynamics simulations of two interacting human chromosomes, we show that the very same interactions that account for genome architecture naturally reproduce the spatial coherence, viscoelasticity, and the subdiffusive behavior of the motion in interphase chromosomes as observed in numerous experiments. The agreement between theory and experiments suggests that even if active processes are involved, an effective quasi-equilibrium landscape model can largely mimic their dynamical effects. PMID- 29987019 TI - Urban mobility and neighborhood isolation in America's 50 largest cities. AB - Influential research on the negative effects of living in a disadvantaged neighborhood assumes that its residents are socially isolated from nonpoor or "mainstream" neighborhoods, but the extent and nature of such isolation remain in question. We develop a test of neighborhood isolation that improves on static measures derived from commonly used census reports by leveraging fine-grained dynamic data on the everyday movement of residents in America's 50 largest cities. We analyze 650 million geocoded Twitter messages to estimate the home locations and travel patterns of almost 400,000 residents over 18 mo. We find surprisingly high consistency across neighborhoods of different race and income characteristics in the average travel distance (radius) and number of neighborhoods traveled to (spread) in the metropolitan region; however, we uncover notable differences in the composition of the neighborhoods visited. Residents of primarily black and Hispanic neighborhoods-whether poor or not-are far less exposed to either nonpoor or white middle-class neighborhoods than residents of primarily white neighborhoods. These large racial differences are notable given recent declines in segregation and the increasing diversity of American cities. We also find that white poor neighborhoods are substantially isolated from nonpoor white neighborhoods. The results suggest that even though residents of disadvantaged neighborhoods travel far and wide, their relative isolation and segregation persist. PMID- 29987018 TI - Preordering of water is not needed for ice recognition by hyperactive antifreeze proteins. AB - Antifreeze proteins (AFPs) inhibit ice growth in organisms living in cold environments. Hyperactive insect AFPs are particularly effective, binding ice through "anchored clathrate" motifs. It has been hypothesized that the binding of hyperactive AFPs to ice is facilitated by preordering of water at the ice-binding site (IBS) of the protein in solution. The antifreeze protein TmAFP displays the best matching of its binding site to ice, making it the optimal candidate to develop ice-like order in solution. Here we use multiresolution simulations to unravel the mechanism by which TmAFP recognizes and binds ice. We find that water at the IBS of the antifreeze protein in solution does not acquire ice-like or anchored clathrate-like order. Ice recognition occurs by slow diffusion of the protein to achieve the proper orientation with respect to the ice surface, followed by fast collective organization of the hydration water at the IBS to form an anchored clathrate motif that latches the protein to the ice surface. The simulations suggest that anchored clathrate order could develop on the large ice binding surfaces of aggregates of ice-nucleating proteins (INP). We compute the infrared and Raman spectra of water in the anchored clathrate motif. The signatures of the OH stretch of water in the anchored clathrate motif can be distinguished from those of bulk liquid in the Raman spectra, but not in the infrared spectra. We thus suggest that Raman spectroscopy may be used to probe the anchored clathrate order at the ice-binding surface of INP aggregates. PMID- 29987020 TI - PICK1 inhibits the E3 ubiquitin ligase activity of Parkin and reduces its neuronal protective effect. AB - Parkin functions as a multipurpose E3 ubiquitin ligase, and Parkin loss of function is associated with both sporadic and familial Parkinson's disease (PD). We report that the Bin/Amphiphysin/Rvs (BAR) domain of protein interacting with PRKCA1 (PICK1) bound to the really interesting new gene 1 (RING1) domain of Parkin and potently inhibited the E3 ligase activity of Parkin by disrupting its interaction with UbcH7. Parkin translocated to damaged mitochondria and led to their degradation in neurons, whereas PICK1 robustly inhibited this process. PICK1 also impaired the protective function of Parkin against stresses in SH-SY5Y cells and neurons. The protein levels of several Parkin substrates were reduced in young PICK1-knockout mice, and these mice were resistant to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-mediated toxicity. Taken together, the results indicate that PICK1 is a potent inhibitor of Parkin, and the reduction of PICK1 enhances the protective effect of Parkin. PMID- 29987022 TI - Retraction for Ganesh et al., Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation. PMID- 29987024 TI - Template and primer requirements for DNA Pol theta-mediated end joining. AB - DNA Pol theta-mediated end joining (TMEJ) is a microhomology-based pathway for repairing double-strand breaks in eukaryotes. TMEJ is also a pathway for nonspecific integration of foreign DNAs into host genomes. DNA Pol theta shares structural homology with the high-fidelity replicases, and its polymerase domain (Poltheta) has been shown to extend ssDNA without an apparent template. Using oligonucleotides with distinct sequences, we find that with Mg2+ and physiological salt concentrations, human Poltheta has no terminal transferase activity and requires a minimum of 2 bp and optimally 4 bp between a template/primer pair for DNA synthesis. Poltheta can tolerate a mismatched base pair at the primer end but loses >90% activity when the mismatch is 2 bp upstream from the active site. Poltheta is severely inhibited when the template strand has a 3' overhang within 3-4 bp from the active site. In line with its TMEJ function, Poltheta has limited strand-displacement activity, and the efficiency and extent of primer extension are similar with or without a downstream duplex. PMID- 29987023 TI - Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice. AB - Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient (cROCK1 /-) and ROCK2-deficient (cROCK2-/-) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1-/- mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2-/- mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1-/- hearts and down regulated in cROCK2-/- hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1-/- mice, whereas their expressions were significantly lower in cROCK2-/- mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent. PMID- 29987021 TI - Ancient drug curcumin impedes 26S proteasome activity by direct inhibition of dual-specificity tyrosine-regulated kinase 2. AB - Curcumin, the active ingredient in Curcuma longa, has been in medicinal use since ancient times. However, the therapeutic targets and signaling cascades modulated by curcumin have been enigmatic despite extensive research. Here we identify dual specificity tyrosine-regulated kinase 2 (DYRK2), a positive regulator of the 26S proteasome, as a direct target of curcumin. Curcumin occupies the ATP-binding pocket of DYRK2 in the cocrystal structure, and it potently and specifically inhibits DYRK2 over 139 other kinases tested in vitro. As a result, curcumin diminishes DYRK2-mediated 26S proteasome phosphorylation in cells, leading to reduced proteasome activity and impaired cell proliferation. Interestingly, curcumin synergizes with the therapeutic proteasome inhibitor carfilzomib to induce apoptosis in a variety of proteasome-addicted cancer cells, while this drug combination exhibits modest to no cytotoxicity to noncancerous cells. In a breast cancer xenograft model, curcumin treatment significantly reduces tumor burden in immunocompromised mice, showing a similar antitumor effect as CRISPR/Cas9-mediated DYRK2 depletion. These results reveal an unexpected role of curcumin in DYRK2-proteasome inhibition and provide a proof-of-concept that pharmacological manipulation of proteasome regulators may offer new opportunities for anticancer treatment. PMID- 29987025 TI - Enhanced brain activity associated with memory access in highly superior autobiographical memory. AB - Brain systems underlying human memory function have been classically investigated studying patients with selective memory impairments. The discovery of rare individuals who have highly superior autobiographical memory (HSAM) provides, instead, an opportunity to investigate the brain systems underlying enhanced memory. Here, we carried out an fMRI investigation of a group of subjects identified as having HSAM. During fMRI scanning, eight subjects with HSAM and 21 control subjects were asked to retrieve autobiographical memories (AMs) as well as non-AMs (e.g., examples of animals). Subjects were instructed to signal the "access" to an AM by a key press and to continue "reliving" it immediately after. Compared with controls, individuals with HSAM provided a richer AM recollection and were faster in accessing AMs. The access to AMs was associated with enhanced prefrontal/hippocampal functional connectivity. AM access also induced increased activity in the left temporoparietal junction and enhanced functional coupling with sensory cortices in subjects with HSAM compared with controls. In contrast, subjects with HSAM did not differ from controls in functional activity during the reliving phase. These findings, based on fMRI assessment, provide evidence of interaction of brain systems engaged in memory retrieval and suggest that enhanced activity of these systems is selectively involved in enabling more efficient access to past experiences in HSAM. PMID- 29987026 TI - Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence. AB - RNA viruses exist as a genetically diverse quasispecies with extraordinary ability to adapt to abrupt changes in the host environment. However, the molecular mechanisms that contribute to their rapid adaptation and persistence in vivo are not well studied. Here, we probe hepatitis C virus (HCV) persistence by analyzing clinical samples taken from subjects who were treated with a second generation HCV protease inhibitor. Frequent longitudinal viral load determinations and large-scale single-genome sequence analyses revealed rapid antiviral resistance development, and surprisingly, dynamic turnover of dominant drug-resistant mutant populations long after treatment cessation. We fitted mathematical models to both the viral load and the viral sequencing data, and the results provided strong support for the critical roles that superinfection and cure of infected cells play in facilitating the rapid turnover and persistence of viral populations. More broadly, our results highlight the importance of considering viral dynamics and competition at the intracellular level in understanding rapid viral adaptation. Thus, we propose a theoretical framework integrating viral and molecular mechanisms to explain rapid viral evolution, resistance, and persistence despite antiviral treatment and host immune responses. PMID- 29987028 TI - Role of elemental carbon in the photochemical aging of soot. AB - Soot, which consists of organic carbon (OC) and elemental carbon (EC), is a significant component of the total aerosol mass in the atmosphere. Photochemical oxidation is an important aging pathway for soot. It is commonly believed that OC is photoactive but EC, albeit its strong light absorption, is photochemically inert. Here, by taking advantage of the different light absorption properties of OC and EC, we provide direct experimental evidence that EC also plays an important role in the photochemical aging of soot by initiating the oxidation of OC, even under red light irradiation. We show that nascent soot, in addition to undergoing photochemical oxidation under blue light with a wavelength of 440 nm, undergoes similar oxidation under red light irradiation of lambda = 648 nm (L648). However, separated OC (extracted from soot by n-hexane) and EC exhibit little reactivity under L648 These observations indicate that EC plays a pivotal role in photoaging of soot by adsorbing light to initiate the oxidation of OC. Comparison of in situ IR spectra and photoelectrochemical behaviors suggests that EC-initiated photooxidation of OC proceeds through an electron transfer pathway, which is distinct from the photoaging induced by light absorption of OC. Since the absorption spectra of EC have a much larger overlap with the solar spectra than those of OC, our results provide insight into the chemical mechanism leading to rapid soot aging by organic species observed from atmospheric field measurements. PMID- 29987027 TI - Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle. AB - Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes. However, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and the muscle molecular circadian clock have never been studied in humans. Here, we investigated insulin sensitivity and muscle metabolism in 14 healthy young lean men [age 22.4 +/- 2.8 years; body mass index (BMI) 22.3 +/- 2.1 kg/m2 (mean +/- SD)] after a 3-d control protocol and a 3.5-d misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that short-term circadian misalignment results in a significant decrease in muscle insulin sensitivity due to a reduced skeletal muscle nonoxidative glucose disposal (rate of disappearance: 23.7 +/- 2.4 vs. 18.4 +/- 1.4 mg/kg per minute; control vs. misalignment; P = 0.024). Fasting glucose and free fatty acid levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the inverted behavioral cycle, and transcriptome analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misalignment. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers. PMID- 29987029 TI - Correction for Stokes and Purdon, A study of problems encountered in Granger causality analysis from a neuroscience perspective. PMID- 29987030 TI - Positional specificity of different transcription factor classes within enhancers. AB - Gene expression is controlled by sequence-specific transcription factors (TFs), which bind to regulatory sequences in DNA. TF binding occurs in nucleosome depleted regions of DNA (NDRs), which generally encompass regions with lengths similar to those protected by nucleosomes. However, less is known about where within these regions specific TFs tend to be found. Here, we characterize the positional bias of inferred binding sites for 103 TFs within ~500,000 NDRs across 47 cell types. We find that distinct classes of TFs display different binding preferences: Some tend to have binding sites toward the edges, some toward the center, and some at other positions within the NDR. These patterns are highly consistent across cell types, suggesting that they may reflect TF-specific intrinsic structural or functional characteristics. In particular, TF classes with binding sites at NDR edges are enriched for those known to interact with histones and chromatin remodelers, whereas TFs with central enrichment interact with other TFs and cofactors such as p300. Our results suggest distinct regiospecific binding patterns and functions of TF classes within enhancers. PMID- 29987033 TI - 1.1-billion-year-old porphyrins establish a marine ecosystem dominated by bacterial primary producers. AB - The average cell size of marine phytoplankton is critical for the flow of energy and nutrients from the base of the food web to higher trophic levels. Thus, the evolutionary succession of primary producers through Earth's history is important for our understanding of the radiation of modern protists ~800 million years ago and the emergence of eumetazoan animals ~200 million years later. Currently, it is difficult to establish connections between primary production and the proliferation of large and complex organisms because the mid-Proterozoic (~1,800 800 million years ago) rock record is nearly devoid of recognizable phytoplankton fossils. We report the discovery of intact porphyrins, the molecular fossils of chlorophylls, from 1,100-million-year-old marine black shales of the Taoudeni Basin (Mauritania), 600 million years older than previous findings. The porphyrin nitrogen isotopes (delta15Npor = 5.6-10.20/00) are heavier than in younger sedimentary sequences, and the isotopic offset between sedimentary bulk nitrogen and porphyrins (epsilonpor = -5.1 to -0.50/00) points to cyanobacteria as dominant primary producers. Based on fossil carotenoids, anoxygenic green (Chlorobiacea) and purple sulfur bacteria (Chromatiaceae) also contributed to photosynthate. The low epsilonpor values, in combination with a lack of diagnostic eukaryotic steranes in the time interval of 1,600-1,000 million years ago, demonstrate that algae played an insignificant role in mid-Proterozoic oceans. The paucity of algae and the small cell size of bacterial phytoplankton may have curtailed the flow of energy to higher trophic levels, potentially contributing to a diminished evolutionary pace toward complex eukaryotic ecosystems and large and active organisms. PMID- 29987031 TI - Recognition of conserved antigens by Th17 cells provides broad protection against pulmonary Haemophilus influenzae infection. AB - Nontypeable Haemophilus influenzae (NTHi) is a major cause of community acquired pneumonia and exacerbation of chronic obstructive pulmonary disease. A current effort in NTHi vaccine development has focused on generating humoral responses and has been greatly impeded by antigenic variation among the numerous circulating NTHi strains. In this study, we showed that pulmonary immunization of mice with killed NTHi generated broad protection against lung infection by different strains. While passive transfer of immune antibodies protected only against the homologous strain, transfer of immune T cells conferred protection against both homologous and heterologous strains. Further characterization revealed a strong Th17 response that was cross-reactive with different NTHi strains. Responding Th17 cells recognized both cytosolic and membrane-associated antigens, while immune antibodies preferentially responded to surface antigens and were highly strain specific. We further identified several conserved proteins recognized by lung Th17 cells during NTHi infection. Two proteins yielding the strongest responses were tested as vaccine candidates by immunization of mice with purified proteins plus an adjuvant. Immunization induced antigen-specific Th17 cells that recognized different strains and, upon adoptive transfer, conferred protection. Furthermore, immunized mice were protected against challenge with not only NTHi strains but also a fully virulent, encapsulated strain. Together, these results show that the immune mechanism of cross protection against pneumonia involves Th17 cells, which respond to a broad spectrum of antigens, including those that are highly conserved among NTHi strains. These mechanistic insights suggest that inclusion of Th17 antigens in subunit vaccines offers the advantage of inducing broad protection and complements the current antibody-based approaches. PMID- 29987032 TI - Protein moonlighting elucidates the essential human pathway catalyzing lipoic acid assembly on its cognate enzymes. AB - The lack of attachment of lipoic acid to its cognate enzyme proteins results in devastating human metabolic disorders. These mitochondrial disorders are evident soon after birth and generally result in early death. The mutations causing specific defects in lipoyl assembly map in three genes, LIAS, LIPT1, and LIPT2 Although physiological roles have been proposed for the encoded proteins, only the LIPT1 protein had been studied at the enzyme level. LIPT1 was reported to catalyze only the second partial reaction of the classical lipoate ligase mechanism. We report that the physiologically relevant LIPT1 enzyme activity is transfer of lipoyl moieties from the H protein of the glycine cleavage system to the E2 subunits of the 2-oxoacid dehydrogenases required for respiration (e.g., pyruvate dehydrogenase) and amino acid degradation. We also report that LIPT2 encodes an octanoyl transferase that initiates lipoyl group assembly. The human pathway is now biochemically defined. PMID- 29987034 TI - Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy. PMID- 29987035 TI - GC content elevates mutation and recombination rates in the yeast Saccharomyces cerevisiae. AB - The chromosomes of many eukaryotes have regions of high GC content interspersed with regions of low GC content. In the yeast Saccharomyces cerevisiae, high-GC regions are often associated with high levels of meiotic recombination. In this study, we constructed URA3 genes that differ substantially in their base composition [URA3-AT (31% GC), URA3-WT (43% GC), and URA3-GC (63% GC)] but encode proteins with the same amino acid sequence. The strain with URA3-GC had an approximately sevenfold elevated rate of ura3 mutations compared with the strains with URA3-WT or URA3-AT About half of these mutations were single-base substitutions and were dependent on the error-prone DNA polymerase zeta. About 30% were deletions or duplications between short (5-10 base) direct repeats resulting from DNA polymerase slippage. The URA3-GC gene also had elevated rates of meiotic and mitotic recombination relative to the URA3-AT or URA3-WT genes. Thus, base composition has a substantial effect on the basic parameters of genome stability and evolution. PMID- 29987036 TI - Observation of highly stable and symmetric lanthanide octa-boron inverse sandwich complexes. AB - While boron forms a wide range of metal borides with important industrial applications, there has been relatively little attention devoted to lanthanide boride clusters. Here we report a joint photoelectron spectroscopy and quantum chemical study on two octa-boron di-lanthanide clusters, Ln2B8- (Ln = La, Pr). We found that these clusters form highly stable inverse sandwich structures, [Ln-B8 Ln]-, with strong Ln and B8 bonding via interactions between the Ln 5d orbitals and the delocalized sigma and pi orbitals on the B8 ring. A (d-p)delta bond, involving the 5ddelta and the antibonding pi orbital of the B8 ring, is observed to be important in the Ln-B8 interactions. The highly symmetric inverse sandwich structures are overwhelmingly more stable than any other isomers. Upon electron detachment, the (d-p)delta orbitals become half-filled, giving rise to a triplet ground state for neutral La2B8 In addition to the two unpaired electrons in the (d-p)delta orbitals upon electron detachment, the neutral Pr2B8 complex also contains two unpaired 4f electrons on each Pr center. The six unpaired spins in Pr2B8 are ferromagnetically coupled to give rise to a septuplet ground state. The current work suggests that highly magnetic Ln...B8...Ln inverse sandwiches or 1D Ln...B8...Ln nanowires may be designed with novel electronic and magnetic properties. PMID- 29987038 TI - Local magnetism in MnSiPt rules the chemical bond. AB - Among intermetallic compounds, ternary phases with the simple stoichiometric ratio 1:1:1 form one of the largest families. More than 15 structural patterns have been observed for several hundred compounds constituting this group. This, on first glance unexpected, finding is a consequence of the complex mechanism of chemical bonding in intermetallic structures, allowing for large diversity. Their formation process can be understood based on a hierarchy of energy scales: The main share is contributed by covalent and ionic interactions in accordance with the electronic needs of the participating elements. However, smaller additional atomic interactions may still tip the scales. Here, we demonstrate that the local spin polarization of paramagnetic manganese in the new compound MnSiPt rules the adopted TiNiSi-type crystal structure. Combining a thorough experimental characterization with a theoretical analysis of the energy landscape and the chemical bonding of MnSiPt, we show that the paramagnetism of the Mn atoms suppresses the formation of Mn-Mn bonds, deciding between competing crystal structures. PMID- 29987037 TI - NADPH oxidase-generated reactive oxygen species in mature follicles are essential for Drosophila ovulation. AB - Ovarian reactive oxygen species (ROS) are believed to regulate ovulation in mammals, but the details of ROS production in follicles and the role of ROS in ovulation in other species remain underexplored. In Drosophila ovulation, matrix metalloproteinase 2 (MMP2) is required for follicle rupture by degradation of posterior follicle cells surrounding a mature oocyte. We recently demonstrated that MMP2 activation and follicle rupture are regulated by the neuronal hormone octopamine (OA) and the octopamine receptor in mushroom body (OAMB). In the current study, we investigated the role of the superoxide-generating enzyme NADPH oxidase (NOX) in Drosophila ovulation. We report that Nox is highly enriched in mature follicle cells and that Nox knockdown in these cells leads to a reduction in superoxide and to defective ovulation. Similar to MMP2 activation, NOX enzymatic activity is also controlled by the OA/OAMB-Ca2+ signaling pathway. In addition, we report that extracellular superoxide dismutase 3 (SOD3) is required to convert superoxide to hydrogen peroxide, which acts as the key signaling molecule for follicle rupture, independent of MMP2 activation. Given that Nox homologs are expressed in mammalian follicles, the NOX-dependent hydrogen peroxide signaling pathway that we describe could play a conserved role in regulating ovulation in other species. PMID- 29987040 TI - QnAs with Dean H. Roemmich. PMID- 29987041 TI - Retraction for Ajees et al., Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases. PMID- 29987039 TI - Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library. AB - The diverse physiological roles of the neurotrophin family have long prompted exploration of their potential as therapeutic agents for nerve injury and neurodegenerative diseases. To date, clinical trials of one family member, brain derived neurotrophic factor (BDNF), have disappointingly failed to meet desired endpoints. Contributing to these failures is the fact that BDNF is pharmaceutically a nonideal biologic drug candidate. It is a highly charged, yet is a net hydrophobic molecule with a low molecular weight that confers a short t1/2 in man. To circumvent these shortcomings of BDNF as a drug candidate, we have employed a function-based cellular screening assay to select activating antibodies of the BDNF receptor TrkB from a combinatorial human short-chain variable fragment antibody library. We report here the successful selection of several potent TrkB agonist antibodies and detailed biochemical and physiological characterization of one such antibody, ZEB85. By using a human TrkB reporter cell line and BDNF-responsive GABAergic neurons derived from human ES cells, we demonstrate that ZEB85 is a full agonist of TrkB, comparable in potency to BDNF toward human neurons in activation of TrkB phosphorylation, canonical signal transduction, and mRNA transcriptional regulation. PMID- 29987042 TI - Integration of cell cycle signals by multi-PAS domain kinases. AB - Spatial control of intracellular signaling relies on signaling proteins sensing their subcellular environment. In many cases, a large number of upstream signals are funneled to a master regulator of cellular behavior, but it remains unclear how individual proteins can rapidly integrate a complex array of signals within the appropriate spatial niche within the cell. As a model for how subcellular spatial information can control signaling activity, we have reconstituted the cell pole-specific control of the master regulator kinase/phosphatase CckA from the asymmetrically dividing bacterium Caulobacter crescentus CckA is active as a kinase only when it accumulates within a microdomain at the new cell pole, where it colocalizes with the pseudokinase DivL. Both proteins contain multiple PAS domains, a multifunctional class of sensory domains present across the kingdoms of life. Here, we show that CckA uses its PAS domains to integrate information from DivL and its own oligomerization state to control the balance of its kinase and phosphatase activities. We reconstituted the DivL-CckA complex on liposomes in vitro and found that DivL directly controls the CckA kinase/phosphatase switch, and that stimulation of either CckA catalytic activity depends on the second of its two PAS domains. We further show that CckA oligomerizes through a multidomain interaction that is critical for stimulation of kinase activity by DivL, while DivL stimulation of CckA phosphatase activity is independent of CckA homooligomerization. Our results broadly demonstrate how signaling factors can leverage information from their subcellular niche to drive spatiotemporal control of cell signaling. PMID- 29987043 TI - A random first-order transition theory for an active glass. AB - How does nonequilibrium activity modify the approach to a glass? This is an important question, since many experiments reveal the near-glassy nature of the cell interior, remodeled by activity. However, different simulations of dense assemblies of active particles, parametrized by a self-propulsion force, [Formula: see text], and persistence time, [Formula: see text], appear to make contradictory predictions about the influence of activity on characteristic features of glass, such as fragility. This calls for a broad conceptual framework to understand active glasses; here, we extend the random first-order transition (RFOT) theory to a dense assembly of self-propelled particles. We compute the active contribution to the configurational entropy through an effective model of a single particle in a caging potential. This simple active extension of RFOT provides excellent quantitative fits to existing simulation results. We find that whereas [Formula: see text] always inhibits glassiness, the effect of [Formula: see text] is more subtle and depends on the microscopic details of activity. In doing so, the theory automatically resolves the apparent contradiction between the simulation models. The theory also makes several testable predictions, which we verify by both existing and new simulation data, and should be viewed as a step toward a more rigorous analytical treatment of active glass. PMID- 29987044 TI - Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication. AB - Rhinoviruses (RVs) are responsible for the majority of upper airway infections; despite their high prevalence and the resulting economic burden, effective treatment is lacking. We report here that RV induces metabolic alterations in host cells, which offer an efficient target for antiviral intervention. We show that RV-infected cells rapidly up-regulate glucose uptake in a PI3K-dependent manner. In parallel, infected cells enhance the expression of the PI3K-regulated glucose transporter GLUT1. In-depth metabolomic analysis of RV-infected cells revealed a critical role of glucose mobilization from extracellular and intracellular pools via glycogenolysis for viral replication. Infection resulted in a highly anabolic state, including enhanced nucleotide synthesis and lipogenesis. Consistently, we observed that glucose deprivation from medium and via glycolysis inhibition by 2-deoxyglucose (2-DG) potently impairs viral replication. Metabolomic analysis showed that 2-DG specifically reverts the RV induced anabolic reprogramming. In addition, treatment with 2-DG inhibited RV infection and inflammation in a murine model. Thus, we demonstrate that the specific metabolic fingerprint of RV infection can be used to identify new targets for therapeutic intervention. PMID- 29987045 TI - Scleral hypoxia is a target for myopia control. AB - Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1alpha (HIF-1alpha)-signaling pathway. Furthermore, experimental myopia selectively induced HIF-1alpha up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O2) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1alpha expression as well as the phosphorylation levels of eIF2alpha and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2alpha phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia. PMID- 29987046 TI - WDR5 modulates cell motility and morphology and controls nuclear changes induced by a 3D environment. AB - Cell migration through extracellular matrices requires nuclear deformation, which depends on nuclear stiffness. In turn, chromatin structure contributes to nuclear stiffness, but the mechanosensing pathways regulating chromatin during cell migration remain unclear. Here, we demonstrate that WD repeat domain 5 (WDR5), an essential component of H3K4 methyltransferase complexes, regulates cell polarity, nuclear deformability, and migration of lymphocytes in vitro and in vivo, independent of transcriptional activity, suggesting nongenomic functions for WDR5. Similarly, depletion of RbBP5 (another H3K4 methyltransferase subunit) promotes similar defects. We reveal that a 3D environment increases the H3K4 methylation dependent on WDR5 and results in a globally less compacted chromatin conformation. Further, using atomic force microscopy, nuclear particle tracking, and nuclear swelling experiments, we detect changes in nuclear mechanics that accompany the epigenetic changes induced in 3D conditions. Indeed, nuclei from cells in 3D environments were softer, and thereby more deformable, compared with cells in suspension or cultured in 2D conditions, again dependent on WDR5. Dissecting the underlying mechanism, we determined that actomyosin contractility, through the phosphorylation of myosin by MLCK (myosin light chain kinase), controls the interaction of WDR5 with other components of the methyltransferase complex, which in turn up-regulates H3K4 methylation activation in 3D conditions. Taken together, our findings reveal a nongenomic function for WDR5 in regulating H3K4 methylation induced by 3D environments, physical properties of the nucleus, cell polarity, and cell migratory capacity. PMID- 29987047 TI - Unrestrained markerless trait stacking in Nannochloropsis gaditana through combined genome editing and marker recycling technologies. AB - Robust molecular tool kits in model and industrial microalgae are key to efficient targeted manipulation of endogenous and foreign genes in the nuclear genome for basic research and, as importantly, for the development of algal strains to produce renewable products such as biofuels. While Cas9-mediated gene knockout has been demonstrated in a small number of algal species with varying efficiency, the ability to stack traits or generate knockout mutations in two or more loci are often severely limited by selectable agent availability. This poses a critical hurdle in developing production strains, which require stacking of multiple traits, or in probing functionally redundant gene families. Here, we combine Cas9 genome editing with an inducible Cre recombinase in the industrial alga Nannochloropsis gaditana to generate a strain, NgCas9+Cre+, in which the potentially unlimited stacking of knockouts and addition of new genes is readily achievable. Cre-mediated marker recycling is first demonstrated in the removal of the selectable marker and GFP reporter transgenes associated with the Cas9/Cre construct in NgCas9+Cre+ Next, we show the proof-of-concept generation of a markerless knockout in a gene encoding an acyl-CoA oxidase (Aco1), as well as the markerless recapitulation of a 2-kb insert in the ZnCys gene 5'-UTR, which results in a doubling of wild-type lipid productivity. Finally, through an industrially oriented process, we generate mutants that exhibit up to ~50% reduction in photosynthetic antennae size by markerless knockout of seven genes in the large light-harvesting complex gene family. PMID- 29987048 TI - Diffusion in networks and the virtue of burstiness. AB - Whether an idea, information, or infection diffuses throughout a society depends not only on the structure of the network of interactions, but also on the timing of those interactions. People are not always available to interact with others, and people differ in the timing of when they are active. Some people are active for long periods and then inactive for long periods, while others switch more frequently from being active to inactive and back. We show that maximizing diffusion in classic contagion processes requires heterogeneous activity patterns across agents. In particular, maximizing diffusion comes from mixing two extreme types of people: those who are stationary for long periods of time, changing from active to inactive or back only infrequently, and others who alternate frequently between being active and inactive. PMID- 29987049 TI - Confinement transition of Z2 gauge theories coupled to massless fermions: Emergent quantum chromodynamics and SO(5) symmetry. AB - We study a model of fermions on the square lattice at half-filling coupled to an Ising gauge theory that was recently shown in Monte Carlo simulations to exhibit [Formula: see text] topological order and massless Dirac fermion excitations. On tuning parameters, a confining phase with broken symmetry (an antiferromagnet in one choice of Hamiltonian) was also established, and the transition between these phases was found to be continuous, with coincident onset of symmetry breaking and confinement. While the confinement transition in pure gauge theories is well understood in terms of condensing magnetic flux excitations, the same transition in the presence of gapless fermions is a challenging problem owing to the statistical interactions between fermions and the condensing flux excitations. The conventional scenario then proceeds via a two-step transition, involving a symmetry-breaking transition leading to gapped fermions followed by confinement. In contrast, here, using quantum Monte Carlo simulations, we provide further evidence for a direct, continuous transition and also find numerical evidence for an enlarged [Formula: see text] symmetry rotating between antiferromagnetism and valence bond solid orders proximate to criticality. Guided by our numerical finding, we develop a field theory description of the direct transition involving an emergent nonabelian [[Formula: see text]] gauge theory and a matrix Higgs field. We contrast our results with the conventional Gross-Neveu-Yukawa transition. PMID- 29987054 TI - Pain clinics grapple with naloxone issues. PMID- 29987050 TI - Estrogen-regulated feedback loop limits the efficacy of estrogen receptor targeted breast cancer therapy. AB - Endocrine therapy resistance invariably develops in advanced estrogen receptor positive (ER+) breast cancer, but the underlying mechanisms are largely unknown. We have identified C-terminal SRC kinase (CSK) as a critical node in a previously unappreciated negative feedback loop that limits the efficacy of current ER targeted therapies. Estrogen directly drives CSK expression in ER+ breast cancer. At low CSK levels, as is the case in patients with ER+ breast cancer resistant to endocrine therapy and with the poorest outcomes, the p21 protein-activated kinase 2 (PAK2) becomes activated and drives estrogen-independent growth. PAK2 overexpression is also associated with endocrine therapy resistance and worse clinical outcome, and the combination of a PAK2 inhibitor with an ER antagonist synergistically suppressed breast tumor growth. Clinical approaches to endocrine therapy-resistant breast cancer must overcome the loss of this estrogen-induced negative feedback loop that normally constrains the growth of ER+ tumors. PMID- 29987052 TI - Size-dependent dynamic structures of supported gold nanoparticles in CO oxidation reaction condition. AB - Gold (Au) catalysts exhibit a significant size effect, but its origin has been puzzling for a long time. It is generally believed that supported Au clusters are more or less rigid in working condition, which inevitably leads to the general speculation that the active sites are immobile. Here, by using atomic resolution in situ environmental transmission electron microscopy, we report size-dependent structure dynamics of single Au nanoparticles on ceria (CeO2) in CO oxidation reaction condition at room temperature. While large Au nanoparticles remain rigid in the catalytic working condition, ultrasmall Au clusters lose their intrinsic structures and become disordered, featuring vigorous structural rearrangements and formation of dynamic low-coordinated atoms on surface. Ab initio molecular dynamics simulations reveal that the interaction between ultrasmall Au cluster and CO molecules leads to the dynamic structural responses, demonstrating that the shape of the catalytic particle under the working condition may totally differ from the shape under the static condition. The present observation provides insight on the origin of superior catalytic properties of ultrasmall gold clusters. PMID- 29987051 TI - Integrative analysis of single-cell genomics data by coupled nonnegative matrix factorizations. AB - When different types of functional genomics data are generated on single cells from different samples of cells from the same heterogeneous population, the clustering of cells in the different samples should be coupled. We formulate this "coupled clustering" problem as an optimization problem and propose the method of coupled nonnegative matrix factorizations (coupled NMF) for its solution. The method is illustrated by the integrative analysis of single-cell RNA-sequencing (RNA-seq) and single-cell ATAC-sequencing (ATAC-seq) data. PMID- 29987053 TI - Phenotypic plasticity of Drosophila suzukii wing to developmental temperature: implications for flight. AB - Phenotypic plasticity has been proposed as a mechanism that facilitates the success of biological invasions. In order to test the hypothesis of an adaptive role for plasticity in invasions, particular attention should be paid to the relationship between the focal plastic trait, the environmental stimulus and the functional importance of the trait. The Drosophila wing is particularly amenable to experimental studies of phenotypic plasticity. Wing morphology is known for its plastic variation under different experimental temperatures, but this plasticity has rarely been investigated in a functional context of flight. Here, we investigate the effect of temperature on wing morphology and flight in the invasive pest species Drosophila suzukii Although the rapid invasion of both Europe and North America was most likely facilitated by human activities, D. suzukii is also expected to disperse actively. By quantifying wing morphology and individual flight trajectories of flies raised under different temperatures, we tested whether (1) invasive populations of D. suzukii show higher phenotypic plasticity than their native counterparts, and (2) wing plasticity affects flight parameters. Developmental temperature was found to affect both wing morphology and flight parameters (in particular speed and acceleration), leaving open the possibility of an adaptive value for wing plasticity. Our results show no difference in phenotypic plasticity between invasive and native populations, rejecting a role for wing plasticity in the invasion success. PMID- 29987056 TI - Drug shortages a daily concern for emergency departments. PMID- 29987057 TI - Option to run outsourcing facility gains ground for hospitals, health systems. PMID- 29987058 TI - Physical compatibility of milrinone with levofloxacin and ceftriaxone injection. PMID- 29987059 TI - Entry-level practice requirements of pharmacy technicians across the United States: A review. AB - PURPOSE: The results of a review of statutes and regulations to determine entry level requirements for pharmacy technicians across the 50 states and the District of Columbia in terms of training and certification are reported. METHODS: Pharmacy practice acts in all 51 jurisdictions were reviewed to ascertain initial qualifications for training, certification, registration, and/or licensure of pharmacy technicians using the keywords technician, registration, licensure, training, education, and certification. One reviewer analyzed statutes and regulations in force as of March 2017. RESULTS: Among the 50 states and the District of Columbia, 86% (44 of 51) required pharmacy board registration and/or licensure in order to practice as a pharmacy technician; 55% (28 of 51) required no education/training or certification, 8% (4 of 51) required education/training only, 10% (5 of 51) required certification only, 14% (7 of 51) required education/training and certification, and 14% (7 of 51) required either education/training or certification. CONCLUSION: There is no consensus among the 50 states and the District of Columbia regarding entry-level requirements for pharmacy technicians, which range from no oversight to mandatory training/education with or without certification requirements. Several national organizations have set recommendations for minimal education/training and certification; however, there is no uniform acceptance across the United States. PMID- 29987060 TI - Clinical and financial effects of smart pump-electronic medical record interoperability at a hospital in a regional health system. AB - PURPOSE: The pharmacist-led implementation of a smart pump-electronic medical record (EMR) interoperability program at a hospital within a regional health system is described. SUMMARY: Smart pump-EMR interoperability involves a wireless, bidirectional connection by which infusion information transmitted by the EMR prepopulates infusion devices, reducing keystokes and opportunities for manual programming errors. The smart pumps transmit time-stamped infusion data to the EMR for nurse documentation. Use of interoperability technology forces the use of dose-error reduction software so that 100% of prepopulated infusions and dosage adjustments are protected. To improve i.v. medication safety and documentation at a 286-bed hospital within an 8-hospital health system, pharmacists led an initiative to implement smart pump-EMR interoperability as a first step toward systemwide implementation. The hospital's smart pump-EMR interoperability initiative resulted in patient safety and revenue-generation gains in the first 8 months after implementation. The mean number of keystrokes needed to program an infusion was reduced from 15 to 2 (an 86% decrease). Pump alerts, alert overrides, and reprogrammed or cancelled infusions were decreased. In addition, the program improved outpatient charge capture, resulting in $370,000 in incremental revenue. CONCLUSION: A pharmacist-led implementation of smart pump-EMR interoperability led to measurable, data-based improvements in i.v. medication safety and improved accuracy, timeliness, and efficiency of i.v. infusion documentation. Revenue was increased due to improved charge capture for outpatient i.v. infusions. PMID- 29987061 TI - Harmonization of technology across an integrated delivery network. AB - PURPOSE: A standardized blueprint for use when harmonizing or standardizing pharmacy automation and technology resources across individual institutions or an integrated delivery network (IDN) of institutions is described. SUMMARY: Whether to strive for standardization (use of the same vendors and equipment) versus harmonization (use of various technologies to meet patient-specific needs and organizational stability requirements) and how to coordinate activities across IDNs consisting of 3-30 or more hospitals are common questions due to consolidations in the healthcare industry. For most IDNs with legacy systems, harmonization may be the better option. Large-scale harmonization initiatives require significant planning and coordination involving all affected parties. Detailed project plans should include the compiling of all associated harmonization costs that involve human resources, information on ongoing services and equipment, and program schedules for multiple concurrent projects in order to provide a framework for planning and coordination. Part of the planning process for harmonization efforts should include an extensive current-state analysis that includes review of contracts and vendors. Final harmonization decisions should be based on a mix of vendor recommendations, best practices, and accommodation of current practices that result in the lowest complexity of system redesign with regard to existing systems. When harmonizing existing technologies, planning must also consider the impact of the change to both the organization and individual users. CONCLUSION: Harmonization is an evaluative process whereby process variation due to automation and technology variability can be reduced and organizational interoperability to meet patient-specific needs can be promoted. PMID- 29987062 TI - Stories and Stuff. PMID- 29987063 TI - Locally Prepared Solutions for Treating AKI in Low-Resource Environments. PMID- 29987064 TI - The Power of the Patient Voice: Conducting and Using Qualitative Research to Improve Care and Outcomes in Peritoneal Dialysis. PMID- 29987065 TI - Increasing Staphylococcus Species Resistance in Peritoneal Dialysis-Related Peritonitis over a 10-Year Period in a Single Taiwanese Center. AB - BACKGROUND: Peritonitis is a major complication of peritoneal dialysis (PD). Staphylococcus species are gram-positive bacteria that are most commonly associated with peritoneal peritonitis. The increasing antimicrobial resistance rate is a severe burden when considering the initial choice of antibiotics. This investigation examined the trends of staphylococcal infection as well as the resistance rate and clinical outcomes from 2006 to 2015 in southern Taiwan. METHODS: We retrospectively investigated all PD-related peritonitis episodes in southern Taiwan between January 2006 and December 2015 and evaluated the clinical characteristics of peritonitis, microbiological prevalence and resistance of Staphylococcus species, and outcomes in patients. RESULTS: Among 244 episodes of peritonitis, Staphylococcus species accounted for approximately 65% of the gram positive bacteria that caused the infection. The methicillin resistance rate among Staphylococcus species substantially increased to 64% by 2015 in both Staphylococcus aureus and coagulase-negative staphylococci in southern Taiwan. Notably, patients with methicillin-resistant staphylococcal infection exhibited a significantly higher hospitalization rate than those with methicillin-sensitive staphylococcal infection. However, the catheter removal rate and transfer to hemodialysis exhibited no differences between the 2 groups. CONCLUSION: Peritonitis is the most serious complication in patients on PD, and microbiological trends have changed over the past 10 years at a single center in southern Taiwan. The number of methicillin-resistant Staphylococcus species has substantially increased. Empirical initial antibiotic therapy should be adapted on the basis of the growing microbiological resistance. PMID- 29987066 TI - A Retrospective Sequential Comparison of Topical Application of Medicated Honey and Povidone Iodine for Preventing Peritoneal Dialysis Catheter-Related Infections. AB - Application of medicated honey (MH) to peritoneal dialysis (PD) catheter exit sites has been found to be as effective as intra-nasal mupirocin for preventing PD catheter-related infections (CRIs), but was associated with increased risk for CRIs in diabetics. The efficacy of topical MH as a prophylactic agent has not been compared with the exit-site application of povidone iodine (PI). This retrospective multicentre cohort study compared cumulative incidence rates of PD CRIs (peritonitis or exit-site infections) and the number of PD CRIs observed per patient over the study period with PD exit-site application of MH or PI, in both diabetic and non-diabetic patients. Outcomes were compared in incident patients in 2 eras: January 2011 - December 2012, when 147 received exit-site care with PI (PI group), and July 2013 - June 2015, when 171 patients applied MH (MH group). Patients were followed until technique failure, death, transplant, or end of study treatment era. Cumulative incidence of PD CRIs was higher in the PI group (hazard ratio [HR] = 1.7, 95% confidence interval [CI] 1.1 - 2.6, p = 0.019) and the benefit of MH was not modified by diabetic status (present/absent, interaction p = 0.723). A similar trend was observed in the cumulative incidence of peritonitis (HR = 1.6, 95% CI 0.99 - 2.6, p = 0.059). After adjusting for months of exposure, the rate ratio for PD CRIs was 1.58 for PI compared to MH (95% CI, 1.03 - 2.42, p = 0.035). We conclude that exit-site application of MH is more effective than PI in preventing PD CRIs, and this effect is not modified by the presence or absence of diabetes. PMID- 29987067 TI - "Why I Chose Hemodialysis Over Peritoneal Dialysis": An Opinion Survey Among In Center Hemodialysis Patients. AB - Peritoneal dialysis (PD) penetration in India remains low despite the huge chronic kidney disease burden and unmet need for renal replacement therapy (RRT). In order to understand the socioeconomic reasons that govern patients' preference for hemodialysis (HD), we carried out an opinion survey among prevalent in-center HD patients at our institution using a multiple response questionnaire that was verbally administered to them at the dialysis facility by the investigators. Close to 80% were self-financed and 49.5% were on twice weekly HD. Despite the majority (95%) receiving RRT education from a nephrologist, 43.4% were not aware of PD as an RRT modality. The treating nephrologist's recommendation was the most important reason given for choosing HD (77.8%) and not choosing PD (69.7%). Other reasons for not choosing PD included lack of a dedicated caregiver or "clean area" at home (15.1%), fear of infection (15.1%), disruption of work (14.1%), and the high cost of PD (7%). The perceived advantages of HD over PD were greater convenience because of need for only twice or thrice weekly sessions (61%), supervised care received in a hospital setting (28.8%), and less disruption of the patient's and family's routine (22%). We discuss the implications of these findings and what policy makers and nephrologists in India and other developing countries can do to improve PD penetration and utilization. PMID- 29987068 TI - Inconsistencies in ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment and The ISPD Catheter-Related Infection Recommendations: 2017 Update. PMID- 29987070 TI - ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment. PMID- 29987069 TI - Concerns Regarding Inconsistencies Within and Between ISPD Recommendations for Peritonitis and Catheter-Related Infections-In Reply. PMID- 29987071 TI - United Kingdom Catheter Study - Protocol Synopsis. PMID- 29987072 TI - Building a Pipeline to Equity. PMID- 29987073 TI - CORRECTIONS. PMID- 29987074 TI - CORRECTIONS. PMID- 29987075 TI - Influence of a New Diabetes Diagnosis on the Health Behaviors of the Patient's Partner. AB - PURPOSE: When a person is given a diagnosis of diabetes, the changes in his or her health behaviors may influence the behaviors of his or her partner. The diabetes diagnosis may affect household members' perceptions of their own health risks, which could trigger behavioral change. The purpose of this study was to assess whether partners of persons with newly diagnosed diabetes changed their health behaviors compared with partners of persons without diabetes. METHODS: The study population consisted of Kaiser Permanente Northern California health plan members from 2007 to 2011. This cohort study assessed differences in change of 8 health behaviors. The study compared coresiding partners of persons with newly diagnosed diabetes before and after a diabetes diagnosis with a 5 to 1 matched sample of coresiding partners of persons without diabetes. RESULTS: A total of 180,910 couples were included in the analysis. After adjusting for baseline characteristics, partners of persons with newly diagnosed diabetes had significantly higher rates of participation in weight management-related health education classes (risk ratio [RR] = 1.50; 95% CI, 1.39-1.63); smoking cessation medication use (RR = 1.25; 95% CI, 1.05-1.50); glucose screening (RR = 1.07; 95% CI, 1.05-1.08); clinically meaningful weight loss (RR = 1.06; 95% CI, 1.02-1.11); lipid screening (RR = 1.05; 95% CI, 1.04-1.07); influenza vaccination (RR = 1.03; 95% CI, 1.02-1.04); and blood pressure screening (RR = 1.02; 95% CI, 1.02-1.03) compared with partners of persons without diabetes. CONCLUSIONS: There were small but significant differences in health-related behavioral changes among partners of persons with newly diagnosed diabetes compared with partners of persons without diabetes, even when no intervention occurred. This finding suggests a diabetes diagnosis within a family may be a teachable moment to improve health behaviors at the household level. PMID- 29987076 TI - Association Between Alcohol Consumption and Nocturnal Leg Cramps in Patients Over 60 Years Old: A Case-Control Study. AB - PURPOSE: Nocturnal leg cramps are a specific kind of cramps affecting almost one half of patients aged 60 years and older. They reduce patients' quality of sleep and have a negative impact on their quality of life. The aim of this study was to evaluate the association between nocturnal leg cramps and the consumption of alcoholic beverages in patients aged 60 years and older attending general practices. METHODS: Case-control study with a Bayesian approach for sensitivity analysis. Participants were voluntary ambulatory patients aged 60 years and older consulting their family doctor. They were recruited in 67 general practices across the Alsace region. Cases (patients having cramps), were matched with controls (patients free from cramps) for age, sex, medical history, and medications known to trigger cramps. Alcohol consumption was assessed through a standardized food frequency questionnaire. RESULTS: We found an association between the global consumption of alcoholic beverages and nocturnal leg cramps (OR = 6.5, 95% credibility interval, 1.68-38.05; posterior probability 99.82%). CONCLUSION: We identified an association between alcohol consumption and nocturnal leg cramps among patients aged 60 years and older attending general practices. These findings have implications for the prevention of cramps. PMID- 29987077 TI - Community College Pathways to Medical School and Family Medicine Residency Training. AB - PURPOSE: Medical students who attend community college are more likely to express intention to train in family medicine. This study examined whether community college attendance is associated with family medicine residency training in a national sample of US medical school graduates. METHODS: We performed a cross sectional analysis using the Association of American Medical Colleges matriculant files of residency trainees who graduated from medical school between 2010 to 2012. Residency specialty (family medicine vs other) was modeled using logistic regression analysis; the key independent variable was community college attendance, with categories of non-community college (reference); community college while in high school; community college after graduating from high school, then transfer to 4-year university; and community college after graduating from a 4-year university or as a postbaccalaureate. The logistic model adjusted for age, sex, race/ethnicity, years in medical school, parental education (a marker of socioeconomic status), and high school US region. RESULTS: Of the 43,382 medical school graduates studied, 25.9% attended community college and 8.7% trained in family medicine. In unadjusted analysis, graduates attending community college while in high school, after graduating from high school with transfer to 4-year university, or after graduating from a 4-year university or as a postbaccalaureate (12.0%, 12.7%, and 10.8%, respectively) were more likely to train in family medicine compared with their peers who did not attend community college (7.7%). Respective adjusted odds ratios were 1.47 (95% CI, 1.33-1.63; P <.001), 1.27 (95% CI, 1.06-1.52; P = .009), and 1.17 (95% CI, 1.06-2.29; P = .002). Among family medicine residents, 32.7% of those who were white, 35.2% of those Asian, 50.8% of those Latino, and 32.7% of those black or African American attended community college. CONCLUSIONS: US medical school graduates who attended community college were more likely to train in family medicine, suggesting community college is an important pathway for increasing the primary care workforce. PMID- 29987078 TI - Finance and Time Use Implications of Team Documentation for Primary Care: A Microsimulation. AB - PURPOSE: To estimate the conditions under which team documentation-having a staff member enter history, place orders, and guide patients-would be financially viable at primary care practices, accounting for implementation costs. METHODS: We applied a validated microsimulation model of practice costs, revenues, and time use to data from 643 US primary care practices. We estimated critical threshold values for time saved from routine visits that would need to be redirected to new visits to avoid net revenue losses under: (1) a clerical documentation assistant (CDA) strategy where a scribe assists with recordkeeping; and (2) an advanced team-based care (ATBC) strategy where medical assistants perform history, documentation, counseling, and order entry. RESULTS: Using a fee for-service model, we estimated that physicians would need to save 3.5 (95% CI, 3.3-3.7) minutes/encounter under a CDA strategy and 7.4 (95% CI, 4.3-10.5) minutes/encounter under an ATBC strategy to prevent net revenue losses. The redirected time would be expected to add 317 visit slots per year under CDA strategy, and 720 under ATBC strategy. Using a capitated payment model, physicians would need to empanel at least 127 (95% CI, 70-187) more patients under CDA and 227 (95% CI, 153-267) under ATBC to prevent revenue losses. Additional patient visits expected would be 279 (95% CI, 140-449) additional visit slots per year under CDA and 499 (95% CI, 454-641) under ATBC. CONCLUSIONS: Financial viability of team documentation under fee-for-service payment may require more physician time to be reallocated to patient encounters than under a capitated payment model. PMID- 29987079 TI - Booklet for Childhood Fever in Out-of-Hours Primary Care: A Cluster-Randomized Controlled Trial. AB - PURPOSE: Fever is the most common reason for a child to be taken to a physician, yet the level of unwarranted antibiotic prescribing remains high. We aimed to determine the effect on antibiotic prescribing of providing an illness-focused interactive booklet on fever in children to out-of-hours primary care clinicians. METHODS: We conducted a cluster-randomized controlled trial in 20 out-of-hours general practice centers in the Netherlands. Children aged younger than 12 years with fever were included. Family physicians at the 10 intervention sites had access to an illness-focused interactive booklet between November 2015 and June 2016. The primary outcome was antibiotic prescribing during the index consultation. Analysis was performed by fitting 2-level random intercept logistic regression models. RESULTS: The trial took place among 3,518 family physicians and 25,355 children. The booklet was used in 28.5% of 11,945 consultations in the intervention group. Compared with usual care, access to the booklet did not significantly alter antibiotic prescribing during the index consultation (odds ratio = 0.90; 95% CI, 0.79-1.02; prescription rate, 23.5% vs 25.2%; intracluster correlation coefficient = 0.005). In contrast, use of the booklet significantly reduced antibiotic prescribing (odds ratio = 0.83; 95% CI, 0.74-0.94; prescription rate, 21.9% vs 25.2%; intracluster correlation coefficient = 0.002). Children managed by family physicians with access to the booklet were less likely to receive any drug prescription, and parents in the booklet group showed a reduced intention to consult again for similar illnesses. CONCLUSIONS: Benefit of an illness-focused interactive booklet in improving outcomes of childhood fever in out-of-hours primary care was largely restricted to the cases in which family physicians actually used the booklet. Insight into reasons for use and nonuse may inform future interventions of this type. PMID- 29987080 TI - Predicting Incident Multimorbidity. AB - PURPOSE: Multimorbidity is associated with adverse outcomes, yet research on the determinants of its incidence is lacking. We investigated which sociodemographic, health, and individual lifestyle (eg, physical activity, smoking behavior, body mass index) characteristics predict new cases of multimorbidity. METHODS: We used data from 4,564 participants aged 50 years and older in the English Longitudinal Study of Aging that included a 10-year follow-up period. Discrete time-to-event (complementary log-log) models were constructed for exploring the associations of baseline characteristics with outcomes between 2002-2003 and 2012-2013 separately for participants with no initial conditions (n = 1,377) developing multimorbidity, any increase in conditions within 10 years regardless of initial conditions, and the impact of individual conditions on incident multimorbidity. RESULTS: The risks of developing multimorbidity were positively associated with age, and they were greater for the least wealthy, for participants who were obese, and for those who reported the lowest levels of physical activity or an external locus of control (believing that life events are outside of one's control) for all groups regardless of baseline conditions (all linear trends <.05). No significant associations were observed for sex, educational attainment, or social detachment. For participants with any increase in conditions (n = 4,564), a history of smoking was the only additional predictor. For participants with a single baseline condition (n = 1,534), chronic obstructive pulmonary disease (COPD), asthma, and arrhythmia showed the strongest associations with subsequent multimorbidity. CONCLUSIONS: Our findings support the development and implementation of a strategy targeting the prevention of multimorbidity for susceptible groups. This approach should incorporate behavior change addressing lifestyle factors and target health-related locus of control. PMID- 29987082 TI - Mental Health Messages in Prominent Mental Health Apps. AB - PURPOSE: Many who seek primary health care advice about mental health may be using mobile applications (apps) claiming to improve well-being or relieve symptoms. We aimed to identify how prominent mental health apps frame mental health, including who has problems and how they should be managed. METHODS: We conducted a qualitative content analysis of advertising material for mental health apps found online in the United States, the United Kingdom, Canada, and Australia during late 2016. Apps were included if they explicitly referenced mental health diagnoses or symptoms and offered diagnosis and guidance, or made health claims. Two independent coders analyzed app store descriptions and linked websites using a structured, open-ended instrument. We conducted interpretive analysis to identify key themes and the range of messages. RESULTS: We identified 61 mental health apps: 34 addressed predominantly anxiety, panic, and stress (56%), 16 addressed mood disorders (26%), and 11 addressed well-being or other mental health issues (18%). Apps described mental health problems as being psychological symptoms, a risk state, or lack of life achievements. Mental health problems were framed as present in everyone, but everyone was represented as employed, white, and in a family. Explanations about mental health focused on abnormal responses to mild triggers, with minimal acknowledgment of external stressors. Therapeutic strategies included relaxation, cognitive guidance, and self-monitoring. Apps encouraged frequent use and promoted personal responsibility for improvement. CONCLUSIONS: Mental health apps may promote medicalization of normal mental states and imply individual responsibility for mental well-being. Within the health care clinician-patient relationship, such messages should be challenged, where appropriate, to prevent overdiagnosis and ensure supportive health care where needed. PMID- 29987081 TI - The Evaluation of Physicians' Communication Skills From Multiple Perspectives. AB - PURPOSE: To examine how family physicians', patients', and trained clinical raters' assessments of physician-patient communication compare by analysis of individual appointments. METHODS: Analysis of survey data from patients attending face-to-face appointments with 45 family physicians at 13 practices in England. Immediately post-appointment, patients and physicians independently completed a questionnaire including 7 items assessing communication quality. A sample of videotaped appointments was assessed by trained clinical raters, using the same 7 communication items. Patient, physician, and rater communication scores were compared using correlation coefficients. RESULTS: Included were 503 physician patient pairs; of those, 55 appointments were also evaluated by trained clinical raters. Physicians scored themselves, on average, lower than patients (mean physician score 74.5; mean patient score 94.4); 63.4% (319) of patient-reported scores were the maximum of 100. The mean of rater scores from 55 appointments was 57.3. There was a near-zero correlation coefficient between physician-reported and patient-reported communication scores (0.009, P = .854), and between physician-reported and trained rater-reported communication scores (-0.006, P = .69). There was a moderate and statistically significant association, however, between patient and trained-rater scores (0.35, P = .042). CONCLUSIONS: The lack of correlation between physician scores and those of others indicates that physicians' perceptions of good communication during their appointments may differ from those of external peer raters and patients. Physicians may not be aware of how patients experience their communication practices; peer assessment of communication skills is an important approach in identifying areas for improvement. PMID- 29987083 TI - Perceptions of Primary Care Notes by Patients With Mental Health Diagnoses. AB - There are concerns regarding whether patients with mental illness should be provided with access to their electronic medical records. This study compared perceptions of patients with (n = 400) and without (n = 2,134) a mental health diagnosis regarding access to primary care clinic notes through secure online portals. Eligible participants viewed at least 1 clinic note during a 12-month period. Administrative data were used to stratify patients by mental health diagnosis. As we hypothesized, patients with and without mental health diagnoses had similar perceptions about online access to notes. PMID- 29987084 TI - Warm Handoffs and Attendance at Initial Integrated Behavioral Health Appointments. AB - Though integrated behavioral health programs often encourage primary care physicians to refer patients by means of a personal introduction (warm handoff), data are limited regarding the benefits of warm handoffs. We conducted a retrospective study of adult primary care patients referred to behavioral health clinicians in an urban, safety-net hospital to investigate the association between warm handoffs and attendance rates at subsequent initial behavioral health appointments. In multivariable analyses, patients referred via warm handoffs were not more likely to attend initial appointments (OR = 0.96; 95% CI, 0.79-1.18; P = .71). A prospective study is necessary to confirm the role of warm handoffs. PMID- 29987086 TI - Solving the Diagnostic Challenge: A Patient-Centered Approach. AB - Arriving at an agreed-on and valid explanation for a clinical problem is important to patients as well as to clinicians. Current theories of how clinicians arrive at diagnoses, such as the threshold approach and the hypothetico-deductive model, do not accurately describe the diagnostic process in general practice. The problem space in general practice is so large and the prior probability of each disease being present is so small that it is not realistic to limit the diagnostic process to testing specific diagnoses on the clinician's list of possibilities. Here, new evidence is discussed about how patients and clinicians collaborate in specific ways, in particular, via a process that can be termed inductive foraging, which may lead to information that triggers a diagnostic routine. Navigating the diagnostic challenge and using patient centered consulting are not separate tasks but rather synergistic. PMID- 29987085 TI - Physicians' Views of Self-Monitoring of Blood Glucose in Patients With Type 2 Diabetes Not on Insulin. AB - This qualitative study examines to what extent and why physicans still prescribe self-monitoring of blood glucose (SMBG) in patients with non-insulin-treated type 2 diabetes (NITT2D) when the evidence shows it increases cost without improving hemoglobin A1c (HbA1c), general well being, or health-related quality of life. Semistructured phone interviews with 17 primary care physicians indicated that the majority continue to recommend routine self-monitoring of blood glucose due to a compelling belief in its ability to promote the lifestyle changes needed for glycemic control. Targeting physician beliefs about the effectiveness of self monitoring of blood glucose, and designing robust interventions accordingly, may help reduce this practice. PMID- 29987087 TI - Continuity and Access in the Era of Part-Time Practice. AB - The number of physicians seeing patients part time is growing, an evolution that challenges the primary care pillars of continuity and access. The growth of part time practice is a response to burnout and to the pressures facing primary care physicians. Physicians who work fewer clinical hours and thereby reduce burnout are more satisfied with their careers, less likely to leave their jobs, and provide a better patient experience. Primary care practices can make a number of adjustments to optimize continuity and access in this era of part-time practice. Moreover, physicians who work fewer clinical hours are equally capable of fostering trusting relationships with patients as physicians seeing patients full time. PMID- 29987088 TI - They Didn't Believe Her Pain: My Education in Interpersonal Violence. AB - In my first year of medical school, I began to care for patients who were survivors of interpersonal violence. As I transitioned from didactics to clinical experiences, I was struck by how common the hidden threads of physical and sexual violence were in my patients' stories of chronic pain, depression, and poor health outcomes. Their symptoms often seemed intangible and challenging to treat, unable to fit neatly into typical diagnostic and therapeutic algorithms. In response, I saw clinicians become frustrated and dissatisfied with their ability to treat these patients. Better care for survivors may begin simply with believing our patients' pain. PMID- 29987090 TI - Fully Integrating Medical Acupuncture Into Family Medicine. PMID- 29987089 TI - On Blindness and Blind Spots. AB - This story is a reflection on the evolving relationship of a family physician with a patient suffering from a severe conversion disorder, expressed inter alia through "blindness." The narrative follows our journey as I attempt to unravel the meaning of the symptoms as a metaphoric expression of her agony. Eventually, I conclude that clinicians at times also may have a "blind spot" that prevents us from entirely grasping patients' complex inner struggles. PMID- 29987091 TI - STFM FOUNDATION LAUNCHES CAMPAIGN TO SUPPORT UNDERREPRESENTED IN MEDICINE. PMID- 29987092 TI - THE IMPERATIVE FOR A COLLECTIVE IMPACT APPROACH AMONG FAMILY MEDICINE ORGANIZATIONS. PMID- 29987093 TI - JOYS OF BEING A PROGRAM DIRECTOR. PMID- 29987094 TI - REVITALIZING GENERALIST PRACTICE: THE MONTREAL STATEMENT. PMID- 29987095 TI - AAFP CREDIT SYSTEM RECONSIDERS FUNCTIONAL MEDICINE TOPICS. PMID- 29987096 TI - AMERICAN BOARD OF FAMILY MEDICINE ELECTS NEW OFFICERS AND BOARD MEMBERS. PMID- 29987097 TI - Association Between Alcohol Consumption and Nocturnal Leg Cramps. PMID- 29987098 TI - Rural-Urban Disparities in Time to Diagnosis and Treatment for Colorectal and Breast Cancer. AB - Background: Longer cancer pathways may contribute to rural-urban survival disparities, but research in this area is lacking. We investigated time to diagnosis and treatment for rural and urban patients with colorectal or breast cancer in Victoria, Australia.Methods: Population-based surveys (2013-2014) of patients (aged >=40, approached within 6 months of diagnosis), primary care physicians (PCPs), and specialists were collected as part of the International Cancer Benchmarking Partnership, Module 4. Six intervals were examined: patient (symptom to presentation), primary care (presentation to referral), diagnostic (presentation/screening to diagnosis), treatment (diagnosis to treatment), health system (presentation to treatment), and total interval (symptom/screening to treatment). Rural and urban intervals were compared using quantile regression including age, sex, insurance, and socioeconomic status.Results: 433 colorectal (48% rural) and 489 breast (42% rural) patients, 621 PCPs, and 370 specialists participated. Compared with urban patients, patients with symptomatic colorectal cancer from rural areas had significantly longer total intervals at the 50th [18 days longer, 95% confidence interval (CI): 9-27], 75th (53, 95% CI: 47-59), and 90th percentiles (44, 95% CI: 40-48). These patients also had longer diagnostic and health system intervals (6-85 days longer). Breast cancer intervals were similar by area of residence, except the patient interval, which was shorter for rural patients with either cancer in the higher percentiles.Conclusions: Rural residence was associated with longer total intervals for colorectal but not breast cancer; with most disparities postpresentation.Impact: Interventions targeting time from presentation to diagnosis may help reduce colorectal cancer rural-urban disparities. Cancer Epidemiol Biomarkers Prev; 27(9); 1036-46. (c)2018 AACR. PMID- 29987099 TI - Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-analysis. AB - It has been shown that human papillomavirus (HPV) and p16 status has prognostic value in some HPV-associated cancers. However, studies examining survival in men with penile cancer according to HPV or p16 status are often inconclusive, mainly because of small study populations. The aim of this systematic review and meta analysis was to examine the association between HPV DNA and p16 status and survival in men diagnosed with penile cancer. Multiple electronic databases were searched. Twenty studies were ultimately included and study-specific and pooled HRs of overall survival and disease-specific survival (DSS) were calculated using a fixed effects model. In the analysis of DSS, we included 649 men with penile cancer tested for HPV (27% were HPV-positive) and 404 men tested for p16 expression (47% were p16-positive). The pooled HRHPV of DSS was 0.61 [95% confidence interval (CI), 0.38-0.98], and the pooled HRp16 of DSS was 0.45 (95% CI, 0.30-0.69). In conclusion, men with HPV or p16-positive penile cancer have a significantly more favorable DSS compared with men with HPV or p16-negative penile cancer. These findings point to the possible clinical value of HPV and p16 testing when planning the most optimal management and follow-up strategy. Cancer Epidemiol Biomarkers Prev; 27(10); 1123-32. (c)2018 AACR. PMID- 29987100 TI - Computed Tomography and Adrenal Venous Sampling in the Diagnosis of Unilateral Primary Aldosteronism. AB - Unilateral primary aldosteronism is the most common surgically correctable form of endocrine hypertension and is usually differentiated from bilateral forms by adrenal venous sampling (AVS) or computed tomography (CT). Our objective was to compare clinical and biochemical postsurgical outcomes of patients with unilateral primary aldosteronism diagnosed by CT or AVS and identify predictors of surgical outcomes. Patient data were obtained from 18 internationally distributed centers and retrospectively analyzed for clinical and biochemical outcomes of adrenalectomy of patients with surgical management based on CT (n=235 patients, diagnosed from 1994-2016) or AVS (526 patients, diagnosed from 1994 2015) using the standardized PASO (Primary Aldosteronism Surgical Outcome) criteria. Biochemical outcomes were highly different according to surgical management approach with a smaller proportion in the CT group achieving complete biochemical success (188 of 235 [80%] patients versus 491 of 526 [93%], P<0.001) and a greater proportion with absent biochemical success (29 of 235 [12%] versus 10 of 526 [2%], P<0.001). A diagnosis by CT was associated with a decreased likelihood of complete biochemical success compared with AVS (odds ratio, 0.28; 0.16-0.50; P<0.001). Clinical outcomes were not significantly different, but the absence of a postsurgical elevated aldosterone-to-renin ratio was a strong marker of complete clinical success (odds ratio, 14.81; 1.76-124.53; P=0.013) in the CT but not in the AVS group. In conclusion, patients diagnosed by CT have a decreased likelihood of achieving complete biochemical success compared with a diagnosis by AVS. PMID- 29987101 TI - Epithelial Sodium Channel in Aldosterone-Induced Endothelium Stiffness and Aortic Dysfunction. AB - Enhanced activation of the endothelial mineralocorticoid receptor contributes to the development of arterial stiffness, which is an independent predictor of cardiovascular disease. Previously, we showed that enhanced endothelium mineralocorticoid receptor signaling in female mice prompts expression and translocation of the alpha-subunit of the epithelial sodium channel to the endothelial cell (EC) surface (EnNaC) inducing vascular fibrosis and stiffness. Further, amiloride, an epithelial sodium channel antagonist, inhibits vascular fibrosis, remodeling, and stiffness induced by feeding a Western diet high in saturated fat and refined carbohydrates. However, how this occurs remains unknown. Thereby, we hypothesized that endothelial cell-specific EnNaC activation is necessary for aldosterone-mediated endothelium stiffness. To address this notion, EnNaC alpha-subunit knockout (EnNaC-/-) and wild-type littermate female mice were administrated aldosterone (250 ug/kg per day) via osmotic minipumps for 3 weeks beginning at 25 to 28 weeks of age. In isolated mouse endothelial cells, inward sodium currents were significantly reduced in amiloride controls, as well as in EnNaC-/-. Likewise, aldosterone-induced endothelium stiffness was increased and endothelium-dependent relaxation less in EnNaC-/- versus wild-type. Further, EnNaC-/- mice exhibited attenuated responses to aldosterone infusion, including aortic endoplasmic reticulum stress, endothelium nitric oxide synthase activation, endothelium permeability, expression of proinflammatory cytokines, oxidative stress, and aortic collagen 1 deposition, supporting the notion that alphaEnNaC subunit activation contributes to these vascular responses. PMID- 29987102 TI - SHIP-AHOY (Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth). AB - Although hypertension is identifiable in children and adolescents, there are many knowledge gaps on how to best define and manage high blood pressure in the young. SHIP-AHOY (Study of High Blood Pressure in Pediatrics: Adult Hypertension Onset in Youth) is being conducted to address these knowledge gaps. Five hundred adolescents will be recruited and will undergo ambulatory blood pressure monitoring, echocardiographic, vascular, and cognitive assessments, as well as epigenetic studies to identify mechanisms that underlie the development of hypertensive target organ damage. Details of the design and methods that will be utilized in SHIP-AHOY are presented here, as well as baseline characteristics of the first 264 study participants. The primary aim of the study is to develop a risk-based definition of hypertension in the young that will result in better understanding of the transition from blood pressure in youth to adult cardiovascular disease. PMID- 29987103 TI - Involvement of Arterial Stiffness and Inflammation in Hyperuricemia-Related Development of Hypertension. AB - This study analyzed repeated measurement data to clarify the longitudinal associations between hyperuricemia and the risk factors for the development of hypertension (ie, increased arterial stiffness, renal dysfunction, and inflammation), and then examined whether these risk factors show longitudinal associations with the development of hypertension. In 3274 Japanese men without hypertension, the brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum uric acid and CRP (C-reactive protein) levels were measured annually over an 8-year period. Of these, 474 subjects developed hypertension by the end of the study period. Mixed model linear regression analysis revealed a significant longitudinal association of hyperuricemia with increase of the brachial-ankle pulse wave velocity (estimate=5.50, P=0.04), decrease of the estimated glomerular filtration rate (estimate=-2.02, P<0.01), and elevation of the CRP (estimate=0.08*10-1, P=0.02). Hyperuricemia at the study baseline was associated with a significant odds ratio for the development of hypertension by the end of the study period. After adjustments for covariates, the brachial-ankle pulse wave velocity (estimate=0.51*10-2, P<0.01) and CRP (estimate=1.91, P=0.03), but not estimated glomerular filtration rate, were found to show independent longitudinal associations with the new onset of hypertension. In Japanese men without hypertension, hyperuricemia may have a longitudinal association with the development of hypertension, and increased arterials stiffness and inflammation may be involved in the risk of development of hypertension associated with hyperuricemia. PMID- 29987105 TI - Objective but Not Subjective Short Sleep Duration Is Associated With Hypertension in Obstructive Sleep Apnea. AB - Extremes of sleep duration and obstructive sleep apnea (OSA) are both associated with hypertension. We aimed to explore whether sleep duration modifies the relationship between OSA and prevalent hypertension, using both objective and subjective measures of total sleep duration. A total of 7107 OSA patients and 1118 primary snorers were included in the study. Hypertension was defined based either on direct blood pressure measures or on diagnosis by a physician. Objective sleep duration was derived by polysomnography and subjective sleep duration was self-reported. Logistic regression models were used to estimate the associations between objective/subjective sleep duration and hypertension prevalence in OSA and primary snorers. Compared with primary snorers, OSA combined with objective sleep duration of 5 to 6 hours increased the odds of hypertension by 45% (odds ratio, 1.45; 95% confidence interval, 1.14-1.84), whereas OSA combined with objective sleep duration <5 hours further increased the odds of hypertension by 80% (odds ratio, 1.80; 95% confidence interval, 1.33 2.42). These results were independent of major confounding factors frequently associated with OSA or hypertension. In stratified analysis by sleep duration, risk of hypertension in those with extremely short sleep (<5 hours) was not significantly different between OSA and primary snorers, whereas odds were significant for OSA in the other 4 sleep duration strata (5-6, 6-7, 7-8, and >8 hours). No significance was evident using subjective sleep duration. We conclude that objective short sleep duration is associated with hypertension in OSA patients. Extremely short sleep duration in itself may actually be even more detrimental than OSA in terms of hypertension risk. PMID- 29987106 TI - Uric Acid and Hypertension Because of Arterial Stiffness. PMID- 29987107 TI - Renin-Angiotensin System in Aortic Aneurysm. PMID- 29987104 TI - Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness. PMID- 29987108 TI - AT2R (Angiotensin AT2 Receptor) Agonist, Compound 21, Prevents Abdominal Aortic Aneurysm Progression in the Rat. AB - The effects of the selective AT2R (angiotensin AT2 receptor) agonist, Compound 21 (C21), on abdominal aortic aneurysm formation were investigated in normotensive Wistar rats. Abdominal aortic aneurysm was induced by perfusion of isolated aortic segments with elastase. Treatment with C21 (0.03 mg/kg daily) was started after operation and continued for 14 days. Sham-operated animals and vehicle treated animals after aneurysm induction served as controls. Aortic diameter, aortic wall distensibility, and pulse propagation velocity were measured via ultrasound. Hemodynamic parameters, aortic tissue protein expression, and serum cytokines were analyzed. On day 14 post aneurysm induction, aortic diameter of vehicle-treated animals was increased 1.6-fold compared with sham-operated rats (2.65+/-0.05 versus 1.70+/-0.06 mm; P<0.0001). C21 decreased aortic diameter in comparison to vehicle (1.9+/-0.06 versus 2.65+/-0.05; P<0.0001). Infrarenal blood velocity and aortic distensibility were reduced, whereas aortic wall stiffness was increased post aneurysm induction. These alterations were significantly ameliorated by treatment with C21 while blood pressure and cardiac contractility remained unchanged. Protein expression of IL-1beta (interleukin-1beta), NFkappaB (nuclear factor kappaB), MMP9 (matrix metalloproteinase 9), TGF-beta1 (transforming growth factor-beta1), and MLKL (mixed lineage kinase domain-like) in the aorta was significantly ( P<0.05) down-regulated in the C21 group compared with vehicle. Serum concentration of TGF-beta1 was decreased by C21 in comparison to vehicle ( P<0.01). AT2R stimulation with C21 prevented extracellular matrix degradation, maintained vascular integrity of the aorta and prevented abdominal aortic aneurysm progression. PMID- 29987109 TI - DPP (Dipeptidyl Peptidase)-4 Inhibition Potentiates the Vasoconstrictor Response to NPY (Neuropeptide Y) in Humans During Renin-Angiotensin-Aldosterone System Inhibition. AB - DPP (dipeptidyl peptidase)-4 inhibitors are antidiabetic drugs that may increase heart failure in high-risk patients. NPY (neuropeptide Y) is coreleased with norepinephrine, causes vasoconstriction via the Y1 receptor, and is degraded by DPP4 to NPY (3-36) in vitro. NPY (3-36) decreases release of norepinephrine via the Y2 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the vasoconstrictor effect of NPY. Eighteen nonsmokers (12 healthy controls and 6 with type 2 diabetes mellitus) participated in 1 of 2 randomized, double-blind, placebo-controlled crossover studies. First, subjects were randomized to order of treatment with sitagliptin 100 mg/d versus placebo for 7 days separated by 4-week washout. On the last day of treatment, NPY was infused by brachial artery and forearm blood flow was measured using plethysmography. Blood samples were collected after each dose. NPY infusions were repeated after 90-minute washout and intra-arterial enalaprilat. Second, 5 healthy subjects were randomized to crossover treatment with sitagliptin 100 mg/d plus valsartan 160 mg/d versus placebo plus valsartan. NPY infusions were performed on the seventh day of treatment. NPY caused dose-dependent vasoconstriction. During enalaprilat, sitagliptin significantly potentiated NPY-induced vasoconstriction in controls and diabetics ( P<=0.02 for forearm blood flow in either group). Baseline norepinephrine release was increased during sitagliptin and enalaprilat, but not further by NPY. Sitagliptin increased the ratio of NPY to NPY (3-36). During valsartan, sitagliptin also significantly potentiated NPY-induced vasoconstriction ( P=0.009 for forearm blood flow). Potentiation of endogenous NPY could contribute to cardiovascular effects of DPP4 inhibitors in patients taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. PMID- 29987110 TI - Renal Outcomes in Medically and Surgically Treated Primary Aldosteronism. AB - Lifelong therapy with mineralocorticoid receptor antagonists (MRAs) or surgical adrenalectomy are the recommended treatments for primary aldosteronism (PA). Whether these treatments mitigate the risk for kidney disease remains unknown. We performed a retrospective cohort study of patients with PA treated with MRAs (N=400) or surgical adrenalectomy (N=120) and age- and estimated glomerular filtration rate-matched patients with essential hypertension (N=15 474) to determine risk for chronic kidney disease and longitudinal estimated glomerular filtration rate decline. Despite similar blood pressures, patients with PA treated with MRAs had a higher risk for incident chronic kidney disease compared with essential hypertension patients (adjusted hazard ratio, 1.63; 95% confidence interval, 1.33-1.99). Correspondingly, the adjusted annual decline in estimated glomerular filtration rate was greater in PA patients treated with MRAs compared with essential hypertension patients (-1.6; 95% confidence interval, -1.4 to -1.8 versus -0.9; 95% confidence interval, -0.9 to -1.0 mL/min per 1.73 m2/y; P<0.001). In contrast, patients with unilateral PA treated with surgical adrenalectomy had no significant difference in risk for incident chronic kidney disease or in an annual decline in estimated glomerular filtration rate compared with essential hypertension patients. Among PA patients with diabetes mellitus treated with MRAs, there was a higher risk for incident albuminuria compared with essential hypertension (adjusted hazard ratio, 2.52; 95% confidence interval, 1.28-4.96). MRA therapy in PA is associated with higher risk for developing chronic kidney disease when compared with essential hypertension, and surgical adrenalectomy may mitigate this risk. When possible, curative surgical adrenalectomy may be superior to lifelong MRA therapy in preventing kidney disease in PA. PMID- 29987112 TI - HCN4 Gene Polymorphisms Are Associated With Occurrence of Tachycardia-Induced Cardiomyopathy in Patients With Atrial Fibrillation. AB - BACKGROUND: Tachycardia-induced cardiomyopathy (TIC) is a reversible cardiomyopathy induced by tachyarrhythmia, and the genetic background of the TIC is not well understood. The hyperpolarization-activated cyclic nucleotide-gated channel gene HCN4 is highly expressed in the conduction system where it is involved in heart rate control. We speculated that the HCN4 gene is associated with TIC. METHODS: We enrolled 930 Japanese patients with atrial fibrillation (AF) for screening, 350 Japanese patients with AF for replication, and 1635 non AF controls. In the screening AF set, we compared HCN4 single-nucleotide polymorphism genotypes between AF subjects with TIC (TIC, n=73) and without TIC (non-TIC, n=857). Of 17 HCN4 gene-tag single-nucleotide polymorphisms, rs7172796, rs2680344, rs7164883, rs11631816, and rs12905211 were significantly associated with TIC. Among them, only rs7164883 was independently associated with TIC after conditional analysis (TIC versus non-TIC: minor allele frequency, 26.0% versus 9.7%; P=1.62*10-9; odds ratio=3.2). RESULTS: We confirmed this association of HCN4 single-nucleotide polymorphism rs7164883 with TIC in the replication set (TIC=41 and non-TIC=309; minor allele frequency, 28% versus 9.9%; P=1.94*10-6; odds ratio=3.6). The minor allele frequency of rs7164883 was similar in patients with AF and non-AF controls (11% versus 10.9%; P=0.908). CONCLUSIONS: The HCN4 gene single-nucleotide polymorphism rs7164883 may be a new genetic marker for TIC in patients with AF. PMID- 29987114 TI - HCN4 Gene Polymorphisms and Tachycardia-Induced Cardiomyopathy: True or Spurious Association? PMID- 29987113 TI - Multiplexed Targeted Resequencing Identifies Coding and Regulatory Variation Underlying Phenotypic Extremes of High-Density Lipoprotein Cholesterol in Humans. AB - BACKGROUND: Genome-wide association studies have uncovered common variants at many loci influencing human complex traits, such as high-density lipoprotein cholesterol (HDL-C). However, the contribution of the identified genes is difficult to ascertain from current efforts interrogating common variants with small effects. Thus, there is a pressing need for scalable, cost-effective strategies for uncovering causal variants, many of which may be rare and noncoding. METHODS: Here, we used a molecular inversion probe target capture approach to resequence both coding and regulatory regions at 7 HDL-C-associated loci in 797 individuals with extremely high HDL-C versus 735 low-to-normal HDL-C controls. Our targets included protein-coding regions of GALNT2, APOA5, APOC3, SCARB1, CCDC92, ZNF664, CETP, and LIPG (>9 kb) and proximate noncoding regulatory features (>42 kb). RESULTS: Exome-wide genotyping in 1114 of the 1532 participants yielded a >90% genotyping concordance rate with molecular inversion probe-identified variants in ~90% of participants. This approach rediscovered nearly all established genome-wide association studies associations in GALNT2, CETP, and LIPG loci with significant and concordant associations with HDL-C from our phenotypic extremes design at 0.1% of the sample size of lipid genome-wide association studies. In addition, we identified a novel, rare, CETP noncoding variant enriched in the extreme high HDL-C group (P<0.01, score test). CONCLUSIONS: Our targeted resequencing of individuals at the HDL-C phenotypic extremes offers a novel, efficient, and cost-effective approach for identifying rare coding and noncoding variation differences in extreme phenotypes and supports the rationale for applying this methodology to uncover rare variation particularly noncoding variation-underlying myriad complex traits. PMID- 29987111 TI - Clonal Hematopoiesis: Somatic Mutations in Blood Cells and Atherosclerosis. AB - The most important prognostic factor for atherosclerotic cardiovascular disease is age, independent of all other recognized risk factors. Recently, exome sequence analyses showed that somatic mutations in blood cells, a process termed clonal hematopoiesis, are common and increase in prevalence with age, with at least 1 in 10 adults older than 70 years affected. Carriers of clonal hematopoiesis have been shown to be not only at heightened risk for hematologic malignancy but also at increased risk for atherosclerotic cardiovascular disease. Here, we review the prior literature of clonal selection and expansion of hematopoietic stem cells and the evidence supporting its causal association with atherosclerotic cardiovascular disease. PMID- 29987115 TI - Letter by Aw et al Regarding Article, "Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention". PMID- 29987116 TI - Response by Lee and Stouffer to Letter Regarding Article, "Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention". PMID- 29987117 TI - Restrict use of antibiotics for COPD, NICE says. PMID- 29987119 TI - Impact of Rapid Ventricular Pacing on Outcome After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Rapid ventricular pacing (RVP) is used commonly during transcatheter aortic valve replacement (TAVR). Little is known about the safety and clinical consequences of this step. The aim of this study was to assess the impact of RVP on immediate and long-term clinical outcomes in a large cohort of non-selected TAVR patients. METHOD AND RESULTS: The study included 412 consecutive patients undergoing TAVR with a mean age of 82+/-7 years, of which 47% were male. Patients were divided according to the number of RVPs during the TAVR procedure comparing patients undergoing no pacing (0), 1 to 2, and >=3 pacing episodes (3+). Patients undergoing 3+ pacing episodes were significantly more likely to develop new atrial fibrillation (5.6% versus 7.3% versus 15%, respectively, for 0, 1-2, and 3+ groups, P=0.047), acute kidney injury (AKI) (18% versus 18% versus 28%, respectively, P<0.001), prolonged procedural hypotension (0%, 16%, and 25%, respectively; P<0.001), and suffered greater in-hospital mortality (1.7%, 1.7%, and 6.5%, respectively, P=0.045), and 1-year mortality (11.1%, 7.7%, and 18%, respectively, P=0.015). Multivariate Cox regression analysis indicated that acute kidney injury (OR 3.27 [1.763-6.09], P<0.001), euroSCORE II (OR 1.06 per unit [1.01-1.12], P=0.03), and 3+ pacing episodes (OR 2.35 [1.18-4.7], P=0.02) were the only independent predictors for 1-year mortality. CONCLUSIONS: In patients undergoing TAVR, multiple RVP episodes and prolonged RVP duration are associated with adverse outcomes including short- and long-term mortality. Thus, operators should attempt to minimize the use of RVP, especially in patients who are at risk for post-procedural acute kidney injury. PMID- 29987118 TI - Atypical APC/C-dependent degradation of Mcl-1 provides an apoptotic timer during mitotic arrest. AB - The initiation of apoptosis in response to the disruption of mitosis provides surveillance against chromosome instability. Here, we show that proteolytic destruction of the key regulator Mcl-1 during an extended mitosis requires the anaphase-promoting complex or cyclosome (APC/C) and is independent of another ubiquitin E3 ligase, SCFFbw7 Using live-cell imaging, we show that the loss of Mcl-1 during mitosis is dependent on a D box motif found in other APC/C substrates, while an isoleucine-arginine (IR) C-terminal tail regulates the manner in which Mcl-1 engages with the APC/C, converting Mcl-1 from a Cdc20 dependent and checkpoint-controlled substrate to one that is degraded independently of checkpoint strength. This mechanism ensures a relatively slow but steady rate of Mcl-1 degradation during mitosis and avoids its catastrophic destruction when the mitotic checkpoint is satisfied, providing an apoptotic timer that can distinguish a prolonged mitotic delay from normal mitosis. Importantly, we also show that inhibition of Cdc20 promotes mitotic cell death more effectively than loss of APC/C activity through differential effects on Mcl 1 degradation, providing an improved strategy to kill cancer cells. PMID- 29987121 TI - Intrapulmonary Vein Ablation Without Stenosis: A Novel Balloon-Based Direct Current Electroporation Approach. AB - BACKGROUND: Current thermal ablation methods for atrial fibrillation, including radiofrequency and cryoablation, have a suboptimal success rate. To avoid pulmonary vein (PV) stenosis, ablation is performed outside of the PV, despite the importance of triggers inside the vein. We previously reported on the acute effects of a novel direct current electroporation approach with a balloon catheter to create lesions inside the PVs in addition to the antrum. In this study, we aimed to determine whether the effects created by this nonthermal ablation method were associated with irreversible lesions and whether PV stenosis or other adverse effects occurred after a survival period. METHODS AND RESULTS: Initial and survival studies were performed in 5 canines. At the initial study, the balloon catheter was inflated to contact the antrum and interior of the PV. Direct current energy was delivered between 2 electrodes on the catheter in ECG gated 100 MUs pulses. A total of 10 PVs were treated demonstrating significant acute local electrogram diminution (mean amplitude decrease of 61.2+/-19.8%). After the survival period (mean 27 days), computed tomography imaging showed no PV stenosis. On histologic evaluation, transmural, although not circumferential, lesions were seen in each treated vein. No PV stenosis or esophageal injury was present. CONCLUSIONS: Irreversible, transmural lesions can be created inside the PV without evidence of stenosis after a 27-day survival period using this balloon based direct current ablation approach. These early data show promise for an ablation approach that could directly treat PV triggers in addition to traditional PV antrum ablation. PMID- 29987120 TI - Mechanisms Responsible for Serotonin Vascular Reactivity Sex Differences in the Internal Mammary Artery. AB - BACKGROUND: The increased adverse cardiac events in women undergoing coronary artery bypass grafting are multifactorial and may include clinical, psychosocial, and biological factors. Potential contributing biological factors could include vascular hyperreactivity of the internal mammary artery (IMA) to endogenous vasoconstrictors in women, resulting in a predilection to myocardial ischemia. This study evaluated sex differences in serotonin and thromboxane A2 dependent vasoconstriction in human isolated IMA, with the mechanistic role of (1) the endothelium, (2) nitric oxide (NO), (3) prostaglandins, and (4) receptor activity investigated for any observed sex difference. METHODS AND RESULTS: Viable isolated human IMA segments were obtained from 116 patients (44 women [mean age, 66.8+/-12.2 years] and 72 men [mean age, 66.6+/-10.4 years]) undergoing coronary artery bypass grafting. Cumulative concentration-response curves for serotonin and thromboxane A2 mimetic, U46619, were determined and revealed an increased sensitivity to serotonin but not U46619 in women. This sex difference to serotonin was further assessed by the following: (1) endothelial denudation, (2) endothelial NO synthase inhibition and NO quantification using electron paramagnetic resonance, (3) cyclooxygenase inhibition and prostaglandin metabolite quantification using mass spectrometry, and (4) quantification of receptor activity status. The female hyperreactivity to serotonin was (1) abolished by endothelial denudation; (2) unaffected by NO synthase inhibition, with no difference in electron paramagnetic resonance-assessed NO levels; (3) abolished by cyclooxygenase inhibition (quantification of prostaglandins in IMA revealed a trend towards reduced 6-keto prostaglandin F1alpha in female IMA; P=0.08); and (4) unrelated to receptor activity. CONCLUSIONS: These data indicate that female IMAs are hyperreactive to serotonin but not U46619, with the former attributable to an endothelium-dependent cyclooxygenase pathway. PMID- 29987123 TI - Characteristics and Treatment Outcomes of Acute Type A Aortic Dissection With Elevated D-Dimer Concentration. AB - BACKGROUND: Clinical characteristics and treatment outcomes of acute type A aortic dissection with D-dimer elevation have not been clarified. METHODS AND RESULTS: D-dimer was measured preoperatively within 24 hours of symptom onset in 262 patients with acute type A aortic dissection. The median (and interquartile range) admission D-dimer concentration in our total patient group was 26.7 (8.3 85.9) MUg/mL. Median (interquartile range) D-dimer concentrations were 5.0 (2.6 18.0) MUg/mL for complete false lumen thrombosis (n=33), 60.9 (19.4-160.4) MUg/mL for partial thrombosis (n=81), 26.5 (10.0-70.6) MUg/mL for a patent false lumen (n=131), and 8.7 (3.2-26.9) MUg/mL for ulcerlike projection (n=17) (P<0.01). With a D-dimer concentration of <=8.3 MUg/mL representing the lower quartile, we then investigated predictors of a low D-dimer level. Multivariate analysis showed dissection limited to the ascending aorta (P<0.01; odds ratio, 9.81) or descending aorta (P<0.01; odds ratio, 7.68), a completely thrombosed false lumen (P<0.01; odds ratio, 4.02), and absence of brain ischemia (P=0.013; odds ratio, 4.74) to be predictors of the lower D-dimer concentration. Compared with patients with a low D-dimer concentration (<=8.3 MUg/mL, n=66), patients with a D-dimer concentration >8.3 MUg/mL (n=196) had a reduced preoperative platelet count and increased operation time and transfusion volume. In-hospital mortality was elevated in this group (1.5% versus 11.2%; P=0.031), although 7-year survival did not differ for hospital survivors (lower versus higher, 93.1% versus 79.1%; P=0.21). CONCLUSIONS: D-dimer concentrations are strongly influenced by the extent of dissection and false lumen status. Operative risks are increased in patients with a relatively high D-dimer concentration. PMID- 29987124 TI - Endothelial Colony-Forming Cells in Young Adults Born Preterm: A Novel Link Between Neonatal Complications and Adult Risks for Cardiovascular Disease. AB - BACKGROUND: Preterm birth is linked to cardiovascular risks and diseases. Endothelial progenitor cells play a critical role in vascular development and repair. Cord blood endothelial progenitor cells of preterm-born infants, especially endothelial colony-forming cells (ECFC), show enhanced susceptibility to prematurity-related pro-oxidant stress. Whether ECFC dysfunction is present in adulthood following preterm birth is unknown. METHODS AND RESULTS: This cross sectional observational study includes 55 preterm-born (<=29 gestational weeks) young adults (18-29 years old, 38% male) and 55 sex- and age-matched full-term controls. ECFC were isolated from peripheral blood; cell proliferative and vascular cord formation capacities were assessed in vitro. Daytime systolic blood pressure was higher, whereas glucose tolerance and body mass index were lower in preterm-born subjects. ECFC colonies grew in culture for 62% of full-term- and 58% of preterm-born participants. Preterm-born participants have formed ECFC colonies later in culture and have reduced proliferation compared with controls. Only in preterm-born individuals, we observed that the later the ECFC colony grows in culture, the worse was overall ECFC function. In addition, in preterms, elevated systolic blood pressure significantly correlated with reduced ECFC proliferation (rS=-0.463; P=0.030) and numbers of branches formed on matrigel (rS=-0.443; P=0.039). In preterm-born subjects, bronchopulmonary dysplasia was associated with impaired ECFC function, whereas exposure to antenatal steroids related to better ECFC function. CONCLUSIONS: This study is the first to examine ECFC in preterm-born adults and to demonstrate ECFC dysfunction compared with full-term controls. In the preterm-born group, ECFC dysfunction was associated with bronchopulmonary dysplasia, the major prematurity-related neonatal morbidity, and with increased systolic blood pressure into adulthood. PMID- 29987122 TI - Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation-Induced Cardiac Proteotoxicity. AB - BACKGROUND: Desmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown. METHODS AND RESULTS: Cardiomyocyte specific overexpression of mutated desmin (a 7 amino acid deletion R172-E178, D7 Des Tg) causes accumulations of electron-dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7-Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7-Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi-1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7-Des overexpression in cardiomyocytes. CONCLUSIONS: Aberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7-Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy-associated cellular dysfunction. PMID- 29987125 TI - Periprocedural Cardiopulmonary Bypass or Venoarterial Extracorporeal Membrane Oxygenation During Transcatheter Aortic Valve Replacement: A Systematic Review. AB - BACKGROUND: There are limited data on the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) or cardiopulmonary bypass (CPB) to provide hemodynamic support periprocedurally during transcatheter aortic valve replacement. This study sought to evaluate patients receiving transcatheter aortic valve replacement with concomitant use of CPB/VA-ECMO. METHODS AND RESULTS: We systematically reviewed the published literature from 2000 to 2018 for studies evaluating adult patients requiring CPB/VA-ECMO periprocedurally during transcatheter aortic valve replacement. Studies reporting short-term and long-term mortality were included. Given the significant methodological and statistical differences between published studies, meta-analysis of the association of CPB/VA-ECMO with mortality was not performed. Of the 537 studies identified, 9 studies representing 5191 patients met our inclusion criteria. Median ages were between 75 and 87 years with 33% to 75% male patients. Where reported, the Edwards SAPIENTM transcatheter heart valve was the most frequently used. A total of 203 (3.9%) patients received periprocedural hemodynamic support with CPB/VA-ECMO. Common indications for CPB/VA-ECMO included left ventricular or aortic annular rupture, rapid hemodynamic deterioration, aortic regurgitation, cardiac arrest, and left main coronary artery obstruction. The use of CPB/VA-ECMO was predominantly an emergent strategy and was used for durations of 1 to 2 hours. Short-term mortality (in-hospital and 30-day) was 29.8%, and 1-year mortality was 52.4%. Major complications such as bleeding, vascular injury, tamponade, stroke, and renal failure were noted in 10% to 50% of patients. CONCLUSIONS: CPB/VA-ECMO was used in 4% in the early experience of patients undergoing transcatheter aortic valve replacement, most commonly for periprocedural complications. There are limited data on preprocedural planned use of VA-ECMO, and the characteristics of this population remain poorly defined. PMID- 29987126 TI - The ceramide ratio: a predictor of cardiometabolic risk. PMID- 29987127 TI - The Prevalence of Bacterial Meningitis in Febrile Infants 29-60 Days With Positive Urinalysis. AB - OBJECTIVES: This study evaluates whether bacterial meningitis prevalence differs by urinalysis result and whether antibiotic treatment of presumed urinary tract infection without cerebrospinal fluid (CSF) culture produces adverse sequelae in febrile infants 29 to 60 days old. METHODS: This retrospective cohort study identified febrile infants 29 to 60 days old presenting to Kaiser Permanente Northern California sites from 2007 to 2015 who underwent urinalysis and blood, urine, and CSF cultures, comparing the prevalence of meningitis among infants with positive versus negative urinalysis results using a two 1-sided test for equivalence. Additionally, febrile infants treated with antibiotics for positive urinalysis results without CSF culture were identified and their charts were reviewed for adverse sequelae. RESULTS: Full evaluation was performed in 833 febrile infants (835 episodes). Three of 337 infants with positive urinalysis (0.9%; 95% confidence interval [CI]: 0.0%-1.9%) and 5 of 498 infants with negative urinalysis (1%; 95% CI: 0.1%-1.9%) had meningitis. These proportions were statistically equivalent within 1%, using two 1-sided test with a P value of .04. There were 341 febrile infants (345 episodes) with positive urinalysis treated with antibiotics without lumbar puncture. Zero cases of missed bacterial meningitis were identified (95% CI: 0%-1.1%). Zero cases of severe sequelae (sepsis, seizure, neurologic deficit, intubation, PICU admission, death) were identified (95% CI: 0%-1.1%). CONCLUSIONS: The prevalence of bacterial meningitis does not differ by urinalysis in febrile infants 29 to 60 days old. Antibiotic treatment of infants with positive results for urinalysis without lumbar puncture may be safe in selected cases. PMID- 29987128 TI - Is It Time to Stop Classifying Febrile Infants With Positive Urinalyses as High Risk for Meningitis? PMID- 29987129 TI - Creating a comprehensive research strategy for cutaneous neurofibromas. AB - OBJECTIVE: Outside of procedural-based methods, there are currently no established medical treatments for cutaneous neurofibroma (cNF), which afflict up to 99% of patients with NF1. Further, adult patients often report cNF are the greatest burden of living with NF1. The Neurofibromatosis Therapeutic Acceleration Program (NTAP) launched a think tank to address core questions to facilitate development of effective therapeutics for cNF in people with NF1. METHODS: Experts (with and without explicit experience with NF1 or cNF) from multiple scientific and medical disciplines, representing the ranks of academia, industry, and government agencies, were invited to become a member of a team addressing a specific subset of questions pertinent to cNF. Teams met monthly to review published and unpublished materials, and created summaries about the material known and unknown that may influence therapeutic development for cNF. Teams prioritized questions and organized supporting data, which was presented to the entire body of experts by each team at a research summit. RESULTS: Four themes were identified as being relevant to creating a comprehensive research strategy for cNF: (1) establishing definitions of cNF, (2) determining the biology of cNF with respect to tumor initiation, progression, and maintenance, (3) outlining the factors that guide therapies development, and (4) defining core considerations for clinical trials design and optimization for cNF. CONCLUSION: Considerations and key questions for each of the thematic areas were identified and provided basis for a request for applications launched by NTAP focused on cNF and are described in the accompanying articles of this supplement. PMID- 29987130 TI - Cutaneous neurofibromas: Current clinical and pathologic issues. AB - OBJECTIVE: To present the current terminology and natural history of neurofibromatosis 1 (NF1) cutaneous neurofibromas (cNF). METHODS: NF1 experts from various research and clinical backgrounds reviewed the terms currently in use for cNF as well as the clinical, histologic, and radiographic features of these tumors using published and unpublished data. RESULTS: Neurofibromas develop within nerves, soft tissue, and skin. The primary distinction between cNF and other neurofibromas is that cNF are limited to the skin whereas other neurofibromas may involve the skin, but are not limited to the skin. There are important cellular, molecular, histologic, and clinical features of cNF. Each of these factors is discussed in consideration of a clinicopathologic framework for cNF. CONCLUSION: The development of effective therapies for cNF requires formulation of diagnostic criteria that encompass the clinical and histologic features of these tumors. However, there are several areas of overlap between cNF and other neurofibromas that make distinctions between cutaneous and other neurofibromas more difficult, requiring careful deliberation with input across the multiple disciplines that encounter these tumors and ultimately, prospective validation. The ultimate goal of this work is to facilitate accurate diagnosis and meaningful therapeutics for cNF. PMID- 29987131 TI - The biology of cutaneous neurofibromas: Consensus recommendations for setting research priorities. AB - OBJECTIVE: A group of experts in dermatology, genetics, neuroscience, and regenerative medicine collaborated to summarize current knowledge on the defined factors contributing to cutaneous neurofibroma (cNF) development and to provide consensus recommendations for future research priorities to gain an improved understanding of the biology of cNF. METHODS: The group members reviewed published and unpublished data on cNF and related diseases via literature search, defined a set of key topic areas deemed critical in cNF pathogenesis, and developed recommendations in a series of consensus meetings. RESULTS: Five specific topic areas were identified as being relevant to providing an enhanced understanding of the biology of cNF: (1) defining the human cells of origin; (2) understanding the role of the microenvironment, focusing on neurons, mast cells, and fibroblasts; (3) defining the genetic and molecular differences between the cNFs, focusing on size and number; (4) understanding if sex hormones are critical for cNF development or progression; and (5) identifying challenges in establishing in vitro and in vivo models representing human cNF. CONCLUSIONS: The complexity of cNF biology stems from its heterogeneity at multiple levels including genetic, spatial involvement, temporal development, and cellular composition. We propose a unified working model for cNF that builds a framework to address the key questions about cNF that, when answered, will provide the necessary understanding of cNF biology to allow meaningful development of therapies. PMID- 29987132 TI - Considerations for development of therapies for cutaneous neurofibroma. AB - OBJECTIVE: The only therapies currently available for cutaneous neurofibromas (cNF) are procedural. The goals of the Therapies Development Working Group were to (1) summarize currently available treatment options for cNF, (2) define key considerations for drug discovery and development generally, and specifically for cNF, and (3) outline recommendations for the successful development of medical therapies for cNF. METHODS: The subgroup reviewed published and unpublished data on procedural, drug/device, and medical treatment approaches utilized for cNFs via literature search. The team defined disease- and patient-specific factors to consider for therapies development in a series of consensus meetings. RESULTS: The team identified 5 approaches entailing procedural and drug/device methods currently under study. There have been 4 clinical studies exploring various interventional therapies, from which outcomes were highly variable. The team identified 4 key factors to prioritize during the development of products for the treatment for cNF: safety, anatomic distribution of cNF, numbers of tumors to be treated, and route of administration. CONCLUSIONS: The number, size, and distribution of cNF is highly variable among patients with NF1 and it is possible that different phenotypes will require different drug development paths. The nonfatal nature of the disease and relatively limited patient numbers suggest that for any product to have a higher likelihood of acceptance, it will have to (1) demonstrate an effect that is clinically meaningful, (2) have a safety profile conducive to long-term dosing, and (3) have a low manufacturing cost. PMID- 29987133 TI - Clinical trial design for cutaneous neurofibromas. AB - OBJECTIVE: Several clinical trials targeting cutaneous neurofibromas (cNF) have been conducted; however, none has resulted in meaningful changes to care. The Clinical Trial Design and Development subgroup's goals were to (1) define key considerations in the design of clinical trials for cNF, (2) summarize existing data in relation to these considerations, and (3) provide consensus recommendations about key elements of trial design to accelerate the clinical development of therapies for cNF. METHODS: The subgroup, with experts from genetics, dermatology, neurology, oncology, and basic science, spanning academia, government research, and regulatory programs, and industry, reviewed published and unpublished data on clinical trials for cNF and other diseases in the skin. Discussions of these data resulted in formulation of a list of priority issues to address in order to develop efficient and effective clinical trials for cNF. RESULTS: The subgroup identified 2 natural history studies of cNF, 4 priority outcome measures, and 6 patient-reported outcome tools for potential use in efficacy trials of cNF. Time to initiate intervention, patient eligibility, mechanism of action, route of administration, safety monitoring, and regulatory agency interactions were identified as key factors to consider when designing clinical trials for cNF. CONCLUSIONS: Alignment on endpoints and methods for the measurement and quantification of cNF represent a priority for therapeutic development for cNF. Advances in technological methods and outcome tools utilized in other skin diseases may be applicable to cNF studies. Patient age is an important factor guiding trial design and clinical development path. PMID- 29987134 TI - X10 expansion microscopy enables 25-nm resolution on conventional microscopes. AB - Expansion microscopy is a recently introduced imaging technique that achieves super-resolution through physically expanding the specimen by ~4*, after embedding into a swellable gel. The resolution attained is, correspondingly, approximately fourfold better than the diffraction limit, or ~70 nm. This is a major improvement over conventional microscopy, but still lags behind modern STED or STORM setups, whose resolution can reach 20-30 nm. We addressed this issue here by introducing an improved gel recipe that enables an expansion factor of ~10* in each dimension, which corresponds to an expansion of the sample volume by more than 1,000-fold. Our protocol, which we termed X10 microscopy, achieves a resolution of 25-30 nm on conventional epifluorescence microscopes. X10 provides multi-color images similar or even superior to those produced with more challenging methods, such as STED, STORM, and iterative expansion microscopy (iExM). X10 is therefore the cheapest and easiest option for high-quality super resolution imaging currently available. X10 should be usable in any laboratory, irrespective of the machinery owned or of the technical knowledge. PMID- 29987135 TI - Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance. AB - Akt is a pro-survival kinase frequently activated in human cancers and is associated with more aggressive tumors that resist therapy. Here, we connect Akt pathway activation to reduced sensitivity to chemotherapy via Akt phosphorylation of Bax at residue S184, one of the pro-apoptotic Bcl-2 family proteins required for cells to undergo apoptosis. We show that phosphorylation by Akt converts the pro-apoptotic protein Bax into an anti-apoptotic protein. Mechanistically, we show that phosphorylation (i) enables Bax binding to pro-apoptotic BH3 proteins in solution, and (ii) prevents Bax inserting into mitochondria. Together, these alterations promote resistance to apoptotic stimuli by sequestering pro-apoptotic activator BH3 proteins. Bax phosphorylation correlates with cellular resistance to BH3 mimetics in primary ovarian cancer cells. Further, analysis of the TCGA database reveals that 98% of cancer patients with increased BAX levels also have an upregulated Akt pathway, compared to 47% of patients with unchanged or decreased BAX levels. These results suggest that in patients, increased phosphorylated anti-apoptotic Bax promotes resistance of cancer cells to inherent and drug-induced apoptosis. PMID- 29987136 TI - Antigen phagocytosis by B cells is required for a potent humoral response. AB - Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen-coated particles, a process thought to be exclusive of specialized antigen-presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR-driven and mechanistically dependent on the GTPase RhoG. Using Rhog-/- mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high-affinity class-switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum-antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1-3 MUm size antigen particles to follicular B cells. PMID- 29987137 TI - Systematic Review and Meta-analysis of the Efficacy of Short-Course Antibiotic Treatments for Community-Acquired Pneumonia in Adults. AB - The duration of therapy for community-acquired pneumonia (CAP) remains undefined. We sought to investigate whether short-course antibiotic treatment for CAP is associated with favorable clinical outcomes in adult patients. We systematically searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies comparing the effectiveness and safety between treatment regimens administered for <=6 days and >=7 days. We defined treatment for <=6 days as short-course treatment and treatment for >=7 days as long-course treatment. Twenty-one clinical trials (4,861 clinically evaluable patients) were included, and 19 out of 21 trials were randomized. Clinical cure was similar between the compared groups (4,069 patients, risk ratio [RR] = 0.99 [95% confidence interval {CI}, 0.97 to 1.01]), irrespective of patient setting (RR = 0.98 [95% CI, 0.96 to 1.00] for the outpatient setting and RR = 1.00 [95% CI, 0.92 to 1.09] for the inpatient setting) or severity of pneumonia (RR = 1.05 [95% CI, 0.96 to 1.14]). Also, relapses were similar between the short- and long course treatment groups (1,923 patients, RR = 0.67 [95% CI, 0.30 to 1.46]). Short course treatment was associated with fewer serious adverse events (1,923 patients, RR = 0.73 [95% CI, 0.55 to 0.97]) and, importantly, resulted in lower mortality than long-course treatment (2,802 patients, RR = 0.52 [95% CI, 0.33 to 0.82]). In CAP, short-course antibiotic treatment (<=6 days) is as effective as and potentially superior to, in terms of mortality and serious adverse events, longer-course treatment. PMID- 29987138 TI - beta-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance. AB - Augmented renal clearance is commonly observed in septic patients and may result in insufficient beta-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of beta-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of >=120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient beta-lactam serum concentrations to treat infections due to Pseudomonas aeruginosa There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r = -0.21, P = 0.01), trough concentrations of piperacillin (r = -0.28, P = 0.0071), concentrations at 50% of the dosage interval (r = -0.41, P < 0.0001), and total body clearance of piperacillin (r = 0.39, P = 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain beta-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens. PMID- 29987139 TI - Bioequivalence of a Fixed-Dose Combination Tablet of the Complete Two-Drug Regimen of Dolutegravir and Rilpivirine for Treatment of HIV-1 Infection. AB - A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.). PMID- 29987140 TI - Repurposing Strategy of Atorvastatin against Trypanosoma cruzi: In Vitro Monotherapy and Combined Therapy with Benznidazole Exhibit Synergistic Trypanocidal Activity. AB - Statins are inhibitors of cholesterol synthesis, but other biological properties, such as antimicrobial effects, have also been assigned to them, leading to their designation as pleiotropic agents. Our goal was to investigate the activity and selectivity of atorvastatin (AVA) against Trypanosoma cruzi by using in vitro models, aiming for more effective and safer therapeutic options through drug repurposing proposals for monotherapy and therapy in combination with benznidazole (BZ). Phenotypic screening was performed with different strains (Tulahuen [discrete typing unit {DTU} VI] and Y [DTU II]) and forms (intracellular forms, bloodstream trypomastigotes, and tissue-derived trypomastigotes) of the parasite. On assay of the Tulahuen strain, AVA was more active against intracellular amastigotes (selectivity index [SI] = 3). Also, against a parasite of another DTU (Y strain), this statin was more active (2.1 fold) and selective (2.4-fold) against bloodstream trypomastigotes (SI = 51) than against the intracellular forms (SI = 20). A cytomorphological approach using phalloidin-rhodamine permitted us to verify that AVA did not induced cell density reduction and that cardiac cells (CC) maintained their typical cytoarchitecture. Combinatory approaches using fixed-ratio methods showed that AVA and BZ gave synergistic interactions against both trypomastigotes and intracellular forms (mean sums of fractional inhibitory concentration indexes [?FICIs] of 0.46 +/- 0.12 and 0.48 +/- 0.03, respectively). Thus, the repurposing strategy for AVA, especially in combination with BZ, which leads to a synergistic effect, is encouraging for future studies to identify novel therapeutic protocols for Chagas disease treatment. PMID- 29987141 TI - Synergy between Circular Bacteriocin AS-48 and Ethambutol against Mycobacterium tuberculosis. AB - The increasing incidence of multidrug-resistant Mycobacterium tuberculosis strains and the very few drugs available for treatment are promoting the discovery and development of new molecules that could help in the control of this disease. Bacteriocin AS-48 is an antibacterial peptide produced by Enterococcus faecalis and is active against several Gram-positive bacteria. We have found that AS-48 was active against Mycobacterium tuberculosis, including H37Rv and other reference and clinical strains, and also against some nontuberculous clinical mycobacterial species. The combination of AS-48 with either lysozyme or ethambutol (commonly used in the treatment of drug-susceptible tuberculosis) increased the antituberculosis action of AS-48, showing a synergic interaction. Under these conditions, AS-48 exhibits a MIC close to some MICs of the first-line antituberculosis agents. The inhibitory activity of AS-48 and its synergistic combination with ethambutol were also observed on M. tuberculosis-infected macrophages. Finally, AS-48 did not show any cytotoxicity against THP-1, MHS, and J774.2 macrophage cell lines at concentrations close to its MIC. In summary, bacteriocin AS-48 has interesting antimycobacterial activity in vitro and low cytotoxicity, so further studies in vivo will contribute to its development as a potential additional drug for antituberculosis therapy. PMID- 29987142 TI - Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection. AB - Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or per os (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% did for Pseudomonas aeruginosa and 3% for Staphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.). PMID- 29987143 TI - Benefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease. AB - The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of Trypanosoma cruzi, leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our in vivo studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection. PMID- 29987145 TI - Effect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients. AB - Intravenous voriconazole (VRC) is formulated by the incorporation of sulfobutylether-beta-cyclodextrin (SBECD), which may accumulate to adversely affect renal function. However, the effect of long-term use of intravenous VRC on renal function is unclear. Our retrospective analysis of data confirmed that worsening of renal function was significantly associated with a cumulative dose of intravenous VRC (>=400 mg/kg), suggesting that a higher cumulative dose of intravenous VRC is a risk factor for renal dysfunction. PMID- 29987144 TI - Randomized, Double-Blind, Placebo-Controlled Studies to Assess Safety and Prophylactic Efficacy of Naphthoquine-Azithromycin Combination for Malaria Prophylaxis in Southeast Asia. AB - New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species. PMID- 29987146 TI - Echinocandin Treatment of Candida albicans Biofilms Enhances Neutrophil Extracellular Trap Formation. AB - The nosocomial pathogen Candida albicans forms biofilms on medical devices that persist in the face of antifungals and host defenses. Echinocandins, the most effective antibiofilm drugs, have recently been shown to augment the activity of neutrophils against biofilms through an unknown mechanism. Here, we show that treatment of C. albicans biofilms with subinhibitory concentrations of echinocandins promotes the formation of neutrophil extracellular traps (NETs), structures of DNA, histones, and antimicrobial proteins with antifungal activity. PMID- 29987147 TI - Efficiency of Target Larvicides Is Conditioned by ABC-Mediated Transport in the Zoonotic Nematode Anisakis pegreffii. AB - Anisakiasis is among the most significant emerging foodborne parasitoses contracted through consumption of thermally unprocessed seafood harboring infective Anisakis species larvae. The efficacy of the currently applied anthelminthic therapy in humans and in model organisms has not proven sufficient, so alternative solutions employing natural compounds combined with chemical inhibitors should be explored. By testing toxicity of the natural monoterpenes nerolidol and farnesol and the conventional anthelminthics abamectin and levamisole in the presence/absence of MK-571 and Valspodar, which inhibit the ABC transporter proteins multidrug resistance protein (MRP-like) and P-glycoprotein (P-gp), we determined the preliminary traits of Anisakis detoxifying mechanisms. We found that Anisakis P-gp and MRP-like transporters have a role in the efflux of the tested compounds, which could be useful in the design of novel anthelminthic strategies. As expected, transporter activation and efflux fluctuated over time; they were synchronously active very early postexposure, whereas the activity of one transporter dominated over the other in a time dependent manner. MRP-like transporters dominated in the efflux of farnesol, and P-gp dominated in efflux of nerolidol, while both were active in effluxing levamisole. The highest toxicity was exerted by abamectin, a P-gp inhibitor per se, which also elicited the highest oxidative stress in treated Anisakis larvae. We suggest that beta-tubulin, observed for the first time as a core element in Anisakis cuticle, might represent an important target for the tested compounds. PMID- 29987148 TI - Molecular Insights into Functional Differences between mcr-3- and mcr-1-Mediated Colistin Resistance. AB - The global emergence of plasmid-mediated colistin resistance genes mcr-1 and mcr 3 has threatened the role of the "last-resort" drug colistin in the defense against infections caused by multidrug-resistant Gram-negative bacteria. However, functional differences between these two genes in mediating colistin resistance remain poorly understood. Protein sequence alignment of MCR-3 and MCR-1 was therefore conducted in Clustal Omega to identify sequence divergence. The molecular recognition of lipid A head group phosphatidylethanolamine and MCR-3 enzyme was studied by homology modeling and molecular docking, with the catalytic mechanism of MCR-3 also being explored. Thr277 in MCR-3 was validated as the key amino acid residue responsible for the catalytic reaction using site-directed mutagenesis and was shown to act as a nucleophile. Lipid A modification induced by the MCR-3 and MCR-1 enzymes was confirmed by electrospray ionization-time of flight mass spectrometry. Far-UV circular dichroism spectra of the MCR-3 and MCR 1 enzymes suggested that MCR-3 was more thermostable than MCR-1, with a melting temperature of 66.19 degrees C compared with 61.14 degrees C for MCR-1. These data provided molecular insight into the functional differences between mcr-3 and mcr-1 in conferring colistin resistance. PMID- 29987149 TI - HIV-1 Integrase Inhibitors That Are Broadly Effective against Drug-Resistant Mutants. AB - Integrase strand transfer inhibitors (INSTIs) have emerged as clinically effective therapeutics that inhibit HIV-1 replication by blocking the strand transfer reaction catalyzed by HIV-1 integrase (IN). Of the three FDA-approved INSTIs, dolutegravir (DTG) is the least apt to select for resistance. However, recent salvage therapy regimens had low response rates with therapies that included DTG, suggesting that DTG resistance can be selected in patients. Using a single-round infection assay, we evaluated a collection of our best inhibitors and DTG against a broad panel of INSTI-resistant mutants. Two of the new compounds, 4c and 4d, had antiviral profiles against the mutants we tested superior to that of DTG. The susceptibility profiles of 4c and 4d suggest that the compounds are candidates for development as INSTIs. Modeling the binding of 4d to HIV-1 IN reinforced the significance of mimicking the DNA substrate in developing compounds that are broadly effective in their abilities to inhibit HIV 1 INs with mutations in the active site. PMID- 29987150 TI - Role of Lock Therapy for Long-Term Catheter-Related Infections by Multidrug Resistant Bacteria. AB - The management of long-term central venous catheter (LTCVC) infections by multidrug-resistant (MDR) bacteria in cancer patient is a challenge. The objectives of this study were to analyze outcomes in cancer patients with LTCVC associated infection, identify risks for unfavorable outcomes, and determine the impact of MDR bacteria and antibiotic lock therapy (ALT) in managing such infections. We evaluated all LTCVC-associated infections treated between January 2009 and December 2016. Infections were reported in accordance with international guidelines for catheter-related infections. The outcome measures were 30-day mortality and treatment failure. We analyzed risk factors by Cox forward-stepwise regression. We identified 296 LTCVC-associated infections; 212 (71.6%) were classified as bloodstream infections (BSIs). The most common agent was Staphylococcus aureus Forty-six (21.7%) infections were due to MDR Gram-negative bacteria. ALT was used in 62 (29.2%) patients, with a 75.9% success rate. Risk factors identified for failure of the initial treatment were having a high sequential organ failure assessment (SOFA) score at diagnosis of infection and being in palliative care; introduction of ALT at the start of treatment was identified as a protective factor. Risk factors identified for 30-day mortality after LTCVC-associated infection were a high SOFA score at diagnosis, infection with MDR bacteria, and palliative care; introduction of ALT at the start of treatment, hematological malignancies, and adherence to an institutional protocol for the management of LTCVC-associated infection were identified as protective factors. Despite the high incidence of infection with MDR bacteria, ALT improves the outcome of LTCVC-associated infection in cancer patients. PMID- 29987151 TI - Prevalence and Molecular Characterization of Escherichia coli Clinical Isolates Carrying mcr-1 in a Chinese Teaching Hospital from 2002 to 2016. PMID- 29987152 TI - The Fungal Cyp51 Inhibitor VT-1129 Is Efficacious in an Experimental Model of Cryptococcal Meningitis. AB - Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with Cryptococcus neoformans Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of >=0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of >=3 mg/kg/day, even >=20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis. PMID- 29987153 TI - Multiclonal Expansion and High Prevalence of beta-Lactamase-Negative Haemophilus influenzae with High-Level Ampicillin Resistance in Japan and Susceptibility to Quinolones. AB - beta-Lactam-resistant Haemophilus influenzae is a clinical concern. A high prevalence (>40%) of beta-lactamase-negative high-level ampicillin-resistant H. influenzae (high-BLNAR) isolates in Japan has been reported. However, the reasons for the expansion are unknown. High-BLNAR strains possess an amino acid substitution, either Asn526Lys (group III) or Arg517His (group III-like) in addition to Ser385Thr, in penicillin-binding protein 3 (PBP3). To determine the current prevalence of high-BLNAR strains and the mechanisms behind their expansion in Japan, their prevalence, PBP3 types, multilocus sequence types, and susceptibilities to quinolones approved in Japan as alternatives were determined. Sixty percent of H. influenzae clinical isolates (62/104 isolates) were beta lactamase-negative ampicillin-resistant H. influenzae (BLNAR) strains. Among BLNAR isolates, 92% (57/62 isolates) were high-BLNAR strains. Most isolates were classified as belonging to group III, which contained many genotypes (11 PBP3 types and 25 sequence types). These results indicated that the expansion of high BLNAR isolates was multiclonal and such strains are still predominant in Japanese clinical settings. One high-BLNAR isolate harbored the novel amino acid substitution Asn526Met in addition to Ser385Thr in PBP3, suggesting a new group (group IV). No quinolone-resistant H. influenzae isolates were identified. The MICs for the quinolones (moxifloxacin, garenoxacin, and tosufloxacin) were similar to that for levofloxacin, whereas sitafloxacin exhibited a lower MIC. However, we obtained 4 H. influenzae isolates with decreased quinolone susceptibility with the amino acid substitution Ser84Leu in GyrA, and 3 of those isolates were high-BLNAR isolates. In summary, this study shows that multiclonal high-BLNAR strains predominate in a Japanese university hospital. Isolates remain sensitive to quinolones, but vigilance is required to prevent the development of fluoroquinolone resistance in high-BLNAR strains. PMID- 29987154 TI - Assessment of the Additional Value of Verapamil to a Moxifloxacin and Linezolid Combination Regimen in a Murine Tuberculosis Model. AB - The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive Mycobacterium tuberculosis and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at the steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 log CFU, respectively), but sterilization was not achieved yet. The spleens of all mice were culture negative after 12 weeks of treatment with both treatment modalities, and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, P = 0.017). In conclusion, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens. PMID- 29987155 TI - In Vitro and In Vivo Characterization of NOSO-502, a Novel Inhibitor of Bacterial Translation. AB - Antibacterial activity screening of a collection of Xenorhabdus strains led to the discovery of the odilorhabdins, a new antibiotic class with broad-spectrum activity against Gram-positive and Gram-negative pathogens. Odilorhabdins inhibit bacterial translation by a new mechanism of action on ribosomes. A lead optimization program identified NOSO-502 as a promising candidate. NOSO-502 has MIC values ranging from 0.5 to 4 MUg/ml against standard Enterobacteriaceae strains and carbapenem-resistant Enterobacteriaceae (CRE) isolates that produce KPC, AmpC, or OXA enzymes and metallo-beta-lactamases. In addition, this compound overcomes multiple chromosome-encoded or plasmid-mediated resistance mechanisms of acquired resistance to colistin. It is effective in mouse systemic infection models against Escherichia coli EN122 (extended-spectrum beta-lactamase [ESBL]) or E. coli ATCC BAA-2469 (NDM-1), achieving a 50% effective dose (ED50) of 3.5 mg/kg of body weight and 1-, 2-, and 3-log reductions in blood burden at 2.6, 3.8, and 5.9 mg/kg, respectively, in the first model and 100% survival in the second, starting with a dose as low as 4 mg/kg. In a urinary tract infection (UTI) model with E. coli UTI89, urine, bladder, and kidney burdens were reduced by 2.39, 1.96, and 1.36 log10 CFU/ml, respectively, after injection of 24 mg/kg. There was no cytotoxicity against HepG2, HK-2, or human renal proximal tubular epithelial cells (HRPTEpiC), no inhibition of hERG-CHO or Nav 1.5-HEK current, and no increase of micronuclei at 512 MUM. NOSO-502, a compound with a new mechanism of action, is active against Enterobacteriaceae, including all classes of CRE, has a low potential for resistance development, shows efficacy in several mouse models, and has a favorable in vitro safety profile. PMID- 29987157 TI - Hanging and near hanging in children: injury patterns and a clinical approach to early management. AB - Near hanging refers to survival following suspension by the neck. This is a devastating injury which can lead to mortality or serious long-term morbidity. Children and young people present to emergency departments following accidental or deliberate near hanging. This article describes the patterns of injury, the initial management and important prognostic factors. PMID- 29987156 TI - In Vivo Pharmacodynamic Characterization of a Novel Odilorhabdin Antibiotic, NOSO 502, against Escherichia coli and Klebsiella pneumoniae in a Murine Thigh Infection Model. AB - NOSO-502 is a novel odilorhabdin antibiotic with potent activity against Enterobacteriaceae The goal of these studies was to determine which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitude best correlated with efficacy in the murine thigh infection model. Six Escherichia coli and 6 Klebsiella pneumoniae isolates were utilized. MICs were determined using CLSI methods and ranged from 1 to 4 mg/liter. A neutropenic murine thigh infection model was utilized for all treatment studies. Single-dose plasma pharmacokinetics were determined in mice after subcutaneous administration of 7.81, 31.25, 125, and 500 mg/kg of body weight. Pharmacokinetic studies exhibited peak concentration (Cmax) values of 1.49 to 84.6 mg/liter, area under the concentration-time curve from 0 h to infinity (AUC0-infinity) values of 1.94 to 352 mg . h/liter, and beta elimination half-lives of 0.41 to 1.1 h. Dose fractionation studies were performed using total drug doses of 7.81 mg/kg to 2,000 mg/kg fractionated into regimens of every 3 h (q3h), q6h, q12h, or q24h. Nonlinear regression analysis demonstrated that AUC/MIC was the PK/PD parameter that best correlated with efficacy (R2, 0.86). In subsequent studies, we used the neutropenic murine thigh infection model to determine the magnitude of NOSO-502 AUC/MIC needed for the efficacy against a diverse group of Enterobacteriaceae Mice were treated with 4-fold-increasing doses (range, 3.91 to 1,000 mg/kg) of NOSO-502 every 6 h. The mean 24-h free-drug AUC/MIC (fAUC)/MIC) magnitudes associated with net stasis and 1-log kill endpoint for K. pneumoniae were 4.22 and 17.7, respectively. The mean fAUC/MIC magnitude associated with net stasis endpoint for E. coli was 10.4. NOSO-502 represents a promising novel, first-in class odilorhabdin antibiotic with in vivo potency against Enterobacteriaceae. PMID- 29987158 TI - What do I need to know about fluoroquinolones for children? PMID- 29987159 TI - Racial Differences in Long-Term Outcomes Among Older Survivors of In-Hospital Cardiac Arrest. AB - BACKGROUND: Black patients have worse in-hospital survival than white patients after in-hospital cardiac arrest (IHCA), but less is known about long-term outcomes. We sought to assess among IHCA survivors whether there are additional racial differences in survival after hospital discharge and to explore potential reasons for differences. METHODS: This was alongitudinal study of patients >=65 years of age who had an IHCA and survived until hospital discharge between 2000 and 2011 from the national Get With The Guidelines-Resuscitation registry whose data could be linked to Medicare claims data. Sequential hierarchical modified Poisson regression models evaluated the proportion of racial differences explained by patient, hospital, and unmeasured factors. Our exposure was black or white race. Our outcome was survival at 1, 3, and 5 years. RESULTS: Among 8764 patients who survived to discharge, 7652 (87.3%) were white and 1112 (12.7%) were black. Black patients with IHCA were younger, more frequently female, sicker with more comorbidities, less likely to have a shockable initial cardiac arrest rhythm, and less likely to be evaluated with coronary angiography after initial resuscitation. At discharge, black patients were also more likely to have at least moderate neurological disability and less likely to be discharged home. Compared with white patients and after adjustment only for hospital site, black patients had lower 1-year (43.6% versus 60.2%; relative risk [RR], 0.72), 3-year (31.6% versus 45.3%; RR, 0.71), and 5-year (23.5% versus 35.4%; RR, 0.67; all P<0.001) survival. Adjustment for patient factors explained 29% of racial differences in 1-year survival (RR, 0.80; 95% confidence interval, 0.75-0.86), and further adjustment for hospital treatment factors explained an additional 17% of racial differences (RR, 0.85; 95% confidence interval, 0.80-0.92). Approximately half of the racial difference in 1-year survival remained unexplained, and the degree to which patient and hospital factors explained racial differences in 3-year and 5-year survival was similar. CONCLUSIONS: Black survivors of IHCA have lower long-term survival compared with white patients, and about half of this difference is not explained by patient factors or treatments after IHCA. Further investigation is warranted to better understand to what degree unmeasured but modifiable factors such as postdischarge care account for unexplained disparities. PMID- 29987160 TI - CRACR2A-Mediated TCR Signaling Promotes Local Effector Th1 and Th17 Responses. AB - Ca2+ release-activated Ca2+ channel regulator 2A (CRACR2A) is expressed abundantly in T cells and acts as a signal transmitter between TCR stimulation and activation of the Ca2+/NFAT and JNK/AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies and was shown to be one of the most sensitive targets of the widely used statin drugs. However, the physiological role of CRACR2A in T cell functions remains unknown. In this study, using transgenic mice for tissue-specific deletion, we show that CRACR2A promotes Th1 responses and effector function of Th17 cells. CRACR2A was abundantly expressed in Th1 and Th17 cells. In vitro, deficiency of CRACR2A decreased Th1 differentiation under nonpolarizing conditions, whereas the presence of polarizing cytokines compensated this defect. Transcript analysis showed that weakened TCR signaling by deficiency of CRACR2A failed to promote Th1 transcriptional program. In vivo, conditional deletion of CRACR2A in T cells alleviated Th1 responses to acute lymphocytic choriomeningitis virus infection and imparted resistance to experimental autoimmune encephalomyelitis. Analysis of CNS from experimental autoimmune encephalomyelitis-induced mice showed impaired effector functions of both Th1 and Th17 cell types, which correlated with decreased pathogenicity. Collectively, our findings demonstrate the requirement of CRACR2A-mediated TCR signaling in Th1 responses as well as pathogenic conversion of Th17 cells, which occurs at the site of inflammation. PMID- 29987161 TI - Role of Peptidylarginine Deiminase 4 in Neutrophil Extracellular Trap Formation and Host Defense during Klebsiella pneumoniae-Induced Pneumonia-Derived Sepsis. AB - Peptidylarginine deiminase 4 (PAD4) catalyzes citrullination of histones, an important step for neutrophil extracellular trap (NET) formation. We aimed to determine the role of PAD4 during pneumonia. Markers of NET formation were measured in lavage fluid from airways of critically ill patients. NET formation and host defense were studied during pneumonia-derived sepsis caused by Klebsiella pneumoniae in PAD4+/+ and PAD4-/- mice. Patients with pneumosepsis, compared with those with nonpulmonary disease, showed increased citrullinated histone 3 (CitH3) levels in their airways and a trend toward elevated levels of NET markers cell-free DNA and nucleosomes. During murine pneumosepsis, CitH3 levels were increased in the lungs of PAD4+/+ but not of PAD4-/- mice. Combined light and electron microscopy showed NET-like structures surrounding Klebsiella in areas of CitH3 staining in the lung; however, these were also seen in PAD4-/- mice with absent CitH3 lung staining. Moreover, cell-free DNA and nucleosome levels were mostly similar in both groups. Moreover, Klebsiella and LPS could still induce NETosis in PAD4-/- neutrophils. Both groups showed largely similar bacterial growth, lung inflammation, and organ injury. In conclusion, these data argue against a major role for PAD4 in NET formation, host defense, or organ injury during pneumonia-derived sepsis. PMID- 29987163 TI - A Tolerogenic Artificial APC Durably Ameliorates Experimental Autoimmune Encephalomyelitis by Directly and Selectively Modulating Myelin Peptide Autoreactive CD4+ and CD8+ T Cells. AB - In this study, a tolerogenic artificial APC (TaAPC) was developed to directly and selectively modulate myelin-autoreactive CD4+ and CD8+ T cells in the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced experimental autoimmune encephalomyelitis in C57BL/6J mice. Cell-sized polylactic-coglycolic acid microparticles were generated to cocouple target Ags (MOG40-54/H-2Db-Ig dimer, MOG35-55/I-Ab multimer), regulatory molecules (anti-Fas and PD-L1-Fc), and "self marker" CD47-Fc and encapsulate inhibitory cytokine (TGF-beta1). Four infusions of the TaAPCs markedly and durably inhibited the experimental autoimmune encephalomyelitis progression and reduced the local inflammation in CNS tissue. They circulated throughout vasculature into peripheral lymphoid tissues and various organs, but not into brain, with retention of 36 h and exerted direct effects on T cells in vivo and in vitro. Two infusions of the TaAPCs depleted 65 79% of MOG35-55-specific CD4+ and 46-62% of MOG40-54-specific CD8+ T cells in peripheral blood, spleen, and CNS tissues in an Ag-specific manner and regulatory molecule-dependent fashion; induced robust T cell apoptosis; inhibited the activation and proliferation of MOG peptide-reactive T cells; reduced MOG peptide reactive Th1, Th17, and Tc17 cells; and expanded regulatory T cells. They also inhibited IFN-gamma/IL-17A secretion and elevated IL-10/TGF-beta1 production in splenocytes but not in CNS tissue. More importantly, the TaAPCs treatment did not obviously suppress the overall immune function of host. To our knowledge, this study provides the first experimental evidence for the capability of TaAPCs to directly modulate autoreactive T cells by surface presentation of multiple ligands and paracrine release of cytokine, thus suggesting a novel Ag-specific immunotherapy for the T cell-mediated autoimmune diseases. PMID- 29987162 TI - CX3CR1+ Macrophages and CD8+ T Cells Control Intestinal IgA Production. AB - Secretory IgA is a key host defense mechanism that controls the intestinal microbiota. We investigated the role of CD11c+CX3CR1+CD64+ macrophages in IgA production in the intestine. Intestinal CX3CR1+ macrophages directly induced IgA secretion by B cells. Ag delivery to lamina propria (LP) CX3CR1+ macrophages specifically induced intestinal IgA production. The induction of IgA by CX3CR1+ macrophages required BAFF, a proliferation-inducing ligand, and TNF-alpha, but was surprisingly independent of TLR-mediated microbial recognition and retinoic acid signaling. IgA secretion by CX3CR1+ macrophages was enhanced by LP CD8+ T cells through the secretion of IL-9 and IL-13. CX3CR1+ macrophages and CD8+ T cells induced IgA production by B cells independently of mesenteric lymph nodes and Peyer patches. Our data reveal a previously unrecognized cellular circuitry in which LP CX3CR1+ macrophages, B cells, and CD8+ T cells coordinate the protective Ig secretion in the small intestine upon peripheral Ag delivery. PMID- 29987164 TI - Risk-Factor Trajectories Preceding Diabetic Polyneuropathy: ADDITION-Denmark. AB - OBJECTIVE: To study cardiometabolic risk-factor trajectories (in terms of levels and changes over time) preceding diabetic polyneuropathy (DPN) 13 years after a screen-detected diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS: We clinically diagnosed DPN in a nested case-control study of 452 people in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION). By linear regression models, we estimated preceding risk-factor trajectories during 13 years. Risk of DPN was estimated by multivariate logistic regression models of each individual's risk factor trajectory intercept and slope adjusting for sex, age, diabetes duration, height, and trial randomization group. RESULTS: Higher baseline levels of HbA1c (odds ratio [OR] 1.76 [95% CI 1.37; 2.27] and OR 1.68 [95% CI 1.33; 2.12] per 1% and 10 mmol/mol, respectively) and steeper increases in HbA1c over time (OR 1.66 [95% CI 1.21; 2.28] and OR 1.59 [95% CI 1.19; 2.12] per 1% and 10 mmol/mol increase during 10 years, respectively) were associated with DPN. Higher baseline levels of weight, waist circumference, and BMI were associated with DPN (OR 1.20 [95% CI 1.10; 1.31] per 5 kg, OR 1.27 [95% CI 1.13; 1.43] per 5 cm, and OR 1.24 [95% CI 1.12; 1.38] per 2 kg/m2, respectively). CONCLUSIONS: Both higher levels and slopes of HbA1c trajectories were associated with DPN after 13 years. Our findings indicate that the rate of HbA1c increase affects the development of DPN over and above the effect of the HbA1c level. Furthermore, this study supports obesity as a risk factor for DPN. PMID- 29987166 TI - The Effect of Lowering Public Insurance Income Limits on Hospitalizations for Low Income Children. AB - BACKGROUND AND OBJECTIVES: Thirty million children are currently covered by public insurance; however, the future funding and structure of public insurance are uncertain. Our objective was to determine the number, estimated costs, and demographic characteristics of hospitalizations that would become ineligible for public insurance reimbursement under 3 federal poverty level (FPL) eligibility scenarios. METHODS: In this retrospective cohort study using the 2014 State Inpatient Databases, we included all pediatric (age <18) hospitalizations in 14 states from January 1, 2014, to December 31, 2014, with public insurance as the primary payer. We linked each patient's zip code to the American Community Survey to determine the likelihood of the patient being below 3 different public insurance income eligibility thresholds (300%, 200%, and 100% of the FPL). Multiple simulations were used to describe newly ineligible hospitalizations under each threshold. RESULTS: In 775 460 publicly reimbursed hospitalizations in 14 states, reductions in eligibility limits to 300%, 200%, or 100% of the FPL would have resulted in large numbers of newly ineligible hospitalizations (~155 000 [20% of hospitalizations] for 300%, 440 000 [57%] for 200%, and 650 000 [84%] for 100% of the FPL), equaling $1.2, $3.1, and $4.4 billion of estimated child hospitalization costs, respectively. Patient demographics differed only slightly under each eligibility threshold. CONCLUSIONS: Reducing public insurance eligibility limits would have resulted in numerous pediatric hospitalizations not covered by public insurance, shifting costs to families, other insurers, or hospitals. Without adequately subsidized commercial insurance, this reflects a potentially substantial economic hardship for families and hospitals serving them. PMID- 29987165 TI - Fine mapping MHC associations in Graves' disease and its clinical subtypes in Han Chinese. AB - BACKGROUND: The classical human leucocyte antigen (HLA) genes were the most important genetic determinant for Graves' disease (GD). The aim of the study was to fine map causal variants of the HLA genes. METHODS: We applied imputation with a Pan-Asian HLA reference panel to thoroughly investigate themajor histocompatibility complex (MHC) associations with GD down to the amino acid level of classical HLA genes in 1468 patients with GD and 1490 controls of Han Chinese. RESULTS: The strongest finding across the HLA genes was the association with HLA-DPbeta1 position 205 (Pomnibus=2.48*10-33). HLA-DPA1*02:02 was the strongest association among the classical HLA alleles, which was in perfect linkage disequilibrium with HLA-DPalpha1 residue Met11 (OR=1.90, Pbinary=1.76*10 31). Applying stepwise conditional analysis, we identified amino acid position 205 in HLA-DPbeta1, position 66 and 99 in HLA-B and position 28 in HLA-DRbeta1 explain majority of the MHC association to GD risk. We further evaluated risk of two clinical subtypes of GD, namely persistent thyroid stimulating hormone receptor antibody -positive (pTRAb+) group and 'non-persistent TRAb positive' (pTRAb-) group after antithyroid drug therapy. We found that HLA-B residues Lys66 Arg69-Val76 could drive pTRAb- GD risk alone, while HLA-DPbeta1 position 205, HLA B position 69 and 199 and HLA-DRbeta1 position 28 drive pTRAb+ GD risk. The risk heterogeneity between pTRAb+ and pTRAb- GD might be driven by HLA-DPalpha1 Met11. CONCLUSIONS: Four amino acid positions could account for the associations of MHC with GD in Han Chinese. These distinct HLA association patterns indicated the two subtypes have distinct molecular mechanisms of pathogenesis. PMID- 29987167 TI - Responding to Parental Incarceration As a Priority Pediatric Health Issue. PMID- 29987168 TI - Parents' Adverse Childhood Experiences and Their Children's Behavioral Health Problems. AB - : : media-1vid110.1542/5789654354001PEDS-VA_2018-0023Video Abstract BACKGROUND AND OBJECTIVES: Adverse childhood experiences (ACEs) include stressful and potentially traumatic events associated with higher risk of long-term behavioral problems and chronic illnesses. Whether parents' ACE counts (an index of standard ACEs) confer intergenerational risk to their children's behavioral health is unknown. In this study, we estimate the risk of child behavioral problems as a function of parent ACE counts. METHODS: We obtained retrospective information on 9 ACEs self-reported by parents and parent reports of their children's (1) behavioral problems (using the Behavior Problems Index [BPI]), (2) attention deficit/hyperactivity disorder diagnosis, and (3) emotional disturbance diagnosis from the 2013 Panel Study of Income Dynamics (PSID) core interview and the linked PSID Childhood Retrospective Circumstances Study and 2014 PSID Child Development Supplement. Multivariate linear and logistic regression models were used to estimate child behavioral health outcomes by parent retrospective ACE count. RESULTS: Children of parents with a history of 4 or more ACEs had on average a 2.3-point (95% confidence interval [CI]: 1.3-3.2) higher score on the BPI, 2.1 times (95% CI: 1.1-3.8) higher odds of hyperactivity, and 4.2 times (95% CI: 1.7 10.8) higher odds of an emotional disturbance diagnosis than children of parents with no ACEs. Maternal ACEs revealed a stronger association with child behavior problems than paternal ACEs. Relationships between parents' 9 component ACEs individually and children's BPI scores revealed consistently positive associations. Mediation by parent emotional distress and aggravation were observed. CONCLUSIONS: Parents with greater exposure to ACEs are more likely to have children with behavioral health problems. PMID- 29987169 TI - Cutting Children's Health Care Costs. PMID- 29987171 TI - What's happening in Neurology(r). PMID- 29987172 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29987170 TI - Health Care Use and Health Behaviors Among Young Adults With History of Parental Incarceration. AB - OBJECTIVES: To determine if longitudinal associations exist between parental incarceration (PI) and health care use or health behaviors among a national sample of young adults. METHODS: We used the National Longitudinal Survey of Adolescent to Adult Health to examine associations between history of mother incarceration (MI) and father incarceration (FI), health care use, and 3 dimensions of health behaviors (eg, general health behaviors, substance use, and other risky behaviors) (N = 13 084). Multivariable logistic regression models accounted for individual, family, and geographic factors and generated adjusted odds ratios (aORs). RESULTS: Over 10% of the sample had a history of PI before the age of 18. History of MI and FI were both associated with forgone health care (aOR = 1.65 [95% confidence interval (CI), 1.20-2.27], aOR = 1.22 [95% CI, 1.02 1.47], respectively), prescription drug abuse (MI aOR = 1.61 [95% CI, 1.02-2.55], FI aOR = 1.46 [95% CI, 1.20-1.79]), and 10 or more lifetime sexual partners (MI aOR = 1.55 [95% CI, 1.08-2.22], FI aOR = 1.19 [95% CI, 1.01-1.41]). MI was associated with higher likelihood of emergency department use (aOR = 2.36 [95% CI, 1.51-3.68]), and FI was associated with illicit injection drug use (aOR = 2.54 [95% CI, 1.27-5.12]). CONCLUSIONS: The effects of incarceration extend beyond incarcerated individuals. PI histories are associated with lower health care use and unhealthy behaviors in young adulthood. By addressing barriers to health care and health-harming behaviors, health care providers and policy makers may reduce health disparities among this population. PMID- 29987173 TI - What's happening in Neurology(r)Genetics. PMID- 29987174 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29987175 TI - What's happening in Innovations in Care Delivery. PMID- 29987176 TI - Deliberate gait scissoring to overcome freezing of gait in Parkinson disease. PMID- 29987177 TI - Child Neurology: Treatable bilateral striatal lesions related to anti-dopamine 2 receptor autoimmunity. PMID- 29987178 TI - Editors' note: Clinical Reasoning: Prognostication after cardiac arrest: What do we really know? PMID- 29987179 TI - Reader response: Clinical Reasoning: Prognostication after cardiac arrest: What do we really know? PMID- 29987181 TI - Editors' note: A predictive model to identify Parkinson disease from administrative claims data. PMID- 29987182 TI - Reader response: A predictive model to identify Parkinson disease from administrative claims data. PMID- 29987180 TI - Author response: Clinical Reasoning: Prognostication after cardiac arrest: What do we really know? PMID- 29987183 TI - Author response: A predictive model to identify Parkinson disease from administrative claims data. PMID- 29987184 TI - Clinical Reasoning: Acute onset of diplopia in pregnancy. PMID- 29987185 TI - Teaching NeuroImages: Cerebral cortex swelling in Creutzfeldt-Jakob disease with V180I mutation. PMID- 29987186 TI - Teaching NeuroImages: Brain MRI and DaT-SPECT imaging in adult GM1 gangliosidosis. PMID- 29987187 TI - Histone citrullination represses miRNA expression resulting in increased oncogene mRNAs in somatolactotrope cells. AB - Peptidylarginine deiminase (PAD) enzymes convert histone arginine residues into citrulline to modulate chromatin organization and gene expression. Although PADs are expressed in anterior pituitary gland cells, their functional role and expression in pituitary adenomas is unknown. To begin to address these questions, we first examined normal human pituitaries and pituitary adenomas and found that PAD2, PAD4 and citrullinated histones are highest in prolactinomas and somatoprolactinomas. In the somatoprolactinoma-derived GH3 cell line, PADs citrullinate histone H3, which is attenuated by a pan-PAD inhibitor. RNA sequencing and ChIP studies show that the expression of microRNAs let-7c-2, miR 23b and miR-29c is suppressed by histone citrullination. Our studies demonstrate that these miRNAs directly target the mRNA of the oncogenes HMGA, IGF-1 and N MYC, which are highly implicated in human prolactinoma/somatoprolactinoma pathogenesis. Our results are the first to define a direct role for PAD catalyzed histone citrullination in miRNA expression, which may underlie the etiology of prolactinoma and somatoprolactinoma tumors through regulation of oncogene expression. PMID- 29987188 TI - Dynamic interactions of eIF4G1 with eIF4E and eIF1 underlie scanning dependent and independent translation. AB - Translation initiation of most mRNAs involves m7G-cap binding, ribosomal scanning and AUG selection. Initiation from a m7G-cap-proximal AUG can be bypassed resulting in leaky-scanning, except for mRNAs bearing the Translation Initiator of Short 5'UTR (TISU) element. m7G-cap-binding is mediated by eIF4E-eIF4G1 complex. eIF4G1 also associates with eIF1 and both promote scanning and AUG selection. Understanding the dynamics and significance of these interactions is lacking. We report that eIF4G1 exists in two complexes, either with eIF4E or with eIF1. Using an eIF1 mutant impaired in eIF4G1 binding, we demonstrate that eIF1 eIF4G1 interaction is important for leaky scanning and for avoiding m7G-cap proximal initiation. Intriguingly, eIF4E-eIF4G1 antagonizes the scanning promoted by eIF1-eIF4G1 and is required for TISU. Mapping eIF1-binding site on eIF4G1 we unexpectedly found that eIF4E also binds it indirectly. These findings uncover the RNA features underlying regulation by eIF4E-eIF4G1 and eIF1-eIF4G1 and suggest that 43S ribosome transition from the m7G-cap to scanning involves relocation of eIF4G1 from eIF4E to eIF1. PMID- 29987191 TI - Improvement in Color-Conversion Efficiency and Stability for Quantum-Dot-Based Light-Emitting Diodes Using a Blue Anti-Transmission Film. AB - In this report, a blue anti-transmission film (BATF) has been introduced to improve the color-conversion efficiency (CCE) and the stability of quantum dot (QD) films. The results indicate that the CCE can be increased by as much as 93% using 15 layers of BATFs under the same QD concentration. Therefore, the same CCE can be achieved using BATF-QD hybrid films with a lower QD concentration when compared with standard QD films. The hybrid and QD films with the same CCE of 60% were aged at an environmental temperature of 25°C and with a 10 mA injection current light-emitting diode source. The CCE and luminous efficacy that are gained by the hybrid film increased by 42.8% and 24.5%, respectively, when compared with that gained by the QD film after aging for the same time period of approximately 65 h. In addition, the hybrid film can effectively suppress the red shift phenomenon of the QD light spectra, as well as an expansion of the full width at half maximum. Consequently, these BATF-QD hybrid films with excellent optical performance and stability show great potential for illumination and display applications. PMID- 29987190 TI - The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology. AB - Fragments of the TAR DNA-binding protein 43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exist, with distinct N termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Previously, we found that specific CTFs accumulate in the absence of the Arg/N-end rule pathway of the ubiquitin proteasome system (UPS) and that their degradation requires arginyl-tRNA protein transferase 1 (ATE1). Here, we examined two specific CTFs of TDP43 (TDP43219 and TDP43247), which are ~85% identical and differ at their N termini by 28 amino acids. We found that TDP43247 is degraded primarily by the Arg/N-end rule pathway, whereas degradation of TDP43219 continues in the absence of ATE1. These fragments also differ in their aggregation propensities and form morphologically distinct aggregates. This work reveals that the N termini of otherwise similar CTFs have profound effects on fragment behavior and may influence clinical outcomes in neurodegeneration associated with aggregation. PMID- 29987189 TI - The Cytotoxicity of Epsilon Toxin from Clostridium perfringens on Lymphocytes Is Mediated by MAL Protein Expression. AB - Epsilon toxin (Etx) from Clostridium perfringens is a pore-forming protein that crosses the blood-brain barrier, binds to myelin, and, hence, has been suggested to be a putative agent for the onset of multiple sclerosis, a demyelinating neuroinflammatory disease. Recently, myelin and lymphocyte (MAL) protein has been identified to be a key protein in the cytotoxic effect of Etx; however, the association of Etx with the immune system remains a central question. Here, we show that Etx selectively recognizes and kills only human cell lines expressing MAL protein through a direct Etx-MAL protein interaction. Experiments on lymphocytic cell lines revealed that MAL protein-expressing T cells, but not B cells, are sensitive to Etx and reveal that the toxin may be used as a molecular tool to distinguish subpopulations of lymphocytes. The overall results open the door to investigation of the role of Etx and Clostridium perfringens on inflammatory and autoimmune diseases like multiple sclerosis. PMID- 29987192 TI - Multi-Toxin Occurrences in Ten French Water Resource Reservoirs. AB - Cyanobacteria are known to produce a wide array of metabolites, including various classes of toxins. Among these, hepatotoxins (Microcystins), neurotoxins (Anatoxin-A and PSP toxins) or cytotoxins (Cylindrospermopsins) have been subjected to numerous, individual studies during the past twenty years. Reports of toxins co-occurrences, however, remain scarce in the literature. The present work is an inventory of cyanobacteria with a particular focus on Nostocales and their associated toxin classes from 2007 to 2010 in ten lakes used for drinking water production in France. The results show that potential multiple toxin producing species are commonly encountered in cyanobacteria populations. Individual toxin classes were detected in 75% of all samples. Toxin co occurrences appeared in 40% of samples as two- or three-toxin combinations (with 35% for the microcystins-anatoxin combination), whereas four-toxin class combinations only appeared in 1% of samples. Toxin co-occurrences could be partially correlated to species composition and water temperature. Peak concentrations however could never be observed simultaneously and followed distinct, asymmetrical distribution patterns. As observations are the key for preventive management and risk assessment, these results indicate that water monitoring should search for all four toxin classes simultaneously instead of focusing on the most frequent toxins, i.e., microcystins. PMID- 29987194 TI - Rapid Ferric Transformation by Reductive Dissolution of Schwertmannite for Highly Efficient Catalytic Degradation of Rhodamine B. AB - In this study, reductive dissolution of iron oxides was considered for the acceleration of the transformation from Fe(III) to Fe(II) to improve the degradation of rhodamine B (RhB) by potassium persulfate (PS) activation on schwertmannite. The addition of hydroxylamine (HA) showed an enhancement effect on the degradation at pH 3 and 5, but insignificant efficiency of the addition was obtained at pH 9. The surface reduction from Fe(III)-OH to Fe(II)-OH by HA was considered dominant for the acceleration of PS activation through the reductive dissolution process, and the hydroxyl and sulfate radicals generated by the decomposition of surface complexes were main primary reactive oxidants that contributed to the degradation of RhB. PMID- 29987193 TI - A Review on the Relationship between Tocotrienol and Alzheimer Disease. AB - Alzheimer’s disease (AD) is plaguing the aging population worldwide due to its tremendous health care and socioeconomic burden. Current treatment of AD only offers symptomatic relief to patients. Development of agents targeting specific pathologies of AD is very slow. Tocotrienol, a member of the vitamin E family, can tackle many aspects of AD, such as oxidative stress, mitochondrial dysfunction and abnormal cholesterol synthesis. This review summarizes the current evidence on the role of tocotrienol as a neuroprotective agent. Preclinical studies showed that tocotrienol could reduce oxidative stress by acting as a free-radical scavenger and promoter of mitochondrial function and cellular repair. It also prevented glutamate-induced neurotoxicity in the cells. Human epidemiological studies showed a significant inverse relationship between tocotrienol levels and the occurrence of AD. However, there is no clinical trial to support the claim that tocotrienol can delay or prevent the onset of AD. As a conclusion, tocotrienol has the potential to be developed as an AD-preventing agent but further studies are required to validate its efficacy in humans. PMID- 29987195 TI - Cholesterol-Bearing Fluorescent G-Quadruplex Potassium Probes for Anchoring at the Langmuir Monolayer and Cell Membrane. AB - The purpose of the present work was to design, synthesize and spectrally characterize cholesterol-anchored fluorescent oligonucleotide probes (Ch(F-TBA T), Ch(py-TBA-py)), based on G-quadruplexes, which were able to incorporate into a lipid structure (Langmuir monolayer, living cell membrane). The probes, based on the thrombin-binding aptamer (TBA) sequence, were labeled with fluorescent dyes which enabled simultaneous monitoring of the formation of G-quadruplex structures and visualization of probe incorporation into the cellular membrane. The combinations of fluorophores used included fluorescence resonance energy transfer (FRET) and excimer emission approaches. The structural changes of the probes upon binding with K+ or Na+ ions were monitored with fluorescence techniques. These systems showed a very high binding preference for K+ over Na+ ions. The use of confocal fluorescence microscopy indicated successful anchoring of the cholesterol-bearing fluorescent probes to the living cell membrane. These structurally simple cholesterol-based fluorescent probes have good potential for opening up new and exciting opportunities in the field of biosensors; e.g., in vivo detection of K+ ions. PMID- 29987197 TI - Methanol as an Unlisted Ingredient in Supposedly Alcohol-Based Hand Rub Can Pose Serious Health Risk. AB - Alcohol-based hand rub (hand sanitizer) is heavily used in the community and the healthcare setting to maintain hand hygiene. Methanol must never be used in such a product because oral, pulmonary and/or skin exposures can result in severe systemic toxicity and even deaths. However, sporadic cases of acute poisoning indicate that alcohol-based hand rub with undeclared methanol may be found in the market from time to time. The unexpected presence of methanol poses a serious threat to public health. Unintentional ingestion by young children and inadvertent consumption by older subjects as alcohol (ethanol) substitute can occur. Methanol is more lethal and poisoning often requires antidotal therapy, in addition to supporting therapy and critical care. However, specific therapy may be delayed because the exposure to methanol is initially not suspected. When repeatedly used as a hand rub, skin absorption resulting in chronic toxicity (e.g., visual disturbances) occurs, particularly if methanol induced desquamation and dermatitis are present. Nationwide surveillance systems, regional/international toxicovigilance networks and situational awareness among the healthcare professionals should facilitate the early detection, management and prevention of such poisoning incidents of public health significance. PMID- 29987196 TI - MiR-663, a MicroRNA Linked with Inflammation and Cancer That Is under the Influence of Resveratrol. AB - Resveratrol (trans-3,5,4′-trihydroxystilbene, RSV) is a non-flavonoid dietary polyphenol with antioxidant, anti-inflammatory and anti-cancer properties that is primarily found in red berries. While RSV displays many beneficial effects in vitro, its actual effects in vivo or in animal models remain passionately debated. Recent publications suggest that RSV pleiotropic effects could arise from its capability to regulate the expression and activity of microRNAs, short regulators themselves capable of regulating up to several hundreds of target genes. In particular, RSV increases microRNA miR-663 expression in different human cell lines, suggesting that at least some of its multiple beneficial properties are through the modulation of expression of this microRNA. Indeed, the expression of microRNA miR-663 is reduced in certain cancers where miR-663 is considered to act as a tumor suppressor gene, as well as in other pathologies such as cardiovascular disorders. Target of miR-663 include genes involved in tumor initiation and/or progression as well as genes involved in pathologies associated with chronic inflammation. Here, we review the direct and indirect effects of RSV on the expression of miR-663 and its target transcripts, with emphasise on TGFβ1, and their expected health benefits, and argue that elucidating the molecular effects of different classes of natural compounds on the expression of microRNAs should help to identify new therapeutic targets and design new treatments. PMID- 29987198 TI - Knowledge and Behavior of Saudi College Athletes toward Energy and Sports Drinks with an Emphasis on Microbial Quality and Safety. AB - The aim of this study was to assess the knowledge and behavior of university athletes in Saudi Arabia regarding energy drinks (EDs) and sports drinks (SDs). In addition, the microbiological quality of available local drinks was also assessed. The presence of total bacterial coliform count, Escherichia coli, Salmonella, and Staphylococcus aureus on these drinks was also determined. Of the 120 university athletes surveyed, 69 were currently using SDs, and 51 were using EDs. The study consisted of a 10-question survey assessing the athletes’ sociodemographic characteristics, personal habits, and SD- and ED-related knowledge and habits. With regard to the question about the primary reason for using EDs, n = 26 respondents (50.98%) reported that providing energy (speed, strength, and power) was the main reason for consuming these beverages. Conversely, n = 25 respondents (36.23%) believed that recovery from injury or illnesses was the main reason for the consumption of SDs. A majority of university athletes (n = 43, 62.32%) who used SDs believed that SDs were safe to use, while n = 22 respondents (43.14%) were unaware of any adverse health effects associated with the consumption of EDs. Of the total of 26 SDs and EDs tested, microbial contamination was present in only two products. Microbial levels and the total bacterial count for most of the samples were very low (<1 log CFU/mL). However, some drinks had a slightly higher microbial level, which could be harmful or cause spoilage with improper storage. Thus, our findings suggest that improvements in microbial quality are needed for these beverages. PMID- 29987199 TI - Comparative Proteomic Profiling between Each of Two Consecutive Developmental Stages of the Solanum Fruit Fly, Bactrocera latifrons (Hendel). AB - The Solanum fruit fly, Bactrocera latifrons (Hendel), has a complex life cycle including multiple stages (egg, larva, pupa, and adult). Understanding the details of “what”, “when”, “where”, “why”, and “how” many hundred thousand proteins operate in this insect, interact, and express between each two consecutive developmental stages at molecular level not only can expand our knowledge, but also lead to the development of novel fruit fly control techniques. We tried to find what, when, and where in this study. Why and how will be presented in upcoming papers. We conducted a proteome profiling using 2-D gel electrophoresis and mass spectrometry. Samples of 3-day-old eggs, 1- and 10-day-old larvae, 1- and 10-day old pupae, 1- and 9-day-old females and males of B. latifrons were used. A custom peptide database, derived from the de novo B. latifrons whole genome assembly was used for peptide identification. Differentially expressed proteins (DEPs) with significant fold expression and protein functions between two consecutive developmental stages were identified, annotated, described, and listed in gel images and/or charts. With this foundational information, we are not only providing valuable information, but also any impacts due to the biotic or abiotic environmental factors can be identified and manipulated, and lead to further research on gene editing and biomarker discovery. PMID- 29987200 TI - Chrysin Inhibits Advanced Glycation End Products-Induced Kidney Fibrosis in Renal Mesangial Cells and Diabetic Kidneys. AB - Advanced glycation end products (AGEs) play a causative role in the development of diabetic nephropathy via induction of matrix protein deposition in kidneys. This study investigated inhibitory effects of chrysin, present in bee propolis and herbs, on glomerulosclerosis in db/db mice and AGEs-exposed renal mesangial cells. The in vivo study explored the demoting effects of 10 mg/kg chrysin on glomerular fibrosis in a type 2 diabetic model. Oral supplementation of chrysin inhibited the collagen fiber accumulation and α-smooth muscle actin (α-SMA) induction in periodic acid schiff-positive renal tissues of db/db mice. Moreover, treating db/db mice with chrysin diminished the level of AGEs increased in diabetic glomeruli. The in vitro study employed human mesangial cells exposed to 100 μg/mL AGE-BSA for 72 h in the presence of 1-20 μM chrysin. Glucose increased mesangial AGE production via induction of receptor for AGEs. Chrysin suppressed the induction of collagens, α-SMA, fibroblast specific protein-1 and matrix metalloproteinases enhanced by AGE-bovine serum albumin. Furthermore, chrysin blunted transforming growth factor-β1 induction and Smad 2/3 activation in AGEs-exposed mesangial cells. These results demonstrate that chrysin attenuated accumulation of myofibroblast-like cells and matrix proteins in AGEs-laden diabetic glomeruli. Therefore, chrysin may be a potential renoprotective agent targeting glucose-mediated AGEs-associated glomerulosclerosis and fibrosis. PMID- 29987201 TI - Oxidative Stress Levels in the Brain Are Determined by Post-Mortem Interval and Ante-Mortem Vitamin C State but Not Alzheimer's Disease Status. AB - The current study highlighted several changes in measures of oxidative stress and antioxidant status that take place in the mouse brain over the course of 24 h post-mortem. Ascorbic acid (vitamin C) and glutathione both decreased significantly in cortex in as little as 2 h and malondialdehyde levels increased. Further change from baseline was observed up to 24 h, including carbonyl and sulfhydryl formation. The greatest changes were observed in brains that began with low ascorbic acid levels (gulo−/− mice) compared to wild-type or 5XFAD mice. Cortical samples from nine Alzheimer’s Disease cases and five controls were also assayed under the same conditions. Post mortem intervals ranged from 6 to 47 h and all samples had low ascorbic acid levels at time of measurement. Malondialdehyde levels were lower in Alzheimer’s Disease cases. Despite a strong positive correlation between ascorbic acid and glutathione levels, no other correlations among oxidative stress measures or post mortem interval were observed. Together the data suggest that molecular changes occurring within the first hours of death may mask differences between patient groups. Care must be taken interpreting studies in human brain tissue where ante mortem nutrient status is not known to avoid bias or confounding of results. PMID- 29987202 TI - Constructing the Elements of the "Recovery in" Model through Positive Assessments during Mental Health Home Visits. AB - The study provides a categorization of the different elements of the “recovery in” model (RIM). The objective is to analyze elements of RIM in positive assessments during home visit interactions. RIM approaches mental illness as a long-term condition that people live with in their daily lives in their communities. The model emphasizes the rights of all citizens to be full members of their communities regardless of their mental health problems or other difficulties. Positive assessments are professionals’ encouraging evaluations of the activities, situations, or inner conditions expressed by the clients. They are essential in creating supportive professional-client communication. The data analyzed in this study consists of 17 audio-recorded home visits of 10 different clients. Home visits were provided by a mental health floating support service in 2012. The data was analyzed using coding and ethnomethodological interaction research (EIR). As a result RIM is divided into two upper-categories: “Encouraging Doing the Right Thing” and “Encouraging the Right Kind of Personal Growth”. These categories include a wide spectrum of elements that are relevant for the client’s agency in the community. The elements embed the client’s performance in everyday routines and the client’s progress in becoming a skillful, knowledgeable, and involved agent in the community. The categorization of the elements of RIM could be used in educating practitioners to identify and operationalize RIM in mental health home visits. PMID- 29987203 TI - Oral Bioavailability of Kinsenoside in Beagle Dogs Measured by LC-MS/MS: Improvement of Ex Vivo Stability of a Lactone-Containing Compound. AB - Kinsenoside (KD), an active compound isolated from Anoectochilus roxburghii, has demonstrated multiple pharmacological activities including hepatoprotection, antihyperliposis, antihyperglycemia, and antiosteoporosis. To the best of our knowledge, there are no available data concerning its preclinical pharmacokinetics and bioavailability in beagle dogs. To support preclinical pharmacokinetic and bioavailability study, a reliable LC-MS/MS method was developed for KD concentration measurements in beagle dog plasma. The chromatographic separation was achieved on a Waters Atlantis® Hilic Silica column with an optimum mobile phase consisting of 5 mM ammonium acetate in water (pH 3.0 adjusted with acetic acid) and acetonitrile at a flow rate of 0.2 mL/min. Mass spectrometric analyses were carried out by monitoring multiple reaction monitoring transitions at m/z 265.2→102.9 for KD and m/z 174.0→128.0 for l-phenyl-d5-alanine-2,3,3-d3 (IS). The stability of KD in beagle dog whole blood and plasma was systematically evaluated. Lowering the temperature played a more critical role in stabilizing KD than decreasing the pH and adding esterase inhibitors, indicating that the major reason for instability of KD was probably due to chemical hydrolysis rather than esterase-mediated degradation. The currently developed method was validated and applied to a pharmacokinetic and bioavailability study of KD in beagle dogs following oral administration at a dose of 3 mg/kg. The absolute oral bioavailability for KD was determined to be 27.6%. Compared with typical glycosides, KD has a better bioavailability and is suitable for developing an oral dosage form. PMID- 29987204 TI - The Effect of Radiative Cooling on Reducing the Temperature of Greenhouses. AB - Currently, greenhouses are widely used for the cultivation of various crops. However, in tropical and subtropical regions, undesired near-infrared radiation (NIR) causes heat loads inside the greenhouse. Recent works have demonstrated that radiative cooling, releasing energy via radiative heat exchange where the heat is dumped directly into outer space, can be achieved by using silica particles designed to emit in the infrared atmospheric transparency window. The purpose of this study is to improve the plastic greenhouse cladding to regulate the temperature inside the greenhouse, mainly by passive cooling. Low-density polyethylene (LDPE)-based formulations with anti-fogging agent, UV stabilizer, and silica particles were prepared by the melt blending technique and were formed into a double film by extrusion molding. Experimental results showed that under 35 °C ambient conditions, the inner temperature of the simulated greenhouse with the newly developed cladding was 4 to 5 °C less than that of the greenhouse with the commercial agricultural polyethylene (PE) film. PMID- 29987205 TI - Antiadipogenic Effects of Loganic Acid in 3T3-L1 Preadipocytes and Ovariectomized Mice. AB - Obesity is caused by an excess storage of body fat, resulting from a chronic imbalance between energy intake and expenditure. Gentiana lutea L. (GL) root has been reported to reduce lipid accumulation in the aortic wall of diabetic rats. Here, we performed fractionation and isolation of the bioactive constituent(s) that may be responsible for the antiadipogenic effects of the GL root extract. A single compound, loganic acid, was identified as a candidate component in the 30% ethanol extract of GL. Loganic acid treatment significantly decreased the adipocyte differentiation of 3T3-L1 preadipocytes in a dose-dependent manner. The expression of key adipogenesis-related genes such as adiponectin (Adipoq), peroxisome proliferator-activated receptor gamma (Pparg), lipoprotein lipase (Lpl), perilipin1 (Plin1), fatty acid binding protein 4 (Fabp4), glucose transporter type 4 (Slc2a4), CCAAT/enhancer-binding protein alpha (Cebpa), and tumor necrosis factor-alpha (Tnf) were significantly reduced following treatment with loganic acid. In vivo experiments in an ovariectomy-induced obesity mouse model showed that loganic acid (oral administration with 10 and 50 mg/kg/day) significantly inhibited body weight gain, total fat increase, fatty hepatocyte deposition in the liver, and adipocyte enlargement in the abdominal visceral fat tissues. These results suggest that loganic acid in the GL root extract has antiadipogenic effects in vitro and in vivo. Loganic acid may be beneficial for the prevention and treatment of obesity, particularly in menopausal obese women. PMID- 29987206 TI - Antileishmanial Activity of Amphotericin B-loaded-PLGA Nanoparticles: An Overview. AB - In recent decades, nanotechnology has made phenomenal strides in the pharmaceutical field, favouring the improvement of the biopharmaceutical properties of many active compounds. Many liposome-based formulations containing antitumor, antioxidant and antifungal compounds are presently on the market and are used daily (for example Doxil®/Caelyx® and Ambisome®). Polymeric nanoparticles have also been used to entrap many active compounds with the aim of improving their pharmacological activity, bioavailability and plasmatic half-life while decreasing their side effects. The modulation of the structural/morphological properties of nanoparticles allows us to influence various technological parameters, such as the loading capacity and/or the release profile of the encapsulated drug(s). Amongst the biocompatible polymers, poly(D,L lactide) (PLA), poly(D,L-glycolide) (PLG) and their co-polymers poly(lactide-co glycolide) (PLGA) are the most frequently employed due to their approval by the FDA for human use. The aim of this review is to provide a description of the foremost recent investigations based on the encapsulation of amphotericin B in PLGA nanoparticles, in order to furnish an overview of the technological properties of novel colloidal formulations useful in the treatment of Leishmaniasis. The pharmacological efficacy of the drug after nanoencapsulation will be compared to the commercial formulations of the drug (i.e., Fungizone®, Ambisome®, Amphocil® and Abelcet®). PMID- 29987207 TI - Whole-Body MRI with Diffusion-Weighted Imaging in Bone Metastases: A Narrative Review. AB - Whole body magnetic resonance imaging (MRI) with diffusion-weighted imaging (WB MRI-DWI) is currently emerging as a diagnostic technique in the evaluation of bone metastases from breast, prostate, lung, thyroid, and melanoma tumors. The most relevant articles regarding the detection of solid tumor bone metastases with MRI have been reviewed and cited. The imaging methods currently used in the detection of bone metastases are bone scintigraphy, computed tomography (CT), and positron emission tomography (PET/CT) with 2-deoxy-2-[fluorine-18] fluoro-d glucose (18F-FDG PET/CT). WB-MRI-DWI allows qualitative and quantitative evaluation of focal lesions through signal intensity evaluation on DWI images and the reconstruction of the apparent diffusion coefficient (ADC) map. In prostate and breast cancer, WB-MRI-DWI is useful in assessing the response of bone lesions to therapy and to detecting early non-responders, while in lung cancer the method shows a similar sensitivity to 18F-FDG PET/CT in the detection of bone metastases. In bone metastases of thyroid tumors and melanoma, the WB-MRI-DWI shows a higher sensitivity when compared to 18F-FDG PET/CT. With a standardization of the WB-MRI-DWI protocol, this method seems to play an important role in the diagnosis of bone solid tumor metastases. PMID- 29987208 TI - Urtica spp.: Ordinary Plants with Extraordinary Properties. AB - Nettles (genus Urtica, family Urticaceae) are of considerable interest as preservatives in foods for both human and animal consumption. They have also been used for centuries in traditional medicine. This paper reviews the properties of nettles that make them suitable for wider applications in the food and pharmaceutical industries. Nettles contain a significant number of biologically active compounds. For example, the leaves are rich sources of terpenoids, carotenoids and fatty acids, as well as of various essential amino acids, chlorophyll, vitamins, tannins, carbohydrates, sterols, polysaccharides, isolectins and minerals. Extracts from the aerial parts of nettles are rich sources of polyphenols, while the roots contain oleanol acid, sterols and steryl glycosides. Due to the variety of phytochemicals and their proportions they contain, nettles show noticeable activity against both Gram-positive and Gram negative bacteria. These properties make nettles suitable for a range of possible applications, including functional food, dietary supplements and pharmacological formulations. Despite these benefits, the nettle is still an underestimated plant source. This paper provides a unique overview of the latest research on nettle plants focusing on the possibilities for transforming a common weed into a commercial plant with a wide range of applications. Special attention is paid to the antimicrobial activity of the active compounds in nettles and to possible uses of these valuable plants in food and feed formulations. PMID- 29987210 TI - An Electroelastic Solution for Functionally Graded Piezoelectric Circular Plates under the Action of Combined Mechanical Loads. AB - In this study, we obtained an electroelastic solution for functionally graded piezoelectric circular plates under the action of combined mechanical loads which include the uniformly distributed loads on the upper surface of the plate and the radial force and bending moment at the periphery of the plate. All electroelastic materials parameters are assumed to vary according to the same gradient function along the thickness direction. The influence of different functionally graded parameters on the elastic displacement and elastic stress, as well as the electric displacement and electric potential, was discussed by a numerical example. The solution presented in this study is not only applicable to the case of combined loads, but also to the case of a single mechanical load. In addition, this solution reflects the influence of the function gradient on the pure piezoelectric plate, which is helpful to the refined analysis and optimization design of similar structures. PMID- 29987209 TI - Perceived Discrimination and Substance Use among Caribbean Black Youth; Gender Differences. AB - Although perceived discrimination in Black youth is a risk factor for a wide range of negative mental health outcomes, recent research has suggested some gender differences in these associations. Gender differences in vulnerability to perceived discrimination among Caribbean Black youth is, however, still unknown. The current cross-sectional study investigated gender variations in the association between perceived discrimination and substance use (SU) in a national sample of Caribbean Black youth. Data came from the National Survey of American Life-Adolescents (NSAL-A), 2003-2004. This analysis included 360 Caribbean Black youth (165 males and 195 females) who were between 13 and 17 years old. Sociodemographic factors, perceived discrimination, and SU were measured. Logistic regressions were used for data analysis. Among Caribbean Black youth, a positive association was found between perceived discrimination and SU (odds ratio (OR) = 1.15 (95% confidence interval (CI) = 1.02-1.29)). A significant interaction was found between gender and perceived discrimination on smoking (OR = 1.23 (95% CI = 1.07-1.41)) suggesting that the association between perceived discrimination and smoking is larger for male than female Caribbean Black youth. The interaction between gender and perceived discrimination on SU was not statistically significant (OR = 1.32 (95% CI = 0.94-1.86)). While perceived discrimination increases SU in Caribbean Black youth, this effect is stronger for males than females, especially for smoking. While discrimination should be reduced at all levels and for all populations, clinicians may specifically address discrimination for SU prevention and treatment among male Caribbean Black youth. PMID- 29987211 TI - On-Device Learning of Indoor Location for WiFi Fingerprint Approach. AB - Indoor positioning is a recent technology that has gained interest in industry and academia thanks to the promising results of locating objects, people or robots accurately in indoor environments. One of the utilized technologies is based on algorithms that process the Received Signal Strength Indicator (RSSI) in order to infer location information without previous knowledge of the distribution of the Access Points (APs) in the area of interest. This paper presents the design and implementation of an indoor positioning mobile application, which allows users to capture and build their own RSSI maps by off line training of a set of selected classifiers and using the models generated to obtain the current indoor location of the target device. In an early experimental and design stage, 59 classifiers were evaluated, using data from proposed indoor scenarios. Then, from the tested classifiers in the early stage, only the top five classifiers were integrated with the proposed mobile indoor positioning, based on the accuracy obtained for the test scenarios. The proposed indoor application achieves high classification rates, above 89%, for at least 10 different locations in indoor environments, where each location has a minimum separation of 0.5 m. PMID- 29987213 TI - Zinc Oxide Coated Tin Oxide Nanofibers for Improved Selective Acetone Sensing. AB - Three-dimensional hierarchical SnO2/ZnO hetero-nanofibers were fabricated by the electrospinning method followed with a low-temperature water bath treatment. These hierarchical hollow SnO2 nanofibers were assembled by the SnO2 nanoparticles through the electrospinning process and then the ZnO nanorods were grown vertically on the surface of SnO2 nanoparticles, forming the 3D nanostructure. The synthesized hollow SnO2/ZnO heterojunctions nanofibers were further employed to be a gas-sensing material for detection of volatile organic compound (VOC) species such as acetone vapor, which is proposed as a gas biomarker for diabetes. It shows that the heterojunction nanofibers-based sensor exhibited excellent sensing properties to acetone vapor. The sensor shows a good selectivity to acetone in the interfering gases of ethanol, ammonia, formaldehyde, toluene, and methanol. The enhanced sensing performance may be due to the fact that n-n 3D heterojunctions, existing at the interface between ZnO nanorods and SnO2 particles in the SnO2/ZnO nanocomposites, could prompt significant changes in potential barrier height when exposed to acetone vapor, and gas-sensing mechanisms were analyzed and explained by Schottky barrier changes in SnO2/ZnO 3D hetero-nanofibers. PMID- 29987212 TI - Senescence Induces Dysfunctions in Endothelial Progenitor Cells and Osteoblasts by Interfering Translational Machinery and Bioenergetic Homeostasis. AB - Age-related bone diseases are partly caused by impaired bone integrity, which are closely related to osteoblasts’ activity and angiogenesis. Endothelial progenitor cells (EPCs) are the initiators of angiogenesis and found to have senescent-induced dysfunctions. The aim of this study is to investigate the effects of senescence in EPCs on osteogenesis and angiogenesis. Human primary EPCs and a murine osteoblast cell line (MC3T3-E1) are utilized in this study. The senescence of EPCs are induced by serial passages. When co-cultured with senescent EPCs, the osteoblasts demonstrate weakened alkaline phosphatase (ALP) activity and mineral deposition. On the other hand, osteoblast-induced migration decreases in senescent EPCs. As for the intracellular alterations of senescent EPCs, the activation of Akt/mTOR/p70S6K pathway, MnSOD and catalase are diminished. In contrast, the level of reactive oxygen species are significantly higher in senescent EPCs. Furthermore, senescent EPCs has decreased level intracellular ATP level and coupling efficiency for oxidative phosphorylation while the non-mitochondrial respiration and glycolysis are elevated. The senescence of EPCs impairs the functions of both osteoblasts and EPCs, suggesting EPCs’ role in the pathophysiology of age-related bone diseases. Targeting the alterations found in this study could be potential treatments. PMID- 29987214 TI - Enhancement of Dynamic Damping in Eco-Friendly Railway Concrete Sleepers Using Waste-Tyre Crumb Rubber. AB - There is no doubt that the use of waste rubber in concrete applications is a genius alternative because Styrene is the main component of rubber, which has a strong toxicity and is harmful to humans. Therefore, it will significantly reduce impacts on the environment when waste rubber can be recycled for genuine uses. In this paper, the dynamic properties of high-strength rubberised concrete have been investigated by carrying out various experiments to retain the compressive strength, tensile strength, flexural strength, electrical resistivity, and damping characteristics by replacing fine aggregates with micro-scale crumb rubber. Over 20 variations of concrete mixes have been performed. The experimental results confirm that a decrease in the compressive strength can be expected when the rubber content is increased. The new findings demonstrate that the high-strength concrete can be enhanced by optimal rubber particles in order to improve splitting tensile and flexural strengths, damping properties, and electrical resistivity. It is therefore recommended to consider the use of rubberised concrete (up to 10 wt. % crumb rubber) in designing railway sleepers as this will improve the service life of railway track systems and reduce wastes to the environment. PMID- 29987216 TI - A Survey on the Knowledge and Attitudes of Italian Medical Students toward Body Donation: Ethical and Scientific Considerations. AB - Post mortem body donation (PMBD) for medical training and research plays a key role in medical-surgical education. The aim of this study is to evaluate Italian medical students’ awareness and attitudes regarding this practice. A questionnaire was sent to 1781 Italian medical students (MS). A total of 472 MS responded: 406 (92.91%) had a strongly positive attitude to PMBD, while 31 (7.09%) were not in favor. The majority of subjects were Catholic (56.36%), while 185 and 21 subjects, said that they did not hold any religious beliefs, or were of other religions, respectively. Multivariate analysis showed significant associations (p-values < 0.05) between PMBD and religion, as well as perceptions of PMBD as an act of altruism, a tool for learning surgical practices, body mutilation, and an act contrary to faith. Although Italian MS believed cadaver dissection to be an important part of their education, they did not know much about it and had not received training on this altruistic choice. As future doctors, MS can play an important role in raising public awareness of the importance of PMBD for medical education and research. Specific educational programs to improve knowledge of this topic among MS are needed. PMID- 29987215 TI - Oncolytic Viruses as Therapeutic Tools for Pediatric Brain Tumors. AB - In recent years, we have seen an important progress in our comprehension of the molecular basis of pediatric brain tumors (PBTs). However, they still represent the main cause of death by disease in children. Due to the poor prognosis of some types of PBTs and the long-term adverse effects associated with the traditional treatments, oncolytic viruses (OVs) have emerged as an interesting therapeutic option since they displayed safety and high tolerability in pre-clinical and clinical levels. In this review, we summarize the OVs evaluated in different types of PBTs, mostly in pre-clinical studies, and we discuss the possible future direction of research in this field. In this sense, one important aspect of OVs antitumoral effect is the stimulation of an immune response against the tumor which is necessary for a complete response in preclinical immunocompetent models and in the clinic. The role of the immune system in the response of OVs needs to be evaluated in PBTs and represents an experimental challenge due to the limited immunocompetent models of these diseases available for pre-clinical research. PMID- 29987217 TI - Optical Biosensing System for the Detection of Survivin mRNA in Colorectal Cancer Cells Using a Graphene Oxide Carrier-Bound Oligonucleotide Molecular Beacon. AB - The anti-apoptotic protein survivin is one of the most promising cancer biomarkers owing to its high expression in human cancers and rare occurrence in normal adult tissues. In this work, we have investigated the role of supramolecular interactions between a graphene oxide (GO) nanosheet nanocarrier and a survivin molecular beacon (SurMB), functionalized by attaching fluorophore Joe and quencher Dabcyl (SurMB-Joe). Molecular dynamics simulations revealed hydrogen bonding of Joe moiety and Dabcyl to GO carriers that considerably increase the SurMB-GO bonding strength. This was confirmed in experimental work by the reduced fluorescence background in the OFF state, thereby increasing the useful analytical signal range for mRNA detection. A new mechanism of hairpin hairpin interaction of GO@SurMB with target oligonucleotides has been proposed. A low limit of detection, LOD = 16 nM (S/N = 3), has been achieved for complementary tDNA using GO@SurMB-Joe nanocarriers. We have demonstrated an efficient internalization of SurMB-Joe-loaded GO nanocarriers in malignant SW480 cells. The proposed tunability of the bonding strength in the attached motifs for MBs immobilized on nanocarriers, via structural modifications, should be useful in gene delivery systems to enhance the efficacy of gene retention, cell transfection and genomic material survivability in the cellular environment. PMID- 29987218 TI - Automatic Annotation for Human Activity Recognition in Free Living Using a Smartphone. AB - Data annotation is a time-consuming process posing major limitations to the development of Human Activity Recognition (HAR) systems. The availability of a large amount of labeled data is required for supervised Machine Learning (ML) approaches, especially in the case of online and personalized approaches requiring user specific datasets to be labeled. The availability of such datasets has the potential to help address common problems of smartphone-based HAR, such as inter-person variability. In this work, we present (i) an automatic labeling method facilitating the collection of labeled datasets in free-living conditions using the smartphone, and (ii) we investigate the robustness of common supervised classification approaches under instances of noisy data. We evaluated the results with a dataset consisting of 38 days of manually labeled data collected in free living. The comparison between the manually and the automatically labeled ground truth demonstrated that it was possible to obtain labels automatically with an 80 85% average precision rate. Results obtained also show how a supervised approach trained using automatically generated labels achieved an 84% f-score (using Neural Networks and Random Forests); however, results also demonstrated how the presence of label noise could lower the f-score up to 64-74% depending on the classification approach (Nearest Centroid and Multi-Class Support Vector Machine). PMID- 29987220 TI - Reset Controller Design Based on Error Minimization for a Lane Change Maneuver. AB - An intelligent vehicle must face a wide variety of situations ranging from safe and comfortable to more aggressive ones. Smooth maneuvers are adequately addressed by means of linear control, whereas more aggressive maneuvers are tackled by nonlinear techniques. Likewise, there exist intermediate scenarios where the required responses are smooth but constrained in some way (rise time, settling time, overshoot). Due to the existence of the fundamental linear limitations, which impose restrictions on the attainable time-domain and frequency-domain performance, linear systems cannot provide smoothness while operating in compliance with the previous restrictions. For this reason, this article aims to explore the effects of reset control on the alleviation of these limitations for a lane change maneuver under a set of demanding design conditions to guarantee a suitable ride quality and a swift response. To this end, several reset strategies are considered, determining the best reset condition to apply as well as the magnitude thereto. Concerning the reset condition that triggers the reset action, three strategies are considered: zero crossing of the controller input, fixed reset band and variable reset band. As far as the magnitude of the reset action is concerned, a full-reset technique is compared to a Lyapunov-based error minimization method to calculate the optimal reset percentage. The base linear controller subject to the reset action is searched via genetic algorithms. The proposed controllers are validated by means of CarSim. PMID- 29987219 TI - Four New C9 Metabolites from the Sponge-Associated Fungus Gliomastix sp. ZSDS1-F7 2. AB - Four new structurally related metabolites, one γ-lactone named gliomasolide F (1), one δ-lactone named gliomasolide G (2), and two medium-chain fatty acids named gliomacids A-B (3-4), each containing nine carbons in total, were identified from the sponge-associated fungus Gliomastix sp. ZSDS1-F7-2. The planar chemical structures of these novel C9 metabolites were elucidated by nuclear magnetic resonance (NMR) spectroscopic methods, in connection with the analysis of high-resolution mass spectrometry (HRMS) and infrared (IR) data. The absolute configuration of 1, was determined by comparisons of experimental circular dichroism (CD) and optical rotation (OR) value with corresponding ones computed by quantum chemistry. The relative configuration of 2 was determined by the Nuclear Overhauser effect spectroscopy (NOESY) spectrum, while its absolute configuration was tentatively determined in view of the biogenetic and biosynthetic relationships between 1 and 2. Compounds 3-4, originally as an inseparable mixture, were successfully isolated after chemical modifications. The stereo-chemistries of compounds 3-4 were assumed by comparison of 13C NMR with those of the similar moiety reported in literature, in addition to the biogenetic and biosynthetic relationships with 1. The plausible biosynthetic relationships among these four C9 metabolites were supposed. Biologically, compounds 1-4 showed no cytotoxic effect against HeLa cell line at concentrations up to 25 μg/mL, while 1 exhibited moderate antifouling activity against the settlement of Balanus amphitrite larvae with IC50 being 12.8 μg/mL and LC50 > 25 μg/mL. The co occurrence of macrolides gliomasolides A—E and four C9 metabolites in the same fermentation culture made us assume that these C9 metabolites might be biosynthetic building blocks toward the construction of more complex macrolides such as gliomasolides A—E or other unidentified polyketides. PMID- 29987221 TI - Energy-Efficient Multicast Service Delivery Exploiting Single Frequency Device-To Device Communications in 5G New Radio Systems. AB - The forthcoming fifth generation (5G) networks are claimed to deliver the large amount of traffic generated by the huge number of heterogeneous devices that constitute the Internet of Things (IoT). This unprecedented volume of both human- and machine-generated traffic to be managed imposes 5G network operators to move the focus from throughput-optimized to energy-efficiency-optimized resource allocation solutions. Device-to-device (D2D) communications are recognized as an effective offloading technique that the 5G network can exploit to boost the capacity and energy efficiency of future 5G networks. In this paper, we design a technique to efficiently deliver multicast traffic in a 5G New Radio (NR) network by exploiting the benefits of D2D communication and single-frequency operation in order to improve the overall network energy efficiency. In the designed solution, the subset of devices in better channel conditions are served through a conventional multicast transmission, while cell-edge devices receive the multicast service from relay nodes that simultaneously transmit in D2D mode the same content. The dimension of the multicast serving area and the set of D2D connections to establish are chosen in order to maximize the overall network energy efficiency. Performed simulation results show the effectiveness of the proposed solution under varying frame configurations and number of multicast devices. PMID- 29987224 TI - Consensual Negotiation-Based Decision Making for Connected Appliances in Smart Home Management Systems. AB - Recently, the concept of Internet of Agent has been introduced as a potential technology that pushes intelligence, data processing, analytics and communication capabilities down to the point where the data originates. In this paper, we introduce a novel approach for a Decentralized Home Energy Management System by applying the Internet of Agent concept. In particular, we first present an Internet of Agent framework in terms of sensing, communicating and collaborating among connected appliances. Then, the decentralized management based on consensual negotiation mechanism with several intelligent techniques are proposed for dynamic scheduling connected appliance. Specifically, by applying the Internet of Agent framework, connected appliances are regarded as smart agents that are able to make individual decisions by reaching agreement over the exchange of operations on competitive resources. Furthermore, in this study, the load balancing problem in which load shifting is able to reduce the electricity demand during peak hours is taken into account in order to emphasize the effectiveness of our approach. For the experiment, we develop a simulation of smart home environment to evaluate our approach using NetLogo, a tool which provides real-time analysis in the modeling and simulation domain of complex systems. PMID- 29987223 TI - Lanthanide-Doped Upconversion Nanocarriers for Drug and Gene Delivery. AB - Compared to traditional cancer treatments, drug/gene delivery is an advanced, safe, and efficient method. Nanoparticles are widely used as nanocarriers in a drug/gene delivery system due to their long circulation time and low multi-drug resistance. In particular, lanthanide-doped upconversion nanoparticles (UCNPs) that can emit UV and visible light by near-infrared (NIR) upconversion demonstrated more efficient and safer drug/gene delivery. Because of the low penetration depth of UV and visible light, a photoinduced reaction such as photocleavage or photoisomerization has proven restrictive. However, NIR light has high tissue penetration depth and stimulates the photoinduced reaction through UV and visible emissions from lanthanide-doped UCNPs. This review discusses the optical properties of UCNPs that are useful in bioapplications and drug/gene delivery systems using the UCNPs as a photoreaction inducer. PMID- 29987222 TI - Interleukin-33: Its Emerging Role in Allergic Diseases. AB - Allergic diseases, which include asthma, allergic rhinitis (AR), chronic rhinosinusitis (CRS), atopic dermatitis (AD), food allergy (FA), allergic keratoconjunctivitis, seriously affect the quality of life of people all over the world. Recently, interleukin-33 (IL-33) has been found to play an important role in these refractory disorders, mainly by inducing T helper (Th) 2 immune responses. This article reviews the mobilization and biological function of IL-33 in allergic disorders, providing novel insights for addressing these hypersensitive conditions. PMID- 29987225 TI - Lignans: A Chemometric Analysis. AB - The physicochemical properties of classical lignans, neolignans, flavonolignans and carbohydrate-lignan conjugates (CLCs) were analysed to assess their ADMET profiles and establish if these compounds are lead-like/drug-like and thus have potential to be or act as leads in the development of future therapeutics. It was found that while no studied compounds were lead-like, a very large proportion (>75%) fulfilled all the requirements to be deemed as present in drug-like space and almost all compounds studied were in the known drug space. Principal component analysis was an effective technique that enabled the investigation of the relationship between the studied molecular descriptors and was able to separate the lignans from their sugar derivatives and flavonolignans, primarily according to the parameters that are considered when defining chemical space (i.e., number of hydrogen bond donors, acceptors, rotatable bonds, polar surface area and molecular weight). These results indicate that while CLCs and flavonolignans are less drug-like, lignans show a particularly high level of drug likeness, an observation that coupled with their potent biological activities, demands future pursuit into their potential for use as therapeutics. PMID- 29987228 TI - Toxicity Assay for Citrinin, Zearalenone and Zearalenone-14-Sulfate Using the Nematode Caenorhabditis elegans as Model Organism. AB - To keep pace with the rising number of detected mycotoxins, there is a growing need for fast and reliable toxicity tests to assess potential threats to food safety. Toxicity tests with the bacterial-feeding nematode Caenorhabditis elegans as the model organism are well established. In this study the C. elegans wildtype strain N2 (var. Bristol) was used to investigate the toxic effects of the food relevant mycotoxins citrinin (CIT) and zearalenone-14-sulfate (ZEA-14-S) and zearalenone (ZEA) on different life cycle parameters including reproduction, thermal and oxidative stress resistance and lifespan. The metabolization of the mycotoxins by the nematodes in vivo was investigated using HPLC-MS/MS. ZEA was metabolized in vivo to the reduced isomers α-zearalenol (α-ZEL) and β-ZEL. ZEA-14-S was reduced to α-/β-ZEL-14-sulfate and CIT was metabolized to mono-hydroxylated CIT. All mycotoxins tested led to a significant decrease in the number of nematode offspring produced. ZEA and CIT displayed negative effects on stress tolerance levels and for CIT an additional shortening of the mean lifespan was observed. In the case of ZEA-14-S, however, the mean lifespan was prolonged. The presented study shows the applicability of C. elegans for toxicity testing of emerging food mycotoxins for the purpose of assigning potential health threats. PMID- 29987227 TI - Interpretation of Cerebral Oxygenation Changes in the Preterm Infant. AB - Near-infrared spectroscopy (NIRS) allows for continuous, non-invasive monitoring of end-organ tissue oxygenation. The use of NIRS, cerebral NIRS (cNIRS) in particular, in neonatal care has increased significantly over the last few years. This dynamic monitoring technique provides real-time information on the cerebral and haemodynamic status of the neonate and has the potential to serve as an important adjunct to patient care with some centres routinely utilising cNIRS to aid decision-making at the bedside. cNIRS values may be influenced by many variables, including cardiac, respiratory and metabolic parameters, and therefore it is essential to understand the pathophysiology behind alterations in cNIRS values. Correct interpretation is required to direct appropriate patient-specific interventions. This article aims to assist clinicians in deciphering cNIRS values by providing an overview of potential causes of fluctuations in cNIRS values, illustrated by common clinical scenarios, with particular emphasis on the preterm infant. PMID- 29987226 TI - Lysophospholipid Signaling in the Epithelial Ovarian Cancer Tumor Microenvironment. AB - As one of the important cancer hallmarks, metabolism reprogramming, including lipid metabolism alterations, occurs in tumor cells and the tumor microenvironment (TME). It plays an important role in tumorigenesis, progression, and metastasis. Lipids, and several lysophospholipids in particular, are elevated in the blood, ascites, and/or epithelial ovarian cancer (EOC) tissues, making them not only useful biomarkers, but also potential therapeutic targets. While the roles and signaling of these lipids in tumor cells are extensively studied, there is a significant gap in our understanding of their regulations and functions in the context of the microenvironment. This review focuses on the recent study development in several oncolipids, including lysophosphatidic acid and sphingosine-1-phosphate, with emphasis on TME in ovarian cancer. PMID- 29987230 TI - Pollutant Removal from Synthetic Aqueous Solutions with a Combined Electrochemical Oxidation and Adsorption Method. AB - Eliminating organic and inorganic pollutants from water is a worldwide concern. In this study, we applied electrochemical oxidation (EO) and adsorption techniques to eliminate ammonia, phenols, and Mo(VI) from aqueous solutions. We analyzed the first stage (EO) with response surface methodology, where the reaction time (1-3 h), initial contaminant concentration (10-50 mg/L), and pH (3 6) were the three independent factors. Sodium sulfate (as an electrolyte) and Ti/RuO2-IrO2 (as an electrode) were used in the EO system. Based on preliminary experiments, the current and voltage were set to 50 mA and 7 V, respectively. The optimum EO conditions included a reaction time, initial contaminant concentration, and pH of 2.4 h, 27.4 mg/L, and 4.9, respectively. The ammonia, phenols, and Mo elimination efficiencies were 79.4%, 48.0%, and 55.9%, respectively. After treating water under the optimum EO conditions, the solution was transferred to a granular composite adsorbent column containing bentonite, limestone, zeolite, cockleshell, activated carbon, and Portland cement (i.e., BAZLSC), which improved the elimination efficiencies of ammonia, phenols, and molybdenum(VI) to 99.9%. The energy consumption value (8.0 kWh kg−1 N) was detected at the optimum operating conditions. PMID- 29987229 TI - Cross-Talk between Wnt and Hh Signaling Pathways in the Pathology of Basal Cell Carcinoma. AB - Basal cell carcinoma (BCC) is the most frequently occurring form of all cancers. The cost of care for BCC is one of the highest for all cancers in the Medicare population in the United States. Activation of Hedgehog (Hh) signaling pathway appears to be a key driver of BCC development. Studies involving mouse models have provided evidence that activation of the glioma-associated oncogene (GLI) family of transcription factors is a key step in the initiation of the tumorigenic program leading to BCC. Activation of the Wnt pathway is also observed in BCCs. In addition, the Wnt signaling pathway has been shown to be required in Hh pathway-driven development of BCC in a mouse model. Cross-talks between Wnt and Hh pathways have been observed at different levels, yet the mechanisms of these cross-talks are not fully understood. In this review, we examine the mechanism of cross-talk between Wnt and Hh signaling in BCC development and its potential relevance for treatment. Recent studies have identified insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a direct target of the Wnt/β-catenin signaling, as the factor that binds to GLI1 mRNA and upregulates its levels and activities. This mode of regulation of GLI1 appears important in BCC tumorigenesis and could be explored in the treatment of BCCs. PMID- 29987231 TI - Evaluation of the Use of TRIzol-Based Protein Extraction Approach for Gel-Based Proteomic Analysis of Dried Seafood Products and Chinese Tonic Foods. AB - Although the emergence of gel-free approaches has greatly enhanced proteomic studies, two-dimensional gel electrophoresis (2-DE) remains one of the most widely used proteomic techniques for its high resolving power, relatively low cost, robustness, and high resolution. Preparation of high-quality protein samples remains the key in high-quality 2-DE for proteomic analysis. Samples with high endogenous levels of interfering molecules, such as salts, nucleic acids, lipids, and polysaccharides, would yield a low-quality 2-DE gel and hinder the analysis. Recently, a TRIzol-based protein extraction method has gained prominence and has attracted attention due to its promising performance in high quality 2-DE. The authors evaluate the use of this approach for four valuable dried food products, namely two dried seafood products (abalone slices and whelk slices) and two traditional Chinese tonic foods (ganoderma and caterpillar fungus). The results indicate that 2-DE gels obtained through the TRIzol-based method are of high-quality and are comparable to those obtained through the trichloroacetic acid-acetone method in terms of spot number, spot intensity, and resolution. The TRIzol-based method is generally applicable to dried food samples and is simple and fast, which greatly streamlines the protein extraction procedure. Additionally, it enables the concurrent extraction and analysis of RNA, DNA, and protein from the same sample. PMID- 29987232 TI - NTyroSite: Computational Identification of Protein Nitrotyrosine Sites Using Sequence Evolutionary Features. AB - Nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species. As an indicator of cell damage and inflammation, protein nitrotyrosine serves to reveal biological change associated with various diseases or oxidative stress. Accurate identification of nitrotyrosine site provides the important foundation for further elucidating the mechanism of protein nitrotyrosination. However, experimental identification of nitrotyrosine sites through traditional methods are laborious and expensive. In silico prediction of nitrotyrosine sites based on protein sequence information are thus highly desired. Here, we report a novel predictor, NTyroSite, for accurate prediction of nitrotyrosine sites using sequence evolutionary information. The generated features were optimized using a Wilcoxon-rank sum test. A random forest classifier was then trained using these features to build the predictor. The final NTyroSite predictor achieved an area under a receiver operating characteristics curve (AUC) score of 0.904 in a 10 fold cross-validation test. It also significantly outperformed other existing implementations in an independent test. Meanwhile, for a better understanding of our prediction model, the predominant rules and informative features were extracted from the NTyroSite model to explain the prediction results. We expect that the NTyroSite predictor may serve as a useful computational resource for high-throughput nitrotyrosine site prediction. The online interface of the software is publicly available at https://biocomputer.bio.cuhk.edu.hk/NTyroSite/. PMID- 29987233 TI - Reallocating Time from Sedentary Behavior to Light and Moderate-to-Vigorous Physical Activity: What Has a Stronger Association with Adiposity in Older Adult Women? AB - This study is the first to use compositional data analysis to investigate movement behaviors of elderly women and their relationships with fat mass percentage (FM%). The focus of the study is on the associations of time reallocations from sedentary behavior (SB) to light physical activity (LIPA) or moderate-to-vigorous physical activity (MVPA) with adiposity. Over 400 older adult women were recruited as part of the cross-sectionally conducted measurements of older adults aged 60+ in Central European countries. An accelerometer was used to assess daily movement behaviors. Body mass index (BMI) and fat mass percentage (FM%) were assessed as adiposity indicators using InBody 720 MFBIA. Using LS-regression, we found positive relationships of BMI and FM% with SB (relative to remaining movement behaviors) (p < 0.001 for both), while their relationship with MVPA (relative to remaining movement behaviors) were negative (p < 0.001 for both). The estimated BMI and FM% associated with a 30-min SB-to-MVPA reallocation were reduced by 1.5 kg/m2 and 2.2 percentage points, respectively, whereas they were not reduced significantly with the reallocation of 30 min from SB to LIPA. The findings highlight that SB and MVPA, but not LIPA, are significantly associated with adiposity in elderly women. The reallocation of time from SB to MVPA could be advocated in weight loss interventions in older women. PMID- 29987234 TI - Impact of Pharmacy Based Travel Medicine with the Evolution of Pharmacy Practice in the UK. AB - Background: Pharmacy has utilised the changes in legislation since 2000 to increase the range and supply function of services such as travel health to travellers. With the number of travellers leaving the UK and trying new destinations there is an increasing need for more travel health provision. Working models: The models of supply of a travel health service vary according to the size of the corporate body. The large multiples can offer assessment via a specialist nurse or doctor service and then supply through the pharmacy. Others will undertake an onsite risk assessment and supply through the pharmacist. The sole Internet suppliers of medication have been reviewed and the assessment standards questioned following survey and inspection. Education: There is no dedicated pharmacist-training programme in advanced level travel health. As a consequence one academic institution allows pharmacists to train on a multidisciplinary course to obtain an academic membership. With training for travel health not being mandatory for any travel health supply function the concern is raised with standards of care. Future: There is a consultation paper on the removal of travel vaccines from NHS supply due to be decided in the future. If these vaccines are removed then they will provide a greater demand on pharmacy services. Discussion: The starting of a travel health service can be made without any additional training and remains unregulated, giving cause for concern to the supply made to the traveller. Conclusions: Pharmacies in the UK offer a range of options for supplying travel health services; however these need to be with improved mandatory training and supply. PMID- 29987235 TI - Biomass-Derived Nitrogen-Doped Carbon Aerogel Counter Electrodes for Dye Sensitized Solar Cells. AB - Dye sensitized solar cells have emerged as an attractive alternative to conventional solar cells due to their easy processing and the abundance and low cost of their materials. However, the counter electrode in these cells employs platinum which significantly impacts their cost. Here, we report biomass-derived, nitrogen-doped carbon aerogel as an effective alternative to conventional platinum-based counter electrodes for dye sensitized solar cells. A stable suspension of biomass-derived, nitrogen-doped carbon aerogel was prepared in DMF by using oleylamine as a binder. The nitrogen-doped carbon aerogel electrode was annealed at different temperatures, and its impact on photovoltaic performance is investigated. I-V measurements confirm that the annealing temperature substantially enhances the photovoltaic parameters of these devices; these enhancements are linked to the removal of the organic binders. Electrochemical impedance spectra of the counter electrodes confirm that removal of oleylamine in nitrogen-doped carbon aerogels reduces the series resistance of the resulting electrodes. The power conversion efficiency of the solar cells from optimized nitrogen-doped carbon aerogel exhibited comparable efficiency to that of a cell fabricated using a platinum-based counter electrode. This study demonstrates the potential of biomass-derived carbon aerogels as a cheap and sustainable replacement of platinum in DSSCs. PMID- 29987236 TI - Pollen-Structured Gold Nanoclusters for X-ray Induced Photodynamic Therapy. AB - Photodynamic therapy (PDT) is a cancer treatment that employs the production of cytotoxic reactive oxygen species (ROS), subsequently triggering tumor apoptosis and tumor size reduction. However, this approach suffers from insufficient light penetration depth. In order to mitigate this issue, pollen-structured gold clusters (PSGCs) were designed for mediating X-ray-induced PDT for radiotherapy enhancement. The structure of PSGCs provides a large surface area that is able to generate ROS upon X-ray irradiation. The synthesized PSGCs were exposed to different X-ray doses and the generated ROS was then quantified by dihydroethidium (DHE) assay. Furthermore, at the cellular level, the PDT efficacy of PSGCs was evaluated via immunofluorescence staining with γ-H2AX and comet assay. The results demonstrated that PSGCs possess a significantly high ROS generating capacity and a remarkable PDT efficacy in the treatment of breast cancer cells, thus showing potential clinical uses in deep-tissue cancer treatment. PMID- 29987237 TI - Antimicrobial Activity of Five Essential Oils against Bacteria and Fungi Responsible for Urinary Tract Infections. AB - Urinary tract infections are frequently encountered in small animal practice. Escherichia coli and Enterococcus spp. are the most common agents associated to these infections, even though other bacteria and yeasts, such as Candida albicans and Candida famata, may be involved. In view of the increasing problem of the multi-drug resistance, the aim of this study was to investigate the antimicrobial activity of essential oils obtained from star anise (Illicium verum Hook.f.), basil (Ocimum basilicum L.), origanum (Origanum vulgare L.), clary sage (Salvia sclarea L.) and thymus (Thymus vulgaris L.) against multidrug-resistant strains of Escherichia coli, Enterococcus spp., Candida albicans and Candida famata previously isolated from dogs and cats with urinary tract infections. Enterococci were resistant to Illicium verum and Salvia sclarea, such as Candida to Salvia sclarea. Thymus vulgaris and Origanum vulgare essential oils showed the best activity against all the tested pathogens, so they could be proposed for the formulation of external and/or intravesical washes in small animals. PMID- 29987238 TI - Asperindoles A-D and a p-Terphenyl Derivative from the Ascidian-Derived Fungus Aspergillus sp. KMM 4676. AB - Four new indole-diterpene alkaloids asperindoles A-D (1-4) and the known p terphenyl derivative 3″-hydroxyterphenyllin (5) were isolated from the marine-derived strain of the fungus Aspergillus sp., associated with an unidentified colonial ascidian. The structures of 1-5 were established by 2D NMR and HRESIMS data. The absolute configurations of all stereocenters of 1-4 were determined by the combination of ROESY data, coupling constants analysis, and biogenetic considerations. Asperindoles C and D contain a 2-hydroxyisobutyric acid (2-HIBA) residue, rarely found in natural compounds. Asperindole A exhibits cytotoxic activity against hormone therapy-resistant PC-3 and 22Rv1, as well as hormone therapy-sensitive human prostate cancer cells, and induces apoptosis in these cells at low-micromolar concentrations. PMID- 29987241 TI - Treatment of Infections Due to Aspergillus terreus Species Complex. AB - The Aspergillus terreus species complex is found in a wide variety of habitats, and the spectrum of diseases caused covers allergic bronchopulmonary aspergillosis, Aspergillus bronchitis and/or tracheobronchitis, and invasive and disseminated aspergillosis. Invasive infections are a significant cause of morbidity and mortality mainly in patients with hematological malignancy. The section Terrei covers a total of 16 accepted species of which most are amphotericin B resistant. Triazoles are the preferred agents for treatment and prevention of invasive aspergillosis. Poor prognosis in patients with invasive A. terreus infections seems to be independent of anti-Aspergillus azole-based treatment. PMID- 29987242 TI - Research on the Thermal Behaviour of a Selectively Laser Melted Aluminium Alloy: Simulation and Experiment. AB - A 3D Finite Element (FE) model was developed to investigate the thermal behaviour within the melt pool during point exposure to Selective Laser Melting (SLM) processed AlSi10Mg powder. The powder-solid transition, temperature-dependent thermal properties, melt pool convection, and recoating phase were taken into account. The effects of Exposure Time (ET) and Point Distance (PD) on SLM thermal behaviour were also investigated and showed that the short liquid phase time and high cooling rate of the melt pool reduced the viscosity of the melt pool at a lower ET or a higher PD. This resulted in poor wettability and the occurrence of balling and micropores. At a higher ET or lower PD the melt pool became unstable and allowed for easy formation of the self-balling phenomenon, as well as further partial remelting in the depth direction resulting in the creation of larger pores. The proper melt pool width (119.8 μm) and depth (48.65 μm) were obtained for a successful SLM process using an ET of 140 μs and a PD of 80 μm. The surface morphologies and microstructures were experimentally obtained using the corresponding processing conditions, and the results aligned with those predicted in the simulation. PMID- 29987239 TI - Marine Carbohydrate-Based Compounds with Medicinal Properties. AB - The oceans harbor a great diversity of organisms, and have been recognized as an important source of new compounds with nutritional and therapeutic potential. Among these compounds, carbohydrate-based compounds are of particular interest because they exhibit numerous biological functions associated with their chemical diversity. This gives rise to new substances for the development of bioactive products. Many are the known applications of substances with glycosidic domains obtained from marine species. This review covers the structural properties and the current findings on the antioxidant, anti-inflammatory, anticoagulant, antitumor and antimicrobial activities of medium and high molecular-weight carbohydrates or glycosylated compounds extracted from various marine organisms. PMID- 29987240 TI - HDV Can Constrain HBV Genetic Evolution in HBsAg: Implications for the Identification of Innovative Pharmacological Targets. AB - Chronic HBV + HDV infection is associated with greater risk of liver fibrosis, earlier hepatic decompensation, and liver cirrhosis hepatocellular carcinoma compared to HBV mono-infection. However, to-date no direct anti-HDV drugs are available in clinical practice. Here, we identified conserved and variable regions in HBsAg and HDAg domains in HBV + HDV infection, a critical finding for the design of innovative therapeutic agents. The extent of amino-acid variability was measured by Shannon-Entropy (Sn) in HBsAg genotype-d sequences from 31 HBV + HDV infected and 62 HBV mono-infected patients (comparable for demographics and virological-parameters), and in 47 HDAg genotype-1 sequences. Positions with Sn = 0 were defined as conserved. The percentage of conserved HBsAg-positions was significantly higher in HBV + HDV infection than HBV mono-infection (p = 0.001). Results were confirmed after stratification for HBeAg-status and patients’ age. A Sn = 0 at specific positions in the C-terminus HBsAg were correlated with higher HDV-RNA, suggesting that conservation of these positions can preserve HDV fitness. Conversely, HDAg was characterized by a lower percentage of conserved residues than HBsAg (p < 0.001), indicating higher functional plasticity. Furthermore, specific HDAg-mutations were significantly correlated with higher HDV-RNA, suggesting a role in conferring HDV replicative-advantage. Among HDAg domains, only the virus-assembly signal exhibited a high genetic conservation (75% of conserved-residues). In conclusion, HDV can constrain HBsAg genetic evolution to preserve its fitness. The identification of conserved regions in HDAg poses the basis for designing innovative targets against HDV-infection. PMID- 29987243 TI - Involvement of Allosteric Effect and KCa Channels in Crosstalk between beta2 Adrenergic and Muscarinic M2 Receptors in Airway Smooth Muscle. AB - To advance the development of bronchodilators for asthma and chronic obstructive pulmonary disease (COPD), this study was designed to investigate the mechanism of functional antagonism between β2-adrenergic and muscarinic M2 receptors, focusing on allosteric effects and G proteins/ion channels coupling. Muscarinic receptor antagonists (tiotropium, glycopyrronium, atropine) synergistically enhanced the relaxant effects of β2-adrenergic receptor agonists (procaterol, salbutamol, formoterol) in guinea pig trachealis. This crosstalk was inhibited by iberitoxin, a large-conductance Ca2+-activated K+ (KCa) channel inhibitor, whereas it was increased by verapamil, a L-type voltage-dependent Ca2+ (VDC) channel inhibitor; additionally, it was enhanced after tissues were incubated with pertussis or cholera toxin. This synergism converges in the G proteins (Gi, Gs)/KCa channel/VDC channel linkages. Muscarinic receptor antagonists competitively suppressed, whereas, β2-adrenergic receptor agonists noncompetitively suppressed muscarinic contraction. In concentration inhibition curves for β2-adrenergic receptor agonists with muscarinic receptor antagonists, EC50 was markedly decreased, and maximal inhibition was markedly increased. Hence, muscarinic receptor antagonists do not bind to allosteric sites on muscarinic receptors. β2-Adrenergic receptor agonists bind to allosteric sites on these receptors; their intrinsic efficacy is attenuated by allosteric modulation (partial agonism). Muscarinic receptor antagonists enhance affinity and efficacy of β2-adrenergic action via allosteric sites in β2-adrenergic receptors (synergism). In conclusion, KCa channels and allosterism may be novel targets of bronchodilator therapy for diseases such as asthma and COPD. PMID- 29987245 TI - Quantum Efficiency Enhancement of a GaN-Based Green Light-Emitting Diode by a Graded Indium Composition p-Type InGaN Layer. AB - We propose a graded indium composition p-type InGaN (p-InGaN) conduction layer to replace the p-type AlGaN electron blocking layer and a p-GaN layer in order to enhance the light output power of a GaN-based green light-emitting diode (LED). The indium composition of the p-InGaN layer decreased from 10.4% to 0% along the growth direction. The light intensity of the LED with a graded indium composition p-InGaN layer is 13.7% higher than that of conventional LEDs according to the experimental result. The calculated data further confirmed that the graded indium composition p-InGaN layer can effectively improve the light power of green LEDs. According to the simulation, the increase in light output power of green LEDs with a graded indium composition p-InGaN layer was mainly attributed to the enhancement of hole injection and the improvement of the radiative recombination rate. PMID- 29987244 TI - Immune Checkpoints as the Immune System Regulators and Potential Biomarkers in HIV-1 Infection. AB - Immune checkpoints are several co-stimulatory and inhibitory pathways that regulate T cell immune responses. Most of the discoveries about immune checkpoints were made in cancer research where inhibitory immune checkpoints cause immune exhaustion and down-regulate anti-tumor responses. In addition to cancer, immune checkpoints are exploited in chronic infectious diseases. In human immunodeficiency virus (HIV) infection, the immune checkpoint molecule called programmed cell death protein 1 (PD-1) has been determined as being a major regulatory factor for T cell exhaustion. Recent studies with antibodies blocking either PD-1 ligand 1 (PD-L1) or PD-1 show not only promising results in the enhancement of HIV-specific immune responses but even in reducing the latent HIV reservoir. Apart from the therapeutic target for a functional cure of HIV-1, immune checkpoint molecules might be used as biomarkers for monitoring disease progression and therapeutic response. In this review, we will summarize and discuss the inhibitory immune checkpoint molecules PD-1, cytotoxic T-lymphocyte associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and T cell immunoglobulin and mucin-domain-containing-3 (TIM3) as well as the co-stimulatory molecules CD40L and CD70, including their role in immunity, with a particular focus on HIV infection, and being potential targets for a functional HIV cure. PMID- 29987246 TI - Spectroscopical Investigations on the Redox Chemistry of [FeFe]-Hydrogenases in the Presence of Carbon Monoxide. AB - [FeFe]-hydrogenases efficiently catalyzes hydrogen conversion at a unique [4Fe 4S]-[FeFe] cofactor, the so-called H-cluster. The catalytic reaction occurs at the diiron site, while the [4Fe-4S] cluster functions as a redox shuttle. In the oxidized resting state (Hox), the iron ions of the diiron site bind one cyanide (CN−) and carbon monoxide (CO) ligand each and a third carbonyl can be found in the Fe-Fe bridging position (µCO). In the presence of exogenous CO, A fourth CO ligand binds at the diiron site to form the oxidized, CO inhibited H-cluster (Hox-CO). We investigated the reduced, CO-inhibited H-cluster (Hred´-CO) in this work. The stretching vibrations of the diatomic ligands were monitored by attenuated total reflection Fourier-transform infrared spectroscopy (ATR FTIR). Density functional theory (DFT) at the TPSSh/TZVP level was employed to analyze the cofactor geometry, as well as the redox and protonation state of the H-cluster. Selective 13CO isotope editing, spectro electrochemistry, and correlation analysis of IR data identified a one-electron reduced, protonated [4Fe-4S] cluster and an apical CN− ligand at the diiron site in Hred´-CO. The reduced, CO-inhibited H-cluster forms independently of the sequence of CO binding and cofactor reduction, which implies that the ligand rearrangement at the diiron site upon CO inhibition is independent of the redox and protonation state of the [4Fe-4S] cluster. The relation of coordination dynamics to cofactor redox and protonation changes in hydrogen conversion catalysis and inhibition is discussed. PMID- 29987247 TI - Performance of Osteoporosis Self-Assessment Tool (OST) in Predicting Osteoporosis A Review. AB - Bone health screening plays a vital role in the early diagnosis and treatment of osteoporosis to prevent fragility fractures among the elderly and high-risk individuals. Dual-energy X-ray absorptiometry (DXA), which detects bone mineral density, is the gold standard in diagnosing osteoporosis but is not suitable for screening. Therefore, many screening tools have been developed to identify individuals at risk for osteoporosis and prioritize them for DXA scanning. The Osteoporosis Self-assessment Tool (OST) is among the first tools established to predict osteoporosis in postmenopausal women. It can identify the population at risk for osteoporosis, but its performance varies according to ethnicity, gender, and age. Thus, these factors should be considered to ensure the optimal use of OST worldwide. Overall, OST is a simple and economical screening tool to predict osteoporosis and it can help to optimize the use of DXA. PMID- 29987248 TI - Physical Frailty and Amyloid-beta Deposits in the Brains of Older Adults with Cognitive Frailty. AB - BACKGROUND: Cognitive frailty and impairment are phenotypically and pathophysiologically correlated with physical frailty. We examined associations between accumulation of amyloid-β in the brain as a brain imaging biomarker and phenotypes of physical frailty (weight loss, weakness, exhaustion, slowness, low physical activity) in older adults with mild cognitive impairment (MCI) and cognitive frailty. METHODS: Cross-sectional associations between brain amyloid β accumulation measured with 11C-Pittsburgh compound B (PiB)-positron emission tomography (PET) and physical frailty were examined in 48 elderly participants (mean age: 75.1 +/- 6.6 years; 73% female). Cortical and regional standard uptake value ratios (SUVRs) were obtained. Main outcome measures included frailty phenotypes and physical functions (gait speed, short physical performance battery, and Timed Up and Go tests). RESULTS: Mean cortical region of interest and regional SUVRs (frontal cortex, temporal cortex, parietal cortex, precuneus/posterior cingulate cortex (PC/PCC), hippocampus, basal ganglia, and global SUVR) were associated with gait speed, Timed Up and Go, and short physical performance battery (PC/PCC, basal ganglia). In addition, SUVRs of all brain regions were significantly linked to weakness. CONCLUSION: SUVRs of all brain regions revealed an association between brain amyloid-β accumulation and weakness. Furthermore, global SUVRs (frontal cortex, temporal cortex, parietal cortex, PC/PCC, hippocampus, basal ganglia) were associated with gait parameters. PMID- 29987249 TI - Analysis of the Coding and Non-Coding RNA Transcriptomes in Response to Bell Pepper Chilling. AB - Increasing evidence suggests that long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and microRNAs (miRNAs) have roles during biotic and abiotic stress, though their exact contributions remain unclear. To explore their biological functions in response to chilling in bell pepper, we examined their accumulation profiles by deep sequencing and identified 380 lncRNAs, 36 circRNAs, 18 miRNAs, and 4128 differentially expressed mRNAs in the chilled versus the non-chilled fruit. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed differentially expressed genes and putative ncRNA targets, including transcription factors of multiple classes, such as myeloblastosis (MYB), basic helix-loop-helix (bHLH), and ethylene response factor (ERF) transcription factors (TFs), enzymes involved in bio-oxidation and oxidative phosphorylation (serine/threonine-protein kinase, polyphenol oxidase, catalase, peroxidase, lipoxygenase, and ATPase), and cell wall metabolism-related enzymes (beta-galactosidase, pectate lyase, pectinesterase, and polygalacturonase). On the basis of the accumulation profiles, a network of putatively interacting RNAs associated with bell pepper chilling was developed, which pointed to ncRNAs that could provide the foundation for further developing a more refined understanding of the molecular response to chilling injury. PMID- 29987250 TI - Vitamin D's Effect on the Proliferation and Inflammation of Human Intervertebral Disc Cells in Relation to the Functional Vitamin D Receptor Gene FokI Polymorphism. AB - Vitamin D is known to have immunomodulatory effects, is involved in osteo cartilaginous metabolism, and may have a role in human intervertebral disc pathophysiology. Although a link between vitamin D receptor (VDR) gene variants and disc degeneration-related pathologies has been observed, its functional contribution to pathologic processes has not been assessed yet. The aim of this study was to investigate the response of disc cells to vitamin D in terms of the regulation of proliferation, metabolism, and inflammatory processes, with a particular focus on the FokI VDR genotype. However, although it was found that vitamin D had a pro-apoptotic effect regardless of genotype, an up-regulation of IL-1Ra and downregulation of IL-6 was found to be evident only in Ff cells. Regarding the metabolic effects, in Ff cells, vitamin D promoted an upregulation of the aggrecan in inflammatory conditions but did not have an effect on the expression of collagen-related markers. Moreover, cells bearing the Ff genotype were the most responsive to vitamin D in the upregulation of catabolic markers. In addition, in contrast to the FF genotype, vitamin D downregulated the vitamin D-dependent signaling pathway in inflamed Ff cells, counteracting the inflammation-mediated catabolic effects. In conclusion, Ff cells were found to be more responsive to the anti-inflammatory and catabolic effects of vitamin D, which is likely to be related to matrix remodeling. PMID- 29987252 TI - Novel Method for Perceiving Key Requirements of Customer Collaboration Low-Carbon Product Design. AB - Low-carbon product design is an important way to reduce greenhouse gas emission. Customer collaborative product innovation (CCPI) has become a new worldwide product design trend. Based on this popularity, we introduced CCPI into the low carbon product design process. An essential step for implementing low carbon CCPI is to clarify key low carbon requirements of customers. This study tested a novel method for perceiving key requirements of customer collaboration low-carbon product design based on fuzzy grey relational analysis and genetic algorithm. Firstly, the study considered consumer heterogeneity, allowing different types of customers to evaluate low carbon requirements in appropriate formats that reflected their degrees of uncertainty. Then, a nonlinear optimization model was proposed to establish the information aggregation factor of customers based on the genetic algorithm. The weight of customers was obtained simultaneously. Next, the key low carbon requirements of customer were identified. Finally, the effectiveness of the proposed method was illustrated with a case related to a low carbon liquid crystal display. PMID- 29987253 TI - Identification and Characterization of Defects in Glass Fiber Reinforced Plastic by Refining the Guided Lamb Waves. AB - In this paper, the disbond-type defect presented on glass fiber reinforced plastic material is analyzed by refining the guided Lamb wave signals. A segment of wind turbine blade is considered as a test sample. The low-frequency ultrasonic measurement system is used for the non-destructive testing of the test sample using guided waves. The P-1 type macro-fiber composite transducer as a transmitter and contact-type piezoceramic transducer as a receiver are used for the testing of a sample. The disbond type defect having a diameter of 81 mm is detected from the experimental results. To improve the accuracy in locating and sizing the defects and estimation of the time of flight and phase velocity of ultrasonic guided waves in defective region, signal processing algorithm is developed by utilizing the promising properties of various ultrasonic signal processing techniques such as wavelet transform, amplitude detection, two dimensional Fast-Fourier transform, Hilbert transform and variational mode decomposition. The discrete wavelet transform is used to denoise the guided wave signals and then, the size and location of defects are estimated by amplitude detection. The reflected wave signals from the opposite edge of the sample are removed by applying the two-dimensional Fast-Fourier transform to the experimental B-scan signal. Afterwards, variational mode decomposition and Hilbert transform are used for the phase velocity and time-delay estimation by comparing the instantaneous amplitudes of the defective and defect-free signal. The validation and the demonstration of reproducibility of the algorithm is performed by extracting the features of a 51 mm defect from another experimental B-scan. PMID- 29987254 TI - A Survey on the Roadmap to Mandate on Board Connectivity and Enable V2V-Based Vehicular Sensor Networks. AB - Vehicles will soon be connected and will be interacting directly with each other and with the road infrastructure, bringing substantial benefits in terms of safety and traffic efficiency. The past decade has seen the development of different wireless access technologies for vehicle-to-everything (V2X) communications and an extensive set of related use cases have been drafted, each with its own requirements. In this paper, focusing on short-range communications, we analyze the technical and economic motivations that are driving the development of new road users' connectivity, discussing the international intentions to mandate on board devices for V2X communication. We also go in depth with the enabling wireless access technologies, from IEEE 802.11p to short-range Cellular-V2X and other complementary technologies, such as visible light communication (VLC) and millimeterWaves, up to hybrid communication and 5G. We conclude our survey with some performance comparison in urban realistic scenarios, underlying that the choice of the future enabling technology is not so easy to predict and mostly depends on mandatory laws at the international level. PMID- 29987251 TI - Senescent Microvesicles: A Novel Advance in Molecular Mechanisms of Atherosclerotic Calcification. AB - Atherosclerosis, a chronic inflammatory disease that causes the most heart attacks and strokes in humans, is the leading cause of death in the developing world; its principal clinical manifestation is coronary artery disease. The development of atherosclerosis is attributed to the aging process itself (biological aging) and is also associated with the development of chronic diseases (premature aging). Both aging processes produce an increase in risk factors such as oxidative stress, endothelial dysfunction and proinflammatory cytokines (oxi-inflamm-aging) that might generate endothelial senescence associated with damage in the vascular system. Cellular senescence increases microvesicle release as carriers of molecular information, which contributes to the development and calcification of atherosclerotic plaque, as a final step in advanced atherosclerotic plaque formation. Consequently, this review aims to summarize the information gleaned to date from studies investigating how the senescent extracellular vesicles, by delivering biological signalling, contribute to atherosclerotic calcification. PMID- 29987255 TI - Prevalence of Vaccine Type Infections in Vaccinated and Non-Vaccinated Young Women: HPV-IMPACT, a Self-Sampling Study. AB - : Background: The human papillomavirus (HPV) vaccination program for young girls aged 11-26 years was introduced in Switzerland in 2008. The objective of this study was to evaluate the prevalence of high- and low-risk HPV in a population of undergraduate students using self-sampling for monitoring the HPV vaccination program's effect. METHODS: Undergraduate women aged between 18-31 years, attending the Medical School and University of Applied Sciences in Geneva, were invited to participate in the study. Included women were asked to perform vaginal self-sampling for HPV testing using a dry cotton swab. RESULTS: A total of 409 students participated in the study-aged 18-31 years-of which 69% of the participants were vaccinated with Gardasil HPV vaccine and 31% did not received the vaccine. About HPV prevalence, 7.2% of unvaccinated women were HPV 16 or 18 positive, while 1.1% of vaccinated women were infected by HPV 16 or 18 (p < 0.01). Prevalence of HPV 6 and 11 was 8.3% in non-vaccinated women versus 2.1% in vaccinated women (p < 0.02). We observed no cross-protection for the other HPV genotypes of a low- and high-risk strain. CONCLUSIONS: Prevalence of HPV 6/11/16/18 was lower in vaccinated women versus unvaccinated women. Continued assessment of HPV vaccine effectiveness in real population is needed. PMID- 29987257 TI - Erratum: Choi, K.-H., et al. Cancer Incidence Trend in the Hebei Spirit Oil Spill Area, from 1999 to 2014: An Ecological Study. Int. J. Environ. Res. Public Health 2018, 15, 1006. AB - Due to an error during production, the legend presented in Figure 2 in the Results section of the published paper [1] were incorrect.[...]. PMID- 29987258 TI - Correction: Huang, H.W.; et al. Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage. Molecules 2018, 23, 849. AB - The authors wish to make the following correction to their paper [1].[...]. PMID- 29987256 TI - Mechanisms of Cellular Internalization of Quantum Dot(r) Conjugated Bone Formation Mimetic Peptide CK2.3. AB - Osteoporosis is a debilitating skeletal disorder that is characterized by loss of bone densityover time. It affects one in two women and one in four men, age 50 and older. New treatmentsthat specifically drive bone formation are desperately needed. We developed a peptide, CK2.3, thatacts downstream of the bone morphogenetic protein receptor type Ia and it induces osteogenesisin-vitro and in vivo. However, its mechanism of action, especially its mode of uptake by cellsremains unknown. To demonstrate CK2.3 internalization within a cell, we conjugated CK2.3to Quantum Dot®s (Qdot®s), semiconductor nanoparticles. We purified CK2.3-Qdot®s by sizeexclusion chromatography and verified the conjugation and stability using UV/VIS and Fouriertransform infrared spectroscopy. Our results show that CK2.3 was conjugated to the Qdot®s andthe conjugate was stable for at least 4 days at 37 °C. Moreover, CK2.3-Qdot®s exerted biologicalresponse similar to CK2.3. Addition of CK2.3-Qdot®s to cells followed by confocal imaging revealedthat CK2.3-Qdot®s were internalized at 6 h post stimulation. Furthermore, using pharmacologicalinhibitors against endocytic pathways, we demonstrated that CK2.3 Qdot®s were internalized bycaveolae. These results show for the first time that the novel peptide CK2.3 is taken up by the cellthrough caveolae mediated endocytosis. PMID- 29987259 TI - Convenient Synthesis and Physiological Activities of Flavonoids in Coreopsis lanceolata L. Petals and Their Related Compounds. AB - Chalcones, flavanones, and flavonols, including 8-methoxybutin isolated from Coreopsis lanceolata L. petals, were successfully synthesized with total yields of 2-59% from O-methylpyrogallols using the Horner-Wadsworth-Emmons reaction as a key reaction. Aurones, including leptosidin, were also successfully synthesized with 5-36% total yields using the Aldol condensation reaction as a key reaction. Each chalcone, flavanone, flavonol, and aurone with the 3,4-dihydroxy groups in the B-ring showed high antioxidant activity. Additionally, each of the chalcones, flavanones, flavonols, and aurones with the 2,4-dihydroxy groups in the B-ring showed an excellent whitening ability. PMID- 29987260 TI - A Novel Monoclonal Antibody Targets Mucin1 and Attenuates Growth in Pancreatic Cancer Model. AB - Mucin1 (MUC1) is a highly glycosylated transmembrane protein that plays a crucial role in the lubrication and protection of normal epithelial cells. However, MUC1 has emerged as a potential target for cancer therapy because it is overexpressed and functions in several types of cancers. Recently, we produced a monoclonal antibody (the anti-hMUC1 antibody) specific to the extracellular region of the MUC1 subunit MUC1-C to evaluate the utility of using anti-MUC1 antibodies in pancreatic cancer models. The anti-hMUC1 antibody recognized the MUC1-C protein in pancreatic cancer cells. Based on immunostaining and confocal image analyses, the anti-hMUC1 antibody initially bound to the cell membrane then was internalized in cancer cells that express MUC1. The anti-hMUC1 antibody suppressed epidermal growth factor (EGF)-mediated extracellular signal-regulated kinase (ERK) phosphorylation and cyclin D1 expression. When the anti-hMUC1 antibody was injected into a xenograft mouse model and traced using an in vivo imaging system, we observed that the anti-hMUC1 antibody was localized to MUC1 expressing pancreatic tumors. Importantly, the anti-hMUC1 monoclonal antibody suppressed pancreatic tumor growth in mice. According to immunohistochemistry analysis using a pancreatic cancer tissue array and the anti-hMUC1 antibody, MUC1 was highly expressed in human pancreatic cancer tissues compared to normal tissues. Therefore, we conclude that the anti-hMUC1 antibody specifically targets MUC1 and suppresses its function in pancreatic cancer in vitro and in vivo and can be further developed as a promising targeted therapy to treat pancreatic cancer. PMID- 29987261 TI - Mechanism of Two-/Four-Electron Reduction of Nitroaromatics by Oxygen-Insensitive Nitroreductases: The Role of a Non-Enzymatic Reduction Step. AB - Oxygen-insensitive NAD(P)H:nitroreductases (NR) reduce nitroaromatics (Ar-NO2) into hydroxylamines (Ar-NHOH) through nitroso (Ar-NO) intermediates. Ar-NO may be reduced both enzymatically and directly by reduced nicotinamide adenine dinucleotide or its phosphate NAD(P)H, however, it is unclear which process is predominant in catalysis of NRs. We found that E. coli NR-A (NfsA) oxidizes 2 mol of NADPH per mol of 2,4,6-trinitrotoluene (TNT) and 4 mol of NADPH per mol of tetryl. Addition of ascorbate, which reduces Ar-NO into Ar-NHOH, changes the stoichiometry NADPH/Ar-NO2 into 1:1 (TNT) and 2:1 (tetryl), and decreases the rate of NADPH oxidation. Ascorbate does not interfere with the oxidation of NADPH during reduction of quinones by NfsA. Our analysis of ascorbate inhibition patterns and both enzymatic and non-enzymatic reduction of nitrosobenzene suggests that direct reduction of Ar-NO by NADPH rather than enzymatic reduction is the predominant mechanism during nitroaromatic reduction. PMID- 29987262 TI - Isolation and Evaluation of Bioactive Protein and Peptide from Domestic Animals' Bone Marrow. AB - In this work, proteins and peptides were isolated from four kinds of animal bone marrow and characterized by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and liquid chromatography-mass spectrometry (LC/MS). The antimicrobial and antioxidant activity of these proteins were investigated in vitro. The nutritional value was evaluated by analyzing their free amino acid composition. The results indicates that all of the extracts appeared two bands at SDS-PAGE, the peptide band at 4.1-10 kDa and protein band at 66 kDa, these data are consistent with LC/MS results. FT-IR analysis showed that the secondary structure of protein mainly consists of alpha-helix. SEM micrographs revealed that the fractions have different morphological characteristics. Horse bone marrow protein (HBMP) showed the highest antioxidant activity to DPPH free radical, IC50 value was 0.573 mg/mL. Most of the obtained fractions showed antimicrobial activities towards Escherichiacoli (EC) and Candida albicans (CA). Total free amino acid content ranged between 5.15-49.60 mg/g, and among them, HBMP displayed the highest abundance, 49.7 mg/g, which amino acid composition ratio approached the Food and Agriculture Organization/World Health Organization (FAO/WHO) ideal amino acid pattern recommendation. This study provides fundamental knowledge and a basic study method for the research into and development of animal bone marrow proteins and peptides as functional food and drug resources. PMID- 29987263 TI - A Novel Cell Penetrating Peptide for the Differentiation of Human Neural Stem Cells. AB - Retinoic acid (RA) is a bioactive lipid that has been shown to promote neural stem cell differentiation. However, the highly hydrophobic molecule needs to first solubilize and translocate across the cell membrane in order to exert a biological response. The cell entry of RA can be aided by cell penetrating peptides (CPPs), which are short amino acid sequences that are able to carry bioactive cargo past the cell membrane. In this work, a novel cell penetrating peptide was developed to deliver RA to human neural stem cells and, subsequently, promote neuronal differentiation. The novel CPP consists of a repeating sequence, whose number of repeats is proportional to the efficiency of cell penetration. Using fluorescence microscopy, the mode of translocation was determined to be related to an endocytic pathway. The levels of β-III tubulin (Tubb3) and microtubule associated protein 2 (MAP2) expression in neural stem cells treated with RA conjugated to the CPP were assessed by quantitative immunocytochemistry. PMID- 29987264 TI - 2-Naphthol Levels and Allergic Disorders in Children. AB - BACKGROUND: The measurement of polycyclic aromatic hydrocarbons (PAH) in ambient air is quite difficult to perform. Using urine biomarkers of PAH such as 2 naphthol is one approach to this problem. This study explored the association between urine 2-naphthol levels and allergic diseases. The associations between 2 naphthol levels and oxidative stress biomarkers for the possible disease pathogenesis were also investigated. METHOD: A total of 453 kindergarten children from the (Childhood Environment and Allergic Diseases Study) CEAS cohort with urine samples were recruited. Urine 2-naphthol levels were measured by high performance liquid chromatography mass spectrometry (HPLC-MS/MS) and markers of oxidative stress (8OHdG) were measured by enzyme-linked immunosorbent assays (ELISA). Information on environmental risk factors and allergic diseases were also collected. The association between 2-naphthol levels, 8OHdG levels, IgE, and allergic diseases were evaluated by multivariate linear regression and logistic regression. RESULTS: Levels of 2-naphthol were positively correlated with 8OHdG levels. A one ln-unit increase in the 2-naphthol level was positively associated to 8OHdG levels (per ln-unit: beta = 100.61, p < 0.001). When dividing 2-naphthol levels into quartiles, asthma was significantly associated with 2-naphthol levels at a concentration of >1.60 ng/mL (adjusted OR: 3.14, 95% CI 1.34-7.35). CONCLUSION: Urine 2-naphthol levels are associated with markers of oxidative stress and the risk of allergic diseases in young children. PMID- 29987265 TI - Oral Health in Pregnant Chinese Women in Singapore: A Call to Go beyond the Traditional Clinical Care. AB - OBJECTIVE: To examine the correlations among oral health knowledge, attitude, practices and oral disease among pregnant Chinese women in Singapore. Methods: A descriptive correlational study was conducted in pregnant Chinese women in Singapore. A questionnaire was used to collect data of oral health knowledge, attitude and practices. Plaque index scores were used to assess the oral health of subjects. Results: A total of 82 pregnant women participated in the study, out of whom 38% showed adequate oral health knowledge, nearly half of them achieved adequate and oral health attitude and practice scores while 34% had good Plaque index scores. The lower income group had higher experience of self-reported dental problems during pregnancy than those in the higher income group (p = 0.03). There were significant positive correlations between scores of oral health practice, attitude and oral health knowledge levels. The plaque index scores negatively correlated with the oral health practice scores (p = 0.02). Conclusions: Our findings provided evidence that oral health knowledge, attitude and practices among Chinese pregnant women were not optimal which implies the importance of promoting their oral health during pregnancy through the improvement of knowledge and attitudes. This would facilitate formulation and implementation of appropriate oral health promotion policies. PMID- 29987266 TI - A Review on Systems-Based Sensory Gloves for Sign Language Recognition State of the Art between 2007 and 2017. AB - Loss of the ability to speak or hear exerts psychological and social impacts on the affected persons due to the lack of proper communication. Multiple and systematic scholarly interventions that vary according to context have been implemented to overcome disability-related difficulties. Sign language recognition (SLR) systems based on sensory gloves are significant innovations that aim to procure data on the shape or movement of the human hand. Innovative technology for this matter is mainly restricted and dispersed. The available trends and gaps should be explored in this research approach to provide valuable insights into technological environments. Thus, a review is conducted to create a coherent taxonomy to describe the latest research divided into four main categories: development, framework, other hand gesture recognition, and reviews and surveys. Then, we conduct analyses of the glove systems for SLR device characteristics, develop a roadmap for technology evolution, discuss its limitations, and provide valuable insights into technological environments. This will help researchers to understand the current options and gaps in this area, thus contributing to this line of research. PMID- 29987268 TI - Assessment of Retrieved N2O, NO2, and HF Profiles from the Atmospheric Infrared Ultraspectral Sounder Based on Simulated Spectra. AB - The Atmospheric Infrared Ultraspectral Sounder (AIUS), the first high-resolution (0.02 cm−1) solar occultation sounder, aboard GF5, was launched in May 2018 from China. However, relevant studies about vertical profiles of atmospheric constituents based on its operational data were not conducted until half a year later. Due to an urgent need for Hin-orbit tests, the real spectra (called reference spectra hereafter) were substituted with simulated spectra calculated from the reference forward model (RFM) plus different random noises at different altitudes. In the generation process of the reference spectra for N2O, NO2, and HF species, ACE-FTS (Atmospheric Chemistry Experiment-Fourier Transform Spectrometer instrument on the SCISAT satellite) level 2 products replace corresponding profiles included in the atmospheric background profiles. The optimal estimation method is employed to extract N2O, NO2, and HF profiles in this study. Comparing the retrieved results with ACE-FTS level 2 products, the relative deviations for these three species are calculated. For N2O, the average relative deviation is less than 6% at altitudes below 25 km, while larger deviations are observed in the range of 25-45 km, with the maximum being at ~25%. Additionally, the difference for NO2 is less than 5% in the 20-45 km range, with a larger discrepancy found below 20 km and above 45 km; the maximum deviation reaches +/-40%. For HF, the relative deviation is less than 6% for all tangent heights, implying satisfactory retrieval. The vertical resolution, averaging kernel, and number of degrees of freedom are used to assess the retrieval algorithm, which indicate that the retrieved information content is much more attributable to the reference spectra contribution than to the a priori profile. Finally, a large number of retrieval tests are performed for N2O, NO2, and HF in selected areas covering the Arctic region, northern middle latitude, tropics, southern middle latitude, and Antarctic region, and reliable results are obtained. Thus, to a great extent, the algorithm adopted in the AIUS system can process retrievals reliably and precisely. PMID- 29987267 TI - DEAD-Box Protein RNA-Helicase DDX6 Regulates the Expression of HER2 and FGFR2 at the Post-Transcriptional Step in Gastric Cancer Cells. AB - The human DEAD/H-box RNA helicase DDX6 (RCK/p54) is a protein encoded by the fusion gene from the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma cell line RC-K8. DDX6 has a variety of functions such as translation initiation, pre-mRNA splicing, and ribosome assembly. However, details of the regulatory mechanism governing DDX6 and the functions of DDX6 are largely unknown. Previously, we reported that DDX6 is overexpressed in most malignant cell lines and clinical colorectal tumor samples and that DDX6 positively contributes to the pathogenesis of various cancers. In the current study, we aimed at revealing the function of DDX6 in HER2 and FGFR2 related human gastric cancer (GC) by using clinical samples and GC cell lines. DDX6 protein was overexpressed in about 60% of the clinical samples; HER2, in 35%; and FGFR2, in 30%, (n = 20). Interestingly, the DDX6 protein was overexpressed in all HER2 positive samples (n = 7), and in 83% (5 of 6) of the FGFR2-positive samples, which could reflect the contribution of DDX6 to the expression of HER2 and FGFR2. In the GC cell line MKN7, which has HER2 amplification, the knockdown of DDX6 by siR-DDX6 led to the decreased expression of the HER2 protein. On the other hand, the knockdown of HER2 did not influence the DDX6 expression. Similar results were also obtained for the KATO-III and HSC39 cell lines having amplified FGFR2 expression. The increased expression of DDX6 induced a significantly increased expression of the HER2 protein without increasing the mRNA expression. The results of an RNP Immunoprecipitation (RIP)-assay using GC cells indicated that the DDX6 protein acted as an RNA-binding protein for HER2 and FGFR2 mRNAs and positively regulated their post-transcriptional processes. These findings demonstrated that DDX6 was an upstream molecule that positively regulated the expression of HER2 and FGFR2 at the post-transcriptional step in GC cells. PMID- 29987269 TI - An Enlarged Goiter Presenting with a Rare Diffuse Lipomatosis of the Thyroid Gland. AB - BACKGROUND Diffuse lipomatosis of the thyroid gland is a particularly rare histopathological condition characterized by diffuse fatty infiltration within the thyroid stroma. CASE REPORT We report a case of a 53-year-old woman who presented with a 2-year history of massive neck goiter and mild dysphagia. A computed tomography (CT) scan revealed heterogeneous enhancing of an enlarged thyroid gland with left lobe cranial extension and compression of the pharynx, and caudal bilateral retrosternal growth. The patient underwent total thyroidectomy and histopathological examination revealed mature fatty tissue diffusely distributed throughout the thyroid gland. Excision of the gland was somewhat challenging due to the very thin thyroid capsule and recurrent protrusion of fat from the capsule. CONCLUSIONS Diffuse thyroid lipomatosis is an extremely rare histopathological condition characterized by diffuse fatty infiltration in thyroid stroma. Despite its rarity, it should be considered in the differential diagnoses of a patient presenting with a goiter. PMID- 29987270 TI - Quercetin Treatment Improves Renal Function and Protects the Kidney in a Rat Model of Adenine-Induced Chronic Kidney Disease. AB - BACKGROUND The aim of this study was to examine the effects of the natural flavonoid, quercetin, in a rat model of adenine-induced chronic kidney disease. MATERIAL AND METHODS Forty male Wister rats were divided into four groups: normal (no adenine or quercetin) (n=10); untreated model (treated withadenine but not quercetin) (n=10); quercetin-treated model (5 mg/kg/day for 21 days) (n=10); quercetin-treated model (10 mg/kg/day for 21 days) (n=10). Urine and blood samples were collected and rat kidneys were examined histologically. RESULTS Comparison of the findings of the model rats treated with quercetin (n=20) with non-treated model rats (n=10) showed reduced levels of fibroblast growth factor 23 (FGF23): normal group, 19.6 pg/ml; untreated group, 73.6 pg/ml; quercetin treated group (5 mg/kg), 34.25 pg/ml; and quercetin-treated group (10 mg/kg), 21.3 pg/ml. Quercetin-treated model rats had reduced serum levels of parathyroid hormone (PTH), inorganic phosphate, increased urine protein-to-creatinine ratio, increased urine antioxidants, serum lactate dehydrogenase (LDH), and interleukin (IL)-8 when compared with the untreated model group and the control group. Quercetin treatment 10 mg/kg (n=10) reduced the levels of creatinine, blood urea nitrogen (BUN), and urinary uric acid. Renal histopathology in model rats treated with quercetin (n=20) showed reduced inflammation compared with the untreated model rats (n=10). CONCLUSIONS In a rat model of adenine-induced chronic kidney disease, treatment with quercetin improved renal function, reduced oxidative stress factors, serum levels of FGF23, and kidney inflammation. PMID- 29987272 TI - An optimised quadrupole mass spectrometer with a dual filter analyser for in field chemical sniffing of volatile organic compounds. AB - We report a novel portable 17 kg system based on a quadrupole mass spectrometer (QMS) with an electronic power consumption of 24 W. The system can be used for the in-field identification of gases and volatile/semivolatile organic compounds (VOCs/SVOCs). The mass analyser is a custom-made quadrupole mass filter with a Brubaker pre-filter that gives a mass range of m/z 1-500. It is an upgrade of the previous m/z 1-200 range triple filter analyser system. Analyser design was optimized using 3D numerical simulations as a performance trade-off between single and triple filter designs while maintaining high sensitivity and ease of integration. This also required enhanced design of the electronic control unit (ECU) compared to the previous triple filter ECU designs with lower power consumption, size, weight and cost of the overall system. Another major ECU improvement includes high stability of DC voltage control and ultra-low RF drift, which is important for in-field applications that require stable mass peaks for reliable quantitative analysis and continuous monitoring. Experimental results are presented for the perfluorotributylamine (PFTBA) calibrant and acetone to assess the functionality of the instrument. Performance comparison between the dual and triple filter quadrupole analysers has also been done. Mass spectra are given for methyl benzoate (cocaine simulant), piperidine (phencyclidine simulant), cyclohexanone (C4 simulant) and 2-nitrotoluene (TNT simulant) to assess potential capability for the identification of threat compounds. All spectral results show good correlation with the NIST library mass spectra with unit resolution obtained for spectral peaks within a m/z 1-400 mass range. PMID- 29987273 TI - Enhancing hot electron collection with nanotube-based three-dimensional catalytic nanodiode under hydrogen oxidation. AB - A novel three-dimensional catalytic nanodiode composed of a Pt thin film on TiO2 nanotubes was designed for the efficient detection of the flux of hot electrons, or chemicurrent, under hydrogen oxidation. We verify a significant increase in the chemicurrent from the fast transport of electrons across the ordered supporting oxide layer. This study demonstrates the direct detection of hot electrons on well-ordered TiO2 nanotubes during the catalytic reaction. PMID- 29987271 TI - Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Acute Cellular Rejection in the Kidney Allograft. AB - BACKGROUND Kidney transplantation is the treatment of choice for end stage kidney disease, but acute rejection remains a limiting factor in optimizing allograft and patient survival. Needle biopsy is the current standard of care for this diagnosis. The potential for complications with repeat biopsies limits the ability to obtain temporal immune surveillance of the allograft. The neutrophil to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be strong predictors of inflammation and of worse prognosis in a variety of conditions. MATERIAL AND METHODS This is a single center retrospective case control study which included all patients who underwent a "for -cause biopsy" of a transplanted kidney. NLR and PLR were calculated 1 month prior, at the time, and 6 months and 1 year after the biopsy. RESULTS A total of 159 biopsies were reviewed; 127 (79.9%) of these satisfied all inclusion and exclusion criteria, and 63.0% of the sample cohort (n=80) demonstrated acute cellular rejection (ACR). Patients without evidence of ACR had an average NLR of 26.8, which was approximately 7-fold greater than those patients with findings of ACR (P<0.01). A similar trend was found for PLR, where patients without ACR had a 5.5-fold greater PLR compared to those with rejection (P<0.01). The ROC showed AUC of 0.715 and 0.716 respectively. The NLR cutoff of 9.5 had a positive predictive value (PPV) of 80% and a negative predictive value (NPV) of 77.8%; the PLR cutoff of 380 had a PPV of 75% and a NPV of 100%. CONCLUSIONS This study showed that NLR and PLR are easily obtainable and reproducible predictors of ACR in the kidney allograft. Serial monitoring of these ratios will help identify subclinical inflammation before evidence of allograft dysfunction. PMID- 29987275 TI - Synthesis, characterization and application of organorhenium(vii) trioxides in metathesis reactions and epoxidation catalysis. AB - Four novel organorhenium(vii) oxides of the type L-ReO3 are presented: [4 (trifluoromethyl)phenyl]trioxorhenium 1b, [4 (trifluoromethoxy)phenyl]trioxorhenium 2b, [4 (trifluoromethyl)tetrafluorophenyl]trioxorhenium(THF) 3b.THF and (2,2,6,6 tetramethylpiperidin-1-yl)trioxorhenium 5. As intermediate products, the novel diarylzinc compounds bis[4-(trifluoromethoxy)phenyl]zinc 2a and bis[2,6 bis(trifluoromethyl)phenyl]zinc 4a were prepared. The properties and structure of 1b-5 were studied by means of 1H, 13C, 19F and 17O NMR, IR, MS, TGA and elemental analysis. Due to the strong Lewis acidity of the Re(vii) centres crystal structures of complexes 1b and 2b were obtained as THF adducts 1b.THF and 2b.THF. Complexes 1b, 2b, 3b.THF and 5 have been examined as catalysts in olefin epoxidation using cis-cyclooctene as a model substrate. Epoxide yields of around 80% and TOFs >1300 h-1 can be obtained with 1b, 2b and 3b.THF using TBHP as an oxidant in CDCl3 at 55 degrees C, exceeding the only reported catalytically active aryl trioxorhenium complex xylyltrioxorhenium (XTO). Moreover, 1b shows catalytic activity in the self-metathesis of 1-hexene with good yields using Et2AlCl as a co-catalyst. Additionally, 1b and 5 were found to be efficient catalysts for the ring-opening metathesis polymerization (ROMP) of norbornene. Polynorbornene with high molecular weight can be obtained in good yields at room temperature using RnAlCl3-n as a co-catalyst. 5 is the first example of an amido trioxorhenium(vii) complex active in olefin metathesis. PMID- 29987276 TI - A nanoclay-induced defective g-C3N4 photocatalyst for highly efficient catalytic reactions. AB - A nanoclay-induced defective graphitic carbon nitride (g-C3N4) catalyst was successfully synthesized through intercalation and in situ calcination. The degradation time for Orange II dye using the as-synthesized g-C3N4/kaolinite (g C3N4/Kaol) catalyst was only 10 min under visible light irradiation, which could be attributed to their special structures and synergistic effects. PMID- 29987277 TI - Variable segment roles: modulation of the packing modes, nanocrystal morphologies and optical emissions. AB - Three isomers were prepared by covalently grafting carbazole (Cz) onto spiro[fluorene-9,9'-xanthene] (SFX) at different positions. Due to the complicated and variable roles of molecular segments, an evolution of the corresponding molecular packing mode was realized, accompanied by the change of nanocrystal morphology and photoluminescence properties. PMID- 29987278 TI - Microfluidics for electrophysiology, imaging, and behavioral analysis of Hydra. AB - The nervous system of the cnidarian Hydra vulgaris exhibits remarkable regenerative abilities. When cut in two, the bisected tissue reorganizes into fully behaving animals in approximately 48 hours. Furthermore, new animals can reform from aggregates of dissociated cells. Understanding how behaviors are coordinated by this highly plastic nervous system could reveal basic principles of neural circuit dynamics underlying behaviors. However, Hydra's deformable and contractile body makes it difficult to manipulate the local environment while recording neural activity. Here, we present the first microfluidic technologies capable of simultaneous electrical, chemical, and optical interrogation of these soft, deformable organisms. Specifically, we demonstrate devices that can immobilize Hydra for hours-long simultaneous electrical and optical recording, and chemical stimulation of behaviors revealing neural activity during muscle contraction. We further demonstrate quantitative locomotive and behavioral tracking made possible by confining the animal to quasi-two-dimensional micro arenas. Together, these proof-of-concept devices show that microfluidics provide a platform for scalable, quantitative cnidarian neurobiology. The experiments enabled by this technology may help reveal how highly plastic networks of neurons provide robust control of animal behavior. PMID- 29987282 TI - Lewis base complexes of sila[2]aluminocenophanes. AB - Several new sila[2]aluminocenophane Lewis base complexes are described, which were synthesized directly from the corresponding sila[2]magnesocenophane and AlX3.base precursors. The compounds are stable at room temperature for weeks, and were characterized in solution by multinuclear NMR spectroscopy and in the solid state by single crystal X-ray diffraction. In all cases, a dynamic structure was observed in solution, due to rapid sigmatropic rearrangements. Bonding energies of the Lewis base ligands to the aluminium center were calculated to be 162.9 213.3 kJ mol-1. PMID- 29987279 TI - Influence of thermal processing on the phase behavior of a novel acylglyceride alkylglyceride lipid-based delivery system. AB - Lipid-based delivery systems have been broadly utilized to enhance bioavailability and bioaccessibility properties of drugs. Loading capacity and drug stability within the lipid matrix is influenced by the phase behavior of the lipid components that make up the vehicle. In this study we have investigated the influence of thermal processing at 50 degrees C on the subsequent phase behavior of a lipid-based delivery system comprised of a blend of monoacylglycerols, diacylglycerols, monoalkylglycerols and dialkylglycerols obtained by enzymatic glycerolysis of ratfish liver oil. Differential scanning calorimetry revealed that crystallization and melting points decreased, while powder X-ray diffraction suggested changes in the crystal structure of the product when heated to 50 degrees C and held for longer than 180 min. Samples heated for a short time, rapidly underwent a polymorphic transition from the alpha to the beta polymorphic phase, whereas samples heated for long times remained in the alpha phase for 3 days. Polarized light microscopy also showed changes in the microstructure of the material due to the thermal treatment. These results suggest that the thermal history of lipidic encapsulation materials, above their melting point, can affect eventual encapsulation efficiency and product performance. PMID- 29987283 TI - A heterobimetallic metal-organic framework as a "turn-on" sensor toward DMF. AB - A non-luminescent 3d-4f heterobimetallic CuEu organic framework (NBU-8) was designedly synthesized with Cu2+ ions as a fluorescence quencher. NBU-8 as a sensor realized selective light recovery with a "turn-on" luminescence response toward N,N'-dimethylformamide (DMF) even in the presence of other amide molecules. PMID- 29987284 TI - In vitro antibacterial activity of oxide and non-oxide bioceramics for arthroplastic devices: I. In situ time-lapse Raman spectroscopy. AB - Over the next two decades, a strong demographic demand for arthroplastic devices coupled with a decreased efficacy of antibiotics has been predicted to result in an exponential increase in the number of periprosthetic joint infections (PJIs). Advanced strategies are therefore required to improve the local peri-implant immune response and curb the pathogenic events of bacterial adhesion and biofilm formation. The use of biomaterials that autonomously counter infections is one approach to improve orthopedic outcomes. Using conventional molecular biology characterization methods and advanced Raman spectroscopy, this study examined the bacteriostatic response of two bioceramic materials commonly employed as prosthetic implants: zirconia-toughened alumina (ZTA) and silicon nitride (Si3N4). Unlike the ZTA, it was found that non-oxide Si3N4 possesses an inherently anti-infective surface chemistry, which acts in a responsive way against bacterial loading. The mechanistic details of its behavior are elucidated. Non-oxide bioceramics appear to be promising, but their full development requires a transitional approach that integrates the fundamental biochemical concepts with clinical outcomes. PMID- 29987285 TI - Selective separation of cadmium(ii) from zinc(ii) by a novel hydrophobic ionic liquid including an N,N,N',N'-tetrakis(2-methylpyridyl)-1,2-phenylenediamine-4 amido structure: a hard-soft donor combined method. AB - A novel hydrophobic ionic liquid including an N,N,N',N'-tetrakis(2-methylpyridyl) 1,2-phenylenediamine-4-amido structure ((IL-1,2-tpbd)+NTf2-) was successfully synthesized. (IL-1,2-tpbd)+NTf2- combined one amido (O-hard donor) and four pyridine (N-soft donor) groups. Its Cd2+ and Zn2+ separation behavior in nitric acid solution was investigated as a function of the extraction time, effect of pH etc. by dissolving (IL-1,2-tpbd)+NTf2- in a room temperature ionic liquid, 1 hexyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ((C6mim)+NTf2-). The extraction kinetics were fairly fast and could reach equilibrium within 4 h. When pHeq >= 1.8, the extraction percentage of Cd2+ and Zn2+ remained constant and the maximum separation factor was calculated as 12.78 at pHeq = 3.1; when pHeq < 1.8, the extraction percentage of Cd2+ and Zn2+ decreased drastically due to the protonation of the pyridine groups. Complete stripping of the extracted Cd2+ and Zn2+ from the ionic liquid phase into an aqueous phase was successfully achieved under highly acidic conditions ([HNO3] = 2 M) without adding any other metal complex forming agents. The extraction mechanism was summarized as a cation exchange due to the independence of nitrate ions in the extraction process. Additionally, the results of the slope analysis and UV-vis titration revealed the formation of a 1 : 2 complex. Furthermore, (IL-1,2-tpbd)+NTf2- showed a higher preference for Cd2+ even under the interference of various co-existing metal ions. PMID- 29987287 TI - All-inorganic bifacial CsPbBr3 perovskite solar cells with a 98.5%-bifacial factor. AB - We present here the construction of all-inorganic bifacial CsPbBr3 perovskite solar cells to harvest solar energy from both sides. The quantum dot modified bifacial device achieves front and rear efficiencies of 7.55% and 7.44% under one sun illumination, respectively. The solar cell without encapsulation retains around 95% of the initial efficiency at 60% RH over a period of 1000 h. PMID- 29987286 TI - On the degradation pathway of glyphosate and glycine. AB - The degradation in water of the most widespread herbicide, glyphosate, is still under debate. Experimental disagreements on this process exist and there are only a few theoretical studies to support any conclusions. Moreover, the relationship between glyphosate and glycine is underestimated. Besides the structural similarity, glycine is a product of glyphosate degradation; hence, their studies are complementary. In this study, two mechanisms for the decomposition of the glyphosate molecule and glycine molecule in water are proposed. These mechanisms were explored by using quantum mechanical calculations. A combined microsolvation/PCM approach was employed to find and characterize their transition states, by which the reaction pathways were determined via the IRC method. The results have shown that the degradation processes might occur via a C C bond cleavage, through a concerted mechanism, whereby the proton transfers and the CO2 detachments occur simultaneously. The second mechanism had two consecutive steps, a decarboxylation followed by the proton transfers. The water molecules served as a conduit for the proton transfers, away from the amine group (or the phosphonate, glyphosate case). Their function was to assist the reactions in a water-mediated decarboxylation. In these particular cases, the free energy of activation was 42.68 and 42.28 kcal mol-1 for the glycine structure and the glyphosate structure, respectively. These results agreed with the photodegradation and thermodegradation of glyphosate, as well as with the spontaneous decarboxylation of glycine. A concerted mechanism might be expected to yield C-P and C-N bond cleavages in the glyphosate molecule. PMID- 29987288 TI - Thermally induced formal [4+2] cycloaddition of 3-aminocyclobutenones with electron-deficient alkynes: facile and efficient synthesis of 4-pyridones. AB - A thermally induced novel formal [4+2] cycloaddition of cyclobutenones with electron-deficient alkynes under metal-free conditions has been developed for the first time. The reaction can proceed in a highly regioselective manner and provides a straightforward and efficient method for the synthesis of 4-pyridone derivatives from readily available starting materials in a single step. PMID- 29987290 TI - Amplification-free, sequence-specific 16S rRNA detection at 1 aM. AB - A nucleic acid amplification-free, optics-free platform has been demonstrated for sequence-specific detection of Escherichia coli (E. coli) 16S rRNA at 1 aM (10-18 M) against a 106-fold (1 pM) background of Pseudomonas putida (P. putida) RNA. This work was driven by the need for simple, rapid, and low cost means for species-specific bacterial detection at low concentration. Our simple, conductometric sensing device functioned by detecting blockage of a nanopore fabricated in a sub-micron-thick glass membrane. Upon sequence-specific binding of target 16S rRNA, otherwise charge-neutral, PNA oligonucleotide probe polystyrene bead conjugates become electrophoretically mobile and are driven to the glass nanopore of lesser diameter, which is blocked, thereby generating a large, sustained and readily observable step decrease in ionic current. No false positive signals were observed with P. putida RNA when this device was configured to detect E. coli 16S rRNA. Also, when a universal PNA probe complementary to the 16S rRNA of both E. coli and P. putida was conjugated to beads, a positive response to rRNA of both bacterial species was observed. Finally, the device readily detected E. coli at 10 CFU mL-1 in a 1 mL sample, also against a million fold background of viable P. putida. These results suggest that this new device may serve as the basis for small, portable, low power, and low-cost systems for rapid detection of specific bacterial species in clinical samples, food, and water. PMID- 29987291 TI - Inter-individual, inter-city, and temporal trends of per- and polyfluoroalkyl substances in human milk from Swedish mothers between 1972 and 2016. AB - Inter-individual, inter-city, and temporal trends of 19 per- and polyfluoroalkyl substances (PFASs) were investigated in human milk collected in Stockholm (1972 2016) and Gothenburg (2007-2015), Sweden. The concentrations of perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA), and perfluorotridecanoate (PFTrDA) in human milk from Stockholm increased significantly over the entire monitoring periods, whereas branched (Br) and linear (L) isomers of perfluorooctane sulfonamide (FOSA) decreased. In human milk from Gothenburg, significant downward trends were detected for perfluorododecanoate (PFDoDA), PFHxS and Br-perfluorooctane sulfonate (Br-PFOS) over the last decade. This declining trend was also observed for perfluorohexanoate (PFHxA), PFHxS, perfluorooctanoate (PFOA) and Br-PFOS in Stockholm over the same time period. No significant differences were observed in concentrations or relative PFAS profiles between Stockholm and Gothenburg. However, a comparison of the PFAS profile in Stockholm milk revealed distinct profiles for the time periods 1972-1996, 2000-2012, and 2013-2016, reflecting a shift in exposure over time. The lower bound estimated daily intake (EDI) for ?PFAS concentrations in infants ranged from 7.1-40 ng per kg body weight per day (ng/kg bw/d) in Stockholm and from 5.2-25 ng/kg bw/d in Gothenburg over the studied time period, consistent with other European countries. Overall these data indicate that exposure to some legacy PFASs via breastmilk is declining, presumably as a result of regulation and phase-out initiatives. However, increasing concentrations for other PFASs and a shift in the overall PFAS profile in recent years may pose an ongoing health risk to infants. PMID- 29987292 TI - Transforming benzylideneamine N,C-chelate boron compounds to BN-cycloocta /cyclohepta-trienes bearing a tetrasubstituted B[double bond, length as m-dash]N unit via photoisomerization. AB - A series of benzylideneamine N,C-chelate boron compounds have been found to undergo rapid multistructural transformations with UV irradiation, yielding new BN-cycloocta-1,3,6-triene ((4Z,6Z)-1,2,3,8-tetrahydro-1,2-azaborocine) and BN cyclohepta-1,3,5-triene (2,7-dihydro-1H-1,2-azaborepine) derivatives with a tetrasubstituted B[double bond, length as m-dash]N unit quantitatively. The simple imine donor also lends itself to achieving photoreactivity in compounds with two phenyl substituents on boron, which is the first example for this type of organoboron photochemistry. PMID- 29987293 TI - Enhanced plasmon-driven photoelectrocatalytic methanol oxidation on Au decorated alpha-Fe2O3 nanotube arrays. AB - Highly ordered, porous alpha-Fe2O3/Au nanotube arrays (NTAs) were successfully synthesized through a facile approach. Benefitting from the plasmonic effect, and unique aligned and porous structural features, the alpha-Fe2O3/Au NTAs offer efficient and stable operation and exhibit a significantly enhanced catalytic activity for photoelectrochemical methanol oxidation with a faradaic efficiency of 79.23%. PMID- 29987294 TI - A flexible ionic synaptic device and diode-based aqueous ion sensor utilizing asymmetric polyelectrolyte distribution. AB - This work reported the development of an ionic diode of high rectification ratio with a simple device structure and a quick fabrication process by utilizing asymmetric polyelectrolyte distribution. Detection of aqueous ions was demonstrated by applying this diode as a pH sensor. Two terminal ionic synaptic devices utilizing a similar structural design were also successfully developed. PMID- 29987295 TI - A highly active diradical cobalt(iii) catalyst for the cycloisomerization of alkynoic acids. AB - The first cobalt-catalysed cycloisomerisation of alkynoic acids is reported, thanks to the design of a well-defined diradical cobalt(iii) catalyst, in the absence of any additives. The high efficiency, regioselectivity and chemoselectivity are comparable to those of noble metal-based systems. The unique reactivity might be attributed to second coordination sphere effects. PMID- 29987296 TI - Ion sensing with thread-based potentiometric electrodes. AB - Potentiometric sensing of ions with ion-selective electrodes (ISEs) is a powerful technique for selective and sensitive measurement of ions in complex matrices. The application of ISEs is generally limited to laboratory settings, because most commercially available ISEs and reference electrodes are large, delicate, and expensive, and are not suitable for point-of-use or point-of-care measurements. This work utilizes cotton thread as a substrate for fabrication of robust and miniaturized ISEs that are suitable for point-of-care or point-of-use applications. Thread-based ISEs selective for Cl-, K+, Na+, and Ca2+ were developed. The cation-selective ISEs were fabricated by coating the thread with a surfactant-free conductive ink (made of carbon black) and then coating the tip of the conductive thread with the ion-selective membrane. The Cl- ISE was fabricated by coating the thread with an Ag/AgCl ink. These sensors exhibited slopes (of electrical potential vs. log concentration of target ion), close to the theoretically-expected values, over four orders of magnitude in concentrations of ions. Because thread is mechanically strong, the thread-based electrodes can be used in multiple-use applications as well as single-use applications. Multiple thread-based sensors can be easily bundled together to fabricate a customized sensor for multiplexed ion-sensing. These electrodes require volumes of sample as low as 200 MUL. The application of thread-based ISEs is demonstrated in the analysis of ions in soil, food, and dietary supplements (Cl- in soil/water slurry, K+ and Na+ in coconut water, and Ca2+ in a calcium supplement), and in detection of physiological electrolytes (K+ and Na+ in blood serum and urine, with sufficient accuracy for clinical diagnostics). PMID- 29987297 TI - Coordination driven self-assembly of [2 + 2 + 2] molecular squares: synthesis, crystal structures, catalytic and luminescence properties. AB - The one-pot self-assembly of three components (metal acetates as the metal precursor, the tridentate polypyridyl ligand, N,N'-bis(2-pyridylmethyl)-tert butylamine (bpta), as a capping ligand and bent dicarboxylic acids, 4,4' (dimethylsilanediyl)bis-benzoic acid (H2L1) or 4,4'-oxybis-benzoic acid (H2L2), as bridging ligands) under ambient conditions has resulted in the formation of a series of discrete [2 + 2 + 2] molecular squares (1-10) of the general formula [M2(bpta)2L2(H2O)2], where M = Mn, Co, Ni, Zn or Cd and L = L1 or L2. In addition to their characterization by elemental analysis and FTIR spectroscopy, a combination of single crystal and powder X-ray diffraction confirmed their isostructural nature. Their chemical (towards various solvents) and thermal stabilities have been established by powder X-ray diffraction and thermogravimetric analysis (TGA), respectively. The presence of metal centers with coordinated water molecules has provided an opportunity for their use as an efficient Lewis acid catalyst for the Knoevenagel condensation reaction of malononitrile with various aldehydes (98-100% conversion in 100 minutes with 2 mol% catalyst in water). Furthermore, the blue emitting nature of 4 and 10 (M = Cd) was utilized for the selective detection of nitrobenzene via the fluorescence quenching mechanism involving host-guest interactions. PMID- 29987298 TI - Characterising knotting properties of polymers in nanochannels. AB - Using a lattice model of polymers in a tube, we define one way to characterise different configurations of a given knot as either "local" or "non-local", based on a standard approach for measuring the "size" of a knot within a knotted polymer chain. The method involves associating knot-types to subarcs of the chain, and then identifying a knotted subarc with minimal arclength; this arclength is then the knot-size. If the resulting knot-size is small relative to the whole length of the chain, then the knot is considered to be localised or "local"; otherwise, it is "non-local". Using this definition, we establish that all but exponentially few sufficiently long self-avoiding polygons (closed chains) in a tubular sublattice of the simple cubic lattice are "non-locally" knotted. This is shown to also hold for the case when the same polygons are subject to an external tensile force, as well as in the extreme case when they are as compact as possible (no empty lattice sites). We also provide numerical evidence for small tube sizes that at equilibrium non-local knotting is more likely than local knotting, regardless of the strength of the stretching or compressing force. The relevance of these results to other models and recent experiments involving DNA knots is also discussed. PMID- 29987299 TI - Reactions of (Ph)tBuP-P(SiMe3)Li.3THF with [(PNP)TiCl2] and [MeNacNacTiCl2.THF]: synthesis of first PNP titanium(iv) complex with the phosphanylphosphinidene ligand [(PNP)Ti(Cl){eta2-P-P(Ph)tBu}]. AB - Herein, the lithium derivative of diphosphane, (Ph)tBuP-P(SiMe3)Li (1), is isolated for the first time and investigated in reactions with beta-diketiminate (MeNacnac- = [Ar]NC(Me)CHC(Me)N[Ar]; Ar = 2,6-iPr2C6H3) and PNP-pincer (PNP = N[2 PiPr2-4-methylphenyl]2) Ti(iii) complexes. The beta-diketiminate titanium(iii) complex containing the phosphanylphosphido ligand [MeNacNacTi(Cl){eta2-P(SiMe3) P(Ph)tBu}] (2) is prepared via the reaction of [MeNacNacTiCl2.THF] with (Ph)tBuP P(SiMe3)Li in toluene solution with good yield and purity. The corresponding titanium(iv) complex involving the phosphanylphosphinidene ligand [MeNacNacTi(Cl){eta2-P-P(Ph)tBu}] (3) is synthesized via the oxidation of complex (2) with [iBu3PAgCl]4. Interestingly, an analogous PNP titanium(iv) complex, [(PNP)Ti(Cl){eta2-P-P(Ph)tBu}] (4), is obtained in the reaction of [(PNP)TiCl2] with (Ph)tBuP-P(SiMe3)Li in toluene solution and a 1 : 1 molar ratio instead of the expected titanium(iii) complex with the phosphanylphosphido ligand. The solid state structures of (Ph)tBuP-P(SiMe3)Li.3THF (1), [MeNacNacTi(Cl){eta2-P(SiMe3) P(Ph)tBu}] (2), [MeNacNacTi(Cl){eta2-P-P(Ph)tBu}] (3) and [(PNP)Ti(Cl){eta2-P P(Ph)tBu}] (4) are determined by single-crystal X-ray diffraction, which reveals that in all obtained complexes, both the phosphanylphosphinidene (Ph)tBuP-P and phosphanylphosphido (Ph)tBuP-P(SiMe3) ligands are bidentate-coordinated to the metal center. PMID- 29987300 TI - Intramolecular strong electronic coupling in a discretely H-aggregated phthalocyanine dimer connected with a rigid linker. AB - Preparation of an accurate assembly of phthalocyanines is rather difficult because of the high aggregation property of phthalocyanines. In this study, a novel discrete phthalocyanine dimer was prepared in which the relative configuration of each component was tightly and accurately fixed in an H aggregate form by a rigid U-shaped linker. Electrochemical measurements showed that there were strong intramolecular electronic interactions between the two phthalocyanines. PMID- 29987301 TI - A novel alpha-enolase-targeted drug delivery system for high efficacy prostate cancer therapy. AB - Prostate cancer, one of the leading causes of disease and death in men all over the world, is challenging to treat. alpha-Enolase, a multifunctional protein, is overexpressed on human prostate carcinoma cells, and thereby it is a potential target for treatment of prostate cancer. In the current study, the pHCT74 peptide was used to construct a kind of highly targeted liposome (pHCT74-lipo) loaded with doxorubicin (pHCT74-lipo-Dox), which specifically targeted alpha-enolase on prostate tumour cells. Compared with liposomes without pHCT74 modification, pHCT74-lipo-Dox displayed a superior intracellular internalization with enhanced tumour cytotoxicity. In the in vivo study, pHCT74-lipo showed much higher tumour accumulation. In addition, loaded into pHCT74-lipo, doxorubicin demonstrated significantly improved anti-tumour activity on prostate tumour-bearing mice. These results suggest that the pHCT74 peptide has potential to be used in the development of a novel drug delivery system for targeted therapy against prostate cancer. PMID- 29987302 TI - Real-time measurement of the crystal violet adsorption behavior and interaction process at the silica-aqueous interface by near-field evanescent wave. AB - The interfacial adsorption and interaction of crystal violet (CV) at the silica water interface was real-time measured based on a total-internal-reflection induced near-field evanescent wave (TIR-NFEW). A silica optical fiber (SOF) was employed as a charged substrate for CV adsorption and as a light transmission waveguide for evanescent wave production for the investigation system. According to the change of evanescent wave intensity, the CV adsorption behavior could be real-time monitored at the silica-aqueous interface. The Langmuir adsorption model and two kinetic models were applied to obtain the related thermodynamic and kinetic data, including the adsorption equilibrium constant (Kads) of (5.9 +/- 1.5) * 104 M-1 and adsorption free energy (DeltaG) of -21.6 +/- 0.6 kJ mol-1. Meanwhile, this method was shown to be able to isolate the elementary processes of adsorption and desorption under steady-state conditions, and gave an adsorption rate constant (ka) and desorption rate constant (kd) of 2089 +/- 6.96 M min-1 and 0.35 +/- 0.0012 min-1 for a 15 rpm flow rate. The surface interaction process was revealed and the adsorption mechanism proposed by a molecular orientation adsorption model with three-stage-concentration, indicating that CV first adsorbed on Si-O- sites through electrostatic attraction, then on Si-OH sites through hydrogen bonding, and lastly on the surface through van der Waals forces with different CV concentrations. This study can provide a molecular-level interpretation of CV adsorption and provides important insights into how CV adsorption can be controlled at the silica-water interface. PMID- 29987303 TI - Impact of PEG additives and pore rim functionalization on water transport through sub-1 nm carbon nanotube porins. AB - Carbon nanotubes represent one of the most interesting examples of a nanofluidic channel that combines extremely small diameters with atomically smooth walls and well-defined chemical functionalities at the pore entrance. In the past, sub-1 nm diameter carbon nanotube porins (CNTPs) embedded in a lipid membrane matrix demonstrated extremely high water permeabilities and strong ion selectivities. In this work, we explore additional factors that can influence transport in these channels. Specifically, we use stopped-flow transport measurements to focus on the effect of chemical modifications of the CNT rims and chaotropic polyethyleneglycol (PEG) additives on CNTP water permeability and Arrhenius activation energy barriers for water transport. We show that PEG, especially in its more chaotropic coiled configuration, enhances the water transport and reduces the associated activation energy. Removal of the static charges on the CNTP rim by converting -COOH groups to neutral methylamide groups also reduces the activation energy barriers and enhances water transport rates. PMID- 29987304 TI - Influence of the surface limiting elasticity modulus on the impact behavior of droplets of difenoconazole-loaded mesoporous silica nanoparticles with associated SDS. AB - The relation between the surface limiting elasticity modulus, epsilon0, of difenoconazole-loaded mesoporous silica nanoparticle (DF-MSN) formulations with associated SDS and the height of the first returning droplet impacting on cabbage and rice leaf surfaces was investigated. The surface dilational rheology properties were determined by means of surface tension relaxation. The impact of a droplet on the leaf surface was recorded with a high-speed camera. The surface limiting elasticity modulus, epsilon0, shows differences with different SDS concentrations. A positive correlation between droplet first rebound height and the surface limiting elasticity modulus, epsilon0, is observed. The pesticide droplet impact on the target leaf surface is a rather complex phenomenon, so the focus of this article is to establish a relationship between the surface limiting elasticity modulus, epsilon0, and droplet first rebound height. These findings introduce a chemical way to affect the impact behavior of pesticide droplets on target crop leaf surfaces, which may be of particular importance for pesticide spraying and crop protection, especially for hydrophobic and superhydrophobic target crops. PMID- 29987305 TI - Molecular dynamics simulation of the electrical conductive network formation of polymer nanocomposites with polymer-grafted nanorods. AB - Grafting chains on the surface of a filler is an effective strategy to tune and control the filler conductive network, which can be utilized to fabricate polymer nanocomposites (PNCs) with high electrical conductivity. In this work, by employing the coarse-grained molecular dynamics simulation, we investigated the effect of polymer-grafted nanorods (NRs) on the conductive probability of PNCs in the quiescent state or under the shear field for different volume fractions of the NRs. The local order structure of the NRs aggregating in the matrix is gradually broken down, and the dispersion state of the NRs improves with increasing grafting density. However, at high grafting densities, the uniform dispersion of the NRs leads to a large NR-NR distance. As a result, the conductive probability first increases and then decreases with the increase of the grafting density. Under the shear field, the conductive probability shows a continuous increase with the grafting density. Compared with that in the quiescent state, the decrease or the increase of the conductive probability depends on the grafting density under the shear field. In particular, the smallest change in the percolation threshold appears at the highest grafting density, which reflects the high conductive stability. In addition, the topological structure of the conductive network nearly remains unchanged with the length of the grafted chain. Finally, compared with the strong attractive interaction between grafted chains and free chains, weakly repulsive interactions can effectively enhance the conductive probability. PMID- 29987306 TI - N-Sulfonyl acetylketenimine as a highly reactive intermediate for the synthesis of N-sulfonyl amidines. AB - A highly reactive intermediate N-sulfonyl acetylketenimine was generated from a 3 butyn-2-one participating CuAAC/ring-opening method. Its high reactivity due to bearing two EWGs allowed us to offer the first example of a reaction between ketenimine and amide to synthesize N-sulfonyl amidines efficiently. PMID- 29987307 TI - 2D library beyond graphene and transition metal dichalcogenides: a focus on photodetection. AB - Two-dimensional layered materials (2DLMs) have attracted a tremendous amount of attention as photodetectors due to their fascinating features, including high potentials in new-generation electronic devices, wide coverage of bandgaps, ability to construct van der Waals heterostructures, extraordinary light-mass interaction, strong mechanical flexibility, and the capability of enabling synthesis of 2D nonlayered materials. Until now, most attention has been focused on the well-known graphene and transition metal dichalcogenides (TMDs). However, a growing number of functional materials (more than 5619) with novel optoelectronic and electronic properties are being re-discovered, thereby widening the horizon of 2D libraries. In addition to showing common features of 2DLMs, these new 2D members may bring new opportunities to their well-known analogues, like wider bandgap coverage, direct bandgaps independence with thickness, higher mechanical flexibility, and new photoresponse phenomena. The impressive results communicated so far testify that they have shown high potentials with photodetections covering THz, IR, visible, and UV ranges with comparable or even higher performances than well-known TMDs. Here, we give a comprehensive review on the state-of-the-art photodetections of two-dimensional materials beyond graphene and TMDs. The review is organized as follows: fundamentals of photoresponse first are discussed, followed by detailed photodetections of new 2D members including both layered and non-layered ones. After that, photodiodes and hybrid structures based on these new 2D materials are summarized. Then, the integration of these 2D materials with flexible substrates is reviewed. Finally, we conclude with the current research status of this area and offer our perspectives on future developments. We hope that, through reading this manuscript, readers will quickly have a comprehensive view on this research area. PMID- 29987308 TI - Hydrogen adsorption on nano-structured platinum electrodes. AB - The "hydrogen region" of platinum is a powerful tool to structurally characterize nanostructured platinum electrodes. In recent years, the understanding of this hydrogen region has improved considerably: on Pt(111) sites, there is indeed only hydrogen adsorption, while on step sites, the hydrogen region involves the replacement of adsorbed hydrogen by adsorbed hydroxyl which interacts with co adsorbed cations. However, the hydrogen region features an enigmatic and less well-understood "third hydrogen peak", which develops on oxidatively roughened platinum electrodes as well as on platinum electrodes with a high (110) step density that have been subjected to a high concentration of hydrogen. In this paper, we present evidence that the peak involves surface-adsorbed hydrogen (instead of subsurface hydrogen) on a locally "reconstructed" (110)-type surface site. This site is unstable when the hydrogen is oxidatively removed. The cation sensitivity of the third hydrogen peak appears different from other step-related peaks, suggesting that the chemistry involved may still be subtly different from the other features in the hydrogen region. PMID- 29987309 TI - Surface chemistry, rheology and microstructure of purified natural and synthetic hectorite suspensions. AB - Natural (N-) and synthetic (S-) hectorite suspensions were found to display significant time-dependent rheology or ageing behaviour and shear thinning flow behaviour. The ageing behaviour was characterised by an increasing yield stress with rest time. The yield stress continued to increase even after a week of rest, a reflection of a long process. An open sponge-like cellular microstructure formed by platelet particles interacting attractively in the overlapping edge face configuration was captured by cryo-SEM of gel samples prepared at high pressure (~2000 bar) and subjected to rapid cryo-freezing, for both N- and S hectorite gels. Even nano-discotic S-hectorite particles formed platelet particles hundreds of nanometres in length in the overlapping coin configuration. This structure, displaying a cell size ranging from tens to several hundred nanometres, is formed by strong attractive and repulsive forces. The platelets showed deformations such as bending and curling of the edges in response to these forces. The S-hectorite platelets are smaller and more rigid. During ageing the particles in the structure experience a net force. These particles will move in response causing force imbalance to be experienced by neighbouring particles and they will move in response. This action and reaction percolate through the network structure causing a high concentration of particles to respond. As a consequence the ageing process takes a long time to reach equilibrium. Various ageing models were used to fit the ageing data. The N-hectorite gels displayed a maximum yield stress at pH ~ 8 and a particle zeta potential of -35 mV. This suggests the presence of critical positive and negative charge density is needed to form a structure with maximum strength. The zeta potential is negative and quite insensitive to pH from pH 4 to 12. PMID- 29987311 TI - Devolution and Devaluation of Fecal Leukocyte Testing: A 100-Year History. PMID- 29987312 TI - Measuring Trends in Infant Mortality Due to Unintentional Suffocation-Reply. PMID- 29987313 TI - Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study. AB - Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary Funding Source: Patient Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development. PMID- 29987314 TI - Measuring Trends in Infant Mortality Due to Unintentional Suffocation. PMID- 29987315 TI - Predictors of Responsible Drinking or Abstinence Among College Students Who Binge Drink: A Multitheory Model Approach. AB - Context: Binge drinking is a salient problem on college campuses, with estimates as high as 40% of students engaging in it. Binge drinking is associated with numerous negative consequences among college students, such as suicide attempts, unsafe sex practices, property damage, and driving under the influence. Several behavioral approaches in this regard have had modest impact and only short-term effects, however. Objective: To use the multitheory model (MTM) of health behavior change to predict initiation and sustenance of responsible drinking or abstinence among binge-drinking college students in a sample drawn from a large southern public university. Methods: This cross-sectional survey study included a sample of college students who binge drank in the past 30 days. A 39-item face- and content-valid instrument was used. In addition, construct validity using confirmatory factor analysis and internal consistency reliability using the Cronbach alpha were established. Hierarchical regression modeling was used to build models. Results: A total of 289 students participated. The Cronbach alpha for the scale and all subscales ranged from 0.81 to 0.94 and demonstrated acceptable internal consistency reliability. Construct validity using confirmatory factor analysis yielded 1-factor solutions for each of the subscales. On hierarchical regression modeling, gender (P=.05), race/ethnicity (P=.004), behavioral confidence (P=.029), and changes in physical environment (P=.001) were associated with intended initiation for drinking responsibly/abstinence behavior change. The addition of MTM constructs led to a significant increase in R2 of 0.20 (F3,194=18.1; P<.001). The sustenance constructs yielded a significant increase in R2 of 0.20 (F3,193=19.4; P<.001). Conclusion: This study provides empirical justification for MTM constructs that can be used to inculcate the intention to drink responsibly or abstain among college students who binge drink. This predictive model may prove valuable in the design of interventions aiming to improve responsible drinking behavior in this population. PMID- 29987316 TI - Measuring Trends in Infant Mortality Due to Unintentional Suffocation. PMID- 29987318 TI - New Insights Into Optimal Timing of Hepatitis C Virus Treatment for Dialysis Patients Waitlisted for Kidney Transplant. PMID- 29987317 TI - Prevalence and Variation of Developmental Screening and Surveillance in Early Childhood. AB - Importance: Since 2001, the American Academy of Pediatrics has recommended universal developmental screening and surveillance to promote early diagnosis and intervention and to improve the outcomes of children with developmental delays and disabilities. Objective: To examine the current prevalence and variation of developmental screening and surveillance of children by various sociodemographic, enabling, and health characteristics. Design, Setting, and Participants: This cross-sectional analysis of the Health Resources and Services Administration's 2016 National Survey of Children's Health-a nationally representative survey of US children completed between June 2016 and February 2017-examined 5668 randomly selected children 9 through 35 months of age whose parent or caregiver responded to the address-based survey by mail or via a website. All analyses were weighted to account for the probability of selection and nonresponse and to reflect population counts of all noninstitutionalized US children residing in housing units. Main Outcomes and Measures: Developmental screening was measured through a validated set of 3 items indicating receipt in the past year of parent-completed screening from a health care professional with age-appropriate content regarding language development and social behavior. Surveillance was determined by an item capturing verbal elicitation of developmental concerns by a health care professional. Results: Of the estimated 9.0 million children aged 9 through 35 months, an estimated 30.4% (95% CI, 28.0%-33.0%) were reported by their parent or guardian to have received a parent-completed developmental screening and 37.1% (95% CI, 34.4%-39.8%) were reported to have received developmental surveillance from a health care professional in the past year. Characteristics associated with screening and/or surveillance that remained significant after adjustment included primary household language, family structure, household education, income, medical home, past-year preventive visit, child health status, and special health care needs. Having health care that meets medical home criteria was significantly associated with both developmental screening (adjusted rate ratio, 1.34; 95% CI, 1.13-1.57) and surveillance (adjusted rate ratio, 1.24; 95% CI, 1.08-1.42), representing an 8 to 9 absolute percentage point increase. State-level differences spanned 40 percentage points for screening (17.2% in Mississippi and 58.8% in Oregon) and surveillance (19.1% in Mississippi and 60.8% in Oregon), with approximately 90% of variation not explained by child and family characteristics. Conclusions and Relevance: Despite more than a decade of initiatives, rates of developmental screening and surveillance remain low. However, state-level variation indicates continued potential for improvement. Systems-level quality improvement efforts, building on the medical home, will be necessary to achieve recommended screening and surveillance goals. PMID- 29987319 TI - Opioid Use Disorder, Stigma, and Transplantation: A Call to Action. PMID- 29987320 TI - Kidney Transplants for Patients With Hepatitis C Virus Infection. PMID- 29987321 TI - Association of Early Introduction of Solids With Infant Sleep: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: The World Health Organization recommends exclusive breastfeeding for 6 months. However, 75% of British mothers introduce solids before 5 months and 26% report infant waking at night as influencing this decision. Objective: To determine whether early introduction of solids influences infant sleep. Design, Setting, and Participants: The Enquiring About Tolerance study was a population based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, that included 1303 exclusively breastfed 3-month-old infants from England and Wales. Clinical visits took place at St Thomas' Hospital, London, England, and the trial studied the early introduction of solids into the infant diet from age 3 months. Interventions: The early introduction group (EIG) continued to breastfeed while nonallergenic and then 6 allergenic foods were introduced. The standard introduction group (SIG) followed British infant feeding guidelines (ie, exclusive breastfeeding to around age 6 months and to avoid any food consumption during this period). Main Outcomes and Measures: Secondary analysis of an a priori secondary outcome of the effect of early food introduction on infant sleep using the standardized Brief Infant Sleep Questionnaire. Results: Of the 1303 infants who were enrolled in the Enquiring About Tolerance study, 1225 participants (94%) completed the final 3-year questionnaire (618 SIG [95%] and 607 EIG [93%]). Randomization was effective and there were no significant baseline differences between the 2 groups. Following the early introduction of solids, infants in the EIG slept significantly longer and woke significantly less frequently than infants in the SIG. Differences between the 2 groups peaked at age 6 months. At this point, in the intention-to-treat analysis infants in the EIG slept for 16.6 (95% CI, 7.8-25.4) minutes longer per night and their night waking frequency had decreased from 2.01 to 1.74 wakings per night. Most clinically important, very serious sleep problems, which were significantly associated with maternal quality of life, were reported significantly more frequently in the SIG than in the EIG (odds ratio, 1.8; 95% CI, 1.22-2.61). Conclusions and Relevance: In a randomized clinical trial, the early introduction of solids into the infant's diet was associated with longer sleep duration, less frequent waking at night, and a reduction in reported very serious sleep problems. Trial Registration: isrctn.org Identifier: ISRCTN14254740. PMID- 29987322 TI - Transplanting Hepatitis C Virus-Infected Versus Uninfected Kidneys Into Hepatitis C Virus-Infected Recipients: A Cost-Effectiveness Analysis. AB - Background: Direct-acting antiviral agents are now available to treat chronic hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD). Objective: To examine whether it is more cost-effective to transplant HCV infected or HCV-uninfected kidneys into HCV-infected patients. Design: Markov state-transition decision model. Data Sources: MEDLINE searches and bibliographies from relevant English-language articles. Target Population: HCV infected patients with ESRD receiving hemodialysis in the United States. Time Horizon: Lifetime. Perspective: Health care system. Intervention: Transplant of an HCV-infected kidney followed by HCV treatment versus transplant of an HCV uninfected kidney preceded by HCV treatment. Outcome Measures: Effectiveness, measured in quality-adjusted life-years (QALYs), and costs, measured in 2017 U.S. dollars. Results of Base-Case Analysis: Transplant of an HCV-infected kidney followed by HCV treatment was more effective and less costly than transplant of an HCV-uninfected kidney preceded by HCV treatment, largely because of longer wait times for uninfected kidneys. A typical 57.8-year-old patient receiving hemodialysis would gain an average of 0.50 QALY at a lifetime cost savings of $41 591. Results of Sensitivity Analysis: Transplant of an HCV-infected kidney followed by HCV treatment continued to be preferred in sensitivity analyses of many model parameters. Transplant of an HCV-uninfected kidney preceded by HCV treatment was not preferred unless the additional wait time for an uninfected kidney was less than 161 days. Limitation: The study did not consider the benefit of decreased HCV transmission from treating HCV-infected patients. Conclusion: Transplanting HCV-infected kidneys into HCV-infected patients increased quality adjusted life expectancy and reduced costs compared with transplanting HCV uninfected kidneys into HCV-infected patients. Primary Funding Source: Merck Sharp & Dohme and the National Center for Advancing Translational Sciences. PMID- 29987323 TI - Cost-effectiveness of the Recommendations of the Advisory Committee on Immunization Practices for the Recombinant Adjuvanted Zoster Subunit Vaccine. PMID- 29987325 TI - The Emerging Role of Inhaled Heroin in the Opioid Epidemic: A Review. AB - Importance: Opioid addiction affects approximately 2.4 million Americans. Nearly 1 million individuals, including a growing subset of 21 000 minors, abuse heroin. Its annual cost within the United States amounts to $51 billion. Inhaled heroin use represents a global phenomenon and is approaching epidemic levels east of the Mississippi River as well as among urban youth. Chasing the dragon (CTD) by heating heroin and inhaling its fumes is particularly concerning, because this method of heroin usage has greater availability, greater ease of administration, and impressive intensity of subjective experience (high) compared with sniffing or snorting, although it also has a safer infectious profile compared with heroin injection. This is relevant owing to peculiar and often catastrophic brain complications. Following the American Medical Association Opioid Task Force mandate, we contribute a description of the pharmacology, pathophysiology, clinical spectrum, neuroimaging, and neuropathology of CTD leukoencephalopathy, as distinct from other heroin abuse modalities. Observations: The unique spectrum of CTD-associated health outcomes includes an aggressive toxic leukoencephalopathy with pathognomonic neuropathologic features, along with sporadic instances of movement disorders and hydrocephalus. Clinical CTD severity is predominantly moderate at admission, frequently unmodified at discharge, and largely improved in the long term. Mild cases survive with minor sequelae, while moderate to severe presentations might deteriorate and progress to death. Other methods of heroin use may complicate with stroke, seizure, obstructive hydrocephalus, and (uncharacteristically) leukoencephalopathy. Conclusions and Relevance: The distinct pharmacology of CTD correlates with its specific clinical and radiological features and prompts grave concern for potential morbidity and long-term disability costs. Proposed diagnostic criteria and standardized reporting would ameliorate the limitations of CTD literature and facilitate patient selection for a coenzyme Q10 therapeutic trial. PMID- 29987324 TI - Effect of Electronic Health Record-Based Medication Support and Nurse-Led Medication Therapy Management on Hypertension and Medication Self-management: A Randomized Clinical Trial. AB - Importance: Complex medication regimens pose self-management challenges, particularly among populations with low levels of health literacy. Objective: To test medication management tools delivered through a commercial electronic health record (EHR) with and without a nurse-led education intervention. Design, Setting, and Participants: This 3-group cluster randomized clinical trial was performed in community health centers in Chicago, Illinois. Participants included 794 patients with hypertension who self-reported using 3 or more medications concurrently (for any purpose). Data were collected from April 30, 2012, through February 29, 2016, and analyzed by intention to treat. Interventions: Clinics were randomly assigned to to groups: electronic health record-based medication management tools (medication review sheets at visit check-in, lay medication information sheets printed after visits; EHR-alone group), EHR-based tools plus nurse-led medication management support (EHR plus education group), or usual care. Main Outcomes and Measures: Outcomes at 12 months included systolic blood pressure (primary outcome), medication reconciliation, knowledge of drug indications, understanding of medication instructions and dosing, and self reported medication adherence. Medication outcomes were assessed for all hypertension prescriptions, all prescriptions to treat chronic disease, and all medications. Results: Among the 794 participants (68.6% women; mean [SD] age, 52.7 [9.6] years), systolic blood pressure at 12 months was greater in the EHR alone group compared with the usual care group by 3.6 mm Hg (95% CI, 0.3 to 6.9 mm Hg). Systolic blood pressure in the EHR plus education group was not significantly lower compared with the usual care group (difference, -2.0 mm Hg; 95% CI, -5.2 to 1.3 mm Hg) but was lower compared with the EHR-alone group (-5.6 mm Hg; 95% CI, -8.8 to -2.4 mm Hg). At 12 months, hypertension medication reconciliation was improved in the EHR-alone group (adjusted odds ratio [OR], 1.8; 95% CI, 1.1 to 2.9) and the EHR plus education group (adjusted odds ratio [OR], 2.0; 95% CI, 1.3 to 3.3) compared with usual care. Understanding of medication instructions and dosing was greater in the EHR plus education group than the usual care group for hypertension medications (OR, 2.3; 95% CI, 1.1 to 4.8) and all medications combined (OR, 1.7; 95% CI, 1.0 to 2.8). Compared with usual care, the EHR tools alone and EHR plus education interventions did not improve hypertension medication adherence (OR, 0.9; 95% CI, 0.6-1.4 for both) or knowledge of chronic drug indications (OR for EHR tools alone, 1.0 [95% CI, 0.6 to 1.5] and OR for EHR plus education, 1.1 [95% CI, 0.7-1.7]). Conclusions and Relevance: The study found that EHR tools in isolation improved medication reconciliation but worsened blood pressure. Combining these tools with nurse-led support suggested improved understanding of medication instructions and dosing but did not lower blood pressure compared with usual care. Trial Registration: ClinicalTrials.gov identifier: NCT01578577. PMID- 29987326 TI - Comparative Benefits and Harms of Basal Insulin Analogues for Type 2 Diabetes: A Systematic Review and Network Meta-analysis. AB - Background: Basal insulin analogues aim for protracted glycemic control with minimal adverse effects. Purpose: To assess the comparative efficacy and safety of basal insulin analogues for adults with type 2 diabetes mellitus (T2DM). Data Sources: Several databases from inception to April 2018 without language restrictions, ClinicalTrials.gov to April 2018, references of reviews, and meeting abstract books. Study Selection: Randomized trials lasting at least 12 weeks that compared efficacy (change in hemoglobin A1c [HbA1c] level from baseline [primary outcome]; percentage of patients with HbA1c level <7% at end of study and change in body weight [secondary outcomes]) and safety (hypoglycemia) of basal insulin analogues. Data Extraction: Two authors independently extracted data and assessed risk of bias for each outcome. All authors evaluated overall confidence in the evidence. Data Synthesis: Thirty-nine trials (26 195 patients) assessed 10 basal insulin analogues. Low- to very-low-quality evidence indicated that thrice-weekly degludec (Deg-3TW) was inferior to most other regimens for reducing HbA1c level, with mean differences ranging from 0.21% (vs. degludec, 100 U/mL [Deg-100]) to 0.32% (vs. glargine, 300 U/mL [Glar-300]). High- to moderate quality evidence suggested that detemir had a favorable weight profile versus all comparators, and Glar-300 was associated with less weight gain than glargine, 100 U/mL (Glar-100); Deg-100; degludec, 200 U/mL (Deg-200); Deg-3TW; and LY2963016. Low- and very-low-quality evidence suggested that Deg-100, Deg-200, and Glar-300 were associated with lower incidence of nocturnal hypoglycemia than detemir, Glar 100, LY2963016, and neutral protamine lispro (NPL). Incidence of severe hypoglycemia did not differ among regimens, except NPL, which was associated with increased risk versus Deg-100, detemir, Glar-100, and Glar-300. Limitations: Results are based mostly on indirect comparisons. Confidence in summary estimates is low or very low due to individual-study limitations, imprecision, or inconsistency. Conclusion: Low-quality evidence suggests that basal insulin analogues for T2DM do not substantially differ in their glucose-lowering effect. Low- and very-low-quality evidence suggests some regimens may be associated with lower risk for nocturnal hypoglycemia (Deg-100, Deg-200, and Glar-300) or less weight gain (detemir and Glar-300). Primary Funding Source: None. (PROSPERO: CRD42016037055). PMID- 29987330 TI - From Colorectal Cancer Screening Guidelines to Headlines: Beware! PMID- 29987329 TI - Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. AB - Importance: Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown. Objective: To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache. Design, Setting, and Participants: A randomized, double blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse. Interventions: Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 MUg/min of CGRP or placebo over 20 minutes on 2 study days. Main Outcomes and Measures: Difference in incidence of cluster headache like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups. Results: Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99). Conclusions and Relevance: Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management. Trial Registration: ClinicalTrials.gov (NCT02466334). PMID- 29987331 TI - Cluster Headache and Calcitonin Gene-Related Peptide-More on Quantum Therapeutics in Headache Medicine. PMID- 29987333 TI - Five Questions That Every Patient Has but Never Asks. PMID- 29987332 TI - Trends in Rates of Lower Extremity Amputation Among Patients With End-stage Renal Disease Who Receive Dialysis. AB - Importance: Patients with end-stage renal disease (ESRD) who receive dialysis are at high risk of lower extremity amputation. Recent studies indicate decreasing rates of lower extremity amputation in non-ESRD populations, but contemporary data for patients with ESRD who receive dialysis are lacking. Objectives: To assess rates of lower extremity amputation among patients with ESRD who receive dialysis during a recent 15-year period; to analyze whether those rates differed by age, sex, diabetes, or geographic region; and to determine 1-year mortality rates in this population after lower extremity amputation. Design, Setting, and Participants: This retrospective study of 3 700 902 records obtained from a US national registry of patients with ESRD who receive dialysis assessed cross sectional cohorts for each calendar year from 2000 through 2014. Adult patients with prevalent ESRD treated with hemodialysis or peritoneal dialysis covered by Medicare Part A and B on January 1 of each cohort year were included. Data analysis was conducted from August 2017 to April 2018. Exposures: Age, sex, diabetes, and hospital referral region. Main Outcomes and Measures: Annual rates per 100 person-years of nontraumatic major (above- or below-knee) and minor (below-ankle) amputations. Results: For each annual cohort, there were fewer women (47.5% in 2000, 46.2% in 2005, 44.9% in 2010, and 44.0% in 2014) than men, more than half the patients were white individuals (58.1% in 2000, 56.9% in 2005, 56.9% in 2010, and 56.7% in 2014), and a small proportion were employed (13.9% in 2000, 15.1% in 2005, 16.1% in 2010, and 16.5% in 2014). The rate of lower extremity amputations for patients with ESRD who receive dialysis decreased by 51.0% from 2000 to 2014, driven primarily by a decrease in the rate of major amputations (5.42 [95% CI, 5.28-5.56] in 2000 vs 2.66 [95% CI, 2.59-2.72] per 100 person-years in 2014). Patients with diabetes had amputation rates more than 5 times as high as patients without diabetes. Patients younger than 65 years had higher adjusted amputation rates than older patients, and men had consistently higher adjusted amputation rates than women. Adjusted 1-year mortality rates after lower extremity amputation for patients with ESRD who receive dialysis decreased from 52.2% (95% CI, 50.9%-53.4%) in 2000 to 43.6% (95% CI, 42.5%-44.8%) in 2013. In general, amputation rates decreased among all regions from 2000 to 2014, but regional variability persisted across time despite adjustment for differences in patient demographics and comorbid conditions. Conclusions and Relevance: Although rates of lower extremity amputations among US patients with ESRD who receive dialysis decreased by 51% during a recent 15-year period, mortality rates remained high, with nearly half of patients dying within a year after lower extremity amputation. Our results highlight the need for more research on ways to prevent lower extremity amputation in this extremely high risk population. PMID- 29987334 TI - The Health Insurance Marketplaces. PMID- 29987335 TI - Building Good Policy From Good Science-The Case for Concussion and Chronic Traumatic Encephalopathy. PMID- 29987336 TI - Association of Antenatal Micronutrient Supplementation With Adolescent Intellectual Development in Rural Western China: 14-Year Follow-up From a Randomized Clinical Trial. AB - Importance: The association of micronutrient supplementation during pregnancy with the intellectual development of adolescent offspring is unknown. Objective: To assess the long-term association of antenatal micronutrient supplementation with adolescent intellectual development. Design, Setting, and Participants: This 14-year follow-up study of a randomized clinical trial of micronutrient supplementation in pregnancy was conducted in 2 counties in rural western China in 2118 adolescent offspring (aged 10 to 14 years) of mothers who were randomized to take a daily capsule of either folic acid, folic acid plus iron, or multiple micronutrients from August 1, 2002, through February 28, 2006. Follow-up was conducted from June 1, 2016, through December 31, 2016. Data analyses took place from April 1, 2017, to June 20, 2017. Main Outcomes and Measures: Adolescent full scale intelligence quotient and aspects of verbal comprehension, working memory, perceptual reasoning, and processing speed indexes were assessed by the Wechsler Intelligence Scale for Children. Results: Of 2118 adolescent offspring, 1252 (59.1%) were boys and 866 (40.9%) were girls, with a mean (SD) age of 11.7 (0.87) years, representing 47.2% of the 4488 single live births that were eligible to participate. Compared with folic acid supplementation, multiple micronutrient supplementation was associated with a 1.13-point higher full-scale intelligence quotient (95% CI, 0.15-2.10) and a 2.03-point higher verbal comprehension index (95% CI, 0.61-3.45); similar results were found in comparison with folic acid plus iron. When mothers initiated supplementation early (<12 weeks of gestation) and had an adequate dose (>=180 capsules), multiple micronutrient capsules were associated with a 2.16-point higher full-scale intelligence quotient (95% CI, 0.41-3.90) and 4.29-point higher verbal comprehension index (95% CI, 1.33-7.24) compared with folic acid capsules. The mean test scores were lower in the substratum of supplementation initiated late (>=12 weeks of gestation) and with an inadequate dose (<180 capsules). The multiple micronutrient group had higher scores than the other 2 treatment groups, and significant differences were observed for full-scale intelligence quotient (adjusted mean difference, 2.46; 95% CI, 0.98-3.94) when compared with the folic acid plus iron group. Conclusions and Relevance: Compared with folic acid plus iron or folic acid capsules supplementation, antenatal multiple micronutrient supplementation appeared to be associated with increased adolescent intellectual development; initiating supplementation in the first trimester and then continuing for at least 180 days were associated with the greatest rewards. Trial Registration: isrctn.org Identifier: ISRCTN08850194. PMID- 29987337 TI - [Impact of nursing staff shortage on intensive care medicine capacity in Germany]. AB - BACKGROUND: Compared to other countries, Germany has the highest number of intensive care unit (ICU) beds, but, despite this, a shortage in ICU care is evident. Currently, little comprehensive data on ICU staffing and on subsequent closure of ICU beds are available. The current survey therefore aimed to systematically investigate the closure of ICU beds. METHOD: A survey was performed among authorized professional trainers in ICU medicine. RESULTS: Overall, a shortage of ICU beds following bed closure was evident in 76% of all ICU floors with 22% reporting daily ICU bed closure. In 47%, two ICU beds were not available. Emergency care was unrestricted in only 18%, while restrictions were reportedly frequent or even constant in 30%. The main reasons for ICU bed closure were the unavailability of ICU nurses (44%) and the co-existing unavailability of nurses and physicians (19%). On average, the nurse/patient ratio was 1:2.5 in the morning, 1:2.6 in the afternoon, and 1:3.1 in the night shift. CONCLUSIONS: ICU bed closure regularly occurs in Germany. The underlying main reason has been identified to be the unavailability of ICU nursing staff. This is suggested to directly interfere with emergency care. For this reason, an action plan is urgently needed. PMID- 29987339 TI - [Role of stereotactic body radiation therapy for unresected pancreatic cancer]. PMID- 29987338 TI - Cost analysis of a wait-and-see strategy after radiochemotherapy in distal rectal cancer. AB - BACKGROUND: Nonoperative management (NOM) of rectal cancer after radiochemotherapy (RtChx) in patients with a clinical complete response is an emerging strategy with the goal to improve quality of life without compromising cure rates. However close monitoring with both magnetic resonance imaging (MRI) and rectoscopy is required for the early detection of possible local regrowths. We therefore performed a cost analysis comparing the costs of immediate surgery with the costs for MRI and rectoscopy during surveillance as in the upcoming CAO/ARO/AIO-16 trial. METHODS: MRIs and rectoscopies of patients with a clinical complete response after RtChx over the course of 5 years were simulated and compared with immediate surgery after RtChx. Transition probabilities between health stages (no evidence of disease, local regrowth and salvage surgery, distant failure) were derived from the literature. Costs for ambulatory imaging and endoscopic studies were calculated according to the "Gebuhrenordnung fur Arzte" (GOA), costs for surgery based on the diagnosis-related groups system. Three different scenarios with higher costs for salvage surgery or higher regrowth rates were simulated. RESULTS: A patient without disease recurrence will generate costs for MRI and rectoscopy of 6344 ? over 5 years compared with costs of 14,511 ? for immediate radical surgery. When 25% local regrowths with subsequent salvage surgery were included in the model, the average costs per patient are 8299 ?. In our simulations a NOM strategy was cost-saving compared with immediate surgery in all three scenarios. CONCLUSION: A NOM strategy with an intensive surveillance using MRI and rectoscopy will produce costs that are expected to remain below those of immediate surgery. PMID- 29987340 TI - [Neoadjuvant chemotherapy before radical hysterectomy in cervical cancer patients response is not survival]. PMID- 29987342 TI - Thermoanaerobacter species differ in their potential to reduce organic acids to their corresponding alcohols. AB - The reduction of organic acids to their corresponding alcohols has been shown for some bacterial species within the Firmicutes super-phylum and a genetically modified strain of the hyperthermophilic archaeon Pyrococcus furiosus. In the latter strain, an aldehyde:ferredoxin oxidoreductase (AOR) catalyzed the reduction of a variety of organic acids to their corresponding aldehydes, as shown by the deletion of the corresponding aor gene. Here, we found that the genomes of a few thermophilic bacterial species within the genus Thermoanaerobacter which have been described to efficiently ferment sugars to ethanol harbor a copy of aor, while others do not. Specific AOR activity was only found in strains with aor, and the gene was highly expressed in Thermoanaerobacter sp. strain X514. The reduction of a variety of organic acids was observed for several Thermoanaerobacter sp.; however, strains with aor reduced, e.g., isobutyrate at much higher rates of up to 5.1 mM h-1 g-1. Organic acid reduction also led to increased growth rates in Thermoanaerobacter sp. strain X514 and in Thermoanaerobacter pseudethanolicus. Organic acid activation may proceed via acyl-CoA with subsequent NADH-dependent reduction by an aldehyde dehydrogenase (ALDH), or via direct reduction by AOR. Cell-free extracts of Thermoanaerobacter sp. strain X514 exhibited both enzyme activities at comparable rates. Therefore, the biochemistry of organic acid reduction to alcohols in Thermoanaerobacter sp. remains to be elucidated; however, relatively high specific activities and the correlation of AOR specific activities with alcohol production rates suggest a role for AOR. PMID- 29987341 TI - Pattern of dysphagia after swallowing-sparing intensity-modulated radiotherapy (IMRT) of head and neck cancers: results of a mono-institutional prospective study. AB - BACKGROUND AND PURPOSE: A prospective instrumental assessment of late dysphagia using swallowing organs at risk (SWOARs)-sparing IMRT for nasopharyngeal and oropharyngeal cancers. MATERIALS AND METHODS: Objective instrumental assessment included fiberoptic endoscopic evaluation of swallowing (FEES) and videofluoroscopy (VFS) at baseline, and at 6 and 12 months after treatment. FEES assessed the pharyngeal residue according to the Farneti pooling score (P-score) as follows: 4-5 no dysphagia; 6-7 mild dysphagia; 8-9 moderate dysphagia; 10-11 severe dysphagia. Three different consistencies were tested for the P-score: liquid (L), semisolid (SS), and solid (S). VFS assessed penetration-aspiration according to the Penetration-Aspiration Scale (PAS) and two different consistencies of the bolus were tested: thin liquid barium (L) and paste barium (S). RESULTS: 38 patients were evaluable. There was a significant worsening of the P-score at 6 months both for SS (p = 0.015) and S (p < 0.001), which persisted only for S at 12 months (p < 0.0001). Similarly, there was a significant worsening of the PAS score at 6 and 12 months (p = 0.065 and 0.039, respectively) for the S bolus. Overall, 3-7 and 10-14% aspiration after L and S was observed, respectively. CONCLUSIONS: Promising results using a SWOARs-sparing IMRT technique are reported. Therefore, treatment plans should be optimized for reducing doses to these structures. PMID- 29987343 TI - Peroxy steroids derived from plant and fungi and their biological activities. AB - Peroxides represent a large and interesting group of biologically active natural compounds. All these metabolites contain a peroxide group (R-O-O-R). This review describes studies of more than 60 peroxides isolated from plants and fungi. Most of the plant peroxy steroids exhibit high antiprotozoal (Plasmodium) activity with a confidence of up to 95%, while steroids harvested from fungi show more antineoplastic activity with a confidence of up to 94%. In addition, more than 20 different activities of both groups of peroxides with a probability of 78 to 90% have also been predicted using computer program PASS. PMID- 29987344 TI - Correction to: Compressive loading of the murine tibia reveals site-specific micro-scale differences in adaptation and maturation rates of bone. AB - This article was originally published under a CC BY-NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly. PMID- 29987345 TI - Anatomical outcomes 1 year after pelvic organ prolapse surgery in patients with and without a uterus at a high risk of recurrence: a randomised controlled trial comparing laparoscopic sacrocolpopexy/cervicopexy and anterior vaginal mesh. AB - INTRODUCTION AND HYPOTHESIS: Few studies have compared the different approaches of mesh surgery in patients with severe pelvic organ prolapse (POP). In addition to laparoscopic sacrocolpopexy/cervicopexy (LSC-Cx), anterior vaginal mesh (AVM) may be an effective approach for correcting anterior vaginal wall associated with apical POP in women with advanced POP. METHODS: A randomised controlled trial (RCT; January 2011 to March 2016) including 120 patients (60/group) with advanced symptomatic POP, with a predominant anterior vaginal wall descent stage III or greater in combination with a stage II or III apical defect (uterus or vaginal vault). Patients underwent four visits: baseline, 3, 6 and12 months after surgery. The main outcome was anatomical success defined as anterior and posterior vaginal wall not descending beyond the hymen and vaginal apex descent no more than one third into the vagina. Secondary variables: PFDI, ICIQ-UI-SF, intraoperative variables, postoperative morbidity and complications. RESULTS: Anatomical success was achieved with LSC-Cx in 79% and with AVM in 76% (NS). No statistically significant differences were found among POP-Q anterior vaginal wall points between groups, whereas better results were obtained with LSC-Cx in posterior vaginal wall points and total vaginal length. Intraoperative outcomes were similar in the two groups, except for operating time (78.05 min LSC-Cx vs 44.28 min AVM). There were no statistically significant differences related to de novo stress urinary incontinence and dyspareunia. Worse results were found in the CRADI-8 in the LSC-Cx group, owing to constipation. Late postoperative complications and reinterventions were similar in the two groups. CONCLUSIONS: No differences were found in the anatomical correction of anterior and apical POP. The LSC-Cx group presented better correction of posterior vaginal wall defects and a longer total vaginal length. PMID- 29987346 TI - Preparation of gold nanoparticles supported on graphene oxide with flagella as the template for nonenzymatic hydrogen peroxide sensing. AB - Gold nanoparticles supported on graphene oxide with flagella as the template were developed as an electrochemical sensor for the detection of hydrogen peroxide (H2O2) in serum. The flagella-Au nanoparticles composite and graphene oxide were dropped onto a glassy carbon electrode (GCE) to form a new H2O2 electrochemical sensor. The structure morphology of the prepared sensor was characterized by transmission electron microscopy (TEM), and the electrocatalytic performance towards H2O2 reduction was evaluated by cyclic voltammetry (CV) and amperometric methods. The response current of the sensor showed a good linear relationship with the concentration of H2O2 in the range of 10-1000 MUM (R2 = 0.9916). The minimum detection limit of 1 MUM was obtained (S/N = 3). Finally, the sensor was applied to the detection of H2O2 in serum, and the recoveries were satisfactory. As the sensor is sensitive, fast, and easy to make, it is expected to be used for rapid detection of H2O2. Graphical abstract ?. PMID- 29987348 TI - ? PMID- 29987347 TI - The Transition of EU Water Policy Towards the Water Framework Directive's Integrated River Basin Management Paradigm. AB - Introduced in 2000 to reform and rationalise water policy and management across the European Union (EU) Member States (MS), the Water Framework Directive (WFD), the EU's flagship legislation on water protection, is widely acknowledged as the embodiment and vessel for the application of the Integrated River Basin Management (IRBM) paradigm. Its ecological objectives, perhaps even more challenging than the prospect of statutory catchment planning itself, were for all EU waters to achieve 'good status' by 2015 (except where exemptions applied) and the prevention of any further deterioration. In support of the upcoming WFD review in 2019, the paper reviews the transition of EU policies that led to the adoption of the WFD, to identify the reasons why the Directive was introduced and what it is trying to deliver, and to place progress with its implementation into context. It further investigates reasons that might have limited the effectiveness of the Directive and contributed to the limited delivery and delays in water quality improvements. Findings reveal that different interpretations on the Directive's objectives and exemptions left unresolved since its negotiation, ambiguity and compromises observed by its Common Implementation Strategy and lack of real support for the policy shift required have all been barriers to the harmonised transposition of the IRBM paradigm, the key to delivering good ecological status. The 2019 WFD review offers a unique opportunity to realign the implementation of the Directive to its initial aspirations and goals. PMID- 29987349 TI - Imaging features of phosphaturic mesenchymal tumors. AB - OBJECTIVE: To examine the CT and MR imaging features of phosphaturic mesenchymal tumors (PMTs). MATERIALS AND METHODS: With IRB approval, our institutional radiology/pathology database was reviewed for pathologically-proven PMTs. CT and MRI examinations were reviewed in consensus noting several imaging features, and if available, comparative molecular imaging tests were analyzed. RESULTS: We identified 39 patients (21 male, 18 females) with 40 PMTs [mean age, 52.9 +/- 14.9 years (range, 14-78)], including 20 bone and 20 soft tissue lesions. Mean maximal lesion diameter was 3.4 +/- 2.0 cm (range, 1.1-9.8). 12/18 primary bone lesions (66.6%) were osteolytic and 15/20 (75.0%) had a narrow zone of transition. Internal matrix was present in 18/32 (56.3%) lesions. PMTs were most commonly T1 isointense (31/37, 83.8%), T2 hyperintense (14/36, 38.9%), and solidly enhancing (21/30, 70.0%). The majority (32/36, 88.9%) contained areas of dark T2 signal. 8/9 PMTs were positive by 99mTc-sestamibi scintigraphy, 2/4 by 111In-pentetreotide scintigraphy, 2/2 by 68Ga-DOTATATE PET/CT and 11/13 by 18F FDG PET/CT. On FDG PET/CT, the mean SUVmax was 4.1 +/- 2.5 (range, 1.5-10.8). CONCLUSIONS: Osseous PMTs are commonly osteolytic with a narrow zone of transition. Both bone and soft tissue PMTs often contain matrix and areas of dark T2 signal on MRI, independent of the presence of matrix. However, PMTs may mimic other bone and soft tissue neoplasms, including fibrous dysplasia, tenosynovial giant cell tumor, and even atypical lipomatous tumor. As such, clinical presentation and laboratory correlation are critical to PMT recognition and accurate diagnosis. PMID- 29987350 TI - Haplo-identical allografting with post-transplant cyclophosphamide in high-risk patients. AB - Haplo-identical transplants (Haplo-Tx) are an important alternative for patients with hematological malignancies who lack a HLA-identical donor. Seventy-one T replete Haplo-Tx were performed in 70 high-risk patients at our center; 22/70 (31%) patients with refractory/relapsed leukemia received sequential salvage therapy (SeqTh) with high-dose chemotherapy followed by Haplo-Tx during the chemotherapy-induced neutropenia. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (days + 3 and + 4) with tacrolimus and mycophenolic acid. After a median follow-up of 29.2 months, 3-year overall survival (OS) and event-free survival (EFS) were 43.8 and 40.2%, while 3-year cumulative incidences (CIs) of non-relapse mortality (NRM) and relapse (RI) were 27 and 33%. Day 100 and day 400 CI of grade III-IV acute and moderate-severe chronic GVHD were 11 and 15%. Three-year RI was significantly lower in patients in complete remission (CR) versus those not in CR at the time of transplant (21.5 vs. 48%, p = 0.009) and in patients who received PBSC as compared to BM (22 vs. 45%, p = 0.009). In patients treated with SeqTh, 3-year OS was 19%, while 3-year RI and NRM were 52 and 28% at a median follow-up of 50 months. Overall, Haplo-Tx was feasible in heavily pretreated high-risk patients without a suitable HLA identical donor. PMID- 29987351 TI - A case of reversible cerebral vasoconstriction syndrome developing during treatment of adult aplastic anemia. PMID- 29987352 TI - Potatoes and risk of chronic disease: a systematic review and dose-response meta analysis. AB - PURPOSE: We aimed to synthesize the evidence on the relation between different types of potato consumption with risk of all-cause mortality, coronary heart disease (CHD), stroke, type 2 diabetes (T2D), colorectal cancer (CRC), and hypertension. METHODS: Systematic searches until May 2018 were conducted in PubMed, Scopus, and Web of Science. Random effects meta-analyses comparing extreme categories, linear and non-linear dose-response analyses were conducted. RESULTS: Twenty-eight reports were identified. Only total potato consumption was available for some endpoints which showed no associations with all-cause mortality (RR: 0.88, 95% CI 0.69-1.12), CHD (RR: 1.03, 95% CI 0.96-1.09), stroke (RR: 0.98, 95% CI 0.93-1.03), and CRC (RR: 1.05, 95% CI 0.92-1.20) per one daily/serving (150 g/day) increase. Consumption of one daily serving of boiled/baked/mashed-potatoes was not associated with risk of hypertension (RR: 1.08, 95% CI 0.96-1.21), but slightly with the risk of T2D (RR: 1.09, 95% 1.01 1.18). Positive associations for the risk of T2D (RR: 1.66, 95% CI 1.43-1.94) and hypertension (RR: 1.37, 95% CI 1.15-1.63) were observed for each 150 g/day increase in French-fries consumption. The quality of evidence was rated mostly low (moderate quality of evidence for the risk-associations of French-fries). CONCLUSION: Total potato consumption is not related to risk for many chronic diseases but could pose a small increase in risk for T2D if consumed boiled. A clear risk relation was found between French-fries consumption and risk of T2D and hypertension. For several outcomes, the impact of different preparation procedures could not be assessed. PMID- 29987353 TI - [A patient who lost the sense of hearing and sight]. PMID- 29987354 TI - Influence of a self-regulated cognitive dual task on time to failure and complexity of submaximal isometric force control. AB - PURPOSE: To determine the effects of performing a self-regulated cognitive dual task on time to failure and neuromuscular force control during submaximal isometric contractions. METHODS: Fifteen young sedentary males performed isometric contractions at 50% of each individual's maximal voluntary contraction (MVC) under single-task (without cognitive load) and dual-task (with self regulated mathematical task) conditions. Force signal complexity and biceps brachialis muscle activity were determined at the start, middle, and end of each trial. The slope of the linear regression of median frequency determined the rate of muscle fatigue. Force-task error was established as any amplitude percentage greater or less than 50% MVC. RESULTS: The dual-task condition resulted in a 42 s longer time to failure than the single-task condition. EMG amplitude did not differ between conditions. The rate of muscle fatigue was higher in the single task (- 0.35%/s) than the dual-task (- 0.2%/s) condition. Force signal complexity was, on average, 22% lower in the dual-task condition. The dual-task condition, as compared to the single-task condition, elicited a higher rate of force-task error below (6.37 versus 4.76%) and over (2.11 versus 1.68%) the force threshold. CONCLUSION: The dual-task condition resulted in a longer time to failure and decreased motor output complexity and fatigue rate when performing a submaximal force task. As the dual task also increased the force-task error, we suggest cognitive dual tasks as a possible strategy for delaying fatigue in sedentary young males when exerting submaximal isometric force, contributing to neuromuscular training when error in force control can be ignored. PMID- 29987355 TI - Disruption of bone morphogenetic protein type IA receptor in osteoblasts impairs bone quality and bone strength in mice. AB - In recent years, several studies have found that the disruption of type IA receptor of bone morphogenetic proteins (BMPR1A) could increase bone mass. However, whether disruption of BMPR1A could have an effect on bone quality and bone strength is currently unknown. Osteoblast-targeted conditional knockout (cKO) of BMPRIA by crossing 3.2-kb Col1-CreERTM mice with BMPR1A fx +/+ mice was conducted. Then, in vitro and in vivo studies were employed to examine the effect of BMPR1A knockout on bone quality and bone strength. It was found that the ultimate force and stiffness of the femora decreased significantly in cKO mice when compared to control mice. The content of collagen and mineralization level decreased as the structure of the collagen became disorganized. The morphology of osteocytes in cKO mice was abnormal as well. The expression level of osteocalcin, a marker for the terminal differentiation of osteoblasts, decreased in cKO mice. This data indicated that the differentiation of osteoblasts in cKO mice was impaired. Immunohistochemistry examination revealed deregulated expression of dickkopf 1(DKK1) in osteocytes in cKO mice. Adding DKK1 to the culture medium reversed these effects. In conclusion, even though disruption of BMPR1A could increase bone mass, it also impairs bone quality and bone strength. PMID- 29987356 TI - Dependence of the interaction mechanisms between L-serine and O-phospho-L-serine with calcium hydroxyapatite and copper modified hydroxyapatite in relation with the acidity of aqueous medium. AB - Motivated by the role of copper ions in biological processes the aim of this study was to elucidate the impact of copper ions bound to hydroxyapatite on L serine (L-Ser) and O-phospho-L-serine (O-Ph-L-Ser) adsorption at different acidity of aqueous solutions. The adsorption phenomenon was studied by FTIR, UV, and AA spectroscopy, XRD and thermal analysis methods together with the evolved gases analysis taking into consideration the ionic state of the amino acids as well as the apatite surface state, which are tightly correlated with the solution pH. In acidic solution, the main process involves apatite dissolution releasing calcium and copper ions. At pH > 5 the complexation of amino acids with Ca2+ or Cu2+ ions is more important leading also to the release of cations. The ability of copper ions to form water soluble complexes with L-Ser and O-Ph-L-Ser leads to an important loss of these ions, while calcium release is very low at this pH. Therefore, the use of copper ions substituting calcium in the apatite structure to enhance the ability of amino acids adsorption on the apatite surface seems problematic even at pH > 5. PMID- 29987357 TI - Thermal effects of the ThunderbeatTM device on the recurrent laryngeal nerve during thyroid surgery. AB - PURPOSE: To investigate the safety of the ThunderbeatTM (TB) device in thyroid surgery by clarifying its thermal effects on the recurrent laryngeal nerve (RLN). METHODS: We performed thyroidectomy using TB on four female pigs under general anesthesia. TB was applied 0, 1, and 2 mm from the RLN. The effects of incisions made in tissues in the vicinity of the RLN were evaluated by intraoperative neuromonitoring and pathological examination. RESULTS: The value of the neural integrity monitor (NIM) was unchanged at 2 and 1 mm, but there was loss of signal at 0 mm. The differences between 2 and 0 mm were not clear from the pathological findings. CONCLUSIONS: When using the TB device during thyroid surgery, it is recommended that it is visually kept from making any contact with the RLN. PMID- 29987358 TI - Association of qualitative and quantitative imaging features on multiphasic multidetector CT with tumor grade in clear cell renal cell carcinoma. AB - PURPOSE: The purpose of the study was to determine if enhancement features and qualitative imaging features on multiphasic multidetector computed tomography (MDCT) were associated with tumor grade in patients with clear cell renal cell carcinoma (ccRCC). METHODS: In this retrospective, IRB approved, HIPAA-compliant, institutional review board-approved study with waiver of informed consent, 127 consecutive patients with 89 low grade (LG) and 43 high grade (HG) ccRCCs underwent preoperative four-phase MDCT in unenhanced (UN), corticomedullary (CM), nephrographic (NP), and excretory (EX) phases. Previously published quantitative (absolute peak lesion enhancement, absolute peak lesion enhancement relative to normal enhancing renal cortex, 3D whole lesion enhancement and the wash-in/wash out of enhancement within the 3D whole lesion ROI) and qualitative (enhancement pattern; presence of necrosis; pattern of; tumor margin; tumor-parenchymal interface, tumor-parenchymal interaction; intratumoral vascularity; collecting system infiltration; renal vein invasion; and calcification) assessments were obtained for each lesion independently by two fellowship-trained genitourinary radiologists. Comparisons between variables included chi2, ANOVA, and student t test. p values less than 0.05 were considered to be significant. Inter-reader agreement was obtained with the Gwet agreement coefficient (AC1) and standard error (SE) was reported. RESULTS: No significant differences were observed between the LG and HG ccRCC cohorts with respect to absolute peak lesion enhancement and relative lesion enhancement ratio. There was a significant inverse correlation between low and high grade ccRCC and tumor enhancement the NP (71 HU vs. 54 HU, p < 0.001) and EX (52 HU vs. 39 HU, p < 0.001) phases using the 3D whole lesion ROI method. The percent wash-in of 3D enhancement from the UN to the CM phase was also significantly different between LG and HG ccRCCs (352% vs. 255%, p = 0.003). HG lesions showed significantly more calcification, necrosis, collecting system infiltration and ill-defined tumor margins (p < 0.05). Overall agreement between the two readers had a mean AC1 of 0.8172 (SE 0.0235). CONCLUSIONS: Quantitatively, high grade ccRCC had significantly lower whole lesion enhancement in the NP and EX phases on MDCT. Qualitatively, high grade ccRCC were significantly more likely to be associated with calcifications, necrosis, collecting system infiltration, and an ill-defined tumor margin. PMID- 29987359 TI - Correction to: Outcomes after rectosigmoid resection for endometriosis: a systematic literature review. AB - The authors of the published version of this article missed to add the second affiliation of Mostafa Shalaby. The new affiliation is now added and presented correctly in this article. The remainder of the article remains unchanged. PMID- 29987360 TI - Risk factors and clinical courses of concomitant primary sclerosing cholangitis and ulcerative colitis: a Korean multicenter study. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare progressive cholestatic liver disease of unknown causes, but is strongly associated with inflammatory bowel diseases (IBDs), particularly ulcerative colitis (UC). However, studies comparing risk factors and clinical courses of patients with concomitant UC and PSC with those of patients with PSC alone are lacking. METHODS: We retrospectively reviewed patients with PSC diagnosed between 2005 and 2017 in four tertiary hospitals in Korea. We compared the risk factors and outcomes of concomitant UC and PSC (UC-PSC) and those of PSC alone. RESULTS: PSC was diagnosed in 50 patients in four different tertiary hospitals in Korea. Of them, 18 patients (36.0%) had UC-PSC and 32 patients (64.0%) had PSC alone. The median age at PSC diagnosis was younger in the UC-PSC group than that in the PSC alone group (37 vs. 54 years, P = 0.002). In multivariate analysis, older age at PSC diagnosis (P = 0.007; odds ratio [OR], 0.884; 95% confidence interval [CI], 0.808-0.966) and current smoking habit (P = 0.033; OR, 0.026; 95% CI, 0.001 0.748) were determined to be independent factors for reducing the possibility of developing concomitant UC after PSC. Additionally, UC-PSC was shown to be an independent risk factor for the development of colorectal dysplasia (P = 0.044; OR, 10.829; 95% CI, 1.065-110.127). CONCLUSIONS: Our analysis showed that UC-PSC is more likely to be negatively associated with current smoking and older age at the time of PSC diagnosis. Moreover, UC-PSC increased the risk of colorectal dysplasia. PMID- 29987361 TI - Clinical and psychological correlates of soiling in adult patients with functional gastrointestinal disorders. AB - BACKGROUND/AIMS: Fecal soiling (FS) is the staining of underwear without loss of significant amounts of fecal material. It is frequently associated with defecation disorders in children. The aim of this study was to search for psychological and clinical correlates of adult patients with soiling. Clinically, the complaint of staining is confused with that of fecal incontinence (FI) in the mind of both patients and attending physicians. DESIGN: Observational study PATIENTS AND METHOD: We included 1454 consecutive outpatients (71% females). They filled out the Rome III questionnaire for functional gastrointestinal disorders (FGIDs); Beck depression inventory, and state and trait anxiety questionnaires; and Likert scales for constipation, diarrhea, bloating, and abdominal pain. Data were analyzed using ANOVA and logistic regression analysis. RESULTS: Soiling was found in 123 patients (8.5%). They reported similar frequencies of esophageal, gastroduodenal, and abdominal pain as patients without soiling. In contrast, patients with soiling reported higher prevalence of IBS, such as IBS-Diarrhea, Mixed-IBS, functional diarrhea, functional constipation, and levator ani syndrome, and higher Likert scale for diarrhea, bloating, abdominal pain, and softer stools. The multivariable logistic regression analysis shows that patients with soiling have increased odds to report IBS (P = 0.019; OR = 1.958; 95% CI = [1.118-3.431]), functional diarrhea (P = 0.040; OR = 1.901; 95% CI = [1.028 3.513]), and high Diarrhea Likert scale (P < 0.001; OR = 1.215; 95% CI = [1.130 1.306]). No association was found with psychological evaluation. CONCLUSION: In FGID patients, soiling is not associated with psychological disorders and is mainly associated with IBS and functional diarrhea. PMID- 29987362 TI - A126 in the active site and TI167/168 in the TI loop are essential determinants of the substrate specificity of PTEN. AB - PTEN prevents tumor genesis by antagonizing the PI3 kinase/Akt pathway through D3 site phosphatase activity toward PI(3,4)P2 and PI(3,4,5)P3. The structural determinants of this important specificity remain unknown. Interestingly, PTEN shares remarkable homology to voltage-sensitive phosphatases (VSPs) that dephosphorylate D5 and D3 sites of PI(4,5)P2, PI(3,4)P2, and PI(3,4,5)P3. Since the catalytic center of PTEN and VSPs differ markedly only in TI/gating loop and active site motif, we wondered whether these differences explained the variation of their substrate specificity. Therefore, we introduced mutations into PTEN to mimic corresponding sequences of VSPs and studied phosphatase activity in living cells utilizing engineered, voltage switchable PTENCiV, a Ci-VSP/PTEN chimera that retains D3 site activity of the native enzyme. Substrate specificity of this enzyme was analyzed with whole-cell patch clamp in combination with total internal reflection fluorescence microscopy and genetically encoded phosphoinositide sensors. In PTENCiV, mutating TI167/168 in the TI loop into the corresponding ET pair of VSPs induced VSP-like D5 phosphatase activity toward PI(3,4,5)P3, but not toward PI(4,5)P2. Combining TI/ET mutations with an A126G exchange in the active site removed major sequence variations between PTEN and VSPs and resulted in D5 activity toward PI(4,5)P2 and PI(3,4,5)P3 of PTENCiV. This PTEN mutant thus fully reproduced the substrate specificity of native VSPs. Importantly, the same combination of mutations also induced D5 activity toward PI(3,4,5)P3 in native PTEN demonstrating that the same residues determine the substrate specificity of the tumor suppressor in living cells. Reciprocal mutations in VSPs did not alter their substrate specificity, but reduced phosphatase activity. In summary, A126 in the active site and TI167/168 in the TI loop are essential determinants of PTEN's substrate specificity, whereas additional features might contribute to the enzymatic activity of VSPs. PMID- 29987363 TI - Non-potable use of Lisbon underground water: microbiological and hydrochemical data from a 4-year case study. AB - Mitigation of global warming scenarios by the United Nations Economic Commission for Europe (UNECE) water convention requires better water use policies by all management parties. One of Lisbon's municipal contributions to target a sustainable urban water cycle has been to assess the microbial and hydrochemical quality of groundwater. The aim is to clarify the possible existence of contaminations and respective sources, seasonality, and to assess non-drinking alternative uses of those waters. To this respect, five water sources over a 4 year period were monitored for physical, chemical, and microbial parameters (temperature, pH, NO2-, NO3-, NO4-, oxidability, conductivity, total hardness, Escherichia coli, total coliforms, enterococci, and heterotrophic plate count at 22 degrees C and 37 degrees C). The results show mean values of physical and chemical parameters within the WHO and national drinking water guidelines and regulations. However, microbial parameters exceed these limits, showing no seasonality. Microbial contamination may not necessarily imply the uselessness of groundwater for uses other than for drinking. For routine water quality assessment, a selection of a more adequate group of microbiological indicators is necessary, in order to evaluate potential public health risks, regarding the use of the identified water sources for non-potable purposes like irrigation or street cleaning. This approach is being promoted by the UNECE's protocol for water and health, article 6, 2 (i); in accordance with the scope of the UN's sustainable goals. PMID- 29987364 TI - Can sarcopenia be a predictor of prognosis for patients with non-metastatic colorectal cancer? A systematic review and meta-analysis. AB - PURPOSE: We aimed to explore whether sarcopenia diagnosed with the third lumbar vertebra skeletal muscle index (L3 SMI) can be a predictor of prognosis for colorectal cancer (CRC) patients. METHODS: A systematic review and meta-analysis was conducted using PubMed, Embase, and the Web of Science databases. All original comparative studies published in English that were related to sarcopenia versus non-sarcopenia in non-metastatic CRC patients based on postoperative and survival outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. RESULTS: A total of 12 studies including 5337 patients were included in our meta-analysis. In our overall analyses of postoperative outcomes, we indicated that CRC patients with sarcopenia would have longer hospital stays, higher incidence of total postoperative morbidity (OR = 1.70, 95% CI = 1.07-2.70, P < 0.01), mortality (OR = 3.45, 95% CI = 1.69-7.02, P < 0.01), and infection (OR = 2.21, 95% CI = 1.50-3.25, P < 0.01) but not anastomosis leakage or intestinal obstruction when compared to non-sarcopenia patients. Regarding survival outcomes, our results showed that sarcopenia predicted a decreased overall survival (HR = 1.63, 95% CI = 1.24-2.14, P < 0.01), disease-free survival, and cancer-specific survival for non-metastatic CRC patients. Moreover, our subgroup analyses showed similar tendency with our overall analyzed results. CONCLUSIONS: Sarcopenia diagnosed with L3 SMI can be a negative predictor of postoperative and survival outcomes for non-metastatic CRC patients. Prospective studies with a uniform definition of sarcopenia are needed to update our findings. PMID- 29987365 TI - Effects of normoxic and hypoxic exercise training on the bactericidal capacity and subsequent apoptosis of neutrophils in sedentary men. AB - Phagocytosis and oxidative burst are essential mechanisms of innate immunity by which neutrophils eliminate invading pathogens. Afterwards, phagocytic neutrophils are dissipated by facilitating apoptosis to control inflammation. This study investigates how exercise training with or without hypoxic exposure affects the bactericidal activity and subsequent apoptosis of neutrophils following strenuous exercise. A total of 60 healthy, sedentary men were randomly divided into four groups (n = 15 in each group), who were exposed to 21% O2 [normoxic control (NC)] or 15% O2 [hypoxic control (HC)] at rest or were trained at 50% of peak work rate at 21% O2 [normoxic training (NT)] or 15% O2 [hypoxic training (HT)] for 30 min/day, 5 days/week for 4 weeks. Before the intervention, acute strenuous exercise (SE) enhanced the phagocytosis of Escherichia coli (E. coli) by neutrophils and the release of neutrophil oxidant products in response to E. coli, accompanied by increases in the expression of adhesion molecules (CD62L, CD11b, and CD11a), an opsonic receptor (FcgammaIIIBR), and complement receptors (C1qRp and CD5aR) on neutrophils. Subsequently, the SE facilitated caspase-3 activation and phosphatidylserine exposure in E. coli-stimulated neutrophils. Furthermore, 4 weeks of HT promoted the expressions of adhesion molecules and opsonic/complement receptors on neutrophils, and it also augmented the bactericidal and apoptotic activities of neutrophils at rest or after SE. However, NT, HC, and NC did not influence these neutrophil-related immune responses to strenuous exercise. Therefore, we conclude that the HT regimen effectively promotes the bactericidal capacity of neutrophils, and facilitates their subsequent apoptosis both at rest and following SE. PMID- 29987366 TI - Contralateral repeated bout effect after eccentric exercise on muscular activation. AB - PURPOSE: The purpose of this study was to investigate the contralateral and ipsilateral repeated bout effects of eccentric contractions (ECCs) on muscle fiber activation using transverse relaxation time (T2) of magnetic resonance imaging (MRI). METHODS: Eleven men (22.3 +/- 2.9 years) performed two bouts of 30 maximal ECCs of the elbow flexors spaced 2 weeks apart. Initially, all subjects performed 30 ECCs for one arm (ECC1). After 2 weeks, they performed 30 ECCs for both ipsilateral arm (IL-RBE) and contralateral arm (CL-RBE). Measurements were maximal voluntary isometric contraction (MVC) torque, range of motion (ROM), muscle soreness, cross-sectional area (CSA), and T2 at before, immediately after, 1, 2, 3, and 5 days after ECCs. RESULTS: The loss of MVC torque, limited ROM, and developed muscle soreness and CSA were inhibited for IL-RBE and CL-RBE compared with ECC1 (p < 0.05). The acute T2, which is an indicator of the activation of muscle fibers, was longer for IL-RBE and CL-RBE than ECC1 (p < 0.05). Otherwise, no significant difference between IL-RBE and CL-RBE was observed in other measurements. CONCLUSION: Our results suggest that one of the mechanisms for CL RBE of ECCs is the increase in muscle fiber activation. In addition, the magnitude of protective effect for CL-RBE was similar to the IL-RBE in untrained young men. PMID- 29987368 TI - Brazilin induces FOXO3A-dependent autophagic cell death by disturbing calcium homeostasis in osteosarcoma cells. AB - PURPOSE: Osteosarcoma is a common primary malignant bone tumour, and its cure rate has stagnated over the past 25-30 years. Brazilin, a purified natural product from sappan wood (Caesalpinia sappan L.), has been proved to possess potent anti-cancer effects. In this study, we investigated the anti-cancer effect of brazilin on human osteosarcoma and elucidated the underlying mechanisms. METHODS: We exposed MG-63 cells to different concentrations of brazilin (5, 10 and 20 uM) for 24 h. Western blotting, immunocytofluorescence, luciferase reporter assays, and RT-PCR were used to evaluate whether brazilin activates FOXO family-dependent autophagy. RESULTS: Brazilin increased autophagic flux in the human osteosarcoma cell line MG-63, as evidenced by the upregulation of LC3-II and the downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blockade of autophagy decreased brazilin-induced cell death, indicating that brazilin triggered autophagic cell death in MG-63 cells. Specifically, brazilin induced FOXO3A(Ser7) phosphorylation, activated FOXO3A nuclear translocation and increased FOXO3A reporter activity, which contributed to the expression of autophagy-related genes and subsequently initiated autophagic cell death in MG-63 cells. Importantly, the increased expression and nuclear translocation of FOXO3A were tightly related to the disturbance of calcium homeostasis, which could be prevented by chelating intracellular calcium. CONCLUSIONS: Taken together, these data demonstrate that brazilin induces osteosarcoma cell death by inducing excessive autophagy, which is mediated through the Ca2+-FOXO3A pathway. Our study provides a new anti-tumour mechanism for brazilin treatment in osteosarcoma patients. PMID- 29987367 TI - Overall and differentiated sensory responses to cardiopulmonary exercise test in patients with cystic fibrosis: kinetics and ability to predict peak oxygen uptake. AB - PURPOSE: We evaluated the validity of predicting peak oxygen uptake ([Formula: see text]O2peak) from submaximal ratings of perceived exertion (RPE) during incremental cardiopulmonary exercise test (CPET) in patients with cystic fibrosis (CF) and compared the predictive accuracy between overall and differentiated RPE scores. METHODS: Thirty-five adults with CF (FEV1 = 58 +/- 23%) performed a CPET on cycle ergometer with gas exchange measurements. Leg, chest and overall RPE were collected every minute throughout the test. Linear regressions between [Formula: see text]O2 and RPE <= 15 were extrapolated to maximal theoretical RPE (i.e. RPE18 and RPE19) to predict [Formula: see text]O2peak. Agreements between measured and all predicted [Formula: see text]O2peak were tested using Bland Altman Plots, for the whole group and for subjects presenting significant exercise intolerance (n = 24). RESULTS: Leg, chest and overall RPE increased similarly with exercise intensity. No differences were found between predicted [Formula: see text]O2peak and measured [Formula: see text]O2peak with RPE18 as maximal RPE, for both overall and differentiated RPE (P range 0.94-0.98). Ranges for Pearson correlations and limits of agreements were 0.88-0.91 and 380-461 mL min-1 for the whole group and 0.92-0.94 and 269-365 mL min-1 for subjects with significant exercise intolerance. The greatest association and narrowest limits of agreements were obtained from chest RPE scores. CONCLUSIONS: Submaximal RPE scores obtained during CPET can provide acceptable estimate of [Formula: see text]O2peak in adults with CF, particularly in those having significant exercise intolerance. Future studies should assess whether the prediction can be improved, particularly by encouraging the regular use of RPE scales during physical activities/exercise rehabilitations sessions. PMID- 29987369 TI - A phase I study of panobinostat in pediatric patients with refractory solid tumors, including CNS tumors. AB - PURPOSE: This was an open label, phase I (3 + 3 design), multi-centre study evaluating panobinostat in pediatric patients with refractory solid tumors. METHODS: Primary endpoints were to establish MTD, define and describe associated toxicities, including dose limiting toxicities (DLT) and to characterize its pharmacokinetics (PK). Secondary endpoints included assessing the anti-tumour activity of panobinostat, and its biologic activity, by measuring acetylation of histones in peripheral blood mononuclear cells. RESULTS: Nine patients were enrolled and treated with intravenous panobinostat at a dosing level of 15 mg/m2 which was tolerated. Six were evaluable for adverse events. Two (33%) patients experienced Grade 3-4 thrombocytopenia, 1 (17%) experienced Grade 3 anemia, and 2 (33%) experienced Grade 3 neutropenia. Grade 4 drug related pain occurred in 2 (33%) of the patients studied. Two (33%) patients experienced a Grade 2 QTcF change (0.478 +/- 0.006 ms). One cardiac DLT (T wave changes) was reported. PK values for 15 mg/m2 (n = 9) dosing were: Tmax 0.8 h, Cmax 235.2 ng/mL, AUC0-t 346.8 h ng/mL and t1/2 7.3 h. Panobinostat significantly induced acetylation of histone H3 and H4 at all time points measured when compared to pre-treatment samples (p < 0.05). Pooled quantitative Western blot data confirmed that panobinostat significantly induced acetylation of histone H4 at 6 h (p < 0.01), 24 h (p < 0.01) and 28-70 h (p < 0.01) post dose. CONCLUSION: A significant biological effect of panobinostat, measured by acetylation status of histone H3 and H4, was achieved at a dose of 15 mg/m2. PK data and drug tolerability at 15 mg/m2 was similar to that previously published. PMID- 29987370 TI - Efficacy and safety of liposome-paclitaxel and carboplatin based concurrent chemoradiotherapy for locally advanced lung squamous cell carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and toxicities of liposome-paclitaxel and carboplatin concurrent with radiotherapy for locally advanced lung squamous cell carcinoma (LSCC). METHODS: The clinical data of 38 patients with locally advanced LSCC treated with liposome-paclitaxel based concurrent chemoradiotherapy were collected and reviewed. The overall response, toxicities, progression-free survival and overall survival were analyzed with SPSS software. RESULT: The efficacy of treatment was classified as complete remission in 4 cases (10.5%), partial remission in 22 cases (57.9%) and stable disease in 12 cases (31.6%). The objective response rate was 68.4% (26/38). The most common types of hematological toxicities were anemia (65.7%) and leukopenia (57.9%), but all the events were transient. No paclitaxel-induced allergic reactions occurred during the treatment. The median PFS and OS time were 17.0 and 29.0 months. CONCLUSIONS: Liposome-paclitaxel and carboplatin concurrent with radiotherapy showed a significant antitumor effect to LSCC with manageable toxicities. Further clinical investigation are warranted to evaluate the efficacy of this regimen. PMID- 29987371 TI - Simultaneous voltammetric determination of acetaminophen and dopamine using a glassy carbon electrode modified with copper porphyrin-exfoliated graphene. AB - Graphene nanosheets (GSs) were prepared via liquid-phase non-covalent exfoliation of graphite powder in N,N-dimethylformamide under the assistance of copper(II) meso-tetra(4-carboxyphenyl)porphyrin tetrasodium salt Na4(CuTCPP). A glassy carbon electrode (GCE) was modified with a film of such GSs which, due to the good electrical conductivity of graphene and the electrocatalytic properties of Na4(CuTCPP), is capable of simultaneous determination of acetaminophen (AC) and dopamine (DA). The peak currents, best measured at voltage of 0.2 V (for DA) and 0.4 V (for AC; both vs. SCE), increase linearly in the 0.0024-3.6 MUM and 0.004 7.6 MUM concentration ranges, respectively. The detection limits are 0.8 nM for DA and 0.7 nM for AC. The sensor was successfully applied to the simultaneous determination of AC and DA in pharmaceutical preparations and spiked human serum. The results were in good agreement with those obtained for the same samples by HPLC. Graphical abstract Graphene nanosheets were prepared via a facile liquid phase exfoliation of graphite with the assistance of copper(II) meso-tetra(4 carboxyphenyl)porphyrin tetrasodium salt. A graphene nanosheet-film modified glassy carbon electrode was fabricated to determine acetaminophen and dopamine through a simple and effective strategy. PMID- 29987372 TI - Spodoptera litura-mediated chemical defense is differentially modulated in older and younger systemic leaves of Solanum lycopersicum. AB - MAIN CONCLUSION: Metabolite profiling, biochemical assays, and transcript analysis revealed differential modulation of specific induced defense responses in local, older, and younger systemic leaves in Solanum lycopersicum upon Spodoptera litura herbivory. Plants reconfigure their metabolome upon herbivory to induce production of defense metabolites involved in both direct and indirect defenses against insect herbivores. Herbivory mediated leaf-to-leaf systemic induction pattern of primary and non-volatile secondary metabolites is not well studied in tomato. Here, we show that, in cultivated tomato Solanum lycopersicum herbivory by generalist insect, Spodoptera litura results in differential alteration of primary metabolites, majorly sugars and amino acids and specific secondary metabolites in local, younger, and older systemic leaves. Cluster analysis of 55 metabolites identified by GC-MS showed correlation between local and younger systemic leaves. Re-allocation of primary metabolites like glucose and amino acids from the local to systemic leaf was observed. Secondary metabolites chlorogenic acid, caffeic acid, and catechin were significantly induced during herbivory in systemic leaves. Among specific secondary metabolites, chlorogenic acid and catechin significantly inhibits S. litura larval growth in all stages. Local leaf exhibited increased lignin accumulation upon herbivory. Differential alteration of induced defense responses like reactive oxygen species, polyphenol oxidase activity, proteinase inhibitor, cell wall metabolites, and lignin accumulation was observed in systemic leaves. The metabolite alteration also resulted in increased defense in systemic leaves. Thus, comparative analysis of metabolites in local and systemic leaves of tomato revealed a constant re-allocation of primary metabolites to systemic leaves and differential induction of secondary metabolites and induced defenses upon herbivory. PMID- 29987373 TI - Predictors of mortality for preterm infants with intraventricular hemorrhage: a population-based study. AB - PURPOSE: The goal of this longitudinal, population-level study was to examine factors affecting mortality in preterm infants with intraventricular hemorrhage (IVH). METHODS: The study examined patients who were born at 36 weeks estimated gestational age (EGA) or less with a diagnosis of IVH between the years 2005 and 2014 using data from the New York and Nebraska State Inpatient Databases. Potential predictors for mortality were investigated with multivariable survival analysis. RESULTS: The cohort included 7437 preterm infants with IVH. All-cause inpatient mortality occurred in 746 (10.0%). The majority of deaths were in infants born at less than 25 weeks EGA (378 or 50.7%) and with birthweight less than 750 g (459 or 61.5%). Mortality was highest for children with grade IV IVH (306/848 or 36.1%), followed by grades III (203/955 or 21.3%), II (103/1328 or 7.8%), and I (134/4306 or 3.1%). Hydrocephalus was diagnosed within 6 months in 627 (8.4%) patients, with cerebrospinal fluid shunts required in 237 (3.2%). Shunts were eventually revised in 122 (51.5% of shunts), and 43 (18.1%) had infections. Multivariable Cox survival analyses found male sex (HR 1.3 [95% CI 1.1-1.5]), Asian race (HR 1.5 [1.1-2.2]), lower EGA (HR 9.9 [6.3-15.5] for < 25 weeks), higher IVH grade (HR 6.1 [4.9-7.6] for grade IV), gastrostomy (HR 4.0 [2.0-7.7]), tracheostomy (HR 3.5 [1.7-7.1]), and shunt infection (HR 3.2 [1.0 9.9]) to be independently associated with increased mortality risk. CONCLUSIONS: This database is the first of its kind assembled for population-based investigations of long-term neurosurgical outcomes in preterm infants with IVH. PMID- 29987374 TI - Pediatric neurocysticercosis. AB - BACKGROUND: Neurocysticercosis (NCC) is an infestation of the nervous system caused by encysted larvae of Taenia solium. NCC is an important acquired cause of epilepsy and other neurological manifestations especially in endemic areas. NCC in children has pleomorphic manifestations depending on the location, number, viability of the cysts, and host response. Even with advancing knowledge of the disease manifestations, many aspects related to diagnosis and treatment, particularly in children, still remain controversial and pose challenges to clinical practice. There is no gold standard test to diagnose NCC and the management recommendations are still emerging. This review provides an overview of diagnosis of NCC in children and its management with special focus on current challenges and future prospects. DISCUSSION: In developing countries, NCC is important not only because of its frequency but also because of high morbidity and mortality rates associated, especially in cases in which it progresses to increased intracranial pressure. Because of its pleomorphic presentation, NCC should be considered in the differential diagnosis of a number of neurological conditions. Treatment with cysticidal therapy leads to reduction in seizure frequency and a faster resolution of lesions. CONCLUSIONS: We have summarized the current approaches to diagnosis and treatment of NCC, recent advances in understanding the biology of NCC, and how one can take advantage of these new insights to formulate the next generation of clinical trials. PMID- 29987375 TI - International Infant Hydrocephalus Study (IIHS): 5-year health outcome results of a prospective, multicenter comparison of endoscopic third ventriculostomy (ETV) and shunt for infant hydrocephalus. AB - INTRODUCTION: One of the most important unanswered questions in pediatric hydrocephalus is determining whether treatment with endoscopic third ventriculostomy (ETV) versus shunt results in improved health status and quality of life (QOL). To answer this, the International Infant Hydrocephalus Study (IIHS) was started in 2005 as a prospective, multicenter study to compare ETV and shunt in infants (< 24 months old) with symptomatic triventricular hydrocephalus from aqueductal stenosis. Herein, we present the 5-year primary outcome results. METHODS: IIHS utilized a prospective comprehensive cohort design, in which patients received ETV or shunt, based on either randomization or parental preference. For this analysis, we pooled the randomized arm and the parental preference arm, analyzing them together. At 5 years of age, children were assessed with the Health Utilities Index Mark 2 (HUI-2) (primary outcome) and the Hydrocephalus Outcome Questionnaire (HOQ), a measure of QOL. Results were compared in an analysis of covariance, adjusting for baseline variables including age at surgery and baseline development status. RESULTS: From a total of 158 patients who met eligibility criteria, complete 5-year outcomes were available on 78 (19 treated initially with shunt, 61 treated initially with ETV), assessed at a mean age of 62.1 months (SD 6.3). The mean 5-year HUI-2 utility score was 0.90 (SD 0.19) for ETV and 0.94 (SD 0.10) for shunt (p = 0.21). The mean 5-year HOQ overall score was 0.81 (SD 0.15) for ETV and 0.85 (SD 0.12) for shunt (p = 0.42). Similarly, there were no significant differences noted between 5-year HOQ subscores (cognitive, social-emotional, physical) or developmental measures at 1, 2, and 3 years. CONCLUSIONS: This is the first prospective direct comparison of long-term outcomes of ETV and shunt for infant hydrocephalus. These results suggest that overall health status and quality of life in this cohort of infants treated for aqueductal stenosis are high, with no significant difference between those treated initially with ETV or shunt. TRIAL REGISTRATION: NCT00652470. PMID- 29987376 TI - Paul Hoffmann (1884-1962 AD) and Jules Tinel (1879-1952 AD), and their legacy to neuroscience: the Hoffmann-Tinel sign. PMID- 29987377 TI - Custom-made hydroxyapatite for cranial repair in a specific pediatric age group (7-13 years old): a multicenter post-marketing surveillance study. AB - BACKGROUND: CustomBone Service (CBS) is a patient-specific, biocompatible, and osteoconductive device made of porous hydroxyapatite, indicated for cranial reconstruction in adults and children. Adult literature data report a failure rate of about 8%. The aim of this Post-Marketing Surveillance study is to verify the hypothesis that CBS in children aged 7-13 years old shows a failure rate not superior to adults. MATERIALS AND METHODS: Inclusion criteria were age at implantation ranging 7-13 years old, with at least 1 year elapsed from the date of surgery. The degree of satisfaction of surgeons and patients was assessed. RESULTS: Data about 76 implants in 67 patients (M:F = 41:26) were obtained from 28 centers across 7 European countries. The mean age at surgery was 10.03 +/- 1.72 years, with age stratification almost equally distributed. Fifty-nine subjects received one CBS, 7 subjects two and one subject received three CBS. Main etiologies were trauma (60.5%), malformation (11.8%), bone tumor (10.5%), and cerebral tumor (7.9%). Main indications to CBS were decompression (47.4%), autologous bone resorption (18.4%), tumor resection (11.8%), malformation (9.2%), comminuted fracture (5.3%), and other materials rejection (5.3%). Main implantation sites were fronto-parieto-temporal (26.3%), parietal (23.7%), frontal (11.8%), fronto-temporal (10.5%), and parieto-temporal (7.9%). CBS was chosen as first line of treatment in 63.1% of the cases. Mean follow-up was about 36 months. Eleven adverse events (14.5%) were reported in nine devices. Five CBS required explantation (three cases of infection, one fracture, and one mobilization). Failure rate was 6.58%, which is statistically not superior to the explantation rate recorded in adults (two-sided 95%, CI 2.2-14.7%). Satisfaction of surgeons and patients was of about 95%. CONCLUSION: CBS is a safe and effective solution for cranial repair in pediatric patients. In particular, over the age of 7, CBS shows a rate of failure as low as in adults. PMID- 29987378 TI - Anatomical description of the upper tarsal plate for reconstruction. AB - BACKGROUND: Reconstruction of the upper eyelids following traumatic, congenital and tumor surgeries is often difficult owing to a variety of reasons including the influence of the lacrimal system, visual system and aesthetic appearance. In most cases of the reconstruction in the upper eyelid tarsal plate is the main anatomical area that should be protected against the damage. The aim of this study is to investigate the types and the measurements of the tarsal plate of the upper eyelids in Anatolian population. METHODS: Fifty cadaver upper eyelids, tarsal plates were exposed to investigate the location, shape, position and their relationships to the upper eyelid. Their morphometric details such as linear analyses (vertical and horizontal) and ratio analyses were studied. As for the shape of the upper tarsal plate, it was categorized into three distinct types: sickle, trapezoid, and triangular type. RESULTS: The vertical height of the upper tarsal plate was the greatest at the central point 10.6 +/- 1.1 mm, followed by the lateral point (7.81 +/- 1.0 mm), and medial point (6.2 +/- 0.8 mm) medially. The mean medial width of the upper tarsal plate was measured as 37.6 +/- 4.1 mm and the lower width as 38.5 +/- 4.6 mm. The base-central height ratio of the upper tarsal plate was approximately 0.28. For the upper eyelids, the shapes of tarsal plates were observed as sickle (48%), trapezoid (28%) and triangular (24%). Sickle type was the most frequent upper eyelid type. CONCLUSIONS: Considering the shielding function of the upper eyelid, tarsal plate, serves as fibrocartilaginous skeleton of the upper tarsal plate. In successful lid oculoplastic reconstructive surgery, tarsal plate may be restored by evaluating each patient individually to have symmetrical and youthful eyes. Although sickle tarsal plate is the most frequent type, personalized treatment requires measurement and classification. The findings manifest the necessity of oculoplastic surgical treatment peculiar to each individual. LEVEL OF EVIDENCE: I, Randomized controlled trial. PMID- 29987379 TI - Development of a TaqMan probe-based quantitative reverse transcription PCR assay for detection of Getah virus RNA. AB - Getah virus (GETV), a mosquito-borne virus that mainly infects horses and pigs, has emerged and spread in China. We developed a highly specific and reproducible TaqMan probe-based quantitative reverse transcription PCR (RT-qPCR) assay targeting the non-structural protein 1 of GETV, whose detection limit is 25.5 copies/uL, which is 100-fold higher than that of conventional RT-PCR. RT-qPCR was used to detect GETV RNA in mosquito and animal clinical samples, showing that the accuracy of RT-qPCR was higher than that of conventional RT-PCR. The newly developed RT-qPCR assay may be a useful alternative tool for rapid, simple and specific diagnosis of GETV infection. PMID- 29987380 TI - Genome polarity of RNA viruses reflects the different evolutionary pressures shaping codon usage. AB - RNA viruses are classified by their genome polarity and replication strategies. Nucleotide composition and codon usage differ among virus groups, for instance positive-sense RNA (+ssRNA) viruses have higher GC-content than the other RNA virus groups. Codon usage of +ssRNA viruses is closer to humans showing significantly higher codon adaptation index (CAI) than those of negative-sense RNA (-ssRNA), double stranded RNA (dsRNA) and retroviruses. Ambisense viruses have high CAI comparable to that of +ssRNA virus despite their lower GC content, whereas dsRNA viruses have the lowest CAI. This may provide a benefit for +ssRNA viruses as their genomes are used as mRNA. However, analyses for influence of nucleotide composition on codon usage did not show a difference between +ssRNA and -ssRNA viruses. This suggests that genome composition and hence mutational pressure remain the major pressure causing the differences in codon usage among RNA viruses with different genome types. PMID- 29987381 TI - Molecular characterization and detection of a novel vitivirus infecting blackberry. AB - Blackberries exhibiting yellow vein disease symptoms were found to be infected by a new virus, a putative member of the genus Vitivirus. Recombination assessment of several vitiviruses revealed multiple events involving the newly identified virus isolate. Occurrence in areas of high disease pressure was investigated and the population structure was studied using the movement and coat protein genes; both under purifying selection. This information was exploited in the development of a detection protocol for routine screening and Rubus certification programs around the globe. PMID- 29987382 TI - Two-stage partial nitritation-anammox process for high-rate mainstream deammonification. AB - Increasing information supported that achieving high-rate mainstream deammonification through two-stage partial nitritation (PN)-anammox process should be a better option than through single-stage process. However, direct experimental evidence was limited so far. Herein, a two-stage PN-anammox process was successfully operated for nitrogen removal from low-strength wastewater in winter. Influent shift from synthetic wastewater to actual anaerobically pretreated sewage had little impact on the process performance. Promising nitrogen removal rates (NRRs) of 0.28-0.07 kg N m-3 d-1 with an average effluent concentration of 5.2 mg TN L-1 were achieved for the anaerobically pretreated sewage treatment at 15-7 degrees C. Moreover, nearly all the degradable COD in the pretreated sewage was steadily removed in the first-stage PN reactor, despite the varied influent COD concentrations of 22-78 mg L-1 and the operating temperature decrease, suggesting the positive role of the first-stage PN in protecting anammox bacteria. The low temperature seemingly was the only deterministic factor inhibiting the anammox activity, and hence made the anammox reaction to be the rate-limiting step for nitrogen removal in the two-stage PN anammox process. Unexpectedly, nearly all the anammox bacteria remained active at low temperatures with the process actual anammox activity reached about 76-85% of their maximum potential, implying that higher NRRs would be easily realized through bioaugmentation or enrichment of anammox bacteria. Overall, the present investigation provides direct and valuable information for implementing the two stage PN-anammox process to treat mainstream municipal wastewater. A control strategy was also proposed to optimize the operation of the two-stage mainstream deammonification process. PMID- 29987383 TI - Improving the fermentation performance of Clostridium acetobutylicum ATCC 824 by strengthening the VB1 biosynthesis pathway. AB - Vitamin B1 (VB1) is an essential coenzyme for carbohydrate metabolism and involved in energy generation in most organisms. In this study, we found that insufficient biosynthesis of VB1 in Clostridium acetobutylicum ATCC 824 is a major limiting factor for efficient acetone-butanol-ethanol (ABE) fermentation. In order to improve the fermentation performance of C. acetobutylicum ATCC 824, the VB1 biosynthesis pathway was strengthened by overexpressing the thiC, thiG, and thiE genes. The engineered strain 824(thiCGE) showed enhanced VB1 and energy synthesis, resulting in better growth, faster sugar consumption, higher solvents production, and lower acids formation than the wild-type strain in both VB1 free and normal P2 medium (1 mg/L). Compared with the wild-type strain, 824(thiCGE) produced 13.0 +/- 0.1% or 12.7 +/- 1.2% more butanol in VB1 free P2 medium when glucose or xylose was used as the substrate, respectively. When mixed sugar (glucose:xylose = 2:1) was used as the substrate in VB1 free P2 medium, the xylose consumption rate and butanol titer of 824(thiCGE) were 45.8 +/- 1.9% and 20.4 +/- 0.3% higher than those of the wild-type strain. All these results demonstrated that this metabolic engineering strategy could provide a new and effective way to improve the cellular performance of solventogenic clostridia. In addition, it may have some potential application value in ABE fermentation using simple medium and/or lignocellulosic biomass. PMID- 29987384 TI - Limited carbon source retards inorganic arsenic release during roxarsone degradation in Shewanella oneidensis microbial fuel cells. AB - Directly relevant to the toxicity, mobility, and fate of arsenic, the biotransformation of inorganic and organic arsenicals has been extensively concerned, including roxarsone, a widely applied organoarsenical feed additive in poultry industry. Yet, little is known about the transformation details of roxarsone in microbial fuel cells (MFC). In this study, a two-chambered Shewanella oneidensis MR-1 microbial fuel cell was employed to investigate the transformation processes of roxarsone at various carbon source levels. Results show that limited carbon source remarkably inhibited inorganic arsenic release along roxarsone transformation, whereas numerous arsenical species were detected to be released into systems with sufficient carbon source supply, including trivalent and pentavalent inorganic arsenics, monomethylarsonous acid (MMA), and 4-hydroxy-3-aminobenzene arsonic acid (HAPA). Shewanella oneidensis MR-1 was able to cleave the C-As bond of trivalent HAPA yielding inorganic arsenics and MMA, even in the absence of the arsI gene encoding ArsI C-As lyase. We proposed a two step nitro- and pentavalent-arsenate group reduction pathway for the roxarsone bioelectrochemical transformation. In addition, results indicated that the attached cells onto the electrode surface played a key function in the two-step reduction of roxarsone to trivalent HAPA, whereas planktonic cells were most likely responsible for the C-As bond breakage and the following dearylation. With these qualitative and quantitative estimations, it provides new insights into the mechanistic understanding of the roxarsone biotransformation process in microbial fuel cells, which is important for the biogeochemical cycling of arsenic. PMID- 29987385 TI - Biochemical and genetic characterization of fungal proline hydroxylase in echinocandin biosynthesis. AB - An intriguing structural feature of echinocandins is the incorporation of hydroxylated amino acids. Elucidation of the machinery and the mechanism responsible for this modification is critical to generate new echinocandin derivatives with enhanced antifungal activity. In our present study, we biochemically characterized the alpha-ketoglutarate/Fe2+-dependent proline hydroxylase (HtyE) from two Aspergillus species, Aspergillus pachycristatus and Aspergillus aculeatus, in the respective echinocandin B and aculeacin A biosynthetic gene clusters. Our results showed that both Ap- and Aa-HtyE converted L-proline to trans-4- and trans-3-hydroxyproline, but at different ratios. Both enzymes also effectively hydroxylated C-3 of 4R-methyl-proline, L pipecolic acid, and D-proline. Our homology modeling and site-directed mutagenesis studies identified Leu182 of Ap-HtyE as a key residue in determining the regioselectivity of Ap-HtyE. Notably, we found that the efficiency in C-3 hydroxylation of 4R-methyl-proline has no direct correlation with the ratio of trans-4-hydroxylproline to trans-3-hydroxylproline catalyzed by HtyE. Deletion of Ap-htyE abolished A. pachycristatus anti-Candida activity and the production of echinocandin B, demonstrating that HtyE is the enzyme responsible for the hydroxylation of L-proline and 4R-methyl-proline in vivo and is essential for the anti-Candida activity of echinocandin B. Our present study thus sheds light on the biochemical basis for the selective hydroxylation of L-proline and 4R-methyl proline and reveals a new type of biocatalyst with potential for the custom production of hydroxylated proline and pipecolic acid derivatives. PMID- 29987386 TI - 'Between a rock and a hard place': family members' experiences of supporting a relative with bipolar disorder. AB - PURPOSE: Clinical guidelines emphasise the central role of family members in supporting people with bipolar disorder. However, there has been little focus on the challenges family members face in supporting their relative. This qualitative study explored the challenges of providing support to a relative with bipolar disorder, and how family members attempted to meet these challenges. Factors that helped or hindered their efforts were also explored, including experiences of professional support. METHODS: Semi-structured interviews were conducted with 18 family members (partners, parents, adult children, and siblings). Transcripts were analysed using the Framework approach. RESULTS: Participants faced numerous challenges pertaining to the nature of the disorder and specific illness phases, their relative's responses to their attempts to help, and the limitations of support from healthcare professionals. Although participants were resourceful in managing these challenges, they strongly valued professional input. Six themes were identified: 'Not knowing: like being in a minefield', 'It's out of my control: sitting waiting for the next thing to happen', 'Treading on eggshells', 'Picking up on signs', 'Times of crisis: between a rock and a hard place', and 'I have to make my voice heard'. CONCLUSIONS: Family members supporting a relative with bipolar disorder face significant challenges but show considerable resourcefulness in managing them. The findings underline the importance of input from healthcare professionals to help family members effectively support their relative and manage the challenges they face. Professional support should be strengths-based, and tailored to family members' needs. PMID- 29987387 TI - Psychiatric diagnosis and other predictors of experienced and anticipated workplace discrimination and concealment of mental illness among mental health service users in England. AB - PURPOSE: This study aims to examine whether psychiatric diagnosis is associated with likelihoods of experienced and anticipated workplace discrimination and the concealment of psychiatric diagnoses. METHODS: 5924 mental health service users in England were interviewed as part of the Viewpoint survey between 2009 and 2014 using the Discrimination and Stigma Scale. Associations of psychiatric diagnosis with experienced and anticipated work-related discrimination or the concealment of mental illness were examined with the use of logistic regression models. RESULTS: 25.6% of the participants reported experiencing discrimination in at least one work-related domain, contrasting with the 53.7% who anticipated workplace discrimination and the 72.9% who had concealed their mental illness. There was strong evidence that patients with schizophrenia and schizoaffective disorder had a decreased risk of experienced discrimination in keeping a job compared to those with depression, anxiety disorder, bipolar disorder or personality disorder. Furthermore, patients with depression were more likely to report anticipated discrimination in applying for education or training compared to those with schizophrenia and schizoaffective disorder. In addition, patients with depression were more likely to conceal their mental illness compared to those with schizophrenia and schizoaffective disorder and bipolar disorder. CONCLUSION: This study suggests that psychiatric diagnosis is a predictor of experienced and anticipated workplace discrimination and the concealment of mental illness and that more support is needed for employees with common mental disorders and their employers to enable better workplace outcomes for this group. PMID- 29987388 TI - Opportunistic screening for osteoporosis in abdominal computed tomography for Chinese population. AB - : This study assessed the possibility of diagnosing and excluding osteoporosis with routine abdominal CT scans in a Chinese population who underwent both DXA and CT for unrelated reasons. Statistical correlation was made between the HU measured of the spine on CT and various parameters on DXA. Diagnostic cutoff points in terms of HU were established for the diagnosis (<= 136 HU) and exclusion (>= 175 HU) of osteoporosis on sagittal reformatted images. There was excellent positive and negative predictive value for the DXA-defined diagnostic subgroups and were also comparable with previous studies in Caucasian populations. The authors exhort radiologists to report these incidental findings to facilitate early detection and treatment of osteoporosis in unsuspecting patients to prevent fractures and related complications. PURPOSE: The suspicion for osteoporosis can be raised in diagnostic computed tomography of the abdomen performed for other indications. We derived cutoff thresholds for the attenuation value of the lumbar spinal vertebrae (L1-5) in Hounsfield units (HU) in a Chinese patient population to facilitate implementation of opportunistic screening in radiologists. METHODS: We included 109 Chinese patients who concomitantly underwent abdominal CT and dual X-ray absorptiometry (DXA) within 6 months between July 2014 and July 2017 at a university hospital in Hong Kong. Images were retrospectively reviewed on sagittal reformats, and region-of-interest (ROI) markers were placed on the anterior portion of each of the L1-L5 vertebra to measure the HU. The mean values of CT HU were then compared with the bone mineral density (BMD) and T-score obtained by DXA. Receiver operator characteristic (ROC) curves were generated to determine diagnostic cutoff thresholds and their sensitivity and specificity values. RESULTS: The mean CT HU differed significantly (p < 0.01) for the three DXA-defined BMD categories of osteoporosis (97 HU), of osteopenia (135 HU), and of normal individuals (230 HU). There was good correlation between the mean CT HU and BMD and T-score (Pearson coefficient of 0.62 and 0.61, respectively, p < 0.001). The optimal cutoff point for exclusion of osteoporosis or osteopenia was HU >= 175 with negative predictive value as 98.9% and with area under curve (AUC) of ROC curve as 0.97. The optimal cutoff point for diagnosis of osteoporosis was HU <= 136 with positive predictive value as 81.2% and with AUC of ROC curve as 0.86. CONCLUSION: This is the first study on osteoporosis diagnosis with routine CT abdominal scans in Chinese population. The cutoff values were comparable with previous studies in Caucasian populations suggesting generalizability. Radiologists should consider routinely reporting these opportunistic findings to facilitate early detection and treatment of osteoporosis to prevent fractures and related complications. PMID- 29987389 TI - Morphological responses to nitrogen stress deficiency of a new heterotrophic isolated strain of Ebro Delta microbial mats. AB - Microorganisms living in hypersaline microbial mats frequently form consortia under stressful and changing environmental conditions. In this paper, the heterotrophic strain DE2010 from a microalgae consortium (Scenedesmus sp. DE2009) from Ebro Delta microbial mats has been phenotypically and genotypically characterized and identified. In addition, changes in the morphology and biomass of this bacterium in response to nitrogen deficiency stress have been evaluated by correlative light and electron microscopy (CLEM) combining differential interference contrast (DIC) microscopy and transmission electron microscopy (TEM) and scanning electron microscopy (SEM). These isolated bacteria are chemoorganoheterotrophic, gram-negative, and strictly aerobic bacteria that use a variety of amino acids, organic acids, and carbohydrates as carbon and energy sources, and they grow optimally at 27 degrees C in a pH range of 5 to 9 and tolerate salinity from 0 to 700/00 NaCl. The DNA-sequencing analysis of the 16S rRNA and nudC and fixH genes and the metabolic characterization highlight that strain DE2010 corresponds to the species Ochrobactrum anthropi. Cells are rod shaped, 1-3 MUm in length, and 0.5 MUm wide, but under deprived nitrogen conditions, cells are less abundant and become more round, reducing their length and area and, consequently, their biomass. An increase in the number of pleomorphic cells is observed in cultures grown without nitrogen using different optical and electron microscopy techniques. In addition, the amplification of the fixH gene confirms that Ochrobactrum anthropi DE2010 has the capacity to fix nitrogen, overcoming N2-limiting conditions through a nifH-independent mechanism that is still unidentified. PMID- 29987390 TI - Bone marrow-derived versus adipose-derived stem cells in wound healing: value and route of administration. AB - The stem cells with their distinct ability of self-renewal and differentiation are considered an innovation in wound healing. However, there is lack of studies comparing the differential effect of the type and administration route of stem cells in the wound healing context. Thus, the current study has been designed to elucidate the effect of two of the most important stem cell types-the bone marrow derived and adipose-derived stem cells in full thickness wound healing-and to evaluate, in this optimized wound model, the effectiveness of intradermal versus intravenous routes using H&E, Masson's trichrome, and PKH26-stained sections. It also evaluated the immunohistochemical expression of the stem cell-related surface markers-Ki67, CD71, CD146, CD90, and CD163-and also assessed the level of TNFalpha and gene expression of NF-kappaB as two important inflammatory markers. The study revealed that the adipose stem cell groups have shown statistically significant improvement in inflammation, granulation tissue re-organization, and collagen deposition relative to their bone marrow-treated counterparts. The intradermally treated adipose stem cell group, in particular, has demonstrated the most supreme features regarding the expression of the proliferation-related surface markers Ki67 and CD71 as well as in the expression of CD90 in keratinocytes and hair follicle dermal sheaths. The same group has shown the lowest level of TNFalpha and the best outcome in the parameters of neo-epidermal thickness, granulation tissue re-organization, and pattern of collagen deposition. The systemically treated wounds have displayed superior expression of CD146-positive endothelial cells and dermal fibroblasts as well as better expression of CD163+ macrophages. PMID- 29987391 TI - Safety Assessment of Formulation Vehicles Following Intravitreal Administration in Rabbits. AB - PURPOSE: Evaluate 21 formulation vehicles administered to rabbits after intravitreal injection for tolerability and safety. METHODS: Forty-two Dutch Belted rabbits were anesthetized, and the eyes received a single intravitreal injection of the excipient formulation. Clinical signs and ocular irritation responses were recorded twice daily for 7 days and microscopic evaluation of the eyes, optic nerve, and eyelids was completed at 1-week post treatment. RESULTS: Saline (>= 300 mOsm and <= 592 mOsm at pH 7.0 or 300 mOsm at pH 8.0) and 10 formulation excipients; (10% w/v PEG 3350 at pH 7.4, 1% polysorbate 21 at pH 7.4, PVA at pH 7.0, 0.2% polysorbate 80 at pH 7.2, 0.2% Pluronic F108(r) at pH 7.3, 2%, 100 mM sodium sulfate at pH 3.2, 2 mM sodium glycocholate at pH 7.4, and 275 mM D-mannitol pH 7.0 in sterile water, and 100 mM sodium phosphate in combination with 0.9% NaCl 300 mOsm and 0.01% or 0.05% polysorbate 80 at pH 7.4) considered as formulation vehicles for intravitreal injectables, were well-tolerated in rabbits. Clinical signs were transient and microscopic changes were not observed. CONCLUSIONS: Of the 21 formulation vehicles evaluated, 10 formulation vehicles were well-tolerated in rabbits and feasible candidates for future investigations. PMID- 29987392 TI - Diffuse vasospasm after transcortical temporal lobectomy for intractable epilepsy. AB - Cerebral delayed ischemia due to arterial vasospasm is a rare complication following epilepsy surgery. Here we report the third known case and first of diffuse vasospasm. A 48-year-old woman underwent a transcortical anterior left temporal lobectomy. Eleven days later, she had new-onset expressive aphasia with narrowing of the anterior, middle, and posterior cerebral arteries, and increased velocities via transcranial Doppler. She was treated with fluids, nimodipine, and permissive hypertension. At 6 months, her speech was near baseline. Cerebral vasospasm may represent a rare cause of morbidity after anterior temporal lobectomy; a literature review on the subject is presented. PMID- 29987394 TI - Reactivity of pyrazole derivatives with halomethanes: A DFT theoretical study. AB - The N-alkylation reaction of pyrazole derivatives with halomethanes was studied using density functional theory (DFT). The hybrid method B3LYP was employed, along with an ECP basis set such as LANL2DZ for halogen atoms (X = Cl, Br, I) and the 6-311 + G(d,p) basis set for all other atoms. In order to predict the specific site at which the pyrazole derivatives interact with halomethanes, local reactivity descriptors such as the Fukui functions were calculated. Detailed analysis of transition-state energies showed that alkylation occurred at the nitrogen atom N2 in the pyrazole derivatives, in agreement with the chemical reactivity results. The reaction mechanisms were elucidated by performing intrinsic reaction coordinate (IRC) calculations that considered the effects of the solvent and the species of halogen in the halomethane. PMID- 29987393 TI - A magnetic adsorbent grafted with pendant naphthyl polymer brush for enrichment of the nonsteroidal anti-inflammatory drugs indomethacin and diclofenac. AB - Poly(2-naphthyl acrylate) was first grafted onto silica-coated magnetic nanoparticles by surface-initiated atom transfer radical polymerization to prepare a reversed-phase magnetic adsorbent. The resulting polymer brush displays enhanced extraction efficiency by offering active sites on the surfaces of adsorbent. It was applied to the preconcentration of the non-steroidal antiinflammatory drugs (NSAIDs) indomethacin (InDo) and diclofenac (DIC). These drugs interact with the sorbent through hydrophobic and pi-interactions, and via electrostatic attraction. By coupling the magnetic solid-phase extraction with HPLC, a method for analysis of InDo and DIC in the environmental water samples was established. The limits of detection range from 0.62 to 0.64 ng.mL-1, and the relative standard deviations for intra-and inter-day analyses of spiked water samples are <11.9%, and relative recoveries are between 62.1 and 96.7%. Graphical abstract A reversed-phase magnetic adsorbent was prepared by grafting poly(2 naphthyl acrylate) brush on the surface of silica coated magnetic nanoparticles. Due to the two conjugated aromatic rings of the monomer, the polymer brush can effectively extract non-steroidal anti-inflammatory drugs through strong pi- and hydrophobic interactions. PMID- 29987395 TI - Assessment of the Remediation Effect of Nano-hydroxyapatite in Exogenous Pb contaminated Soil Using Toxicity Characteristic Leaching Procedure and Soil Enzyme Activities. AB - Lead (Pb) is one of the most abundant metal soil pollutants. In this research, effects of nano-hydroxyapatite (NHAP) on remediation of Pb-contaminated soil were evaluated by the measure of extractable Pb using toxicity characteristic leaching procedure (TCLP) and soil enzyme activities. Results suggested NHAP significantly decreased the concentrations of extractable Pb, achieving the maximum decrement rate of 75.71%. Activity of urease decreased with increasing Pb concentrations. Moreover, activities of alkaline phosphatase, dehydrogenase, and catalase increased at the lower Pb levels and decreased at the higher Pb levels. NHAP had a positive effect on regulating soil enzymes. Thus, soil enzyme activities, especially dehydrogenase, could be used as biological indicators of Pb pollution and NHAP remediation. Moreover, NHAP could reduce the mobility and bioavailability of Pb, while increasing enzyme activities, thereby lowering the leaching risk and biotoxicity of Pb. PMID- 29987396 TI - Concentrations of Mercury and Other Inorganic Ions in Wet Precipitation Collected from a Mountain Mining Zone and an Urban Area in Central Mexico. AB - We measured and compared mercury (Hg) and other ions in rainwater collected in San Joaquin (mining zone) and Juriquilla (urban area), central Mexico, from 2009 to 2012. A total of 274 rainwater samples were collected and analyzed for pH, electrical conductivity, [Formula: see text] Cl-, [Formula: see text] Na+, K+, Ca2+, Mg2+ and Hg. Mercury concentrations in rainwater varied from 24.21 to 248.89 (x-bar = 86.97 +/- 10.77) ug L- 1 in San Joaquin (mining zone) and 11.26 to 176.91 (x-bar = 81.51 +/- 10.24) ug L- 1 in Juriquilla (urban area). Rainwater sample were collected over periods 1-3 days, depending upon precipitation frequency. Significant correlations (p < 0.05) were found between [Formula: see text] Cl-, [Formula: see text] Na+, K+, Ca2+, Mg2+ and Hg at the San Joaquin site. Significant correlations were obtained between [Formula: see text] Na+, K+, Ca2+, Mg2+ and Hg at the Juriquilla site. In order to determine if there were significant differences among each measured parameter in rainwater collected in San Joaquin and Juriquilla, Kruskal-Wallis test was applied to data. We emphasized that the distribution and concentrations of Hg and the studied ions in rainwater samples were affected by atmospheric dust and local meteorological conditions of wind-speed and direction. PMID- 29987399 TI - The hyperdense crescent sign. PMID- 29987397 TI - Electrochemical dopamine sensor using a nanoporous gold microelectrode: a proof of-concept study for the detection of dopamine release by scanning electrochemical microscopy. AB - Nanoporous gold (NPG) structures were prepared on the surface of a gold microelectrode (Au-MUE) by an anodization-reduction method. Cyclic voltammetry and field emission scanning electron microscopy were used to study the electrochemical properties and the morphology of the nanostructured film. Voltammetry showed an improved sensitivity for dopamine (DA) oxidation at this microelectrode when compared to a bare gold microelectrode, with a peak near 0.2 V (vs. Ag/AgCl) at a scan rate of 0.1 V s-1. This is due to the increased surface area and roughness. Square wave voltammetry shows a response that is linear in the 0.1-10 MUmol L-1 DA concentration range, with a 30 nmol L-1 detection limit and a sensitivity of 1.18 mA (MUmol L-1)-1 cm-2. The sensor is not interfered by ascorbic acid. The reproducibility, repeatability, long-term stability and real sample analysis (spiked urine) were assessed, and acceptable performance was achieved. The "proof-of-concept" detection of dopamine release was demonstrated by using scanning electrochemical microscopy (SECM) with the aim of future applications for single cell analysis. Graphical abstract A reproducible electrochemical approach was proposed to fabricate an NPG-microelectrode for DA detection, with enhanced sensitivity and selectivity. Besides, a proof-of-concept detection of DA release was also demonstrated by using SECM. PMID- 29987400 TI - Target sign: appendicitis. PMID- 29987398 TI - A Multiscale Physiologically-Based Pharmacokinetic Model for Doxorubicin to Explore its Mechanisms of Cytotoxicity and Cardiotoxicity in Human Physiological Contexts. AB - PURPOSE: The mechanisms underlying doxorubicin cytotoxicity and cardiotoxicity were broadly explored but remain incompletely understood. A multiscale physiologically-based pharmacokinetic (PBPK) model was developed to assess doxorubicin dispositions at levels of system, tissue interstitial, cell, and cellular organelles. This model was adopted to explore the mechanisms-of action/toxicity of doxorubicin in humans. METHODS: The PBPK model was developed by analyzing data from mice and the model was verified by scaling up to predict doxorubicin multiscale dispositions in rats and humans. The multiscale dispositions of doxorubicin in human heart and tumors were explicitly simulated to elucidate the potential mechanisms of its cytotoxicity and cardiotoxicity. RESULTS: The developed PBPK model was able to adequately describe doxorubicin dispositions in mice, rats and humans. In humans, prolonged infusion, a dosing regimen with less cardiotoxicity, was predicted with substantially reduced free doxorubicin concentrations at human heart interstitium, which were lower than the concentrations associated with oxidative stress. However, prolonged infusion did not reduce doxorubicin-DNA adduct at tumor nucleus, consistent with clinical observations that prolonged infusion did not compromise anti-tumor effect, indicating that one primary anti-tumor mechanism was DNA torsion. CONCLUSIONS: A multiscale PBPK model for doxorubicin was developed and further applied to explore its cytotoxic and cardiotoxic mechanisms. PMID- 29987401 TI - Imaging strategy in recurrent ovarian cancer: a practical review. AB - Ovarian cancer is one of the most aggressive gynaecologic malignancies in women worldwide. The lack of proper screening programs and the characteristic abdominal spreading with minimal clinical symptoms give rise of its high lethality. Most patients show advanced disease at diagnosis and have a poor prognosis. The surveillance of ovarian cancer patients after initial treatment is a challenging question in clinical practice and there is no consensus in literature about the most appropriate follow-up strategy for these women. The role of Imaging has become increasingly important, allowing to properly monitor patients, distinguishing the different relapse patterns, thus guiding the correct management and therapy. In this review, we report and analyze the scientific evidence about the role of the different imaging modalities now available in the follow-up strategy and management of Epithelial Ovarian Cancer patients with recurrent disease. PMID- 29987402 TI - Hemobilia after CT-guided radiofrequency ablation of liver tumors: frequency, risk factors, and clinical significance. AB - PURPOSE: The purpose of the study is to evaluate the frequency, risk factors, and clinical significance of hemobilia after percutaneous computed tomography (CT) guided radiofrequency ablation (RFA) of liver tumors. MATERIALS AND METHODS: From January 2013 to September 2016, 195 patients received 267 sessions of CT-guided RFA for liver tumors at our institution. The CT images during and immediately after the RFA were retrospectively reviewed. The frequency of hemobilia development and clinical outcome of patients with hemobilia were studied. Risk factors were identified by comparison between the hemobilia and non-hemobilia groups using univariate and multivariate analysis. The clinical courses of patients with hemobilia were also reviewed. RESULTS: The frequency of CT detected hemobilia after RFA was 8.2% (22/267). The majority of the clinical courses were self-limited. Univariate analysis showed that the tumor numbers (p = 0.015), the central type puncture track (p < 0.001), the length of the puncture track (p = 0.033), and the platelet count (p = 0.026) were significantly associated with the development of hemobilia. Multivariate analysis demonstrated that the central type puncture track (p < 0.024) and the platelet count (p = 0.023) were significant independent risk factors. CONCLUSION: Detection of hemobilia on CT images immediately after percutaneous RFA for liver tumors was not rare. Low platelet count and central type puncture track are independent risk factors. In most cases, hemobilia presented as a minor complication with favorable prognosis. PMID- 29987403 TI - Liver involvement in hereditary hemorrhagic telangiectasia. AB - Liver vascular malformations (VMs) in hereditary hemorrhagic telangiectasia (HHT) are typically diffuse and can evolve from small telangiectasias to large arteriovenous malformations, with various stages of severity. Doppler US is the ideal first-line investigation for the assessment of liver VMs in HHT due to its safety, tolerability, low costs, and accuracy for the detection of liver VMs. The caliber, course, and flow characteristics in the hepatic artery, portal vein, and hepatic vein as determined by Doppler US, together with parenchymal abnormalities, support the diagnosis of liver VMs in HHT and their severity staging. When Doppler US expertise is lacking or an assessment of HHT patients with symptoms/signs suggestive of complicated liver VMs is required, particularly if OLT is considered, multiphase CT or MRI is suitable to investigate symptomatic liver VMs. Liver biopsy is neither necessary for the diagnosis of hepatic VMs related to HHT nor should be considered in HHT patients with liver mass/es suggestive of focal nodular hyperplasia. PMID- 29987404 TI - A 2-year field trial reveals no significant effects of GM high-methionine soybean on the rhizosphere bacterial communities. AB - Genetically modified (GM) crops have brought various economic benefits but may also have adversely affected soil microorganisms. To examine whether transgenic high-methionine soybean ZD91 alters the bacterial community structure in the rhizosphere, we performed a 2-year follow-up study using the transgenic high methionine soybean cultivar ZD91 and wild type cultivar ZD. The community composition and the relative abundance of bacteria in rhizosphere soil were determined by sequencing of the 16S rRNA amplicon. Our results indicated that transgenic soybean ZD91 had no significantly effects on rhizosphere bacterial communities. Instead, the plant growth stage and year appeared to have a stronger effect on bacterial communities. Our findings therefore provided reliable scientific evidence for potential commercial cultivation of cultivar ZD91. PMID- 29987405 TI - Inflammation: a highly conserved, Janus-like phenomenon-a gastroenterologist' perspective. AB - Inflammation is the result of the loss of host's resilience towards the surrounding world. At gross tissue level, inflammation coincides with fluid leakage from vessels, swelling, and blood stasis and extravasation of mononuclear/macrophage cells. Biochemically, these events lead to anoxia and dramatic changes: interruption of the mitochondrial oxidative phosphorylation, influx of the M1 macrophage subset, which live on anaerobic glycolysis. Fall of ATP then leads to energy shortage and debt. In their chronic forms, these phenomena are now known to mark a number of degenerative disorders that have invaded the Western World since the last century: Parkinson's disease, Alzheimer's syndromes, rheumatic diseases, metabolic diseases. Intriguingly, these affections seem to derive from the gut, along two possible pathways. A sort of ascending loss of function caused by accumulation of (and hyperreactivity to) proteins released to restrain spread of enteric viruses: the alpha-synucleins, now increasingly spotted in relation to Parkinson's pathogenesis. The second pathway would entail the intellectual decline perhaps brought about by large use of food containing the proteins of red processed meat. The bacterium Bilophila wadsworthia, thriving in this meat, can erode the mucus layer on colon surfaces, allowing further bacterial flora to approach lining cells, so upgrading the alarm state. We discuss two strategies to prevent such instability from ending up to full-blown inflammatory bowel disease: physical exercise and systematic switch to fibre-containing diets. PMID- 29987407 TI - Enzymatic removal of protein fouling from self-assembled cellulosic nanofilms: experimental and modeling studies. AB - Protein fouling is a serious problem in many food, pharmaceutical and household industries. In this work, the removal of rubisco protein fouling from cellulosic surfaces using a protease (subtilisin A) has been investigated experimentally and mathematically. The cellulosic surfaces were prepared using self-assembled monolayers (SAMs) on a surface plasmon resonance biosensor (chip) surface after conjugating cellulose to alpha-lipoic acid. Rubisco adsorption on the prepared cellulosic SAMs was found to be irreversible, leading to the creation of a tough protein fouling. The heterogeneous enzymatic cleansing of such tough fouling involves enzyme transfer to the surface and the subsequent removal of the rubisco via protease activity. In this work, these two processes were decoupled, allowing enzyme transfer and enzymatic surface reaction to be parameterized separately. Mathematical modeling of the enzymatic cleaning of protein fouling from cellulosic SAMs revealed that enzymatic mobility at the interface is an important factor. The approach presented in this work might be useful in designing better protein fouling-resistant surfaces. It could also be used to guide efforts to screen and gauge the cleaning performance of detergent-enzyme formulations. PMID- 29987406 TI - Manipulating the tumor microenvironment by adoptive cell transfer of CAR T-cells. AB - T-cells expressing synthetic chimeric antigen receptors (CARs) have revolutionized immuno-oncology and highlighted the use of adoptive cell transfer, for the treatment of cancer. The phenomenal clinical success obtained in the treatment of hematological malignancies with CAR T-cells has not been reproduced in the treatment of solid tumors, mainly due to the suppressive and hostile tumor microenvironment (TME). This review will address the immunosuppressive features of the TME, which include the stroma, cytokine and chemokine milieu, suppressive regulatory cells and hypoxic conditions, which can all pose formidable barriers for the effective anti-tumor function of CAR T-cells. Some of the novel next generation CARs that have been developed and tested against the TME, will be discussed, to highlight the status of current research in CAR T-cell therapy for solid tumors. PMID- 29987408 TI - Genetic ablation of pannexin1 counteracts liver fibrosis in a chemical, but not in a surgical mouse model. AB - Liver fibrosis is the final common pathway for almost all causes of chronic liver injury. This chronic disease is characterized by excessive deposition of extracellular matrix components mainly due to transdifferentiation of quiescent hepatic stellate cell into myofibroblasts-like cells, which in turn is driven by cell death and inflammation. In the last few years, paracrine signaling through pannexin1 channels has emerged as a key player in the latter processes. The current study was set up to investigate the role of pannexin1 signaling in liver fibrosis. Wild-type and whole body pannexin1 knock-out mice were treated with carbon tetrachloride or subjected to bile duct ligation. Evaluation of the effects of pannexin1 deletion was based on a number of clinically relevant read outs, including markers of liver damage, histopathological analysis, oxidative stress, inflammation and regenerative capacity. In parallel, to elucidate the molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. While pannexin1 knock-out mice treated with carbon tetrachloride displayed reduced collagen content, hepatic stellate cell activation, inflammation and hepatic regeneration, bile duct ligated counterparts showed increased hepatocellular injury and antioxidant enzyme activity with a predominant immune response. Gene expression profiling revealed a downregulation of fibrotic and immune responses in pannexin1 knock-out mice treated with carbon tetrachloride, whereas bile duct ligated pannexin1-deficient animals showed a pronounced inflammatory profile. This study shows for the first time an etiology dependent role for pannexin1 signaling in experimental liver fibrosis. PMID- 29987409 TI - Stem cells are the most sensitive screening tool to identify toxicity of GATA4 targeted novel small-molecule compounds. AB - Safety assessment of drug candidates in numerous in vitro and experimental animal models is expensive, time consuming and animal intensive. More thorough toxicity profiling already in the early drug discovery projects using human cell models, which more closely resemble the physiological cell types, would help to decrease drug development costs. In this study we aimed to compare different cardiac and stem cell models for in vitro toxicity testing and to elucidate structure toxicity relationships of novel compounds targeting the cardiac transcription factor GATA4. By screening the effects of eight compounds at concentrations ranging from 10 nM up to 30 uM on the viability of eight different cell types, we identified significant cell type- and structure-dependent toxicity profiles. We further characterized two compounds in more detail using high-content analysis. The results highlight the importance of cell type selection for toxicity screening and indicate that stem cells represent the most sensitive screening model, which can detect toxicity that may otherwise remain unnoticed. Furthermore, our structure-toxicity analysis reveals a characteristic dihedral angle in the GATA4-targeted compounds that causes stem cell toxicity and thus helps to direct further drug development efforts towards non-toxic derivatives. PMID- 29987410 TI - The role of SerpinB2 in human bronchial epithelial cells responses to particulate matter exposure. AB - Exposure to particulate matter (PM) has been related to the onset of adverse health effects including lung cancer, but the underlying molecular mechanisms are still under investigation. Epithelial-to-mesenchymal transition (EMT) is regarded as a crucial step in cancer progression. In a previous study, we reported EMT related responses in the human bronchial epithelial cell line HBEC3-KT, exposed to Milan airborne winter PM2.5. We also found a strong modulation of SERPINB2, encoding for the PAI-2 protein and previously suggested to play an important role in cancer. Here we investigate the role of SERPINB2/PAI-2 in the regulation of EMT-related effects induced by PM exposure in HBEC3-KT. PM exposure (up to 10 ug/cm2) increased SERPINB2 expression, reduced cell migration and induced morphological alterations in HBEC3-KT. Changes in actin structure and cadherin-1 relocalization were observed in PM-exposed samples. Knockdown of SERPINB2 by siRNA down-regulated the CDH1 gene expression, as well as PAI-2 and cadherin-1 protein expression. SERPINB2 knockdown also increased cell migration rate, and counteracted the PM-induced reduction of cell migration and alteration of cell morphology. SERPINB2 was found to be greatly down-regulated in a HBEC2-KT transformed cell line, supporting the importance of this gene in the regulation of EMT. In conclusion, here we show that PAI-2 regulates CDH1 gene/cadherin-1 protein expression in bronchial HBEC3-KT cells, and this mechanism might be involved in the regulation of cell migration. SERPINB2 down-regulation should be considered part of EMT, and the over-expression of SERPINB2 in PM-exposed samples might be interpreted as an initial protective mechanism. PMID- 29987411 TI - Identification of a novel piscine Cryptosporidium genotype and Cryptosporidium parvum in cultured rainbow trout (Oncorhynchus mykiss). AB - This study reports for the first time the presence and molecular characterization of Cryptosporidium in farmed rainbow trout (Oncorhynchus mykiss Walbaum, 1792). A total of 360 fish, with no apparent clinical signs of disease, were collected and classified into groups according to their size. Cryptosporidium oocysts were detected by immunofluorescence microscopy in 33 specimens (9.2%), which were located in pyloric caeca samples (42.4%), intestinal scrapings (39.4%), or at both locations (18.2%). In the smallest (youngest) fish group, a higher percentage of positive samples were detected in the pyloric caeca relative to the intestinal location (58.8 vs. 17.6%; P = 0.01), including a cluster with more than 10 oocysts observed in the pyloric caeca of one specimen. PCR amplification and sequencing of fragments of SSU-rDNA and hsp70 genes identified a novel Cryptosporidium piscine genotype (genotype 9) in two specimens and Cryptosporidium parvum in seven fish, including the specimen in which the oocyst cluster was observed. Moreover, Cryptosporidium oocysts were detected in farm water samples (41.7 and 16.7% from influent and effluent, respectively). Although Giardia was not found in gastrointestinal samples, Giardia cysts were observed in 50.0 and 33.3% of the influent and effluent water samples, respectively. The results support the existence of natural infections by C. parvum in freshwater cultured fish, suggesting that the rainbow trout could shed infectious oocysts in aquatic environments and it may be a potential source of human infection when this edible fish is handled. PMID- 29987412 TI - Prevalence of two Entamoeba gingivalis ST1 and ST2-kamaktli subtypes in the human oral cavity under various conditions. AB - Advances in molecular biology have facilitated analyses of the oral microbiome; however, the parasites role is poorly understood. Periodontal disease is a multifactorial process involving complex interactions among microorganisms, the host, and environmental factors. At present, the precise composition of the mouth parasites microbiota is unclear. Two protozoan species have been detected in the oral microbiota: Trichomonas tenax and Entamoeba gingivalis, and a new variant, E. gingivalis-ST2-kamaktli, was recently identified by us. In this study, both E. gingivalis and the new E. gingivalis-ST2-kamaktli variant were detected in the oral cavities of people with healthy periodontium, individuals undergoing orthodontic treatment, and patients with periodontal disease. In the group with healthy periodontium, the prevalence of E. gingivalis-ST1 was 48.6% and that of E. gingivalis-ST2-kamaktli 29.5%, with a combined prevalence of 54.3%. In patients undergoing orthodontics treatment, 81.2% carried both amoebas, with 47.5% having E. gingivalis-ST1 and 73.8% E. gingivalis-ST2-kamaktli. In people with periodontal disease, the prevalence of E. gingivalis-ST1 was 57.8%, and that of E. gingivalis-ST2-kamaktli 50.0%, with a combined prevalence of 73.5%; hence, E. gingivalis-ST1 and E gingivalis-ST2-kamaktli were detected in all three groups. The question arises, what are E. gingivalis-ST1 and E. gingivalis-ST2 kamaktli doing in the oral cavity? Although, the answer remains unclear, our results suggest that each amoeba subtype is genetically distinct, and they exhibit different patterns of infectious behavior. We hypothesize that E. gingivalis-ST1 and E. gingivalis-ST2-kamaktli may represent separate species. Our data contribute to better understanding of the roles of E. gingivalis-ST1 and E. gingivalis-ST2-kamaktli in the oral microbiota. PMID- 29987413 TI - Effect of oxidative stress on vital indicators of Acanthamoeba castellanii (T4 genotype). AB - Acanthamoeba has 22 genotypes with the T4 genotype being the main causative agent of amoebic granulomatous encephalitis and keratitis. Because the molecular mechanisms of the immune defenses of neutrophils and macrophages against histoparasites are based on oxidative stress, parasites may rely on their antioxidant systems to preclude immune defenses. Therefore, understanding of the effect of oxidative stress on vital characteristics of Acanthamoeba castellanii (T4 genotype) and the antioxidant defense responses of Acanthamoeba to oxidative status will cast light on immune cell-parasite interactions. Acanthamoeba T4 cells were cultured in RPMI-1640 medium containing different concentrations of hydrogen peroxide (H2O2). The survival of Acanthamoeba was evaluated by MTT assay and the IC50 concentration was calculated. The total antioxidant capacity (TAC) of the parasite was determined by the cupric reducing antioxidant capacity (CUPRAC) method. Malondialdehyde (MDA) as a marker of lipid peroxidation, protein carbonyl content as a measure of oxidized protein, total thiol (-SH) groups present on proteins as a major source of cellular antioxidants, and total oxidant status (TOS) were evaluated by colorimetric methods. The reactive oxygen species level increased markedly after induction of oxidative stress by the treatment of Acanthamoeba T4 with H2O2. Exposure to H2O2 also significantly increased the MDA and protein carbonyl content. The TOS level and total thiol groups also increased in the treated group compared to those in untreated parasites, although the results were not statistically significant. The TAC level was found to be significantly higher in H2O2-treated parasites, confirming that the parasite fosters its total antioxidant capacity to overcome oxidative conditions. This study showed that under oxidative stress, the defense reactions of the parasite are in part mediated by increasing its antioxidant activity, which is important for the survival of the parasite. PMID- 29987414 TI - Early segmentation in the mite Archegozetes longisetosus reveals conserved and derived aspects of chelicerate development. AB - The arthropod body plan is comprised of several repeating segments along the anteroposterior body axis. This high degree of conservation, however, obfuscates the wide degree of underlying developmental variation present across and within arthropod groups. In chelicerates, the arthropod clade containing mites, spiders, scorpions, and horseshoe crabs, development is the most similar at the stages following early germ band segmentation. Comparative studies of chelicerate segmentation prior to these events, however, remain scarce. In order to elucidate and identify possible shared and derived aspects of chelicerate segmentation, we followed the early prosomal (anterior) segmentation in the model mite Archegozetes longisetosus using the expression of the conserved segmental marker hedgehog (hh). Our data indicate that the ancestral chelicerate likely utilized the gene hedgehog in a group of cells surrounding the germ disc. We also provide evidence that chelicerate segmentation, albeit via the conserved "short/intermediate germ" mode, progresses differently in the prosoma between Archegozetes and spiders and thus early, anterior segmentation in chelicerates is heterochronic. PMID- 29987415 TI - Compliance assessment and flip-angle measurement of the median nerve: sonographic tools for carpal tunnel syndrome assessment? AB - OBJECTIVES: To assess the diagnostic performance of median nerve (MN) flip-angle measurements, deformation during wrist flexion [transit deformation coefficient (TDC)], during compression [compression deformation coefficient (CDC)] and fascicular freedom to potentially identify fibrotic MN changes in patients with carpal tunnel syndrome (CTS). METHODS: This prospective study was performed with institutional review board approval; all participants provided oral and written informed consent. Wrists in 21 healthy participants and 29 patients with CTS were examined by ultrasound. MN movement during wrist flexion, MN deformation during transition over the flexor tendons (TDC) and during controlled compression (CDC) as well as fascicular freedom were assessed. Diagnostic properties of these parameters were calculated and compared to clinical findings and cross-section area measurements (DeltaCSA). RESULTS: Low flip angles were associated with high DeltaCSA at a receiver-operator characteristics area under the curve (AUC) of 0.62 (0.51-0.74). TDC [AUC, 0.83 (0.73-0.92), 76.3% (59.8-88.6%) sensitivity, 88.5% (76.6-95.7%) specificity], restricted fascicular movement [AUC, 0.86 (0.78 0.94), 89.5% (75.2-97.1%) sensitivity, 80.8% (67.5-90.4%) specificity] and compression-based CDC [AUC, 0.97 (0.94-1.00), 82.1% (66.5-92.5%) sensitivity, 94.2% (84.1-98.8%) specificity] demonstrated substantial diagnostic power (95% confidence intervals in parentheses). CONCLUSIONS: Fascicular mobility, TDC and CDC show substantial diagnostic power and may offer insights into the underlying pathophysiology of CTS. KEY POINTS: * Dynamic ultrasonography during wrist flexion and compression enables median nerve deformability assessment. * Overall, reduced median nerve deformability is highly indicative of CTS. * Median nerve compressibility shows higher diagnostic power than conventional cross-section area measurements. PMID- 29987416 TI - Radiation dose reduction with frame rate conversion in X-ray fluoroscopic imaging systems with flat panel detector: basic study and clinical retrospective analysis. AB - OBJECTIVES: To (a) evaluate the interpolation frames of frame rate conversion (FRC) compared with fluoroscopic frames of conventional method, and (b) compare radiation dose and fluoroscopy time between various clinical examinations without and with FRC retrospectively. METHODS: This study consisted of a basic study and a clinical retrospective analysis. The radiation dosimetry, visual assessment and measurements of contrast to noise ratio were examined. Similarity between interpolation frames and fluoroscopic frames was evaluated using normalised cross correlation values. In the clinical retrospective analysis approved by the institutional review board, we extracted 270 examinations performed without FRC (conventional group, 12.5 pulses/s) and with FRC (FRC group, 6.25 pulses/s) from 23 May to 31 December 2016. The fluoroscopy parameters and demographics of the two groups of the clinical examinations were compared. Statistical analyses were performed with Wilcoxon signed-rank test, Brunner-Munzel test and chi2 test. RESULTS: In the basic study, the only significant difference was that the radiation dose of FRC was approximately half that of the conventional method in the same fluoroscopy time (p = .031). The interpolation frames of FRC were similar to the fluoroscopic frames of the conventional method. In the clinical retrospective analysis, the only significant difference was that FRC reduced the fluoroscopy dose by 48% and the total dose by 31% compared with the conventional method (p < .001). There was no significant difference in the others. CONCLUSION: FRC significantly reduced the radiation dose without extending the fluoroscopy time and maintaining the image quality compared to the conventional method. KEY POINTS: * Although X-ray fluoroscopic techniques are widely used for various clinical purposes, X-ray fluoroscopic examinations have radiation risks. * Frame rate conversion is an image processing technique for radiation dose reduction. * Clinical retrospective analysis showed that FRC reduces radiation doses of patients. PMID- 29987417 TI - Correction to: MRI assessment of the thigh musculature in dermatomyositis and healthy subjects using diffusion tensor imaging, intravoxel incoherent motion and dynamic DTI. AB - The original version of this article, published on 04 June 2018, unfortunately contained a mistake. PMID- 29987418 TI - BOLD cardiac MRI for differentiating reversible and irreversible myocardial damage in ST segment elevation myocardial infarction. AB - OBJECTIVES: BOLD imaging is a quantitative MRI technique allowing the evaluation of the balance between supply/demand in myocardial oxygenation and myocardial haemorrhage. We sought to investigate the ability of BOLD imaging to differentiate reversible from irreversible myocardial injury as well as the chronological progression of myocardial oxygenation after reperfusion in patients with ST segment elevation myocardial infarction (STEMI). METHODS: Twenty-two patients (age, 60 +/- 11 years; 77.3% male) with STEMI underwent cardiac MRIs on four occasions: on days 1, 3, 7 and 30 after reperfusion. BOLD MRI was obtained with a multi-echo turbo field echo (TFE) sequence on a 3-T scanner to assess myocardial oxygenation in MI. RESULTS: T2* value in MI with intramyocardial haemorrhage (IMH) was the lowest (9.77 +/- 3.29 ms), while that of the salvaged zone was the highest (33.97 +/- 3.42 ms). T2* values in salvaged myocardium demonstrated a unimodal temporal pattern from days 1 (37.91 +/- 2.23 ms) to 30 (30.68 +/- 1.59 ms). T2* values in the MI regions were significantly lower than those in remote myocardium, although the trends in both were constant overall. There was a slightly positive correlation between T2* in MI regions and EF (Rho = 0.27, p < 0.05) or SV (Rho = 0.22, p = 0.04) and a slightly negative correlation between T2* in salvaged myocardium and LVEDV (Rho = - 0.23, p < 0.05). CONCLUSIONS: BOLD MRI performed in post-STEMI patients allows accurate evaluation of myocardial damage severity and could differentiate reversible from irreversible myocardial injury. The increased T2* values may imply the pathophysiological mechanism of salvaged myocardium. BOLD MRI could represent a more accurate alternative to the other currently available options. KEY POINTS: * Myocardial oxygenation and haemorrhage after myocardial infarction affect BOLD MRI values * BOLD MRI could be used to differentiate irreversible from reversible myocardial damage * Changed oxygenation implies the pathophysiological mechanism of salvaged myocardium. PMID- 29987419 TI - Validation of scoring hip osteoarthritis with MRI (SHOMRI) scores using hip arthroscopy as a standard of reference. AB - PURPOSE: To validate SHOMRI gradings in preoperative hip magnetic resonance imaging (MRI) with intra-arthroscopic evaluation of intraarticular hip abnormalities. METHODS: Preoperative non-arthrographic 3.0-T MRIs of 40 hips in 39 patients (1 patient with bilateral hip surgery) with femoroacetabular impingement (FAI) syndrome (mean age, 34.7 years +/- 9.0; n = 16 females), refractory to conservative measures, that underwent hip arthroscopy were retrospectively assessed by two radiologists for chondrolabral abnormalities and compared with intra-arthroscopic findings as the standard of reference. Arthroscopically accessible regions were compared with the corresponding SHOMRI subregions and assessed for the presence and grade of cartilaginous pathologies in the acetabulum and femoral head. The acetabular labrum was assessed for the presence or absence of labral tears. For the statistical analysis sensitivity and specificity as well as intraclass correlation (ICC) for interobserver agreement were calculated. RESULTS: Regarding chondral abnormalities, 58.8% of the surgical cases showed chondral defects. SHOMRI scoring showed a sensitivity of 95.7% and specificity of 84.8% in detecting cartilage lesions. Moreover, all cases with full-thickness defects (n = 9) were identified correctly, and in n = 6 cases (out of n = 36 with partial-thickness defects) the defective cartilage was identified but the actual depth overestimated. Labral tears were present in all cases and the MR readers identified 92.5% correctly. ICC showed a good interobserver agreement with 86.3% (95% CI 80.0, 90.6%) CONCLUSION: Using arthroscopic correlation, SHOMRI grading of the hip proves to be a reliable and precise method to assess chondrolabral hip joint abnormalities. KEY POINTS: * Assessment of hip abnormalities using MRI with surgical correlation. * Comparing surgery and MRI by creating a hybrid anatomic map that covers both modalities. * Non-arthrographic use of 3.0-T MRI provides detailed information on cartilage and labral abnormalities in hip joints. PMID- 29987420 TI - The effect of tube voltage combination on image artefact and radiation dose in dual-source dual-energy CT: comparison between conventional 80/140 kV and 80/150 kV plus tin filter for gout protocol. AB - OBJECTIVES: In dual-source CT, dual-energy (DE) performance is affected by various X-ray tube voltage combinations with and without tin filter (Sn). The purpose of this study was to assess the utility of the 80/150 Sn kV voltage combination in terms of image artefact and radiation dose for DECT gout protocol, compared with the conventional 80/140 kV. METHODS: Seventy-four patients with suspected gout who underwent dual-source DECT examinations scanned at 80/140 kV (n = 37) and at 80/150 Sn kV (n = 37) were included. Patients' age, sex, and serum uric acid levels were matched between the two groups. The types and incidence of image artefacts and radiation dose were evaluated. RESULTS: The 80/150 Sn kV group had significantly fewer patients with artefacts, compared to the 80/140 kV group [11 (30 %) of 37 vs 35 (94.6 %) of 37, p < 0.001]. Except for the motion artefact, the rest of the artefacts-skin, nail bed, submillimetre, motion, vascular, beam-hardening, clumpy artefact along tendon-were significantly less observed in the 80/150 Sn kV acquisitions. The dose-length product (DLP) and effective dose were significantly lower for the 80/150 Sn kV acquisitions compared with the 8s0/140 kV scans (DLP: 104.46 +/- 10.66 mGy.cm vs 344.70 +/- 56.39 mGy.cm, p < 0.001; effective dose: 1.04 +/- 0.11 mSv vs 3.45 +/- 0.56 mSv, p < 0.001). CONCLUSIONS: The 80/150 Sn kV voltage combination in dual-source DECT system could be used as one of the artefact reduction methods while reducing radiation dose for gout protocol when compared to the conventional 80/140 kV. KEY POINTS: * DECT has emerged as the leading modality for non-invasive diagnosis of gout. * Various X-ray tube voltage combinations are now feasible in dual-source DECT. * The 80/150 Sn kV acquisition could facilitate artefact reduction in gout protocol. PMID- 29987421 TI - Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke. AB - OBJECTIVE: The putative mechanism for the favourable effect of endovascular treatment (EVT) on functional outcome after acute ischaemic stroke is preventing follow-up infarct volume (FIV) progression. We aimed to assess to what extent difference in FIV explains the effect of EVT on functional outcome in a randomised trial of EVT versus no EVT (MR CLEAN). METHODS: FIV was assessed on non-contrast CT scan 5-7 days after stroke. Functional outcome was the score on the modified Rankin Scale at 3 months. We tested the causal pathway from intervention, via FIV to functional outcome with a mediation model, using linear and ordinal regression, adjusted for relevant baseline covariates, including stroke severity. Explained effect was assessed by taking the ratio of the log odds ratios of treatment with and without adjustment for FIV. RESULTS: Of the 500 patients included in MR CLEAN, 60 died and four patients underwent hemicraniectomy before FIV was assessed, leaving 436 patients for analysis. Patients in the intervention group had better functional outcomes (adjusted common odds ratio (acOR) 2.30 (95% CI 1.62-3.26) than controls and smaller FIV (median 53 vs. 81 ml) (difference 28 ml; 95% CI 13-41). Smaller FIV was associated with better outcome (acOR per 10 ml 0.60, 95% CI 0.52-0.68). After adjustment for FIV the effect of intervention on functional outcome decreased but remained substantial (acOR 2.05, 95% CI 1.44-2.91). This implies that preventing FIV progression explains 14% (95% CI 0-34) of the beneficial effect of EVT on outcome. CONCLUSION: The effect of EVT on FIV explains only part of the treatment effect on functional outcome. KEY POINTS: * Endovascular treatment in acute ischaemic stroke patients prevents progression of follow-up infarct volume on non contrast CT at 5-7 days. * Follow-up infarct volume was related to functional outcome, but only explained a modest part of the effect of intervention on functional outcome. * A large proportion of treatment effect on functional outcome remains unexplained, suggesting FIV alone cannot be used as an early surrogate imaging marker of functional outcome. PMID- 29987422 TI - Micro-RNAs involved in cellular proliferation have altered expression profiles in granulosa of young women with diminished ovarian reserve. AB - PURPOSE: The study aims to determine differences in micro-RNA (miRNA) expression in granulosa (GC) and cumulus cells (CC) between young women with diminished ovarian reserve (DOR) or normal ovarian reserve (NOR). Secondary objective was to identify downstream signaling pathways that could ultimately indicate causes of lower developmental competence of oocytes from young women with DOR. METHODS: The method of the study is prospective cohort study. RESULTS: Of the miRNA, 125 are differentially expressed in GC between DOR and NOR. Only nine miRNA were different in CC; therefore, we focused analysis on GC. In DOR GC, miR-100-5p, miR 16-5p, miR-30a-3p, and miR-193a-3p were significantly downregulated, while miR 155-5p, miR-192-5p, miR-128-3p, miR-486-5p, miR130a-3p, miR-92a-3p, miR-17-3p, miR-221-3p, and miR-175p were increased. This pattern predicted higher cell proliferation in the DOR GC. The primary pathways include MAPK, Wnt, and TGFbeta. CONCLUSIONS: The miRNA pattern identified critical functions in cell proliferation and survival associated with DOR. GC in women with DOR seems to respond differently to the LH surge. PMID- 29987423 TI - Technique of full-endoscopic lumbar discectomy via an interlaminar approach. PMID- 29987424 TI - Spino-pelvic balance and surgical treatment of L5-S1 isthmic spondylolisthesis. PMID- 29987425 TI - Correction to: Precise and economic FIB/SEM for CLEM: with 2 nm voxels through mitosis. AB - Unfortunately, part of the legend to Fig. 6 has been incorrectly published. PMID- 29987426 TI - Clinical characteristics and risk factors of infections in patients with systemic lupus erythematosus. AB - To investigate the clinical characteristics of infection in SLE patients and analyze the risk factors of infection. A retrospective analysis method was used and the data were collected from 173 case times of 142 hospitalized patients. We found the incidence rate of infections in SLE was 50.7%. The most common infection sites were lungs, followed by upper respiratory tracts and urinary tracts. The most common pathogens were bacteria, followed by fungi. The infection associated risk factors were duration of hospitalization, lupus activity state, the use of high-dose corticosteroids and immunosuppressive agents, the low serum level of complements 3 and 4 (C3 and C4), fever, the high level of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), the abnormality of white blood cell (< 4 * 109/L or > 10 * 109/L), and the low level of albumin (P < 0.05 or P < 0.001). The independent risk factors for SLE patients with infection consist of the abnormality of white blood cells, the high level of CRP, the low serum level of C4, and longtime hospitalization. Attention should be paid to the risk factors of infection, and treatment to enhance immunity should be carried out to reduce the chance of infection. PMID- 29987427 TI - Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function. AB - Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function. PMID- 29987428 TI - MicroRNA-146a expression and microRNA-146a rs2910164 polymorphism in Behcet's disease patients. AB - Behcet's disease is a chronic, multisystem, inflammatory disease of unknown etiology. Oral ulcers, genital ulcers, cutaneous lesions, and ocular and articular involvement are the prominent features of the disease. The aim of the study was to assess expression of microRNA-146a and its gene polymorphism in Egyptian Behcet's disease (BD) patients and to evaluate their possible relation with clinical manifestations and activity. This is a case-control study, included 47 BD Egyptian patients, recruited from the Rheumatology outpatient clinic, Kasr Alainy Hospital, Cairo University Hospitals, and 50 healthy controls. BD activity was assessed using the BD Current Activity Score. Quantitative expressions of serum microRNA-146a and microRNA-146a rs2910164 SNP genotyping were performed by real-time polymerase chain reaction (RT-PCR). P values < 0.05 were considered statistically significant. Serum microRNA-146a expression was significantly higher in BD patients than in controls (7. 27 +/- 4.11, 1.13 +/- .37) (P < 0.001). There was a significant association between microRNA-146a expression and eye activity (P = 0.033) and vascular activity (P = 0.041). miRNA-146a rs2910164 genotyping revealed that the frequency of CC genotype was higher in controls (12 vs 8.5%) and the frequency of GG genotype of rs2910164 was higher in the BD patients (59.6 vs 24%) (P = 0.138). MicroRNA-146a expression in Egyptian BD patients is significantly higher than that in controls; there is significant association between microRNA-146a expression and eye and vascular activity of BD. The frequency of CC genotype of rs2910164 was decreased; frequency of GG genotype of rs2910164 was increased in BD patients as compared to controls, suggesting that GG genotype of rs2910164 confers susceptibility to BD while CC genotype has a protective role against BD development. PMID- 29987429 TI - Arbuscular mycorrhizal inoculum sources influence bacterial, archaeal, and fungal communities' structures of historically dioxin/furan-contaminated soil but not the pollutant dissipation rate. AB - Little is known about the influence of arbuscular mycorrhizal fungi (AMF) inoculum sources on phytoremediation efficiency. Therefore, the aim of this study was to compare the effects of two mycorrhizal inocula (indigenous and commercial inocula) in association with alfalfa and tall fescue on the plant growth, the bacterial, fungal, and archaeal communities, and on the removal of dioxin/furan (PCDD/F) from a historically polluted soil after 24 weeks of culture in microcosms. Our results showed that both mycorrhizal indigenous and commercial inocula were able to colonize plant roots, and the growth response depends on the AMF inoculum. Nevertheless, the improvement of root dry weight in inoculated alfalfa with indigenous inoculum and in inoculated tall fescue with commercial inoculum was clearly correlated with the highest mycorrhizal colonization of the roots in both plant species. The highest shoot dry weight was obtained in inoculated alfalfa and tall fescue with the commercial inoculum. AMF inoculation differently affected the number of bacterial and archaeal OTUs and bacterial diversity, with elevated bacterial and archaeal OTUs and bacterial diversity observed with indigenous inoculum. Mycorrhizal inoculation increases the abundance of bacterial OTUs (in particular with indigenous inoculum) and microbial richness but it does not improve PCDD/F dissipation. Vegetation had no effect on the abundance of microbial OTUs nor on richness but stimulated specific communities (Planctomycetia and Gammaproteobacteria) likely to be involved in the dissipation of PCDD/F. The reduction of toxic equivalency PCDD/F concentration also could be explained by the stimulation of soil microbial activities estimated with dehydrogenase and fluorescein diacetate hydrolase. PMID- 29987430 TI - Multi-parametric cardiorespiratory analysis in late-preterm, early-term, and full term infants at birth. AB - Infants born at 35-37 weeks' gestational age (GA) are at higher risk for a range of pathological conditions and poorer neurodevelopmental outcomes. However, mechanisms responsible are not fully understood. The purpose of this paper is to use traditional and novel techniques to assess newborn autonomic development as a function of GA at birth, focusing on cardiorespiratory regulation. ECG and respiration were acquired during sleep on 329 healthy newborns. Infants were divided into GA groups: 35-36 weeks (late preterm (LPT)), 37-38 weeks (early term (ET)), and 39-40 weeks (full term (FT)). Time domain, frequency domain, and non linear measures were calculated. Increased heart rate short-term variability and complexity as a function of GA were observed in time domain and non-linear measures. Decreasing inter-breath interval variability was found as a function of GA, with increasing linear cardiorespiratory coupling. A complexity parameter (quadratic sample entropy) was less affected by arrhythmias and artifacts when compared to traditional measures. Results suggest lower maturation in LPT, with less developed cardiorespiratory regulation. This may confer risk for altered outcome, convergent with epidemiological findings. Reported examples show that a combination of methodological approaches can be beneficial to characterize autonomic maturation. Graphical abstract ?. PMID- 29987431 TI - Insectivorous birds consume an estimated 400-500 million tons of prey annually. AB - In this paper, we present an estimate of the predation impact of the global population of insectivorous birds based on 103 (for the most part) published studies of prey consumption (kg ha-1 season-1) of insectivorous birds in seven biome types. By extrapolation-taking into account the global land cover of the various biomes-an estimate of the annual prey consumption of the world's insectivorous birds was obtained. We estimate the prey biomass consumed by the world's insectivorous birds to be somewhere between 400 and 500 million metric tons year-1, but most likely at the lower end of this range (corresponding to an energy consumption of ~ 2.7 * 1018 J year-1 or ~ 0.15% of the global terrestrial net primary production). Birds in forests account for > 70% of the global annual prey consumption of insectivorous birds (>= 300 million tons year-1), whereas birds in other biomes (savannas and grasslands, croplands, deserts, and Arctic tundra) are less significant contributors (>= 100 million tons year-1). Especially during the breeding season, when adult birds feed their nestlings protein-rich prey, large numbers of herbivorous insects (i.e., primarily in the orders Coleoptera, Diptera, Hemiptera, Hymenoptera, Lepidoptera, and Orthoptera) supplemented by spiders are captured. The estimates presented in this paper emphasize the ecological and economic importance of insectivorous birds in suppressing potentially harmful insect pests on a global scale-especially in forested areas. PMID- 29987432 TI - Role of AGEs in the progression and regression of atherosclerotic plaques. AB - The formation of advanced glycation end-products(AGEs) is an important cause of metabolic memory in diabetic patients and a key factor in the formation of atherosclerosis(AS) plaques in patients with diabetes mellitus. Related studies showed that AGEs could disrupt hemodynamic steady-state and destroy vascular wall integrity through the endothelial barrier damage, foam cell(FC) formation, apoptosis, calcium deposition and other aspects. At the same time, AGEs could initiate oxidative stress and inflammatory response cascade via receptor-depended and non-receptor-dependent pathways, promoting plaques to develop from a steady state to a vulnerable state and eventually tend to rupture and thrombosis. Numerous studies have confirmed that these pathological processes mentioned above could lead to acute coronary heart disease(CHD) and other acute cardiovascular and cerebrovascular events. However, the specific role of AGEs in the progression and regression of AS plaques has not yet been fully elucidated. In this paper, the formation, source, metabolism, physical and chemical properties of AGEs and their role in the migration of FCs and plaque calcification are briefly described, we hope to provide new ideas for the researchers that struggling in this field. PMID- 29987433 TI - Wake-up stroke and CT perfusion: effectiveness and safety of reperfusion therapy. AB - OBJECTIVE: Ischemic stroke is a neuroemergency condition highly treatable with thrombolysis and thrombectomy. Recently, observational studies have brought insights into clinical and imaging characteristics of wake-up stroke, which interested up to 25% of ischemic stroke patients. In clinical practice, wake-up strokes are usually not considered for reperfusion therapy. The aim of this study was to investigate the use CT perfusion imaging in patients with wake-up stroke and to assess the effect of neuroimaging information provided by CT perfusion maps on the efficacy and safety of thrombolysis and thrombectomy. PATIENTS AND METHOD: We studied 22 wake-up stroke (WUS) patients (13F/9M mean age) who underwent reperfusion therapy after the eligibility assessed by the CT perfusion imaging (< 50% core-to-penumbra ratio and negative CT perfusion). RESULTS: Mean National Institutes of Health Stroke Scale (NIHSS) was 8.1 +/- 4.9 at admission while 3.3 +/- 5.1 at discharge, significantly different from admission (p < 0.001). As many as ten patients had mRS lower than 3 at discharge. Intracranial hemorrhage occurred in five patients and caused symptoms worsening only in two patients (decrease of NIHSS score of 4 points) of which one patient died. CONCLUSION: The main finding of this study is that wake-up stroke with adequate selection by CT perfusion may benefit reperfusion treatment. PMID- 29987434 TI - Acute-on-chronic subdural hematoma: the death of the famous XIX century soprano Maria Malibran-a study of the sources. AB - Maria Malibran (1808-1836) is one of the most famous sopranos of the nineteenth century. In 1825, along with her father, the renowned tenor Manuel Garcia, she introduced the Italian opera in America for the first time. The European debut in Paris (1828) definitively crowned her as a star. Thus, she was requested by the most famous European theaters. In July 1836, during an equestrian excursion in London, she fell from her horse dashing her head against the ground, resulting in a state of insensibility. Since that accident, she had suffered from continual headache and nervous attacks, but she continued to work. In September 1836, she attended a music festival in Manchester, but her health rapidly worsened: episodes of nervous attacks, headache, and fainting occurred with higher frequency. At the end of a representation, she was attacked by violent convulsions. In the following days, she was laid in a kind of stupor. Afterward, she died at the age of 28. The hypothesis that prolonged efforts during her performance could have provoked a rebleeding of a pre-existent chronic subdural hematoma should be taken into account as a possible cause of death. PMID- 29987435 TI - Radiographic and microsurgical characteristics of proximal (A1) segment aneurysms of the anterior cerebral artery. AB - BACKGROUND: Proximal A1 segment aneurysms of the anterior cerebral artery (ACA) radiologically resemble internal carotid artery bifurcation (ICBIF) aneurysms because of their anatomical proximity. However, proximal A1 aneurysms exhibit distinguishing features, relative to ICBIF aneurysms. We report our experience of managing proximal A1 aneurysms, then compare them to ICBIF aneurysms. METHODS: Among 2191 aneurysms treated between 2000 and 2016 in a single institution, we retrospectively reviewed 100 cases categorized as ICBIF or A1 aneurysms. We included aneurysms originating from the ICBIF and ACA, proximal to the anterior communicating artery (A1 segment) and divided them into two groups: proximal A1 (n = 32) and ICBIF (n = 50). If any portion of the aneurysm involved the ICBIF, it was classified as ICBIF. Aneurysms wholly located in the A1 segment were classified as proximal A1. Patient factors and angiographic factors were evaluated and compared. RESULTS: The proximal A1 group exhibited differences in aneurysm size (p = 0.013), posterior aneurysm direction (p = 0.001), and A1 perforators as incorporating vessels (p = 0.001). The proximal A1 group tended to rupture more frequently when the aneurysm was smaller (p = 0.046). One case of morbidity occurred in the proximal A1 group. CONCLUSION: Compared to ICBIF aneurysms, proximal A1 aneurysms were smaller and directed posteriorly, with incorporating perforators. Because of these characteristics, it may be difficult to perform clipping with 360 degrees view in microsurgical field. Therefore, when planning to treat proximal A1 aneurysms, different treatment strategies may be necessary, relative to those used for ICBIF aneurysms. PMID- 29987436 TI - Symptomatic intracranial atherosclerotic disease: an ultrasound 2-year follow-up pilot study. AB - INTRODUCTION: The objective of this single-center pilot study was to assess if symptomatic intracranial atherosclerotic disease (ICAD) ultrasound features change through the 2 years after acute ischemic stroke or TIA, being ICAD a relevant cause of acute ischemic stroke or TIA, linked to high rates of recurrent stroke. METHODS: We consecutively enrolled 48 patients with acute ischemic stroke or TIA with symptomatic ICAD detected by transcranial color-coded duplex sonography (TCCS) and confirmed by MR-angiography and/or CT-angiography. We set a neurosonological and clinical follow-up at 3, 6, 12, and 24 months (T0, T1, T2, T3, and T4). RESULTS: We observed that the hemodynamic effect of the stenosis changed during the 2-year follow-up, as revealed by the modifications of Peak Systolic Velocity (PSV) (Friedman-ANOVA test, p < 0.001). The pairwise post-hoc analysis showed a statistically significant difference between PSV at T0 and PSV at T3 (p = 0.005) and between PSV at T0 and PSV at T4 (p < 0.001) being PSV at T3 and T4 lower than PSV at T0. Seven patients had a new event in the first 12 months. CONCLUSIONS: The high rate of recurrent stroke or death among ICAD patients seems to be independent of progressive arterial narrowing. A wide multicenter follow-up study is needed in order to identify the factors that, alongside the hemodynamic features, contribute to the high risk of recurrent stroke among patient with symptomatic ICAD. PMID- 29987437 TI - Amyloid-positive late-onset semantic variant primary progressive aphasia. PMID- 29987438 TI - Balint syndrome caused by bilateral medial occipital infarcts. PMID- 29987439 TI - The Construction and Application of C=S Bonds. AB - The current section presents an overview of the fundamental aspects of thiocarbonyl compounds, such as thioaldehydes and thioketones. Firstly, a theoretical approach and a physical-organic experimental approach disclose their properties. Secondly, their synthetic reactions are introduced. Finally, a focus is given to their synthetic applications, including nucleophilic and electrophilic reactions, as well as concerted reactions. PMID- 29987440 TI - Rotator cable in pathological shoulders: comparison with normal anatomy in a cadaveric study. AB - The rotator cable is a semicircular thickening of the glenohumeral joint capsule. It travels between tubercles of the humerus and interweaves with the supra- and infraspinatus muscle tendons. The rotator cable anchors these tendons to the tubercles, playing the role of a suspension bridge. However, little is known about the modifications of this cable that result from pathologies to the rotator cuff tendons. Thus, we aim to compare the morphology of the normal rotator cable with cables in specimens with rotator cuff injuries. The glenohumeral joint was dissected in 30 cadaveric shoulders. The supra-, infraspinatus and teres minor muscles were inspected for injuries and the rotator cable was visualised. The cables course was determined and the width, length and thickness were measured. The rotator cable was found present in all cadavers dissected. In three specimens there was a partial injury of the supraspinatus tendon (two from capsular side and one from bursal side). The rotator cable was thickened in the cases of capsular tears. In another two specimens the supraspinatus and infraspinatus muscles were torn completely and in these cases the rotator cable was blended with retracted stumps and elongated to the level of the glenoid rim. The rotator cable creates a functional complex with the supra- and infrasinatus muscles. The morphology of the cable differs in cases of rotator cuff injury. PMID- 29987441 TI - Enhancement of mixing by rodlike polymers. AB - We study the mixing of a passive scalar field dispersed in a solution of rodlike polymers in two dimensions, by means of numerical simulations of a rheological model for the polymer solution. The flow is driven by a parallel sinusoidal force (Kolmogorov flow). Although the Reynolds number is lower than the critical value for inertial instabilities, the rotational dynamics of the polymers generates a chaotic flow similar to the so-called elastic-turbulence regime observed in extensible polymer solutions. The temporal decay of the variance of the scalar field and its gradients shows that this chaotic flow strongly enhances mixing. PMID- 29987443 TI - Coordination between photorespiration and carbon concentrating mechanism in Chlamydomonas reinhardtii: transcript and protein changes during light-dark diurnal cycles and mixotrophy conditions. AB - Carbon concentrating mechanism (CCM) and photorespiration (PR) are interlinked and co-regulated in Chlamydomonas reinhardtii, but conditions where co-regulation alters are not sufficiently explored. Here, we uncover that PR gene transcripts, like CCM transcripts, are induced even in the dark when both processes are not active. Such diurnal cycles show that transcript levels peak in the middle of 12 h day, decline by early part of 12-h dark followed by their onset again at mid dark. Interestingly, the onset in the mid-dark phase is sensitive to high CO2, implying that the active carbon sensing mechanism operates even in the dark. The rhythmic alterations of both CCM and PR transcript levels are unlinked to circadian clock: the "free-running state" reveals no discernible rhythmicity in transcript changes. Only continuous light leads to high transcript levels but no detectable transcripts were observed in continuous dark. Asynchronous continuous light cultures, upon shifting to low from high CO2 exhibit only transient induction of PR transcripts/proteins while CCM transcript induction is stable, indicating the loss of co-regulation between PR and CCM gene transcription. Lastly, we also describe that both CCM and PR transcripts/proteins are induced in low CO2 even in mixotrophic cultures, but only in high light, the same being attenuated in high CO2, implying that high light is a mandatory "trigger" for CCM and PR induction in low CO2 mixotrophy. Our study provides comprehensive analyses of conditions where CCM and PR were differently regulated, setting a paradigm for a detailed mechanistic probing of these responses. PMID- 29987442 TI - The effectiveness of a model-based health education intervention to improve ergonomic posture in office computer workers: a randomized controlled trial. AB - PURPOSE: Lack of knowledge about computer ergonomics predisposes users to musculoskeletal and visual disorders. The present study examined the effect of a trans-theoretical model (TTM)-based educational program on work-related posture in office computer users. METHODS: This experimental study examined 102 hospital personnel whose primary job involved working at a computer. Participants were randomized to intervention and control groups. An educational intervention based on TTM was conducted over five sessions. A self-report questionnaire was used to collect data including stages of change, processes of change, pros and cons of change, and self-efficacy. A pen-paper-based observational method (i.e., Rapid Office Strain Assessment or ROSA) was used for assessing work posture. A visual analogue scale assessed pain intensity. Data were collected at baseline and 3 month follow-up. RESULTS: Significant differences were found on TTM's constructs and ROSA score between intervention and control groups at follow-up (p < 0.05). The mean ROSA score decreased from 5.65 (SD 1.03) to 3.95 (SD 0.83) in the intervention group, while no significant change was found in the control group. Pain intensity also decreased significantly among those in the intervention vs. control group (p < 0.001). CONCLUSION: An educational intervention based on TTM was effective in improving ergonomic posture in computer workers. Further research is needed to determine if these results can be generalized to computer workers in other settings. PMID- 29987444 TI - Preparation of polyetherimide membrane from non-toxic solvents for the separation of hydrogen from methane. AB - Polymeric membranes are usually prepared from solvents like n-methylpyrrolidone (NMP) because of the strong dissolving power and high boiling point. Yet, the solvent is costly, toxic and has environmental issues. In this work, nontoxic solvents such as methyl L-lactate, ethyl lactate, propylene carbonate, tributyl o acetylcitrate, tributyl citrate, triethyl phosphate, and gamma-butyrolactone (GBL) were introduced during membrane preparation. It was found that all the solvents were unable to dissolve polyetherimide except GBL. The membranes made by GBL and NMP were evaluated for gas separation, and they have almost similar hydrogen-to-methane selectivity, but, hydrogen permeance was better in NMP membranes. PMID- 29987445 TI - Biomarkers for the identification of cardiac fibroblast and myofibroblast cells. AB - Experimental research has recognized the importance of cardiac fibroblast and myofibroblast cells in heart repair and function. In a normal healthy heart, the cardiac fibroblast plays a central role in the structural, electrical, and chemical aspects within the heart. Interestingly, the transformation of cardiac fibroblast cells to cardiac myofibroblast cells is suspected to play a vital part in the development of heart failure. The ability to differentiate between the two cells types has been a challenge. Myofibroblast cells are only expressed in the stressed or failing heart, so a better understanding of cell function may identify therapies that aid repair of the damaged heart. This paper will provide an outline of what is currently known about cardiac fibroblasts and myofibroblasts, the physiological and pathological roles within the heart, and causes for the transition of fibroblasts into myoblasts. We also reviewed the potential markers available for characterizing these cells and found that there is no single-cell specific marker that delineates fibroblast or myofibroblast cells. To characterize the cells of fibroblast origin, vimentin is commonly used. Cardiac fibroblasts can be identified using discoidin domain receptor 2 (DDR2) while alpha-smooth muscle actin is used to distinguish myofibroblasts. A known cytokine TGF-beta1 is well established to cause the transformation of cardiac fibroblasts to myofibroblasts. This review will also discuss clinical treatments that inhibit or reduce the actions of TGF-beta1 and its contribution to cardiac fibrosis and heart failure. PMID- 29987446 TI - The Demands of Beauty: Editors' Introduction. AB - This article introduces a Special Issue comprising four papers emerging from the Beauty Demands Network project, and maps key issues in the beauty debate. The introduction first discusses the purpose of the Network; to consider the changing demands of beauty across disciplines and beyond academia. It then summarises the findings of the Network workshops, emphasising the complex place of notions of normality, and the different meanings and functions attached to 'normal' in the beauty context. Concerns are raised here about the use of normal to justify and motivate engaging in beauty practices such as cosmetic surgery and 'non-invasive' procedures. Other workshop findings included the recognition of beauty as increasingly a global value rather than a culturally distinct ideal, and the understanding that there is no clear distinction between beauty practices that are considered standard and those that are considered extreme. These themes, especially the concerns around understanding of normal, are reflected in the recommendations made by the Network in its Briefing Paper, which are presented next in this introduction. A further theme picked up by these recommendations is the extent to which individuals who are not traditionally vulnerable may be so in the beauty context. Finally, the introduction highlights the key matters covered in the four papers of the Special Issue: regulatory concerns around cosmetic surgery tourism; the impact of digitally altered images from psychological and philosophical perspectives; the ethics of genetic selection for fair skin; and the attraction and beauty of the contemporary athletic body. PMID- 29987447 TI - Magnetic resonance imaging of sacroiliitis in children: frequency of findings and interobserver reliability. AB - BACKGROUND: Clinicians increasingly rely on imaging in juvenile idiopathic arthritis (JIA) to identify sacroiliitis and guide treatment. However, there is limited evidence about magnetic resonance imaging (MRI) for sacroiliitis in children, and interobserver reliability is variable. OBJECTIVE: Identify the frequency of MRI findings in children with suspected sacroiliitis, calculate inter-reporter reliability and assess the value of diffusion-weighted imaging and contrast-enhanced sequences. MATERIALS AND METHODS: We retrospectively reviewed 3 years of sacroiliac joint MRI records for suspected sacroiliitis in patients <21 years at a United Kingdom tertiary referral paediatric hospital. Five radiologists (panel of three radiologists and two independent radiologists) reviewed all MRI examinations using a pictorial checklist to identify oedema, effusions, diffusion-weighted signal abnormality, enhancement, erosions and sclerosis. The frequency of panel findings was reported. Interobserver agreement was calculated using the Cohen kappa coefficient. RESULTS: An MRI diagnosis of sacroiliitis was made in 12 of 99 examinations (12%). The findings in all scans included oedema (9%), erosions (8%), diffusion-weighted signal abnormality (6%), abnormal enhancement (6%) and effusion (4%). All scans with abnormal contrast enhancement had other MRI features of sacroiliitis. Interobserver agreement was slight to moderate. CONCLUSION: Oedema and erosions were the most common findings. Inter-reporter reliability was variable with at best moderate agreement for the presence of sacroiliitis and erosions. The use of contrast enhancement for diagnosing sacroiliitis in children with JIA may be questionable. PMID- 29987448 TI - Inhibition of macrophage inflammatory protein-1beta improves endothelial progenitor cell function and ischemia-induced angiogenesis in diabetes. AB - Systemic inflammation might contribute to the impairment of neovasculogenesis and endothelial progenitor cell (EPC) function in clinical diabetes mellitus (DM). Macrophage inflammatory protein-1beta (MIP-1beta) is an inflammatory chemokine that may be up-regulated in clinical DM. Its role in diabetic vasculopathy was not clarified. This study aimed to investigate the role of MIP-1beta in human EPCs and in neovasculogenesis in different diabetic animal models with hindlimb ischemia. EPCs chamber assay and in vitro tube formation assay were used to estimate the degree of EPC migration and tube formation abilities. Leprdb/JNarl mice, C57BL/6 mice fed a high-fat diet, and streptozotocin-induced diabetic mice were used as different diabetic animal models. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively. MIP-1beta impaired human EPC function for angiogenesis in vitro. Plasma MIP-1beta levels were up-regulated in type 2 DM patients. MIP-1beta inhibition enhanced the function and the C-X-C chemokine receptor type 4 expression of EPCs from type 2 diabetic patients, and improved EPC homing for ischemia-induced neovasculogenesis in different types of diabetic animals. MIP-1beta directly impaired human EPC function. Inhibition of MIP-1beta improved in vitro EPC function, and enhanced in vivo EPC homing and ischemia induced neovasculogenesis, suggesting the critical role of MIP-1beta for vasculopathy in the presence of DM. PMID- 29987449 TI - Fetal Physiologically Based Pharmacokinetic Models: Systems Information on the Growth and Composition of Fetal Organs. AB - BACKGROUND: The growth of fetal organs is a dynamic process involving considerable changes in the anatomical and physiological parameters that can alter fetal exposure to xenobiotics in utero. Physiologically based pharmacokinetic models can be used to predict the fetal exposure as time-varying parameters can easily be incorporated. OBJECTIVE: The objective of this study was to collate, analyse and integrate the available time-varying parameters needed for the physiologically based pharmacokinetic modelling of xenobiotic kinetics in a fetal population. METHODS: We performed a comprehensive literature search on the physiological development of fetal organs. Data were carefully assessed, integrated and a meta-analysis was performed to establish growth trends with fetal age and weight. Algorithms and models were generated to describe the growth of these parameter values as functions of age and/or weight. RESULTS: Fetal physiologically based pharmacokinetic parameters, including the size of the heart, liver, brain, kidneys, lungs, spleen, muscles, pancreas, skin, bones, adrenal and thyroid glands, thymus, gut and gonads were quantified as a function of fetal age and weight. Variability around the means of these parameters at different fetal ages was also reported. The growth of the investigated parameters was not consistent (with respect to direction and monotonicity). CONCLUSION: Despite the limitations identified in the availability of some values, the data presented in this article provide a unique resource for age-dependent organ size and composition parameters needed for fetal physiologically based pharmacokinetic modelling. This will facilitate the application of physiologically based pharmacokinetic models during drug development and in the risk assessment of environmental chemicals and following maternally administered drugs or unintended exposure to environmental toxicants in this population. PMID- 29987450 TI - EphB4 mediates resistance to antiangiogenic therapy in experimental glioma. AB - INTRODUCTION: Alterations in vascular morphogenesis are hallmarks of antiangiogenesis-resistant tumor vessels. Vascular morphogenesis is regulated by ephrinB2-EphB4 system which may induce different biological effects depending on the oncological and molecular contexts. It was the aim of the current study to characterize the influence of EphB4 on tumor microcirculation after antiangiogenic treatment using different SF126 glioma models. MATERIALS AND METHODS: Using an ecotropic transfection system, empty vector (pLXSN) or EphB4 (EphB4OE) overexpressing Phoenix-ECO cells were coimplanted with SF126 glioma cells subcutaneously (dorsal skinfold chamber, DSC) and orthotopically (cranial window, CW). Tumor volume was assessed by MRI. Intravital microscopy (IVM) allowed microcirculatory analysis (total {TVD} and functional vessel density {FVD}, diameter {D}, and permeability index {PI}) before and after antiangiogenic treatment (Sunitinib: DSC: 40 mg/kg BW, 6 days; CW: 80 mg/kg BW, 4 days). Immunohistochemistry included Pecam-Desmin, Ki67, TUNEL, and Caspase 3 stainings. RESULTS: EphB4OE induced large and treatment-resistant tumor vessels (FVD: Control/Su: 110 +/- 23 cm/cm2 vs. EphB4OE/Su: 103 +/- 42 cm/cm2). Maintenance of pericyte-endothelial cell interactions (Control: 80 +/- 12 vs. Control/Su: 47 +/- 26%; EphB4OE: 88 +/- 9 vs. EphB4OE/Su: 74 +/- 25%) and reduced antiproliferative (Control: 637 +/- 80 vs. Control/Su: 110 +/- 22; EphB4OE: 298 +/- 108 vs. EphB4OE/Su: 213 +/- 80) and proapoptotic responses (Control: 196 +/- 25 vs. Control / Su: 404 +/- 60; EphB4OE: 183 +/- 20 vs. EphB4OE/Su: 270 +/- 66) were observed under EphB4 overexpression. CONCLUSION: EphB4 overexpression leads to vascular resistance by altering vascular morphogenesis, pericyte coverage, and cellular proliferation/apoptosis in experimental SF126 glioma models. PMID- 29987451 TI - Wastewaters treatment containing phenol and ammonium using aerobic submerged membrane bioreactor. AB - Phenolic wastewater was treated using anaerobic submerged membrane bioreactor (ASMBR). Effect of different solids retention times on MBR performance was studied. Various ratios of carbon to nitrogen were used in the synthetic wastewaters. During the operation, phenol concentration of feed was changed from 100 to 1000 mg L-1. Phenol concentration was increased stepwise over the first 30 days and kept constant at 1000 mg L-1, thereafter. For the first 100 days, a chemical oxygen demand (COD) to N ratio of 100:5.0 was used and this resulted in phenol and COD removal more than 99 and 95%, respectively. However, the ammonium removal decreased from 95 to 40% by increasing the phenol concentration of feed, from 100 to 1000 mg L-1. For the last 25 days, a COD to N ratio of 100:2.1 was used due to the ammonium accumulation in the ASMBR. This led to the complete ammonium removal and no ammonium was detected in the ASMBR permeate. These results suggest that in the ASMBR at high phenol loading of 1000 mg L-1, COD to N ratio of the phenolic wastewater must be 100:2.1 for ammonium removal, while at low phenol loading, COD to N ratio of 100:5.0 can be used. PMID- 29987452 TI - Theoretical study on host-guest interaction between pillar[4]arene and molecules or ions. AB - In order to systematically explore the general rule of the host-guest chemistry for pillararenes, this work investigates the weak interactions between pillar[4]arene and some typical guests (anions, cations, and dumbbell-shaped molecules) by using density functional theory (DFT) calculations at the omegaB97XD/6-311G(d,p) level. The strong molecular recognition ability of pillar[4]arene has been discussed based on the geometry structure, electronic structure, and thermodynamic properties of the host-guest complexes. The results show that the equivalent lower and upper rims of the pillar[4]arene can be combined with both anion and cation, and its cavity can accommodate the alkyl part of the dumbbell-shaped molecule. The main host-guest interactions between pillar[4]arene and guests are hydrogen bond, cation-pi, anion-pi, and hydrophobic interaction by visualization of weak interactions using the Multiwfn program. Pillar[4]arene will form a more stable host-guest complex with the guest, which possesses conjugate structure and weak steric repulsion. This work intends to provide a theoretical basis for enriching the host-guest chemistry, understanding the supramolecular morphology, and expanding the applications of the pillararenes. PMID- 29987453 TI - Utilization of the renal angina index in PICU of a developing country for prediction of subsequent severe acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is independently associated with worsened morbidity and increased mortality in the pediatric intensive care unit (PICU). AKI risk score, termed renal angina index (RAI) is used in developed countries to predict subsequent severe AKI. Very few studies have investigated application of RAI in the PICU of a developing country. This prospective observational study aimed to predict severe subsequent AKI in children admitted to PICU using RAI. METHODS: Over 1 year, children admitted to PICU aged 1 month-18 years old, with no previous kidney disease, were included. RAI was assessed from 8 to 12 h of PICU admission (day 0). RAI was calculated from product of the renal risk and renal injury score. Renal angina positivity was defined as RAI >= 8. On day 3, serum creatinine was estimated and estimated glomerular filtrration rate (eGFR) calculated. RAI was correlated with presence/absence of subsequent (day 3) severe AKI. RAI positivity was also correlated with duration of PICU stay, need for dialysis, mechanical ventilation, and mortality. RESULTS: RAI positivity was seen in 16.7% cases, of which 36.2% developed AKI at 4 days vs. 2.3% in RAI-negative cases (p < 0.001). Mean duration of PICU stay in the RAI-positive group was 7.19 +/- 5.13 days vs. 4.72 +/- 2.71 days in the RAI-negative group (p < 0.001). Mortality was seen in 31.9% of RAI-positive cases vs. 2% in RAI-negative cases (p < 0.001). CONCLUSIONS: RAI could be used as a simple and important bedside tool to predict patients at risk of severe AKI. PMID- 29987454 TI - Artificial intelligence outperforms experienced nephrologists to assess dry weight in pediatric patients on chronic hemodialysis. AB - BACKGROUND: Dry weight is the lowest weight patients on hemodialysis can tolerate; correct dry weight estimation is necessary to minimize morbi-mortality, but is difficult to achieve. Here, we used artificial intelligence to improve the accuracy of dry weight assessment in hemodialysis patients. METHODS/RESULTS: We designed a neural network which used bio-impedancemetry, blood volume monitoring, and blood pressure values as inputs; output was artificial intelligence dry weight. Fourteen pediatric patients were switched from nephrologist to artificial intelligence dry weight. Artificial intelligence dry weight was higher (28.6%), lower (50%), or identical to nephrologist dry weight. Mean difference between artificial intelligence and nephrologist dry weights was 0.497 kg (- 1.33 to + 1.29 kg). In patients for whom artificial intelligence dry weight was lower than nephrologist dry weight, systolic blood pressure significantly decreased after dry weight decrease to artificial intelligence dry weight (77th to 60th percentile, p = 0.022); anti-hypertensive treatments were successfully decreased or discontinued in 28.7% of cases. In patients for whom artificial intelligence dry weight was higher than nephrologist dry weight, no hypertension was observed after dry weight increase to artificial intelligence dry weight; when present, symptoms of dry weight underestimation receded. CONCLUSIONS: Neural network predictions outperformed those of experienced nephrologists in most cases, proving artificial intelligence is a powerful tool for predicting dry weight in hemodialysis patients. PMID- 29987455 TI - Nephrotoxin exposure and acute kidney injury in critically ill children undergoing congenital cardiac surgery. AB - BACKGROUND: Though acute kidney injury (AKI) is often multifactorial, investigators are now emphasizing the specific contribution of nephrotoxins. This study examines the epidemiology of nephrotoxin exposure and nephrotoxin associated AKI among children undergoing congenital heart surgery (CHS). METHODS: This is a retrospective cohort study of children admitted following CHS between June 1, 2014, and September 30, 2014. Nephrotoxins were defined according to the Nephrotoxic Injury Negated by Just-in-time-Action (NINJA) collaborative; high nephrotoxin exposure was defined as receipt of >= 3 nephrotoxins concurrently. AKI was diagnosed according to KDIGO creatinine criteria. Severe AKI was defined as KDIGO stage >= 2. Poisson models were used to compute adjusted relative risk (aRR) of high nephrotoxin exposure for AKI. RESULTS: One hundred fifty-four children (median age 20.4 months, IQR 2.3-59.5) were included. One hundred thirty one (85.1%) received at least one nephrotoxin; 32 (20.8%) received >= 3 nephrotoxins. The most commonly administered medications were ketorolac (n = 74, 48.1%), aspirin (n = 62, 40.3%), ibuprofen (n = 51, 33.1%), vancomycin (n = 39, 25.3%), piperacillin/tazobactam (n = 35, 22.7%), and enalapril (n = 14, 9.1%). AKI occurred more commonly in those exposed to >= 3 nephrotoxins (62.5 vs. 50.8%); this was not statistically significant after adjusting for confounders (aRR = 1.2, 95% CI 0.9-1.7). Severe AKI was similar between those with and without high nephrotoxin exposure (21.9 vs. 19.7%, p = 0.78). CONCLUSIONS: Nephrotoxin use is common following pediatric CHS. While we found no association between high nephrotoxin exposure and AKI, this may be related to the multifactorial nature of AKI in this population. For many common nephrotoxins, less injurious agents exist and nephrotoxin exposure may represent a modifiable risk factor for AKI. PMID- 29987456 TI - Combination therapy with or without warfarin and dipyridamole for severe childhood IgA nephropathy: an RCT. AB - BACKGROUND: Two previous randomized controlled trials showed that treatment of severe childhood immunoglobulin A (IgA) nephropathy using prednisolone with azathioprine, heparin-warfarin, or dipyridamole prevented the increase of sclerosed glomeruli. Prednisolone alone, however, did not prevent further increase. These studies indicated the importance of immunosuppressants in the treatment. An additional pilot study using mizoribine instead of azathioprine enabled us to complete 2 years of combined regimen. It showed non-numerical inferior effectiveness compared with the azathioprine regimen. Further examination of the additional efficacy of warfarin and dipyridamole was required. METHODS: A randomized control trial of prednisolone and mizoribine with (group 1) or without (group 2) warfarin and dipyridamole was administered for treatment of 71 children with severe IgA nephropathy to evaluate the efficacy of additional warfarin and dipyridamole. RESULTS: Thirty of 34 patients (88.2%) in group 1, and 27 of 36 patients (75.0%) showed the disappearance of proteinuria as defined by early morning urinary protein to creatinine ratio of < 0.2 during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan-Meier method showed that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 (log-rank P = 0.04). There was no significant difference in pathological findings, but there was a tendency of increase of global sclerosis in group1 which might be related to warfarin. Most of the adverse effects were related to prednisolone, but fortunately transient. CONCLUSIONS: The balance between minimal benefits of warfarin/dipyridamole and potential adverse effects may be in favor of avoiding them in children with IgA nephropathy. PMID- 29987457 TI - Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible? AB - BACKGROUND: Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase enzyme deficiency. We present clinical, biochemical, and histologic findings in children with classical phenotypic presentation of Fabry disease. METHODS: A retrospective analysis was performed using charts from 14 children with confirmed diagnosis. Clinical parameters were evaluated. Globotriaosylsphingosine -lysoGb3- detection in plasma, podocyturia, and kidney biopsy were carried out in all cases. RESULTS: All patients except one demonstrated at least one symptom of Fabry disease. LysoGb3 levels were above the normal range in all patients. Podocyturia was documented in all patients. Kidney biopsy revealed glomerular, interstitial, vascular, and tubular changes on light microscopy in nearly all patients. Electron microscopy showed podocyte inclusions in all patients. CONCLUSIONS: No difference in symptomatology was discernible between boys and girls. Podocyturia was detectable in children serving as a possible early marker of kidney injury. LysoGb3 was elevated in all cases, emphasizing the importance for diagnosis especially in female patients with normal alphaGal A activity. A possible association between lysoGb3 and symptom severity and histological involvement in kidney biopsy should be assessed in prospective studies with enough statistical power to determine if lysoGb3 can be used to predict nephropathy in children with Fabry disease. PMID- 29987459 TI - Ab-normal saline in abnormal kidney function: risks and alternatives. AB - Intravenous 0.9% saline has saved countless lives since it was introduced over a century ago. It remains the most widespread crystalloid in both adult and pediatric practice. However, in recent years, evidence of deleterious effects is accruing. These include increased mortality, acute kidney injury (AKI), metabolic acidosis, and coagulopathy. The predominant cause for these sequelae appears to be the excess chloride concentration of 0.9% saline relative to plasma. This has led to development of balanced isotonic solutions such as PlasmaLyte. This review summarizes current evidence for adverse effects of chloride-rich intravenous fluid and considers whether 0.9% saline should still be used in 2018 or abandoned as a historical treatment in favor of balanced crystalloid solutions. PMID- 29987458 TI - Renal progression factors in young patients with tuberous sclerosis complex: a retrospective cohort study. AB - BACKGROUND: Renal pathology in tuberous sclerosis complex (TSC) is characterized by the growth of angiomyolipoma and renal cysts, and in rare cases renal cell carcinoma. Other consequences of renal involvement in TSC, including hypertension, proteinuria, and hyperfiltration, are not well studied. We aimed to analyze the early manifestations of the renal TSC phenotype in a young TSC cohort and to explore common, modifiable risk factors. METHODS: In this retrospective cohort study, TSC patients attending the TSC clinics of two tertiary hospitals were included. Data on demographics, history, genotype, kidney function, hematuria, proteinuria, blood pressure, and renal imaging were collected. RESULTS: Eighty patients were included, with a median age of 0.8 years (0.0-63.0) at first presentation, and a median follow-up time of 10.2 (0.4-41.0) years. Mutation analysis was available in 64 patients (80%). Renal lesions (cysts or angiomyolipoma) were observed in 55/73 (75%). Thirty-two percent (19/60) were hypertensive, 8/51 (16%) had proteinuria, and 18/71 (25%) had hyperfiltration (median eGFR 154 ml/min/m2). Six (7.5%) patients had developed end stage renal disease at the last follow-up. No association was found between hyperfiltration, hypertension, or proteinuria and CKD >= 3. Cox regression showed a significant positive association between the presence of a renal intervention and CKD >= 3 (Hazard-Ratio 3.91, P < 0.05). CONCLUSIONS: Besides renal cysts and angiomyolipoma, the modifiable progression factors hypertension, proteinuria, and hyperfiltration occur frequently and early in TSC patients. This represents a preventive treatment target. PMID- 29987460 TI - Expert consensus guidelines for the genetic diagnosis of Alport syndrome. AB - Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9 related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability. PMID- 29987461 TI - Hydroxyobtustyrene protects neuronal cells from chemical hypoxia-induced cell death. AB - Hydroxyobtustyrene is a derivative of cinnamyl phenol isolated from Dalbergia odorifera T. Chen. The heartwood, known as 'JiangXiang', is a traditional Chinese medicine. Previous studies showed that hydroxyobtustyrene inhibited the biosynthesis of prostaglandins, which are mediators of neuronal cell death in ischemia. However, it currently remains unclear whether hydroxyobtustyrene protects neurons against ischemic stress. In the present study, we investigated the protective effects of hydroxyobtustyrene against sodium cyanide (NaCN) induced chemical ischemia. Hippocampal neurons were cultured from the cerebral cortices of E18 Wistar rats. The effects of hydroxyobtustyrene on neuronal survival and trophic effects were estimated under lower and higher cell density conditions. After the treatment of 1 mM NaCN with or without hydroxyobtustyrene, an MTT assay, Hoechst staining, and immunocytochemistry for cyclooxygenase (COX) 2 were performed. Hydroxyobtustyrene increased cell viability under lower, but not normal density conditions. Neither the neurite number nor the length was influenced by hydroxyobtustyrene. NaCN significantly decreased viability and increased fragmentation in cell nuclei, and these changes were prevented by hydroxyobtustyrene. Moreover, NaCN increased the number of COX-2-positive neurons, and this was significantly prevented by the co-treatment with hydroxyobtustyrene. Therefore, hydroxyobtustyrene protected cultured hippocampal neurons against NaCN-induced chemical ischemia, which may be mediated by the inhibition of COX-2 production. PMID- 29987462 TI - CH4 flux and methanogen community dynamics from five common emergent vegetations in a full-scale constructed wetland. AB - To investigate the effects of emergent plants on CH4 efflux and elucidate the key factors responsible for these effects, annual monitoring of CH4 emissions and methanogen community dynamics in a full-scale constructed wetland (CW) was conducted. Five emergent plants (Typha orientalis, Cyperus alternifolius, Arundo domax, Iris pseudacorus, and Thalia dealbata) commonly used in CWs were selected for investigation. The greatest CH4 flux (annual mean 19.4 mg m-2 h-1) was observed from I. pseudacorus, while the lowest CH4 flux (7.1 mg m-2 h-1) was observed from Thalia dealbata. The CH4 flux from five emergent plants showed marked seasonal variation. Total nitrogen (TN) and total phosphorous (TP) were weakly correlated with CH4 emissions, whereas total carbon (TC) and root biomass of plants were positively correlated with CH4 emissions. Quantitative real-time PCR (q-PCR) analysis indicated that the gene abundance of eubacterial 16S rRNA, particulate methane monooxygenase (pmoA) and methyl coenzyme M reductase (mcrA) significantly differed among plant species. Differences in TC, root biomass, and dissolved oxygen (DO) caused by plant species were potential factors responsible for differences in methanogens, methanotrophs, and CH4 emissions. Methanobacteriaceae, Methanoregulaceae, Methanomicrobiaceae, and Methanosarcinaceae were the dominant families of methanogens. The pathways of methanogenesis from the five emergent plants differed, with the main pathway being hydrogenotrophic, while both hydrogenotrophic and acetotrophic methanogens were involved in A. domax. Redundancy analysis (RDA) further indicated that emergent plant types had a profound influence on the methanogenic communities. Taken together, these results suggest emergent plant species can significantly influence CH4 fluxes in CW through microbial communities, biochemical pathways for methanogenesis, TC, and DO. Furthermore, plant species in CWs should be considered an important factor in evaluating greenhouse gases emission. Finally, it is necessary to effectively manage CWs vegetation to maximize their environmental benefits. Graphical abstract ?. PMID- 29987463 TI - New applied pharmacological approach/trend on utilization of agro-industrial wastes. AB - This study aimed to transform the locally available lignocellulosic residual palm frond (PF) and rice straw (RS) wastes into multifunction added products like methylated cellulose and sulfated and phosphorylated hemicelluloses by simple processes. Hydrolysis with 2 N sulfuric acid was the most suitable reaction for microcrystalline cellulose production. The characteristics of the prepared products were studied to obtain the optimum reaction conditions. Palm frond hemicellulose (PFHC) recorded the highest antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans (22, 22, 26 mm), respectively, and phosphorylated palm frond hemicellulose (PPFHC) exhibited the highest potential antioxidant activity of approximately 60%, suggesting a possible correlation between the two bioactivities. Most of extracted celluloses and their derivatives had a variety of promising probiotic activities which are expected to reduce the side effects of the gastric mucosa and possibly play a role in curing the gastric ulcer. Accordingly, the determination of anti inflammatory and gastroprotective activity results revealed that methylcellulose, sulfated and phosphorylated hemicelluloses showed anti-inflammatory and gastroprotective activities and the capability of all tested compounds to ameliorate the ethanol-induced gastric ulcer in rats' stomach. All results recommended PF and RS and their derivatives to be used as a medicinal food. PMID- 29987464 TI - Process optimization via response surface methodology in the physico-chemical treatment of vegetable oil refinery wastewater. AB - The present paper investigates the efficiency of coagulation/flocculation process using aluminum sulfate as coagulant and CHT industrial flocculent as coagulant aid/flocculent in the treatment of vegetable oil refinery wastewater (VORW). The process optimization was conducted in two steps, jar test experiments for preliminary evaluation to identify the most influencing factors and response surface methodology using Box-Behnken design to investigate the effects of three major factors and their interactions. The variables involved were the coagulant concentration (X1), flocculent dosage (X2), and initial pH (X3) of water samples, while the responses were COD removal (Y1) and residual turbidity (Y2). The optimal conditions obtained by solving the quadratic regression models, as well as by analyzing the response surface contour plots, were as follows: 2.4 g/L of coagulant (aluminum sulfate), 60.05 mg/L of flocculent, and about 9.23 as initial pH. Under these conditions, the coagulation/flocculation treatment was able to achieve 99% of COD removal with total turbidity elimination (100% removal). Analysis of variance showed high variance coefficient (R2) values of 0.929 and 0.836 for COD and turbidity removals, respectively, thus ensuring a satisfactory adjustment of the second-order regression model with the experimental data. This statistical design methodology was demonstrated as an efficient and feasible approach for the optimization of coagulation/flocculation treatment. PMID- 29987465 TI - Correction to: Brevibacillus laterosporus isolated from the digestive tract of honeybees has high antimicrobial activity and promotes growth and productivity of honeybee's colonies. AB - The original publication of this paper contains a mistake. The correct affiliation no. 3 is shown in this paper. PMID- 29987466 TI - Comparative effect of organic amendments on physio-biochemical traits of young and old bean leaves grown under cadmium stress: a multivariate analysis. AB - The current study investigated the influence of organic amendments on cadmium (Cd) uptake and its effects on biochemical attributes of young and old leaves of bean. Bean seedlings were exposed to two levels of Cd (25 and 100 MUM) in the presence and absence of different levels of ethylenediaminetetraacetic acid (EDTA) and citric acid (CA). An increase in Cd concentration in growth medium significantly enhanced Cd accumulation in bean roots and shoot. Cadmium stress increased the production of H2O2 which resulted in lipid peroxidation and decreased chlorophyll contents. The presence of organic amendments significantly affected Cd accumulation and toxicity to bean plants. Application of EDTA alleviated Cd toxicity in terms of chlorophyll contents, H2O2 contents, and lipid peroxidation possibly by chelating toxic Cd ions, and as such forming Cd-EDTA complexes. The presence of CA decreased Cd toxicity by decreasing its uptake. The biochemical responses (H2O2 contents, lipid peroxidation, and chlorophyll contents) of bean plants were more severely affected by Cd treatments in old leaves compared to young leaves. This study shows that the effect of CA and EDTA on biochemical behavior of Cd varies greatly with applied levels of Cd and amendments as well as the age of leaves. Based on the results, it is proposed that the presence of organic amendments can greatly affect biogeochemical behavior of Cd in the soil-plant system (ecosystem). PMID- 29987467 TI - Valorization of biochars from pinewood gasification and municipal solid waste torrefaction as peat substitutes. AB - Gasification and torrefaction have both gained significant interest as bioenergy techniques. During biomass gasification together with fuel gas, carbon-rich solid substances are produced, whereas torrefaction process is mainly used to prepare a final product with higher calorific value and carbon content than the feedstock, through a low temperature pyrolysis. Both materials (carbon wastes from gasification and torrefied product) could be classified as alternatives to biochar obtained from slow pyrolysis of biomass. The use of biochar, typically from the slow pyrolysis of biomass, as soil amendment and, more recently, as growing media components has been widely researched. However, to our knowledge, no studies have compared the use of biochar from gasification and torrefaction as growing media component for growing media formulation. The objective of this work was to study the effect of two biochars on peat-based growing media: a pinewood gasification biochar (BG) and a biochar (BT) obtained by torrefaction of the organic fraction of municipal solid waste. Growing media mixing PT (peat) with 50%vol of BG or BT were prepared and characterized according to their chemical, thermal and hydrophysical properties. Phytotoxic experiments and growth of Lolium perenne were also performed. Results indicated that peat substitution in growing media by BG and BT at a 50%vol ratio improved their hydrophysical properties. Specifically, bulk density increased more than 50%, air space increased by 43%, the increment of the total porosity was 20%, and, finally, the water holding capacity increased by 18.3%. Significantly, a positive effect on plant biomass production (yield increment: 274%) was observed after addition of BT, whereas no significant differences were observed after addition of BG biochar. Therefore, it can be concluded that both BT and BG could be used as peat substitutes in growing media formulation. PMID- 29987468 TI - Concentrations of PCDD/Fs in the neighborhood of a hazardous waste incinerator: human health risks. AB - In 1996-1998, a wide surveillance program was initiated in the vicinity of a new hazardous waste incinerator (HWI) placed in Constanti (Catalonia, Spain), which started its regular operations in 1999. The program was aimed at assessing the environmental impact of the facility on the surrounding environment, as well as to evaluate the potential risks for the population living in the neighborhood. Since then, among other measurements, the concentrations of polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) have been periodically determined in soil and herbage samples. This study shows the results, corresponding to the period 2013-2016. Data were compared with those obtained in the baseline survey (1996 1998), as well as with those of the previous survey (2011-2012). The median PCDD/F concentrations in soils were 0.44 and 0.33 ng toxic equivalent (I-TEQ)/kg in 2015 and 2016, respectively, with a significant decrease in relation to the baseline survey, and a non-significant decrease between 2015 and 2016. In turn, PCDD/F levels in vegetation showed some fluctuations over time, being the concentrations of PCDD/Fs in 2013 very similar to those found in 2012 (1.11 and 1.23 ng I-TEQ/kg, respectively). These concentrations notably decreased along the three last campaigns (0.16, 0.23, and 0.17 ng I-TEQ/kg in 2014, 2015, and 2016, respectively). These changes would be more related to a number of environmental factors rather than to a variation of PCDD/F emissions by the HWI. With respect to human health risks, exposure to PCDD/Fs in the area under potential influence of the HWI is not of concern, as the current environmental concentrations of PCDD/Fs do not mean additional carcinogenic or non-carcinogenic risks for the local population. PMID- 29987469 TI - Emerging contaminants removal by granular activated carbon obtained from residual Macauba biomass. AB - The removal of emergent contaminants via adsorption on granular activated carbon, prepared from Macauba palm, has been studied, contributing to the recovery of the residual biomass, endocarp, obtained in the Macauba palm oil extraction process. The material was characterized by different techniques, such as Raman spectroscopy, thermal analysis, adsorption/desorption of N2, zeta potential, and scanning electron microscopy. The N2 adsorption studies showed that the material presents wide micropores and narrow mesopores, and has a surface area of 907.0 m2 g-1. Its maximum adsorption capacity towards the three main emerging contaminants (bisphenol A, ethinylestradiol, and amoxicillin) is much higher than that obtained with benchmark adsorbents (0.148, 0.104, and 0.072 mmol g-1, respectively). The influence of temperature and pH on the adsorption was also analyzed, allowing an improved description of the adsorption mechanism and showing very promising results. PMID- 29987470 TI - Several newly discovered Mo-enriched plants with a focus on Macleaya cordata. AB - Phytoremediation as an alternative strategy has been a widespread attention. The screening of enriched plants and hyperaccumulators is the key of the strategy. So this study examined the status of heavy metal pollution in molybdenum (Mo) mine soils, metal accumulation in plants growing on mine, and their tolerance strategies. The analysis of 14 soils and 27 plant samples in mining area showed that Mo, zinc (Zn), and cadmium (Cd) concentrations exceeded soil safety standards and their levels varied in 27 plant samples. Mo was the heavy pollution with an average total content of 256.1 mg/kg in soils. As Mo-enriched plants, Mo concentrations of Macleaya cordata (Willd.) R. Br. and Morus australis Poir. were 704.4 and 772.4 mg/kg, respectively. M. cordata was selected as the research material, due to its high biomass. Molybdenum significantly decreased the biomass and photosynthesis of M. cordata at high concentration (> 200 MUmol/L), but its biomass and photosynthesis reached the maximum after 50 MUmol/L Mo treatment, respectively. Analysis of the subcellular distribution and chemical speciation showed that Mo was distributed a certain way in the extracts and that this suggested that it may be present in cell wall and soluble fraction of roots (51.9 63.9%; 26.1-44.7%) or shoots (30.0-44.4%; 47.3-56.0%) and complexed to organic acid, pectate, oxalate, and protein. This might be responsible for the adaptation of M. cordata to Mo stress. Therefore, M. cordata could serve as a potential plant to utilize for the phytoremediation of Mo-contaminated soil. PMID- 29987471 TI - The joint toxicity effect of five antibiotics and dibutyl phthalate to luminescent bacteria (Vibrio fischeri). AB - Antibiotics and phthalate esters are two kinds of emerging pollutants and are ubiquitous in the aquatic ecosystem. To date, few studies analyzed the combined toxicity of the mixtures of antibiotics and phthalate esters, and their joint toxicity effect mode remains unknown. Here, we investigated the single and joint toxicity of dibutyl phthalate (DBP) and five antibiotics, namely, oxytetracycline hydrochloride (OTC), chlortetracycline hydrochloride (CTC), sulfamethazine (SMZ), sulfamerazine (SMR), and sulfadiazine (SD), to luminescent bacteria of Vibrio fischeri. The median effect concentration (EC50) values of the test chemicals were ranked as CTC (6.67 mg/L) > OTC (25.12 mg/L) > SD (67.61 mg/L) > SMR (141.51 mg/L) > DBP (148.38 mg/L) > SMZ (245.07 mg/L). The joint toxicities of the binary mixtures of antibiotics and DBP were evaluated by the concentration addition (CA) and independent action (IA) models. The joint toxicity effects of CTC-DBP, OTC DBP, SMZ-DBP, SMR-DBP, and SD-DBP all appeared to be synergism. Our study revealed that sulfonamides combined with DBP could be as toxic as or even more toxic than tetracycline. Thus, the joint toxicity effect should be considered when assessing the ecological risks of binary or multicomponent pollutants. PMID- 29987472 TI - A Facile Approach for the Preparation of Nano-size Zinc Oxide in Water/Glycerol with Extremely Concentrated Zinc Sources. AB - A facile process to prepare zinc oxide (ZnO) nanoparticles from an aqueous zinc chloride (ZnCl2) solution and an aqueous hydroxide solution under a glycerol stabilizer at room temperature was developed. ZnCl2 aqueous solutions as concentrated as 65-80 wt% were used as the concentrated zinc source. The concentration of ZnCl2 solutions and the molar ratio of glycerol to Zn2+ had obvious effects on the sizes and shapes of the ZnO nanoparticles. The shape of ZnO nanoparticles changed from rods approximately 50-120 nm long and 30-70 nm in diameter to globular with diameters of approximately 20 nm with the increasing of the concentration of the ZnCl2 solution and the mole ratio of glycerol to Zn2+. Glycerol, as a stabilizer, played an important role in the formation of ZnO nanostructures at room temperature, even for a highly concentrated zinc source. PMID- 29987473 TI - The safety paradox in ethics training: a case study on safety dynamics within a military ethics train-the-trainer course. AB - There is considerable support for the idea that an atmosphere of safety can foster learning in groups, especially during ethics training courses. However, the question how safety dynamics works during ethics courses is still understudied. This article aims to investigate safety dynamics by examining a critical incident during a military ethics train-the trainer course during which safety was threatened. We examine this incident by means of a four-factor analysis model from the field of Theme-Centered Interaction (TCI). We show that during ethics training courses a safety paradox can occur, involving a tension between honesty and openness to other perspectives and values. Finally, we discuss how trainers can foster safety during ethics training. PMID- 29987474 TI - Magnesium deficiency prevents high-fat-diet-induced obesity in mice. AB - AIMS/HYPOTHESIS: Hypomagnesaemia (blood Mg2+ <0.7 mmol/l) is a common phenomenon in individuals with type 2 diabetes. However, it remains unknown how a low blood Mg2+ concentration affects lipid and energy metabolism. Therefore, the importance of Mg2+ in obesity and type 2 diabetes has been largely neglected to date. This study aims to determine the effects of hypomagnesaemia on energy homeostasis and lipid metabolism. METHODS: Mice (n = 12/group) were fed either a low-fat diet (LFD) or a high-fat diet (HFD) (10% or 60% of total energy) in combination with a normal- or low-Mg2+ content (0.21% or 0.03% wt/wt) for 17 weeks. Metabolic cages were used to investigate food intake, energy expenditure and respiration. Blood and tissues were taken to study metabolic parameters and mRNA expression profiles, respectively. RESULTS: We show that low dietary Mg2+ intake ameliorates HFD-induced obesity in mice (47.00 +/- 1.53 g vs 38.62 +/- 1.51 g in mice given a normal Mg2+-HFD and low Mg2+-HFD, respectively, p < 0.05). Consequently, fasting serum glucose levels decreased and insulin sensitivity improved in low Mg2+-HFD fed mice. Moreover, HFD-induced liver steatosis was absent in the low Mg2+ group. In hypomagnesaemic HFD-fed mice, mRNA expression of key lipolysis genes was increased in epididymal white adipose tissue (eWAT), corresponding to reduced lipid storage and high blood lipid levels. Low Mg2+-HFD-fed mice had increased brown adipose tissue (BAT) Ucp1 mRNA expression and a higher body temperature. No difference was observed in energy expenditure between the two HFD groups. CONCLUSIONS/INTERPRETATION: Mg2+-deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity. PMID- 29987475 TI - Modelling perception-action coupling in the phenomenological experience of "hitting the wall" during long-distance running with exercise induced muscle damage in highly trained runners. AB - BACKGROUND: "Hitting the wall" (HTW) can be understood as a psychophysiological stress process characterised by (A) discrete and poignant onset, (B) dynamic interplay between physiological, affective, motivational, cognitive, and behavioural systems, and (C) unintended alteration of pace and performance. A preceding companion article investigated the psychophysiological responses to 20 km self-paced treadmill time trials after producing exercise-induced muscle damage (EIMD) via a standardised muscle-lengthening contraction protocol. METHODS: A 5-step procedure was applied determining the extent to which the observed data fit the hypothesised cause-effect relationships. Running with EIMD negatively impacts performance fatigability via (A) amplified physiological responses and a non-adaptive distress response and (B) deterioration in perceived fatigability: increase in perceived physical strain precedes decrease in valence, which in turn precedes increase in action crisis, eventually dissolving the initially aspired performance goal. RESULTS: First, haematological indicators of EIMD predicted increased blood cortisol concentration, which in turn predicted increased performance fatigability. Second, perceived physical strain explained 44% of the relationship between haematological indicators of EIMD and valence, which in turn predicted increased action crisis, which in turn predicted increased performance fatigability. The observed data fitted the hypothesised dual-pathway model well with good model-fit indices throughout. CONCLUSIONS: The hypothesised interrelationships between physiological strain, perception, and heuristic and deliberative decision-making processes in self-regulated and goal directed exercise behaviour were applied, tested, and confirmed: amplified physiological strain and non-adaptive distress response as well as strain perception-thinking-action coupling impact performance fatigability. The findings provide novel insights into the psychophysiological processes that underpin the phenomenological experience of HTW and alteration in pacing behaviour and performance. PMID- 29987476 TI - Medicare, Metrics and Trust in the Future. AB - System improvements to Medicare are critical to ensure a stable and sustainable future. Measures and outcomes in Medicare are collaborative in foundation and have the potential to become even stronger. Utilization research, comparative effectiveness research and regulatory considerations must strive for best practice for the Medicare population. Government, regulatory, industry and academia should continue to work together for cost effective approaches that yield evidence-based interventions for positive health outcomes. Recommendations for improvements to the Medicare program are abundant and show strong potential to positively impact all of healthcare. These improvements will establish and maintain an even greater trust and positive view on what many consider a popular, vital social healthcare program in the U.S. PMID- 29987477 TI - The influence of BoLA-DRB3 alleles on incidence of clinical mastitis, cystic ovary disease and milk traits in Holstein Friesian cattle. AB - The major histocompatibility complex in cattle (BoLA) is regulated by genes that are closely related to the development of the immunological response to pathogens. The most polymorphic BoLA-DRB3.2 locus was analysed in 209 black-and white Holstein-Friesian cows in Poland in order to a better explanation of influence of MHC on immunity to diseases in dairy cattle. A total of 23 alleles were identified, among which the *24, *16 and *22 alleles were observed with the highest frequency. These alleles were analysed in terms of their association with the occurrence of mastitis, ovarian cysts, retained placenta and uterine abscesses as well as their contribution to production traits (milk yield, protein and fat percentage in milk). It was determined that the BoLA-DRB3.2 *22 and *16 alleles were associated with a lower risk of clinical mastitis; however, a statistical significance was observed only for the *22 allele. Clinical mastitis was observed at a frequency lower by 8% in cows with one copy of the *22 allele compared to cows with 0 copies of the allele. The presence of the *22 allele in the genotype was also associated with higher milk yield, although this association was not statistically significant. PMID- 29987478 TI - Cancer immune therapy for myeloid malignancies: present and future. AB - The myelodysplastic syndromes, the chronic myeloproliferative neoplasms, and the acute myeloid leukemia are malignancies of the myeloid hematopoietic stem cells of the bone marrow. The diseases are characterized by a dysregulation of the immune system as both the cytokine milieu, immune phenotype, immune regulation, and expression of genes related to immune cell functions are deregulated. Several treatment strategies try to circumvent this deregulation, and several clinical and preclinical trials have shown promising results, albeit not in the same scale as chimeric antigen receptor T cells have had in the treatment of refractory lymphoid malignancies. The use of immune checkpoint blocking antibodies especially in combination with hypomethylating agents has had some success-a success that will likely be enhanced by therapeutic cancer vaccination with tumor specific antigens. In the chronic myeloproliferative neoplasms, the recent identification of immune responses against the Januskinase-2 and calreticulin exon 9 driver mutations could also be used in the vaccination setting to enhance the anti-tumor immune response. This immune response could probably be enhanced by the concurrent use of immune checkpoint inhibitors or by vaccination with epitopes from immune regulatory proteins such as arginase-1 and programmed death ligand-1. Herein, we provide an overview of current cancer immune therapeutic treatment strategies as well as potential future cancer immune therapeutic treatment options for the myeloid malignancies. PMID- 29987479 TI - Exercise Oximetry and Laser Speckle Contrast Imaging to Assess Microvascular Function in Lower Extremity Peripheral Artery Disease. PMID- 29987480 TI - Clinical Implications for the Early Treatment of Benign Prostatic Enlargement (BPE): a Systematic Review. AB - PURPOSE OF REVIEW: Therapeutic options for the management of lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE) have considerably increased in recent years. However, the ideal timing to initiate medical treatment of LUTS/BPE has not been fully established. The aim of this review was to systematically collect available evidence on the influence of early treatment on the natural history of LUTS/BPE patients. RECENT FINDINGS: A systematic literature search from January 1996 until April 2018 was performed by combining the following MESH terms: Lower Urinary Tract Symptoms, Benign Prostatic Enlargement, male, medical treatment, surgical treatment, early treatment/intervention, and early intervention/treatment. The Medline, PubMed, and Scopus databases were searched. Each article title and abstract was reviewed for relevance and appropriateness with regard to the topic of this review. In recent years, the medical armamentarium for the management of LUTS secondary to BPE has been extensively implemented, significantly improving treatment outcomes and markedly reducing the need for BPE surgery. Early intervention in patients at risk for disease progression may offer better clinical outcomes compared to a deferred approach. However, evidences supporting early treatment are scarce, and criteria to discriminate patients that could mostly benefit from immediate treatment remain poorly defined. Moreover, as a result of delayed surgery after prolonged medical treatment, patients undergoing surgical relief show larger prostates, older age, and comorbidities. Nevertheless, technological advancements in surgical techniques have largely counterweighed this critical scenario, and commonly, a non-pejorative trend has been reported in perioperative complications. The timeliest moment to start a medical treatment in LUTS/BPE patients is still undefined, and unexpectedly, peer-reviewed evidence remains scarce. Further studies are awaited to better discriminate patients who mostly benefit from early treatment of LUTS/BPE. PMID- 29987481 TI - Luteoloside Protects the Uterus from Staphylococcus aureus-Induced Inflammation, Apoptosis, and Injury. AB - Luteoloside is a flavonoid extracted from several natural herbs that exhibits anti-microbial and anti-inflammation properties. Our study mainly identified the anti-inflammatory mechanism of action of luteoloside in Staphylococcus aureus induced endometritis. Histopathological observations and myeloperoxidase (MPO) activity showed that luteoloside could protect the uterus from S. aureus-induced damage and ameliorate the infiltration of inflammatory cells. Quantitative PCR (qPCR) and ELISA analysis also revealed that luteoloside could decrease the expression of the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 and increase the expression of the anti-inflammatory cytokine IL-10 both in vivo and in vitro. However, western blot analysis revealed that luteoloside inhibited the expression of TLR2 and IL-8 and inhibited the phosphorylation of IkappaBalpha and NF-kappaB p65. Moreover, luteoloside inhibited the apoptosis of endometrial epithelial cells (EECs), suppressed the phosphorylation of p53, and decreased the expression of caspase-3 induced by S. aureus. Furthermore, this study showed that luteoloside inhibited the expression of Bax but increased the expression of Bcl 2. These results indicate that luteoloside has anti-inflammatory properties by inhibiting the TLR2 and NF-kappaB signaling pathways and plays an anti-apoptotic role in S. aureus-induced endometritis, which may be valuable for the clinical treatment of S. aureus-induced inflammation. PMID- 29987482 TI - IDH2 Deficiency in Microglia Decreases the Pro-inflammatory Response via the ERK and NF-kappaB Pathways. AB - In various neuronal diseases, the activation of microglia contributes to the production of excessive neurotoxic factors, such as pro-inflammatory mediators. In particular, the overproduction of pro-inflammatory cytokines and nitric oxide (NO) has critical effects on the development of neurodegenerative diseases and gliomas in the brain. Recent studies have suggested that isocitrate dehydrogenase 2 (IDH2) plays a key role in inducing gliomas and neurodegeneration. IDH2 dysfunction has been linked to various cancers and neurodegenerative diseases associated with uncontrolled inflammatory responses, such as the excessive generation of pro-inflammatory cytokines. In this study, we demonstrate that IDH2 contributes to the regulation of pro-inflammatory mediators in microglia. The downregulation of IDH2 decreased the lipopolysaccharide (LPS)-induced pro inflammatory response in BV-2 and primary microglial cells. Furthermore, IDH2 deficiency downregulated pro-inflammatory mediators via modulation of the ERK and NF-kappaB pathways. These results indicate that IDH2 is a potential target for the regulation of pro-inflammatory responses in LPS-activated microglial cells. Our findings also provide a basis for the development of new therapies for pro inflammatory responses in dysfunction-associated neuronal diseases. PMID- 29987483 TI - Discussion of Shue et al. "Fat Injection: A Systemic Review of Injection Volumes by Facial Subunit". PMID- 29987484 TI - Correction to: Buttock Lifting Using Elastic Thread (Elasticum(r)) with a New Classification of Gluteal Ptosis. AB - The original version of this article unfortunately contained a mistake. On page 8, in Table 2, the superscripts for the vertical and horizontal axes are incorrect. The correct information is shown below. PMID- 29987485 TI - Muscle Insertion and Strength of the Muscle Contraction as Guidelines to Enhance Duration of the Botulinum Toxin Effect in the Upper Face. AB - BACKGROUND: In this series of patients the cutaneous insertion and strength of voluntary contraction of the muscles in the upper third of the face were used as guidelines for botulinum toxin application named "BTA Codes." METHOD: Anatomical dissection of fresh cadavers identified the shape and cutaneous insertions of the muscles in the upper third of the face. Patient voluntary contraction of the muscles in the upper third of the face created different patterns of skin lines classified by the 4-grade Facial Wrinkle Scale. For botulinum toxin application injections points followed the muscle cutaneous insertion and dose the 4-grade Facial Wrinkle Scale. RESULTS: Injection points ranged from 3 to 23 points per patient, average of 9.4 points. Dose per point varied from 2.5 to 7.5 U, ranging from 12.5 to 72.5 U per patient, average of 33.82 U. Skin lines resulting from the voluntary contraction of the muscle prior to toxin application were stated as baseline 1. The absence of skin lines and muscle activity on day fifteen after toxin application defined baseline 2. Skin lines resulting from the recovered voluntary contraction of the muscle after toxin application like those of baseline 1 established baseline 3. The botulinum toxin effect was the time elapsed between baselines 2 and 3, ranging from 171 to 204 days, average of 183.72 days, greater than the 3 or 4 months reported in the literature. CONCLUSION: "BTA Codes" is a set of rules to apply botulinum toxin supported by muscle anatomy and degree of voluntary contraction to enhance the duration of its effect. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29987486 TI - Ideals of Facial Beauty Amongst the Chinese Population: Results from a Large National Survey. AB - : Surgical and non-surgical aesthetic treatments are very popular throughout Asia and in particular in China. With the globalisation and immigration of Chinese people to other countries where many seek treatment from Western-trained doctors, it is important to understand the ideals of beauty amongst Chinese people so as to achieve optimal results. We conducted an online survey to understand the preference of Han Chinese laypersons for facial shape, profile (straight, convex, concave), jaw angle and shape, and shape of the chin, nose, and lips. In addition, the participants were asked about their educational level, geographic location, likelihood to have cosmetic surgery, preference for surgical or non surgical cosmetic procedures and whether "being beautiful" would affect their daily life. A total of 1417 responses were collected from 599 male and 818 female participants, the majority of them who were 25-35 years old (58.93%). The responses showed that the majority of participants preferred an oval face shape, with a smoothly tapered jaw angle for both men and women, round and pointy chin for both genders, straight to concave nose profile and full lips with well defined cupid's bow. Most responders indicated they were not willing to undergo cosmetic surgery; however, when given a choice between surgical and non-surgical cosmetic procedures, 82.22% of the participants preferred non-surgical procedures. The majority of respondents (83%) thought that being beautiful has an effect on daily life and improves quality of life. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29987487 TI - "No Drain, No Gain": Simultaneous Seroma Drainage and Tissue Expansion in Pre pectoral Tissue Expander-Based Breast Reconstruction. AB - Seromas represent the most frequent complication following immediate breast reconstruction surgery, in particular when acellular dermal matrix or synthetic meshes are used to add coverage to implants. Little information regarding breast seroma management is available in the literature. When seroma becomes clinically significant, current methods for its management consist of repeated needle aspiration. We report a fast, efficient, easy and riskless technique to perform serum aspiration in patients who underwent breast reconstruction with a tissue expander that allows simultaneous drainage and expansion of the implant at once. This procedure is safe, painless, does not need special supplies or additional costs and can be easily performed in ambulatory setting to manage breast seromas.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29987488 TI - Why Choose the Septum-Supero-Medial (SSM)-Based Mammaplasty in Patients with Severe Breast Ptosis: An Anatomical Point of View. AB - : Nipple-areola complex (NAC) loss is one of the most devastating complications of mastopexy or breast reduction, and it requires revisional procedures with poor aesthetic outcome. In high-risk patients, a free nipple graft could be a choice, but it is associated with the same aesthetic concerns for both patients and surgeons. We report our experience with the septum-supero-medial-based mammaplasty to treat 22 patients with severe breast ptosis (nipple-to-sternal notch distance > 40 cm). No NAC loss was observed. The study highlights surgical technical details and discusses anatomical considerations to justify the successful result. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29987489 TI - Intravenously Administered Novel Liposomes, DCL64, Deliver Oligonucleotides to Cerebellar Purkinje Cells. AB - Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra cerebral ventricular, or stereotactic parenchymal administration. We have developed a novel liposome (100 to 200 nm in diameter) formulation, DCL64, composed of dipalmitoyl-phosphatidylcholine, cholesterol, and poloxamer L64, which incorporates oligonucleotides efficiently (>= 70%). Confocal microscopy showed that DCL64 was selectively taken up by brain microvascular endothelial cells by interacting with low-density lipoprotein receptor (LDLr) family members on cell surface, but not with other types of lipid receptors such as caveolin or scavenger receptor class B type 1. LDLr family members are implicated in brain microvascular endothelial cell endocytosis/transcytosis, and are abundantly localized on cerebellar PCs. Intravenous administration of DCL64 in normal mice showed distribution of oligonucleotides to the brain, preferentially in PCs. Mice that received DCL64 showed no adverse effect on hematological, hepatic, and renal functions in blood tests, and no histopathological abnormalities in major organs. These studies suggest that DCL64 delivers oligonucleotides to PCs across the BBB via intravenous injection with no detectable adverse effects. This property potentially makes DCL64 particularly attractive as a delivery vehicle in treatments of SCAs. PMID- 29987490 TI - Molecular Epidemiology of Porcine Circovirus Type 3 Infection in Swine Herds in China. PMID- 29987491 TI - Haplogroup Context is Less Important in the Penetrance of Mitochondrial DNA Complex I Mutations Compared to mt-tRNA Mutations. AB - Mitochondrial diseases are a highly complex, heterogeneous group of disorders. Mitochondrial DNA variants that are linked to disease can exhibit variable expression and penetrance. This has an implication for mitochondrial diagnostics as variants that cause disease in one individual may not in another. It has been suggested that the sequence context in which a variant arises could influence the genotype-phenotype relationship. However, the consequence of sequence variation between different haplogroups on the expression of disease is not well understood. European haplogroups are the most widely studied. To ensure accurate diagnostics for patients globally, we first need to understand how, if at all, the sequence context in which a variant arises contributes to the manifestion of disease. To help us understand this, we used 2752 sequences from 33 non-human species that do not have disease. We searched for variants in the seven complex I genes that are associated with disease in humans. Our findings indicate that only three reported pathogenic complex I variants have arisen in these species. More importantly, only one of these, m.3308T>C, has arisen with its associated amino acid change in the studied non-human species. With the status of m.3308T>C as a disease causing variant being a matter of debate. This is a stark contrast to previous findings in the mitochondrial tRNA genes and suggests that sequence context may be less important in the complex I genes. This information will help us improve the identification and diagnosis of mitochondrial DNA variants in non European populations. PMID- 29987492 TI - Results from a 78-week, single-arm, open-label Phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD). AB - Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food. PMID- 29987493 TI - Dementia-a major public health problem: the role of in-patient psychiatric facilities. AB - This paper reviews data on admissions to Irish psychiatric units and hospitals for those suffering from organic mental disorders, in particular dementia, over the course of the last half century. Admission and census data from the National Psychiatric In-patient Reporting System (NPIRS) from 1963 to 2016 are examined and discussed in light of Ireland's ageing population. The NPIRS database was established in the 1960s to record admission and discharge activity in Irish psychiatric units and hospitals. Admission data from the database are presented in 5-yearly intervals from 1965 to 2015, while census data are presented for 1963 and 2016. PMID- 29987494 TI - Real-world incidence and prevalence of systemic lupus erythematosus in Alberta, Canada. AB - Systemic lupus erythematosus (SLE) is rather uncommon than rare. The purpose of this study was to estimate the incidence and prevalence of SLE in the population of Alberta, Canada, using administrative health data. Multiple population-based data sources, including the Alberta Health Care Insurance Plan Central Stakeholder Registry (AHCIP CSR), Fee-For-Service, and Hospital Discharge Abstract Database were used. Age- and sex-specific incidence and prevalence rates, and 95% confidence intervals (CI), were computed using the AHCIP CSR mid year population estimates as the denominator, for the period of 2000-2015. The overall incidence of SLE for all age groups was 4.43 (95% CI 3.65, 5.04) per 100,000 population. The overall incidence in male and female of all age groups was 1.26 (95% CI 0.72, 1.76) and 7.69 (95% CI 6.22, 8.81) per 100,000 population, respectively. A prevalence of 47.99 per 100,000 (male = 13.5, female = 83.2) of SLE was observed for the year 2000 and has increased to 90 (male = 25.5, female = 156.7) per 100,000 population in 2015. Over the 16-year period, the incidence of SLE in women was approximately six times higher than in men (odds ratio = 6.16). The highest and lowest incidence was recorded in 2001 and 2015, respectively. Despite the stable incidence of SLE, the findings of the study confirms that the prevalence of SLE has increased over the 16-year period. The increase in prevalence of SLE in Alberta will have an impact on health service utilizations. This finding can be used for planning and evaluating health services for this group of patients. Further studies are required to determine the economic burden of the condition. PMID- 29987495 TI - Inhalation exposure and potential health risk estimation of lanthanides elements in PM2.5 associated with rare earth mining areas: a case of Baotou city, northern China. AB - Particulate pollution, especially PM2.5 (particles with an aerodynamic equivalent diameter of 2.5 MUm or less), has received increased attention in China recently. In this study, PM2.5 samples were collected in August 2013 and April 2014 from different regions of Baotou, the largest rare earth elements (REEs) processing city in northern China. The concentrations and distribution patterns of REEs in PM2.5 were analyzed, and the inhalation exposure to REEs associated with PM2.5 was assessed. The results showed that the REEs levels were 56.9 and 15.3 ng m-3 in August 2013 and April 2014, respectively. These values are much higher than those in non-REEs mining areas. The distribution patterns of REEs exhibited LREE enrichment. The Eu and Ce anomalies displayed slightly positive and negative values, respectively, which were in accordance with the background soil and ore. The average daily intake amounts of REEs for population through inhalation exposure of PM2.5 in Baotou were in the range of 5.09 * 10-7 to 2.25 * 10-5 mg kg 1 day-1. PMID- 29987496 TI - Interactive effects of single, binary and trinary trace metals (lead, zinc and copper) on the physiological responses of Kandelia obovata seedlings. AB - Heavy metals are considered important environmental contaminants, and their mixture toxicity on plants has complex mutual interactions. The interactive effects of heavy metals on growth, photosynthetic parameters, lipid peroxidation and compatible osmolytes were studied in Kandelia obovata grown for 5 months in sediment treated with combinations of lead (Pb), zinc (Zn) and copper (Cu). The results showed no significant reduction of biomass under heavy metal stresses, except for decreased root biomass under higher Pb + Cu treatment, indicating high tolerance of K. obovata to heavy metal stress. Only the photosynthetic parameters, including net photosynthetic rate (Pn), stomatal conductance (Gs) and transpiration rate (Tr), decreased with increasing concentration of treatments (except for Pb + Cu and Pb + Zn + Cu). Trinary treatment (Pb + Zn + Cu) increased biomass and the photosynthetic parameters when compared to the external addition of binary metals. In the roots, biomass and soluble sugar content were lower under binary than trinary treatments, indicating that the combination of Zn and Cu exhibited improved effects of alleviating toxicity than each of them alone in Pb-containing combined treatments. In the leaves, Zn-containing combined treatments significantly decreased malondialdehyde (MDA), soluble sugar and proline content in low concentration, while Pb + Cu treatments significantly increased these parameters (P < 0.05). The correlation analysis showed that leaf MDA and proline content were negatively correlated with Zn concentration (P < 0.05). Zn could alleviate the effects of combined heavy metal stress, and Pb + Cu treatment showed synergistic effects in leaves. The positive correlations between MDA content and the osmotic parameters showed that osmotic stress and lipid membranes oxidation exist simultaneously under multiple heavy metal stresses. Therefore, biomass, Tr, leaf MDA, leaf proline content and soluble sugar content could indicate metal mixture toxicity to mangrove seedlings. PMID- 29987497 TI - Occipital Headaches and Neuroimaging in Children. AB - PURPOSE OF REVIEW: The goal of this review is to outline the prevalence and significance of occipital headaches in children and how they relate to neuroimaging findings. We seek to evaluate the concern that occipital headaches in children are indicative of secondary headache pathology by reviewing the yield of neuroimaging in pediatric patients with occipital headache location. RECENT FINDINGS: Occipital headaches are a common presentation of primary headache disorders in children, seen in 7-16% of children presenting for evaluation of headache and in up to 20% of children diagnosed with migraine in the emergency department. Review of recent literature confirms that in and of itself, occipital location of headache in a child with recurrent headache and a normal physical examination should not be regarded as worrisome. Headaches with associated signs on neurologic examination should be investigated for a secondary cause, regardless of headache location. Occipital headaches that do not meet criteria for a primary headache disorder should be evaluated for site-specific occipital headache conditions. Neuroimaging for recurrent headache in children who have normal neurological examinations has an overall low yield (0-4.1%) for actionable findings in recent studies. Importantly, an abnormal neurologic examination often predicts the presence of neuroimaging abnormalities. In the absence of an atypical history or abnormalities on clinical examination, occipital headaches in children are no more likely to be associated with intracranial pathology than headaches in other locations. If the child's headaches are otherwise consistent with migraine or another primary headache disorder, and the neurologic examination is normal, the yield of neuroimaging is low, and imaging can generally be deferred. PMID- 29987498 TI - The Confounding Effects of Non-cardiac Pathologies on the Interpretation of Cardiac Biomarkers. AB - PURPOSE OF REVIEW: Cardiac biomarkers play important roles in routine evaluation of cardiac patients. But while these biomarkers can be extremely valuable, none of them should ever be used by themselves-without adding the clinical context. This paper explores the non-cardiac pathologies that can be seen with the cardiac biomarkers most commonly used. RECENT FINDINGS: High-sensitivity troponin assay gained FDA approval for use in the USA, and studies demonstrated its diagnostic utility can be extended to patients with renal impairment. Gender-specific cut points may be utilized for high-sensitivity troponin assays. In the realm of the natriuretic peptides, studies demonstrated states of natriuretic peptide deficiency in obesity and in subjects of African-American race. Regardless, BNP and NT-proBNP both retained prognostic utilities across a variety of comorbid conditions. We are rapidly gaining clinical evidence with use of soluble ST2 and procalcitonin levels in management of cardiac disease states. In order to get the most utility from their measurement, one must be aware of non-cardiac pathologies that may affect the levels of biomarkers as although many of these are actually true values, they may not represent the disease we are trying to delineate. A few take-home points are as follows: 1. A biomarker value should never be used without clinical context 2. Serial sampling of biomarkers is often helpful 3. Panels of biomarkers may be valuable. PMID- 29987500 TI - [Is breastfeeding in public socially accepted? : Experiences and attitudes of the general population and breastfeeding mothers]. AB - BACKGROUND: Despite the undeniable benefits, breastfeeding in public has led in the past to controversies that gained a lot of media coverage. For this reason, the attitudes of the general population towards breastfeeding in public and the experiences of mothers who breastfeed in public were examined. OBJECTIVE: The objectives were to collect current data on the perception and acceptance of breastfeeding in public. MATERIALS AND METHODS: We surveyed 1003 respondents from the general population aged 14 years and over and 306 mothers with children of breastfeeding age on the subject of breastfeeding in public by means of computer assisted web interviewing. RESULTS: Of mothers, 6% reported that their experiences of breastfeeding in public tended to be rather or very negative. Of the general population sample, 66% held the fundamental opinion that breastfeeding should be possible everywhere at all times, compared to 80% of mothers (p < 0.05). Special differences can be seen for breastfeeding in restaurants and cafes. Although only just under 50% of the population sample approves of breastfeeding in these locations, it is not avoided by the majority of mothers (54%). Overall, knowledge of the benefits of breastfeeding is associated with increased acceptance of breastfeeding in public. No special demographic characteristics were observed for the group of persons with a negative attitude towards breastfeeding in public (6%). CONCLUSIONS: No special target group for improving acceptance of breastfeeding in public can be identified in the population on the basis of the present findings. A conflict potential was identified for certain places and situations, however, which enables the development of strategies to increase acceptance. PMID- 29987501 TI - Quality of life and anorexia/cachexia in lung cancer: validation of the Spanish version of the FAACT instrument. AB - PURPOSE: The cancer anorexia-cachexia syndrome (CACS) is highly prevalent in lung cancer (LC) patients (57-61%), and represents the direct cause of death in 20% of cases. Accurately quantifying CACS has been a challenging issue; consequently, this study presents the clinical validation of the Spanish version of the Functional Assessment of Anorexia-Cachexia Therapy (FAACT) scale in LC patients from Latin America. METHODS: The Spanish version of the FAACT and the Mexican Spanish version of the EORTC-QLQ-C30 instruments were applied to a cohort of patients with LC at the National Cancer Institute of Mexico. Reliability and validity tests were performed to assess the psychometric properties of the scales, and clinical validation was assessed considering the association of scales with subjective and objective clinical data. RESULTS: Two hundred patients were included. Questionnaire compliance rates were high (100%) and the instrument was well accepted in all cases; internal consistency tests demonstrated good convergent and divergent validity of the scale structure. Cronbach's alpha coefficient for three out of five basic multi-item scales was > 0.7 (0.55-0.86). FAACT scales presented significant associations with clinical parameters, including biochemical and nutritional variables (i.e., energy intake, p = 0.002), as well as strongly correlated with the appetite loss subscale of the QLQ-C30 questionnaire (r = - 0.624). Physical well-being (p < 0.0009), functional well being (p = 0.004), anorexia/cachexia scale (p = 0.029), and FAACT total scores (p = 0.0009) were strongly associated to overall survival. CONCLUSION: The Spanish version of the FAACT questionnaire is reliable and valid for the assessment of health-related quality of life and CACS in LC patients and can be used in clinical trials. PMID- 29987499 TI - Decompensated Heart Failure and Renal Failure: What Is the Current Evidence? AB - PURPOSE OF REVIEW: Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite several advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. The aim of the current review is to provide an overview on current as well as future approaches in cardiorenal interactions in patients with ADHF. RECENT FINDINGS: One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndromes (CRS) or cardiorenal interactions. Patients with ADHF frequently develop worsening of renal function (WRF) and/or acute kidney injury (AKI). Recent studies brought new information about biomarkers in diagnosing and predicting prognosis of CRS. Among others, dry weight at hospital discharge is considered a surrogate marker of successful treatment in ADHF patients with/without renal dysfunction. The etiology of WRF appears to be an important factor for determining risk related to WRF as well as clinical management. The hypertonic saline used as adjunctive therapy for intravenous loop diuretics and/or induction of aquaresis (e.g., using tolvaptan) may be promising and efficient approaches in the future. PMID- 29987502 TI - GhKLCR1, a kinesin light chain-related gene, induces drought-stress sensitivity in Arabidopsis. AB - Drought stress results in significant losses in agricultural production, and especially that of cotton. The molecular mechanisms that coordinate drought tolerance remain elusive in cotton. Here, we isolated a drought-response gene GhKLCR1, which is a close homolog of AtKLCR1, which encodes a kinesin light chain related protein enriched with a tetratrico peptide-repeat region. A subcellular localization assay showed that GhKLCR1 is associated with the cell membrane. A tissue-specific expression profile analysis demonstrated that GhKLCR1 is a cotton root-specific gene. Further abiotic and hormonal stress treatments showed that GhKLCR1 was upregulated during abiotic stresses, especially after polyethylene glycol treatments. In addition, the glucuronidase (GUS) staining activity increased as the increment of mannitol concentration in transgenic Arabidopsis plants harboring the fusion construct PGhKLCR1::GUS. The root lengths of 35S::GhKLCR1 lines were significantly reduced compared with that of wild type. Additionally, seed germination was strongly inhibited in 35S::GhKLCR1 lines after 300-mmol L-1 mannitol treatments as compared with Columbia-0, indicating the sensitivity of GhKLCR1 to drought. These findings provide a better understanding of the structural, physiological and functional mechanisms of kinesin light chain related proteins. PMID- 29987503 TI - Impact of a Child Abuse Primary Prevention Strategy for New Mothers. AB - First Steps (FS) is a brief obstetrics-based primary prevention strategy that aims to strengthen protective factors to prevent child maltreatment. This randomized controlled trial assessed how well FS services aligned with family interests and needs, how FS providers used communication strategies to build partnership with mothers, and the impact of FS on mothers' parenting knowledge in core content areas and access to services. Mothers completed a baseline survey and were randomly assigned to FS and control conditions (n = 374 and 375, respectively). The parenting education services provided to mothers were assessed by independent participant report immediately postintervention for the full FS group and by analysis of audio-recordings of the FS encounter for a subsample (n = 150). Outcomes were measured at 4 months via maternal survey. Compared to controls at follow-up, FS mothers had significantly higher knowledge scores in some areas but similar access to needed services. Few mothers lacked access to most services at baseline, and FS content was similar to that provided by other hospital personnel. FS providers' communication style promoted rapport, but providers did not tailor content to mothers' educational and service access needs. Implications of the findings for similar services are discussed. PMID- 29987504 TI - Preparation and Antibiofilm Properties of Zinc Oxide/Porous Anodic Alumina Composite Films. AB - The PAA (porous anodic alumina) films were prepared by two-step anodic oxidation after different times, and then the ZnO/PAA composite films were prepared by sol gel method on their surface. Meanwhile, the ZnO/PAA composite films were characterized by X-ray diffraction (XRD), thermogravimetric/differential thermal analyzer (TG/DTA), Fourier transform infrared spectrometer (FT-IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), selected area electron diffraction (SAED), and water contact angle (CA). The antibiofilm properties of ZnO/PAA composite films on Shewanella putrefaciens were measured simultaneously. The results show that the micromorphologies of PAA and ZnO/PAA composite films are affected by second anodization time. ZnO is a hexagonal wurtzite structure, and ZnO particles with a diameter of 10-30 nm attach to the inner or outer surfaces of PAA. After being modified by Si69, the ZnO films translate from hydrophilia to hydrophobicity. The ZnO/PAA film with the optimal antibiofilm properties is prepared on the PAA surface by two-step anodization for 40 min. The adherence of Shewanella putrefaciens is restrained by its super hydrophobicity, and the growth of biofilm bacteria is inhibited by its abundant ZnO particles. PMID- 29987505 TI - Synthesis and properties of novel styrene acrylonitrile/polypropylene blends with enhanced toughness. AB - BACKGROUND: Although polypropylene (PP) has been widely used, its brittleness restricts even further applications. METHODS: In this study, we have used a melt blending process to synthesize styrene acrylonitrile (SAN)/PP blends containing 0, 5, 10, 15 and 20 wt% SAN. The effects of adding various amount of SAN on the blends characteristics, mechanical properties, thermal behavior and morphology were investigated. RESULTS: The results demonstrated that SAN had no obviously effect on crystal form but reduced the crystallinity of PP and increased the viscosity. The heat deflection temperature and Vicat softening temperature were enhanced for all SAN/PP blends, in particular for blends with low SAN content (5 and 10 wt%). The morphology of SAN/PP blends with 10 wt% SAN revealed the presence of nanoparticles dispersed on the surface, while SAN/PP blends with 20 wt% SAN exhibited the presence of spherical droplets and dark holes. All SAN/PP blends showed higher impact strength compared to pure PP, especially for SAN/PP blend containing 10 wt% SAN for which the impact strength was 2.3 times higher than that of pure PP. CONCLUSIONS: The reason for significant increase in impact properties seemed to have a strong correlation with nanoparticles morphology and the decrease of PP crystallinity. PMID- 29987506 TI - Cortical networks of the mouse brain elaborate within the gray matter. AB - In primates, proximal cortical areas are interconnected via within-cortex "intrinsic" pathway, whereas distant areas are connected via "extrinsic" white matter pathway. To date, such distinction has not been clearly done for small brained mammals like rodents. In this study, we systematically analyzed the data of Allen Mouse Brain Connectivity Atlas to answer this question and found that the ipsilateral cortical connections in mice are almost exclusively contained within the gray matter, although we observed exceptions for projections from the retrosplenial area and the medial/orbital frontal areas. By analyzing axonal projections within the gray matter using Cortical Box method, which enabled us to investigate the layer patterns across different cortical areas, we obtained the following results. First, widespread axonal projections were observed in both upper and lower layers in the vicinity of injections, whereas highly specific "point-to-point" projections were observed toward remote areas. Second, such long range projections were predominantly aligned in the anteromedial-posterolateral direction. Third, in the majority of these projections, the connecting axons traveled through layer 6. Finally, the projections from the primary and higher order areas to distant targets preferentially terminated in the middle and superficial layers, respectively, suggesting hierarchical connections similar to those of primates. Overall, our study demonstrated conspicuous differences in gray/white matter segregation of axonal projections between rodents and primates, despite certain similarities in the hierarchical cortical organization. PMID- 29987507 TI - Bradykinin B2 receptor is essential to running-induced cell proliferation in the adult mouse hippocampus. AB - Physical exercise is a strong external effector that induces precursor cell proliferation in the adult mouse hippocampus. Research into mechanisms has focused on central changes within the hippocampus and we have established that serotonin is the signaling factor that transduces physical activity into adult neurogenesis. Less focus has been given on potential peripheral signals that may cause pro-mitotic running effects. Vasoactive kinin peptides are important for blood pressure regulation and inflammatory processes to maintain cardiovascular homeostasis. Acting via the two receptors termed B1 (B1R) and B2R, the peptides also function in the brain. In particular, studies attribute B2R a role in cell proliferation and differentiation into neurons in vitro. Here, we determined B1R and B2R mRNA expression levels in the adult mouse hippocampus and prefrontal cortex in vivo, and in response to running exercise. Using mice depleted in either or both receptors, B1-knockout (KO), B2KO and B1/2KO we observed changes in running performance overnight and in running distances. However, voluntary exercise led to the known pro-mitotic effect in the dentate gyrus of B1KO mice while it was attenuated in B2KO accompanied by an increase in microglia cells. Our data identify B2R as an important factor in running-induced precursor cell proliferation. PMID- 29987508 TI - Screening for dementia with the Vienna Visuo-Constructional Test 3.0 screening (VVT 3.0 screening). AB - BACKGROUND: Visuo-constructive functions are an important cognitive domain for the diagnosis and early detection of dementia. Using the Vienna Visuo Constructional Test 3.0 Screening (VVT 3.0 Screening), we assessed visuo constructive performance in subjective cognitive decline (SCD), mild cognitive impairment (MCI), Alzheimer's disease (AD), and healthy control (HC) groups to determine whether VVT scores can be used to distinguish the mentioned diagnostic groups and predict disease progression to more advanced stages. METHODS: We analyzed the data of 422 patients referred to the Department of Neurology, Medical University of Vienna, for assessment of neurocognitive status. We also examined 110 of these patients in a follow-up with regard to stability of performance and disease progression. We compared VVT performance across diagnostic groups and explored associations with relevant sociodemographic and clinical variables. Predictive validity was assessed using receiver operator characteristic (ROC) curves and multinomial logistic regression analyses. RESULTS: We found that most diagnostic groups differed significantly regarding VVT scores. These were shown to reliably identify cases suffering from visuo constructive impairment but were not sufficient for classification into all diagnostic groups. Progression to more advanced disease stages could not be reliably predicted using VVT scores, possibly because subsamples of progressors were quite small. CONCLUSION: VVT scores are useful indicators for identifying visuo-constructive impairment but are limited by factors such as similar disease manifestations when used to discriminate between several diagnostic groups. The same factors complicate the use of VVT scores for predicting disease progression to more advanced stages. PMID- 29987509 TI - Limbic encephalitis as a relapse of Whipple's disease with digestive involvement and spondylodiscitis. AB - INTRODUCTION: Many clinical manifestations can be related to Tropheryma whipplei infection. CASE REPORT: We report a Tropheryma whipplei limbic encephalitis developed as a relapse of classical Whipple's disease. DISCUSSION: This case is to the best of our knowledge the first proof of the effective brain-blood barrier crossing of both doxycycline and hydroxychloroquine as demonstrated by direct concentration monitoring on brain biopsy. PMID- 29987510 TI - Evaluation of Bremsstrahlung radiation dose in stereotactically radiocolloid therapy of cystic craniopharyngioma tumors with 32P radio-colloid. AB - Over 90% of craniopharyngeal brain tumors are cystic, which enables the injection of beta emitters such as phosphorus-32 (32P) radio-colloid into cysts for their treatment. The aim of this study was to evaluate the clinical and theoretical modelling of Bremsstrahlung radiation dose resulting from stereotactic radio colloid therapy of cystic craniopharyngioma tumors with 32P. 32P radio-colloid with appropriate activity concentration was injected to a head phantom, and then the Bremsstrahlung radiation spectrum and planar images were obtained using a gamma camera. Both phantom and gamma camera were simulated using MCNPX code, and the results were compared with practical results. Bremsstrahlung radiation spectrum was measured using a handheld gamma spectrometer for two patients treated with stereotactic radio-colloid therapy with 32P in different positions and compared to Monte Carlo simulation. Results of counting and determining sensitivity coefficients in the air and the attenuating environment were obtained. Also, comparing the counting sensitivity from practical and simulation methods indicated the agreement of the data between the two methods. Comparison of the spectra from different positions around patient's head indicated the ability to use this detector to quantify the activity in the operating room. Selection of the spectrum is important in Bremsstrahlung radiation imaging. We can take advantage of spectrometry measurement using gamma camera, handheld gamma spectrometer for patient, and theoretical modeling with Monte Carlo code to evaluate radiopharmaceutical distribution, leakage, as well as estimate activity and predict therapeutic effects in other adjacent structures and ultimately optimize radio-colloid therapy in cystic craniopharyngeal patients. PMID- 29987511 TI - The association between polypharmacy and medication regimen complexity and antibiotic use in bronchiectasis. AB - Background Polypharmacy is associated with an increased risk of adverse drug events, inappropriate prescribing and medication errors. People with bronchiectasis have frequent pulmonary exacerbations that require antibiotic therapy. Objective This study aimed to measure polypharmacy and medication regimen complexity in bronchiectasis patients and to explore associations between these factors and oral and intravenous (IV) antibiotic use for suspected pulmonary exacerbations. Setting Patients were sampled from the Regional Bronchiectasis Clinic at the Belfast Health and Social Care Trust, Northern Ireland. Method Data on medicines were collected from patients' records and used to measure polypharmacy using three thresholds (>= 4, >= 10, and >= 15 medicines'). Medication regimen complexity was calculated using the medication regimen complexity index (MRCI). Data analysis investigated differences in outcomes across polypharmacy thresholds and correlations with MRCI. Main outcome measure Primary outcomes were prescriptions for oral antibiotics and IV antibiotics, in the past 6 months and 2 years, respectively. Results Over three quarters of the sample (N = 95) were prescribed >= 4 medicines (n = 74; 77.9%), 31 patients were prescribed >= 10 medicines (33.0%), and 12 patients (12.8%) were prescribed >= 15 medicines. The median MRCI was 26. Patients prescribed >= 10 medicines were over three times more likely to have had an IV antibiotic in the past 2 years (adjusted odd ratio 3.44, 95% confidence intervals 1.15-10.31). Conclusion There were significant differences in all outcomes across the '>= 10 medicines' threshold. MRCI was positively correlated with oral and IV antibiotic usage. These findings also suggest a possible link between polypharmacy and medicines regimen complexity, and poorer outcomes. PMID- 29987512 TI - A qualitative study of the perspectives of older people in remote Scotland on accessibility to healthcare, medicines and medicines-taking. AB - Background Recent evidence highlights the disproportionate rates of health inequality often experienced within remote and rural communities. Access to medicines within remote and rural communities may also prove problematic. Objective The aim was to understand the perspectives of older people in the most remote areas of the Scottish Highlands on issues of accessibility to healthcare, medicines and medicines-taking. Method Qualitative, semi-structured one-to-one interviews with 13 residents aged 65 years and over in the most remote and rural areas of the Scottish Highlands. Interviews were audio-recorded, transcribed and analysed using a framework approach. Setting Remote and rural areas in the Scottish Highlands. Participants had previously completed a cross-sectional survey. Main outcome measure Themes surrounding the perspectives of older people in the most remote areas of the Scottish Highlands on issues of accessibility to healthcare, medicines and medicines-taking. Results Healthcare was considered convenient, and positive relationships with providers being important. Review of medicines was perceived to be the remit of the doctor, with pharmacists seen as valuable suppliers of medicines. Conclusion Based on this qualitative study, experiences of access to healthcare, including community pharmacy, medicines and medicines-taking within this sample of older adults resident in the most remote areas of the Scottish Highlands are widely variable. There may be an unmet educational need, amongst residents, with regard to awareness of the role of pharmacists, the services they can provide and the benefits which may be experienced as a consequence of engagement. PMID- 29987513 TI - [Avoidance-endurance fast screening (AE-FS) : Content and predictive validity of a 9-item screening instrument for patients with unspecific subacute low back pain]. AB - BACKGROUND: Among screening measures to assess psychosocial risk factors (yellow flags) for chronic low back pain (LBP) economic tools which address dysfunctional endurance pain responses besides emotional distress and fear-avoidance pain processing are rare. Targeting contrasting types of pain processing might improve stratified patient counselling. OBJECTIVE: The aim of the study was to develop a short screening method, based on the avoidance-endurance model of pain and to investigate the prognostic validity for pain intensity, disability and physical function. MATERIAL AND METHODS: A prospective observational study was carried out on 144 patients with subacute LBP (<3 months) from 7 general practitioners and 5 orthopedic practices. The 9-item avoidance-endurance fast screening (AE-FS) was derived from a previous 37-item screening using correlational and receiver operating curve (ROC) analyses and the agreement of subgrouping was calculated using Cohen's kappa. Primary outcomes were assessed after 6 months by mail in 124 patients (86%). Endpoints were pain intensity and disability. RESULTS: The classification of subgroups as high and low risk by both measures had considerable agreement with a value of 0.71 (Cohen's Kappa). The sensitivity to predict pain intensity >2 was high (82%) as was the positive predictive value (80%) but the negative predictive value was moderate (61%). The ROC (AUC) characteristics (95% confidence interval CI) were 0.70 (0.60-0.80) for pain intensity and for limitations in the pain disability index (PDI) 0.70 (0.55 0.87). DISCUSSION: The 9-item AE-FS displayed sufficient prognostic validity for all three outcomes in a sample of primary care patients with subacute LBP. The differentiation of the high-risk patients into fear-avoidance and endurance related pain processing enables the physician to provide an individualized counselling with the aim of a healthy balance between stress and relaxation. PMID- 29987514 TI - The relationship between obstructive sleep apnea hypopnea syndrome and gastroesophageal reflux disease: a meta-analysis. AB - BACKGROUND: Obstructive sleep apnea hypopnea syndrome (OSAHS) means apnea and hypopnea caused by partial or complete obstruction of upper airway collapse during sleep. Gastroesophageal reflux disease (GERD) is believed to be associated with various manifestations in the otorhinolaryngology and has been found to be an additional risk factor for OSAHS. AIM: A meta-analysis was performed to identify the association between obstructive sleep apnea hypopnea syndrome and gastroesophageal reflux disease. METHODS: To identify eligible original articles, we searched a series of computerized databases, including Medline via PubMed, EMBASE, Web of Science, and CNKI with a systematic searching strategy. The characteristics of each article and pooled odds ratios (ORs) with corresponding confidence intervals (CIs) were calculated and subgroup analysis was performed to analyze the source of heterogeneity. RESULTS: A total of 2699 patients from seven articles were included in the meta-analysis. We identified a significant relationship between obstructive sleep apnea syndrome and gastroesophageal reflux disease, with a pooled OR of 1.75 (95% CI 1.18-2.59, P < 0.05). The pooled data was calculated under the random-effects model as a significant moderate heterogeneity was found among the meta-analysis. CONCLUSIONS: The meta-analysis showed that there was a significant correlation between obstructive sleep apnea hypopnea syndrome and gastroesophageal reflux disease. PMID- 29987516 TI - Kinetic Modeling of Cr(VI) Reduction by nZVI in Soil: The Influence of Organic Matter and Manganese Oxide. AB - The effect of soil composition on the reduction of hexavalent chromium (Cr(VI)) by zero valent iron nanoparticles was studied. A model was proposed, to investigate both the effect of manganese oxide and the simultaneous effect of manganese dioxide and soil organic matter on the kinetic of Cr(VI) reduction. Fe(0) nanoparticles consumption by the reaction with dissolved oxygen, water and soluble Cr(VI) was taken into account. The model was validated through experimental tests performed on soil samples collected at an industrial polluted site, and on artificially contaminated samples from the same site, in the presence of selected amount of leonardite. PMID- 29987515 TI - Complexities of Perioperative Pain Management in Orthopedic Trauma. AB - PURPOSE OF REVIEW: This review discusses both obvious and hidden barriers in trauma patient access to pain management specialists and provides some suggestions focusing on outcome optimization in the perioperative period. RECENT FINDINGS: Orthopedic trauma surgeons strive to provide patients the best possible perioperative pain management, while balancing against potential risks of opioid abuse and addiction. Surgeons often find they are ill-prepared to effectively manage postoperative pain in patients returning several months following trauma surgery, many times still dependent on opioids for pain control. Some individuals from this trauma patient population may also require the care of pain management specialists and/or consultation with drug addiction specialists. As the US opioid epidemic continues to worsen, orthopedic trauma surgeons can find it difficult to obtain access to pain management specialists for those patients requiring complex pain medication management and substance abuse counseling. The current state of perioperative pain management for orthopedic trauma patients remains troubling due to reliance on only opioid analgesics, society-associated risks of opioid medication addiction, an "underground" prescription drug marketplace, and an uncertain legal atmosphere related to opioid pain medication management that can deter pain management physicians from accepting narcotic-addicted patients and discourage future physicians from pursuing advanced training in the specialty of pain management. Additionally, barriers continue to exist among Medicaid patients that deter this patient population from access to pain medicine subspecialty care, diminishing medication management reimbursement rates make it increasingly difficult for trauma patients to receive proper opioid analgesic pain medication management, and a lack of proper opioid analgesic medication management training among PCPs and orthopedic trauma surgeons further contributes to an environment ill-prepared to provide effective perioperative pain management for orthopedic trauma patients. PMID- 29987517 TI - White Matter Deficits Underlying the Impaired Consciousness Level in Patients with Disorders of Consciousness. AB - In this study, we aimed to (1) identify white matter (WM) deficits underlying the consciousness level in patients with disorders of consciousness (DOCs) using diffusion tensor imaging (DTI), and (2) evaluate the relationship between DTI metrics and clinical measures of the consciousness level in DOC patients. With a cohort of 8 comatose, 8 unresponsive wakefulness syndrome/vegetative state, and 14 minimally conscious state patients and 25 patient controls, we performed group comparisons of the DTI metrics in 48 core WM regions of interest (ROIs), and examined the clinical relevance using correlation analysis. We identified multiple abnormal WM ROIs in DOC patients compared with normal controls, and the DTI metrics in these ROIs were significantly correlated with clinical measures of the consciousness level. Therefore, our findings suggested that multiple WM tracts are involved in the impaired consciousness levels in DOC patients and demonstrated the clinical relevance of DTI for DOC patients. PMID- 29987518 TI - Acute Restraint Stress Augments 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Neurotoxicity via Increased Toxin Uptake into the Brain in C57BL/6 Mice. AB - As an environmental risk factor, psychological stress may trigger the onset or accelerate the progression of Parkinson's disease (PD). Here, we evaluated the effects of acute restraint stress on striatal dopaminergic terminals and the brain metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been widely used for creating a mouse model of PD. Exposure to 2 h of restraint stress immediately after injection of a low dose of MPTP caused a severe loss of striatal dopaminergic terminals as indicated by decreases in the dopamine transporter protein and dopamine levels compared with MPTP administration alone. Both striatal 1-methyl-4-phenylpyridinium ion (MPP+) and MPTP concentrations were significantly increased by the application of restraint stress. Striatal monoamine oxidase-B, which catalyzes the oxidation of MPTP to MPP+, was not changed by the restraint stress. Our results indicate that the enhanced striatal dopaminergic terminal loss in the stressed mice is associated with an increase in the transport of neurotoxin into the brain. PMID- 29987519 TI - Effects of ecological and anthropogenic factors on waterbird abundance at a Ramsar Site in the Yangtze River Floodplain. AB - Continuing declines in abundance of many waterbird species on wetland ecosystems require explanations to support effective management interventions. We used 6 year survey data from Shengjin Lake National Nature Reserve in the Yangtze River Floodplain, China, to study the effects of ecological and anthropogenic variables as determinants of waterbird species abundance. Our results showed that effects were guild-dependent, although distance to nearest human settlements had the largest adverse effects on bird abundance across all guilds. These results suggested that although the abundance of waterbird species could be affected by habitat conditions and buffalo grazing activities, Yangtze River Wetlands would most likely benefit most from reduced pressure from the proximity to the surrounding human population. We suggest that screening and/or restricting public access at some key sites may be the most cost-efficient way to restrict or reduce human activity in these wetlands, to improve the conservation status and wintering conditions for these waterbirds. PMID- 29987520 TI - Transcriptional Study of the RsmZ-sRNAs and Their Relationship to the Biosynthesis of Alginate and Alkylresorcinols in Azotobacter vinelandii. AB - The GacS/A system in Azotobacter vinelandii regulates alginate and alkylresorcinols production through RsmZ1, a small regulatory RNA (sRNA) that releases the translational repression of the algD and arpR mRNAs caused by the RsmA protein. In the Pseudomonadaceae family, the Rsm-sRNAs are grouped into three families: RsmX, RmsY and RsmZ. Besides RsmZ1, A. vinelandii has six other isoforms belonging to the RsmZ family and another one to the RsmY. Environmental signals controlling rsmsRNAs genes in A. vinelandii are unknown. In this work, we present a transcriptional study of the A. vinelandii rsmZ1-7-sRNAs genes, whose transcriptional profiles showed a differential expression pattern, but all of them exhibited their maximal expression at the stationary growth phase. Furthermore, we found that succinate promoted higher expression levels of all the rsmZ1-7 genes compared to glycolytic carbon sources. Single mutants of the rsmZ sRNAs family were constructed and their impact on alginate production was assessed. We did not observe correlation between the alginate phenotype of each rsmZ-sRNA mutant and the expression level of the corresponding sRNA, which suggests the existence of additional factors affecting their impact on alginate production. Similar results were found in the regulation exerted by the RsmZ sRNAs on alkylresorcinol synthesis. PMID- 29987521 TI - A Dual-Replicon Shuttle Vector System for Heterologous Gene Expression in a Broad Range of Gram-Positive and Gram-Negative Bacteria. AB - Origin of replication (ori in theta-replicating plasmids or dso in rolling circle replicating plasmids) initiates plasmid replication in a broad range of bacteria. These two kinds of plasmids were both identified in Streptococcus, a genus composed of both human commensal bacteria and pathogens with the ability to cause severe community-acquired infections, including meningitides, septicemia, and respiratory tract diseases. Given the important roles of Streptococcus in the exchange of genetic elements with other symbiotic microbes, the genotypes and phenotypes of both Streptococcus spp. and other symbiotic species could be changed during colonization of the host. Therefore, an improved plasmid system is required to study the functional, complicated, and changeable genomes of Streptococcus. In this study, a dual-replicon shuttle vector system named pDRE was constructed to achieve heterologous gene expression. The vector system contained theta replicon for Escherichia coli. The origin of rolling circle replicon was synthesized according to pMV158 in Gram-positive bacteria. By measuring the products of inserted genes at multiple cloning sites, the ability of this vector system in the replication and expression of heterologous genes was assessed in four Streptococcus and three other Gram-positive bacteria: Bacillus subtilis, Lactococcus lactis, and Staphylococcus aureus. The results showed that the newly constructed vector could simultaneously replicate and express heterologous genes in a broad range of Gram-positive and Gram-negative bacteria, thus providing a potentially powerful genetic tool for further functional analysis. PMID- 29987522 TI - The Psychophysiological Regulation of Pacing Behaviour and Performance Fatigability During Long-Distance Running with Locomotor Muscle Fatigue and Exercise-Induced Muscle Damage in Highly Trained Runners. AB - BACKGROUND: Locomotor muscle fatigue (LMMF) and exercise-induced muscle damage (EIMD) are common conditions experienced during long-distance running due to the pooled effect of mechanical and metabolic strain on the locomotor muscles. However, little is known about the instant effects of combined LMMF and EIMD on pacing behaviour and performance during the decisive final stages of 'real-world' long-distance running events. METHODS: Twenty-two highly trained runners (11 females) completed two maximal self-paced 20-km treadmill time trials in a counterbalanced crossover design: (A) in a tapered condition and (B) with LMMF and EIMD. Indicators of muscle damage, muscle metabolic strain, and endocrinological stress were assessed to investigate the physiological effects, and a three-dimensional framework of perceived fatigability was applied to investigate the perceptual effects of running with LMMF and EIMD on performance fatigability. RESULTS: LMMF and EIMD caused restrictions in work capacity and medium increases in blood leucocyte and neutrophil count, interleukin-6, and cortisol concentrations, collectively constituting a physiological milieu likely not conducive to high performance. LMMF and EIMD further caused large increases in perceived physical strain and large decreases in valence as well as large increases and decreases in action crisis and flow state, respectively. CONCLUSIONS: Under the constraint of amplified physical duress, findings are suggestive of heuristic and rational antecedents in the goal disengagement process. Dynamic changes in physiological and perceptual effects of LMMF and EIMD are hypothesised to underpin the observed alterations in pacing behaviour and performance fatigability during long-distance running. The applied three dimensional framework provides a more comprehensive understanding of strain perception-thinking-action coupling in centrally regulated and goal-directed exercise behaviour. PMID- 29987523 TI - Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2. AB - The 2-hydroxyglutaric aciduria (2-HGA) is a rare neurometabolic disorder that leads to the development of brain damage. It is classified into three categories: D-2-HGA, L-2-HGA, and combined D,L-2-HGA. The D-2-HGA includes two subtypes: type I and type II caused by the mutations in D2HGDH and IDH2 proteins, respectively. In this study, we studied six mutations, four in the D2HGDH (I147S, D375Y, N439D, and V444A) and two in the IDH2 proteins (R140G, R140Q). We performed in silico analysis to investigate the pathogenicity and stability changes of the mutant proteins using pathogenicity (PANTHER, PhD-SNP, SIFT, SNAP, and META-SNP) and stability (i-Mutant, MUpro, and iStable) predictors. All the mutations of both D2HGDH and IDH2 proteins were predicted as disease causing except V444A, which was predicted as neutral by SIFT. All the mutants were also predicted to be destabilizing the protein except the mutants D375Y and N439D. DSSP plugin of the PyMOL and Molecular Dynamics Simulations (MDS) were used to study the structural changes in the mutant proteins. In the case of D2HGDH protein, the mutations I147S and V444A that are positioned in the beta sheet region exhibited higher Root Mean Square Deviation (RMSD), decrease in compactness and number of intramolecular hydrogen bonds compared to the mutations N439D and D375Y that are positioned in the turn and loop region, respectively. While the mutants R140Q and R140QG that are positioned in the alpha helix region of the protein. MDS results revealed the mutation R140Q to be more destabilizing (higher RMSD values, decrease in compactness and number of intramolecular hydrogen bonds) compared to the mutation R140G of the IDH2 protein. This study is expected to serve as a platform for drug development against 2-HGA and pave the way for more accurate variant assessment and classification for patients with genetic diseases. PMID- 29987525 TI - Applying Reflective Multicriteria Decision Analysis (MCDA) to Patient-Clinician Shared Decision-Making on the Management of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NET) in the Spanish Context. AB - INTRODUCTION: Unresectable, well-differentiated nonfunctioning gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be monitored (watchful waiting, WW) or treated with systemic therapy such as somatostatin analogues (SSAs) to delay progression. We applied a reflective multicriteria decision analysis (MCDA) shared-decision framework (previously developed for the USA) to explore what matters to Spanish patients and clinicians considering GEP NET treatment options. METHODS: The EVIDEM-derived framework was updated and adapted to the Spanish context. During a Chatham House session, five patients and six physicians assigned criteria weights using hierarchical point allocation and direct rating scale (alternative analysis). Informed by synthesized evidence embedded in the framework, participants scored how each criterion favored SSA treatment (reference case lanreotide) or WW and shared insights and knowledge. Weights and scores were combined into value contributions (norm. weight * score/5), which were added across criteria to derive the relative benefit-risk balance (RBRB, scale - 1 to + 1). Exploratory comparisons to US study findings were performed. RESULTS: Focusing on intervention outcomes (effectiveness, patient-reported, and safety), the mean RBRB favored treatment over WW (+ 0.32 +/ 0.24), with the largest contributions from progression-free survival (+ 0.11 +/- SD 0.07), fatal adverse events (+ 0.06 +/- SD 0.08), and impact on HRQoL (+ 0.04 +/- SD 0.04). Consideration of modulating criteria (type of benefit, need, costs, evidence, and feasibility) increased the RBRB to + 0.50 +/- 0.14, with type of therapeutic benefit (+ 0.10 +/- SD 0.08) and quality of evidence (+ 0.08 +/- SD 0.06) contributing most towards treatment. Alternative weighting yielded similar results. Results were broadly comparable to those derived from the US study. CONCLUSION: The multicriteria framework helped Spanish patients and clinicians identify and express what matters to them. The approach is transferable across decision-making contexts. FUNDING: IPSEN Pharma. PMID- 29987524 TI - The effects of repetitive stress on tat protein-induced pro-inflammatory cytokine release and steroid receptor expression in the hippocampus of rats. AB - Human immunodeficiency virus type 1 (HIV-1) affects the central nervous system (CNS) that may lead to the development of HIV-associated neuropathologies. Tat protein is one of the viral proteins that have been linked to the neurotoxic effects of HIV. Since many individuals living with HIV often experience significant adverse circumstances, the present study investigated whether exposure to stressful conditions would exacerbate harmful effects of tat protein on brain function. Tat protein (10 MUg/10 MUl) was injected bilaterally into the dorsal hippocampus of the animal using stereotaxic techniques. The control group received an injection of saline (10 MUl). Some control and tat protein-treated animals were subjected to restrain stress for 6 h per day for 28 days and compared to a non-stress group. All animals underwent two behavioural tests, the open field test (OFT) and the novel object recognition test (NORT) to assess their mood state and cognitive function respectively. The release of pro inflammatory cytokines (TNF-alpha and IL-1beta) and the expression of mineralocorticoid (MR) and glucocorticoid (GR) receptors were also measured to see whether the impact of the repetitive stress on Tat protein-induced behavioural effects was mediated by elements of the immune system and the HPA axis. Rats treated with tat protein showed the following behavioural changes when compared to control animals: there was a significant decrease in time spent in the center of the open field during the OFT, a significant reduction in time spent with the novel object during the NORT, but no change in locomotor activity. Real-time PCR data showed that the expression levels of GR and MR mRNA were significantly reduced, while Western blot analysis showed that the protein expression levels of TNF-alpha and IL-1beta were significantly increased. The present findings indicated that injection of tat protein into the hippocampus of rats not subjected to stress may lead to anxiety-like behaviour and deficits in learning and memory. Tat-treated animals subjected to stress evoked only a modest effect on their behaviour and neurochemistry, while stress alone led to behavioural and neurochemical changes similar to tat protein. PMID- 29987526 TI - Impact of Left Colonic Artery Preservation on Anastomotic Leakage in Laparoscopic Sigmoid Resection and Anterior Resection for Sigmoid and Rectosigmoid Colon Cancer. AB - OBJECTIVES: To investigate the effect of left colonic artery (LCA) preservation on laparoscopic sigmoidectomy outcomes METHODS: We identified 447 consecutive patients who underwent laparoscopic sigmoidectomy at our hospital group between January 2010 and December 2016. We divided the patients into groups with and without LCA preservation and with and without anastomotic leakage (AL). We compared the patient age and gender, tumor location, stage, D2/D3 lymph node dissection, comorbidities, operating time, and blood loss between these groups. Univariate and multivariate analyses were performed to determine the risk factors for AL. RESULTS: There were significant differences in age, sex, tumor location, D2/D3 lymph node dissection, hypertension, operating time, blood loss, and AL for groups with and without LCA preservation. There were significant differences in sex, tumor location, and LCA preservation for groups with and without AL. Multivariate analysis showed male sex (hazard ratio (HR) = 6.37, 95% confidence interval (CI) 2.39-20.6; p < 0.0001), non-LCA preservation (HR = 5.01, 95% CI 1.41-31.8.0; p = 0.01), and rectosigmoidal tumor location (HR = 2.51, 95% CI 1.15 5.61; p = 0.01) as significant independent risk factors for AL. CONCLUSIONS: Based on the results obtained by performing laparoscopic operation for sigmoid colon cancer and rectosigmoid cancer, the LCA preservative procedure is warranted for prevention of AL. PMID- 29987527 TI - Herpes zoster ophthalmicus caught in the (Tr)act! AB - To emphasize the utility of contrast enhanced MRI for identifying the extent of disease in herpes zoster ophthalmicus with intracranial extension to help determine proper management. We present a rare case of herpes zoster ophthalmicus (HZ/HZO) with intracranial extension and MRI demonstration of involvement of the trigeminal nerve, the trigeminal nucleus, and the spinal trigeminal nucleus and tract. Herpes zoster is caused by reactivation of varicella zoster virus. Herpes zoster ophthalmicus with involvement of the ophthalmic division of the trigeminal nerve has been estimated to account for 10-20% of the cases (Yawn et al. in Mayo Clin Proc 88:562-570, 2013). While postherpetic neuralgia is the most common complication, HZ/HZO can rarely manifest in a more sinister manner resulting in multi-dermatomal involvement, disseminated disease, cranial arteritis (Walker in Radiology 107:109-110, 1973), cranial nerve paresis (O.d in Clinical Eye and Vision Care 11:75-80, 1999), hemiplegia (Cavaletti in The Italian Journal of Neurological Sciences 11:297-300, 1990), ocular/dysfunction (Kocaoglu in Turk Oftalmoloji Dergisi 48:42-46, 2018), and intracranial extension (Chen in BMC Infectious Diseases 17:213, 2017; Yawn in Mayo Clin Proc. 88:562-570, 2013). Contrast enhanced MRI (CE-MRI) can be of great benefit to elucidate the extent of disease and intracranial involvement for institution of more aggressive management to prevent further complications. PMID- 29987528 TI - An unusual case of mycobacterium tuberculous coronary arteritis and thrombosis resulting in acute myocardial infarction. AB - Tuberculosis (TB) is a prevalent infection worldwide and an endemic infection in Singapore. The most common presentation is that of pulmonary tuberculosis. Extra pulmonary tuberculosis usually involves the lymph nodes, pleura, central nervous system, or abdominal cavity. Involvement of the heart is rare (0.14-2% of TB cases), and when it is involved, it tends to be in the pericardium or myocardium. Here, a rare case of sudden death due to tuberculous coronary arteritis with tuberculous coronary thrombosis resulting in acute myocardial infarction is presented. PMID- 29987529 TI - Characterisation of the Pacific Oyster Microbiome During a Summer Mortality Event. AB - The Pacific oyster, Crassostrea gigas, is a key commercial species that is cultivated globally. In recent years, disease outbreaks have heavily impacted C. gigas stocks worldwide, with many losses incurred during summer. A number of infectious agents have been associated with these summer mortality events, including viruses (particularly Ostreid herpesvirus 1, OsHV-1) and bacteria; however, cases where no known aetiological agent can be identified are common. In this study, we examined the microbiome of disease-affected and disease-unaffected C. gigas during a 2013-2014 summer mortality event in Port Stephens (Australia) where known oyster pathogens including OsHV-1 were not detected. The adductor muscle microbiomes of 70 C. gigas samples across 12 study sites in the Port Stephens estuary were characterised using 16S rRNA (V1-V3 region) amplicon sequencing, with the aim of comparing the influence of spatial location and disease state on the oyster microbiome. Spatial location was found to be a significant determinant of the disease-affected oyster microbiome. Furthermore, microbiome comparisons between disease states identified a significant increase in rare operational taxonomic units (OTUs) belonging to Vibrio harveyi and an unidentified member of the Vibrio genus in the disease-affected microbiome. This is indicative of a potential role of Vibrio species in oyster disease and supportive of previous culture-based examination of this mortality event. PMID- 29987530 TI - Corneal crosslinking for keratoconus in Japanese populations: one year outcomes and a comparison between conventional and accelerated procedures. AB - PURPOSE: We retrospectively investigated the efficacy of corneal crosslinking (CXL) on progressive keratoconus in a Japanese population and compared the outcomes of conventional and accelerated CXL. STUDY DESIGN: A retrospective cohort study METHODS: A total of 108 consecutive eyes in 95 patients (75 men; 21.9 +/- 6.2 years) with progressive keratoconus were enrolled. The epithelium was ablated in all eyes. After presoaking the corneal stroma in riboflavin, UV-A was irradiated at 3.0 mW/cm2 (conventional CXL) for 30 min on 23 eyes and 18.0 mW/cm2 for 5 min (accelerated CXL) on 85 eyes. Best spectacle-corrected visual acuity (BSCVA), manifest refraction, keratometric value, corneal thickness, corneal endothelial cell density (ECD), intraocular pressure, and complications were evaluated at 1, 3, 6, and 12 months after the procedure. RESULTS: BSCVA, manifest refraction, ECD, and corneal thickness did not change significantly after both procedures. The keratometric value was significantly decreased from the preoperative value at 12 months (p < 0.001). Progression to more than 1.0 D after CXL was observed in 10 eyes (9.3%). The DeltaKmax was negatively associated with preoperative Kmax (p < 0.001) and positively associated with preoperative thinnest corneal thickness (p < 0.001). Both treatment modules showed no significant difference in all parameters. CONCLUSION: CXL was as effective in treating keratoconus in Japanese patients as in individuals of other ethnicities. Overall, CXL could be performed using either the conventional or accelerated approach to halt the progression of keratoconus in Japanese populations. PMID- 29987531 TI - Clinical and radiologic evaluation of the posterior cruciate ligament-injured knee. AB - PURPOSE OF REVIEW: Accurate isolated PCL diagnosis continues to present a challenge. This article reviews the current literature regarding clinical and radiographic evaluation of PCL injuries. RECENT FINDINGS: A thorough history to understand the mechanism of injury should begin any evaluation. Several clinical tests have been shown to effectively assess PCL laxity, with the posterior drawer test possessing the highest sensitivity and specificity. Any thorough exam should compare the contralateral, uninjured leg. If a PCL or multi-ligament injury is suspected, plain radiographs should be performed to avoid missing a fracture or avulsion. An MRI represents the current gold standard for diagnosing ligament injuries in the knee and should always be obtained in these cases. Due to the significant incidence of nerve injuries (25%) and vascular injuries (18%) with knee dislocations, any suspicion of neurovascular compromise necessitates further studies. A combination of a thorough clinical history and examination, followed by appropriate imaging optimizes PCL and multi-ligament injury evaluation. PMID- 29987532 TI - Effects of canonical color, luminance, and orientation on sustained inattentional blindness for scenes. AB - Whether scene gist perception occurs automatically and unconsciously has been the subject of much debate. In addition to demonstrating a new method that adapts the Mack and Rock (1998) inattentional blindness cross procedure to allow for sustained inattentional blindness over a large number of trials, we report evidence from a series of experiments that shows that canonical scene features reduce inattentional blindness to scenes by facilitating the extraction of scene gist. When attentional demands are high, the combination of canonical color, canonical luminance, and canonical orientation reduces rates of inattentional blindness. However, when attentional demands are reduced, canonical features are independently sufficient to facilitate gist extraction and to capture attention. These results demonstrate that canonical color, canonical luminance, and canonical orientation all contribute to scene gist perception, and that when attentional demands are high, only highly canonical stimuli are sufficient to capture attention. PMID- 29987533 TI - Precues' elevation of sensitivity is not only preattentive, but largely monocular. AB - Visual sensitivity can be heightened in the vicinity of an appropriate precue. Experiments with multiple, noninformative precues suggest that this facilitation should not be attributed to focal attention. The number of simultaneously appearing precues seems to be irrelevant; contrast thresholds are lowest for targets that appear in a precued position. Here we report that precues become less effective when they and the target are delivered to different eyes. We conclude that the mechanism responsible for such heightened sensitivity has largely monocular input. PMID- 29987534 TI - A Review of Dementia with Lewy Bodies' Impact, Diagnostic Criteria and Treatment. AB - Dementia with Lewy bodies is one of the most common causes of dementia. It is not as common as Alzheimer's disease; the general public's awareness of the disease is poor in comparison. Its effects on caregivers and patients alike are not well known to the general population. There are currently no FDA-approved medications specifically for the treatment of DLB. Many of the medications that are approved for Alzheimer's disease are widely used in the treatment of DLB with varying degrees of success. Treatment of DLB is life long and requires a dedicated team of physicians and caregivers to minimize the degree of morbidity and mortality experienced by the patients suffering from the disease as it progresses. PMID- 29987535 TI - Commentary: Peripheral and Central Aortic Pressure, Wave-Derived Reflection Parameters, Local and Regional Arterial Stiffness and Structural Parameters in Children and Adolescents: Impact of Body Mass Index Variations. PMID- 29987536 TI - Responses of biomarkers in Atlantic salmon (Salmo salar) following exposure to environmentally relevant concentrations of complex metal mixture (Zn, Cu, Ni, Cr, Pb, Cd). Part II. AB - The aim of this research was to assess interactions between metals at low exposure concentrations (Maximum-Permissible-Concentrations accepted for the inland waters in EU) and to assess possible influence of background exposure (10 times reduced concentration of a single metal) on toxicological significance of selected biomarkers in Salmo salar after treatment with metal mixture (Zn - 0.1, Cu - 0.01, Ni - 0.01, Cr - 0.01, Pb - 0.005 and Cd - 0.005 mg/L). The tissue specific bioaccumulation, genotoxicity and cytotoxicity responses (erythrocytic nuclear abnormalities assay) in peripheral blood, kidneys, gills and liver erythrocytes of fish to metal mixtures were assessed after 14 days treatment. Treatment with primary mixture (MIX) or two variants of this mixture (Cr? (10 times reduced Cr6+ concentration) and Cu? (10 times reduced Cu2+ concentration)) induced the strongest responses in genotoxicity and cytotoxicity endpoints. Exposure to these mixtures highly affected Zn, Cu and Cd bioaccumulation in liver tissue. The highest amount of Ni accumulated was measured after Cd? treatment in all tissues. Treatments with reduced concentration of non-essential metal resulted in an increased accumulation of Pb, Ni, or Cd; treatments with reduced concentration of essential metal resulted in a reduced accumulation of certain metals (especially Cd and Pb) in tissues compared between treatments. Glucose content in blood and behavioural endpoints were evaluated after short-term exposure to metal mixtures (MIX, Cr?, Cu?). Significant increase in blood glucose concentration was measured after all treatments. These metal mixtures elicit significant behavioural alterations in fish. Consequently, this research revealed a significant influence of background exposure considering mixture toxicity. PMID- 29987538 TI - Qualitative and Quantitative Evaluation of a Novel Detergent-Based Method for Decellularization of Peripheral Nerves. AB - Tissue engineering is an emerging strategy for the development of nerve substitutes for peripheral nerve repair. Especially decellularized peripheral nerve allografts are interesting alternatives to replace the gold standard autografts. In this study, a novel decellularization protocol was qualitatively and quantitatively evaluated by histological, biochemical, ultrastructural and mechanical methods and compared to the protocol described by Sondell et al. and a modified version of the protocol described by Hudson et al. Decellularization by the method described by Sondell et al. resulted in a reduction of the cell content, but was accompanied by a loss of essential extracellular matrix (ECM) molecules such as laminin and glycosaminoglycans. This decellularization also caused disruption of the endoneurial tubes and an increased stiffness of the nerves. Decellularization by the adapted method of Hudson et al. did not alter the ECM composition of the nerves, but an efficient cell removal could not be obtained. Finally, decellularization by the method developed in our lab by Roosens et al. led to a successful removal of nuclear material, while maintaining the nerve ultrastructure and ECM composition. In addition, the resulting ECM scaffold was found to be cytocompatible, allowing attachment and proliferation of adipose-derived stem cells. These results show that our decellularization combining Triton X-100, DNase, RNase and trypsin created a promising scaffold for peripheral nerve regeneration. PMID- 29987539 TI - Drill-Specific Head Impacts in Collegiate Football Practice: Implications for Reducing "Friendly Fire" Exposure. AB - This study investigated drill-specific head impact biomechanics in a Division 1 collegiate football team using the Head Impact Telemetry System (HITS). A total of 32,083 impacts were recorded across 2 years of practices. Precise tracking of instrumented athletes, head impacts, and drill participation allowed quantification of hits sustained per person per minute (H/P/M) for each specific drill. We found significant H/P/M variability between 14 drills and player position, ranging from 0.02 to 0.41 H/P/M for Linemen and 0.01 to 0.15 H/P/M for Non-Linemen. Impact magnitude data are also reported for practice term (Spring, Training Camp, In-Season) and dress-type (Helmets Only, Spyders, Shells, Full Pads). Recommendations for shortening high-risk drills, based on H/P/M drill impact frequencies, suggest possible "friendly fire" reductions of 1000 impacts for Linemen and 300 impacts for Non-Linemen over their collegiate career. Over 80% of potentially avoidable head impacts were attributable to just three drills "Team Run," "Move the Field," and "Team." Recommending drill-specific modifications based on practical considerations (the drill's impact frequency, dress-types when performing the drill, and duration) could improve acceptance from coaches and efficiently reduce head impact exposure without drastically altering overall practice structure. PMID- 29987540 TI - Effect of Subject-Specific Vertebral Position and Head and Neck Size on Calculation of Spine Musculoskeletal Moments. AB - Spine musculoskeletal models used to estimate loads and displacements require many simplifying assumptions. We examined how assumptions about subject size and vertebral positions can affect the model outcomes. Head and neck models were developed to represent 30 subjects (15 males and 15 females) in neutral posture and in forward head postures adopted while using tablet computers. We examined the effects of (1) subject size-specific parameters for head mass and muscle strength; and (2) vertebral positions obtained either directly from X-ray or estimated from photographs. The outcome metrics were maximum neck extensor muscle moment, gravitational moment of the head, and gravitational demand, the ratio between gravitational moment and maximum muscle moment. The estimates of maximum muscle moment, gravitational moment and gravitational demand were significantly different when models included subject-specific vertebral positions. Outcome metrics of models that included subject-specific head and neck size were not significantly different from generic models on average, but they had significant sex differences. This work suggests that developing models from X-rays rather than photographs has a large effect on model predictions. Moreover, size-specific model parameters may be important to evaluate sex differences in neck musculoskeletal disorders. PMID- 29987537 TI - A jugular vein compression collar prevents alterations of endogenous electrocortical dynamics following blast exposure during special weapons and tactical (SWAT) breacher training. AB - Exposure to explosive blasts places one at risk for traumatic brain injury, especially for special weapons and tactics (SWAT) and military personnel, who may be repeatedly exposed to blasts. In the current study, the effectiveness of a jugular vein compression collar to prevent alterations in resting-state electrocortical activity following a single-SWAT breacher training session was investigated. SWAT team personnel were randomly assigned to wear a compression collar during breacher training and resting state electroencephalography (EEG) was measured within 2 days prior to and two after breacher training. It was hypothesized that significant changes in brain dynamics-indicative of possible underlying neurodegenerative processes-would follow blast exposure for those who did not wear the collar, with ameliorated changes for the collar-wearing group. Using recurrence quantification analysis (RQA) it was found that participants who did not wear the collar displayed longer periods of laminar electrocortical behavior (as indexed by RQA's vertical max line measure) after breacher training. It is proposed that the blast wave exposure for the no-collar group may have reduced the number of pathways, via axonal disruption-for electrical transmission resulting in the EEG signals becoming trapped in laminar states for longer periods of time. Longer laminar states have been associated with other electrocortical pathologies, such as seizure, and may be important for understanding head trauma and recovery. PMID- 29987542 TI - Role of Dynamic Loading on Early Stage of Bone Fracture Healing. AB - After fracture, mesenchymal stem cells (MSCs) and growth factors migrate into the fracture callus to exert their biological actions. Previous studies have indicated that dynamic loading induced tissue deformation and interstitial fluid flow could produce a biomechanical environment which significantly affects the healing outcomes. However, the fundamental relationship between the various loading regimes and different healing outcomes has not still been fully understood. In this study, we present an integrated computational model to investigate the effect of dynamic loading on early stage of bone fracture healing. The model takes into account cell and growth factor transport under dynamic loading, and mechanical stimuli mediated MSC differentiation and tissue production. The developed model was firstly validated by the available experimental data, and then implemented to identify the loading regimes that produce the optimal healing outcomes. Our results demonstrated that dynamic loading enhances MSC and growth factor transport in a spatially dependent manner. For example, compared to free diffusion, dynamic loading could significantly increase MSCs concentration in endosteal zone; and chondrogenic growth factors in both cortical and periosteal zones in callus. Furthermore, there could be an optimal dynamic loading regime (e.g. 10% strain at 1 Hz) which could potentially significant enhance endochondral ossification. PMID- 29987541 TI - Immuno-driven and Mechano-mediated Neotissue Formation in Tissue Engineered Vascular Grafts. AB - In vivo development of a neovessel from an implanted biodegradable polymeric scaffold depends on a delicate balance between polymer degradation and native matrix deposition. Studies in mice suggest that this balance is dictated by immuno-driven and mechanotransduction-mediated processes, with neotissue increasingly balancing the hemodynamically induced loads as the polymer degrades. Computational models of neovessel development can help delineate relative time dependent contributions of the immunobiological and mechanobiological processes that determine graft success or failure. In this paper, we compare computational results informed by long-term studies of neovessel development in immuno compromised and immuno-competent mice. Simulations suggest that an early exuberant inflammatory response can limit subsequent mechano-sensing by synthetic intramural cells and thereby attenuate the desired long-term mechano-mediated production of matrix. Simulations also highlight key inflammatory differences in the two mouse models, which allow grafts in the immuno-compromised mouse to better match the biomechanical properties of the native vessel. Finally, the predicted inflammatory time courses revealed critical periods of graft remodeling. We submit that computational modeling can help uncover mechanisms of observed neovessel development and improve the design of the scaffold or its clinical use. PMID- 29987544 TI - Deviant Cyber-Sexual Activities in Young Adults: Exploring Prevalence and Predictions Using In-Person Sexual Activities and Social Learning Theory. AB - Technology has shifted some human interactions to the virtual world. For many young adults, sexual encounters now occur through virtual means, as social media, picture exchanges, sexually explicit Web sites, and video chatting have become popular alternative outlets for these activities to occur. This study used the self-report responses of 812 undergraduate students (282 men and 530 women), collected from an online survey. In addition to using 10 personal demographic control variables, this study used five sexual activity/relationship characteristics (number of sexual partners, relationship status, age to first use pornography, frequency of sexual activity/intercourse, and frequency of masturbation), and the four constructs of Akers' social learning theory (identified as differential association, differential reinforcement, imitation/modeling, and definitions favorable) to predict a seven-item count of deviant cyber-sexual activities, and two measures of "sexting" behaviors. Gender, self-esteem, sexual orientation, race, and religion were strongly significant predictors in the models, but Akers' four elements of social learning performed the strongest in predicting the two measures of sexting and the overall deviant cyber-sexual activities scale. This finding indicates that peer associations and peer reinforcements have a strong influence on individuals' willingness to engage in deviant cyber-sexual activities. This study explored different avenues for young adults' engagement in sexual deviancy and the results suggest that sexual behaviors performed in-person may not be the strongest predictors of online sexual behavior. PMID- 29987543 TI - A Review of Arterial Phantom Fabrication Methods for Flow Measurement Using PIV Techniques. AB - Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the western world. In the last three decades, fluid dynamics investigations have been an important component in the study of the cardiovascular system and CVD. A large proportion of studies have been restricted to computational fluid dynamic (CFD) modeling of blood flow. However, with the development of flow measurement techniques such as particle image velocimetry (PIV), and recent advances in additive manufacturing, experimental investigation of such flow systems has become of interest to validate CFD studies, testing vascular implants and using the data for therapeutic procedures. This article reviews the technical aspects of in-vitro arterial flow measurement with the focus on PIV. CAD modeling of geometries and rapid prototyping of molds has been reviewed. Different processes of casting rigid and compliant models for experimental analysis have been reviewed and the accuracy of construction of each method has been compared. A review of refractive index matching and blood mimicking flow circuits is also provided. Methodologies and results of the most influential experimental studies are compared to elucidate the benefits, accuracy and limitations of each method. PMID- 29987545 TI - The Roles of Self-Socialization and Parent Socialization in Toddlers' Gender Typed Appearance. AB - Children's gender-stereotypical dress and appearance might be one of the first representations of children's emerging sense of gender identity. Gender self socialization theories posit that as children become more aware of gender categories, they become motivated to adhere to gender stereotypes, such as by expressing interest in dressing in feminine or masculine ways. Socialization theories predict that children's gender-typed appearance reflects parents' choices. For example, gender-traditional parents might dress their children in gender-stereotypical ways. At the same time, dressing in gender-stereotypical ways might contribute to children's growing awareness of gender categories. The current study investigated the factors associated with gender-typed appearance among 175 (87 girls, 88 boys) Mexican American, Dominican American, and African American 2-year-olds. We examined both child and parent contributions to early gender-typed appearance. To measure children's early conceptual understanding of gender categories, we assessed children's use and recognition of gender verbal labels. To examine the influence of parent socialization, we assessed mothers' gender-role attitudes. Children's gender-typed appearance was observed and coded during an assessment. Surprisingly, mothers' gender-role attitudes were not significantly associated with toddlers' gender-typed appearance. However, toddlers' gender labeling was associated with their gender-typed appearance, suggesting that self-socialization processes can be found as early as 24 months of age. PMID- 29987546 TI - Sexual Activity and Sexual Satisfaction Among Older Adults in Four European Countries. AB - The aim of this article was to describe partnered and non-partnered sexual activity and sexual satisfaction in older men and women from Norway, Denmark, Belgium, and Portugal, and to explore sociodemographic correlates of sexual activity and satisfaction. Data were collected in 2016 using postal, anonymous questionnaires in probability samples of the population aged 60-75 years recruited by phone registers in Norway (676 men, 594 women), Denmark (530 men, 515 women), Belgium (318 men, 672 women), and Portugal (236 men, 273 women). In men, the percentage of sexually active participants in the past year ranged from 83% in Portugal to 91% in Norway. In women, the percentage of sexually active participants during the last year ranged from 61% in Belgium to 78% in Denmark. Regarding frequency of sexual intercourse activity during the past month, men in Norway, Denmark, and Belgium (23-24%) most often reported 2-3 times per month, whereas most men in Portugal (29%) reported 1-3 times per week. Masturbation was most commonly reported among Norwegian men (65%) and women (40%), and least commonly in Portugal. Concerning sexual satisfaction, across all countries, 40 60% of participants reported that they were sexually satisfied. Portuguese men and Danish women reported being most sexually satisfied. Having a partner was the most important positive predictor of sexual activity and sexual satisfaction in all subgroups except Portuguese men. In conclusion, partnered sexual activity was more frequent in the south of Europe, and solitary sexual activity more frequent in Northern Europe. PMID- 29987547 TI - Correction to: Changes in global longitudinal strain in renal transplant recipients following 12 months of exercise. AB - In the original publication, the given name and family name of the first author Dr. Enrico Minetti were incorrectly published. PMID- 29987548 TI - Oral Antiplatelet Therapy for Secondary Prevention of Acute Coronary Syndrome. AB - Patients surviving an acute coronary syndrome (ACS) remain at increased risk of ischemic events long term. This paper reviews current evidence and guidelines for oral antiplatelet therapy for secondary prevention following ACS, with respect to decreased risk of ischemic events versus bleeding risk according to individual patient characteristics and risk factors. Specifically, data are reviewed from clinical studies of clopidogrel, prasugrel, ticagrelor and vorapaxar, as well as the results of systematic reviews and meta-analyses looking at the benefits and risks of oral antiplatelet therapy, and the relative merits of shorter versus longer duration of dual antiplatelet therapy, in different patient groups. PMID- 29987549 TI - Influence of nitrogen source on photochemistry and antenna size of the photosystems in marine green macroalgae, Ulva lactuca. AB - Ulva lactuca is regarded as a prospective energy crop for biorefinery owing to its affluent biochemical composition and high growth rate. In fast-growing macroalgae, biomass development strictly depends on external nitrogen pools. Additionally, nitrogen uptake rates and photosynthetic pigment content vary with type of nitrogen source and light conditions. However, the combined influence of nitrogen source and light intensity on photosynthesis is not widely studied. In present study, pale green phenotype of U. lactuca was obtained under high light (HL) condition when inorganic nitrogen (nitrate) in the media was substituted with organic nitrogen (urea). Further, pale green phenotype survived the saturating light intensities in contrast to the normal pigmented control which bleached in HL. Detailed analysis of biochemical composition and photosynthesis was performed to understand functional antenna size and photoprotection in pale green phenotype. Under HL, urea-grown cultures exhibited increased growth rate, carbohydrate and lipid content while substantial reduction in protein, chlorophyll content and PSII antenna size was observed. Further, in vivo slow and polyphasic chlorophyll a (Chl a) fluorescence studies revealed reduction in excitation pressure on PSII along with low non-photochemical quenching thus, transmitting most of the absorbed energy into photochemistry. The results obtained could be correlated to previous report on cultivation of U. lactuca through saturating summer intensities (1000 umole photons m-2 s-1) in urea based: poultry litter extract (PLE). Having proved critical role of urea in conforming photoprotection, the application PLE was authenticated for futuristic, sustainable and year-round biomass cultivation. PMID- 29987551 TI - ? PMID- 29987550 TI - Efficacy analysis of hydroxychloroquine therapy in systemic lupus erythematosus: a study on disease activity and immunological biomarkers. AB - BACKGROUND: Hydroxychloroquine (HCQ) is a widely prescribed medication to patients with systemic lupus erythematosus (SLE), with potential anti inflammatory effects. This study was performed to investigate the efficacy of HCQ therapy by serial assessment of disease activity and serum levels of proinflammatory cytokines in SLE patients. METHODS: In this prospective cohort study, 41 newly diagnosed SLE patients receiving 400 mg HCQ per day were included. Patients requiring statins and immunosuppressive drugs except prednisolone at doses lower than 10 mg/day were excluded. Outcome measures were assessed before commencement of HCQ therapy (baseline visit) as well as in two follow-up visits (1 and 2 months after beginning the HCQ therapy). Serum samples of 41 age-matched healthy donors were used as controls. RESULTS: Median levels of IL-1beta (p < 0.001), IL-6 (p = 0.001), and TNF-alpha (p < 0.001) were significantly higher, whereas, median CH50 level was significantly lower (p < 0.001) in SLE patients compared with controls. Two-month treatment with HCQ resulted in significant decrease in SLEDAI-2K (p < 0.001), anti-dsDNA (p < 0.001), IL-1beta (p = 0.003), IL-6 (p < 0.001) and TNF-alpha (p < 0.001) and a significant increase in CH50 levels (p = 0.012). The reductions in SLEDAI-2K and serum levels of IL-1beta and TNF-alpha were significantly greater in the first month compared with the reductions in the second month. CONCLUSION: HCQ therapy is effective on clinical improvement of SLE patients through interfering with inflammatory signaling pathways, reducing anti-DNA autoantibodies and normalizing the complement activity. PMID- 29987553 TI - Unilateral deep cerebral venous sinus thrombosis with reversible secondary parkinsonism. PMID- 29987552 TI - Positive effect of alendronate on bone turnover in ovariectomised rats' osteoporosis: comparison of transdermal lipid-based delivery with conventional oral administration. AB - Alendronate (ALD) is clinically indicated for the treatment of osteoporosis, but its therapeutic use has been marred by severe GIT adverse effects affecting quality of life in patients. In this study, we selected novel transdermal microemulsion (TDME) as a suitable carrier for ALD as the way of avoiding intestinal toxicity and highlighted its anti-osteoporotic efficacy with extensive pharmacokinetic and pharmacodynamic analysis. TDME achieved two fold increase in bioavailability as compared to oral administration in pharmacokinetic studies. To investigate the capability of TDME in alleviating symptoms of osteoporosis, it was administered to ovariectomised rats 2 months post-surgery. The results obtained after 2 months of treatment with ALD by trans-epidermal route exhibited improved bone density in DEXA scan of rats. These observations were further supported by biochemical investigations including analysis of bone formation and resorption markers. Moreover, TDME effectively suppressed the decline in bone mass of osteoporotic rats as determined through the biometric analysis and histopathological examination of bones. Additionally, skin histopath results showed no significant skin damage at the end of treatment. Overall, these findings demonstrate that the TDME system is a promising approach for the effective delivery of ALD, bypassing the adverse effects associated with oral administration. PMID- 29987554 TI - Magnetic resonance imaging findings of mixed neuronal-glial tumors with pathologic correlation: a review. AB - Mixed neuronal-glial tumors are rare, and MRI diagnosis of them presents a challenge. In this review, we discuss the MRI findings of ganglioglioma, anaplastic ganglioglioma, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, rosette-forming glioneuronal tumor, and primary diffuse leptomeningeal glioneuronal tumor with clinicopathologic correlation. There is overlap of imaging features both with each other and some other tumors, which complicates diagnosis. The combination of imaging findings and the age, location, and appropriate clinical picture should allow the radiologist and the clinicians to raise a provisional diagnosis of a mixed neuronal glial tumor, and guide patient management. PMID- 29987555 TI - Update on the clinical application of deep brain stimulation in sleep dysfunction of Parkinson's disease. AB - Sleep dysfunctions, including rapid eye movement sleep behavior disorder, sleep fragmentation, excessive daytime sleepiness and various other dysfunctions, can seriously affect quality of life in patients with Parkinson's disease (PD). Emerging evidence suggests that deep brain stimulation (DBS) exerts a substantial effect when used to treat sleep dysfunctions, which are common nonmotor symptoms experienced by patients with PD. However, far less is known about the specific mechanisms underlying the effects of DBS on sleep processes and the factors that potentially influence these effects. These issues therefore need to be further clarified. Intriguingly, a number of recent studies have evaluated the effects of applying DBS to various brain targets on sleep in patients with PD. Deeper research into the efficacy of applying DBS to each brain target may help determine which region should be targeted during surgery in PD patients. Furthermore, compared with pharmacological therapy, DBS had more beneficial effects on sleep symptoms, and appropriate management involving the joint application of dopamine replacement therapy and DBS might accelerate the effects of treatment. Here, we review the potential roles DBS may play and provide clinical guidance for the use of DBS in treating sleep dysfunctions in PD patients. PMID- 29987556 TI - The contribution of the scapula to active shoulder motion and self-assessed function in three hundred and fifty two patients prior to elective shoulder surgery. AB - PURPOSE: Scapular motion is an important component of shoulder function. This study determined the contribution of the scapula to active shoulder motion in control subjects and patients with loss of shoulder function. METHODS: The Kinect system was used to assess active scapulothoracic (ST) and humerothoracic (HT) abduction in 12 controls and in 352 patients before elective shoulder surgery. RESULTS: For the controls, ST abduction averaged 26 +/- 7 degrees or 19% of the active HT abduction (135 +/- 5 degrees ). For the 352 patients having elective surgery, active ST abduction averaged 12 +/- 10 degrees , or 17% of the active HT abduction (72 +/- 38). For 10 of the 12 SST functions, patients unable to perform the function had significantly less scapulothoracic abduction, e.g., shoulders unable to lift one pound to shoulder level had 9 +/- 8 degrees of ST abduction in contrast to 17 +/- 10 for those able to perform this function (p < .001). CONCLUSIONS: Scapulothoracic motion is an important component of active shoulder motion and function in both healthy shoulders and in those compromised by common pathologies. This study suggests that rehabilitation directed at improving active scapulothoracic motion may improve the function of shoulders with loss of glenohumeral motion. LEVEL OF EVIDENCE: Level III Prognostic Study. PMID- 29987557 TI - Multicentre comparative study of Z-shape elevating-pulling reduction and skull traction reduction for treatment of lower cervical locked facets. AB - PURPOSE: The aim of this study was to assess the clinical efficacy and safety of Z-shape elevating-pulling reduction as compared to that of conventional skull traction in the treatment of lower cervical locked facet. METHODS: Patients with cervical locked facet (n = 63) were retrospectively enrolled from four medical centers and divided into two groups according to the pre-operative reduction method used: Z-shape elevating-pulling reduction (Z-shape elevating group; n = 20) or traditional skull traction reduction (skull traction group; n = 43). RESULTS: The success rates, efficacy of reduction, and safety were compared between the two groups. The success rates were significantly better in the Z shape elevating group than in the skull traction group: 87.5% (7/8) vs. 35.3% (6/17) for unilateral locked facet reduction (P = 0.03) and 100% (12/12) vs. 69.2% (18/26) for bilateral locked facet reduction (P = 0.04). There was no obvious change in American Spinal Injury Association (ASIA) grade after the reduction in either group. Combined surgery was necessary in 5% in the Z-shape elevating group vs. 27.9% in the skull traction group. Imaging showed that the segment angle and horizontal displacement were significantly improved after surgery in both groups, with no significant difference between the groups. Follow up with radiography showed good recovery of the cervical spine sequence; all internal fixation sites were stable, with no loosening, prolapse, or breakage of internal fixators. CONCLUSIONS: Halo vest-assisted Z-shape elevating-pulling reduction appears to be a simple, safe, and effective technique for pre-operative reduction of lower cervical locked facets. PMID- 29987558 TI - Clinical outcomes of anterior correction and reconstruction for neurofibromatosis associated severe cervical kyphotic deformity. AB - PURPOSE: To assess the clinical outcome of anterior correction and reconstruction for severe cervical kyphotic deformity due to neurofibromatosis type 1 (NF-1). METHODS: In this study, we reviewed a series of seven patients who underwent anterior procedures for correction of NF-1-associated cervical kyphotic deformity. After continuous preoperative skull traction, all patients received anterior corpectomy and fusion (ACCF), anterior discectomy and fusion (ACDF), or combined ACCF and ACDF for surgical correction and reconstruction. Pre- and postoperative local and global Cobb angles, correction rate, sagittal vertical axis (SVA), and T1-slope were assessed by X-ray. Japanese Orthopaedic Association (JOA) score, JOA recovery rate, visual analog scale (VAS), and Neck Disability Index (NDI) scores were recorded to assess the outcome. RESULTS: Kyphosis was corrected successfully in all patients in terms of local and global Cobb angles (P < 0.05), with a correction rates of 83.1% (range, 66.0 to 115.5%) and 88.6% (range, 61.1 to 125.0%), respectively. JOA scores of patients were improved from preoperative 10.4 (range, 6 to 14) to postoperative 15.4 (range, 14 to 17), with a recovery rate as 77.6% (range, 66.7 to 100%). NDI scores were reduced from preoperative 25.1 (range, 13 to 35) to postoperative 8.7 (range, 5 to 12). VAS scores were reduced from preoperative 7.0 (range, 4 to 9) to postoperative 2.3 (range, 1 to 3). CONCLUSION: This study has demonstrated that anterior correction and reconstruction is an alternative option for the treatment of NF-1-associated severe cervical kyphosis when deformity is localized, flexible, or fixed. PMID- 29987559 TI - Changes in irrational beliefs are responsible for the efficacy of the REThink therapeutic game in preventing emotional disorders in children and adolescents: mechanisms of change analysis of a randomized clinical trial. AB - The mechanisms of change are rarely investigated in the field of gamified interventions for preventing emotional disorders in children and adolescents despite the wide recognition for the advantages they offer as prevention tool. Therefore, the aim of the present study was to investigate the mechanisms of change of a therapeutic game (REThink), specifically mediators and moderators of its efficacy. We conducted a randomized controlled trial, involving 165 children (age range 10-16 years), who were randomly distributed across three groups: the REThink group (N = 54), the Rational Emotive Behavior Education group (N = 55) and the Waitlist condition (N = 56). Results indicated that changes in irrational beliefs were significant mediators for the REThink intervention on depressive mood and overall negative emotions. Age did not moderate the effect of REThink, which indicates that the program was equally effective for children and adolescents.Trial Registration ClinicalTrials.gov NCT03308981. PMID- 29987560 TI - A Proposed Solution and Future Direction for Blockchain-Based Heterogeneous Medicare Data in Cloud Environment. AB - The healthcare data is an important asset and rich source of healthcare intellect. Medical databases, if created properly, will be large, complex, heterogeneous and time varying. The main challenge nowadays is to store and process this data efficiently so that it can benefit humans. Heterogeneity in the healthcare sector in the form of medical data is also considered to be one of the biggest challenges for researchers. Sometimes, this data is referred to as large scale data or big data. Blockchain technology and the Cloud environment have proved their usability separately. Though these two technologies can be combined to enhance the exciting applications in healthcare industry. Blockchain is a highly secure and decentralized networking platform of multiple computers called nodes. It is changing the way medical information is being stored and shared. It makes the work easier, keeps an eye on the security and accuracy of the data and also reduces the cost of maintenance. A Blockchain-based platform is proposed that can be used for storing and managing electronic medical records in a Cloud environment. PMID- 29987561 TI - Towards spill-free in-bag morcellation: a health failure mode and effects analysis. AB - BACKGROUND: To assess potential risks of new surgical procedures and devices before their introduction into daily practice, a prospective risk inventory (PRI) is a required step. This study assesses the applicability of the Health Failure Mode and Effects Analysis (HFMEA) as part of a PRI of new technology in minimally invasive gynecologic surgery. METHODS: A reference case was defined of a patient with presumed benign leiomyoma undergoing a laparoscopic hysterectomy or myomectomy including in-bag power morcellation; however, pathology defined a stage I uterine leiomyosarcoma. Using in-bag morcellation as a template, a HFMEA was performed. All steps of the in-bag morcellation technique were identified. Next, the possible hazards of these steps were explored and possible measures to control these hazards were discussed. RESULTS: Five main steps of the morcellation process were identified. For retrieval bags without openings to accommodate instruments inside the bag, 120 risks were identified. Of these risks, 67 should be eliminated. For containment bags with openings 131 risks were identified of which 68 should be eliminated. Of the 10 causes most at risk to cause spillage, two can be eliminated by using appropriate bag materials. Myomectomy appears to be more at risk for residual tissue spillage compared to total hysterectomy. CONCLUSION: The HFMEA has provided important new insights regarding potential weaknesses of the in-bag morcellation technique, particularly with respect to hazardous steps in the morcellation process as well as requirements that bags should meet. As such, this study has shown HFMEA to be a valuable method that identifies and quantifies potential hazards of new technology. PMID- 29987562 TI - Does obesity impact postoperative outcomes following robotic-assisted surgery for rectal cancer? AB - INTRODUCTION: Obesity has been identified as a risk factor for both conversion and severe postoperative morbidity in patients undergoing laparoscopic rectal resection. Robotic-assisted surgery (RAS) is proposed to overcome some of the technical limitations associated with laparoscopic surgery for rectal cancer. The aim of our study was to determine if obesity remains a risk factor for severe morbidity in patients undergoing robotic-assisted rectal resection. PATIENTS: This study was a retrospective review of a prospective database. A total of 183 patients undergoing restorative RAS for rectal cancer between 2007 and 2016 were divided into 2 groups: control (BMI < 30 kg/m2; n = 125) and obese (BMI >= 30 kg/m2; n = 58). Clinicopathologic data, 30-day postoperative morbidity, and perioperative outcomes were compared between groups. The main outcome was severe postoperative morbidity defined as any complication graded Clavien-Dindo >= 3. RESULTS: Control and obese groups had similar clinicopathologic characteristics. Severe complications were observed in 9 (7%) and 4 (7%) patients, respectively (p > 0.99). Obesity did not impact conversion, anastomotic leak rate, length of stay, or readmission but was significantly associated with increased postoperative morbidity (29 vs. 45%; p = 0.04) and especially more postoperative ileus (11 vs. 26%; p = 0.01). Obesity and male gender were the two independent risk factors for postoperative overall morbidity (OR 1.97; 95% CI 1.02-3.94; p = 0.04 and OR 2.23; 95% CI 1.10-4.76; p = 0.03, respectively). CONCLUSION: Obesity did not impact severe morbidity or conversion rate following RAS for rectal cancer but remained a risk factor for overall morbidity and especially postoperative ileus. PMID- 29987564 TI - Effects of transabdominal preperitoneal and totally extraperitoneal inguinal hernia repair: an update systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Compared with open herniorrhaphy, laparoscopic herniorrhaphy can yield more favorable clinical outcomes. However, previous studies failed to give definite answer for comparison between laparoscopic inguinal hernia repair approaches. This study aimed to systematically determine the differences in recurrence rate, duration of return to work, pain, surgery duration, and duration of hospital stay between transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) approach for inguinal hernia. METHODS: PubMed, Embase, and Cochrane Library (including the Cochrane Central Register of Controlled Trials) abstracts up to September 2017 were searched for randomized controlled trials (RCTs) comparing TAPP or TEP hernia repairing. The hernia recurrence rate, time to return to work, analgesic consumption, surgery duration, hospital stay, and the pain score were recorded with subgroup analysis of the hernia type. RESULTS: Sixteen RCTs that randomized 1519 patients with hernia into TEP and TAPP repair groups were analyzed in this study. The results revealed that TEP repair resulted in shorter hospital stay of primary cases (MD - 0.87, 95% CI - 1.67 to - 0.07) but was associated with a longer operative duration in recurrent hernia group (MD 3.35, 95% CI 0.16 - 6.54). CONCLUSIONS: TEP and TAPP have their own advantages. TEP repair reduces short-term postoperative pain more effectively than TAPP repair and results in shorter hospital stay of primary cases. In contrast, TAPP repair is correlated with shorter surgery duration. These findings show that shared decision-making regarding both approaches of laparoscopic hernia repair may be needed. PMID- 29987563 TI - Risk factors and consequences of conversion to open surgery in laparoscopic common bile duct exploration. AB - BACKGROUND: Although laparoscopic common bile duct exploration (LCBDE) has shown many obvious advantages compared with open surgery in the treatment of common bile duct (CBD) stones, it remains unclear regarding risk factors of conversion from LCBDE to open surgery and whether conversion will counteract the advantages of LCBDE. The purpose of this study was to explore risk factors and consequences of conversion from LCBDE to open surgery. METHODS: A retrospective study was conducted, using a database of 644 patients with LCBDE between 2011 and 2017. Risk factors for conversion to open surgery were determined based on univariable and multivariable analysis. The consequences of conversion to open surgery in LCBDE were analyzed. RESULTS: Conversion was required in 27 (4.2%) of 644 patients undergoing LCBDE. Independent risk factors for conversion were as follows: the max diameter of stones in CBD (odds ratio (OR) 2.234, 95%CI 1.031 4.842; p = 0.042), edema of CBD (OR 12.530, 95%CI 4.633-33.887; p < 0.001), and multiple stones in CBD (OR 3.438, 95%CI: 1.133-10.428; p = 0.029). These risk factors and their combined were good predictors for conversion in LCBDE. More blood loss, longer operative time, longer postoperative hospital stay, and higher incision infection were identified in patients with conversion than those without conversion. However, no significant differences were observed regarding mortality, readmission within 30 days, reoperation, bile leakage, and intra abdominal fluid collection. CONCLUSION: Conversion to open surgery in LCBDE was associated with acute edematous CBD with large and multiple stones. Conversion can offset the advantages of LCBDE. PMID- 29987566 TI - Enhanced recovery after surgery protocol allows ambulatory laparoscopic appendectomy in uncomplicated acute appendicitis: a prospective, randomized trial. AB - BACKGROUND: Previous observational studies have demonstrated the safety of discharging patients after laparoscopic appendectomy within the same day without hospitalization. The application of Enhanced Recovery After Surgery (ERAS) guidelines has resulted in shorter length of stay, fewer complications, and reduction in medical costs. The aim of this study was to investigate if ERAS protocol implementation in patients with acute uncomplicated appendicitis decreases the length of stay enough to allow for ambulatory laparoscopic appendectomy. METHODS: In this prospective, randomized controlled clinical trial, 108 patients were randomized into two groups: laparoscopic appendectomy with ERAS (LA-E) or laparoscopic appendectomy with conventional care (LA-C). The primary endpoint was postoperative length of stay. The secondary end points were time to resume diet, postoperative pain, postoperative complications, re-admission rate, and reoperation rate. RESULTS: From January 2016 through May 2017, 50 patients in the LA-E group and 58 in the LA-C were analyzed. There were no significant differences in preoperative data. Regarding the primary end point of the study, the ERAS protocol significantly reduced the postoperative length of stay with a mean of 9.7 h (SD: 3.1) versus 23.2 h (SD: 6.8) in the conventional group (p < 0.001). The ERAS protocol allowed ambulatory management in 90% of the patients included in this group. There was a significant reduction in time to resume diet (110 vs. 360 min, p < 0.001) and less moderate-severe postoperative pain (28 vs. 62.1%, p < 0.001) in the LA-E versus LA-C group. The rate of complications, readmissions, and reoperations were comparable in both groups (p = 0.772). CONCLUSIONS: ERAS implementation was associated with a significantly shorter length of stay, allowing for the ambulatory management of this group of patients. Ambulatory laparoscopic appendectomy is safe and feasible with similar rates of morbidity and readmissions compared with conventional care. PMID- 29987565 TI - Perioperative and long-term outcomes of laparoscopic versus open liver resection for hepatocellular carcinoma with well-preserved liver function and cirrhotic background: a propensity score matching study. AB - BACKGROUND: Although laparoscopic liver resection (LLR) has advanced into a safe and effective alternative to conventional open liver resection (OLR), it has not been widely accepted by surgeons. This article aimed to investigate the perioperative and long-term benefits of LLR versus OLR for hepatocellular carcinoma (HCC) in selected patients with well-preserved liver function and cirrhotic background. METHODS: A retrospective study was conducted on 1085 patients with HCC who underwent liver resection at Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University from July 2010 to July 2015, and 346 patients with well preserved liver function and cirrhotic background were selected. A 1:1 propensity score matching (PSM), which is the best option to overcome selection bias, was conducted to compare the surgical outcomes and long-term prognosis between LLR and OLR. After PSM, a logistic regression analysis was used to identify the predictive risk factors of posthepatectomy liver failure (PHLF). RESULTS: By using PSM, the two groups were well balanced with 86 patients in each group. In the LLR group, only the median operation time was significantly longer than the OLR group, but the hospital stay, overall morbidity, and the incidence of PHLF were significantly decreased compared to OLR. There were no significant differences in the overall survival and disease-free survival rates between the two groups. On multivariate analysis, OLR was identified to be the only independent risk factor for PHLF. CONCLUSIONS: In selected HCC patients with well preserved liver function and cirrhotic background, LLR could be a better option compared to OLR. PMID- 29987567 TI - Surgeon leadership style and risk-adjusted patient outcomes. AB - BACKGROUND: There are many reasons to believe that surgeon personality traits and related leadership behaviors influence patient outcomes. For example, participation in continuing education, effective self-reflection, and openness to feedback are associated with certain personalities and may also lead to improvement in outcomes. In this context, we sought to determine if an individual surgeon's thinking and behavior traits correlate with patient level outcomes after bariatric surgery. METHODS: Practicing surgeons from the Michigan Bariatric Surgery Collaborative (MBSC) were administered the Life Styles Inventory (LSI) assessment. The results of this assessment were then collapsed into three major styles that corresponded with particular patterns of an individual's thinking and behavior: constructive (achievement, self-actualizing, humanistic-encouraging, affiliative), passive/defensive (approval, conventional, dependent, avoidance), and aggressive/defensive (perfectionistic, competitive, power, oppositional). We compared patients level outcomes for surgeons in the lowest, middle, and highest quintiles for each style. We then used patient level risk-adjusted rates of complications after bariatric surgery to quantify the impact surgeon style on post-operative outcomes. RESULTS: We found that patients undergoing bariatric surgery performed by surgeons with high levels of constructive (achievement, self actualizing, humanistic-encouraging, affiliative) and passive/defensive (approval, conventional, dependent, avoidance) styles had lower rates of adverse events compared with surgeons with low levels of the respective styles [High constructive: 14.7% (13.8-15.6%), low constructive: 17.7% (16.8-18.6%); high passive: 14.8% (13.4-16.1%), low passive: 18.7% (17.3-19.9%)]. Conversely, surgeons identified with high aggressive styles (perfectionistic, competitive, power, oppositional) had similar rates of post-operative adverse events compared with surgeons with low levels [high aggressive: 15.2% (14.3-16.1%), low aggressive: 14.9% (14.2-15.6%)]. CONCLUSION: Our analysis demonstrates that surgeons' leadership styles are correlated with surgical outcomes for individual patients. This finding underscores the need for professional development for surgeons to cultivate strengths in the constructive domains including intentional self-improvement, development of interpersonal skills, and the receptiveness to feedback. PMID- 29987568 TI - The ASGE grading system for ERCP can predict success and complication rates in a tertiary referral hospital. AB - BACKGROUND: The utility of the American Society for Gastrointestinal Endoscopy (ASGE) grading scale assessing complexity of endoscopic retrograde cholangiopancreatography (ERCP) has not been evaluated in clinical practice. METHODS: Patients that underwent ERCP between January 2015 and December 2015 were included. Procedural difficulty was graded according to the grading system proposed by the ASGE workshop. Technical success rates and complications were recorded. RESULTS: A total of 1355 ERCPs were performed on 934 patients. Patients were equally divided with respect to gender and had a mean age of 58 years (range 29-86). 391 cases were grade 1, 2 (29%), 695 were grade 3 (51%), and 269 were grade 4 (20%). Altered anatomy was observed in 88% of grade 4 patients. Cannulation was achieved in 98% of cases graded 1-3 and in 88% of cases graded 4 (p < 0.05). Complications were recorded in 10% of all cases with post-ERCP pancreatitis (5.4%) and procedure-related bleeding (1.5%) being the more common ones. No statistically significant difference was noted between the groups with regard to complications. Three perforations were seen in grade 1-3 cases (0.3%) compared to 4 cases in grade 4 cases (1.5%), (p = 0.01). CONCLUSION: The grading system proposed by the ASGE workshop can aid in predicting cannulation success and perforation rates in ERCP. Based on this retrospective study, the most complex ERCP procedures can be achieved with encouraging rates of success. There is a need to validate our study with prospective ones performed in other high volume centers. PMID- 29987569 TI - Trans-perineal minimally invasive surgery during laparoscopic abdominoperineal resection for low rectal cancer. AB - BACKGROUND: Laparoscopic abdominoperineal resection (APR) for low rectal cancer (LRC) is performed worldwide. However, APR involves technical difficulties and often causes intractable perineal complications. Therefore, a novel and secure technique during APR is required to overcome these critical issues. Although the usefulness of the endoscopic trans-anal approach has been documented, no series of the endoscopic trans-perineal approach during laparoscopic APR for LRC has been reported. METHODS: Trans-perineal minimally invasive surgery (TpMIS) has been used during laparoscopic APR in our institution since April 2014. TpMIS is defined as an endoscopic trans-perineal approach using a single-port device and laparoscopic instruments. In this study, we retrospectively evaluated 50 consecutive patients with LRC who underwent laparoscopic APR at our institution from February 2011 to June 2017 and compared the outcomes of the patients who underwent TpMIS [trans-perineal APR (TpAPR) group, n = 21] versus the conventional trans-perineal approach (conventional group, n = 29). We investigated our experiences with TpMIS in detail and evaluated the safety and utility of TpMIS for patients with LRC. Moreover, major features and difficulties of TpMIS were examined from a surgical viewpoint. RESULTS: Intraoperative blood loss (median (range) 55 (10-600) vs. 120 (20-1650) ml) and severe perineal wound infection (Clavien-Dindo grade 3, 0 vs. 5 cases) were significantly lower in the TpAPR than conventional group. TpMIS led to a shortened hospital stay (median (range), 14 (10-74) vs. 23 (10-84) days), and neither mortality nor conversion to open surgery occurred in the TpAPR group. CONCLUSIONS: Magnified visualization via endoscopy provided more accurate dissection and less blood loss during surgery. Minimal skin incisions enabled a reduction in postoperative perineal complications, and consequently shortened the hospital stay. TpMIS during laparoscopic APR is safe and beneficial for patients with LRC. PMID- 29987570 TI - Low socioeconomic status is associated with lower weight-loss outcomes 10-years after Roux-en-Y gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the criterion standard operation for weight loss. Low socioeconomic status (SES) is common in the Veteran population undergoing bariatric surgery, but the impact of SES on long-term weight-loss outcomes is not known. We hypothesize that low socioeconomic status is associated with less weight loss after gastric bypass in long-term follow-up. METHODS: We performed a retrospective review of patients undergoing RYGB at a single Veterans Affairs (VA) hospital. Patients with at least 10 years of follow up data in the electronic health record were included in the analysis. Weight loss was measured as percent excess body mass index loss (%EBMIL). The primary predictor variable, median household income, was determined using zip codes of patient residences matched to publicly available 2010 U.S. census data. Univariate relationships between income, weight loss, and other patient characteristics were evaluated. We calculated a multivariate generalized linear model of %EBMIL to estimate independent relationships with median household income quartile while controlling for patients' age, race, sex, and VA distance. RESULTS: Complete 10-year follow-up data were available for 83 of 92 patients (90.2%) who underwent RYGB between 2001 and 2007 and survived at least 10 years. The majority of patients were male (79.5%) and white (73.5%). The mean 10-year %EBMIL was 57.8% (SD: 29.5%, range - 36.0% - 132.8%). In univariate analysis, income was significantly associated with race (p < 0.001) and median distance to the VA bariatric center (p = 0.034), but income did not differ by gender (p = 0.73) or age (p = 0.45). Multivariate analysis revealed significantly lower 10 year %EBMIL for patients with the lowest income compared to patients with low-mid income (p = 0.03) and mid-high income (p = 0.01), after controlling for gender, race, age, and VA distance. CONCLUSIONS: Low socioeconomic status is associated with lower weight-loss outcomes, 10 years after RYGB. Durable weight loss is observed in all income groups. PMID- 29987571 TI - Professional fee payments by specialty for inpatient open ventral hernia repair: who gets paid for treating comorbidities and complications? AB - BACKGROUND: The purpose of this study was to determine perioperative professional fee payments to providers from different specialties for the care of patients undergoing inpatient open ventral hernia repair (VHR). METHODS: Perioperative data of patients undergoing VHR at a single center over 3 years were selected from our NSQIP database. 180-day follow-up data were obtained via retrospective review of records and phone calls to patients. Professional fee payments (PFPs) to all providers were obtained from our physician billing system for the VHR hospitalization, the 180 days prior to operation (180Prior) and the 180 days post discharge (180Post). RESULTS: PFPs for 283 cases were analyzed. Average total 360 day PFPs per patient were $3409 +/- SD 3294, with 14.5% ($493 +/- 1546) for services in the 180Preop period, 72.5% ($2473 +/- 1881) for the VHR hospitalization, and 13.0% ($443 +/- 1097) in the 180Postop period. The surgical service received 62% of PFPs followed by anesthesia (18%), medical specialties (9%), radiology (6%), and all other provider services (5%). Medical specialties received increased PFPs for care of patients with COPD and HCT < 38% ($90 and $521, respectively) and for the pulmonary complications ($2471) and sepsis ($2714) that correlated with those patient comorbidities; surgeons did not. Operative duration, mesh size, and separation of components were associated with increased surgeon PFPs (p < .05). At 6 months, wound complications were associated with increased surgeon and radiology payments (p < .01). CONCLUSIONS: Management of acute comorbid conditions and the associated higher postoperative morbidity is not reimbursed to the surgeon under the 90-day global fee. These represent opportunity costs of care that pressure busy surgeons to select against these patients or to delegate more management to their medical specialty colleagues, thereby increasing total system costs. A comorbid risk adjustment of procedural reimbursement is warranted. In negotiating bundled payments, surgeon groups should keep in mind that surgeon reimbursement, unlike medical specialty and hospital reimbursement, have been bundled since the 1990s. PMID- 29987572 TI - Surgeon utilization of minimally invasive techniques for inguinal hernia repair: a population-based study. AB - BACKGROUND: MIS utilization for inguinal hernia repair is low compared to in other procedures. The impact of low adoption in surgeons is unclear, but may affect regional access to minimally invasive surgery (MIS). We explored the impact of surgeon MIS utilization in inguinal hernia repair across a statewide population. METHODS: We analyzed 6723 patients undergoing elective inguinal hernia repair from 2012 to 2016 in the Michigan Surgical Quality Collaborative. The primary outcome was surgeon MIS utilization. The geographic distribution of high MIS-utilizing surgeons was compared across Hospital Referral Regions using Pearson's Chi-squared test. Hierarchical logistic regression was used to identify patient and hospital factors associated with MIS utilization. RESULTS: Surgeon MIS utilization varied, with 58% of 540 surgeons performing no MIS repair. For the remaining surgeons, MIS utilization was bimodally distributed. High utilization surgeons were unevenly distributed across region, with corresponding differences in regional MIS rate ranging from 10 to 48% (p < 0.001). MIS was used in 41% of bilateral and 38% of recurrent hernia. MIS repair was more likely with higher hospital volume and less likely for patients aged 65+ (OR 0.68, p = 0.003), black patients (OR 0.75, p = 0.045), patients with COPD (OR 0.57, p < 0.001), and patients in ASA class > 3 (OR 0.79 p < 0.001). CONCLUSIONS: MIS utilization varies between surgeons, likely driving differences in regional MIS rates and leading to guideline-discordant care for patients with bilateral or recurrent hernia. Interventions to reduce this practice gap could include training programs in MIS repair, or regionalization of care to improve MIS access. PMID- 29987573 TI - Laparoscopic splenectomy for immune thrombocytopenia (ITP): long-term outcomes of a modern cohort. AB - BACKGROUND: The advent of newer second-line medical therapies (SLMT) for immune thrombocytopenia (ITP) has contributed to decreased rates of splenectomy, following a trend to avoid or delay surgery. We aimed to characterize the long term outcomes of laparoscopic splenectomy (LS) for ITP at our institution, examining differences in LS efficiency when performed before or after SLMTs. METHODS: Adults with primary ITP who underwent LS between 2002 and 2016 were identified. Retrospective review of electronic medical records was supplemented with telephone interviews. Treatment response was defined according to current guidelines as complete responders (CR), responders (R), and non-responders (NR). Kaplan-Meier estimates assessed relapse-free rates, and predictors of long-term response were investigated using logistic regression. RESULTS: 109 patients met inclusion criteria, from which 42% were treated with an SLMT before referral to LS. LS was completed in all cases, with no conversions or intraoperative complications. The perioperative morbidity was 7.3%, including 3 deep vein and 2 portal vein thrombosis, one reoperation for bleeding, and no mortalities. Splenectomy was initially effective in 99 patients (CR + R = 90.8%), and 10 patients were NR. At a median 62-month follow-up, 25 patients relapsed, resulting in a 68% CR + R rate. Proportion of CR + R was similar in patients who previously received SLMT and those who did not (61 vs. 76.7%, p = 0.08). CR + R patients were younger (45 vs. 53, p = 0.03), had higher preoperative platelet counts (36 vs. 19, p = 0.01), and experienced a higher increment in platelet counts during hospital stay (117 vs. 38, p < 0.001) as well as 30-days postoperatively (329 vs. 124, p < 0.001). Only a robust response in platelet count at 30-days postoperatively was independently associated with long-term response (OR 1.005, p = 0.006). CONCLUSION: LS was curative in 68% of patients, with no statistically significant difference when performed before or after SLMTs. Outcomes remain challenging to predict preoperatively, with only a robust increase in platelet counts on short term being associated with long-term response. PMID- 29987574 TI - Mathematical analysis and drug exposure evaluation of pharmacokinetic models with endogenous production and simultaneous first-order and Michaelis-Menten elimination: the case of single dose. AB - Drugs with an additional endogenous source often exhibit simultaneous first-order and Michaelis-Menten elimination and are becoming quite common in pharmacokinetic modeling. In this paper, we investigate the case of single dose intravenous bolus administration for the one-compartment model. Relying on a formerly introduced transcendent function, we were able to analytically express the concentration time course of this model and provide the pharmacokinetic interpretation of its components. Using the concept of the corrected concentration, the mathematical expressions for the partial and total areas under the concentration time curve (AUC) were also given. The impact on the corrected concentration and AUC is discussed as well as the relative contribution of the exogenous part in presence of endogenous production. The present findings theoretically elucidate several pharmacokinetic issues for the considered drug compounds and provide guidance for the rational estimation of their pharmacokinetic parameters. PMID- 29987575 TI - Snack cost and percentage of body fat in Chinese children and adolescents: a longitudinal study. AB - PURPOSE: Only a few studies examined the relationship between snack cost and change in the percentage of body fat in children. We thus conducted a longitudinal study to investigate whether high snack cost is associated with fast increase in the percentage of body fat in Chinese children. METHODS: The study included 2368 children (1126 girls and 1242 boys, aged 6-14 years). Percentage of body fat was repeatedly assessed by bioelectrical impedance analysis in 2014 (baseline), 2015 and 2016. Snack cost in 2014 was estimated by self-report associated with purchasing snacks at school and classified into low, moderate, and high group. Association between snack cost and repeated percentage of body fat was analyzed with linear mixed models, adjusting for demographic factors, diet, physical activity, and parental BMI and education. RESULTS: High snack cost was significantly associated with a fast increase in the percentage of body fat over time (p trend = 0.04). Adjusted difference in annual increase rate in percentage of body fat between the high and low snack cost group was 0.31% [95% confident interval (CI) 0.04%, 0.58%], after adjusting for potential confounders. The impacts of snack cost on change in the percentage of body fat were more pronounced in boys, younger participants and those with higher BMI z-score at the baseline, relative to their counterparts (p interaction < 0.001 for all). CONCLUSIONS: High snack cost was associated with more gain of body fat in Chinese school-aged children. PMID- 29987576 TI - Green Fluorescent Protein Expression in Pseudogymnoascus destructans to Study Its Abiotic and Biotic Lifestyles. AB - Pseudogymnoascus destructans (Pd) is the etiologic agent of bat White-nose syndrome, a disease that has caused the unprecedented reduction in the hibernating bat populations across eastern North America. The Pd pathogenesis appears to be a complex adaptation of fungus in its abiotic (caves and mines) and biotic (bats) environments. There is a general lack of experimental tools for the study of Pd biology. We described the successful expression of codon-optimized synthetic green fluorescent protein sGFP in Pd. The sGFP(S65T) gene was first fused in frame with the Aspergillus nidulans promoter in the tumor-inducing plasmid pRF-HUE, and the resulting plasmid pHUE-sGFP(S65T) was transformed into Pd by Agrobacterium tumefaciens-mediated transformation system. The integration of sGFP(S65T) in Pd genome was analyzed by PCR, and single integration frequency of approximately 66% was confirmed by Southern hybridization. Fluorescent microscopy and flow cytometric analyses of two randomly selected transformants with single integration revealed high expression of sGFP in both spores and hyphal structures. The biology of mutants as judged by sporulation, growth rate, and urease production was not altered indicating sGFP is not toxic to Pd. Thus, we have generated a valuable tool that will facilitate the elucidation of Pd biology, ecology, and pathogenicity in real time. PMID- 29987577 TI - Epithelial-myoepithelial carcinoma of the lung: a case report. AB - BACKGROUND: Pulmonary epithelial-myoepithelial carcinoma (P-EMC) is a rare subset of salivary gland-type tumors of the lung. Because of its rarity and unproven malignant potential, the optimal therapy for P-EMC has not been defined. Here, we report a typical case of P-EMC and a review of the literature to consider appropriate treatment. CASE PRESENTATION: A 54-year-old woman presented with an abnormal lung shadow on a routine chest X-ray. A chest computed tomography (CT) scan verified an 18-mm endobronchial nodule on the middle lobe. We performed a bronchoscopic biopsy, and the patient was diagnosed with P-EMC. After confirming the absence of tumors in the salivary glands, she underwent a right middle lobectomy along with hilar and mediastinal lymph node dissections. Currently, the patient is doing well, without any sign of recurrence 3 years after surgery. CONCLUSIONS: Although a majority of P-EMC cases, as in our case, behave indolently, several poor progression cases have been reported. For distinguishing the minor malignancy cases from others, histological findings such as myoepithelial anaplasia could be a predictive factor. Complete resection is needed to evaluate the whole tumor, because P-EMCs often show histological heterogeneity. Moreover, incomplete excision may be a poor prognostic factor. Although lobectomies as well as lymph node dissections, sleeve lobectomies, or pneumonectomies are routinely performed for complete resection, further investigation is required to establish the optimal treatment strategy. PMID- 29987578 TI - Insular cortex lesion and autonomic instability in a herpes simplex virus encephalitis patient. AB - The cardiovascular system is regulated by a central autonomic network (CAN) consisting of the insular cortex, anterior cingulate gyrus, and amygdala. Because the insular cortex often tends to be damaged in patients with herpes simplex virus (HSV) encephalitis, the autonomic instability observed in these patients was suggested to be moderated by an insular cortex lesion. Here, we report the case of a 51-year-old Japanese male who was hospitalized following a collapse 5 days earlier; he was diagnosed as herpes encephalitis. Diffusion-weighted MRI revealed asymmetric right greater hyperintensity throughout his insular cortex and anterior cingulate gyrus. At 1 week after admission, transthoracic echo showed diffuse hypokinesis in the left ventricle (LV). Cardiac 123I-meta iodobenzylguanidine uptake (123I-MIBG) scintigraphy revealed reduced uptake in the inferior and posterior wall. Electrocardiograhy at rest showed that the coefficient variation of RR intervals (CVR-R) was reduced, and the corrected QT (QTc) interval length was prolonged. In this HSV encephalitis patient, signs of a right insular cortex lesion and autonomic instability were observed: LV hypokinesis, regional reduced 123I-MIBG uptake, decreased CVR-R, and QTc interval prolongation. Our patient's autonomic instability may thus be derived from disrupted autonomic balance due to the right insular cortex lesion. PMID- 29987579 TI - Meningomyeloradiculitis following yellow fever 17D vaccination: a case report. AB - The yellow fever 17D vaccine contains live-attenuated virus. Initial efficacy and safety reports were favorable. Recently, however, neurologic and viscerotropic adverse events (AE) were described. We managed a 61-year-old man who experienced meningomyeloradiculitis 18 days after receiving the yellow fever 17D vaccine. The manifestations were atypical. The cerebrospinal fluid contained high titers of anti-yellow fever immunoglobulins M and G and of anti-flavivirus immunoglobulins G. After methylprednisolone (1 g/day for 3 days), intravenous human immunoglobulins (140 g over 5 days), and two plasma exchanges, the symptoms improved only slightly. Neurological adverse events after yellow fever vaccination are rare or underestimated. To our knowledge, this is the first reported case of meningomyeloradiculitis after yellow fever vaccination. A remarkable feature is the intrathecal production of yellow fever antibodies, which probably played a pathogenic role and may have been related to a recent episode of influenza. PMID- 29987580 TI - Expression of pseudorabies virus-encoded long noncoding RNAs in epithelial cells and neurons. AB - Long noncoding RNAs (lncRNAs) play important roles in regulating eukaryotic genome replication and gene expression in diverse biological systems. Here, we identified lncRNAs transcribed from pseudorabies virus (PRV)-infected PK-15 cells. Based on high-throughput sequencing data, we obtained 87,263,926 and 93,947,628 clean reads from mock-infected and PRV-infected PK-15 cells, respectively. Through a normalized analytic protocol, we identified three novel viral lncRNAs. According to an analysis of differential expression between the mock-infected and PRV-infected cells, 4151 host lncRNAs were significantly upregulated and 2327 host lncRNAs were significantly downregulated in the latter group. Viral lncRNAs and several host lncRNAs were verified by northern blotting and real-time PCR. The findings showed that the viral lncRNA LDI might regulate the expression of IE180, a potent transcriptional activator of viral genes. Furthermore, we characterized the expression of viral lncRNAs in a culture of infected primary chicken dorsal root ganglia (DRG). Collectively, the obtained data suggest that PRV generates lncRNAs in both epithelial cells and chick DRG neurons. PMID- 29987581 TI - Avian influenza A H7N9 virus infects human astrocytes and neuronal cells and induces inflammatory immune responses. AB - Seasonal, pandemic, and avian influenza virus infections may be associated with central nervous system pathology, albeit with varying frequency and different mechanisms. Here, we demonstrate that differentiated human astrocytic (T98G) and neuronal (SH-SY5Y) cells can be infected by avian H7N9 and pandemic H1N1 viruses. However, infectious progeny viruses can only be detected in H7N9 virus infected human neuronal cells. Neither of these viral strains can generate infectious progeny virus in human astrocytes despite replication of viral genome was observed. Furthermore, H7N9 virus triggered high pro-inflammatory cytokine expression, while pandemic H1N1 virus induced only low cytokine expression in either brain cell type. The experimental finding here is the first data to demonstrate that avian H7N9 virus can infect, transcribe, and replicate its viral genome; induce cytokine upregulation; and cause cytopathic effects in human brain cells, which may potentially lead to profound central nervous system injury. Observation for neurological problems due to H7N9 virus infection deserves further attention when managing these patients. PMID- 29987583 TI - Successful treatment of progressive multifocal leukoencephalopathy with recombinant interleukin-7 and maraviroc in a patient with idiopathic CD4 lymphocytopenia. AB - Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive, often fatal viral infection of the brain without a known treatment. Recently, case reports have demonstrated survival from PML with therapies that improve cell mediated immunity, including interleukin-7 (IL-7) or the chemokine receptor type 5 (CCR5) antagonist, maraviroc (MVC). We present the first known case of a patient with PML successfully treated with both IL-7 and MVC. A 63-year-old woman presented to our center with a 6-month history of progressive left hemiparesis. Extensive laboratory testing was negative except for a severe CD4 lymphocytopenia (140/MUL). Serial brain MRIs done prior to presentation revealed an enlarging, non-enhancing T2-hyperintense lesion in the right fronto-parietal white matter. PML was confirmed through detection of the JC virus by PCR in the cerebrospinal fluid and by brain biopsy, and she was started on mirtazapine and mefloquine. She continued to deteriorate and was then given a course of recombinant IL-7. Though she remained clinically stable after IL-7 treatment and serum JCV PCR decreased from 1000 copies/mL to a nadir of 238 copies/mL, a repeat MRI 3 months later showed lesion enlargement. MVC was then initiated. Now, more than 2 years after initial presentation, she remains stable and serum JCV PCR is undetectable. This case demonstrates successful treatment of PML in a patient with idiopathic CD4 lymphocytopenia and highlights the potential benefits of IL-7 and MVC in the treatment of PML. Treatment with IL-7 and MVC led to clinical stability and improvement in JC virus titers. PMID- 29987584 TI - Clearance of attenuated rabies virus from brain tissues is required for long-term protection against CNS challenge with a pathogenic variant. AB - Rabies virus is a neurotropic lyssavirus which is 100% fatal in its pathogenic form when reaching unprotected CNS tissues. Death can be prevented by mechanisms delivering appropriate immune effectors across the blood-brain barrier which normally remains intact during pathogenic rabies virus infection. One therapeutic approach is to superinfect CNS tissues with attenuated rabies virus which induces blood-brain barrier permeability and immune cell entry. Current thinking is that peripheral rabies immunization is sufficient to protect against a challenge with pathogenic rabies virus. While this is undoubtedly the case if the virus is confined to the periphery, what happens if the virus reaches the CNS is less well understood. In the current study, we find that peripheral immunization does not fully protect mice long-term against an intranasal challenge with pathogenic rabies virus. Protection is significantly better in mice that have cleared attenuated virus from the CNS and is associated with a more robust CNS recall response evidently due to the presence in CNS tissues of elevated numbers of lymphocytes phenotypically resembling long-term resident immune cells. Adoptive transfer of cells from rabies-immune mice fails to protect against CNS challenge with pathogenic rabies virus further supporting the concept that long-term resident immune cell populations must be established in brain tissues to protect against a subsequent CNS challenge with pathogenic rabies virus. PMID- 29987582 TI - Aging and Apolipoprotein E in HIV Infection. AB - With the implementation of increasingly effective antiretroviral therapy (ART) over the past three decades, individuals infected with HIV live a much longer life. HIV infection is no longer a terminal but rather a chronic disease. However, the lifespan of infected individuals remains shorter than that of their uninfected peers. Even with ART, HIV infection may potentiate "premature" aging. Organ-associated disease and systemic syndromes that occur in treated HIV infection are like that of older, uninfected individuals. Brain aging may manifest as structural changes or neurocognitive impairment that are beyond the chronological age. The spectrum of neurological, cognitive, and motor deficiencies, currently described as HIV-associated neurocognitive disorders (HAND), may reflect earlier onset of mechanisms common to HIV infection and aging (accelerated aging). HAND could also reflect the neurological impact of HIV infection superimposed on comorbidities linked to age and chronic inflammation, leading to a higher prevalence of neurocognitive impairment across the age span (accentuated aging). In addition, apolipoprotein E (ApoE), one of the most influential host risk factors for developing Alzheimer's disease, has been implicated in the development of HAND. But studies differ as to whether ApoE is relevant, and whether age and ApoE interact to impair brain function in the HIV infected patient. What is clear is that HIV-infected individuals are living longer with HIV, and therefore factors related to aging and health need to be examined in the context of current, effective ART. This review addresses the recent evidence for the influence of aging and ApoE on HIV-associated neurocognitive impairment. PMID- 29987585 TI - Peripheral and cerebrospinal fluid immune activation and inflammation in chronically HIV-infected patients before and after virally suppressive combination antiretroviral therapy (cART). AB - Cerebrospinal fluid (CSF)/plasma HIV-RNA ratio has been associated with residual neurocognitive impairment on cART, leading us to hypothesize a specific peripheral and/or CSF immune feature in patients with high CSF/plasma ratio (>= 1). In patients with diverse pre-cART CSF/plasma ratio (61/70 with CSF/plasma ratio < 1, L-CSF, 9/70 with CSF/plasma ratio >= 1, H-CSF), we investigated the effects of 12 months of effective cART on peripheral and CSF inflammatory markers, on T cell activation/maturation and HIV/CMV-specific intracellular cytokine pattern. We also studied the possible clinical association between peripheral/CSF pro-inflammatory milieu and neurocognitive screening tests (MMSE, FAB, IHDS). Prior to cART, the two groups were comparable for peripheral and CSF inflammation, T cell activation/proliferation and maturation, and HIV/CMV specific response. Upon cART initiation, both H-CSF and L-CSF featured a significant reduction in plasma TNF-alpha and circulating CD8 activation, with a redistribution of memory/naive T cell subsets in L-CSF alone. In the CSF compartment, cART seemed able to reduce pro-inflammatory cytokine/chemokine levels in both H-CSF and L-CSF patients. Interestingly, despite a reduction in the pro-inflammatory milieu, no changes were shown in neurocognitive screening tests in both patients' groups. We hereby show that 12-month cART is able to reduce intratechal and peripheral pro-inflammatory burden; a longer cART exposure and a more comprehensive neuropsychological evaluation might be necessary to gain a broader insight into the possible effects on neurocognitive performance. PMID- 29987586 TI - Evaluation of Health Belief Model-Based Intervention on Breast Cancer Screening Behaviors among Health Volunteers. AB - Breast cancer is the most common cancer and the second leading cause of death among women. Regarding the lack of knowledge about the cause of breast cancer and considering the fact that all women are prone to this disease, training on methods of early diagnosis to reduce its complications is of great importance. Thus, this study aimed to determine the effect of education based on the health belief model on breast cancer screening behaviors in health volunteers of health centers in Isfahan. In this experimental study, 480 healthy volunteers were randomly divided into two groups: the case (n = 240) and control (n = 240). The training program was designed according to health belief model structures. Before the training interventional program, the Champion standard questionnaire and functional checklist were completed for both groups. A standard questionnaire was completed during three stages (before, immediately after, and 2 months after the training). The experimental group received the educational intervention during eight sessions, and the collected data was eventually analyzed using the SPSS statistical software version 16 with relevant statistical tests. Participation of all individuals in the present research was voluntary and with informed consent. The results showed that mean scores of knowledge, perceived susceptibility, severity, benefits, barriers, self-efficacy, and behavioral intention related to breast self-examination (BSE) and mammography in the intervention group significantly increased compared with those of the control group immediately after and 2 months after educational intervention. There was a significant difference between groups in BSE skill 2 months after the intervention, but there was no significant difference between the two groups in BSE behavior and mammography 2 months after the intervention. The results confirmed the efficiency and effectiveness of an educational intervention based on the health belief model on improving factors affecting breast cancer screening behaviors. PMID- 29987587 TI - Botulinum toxin therapy of hemifacial spasm: bilateral injections can reduce facial asymmetry. AB - Botulinum toxin (BT) is the treatment of choice for hemifacial spasm (HFS). When BT is injected into the affected side, patients may experience increased facial asymmetry. We wanted to evaluate in a prospective, randomised, placebo-controlled study whether bilateral BT injections may reduce this facial asymmetry. For this, we treated 19 HFS patients with unilateral and 24 with bilateral BT therapy using CBTX-A (Lanzhou Biological Products Institute, Lanzhou, China). BT doses on the affected side were standard doses, on the non-affected side they were one-third of those. Facial asymmetry was studied with the Sunnybrook facial grading system (SFGS), the Facial Clinimetric Evaluation Scale (FaCE), the Symmetry Scale for Hemifacial Spasm (SSHS) and a self-assessment scale. As shown in SFGS and SSHS, bilateral BT therapy reduces facial asymmetry, whilst unilateral BT therapy increases it. Both effects are more pronounced during voluntary facial movements than at rest. BT effect delay, BT effect duration, adverse effect frequency and severity were not affected. FaCE total score, some of its subscores and the self assessment scale did not show an effect. Bilateral BT therapy may improve the outcome of BT therapy for HFS without producing additional adverse effects. This strategy, however, raises drug costs (by about a third). Using even higher doses in the non-affected side may intensify the improvement even further. Future studies may also monitor the patient's quality of life and the naive public's overall perception of the patient's facial expression. PMID- 29987588 TI - The discriminative value of blood gas analysis parameters in the differential diagnosis of transient disorders of consciousness. AB - AIM: The differentiation between epileptic and non-epileptic episodes can be challenging. Our aim was to compare lactate, anion gap (AG), bicarbonate and the Denver Seizure Score (DSS) as point-of-care test (POCT) markers for episodes of transient alterations of consciousness. METHODS: The blood serum parameters were drawn at arrival in the emergency department (ED) within 2 h of the episode. After calculating AG and DSS values, the four parameters were compared retrospectively between patients with generalized tonic-clonic seizures (GTCS) (n = 165) and patients with other disorders of consciousness [syncopes (n = 43), and psychogenic non-epileptic seizures (n = 15)]. Additionally, we compared all values among men and women. RESULTS: In GTCS patients, all four parameters differed significantly compared to non-epileptic episode patients (p < 0.001). Serum lactate showed significant additional benefit over the remaining values, with an AUC of 0.947 (95% CI 0.92-0.975) and a high sensitivity and specificity for an optimal cut-off value of 2.45 mmol/l. For DSS, the AUC was 0.857 (95% CI 0.808-0.906; cut-off: 0.35), and for AG 0.836 (95% CI 0.783-0.889; cut-off: 12.45 mmol/l). In the case of serum bicarbonate, the AUC was 0.831 (95% CI 0.775-0.886; cut-off: 22.75 mmol/l). In the sex-dependent comparison, the results were similar. Men showed more significant differences in the compared values than women. CONCLUSIONS: Serum lactate is best suited as POCT marker in the differential diagnosis of epileptic and non-epileptic episodes and is superior to AG, DSS and bicarbonate. The differences among sexes may pose a challenge in their implementation and interpretation. PMID- 29987589 TI - Low specificity of voltage-gated calcium channel antibodies in Lambert-Eaton myasthenic syndrome: a call for caution. AB - As testing for neuronal antibodies become more readily available, the spectrum of conditions potentially associated with these autoantibodies has been widening. Voltage-gated calcium channel antibodies (VGCC-Ab) are no exception to this trend. The significance of an elevated VGCC-Ab titer beyond its original clinicopathological correlate, Lambert-Eaton myasthenic syndrome (LEMS) remains undetermined. We sought to determine the diagnostic significance of an elevated serum VGCC-Ab titer in a large single-center cohort of 100 patients. The majority of patients (58%) with elevated VGCC-Ab levels lacked an inflammatory or autoimmune etiology of their neurologic diagnosis. Only six cases (6%) of LEMS and two cases (2%) of SCLC (without LEMS) were identified. No significant differences in antibody titers were seen between the autoimmune and non autoimmune groups. These findings support the notions that: (a) elevated VGCC-Ab titers without clinical correlation must be interpreted with caution, and (b) the clinical and electrodiagnostic criteria for LEMS should remain the mainstay in the diagnosis of LEMS. PMID- 29987591 TI - Ethanol's Effects on Transient Receptor Potential Channel Expression in Brain Microvascular Endothelial Cells. AB - Ethanol (EtOH), the main ingredient in alcoholic beverages, is well known for its behavioral, physiological, and immunosuppressive effects. There is evidence that EtOH acts through protein targets to exert its physiological effects; however, the mechanisms underlying EtOH's effects on inflammatory processes, particularly at the blood-brain barrier (BBB), are still poorly understood. Transient receptor potential (TRP) channels, the vanguards of human sensory systems, are novel molecular receptors significantly affected by EtOH, and are heavily expressed in brain microvascular endothelial cells (BMVECs), one of the cellular constituents of the BBB. EtOH's actions on endothelial TRP channels could affect intracellular Ca2+ and Mg2+ dynamics, which mediate leukocyte adhesion to endothelial cells and endothelial permeability at the BBB, thus altering immune and inflammatory responses. We examined the basal expression profiles of all 29 known mammalian TRP channels in mouse BMVECs and determined both EtOH concentration- and time dependent effects on TRP expression using a PCR array. We also generated an in vitro BBB model to examine the involvement of a chosen TRP channel, TRP melastatin 7 (TRPM7), in EtOH-mediated alteration of BBB permeability. With the exception of the akyrin subfamily, members of five TRP subfamilies were expressed in mouse BMVECs, and their expression levels were modulated by EtOH in a concentration-dependent manner. In the in vitro BBB model, TRPM7 antagonists further enhanced EtOH-mediated alteration of BBB permeability. Because of the diversity of TRP channels in BMVECs that regulate cellular processes, EtOH can affect Ca2+/Mg2+ signaling, immune responses, lysosomal functions as well as BBB integrity. PMID- 29987593 TI - Optimal glycaemic control during caesarean section provided by sensor-augmented pump therapy with predictive low-glucose suspend function. PMID- 29987592 TI - Dimethyl Fumarate Prevents HIV-Induced Lysosomal Dysfunction and Cathepsin B Release from Macrophages. AB - HIV-associated neurocognitive disorders (HAND) are prevalent despite combined antiretroviral therapy, affecting nearly half of HIV-infected patients worldwide. During HIV infection of macrophages secretion of the lysosomal protein, cathepsin B, is increased. Secreted cathepsin B has been shown to induce neurotoxicity. Oxidative stress is increased in HIV-infected patients, while antioxidants are decreased in monocytes from patients with HIV-associated dementia (HAD). Dimethyl fumarate (DMF), an antioxidant, has been reported to decrease HIV replication and neurotoxicity mediated by HIV-infected macrophages. Thus, we hypothesized that DMF will decrease cathepsin B release from HIV-infected macrophages by preventing oxidative stress and enhancing lysosomal function. Monocyte-derived macrophages (MDM) were isolated from healthy donors, inoculated with HIV-1ADA, and treated with DMF following virus removal. After 12 days post-infection, HIV-1 p24 and total cathepsin B levels were measured from HIV-infected MDM supernatants using ELISA; intracellular reactive oxygen and nitrogen species (ROS/RNS) were measured from MDM lysates, and functional lysosomes were assessed using a pH-dependent lysosomal dye. Neurons were incubated with serum-free conditioned media from DMF treated MDM and neurotoxicity was determined using TUNEL assay. Results indicate that DMF reduced HIV-1 replication and cathepsin B secretion from HIV-infected macrophages in a dose-dependent manner. Also, DMF decreased intracellular ROS/RNS levels, and prevented HIV-induced lysosomal dysfunction and neuronal apoptosis. In conclusion, the improvement in lysosomal function with DMF treatment may represent the possible mechanism to reduce HIV-1 replication and cathepsin B secretion. DMF represents a potential therapeutic strategy against HAND. PMID- 29987594 TI - Correction to: Integrating basic science in academic cardiology training: two international perspectives on a common challenge. AB - Unfortunately, the + and - signs marking the benefits and challenges in Table 1 have been omitted during the typesetting of the article. PMID- 29987595 TI - Prognostic significance of atrial fibrillation in acute decompensated heart failure with reduced versus preserved ejection fraction. AB - OBJECTIVE: The prognostic impact of atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) has not been fully elucidated yet. Aim of the present study was thus to investigate the association of AF with all-cause mortality in patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). METHODS: We performed a retrospective single center study and analyzed data of 1286 patients admitted for ADHF. Patients were grouped according to AF status (i.e., "never AF", "history of AF", or "AF on admission") and type of heart failure. Patient and treatment characteristics were extracted by chart review. The primary outcome of all-cause mortality within 3 years following index hospitalization was determined by death registry linkage. RESULTS: In total, 529 (41.1%), 215 (16.7%), and 542 (42.1%) patients were grouped as "never AF", "history of AF", and "AF on admission", respectively. With regard to type of heart failure, 558 (43.4%) and 728 (56.6%) had HFrEF and HFpEF, respectively. Compared to "never AF", "AF on admission" was associated with increased all-cause mortality in an adjusted Cox regression model [hazard ratio, 1.64 (95% confidence interval 1.32-2.04); P < 0.001]. However, this association remained significant only for patients with HFpEF [2.16 (1.58-2.95)], but not for patients with HFrEF [1.18 (0.85-1.63)] in a subgroup analysis (P for effect modification = 0.020). CONCLUSIONS: AF is common in the setting of ADHF and is associated with increased all-cause mortality. However, this association remained significant only in patients with HFpEF, but not in patients with HFrEF. PMID- 29987596 TI - Therapeutic options in advanced heart failure. PMID- 29987597 TI - Theories for Race and Gender Differences in Management of Social Identity-Related Stressors: a Systematic Review. AB - Sociodemographic group-specific strategies for stress management may contribute to racial and gender disparities in health outcomes in the USA. We aimed to systematically review theoretical and empirical investigations of factors influencing variation in response to and management of identity-related stress among black and white Americans. OvidPsychInfo and PubMed databases were searched to identify eligible studies. Criteria were participant age of >= 18 years, conducted in the US sampling black or white participants, and published in English in a peer-reviewed journal. The final sample included 167 articles. Theories suggesting social status inequities as the primary contributor to disparate strategies employed by black and white women and men to manage social identity-related stress were most frequently tested and supported. Studies disproportionally focused on how women and black persons cope as targets of prejudice and discrimination rather than on how management strategies of men or white persons are affected as perpetrators. Finally, there was theoretical support for an interactive effect of race and gender on stress management, but empirical evidence was lacking, particularly among black men, white women, and white men. The literature could be strengthened through the use of prospective cohorts and nationally representative samples, as well as study designs accounting for potential within-race and within-gender variation in the effects of social identity-related stressors on coping. With greater consistency in methodology, future empirical studies may yield additional information regarding group differences in stress management pertinent to clarifying mechanisms for the health consequences of exposure to social inequity among black and white women and men. PMID- 29987598 TI - American Society of Breast Surgeons' Practice Patterns After Publication of the SSO-ASTRO-ASCO DCIS Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation. AB - BACKGROUND: The SSO-ASTRO-ASCO consensus guideline on margins for breast conserving surgery with whole breast irradiation in ductal carcinoma in situ (DCIS) recommended a 2-mm margin. We sought to determine the impact of guideline publication on clinician practice. METHODS: A total of 3081 members of the American Society of Breast Surgeons (ASBrS) received a survey. Respondents' clinical practice type and duration, guideline familiarity, and margin width preferences before and after publication were assessed. Clinical practice pattern differences before and after publication were investigated using McNemar's test. RESULTS: A total of 767 (24.9%) of those surveyed responded. Most (92.4%) indicated guideline familiarity. Of those familiar, re-excision preference for DCIS and a positive margin remained the same before (94.4%) and after (94.3%) publication (McNemar's test p = 1.0). Following publication, surgeons were more likely to avoid re-excision to achieve margins wider than 2-mm (82.3% pre versus 87.5% post, p = 0.002). More surgeons performed re-excision for a close margin with pure DCIS (25.9% pre versus 36.5% post, p < 0.001) and with DCIS with microinvasion (DCIS-M) (40.7% pre versus 52.3% post, p < 0.001). For patients with invasive disease with extensive intraductal component (EIC) and a close margin, preference to avoid re-excision was similar (51.2% per versus 55.2% post, p = 0.071). CONCLUSION: Since guideline publication, surgeons are less likely to perform re-excision to obtain a margin greater than 2-mm and more likely to perform re-excision to obtain a 2-mm margin for both pure DCIS and DCIS-M. Preference to avoid re-excision with a close margin and EIC was similar before and after publication. PMID- 29987599 TI - Reducing Breast Cancer-Related Lymphedema (BCRL) Through Prospective Surveillance Monitoring Using Bioimpedance Spectroscopy (BIS) and Patient Directed Self Interventions. AB - BACKGROUND: Breast cancer-related lymphedema (BCRL) is a chronic progressive disease that results from breast cancer treatment and nodal surgery. NCCN guidelines support baseline measurements with prospective assessment for early diagnosis and treatment. We sought to determine if baseline measurement with bioimpedance spectroscopy (BIS) and serial postoperative evaluations provide early detection amenable to conservative interventions that reduce BCRL. METHODS: Breast cancer patients with unilateral disease high-risk for BCRL from a single institution were evaluated from November 2014 to December 2017. High risk was defined as axillary lymph node dissection with radiation and/or taxane chemotherapy. Patients received preoperative baseline BIS measurements followed by postoperative measurements with at least two follow-ups. Patients with BIS results that were 2 standard deviations above baseline (10 + points) started home conservative interventions for 4-6 weeks. Postintervention measurements were taken to assess improvement. RESULT: A total of 146 patients high-risk for BCRL were included. Forty-nine patients (34%) developed early BCRL and started self directed treatment. Forty patients (82%) had elevated BIS measurements return to normal baseline range. Nine (6%) patients had persistent BCRL requiring referral for advanced therapy. Patients with persistent BCRL had significant nodal burden on surgical pathology; eight (89%) had N2/N3 disease. Six (76%) with BCRL refractory to conservative measures died of their breast cancer. CONCLUSION: Our results demonstrated that early conservative intervention for breast cancer patients high risk for BCRL who were prospectively monitored by utilizing BIS significantly lowers rates of BCRL. These findings support early prospective screening and intervention for BCRL. Early detection with patient-directed interventions improves patient outcomes and decreases the risk of persistent BCRL. PMID- 29987601 TI - Cervical Esophageal Cancer Treatment Strategies: A Cohort Study Appraising the Debated Role of Surgery. AB - BACKGROUND: Few studies have examined optimal treatment specifically for cervical esophageal carcinoma. This study evaluated the outcome of three common treatment strategies with a focus on the debated role of surgery. METHODS: All patients with cervical esophageal cancer treated at a single center were identified and their outcomes analyzed in terms of morbidity, mortality, and recurrence according to the treatment they received, i.e. surgery alone, definitive platinum based chemoradiation (CRT), or CRT followed by surgery. RESULTS: The study population included 148 patients with cervical esophageal cancer from a prospective database of 3445 patients. Primary surgery was the treatment of choice for 56 (37.83%) patients, definitive CRT was the treatment of choice for 52 (35.13%) patients, and CRT followed by surgery was the treatment of choice for 40 (27.02%) patients. CRT-treated patients obtained 36.96% complete clinical response, with overall morbidity and mortality rates of 36.95 and 2.17%, respectively. Surgical complete resection was achieved in 71.88% of surgically treated cases, with morbidity and mortality rates of 52.17 and 6.25%, respectively. No significant survival difference existed among the three treatments, but patients who underwent surgery alone had a significantly lower stage of disease (p = 0.031). Compared with patients with complete response after CRT, surgery did not confer any significant survival benefit, and overall 5-year survival was lower than definitive CRT alone. In contrast, surgery improved survival significantly in patients with non-complete response after definitive CRT (p = 0.023). CONCLUSIONS: Definitive platinum-based CRT should be the treatment of choice for cervical esophageal cancer. Surgery has a role for patients with non-complete response as it adds significant survival benefit, with acceptable morbidity and mortality. PMID- 29987600 TI - Identification of microRNA Biomarkers of Response to Neoadjuvant Chemoradiotherapy in Esophageal Adenocarcinoma Using Next Generation Sequencing. AB - BACKGROUND: Clinical trials report improved overall survival following neoadjuvant chemoradiotherapy in patients undergoing surgery for esophageal adenocarcinoma, with a 10-15% survival improvement. MicroRNAs (miRNAs) are small noncoding RNAs that are known to direct the behavior of cancers, including response to treatment. We investigated the ability of miRNAs to predict outcomes after neoadjuvant chemoradiotherapy. METHODS: Endoscopic biopsies from esophageal adenocarcinomas were obtained before neoadjuvant chemoradiotherapy and esophagectomy. miRNA levels were measured in the biopsies using next generation sequencing and compared with pathological response in the surgical resection, and subsequent survival. miRNA ratios that predicted pathological response were identified by Lasso regression and leave-one-out cross-validation. Association between miRNA ratio candidates and relapse-free survival was assessed using Kaplan-Meier analysis. Cox regression and Harrell's C analyses were performed to assess the predictive performance of the miRNAs. RESULTS: Two miRNA ratios (miR 4521/miR-340-5p and miR-101-3p/miR-451a) that predicted the pathological response to neoadjuvant chemoradiotherapy were found to be associated with relapse-free survival. Pretreatment expression of these two miRNA ratios, pretreatment tumor differentiation, posttreatment AJCC histopathological tumor regression grading, and posttreatment tumor clearance/margins were significant factors associated with survival in Cox regression analysis. Multivariate analysis of the two ratios together with pretherapy factors resulted in a risk prediction accuracy of 85% (Harrell's C), which was comparable with the prediction accuracy of the AJCC treatment response grading (77%). CONCLUSIONS: miRNA-ratio biomarkers identified using next generation sequencing can be used to predict disease free survival following neoadjuvant chemoradiotherapy and esophagectomy in patients with esophageal adenocarcinoma. PMID- 29987602 TI - Preoperative Therapy for Gastric Adenocarcinoma is Protective for Poor Oncologic Outcomes in Patients with Complications After Gastrectomy. AB - BACKGROUND: Postoperative complications (POC) are associated with poor oncologic outcomes in gastric cancer. We sought to evaluate the impact of POC on survival in patients with gastric cancer treated with upfront surgery (UpSurg) versus those treated with preoperative therapy (PreT). METHODS: We analyzed data from a prospectively maintained database of patients who had undergone resection of their gastric cancer at our institution. Patients with T1N0 or M1 lesions, recurrent disease, and mortality within 90 days were excluded. Survival was compared between patients with and without POC in the UpSurg and PreT groups. Cox regression analyses were used to examine factors associated with overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 421 patients underwent resection of gastric cancer: 30% underwent upfront surgery, and 51% had a POC. Among patients who had POCs, 71% were infectious and 53% were Clavien-Dindo grade III or IV. UpSurg patients with a POC had shorter OS (5-year, 47 vs. 85%; p < 0.001) and DFS (5-year, 46 vs. 76%; p < 0.001) than those without a POC. In contrast, there was no difference in OS (5-year, 57 vs. 63%; p = 0.77) and DFS (5 year, 52 vs. 52%; p = 0.52) between PreT patients with and without POC. Multivariable Cox regression model demonstrated that a POC in UpSurg patients had significant impact on DFS (2.6 [95% confidence interval (CI) 1.48-4.74]), whereas it did not in PreT patients (0.9 [95% CI 0.70-1.33]). CONCLUSIONS: The use of preoperative therapy negated the impact of POCs on OS and DFS in patients undergoing resection for gastric cancer. PMID- 29987603 TI - Phase 2 Open-Label Trial Investigating Percutaneous Laser Ablation for Treatment of Early-Stage Breast Cancer: MRI, Pathology, and Outcome Correlations. AB - BACKGROUND: An institutional review board-approved, multicenter clinical trial was designed to determine the efficacy and outcome of percutaneous laser ablation (PLA) in the treatment of invasive ductal breast carcinoma (IDC). Post-ablation magnetic resonance imaging (MRI) was compared with surgical pathology in evaluation of residual post-ablation IDC and ductal carcinoma in situ. METHODS: Patients with a single focus of IDC 20 mm or smaller by pre-ablation MRI were treated with PLA. The patients underwent a 28-day post-ablation MRI, followed by surgical resection. Cell viability criteria were applied to pre- and post ablation pathology specimens, which evaluated hematoxylin-eosin (H&E), cytokeratin (CK) 8/18, estrogen receptor, and Ki67 staining patterns. RESULTS: In this study, 61 patients were reported as the intention-to-treat cohort for determination of PLA efficacy. Of these 61 patients, 51 (84%) had complete tumor ablation confirmed by pathology analysis. One subject's MRI imaging was not performed per protocol, which left 60 subjects evaluable for MRI pathology correlation. Five patients (8.3%) had residual IDC shown by both MRI and pathology. Post-ablation discordance was noted between MRI and pathology, with four patients (6.7%) false-positive and four patients (6.7%) false-negative. The negative predictive value (NPV) of MRI for all the patients was 92.2% (95% confidence interval [CI], 71.9-91.9%). Of the 47 patients (97.9%) with tumors 15 mm or smaller, 46 were completely ablated, with an MRI NPV of 97.7% (95% CI, 86.2 99.9%). CONCLUSIONS: Percutaneous laser ablation is a potential alternative to surgery for treatment of early-stage IDC. Strong correlations exist between post ablation MRI and pathologic alterations in CK8/18, ER, and Ki67 staining. PMID- 29987604 TI - Long-Term Oncologic Outcomes Following Robotic Liver Resections for Primary Hepatobiliary Malignancies: A Multicenter Study. AB - OBJECTIVE: Robotic liver surgery (RLS) has emerged as a feasible alternative to laparoscopic or open resections with comparable perioperative outcomes. Little is known about the oncologic adequacy of RLS. The purpose of this study was to investigate the long-term oncologic outcomes for patients undergoing RLS for primary hepatobiliary malignancies. METHODS: We performed an international, multicenter, retrospective study of patients who underwent RLS for hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), or gallbladder cancer (GBC) between 2006 and 2016. Age, gender, histology, resection margin status, extent of surgical resection, disease-free survival (DFS), and overall survival (OS) were retrospectively collected and analyzed. RESULTS: Of the 61 included patients, 34 (56%) had RLS performed for HCC, 16 (26%) for CC, and 11 (18%) for GBC. The majority of resections were nonanatomical or segmental resections (39.3%), followed by central hepatectomy (18%), left-lateral sectionectomy (14.8%), left hepatectomy (13.1%), right hepatectomy (13.1%), and right posterior segmentectomy (1.6%). R0 resection was achieved in 94% of HCC, 68% of CC, and 81.8% of GBC patients. Median hospital stay was 5 days, and conversion to open surgery was needed in seven patients (11.5%). Grade III-IV Dindo-Clavien complications occurred in seven patients with no perioperative mortality. Median follow-up was 75 months (95% confidence interval 36-113), and 5-year OS and DFS were 56 and 38%, respectively. When stratified by tumor type, 3-year OS was 90% for HCC, 65% for GBC, and 49% for CC (p = 0.01). CONCLUSIONS: RLS can be performed for primary hepatobiliary malignancies with long-term oncologic outcomes comparable to published open and laparoscopic data. PMID- 29987605 TI - The Feasibility of Breast-Conserving Surgery for Multiple Ipsilateral Breast Cancer: An Initial Report from ACOSOG Z11102 (Alliance) Trial. AB - BACKGROUND: Historically, multiple ipsilateral breast cancer (MIBC) has been a contraindication to breast-conserving therapy (BCT). We report the feasibility of BCT in MIBC from the ACOSOG Z11102 trial [Alliance], a single arm noninferiority trial of BCT for women with two or three sites of malignancy in the ipsilateral breast. METHODS: Women who enrolled preoperatively in ACOSOG Z11102 were evaluated for conversion to mastectomy and need for reoperation to obtain negative margins. Characteristics of women who successfully underwent BCT and those who converted to mastectomy were compared. Factors were examined for association with the need for margin reexcision. RESULTS: Of 198 patients enrolled preoperatively, 190 (96%) had 2 foci of disease. Median size of the largest tumor focus was 1.5 (range 0.1-7.0) cm; 49 patients (24.8%) had positive nodes. There were 14 women who underwent mastectomy due to positive margins, resulting in a conversion to mastectomy rate of 7.1% (95% confidence interval [CI] 3.9-10.6%). Of 184 patients who successfully completed BCT, 134 completed this in a single operation. Multivariable logistic regression analysis did not identify any factors significantly associated with conversion to mastectomy or need for margin reexcision. CONCLUSIONS: Breast conservation is feasible in MIBC with 67.6% of patients achieving a margin-negative excision in a single operation and 7.1% of patients requiring conversion to mastectomy due to positive margins. No characteristic was identified that significantly altered the risk of conversion to mastectomy or need for reexcision. CLINICALTRIALS. GOV IDENTIFIER: NCT01556243. PMID- 29987606 TI - Post-mastectomy Radiation Therapy in Breast Cancer Patients with Nodal Micrometastases. AB - BACKGROUND: Recent data support the use of post-mastectomy radiation therapy (PMRT) in women with one to three positive lymph nodes; however, the benefit of PMRT in patients with micrometastatic nodal disease (N1mi) is unknown. We evaluated the survival impact of PMRT in patients with N1mi within the National Cancer Database. METHODS: The pattern of care and survival benefit of PMRT was examined in women with pT1-2N1mi breast cancer who underwent mastectomy without neoadjuvant chemotherapy. Univariable and multivariable Cox proportional hazard models were employed for survival analysis, and subanalyses of high-risk patients and a propensity score-matched (PSM) cohort were completed. RESULTS: From 2004 to 2014, we identified 14,019 patients who fitted the study criteria. PMRT was delivered in 18.5% of patients and its use increased over the study period. Patients treated with PMRT were younger, had better performance status and larger primaries, were estrogen receptor (ER)-negative, had higher grade, lymphovascular invasion and positive surgical margins, and more often received systemic therapy. PMRT was significantly associated with overall survival (OS) in univariable analysis (hazard ratio [HR] 0.75 [0.64-0.89]), but was not significant in multivariable analysis (adjusted HR 1.01 [0.84-1.20]). There was no survival benefit to PMRT in ER-negative, high-grade, and/or young patients. There were 2 (0.9%) death events in the sentinel lymph node biopsy (SLNB) + PMRT group versus 21 (2.9%) in the SLNB-alone group (log-rank p = 0.053), and 8 (3.9%) death events in the axillary lymph node biopsy (ALNB) + PMRT group versus 27 (3.6%) in the axillary lymph node dissection-alone group (p = 0.82). There was no significant association between PMRT and OS within the PSM subgroup. CONCLUSION: In this largest reported retrospective study, no OS differences were associated with PMRT, which suggests that PMRT may not benefit every patient with microscopic nodal disease. PMID- 29987607 TI - Trends in the Diagnosis of Phyllodes Tumors and Fibroadenomas Before and After Release of WHO Classification Standards. AB - BACKGROUND: In 2012, the World Health Organization (WHO) released diagnostic criteria for grading phyllodes tumors based on histologic features. This study sought to examine the application of the WHO criteria and the changing epidemiology of fibroepithelial tumors. METHODS: A retrospective review of surgically excised fibroepithelial lesions from 2007 to 2017 at a single tertiary care institution was conducted. Data regarding the WHO criteria (tumor border, stromal cellularity, stromal cell atypia, stromal overgrowth, mitotic activity) and traditional descriptors (leaf-like architecture, periductal stromal condensation) were collected. Clinical and pathologic characteristics of cases with diagnoses determined before and after 2012 were compared. RESULTS: During the study period, 305 fibroepithelial tumors were identified. No significant differences were observed in terms of mean age, race/ethnicity, presenting symptoms, or method of diagnosis between cases diagnosed before and after 2012. After 2012, the findings showed statistically significant increases in reporting of WHO and traditional histologic features, a decrease in diagnoses of fibroadenomas (85.9% [116/135] before vs 70.0% [119/170] after 2012), and an increase in benign phyllodes tumors (0% [0/135] before vs 12.9% [22/170] after 2012). Patients with a diagnosis of benign phyllodes tumors were significantly younger than those with a diagnosis of borderline, malignant, or non-graded phyllodes tumors (mean age, 25.7 +/- 10.6 vs 52.8 +/- 9.9, 40.7 +/- 24, 46.3 +/- 1.5 years, respectively; p = 0.006). CONCLUSIONS: The expanding use of the 2012 WHO criteria has been accompanied by an increased diagnostic frequency of benign phyllodes tumors and a decrease in fibroadenomas. As fibroepithelial diagnoses become more distinct, evidence-based management recommendations for less virulent phyllodes diagnoses should be developed. PMID- 29987608 TI - Treatment Intensity for Mammographically Detected Tumors: An Alternative Viewpoint. PMID- 29987609 TI - Survival Trends in Gastric Adenocarcinoma: A Population-Based Study in Sweden. AB - BACKGROUND: Gastric adenocarcinoma is the second most common cancer-related death globally. Assessing survival trends can help evaluate changes in detection and treatment. We aimed to determine recent prognosis trends in gastric non-cardia and cardia adenocarcinoma in an unselected cohort with complete follow-up. METHODS: Population-based nationwide cohort study, including 17,491 patients with gastric non-cardia adenocarcinoma and 4698 with cardia adenocarcinoma recorded in the Swedish Cancer Registry in 1990-2013 with follow-up until 2017. Observed and relative 5-year survival was calculated and stratified by resectional surgery and no such surgery. Prognostic factors were evaluated using multivariable Cox regression. RESULTS: The relative overall 5-year survival remained stable at 18% for gastric non-cardia adenocarcinoma throughout the study period and increased from 12 to 18% for cardia adenocarcinoma. Concurrently, the proportion of patients who underwent resectional surgery decreased from 49 to 38% for non cardia adenocarcinoma and from 48 to 33% for cardia adenocarcinoma. The relative postoperative 5-year survival increased from 33 to 44% for non-cardia adenocarcinoma and from 21 to 43% for cardia adenocarcinoma, whereas in nonoperated patients it decreased from 3 to 2% in non-cardia adenocarcinoma and increased from 3 to 5% in cardia adenocarcinoma. Poor prognostic factors were higher tumor stage, older age, and more comorbidity. CONCLUSIONS: Despite decreasing resectional rates, the 5-year overall survival has remained unchanged for gastric non-cardia adenocarcinoma and improved for cardia adenocarcinoma over the last two decades in Sweden and is now similar for these sublocations. The postoperative survival has improved for both sublocations, but particularly for cardia adenocarcinoma. PMID- 29987610 TI - ASBRS Great Debate: Sentinel Node Biopsy in Patients Over 70 Years of Age. AB - INTRODUCTION: Controversy over the need for sentinel node biopsy (SNB) continues to exist for the optimal treatment of breast cancer in patients >= 70 years of age, especially in those with lower-risk disease. Clinicians must balance competing risks to give the best individualized care. METHODS: The American Society of Breast Surgeons (ASBrS) conducted a debate discussing the pros and cons of routinely performing SNB in this age group. Small, randomized studies have been conducted that show no overall survival benefit to axillary intervention (either axillary dissection or SNB) in patients with clinically T1N0 estrogen receptor (ER)- and progesterone receptor (PR)-positive, HER2/neu negative tumors. There may be a small local recurrence benefit to axillary staging in patients who do not undergo radiation. Alternatively, axillary ultrasound, which carries a low false-negative rate for heavy disease burden, can be used to select patients who can avoid SNB. CONCLUSION: Surgeons must continue to individualize care of breast cancer patients over 70 years of age in whom competing comorbidities may dictate care. No randomized clinical trials (RCTs) have found a survival benefit to axillary staging in this low-risk population. However, in healthy patients, axillary staging may improve local control, provide prognostic information, and help guide decisions regarding adjuvant therapy such as chemotherapy and radiation. Ongoing RCTs are evaluating the benefit of SNB in patients with a negative axillary ultrasound. Until those results are available, clinicians and patients must balance the risk and benefits to determine if SNB adds significant value to their overall care. PMID- 29987611 TI - Practices and Perceptions Among Surgical Oncologists in the Perioperative Care of Obese Cancer Patients. AB - BACKGROUND: Obesity and cancer are two common diseases in the United States. Although there is an interaction of obesity and cancer, little is known about surgeon perceptions and practices in the care of obese cancer patients. We sought to characterize perceptions and practices of surgical oncologists regarding the perioperative care of obese patients being treated for cancer. METHODS: A cross sectional survey was designed, pilot tested, and utilized to assess perceptions and practices of surgeons treating cancer patients. Surgical oncologists were identified using a commercially available database, and Qualtrics(r) was used to distribute and manage the survey. Statistical analyses were completed by using SPSS. RESULTS: Of the 1731 electronic invitations, 172 recipients initiated the survey, and 157 submitted responses (91.2%). Many surgeons (65.7%) believed that obese patients are more likely to present with more advanced cancers and were more likely than system factors to explain this delayed treatment [t(87) = 4.84; p < 0.001]. Nearly two-thirds of providers (64.5%) reported that obesity had no impact on the timing of surgery; however, one-third of respondents (34.2%) were more likely to recommend preoperative nonsurgical therapy rather than upfront surgery among obese patients. For operations of the chest/abdomen and breast/soft tissue, surgeons perceived obesity to be more related to risk of postoperative than intraoperative complications (chest/abdomen mean 4.13 vs. 3.26; breast/soft tissue 4.11 vs. 2.60; p < 0.001). CONCLUSIONS: One in three surgeons reported that patient obesity would change the timing/sequence of when resection would be offered. Many surgeons perceived that obesity was related to a wide array of intra- and postoperative adverse outcomes. PMID- 29987612 TI - Impact of Screening Mammography on Treatment in Women Diagnosed with Breast Cancer. AB - BACKGROUND: Screening mammography reduces breast cancer mortality; however, screening recommendations, ordering, and compliance remain suboptimal and controversies regarding the value of screening persist. We evaluated the influence of screening mammography on the extent of breast cancer treatment. METHODS: Patients >= 40 years of age diagnosed with breast cancer from September 2008 to May 2016 at a single institution were divided into two groups: those with screening 1-24 months prior to diagnosis, and those with screening at 25+ months, including patients with no prior mammography. The association between the two groups and various clinical factors were assessed using logistic regression models. Subgroup analysis was performed based on age groups. RESULTS: Analysis included 1125 patients, 819 (73%) with screening at 1-24 months, and 306 (27%) with screening at 25+ months, including 65 (6%) who never had mammography. Overall, patients in the 25+ months group were more likely to receive chemotherapy [odds ratio (OR) 1.51, p = 0.0040], undergo mastectomy (OR 1.32, p = 0.0465), and require axillary dissection (AD; OR 1.66, p = 0.0045) than those in 1-24 months group. On subgroup analysis, patients aged 40-49 years with no prior mammography were more likely to have larger tumors (p = 0.0323) and positive nodes (OR 4.52, p = 0.0058), undergo mastectomy (OR 3.44, p = 0.0068), undergo AD (OR 4.64, p = 0.0002), and require chemotherapy (OR 2.52, p = 0.0287) than the 1 24 months group. CONCLUSIONS: Screening mammography is associated with decreased stage at diagnosis and receipt of less-extensive treatment. This was evident in all groups, including the 40-49 years age group, where controversy exists on whether screening is even necessary. PMID- 29987613 TI - Tapered Quantum Cascade Laser Arrays Integrated with Talbot Cavities. AB - Power scaling in broad area quantum cascade laser (QCL) usually leads to the deterioration of the beam quality with an emission of multiple lobes far-field pattern. In this letter, we demonstrate a tapered QCL array integrated with Talbot cavity at one side of the array. Fundamental supermode operation is achieved in the arrays with taper straight-end connected to the Talbot cavity. Lateral far-field of the fundamental supermode shows a near diffraction limited beam divergence of 2.7 degrees . The output power of a five-element array is about three times as high as a single-ridge laser with an emission wavelength of around 4.8 MUm. However, arrays with the taper-end connected to the Talbot cavity always show a high-order supermode operation whatever Talbot cavity length is. PMID- 29987615 TI - Imaging Pulmonary Foreign Body Reaction Using [125I]iodo-DPA-713 SPECT/CT in Mice. AB - PURPOSE: Foreign body reactions elicit granulomatous inflammation composed of reactive macrophages. We hypothesized that [125I]iodo-DPA-713 single-photon emission computed tomography (SPECT), a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by phagocytes, could be used to detect foreign body reactions in a murine model. PROCEDURES: C57BL/6 mice intratracheally inoculated with dextran beads, which developed foreign body lesions, were imaged after injection of [125I]iodo-DPA-713 or DPA-713-IRDye800CW using SPECT and optical imaging, respectively. RESULTS: Foreign body lesions were clearly observed in the lungs of the dextran-treated mice on computer tomography imaging and demonstrated significantly higher [125I]iodo-DPA-713 uptake compared with control animals (p < 0.01). Ex vivo studies demonstrated granulomatous reactions in the lungs of dextran-treated mice and localization of DPA-713-IRDye800CW at the diseased sites confirming the imaging findings. CONCLUSION: Radioiodinated DPA-713 may be used as a noninvasive biomarker for the detection of pulmonary foreign body reactions. PMID- 29987614 TI - Eosinophils in the gastrointestinal tract: how much is normal? AB - The normal density of eosinophils in the digestive mucosa of children has been rarely addressed despite being important to provide baseline counts for the diagnosis of eosinophilic gastrointestinal disorders (EGID). Histopathological criteria for EGID remain undefined and there has been little consistency of results in different populations. We aimed to establish the eosinophil density of the normal digestive mucosa in a paediatric population submitted to endoscopic procedures with normal histological features. Biopsies from endoscopies of 33 patients were evaluated. Quantification of eosinophils was performed manually. Review of the pathology reports confirmed absence of abnormality in the biopsy specimens. Counts were expressed in eosinophils per high power field and per mm2. Oesophagus (n = 33): eosinophils were uniformly absent in all biopsies. Stomach: counting was performed, separately, in the superficial and deep lamina propria of the fundus (n = 13), corpus (n = 13) and antrum (n = 16). Mean eosinophilic density was higher in the deep lamina propria. Small intestine: eosinophil counts revealed 18.1 +/- 17.0, 14.4 +/- 12.0, and 51.5 +/- 35.3 in the lamina propria of the bulb (n = 13), D2 (n = 13), and ileum (n = 16), respectively. Large intestine: the highest peak count was observed in the caecum (125 mm2; n = 16) with a mean of 51.8 +/- 33.5. The eosinophil counts were lower in the ascending (n = 16; 40.9 +/- 27.4), transverse (n = 14; 34.3 +/- 21.9), descending (n = 15; 40.0 +/- 26.6), and sigmoid (n = 17; 25.8 +/- 17.8) colon and in the rectum (n = 17; 13.9 +/- 10.1). These data provide a baseline count and distribution of eosinophils in the gastrointestinal tract of paediatric patients with normal mucosa, thus expanding the scarce published data. PMID- 29987616 TI - Differentiation of Malignant and Benign Head and Neck Tumors with Amide Proton Transfer-Weighted MR Imaging. AB - PURPOSE: To prospectively evaluate the feasibility and capability of amide proton transfer-weighted (APTw) imaging for the characterization of head and neck tumors. PROCEDURES: Twenty-nine consecutive patients with suspected head and neck tumors were enrolled in this study and underwent APTw magnetic resonance imaging (MRI) on a 3.0-T MRI scanner. The patients were divided into malignant (n = 16) and benign (n = 13) groups, based on pathological results. A map of magnetization transfer ratio asymmetry at 3.5 ppm [MTRasym (3.5 ppm)] was generated for each patient. Interobserver agreement was evaluated and comparisons of MTRasym (3.5 ppm) were made between the malignant and benign groups. Receiver operating characteristic analysis was used to determine the appropriate threshold value of MTRasym (3.5 ppm) for the differentiation of malignant from benign tumors. RESULTS: The intraclass correlation coefficients of the malignant and benign groups were 0.96 and 0.90, respectively, which indicated a good interobserver agreement. MTRasym (3.5 ppm) was significantly higher for the malignant group (3.66 +/- 1.15 %) than for the benign group (1.94 +/- 0.93 %, P < 0.001). APTw MRI revealed an area under the curve of 0.904 in discriminating these two groups, with a sensitivity of 81.3 %, a specificity of 92.3 %, and an accuracy of 86.2 %, at the threshold of 2.62 % of MTRasym (3.5 ppm). CONCLUSIONS: APTw MRI is feasible for use in the head and neck tumors and is a valuable imaging biomarker for distinguishing malignant from benign lesions. PMID- 29987617 TI - How Long of a Dynamic 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) PET Acquisition Is Needed for Robust Kinetic Analysis in Breast Cancer? AB - PURPOSE: To quantitatively evaluate the minimally required scanning time of 3' deoxy-3'-[18F]fluorothymidine ([18F]FLT) positron emission tomography (PET) dynamic acquisition for accurate kinetic assessment of the proliferation in breast cancer tumors. PROCEDURES: Within a therapeutic intervention trial, 26 breast tumors of 8 breast cancer patients were analyzed from 30-min dynamic [18F]FLT-PET acquisitions. PET/CT was acquired on a Gemini TF 64 system (Philips Healthcare) and reconstructed into 26 frames (8 * 15 s, 6 * 30 s, 5 * 1 min, 5 * 2 min, and 2 * 5 min). Maximum activity concentrations (Bq/ml) of volume of interests over tumors and plasma in descending aorta were obtained over time frames. Kinetic parameters were estimated using in-house developed software with the two-tissue three-compartment irreversible model (2TCM) (K1, k2, k3, and Ki; k4 = 0) and Patlak model (Ki) based on different acquisition durations (Td) (10, 12, 14, 16, 20, 25, and 30 min, separately). Different linear regression onset time (T0) points (1, 2, 3, 4, and 5 min) were applied in Patlak analysis. Ki of the 30-min data set was taken as the gold standard for comparison. Pearson product-moment correlation coefficient (R) of 0.9 was chosen as a limit for the correlation. RESULTS: The correlation of kinetic parameters between the gold standard and the abbreviated dynamic data series increased with longer Td from 10 to 30 min. k2 and k3 using 2TCM and Ki using Patlak model revealed poor correlations for dynamic PET with Td <= 14 min (k2: R = 0.84, 0.85, 0.86; k3: R = 0.67, 0.67, 0.67; Ki: R = 0.72, 0.78, 0.87 at Td = 10, 12, and 14 min, respectively). Excellent correlations were shown for all kinetic parameters when Td >= 16 min regardless of the kinetic model and T0 value (R > 0.9). CONCLUSIONS: This study indicates that a 16-min dynamic PET acquisition appears to be sufficient to provide accurate [18F]FLT kinetics to quantitatively assess the proliferation in breast cancer lesions. PMID- 29987618 TI - Evaluation of Glucose Uptake and Uncoupling Protein 1 Activity in Adipose Tissue of Diabetic Mice upon beta-Adrenergic Stimulation. AB - PURPOSE: Regulation of metabolic activity in adipose tissue is of great concern for treating obesity. This study aimed to evaluate the adrenergic regulation of glucose uptake and the thermogenic program in adipose tissues in mouse models of both type 1 and 2 diabetes mellitus (DM). PROCEDURES: Male mice were treated with streptozotocin to induce type 1 (T1) DM, and obese ob/ob mice were used for the type 2 (T2) DM model. After selective beta3-adrenoreceptor stimulation by CL 316,243 (CL) treatment, 2-deoxy-D-[14C]glucose ([14C]DG) was administered to DM and corresponding control mice. Radioactivity and uncoupling protein 1 (UCP1) expression were measured and analyzed in adipose tissues. RESULTS: In T1DM, [14C]DG uptake in brown adipose tissue (BAT) decreased both at rest and upon CL stimulation, and UCP1 expression was preserved. However, CL treatment enhanced [14C]DG uptake without impairing UCP1 expression in inguinal white adipose tissue (iWAT). In this model, CL could not alter blood glucose levels. In T2DM mice, the blood glucose level was significantly lowered by CL treatment. There was no decrease in CL-induced [14C]DG uptake in BAT, and UCP1 expression was maintained. However, [14C]DG uptake was not increased in iWAT and no UCP1 expression was observed in iWAT (browning). CONCLUSIONS: The metabolic response against adrenergic stimulation varied depending on the type of adipose tissue and DM. This could be important for the therapeutic activation of adipose tissue metabolism in obese diabetic patients. PMID- 29987619 TI - Test-Retest Stability of Cerebral 2-Deoxy-2-[18F]Fluoro-D-Glucose ([18F]FDG) Positron Emission Tomography (PET) in Male and Female Rats. AB - PURPOSE: An important issue in rodent imaging is the question whether a mixed population of male and female animals can be used rather than animals of a single sex. For this reason, the present study examined the test-retest stability of positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) in male rats and female rats at different phases of the estrous cycle. PROCEDURES: Long-Evans rats (age 1 year) were divided into three groups: (1) males (n = 6), (2) females in metestrous (low estrogen levels, n = 9), and (3) females in proestrous (high estrogen levels, n = 7). Two standard [18F]FDG scans with rapid arterial blood sampling were made at an interval of 10 days in subjects anesthetized with isoflurane and oxygen. Body temperature, heart rate, and blood oxygenation were continuously monitored. Regional cerebral metabolic rates of glucose were calculated using a Patlak plot with plasma radioactivity as input function. RESULTS: Regional metabolic rate of glucose (rCMRglucose) in male and female rats, or [18F]FDG uptake in females at proestrous and metestrous, was not significantly different, but females showed significantly higher standardized uptake values (SUVs) and Patlak flux than males, particularly in the initial scan. The relative difference between the scans and the test-retest variability (TRV) were greater in females than in males. Intra-class correlation coefficients (ICCs) of rCMRglucose, SUV, normalized SUV, and glucose flux were good to excellent in males but poor to moderate in females. CONCLUSIONS: Based on these data for [18F]FDG, the mixing of sexes in imaging studies of the rodent brain will result in an impaired test-retest stability of PET data and a need for larger group sizes to maintain statistical power in group comparisons. The observed differences between males and females do not indicate any specific gender difference in cerebral metabolism but are related to different levels of non-radioactive glucose in blood plasma during isoflurane anesthesia. PMID- 29987620 TI - Linked Hexokinase and Glucose-6-Phosphatase Activities Reflect Grade of Ovarian Malignancy. AB - PURPOSE: Malignant cells exhibit increased rates of aerobic glycolysis. Here, we tested whether the accumulation of fluoro-deoxyglucose-6-phosphate (FDG6P) in ovarian cancers of differential malignancy reflects inversely correlated elevations of hexokinase (HK) and glucose-6-phosphatase (G6Pase) activities. PROCEDURES: Twenty-nine women with suspected ovarian cancer had positron emission tomography (PET) prior to surgery. From fresh-frozen tissue, we determined the activities of HK and G6Pase, and from the PET images, we determined the tumor maximum standardized uptake value (SUVmax) of 2-deoxy-2-[18F]fluoro-D-glucose. RESULTS: The SUVmax of malignant lesions significantly exceeded the SUVmax of benign (p < 0.005) and borderline lesions (p < 0.0005) that did not differ significantly. We found no significant correlation between measured HK or G6Pase activities and histological tumor type or SUVmax except that G6Pase activities were higher in malignant than borderline lesions (p < 0.05). Measured HK and G6Pase activities correlated inversely (p < 0.05). The slopes from the regression lines of the three correlations yielded positively correlated abscissa and ordinate intercepts, designated HKmax and G6Pasemax, respectively (r = 0.67, p < 0.0001). The positive correlations between the abscissa and ordinate intercepts with SUVmax had regression coefficients of r = 0.44, p < 0.05; and r = 0.39, p < 0.05, respectively. CONCLUSIONS: The results distinguished two ovarian cancer phenotypes, one with elevated HK activity and low G6Pase activity, and another with the opposite characteristics. PMID- 29987621 TI - Quantitative Intensity Harmonization of Dopamine Transporter SPECT Images Using Gamma Mixture Models. AB - PURPOSE: Differences in site, device, and/or settings may cause large variations in the intensity profile of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) images. However, the current standard to evaluate these images, the striatal binding ratio (SBR), does not efficiently account for this heterogeneity and the assessment can be unequivalent across distinct acquisition pipelines. In this work, we present a voxel-based automated approach to intensity normalize such type of data that improves on cross-session interpretation. PROCEDURES: The normalization method consists of a reparametrization of the voxel values based on the cumulative density function (CDF) of a Gamma distribution modeling the specific region intensity. The harmonization ability was tested in 1342 SPECT images from the PPMI repository, acquired with 7 distinct gamma camera models and at 24 different sites. We compared the striatal quantification across distinct cameras for raw intensities, SBR values, and after applying the Gamma CDF (GDCF) harmonization. As a proof-of concept, we evaluated the impact of GCDF normalization in a classification task between controls and Parkinson disease patients. RESULTS: Raw striatal intensities and SBR values presented significant differences across distinct camera models. We demonstrate that GCDF normalization efficiently alleviated these differences in striatal quantification and with values constrained to a fixed interval [0, 1]. Also, our method allowed a fully automated image assessment that provided maximal classification ability, given by an area under the curve (AUC) of AUC = 0.94 when used mean regional variables and AUC = 0.98 when used voxel-based variables. CONCLUSION: The GCDF normalization method is useful to standardize the intensity of DAT SPECT images in an automated fashion and enables the development of unbiased algorithms using multicenter datasets. This method may constitute a key pre-processing step in the analysis of this type of images. PMID- 29987622 TI - Convolutional Neural Network for Segmentation and Measurement of Intima Media Thickness. AB - The measurement of Carotid Intima Media Thickness (IMT) on Common Carotid Artery (CCA) is a principle marker of risk of cardiovascular disease. This paper presents a novel method of using deep Convolutional Neural Network (CNN) for identification and measurement of IMT on the far wall of the artery. The Region of Interest (ROI) is extracted using CNN architecture with 8 layers. 110 subjects are taken for the study. Each subject is recorded with one Right Common Carotid Artery (RCCA) and Left Common Carotid Artery (LCCA) frame resulting in 220 recordings. Patch based segmentation with 2640 patches are given to the training network for ROI localization. Intima Media Complex (IMC) is the area where IMT is measured. This region is extracted after defining the ROI. Keeping in mind the end objective of measurement of IMT values binary threshold with snake algorithm is applied to extract the lumen-intima and media-adventitia boundary. IMT values are measured for 20 cases and mean difference is found to be 0.08 mm. PMID- 29987624 TI - Transoral robotic resection of a retropharyngeal parathyroid adenoma: a case report. AB - Transoral robotic surgery (TORS) has become an increasingly popular option for early malignancies of the oropharynx. It offers superior visualization and has been proven to have acceptable functional and oncologic outcomes. Additionally, indications in head neck have expanded to manage tumors of the thyroid, neck, parapharyngeal space and salivary glands. A 58-year-old female had an incidental finding on CT imaging of a retropharyngeal mass at the level of the hyoid bone. She was referred to a tertiary medical center for further workup and removal of this mass. Due to the midline position of the mass, favorable access and potentially decreased surgical morbidity, TORS excision of the mass was performed for diagnosis and treatment. Histopathology confirmed this to be a hypercellular parathyroid mass consistent with parathyroid adenoma. We report a relatively unusual location of parathyroid adenoma in an asymptomatic patient with normal parathyroid and calcium levels. TORS proves to be a feasible and safe method for complete surgical excision of retropharyngeal parathyroid adenoma without tumor spillage or violation. PMID- 29987623 TI - Coronary Artery Calcium Score: the "Mammogram" of the Heart? AB - PURPOSE OF REVIEW: To discuss the classic analogy of "coronary artery calcium (CAC) as a mammogram of the heart", by evaluating the conceptual strengths, weaknesses, opportunities, and threats of a potential cardiovascular disease (CVD) screening strategy using CAC in apparently healthy adults. RECENT FINDINGS: CAC is typically used for further CVD risk assessment. CAC is also currently being used as a screening test in specific subgroups of individuals, particularly in some Asian countries. Although this has yielded valuable insights on the determinants and pathophysiology of CVD, whether this approach results in improved clinical outcomes compared to other assessment and management approaches is currently unclear. Although CAC and mammograms share a number of characteristics, there are also important conceptual differences. The evidence supporting CAC, which is a robust CVD risk assessment tool, for CVD screening purposes is currently very limited, and further research is needed. PMID- 29987625 TI - Alterations in Polyunsaturated Fatty Acid Metabolism and Reduced Serum Eicosadienoic Acid Level in Ulcerative Colitis: Is There a Place for Metabolomic Fatty Acid Biomarkers in IBD? PMID- 29987626 TI - Does Medical Acceleration Improve Outcomes in Ulcerative Colitis Patients Who Are in Clinical Remission but Have Endoscopic Inflammation? AB - BACKGROUND: Discrepancies between clinical symptoms and mucosal inflammation have been reported in up to 50% of patients with ulcerative colitis (UC). However, there are no guidelines and only limited information for appropriate treatment manipulation. AIM: We aimed to evaluate long-term outcomes according to treatment strategies and determine predictive factors for disease relapse in UC patients who are in clinical remission (CR) but still have endoscopic inflammation. METHODS: A total of 204 patients who were confirmed as achieving CR but still had mucosal inflammation were included. CR was defined as "partial Mayo score <= 1" with no changes in medications or use of any corticosteroids during the past 3 months. An active mucosal lesion was defined as "endoscopic Mayo subscore > 0." RESULTS: The mean patient age was 43.5 years, and 53.9% were male. The mean disease duration was 89.9 months. During a mean follow-up of 34 months, 90 patients (44%) experienced disease relapse. The cumulative relapse-free rate did not differ by treatment strategy (maintenance of current therapy vs. dose elevation or step-up therapy). Multivariate analysis revealed that left-side colitis or pancolitis at diagnosis (OR 2.10; 95% CI 1.04-4.27; P = 0.040) and number of extraintestinal manifestations >= 2 (OR 5.62; 95% CI 1.10-28.68; P = 0.038) were independent predictive factors for disease relapse. CONCLUSIONS: The current medical acceleration treatment strategy did not have a significant influence on the long-term outcomes of UC patients in CR but with active mucosal inflammation. Disease extent at diagnosis and extraintestinal manifestations were independently predictive of disease relapse. PMID- 29987627 TI - Gastritis Cystica Polyposa: A Rare Cause of Abdominal Pain and Early Satiety Treated with Endoscopic Resection. PMID- 29987628 TI - Production of Recombinant N Protein of Infectious Bronchitis Virus Using the Baculovirus Expression System and Its Assessment as a Diagnostic Antigen. AB - The avian coronavirus-infectious bronchitis virus (AvCoV-IBV) is recognized as an important avian pathogen, and new viral variants are a continuous threat to the poultry industry worldwide. Sensitive diagnostics and efficacious vaccines are necessary to combat IBV infections in chickens. The aim of this study was to produce recombinant N protein of IBV in the baculovirus system to use in ELISA diagnostic tests in order to enable the assessment of the sero-prevalence and risk of IBV infections in chickens in Turkey. For this, the gene encoding the N protein of the Beaudette strain of IBV was expressed using a recombinant baculovirus expression system. The recombinant N protein was purified using Ni NTA affinity chromatography. An estimated 50-kDa recombinant protein corresponding to the expected molecular weight of IBV N including the 6xHis tag was detected using an anti-His monoclonal antibody. Specific immunoreactivity of the recombinant protein was confirmed by Western blot using antiserum obtained from vaccinated and naturally infected chicken from Turkey as well as using a monoclonal antibody raised against the N protein of the IBV Massachusetts strain. The results obtained with the in-house ELISA had high agreement with a commercial ELISA. Immunoreactivity analysis using antisera in Western blotting and the in house ELISA suggests that the recombinant IBV N protein could be broadly cross reactive with antisera produced against different IBV strains. We conclude that the recombinant baculovirus expressed IBV N protein could serve as a useful diagnostic antigen for detection of IBV infections in chickens by ELISA. PMID- 29987629 TI - Genome Sequencing and Analysis of Strains Bacillus sp. AKBS9 and Acinetobacter sp. AKBS16 for Biosurfactant Production and Bioremediation. AB - Microbial genomics facilitates the analysis of microbial attributes, which can be applied in bioremediation of pollutants and oil recovery process. The biosurfactants derived from microbes can replace the chemical surfactants, which are ecologically detrimental. The aim of this work was to study the genetic organization responsible for biodegradation of aromatics and biosurfactant production in potential microbes isolated from polluted soil. Bacterial isolates were tested for biosurfactant production, wherein Bacillus sp. AKBS9 and Acinetobacter sp. AKBS16 exhibited highest biosurfactant production potential. Whole genome sequencing and annotations revealed the occurrence of sfp and NPRS gene in the Bacillibactin biosynthetic gene cluster in AKBS9 strain and emulsan biosynthetic gene cluster in AKBS16 strain for biosurfactant production. Various aromatic compound ring cleaving oxygenases scavenging organic molecules could be annotated for strain AKBS16 using RAST annotations. PMID- 29987631 TI - Early infected aneurysm with 18F-FDG uptake prior to substantial anatomical changes. PMID- 29987630 TI - Self-reported work conditions in Canada: examining changes between 2002 and 2012. AB - OBJECTIVES: To examine changes in self-reported work conditions over a 10-year time period in Canada, as measured using two comparable cross-sectional surveys conducted in 2002 and 2012. METHODS: Population-based data were obtained from the Canadian Community Health Survey. Work conditions (psychosocial work conditions, work hours, work demands, job satisfaction) were measured using the same modules across survey cycles. Regression models provided estimates for trends in work conditions, adjusting for differences in socio-demographic and survey administration characteristics over time. RESULTS: We observed changes in self reported work conditions across cycles, including higher levels of co worker/supervisor support and job security; lower levels of psychological demands; and increases in shorter/regular work hours over time. These findings were consistent in both the base and adjusted models. Although skill discretion, decision authority, and job satisfaction improved over time in our base models, these findings were attenuated towards the null in adjusted models. Respondents in 2012 had a greater odds of reporting a physically demanding work environment compared to 2002. Differential time trends were observed by geographic region. CONCLUSIONS: Our study found improvements in some self-reported measures of the psychosocial work environment in Canada over time. These changes were not accounted for by socio-demographic or survey administration differences across survey cycles. Despite these overall trends, absolute levels of some work conditions have not changed. Given the relevance of work conditions as a determinant of health, a continued focus on improving all aspects of the work environment should remain a public health priority to improve the health of working-aged Canadians. PMID- 29987632 TI - Integrating imaging modalities for diagnosing cardiac amyloidosis. PMID- 29987633 TI - "Practice makes perfect?" white matter microstructural characteristic predicts the degree of improvement in within-trial conflict processing across two weeks. AB - Several studies have investigated the trait-like characteristics of conflict processing at different levels. Our study extends these findings by reporting a practice-based improvement in within-trial conflict processing across two sessions. Eighty-three participants performed the same flanker task on two occasions 2 weeks apart. A subset of 37 subjects also underwent diffusion tensor imaging (DTI) scanning the day before the first behavioral task. Despite the trait-like characteristics of conflict processing, within-trial conflict processing in the second behavioral session was significantly shorter than that in the first session, indicating a practice-based improvement in conflict processing. Furthermore, changes in within-trial conflict processing across the two sessions exhibited significant individual differences. Tract-based spatial statistics revealed that the improvement across two sessions was related to the axial diffusivity values in white matter regions, including the body and splenium of the corpus callosum, right superior and posterior corona radiate, and right superior longitudinal fasciculus. Subsequently, lasso regression with leave-one out cross validation was used to assess the predictive ability of white matter microstructural characteristics in significant regions. The results showed that 61% of individual variability in the improvement in the within-trial conflict processing could be explained by variations in the axial diffusivity values in the four significant regions and the within-trial conflict processing in the first session. These results suggest that axonal morphology in the white tracts connecting conflict-related regions predicts the degree of within-trial conflict processing improvement across two sessions. PMID- 29987634 TI - Ability of two single-step restorative materials to avoid crown darkening caused by intracanal minocycline paste. AB - OBJECTIVES: This study aimed to quantitatively assess the ability of two single step restorative materials to avoid crown darkening caused by the use of minocycline as an intracanal medicament. MATERIALS AND METHODS: After coronal access and instrumentation, 120 maxillary incisors were divided into four groups (n = 30). Two experimental groups according to the restorative material applied to the inner walls of the access cavity: OB, OptiBond All-In-One + minocycline intracanal paste; U200, RelyX U200 + minocycline intracanal paste. Two control groups without restorative materials: MIN, minocycline intracanal paste and SL, saline intracanal. Color determination was performed using a spectrophotometer at five time points, immediately after materials were applied (baseline), and at 7, 14, 21, and 28 days from the baseline. RESULTS: Decrease in the mean values of L* (luminosity) was observed after insertion of minocycline paste in all groups at all time points. Statistically significant differences were absent between the time points (P > .05). After 28 days, MIN showed significantly more darkening (DeltaL*) (- 10.6 +/- 7.3) than OB (- 5.4 +/- 6.2), U200 (- 5.8 +/- 3.9) and SL ( 2.3 +/- 1.2) (P < .05). CONCLUSIONS: Crown darkening can be minimized by the previous application of RelyX U200 or OptiBond All-In-One to the inner walls of the access cavity before a minocycline-containing paste is applied as an intracanal medication. CLINICAL RELEVANCE: The American Association of Endodontists Clinical Considerations for Regenerative Procedures in necrotic immature teeth suggests the triple antibiotic paste as an intracanal medication (2018). However, discoloration and crown darkening are common unfavorable outcomes. The clinical protocol suggested in this paper has shown to be able to minimize crown darkening, predictably leading to a better patient-centered clinical success. PMID- 29987635 TI - Management of deep carious lesions and pulps exposed during carious tissue removal in adults: a questionnaire study among dentists in Finland. AB - OBJECTIVES: To find out which management methods are preferred by dentists in Finland for a deep carious lesion or a pulp exposed during carious tissue removal in adult patients. MATERIALS AND METHODS: An electronic questionnaire consisting of 25 questions was sent to 1000 randomly sampled dentists in Finland. The response rate was 32%. RESULTS: Less invasive excavation strategies (stepwise or selective removal) were preferred by 64% for an asymptomatic deep lesion, while 34% chose nonselective removal to hard dentine. In the presence of an asymptomatic pulpal exposure, vital pulp therapy was preferred, as 71% of the respondents chose direct pulp capping (DPC) or partial pulpotomy, compared to root canal treatment (26%). Mineral trioxide aggregate (MTA) and calcium hydroxide-based materials were both chosen by 40% for vital pulp therapy. In the management of a deep carious lesion, less invasive excavation strategies were significantly associated with having clinical guidelines vs. no guidelines at the practice [odds ratio (OR) 3.5, confidence interval (CI) 1.4-9.0]. MTA was favored over other DPC materials significantly more often by those who had attended continuing education courses during the last 3 years (OR 2.8, CI 1.2-6.5). CONCLUSIONS: Less invasive management strategies have been adopted into clinical practice by the majority of dentists in Finland. There is a need to encourage the use of MTA in the case of a pulpal exposure. CLINICAL RELEVANCE: The results of this study can be utilized in continuing education, to raise awareness of management strategies supported by present scientific evidence. PMID- 29987636 TI - In vitro visual and visible light transillumination methods for detection of natural non-cavitated approximal caries. AB - OBJECTIVES: The objective was to evaluate a visible-light-transillumination (using Digital Imaging Fiber-Optic Transillumination machine: DIFOTI) method using occlusal view (DIFOTI-occl), axial view (buccal and lingual: DIFOTI-axial), and combination of all views (DIFOTI-all) for detecting non-cavitated approximal caries and to compare its performance to visual examination (International Caries Detection and Assessment System: ICDAS). MATERIALS AND METHODS: Thirty extracted human premolars were selected (sound to lesions into the outer one-third of the dentine) based on micro-computed tomography (MU-CT). Teeth were mounted in a custom-made device to simulate approximal contact. DIFOTI (Electro-Optical Sciences Inc., Irvington, NY, USA) images were obtained from the occlusal, buccal, and lingual views. DIFOTI image and ICDAS examinations were performed and repeated by three trained/calibrated examiners. Sensitivity, specificity, area under receiver operating characteristics curve (Az), inter- and intra-class correlation coefficients (ICCs), and correlation were determined. RESULTS: Sensitivity/specificity was for DIFOTI-occl: 0.42/0.75, DIFOTI-axial: 0.86/0.93, DIFOTI-all: 0.91/0.69, and for ICDAS: 0.89/0.83. Az for DIFOTI-occl was significantly lower than that of DIFOTI-axial (p < 0.001), DIFOTI-all (p = 0.002), and ICDAS (p = 0.005). Spearman correlation coefficients with MU-CT for DIFOTI-occl (r = 0.39) showed weak association, while DIFOTI-axial (r = 0.80), DIFOTI-all (r = 0.91), and ICDAS (r = 0.90) showed moderate association. ICCs for intra-examiner repeatability/inter-examiner agreement were for DIFOTI-occl (0.64/0.58), DIFOTI-axial (0.92/0.89), DIFOTI-all (0.85/0.83), and ICDAS (0.79/0.72). CONCLUSIONS: The results of the current in vitro study suggest that, for detection of non-cavitated approximal caries lesions, DIFOTI performs better using axial than occlusal view. CLINICAL RELEVANCE: Approximal non-cavitated caries detection is challenging. DIFOTI can observe images from occlusal-, buccal , and lingual views. DIFOTI and visual (ICDAS) examinations of buccal- and lingual- and all-views are more suitable than those of occlusal view for a detection of non-cavitated approximal caries. PMID- 29987637 TI - Synthesis of tellurium nanosheet for use in matrix assisted laser desorption/ionization time-of-flight mass spectrometry of small molecules. AB - Two-dimensional tellurium nanosheets were prepared by a hydrothermal method and characterized by scanning electron microscopy, powder X-ray diffractometry, and UV-vis spectroscopy. The nanosheets were explored as a novel matrix for desorption/ionization of small molecules including nucleobases, fatty acids and amino acids by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. The results show that the tellurium nanosheets have good UV light absorption, cause low matrix ion interference in the low-molecule-mass region, and have high desorption/ionization efficiency in the negative ion mode. Hence, they are a viable matrix for negative ion desorption/ionization in MALDI-TOF MS of small molecules. In order to investigate the desorption/ionization mechanisms, benzylpyridinium salt and bisphenol A were adopted as probes. The results show that both of the electronic transitions mechanism and laser-induced thermal mechanism play important roles in desorption/ionization process. Graphical abstract Two-dimensional tellurium (Te) nanosheet was synthesized by a hydrothermal method and explored as a novel matrix for desorption/ionization of small molecules by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). PMID- 29987638 TI - Neural pathways of maternal responding: systematic review and meta-analysis. AB - Functional magnetic resonance imaging (fMRI) has increasingly been employed to establish whether there is a specific brain neural network dedicated to maternal responsiveness. We undertook systematic review and meta-analysis of all studies in which healthy new mothers were exposed to visual stimuli of own versus other infants to determine the quality of evidence for a dedicated maternal neural network. Systematic literature review revealed a pattern of specific neural responses commonly induced by visual infant paradigms. Brain areas consistently reported as activated in mothers in response to own versus unknown infant included the left thalamus, bilateral pre-central gyrus, left limbic lobe, uncus, amygdala and left caudate. These regions are implicated in reward, attention, emotion processing and other core social cognitive skills. Meta-analysis, however, revealed a more limited subset of brain areas activated in mothers specifically in response to their own versus unknown infant and suggested considerable inter-study variability. Further work is needed if functional imaging is to become an objective tool for the assessment of neural pathways associated with distinct patterns of maternal care behaviour. Such a tool would be invaluable in developing biomarkers of neural activity associated with healthy maternal care and for monitoring treatment/intervention effects of costly parenting interventions. PMID- 29987639 TI - Immigrant Youth Have Significantly Lower Rates of Externalizing Behavior than Native-Born Americans: Differences by Region of Birth. AB - A large proportion of Americans have the opinion that immigrants increase crime. Although past research has not found immigrant status to be associated with criminal behavior, American immigration policy has historically discriminated against certain groups based on their region of birth due to safety concerns. The purpose of the present study was to examine differences in externalizing behavior by immigrant's region of birth. Data was used from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K), a nationally representative and longitudinal study of 21,260 kindergarteners. A series of Poisson regression models were used to predict externalizing behavior of fifth grade students from immigrant status and parent's region of birth. Analyses controlled for demographic characteristics of the child and family and were adjusted by probability weights and primary sampling unit provided by the ECLS-K. After controlling for family income and parents' educational status, immigrant youth had 0.04 lower externalizing behavior scores compared to native-born American youth (B = - 0.04, 95% CI - 0.06 to - 0.01). When considering differences by region of origin, youth from Asia (B = - 0.12, 95% CI - 0.17 to - 0.07) and Central America (B = - 0.10, 95% CI - 0.14 to - 0.05) had significantly lower externalizing behavior compared to native-born American youth, after controlling for covariates. In fifth grade, immigrant youth have significantly lower rates of externalizing behavior than native-born Americans. In particular, immigrant youth from Asia and Central America engaged in significantly less externalizing behavior than native-born Americans. No region of origin engaged in significantly more externalizing behavior than native-born youth. PMID- 29987640 TI - Uptake of Gynecological Cancer Screening and Performance of Breast Self Examination Among 50-Year-Old Migrant and Non-migrant Women in Germany: Results of a Cross-Sectional Study (InEMa). AB - Our aim was to provide data regarding uptake of gynecological early detection measures and performance of breast self-examinations among migrant women in Germany. Cross-sectional self-reported data were collected using paper-and-pencil questionnaires. Descriptive analyses, Chi square-tests, and logistic regression were applied. Results were adjusted for educational level. Of 5387 women, 89.9% were autochthonous, 4.1% German resettlers, 2.8% Turkish, 3.1% other migrants. Participation rates regarding cancer screening differed significantly, with the lowest proportion in Turkish migrants (65.0%), resettlers (67.8%), other migrants (68.2%) and autochthonous population (78.2%). No differences in performance of breast self-examinations were detected. When adjusted for education, results indicated only slight changes in the odds to participate in screening irregularly or not at all. Results support existing evidence by showing lower participation rates in cancer screening among migrant women, but there were no differences regarding breast self-examinations. Migrant women form a potential high-risk group for late-stage diagnosis of cervical or breast cancer. PMID- 29987641 TI - Increased Early Sensitivity to Eyes in Mouthless Faces: In Support of the LIFTED Model of Early Face Processing. AB - The N170 ERP component is a central neural marker of early face perception usually thought to reflect holistic processing. However, it is also highly sensitive to eyes presented in isolation and to fixation on the eyes within a full face. The lateral inhibition face template and eye detector (LIFTED) model (Nemrodov et al. in NeuroImage 97:81-94, 2014) integrates these views by proposing a neural inhibition mechanism that perceptually glues features into a whole, in parallel to the activity of an eye detector that accounts for the eye sensitivity. The LIFTED model was derived from a large number of results obtained with intact and eyeless faces presented upright and inverted. The present study provided a control condition to the original design by replacing eyeless with mouthless faces, hereby enabling testing of specific predictions derived from the model. Using the same gaze-contingent approach, we replicated the N170 eye sensitivity regardless of face orientation. Furthermore, when eyes were fixated in upright faces, the N170 was larger for mouthless compared to intact faces, while inverted mouthless faces elicited smaller amplitude than intact inverted faces when fixation was on the mouth and nose. The results are largely in line with the LIFTED model, in particular with the idea of an inhibition mechanism involved in holistic processing of upright faces and the lack of such inhibition in processing inverted faces. Some modifications to the original model are also proposed based on these results. PMID- 29987642 TI - Commentary on: "Implementing a Mediterranean-Style Diet Outside the Mediterranean Region". PMID- 29987643 TI - The Role of One-Stage Exchange for Prosthetic Joint Infection. AB - PURPOSE OF REVIEW: In an era of increasing numbers of hip and knee replacements, strategies to manage prosthetic joint infection (PJI) that are effective at infection control with good patient-reported outcomes and cost containment for health systems are needed. Interest in single-stage exchange for PJI is rising and we assess evidence from the last 5 years related to this treatment strategy. RECENT FINDINGS: Only five series for total knee replacement and ten series for total hip replacement have been reported in the last five years. More review articles and opinion pieces have been written. Reinfection rates in these recent studies range from 0 to 65%, but a meta-analysis and systematic review of all studies showed a reinfection rate of 7.6% (95% CI 3.4-13.1) and 8.8% (95% CI 7.2 10.6) for single-stage and two-stage revisions respectively. There is emerging evidence to support single-stage revision in the setting of significant bony deficiency and atypical PJIs such as fungal infections. Prospective randomised studies are recruiting and are necessary to guide the direction of single-stage revision selection criteria. The onus of surgical excellence in mechanical removal of implants, necrotic tissue, and biofilms lies with the arthroplasty surgeon and must remain the cornerstone of treatment. Single-stage revision may be considered the first-line treatment for all PJIs unless the organism is unknown, the patient is systemically septic, or there is a poor tissue envelope. PMID- 29987644 TI - Management of Pediatric Ankle Fractures. AB - PURPOSE OF REVIEW: Summarize classic and recent information regarding the unique subset of ankle fractures in children with open growth plates and share the authors' decision-making and surgical techniques. RECENT FINDINGS: Recent research on pediatric ankle fractures has centered on the accurate prediction and prevention of growth arrest following fractures of the distal tibia. Another source of discussion is the necessity and benefit of CT scanning in classification and treatment approach. Pediatric ankle fractures continue to pose clinical challenges for orthopedic surgeons. While open anatomic reduction and internal fixation continue to produce good outcomes for intra-articular fractures, outcomes of physeal injuries are more difficult to predict. More studies are needed to determine which patients may benefit more from surgical treatment of physeal injuries. PMID- 29987646 TI - Pesticide-Poisoned Patients: Can They Be Used as Potential Organ Donors? AB - INTRODUCTION: The gap between the number of patients on transplant waiting lists and patients receiving transplants is growing. Use of organs from donors who have died following pesticide exposure remains controversial. This study reviews the literature related to transplantation from this group. METHODS: A literature search was undertaken on PubMed using the following keywords: 'insecticide', 'pesticide', 'rodenticide', 'organophosphate', 'carbamate', 'paraquat', 'poisoning', 'toxicity', 'overdose', 'intoxication', 'ingestion', 'organ donation or procurement', 'transplant', 'allograft transplant', and 'expanded criteria organ donation'; 21 specific pesticides/insecticides were also added to the search; the indexes for EAPCCT/NACCT meeting abstracts 2008-2017 were also searched. Identified publications were reviewed and if described human donation/transplantation of >= 1 solid organ(s), the following was extracted: (i) compound(s) ingested; (ii) donor demographics; (iii) organ(s) transplanted; and (iv) graft function at follow-up. RESULTS: Ten papers were identified describing 20 fatalities (1999-2017) related to the following pesticide exposures: organophosphate, 8 cases; aldicarb, 4; paraquat, 3; parathion, 1; malathion, 1; carbofuran/carbamate, 1; carbamate, 1; and brodifacoum, 1 and no further cases were identified from EAPCCT/NACCT abstracts. Donors were aged 12-50 (25.9 +/- 11.9) years. Forty-four organs were transplanted: 28 kidneys, 7 livers, 6 corneas, and 3 hearts. Forty recipients had outcome reported: 3 (7.5%) patients died, 3 (7.5%) had graft failure/dysfunction and 34 (85.0%) had good graft function. Overall survival with good function was 96%, 71%, 83%, and 67% for kidneys, livers, corneas and hearts respectively. CONCLUSION: Review of the published literature suggests that solid organ donation following exposure to a pesticide is associated with good short-to-medium-term graft organ function following transplantation, particularly for transplanted kidneys and corneas. PMID- 29987645 TI - Staphylococcus aureus Evasion of Host Immunity in the Setting of Prosthetic Joint Infection: Biofilm and Beyond. AB - PURPOSE OF REVIEW: The incidence of complications from prosthetic joint infection (PJI) is increasing, and treatment failure remains high. We review the current literature with a focus on Staphylococcus aureus pathogenesis and biofilm, as well as treatment challenges, and novel therapeutic strategies. RECENT FINDINGS: S. aureus biofilm creates a favorable environment that increases antibiotic resistance, impairs host immunity, and increases tolerance to nutritional deprivation. Secreted proteins from bacterial cells within the biofilm and the quorum-sensing agr system contribute to immune evasion. Additional immunoevasive properties of S. aureus include the formation of staphylococcal abscess communities (SACs) and canalicular invasion. Novel approaches to target biofilm and increase resistance to implant colonization include novel antibiotic therapy, immunotherapy, and local implant treatments. Challenges remain given the diverse mechanisms developed by S. aureus to alter the host immune responses. Further understanding of these processes should provide novel therapeutic mechanisms to enhance eradication after PJI. PMID- 29987647 TI - The Associations between Paraoxonase 1 L55M/Q192R Genetic Polymorphisms and the Susceptibilities of Diabetic Macroangiopathy and Diabetic Microangiopathy: A Meta Analysis. AB - INTRODUCTION: Plenty of studies have focused on the associations of paraoxonase 1 Q192R and L55M genetic polymorphisms with diabetic macroangiopathy and microangiopathy susceptibility, but these associations remain controversial. Therefore, this meta-analysis was conducted to demonstrate these relationships. METHODS: Relevant studies published in English or Chinese were identified in PubMed, Embase, Wanfang Database, and CNKI by applying specific inclusion and exclusion criteria. Statistical analyses were performed using the STATA 12.0 statistical software. RESULTS: 25 Case-control studies were included in the meta analyses: six on the association between paraoxonase 1 L55M genetic polymorphism and diabetic macroangiopathy risk, nine on the association between L55M and diabetic microangiopathy risk, 12 on the association between Q192R and diabetic macroangiopathy risk, and 12 on the association between Q192R and diabetic microangiopathy risk. Paraoxonase 1 L55M genetic polymorphism was significantly associated with diabetic microangiopathy susceptibility in the dominant model [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.33-0.83, P = 0.006], the homozygous model (OR 0.37, 95% CI 0.16-0.86, P = 0.021), the allelic contrast model (OR 0.62, 95% CI 0.43-0.90, P = 0.011), the recessive model (OR 12.04, 95% CI 8.02-18.06, P = 0.000), and the heterozygous model (OR 0.57, 95% CI 0.38-0.85, P = 0.006), but L55M was not significantly associated with macroangiopathy susceptibility. Paraoxonase 1 Q192R genetic polymorphism was significantly associated with diabetic macroangiopathy susceptibility in the homozygous model (OR 1.88, 95% CI 1.06-3.32, P = 0.030), the allelic contrast model (OR 1.31, 95% CI 1.02-1.69, P = 0.038), and the recessive model (OR 1.55, 95% CI 1.11-2.16, P = 0.010), but not in the dominant and heterozygous models. Meanwhile, there was no significant association between paraoxonase 1 Q192R genetic polymorphism and diabetic microangiopathy susceptibility. CONCLUSION: Paraoxonase 1 L55M and Q192R genetic polymorphisms play important roles in diabetic macroangiopathy and microangiopathy susceptibility. Further well-designed studies based on large samples are needed to confirm these results. PMID- 29987648 TI - High frequency of genital carriers of Leptospira sp. in sheep slaughtered in the semi-arid region of northeastern Brazil. AB - Although some studies in sheep have indicated leptospire colonization of the genital tract, further studies are needed to clarify the role of genital carriers in this species. Thus, this study aimed to evaluate the colonization of pathogenic leptospires in the genital and urinary tract of slaughtered sheep. Fifty-seven adult, female woolless sheep destined for slaughter were used. Renal (n = 57), bladder (n = 57), ovary (n = 34), uterine tube (n = 44), and uterus (n = 33) samples were collected for molecular detection of Leptospira sp. DNA, and blood samples (n = 57) for serological testing. The molecular testing was performed using polymerase chain reaction (PCR), and the serological testing was performed using microscopic serum agglutination test (MAT). Samples with amplifying DNA were subjected to genetic sequencing. In total, leptospiral DNA was found in the tissues of 44 (77.2%) sheep, whereas only nine animals were positive on both PCR and MAT; there was slight agreement between PCR and MAT techniques (k = 0.0268; p = 0.684). In 61 (54.9%) genital tract and in five (4.4%) urinary tract samples, the leptospiral DNA was detected, with significant difference (p < 0.001). The genes of one sample from the uterine tube and another from the bladder were sequenced and demonstrated 99% similarity to Leptospira interrogans. Anti-Leptospira antibodies were detected in 11 (19.3%) of the tested animals. The results reinforce the importance of the genital tract as an extra renal site of colonization, suggesting the possibility of venereal transmission in sheep. PMID- 29987649 TI - Reproductive performance of Ankole cattle and its crossbreds in Rwanda. AB - The aim of this study was to assess the reproductive performance of Ankole cattle and its crossbreds with Friesian (F), Jersey (J), and Sahiwal (S). The traits (number of records) studied were calving to first insemination, CFI (797); calving to last insemination, CLI (797); conception rate, CR (4354); number of inseminations, NINS (936); and calving interval, CI (259). The overall means of intervals CFI, CLI and CI, CR, and NINS were 192, 198 and 480 days, 67%, and 1.23 respectively. Breed group was significant (P < 0.05) for all traits except NINS, while season of calving was significant for CFI, CLI, and CI, and season of insemination was significant for CR. The breed group AF had better CR than the purebred Ankole and AS, and AS had lower CR than AJxS and AJ. On the other hand, Ankole (and to some extent AF) had longer CFI and CLI than AJ, AS, and FF. Ankole had 54 days longer CI than all crossbreds taken together. The prolonged intervals CFI, CLI, and CI observed in this study call for proper postpartum anestrus management both in terms of nutrition and calf suckling management. PMID- 29987650 TI - Diagnosis and Treatment of Vulvar Lichen Sclerosus: An Update for Dermatologists. AB - Vulvar lichen sclerosus is an important skin disease that is common in women in their 50 s and beyond; however, it can also affect females of any age, including children. If not treated, it has the potential to cause significant and permanent scarring and deformity of the vulvar structure. In addition, if untreated, it is associated with a 2-6% lifetime risk of malignant squamous neoplasia of the vulva. Lichen sclerosus has been considered a difficult to manage condition; however, both serious complications can potentially be prevented with early intervention with topical corticosteroid, suggesting that the course of the disease can be treatment modified. PMID- 29987651 TI - Fabrication of Optical Switching Patterns with Structural Colored Microfibers. AB - Structural color was generated using electrospinning and hydrothermal growth of zinc oxide (ZnO). An aligned seed layer was prepared by electrospinning, and the hydrothermal growth time control was adjusted to generate various structural colors. The structural color changed according to the angle of the incident light. When the light was parallel to the direction of the aligned nanofibers, no pattern was observed. This pattern is referred to as an "optical switching pattern." Replication using polydimethylsiloxane (PDMS) also enabled the generation of structural colors; this is an attractive approach for mass production. Additionally, the process is quite tunable because additional syntheses and etching can be performed after the patterns have been fabricated. PMID- 29987652 TI - Left bundle branch block during antegrade balloon aortic valvuloplasty caused by stiff-wire loop stress. PMID- 29987653 TI - Short-term outcome of percutaneous coronary intervention with directional coronary atherectomy followed by drug-coated balloon: a preliminary report. AB - Directional coronary atherectomy (DCA) is a unique technique used in percutaneous coronary intervention (PCI) which involves the removal of plaque from the coronary artery. Treatment with a drug-coated balloon (DCB) appears to be effective, especially when a predilatation of the lesion is performed appropriately. We hypothesize that the combination therapy of DCA with DCB is an effective strategy in PCI. PCI with DCA followed by DCB was performed for 23 patients from December 2014 to April 2017. All DCA procedures were performed under the guidance of intravascular ultrasound (IVUS) findings and all procedures were successfully performed without incurring major complications such as a coronary perforation. Plaque area (PA) was reduced from 77.3 +/- 10.4% at baseline to 50.9 +/- 9.2% after DCA and luminal cross-sectional area (CSA) after PCI was enlarged from 3.6 +/- 1.8 to 9.3 +/- 3.3 mm2. Follow-up coronary angiography (CAG) performed at 6-10 months showed no cases having incurred restenosis. Plaque area at follow-up CAG was 52.0 +/- 8.5% and luminal CSA was 9.5 +/- 2.1 mm2. There were no cases undergoing target vessel revascularization (TVR) and target lesion revascularization (TLR) during the follow-up periods. PCI with DCA followed by DCB might be an effective strategy for de novo lesions. PMID- 29987655 TI - Effect of Tumor Relevant Acidic Environment in the Interaction of a N hydroxyindole-2-Carboxylic Derivative with the Phospholipid Bilayer. AB - PURPOSE: The inhibitors of the human isoform 5 of lactate dehydrogenase (hLDH5) have attracted growing interest as efficient anti-cancer agents. In the present paper, the interactions between an efficient hLDH5 inhibitor (N-hydroxyindole-2 carboxylic derivative) and lipid bilayers based on dipalmitoylphosphatidylcholine (DPPC) were investigated. Additionally, since interstitial acidification plays a key role in tumor pathogenesis and tumor drug therapy, the effect of acidic pH was assessed and correlated to DPPC/drug interaction. METHODS: Four different techniques were used: differential scanning calorimetry, dynamic light scattering, UV-VIS second derivative spectrometry and attenuated total reflection Fourier transformed infrared spectroscopy. RESULTS: All techniques concur in highlighting a structural change of lipid assembly, susceptible both to pH change and to the presence of the antitumor compound. Lipid vesicles appeared more compact at the lower pH, since the thermal pre-transition from the lamellar gel phase to the ripple gel phase was absent at pH 7.4 and the infrared analysis revealed a stronger acyl chain packing as well as a different hydration degree. Drug interaction was mainly detected in the lipid region including the ester linkages and the first portion of the acyl chains. Furthermore, a lower drug partitioning was recorded at pH 6.6. CONCLUSIONS: The investigated antitumor agent possesses a stable negative charge at the investigated pH values, thus the lower interaction at the acidic pH is mainly ascribable to an environmental effect on lipid assembly. Therefore, drug efficacy under tumor acid conditions may be hampered by the observed lipid membrane constraints, and suggest for the development of suitable prodrugs. PMID- 29987656 TI - Bladder metastasis from primary breast cancer: a case report. AB - BACKGROUND: Breast cancer frequently metastasizes to the bone, lung, and liver. However, metastasis to the bladder is uncommon. Bladder metastasis due to direct infiltration from peripheral organs, such as the colon and rectum, prostate, and cervix, occurs more frequently than metastasis from distant organs, such as the breast. CASE PRESENTATION: We report a case of bladder metastasis identified during treatment for recurrent breast cancer. Fifteen years after her initial surgery, a known breast cancer patient complained of a left lower abdominal pain, anuria, and body swelling. Computed tomography imaging revealed an irregular thickening of the left bladder wall, left hydronephrosis, and hydroureter. A bladder metastasis from breast cancer was diagnosed based on a histological examination of a cystoscopic biopsy specimen. She is currently receiving chemotherapy with eribulin mesylate. CONCLUSIONS: Routine screening of the lower urinary tract is not necessary for all patients, but women with a history of breast cancer presenting with urinary symptoms should undergo a thorough examination of the urinary tract. PMID- 29987654 TI - A vascular endothelial growth factor receptor gene variant is associated with susceptibility to acute respiratory distress syndrome. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is one of the main causes of mortality in adults admitted to intensive care units. Previous studies have demonstrated the existence of genetic variants involved in the susceptibility and outcomes of this syndrome. We aimed to identify novel genes implicated in sepsis-induced ARDS susceptibility. METHODS: We first performed a prioritization of candidate genes by integrating our own genomic data from a transcriptomic study in an animal model of ARDS and from the only published genome-wide association study of ARDS study in humans. Then, we selected single nucleotide polymorphisms (SNPs) from prioritized genes to conduct a case-control discovery association study in patients with sepsis-induced ARDS (n = 225) and population-based controls (n = 899). Finally, we validated our findings in an independent sample of 661 sepsis-induced ARDS cases and 234 at-risk controls. RESULTS: Three candidate genes were prioritized: dynein cytoplasmic-2 heavy chain 1, fms-related tyrosine kinase 1 (FLT1), and integrin alpha-1. Of those, a SNP from FLT1 gene (rs9513106) was associated with ARDS in the discovery study, with an odds ratio (OR) for the C allele of 0.76, 95% confidence interval (CI) 0.58 0.98 (p = 0.037). This result was replicated in an independent study (OR = 0.78, 95% CI = 0.62-0.98, p = 0.039), showing consistent direction of effects in a meta analysis (OR = 0.77, 95% CI = 0.65-0.92, p = 0.003). CONCLUSIONS: We identified FLT1 as a novel ARDS susceptibility gene and demonstrated that integration of genomic data can be a valid procedure to identify novel susceptibility genes. These results contribute to previous firm associations and functional evidences implicating FLT1 gene in other complex traits that are mechanistically linked, through the key role of endothelium, to the pathophysiology of ARDS. PMID- 29987657 TI - Characterization of doxycycline-loaded calcium phosphate cement: implications for treatment of aneurysmal bone cysts. AB - Percutaneous doxycycline for treatment for aneurysmal bone cysts (ABCs) has been shown to decrease recurrence rates, however, this requires multiple procedures, includes the risks soft tissue necrosis, and does not provide structural support. We propose utilizing curettage with doxycycline-loaded calcium phosphate cement. This study aimed to evaluate the elution profile of doxycycline from calcium phosphate cement. Calcium phosphate cement underwent an in vitro elution protocol evaluating doxycycline concentrations of 0, 5, 10, and 15 mg/mL. Eluted concentrations were quantified utilizing high performance liquid chromatography at predetermined time points over 96 h. Compressive strength was evaluated both pre- and post-elution and micro-computed tomography was utilized to assess changes in cement porosity. Cement with 15 mg/mL of doxycycline maintained a higher average concentration (mean, 95% confidence intervals) (14.5 ug/mL [9.2 19.9 ug/mL]) compared to both 5 mg/mL (5.8 ug/mL [3.1-8.6 ug/mL]; P < 0.001) and 10 mg/mL (8.4 +/- ug/mL [6.0-10.9 ug/mL]; P < 0.001). Ultimate stress significantly decreased between pre- and post-elution samples for 10 mg/mL (P= 0.001) and 15 mg/mL (P = 0.004) groups. This study demonstrated a dose-dependent response in ultimate strength and compressive modulus with addition of doxycycline to calcium phosphate cement. PMID- 29987658 TI - Electrical tree inhibition by SiO2/XLPE nanocomposites: insights from first principles calculations. AB - It has been extensively observed in experiments that nanoparticle additives can efficiently inhibit the electrical tree growth of the cross-linked polyethylene (XLPE) matrix of power cables. Inspired by this, the first-principles calculations employing the density functional theory (DFT) method were performed in this study to investigate the significant role of SiO2 nanosized fillers as a voltage stabilizer for power cable insulation. Several different types of alpha SiO2 fillers, including hydroxylated, reconstructed, doped or oxygen vacancy surface structures, were constructed to model the interfacial interaction for SiO2/XLPE nanocomposites. It is found that the SiO2 additives can restrict the movement of the polyethylene chain through van der Waals physical interaction. More importantly, based on the Bader charge analysis we reveal that SiO2 could effectively capture hot electrons to suppress space charge accumulation in XLPE. However, some particular modified-surface SiO2, such as incompletely hydroxylated, B-doped, and oxygen vacancy defect on the top layer, could induce the H migration reaction and consequent electrical tree growth of the XLPE chain. In contrast, the SiO2 particles that have N-doped or oxygen vacancy on the lower layer with completely hydroxylated surfaces, as well as the reconstructed surface, are predicted to be favorable additives because of their quite strong physical interaction and very weak chemical activity with XLPE. The present study is useful to understand the mechanism of the nanosized voltage stabilizer and also provide important information for further experimental investigation. PMID- 29987659 TI - The social value of pharmaceutical interventions, the Portuguese contribution to sustainable development. AB - This commentary focuses on a description of solidarity initiatives developed by pharmacists in different practice areas. These are varied initiatives which contribute to improve the life of human beings in a wide range of formats with one common vector, the pharmacist's involvement. Each of the initiatives described is related to the sustainable development goal it contributes to, whilst also referring to its link to international health policy documents, mostly issued by FIP. We expect this commentary further contributes to boost such initiatives in other parts of the world. PMID- 29987660 TI - Medical Malpractice Trends: Errors in Automated Speech Recognition. PMID- 29987661 TI - Method for Quantifying Oxidized Methionines and Application to HIV-1 Env. AB - Recombinantly expressed proteins are susceptible to oxidation during expression, purification, storage, and analysis; the residue most susceptible to oxidation is methionine. Methionine oxidation can be overestimated using current quantitative analysis methods because oxidation can occur during sample preparation, and researchers often do not use methods that account for this possibility. An experimental strategy had been developed previously to solve this problem through the use of an 18O-labeled hydrogen peroxide reagent. However, the method did not address the analysis of peptides that contained multiple methionine residues. Herein, we develop and validate a new analysis method that uses theoretical isotope distributions and experimental spectra to quantify methionine oxidation that is present prior to sample preparation. The newly described approach is more rapid than the previously described method, and it needs only half the amount of protein for analysis. This method was validated using model proteins; then, it was applied to the analysis of recombinant HIV-1 Env, the key protein in HIV vaccine candidates. While Met oxidation of this protein could not be analyzed using previous methods, the approach described herein was useful for determining the oxidation state of HIV-Env. Graphical Abstract ?. PMID- 29987662 TI - Using Digital Waveforms to Mitigate Solvent Clustering During Mass Filter Analysis of Proteins. AB - With advances in the precision of digital electronics, waveform generation technology has progressed to a state that enables the creation of m/z filters that are purely digitally driven. These advances present new methods of performing mass analyses that provide information from a chemical system that are inherently difficult to achieve by other means. One notable characteristic of digitally driven mass filters is the capacity to transmit ions at m/z ratios that vastly exceed the capabilities of traditional resonant systems. However, the capacity to probe ion m/z ratios that span multiple orders of magnitudes across multiple orders of magnitude presents a new set of issues requiring a solution. In the present work, when probing multiply charged protein species beyond m/z 2000 using a gentle atmospheric pressure interface, the presence of solvent adducts and poorly resolved multimers can severely degrade spectral fidelity. Increasing energy imparted into a target ion population is one approach minimizing these clusters; however, the use of digital waveform technology provides an alternative that maximizes ion transport efficiency and simultaneously minimizes solvent clustering. In addition to the frequency of the applied waveform, digital manipulation also provides control over the duty cycle of the target waveform. This work examines the conditions and approach leading to optimal digital waveform operation to minimize solvent clustering. Graphical Abstract ?. PMID- 29987663 TI - Optimized Electrostatic Linear Ion Trap for Charge Detection Mass Spectrometry. AB - In charge detection mass spectrometry (CDMS), ions are passed through a detection tube and the m/z ratio and charge are determined for each ion. The uncertainty in the charge and m/z determinations can be dramatically reduced by embedding the detection tube in an electrostatic linear ion trap (ELIT) so that ions oscillate back and forth through the detection tube. The resulting time domain signal can be analyzed by fast Fourier transforms (FFTs). The ion's m/z is proportional to the square of the oscillation frequency, and its charge is derived from the FFT magnitude. The ion oscillation frequency is dependent on the physical dimensions of the trap as well as the ion energy. A new ELIT has been designed for CDMS using the central particle method. In the new design, the kinetic energy dependence of the ion oscillation frequency is reduced by an order of magnitude. An order of magnitude reduction in energy dependence should have led to an order of magnitude reduction in the uncertainty of the m/z determination. In practice, a factor of four improvements was achieved. This discrepancy is probably mainly due to the trajectory dependence of the ion oscillation frequency. The new ELIT design uses a duty cycle of 50%. We show that a 50% duty cycle produces the lowest uncertainty in the charge determination. This is due to the absence of even-numbered harmonics in the FFT, which in turn leads to an increase in the magnitude of the peak at the fundamental frequency. Graphical Abstract ?. PMID- 29987664 TI - Disulfide Connectivity Analysis of Peptides Bearing Two Intramolecular Disulfide Bonds Using MALDI In-Source Decay. AB - Disulfide connectivity in peptides bearing at least two intramolecular disulfide bonds is highly important for the structure and the biological activity of the peptides. In that context, analytical strategies allowing a characterization of the cysteine pairing are of prime interest for chemists, biochemists, and biologists. For that purpose, this study evaluates the potential of MALDI in source decay (ISD) for characterizing cysteine pairs through the systematic analysis of identical peptides bearing two disulfide bonds, but not the same cysteine connectivity. Three different matrices have been tested in positive and/or in negative mode (1,5-DAN, 2-AB and 2-AA). As MALDI-ISD is known to partially reduce disulfide bonds, the data analysis of this study rests firstly on the deconvolution of the isotope pattern of the parent ions. Moreover, data analysis is also based on the formed fragment ions and their signal intensities. Results from MS/MS-experiments (MALDI-ISD-MS/MS) constitute the last reference for data interpretation. Owing to the combined use of different ISD-promoting matrices, cysteine connectivity identification could be performed on the considered peptides. Graphical Abstract ?. PMID- 29987665 TI - Proliferative glomerulonephritis with unusual microlamellar organized deposits related to monoclonal immunoglobulin G3 (IgG3) kappa. AB - A 71-year-old woman presented with massive proteinuria and microhematuria. Renal biopsy showed diffuse global membranoproliferative and endocapillary proliferative lesions with leukocytic infiltration and an irregular duplication of the glomerular basement membrane on light microscopy. Immunofluorescence study showed granular deposits of monoclonal immunoglobulin G3 (IgG3) kappa, C3, and C1q in the glomeruli. Electron microscopy revealed unique structurally organized microlamellar electron-dense deposits. There was no evidence of systemic diseases such as paraproteinemia, cryoglobulinemia, or systemic lupus erythematosus. Following renal biopsy, the oral administration of mizoribine in addition to predonisolone gradually improved the patient's clinical status. So far, partial remission has continued for a year, and she has not been affected with hematopoietic or lymphoproliferative disorders. We report a case of proliferative glomerulonephritis with unusual microlamellar organized deposits related to monoclonal IgG3 kappa. Our case was immunologically identical to proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID). Therefore, we concluded that our case should be categorized as an atypical form of PGNMID, though it was difficult to diagnose using the usual diagnostic approach to glomerular diseases with organized deposits. PMID- 29987666 TI - Ruptured infected aneurysm of the thoracic aorta associated with tunneled dialysis catheter-related methicillin-resistant Staphylococcus aureus bacteremia in a hemodialysis patient. AB - Patients with an indwelling tunneled dialysis catheter (TDC) for hemodialysis access are at a high risk of developing methicillin-resistant Staphylococcus aureus (MRSA) infection. MRSA bacteremia complications rarely include infected aneurysm. Here, we report the first case of an infected thoracic aneurysm associated with TDC-related MRSA bacteremia. An 86-year-old Japanese male with a TDC for hemodialysis access developed TDC-related MRSA bacteremia. Intravenous vancomycin was initiated, and the TDC was removed on day 3. Despite removal of the catheter and initiation of vancomycin treatment, MRSA bacteremia persisted. Chest computed tomography (CT) showed no aneurysm; however, calcification of the thoracic aorta was detected on admission. The patient subsequently developed hemosputum. CT revealed a thoracic aneurysm, which turned out to be caused by MRSA bacteremia. The patient eventually died because of the rupture of the infected aneurysm, as confirmed by autopsy. This report demonstrates TDC management in a patient with TDC-related MRSA bacteremia and the importance of investigating a metastatic infection to a calcified artery if bacteremia persists. PMID- 29987667 TI - Correction to: Predictive and prognostic clinical and pathological factors of nivolumab efficacy in non-small-cell lung cancer patients. AB - Clinical and Translational Oncology. PMID- 29987668 TI - Knowledge, experiences and attitudes of dental and health care personnel in Sweden towards infant dental enucleation. AB - PURPOSE: To examine self-rated knowledge of clinical experiences and attitudes towards the practice of infant dental enucleation among dental and health care personnel in Sweden. METHODS: A questionnaire survey was performed among 776 licensed dental and health care personnel working in emergency departments, midwifery, child health centres, school health services and public dental health services in 10 Swedish cities. The response rate was 56.2% (n = 436). RESULTS: Fewer than a fifth of the respondents reported self-rated knowledge of the practice. Approximately 13% of personnel encountering children professionally believed they had seen subjected patients in their clinical practice. Personnel with self-rated knowledge and clinical experience worked mostly in dental care. Additionally, the personnel had diverging attitudes regarding agreement and disagreement concerning professional responsibility for patients subjected to or at risk of infant dental enucleation. CONCLUSIONS: The study indicated there is need for increased knowledge about the practice and for clarification of obligatory responsibilities among dental and health care personnel regarding management and prevention of cases of infant dental enucleation. PMID- 29987669 TI - Horner syndrome in ipsilateral lenticulostriate stroke: a novel localization for a classic stroke syndrome. AB - Horner's syndrome has important localizing and etiological value in acute ischemic stroke. In a prospective series of consecutive acute ischemic stroke patients, we identified three patients with Horner's syndrome and contralateral hemiparesis due to ipsilateral small deep infarction in the middle cerebral artery territory (lenticulostriate arteries). Lacunar stroke was the most likely stroke mechanism in all three patients. This observation might suggest the existence of an uncrossed cortico-hypothalamic sympathetic pathway passing through the basal ganglia and modulating oculosympathetic function. PMID- 29987670 TI - Correction to: Efficacy and Safety of Sublingual Fentanyl Tablets in Breakthrough Cancer Pain Management According to Cancer Stage and Background Opioid Medication. AB - In the Original Publication. PMID- 29987671 TI - The therapeutic targeting of the FGFR1/Src/NF-kappaB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity. AB - The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF kappaB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH-) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-kappaB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFkappaB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-kappaB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the 'difficult-to-treat', 'quick-to-relapse' PDAC patients. Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-kappaB signaling axis and activation of the cell death signaling pathway. PMID- 29987672 TI - Correction to: Geographic region, socioeconomic position and the utilisation of primary total joint replacement for hip or knee osteoarthritis across western Victoria: a cross-sectional multilevel study of the Australian Orthopaedic Association National Joint Replacement Registry. AB - The names of the co-authors Steven Graves and Michelle Lorimer were missing from the manuscript supplied for publication. The lead authors regret this error and apologize for any inconvenience. PMID- 29987673 TI - Macular staphyloma in patients affected by Joubert syndrome with retinal dystrophy: a new finding detected by SD-OCT. AB - PURPOSE: Joubert syndrome (JS) is an inherited autosomal recessive or X-lined disorder characterized by a congenital malformation of the mid-hindbrain and a large spectrum of clinical features. It is estimated that retinal dystrophy is present in association with the typical neurological findings in about one-third of the patients. The aim of this study is to better characterize the macular region in JS patients with and without retinal dystrophy. METHODS: We describe six individuals affected by JS as demonstrated by the presence of the typical "molar tooth sign" on MRI. The presence of retinal dystrophy was assessed by fundus examination and electrophysiology by means of full-field electroretinogram (ERG) and visual evoked potentials (VEP) at five spatial frequencies (300-15 min of arc). The macular region was examined with spectral domain optical coherence tomography (SD-OCT). All the exams were performed in awake conditions. All the patients underwent next-generation-sequencing analysis of known JS genes. RESULTS: Pathogenic biallelic variants in either the INPP5E gene or the AHI1 gene were detected in two pairs of siblings, all positive for retinal dystrophy. Genetic testing yielded no results in the remaining two patients, one with bilateral coloboma and retinal dystrophy and the other with normal fundus appearance. Decimal best-corrected visual acuity was between 0.1 and 1.0. In the two pairs of siblings, SD-OCT revealed a posterior staphyloma centred on the fovea, in one case associated with cystoid macular oedema. Macular morphology was just slightly altered in the fifth patient and completely normal in the last patient. Refractive error was between + 2.50 diopter sphere (DS) and - 8 DS and - 4 diopter cylinder ax 45 degrees . ERG waves were markedly lower than the normal limits in both scotopic and photopic components in the two pairs of siblings and in the fifth subject, with VEP P100 latencies and amplitudes delayed and reduced in all spatial frequencies. ERG and VEP were within normal limits in the last patient. CONCLUSIONS: To our knowledge, macular staphyloma has not been described before in JS. Further work is warranted to assess the true prevalence of staphyloma in JS and its connection to retinal dystrophy. PMID- 29987674 TI - Correction to: The Effectiveness of Resisted Sled Training (RST) for Sprint Performance: A Systematic Review and Meta-analysis. AB - Page 1: Abstract, Conclusions, sentence 4. The following sentence, which read. PMID- 29987675 TI - International Paralympic Committee (IPC) and International Blind Sports Federation (IBSA) Joint Position Stand on the Sport-Specific Classification of Athletes with Vision Impairment. AB - Classification is a defining characteristic of para-sports whereby eligible athletes are allocated a sport class to compete against others with similar activity limitations. To account for the unique characteristics of each sport, para-sports should develop their own classification system using evidence that demonstrates the impact of impairment on performance in that sport. Although the move towards sport-specific classification has progressed in sports for athletes with physical and intellectual impairments, sports for athletes with vision impairment (VI) continue to use the same three classes irrespective of the sport, with classes delineated by legal definitions of low vision and blindness. The aim of this joint International Paralympic Committee/International Blind Sports Federation (IPC/IBSA) Position Stand is to provide guidance for how evidence based sport-specific classification should be achieved in VI sports. It does so by outlining three conceptual research models (correlation, simulation, and component analysis) that can be used to establish both the minimum impairment required to compete plus the appropriate number of sport classes and their inclusion criteria. The present evaluation of vision relies on measures of visual acuity and field, but new criteria may require a sport-specific combination of additional measures of visual function (e.g. contrast, motion, and light sensitivity) to better account for the impact of VI on sport performance. Moreover, the test procedures used during athlete evaluation (e.g. whether to evaluate both eyes individually or together) should be chosen to better represent the habitual viewing situation experienced in that sport. The development of sport-specific criteria should enhance the legitimacy of competition and encourage increased grassroots participation in VI sports. PMID- 29987677 TI - Biography: Joel Faintuch, MD, PhD. PMID- 29987676 TI - Head and Neck Cancer Survivorship Care: A Review of the Current Guidelines and Remaining Unmet Needs. AB - OPINION STATEMENT: A larger proportion of patients with head and neck cancers (HNC) are now surviving, constituting up to 3% of all cancer survivors. This is likely due in part to the increase in HPV-related oropharyngeal cancers affecting younger individuals and with a better prognosis and to the improved outcomes of other HNCs as well over the last two decades. Most studies have previously been focusing on improving risk stratification, treatment and disease-related outcomes. Over the last decade, there has been an evolving interest in the field of survivorship care. Despite the collaborative efforts from a multidisciplinary team in managing cancer and treatment-related side-effects and in improving survivors' overall quality of life (QOL), it has been reported that up to 60-65% of patients have at least one unmet need. The purpose of this article is to review current guidelines for HNC survivorship care and identify areas of unmet need. Over the last 5 years, multiple groups have published guidelines describing survivorship care issues and their possible management. Although a very comprehensive and informative first initiative, multiple issues need to be further evaluated. These include how to best support patients and their partners' fear of cancer recurrence, to provide coordinated care among all physicians, to identify and meet patients' needs in local multidisciplinary teams and to institute measures to ensure every individual's access to high-quality patient centred care. Furthermore, experts may consider engaging in further dialog with primary care physicians (PCP) to improve sharing of survivorship care. More should be learned about PCPs' comfort levels in providing such care and whether further steps are required to facilitate a seamless. Transition of care and accessibility to specialized care as needed. PMID- 29987678 TI - Increased Bile Acids and FGF19 After Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Correlate with Improvement in Type 2 Diabetes in a Randomized Trial. AB - BACKGROUND: Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) are both effective bariatric procedures to treat type 2 diabetes (T2DM) and obesity. The contribution of changes in bile acids (BAs) and fibroblast growth factor19 (FGF19) to such metabolic improvements is unclear. METHODS: We examined associations between changes in BAs, FGF19 (fasting and prandial), with changes in body weight, glycemia, and other metabolic variables in 61 obese patients with T2DM before and 1 year after randomization to SG or RYGB. RESULTS: Weight loss and diabetes remission (defined by HbA1c < 39 mmol/mol [< 5.7%] in the absence of glucose-lowering therapy) after RYGB and SG was similar (mean weight loss - 29 vs - 31 kg, p = 0.50; diabetes remission proportion 37.5 vs 34%, p = 1.0). Greater increments in fasting and prandial levels of total, secondary, and unconjugated BAs were seen after RYGB than SG. Fasting and prandial increases in total (r = - 0.3, p = 0.01; r = - 0.2, p = 0.04), secondary (r = - 0.3, p = 0.01; r = - 0.4, p = 0.01) and unconjugated BA (r = - 0.3, p = 0.01; r = 0.4, p < 0.01) correlated with decreases in HbA1c, but not weight. Changes in 12alpha-OH/non 12alpha-OH were positively associated with prandial glucose increments (r = 0.2, p = 0.03), HbA1c (r = 0.3, p = 0.01), and negatively associated with changes in insulinogenc index (r = - 0.3, p = 0.01). Only changes in prandial FGF19 were negatively associated with HbA1c (r = - 0.4, p < 0.01) and visceral fat (r = - 0.3, p = 0.04). CONCLUSIONS/INTERPRETATION: The association between increases in secondary, unconjugated BAs and improvements in HBA1c (but not weight) achieved after both RYGB and SG suggest manipulation of BA as a potential strategy for controlling T2DM through weight-independent means. PMID- 29987679 TI - Laparoscopic Sleeve Gastrectomy in Patients with Situs Inversus. AB - BACKGROUND: Situs inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. Situs inversus is found in about 0.01% of the population. In the most common situation, situs inversus totalis involves complete transposition (right to left reversal) of all of the abdominal organs. Several successful and safe laparoscopic weight loss surgeries were previously reported in morbidly obese patients with situs inversus (Aziret et al. Obes Res Clin Pract. 32;11(5S1):144-51, 2017; Catheline et al. Obes Surg.;16(8):1092-5, 2006). METHODS: We present a case of a 47-year-old female patient with a BMI of 51 kg/m2, who was referred to our clinic for the treatment of morbid obesity. Her past medical history included hypertension, type II diabetes mellitus, asthma, and situs inversus. During the preoperative evaluation, the chest x-ray showed dextrocardia and upper GI series showed the stomach and duodenum in a mirror position. RESULTS: The operative time was 62 min, oral intake started on postoperative day 1, and the patient was discharged on postoperative day 2 in good medical condition. CONCLUSIONS: Situs inversus is a rare condition that can be challenging for a laparoscopic surgeon. LSG is feasible and safe for morbidly obese patients with this anomaly. Well understanding of the mirrored image anatomy will facilitate the performance of the procedure without special difficulties by an experienced surgeon. PMID- 29987681 TI - A clinical analysis of 114 cases of sarcomatoid carcinoma of the lung. AB - The aim was to investigate the clinicopathological characteristics, diagnosis, and prognosis of sarcomatoid carcinoma of the lung. We reviewed 114 cases of sarcomatoid carcinoma of the lung in patients that were admitted to the First Affiliated Hospital of Zhengzhou University and Anyang Tumor Hospital from January 2009 to March 2018. We analyzed the clinical characteristics, immunohistochemical profiles, treatments, and overall survival of the patients. The patient population included 88 men and 26 women. Median patient age was 65 years (range 37-88 years), and the gender ratio (M/F) was 3.4:1. Median survival was 3.5 months (range 0.5-60 months). Univariate analysis showed that tumor location, tumor size, M stage, TNM stage, chemotherapy, and surgery were all prognostic factors for survival (P < 0.05). We found that T stage, surgery, and chemotherapy were independent prognostic factors for sarcomatoid carcinoma (P < 0.05). Pulmonary sarcomatoid carcinoma is a rare tumor with a poor prognosis. Patients with smaller T stage, complete resection, and chemotherapy exhibited a better prognosis. Early diagnosis and early treatment are important to improve the prognosis of these patients. PMID- 29987680 TI - A Review of Recent Advances in Ultrasound, Placed in the Context of Pain Diagnosis and Treatment. AB - Ultrasound plays a significant role in the diagnosis and treatment of pain, with significant literature reaching back many years, especially with regard to diagnostic ultrasound and its use for guiding needle-based delivery of drugs. Advances in ultrasound over at least the last decade have opened up new areas of inquiry and potential clinical efficacy in the context of pain diagnosis and treatment. Here we offer an overview of the recent literature associated with ultrasound and pain in order to highlight some promising frontiers at the intersection of these two subjects. We focus first on peripheral application of ultrasound, for which there is a relatively rich, though still young, literature. We then move to central application of ultrasound, for which there is little literature but much promise. PMID- 29987682 TI - Atrial resynchronization therapy in patients with atrial fibrillation and heart failure with and without systolic left ventricular dysfunction: a pilot study. AB - BACKGROUND: We examined the long-term (>= 5 years) outcomes of dual-site atrial pacing (DAP) when added to background antiarrhythmic drugs (AADs) and/or ablation in patients with refractory atrial fibrillation (AF) and heart failure (HF). METHODS: Seventy-three patients with HF (mean NYHA HF class of 2.5) and AF refractory to AADs and/or ablation were implanted with DAP systems to achieve biatrial electrical and mechanical resynchronization (ART) and rhythm control (RC). RESULTS: Thirty-eight patients with refractory AF and HF with preserved ejection fraction (HFpEF) and 35 with reduced ejection fraction (HFrEF) were enrolled. HFpEF patients had higher left ventricular ejection fraction compared to HFrEF (53 +/- 5 vs. 31 +/- 10% p < 0.001). Median follow-up for survival was 9.3 years (mean 9.0 years, SE 0.63) and was similar across subgroups (p = 0.127). After DAP, 87% maintained RC with improvement in NYHA HF class (mean 1.8) at 3 years. RC was similar in HFpEF compared with HFrEF patients (89 vs. 85% respectively, p = NS) and in paroxysmal versus persistent AF (90 vs. 85% respectively, p = NS). Total survival was superior in HFpEF compared HFrEF patients (75% in HFpEF vs. 45% in HFrEF at 5 years, and 60% in HFpEF vs. 34% in HFrEF at 10 years, p = 0.036). Survival trended to be better in patients with RC than those without RC (75 vs. 54% respectively at 5 years, p = .13). CONCLUSIONS: ART using DAP as add on therapy improved HF and established long-term RC in many patients with HFrEF and HFpEF with refractory AF. Long-term survival rates were superior in HFpEF than HFrEF. PMID- 29987683 TI - Patient Reported Improvement After Patch Testing and Allergen Avoidance Counseling: A Retrospective Analysis. AB - INTRODUCTION: Our objectives were to assess patient-reported improvement after patch testing at the 2-3-month follow-up visit in patients referred for patch testing with relevant positive patch test reactions at the University of California, San Francisco. METHODS: Cross-sectional analyses of patients patch tested between 2013 and 2016 who returned for a follow-up visit approximately 2-3 months after patch testing. We examined positive patch test results considered of definite, probable or possible relevance to the patient's eczematous eruptions. Patients reported improvement after patch testing as a percentage: 0-100%. Patients were categorized into four groups: (1) those that reported no improvement or worsened, (2) those that reported > 0% and <= 60% improvement, (3) those that reported > 60% but < 100% improvement and (4) those that reported 100% improvement. Secondary measures included the association of allergens, gender, age and location of the rash. RESULTS: The majority (81%) of patients seen at follow-up reported improvement after patch testing. Women reported more improvement than men with statistical significance. Notably, there does not appear to be a statistically significant relationship in patient-reported improvement and age, atopy, strength of a the patient's positive reactions, number of positive reactions and follow-up time or with potential systemic contact allergens (i.e., balsam of Peru, nickel, chrome and cobalt). CONCLUSION: We find the large percentage of patients that self-report global benefit from patch testing encouraging, as we believe this to be a powerful measure of disease and symptom activity, as well as quality of life. The gender differences we found contradict the previous literature. PMID- 29987684 TI - Genetic diversity of bovine Picobirnavirus, Brazil. AB - Picobirnaviruses (PBVs) are emerging and opportunistic viruses with possible zoonotic potential. In this study, we present the detection, molecular characterization, and genotypic differentiation of PBVs from genogroup I in bovine stool samples from different Brazilian regions. A high proportion of PCR positive samples (23.4%) was detected in a total of 77 analyzed. Nucleotide identity, alignment, and phylogenetic analyses revealed high diversity among the studied sequences. The results obtained indicate, for the first time, the circulation of bovine PBVs belonging to genogroup I in different Brazilian states, with heterogeneous phylogenetic-clustering profiles. PMID- 29987685 TI - Correction to: Influence of Single-Dose Antibiotic Prophylaxis for Early-Onset Pneumonia in High-Risk Intubated Patients. AB - Due to an error introduced during the production process, J. Dedrick Jordan's name was improperly tagged in the original publication of this article. It is tagged correctly here. PMID- 29987686 TI - Effect of Intra-aortic Balloon Pump on Reversal of Diastolic Cerebral Flow: Deflated Too Early? PMID- 29987687 TI - Plastic in the Brain: Delayed Recognition of Progressive Unilateral Hemispheric Lesions. AB - BACKGROUND: Flow diverters are increasingly used to treat complex ruptured intracranial aneurysms. Most complications are ischemic and seen early after placement. METHODS: We present a patient with 3 year duration of neurologic symptoms and seizures as a result of lesions associated with a inflammatory response to embolized polymer coating. RESULTS: Over a period of 3 years MRI abnormalities were noted with substantial gadolinium enhancement of the stent but with resolution after corticosteroids. CONCLUSION: Polymer embolization associated with a flow diverter may cause fluctuating unilateral hemisheric lesions and become symptomatic. Inflammatory response to a foreign body (polymer strands) can be succesfully treated with corticosteroids. PMID- 29987688 TI - Continuous Assessment of "Optimal" Cerebral Perfusion Pressure in Traumatic Brain Injury: A Cohort Study of Feasibility, Reliability, and Relation to Outcome. AB - BACKGROUND: Guidelines recommend maintaining cerebral perfusion pressure (CPP) between 60 and 70 mmHg in patients with severe traumatic brain injury (TBI), but acknowledge that optimal CPP may vary depending on cerebral blood flow autoregulation. Previous retrospective studies suggest that targeting CPP where the pressure reactivity index (PRx) is optimized (CPPopt) may be associated with improved recovery. METHODS: We performed a retrospective cohort study involving TBI patients who underwent PRx monitoring to assess issues of feasibility relevant to future interventional studies: (1) the proportion of time that CPPopt could be detected; (2) inter-observer variability in CPPopt determination; and (3) agreement between manual and automated CPPopt estimates. CPPopt was determined for consecutive 6-h epochs during the first week following TBI. Sixty PRx-CPP tracings were randomly selected and independently reviewed by six critical care professionals. We also assessed whether greater deviation between actual CPP and CPPopt (DeltaCPP) was associated with poor outcomes using multivariable models. RESULTS: In 71 patients, CPPopt could be manually determined in 985 of 1173 (84%) epochs. Inter-observer agreement for detectability was moderate (kappa 0.46, 0.23-0.68). In cases where there was consensus that it could be determined, agreement for the specific CPPopt value was excellent (weighted kappa 0.96, 0.91-1.00). Automated CPPopt was within 5 mmHg of manually determined CPPopt in 93% of epochs. Lower PRx was predictive of better recovery, but there was no association between DeltaCPP and outcome. Percentage time spent below CPPopt increased over time among patients with poor outcomes (p = 0.03). This effect was magnified in patients with impaired autoregulation (defined as PRx > 0.2; p = 0.003). CONCLUSION: Prospective interventional clinical trials with regular determination of CPPopt and corresponding adjustment of CPP goals are feasible, but measures to maximize consistency in CPPopt determination are necessary. Although we could not confirm a clear association between DeltaCPP and outcome, time spent below CPPopt may be particularly harmful, especially when autoregulation is impaired. PMID- 29987689 TI - Long-Term Outcomes in Patients with Anemia And Cerebral Venous Thrombosis. AB - BACKGROUND: Anemia is associated with unfavorable functional outcome in ischemic and hemorrhagic stroke. However, the relationship between anemia and prognosis in patients with cerebral venous thrombosis (CVT) has not been studied. METHODS: Consecutive CVT patients were retrospectively identified from November 2011, through January 2017. Anemia was defined according to the World Health Organization criteria (non-pregnant female hemoglobin level < 120 g/L, pregnant female < 110 g/L and male < 130 g/L), which was further classified as mild, moderate, and severe anemia according to hemoglobin concentration, and as microcytic, normocytic, and macrocytic anemia according to mean corpuscular volume. Unfavorable outcome was defined as modified Rankin Scale (mRS) of 3-6. Factors such as age, sex, coma, malignancy, intracerebral hemorrhage, and straight sinus and/or deep CVT involved, premorbid mRS were adjusted to evaluate the relationship between anemia and prognosis in CVT patients. RESULTS: A total of 238 CVT patients were included, among whom 73 patients (30.67%) were diagnosed with anemia. Multivariate logistic regression analysis showed that patients with anemia had a higher risk of mRS of 3-6 (OR = 3.62; 95% CI, 1.45-9.01; P = 0.006) and mortality (OR = 5.46; 95% CI, 1.90-15.70; P = 0.002). Subgroup analysis showed that severe anemia was independently associated with mRS of 3-6 (OR = 8.80; 95% CI, 1.90-40.81; P = 0.005) and mortality (OR = 9.82; 95% CI, 1.81 53.25; P = 0.010). Similarly, microcytic anemia increased the risk of mRS of 3-6 (OR = 4.64; 95% CI, 1.48-14.52; P = 0.008) and mortality (OR = 9.68; 95% CI, 2.61 35.91; P = 0.001). In addition, our study also revealed that lower hemoglobin level, evaluated as a continuous variable, was inversely associated with mRS of 3 6 (OR = 0.98; 95% CI, 0.96-0.99; P = 0.007) and mortality (OR = 0.97; 95% CI, 0.95-0.99; P = 0.005). CONCLUSIONS: Anemia was a significant and independent predictor of unfavorable functional outcome in patients with CVT. PMID- 29987690 TI - Hyperbaric Oxygen Protects Against Cerebral Damage in Permanent Middle Cerebral Artery Occlusion Rats and Inhibits Autophagy Activity. AB - BACKGROUND: To investigate the effects of hyperbaric oxygen (HBO) on brain damage and autophagy levels in a rat model of middle cerebral artery occlusion. METHODS: Neurologic injury and infarcted areas were evaluated according to the modified neurological severity score and 2,3,5-triphenyltetrazolium chloride staining. Western blots were used to determine beclin1, caspase-3 and fodrin1 protein expression. Beclin1 protein expression (an autophagy marker), positive terminal dUTP nick-end labeling (TUNEL) staining (an apoptosis marker) and positive propidium iodide (PI) staining (a necrosis marker) were detected by immunofluorescence. RESULTS: Our results indicated that HBO could decrease the infarct volume and speed up the recovery of the neurological deficit scores in ischemic rats. Beclin1 was down-regulated after HBO treatment. HBO treatment inhibited fodrin1 protein expression and decreased the number of PI-positive cells. HBO also down-regulated caspase-3 and decreased the number of TUNEL positive cells. CONCLUSION: Cerebral ischemia caused early neuronal death due to necrosis, followed by delayed neuronal death due to apoptosis. Consequently, autophagy might be involved in all processes of ischemia. HBO could protect the brain against ischemic injury, and the possible mechanisms might be correlated with decreased autophagy activity and decreased apoptosis and necrosis levels. PMID- 29987692 TI - Various epileptic seizure detection techniques using biomedical signals: a review. AB - Epilepsy is a chronic chaos of the central nervous system that influences individual's daily life by putting it at risk due to repeated seizures. Epilepsy affects more than 2% people worldwide of which developing countries are affected worse. A seizure is a transient irregularity in the brain's electrical activity that produces disturbing physical symptoms such as a lapse in attention and memory, a sensory illusion, etc. Approximately one out of every three patients have frequent seizures, despite treatment with multiple anti-epileptic drugs. According to a survey, population aged 65 or above in European Union is predicted to rise from 16.4% (2004) to 29.9% (2050) and also this tremendous increase in aged population is also predicted for other countries by 2050. In this paper, seizure detection techniques are classified as time, frequency, wavelet (time frequency), empirical mode decomposition and rational function techniques. The aim of this review paper is to present state-of-the-art methods and ideas that will lead to valid future research direction in the field of seizure detection. PMID- 29987691 TI - A Non-invasive Liquid Biopsy Screening of Urine-Derived Exosomes for miRNAs as Biomarkers in Endometrial Cancer Patients. AB - Exosomes have great potential to serve as a source of diagnostic and prognostic biomarkers for endometrial cancer (EC). Urine-derived exosomes from patients with EC and patients with symptoms of EC, but without established EC, were used to evaluate a unique miRNA expression profile. Of the 84 miRNA studied, 57 were amplified in qPCR, suggesting the differential packaging of miRNA in exosomes. Further, hsa-miR-200c-3p was identified to be enriched the most. Various bioinformatics and in silico tools were used to evaluate the biological significance of hsa-miR-200c-3p in EC. We conclude that differential miRNA in exosomes can be utilized for discovery of biomarker signatures and EC diagnosis; hsa-miR-200c-3p is one such candidate. Urine-derived exosomes pave the way for the development of non-invasive biomarkers. PMID- 29987694 TI - Sclerosing Microcystic Adenocarcinoma: Report of a Rare Case and Review of Literature. AB - Sclerosing microcystic adenocarcinoma is an exceedingly rare entity occurring in the mucosal surfaces of the head and neck that closely resembles cutaneous microcystic adnexal carcinoma. Here, we report a case of sclerosing microcystic adenocarcinoma that presented as a vague mass at the floor of the mouth in a 55 year-old woman. The pathology features and the diagnostic challenges, especially in the biopsy and margin evaluation are discussed here. Similar cases published in the English literatures are reviewed. PMID- 29987693 TI - Effects of rTMS on Hippocampal Endocannabinoids and Depressive-like Behaviors in Adolescent Rats. AB - Depression is a common mental disorder in adolescents, with a prevalence rate of 5.6%. Current anti-depressive options for adolescents are limited: psychological intervention and conventional antidepressants have low efficacy, a delayed onset of action and increased possibility of suicidal risk. Repetitive transcranial magnetic stimulation (rTMS) as an effective and noninvasive physical therapy for adult depression has been investigated in recent years. However, whether it also produces similar effects on juvenile depression and the underlying mechanism are not clearly understood. In this study, chronic unpredictable mild stress (CMS) was applied to 3-week-old male Sprague Dawley rats for 21 days. Then rTMS was performed for seven consecutive days, and the anti-depressive effects were evaluated by behavioral tests including the sucrose preference test (SPT), the forced swimming test (FST), and the novelty suppressed feeding test (NSF). Expression of hippocampal cannabinoid type I receptor (CB1R), 2 arachidonoylglycerol (2-AG) and relative synthetase and degradative enzymes diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) were also investigated. The behavioral parameters were also observed after the administration of the selective CB1 receptor antagonist AM251. The results showed that CMS induced a significant decrease in sucrose preference, a significant increase of immobility time in the FST, and an increased latency to feed in the NSF. In addition, reduced hippocampal CB1 receptor, 2-AG level and increased MAGL protein expression level were also observed in CMS rats. Meanwhile, rTMS treatment upregulated 2-AG level in the hippocampus and ameliorated depressive like behaviors. The anti-depressive effect of rTMS was attenuated by AM251, a specific CB1R antagonist that was administered 30 min before the onset of rTMS by either intraperitoneal administration or hippocampal microinjection. These results indicate that rTMS can be used as an antidepressive therapy for juvenile depression at least partly mediated by increasing hippocampal 2-AG and CB1 receptor expression levels. PMID- 29987695 TI - Robotic transanal minimally invasive surgery (TAMIS) for local excision of rectal lesions with the da Vinci Xi (dVXi): technical considerations and video vignette. AB - Robotic transanal minimally invasive surgery (TAMIS) (RT) represents a compelling new alternative capable of overcoming the limitations of conventional TAMIS for the local excision of rectal lesions. We describe our RT technique using the dVXiTM (Intuitive Surgical, Sunnyvale, CA, USA) which we have used to efficiently and completely excise eight cases of rectal lesions which were not endoscopically resectable. We also include a video vignette of the procedure. With the patient in the prone jackknife position, we insert a GelPOINTTM Path Transanal Access Platform (Applied Medical, Rancho Santa Margarita, CA, USA) in combination with the dVXi and AirSealTM insufflation system (Conmed, Niagara. Falls, ON, Canada). Our technique aims to be ergonomically efficient to minimise docking difficulties and to reduce instrument clash in the limited space, whilst maximising the capabilities of the dVXi for RT. At 3-month endoscopic follow-up, no evidence of recurrence was detected in any of the eight patients. RT is safe, feasible and has advantages over conventional laparoscopic TAMIS (LT). Our described technique addresses some of the long-standing challenges of LT and the novel RT. The immediate challenge to its widespread use remains the cost, expertise and availability. PMID- 29987696 TI - Effects of dietary manipulation on compensatory growth of juvenile genetically improved farmed tilapia (Oreochromis niloticus). AB - A 40-day feeding trial was conducted to investigate whether feeding a low-protein diet (25%) once daily for either 10 (L10H30) or 20 (L20H20) days then re-feeding a high-protein diet (35%) thrice daily elicit compensatory growth (CG) in genetically improved farmed tilapia (GIFT), Oreochromis niloticus (11.02 +/- 0.05 g). Fish on the control treatment were fed 35% protein diet over 40 days (H40). Fish were stocked into nine 100-L tanks (30 fish per tank) with 3 replicate tanks for each group. Growth performance, feed utilization, proximate composition of body compartment, serum biochemical parameters, and hepatopancreatic histology and expressions of some genes related to inflammatory cytokine were evaluated every 10 days. Growth of L10H30 fish were similar to the control, whereas the weight of L20H20 fish were lower (P < 0.05) at day 20, but this significant difference disappeared at the end of the experiment. During 20-30 days, specific growth rate and feed intake were significantly higher (P < 0.05) and feed efficiency was lower (P < 0.05) in L20H20 fish than those in H40 fish. Dietary manipulations did not affect (P > 0.05) viscerosomatic and hepatosomatic indices, condition factors, serum biochemical parameters, and hepatopancreatic histology. Significant differences (P < 0.05) in proximate composition were observed only in viscera and muscle between L20H20 fish and H40 fish at day 20. The mRNA expressions of heat shock protein 70 kDa, tumor necrosis factor-alpha and interleukin (IL)-1beta were higher (P < 0.05) in L10H30 and L20H20 fish at day 10, while IL-1beta mRNA expression was lower (P < 0.05) in L20H20 fish at day 30 than those in H40 fish. Our results indicated that L20H20 fish elicited a complete CG and induced reversible physiological variations in juvenile GIFT. PMID- 29987697 TI - Subtle Nanostructuring of the Au/Ru(0001) Surface. AB - We report on a scanning tunneling microscopy (STM) study of the nanostructuring of the Au/Ru(0001) thin film system for the cases of 5 monolayers (ML) and 9 ML of Au deposited at 300 K and subsequently annealed at 1050 K. A new laterally periodic superstructure is observed at the surface of the 9 ML film, which is essentially a rippling in height of the surface atomic layer with the magnitude up to 0.03 +/- 0.01 nm and in-plane periodicity of 4.6 +/- 0.4 nm, the long-range order being absent. PMID- 29987698 TI - Genome sequence comparison between Chinese hamster ovary (CHO) DG44 cells and mouse using end sequences of CHO BAC clones based on BAC-FISH results. AB - Chinese hamster ovary (CHO) cells have frequently been used in biotechnology as a mammalian host cell platform for expressing genes of interest. Previously, we constructed a detailed physical chromosomal map of the CHO DG44 cell line by fluorescence in situ hybridization (FISH) imaging using 303 bacterial artificial chromosome (BAC) clones as hybridization probes (BAC-FISH). BAC-FISH results revealed that the two longest chromosomes were completely paired. However, other chromosomes featured partial deletions or rearrangements. In this study, we determined the end sequences of 303 BAC clones (BAC end sequences), which were used for BAC-FISH probes. Among 606 BAC-end sequences (BESs) (forward and reverse ends), 558 could be determined. We performed a comparison between all determined BESs and mouse genome sequences using NCBI BLAST. Among these 558 BESs, 465 showed high homology to mouse chromosomal sequences. We analyzed the locations of these BACs in chromosomes of the CHO DG44 cell line using a physical chromosomal map. From the obtained results, we investigated the regional similarities among CHO chromosomes (A-T) and mouse chromosomes (1-19 and sex) about 217 BESs (46.7% of 465 high homologous BESs). Twenty-three specific narrow regions in 13 chromosomes of the CHO DG44 cell line showed high homology to mouse chromosomes, but most of other regions did not show significant correlations with the mouse genome. These results contribute to accurate alignments of chromosomes of Chinese hamster and its genome sequence, analysis of chromosomal instability in CHO cells, and the development of target locations for gene and/or genome editing techniques. PMID- 29987699 TI - The homeostatic ensemble for cells. AB - Cells are quintessential examples of out-of-equilibrium systems, but they maintain a homeostatic state over a timescale of hours to days. As a consequence, the statistics of all observables is remarkably consistent. Here, we develop a statistical mechanics framework for living cells by including the homeostatic constraint that exists over the interphase period of the cell cycle. The consequence is the introduction of the concept of a homeostatic ensemble and an associated homeostatic temperature, along with a formalism for the (dynamic) homeostatic equilibrium that intervenes to allow living cells to evade thermodynamic decay. As a first application, the framework is shown to accurately predict the observed effect of the mechanical environment on the in vitro response of smooth muscle cells. This includes predictions that both the mean values and diversity/variability in the measured values of observables such as cell area, shape and tractions decrease with decreasing stiffness of the environment. Thus, we argue that the observed variabilities are inherent to the entropic nature of the homeostatic equilibrium of cells and not a result of in vitro experimental errors. PMID- 29987700 TI - Comparison of HR-pQCT- and microCT-based finite element models for the estimation of the mechanical properties of the calcaneus trabecular bone. AB - The calcaneus bone is formed of extensive trabecular bone and is therefore well suited to be used as an example of loaded bone to establish the ability of combining microfinite element (microFE) technique with high-resolution peripheral quantitative computed tomography (HR-pQCT) in determining its mechanical properties. HR-pQCT is increasingly used as a tool for in vivo bone clinical research, but its use has been limited to the distal radius and tibia. The goal of this study was to determine the applicability of HR-pQCT-derived microFE models of the calcaneus trabecular bone with 82 MUm voxel size with reference to higher-resolution microCT-based models taken as gold standard. By comparing the outputs of microFE models generated from both HR-pQCT and microCT images of the trabecular bone of five calcaneus cadaveric specimens, it was found that the HR pQCT-based models predicted mechanical properties for fracture load, total reaction force and von Mises stress are considerably different from microCT-based counterparts by 33, 64 and 70%, respectively. Also, the morphological analysis showed a comprehensive geometrical difference between HR-pQCT-based microFE models and their microCT-based equivalents. The results of the HR-pQCT-based models were found to have strong dependency on the threshold value chosen to binarise the images prior to finite element modelling. In addition, it was found that the voxel size has a strong impact on accuracy of imaged-based microFE models compared to other factors such as the presence of soft tissue and image scanning integration time. Therefore, although HR-pQCT has shown to be useful to predict overall structural and biomechanical changes, it is limited in providing local accurate biomechanical properties of trabecular bone and therefore should be used with caution when assessing bone remodelling through local changes of trabecular bone apposition and resorption in disease treatment monitoring. PMID- 29987701 TI - Integrating expert knowledge and ecological niche models to estimate Mexican primates' distribution. AB - Ecological niche modeling is used to estimate species distributions based on occurrence records and environmental variables, but it seldom includes explicit biotic or historical factors that are important in determining the distribution of species. Expert knowledge can provide additional valuable information regarding ecological or historical attributes of species, but the influence of integrating this information in the modeling process has been poorly explored. Here, we integrated expert knowledge in different stages of the niche modeling process to improve the representation of the actual geographic distributions of Mexican primates (Ateles geoffroyi, Alouatta pigra, and A. palliata mexicana). We designed an elicitation process to acquire information from experts and such information was integrated by an iterative process that consisted of reviews of input data by experts, production of ecological niche models (ENMs), and evaluation of model outputs to provide feedback. We built ENMs using the maximum entropy algorithm along with a dataset of occurrence records gathered from a public source and records provided by the experts. Models without expert knowledge were also built for comparison, and both models, with and without expert knowledge, were evaluated using four validation metrics that provide a measure of accuracy for presence-absence predictions (specificity, sensitivity, kappa, true skill statistic). Integrating expert knowledge to build ENMs produced better results for potential distributions than models without expert knowledge, but a much greater improvement in the transition from potential to realized geographic distributions by reducing overprediction, resulting in better representations of the actual geographic distributions of species. Furthermore, with the combination of niche models and expert knowledge we were able to identify an area of sympatry between A. palliata mexicana and A. pigra. We argue that the inclusion of expert knowledge at different stages in the construction of niche models in an explicit and systematic fashion is a recommended practice as it produces overall positive results for representing realized species distributions. PMID- 29987702 TI - Severe Graves' Orbitopathy occurring in a patient with thyroid hemiagenesis. PMID- 29987703 TI - Anti-prion Protein Antibody 6D11 Restores Cellular Proteostasis of Prion Protein Through Disrupting Recycling Propagation of PrPSc and Targeting PrPSc for Lysosomal Degradation. AB - PrPSc is an infectious and disease-specific conformer of the prion protein, which accumulation in the CNS underlies the pathology of prion diseases. PrPSc replicates by binding to the cellular conformer of the prion protein (PrPC) expressed by host cells and rendering its secondary structure a likeness of itself. PrPC is a plasma membrane anchored protein, which constitutively recirculates between the cell surface and the endocytic compartment. Since PrPSc engages PrPC along this trafficking pathway, its replication process is often referred to as "recycling propagation." Certain monoclonal antibodies (mAbs) directed against prion protein can abrogate the presence of PrPSc from prion infected cells. However, the precise mechanism(s) underlying their therapeutic propensities remains obscure. Using N2A murine neuroblastoma cell line stably infected with 22L mouse-adapted scrapie strain (N2A/22L), we investigated here the modus operandi of the 6D11 clone, which was raised against the PrPSc conformer and has been shown to permanently clear prion-infected cells from PrPSc presence. We determined that 6D11 mAb engages and sequesters PrPC and PrPSc at the cell surface. PrPC/6D11 and PrPSc/6D11 complexes are then endocytosed from the plasma membrane and are directed to lysosomes, therefore precluding recirculation of nascent PrPSc back to the cell surface. Targeting PrPSc by 6D11 mAb to the lysosomal compartment facilitates its proteolysis and eventually shifts the balance between PrPSc formation and degradation. Ongoing translation of PrPC allows maintaining the steady-state level of prion protein within the cells, which was not depleted under 6D11 mAb treatment. Our findings demonstrate that through disrupting recycling propagation of PrPSc and promoting its degradation, 6D11 mAb restores cellular proteostasis of prion protein. PMID- 29987705 TI - Pars plana vitrectomy with or without intraoperative 360 degrees peripheral endolaser for rhegmatogenous retinal detachment treatment. AB - PURPOSE: The aim of this study was to investigate whether intraoperative 360 degrees prophylactic endolaser photocoagulation is necessary for the treatment of uncomplicated retinal detachment. METHODS: This prospective, randomized, comparative and interventional study includes 50 consecutive patients with primary rhegmatogenous retinal detachment (RRD) who were treated by pars plana vitrectomy. The patients were divided into two groups: in Group A endolaser applied to all existing breaks as well as a 360 degrees laser retinopexy, while Group B received endolaser only to the retinal breaks. Primary anatomical success rate, a final best-corrected visual acuity (BCVA) and postoperative complications were analyzed and compared between the groups at 1 and 3 months. RESULTS: After the primary procedure, the retina was reattached in 96% (24 of 25) of patients in Group A and in 88% (22 of 25) of patients in Group B at 1 and 3 months. The mean final BCVA (logarithm of the minimum angle of resolution) improved from 1.26 to 0.52 in Group A with 17 cases (68%) macula-off and 1.19 to 0.77 in Group B with 18 cases (72%) macula-off at preoperative and final follow-up visit. Epiretinal membranes were seen in four cases in Group A and four cases in Group B at 3 months. No statistically significant difference in the anatomical, functional and complication outcomes between the two groups was recorded. CONCLUSIONS: Pars plana vitrectomy without the 360 degrees peripheral endolaser can provide successful anatomic outcomes and functional improvement in uncomplicated primary RRDs. PMID- 29987704 TI - From Religion to Secularism: the Benefits of Fasting. AB - PURPOSE OF REVIEW: Since the early development of human societies, religious beliefs, and practices has been integral to their identity, culture, and social structure, traditions are influenced by the area, era, and culture wherein they developed. Some religions offer advice on behavioral and diet modifications as strategies to fortify the body, purify the spirit, and elevate consciousness. This review is an attempt to compare different practices, describe the health benefits and risks of fasting, and reconcile these age-old recommendations with practical modern life. RECENT FINDINGS: Research to clarify and quantify the impact of these dietary modifications is challenging due to the variability in recommendations among various religions and in day-to-day practices. Most religions share common goals of well-being, body-mind integration, and spiritual attainment. Historically, the transformational power of fasting periods has been appreciated, but there is still much to discover about the underlying beneficial physiologic mechanisms of fasting in preventing and treating metabolic diseases. PMID- 29987706 TI - Investigation of conjunctivochalasis histopathology with light and electron microscopy in patients with conjunctivochalasis in different locations. AB - PURPOSE: To investigate changes in conjunctival tissue of conjunctivochalasis (CCh) patients and to determine the relationship between pathological findings and localization of loose conjunctiva. METHODS: Our study included nineteen eyes of 19 patients who were referred to Cukurova University Ophthalmology Department based on ocular surface symptoms and CCh detected in ocular examination. Amniotic membrane was applied after conjunctival excision as surgical treatment. The control group was formed with five eyes of five patients who are similar in terms of age and gender distribution with our study group. Tissue samples obtained from the study and control groups were investigated with light and electron microscopy. RESULTS: Results of pathological examination of conjunctival tissues revealed increased inflammation in 13 patients (68%), lymphatic ectasia in 12 patients (63%), and loss of goblet cells in 17 patients (89%). Destruction of elastic fibers was detected in all cases by staining with elastic van Gieson. After semiquantitative assessment, varying degrees of light microscopic findings were noted considering the localization of CCh. No statistically significant relationship was observed between light microscopic findings and CCh location (p > 0.05 for all). Electron microscopic investigation revealed increase in intercellular spaces, increased cytoplasmic electron density, and the presence of slight vacuolization in cell cytoplasm, and heterochromatin clumping in nuclei of cells in conjunctival samples. CONCLUSIONS: Mechanical and inflammatory factors induce development of CCh, and signs associated with these factors can be detected with light and electron microscopy of conjunctival tissue. No relationship was observed between CCh localization and pathological changes in tissues examined in our study, and large-scale case series are required to evaluate the possible effect of CCh localization on pathological findings. PMID- 29987707 TI - Oxidative fermentations and exopolysaccharides production by acetic acid bacteria: a mini review. AB - Acetic acid bacteria are versatile organisms converting a number of carbon sources into biomolecules of industrial interest. Such properties, together with the need to limit chemical syntheses in favor of more sustainable biological processes, make acetic acid bacteria appropriate organisms for food, chemical, medical, pharmaceutical and engineering applications. At current, well established bioprocesses by acetic acid bacteria are those derived from the oxidative pathways that lead to organic acids, ketones and sugar derivates. Whereas emerging applications include biopolymers, such as bacterial cellulose and fructans, which are getting an increasing interest for the biotechnological industry. However, considering the industrial demand of high performing bioprocesses, the production yield of metabolites obtained by acetic acid bacteria, is still not satisfying. In this paper we review the major acetic acid bacteria industrial applications, considering the current status of bioprocesses. We will also describe new biotechnological advances in order to optimize the industrial production, offering also an overview on future directions. PMID- 29987708 TI - A Doubly Latent Space Joint Model for Local Item and Person Dependence in the Analysis of Item Response Data. AB - Item response theory (IRT) is one of the most widely utilized tools for item response analysis; however, local item and person independence, which is a critical assumption for IRT, is often violated in real testing situations. In this article, we propose a new type of analytical approach for item response data that does not require standard local independence assumptions. By adapting a latent space joint modeling approach, our proposed model can estimate pairwise distances to represent the item and person dependence structures, from which item and person clusters in latent spaces can be identified. We provide an empirical data analysis to illustrate an application of the proposed method. A simulation study is provided to evaluate the performance of the proposed method in comparison with existing methods. PMID- 29987709 TI - Conformational ensemble comparison for small molecules in drug discovery. AB - Quantification of three-dimensional similarity between small molecules is a fundamental tool of rational drug design. However, there are no widely-adopted scoring approaches for comparing whole conformational ensembles between molecules. Such scores would be desirable for scenarios in which properties of a molecule have been measured (e.g. activity against a target) but the relevant three dimensional structure is not known. In this study, a set of three complementary ensemble comparison scores is proposed. These are the maximum similarity between any pair of conformations; the proportion of the whole set of the conformations that are matched to within a threshold 3D similarity score; and the average value over these matched conformations of the molecular shape descriptor 'sigma-fct', introduced by Ballester et al. The utility of this scoring set is demonstrated in three case studies. The first is an attempt to discriminate between the conformational behaviours of a series of compounds with varying types of cyclisations and other conformationally-significant modifications; the second is an analysis of the more and less active members of a series of GPR119 agonists plus an analysis of a series of orexin-1 antagonists; and the third case study is an attempt to obtain enrichment of active against inactive compounds for a subset of the DUD.E dataset, by ensemble comparison against an active reference compound. PMID- 29987711 TI - Primary Endosymbiosis: Emergence of the Primary Chloroplast and the Chromatophore, Two Independent Events. AB - The emergence of semiautonomous organelles, such as the mitochondrion, the chloroplast, and more recently, the chromatophore, are critical steps in the evolution of eukaryotes. They resulted from primary endosymbiotic events that seem to share general features, i.e., an acquisition of a bacterium/cyanobacteria likely via a phagocytic membrane, a genome reduction coinciding with an escape of genes from the organelle to the nucleus, and finally the appearance of an active system translocating nuclear-encoded proteins back to the organelles. An intense mobilization of foreign genes of bacterial origin, via horizontal gene transfers, plays a critical role. Some third partners, like Chlamydia, might have facilitated the transition from cyanobacteria to the early chloroplast. This chapter describes our current understanding of primary endosymbiosis, with a specific focus on primary chloroplasts considered to have emerged more than one billion years ago, and on the chromatophore, having emerged about one hundred million years ago. PMID- 29987710 TI - Gene editing the phytoene desaturase alleles of Cavendish banana using CRISPR/Cas9. AB - Bananas are a staple food source and a major export commodity worldwide. The Cavendish dessert banana is a triploid AAA genome type and accounts for around 47% of global production. Being essentially sterile, genetic modification is perhaps the only pathway available to improve this cultivar. In this study, we used the CRISPR/Cas9 gene editing system to deliver a self-cleaving polycistronic guide RNA (gRNA) designed to target exon 1 of the Phytoene desaturase (PDS) gene in the Cavendish cultivar "Williams". Genotyping of 19 independent events showed a 100% PDS modification rate primarily in the form of insertions (1-105 nt) or deletions (1-55 nt) (indels) at the predicted cleavage site. Tri-allelic disruptive modifications were observed in 63% of plants and resulted in both albinism and dwarfing. Pale green (16%) and wildtype green (21%) phenotypes generally correlated with in-frame indels in at least one of the three PDS alleles. Editing efficiency was dependent on both target site selection and Cas9 abundance. This is the first report of a highly effective CRISPR/Cas9 modification system using a polycistronic gRNA in Cavendish banana. Such an editing platform will be of considerable utility for the development of disease resistance and novel agro-traits in this commercially important cultivar into the future. PMID- 29987712 TI - Complex Endosymbioses I: From Primary to Complex Plastids, Multiple Independent Events. AB - A substantial portion of eukaryote diversity consists of algae with complex plastids, i.e., plastids originating from eukaryote-to-eukaryote endosymbioses. These plastids are characteristic by a deviating number of envelope membranes (higher than two), and sometimes a remnant nucleus of the endosymbiont alga, termed the nucleomorph, is present. Complex plastid-bearing algae are therefore much like living matryoshka dolls, eukaryotes within eukaryotes. In comparison, primary plastids of Archaeplastida (plants, green algae, red algae, and glaucophytes) arose upon a single endosymbiosis event with a cyanobacterium and are surrounded by two membranes. Complex plastids were acquired several times by unrelated groups nested within eukaryotic heterotrophs, suggesting complex plastids are somewhat easier to obtain than primary plastids. This is consistent with the existence of higher-order and serial endosymbioses, i.e., engulfment of complex plastid-bearing algae by (tertiary) eukaryotic hosts and functional plastid replacements, respectively. Plastid endosymbiosis is typical by a massive transfer of genetic material from the endosymbiont to the host nucleus and metabolic rearrangements related to the trophic switch to phototrophy; this is necessary to establish metabolic integration of the plastid and control over its division. Although photosynthesis is the main advantage of plastid acquisition, algae that lost photosynthesis often maintain complex plastids, suggesting their roles beyond photosynthesis. This chapter summarizes basic knowledge on acquisition and functions of complex plastid. PMID- 29987713 TI - Complex Endosymbioses II: The Nonphotosynthetic Plastid of Apicomplexa Parasites (The Apicoplast) and Its Integrated Metabolism. AB - Chloroplasts are essential organelles that are responsible for photosynthesis in a wide range of organisms that have colonized all biotopes on Earth such as plants and unicellular algae. Interestingly, a secondary endosymbiotic event of a red algal ancestor gave rise to a group of organisms that have adopted an obligate parasitic lifestyle named Apicomplexa parasites. Apicomplexa parasites are some of the most widespread and poorly controlled pathogens in the world. These infectious agents are responsible for major human diseases such as toxoplasmosis, caused by Toxoplasma gondii, and malaria caused by Plasmodium spp. Most of these parasites harbor this relict plastid named the apicoplast, which is essential for parasite survival. The apicoplast has lost photosynthetic capacities but are metabolically similar to plant and algal chloroplasts. The apicoplast is considered a novel and important drug target against Apicomplexa parasites. This chapter focuses on the apicoplast of apicomplexa parasites, its maintenance, and its metabolic pathways. PMID- 29987714 TI - Diversity and Plasticity of Plastids in Land Plants. AB - Plastids represent a largely diverse group of organelles in plant and algal cells that have several common features but also a broad spectrum of differences in respect of how they look (color, size, and ultrastructure), and what their specific function and molecular composition is. Plastids and their structural and metabolic diversity significantly contribute to the functionality and developmental flexibility of the plant body throughout its lifetime. In addition, to the multiple roles of given plastid types, this diversity is accomplished in some cases by interconversions between different plastids as a consequence of developmental and environmental signals that regulate plastid differentiation and specialization. PMID- 29987715 TI - The Main Functions of Plastids. AB - Plastids are semiautonomous organelles like mitochondria, and derive from a cyanobacterial ancestor that was engulfed by a host cell. During evolution, they have recruited proteins originating from the nuclear genome, and only parts of their ancestral metabolic properties were conserved and optimized to limit functional redundancy with other cell compartments. Furthermore, large disparities in metabolic functions exist among various types of plastids, and the characterization of their various metabolic properties is far from being accomplished. In this review, we provide an overview of the main functions, known to be achieved by plastids or shared by plastids and other compartments of the cell. In short, plastids appear at the heart of all main plant functions. PMID- 29987716 TI - Plastid Transient and Stable Interactions with Other Cell Compartments. AB - Plastids are organelles delineated by two envelopes that play important roles in different cellular processes such as energy production or lipid biosynthesis. To regulate their biogenesis and their function, plastids have to communicate with other cellular compartments. This communication can be mediated by signaling molecules and by the establishment of direct contacts between the plastid envelope and other organelles such as the endoplasmic reticulum, the mitochondria, the plasma membrane, the peroxisomes and the nucleus. These interactions are highly dynamic and respond to different biotic and abiotic stresses. However, the mechanisms involved in the formation of plastid-organelle contact sites and their functions are still enigmatic. In this chapter, we summarize our current knowledge about plastid contact sites and their role in the regulation of plastid biogenesis and function. PMID- 29987717 TI - Imaging Plastids in 2D and 3D: Confocal and Electron Microscopy. AB - Internal chloroplast structures present complex and various characteristics, which are still largely undetermined due to insufficient imaging investigation. Information on chloroplast morphology has traditionally been collected using light microscopy (LM), confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM) techniques. However, recent technological progresses in the field of microscopy have made it possible to visualize the internal structure of chloroplast in far greater detail and in 3D. Here we recapitulate protocols to visualize chloroplasts from Arabidopsis leaves and Phaeodactylum tricornutum cells with confocal and transmission electron microscopy together with a new technique using a focused ion beam-scanning electron microscope (FIB-SEM) allowing for 3D imaging. PMID- 29987718 TI - Purification of Chloroplasts and Chloroplast Subfractions: Envelope, Thylakoids, and Stroma-From Spinach, Pea, and Arabidopsis thaliana. AB - Chloroplasts are specific organelles of plant cells dedicated to photosynthesis and delimited by a two-membrane chloroplast envelope. Their photosynthetic function is based on the development of an operational large internal membrane network, called the thylakoids, and on enzymatic processes present in the chloroplast matrix, called the stroma. Thylakoid membranes are clearly different from the chloroplast envelope and their biogenesis is dependent on biosynthetic and transport activities specific of the chloroplast envelope. Starting with the isolation of intact chloroplasts, the method presents the separation by differential centrifugation of the three main compartments of the chloroplast: the stroma, the thylakoids, and the chloroplast envelope. Three different protocols are provided, adapted for starting leaves of spinach, Arabidopsis, and pea. PMID- 29987719 TI - Isolation of Inner and Outer Membranes of the Chloroplast Envelope from Spinach and Pea. AB - The outer membrane and the inner membrane of the chloroplast envelope, also called OEM and IEM, have distinct functions connected with chloroplast biogenesis and chloroplast communication with the rest of the cell. Here we describe a method for the isolation of these membranes starting from intact chloroplast preparations, with two alternative procedures based on the starting material. One was developed from spinach leaves, the other one from pea leaves. The two procedures differ by the means that are used to isolate and rupture chloroplasts and to liberate each membrane. PMID- 29987720 TI - Purification of Nongreen Plastids (Proplastids and Amyloplasts) from Angiosperms, and Isolation of Their Envelope Membranes. AB - Plastids, a wide family of plant specific organelles, exist in all plant cells in a number of different forms with different functions essential for plant life. Among them, chloroplasts are by far the more extensively studied owing to their central role in photosynthesis. However, other plastid family members, often referred to as nongreen plastids, play also major roles in the physiology of higher plants and could be better suited for studies of specific metabolic processes in heterotrophic plant cells. Unfortunately, serious technical problems are frequently encountered with separating intact, active nongreen plastids from contaminating membranes and mitochondria. Here, we provide detailed protocols suitable for the large scale preparation of intact and highly pure proplastids from cauliflower buds, as well as amyloplasts from sycamore cultured cells, and for the subsequent separation of their surrounding envelope membranes from the stroma and other plastid fractions. Both methods proved to be highly reliable and have been instrumental for in-depth investigations on biochemistry and physiology of nongreen plastids. PMID- 29987721 TI - In Vitro Protein Import into Isolated Chloroplasts. AB - Chloroplasts contain about 3000 proteins, with approximately 400 of them located in the chloroplast envelope membranes, 1300 in the soluble stroma, and 1300 in the thylakoid membranes. Most of them are encoded by nuclear genes and translated as precursor proteins in the cytosol before their transport into chloroplasts. As a tool to control and characterize their import into plastids, we here describe an assay for in vitro protein import with isolated pea chloroplasts. PMID- 29987722 TI - Analysis of the MTL Supercomplex at Contact Sites Between Mitochondria and Plastids. AB - Plastids are organelles playing fundamental roles in different cellular processes such as energy metabolism or lipid biosynthesis. To fulfill their biogenesis and their function in the cell, plastids have to communicate with other cellular compartments. This communication can be mediated by the establishment of direct contact sites between plastids envelop and other organelles. These contacts are dynamic structures that are modified in response to stress. As example, during phosphate (Pi) starvation, the number of contact sites between plastids and mitochondria significantly increases. In this situation, these contacts play an important role in the transfer of galactoglycerolipids from plastids to mitochondria. Recently, Pi starvation stress was used to identify key proteins involved in the traffic of galactoglycerolipids from plastids to mitochondria in Arabidopsis thaliana. A mitochondrial lipoprotein complex called MTL (mitochondrial transmembrane lipoprotein complex) was identified. This complex contains mitochondrial proteins but also proteins located in the plastid envelope, suggesting its presence at the plastid-mitochondria junction. This chapter describes the protocol to isolate the MTL complex by clear-native polyacrylamide gel electrophoresis (CN-PAGE) from the mitochondrial fraction of Arabidopsis cell cultures and the methods to study different features of this complex. PMID- 29987723 TI - Isolation of Plastid Fractions from the Diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. AB - The so-called "complex" plastids from diatoms possessing four envelope membranes are a typical feature of algae that arose from secondary endosymbiosis. Studying isolated plastids from these algae may allow answering a number of fundamental questions regarding diatom photosynthesis and plastid functionality. Due to their complex architecture and their integration into the cellular endoplasmic reticulum (ER) system, their isolation though is still challenging. In this work, we report a reliable isolation technique that is applicable for the two model diatoms Thalassiosira pseudonana and Phaeodactylum tricornutum. The resulting plastid-enriched fractions are of homogenous quality, almost free from cellular contaminants, and feature structurally intact thylakoids that are capable to perform oxygenic photosynthesis, though in most cases they seem to lack most of the stromal components as well as plastid envelopes. PMID- 29987724 TI - Isolating the Plasmodium falciparum Apicoplast Using Magnetic Beads. AB - Plastids are key organelles in both photosynthetic and nonphotosynthetic organisms. In photosynthetic organisms, plastids can be readily purified using differential centrifugations due to the high density of photosynthetic membranes or thylakoids. The apicomplexan plastid (the apicoplast) is an essential nonphotosynthetic plastid that lacks thylakoid and was not readily purified using conventional methods. Here, we describe a tractable method to purify intact apicoplasts from Plasmodium falciparum blood stages using magnetic beads and affinity purification. PMID- 29987725 TI - Extraction and Quantification of Lipids from Plant or Algae. AB - In plants and algae, the glycerolipidome changes in response to environmental modifications. For instance, in phosphate starvation, phospholipids are degraded and replaced by nonphosphorus lipids and in nitrogen starvation, storage lipids accumulate. In addition to the well-known applications of oil crops for food, algae lipids are becoming a model for potential applications in health, biofuel, and green chemistry and are used as a platform for genetic engineering. It is therefore important to measure accurately and quickly the glycerolipid content in plants and algae. Here we describe the methods to extract the lipid, quantify the fatty acid amount of the lipid extract and to quantify the different lipid classes that are present in these samples. PMID- 29987726 TI - Quantitative Assessment of the Chloroplast Lipidome. AB - In plants and algae, photosynthetic membranes have a unique lipid composition. They differ from all other cellular membranes by their very low amount of phospholipids, besides some phosphatidylglycerol (PG), and high proportion of glycolipids. These glycolipids are the uncharged galactolipids, i.e., monogalactosyldiacylglycerol and digalactosyldiacylglycerol (MGDG and DGDG), and an anionic sulfolipid, i.e., sulfoquinovosyldiacylglycerol (SQDG). In all photosynthetic membranes analyzed to date, from cyanobacteria to algae, protists, and plants, the lipid quartet constituted by MGDG, DGDG, SQDG, and PG has been highly conserved but the composition in fatty acids of these lipids can vary a lot from an organism to another. To better understand chloroplast biogenesis, it is therefore essential to know their lipid content. Establishing chloroplast lipidome requires first to purify chloroplast from plant or algae tissue. Here we describe the methods to extract lipids, quantify the lipids of the chloroplast, and qualify and quantify the different lipid classes that might be present in these fractions. PMID- 29987727 TI - Determination of the DNA/RNA-Associated Subproteome from Chloroplasts and Other Plastid Types. AB - Plastids of plant and algae cells are of endosymbiotic origin. They possess their own genome and a sophisticated protein machinery to express it. Studies over the recent years uncovered that the regulation of plastid gene expression is highly complex involving a multiplicity of regulatory protein factors that are mostly imported from the cytosol. Proper expression of the chloroplast genome in coordination with nuclear genome was found to be absolutely essential for efficient growth and development of plants especially during early steps of photomorphogenesis, but also at later stages of the plant life cycle. Protein factors being responsible for such essential steps, therefore, are highly interesting for fundamental science as well as for industrial applications targeting crop improvement and yield increase. Nevertheless, many proteins involved in regulation of plastid gene expression are still unidentified and/or uncharacterized. This asks for appropriate methods to analyze this special subproteome. Here, we describe suitable methods that proved to be successful in the analysis of the plastid subproteome of DNA/RNA-binding proteins. PMID- 29987728 TI - Mapping Plastid Transcript Population by Circular Reverse Transcription Polymerase Chain Reaction. AB - During evolution of photosynthetic organisms, the genetic information provided by the internalized cyanobacteria has been transferred to the nucleus. The small genome kept by the chloroplast, the so-called plastome, displays a complex organization, comprising operons under the control of multiples promoters. In addition, polycistronic transcripts undergo multiple processing events, thus generating a complex population of mRNAs from a single gene. This chapter describes a method to investigate the diversity of the mRNA population from a single gene by circular RT-PCR. The protocol provided here allows for the simultaneous mapping of both 5' and 3' ends of the same RNA molecule. PMID- 29987729 TI - Bioinformatic Analysis of Chloroplast Gene Expression and RNA Posttranscriptional Maturations Using RNA Sequencing. AB - Sequencing of total RNA enables the study of the whole plant transcriptome resulting from the simultaneous expression of the three genomes of plant cells (located in the nucleus, mitochondrion and chloroplast). While commonly used for the quantification of the nuclear gene expression, this method remains complex and challenging when applied to organellar genomes and/or when used to quantify posttranscriptional RNA maturations. Here we propose a complete bioinformatical and statistical pipeline to fully characterize the differences in the chloroplast transcriptome between two conditions. Experimental design as well as bioinformatics and statistical analyses are described in order to quantify both gene expression and RNA posttranscriptional maturations, i.e., RNA splicing, editing, and processing, and identify statistically significant differences. PMID- 29987730 TI - A Guide to the Chloroplast Transcriptome Analysis Using RNA-Seq. AB - Since its first use in plants in 2007, high-throughput RNA sequencing (RNA-Seq) has generated a vast amount of data for both model and nonmodel species. Organellar transcriptomes, however, are virtually always overlooked at the data analysis step. We therefore developed ChloroSeq, a bioinformatic pipeline aimed at facilitating the systematic analysis of chloroplast RNA metabolism, and we provide here a step-by-step user's manual. Following the alignment of quality controlled data to the genome of interest, ChloroSeq measures genome expression level along with splicing and RNA editing efficiencies. When used in combination with the Tuxedo suite (TopHat and Cufflinks), ChloroSeq allows the simultaneous analysis of organellar and nuclear transcriptomes, opening the way to a better understanding of nucleus-organelle cross talk. We also describe the use of R commands to produce publication-quality figures based on ChloroSeq outputs. The effectiveness of the pipeline is illustrated through analysis of an RNA-Seq dataset covering the transition from growth to maturation to senescence of Arabidopsis thaliana leaves. PMID- 29987731 TI - A Toolkit for the Characterization of the Photoprotective Capacity of Green Algae. AB - While light is a crucial energy source in photosynthetic organisms, if its intensity exceeds their photosynthetic capacity it may cause light-induced damage. A dominant photoprotective mechanism in plants and algae is the qE (quenching of energy), the major component of nonphotochemical quenching (NPQ). qE is a process that dissipates absorbed excitation energy as heat, ensuring cell survival even under adverse conditions. The present protocol gathers together a set of experimental approaches (in vivo chlorophyll fluorescence, western blotting, growth and cellular chlorophyll content at very strong light) that collectively allow for the characterization of the qE capacity of the model green algae Chlamydomonas reinhardtii. PMID- 29987732 TI - Rescue of Deletion Mutants to Isolate Plastid Transformants in Higher Plants. AB - Plastid transformation is an attractive alternative to nuclear transformation enabling manipulation of native plastid genes and the insertion of foreign genes into plastids for applications in agriculture and industrial biotechnology. Transformation is achieved using dominant positive selection markers that confer resistance to antibiotics. The very high copy number of plastid DNA means that a prolonged selection step is required to obtain a uniform population of transgenic plastid genomes. Repair of mutant plastid genes with the corresponding functional allele allows selection based on restoration of the wild type phenotype. The use of deletion rather than point mutants avoids spontaneous reversion back to wild type. Combining antibiotic resistance markers with native plastid genes speeds up the attainment of homoplasmy and allows early transfer of transplastomic lines to soil where antibiotic selection is replaced by selection for photoautotrophic growth. Here we describe our method using the wild type rbcL gene as a plastid transformation marker to restore pigmentation and photosynthesis to a pale green heterotrophic rbcL mutant. PMID- 29987733 TI - Genetic Analysis of Chloroplast Biogenesis, and Function and Mutant Collections. AB - Since the time DNA was discovered as the code of life, genetic analysis has greatly advanced our understanding of the relation between genotype and phenotype and associated molecular mechanisms in various organisms including plants and algae. Forward genetics from phenotype to genotype has identified causal genes of interesting phenotypes induced by chemical, ionizing-radiation, or DNA insertional mutagenesis. Meanwhile, reverse genetics from genotype to phenotype has revealed physiological and molecular roles of known gene sequences. During the past dozen years, many molecular genetic tools have been developed to investigate gene functions quickly and efficiently. In this chapter, we introduce several approaches of forward and reverse genetics, including random chemical and DNA insertional mutagenesis, activation tagging, RNA interference, and gene overexpression and induction systems, with some examples of genetic studies of chloroplast biology mainly in Arabidopsis thaliana. We also briefly describe methods for chemical and DNA insertion mutagenesis and how to obtain sequence tagged mutants from public collections. With greatly improved DNA sequencing and genome-editing technologies, model organisms as well as diverse species can be used for molecular biology. Genetic analysis can play an increasingly important role in elucidating chloroplast biogenesis and functions. PMID- 29987734 TI - Generation of Mutants of Nuclear-Encoded Plastid Proteins Using CRISPR/Cas9 in the Diatom Phaeodactylum tricornutum. AB - Genome modifications in microalgae are becoming a widespread and mandatory tool for research in both fundamental and applied biology. Among genome editing methods in these photosynthetic organisms, CRISPR/Cas9 offers a specific, powerful and efficient tool for genome engineering by inducing mutations in targeted regions of the genome. Here we described a protocol that allows the generation of knockout mutants by CRISPR/Cas9 in the diatom Phaeodactylum tricornutum using biolistic transformation. PMID- 29987735 TI - In Silico Tools for the Prediction of Protein Import into Secondary Plastids. AB - The in silico identification of proteins targeting to secondary plastids is a difficult task. Such plastids are complex in structure and can be surrounded by up to four membranes, which have to be crossed during import. Nucleus-encoded plastidial preproteins in organisms with secondary plastids contain specific N terminal targeting signals, the so-called bipartite targeting signal (BTS) sequences consisting of a classical signal peptide followed by a transit peptide like sequence, mediating this intricate process. As these signal sequences differ significantly from transit peptides of plastid preproteins in plants and other organisms with primary plastids, existing in silico tools for primary plastid targeting prediction are not directly suitable to detect nucleus-encoded proteins destined for the import into secondary plastids. In this chapter I describe the current state-of-the-art methods to reliably predict proteins that might be imported into secondary plastids of red- and green-algal origin using either the "classical" approach, which involves a combination of bits of information produced by existing in silico tools, or, if available, via consulting specifically developed algorithms. PMID- 29987737 TI - Slipped Liver Segment Mimicking an Esophageal Stromal Tumor. PMID- 29987736 TI - AT_CHLORO: The First Step When Looking for Information About Subplastidial Localization of Proteins. AB - Plastids contain several key subcompartments. The two limiting envelope membranes (inner and outer membrane of the plastid envelope with an intermembrane space between), an aqueous phase (stroma), and an internal membrane system terms (thylakoids) formed of flat compressed vesicles (grana) and more light structures (lamellae). The thylakoid vesicles delimit another discrete soluble compartment, the thylakoid lumen. AT_CHLORO ( http://at-chloro.prabi.fr/at_chloro/ ) is a unique database supplying information about the subplastidial localization of proteins. It was created from simultaneous proteomic analyses targeted to the main subcompartments of the chloroplast from Arabidopsis thaliana (i.e., envelope, stroma, thylakoid) and to the two subdomains of thylakoid membranes (i.e., grana and stroma lamellae). AT_CHLORO assembles several complementary information (MS-based experimental data, curated functional annotations and subplastidial localization, links to other public databases and references) which give a comprehensive overview of the current knowledge about the subplastidial localization and the function of chloroplast proteins, with a specific attention given to chloroplast envelope proteins. PMID- 29987738 TI - Alvimopan, Regardless of Ileus Risk, Significantly Impacts Ileus, Length of Stay, and Readmission After Intestinal Surgery. AB - BACKGROUND: Previous analyses evaluating alvimopan included patients at varying risk for ileus after intestinal resection, which may have precluded its widespread adoption. We assess the early and delayed effects of alvimopan in patients stratified by risk for ileus after intestinal and colon resection. METHODS: From the Premier Perspective database, patients with elective small and large bowel resections from 2012 to 2014 were identified. Multivariable analysis identified 14 perioperative risk factors for postoperative ileus. Within low- (0 4 factors), intermediate- (5 factors), and high-risk (6-12 factors) ileus categories, alvimopan and no-alvimopan patients were propensity-score matched for demographics, morbidities, diagnosis, surgery and approach, postoperative complications, surgeon specialty, and hospital features. In-hospital postoperative ileus, length of stay, discharge destination, and ileus-related readmission were compared. RESULTS: Of 52,948 patients, 15,719 (29.7%) received alvimopan. Risk for ileus in low- (18,784), intermediate- (14,370), and high-risk (19,794) categories was 8.9, 13, and 22% (p <= .0001) respectively. After matching, alvimopan was associated with significantly reduced in-hospital postoperative ileus in all (low, 6%; intermediate, 9.4%; and high risk, 16.2%) categories. Hospital stay and 30-, 60-, and 90-day postdischarge ileus were also significantly lower with alvimopan. For low-risk patients, alvimopan increased discharge to home, while 90-day emergency readmission was reduced. CONCLUSIONS: Alvimopan, regardless of ileus risk, improves ileus, hospital stay, and ileus related readmission after intestinal resection and these effects are sustained over the long term. Since fewer than a third of patients currently receive alvimopan, its routine adoption with small and large intestinal resection will significantly impact patients and health systems. PMID- 29987739 TI - Predictive Value of Preoperative Sarcopenia in Patients with Gastric Cancer: a Meta-analysis and Systematic Review. AB - PURPOSE: The impact of preoperative sarcopenia on postoperative complications and overall survival has been recently debated. Our meta-analysis aims to ascertain whether preoperative sarcopenia increases the risk of poor outcomes and to attempt to provide new ideas for the prognosis of outcomes for patients with gastric cancer. METHODS: We searched for all relevant articles on PubMed, the EMBASE database, and Web of Science (up to September 1, 2017). Data synthesis and statistical analysis were carried out using RevMan 5.3 software. RESULTS: Thirteen studies involving 4262 patients who underwent gastrectomy for gastric cancer were analyzed (sarcopenia group = 1234; non-sarcopenia group = 3028). The results showed that preoperative sarcopenia significantly associated with poor pathological staging (high pT: OR = 1.86, 95% CI = 1.49-2.31; P < 0.01; pN+: OR = 1.61, 95% CI = 1.33-1.94; P < 0.01; high TNM category: OR = 1.84, 95% CI = 1.53 2.22; P < 0.01). Patients with preoperative sarcopenia had an increased risk of total postoperative complications (OR = 2.17, 95% CI = 1.53-3.08; P < 0.01), severe complications (OR = 1.65, 95% CI = 1.09-2.50; P = 0.02), and poorer OS (HR = 1.70, 95% CI = 1.45-1.99; P < 0.01). The results of subgroup analyses revealed that patients with preoperative sarcopenia over 65 years old and those from Asian populations had higher risks for total postoperative complications and severe complications. CONCLUSION: This meta-analysis reveals that preoperative sarcopenia may be used as a new indicator of poor pathological staging, impaired overall survival, and increased postoperative complications. Notably, patients with gastric cancer who are over 65 years old and from Asia should be routinely screened for sarcopenia before surgery to adequately assess the risk of postoperative complications in clinical practice. PMID- 29987740 TI - Impact of time perspectives on texting intervention to reduce HIV/STI transmission among female sex workers in Tijuana and Ciudad Juarez, Mexico. AB - Text messages may sustain post-counseling gains in behavioral improvements and reduce HIV/STI incidence. However, their effectiveness may depend on the messages' time perspective and characteristics of the individual. We evaluated the impact of time perspective on a text messaging intervention designed to maintain improvements in safer sex practices among drug-using and non-drug-using female sex workers (FSWs) in Tijuana (n = 141) and Cd. Juarez (n = 129), Mexico. FSWs received the efficacious Mujer Segura intervention, and were randomized to receive safer sex maintenance text messages with either a short-term or future oriented time perspective. The outcome was HIV/STI incidence rate over 6-month follow-up. In Tijuana, combined HIV/STI incidence density was lower among FSWs in the FUTURE group (31.67 per 100 py) compared to women in the SHORT-TERM group (62.40 per 100 py). Conversely, in Cd. Juarez, HIV/STI incidence density was lower (although non-significant) among FSWs in the SHORT-TERM group (19.80 per 100 py) compared to those in the FUTURE group (35.05 per 100 py). These findings suggest that future-oriented text messages may sustain post-counseling improvements in sexual risk behavior among FSWs, but findings may vary by FSWs' characteristics (e.g., drug use), and by region and context. PMID- 29987742 TI - The Glucocorticoid Receptor Is a Critical Regulator of HIV Latency in Human Microglial Cells. AB - We have developed models of HIV latency using microglia derived from adult human patient brain cortex and transformed with the SV40 T large and hTERT antigens. Latent clones infected by HIV reporter viruses display high levels of spontaneous HIV reactivation in culture. BrainPhys, a medium highly representative of the CNS extracellular environment, containing low glucose and 1% FBS, reduced, but did not prevent, HIV reactivation. We hypothesized that spontaneous HIV reactivation in culture was due to the expression of pro-inflammatory genes, such as TNF alpha, taking place in the absence of the natural inhibitory signals from astrocytes and neurons. Indeed, expression and secretion of TNF-alpha is strongly reduced in HIV-latently infected microglia compared to the subset of cells that have undergone spontaneous HIV reactivation. Whereas inhibitors of NF-kappaB or of macrophage activation only had a short-term silencing effect, addition of dexamethasone (DEXA), a glucocorticoid receptor (GR) agonist and mediator of anti inflammation, silenced the HIV provirus in a long-term, and shRNA-mediated knock down of GR activated HIV. DEXA also decreased secretion of a number of cytokines, including TNF-alpha. Chromatin immunoprecipitation analysis revealed that DEXA strongly increased GR occupancy at the HIV promoter, and reduced histone 3 acetylated levels. Moreover, TNF-alpha expression inhibitors in combination with DEXA induced further HIV silencing and increased the histone 3 lysine 27 tri methylated epigenetic mark of repression at the HIV promoter region. We conclude that GR is a critical repressor of HIV transcription in microglia, and a novel potential pharmacological target to restrict HIV expression in the CNS. PMID- 29987743 TI - A Conceptual Model of Angelman Syndrome and Review of Relevant Clinical Outcomes Assessments (COAs). AB - BACKGROUND: Angelman syndrome (AS) is a rare, neurological genetic disorder for which no clinical outcomes assessments (COAs) or conceptual models (CM) have been developed. OBJECTIVE: This study aimed to identify symptoms and impacts relevant and important in this patient population and develop a conceptual model of AS, and to evaluate the content validity of selected COA instruments with potential for inclusion in clinical studies of AS to capture treatment benefit. METHODS: For both concept elicitation (CE) and cognitive interviews (CI), caregivers of children, adolescents, and adults with AS and clinicians with AS experience were targeted. For CI, clinicians discussed the Modified Performance-Oriented Mobility Assessment (MPOMA-G) and ProtoKinetics Zeno WalkwayTM and caregivers reviewed the Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT), the Anxiety, Depression and Mood Scale (ADAMS), the Aberrant Behavior Checklist Community (ABC-C), and the Morning Diary. RESULTS: Four clinicians and 34 caregivers participated in CE interviews; three clinicians and 36 caregivers participated in CI. A conceptual model, initially informed by literature, was refined based on interview data. Five domains of symptoms, signs, and characteristics of AS were identified: cognitive and executive functioning, social-emotional, emotional-expressive behavior, sensory-compulsive behavior, and physical. Patient impacts were identified in three domains: activities of daily living, school, and social/community. Caregiver impacts were identified in five domains: mental health, physical health, work, home, and social. While all instruments demonstrated the ability to provide relevant data for the AS population, each instrument either contained some items irrelevant to individuals with AS or was missing important concepts based on the interviews. No single instrument covered all relevant domains specific to AS. CONCLUSION: Future work should consider the adaptation of existing COAs and the development of a novel AS specific instrument for use in clinical research to ensure outcomes important to this patient population are captured. PMID- 29987741 TI - Robust extraction for low-contrast liver tumors using modified adaptive likelihood estimation. AB - PURPOSE: Liver tumor extraction is essential for liver ablation surgery planning and treatment. For accurate and robust tumor segmentation, we propose a semiautomatic method using adaptive likelihood classification with modified likelihood model. METHODS: First, a minimal ellipse (or quasi-ellipsoid) that encloses a liver tumor is generated for initialization. Then, a hybrid intensity likelihood modification based on nonparametric density estimation is proposed to enhance local likelihood contrast and reduce its inhomogeneity. A prior elliptical (or quasi-ellipsoid) shape constraint is directly integrated into the likelihood to further prevent leakage of the algorithm into adjacent tissues with similar intensity. Finally, an adaptive likelihood classification is proposed for accurate segmentation of tumors with low contrast, high noise or heterogeneous densities. RESULTS: Experiments were performed on 3Dircadb and LiTS datasets. The average volumetric overlap errors of the 3Dircadb and LiTS datasets were 27.05 and 35.72%, respectively. The algorithm's robustness was validated by comparing results of 5 operators with multiple selections on different tumors. CONCLUSIONS: The proposed method achieved good results in different tumors, even in low contrast tumors with blurred boundaries. Reliable results can still be achieved over different initializations by different operators using the proposed method. PMID- 29987744 TI - Invasive Scopulariopsis alboflavescens infection in patient with acute myeloid leukemia. AB - Scopulariopsis alboflavescens is a soil saprophyte that is widely distributed in nature. Recently, there have been increasing number of reports of invasive infections with Scopulariopsis species in immunocompromised patients. In this report, we described an adult woman with acute myeloid leukemia and who developed S. alboflavescens pneumonia. Liposomal amphotericin B and voriconazole combination therapy was unsuccessful and the patient died because of pneumonia. Scopulariopsis is highly resistant to available antifungal agents and almost invariably fatal. This case report should alert clinicians to the importance of listing Scopulariopsis as a pathogenic fungus in immunocompromised patients. PMID- 29987745 TI - Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia. AB - A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients. PMID- 29987746 TI - Application of tumor treating fields for newly diagnosed glioblastoma: understanding of nationwide practice patterns. AB - BACKGROUND: Tumor treating fields (TTF) harness magnetic fields to induce apoptosis in targeted regions. A 2015 landmark randomized phase III trial of newly diagnosed glioblastoma (GBM) patients demonstrated TTF + temozolomide to be superior to temozolomide alone. Given these results, we sought to assess practice patterns of providers in TTF utilization for GBM. METHODS: A survey was administered to practices in the United States self-identifying as specializing in radiation oncology, medical oncology, neuro-oncology, neurosurgery, and/or neurology. Responses were collected anonymously; analysis was performed using Fisher's exact test. RESULTS: A total of 106 providers responded; a minority (36%) were in private practice. Regarding case volume, 82% treated at least six high-grade gliomas/year. The provider most commonly certified to offer TTF therapy to GBM patients was the neuro-oncologist (40%), followed by the radiation oncologist (34%); 31% reported no TTF-certified physician in their practice. TTF users were more likely to have high volume, and be aware of TTF inclusion in National Comprehensive Cancer Network (NCCN) guidelines (p < 0.05). CONCLUSIONS: More than 80% of TTF for GBM in the United States is performed by groups who treat at least six high-grade gliomas per year; unfortunately more than 30% were in practices bereft of anyone certified to offer TTF therapy. These results indicate that there remains fertile soil for TTF therapy nationwide to be introduced into practices for GBM treatment. Providers seeking to refer newly diagnosed GBM patients for TTF should seek out practices with TTF user-associated characteristics to ensure optimal access for their patients. PMID- 29987747 TI - Optimal strategy of gamma knife radiosurgery for craniopharyngiomas. AB - OBJECT: To analyze the outcomes of gamma knife radiosurgery (GKS) for craniopharyngiomas and elucidate the optimal strategy. METHODS: Between 1998 and 2016, 35 patients underwent GKS for the treatment of 40 recurrent or residual craniopharyngiomas. Among 40 GKSs, 22 procedures were single-session GKSs and 18 procedures were fractionated GKSs. In cases of single-session GKS, the median marginal dose was 15 Gy (range 10-20 Gy). In cases of fractionated GKS, the median marginal dose was 6 Gy (range 5-7.5 Gy) of three fractions. The radiation dose was calculated to the biologic equivalent dose (BED) using alpha/beta ratios of 10 and 2. RESULT: The location of the tumor, the distance between the optic nerve and tumor (> 10 mm), BED 10 (> 35 Gy), and BED2 (> 80 Gy) were statistically significant with overall response rate (P = 0.008, 0.02, 0.03, and 0.002, respectively). There was a statistically significant difference in progression-free survival according to the distance between the optic nerve and tumor (> 10 mm) and the location of tumor (P = 0.03 and 0.03, respectively). Multivariate logistic regression analysis showed the hypothalamus group had an odds ratio of 0.04 compared with the suprasellar group for tumor progression. The group with BED2 > 80 Gy had an odds ratio of 0.049 compared with the group with BED2 < 80 Gy. CONCLUSION: A sufficient dose is required for treating craniopharyngiomas using single-session and fractionated GKS. The outcomes of GKS can be predicted according to the location of tumor, the distance between the optic nerve and tumor and BED value. PMID- 29987749 TI - Jaccoud's Arthropathy. PMID- 29987751 TI - A personal tribute to Johann Caspar Ruegg (1930-2018): milestones of muscle research. PMID- 29987750 TI - Risk factors for inflammatory bowel disease: A prospective multi-center study. AB - INTRODUCTION: Environmental risk factors have been associated with inflammatory bowel disease (IBD). With rising incidence, it is important to know risk factors associated with IBD in our population. This study was aimed to evaluate risk factors for IBD from western India. METHODS: This was prospective, multi-center case-control study which included 1054 patients with IBD of which 765 (72.5%) were ulcerative colitis (UC) and 289 (27.4%) Crohn's disease (CD). Asymptomatic individuals without a history of any major illness served as controls. The questionnaire containing risk factors for IBD was given to patients and control group. Odds ratio and 95% confidence interval were calculated for each variable. RESULT: Significant numbers of patients with CD were from rural area. Rural environment (OR 1.071, 0.82-1.38 and OR 1.441, 1.02-2.02), higher education (OR 1.830, 1.52-2.19 and OR 1.519, 1.16-1.97), professional by occupation (OR 1.754, 1.46-2.09 and OR 1.293, 0.99-1.67), annual family income >100,000 Indian national rupees (OR 2.185, 1.52-3.13 and OR 4.648, 3.10-6.95), history of appendectomy (OR 3.158, 1.71-5.80 and OR 3.158, 1.71-5.80), and family history of IBD (OR 4.510, 2.19-9.25 and OR 3.972, 1.58-9.96) were the risk factors for UC and CD, respectively. Vegetarian diet was protective factor for UC (OR 0.29, 0.27-0.39) and risk for CD (OR 1.179, 0.88-1.57). Smoking and chronic alcoholism were not found to be the risk factors. CONCLUSION: This study highlights association between socioeconomic, dietary factors, appendectomy, and family history as risk factors for IBD. PMID- 29987748 TI - RAGE and Its Ligands: Molecular Interplay Between Glycation, Inflammation, and Hallmarks of Cancer-a Review. AB - Risk of cancer especially of colon, breast, and pancreas is high in diabetic and obese patients, with potential involvement of augmented expression of RAGE (receptor for advanced glycation end products) and its ligands, namely AGEs (advanced glycation end products), HMGB1 (high-mobility group box 1 protein), and S100 group of proteins. Studies have reported the involvement of RAGE activation by its ligands in growth and survival of cancers, including metastasis and poor prognosis. We propose that this receptor-ligand axis provides the molecular link between certain pre-existing states as hypoxia, hyperglycemia, glycation, inflammation, oxidative stress, and onset of cancers. The chronic inflammatory, hyperglycemic milieu accompanied by glycoxidative stress as in diabetes and obesity, concomitant with the formation of RAGE ligands, instigates RAGE and cancer stem cells, leading to the oncogenic transformation of normal and pre malignant tissues towards development of neoplasms. We have aimed to elucidate the complete signalling map initiated upon RAGE-ligand splicing, from oncogenesis to progression, epithelial-mesenchymal transition, invasion, cancer stem cell renewal, chemo-resistance, and cancer relapse. We have attributed the complex molecular functions of RAGE-ligand signalling cues to every aspect of cancer promotion, explaining the central network in bridging glycation, inflammation, oxidation, and the hallmarks of cancer. Underlining the substantial requisite for anti-neoplastic agents targeting RAGE and its ligands, we have explicitly discoursed RAGE and its allied components (AGEs, soluble RAGE, RAGE gene polymorphisms) as potential diagnostic and prognostic biomarkers for prompt detection of cancers and implication in impending RAGE-ligand directed, novel combinatorial, and targeted onco-therapeutics. PMID- 29987753 TI - Effects of Different Forms and Levels of Selenomethionine on Productive Performance and Antioxidant Status of Broiler Breeders and Its Offspring. AB - This study was conducted to investigate the effects of different selenomethionine (SM) forms and levels on productive performance and antioxidant status of broiler breeders and its offspring. Four hundred eighty 48-week-old Lingnan Yellow broiler breeders were randomly divided into four groups, provided basal diet with 0.15 or 0.30 mg/kg Se coming from two SM forms of DL-SM and L-SM. The experiment included a 4-week pretreatment period and an 8-week trial period. During the trial period, eggs were incubated once a week under standard conditions. The broiler breeders were slaughtered after the trial period. At the same time, 15 1 day-old chicks were selected at random per replicate and killed. The results showed that different SM forms and levels had no significant differences in average egg weight, feed intake, and feed-to-egg ration. The DL-SM group in contrast to the L-SM group induced a notable elevation of glutathione peroxidase (GPx) activity in serum (P < 0.01) and liver (P < 0.05), and the 0.15 mg/kg group had higher GPx activity than 0.30 mg/kg in serum (P < 0.01) and pancreas (P < 0.05). Different SM forms showed no significant differences in total antioxidant capability (T-AOC). Diets with 0.15 mg/kg Se exhibited a higher level of T-AOC in serum (P < 0.01) and some tissues. Besides, malondialdehyde (MDA) concentrations in serum, liver, and kidney significantly decreased due to the supplementation of DL-SM. Supplemental 0.15 mg/kg Se reduced MDA concentrations in kidney and muscle. The offspring of broiler breeders fed on DL-SM had higher GPx activity in liver and kidney than L-SM treatment. Supplemental 0.15 mg/kg Se also improved GPx activity in kidney and muscle and T-AOC in kidney of 1-day-old chicks. In summary, our study demonstrated that compared with L-SM, DL-SM was more effective for enhancing the antioxidant status of broiler breeders and its offspring. Moreover, the recommended level of Se supplementation was 0.15 mg/kg Se in Lingnan Yellow broiler breeder diets. PMID- 29987754 TI - Functional rhythmic tongue movements. PMID- 29987752 TI - Riding the waves of the intercalated disc of the heart. AB - Cardiomyocytes interact with each other at their ends through the specialised membrane complex, the intercalated disck (ID). It is a fascinating structure. It allows cardiomyocytes to interact with several neighbouring cells, thereby allowing the complex structure of the heart to develop. It acts as tension transducer, structural prop, and multi signalling domain as well as a regulator of growth. It achieves its many functions through a number of specialised domains and intercellular junctions associated with its complex folded membrane. This review outlines the results of some 20 years of fascination with the ups and downs of the ID. These include locating the spectrin-associated membrane cytoskeleton in the ID and investigating the role of Protein 4.1R in calcium signalling; structural studies of the relationship of the ID to myofibrils, sarcoplasmic reticulum and mitochondria and, finally, consideration of the role of the ID in cardiomyocyte growth and heart disease. PMID- 29987755 TI - Adjustment of insulin doses when switching from glargine 100 U/ml or detemir to degludec: an observational study. AB - BACKGROUND: Degludec is a long-acting insulin with a longer duration of action and a greater day-to-day reproducibility of absorption in comparison with previous long-acting insulin formulations. The aim is the definition of the change in insulin needs in patients switching from detemir/glargine to degludec in real-life conditions. METHODS: In this retrospective cohort observational study, all outpatients with either type 1 or type 2 diabetes, starting therapy with degludec insulin-after a prior treatment with either detemir or glargine insulin for at least 6 months-were included. RESULTS: The analysis was performed on 266 patients, 172 and 96 with type 1 and type 2 diabetes, respectively. The equations describing the relationship between baseline and follow-up doses of basal insulin (6 months) were Y = 3.39 + 0.78X and Y = 0.44 + 0.69X, in patients receiving detemir/glargine either once or twice daily, respectively (Y = degludec dose at 6 months and X = basal insulin dose at switch). The corresponding equations for prandial insulin doses were y = 1.83 + 0.83*x and y = 2.85 + 0.80*x for those on pre-switch once or twice-daily basal insulin, respectively. In type 2 diabetes, the switch was associated with a reduction of basal insulin doses only in those with a prior twice-daily treatment with basal insulin. The reduction of prandial insulin reached statistical significance only in patients previously treated with basal insulin once daily. CONCLUSIONS: The present results provide a suggestion for a simple method for the adjustment of basal and prandial insulin doses in type 1 diabetic patients, switching from glargine or detemir to degludec. PMID- 29987756 TI - The diagnostic accuracy of increased late night salivary cortisol for Cushing's syndrome: a real-life prospective study. AB - INTRODUCTION AND AIM: A prompt diagnosis of Cushing's Syndrome (CS) in high-risk populations is mandatory: 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), and urinary-free cortisol (UFC) are recommended, despite thresholds calculated in retrospective studies. Our aim was to study the diagnostic accuracy of LNSC measured with chemiluminescence assay in a prospective study, confirming discrepancies with mass spectrometry (MS). MATERIALS AND METHODS: We enrolled 117 controls and 164 suspected CS (CS = 47, non-CS = 117). In case of increased LNSC, high clinical suspicion of CS or adrenal incidentaloma, patients were hospitalized to exclude/confirm CS. RESULTS: LNSC levels were higher in patients with suspected CS, CS, and non-CS than controls. Considering 16 nmol/L as threshold for CS, overall LNSC revealed SE 97% and SP 84% in the whole group of subjects considered, achieving positive/negative likelihood ratio of 5.56/0.045, respectively. 35 out of 81 subjects with increased LNSC were non-CS (15 diabetic and 20 obese): considering only those patients with increased likelihood to have a CS (the non-CS patients) SP decreased to 70%, and further reduced to 60% if we discharged subjects with adrenal incidentaloma. MS analyses reduced partially the number of false-positive LNSC. CONCLUSIONS: LNSC measured in automated chemiluminescence is reliable in clinical practice: it present a high diagnostic accuracy to exclude hypercortisolism in patients with normal cortisol levels. MS could be used to reduce the number of false-positive results; nevertheless, some non-CS subjects with functional hypercortisolism could have a mild impairment of cortisol rhythm. PMID- 29987757 TI - Changes in Outpatient Use of Antibiotics by Adults in the United States, 2006 2015. AB - INTRODUCTION: Numerous initiatives over the past decade have targeted the problem of antibiotic overuse in the US; however, the cumulative impact of such initiatives upon recent patterns of use is not known. OBJECTIVES: The aims of this study were to (1) describe general trends in outpatient antibiotic use among adults over the period 2006-2015; and (2) identify rapid shifts in use during this time period as potential indicators for key events. METHODS: This was an observational study set in the ambulatory setting. Patients >= 18 years of age were selected from the Optum Clinformatics DatamartTM, a commercial insurance claims database. The outcome measures of interest were prescriptions filled/1000 enrolled individuals, by year or quarter. We used linear regression to identify trends in use over multiple years, and change-point regression to identify rapid shifts in use within individual years. RESULTS: From 2006 to 2015, antibiotic use declined significantly, decreasing by 12% for adults younger than 65 years of age (913-807 prescriptions/1000 individuals, p = 0.0001) and by 5% for adults >= 65 years of age (991-943 prescriptions/1000 individuals, p = 0.018). With change point regression, we identified a number of rapid shifts in the use of specific antibiotic classes, such as downward shifts in the use of quinolones and macrolides during the second quarter of 2008 and 2013, respectively. CONCLUSIONS: Over the period 2006-2015 outpatient use of antibiotics decreased substantially among adults. Rapid shifts in use occurring in 2008 and 2013 may reflect the presence of key drivers of change, such as abrupt changes in access to care or perceived antibiotic safety. PMID- 29987758 TI - How Common is Statin Use in the Oldest Old? AB - There is a lack of evidence surrounding the efficacy of statins in the oldest old (>= 80 years of age). As such, there is controversy surrounding use of statins in this population. We sought to evaluate the prevalence of statin use in the oldest old worldwide to understand the scope of this issue. We searched PubMed and grey literature over the last 5 years. Studies had to report the prevalence of statin use in adults >= 80 years of age. The first author performed screening and extracted data. Our search produced 1870 hits; 14 articles were considered eligible. We found three studies of nursing home residents, eight studies of community-dwelling patients and three studies in the combined population (i.e., both community-dwelling patients and nursing home residents). The prevalence of statin use ranged from 17 to 39% in nursing home residents, 12 to 59% for community-dwelling patients and 18 to 45% in combined populations. Beyond age 80 years, the prevalence of statin use appeared to decrease with advancing age. Statin use was more common as secondary prevention compared with primary prevention. The prevalence of statin use in the oldest old has increased over recent decades. The increase in prevalence appears to be more pronounced in the oldest old compared with younger old, as reported by two studies. Statins are widely used in the oldest old despite the lack of evidence in this population. Given how common statin use is in the oldest old, clinical evidence surrounding their efficacy in this group is urgently needed to guide appropriate use and shared decision-making. PMID- 29987759 TI - Shaping Pharmaceutical Tenders for Effectiveness and Sustainability in Countries with Expanding Healthcare Coverage. AB - Policy makers in countries, aiming to build and expand their healthcare systems and coverage, need effective procedures to support the most efficient use of limited financial resources. Tendering is commonly deployed to minimize and fix the purchasing price for the contract duration, especially for off-patent pharmaceuticals. While tenders can reduce acquisition costs, they may also expose the healthcare systems to risks including drug shortages, quality trade-offs, and ultimately, compromised patient health outcomes. Careful planning is therefore required. The effectiveness and impact of tendering were examined in different healthcare settings to establish good tender practices and to develop guidance for tender stakeholders in countries with expanding healthcare coverage for the effective conduct. The literature was reviewed for tender practices and outcomes in all countries, and tender experts from one multi-national pharmaceutical company in 17 countries with expanding healthcare coverage were surveyed on current tender practices. Tendering is a common practice for multisource pharmaceuticals in most countries worldwide. However, countries with expanding healthcare coverage specifically are vulnerable to the risks of defective tendering practices. Risk factors include non-transparent tender practices, a lack of consistency, unclear tender award criteria, a focus on lowest price only, single-winner tendering, and generally, a lack of impact monitoring. If well planned, managed, and conducted, tenders can be advantageous. Countries with expanding healthcare coverage should approach tenders strategically to achieve the desired improvements in healthcare. The good tender practices derived from this study may guide policy makers and purchasers in countries with expanding healthcare coverage on how to expand access to healthcare at an affordable cost. These include the use of multiple selection criteria and performance monitoring. Plain Language Summary Decision makers in countries aiming to expand their healthcare systems must best use the limited money available for healthcare. Tendering is commonly deployed for pharmaceuticals produced by multiple manufacturers (so-called multisource pharmaceuticals), to choose the product with the lowest price. Through tenders, purchasers request offers from suppliers for the needed products.The ultimate purpose of our research was to develop a guidance on robust tender processes. Therefore, we reviewed the literature to examine the effectiveness and impact of current tendering practices. In addition, we conducted a survey among tender experts from one pharmaceutical company in 17 countries with expanding healthcare coverage.In both the survey and the literature review, we confirmed that worldwide, tendering is a common practice for multisource pharmaceuticals. However, defective tendering practices may increase the vulnerability for some risks including abuse due to intransparent processes, lack of consistency, unclear tender award criteria, a focus on lowest price only, single winner tendering, and generally, a lack of impact monitoring after the end of the tender process.Hence, tenders must be well planned, managed, and conducted to be advantageous. Countries with defined and transparent tender frameworks and processes will be better equipped to achieve the desired improvements in the healthcare systems. 'Good tender practices' include the clear definition of requirements to be used as selection criteria in addition to acquisition costs, and for monitoring of the tender success. 'Good tender practices' may help to manage cost and improve healthcare at the same time. PMID- 29987760 TI - Abstracts of 20th Annual ASENT Meeting. PMID- 29987762 TI - Angiotensin Type 1 Receptor Antagonists Protect Against Alpha-Synuclein-Induced Neuroinflammation and Dopaminergic Neuron Death. AB - The loss of dopaminergic neurons and alpha-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of alpha-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin 1beta, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD. PMID- 29987764 TI - Shared or separated representations for letters with diacritics? AB - Understanding the front end of visual word recognition requires us to identify the processes by which letters are identified. Since most of the work on letter recognition has been conducted in English, letter perception modeling has been limited to the 26 letters of the Latin alphabet. However, many writing systems include letters with diacritic marks. In the present study, we examined whether diacritic letters are a mere variant of their base letter, and thus share the same abstract representation, or whether they function as separate elements from any other letters, and thus have separate representations. In Experiments 1A and 1B, participants performed an alphabetical decision task combined with masked priming. Target letters were preceded by the same letter (e.g., a-A), by a diacritic letter (e.g., a-A), or by an unrelated letter (e.g., z-A). The results showed that the primes sharing nominal identity (e.g., a) facilitated target processing as compared to unrelated primes (e.g., z), but that primes that included a diacritic mark (e.g., a) did not, with reaction times being similar to those in the unrelated priming condition. In Experiment 2 we replicated these results in a lexical decision task. Overall, this demonstrates that as long as diacritics are used in scripts to distinguish between lexical entries, the diacritic letters are not mere variants of their base letters but constitute unitary elements of the script in their own right, with diacritics contributing to the overall visual shape of a letter. PMID- 29987761 TI - Retraining Reflexes: Clinical Translation of Spinal Reflex Operant Conditioning. AB - Neurological disorders, such as spinal cord injury, stroke, traumatic brain injury, cerebral palsy, and multiple sclerosis cause motor impairments that are a huge burden at the individual, family, and societal levels. Spinal reflex abnormalities contribute to these impairments. Spinal reflex measurements play important roles in characterizing and monitoring neurological disorders and their associated motor impairments, such as spasticity, which affects nearly half of those with neurological disorders. Spinal reflexes can also serve as therapeutic targets themselves. Operant conditioning protocols can target beneficial plasticity to key reflex pathways; they can thereby trigger wider plasticity that improves impaired motor skills, such as locomotion. These protocols may complement standard therapies such as locomotor training and enhance functional recovery. This paper reviews the value of spinal reflexes and the therapeutic promise of spinal reflex operant conditioning protocols; it also considers the complex process of translating this promise into clinical reality. PMID- 29987765 TI - Model-guided search for optimal natural-science-category training exemplars: A work in progress. AB - Under the guidance of a formal exemplar model of categorization, we conduct comparisons of natural-science classification learning across four conditions in which the nature of the training examples is manipulated. The specific domain of inquiry is rock classification in the geologic sciences; the goal is to use the model to search for optimal training examples for teaching the rock categories. On the positive side, the model makes a number of successful predictions: Most notably, compared with conditions involving focused training on small sets of training examples, generalization to novel transfer items is significantly enhanced in a condition in which learners experience a broad swath of training examples from each category. Nevertheless, systematic departures from the model predictions are also observed. Further analyses lead us to the hypothesis that the high-dimensional feature-space representation derived for the rock stimuli (to which the exemplar model makes reference) systematically underestimates within-category similarities. We suggest that this limitation is likely to arise in numerous situations in which investigators attempt to build detailed feature space representations for naturalistic categories. A low-parameter extended version of the model that adjusts for this limitation provides dramatically improved accounts of performance across the four conditions. We outline future steps for enhancing the current feature-space representation and continuing our goal of using formal psychological models to guide the search for effective methods of teaching science categories. PMID- 29987763 TI - Robotic Rehabilitation and Spinal Cord Injury: a Narrative Review. AB - Mobility after spinal cord injury (SCI) is among the top goals of recovery and improvement in quality of life. Those with tetraplegia rank hand function as the most important area of recovery in their lives, and those with paraplegia, walking. Without hand function, emphasis in rehabilitation is placed on accessing one's environment through technology. However, there is still much reliance on caretakers for many activities of daily living. For those with paraplegia, if incomplete, orthoses exist to augment walking function, but they require a significant amount of baseline strength and significant energy expenditure to use. Options for those with motor complete paraplegia have traditionally been limited to the wheelchair. While wheelchairs provide a modified level of independence, wheelchair users continue to face difficulties in access and mobility. In the past decade, research in SCI rehabilitation has expanded to include external motorized or robotic devices that initiate or augment movement. These robotic devices are used with 2 goals: to enhance recovery through repetitive, functional movement and increased neural plasticity and to act as a mobility aid beyond orthoses and wheelchairs. In addition, lower extremity exoskeletons have been shown to provide benefits to the secondary medical conditions after SCI such as pain, spasticity, decreased bone density, and neurogenic bowel. In this review, we discuss advances in robot-guided rehabilitation after SCI for the upper and lower extremities, as well as potential adjuncts to robotics. PMID- 29987766 TI - Exploring the neurocognitive basis of episodic recollection in autism. AB - Increasing evidence indicates that the subjective experience of recollection is diminished in autism spectrum disorder (ASD) compared to neurotypical individuals. The neurocognitive basis of this difference in how past events are re-experienced has been debated and various theoretical accounts have been proposed to date. Although each existing theory may capture particular features of memory in ASD, recent research questions whether any of these explanations are alone sufficient or indeed fully supported. This review first briefly considers the cognitive neuroscience of how episodic recollection operates in the neurotypical population, informing predictions about the encoding and retrieval mechanisms that might function atypically in ASD. We then review existing research on recollection in ASD, which has often not distinguished between different theoretical explanations. Recent evidence suggests a distinct difficulty engaging recollective retrieval processes, specifically the ability to consciously reconstruct and monitor a past experience, which is likely underpinned by altered functional interactions between neurocognitive systems rather than brain region-specific or process-specific dysfunction. This integrative approach serves to highlight how memory research in ASD may enhance our understanding of memory processes and networks in the typical brain. We make suggestions for future research that are important for further specifying the neurocognitive basis of episodic recollection in ASD and linking such difficulties to social developmental and educational outcomes. PMID- 29987767 TI - Proficiency-based training of medical students using virtual simulators for laparoscopy and robot-assisted surgery: results of a pilot study. AB - Proficiency-based training has become essential in the training of surgeons such that on completion they can execute complex operations with novel surgical approaches including direct manual laparoscopic surgery (DMLS) and robotically assisted laparoscopic surgery (RALS). To this effect, several virtual reality (VR) simulators have been developed. The objective of the present study was to assess and establish proficiency gain curves for medical students on VR simulators for DMLS and RALS. Five medical students participated in training course consisting of didactic teaching and practical hands-on training with VR simulators for DMLS and RALS. Evaluation of didactic component was by questionnaire completed by participating students, who also were required to undertake selected exercises to reach proficiency at each VR simulator: (1) 12 tasks on LapSim VR (Surgical Science, Gothenburg, Sweden) for DMLS, and (2) six selected exercises on the dV-Trainer Mimic (Seattle, WA, United States). The five medical students reached the 60% threshold on the questionnaire-based didactic component. During selected hands-on simulation on VR simulators, students with previous experience with simulators (n = 3) outperformed those without (n = 2) in ten out of twelve LapSim tasks and all six at dV-Trainer, by requiring fewer attempts to reach proficiency although the difference was not significant (p < 0.05). In this work, we developed a proficiency-based training program for medical undergraduates based on surgical simulation for DMLS and RALS.z. Larger studies are needed to evaluate the benefit of this program in stimulating interest for surgical career amongst medical students after the qualify. PMID- 29987768 TI - The Burden of Depression in New York City Adults: Results from the 2013-14 NYC Health and Nutrition Examination Survey. AB - Depression is responsible for a large burden of disability in the USA. We estimated the prevalence of depression in the New York City (NYC) adult population in 2013-14 and examined associations with demographics, health behaviors, and employment status. Data from the 2013-14 New York City Health and Nutrition Examination Survey, a population-based examination study, were analyzed, and 1459 participants met the inclusion criteria for this analysis. We defined current symptomatic depression by a Patient Health Questionnaire (PHQ-9) score >= 10. Overall, 8.3% of NYC adults had current symptomatic depression. New Yorkers with current symptomatic depression were significantly more likely to be female, Latino, and unemployed yet not looking for work; they were also significantly more likely to have less than a high school education and to live in a high-poverty neighborhood. Socioeconomic inequalities in mental health persist in NYC and highlight the need for better diagnosis and treatment. PMID- 29987769 TI - Disparities in Sleep Problems by Sexual Orientation among New York City Adults: an Analysis of the New York City Health and Nutrition Examination Survey, 2013 2014. AB - We examined disparities in sleep problems by sexual orientation among a population-based sample of adults, using data from the New York City (NYC) Health and Nutrition Examination Survey (NYC HANES), a population-based, cross-sectional survey conducted in 2013-2014 (n = 1220). Two log binomial regression models were created to assess the relative prevalence of sleep problems by sexual orientation. In model 1, heterosexual adults served as the reference category, controlling for gender, age, race/ethnicity, education, marital status, and family income. And in model 2, heterosexual men served as the reference category, controlling for age, race/ethnicity, education, marital status, and family income. We found that almost 42% of NYC adults reported sleep problems in the past 2 weeks. Bisexual adults had 1.4 times the relative risk of sleep problems compared to heterosexual adults (p = 0.037). Compared to heterosexual men, heterosexual and bisexual women had 1.3 and 1.6 times the risk of sleep problems, respectively (p < 0.05). Overall, adults who self-identified as bisexual had a significantly greater risk of sleep problems than adults who self-identified as heterosexual. PMID- 29987770 TI - NYC HANES 2013-14 and Reflections on Future Population Health Surveillance. PMID- 29987771 TI - Change in Diabetes Prevalence and Control among New York City Adults: NYC Health and Nutrition Examination Surveys 2004-2014. AB - National examination surveys provide trend information on diabetes prevalence, diagnoses, and control. Few localities have access to such information. Using a similar design as the National Health and Nutrition Examination Survey (NHANES), two NYC Health and Nutrition Examination Surveys (NYC HANES) were conducted over a decade, recruiting adults >= 20 years using household probability samples (n = 1808 in 2004; n = 1246 in 2013-2014) and physical exam survey methods benchmarked against NHANES. Participants had diagnosed diabetes if told by a health provider they had diabetes, and undiagnosed diabetes if they had no diagnosis but a fasting plasma glucose >= 126 mg/dl or A1C >= 6.5%. We found that between 2004 and 2014, total diabetes prevalence (diagnosed and undiagnosed) in NYC increased from 13.4 to 16.0% (P = 0.089). In 2013-2014, racial/ethnic disparities in diabetes burden had widened; diabetes was highest among Asians (24.6%), and prevalence was significantly lower among non-Hispanic white adults (7.7%) compared to that among other racial/ethnic groups (P < 0.001). Among adults with diabetes, the proportion of cases diagnosed increased from 68.3 to 77.3% (P = 0.234), and diagnosed cases with very poor control (A1C > 9%), decreased from 26.9 to 18.0% (P = 0.269), though both were non-significant. While local racial/ethnic disparities in diabetes prevalence persist, findings suggest modest improvements in diabetes diagnosis and management. PMID- 29987772 TI - Gender and Race Disparities in Cardiovascular Disease Risk Factors among New York City Adults: New York City Health and Nutrition Examination Survey (NYC HANES) 2013-2014. AB - While gender and racial/ethnic disparities in cardiovascular disease (CVD) risk factors have each been well characterized, few studies have comprehensively examined how patterns of major CVD risk factors vary and intersect across gender and major racial/ethnic groups, considered together. Using data from New York City Health and Nutrition Examination Survey 2013-2014-a population-based, cross sectional survey of NYC residents ages 20 years and older-we measured prevalence of obesity, hypertension, hypercholesterolemia, smoking, and diabetes across gender and race/ethnicity groups for 1527 individuals. We used logistic regression with predicted marginal to estimate age-adjusted prevalence ratio by gender and race/ethnicity groups and assess for potential additive and multiplicative interaction. Overall, women had lower prevalence of CVD risk factors than men, with less hypertension (p = 0.040), lower triglycerides (p < 0.001), higher HDL (p < 0.001), and a greater likelihood of a heart healthy lifestyle, more likely not to smoke and to follow a healthy diet (p < 0.05). When further stratified by race/ethnicity, however, the female advantage was largely restricted to non-Latino white women. Non-Latino black women had significantly higher risk of being overweight or obese, having hypertension, and having diabetes than non-Latino white men or women, or than non-Latino black men (p < 0.05). Non-Latino black women also had higher total cholesterol compared to non Latino black men (184.4 vs 170.5 mg/dL, p = 0.010). Despite efforts to improve cardiovascular health and narrow disparities, non-Latino black women continue to have a higher burden of CVD risk factors than other gender and racial/ethnic groups. This study highlights the importance of assessing for intersectionality between gender and race/ethnicity groups when examining CVD risk factors. PMID- 29987773 TI - Change in Obesity Prevalence among New York City Adults: the NYC Health and Nutrition Examination Survey, 2004 and 2013-2014. AB - The objective of this study was to measure change in obesity prevalence among New York City (NYC) adults from 2004 to 2013-2014 and assess variation across sociodemographic subgroups. We used objectively measured height and weight data from the NYC Health and Nutrition Examination Survey to calculate relative percent change in obesity (>= 30 kg/m2) between 2004 (n = 1987) and 2013-2014 (n = 1489) among all NYC adults and sociodemographic subgroups. We also examined changes in self-reported proxies for energy imbalance. Estimates were age standardized and statistical significance was evaluated using two-tailed T tests and multivariable regression (p < 0.05). Between 2004 and 2013-2014, obesity increased from 27.5 to 32.4% (p = 0.01). Prevalence remained stable and high among women (31.2 to 32.8%, p = 0.53), but increased among men (23.4 to 32.0%, p = 0.002), especially among non-Latino White men and men age >= 65 years. Black adults had the highest prevalence in 2013-2014 (37.1%) and Asian adults experienced the largest increase (20.1 to 29.2%, p = 0.06), especially Asian women. Foreign-born participants and participants lacking health insurance also had large increases in obesity. We observed increases in eating out and screen time over time and no improvements in physical activity. Our findings show increases in obesity in NYC in the past decade, with important sociodemographic differences. PMID- 29987774 TI - Medical Students Actively Seek Gun Violence Education. PMID- 29987775 TI - Test-retest reliability of value-driven attentional capture. AB - Attention is biased toward learned predictors of reward. The degree to which attention is automatically drawn to arbitrary reward cues has been linked to a variety of psychopathologies, including drug dependence, HIV-risk behaviors, depressive symptoms, and attention deficit/hyperactivity disorder. In the context of addiction specifically, attentional biases toward drug cues have been related to drug craving and treatment outcomes. Given the potential role of value-based attention in psychopathology, the ability to quantify the magnitude of such bias before and after a treatment intervention in order to assess treatment-related changes in attention allocation would be desirable. However, the test-retest reliability of value-driven attentional capture by arbitrary reward cues has not been established. In the present study, we show that an oculomotor measure of value-driven attentional capture produces highly robust test-retest reliability for a behavioral assessment, whereas the response time (RT) measure more commonly used in the attentional bias literature does not. Our findings provide methodological support for the ability to obtain a reliable measure of susceptibility to value-driven attentional capture at multiple points in time, and they highlight a limitation of RT-based measures that should inform the use of attentional-bias tasks as an assessment tool. PMID- 29987776 TI - Determinants of metabolic syndrome in obese workers: gender differences in perceived job-related stress and in psychological characteristics identified using artificial neural networks. AB - OBJECTIVE: The metabolic syndrome (MS) is a multifactorial disorder associated with a higher risk of developing cardiovascular diseases and type 2 diabetes. However, its pathophysiology and risk factors are still poorly understood. In this study, we investigated the associations among gender, psychosocial variables, job-related stress and the presence of MS in a cohort of obese Caucasian workers. METHODS: A total of 210 outpatients (142 women, 68 men) from an occupational medicine service was enrolled in the study. Age, BMI, waist circumference, fasting glucose, blood pressure, triglycerides and HDL cholesterol were collected to define MS. In addition, we evaluated eating behaviors, depressive symptoms, and work-related stress. Data analyses were performed with an artificial neural network algorithm called Auto Semantic Connectivity Map (AutoCM), using all available variables. RESULTS: MS was diagnosed in 54.4 and 33.1% of the men and women, respectively. AutoCM evidenced gender-specific clusters associated with the presence or absence of MS. Men with a moderate occupational physical activity, obesity, older age and higher levels of decision making freedom at work were more likely to have a diagnosis of MS than women. Women with lower levels of decision-making freedom, and higher levels of psychological demands and social support at work had a lower incidence of MS but showed higher levels of binge eating and depressive symptomatology. CONCLUSION: We found a complex gender-related association between MS, psychosocial risk factors and occupational determinants. The use of these information in surveillance workplace programs might prevent the onset of MS and decrease the chance of negative long-term outcomes. LEVEL OF EVIDENCE: Level V, observational study. PMID- 29987777 TI - Associations of dietitian follow-up counselling visits and physical exercise with weight loss one year after sleeve gastrectomy. AB - PURPOSE: To examine associations of patients' attendance to follow-up meetings with a registered dietitian (RD) and physical exercise practices with weight loss during the 1 year following laparoscopic sleeve gastrectomy (SG). METHODS: Of 241 patients with obesity who underwent SG during 2012, 184 (76.3%) participated in a 1-year follow-up telephone interview and had information on number of RD follow up meetings. Clinical information was available from computerized patient files. Multiple logistic regression analysis, adjusting for propensity score, was computed to reveal factors associated with greater weight loss. RESULTS: The mean %TWL was 31.4 +/- 6.1 and the mean number of reported RD meetings during the year following SG was 4.6. The proportion of physically active patients increased by 15% (from 23 to 42) among those who attended at least 3 RD follow-up meetings (n = 123), and by 5% (from 18 to 23) among those who attended fewer than 3 meetings (n = 61) (p = 0.05). Patients conducting physical exercise reported a lower level of pain/discomfort on the EQ5D quality-of-life questionnaire (p = 0.03). The adjusted regression model revealed no association between the number of RD follow up meetings and weight-reduction success, but physical exercise during the year following SG conferred a 2.6 times greater odds of belonging to the upper two tertiles of the % excess body weight loss ( 95% CI 1.2-5.3). CONCLUSIONS: Patients with better adherence to RD follow-up meetings were also more physically active. Patients on physical exercise also achieved greater weight reduction following SG, and reported less pain or discomfort. Nutritional counselling and physical exercise are necessary to ensure maximal and sustainable benefits from SG. LEVEL OF EVIDENCE: Level III, Cohort study. PMID- 29987778 TI - 500 Million Alveoli from 30,000 Feet: A Brief Primer on Lung Anatomy. AB - The lungs are a complex organ that fulfill multiple life-sustaining roles including transfer of oxygen and carbon dioxide between the ambient environment and the bloodstream, host defense, and immune homeostasis. As in any biological system, an understanding of the underlying anatomy is prerequisite for successful experimental design and appropriate interpretation of data, regardless of the precise experimental model or procedure in use. This chapter provides an overview of human lung anatomy focused on the airways, the ultrastructure or parenchyma of the lung, the pulmonary vasculature, the innervation of the lungs, and the pulmonary lymphatic system. We will also discuss notable anatomic differences between mouse and human lungs. PMID- 29987779 TI - Overview of Innate Lung Immunity and Inflammation. AB - The nasal passages, conducting airways and gas-exchange surfaces of the lung, are constantly exposed to substances contained in the air that we breathe. While many of these suspended substances are relatively harmless, some, for example, pathogenic microbes, noxious pollutants, and aspirated gastric contents can be harmful. The innate immune system, lungs and conducting airways have evolved specialized mechanisms to protect the respiratory system not only from these harmful inhaled substances but also from the overly exuberant innate immune activation that can arise during the host response to harmful inhaled substances. Herein, we discuss the cell types that contribute to lung innate immunity and inflammation and how their activities are coordinated to promote lung health. PMID- 29987781 TI - Isolation and Characterization of Mouse Neutrophils. AB - Isolation of murine neutrophils from several anatomical compartments allows for functional characterization and analysis of these cells. Here we describe the isolation of bone marrow, peripheral blood, and lung airspace and interstitial neutrophil populations, using density gradient separation, lavage, and flow cytometry techniques. PMID- 29987780 TI - Isolation and Characterization of Mononuclear Phagocytes in the Mouse Lung and Lymph Nodes. AB - There is a diverse population of mononuclear phagocytes (MPs) in the lungs, comprised of macrophages, dendritic cells (DCs), and monocytes. The existence of these various cell types suggests that there is a clear division of labor and delicate balance between the MPs under steady-state and inflammatory conditions. Here we describe how to identify pulmonary MPs using flow cytometry and how to isolate them via cell sorting. In steady-state conditions, murine lungs contain a uniform population of alveolar macrophages (AMs), three distinct interstitial macrophage (IM) populations, three DC subtypes, and a small number of tissue trafficking monocytes. During an inflammatory response, the monocyte population is more abundant and complex since it acquires either macrophage-like or DC-like features. All in all, studying how these cell types interact with each other, structural cells, and other leukocytes within the environment will be important to understanding their role in maintaining homeostasis and during the development of disease. PMID- 29987782 TI - Isolation and Characterization of Mouse Fibroblasts. AB - The lung parenchyma is comprised of many cells including the structurally important stromal fibroblasts. Fibroblasts function to produce extracellular matrix and are important in the maintenance of alveolar epithelial cells. To understand the role of fibroblasts both in homeostasis and disease, we isolate fibroblasts and grow them in culture. Two methods are presented here for the isolation and maintenance of mouse primary lung fibroblasts. PMID- 29987783 TI - Isolation of Rat and Mouse Alveolar Type II Epithelial Cells. AB - The gas exchange surface of the lungs is lined by an epithelium consisting of alveolar type (AT) I and ATII cells. ATII cells function to produce surfactant, play a role in host defense and fluid and ion transport, and serve as progenitors. ATI cells are important for gas exchange and fluid and ion transport. Our understanding of the biology of these cells depends on the investigation of isolated cells. Here, we present methods for the isolation of mouse and rat ATII cells. PMID- 29987784 TI - Isolation and Characterization of Human Alveolar Type II Cells. AB - Alveolar type II (ATII) cells synthesize, store, and secrete pulmonary surfactant and restore the epithelium after damage to the alveolar epithelium. Isolation of human ATII cells provides a valuable tool to study their function under normal and pathophysiological conditions. Moreover, maintenance of their differentiated phenotype in vitro allows further study of their function. Here we describe a protocol for efficient ATII cell isolation, characterization, and culture. PMID- 29987785 TI - Air-Liquid Interface Culture of Human and Mouse Airway Epithelial Cells. AB - Air-liquid interface culture enables airway epithelial cells to differentiate into a pseudostratified cell layer, consisting of ciliated cells, goblet/secretory cells, and basal cells (Ghio et al., Part Fibre Toxicol 10:25, 2013). This technique is critically important for in vitro studies of lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, since differentiated airway epithelial cells are more representative of the in vivo lung environment than non-differentiated cells (Derichs et al., FASEB J 25:2325-2332, 2011; Hackett et al., Am J Respir Cell Mol Biol 45:1090-1100, 2011;Schneider et al., Am J Respir Crit Care Med 182: 332-340, 2010). Here we describe the process of isolating and expanding human and mouse airway epithelial cells, as well as differentiation of airway epithelial cells by air-liquid interface culture. PMID- 29987786 TI - Isolation and Characterization of Human Lung Myeloid Cells. AB - Multiparameter flow cytometry of human lungs allows for characterization, isolation, and examination of human pulmonary immune cell composition, phenotype, and function. Here we describe an approach to process lung tissues and then utilize a base antibody panel to define all of the major immune cell types in a single staining condition. This base antibody panel can also be used to identify major immune cell types in human blood and bronchoalveolar lavage (BAL) fluid. PMID- 29987787 TI - Measurement of Protein Permeability and Fluid Transport of Human Alveolar Epithelial Type II Cells Under Pathological Conditions. AB - Alveolar epithelial barrier dysfunction contributes to the influx of protein-rich edema fluid and the accumulation of inflammatory cells in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To study the alveolar epithelial barrier function under pathological conditions, we developed an in vitro model of acute lung injury using cultured human alveolar epithelial type II (ATII) cells. Here we describe the methods that we use to measure protein permeability and fluid transport across human ATII cell monolayers under stimulated conditions. Both proinflammatory cytokines and edema fluid from ALI/ARDS patients can increase protein permeability and decrease fluid transport across the human ATII cells monolayer. PMID- 29987788 TI - Measuring Innate Immune Function in Mouse Mononuclear Phagocytes. AB - While serving as a conduit for gas exchange, the lung continually encounters potentially harmful airborne and bloodborne substances including particulate matter, allergens, toxins, and infectious agents. Resident alveolar and interstitial macrophages coordinate with neutrophils, dendritic cells, and recruited blood-derived monocytes to provide phagocytic host defense that aids in the removal and destruction of antigenic material following this myriad of exposures. Here we describe flow cytometric methods for specifically assessing phagocytic activity ex vivo in isolated mouse lung macrophages and monocytes utilizing fluorescently labeled Streptococcus pneumoniae. PMID- 29987789 TI - Measuring Neutrophil Bactericidal Activity. AB - The best-known role of neutrophils is control of pathogen growth. Neutrophils contain and kill pathogens through a variety of antimicrobial activities. Regardless of the mechanism, the ability to kill pathogens is a vital outcome. This chapter describes a method to measure the in vitro bactericidal activity of isolated neutrophils as the endpoint of converging innate immune functions. PMID- 29987790 TI - Modulation of Myeloid Cell Function Using Conditional and Inducible Transgenic Approaches. AB - Transgenic mice have emerged as a central tool in the study of lung myeloid cells during homeostasis and disease. The use of Cre/Lox site-specific recombination allows for conditional deletion of a gene of interest in a spatially controlled manner. The basic Cre/Lox system can be further refined to include an inducible trigger, enabling conditional deletion of a gene of interest in a spatially and temporally controlled manner. Here we provide an overview of commercially available conditional and inducible conditional mouse strains that target lung myeloid cells and describe the appropriate breeding schemes and controls for transgenic animal systems that can be used to modulate myeloid cell function. PMID- 29987791 TI - Modulation of Lung Epithelial Cell Function Using Conditional and Inducible Transgenic Approaches. AB - In the lungs, the epithelium is a first line of innate defense. In acute settings, such as infection or particulate exposure, the epithelium is protective. Protection is conferred by the epithelium's role as a physical barrier and by its ability to synthesize proteins that promote defense directly through physical interactions (e.g., mucins and anti-microbial peptides) and indirectly through the production of proteins that regulate inflammation (e.g., cytokines and chemokines). Despite its importance as a first line of host defense, the epithelium is also a significant target and an effector in lung pathologies. Accordingly, to determine the significance and biological mechanisms of genes involved in pulmonary defense, it is important to be able to interrogate the lung epithelium. In mice, this presents challenges related to the cellular location and timing of interventions. Effective genetic strategies for targeting the lung epithelium using tissue-/cell-specific and inducible control have been developed over the past decade. Methods for spatiotemporal targeting of gene expression are described here. PMID- 29987792 TI - Computational Analysis of RNA-Seq Data from Airway Epithelial Cells for Studying Lung Disease. AB - Airway epithelial cells (AECs) play a central role in the pathogenesis of many lung diseases. Consequently, advancements in our understanding of the underlying causes of lung diseases, and the development of novel treatments, depend on continued detailed study of these cells. Generation and analysis of high throughput gene expression data provide an indispensable tool for carrying out the type of broad-scale investigations needed to identify the key genes and molecular pathways that regulate, distinguish, and predict distinct pulmonary pathologies. Of the available technologies for generating genome-wide expression data, RNA sequencing (RNA-seq) has emerged as the most powerful. Hence many researchers are turning to this approach in their studies of lung disease. For the relatively uninitiated, computational analysis of RNA-seq data can be daunting, given the large number of methods and software packages currently available. The aim of this chapter is to provide a broad overview of the major steps involved in processing and analyzing RNA-seq data, with a special focus on methods optimized for data generated from AECs. We take the reader from the point of obtaining sequence reads from the lab to the point of making biological inferences with expression data. Along the way, we discuss the statistical and computational considerations one typically confronts during different phases of analysis and point to key methods, software packages, papers, online guides, and other resources that can facilitate successful RNA-seq analysis. PMID- 29987793 TI - Application of Proteomics in Lung Research. AB - Proteomics has enabled researchers to evaluate global protein changes in a relatively rapid and comprehensive manner. Applications of these technologies in lung research include biomarker and drug discovery, elucidating disease mechanisms, and quantitative clinical assays. Two common workflows exist for quantitative proteomics studies that are aimed at determining differences in protein levels: label-free and labeling methods. Here we describe specific techniques involved in both quantitative workflows; these include extensive sample preparation methods for several lung-specific sample types. Methods are also included for mass spectrometry-based sample analysis and data analysis. While the focus is on quantitative, clinical proteomics, these strategies are appropriate for a wide array of sample types and applications. PMID- 29987794 TI - Application of Metabolomics in Lung Research. AB - Advancements in omics technologies have increased our potential to evaluate molecular changes in a rapid and comprehensive manner. This is especially true in mass spectrometry-based metabolomics where improvements, including ease of use, in high-performance liquid chromatography (HPLC), column chemistries, instruments, software, and molecular databases, have advanced the field considerably. Applications of this relatively new omics technology in clinical research include discovering disease biomarkers, finding new drug targets, and elucidating disease mechanisms. Here we describe a typical clinical metabolomics workflow, which includes the following steps: (1) extraction of metabolites from the lung, plasma, bronchoalveolar lavage, or cells; (2) sample analysis via liquid chromatography-mass spectrometry; and (3) data analysis using commercial and freely available software packages. Overall, the methods delineated here can help investigators use metabolomics to discovery novel biomarkers and to understand lung diseases. PMID- 29987795 TI - Functional Genomics in Murine Macrophages. AB - In this chapter, we describe methods for functional genomics studies in mouse macrophages. In particular, we describe complementary methods for gene inhibition using RNA interference (RNAi) and gene overexpression. These methods are readily amenable to medium- and high-throughput functional genomics investigations. These complementary loss-of-function and gain-of-function genomic approaches provide a rapid means of investigating the function of candidate genes prior to initiating more cumbersome studies in vivo. PMID- 29987796 TI - Assessment of Ozone-Induced Lung Injury in Mice. AB - Ozone is a major pollutant in the air we breathe, and elevated levels lead to significant morbidity and mortality. As the climate warms, levels of ozone are predicted to increase. Accordingly, studies to assess the mechanisms of ozone induced lung diseases are paramount. This chapter describes mouse models of ozone exposure and methods for assessing the effects of ozone in the lungs. These include bronchoalveolar lavage, necropsy, and measurement of lung function. Lavage allows for assessment of cell infiltration, cytokine production, tissue damage and capillary leakage in the airspaces. Necropsy provides tissue for gene expression, histology, and protein assessment in the whole lung. Lung physiology is used to assess airway hyperresponsiveness, tissue and total lung resistance, compliance, and elastance. PMID- 29987797 TI - Lung Histological Methods. AB - The lung is ideally suited to the application of histological methods to study its structure, cellular composition, and molecular characteristics of more than 30 types of cells. The key in these endeavors are proper tissue preservation/fixation, well-established protocols aimed at sectioning and staining, and understanding of lung morphology. Molecular studies can be performed in laser-captured cells and microscopic structures. PMID- 29987798 TI - Intravital Microscopy in the Mouse Lung. AB - While reductionist in vitro approaches have allowed for careful interrogation of cellular pathways that underlie innate immune responses, they often fail to capture the complex multicellular interactions characteristic of acute inflammation. Intravital microscopy, by directly observing alveolar cell-cell interactions, provides unique insight into the complex intercellular mechanisms responsible for alveolar inflammation. This review discusses multiple potential approaches to intravital pulmonary imaging, with specific attention to in vivo microscopy of the freely moving mouse lung. PMID- 29987799 TI - Mouse Models of Acute Lung Injury and ARDS. AB - The acute respiratory distress syndrome (ARDS) is a devastating illness characterized by severe hypoxemia and diffuse alveolar damage. Direct lung infection is the leading cause of ARDS and can be modeled in mice using sterile models of inflammation or live pathogens. In this chapter, two mouse models for ARDS are defined. These include an infectious model of ARDS driven by direct administration of Streptococcus pneumoniae and a sterile inflammatory model mediated by intratracheal administration of lipopolysaccharide. Methods for growth and preparation of Streptococcus pneumoniae are provided as methods to assess lung inflammation and injury. PMID- 29987800 TI - Mouse Models of Asthma. AB - Mouse models are critical for delineating the mechanisms that underlie asthma pathogenesis and developing new treatments. In this chapter we describe four different asthma models that offer unique benefits and allow investigators to answer distinct research questions. We also describe key surgical procedures that are necessary for assessing experimental asthma. PMID- 29987801 TI - Animal Models of Pulmonary Fibrosis. AB - Pulmonary fibrosis is a debilitating disease and is often fatal. It may be the consequence of direct lung injury or the result of genetic defects and occupational, environmental, or drug-related exposures. In many cases the etiology is unknown. The pathogenesis of all forms of pulmonary fibrosis regardless of type of injury or etiology is incompletely understood. These disorders are characterized by the accumulation of extracellular matrix in the lung interstitium with a loss of lung compliance and impaired gas exchange that ultimately leads to respiratory failure. Animal models of pulmonary fibrosis have become indispensable in the improved understanding of these disorders. Multiple models have been developed each with advantages and disadvantages. In this chapter we discuss the application of two of the most commonly employed direct lung instillation models, namely, the induction of pulmonary fibrosis with bleomycin or fluorescein isothiocyanate (FITC). We provide details on design, materials, and methods and describe how these models can be best undertaken. We also discuss methods to induce fibrosis in aged mice using murine gamma herpesvirus (gammaHV-68) and approaches to exacerbate bleomycin- or FITC-induced fibrosis using gammaHV-68. PMID- 29987802 TI - Mouse Models of COPD. AB - Elastase and chronic cigarette smoke exposure animal models are commonly used to study lung morphologic and functional changes associated with emphysema-like airspace enlargement in various animal species. This chapter describes the rationale for using these two models to study mechanisms of COPD pathogenesis and provides protocols for their implementation. E-cigarettes are an emerging health concern and may also contribute to lung disease. Accordingly, approaches to study e-cigarette vapors are provided. This chapter also includes methods and tools necessary to assess lung morphologic and functional changes in animals with emphysema-like airspace enlargement. PMID- 29987803 TI - Mouse Models of Viral Infection. AB - Viral respiratory tract infections are common in both children and adults. Mouse models of viral infection enable the characterization of host immune factors that protect against or promote virus infection; thus, mouse models are essential for interrogation of potential therapeutic targets. Moreover, they serve as critical models for the development of novel vaccine strategies. In this chapter, we describe methods for establishing mouse models of respiratory syncytial virus (RSV) and H1N1 influenza A virus infection. Protocols are provided for viral culture and expansion, plaque-forming assays for viral quantification, and infection of mice. Alternate modifications to the models are also described, and their potential impact is discussed. PMID- 29987804 TI - Delivery of Therapeutics to the Lung. AB - Pulmonary delivery in animal models can be performed using either direct administration methods or by passive inhalation. Direct pulmonary delivery requires the animal to be endotracheally intubated, whereas passive delivery uses a nose-only or a whole-body chamber. Endotracheal delivery of therapeutics and vaccines allows investigators to deliver the payload directly into the lung without the limitations associated with passive pulmonary administration methods. Additionally, endotracheal delivery can achieve deep lung delivery without the involvement of other exposure routes and is more reproducible and quantitative than passive pulmonary delivery in terms of accurate dosing. Here we describe the endotracheal delivery of both liquids and dry powders for preclinical models of treatment and exposure. PMID- 29987805 TI - The impact of analgesic intervention during the second stage of labour: a retrospective cohort study. AB - PURPOSE: The incidence of epidural top-ups received in the second stage of labour in nulliparous women and the obstetrical and neonatal implications associated with these boluses are explored in this retrospective observational study. We hypothesized that an epidural top-up in the second stage of labour reduces operative deliveries by resolving inadequate analgesia. METHODS: A population based cohort analysis was performed using perinatal data from 1 January 2013 through 31 December 2014. An anesthesia database provided information to determine the top-up incidence. Women with or without a top-up for second-stage duration were compared for method of delivery and neonatal characteristics using descriptive statistics. Logistic regression identified predictive factors for method of delivery. RESULTS: Of the 1,462 women with a second stage of labour > one hour who received epidural analgesia, 105 (7%) required a top-up during the second stage of labour. Women who received a top-up were more likely to have had induction of labour and/or augmentation (89% vs 76%; odds ratio [OR], 2.43; 95% confidence interval [CI], 1.32 to 4.49; P = 0.003), a longer second stage (303 min vs 171 min; mean difference, 132 min; 95% CI, 113 to 151; P < 0.001), and more assisted vaginal (41% vs 17%; OR, 3.35; 95% CI, 2.21 to 5.1; P < 0.001) or Cesarean deliveries (26% vs 11%; OR, 3.04; 95% CI, 1.91 to 4.8; P < 0.001) than women without a top-up. CONCLUSION: Most women who received a top-up had a vaginal (spontaneous or assisted) delivery. Compared with women without a top-up, women requiring a top-up had more predictors of difficult labour and higher rates of assisted vaginal delivery and Cesarean delivery. PMID- 29987807 TI - Experimental Models of Cardiovascular Diseases: Overview. AB - Cardiovascular disease is one of the most common causes of deaths in clinics. Experimental models of cardiovascular diseases are essential to understand disease mechanism, to provide accurate diagnoses, and to develop new therapies. Large numbers of experimental models have been proposed and replicated by many laboratories in the past. Models with significant advantages are chosen and became more popular. Particularly, feasibility, reproducibility, and human disease resemblance are the common key factors for frequently used cardiovascular disease models. In this chapter, we provide a brief overview of these experimental models used for in vitro, in vivo, and in silico studies of cardiovascular diseases. PMID- 29987806 TI - Hamilton-DONATE: a city-wide pilot observational study of the ICU management of deceased organ donors. AB - PURPOSE: Improving the medical care of deceased organ donors to increase transplant rates and improve allograft function requires an understanding of the current epidemiology and clinical practices of deceased donation within intensive care units (ICUs). Herein, we report the results of our investigation into the feasibility of a multicentre prospective cohort study addressing the afformentioned issues. METHODS: We conducted a 12-month prospective observational cohort study in six ICUs and one coronary care unit in Hamilton, Canada. We included consecutive children and adults following consent for deceased organ donation (including neurologic determination of death [NDD] or donation after circulatory death [DCD]). Intensive care unit research staff recorded donor management data from hospital records, extending from one day prior to the consent for organ donation up to the time of organ retrieval. The provincial Organ Donation Organization (ODO) supplemented these data and, additionally, provided data on corresponding organ recipients. We identified, evaluated, and measured three potential obstacles to the feasibility of a national cohort study: obtaining authorization to implement the study with a waiver of research consent, accessibility of transplant recipient data, and the time required to complete very detailed case report forms (CRFs), with valuable lessons learned for implementation in future projects. RESULTS: The local Research Ethics Board and the ODO Privacy Office both authorized the recording of donor and recipient study data with a waiver of research consent. Sixty-seven consecutive consented donors were included (31 NDD and 36 DCD donors); 50 of them provided 144 organs for transplantation to 141 recipients. We identified the age and sex of the recipients as well as the location and date of transplant for all organ recipients in Ontario; however, we obtained no recipient data for six organs transported outside of Ontario. Intensive care unit research staff estimated that future CRF completion will require five to seven hours per patient. CONCLUSION: The Hamilton-DONATE pilot study supports the feasibility of a larger cohort study to describe the epidemiology and clinical practices related to deceased donor care in Canada. TRIAL REGISTRATION: wwwclinicaltrials.gov (NCT02902783). Registered 16 September 2016. PMID- 29987808 TI - An Introduction to Computational Modeling of Cardiac Electrophysiology and Arrhythmogenicity. AB - Mathematical modeling is a powerful tool to study the complex and orchestrated biological process of cardiac electrical activity. By integrating experimental data from key components of cardiac electrophysiology, systems biology simulations can complement empirical findings, provide quantitative insight into physiological and pathophysiological mechanisms of action, and guide new hypotheses to better understand this complex biological system to develop novel cardiotherapeutic approaches. In this chapter, we briefly introduce in silico methods to describe the dynamics of physiological and pathophysiological single cell and tissue-level cardiac electrophysiology. Using a "bottom-up" approach, we first describe the basis of ion channel mathematical models. Next, we discuss how the net flux of ions through such channels leads to changes in transmembrane voltage during cardiomyocyte action potentials. By applying these fundamentals, we describe how action potentials propagate in models of cardiac tissue. In addition, we provide case studies simulating single-cell and tissue-level arrhythmogenesis, as well as promising approaches to circumvent or overcome such adverse events. Overall, basic concepts and tools are discussed in this chapter as an accessible introduction to nonmathematicians to foster an understanding of electrophysiological modeling studies and help facilitate communication with dry lab colleagues and collaborators. PMID- 29987809 TI - Isolation of Atrial and Ventricular Cardiomyocytes for In Vitro Studies. AB - High quality cardiomyocyte isolation is of critical importance for successful studies of myocardial function at the cellular and molecular level. Although previous work has established isolation procedures for various species, it still remains challenging to produce consistently a high yield of viable and healthy cardiomyocytes. The basis for the most successful and reproducible isolation of cardiomyocytes from intact hearts is the Langendorff retrograde perfusion technique. Here, we will illustrate in detail all practical aspects of the enzyme based Langendorff isolation of rat atrial and ventricular cardiomyocytes. This includes a series of obligatory steps starting from quick aortic cannulation to rinse the heart from blood, short perfusion of the heart with Ca2+-free solution to dissociate cells at the level of intercalated discs, followed by longer perfusion with low Ca2+-containing enzyme solution in order to disrupt the extracellular matrix network, extraction of the released cardiomyocytes and gentle Ca2+ reintroduction to allow cells to return gradually to normal cytosolic Ca2+ levels. The average yield of intact viable ventricular myocytes that can be achieved with our protocol is ~70% (range ~50-90%). For atrial myocytes, in general, it is slightly (~10%) lower than for ventricular myocytes. The yield depends on the age of the rat and the degree of cardiac remodeling such that digestion of older and more remodeled hearts (more fibrosis) usually results in lower yields. Isolated atrial and ventricular cardiomyocytes may be employed for studies of cardiomyocyte function (e.g., shortening/contraction, intracellular [Ca2+] transients) as well as for biochemical and molecular biological studies (e.g., immunoblotting, PCR). PMID- 29987810 TI - Cardiomyocyte Differentiation from Mouse Embryonic Stem Cells. AB - In vitro generated mammalian cardiomyocytes provide experimental models for studying normal mammalian cardiomyocyte development, for disease modeling and for drug development. They also promise to inform future therapeutic strategies for repair of injured or diseased myocardium. Here we provide reliable protocols for differentiation of mouse embryonic stem cells into functional cardiomyocytes, together with Notes about trouble shooting and optimizing such protocols for specific cell lines. PMID- 29987811 TI - Cardiomyocyte Differentiation from Human Embryonic Stem Cells. AB - In vitro generated human cardiomyocytes hold the ultimate promise for heart patients for repair of injured or diseased myocardium, but they also provide experimental models for studying normal cardiomyocyte development, for disease modeling and for drug development. Here we provide reliable protocols for differentiation of human embryonic stem cells into functional cardiomyocytes, together with Notes about troubleshooting and optimizing such protocols for specific cell lines. This chapter also briefly discusses other published protocols and those further adapted for differentiation of induced pluripotent stem cells into cardiomyocytes. PMID- 29987812 TI - Induction of Human Induced Pluripotent Stem Cells to Cardiomyocytes Using Embryoid Bodies. AB - Specific cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are promising sources for cell replacement therapy and are useful biomedical research tools for research on disease mechanisms and drug discovery. Among the different lineages, cardiac lineage has been one of the most efficiently differentiated through several established protocols. In this chapter, we describe our reproducible and highly efficient methodology for differentiating iPSCs into cardiomyocytes using embryoid bodies. We also describe methods to dissociate iPSC-derived cardiomyocytes and to evaluate iPSC-derived cardiomyocytes. PMID- 29987813 TI - Measuring Cardiomyocyte Contractility and Calcium Handling In Vitro. AB - In vitro measurements of cardiomyocyte contractility and Ca2+ handling have been used as a platform for determining physiological consequence of various genetic manipulations and identifying potential therapeutic targets for the treatment of heart failure. The Myocyte Calcium and Contractility System (IonOptix) offers a simultaneous trace of sarcomere movements and changes of intracellular Ca2+ levels in a single cardiomyocyte. Herein, we describe a modified protocol for the isolation of adult cardiomyocytes from murine hearts and provide a step-by-step description on how to analyze cardiomyocyte Ca2+ transient and contractility data collected using the IonOptix system. In our modified protocol, we recommend a novel cannulation technique which simplifies this difficult method and leads to improved viability of isolated cardiomyocytes. In addition, a comprehensive analysis of intracellular Ca2+ handling, SR Ca2+ load, myofilament Ca2+ sensitivity, and cardiomyocyte contractility is described in order to provide important insights into myocardial mechanics. PMID- 29987814 TI - Langendorff Perfusion Method as an Ex Vivo Model to Evaluate Heart Function in Rats. AB - The Langendorff Perfused Heart Model is an experimental procedure developed at the end of the nineteenth century by Oskar Langendorff. In this procedure, an excised heart has a cannula inserted into its aorta so that the heart can be retrogradely perfused via the coronary artery. The procedure has been improved in recent times, and these improvements are used to evaluate the direct effect of medication on the heart as well as the effect of ischemia-reperfusion injury on heart function. In this chapter, we describe protocols for evaluating heart function in Langendorff perfused rat heart. PMID- 29987815 TI - Methods for the Preparation of an Excised, Cross-Circulated Rat Heart. AB - The Emax-Pressure-Volume Area (PVA)-VO2 framework proposed by Dr. Suga for canine hearts has dramatically advanced the field of cardiac mechanical work and energetics, i.e., mechanoenergetics. He and his collaborators investigated mechanoenergetics in the left ventricle (LV) of excised, cross-circulated canine heart preparations. We instituted the excised cross-circulated rat whole heart preparations and found a curvilinear end-systolic pressure-volume relation (ESPVR) in the rat LV, in contrast to the linear ESPVR in canine, rabbit, and human LVs. Although Emax, the slope of the linear ESPVR, could be used as an index of LV contractility, it was not applicable for evaluating LV contractility in the rat LV. Thus, we proposed a new index of contractility, equivalent Emax (eEmax) in the rat LV. We also found a linear VO2-PVA relationship in the rat LV. Here, we introduce the methods for the preparation of excised, cross-circulated rat whole hearts and the eEmax-PVA-VO2 framework in the rat LV. Using this method, we can obtain accurate LV volume and myocardial O2 consumption in real time for estimating cardiac mechanoenergetics, which is very challenging in in vivo experiments. PMID- 29987816 TI - Optical Action Potential Mapping in Acute Models of Ischemia-Reperfusion Injury: Probing the Arrhythmogenic Role of the Mitochondrial Translocator Protein. AB - Ischemia-reperfusion (I/R) injury causes dynamic changes in electrophysiological properties that promote the incidence of post-ischemic arrhythmias. High resolution optical action potential mapping allows for a quantitative assessment of the electrophysiological substrate at a cellular resolution within the intact heart, which is critical for elucidation of arrhythmia mechanisms. We and others have found that pharmacological inhibition of the translocator protein (TSPO) is highly effective against postischemic arrhythmias. A major hurdle that has limited the translation of this approach to patients is the fact that available TSPO ligands have several confounding effects, including a potent negative ionotropic property. To circumvent such limitations we developed an in vivo cardiac specific TSPO gene silencing approach as an alternative. Here, we provide the methodological details of our optical action potential mapping studies that were designed to probe the effects of TSPO silencing in hearts from spontaneously hypertensive rats (SHR) that are prone to I/R injury. PMID- 29987817 TI - Cardiac Tissue Engineering Models of Inherited and Acquired Cardiomyopathies. AB - The lack of biomimetic in vitro models of the human heart has posed a critical barrier to progress in the field of modeling cardiac disease. Human engineered cardiac tissues (hECTs)-autonomous, beating structures that recapitulate key aspects of native cardiac muscle physiology-offer an attractive alternative to traditional in vitro models. Here we describe the use of hECTs to advance our understanding and modeling of cardiac diseases in order to test therapeutic interventions, with a focus on contractile dysfunction in the setting of inherited and acquired forms of cardiomyopathies. Four major procedures are discussed in this chapter: (1) preparation of hECTs from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) on single-tissue and multitissue bioreactors; (2) data acquisition of hECT contractile function on both of these platforms; (3) hECT modeling of hereditary phospholamban-R14 deletion-dilated cardiomyopathy; and (4) cryo-injury and doxorubicin-induced hECT models of acquired cardiomyopathy. PMID- 29987818 TI - Badimon Perfusion Chamber: An Ex Vivo Model of Thrombosis. AB - The Badimon perfusion chamber is an ex vivo model of thrombosis that assesses the thrombogenicity of blood in humans and large animals. It works with native blood thereby excluding any interfering effects of anticoagulants unavoidable with the majority of platelet function testing methodologies. Each variable of the Virchow's triad (blood, blood flow, and endothelial wall) that modulates blood vessel wall interaction and thrombus formation is incorporated in this perfusion model. These features make this device a valuable tool for the assessment of thrombogenic potential of various diseases and also gauging the efficacy of antithrombotic (anticoagulant and antiplatelet) treatments. PMID- 29987819 TI - Ischemic Model of Heart Failure in Rats and Mice. AB - Temporary or permanent left coronary artery (LCA) ligation is the most widely used model of heart failure. In the present protocol, we describe the materials necessary for the procedure, key steps of the LCA ligation, triphenyl tetrazolium chloride (TTC) staining, and calculation of myocardial infarction (MI) size after ischemia-reperfusion (I/R) injury (30 min/24 h) in rats and mice. We discuss precautions and tips regarding the operation before and after surgery, both in vivo and ex vivo. The aim of this chapter is to describe the details of LCA surgery and provide recommendations for current and future surgical operators. PMID- 29987820 TI - Conventional Method of Transverse Aortic Constriction in Mice. AB - Transverse aortic constriction is a widely used surgical model to reflect the progression from cardiac hypertrophy to heart failure states due to left ventricular pressure overload in mice. It produces afterload increase on the left ventricle in which compensated hypertrophy initially occurs in the first 2 weeks. This develops into maladaptive remodeling of the left ventricle and atrium, leading to heart failure. This model is useful for cardiac studies since transverse aortic constriction can be consistently replicated and has low surgical mortality. Additionally, the gradual progression to cardiac failure makes it a valuable method to evaluate the efficacy of potential therapeutic intervention. We introduce this chapter to offer practical approaches to facilitate a simple methodology for transverse aortic constriction. PMID- 29987821 TI - Characterization of the Differential Progression of Left Ventricular Remodeling in a Rat Model of Pressure Overload Induced Heart Failure. Does Clip Size Matter? AB - Despite the use of inbred animals, phenotypic variability is usually encountered in rats subjected to pressure overload. This chapter describes techniques for creating a rat model of pressure overload by ascending aortic banding procedure and noninvasive characterization of the variable phenotypes by means of echocardiography. We address the variable phenotypes encountered in this model with moderate versus severe ascending aortic banding. We also describe some of the echocardiographic and hemodynamic parameters and the degree of interstitial fibrosis and extracellular matrix remodeling encountered in each of the different phenotypes. PMID- 29987822 TI - Isoproterenol-Induced Heart Failure Mouse Model Using Osmotic Pump Implantation. AB - Isoproterenol is used widely for inducing heart failure in mice. Isoproterenol is a nonselective beta-adrenergic agonist. The acute model mimics stress-induced cardiomyopathy. The chronic model mimics advanced heart failure in humans. In this chapter, we describe a protocol that we used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation and echocardiography are described in detail. We also discuss the impact of drug dosage, duration, mortality, age, gender, and strain on cardiac remodeling responses. The success of model creation may be assessed by echocardiogram or molecular markers. This chapter may be relevant to those who are interested in using this heart failure model. PMID- 29987823 TI - Rat Model of Cardiotoxic Drug-Induced Cardiomyopathy. AB - Cardiotoxicity from cancer drugs remains a clinical problem. To find reliable markers of cardiotoxicity, animal models were proposed and potential new diagnostic markers have been actively investigated using these models. Here we describe our protocols, using male Sprague-Dawley rats, for inducing cardiomyopathy by single injection of high-dose doxorubicin (5-10 mg/kg) or multiple injections (2-4 times) of low-dose doxorubicin (2.5 mg/kg) with combined single injection of trastuzumab (10 mg/kg). The cardiotoxicity is evaluated by imaging modalities (echocardiography and nuclear imaging), serum troponin levels, and histopathological analyses. PMID- 29987824 TI - Pulmonary Artery Hypertension Model in Rats by Monocrotaline Administration. AB - Pulmonary arterial hypertension (PAH) is a syndrome characterized by pulmonary vascular remodeling and vasoconstriction, leading to increased pulmonary vascular resistance, right ventricular pressure overload and, eventually, to right ventricular failure and premature death. Animal models have been an essential tool for understanding pulmonary hypertension pathophysiology and for the discovery and development of novel therapies.MCT-induced PAH in rats leads to a significant increase in RV pressure and pulmonary vascular remodeling, as well as greater RV hypertrophy. In this chapter, we describe protocols for inducing and assessing the monocrotaline (MCT) rat model, the most classical and widely used in vivo model of PAH. Using this protocol, rats reproducibly develop pulmonary hypertension with a mean pulmonary pressure of ~40 mmHg approximately 4 weeks after single MCT administration. PMID- 29987825 TI - The Sugen 5416/Hypoxia Mouse Model of Pulmonary Arterial Hypertension. AB - Pulmonary hypertension is a rapidly progressive, life-threatening, and often fatal disease. Despite many new developments in pulmonary arterial hypertension (PAH) therapy, there is currently no cure for PAH, and new therapies are desperately needed. PAH pathobiology involves a remodeling process in pulmonary arteries that plays a critical role in elevating pulmonary arterial and right ventricle pressures. The discovery and development of new therapies requires animal models of PAH that mimic the human disease, including vascular remodeling.Here we review and describe a detailed protocol for creating an in vivo model of Sugen/Hypoxia-induced PAH in mice that is commonly used to assess the efficiency of new therapies in PAH. Severe pulmonary hypertension can be established in 1 month using this protocol. Additional protocols to evaluate the model by invasive pressure measurements and histology are provided. PMID- 29987826 TI - Mouse Model of Wire Injury-Induced Vascular Remodeling. AB - We introduced the vascular remodeling mouse system induced by the wire injury to investigate the molecular and cellular mechanisms of cardiovascular diseases. Using these models, we focus on the adventitial cell population in the outermost layer of the adult vasculature as a vascular progenitor niche. Firstly we used the standard wire injury approach, leaving the wire for 1 min in the artery and retracting the wire by twisting out to expand the artery and denude the inner layer endothelial cells in the both peripheral artery and femoral artery. This method leads to adventitial lineage cell accumulation on the medial-adventitial border, but no contribution into the hyperplastic neointima. Since advanced atherosclerotic plaques in the mouse models and human clinical specimens show the elastic lamina in the media broken, we hypothesized that adventitial lineage cells contribute to acute neointima formation induced by the mechanical damage in both endothelial and medial layers. To make this intensive damage, next, we used the bigger diameter wire with no hydrophilic coating and repeated the ten-times insertion and retraction of the wire after leaving for 1 min in the femoral artery. The additional ten-times intensive movements of the wire lead to breakdown and rupture of the elastic lamina together with a contribution of adventitial lineage cells to the hyperplastic neointima. Here we describe these two different wire injury methods to induce different types of vascular remodeling at the point of adventitial lineage cell contribution to the hyperplastic neointima by targeting two separate locations of hind limb artery, the peripheral artery and femoral artery, and using two different diameter wires. PMID- 29987827 TI - The Mouse Aortocaval Fistula Model with Intraluminal Drug Delivery. AB - The arteriovenous fistula (AVF) is the most common type of vascular access currently used for hemodialysis, but long-term outcomes remain poor in many patients; understanding the basic mechanisms of venous remodeling within the fistula environment is critical to improve our understanding of AVF maturation. In this chapter, we describe a method to create a murine aortocaval fistula that allows intraluminal drug delivery. This model reliably recapitulates human AVF maturation and therefore is a good consideration to study venous remodeling. PMID- 29987828 TI - A Pig Model of Myocardial Infarction: Catheter-Based Approaches. AB - Despite enormous efforts in treating myocardial infarction (MI) and subsequent heart failure, the recent statistics from the American Heart Association evidently show that there still remains room for improvements. To develop and translate new therapeutics toward clinics, large animal models that allow us to test new therapies in human-like conditions are of extraordinary importance. In this chapter, we describe detailed protocols for the creation of a closed-chest MI model in pigs. The advantages of this model include high survival rate (>90% after ischemia-reperfusion), adjustable MI size depending on coronary occlusion site, reproducible cardiac dysfunction, and relatively low invasive method. The temporary coronary occlusion method for ischemia-reperfusion injury as well as the permanent occlusion method, using clot injection or embolic coil implantation, are described. Furthermore, we describe the key steps needed for understanding, performing, and analyzing cardiac angiography and echocardiography in pigs. PMID- 29987830 TI - Canine Model of Pacing-Induced Heart Failure. AB - Tachypacing-induced heart failure is a well-established large animal model that recapitulates numerous pathophysiological, structural and molecular features of dilated cardiomyopathy and, more in general, of end-stage congestive heart failure. The left or the right ventricle is instrumented with pacing electrodes to impose supernormal heart rates, usually three times higher than baseline values, for a length of time that typically ranges between 3 and 5 weeks. The animal of choice is the dog, although this protocol has been successfully implemented also in pigs, sheep, and rabbits. This chapter provides detailed methodology and description of the dog model utilized in our laboratory, which is one of the variants described in literature. Chronic instrumentation is completed by adding probes and catheters necessary to obtain measures of cardiac function and hemodynamics and to withdraw blood samples from various vascular districts. The progression from compensated to decompensated heart failure is highly reproducible, therefore, due also to the phylogenetic proximity of dogs to humans, tachypacing-induced heart failure is considered a highly clinically relevant model for testing the efficacy of novel pharmacological and nonpharmacological therapeutic agents. This model typically produces heart failure as defined by an LV dP/dt max <1500 mmHg/s, end-diastolic pressure >25 mmHg, mean arterial pressure <85 mmHg, and an ejection fraction <35%. One can expect a mortality rate of 5-10% due to fatal arrhythmias. PMID- 29987829 TI - Ovine Model of Ischemic Mitral Regurgitation. AB - Ischemic mitral regurgitation (IMR) is a common complication of ischemic heart disease that doubles mortality after myocardial infarction and is a major driving factor increasing heart failure. IMR is caused by left ventricular (LV) remodeling which displaces the papillary muscles that tether the mitral valve leaflets and restrict their closure. IMR frequently recurs even after surgical treatment. Failed repair associates with lack of reduction or increase in LV remodeling, and increased heart failure and related readmissions. Understanding mechanistic and molecular mechanisms of IMR has largely attributed to the development of large animal models. Newly developed therapeutic interventions targeted to the primary causes can also be tested in these models. The sheep is one of the most suitable models for the development of IMR. In this chapter, we describe the protocols for inducing IMR in sheep using surgical ligation of obtuse marginal branches. After successful posterior myocardial infarction involving posterior papillary muscle, animals develop significant mitral regurgitation around 2 months after the surgery. PMID- 29987831 TI - Swine Model of Mitral Regurgitation Induced Heart Failure. AB - Mitral regurgitation (MR) is among the most common valvular heart diseases in clinics. MR induces volume overload of the heart and leads to heart failure (HF). Because physiological and molecular mechanisms in nonischemic HF are distinct from that of ischemic HF, a clinically relevant animal model of nonischemic HF is important for understanding the pathophysiology and developing new therapeutics targeting this HF phenotype. Additionally, the large animal model of MR provides opportunities to test new surgical and percutaneous approaches for correcting mitral valve insufficiency.In this chapter, we describe protocols for inducing MR in pigs using percutaneous approaches. Specifically, mitral valve chords are cut by a cardiac biopsy catheter inserted either antegrade (transseptal through venous access) or retrograde (arterial access) into the left ventricle. Both acute and chronic HF can be induced using this technique, and left atrial enlargement can be found at the chronic stage. PMID- 29987832 TI - Pig Model of Increased Cardiac Afterload Induced by Ascending Aortic Banding. AB - Increase in cardiac afterload as represented by hypertension is an established risk factor for cardiovascular diseases. Animal models of increased cardiac afterload offer studies aiming at identifying key molecular mechanisms and developing new therapeutic approaches. We have reported that banding of the ascending aorta in pigs results in significant cardiac hypertrophy and increased myocardial fibrosis at the chronic stages. These changes were accompanied by increased stiffness of the heart, but not by systolic dysfunction. In this chapter, we describe methods to surgically band the ascending aorta in pigs. After 3 months, animals develop systolic left ventricular pressure of >200 mmHg with above described changes in the heart. PMID- 29987833 TI - Large Porcine Model of Profound Acute Ischemic Cardiogenic Shock. AB - Cardiogenic shock is one of the leading causes of death following acute myocardial infarction affecting 10% of patients with large myocardial infarcts with a subsequent mortality rate of 50%. Here we describe a large porcine model of acute ischemic cardiogenic shock. Acute left or right ventricular failure can be achieved with close to a 100% success rate by stepwise injection of microspheres into the left or right coronary artery, respectively, and the method allows for titration of heart failure to a prespecified level. PMID- 29987834 TI - Chronic Pulmonary Artery Embolization Models in Large Animals. AB - A wide range of approaches have been described to develop animal models of pulmonary vascular disease (PVD). Clinical heterogeneity in patients with pulmonary hypertension (PH) has prompted development of different techniques to create PH models in several animal species with the objective to recapitulate specific PH/PVD phenotypes. Chronic thromboembolic PH (CTEPH) is a clinically important phenotype of PH with a documented prevalence of 0.4-9.1% in patients with history of pulmonary embolism. A well-established large animal model of CTEPH is thus necessary for studying this disease in preclinical research. Different experimental protocols with inconsistent outcomes have been reported in the literature.We have focused on characterizing PH large animal models in a common framework; pulmonary hemodynamics, right ventricular (RV) function, and histological characterization of PVD. This research framework allows optimal evaluation of novel diagnostic tools, as well as new therapeutic strategies. The purpose of this protocol is to describe approaches to create experimental CTEPH models using recurrent pulmonary embolizations of dextran microspheres in swine. The key features of this experimental modeling approach are (1) nonsurgical, fully percutaneous techniques, (2) a minimum of four embolization procedures, with 1-2 month time period, (3) mild to moderate PH hemodynamics (mean PA pressure increase ~20-60%), (4) severe pulmonary vascular remodeling, (5) mild RV remodeling, and (6) a high reproducibility and low mortality (<10%). PMID- 29987835 TI - Modeling Pulmonary Hypertension: A Pig Model of Postcapillary Pulmonary Hypertension. AB - Pulmonary hypertension (PH) is a pathophysiological condition defined as an increase in mean pulmonary arterial pressure >=25 mmHg at rest assessed by right heart catheterization.Based on hemodynamic criteria, precapillary PH is characterized by a mean pulmonary capillary wedge pressure <=15 mmHg as opposed to the postcapillary PH by >15 mmHg. Postcapillary PH is one of the most common forms of PH, often caused by left ventricular dysfunction and heart failure.In this chapter, we describe protocols for creating a large animal model of postcapillary PH. It is induced by open chest surgery (lateral thoracotomy) to band the pulmonary veins. The model is characterized by low mortality, relatively easy surgical procedure with well reproducible results, and pulmonary and cardiac remodeling at the structural, functional, and molecular levels. The presence of right ventricular (RV) remodeling is of significant importance since right heart failure is the main cause of death in patients suffering from PH. One of the advantages of the model described in this chapter is that both adaptive and maladaptive forms of RV remodeling can be observed during the progression of the disease. This can help understand the progressive pathophysiology of RV failure in humans. Besides the description of the model, a detailed guidance of the RV functional assessment in pigs for both invasive (heart catheterization) and noninvasive (echocardiography) approaches is provided. PMID- 29987836 TI - Development and Multiparametric Evaluation of Experimental Atherosclerosis in Rabbits. AB - Several animal models have been developed to study atherosclerosis. Here we present a rabbit atherosclerosis model generated by surgical denudation of the aortic endothelium in combination with a high-fat and cholesterol-enriched diet. This model is characterized by the formation of vascular lesions that exhibit several hallmarks of human atherosclerosis. Due to the rabbit's relative large size, as compared to rodents, this model is suited for the imaging-guided evaluation of novel therapeutic strategies using clinical scanners. In this chapter, we present an extensive outline of the procedures to induce aortic atherosclerotic lesions in rabbits as well as methods to evaluate the disease, including noninvasive in vivo multiparametric imaging and histopathology. PMID- 29987837 TI - The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis. AB - Cladribine Tablets (MAVENCLAD(r)) are used to treat relapsing multiple sclerosis (MS). The recommended dose is 3.5 mg/kg, consisting of 2 annual courses, each comprising 2 treatment weeks 1 month apart. We reviewed the clinical pharmacology of Cladribine Tablets in patients with MS, including pharmacokinetic and pharmacometric data. Cladribine Tablets are rapidly absorbed, with a median time to reach maximum concentration (Tmax) of 0.5 h (range 0.5-1.5 h) in fasted patients. When administered with food, absorption is delayed (median Tmax 1.5 h, range 1-3 h), and maximum concentration (Cmax) is reduced by 29% (based on geometric mean). Area under the concentration-time curve (AUC) is essentially unchanged. Oral bioavailability of cladribine is approximately 40%, pharmacokinetics are linear and time-independent, and volume of distribution is 480-490 L. Plasma protein binding is 20%, independent of cladribine plasma concentration. Cladribine is rapidly distributed to lymphocytes and retained (either as parent drug or its phosphorylated metabolites), resulting in approximately 30- to 40-fold intracellular accumulation versus extracellular concentrations as early as 1 h after cladribine exposure. Cytochrome P450 mediated biotransformation of cladribine is of minor importance. Cladribine elimination is equally dependent on renal and non-renal routes. In vitro studies indicate that cladribine efflux is minimally P-glycoprotein (P-gp)-related, and clinically relevant interactions with P-gp inhibitors are not expected. Cladribine distribution across membranes is primarily facilitated by equilibrative nucleoside transporter (ENT) 1, concentrative nucleoside transporter (CNT) 3 and breast cancer resistance protein (BCRP), and there is no evidence of any cladribine-related effect on heart rate, atrioventricular conduction or cardiac repolarisation (QTc interval prolongation). Cladribine Tablets are associated with targeted lymphocyte reduction and durable efficacy, with the exposure-effect relationship showing the recommended dose is appropriate in reducing relapse risk. PMID- 29987838 TI - Anti-Mullerian hormone and breast cancer risk-is the correlation possibly associated with the PCOS? PMID- 29987840 TI - Inflammation and immune resolution. AB - Inspired by the advances presented at the Inflammation and Immune Resolution Plenary Session at the British Society for Immunology Congress, December 2017, in this issue of Clinical & Experimental Immunology we present a Review Series on Inflammation and Immune Resolution. Our selection ranges from an overview of current genetic understanding of the similarities and differences between immune mediated inflammatory diseases (IMIDs); discussion of several biological mechanisms underlying the aberrant activation of myeloid cells in RA, and how myeloid cell relevant anti-inflammatory mediators may contribute to immune resolution; presentation of fascinating evidence for the existence of innate immune memory in stromal cells and how this may exacerbate or restrain inflammatory disease; and a review of how the interleukin (IL)-6 family members IL-6 and IL-27 may drive or regulate inflammation. Inflammation and immune resolution are two sides of the same coin: the reviews presented in this series aim to equip readers with greater insight into the delicate balance between the two. PMID- 29987839 TI - Synergistic cross-talk of hedgehog and interleukin-6 signaling drives growth of basal cell carcinoma. AB - Persistent activation of hedgehog (HH)/GLI signaling accounts for the development of basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer with rising incidence. Targeting HH/GLI signaling by approved pathway inhibitors can provide significant therapeutic benefit to BCC patients. However, limited response rates, development of drug resistance, and severe side effects of HH pathway inhibitors call for improved treatment strategies such as rational combination therapies simultaneously inhibiting HH/GLI and cooperative signals promoting the oncogenic activity of HH/GLI. In this study, we identified the interleukin-6 (IL6) pathway as a novel synergistic signal promoting oncogenic HH/GLI via STAT3 activation. Mechanistically, we provide evidence that signal integration of IL6 and HH/GLI occurs at the level of cis-regulatory sequences by co-binding of GLI and STAT3 to common HH-IL6 target gene promoters. Genetic inactivation of Il6 signaling in a mouse model of BCC significantly reduced in vivo tumor growth by interfering with HH/GLI-driven BCC proliferation. Our genetic and pharmacologic data suggest that combinatorial HH-IL6 pathway blockade is a promising approach to efficiently arrest cancer growth in BCC patients. PMID- 29987841 TI - Report of second case and clinical and molecular characterization of Eiken syndrome. AB - We report a boy with Eiken syndrome caused by a homozygous missense variant in Parathyroid hormone 1 receptor (PTH1R) c.103G > A [p.(Glu35Lys)]. Eiken syndrome is a very rare skeletal dysplasia due to bi-allelic variants in PTH1R. Only one affected family has been known to-date. The hallmarks include delayed ossification of bone including the epiphyses, pubic symphysis, and primary ossification centers of the short tubular bones, coarse bone trabeculae, and modeling abnormalities. The phenotype being described here recapitulates the delayed ossification and modeling abnormalities of Eiken syndrome. In addition, supernumerary epiphyses of the tubular bones of the hands and primary failure of eruption of teeth were observed in our proband. This report characterizes Eiken syndrome and confirms that bi-allelic hypomorphic variants in PTH1R are probably to cause this condition. PMID- 29987842 TI - sIgE and sIgG to airborne atopic allergens: Coupled rather than inversely related responses. PMID- 29987843 TI - Erythema multiforme major induced by exotic wood. PMID- 29987844 TI - Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes. AB - In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings. PMID- 29987845 TI - Interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. AB - BACKGROUND: Brain radionecrosis (tissue death caused by radiation) can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QoL) and function. The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging. OBJECTIVES: To assess the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old. SEARCH METHODS: In October 2017, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies. We also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and handsearched relevant conference material. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain. We anticipated a limited number of RCTs, so we also planned to include all comparative prospective intervention trials and quasi-randomised trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e. placebo or corticosteroids). Selection bias was likely to be an issue in all the included non-randomised studies therefore results are interpreted with caution. DATA COLLECTION AND ANALYSIS: Two review authors (CC, PB) independently extracted data from selected studies and completed a 'Risk of bias' assessment. For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported. For continuous outcomes, treatment effect was reported as mean difference (MD) between treatment arms with 95% confidence intervals (CIs). MAIN RESULTS: Two RCTs and one prospective non-randomised study evaluating pharmacological interventions met the inclusion criteria for this review. As each study evaluated a different drug or intervention using different endpoints, a meta-analysis was not possible. There were no trials of non-pharmacological interventions that met the inclusion criteria.A very small randomised, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100% (7/7) of participants on bevacizumab had reduction in brain oedema by at least 25% and reduction in post gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both. This was an encouraging finding but due to the small sample size we did not report a relative effect. The authors also failed to provide adequate details regarding the randomisation and blinding procedures Therefore, the certainty of this evidence is low and a larger RCT adhering to reporting standards is needed.An open-label RCT demonstrated a greater reduction in brain oedema (T2 hyperintensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95% CI 0.14 to 5.92; low certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95% CI - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).In the RCT of bevacizumab versus placebo, all seven participants receiving bevacizumab were reported to have neurological improvement, whereas five of seven participants on placebo had neurological worsening (very low certainty evidence due to small sample size and concerns over validity of analyses). While no adverse events were noted with placebo, three severe adverse events were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis. In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95% CI 1.26 to 5.01; low-certainty evidence due to open-label design). No differences in treatment toxicities were observed between arms.One included prospective non randomised study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment. As only one included study was a double-blinded randomised controlled trial, the other studies were prone to selection and detection biases.None of the included studies reported quality of life outcomes or adequately reported details about corticosteroid requirements.A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable endpoints. AUTHORS' CONCLUSIONS: There is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery. In an RCT of 14 patients, bevacizumab showed radiological response which was associated with minimal improvement in cognition or symptom severity. Although it was a randomised trial by design, the small sample size limits the quality of data. A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding oedema with combination treatment but no effect on the enhancing radionecrosis lesion. Due to the open-label design and wide confidence intervals in the results, the quality of this data was also low. There was no evidence to support any non pharmacological interventions for the treatment of radionecrosis. Further prospective randomised studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence. Two ongoing RCTs, one evaluating bevacizumab and one evaluating hyperbaric oxygen therapy were identified. PMID- 29987846 TI - Dietary assessment and the development of asthma in Korean adolescents and adults. PMID- 29987847 TI - Prospective survey of implantable defibrillator shock anxiety in Japanese patients: Results from the DEF-Chiba study. AB - BACKGROUND: Patient-reported outcomes of implantable cardioverter defibrillator (ICD), such as those with shock anxiety, have emerged as important endpoints that are related to quality of life (QOL), but they have not been well studied in a sample of the Japanese population. Therefore, we prospectively examined changes in shock anxiety in a large sample of Japanese patients with an ICD. METHODS: We recruited 214 consecutive patients with an ICD who visited the outpatient clinic. At registration and 12 months later, all patients completed the Florida Shock Anxiety Scale (FSAS) questionnaire to allow us to examine changes in shock anxiety over the course of the first year after registration. RESULTS: During the 12-month follow-up period, 10.5% of the patients received ICD shock therapy. Female sex, secondary prevention, and experience of ICD shock therapy were associated with high FSAS scores at registration. The FSAS scores in both patients with appropriate and inappropriate shock were significantly higher at the 12-month follow-up interval than at registration, and there was no significant difference in the extent of changes in FSAS scores (Delta = 5.2 +/- 5.1 and Delta = 6.3 +/- 9.9, respectively, P = 0.62). CONCLUSIONS: Female sex, secondary prevention, and experience of ICD shock therapy are important risk factors affecting shock anxiety in Japanese patients. Attention should be paid to the after-effects of ICD shock in these patients, regardless of the shock type, with particular attention to women and patients who require secondary prevention. PMID- 29987848 TI - Enzyme biotechnology in degradation and modification of plant cell wall polymers. AB - Lignocelluloses are abundant raw materials for production of fuels, chemicals and materials. The purpose of this paper is to review the enzyme-types and enzyme technologies studied and applied in the processing of the lignocelluloses into different products. The enzymes here are mostly glycoside hydrolases, esterases and different redox enzymes. Enzymatic hydrolysis of lignocellulosic polysaccharides to platform sugars has been widely studied leading to development of advanced commercial products for this purpose. Restricted hydrolysis or oxidation of cellulosic fibers have been applied in processing of pulps to paper products, nanocelluloses and textile fibers. Oxidation, transglycosylation and derivatization have been utilized in functionalization of fibers, cellulosic surfaces and polysaccharides. Enzymatic polymerization, depolymerization and grafting methods are being developed for lignin valorization. PMID- 29987849 TI - Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model. AB - BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear. METHODS: In order to elucidate potential mechanisms leading to CRS in humans, we have established a Type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. Sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs). RESULTS: After 22 weeks, a typical Type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired. CONCLUSIONS: Our mouse model of CRS displayed an allergic response to HDM+SEB administration, including the Type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia. This article is protected by copyright. All rights reserved. PMID- 29987850 TI - Implicit decision framing as an unrecognized source of confusion in endangered species classification. AB - Legal classification of species requires scientific and values-based components, and how those components interact depends on how people frame the decision. Is classification a negotiation of trade-offs, a decision on how to allocate conservation efforts, or simply a comparison of the biological status of a species to a legal standard? The answers to problem-framing questions such as these influence decision making in species classifications. In our experience, however, decision makers, staff biologists, and stakeholders often have differing perspectives of the decision problem and assume different framings. In addition to differences between individuals, in some cases it appears individuals themselves are unclear about the decision process, which contributes to regulatory paralysis, litigation, and a loss of trust by agency staff and the public. We present 5 framings: putting species in the right bin, doing right by the species over time, saving the most species on a limited budget, weighing extinction risk against other objectives, and strategic classification to advance conservation. These framings are inspired by elements observed in current classification practices. Putting species in the right bin entails comparing a scientific status assessment with policy thresholds and accounting for potential misclassification costs. Doing right by the species adds a time dimension to the classification decision, and saving the most species on a limited budget classifies a suite of species simultaneously. Weighing extinction risk against other objectives would weigh ecological or socioeconomic concerns in classification decisions, and strategic classification to advance conservation would make negotiation a component of classification. We view these framings as a means to generate thought, discussion, and movement toward selection and application of explicit classification framings. Being explicit about the decision framing could lead decision makers toward more efficient and defensible decisions, reduce internal confusion and external conflict, and support better collaboration between scientists and policy makers. PMID- 29987851 TI - One-Step Controllable Synthesis of Mesoporous MgCo2 O4 Nanosheet Arrays with Ethanol on Nickel Foam as an Advanced Electrode Material for High-Performance Supercapacitors. AB - In recent years, ternary transition metal oxides (TTMOs), especially spinel type TTMOs have attracted widespread attention as promising candidates for electrode materials. Among all of the popular TTMOs, MgCo2 O4 is an outstanding one, owing to its superior theoretical capacitance. In this work, MgCo2 O4 nanosheet arrays (NSAs) grown directly on nickel foams were fabricated through a facile hydrothermal process at 120 degrees C for 4 h. With a series of structural and morphological characterization techniques, it was found that the ethanol played a key role in controlling the composition and morphology during the synthesis process. The MgCo2 O4 NSAs exhibited a superior specific capacitance of 853.06 C g-1 (at 1 mA cm-2 ) and enhanced cycling performance, with 94.65 % of initial capacitance retained after 3000 cycles when used as a binder-free integrated electrode for electrochemical supercapacitors; much higher than other reported data for MgCo2 O4 as well. The excellent electrochemical properties mainly came from the unique morphology of the MgCo2 O4 NSAs. This study will demonstrate the applications of MgCo2 O4 NSAs based large-scale supercapacitors grown on low-cost nickel foams. PMID- 29987852 TI - LncRNA FAL1 is a negative prognostic biomarker and exhibits pro-oncogenic function in osteosarcoma. AB - Long noncoding RNA focally amplified lncRNA on chromosome 1 (FAL1) plays an important role in the development of several human malignancy entities. However, the expression and function of FAL1 in the carcinogenesis and development of osteosarcoma remain unknown. In this study, we detected the FAL1 levels in human osteosarcoma tissues and cell lines by quantitative real-time polymerase chain reaction and investigated its role in osteosarcoma using in vitro assays. Our results showed that FAL1 expression was significantly upregulated in human osteosarcoma tissues and cell lines compared with their normal controls. FAL1 expression level was positively correlated with the distance metastasis (P = .008) and tumor stage ( P = .013). Higher expression of FAL1 conferred a significantly poorer survival, as determined by the Kaplan-Meier method with the log-rank test. Multivariate Cox proportional hazards analysis revealed that FAL1 was probably an independent risk of overall survival. Additionally, the serum FAL1 expression level was associated with osteosarcoma status in patients. Receiver operating characteristic curve analysis demonstrated that FAL1 expression was different between patients with osteosarcoma and healthy cohorts (area under the curve, 0.839; P < .001). Furthermore, knockdown of FAL1 by small interfering RNA significantly inhibited cell proliferation via inducing G2/M arrest in osteosarcoma cells. Depletion of FAL1 also suppressed osteosarcoma cell migration and invasion, which might be mediated by inhibiting the epithelial mesenchymal transition (EMT) program. Taken together, our study showed that lncRNA FAL1 exhibits an important pro-oncogenic effect on osteosarcoma progression by targeting EMT, which may serve as a potential therapeutic target for osteosarcoma. PMID- 29987853 TI - Health-related quality of life in diabetes mellitus and its social, demographic and clinical determinants: A nationwide cross-sectional survey. AB - AIMS AND OBJECTIVES: To investigate health-related quality of life in a representative sample of adults with diabetes mellitus in Spain, as well as its clinical and sociodemographic determinants. BACKGROUND: Diabetes mellitus is a chronic disease causing considerable morbidity and mortality worldwide, resulting in an impaired quality of life in affected people. DESIGN: A nationwide cross sectional study, based on an online survey and carried out between February-March 2016, was performed on diabetic subjects recruited through diabetic patients' organisations. METHODS: A validated Spanish-language version of the self administered Diabetes Quality of Life questionnaire was used, with 0 being the worst and 100 the best QoL level. Determinant factors of health-related quality of life were assessed with the aid of multivariate analysis to control for confounding factors. RESULTS: The responses provided by 456 patients (52.4% being women) revealed an overall mean score of 66.4 +/- 13.3. Social/vocational worries and diabetes-related worries were the dimensions with the highest (74.3 +/- 20.1) and lowest (61.1 +/- 20.6) scores, respectively. Younger age, female gender, having no studies and poor glycaemic control were all independent determinants for an impaired overall health-related quality of life, with most of these factors having a higher impact than the dimensions negative impact of therapy on daily life, satisfaction with therapy and diabetes-related worries. Married (or equivalent) subjects had better scores in the diabetes-related worries dimension. The perception of health-related quality of life progressively worsens as glycaemic control deteriorates and with an increased number of disease complications. Most of the associations did not vary significantly with the type of diabetes mellitus. CONCLUSION: Overall health-related quality of life perception in the Spanish diabetic population is moderate and depends on several sociodemographic factors. Adequate glycaemic control to avoid disease complications improves perception. RELEVANCE TO CLINICAL PRACTICE: The results can help health professionals to develop strategies to promote diabetic patient self-care, in order to improve the metabolic control of the disease and avoid its complications, as a therapeutic goal towards an improvement in health-related quality of life perception. PMID- 29987854 TI - The psychic readiness for destruction among contemporary adolescents. AB - AIMS AND OBJECTIVES: To verify the existence of psychic readiness for destruction among adolescent girls and to determine how psychic readiness for destruction is related to suicidal or violent behaviour in adolescence. BACKGROUND: The psychic readiness for destruction can be treated as a generalised tendency (personality disposition) to behave in a way that increases the probability of negative consequences which directly and indirectly threaten one's life, health and its quality. DESIGN: A retrospective cross-sectional study. METHODS: The study involved 140 participants, aged 13-17, including 40 girls after suicide attempts (GS group), 40 girls using violence against others (GA group) and 60 girls without destructive behaviour at all (CG group). To measure psychic readiness for destruction, the polish adaptation of the Chronic Self-Destructiveness Scale (CS DS) by Kelly was used. RESULTS: No significant differences were found between the GS group and GA group. A significant difference was found between the girls who engage in interpersonal violence (GA) and the control group (CG). In this case, the results showed a significantly higher score among those participants who were involved in extremely aggressive behaviours. A similar trend was also observed when comparing the group of girls who attempted suicide (GS) with the CG. CONCLUSIONS: Based on the conducted analyses, a clear trend was observed in consistency of destructive behaviours (tendency for destruction)-both active (seeking to violate norms, risky behaviours) and passive (omission, neglect) among the girls from both groups indicating even a single act of this kind (no significant differences between the groups). RELEVANCE TO CLINICAL PRACTICE: Due to the complex nature of readiness for destruction and its negative consequences on health, it is imperative to investigate the risk factors for the tendency for destruction and to conduct health education among adolescents. PMID- 29987855 TI - The effects of dietary restriction and administration of beta-glucan from Euglena gracilis on the sperm characteristics and reproductive organs of rats. AB - The aim of this study was to demonstrate the possible individual and/or synergistic effects of beta-glucan and dietary restrictions on the reproductive parameters of rats. For this purpose, forty male Sprague-Dawley rats were randomly divided into four equal groups (n = 10 per group). The first group was the control, the second group was kept under dietary restriction (DR), the third group was kept under a dietary restriction and given beta-glucan (DR + betaG) and the fourth group was supplemented only with beta-glucan (betaG; 20 mg/kg) intragastrically for 14 days. Motility, vitality and morphology of spermatozoa, reproductive organ weights (testis, vesicula seminalis and epididymis) and seminiferous tubule diameters were evaluated in experimental rats. beta-glucan had excellent effects on motility, live spermatozoa rate and the acrosome integrity when compared to the control group (p < 0.05). We also observed that beta-glucan administration to rats having dietary restriction could improve sperm motility and acrosome integrity (p < 0.05). While the beta-glucan improved seminiferous tubule diameter (p < 0.05), weights of the reproductive organs did not change positively as a result. This study demonstrated that beta-glucan treatment significantly improved some spermatological characteristics in rats. Therefore, treatment with beta-glucan could be used for its positive effects on motility, spermatozoa vitality rate and acrosome integrity for infertile men. PMID- 29987856 TI - Efficient Near-Infrared Electroluminescence at 840 nm with "Metal-Free" Small Molecule:Polymer Blends. AB - Due to the so-called energy-gap law and aggregation quenching, the efficiency of organic light-emitting diodes (OLEDs) emitting above 800 nm is significantly lower than that of visible ones. Successful exploitation of triplet emission in phosphorescent materials containing heavy metals has been reported, with OLEDs achieving remarkable external quantum efficiencies (EQEs) up to 3.8% (peak wavelength > 800 nm). For OLEDs incorporating fluorescent materials free from heavy or toxic metals, however, we are not aware of any report of EQEs over 1% (again for emission peaking at wavelengths > 800 nm), even for devices leveraging thermally activated delayed fluorescence (TADF). Here, the development of polymer light-emitting diodes (PLEDs) peaking at 840 nm and exhibiting unprecedented EQEs (in excess of 1.15%) and turn-on voltages as low as 1.7 V is reported. These incorporate a novel triazolobenzothiadiazole-based emitter and a novel indacenodithiophene-based transport polymer matrix, affording excellent spectral and transport properties. To the best of knowledge, such values are the best ever reported for electroluminescence at 840 nm with a purely organic and solution processed active layer, not leveraging triplet-assisted emission. PMID- 29987857 TI - Identification and characterization of stress degradation products of sumatriptan succinate by using LC/Q-TOF-ESI-MS/MS and NMR: Toxicity evaluation of degradation products. AB - Sumatriptan succinate, a selective 5-HT1B receptor agonist, was subjected to forced degradation studies as per to International Conference on Harmonization specified conditions. The drug exclusively showed its degradation under basic, photolytic, and oxidative stress conditions, whereas it was found to be stable under acidic, thermal, and neutral conditions. Eight (DP-1 to DP-8) degradation products were identified and characterized by UPLC-ESI/MS/MS experiments combined with accurate mass measurements. The effective chromatographic separation was achieved on Hibar Purospher STAR, C18 (250 * 4.6 mm, 5 MUm) column using mobile phase consisting of 0.1% formic acid and methanol at a flow rate of 0.6 mL/minute in gradient elution method. It is noteworthy that 2 major degradation products DP 3 and DP-7 were isolated using preparative HPLC and characterized by advanced NMR experiments. The degradation pathway of the sumatriptan was established, which was duly justified by mechanistic explanation. In vitro cytotoxicity of isolated DPs was tested on normal human cells such as HEK 293 (embryonic kidney cells) and RWPE-1 (normal prostate epithelial cells). This study revealed that they were nontoxic up to 100 MUm concentration. Further, in silico toxicity of the drug and its degradation products was determined using ProTox-II prediction tool. This study revealed that DP-4 and DP-8 are predicted for immune toxicity. Amine oxidase A and prostaglandin G/H synthase 1 are predicted as toxicity targets for DP-3, DP-4, and DP-6 whereas DP-1 and DP-2 are predicted for amine oxidase A target. PMID- 29987858 TI - Methotrexate-associated lymphoproliferative disorders with angioimmunoblastic T cell lymphoma-like features accompanied by gamma-heavy chain disease in a patient with rheumatoid arthritis. AB - Although gamma heavy chain disease (gamma-HCD) lesions occasionally morphologically resemble angioimmunoblastic T-cell lymphoma (AITL), no association has been described in detail due to the rarity of the disease. In this report, we present a rare manifestation of methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) with AITL-like features accompanied by gamma HCD in a 75-year-old man with rheumatoid arthritis (RA). A biopsy specimen was evaluated using immunohistochemistry, clonal analyses of immunoglobulin VH and T cell receptor gamma gene rearrangements by polymerase chain reaction, and Sanger sequencing for confirmation of the structure of deleted gamma-HCD clones. The histological features characterized by proliferation of CD4- and PD-1-positive medium-sized T cells and arborizing high endothelial venules together with numbers of small lymphocytes, eosinophils, plasma cells, and histiocytes in the background mimicked those of AITL, but did not completely fulfill the diagnostic criteria. Clonal analysis demonstrated that the specimen contained multiple LPDs of both B-cell and T-cell lineages. Sequence analysis confirmed the co-existence of a clone responsible for production of the abnormal heavy chain. This report provides new insights into the pathology of gamma-HCD. Multiple host-derived factors (e.g., RA and/or use of MTX) may be responsible for the occurrence of LPDs of multiple lineages within a single lymph node. PMID- 29987859 TI - Health-promoting leadership: A qualitative study from experienced nurses' perspective. AB - AIMS AND OBJECTIVES: To increase knowledge about experienced nurses' understanding of a health-promoting work environment, health-promoting leadership and its role in retention of staff in the nursing workplace. BACKGROUND: The quality of leadership is imperative in creating supportive and health-promoting work environments to ensure workforce productivity and ethically sustainable caring cultures. More knowledge on how leaders can promote health and sustainable careers among nurses is needed. At a time of current and projected nursing shortage, it is important to understand the reasons why nurses intend to remain in their jobs. DESIGN: Qualitative descriptive. METHOD: Twelve experienced registered nurses participated in an individual, digitally recorded, semi structured interview. Data were transcribed verbatim and subjected to qualitative content analysis of manifest and latent content. RESULTS: A health-promoting work environment should provide autonomy, participation in decision-making, skills development and social support. Health-promoting leaders should be attentive and take action. CONCLUSION: Health-promoting work environments enable nurses to flourish. Having ample autonomy is therefore important to nurses so that when they face new challenges, they see them as a way of using and developing their competencies. Although most nurses claim their own leaders are not health promoting, they have a clear understanding of how a health-promoting leader should act. The health-promoting leader should not only be attentive and promote skills development, but also cater for nurses' meaningfulness. RELEVANCE TO CLINICAL PRACTICE: Nurses in primary health care understand a health-promoting work environment to be a workplace where they can develop, not only clinical skills, but also flourish as human beings. Further, nurses find it health promoting to have a meaningful job, using their competence to make a difference for patients and their families. Nurse Managers have an important role in facilitating meaningfulness in nurses' jobs to retain nurses as a valuable asset for the organisation. PMID- 29987861 TI - Imaging studies of kleptomania in a middle-aged woman with obsessive-compulsive disorder: a case report. AB - A 57-year-old woman who had been arrested for shoplifting visited our hospital. She was diagnosed with kleptomania. She had previously been diagnosed with CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome and obsessive-compulsive disorder. Cranial magnetic resonance imaging showed mild atrophy of the bilateral dorsolateral prefrontal cortices, left hippocampus, and occipital cortex, as well as diffuse mild T2 hyperintensity in the deep and subcortical white matter, including the frontal region. During a single-photon emission computed tomography scan, significant hyperperfusion was observed in the right ventral striatum, including the nucleus accumbens, ventral thalamus, and right ventrolateral prefrontal areas. Patchy hypoperfusion was found in the bilateral posterior cingulate, parietal, and occipital regions. The patient's neurocognitive function was normal, except for slight impairment of her executive function. Her symptoms and neuroimaging findings were not suggestive of a specific neurocognitive disorder. Hyperactivity of the right ventral striatum may contribute to both obsessive-compulsive disorder and kleptomania. Although frontotemporal lobar degeneration is a major neurocognitive disorder related to illegal behaviours, CREST syndrome-induced white matter microstructural damage in the orbitofrontal lobe could have caused our patient's kleptomania. PMID- 29987860 TI - Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy. AB - AIM: Trefoil factor 3 (TFF3) is a small peptide that is involved in mucosal protection. TFF3 is widely expressed in multiple tissues including kidney tissue. Previous studies have reported that the levels of urinary TFF3 are significantly increased in patients with chronic kidney disease. The aim of this study is to detect the TFF3 mRNA in kidney and elucidate the relationship between renal TFF3 mRNA and tubulointerstitial fibrosis in IgA nephropathy (IgAN). METHODS: We investigated the renal mRNA expression of TFF3 by real-time PCR analysis in biopsy specimens from patients with IgAN, other glomerulonephritis (OGN) and minor glomerular abnormalities (MGA). We also determined the renal localization of TFF3 and the levels of urinary TFF3 by immunostaining and ELISA, respectively. RESULTS: The renal TFF3 mRNA expression was significantly associated with the urinary TFF3 secretion and the tubulointerstitial fibrosis score in the IgAN group alone. Immunostaining of the renal specimen of IgAN patients revealed that TFF3 is located in the renal tubular epithelial cells. The locations were almost the same as those that showed uromodulin positivity; specifically, the thick ascending limb (TAL) of the loop of Henle and the early portion of the distal tubule. The urinary TFF3 levels were positively correlated with the levels of urinary biomarkers of tubulointerstitial injury in such patients. CONCLUSION: Renal TFF3 mRNA is associated with renal tubulointerstitial fibrosis in IgAN patients. The TFF3 located in the renal tubular epithelial cells may play a role in the progression of tubulointerstitial fibrosis in IgAN patients. PMID- 29987862 TI - Perception of domestic risks among carers for dependent older persons. AB - BACKGROUND: Despite growing interest for home care, little evidence exists on the perception of domestic risk among carers for dependent older persons. This study aims to characterize the risks to which carers of aging dependent individuals are exposed, and to determine whether these risk dimensions are predictive for effective support, for burden, and for psychological distress. METHODS: Seventy care partners were questioned about the risk situations identified at the homes of the old people they care for, about the burden they felt in their role, and about their feelings of psychological distress. Securing was evaluated by means of sensibility measures, and overprotection was evaluated by means of specificity measures. RESULTS: Risk rates were high for loneliness of the old people, wandering, burns, and unsatisfactory health monitoring. There was very little overlap between identification of the risks and implementation of solutions by the caregiver, except for the risks that involved heat. The distinction between accurate securing and overprotection is especially important, because the burden of care partners was linked to uncontrolled domestic risks. CONCLUSION: Typologies of reactions to risk, characterized by a signal detection approach, could contribute to a better understanding of the situations experienced by care partners, especially situations of neglect and of overprotection. PMID- 29987863 TI - Loneliness in Chinese older adults in primary care: prevalence and correlates. AB - BACKGROUND: Loneliness is a significant public health concern among older adults (OA) given its association with a wide range of adverse health outcomes. Primary care is an opportune setting to manage loneliness. However, the epidemiology of loneliness in Chinese OA treated in primary care remains unclear. The present study investigated the prevalence and correlates of loneliness in OA treated in Chinese primary care. METHODS: A total of 744 OA patients (65+ years) were consecutively recruited from 13 primary care clinics in Wuhan, China, and interviewed with a standardized questionnaire, concerning sociodemographic characteristics, lifestyle, relationships with family and others, physical health, and sensory impairments. Consistent with prior research on the construct, loneliness was measured with a single-item self-report question. Logistic regression was used to identify correlates of loneliness. RESULTS: Of primary care OA patients, 26.2% endorsed loneliness. Factors significantly and independently associated with loneliness included 75+ age group (odds ratio [OR]: 1.61, 95% confidence interval [CI]: 1.07, 2.44, P: 0.023), being illiterate (OR: 2.07, 95%CI: 1.26, 3.42, P: 0.004), unmarried (OR: 2.30, 95%CI: 1.40, 3.78, P: 0.001), living alone (OR: 4.37, 95%CI: 2.27, 8.41, P < 0.001), having fair and poor family (OR: 2.44, 95%CI: 1.48, 4.00, P < 0.001) and non-family relationships (OR: 1.75, 95%CI: 1.10, 2.78, P: 0.019), and >=2 chronic medical conditions (OR: 2.91, 95%CI: 1.22, 6.95, P: 0.016). CONCLUSIONS: Loneliness is common in Chinese primary care OA. The high prevalence and many negative health consequences of loneliness for OA highlight the importance of routine screening, assessment, and interventions to reduce loneliness in the primary health-care setting. PMID- 29987864 TI - Knowledge and attitudes of older psychiatric patients and their caregivers towards electroconvulsive therapy. AB - BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for older patients with severe psychiatric disorders, but their knowledge and attitudes regarding ECT have not been well studied. This study examined the knowledge and attitudes of older Chinese patients and their caregivers towards ECT. METHOD: A total of 216 participants comprising older patients treated with ECT (n = 108) and their caregivers (n = 108) were recruited. Their knowledge and attitudes regarding ECT were assessed using self-reported questionnaires. RESULTS: Most caregivers received sufficient information on the therapeutic effects of ECT, but inadequate information about the ECT process, its adverse effects, and risks was provided to caregivers and patients before treatment. Although ECT was generally viewed as beneficial, effective, and safe, around two-thirds of patients and caregivers believed that ECT should be used only for critically ill patients. Over half of the patients reported adverse effects caused by ECT, with memory impairment being the most commonly reported. CONCLUSIONS: Clinicians in Chinese psychiatric hospitals need to provide sufficient information on ECT to older patients and their caregivers before treatment, particularly regarding the treatment process and adverse effects. PMID- 29987865 TI - Differences in cancer survival between immigrants in Norway and the host population. AB - Cancer survival is an important indicator for quality of cancer care. We sought to determine if there are differences in cancer survival between immigrants and the host population in Norway. We performed a nationwide registry-based study comprising subjects diagnosed with cancer between 1990 and 2014, and followed until the end of 2016. Survival was estimated for 13 cancer sites with cause specific survival. Adjustments were made for common confounders (age, sex, year of diagnosis and place of residence) and defined mediators (stage at diagnosis, comorbidity and socioeconomic factors). A total of 500,255 subjects were available for analysis, of which 11,252 were Western and 8,701 non-Western immigrants. We did not find differences in cancer survival between Western immigrants and Norwegians, while non-Western immigrants, with some exceptions, had similar or better survival. Better lung cancer survival in non-Western immigrants than Norwegians was notable (hazard ratio (95% confidence interval): 0.78 (0.71-0.85)), and not explained by defined mediators. Immigrants from Eastern Europe and Balkan with melanoma (hazard ratio: 1.54 (1.12-2.12)) and prostate cancer (hazard ratio: 1.34 (1.08-1.67)), and possibly from sub-Saharan Africa with breast cancer (hazard ratio: 1.41 (0.94-2.12)) had worse survival than Norwegians. The results suggest that immigrants in Norway have good cancer survival relative to the host population. Poor survival in immigrants from Eastern Europe and Balkan with melanoma and prostate cancer, and sub-Saharan Africa with breast cancer might be a concern. PMID- 29987867 TI - Assessment of 16-year retrospective cohort study of factors associated with non compliance with a tuberculosis contact tracing programme at a Spanish hospital. AB - RATIONALE, AIMS, AND OBJECTIVE: Contact tracing and screening is an essential strategy in tuberculosis (TB) control. Our aim is to assess factors associated with the degree of compliance with the main recommendations made to contacts of TB cases as part of the contact tracing programme, and to identify factors associated with non-compliance. METHODS: We conducted a retrospective cohort study to assess the TB contact tracing programme at a Spanish hospital over the period 1998-2013. RESULTS: A total 2269 contacts were identified corresponding to 644 active TB index cases, and initial screening indicated that 3.2% had active TB and 41.3% had latent TB infection (LTBI). Compliance with the recommendation for primary chemoprophylaxis increased significantly over the study period, rising from 76.5% in the period 1998 to 2002 to 82.7% in the period 2010 to 2013. A similar significant increase was also observed for latent tuberculosis infection treatment (46.1% in the first period to 68.0% in the latter period). Factors that were significantly associated with non-compliance with the recommendations were: being of foreign origin, alcoholism, being recommended latent tuberculosis infection treatment, repeating the tuberculin skin test at 3 months, a smear-positive index case, and an index case aged under 35 years old. CONCLUSIONS: Although compliance levels have improved over the years, it remains necessary to adopt strategies that target contacts in groups identified as being at risk of non-compliance. PMID- 29987866 TI - Enhance quality care performance: Determination of the variables for establishing a common database in French paediatric critical care units. AB - : Selected variables for the French Paediatric Intensive Care registry. RATIONALE, AIMS, AND OBJECTIVES: Providing quality care requires follow-up in regard to clinical and economic activities. Over the past decade, medical databases and patient registries have expanded considerably, particularly in paediatric critical care medicine (eg, the Paediatric Intensive Care Audit Network (PICANet) in the UK, the Australian and New Zealand Paediatric Intensive Care (ANZPIC) Registry in Australia and New Zealand, and the Virtual Paediatric Intensive Care Unit Performance System (VPS) in the USA). Such a registry is not yet available in France. The aim of this study was to determine variables that ought to be included in a French paediatric critical care registry. METHODS: Variables, items, and subitems from 3 foreign registries and 2 French local databases were used. Items described each variable, and subitems described items. The Delphi method was used to evaluate and rate 65 variables, 90 items, and 17 subitems taking into account importance or relevance based on input from 28 French physicians affiliated with the French Paediatric Critical Care Group. Two ratings were used between January and May 2013. RESULTS: Fifteen files from 10 paediatric intensive care units were included. Out of 65 potential variables, 48 (74%) were considered to be indispensable, 16 (25%) were considered to be optional, and 1 (2%) was considered to be irrelevant. Out of 90 potential items, 62 (69%) were considered to be relevant, 23 (26%) were considered to be of little relevance, and 5 (6%) were considered to be irrelevant. Out of 17 potential subitems, 9 (53%) were considered to be relevant, 6 (35%) were considered to be of little relevance, and 2 (12%) were considered to be irrelevant. CONCLUSIONS: The necessary variables that ought to be included in a French paediatric critical care registry were identified. The challenge now is to develop the French registry for paediatric intensive care units. PMID- 29987868 TI - Personal computer-based cognitive training in Parkinson's disease: a case study. AB - Parkinson's disease (PD) is a neurodegenerative disorder that is best managed by a combination of medication and regular physiotherapy. PD's main symptoms involve the motor system, but cognitive disorders can be very severe as well. The aim of this study was to evaluate the effects of the computerized rehabilitative tool Esercizi di Riabilitazione Cognitiva (ERICA) in the cognitive recovery of a patient with PD. The patient was a 65-year-old man affected by PD with motor complications and severe cognitive and behavioural alterations. He underwent two different types of intensive rehabilitation training: standard cognitive rehabilitation alone and in combination with specific personal computer (PC) based cognitive training. We evaluated his neuropsychological profile before and after the two types of training by using a specific psychometric battery. Only at the end of the PC training did we observe improvement in cognitive function as well as mood stabilization. When used in addition to standard cognitive rehabilitation, PC-based cognitive training may be a valuable tool in improving cognitive skills, with regard to attention, memory process, and executive functions. PC-based cognitive training may be able to help optimize managing the symptoms of PD. PMID- 29987869 TI - A missense mutation of the plasminogen gene in hereditary angioedema with normal C1 inhibitor in Japan. PMID- 29987870 TI - Association of characteristics of people with type 2 diabetes mellitus with discordant values of fasting glucose and HbA1c. AB - BACKGROUND: Primary care physicians frequently encounter people with type 2 diabetes mellitus (T2DM) with discordant values for fasting glucose and HbA1c. The aim of this study was to identify the prevalence and characteristics of people in whom blood glucose and HbA1c did not match. METHODS: Overall, 64 553 people with T2DM from 939 general or internal medicine practices (Disease Analyzer database, Germany; January 2013-December 2015) were analyzed. Multivariable logistic regression models were used to identify associations between baseline clinical characteristics, comorbidity, and glucose-lowering treatment and discordance of fasting glucose and HbA1c values measured at the same visit. RESULTS: Overall, 8582 (13%) patients had fasting glucose >=140 mg/dL and HbA1c <7% (<53 mmol/mol), and 6508 (10%) had HbA1c >=7% (>=53 mmol/mol) and fasting glucose <140 mg/dL. Using patients with both fasting glucose <140 mg/dL and HbA1c <7% as the reference (n = 31 834; 49%), solitary high fasting glucose values (and HbA1c <7%) were positively associated with higher age, male sex, longer diabetes duration, obesity, liver disease, low estimated glomerular filtration rate (eGFR), and glucose-lowering treatment. High HbA1c (and fasting glucose <140 mg/dL) was positively related to longer diabetes duration, obesity, neuropathy, retinopathy, low eGFR, and insulin treatment. There were lower odds of having solitary increased HbA1c >=7% (fasting glucose <140 mg/dL) with higher age, hypertension, depression, and the number of diabetes patients (>200) per practice. CONCLUSIONS: A considerable number of people with T2DM in primary care practices have discordant fasting blood glucose and HbA1c values. People who have discordant glycemic values have different characteristics. PMID- 29987871 TI - Novel murine model of congenital diabetes: The insulin hyposecretion mouse. AB - AIMS/INTRODUCTION: Diabetic animal models have made an enormous contribution to our understanding of the etiology of diabetes and the development of new medications. The aim of the present study was to develop and characterize a novel, non-obese murine strain with spontaneous diabetes - the insulin hyposecretion (ihs) mouse. MATERIALS AND METHODS: During the development of the ICGN.B6-Tns2WT strain as the control for the ICGN-Tns2nph congenital nephrotic strain, diabetic mice were discovered and named ihs mice. Intraperitoneal insulin tolerance test, oral glucose tolerance test and an insulin secretion experiment by the pancreas perfusion system were carried out on ihs mice. The pancreatic islets were examined histologically, and the mRNA expression of pancreatic beta cell-specific genes or genes associated with monogenic diabetes was examined by RT-qPCR. RESULTS: The ihs mice showed several distinctive diabetes-related characteristics: (i) the onset of diabetes was observed only in the male mice; (ii) there were no differences in insulin content between the ihs and control mice; (iii) impaired insulin secretion was elicited by glucose, potassium chloride and sulfonylureas; (iv) there was a significant reduction of relative beta-cell volume with no signs of inflammation or fibrosis; (v) they showed a normal glycemic response to exogenous insulin; and (vi) the mice were not obese. CONCLUSIONS: The ihs mouse provides a novel murine model of congenital diabetes that shows insulin secretion failure. This model allows not only an analysis of the progression of diabetes, but also the identification of unknown genes involved in insulin secretion. PMID- 29987872 TI - Eicosapentaenoic Acid and Prevalence of Cardiovascular Disease in Hemodialysis Patients. AB - Eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio showed inverse associations with cardiovascular disease (CVD) in general population. However, this has not been examined enough in dialysis patients. We cross-sectionally investigated the relationship between EPA/AA ratio and prevalence of CVD in 321 chronic hemodialysis patients (64 +/- 11 years old; 110 women; dialysis vintage 10 +/- 8 years) in an urban area of Tokyo. CVD was defined as a composite of ischemic heart disease, ischemic stroke and hemorrhagic stroke. The frequency of dietary fish intake was also examined. Logistic regression was used to quantify the association of EPA/AA ratio with CVD. EPA/AA ratio was 0.31 +/- 0.19 and 154 patients (48%) consumed fish once or less weekly. One hundred and thirty patients (41%) had CVD, including 65 with ischemic heart disease, 70 with ischemic stroke, and 20 with hemorrhagic stroke. Age (odds ratio [OR], 1.04; P = 0.01), hypertension (OR, 2.25; P = 0.002), and dialysis vintage (OR, 1.04; P = 0.02) were associated with CVD; however, EPA/AA was not after adjustment for other risk factors. A similar relationship was observed between fish intake and CVD prevalence. We did not find any significant association between EPA/AA ratio and prevalence of CVD, although traditional risk factors such as age, hypertension and dialysis vintage were associated with CVD. These results might have been influenced by the fact that only a small proportion of our patients showed a high EPA/AA ratio. PMID- 29987873 TI - Metformin use during pregnancy: Is it really safe? PMID- 29987874 TI - Orthogonal contrast based models for quantitative genetic analysis in autotetraploid species. AB - Dissecting the genetic architecture of quantitative traits is a crucial goal for efficient breeding of polyploid plants, including autotetraploid crop species, such as potato and coffee, and ornamentals such as rose. To meet this goal, a quantitative genetic model is needed to link the genetic effects of genes or genotypes at quantitative trait loci (QTL) to the phenotype of quantitative traits. We present a statistically tractable quantitative genetic model for autotetraploids based on orthogonal contrast comparisons in the general linear model. The new methods are suitable for autotetraploid species with any population genetic structure and take full account of the essential features of autotetrasomic inheritance. The statistical properties of the new methods are explored and compared to an alternative method in the literature by simulation studies. We have shown how these methods can be applied for quantitative genetic analysis in autotetraploids by analysing trait phenotype data from an autotetraploid potato segregating population. Using trait segregation analysis, we showed that both highly heritable traits of flowering time and plant height were under the control of major QTL. The orthogonal model directly dissects genetic variance into independent components and gives consistent estimates of genetic effects provided that tetrasomic gene segregation is considered. PMID- 29987875 TI - Programmable Negative Differential Resistance Effects Based on Self-Assembled Au@PPy Core-Shell Nanoparticle Arrays. AB - The negative differential resistance (NDR) effect observed in conducting polymer/Au nanoparticle composite devices is not yet fully clarified due to the random and disordered incorporation of Au nanoparticles into conducting polymers. It remains a formidable challenge to achieve the sequential arrangement of various components in an optimal manner during the fabrication of Au nanoparticle/conducting polymer composite devices. Here, a novel strategy for fabricating Au nanoparticle/conducting polymer composite devices based on self assembled Au@PPy core-shell nanoparticle arrays is demonstrated. The interval between the two Au nanoparticles can be precisely programmed by modulating the thickness of the shell and the size of the core. Programmable NDR is achieved by regulating the spacer between two Au nanoparticles. In addition, the Au/conducting polymer composite device exhibits a reproducible memory effect with read-write-erase characteristics. The sequentially controllable assembly of Au@PPy core-shell nanoparticle arrays between two microelectrodes will simplify nanodevice fabrication and will provide a profound impact on the development of new approaches for Au/conducting polymer composite devices. PMID- 29987876 TI - Protected clinical support time should be a given: Yes. PMID- 29987878 TI - Speedy stomata, photosynthesis and plant water use efficiency. AB - Contents Summary 93 I. Introduction 93 II. Influence of the speed of gs responses on A and Wi 93 III. Determinants of the rapidity of gs responses 95 IV. Conclusion 97 Acknowledgements 97 References 97 SUMMARY: Stomatal movements control CO2 uptake for photosynthesis and water loss through transpiration, and therefore play a key role in plant productivity and water use efficiency. The predicted doubling of global water usage by 2030 mean that stomatal behaviour is central to current efforts to increase photosynthesis and crop yields, particularly under conditions of reduced water availability. In the field, slow stomatal responses to dynamic environmental conditions add a temporal dimension to gaseous fluxes between the leaf and atmosphere. Here, we review recent work on the rapidity of stomatal responses and present some of the possible anatomical and biochemical mechanisms that influence the rapidity of stomatal movements. PMID- 29987879 TI - Healthcare resource utilization and costs associated with incremental systemic corticosteroid exposure in asthma. AB - BACKGROUND: Although systemic corticosteroid (SCS) treatment, irrespective of duration or dosage, is associated with adverse outcomes for patients with asthma, the longitudinal effects of this treatment on adverse outcomes, healthcare resource utilization (HCRU), and healthcare costs are unknown. METHODS: We identified patients initiating intermittent or long-term SCS who were diagnosed with active asthma from UK general practice with linked secondary care data. Control (non-SCS) patients were matched by sex and index date with those initiating SCS. Minimum baseline period was 1 year prior to index date; minimum follow-up duration was 2 years post-index date. Cumulative incidence of SCS associated adverse outcomes and associated HCRU and costs were compared between SCS and non-SCS patient groups and among average SCS daily exposure categories. Associations between exposure and annualized HCRU and costs were assessed, adjusted for confounders. RESULTS: Analyses included 9413 matched pairs. Median (interquartile range) follow up was as follows: SCS group: 7.1 (4.1-11.8) years; control group: 6.4 (3.8-10.0) years. Greater SCS dosages were correlated with greater cumulative incidence. For example, patients with type 2 diabetes receiving an average daily dosage of >=7.5 mg had a 15-year cumulative incidence (37.5%) that was 1.5-5 times greater than those receiving lower dosages. HCRU and costs increased annually for SCS patients but not for non-SCS patients. Increases in all-cause adverse outcome (excluding asthma)-associated HCRU and costs were dose-dependent. CONCLUSIONS: Over the long term, adverse outcomes associated with SCS initiation were relatively frequent and costly, with a positive dosage response relationship with SCS exposure. PMID- 29987877 TI - Systemic DPP4 activity is reduced during primary HIV-1 infection and is associated with intestinal RORC+ CD4+ cell levels: a surrogate marker candidate of HIV-induced intestinal damage. AB - INTRODUCTION: Combined anti-retroviral therapy (cART) transformed HIV-1 from a deadly disease into a chronic infection, but does not cure HIV infection. It also does not fully restore HIV-induced gut damage unless administered extremely early after infection. Additional biomarkers are needed to evaluate the capacity of therapies aimed at HIV remission/cure to restore HIV-induced intestinal immune damage and limit chronic inflammation. Herein, we aimed to identify a systemic surrogate marker whose levels would reflect gut immune damage such as intestinal Th17 cell loss starting from primary HIV-1 infection. METHODS: Biomarker discovery approaches were performed in four independent cohorts, covering HIV-1 primary and chronic infection in 496 naive or cART-treated patients (Amsterdam cohort (ACS), ANRS PRIMO, COPANA and CODEX cohorts). The concentration and activity of soluble Dipeptidylpeptidase 4 (sDPP4) were quantified in the blood from these patients, including pre- and post-infection samples in the ACS cohort. For quantification of DPP4 in the gut, we utilized two non-human primate models, representing pathogenic (macaque) and non-pathogenic (African green monkey) SIV infection. Four gut compartments were analysed in each animal model (ileum, jejunum, colon and rectum) for quantification of DPP4, RORC and TBX21 gene expression in sorted CD4+ cells. To analyse if sDPP4 levels increase when Th17 cells were restored, we quantified sDPP4 in plasma from SIV-infected macaques treated with IL-21. RESULTS: We showed that sDPP4 levels were strongly decreased in primary HIV-1 infection. Strikingly, sDPP4 levels in primary HIV-1 infection predicted time to AIDS. They were not increased by cART in chronic HIV-1 infection (median 36 months on cART). In the gut of SIV-infected non-human primates, DPP4 mRNA was higher in CD4+ than CD4- leucocytes. DPP4 specifically correlated with RORC expression, a Th17 marker, in CD4+ cells from the intestine. We further demonstrated that sDPP4 activity levels were increased in animals treated with IL-21 and that this increase was associated with restoration of the Th17 compartment and reduced inflammation. Furthermore, DPP4 mRNA levels in small intestine CD4+ cells positively correlated with circulating DPP4 activity. CONCLUSION: These data provide evidence that blood sDPP4 levels could be useful as a correlate for HIV-induced intestinal damage. PMID- 29987880 TI - These aren't the loci you'e looking for: Principles of effective SNP filtering for molecular ecologists. AB - Sequencing reduced-representation libraries of restriction site-associated DNA (RADseq) to identify single nucleotide polymorphisms (SNPs) is quickly becoming a standard methodology for molecular ecologists. Because of the scale of RADseq data sets, putative loci cannot be assessed individually, making the process of filtering noise and correctly identifying biologically meaningful signal more difficult. Artefacts introduced during library preparation and/or bioinformatic processing of SNP data can create patterns that are incorrectly interpreted as indicative of population structure or natural selection. Therefore, it is crucial to carefully consider types of errors that may be introduced during laboratory work and data processing, and how to minimize, detect and remove these errors. Here, we discuss issues inherent to RADseq methodologies that can result in artefacts during library preparation and locus reconstruction resulting in erroneous SNP calls and, ultimately, genotyping error. Further, we describe steps that can be implemented to create a rigorously filtered data set consisting of markers accurately representing independent loci and compare the effect of different combinations of filters on four RAD data sets. At last, we stress the importance of publishing raw sequence data along with final filtered data sets in addition to detailed documentation of filtering steps and quality control measures. PMID- 29987881 TI - Comparison of enhanced male mice sexual function among three medicinal materials. AB - To compare the effect of Epimedium brevicornum Maxim., Cynomorium songaricum Rupr. and Morindae officinalis F.C. How on enhancing sexual function effect, mice were administered gavage by the extracts from three materials, serum testosterone and nitric oxide(NO) levels in male mice were detected and the changes of sexual organs were measured. Results showed that testosterone level, NO level and sexual organs weights of Epimedium brevicornum Maxim. treatment were significantly (p < 0.01) higher than those of Cynomorium songaricum Rupr. and Morindae officinalis F. C. How treatments, which indicated that Epimedium brevicornum Maxim. was more effective to improve sexual function than the other two plants. Subsequently, Epimedium brevicornum Maxim. was selected for the second experiment, with shenbao syrup as a positive reference drug, the male sexual behaviours and female vaginal copulation plug were measured. Results showed that Epimedium brevicornum Maxim. treatment exhibited higher male capture frequency, mount frequency and vaginal plug rate, and lower capture latency and mount latency than shenbao syrup treatment, which indicated that Epimedium brevicornum Maxim. was effective to enhance male mice sexual function. Thus, this finding might bring into perspective the treatment strategy for those doctors who treat erectile dysfunction and might be suitable for use in functional food. PMID- 29987882 TI - Assessing wandering risk among individuals with Alzheimer's disease and dementia: a pilot study. AB - BACKGROUND: We examined a screening instrument to assess risk for wandering among individuals with Alzheimer's disease and dementia according to caregiver informants. METHODS: Pilot data were collected on the Risk of Wandering (RoW) screening instrument by 48 responses from an online survey using the Alzheimer's Association Trial Match system. RESULTS: Results indicated acceptable evidence of the internal consistency of scores for the data obtained, alpha = 0.81. Receiver operating characteristic curve results indicated acceptable evidence of the screening instrument scores' ability to discriminate between individuals who eloped and those who did not wander off, AUC = 0.72, P = 0.003. CONCLUSIONS: A cut-off score for future use is suggested along with directions for future research. The development of a screening instrument would appear to be preferable to restricting the movement of these individuals or unnecessarily invading their privacy through monitoring devices while simultaneously balancing the desire to prevent distress, serious injury, or death. PMID- 29987883 TI - Managing clinical uncertainty: An ethnographic study of the impact of critical care outreach on end-of-life transitions in ward-based critically ill patients with a life-limiting illness. AB - : Rapid response teams, such as critical care outreach teams, have prominent roles in managing end-of-life transitions in critical illness, often questioning appropriateness of treatment escalation. Clinical uncertainty presents clinicians with dilemmas in how and when to escalate or de-escalate treatment. AIMS AND OBJECTIVES: To explore how critical care outreach team decision-making processes affect the management of transition points for critically ill, ward-based patients with a life-limiting illness. METHODS: An ethnographic study across two hospitals observed transition points and decisions to de-escalate treatment, through the lens of critical care outreach. In-depth interviews were carried out to elucidate rationales for practices witnessed in observations. Detailed field notes were taken and placed in a descriptive account. Ethnographic data were analysed, categorised and organised into themes using thematic analysis. FINDINGS: Data were collected over 74 weeks, encompassing 32 observation periods with 20 staff, totalling more than 150 hr. Ten formal staff interviews and 20 informal staff interviews were undertaken. Three main themes emerged: early decision-making and the role of critical care outreach; communicating end-of-life transitions; end-of-life care and the input of critical care outreach. Findings suggest there is a negotiation to achieve smooth transitions for individual patients, between critical care outreach, and parent or ward medical teams. This process of negotiation is subject to many factors that either hinder or facilitate timely transitions. CONCLUSIONS: Critical care outreach teams have an important role in shared decision-making. Associated emotional costs relate to conflict with parent medical teams, and working as lone practitioners. The cultural contexts in which teams work have a significant effect on their interactions and agency. RELEVANCE TO PRACTICE: There needs to be a cultural shift towards early and open discussion of treatment goals and limitations of medical treatment, particularly when facing serious illness. With training and competencies, outreach nurses are well placed to facilitate these discussions. PMID- 29987884 TI - Comparison of conference abstracts and full-text publications of randomized controlled trials presented at four consecutive World Congresses of Pain: Reporting quality and agreement of results. AB - BACKGROUND: Conference abstracts are a potential source of new and relevant information about randomized controlled trials (RCTs). However, their dependability is questionable. The objectives of this study were to quantify the agreement between results of RCTs reported in abstracts presented at the four most recent World Congresses on Pain (WCP) and their corresponding full publications, and to analyse the completeness of reporting in those abstracts. METHODS: To identify RCTs, we screened all abstracts presented at four WCPs from 2008 to 2014. Two independent authors identified corresponding full-text reports published through August 2016. Data about the main outcomes in each abstract and full publication were extracted, including the outcome domains and numerical results reported. We reported discordance between abstracts and full texts. We evaluated abstracts against the CONSORT for Abstracts checklist. RESULTS: Approximately half of the 614 included abstracts had been fully published. Among the 306 abstract/publication pairs, eight pairs were not evaluable, and in the remaining 298 we found some form of discordance in 31% of the cases; the majority of discordances were quantitative, i.e. numerical results were different in the two locations, but with the same direction of effect. In the abstract-publication pairs where the abstract presented only preliminary/interim results, 79% had some form of discordance, mostly quantitative. CONCLUSIONS: The reporting quality of the 614 abstracts was suboptimal; the median adherence across all domains for all abstracts was 26%. In conclusion, conference abstracts of pain research are often not necessarily dependable information. Authors should be required to report abstracts according to reporting guidelines. SIGNIFICANCE: Abstracts of RCTs addressing pain are not often dependable information sources; half of them are not published, their reporting quality is suboptimal. When published, 30% of abstracts-full text pairs have discordant results, with 78% discordance when abstracts present preliminary results. PMID- 29987885 TI - Visceral leishmaniasis-associated nephropathy in hospitalised Brazilian patients: new insights based on kidney injury biomarkers. AB - OBJECTIVE: To evaluate the usefulness of early acute kidney injury (AKI) biomarkers in clinical management of visceral leishmaniasis. METHODS: Prospective study with 50 hospitalised VL patients. AKI biomarkers, that is, serum and urinary neutrophil gelatinase-associated lipocalin (sNGAL, uNGAL, respectively), urinary kidney injury molecule-1 (uKIM-1) and urinary monocyte chemotactic protein-1 (uMCP-1), were quantified by immunoassay (ELISA). Also, interferon gamma (INF-y) and C-reactive protein (CRP) were evaluated as inflammatory biomarkers possibly related to VL severity. RESULTS: VL patients had hyponatremia, hypoalbuminemia, hypergammaglobulinemia, haematologic and hepatic disorders. AKI was found in 46%, and one death (2%) occurred. The AKI group had significant longer hospital stay, lower levels of IFN-y and higher levels of CRP, more clinical renal abnormalities and higher levels of sNGAL, uNGAL, uKIM-1 and uMCP-1. Overall, sNGAL, uKIM-1 and uMCP-1 showed correlations with important clinical renal abnormalities, such as proteinuria, albuminuria, serum creatinine and glomerular filtration rate using adjusted correlations with CRP and IFN-y. Only sNGAL showed an early association with AKI development (OR = 2.78, 95% CI = 1.429-5.428, per each increase of 50 ng/ml), even after adjusting for clinical signals of VL severity and for immune biomarkers. Moreover, sNGAL showed a better performance in predicting AKI development (AUC-ROC = 0.81, 95% CI = 0.69-0.93; cut-off = 154 ng/ml, sensitivity = 82.6%, specificity = 74.1%, P < 0.001). CONCLUSIONS: Visceral leishmaniasis-associated nephropathy showed important proximal tubular injury and glomerular inflammation. Serum NGAL showed an early association with VL-associated nephropathy and may be used to improve clinical management strategies and decrease morbimortality in VL patients. PMID- 29987886 TI - New CTSA mutation in early infantile galactosialidosis. PMID- 29987887 TI - Peculiar Triarylamine-Based Co-assembled Supramolecular Polymers That Exhibit Two Transition Temperatures in the Formation of a Coiled Helical Bundle. AB - This paper describes the peculiar co-assembly supramolecular polymerization behavior of triphenylamine trisamide derivatives with d-alanine (T-ala) or glycine (T-gly) moieties. Concentration and temperature-dependent circular dichroism (CD) spectroscopy revealed that the heating curves of co-assemblies obtained at various molar ratios of T-ala to T-gly exhibited two distinct transition temperatures. The first transition was due to the transformation from coiled helical bundles to single helical fibers without handedness. The second was due to a change from typical elongation to nucleation. These phenomena were confirmed by solvent-dependent decoiling of coiled helical structures and concentration-dependent morphological analysis. The two transitioning temperatures were dependent on the concentration of T-ala in the co-assemblies, suggesting that T-ala concentration plays an important role in the formation of coiled helical bundles. Our study demonstrated the first observation of two distinct transition temperatures in supramolecular polymers. PMID- 29987888 TI - Eucalyptol Inhibits Advanced Glycation End Products-Induced Disruption of Podocyte Slit Junctions by Suppressing Rage-Erk-C-Myc Signaling Pathway. AB - SCOPE: The maintenance of interpodocyte slit diaphragm is critical in the sieving function of glomerular filtration barrier. Eucalyptol is a natural constituent in aromatic plants with antioxidant properties. This study investigates whether and how eucalyptol inhibits podocyte slit diaphragm malfunction in glucose-exposed podocytes and diabetic mouse kidneys. METHODS AND RESULTS: Podocytes were incubated in media containing 33 mm glucose with 1-20 MUm eucalyptol. The in vivo model employed db/db mice orally administrated with 10 mg kg-1 eucalyptol. Nontoxic eucalyptol enhanced podocyte expression of nephrin, podocin, FAT-1, CD2AP, and alpha-actinin-4 diminished by glucose. Oral administration of eucalyptol augmented the induction of the slit diaphragm proteins, alpha-actinin 4, and integrin beta1 in diabetic kidneys, and ameliorated glomerular fibrosis and foot process effacement. Eucalyptol counteracted the receptor of advanced glycation end products (RAGE) induction in podocytes with glucose or AGE-BSA, and elevated the reduction of the slit diaphragm proteins by AGE-BSA. Eucalyptol attenuated the RAGE induction and AGE accumulation in diabetic kidneys. The blockade of ERK-c-Myc signaling enhanced the nephrin and CD2AP expression downregulated in AGE-exposed podocytes. These results indicate that eucalyptol blocked glucose-induced AGE-RAGE axis and podocyte injury through disturbing RAGE ERK-c-Myc signaling. CONCLUSION: Eucalyptol may be a potent agent antagonizing diabetes-associated malformation of interpodocyte slit junction and podocyte actin cytoskeleton. PMID- 29987889 TI - The distribution of BCG prostatitis: A clue for pathogenetic processes? AB - BACKGROUND: We observed in cystoprostatectomy specimens that Bacillus Calmette Guerin (BCG) granulomatous prostatitis tended preferentially to affect the peripheral zone (PZ) and aimed to study the matter, postulating that assessment of its distribution might contribute to understanding pathogenetic processes. METHODS: Entire prostate glands from 27 men (47-83 years; mean = 69 years), who had previously received intravesical BCG therapy for non-muscle-invasive urothelial carcinoma of the bladder, were studied as whole-mount sections to determine the anatomical distribution and histopathological characteristics of BCG prostatitis. RESULTS: Twenty-two (81.5%) showed BCG-type granulomatous inflammation. It often radiated from close to the prostatic urethra toward to the gland periphery as a wedge-shaped area related to one or more duct systems. Twenty-one of these prostate glands (95.5%) showed predominantly or exclusively PZ involvement. Eighteen (81.8%) involved only the PZ, while three cases (13.6%) also showed involvement of the transitional zone (TZ). One case (4.5%) involved only the TZ. No granulomas were seen in the central zone or anterior fibromuscular septum. CONCLUSIONS: Our observations imply the microanatomical arrangement of prostatic ducts is a factor in the pathogenesis of BCG prostatitis. PZ ducts enter the urethra at less obtuse angles than those from other zones and are likely to be more prone to urine reflux and damage from suspended BCG. We speculate that prostatic duct microanatomy could also play a role in the pathogenesis of other prostatic diseases, including conventional prostatitis and adenocarcinoma. PMID- 29987890 TI - Little evidence that farmers should consider abundance or diversity of arbuscular mycorrhizal fungi when managing crops. AB - Contents Summary 1092 I. Introduction 1093 II. Investigating activity of AMF in agroecosystems 1093 III. Crop benefit from AMF: agronomic and mycorrhizal literature differ 1094 IV. Flawed methodology leads to benefits of mycorrhizas being overstated 1094 V. Rigorous methodology suggests low colonisation by AMF can sometimes reduce crop yield 1095 VI. Predicting when mycorrhizas matter for crop yield 1096 VII. Crop genotype 1099 VIII. Fungal genotype 1100 IX. Complex interactions between the mycorrhizal fungal and soil microbial communities 1102 X. Phosphorus-efficient agroecosystems 1102 XI. Conclusions 1103 Acknowledgements 1104 References 1104 SUMMARY: Arbuscular mycorrhizal fungi (AMF) are ubiquitous in agroecosystems and often stated to be critical for crop yield and agroecosystem sustainability. However, should farmers modify management to enhance the abundance and diversity of AMF? We address this question with a focus on field experiments that manipulated colonisation by indigenous AMF and report crop yield, or investigated community structure and diversity of AMF. We find that the literature presents an overly optimistic view of the importance of AMF in crop yield due, in part, to flawed methodology in field experiments. A small body of rigorous research only sometimes reports a positive impact of high colonisation on crop yield, even under phosphorus limitation. We suggest that studies vary due to the interaction of environment and genotype (crop and mycorrhizal fungal). We also find that the literature can be overly pessimistic about the impact of some common agricultural practices on mycorrhizal fungal communities and that interactions between AMF and soil microbes are complex and poorly understood. We provide a template for future field experiments and a list of research priorities, including phosphorus-efficient agroecosystems. However, we conclude that management of AMF by farmers will not be warranted until benefits are demonstrated at the field scale under prescribed agronomic management. PMID- 29987891 TI - Control of amino acid transport into Chinese hamster ovary cells. AB - Amino acid transporters (AATs) represent a key interface between the cell and its environment, critical for all cellular processes: Energy generation, redox control, and synthesis of cell and product biomass. However, very little is known about the activity of different functional classes of AATs in Chinese hamster ovary (CHO) cells, how they support cell growth and productivity, and the potential for engineering their activity and/or the composition of amino acids in growth media to improve CHO cell performance in vitro. In this study, we have comparatively characterized AAT expression in untransfected and monoclonal antibody (MAb)-producing CHO cells using transcriptome analysis by RNA-seq, and mechanistically dissected AAT function using a variety of transporter-specific chemical inhibitors, comparing their effect on cell proliferation, recombinant protein production, and amino acid transport. Of a possible 56 mammalian plasma membrane AATs, 16 AAT messenger RNAs (mRNAs) were relatively abundant across all CHO cell populations. Of these, a subset of nine AAT mRNAs were more abundant in CHO cells engineered to produce a recombinant MAb. Together, upregulated AATs provide additional supply of specific amino acids overrepresented in MAb biomass compared to CHO host cell biomass, enable transport of synthetic substrates for glutathione synthesis, facilitate transport of essential amino acids to maintain active protein synthesis, and provide amino acid substrates for coordinated antiport systems to maintain supplies of proteinogenic and essential amino acids. PMID- 29987892 TI - Neuromedin U directly induces degranulation of skin mast cells, presumably via MRGPRX2. PMID- 29987893 TI - Two New Chromone Glycosides from the Roots of Saposhnikovia divaricata. AB - Five chromone glycosides were isolated from the water-soluble portions of 70% EtOH extract of the roots of Saposhnikovia divaricata, including two new chromone glycosides 1 and 2. The structures of the chromone glycosides were identified as (3'S)-3'-O-beta-d-apiofuranosyl-(1 -> 6)-beta-d-glucopyranosylhamaudol (1), (2'S) 4'-O-beta-d-apiofuranosyl-(1 -> 6)-beta-d-glucopyranosylvisamminol (2), 3'-O glucopyranosylhamaudol (3), 4'-O-beta-d-glucopyranosylvisamminol (4), and 4'-O beta-d-glucopyranosyl-5-O-methylvisamminol (5) on the basis of extensive spectroscopic methods, and the absolute configurations of the new compounds were elucidated by the electronic circular dichroism (ECD) calculation and acid hydrolysis. The cytotoxic activities of the glycosides 1 - 5 against three human cancer cell lines (PC-3, SK-OV-3, and H460) were evaluated. The result showed that compounds 1 - 5 had weak cytotoxic activities against the human cancer cell lines with IC50 values in the range of 48.54 +/- 0.80 - 94.25 +/- 1.45 MUm. PMID- 29987894 TI - Risk of Kaposi sarcoma after solid organ transplantation in the United States. AB - Due to treatment with immunosuppressive medications, solid organ transplant recipients have elevated risk for Kaposi sarcoma (KS), which is caused by human herpesvirus 8 (HHV8). Other risk factors for KS are poorly understood. We linked the United States solid organ transplant registry with 17 population-based cancer registries to ascertain KS incidence among 244,964 transplant recipients from 1987-2014. To compare incidence rates of KS according to patient and transplant characteristics, we calculated incidence rate ratios (IRRs) using Poisson regression. To compare associations of KS with other skin cancers occurring before or within 12 months of KS diagnosis, we computed odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression. All statistical tests were two-sided. We identified 163 KS cases during follow-up. Among transplant recipients, we found significantly increased risk of KS associated with male sex (IRR = 1.87; 95%CI:1.32,2.71), nonwhite race (IRR = 2.67; 95%CI:1.92,3.72), non-US citizenship (IRR = 2.10; 95%CI:1.19,3.47), lung transplant (IRR = 2.22; 95%CI:1.03,4.24, vs. kidney), and older age at transplant. KS risk decreased significantly with time since transplant and recent calendar year, however, no specific induction or maintenance medication was associated with KS. KS incidence was not significantly associated with ambient ultraviolet radiation (IRR = 1.32 95%CI:0.87,2.02, tertile 3 vs. 1). KS incidence has decreased in recent calendar years. In a cross-sectional sample, we found cutaneous squamous cell carcinoma was associated with KS (OR = 4.83; 95%CI:1.30,14.69). KS risk factors included those potentially associated with HHV8 infection and increased immunosuppression. Our findings suggest that transplant recipients with a non-KS skin cancer may also be at high KS risk. PMID- 29987895 TI - Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma. AB - Somatic mutations in the telomerase reverse transcriptase (TERT) promoter are related to telomerase activation and frequently occur at two hot spots located at -124 and -146 bp relative to the start codon in various cancers. Here, we investigated the occurrence and implications of genetic alterations in the TERT promoter in hepatitis B viral hepatocellular carcinoma (B viral HCC). TERT promoter mutations, especially -124C>T, clearly enhanced transcriptional activity in HCC cell lines. In contrast, TERT mRNA expression was lower in B viral HCC patients with TERT promoter mutations than in those without. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator of TERT; this protein was shown to have particularly strong binding affinity for the mutant TERT promoter. However, stable expression of the hepatitis B virus X (HBx) protein inhibited PROX1-mediated TERT expression in vitro. Our data suggest that TERT promoter mutations can enhance the promoter activity in HCC cell lines expressing PROX1 but are not the predominant mechanism of TERT upregulation in B viral HCC patients, based on the inhibition of PROX1-dependent transcriptional activation by HBx. PMID- 29987896 TI - Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer. AB - In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In this study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors. Multivariate analysis showed that WDR54-high tumors were an independent risk factor for DSS, with a hazard ratio of 2.981 (95% confidence interval, 1.425-6.234; p = 0.004). Knockdown of WDR54 significantly inhibited the growth and aggressiveness of CRC cells and reduced tumor growth in a xenograft model. Each WDR54 isoform (a, b, and c) was found to reverse the inhibitory effect of WDR54 knockdown; however, only isoform c, which exhibited the highest expression, was increased in CRC cells. Sensitization of WDR54 knockdown to an SHP2 inhibitor was consistently found in CRC cells, and the underlying mechanism involved their common function in regulating AKT and ERK signaling. In conclusion, the present study is the first to investigate the significance of WDR54 in cancer and to conclude that WDR54 serves as an oncogene in CRC and may be a potential prognostic marker and therapeutic target. This article is protected by copyright. All rights reserved. PMID- 29987897 TI - Impaired chronic pain-like behaviour and altered opioidergic system in the TASTPM mouse model of Alzheimer's disease. AB - BACKGROUND: Chronic pain conditions, especially osteoarthritis (OA), are as common in individuals with Alzheimer's disease (AD) as in the general elderly population, which results in detrimental impact on patient's quality of life. However, alteration in perception of pain in AD coupled with deteriorating ability to communicate pain sensations often result in under-diagnosis and inappropriate management of pain. Therefore, a better understanding of mechanisms in chronic pain processing in AD is needed. Here, we explored the development and progression of OA pain and the effect of analgesics in a transgenic mouse model of AD. METHODS: Unilateral OA pain was induced chemically, via an intra-articular injection of monosodium iodoacetate (MIA) in the left knee joint of AD-mice (TASTPM) and age- and gender-matched C57BL/6J (WT). Pharmacological and biochemical assessments were conducted in plasma and spinal cord tissue. RESULTS: MIA resulted in hind paw mechanical hypersensitivity (allodynia), initiating on day 3, in TASTPM and WT controls. However, from 14 to 28 days, TASTPM displayed partial attenuation of allodynia and diminished spinal microglial response compared to WT controls. Naloxone, an opioid antagonist, re-established allodynia levels as observed in the WT group. Morphine, an opioid agonist, induced heightened analgesia in AD-mice whilst gabapentin was devoid of efficacy. TASTPM exhibited elevated plasma level of beta-endorphin post-MIA which correlated with impaired allodynia. CONCLUSIONS: These results indicate an alteration of the opioidergic system in TASTPM as possible mechanisms underlying impaired persistent pain sensitivity in AD. This work provides basis for re-evaluation of opioid analgesic use for management of pain in AD. SIGNIFICANCE: This study shows attenuated pain-like behaviour in a transgenic mouse model of Alzheimer's disease due to alterations in the opioidergic system and central plasticity mechanisms of persistent pain. PMID- 29987898 TI - Effect of betaine versus arsenite-induced alterations of testicular oxidative stress and circulating androgenic indices in rats. AB - The aim of this work was to study the alleviative role of betaine versus arsenite provoked alterations in testis oxidative status and circulating androgenic indices. Twenty-four adult male rats (204.5 +/- 21 g) were divided into four groups, equally. Control group was given basal diet and tap water. Group 2 rats received arsenite (100 mg/L) in drinking water. Rats in group 3 received betaine (2% of the diet) during arsenite exposure. Group 4 received betaine at 2% of the diet during study period (30 days). The results revealed significant decrease in testicular glutathione peroxidase, catalase and glutathione in arsenite-treated animals relative to controls. Significant increase in testicular malondialdehyde was also detected in arsenite-exposed group. Concurrent administration of betaine with arsenite significantly increased glutathione and catalase amounts in comparison with arsenite group. Arsenite exposure resulted in a significant decrease in plasma testosterone and dihydrotestosterone levels over control rats, whereas supplementation of betaine augmented the hormones concentrations to the levels that had no significant difference in comparison with controls. Concentration of all measured oxidative status and hormonal variables in the betaine plus arsenite and betaine groups was not significantly different relative to controls. Taken together, betaine may be proposed as an alleviative agent against arsenite-induced male reprotoxicity. PMID- 29987899 TI - Effects of a micronutrient supplementation combined with a phosphodiesterase type 5 inhibitor on sperm quantitative and qualitative parameters, percentage of mature spermatozoa and sperm capacity to undergo hyperactivation: A randomised controlled trial. AB - The main objective of this study was to evaluate the effects of a micronutrient supplementation (MS) combined with avanafil on sperm function. Oligoasthenospermic men (n = 217) were treated daily for 90 days with either an MS (45 men, Group A), l-carnitine (44 men, Group B), MS plus avanafil (43 men, Group C) or avanafil (43 men, Group D); another group of 42 men with oligoasthenospermia (Group E) received no treatment. Sperm parameters were evaluated before and after the end of treatment in each Group A, B, C and D respectively. The same sperm parameters were measured in each participant of Group E before and at the 90-day experimental period. Within Groups A, C or D, the total percentage of motile spermatozoa, the hypoosmotic swelling test (HOST) result and the percentage of hyperactivated spermatozoa after incubation under conditions known to induce sperm capacitation were significantly greater after MS or MS plus avanafil treatment, or avanafil treatment than before the respective treatment. We suggest that MS or MS plus avanafil combined administration or avanafil alone improves sperm membrane permeability with an overall result improvement in sperm motility, outcome of HOST and increase in the percentage of hyperactivated spermatozoa. PMID- 29987900 TI - Film Flip and Transfer Process to Enhance Light Harvesting in Ultrathin Absorber Films on Specular Back-Reflectors. AB - Optical interference is used to enhance light-matter interaction and harvest broadband light in ultrathin semiconductor absorber films on specular back reflectors. However, the high-temperature processing in oxygen atmosphere required for oxide absorbers often degrades metallic back-reflectors and their specular reflectance. In order to overcome this problem, a newly developed film flip and transfer process is presented that enables high-temperature processing without degradation of the metallic back-reflector and without the need of passivation interlayers. The film flip and transfer process improves the performance of photoanodes for photoelectrochemical water splitting comprising ultrathin (<20 nm) hematite (alpha-Fe2 O3 ) films on silver-gold alloy (90 at% Ag 10 at% Au) back-reflectors. Specular back-reflectors are obtained with high reflectance below hematite films, which is necessary for maximizing the productive light absorption in the hematite film and minimizing nonproductive absorption in the back-reflector. Furthermore, the film flip and transfer process opens up a new route to attach thin film stacks onto a wide range of substrates including flexible or temperature sensitive materials. PMID- 29987901 TI - Epithelial activators of type 2 inflammation: Elevation of thymic stromal lymphopoietin, but not IL-25 or IL-33, in chronic rhinosinusitis with nasal polyps in Chicago, Illinois. PMID- 29987903 TI - Functional recovery of older stroke patients discharged from hospital to home: The effects of cognitive status and different levels of therapy intensity. AB - AIMS AND OBJECTIVES: To determine whether and how cognitive impairment interacts with therapy intensity to affect functional improvements in older stroke patients over an 8-week postdischarge intervention delivered in a community setting. BACKGROUND: Cognitive status is an important predictor of success of community based rehabilitation, but little has been known as to how cognitive impairment may affect outcomes through its interaction with the rehabilitation process. DESIGN: A prospective follow-up evaluation was conducted in Hong Kong of older stroke patients (n = 384) who were admitted to an 8-week home-based rehabilitation intervention after discharge in Hong Kong between 2012-2014. METHODS: Cognitive screening was conducted among patients at the time of discharge from hospital. The intervention process was monitored, and individuals' therapy intensity was assessed and recorded by physical or occupational therapists independently in each therapy session. Outcomes were measured using the 10-item Barthel ADL index at discharge and after the intervention. RESULTS: Therapy intensity significantly moderated the relationship between cognitive impairment and functional recovery. Cognitively impaired stroke patients with moderate-intensity rehabilitation reported significantly higher increase in functional performance than that of patients with low- and high-intensity rehabilitation. In patients with no cognitive impairment, those who received high intensity treatment showed significantly more functional gains than that of patients being treated with less intensive rehabilitation. CONCLUSION: Cognitive impairment affected functional outcomes through its interaction with different levels of therapy intensity among poststroke older patients. RELEVANCE TO CLINICAL PRACTICE: Increasing therapy intensity from moderate to high benefitted cognitively intact but not cognitively impaired patients. These results should inform decisions about community-based rehabilitation and be used to identify the most cost-effective service delivery model. PMID- 29987904 TI - Caregivers' education decreases depression symptoms and burden in caregivers of patients with dementia. AB - OBJECTIVE: To determine whether providing education to caregivers of patients with dementia decreases their depression symptoms and burden. METHODS: Eighty three outpatients with dementia being treated at the Memory Clinic of Tokyo Medical University Hospital and their caregivers were enrolled. Forty-seven caregivers were enrolled in the caregivers' education (EDU) group and 36 were enrolled in the control (CTL) group. Caregivers were assessed for depression, burden, and quality of life (QoL). Patients were assessed for cognition, psychological symptoms, and QoL. Assessments were carried out at baseline and at 3 months (3M). Caregivers in the EDU group received lectures on symptoms and progression of dementia, management of symptoms, use of social resources etc. RESULTS: At 3M, prevalence of depression symptoms in the EDU group significantly decreased from 36% to 17%, whereas it significantly increased from 22% to 50% in the CTL group. Depression and burden were significantly improved at 3M in the EDU group, whereas they significantly worsened in the CTL group. Psychological symptoms showed a lower tendency at 3M for the EDU group. No significant changes in QoL of caregivers and patients were found in either group. CONCLUSIONS: Providing education to caregivers of patients with dementia improves their depression symptoms and sense of burden, and tends to improve the behaviour and psychological symptoms of dementia in the patients. Providing education to caregivers of dementia patients may hence result in beneficial effects for both the patients and their caregivers, and should be widely used in dementia care. PMID- 29987902 TI - Identification of ENTPD8 and cytidine in pancreatic cancer by metabolomic and transcriptomic conjoint analysis. AB - To identify metabolic pathways that were perturbed in pancreatic cancer (PC), we investigated gene-metabolite networks by integration of metabolomic and transcriptomic. In this research, we undertook the metabolomic study of 43 paired human PC samples, aiming to identify key metabolic alterations in PC. We also carried out in vitro experiments to validate that the key metabolite cytidine and its related gene ENTPD8 played an important role in PC cell proliferation. We screened out 13 metabolites differentially expressed in PC tissue (PCT) by liquid chromatography/mass spectrometry analysis on 34 metabolites, and the partial least square discrimination analysis results revealed that 9 metabolites among them were remarkably altered in PCT compared to adjacent noncancerous tissue (variable importance in projection >1, P < .05). Among the 9 metabolites, 7 might be potential biomarkers. The most significantly enriched metabolic pathway was pyrimidine metabolism. We analyzed 351 differentially expressed genes from The Cancer Genome Atlas and intersected them with Kyoto Encyclopedia of Genes and Genomes metabolic pathways. We found that ENTPD8 had a gene-metabolite association with cytidine in the CTP dephosphorylation pathway. We verified by in vitro experiments that the CTP dephosphorylation pathway was changed in PCT compared with adjacent noncancerous tissue. ENTPD8 was downregulated in PCT, causing a reduction in cytidine formation and hence weakened CTP dephosphorylation in pyrimidine metabolism. PMID- 29987905 TI - Simple Formula for Predicting Drug Removal Rates During Hemodialysis. AB - The present study sought to derive a simple formula for predicting the drug removal rates during hemodialysis. We examined the relationship between drug removal rates during hemodialysis and the molecular weights or pharmacokinetic parameters of injectable drugs (N = 90) obtained from pharmaceutical interview forms in Japan. Stepwise multiple regression analysis with the removal rate by hemodialysis as the objective variable adjusted for molecular weight or pharmacokinetic parameters as explanatory variables, showed that the logarithm of molecular weight (B = -18.87), the protein binding rate (B = -0.40), and the fraction of the unchanged drug excreted into the urine/volume of distribution (B = 0.05) were significantly and independently associated with drug removal rate by hemodialysis (alpha = 90.78, adjusted R2 = 0.64, P = 2.2e-16 ). Our data demonstrated that molecular weight, protein binding rate, and volume of distribution were important factors affecting drug removal during hemodialysis, and that our simple regression equation could be used to predict the drug removal rate during hemodialysis. PMID- 29987906 TI - Thermal stability and catalytic properties of protease from Bacillus sp. P45 active in organic solvents and ionic liquid. AB - The parameters half-life, z value, enthalpy, entropy, and free energy were evaluated in the temperature range of 40 to 55 degrees C for a Bacillus sp. P45 protease present in a medium composed of ionic liquid (IL) and organic solvent. The protease was previously treated in IL [Emim][Tf2 N] and increased activity was observed in four out of five organic solvents tested. The reaction medium containing acetone and IL (1:1 v/v ratio) was more stable than the buffer medium, with half-life of 2.4 h at 55 degrees C. Thermodynamic parameters values showed there was probably less rupture of non-covalent bonds that stabilize the protein structure, which promoted the protease P45 stabilization. According to this study it was concluded that the protease P45 in a medium composed of [Emim][Tf2 N] and acetone may be used at higher temperatures than those employed in buffer or medium containing organic solvent. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018 (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1102-1108, 2018. PMID- 29987908 TI - Maternal pregestational or gestational diabetes and childhood wheezing: A population-based cohort study. PMID- 29987907 TI - Design, Synthesis and Antibacterial Evaluation of 1-[(1R,2S)-2 Fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione Hybrids. AB - A new class of 1-[(1R,2S)-2-fluorocyclopropyl]ciprofloxacin (CPFX)-1,2,4-triazole 5(4H)-thione hybrids 6a - 6o was designed, synthesized and evaluated for their in vitro antibacterial activities against a panel of clinically important drug sensitive and drug-resistant Gram-positive and Gram-negative pathogens. Our results revealed that all hybrids 6a - 6o had great potency against the tested strains, especially Gram-negative pathogens. The synthesized hybrids were more potent than the parent 1-[(1R,2S)-2-fluorocyclopropyl]CPFX (1) and comparable to CPFX and levofloxacin against the majority of the tested pathogens, worth to be further investigated. PMID- 29987909 TI - Ultrafast cell edge detection by line-scan time-stretch microscopy. AB - Ultrafast time-stretch imaging technique recently attracts an increasing interest for applications in cell classification due to high throughput and high sensitivity. A novel imaging modality of time-stretch imaging technique for edge detection is proposed. Edge detection based on the directional derivative is realized using differential detection. As the image processing is mainly implemented in the physical layer, the computation complexity of edge extraction is significantly reduced. An imaging system for edge detection with the scan rate of 77.76 MHz is experimentally demonstrated. Resolution target is first measured to verify the feasibility of the edge extraction. Furthermore, various cells, including red blood cells, lung cancer cells and breast cancer cells, are detected. The edges of cancerous cells present in a completely different form. The imaging system for edge detection would be a good candidate for high throughput cell classification. PMID- 29987910 TI - Electrostatic-Driven Dynamic Jamming of 2D Nanoparticles at Interfaces for Controlled Molecular Diffusion. AB - Dynamically engineering the interfacial interaction of nanoparticles has emerged as a new approach for bottom-up fabrication of smart systems to tailor molecular diffusion and controlled release. Janus zwitterionic nanoplates are reported that can be switched between a locked and unlocked state at interfaces upon changing surface charge, allowing manipulation of interfacial properties in a fast, flexible, and switchable manner. Combining experimental and modeling studies, an unambiguous correlation is established among the electrostatic energy, the interface geometry, and the interfacial jamming states. As a proof-of-concept, the well-controlled interfacial jamming of nanoplates enabled the switchable molecular diffusion through liquid-liquid interfaces, confirming the feasibility of using nanoparticle-based surfactants for advanced controlled release. PMID- 29987911 TI - Significance of leukocytosis prior to cardiac device implantation. AB - INTRODUCTION: Infection remains a dreaded complication after cardiac implanted electronic device (CIED) placement. The prognostic value of the preoperative white blood cell (WBC) count, in the absence of other signs of infection, at time of CIED placement as a predictor of postoperative infection, has not been previously examined. METHODS: The study population included 1,247 consecutive device implantations over a 4-year period that met inclusion criteria. The association between preoperative WBC count and resultant infection postoperatively was examined. Early infection was defined as definite infection of the pocket or lead system or development of systemic infection identified <60 days after implantation. Preoperative WBC counts were obtained within 48 hours of the procedure. RESULTS: Baseline characteristics of the population studied were mean age of 65 years, 66% men, and 72% Caucasian. Pacemakers, implantable cardioverter defibrillators (ICDs), and biventricular ICDs were implanted in 41%, 44%, and 15%, respectively. Average procedure time was 174 minutes +/- 80. Of 1,247 device implantations, there were 10 infections (0.8%). Mean preprocedure WBC count in those diagnosed with infection was 8.1 * 103 /uL (range 5-11.7) and in those without infection was 7.8 * 10^3/uL (range 2.3-29) (P = 0.73). Cases resulting in infection demonstrated minimal change in WBC count (mean +5.5 +/- 26.5%). There was no statistically significant difference in preprocedure WBC count between the two groups (P = 0.7). Regardless of preprocedural WBC, no patients had other signs and symptoms of infection at time of device implantation. CONCLUSION: As an isolated finding, an elevated preprocedure WBC should not delay the implantation of an indicated device. PMID- 29987912 TI - Undetectable prostate-specific antigen after short-course androgen deprivation therapy for biochemically recurrent patients correlates with metastasis-free survival and prostate cancer-specific survival. AB - BACKGROUND: Optimal utilization of novel therapies for advanced prostate cancer is challenging without a validated surrogate efficacy endpoint. Ongoing trials are using durable undetectable prostate-specific antigen (PSA) levels as a marker of efficacy. The clinical relevance of prolonged undetectable PSA after a short course of androgen deprivation therapy (ADT) is uncertain. METHODS: The University of Washington Caisis database was queried for radical prostatectomy patients who received 6-12 months of ADT after biochemical recurrence (BCR), defined as PSA >=0.2 ng/mL and no radiographically detectable metastasis. Proportions of men with undetectable PSA 12 and 24 months after ending ADT were compared to a hypothesized 5% rate using exact binomial tests. Associations with patient and tumor characteristics were examined using logistic regression, and associations with risk of subsequent metastasis and death were evaluated by log rank tests. RESULTS: After ineligibility exclusions, 23/93 (25%; 95%CI 16-35%; P < 0.001) and 14/93 (15%; 95%CI 9-24%; P < 0.001) had undetectable PSA 12 and 24 months after ending ADT, respectively. Detectable PSA at 12 months was associated with increased risk of metastasis (P = 0.006), prostate cancer-specific death (P = 0.028), and death from any cause (P = 0.065). Being 1 year older at diagnosis was associated with a 14% (95%CI 5-24%; P = 0.006) decrease in the odds of having a detectable PSA after controlling for PSA at diagnosis, PSA doubling time, grade group, and time from initial therapy to BCR. CONCLUSIONS: This single-institution retrospective analysis shows that it is not uncommon to have undetectable PSA 12 or 24 months after a short course of ADT. No baseline prognostic characteristic other than age was associated with a durable (12 month) undetectable PSA. Because a durable undetectable PSA was associated with lower risks of metastasis and prostate cancer-specific death, it may be a reasonable clinical trial endpoint. PMID- 29987913 TI - Stable overexpression of p130/E2F4 affects the multipotential abilities of bone marrow-derived mesenchymal stem cells. AB - Bone-marrow-derived mesenchymal stem cells (MSCs) have great potential in transplantation medicine due to their multiple advantages. However, the controlled differentiation of MSCs is one of the key aspects of effective clinical transplantation. Growing evidence suggests that the cell cycle plays an important role in regulating differentiation, while p130 and E2F4 are key to cell cycle checkpoints. The aim of the study is to evaluate the effects and mechanism of p130/E2F4 on the multidifferentiation of MSCs. Our data showed that the transduction efficiencies of p130 or E2F4 mediated by lentiviral vectors were 80.3%-84.4%. p130 and E2F4 mRNA expression was significantly higher in MSC-p130 and MSC-E2F4 cells than in MSC normal control (NC) cells. Similar results were also observed for p130 and E2F4 protein expression. After osteogenic or adipogenic differentiation, the G1 phase was significantly delayed in the MSC p130 and MSC-E2F4 groups compared with that in the MSC-NC group. However, the G1 phase in the MSC-p130 and MSC-E2F4 groups did the opposite after chondrogenic differentiation. Moreover, overexpressing p130 or E2F4 significantly improved osteogenic differentiation while inhibiting adipogenic and chondrogenic differentiation of mouse MSCs (mMSCs). Moreover, overexpressing p130 or E2F4 significantly improved migration but not proliferation of mMSCs. Our data suggest that cell cycle regulation may be involved in p130/E2F4-mediated changes in the multipotential abilities of bone-marrow-derived mMSCs. PMID- 29987914 TI - Comparison between PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, and atezolizumab) in pretreated NSCLC patients: Evidence from a Bayesian network model. PMID- 29987915 TI - Antipsychotic drugs and risk of newly diagnosed tuberculosis in schizophrenia. AB - AIM: Patients with schizophrenia have a higher incidence of tuberculosis than do people in the general population. Information is limited regarding the association between antipsychotic agents and the risk of tuberculosis in patients with schizophrenia. This exploratory study assessed the risk of tuberculosis among patients with schizophrenia on antipsychotic therapy. METHODS: Among a nationwide schizophrenia cohort derived from the National Health Insurance Research Database in Taiwan (n = 32 399), we identified 284 patients who had developed newly diagnosed tuberculosis after their first psychiatric admission. Ten or fewer matched controls were selected randomly from the cohort for each patient based on risk-set sampling. We categorized exposure to antipsychotic medications by type and defined daily dose. Using multivariate methods, we explored individual antipsychotic agents for the risk of tuberculosis and employed a propensity-scoring method in sensitivity analyses to validate any associations. RESULTS: Among the antipsychotic agents studied and after adjustment for covariates, current use of clozapine was the only antipsychotic agent associated with a 63% increased risk of tuberculosis (adjusted risk ratio = 1.63, P = 0.014). In addition, the association did not show a clear dose dependent relationship. Clozapine combined with other antipsychotic agents showed a potential synergistic risk for tuberculosis (adjusted risk ratio = 2.30, P = 0.044). CONCLUSION: This exploratory study suggests the potential risk of clozapine on the risk of tuberculosis, especially for those on clozapine in combination with other antipsychotics. Future studies are needed to verify the association. PMID- 29987916 TI - On the Mechanism of the Reactivity of 1,3-Dialkylimidazolium Salts under Basic to Acidic Conditions: A Combined Kinetic and Computational Study. AB - Comprehensive spectroscopic kinetic studies illustrate an alternative mechanism for the traditional free-carbene intermediated H/D exchange reaction of 1,3 dialkylimidazolium salts under neutral (D2 O) and acidic conditions (DCl/D2 O 35 wt % solution). The deuteration of high purity [bmim]Cl in D2 O is studied at different temperatures, in absence of catalyst or impurities, to yield an activation energy. DFT transition-state modelling, of a small water cluster and [bmim] cation, also yields an activation energy which strongly supports the proposed mechanism. The presence of basic impurities are shown to significantly enhance the exchange reaction, which brings into question the need for further analysis of technical purities of ionic liquids and the implications for a wide range of chemical reactions in such media. PMID- 29987917 TI - Chemical Synthesis of Bioactive Naturally Derived Cyclic Peptides Containing Ene Like Rigidifying Motifs. AB - The development of synthetic methods to prepare conformationally constrained peptides and peptide-polyketide hybrids remain an important chemical challenge. It is known that structural rigidity correlates with the specificity, bioactivity, and stability of these peptide systems, thus rigid systems are particularly attractive leads for development of potent biopharmaceuticals. Herein we provide an overview of recent developments in the syntheses of naturally derived constrained peptides and peptide-polyketide hybrids, with a particular emphasis on those systems containing an ene-like bond. PMID- 29987918 TI - Inter-alpha-inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach. AB - In recent years, several genome-wide association studies have identified candidate regions for genetic susceptibility in major mood disorders. Most notable are regions in a locus in chromosome 3p21, encompassing the genes NEK4 ITIH1-ITIH3-ITIH4. Three of these genes represent heavy chains of the composite protein inter-alpha-inhibitor (IalphaI). In order to further establish associations of these genes with mood disorders, we evaluated behavioral phenotypes in mice deficient in either Ambp/bikunin, which is necessary for functional ITIH1 and ITIH3 complexes, or in Itih4, the gene encoding the heavy chain Itih4. We found that loss of Itih4 had no effect on the behaviors tested, but loss of Ambp/bikunin led to increased anxiety-like behavior in the light/dark and open field tests and reduced exploratory activity in the elevated plus maze, light/dark preference and open field tests. Ambp/bikunin knockout mice also exhibited a sex-dependent exaggeration of acoustic startle responses, alterations in social approach during a three-chamber choice test, and an elevated fear conditioning response. These results provide experimental support for the role of ITIH1/ITIH3 in the development of mood disorders. PMID- 29987919 TI - N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts the cardio-renal response to aliskiren in patients with type 2 diabetes at high renal and cardiovascular risk. AB - Sodium retention and volume overload are the main determinants of poor response to renin-angiotensin-aldosterone system (RAAS) inhibition in patients with diabetes. As volume excess can exist without symptoms, biomarkers are needed to identify a priori which patients are volume overloaded and may experience less benefit from RAAS inhibition. N-terminal pro-brain natriuretic peptide (NT proBNP) is released in the setting of increased cardiac wall stress and volume overload. We conducted a post hoc analysis among 5081 patients with type 2 diabetes mellitus participating in the ALTITUDE trial to investigate whether NTproBNP can predict the effects of additional therapy with aliskiren on cardio renal endpoints. Aliskiren compared to placebo reduced the risk of the primary cardio-renal endpoint events by 20% (95% confidence interval [CI] 16 to 61) and 2% (95% CI -42 to 30) in the two lowest NT-proBNP tertiles, and it increased the risk by 25% (95% CI -4 to 96) in the highest NT-proBNP tertile (P value for trend = 0.009). Similar trends were observed for the cardiovascular and end-stage renal disease endpoints. Effects of aliskiren compared to placebo on safety outcomes (hyperkalaemia and hospitalization for acute kidney injury) were independent of NT-proBNP. In conclusion, baseline NT-proBNP may be used as a marker to predict the response to aliskiren with regard to cardio-renal outcomes when added to standard therapy with RAAS inhibition. PMID- 29987921 TI - Prevalence and characterization of carbapenem-resistant bacteria in water bodies in the Los Angeles-Southern California area. AB - Carbapenems are beta-lactam antibiotics used in healthcare settings as last resort drugs to treat infections caused by antibiotic-resistant bacteria. Carbapenem-resistant bacteria are increasingly being isolated from healthcare facilities; however, little is known about their distribution or prevalence in the environment, especially in the United States, where their distribution in water environments from the West Coast has not been studied before. The aim of this study was to determine the prevalence of carbapenem-resistant bacteria and carbapenemase genes in water bodies from the Los Angeles area (California, USA). All samples that were analyzed contained carbapenem-resistant bacteria with a frequency of between 0.1 and 324 carbapenem-resistant cfu per 100 mls of water. We identified 76 carbapenem-resistant or -intermediate isolates, most of which were also resistant to noncarbapenem antibiotics, as different strains of Enterobacter asburiae, Aeromonas veronii, Cupriavidus gilardii, Pseudomonas, and Stenotrophomonas species. Of them, 52 isolates were carbapenemase-producers. Furthermore, PCR and sequence analysis to identify the carbapenemase gene of these carbapenemase-producing isolates revealed that all Enterobacter asburiae isolates had a blaIMI-2 gene 100% identical to the reference sequence, and all Stenotrophomonas maltophlia isolates had a blaL1 gene 83%-99% identical to the reference blaL1 . Our findings indicate that water environments in Southern California are an important reservoir of bacteria-resistant to carbapenems and other antibiotics, including bacteria carrying intrinsic and acquired carbapenemase genes. PMID- 29987920 TI - Aberrant methylation and silencing of the SPINT2 gene in high-grade gliomas. AB - Hepatocyte growth factor activator inhibitor type 2 (HAI-2), encoded by the SPINT2 gene, is a membrane-anchored protein that inhibits proteases involved in the activation of hepatocyte growth factor (HGF), a ligand of MET receptor. Epigenetic silencing of the SPINT2 gene has been reported in a human glioblastoma cell line (U87) and glioblastoma-derived cancer stem cells. However, the incidence of SPINT2 methylation in tumor tissues obtained from glioma patients is unknown. In this study, we analyzed the methylation status of the SPINT2 gene of eight human glioblastoma cell lines and surgically resected glioma tissues of different grades (II, III, and IV) by bisulfite sequence analysis and methylation specific PCR. Most glioblastoma lines (7/8) showed methylation of the SPINT2 gene with a significantly reduced level of SPINT2mRNA compared to cultured astrocytes and normal brain tissues. However, all glioblastoma lines expressed mRNA for HGF activator (HGFAC), a target protease of HAI-2/SPINT2. Forced expression of SPINT2 reduced MET phosphorylation of U87 glioblastoma cells both in vitro and in intracranial xenografts in nude mice. Methylation-specific PCR analysis of the resected glioma tissues indicated notable methylation of the SPINT2 gene in 33.3% (2/6), 71.4% (10/14), and 74.3% (26/35) of grade II, III, and IV gliomas, respectively. Analysis of RNA sequencing data in a public database indicated an increased HGFAC/SPINT2 expression ratio in high-grade compared to low-grade gliomas (P = .01). In summary, aberrant methylation of the SPINT2 gene is frequently observed in high-grade gliomas and might confer MET signaling in the glioma cells. PMID- 29987922 TI - Metal-Organic Framework Nanosheet Electrocatalysts for Efficient H2 Production from Methanol Solution: Methanol-Assisted Water Splitting or Methanol Reforming? AB - Hydrogen (H2) is presently one of the most promising clean and renewable energy sources, but the conventional hydrogen production by electrochemical water splitting, though of great potential and extensively studied, is seriously obstructed especially by the anodic oxygen evolution reaction because of its sluggish kinetics. Herein, we report the efficient hydrogen production from methanol solution using facile-synthesized ultrathin 2D bi-metal-organic framework nanosheets (UMOFNs) as a precious metal-free anodic catalyst. The prepared UMOFNs showed a much lowered anodic potential of 1.365 (V vs reversible hydrogen electrode) at 10 mA cm-2, which was markedly 232 mV lower than that in conventional water splitting, and moreover, the average turnover frequency reached 19.62 s-1. Benefiting from nearly 100% Faraday efficiency of H2 production on the counter graphite carbon electrodes without additional electrocatalysts, high-purity hydrogen was produced with enhanced efficiency. More importantly, the anodic electro-reaction mechanism has been evidenced experimentally: the electrocatalytic hydrogen production from the methanol solution is a methanol-assisted water splitting, rather than a methanol-reforming process as claimed in a number of literature studies, in which methanol is oxidized as a sacrificing agent in place of water oxidization in pure water. PMID- 29987923 TI - Noninvasive and Accurate Detection of Hereditary Hearing Loss Mutations with Buccal Swab Based on Droplet Digital PCR. AB - Hereditary hearing loss is a common clinical neurosensory disorder in humans and has a high demand for genetic screening. Current screening techniques using peripheral blood or dried blood spots (DBSs) are invasive. Therefore, this study aims to develop a noninvasive and accurate detection method for eight hotspot deafness-associated mutations based on buccal swab and droplet digital PCR (ddPCR). First, this method was evaluated for analytic performance including specificity, detection limit, dynamic range using plasmid DNA. The specificity was 100% and the detection limit was 5 copies. The dynamic range of this ddPCR based method was from 10 to 105 copies/MUL. Next, the method was found to accurately quantify mitochondrial gene heteroplasmy rate as low as 1% for both m.1494C > T and m.1555A > G sites. Then, we demonstrated that buccal swab was a reliable sample. DNA can be extracted and accurately quantified after a buccal swab had been stored for 90 days at either room temperature or -20 degrees C. Finally, clinical samples (23 DBSs and 42 buccal swabs) were tested to further evaluate the accuracy and clinical applicability of this method. All clinical samples were accurately quantified and genotyped. This noninvasive and accurate method is highly promising as a genetic screening method for deafness-associated mutations due to its high sensitivity and accuracy. PMID- 29987924 TI - Applying an Electrophilicity-Based Strategy to Develop a Novel Nrf2 Activator Inspired from Dietary [6]-Shogaol. AB - Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial cellular defense mechanisms against oxidative stress and also an effective means to decrease the risk of oxidative stress-related diseases including cancer. Thus, identifying novel Nrf2 activators is highly anticipated. Inspired from [6] shogaol (6S), an active component of ginger, herein we developed a novel potent Nrf2 activator, (1E,4E)-1-(4-hydroxy-3-methoxyphenyl)-7-methylocta-1,4,6-trien-3 one (SA) by an electrophilicity-based strategy. Compared with the parent 6S, SA bearing a short but entirely conjugated unsaturated ketone chain manifested the improved electrophilicity and cytoprotection (cell viability for the 10 MUM 6S- and SA-treated group being 48.9 +/- 5.3% and 76.1 +/- 3.2%, respectively) against tert-butylhydroperoxide ( t-BHP)-induced cell death (cell viability for the t-BHP stimulated group being 42.4 +/- 0.4%) of HepG2. Mechanistic study uncovers that SA works as a potent Nrf2 activator by inducing Keap1 modification, inhibiting Nrf2 ubiquitylation and phosphorylating ERK in a Michael acceptor-dependent fashion. Taking 6S as an example, this works illustrates the feasibility and importance of applying an electrophilicity-based strategy to develop Nrf2 activators with dietary molecules as an inspiration due to their low toxicity and extraordinarily diverse chemical scaffolds. PMID- 29987925 TI - Unraveling the Mechanism of Photoinduced Charge-Transfer Process in Bilayer Heterojunction. AB - Charge transfer is a fundamental process that determines the performance of solar cell devices. Although great efforts have been made, the detailed mechanism of charge-transfer process across the two-dimensional van der Waals (vdW) heterostructure remains elusive. Here, on the basis of the ab initio nonadiabatic molecular dynamics simulation, we model the photoinduced charge-transfer dynamics at the InSe/InTe vdW heterostructures. Our results show that carriers can follow either the R-scheme or Z-scheme transfer path, depending on the coupling between the interlayer states at the band-edge positions. In addition, the charge transfer dynamics can be effectively controlled by the external parameters, such as strains and interlayer stacking configurations. The predicated electron-hole recombination lifetime in the R-scheme transfer path is up to 1.4 ns, whereas it is shortened to 1.2 ps in the Z-scheme transfer path. The proposed R-scheme and Z scheme are further verified by the quantum transport simulations on the basis of the density functional theory (DFT) method combined with nonequilibrium Green's functions (NEGF-DFT). The analysis reveals that the system dominated by the Z scheme shows better performance, which can be attributed to the built-in electric field that facilitates the charge transfer. Our work may pave the way for the designing of next-generation devices for light detecting and harvesting. PMID- 29987926 TI - An MOF-like Interpenetrated 2D Plus 2D to 3D Inorganic Grid Assembled by Linear Inorganic Pillars, Structures, and Properties in Supercapacitance. AB - Remarkable progresses regarding pure inorganic frameworks and metal-organic frameworks (MOF) have been made. However, pure inorganic frameworks with MOF-like grid structures are rarely reported due to the weakness of inorganic moiety as a long linear linker. We report herein a fascinating inorganic framework assembled by a [Ge4S10]4- cluster node and a linear [-Cu-MS4-Cu-] (M = Mo (1) and W (2)) inorganic pillar. Their network shows MOF-like orthogonal structure with two interpenetrated two-dimensional (2D) plus 2D to 3D framework and a 1D nano tunnel. Electrodes with crystalline sample of 1 and 2, inorganic sulfide framework, were prepared, and their quasi-capacitance behaviors were investigated. Electrochemical performances were evaluated by cyclic voltammetry and galvanostatic charge-discharge techniques in CsOH, KOH, NaOH, and LiOH electrolytes. The results revealed that the crystal materials exhibit moderate specific capacitance values that are comparable to those of porous sulfide materials. PMID- 29987927 TI - Fungistatic Activity of Multiorigin Humic Acids in Relation to Their Chemical Structure. AB - Humic acid (HA) has an inhibitory effect on phytopathogenic fungi, but the structure-activity relationship remains unclear. HAs were extracted from 14 different materials, and their fungistatic activities and elemental C, N, S, and O contents were measured. Cross-polarization magic-angle spinning 13C nuclear magnetic resonance (CPMAS 13C NMR) was used to measure the organic carbon composition. The results showed that all HAs suppressed phytopathogenic fungi growth, with Yunnan lignite HAs showing the highest inhibition (85.3%) against Physalospora piricola. The soil and compost HA aromaticity (ARO) was <50%, except for black soil HAs, while the ARO of all coal HAs was >60%. The ARO of meadow and moss peat HAs was <50%, while the ARO of woody peat HAs was 50.61%. Mantel test and redundancy analysis (RDA) were applied to evaluate the structure-activity relationship. The Mantel test revealed that the N, S, O, N/O, carbonyl C, aromatic C-O, and anomeric C contents were significantly correlated with fungistatic activity. The RDA analysis showed that the S content was positively correlated with fungistatic activity, while the O content was negatively correlated. The carbonyl C content had a positive correlation with fungistatic activity, while the anomeric C and aromatic C-O content had a negative correlation. A high S content and an active composition (carbonyl C) in HAs would lead to a high degree of fungistatic activity. Phytotoxicity test indicated all HAs were beneficial to plant growth. This work identified the basic properties of HAs from various raw materials that control their fungistatic activities. PMID- 29987928 TI - Low-Bleed Silica-Based Stationary Phase for Hydrophilic Interaction Liquid Chromatography. AB - Bleeding of hydrophilic interaction liquid chromatographic (HILIC) phases is a major problem. A hydrophobic silica surface exhibits low bleeding but does not behave as a HILIC phase. A hydrophilic coating, such as that of poly(vinyl alcohol) (PVA) on a hydrophobic particle should result in a low-bleed hydrophilic phase. However, a silica particle functionalized in a hydrophobic manner is not wetted by PVA and cannot be coated with it. Coating with PVA becomes possible if one region of the hydrophobic functionality is polar. We describe a low-bleed HILIC stationary phase, PVA-coated benzylthioethyl-silica. The benzyl groups shield the silica from water erosion, while the thiol group provides sufficient local polarity for PVA to wet the material. The new stationary phase demonstrated good chromatographic performance and typical HILIC retention behavior. The measured silica concentration in the effluent was ~80-fold lower than that from a bare silica column. The new stationary phase exhibited a lower background level, lower background noise, and lower background drift under gradient conditions than benchmark commercial columns. PMID- 29987929 TI - Molecular Borromean Rings Based on Half-Sandwich Organometallic Rectangles. AB - Over the last two decades, interlocked molecular species have received considerable attention, not only because of their intriguing structures and topological importance, but also because of their potential applications as smart materials, nanoscale devices, and molecular machines. Through judicious choice of metal centers and their adjoining ligands, a range of interesting interlocked structures have been realized by coordination-driven self-assembly. In addition, researchers have extensively developed synthetic methodologies for the construction of organized self-assemblies. One fascinating and challenging synthetic target in this field is the family of molecular Borromean rings, which consist of three chemically independent rings that are locked in such a way that no two of the three rings are linked with each other. Toward this goal, we have developed a template-free self-assembly method for synthesizing molecular Borromean rings by rationally designing metal-containing precursors and organic ligands. In this Account, we present our recent work, focusing on interlocked structures comprising half-sandwich iridium- and rhodium-based organometallic assemblies obtained by rational design. We first describe a series of template free self-assembled organometallic molecular Borromean rings, which we constructed from preorganized binuclear half-sandwich molecular clips and suitable pyridyl ligands. These molecular Borromean rings can be sorted into four types according to their different bridging ligands, including those based on metallaligands, dihalogenated ligands, naphthazarin and pi-acceptor ligands. By single-crystal X-ray crystallographic analysis, NMR experiment, and DFT calculation, we discuss their driving forces and the inter-ring interactions. Furthermore, we took advantage of the dissimilarity in their interactions to realize selective, reversible conversions between molecular Borromean rings and monomeric rectangles by the use of suitable solvents or guest molecules. Subsequently, a stepwise chemoseparation method based on molecular Borromean rings was established, with the molecular Borromean rings used in the separation being recoverable and recyclable. Due to their structural complexity and difficult synthesis, useful guidelines or rules to help design complicated interlocked molecules are highly desirable. We also highlight our efforts to develop empirical guidelines to uncover the relationship between the aspect ratio of metallarectangles and the formation or stability of molecular Borromean rings. An empirical formula has further been established to show the approximate ratio of lengths of the short arm and the long arm in molecular Borromean rings based on pi-pi (or p-pi) stacking. We then demonstrate how to use these guidelines to design new molecular Borromean rings and further lead to other interlocked structures, for example, [2]- and [3]catenane structures. Taken together, our results may lead to a promising future for the design of fascinating and useful interlocked structures by coordination-driven self-assembly. PMID- 29987930 TI - Controllable Synthesis of SERS-Active Magnetic Metal-Organic Framework-Based Nanocatalysts and Their Application in Photoinduced Enhanced Catalytic Oxidation. AB - Fabrication of multifunctional nanocatalysts with surface-enhanced Raman scattering (SERS) activity is of vital importance for monitoring catalytic courses in situ and studying the reaction mechanisms. Herein, SERS-active magnetic metal-organic framework (MOF)-based nanocatalysts were successfully prepared via a three-step method, including a solvothermal reaction, an Au seed induced growth process, and a low-temperature cycling self-assembly technique. The as-synthesized magnetic MOF-based nanocatalysts not only exhibit outstanding peroxidase-like activity, but can also be applied as a SERS substrate. Owing to these features, they can be used for monitoring in situ catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 via a SERS technique, and the concentration of H2O2 was determined. Owing to the intrinsic character of the Fe based MOF material (MIL-100(Fe)), a novel photoinduced enhanced catalytic oxidation effect was demonstrated, in which the catalytic oxidation of TMB and o phenylenediamine was accelerated. This study provides a versatile approach for the fabrication of functional MOF-based nanocomposites as a promising SERS substrate with a unique photoinduced enhanced peroxidase-like activity for potential applications in ultrasensitive monitoring, biomedical treatment, and environmental evaluation. PMID- 29987931 TI - Anisotropic Pauli Spin-Blockade Effect and Spin-Orbit Interaction Field in an InAs Nanowire Double Quantum Dot. AB - We report on experimental detection of the spin-orbit interaction field in an InAs nanowire double quantum dot device. In the spin blockade regime, leakage current through the double quantum dot is measured and is used to extract the effects of spin-orbit interaction and hyperfine interaction on spin state mixing. At finite magnetic fields, the leakage current arising from the hyperfine interaction can be suppressed, and the spin-orbit interaction dominates spin state mixing. We observe dependence of the leakage current on the applied magnetic field direction and determine the direction of the spin-orbit interaction field. We show that the spin-orbit field lies in a direction perpendicular to the nanowire axis but with a pronounced off-substrate-plane angle. The results are expected to have an important implication in employing InAs nanowires to construct spin-orbit qubits and topological quantum devices. PMID- 29987932 TI - Supramolecular Polymer-Based Fluorescent Microfibers for Switchable Optical Waveguides. AB - We report the switchable optical waveguide microfibers based on fluorescent supramolecular polymer for the first time. The pillar[5]arene-based supramolecular polymeric microfibers were prepared easily from the viscous solution of bispillar[5]arene host (bisP5A) and diphenylanthracene-derived guest (GD). The resulting microfibers act as an active optical waveguide material with long propagation distance (400 MUm) and low optical propagation loss (0.01 dB/MUm). When photoresponsive dithienylethene-derived guest (GDTE) was added, the resulting ternary microfibers show switchable optical waveguide by the noninvasive control of UV/vis light with negligible fatigue over four cycles. This convenient preparation method is also applied for the quadruple-hydrogen bonded fluorescent supramolecular polymeric microfibers which imply good light propagation property with an optical loss coefficient of 0.02 dB/MUm. PMID- 29987934 TI - Structural Analysis and Conduction Mechanisms in Polycrystalline Zinc Hydroxide Nitrate. AB - The conduction and dielectric properties in zinc hydroxide nitrate (Z5HN) were studied in detail as a function of the temperature and relative humidity by impedance spectroscopy, and the structure was investigated by X-ray diffraction (XRD). Elemental analysis indicated a layered material containing carbonate anions [Zn5(OH)8(NO3)1.6(CO3)0.2.1.7H2O] due to the high capability of adsorption of Z5HN, which makes this material appropriate for applications in real conditions. The water content affected the interlayer distance, conductivity, and dielectric response of the layered material. An electrostatic repulsive interaction after reduction of the water content as a function of the temperature causes an increase of the interlayer distance and a decrease in the conductivity response and dielectric behavior. The highest conductivity, 10-7 Omega-1 cm-1, was obtained at a shorter interlayer distance for the sample heat-treated at 25 degrees C. The Z5HN synthesized was also characterized at different temperatures using thermogravimetric analysis and Fourier transform infrared and Raman spectroscopy. Multipeak analysis of the XRD patterns at various relative humidity levels showed the formation of a most hydrated phase and an increase of the interlayer distance related with the adsorption of water molecules. This layered material presented a conductivity of 10-5 Omega-1 cm-1 at high relative humidity (92%). The dipole-dipole interaction appeared to be the dominant mechanism for the dielectric behavior at the lowest temperatures and highest humidity due to the high water content in the Z5HN structure. Taking into account its crystallization water and high adsorption of water molecules in the interlayer region, a conduction pathway in the Z5HN structure was proposed, which provides the route for proton transport by hydrogen-bonding networks on the basis of a Grotthuss-type mechanism in facilitating the long-range proton hopping at 25 degrees C. The results for high relative humidity imply that a vehicular conduction mechanism also may contribute to the electrical response. PMID- 29987933 TI - Pectin Alleviates High Fat (Lard) Diet-Induced Nonalcoholic Fatty Liver Disease in Mice: Possible Role of Short-Chain Fatty Acids and Gut Microbiota Regulated by Pectin. AB - Consumption of pectin contributes to changes in the gut microbiota and the metabolism of short-chain fatty acids (SCFAs). We aimed to investigate the effects of and mechanism by which pectin prevented nonalcoholic fatty liver disease (NAFLD) in mice that were fed a high-fat diet containing 30% lard (HF). HF-fed mice that orally ingested pectin for 8 weeks exhibited improvements in lipid metabolism and decreased oxidative stress and inflammation through a mechanism regulated by the mitogen-activated protein kinase pathway. Pectin dose dependently generated an increase in acetic acid (from 566.4 +/- 26.6 to 694.6 +/ 35.9 MUmol/mL, p < 0.05) and propionic acid (from 474.1 +/- 84.3 to 887.0 +/- 184.7 MUmol/mL, p < 0.05) contents and significantly increased the relative abundance of Bacteroides (from 0.27% to 11.6%), Parabacteroides (from 3.90/00 to 5.3%), Olsenella (from 2.90/00 to 1.3%), and Bifidobacterium (from 0.03% to 1.9%) in the gut of HF-fed mice. Intestinal microbiota and SCFAs may thus contribute to the well-established link between pectin consumption and NAFLD. PMID- 29987935 TI - Metabolomic approaches for phospholipid analysis: advances and challenges. PMID- 29987936 TI - A bridging immunogenicity assay for monoclonal antibody: case study with SHR 1222. AB - AIM: SHR-1222 is a humanized monoclonal antibody targeted to soluble sclerostin. To support the preclinical study of SHR-1222 in cynomolgus monkeys, a method for the detection of anti-drug antibodies is required. RESULTS: A bridging immunogenicity method for the detection of anti-SHR-1222 antibodies was developed and validated. In the method, minimal required dilution, normalization factor and confirmatory cut point were 1:20, 4.35 and 10.45%, respectively. The method was successfully applied to evaluate a multiple-dose toxicity study in monkeys. CONCLUSION: The proposed method allows for the detection of anti-SHR-1222 antibodies in preclinical studies and aids in the interpretation of pharmacokinetic changes in certain animals. The soluble targets interference on anti-drug antibody detection can be blocked or decreased by the therapeutic drug. PMID- 29987937 TI - The many (inter-)faces of supercritical fluid chromatography: the present and future prospects of online supercritical fluid extraction-supercritical fluid chromatography. AB - Automated supercritical fluid extraction-supercritical fluid chromatography is an innovative method with low-effort sampling strategies (e.g., dried blood spots) that may make large-scale application faster, cheaper and greener than currently thought possible. PMID- 29987938 TI - Real-Time Surveys Reveal Important Safety Risks During Interhospital Care Transitions for Neurologic Emergencies. AB - Critically ill patients may be exposed to unique safety threats as a result of the complexity of interhospital and intrahospital transitions involving the emergency department (ED). Real-time surveys were administered to clinicians in the ED and neuroscience intensive care unit of a tertiary health care system to assess perceptions of handoff safety and quality in transitions involving critically ill neurologic patients. In all, 115 clinical surveys were conducted among 26 patient transfers. Among all clinician types, 1 in 5 respondents felt the handoff process was inadequate. Risks to patient safety during the transfer process were reported by 1 in 3 of respondents. Perceived risks were reported more frequently by nurses (44%) than physicians/advanced practice providers (28%). Real-time survey methodology appears to be a feasible and valuable, albeit resource intensive, tool to identify safety risks, expose barriers to communication, and reveal challenges not captured by traditional approaches to inform multidisciplinary quality improvement efforts. PMID- 29987939 TI - Sexual well-being after menopause: An International Menopause Society White Paper. AB - Sexual well-being frequently declines following the menopause transition and can be associated with significant personal and relationship distress. This distress is the hallmark of female sexual dysfunction (FSD). FSD is highly prevalent in postmenopausal women. The prevalence of sexual problems increases with age, but conversely this is associated with decreasing distress with advancing age. This pattern has been seen across multiple international populations with varied cultural norms. While the etiology of FSD is multifactorial, the physiological changes of sex hormone insufficiency and postmenopausal symptoms, such as dyspareunia, are primary factors contributing to FSD at midlife. The International Menopause Society is working to increase awareness of FSD and to provide a framework for practitioners to address sexual medicine concerns. This White Paper aims to review the process of care for female sexual well-being following menopause, from initially approaching the discussion of FSD, to identifying clinical signs and symptoms, and ultimately determining the best available biopsychosocial therapies. As with most processes of care, the first step is often the most difficult. Health-care practitioners need to broach the topic of sexuality in the clinical setting. Lack of information on, comfort with, and biases about the topic of sexuality after menopause are significant hurdles that the International Menopause Society addresses in this document. Each member of the Writing Group remains committed to continued advocacy for the validity of FSD as a diagnosis, the need for therapies for women to be both available and included in health insurance coverage, and continued therapeutic research to provide evidence-based solutions. PMID- 29987940 TI - Anxiety and depressive symptoms during pregnancy, perceived control and posttraumatic stress symptoms after childbirth: A longitudinal mediation analysis. AB - This longitudinal study evaluated the mediating role of sense of control during labour in the association between anxiety and depression levels during pregnancy and postpartum posttraumatic stress disorder symptoms. Participants were 57 women. Anxiety and depression were assessed during pregnancy; sense of control and childbirth-related posttraumatic stress disorder symptoms were collected 6-8 weeks after childbirth. Higher levels of anxiety and depression were associated with more postpartum posttraumatic stress disorder symptoms through lack of perceived control. For depression, this happened only for primiparous. Interventions targeting mechanisms enhancing perceptions/feelings of control should be offered to these women to prevent/minimize childbirth-related posttraumatic stress disorder. PMID- 29987942 TI - The use of the international classification of functioning, disability and health in an interactive perspective: the assessment and intervention of students' additional support needs in Portugal. AB - PURPOSE: Evaluating the influence of person-environment interactions on students' performance is a fundamental requirement for planning individualized educational interventions. Such understanding grounded the use of the International Classification of Functioning, Disability and Health as a reference framework to support special needs assessment in the Portuguese educational system. This study sought to investigate the extent to which special education teams reported relationships between Body Functions, Activities and Participation, and Environmental Factors in Individualized Education Programmes for students with additional support needs and what types of relations were mostly described. MATERIALS AND METHODS: Using content analysis, 176 Individualized Education Programmes were examined. A coding scheme based on the International Classification of Functioning, Disability and Health was developed to categorize and quantify code-relations. RESULTS AND CONCLUSIONS: Code-relations consisted in 6.1% out of the total of meaning units found in textual segments concerning assessment and intervention processes. Code-relations were chiefly focused on mental functions, learning and applying knowledge, and products and technology. Intervention plans were predominantly presented as separate lists of goals and strategies, focusing Activities and Participation (67.8%), Body Functions (16.1%) and Environmental Factors (16.2%). Within the reduced amount of contents in which there was a match between goals and strategies, only 8.2% were directly connected with assessment data. Recommendations are made for the implementation of an interactive approach when using the International Classification of Functioning, Disability and Health in educational contexts. Implications for rehabilitation The adoption of the International Classification of Functioning, Disability and Health in the educational context goes beyond the use of a universal language including, as well, the potential to foster a multidimensional and comprehensive approach to students' needs. Professionals' approach in special needs assessment is often partial and segmented, suggesting a narrow understanding of the relationships between body functions, activities and participation, and environmental factors. Our findings support the need for an expanded focus on person-environment interactions, considering students' participation in different domains of life - besides learning - as well as the impact of environmental barriers over students' participation; Training programmes centred on a biopsychosocial understanding of human functioning, the establishment of a transdisciplinary collaborative culture and the use of dynamic assessment tools may equip professionals with appropriate conditions to use the International Classification of Functioning, Disability and Health within an interactive perspective. PMID- 29987941 TI - Good stability of a cementless, anatomically designed femoral stem in aging women: a 9-year RSA study of 32 patients. AB - Background and purpose - We previously reported a transient, bone mineral density (BMD)-dependent early migration of anatomically designed hydroxyapatite-coated femoral stems with ceramic-ceramic bearing surfaces (ABG-II) in aging osteoarthritic women undergoing cementless total hip arthroplasty. To evaluate the clinical significance of the finding, we performed a follow-up study for repeated radiostereometric analysis (RSA) 9 years after surgery. Patients and methods - Of the 53 female patients examined at 2 years post-surgery in the original study, 32 were able to undergo repeated RSA of femoral stem migration at a median of 9 years (7.8-9.3) after surgery. Standard hip radiographs were obtained, and the subjects completed the Harris Hip Score and Western Ontario and McMaster Universities Osteoarthritis Index outcome questionnaires. Results - Paired comparisons revealed no statistically significant migration of the femoral stems between 2 and 9 years post-surgery. 1 patient exhibited minor but progressive RSA stem migration. All radiographs exhibited uniform stem osseointegration. No stem was revised for mechanical loosening. The clinical outcome scores were similar between 2 and 9 years post-surgery. Interpretation - Despite the BMD-related early migration observed during the first 3 postoperative months, the anatomically designed femoral stems in aging women are osseointegrated, as evaluated by RSA and radiographs, and exhibit good clinical function at 9 years. PMID- 29987943 TI - A review and critique of published real-world weight management program studies. AB - BACKGROUND: Beyond the essential but somewhat artificial conditions that typify formal clinical studies, real-world evidence (RWE) of weight loss program effectiveness is paramount for an accurate assessment of such programs and refinement of best practices. OBJECTIVES: To evaluate the current state of RWE studies and publications on weight loss, identify the range of weight loss components being used in RWE programs, and to provide a general overview of the consistency or lack of consistency with regard to measuring and reporting outcomes. METHODS: A structured search of PubMed was performed to identify relevant English-language publications from 2006 to December 2017 that reported real-world studies of weight loss among adults. Duplicates, non-relevant publications, articles on weight loss surgery, pediatric studies, randomized controlled trials, studies with self-reported weight loss, no objective weight measures, or that failed to include weight loss results were excluded. RESULTS: This review included 62 RWE publications. Forty-nine studies included dietary intervention, 37 included exercise, 29 included motivational counseling, and 5 contained some patients who had pharmacologic treatment as part of their weight loss regimen. The numbers of participants per study ranged from 10 to more than 3 million. The interventions reported in the publications included diet, exercise, counseling to promote diet and/or exercise, motivational counseling, and pharmacotherapy, and various combinations of these. CONCLUSIONS: Despite general acceptance that weight loss programs are capable of facilitating successful outcomes, this review revealed substantial inconsistency in the design and reporting of such programs, making it very difficult to draw conclusions about the comparative merits of different real-world weight loss strategies/components. In addition, there was a marked lack of congruence with current weight loss management guidelines, and notably few studies incorporating anti-obesity medications. There clearly is a need for greater rigor and standardization among designing and reporting RWE weight-loss studies. PMID- 29987945 TI - Incidence and demographics of giant cell tumor of bone in The Netherlands: First nationwide Pathology Registry Study. AB - Background and purpose - Giant cell tumors of bone (GCT-B) are rare, locally aggressive tumors characterized by an abundance of giant cells. Incidence studies for GCT-B are rare. This is the first study using a fully automated 100% covering pathology database, the nationwide Dutch Pathology Registry (17 million inhabitants), PALGA, to calculate incidence rates for GCT-B. Patients and methods - From PALGA, all pathology excerpts were retrieved for patients diagnosed with GCT-B, giant cell tumors of tenosynovium, and giant cell tumors of soft tissue between January 1, 2009 and December 31, 2013. The incidence of GCT-B was calculated. Results - In total, 8,156 excerpts of 5,922 patients were retrieved; these included 138 first GCT-B diagnosis. For GCT-B the incidence was 1.7 per million inhabitants per year with a male to female ratio of 1:1.38 and a median age of 35 years (9-77). Most common localization was the femur (35%), followed by the tibia (18%). No differences in localization according to age and sex were found. The incidence rate of local recurrence was 0.40 per million inhabitants per year. Interpretation - This is the first nationwide study reporting the incidence of GCT-B, based on a nationwide pathology database with 100% coverage of pathology departments. Current incidence calculations are based only on doctor driven registries. We confirmed that GCT-B is a rare disease with an incidence that is slightly higher than previously published. The relatively young median age of patients and the high incidence of recurrence stresses the importance of developing more effective treatments for this disease. PMID- 29987946 TI - Rasch analysis of the Lower Extremity Functional Scale for foot and ankle patients. AB - PURPOSE: The Lower Extremity Functional Scale (LEFS) is a widely used 20-item patient-reported outcome instrument with five response categories. We investigated the measurement properties of the Finnish version of the LEFS among foot and ankle patients to refine the scale to measure more accurately what is relevant for patients. MATERIALS AND METHODS: Data were obtained from 182 patients who had undergone foot and ankle surgery for various reasons. The Rasch Measurement Theory and Cronbach's alpha were employed for analyses of model and item fit, response category thresholds, targeting, person separation index, and internal consistency. RESULTS: Threshold misfit was noted in 13 of the 20 items. After collapsing the response categories 1 ("Quite a bit of difficulty") and 2 ("Moderate difficulty"), five items were removed one by one to make the scale fit the model. This new 15-item scale with four response categories had a unidimensional structure with good item fit, ordered thresholds, and good coverage/targeting. The person separation index and Cronbach's alpha were 0.85 and 0.95, respectively. CONCLUSIONS: This study provides a new 15-item LEFS with four response categories for clinicians and researchers to measure function in foot and ankle patients in a relevant way. Implications for rehabilitation Assessing foot and ankle function and rehabilitation effectiveness is of high importance. The Lower Extremity Functional Scale (LEFS) is a widely used 20-item patient-reported outcome instrument with five response categories. The Finnish LEFS was revised to better fit into the Rasch model. The new LEFS with 15 items and four response categories for foot and ankle patients is a psychometrically sound, meaningful, and operable instrument. PMID- 29987947 TI - Sensory studies, or when physics was psychophysics: Ernst Mach and physics between physiology and psychology, 1860-71. AB - This paper highlights the significance of sensory studies and psychophysical investigations of the relations between psychic and physical phenomena for our understanding of the development of the physics discipline, by examining aspects of research on sense perception, physiology, esthetics, and psychology in the work of Gustav Theodor Fechner, Hermann von Helmholtz, Wilhelm Wundt, and Ernst Mach between 1860 and 1871. It complements previous approaches oriented around research on vision, Fechner's psychophysics, or the founding of experimental psychology, by charting Mach's engagement with psychophysical experiments in particular. Examining Mach's study of the senses and esthetics, his changing attitudes toward the mechanical worldview and atomism, and his articulation of comparative understandings of sensual, geometrical, and physical spaces helps set Mach's emerging epistemological views in the context of his teaching and research. Mach complemented an analytic strategy focused on parallel psychic and physical dimensions of sensation, with a synthetic comparative approach - building analogies between the retina, the individual, and social life, and moving between abstract and sensual spaces. An examination of the broadly based critique that Mach articulated in his 1871 lecture on the conservation of work shows how his historical approach helped Mach cast what he now saw as a narrowly limiting emphasis on mechanics as a phase yet to be overcome. PMID- 29987948 TI - Resting-State Functional Magnetic Resonance Imaging and Probabilistic Diffusion Tensor Imaging Demonstrate That the Greatest Functional and Structural Connectivity in the Hand Motor Homunculus Occurs in the Area of the Thumb. AB - The primary hand motor region is classically believed to be in the "hand knob" area in the precentral gyrus (PCG). However, hand motor task-based activation is often localized outside this area. The purpose of this study is to investigate the structural and functional connectivity driven by different seed locations corresponding to the little, index, and thumb in the PCG using probabilistic diffusion tractography (PDT) and resting-state functional magnetic resonance imaging (rfMRI). Twelve healthy subjects had three regions of interest (ROIs) placed in the left PCG: lateral to the hand knob (thumb area), within the hand knob (index finger area), and medial to the hand knob (little finger area). Connectivity maps were generated using PDT and rfMRI. Individual and group level analyses were performed. Results show that the greatest hand motor connectivity between both hemispheres was obtained using the ROI positioned just lateral to the hand knob in the PCG (the thumb area). The number of connected voxels in the PCG between the two hemispheres was greatest in the lateral-most ROI (the thumb area): 279 compared with 13 for the medial-most ROI and 9 for the central hand knob ROI. Similarly, the highest white matter connectivity between the two hemispheres resulted from the ROI placed in the lateral portion of PCG (p < 0.003). The maximal functional and structural connectivity of the hand motor area between hemispheres occurs in the thumb area, located laterally at the "hand knob." Thus, this location appears maximal for rfMRI and PDT seeding of the motor area. PMID- 29987949 TI - Establishing thresholds for metal ion levels in patients with bilateral Articular Surface Replacement hip arthroplasty. AB - INTRODUCTION: The primary aim of the current study was to determine whether metal ion levels could identify well- from poorly-functioning implants in patients after undergoing bilateral Articular Surface Replacement (ASR) Hip System. The secondary aim was to establish threshold values for Co and Cr that could be used to predict clinical problems in these patients. MATERIALS AND METHODS: The study included 125 patients treated with bilateral ASR hip resurfacing (HRA) and 93 patients treated with bilateral ASR XL total hip arthroplasty (THA) at a mean follow-up of 7.1 years post-surgery. Patients were labelled as well- or poorly functioning based on strict criteria. We calculated the Co and Cr safe upper ion limits (SUL) for ASR HRA and ASR XL THA separately and assessed these cutoffs ability to predict clinical problems. RESULTS: In patients with bilateral ASR HRA, the well-functioning group had lower ions than the poorly-functioning. In ASR THA patients, there was no difference in blood Co or Cr levels between well- and poorly-functioning implant groups ( p = 0.118 and p = 0.379, respectively). Both Co and Cr could effectively discriminate between well-functioning and poorly functioning ASR HRA implants ( p < 0.001 and p < 0.001, respectively), but not for ASR THA implants ( p = 0.118 and p = 0.564, respectively). SULs of 4.0 ppb for Co and 4.0 ppb for Cr could differentiate between well- and poorly functioning implants with high specificity. CONCLUSIONS: Metal ion levels are a more reliable tool in MoM HRA than THA when discriminating well- from poorly functioning implants in bilateral patients. For patients treated with bilateral ASR HRA, ion levels above 4.0 ppb are highly specific for the detection of clinical problems. PMID- 29987950 TI - Upregulation of long noncoding RNA MALAT1 in papillary thyroid cancer and its diagnostic value. AB - AIM: To investigate the expression level of lncRNA MALAT1 in papillary thyroid cancer (PTC) and evaluate its clinical diagnostic value as a biomarker in PTC. METHODS: MALAT1 lncRNA expression in tissues was detected by qRT-PCR. The diagnostic value of MALAT1 as a biomarker in PTC was evaluated with receiver operating characteristics. RESULTS: MALAT1 expression was upregulated in PTC tissues compared with paired corresponding noncancerous tissues. We also found that upregulated MALAT1 expression was correlated with tumor size, lymph node metastases (p = 0.011) and WHO disease stage. The area under the curve was 0.6320, 0.7192, 0.7089 and 0.7000 for PTC, lymph node metastasis, extrathyroidal extension and WHO disease stage prediction, respectively. CONCLUSION: Our finding suggests that MALAT1 may exert oncogenic function in PTC and may be a potential diagnostic marker for this cancer. PMID- 29987951 TI - Outcome of continued infliximab therapy in Crohn's disease patients with response but without remission after one year of infliximab - a retrospective cohort study. AB - BACKGROUND: Optimal management of Crohn's disease patients having responded to infliximab but without achieving remission is not well defined. The present study examined if these patients benefit from continued long-term infliximab maintenance therapy. METHOD: Retrospective cohort study including all patients treated with infliximab for 1 year until the end of 2017 who have had a response but not reached remission on infliximab. Clinical outcomes were defined by the physicians' global evaluation, supported by clinical indices and objective markers of disease activity. RESULTS: In total, 376 Crohn's disease patients received infliximab. Among these, 76 (20%) were classified as having response but non-remission (RNR) after 1 year of therapy. A great majority (n = 54; 71%) experienced no additional therapeutic benefit after a further year of infliximab maintenance therapy, thus still having RNR. Nineteen patients (25%) obtained remission during continued infliximab, whereas only 4% (n = 3) experienced treatment failure. Although infliximab therapy beyond 2 years (follow-up median 35 months, IQR: 23-55) was accompanied by a higher proportion attaining remission (40%), nearly half (46%) still failed to improve. Among patients who had discontinued infliximab while having RNR (n = 21), half (n = 11) experienced disease flare within five months (median 22 weeks, IQR: 12-31). CONCLUSION: Most patients (71%) had no additional therapeutic benefit after an additional year of infliximab therapy, and after a median maintenance infliximab treatment period of 3 years, half still failed to improve further. Considering the importance of achieving complete remission, these patients appear to have an unmet medical need. PMID- 29987952 TI - Hospital Rooms. PMID- 29987953 TI - Mid-term outcome after arthroscopic treatment of femoroacetabular impingement: development of a predictive score. AB - PURPOSE: To build a post-arthroscopy outcome-predictive score (POPS) associated with the likelihood of lasting benefit after arthroscopic treatment of femoroacetabular impingement (FAI) and based solely on unambiguous preoperative information. METHODS: A population of 220 FAI patients, operated on with standard techniques by orthopaedic surgeons trained in hip arthroscopy in 6 different centres, was evaluated physically or by telephone interview 2 to 5 years after surgery. The criteria of successful mid-term outcome (SMO) were agreed upon by all authors. A multivariate logistic regression, adjusted for patient's age and centre, was applied to predict SMO. In the model, the variables associated with the outcome were included and the relative ORs (odds ratios) were used to compute the FAI-POPS (FAI - post-arthroscopy outcome-predictive score). A ROC (receiver operating characteristic) curve was plotted and the optimum cut-off was calculated. RESULTS: 155 patients out of 220 showed a successful mid-term outcome. The optimum cut-off of FAI-POPS was calculated to be 6.3 and with this threshold it proved a sensitivity of 0.66 and a specificity of 0.69, a positive predictive value of 0.84 and a negative predictive value of 0.46. CONCLUSIONS: The standard arthroscopic treatment of FAI resulted in satisfactory persistent symptom relief for about 70% of patients. No or minimal osteoarthritis, short time elapsed from the appearance of symptoms and high preoperative modified Harris Hip Score are independent predictive factors of SMO. The FAI-POPS is obtained as sum of 3 odds ratios corresponding to the above prognostic factors and is a useful predictor of mid-term outcome after conventional arthroscopic FAI treatment. PMID- 29987954 TI - James Jerger, a life in audiology. PMID- 29987955 TI - Siblings' experiences of their relationship with a brother or sister with a pediatric acquired brain injury. AB - PRIMARY PURPOSE: Child acquired brain injury has significant impact on the family, including siblings. This study aimed to explore siblings' experiences of their relationship with their brother or sister with acquired brain injury in order to make recommendations for health professionals working with this population. RESEARCH DESIGN: Semi-structured interviews were conducted with five siblings of children with acquired brain injury aged between 9 and 12 years and analyzed using interpretative phenomenological analysis. RESULTS: The analysis resulted in four themes: (i) Coping with "a nightmare that you live"; (ii) Disconnection from family relationships; (iii) My sibling is different but "still the same underneath all this thing"; and (iv) Changing togetherness. CONCLUSIONS: The siblings in this study experienced a high level of distress with the near loss of their brother or sister. This was followed by difficulty in adjusting to the physical and psychological changes in their injured sibling and the impact on their sibling role and relationship. The changes were experienced alongside disruption to family relationships. Important clinical implications include the inclusion of siblings in their injured sibling's care and the provision of information and support for this group. Implications for Rehabilitation Siblings of children with an acquired brain injury experience significant challenges while trying to adapt to their changing sibling relationship and feelings of disconnection with their family. This study highlights a need to work systemically with families of childhood brain injury and recognize siblings' important role in their family unit and therefore involve them in their brother/sister's care and rehabilitation. This study also highlights a need to support siblings to cope with the trauma and provide information to validate and understand their experience. PMID- 29987956 TI - Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae alpha- and beta class enzymes. AB - The synthesis of a new series of sulfamides incorporating ortho-, meta, and para benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the alpha- and beta CA classes (VchCAalpha, VchCAbeta). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAalpha, with several compounds showing KIs < 100 nM. The activity was lower against hCA II and VchCAbeta, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives. PMID- 29987957 TI - DEB-TACE: a standard review. AB - Drug-eluting bead transarterial chemoembolization (DEB-TACE) is a relative new endovascular treatment based on the use of microspheres to release chemotherapeutic agents within a target lesion with controlled pharmacokinetics. This aspect justifies the immediate success of DEB-TACE, that nowadays represents one of the most used treatments for unresectable hepatocellular carcinoma. However, there is no consensus about the choice of the best embolotherapy technique. In this review, we describe the available microspheres and report the results of the main comparative studies, to clarify the role of DEB-TACE in the hepatocellular carcinoma management. We underline that there is no evidence about the superiority of DEB-TACE over conventional TACE in terms of efficacy, but there may be some benefits with respect to safety especially with the improvement of new technologies. PMID- 29987958 TI - Contending with the minimum data set: Subjectivity, linearity and dividualising experiences in Improving Access to Psychological Therapies. AB - Improving Access to Psychological Therapies has lead to a huge increase in the delivery of psychological therapy within the United Kingdom over the past 10 years. Central to the culture of Improving Access to Psychological Therapies is outcome monitoring, brought into every therapeutic encounter through the compulsory collection of the minimum data set in each session. This article explores the role of compulsory outcome monitoring in service users' experiences of using Improving Access to Psychological Therapies, with a focus on how these forms are folded into distress, therapy and recovery. Data from a small-scale qualitative study are drawn upon. Thematic analysis was conducted on multimodal interviews with current service users. The article explores the ways in which the minimum data set acted as a 'quasi object', exploring three main roles of the minimum data set: as an authorising mediator, an alienating adversary and a deferring gatekeeper. Pictures of therapeutic progress, as presented via outcome measures, often ran counter to users' reported experience of distress. We conclude that far from being a neutral and objective assessment tool, the minimum data set functions as a living actant in the therapeutic encounter. PMID- 29987959 TI - Review of Chlamydia trachomatis viability methods: assessing the clinical diagnostic impact of NAAT positive results. AB - INTRODUCTION: Chlamydia trachomatis (chlamydia) is the most commonly diagnosed bacterial sexually transmitted infection (STI) worldwide. The advancement of molecular techniques has made chlamydia diagnostics infinitely easier. However, molecular techniques lack the information on chlamydia viability. Where in routine diagnostics the detection of chlamydia DNA or RNA might suffice, in other patient scenarios, information on the viability of chlamydia might be essential. Areas covered: In this review, the authors discuss the specific strengths and limitations of currently available methods to evaluate chlamydia viability: conventional cell culture, messenger RNA (mRNA) detection and viability-PCR (V PCR). PubMed and Google Scholar were searched with the following terms: Chlamydia trachomatis, Treatment failure, Anal chlamydia, Microbial viability, Culture, Viability-PCR, Messenger RNA, and Molecular diagnostics Expert commentary: Several techniques are currently available to determine chlamydia viability and thus the clinical relevance of a positive test result in clinical samples. Depending on the underlying research question, all three discussed techniques have their merits when testing for viability. However, mRNA methods show the most promise in determining the presence of a true infection, in case the chlamydia reticulate body can be specifically detected. Further research is needed to understand how to best apply viability testing in current chlamydia diagnostics. PMID- 29987960 TI - Health risk communication message comprehension is influenced by image inclusion. AB - The impact of images on risk communications such as public service announcements is unknown. Whether images contained within a printed message such as a food safety warning alters the comprehension of the underlying text, has not previously been explored. The present study examined three factors of a risk communication in the print form: (1) the role images play in promoting comprehension of risk messages, (2) how demographic variables such as gender impacts message reception and (3) the need for cognition, or the degree to which some individuals are innately motivated to comprehend and understand information. Examples of risk communications in the print form are warnings on food or tobacco and alcohol warnings. In the present study, students at an undergraduate university (N = 92, 61 females, age 19.89 (SD =1.94) years, range 18-32), read risk communications with and without images. The purpose of the study was to ascertain the affect images have on message comprehension and receptivity. Comprehension was assessed by the structural knowledge test. Negative/fear arousing images increase message receptivity and subsequent learning when accompanying printed risk communications. Gender alone did not significantly impact message receptivity, although males tended to show greater change in structural knowledge pre- to post-test. This was true especially for the negative fear-arousing images condition. Need for cognition plays a significant role in message receptivity. Nevertheless, for risk communications illustrated with fear arousing images, it appears that the need for cognition is not a necessary condition to learn the message. Further research is needed to determine how these factors impact the degree or depth of message processing. PMID- 29987961 TI - Rapid and persistent decline in soluble CD163 with successful direct-acting antiviral therapy and associations with chronic hepatitis C histology. AB - BACKGROUND AND AIM: Soluble CD 163 (sCD163) is released from activated liver macrophages in chronic viral hepatitis C (HCV) and serum levels reflect liver disease severity. The impact of direct-acting antiviral (DAA)-therapy on sCD163 levels and the ability of sCD163 to predict the presence of liver fibrosis remain unclear. In a combined observational and prospective study, we aimed to investigate changes in sCD163 with DAA-treatment, to investigate associations between sCD163 and histopathological activity and fibrosis and to validate the sCD163-based fibrosis score in HCV-patients. METHODS: We examined three groups of patients: an Australian (n = 28) treated with pegylated-interferon and a first generation DAA, a Danish (n = 38) treated with sofosbuvir-based DAA-regimens and a Japanese (n = 562) assessed for activity and fibrosis (Metavir scoring system) in liver biopsies. Serum sCD163-levels were quantified by ELISA. RESULTS: Thirteen (46%) of the Australian patients achieved sustained virological response (SVR) and only these patients had significant decreases in sCD163-levels (2.7 (95%CI:1.9-3.6) vs. 4.1(2.9-5.7) mg L - 1, p = .008). In the Danish group, 37 (97%) patients achieved SVR at 12-weeks post-treatment with 32% reduction in sCD163-levels (5.0 (4.3-5.8) vs. 7.4 (6.3-8.7), p < .001). The decline was rapid and persisted 12 months after treatment cessation (p < .007). sCD163 levels increased in parallel with inflammatory activity and fibrosis (p < .001). The sCD163-based fibrosis score outperformed established fibrosis scores for significant fibrosis (areas under the receiver operating characteristics curves (AUROCs): 0.79 (0.75-0.83) vs. aspartate aminotransferase to platelet ratio index (APRI) 0.73 (0.69-0.77), Fibrosis-4 (FIB-4) 0.74 (0.70-0.78), p < .001). CONCLUSION: sCD163-levels decline rapidly with successful DAA therapy and are associated with histological inflammatory activity and fibrosis, confirming a key role for macrophages in HCV inflammation and fibrosis and supporting sCD163 as a biomarker of treatment response. PMID- 29987962 TI - Is quality of life reduced in people with patellofemoral osteoarthritis and does it improve with treatment? A systematic review, meta-analysis and regression. AB - PURPOSE: To determine if quality of life is reduced in individuals with patellofemoral osteoarthritis, whether it can be improved with treatment, and potential factors associated with quality of life in individuals with patellofemoral osteoarthritis. MATERIALS AND METHODS: Published articles were identified by using electronic and manual searches. Studies reporting quality of life in individuals with patellofemoral osteoarthritis relative to a comparator group (e.g., no osteoarthritis) and intervention studies reporting quality of life in patellofemoral osteoarthritis following treatment relative to baseline/control group were included. RESULTS: Seventeen studies (seven cross sectional, 10 intervention) were included in this systematic review. Relative to those without osteoarthritis, individuals with patellofemoral osteoarthritis had worse knee-related quality of life (five studies) and health-related quality of life (two studies). Non-surgical treatments appear to improve knee-related quality of life compared to pre-treatment (three studies) but not control (three studies). Surgical-treatments also improved knee-related quality of life compared to pre-treatment (five studies). Worse knee-related quality of life was associated with younger age, worse pain, symptoms, function in activities of daily living, and function in sport and recreation. CONCLUSIONS: Individuals with patellofemoral osteoarthritis had worse knee-related and health-related quality of life compared to those without knee osteoarthritis. Non-surgical and surgical interventions may be effective in improving knee-related quality of life in individuals with patellofemoral osteoarthritis, but the intervention results are based on limited studies, and further research is needed to determine optimal strategies. Implications for rehabilitation Clinicians and researchers should consider knee-related and health-related quality of life when developing treatment strategies for patellofemoral osteoarthritis. Researchers investigating the effectiveness of a treatment should compare intervention to a control group. Addressing knee pain and functional limitations may aid in improving knee-related quality of life in individuals with patellofemoral osteoarthritis. PMID- 29987963 TI - Analyzing walking speeds with ankle and wrist worn accelerometers in a cohort with myotonic dystrophy. AB - BACKGROUND: Accelerometers are accurate tools to assess movement and physical activity. However, interpreting standardly used outputs is not straightforward for populations with impaired mobility. METHODS: The applicability of GENEActiv was explored in a group of 30 participants with myotonic dystrophy and compared to a group of 14 healthy-controls. All participants performed a set of tests while wearing four different accelerometers (wrists and ankles): [1] standing still; [2] ten-meters walk test; [3] six-minutes walking test; and, [4] ten meters walk/run test. RESULTS: Relevant findings were: [1] high intra accelerometer reliability (i.e. 0.97 to 0.99; p < 0.001); [2] each test acceleration values differ significantly between each other; [3] no inter accelerometer reliability between wrist-worn devices and ankle-worn; and [4] a significant difference between the myotonic dystrophy group and the healthy controls detectable at each test (i.e. Left-ankle values at six-minutes walking test: 48+/-17 for the myotonic dystrophy group, vs, 74+/-16 for the healthy controls; p < 0.001). CONCLUSIONS: GENEActiv demonstrated to be valid and reliable, capable of detecting walking periods and discriminating different speeds. However, inter-accelerometer reliability only applied when comparing opposite sides of the same limb. Specific movement characteristics of the myotonic dystrophy group were identified and muscle strength showed not to be a full determinant of limb acceleration. Implications for rehabilitation Rehabilitation professionals in the field of neuromuscular disorders should be aware of the potential use of objective monitoring tools such as accelerometers whilst acknowledging the implications of assessing populations with altered movement patterns. Researchers should be cautious when translating accelerometry outputs previously validated in healthy populations to functionally impaired cohorts like myotonic dystrophy. Accelerometers can objectively expose movement disturbances allowing further investigations for the source of these disturbances. PMID- 29987964 TI - Evaluating the readability levels of medical infographic materials for public consumption. AB - Readability is an important element of any published material. In recent years, various health organisations have utilised infographics to communicate important medical information. Established guidelines for readability suggest levels should be targeted between a 4th and 6th grade education level (United States) in order to avoid disadvantaging individuals with lower literacy skills. The purpose of this case study was to evaluate the readability levels of several published materials from the field of athletic training and demonstrate a model for evaluating readability levels in other medical and health professions. PMID- 29987965 TI - Sustained participation in community-based physical activity by adolescents with cerebral palsy: a qualitative study. AB - PURPOSE: Short-term physical activity programs may encourage adolescents with cerebral palsy to participate in physical activity but how to sustain their involvement is not well known. This qualitative study aimed to identify facilitators that successfully sustain physical activity participation by adolescents with cerebral palsy. MATERIALS AND METHODS: Adolescents (12-18 years) with cerebral palsy [Gross Motor Function Classification System (GMFCS) levels I V, without moderate-severe intellectual disability] who participated in regular physical activity were eligible, as well as one parent and an individual who facilitated their physical activity. Data were gathered using semi-structured interviews; verbatim transcripts were analysed using inductive thematic analysis within individuals (n = 15), triads (n = 5), and across participant groups (adolescents, parents and facilitators). RESULTS: Five triads participated (male adolescents, 13-16 years, GMFCS levels I-III). Seven themes emerged: getting started, wanting to succeed, a sense of belonging, the coach is important, endorsement to continue, endorsement to support and being passionate. The themes were synthesized into the Framework for Sustained Participation, which describes the interaction among themes. CONCLUSIONS: The Framework for Sustained Participation highlights strategies that may be useful for adolescents, parents, sports facilitators, clinicians and researchers to help ambulatory male adolescents with cerebral palsy continue to participate in physical activity. Implications for rehabilitation Sustaining participation in physical activity has the potential to enhance long-term health benefits of young people with cerebral palsy. Key facilitators of sustained physical activity in adolescents with cerebral palsy included tailoring the activity, getting the right coach and the adolescents' desire for health and fitness. The Framework of Sustained Participation may assist clinicians and facilitators who work with young people with cerebral palsy to structure their support in ways that will successfully sustain the adolescents' participation in physical activity. PMID- 29987966 TI - Attending a social event and consuming alcohol is associated with changes in serum microRNA: a before and after study in healthy adults. AB - PURPOSE: Circulating microRNAs represent a reservoir for biomarker discovery. Our objective was to profile the change in human circulating microRNA associated with recreational use of alcohol at a social event. MATERIAL AND METHODS: Blood was collected from healthy volunteers (N = 16) before and after recreational consumption of alcohol (ethanol). Biochemistry, hematology and ethanol measurements were performed. The change in the serum small RNA fraction was quantified by RNA sequencing. RESULTS: Blood ethanol was undetectable at study entry in all subjects [<10 mg/dL]. After consuming alcohol the median concentration was 89 mg/dL [IQR: 71-138. Min-max 20-175]. There were no changes in biochemistry and hematology parameters. Serum RNA sequencing identified 1371 small RNA species (1305 microRNAs). There were significant increases [adjusted p value <0.05, fold increase 2 or more] in 265 microRNAs, around a fifth of the total [median fold increase 2.3 [IQR: 2.1-2.5; Max: 3.7]]. miR-185-5p decreased following alcohol exposure [adjusted p-value <0.05, fold decrease 2 or more]. CONCLUSIONS: The microRNA composition of human serum is dynamic and environmental factors may have a significant impact. Within its context of use the fold change 'signal' of a microRNA must be large enough to negate the risk of false results due to background 'noise'. PMID- 29987968 TI - Cardiac Injuries at Estonian Major Trauma Facilities: A 23-year Perspective. AB - BACKGROUND AND AIMS: Cardiac injuries are highly lethal lesions following trauma and most of the patients decease in pre-hospital settings. However, studies on cardiac trauma in Estonia are scarce. Thus, we set out to study cardiac injuries admitted to Estonian major trauma facilities during 23 years of Estonian independence. MATERIALS AND METHODS: After the ethics review board approval, all consecutive patients with cardiac injuries per ICD-9 (861.0 and 861.1) and ICD-10 codes (S.26) admitted to the major trauma facilities between 1 January 1993 and 31 July 2016 were retrospectively reviewed. Cardiac contusions were excluded. Data collected included demographics, injury profile, and in-hospital outcomes. Primary outcome was mortality. Secondary outcomes were cardiac injury profile and hospital length of stay. RESULTS: During the study period, 37 patients were included. Mean age was 33.1 +/- 12.0 years and 92% were male. Penetrating and blunt trauma accounted for 89% and 11% of the cases, respectively. Thoracotomy and sternotomy rates for cardiac repair were 80% and 20%, respectively. Most frequently injured cardiac chamber was left ventricle at 49% followed by right ventricle, right atrium, and left atrium at 34%, 17%, and 3% of the patients, respectively. Multi-chamber injury was observed at 5% of the cases. Overall hospital length of stay was 13.5 +/- 16.7 days. Overall mortality was 22% (n = 8) with uniformly fatal outcomes following left atrial and multi-chamber injuries. CONCLUSION: Overall, 37 patients with cardiac injuries were hospitalized to national major trauma facilities during the 23-year study period. The overall in hospital mortality was 22% comparing favorably with previous reports. Risk factors for mortality were initial Glasgow Coma Scale < 9, pre-hospital cardiopulmonary resuscitation, and alcohol intoxication. PMID- 29987967 TI - Success and safety of high infliximab trough levels in inflammatory bowel disease. AB - OBJECTIVE: A prospective trial suggests target infliximab trough levels of 3-7 MUg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce. AIM: To explore whether high infliximab trough levels (>=7 MUg/mL) are more effective and still safe. MATERIAL AND METHODS: In this cohort study of 183 patients (109 Crohn's disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7 MUg/mL during 420 patient-years. RESULTS: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66 mg/kg [30-257]; C-reactive protein 3 mg/L [3-3]) compared to trough levels below 7 MUg/mL (fecal calprotectin 155 mg/kg [72-474]; C-reactive protein 3 mg/L [3-14.5]) (p < .001). High trough levels were superior also after excluding samples with trough levels <3 MUg/mL from analysis. No differences in rates of infections were observed in quadrimesters with high trough levels (16/129 [12.4%]) compared to quadrimesters with trough levels <7 MUg/mL (32/344 [9.3%]) (p = .32). Maintaining high trough levels resulted in 32% (interquartile range: 2-54%) increase of infliximab consumption. CONCLUSION: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection. PMID- 29987969 TI - Manipulation of Hematopoietic Stem Cell Fate by Small Molecule Compounds. AB - Self-renewal and multipotential differentiation are two important features of hematopoietic stem/progenitor cells (HS/PCs) that make them as an ideal source of stem cells for treatment of many hematologic disorders and cancers. Regarding the limited number of cord blood HS/PCs, proper ex vivo expansion can significantly increase the clinical use of cord blood stem cells. Meanwhile, expansion of HS/PCs will be feasible through bypassing the quiescent state of HS/PCs and simultaneously enhancing their proliferative potential and survival while delaying the terminal differentiation and exhaustion. Previous investigations have demonstrated that defined sets of exogenous hematopoietic cytokines/growth factors such as stem cell factor, Flt-3 ligand, and thrombopoietin are able to expand HS/PCs. However, in recent years, small molecule compounds (SMCs) have emerged as a powerful tool for the effective expansion of HS/PCs by modulating multiple cellular processes including different signaling pathways and epigenetics. In this review, recent progress toward the use of SMCs in HS cell research is presented. We focus on the significant applications of SMCs related to HS/PC expansion and discuss the associated mechanism. At the end we present a list of those SMCs which enter to clinical trials. PMID- 29987970 TI - Occupational noise-induced hearing loss in South African large-scale mines: exploring hearing conservation programmes as complex interventions embedded in a realist approach. AB - BACKGROUND: Complex interventions have been conducted in the field of public health to improve health at the individual, organizational policy or population level. In occupational audiology, hearing conservation programmes (HCPs), which are interventions to minimize or eliminate occupational noise-induced hearing loss, are currently not defined as complex interventions, despite them fitting the definition and features of complex interventions. Therefore, this study aimed to explore whether HCPs are a complex intervention, fitting the predefined criteria for complex interventions. METHOD: A qualitative, descriptive research design was conducted using three sources of data - document analysis, interviews and systematic review - to allow for triangulation. Data were collected through purposive sampling and qualitative content analysis was used. RESULTS: This study confirmed that HCPs are a complex intervention founded on solid and consolidated theories. Therefore, these results paved the way for realist reviews to be conducted in the mining sector in South Africa in order to understand the mechanisms influencing the success or failure of HCPs locally. CONCLUSION: The success of HCPs in the mining sector depends on conducting contextually evidence based evaluations such as realist reviews which can provide policy-makers with contextual evidence for why certain programmes do or do not work in certain settings. PMID- 29987971 TI - Use of Head Computed Tomography (CT) in the Pediatric Emergency Department in Evaluation of Children With New-Onset Afebrile Seizure. AB - OBJECTIVE: Cranial computed tomography (CT) is not recommended in the routine evaluation of children with first afebrile seizure due to its low yield. The objective was to assess the current practice in our pediatric emergency department regarding the use of head CT in children with first afebrile seizure and to identify the factors that lead to ordering a head CT. METHODS: Medical records of patients between 1 month and 18 years old evaluated at our emergency department for presentation of first afebrile seizure between 2010 and 2014 were retrospectively reviewed. Data extracted include age, gender, seizure type, single or multiple seizures at presentation, seizure duration, predisposing conditions to seizures (ie, history of developmental delay), and whether a head CT was performed. Contingency tables with chi-square analyses were used to determine which variables were associated with increased use of head CT. RESULTS: Of 155 patients (88M/67F) included in the study, 72 (46.5%) underwent head CT and only 3 had clinically significant findings that did not require acute management. There were no differences in CT use by age, sex, seizure type, seizure number, seizure risk factors, or findings on physical examination. Head CT was performed more frequently in cases with seizures >=5 minutes and unknown seizure duration ( P = .04). CONCLUSION: Despite existing evidence, the emergent head CT rate was high in our cohort. Children with seizure duration of >=5 minutes or of unknown duration were more likely to undergo head CT in our emergency department. PMID- 29987972 TI - Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study. AB - Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date. PMID- 29987973 TI - The role of the ventrolateral prefrontal cortex in emotional enhancement of memory: A TMS study. AB - Negative stimuli are often remembered better than neutral stimuli, which is called the emotional enhancement of memory (EEM). We tested whether the role of the ventrolateral prefrontal cortex (VLPFC) in the EEM depended on stimulus valence and/or arousal, and attentional resources. Continuous theta burst stimulation (cTBS) was applied over the left VLPFC, right VLPFC and vertex before encoding 'negative arousing,' 'negative nonarousing,' and 'neutral' words under full and divided attention, followed by a recognition test. The vertex condition showed the EEM effect for 'negative arousing' and 'negative nonarousing' words. However, the right VLPFC condition showed no evidence of the EEM effect for 'negative arousing' or 'negative nonarousing' words, under full attention. In contrast, the left VLPFC condition showed the EEM effect for 'negative arousing' words, but not 'negative nonarousing' words, under full attention. Thus, the left and right VLPFC have different roles in the EEM, depending on valence and arousal. PMID- 29987974 TI - GSK-3beta inhibition confers cardioprotection associated with the restoration of mitochondrial function and suppression of endoplasmic reticulum stress in sevoflurane preconditioned rats following ischemia/reperfusion injury. AB - BACKGROUND:: Sevoflurane has been shown to protect against myocardial ischemia/reperfusion (I/R) injury in animals, while its cardioprotection is lost if the ischemic insult is too long. In this study, we proposed a prevailing hypothesis that GSK-3beta inhibitor-mediated activation of GSK-3beta/beta-catenin signaling pathway provides additional cardioprotection in sevoflurane preconditioned rats following I/R injury. METHODS:: Rats were subjected to treatment with TDZD-8, a GSK-3beta inhibitor, 5 minutes prior to sevoflurane preconditioning and 30-minute ischemia and 120-minute reperfusion. Furthermore, in order to find out whether this cardioprotection is linked with mitochondrial function and endoplasmic reticulum stress (ERS), we isolated mitochondria from rat hearts perfused with TDZD-8 and determined the alternations of ERS markers. RESULTS:: Sevoflurane preconditioning or GSK-3beta inhibitor treatment prevented cardiomyocyte apoptosis, phosphorylated GSK-3beta and accelerated total beta catenin expression levels, reduced mitochondrial permeability transition pore (MPTP) activity, promoted the recovery of mitochondrial membrane potential and decreased the expression levels of GRP78, caspase-12 and C/EBP homology protein (CHOP) in rats under I/R condition, suggesting sevoflurane preconditioning or TDZD-8 activate the GSK-3beta/beta-catenin signaling pathway, improve mitochondria function and suppress ERS occurrence. CONCLUSIONS:: Taken together, the findings obtained from the study support the concept that sevoflurane preconditioning confers cardioprotection against myocardial I/R injury and GSK 3beta/beta-catenin signaling activation mediated by TDZD-8 as a novel target to prolong cardioprotection by sevoflurane anaesthesia. PMID- 29987976 TI - Helicobacter pylori: a perspective in low- and middle-income countries. AB - Background In adults, Helicobacter pylori is aetiologically associated with peptic ulcer disease and gastric cancer. However, the relationship between this bacteria and gastro-intestinal symptoms in children is less clear. Aims To review the recent literature on H. pylori in children and to outline the approach to diagnosis and management. Methods The English language literature was searched for articles on H. pylori in children. Special attention was paid to prevalence, diagnosis and management pertinent to low- and middle-income countries (LMIC). Results Although the prevalence of H. pylori is 60-80% in LMIC, only 5% of infected children develop peptic ulcer disease. The virulence of the organism determines the outcome. There is a suggestion that H. pylori causes iron deficiency anaemia, growth retardation and idiopathic thrombocytopenic purpura, but the evidence is not sufficiently strong to justify screening. There is no evidence to suggest a link between H. pylori infection and recurrent abdominal pain. Endoscopy (with invasive tests) is the preferred method of investigation as the primary goal is to determine the underlying cause of the symptoms. Children with H. pylori-related diseases should be treated with a standard triple-drug regimen consisting of a protein pump inhibitor and two antibiotics for 10-14 days. All treated patients should be monitored for eradication with non-invasive tests such as the urea (13-C) breath test or stool antigen tests. Conclusions Although H. pylori infection is common in LMIC, most children are asymptomatic. There is no association between H. pylori and recurrent abdominal pain. Invasive tests are preferred for diagnosis and a triple-drug regimen is the treatment of choice. PMID- 29987975 TI - Development and testing of a framework for analysing health literacy in public policy documents. AB - Health literacy is a driver of community empowerment and a key determinant of health and equity. The World Health Organisation has established a strong global mandate for addressing health literacy through public policy action, by positioning it as one of three key pillars for achieving sustainable development and health equity in the Shanghai Declaration on Health Promotion. Policy document analysis is a useful way of determining the strengths and limitations of past and current policies, as well as the likely success of their implementation and impact on health outcomes. In this study, we developed a framework for analysing policy documents to assess the extent to which they prioritise and operationalise an emergent public health issue, in this case health literacy. Specifically, the framework enables a systematic exploration of (i) the stated policy goals and strategic objectives; (ii) the stated policy actions; and (iii) whether there is an intention to resource and monitor the stated policy activities. We tested the utility of the framework by applying it to a set of public policies in the Australian context. The framework presented in this study may be a useful tool for systematically analysing policy documents to reveal their strengths and limitations, and the extent to which they prioritise and operationalise health literacy. PMID- 29987977 TI - Polynomial regression with heteroscedastic measurement errors in both axes: Estimation and hypothesis testing. AB - This article investigates point estimation and hypothesis testing in a polynomial regression model with heteroscedastic measurement errors present in both response and regressor variables. For point estimation, the adjusted least squares method and its modifications are developed. These methods can treat both functional and structural models, and models with or without an equation error. For hypothesis testing, the Wald-type and score-type tests are discussed. Their performance is investigated in a simulation study. Applications of these methods are also illustrated with real datasets. PMID- 29987978 TI - Early stage memory impairment, visual hallucinations, and myoclonus combined with temporal lobe atrophy predict Alzheimer's disease pathology in corticobasal syndrome. AB - Corticobasal syndrome (CBS) is a typical phenotype of corticobasal degeneration (CBD). However, autopsy series have shown that many CBS cases emerge from various types of non-CBD pathology. We report a 73-year-old Korean man who was clinically diagnosed with CBS whose underlying pathology was Alzheimer's disease (AD) at autopsy (CBS-AD). This case suggests that early developing memory impairment and myoclonus, severe temporoparietal atrophy, and visual hallucinations may support a more specific prediction of CBS-AD. PMID- 29987979 TI - MR targeted imaging for the expression of tenascin-C in cervical cancer. AB - OBJECTIVE:: To detect cervical cancer and compare tumor invasiveness using a molecular targeted probe. METHODS:: Tenascin-C expression was evaluated in 15 specimens. Five of them were cervical cancer with node metastasis (group A), five were cervical cancer without node metastasis (group B), and another five were normal cervix tissues (group C). Superparamagnetic iron oxide (SPIO) nanoparticles and tenascin-C antibody were conjugated as an MR probe. After the fresh tissues incubated with the probe for 24 h, MR was performed to analysis the tissue signal changes. RESULTS:: Cervical cancer tissues with node metastasis showed highest tenascin-C expression, while normal cervix showed little expression. For the non-metastatic cervical cancer patients, tenascin-C showed moderate expression. Tenascin-C was found diffusely in the stromal surrounding malignant tumor cells. After MR, the image signal changes (contrast-to-noise ratio) kept consistent with tenascin-C expression and showed statistical difference between the three groups (A: 3.87 +/- 1.45 vs B: 2.33 +/- 1.04 vs C: 0.66 +/- 0.31; p = 0.002). CONCLUSION:: Tenascin-C expression can help to detect cervical cancer. MRI with SPIO-antitenascin-C may be used to evaluate the preoperative cervical cancer patients with node metastasis. ADVANCES IN KNOWLEDGE:: Tenascin-C expression can help to detect cervical cancer and compare cancer invasiveness. Protein expression difference can be captured and compared on MR with SPIO-antitenascin-C. PMID- 29987980 TI - MR imaging and CT features of oncocytic papilloma of the sinonasal tract with comparison to inverted papilloma. AB - OBJECTIVE:: To evaluate and compare the imaging feature of sinonasal oncocytic papilloma (OP) with inverted papilloma (IP). METHODS:: The CT and MR imaging manifestations of 17 pathology proven sinonasal OPs were reviewed and compared with 17 IPs randomly selected as a control group over the same period. RESULTS:: Seventeen sinonasal OPs had unilateral occurrence and 16 of them (94.1%) had a lobulated configuration.The distribution of original sites differed significantly between OPs and IPs (p < 0.05).OPs (47.1%) particularly involved the maxillary sinus,while IPs (64.7%) usually arose from the lateral nasal wall.OPs exhibited isointense in 5 cases and grape- or patchy-like hyperintense in 12 on T1 weighted image, and isointense in 13 and hyperintense in 4 on T2 weighted image, with moderate enhancement. 10 OPs appeared as a Type II time intensity curve (TIC).There was significant difference of pre-contrast T1 signal intensity between OPs and IPs (p < 0.05).The prevalence of the imaging findings of "focal osteitis" (11.8% vs 94.1%) and "cystic change" (94.1% vs 17.6%) differed significantly between OPs and IPs (p < 0.05), but not for "cerebriform"sign (82.4% vs 94.1%) (p > 0.05). CONCLUSION:: Three imaging features including high signal on T1 weighted image, cystic change and only a rare association of focal osteitis may help the diagnosis of OP distinguished from IP. ADVANCES IN KNOWLEDGE:: The typical imaging characteristics should prompt an accurate diagnosis of sinonasal OPs in routine clinical practice. Combination of CT and MR imaging characteristics can be more helpful in discriminating OPs from IPs. PMID- 29987981 TI - A pictorial review: multimodality imaging of benign and suspicious features of fat necrosis in the breast. AB - Fat necrosis of the breast is a well-described benign entity that can result in unnecessary biopsy of breast lesions. The pathogenesis of fat necrosis is a non suppurative inflammatory process of adipose tissue, which may be seen after trauma, surgery, biopsy, post-breast reconstruction, post-fat grafting, post radiotherapy, infection, and duct ectasia, among other conditions. Clinically, these patients may be asymptomatic or may present with a palpable lump, skin tethering, induration, and occasionally axillary lymphadenopathy. Depending on the time at which diagnostic imaging is performed, fat necrosis can have highly variable appearances on different modalities as it evolves. This is directly related to whether inflammation or fibrosis is predominating within the lesion, and correlation with clinical history is paramount in evaluating these patients. This review aims to analyze benign and suspicious imaging features of fat necrosis confirmed by tissue sampling. Knowledge of both benign and malignant appearing features of fat necrosis on conventional modalities such as mammography and ultrasound, as well as newer applications including digital breast tomosynthesis, PET/CT, and MRI, should help the radiologist minimize the number of unnecessary biopsies. PMID- 29987982 TI - Mammographic detection of breast cancer in a non-screening country. AB - OBJECTIVE:: To compare the diagnostic accuracy between radiologists' from a country with and without breast cancer screening. METHODS:: All participating radiologists gave informed consent. A test-set involving 60 mammographic cases (20 cancer and 40 non-cancer) were read by 11 radiologists from a non-screening (NS) country during a workshop in July 2016. 52 radiologists from a screening country read the same test-set at the Royal Australian and New Zealand College of Radiologists' meetings in July 2015. The screening radiologists were classified into two groups: those with less than or equal to 5 years of experience; those with more than 5 years of experience, and each group was compared to the group of NS radiologists. A Kruskal-Wallis test followed by post-hoc multiple comparisons test were used to compare measures of diagnostic accuracy among the reader groups. RESULTS:: The diagnostic accuracy of the NS radiologists was significantly lower in terms of sensitivity [mean = 54.0; 95% confidence interval (CI) (40.0-67.0)], location sensitivity [mean = 26.0; 95% CI (16.0-37.0)], receive roperating characteristic area under curve [mean = 73.0; 95% CI (66.5 81.0)] and Jackknifefree-response receiver operating characteristics figure-of merit [mean = 45.0; 95% CI (40.0-50.0)] when compared with the less and more experienced screening radiologists, whilst no difference in specificity [mean = 75.0; 95% CI (70.0- 81.0)] was found. No significant differences in all measured diagnostic accuracy were found between the two groups of screening radiologists. CONCLUSION:: The mammographic performance of a group of radiologists from a country without screening program was suboptimal compared with radiologists from Australia. ADVANCES IN KNOWLEDGE:: Identifying mammographic performance in developing countries is required to optimize breast cancer diagnosis. PMID- 29987983 TI - Evaluation of optic nerve functions in subacute combined degeneration using visual evoked potential and diffusion tensor imaging-a pilot study. AB - OBJECTIVE:: To evaluate optic nerve involvement in subacute combined degeneration (SACD) using diffusion tensor imaging (DTI) and visual evoked potential (VEP) studies, and their changes following cobalamine treatment. METHODS:: Six patients with SACD and six healthy matched controls were included. Visual acuity, field of vision, and color vision were tested. Pattern shift VEP was done, and P100 latency and amplitude were measured. Optic nerve MRI, and DTI of optic nerve to muscle ratio were measured, and fractional anisotropy ratio (FAR), axial diffusivity ratio (ADR), radial diffusivity ratio (RDR), and mean diffusivity ratio (MDR) were calculated. The patients received hydroxyl cobalamine 1000 ug intramuscularly and their clinical examination, VEP and DTI studies were repeated at 3 months. RESULTS:: The age of the patients ranged between 16 and 60 years and two were females. Their visual acuity, field of vision, and color vision were normal. P100 latency was prolonged in five patients (10 eyes) and amplitude was reduced in one (1 eye). The SACD patients had reduced FAR (1.94 +/- 0.55 vs 2.81 +/- 0.42; p = 0.01) and increased MDR (1.00 +/- 0.04 vs 0.95 +/- 0.01; p = 0.01) and RDR (0.96 +/- 0.03 vs 0.89 +/- 0.01; p = 0.002) compared to the controls. The FAR value correlated with P100 latency (r = -0.88). At 3 months, FAR value increased which was associated with improvement in P100 latency. CONCLUSION:: In SACD patients, optic nerve FAR is reduced and correlates with P100 latency. Both these parameters improve on cobalamine treatment. ADVANCES IN KNOWLEDGE:: Subclinical VEP abnormalities are common in SACD but conventional MRI sequence of optic nerve is normal. DTI of optic nerve reveals reduced fractional anisotropy (FA) values which improve after cobalamine treatment. FA values correlate with prolongation of P100 latency. DTI and VEP abnormalities suggest subclinical optic nerve myelin dysfunction. PMID- 29987984 TI - Mandibular indexes and fractal properties on the panoramic radiographs of the patients using aromatase inhibitors. AB - OBJECTIVE:: This study was conducted to evaluate fractal dimension (FD), mandibular cortical width (MCW), panoramic mandibular index (PMI), and mandibular cortical index (MCI) on panoramic radiographs to determine the mandibular cortical and trabecular bone changes in females with breast cancer undergoing aromatase inhibitors (AIs) treatment. METHODS:: In this retrospective study, FD analysis, PMI, MCI, and MCW were assessed over panoramic radiographs of 34 females under AI therapy as a patient group and 34 healthy age-gender matched individuals as a control group. RESULTS:: Mean FD values and MCW were slightly but not significantly lower in the patient group (1.47 +/- 0.06 and 4.1 +/- 1.2 respectively). FDs measured onthe supracortical area above the angulus mandibula (FD2) and anterior to the mental foramen (FD4) were significantly lower in patients (p = 0.037 and p = 0.046 respectively). Among the measured regions in patients, FD2 was significantly lower (p = 0.001). PMI was also significantly lower in patients (p = 0.001) and MCI were similar in both groups (p = 0.604). CONCLUSION:: AI use affects bone quality and evaluating FD, PMI, and MCW in panoramic radiography can be used to determine the effect of this drug on the jaw bones in the early period. ADVANCES IN KNOWLEDGE:: Aromatase inhibitors are the most commonly used drugs in breast cancer patients. This drug is thought to have osteoporotic effects on the jawbone. This study is the first study to evaluate osteoporotic changes with measurements made on panoramic radiographs and the results of the study are significant. We think this study will shed light on the studies that will investigate the effects of the drug on the jaw bones. PMID- 29987985 TI - Evaluation of intracranial tuberculomas using diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS) and susceptibility weighted imaging (SWI). AB - OBJECTIVE:: The present study was aimed to evaluate patients of suspected intracranial tuberculomas with diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS) and susceptibility-weighted imaging (SWI). METHODS:: The present study evaluated 116 patients known or suspected of having central nervous system tuberculosis with advanced MRI techniques comprising of DWI, MRS and SWI in addition to the conventional MRI. RESULTS:: Apparent diffusion coefficient value of tuberculomas was not significantly different (p > 0.05) from apparent diffusion coefficient value of metastatic lesions and high-grade gliomas. MRS revealed that NAA/Cr and NAA/Cho ratios of tuberculomas were not significantly different (p > 0.05) from that of malignant brain lesions. However, Cho/Cr ratio of tuberculomas (1.36 +/- 0.41) was significantly lower from that of malignant brain lesions (2.63 +/- 0.99). SWI revealed a complete and regular hypointense peripheral ring in 42 cases of tuberculomas (58%) and in none of the malignant brain lesions. CONCLUSION:: DWI offers no clear advantage in differentiating tuberculomas from metastasis and gliomas. Tuberculomas may be differentiated from metastases and gliomas by their unique metabolite pattern on MRS. Presence of a complete and regular peripheral hypointense ring in SWI favors the diagnosis of tuberculomas. ADVANCES IN KNOWLEDGE:: The results from the present study suggest promising role of SWI in the discrimination of tuberculomas from metastatic brain lesions and gliomas with the presence of a complete and regular peripheral hypointense ring favoring the diagnosis of tuberculomas. PMID- 29987986 TI - Use of uncertainty factors by the European Commission Scientific Committee on Occupational Exposure Limits: a follow-up. AB - Decision on the safety margin, for instance by using uncertainty factors (UFs), is a key aspect in setting Occupational Exposure Limits (OELs). We analyzed the UFs in 128 OEL recommendations from the European Commission's Scientific Committee on Occupational Exposure Limits (SCOEL). We investigated factors expected to potentially influence the UFs, as well as a selection of factors that might influence how expert groups perceive quality or reliability of key studies. We extracted UFs explicitly stated in the recommendations (EUFs) and, when EUFs were missing, calculated an implicit safety margin (ISM) by dividing the point of departure (PoD) by the OEL. EUFs and ISMs were lower for recommendations based on human data than those based on animal data. EUFs and ISMs were also lower for No Observed Adverse Effect Concentrations (NOAECs) than Lowest Observed Adverse Effect Concentrations (LOAECs). We saw no differences based on local vs systemic critical effects. Acute data resulted in lower EUFs and ISMs than subchronic. We saw no influence from status of key study (publication status, performer or funder), but high tonnage substances (1,000,000+ tonnes) have lower EUFs and ISMs than substances currently not registered under REACH. Although SCOEL methodology stated that UF should be documented, only 65 out of 128 OEL recommendations included an EUF. Indeed, the ratio of EUFs to ISMs even decreased from 1991-2003 to 2004-2017. Additionally, EUFs were, on average, 1.8 times higher than ISMs. We conclude that a more articulate framework for using UFs could enhance consistency and transparency of the SCOEL recommendations. PMID- 29987987 TI - A reply to: Lingua patientis: new words for patient communication and history taking. PMID- 29987990 TI - Anisotropic cytocompatible electrospun scaffold for tendon tissue engineering elicits limited inflammatory response in vitro. AB - Tendon tears are a relevant concern for today's national health systems because of their social impact and high recurrence rate. The current gold standard for fixing tendon tears is surgical repair; however, this strategy is not able to fully re-establish tendon integrity and functionality. Tissue engineering approaches aim at promoting tissue regeneration by delivering the opportune signals to the injured site combining biomaterials, cells and biochemical cues. Electrospinning is currently one of the most versatile polymer processing techniques that allows manufacturing of nano- and micro-fibres substrates. Such fibrous morphology is deemed to be an ideal substrate to convey topographical cues to cells. Here we evaluated the potential of polycaprolactone processed by means of electrospinning technology for tendon tissue engineering. Fibrous free of-defects substrate with random and aligned fibres were successfully fabricated. Rat tenocytes were used to assess the cytocompatibility of the substrates for application as tendon tissue engineered devices. Tenocytes were able to proliferate and adapt to the substrates topography acquiring an elongated morphology, which is the precondition for oriented collagen deposition, when seeded on aligned fibres. Real time Polymerase Chain Reaction (Rt-PCR) also revealed the overall maintenance of tenocyte phenotype over 7 days culture. To verify suitability for in vivo implantation, the level of inflammatory cytokine genes expressed by THP-1 cells cultured in presence of electrospun polycaprolactone substrates was evaluated. Inflammatory response was limited. The novel preliminary in vitro work presented herein showing tenocytes compatibility and limited inflammatory cytokines synthesis suggests that electrospun polycaprolactone may be taken into consideration as substrate for tendon healing applications. PMID- 29987991 TI - Potential of milk mid-IR spectra to predict metabolic status of cows through blood components and an innovative clustering approach. AB - Unbalanced metabolic status in the weeks after calving predisposes dairy cows to metabolic and infectious diseases. Blood glucose, IGF-I, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB) are used as indicators of the metabolic status of cows. This work aims to (1) evaluate the potential of milk mid-IR spectra to predict these blood components individually and (2) to evaluate the possibility of predicting the metabolic status of cows based on the clustering of these blood components. Blood samples were collected from 241 Holstein cows on six experimental farms, at days 14 and 35 after calving. Blood samples were analyzed by reference analysis and metabolic status was defined by k means clustering (k=3) based on the four blood components. Milk mid-IR analyses were undertaken on different instruments and the spectra were harmonized into a common standardized format. Quantitative models predicting blood components were developed using partial least squares regression and discriminant models aiming to differentiate the metabolic status were developed with partial least squares discriminant analysis. Cross-validations were performed for both quantitative and discriminant models using four subsets randomly constituted. Blood glucose, IGF I, NEFA and BHB were predicted with respective R 2 of calibration of 0.55, 0.69, 0.49 and 0.77, and R 2 of cross-validation of 0.44, 0.61, 0.39 and 0.70. Although these models were not able to provide precise quantitative values, they allow for screening of individual milk samples for high or low values. The clustering methodology led to the sharing out of the data set into three groups of cows representing healthy, moderately impacted and imbalanced metabolic status. The discriminant models allow to fairly classify the three groups, with a global percentage of correct classification up to 74%. When discriminating the cows with imbalanced metabolic status from cows with healthy and moderately impacted metabolic status, the models were able to distinguish imbalanced group with a global percentage of correct classification up to 92%. The performances were satisfactory considering the variables are not present in milk, and consequently predicted indirectly. This work showed the potential of milk mid-IR analysis to provide new metabolic status indicators based on individual blood components or a combination of these variables into a global status. Models have been developed within a standardized spectral format, and although robustness should preferably be improved with additional data integrating different geographic regions, diets and breeds, they constitute rapid, cost-effective and large-scale tools for management and breeding of dairy cows. PMID- 29987993 TI - A genome scan for selection signatures in Taihu pig breeds using next-generation sequencing. AB - Taihu pig breeds are the most prolific breeds of swine in the world, and they also have superior economic traits, including high resistance to disease, superior meat quality, high resistance to crude feed and a docile temperament. The formation of these phenotypic characteristics is largely a result of long term artificial or natural selection. Therefore, exploring selection signatures in the genomes of the Taihu pigs will help us to identify porcine genes related to productivity traits, disease and behaviour. In this study, we used both intra population (Relative Extend Haplotype Homozygosity Test (REHH)) and inter population (the Cross-Population Extend Haplotype Homozygosity Test (XPEHH); F STATISTICS, F ST ) methods to detect genomic regions that might be under selection process in Taihu pig breeds. As a result, we found 282 (REHH) and 112 (XPEHH) selection signature candidate regions corresponding to 159.78 Mb (6.15%) and 62.29 Mb (2.40%) genomic regions, respectively. Further investigations of the selection candidate regions revealed that many genes under these genomic regions were related to reproductive traits (such as the TLR9 gene), coat colour (such as the KIT gene) and fat metabolism (such as the CPT1A and MAML3 genes). Furthermore, gene enrichment analyses showed that genes under the selection candidate regions were significantly over-represented in pathways related to diseases, such as autoimmune thyroid and asthma diseases. In conclusion, several candidate genes potentially under positive selection were involved in characteristics of Taihu pig. These results will further allow us to better understand the mechanisms of selection in pig breeding. PMID- 29987992 TI - Dietary patterns and risk of self-reported activity limitation in older adults from the Three-City Bordeaux Study. AB - Few studies have been interested in the relationship between dietary patterns and activity limitation in older adults yet. We analysed the association between dietary patterns and the risk of self-reported activity limitation - that is mobility restriction, limitation in instrumental activities in daily living (IADL) and in activities in daily living (ADL) - in community-dwellers aged 67+ years initially free of activity limitation in 2001-2002 and re-examined at least once over 10 years - that is 583 participants for mobility restriction, 1114 for IADL limitation and 1267 for ADL limitation. At baseline, five sex-specific dietary clusters were derived by hybrid clustering method from weekly frequency of intake of twenty food and beverage items. Self-reported mobility restriction, limitations in IADL and in ADL were assessed using the Rosow-Breslau, the Lawton Brody and the Katz scales, respectively. Associations between dietary clusters and the risk of each activity limitation were assessed using Cox proportional hazard models. In models adjusted for socio-demographic and health-related covariates, compared with the 'Healthy' cluster the 'Biscuits and snacking' cluster was associated with a higher risk of mobility restriction (hazard ratio (HR)=3.0; 95 % CI 1.6, 5.8) and limitation in IADL (HR=2.1; 95 % CI 1.1, 4.2) in men and limitation in ADL in women (HR=2.3; 95 % CI 1.3, 4.0). In this French cohort of community-dwellers aged 67+ years, some unhealthy dietary patterns may increase the risk of activity limitation all along the disablement process in older adults. PMID- 29987994 TI - PATIENT PRIORITIES FOR TREATMENT ATTRIBUTES IN ADJUNCTIVE DRUG THERAPY OF SEVERE HYPERCHOLESTEROLEMIA IN GERMANY: AN ANALYTIC HIERARCHY PROCESS. AB - OBJECTIVES: Severe hypercholesterolemia is a major cause of death in coronary heart disease. New adjunctive drug therapies have passed authorization processes and been launched recently. So far it is not known which properties of the new treatment options generate the highest benefit for patients. The aim was to evaluate patient priorities in the field of adjunctive drug therapy with apheresis. Therapy characteristics were examined as to their relevance to hypercholesterolemia patients. METHODS: To identify all potential patient relevant treatment characteristics, a systematic literature review and ten interviews with patients were conducted. Seven key characteristics were identified from the patient perspective. Patients' priorities were elicited using an analytic hierarchy process (AHP). RESULTS: In total, N = 61 patients diagnosed with severe hypercholesterolemia and undergoing apheresis participated in the study. The analysis showed predominance for the attribute "reduction of LDL-C level in blood" (Wglobal:0.362). The "risk of myopathy" (Wglobal:0.164), "risk of neurocognitive impairment" (Wglobal:0.161) and "frequency of apheresis" (Wglobal:0.119) were ranked second, third and fourth. Subgroup analyses revealed that "frequency of apheresis" is of greater importance to younger patients, men and/or patients who indicated a reduction in quality of life due to apheresis. CONCLUSIONS: The essential decision criteria for optimal therapy from the patients' perspective were obtained. "Reduction of lipoprotein in blood" was ranked highest compared with the "mode of administration" and "side effects" characteristics. The study offers a transparent approach for the identification of patient priorities for adjunctive PCSK9-inhibitor therapy in apheresis-treated hypercholesterolemia. The project can be used by healthcare decision makers to understand the importance of each patient-relevant endpoint. PMID- 29987995 TI - DEVELOPMENT OF THE ONTARIO DECISION FRAMEWORK: A VALUES BASED FRAMEWORK FOR HEALTH TECHNOLOGY ASSESSMENT. AB - OBJECTIVES: In 2007, the Ontario Health Technology Advisory Committee (OHTAC) developed a decision framework to guide decision making around nondrug health technologies. In 2012, OHTAC commissioned a revision of this framework to enhance its usability and deepen its conceptual and theoretical foundations. METHODS: The committee overseeing this work used several methods: (a) a priori consensus on guiding principles, (b) a scoping review of decision attributes and processes used globally in health technology assessment (HTA), (c) presentations by methods experts and members of review committees, and (d) committee deliberations over a period of 3 years. RESULTS: The committee adopted a multi-criteria decision making approach, but rejected the formal use of multi-criteria decision analysis. Three broad categories of attributes were identified: (I) context criteria attributes included factors such as stakeholders, adoption pressures from neighboring jurisdictions, and potential conflicts of interest; (II) primary appraisal criteria attributes included (i) benefits and harms, (ii) economics, and (iii) patient-centered care; (III) feasibility criteria attributes included budget impact and organizational feasibility. CONCLUSION: The revised Ontario Decision Framework is similar in some respects to frameworks used in HTA worldwide. Its distinctive characteristics are that: it is based on an explicit set of social values; HTA paradigms (evidence based medicine, economics, and bioethics/social science) are used to aggregate decision attributes; and that it is rooted in a theoretical framework of optimal decision making, rather than one related to broad social goals, such as health or welfare maximization. PMID- 29987996 TI - DEFINING INNOVATION WITH RESPECT TO NEW MEDICINES: A SYSTEMATIC REVIEW FROM A PAYER PERSPECTIVE. AB - OBJECTIVES: The aim of this study was to investigate how innovation is defined with respect to new medicines. METHODS: MEDLINE, Embase, and EconLit databases were searched for articles published between January 1, 2010 and May 25, 2016 that described a relevant definition of innovation. Identified definitions were analyzed by mapping the concepts described onto a set of ten dimensions of innovation. RESULTS: In total, thirty-six articles were included, and described a total of twenty-five different definitions of innovation. The most commonly occurring dimension was therapeutic benefit, with novelty and the availability of existing treatments the second and third most common dimensions. Overall, there was little agreement in the published literature on what characteristics of new medicines constitute rewardable innovation. CONCLUSIONS: Alignment across countries and among regulators, health technology assessment bodies and payers would help manufacturers define research policies that can drive innovation, but may be challenging, as judgements about what aspects of innovation should be rewarded vary among stakeholders, and depend on political and societal factors. PMID- 29987997 TI - CHALLENGES AND METHODOLOGIES IN USING PROGRESSION FREE SURVIVAL AS A SURROGATE FOR OVERALL SURVIVAL IN ONCOLOGY. AB - OBJECTIVES: A primary outcome in oncology trials is overall survival (OS). However, to estimate OS accurately requires a sufficient number of patients to have died, which may take a long time. If an alternative end point is sufficiently highly correlated with OS, it can be used as a surrogate. Progression-free survival (PFS) is the surrogate most often used in oncology, but does not always satisfy the correlation conditions for surrogacy. We analyze the methodologies used when extrapolating from PFS to OS. METHODS: Davis et al. previously reviewed the use of surrogate end points in oncology, using papers published between 2001 and 2011. We extend this, reviewing papers published between 2012 and 2016. We also examine the reporting of statistical methods to assess the strength of surrogacy. RESULTS: The findings from 2012 to 2016 do not differ substantially from those of 2001 to 2011: the same factors are shown to affect the relationship between PFS and OS. The proportion of papers reporting individual patient data (IPD), strongly recommended for full assessment of surrogacy, remains low: 33 percent. A wide range of methods has been used to determine the appropriateness of surrogates. While usually adhering to reporting standards, the standard of scholarship appears sometimes to be questionable and the reporting of results often haphazard. CONCLUSIONS: Standards of analysis and reporting PFS to OS surrogate studies should be improved by increasing the rigor of statistical reporting and by agreeing to a minimum set of reporting guidelines. Moreover, the use of IPD to assess surrogacy should increase. PMID- 29987998 TI - Genomic Investigation of a Mycobacterium tuberculosis Outbreak Involving Prison and Community Cases in Florida, United States. AB - We used whole-genome sequencing to investigate a tuberculosis outbreak involving U.S.-born persons in the prison system and both U.S.- and foreign-born persons in the community in Florida over a 7-year period (2009-2015). Genotyping by spacer oligonucleotide typing and 24-locus mycobacterial interspersed repetitive unit variable number tandem repeat suggested that the outbreak might be clonal in origin. However, contact tracing could not link the two populations. Through a multidisciplinary approach, we showed that the cluster involved distinct bacterial transmission networks segregated by country of birth. The source strain is of foreign origin and circulated in the local Florida community for more than 20 years before introduction into the prison system. We also identified novel transmission links involving foreign and U.S.-born cases not discovered during contact investigation. Our data highlight the potential for spread of strains originating from outside the United States into U.S. "high-risk" populations, such as prisoners, with subsequent movement back to the general community. PMID- 29988000 TI - Seroepidemiology of Dengue, Zika, and Yellow Fever Viruses among Children in the Democratic Republic of the Congo. AB - Flaviviruses such as Zika, dengue, and yellow fever cause epidemics throughout the tropics and account for substantial global morbidity and mortality. Although malaria and other vector-borne diseases have long been appreciated in Africa, flavivirus epidemiology is incompletely understood. Despite the existence of an effective vaccine, yellow fever continues to cause outbreaks and deaths, including at least 42 fatalities in the Democratic Republic of the Congo (DRC) in 2016. Here, we leveraged biospecimens collected as part of the nationally representative 2013-2014 Demographic and Health Survey in the DRC to examine serological evidence of flavivirus infection or vaccination in children aged 6 months to 5 years. Even in this young stratum of the Congolese population, we find evidence of infection by dengue and Zika viruses based on results from enzyme-linked immunosorbent assay and neutralization assay. Surprisingly, there was remarkable discordance between reported yellow fever vaccination status and results of serological assays. The estimated seroprevalences of neutralizing antibodies against each virus are yellow fever, 6.0% (95% confidence interval [CI] = 4.6-7.5%); dengue, 0.4% (0.1-0.9%); and Zika, 0.1% (0.0-0.5%). These results merit targeted, prospective studies to assess effectiveness of yellow fever vaccination programs, determine flavivirus seroprevalence across a broader age range, and investigate how these emerging diseases contribute to the burden of acute febrile illness in the DRC. PMID- 29988001 TI - Periplasmic Chaperones and Prolyl Isomerases. AB - The biogenesis of periplasmic and outer membrane proteins (OMPs) in Escherichia coli is assisted by a variety of processes that help with their folding and transport to their final destination in the cellular envelope. Chaperones are macromolecules, usually proteins, that facilitate the folding of proteins or prevent their aggregation without becoming part of the protein's final structure. Because chaperones often bind to folding intermediates, they often (but not always) act to slow protein folding. Protein folding catalysts, on the other hand, act to accelerate specific steps in the protein folding pathway, including disulfide bond formation and peptidyl prolyl isomerization. This review is primarily concerned with E. coli and Salmonella periplasmic and cellular envelope chaperones; it also discusses periplasmic proline isomerization. PMID- 29988002 TI - Relative Contribution of Schistosomiasis and Malaria to Anemia in Western Kenya. AB - Because anemia is one of the markers of morbidity associated with schistosomiasis, it has been proposed as a potential measure to evaluate the impact of control programs. However, anemia is also a common consequence of malaria, and schistosomiasis and malaria are often co-endemic. To estimate the attributable fraction of anemia due to Schistosoma mansoni and Plasmodium falciparum infections, we applied a log-binomial model to four studies measuring these parameters of a combined 5,849 children in western Kenya. In our studies, malaria contributed 23.3%, schistosomiasis contributed 6.6%, and co-infection contributed 27.6% of the anemia. We conclude that in areas where S. mansoni and P. falciparum are co-endemic, the contribution of schistosomiasis to anemia is masked by anemia resulting from malaria, thus limiting anemia as a useful measure for schistosomiasis control programs in these settings. PMID- 29988003 TI - Non-Respiratory and Non-Diarrheal Causes of Acute Febrile Illnesses in Children Requiring Hospitalization in a Tertiary Care Hospital in North India: A Prospective Study. AB - Acute febrile illnesses (AFIs) in children from the developing world can have varying etiologies. Awareness of local epidemiology helps in prioritizing investigations and empiric treatment. This prospective study was carried out in a tertiary care center in North India, aiming to determine the burden, etiology, and outcome of AFI other than pneumonia and diarrhea in hospitalized children. A total of 613 consecutive children aged 3 months to 12 years with febrile illness of < 7 days during four selected months of 2014 representing different seasons were screened for eligibility. Those with acute respiratory diseases (N = 175, 28.5%) and diarrheal illness (N = 46, 7.5%) were excluded and 217 children were enrolled. Mean (standard deviation) age was 4.8 (3.4) years. Nearly half (N = 91, 41.9%) presented in post-monsoon season. Diagnosis could be established in 187 (86.2%) children. Acute central nervous system infections were the most common (N = 54, 24.8%). Among specific infections, scrub typhus was the most frequent (N = 23, 10.5%) followed by malaria (N = 14, 6.4%), typhoid (N = 14, 6.5%), and viral hepatitis (N = 13, 6.0%). Blood culture had a low (6.5%) yield; Salmonella typhi (N = 6) and Staphylococcus aureus (N = 5) were the common isolates. Serological tests were helpful in 50 (23%) cases. In multivariate analysis, hepatomegaly and/or splenomegaly independently predicted scrub typhus. Mortality rate was 10.1%. We conclude that AFI other than pneumonia and diarrhea are a significant burden and follow a seasonal trend. Scrub typhus has emerged as an important etiology of childhood AFIs in northern India. Periodic review of regional epidemiology will help in understanding the changing pattern of infectious diseases. PMID- 29988005 TI - Stopping Medications before Vestibular Testing: Evidence-Based or Neuromythology? PMID- 29988004 TI - Accuracy of a Rapid Diagnostic Test Based on Antigen Detection for the Diagnosis of Cutaneous Leishmaniasis in Patients with Suggestive Skin Lesions in Morocco. AB - In rural areas in Morocco, diagnosing cutaneous leishmaniasis (CL) can be challenging. We evaluated the accuracy of a rapid diagnostic test (RDT) based on antigen detection, CL Detect Rapid TestTM (Inbios International Inc., Seattle, WA), in this setting. We consecutively recruited patients with new skin ulcers in nine primary health centers. We took a dental broach sample for the RDT and two other tissue samples by scraping the border and center of the lesion with a scalpel and smearing it on a slide. We duplicated each smear by pressing a clean slide against it and processed the slides by microscopy, polymerase chain reaction (PCR) internal transcribed spacer 1, and kDNA minicircle PCR. In a subgroup with positive PCR, the Leishmania species was identified using PCR restriction fragment length polymorphism and PCR-sequencing of hsp70 genes. A participant with positive microscopy and/or PCR was considered a confirmed CL case. We computed sensitivity (Se) and specificity (Sp) of the RDT compared with this reference standard (ClinicalTrials.gov registration: NCT02979002). Between December 2016 and July 2017, we included 219 patients, 50% of them were under 18 years old. Rapid diagnostic test Se was 68% [95% confidence interval (CI): 61 74], Sp 94% [95% CI: 91-97], positive predictive value 95% [95% CI: 92-98], and negative predictive value 64% [95% CI: 58-70]. Despite its low Se, this novel RDT is a useful addition to clinical management of CL in Morocco, especially in isolated localities. Rapid diagnostic test-positive lesions can be treated as CL; but when RDT negative, microscopy should be done in a second step. The Se of the RDT can probably be optimized by improving the sampling procedure. PMID- 29988006 TI - Impact of Personal Frequency Modulation Systems on Behavioral and Cortical Auditory Evoked Potential Measures of Auditory Processing and Classroom Listening in School-Aged Children with Auditory Processing Disorder. AB - BACKGROUND: Personal frequency modulation (FM) systems are often recommended for children diagnosed with auditory processing disorder (APD) to improve their listening environment in the classroom. Further evidence is required to support the continuation of this recommendation. PURPOSE: To determine whether personal FM systems enhance auditory processing abilities and classroom listening in school-aged children with APD. RESEARCH DESIGN: Two baseline assessments separated by eight weeks were undertaken before a 20-week trial of bilateral personal FM in the classroom. The third assessment was completed immediately after the FM trial. A range of behavioral measures and speech-evoked cortical auditory evoked potentials (CAEPs) in quiet and in noise were used to assess auditory processing and FM outcomes. Perceived listening ability was assessed using the Listening Inventory for Education-United Kingdom version (LIFE-UK) questionnaire student and teacher versions, and a modified version of the LIFE-UK questionnaire for parents. STUDY SAMPLE: Twenty-eight children aged 7-12 years were included in this intervention study. Of the 28 children, there were 22 males and six females. DATA COLLECTION AND ANALYSIS: APD Tests scores and CAEP peak latencies and amplitudes were analyzed using repeated measures analysis of variance to determine whether results changed over the two baseline assessments and after the FM trial. The LIFE-UK was administered immediately before and after the FM trial. Student responses were analyzed using paired t-tests. Results are described for the (different) pre- and post-trial teacher versions of the LIFE UK. RESULTS: Speech in spatial noise (SSN) scores improved by 13% on average when participants wore the FM system in the laboratory. Noise resulted in increased P1 and N2 latencies and reduced N2 amplitudes. The impact of noise on CAEP latencies and amplitudes was significantly reduced when participants wore the FM. Participants' LIFE-UK responses indicated significant improvements in their perceived listening after the FM trial. Most teachers (74%) reported the trial as successful, based on LIFE-UK ratings. Teachers' and parents' questionnaire ratings indicated good agreement regarding the outcomes of the FM trial. There was no change in compressed and reverberated words, masking level difference, and sustained attention scores across visits. Gaps in noise, dichotic digits test, and SSN (hard words) showed practice effects. Frequency pattern test and SSN easy word scores did not change between baseline visits, and improved significantly after the FM trial. CAEP N2 latencies and amplitudes changed significantly across visits; changes occurred across the baseline and the FM trial period. CONCLUSIONS: Personal FM systems produce immediate speech perception benefits and enhancement of speech-evoked cortical responses in noise in the laboratory. The 20-week FM trial produced significant improvements in behavioral measures of auditory processing and participants' perceptions of their listening skills. Teacher and parent questionnaires also indicated positive outcomes. PMID- 29988007 TI - The Influence of Caffeine on Rotary Chair and Oculomotor Testing. AB - BACKGROUND: When patients are given instructions before vestibular function testing, they are often asked to refrain from ingesting caffeine 24 h before testing. However, research regarding the effects of caffeine on the outcome of vestibular function testing is limited. PURPOSE: To evaluate whether the results from rotational chair tests are influenced by caffeine. RESEARCH DESIGN: Participants were tested after consuming a caffeinated beverage (i.e., coffee containing ~300 mg of caffeine), as well as after abstaining from caffeinated beverages. The participants underwent oculomotor testing, sinusoidal harmonic acceleration testing, optokinetic testing, visual enhancement/suppression testing, subjective visual vertical/horizontal testing, trapezoidal step testing, and unilateral utricular centrifugation testing. STUDY SAMPLE: Thirty healthy young controls aged 18-40 yr (mean = 23.28 yr; 9 males, 21 females) participated in the study. DATA COLLECTION AND ANALYSIS: Rotational chair tests were completed with the Neuro Kinetics rotary chair (Pittsburgh, PA). VEST 7.0 software was used to collect and analyze the participants' eye movements (I-Portal VOG; Neuro Kinetics). IBM SPSS was used to statistically analyze the results. RESULTS: Statistically significant differences were found for the results from several oculomotor tests (i.e., vertical saccades [SCs], horizontal SCs, and optokinetics), whereas the remaining rotational chair tests did not reveal any statistically significant differences between sessions. If a statistically significant difference was found, the participants were then stratified based on the amount of caffeine they consumed on a daily basis. This stratification was accomplished based on the guidelines from the International Coffee Organization. When the data were analyzed based on the stratified groups, statistically significant results remained in the no/low caffeine intake group, whereas no statistically significant results remained in the moderate/high caffeine intake group. Clinically speaking, the largest effect was seen in those individuals who did not typically ingest large amounts of caffeine, whereas the results were not found to be significantly different in those individuals who were typical caffeine consumers. This strengthens the argument that it is not necessary to require that individuals refrain from consuming caffeinated beverages before oculomotor/rotary chair testing as the results from typical caffeine consumers are not significantly affected. CONCLUSIONS: Although statistically significant results were found for a number of the oculomotor function tests, the ingestion of caffeine had little influence on the clinical interpretation of the responses. Therefore, the results from the present study indicate that it is not necessary to require that healthy young individuals abstain from caffeine before undergoing rotary chair/oculomotor testing. Further research is necessary to determine whether there is also a limited effect of caffeine on rotary chair/oculomotor test results from older individuals, as well as individuals diagnosed with a vestibular impairment. PMID- 29988008 TI - The Influence of Speech Rate on Acceptable Noise Levels. AB - BACKGROUND: Older adults often struggle with accurate perception of rate-altered speech and have difficulty understanding speech in noise. The acceptable noise level (ANL) quantifies a listener's willingness to listen to speech in background noise and has been found to accurately predict hearing aid success. Based on the difficulty older adults experience with rapid speech, we were interested in how older adults may change the amount of background noise they willingly accept in a variety of speech rate conditions. PURPOSE: To determine the effects of age and speech rate on the ANL. RESEARCH DESIGN: A quasi-experimental mixed design was employed. STUDY SAMPLE: Fifteen young adults (19-27 yr) and fifteen older adults (55-73 yr) with audiometrically normal hearing or hearing loss within age-normed limits served as participants. DATA COLLECTION AND ANALYSIS: Most comfortable listening levels (MCLs) and background noise levels (BNLs) were measured using three different speech rates (slow, normal, and fast). The ANL was calculated by subtracting BNL from MCL. Repeated measures analysis of variances were used to analyze the effects of age and speech rate on ANL. RESULTS: A significant main effect of speech rate was observed; however, a significant main effect of age was not found. Results indicated that as speech rate increased the ANLs increased. This suggests that participants became less accepting of background noise as speech rates increased. CONCLUSIONS: The findings of the present study provide support for communication strategies that recommend slowing an individual's speaking rate and/or reducing background noise, if possible. Participants in the present study were better able to cope with background noise when the primary stimulus was presented at slow and normal speaking rates. PMID- 29988009 TI - Psychometric Validity, Reliability, and Responsiveness of the Tinnitus Functional Index. AB - BACKGROUND: The effects of treatments on tinnitus have been difficult to quantify. The Tinnitus Functional Index (TFI) has been proposed as a standard questionnaire for measurement of tinnitus treatment outcomes. For a questionnaire to achieve wide acceptance, its psychometric properties need to be confirmed in different populations. OBJECTIVE: To determine if the TFI is a reliable and valid measure of tinnitus, and if its psychometric properties are suitable for use as an outcome measure. RESEARCH DESIGN: A psychometric evaluation of the TFI from secondary data obtained from a cross-sectional clinic survey and a clinical trial undertaken in New Zealand. STUDY SAMPLE: Confirmatory factor analysis and evaluation of internal consistency reliability were undertaken on a sample of 318 patients with the primary complaint of tinnitus. In a separate sample of 40 research volunteers, test-retest reliability, convergent and divergent validity were evaluated. Both samples consisted of predominantly older Caucasian male patients with tinnitus. RESULTS: The internal structure of the original US TFI was confirmed. The Cronbach's Alpha and Intraclass correlation coefficients were >0.7 for the TFI overall and each of its subscales, indicating high internal consistency and test-retest reliability. Strong Pearson correlations with the Tinnitus Handicap Questionnaire and tinnitus numerical rating scales indicated excellent convergent validity, and a moderate correlation with the Hearing Handicap Inventory, indicated moderate divergent validity. Evaluation of the clinical trial showed good test-retest reliability and agreement between no treatment baselines with a smallest detectable change of 4.8 points. CONCLUSIONS: The TFI is a reliable and valid measure of tinnitus severity in the population tested and is responsive to treatment-related change. Further research as to the TFI's responsiveness to treatment is needed across different populations. PMID- 29988010 TI - Prevalence and Characteristics of Patients with Severe Hyperacusis among Patients Seen in a Tinnitus and Hyperacusis Clinic. AB - PURPOSE: The purpose was to assess the proportion of patients seeking help for tinnitus and/or hyperacusis who have severe hyperacusis and to examine factors associated with severe hyperacusis. RESEARCH DESIGN: This was a retrospective cross-sectional study based on 362 consecutive patients who attended a National Health Service audiology clinic for tinnitus and/or hyperacusis rehabilitation and for whom uncomfortable loudness levels (ULLs) had been measured. The criterion for severe hyperacusis was taken as a ULL of 30 dB HL or less for at least one of the measured frequencies for at least one ear. RESULTS: Thirteen patients had severe hyperacusis, and eight of those had normal hearing. The lowest average ULL across frequencies was 28 dB HL. The difference in average ULLs between ears was 5 dB or less for nine patients. The range of ULLs across frequencies was between 5 and 60 dB, ULLs often being lowest at 8 kHz. Eleven patients had tinnitus, eight had otological abnormalities, twelve had mental health problems, and six were taking antidepressants. CONCLUSIONS: Severe hyperacusis is characterized by low ULLs for specific frequencies and no or mild hearing loss. Given the high incidence of tinnitus, otological abnormalities, and mental health problems, the management of patients with severe hyperacusis should involve otologists and psychiatrists in addition to audiologists. PMID- 29988011 TI - An Evaluation of the World Health Organization and American Medical Association Ratings of Hearing Impairment and Simulated Single-Sided Deafness. AB - BACKGROUND: According to the World Health Organization (WHO), a pure-tone threshold average (PTA) <=25 dB HL for the better ear represents "no impairment." This implies that patients with single-sided deafness (SSD) would have "no or very slight hearing problems." According to the American Medical Association (AMA), a patient with SSD would receive a binaural hearing impairment rating of 16.7%. The premise of the WHO and AMA methods is that PTA is related to the ability to perceive speech in everyday environments. PURPOSE: The overall goal of the study was to evaluate the WHO and AMA criteria for the rating of hearing impairment. The purpose of this study was to quantify the impact of simulated SSD on the ability to recognize speech in the presence of background noise in terms of binaural and spatial advantage measures. RESEARCH DESIGN: Study participants were tested using the standard protocol for the Hearing in Noise Test (HINT) in both binaural and monaural conditions using a simulated soundfield environment under headphones. The target sentences were presented at 0 degrees . Binaural thresholds were obtained for the Noise Front (0 degrees ), Noise Left (270 degrees ), and Noise Right (90 degrees ) listening conditions. Monaural thresholds were collected for each ear for the Noise Front condition and for the unshadowed ear for the Noise Left and Noise Right conditions. Binaural advantage was determined by subtracting the binaural from the monaural thresholds. Spatial advantage was determined by subtracting the Noise Side from the Noise Front thresholds. STUDY SAMPLE: Twenty-five young native speakers of English with normal pure-tone thresholds (<=25 dB HL, 250-8000 Hz) participated in the study. DATA COLLECTION AND ANALYSIS: Pure-tone threshold data were collected using the modified Hughson-Westlake procedure. Speech recognition in noise data were collected using a Windows-based HINT software system. The binaural and spatial advantage measures were calculated from the HINT thresholds. Statistical analyses included descriptive statistics, correlation coefficients, and matched-pairs t tests. RESULTS: The average binaural advantage for the Noise Front conditions was 1.21 dB (p < 0.01) or a maximum estimated intelligibility improvement of 12.01% when the speech and noise were presented at 0 degrees . The average binaural advantage across the Noise Side conditions was 11.25 dB (p < 0.01) or a maximum estimated intelligibility improvement of 84.09% when the noise was spatially separated from the speech. The average spatial advantage for the binaural conditions was 6.72 dB (p < 0.01) or a maximum estimated intelligibility improvement of 60.03%. The average spatial advantage for the monaural conditions was -3.32 dB or a maximum estimated decrease in intelligibility of 32.27%. CONCLUSIONS: The results do not support the WHO or AMA hearing impairment ratings for SSD. The WHO and AMA criteria for the determination of hearing impairment should be updated to include speech recognition in noise testing with and without the spatial separation of the speech and noise stimuli. In this way actual, as opposed to inferred perceptions of speech in noisy environments, may be determined. This will provide a much-needed improvement in the ratings of hearing impairment. PMID- 29988012 TI - Impact of Hearing Loss and Amplification on Performance on a Cognitive Screening Test. AB - BACKGROUND: There have been numerous recent reports on the association between hearing impairment and cognitive function, such that the cognition of adults with hearing loss is poorer relative to the cognition of adults with normal hearing (NH), even when amplification is used. However, it is not clear the extent to which this is testing artifact due to the individual with hearing loss being unable to accurately hear the test stimuli. PURPOSE: The primary purpose of this study was to examine whether use of amplification during cognitive screening with the Montreal Cognitive Assessment (MoCA) improves performance on the MoCA. Secondarily, we investigated the effects of hearing ability on MoCA performance, by comparing the performance of individuals with and without hearing impairment. STUDY SAMPLE: Participants were 42 individuals with hearing impairment and 19 individuals with NH. Of the individuals with hearing impairment, 22 routinely used hearing aids; 20 did not use hearing aids. DATA COLLECTION AND ANALYSIS: Following a written informec consent process, all participants completed pure tone audiometry, speech testing in quiet (Maryland consonant-nucleus-consonant [CNC] words) and in noise (Quick Speech in Noise [QuickSIN] test), and the MoCA. The speech testing and MoCA were completed twice. Individuals with hearing impairment completed testing once unaided and once with amplification, whereas individuals with NH completed unaided testing twice. RESULTS: The individuals with hearing impairment performed significantly less well on the MoCA than those without hearing impairment for unaided testing, and the use of amplification did not significantly change performance. This is despite the finding that amplification significantly improved the performance of the hearing aid users on the measures of speech in quiet and speech in noise. Furthermore, there were strong correlations between MoCA score and the four frequency pure tone average, Maryland CNC score and QuickSIN, which remain moderate to strong when the analyses were adjusted for age. CONCLUSIONS: It is concluded that the individuals with hearing loss here performed less well on the MoCA than individuals with NH and that the use of amplification did not compensate for this performance deficit. Nonetheless, this should not be taken to suggest the use of amplification during testing is unnecessary because it might be that other unmeasured factors, such as effort required to perform or fatigue, were decreased with the use of amplification. PMID- 29988013 TI - Measuring Perceptions of Classroom Listening in Typically Developing Children and Children with Auditory Difficulties Using the LIFE-UK Questionnaire. AB - BACKGROUND: Classrooms can be noisy and are challenging listening environments for children with auditory processing disorder (APD). This research was undertaken to determine if the Listening Inventory for Education-UK version (LIFE UK) can differentiate children with listening difficulties and APD from their typically developing peers. PURPOSE: To investigate reliability and validity of the student and teacher versions LIFE-UK questionnaire for assessing classroom listening difficulties. RESEARCH DESIGN: Cross-sectional quantitative study comparing children with listening difficulties with typically developing children. STUDY SAMPLE: In total, 143 children (7-12 yr) participated; 45 were diagnosed with APD. Fifteen participants with reported listening difficulties who passed the APD test battery were assigned to a "listening difficulty" (LiD) group. Eighty three children from nine classrooms formed a Control group. DATA COLLECTION AND ANALYSIS: Children and teachers completed the LIFE-UK questionnaire student and teacher versions. Factor analysis was undertaken, and item reliability was assessed using Cronbach's alpha. Teacher and student ratings were compared using Spearman correlations. Correlations between LIFE-UK ratings and APD test results were also investigated. RESULTS: Factor analysis revealed three factors accounting for 60% of the variance in the Control group LIFE-UK ratings. After removing six items with low factor loadings, a shortened seven item version with three factors accounted for 71.8% of the variance for the student questionnaire; Cronbach's alpha indicated good internal reliability for this seven-item version of the student questionnaire. Factors were also derived for the teacher questionnaire. Teacher and student ratings were correlated when participant groups were combined. LIFE-UK ratings correlated weakly with some APD measures, providing some support for the questionnaire validity. CONCLUSIONS: The results support the use of either the 13- or 7-item student and the teacher versions of the LIFE-UK to evaluate classroom listening and functional consequences of APD. Factor analysis resulted in groupings of items reflecting differences in listening demands in quiet versus noise for the student questionnaire and attentional versus class participation demands for the teacher questionnaire. Further research is needed to confirm the robustness of these factors in other populations. PMID- 29988016 TI - Inert and seed-competent tau monomers suggest structural origins of aggregation. AB - Tauopathies feature progressive accumulation of tau amyloids. Pathology may begin when these amplify from a protein template, or seed, whose structure is unknown. We have purified and characterized distinct forms of tau monomer-inert (Mi) and seed-competent (Ms). Recombinant Ms triggered intracellular tau aggregation, induced tau fibrillization in vitro, and self-assembled. Ms from Alzheimer's disease also seeded aggregation and self-assembled in vitro to form seed competent multimers. We used crosslinking with mass spectrometry to probe structural differences in Mi vs. Ms. Crosslinks informed models of local peptide structure within the repeat domain which suggest relative inaccessibility of residues that drive aggregation (VQIINK/VQIVYK) in Mi, and exposure in Ms. Limited proteolysis supported this idea. Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form. PMID- 29988015 TI - Stem cell heterogeneity drives the parasitic life cycle of Schistosoma mansoni. AB - Schistosomes are parasitic flatworms infecting hundreds of millions of people. These parasites alternate between asexual reproduction in molluscan hosts and sexual reproduction in mammalian hosts; short-lived, water-borne stages infect each host. Thriving in such disparate environments requires remarkable developmental plasticity, manifested by five body plans deployed throughout the parasite's life cycle. Stem cells in Schistosoma mansoni provide a potential source for such plasticity; however, the relationship between stem cells from different life-cycle stages remains unclear, as does the origin of the germline, required for sexual reproduction. Here, we show that subsets of larvally derived stem cells are likely sources of adult stem cells and the germline. We also identify a novel gene that serves as the earliest marker for the schistosome germline, which emerges inside the mammalian host and is ultimately responsible for disease pathology. This work reveals the stem cell heterogeneity driving the propagation of the schistosome life cycle. PMID- 29988017 TI - The two shapes of the Tau protein. AB - Tau proteins can convert from an inert shape to a misfolded shape that seeds the growth of fibers that contribute to the pathology of Alzheimer's disease. PMID- 29988018 TI - A promoter interaction map for cardiovascular disease genetics. AB - Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs); however, most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci. PMID- 29988021 TI - Plasmonic silvered nanostructures on macroporous silicon decorated with graphene oxide for SERS-spectroscopy. AB - A method for fabricating surface-enhanced Raman scattering (SERS)-active substrates by immersion deposition of silver on a macroporous silicon (macro-PS) template with pore diameters and depth ranging from 500-1000 nm is developed. The procedure for the formation of nanostructured silver films in the layers of macro PS was optimized. Silver particles of dimensions in the nano- and submicron-scale were formed on the external surface of the macro-PS immersed in the water-ethanol solution of AgNO3, while the inner pore walls were covered by smaller, 10-30 nm diameter, silver nanoparticles. Upon introducing the hydrofluoric acid to the reaction mixture, the size of nanoparticles grown on the pore walls increased up to 100-150 nm. Such nanostructures were found to yield SERS-signal intensities from CuTMpyP4 analyte molecules of the same order to those obtained from silvered mesoporous silicon reported previously. The tested storage stability for the silvered macro-PS-based samples reached up to 8 months. However, degradation of the SERS intensity under illumination by the laser beam during spectral measurements was observed. To improve the stability of the SERS-signal a hybrid structure involving graphene oxide deposited on the top of analyte molecules adsorbed on the Ag/macro-PS was formed. A systematic observation of the time evolution of the characteristic peak at 1365 cm-1 showed that the addition of the oxidized graphene layer over the analyte results in ~2 times slower decay of the Raman intensity, indicating that the graphene coating can be used to enhance the stability of the SERS-signal from the CuTMpyP4 molecules. PMID- 29988022 TI - Use and mis-use of x-ray photoemission spectroscopy Ce3d spectra of Ce2O3 and CeO2. AB - X-ray photoemission spectroscopy (XPS) work on Ce2O3 and CeO2 oxides has been an active topic of research over the past four decades or so. Such research aimed to find the reasons for the unusual complexity of Ce3d spectra of the two oxides, and it studied catalytic properties of materials that contained them. I discuss how theoretical and experimental studies exploited the diagnostic potential of XPS to reach our current knowledge of the electronic properties of the two oxides. A part of these studies provided peak-fitting guidelines to resolve Ce3d spectra produced by the co-existence of both oxides into the individual spectral components arising from Ce3+ and Ce4+ ions. Basing myself on the analysis of several peak-fittings of Ce3d spectra carried out in studies of the catalytic applications of CeO2-based materials, I show that more often than not they largely ignore the findings of theoretical, experimental, and methodological XPS work. I discuss typical problems that flaw Ce3d peak-fittings, and how they affect their accuracy. I argue that, although several XPS studies do list primary literature of Ce3d spectra in their bibliography, they often do so for decorative purposes, rather than practical purposes. PMID- 29988019 TI - Biophysical clocks face a trade-off between internal and external noise resistance. AB - Many organisms use free running circadian clocks to anticipate the day night cycle. However, others organisms use simple stimulus-response strategies ('hourglass clocks') and it is not clear when such strategies are sufficient or even preferable to free running clocks. Here, we find that free running clocks, such as those found in the cyanobacterium Synechococcus elongatus and humans, can efficiently project out light intensity fluctuations due to weather patterns ('external noise') by exploiting their limit cycle attractor. However, such limit cycles are necessarily vulnerable to 'internal noise'. Hence, at sufficiently high internal noise, point attractor-based 'hourglass' clocks, such as those found in a smaller cyanobacterium with low protein copy number, Prochlorococcus marinus, can outperform free running clocks. By interpolating between these two regimes in a diverse range of oscillators drawn from across biology, we demonstrate biochemical clock architectures that are best suited to different relative strengths of external and internal noise. PMID- 29988020 TI - Adaptive coding for dynamic sensory inference. AB - Behavior relies on the ability of sensory systems to infer properties of the environment from incoming stimuli. The accuracy of inference depends on the fidelity with which behaviorally relevant properties of stimuli are encoded in neural responses. High-fidelity encodings can be metabolically costly, but low fidelity encodings can cause errors in inference. Here, we discuss general principles that underlie the tradeoff between encoding cost and inference error. We then derive adaptive encoding schemes that dynamically navigate this tradeoff. These optimal encodings tend to increase the fidelity of the neural representation following a change in the stimulus distribution, and reduce fidelity for stimuli that originate from a known distribution. We predict dynamical signatures of such encoding schemes and demonstrate how known phenomena, such as burst coding and firing rate adaptation, can be understood as hallmarks of optimal coding for accurate inference. PMID- 29988023 TI - Water-induced reordering in ultrathin ionic liquid films. AB - Water-induced reordering in ultrathin ionic liquid films has been observed using in situ x-ray photoelectron spectroscopy. An ultrathin layer of 1-butyl-3 methylimidazolium tetrafluoroborate ([C4C1Im][BF4]) was deposited on a rutile TiO2 (1 1 0) single crystal and exposed to water vapour at a relative humidity of ~70% in an in situ cell. Water was found to adsorb onto the ionic liquid surface, causing a reordering of the ions at the interface. Water initially remained trapped on the ionic liquid surface as the in situ cell was evacuated. This could have negative implications for supported ionic liquid phase catalysis, where reactants and products move in and out of an ionic liquid containing the catalyst. This insight into the behaviour at the water/ionic liquid interface provides a basis for understanding interfacial behaviour in more complex gas/ionic liquid systems. PMID- 29988024 TI - Pressure induced anomalous magnetic behaviour in nanocrystalline YCrO3 at room temperature. AB - High pressure behaviour of nanocrystalline YCrO3 is investigated up to 10 GPa using electrical, magnetic, synchrotron x-ray diffraction and Raman spectroscopy measurements. High pressure dielectric constant measurements show a sharp peak at 4.5 GPa, though the sample is found to be in ferroelectric phase up to the highest pressure of our study from piezoelectric current measurements. X-ray diffraction measurements show absence of any structural phase transition, however anomalies are observed in the unit cell structural parameters at about 4.3 GPa and the Y-atom position shows a maximum shift at the same pressure. In the absence of any structural transition, anomalous behaviour of relevant Raman modes with minimum in the Raman band width at about same pressure indicate towards a spin-phonon interaction. AC magnetic measurements in the toroid anvil cell show an anomalous enhancement of magnetic moment above 4 GPa indicating a collective magnetic response of nanoparticles. PMID- 29988025 TI - Resistive switching control for conductive Si-nanocrystals embedded in Si/SiO2 multilayers. AB - In this paper, we report on the enhanced control of resistive switching in multilayer Si/SiO2 structures, which permit the formation of Si nanocrystals with a typical size of 5.88 nm and overall good shape homogeneity. The deposition of a different number of Si and SiO2 bilayers (6, 8 and 10) allowed control of SET/RESET voltages in negative bias ranges 4.5-10 V and 6.3-13 V for six- and ten bilayer devices, respectively. The corresponding resistance ratio between ON/OFF states varied in the ranges 107-105 for the aforementioned number of bilayers. Based on the result of XPS measurements, we suggest that the resistive switching in the studied system occurs due to the formation and annihilation of Si-Si and Si-O bonds, which serve as conductive pathways and isolating material, respectively. PMID- 29988026 TI - Luminal/extracellular domains of chimeric CI-M6PR-C proteins interfere with their retrograde endosome-to-TGN trafficking in the transient expression system. AB - The membrane trafficking of cation-independent mannose 6-phosphate receptor (CI M6PR) between the trans-Golgi network (TGN) and endosomal compartments is not only critical for maintaining lysosomal function but also a well-known event for understanding molecular and cellular mechanisms in retrograde endosome-to-TGN trafficking. Although it has been well established in literature that the C terminus of bovine CI-M6PR determines its retrograde trafficking, it remains unclear whether the luminal domain of the protein plays a role on these sorting events. In this study, we found that partial deletion of luminal domain of human CI-M6PR mistargeted the mutant protein to non-TGN compartments. Moreover, replacing the luminal domain of both bovine and human CI-M6PR with that from irrelevant membrane proteins such as CD8 or Tac also altered the TGN targeting of the chimeric proteins. On the other hand, only short sequence from HA fused with the transmembrane domain and C-terminus of the receptor, HA-hCI-M6PR-tail, resulted in its preferential targeting to TGN as for the full length receptor, strongly suggesting that sorting of the receptor may be influenced by luminal sequence. Furthermore, using this luminal truncated form of HA-hCI-M6PR as a model cargo, we found that the trafficking of the chimeric protein was regulated by the retromer complex through interacting with SNX5. In conclusion, our study strongly suggested that the disrupted luminal domain from hCI-M6PR or other irrelevant membrane proteins interfere with the process of membrane trafficking and TGN targeting of CI-M6PR. PMID- 29988027 TI - Increased Expression of the YPEL3 Gene in Human Colonic Adenocarcinoma Tissue and the Effects on Proliferation, Migration, and Invasion of Colonic Adenocarcinoma Cells In Vitro via the Wnt/b-Catenin Signaling Pathway. AB - BACKGROUND The aim of this study was to investigate the effects of the expression of the YPEL3 gene in colonic adenocarcinoma cells grown in vitro and in colonic adenocarcinoma tissue from patients treated by surgical resection. MATERIAL AND METHODS The study included 108 patients diagnosed with primary colon cancer (Stages I to IV). The expression of the YPEL3 gene in colonic adenocarcinoma tissue and adjacent normal colonic tissue was detected by real-time quantitative PCR (qRT-PCR). The normal human colonic cell line CCD-1Co and colorectal adenocarcinoma cell lines HT-29 and HCT-8 were induced to overexpress the YPEL3 gene, and the effects on cell proliferation, migration, and invasion of colonic adenocarcinoma cells were investigated by the Cell Counting Kit-8 (CCK-8) assay, a transwell migration assay, and a transwell invasion assay, respectively. The effects of YPEL3 gene overexpression on the Wnt/beta-catenin signaling pathway were detected by Western blot. RESULTS Increased expression levels of the YPEL3 gene were present in colon adenocarcinoma tissue compared with adjacent normal colonic tissue in 98 of 108 patients. Overexpression of the YPEL3 gene inhibited the proliferation, migration, and invasion of the HT-29 and HCT-8 colonic adenocarcinoma cells, and inactivated the Wnt/beta-catenin signaling pathway; treatment with the Wnt agonist, CAS 853220-52-7, reduced the inhibitory effects of YPEL3 overexpression on proliferation, migration, and invasion in vitro. CONCLUSIONS Expression of the YPEL3 gene was upregulated in human colonic adenocarcinoma tissue, and also inhibited the proliferation, migration, and invasion of colonic adenocarcinoma cells in vitro by inactivating the Wnt/beta catenin signaling pathway. PMID- 29988028 TI - A novel phosphorylation by AMP-activated kinase regulates RUNX2 from ubiquitination in osteogenesis over adipogenesis. AB - Mesenchymal stem cells (MSCs) function as progenitors to a variety of cell types. The reported association between osteogenic and adipogenic commitment during differentiation is due to the regulation of key transcription factors in the signaling pathways. However, the process of adipogenesis at the expense of osteogenic phenotype during metabolic stress is still unclear. In this study, we showed for the first time that RUNX2 is a novel substrate of AMP-activated kinase (AMPK), which directly phosphorylates at serine 118 residue in the DNA-binding domain of RUNX2. Our results in in vitro MSC lineage differentiation models confirmed that active AMPK and RUNX2-S118 phosphorylation are preferentially associated with osteogenic commitment, whereas the lack of this phosphorylation leads to adipogenesis. This interplay is regulated by the ubiquitination of non phosphorylated RUNX2-S118, which is evident in the dominant mutant RUNX2-S118D. Pharmacological activation of AMPK by metformin significantly abrogated the loss of RUNX2-S118 phosphorylation and protected from tunicamycin-induced endoplasmic reticulum stress, high glucose-induced in vitro adipogenesis and streptozotocin induced in vivo bone adiposity and bone phenotype. In conclusion, results from this study demonstrated that RUNX2 is a direct target of AMPK which simplified the outlook towards several complex mechanisms that are currently established concerning cellular metabolism and pathogenesis. PMID- 29988029 TI - Downregulation of miR-130a, antagonized doxorubicin-induced cardiotoxicity via increasing the PPARgamma expression in mESCs-derived cardiac cells. AB - Doxorubicin (Dox) is a widely used powerful chemotherapeutic component for cancer treatment. However, its clinical application has been hampered due to doxorubicin induced cardiomyopathy upon the cessation of chemotherapy. Previous studies revealed that PPARgamma plays a crucial protective role in cardiomyocytes. Modulation of miRNA expression is an applicable approach for prohibition of toxicity induction. Therefore, the aim of present study is uprising of PPARgamma transcript levels via manipulation of miRNAs to limit Dox-induced cardiotoxicity in mESCs-derived cardiac cells, as in vitro model cell to provide a simple direct approach for further clinical therapies. Based on bioinformatics data mining, eventually miR-130a was selected to target PPARgamma. This miRNA is highly expressed in heart. The expression of miR-130a increases sharply upon Dox treatment while specific antagomiR-130a reverses Dox-induced reduced expression of PPARgamma, cellular apoptosis, and inflammation. Our data strongly suggest that antagomiR-130a limits Dox-induced cellular toxicity via PPARgamma upregulation and may have clinical relevance to limit in vivo Dox toxicity. PMID- 29988030 TI - CD45+CD33lowCD11bdim myeloid-derived suppressor cells suppress CD8+ T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer. AB - Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45+CD33lowCD11bdim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45+CD33lowCD11bdim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45+CD33lowCD11bdim MDSCs effectively suppressed CD8+ T cells activity through the inhibition of CD8+ T cell proliferation and interferon-gamma (IFN-gamma) and granzyme B (GrB) production. The proportion of CD45+CD33lowCD11bdim MDSCs also negatively correlated with the proportion of IFN gamma+CD8+ T cell in the peripheral blood of GC patients. GC patient serum derived IL-6 and IL-8 activated and induced CD45+CD33lowCD11bdim MDSCs to express arginase I via the PI3K-AKT signaling pathway. This pathway contributed to CD8+ T cell suppression as it was partially rescued by the blockade of the IL-6/IL-8 arginase I axis. Peripheral blood CD45+CD33lowCD11bdim MDSCs, as well as IL-6, IL 8, and arginase I serum levels, positively correlated with GC progression and negatively correlated with overall patient survival. Altogether, our results highlight that a subset of neutrophilic CD45+CD33lowCD11bdim MDSCs is functionally immunosuppressive and activated via the IL-6/IL-8-arginase I axis in GC patients. PMID- 29988031 TI - BET bromodomain inhibitor JQ1 preferentially suppresses EBV-positive nasopharyngeal carcinoma cells partially through repressing c-Myc. AB - The management of advanced nasopharyngeal carcinoma (NPC) remains a challenge. The ubiquitous nature of Epstein-Barr virus (EBV) infection in nonkeratinizing NPC has forced us to investigate novel drugs for NPC in the presence of EBV. In this study, we performed a small-scale screening of a library of compounds that target epigenetic regulators in paired EBV-positive and EBV-negative NPC cell lines. We found that bromodomain and extra-terminal (BET) inhibitor JQ1 preferentially inhibits the growth of EBV-positive NPC cells. JQ1 induces apoptosis, decreases cell proliferation and enhances the radiosensitivity in NPC cells, especially EBV-positive cells. Significantly, JQ1-induced cell death is c Myc-dependent. Notably, RNA-seq analysis demonstrated that JQ1 represses TP63, TP53 and their targets. JQ1 also lessens the expression of PD-L1 in NPC. Moreover, the high potency of JQ1 in NPC cells was further confirmed in vivo in CNE2-EBV+ tumor-bearing mice. These findings indicate that JQ1 is a promising therapeutic candidate for advanced NPC. PMID- 29988032 TI - M2 macrophage-mediated interleukin-4 signalling induces myofibroblast phenotype during the progression of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a progressive disease in elderly men, but potential factors accelerating its progression remain largely unknown. The aim of this study was to elucidate the factors affecting BPH progression by understanding the complex mechanisms causing early- progressed BPH, which progresses rapidly and requires surgical intervention before the age of 50. Three groups of human prostate tissue samples, from patients with early-progressed BPH, age-matched prostate and elderly BPH tissues, were collected (n = 25 each). We compared these tissues to determine the histologic features and molecular mechanisms underlying BPH progression. We found that early-progressed BPH samples were characterised by aberrant stromal hyper-proliferation, collagen deposition and increased M2 macrophage infiltration, compared to those from age-matched prostate and elderly BPH tissues. The M2 macrophage-fibroblast co-culture system demonstrated that the myofibroblast phenotypes were strongly induced only in fibroblasts from the early-progressed BPH samples, while the co-cultured M2 macrophages expressed high levels of pro-fibrotic cytokines, such as IL4 and TGFbeta1. M2 macrophage-derived IL4, but not TGFbeta1, selectively induced the myofibroblast phenotype through the JAK/STAT6, PI3K/AKT and MAPK/ERK signalling pathways in the early-progressed BPH prostate fibroblasts. Taken together, our results indicate that induction of the myofibroblast phenotype may lead to BPH progression through M2 macrophage-mediated IL4 signalling, and that IL4 may represent a potential therapeutic target, allowing the prevention of M2 macrophage activation and fibroblast-to-myofibroblast differentiation. PMID- 29988033 TI - alpha-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis. AB - Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described alpha ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular alpha-ketoglutarate (alpha-KG) accumulation. Consequently, the activity of the alpha-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an alpha-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an alpha-KG-dependent epigenetic regulation of the TET-miR200 Zeb1/CtBP1-MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis. PMID- 29988034 TI - Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice. AB - Progressive pancreatic beta-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes (T2D). Recently, mesenchymal stem cells (MSCs) have been identified in protection of islets function in T2D individuals. However, the underlying mechanisms remain elusive. It is widely accepted that beta-cell dysfunction is closely related to improper accumulation of macrophages in the islets, and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state. In this study, we induced a T2D mouse model with a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ), and then performed human umbilical cord-derived MSCs (hUC-MSCs) infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets. hUC-MSCs infusion exerted anti-diabetic effects and significantly promoted islets recovery in T2D mice. Interestingly, pancreatic inflammation was remarkably suppressed, and local M1 macrophages were directed toward an anti inflammatory M2-like state after hUC-MSC infusion. In vitro study also proved that hUC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs) and in THP-1 cells. Further analysis showed that M1-stimulated hUC-MSCs increased the secretion of interleukin (IL)-6, blocking which by small interfering RNA (siRNA) largely abrogated the hUC-MSCs effects on macrophages both in vitro and in vivo, resulting in dampened restoration of beta-cell function and glucose homeostasis in T2D mice. In addition, MCP-1 was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state. These data may provide new clues for searching for the target of beta-cell protection. Furthermore, hUC-MSCs may be a superior alternative in treating T2D for their macrophage polarization effects. PMID- 29988035 TI - Author Correction: Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding. AB - In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to also include support from the National Institutes of Health grant T32GM008280 to Sarah Alvarado. PMID- 29988036 TI - Author Correction: HuR regulates telomerase activity through TERC methylation. AB - In the original version of this Article, the affiliation details for Fan Yang were incorrectly given as 'Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China' and 'Leibniz Institute for Age Research - Fritz Lipmann Institute, Friedrich-Schiller University of Jena, Jena, 07745, Germany'. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29988037 TI - Author Correction: Next generation histology methods for three-dimensional imaging of fresh and archival human brain tissues. AB - In the original version of this Article, the concentration of boric acid buffer for the SDS clearing solution was given incorrectly as '1 M sodium borate' and should have read '0.2 M boric acid'. Also, the composition of PBST incorrectly read '1% Triton X-100 (vol/vol) and 0.1% sodium azide (wt/vol)' and should have read '0.1% Triton X-100 (vol/vol) and 0.01% sodium azide (wt/vol)'. Further, the pH of the OPTIClear solution was not stated, and should have read 'with a pH between 7 to 8 adjusted with hydrochloric acid'. These errors have been corrected in both the PDF and HTML versions of the Article. PMID- 29988038 TI - ER stress regulating protein phosphatase 2A-B56gamma, targeted by hepatitis B virus X protein, induces cell cycle arrest and apoptosis of hepatocytes. AB - Hepatitis B virus X (HBx) protein contributes to the progression of hepatitis B virus (HBV)-related hepatic injury and diseases, but the exact mechanism remains unclear. Protein phosphatase 2 A (PP2A) is a major serine/threonine phosphatase involved in regulating many cellular phosphorylation signals that are important for regulation of cell cycle and apoptosis. Does HBx target to PP2A-B56gamma and therefore affect HBx-induced hepatotoxicity? In the present study, the expression of B56gamma positively correlated with the level of HBx in HBV-infected primary human hepatocytes in human-liver-chimeric mice, HBx-transgenic mice, HBV-infected cells, and HBx-expressing hepatic cells. B56gamma promoted p53/p21-dependent cell cycle arrest and apoptosis. Mechanistically, B56gamma was transactivated by AP-1, which was under the regulation of endoplasmic reticulum (ER) stress induced CREBH signaling in HBx-expressing hepatic cells. B56gamma dephosphorylated p-Thr55-p53 to trigger p53/p21 pathway-dependent cell cycle G1 phase arrest, resulting in apoptosis of hepatic cells. In conclusion, this study provides a novel insight into a mechanism of B56gamma mediating cell cycle arrest and apoptosis of HBx expressing hepatic cells and a basis for B56gamma being a potential therapeutic target for HBV-infected hepatic cells. PMID- 29988039 TI - Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. AB - Glutathione (GSH) protects against oxidative damage in many tissues, including retinal pigment epithelium (RPE). Oxidative stress-mediated senescence and death of RPE and subsequent death of photoreceptors have been observed in age-related macular degeneration (AMD). Although the consequences of GSH depletion have been described previously, questions remain regarding the molecular mechanisms. We herein examined the downstream effects of GSH depletion on stress-induced premature senescence (SIPS) and cell death in human RPE cells. Briefly, cultured ARPE-19 cells were depleted of GSH using: (1) incubation in cystine (Cys2)-free culture medium; (2) treatment with buthionine sulphoximine (BSO, 1000 uM) to block de novo GSH synthesis for 24-48 h; or (3) treatment with erastin (10 uM for 12-24 h) to inhibit Cys2/glutamate antiporter (system xc-). These treatments decreased cell viability and increased both soluble and lipid reactive oxygen species (ROS) generation but did not affect mitochondrial ROS or mitochondrial mass. Western blot analysis revealed decreased expression of ferroptotic modulator glutathione peroxidase 4 (GPX4). Increased autophagy was apparent, as reflected by increased LC3 expression, autophagic vacuoles, and autophagic flux. In addition, GSH depletion induced SIPS, as evidenced by increased percentage of the senescence-associated beta-galactosidase-positive cells, increased senescence associated heterochromatin foci (SAHF), as well as cell cycle arrest at the G1 phase. GSH depletion-dependent cell death was prevented by selective ferroptosis inhibitors (8 MUM Fer-1 and 600 nM Lip-1), iron chelator DFO (80 MUM), as well as autophagic inhibitors Baf-A1 (75 nM) and 3-MA (10 mM). Inhibiting autophagy with Baf-A1 (75 nM) or 3-MA (10 mM) promoted SIPS. In contrast, inducing autophagy with rapamycin (100 nM) attenuated SIPS. Our findings suggest that GSH depletion induces ferroptosis, autophagy, and SIPS. In addition, we found that autophagy is activated in the process of ferroptosis and reduces SIPS, suggesting an essential role of autophagy in ferroptosis and SIPS. PMID- 29988041 TI - Increased Use of Medications for Erectile Dysfunction in Men With Ulcerative Colitis and Crohn's Disease Compared to Men Without Inflammatory Bowel Disease: A Nationwide Cohort Study. AB - BACKGROUND: Men with inflammatory bowel disease (IBD) may have decreased sexual function due to factors related to the underlying disease, medication, and/or surgery. We aimed to examine the use of erectile dysfunction (ED) medications in men with IBD. METHODS: This is a nationwide cohort study based on the Danish registries, comprising all men >18 years old with IBD during 1 January 1995 through December 2016. The cohorts included 31,498 men with IBD and 314,980 age matched men without IBD. Our main outcome was a first prescription of an ED medication. Cox regression analyses were used to estimate the hazard rate (HR) for use of ED medications, controlled for multiple time-varying covariates. RESULTS: Overall, 21,966 (69.7%) men had ulcerative colitis (UC) while 9532 (30.3%) had Crohn's disease (CD). Men with a first ED prescription numbered 3749 (11.9%) (men with IBD) and 30,635 (9.7%) (men without IBD). Adjusting for central nervous system and intestinal anti-inflammatory medications, systemic corticosteroids and co-morbidities, the HR was 1.19 (95% CI: 1.13-1.26) (IBD and no prior IBD operation), and 1.31 (95% CI: 1.20-1.43) (IBD and prior IBD operation). The adjusted HR for UC was 1.17 (95% CI: 1.10-1.24) (no operation) and 1.43 (95% CI: 1.27-1.61) (prior operation), and for CD 1.26 (95% CI: 1.15 1.38) (no operation) and 1.20 (95% CI: 1.06-1.35) (prior operation). DISCUSSION: Men with IBD are more likely to fill an ED prescription than men without IBD. This result is significant regardless of a history of IBD surgery. PMID- 29988042 TI - Publisher Correction: Post-translational modifications in DNA topoisomerase 2alpha highlight the role of a eukaryote-specific residue in the ATPase domain. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29988040 TI - Annonacin promotes selective cancer cell death via NKA-dependent and SERCA dependent pathways. AB - In the healthcare sector, phytocompounds are known to be beneficial by contributing or alleviating a variety of diseases. Studies have demonstrated the progressive effects of phytocompounds on immune-related diseases and to exhibit anticancer effects. Graviola tree is an evergreen tree with its extracts (leafs and seeds) been reported having anticancer properties, but the precise target of action is not clear. Using an in silico approach, we predicted that annonacin, an Acetogenin, the active agent found in Graviola leaf extract (GLE) to potentially act as a novel inhibitor of both sodium/potassium (NKA) and sarcoplasmic reticulum (SERCA) ATPase pumps. We were able to validate and confirm the in silico studies by showing that GLE inhibited NKA and SERCA activity in intact cells. In the present study, we also demonstrated the antiproliferative and anticancer effects of GLE in a variety of cancer cell lines with limited toxic effects on non-transformed cells. Moreover, our results revealed that known inhibitors of both NKA and SERCA pumps could also promote cell death in several cancer cell lines. In addition, a mouse xenograft cancer model showed GLE as able to reduce tumor size and progression. Finally, bioprofiling studies indicated a strong correlation between overexpression of both NKA and SERCA gene expression vs. survival rates. Overall, our results demonstrated that GLE can promote selective cancer cell death via inhibiting NKA and SERCA, and thus can be considered as a potential novel treatment for cancer. After molecular analysis of GLE by liquid chromatography-mass spectrometry and ESI-QTOF-MS analysis, it was found that the MS spectrum of the high abundant chromatographic peak purified sample highly consisted of annonacin. PMID- 29988043 TI - Is there a link between stress and autoimmunity? PMID- 29988044 TI - Pain relief with secukinumab treatment. PMID- 29988045 TI - Predicting progression to disease in an at-risk cohort. PMID- 29988046 TI - Understanding immunopathology of sacroiliitis. PMID- 29988047 TI - Growth factors respond to cartilage damage. PMID- 29988049 TI - Graphene quantum dots prevent alpha-synucleinopathy in Parkinson's disease. AB - Though emerging evidence indicates that the pathogenesis of Parkinson's disease is strongly correlated to the accumulation1,2 and transmission3,4 of alpha synuclein (alpha-syn) aggregates in the midbrain, no anti-aggregation agents have been successful at treating the disease in the clinic. Here, we show that graphene quantum dots (GQDs) inhibit fibrillization of alpha-syn and interact directly with mature fibrils, triggering their disaggregation. Moreover, GQDs can rescue neuronal death and synaptic loss, reduce Lewy body and Lewy neurite formation, ameliorate mitochondrial dysfunctions, and prevent neuron-to-neuron transmission of alpha-syn pathology provoked by alpha-syn preformed fibrils5,6. We observe, in vivo, that GQDs penetrate the blood-brain barrier and protect against dopamine neuron loss induced by alpha-syn preformed fibrils, Lewy body/Lewy neurite pathology and behavioural deficits. PMID- 29988048 TI - African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat. AB - The African trypanosome Trypanosoma brucei spp. is a paradigm for antigenic variation, the orchestrated alteration of cell surface molecules to evade host immunity. The parasite elicits robust antibody-mediated immune responses to its variant surface glycoprotein (VSG) coat, but evades immune clearance by repeatedly accessing a large genetic VSG repertoire and 'switching' to antigenically distinct VSGs. This persistent immune evasion has been ascribed exclusively to amino-acid variance on the VSG surface presented by a conserved underlying protein architecture. We establish here that this model does not account for the scope of VSG structural and biochemical diversity. The 1.4-A resolution crystal structure of the variant VSG3 manifests divergence in the tertiary fold and oligomeric state. The structure also reveals an O-linked carbohydrate on the top surface of VSG3. Mass spectrometric analysis indicates that this O-glycosylation site is heterogeneously occupied in VSG3 by zero to three hexose residues and is also present in other VSGs. We demonstrate that this O-glycosylation increases parasite virulence by impairing the generation of protective immunity. These data alter the paradigm of antigenic variation by the African trypanosome, expanding VSG variability beyond amino-acid sequence to include surface post-translational modifications with immunomodulatory impact. PMID- 29988051 TI - Estimate suggests many infant deaths in sub-Saharan Africa attributable to air pollution. PMID- 29988050 TI - Superfast DNA replication causes damage in cancer cells. PMID- 29988052 TI - Self-organizing multicellular structures designed using synthetic biology. PMID- 29988055 TI - The imperial roots of climate science. PMID- 29988058 TI - How rats wreak havoc on coral reefs. PMID- 29988060 TI - How to start a lab when funds are tight. PMID- 29988061 TI - Haploidentical versus matched donor stem cell transplantation for patients with hematological malignancies: a systemic review and meta-analysis. AB - We compared the safety and efficacy of haploidentical stem cell transplantation (haplo-SCT) to matched donor SCT (matched-SCT) in treating hematological malignancies. The Medline, Cochrane, EMBASE, and Google Scholar databases were searched through 21 June 2017 using the search term "(hematological disease) AND matched AND (haploidentical OR haplo-identical OR haplo identical OR haplo transplantation OR haplo transplant OR haplo-SCT OR haplo-HSCT OR haplo-HCT)." Twenty-five studies enrolling 11,359 patients (haplo-SCT: 2677; matched-SCT: 8682) were included. The primary outcomes were acute and chronic graft-versus host disease (GVHD), non-relapse mortality, and 1-year cumulative incidence of relapse. Haplo-SCT was associated with similar risks as matched-SCT for all primary endpoints. Subgroup analysis of patients who received a matched-SCT from a related donor revealed that patients who received haplo-SCT had a lower risk of acute GVHD. Among patients who received reduced-intensity conditioning (RIC), those who received haplo-SCT had a higher risk of acute grade II-IV GVHD and non relapse mortality than did patients who received a matched-SCT from a related or unrelated donor. Haplo-SCT should continue to be considered as a safe and effective transplant option when a matched donor is unavailable, but it may not be suitable for patients who receive RIC. PMID- 29988062 TI - Utilization of hematopoietic stem cell transplantation for the treatment of multiple myeloma: a Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus statement. AB - Over the last two decades, the utilization of various novel therapies in the upfront or salvage settings has continued to improve survival outcomes for patients with Multiple Myeloma (MM). Thus, the conventional role for hematopoietic stem cell transplantation (HSCT) in MM either in the form of an autologous stem cell transplant (ASCT) or an allogeneic stem cell transplant (Allo-SCT) warrants re-evaluation, given the aforementioned clinical advances. Here, we present a consensus statement of our multidisciplinary group of over 30 Mayo Clinic physicians with a special interest in the care of patients with MM and provide evidence-based recommendations on the use of HSCT in MM. We specifically address topics that include the role and timing of an ASCT for MM in the era of novel agents, eligibility for an ASCT, post-ASCT consolidation, and maintenance options, and finally the utility of an upfront tandem ASCT, salvage second ASCT, and an allo-SCT in MM. PMID- 29988063 TI - Patient eligibility for hematopoietic stem cell transplantation: a review of patient-associated variables. AB - Assessing patient eligibility for hematopoietic stem cell transplantation (HSCT) remains a complex, multifaceted challenge. Among these challenges, the paucity of comprehensive clinical data to guide decision making remains problematic coupled with unclear trade-offs between patient, disease and local HSCT center factors. Moreover, it is unclear that the modification of poor patient characteristics will improve post-HSCT outcomes. However, the use of Comorbidity Indices and Comprehensive Geriatric Assessments helps meet this challenge, but may be limited by overlapping patient characteristics. The increasing consideration for pre-HSCT psychosocial assessments and interventions remains to be studied. Ultimately, the decision to proceed with a HSCT remains interdisciplinary while considering the available evidence discussed in this review. PMID- 29988064 TI - Environmental radiation alters the gut microbiome of the bank vole Myodes glareolus. AB - Gut microbiota composition depends on many factors, although the impact of environmental pollution is largely unknown. We used amplicon sequencing of bacterial 16S rRNA genes to quantify whether anthropogenic radionuclides at Chernobyl (Ukraine) impact the gut microbiome of the bank vole Myodes glareolus. Exposure to elevated levels of environmental radionuclides had no detectable effect on the gut community richness but was associated with an almost two-fold increase in the Firmicutes:Bacteroidetes ratio. Animals inhabiting uncontaminated areas had remarkably similar gut communities irrespective of their proximity to the nuclear power plant. Hence, samples could be classified to high-radiation or low-radiation sites based solely on microbial community with >90% accuracy. Radiation-associated bacteria had distinct inferred functional profiles, including pathways involved in degradation, assimilation and transport of carbohydrates, xenobiotics biodegradation, and DNA repair. Our results suggest that exposure to environmental radionuclides significantly alters vertebrate gut microbiota. PMID- 29988066 TI - PAINTing translation. PMID- 29988065 TI - Lack of evidence for a causal role of CALR3 in monogenic cardiomyopathy. AB - The pathogenicity of previously published disease-associated genes and variants is sometimes questionable. Large-scale, population-based sequencing studies have uncovered numerous false assignments of pathogenicity. Misinterpretation of sequence variants may have serious implications for the patients and families involved, as genetic test results are increasingly being used in medical decision making. In this study, we assessed the role of the calreticulin-3 gene (CALR3) in cardiomyopathy. CALR3 has been included in several cardiomyopathy gene panels worldwide. Its inclusion is based on a single publication describing two missense variants in patients with hypertrophic cardiomyopathy. In our national cardiomyopathy cohort (n = 6154), we identified 17 unique, rare heterozygous CALR3 variants in 48 probands. Overall, our patient cohort contained a significantly higher number of rare CALR3 variants compared to the ExAC population (p = 0.0036). However, after removing a potential Dutch founder variant, no statistically significant difference was found (p = 0.89). In nine probands, the CALR3 variant was accompanied by a disease-causing variant in another, well-known cardiomyopathy gene. In three families, the CALR3 variant did not segregate with the disease. Furthermore, we could not demonstrate calreticulin-3 protein expression in myocardial tissues at various ages. On the basis of these findings, it seems highly questionable that variants in CALR3 are a monogenic cause of cardiomyopathy. PMID- 29988067 TI - Noncanonical translation via deadenylated 3' UTRs maintains primordial germ cells. AB - Primordial germ cells (PGCs) form during early embryogenesis with a supply of maternal mRNAs that contain shorter poly(A) tails. How translation of maternal mRNAs is regulated during PGC development remains elusive. Here we describe a small-molecule screen with zebrafish embryos that identified primordazine, a compound that selectively ablates PGCs. Primordazine's effect on PGCs arises from translation repression through primordazine-response elements in the 3' UTRs. Systematic dissection of primordazine's mechanism of action revealed that translation of mRNAs during early embryogenesis occurs by two distinct pathways, depending on the length of their poly(A) tails. In addition to poly(A)-tail dependent translation (PAT), early embryos perform poly(A)-tail-independent noncanonical translation (PAINT) via deadenylated 3' UTRs. Primordazine inhibits PAINT without inhibiting PAT, an effect that was also observed in quiescent, but not proliferating, mammalian cells. These studies reveal that PAINT is an alternative form of translation in the early embryo and is indispensable for PGC maintenance. PMID- 29988068 TI - Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle. AB - Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex. PMID- 29988069 TI - The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. AB - Early prenatal stress disrupts maternal-to-offspring microbiota transmission and has lasting effects on metabolism, physiology, cognition, and behavior in male mice. Here we show that transplantation of maternal vaginal microbiota from stressed dams into naive pups delivered by cesarean section had effects that partly resembled those seen in prenatally stressed males. However, transplantation of control maternal vaginal microbiota into prenatally stressed pups delivered by cesarean section did not rescue the prenatal-stress phenotype. Prenatal stress was associated with alterations in the fetal intestinal transcriptome and niche, as well as with changes in the adult gut that were altered by additional stress exposure in adulthood. Further, maternal vaginal transfer also partially mediated the effects of prenatal stress on hypothalamic gene expression, as observed after chronic stress in adulthood. These findings suggest that the maternal vaginal microbiota contribute to the lasting effects of prenatal stress on gut and hypothalamus in male mice. PMID- 29988070 TI - Author Correction: Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear. AB - In the version of this article initially published, the traces in Fig. 1j and in Fig. 1k, right, were duplicated from the corresponding traces in Fig. 1c, bottom, and Fig. 1d, bottom right. The error has been corrected in the HTML and PDF versions of the article. PMID- 29988071 TI - Ocular morbidity in natural disasters: field hospital experience 2010-2015. AB - PURPOSE: To determine the characteristics of ocular injuries treated by Israel Defense Forces (IDF) field hospital following three natural disasters: the 2010 earthquake in Haiti, the 2013 typhoon in the Philippines, and the 2015 earthquake and avalanche in Nepal. The purpose was to provide data, which would assist allocation of ocular resources for future disasters. DESIGN: Retrospective database study. METHODS: Ocular clinical data collected from the IDF database. Time postdisaster was divided into three periods: 4-8, 9-12, and 13-16 days. Diagnoses were categorized as disaster-related (DRD), defined as directly resulting from the disaster (mostly ocular trauma), and nondisaster-related (NDRD), defined as preexisting conditions or results of postevent living conditions problems. RESULTS: The field hospitals began functioning 3-8 days after the disaster and continued for 10.3 +/- 1.5 days. Ocular conditions were treated in 265 (4.9%) of the total 5356 patients. Sixty-five cases were DRD and 200 were NDRD. Around day 9 postdisaster the predominant ocular referral changed from DRD to NDRD. CONCLUSIONS: Deployment of a field hospital to a natural disaster area should take into account the type and geographic location of the disaster as well as the high number of nontraumatic ocular conditions. PMID- 29988072 TI - Efficacy of selective laser trabeculoplasty in primary angle closure disease. AB - BACKGROUND: To study the role of selective laser trabeculoplasty (SLT) in intraocular pressure (IOP) reduction in post-laser iridotomy primary angle closure disease patients with inadequately controlled IOP. METHODS: In this prospective cross-sectional study, 34 patients with primary angle-closure disease with post-laser iridotomy open angles up to at least 180 degrees were recruited. Following SLT, patients were examined at 1 day, 1 week, 1 and 3 months, 6 months and 1 year post SLT. RESULTS: Data of 34 patients (34 eyes; 8 males and 26 females), with a mean age of 57.80 +/- 6.44 years, were analysed. The reduction in IOP at each follow-up visit was significant (p < 0.001). The maximum reduction in IOP was noticed on post-laser day 1 and the least reduction was noticed 1 week post laser. Post-SLT range of IOP reduction varied from 9 to 46% at 1 year, which indicates the variability of a response to SLT. Mean IOP in both primary angle closure (PAC) and primary angle closure glaucoma (PACG) groups was comparable at all visits except at post-SLT week 1 when IOP in the PACG group was significantly higher than that in the PAC group (p = 0.035). None of the patients complained of pain and/or discomfort or had any clinically significant anterior segment inflammation on any of the follow-up visits. None of the patients underwent repeat SLT or surgery. The mean pre-SLT and post-SLT visual field index at 1-year follow-up was 95.47 +/- 3.58 and 95.90 +/- 4.13, respectively, which was not significant (p = 0.84). CONCLUSIONS: High baseline IOP significantly correlated with reduction in IOP. Our results suggest that SLT is a safe, cost-effective modality for reducing IOP in primary angle-closure disease with patent laser iridotomy with a visible trabecular meshwork. PMID- 29988074 TI - Christmas tree cataract and myotonic dystrophy type 1. PMID- 29988073 TI - Gender variation in central serous chorioretinopathy. AB - BACKGROUND: Comparison of presentation and outcomes of central serous chorioretinopathy (CSC) between male and female subjects in different ethnic populations. METHODS: Retrospective comparison between male and female subjects with CSC was completed. Demographic details, clinical presentations, imaging features and treatment outcomes were compared at baseline and at last follow-up. RESULTS: This study included 155 male and 155 female subjects with a mean (CSD) age of 43.8 +/- 10.3 and 57.0 +/- 12.1 years, respectively, and a mean duration of follow-up of 8.49 +/- 12.6 months. At presentation, there was no difference in visual acuity; however, visual acuity was significantly higher for female subjects at last follow-up (p = 0.02). Optical coherence tomography (OCT) analysis showed that subretinal deposits (p < 0.001), hyperreflective foci (p = 0.001), retinal pigment epithelial detachment (p = 0.01) and retinal pigment epithelium (RPE) irregularities (p = 0.03) were higher in male subjects at presentation. Angiographic analysis showed that diffuse leakage and RPE tracts were common in males (p = 0.01 and p = 0.02). No significant differences in choroidal dilatation or diffuse choroidal leakages were noted. CONCLUSIONS: Female subjects with CSC appear to have better outcomes, with less chances of diffuse RPE damage and other OCT features compared to males. PMID- 29988075 TI - Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. AB - Platinum-based chemotherapies can result in ovarian insufficiency by reducing the ovarian reserve, a reduction believed to result from apoptosis of immature oocytes via activation/phosphorylation of TAp63alpha by multiple kinases including CHEK2, CK1, and ABL1. Here we demonstrate that cisplatin (CDDP) induces oocyte apoptosis through a novel pathway and that temporary repression of this pathway fully preserves ovarian function in vivo. Although ABL kinase inhibitors effectively block CDDP-induced apoptosis of oocytes, oocytic ABL1, and ABL2 are dispensable for damage-induced apoptosis. Instead, CDDP activates TAp63alpha through the ATR > CHEK1 pathway independent of TAp63alpha hyper-phosphorylation, whereas X-irradiation activates the ATM > CHEK2 > TAp63alpha-hyper phosphorylation pathway. Furthermore, oocyte-specific deletion of Trp73 partially protects oocytes from CDDP but not from X-ray, highlighting the fundamental differences of two pathways. Nevertheless, temporary repression of DNA damage response by a kinase inhibitor that attenuates phosphorylation of ATM, ATR, CHEK1, and CHEK2 fully preserves fertility in female mice against CDDP as well as X-ray. Our current study establishes the molecular basis and feasibility of adjuvant therapies to protect ovarian function against two distinctive gonadotoxic therapeutics, CDDP, and ionizing radiation. PMID- 29988076 TI - SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2. AB - The progression of localized breast cancer to distant metastasis results in a poor prognosis and a high mortality rate. In this study, the contributions of miRNAs to tumor progression and the regulatory mechanisms leading to their expression alterations were investigated. Using highly lung-metastatic sub-lines from parental breast cancer cells, miRNA expression profiling revealed that the miR-17-92 cluster is significantly downregulated and the miR-18a-5p is the most evidently decreased. Ectopic expression and inhibition of miR-18a-5p demonstrated its capacity in suppressing migration and invasion of breast cancer cells. Further research identified sterol regulatory element binding transcription protein 1 (SREBP1), the master transcription factor that controls lipid metabolism, as a candidate target of miR-18a-5p. SREBP1 is overexpressed and strongly associated with worse clinical outcomes in breast cancer. Functionally SREBP1 promotes growth and metastasis of breast cancer both in vitro and in vivo. To unravel the underlying mechanism of SREBP1-mediated metastasis, mRNA profiling and subsequent gene set enrichment analyses (GSEA) were performed and SREBP1 was demonstrated to be significantly associated with epithelial-mesenchymal transition (EMT). Furthermore, SREBP1-mediated repression of E-cadherin was found to be deacetylation dependent and was augmented by recruiting Snail/HDAC1/2 repressor complex. In the light of these data, we propose that reduced expression of miR-18a-5p and concomitant overexpression of SREBP1 lead to induction of EMT states that in turn, promote breast cancer progression and metastasis. Taken together, our study reveals the crucial role of miR-18a-5p and SREBP1 in the EMT and metastasis, thus providing promising drug targets for tailored therapy in the advanced breast cancer setting. PMID- 29988077 TI - Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 HBOC families. AB - PURPOSE: Integration of gene panels in the diagnosis of hereditary breast and ovarian cancer (HBOC) requires a careful evaluation of the risk associated with pathogenic or likely pathogenic variants (PVs) detected in each gene. Here we analyzed 34 genes in 5131 suspected HBOC index cases by next-generation sequencing. METHODS: Using the Exome Aggregation Consortium data sets plus 571 individuals from the French Exome Project, we simulated the probability that an individual from the Exome Aggregation Consortium carries a PV and compared it to the estimated frequency within the HBOC population. RESULTS: Odds ratio conferred by PVs within BRCA1, BRCA2, PALB2, RAD51C, RAD51D, ATM, BRIP1, CHEK2, and MSH6 were estimated at 13.22 [10.01-17.22], 8.61 [6.78-10.82], 8.22 [4.91-13.05], 4.54 [2.55-7.48], 5.23 [1.46-13.17], 3.20 [2.14-4.53], 2.49 [1.42-3.97], 1.67 [1.18 2.27], and 2.50 [1.12-4.67], respectively. PVs within RAD51C, RAD51D, and BRIP1 were associated with ovarian cancer family history (OR = 11.36 [5.78-19.59], 12.44 [2.94-33.30] and 3.82 [1.66-7.11]). PALB2 PVs were associated with bilateral breast cancer (OR = 16.17 [5.48-34.10]) and BARD1 PVs with triple negative breast cancer (OR = 11.27 [3.37-25.01]). Burden tests performed in both patients and the French Exome Project population confirmed the association of PVs of BRCA1, BRCA2, PALB2, and RAD51C with HBOC. CONCLUSION: Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of HBOC and suggest that the other genes are involved in an oligogenic determinism. PMID- 29988078 TI - Accelerating evidence gathering and approval of precision medicine therapies: the FDA takes aim at rare mutations. PMID- 29988079 TI - Navigating the nuances of clinical sequence variant interpretation in Mendelian disease. AB - Understanding clinical genetic test results in the era of next-generation sequencing has become increasingly complex, necessitating clear and thorough guidelines for sequence variant interpretation. To meet this need the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for a systematic approach for sequence variant interpretation in 2015. This framework is intended to be adaptable to any Mendelian condition, promoting transparency and consistency in variant interpretation, yet its comprehensive nature yields important challenges and caveats that end users must understand. In this review, we address some of these nuances and discuss the evolving efforts to refine and adapt this framework. We also consider the added complexity of distinguishing between variant-level interpretations and case-level conclusions, particularly in the context of the large gene panel approach to clinical diagnostics. PMID- 29988080 TI - The functional impact of variants of uncertain significance in BRCA2. AB - PURPOSE: Genetic testing has uncovered large numbers of variants in the BRCA2 gene for which the clinical significance is unclear. Cancer risk prediction of these variants of uncertain significance (VUS) can be improved by reliable assessment of the extent of impairment of the tumor suppressor function(s) of BRCA2. METHODS: Here, we evaluated the performance of the mouse embryonic stem cell (mESC)-based functional assay on an extensive set of BRCA2 missense variants. RESULTS: Whereas all 20 nonpathogenic (class 1/2) variants were able to complement the cell lethal phenotype induced by loss of endogenous mouse Brca2, only 1 out of 15 pathogenic (class 4/5) variants (p.Gly2609Asp) was able to do so. However, in this variant the major tumor suppressive activity of BRCA2, i.e., homology directed repair (HDR), was severely abrogated. Among 43 evaluated VUS (class 3), 7 were unable to complement the lethal phenotype of mouse Brca2 loss while 7 other variants displayed a more severe reduction of HDR activity than observed for class 1/ 2 variants. CONCLUSION: The mESC-based BRCA2 functional assay can reliably determine the functional impact of VUS, distinguish between pathogenic and nonpathogenic variants, and may contribute to improved cancer risk estimation for BRCA2 VUS carriers. PMID- 29988081 TI - A two-million-year-long hydroclimatic context for hominin evolution in southeastern Africa. AB - The past two million years of eastern African climate variability is currently poorly constrained, despite interest in understanding its assumed role in early human evolution1-4. Rare palaeoclimate records from northeastern Africa suggest progressively drier conditions2,5 or a stable hydroclimate6. By contrast, records from Lake Malawi in tropical southeastern Africa reveal a trend of a progressively wetter climate over the past 1.3 million years7,8. The climatic forcings that controlled these past hydrological changes are also a matter of debate. Some studies suggest a dominant local insolation forcing on hydrological changes9-11, whereas others infer a potential influence of sea surface temperature changes in the Indian Ocean8,12,13. Here we show that the hydroclimate in southeastern Africa (20-25 degrees S) is controlled by interplay between low-latitude insolation forcing (precession and eccentricity) and changes in ice volume at high latitudes. Our results are based on a multiple-proxy reconstruction of hydrological changes in the Limpopo River catchment, combined with a reconstruction of sea surface temperature in the southwestern Indian Ocean for the past 2.14 million years. We find a long-term aridification in the Limpopo catchment between around 1 and 0.6 million years ago, opposite to the hydroclimatic evolution suggested by records from Lake Malawi. Our results, together with evidence of wetting at Lake Malawi, imply that the rainbelt contracted toward the Equator in response to increased ice volume at high latitudes. By reducing the extent of woodland or wetlands in terrestrial ecosystems, the observed changes in the hydroclimate of southeastern Africa-both in terms of its long-term state and marked precessional variability-could have had a role in the evolution of early hominins, particularly in the extinction of Paranthropus robustus. PMID- 29988084 TI - Shank3 mutation in a mouse model of autism leads to changes in the S-nitroso proteome and affects key proteins involved in vesicle release and synaptic function. AB - Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO*)-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions. SNO proteins in two ASD-related brain regions, cortex and striatum of young and adult InsG3680(+/+) mice (a human mutation-based Shank3 mouse model), were identified by an innovative mass spectrometric method, SNOTRAP. We found changes of the SNO proteome in the mutant compared to WT in both ages. Pathway analysis showed enrichment of processes affected in ASD. SNO-Calcineurin in mutant led to a significant increase of phosphorylated Synapsin1 and CREB, which affect synaptic vesicle mobilization and gene transcription, respectively. A significant increase of 3-nitrotyrosine was found in the cortical regions of the adult mutant, signaling both oxidative and nitrosative stress. Neuronal NO* Synthase (nNOS) was examined for levels and localization in neurons and no significant difference was found in WT vs. mutant. S-nitrosoglutathione concentrations were higher in mutant mice compared to WT. This is the first study on NO*-related molecular changes and SNO-signaling in the brain of an ASD mouse model that allows the characterization and identification of key proteins, cellular pathways, and neurobiological mechanisms that might be affected in ASD. PMID- 29988083 TI - A rare loss-of-function variant of ADAM17 is associated with late-onset familial Alzheimer disease. AB - Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Abeta formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD. PMID- 29988082 TI - Prediction of acute myeloid leukaemia risk in healthy individuals. AB - The incidence of acute myeloid leukaemia (AML) increases with age and mortality exceeds 90% when diagnosed after age 65. Most cases arise without any detectable early symptoms and patients usually present with the acute complications of bone marrow failure1. The onset of such de novo AML cases is typically preceded by the accumulation of somatic mutations in preleukaemic haematopoietic stem and progenitor cells (HSPCs) that undergo clonal expansion2,3. However, recurrent AML mutations also accumulate in HSPCs during ageing of healthy individuals who do not develop AML, a phenomenon referred to as age-related clonal haematopoiesis (ARCH)4-8. Here we use deep sequencing to analyse genes that are recurrently mutated in AML to distinguish between individuals who have a high risk of developing AML and those with benign ARCH. We analysed peripheral blood cells from 95 individuals that were obtained on average 6.3 years before AML diagnosis (pre-AML group), together with 414 unselected age- and gender-matched individuals (control group). Pre-AML cases were distinct from controls and had more mutations per sample, higher variant allele frequencies, indicating greater clonal expansion, and showed enrichment of mutations in specific genes. Genetic parameters were used to derive a model that accurately predicted AML-free survival; this model was validated in an independent cohort of 29 pre-AML cases and 262 controls. Because AML is rare, we also developed an AML predictive model using a large electronic health record database that identified individuals at greater risk. Collectively our findings provide proof-of-concept that it is possible to discriminate ARCH from pre-AML many years before malignant transformation. This could in future enable earlier detection and monitoring, and may help to inform intervention. PMID- 29988086 TI - Adiponectin modulates ventral tegmental area dopamine neuron activity and anxiety related behavior through AdipoR1. AB - Adiponectin, a metabolic hormone secreted by adipocytes, can cross the blood brain barrier to act on neurons in different brain regions, including those involved in stress-related disorders. Here we show that dopamine neurons in the ventral tegmental area (VTA) express adiponectin receptor 1 (AdipoR1). Intra-VTA infusion of adiponectin or the adiponectin mimetic AdipoRon in wild-type mice decreases basal dopamine neuron population activity and firing rate and reverses the restraint stress-induced increase in dopamine neuron activity and anxiety behavior. Adiponectin haploinsufficiency leads to increased dopamine neuron firing and anxiety behavior under basal conditions. Ablation of AdipoR1 specifically from dopamine neurons enhances neuronal and anxiogenic responses to restraint stress. The effects of intra-VTA infusion of adiponectin on neuronal activity and behavior were abolished in mice lacking AdipoR1 in dopamine neurons. These observations indicate that adiponectin can directly modulate VTA dopamine neuron activity and anxiety behavior, and that AdipoR1 is required for adiponectin-induced inhibition of dopamine neurons and anxiolytic effects. These results strengthen the idea of adiponectin as a key biological factor that links metabolic syndrome and emotional disorders. PMID- 29988087 TI - Leucine competes with kynurenine for blood-to-brain transport and prevents lipopolysaccharide-induced depression-like behavior in mice. AB - Inflammation activates indoleamine 2,3-dioxygenase (IDO) which metabolizes tryptophan into kynurenine. Circulating kynurenine is transported into the brain by the large amino transporter LAT1 at the level of the blood-brain barrier. We hypothesized that administration of leucine that has a high affinity for LAT1 should prevent the entry of kynurenine into the brain and attenuate the formation of neurotoxic kynurenine metabolites. To test whether leucine could prevent inflammation-induced depression-like behavior, mice were treated with lipopolysaccharide (LPS, 0.83 mg/kg IP) or saline and treated with L-leucine (50 mg/kg, IP) or vehicle administered before and 6 h after LPS. Depression-like behavior was measured by increased duration of immobility in the forced swim test and decreased sucrose preference. Leucine decreased brain kynurenine levels, blocked LPS-induced depression-like behavior and had antidepressant-like effects in control mice. Leucine had no effect of its own on sickness behavior and neuroinflammation. To confirm that leucine acts by interfering with the transport of kynurenine into the brain, mice were injected with L-leucine (300 mg/kg, IP) immediately before kynurenine (33 mg/kg IP) and brain kynurenine and depression like behavior were measured 3 h later. Leucine did prevent the entry of exogenous kynurenine into the brain and abrogated depression-like behavior measured by increased duration of immobility in the forced swim test. Additional experiments using an in vitro model of the blood-brain barrier confirmed that kynurenine competes with leucine at the level of the amino acid transporter LAT1 for brain uptake. These experiments also revealed that efflux was the dominant direction of kynurenine transport and was largely independent of LAT1 and leucine, which explains why leucine could block brain uptake of kynurenine without affecting brain clearance. These findings demonstrate that leucine has antidepressant properties vis-a-vis inflammation-induced depression and one mechanism for this is by blocking the ability of kynurenine to enter the brain. PMID- 29988088 TI - An RNA checkpoint that keeps immunological memory at bay. PMID- 29988089 TI - Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells. AB - Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3' untranslated region (3' UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3' UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, AREs blocked the recruitment of cytokine-encoding mRNA to ribosomes; this block depended on the ARE-binding protein ZFP36L2. Thus, AREs mediate repression of translation in mouse and human memory T cells by preventing undesirable protein production from pre-formed cytokine-encoding mRNAs in the absence of infection. PMID- 29988085 TI - Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium. AB - Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 * 10-6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake. PMID- 29988091 TI - Maintenance of CD4 T cell fitness through regulation of Foxo1. AB - Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor beta-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division. PMID- 29988092 TI - B cells race the clock to get a second wind. PMID- 29988090 TI - Second signals rescue B cells from activation-induced mitochondrial dysfunction and death. AB - B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylation and glycolysis. In the absence of a second signal, B cells progressively lost mitochondrial function and glycolytic capacity, which led to apoptosis. Mitochondrial dysfunction was a result of the gradual accumulation of intracellular calcium through calcium response-activated calcium channels that, for approximately 9 h after the binding of B cell antigens, was preventable by either helper T cells or signaling via the receptor TLR9. Thus, BCR signaling seems to activate a metabolic program that imposes a limited time frame during which B cells either receive a second signal and survive or are eliminated. PMID- 29988093 TI - STAT3 on the brain. PMID- 29988095 TI - Fast reversibly photoswitching red fluorescent proteins for live-cell RESOLFT nanoscopy. AB - Reversibly photoswitchable fluorescent proteins (rsFPs) are gaining popularity as tags for optical nanoscopy because they make it possible to image with lower light doses. However, green rsFPs need violet-blue light for photoswitching, which is potentially phototoxic and highly scattering. We developed new rsFPs based on FusionRed that are reversibly photoswitchable with green-orange light. The rsFusionReds are bright and exhibit rapid photoswitching, thereby enabling nanoscale imaging of living cells. PMID- 29988094 TI - Genome-wide SWAp-Tag yeast libraries for proteome exploration. AB - Yeast libraries revolutionized the systematic study of cell biology. To extensively increase the number of such libraries, we used our previously devised SWAp-Tag (SWAT) approach to construct a genome-wide library of ~5,500 strains carrying the SWAT NOP1promoter-GFP module at the N terminus of proteins. In addition, we created six diverse libraries that restored the native regulation, created an overexpression library with a Cherry tag, or enabled protein complementation assays from two fragments of an enzyme or fluorophore. We developed methods utilizing these SWAT collections to systematically characterize the yeast proteome for protein abundance, localization, topology, and interactions. PMID- 29988096 TI - Genome-wide C-SWAT library for high-throughput yeast genome tagging. AB - Here we describe a C-SWAT library for high-throughput tagging of Saccharomyces cerevisiae open reading frames (ORFs). In 5,661 strains, we inserted an acceptor module after each ORF that can be efficiently replaced with tags or regulatory elements. We validated the library with targeted sequencing and tagged the proteome with bright fluorescent proteins to quantify the effect of heterologous transcription terminators on protein expression and to localize previously undetected proteins. PMID- 29988097 TI - Disparities in Hispanic/Latino and non-Hispanic Black men with low-risk prostate cancer and eligible for active surveillance: a population-based study. AB - BACKGROUND: Non-Hispanic Black (NHB) men are at an increased risk for aggressive prostate cancer (PCa), making active surveillance (AS) potentially less optimal in this population. This concern has not been explored in other minority populations-specifically, Hispanic/Latino men. We recently found that Mexican American men demonstrate an increased risk of PCa-specific mortality, and we hypothesized that they may also be at risk for an adverse outcome on AS. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) program, we extracted a population-based cohort of men diagnosed from 2004 to 2013 with localized or regional PCa, who had <=2 cores of only Grade Group (GG) 1 cancer, and underwent radical prostatectomy (RP) with available biopsy and surgical pathology results. We measured discovery of high-risk PCa at RP and collected socioeconomic status (SES) data across different racial/ethnic groups. We defined aggressive tumors as either an upgrade to GG 3 or higher (GG3+) cancer or non organ-confined disease (>=pT3a or N1). Univariate and multivariate logistic regression models were developed to assess the association between racial/ethnic categories and the previously mentioned adverse oncologic outcomes both with and without adjusting for SES factors. RESULTS: NHB and Mexican-American men were significantly more likely to have aggressive PCa, following RP. In multivariable logistic regression adjusting for SES factors and relative to non-Hispanic White (NHW) men, Mexican-American men had at increased odds of upgrading to GG3+ (OR 1.67; 95% CI [1.00-2.90]). NHB men were more likely to have non-organ-confined disease (OR 1.34; 95% CI [1.06-1.69]), while Mexican-American men had a similar risk to NHW men. CONCLUSION: Among individuals with low-risk PCa and eligible for AS, Mexican-American and NHB men are at an increased risk of harboring more aggressive disease at RP. This novel finding among Mexican-Americans deserves further evaluation. PMID- 29988098 TI - Cost and efficacy comparison of five prostate biopsy modalities: a platform for integrating cost into novel-platform comparative research. AB - BACKGROUND: The cornerstone of prostate cancer diagnosis remains the transrectal ultrasound-guided biopsy (TRUS-BX), which most frequently occurs in the office setting under local anesthesia. However, there are now other techniques of prostate biopsy aimed at improving outcomes such as patient comfort, significant cancer detection, and infectious complications. The purpose of the present study is to compare the cost and efficacy outcomes of five different approaches. METHODS: We compared the comprehensive costs of a random sample size of 20-30 cases from each of the following: (1) local anesthesia TRUS-BX (reference), (2) sedation TRUS-BX, (3) general anesthesia transperineal template biopsy (TP), (4) sedation MRI-TRUS fusion biopsy (FB), and (5) sedation in-bore MRI biopsy (IB MRI). Cost categories included pre-procedure, anesthesia pharmacy and recovery, and the technical/professional costs from urology, radiology, and pathology services. For procedure outcomes, we compared the larger cohorts of TRUS-BX, TP, and FB in terms of indication, cancer yield, and downstream decision impact. RESULTS: Compared with standard TRUS-BX, the total costs of sedation TRUS-BX, TP, FB, and IB-MRI increased significantly *1.9 (90%), *2.5 (153%), *2.5 (150%), and *2.2 (125%), respectively (p < 0.001). Although there was no statistical difference between the total costs of TP, FB, and IB-MRI, these costs were significantly higher than those of TRUS-BX under either local anesthesia or sedation (p < 0.05). The cost of TRUS-BX under sedation was significantly higher than that of TRUS-BX under local anesthesia (p < 0.001). Compared to TRUS-BX, more significant cancers were detected in FB (16% vs. 36%) and TP (16% vs. 34%) groups (p < 0.001). CONCLUSIONS: Compared with standard TRUS-BX, the additions of imaging, sedation anesthesia, and transperineal template increase costs significantly, and can be considered along with known improvements in accuracy and side effects. Ongoing efforts to combine imaging and transperineal biopsy, especially in an outpatient/local anesthesia setting may lead to a higher cost/benefit. PMID- 29988099 TI - Association of androgen deprivation therapy with thromboembolic events in patients with prostate cancer: a systematic review and meta-analysis. AB - BACKGROUND: Whether androgen deprivation therapy (ADT) causes excess thromboembolic events (TEs) in men with prostate cancer (PCa) remains controversial and is the subject of the US Food and Drug Administration safety warning. This study aims to perform a systematic review and meta-analysis on previous studies to determine whether ADT is associated with TEs in men with PCa. METHODS: Medline, Embase, and Cochrane Library databases were searched for relevant studies. These studies comprised those that compared ADT versus control to treat PCa, reported TEs as outcome, and were published before January 2018. Multivariate adjusted hazard ratios (HRs) and associated 95% confidence intervals (CIs) were calculated using random- or fixed-effects models. RESULTS: Five retrospective population-based cohort studies involving 170,851 ADT users and 256,704 non-ADT users were identified. Deep venous thrombosis (DVT) was found significantly associated with gonadotropin-releasing hormone (GnRH) agonists alone (HR = 1.47, 95% CI: 1.07-2.03; P = 0.017; I2 = 96.3%), GnRH agonists plus oral antiandrogen (AA) (HR = 2.55, 95% CI: 2.21-2.94; P < 0.001; I2 = 0.0%), and AA alone (HR = 1.49, 95% CI: 1.13-1.96; P = 0.004; I2 = 0.0%), but not with orchiectomy (HR = 1.80, 95% CI: 0.93-3.47; P = 0.079; I2 = 94.8%). In addition, pulmonary embolism (PE) was significantly associated with GnRH agonists alone (HR = 2.26, 95% CI: 1.78-2.86; P < 0.001; I2 was unavailable) and orchiectomy (HR = 2.12, 95% CI: 1.44-3.11; P < 0.001; I2 = 57.2%). This relationship was also supported with subgroup analyses based on different continents and races. CONCLUSIONS: GnRH agonists alone, GnRH plus AA, and AA alone cause excess DVT in men with PCa after controlling the demographic and disease characteristics and other confounding factors, although statistically significant difference was not observed in orchiectomy group. Additionally, GnRH agonists alone and orchiectomy can increase the incidence of PE. PMID- 29988100 TI - Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer. AB - BACKGROUND: Patients with prostate cancer are at risk of impaired bone health. Prostate cancer has a propensity to metastasize to bone, after which patients are at risk of skeletal-related events (SREs). These complications are associated with increased mortality, substantial pain, and reduced quality of life. Patients are also at risk of bone loss due to androgen deprivation therapy (ADT), which can be compounded in elderly patients with reduced bone density. It is essential, therefore, that aspects of bone health and therapies able to prevent the occurrence of SREs are considered throughout the clinical course of prostate cancer. METHODS: We reviewed the literature regarding the molecular mechanisms underpinning bone lesion formation, the modes of action of therapies that prevent SREs, and the efficacy and safety of these therapies in patients with hormone sensitive or castration-resistant prostate cancer (CRPC). RESULTS: Therapies such as denosumab (a RANKL inhibitor) and zoledronic acid (a bisphosphonate) were indicated for prevention of SREs. Radium-223 dichloride also has proven efficacy in delaying symptomatic SREs, as well as in improving overall survival through effects on bone metastases. Before development of bone metastases, low-dose denosumab may also be used for treatment of ADT-associated bone loss. Denosumab may also have the potential to delay bone metastases development in patients with CRPC, although this is not currently an approved indication. The safety profile of therapies to prevent SREs should be considered. This review consolidates the available evidence on use of denosumab and bisphosphonates in prostate cancer, differentiated by hormone-sensitive and castration-resistant disease. CONCLUSIONS: There is convincing evidence to support the use of denosumab and bisphosphonates to maintain bone health in patients with prostate cancer. Clinicians should be mindful of the adverse event risk profile of these therapies. PMID- 29988101 TI - Targets missed: predictors of MRI-targeted biopsy failing to accurately localize prostate cancer found on systematic biopsy. AB - BACKGROUND: Magnetic resonance imaging (MRI)/ultrasound (US) fusion-guided biopsy has improved the ability to localize and detect prostate cancer (PCa) with efficiency surpassing systematic biopsy. Nevertheless, some patients have PCa missed using the MRI-targeted biopsy sampling alone. We aim to identify clinical and imaging parameters associated with cases where targeted biopsy did not detect PCa compared to systematic biopsy. METHODS: We conducted a retrospective review of patients who underwent MRI/US fusion-guided biopsy in addition to concurrent systematic, extended-sextant biopsy between 2014 and 2017. For patients with PCa detected on systematic biopsy not properly localized by MRI/US fusion-guided biopsy, the sextant distance from MRI-targeted lesion to the cancer-positive sextant was calculated and parameters potentially predicting this targeting miss were evaluated. RESULTS: In all, 35/127 (27.6%) patients with single-session MRI/US fusion-guided biopsy plus standard biopsy finding PCa had lesions incorrectly localized. Of these, 15/35 (42.9%) were identified as possible fusion software misregistrations. The remainder, 12/35 (34.3%), represented targeted biopsies one sextant away from the cancer focus and 8/35 (22.9%) targeted biopsies two sextants away from the cancer focus. Only 7/35 (20.0%) patients were determined to have clinically significant PCa, which represents 7/127 (5.5%) of the overall population. Lower MRI lesion volumes (p = 0.022), lesion density (p < 0.001), and PI-RADS scores (p < 0.001) were significantly associated with targeted biopsy missing PCa detected on systematic biopsy. CONCLUSION: Clinically significant PCa is rarely missed utilizing MRI/US fusion-guided biopsy. With the majority of missed tumors representing targeting misregistrations or cases of low grade cancer in sextants immediately adjacent to MRI suspicious lesions. Lower MRI lesion volumes, lesion density, and PI-RADS are predictors of cases with targeted biopsies missing cancer, for which systematic sampling of the sextants containing MRI targets and adjacent sextants would most optimize PCa detection. PMID- 29988102 TI - Compositional differences in gastrointestinal microbiota in prostate cancer patients treated with androgen axis-targeted therapies. AB - BACKGROUND: It is well known that the gastrointestinal (GI) microbiota can influence the metabolism, pharmacokinetics, and toxicity of cancer therapies. Conversely, the effect of cancer treatments on the composition of the GI microbiota is poorly understood. We hypothesized that oral androgen receptor axis targeted therapies (ATT), including bicalutamide, enzalutamide, and abiraterone acetate, may be associated with compositional differences in the GI microbiota. METHODS: We profiled the fecal microbiota in a cross-sectional study of 30 patients that included healthy male volunteers and men with different clinical states of prostate cancer (i.e., localized, biochemically recurrent, and metastatic disease) using 16S rDNA amplicon sequencing. Functional inference of identified taxa was performed using PICRUSt. RESULTS: We report a significant difference in alpha diversity in GI microbiota among men with versus without a prostate cancer diagnosis. Further analysis identified significant compositional differences in the GI microbiota of men taking ATT, including a greater abundance of species previously linked to response to anti-PD-1 immunotherapy such as Akkermansia muciniphila and Ruminococcaceae spp. In functional analyses, we found an enriched representation of bacterial gene pathways involved in steroid biosynthesis and steroid hormone biosynthesis in the fecal microbiota of men taking oral ATT. CONCLUSIONS: There are measurable differences in the GI microbiota of men receiving oral ATT. We speculate that oral hormonal therapies for prostate cancer may alter the GI microbiota, influence clinical responses to ATT, and/or potentially modulate the antitumor effects of future therapies including immunotherapy. Given our findings, larger, longitudinal studies are warranted. PMID- 29988103 TI - Evoking and tracking zebrafish eye movement in multiple larvae with ZebEyeTrack. AB - Reliable measurement of spontaneous and evoked eye movement is critical for behavioral vision research. Zebrafish are increasingly used as a model organism for visual neural circuits, but ready-to-use eye-tracking solutions are scarce. Here, we present a protocol for automated real-time measurement of angular horizontal eye position in up to six immobilized larval fish using a custom-built LabVIEW-based software, ZebEyeTrack. We provide its customizable source code, as well as a streamlined and compiled version, ZebEyeTrack Light. The full version of ZebEyeTrack controls all required hardware and synchronizes six essential aspects of the experiment: (i) stimulus design; (ii) visual stimulation with moving bars; (ii) eye detection and tracking, as well as general motion detection; (iv) real-time analysis; (v) eye-position-dependent closed-loop event control; and (vi) recording of external event times. This includes optional integration with external hardware such as lasers and scanning microscopes. Once installation is complete, experiments, including stimulus design, can be completed in <10 min, and recordings can last anywhere between seconds and many hours. Results include digitized angular eye positions and hardware status, which can be used to compute tuning curves, optokinetic gain, and other custom data analysis. After the experiment, or based on existing videos, optokinetic response (OKR) performance can be analyzed semi-automatically via the graphical user interface, and results can be exported. ZebEyeTrack has been used successfully for psychophysics experiments, for optogenetic stimulation, and in combination with calcium imaging. PMID- 29988105 TI - Programming DNA origami assembly for shape-resolved nanomechanical imaging labels. AB - Atomic force microscopy (AFM)-based nanomechanical imaging provides a high resolution approach for imaging biomolecules with nanometer resolution. Nevertheless, the lack of appropriate nanomechanical labels poses a limit to biological applications. Here, we describe how to generate a set of shape resolved nanomechanical labels by exploiting self-assembled DNA origami technology. By designing 'mediator' strands that can hybridize with both the origami shapes and the target DNA, these origami shape IDs can be used to site specifically label genomic DNA with high efficiency and high throughput. When DNA origami shape IDs are used to label target sequences containing two single nucleotide polymorphisms (SNPs), this approach is capable of differentiating adjacent labeling sites separated by only 30 nucleobases (~10 nm) under AFM imaging. This resolution is a threefold improvement of that which can be obtained with imaging-based genotyping using super-resolution imaging. We further demonstrate how to use origami shape IDs for high-resolution genotyping of SNPs in disease-associated genes in patients. The entire protocol takes ~2 d to complete. PMID- 29988104 TI - Sucrose preference test for measurement of stress-induced anhedonia in mice. AB - Anhedonia is the inability to experience pleasure from rewarding or enjoyable activities and is a core symptom of depression in humans. Here, we describe a protocol for the measurement of anhedonia in mice, in which anhedonia is measured by a sucrose preference test (SPT) based on a two-bottle choice paradigm. A reduction in the sucrose preference ratio in experimental relative to control mice is indicative of anhedonia. To date, inconsistent and variable results have been reported following the use of the SPT by different groups, probably due to the use of different protocols and equipment. In this protocol, we describe how to set up a clearly defined apparatus for SPT and provide a detailed protocol to ensure greater consistency when carrying out SPT. This optimized protocol is highly sensitive, reliable, and adaptable for evaluation of chronic stress related anhedonia, as well as morphine-induced dependence. The whole SPT, including adaptation, baseline measurement, and testing, takes 8 d. PMID- 29988106 TI - In vitro generation of mouse polarized embryo-like structures from embryonic and trophoblast stem cells. AB - Mammalian embryogenesis requires the coordination of embryonic and extra embryonic tissues to enable implantation into the uterus and post-implantation development to establish the body plan. Mouse embryonic stem cells (ESCs) are a useful tool for studying pluripotent embryonic tissue in vitro. However, they cannot undertake correct embryogenesis alone. Many attempts to model the early embryo in vitro involve the aggregation of ESCs into spheroids of variable size and cell number that undertake germ-layer specification but fail to recapitulate the characteristic architecture and arrangement of tissues of the early embryo. Here, we describe a protocol to generate the first embryo-like structures by directing the assembly of mouse ESCs and extra-embryonic trophoblast stem cells (TSCs) in a 3D extracellular matrix (ECM) into structures we call 'polarized embryo-like structures'. By establishing the medium and culture conditions needed to support the growth of both stem cell types simultaneously, embryonic architecture is generated within 4 d of co-culture. This protocol can be performed by those proficient in standard ESC culture techniques and can be used in developmental studies to investigate the interactions between embryonic and extra-embryonic tissues during mammalian development. PMID- 29988107 TI - Integrated analysis of anatomical and electrophysiological human intracranial data. AB - Human intracranial electroencephalography (iEEG) recordings provide data with much greater spatiotemporal precision than is possible from data obtained using scalp EEG, magnetoencephalography (MEG), or functional MRI. Until recently, the fusion of anatomical data (MRI and computed tomography (CT) images) with electrophysiological data and their subsequent analysis have required the use of technologically and conceptually challenging combinations of software. Here, we describe a comprehensive protocol that enables complex raw human iEEG data to be converted into more readily comprehensible illustrative representations. The protocol uses an open-source toolbox for electrophysiological data analysis (FieldTrip). This allows iEEG researchers to build on a continuously growing body of scriptable and reproducible analysis methods that, over the past decade, have been developed and used by a large research community. In this protocol, we describe how to analyze complex iEEG datasets by providing an intuitive and rapid approach that can handle both neuroanatomical information and large electrophysiological datasets. We provide a worked example using an example dataset. We also explain how to automate the protocol and adjust the settings to enable analysis of iEEG datasets with other characteristics. The protocol can be implemented by a graduate student or postdoctoral fellow with minimal MATLAB experience and takes approximately an hour to execute, excluding the automated cortical surface extraction. PMID- 29988109 TI - Surface-wetting characterization using contact-angle measurements. AB - Wetting, the process of water interacting with a surface, is critical in our everyday lives and in many biological and technological systems. The contact angle is the angle at the interface where water, air and solid meet, and its value is a measure of how likely the surface is to be wetted by the water. Low contact-angle values demonstrate a tendency of the water to spread and adhere to the surface, whereas high contact-angle values show the surface's tendency to repel water. The most common method for surface-wetting characterization is sessile-drop goniometry, due to its simplicity. The method determines the contact angle from the shape of the droplet and can be applied to a wide variety of materials, from biological surfaces to polymers, metals, ceramics, minerals and so on. The apparent simplicity of the method is misleading, however, and obtaining meaningful results requires minimization of random and systematic errors. This article provides a protocol for performing reliable and reproducible measurements of the advancing contact angle (ACA) and the receding contact angle (RCA) by slowly increasing and reducing the volume of a probe drop, respectively. One pair of ACA and RCA measurements takes ~15-20 min to complete, whereas the whole protocol with repeat measurements may take ~1-2 h. This protocol focuses on using water as a probe liquid, and advice is given on how it can be modified for the use of other probe liquids. PMID- 29988110 TI - ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer. AB - BACKGROUND: In colorectal cancer (CRC), BRAF mutations influence tumour progression. In mismatch repair-deficient (dMMR) tumours, BRAF mutations are associated with a good prognosis, whereas in MMR-competent tumours, they are detrimental. The differential expression of the downstream MAPK pathway members, which are constitutively activated in BRAF mutant patients, may account for these differences. METHODS: Phosphorylation of ERK, p38MAPK and JNK was assessed by immunohistochemistry, utilising CRC tissue microarrays. A discovery cohort (n = 187) and a validation cohort (n = 801) were analysed for associations with BRAF mutations, clinicopathological characteristics and cancer-specific survival (CSS). RESULTS: In 801 CRC patients, nuclear ERK phosphorylation (HR 0.65 95% CI 0.48-0.88, p = 0.004) and the combined nuclear pERK/p-p38 score (HR 0.61 95% CI 0.45-0.82, p = 0.001) were independently associated with CSS, and were further associated with increased BRAF mutations (p = 0.003 and p = 0.002). When stratified for BRAF status, only MMR-competent patients harbouring the mutation and a strong combined nuclear pERK/p-p38 score (HR 0.49 95% CI 0.27-0.89, p = 0.016) demonstrated improved CSS. This improvement in CSS was specific to stage III CRC (HR 0.25 95% CI 0.10-0.64, p = 0.002). CONCLUSIONS: MMR-competent stage III tumours harbouring BRAF mutations have an improved prognosis when strong nuclear phosphorylation of both ERK and p38MAPK is present. PMID- 29988108 TI - Reproducible workflow for multiplexed deep-scale proteome and phosphoproteome analysis of tumor tissues by liquid chromatography-mass spectrometry. AB - Here we present an optimized workflow for global proteome and phosphoproteome analysis of tissues or cell lines that uses isobaric tags (TMT (tandem mass tags) 10) for multiplexed analysis and relative quantification, and provides 3* higher throughput than iTRAQ (isobaric tags for absolute and relative quantification)-4 based methods with high intra- and inter-laboratory reproducibility. The workflow was systematically characterized and benchmarked across three independent laboratories using two distinct breast cancer subtypes from patient-derived xenograft models to enable assessment of proteome and phosphoproteome depth and quantitative reproducibility. Each plex consisted of ten samples, each being 300 MUg of peptide derived from <50 mg of wet-weight tissue. Of the 10,000 proteins quantified per sample, we could distinguish 7,700 human proteins derived from tumor cells and 3100 mouse proteins derived from the surrounding stroma and blood. The maximum deviation across replicates and laboratories was <7%, and the inter-laboratory correlation for TMT ratio-based comparison of the two breast cancer subtypes was r > 0.88. The maximum deviation for the phosphoproteome coverage was <24% across laboratories, with an average of >37,000 quantified phosphosites per sample and differential quantification correlations of r > 0.72. The full procedure, including sample processing and data generation, can be completed within 10 d for ten tissue samples, and 100 samples can be analyzed in ~4 months using a single LC-MS/MS instrument. The high quality, depth, and reproducibility of the data obtained both within and across laboratories should enable new biological insights to be obtained from mass spectrometry-based proteomics analyses of cells and tissues together with proteogenomic data integration. PMID- 29988111 TI - Randomised phase II trial to investigate catumaxomab (anti-EpCAM * anti-CD3) for treatment of peritoneal carcinomatosis in patients with gastric cancer. AB - BACKGROUND: Peritoneal carcinomatosis (PC) represents an unfavourable prognostic factor for patients with gastric cancer (GC). Intraperitoneal treatment with the bispecific and trifunctional antibody catumaxomab (EpCAM, CD3), in addition to systemic chemotherapy, could improve elimination of PC. METHODS: This prospective, randomised, phase II study investigated the efficacy of catumaxomab followed by chemotherapy (arm A, 5-fluorouracil, leucovorin, oxaliplatin, docetaxel, FLOT) or FLOT alone (arm B) in patients with GC and PC. Primary endpoint was the rate of macroscopic complete remission (mCR) of PC at the time of second diagnostic laparoscopy/laparotomy prior to optional surgery. RESULTS: Median follow-up was 52 months. Out of 35 patients screened, 15 were allocated to arm A and 16 to arm B. mCR rate was 27% in arm A and 19% in arm B (p = 0.69). Severe side effects associated with catumaxomab were nausea, infection, abdominal pain, and elevated liver enzymes. Median progression-free (6.7 vs. 5.4 months, p = 0.71) and overall survival (13.2 vs. 13.0 months, p = 0.97) were not significantly different in both treatment arms. CONCLUSIONS: Addition of catumaxomab to systemic chemotherapy was feasible and tolerable in advanced GC. Although the primary endpoint could not be demonstrated, results are promising for future investigations integrating intraperitoneal immunotherapy into a multimodal treatment strategy. PMID- 29988112 TI - Constitutively active androgen receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in castration-resistant prostate cancer metastases. AB - BACKGROUND: A significant subset of prostate cancer (PC) patients with a castration-resistant form of the disease (CRPC) show primary resistance to androgen receptor (AR)-targeting drugs developed against CRPC. As one explanation could be the expression of constitutively active androgen receptor splice variants (AR-Vs), our current objectives were to study AR-Vs and other AR aberrations to better understand the emergence of CRPC. METHODS: We analysed specimens from different stages of prostate cancer by next-generation sequencing and immunohistochemistry. RESULTS: AR mutations and copy number variations were detected only in CRPC specimens. Genomic structural rearrangements of AR were observed in 5/30 metastatic CRPC patients, but they were not associated with expression of previously known AR-Vs. The predominant AR-Vs detected were AR-V3, AR-V7 and AR-V9, with the expression levels being significantly higher in CRPC cases compared to prostatectomy samples. Out of 25 CRPC metastases that expressed any AR variant, 17 cases harboured expression of all three of these AR-Vs. AR-V7 protein expression was highly heterogeneous and higher in CRPC compared to hormone-naive tumours. CONCLUSIONS: AR-V3, AR-V7 and AR-V9 are co-expressed in CRPC metastases highlighting the fact that inhibiting AR function via regions common to all AR-Vs is likely to provide additional benefit to patients with CRPC. PMID- 29988113 TI - Immunomodulatory role of histamine H4 receptor in breast cancer. AB - BACKGROUND: Although the role of histamine H4 receptor (H4R) in immune cells is being extensively investigated, its immunomodulatory function in cancer is completely unknown. This study aimed to investigate the role of H4R in antitumour immunity in a model of triple-negative breast cancer. METHODS: We evaluated growth parameters, histological characteristics and the composition of tumour, splenic and tumour draining lymph node (TDLN) immune subsets, in a syngeneic model, developed orthotopically with 4T1 cells in H4R knockout (H4R-KO) and wild type mice. RESULTS: Mice lacking H4R show reduced tumour size and weight, decreased number of lung metastases and percentage of CD4+ tumour-infiltrating T cells, while exhibiting increased infiltration of NK cells and CD19+ lymphocytes. Likewise, TDLN of H4R-KO mice show decreased CD4+ T cells and T regulatory cells (CD4+CD25+FoxP3+), and increased percentages of NK cells. Finally, H4R-deficient mice show decreased Tregs in spleens and non-draining lymph nodes, and a negative correlation between tumour weight and the percentages of CD4+, CD19+ and NK splenic cells, suggesting that H4R also regulates antitumour immunity at a systemic level. CONCLUSIONS: This is the first report that demonstrates the participation of H4R in antitumour immunity, suggesting that H4R could be a target for cancer treatment. PMID- 29988114 TI - Pathophysiology of environmental enteric dysfunction and its impact on oral vaccine efficacy. AB - Environmental enteric dysfunction (EED) refers to a subclinical disorder of intestinal function common in tropical countries and in settings of poverty and economic disadvantage. The enteropathy that underlies this syndrome is characterized by mucosal inflammation and villus blunting mediated by T cell activation. Epithelial cell disruption and microbial translocation drive systemic inflammation. EED in young children is associated geographically with growth failure, malnutrition, and greatly impaired responses to oral vaccines, notably rotavirus and poliovirus vaccines. In this review, we describe the pathophysiology of EED and examine the evidence linking EED and oral vaccine failure. This evidence is far from conclusive. Although our understanding of EED is still sketchy, there is limited evidence of disturbed innate immunity, B cell disturbances including aggregation into lymphoid follicles, and autoantibody generation. Pathways of T cell activation and the possibility of dendritic cell anergy, which could help explain oral vaccine failure, require further work. PMID- 29988115 TI - The mouse autonomic nervous system modulates inflammation and epithelial renewal after corneal abrasion through the activation of distinct local macrophages. AB - Inflammation and reepithelialization after corneal abrasion are critical for the rapid restoration of vision and the prevention of microbial infections. However, the endogenous regulatory mechanisms are not completely understood. Here we report that the manipulation of autonomic nervous system (ANS) regulates the inflammation and healing processes. The activation of sympathetic nerves inhibited reepithelialization after corneal abrasion but increased the influx of neutrophils and the release of inflammatory cytokines. Conversely, the activation of parasympathetic nerves promoted reepithelialization and inhibited the influx of neutrophils and the release of inflammatory cytokines. Furthermore, we observed that CD64+CCR2+ macrophages in the cornea preferentially expressed the beta-2 adrenergic receptor (AR), whereas CD64+CCR2- macrophages preferentially expressed the alpha-7 nicotinic acetylcholine receptor (alpha7nAChR). After abrasion, the topical administration of a beta2AR agonist further enhanced the expression of the proinflammatory genes in the CD64+CCR2+ cell subset sorted from injured corneas. In contrast, the topical administration of an alpha7nAChR agonist further enhanced the expression of the anti-inflammatory genes in the CD64+CCR2- subset. Thus crosstalk between the ANS and local macrophage populations is necessary for the progress of corneal wound repair. Manipulation of ANS inputs to the wounded cornea may represent an alternative approach to the treatment of impaired wound healing. PMID- 29988116 TI - Herpes simplex virus-binding IgG traps HSV in human cervicovaginal mucus across the menstrual cycle and diverse vaginal microbial composition. AB - IgG possesses an important yet little recognized effector function in mucus. IgG bound to viral surface can immobilize otherwise readily diffusive viruses to the mucin matrix, excluding them from contacting target cells and facilitating their elimination by natural mucus clearance mechanisms. Cervicovaginal mucus (CVM) is populated by a microbial community, and its viscoelastic and barrier properties can vary substantially not only across the menstrual cycle, but also in women with distinct microbiota. How these variations impact the "muco-trapping" effector function of IgGs remains poorly understood. Here we obtained multiple fresh, undiluted CVM specimens (n = 82 unique specimens) from six women over time, and employed high-resolution multiple particle tracking to quantify the mobility of fluorescent Herpes Simplex Viruses (HSV-1) in CVM treated with different HSV-1-binding IgG. The IgG trapping potency was then correlated to the menstrual cycle, and the vaginal microbial composition was determined by 16 s rRNA. In the specimens studied, both polyclonal and monoclonal HSV-1-binding IgG appeared to consistently and effectively trap HSV-1 in CVM obtained at different times of the menstrual cycle and containing a diverse spectrum of commensals, including G. vaginalis-dominant microbiota. Our findings underscore the potential broad utility of this "muco-trapping" effector function of IgG to reinforce the vaginal mucosal defense, and motivates further investigation of passive immunization of the vagina as a strategy to protect against vaginally transmitted infections. PMID- 29988117 TI - The JAK inhibitor ruxolitinib reduces inflammation in an ILC3-independent model of innate immune colitis. AB - Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune mediated IBD. PMID- 29988118 TI - Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. AB - Tumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn's disease. Tl1a overexpression in mice lead to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been investigated. We demonstrate that the pro-fibrotic and inflammatory phenotype resulting from Tl1a-overexpression is abrogated in the absence of resident microbiota. To evaluate if this is due to the absence of a unique bacterial population, as opposed to any bacteria per se, we gavaged germ-free (GF) wild-type and Tl1a-transgenic (Tl1a-Tg) mice with stool from specific pathogen free (SPF) mice and a healthy human donor (Hu). Reconstitution with SPF, but not Hu microbiota, resulted in increased intestinal collagen deposition and fibroblast activation in Tl1a-Tg mice. Notably, there was reduced fibroblast migration and activation under GF conditions compared to native conditions. We then identified several candidate organisms that correlated directly with increased fibrosis in reconstituted mice and showed that these organisms directly impact fibroblast function in vitro. Thus, Tl1a-mediated intestinal fibrosis and fibroblast activation are dependent on specific microbial populations. PMID- 29988120 TI - Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. AB - The communities of bacteria that reside in the intestinal tract are in constant competition within this dynamic and densely colonized environment. At homeostasis, the equilibrium that exists between these species and strains is shaped by their metabolism and also by pathways of active antagonism, which drive competition with related and unrelated strains. Importantly, these normal activities contribute to colonization resistance by the healthy microbiota, which includes the ability to prevent the expansion of potential pathogens. Disruption of the microbiota, resulting from, for example, inflammation or antibiotic use, can reduce colonization resistance. Pathogens that engraft following disruption of the microbiota are often adapted to expand into newly created niches and compete in an altered gut environment. In this review, we examine both the interbacterial mechanisms of colonization resistance and the strategies of pathogenic strains to exploit gaps in colonization resistance. PMID- 29988119 TI - Expanded TCRbeta CDR3 clonotypes distinguish Crohn's disease and ulcerative colitis patients. AB - We aimed to determine whether the TCR repertoires of Crohn's disease (CD) patients contain highly prevalent disease-specific T-cell clonotypes reflective of the characteristic and highly shared aberrant serum antibody reactivity to gut commensal flagellin antigens. The CD4 TCRbeta CDR3 sequence repertoires from active CD (n = 20) and ulcerative colitis (UC) (n = 10) patients were significantly more diverse, and individual sequences over-represented, compared to healthy controls (HC) (n = 97). While a very small number of expanded public CDR3 sequences are highly shared between active CD and UC, the majority of significantly expanded TCRbeta CDR3 clonotypes are private to CD and UC patients with equivalent prevalence among IBD patients. Further defining TCR clonotypes by Vbeta-CDR3 linkage showed significant differences in the TCR repertoires between UC and CD. Flagellin antigen exposure induced expansion of several TCRbeta CDR3 sequences in CD4 cells from a flagellin-seropositive subject including sequences highly shared by or relatively private to CD (and UC) patients. These data suggest that flagellin-reactivity contributes to the expansion of a small number of CD4 clonotypes but does not support flagellin antigens as predominantly driving CD4 cell proliferation in CD. Disease-specific expanded TCRbeta CDR3 clonotypes characterize CD and UC and the shared exposure to the gamut of gut microbial antigens. PMID- 29988121 TI - Enhancer hubs and loop collisions identified from single-allele topologies. AB - Chromatin folding contributes to the regulation of genomic processes such as gene activity. Existing conformation capture methods characterize genome topology through analysis of pairwise chromatin contacts in populations of cells but cannot discern whether individual interactions occur simultaneously or competitively. Here we present multi-contact 4C (MC-4C), which applies Nanopore sequencing to study multi-way DNA conformations of individual alleles. MC-4C distinguishes cooperative from random and competing interactions and identifies previously missed structures in subpopulations of cells. We show that individual elements of the beta-globin superenhancer can aggregate into an enhancer hub that can simultaneously accommodate two genes. Neighboring chromatin domain loops can form rosette-like structures through collision of their CTCF-bound anchors, as seen most prominently in cells lacking the cohesin-unloading factor WAPL. Here, massive collision of CTCF-anchored chromatin loops is believed to reflect 'cohesin traffic jams'. Single-allele topology studies thus help us understand the mechanisms underlying genome folding and functioning. PMID- 29988123 TI - Biochemical autoregulatory gene therapy for focal epilepsy. AB - Despite the introduction of more than one dozen new antiepileptic drugs in the past 20 years, approximately one-third of people who develop epilepsy continue to have seizures on mono- or polytherapy1. Viral-vector-mediated gene transfer offers the opportunity to design a rational treatment that builds on mechanistic understanding of seizure generation and that can be targeted to specific neuronal populations in epileptogenic foci2. Several such strategies have shown encouraging results in different animal models, although clinical translation is limited by possible effects on circuits underlying cognitive, mnemonic, sensory or motor function. Here, we describe an autoregulatory antiepileptic gene therapy, which relies on neuronal inhibition in response to elevations in extracellular glutamate. It is effective in a rodent model of focal epilepsy and is well tolerated, thus lowering the barrier to clinical translation. PMID- 29988122 TI - Genetic determinants of co-accessible chromatin regions in activated T cells across humans. AB - Over 90% of genetic variants associated with complex human traits map to non coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed ATAC-seq and RNA-seq profiles from stimulated primary CD4+ T cells in up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co accessible at kilobase and megabase resolution, consistent with the three dimensional chromatin organization measured by in situ Hi-C in T cells. Fifteen percent of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak (local-ATAC-QTLs). Local-ATAC-QTLs have the largest effects on co-accessible peaks, are associated with gene expression and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis-regulatory elements, in isolation or in concert, to influence gene expression. PMID- 29988125 TI - Verapamil and beta cell function in adults with recent-onset type 1 diabetes. AB - Pancreatic beta cell loss is a key factor in the pathogenesis of type 1 diabetes (T1D), but therapies to halt this process are lacking. We previously reported that the approved antihypertensive calcium-channel blocker verapamil, by decreasing the expression of thioredoxin-interacting protein, promotes the survival of insulin-producing beta cells and reverses diabetes in mouse models1. To translate these findings into humans, we conducted a randomized double-blind placebo-controlled phase 2 clinical trial ( NCT02372253 ) to assess the efficacy and safety of oral verapamil added for 12 months to a standard insulin regimen in adult subjects with recent-onset T1D. Verapamil treatment, compared with placebo was well tolerated and associated with an improved mixed-meal-stimulated C peptide area under the curve, a measure of endogenous beta cell function, at 3 and 12 months (prespecified primary endpoint), as well as with a lower increase in insulin requirements, fewer hypoglycemic events and on-target glycemic control (secondary endpoints). Thus, addition of once-daily oral verapamil may be a safe and effective novel approach to promote endogenous beta cell function and reduce insulin requirements and hypoglycemic episodes in adult individuals with recent onset T1D. PMID- 29988124 TI - Suppression of antitumor T cell immunity by the oncometabolite (R)-2 hydroxyglutarate. AB - The oncometabolite (R)-2-hydroxyglutarate (R-2-HG) produced by isocitrate dehydrogenase (IDH) mutations promotes gliomagenesis via DNA and histone methylation. Here, we identify an additional activity of R-2-HG: tumor cell derived R-2-HG is taken up by T cells where it induces a perturbation of nuclear factor of activated T cells transcriptional activity and polyamine biosynthesis, resulting in suppression of T cell activity. IDH1-mutant gliomas display reduced T cell abundance and altered calcium signaling. Antitumor immunity to experimental syngeneic IDH1-mutant tumors induced by IDH1-specific vaccine or checkpoint inhibition is improved by inhibition of the neomorphic enzymatic function of mutant IDH1. These data attribute a novel, non-tumor cell-autonomous role to an oncometabolite in shaping the tumor immune microenvironment. PMID- 29988127 TI - Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring. AB - Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia. PMID- 29988126 TI - Reducing protein oxidation reverses lung fibrosis. AB - Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen in the lung, leading to chronically impaired gas exchange and death1-3. Oxidative stress is believed to be critical in this disease pathogenesis4-6, although the exact mechanisms remain enigmatic. Protein S-glutathionylation (PSSG) is a post-translational modification of proteins that can be reversed by glutaredoxin-1 (GLRX)7. It remains unknown whether GLRX and PSSG play a role in lung fibrosis. Here, we explored the impact of GLRX and PSSG status on the pathogenesis of pulmonary fibrosis, using lung tissues from subjects with idiopathic pulmonary fibrosis, transgenic mouse models and direct administration of recombinant Glrx to airways of mice with existing fibrosis. We demonstrate that GLRX enzymatic activity was strongly decreased in fibrotic lungs, in accordance with increases in PSSG. Mice lacking Glrx were far more susceptible to bleomycin- or adenovirus encoding active transforming growth factor beta-1 (AdTGFB1)-induced pulmonary fibrosis, whereas transgenic overexpression of Glrx in the lung epithelium attenuated fibrosis. We furthermore show that endogenous GLRX was inactivated through an oxidative mechanism and that direct administration of the Glrx protein into airways augmented Glrx activity and reversed increases in collagen in mice with TGFB1- or bleomycin-induced fibrosis, even when administered to fibrotic, aged animals. Collectively, these findings suggest the therapeutic potential of exogenous GLRX in treating lung fibrosis. PMID- 29988129 TI - Phenotype molding of stromal cells in the lung tumor microenvironment. AB - Cancer cells are embedded in the tumor microenvironment (TME), a complex ecosystem of stromal cells. Here, we present a 52,698-cell catalog of the TME transcriptome in human lung tumors at single-cell resolution, validated in independent samples where 40,250 additional cells were sequenced. By comparing with matching non-malignant lung samples, we reveal a highly complex TME that profoundly molds stromal cells. We identify 52 stromal cell subtypes, including novel subpopulations in cell types hitherto considered to be homogeneous, as well as transcription factors underlying their heterogeneity. For instance, we discover fibroblasts expressing different collagen sets, endothelial cells downregulating immune cell homing and genes coregulated with established immune checkpoint transcripts and correlating with T-cell activity. By assessing marker genes for these cell subtypes in bulk RNA-sequencing data from 1,572 patients, we illustrate how these correlate with survival, while immunohistochemistry for selected markers validates them as separate cellular entities in an independent series of lung tumors. Hence, in providing a comprehensive catalog of stromal cells types and by characterizing their phenotype and co-optive behavior, this resource provides deeper insights into lung cancer biology that will be helpful in advancing lung cancer diagnosis and therapy. PMID- 29988128 TI - Anatomical and functional dichotomy of ocular itch and pain. AB - Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies. PMID- 29988131 TI - A pig model of Huntington's disease. PMID- 29988132 TI - Searching for Alzheimer's disease therapies. PMID- 29988133 TI - Understanding genetic disease with electronic medical records. PMID- 29988134 TI - Homeward bound. PMID- 29988130 TI - Senolytics improve physical function and increase lifespan in old age. AB - Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice. PMID- 29988136 TI - Green light for data sharing. PMID- 29988135 TI - Predicting colon cancer recurrence. PMID- 29988137 TI - Detecting dengue. PMID- 29988138 TI - Fire prevention in the Parkinson's disease brain. PMID- 29988139 TI - A treatment strategy for KRAS-driven tumors. PMID- 29988140 TI - Matching up. PMID- 29988141 TI - Actionable equality. AB - In the past decade, many challenges faced by women seeking to advance their scientific careers have been identified. Although new policies encouraging equal opportunities in academic research are closing the gap, multipronged measures are needed in order to achieve long-lasting changes that make science gender-blind. PMID- 29988142 TI - Predicting progression to AML. PMID- 29988143 TI - Somatic mutations precede acute myeloid leukemia years before diagnosis. AB - The pattern of somatic mutations observed at diagnosis of acute myeloid leukemia (AML) has been well-characterized. However, the premalignant mutational landscape of AML and its impact on risk and time to diagnosis is unknown. Here we identified 212 women from the Women's Health Initiative who were healthy at study baseline, but eventually developed AML during follow-up (median time: 9.6 years). Deep sequencing was performed on peripheral blood DNA of these cases and compared to age-matched controls that did not develop AML. We discovered that mutations in IDH1, IDH2, TP53, DNMT3A, TET2 and spliceosome genes significantly increased the odds of developing AML. All subjects with TP53 mutations (n = 21 out of 21 patients) and IDH1 and IDH2 (n = 15 out of 15 patients) mutations eventually developed AML in our study. The presence of detectable mutations years before diagnosis suggests that there is a period of latency that precedes AML during which early detection, monitoring and interventional studies should be considered. PMID- 29988144 TI - A path to efficient gene editing. PMID- 29988145 TI - Microbiome metabolomics reveals new drivers of human liver steatosis. PMID- 29988146 TI - Impacts of surface depletion on the plasmonic properties of doped semiconductor nanocrystals. AB - Degenerately doped semiconductor nanocrystals (NCs) exhibit a localized surface plasmon resonance (LSPR) in the infrared range of the electromagnetic spectrum. Unlike metals, semiconductor NCs offer tunable LSPR characteristics enabled by doping, or via electrochemical or photochemical charging. Tuning plasmonic properties through carrier density modulation suggests potential applications in smart optoelectronics, catalysis and sensing. Here, we elucidate fundamental aspects of LSPR modulation through dynamic carrier density tuning in Sn-doped In2O3 (Sn:In2O3) NCs. Monodisperse Sn:In2O3 NCs with various doping levels and sizes were synthesized and assembled in uniform films. NC films were then charged in an in situ electrochemical cell and the LSPR modulation spectra were monitored. Based on spectral shifts and intensity modulation of the LSPR, combined with optical modelling, it was found that often-neglected semiconductor properties, specifically band structure modification due to doping and surface states, strongly affect LSPR modulation. Fermi level pinning by surface defect states creates a surface depletion layer that alters the LSPR properties; it determines the extent of LSPR frequency modulation, diminishes the expected near field enhancement, and strongly reduces sensitivity of the LSPR to the surroundings. PMID- 29988147 TI - Exosomal secretion of alpha-synuclein as protective mechanism after upstream blockage of macroautophagy. AB - Accumulation of pathological alpha-synuclein aggregates plays a major role in Parkinson's disease. Macroautophagy is a mechanism to degrade intracellular protein aggregates by wrapping them into autophagosomes, followed by fusion with lysosomes. We had previously shown that pharmacological activation of macroautophagy protects against alpha-synuclein-induced toxicity in human neurons. Here, we hypothesized that inhibition of macroautophagy would aggravate alpha-synuclein-induced cell death.Unexpectedly, inhibition of autophagosome formation by silencing of ATG5 protected from alpha-synuclein-induced toxicity. Therefore, we studied alternative cellular mechanisms to compensate for the loss of macroautophagy. ATG5 silencing did not affect the ubiquitin-proteasome system, chaperone systems, chaperone-mediated autophagy, or the unfolded protein response. However, ATG5 silencing increased the secretion of alpha-synuclein via exosomes. Blocking exosomal secretion exacerbated alpha-synuclein-induced cell death.We conclude that exosomal secretion of alpha-synuclein is increased after impaired formation of autophagosomes to reduce the intracellular alpha-synuclein burden. This compensatory mechanism prevents alpha-synuclein-induced neuronal cell death. PMID- 29988148 TI - Cisplatin-activated PAI-1 secretion in the cancer-associated fibroblasts with paracrine effects promoting esophageal squamous cell carcinoma progression and causing chemoresistance. AB - Preoperative chemotherapy is a promising strategy for the treatment of esophageal squamous cell carcinoma (ESCC). Acquired resistance to chemotherapy is a major obstacle in improving patient prognosis. Cancer-associated fibroblasts (CAFs) are the primary components of the tumor microenvironment and play a crucial role in tumor development; these cells are also potential therapeutic targets for cancer. Using protein arrays, we identified a key secreted cytokine, PAI-1, from CAFs pretreated with cisplatin that was induced after DNA damage of CAFs. The PAI-1 in the tumor microenvironment promoted tumor growth and attenuated the effects of cisplatin treatment. Extracellular PAI-1 activated the AKT and ERK1/2 signaling pathways and inhibited caspase-3 activity and reactive oxygen species accumulation. Tiplaxtinin as a PAI-1 inhibitor could play synergistic effects with cisplatin in vitro and in vivo. In clinical samples, ESCC patients with high expression of PAI-1 in CAFs presented a significantly worse progression-free survival. Taken together, our results showed that PAI-1 secreted from cisplatin activated CAFs promoted tumor growth and reduced the effects of cisplatin in a paracrine manner, establishing a preclinical rationale to target this cytokine to further improve the clinical response of esophageal squamous cell carcinoma. PMID- 29988150 TI - Approaching sub-ppm-level asymmetric organocatalysis of a highly challenging and scalable carbon-carbon bond forming reaction. AB - The chemical synthesis of organic molecules involves, at its very essence, the creation of carbon-carbon bonds. In this context, the aldol reaction is among the most important synthetic methods, and a wide variety of catalytic and stereoselective versions have been reported. However, aldolizations yielding tertiary aldols, which result from the reaction of an enolate with a ketone, are challenging and only a few catalytic asymmetric Mukaiyama aldol reactions with ketones as electrophiles have been described. These methods typically require relatively high catalyst loadings, deliver substandard enantioselectivity or need special reagents or additives. We now report extremely potent catalysts that readily enable the reaction of silyl ketene acetals with a diverse set of ketones to furnish the corresponding tertiary aldol products in excellent yields and enantioselectivities. Parts per million (ppm) levels of catalyst loadings can be routinely used and provide fast and quantitative product formation in high enantiopurity. In situ spectroscopic studies and acidity measurements suggest a silylium ion based, asymmetric counteranion-directed Lewis acid catalysis mechanism. PMID- 29988149 TI - Dynamic placement of the linker histone H1 associated with nucleosome arrangement and gene transcription in early Drosophila embryonic development. AB - The linker histone H1 is critical to maintenance of higher-order chromatin structures and to gene expression regulation. However, H1 dynamics and its functions in embryonic development remain unresolved. Here, we profiled gene expression, nucleosome positions, and H1 locations in early Drosophila embryos. The results show that H1 binding is positively correlated with the stability of beads-on-a-string nucleosome organization likely through stabilizing nucleosome positioning and maintaining nucleosome spacing. Strikingly, nucleosomes with H1 placement deviating to the left or the right relative to the dyad shift to the left or the right, respectively, during early Drosophila embryonic development. H1 occupancy on genic nucleosomes is inversely correlated with nucleosome distance to the transcription start sites. This inverse correlation reduces as gene transcription levels decrease. Additionally, H1 occupancy is lower at the 5' border of genic nucleosomes than that at the 3' border. This asymmetrical pattern of H1 occupancy on genic nucleosomes diminishes as gene transcription levels decrease. These findings shed new lights into how H1 placement dynamics correlates with nucleosome positioning and gene transcription during early Drosophila embryonic development. PMID- 29988151 TI - Towards simple kinetic models of functional dynamics for a kinase subfamily. AB - Kinases are ubiquitous enzymes involved in the regulation of critical cellular pathways. However, in silico modelling of the conformational ensembles of these enzymes is difficult due to inherent limitations and the cost of computational approaches. Recent algorithmic advances combined with homology modelling and parallel simulations have enabled researchers to address this computational sampling bottleneck. Here, we present the results of molecular dynamics studies for seven Src family kinase (SFK) members: Fyn, Lyn, Lck, Hck, Fgr, Yes and Blk. We present a sequence invariant extension to Markov state models, which allows us to quantitatively compare the structural ensembles of the seven kinases. Our findings indicate that in the absence of their regulatory partners, SFK members have similar in silico dynamics with active state populations ranging from 4 to 40% and activation timescales in the hundreds of microseconds. Furthermore, we observe several potentially druggable intermediate states, including a pocket next to the adenosine triphosphate binding site that could potentially be targeted via a small-molecule inhibitor. PMID- 29988152 TI - PORCUPINE regulates development in response to temperature through alternative splicing. AB - Recent findings suggest that alternative splicing has a critical role in controlling the responses of plants to temperature variations. However, alternative splicing factors in plants are largely uncharacterized. Here we establish the putative splice regulator, PORCUPINE (PCP), as temperature-specific regulator of development in Arabidopsis thaliana. Our findings point to the misregulation of WUSCHEL and CLAVATA3 as the possible cause for the meristem defects affecting the pcp-1 loss-of-function mutants at low temperatures. PMID- 29988153 TI - OsMATL mutation induces haploid seed formation in indica rice. AB - Intraspecific haploid induction in maize (Zea mays) is triggered by a native frameshift mutation in MATRILINEAL (MATL), which encodes a pollen-specific phospholipase. To develop a haploid inducer in rice (Oryza sativa), we generated an allelic series in the putative ZmMATL orthologue, OsMATL, and found that knockout mutations led to a reduced seed set and a 2-6% haploid induction rate. This demonstrates MATL functional conservation and represents a major advance for rice breeding. PMID- 29988154 TI - BIL1-mediated MP phosphorylation integrates PXY and cytokinin signalling in secondary growth. AB - Vascular cambium proliferation in plants is crucial for the generation of vascular tissues and for mechanical strength. Phytohormones and mobile peptides are key regulators of vascular cambial activity during secondary growth; however, the signalling cross-talk underlying their coordinated action is largely unknown. Here, we reveal that BIN2-LIKE 1 (BIL1), a glycogen synthase kinase 3, integrates the PHLOEM INTERCALATED WITH XYLEM/tracheary element differentiation inhibitory factor (TDIF) RECEPTOR (PXY/TDR) module into MONOPTEROS/AUXIN RESPONSE FACTOR 5 (MP/ARF5) transcription factor action during secondary growth. BIL1-mediated phosphorylation of MP/ARF5 enhances its negative effect on vascular cambial activity, which upregulates the negative regulators of cytokinin signalling ARABIDOPSIS RESPONSE REGULATOR 7 (ARR7) and ARR15. PXY/TDR inhibits BIL1 activity, which attenuates the effect of MP/ARF5 on ARR7 and ARR15 expression, thus increasing vascular cambial activity. Together, these results suggest that BIL1 is a key mediator that links peptide signalling with auxin-cytokinin signalling for the maintenance of cambial activity. PMID- 29988155 TI - Polymorphic residues in rice NLRs expand binding and response to effectors of the blast pathogen. AB - Accelerated adaptive evolution is a hallmark of plant-pathogen interactions. Plant intracellular immune receptors (NLRs) often occur as allelic series with differential pathogen specificities. The determinants of this specificity remain largely unknown. Here, we unravelled the biophysical and structural basis of expanded specificity in the allelic rice NLR Pik, which responds to the effector AVR-Pik from the rice blast pathogen Magnaporthe oryzae. Rice plants expressing the Pikm allele resist infection by blast strains expressing any of three AVR-Pik effector variants, whereas those expressing Pikp only respond to one. Unlike Pikp, the integrated heavy metal-associated (HMA) domain of Pikm binds with high affinity to each of the three recognized effector variants, and variation at binding interfaces between effectors and Pikp-HMA or Pikm-HMA domains encodes specificity. By understanding how co-evolution has shaped the response profile of an allelic NLR, we highlight how natural selection drove the emergence of new receptor specificities. This work has implications for the engineering of NLRs with improved utility in agriculture. PMID- 29988156 TI - Ben Collen (1978-2018). PMID- 29988157 TI - Information integration. PMID- 29988158 TI - Genomic signatures of mitonuclear coevolution across populations of Tigriopus californicus. AB - The copepod Tigriopus californicus shows extensive population divergence and is becoming a model for understanding allopatric differentiation and the early stages of speciation. Here, we report a high-quality reference genome for one population (~190 megabases across 12 scaffolds, and ~15,500 protein-coding genes). Comparison with other arthropods reveals 2,526 genes presumed to be specific to T. californicus, with an apparent proliferation of genes involved in ion transport and receptor activity. Beyond the reference population, we report re-sequenced genomes of seven additional populations, spanning the continuum of reproductive isolation. Populations show extreme mitochondrial DNA divergence, with higher levels of amino acid differentiation than observed in other taxa. Across the nuclear genome, we find elevated protein evolutionary rates and positive selection in genes predicted to interact with mitochondrial DNA and the proteins and RNA it encodes in multiple pathways. Together, these results support the hypothesis that rapid mitochondrial evolution drives compensatory nuclear evolution within isolated populations, thereby providing a potentially important mechanism for causing intrinsic reproductive isolation. PMID- 29988160 TI - Copepod incompatibilities. PMID- 29988159 TI - Personal and transgenerational cues are nonadditive at the phenotypic and molecular level. AB - Organisms can gain information about their environment from their ancestors, their parents or their own personal experience. 'Cue integration' models often start with the simplifying assumption that information from different sources is additive. Here, we test key assumptions and predictions of cue integration theory at both the phenotypic and molecular level in threespined sticklebacks (Gasterosteus aculeatus). We show that regardless of whether cues about predation risk were provided by their father or acquired through personal experience, sticklebacks produced the same set of predator-adapted phenotypes. Moreover, there were nonadditive effects of personal and paternal experience: animals that received cues from both sources resembled animals that received cues from a single source. A similar pattern was detected at the molecular level: there was a core set of genes that were differentially expressed in the brains of offspring regardless of whether risk was experienced by their father, themselves or both. These results provide strong support for cue integration theory because they show that cues provided by parents and personal experience are comparable at both the phenotypic and molecular level, and draw attention to the importance of nonadditive responses to multiple cues. PMID- 29988161 TI - Morphological novelty emerges from pre-existing phenotypic plasticity. AB - Plasticity-first evolution (PFE) posits that novel features arise when selection refines pre-existing phenotypic plasticity into an adaptive phenotype. However, PFE is controversial because few tests have been conducted in natural populations. Here we present evidence that PFE fostered the origin of an evolutionary novelty that allowed certain amphibians to invade a new niche-a distinctive carnivore morph. We compared morphology, gene expression and growth of three species of spadefoot toad tadpoles when reared on alternative diets: Scaphiopus holbrookii, which (like most frogs) never produce carnivores; Spea multiplicata, which sometimes produce carnivores, but only through diet-induced plasticity; and Spea bombifrons, which often produce carnivores regardless of diet. Consistent with PFE, we found diet-induced plasticity-in morphology and gene expression-in Sc. holbrookii, adaptive refinement of this plasticity in Sp. multiplicata, and further refinement of the carnivore phenotype in Sp. bombifrons. Generally, phenotypic plasticity might play a significant, if underappreciated, role in evolutionary innovation. PMID- 29988163 TI - Simplicity from complex interactions. PMID- 29988162 TI - Drug-mediated metabolic tipping between antibiotic resistant states in a mixed species community. AB - Microbes rarely exist in isolation, rather, they form intricate multi-species communities that colonize our bodies and inserted medical devices. However, the efficacy of antimicrobials is measured in clinical laboratories exclusively using microbial monocultures. Here, to determine how multi-species interactions mediate selection for resistance during antibiotic treatment, particularly following drug withdrawal, we study a laboratory community consisting of two microbial pathogens. Single-species dose responses are a poor predictor of community dynamics during treatment so, to better understand those dynamics, we introduce the concept of a dose-response mosaic, a multi-dimensional map that indicates how species' abundance is affected by changes in abiotic conditions. We study the dose-response mosaic of a two-species community with a 'Gene * Gene * Environment * Environment' ecological interaction whereby Candida glabrata, which is resistant to the antifungal drug fluconazole, competes for survival with Candida albicans, which is susceptible to fluconazole. The mosaic comprises several zones that delineate abiotic conditions where each species dominates. Zones are separated by loci of bifurcations and tipping points that identify what environmental changes can trigger the loss of either species. Observations of the laboratory communities corroborated theory, showing that changes in both antibiotic concentration and nutrient availability can push populations beyond tipping points, thus creating irreversible shifts in community composition from drug-sensitive to drug-resistant species. This has an important consequence: resistant species can increase in frequency even if an antibiotic is withdrawn because, unwittingly, a tipping point was passed during treatment. PMID- 29988164 TI - Concordant divergence of mitogenomes and a mitonuclear gene cluster in bird lineages inhabiting different climates. AB - Metabolic processes in eukaryotic cells depend on interactions between mitochondrial and nuclear gene products (mitonuclear interactions). These interactions could have a direct role in population divergence. Here, we study mitonuclear co-evolution in a widespread bird that experienced population divergence followed by bidirectional mitochondrial introgression into different nuclear backgrounds. Using >60,000 single nucleotide polymorphisms, we quantify patterns of nuclear genetic differentiation between populations that occupy areas with different climates and harbour deeply divergent mitochondrial lineages despite ongoing nuclear gene flow. We find that strong genetic differentiation and sequence divergence in a region of ~15.4 megabases on chromosome 1A mirror the geographic pattern of mitochondrial DNA divergence. This result is seen in two different transects representing populations with different nuclear backgrounds. The chromosome 1A region is enriched for genes performing mitochondrial functions (N-mt genes). Molecular signatures of selective sweeps in this region alongside those in the mitochondrial genome suggest a history of adaptive mitonuclear co-introgression. Moreover, evidence for large linkage disequilibrium blocks in this genomic region suggests that low recombination could facilitate functional interactions between co-evolved nuclear alleles. Our results are consistent with mitonuclear co-evolution as an important mechanism for population divergence and local adaptation. PMID- 29988165 TI - Handling unpredictable ecosystems. PMID- 29988166 TI - A reindeer cull to prevent chronic wasting disease in Europe. PMID- 29988167 TI - Coexistence of many species in random ecosystems. AB - Rich ecosystems harbour thousands of species interacting in tangled networks encompassing predation, mutualism and competition. Such widespread biodiversity is puzzling, because in ecological models it is exceedingly improbable for large communities to stably coexist. One aspect rarely considered in these models, however, is that coexisting species in natural communities are a selected portion of a much larger pool, which has been pruned by population dynamics. Here we compute the distribution of the number of species that can coexist when we start from a pool of species interacting randomly, and show that even in this case we can observe rich, stable communities. Interestingly, our results show that, once stability conditions are met, network structure has very little influence on the level of biodiversity attained. Our results identify the main drivers responsible for widespread coexistence in natural communities, providing a baseline for determining which structural aspects of empirical communities promote or hinder coexistence. PMID- 29988168 TI - CO2 emissions boost the benefits of crop production by farming damselfish. AB - Farming is a technique employed by both humans and animals to enhance crop yields, allowing their populations to increase beyond the natural carrying capacity of the environment. Using volcanic CO2 vents, we investigate how a species of herbivorous fish (the black scalyfin Parma alboscapularis) may use increasing anthropogenic CO2 emissions to enhance its crop yields. We found that these farming fish can take advantage of this resource enrichment, to grow crops within smaller territories and increase the capacity of the environment to support more densely packed fish populations. PMID- 29988169 TI - An early trend towards gigantism in Triassic sauropodomorph dinosaurs. AB - Dinosaurs dominated the terrestrial ecosystems for more than 140 Myr during the Mesozoic era, and among them were sauropodomorphs, the largest land animals recorded in the history of life. Early sauropodomorphs were small bipeds, and it was long believed that acquisition of giant body size in this clade (over 10 tonnes) occurred during the Jurassic and was linked to numerous skeletal modifications present in Eusauropoda. Although the origin of gigantism in sauropodomorphs was a pivotal stage in the history of dinosaurs, an incomplete fossil record obscures details of this crucial evolutionary change. Here, we describe a new sauropodomorph from the Late Triassic of Argentina nested within a clade of other non-eusauropods from southwest Pangaea. Members of this clade attained large body size while maintaining a plesiomorphic cyclical growth pattern, displaying many features of the body plan of basal sauropodomorphs and lacking most anatomical traits previously regarded as adaptations to gigantism. This novel strategy highlights a highly accelerated growth rate, an improved avian-style respiratory system, and modifications of the vertebral epaxial musculature and hindlimbs as critical to the evolution of gigantism. This reveals that the first pulse towards gigantism in dinosaurs occurred over 30 Myr before the appearance of the first eusauropods. PMID- 29988170 TI - ? PMID- 29988172 TI - Principal component analysis of factors for sensitization to Anisakis spp. in postpartum women. AB - Introduction: Immunoreactivity to Anisakis spp. is believed to be associated with frequency of fish intake. The objective of this study was to evaluate, using principal component analysis, the main factors potentially involved in reactivity to these nematodes in postpartum women. Methods: Retrospective study conducted on a database of 309 postpartum women. All completed a structured questionnaire and had blood samples collected for ELISA analysis of specific immunoglobulins against total Anisakis spp. antigens and assessment of reactivity. Parametric and nonparametric tests were used to assess factors for sensitization in the reactive and nonreactive groups, and a principal component analysis was performed. A Pearson correlation matrix with varimax rotation was used to assess the variables of interest (place of residence, age, number of prenatal visits, type of birth facility, fish intake and frequency, raw fish intake, fish handling, history of allergies). Results: After exclusions, samples from 203 women were assessed. Of these, 52 (25.6%) were reactive for anti-Anisakis IgG. Most women claimed not to handle fish (n = 121) and eat fish only sporadically (n = 71). Significant differences in age were seen between the reactive and nonreactive groups (p = 0.001). The first two components explained 32.55% and 38.94% of variances in the nonreactive and reactive groups respectively. The adjusted matrix assigned greater probabilistic weight to weekly intake frequency (0.804), followed by raw fish intake (0.759), with differences in relation to the nonreactive group. Conclusion: Correlation matrices revealed a direct relationship between seroreactivity to Anisakis spp. and frequency of fish intake in a sample of postpartum women. PMID- 29988171 TI - Detection, molecular typing and phylogenetic analysis of Leishmania isolated from cases of leishmaniasis among Syrian refugees in Lebanon. AB - Leishmania is a parasitic protozoan with more than two-dozen species causing the disease leishmaniasis. It is transmitted to humans through the bite of an infected female phlebotomine sand-fly vector. In the past two years the incidence of leishmaniasis has been drastically increasing in Lebanon. This was in parallel with the deterioration of the security in Syria forcing thousands to flee and seek shelter in poorly maintained refugee camps and collective shelters. Cutaneous leishmaniasis (CL) is now considered a public health problem, but its epidemiology has not been fully elucidated. To our knowledge, this is the first study comparing two different molecular methods for the detection and identification of Leishmania tropica in Lebanon. Two molecular typing methods of 39 FFPE Leishmania isolates were used: the ITS1-PCR RFLP and the nested ITS1-5.8S rDNA gene amplification followed by sequencing and phylogenetic analysis. The efficiency of these two techniques in Leishmania identification was compared and the phylogenetic relationships among these isolates were illustrated based on the neighbor-joining (NJ) method. The results were statistically correlated with the parasitic index (PI). The DNA storage in formalin-fixed paraffin embedded (FFPE) tissues was assessed as well. The parasites identified were all L. tropica as determined by both techniques. ITS1-5.8S rDNA gene based typing proved to be more sensitive in the detection of parasites (positive in 69.2% of the isolates) as opposed to the ITS1-PCR RFLP method that was successful in identifying L. tropica in only 43.6% of the isolates. Sequencing and phylogenetic analysis revealed high levels of heterogeneity. A statistically significant correlation was observed between PI and the results of the nested ITS1-5.8S rDNA gene PCR. Genotyping at the species level is essential for monitoring the relative frequency of CL in the Mediterranean area that is correlated to three different Leishmania species (Leishmania infantum, Leishmania major and L. tropica), each characterized by distinct epidemiological features. The obtained results highlight the need to find a universally accepted diagnostic tool for Leishmania typing. PMID- 29988173 TI - Assessment and determination of LC50 of carvacrol and salicylic acid analogues with acaricide activity in larvae and adult ticks of Rhipicephalus (Boophilus) microplus. AB - Rhipicephalus (Boophilus) microplus is a tick that causes huge economic losses in cattle. The indiscriminate use of acaricides has generated resistance to most compounds present on the market. Carvacrol and salicylic acid have been widely studied for their biological activities and have been evaluated in different strains of Rhipicephalus. In this research the analogues carvacrol and salicylic acid were evaluated in larvae of R. (B.) microplus with data obtained in larval packet test (LPT) and larval immersion test (LIT). A lethal concentration 50 (LC50) was assessed. The most potent compounds were evaluated in the adult ticks since there are no reports of evaluation in the life state of the parasite. From all the tested compounds, the ethyl 2-methoxybenzoate (91.82 +/- 1.66%, 0.91 MUmol/mL) and ethyl 2,5-dihydroxybenzoate (89.14 +/- 1.61%, 2.04 MUmol/mL) showed the highest percentage of mortality and the lowest LC50. They were found to be the best candidates for a study in vivo. PMID- 29988174 TI - Effect of gamma radiation on life history traits of Aedes aegypti (L.). AB - Aedes aegypti is an important vector for Dengue and Dengue hemorrhagic fever. Considering its medical importance and its relevance as a model system, this study was undertaken to evaluate the impact of different doses of gamma radiation for three generations of A. aegypti. Two to three days old virgin males of A. aegypti were irradiated with 15 doses of gamma radiation, ranging from 1 to 50 Gy and were immediately mass mated with the same aged virgin females. Observations were made for changes on their life history traits, particularly fecundity, hatchability, adult emergence, sex ratio and longevity, for three generations. Adult males exposed 30, 35, 40, 45 and 50 Gy doses showed a significant decrease in fecundity in F0 generations. While hatchability was observed to have decreased with increasing radiation doses from 3 Gy onwards in the F1 generation, samples irradiated with 30, 35, 40, 45 and 50 Gy maintained significant decline in hatchability in their succeeding generations, F2 and F3 also. Similarly, a decline was observed in adult emergence from 3 Gy onwards in all three generations. A male favoring sex ratio distortion was observed at the doses of 35, 40, 45 and 50 Gy in all three generations. Following exposure to 4 Gy, parental males and the resultant progeny showed increased longevity by 10.56 and 8.66 days respectively. Similarly, the F1 generations of samples irradiated with 30, 35 and 40 Gy exhibited an increase in longevity by 7.16, 7.44 and 6.64 days respectively. Dose response curve for fertility among the three generations was drawn and presented. The effect of radiological exposure on the life history traits of A. aegypti varies with dose for the three generations studied. These results have potential implications in mutational studies and risk assessment and also contribute to a better understanding towards employment of the sterile insect technique in A. aegypti, plausibly paving the way to an effective mosquito genetic control program. PMID- 29988175 TI - Study of the pathogenic potential of Dientamoeba fragilis in experimentally infected mice. AB - Dientamoebafragilis (D. fragilis) is a protozoan parasite whose pathogenic potential is still disputable. The aim of this study was to illustrate the pathogenicity of D. fragilis infection and to determine the infective dose for experimental mice infection. Three groups of mice (8/each) were orally inoculated with in vitro cultured D. fragilis. The infected groups (G1- G3) received 103, 105 and 4 * 106D. fragilis/0.5 ml culture, respectively. A control group (G4) only received parasite-free culture. Two weeks post-inoculation all mice were euthanized for histopathological examination. All mice of G3 (100%) and three mice of G2 (37.5%) were infected, and the results were confirmed by PCR and different staining methods. On the other hand, all mice from group G1 showed a completely negative result. Histopathological examination of the colon and caecum of the highly infected group G3 showed active colitis, with infiltration of mixed inflammatory cells such as eosinophils, neutrophils and lymphocytes within the lamina propria of the intestinal wall. The parasite was not invading the colonic mucosa. This study revealed that infection with D. fragilis is dose-dependent. Moreover, a dose of 105D. fragilis/mouse or higher is necessary to infect mice through the oral route. In addition, this route of infection, although non invasive, can induce severe inflammatory changes to the colonic and caecal mucosa in experimentally infected mice. PMID- 29988176 TI - Environmental factors and the risk of urinary schistosomiasis in Ile Oluji/Oke Igbo local government area of Ondo State. AB - Geographic information systems are being increasingly used to show the distributions of disease where data for specific environmental risk factors are available. For successful transmission of schistosomiasis, suitable climatic conditions and biological events must coincide; hence its distribution and prevalence are greatly influenced by environmental factors affecting the population of snail intermediate hosts and human hosts. Prevalence and demographic data was obtained by parasitological examination of urine samples and questionnaire administration. The mean values of environmental factors corresponding to the local government area were obtained from remotely sensed images and data from climate research unit. The effects of the environmental factors were determined by using regression analysis to analyse the correlation of environmental factors to prevalence of schistosomiasis. There was a negative correlation between infection and elevation. There was a positive correlation between vegetation, rainfall, slope, temperature and prevalence of infection. There was also a weak negative correlation between proximity to water body and prevalence. The result shows the study area to be at low to high risk of infection. PMID- 29988177 TI - Current status of schistosomiasis in Sokoto, Nigeria. AB - The study was conducted in poor communities, where most of the population is dependent on river and well for their everyday activities. In this study 5 years 15 years aged children were sampled for schistosomiasis (Urinary and intestinal), using of urine and stool samples. The stool samples were analyzed using kato-katz thick faecal smear technique while the urine samples were analyzed by filtration technique. The overall prevalence of urinary schistosomiasis (Schistosoma haematobium) was 60.8% (228 positive cases in 375 samples), and for intestinal schistosomiasis (Schistosoma mansoni) was 2.93% (11 positive in 375 samples). The order of infection based on social status (occupation of pupil's parents) was farmers > fishermen > traders > civil servents > others. The prevalence of infection based on pupil's water contact activities such as farming associated 84.87% urinary schistosomiasis, followed by swimming (78.21%). Occurrence of urinary schistosomiasis based on source of pupil's drinking water; highest infection was reported among those that drink dam water (75.24%) while least infection was occurred whose drinking water was from bore-whole (17.64%). Prevalence of urinary schistosomiasis in the studied area is therefore very high and family status, means of water contact and availability of drinking water dependent. Therefore there is urgent need to adapt preventive measures, provision of safe drinking water as well as control programmes for vector snails, immediately. PMID- 29988178 TI - Seroepidemiology of Strongyloides stercoralis amongst immunocompromised patients in Southwest Iran. AB - Strongyloidiasis is a life-threatening parasitic infection, especially in immunosuppressed patients, with death often occurring within several days. The disease has a worldwide distribution and is endemic in tropical and subtropical regions. Therefore, this study was conducted to investigate seroepidemiology of Strongyloides infection amongst immunocompromised patients in Southwest Iran. This cross-sectional study was conducted amongst a population of immunocompromised patients who were referred to health care or hospital referral centres in Ahvaz, Southwest Iran. Serum samples were tested by an enzyme immunoassay for anti-IgG Strongyloides antibody. Anti-Strongyloides stercoralis antibody was detected in 39 of 270 immunocommpromised cases, yielding a prevalence of 14.4%. No significant differences were indicated in terms of gender, age, or type of immunocompromised disorder with anti-Strongyloides stercoralis antibody levels. In conclusion, our results demonstrated high seroepidemiology of infection with this parasite in the region. Therefore, it appears immunocompromised patients should be tested for this infection using sensitive tests. However, current research underscores that strongyloidosis must not be neglected, and further assessments in high risk population are warranted. PMID- 29988180 TI - Spatial analysis and identification of environmental risk factors affecting the distribution of Indoplanorbis and Lymnaea species in semi-arid and irrigated areas of Haryana, India. AB - Fasciolosis, amphistomosis and schistosomosis, transmitted by the freshwater snail species Indoplanorbis and Lymnaea, are important snail-borne diseases in India as they affect the entire spectrum of domestic animals causing substantial mortality and economic loss. Identifying any heterogeneity in the spatial distribution of these snail-borne diseases will allow for targeted disease control and efficient use of resources. The objectives of this study were threefold: (i) to describe and explore the spatial distribution of Indoplanorbis and Lymnaea in Rohtak and Jhajjar districts of Haryana, India (ii) to identify factors associated with occurrence of these freshwater snail species and (iii) to produce a map showing the predicted risk of occurrence of Lymnaea and Indoplanorbis spp. in the study area. Snails were collected from water bodies of 99 settlements out of a total of 453 in the study area. Kernel smoothing was used to generate a kernel ratio map while Kulldorff's spatial scan statistic was used to detect clusters of settlements with a high/low risk. Multivariable logistic regression showed that snails were almost ten times more likely to be present in rice-growing areas than in those not growing rice (OR 9.24) and that snails were less likely to be present with each 1 km increase in distance from a canal (OR 0.86). The regression model was used to produce a map illustrating the predicted risk of snail occurrence. Since the distribution of vector snails mirrors the distribution of snail-borne parasitic diseases, such spatial analysis helps to determine the relative risk of snail-infestation as well as snail-borne diseases' distribution and planning of control activities. PMID- 29988179 TI - Orally-transmitted Chagas disease: Epidemiological, clinical, serological and molecular outcomes of a school microepidemic in Chichiriviche de la Costa, Venezuela. AB - Oral transmission of Trypanosoma cruzi is a frequent cause of acute Chagas disease (ChD). In the present cross-sectional study, we report the epidemiological, clinical, serological and molecular outcomes of the second largest outbreak of oral ChD described in the literature. It occurred in March 2009 in Chichiriviche de la Costa, a rural seashore community at the central littoral in Venezuela. The vehicle was an artisanal guava juice prepared at the local school and Panstrongylus geniculatus was the vector involved. TcI genotype was isolated from patients and vector; some showed a mixture of haplotypes. Using molecular markers, parasitic loads were high. Eighty-nine cases were diagnosed, the majority (87.5%) in school children 6-15 years of age. Frequency of symptomatic patients was high (89.9%) with long-standing fever in 87.5%; 82.3% had pericardial effusion detected by echocardiogram and 41% had EKG abnormalities. Three children, a pregnant woman and her stillborn child died (5.6% mortality). The community was addressed by simultaneous determination of specific IgG and IgM, confirmed with indirect hemagglutination and lytic antibodies. Determination of IgG and IgA in saliva had low sensitivity. No individual parasitological or serological technique diagnosed 100% of cases. Culture and PCR detected T. cruzi in 95.5% of examined individuals. Based on the increasing incidence of oral acute cases of ChD, it appears that food is becoming one of the most important modes of transmission in the Amazon, Caribbean and Andes regions of America. PMID- 29988181 TI - Spatial analysis on the risk of bovine cysticercosis occurrence in the state of Espirito Santo, Brazil. AB - A map of the risk of bovine cysticercosis occurrence was developed for the state of Espirito Santo, Brazil, and it was based in a mathematic model based on following variables: inadequate sewage, bovine population by county, use and occupation of the land and flood risks in GIS environ by means of the ArcGIS/ArcINFO 10.1 program. The work aims to spatially analyze the risk of bovine cysticercosis occurrence in the state of Espirito Santo, by means of risk factors related to cysticercosis and compare with the prevalence obtained from slaughterhouses in the same area. The map of risk showed areas high risk and very high risk located mainly in Ecoporanga, Linhares, counties, where the prevalence from slaughterhouses are low, and in two counties of south macro-region, Presidente Kennedy and Itapemirim, where prevalence from slaughterhouses are higher. PMID- 29988182 TI - Histochemical and molecular evaluation of the prevalence of Leishmania spp. in hematophagous insects. AB - The prevalence study of Leishmania spp. in hematophagous insects captured from the environment in bat roosts and pigeon nests, or feeding their hosts (cattle, pigs, horses, dogs and humans) in urban, peri-urban and rural areas, between 2012 and 2014. For this study, the amastigotes present in these insects were detected by histochemical and PCR techniques. Positive gene amplification for Leishmania was found in two horseflies of the species Tabanus importunus collected in the environment, and amastigote forms of Leishmania spp., as well as erythrocytes and leukocytes, were histochemically detected in one of that insect. The other analyzed insects were not positive by PCR our by direct parasitological examination. Only horseflies captured in urban and peri-urban areas were positive. During the collection, no phlebotomine sand flies were captured in rural areas far from the city limits. It can be concluded that the discovery of horseflies positive for Leishmania spp. in urban and peri-urban areas indicates the likelihood that urban areas and their surroundings provide vector parasites with an environment suitable for the spread and consequent perpetuation of the biological cycle of this protozoan. PMID- 29988183 TI - Short communication: Epidemiological assessment of Strongyloides stercoralis in Fijian children. AB - As a part of the lymphatic filariasis (LF) transmission assessment survey (TAS)/soil-transmitted helminths (STH) prevalence survey in Western Division of Fiji, a pilot screen for Strongyloides stercoralis (SS) in school children was undertaken using a combination of the Baermann concentration (BC) method and real time PCR assays. Using BC, faecal samples collected from 111 children of 7 schools were examined. A single child was positive for larvae of SS and underwent a clinical examination finding an asymptomatic infection. Other members of this child's household were screened with BC, finding none infected. Aliquots of 173 faecal samples preserved in ethanol originating from all schools were examined by real-time PCR, and the prevalence of SS infection was 3.5%. Our study confirms the existence of SS infection on Fiji and showed that assessing SS prevalence alongside TAS/STH survey is a convenient access platform, allowing introduction of other surveillance techniques such as BC and real-time PCR. PMID- 29988184 TI - Anthelmintics efficacy against intestinal strongyles in horses of Sardinia, Italy. AB - Intestinal strongyles (IS) are the most important parasites of equids, due to their high prevalence worldwide, pathogenicity and the spread of drug-resistant populations. Despite the large number of horses bred in Sardinia Island, Italy, no data are available on the efficacy of anthelmintic compounds in the control of horse strongylosis. Therefore the aim of the present study was to evaluate the efficacy of five commercial anthelmintic formulations containing fenbendazole (FBZ), pyrantel (PYR), moxidectin (MOX) and two ivermectin formulations (IVM1 and IVM2) against IS in Sardinia by performing a fecal egg count reduction test (FECRT) and investigating the egg reappearance period (ERP) after treatment. In total, 74 horses from 7 farms were examined. Coprocultures performed for individual fecal samples collected at the day of the treatment revealed that cyathostomins were the predominant parasitic species (98.6%). The FECR for all horses belonging to the treatment groups after two weeks was >= 95% with a 95% C.I. > 90%. The expected ERP did not decrease in any of the treatment group as FECR values < 90% were found at D60 for FBZ, at D90 for PYR and IVM1, at D150 for IVM2. All horses treated with MOX showed FECRT > 90% for the entire duration of the trial until D150. The results of the present survey indicate that drug resistant cyathostomin populations are not present in the examined horse population, contrariwise to what observed in other Italian and European regions. The reasons and implications of these results are discussed. PMID- 29988185 TI - Prevalence and intensity of human soil transmitted helminth infections in the Akonolinga health district (Centre Region, Cameroon): Are adult hosts contributing in the persistence of the transmission? AB - Background: Soil-transmitted helminthiases (STHs) are among the most prevalent afflictions of the developing world, with approximately 2 billion people infected worldwide. Heavily infected individuals suffer from severe morbidity that can result in death. These parasitic diseases also impair physical and mental growth in childhood, thwart educational advancement, and hinder economic development. Periodic deworming with Albendazole or Mebendazole of high-risk groups (school age children, preschool children, and pregnant women) can significantly lower the levels of infections below the threshold associated with morbidity. However, an important proportion of the population (adults) is excluded from this high-risk group treatment based-strategy, and might lead to the persistence of these diseases in endemic areas despite the repeated treatments. The main objective of this study was to evaluate the contribution of this neglected at-risk group in the spread and persistence of STH in Cameroon. Methods: A cross sectional survey was conducted in the Akonolinga health district (Centre Region, Cameroon) to assess the prevalence and intensity of these helminth infections. Stool samples were collected from males and females, aged 18 years and over, and analyzed using the Kato-Katz technique. Results: A total of 334 patients, among which 181 (54.2%) females and 153 (45.8%) males, were examined. The STH of major concern was found in this group of individuals, with overall prevalence equal to 18.0% (95% CI: 14.2-22.4) for Ascaris lumbricoides, 43.7% (95% CI: 38.5-49.1) for Trichuris trichiura, and 7.5% (95% CI: 5.1-10.8) for Necator americanus. Conclusion: This study reveals that STH infections are prevalent in adults in the Akonolinga health district, with moderate to high risk and light intensity of infection. These infected adults might constitute a potential parasite reservoir and a source of dissemination and persistence of these infections, highlighting the need to really take into account this neglected group of individuals in the mass treatment policy. PMID- 29988186 TI - Analysing risk factors of co-occurrence of schistosomiasis haematobium and hookworm using bivariate regression models: Case study of Chikwawa, Malawi. AB - Schistosomiasis and soil-transmitted helminth (STH) infections constitute a major public health problem in many parts of sub-Saharan Africa. In areas where prevalence of geo-helminths and schistosomes is high, co-infection with multiple parasite species is common, resulting in disproportionately elevated burden compared with single infections. Determining risk factors of co-infection intensity is important for better design of targeted interventions. In this paper, we examined risk factors of hookworm and S. haematobium co-infection intensity, in Chikwawa district, southern Malawi in 2005, using bivariate count models. Results show that hookworm and S. haematobium infections were much localised with small proportion of individuals harbouring more parasites especially among school-aged children. The risk of co-intensity with both hookworm and S. haematobium was high for all ages, although this diminished with increasing age, increased with fishing (hookworm: coefficient. = 12.29; 95% CI = 11.50-13.09; S. haematobium: 0.040; 95% CI = 0.0037, 3.832). Both infections were abundant in those with primary education (hookworm: coef. = 0.072; 95% CI = 0.056, 0.401 and S. haematobium: coef. = 0.286; 95% CI = 0.034, 0.538). However, much lower risk was observed for those who were farmers (hookworm: coef. = - 0.349, 95% CI = - 0.547,-0.150; S. haematobium: coef. - 0.239, 95% CI = - 0.406, 0.072). In conclusion, our findings suggest that efforts to control helminths infection should be co-integrated and health promotion campaigns should be aimed at school-going children and adults who are in constant contact with water. PMID- 29988187 TI - ? PMID- 29988188 TI - ? PMID- 29988189 TI - Review on distribution of endo-parasites of fish in Ethiopia. AB - Recently the government of Ethiopia paid great attention to livestock and fish production sectors of the country. As evidence, the sector is organized in the form of ministry, Ethiopian Ministry of Livestock and Fisheries. This is great progress in the history of the country. These and other focuses given to the sector are expected to dramatically change the eating habit of the community towards fish meat as well as fish production trends of the country. However; parasitic diseases of fish are great challenges in the processes of fish production in Ethiopia and hence, the primary goal of this paper is to compile all available information concerning distribution of endo-parasites of fish in the country and provide the necessary information for policy makers, investors and researchers interested in the field. In line with the objective of this paper, there are many reports on helminth endo-parasites of fish in Ethiopia reported by different authors with different prevalence's from different corners of the country. Digenean trematodes, nematodes and cestodes are the major endo parasites reported from the different water bodies of the country. To mention some of the major species of parasites affecting different species of fish are: Clinostomum and Euclinostomum species of trematodes, Contracaecum and Eustrongylides species of nematodes and Ligula intestinalis and Proteocephalus species of cestodes mainly affecting: Clarias gariepinus, Oreochromis niloticus, Barbus and Cyprinus carpio species of fish. Most reports showed that fish Endo parasite are more prevalent in Ethiopia in Lake Awassa, Lake Lugo (Hayke) and Lake Tana. In conclusion, endo-parasites of fish are highly prevalent in different water bodies of Ethiopia. Therefore, there should be a nationwide strategy in prevention and control of endo-parasites of fish, and further study on the economic and public health impact of these parasites should be studied. PMID- 29988190 TI - Bioefficacy of ecbolin A and ecbolin B isolated from Ecbolium viride (Forsk.) Alston on dengue vector Aedes aegypti L. (Diptera: Culicidae). AB - Ecbolin A and ecbolin B were isolated from ethyl acetate extract of Ecbolium viride (Forsk.) Alston root and evaluated for larvicidal and growth disturbance activities against Aedes aegypti L. (Diptera: Culicidae). For larvicidal activity, the third instar larvae of A. aegypti were exposed to different concentrations viz., 1.0, 2.5, 5.0 and 10 ppm for each compound. Among the two compounds screened, ecbolin B recorded highest larvicidal activity with LC50 and LC90 values of 0.70 and 1.42 ppm, respectively. In control, the larval behaviour was normal. The active compound ecbolin B was tested for growth disruption activity at sub lethal concentrations viz., 0.5, 1.0 ppm and observed for malformation like larval gut elongation, larval longevity, intermediates, malformed adults, failed adult emergence and compared with methoprene. The results showed significant level of larva-pupa intermediates, pupa-adult intermediates, malformed adult emergence and less adult formation against A. aegypti. The histopathological results revealed a severe damage on the midgut epithelial columnar cells (CC) and cuboidal cells (CU) in ecbolin B treated larvae of A. aegypti. Similarly peritrophic membrane (pM) was also observed to be damaged in the treated larvae. The present results suggest that, ecbolin B could be used as a larvicidal agent against dengue vector A. aegypti. PMID- 29988191 TI - Analysis of Plasmodium vivax Apical Membrane Antigen-1 (PvAMA-1) Haplotypes among Iranian Isolates. AB - Plasmodium vivax apical membrane antigen-1(PvAMA-1) is a surface protein with polymorphic sites. This study was aimed to analyze the polymorphic amino acid residues at PvAMA-1 in different infected age groups. 92 blood samples were collected from the south and southeast of Iran. The DNA coding for the domain I (DI), DII, and partial DIII of this antigen was amplified by Nested-PCR, and sequenced. Nucleotide mutations were found in 49 sites and based on the amino acid sequence, 30 variable sites were detected. Age distribution of malaria cases showed that the majority of the patients were between 10 to 30 years old. The scattering plot haplotypes by age showed an increasing incidence rate with age during childhood, whereas, incidence was the lowest in patients under five years old. Comparison of the polymorphic sites of PvAMA-1 in Iranian isolates with those found in other geographic regions of the world indicated nine common variable positions. In addition, a significant dependence was found between some particular substitutions and age categories. Dependence between particular substitutions and age groups suggests that certain residues in AMA-1 are responsible for clinical attacks in different ages, likely as a result of host immune pressure. The crystal structure of the PvAMA-1 showed that the amino acid substitutions that changed the protein charge were exclusively located in loops and turns where, the interactions with antibodies could occur. These data provide the necessary information for an AMA-1 based malaria vaccine design to be effective across all ages. PMID- 29988192 TI - Evaluation of recombinant K39 antigen and various promastigote antigens in sero diagnosis of visceral leishmaniasis in Bangladesh. AB - Background: Definitive diagnosis of visceral leishmaniasis (VL) by demonstrating parasites in tissue smears or by culture involves invasive procedures, technical expertise and adequate laboratory facilities. Endemic countries rely mainly on serological tests to diagnose VL. Currently, the immunochromatographic test incorporating the recombinant K39 antigen (rK39 ICT) is the reference test for rapid diagnosis of VL in the Indian subcontinent. The performance of serological tests using rK39 and other promastigote antigens can vary due to differences in antigen expression, the various hosts and environmental factors. To achieve elimination of VL, diagnostic accuracy will be necessary for active case detection especially in those who carry asymptomatic infections. We evaluated the performance of rK39 ICT, enzyme linked immunosorbent assay using mixed Leishmania promastigotes from different Leishmania species (p-ELISA) and indirect fluorescent antibody test (IFAT) utilizing whole promastigotes from the Leishmania donovani complex for sero-diagnosis of VL in Bangladesh. Methods: The sensitivity of each serological test was evaluated on 155 patients who were diagnosed to have VL by microscopy and/or by culture methods. Test specificities were calculated on 706 healthy blood donors, 91 diagnostic sera from patients with a febrile illness and sera from patients positive for malaria (n = 91) and Chagas disease (n = 91). All statistical calculations were at 95% confidence intervals. Results: The sensitivities of rK39 ICT, p-ELISA and IFAT were 100%, 86.5% and 92.3%, respectively. All three serological methods had a pooled sensitivity of 82.6%. The specificities of rK39 ICT, p-ELISA and IFAT from combined control groups were 100%, 93.1% and 99.9%, respectively. The respective positive and negative predictive values of the tests were both 100% for rK39 ICT, 66.3% and 97.8% for p-ELISA and 99.3% and 98.8% for IFAT. The p-ELISA showed cross reactivity with 36.3% of sera positive for malaria and 28.6% of sera positive for Chagas disease while rK39 ICT and IFAT showed no cross reactivity. Conclusion: This study confirms the efficiency of rK39 ICT for rapid diagnosis of VL. The p-ELISA using mixed promastigote antigens did not perform well as a serological test for VL in Bangladesh. Due to high sensitivity and specificity of whole promastigote antigen of L. donovani complex utilized in IFAT, this test can be considered in combination with rK39 ICT to confirm VL diagnosis when clinical diagnosis cannot distinguish between other diseases. PMID- 29988193 TI - Sarcoptic mange and other ectoparasitic infections in a red fox (Vulpes vulpes) population from central Italy. AB - Fifty red foxes (Vulpes vulpes) from the district of Pisa (central Italy) were examined for ectoparasites. Sarcoptic mange was diagnosed on the presence of clearly visible skin lesions with confirmatory demonstration of Sarcoptes scabiei at parasitological and histopathological analysis. Ticks and fleas were collected directly from the carcases during post mortem examination, fixed and identified by morphological examination. For the detection of ear Malassezia and mite infections, cytological and parasitological examinations of ear wax samples were performed. All data were statistically analysed using a chi2 test with the Yates correction. An overall prevalence of 84% for ectoparasitic infections was found in examined subjects. In regard to isolated ectoparasites, 38%, 8%, 82%, 6% and 8% of foxes resulted positive for S. scabiei, Otodectes cynotis, Malassezia spp., fleas (Archaeopsylla erinacei, Pulex irritans, Ctenocephalides canis) and ticks (Ixodes ricinus and Rhipicephalus sanguineus), respectively. Malassezia ear infection was significantly more prevalent in animals older than 1 year (P < 0.01). Prevalence (38%), severity of lesions and poor body conditions observed in most Sarcoptes-infected animals indicate that sarcoptic mange should be considered the most important ectoparasitic infection of red foxes in the examined area. PMID- 29988194 TI - Trends and spatial patterns of mortality related to neglected tropical diseases in Brazil. AB - We analysed nationwide trends and spatial distribution of NTD-related mortality in Brazil. We included all death certificates in Brazil from 2000 to 2011, in which NTDs were recorded as any causes of death. A total of 100,814/12,491,280 (0.81%) death certificates were identified, which mentioned at least one NTD. Age adjusted NTD-related mortality rates showed a significant decrease over time (annual percent change [APC]: - 2.1%; 95% CI: - 2.8 to - 1.3), with decreasing mortality rates in the Southeast, South, and Central-West regions, stability in the Northeast region, and increase in the North region. We identified spatial and spatiotemporal high-risk clusters for NTD-related mortality in all regions, with a major cluster covering a wide geographic range in central Brazil. Despite nationwide decrease of NTD-related mortality in the observation period, regional differences remain, with increasing mortality trends especially in the socioeconomically disadvantaged regions of the country. The existence of clearly defined high-risk areas for NTD-related deaths reinforces the need for integrated prevention and control measures in areas with highest disease burden. PMID- 29988195 TI - Phytotherapy of chlorophyllin exposed Lymnaea acuminata: A new biotechnological tool for fasciolosis control. AB - Phytotherapy of chlorophyllin formulations against Fasciola gigantica infected Lymnaea acuminata under sunlight exposure was highly toxic against redia and cercaria larvae. Binary combinations (1:1 ratio) of chlorophyllin (CHL) + freeze dried cow urine (FCU) were more toxic against cercariae (8 h LC50: 9.6 mg L- 1) than single treatment with chlorophyllin (8 h LC50: 12.6 mg L- 1) in sunlight. The larvicidal activity of sunlight exposed CHL against rediae (8 h LC50: 13.5 mg L- 1) and cercariae (8 h LC50: 12.6 mg L- 1) was more pronounced than laboratory conditions CHL treatment (rediae- 8 h LC50: 305.9 mg L- 1; cercariae- 8 h LC50: 765.4 mg L- 1). Larvicidal activity of FCU was less than CHL and CHL + FCU against both redia and cercaria. Chlorophyllin and its formulations were more toxic against redia and cercaria larvae in sunlight than laboratory conditions. CHL and its different formulations may be used as potent larvicides against Fasciola gigantica larvae. Chlorophyllin formulations will be economical, ecologically sounder and their use in aquatic environment will be safe. PMID- 29988196 TI - Population genetic analysis of Anisakis simplex s.l. and Anisakis pegreffii (Nematoda, Anisakidae) from parapatric areas and their contact zone. AB - Genetic markers (ribosomal DNA and mitochondrial DNA) were used for molecular dissection of the Anisakis simplex sensu lato (s.l). complex populations. Host fish were caught off Moroccan coasts, where only Anisakis pegreffii is present, the sympatric area comprising Spanish coasts, and the Little Sole Bank fishing area from Nordeast Atlantic Ocean where the only present species is A. simplex sensu stricto(s.s.). Sequence variations in the amplification products were then assessed indirectly by digestion with restriction endonucleases or directly by sequencing for 623 L3 larvae. The sequences were used to infer the relationships between the two species under study using various methodological approaches. We reveal the high genetic diversity of Anisakis simplex s.s. and A. pegreffii in both mitochondrial and nuclear genes. We detected 10 and 2 fixed differences between A. simplex s.s and A. pegreffii in the Cox2 and ITS1, respectively. We found a proportion of putative hybrids below 20% with similar figures on the Atlantic and Mediterranean coasts. Moroccan hybrids were more similar to A. pegreffii reflecting backcrosses between these mixed genotypes and his ancestor A. pegreffii. We discuss the possible interpretation of these putative hybrids. PMID- 29988198 TI - First report of Anatoecus dentatus in domestic duck (Anas platyrhynchos domesticus, Linnaeus, 1978) from Southern India. AB - Parasitic infection is one of the prime causes for morbidity and mortality of ducks in India. Ducks have the habit of wading through the water resources especially paddy fields and feeding on snail which favours occurrence of various parasites. Among the parasites, lice infestation affects growth and productivity of ducks by way of irritation. Lice are well adapted as external parasites and usually are more a nuisance than a threat to their hosts. A nomadic farmer from Mannargudi area of Cauvery delta region of Tamil Nadu, India who had a flock of 1600 ducks reported continuous death of 700 ducks within a period of one month and brought a dead duck to Dept. of Veterinary Pathology for postmortem examination. Examination of entire body of duck prior to necropsy revealed the presence of live lice in the hairs around the junction of beak and head. About 7 lice specimens were collected and brought to Dept. of Veterinary Parasitology for identification. The lice specimens were processed and identified as Anatoecus dentatus based on the presence of 'tin opener' shaped effracter in the male genitalia. This is the first report of occurrence of these lice in ducks from Southern India. PMID- 29988197 TI - Macroecological patterns of American Cutaneous Leishmaniasis transmission across the health areas of Panama (1980-2012). AB - American Cutaneous Leishmaniasis (ACL) is a neglected vector-borne zoonosis that persists despite increasing socio-economic development and urbanization in Panama. Here, we investigate the association between environmental changes and spatio-temporal ACL transmission in the Republic of Panama (1980-2012). We employ a macroecological approach, where patterns of variation in ACL incidence at the spatially coarse-grained scale of health areas are studied considering factors linked to the ecology of ACL transmission. We specifically study impacts of climatic variability, measured by the different phases of El Nino Southern Oscillation (ENSO), within diverse ecosystems and sand fly (Diptera: Psychodidae) vector species, as well as heterogeneous local climatic patterns, deforestation, population growth rates, and changes in social marginalization. We found that over the study period, patterns of ACL incidence: (i) were asynchronous with clusters changing from east to west of the Panama Canal, (ii) trends increased in the west, and decreased or remained nearly constant in the east, independent of human population growth, (iii) generally increased in years following El Nino, and (iv) decreased as forest cover increased. We found no significant association between changes in socio-economic indicators and ACL transmission. Regarding vector abundance and presence, we found that studies had been biased to locations east of the Panama canal, and that, in general, the abundance of dominant vector species decreased during the cold phase of ENSO. Finally, our results indicate that a macroecological approach is useful to understand heterogeneities related to environmental change impacts on ACL transmission. PMID- 29988199 TI - The relation between climatic factors and malaria incidence in Kerman, South East of Iran. AB - Background and objectives: Malaria is among the most important parasitic diseases, and is one of the endemic diseases in Iran. This disease is often known as a disease related to climate changes. Due to the health and economic burden of malaria and the location of Kerman province in an area with high incidence of malaria, the present study aimed to evaluate the effects of climatic factors on the incidence of this disease. Material and methods: Data on the incidence of malaria in Kerman province was inquired from Kerman and Jiroft Medical Universities and climatic variables were inquired from the meteorological organization of Kerman. The data was analyzed monthly from 2000 to 2012. Variations in incidence of malaria with climatic factors were assessed with negative binomial regression model in STATA11software. In order to determine the delayed effects of meteorological variables on malaria incidence, cross correlation analysis was done with Minitab16. Results: The most effective meteorological factor on the incidence of malaria was temperature. As the mean, maximum, and minimum of monthly temperature increased, the incidence rate raised significantly. The multivariate negative binomial regression model indicates that a 1 degrees C increase in maximum temperature in a given month was related to a 15% and 19% increase on malaria incidence on the same and subsequent month, respectively (p-value = 0.001). Humidity and Rainfall were not significant in the adjusted model. Conclusion: Temperature is among the effective climatic parameters on the incidence of malaria which should be considered in planning for control and prevention of the disease. PMID- 29988200 TI - Repellent and insecticidal efficacy of a combination of dinotefuran, pyriproxyfen and permethrin (Vectra(r) 3D) against Culex pipiens in dogs. AB - Culex pipiens is an important vector of pathogens of substantial medical and veterinary importance such as Dirofilaria immitis and Dirofilaria repens or the West Nile Virus. The control of these mosquitoes is therefore essential to control the transmission of mosquito-borne agents to humans and animals. A combination of dinotefuran, permethrin and pyriproxyfen (Vectra(r) 3D) has already shown its efficacy against Aedes aegypti. The aim of this study was to confirm the efficacy of this combination in repelling and killing another species of mosquito, Culex pipiens, after a single topical application to dogs. Twelve adult Beagle dogs with an equal receptivity to mosquitoes were included in the study and divided in two groups of six dogs: an untreated control group and a group treated with a combination containing 54 mg/mL dinotefuran + 4.84 mg/mL pyriproxyfen + 397 mg/mL permethrin (Vectra(r) 3D). All dogs were challenged with 80 Culex pipiens females for 90 +/- 5 min on Days - 28, 1, 7, 14, 21 and 28. The treatment was applied once topically on Day 0. Count and engorgement determination of dead and live mosquitoes were performed after each exposure to treated and untreated dogs. Compared to control dogs, the spot-on formulation provided a repellent efficacy (anti-feeding effect) against mosquitoes of 98.9%, 98.8%, 98.6%, 96.7% and 97.9% on Days 1, 7, 14, 21 and 28 respectively. There was a significant difference (p <= 0.05) between the treated and controlled groups on every assessment day. The insecticidal efficacy on treated dogs at 90 min was 34.7%, 50.3%, 39.7%, 22.8% and 11.4% on Days 1, 7, 14, 21 and 28 respectively. There was a significant difference between the treated and controlled groups for live mosquitoes for all assessment days (p < 0.05). A single topical application of a combination of dinotefuran, permethrin and pyriproxyfen showed a significant repellent effect (i.e. > 96%) against Culex pipiens which lasted for 28 days. The results suggest that the Vectra(r) 3D spot-on solution could be used as an effective mosquito control strategy in dogs and is therefore recommended for use in a dirofilariosis prevention programme. PMID- 29988201 TI - Effect of sodium metabisulfite gel on the bond strength of dentin of bleached teeth. AB - Objective: This study aimed to evaluate the effect of the application of sodium metabisulfite (SMB) on the bond strength of bleached teeth. Materials and Methods: The study was divided into two parts. The first part evaluated the application of various concentrations of SMB for 1 h prior to the completion of bonding procedures. Fifty blocks were divided into five groups (n = 10): control; bleaching with 35% hydrogen peroxide (HP); HP + 5% SMB; HP + 12.5% SMB; and HP + 25% SMB. The second part evaluated the application of 25% gel SMB to either enamel or dentin, including the application time. Sixty blocks were divided into six groups (n = 10): control; bleaching with 35% HP; HP + 25% SMB for 1 h in enamel; HP + 25% SMB for 1 h in dentin; HP + 25% SMB for 10 min in enamel; and HP + 25% SMB for 10 min in dentin. Statistical Analysis: Following the completion of microshear bond testing, data were analyzed using one-way analysis of variance as well as Tukey's and Dunnett's tests. Results: In part 1, data analysis revealed statistical differences (P < 0.0001) between HP and HP + 5% SMB. No statistical differences were found between the control and both HP + 12.5% SMB and HP + 25% SMB. Part 2 revealed a statistical difference (P = 0.001359) only between the bleached group and others. Conclusions: The use of 25% SMB gel immediately after bleaching was able to reverse the deleterious effect of bleaching on the bond strength of dental composites to dentin. PMID- 29988202 TI - A Randomized Controlled Trial Comparing Er:YAG Laser and Rotary Bur in the Excavation of Caries - Patients' Experiences and the Quality of Composite Restoration. AB - Objective: The aim of this study was to evaluate patients' experiences of two excavation methods, Er:YAG laser and rotary bur and time required by the methods as well as objective assessments of quality and durability of restorations over a two-year period. Methods: A prospective, single-blind, randomized and controlled investigation was performed. Patients aged 15 to 40 years with at least two primary caries lesions, which had been radiographically assessed as of the same size, were recruited. In each patient, one cavity was excavated using rotary bur and one using Er:YAG laser technique. The time required for excavations and, where applicable, local anaesthesia, was measured during the treatments. Patient experiences were measured using questionnaires. The quality and durability of restorations were assessed over a two-year period in accordance with modified Ryges criteria and radiographs. Twenty-five patients (mean age 22.6 years) participated in the study. In total, 56 cavities were included of which 28 were treated with Er:YAG laser and 28 were treated with a rotary bur. Results: The patients associated the laser method with less discomfort. The mean time for excavation by laser was three times longer than by rotary bur (13.2 min vs. 4.3 min, P<0.0001). Over a two-year period, no statistically significant differences with regard to quality or durability could be seen between the restorations associated with the methods. Conclusion: The Er:YAG laser technique was more time consuming than the rotary bur. Despite this, the laser technique caused less discomfort and was preferred as an excavation method by patients. PMID- 29988203 TI - Cretaceous-Tertiary Foraminifera and Palynomorphs from Djega Section and Inferred Paleodepositional Environments, Rio Del Rey Basin, Cameroon, West Africa. AB - Late Cretaceous-Paleocene foraminiferans and palynomorphs were recovered from the upper section of the Djega outcrop in the Rio del Rey Basin. Only a few planktonic foraminiferan species of the genera Heterohelix and Hedbergella were recovered among an assemblage dominated by calcareous and agglutinated benthonics. Marine dinocysts are curiously absent from among the palynomorph assemblage, which consists dominantly of pollen grains from land plants (angiosperms and gymnosperms) and pteridophytic spores, together with a few fungal remains. Two benthonic foraminiferal assemblages that include the Campanian-Maastrichtian Bolivina afra-Haplophragmoides talokensis and the Paleocene Anomalinoides umboniferus-Eponides pseudoelevatus are well established at this outcrop. The palynomorphs include a few typical Late Cretaceous and typical Paleogene species, while the majority are long ranging forms that straddle the Cretaceous-Tertiary boundary. The foraminiferal and palynomorph biostratigraphic distributions permitted us to recognize the succession of Campanian-Maastrichtian and Paleocene strata and the Cretaceous-Tertiary boundary for the first time in this basin. Lithofacies change from a monotonous thick pile of shales below, succeeded by sandstones, frequently alternating with mudstone, above. This indicates a general fall in sea level during the Early Paleocene earlier reported within this subregion, and the boundary marks the start of the out building of the Niger Delta which the Tertiary Rio del Rey Basin is part of. Both microfossils and lithofacies analyses aided the reconstruction of an open marine, probably middle to inner neritic shallow and transitional intertidal paleodepositional environments for the sediments exposed at this outcrop. PMID- 29988204 TI - Behavioral management using sequenced treatment paradigm and audiovisual distraction during dental treatment in children with attention deficit/hyperactivity disorder. AB - Objective: The present study aimed to assess behavioral management using sequenced treatment approach and audiovisual distraction (AVD) with/without video eyewear during dental procedure in children with attention deficit/hyperactivity disorder (ADHD). Materials and Methods: This clinical trial included 31 children (n = 21 boys; n = 10 girls), aged between 6.5 and 8.1 years, distributed into Group A (n = 17, children not on ADHD medication) and Group B (n = 14, children taking medication for ADHD symptoms). The study involved four sessions, 1 week apart. Sessions I and II included behavioral management assessment and dental screening, respectively, while participants watched cartoon movie using an AV distracter with/without a video eyewear. During Sessions III and IV, dental prophylaxis and sealants were placed on first permanent molars, respectively, for both upper and lower jaws in both the groups. During the procedure, children were distracted with AV distracter with/without a video eyewear, and the mean changes in blood oxygen saturation (SaO2) and pulse rate were recorded every 5 min. Independent samples t-test was used, assessing for significant changes in pulse rate and SaO2 during each visit in both groups. Results: Almost 95% (n = 113) of the first permanent molars showed signs of pit and fissure demineralization of varying severities, classified as the International Caries Detection and Assessment System-codes 1-3. During Session IV, there were significant differences (P <= 0.03 and P <= 0.05) in mean pulse rate in both groups of children, respectively, during fissure sealants or preventive resin restoration application on their permanent molars while being distracted using AVD with video eyewear. Conclusion: Our study recommends splitting of dental visits into multiple short sessions and video eyewear distraction for optimum behavioral management during dental procedures of children with ADHD. PMID- 29988205 TI - Characteristics of Potential Protein Biomarkers Extracted with 10% TCA from Blood Serum of Non-Hodgkin's Lymphoma and Multiple Myeloma Patients. PMID- 29988206 TI - A national survey of tooth wear on facial and oral surfaces and risk factors in young Nigerian adults. AB - Objective: The objective of this study is to assess the prevalence of tooth wear and to identify risk factors in a sample of young Nigerian adults. Materials and Methods: Participants were individuals aged 18-35 years, attending dental clinics located in eight centers representing the six geopolitical zones of the country. Calibrated examiners measured tooth wear using basic erosive wear examination (BEWE) index. Individuals were characterized by the highest BEWE score recorded for any facial/oral tooth surface. Previously validated questionnaire was used to gather information on demographics and risk factors. Results: A total of 1349 participants were examined. The prevalence of tooth wear was 60.2%. Bivariate analysis showed significant differences in the prevalence of tooth wear with age, educational level, and occupation (P <= 0.05). There were significant differences in tooth wear among the participants from the different states. Tooth wear was found to increase with smoking. Tooth wear was associated with brushing frequency, use of chewing stick, and other local cleaning agents. Multiple regression analysis showed that age, brushing frequency, brushing after breakfast added statistically significantly to the prediction of tooth wear (P < 0.05). Conclusion: Tooth wear was common in the population. The frequency of tooth brushing, use of chewing sticks and other local tooth cleaning agents may be contributory. PMID- 29988207 TI - Comparison of the biocompatibility of calcium silicate-based materials to mineral trioxide aggregate: Systematic review. AB - The objective of this systematic review was to evaluate the biocompatibility and interaction of bioceramic materials with animal and human mesenchymal cells in vitro and in vivo and to compare them with mineral trioxide aggregate (MTA). Two independent researchers conducted PubMed/Medline, Web of Science, and Scopus searches to identify studies published in English, without restrictions on year of publication using the following keywords: "root canal sealer," "root repair material," "cytotoxicity," and "bioceramics." The articles were selected following the PRISMA statement. A total of 1486 titles were identified in the initial search. However, only 18 studies met the inclusion and exclusion criteria. The results showed that bioceramic materials have biological properties similar to those of MTA, including low cytotoxicity as well as promoting cell proliferation and adhesion, low expression of inflammatory cytokines, and reduced pulp inflammation. This systematic review therefore suggests that the choice of repair bioceramic materials or MTA based on biocompatibility should be the professional's decision. PMID- 29988208 TI - Management preferences of deep caries in permanent teeth among dentists in Saudi Arabia. AB - Objective: To report the management preferences of deep caries in permanent teeth among dentists. Materials and Methods: This observational cross-sectional study included a convenience sample of 177 dentists selected from private and public dental clinics in different cities of the Eastern Province of Saudi Arabia. Four clinical scenarios about the absence or presence of pain/symptoms and the risk of pulp exposure in deep caries were presented to the dentists in a pilot-tested questionnaire. Results: Most dentists (82.5%) preferred complete caries excavation when there was no risk of pulp exposure and no pain/symptom was associated with deep caries in permanent teeth. The stepwise technique was the procedure of choice reported by 57.8% of dentists when there was no pain but a risk of exposure was present. In case of no exposure risk but the presence of nonspontaneous pain (pain on thermal testing), complete caries removal was chosen by 55.9% of the respondents. Root canal treatment and stepwise caries removal were preferred by 42.4% and 38.4%, respectively, when there was a risk of exposure and nonspontaneous pain. The risk of exposure (81.4%), the progression of caries (73.4%), and treatment failure (58.8%) were the most common concerns with different caries removal techniques. The hardness was the most commonly used criterion (85.3%) followed by the color of caries (50.3%) during caries excavation. Conclusions: The majority of dentists preferred to completely remove caries in case of no risk of pulp exposure. The dentists should update their knowledge and adopt latest concepts about minimally invasive caries removal approaches. PMID- 29988209 TI - In vitro evaluation of microbial adhesion on the different surface roughness of acrylic resin specific for ocular prosthesis. AB - Objective: The purpose of this study was to evaluate the influence of surface roughness in biofilm formation of four microorganisms (Staphylococcus epidermidis, Staphylococcus aureus, Enterococcus faecalis, and Candida albicans) on acrylic resin surface of ocular prostheses. Materials and Methods: Acrylic resin samples were divided into six groups according to polishing: Group 1200S (1200 grit + silica solution); Group 1200; Group 800; Group 400; Group 120 and Group unpolished. Surface roughness was measured using a profilometer and surface images obtained with atomic force microscopy. Microbial growth was evaluated after 4, 24, and 48 hours of incubation by counting colony-forming units. Statistical Analysis Used: For roughness, it was performed 1-way ANOVA and parametric Tukey test alpha5% (P <= 0.05). For CFU data found, it was applied Kruskal-Wallis and Mann-Whitney tests. Results: Group 120 and 400 presented the highest roughness values. For S. epidermidis and S. aureus, Group 1200S presented the lowest values of microbial growth. For E. faecalis at 4 hour, microbial growth was not observed. C. albicans did not adhere to the acrylic resin. Except for Group 1200S, different surface roughnesses did not statistically interfere with microbial adhesion and growth on acrylic surfaces of ocular prostheses. Conclusions: The roughness did not interfere with the microbial adhesion of the microorganisms evaluated. The use of silica decreases significantly microbial growth. PMID- 29988210 TI - Anticariogenic potential of white cheese, xylitol chewing gum, and black tea. AB - Objective: This study aimed to examine the effects of these foods on plaque pH and the potential development of tooth decay. Materials and Methods: Plaque pH was measured using the sampling method before and after 1, 5, 10, 20, 30, 45, and 60 min following consumption of these foods individually and after rinsing with a 10% sucrose solution. Statistical analysis was performed using one-way ANOVA and Tukey honestly significant difference post hoc tests (alpha = 0.05). Results: Although there were statistically significant differences in all test groups except the BT (P = 0.620) and sucrose + XCG (P = 0.550) groups in time, none of the participants chosen for this study were having a plaque pH value anywhere close to the critical value (pH = 5.5). Conclusion: WC, BT, and XCG are advisable as anticariogenic foods because pH values are not below critical value. PMID- 29988211 TI - Association of CpG-SNP and 3'UTR-SNP of WFS1 with the Risk of Type 2 Diabetes Mellitus in an Iranian Population. AB - Type 2 diabetes mellitus (T2DM) is one of the most common multifactorial disorders in Iran. Recent genome wide association studies (GWASs) and functional studies have suggested that WFS1 may predispose individuals to T2DM. However, to date, the possible association of such variants with T2DM in Iranians remained unknown. Here, we investigated the association of the two polymorphisms of WFS1 (rs1801214 a CpG-SNP, and rs1046320 a 3'UTR-SNP) with T2DM in an Iranian population. The study population comprised 432 unrelated Iranian individuals including 220 patients with T2DM, and 211 unrelated healthy control subjects. Genotyping was performed using PCR-RFLP, and confirmed with sequencing. In a logistic regression analysis, the rs1801214-T allele was associated with a significantly lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.52-0.91, P= 0.007539). Moreover, the G allele of rs1046320 was associated with a lower risk of T2DM assuming the log-additive model (OR: 0.68, 95% CI: 0.50 0.91, P= 0.008313). Haplotype analysis revealed that haplotypes that carry at least one protective allele are associated with a lower risk of T2DM. This is a first evidence for the association of WFS1 rs1801214, and rs1046320 with T2DM in an Iranian population. PMID- 29988212 TI - Assessment of schoolteachers' knowledge about management of traumatic dental injuries in Al-Madinah city, Saudi Arabia. AB - Objective: This study aimed to assess the knowledge of primary and intermediate schoolteachers about the management of TDIs in Al-Madinah city, Saudi Arabia. Materials and Methods: A previously validated, self-administered, anonymous, close-ended structured questionnaire was administered to schoolteachers in 13 different schools. It included two parts: basic demographic information (part one) and questions regarding the management of dental traumatic injuries (part two). Results: A total of 178 schoolteachers voluntarily completely filled in the questionnaire. Nearly 28.1% of the teachers acquired a first-aid training program and 6.2% only learned about dental injury management in first-aid training. Concerning the knowledge about the management of dental traumatic injuries, 55.1% of teachers realized the appropriate time for treatment of dental traumatic injuries. A few percentage of teachers selected correct answers for the suitable storage medium. The most commonly selected storage media were found to be cold milk, physiological saline, and patient's saliva at 14.6%, 6.7%, and 2.2%, respectively. Conclusion: The knowledge among primary and intermediate schoolteachers in the management of dental traumatic injuries is unsatisfactory. PMID- 29988213 TI - Twenty Years of Full-Mouth Disinfection: The Past, the Present and the Future. AB - Background: Conventional periodontal treatment, performed quadrant by quadrant in multiple visits, was re-evaluated in the early 1990s when the full-mouth disinfection concept was introduced. Over the years, several modifications to the full-mouth disinfection approach have been suggested. Objective: The purpose of this article is to review the evolution of full-mouth disinfection during the past 20 years, to specify its indications and to consider the prospects for this approach. Materials and Methods: An electronic and manual search of the literature, ending in December 2016, was performed by two independent researchers. Only pivotal studies and randomized controlled clinical trials published in the English language that evaluated a new approach to full-mouth disinfection were selected. Results: According to the studies included in our analysis (21 articles), several modified full-mouth disinfection protocols have been designed including: full-mouth treatment without chlorhexidine, the extension of hygiene methods and an increase in the duration of post-treatment chlorhexidine use, the replacement of chlorhexidine with other antiseptics, supplementation with antibiotics or probiotics, full-mouth antimicrobial photodynamic therapy and one-stage full-mouth disinfection combined with a periodontal dressing. Conclusion: Since 1995, several modifications have been suggested to improve the effectiveness of full-mouth disinfection. The majority of the studies demonstrate that the results obtained with full-mouth disinfection and its variants are equivalent to each other and to those obtained with the conventional quadrant method. Currently, the selection of this technique remains empirical and depends on the preferences of the practitioner and the patient. In the future, a patient-centered approach should be the best indication for the use of this technique. PMID- 29988214 TI - Fracture resistance of veneers in premolars. AB - Objective: The purpose of the study was to compare the fracture resistance of ceramic veneers and composite resin veneers with and without dental preparation. Materials and Methods: Forty freshly extracted mandibular premolars were selected and randomly assigned into four groups (n = 10): Group NPR = no dental preparation and direct veneer with 0.2 mm thick composite resin (Amelogen Plus, Ultradent); Group NPC = no dental preparation and 0.2 mm thick lithium disilicate ceramic veneer (IPS e.max Press, Ivoclar Vivadent); Group P2C = Tooth preparation of 0.2 mm and 0.2 mm thick ceramic veneer (IPS e.max Press); and Group P5C = Tooth preparation of 0.5 mm and 0.5 mm-thick ceramic veneer (IPS e.max Press). In all groups, the restorations covered 1 mm of the occlusal surface of the buccal cusp, and the thickness of this area was the same of the buccal area (0.2 mm or 0.5 mm). After the luting procedure, all groups were thermocycled (10,000 cycles, 5 degrees C-55 degrees C) and subjected to fracture resistance test under compression (Instron 4444 with a crosshead speed of 0.5 mm/min). The mode of failure analysis was performed under a *10 magnification. Data were subjected to one-way ANOVA and Duncan's post hoc test (P < 0.05). Results: The mean fracture resistance (men +/- standard deviation) was NPR = 690.33 +/- 233, NPC = 790.52 +/ 408, P2C = 1131.34 +/- 341, and P5C = 983.56 +/- 202. There were significant differences of the fracture resistance values between all groups (P = 0.013). NPR and NPC groups showed mean values of fracture resistance significantly lower than P2C. However, P5C presented intermediate values without a significant difference from the other groups. The mode of failure for all groups was mixed (60%), cohesive failures (20%), root failures (15%), and adhesive failures (5%). Conclusion: Minimally invasive tooth preparation (0.2-mm) allowed to achieve higher fracture resistance in premolars restored with lithium disilicate ceramic veneers. Attention should be given to the 0.5 mm preparation since catastrophic fractures only happened when this preparation depth was performed. PMID- 29988216 TI - High Grade B- Cell Non- Hodgkin's Lymphoma Arising in a Mature Cystic Teratoma of The Ovary: A Case Report. AB - Mature cystic teratoma (MCT) is the most common type of ovarian germ cell tumor occurring in females of reproductive age. It is typically benign, but rare malignant transformations have been reported in 1-2% of the cases. Among a wide variety of malignancies arising in MCTs, high grade lymphomas are the least common. We present a case of a 45- years -old female with a unilateral adnexal mass. Gross examination revealed a unilocular cyst with a smooth and intact capsule. The cyst lumen was filled with sebaceous material and hair. Except for a 5.0 cm Rokitansky nodule, no other nodule or papillary structures were identified. Microscopic examination revealed an array of mature tissues arising from different germ cell layers, and foci of diffuse sheets of large atypical lymphoid cells. These were positive for CD-20 marker, confirming their B lymphoid series cell origin. A final diagnosis of a high grade B cell non Hodgkin's lymphoma arising in an ovarian MCT was made. Such cases have been known to be associated with a very poor prognosis, and there are no established criteria for their pre-operative diagnosis. Risk factors for malignant transformation in an MCT including tumor size, post menopausal status and serum tumor markers are thus analyzed routinely to make a presumptive diagnosis. These coupled with extensive gross sampling of the tumor specimens, and a diligent histopathological examination may aid in an accurate diagnosis of a malignant neoplasm arising in MCTs. PMID- 29988217 TI - The Survey of Double Robertsonian Translocation 13q; 14q in the Pedigree of 44; XX Woman: A Case Report. AB - Robertsonian translocations (RBTs) are associated with an increased risk of aneuploidy. Single RBT carriers are the most common balanced rearrangements among the carrier couples with the history of spontaneous abortions. However, double Robertsonian translocations (DRBTs), in which two balanced RBTs occur simultaneously, are extremely rare conditions. A 9-year-old mentally normal girl with multiple skeletal disorders was found to carry a balanced 13/14 RBT (45, XX, t(13q; l4q)). Three generations of her family, including her parents and her maternal grandparents were investigated for cytogenetic analysis. All of them were phenotypically normal. Her mother appeared in a peculiar karyotype of 44, XX, t (13q; 14q) *2, while her father revealed a normal karyotype 46, XY. Chromosomal constitution of her grandparents showed that both of them carried this balanced reciprocal translocation (45, XY t (13q; 14q) as well as 45, XX, t (13q;14q)). Cytogenetic evaluations on the basis G-banding technique were performed for participants. Except the 9- year-old girl, all RBT carriers in this family appeared phenotypically normal, her skeletal disorders might not be due to chromosomal rearrangement. Meanwhile, all offsprings of 44, XX woman are obligatory carriers of this translocation, and should be candidates for prenatal diagnosis (PND) or preimplantation genetic diagnosis (PGD), for their future pregnancies. PMID- 29988215 TI - Overview of Calcium Phosphates used in Biomimetic Oral Care. AB - Background: The use of biomimetic agents is an emerging field in modern oral care. Promising biomimetic substances for such applications are calcium phosphates, because their chemical composition is very similar to that of the mineral phase in human teeth, especially of natural enamel. Examples for their application include the remineralization of early caries lesions and repair of small enamel defects. Objective: This review provides an interdisciplinary view on calcium phosphates and their applications in biomimetic oral care. The aim of this work is to give an overview of in vivo and in situ studies comparing several calcium phosphates in preventive dentistry that can be used as a knowledge base for the development of innovative alternative oral care concepts. Methods: Books, reviews, and original research papers with a focus on in vivo and in situ studies were included. The databases PubMed(r) and SciFinder(r) were used for literature search. Calcium phosphates that are frequently utilized in oral care products are covered in this review and were used as search terms alone and together with the following key words: in vivo, in situ, caries, clinical study, and remineralization. From 13,470 studies found, 35 studies complied with the inclusion criteria and were used for this review. Results: Published in vivo and in situ studies demonstrate calcium phosphates' potential in enamel remineralization. However, more studies are needed to further substantiate existing results and to extend and refine the application of calcium phosphates in modern oral care. Conclusion: Calcium phosphates represent an innovative biomimetic approach for daily oral care because of their high similarity to natural enamel that will broaden the range of future treatments in preventive dentistry. PMID- 29988218 TI - Purification of a Fe-SOD excreted by Leishmania braziliensis for specific antibodies detection in Mexican human sera: Cutting-edge the knowledge. AB - Clinical diagnosis of leishmaniasis is highly complex, presenting a wide range of clinical manifestations, sometimes non-specific, and thus the epidemiological study and diagnostic need specific molecular markers for each Leishmania species. Leishmania spp. posses different Fe-SOD isoforms, one of which is excreted into the external milieu and, presenting immunogenic characteristics, is a very reliable molecular marker. Superoxide dismutases (SODs) are antioxidant metal enzymes responsible for the dismutation of superoxide ion into hydrogen peroxide and molecular oxygen, and it is considered an important virulence factor. In this manuscript we have purified the iron(Fe)-SOD excreted by Leishmania braziliensis using ion-exchange and molecular-sieve chromatography and we have studied it as an antigen in serodiagnostic analyses in ELISA and Western blot techniques, testing 213 human sera from Mexico. Indeed, L. braziliensis Fe-SODe has been purified 123.26 times with a specific activity of about 893.66 U/mg of protein. Applying the purified enzymes in serological tests we found 17.84% sera positive. We have demonstrated that the purified enzyme is more sensitive than the non purified ones and we also demonstrated, for the first time, the presence of antibodies against L. braziliensis, not the main species in the country, in human population from Hidalgo and Nuevo Leon States. PMID- 29988219 TI - Survey of gastrointestinal parasites, liver flukes and lungworm in feces from dairy cattle in the high tropics of Antioquia, Colombia. AB - A cross sectional study was undertaken to determine the prevalence and intensity of parasitic infections in dairy cattle in the high tropics of Colombia. A total of 1003 rectal samples were collected from dairy cows at 29 farms between May and June 2014 to represent the number of farms, age groups, and size of the 65,000 cow population in the municipality of San Pedro de los Milagros. Coprological techniques were used to detect gastrointestinal nematodes, liver flukes, coccidian oocysts, and first larval stage counts of Dictyocaulus viviparus. In order of decreasing prevalence, the following parasites were detected: coccidial oocyst (36.7%; 95% CIs, 31.6-42.7), strongyle nematodes (31.6%, 27.8-35.4), liver flukes (30.9%, 21.5-37.5), cestodes (8.4%, 7.1-9.7), and D. viviparus (5.4%, 3.4 7.5). Co-infections by all possible combinations of the three most predominant groups occurred in 11 to 15% of the animals. There were significant differences in infection rates between age groups, with higher risk of liver fluke infection in animals older than 1 year of age (odds ratio (OR) = 3.2), but lower presence for coccidia and strongyles (OR = 0.19 and 0.51, respectively). For Fasciola hepatica, within-herd prevalences of > 25% in 16 farms and 94 of 281 (33.5%) animals with > 5 eggs per gram (epg) indicate that significant production losses are likely occurring. The variation in the prevalence of gastrointestinal parasites and liver flukes, together with the level of infection among age groups, could be used in integrated management programs to establish selective anthelmintic treatments and select for heritable traits of host resistance. These results serve as a baseline for future studies to determine the success of control measures and should increase awareness that subclinical parasitism is widespread in the livestock sector. PMID- 29988220 TI - Spatial cluster analysis of Crimean-Congo hemorrhagic fever virus seroprevalence in humans, Greece. AB - Crimean-Congo hemorrhagic fever (CCHF) is a viral disease transmitted to humans by bite of infected ticks or by direct contact with blood or tissues of viremic patients or livestock. The present cross-sectional meta-analysis study is based on previous data which have shown that the human CCHFV seroprevalence in specific regions of Greece is high (> 5%). In the absence of human cases, it has been suggested that a non- or low-pathogenic strain is circulating in the country causing asymptomatic infections. A spatial cluster analysis was performed to assess the geographical variations in CCHFV seropositivity and to identify the risk factors. The overall CCHFV seroprevalence is 3.8%, with significant rate difference between the eastern and western part of the country. Apart the risk factors described in previous studies (age, sex, tick bite, agropastoral activities), the altitude, the land cover type and the transitional woodland/shrub land per person, as well as the number of livestock per person, and specifically the number of goats, sheep and cattle per person, were shown to affect significantly the seroprevalence. Tick studies are needed to identify the circulating strains and unravel the mystery of CCHF epidemiology in Greece. PMID- 29988221 TI - Effect of heat treatment on cytotoxicity of self-adhesive resin cements: Cell viability analysis. AB - Objective: The aim of the study was to assess, in vitro, the influence on cytotoxicity of heat treatment applied before photopolymerization, while mixing three self-adhesive resin cements, in an NIH/3T3 fibroblast cell culture, based on cell viability measures. Methods: Samples were divided into three groups: (1) no heat treatment while mixing (control), (2) 37 degrees C, and (3) 60 degrees C heat treatment while mixing. Cements were light-cured immediately after mixing and immersed in Dulbecco's Modified Eagle Media for the extraction of possibly uncured products after 24 h and 7 days. Cultures contained 0.5 mL of NIH/3T3 fibroblasts per well at a concentration of 0.4 * 105 cells/mL and specific extracts for each sample. Statistical Analysis Used: Data were statistically analyzed with ANOVA and post hoc Student-Newman-Keuls (significance of 5%). Results: Cement cytotoxicity increased with time, as shown by the higher values observed at 7 days. There was a slight difference in intragroup cytotoxicity levels between 24 h and 7 days. Heat treatment at 60 degrees C was associated with a major decrease in cytotoxicity levels in all three groups, both at 24 h and at 7 days, with no differences among the cements. Conclusions: Heat treatment at 60 degrees C should be considered as a strategy to reduce cytotoxicity of self adhesive resin cements, as evidenced by the results observed at 24 h and 7 days of analysis. PMID- 29988222 TI - Oral Aspects Identified in Atopic Dermatitis Patients: A Literature Review. AB - Introduction: Atopic dermatitis is a chronic inflammatory skin condition that is more prevalent in children (10-20% of the world's population) than in adults. As its etiology is multifactorial, it is important to know the most frequent oral manifestations in atopic dermatitis patients. Methodology: In the last decades, the correlation between atopic dermatitis and conditions and/or changes in the oral cavity has been demonstrated by several studies. The objective of this paper was to describe, through a review of the literature, the oral health conditions and/or oral aspects identified in patients with atopic dermatitis. Search Strategy: A descriptive literature review was carried out through a bibliographical survey based on the last 10 years, in order to answer the study questions. Results: As a result, we found six studies with different sample sizes, ranging from 43 to 468 patients, and the majority of them were of cross sectional study design. Discussion: Two studies performed their analysis through dental exams and reported that patients with atopic dermatitis tend to have a greater frequency of carious lesions, and two studies correlated Candida with atopic dermatitis through mycological analyzes. Conclusion: There are a few studies in the literature that identify the oral aspects of atopic dermatitis. More investigations are needed in order to contribute to the knowledge of such oral aspects and the approach to treat these patients regarding oral health. PMID- 29988223 TI - Dysregulated Expression of Long Intergenic Non-coding RNAs (LincRNAs) in Urothelial Bladder Carcinoma. AB - Long intergenic non-coding RNA (lincRNA) has been introduced as key regulators of diverse biological processes, including transcription, chromatin organization, cell growth and tumorigenesis. With regard to the potential role of lincRNAs in cancer development, one may postulate that differential expression of lincRNAs could be employed as a tool in cancer diagnosis, prognosis, and targeted therapy. In this study, we aimed to explore the putative correlation between the expression levels of two lincRNAs: LINC00152 and LINC01082 in the bladder cancer (BC), in comparison with its adjacent non-cancerous tissue. Fifty Iranian subjects diagnosed with BC, representing in different stages and grades participated in this study The mRNA expression levels of the abovementioned lincRNAs were comparatively analyzed in cancerous and their adjacent non cancerous counterpart tissues, of each subject by Real-Time PCR. The expression levels of LINC00152, and LINC01082 were significantly lower in tumor tissues in comparison with their adjacent normal tissues (P<0.001). More notably, in the case of LINC01082 the reduced expression was differentiated by the muscle invasiveness pattern of the tumor (P= 0.05). Our study presents a new finding about the tumor suppressor potentiality of these lincRNAs in BC development that in turn may suggest them as candidate biomarkers. Replicating this study in higher number of BC subjects, coupled with functional analysis, is necessary to investigate interconnections between these RNAs and cancer development, leading to better understanding of cancer biology. PMID- 29988224 TI - Prevalence and risk factors for shedding of Cryptosporidium spp. oocysts in dairy calves of Buenos Aires Province, Argentina. AB - In order to determine the prevalence and risk factors for shedding of Cryptosporidium spp. in dairy calves, a cross-sectional study was carried out in the northeastern region of Buenos Aires Province, Argentina. Fecal samples from a total of 552 calves from 27 dairy herds were collected, along with a questionnaire about management factors. Cryptosporidium spp. oocysts were detected by light microscopy using Kinyoun staining. Putative risk factors were tested for association using generalized linear mixed models (GLMMs). Oocyst shedding calves were found in 67% (CI95% = 49-84) of herds (corresponding to a true herd prevalence of 98%) and 16% (CI95% = 13-19) of calves (corresponding to a true calve prevalence of 8%). Within-herd prevalence ranged from 0 to 60%, with a median of 8%. Cryptosporidium spp. excretion was not associated with the type of liquid diet, gender, time the calf stayed with the dam after birth, use of antibiotics, blood presence in feces, and calving season. However, important highly significant risk factors of oocyst shedding of calves was an age of less or equal than 20 days (OR = 7.4; 95% CI95% = 3-16; P < 0.0001) and occurrence of diarrhea (OR = 5.5; 95% CI95% = 2-11; P < 0.0001). The observed association with young age strongly suggests an early exposure of neonatal calves to Cryptosporidium spp. oocysts in maternity pens and/or an age-related susceptibility. Association with diarrhea suggests that Cryptosporidium spp. is an important enteropathogen primarily responsible for the cause of the observed diarrheal syndrome. Results demonstrate that Cryptosporidium spp. infection is widespread in the study region. Monitoring and control of this parasitic protozoan infection in dairy herds is recommended. PMID- 29988225 TI - Nanobiomaterials in dentistry: What's the consequent level. PMID- 29988226 TI - Novel Mutations in TACSTD2 Gene in Families with Gelatinous Drop-like Corneal Dystrophy (GDLD). AB - In the current study, we conducted a mutation screening of tumor-associated calcium signal transducer 2 (TACSTD2) gene in six consanguineous Iranian families with gelatinous drop-like corneal dystrophy (GDLD), in order to find the causative mutations. Detailed eye examination was performed by ophthalmologist to confirm GDLD in patients. To detect the possible mutations, direct Sanger sequencing was performed for the only exon of TACSTD2 gene, and its boundary regions in all patients. In the patients with GDLD, the corneal surface showed lesions with different shapes from mild to severe forms depending on the progress of the disease. The patients showed grayish corneal deposits as a typical mulberry form, corneal dystrophy along with corneal lipid deposition, and vascularization. Targeted Sanger sequencing in TACSTD2 gene revealed the causative mutations in this gene in all studied families. Our study expanded the mutational spectrum of TACSTD2 which along with the related symptoms could help with the diagnosis, and management of the disease. PMID- 29988227 TI - A comparison of microleakage in self-etch fissure sealants and conventional fissure sealants with total-etch or self-etch adhesive systems. AB - Objective: The present study was conducted to compare microleakage in self etching fissure sealants and conventional fissure sealants with total-etch or self-etch adhesive systems. Settings and Design: This experimental in vitro study was conducted on 60 healthy third molars extracted from humans. The first group received Acid etch + Clinpro sealant, the second group received Acid etch + Single bond 2 + Clinpro sealant, the third group received Single bond universal (self-etching bonding) + Clinpro sealant, and the fourth group received prevent seal self-etching sealant. Materials and Methods: An incision was made on the teeth after they were immersed in methylene blue 5%. The samples were then examined under a stereomicroscope and the dye penetration rate was measured based on the Williams and Winter criteria. Statistical Analysis Used: The Kruskal Wallis and Mann-Whitney tests were used for data analysis in SPSS-18 (P < 0.05). Results: Group 1 which was treated with the conventional technique (acid + fissure sealant) had the highest rate of microleakage compared to Groups 2 and 3 (P < 0.001). Conclusion: The results showed that the use of bonding results in a significant reduction in the microleakage of fissure sealants. The microleakage caused when using self-etch fissure sealant was not different from that caused by the use of the conventional method. PMID- 29988229 TI - Dimensional Changes of the Soft Tissue after Alveolar Ridge Preservation with a Collagen Material. A Clinical Randomized Trial. AB - Background: Reduction of the soft tissue is an unavoidable consequence of tooth extraction without appropriate measures of Alveolar Ridge Preservation (ARP). Objectives: The objective of this study is the volumetric investigation of the dimensional change of the soft tissue post tooth extraction to compare an Alveolar Ridge Preservation (ARP) measure with the insertion of a combination material with a collagen cone to fill the alveolus, combined with a collagen membrane, with untreated extraction alveoli. Methods: In the context of a randomized clinical trial, 31 patients were treated with the combination material directly post tooth extraction in the maxilla (ARP). In 29 further patients, the extraction alveoli were left without further measures (control group).The changes of the soft tissue contour were measured 6 (+/- 1) weeks post extraction. The measurements were performed by superimposing digital models. The groups were compared using the Wilcoxon rank-sum-test. Results: The premolar subgroup revealed a significant difference of the soft tissue dimension post insertion of a collagen material into the alveolus in comparison to untreated alveoli. In these cases, the mean loss of soft tissue volume after use of the collagen material was significantly lower. Conclusion: The proposed hypothesis that there is a difference of the soft tissue preservation between alveoli with and without the use of a collagen material can be accepted with restrictions to the premolar region. A statistically significant lower volume reduction of the soft tissue by implantation of the collagen material could be detected with premolars. PMID- 29988228 TI - Atrial Fibrillation in Hypertrophic Cardiomyopathy: Diagnosis and Considerations for Management. AB - Atrial fibrillation is common in hypertrophic cardiomyopathy with a prevalence of 22-32 %. The impact of atrial fibrillation on overall survival, left ventricular function, thromboembolic stroke and quality of life is crucial. This review enlightens incidence, pathophysiology, and clinical symptoms. Early recognition of atrial fibrillation is essential. Monitoring methods for early detection are described. Finally effective therapy options are discussed including oral anticoagulation and the role of interventional catheter-based ablation in the treatment of atrial fibrillation in HCM patients. PMID- 29988230 TI - Evaluating the risk factors that link obesity and dental caries in 11-17-year-old school going children in the United Arab Emirates. AB - Objective: The objective is to study the effect of obesity on dental caries among schoolchildren in Sharjah, United Arab Emirates. Materials and Methods: The sample comprised 803, 11-17-year-old schoolchildren. The study was in the form of a randomized cross-sectional manner. Method used was two questioners. The first assessed socioeconomic and general health and the second detailed their demographic, oral hygiene, and dietary habits. Dental examination included dental caries assessment using the World Health Organization 1997 criteria and gingival health valuation. Clinical examination consisted of height, weight, and body mass index (BMI). Data analysis was done by descriptive, univariate, and multiple regressions. Results: In this sample, 75% had dental caries and the mean decayed, missing, and filled teeth (DMFT) was 3.19 (standard deviation: 2.9). Obesity was seen in 15% of the adolescents and the mean BMI was 21. The link between DMFT and BMI, when evaluated using univariate analysis, showed a significant correlation (r = 0.097, P = 0.006), indicating that the rise in BMI by 10 points resulted in an increase in DMFT by 0.57. However, in the multivariate analysis, a significant relationship was observed only between father's education (P < 0.001), adolescent's age (P < 0.001), gender (P = 0.008), ethnicity (P = 0.001), and soft drink consumption with DMFT while BMI showed a significant association with age (P < 0.001), school fees (P = 0.005), obesity in family (P < 0.001), and soft drink consumption (P < 0.001). Conclusions: Obesity and dental caries were not significantly associated. The most important predictor for obesity and dental caries was soft drink consumption. PMID- 29988231 TI - Bruxism-Related Signs and Periodontal Disease: A Preliminary Study. AB - Background: The effect of awake and sleep bruxism on periodontal disease has not been evaluated separately to date. Furthermore, there are few studies that have focused on awake bruxism with light force. Objective: The study aimed to investigate the frequency of sleep and awake bruxism in patients with periodontal disease. Methods: The subjects were 57 patients with periodontal disease who visited the Department of Periodontics of the Dental Hospital affiliated with Tokyo Medical and Dental University. Subjects were asked to fill out a questionnaire consisting of three items on bruxism (sleep and awake bruxism), and the maximum community periodontal index was investigated. Results: The proportions of individuals with high sleep bruxism-related signs and high awake bruxism-related signs were 6.0% and 44.0%, respectively. No significant difference was found in the comparison of maximum community periodontal index proportions between individuals with high sleep bruxism-related signs and high awake bruxism-related signs. Conclusion: The results of this survey of patients with periodontal disease showed that the proportion of subjects with high awake bruxism-related signs subjects was higher than those of the subjects with high sleep bruxism-related signs. Sleep bruxism has attracted attention as a factor influencing periodontal disease, and our data suggest that patients with periodontal disease demonstrate more bruxism while being awake than during sleep. PMID- 29988232 TI - A retrospective study of causes, management, and complications of pediatric facial fractures. AB - Objectives: The objective of this study was to report causes, management options, and complications of facial fractures among children. Materials and Methods: The groups were defined on the basis of age, gender, cause of injuries, location, and type of injuries. The treatment modalities ranged from no intervention, closed reduction alone or with open reduction internal fixation (ORIF). Statistical Analysis: Descriptive statistics were generated by using SPSS software for the entire range of the variables under study. Results: Records of 240 pediatric patients were obtained and a total of 322 fractures were found among a study sample. Among these, one-thirds were due to road traffic accidents (RTAs) (37.26%) and fall injuries (36.64%), making them the leading causes of facial fractures. Mandibular fractures were the most common and they accounted for 46% (n = 148) of all fractures. The highest number of RTA (n = 27) was found in adolescents and fall injuries were more prevalent in preschool children (n = 34). Forty-two percent of the fractures (n = 101) were treated with close treatment using arch bars and splints, followed by ORIF (n = 68). The rest, 29.6% (n = 71), received conservative treatments. Postoperative complications were observed in 18.33% (n = 44) of cases, of which jaw deviation, growth disturbance, and trismus were more frequently encountered. Conclusion: Pediatric facial fractures if not managed properly can cause severe issues; therefore, injury prevention strategies should be strictly followed to reduce pediatric injuries in low socioeconomic countries. PMID- 29988233 TI - Oxidative stress in chronic periodontitis patients with type II diabetes mellitus. AB - Objective: Oxidative stress (OS) refers to the disequilibrium between free radicals and antioxidant defense mechanisms and is significantly implicated in the pathogenesis of chronic degenerative and inflammatory diseases such as chronic periodontal disease (CP) and diabetes mellitus (DM). This study aimed to evaluate the total antioxidants capacity (TAOC) and total oxidants status (TOS) in the gingival crevicular fluid (GCF) in CP participants with type II DM. Materials and Methods: A total of 80 participants were allotted into four groups as follows: Group 1: Generalized CP (GCP) without type II DM (n = 20); Group 2: GCP with type II DM (n = 20); Group 3: Type II DM without CP (n = 20); and Group 4: Systemically and periodontally healthy (PH) (n = 20). Clinical parameters such as plaque index, gingival index, probing pocket depth, and clinical attachment level were recorded. Pooled GCF was collected followed by the estimation of TAOC, TOS, and OS index (OSI) using Erel O Colorimetric analysis. Results: The clinical parameters recorded showed the statistically significant difference (P < 0.001) between the groups. The mean TAOC value was the highest in PH group. The mean TOS and OSI were higher in Group 1, 2, and 3 participants when compared to the PH participants. All the biochemical parameters evaluated showed a statistically significant difference (P < 0.001) between groups. Conclusions: The study further validates the use of OSI as a marker for periodontal disease activity and emphasizes the role of OS in the pathogenesis of Type II diabetic patients with the chronic periodontal disease. PMID- 29988234 TI - 'CLOSE'-Guided Pulmonary Vein Isolation and Changes in Local Bipolar and Unipolar Atrial Electrograms: Observations from the EP Lab. AB - Background: 'CLOSE'-guided pulmonary vein isolation (PVI) is a point-by-point, contact force (CF)-guided radiofrequency (RF) approach aiming to enclose the PVs with contiguous RF lesions by targeting strict criteria for interlesion distance and ablation index (AI). We characterized real-time changes in bipolar (B-EGMs) and unipolar electrograms (U-EGMs) during AI-targeted RF delivery. Methods: EGM changes during 56 RF applications in 7 patients with paroxysmal atrial fibrillation (AF) undergoing 'CLOSE'-guided PVI were studied. CF-guided RF was delivered with 35W targeting an AI of 400 at posterior and 550 at anterior wall. 336 B-EGMs and 336 U-EGMs before, during and after RF delivery were analyzed with their RF characteristics. Amplitude of the B-and U-EGM and morphology of the U EGM were measured at each 5-second step using custom-made software. Results: We observed a significant reduction in B-EGM amplitude (0.43 [IQR=0.25, 0.55] to 0.11 [0.07, 0.22] mV, p<0.001) and U-EGM amplitude (0.57 [0.40, 0.87] to 0.22 [0.10, 0.34] mV, p<0.001) within 5 seconds, after which no more changes were observed. Impedance drop was 18.3+/-1.1Omega. Loss of the unipolar terminal S wave occurred in 59% of applications. There was no correlation between U-EGM morphology changes and RF characteristics. Conclusion: In AI-guided RF delivery there is a significant reduction in EGM amplitude within 5 seconds. Loss of the unipolar terminal S wave occurred in 59% of applications and was not related to RF characteristics suggestive of adequate lesion formation. These findings suggest that there is a limited value in monitoring electrograms to further optimize 'CLOSE'-guided PVI. PMID- 29988235 TI - Efficacy of erbium-doped yttrium aluminum garnet laser with casein phosphopeptide amorphous calcium phosphate with and without fluoride for remineralization of white spot lesions around orthodontic brackets. AB - Objective: This study aimed to assess the efficacy of erbium-doped yttrium aluminum garnet (Er:YAG) laser, pastes containing casein phosphopeptide amorphous calcium phosphate (CPP-ACP) with and without fluoride and their combination for prevention of white spot lesions in the enamel. Materials and Methods: This in vitro experimental study was conducted on 90 extracted sound premolars. The teeth were then randomly divided into six groups of 15: (1) Control, (2) laser, (3) CPP ACP with fluoride (GC MI Paste, RecaldentTM 900 ppm as NaF), (4) CPP-ACP without fluoride (GC Tooth Mousse RecaldentTM), (5) laser + CPP-ACP with fluoride, and (6) laser + CPP-ACP without fluoride. In each group, enamel surface was exposed to the remineralizing agent. The teeth were then subjected to pH cycling for 14 days. The teeth were then sectioned, polished, and underwent cross-sectional microhardness testing at 20-160 MU depth quantitatively. Using the Simpson's rule, the amount of mineral loss was calculated in each group. Statistical Analysis Used: ANOVA was used for the comparisons, and Tukey's test was applied for pairwise comparisons. Results: The highest mean volume percentage of microhardness at 20-60 MU depth belonged to the group laser + CPP-ACP with fluoride and the lowest belonged to the control group (P = 0.001). The differences were not significant at 80-120 MU depth (P > 0.05). These finding are confirmed according to ?Z (mineral loss). Conclusion: Based on these results, Er: YAG laser was able to decrease demineralization and was a potential alternative to preventive dentistry and was more effective when combined with CPP-ACP products. PMID- 29988236 TI - Cephalometric association of mandibular size/length to the surface area and dimensions of the frontal and maxillary sinuses. AB - Objective: This study aimed to determine the cephalometric association of mandibular size/length to the surface area and dimensions of the frontal and maxillary sinuses. Materials and Methods: This descriptive study was conducted on 116 digital lateral cephalograms of 38 patients with skeletal Class I malocclusion (normal), 40 patients with skeletal Class II malocclusion with mandibular deficiency, and 38 patients with skeletal Class III malocclusion with mandibular excess. Both male and female patients were included. Using AutoCAD 2016 software, the anteroposterior dimension, height and surface area of the frontal and maxillary sinuses, mandibular body length and cephalometric indices including anterior and posterior cranial bases, and growth pattern indices were measured on lateral cephalograms. Results: Dimensions and surface area of the frontal and maxillary sinuses in skeletal Class III malocclusion were greater than those in other groups. These variables were significantly correlated with the mandibular body length. The coefficient for the correlation of height, width, and surface area of the frontal sinus with mandibular body length was 0.253, 0.284, and 0.490, respectively. The coefficient for the correlation of height, length, and surface area of the maxillary sinus with mandibular body length was 0.346, 0.657, and 0.661, respectively. These variables (except for the frontal sinus width) had a significant correlation with the anterior and posterior cranial bases. The frontal sinus width had a significant correlation with the anterior cranial base. These variables in males were greater than those in females. Conclusion: The dimensions and surface area of the frontal and maxillary sinuses in skeletal Class III malocclusion were greater than those in other groups. These variables (except for the frontal sinus width) had a significant correlation with the anterior and posterior cranial bases and mandibular body length. PMID- 29988237 TI - Early Recurrences During the Blanking Period after Atrial Fibrillation Ablation. AB - Early recurrences of atrial arrhythmias (ERAA) after ablation are common and predict late recurrences and ablation failure.However,becausea proportion of patients with ERAA will have no subsequent arrhythmias after the blanking period, consensus guidelines recommend against immediate repeat ablation for ERAA episodes occurring during the first 3 months post-ablation. In this review, we summarize the predictors, significance, and treatment of ERAA after AF ablation. PMID- 29988238 TI - Label-free Imaging of Myocardial Remodeling in Atrial Fibrillation Using Nonlinear Optical Microscopy: A Feasibility Study. AB - Atrial fibrillation, characterized by rapid disorganized electrical activation of myocardium, is caused by and accompanied by remodeling of myocardial tissue. We applied nonlinear optical microscopy (NLOM) to visualize typical myocardial features and atrial fibrillation effects in order to test anon-destructive imaging technology that in principle can be applied in vivo.Coherent anti-Stokes Raman scattering, endogenous two-photon excited fluorescence, and second harmonic generation were used to inspect unstained human atrial myocardium from three patients who underwent surgical Cox-MAZE procedure with amputation of left atrial appendage. Using NLOM techniques, we collected detailrich pictures of unstained tissue that enable comprehensive characterization of myocardial characteristics like myocyte structure, collagen and lipofuscin deposition, intercalating disc width, and fatty degradation. Development of in vivo application of the NLOM technique may represent a revolutionary approach in characterizing atrial fibrillation associated myocardial remodeling with important implications for therapy individualization and monitoring. PMID- 29988239 TI - Recent Trends in Oral Anticoagulant Use and Post-Discharge Complications Among Atrial Fibrillation Patients with Acute Myocardial Infarction. AB - Background: Atrial fibrillation (AF) is a common complication of acute myocardial infarction (AMI).The CHA2DS2VAScand CHADS2risk scoresare used to identifypatients with AF at risk for strokeand to guide oral anticoagulants (OAC) use, including patients with AMI. However, the epidemiology of AF, further stratifiedaccording to patients' risk of stroke, has not been wellcharacterized among those hospitalized for AMI. Methods: We examined trends in the frequency of AF, rates of discharge OAC use, and post-discharge outcomes among 6,627 residents of the Worcester, Massachusetts area who survived hospitalization for AMI at 11 medical centers between 1997 and 2011. Results: A total of 1,050AMI patients had AF (16%) andthe majority (91%)had a CHA2DS2VAScscore >2.AF rates were highest among patients in the highest stroke risk group.In comparison to patients without AF, patients with AMI and AF in the highest stroke risk category had higher rates of post-discharge complications, including higher 30-day re-hospitalization [27 % vs. 17 %], 30-day post-discharge death [10 % vs. 5%], and 1-year post-discharge death [46 % vs. 18 %] (p < 0.001 for all). Notably, fewerthan half of guideline eligible AF patientsreceived an OACprescription at discharge. Usage rates for other evidence-based therapiessuch as statins and beta-blockers,lagged in comparison to AMI patients free from AF. Conclusions: Our findings highlight the need to enhance efforts towards stroke prevention among AMI survivors with AF. PMID- 29988240 TI - Ablation of Complex Fractionated Electrograms Improves Outcome in Persistent Atrial Fibrillation of Over 2 Year's Duration. AB - Aim: There is controversy and sparse data on whether substrate based techniques in addition to pulmonary vein isolation (PVI) confer benefit in the catheter ablation of persistent atrial fibrillation (AF), especially if long standing. We performed an observational study to assess whether substrate based ablation improved freedom from atrial arrhythmia. Methods: A total of 286 patients undergoing first ablation procedures for persistent AF with PVI only(n = 79), PVI plus linear ablation(n = 85), or PVI plus complex fractionated electrogram (CFAE) and linear ablation(n = 107) were followed. Primary end point was freedom from atrial arrhythmia at one year. Results: Mean duration of pre-procedure time in AF was 28+/-27 months.There were no differences in baseline characteristics between groups except a higher proportion of patients with a severely dilated LA in those receiving PVI+CFAEs+lines. Freedom from atrial arrhythmia was higher with a PVI+CFAE+lines strategy then for PVI alone (HR 1.56, 95% CI: 1.04-2.34, p=0.032) but was not higher with PVI+lines. Benefit of substrate modification was conferred for preprocedure times in AF of over 30 months. The occurrence of atrial tachycardia was higher when lines were added to the ablation strategy (HR 0.08, 95% CI: 0.01-0.59, p=0.014). Freedom from atrial arrhythmia at 1 year was higher with lower patient age, use of general anaesthetic (GA), normal or mildly dilated left atrium and decreasing time in AF. Conclusions: In patients with long standing persistent AF of over 30 months duration,CFAE ablation resulted in improved freedom from atrial arrhythmia. Increased freedom from atrial arrhythmia occurs in patients who are younger and have smaller atria, and with GA procedures. Linear ablation did not improve outcome and resulted in a higher incidence of atrial tachycardia. PMID- 29988242 TI - Interrupting the Natural History of Atrial Fibrillation. Image from the Future. AB - An injectable loop recorder was implanted in a 76-year old patient due to recurrent unexplained syncope.In the first week after implantation, asymptomatic short-term atrial fibrillation was recorded and oral anticoaguation was prescribed. Two weeks later the patient suffered a presyncope and a 5.8 seconds pause was recorded at the time of conversion of atrial fibrillation to sinus rhythm. A Micra Transcatheter Pacing System was implanted based on the minimum pacing needs. Atrial fibrillation episodes became frequent and severe symptomatic without syncope relapse. Antiarrhythmic treatment was initiated and failed and the patient underwent pulmonary vein isolation 6 months later. Antiarrhythmics were discontinued right after atrial fibrillation ablation.The patient remains free of atrial fibrillation episodes based on the injectable loop recorder 1 year follow up. PMID- 29988241 TI - Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same? AB - Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients' vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results. PMID- 29988244 TI - Stepwise Approach to the Different Parts of Vasovagal Syncope in a Patient Undergoing Cardioneuro Ablation. AB - A 30-year-old man underwent ganglionated plexi ablation due to cardioinhibitory type vasovagal syncope with asystole. After asymptomatic period of 15-month following the procedure, the patient experienced 2 new syncope episodes. Tilt test demonstrated vasodepressor response without significant bradycardia. Following the onset of midodrine therapy, the patient was asymptomatic for 1 year and tilt test demonstrate normal response. PMID- 29988243 TI - Anesthetic Management In Electrophysiology Laboratory: A Multidisciplinary Review. AB - Many clinical challenges have been encountered in electrophysiology laboratories (EP) while implanting intracardiac defibrillators for lethal arrhythmias, using pacemakers for bradyarrhythmias, placing pacemakers with multiple leads in patients with heart failure and cardiac ablation procedures. In this environment, anesthesiology plays a very critical role to ensure patients comfort, as well as maintains operator's convenience and facilitate management of undesired situations. EP laboratories are mostly used for diagnosis of certain heart diseases. Meanwhile, with the exponential increase in interventional procedures in our decade, electrophysiologists' need to cooperate with the anesthesiologists more frequently. The literature is still unclear about the effects of anesthetic agents on cardiac conduction pathways, but as we know with our previous data, the most agents we are using currently have more or less effect on the cardiac conduction systems. In this review, we aimed to describe the safe anesthesia methods in cardiac diagnostic procedures and have a closer look up the anesthetic outcomes of these procedures. This article comprehensively reviews the anesthesia practice encountered in electrophysiology laboratories. PMID- 29988245 TI - Clinical Factors Relevant to the Recurrence of Atrial Tachyarrhythmia after Extensive Defragmentation Followed by Thoracic Vein Isolation. AB - Introduction: The efficacy of thoracic vein isolation (TVI), an approach to trigger atrial fibrillation (AF), for the management of AF has been established. Our goal was to identify the predictors for late recurrence of atrial tachyarrhythmias (ATAs), for which the patients and procedural and/or echocardiographic parameters were retrospectively analyzed. Although substrate modification in the atrium for the treatment of AF ablation remains controversial, the background associated with the outcome has not been fully investigated. We retrospectively studied 33 patients with paroxysmal AF and 21 with persistent AF undergoing defragmentation followed by TVI. We evaluated the late/early recurrences, defined as ATA at 3 months after/within the single procedure. Methods and Results: During a median follow-up period of 22 (11-37) months, 28 patients (52%) experienced a late recurrence. There was a higher incidence of late recurrences in the patients with disease durations of >=12.4 months, which was the optimal cut-off point measured in the receiver operating characteristic curve analysis, or in those with left atrial diameter >50 mm or with earlier recurrences than the others (19% versus 72%, p=0.01; 0% versus 37%, p=0.02; or 13% versus 53%, p<0.0001 by the log-rank test, respectively). Moreover, there was a trend toward a higher atrial tachycardia (AT)-free rate in the patients with AF termination during the procedure (75% versus 54%, p=0.07 by the log-rank test). A multivariate analysis based on the Cox proportional hazard model showed that disease duration >=12.4 months or early recurrence was highly associated with the outcomes (HR 3.72, 95%CI 1.42-12.79, p<0.006; HR 4.80, 95%CI 2.24-10.56, p<0.0001). Conclusion: The AF duration and early ATA recurrence are the peri-procedural factors significantly relevant to the outcome after extensive defragmentation followed by TVI. PMID- 29988246 TI - Central giant cells lesion: Report of a conservative management. AB - Central giant cells lesion (CGCL) is defined as a benign intraosseous destructive pathology. It is classified as aggressive or nonaggressive, depending on their clinical, imaginologic, and histological behavior. The behavior, location, and extension of the lesion added to the patient's age will determine the choice of the treatment, either surgical or clinical. Thereby, the aim of this work is to review the literature related to the CGCL, as well as to present a clinical case report of a 22-year-old female patient, affected with an injury on the left side of her jaw. After the diagnosis, it was decided to carry out a conservative treatment with intralesional injections of triamcinolone (10 mg/ml). The injections were performed once a week for 6 weeks. The progress of the patient was satisfactory, and after 4 years, it has been observed through imaging and clinical bone formation examinations with complete remission of the injury and no signs of recurrence. PMID- 29988247 TI - The utility of phospholipase A2 receptor autoantibody in membranous nephropathy after kidney transplantation. AB - Membranous nephropathy (MN) is estimated to cause end-stage renal disease in ~ 5% of patients, in whom renal transplantation is the therapy of choice. Among patients receiving a transplant for MN, the disease will recur in the graft in 30 50%; among these, graft loss will occur in 50% within 10 years. Several studies have suggested that phospholipase A2 receptor autoantibody (aPLA2R) levels before transplantation might be useful in predicting recurrence, and their titration after transplantation is clinically relevant to assess the risk of recurrence and progression, to guide treatment indications and to monitor treatment response. In this review we describe the evolving role of aPLA2R as a biomarker in primary MN and its current usefulness in predicting recurrence of this autoimmune podocytopathy after renal transplantation. PMID- 29988248 TI - Prevalence, severity, and request for treatment of dental fluorosis among adults in an endemic region of Northern Nigeria. AB - Objectives: The objective was to assess the prevalence of all forms of dental fluorosis (DF), the severity, and the request for treatment as a measure of the burden of the condition among adult patients seen at a tertiary health facility in an endemic region of Northeastern Nigeria. Materials and Methods: This was a cross-sectional study that collected required information using a questionnaire from adult dental patients followed by dental examination to assess for DF. Statistical Analysis Used: Associations between sociodemographic distributions (age and gender) and prevalence were analyzed on the Statistical Package for the Social Sciences using the Chi-square test. Analysis was done at 95% confidence interval and the level of statistical significance was set at P < 0.05. Results: Three hundred and twelve patients (41.7%) were diagnosed with DF among the patients who resided in the endemic region with a calculated Community Fluorosis Index of 0.62. The mean age of the affected patients was 33.8 +/- 9.2 years, with a majority of the patients in the 16-25 (47.4%) years' age group and a preponderance among females (P = 0.003). A greater proportion of the 312 diagnosed patients, 201 (64.3%), had fluorosis of esthetic concern, while only 9.3% sought treatment. Most of these patients that sought treatment had the severe form of the enamel defect. Conclusions: DF should be considered as a condition of public health importance in this region. It is necessary to conduct a community-based study and fluoride mapping of the northeastern region as well to determine other factors that may contribute to its occurrence in this population. PMID- 29988249 TI - Influence of chloramine-T disinfection on elastomeric impression stability. AB - Objective: The aim of this study was to evaluate the stability of elastomer through detail reproduction and its dimensional stability (DS) after disinfection with 0.2% chloramine-T. Materials and Methods: The elastomeric impression dental materials used in this study were polydimethylsiloxane (Oranwash L), polyvinyl siloxane (Express), polysulfide (Permlastic), and polyether (Impregum Soft). The entire press procedure was performed on a matrix in accordance with the ISO 4823. Detail reproduction was analyzed using an optical microscope (Stereozoom Microscope) over the 20-MUm line with 25 mm of length at a magnification of *4. DS was measured using an optical microscope (Scanning Tunneling Microscope) by subtracting the distance between the lines X and X' over the 20-MUm line on the matrix (DM) from the distance between the lines on the impression material (DI) divided by DM and multiplied by 100 establishing the equation: DS = ([DI - DM]/DM) *100; then, 100% was added to the results of the equation. The detail reproduction values were subsequently subjected to descriptive analysis by percentage (%), and the DS values (%) were submitted to Kolmogorov-Smirnov test, two-way ANOVA (material * disinfectant), and Tukey's test (alpha = 0.05). Results: All elastomeric impression materials showed 100% of detail reproduction, regardless of the disinfection procedure. Polysulfide (not disinfected) and polysulfide and polydimethylsiloxane (after disinfection with 0.2% chloramine-T) showed the smaller mean values of DS. Conclusion: According to the stability properties analyzed, chloramine-T can be used for disinfection of elastomer molds. PMID- 29988250 TI - Comparative evaluation of apical constriction position in incisor and molar teeth: An in vitro study. AB - Objective: The apical constriction (AC) and the apical foramen (AF) are the principal reference points used to determine the apical limit for instrumentation and root canal filling. AC varies in different races, and the aim of the current study was to measure and compare the distances from AC to AF and the anatomical apex (AA) in incisor and molar teeth in the Iranian population. Materials and Methods: Forty-five roots of incisor teeth and 45 roots of molar teeth were selected randomly in Isfahan Province, Iran. If the foramen was located toward the mesial or distal side of the apex, the cut was made mesiodistally, and if it was toward the buccal or lingual side, the section was made accordingly. Roots were examined under a microscope at *25 magnification. The distances from AC to AF and AA were then estimated using a Motic camera. Descriptive statistics were used. The independent t-test was also used to compare distances in incisors and molars, and P = 0.05 was deemed to indicate statistical significance. Results: The mean distances between AC and AF were 0.847 +/- 0.33 mm in incisors and 0.709 +/- 0.27 mm in molars. The mean distances between AC and AA were 1.23 +/- 0.39 mm in incisors and 1.01 +/- 0.38 mm in molars. In an independent t-test, the distances between AC and AF differed significantly in incisors and molars (P = 0.035), but the distances between AC and AA did not (P = 0.172). Conclusion: The end points for root canal therapy should be 0.85 mm in incisors and 0.70 mm in molars. PMID- 29988251 TI - Patterns of stereotactic radiotherapy utilization and fractionation for acoustic neuroma in the United States. AB - Objective: Stereotactic radiosurgery is a commonly offered modality utilized for the treatment of acoustic neuromas. In this study we sought to analyze the national practice patterns and utilization of GK compared to LINAC based radiosurgery. Methods: Patients diagnosed with an acoustic neuroma between 2004 2013 and treated with LINAC or GK radiosurgery in 1-5 fractions were identified in the National Cancer Database. Results: There were 2,705 patients analyzed, of which 2,222 (82.1%) received GK and 483 (17.9%) received LINAC based radiosurgery. Single fraction treatment was observed in 98.8% of GK patients, versus 19.5% of LINAC patients. LINAC based radiosurgery use increased from 3.5 3.7% in 2004-2005 to 15-26% from 2007-2013. On multivariable logistic regression the use of 3-5 fractions was strongly associated with LINAC based radiosurgery (p<0.001). Conclusion: GK remains the predominant modality for delivering radiosurgery to acoustic neuroma. LINAC based radiosurgery is being cautiously adopted and often utilizes a hypofractionated approach. PMID- 29988252 TI - Assessment of cell viability in four novel endodontic sealers. AB - Objective: The aim of this study was to evaluate the viability of human periodontal ligament (PDL) cells on MTA-Fillapex, GuttaFlow 2, TotalFill Sealer, and BioRootTM RCS in comparison to conventional epoxy resin-based (AH Plus) and zinc oxide-eugenol-based (Roth's 801) sealers. Materials and Methods: Sealers were divided into two groups, and five coverslips for each material per group were prepared. In the first group, PDLs were added immediately after the preparation of sealers (Fresh Group), and in the second, PDLs were added after 24 h. PDLs were cultured for 72 h and afterward, counted using standard hematocytometry. A Mann-Whitney U-test and Kruskal-Wallis test were used for the statistical analysis. The level of significance was set at 5%. Furthermore, cell morphology was assessed by confocal microscopy. Results: The number of viable cells for the 24 h-set groups was higher than the freshly mixed in all sealers except Roth's 801. In both groups, GuttaFlow 2 presented the highest number of viable cells. In a descending order of cells' survival, TotalFill, BioRoot, and MTA-Fillapex are following and the conventional sealers, AH Plus and Roth's 801, seem not to exhibit the biological properties of the others. Cells grown on GuttaFlow 2, TotalFill, and BioRoot were observed to be well-formed. In contrast, MTA-Fillapex exhibited untypical morphology. No cells were detected on the surfaces of AH Plus, as well as Roth's 801. Conclusions: All novel sealers presented increased cell viability in comparison to conventional sealers. GuttaFlow 2 exhibited the highest cell viability. PMID- 29988253 TI - Erratum: Cone-beam computed tomography in the assessment of periapical lesions in endodontically treated teeth. AB - [This corrects the article on p. 136 in vol. 12, PMID: 29657539.]. PMID- 29988254 TI - Reasons for choosing dentistry as a career among dental students in Saudi Arabia. AB - Objective: This study aimed to identify reasons and influential factors for choosing dentistry as a career among dental students in Saudi Arabia. The preferred field of dental specialty following graduation will also be investigated. Materials and Methods: A questionnaire was developed and circulated among undergraduate dental students studying at a private dental college in Saudi Arabia. A list of 16 reasons that possibly influenced students' decision to study dentistry was presented and participants were invited to indicate on a 5-point Likert scale the extent each reason influenced their choice of dentistry as a career. The listed reasons were categorized into economic, professional, vocational, social and personal reasons. Results: Totally, 788 out of 970 questionnaires were completed (response rate: 81%). Proportion of female students exceeded proportion of male students (59% and 41%, respectively) and most participants were Saudi students (73%). The top three influential factors on students' decision to study dentistry were "Dentistry is a prestigious profession," "I like to treat people and improve their appearance," and "I like working with people and caring for them." Variations were identified between male and female students and also between Saudi and non-Saudi students in the reasons to choose dentistry as a career. The vast majority of participants (94%) expressed a desire to follow a postgraduate study. Orthodontics and oral surgery were the most preferred dental specialties. Conclusion: The social and vocational reasons were the main factors that motivated this group of dental students to attend a dental program. Greater training opportunities should be planned to accommodate the speculated increasing demand for postgraduate dental education in Saudi Arabia. PMID- 29988255 TI - Use of Intraprocedural Ibutilide During Stepwise Ablation of Long-Standing Persistent Atrial Fibrillation. AB - Purpose: Catheter ablation is an effective therapy for symptomatic atrial fibrillation (AF). The aim of this study was to assess the effect of ibutilide administration in patients with long standing persistent AF undergoing catheter ablation. Methods: We included 25 patients undergoing stepwise catheter ablation with ibutilide 1.0 mg infused prior to mapping and ablation as first step. Procedural and long-term outcomes were compared to a matched cohort of 25 patients in which ibutilide was not used but all other steps remained the same. Results: Mean age of the cohort was 65.6+/-8.2 years, and duration of persistent AF 71.7+/-96.8 months. Termination to sinus rhythm (SR) directly or through an atrial tachycardia (AT) was achieved in 88% of patients administered ibutilide (32% SR/68% AT) vs. 64% in the control group. Ibutilide was associated with increased AF mean cycle-length (mCL) (208.3+/-31.6 vs. 156.0+/-23.7 ms; p<0.001) and decreased CFE mean surface area (29.2+/-20.2% vs. 47.3+/-13.7%; p=0.002). Procedure and radiofrequency (RF) times were less in the ibutilide group (288.8+/ 49.6 vs. 335.3+/-47.4 min and 66.0+/-16.0 vs. 78.0+/-18.2 min; p=0.002 and 0.029 respectively). The 1-year recurrence was 44% in the ibutilide group and 60% in the control groups (p=0.29). Ibutilide patients had significantly reduced ShEn (6.1+/-0.14 vs. 7.09+/-0.14; p<0.001) and ShEn was higher in patients that recurred (6.47+/-0.24 vs. 5.73+/-0.15; p<0.001). Conclusion: In long-standing persistent AF the use of ibutilide in the context of a stepwise ablation results in increased AF mCL, reduction of fractionation and ShEn and higher rates of AF termination, more often through an intermediate AT. Procedure and RF times are also decreased, without compromising long-term outcomes. PMID- 29988256 TI - Real-Time Recordings in Cryoballoon Pulmonary Veins Isolation: Comparison Between the 25mm and the 20mm Achieve Catheters. AB - Aims: Real Time Recordings (RTR) of pulmonary vein (PV) activity provide important information in the setting of the 2nd generation Cryoballoon (CB-A), as a funcion of time to isolation. Visualization of RTR with the standard inner lumen mapping catheter (ILMC) 20mm Achieve (AC) is possible in roughly 50% of PVs. A novel 25mm-Achieve Advance (AC-A) has been developed with the aim of increasing the detection of RTR. The purpose of this study is to compare the AC-A with the AC, to feasibility and improvement of RTR. Methods: We assigned 50 patients with paroxysmal or persistent atrial fibrillation to CB-A PVI, using the AC-A as ILMC. We compared this group with 50 patients, matched for age and left atrial volume, who previously underwent the CB-A PVI using the AC. Results: RTR were more frequently observed with the AC-A than with the AC (74% vs 49%; p= 0.02). RTR in the left superior PVs was similar in both groups (74% vs 72%, p= 0.8). RTR with the AC-A were equally appreciated in left or right sided, superior or inferior PVs. No significant differences were found in terms of feasibility, procedure fluoroscopy and freezing times, nadir temperatures, and acute PVI. Conclusions: CB-A PVI with the AC-A is feasible and safe in all PVs. The AC-A has proven significantly superior in visualising RTR if compared to the AC, affording RTR in 74% of PVs. PMID- 29988257 TI - Surgical Closure of the Left Atrial Appendage: The Past, The Present, The Future. AB - Occlusion of the left atrial appendage (LAA) may protect against stroke in patients with atrial fibrillation. While percutaneous LAA closure devices have demonstrated efficacy in stroke reduction, surgical LAA occlusion has been performed with mixed results to date. Although surgical exclusion via internal sutures or noncutting stapler is ineffective due to recanalization of the LAA, surgical excision and certain exclusion devices including the AtriClip device are effective methods to achieve complete closure of the LAA. No data currently exists to support routine, prophylactic LAA closure at the time of cardiac surgery, but this practice may benefit certain patients at high risk for stroke. The currently enrolling Left Atrial Appendage Occlusion Study (LAAOS) III is the largest study to date designed to assess the efficacy of LAA occlusion for stroke prevention. The results of this trial will inform future clinical practice regarding stroke prevention with surgical LAA occlusion for patients with atrial fibrillation. Meanwhile, the ATLAS trial is investigating the efficacy of LAA occlusion in surgical patients who do not have atrial fibrillation but are at increased risk for developing it post-operatively. PMID- 29988258 TI - Influence of experimental staining on the color stability of indirect computer aided design/computer-aided manufacturing dental provisional materials. AB - Objective: This study presents a comparative analysis of the color stability of computer-aided design/computer-aided manufacturing (CAD/CAM)-fabricated provisional restorations with those of conventional restorations. Materials and Methods: Three different provisional restorative materials (Systemp C&B, 3M Protemp 4, and Telio CAD) were inspected for their color stability using four solutions (Pepsi, coffee, tea, and distilled water). All samples used were fabricated using A1 shade by following the manufacturer's instructions. Color assessment was performed using CIELAB system and a colorimeter. After baseline color measurement, color assessments were done weekly after immersion in specified solutions. Triplicate readings were taken for every sample and the mean value of the color coordinates (L*), (a*), and (b*) were recorded at baseline, week 1, week 2, week 3, and week 4. The data within different groups were compared statistically using analysis of variance (alpha = 0.05). Results: Overall, the highest color stability was found in CAD/CAM material, followed by Protemp and SystempC&B. It was also observed that the maximum color variation was observed in case of coffee, followed by tea and Pepsi. Conclusions: CAD/CAM provisional material (Telio CAD) showed better color stability compared to conventional materials (Protemp 3M ESPE and SystempC&B Ivoclar Vivadent). CAD/CAM provisional materials are recommended for long-term temporization procedures. This is attributed to the prepolymerization, higher monomer conversion, and minimal preparation errors in CAD/CAM materials. PMID- 29988259 TI - Atrial Fibrillation as a Cause of Incident Heart Failure: A Discrete Clinical Phenotype. PMID- 29988261 TI - A Rare Cause of Resistant Epistaxis: Lobular Capillary Hemangioma Arising from the Inferior Turbinate. PMID- 29988262 TI - Different treatment approaches for the localized gingival overgrowths: Case series. AB - Localized gingival overgrowths belong to a common group of lesions designated as focal reactive overgrowths. They occur in response to chronic, low-grade irritation caused by plaque or any other irritant. They have multifactorial etiopathology but exhibit similar clinical features with slight variations in patient complaints. Success of the lesions' management depends on formation of healthy contours of the surgical area after excision of lesion and absence of a recurrence. The purpose of case series is to present 6 different cases of localized gingival overgrowths and their management with the following techniques: nonsurgical periodontal treatment, gingivectomy, flap surgery, free gingival graft, gingival unit, and connective tissue graft. PMID- 29988260 TI - Capillary rarefaction from the kidney point of view. AB - Capillary rarefaction is broadly defined as a reduction in vascular density. Capillary rarefaction in the kidneys is thought to promote hypoxia, impair hemodynamic responses and predispose to chronic kidney disease (CKD) progression and hypertension development. Various mechanisms have been suggested to play a role in the development of capillary rarefaction, including inflammation, an altered endothelial-tubular epithelial cell crosstalk, a relative deficiency in angiogenic growth factors, loss of pericytes, increased activity of Transforming growth factor -beta1 and thrombospondin-1, vitamin D deficiency, a link to lymphatic neoangiogenesis and INK4a/ARF (Cylin-dependent kinase inhibitor 2a; CDKN2A). In this review, we summarize the tools available to monitor capillary rarefaction noninvasively in the clinic, the contribution of capillary rarefaction to CKD and hypertension, the known mechanisms of capillary rarefaction, and potential future strategies to attenuate capillary rarefaction and reduce its negative impact. Therapeutic strategies to be explored in more detail include optimization of antihypertensive therapy, vitamin D receptor activators, sirtuin 1 activators, Hypoxia inducible factor prolyl hydroxylase inhibitors and stem cell therapy. PMID- 29988263 TI - Esthetic restorative materials and glass ionomer cements: Influence of acidic drink exposure on bacterial adhesion. AB - Objective: The purpose of this research was to evaluate and compare bacterial adhesion on five esthetic restorative materials, three glass ionomer cements (GIC), and two GIC with coat. All the materials were considered after acidic drink exposure. Materials and Methods: Thirty cylindrical sample of each of the 10 materials were prepared and then divided into three groups: group 1 (baseline), Group 2 (1 day in acidic soft drink), and Group 3 (7 days in acidic soft drink). Bacterial suspension of Streptococcus mutans was cultured and deposited onto each material, and the adhesion was evaluated through the colony forming units determination. One-way ANOVA and Bonferroni's post hoc tests were applied to estimate significant differences between the esthetic materials. Results: The highest amount of S. mutans was recorded in Group 3 and the lowest in Group 1 (baseline). In general, the GIC showed bacterial adhesion values higher than the ones related to composites both in Group 2 than in Group 3. Acidic soft drinks lead a time-dependent degradation of restorative materials causing an increase of the surface rugosity. In fact, a general increase in S. mutans cells adhesion to treated samples was observed. Conclusions: The use of acidic soft drink resulted in a degradation of the surface layer of the restorative material with consequent increase of bacterial adhesion. The GIC can be considered a more friendly environment for bacterial adhesion. This is true in particular if acid substances have already deteriorated the surface. PMID- 29988264 TI - Computational Flow Dynamic Analysis of Right and Left Atria in Patent Foramen Ovale: Potential Links with Atrial Fibrillation. AB - Background: An impairment of the left atrial function similar to that usually observed in atrial fibrillation (AF) has been observed also in patients with patent foramen ovale (PFO) and permanent right-to-left shunting (RLS). Methods: We reconstructed the geometrical model of right atrium (RA), PFO, left atrium (LA) and left atrial appendage (LAA) of 65 patients with mild (36 patients mean age 45.5+/-6.8 years, 24 females) or permanent (29 patients, mean age 45.1+/-5.3 years, 21 females) RLS using anatomical data obtained by transoesophageal echocardiography (TEE) and cardiac MRI, performed as a part of our institutional screening protocol for paradoxical embolism. Using computational fluid dynamic analysis (CFD) we assessed the vorticity magnitude in both the LA and LAA to analyse a possible rheological relationship between PFO and AF. Results: The anatomical models, in terms of dimensions, were comparable among the patients with mild and permanent RLS. A higher vorticity magnitude was observed in the mild shunt both in the LA (101.12+/-21.3 vs 88.3+/-22.6, p=0.02) and LAA (62+/ 14.4 vs 32.4+/-12.3, p<0.01) when compared to the permanent R-L shunting. Conclusion: The lower vorticity magnitude across the LA and LAA in patients with permanent RLS suggests a possible higher stagnation of the blood in these anatomical sites, similarly as previously observed in patients with AF. PMID- 29988265 TI - Can We Predict Vagal Response to Cryoballoon Application Using Intracardiac Recordings? AB - The effects of cryoballoon (CB) ablation in non-pulmonary vein sites have not clearly elucidated. Herein we present a new definition method which helps to predict autonomic modification effect of CB application using atrial electrogram (EGM) characteristics and vagal responses (VRs). A 54-year-old man underwent pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation. Both atria were mapped with the aid of electroanatomical mapping system prior to ablation procedure. The atrial EGMs were divided into 3 groups according to duration, amplitude, and number of deflections. The sites demonstrating fractionated pattern on 2.5 centimeters outside of pulmonary vein ostia were tagged on the mapping to predict the relationship between VR and EGM characteristics during CB application. CB application in the PV demonstrating intensive fractionated EGMs caused a significant VR. We concluded that our case may be starting point to understand mechanism of PVI induced VR during CB application. PMID- 29988266 TI - Esophageal laceration related to mechanical trauma from a General Purpose (esophageal/rectal) temperature probe introducer sheath during atrial fibrillation ablation. AB - Catheter Radiofrequency ablation (RFA) for the management of atrial fibrillation (AF) can be associated with serious thermal injuries of the esophagus due to the close proximity of later. Use of Esophageal/Rectal temperature monitoring probes have become a standard practice now during these procedures in order to prevent such complications. However these probes need small introducer sheaths in order to guide them into the esophagus without coiling. Due to the small size of these sheaths, they can easily get dislodged into the trachea or esophagus and cause serious complications including mucosal lacerations. PMID- 29988267 TI - ABO and RhD Blood Groups in Nasal Polyposis. AB - Objective: The aim of this study was to determine ABO and RhD blood group distribution in nasal polyposis (NP) patients and whether there is a specific ABO or RhD blood phenotype associated with susceptibility to or protection with respect to development of NP. Methods: The study group comprised 126 consecutive patients with chronic rhinosinusitis and bilateral NP. The control group comprised 126 healthy blood donors. All participants were from the same geographical region. Distribution of ABO and RhD phenotypes in all participants was studied. Results: There were no significant differences between patients and controls in the distribution of the A (p=0.520), B (p=0.306), AB (p=0.673), O (p=0.894), and RhD (p=0.742) phenotypes. Conclusion: According to the present results, the ABO and RhD blood group systems are not associated with development of NP. PMID- 29988268 TI - Prospective Evaluation of Lesion Index-Guided Pulmonary Vein Isolation Technique in Patients with Paroxysmal Atrial Fibrillation: 1-year Follow-Up. AB - Introduction: Pulmonary vein isolation (PVI) using contact force (CF) sensing ablation catheters currently relies on CF and force-time integral (FTI) guidelines. Such measurement of lesion effectiveness still lacks information on current delivery to the tissue, influenced by system impedance and power. Lesion Index (LSI) is a multi-parametric index incorporating CF and radiofrequency current data across time. We aimed to prospectively assess the efficacy of an LSI guided approach to PVI in patients with paroxysmal atrial fibrillation (PAF). Methods and Results: The study prospectively enrolled 28 consecutive patients with PAF undergoing PVI with a CF sensing catheter (TactiCathTM, Abbott). LSI guided ablation target was adapted according to the mean regional thickness of pulmonary vein antra (PVA): LSI range 5.5-6 was pursued in the anterior and septal portions of PVA, 5-5.5 elsewhere. Data from 32 consecutive PAF patients who underwent PVI ablation with a non-CF guided approach (NCF-group) were retrospectively collected for comparison of procedural and clinical outcome.AF free survival rate at follow-up (17+/-6 months) was higher for LSI-guided group than NCF-group (89.3% vs 65.6%, p=0.037), with no increase in periprocedural complication rate (no tamponades or other major adverse events reported). Among 1126 lesions with LSI within target range (5-6), average CF was >10g and <30g for 976 lesions (86.7%). Moreover, 1015 lesions (90.1%) had FTI>400gs, but with wide distribution: 30.2% within 400-500gs, 30.0% within 501-600gs, 29.9% over 600gs. Conclusion: In this first prospective study, LSI-guided PVI improved clinical outcome without any increase in complication rate when compared with standard, non-LSI-guided approach. PMID- 29988269 TI - 3D Mapping for PVI- Geometry, Image Integration and Incorporation of Contact Force Into Work Flow. AB - Catheter ablation of atrial fibrillation has evolved enormously thanks to rapid improvement of modern mapping technologies, progress in catheter development and current possibilities for reduction of radiation exposure. Pulmonary vein isolation is thereby the cornerstone in this interventional treatment. Increased precision of catheter localization by modern three-dimensional mapping systems, faster and better processing of local electrograms and their immediate color based visualization make it possible to treat even challenging arrhythmias very effectively. The commonly used three-dimensional mapping systems CARTO 3 (Biosense Webster, Irvine, Ca.) and Ensite Precision (St. Jude Medical, St. Paul, Min) differ in construction and principles of the underlying mapping technology. In this review article, we aim to emphasize the most important aspects of possibilities that make both systems so valuable for interventional treatment of atrial fibrillation. We present a modern workflow, that unites three-dimensional LA mapping with collecting relevant local information, image integration for refining the map and beneficial use of contact force based ablation approach. PMID- 29988270 TI - School-aged children based seasonal malaria chemoprevention using artesunate amodiaquine in Mali. AB - Introduction: Malaria is still a public health problem in Africa. Seasonal Malaria Chemoprevention (SMC) is an efficient control strategy recommended by WHO that targets children under five year old living in areas of seasonal malaria transmission. SMC uses the combination amodiaquine (AQ) - sulfadoxine pyrimethamine (SP). However SP selects rapidly drug resistant parasites. And malaria burden may increase in older children where SMC is implemented. We initiated a pilot study to assess an alternative approach to SMC in older children in Mali. Methods: A randomized open-label clinical trial was conducted to test the efficacy and safety of SMC using artesunate - amodiaquine in school aged children in Mali. Two hundred pupils aged 6-15 years old were enrolled and randomized into two arms of 100 each, to receive either artesunate-amodiaquine (ASAQ) monthly or no intervention. Both arms were followed and clinical malaria were diagnosed and treated with arthemeter-lumefanthrine as recommended by Mali National Malaria Control Program. ASAQ was administered 3 days under study team direct observation and during 4 consecutive months starting in October 2013. Follow up was continued until April 2014. Results: Overall, 20 cases of uncomplicated clinical malaria were encountered in the Control arm and three cases in the ASAQ arm, showing a protective efficacy of 85% 95% CI [80.1-89.9] against clinical malaria. Protective efficacy against malaria infection was 69.6% 95% CI [58.6-21.4]. No effect on anemia was observed. ASAQ was well tolerated. Most common solicited adverse events were abdominal pain and headaches of mild intensity in respectively 64% and 44% of children that swallowed ASAQ. Conclusion: ASAQ is effective and well tolerated as SMC targeting older children in a peri urban setting in Mali. Its administration at schools is a feasible and accepted strategy to deliver the intervention. PMID- 29988271 TI - Histopathologic Evaluation of Hyaluronic Acid and Plasma-Rich Platelet Injection into Rabbit Vocal Cords: An Experimental Study. AB - Objective: Various materials are used by otolaryngologists for vocal cord injections in the management of vocal cord paralysis. An ideal injection material should be long-term effective, readily available, cheap, easy to prepare, have no donor morbidity, easy to use, biocompatible, resistant to resorption or migration, and easy to extract during revision. In this study, we aimed to see the histopathological effects of hyaluronic acid (HYA) and platelet-rich plasma (PRP) injections into the vocal cords of New Zealand rabbits. Methods: PRP was injected into the right vocal cords of twelve rabbits, which was prepared from their serum (PRP group). HYA was injected into the left vocal cords of first six rabbits (numbered 1-6) (HYA group), and the left vocal cords of the other six rabbits (numbered 7-12) were followed with no intervention (control group). Two months later, histomorphological findings in the vocal cords were assessed by two experienced pathologists in seven parameters: chronic inflammation, mucosal atrophy, necrosis, neovascularization, fibrosis, foreign body reaction, and muscular atrophy. They were scored double-blinded as negative (0), mild (+1), moderate (+2), and severe (+3). Fisher's chi-square test was used to evaluate any statistical significance among the three groups. Results: Chronic inflammation, mucosal atrophy, necrosis, foreign body reaction, and muscular atrophy parameters were scored as "0" for each preparate by both pathologists. For neovascularization and fibrosis, a stasistically significant difference was seen among the three groups (p<0.05). Neovascularization was increased in the PRP and HYA groups compared with the control group. No significant difference was observed in fibrosis when the groups were compared separately. After two months, two of the six vocal cords injected with HYA revealed HYA; however, none of the PRP-injected vocal cords showed PRP. Conclusion: HYA and PRP can be safely injected into vocal cords. Our findings show that HYA is a biocompatible and safe injection material for clinical use. Only two of the six vocal cords showed HYA at the end of two months, suggesting that HYA is a short-term effective material. Similarly, PRP was also shown to be a short-term effective material and can be used in patients for testing purpose before using a long-term effective material. The advantages of PRP are that it is inexpensive, readily available, and completely inert as it is prepared from the subject itself. PMID- 29988272 TI - Outcomes of Cochlear Implantation in Auditory Neuropathy Spectrum Disorder and the Role of Cortical Auditory Evoked Potentials in Benefit Evaluation. AB - Objective: To compare the outcomes of cochlear implantation (CI) in children with auditory neuropathy spectrum disorder (ANSD) and age-matched controls with profound sensorineural hearing loss, using categories of auditory performance (CAP), speech intelligibility rate (SIR), meaningful auditory integration scale (MAIS), and meaningful use of speech scale (MUSS), and to determine the role of Cortical Auditory Evoked Potentials (CAEP) in benefit evaluation after CI. Methods: Ten patients (8 males and two females) with ANSD who underwent CI were included in the study. Auditory and speech scores were compared between baseline and after 12 months of habilitation in children with ANSD. Post CI speech scores in children with ANSD were compared with the control group (age-matched children with profound sensorineural hearing loss) at 12 months of habilitation. P1 latency of CAEP has a good correlation with auditory and speech scores in children with ANSD in the study group. Results: Significant benefits were seen in children with ANSD who underwent CI compared to the baseline CAP and SIR scores and one year after habilitation. There is no statistically significant difference in outcomes between the two groups with CI (ANSD and profound sensorineural hearing loss) (p-value: CAP=1.00, SIR=0.84, MAIS=0.33, MUSS=0.08). Speech perception in noise test (SPIN) scores in children with ANSD were 63% and 80% with 0 dB signal noise ratio (SNR) and +10dB SNR, respectively. P1 wave of CAEP has a good correlation with the subjective outcomes. Conclusion: CI in children with ANSD has showed benefits comparable to children with profound sensorineural hearing loss. CAEP is a useful tool in objectively assessing cortical maturity in children with ANSD following CI. PMID- 29988273 TI - Audit of Bilateral Simultaneous Cochlear Implantation in Pediatric Population: South Indian Study. AB - Objective: To conduct a medical audit of bilateral simultaneous cochlear implantation (CI) in patients with severe prelingual sensorineural hearing loss (SNHL). Methods: A medical audit of a tertiary care ear, nose, and throat center in Southern India was conducted on data collected from January 2007 to December 2014. All cochlear implantees <6 years of age with severe bilateral SNHL who underwent bilateral simultaneous CI were included in the present study. The exclusion criteria were children >6 years, sequential bilateral CI, revision cases, abnormal or malformed cochlea, and children with global developmental delay in milestones. Subjective outcome scores used were Category of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR). Results: The CAP and SIR results showed that 20% of implantees achieved peak scores of 7 and 5, respectively. Mean CAP and SIR scores at 12 months were 5.4 and 3.1, respectively. Conclusion: The present study supports the claim that bilateral CI in severe prelingual bilateral SNHL is better than unilateral and recommends that bilateral CI should be the standard of care in children. PMID- 29988274 TI - Combining Spreader Grafts with Suture Suspension for Management of Narrow Internal Nasal Valve Angles. AB - Objective: The present study aimed to evaluate the long-term results of combining spreader grafts with lateral suspension techniques for management of narrow internal nasal valves. Methods: This prospective study included 79 patients who underwent surgical interference for dysfunctional nasal valve. The surgical intervention was a combination of two commonly used techniques for management of internal nasal valve dysfunction: spreader graft insertion and lateral suspension of the upper lateral cartilages. The patients were assessed using the nasal obstruction symptom evaluation (NOSE) tool, computed tomography (CT) scans, and endoscopic examinations. Results: All patients reported initial improvement and satisfaction in nasal breathing. Seventy-two patients (91%) reported sustained relief of nasal breathing for at least 3 years postoperatively. The mean NOSE scores decreased from 69.8 to 20.65 postoperatively. The internal nasal valve angle, as measured endoscopically, increased from 7.23 degrees to 13.05 degrees on the right side and from 6.75 degrees to 11.98 degrees on the left side; the increase was statistically significant. The angle, as measured on axial CT scans, increased from 8.11 degrees to 14.15 degrees on the right side and from 6.98 degrees to 12.13 degrees on the left side' this increase, too, was statistically significant. Conclusion: Combining spreader grafts with lateral suspension sutures provide good, stable, and sustained repair of dysfunctional narrowed internal nasal valves. PMID- 29988275 TI - The Ignored Parameter in the Diagnosis of Obstructive Sleep Apnea Syndrome: The Oxygen Desaturation Index. AB - Objective: The apnea-hypopnea index (AHI) does not provide information about the apnea depth and length. We aimed to evaluate the correlation of the oxygen desaturation index (ODI) with AHI and the subjective symptoms because it is known that hypoxia plays an important role in morbidity and complications of obstructive sleep apnea syndrome (OSAS). Methods: We reviewed the data of patients who applied to our clinic between 2010 and 2014 and underwent polysomnography (PSG) with a diagnosis of suspected sleep apnea. The demographic and anthropometric data of the patients were recorded. Epworth sleepiness scale (ESS) and values of AHI and ODI were analyzed in PSG. Results: A total of 321 patients were divided into four groups, according to AHI as follows: 82 (25.5%) common snoring, 77 (24%) mild obstructive sleep apnea (OSA), 71 (22.1%) moderate OSA, and 91 (28.3%) severe OSA. A strong correlation was detected between AHI and ODI (p<0.005 and r=0.904) in all patient groups. There was a positive correlation between AHI and ESS (p<0.05 and r=0.435), but the correlation of ESS with ODI was stronger than that with AHI (p<0.05 and r=0.504). Conclusion: The subjective symptoms of sleep apnea syndrome seem to be closely related to oxygen desaturations. Hypoxia during apnea periods of OSA is important; therefore, we suggest that ODI is as valuable as AHI in diagnosing and grading the OSAS. PMID- 29988276 TI - Myxoma of the Middle Ear Mimicking Chronic Otitis Media. AB - Myxoma is a benign connective tissue tumor that arises mostly from the heart. Temporal bone myxomas are extremely rare and these patients should be evaluated for the Carney complex association. Herein, our aim was to present a middle ear myxoma case operated with an initial diagnosis of chronic otitis media (COM) and to underline the fact that myxomas should be kept in mind in the differential diagnosis of aural polyps. PMID- 29988277 TI - Inhibition efficiency of a newly isolated flavonoid compound from Vitex negundo L. leaves against cattle-endosymbiont Setaria cervi: Phytomedicine for lymphatic filariasis. AB - Experimental studies has been carried out to isolate and identify an active antifilarial compound from Vitex negundo L. plant as it has been used for treatment against filariasis in Indian traditional system of medicine. In vitro antifilarial assay has been carried out against adult filarial parasite Setaria cervi worms by both worm motility and MTT reduction assays. Levels of oxidative stress parameters MDA, carbonyl content and nitric oxide levels have been detected. The isolated compound exhibited significant antifilarial activity in dose dependent manner. The active compound has been chemically characterized and identified as 4,5-diethyl-3'-ethoxy-pyro-flavone. PMID- 29988278 TI - Intraosseous Mucoepidermoid Carcinoma of the Jaw: Report of Three Cases. AB - Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands and is seen most commonly in the parotid gland. Intraosseous MECs can be rarely seen and is mostly detected in the posterior part of the mandible. This condition can be acknowledged as an entity different from salivary gland MECs. In this case series, we delineated three patients of intraosseous MEC, two mandible tumors and one maxillary tumor and discussed the diagnostic characteristics and treatment methods of this rare entity. PMID- 29988279 TI - Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Predictor of Incident Atrial Fibrillation. AB - Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker of chronic low-grade inflammation and a potent predictor of cardiovascular events. We hypothesized that plasma suPAR levels would predict new-onset atrial fibrillation (AF) in a large cohort of con-secutively admitted acute medical patients during long-term follow-up. In 14,764 acutely ad-mitted patients without prior or current AF, median suPAR measured upon admission was 2.7 ng/ml (interquartile range (IQR) 1.9-4.0). During a median follow-up of 392 days (IQR 218-577), 349 patients (2.4%) were diagnosed with incident AF. suPAR levels at admission significantly predicted subsequent incident AF (HR per doubling of suPAR: 1.21, 95% CI 1.05-1.41, adjusted for age and sex). After further adjustment for Charlson score, plasma C-reactive protein (CRP), plasma creatinine and blood hemoglobin-levels, the result remained essentially unaltered (HR per doubling of suPAR: 1.20, 95% CI: 1.01-1.42). In multivariate ROC curve analysis, combining age, sex, Charlson score, CRP, creatinine, and hemoglobin (AUC 0.77, 95% CI 0.75-0.79), the addition of suPAR did not improve the prediction of incident AF (AUC 0.77, 95% CI 0.75-0.79, P=0.89). Plasma suPAR is independently associated with subsequent new-onset AF in a population of recently hospitalized patients, but the addition of suPAR to baseline risk markers appears not to improve the prediction of AF. PMID- 29988280 TI - Abnormal Atrial Activation at Surface Electrocardiogram Examination in Born Underweight Young Adults. AB - Introduction: Recent published data demonstrated how subjects born preterm are at higher risk of developing early atrial fibrillation (AF). Materials and Methods: The surface ECG of twenty-four adults, former preterm infants born with an extremely low birth weight (ex-ELBW; mean age at study: 23.2+/-3.3 years; mean gestational age: 27.8+/-2.3 weeks; mean birth weight: 840+/-120.1 grams), were compared with those of 24 healthy counterparts born at term (C). A few parameters known to be capable of predicting a predisposition to develop AF were examined: P wave duration and dispersion, P terminal force, isoelectric interval length, PR interval length, and advanced interatrial blocks. Results: A shorter PR interval length was found in ex-ELBW compared to C (p<0.0003) as well as longer P wave duration and dispersion, p terminal force, and isoelectric interval (p<0.0001, p<0.0001, p<0.01, and p<0.0004, respectively). Four cases of advanced interatrial block were detected in ex-ELBW, and none in C (p<0.0001). P wave duration, PR interval length, and P wave dispersion were significantly correlated with birth weight (r=0.51 p<0.01, r=0.46 p<0.02, and r=0.42 p<0.04, respectively). When excluding the possible influence of gestational age on birth weight, P wave duration and dispersion were found to be the only statistically significant determinants of abnormal atrial electrical activation (p<0.03 and p<0.04, respectively). On the contrary, when excluding the possible influence of birth weight on gestational age, only P wave duration remained statistically significant (p<0.05). Conclusion: Surface ECG findings of abnormal atrial activity in ex-ELBW may explain their previously reported predisposition to developing AF. PMID- 29988281 TI - Perspectives of Immune Suppression in the Tumor Microenvironment Promoting Oral Malignancy. AB - Introduction: In order to survive, cancers control immune systems and evade immune detection using mediators consisting of immune checkpoint molecules and cellular systems associated with immune suppression. Methodology: During the development of cancer and chronic infections, the immune checkpoints and cellular components including regulatory T cells, myeloid derived suppressor cells and cancer associated fibroblasts are often enhanced as a mechanism of immune subversion and have therefore become very important therapeutic targets. Conclusion: In this review, we will discuss the complexity of immune-suppressive mechanisms in the tumor milieu of cancers, including oral malignancy. PMID- 29988282 TI - What is the Impact of Frailty on Prescription of Anticoagulation in Elderly Patients with Atrial Fibrillation? A Systematic Review and Meta-Analysis. AB - Background: Atrial fibrillation (AF) and frailty are both associated with advanced age. Oral anticoagulants (OAC) effectively prevent strokes in AF patients but are underutilized in the elderly, possibly due to misperception of frailty. Objective: We performed a systematic review to determine the prevalence of frailty in patients with AF, and whether frailty was associated with reduced prescription of OAC. Methods: We systematically searched Cochrane, MEDLINE, EMBASE, and PubMed databases. Search terms combined relevant words and MeSH headings: 1) atrial fibrillation, 2) frail elderly, and 3) geriatric assessments. Studies that measured frailty using a validated instrument, and involved OAC for AF in frail and non-frail patients were eligible for inclusion. Pooled odds ratios were calculated using random-effects model. Results: Of 166 reviewed titles, only 3 studies (1204 patients) met the inclusion criteria. Two used the Reported Edmonton Frail Scale (total 509 patients), and one used the Canadian Study of Health and Aging Clinical Frailty Scale (682 patients). All 3 studies involved hospitalized patients with an average age of 85 +/- 6 and 45% were male. The weighted mean prevalence of frailty in patients with atrial fibrillation was 39% (95%CI 36-42). The weighted mean rate of OAC use was 57+/-11%. Frailty was associated with non-prescription of OAC compared to non-frail (OR 0.49, 95% CI 0.32-0.74, I2 =45%). Conclusion: The prevalence of frailty in hospitalized elderly patients with AF is high, and the use of OAC is low in these patients. Frail elderly are significantly less likely to receive OAC. PMID- 29988283 TI - Paternal sepsis induces alterations of the sperm methylome and dampens offspring immune responses-an animal study. AB - Background: Sepsis represents the utmost severe consequence of infection, involving a dysregulated and self-damaging immune response of the host. While different environmental exposures like chronic stress or malnutrition have been well described to reprogram the germline and subsequently offspring attributes, the intergenerational impact of sepsis as a tremendous immunological stressor has not been examined yet. Methods: Polymicrobial sepsis in 12-week-old male C57BL/6 mice was induced by cecal ligation and puncture (CLP), followed by a mating of the male survivors (or appropriate sham control animals) 6 weeks later with healthy females. Alveolar macrophages of offspring animals were isolated and stimulated with either LPS or Zymosan, and supernatant levels of TNF-alpha were quantified by ELISA. Furthermore, systemic cytokine response to intraperitoneally injected LPS was assessed after 24 h. Also, morphology, motility, and global DNA methylation of the sepsis survivors' sperm was examined. Results: Comparative reduced reduction bisulfite sequencing (RRBS) of sperm revealed changes of DNA methylation (n = 381), most pronounced in the intergenic genome as well as within introns of developmentally relevant genes. Offspring of sepsis fathers exhibited a slight decrease in body weight, with a more pronounced weight difference in male animals (CLP vs. sham). Male descendants of sepsis fathers, but not female descendants, exhibited lower plasma concentrations of IL-6, TNF-alpha, and IL-10 24 h after injection of LPS. In line, only alveolar macrophages of male descendants of sepsis fathers produced less TNF-alpha upon Zymosan stimulation compared to sham descendants, while LPS responses kept unchanged. Conclusion: We can prove that male-but surprisingly not female-descendants of post-sepsis fathers show a dampened systemic as well as pulmonary immune response. Based on this observation of an immune hypo-responsivity, we propose that male descendants of sepsis fathers are at risk to develop fungal and bacterial infections and might benefit from therapeutic immune modulation. PMID- 29988284 TI - A Chromosome 4q25 Variant is Associated with Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-Analysis. AB - Background: Recent studies suggested that variants on chromosome loci 4q25, 1q21, and 16q22 were associated with atrial fibrillation recurrence after catheter ablation. In this study, we performed a systematic review and meta-analysis to explore the association between variants on chromosome loci 4q25, 1q21, and 16q22 and atrial fibrillation recurrence after catheter ablation. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to January 2017. Included studies were published prospective or retrospective cohort and case control studies that compared the risk of atrial fibrillation recurrence after catheter ablation in AF patients with chromosome 4q25, 1q21, and 16q22 variants versus no variants. Single-nucleotide polymorphism rs1906617, rs2106261, rs7193343, rs2200733, rs10033464, rs13376333, and rs6843082 were included in this analysis. Data from each study were combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate the risk ratios and 95% confidence intervals. Results: Seven studies from January 2010 to June 2017 involving 3,322 atrial fibrillation patients were included in this meta-analysis. According to the pooled analysis, there was a strong independent association between chromosome 4q25 variant (rs2200733) and the risk of atrial fibrillation recurrence after catheter ablation (risk ratio 1.45 [95% confidence interval 1.15 1.83], P = 0.002). No association was found in other variants. Conclusion: Our meta-analysis demonstrates a statistically significant increased risk of atrial fibrillation recurrence after catheter ablation in 4q25 variant (only in rs2200733) but not in 1q21 or 16q22 variants. PMID- 29988285 TI - Effects of Strength Training on Muscle Properties, Physical Function, and Physical Activity among Frail Older People: A Pilot Study. AB - The aim of this study was to determine the effects of a 10-week strength training intervention on isometric strength, rate of force development (RFD), physical function (stair climbing, rising from a chair, and preferred and maximal walking speed), and physical activity among frail elderly people receiving home-care services. Thirty participants were randomly assigned (by sex) to a control group (CON) or a strength training group (ST) performing a supervised training programme using elastic bands, box-lifting, and body weight exercises twice per week. Twenty-three participants were selected to complete the study (age 84.9 +/- 6.1 years). For the ST, only improvement in muscle properties was the peak RFD in leg extension (p=0.04). No significant differences were observed in muscle properties for the control group (CON) (p=0.16-1.00) or between groups (p=0.39 1.00). There were no changes within and between the groups in physical function (p=0.12-0.19) or physical activity levels (p=0.06-0.73). The results of this pilot study did not demonstrate greater improvements in muscle properties and physical function and improved physical activity after attending a home-based resistance program compared to physical activity advise; however, larger population studies should examine these findings. This trial is registered with ISRCTN10967873. PMID- 29988286 TI - Trends and outcomes of the use of percutaneous native kidney biopsy in the United States: 5-year data analysis of the Nationwide Inpatient Sample. AB - Background: Despite an inordinate share of health care resources being utilized by patients with kidney disease, morbidity and mortality in these patients remain high. Although renal biopsy is an intervention to identify potential treatment modifiable causes of disease, large-scale data studying the safety and outcomes of percutaneous native kidney biopsy in hospitalized patients are lacking. Methods: We queried the Nationwide Inpatient Sample database from 2008 to 2012 and identified all hospital admissions during which a percutaneous renal biopsy was performed. Patients <18 years of age or with a transplanted kidney were excluded. Data regarding associated renal pathology and procedure-related complications were collected and analyzed. Outcomes studied were length of stay, mortality and cost adjusted for inflation. Results: A total of 118 064 hospital admissions were included in our analysis. The most common complications reported after percutaneous kidney biopsy were packed red blood cell transfusion (261/1000 cases), hematuria (129/1000 cases) and bleeding (78/1000 cases). Patients had an overall mortality of 1.8%. The mean length of stay for each hospitalization was 10.65 days, with a significant difference between elective and nonelective admissions (6.3 versus 11.7; P < 0.01). The average cost per hospitalization was US$22 917 after adjusting for inflation, again with a significant difference between elective and nonelective admissions (15 168 versus 24 780; P < 0.01). Conclusion: Overall, percutaneous renal biopsy is considered a safe procedure; however, our study based on a national database demonstrates a relatively higher complication rate as compared with the limited prior available studies. PMID- 29988287 TI - Primary Immunodeficiencies Unravel the Role of IL-2/CD25/STAT5b in Human Natural Killer Cell Maturation. AB - Natural killer (NK) cells play a pivotal role during immunity against viruses and circumstantial evidence also indicates that they can protect the host against developing tumors. Peripheral blood NK cells comprise CD56brightCD16lo/- cells that constitutively express CD25 (IL-2Ralpha) and CD56dimCD16hi cells that express CD25 upon activation. Using NK cells from two patients, one with a primary immunodeficiency characterized by a homozygous mutation in CD25 (born in year 2007 and studied since she was 3 years old) and one with a homozygous mutation in STAT5b (born in year 1992 and studied since she was 10 years old), we observed that the absence of IL-2 signaling through CD25 promotes the accumulation of CD56brightCD16high NK cells, and that CD56brightCD16lo, CD56brightCD16high, and CD56dimCD16high NK cells of this patient exhibited higher content of perforin and granzyme B, and proliferation capacity, compared to healthy donors. Also, CD56bright and CD56dim NK cells of this patient exhibited a reduced IFN-gamma production in response to cytokine stimulation and increased degranulation against K562 cells. Also, the CD25-deficient patient presented a lower frequency of terminally differentiated NK cells in the CD56dimCD16hi NK subpopulation compared to the HD (assessed by CD57 and CD94 expression). Remarkably, CD56dimCD16high NK cells from both patients exhibited notoriously higher expression of CD62L compared to HD, suggesting that in the absence of IL-2 signaling through CD25 and STAT5b, NK cells fail to properly downregulate CD62L during their transition from CD56brightCD16lo/- to CD56dimCD16hi cells. Thus, we provide the first demonstration about the in vivo requirement of the integrity of the IL-2/CD25/STAT5b axis for proper human NK cell maturation. PMID- 29988288 TI - A Review of the Anatomical and Histological Attributes of the Left Atrial Appendage with Descriptive Pathological Examination of Morphology and Histology. AB - The left atrial appendage (LAA) has a key role in the embolic complications of atrial fibrillation (AF). It has been studied extensively, from recent interest in the thrombotic implications of various LAA morphologies to LAA occlusion and ablation. We collected eleven post-mortem LAA samples for visual analysis, two were not included due to poor sample quality. On examination of the nine remaining samples, several common patterns of pectinate muscle orientation were noted. The LAA samples were noted to have a smooth circumferential neck of muscular tissue giving rise to a dominant singular smooth trunk of papillary muscle in 6 cases and two trunks in 3 cases. These trunks were either shallow (5 samples) or more muscular and raised (4 samples). Shallow trunks tended to be wider than the raised trunks and may even be circumferential (2 samples). The main trunk arborized to give off papillary muscle branches down to third or fourth order branches. The samples were visually assessed for the percentage of smooth papillary muscle versus non-papillary recesses and were found to have <=50% smooth muscle in 3 samples, 50-75% in 3 samples and >75% in 3 samples. We performed histological analysis of further LAA samples collected during cardiac surgery in a parallel study. We identified a distinct pattern of myocyte orientation from the neck, mid-section and apical section of the LAA demonstrating arborization of myocyte fibers with minimal communication in distal segments of the LAA. We feel that this information may help understanding of the issues surrounding LAA ablation strategies. PMID- 29988289 TI - Assessment of concurrent stereotactic radiosurgery and bevacizumab treatment of recurrent malignant gliomas using multi-modality MRI imaging and radiomics analysis. AB - Purpose: To assess the response and predict the overall survival (OS) of recurrent malignant gliomas (MG) patients treated with concurrent BVZ/SRS using multi-modality MRI imaging and radiomics analysis.Methods and materials: SRS was delivered in a single fraction (18/24Gy) or 25Gy in 5 fractions. BVZ was administered immediately before SRS and 2 weeks after. MRI scans were performed before SRS, 1 week and 2 months after SRS. The MR protocol included 2 anatomical (T1w and T2w) and 2 functional (dynamic contrast-enhanced DCE-MRI and diffusion weighted DW-MRI) modalities. Functional biomarkers including apparent diffusion coefficient (ADC), micro-vascular transfer constant Ktrans, brain blood flow FB, and blood volume VB were analyzed. Radiomics analysis was performed to extract imaging features from anatomical MRI images and functional biomarker maps. Wicoxon signed rank tests were performed to evaluate treatment-induced changes, and Mann-Whitney U tests were performed to compare the differences of treatment induced changes between different patient groups. Selected biomarkers and radiomics features were used to predict the OS after treatment using Support Vector Regression (SVR) with leave-one-out cross validation (LOOCV). Results: Twelve patients with recurrent MG were studied. The median OS was 13.8 months post SRS. DCE results showed that Ktrans (p=0.035) and VB (p=0.035) showed significant decrease 2 months after SRS, and FB showed significant decrease as early as 1 week (p=0.017) after SRS. No functional parameters reflected statistically significant treatment response 1 week after SRS. A total of 888 radiomics features were extracted. 31/126 features demonstrated significant changes 1 week/2 months after SRS, respectively. 9 features' changes were significantly different between WHO Grade III vs IV patient groups, and 6 features' changes were found to be linearly correlated with OS. Using 5 selected features, 9 patients' survival time could be accurately predicted (Mean absolute error = 1.47 months, RMSE = 2.10 months). Conclusion: The results of this work demonstrate the potential of combined radiomics analysis and functional MR imaging in quantitatively identifying early treatment response of concurrent SRS/BVZ. PMID- 29988290 TI - Aorto-enteric Fistula After Endovascular Abdominal Aortic Aneurysm Repair for Behcet's Disease Patient: A Case Report. AB - Introduction: A 42 year old male with Behcet's disease (BD) had endovascular treatment of a symptomatic infrarenal abdominal aortic aneurysm (AAA). Thirteen months later he developed haematemesis and melaena. Methods: Computed tomography (CT) and angiography showed an aorto-enteric fistula with migration and kinking of the stent graft. Explantation of the infected graft and axillobifemoral bypass, aneurysm sac debridement, and jejunal repair with omental interposition was performed on this severely contaminated patient. Discussion: There are no reports of an aorto-enteric fistula secondary to endovascular repair in the literature and this case describes the potential consequences of endovascular repair of AAA in BD. The aorto-enteric fistula was associated with persistent inflammatory aortitis, stent graft kinking, and infection. Five cases of secondary aorto-enteric fistulas following open AAA repair in BD patients have been reported including this case resulting from endovascular repair. PMID- 29988291 TI - Schwannoma in the Supraclavicular Region: Case Report. AB - Schwannomas are benign tumors arising from schwann cells in peripheral, cranial, and autonomic nerve sheaths. Approximately half of all cases of schwannomas are observed in the head and neck region. In this study, a 71-year-old male patient presenting with a stiff mobile mass in the left supraclavicular region and diagnosed as a schwannoma after total excision was presented. PMID- 29988292 TI - High Density Mapping of Pre-Excitation 3D-Illustration of Anatomical Features. AB - While ablation of accessory pathways is usually performed without 3D mapping system, we present a case where high-density mapping helps in illustrating the anatomical features of epicardial and oblique AP connections. PMID- 29988293 TI - Paclitaxel-coated balloon dilation for central airway obstruction. AB - Introduction: Central airway obstruction (CAO) often requires repeated interventional procedures which offer variable efficacy, a time-limited effect, and have inherent limitations. Paclitaxel has been used to prevent restenosis in blood vessels. The literature describing the use of paclitaxel to prevent recurrent airway stenosis is limited. We sought to describe our experience using a paclitaxel-coated balloon (PCB) for CAO. Material and methods: We performed a retrospective review of all patients who underwent PCB airway dilation. We collected: basic demographics, details of the CAO, details of the bronchoscopes used, PCB size, PCB dilation pressure, duration of PCB inflation, concurrent non PCB interventions, estimated pre- and post-PCB CAO luminal diameter, follow up bronchoscopy date and luminal diameter, and spirometry results. Results: PCB dilation was performed in 10 cases on 5 patients. Eight PCB dilations were performed for CAO related to distal airway stent stenosis. Concurrent non-PCB interventions were performed with 6 PCB dilations. Nine cases documented improvements and 1 was unchanged immediately post-PCB dilation. Median luminal diameter pre-PCB dilation was 2 mm. Immediately post-PCB dilation, the median change in luminal diameter was 2 mm. Follow up bronchoscopy information was available for 9 cases. For these 9 cases, luminal diameter was unchanged in 5 and worse in 4 when compared to immediate post-PCB dilation. Conclusion: PCB dilation in benign CAO produced a modest effect in this cohort of challenging airways. Larger prospective studies are needed to assess how a PCB would perform when compared to a non-drug coated balloon. PMID- 29988294 TI - Successful stereotactic body radiation therapy for stage I non-small cell lung cancer with malignant hypercalcemia - Case report. AB - In patients with lung malignancy, the development of malignant hypercalcemia (MH) carries a dismal prognosis and represents a major therapeutic challenge given that conventional medical treatments have limited durability. Robust and lasting hypercalcemic reversal and symptomatic relief have been documented following surgical tumor resection. Stereotactic body radiation therapy (SBRT) has emerged as an effective treatment modality in medically inoperable patients with Stage I non-small cell lung cancer (NSCLC). In the current report, SBRT achieved durable tumor control and calcemic correction in a medically inoperable 79 year-old man with Stage I NSCLC patient with parathyroid hormone-related peptide (PTHrP) induced MH. PMID- 29988295 TI - Biomarkers of Myocardial Injury and Inflammation after Permanent Pacemaker Implantation: The Lead Fixation Type Effect. AB - Background: Permanent pacemaker implantation is accompanied by minor myocardial damage, indicated by elevated serum levels of cardiac biomarkers. Aim of this prospective study was to comparably investigate the lead fixation type effect on the extent of myocardial injury and inflammation following pacemaker implantation, and to assess the possible clinical implications. Methods: Cardiac troponin I (cTnI) and C-reactive protein (CRP) were measured at baseline, 6 and 24h after implantation in 101 patients, categorized into the active and passive lead fixation group. Patients were followed up for clinical adverse events or abnormal pacing parameters at 24h, 7 and 30 days post-procedure. Results: cTnI increased at 6h post-procedure (p<0.05) in 23.8% of patients, and returned to baseline after 24h. The passive group demonstrated significantly higher cTnI at 6h compared to the active group (p=0.006). CRP increased significantly at 6h, and maintained an upward trend after 24h (p<0.01) in both groups. The active group demonstrated significantly higher CRP at 6h compared to the passive group. We did not identify an association of positive biomarkers with adverse events. Conclusion: cTnI and CRP can increase early after permanent pacemaker implantation, indicating mechanical myocardial injury and inflammation. The extent of these biomarkers elevation depends on the lead fixation type, and is not related to worse short-term prognosis. PMID- 29988296 TI - Long Term Risk of Recurrent Atrial Fibrillation and Ischemic Stroke after Post Operative Atrial Fibrillation Complicating Cardiac and Non-Cardiac Surgeries. AB - Background: New onset post-operative atrial fibrillation (POAF) can complicate both non-cardiac(NCS) and cardiac(CS) surgeries. Long term differences in recurrence of atrial fibrillation (AF) and incidence of ischemic stroke/transient ischemic attack(CVA)between these types of POAFare lacking. Objective: To compare thelong term recurrence rate of AF and incidence of CVAin patients withnew onset POAF after CS and NCS. Methods: All patients who developed POAF between May 2010 and April 2014 were included in this single-center, retrospective study Exclusion criteria included a prior history of atrial tachyarrhythmias and pre-operative use of anti-arrhythmic drugs. Recurrence of atrial fibrillation and CVA was identified by review of medical records, electrocardiogram and Holter monitor. Results: patients identified by the ICD9 code=523, 112 patients (61 cardiac; 51 non-cardiac) met inclusion criteria. Mean follow up was 943 days (range 32-2052 days).AF recurrence rate within 30 days after hospital discharge was higher in CS compared with NCS(10% vs 0%, p =0.03). Kaplan Meier analysis showed a trend towards higher recurrence in NCS compared with CS(HR 2.8; 95% CI 0.78-10.6, log rank p =0.03).In long term follow-up, CVA was numerically more common in patients with POAF after CS compared withNCS(10% vs 2%) though this difference was non significant(HR 3.1; 95% CI 0.72-13.3; log rank p =0.26). Conclusion: The risk of recurrent AF and ischemic stroke is not different between POAF after CS or NCS. The overall high rate of AF recurrence and risk of ischemic stroke mandate careful long term follow-up. PMID- 29988298 TI - Metastatic Renal Cell Carcinoma of the Nasal Septum: A Case Report. AB - Metastatic lesions of the nasal cavity and paranasal sinuses are rare tumors. Carcinomas originating from intrapelvic organs play an important role in the differential diagnosis of these masses because of their paradoxic spread to the head and neck region. In this study we report a case with metastatic renal cell carcinoma of the caudal nasal septum. PMID- 29988297 TI - European health examination surveys - a tool for collecting objective information about the health of the population. AB - Background: Representative and reliable data on health and health determinants of the population and population sub-groups are needed for evidence-informed policy making; planning and evaluation of prevention programmes; and research. Health examination surveys (HESs) including questionnaires, objective health measurements and analysis of biological samples, provide information on many health indicators that are available not at all or less reliably or completely through administrative registers or health interview surveys. Methods: Standardized cross-sectional HESs were already conducted in the 1980's and 1990's, in the framework of the WHO MONICA Project. The methodology was developed and finally, in 2010-2012, a European Health Examination Survey (EHES) Pilot Project was conducted. During this pilot phase, an EHES Coordinating Centre (EHES CC, formerly EHES Reference Centre) was established. Standardized protocols, guidelines and quality control procedures were prepared and tested in 12 countries which conducted pilot surveys, demonstrating the feasibility of standardized HES data collection in the European Union (EU).Currently, the EHES CC operates at the National Institute for Health and Welfare (THL), Finland. Its activities include maintaining and developing the standardized protocols, guidelines and training programme; maintaining the EHES network; providing professional support for countries planning and organizing their national HESs; external quality assessment for surveys organized in the EU Member States; and development of a centralized database and joint reporting system for HES data. Results: An increasing number of EU Member States are conducting national HESs, demonstrating a strong need for such surveys as part of the national health monitoring systems. Standardization of the data collection is essential to ensure that HES data are comparable across countries and over time. The work of the EHES CC helps to ensure the quality and comparability of HES data across the EU. Conclusions: HES data have been used for health monitoring and identifying public health problems; to develop health and prevention programmes; to support health policies and preparation of health-related legislation and regulations; and to develop clinical treatment guidelines and population reference values. HESs have also been utilized to prepare health measurement tools and diagnostic methods; in training and research and to increase health awareness among population. PMID- 29988299 TI - Direct Observation of Procedural Skills in Otorhinolaryngology Training. AB - Objective: To assess the experience on using direct observation of procedural skills (DOPS) by trainees and trainers and to evaluate its use during the training process of Otorhinolaryngology (ORL) residency. Methods: This study was designed as a prospective educational research. For the quantitative assessment, the "construct validity" of the assessment tool was examined. For the qualitative assessment, the trainees and trainers' experiences regarding the use of DOPS in training process were investigated. Results: A total of 55 DOPS assessment forms were filled during the study. The mean observation time was 7.14+/-4.83 (range: 1 20) minutes, and the mean feedback time was 2.11+/-2.01 (range: 0.5-10) minutes. A significant difference was detected between the first year trainees and the older ones, whereas no significant difference was observed between the third, fourth, and fifth year trainees. A statistically significant, positive correlation was found between the years of education and the average score. According to the results of the qualitative assessment, the trainees stated that they realized their technical inadequacy in some procedures and it helped them to improve their skills during their residency training. The trainers confirmed that they gave feedback after each assessment. Both the trainers and trainees suggested that specific guidelines should be prepared for every procedure. Conclusion: DOPS is a useful, valid, and fair tool for assessing Otorhinolaryngology trainees. The data obtained from the DOPS forms can be used for demonstrating the success of a training clinic and to evaluate the training program. PMID- 29988300 TI - Microalgae Chlorella vulgaris biomass harvesting by natural flocculant: effects on biomass sedimentation, spent medium recycling and lipid extraction. AB - Background: Microalgal biomass harvesting using traditional chemicals is costly for the production of biofuels, hindering the scale-up process of the technology. Thus, the search for a cost-effective microalgal harvesting method is extremely important. Using chitosan as a natural flocculant to harvest microalgal biomass seems to be an efficient and convenient solution. Although microalgal biomass flocculation by chitosan has been reported in some previous studies, literature on the harvesting of microalgae C. vulgaris biomass using such polymer is scanty. In addition, there is limited information available on whether the usage of chitosan during the harvesting will affect downstream lipid extraction. Still, whether microalgae can be re-grown with the spent medium after chitosan flocculation is still unknown. Results: In this study, microalgal biomass harvesting using chitosan as a natural flocculant and aluminum sulfate as a traditional flocculant was compared and evaluated. Optimal doses and effects on biomass sedimentation, spent medium recycling and lipid extraction were investigated. The results showed that the optimal doses for chitosan and aluminum sulfate to achieve more than 90% biomass recovery were 0.25 and 2.5 g/L, respectively. The sedimentation time of 10 min was found to be the most appropriate to remove over 90% biomass from culture. The spent medium after chitosan flocculation could be potentially recycled for the re-cultivation of microalgae, which demonstrated robust growth in comparison with those grown in the recycled medium from aluminum sulfate flocculation. The lipid content of microalgae harvested by chitosan reached 32.9, 4.6% higher than that of those harvested by aluminum sulfate, indicating that the application of the natural flocculant would not impact the downstream extraction of microalgal lipids. Conclusion: The results herein presented, demonstrated that chitosan is applicable for microalgal harvesting during the upscaling process. Flocculation method developed by using chitosan as a natural flocculant is a worthy microalgal harvesting method for microalgae-based biofuel production. There is hope that chitosan can be reasonably and technically realistically applied in a full-scale process for the harvesting of microalgal biomass. PMID- 29988301 TI - Correlation between small-volume spinal cord doses for spine stereotactic body radiotherapy (SBRT). AB - Purpose: Doses to small spinal cord isodose volume (such as those ranging from Dmax 0.0 cc to 0.5 cc) as well as to large volumes (such as those ranging from 0.5 cc to 3.0 cc) are critical parameters to guide safe practice of spine SBRT. We here report a mathematical formula that links the most probable dose volume limits together for common spine SBRT cases.Methods and materials: A dose ripple formula parameterized with equivalent dose radius (EDR) was derived to model spinal cord small-volume doses for a spine SBRT treatment. A cohort of spine SBRT cases (n=68), treated with either a robotic x-band linac or a conventional S-band linac, was selected to verify the model predictions. The mean prescription dose was 22+/- 4 Gy (range, 12-40 Gy) delivered in 2+/-1 fractions. The mean and median target volume was 39.4+/-42.5 cc and 30.3 cc (range, 0.24-264.2 cc), respectively. Direct correlations between the spinal cord Dmax and variable spinal cord doses of increasing isodose volumes (ranging from 0.0 cc to 3.0 cc) of different planning organ-at-risk volumes (PRVs) were investigated. The PRV structures for the study included the true cord, thecal sac and the true cord plus variable margins ranging from 1.0 mm to 3.0 mm. Results: No direct linear correlation was observed amongst the small volume doses to the spinal cord PRVs. However, strong linear correlations (R2 > 0.96) for all the studied PRVs were observed when correlating EDRs amongst isodose volumes ranging from 0.0 cc to 3.0 cc. In particular, EDR dependence was found to differ significantly for the thecal sac versus the spinal cord with or without 1-3 millimeter margins. With strong EDR correlation, the most probable relationship among the small-volume dose limits was derived for the spinal cord PRVs. Conclusion: An analytical formula linked the most probable pin-point/small isodose volume doses with relatively large isodose volume doses of the spinal cord for spine SBRT. As a result, a small number of dose limits such as Dmax or D(0.35cc) are likely sufficient to surrogate the spinal cord dose tolerance for consistent treatment planning optimization and outcome analysis. PMID- 29988302 TI - Multidisciplinary Team Work is Necessary for the Optimization of Clinical Effectiveness in Otorhinolaryngology: Implications from a Case Paradigm. PMID- 29988303 TI - Epidemiology of soil transmitted Helminth infections in the middle-belt of Ghana, Africa. AB - Background: Helminths are among the most widespread infectious agents prevalent in tropical and sub-tropical regions of the developing world defined by inadequate sanitation, poverty and unsafe water sources. This study was carried out to describe the distribution of helminth and malaria parasite infections in the middle-belt of Ghana in sub-Saharan Africa where disease burden, including anaemia is rife and helminths are perceived to be significant contributors of the burden. Methods: A cross-sectional survey involving 1826 residents located in the middle belt of Ghana where no or very little previous community-based helminth work had been carried out. The participants randomly recruited at household level provided biological samples collected over a 12-month period following a rigorous consenting process and these were analysed to describe the different types and seasonal distribution of helminths. Findings: Overall, 19.3% intestinal helminth infection prevalence was documented. Also based on parasites targeted for elimination, 12.1% Hookworm, 4.0% Hymenolepis nana/Hymenolepis dimunita, 1.5% Ascaris lumbricoides, 1.5% Taenia species, 0.9% Strongyloides stercoralis and 0.8% Trichuris trichiura, with about 1.0% polyphelminthiasis were recorded in the survey. About 55.4% and 44.4% of the participants had heavy hookworm and Trichuris infections respectively. Most of the Ascariasis (83.3%) infections were light in intensity. Hookworm infection was identified with significant odds considering decreasing age (OR = 2.09, p = 0.03), inappropriate footwear use (OR = 1.88, p = 0.021), malaria parasite co-infection (OR = 1.62, p = 0.018), not scrubbing nails during hand washing (OR = 0.68, p = 0.048), source of drinking water (OR = 2.51, p = 0.027) and religion (OR = 4.36, p = 0.002). Conclusions: Hookworm infection was significantly higher in younger age groups and among those who did not have safe drinking water. Proper sanitation, protective footwear, religion and good personal hygiene practices were found to influence helminth and hookworm prevalence in the area. Malaria parasite coinfection with helminths, especially hookworm infections increased 2-fold. PMID- 29988304 TI - Stereotactic radiosurgery for resected brain metastasis: Cavity dynamics and factors affecting its evolution. AB - Objective: To determine changes in post-surgical cavity volume for metastases based on time from surgery, pre-operative tumor dimensions and other predictors, in patients planned for post-operative stereotactic radiosurgery (SRS). Methods: Patients with resected brain metastases from a primary solid tumor, treated with post-operative surgical cavity SRS from 2008 to 2014 were identified from an institutional prospective database. The segmented three-dimensional (3D) volume of the pre-operative tumor and post-operative surgical cavity were determined based on MRI and percent volume change was calculated. Patients were grouped according to early (<21 days), intermediate (22-42 days), and late (>42 days) intervals based on the number of days between the date of surgery and the treatment planning MRI. Potential predictive factors including tumor size, location, age, dural involvement, and degree of surgical resection were also analyzed. Results: Sixty-one cavities in 59 patients were evaluated. Overall, a significant volume reduction (4cm3, p=0.03) was observed comparing tumor and cavity volumes. For larger tumors, an average volume reduction of 11.6% (p=0.01) was observed compared to an increase of 34.4% in smaller tumors (p=0.69). For both large and small tumors, cavities were larger in the early interval especially for smaller tumors. During the intermediate interval, a significant volume reduction was observed for larger tumors (28%, p=0.0007). Tumor size, dural involvement, age and time from surgery were significant predictors for volume change on univariate analysis. On multivariate analysis, tumor size, dural involvement and time from surgery were significant. Conclusion: Tumor size (>3cm), dural involvement and longer time from surgery were significant predictors of cavity volume reduction. Caution must be taken when treating cavities in the early (<21 days) interval after surgery as it may lead to irradiating more normal tissue especially in small tumors. PMID- 29988305 TI - Small steps towards an EU health information system. PMID- 29988306 TI - ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/beta-catenin signaling pathway. AB - Background: Mishandling of intracellular chloride (Cl-) concentration ([Cl-]i) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl- efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII). Methods: Cell proliferation and motility were determined using the CCK-8, bromodeoxyuridine staining, wound healing and invasion assays. ClC-2, PCNA, Ki67, survivin and cyclin D1 expression, and beta-catenin and GSK-3beta phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and alpha-SMA staining. Results: Our results showed that AngII-induced HBVSMC proliferation was accompanied by a decrease in [Cl-]i and an increase in ClC-2 expression. Inhibition of ClC-2 by siRNA prevented AngII from inducing the efflux of Cl-. AngII-induced HBVSMC proliferation, migration and invasion were significantly attenuated by ClC-2 downregulation. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/beta-catenin signaling pathway, as evidenced by inhibition of beta-catenin phosphorylation and nuclear translocation, and decrease of GSK-3beta phosphorylation and survivin and cyclin D1 expression. Recombinant Wnt3a treatment markedly reversed the effect of ClC-2 knockdown on HBVSMC viability. An in vivo study revealed that knockdown of ClC-2 with shRNA adenovirus ameliorated basilar artery remodeling by inhibiting Wnt/beta-catenin signaling in AngII-treated mice. Conclusion: This study demonstrates that blocking ClC-2-mediated Cl- efflux inhibits AngII-induced cerebrovascular smooth muscle cell proliferation and migration by inhibiting the Wnt/beta-catenin pathway. Our data indicate that downregulation of ClC-2 may be a viable strategy in the prevention of hyperplasia and remodeling of cerebrovascular smooth muscle cells. PMID- 29988307 TI - Assessing the impact of specialist home visiting upon maltreatment in England: a feasibility study of data linkage from a public health trial to routine health and social care data. AB - Background: Follow-up for public health trials may benefit from greater use of routine data. Our trial of a home-visiting intervention for first-time teenage mothers assessed outcomes to the child's second birthday. To examine its medium term impact, particularly upon maltreatment outcomes, we designed a study using routine records. Methods: We aimed to establish the feasibility of our study design, which combines trial data with routine health, social care and education data using a dissent-based linkage model. Trial participant identifiers were linked to routine health, social care and education data if women did not dissent. Data were forwarded to a safe haven and further linked to de-identified trial outcome data. The feasibility study aimed first to establish the acceptability of data linkage through a discussion group of young mothers and by levels of dissent received by the research team. Second, we assessed levels of accurate linkage to both health (via NHS Digital) and education and social care (both via National Pupil Database, NPD). Third, we assessed the availability of data and levels of missingness for key outcomes received for a sample of target study years. Results: Of 1545 mother-child dyads contacted, eight women opted out. The engagement exercise with stakeholders found support for the principle of data linkage, including in the context of maltreatment. Some contributors preferred opt-in consent. Most (99.9%) health records were matched on either three or all four identifiers. Fifty participants were not matched to any health data. Primary outcome data from NPD are derived from any one of three fields, all of which were satisfactorily returned and provided an indication of cases for analysis. Missing data for secondary outcomes varied from 0% (Child looked after status) to 70% (Anatomical Area A&E diagnosis) however when combined with other variables the levels of missingness for outcome decrease. Conclusions: Through study set-up and in this pilot, we provide evidence that the main study is feasible, satisfies governance requirements and is likely to generate data of sufficient quality to address our main research questions. Observed levels of missingness or low event rates are likely to affect some secondary analysis (e.g. state transition modelling) although overall were satisfactory. PMID- 29988309 TI - The use of the global activity limitation Indicator and healthy life years by member states and the European Commission. AB - Background: In 2005, the European Union (EU) started to use a disability-free life expectancy, known as Healthy Life Years (HLY), to monitor progress in the strategic European policies such as the 2000 Lisbon strategy. HLY are based on the underlying measure: the Global Activity Limitation Indicator (GALI). Twelve years after its implementation, this study aims to assess its current use in EU Member States and the European Commission. Methods: In March 2017, a questionnaire was sent to 28 Member states and the European Commission. The questionnaire inquired how the GALI and HLY are used to set policy targets, in which surveys the GALI has been introduced since 2005, how the GALI and HLY are presented, and what the capacity in each country is to investigate the GALI and HLY. Results: The survey was answered by 22 Member States and by the Commission. HLY are often used to set targets and develop strategies in health such as national health plans. Analysis of HLY has even led to policy change. In some countries, HLY have become the main indicator for health, gaining more importance than life expectancy. More recently, the GALI and HLY have also been used for policy targets outside the health sector such as in the area of pension and retirement age or in the context of sustainable development. Regarding surveys, the GALI is mostly obtained from the EU-SILC, SHARE and EHIS, but is also increasingly introduced in national surveys. National health reporting systems usually present HLY on their national statistics websites. Most countries have up to three specialists working on the GALI and HLY, which has been consistent through time. Others have increased their capacity over various institutions. Conclusion: HLY is an indicator that is systematically used to monitor health developments in most EU countries. The SHARE, EU-SILC and EHIS are commonly used to assess HLY through the GALI. The results are then described in reports and presented on national statistics websites and used in different policy settings. Expertise to analyse the GALI and HLY is available in most countries. PMID- 29988308 TI - Somatic symptom and related disorders in children and adolescents: evaluation of a naturalistic inpatient multidisciplinary treatment. AB - Background: This naturalistic study assesses the effectiveness of inpatient multidisciplinary treatment of children and adolescents with somatic symptom disorders (SSD) and investigates the role of pain coping strategies and psychiatric comorbidity (anxiety, depression). Methods: Sixty children and adolescents (mean age 14.4 years) with SSD who underwent inpatient multidisciplinary treatment were assessed regarding their school attendance, levels of discomfort, coping strategies and psychiatric comorbidity (depression, anxiety) at pretreatment, discharge and 6 months following treatment. Results: At discharge, the children and adolescents reported improvements in their level of discomfort, psychiatric comorbidities (anxiety, depression) and pain coping strategies, with medium to large effect sizes. Six months following treatment, the improvements remained stable, including significantly higher school attendance rates (d = 1.6; p < 0.01). Improvement in pain coping was associated with increased school attendance. Conclusion: Inpatient multidisciplinary treatment is effective in reducing levels of discomfort, psychiatric comorbidity (anxiety, depression), and school absence and in improving coping strategies. PMID- 29988310 TI - Testing a strength and conditioning program to prevent common manipulative technique training injuries in chiropractic students: a study protocol for a randomised controlled trial. AB - Background: Spinal manipulation is the primary therapy utilised by chiropractors in the management of their patients. The skills required may feel foreign to chiropractic students as they need strength and endurance in movement patterns they may not have otherwise been exposed to. This may lead to injury while learning manipulative techniques. It is plausible to suggest that the implementation of a strength and conditioning program early in a practitioner's career could reduce the incidence and progression of injuries. The study aims to test the effectiveness of a strength and conditioning program in reducing the risk of chiropractic students' acquiring injuries while learning the skill of spinal manipulation. Methods: This study will involve a prospective cohort of chiropractic students who are currently learning manual therapy at an undergraduate level. Participants will be eligible for inclusion if they are enrolled in 3rd or 4th-year chiropractic manual therapy units at Murdoch University chiropractic course. The intervention group will follow a 12-week strength and conditioning program comprised of preventative exercises that address each body region previously identified as being prone to injury. The control group will complete a 12-week walking program. The primary outcome is injury rate, measured via a short questionnaire. The secondary outcome will be strength, measured via submaximal strength tests. Discussion: The prescribed exercises are aimed at improving the strength and endurance of those muscle groups involved in commonly taught manual therapy tasks. The resistance bands have been chosen as they are inexpensive, simple to implement for the purposes of the study, and acceptably safe. A video format was selected to allow ease of access for participants, provide a detailed description and a visual representation of the exercises to be performed. A questionnaire was designed as a means to assess the influence of the strength and conditioning program on injury rate and the impact this may have on the students' ability to continue practicing. The International Physical Activity Questionnaire has been chosen to measure the participants level of activity before beginning the exercise program. Conclusion: This research protocol will be the first large-scale study to investigate the effectiveness of a strength and conditioning program to reduce injuries within chiropractic students learning manual therapy. Trial registration: Australia New Zealand Clinical Trials Registry (ACTRN12617001638325p). PMID- 29988311 TI - Interactions between climatic changes and intervention effects on malaria spatio temporal dynamics in Uganda. AB - Background: Although malaria burden in Uganda has declined since 2009 following the scale-up of interventions, the disease is still the leading cause of hospitalization and death. Transmission remains high and is driven by suitable weather conditions. There is a real concern that intervention gains may be reversed by climatic changes in the country. In this study, we investigate the effects of climate on the spatio-temporal trends of malaria incidence in Uganda during 2013-2017. Methods: Bayesian spatio-temporal negative binomial models were fitted on district-aggregated monthly malaria cases, reported by two age groups, defined by a cut-off age of 5 years. Weather data was obtained from remote sensing sources including rainfall, day land surface temperature (LSTD) and night land surface temperature (LSTN), Normalized Difference Vegetation Index (NDVI), altitude, land cover, and distance to water bodies. Spatial and temporal correlations were taken into account by assuming a conditional autoregressive and a first-order autoregressive process on district and monthly specific random effects, respectively. Fourier trigonometric functions modeled seasonal fluctuations in malaria transmission. The effects of climatic changes on the malaria incidence changes between 2013 and 2017 were estimated by modeling the difference in time varying climatic conditions at the two time points and adjusting for the effects of intervention coverage, socio-economic status and health seeking behavior. Results: Malaria incidence declined steadily from 2013 to 2015 and then increased in 2016. The decrease was by over 38% and 20% in children <5 years and individuals >=5 years, respectively. Temporal trends depict a strong bi-annual seasonal pattern with two peaks during April-June and October December. The annual average of rainfall, LSTD and LSTN increased by 3.7 mm, 2.2 degrees C and 1.0 degrees C, respectively, between 2013 and 2017, whereas NDVI decreased by 6.8%. On the one hand, the increase in LSTD and decrease in NDVI were associated with a reduction in the incidence decline. On the other hand, malaria interventions and treatment seeking behavior had reverse effects, that were stronger compared to the effects of climatic changes. Important interactions between interventions with NDVI and LSTD suggest a varying impact of interventions on malaria burden in different climatic conditions. Conclusion: Climatic changes in Uganda during the last five years contributed to a favorable environment for malaria transmission, and had a detrimental effect on malaria reduction gains achieved through interventions scale-up efforts. The NMCP should create synergies with the National Meteorological Authority with an ultimate goal of developing a Malaria Early Warning System to mitigate adverse climatic change effects on malaria risk in the country. PMID- 29988312 TI - Evidence-Based Causal Chains for Linking Health, Development, and Conservation Actions. AB - Sustainability challenges for nature and people are complex and interconnected, such that effective solutions require approaches and a common theory of change that bridge disparate disciplines and sectors. Causal chains offer promising approaches to achieving an integrated understanding of how actions affect ecosystems, the goods and services they provide, and ultimately, human well being. Although causal chains and their variants are common tools across disciplines, their use remains highly inconsistent, limiting their ability to support and create a shared evidence base for joint actions. In this article, we present the foundational concepts and guidance of causal chains linking disciplines and sectors that do not often intersect to elucidate the effects of actions on ecosystems and society. We further discuss considerations for establishing and implementing causal chains, including nonlinearity, trade-offs and synergies, heterogeneity, scale, and confounding factors. Finally, we highlight the science, practice, and policy implications of causal chains to address real-world linked human-nature challenges. PMID- 29988313 TI - Cardiovascular diseases monitoring: lessons from population-based registries to address future opportunities and challenges in Europe. AB - Background: Population-based registries implement the comprehensive collection of all disease events that occur in a well-characterized population within a certain time period and represent the preferred tools for disease monitoring at a population level. Main characteristics of a Population-based registry are to provide answers to defined research questions, also related to clinical and health policy purposes, assuring completeness of event identification, and implementing a process of case adjudication (validation) according to standardised diagnostic criteria. Methods: The application of a standard methodology results in the availability of reliable and comparable data and facilitates the transferability of health information for research and evidence based health policies. Although registries are extremely useful, they require considerable resources to be implemented and maintained, high cost and efforts, to produce stable and reliable indicators. Results: Thanks to available health information and information technology, current administrative databases on hospital admissions and discharges, medication use, in-patient care utilization, surgical operations, drug dispensations, ticket exemption and invasive procedures are increasingly available. They represent basic sources of information for implementing Population-based registries.Main strengths and limitations of Population-based registries are described taking into consideration the example of cardiovascular diseases, as well as future challenges and opportunities for implementing Population-based registries at European level. Conclusions: The integration of population-based registries and current administrative health databases may help to complete the picture of the disease rebuilding the evolution of the disease as a continuum from the onset to the possible consequent complications. PMID- 29988314 TI - Cognitive and psychiatric changes as first clinical presentation in Sneddon syndrome. AB - Sneddon syndrome (SS) is a rare progressive non-inflammatory thrombotic vasculopathy affecting small/medium-sized blood vessels of unknown origin. It is strongly associated with the presence of antiphospholipid antibodies (AA). The presence of livedo reticularis and cerebrovascular disease are hallmark features. The condition is far more common in young women. We report a case of SS in a 43 year-old male with a two-year history of progressive cognitive impairment consistent with dementia syndrome, and major personality changes, besides livedo reticularis and cerebral angiographic pattern of vasculitis. AA were borderline. The recognition of skin blemishes that precede strokes should raise the hypothesis of SS. AA are elevated in more than half of cases, but their role in the pathogenesis or association of positive antibodies and SS remains unclear. Dementia syndrome in young patients should be extensively investigated to rule out reversible situations. Typical skin findings, MRI and angiography may aid diagnosis. PMID- 29988316 TI - Topoisomerase II Poisons for Glioblastoma; Existing Challenges and Opportunities to Personalize Therapy. AB - Despite advances in surgery, radiotherapy, and chemotherapy, glioblastoma (GBM) remains a malignancy with poor prognosis. The molecular profile of GBM is diverse across patients, and individual responses to therapy are highly variable. Yet, patients diagnosed with GBM are treated with a rather uniform paradigm. Exploiting these molecular differences and inter-individual responses to therapy may present an opportunity to improve the otherwise bleak prognosis of patients with GBM. This review aims to examine one group of chemotherapeutics: Topoisomerase 2 (TOP2) poisons, a class of drugs that enables TOP2 to induce DNA damage, but interferes with its ability to repair it. These potent chemotherapeutic agents are currently used for a number of malignancies and have shown promise in the treatment of GBM. Despite their robust efficacy in vitro, some of these agents have fallen short of achieving similar results in clinical trials for this tumor. In this review, we explore reasons for this discrepancy, focusing on drug delivery and individual susceptibility differences as challenges for effective TOP2-targeting for GBM. We critically review the evidence implicating genes in susceptibility to TOP2 poisons and categorize this evidence as experimental, correlative or both. This is important as mere experimental evidence does not necessarily lead to identification of genes that serve as good biomarkers of susceptibility for personalizing the use of these drugs. PMID- 29988317 TI - A 10-year experience of linear accelerator-based stereotactic radiosurgery/radiotherapy (SRS/SRT) for paraganglioma: A single institution experience and review of the literature. AB - Objective: Patients with paragangliomas were treated with LINAC-SRS/SRT in this retrospective review to evaluate tumor control, clinical control, and toxicity. Methods: 16 patients (median age = 65) with paragangliomas were treated with LINAC-SRS/SRT. Patients were treated to a median dose of 25 Gy in 5 Fx and were evaluated for long-term tumor control, symptom control, and toxicity. Median follow-up was 44 months. Results: 16 paragangliomas with a median PTV of 11.7 cc were treated as above. All but 2 lesions were controlled at last follow-up, with a 5-year control rate of 88%. Eighty-one percent of patients reported improved or resolved symptoms after treatment. Toxicities included grade 2 vertigo in 1 patient and grade 3 headache from hydrocephalus requiring ventriculoperitoneal shunt. Discussion: Linear accelerator based SRS/SRT appears to be an effective treatment option for paragangliomas. Recurrences in this cohort occurred 4-5 years after treatment, highlighting the importance of long term follow up. PMID- 29988318 TI - Comparison of outcomes of stereotactic body radiation therapy delivered with three different technologies to the lung. AB - Purpose/objectives: Since the inception of stereotactic body radiation therapy (SBRT), treatment delivery has been performed with volumetric modulated arc therapy (VMAT), helical tomotherapy (HT) and noncoplanar static fields (SF). The purpose of this study is to compare SBRT delivery among these treatment modalities to the lung. Materials/methods: A retrospective review of SBRT treatments of 30 to 60 Gy in 1 to 5 fractions from 2007 to 2015 was performed. Dosimetric parameters included V5, V20, D2cm, gross tumor volume (GTV) and planning target volume (PTV) size and coverage, rib/esophageal minimum/maximum doses, R30Gy, R50%, and the conformality index (CI). Clinical outcomes evaluated included local control, pneumonitis and other toxicities. ANOVA, Student's t-test and Kruskal-Wallis test were used to compare the parameters among modalities. Kaplan-Meier estimates of time-to-local failure were produced. Results: 176 Treatments included 106 SF, 36 VMAT and 34 HT. HT had better PTV coverage (p=0.0166) but higher lung V5 and esophageal doses (p<0.001 and p=0.0032). R30Gy, R50%, and CI were significantly better with VMAT SBRT (p<0.001). Clinically, Grade 2+ pneumonitis was associated with larger median GTV's of 21.39 cc versus 7.65 cc (p=0.0016), larger median PTV's of 65.62 cc versus 31.75 cc (p=0.0030), and higher V20 6.62% versus 4.08% (p=0.0408). For patients surviving >1 year, overall local failure rate was 9.4%. Actuarial control rates trended toward statistical significance with time to local failure with VMAT being the most favorable group on the Kaplan-Meier curve (p=0.0733). Conclusion: VMAT showed superior conformality compared to the other modalities. Among the modalities examined, HT had higher values for parameters associated with toxicity such as V5 and maximum esophageal dose, but all were within acceptable limits. There was a trend to better local control with VMAT. PMID- 29988319 TI - Gamma Knife treatment of malignant infantile brain tumors - Case report. AB - Stereotactic radiosurgery (SRS) is a treatment option, which is capable of pinpoint irradiation and thus, reduce the potential late complications. However, any type of radiation therapy is not recommended for brain tumor patients under the age of 3 years. SRS is not routinely recommended for patients than 2 years of age in consideration of infant skull brittleness for frame fixation, and lack of treatment evidence for the safety and effects of stereotactic radiosurgery in infants. We experienced the case of Gamma Knife treatment upon an infantile pineoblastoma where repeated tumor excision had already been perfromed and chemotherapy resistance was apparent. Radiosurgery resulted in symptom improvement and dramatic tumor shrinkage on MRI after radiosurgery. Therefore, here we report on the difficulty and usefulness of Gammaknife radiosurgery in this infant patient. PMID- 29988320 TI - Editorial: Clinical and Hemodynamic Performance of Aortic Endografts. PMID- 29988322 TI - High levels of alexithymia in patients with multiple sclerosis. AB - : Alexithymia is a personality trait characterized by difficulties identifying and describing feelings. Some researchers describe high levels of alexithymia among patients with multiple sclerosis (MS) but literature data on this subject are scarce. Objective: The objective of the present study was to characterize findings of alexithymia in patients with MS. Methods: This cross-sectional case control study included 180 patients with MS and a matched control group. Data for patients with MS included disease duration, number of demyelinating relapses and degree of neurological disability, as assessed by the Expanded Disability Scale Score (EDSS). In addition, the Hospital Anxiety and Depression (HAD) scale and the Toronto Alexithymia Scale (TAS) were used. Results: There were 126 women and 54 men in each group, with median age of 37 years and median education of 16 years. Patients with MS had higher degrees of depression (p<0.01), anxiety (p=0.01) and alexithymia (p<0.01) than did control subjects. For individuals with MS, depressive traits (p<0.01), anxious traits (p=0.03), higher age (p=0.02), lower education level (p=0.02), higher degree of disability (p<0.01) and not being actively employed (p=0.03) were associated with higher rates of alexithymia. Conclusion: Alexithymia was a relevant finding in patients with MS. PMID- 29988321 TI - Case-control meta-analysis of blood DNA methylation and autism spectrum disorder. AB - Background: Several reports have suggested a role for epigenetic mechanisms in ASD etiology. Epigenome-wide association studies (EWAS) in autism spectrum disorder (ASD) may shed light on particular biological mechanisms. However, studies of ASD cases versus controls have been limited by post-mortem timing and severely small sample sizes. Reports from in-life sampling of blood or saliva have also been very limited in sample size and/or genomic coverage. We present the largest case-control EWAS for ASD to date, combining data from population based case-control and case-sibling pair studies. Methods: DNA from 968 blood samples from children in the Study to Explore Early Development (SEED 1) was used to generate epigenome-wide array DNA methylation (DNAm) data at 485,512 CpG sites for 453 cases and 515 controls, using the Illumina 450K Beadchip. The Simons Simplex Collection (SSC) provided 450K array DNAm data on an additional 343 cases and their unaffected siblings. We performed EWAS meta-analysis across results from the two data sets, with adjustment for sex and surrogate variables that reflect major sources of biological variation and technical confounding such as cell type, batch, and ancestry. We compared top EWAS results to those from a previous brain-based analysis. We also tested for enrichment of ASD EWAS CpGs for being targets of meQTL associations using available SNP genotype data in the SEED sample. Findings: In this meta-analysis of blood-based DNA from 796 cases and 858 controls, no single CpG met a Bonferroni discovery threshold of p < 1.12 * 10- 7. Seven CpGs showed differences at p < 1 * 10- 5 and 48 at 1 * 10- 4. Of the top 7, 5 showed brain-based ASD associations as well, often with larger effect sizes, and the top 48 overall showed modest concordance (r = 0.31) in direction of effect with cerebellum samples. Finally, we observed suggestive evidence for enrichment of CpG sites controlled by SNPs (meQTL targets) among the EWAS CpG hits, which was consistent across EWAS and meQTL discovery p value thresholds. Conclusions: No single CpG site showed a large enough DNAm difference between cases and controls to achieve epigenome-wide significance in this sample size. However, our results suggest the potential to observe disease associations from blood-based samples. Among the seven sites achieving suggestive statistical significance, we observed consistent, and stronger, effects at the same sites among brain samples. Discovery-oriented EWAS for ASD using blood samples will likely need even larger samples and unified genetic data to further understand DNAm differences in ASD. PMID- 29988323 TI - Plasmodium falciparum malaria cases detected for prompt treatment by rapid diagnostic tests in the Ho Teaching Hospital of the Volta Region of Ghana. AB - Background: Prompt diagnosis and effective treatment of malaria cases with efficacious drugs is an important strategy in the management and control of malaria in endemic populations. As part of a study investigating the factors modulating the development of Plasmodium falciparum gametocytes in the human host, we assessed the rate of RDT positivity of patients in different departments of the Ho Teaching Hospital and the relation with age and anaemia. Materials and methods: Eight-hundred and ten individuals attending clinic at various departments within the Ho Teaching Hospital were screened for malaria antigenaemia using RDT as a point-of-entry investigation. RDT positive individuals were immediately treated for malaria whereas RDT negative individuals were treated for other ailments. Haematological analyses were performed for 69 of these patients and the relationship between RDT results and haemoglobin levels were investigated. Results: The overall RDT positivity rate was 19.8% (160/810) of all individuals screened. There was no significant difference in the haemoglobin levels of RDT-positive and RDT-negative individuals (p value = 0.272). The highest number of attendees screened was children in the paediatric outpatient department and paediatric ward, 62% (507/810), with RDT positivity rate of 17% (91/507). We found the highest RDT positivity rate of 51% (19/37) in the male medical ward. Conclusions: This study shows that RDT is a useful tool in promoting prompt diagnosis and management of malaria and though children form a majority of hospital attendees and malaria infections, the frequency of malaria detection may be higher in adults as compared to children. PMID- 29988324 TI - Gamma Knife and volumetric modulated arc therapy stereotactic radiosurgery plan quality and OAR sparing comparison for pituitary adenomas and vestibular schwannomas. AB - Purpose: To compare the plan quality and organs at risk (OAR) sparing of auto planned volumetric modulated art therapy (VMAT) and Gamma Knife (GK) for stereotactic radiosurgery of pituitary adenomas (PA) and vestibular schwannomas (VS). Methods: VMAT radiosurgery plans were made using auto planning tool for eight vestibular schwannoma and eight pituitary adenoma patients previously treated with GK. VMAT plans were made with three non-coplanar arcs using 315, 0 and 45 degrees angles, 6MV FFF energy at 1400 MU/min dose rate and 2.5 mm thick MLC leaves. Both GK and VMAT plans were prescribed to similar isodose lines (50% 60%). Results: Respectively for GK and VMAT, the mean Paddick conformity index (PCI) was 0.62 +/- 0.08 and 0.67 +/- 0.10 (p > 0.05) for PA and 0.72 +/- 0.09 and 0.660 +/- 0.13 (p > 0.05) for VS; the mean gradient index (GI) was 2.76 +/- 0.14 and 3.14 +/- 0.40 Gy (p < 0.05) for PA and 3.71 +/- 1.83 and 3.60 +/- 0.84 Gy (p > 0.05) for VS; mean brainstem maximum dose was 9.13 +/- 3.50 Gy and 7.31 +/- 2.01 Gy (p > 0.05) for PA and 11.67 +/- 4.56 Gy and 12.22 +/- 4.55 Gy (p > 0.05) for VS; mean optic nerve maximum dose was 9.66 +/- 1.0 Gy and 7.67 +/- 2.58 Gy (p < 0.05); mean cochlea mean dose was 7.31 +/- 2.7 Gy and 7.23 +/- 3.13 Gy (p > 0.05); and mean treatment time was 68 min and 5 min for PA and 40 min and 3 min for VS. Conclusions: Auto planning with standard template simplified the planning stage for VMAT and provided clinically acceptable plans. Comparison of GK and VMAT for plan quality and OAR sparing varied across patients but both were overall comparable. PMID- 29988325 TI - Use of VIABAHN Open Revascularisation TEChnique (VORTEC) for Iliofemoral Bypass. AB - Introduction: The VIABAHN Open Revascularisation TEChnique (VORTEC) was initially described for visceral revascularisation and supra-aortic reconstruction for complex aortic hybrid surgery. Herein is reported the use of this innovative technique for revascularisation of the iliofemoral arteries. Report: The use of the VORTEC to perform proximal anastomosis of a prosthetic iliofemoral bypass in two symptomatic patients with heavily calcified iliac artery lesions and redo surgery, respectively, is reported. Discussion: In case of loco-regional hostile conditions, a sutureless telescoping iliac anastomosis should be considered as a valuable adjunct in iliofemoral revascularisation. PMID- 29988326 TI - Reducing errors in prostate tracking with an improved fiducial implantation protocol for CyberKnife based stereotactic body radiotherapy (SBRT). AB - Purpose: Ultra-hypofractionated radiotherapy with SBRT is an established technique for treating localized prostate cancer. CyberKnife based SBRT requires implantation of fiducial markers for soft tissue target tracking by the orthogonal KV X-ray imaging system. The spatial distribution of fiducial markers must allow accurate calculation of a 3D transformation that describes the position of the prostate within the reference frame of the planning CT scan. Accuray provides a fiducial implantation guideline for tracking soft tissue lesions. Despite using the guideline we experienced an unacceptably high rate of rotational tracking failure due to problems with fiducial placement. We adapted the Accuray guideline to prostate SBRT for improved fiducial placement and more reliable target tracking.Methods and materials: 54 patients with prostate adenocarcinoma were treated with ultra-hypofractionated radiotherapy on CyberKnife. Patients had platinum fiducial markers implanted transrectally under ultrasound guidance by a Radiologist. For the first 26 patients, fiducial markers were positioned following the Accuray fiducial placement guidelines for soft tissue lesions (cohort 1). The initial rotational tracking error rate was unacceptably high (23%). On review, inappropriate fiducial placement was identified as the cause of error (especially insufficient spacing between seeds). In October 2016 we developed a seed placement protocol specifically for implanting fiducial markers within the prostate and a second cohort of patients was treated thereafter (cohort 2, 28 patients). The stipulations of the original guideline are maintained while the modified protocol requires that 4 fiducial markers be implanted in the postero-lateral peripheral zone in a single coronal plane. Results: In cohort 1, patients had a median age of 64 years (50 - 74), PSA of 6.6mcg/L (1.1 - 14.7), and prostate volume of 56 cc (22 - 125), while in cohort 2 they had a mean age of 65 years (53 - 75), PSA of 6.2 mcg/L (1 - 12) and prostate volume of 47 cc (21 - 106). The fiducial markers were easily visualized and there were no cases of urosepsis related to fiducial implantation. In 6 of 26 patients (23%) from cohort 1, only translational mapping without accurate spatial rotations could be calculated. After adopting the prostate specific fiducial implantation protocol, rotational tracking error was eliminated. Accurate 6 degree tracking (accounting for translations and rotations) was achieved in all 28 patients from cohort 2. Using an in-house computer script we analyzed the dose distributions resulting from rotational misalignments of -10, -5, -3, 3, 5, and 10 degrees along all three rotational axes (pitch, roll and yaw). Rotational misalignments result in decreased minimum dose to the PTV and increased maximum dose to OARs. Conclusion: Implementing a prostate specific fiducial placement protocol for SBRT significantly improved our ability to track prostate motion in 6 degrees 77% to 100% reliability. Failure to track rotations can potentially lead to underdosing and overdosing of portions of the prostate and OARs respectively. PMID- 29988327 TI - Daily use of extracorporeal CO2 removal in a critical care unit: indications and results. AB - Background: While outcome improvement with extracorporeal CO2 removal (ECCO2R) is not demonstrated, a strong pathophysiological rational supports its use in the setting of acute respiratory distress syndrome (ARDS) and COPD exacerbation. We aimed to describe our single-center experience of ECCO2R indications and outcome. Methods: Patients treated with ECCO2R in our medial ICU, from March 2014 to November 2017, were retrospectively enrolled. Primary end point was evolution of ventilator settings during the two first days following ECCO2R start. Results: Thirty-three patients received ECCO2R. Seventeen were managed with Hemolung(r), 10 with Prismalung(r), 4 with ILA(r), and 2 with Cardiohelp(r). Indications for ECCO2R were mild or moderate ARDS (n = 16), COPD exacerbation (n = 11), or uncontrolled hypercapnia due to other causes (n = 6). Four patients were not intubated at the time of ECCO2R start. Median duration of ECCO2R treatment was 7 days [5-10]. In ARDS patients, between baseline and day 2, median tidal volume and driving pressure decreased from 5.3 [4.4-5.9] mL/kg and 10 [8-15] to 3.8 [3.3 4.1] mL/kg and 9 [8-11], respectively. Prone positioning was performed in 10 of the 16 patients, without serious adverse event. In COPD patients, between baseline and day 2, median ventilation minute and PaCO2 decreased significantly from respectively 7.6 [6.6-8.7] L/min and 9.4 [8.4-10.1] kPa to 5.8 [4.9-6.2] L/min and 6 [5.3-6.8] kPa. Four out of 11 COPD patients were extubated while on ECCO2R. Device thrombosis occurred in 5 patients (15%). Hemolysis was documented in 16 patients (48%). One patient died of intracranial hemorrhage, while on ECCO2R. Twenty-four patients were discharged from ICU alive. Twenty-eight day mortality was 31% in ARDS, 9% in COPD patients, and 50% in other causes of refractory hypercapnic respiratory failure. Conclusion: ECCO2R was useful to apply ultra-protective ventilation among ARDS patients and improved PaCO2, pH, and minute ventilation in COPD patients. PMID- 29988328 TI - An Interdisciplinary Approach for Hypoplastic Amelogenesis Imperfecta: A Case Report. AB - Introduction: Generally, the appropriate rehabilitation concepts of patients with Amelogenesis Imperfecta (AI) should include a multidisciplinary treatment approach. Case Report: This case report describes full mouth rehabilitation of a patient with AI. A 20 years old woman was referred to our clinic with a chief complaint of tooth discoloration, diastema, unsatisfactory esthetics and slight tooth sensitivity. Clinical, histological and radiographic examination revealed hypoplastic AI. Short crowns, diastema, occlusal wear with exposed dentin in the posterior areas, the lack of contact points, dental caries and discoloration were the other clinical findings. Results: As a result of the periodontal and prosthetic evaluation, gingivectomy and ostectomy were planned, and they followed a full mouth fixed prosthetic restoration. Conclusion: There was no complication or complaint in a 3-year follow-up. At the end of this follow-up period, the patient was satisfied with esthetics, function and phonation properties of her prostheses. PMID- 29988330 TI - Physical exercise, IGF-1 and cognition A systematic review of experimental studies in the elderly. AB - : One of hypothetical mechanisms related to cognition is exercise-induced IGF-1. Objective: The aim of this study was to analyze the effects of exercise on IGF-1 levels and cognition in the elderly. Methods: The article searches were conducted on Pubmed, Web of Science, PsycINFO and Scielo databases and reviewed according to PRISMA guidelines. The inclusion criteria were: [1] original articles published up to 2017; [2] samples including elderly; [3] protocols including physical exercise; [4] longitudinal studies having exercise as main outcome; [5] assessment of IGF-1; [6] cognition assessment. Results: Seven studies were included in this review. Three of the studies showed an exercise-induced increase in IGF-1; three found stable IGF-1 levels and one found a reduction in IGF-1; with and without improvement in cognition. Conclusion: Disparities in the type of physical exercise, protocols and samples under different conditions hinder the establishment of a consensus on IGF-1, cognition and physical exercise. PMID- 29988329 TI - Hybrid phenolic-inducible promoters towards construction of self-inducible systems for microbial lignin valorization. AB - Background: Engineering strategies to create promoters that are both higher strength and tunable in the presence of inexpensive compounds are of high importance to develop metabolic engineering technologies that can be commercialized. Lignocellulosic biomass stands out as the most abundant renewable feedstock for the production of biofuels and chemicals. However, lignin a major polymeric component of the biomass is made up of aromatic units and remains as an untapped resource. Novel synthetic biology tools for the expression of heterologous proteins are critical for the effective engineering of a microbe to valorize lignin. This study demonstrates the first successful attempt in the creation of engineered promoters that can be induced by aromatics present in lignocellulosic hydrolysates to increase heterologous protein production. Results: A hybrid promoter engineering approach was utilized for the construction of phenolic-inducible promoters of higher strength. The hybrid promoters were constructed by replacing the spacer region of an endogenous promoter, PemrR present in E. coli that was naturally inducible by phenolics. In the presence of vanillin, the engineered promoters Pvtac, Pvtrc, and Pvtic increased protein expression by 4.6-, 3.0-, and 1.5-fold, respectively, in comparison with a native promoter, PemrR. In the presence of vanillic acid, Pvtac, Pvtrc, and Pvtic improved protein expression by 9.5-, 6.8-, and 2.1-fold, respectively, in comparison with PemrR. Among the cells induced with vanillin, the emergence of a sub-population constituting the healthy and dividing cells using flow cytometry was observed. The analysis also revealed this smaller sub-population to be the primary contributor for the increased expression that was observed with the engineered promoters. Conclusions: This study demonstrates the first successful attempt in the creation of engineered promoters that can be induced by aromatics to increase heterologous protein production. Employing promoters inducible by phenolics will provide the following advantages: (1) develop substrate inducible systems; (2) lower operating costs by replacing expensive IPTG currently used for induction; (3) develop dynamic regulatory systems; and (4) provide flexibility in operating conditions. The flow cytometry findings strongly suggest the need for novel approaches to maintain a healthy cell population in the presence of phenolics to achieve increased heterologous protein expression and, thereby, valorize lignin efficiently. PMID- 29988331 TI - Type 2 immunity in asthma. AB - Type 2-immunity represents the typical adaptive response to allergen exposure in atopic individuals. It mainly involves Th2 cells and immunoglobulin E, as the main orchestrators of type 2-inflammation. Recently, it has been highlighted that allergens may be responsible for a Th2 response beside specific IgE activation and that a number of other environmental stimuli, such as viruses and pollutants, can trigger the same pattern of inflammation beyond atopy. Emerging data sustain a substantial role of the so-called epithelial dysfunction in asthma pathogenesis, both from anatomic and functional point of view. Furthermore an increasing amount of evidence demonstrates the relevance of innate immunity in polarizing a Th2 impaired response in asthmatic patients. Under this perspective, the complex cross-talking between airway epithelium, innate and adaptive immunity is emerging as a major determinant of type 2-inflammation beyond allergens. This review will include an update on the relevance of dysregulation of innate and adaptive type 2-immunity in asthma pathogenesis, particularly severe asthma, and on the role of the allergens that are associated with severe asthma. Type 2 immunity also will be reviewed in the light of the current and upcoming targeted treatments for severe asthma. PMID- 29988333 TI - The association between systemic lupus erythematosus and dementia A meta analysis. AB - : A growing body of evidence indicates that systemic lupus erythematosus (SLE) is associated with increased risk of cognitive impairment and dementia. However, to date, no studies have been conducted to quantitatively summarize and evaluate the consistency of data. Objective: To quantitatively evaluate the relationship of SLE and antiphospholipid antibodies (aPL) with cognitive dysfunction and dementia. Methods: All relevant literature was retrieved from Pubmed, Scopus, and PsycINFO databases. The meta-analysis was performed using effect estimates and 95% confidence intervals (CIs) to calculate pooled risk estimates. The heterogeneity among studies was also examined. Results: The meta-analysis included 11 original studies involving a total of 81,668 patients with dementia and 407 patients with cognitive dysfunction. There were significant associations on fixed-effect models between SLE and dementia (3 studies; RR=1.50; 95% CI=1.37 1.64), SLE and cognitive dysfunction (4 studies; OR=2.97; 95% CI=1.72-5.15), and aPL and cognitive dysfunction (5 studies, OR=1.97; 95% CI=1.55-2.52). We also combined cognitive dysfunction and dementia outcomes as they both represented cognitive impairment. There were significant associations between aPL and cognitive impairment (6 studies; OR=2.03; 95% CI=1.62-2.55), and SLE and cognitive impairment (7 studies; OR=1.83; 95% CI=1.42-2.35). Moderate heterogeneity (I2=45.7%) was found in the association between SLE and cognitive impairment, low heterogeneity (I2=21.8%) in the association between SLE and dementia, and near zero heterogeneity for the other three main analyses. Conclusion: Both SLE and aPL are associated with cognitive impairment. PMID- 29988334 TI - Circulation of dengue serotypes in the Union Territory of Dadra & Nagar Haveli (India). AB - The presence of chronological infection by the multi serotype of dengue virus (DENV) is a major contributing factor for the induction of Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). The results indicate that all serotype of dengue along with concurrent infection were reported from the third smallest Union Territory of India furthermore, rare serotype DENV 4, gradually spreads in new areas of India. Therefore, a need to understand the epidemiology of locally circulating serotype and accordingly the control strategy can be implemented. The study was conducted during 2014-2017 in the Union Territory of Dadra & Nagar Haveli (India). PMID- 29988332 TI - A precision therapeutic strategy for hexokinase 1-null, hexokinase 2-positive cancers. AB - Background: Precision medicine therapies require identification of unique molecular cancer characteristics. Hexokinase (HK) activity has been proposed as a therapeutic target; however, different hexokinase isoforms have not been well characterized as alternative targets. While HK2 is highly expressed in the majority of cancers, cancer subtypes with differential HK1 and HK2 expression have not been characterized for their sensitivities to HK2 silencing. Methods: HK1 and HK2 expression in the Cancer Cell Line Encyclopedia dataset was analyzed. A doxycycline-inducible shRNA silencing system was used to examine the effect of HK2 knockdown in cultured cells and in xenograft models of HK1-HK2+ and HK1+HK2+ cancers. Glucose consumption and lactate production rates were measured to monitor HK activity in cell culture, and 18F-FDG PET/CT was used to monitor HK activity in xenograft tumors. A high-throughput screen was performed to search for synthetically lethal compounds in combination with HK2 inhibition in HK1-HK2+ liver cancer cells, and a combination therapy for liver cancers with this phenotype was developed. A metabolomic analysis was performed to examine changes in cellular energy levels and key metabolites in HK1-HK2+ cells treated with this combination therapy. The CRISPR Cas9 method was used to establish isogenic HK1+HK2+ and HK1-HK2+ cell lines to evaluate HK1-HK2+ cancer cell sensitivity to the combination therapy. Results: Most tumors express both HK1 and HK2, and subsets of cancers from a wide variety of tissues of origin express only HK2. Unlike HK1+HK2+ cancers, HK1-HK2+ cancers are sensitive to HK2 silencing-induced cytostasis. Synthetic lethality was achieved in HK1-HK2+ liver cancer cells, by the combination of DPI, a mitochondrial complex I inhibitor, and HK2 inhibition, in HK1-HK2+ liver cancer cells. Perhexiline, a fatty acid oxidation inhibitor, further sensitizes HK1-HK2+ liver cancer cells to the complex I/HK2-targeted therapeutic combination. Although HK1+HK2+ lung cancer H460 cells are resistant to this therapeutic combination, isogenic HK1KOHK2+ cells are sensitive to this therapy. Conclusions: The HK1-HK2+ cancer subsets exist among a wide variety of cancer types. Selective inhibition of the HK1-HK2+ cancer cell-specific energy production pathways (HK2-driven glycolysis, oxidative phosphorylation and fatty acid oxidation), due to the unique presence of only the HK2 isoform, appears promising to treat HK1-HK2+ cancers. This therapeutic strategy will likely be tolerated by most normal tissues, where only HK1 is expressed. PMID- 29988335 TI - Challenges faced and lessons learned A multi-component prospective memory training program for Malaysian older adults. AB - : The surrounding circumstances and environments of Malaysian older adults could make conducting interventions (mainly in terms of clinical or randomized controlled trials) a challenge. Working with older adults and facing cultural issues could be challenging. Objective: This paper illustrates a significant perspective of some of the challenges faced while conducting a randomized controlled trial exploring the impact of a multi-component intervention that included strategy- and process-based prospective memory (PM) training among Malaysian older adults. Methods: The current study was a randomized controlled trial (RCT) and therefore the challenges were presented in accordance with the CONSORT statement style. Results: A discussion on how these issues were addressed is provided. Conclusion: Some suggestions were presented to help researchers plan and create interventions for similar studies and to support a practical method of addressing all related challenges. PMID- 29988336 TI - The limbic-reticular coupling theory of memory processing in the brain and its greater compatibility over other theories. AB - The limbic-reticular coupling theory suggests that the hippocampus and amygdala regulate such descending limbic structures as the mammillary bodies, septum, hypothalamus and epithalamus to regulate the ascending noradrenergic, serotonergic, dopaminergic and cholinergic systems, performing declarative memory consolidation and recall. Recent studies have revealed that, less sensitive to familiarity, the hippocampus functions via the fornix, mammillary bodies and hypothalamus for memory recall. Lesions to the thalamic nuclei were complicated with damage to adjacent fornix, stria medullaris and habenula, simultaneously destroying two kinds of structures respectively for familiarity and recall. Furthermore, the orbitofrontal cortex was shown to be clinically irrelevant for memory recall. Electrophysiologically, the hippocampus regulates the raphe nuclei in complex ways, and the hippocampal theta wave activates the dopaminergic cells in ventral tegmental area and cholinergic neurons in basal forebrain, while cholinergic-modulated theta-gamma coupling mediates cortical recall. These concurrent advances support the limbic-reticular coupling theory for elucidation of memory recall. PMID- 29988337 TI - Changes in foot pain, structure and function following bariatric surgery. AB - Background: Bariatric surgery candidates have a high prevalence of foot pain, depression and elevated plantar pressures. There is, however, limited research into how these factors interact pre- and post-surgery. The aims of this study were therefore to investigate the mechanical and non-mechanical factors associated with foot pain severity before, and the change after, surgery. Methods: Bariatric surgery candidates underwent baseline and six-month follow-up measures. Foot pain was measured with the Manchester-Oxford Foot Questionnaire. Mechanical measures included body mass index (BMI), dynamic plantar pressures, radiographic foot posture, and hindfoot range of motion. Depressive symptoms, the non-mechanical measure, were assessed by questionnaire. Multivariable linear regression was used to determine which variables were associated with foot pain at baseline and at follow-up. Multilevel repeated models assessed the associations between foot pain and plantar pressure, adjusting for the interaction between group and follow-up time. Results: Forty-five participants (84% female), with mean (SD) age of 45.7 (9.4) years were recruited. Twenty-nine participants had bariatric surgery and 16 participants remained on the waiting list (controls). Following bariatric surgery, foot pain reduced significantly by 35.7 points (95% CI -42.2 to - 28.8), while depressive symptoms and whole foot peak pressures had a significant mean change of - 5.9 points (95% CI -10.3 to - 1.5) and - 36 kPa (95% CI -50 to - 22), respectively. In multivariable analysis, depressive symptoms were associated with foot pain at baseline beta = 0.7 (95% CI 0.2 to 1.2) after controlling for age, gender, BMI, foot posture and plantar pressure. Depressive symptoms were also associated with foot pain at follow-up in those undergoing bariatric surgery, beta = 1.2 (95% CI 0.8 to 1.7). Foot posture and hindfoot range of motion did not change following surgery and a change in plantar pressures was not associated with a change in foot pain. Conclusions: Foot pain severity in bariatric surgery candidates was associated with depressive symptoms at baseline. Reduced foot pain following bariatric surgery was associated with an improvement in depressive symptoms, without a significant change in foot posture or foot function. Foot pain severity in bariatric candidates may be mediated by non-mechanical or non-local factors before and following surgery. PMID- 29988338 TI - Two new virtual reality tasks for the assessment of spatial orientation Preliminary results of tolerability, sense of presence and usability. AB - : Spatial orientation is a cognitive domain frequently impaired in Alzheimer's Disease and can be one of its earliest symptoms. Objective: This paper describes the results of tolerability, sense of presence and usability of two immersive virtual reality tasks for the assessment of spatial orientation, using VR headset in adults. Methods: 31 healthy adults recruited from university and the local community performed two experimental immersive virtual reality tasks of spatial orientation: the SOIVET-Maze for the assessment of allocentric to egocentric spatial abilities and the SOIVET-Route for the assessment of spatial memory and landmark recognition. Participants completed questionnaires about sense of presence, cybersickness symptoms, technology use profile and motion sickness history. Usability measures were assessed by spontaneous feedback from participants. Results: All participants were able to understand the task instructions and how to interact with the system. Both tasks seemed to induce a strong sense of presence, as assessed by the Witmer and Singer Presence Questionnaires (M=128 and 143 for SOIVET-Maze and SOIVET-Route, respectively). The SOIVET-Route had a small numeric advantage over the SOIVET-Maze tolerability scores assessed by the Cybersickness Questionnaire (M=4.19, SD=5.576 and M=3.52, SD=6.418 for SOIVET-Maze and SOIVET-Route respectively). Also, there were no drop outs on the SOIVET-Route due to tolerability issues, unlike the SOIVET-Maze, which had two drop-outs. However, this difference was not statistically significant (Z= -.901, p= 0.368, Wilcoxon signed-rank test). PMID- 29988339 TI - Vocal Fold Cancer Transoral Laser Microsurgery Following European Laryngological Society Laser Cordectomy Classification. AB - Background: The surgical treatment of glottic, or vocal cord, cancer has seen considerable progression over the past several decades. Specifically, there has been a stark transition from open partial laryngectomy surgery to endoscopic laser microsurgical techniques which have been inspired in large part by two landmark studies: Professor Wolfgang Steiner's original case series describing transoral laser microsurgery for glottic cancer (1993) and the European Laryngological Society's (ELS) classification scheme (2000). We performed a comprehensive review of published literature to characterize the pattern of this novel modality as compared with two landmark studies over the past four decades. Methods: An English literature search was conducted on PubMed for available original investigations on surgical treatment of glottic laryngeal cancer published over the past 40 years. Our Boolean criteria included the following terms: cancer, glottic, laryngeal, surgery, endoscopic, and laser. The publication rates were calculated as annual compound growth as well as corrected growth rates as defined by the Fisher equation for inflation effects. Results: Our review identified 13,372 studies covering larynx cancer and 3,557 studies covering glottic cancer original studies. Among these, we analyzed the compound annual growth rates and correct growth rates for three distinct publication periods or epochs, prior to 1993, 1993-1999, and 2000-2017. For all but two of the search term groups covering both glottic cancer as well as larynx cancer, there was a substantial growth improvement in the time period following the ELS classification scheme as compared with the growth rate of the time period following Steiner's case series. Conclusion: The progress toward minimally invasive treatment of glottic cancer has progressed steadily over the past several decades. Analysis of publication show increased growth during the time period following the ELS classification scheme over the time period following Steiner's landmark study. A mistake would be concluding any diminished importance of Professor Steiner's work, instead, our analysis demonstrates the wide-spread adoption of the endoscopic laser cordectomy procedure following the ELS classification system. Complex surgical techniques such as transoral laser microsurgery are optimally disseminated within well-defined classification schemes, though further validation is warranted. PMID- 29988340 TI - Body Mass Index Differences in the Gut Microbiota Are Gender Specific. AB - Background: The gut microbiota is increasingly recognized as playing an important role in the development of obesity, but the influence of gender remains elusive. Using a large cohort of Chinese adults, our study aimed to identify differences in gut microbiota as a function of body mass index (BMI) and investigate gender specific features within these differences. Methods: Five hundred fifty-one participants were categorized as underweight, normal, overweight, or obese, based on their BMI. Fecal microbiome composition was profiled via 16S rRNA gene sequencing. Generalized linear model (GLM), BugBase, PICRUSt, and SPIEC-EASI were employed to assess the variabilities in richness, diversity, structure, organism level microbiome phenotypes, molecular functions, and ecological networks of the bacterial community that associated with BMI and sex. Results: The bacterial community of the underweight group exhibited significantly higher alpha diversity than other BMI groups. When stratified by gender, the pattern of alpha diversity across BMI was maintained in females, but no significant difference in alpha diversity was detected among the BMI groups of males. An enrichment of Fusobacteria was observed in the fecal microbiota of obese males, while obese females demonstrated an increased relative abundance of Actinobacteria. Analysis of microbial community-level phenotypes revealed that underweight males tend to have more anaerobic and less facultatively anaerobic bacteria, indicating a reduced resistance to oxidative stress. Functionally, butyrate-acetoacetate CoA transferase was enriched in obese individuals, which might favor energy accumulation. PhoH-like ATPase was found to be increased in male obese subjects, indicating a propensity to harvest energy. The microbial ecological network of the obese group contained more antagonistic microbial interactions as well as high-degree nodes. Conclusion: Using a large Chinese cohort, we demonstrated BMI associated differences in gut microbiota composition, functions, and ecological networks, which were influenced by gender. Results in this area have shown variability across several independent studies, suggesting that further investigation is needed to understand the role of the microbiota in modulating host energy harvest and storage, and the impact of sex on these functions. PMID- 29988341 TI - Dendritic Cells Actively Limit Interleukin-10 Production Under Inflammatory Conditions via DC-SCRIPT and Dual-Specificity Phosphatase 4. AB - Dendritic cell (DC)-based immunotherapy makes use of the DC's ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under tight regulation, as it needs to be predominantly expressed during the resolution phase of the immune response. Currently it is not clear whether there is active suppression of IL-10 by DCs at the initial pro-inflammatory stage of the immune response. Previously, knockdown of the DC-specific transcription factor DC-SCRIPT has been demonstrated to mediate an extensive increase in IL-10 production upon encounter with pro inflammatory immune stimuli. Here, we explored how DC-SCRIPT contributes to IL-10 suppression under pro-inflammatory conditions by applying chromatin immunoprecipitation sequencing analysis of DC-SCRIPT and the epigenetic marks H3K4me3 and H3K27ac in human DCs. The data showed binding of DC-SCRIPT to a GA rich motif at H3K27ac-marked genomic enhancers that associated with genes encoding MAPK dual-specificity phosphatases (DUSPs). Functional studies revealed that upon knockdown of DC-SCRIPT, human DCs express much less DUSP4 and exhibit increased phosphorylation of the three major MAPKs (ERK, JNK, and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown-DCs led to higher production of IL-10, which was reverted by rescuing DUSP4 expression. Finally, DC-SCRIPT-knockdown-DCs induced less IFN-gamma and increased IL-10 production in naive T cells, indicative for a more anti-inflammatory phenotype. In conclusion, we have delineated a new mechanism by which DC-SCRIPT allows DCs to limit IL-10 production under inflammatory conditions and potentiate pro-inflammatory Th1 responses. These insights may be exploited to improve DC-based immunotherapies. PMID- 29988343 TI - Qualitative analysis and identification of pattern of errors in Clock Drawing Tests of community-dwelling older adults. AB - : The Clock Drawing Test (CDT) is a frequently employed screening tool with different scoring systems. Quantitative and semi-quantitative scoring systems, such as Sunderland's et al. (1989), do not discriminate different error patterns. Thus, the same score can represent a number of different neuropsychological profiles. Therefore, the use of a scoring method that emphasizes qualitative aspects to determine specific error patterns is fundamental. Objective: To use a qualitative scale to analyze error patterns in the CDTs of older adults who scored 5 in a previous study. Methods: 49 CDTs with score of 5 were analyzed using the qualitative scale. Linear regression and hierarchical and non hierarchical cluster analyses were performed. Results: The linear regression showed a significant association between the total score and all the error patterns of the qualitative scale. The hierarchical cluster yielded three groups. However, due to the heterogeneity observed among the groups, a non-hierarchical cluster analysis was performed to better understand the results. Three groups were determined with different neuropsychological profiles and patterns of errors. Conclusion: The qualitative scoring of the CDT is important when examining and analyzing specific neuropsychological domains in older adults, especially executive functions. PMID- 29988342 TI - Alternative Pathway Is Essential for Glomerular Complement Activation and Proteinuria in a Mouse Model of Membranous Nephropathy. AB - Membranous nephropathy is an immune kidney disease caused by IgG antibodies that form glomerular subepithelial immune complexes. Proteinuria is mediated by complement activation, as a result of podocyte injury by C5b-9, but the role of specific complement pathways is not known. Autoantibodies-mediating primary membranous nephropathy are predominantly of IgG4 subclass, which cannot activate the classical pathway. Histologic evidence from kidney biopsies suggests that the lectin and the alternative pathways may be activated in membranous nephropathy, but the pathogenic relevance of these pathways remains unclear. In this study, we evaluated the role of the alternative pathway in a mouse model of membranous nephropathy. After inducing the formation of subepithelial immune complexes, we found similar glomerular IgG deposition in wild-type mice and in factor B-null mice, which lack a functional alternative pathway. Unlike wild-type mice, mice lacking factor B did not develop albuminuria nor exhibit glomerular deposition of C3c and C5b-9. Albuminuria was also reduced but not completely abolished in C5 deficient mice. Our results provide the first direct evidence that the alternative pathway is necessary for pathogenic complement activation by glomerular subepithelial immune complexes and is, therefore, a key mediator of proteinuria in experimental membranous nephropathy. This knowledge is important for the rational design of new therapies for membranous nephropathy. PMID- 29988344 TI - Hyper memory, synaesthesia, savants Luria and Borges revisited. AB - In this paper, we investigated two subjects with superior memory, or hyper memory: Solomon Shereshevsky, who was followed clinically for years by A. R. Luria, and Funes the Memorious, a fictional character created by J. L. Borges. The subjects possessed hyper memory, synaesthesia and symptoms of what we now call autistic spectrum disorder (ASD). We will discuss interactions of these characteristics and their possible role in hyper memory. Our study suggests that the hyper memory in our synaesthetes may have been due to their ASD-savant syndrome characteristics. However, this talent was markedly diminished by their severe deficit in categorization, abstraction and metaphorical functions. As investigated by previous studies, we suggest that there is altered connectivity between the medial temporal lobe and its connections to the prefrontal cingulate and amygdala, either due to lack of specific neurons or to a more general neuronal dysfunction. PMID- 29988345 TI - Descriptive data in different paper-based cognitive assessments in elderly from the community Stratification by age and education. AB - : Cognitive aging is dynamic and heterogeneous in elderly, thus adequate tools such as paper-based tests are relevant to describe the cognitive profile of this population. Objective: To describe different paper-based cognitive assessments tests in elderly people stratified by age and education. Methods: A cross sectional study of 667 elderly (>=60 years) living in the community was conducted. Sociodemographic information was collected. Global cognition was assessed by the Addenbrooke's Cognitive Examination-Revised (ACE-R), Mini Addenbrooke's Cognitive Examination (M-ACE) and Mini-Mental State Examination (MMSE). The data were analyzed using descriptive statistics, the t-test and Pearson's Correlation Coefficient. Results: The findings showed a predominance of women (53.8%), mean age of 71.3 (+/-7.7) years and 3.6 (+/-3.5) years of education. The best global cognitive performance and cognitive domain assessment scores were found in the group with higher formal educational level. Each year of education was associated with an increase of up to 10% in scores on the M-ACE and MMSE and up to 11% in ACE-R scores. The mean values of the scores varied according to age, where the 60-69 years group had better scores than other age groups. The correlation matrix between the cognitive tests showed that near perfect correlations (r=1) were frequent in the subgroup with higher education. Conclusion: Younger elderly and those with higher educational level had greater global and domain scores. This study describes the scores of elderly for different strata of education and age. In practice, it is important to choose the most suitable screening instrument, considering the characteristics of the elderly. PMID- 29988346 TI - Human CD8+CD28- T Suppressor Cells Expanded by IL-15 In Vitro Suppress in an Allospecific and Programmed Cell Death Protein 1-Dependent Manner. AB - CD8+CD28- T suppressor cells (Ts) have been recently documented to play an important role in alloimmunity. Therefore, understanding and optimizing the conditions under which these cells are generated and/or expanded would greatly facilitate further research and potential clinical use. In this study, we describe rapid expansion of human allospecific CD8+CD28- Ts cells through coculture of CD8+ T cells with human leukocyte antigen-mismatched donor antigen presenting cells plus IL-15 in a relative short period of time in vitro. Interestingly, IL-15 promotes the expansion of CD8+CD28- Ts cells through several parallel mechanisms. The expanded CD8+CD28- Ts cells upregulate expression of CD132, CD25, and programmed cell death protein 1 (PD-1), but downregulate expression of CD122, GZM-B, and perforin, while exhibiting no cytotoxicity. Most importantly, the expanded CD8+CD28- Ts cells vigorously inhibit CD4+ T cells proliferation in a contact-dependent and donor-specific manner both in vitro and in vivo. Interestingly, the co-inhibitory molecules PD-1 and programmed death ligand 1 play an obligatory role in the mechanisms of CD8+CD28- Ts cells suppression. Taken together, our study report novel methodology for IL-15-induced expansion of human CD8+CD28- Ts cells and possible mechanisms. These findings may facilitate understanding of transplant rejection and promote clinical application of CD8+CD28- Ts cell-based strategies for inducing and monitoring transplant tolerance in the future. PMID- 29988347 TI - Can musical intervention improve memory in Alzheimer's patients? Evidence from a systematic review. AB - : Treatment with music has shown effectiveness in the treatment of general behavioural and cognitive symptoms of patients with various types of dementia. Objective: To assess the effectiveness of treatment with music on the memory of patients with Alzheimer's disease (AD). Methods: A systematic search was performed on PubMed (Medline), Cochrane Library, PsycINFO and Lilacs databases up to June 2017 and included all randomized controlled trials that assessed memory using musical interventions in patients with AD. Results: Forty-two studies were identified, and 24 studies were selected. After applying the exclusion criteria, four studies involving 179 patients were included. These studies showed the benefits of using music to treat memory deficit in patients with AD. Conclusion: To the best of our knowledge, this is the first systematic review focusing on randomized trials found in the literature that analysed the role of musical interventions specifically in the memory of patients with AD. Despite the positive outcome of this review, the available evidence remains inconsistent due to the small number of randomized controlled trials. PMID- 29988348 TI - Headline indicators for monitoring the performance of health systems: findings from the european Health Systems_Indicator (euHS_I) survey. AB - Background: Cross-country comparisons of health system performance have become increasingly important. Clear evidence is needed on the prioritization of health system performance assessment (HSPA) indicators. Selected "leading" or "headline" HSPA indicators may provide early warnings of policy impacts. The goal of this paper is to propose a set of headline indicators to frame and describe health system performance. Methods: We identified overlaps and gaps in the availability of reported indicators by looking at HSPA initiatives in Member States (MSs) of the European Union (EU), the European Commission as well as international institutions (e.g. OECD, WHO-EUR). On that basis, we conducted a two-stage online survey, the european Health System_Indicator (euHS_I) survey. The survey sought to elicit preferences from a wide range of HSPA experts on i) the most relevant HSPA domain(s), i.e. access, efficiency, quality of care, equity, for a specific indicator, and ii) the importance of indicators regarding their information content, i.e. headline, operational, explanatory. Frequency analysis was performed. Results: We identified 2168 health and health system indicators listed in 43 relevant initiatives. After adjusting for overlaps, a total of 361 indicators were assessed by 28 experts in the 1st stage of the survey. In the 2nd stage, a more balanced set of 95 indicators was constructed and assessed by 72 experts from 22 EU MSs and 3 non-EU countries. In the domain access experts assessed share of population covered by health insurance as the top headline indicator. In the domain efficiency, the highest rank was given to Total health care expenditure by all financing agents, and in the domain quality of care to rate of hospital-acquired infections. Percentage of households experiencing high levels/catastrophic of out-of-pocket health expenditures results as the top headline indicator for domain equity. Conclusions: HSPA indicators from different initiatives largely overlap and public health indicators dominate over health systems aspects. The survey allowed to quantify overlaps and gaps in HSPA indicators, their expert allocation to domain areas and establishment of an informed hierarchy structure. Yet, results show that more multidisciplinary work is needed to ensure the availability of accurate efficiency indicators which are comparable across countries. PMID- 29988349 TI - Correction to: Mid-upper-arm circumference based case-detection, admission, and discharging of under five children in a large-scale community-based management of acute malnutrition program in Nigeria. AB - [This corrects the article DOI: 10.1186/s13690-018-0266-4.]. PMID- 29988350 TI - Plasmablastic lymphoma in Malawi. AB - Plasmablastic lymphoma (PBL) clinical descriptions are scarce from sub-Saharan Africa (SSA) where both HIV and EBV are highly endemic. We identified 12 patients with pathologically confirmed PBL from a prospective cohort in Lilongwe, Malawi. Median age was 46 (range 26-71), seven (58%) were male, and six (50%) were HIV positive. Eight patients were treated with CHOP and four with a modified EPOCH regimen. One-year overall survival was 56% (95% CI 24-79%), without clear differences based on HIV status. PBL occurs in Malawi in HIV-positive and HIV negative individuals and can be treated successfully with curative intent, even in a low-resource setting in SSA. PMID- 29988351 TI - Molecular cloning and characterization of the endothelin 3 gene in black bone sheep. AB - Background: Black bone sheep was first discovered in Yunnan province of China in 1970, with unique black pigmentation on the body and internal organs. Endothelin 3 (EDN3) has been known as a key gene causing hyperpigmentation in black bone chicken, the Silky fowl. Methods: In this study, EDN3 was employed as a candidate gene for regulating black color pigmentation. First, EDN3 was cloned from sheep to obtain the full-length cDNA by using the rapid amplification of cDNA ends (RACE). Genomic EDN3 was screened and a total of thirty predicted single nucleotide polymorphisms (SNPs) were genotyped for allele and genotype frequency analysis in a case-control study involving two black bone sheep populations. Genomic copy number analysis of EDN3 in sheep was conducted to measure the variation in copy number. EDN3 expression levels were observed among the groups in adult liver, lymph node, and kidney tissues, as well as embryo kidney samples. Also, among the tissues of black bone and non-black bone sheep. Results: The size of the full-length cDNA was 1,578 bp, which included 426 bp of 5'-untranslated region (5'-UTR), an open reading frame (ORF) of 639 bp encoding a protein of 212 amino acids, and a 3'-UTR of 513 bp. Genotype and allele frequencies of all the discovered SNPs were found insignificantly different in black bone and non-black bone sheep (P > 0.05). Genomic copy number analysis of EDN3 in sheep revealed no significant difference between the two sheep groups. No significant variations were found in the adult liver and kidney embryo samples. However, the expression in lymph node and kidney tissue was significantly higher in black bone sheep than that in non-black bone sheep (P < 0.05). Significant variations in the EDN3 expression levels were observed among the tissues of non-black bone sheep. Conclusions: The findings of the present study indicate that unlike in Silky chickens, EDN3 is not responsible for hyperpigmentation but may play a key functional role in immune and excretory systems of black bone sheep. PMID- 29988353 TI - Exploratory Analysis of the Microbiological Potential for Efficient Utilization of Fiber Between Lantang and Duroc Pigs. AB - There is growing interest in the use of unconventional feed ingredients containing higher dietary fiber for pig production due to increasing prices of cereal grains and the potential health benefits of dietary fiber on host animals. This study aimed to gain insight into the community-wide microbiome population between the Chinese native Lantang pigs and the commercial Duroc pigs to uncover the microbiological mechanisms for the degradation capacity of fiber in pigs. Utilizing the metagenomics approach, we compared the phylogeny and functional capacity of the fecal microbiome from approximately 150-day-old female Lantang and Duroc pigs fed a similar diet. The structure of the fecal microbial community from the two pig breeds was different at the genus level; the number of genes associated with fiber degradation was higher in Lantang pigs. Further analysis and prediction of their functions from the fecal microbiomes of the two pig breeds revealed that the degradation capacities of fiber, branched chain fatty acids, and oligosaccharides were higher in Lantang pigs. The ability of lignocellulose bonding modules and the transport capacities of xylose, L arabinose, ribose and methyl galactose were also higher in Lantang pigs. Similarly, the metabolic capacities of xylose, ribose, and fucose and the potential effectiveness of the tricarboxylic acid cycle (TCA) and gene abundance in the hydrogen sink pathway were higher in the fecal microbiome from Lantang pigs. Lantang pigs have a higher capacity to utilize dietary fiber than Duroc pigs, and the differences in the capability to utilize dietary fiber between the indigenous and commercial pigs could be differences in the composition and biological function of the gut microbiota. PMID- 29988352 TI - Low ecological representation in the protected area network of China. AB - Protected areas are considered as an essential strategy to halt the decline of biodiversity. Ecological representation in protected areas is crucial for assessment on the progress toward conservation targets. Although China has established a large number of protected areas since the 1950s, ecological representation of protected areas is poorly understood. Here, we performed the complementarity analysis to evaluate ecological representation of protected areas in China. We used a database of the geographical distribution for 10,396 woody plant species, 2,305 fern species, 406 amphibian species, 460 reptile species, 1,364 bird species, and 590 mammal species from 2,376 counties across China. We identified complementary sets of counties for all species or threatened species of plant and vertebrate species using a complementarity algorithm. We evaluated ecological representation of 3,627 protected areas and discerned conservation gaps by comparing the distribution of protected areas with complementary sets. The results show that the spatially representative and complementary sites for biodiversity are poorly covered, and a fairly large proportion of protected areas is not designed to efficiently represent biodiversity at the national scale. Our methodology can serve as a generic framework for assessment on ecological representation of protected areas at the national scale. PMID- 29988354 TI - Evaluation of the Impact of Genetically Modified Cotton After 20 Years of Cultivation in Mexico. AB - For more than 20 years cotton has been the most widely sown genetically modified (GM) crop in Mexico. Its cultivation has fulfilled all requirements and has gone through the different regulatory stages. During the last 20 years, both research institutions and biotech-companies have generated scientific and technical information regarding GM cotton cultivation in Mexico. In this work, we collected data in order to analyze the environmental and agronomic effects of the use of GM cotton in Mexico. In 1996, the introduction of Bt cotton made it possible to reactivate this crop, which in previous years was greatly reduced due to pest problems, production costs and environmental concerns. Bt cotton is a widely accepted tool for cotton producers and has proven to be efficient for the control of lepidopteran pests. The economic benefits of its use are variable, and depend on factors such as the international cotton-prices and other costs associated with its inputs. So far, the management strategies used to prevent development of insect resistance to GM cotton has been successful, and there are no reports of insect resistance development to Bt cotton in Mexico. In addition, no effects have been observed on non-target organisms. For herbicide tolerant cotton, the prevention of herbicide resistance has also been successful since unlike other countries, the onset of resistance weeds is still slow, apparently due to cultural practices and rotation of different herbicides. Environmental benefits have been achieved with a reduction in chemical insecticide applications and the subsequent decrease in primary pest populations, so that the inclusion of other technologies-e.g., use of non-Bt cotton- can be explored. Nevertheless, control measures need to be implemented during transport of the bolls and fiber to prevent dispersal of volunteer plants and subsequent gene flow to wild relatives distributed outside the GM cotton growing areas. It is still necessary to implement national research programs, so that biotechnology and plant breeding advances can be used in the development of cotton varieties adapted to the Mexican particular environmental conditions and to control insect pests of regional importance. PMID- 29988355 TI - Olfactory dysfunction in Alzheimer's disease Systematic review and meta-analysis. AB - : Alzheimer's disease (AD), a neurodegenerative condition, is one of the most prevalent kinds of dementia, whose frequency doubles for every 5 years of age in elderly. Objective: To determine the correlation between AD and olfactory alterations, identifying the most affected domains and exploring the utility of olfactory tests for complementing early diagnosis. Methods: Databases were searched using the terms "olfactory OR smell OR olfaction AND alzheimer" for articles related to the proposed theme. The selected studies were categorized and evaluated separately depending on the method of analysis of the olfactory tests: identification of odors, discrimination and recognition, and a meta-analysis was carried out. Results: Fifty-one articles were selected for analysis. The effect size for most studies was large, as were the summary values for each category of individualized olfactory analysis. Conclusion: Among the olfactory domains, except memory, identification appears to be the most altered in AD. The possibility of including tests that specifically evaluate the identification of odors as an item in early diagnostic evaluation should be explored. PROSPERO registration: CRD42018089076. PMID- 29988356 TI - Environmental health surveillance in a future European health information system. AB - Background: To date Health information (HI) in the European Union does not comprise indicators or other information related to impacts of hazardous chemicals in consumer products, food, drinking water or air on the health status of the population. Therefore, we inventorised and evaluated the potential of environmental health surveillance and research data sources in the European population to provide HBM-based indicators of internal human exposure and health impact of relevant chemicals. Methods: We established an up-dated inventory of European cross-sectional Human Biomonitoring (HBM) surveys and of birth cohorts, and compared chemicals and chemical groups addressed by HBM with indicators and health end points collected via European Core Health Indicators (ECHI), in birth registries, as well as in environmental and food data bases and health registries to see on how data collection could be aligned. Finally, we investigated study designs of HBM survey and health examination surveys for potential synergies. Results: The inventory covers a total of 11 European cross-sectional national programmes and a large number of birth cohorts and includes information on study population, age groups, covered substances, sampled matrices, and frequency. The comparison of data collections shows that there are many overlaps between environmental chemicals with environmental and health reporting. HBM data could be linked with ECHI indicators for work-related risks, body mass index (BMI), and low birth weight, with perinatal disease, neurologic disorders, and some chronic diseases, or with data bases for e.g. indoor air, food, or consumer products. Existing initiatives to link data collections at European Environment Agency (EEA) and Joint Research Center (JRC) or at World Health Organization (WHO) are good options to further develop linkage of HBM with exposures sources and health end points. Conclusions: There is potential to use HBM based information in a number of public health policies, and this would help to align reporting to international commitments. Environmental health surveillance based on HBM and HBM based indicators, is an excellent tool to inform public health policies about risks from environmental chemicals, and the EU health information system would benefit from additional HBM-based indicators for monitoring exposure burden from environmental chemicals. Considerable efforts are needed to align and establish routine data collections and to develop a surveillance system and indicators which may inform public health policies. PMID- 29988357 TI - The Reliability of the Brief Visuospatial Memory Test - Revised in Brazilian multiple sclerosis patients. AB - : Cognitive Impairment (CI) is a common and distressing problem in Multiple Sclerosis (MS). Its identification is complicated and sometimes omitted in the routine evaluation by neurologists. The BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) is a promising tool to overcome this difficulty. However, there is some concern regarding the subjectivity in scoring of the BVMT-R (Brief Visuospatial Memory Test - Revised), one of its components. Objective: To evaluate the reliability of the BVMT-R in a sample of Brazilian MS patients, with the measure being administered and scored by neurologists. Methods: BICAMS was applied to seventy subjects comprising forty patients diagnosed with MS and thirty healthy controls. In the MS patients group, the coefficients of agreement between three different raters, using the same protocols, and the internal consistency of the BVMT-R were assessed. Also, the coefficients of correlation of the BVMT-R with the other tests of the BICAMS, CVLT II (California Verbal Learning Test II) and SDMT (Symbol Digit Modalities Test), and their respective effect sizes were calculated. Results: the BVMT-R presented a moderate inter-rater coefficient of agreement (k=0.62), an excellent Intraclass Correlation Coefficient (ICC=0.85), and high internal consistency (alpha=0.92). The correlation between the BVMT-R and CVLT II was moderate (rho=0.36; p<0.025), but strong with the SDMT (rho=0.60; p<0.01), with a large effect size. Conclusion: The BVMT-R is a reliable instrument for assessing CI in patients with MS, having a significant association with information processing speed, an aspect which should be considered when evaluating its score. PMID- 29988358 TI - Benzimidazoisoquinoline derivatives inhibit glioblastoma cell proliferation through down-regulating Raf/MEK/ERK and PI3K/AKT pathways. AB - Background: Recent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzimidazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells. Methods: Human U87 and LN229 cell lines were used to perform the experiments. MTT was applied to screen the effective small molecular inhibitors suppressing growth of GBM cells. Colony formation and BrdU staining assays were performed to assess the inhibition effect of compound-1H on the proliferation of GBM cells. The cell cycle and apoptosis were measured by flow cytometry and western blot to analyze the changes of the relative protein expressions and their signal pathways. Results: Compound-1H could suppress GBM cells in a time- and dose-dependent manner. Treatment of compound-1H could arrest cell cycle in S phase through up-regulating P21 and P53, and down-regulating cyclin A and E in a dose-dependent manner. Compound-1H also induced mitochondrial dependent apoptosis by increasing Bax, cleaved caspase-3, cleaved caspase-9 and poly ADP-ribose polymerase expression, and decreasing Bcl-2 expression. Moreover, phosphorylated (p)-AKT and p-ERK levels relating to cell proliferation were dramatically decreased in U87 and LN229 cells. Conclusions: Our results suggest that it is the first time to report the compound-1H with benzimidazoleisoquinolinone core playing antitumor activity in human glioblastoma cells by inhibiting Raf/MEK/ERK and PI3K/AKT signaling pathways, and it could be as a lead compound for the further development of targeted glioblastoma cancer therapy. PMID- 29988359 TI - Designing miRNA-Based Synthetic Cell Classifier Circuits Using Answer Set Programming. AB - Cell classifier circuits are synthetic biological circuits capable of distinguishing between different cell states depending on specific cellular markers and engendering a state-specific response. An example are classifiers for cancer cells that recognize whether a cell is healthy or diseased based on its miRNA fingerprint and trigger cell apoptosis in the latter case. Binarization of continuous miRNA expression levels allows to formalize a classifier as a Boolean function whose output codes for the cell condition. In this framework, the classifier design problem consists of finding a Boolean function capable of reproducing correct labelings of miRNA profiles. The specifications of such a function can then be used as a blueprint for constructing a corresponding circuit in the lab. To find an optimal classifier both in terms of performance and reliability, however, accuracy, design simplicity and constraints derived from availability of molcular building blocks for the classifiers all need to be taken into account. These complexities translate to computational difficulties, so currently available methods explore only part of the design space and consequently are only capable of calculating locally optimal designs. We present a computational approach for finding globally optimal classifier circuits based on binarized miRNA datasets using Answer Set Programming for efficient scanning of the entire search space. Additionally, the method is capable of computing all optimal solutions, allowing for comparison between optimal classifier designs and identification of key features. Several case studies illustrate the applicability of the approach and highlight the quality of results in comparison with a state of the art method. The method is fully implemented and a comprehensive performance analysis demonstrates its reliability and scalability. PMID- 29988360 TI - Mild cognitive impairment in the elderly Relationship between communication and functional capacity. AB - : Mild Cognitive Impairment is characterized as an intermediate form between age related change and dementia. For the elderly, autonomy and independence are related to the ability to remain active in conducting their social activities and, for this to occur, communication is fundamental in this process. Objective: To assess the association between communication and the abilities of elderly people with mild cognitive impairment to perform instrumental activities of daily living. Methods: A cross-sectional, quantitative, analytical, correlational study was conducted at the Open University of the Third Age (UnATI), a program of the Federal University of Pernambuco. This study included 92 people, comprising 46 elderly with mild cognitive impairment and a caregiver or family member who met the inclusion criteria. The elderly were asked to complete a sociodemographic questionnaire and Lawton-Brody's Instrumental Activities of Daily Living Scale. The caregivers were asked to complete the Functional Assessment of Communication Skills. The following variables were studied: social communication skills and instrumental activities of daily living. Data were stored in an Excel(r) 2007 spreadsheet, and the Pearson correlation test was used for the statistical analysis. Results: There were statistically significant correlations in four domains of social communication: referring to family members by name (p=0.0033); requesting information about people or events (p=0.0355); understanding conversations in a noisy environment (p=0.0448); and understanding what they watch on television or listen to on the radio (p=0.0127). Conclusion: Changes in the communication of elderly people with mild cognitive impairment interfere with their ability to perform instrumental activities autonomously and independently. PMID- 29988361 TI - Evidence for Shaping of Light Chain Repertoire by Structural Selection. AB - The naive immunoglobulin (IG) repertoire in the blood differs from the direct output of the rearrangement process. These differences stem from selection that affects the germline gene usage and the junctional nucleotides. A major complication obscuring the details of the selection mechanism in the heavy chain is the failure to properly identify the D germline and determine the nucleotide addition and deletion in the junction region. The selection affecting junctional diversity can, however, be studied in the light chain that has no D gene. We use probabilistic and deterministic models to infer and disentangle generation and selection of the light chain, using large samples of light chains sequenced from healthy donors and transgenic mice. We have previously used similar models for the beta chain of T-cell receptors and the heavy chain of IGs. Selection is observed mainly in the CDR3. The CDR3 length and mass distributions are narrower after selection than before, indicating stabilizing selection for mid-range values. Within the CDR3, proline and cysteine undergo negative selection, while glycine undergoes positive selection. The results presented here suggest structural selection maintaining the size of the CDR3 within a limited range, and preventing turns in the CDR3 region. PMID- 29988362 TI - Metformin Alters Gut Microbiota of Healthy Mice: Implication for Its Potential Role in Gut Microbiota Homeostasis. AB - In recent years, the first-line anti-diabetic drug metformin has been shown to be also useful for the treatment of other diseases like cancer. To date, few reports were about the impact of metformin on gut microbiota. To fully understand the mechanism of action of metformin in treating diseases other than diabetes, it is especially important to investigate the impact of long-term metformin treatment on the gut microbiome in non-diabetic status. In this study, we treated healthy mice with metformin for 30 days, and observed 46 significantly changed gut microbes by using the 16S rRNA-based microbiome profiling technique. We found that microbes from the Verrucomicrobiaceae and Prevotellaceae classes were enriched, while those from Lachnospiraceae and Rhodobacteraceae were depleted. We further compared the altered microbiome profile with the profiles under various disease conditions using our recently developed comparative microbiome tool known as MicroPattern. Interestingly, the treatment of diabetes patients with metformin positively correlates with colon cancer and type 1 diabetes, indicating a confounding effect on the gut microbiome in patients with diabetes. However, the treatment of healthy mice with metformin exhibits a negative correlation with multiple inflammatory diseases, indicating a protective anti-inflammatory role of metformin in non-diabetes status. This result underscores the potential effect of metformin on gut microbiome homeostasis, which may contribute to the treatment of non-diabetic diseases. PMID- 29988363 TI - Delirium in elderly inpatients admitted to clinical wards Prevalence and investigation of clinical conditions in a Brazilian sample. AB - : In Brazil there is scarce data about the occurrence of delirium among hospitalized elderly patients. Objective: This study aimed to evaluate the prevalence of delirium among elderly patients hospitalized in clinical wards. Methods: This cross-sectional study examined a sample of elderly inpatients admitted to three clinical wards of a general hospital between July 2011 and May 2012. The presence of delirium was detected by applying the Confusion Assessment Method (CAM). Dementia diagnosis was conducted in two steps: screening and diagnosis (Cambridge Examination, CAMDEX, was applied during hospitalization at a second timepoint). Other medical diagnoses and medications in use were extracted from medical records. Results: A sample of 173 elderly inpatients was examined; mean age 71.2 years (SD: 7.8; 60-92 years); 64.2% male. Thirty-one patients were diagnosed with delirium; prevalence of 17.9% (95% CI: 12.2-23.6). Delirium was directly associated with Urinary Tract Infection, Renal Failure and Dementia (p<0.05). Conclusion: The principal findings of this study were a high prevalence of delirium and the identification of associated factors, helping to guide preventive approaches and clinical management for at-risk patients in a Brazilian sample. PMID- 29988364 TI - Prostaglandin E2 Antagonizes TGF-beta Actions During the Differentiation of Monocytes Into Dendritic Cells. AB - Inflammatory dendritic cells (DCs) are a distinct subset of DCs that derive from circulating monocytes infiltrating injured tissues. Monocytes can differentiate into DCs with different functional signatures, depending on the presence of environment stimuli. Among these stimuli, transforming growth factor-beta (TGF beta) and prostaglandin E2 (PGE2) have been shown to modulate the differentiation of monocytes into DCs with different phenotypes and functional profiles. In fact, both mediators lead to contrasting outcomes regarding the production of inflammatory and anti-inflammatory cytokines. Previously, we have shown that human semen, which contains high concentrations of PGE2, promoted the differentiation of DCs into a tolerogenic profile through a mechanism dependent on signaling by E-prostanoid receptors 2 and 4. Notably, this effect was induced despite the huge concentration of TGF-beta present in semen, suggesting that PGE2 overrides the influence exerted by TGF-beta. No previous studies have analyzed the joint actions induced by PGE2 and TGF-beta on the function of monocytes or DCs. Here, we analyzed the phenotype and functional profile of monocyte-derived DCs differentiated in the presence of TGF-beta and PGE2. DC differentiation guided by TGF-beta alone enhanced the expression of CD1a and abrogated LPS induced expression of IL-10, while differentiation in the presence of PGE2 impaired CD1a expression, preserved CD14 expression, abrogated IL-12 and IL-23 production, stimulated IL-10 production, and promoted the expansion of FoxP3+ regulatory T cells in a mixed lymphocyte reaction. Interestingly, DCs differentiated in the presence of TGF-beta and PGE2 showed a phenotype and functional profile closely resembling those induced by PGE2 alone. Finally, we found that PGE2 inhibited TGF-beta signaling through an action exerted by EP2 and EP4 receptors coupled to cyclic AMP increase and protein kinase A activity. These results indicate that PGE2 suppresses the influence exerted by TGF-beta during DC differentiation, imprinting a tolerogenic signature. High concentrations of TGF beta and PGE2 are usually found in infectious, autoimmune, and neoplastic diseases. Our observations suggest that in these scenarios PGE2 might play a mandatory role in the acquisition of a regulatory profile by DCs. PMID- 29988366 TI - Frailty and cognitive performance of elderly in the context of social vulnerability. AB - : Elderly who live in the context of social vulnerability have lower education and socioeconomic status. Objective: To analyze cognitive performance as a factor associated with frailty status in elderly living in contexts of social vulnerability. Methods: An exploratory, comparative, cross-sectional study using a quantitative method was conducted with elderly people registered at Social Assistance Reference Centers. A semi-structured interview, the Edmonton Frail Scale and Montreal Cognitive Assessment were applied. The project was approved by the Research Ethics Committee. To analyze the data, a logistic regression was performed considering two groups (frail and non-frail). Results: 247 elderly individuals participated in the study, with a mean age of 68.52 (+/-SD =7.28) years and education of 1-4 years (n=133). All the elderly evaluated resided in vulnerable regions. Regarding frailty, 91 (36.8%) showed frailty at some level (mild, moderate or severe) and 216 (87.4%) had cognitive impairment. On the regression analysis, frailty was associated with number of diseases (OR:1.60; 95%CI: 1.28-1.99) and cognition (OR:0.93; 95%CI: 0.89-0.98). Conclusion: Identifying level of frailty and cognition in socially vulnerable elderly reinforces the need for early detection in both these conditions by the public services that provide care for this population with a focus on prevention. PMID- 29988365 TI - Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common form of dementia, with over 5. 4 million cases in the US alone (Alzheimer's Association, 2016). Clinically, AD is defined by the presence of plaques composed of Abeta and neurofibrillary pathology composed of the microtubule associated protein tau. Another key feature is the dysregulation of autophagy at key steps in the pathway. In AD, disrupted autophagy contributes to disease progression through the failure to clear pathological protein aggregates, insulin resistance, and its role in the synthesis of Abeta. Like many psychiatric and neurodegenerative diseases, the risk of developing AD, and disease course are dependent on the sex of the patient. One potential mechanism through which these differences occur, is the effects of sex hormones on autophagy. In women, the loss of hormones with menopause presents both a risk factor for developing AD, and an obvious example of where sex differences in AD can stem from. However, because AD pathology can begin decades before menopause, this does not provide the full answer. We propose that sex-based differences in autophagy regulation during the lifespan contribute to the increased risk of AD, and greater severity of pathology seen in women. PMID- 29988367 TI - Interactions Between Emodin and Efflux Transporters on Rat Enterocyte by a Validated Ussing Chamber Technique. AB - Emodin, a major active anthraquinone, frequently interacts with other drugs. As changes of efflux transporters on intestine are one of the essential reasons why the drugs interact with each other, a validated Ussing chamber technique was established to detect the interactions between emodin and efflux transporters, including P-glycoprotein (P-gp), multidrug-resistant associated protein 2 (MRP2), and multidrug-resistant associated protein 3 (MRP3). Digoxin, pravastatin, and teniposide were selected as the test substrates of P-gp, MRP2, and MRP3. Verapamil, MK571, and benzbromarone were their special inhibitors. The results showed that verapamil, MK571, and benzbromarone could increase digoxin, pravastatin, and teniposide absorption, and decrease their Er values, respectively. Verapamil (220 MUM) could significantly increase emodin absorption at 9.25 MUM. In the presence of MK571 (186 MUM), the Papp values of emodin from M S were significantly increased and the efflux ratio decreased. With the treatment of emodin (185, 370, and 740 MUM), digoxin absorption was significantly decreased while teniposide increased. These results indicated that emodin might be the substrate of P-gp and MRP2. Besides, it might be a P-gp inducer and MRP3 inhibitor on enterocyte, which are reported for the first time. These results will be helpful to explain the drug-drug interaction mechanisms between emodin and other drugs and provide basic data for clinical combination therapy. PMID- 29988370 TI - The Burden of Pediatric Asthma. AB - Asthma is the most common chronic disease in children, imposing a consistent burden on health system. In recent years, prevalence of asthma symptoms became globally increased in children and adolescents, particularly in Low-Middle Income Countries (LMICs). Host (genetics, atopy) and environmental factors (microbial exposure, exposure to passive smoking and air pollution), seemed to contribute to this trend. The increased prevalence observed in metropolitan areas with respect to rural ones and, overall, in industrialized countries, highlighted the role of air pollution in asthma inception. Asthma accounts for 1.1% of the overall global estimate of "Disability-adjusted life years" (DALYs)/100,000 for all causes. Mortality in children is low and it decreased across Europe over recent years. Children from LMICs particularly suffer a disproportionately higher burden in terms of morbidity and mortality. Global asthma-related costs are high and are usually are classified into direct, indirect and intangible costs. Direct costs account for 50-80% of the total costs. Asthma is one of the main causes of hospitalization which are particularly common in children aged < 5 years with a prevalence that has been increased during the last two decades, mostly in LMICs. Indirect costs are usually higher than in older patients, including both school and work-related losses. Intangible costs are unquantifiable, since they are related to impairment of quality of life, limitation of physical activities and study performance. The implementation of strategies aimed at early detect asthma thus providing access to the proper treatment has been shown to effectively reduce the burden of the disease. PMID- 29988369 TI - The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health. AB - SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na+ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line. PMID- 29988371 TI - Constraint-Free Natural Image Reconstruction From fMRI Signals Based on Convolutional Neural Network. AB - In recent years, research on decoding brain activity based on functional magnetic resonance imaging (fMRI) has made eye-catching achievements. However, constraint free natural image reconstruction from brain activity remains a challenge, as specifying brain activity for all possible images is impractical. The problem was often simplified by using semantic prior information or just reconstructing simple images, including digitals and letters. Without semantic prior information, we present a novel method to reconstruct natural images from the fMRI signals of human visual cortex based on the computation model of convolutional neural network (CNN). First, we extracted the unit output of viewed natural images in each layer of a pre-trained CNN as CNN features. Second, we transformed image reconstruction from fMRI signals into the problem of CNN feature visualization by training a sparse linear regression to map from the fMRI patterns to CNN features. By iteratively optimization to find the matched image, whose CNN unit features become most similar to those predicted from the brain activity, we finally achieved the promising results for the challenging constraint-free natural image reconstruction. The semantic prior information of the stimuli was not used when training decoding model, and any category of images (not constraint by the training set) could be reconstructed theoretically. We found that the reconstructed images resembled the natural stimuli, especially in position and shape. The experimental results suggest that hierarchical visual features may be an effective tool to express the human visual processing. PMID- 29988372 TI - Risk Factors of Subclinical Atherosclerosis and Plaque Burden in High Risk Individuals: Results From a Community-Based Study. AB - China is going through major change and the incidence of first-ever stroke has increased dramatically. In this study, we aim to determine the ultrasound characteristics of carotid intima-media thickness (CIMT) and carotid plaques (CP) in the Chinese community-based population with high risk of stroke. 1009 stroke free participants from Datun community were classified at high risk of stroke and included in this cross-sectional study. We performed B-mode carotid ultrasound imaging in all of the study subjects to measure the CIMT in the common carotid artery (CCA) far wall and CP in the CCA, bifurcation and internal carotid artery. Stepwise logistic regression analyses were used to determine factors associated with elevated CIMT and subclinical atherosclerosis, as well as plaque burden (>=2 plaques). Our results showed that traditional risk factors including aging, hypertension, current smoking and the level of high density lipoprotein cholesterol are associated with subclinical atherosclerosis and plaque burden in high-risk community residents. To improve primary prevention in this population, we may consider intense blood pressure and lipid management, and smoking cessation. PMID- 29988368 TI - Brain Energy and Oxygen Metabolism: Emerging Role in Normal Function and Disease. AB - Dynamic metabolic changes occurring in neurons are critically important in directing brain plasticity and cognitive function. In other tissue types, disruptions to metabolism and the resultant changes in cellular oxidative state, such as increased reactive oxygen species (ROS) or induction of hypoxia, are associated with cellular stress. In the brain however, where drastic metabolic shifts occur to support physiological processes, subsequent changes to cellular oxidative state and induction of transcriptional sensors of oxidative stress likely play a significant role in regulating physiological neuronal function. Understanding the role of metabolism and metabolically-regulated genes in neuronal function will be critical in elucidating how cognitive functions are disrupted in pathological conditions where neuronal metabolism is affected. Here, we discuss known mechanisms regulating neuronal metabolism as well as the role of hypoxia and oxidative stress during normal and disrupted neuronal function. We also summarize recent studies implicating a role for metabolism in regulating neuronal plasticity as an emerging neuroscience paradigm. PMID- 29988374 TI - Time Heals all Wounds- but Scars Remain. Can Personalized Medicine Help? PMID- 29988373 TI - Function of Selective Neuromodulatory Projections in the Mammalian Cerebral Cortex: Comparison Between Cholinergic and Noradrenergic Systems. AB - Cortical processing is dynamically modulated by different neuromodulators. Neuromodulation of the cerebral cortex is crucial for maintaining cognitive brain functions such as perception, attention and learning. However, we do not fully understand how neuromodulatory projections are organized in the cerebral cortex to exert various functions. The basal forebrain (BF) cholinergic projection and the locus coeruleus (LC) noradrenergic projection are well-known neuromodulatory projections to the cortex. Decades of studies have identified anatomical and physiological characteristics of these circuits. While both cholinergic and noradrenergic neurons widely project to the cortex, they exhibit different levels of selectivity. Here, we summarize their anatomical and physiological features, highlighting selectivity and specificity of these circuits to different cortical regions. We discuss the importance of selective modulation by comparing their functions in the cortex. We highlight key features in the input-output circuits and target selectivity of these neuromodulatory projections and their roles in controlling four major brain functions: attention, reinforcement, learning and memory, sleep and wakefulness. PMID- 29988376 TI - NKG2A Expression Is Not per se Detrimental for the Anti-Multiple Myeloma Activity of Activated Natural Killer Cells in an In Vitro System Mimicking the Tumor Microenvironment. AB - Natural killer (NK) cell-based immunotherapy is a promising therapy for cancer patients. Inhibitory killer immunoglobulin-like receptors (KIRs) and NKG2A are required for NK cell licensing, but can also inhibit NK cell effector function. Upon reconstitution in a stem cell transplantation setting or after ex vivo NK expansion with IL-2, NKG2A is expressed on a large percentage of NK cells. Since the functional consequences of NKG2A co-expression for activated NK cells are not well known, we compared NKG2A+ vs NKG2A- NK cell subsets in response to K562 cells, multiple myeloma (MM) cell lines and primary MM cells. NK cells were isolated from healthy donors (HLA-C1+C2+Bw4+) and activated overnight with 1,000 U/ml IL-2. NK cell degranulation in subsets expressing KIRs and/or NKG2A was assessed at 21 or 0.6% O2. Activated NKG2A+ NK cell subsets degranulated more vigorously than NKG2A- subsets both at 21 and 0.6% O2. This was irrespective of the presence of KIR and occurred in response to HLA-deficient K562 cells as well as HLA competent, lowly expressing HLA-E MM cell lines. In response to primary MM cells, no inhibitory effects of NKG2A were observed, and NKG2A blockade did not enhance degranulation of NKG2A+ subsets. KIR- NK cells expressing NKG2A degranulated less than their NKG2A- counterparts in response to MM cells having high levels of peptide-induced membrane HLA-E, suggesting that high surface HLA-E levels are required for NKG2A to inhibit activated NK cells. Addition of daratumumab, an anti-CD38 to trigger antibody-dependent cell-mediated cytotoxicity, improved the anti-MM response for all subsets and degranulation of the KIR-NKG2A- "unlicensed" subset was comparable to KIR+ or NKG2A+ licensed subsets. This demonstrates that with potent activation, all subsets can contribute to tumor clearance. Additionally, subsets expressing KIRs mismatched with the HLA ligands on the target cell had the highest level of activation in response to MM cell lines as well as against primary MM. Our current study demonstrated that if NK cells are sufficiently activated, e.g., via cytokine or antibody activation, the (co-)expression of NKG2A receptor may not necessarily be a disadvantage for NK cell-based therapy. PMID- 29988377 TI - GlnR-Mediated Regulation of Short-Chain Fatty Acid Assimilation in Mycobacterium smegmatis. AB - Assimilation of short-chain fatty acids (SCFAs) plays an important role in the survival and lipid biosynthesis of Mycobacteria. However, regulation of this process has not been thoroughly described. In the present work, we demonstrate that GlnR as a well-known nitrogen-sensing regulator transcriptionally modulates the AMP-forming propionyl-CoA synthetase (MsPrpE), and acetyl-CoA synthetases (MsAcs) is associated with SCFAs assimilation in Mycobacterium smegmatis, a model Mycobacterium. GlnR can directly activate the expression of MsprpE and Msacs by binding to their promoter regions based upon sensed nitrogen starvation in the host. Moreover, GlnR can activate the expression of lysine acetyltransferase encoding Mspat, which significantly decreases the activity of MsPrpE and MsAcs through increased acylation. Next, growth curves and resazurin assay show that GlnR can further regulate the growth of M. smegmatis on different SCFAs to control the viability. These results demonstrate that GlnR-mediated regulation of SCFA assimilation in response to the change of nitrogen signal serves to control the survival of M. smegmatis. These findings provide insights into the survival and nutrient utilization mechanisms of Mycobacteria in their host, which may enable new strategies in drug discovery for the control of tuberculosis. PMID- 29988378 TI - Feasibility of Nitrogen Doped Ultrananocrystalline Diamond Microelectrodes for Electrophysiological Recording From Neural Tissue. AB - Neural prostheses that can monitor the physiological state of a subject are becoming clinically viable through improvements in the capacity to record from neural tissue. However, a significant limitation of current devices is that it is difficult to fabricate electrode arrays that have both high channel counts and the appropriate electrical properties required for neural recordings. In earlier work, we demonstrated nitrogen doped ultrananocrystalline diamond (N-UNCD) can provide efficacious electrical stimulation of neural tissue, with high charge injection capacity, surface stability and biocompatibility. In this work, we expand on this functionality to show that N-UNCD electrodes can also record from neural tissue owing to its low electrochemical impedance. We show that N-UNCD electrodes are highly flexible in their application, with successful recordings of action potentials from single neurons in an in vitro retina preparation, as well as local field potential responses from in vivo visual cortex tissue. Key properties of N-UNCD films, combined with scalability of electrode array fabrication with custom sizes for recording or stimulation along with integration through vertical interconnects to silicon based integrated circuits, may in future form the basis for the fabrication of versatile closed-loop neural prostheses that can both record and stimulate. PMID- 29988375 TI - Bacille Calmette-Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010-2017. AB - Bacille Calmette-Guerin (BCG) vaccine is widely used as a prevention strategy against tuberculosis. BCG is a live vaccine, usually given early in life in most countries. While safe to most recipients, it poses a risk to immunocompromised patients. Several primary immunodeficiency diseases (PIDD) have been classically associated with complications related to BCG vaccine. However, a number of new inborn errors of immunity have been described lately in which little is known about adverse reactions following BCG vaccination. The aim of this review is to summarize the existing data on BCG-related complications in patients diagnosed with PIDD described since 2010. When BCG vaccination status or complications were not specifically addressed in those manuscripts, we directly contacted the corresponding authors for further clarification. We also analyzed data on other mycobacterial infections in these patients. Based on our analysis, around 8% of patients with gain-of-function mutations in STAT1 had mycobacterial infections, including localized complications in 3 and disseminated disease in 4 out of 19 BCG-vaccinated patients. Localized BCG reactions were also frequent in activated PI3Kdelta syndrome type 1 (3/10) and type 2 (2/18) vaccinated children. Also, of note, no BCG-related complications have been described in either CTLA4 or LRBA protein-deficient patients; and not enough information on BCG-vaccinated NFKB1 or NFKB2-deficient patients was available to drive any conclusions about these diseases. Despite the high prevalence of environmental mycobacterial infections in GATA2-deficient patients, only one case of BCG reaction has been reported in a patient who developed disseminated disease. In conclusion, BCG complications could be expected in some particular, recently described PIDD and it remains a preventable risk factor for pediatric PIDD patients. PMID- 29988380 TI - Kainate Receptors: Role in Epilepsy. AB - Kainate (KA) is a potent neurotoxin that has been widely used experimentally to induce acute brain seizures and, after repetitive treatments, as a chronic model of temporal lobe epilepsy (TLE), with similar features to those observed in human patients with TLE. However, whether KA activates KA receptors (KARs) as an agonist to mediate the induction of acute seizures and/or the chronic phase of epilepsy, or whether epileptogenic effects of the neurotoxin are indirect and/or mediated by other types of receptors, has yet to be satisfactorily elucidated. Positing a direct involvement of KARs in acute seizures induction, as well as a direct pathophysiological role of KARs in the chronic phase of TLE, recent studies have examined the specific subunit compositions of KARs that might underly epileptogenesis. In the present mini-review, we discuss the use of KA as a convulsant in the experimental models of acute seizures of TLE, and consider the involvement of KARs, their subunit composition and the mode of action in KAR mediated epilepsy. In acute models, evidence points to epileptogenesis being precipitated by an overall depression of interneuron GABAergic transmission mediated by GluK1 containing KARs. On glutamatergic principal cell in the hippocampus, GluK2-containing KARs regulate post-synaptic excitability and susceptibility to KA-mediated epileptogenesis. In chronic models, a role GluK2 containing KARs in the hippocampal CA3 region provokes limbic seizures. Also observed in the hippocampus, is a 'reactive plasticity', where MF sprouting is seen with target granule cells at aberrant synapses recruiting de novo GluR2/GluR5 heteromeric KARs. Finally, in human epilepsy and animal models, astrocytic expression of GluK1, 2, 4, and 5 is reported. PMID- 29988381 TI - Anti-Allergic Inflammatory Activity of Interleukin-37 Is Mediated by Novel Signaling Cascades in Human Eosinophils. AB - IL-1 family regulatory cytokine IL-37b can suppress innate immunity and inflammatory activity in inflammatory diseases. In this study, IL-37b showed remarkable in vitro suppression of inflammatory tumor necrosis factor-alpha, IL 1beta, IL-6, CCL2, and CXCL8 production in the coculture of human primary eosinophils and human bronchial epithelial BEAS-2B cells with the stimulation of bacterial toll-like receptor-2 ligand peptidoglycan, while antagonizing the activation of intracellular nuclear factor-kappaB, PI3K-Akt, extracellular signal regulated kinase 1/2, and suppressing the gene transcription of allergic inflammation-related PYCARD, S100A9, and CAMP as demonstrated by flow cytometry, RNA-sequencing, and bioinformatics. Results therefore elucidated the novel anti inflammation-related molecular mechanisms mediated by IL-37b. Using the house dust mite (HDM)-induced humanized asthmatic NOD/SCID mice for preclinical study, intravenous administration of IL-37b restored the normal plasma levels of eosinophil activators CCL11 and IL-5, suppressed the elevated concentrations of Th2 and asthma-related cytokines IL-4, IL-6, and IL-13 and inflammatory IL-17, CCL5, and CCL11 in lung homogenate of asthmatic mice. Histopathological results of lung tissue illustrated that IL-37b could mitigate the enhanced mucus, eosinophil infiltration, thickened airway wall, and goblet cells. Together with similar findings using the ovalbumin- and HDM-induced allergic asthmatic mice further validated the therapeutic potential of IL-37b in allergic asthma. The above results illustrate the novel IL-37-mediated regulation of intracellular inflammation mechanism linking bacterial infection and the activation of human eosinophils and confirm the in vivo anti-inflammatory activity of IL-37b on human allergic asthma. PMID- 29988383 TI - The Expression of Uncoupling Protein 3 Coincides With the Fatty Acid Oxidation Type of Metabolism in Adult Murine Heart. AB - The involvement of mitochondrial uncoupling proteins 2 and 3 in the pathogenesis of cardiovascular diseases is widely acknowledged. However, contradictory reports show that the functions of UCP2/UCP3 are still disputed. We have previously described that UCP2 is highly abundant in cells that rely on glycolysis, such as stem, cancer and activated immune cells. In contrast, high amounts of UCP3 are present in brown adipose tissue, followed by heart and skeletal muscles - all known to metabolize fatty acids (FA) to a high extent. Using two different models - mouse embryonic stem cell (mESC) differentiation to cardiomyocytes (CM) and murine heart at different developmental stages - we now tested the concept that the expression ratio between UCP2 and UCP3 indicates the metabolism type in CM. Our results revealed the tight correlation between UCP3 abundance, expression of mitochondrial fatty acid oxidation (FAO) markers and presence of multiple connections between mitochondria and lipid droplets. We further demonstrated that the time course of UCP3 expression neither coincided with the onset of the electrical activity in CM, derived from mESC, nor with the expression of respiratory chain proteins, the observation which rendered protein participation in ROS regulation unlikely. The present data imply that UCP3 may facilitate FAO by transporting FAs into mitochondria. In contrast, UCP2 was highly abundant at early stages of heart development and in mESC. Understanding, that the expression patterns of UCP3 and UCP2 in heart during development reflect the type of the cell metabolism is key to the uncovering their different functions. Their expression ratio may be an important diagnostic criterion for the degree of CM differentiation and/or severity of a heart failure. PMID- 29988384 TI - Successful Cardiopulmonary Resuscitation in a Sevoflurane Anaesthetized Horse That Suffered Cardiac Arrest at Recovery. AB - A 17-year-old mare undergoing dental surgery suffered a cardiac arrest while being transferred from the surgical theatre to the recovery box. This complication was diagnosed early, thus allowing a prompt start to the cardiopulmonary resuscitation maneuvers. External thoracic compressions, intermittent positive pressure ventilation, and adrenaline administration were at the core of this successful resuscitation. Although it was not possible to confirm the cause of cardiac arrest in this horse, a Bezold-Jarisch reflex due to potential decrease on venous return because of postural change and drug interactions was hypothesized. Based on this report, it appears advisable to smoothly change the position of anaesthetized patient; furthermore, the administration of drugs affecting cardiovascular hemodynamics or sympatho-vagal balance to animals while changing their recumbency should be avoided. PMID- 29988379 TI - Streptococcus pneumoniae's Virulence and Host Immunity: Aging, Diagnostics, and Prevention. AB - Streptococcus pneumoniae is an infectious pathogen responsible for millions of deaths worldwide. Diseases caused by this bacterium are classified as pneumococcal diseases. This pathogen colonizes the nasopharynx of its host asymptomatically, but overtime can migrate to sterile tissues and organs and cause infections. Pneumonia is currently the most common pneumococcal disease. Pneumococcal pneumonia is a global health concern and vastly affects children under the age of five as well as the elderly and individuals with pre-existing health conditions. S. pneumoniae has a large selection of virulence factors that promote adherence, invasion of host tissues, and allows it to escape host immune defenses. A clear understanding of S. pneumoniae's virulence factors, host immune responses, and examining the current techniques available for diagnosis, treatment, and disease prevention will allow for better regulation of the pathogen and its diseases. In terms of disease prevention, other considerations must include the effects of age on responses to vaccines and vaccine efficacy. Ongoing work aims to improve on current vaccination paradigms by including the use of serotype-independent vaccines, such as protein and whole cell vaccines. Extending our knowledge of the biology of, and associated host immune response to S. pneumoniae is paramount for our improvement of pneumococcal disease diagnosis, treatment, and improvement of patient outlook. PMID- 29988382 TI - Diverse Impacts of HIV Latency-Reversing Agents on CD8+ T-Cell Function: Implications for HIV Cure. AB - Antiretroviral therapy regimens durably suppress HIV replication, but do not cure infection. This is partially attributable to the persistence of long-lived pools of resting CD4+ T-cells harboring latent replication-competent virus. Substantial clinical and pre-clinical research is currently being directed at purging this viral reservoir by combining pharmacological latency reversal with immune effectors, such as HIV-specific CD8+ T-cells, capable of eliminating reactivated targets-the so-called "shock-and-kill" approach. However, several studies indicate that the latency-reversing agents (LRAs) may affect CD8+ T-cell function. The current review aims to frame recent advances, and ongoing challenges, in implementing "shock-and-kill" strategies from the perspective of effectively harnessing CD8+ T-cells. We review and contextualize findings indicating that LRAs often have unintended impacts on CD8+ T-cell function, both detrimental and beneficial. We identify and attempt to bridge the gap between viral reactivation, as measured by the detection of RNA or protein, and bona fide presentation of viral antigens to CD8+ T-cells. Finally, we highlight factors on the effector (CD8+) and target (CD4+) cell sides that contribute to whether or not infected-cell recognition results in killing/elimination. These perspectives may contribute to an integrated view of "shock-and-kill," with implications for therapeutic development. PMID- 29988385 TI - Role of Interleukin-38 in Chronic Inflammatory Diseases: A Comprehensive Review. AB - Interleukin (IL)-38 is the newest member of the IL-1 family. It can bind to several receptors, regulate the generation, function of inflammatory cytokines through the downstream signaling pathways. IL-38 is expressed in several tissues, such as placenta, heart, and brain. It is involved in a wide variety of diseases, including chronic inflammatory diseases. In this review, we discuss the expression and biological functions of IL-38, especially the role in rheumatic autoimmune diseases. Collection of the information may improve the understanding of IL-38, and may give potential for theoretical basis for clinical trials and drug development in the future. PMID- 29988386 TI - The distribution and host-association of a haemoparasite of damselfishes (Pomacentridae) from the eastern Caribbean based on a combination of morphology and 18S rDNA sequences. AB - Coral reefs harbor the greatest biodiversity per unit area of any ecosystem on earth. While parasites constitute the majority of this biodiversity, they remain poorly studied due to the cryptic nature of many parasites and the lack of appropriate training among coral reef ecologists. Damselfishes (Pomacentridae) are among the most abundant and diverse fishes on coral reefs. In a recent study of blood parasites of Caribbean reef fishes, the first ever apicomplexan blood parasites discovered in damselfishes were reported for members of the genus Stegastes. While these blood parasites were characterized as "Haemohormidium like", they appear to be distinct from any other known apicomplexan. In this study, we examined host associations, geographic distributions, and provide further insights on the phylogenetic affiliation of this parasite. A combination of morphological characteristics and 18S rDNA sequences suggest that this parasite may be the same species at multiple sites and occurs from the southern to the northern extreme of the eastern Caribbean, although it appears rare in the north. At present it appears to be limited to members of the genus Stegastes and infects all life history stages. It is most common in benthophagous species that occur in high population densities and appears basal to a major monophyletic clade containing species of coccidia, distinct from the Piroplasmida, the order to which Haemohormidium spp. have been assigned. These findings suggest a possible fecal-oral mode of transmission. PMID- 29988387 TI - Establishing Monitored Premises Status for Continuity of Business Permits During an HPAI Outbreak. AB - Recent experiences with avian influenza outbreaks in poultry in the United States have tested biosecurity protocols and outbreak management strategies. During an outbreak, regulatory officials managing the emergency response need to make timely decisions in order to achieve disease control and eradication goals while simultaneously decreasing the unintended consequences of the response. To move susceptible animals or animal products out of a disease Control Area via a secure food supply continuity of business (COB) permit without the risk of expanding a disease outbreak, premises must be designated as Monitored Premises (MP) by regulatory officials. The experience of and lessons learned from the 2014 to 2015 highly pathogenic avian influenza (HPAI) outbreak have resulted in defined criteria necessary to establish MP status during an HPAI outbreak and highlighted the need for a clear method to determine that those criteria have been met. Establishing MP status is different from an epidemiologic investigation, though they both require analyses of how avian influenza virus may enter poultry premises and can take significant staff time. MP status of premises seeking to move animals or animal products must be continuously re-evaluated as Infected Premises status, and resulting epidemiologic contacts, can rapidly change during an outbreak. We present here a questionnaire to establish MP status, designed to be initially completed by industry representatives in an attempt to streamline processes and conserve resources. During an outbreak, the MP status questionnaire is an essential risk-based management tool used to establish premises status, as part of operationalizing permitted movement to support COB. PMID- 29988388 TI - Spatial Expression and Functional Analysis of Casparian Strip Regulatory Genes in Endodermis Reveals the Conserved Mechanism in Tomato. AB - Casparian strip (CS) is an impregnation of endodermal cell wall, forming an apoplastic diffusion barrier which forces the symplastic and selective transport of nutrients across endodermis. This extracellular structure can be found in the roots of all higher plants and is thought to provide the protection of vascular tissues. In Arabidopsis, a genetic toolbox regulating the formation of Casparian strips has emerged recently. However, Arabidopsis has the stereotypical root which is much simpler than most other plant species. To understand the Casparian strip formation in a more complex root system, we examined CS regulatory pathways in tomato. Our results reveal a spatiotemporally conserved expression pattern of most essential components of CS machinery in tomato. Further functional analyses verify the role of homologous CS genes in the Casparian strip formation in tomato, indicating the functional conservation of CS regulatory cascade in tomato. PMID- 29988389 TI - Influence of the Potential Carbon Sources for Field Denitrification Beds on Their Microbial Diversity and the Fate of Carbon and Nitrate. AB - Nitrogen based eutrophication of ecosystems is a global problem that gains momentum through a growing global population. The water quality of nitrate or ammonium contaminated rivers and streams cannot always be amended in centralized waste water treatment plants. Field denitrification plants were suggested as a solution for a decentralized reduction of nitrate to dinitrogen. Here, stable and cheap organic carbon sources serve as carbon and electron source for a microbial community. Still, our knowledge on the impact of these organic carbon sources on the development and diversity of these cultures is sparse. Moreover, the stability of these denitrification plants at different nitrate loading rates especially in the higher concentration regime were not tested so far. In this study, we compare the fate of carbon and nitrogen as well as the microbial community of wood pellet (WP) (pressed sawdust), wheat straw, and wood chips (WC) based laboratory denitrification reactors. Our study reveals that the diversity and composition of the community is strongly dependent on the carbon source. The diversity decreased in the order WC, wheat straw, and WPs. The three reactor types were characterized by different nitrate reduction kinetics and were affected differently by high nitrate loading rates. While the nitrate reduction kinetics were negatively influenced by higher nitrate doses in the wheat straw reactors, WPs as carbon source sustained the opposite trend and WC lead to an overall slower but concentration independent nitrate reduction rate. Counterintuitively, the concentration of soluble organic carbon was highest in the WP reactors but methane emission was not detectable. This is corroborated by the microbial diversity data in which methanogenic species were highly underrepresented compared to the other two reactor types. In contrary, the methane emissions in the wheat straw and WC reactors were comparable to each other. PMID- 29988391 TI - Inducible T-Cell Co-Stimulator Impacts Chronic Graft-Versus-Host Disease by Regulating Both Pathogenic and Regulatory T Cells. AB - The incidence of chronic graft-versus-host disease (cGVHD) is on the rise and still the major cause of morbidity and mortality among patients after allogeneic hematopoietic stem cell transplantation (HCT). Both donor T and B cells contribute to the pathogenesis of cGVHD. Inducible T-cell co-stimulator (ICOS), a potent co-stimulatory receptor, plays a key role in T-cell activation and differentiation. Yet, how ICOS regulates the development of cGVHD is not well understood. Here, we investigated the role of ICOS in cGVHD pathogenesis using mice with germline or regulatory T cell (Treg)-specific ICOS deficiency. The recipients of ICOS-/- donor grafts had reduced cGVHD compared with wild-type controls. In recipients of ICOS-/- donor grafts, we observed significant reductions in donor T follicular helper (Tfh), Th17, germinal center B-cell, and plasma cell differentiation, coupled with lower antibody production. Interestingly, Tregs, including follicular regulatory T (Tfr) cells, were also impaired in the absence of ICOS. Using ICOS conditional knockout specific for Foxp3+ cells, we found that ICOS was indispensable for optimal survival and homeostasis of induced Tregs during cGVHD. Furthermore, administration of anti ICOS alleviated cGVHD severity via suppressing T effector cells without affecting Treg generation. Taken together, ICOS promotes T- and B-cell activation and differentiation, which can promote cGVHD development; however, ICOS is critical for the survival and homeostasis of iTregs, which can suppress cGVHD. Hence, ICOS balances the development of cGVHD and could offer a potential target after allo HCT in the clinic. PMID- 29988390 TI - Peculiarities of Precocious Puberty in Boys and Girls With McCune-Albright Syndrome. AB - McCune-Albright Syndrome (MAS; OMIM # 174800) is a rare, sporadic disease caused by a post-zygotic, activating mutation in the guanine-nucleotide binding protein alpha-subunit (GNAS1) gene. MAS is characterized by the clinical triad of polyostotic fibrous dysplasia of bone, cafe-au-lait skin pigmentation and peripheral precocious puberty. However, clinical presentation is highly variable depending on mosaic tissue distribution of mutant-bearing cells. Precocious puberty is the most common endocrine manifestation of MAS and is often the presenting, and sometimes the only, clinical sign of MAS. Due to the very low prevalence of MAS, data on course of precocious puberty, effectiveness of treatments and gonadal function during post-pubertal period are lacking. Our knowledge on this issue derives essentially from case reports and small cohorts of patients. The aim of this review is to report all available literature data on clinical aspects, therapeutic management and outcomes of precocious puberty in children with MAS. A systematic research was carried out through MEDLINE via PubMed, EMBASE, Web of Science, Semantic Scholar, Cochrane Library. PMID- 29988392 TI - Epidermal T Cell Dendrites Serve as Conduits for Bidirectional Trafficking of Granular Cargo. AB - Dendritic epidermal T cells (DETCs) represent a prototypical lineage of intraepithelial gammadelta T cells that participate in the maintenance of body barrier homeostasis. Unlike classical T cells, DETCs do not recirculate and they remain persistently activated through their T cell receptors (TCR) at steady state, i.e., in absence of infection or tissue wounding. The steady state TCR signals sustain the formation of immunological synapse-like phosphotyrosine-rich aggregates located on projections (PALPs) which act to anchor and polarize DETC's long cellular projections toward the apical epidermis while the cell bodies reside in the basal layers. The PALPs are known to contain pre-synaptic accumulations of TCR-containing and lysosomal granules, but how this cargo accumulates there remains unclear. Here, we combined anti-Vgamma5 TCR, cholera toxin subunit B (CTB), and LysoTracker (LT)-based intravital labeling of intracellular granules, with high resolution dynamic microscopy and fluorescence recovery after photobleaching (FRAP) to characterize the steady state composition and transport of DETC granules in steady state epidermis. Intradermal fluorescent Vgamma5 antibody decorated DETCs without causing cellular depletion, dendrite mobilization or rounding up and became slowly internalized over 48 h into intracellular granules that, after 6 days, colocalized with LAMP-1 and less so with LT or early endosomal antigen-1. Intradermal CTB was likewise internalized predominantly by DETCs in epidermis, labeling a partly overlapping set of largely LAMP-1+ intracellular granules. These as well as LT-labeled granules readily moved into newly forming dendrites and accumulated at the apical endings. FRAP and spatiotemporal tracking showed that the inside tubular lengths of DETC cellular projections supported dynamic trafficking of lysosomal cargo toward and away from the PALPs, including internalized TCR and lipid raft component ganglioside GM1 (labeled with CTB). By contrast, the rate of GM1 granules transport through comparable dendrites of non-DETCs was twice slower. Our observations suggest that DETCs use chronic TCR activation to establish a polarized conduit system for long-range trans-epithelial transport aimed to accumulate mature lysosomes at the barrier-forming apical epidermis. The biological strategy behind the steady state lysosome polarization by DETCs remains to be uncovered. PMID- 29988393 TI - Implication of G Protein-Coupled Receptor 43 in Intestinal Inflammation: A Mini Review. AB - Short chain fatty acids (SCFAs, e.g., acetate, propionate, and butyrate) are a subset of fatty acids that are produced by gut microbiota during the fermentation of dietary fiber. They modulate different processes in the gastrointestinal tract and play various positive roles in mediating the intestinal health. Most beneficial roles of SCFAs in the gastrointestinal tract are mediated by directly activating its receptor, G protein-coupled receptor 43 (GPR43, also known as FFAR2). Various recent studies have demonstrated the role of GPR43 in intestinal inflammatory diseases, such as inflammatory bowel diseases. These SCFAs-mediated regulations of intestinal health are associated with neutrophil chemotaxis, T cell differentiation, activation, and subsequent cytokines production. Therefore, GPR43 could potentially be a drug target for intestinal inflammatory diseases. In this review, we review the current knowledge on the regulatory mechanisms associated with GPR43 in intestinal inflammation. The role of GPR43-mediated regulation of antibody responses is also discussed. PMID- 29988394 TI - Candida-Reactive T Cells for the Diagnosis of Invasive Candida Infection-A Prospective Pilot Study. AB - Background: Blood or tissue culture or histology prove invasive Candida infection, but long time to result, limited feasibility and sensitivity call for new approaches. In this pilot project, we describe the diagnostic potential of quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes in blood of patients with invasive Candida infection. Methods: We used flow cytometry quantitating Candida-reactive, CD4/CD69/CD154 positive lymphocytes from peripheral blood of patients with invasive Candida infection, from patients at risk and healthy volunteers as controls. Results: Elevated levels of Candida reactive lymphocytes were measured in 13 patients with proven invasive Candida infection and in one patient with probable hepatosplenic candidiasis. Results of three candidemia patients were uninterpretable due to autofluorescence of samples. Twelve of 13 patients had Candida identified to species level by conventional methods, and T cell reactivity correctly identified Candida species in 10 of 12 patients. Nine hematological high-risk patients and 14 healthy donors had no elevated Candida-reactive T cell counts. Conclusions: This Candida reactive lymphocyte assay correctly identified the majority of patients with invasive Candida infection and the respective species. Our assay has the potential to support diagnosis of invasive Candida infection to species level and to facilitate tailored treatment even when biopsies are contraindicated or cultures remain negative. PMID- 29988395 TI - Overexpression of Outer Membrane Protein X (OmpX) Compensates for the Effect of TolC Inactivation on Biofilm Formation and Curli Production in Extraintestinal Pathogenic Escherichia coli (ExPEC). AB - Our previous study showed that the inactivation of the efflux pump TolC could abolish biofilm formation and curli production of extraintestinal pathogenic Escherichia coli (ExPEC) strain PPECC42 under hyper-osmotic conditions. In this study we investigated the role of OmpX in biofilm formation and curli production of ExPEC PPECC42. Our data showed that OmpX disruption or overexpression didn't significantly affect the biofilm formation and curli production of the wild-type strain. However, in the tolC-deleted mutant, overexpressing OmpX suppressed the effect of TolC inactivation on ExPEC biofilm formation and curli production under hyper-osmotic growth conditions. Real-time qRT-PCR confirmed that OmpX overexpression affected curli production by regulating the transcription of the curli biosynthesis-related genes in the DeltatolC strain. Our findings suggest that OmpX is involved in biofilm formation and curli production. PMID- 29988396 TI - Impact of Intestinal Peptides on the Enteric Nervous System: Novel Approaches to Control Glucose Metabolism and Food Intake. AB - The gut is one of the most important sources of bioactive peptides in the body. In addition to their direct actions in the brain and/or peripheral tissues, the intestinal peptides can also have an impact on enteric nervous neurons. By modifying the endogenousproduction of these peptides, one may expect modify the "local" physiology such as glucose absorption, but also could have a "global" action via the gut-brain axis. Due to the various origins of gut peptides (i.e., nutrients, intestinal wall, gut microbiota) and the heterogeneity of enteric neurons population, the potential physiological parameters control by the interaction between the two partners are multiple. In this review, we will exclusively focus on the role of enteric nervous system as a potential target of gut peptides to control glucose metabolism and food intake. Potential therapeutic strategies based on per os administration of gut peptides to treat type 2 diabetes will be described. PMID- 29988397 TI - Differences in Brain Structure and Function Among Yoga Practitioners and Controls. AB - Background: Yoga is a mind-body based physical activity that has demonstrated a variety of physiological, psychological and cognitive health benefits. Although yoga practice has shown to improve cognitive performance, few studies have examined the underlying neurological correlates. Objective: The current study aimed to determine the differences in gray matter volume of the hippocampus, thalamus and caudate nucleus and brain activation during the Sternberg working memory task. Method: Participants were 13 experienced yoga practitioners (mean age = 35.8), defined as having more than 3 years of regular yoga practice, and 13 age- and sex-matched controls (mean age = 35.7). All participants completed a 6 min walk test to assess fitness, psychosocial and demographic questionnaires; and underwent magnetic resonance imaging to assess gray matter volume and brain activation. Results: There were no group differences on demographic measures of income, education and on estimated VO2max or physical activity levels. Gray matter volume differences were observed in the left hippocampus, showing greater volume in experienced yoga practitioners compared to controls (p = 0.017). The functional MRI results revealed less activation in the dorsolateral prefrontal cortex in yoga practitioners compared to controls during the encoding phase of the Sternberg task (p < 0.05). Reaction time and accuracy on the task did not differ between the groups. Conclusions: Our results suggest an association between regular long-term yoga practice and differential structure and function of specific brain regions involved in executive function, specifically working memory, which has previously shown to improve with yoga practice. Future studies need to examine intervention effects of yoga and explore its potential to maintain and improve cognitive health across the lifespan through longitudinal and intervention studies. PMID- 29988398 TI - CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-alpha. AB - Juvenile dermatomyositis (JDM) is a rare form of childhood autoimmune myositis that presents with proximal muscle weakness and skin rash. B cells are strongly implicated in the pathogenesis of the disease, but the underlying mechanisms are unknown. Therefore, the main objective of our study was to investigate mechanisms driving B cell lymphocytosis and define pathological features of B cells in JDM patients. Patients were recruited through the UK JDM Cohort and Biomarker study. Peripheral blood B cell subpopulations were immunophenotyped by flow cytometry. The results identified that immature transitional B cells were significantly expanded in active JDM, actively dividing, and correlated positively with disease activity. Protein and RNAseq analysis revealed high interferon alpha (IFNalpha) and TLR7-pathway signatures pre-treatment. Stimulation of B cells through TLR7/8 promoted both IL-10 and IL-6 production in controls but failed to induce IL-10 in JDM patient cells. Interrogation of the CD40-CD40L pathway (known to induce B cell IL-10 and IL-6) revealed similar expression of IL-10 and IL-6 in B cells cultured with CD40L from both JDM patients and controls. In conclusion, JDM patients with active disease have a significantly expanded immature transitional B cell population which correlated with the type I IFN signature. Activation through TLR7 and IFNalpha may drive the expansion of immature transitional B cells in JDM and skew the cells toward a pro-inflammatory phenotype. PMID- 29988399 TI - Anticonvulsants for Psychiatric Disorders in Children and Adolescents: A Systematic Review of Their Efficacy. AB - Aim: Anticonvulsant medications are frequently used in clinical practice to treat psychiatric disorders in children and adolescents, but the evidence for their efficacy is uncertain. We conducted a systematic review of published randomized controlled trials (RCT) that assessed the psychiatric benefit of anticonvulsants in patients under 18 years of age. Method: The Medline, Scopus, Web of Science, and ClinicalTrials.gov databases were systematically searched for peer-reviewed primary publications of RCTs with a minimum of 10 patients per treatment arm through December 2017. Results: Out of 355 identified non-duplicative publications, 24 met the inclusion criteria. Most RCTs were to treat bipolar disorder (n = 12) or manage recurrent aggression (n = 9). Few (n = 3) had both a multisite design and adequate statistical power. Valproate was the most frequently studied anticonvulsant (n = 15). Out of three placebo-controlled RCTs of valproate in bipolar disorder, none showed efficacy. In four RCTs, valproate was inferior to the antipsychotic risperidone. In several small, single-site RCTs, valproate and sulthiame were better than placebo for the management of recurrent aggression. Conclusions: Currently available RCTs do not support the efficacy of anticonvulsants as mood stabilizers in children. There is some preliminary evidence from small RCTs of the efficacy of some anticonvulsants in the control of aggression and behavioral dyscontrol in conduct disorder, autism, and intellectual disability. PMID- 29988400 TI - 15N Natural Abundance Evidences a Better Use of N Sources by Late Nitrogen Application in Bread Wheat. AB - This work explores whether the natural abundance of N isotopes technique could be used to understand the movement of N within the plant during vegetative and grain filling phases in wheat crop (Triticum aestivum L.) under different fertilizer management strategies. We focus on the effect of splitting the same N dose through a third late amendment at flag leaf stage (GS37) under humid Mediterranean conditions, where high spring precipitations can guarantee the incorporation of the lately applied N to the soil-plant system in an efficient way. The results are discussed in the context of agronomic parameters as N content, grain yield and quality, and show that further splitting the same N dose improves the wheat quality and induces a better nitrogen use efficiency. The nitrogen isotopic natural abundance technique shows that N remobilization is a discriminating process that leads to an impoverishment in 15N of senescent leaves and grain itself. This technique also reflects the more efficient use of N resources (fertilizer and native soil-N) when plants receive a late N amendment. PMID- 29988401 TI - Rolling Motion Along an Incline: Visual Sensitivity to the Relation Between Acceleration and Slope. AB - People easily intercept a ball rolling down an incline, despite its acceleration varies with the slope in a complex manner. Apparently, however, they are poor at detecting anomalies when asked to judge artificial animations of descending motion. Since the perceptual deficiencies have been reported in studies involving a limited visual context, here we tested the hypothesis that judgments of naturalness of rolling motion are consistent with physics when the visual scene incorporates sufficient cues about environmental reference and metric scale, roughly comparable to those present when intercepting a ball. Participants viewed a sphere rolling down an incline located in the median sagittal plane, presented in 3D wide-field virtual reality. In different experiments, either the slope of the plane or the sphere acceleration were changed in arbitrary combinations, resulting in a kinematics that was either consistent or inconsistent with physics. In Experiment 1 (slope adjustment), participants were asked to modify the slope angle until the resulting motion looked natural for a given ball acceleration. In Experiment 2 (acceleration adjustment), instead, they were asked to modify the acceleration until the motion on a given slope looked natural. No feedback about performance was provided. For both experiments, we found that participants were rather accurate at finding the match between slope angle and ball acceleration congruent with physics, but there was a systematic effect of the initial conditions: accuracy was higher when the participants started the exploration from the combination of slope and acceleration corresponding to the congruent conditions than when they started far away from the congruent conditions. In Experiment 3, participants modified the slope angle based on an adaptive staircase, but the target never coincided with the starting condition. Here we found a generally accurate performance, irrespective of the target slope. We suggest that, provided the visual scene includes sufficient cues about environmental reference and metric scale, joint processing of slope and acceleration may facilitate the detection of natural motion. Perception of rolling motion may rely on the kind of approximate, probabilistic simulations of Newtonian mechanics that have previously been called into play to explain complex inferences in rich visual scenes. PMID- 29988402 TI - Mycobacterium smegmatis Induces Neurite Outgrowth and Differentiation in an Autophagy-Independent Manner in PC12 and C17.2 Cells. AB - Both pathogenic and non-pathogenic Mycobacteria can induce the differentiation of immune cells into dendritic cells (DC) or DC-like cells. In addition, pathogenic Mycobacteria is found to stimulate cell differentiation in the nerves system. Whether non-pathogenic Mycobacteria interacts with nerve cells remains unknown. In this study, we found that co-incubation with fast-growing Mycobacteria smegmatis induced neuron-like morphological changes of PC12 and C17.2 cells. Moreover, the M. smegmatis culture supernatant which was ultrafiltrated through a membrane with a 10 kDa cut-off, induced neurite outgrowth and differentiation in an autophagy-independent pathway in PC12 and C17.2 cells. Further analysis showed that IFN-gamma production and activation of the PI3K-Akt signaling pathway were involved in the neural differentiation. In conclusion, our finding demonstrated that non-pathogenic M. smegmatis was able to promote neuronal differentiation by its extracellular proteins, which might provide a novel therapeutic strategy for the treatment of neurodegenerative disorders. PMID- 29988403 TI - Flavonoids as a Natural Treatment Against Entamoeba histolytica. AB - Over the past 20 years, gastrointestinal infections in developing countries have been a serious health problem and are the second leading cause of morbidity among all age groups. Among pathogenic protozoans that cause diarrheal disease, the parasite Entamoeba histolytica produces amebic colitis as well as the most frequent extra-intestinal lesion, an amebic liver abscess (ALA). Usually, intestinal amebiasis and ALA are treated with synthetic chemical compounds (iodoquinol, paromomycin, diloxanide furoate, and nitroimidazoles). Metronidazole is the most common treatment for amebiasis. Although the efficacy of nitroimidazoles in killing amebas is known, the potential resistance of E. histolytica to this treatment is a concern. In addition, controversial studies have reported that metronidazole could induce mutagenic effects and cerebral toxicity. Therefore, natural and safe alternative drugs against this parasite are needed. Flavonoids are natural polyphenolic compounds. Flavonoids depend on malonyl-CoA and phenylalanine to be synthesized. Several flavonoids have anti oxidant and anti-microbial properties. Since the 1990s, several works have focused on the identification and purification of different flavonoids with amebicidal effects, such as, -(-)epicatechin, kaempferol, and quercetin. In this review, we investigated the effects of flavonoids that have potential amebicidal activity and that can be used as complementary and/or specific therapeutic strategies against E. histolytica trophozoites. Interestingly, it was found that these natural compounds can induce morphological changes in the amebas, such as chromatin condensation and cytoskeletal protein re-organization, as well as the upregulation and downregulation of fructose-1,6-bisphosphate aldolase, glyceraldehyde-phosphate dehydrogenase, and pyruvate:ferredoxin oxidoreductase (enzymes of the glycolytic pathway). Although the specific molecular targets, bioavailability, route of administration, and doses of some of these natural compounds need to be determined, flavonoids represent a very promising and innocuous strategy that should be considered for use against E. histolytica in the era of microbial drug resistance. PMID- 29988405 TI - When is an herbivore not an herbivore? Detritivory facilitates herbivory in a freshwater system. AB - Herbivory is thought to be an inefficient diet, but it independently evolved from carnivorous ancestors in many metazoan groups, suggesting that plant-eating is adaptive in some circumstances. In this study, we tested two hypotheses to explain the adaptive evolution of herbivory: (i) the Heterotroph Facilitation hypothesis (herbivory is adaptive because herbivores supplement their diets with heterotrophic microbes); and (ii) the Lipid Allocation hypothesis (herbivory is adaptive because algae, which have high lipid concentrations, are nutritionally similar to carnivory). We tested these hypotheses using enclosure cages placed in the Everglades and stocked with Sailfin Mollies (Poecilia latipinna), a native herbivore. Using shading and phosphorus addition (P), we manipulated the heterotrophic microbe and lipid composition of colonizing epiphyton and examined the effects of varying food quality on Sailfin Molly life history. Epiphyton grown in "shade only" conditions had a 55% increase in bacterial fatty acids and 34% lower ratios of saturated + monounsaturated to polyunsaturated fatty acids relative to the other treatments. Ratio of autotroph to heterotroph biovolume varied throughout the experiment, with a 697% increase at 3 weeks and 98% decrease at 6 weeks compared to the other treatments. Gut contents revealed that fish fed selectively on epiphyton to compensate for apparent deficiencies in the available food. Fish raised in "shade only" cages experienced the highest survival, which was best explained by autotrophic biovolume and algal- and bacterial-derived fatty acids at 3 weeks (2-6* more likely than alternative models with ?AICc > 2.00), and by percentage of bacterial fatty acids in the diet at 6 weeks (3-8* more likely than alternative models with ?AICc > 2.00). There were no differences in fish growth among treatments. Autotrophic lipids play a role in early fish life history, but we did not find these to be the best predictors of life history later in the juvenile period. Instead, heterotrophic lipids facilitated the herbivorous diet and enhanced survival of juvenile fish in our experiment. Bacterial fatty acid content of the diet promoted herbivore survival, consistent with the Heterotroph Facilitation hypothesis. This is the first study to explicitly contrast Heterotrophic Facilitation and Lipid Allocation hypotheses for the adaptive evolution of herbivory in an aquatic system. PMID- 29988404 TI - Does Adjuvant Treatment With Ginkgo Biloba to Statins Have Additional Benefits in Patients With Dyslipidemia? AB - Objective: Ginkgo biloba are widely used alone or in combination with other lipid lowering agents in the treatment of dyslipidemia in China. We conducted this meta analysis to investigate whether adjuvant treatment with ginkgo biloba leaves to statins has incremental benefits in patients with dyslipidemia. Methods: Potential studies were searched from PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang database up to October 2017. Only randomized controlled trials (RCTs) comparing the efficacy and safety of ginkgo biloba leaves plus statins versus statins alone in patients with dyslipidemia were included. Results: Eight RCTs involving 664 patients were included. Compared with statins therapy alone, combination of statins and ginkgo biloba leaves therapy achieved greater reductions in triglycerides [mean difference (MD) -0.32 mmol/L; 95% confidence interval (CI) -0.43 to -0.20], total cholesterol (MD -0.61 mmol/L; 95% CI -0.90 to -0.33), or low-density lipoprotein cholesterol (LDL-C) (MD -0.32 mmol/L; 95% CI -0.48 to -0.16), and a greater increment in high-density lipoprotein cholesterol (MD 0.26 mmol/L; 95% CI 0.15 to 0.37). Subgroup analyses showed that ginkgo biloba leaves plus simvastatin appeared to achieve a greater reduction in serum levels of triglycerides, total cholesterol, and LDL-C than in combination with atorvastatin therapy. Conclusion: This meta-analysis suggests that adjuvant treatment with ginkgo biloba leaves appears to improve blood lipid parameters than statins therapy alone. More well designed RCTs are needed to investigate the benefits of the combination of statins and ginkgo biloba leaves. PMID- 29988406 TI - Male-biased dispersal and the potential impact of human-induced habitat modifications on the Neotropical bat Trachops cirrhosus. AB - Gene flow, maintained through natal dispersal and subsequent mating events, is one of the most important processes in both ecology and population genetics. Among mammalian populations, gene flow is strongly affected by a variety of factors, including the species' ability to disperse, and the composition of the environment which can limit dispersal. Information on dispersal patterns is thus crucial both for conservation management and for understanding the social system of a species. We used 16 polymorphic nuclear microsatellite loci in addition to mitochondrial DNA sequences (1.61 kbp) to analyse the population structure and the sex-specific pattern of natal dispersal in the frog-eating fringe-lipped bat, Trachops cirrhosus, in Central Panama. Our study revealed that-unlike most of the few other investigated Neotropical bats-gene flow in this species is mostly male mediated. Nevertheless, distinct genetic clusters occur in both sexes. In particular, the presence of genetic differentiation in the dataset only consisting of the dispersing sex (males) indicates that gene flow is impeded within our study area. Our data are in line with the Panama Canal in connection with the widening of the Rio Chagres during the canal construction acting as a recent barrier to gene flow. The sensitivity of T. cirrhosus to human-induced habitat modifications is further indicated by an extremely low capture success in highly fragmented areas. Taken together, our genetic and capture data provide evidence for this species to be classified as less mobile and thus vulnerable to habitat change, information that is important for conservation management. PMID- 29988407 TI - Benthic species of the Kerguelen Plateau show contrasting distribution shifts in response to environmental changes. AB - Marine life of the Southern Ocean has been facing environmental changes and the direct impact of human activities during the past decades. Benthic communities have particularly been affected by such changes although we only slowly understand the effect of environmental changes on species physiology, biogeography, and distribution. Species distribution models (SDM) can help explore species geographic responses to main environmental changes. In this work, we modeled the distribution of four echinoid species with contrasting ecological niches. Models developed for [2005-2012] were projected to different time periods, and the magnitude of distribution range shifts was assessed for recent past conditions [1955-1974] and for the future, under scenario RCP 8.5 for [2050 2099]. Our results suggest that species distribution shifts are expected to be more important in a near future compared to the past. The geographic response of species may vary between poleward shift, latitudinal reduction, and local extinction. Species with broad ecological niches and not limited by biogeographic barriers would be the least affected by environmental changes, in contrast to endemic species, restricted to coastal areas, which are predicted to be more sensitive. PMID- 29988408 TI - Regulation of Neurological Devices and Neurointerventional Endovascular Approaches for Acute Ischemic Stroke. AB - The United States Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) is charged with ensuring patients in the US have timely access to high-quality, safe, and effective medical devices of public health importance. Within CDRH, the Division of Neurological and Physical Medicine Devices reviews medical technologies that interface with the central and peripheral nervous system (neurotechnologies), including neurointerventional medical devices that are used in the treatment of stroke. Endovascular treatments have demonstrated recent advances in reaching the marketplace and providing more options for patients with acute ischemic stroke and intracranial aneurysms specifically. Depending upon the pathway chosen for regulatory approval, and the evidentiary standard for different regulatory pathways, neurotechnologies can have well-established safety and effectiveness profiles, varying degrees of scientific and clinical uncertainty regarding safety and effectiveness, or when a humanitarian use exists, need only demonstrate a probable benefit and safety to the patient so potentially life-saving treatments can reach the marketplace. Reperfusion therapies have had specific advances in the treatment of stroke patients that originally had limited or no treatment options and for preventative treatments in providing care to patients with intracranial aneurysms to avoid potentially more catastrophic outcomes. Collaboration in multiple forums and environments will be important to continue to foster the neurointerventional technology sector and positively impact clinical medicine, from diagnosing and treating a neurological disorder, to potentially altering the progression of disease, and in many ways, contemporary approved devices have brought a new sense of hope and optimism that serious and otherwise disabling neurological diseases can be treated and in many cases cured with modern therapy. We present here the scope of FDA's regulatory landscape for neurological devices and neurointerventional endovascular approaches for acute ischemic stroke; this is essential information for those seeking to successfully translate medical device neurotechnologies for patient and consumer use. PMID- 29988409 TI - A Protoplast Transient Expression System to Enable Molecular, Cellular, and Functional Studies in Phalaenopsis orchids. AB - The enigmatic nature of the specialized developmental programs of orchids has fascinated plant biologists for centuries. The recent releases of orchid genomes indicate that orchids possess new gene families and family expansions and contractions to regulate a diverse suite of developmental processes. However, the extremely long orchid life cycle and lack of molecular toolkit have hampered the advancement of orchid biology research. To overcome the technical difficulties and establish a platform for rapid gene regulation studies, in this study, we developed an efficient protoplast isolation and transient expression system for Phalaenopsis aphrodite. This protocol was successfully applied to protein subcellular localization and protein-protein interaction studies. Moreover, it was confirmed to be useful in delineating the PaE2F/PaDP-dependent cell cycle pathway and studying auxin response. In summary, the established orchid protoplast transient expression system provides a means to functionally characterize orchid genes at the molecular level allowing assessment of transcriptome responses to transgene expression and widening the scope of molecular studies in orchids. PMID- 29988410 TI - Functional Partitioning of Genomic Variance and Genome-Wide Association Study for Carcass Traits in Korean Hanwoo Cattle Using Imputed Sequence Level SNP Data. AB - Quantitative traits are usually controlled by numerous genomic variants with small individual effects, and variances associated with those traits are explained in a continuous manner. However, the relative contributions of genomic regions to observed genetic variations have not been well explored using sequence level single nucleotide polymorphism (SNP) information. Here, imputed sequence level SNP data (11,278,153 SNPs) of 2109 Hanwoo steers (Korean native cattle) were partitioned according to functional annotation, chromosome, and minor allele frequency (MAF). Genomic relationship matrices (GRMs) were constructed for each classified region and fitted in the model both separately and together for carcass weight (CWT), eye muscle area (EMA), backfat thickness (BFT), and marbling score (MS) traits. A genome-wide association study (GWAS) was performed to identify significantly associated variants in genic and exon regions using a linear mixed model, and the genetic contribution of each exonic SNP was determined using a Bayesian mixture model. Considering all SNPs together, the heritability estimates for CWT, EMA, BFT, and MS were 0.57 +/- 0.05, 0.46 +/- 0.05, 0.45 +/- 0.05, and 0.49 +/- 0.05, respectively, which reflected substantial genomic contributions. Joint analysis revealed that the variance explained by each chromosome was proportional to its physical length with weak linear relationships for all traits. Moreover, genomic variances explained by functional category and MAF class differed greatly among the traits studied in joint analysis. For example, exon regions had larger contributions for BFT (0.13 +/- 0.08) and MS (0.22 +/- 0.08), whereas intron and intergenic regions explained most of the total genomic variances for CWT and EMA (0.22 +/- 0.09-0.32 +/- 0.11). Considering different functional classes of exon regions and the per SNP contribution revealed the largest proportion of genetic variance was attributable to synonymous variants. GWAS detected 206 and 27 SNPs in genic and exon regions, respectively, on BTA4, BTA6, and BTA14 that were significantly associated with CWT and EMA. These SNPs were harbored by 31 candidate genes, among which TOX, FAM184B, PPARGC1A, PRKDC, LCORL, and COL1A2 were noteworthy. BayesR analysis found that most SNPs (>93%) had very small effects and the 4.02-6.92% that had larger effects (10-4 * sigmaA2 , 10-3 * sigmaA2 , and 10-2 * sigmaA2 ) explained most of the total genetic variance, confirming polygenic components of the traits studied. PMID- 29988411 TI - Genetic signals of artificial and natural dispersal linked to colonization of South America by non-native Chinook salmon (Oncorhynchus tshawytscha). AB - Genetics data have provided unprecedented insights into evolutionary aspects of colonization by non-native populations. Yet, our understanding of how artificial (human-mediated) and natural dispersal pathways of non-native individuals influence genetic metrics, evolution of genetic structure, and admixture remains elusive. We capitalize on the widespread colonization of Chinook salmon Oncorhynchus tshawytscha in South America, mediated by both dispersal pathways, to address these issues using data from a panel of polymorphic SNPs. First, genetic diversity and the number of effective breeders (Nb) were higher among artificial than natural populations. Contemporary gene flow was common between adjacent artificial and natural and adjacent natural populations, but uncommon between geographically distant populations. Second, genetic structure revealed four distinct clusters throughout the Chinook salmon distributional range with varying levels of genetic connectivity. Isolation by distance resulted from weak differentiation between adjacent artificial and natural and between natural populations, with strong differentiation between distant Pacific Ocean and Atlantic Ocean populations, which experienced strong genetic drift. Third, genetic mixture analyses revealed the presence of at least six donor geographic regions from North America, some of which likely hybridized as a result of multiple introductions. Relative propagule pressure or the proportion of Chinook salmon propagules introduced from various geographic regions according to government records significantly influenced genetic mixtures for two of three artificial populations. Our findings support a model of colonization in which high-diversity artificial populations established first; some of these populations exhibited significant admixture resulting from propagule pressure. Low-diversity natural populations were likely subsequently founded from a reduced number of individuals. PMID- 29988412 TI - Variations in Species-Level N:P Stoichiometry of Charophytes and Aquatic Angiosperms on the Tibetan Plateau. AB - The variations in nitrogen (N) and phosphorus (P) stoichiometry between species and along environmental gradients reflects plant growth and survival under certain conditions. Exploring the determinants of plant N and P stoichiometry at species level could help us understand the mechanisms of plant distribution. Temperature is considered a driving factor in forming the geographical patterns of plant N and P stoichiometry at the community level. Here we selected four common aquatic plants to explore the divergence of plant N and P stoichiometry between species and the species-level variations across large geographical gradients on the Tibetan Plateau. We found that plant N and P concentrations and N:P ratios were significantly different among the four species/groups. Charophytes had the lowest N and P concentrations, but the N:P ratio did not differ significantly from those of angiosperms. All four species/groups plant N concentrations were positively correlated with P concentrations. The temperature was also the primary explanatory variable, while the habitats properties showed weak and inconsistent effects on plant N and P stoichiometry. Plant N and P concentrations increased, but N:P ratios decreased, with decreasing temperature. Altitude, rather than latitude, determined the environmental patterns of plant N and P stoichiometry by affecting the temperature. These findings indicated that, after removing the influences of species replacement at the community level, temperature still plays a primary role in forming the geographical patterns of plant N and P stoichiometry at species level. Plants of each species could optimize their investment strategies of elements under different environmental conditions. The Tibetan Plateau is recognized as an area that is sensitive to global warming. Our results provided evidence, in terms of N and P stoichiometry, of potential variations among aquatic plants in nutrient absorption and element cycling under climatic warming. PMID- 29988413 TI - Rapid Eye Movement Sleep, Sleep Continuity and Slow Wave Sleep as Predictors of Cognition, Mood, and Subjective Sleep Quality in Healthy Men and Women, Aged 20 84 Years. AB - Sleep and its sub-states are assumed to be important for brain function across the lifespan but which aspects of sleep associate with various aspects of cognition, mood and self-reported sleep quality has not yet been established in detail. Sleep was quantified by polysomnography, quantitative Electroencephalogram (EEG) analysis and self-report in 206 healthy men and women, aged 20-84 years, without sleep complaints. Waking brain function was quantified by five assessments scheduled across the day covering objectively assessed performance across cognitive domains including sustained attention and arousal, decision and response time, motor and sequence control, working memory, and executive function as well as self-reports of alertness, mood and affect. Controlled for age and sex, self-reported sleep quality was negatively associated with number of awakenings and positively associated with the duration of Rapid Eye Movement (REM) sleep, but no significant associations with Slow Wave Sleep (SWS) measures were observed. Controlling only for age showed that associations between objective and subjective sleep quality were much stronger in women than in men. Analysis of 51 performance measures demonstrated that, after controlling for age and sex, fewer awakenings and more REM sleep were associated significantly with better performance on the Goal Neglect task, which is a test of executive function. Factor analysis of the individual performance measures identified four latent variables labeled Mood/Arousal, Response Time, Accuracy, and Visual Perceptual Sensitivity. Whereas Mood/Arousal improved with age, Response Times became slower, while Accuracy and Visual perceptual sensitivity showed little change with age. After controlling for sex and age, nominally significant association between sleep and factor scores were observed such that Response Times were faster with more SWS, and Accuracy was reduced where individuals woke more often or had less REM sleep. These data identify a positive contribution of SWS to processing speed and in particular highlight the importance of sleep continuity and REM sleep for subjective sleep quality and performance accuracy across the adult lifespan. These findings warrant further investigation of the contribution of sleep continuity and REM sleep to brain function. PMID- 29988414 TI - Spring migration patterns, habitat use, and stopover site protection status for two declining waterfowl species wintering in China as revealed by satellite tracking. AB - East Asian migratory waterfowl have greatly declined since the 1950s, especially the populations that winter in China. Conservation is severely hampered by the lack of primary information about migration patterns and stopover sites. This study utilizes satellite tracking techniques and advanced spatial analyses to investigate spring migration of the greater white-fronted goose (Anser albifrons) and tundra bean goose (Anser serrirostris) wintering along the Yangtze River Floodplain. Based on 24 tracks obtained from 21 individuals during the spring of 2015 and 2016, we found that the Northeast China Plain is far-out the most intensively used stopover site during migration, with geese staying for over 1 month. This region has also been intensely developed for agriculture, suggesting a causal link to the decline in East Asian waterfowl wintering in China. The protection of waterbodies used as roosting area, especially those surrounded by intensive foraging land, is critical for waterfowl survival. Over 90% of the core area used during spring migration is not protected. We suggest that future ground surveys should target these areas to confirm their relevance for migratory waterfowl at the population level, and core roosting area at critical spring staging sites should be integrated in the network of protected areas along the flyway. Moreover, the potential bird-human conflict in core stopover area needs to be further studied. Our study illustrates how satellite tracking combined with spatial analyses can provide crucial insights necessary to improve the conservation of declining Migratory species. PMID- 29988415 TI - Molecular Markers Associated With Chemical Analysis: A Powerful Tool for Quality Control Assessment of Copalchi Medicinal Plant Complex. AB - The copalchi complex, Hintonia latiflora, H. standleyana, and Exostema caribaeum, is widely used in Mexico for treating diabetes and gastrointestinal disorders. The first therapeutic use for H. latiflora bark was registered in the "Florentine Codex" in the sixteenth century. The latest pharmacological and phytochemical studies revealed that the infusion of the leaves have hypoglycemic, antihyperglycemic and gastroprotective activities. For these reasons the monograph of the main copalchi species, H. latiflora, was recently added to the Mexican Herbal Pharmacopoeia. Nevertheless, quality control parameters are focused to the bark but not to the leaves. Moreover, information about other Rubiaceae species is needed. The main goal of this study was to generate molecular and chemical markers for quality control of the copalchi complex raw material. In addition, the resolution of the taxonomical ambiguity between H. latiflora and H. standleyana, as well as the testing of the molecular and chemical markers in different geographical batches, were aims of this study. The molecular markers and chemical profiles of the leaf infusions were generated considering three different populations for H. latiflora and separate individuals of the three species (HL, n = 10; HS, n = 3; EC, n = 4). The molecular markers matK, rbcL, trnH-psbA, rpl32-trnL, and ITS2 were tested for their discriminating capabilities. Chemical profiles of the leaf infusions were obtained by means of HPLC analyses using chlorogenic acid and 4-phenylcoumarins as chemical markers. The concatenated sequence of the molecular markers trnH-psbA, rpl32-trnL, and ITS2 clearly distinguished the three taxa, clarifying the taxonomical ambiguity of the Hintonia genus. Additionally, the chemical profiles allowed the unequivocal identification of each species supporting the molecular results; the geographical origin of the samples did not modify neither the chemical profiles nor the concatenated sequence of H. latiflora, suggesting that it is a robust identity test. The complementary use of molecular and chemical markers will assure the quality of plant material used in traditional medicine for therapeutic purposes, and should be valuable new information for the National Health authorities as a part of the Mexican Herbal Pharmacopoeia. PMID- 29988416 TI - Editorial: Gene Silencing and Editing Strategies for Neurodegenerative Diseases. PMID- 29988417 TI - Unique maternal and environmental effects on the body morphology of the Least Killifish, Heterandria formosa. AB - An important step in diagnosing local adaptation is the demonstration that phenotypic variation among populations is at least in part genetically based. To do this, many methods experimentally minimize the environmental effect on the phenotype to elucidate the genetic effect. Minimizing the environmental effect often includes reducing possible environmental maternal effects. However, maternal effects can be an important factor in patterns of local adaptation as well as adaptive plasticity. Here, we report the results of an experiment with males from two populations of the poeciliid fish, Heterandria formosa, designed to examine the relative influence of environmental maternal effects and environmental effects experienced during growth and development on body morphology, and, in addition, whether the balance among those effects is unique to each population. We used a factorial design that varied thermal environment and water chemistry experienced by mothers and thermal environment and water chemistry experienced by offspring. We found substantial differences between the two populations in their maternal and offspring norms of reaction of male body morphology to differences in thermal environment and water chemistry. We also found that the balance between maternal effects and postparturition environmental effects differed from one thermal regime to another and among traits. These results indicate that environmental maternal effects can be decidedly population specific and, as a result, might either contribute to the appearance of or blur evidence for local adaptation. These results also suggest that local adaptation might also occur through the evolution of maternal norms of reaction to important, and varying, environmental factors. PMID- 29988418 TI - Combination types between graphene oxide and substrate affect the antibacterial activity. AB - Duo to their superior physicochemical properties, graphene and its derivatives (GDs), such as graphene oxide (GO) and reduced graphene oxide (rGO), have attracted extensive research interests around the world. In recent years, antibacterial activities of GDs have aroused wide concern and substantial works have been done. However, the underlying antibacterial mechanisms still remain controversial. Antibacterial activities of GDs vary with various factors, such as size, number of layers, oxygen-containing groups, and experimental surroundings. We assume that combination types between graphene oxide and substrate may affect the antibacterial activity. Therefore, in this work, GO was fixed on the titanium surface with three kinds of combination types including drop with gravitational effects (GO-D), electrostatic interaction (GO-APS) and electrophoretic deposition (GO-EPD), and the antibacterial activities in vitro were systematically investigated. Results showed that combination types affected the ability of GO for preventing Staphylococcus aureus (S. aureus) from gathering, sharpness of wrinkles or edges and reactive oxygen spices (ROS) levels. Once S. aureus are in the form of separation without aggregation, GO can effectively interact with them and kill them with sharp wrinkles or edges and high ROS levels. GO-EPD could effectively prevent S. aureus from gathering, own sharp wrinkles or edges and could generate higher ROS levels. As a result, GO-EPD exhibited optimal antibacterial activity against S. aureus, followed by GO-APS and GO-D. PMID- 29988419 TI - Introduction of mammalian seed predators and the loss of an endemic flightless bird impair seed dispersal of the New Zealand tree Elaeocarpus dentatus. AB - Understanding the mutualistic services provided by species is critical when considering both the consequences of their loss or the benefits of their reintroduction. Like many other Pacific islands, New Zealand seed dispersal networks have been changed by both significant losses of large frugivorous birds and the introduction of invasive mammals. These changes are particularly concerning when important dispersers remain unidentified. We tested the impact of frugivore declines and invasive seed predators on seed dispersal for an endemic tree, hinau Elaeocarpus dentatus, by comparing seed dispersal and predation rates on the mainland of New Zealand with offshore sanctuary islands with higher bird and lower mammal numbers. We used cameras and seed traps to measure predation and dispersal from the ground and canopy, respectively. We found that canopy fruit handling rates (an index of dispersal quantity) were poor even on island sanctuaries (only 14% of seeds captured below parent trees on islands had passed through a bird), which suggests that hinau may be adapted for ground-based dispersal by flightless birds. Ground-based dispersal of hinau was low on the New Zealand mainland compared to sanctuary islands (4% of seeds dispersed on the mainland vs. 76% dispersed on islands), due to low frugivore numbers. A flightless endemic rail (Gallirallus australis) conducted the majority of ground based fruit removal on islands. Despite being threatened, this rail is controversial in restoration projects because of its predatory impacts on native fauna. Our study demonstrates the importance of testing which species perform important mutualistic services, rather than simply relying on logical assumptions. PMID- 29988420 TI - Ecosystem-based management of coral reefs under climate change. AB - Coral reefs provide food and livelihoods for hundreds of millions of people as well as harbour some of the highest regions of biodiversity in the ocean. However, overexploitation, land-use change and other local anthropogenic threats to coral reefs have left many degraded. Additionally, coral reefs are faced with the dual emerging threats of ocean warming and acidification due to rising CO 2 emissions, with dire predictions that they will not survive the century. This review evaluates the impacts of climate change on coral reef organisms, communities and ecosystems, focusing on the interactions between climate change factors and local anthropogenic stressors. It then explores the shortcomings of existing management and the move towards ecosystem-based management and resilience thinking, before highlighting the need for climate change-ready marine protected areas (MPAs), reduction in local anthropogenic stressors, novel approaches such as human-assisted evolution and the importance of sustainable socialecological systems. It concludes that designation of climate change-ready MPAs, integrated with other management strategies involving stakeholders and participation at multiple scales such as marine spatial planning, will be required to maximise coral reef resilience under climate change. However, efforts to reduce carbon emissions are critical if the long-term efficacy of local management actions is to be maintained and coral reefs are to survive. PMID- 29988422 TI - IL-33/ST2 Pathway and Galectin-3 as a New Analytes in Pathogenesis and Cardiometabolic Risk Evaluation in Psychosis. AB - Schizophrenia and treatment of this disorder are often accompanied with metabolic syndrome and cardiovascular issues. Alterations in the serum level of innate immune mediators, such as interleukin-33 (IL-33) and its receptor IL-33R (ST2) and Galectin-3 (Gal-3) were observed in these conditions. Moreover, these parameters are potential prognostic and therapeutic markers. There is also accumulating evidence that these molecules play a role in neuroinflammation. Therefore, in this study we have investigated the serum level of Gal-3, IL-33 and soluble ST2 (sST2) in different stages of schizophrenia. Gal-3 levels were elevated in remission and lower in schizophrenia exacerbation in comparison with controls. Levels of IL-33 and sST2 are higher in schizophrenia exacerbation in comparison with controls and patients in remission. This initial analysis of new markers of neuroinflammation suggested their involvement in schizophrenia pathophysiology and/or cardiometabolic comorbidity. PMID- 29988421 TI - Effects of Bovine Immunoglobulins on Immune Function, Allergy, and Infection. AB - This review aims to provide an in depth overview of the current knowledge of the effects of bovine immunoglobulins on the human immune system. The stability and functional effects of orally ingested bovine immunoglobulins in milk products are described and potential mechanisms of action are discussed. Orally ingested bovine IgG (bovine IgG) can be recovered from feces, ranging from very low levels up to 50% of the ingested IgG that has passed through the gastrointestinal tract. In infants the recovered levels are higher than in adults most likely due to differences in stomach and intestinal conditions such as pH. This indicates that bovine IgG can be functionally active throughout the gastrointestinal tract. Indeed, a large number of studies in infants and adults have shown that bovine IgG (or colostrum as a rich source thereof) can prevent gastrointestinal tract infections, upper respiratory tract infections, and LPS-induced inflammation. These studies vary considerably in target group, design, source of bovine IgG, dosage, and endpoints measured making it hard to draw general conclusions on effectiveness of bovine immunoglobulin rich preparations. Typical sources of bovine IgG used in human studies are serum-derived IgG, colostrum, colostrum derived IgG, or milk-derived immunoglobulins. In addition, many studies have used IgG from vaccinated cows, but studies using IgG from nonimmunized animals have also been reported to be effective. Mechanistically, bovine IgG binds to many human pathogens and allergens, can neutralize experimental infection of human cells, and limits gastrointestinal inflammation. Furthermore, bovine IgG binds to human Fc receptors which, enhances phagocytosis, killing of bacteria and antigen presentation and bovine IgG supports gastrointestinal barrier function in in vitro models. These mechanisms are becoming more and more established and explain why bovine IgG can have immunological effects in vivo. The inclusion of oral bovine immunoglobulins in specialized dairy products and infant nutrition may therefore be a promising approach to support immune function in vulnerable groups such as infants, children, elderly and immunocompromised patients. PMID- 29988423 TI - Prevalence and Characterization of Staphylococcus aureus Cultured From Raw Milk Taken From Dairy Cows With Mastitis in Beijing, China. AB - The colonization of dairy herds and subsequent contamination of raw milk by Staphylococcus aureus (S. aureus), especially those expressing a multi-drug resistance (MDR), biofilm and toxins producing ability, remains an important issue for both the dairy producer and public health. In this study, we investigated the prevalence, antimicrobial resistance, virulence, and genetic diversity of S. aureus in raw milk taken from 2 dairy farms in Beijing, China. Ninety (46.2%, 90/195) samples were positive for S. aureus. Resistant to penicillin (PEN) (31.3%), ciprofloxacin (18.8%) and enrofloxacin (15.6%) were the most often observed. Isolates cultured from farm B showed significantly higher resistance to penicillin (73.9%), ciprofloxacin (34.8%), enrofloxacin (34.8%), tilmicosin (17.4%), and erythromycin (17.4%) than those from farm A (p < 0.05). Totally, 94.8% S. aureus harbored at least one virulence gene and the pvl (93.8%), sec (65.6%), and sea (60.4%) genes were the most frequently detected. The pvl and sec genes were more often detected in isolates from farm A (97.3% and 84.9% respectively) than those from farm B (p < 0.05). Of all 77 staphylococcus enterotoxin (SE)-positive isolates, more than 90% could produce enterotoxins and 70.1% could produce two types. Biofilm related genes (icaA/D, clf/B, can, and fnbA) were detected in all96 isolates. All 96 isolates could produce biofilm with 8.3, 70.8, and 18.8% of the isolates demonstrating weak, moderate and strong biofilm formation, respectively. A total of 5 STs, 7 spa types (1 novel spa type t17182), 3agr types (no agrII), and 14 SmaI-pulso-types were found in this study. PFGE cluster II-CC1-ST1-t127-agr III was the most prevalent clone (56.3%). Isolates of agr III (PFGE Cluster I/II-CC1-ST1-t127/2279) had higher detection of virulence genes than those of agr I and agr IV. TheMSSA-ST398-t1456-agr I clone expressed the greatest MDRbut with no virulence genes and weakly biofilm formation. Our finding indicated a relatively high prevalence of S. aureus with less antimicrobial resistance but often positive for enterotoxigenicity and biofilm formation. This study could help identify predominant clones and provide surveillance measures to eliminate and decrease the contamination of S. aureus in raw milk of dairy cows with mastitis. PMID- 29988425 TI - Instagram Likes for Architectural Photos Can Be Predicted by Quantitative Balance Measures and Curvature. AB - "3,058 people like this." In the digital age, people very commonly indicate their preferences by clicking a Like button. The data generated on the photo-sharing platform Instagram potentially represents a vast, freely accessible resource for research in the field of visual experimental aesthetics. Therefore, we compiled a photo database using images of five different Instagram accounts that fullfil several criteria (e.g., large followership, consistent content). The final database consists of about 700 architectural photographs with the corresponding liking data generated by the Instagram community. First, we aimed at validating Instagram Likes as a potential measure of aesthetic appeal. Second, we checked whether previously studied low-level features of "good" image composition also account for the number of Instagram Likes that architectural photographs received. We considered two measures of visual balance and the preference for curvature over angularity. In addition, differences between images with "2D" vs. "3D" appearance became obvious. Our findings show that visual balance predicts Instagram Likes in more complex "3D" photographs, with more balance meaning more Likes. In the less complex "2D" photographs the relation is reversed, more balance led to fewer Likes. Moreover, there was a general preference for curvature in the Instagram database. Together, our study illustrates the potential of using Instagram Likes as a measure of aesthetic appeal and provides a fruitful methodological basis for future research. PMID- 29988426 TI - Warming delays the phenological sequences of an autumn-flowering invader. AB - Phenology can play an important role in driving plant invasions; however, little is known about how climate warming, nitrogen (N) deposition, and invasion stages influence the phenological sequences of autumn-flowering invaders in a subtropical climate. Accordingly, we conducted an experiment to address the effects of experimental warming, N-addition, and community types on the first inflorescence buds, flowering, seed-setting, and dieback of invasive Solidago canadensis. Warming delayed the onset of first inflorescence buds, flowering, seed-setting, and dieback; N-addition did not influence these four phenophases; community types influenced the onset of first seed-setting but not the other phenological phases. Seed-setting was more sensitive to experimental manipulations than the other phenophases. The onset of first inflorescence buds, flowering, and seed-setting was marginally or significantly correlated with ramet height but not ramet numbers. Our results suggest that future climate warming might delay the phenological sequences of autumn-flowering invaders and some phenophases can shift with invasion stages. PMID- 29988427 TI - Local adaptation through genetic differentiation in highly fragmented Tilia cordata populations. AB - We assessed the level of geographic differentiation of Tilia cordata in Denmark based on tests of 91 trees selected from 12 isolated populations. We used quantitative analysis of spring phenology and population genetic analysis based on SSR markers to infer the likely historical genetic processes within and among populations. High genetic variation within and among populations was observed in spring phenology, which correlated with spring temperatures at the origin of the tested T. cordata trees. The population genetic analysis revealed significant differentiation among the populations, but with no clear sign of isolation by distance. We infer the findings as indications of ongoing fine scale selection in favor of local growth conditions made possible by limited gene flow among the small and fragmented populations. This hypothesis fits well with reports of limited fruiting in the investigated Danish T. cordata populations, while the species is known for its ability to propagate vegetatively by root suckers. Our results suggest that both divergent selection and genetic drift may have played important roles in forming the genetic patterns of T. cordata at its northern distribution limit. However, we also speculate that epigenetic mechanism arising from the original population environment could have created similar patterns in regulating the spring phenology. PMID- 29988429 TI - Systematic Review of Phytotherapeutic Treatments for Different Farm Animals Under European Conditions. AB - The emergence and spread of antibiotic resistance is a growing global threat and has aroused a global interest in limiting antibiotic use in animal agriculture. As we are entering the post-antibiotic era, there is a growing need for identifying alternatives to antibiotics for prevention and treatment. Although phytotherapeutic remedies are available and are used in Europe, evidence of their efficacy is currently very limited but is nevertheless still necessary. A systematic review of phytotherapy used for the treatment and prevention of infectious diseases in farm animals has been conducted using the PICOS approach. Analysis and extraction of information from studies was performed according to a protocol, and included: publication year and source, research body, species, farming system, purpose of application, disease in focus, diagnostic method, remedy used (origin and ingredients of the remedy), producer of remedy, way of administration, study design, and control groups, measure of effect, and outcome of the study. A total of 1,705 papers were screened, but only 44 (comprising 53 independent studies) met the inclusion criteria. The majority of the scientific studies identified show limitations in the study design as well as in presentation and standardization of the botanical remedies studied, which limits the possibilities of drawing firm conclusions. Preventive effect was investigated in 89% of the studies. Half of the studies reported uncertain effects of the botanical remedies on subclinical measures in comparison to a control group. The review highlights unresolved questions such as the need for standardized controlled trials and for improved standardization of the botanical products by analytical methods, such as high-performance liquid chromatography. It is necessary to consider this in order to achieve replicable outcomes and establish efficacy and safety of phytotherapy in farm practice. The manageability of alternative medicine in farm animals also warrants further investigation so as to ascertain whether all necessary preconditions for their use are being granted. PMID- 29988428 TI - Parallel evolution of site-specific changes in divergent caribou lineages. AB - The parallel evolution of phenotypes or traits within or between species provides important insight into the basic mechanisms of evolution. Genetic and genomic advances have allowed investigations into the genetic underpinnings of parallel evolution and the independent evolution of similar traits in sympatric species. Parallel evolution may best be exemplified among species where multiple genetic lineages, descended from a common ancestor, colonized analogous environmental niches, and converged on a genotypic or phenotypic trait. Modern North American caribou (Rangifer tarandus) originated from three ancestral sources separated during the Last Glacial Maximum (LGM): the Beringian-Eurasian lineage (BEL), the North American lineage (NAL), and the High Arctic lineage (HAL). Historical introgression between the NAL and the BEL has been found throughout Ontario and eastern Manitoba. In this study, we first characterized the functional differentiation in the cytochrome-b (cytB) gene by identifying nonsynonymous changes. Second, the caribou lineages were used as a direct means to assess site specific parallel changes among lineages. There was greater functional diversity within the NAL despite the BEL having greater neutral diversity. The patterns of amino acid substitutions occurring within different lineages supported the parallel evolution of cytB amino acid substitutions suggesting different selective pressures among lineages. This study highlights the independent evolution of identical amino acid substitutions within a wide-ranging mammal species that have diversified from different ancestral haplogroups and where ecological niches can invoke parallel evolution. PMID- 29988430 TI - Local weather and body condition influence habitat use and movements on land of molting female southern elephant seals (Mirounga leonina). AB - Southern elephant seals (Mirounga leonina) are known to move and aggregate while molting, but little is known about their behavior on land during this time. In this study, 60 adult females were monitored (23 with GPS tags) during four molting seasons, between 2012 and 2016 at Kerguelen Archipelago, Indian Ocean. Population surveys were recorded each year (N = 230 daily counts), and habitat use was analyzed in relation to the stage of the molt and local weather. Based on stage of molt, habitat use, and movements on land, we classified the molt of elephant seals into three phases: (1) a "search phase" at the initial stage of molt when grass and wallow habitats were used and characterized by greater mean distances travelled on land per day compared with the two other phases; (2) a "resident phase": during initial and mid-stage of molt when animals were found in grass and wallow habitats but with less distance moved on land; and (3) a "termination phase" at the final stage of molt where grass and beach habitats were occupied with no change in distances. Windchill and solar radiation influenced individual distances moved per day (mean 590 +/- 237.0 m) at the mid- and final stage of molt such that animals travelled greater distances on days of low windchill or high solar radiation. Individual variation in distance moved and relative habitat use were also linked to body mass index (BMI) at arrival on the colony, as females with higher BMI moved less and preferred beach habitat. Moreover, the individual rate of molt increased with the use of wallows. Aggregation rate tended to be negatively correlated with distances moved. We therefore suggest that individuals face an energetic trade-off while molting, balancing energy expenditure between movement and thermoregulation. PMID- 29988431 TI - Integrating trait-based empirical and modeling research to improve ecological restoration. AB - A global ecological restoration agenda has led to ambitious programs in environmental policy to mitigate declines in biodiversity and ecosystem services. Current restoration programs can incompletely return desired ecosystem service levels, while resilience of restored ecosystems to future threats is unknown. It is therefore essential to advance understanding and better utilize knowledge from ecological literature in restoration approaches. We identified an incomplete linkage between global change ecology, ecosystem function research, and restoration ecology. This gap impedes a full understanding of the interactive effects of changing environmental factors on the long-term provision of ecosystem functions and a quantification of trade-offs and synergies among multiple services. Approaches that account for the effects of multiple changing factors on the composition of plant traits and their direct and indirect impact on the provision of ecosystem functions and services can close this gap. However, studies on this multilayered relationship are currently missing. We therefore propose an integrated restoration agenda complementing trait-based empirical studies with simulation modeling. We introduce an ongoing case study to demonstrate how this framework could allow systematic assessment of the impacts of interacting environmental factors on long-term service provisioning. Our proposed agenda will benefit restoration programs by suggesting plant species compositions with specific traits that maximize the supply of multiple ecosystem services in the long term. Once the suggested compositions have been implemented in actual restoration projects, these assemblages should be monitored to assess whether they are resilient as well as to improve model parameterization. Additionally, the integration of empirical and simulation modeling research can improve global outcomes by raising the awareness of which restoration goals can be achieved, due to the quantification of trade-offs and synergies among ecosystem services under a wide range of environmental conditions. PMID- 29988424 TI - Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System. AB - Much research on infectious diseases focuses on clearing the pathogen through the use of antimicrobial drugs, the immune response, or a combination of both. Rapid clearance of pathogens allows for a quick return to a healthy state and increased survival. Pathogen-targeted approaches to combating infection have inherent limitations, including their pathogen-specific nature, the potential for antimicrobial resistance, and poor vaccine efficacy, among others. Another way to survive an infection is to tolerate the alterations to homeostasis that occur during a disease state through a process called host tolerance or resilience, which is independent from pathogen burden. Alterations in homeostasis during infection are numerous and include tissue damage, increased inflammation, metabolic changes, temperature changes, and changes in respiration. Given its importance and sensitivity, the lung is a good system for understanding host tolerance to infectious disease. Pneumonia is the leading cause of death for children under five worldwide. One reason for this is because when the pulmonary system is altered dramatically it greatly impacts the overall health and survival of a patient. Targeting host pathways involved in maintenance of pulmonary host tolerance during infection could provide an alternative therapeutic avenue that may be broadly applicable across a variety of pathologies. In this review, we will summarize recent findings on tolerance to host lung infection. We will focus on the involvement of innate immune responses in tolerance and how an initial viral lung infection may alter tolerance mechanisms in leukocytic, epithelial, and endothelial compartments to a subsequent bacterial infection. By understanding tolerance mechanisms in the lung we can better address treatment options for deadly pulmonary infections. PMID- 29988432 TI - Improving geographically extensive acoustic survey designs for modeling species occurrence with imperfect detection and misidentification. AB - Acoustic recording units (ARUs) enable geographically extensive surveys of sensitive and elusive species. However, a hidden cost of using ARU data for modeling species occupancy is that prohibitive amounts of human verification may be required to correct species identifications made from automated software. Bat acoustic studies exemplify this challenge because large volumes of echolocation calls could be recorded and automatically classified to species. The standard occupancy model requires aggregating verified recordings to construct confirmed detection/non-detection datasets. The multistep data processing workflow is not necessarily transparent nor consistent among studies. We share a workflow diagramming strategy that could provide coherency among practitioners. A false positive occupancy model is explored that accounts for misclassification errors and enables potential reduction in the number of confirmed detections. Simulations informed by real data were used to evaluate how much confirmation effort could be reduced without sacrificing site occupancy and detection error estimator bias and precision. We found even under a 50% reduction in total confirmation effort, estimator properties were reasonable for our assumed survey design, species-specific parameter values, and desired precision. For transferability, a fully documented r package, OCacoustic, for implementing a false-positive occupancy model is provided. Practitioners can apply OCacoustic to optimize their own study design (required sample sizes, number of visits, and confirmation scenarios) for properly implementing a false-positive occupancy model with bat or other wildlife acoustic data. Additionally, our work highlights the importance of clearly defining research objectives and data processing strategies at the outset to align the study design with desired statistical inferences. PMID- 29988434 TI - Geography and island geomorphology shape fish assemblage structure on isolated coral reef systems. AB - We quantify the relative importance of multi-scale drivers of reef fish assemblage structure on isolated coral reefs at the intersection of the Indian and Indo-Pacific biogeographical provinces. Large (>30 cm), functionally important and commonly targeted species of fish, were surveyed on the outer reef crest/front at 38 coral reef sites spread across three oceanic coral reef systems (i.e. Christmas Island, Cocos (Keeling) Islands and the Rowley Shoals), in the tropical Indian Ocean (c. 1.126 x 106 km2). The effects of coral cover, exposure, fishing pressure, lagoon size and geographical context, on observed patterns of fish assemblage structure were modelled using Multivariate Regression Trees. Reef fish assemblages were clearly separated in space with geographical location explaining ~53 % of the observed variation. Lagoon size, within each isolated reef system was an equally effective proxy for explaining fish assemblage structure. Among local-scale variables, 'distance from port', a proxy for the influence of fishing, explained 5.2% of total variation and separated the four most isolated reefs from Cocos (Keeling) Island, from reefs with closer boating access. Other factors were not significant. Major divisions in assemblage structure were driven by sister taxa that displayed little geographical overlap between reef systems and low abundances of several species on Christmas Island corresponding to small lagoon habitats. Exclusion of geographical context from the analysis resulted in local processes explaining 47.3% of the variation, highlighting the importance of controlling for spatial correlation to understand the drivers of fish assemblage structure. Our results suggest reef fish assemblage structure on remote coral reef systems in the tropical eastern Indian Ocean reflects a biogeographical legacy of isolation between Indian and Pacific fish faunas and geomorphological variation within the region, more than local fishing pressure or reef condition. Our findings re-emphasise the importance that historical processes play in structuring contemporary biotic communities. PMID- 29988435 TI - Longevity and population age structure of the arroyo southwestern toad (Anaxyrus californicus) with drought implications. AB - The arroyo southwestern toad is a specialized and federally endangered amphibian endemic to the coastal plains and mountains of central and southern California and northwestern Baja California. It is largely unknown how long these toads live in natural systems, how their population demographics vary across occupied drainages, and how hydrology affects age structure. We used skeletochronology to estimate the ages of adult arroyo toads in seven occupied drainages with varying surface water hydrology in southern California. We processed 179 adult toads with age estimates between 1 and 6 years. Comparisons between skeletochronological ages and known ages of PIT tagged toads showed that skeletochronology likely underestimated toad age by up to 2 years, indicating they may live to 7 or 8 years, but nonetheless major patterns were evident. Arroyo toads showed sexual size dimorphism with adult females reaching a maximum size of 12 mm greater than males. Population age structure varied among the sites. Age structure at sites with seasonally predictable surface water was biased toward younger individuals, which indicated stable recruitment for these populations. Age structures at the ephemeral sites were biased toward older individuals with cohorts roughly corresponding to higher rainfall years. These populations are driven by surface water availability, a stochastic process, and thus more unstable. Based on our estimates of toad ages, climate predictions of extreme and prolonged drought events could mean that the number of consecutive dry years could surpass the maximum life span of toads making them vulnerable to extirpation, especially in ephemeral freshwater systems. Understanding the relationship between population demographics and hydrology is essential for predicting species resilience to projected changes in weather and rainfall patterns. The arroyo toad serves as a model for understanding potential responses to climatic and hydrologic changes in Mediterranean stream systems. We recommend development of adaptive management strategies to address these threats. PMID- 29988433 TI - Urban Diets Linked to Gut Microbiome and Metabolome Alterations in Children: A Comparative Cross-Sectional Study in Thailand. AB - Loss of traditional diets by food globalization may have adverse impact on the health of human being through the alteration of gut microbial ecosystem. To address this notion, we compared the gut microbiota of urban (n = 17) and rural (n = 28) school-aged children in Thailand in association with their dietary habits. Dietary records indicated that children living in urban Bangkok tended to consume modern high-fat diets, whereas children in rural Buriram tended to consume traditional vegetable-based diets. Sequencing of 16S rRNA genes amplified from stool samples showed that children in Bangkok have less Clostridiales and more Bacteroidales and Selenomonadales compared to children in Buriram and bacterial diversity is significantly less in Bangkok children than in Buriram children. In addition, fecal butyrate and propionate levels decreased in Bangkok children in association with changes in their gut microbial communities. Stool samples of these Thai children were classified into five metabolotypes (MTs) based on their metabolome profiles, each characterized by high concentrations of short and middle chain fatty acids (MT1, n = 17), amino acids (MT2, n = 7), arginine (MT3, n = 6), amino acids, and amines (MT5, n = 8), or an overall low level of metabolites (MT4, n = 4). MT1 and MT4 mainly consisted of samples from Buriram, and MT2 and MT3 mainly consisted of samples from Bangkok, whereas MT5 contained three samples from Bangkok and five from Buriram samples. According to the profiles of microbiota and diets, MT1 and MT2 are characteristic of children in Buriram and Bangkok, respectively. Predicted metagenomics indicated the underrepresentation in MT2 of eight genes involved in pathways of butyrate biosynthesis, notably including paths from glutamate as well as pyruvate. Taken together, this study shows the benefit of high-vegetable Thai traditional diets on gut microbiota and suggests that high-fat and less-vegetable urban dietary habits alter gut microbial communities in Thai children, which resulted in the reduction of colonic short chain fatty acid fermentation. PMID- 29988436 TI - Genetic diversity of melon aphids Aphis gossypii associated with landscape features. AB - Despite increasing evidence that landscape features strongly influence the abundance and dispersal of insect populations, landscape composition has seldom been explicitly linked to genetic structure. We conducted a genetic study of the melon aphid, Aphis gossypii, in two counties of Beijing, China during spring migration using samples from watermelon. We performed aphid genetic analysis using restriction site associated DNA sequencing (2b-RAD) and investigated the relationship between land cover and the genetic diversity. The percentage area of land cover (cropland, vegetable, orchard, grassland, woodland) was quantified in each particular scale (ranging from 0.5 km to 3 km) and was used as a predictor variable in our generalized linear models. We found a moderate level of genetic differentiation among nine sampled populations. Geographic distance and genetic distance were not significantly associated, indicating that geographic location was not a barrier to migration. These nine populations could be clustered depending on their level of genetic diversity (high and low). The genetic diversity (Shannon's information index) was positively correlated with grassland at the spatial scales of 1 and 2 km and negatively with orchard and vegetable at 0.5 and 1 km. Genetic diversity was best predicted by the grassland + orchard + vegetable model at a spatial scale of 1 km. Based on the method of relative weights, orchard land had the greatest relative importance, followed by grassland and vegetable land, in that order. This study contributes to our understanding of the genetic variation of aphids in agricultural landscapes. PMID- 29988437 TI - Abnormal Regional Homogeneity and Functional Connectivity of Baseline Brain Activity in Hepatitis B Virus-Related Cirrhosis With and Without Minimal Hepatic Encephalopathy. AB - Background and Aims: Abnormalities in neural activity have been reported in cirrhosis with minimal hepatic encephalopathy (MHE). However, little is known about the neurophysiological mechanisms in this disorder. We aimed to investigate the altered patterns of regional synchronization and functional connections in hepatitis B virus-related cirrhosis (HBV-RC) patients with and without MHE using both regional homogeneity (ReHo) and region of interest (ROI)-based functional connectivity (FC) computational methods. Methods: Data of magnetic resonance imaging scans were collected from 30 HBV-RC patients with MHE, 32 HBV-RC patients without MHE (NMHE) and 64 well-matched controls. Several regions showing differences in ReHo after one-way analysis of variance (ANOVA) were defined as ROIs for FC analysis. Next, post hoc t-tests were applied to calculate the group differences in ReHo and FC (false discovery rate (FDR) correction, p < 0.05). Correlations between clinical variables and the altered ReHo and FC were then assessed in patient groups. Results: Across three groups, significant ReHo differences were found in nine ROI regions mainly within the visual network (VN), dorsal attention network (DAN), somatomotor network (SMN), fronto parietal control (FPC) network and thalamus. Compared with healthy controls (HC), the MHE group exhibited abnormal FC mainly between the right calcarine (CAL.R) and middle frontal gyrus (MFG.L)/right thalamus. The MHE patients showed increased FC between the MFG.L and CAL.R compared to NMHE patients. Disease duration of MHE patients was positively correlated with increased mean ReHo values in the right fusiform gyrus (FFG); psychometric hepatic encephalopathy score (PHES) test scores were negatively correlated with increased FC between MFG.L and CAL.R and positively correlated with reduced FC between the CAL.R and THA.R. For NMHE patients, the mean ReHo values in the right frontal pole were positively correlated with disease duration and positively correlated with the PHES scores. Conclusion: Our results exhibited that the functional brain modifications in patients with and without MHE are characterized by compound alterations in local coherence and functional connections in the VN, SMN, DAN, FPC networks and thalamus by using a combination of ReHo and ROI-based FC analysis. These functional imaging changes are correlated with disease duration/PHES. This study helped us gain a better understanding of the features of brain network modifications in cirrhosis. PMID- 29988438 TI - The bacterial community structure and functional profile in the heavy metal contaminated paddy soils, surrounding a nonferrous smelter in South Korea. AB - The pollution of agricultural soils by the heavy metals affects the productivity of the land and has an impact on the quality of the surrounding ecosystems. This study investigated the bacterial community structure in the heavy metal contaminated sites along a smelter and a distantly located paddy field to elucidate the factors that are related to the alterations of the bacterial communities under the conditions of heavy metal pollution. Among the study sites, the bacterial communities in the soil did not show any significant differences in their richness and diversity. The soil bacterial communities at the three study sites were distinct from one another at each site, possessing a distinct set of bacterial phylotypes. Among the study sites, significant changes were observed in the abundances of the bacterial phyla and genera. The variations in the bacterial community structure were mostly related to the general soil properties at the phylum level, while at the finer taxonomic levels, the concentrations of arsenic (As) and lead (Pb) were the significant factors, affecting the community structure. The relative abundances of the genera Desulfatibacillum and Desulfovirga were negatively correlated to the concentrations of As, Pb, and cadmium (Cd) in the soil, while the genus Bacillus was positively correlated to the concentrations of As and Cd. According to the results of the prediction of bacterial community functions, the soil bacterial communities of the heavy metal polluted sites were characterized by the more abundant enzymes involved in DNA replication and repair, translation, transcription, and the nucleotide metabolism pathways, while the amino acid and lipid metabolism, as well as the biodegradation potential of xenobiotics, were reduced. Our results showed that the adaptation of the bacterial communities to the heavy metal contamination was predominantly attributed to the replacement process, while the changes in community richness were linked to the variations in the soil pH values. PMID- 29988439 TI - Mito-nuclear discordance across a recent contact zone for California voles. AB - To examine the processes that maintain genetic diversity among closely related taxa, we investigated the dynamics of introgression across a contact zone between two lineages of California voles (Microtus californicus). We tested the prediction that introgression of nuclear loci would be greater than that for mitochondrial loci, assuming ongoing gene flow across the contact zone. We also predicted that genomic markers would show a mosaic pattern of differentiation across this zone, consistent with genomes that are semi-permeable. Using mitochondrial cytochrome b sequences and genome-wide loci developed via ddRAD seq, we analyzed genetic variation for 10 vole populations distributed along the central California coast; this transect included populations from within the distributions of both parental lineages as well as the putative contact zone. Our analyses revealed that (1) the two lineages examined are relatively young, having diverged ca. 8.5-54 kya, (2) voles from the contact zone in Santa Barbara County did not include F1 or early generation backcrossed individuals, and (3) there appeared to be little to no recurrent gene flow across the contact zone. Introgression patterns for mitochondrial and nuclear markers were not concordant; only mitochondrial markers revealed evidence of introgression, putatively due to historical hybridization. These differences in genetic signatures are intriguing given that the contact zone occurs in a region of continuous vole habitat, with no evidence of past or present physical barriers. Future studies that examine specific isolating mechanisms, such as microhabitat use and mate choice, will facilitate our understanding of how genetic boundaries are maintained in this system. PMID- 29988440 TI - Convergence in reduced body size, head size, and blood glucose in three island reptiles. AB - Many oceanic islands harbor diverse species that differ markedly from their mainland relatives with respect to morphology, behavior, and physiology. A particularly common morphological change exhibited by a wide range of species on islands worldwide involves either a reduction in body size, termed island dwarfism, or an increase in body size, termed island gigantism. While numerous instances of dwarfism and gigantism have been well documented, documentation of other morphological changes on islands remains limited. Furthermore, we lack a basic understanding of the physiological mechanisms that underlie these changes, and whether they are convergent. A major hypothesis for the repeated evolution of dwarfism posits selection for smaller, more efficient body sizes in the context of low resource availability. Under this hypothesis, we would expect the physiological mechanisms known to be downregulated in model organisms exhibiting small body sizes due to dietary restriction or artificial selection would also be downregulated in wild species exhibiting dwarfism on islands. We measured body size, relative head size, and circulating blood glucose in three species of reptiles-two snakes and one lizard-in the California Channel Islands relative to mainland populations. Collating data from 6 years of study, we found that relative to mainland population the island populations had smaller body size (i.e., island dwarfism), smaller head sizes relative to body size, and lower levels of blood glucose, although with some variation by sex and year. These findings suggest that the island populations of these three species have independently evolved convergent physiological changes (lower glucose set point) corresponding to convergent changes in morphology that are consistent with a scenario of reduced resource availability and/or changes in prey size on the islands. This provides a powerful system to further investigate ecological, physiological, and genetic variables to elucidate the mechanisms underlying convergent changes in life history on islands. PMID- 29988441 TI - A simple function for full-subsets multiple regression in ecology with R. AB - Full-subsets information theoretic approaches are becoming an increasingly popular tool for exploring predictive power and variable importance where a wide range of candidate predictors are being considered. Here, we describe a simple function in the statistical programming language R that can be used to construct, fit, and compare a complete model set of possible ecological or environmental predictors, given a response variable of interest and a starting generalized additive (mixed) model fit. Main advantages include not requiring a complete model to be fit as the starting point for candidate model set construction (meaning that a greater number of predictors can potentially be explored than might be available through functions such as dredge); model sets that include interactions between factors and continuous nonlinear predictors; and automatic removal of models with correlated predictors (based on a user defined criterion for exclusion). The function takes continuous predictors, which are fitted using smoothers via either gam, gamm (mgcv) or gamm4, as well as factor variables which are included on their own or as two-level interaction terms within the gam smooth (via use of the "by" argument), or with themselves. The function allows any model to be constructed and used as a null model, and takes a range of arguments that allow control over the model set being constructed, including specifying cyclic and linear continuous predictors, specification of the smoothing algorithm used, and the maximum complexity allowed for smooth terms. The use of the function is demonstrated via case studies that highlight how appropriate model sets can be easily constructed and the broader utility of the approach for exploratory ecology. PMID- 29988443 TI - Phenomenology and Clinical Correlates of Stimulus-Bound Tics in Gilles de la Tourette Syndrome. AB - Introduction: Stimulus-bound tics (SBTs) belong to stimulus-induced behaviors and are defined as tics that occur in response to internal or external stimuli. The aim of the study was to assess the prevalence and associations of SBTs with other stimulus-triggered behaviors, premonitory urges and stimulus sensitization in Gilles de la Tourette syndrome (GTS). Methods: We performed a prospective, one registration study in a cohort of 140 consecutive patients with GTS. Duration of GTS was 10.6 +/- 8.7 years (range: 0-39 years). SBTs were diagnosed during the interview. Results: SBTs occurred at some point in the lifetime of 20.7% of patients. The presence of SBTs in adults was four times as frequent as in children (35.5% vs. 9.0%) with the most frequent onset in adolescence (58.8%) and adulthood (29.4%). These tics started 9.1 +/- 4.7 years after the onset of tics. One stimulus and mental stimulus preceded tics most frequently, 44.8 and 33.3%, respectively. There was no established pattern of tics triggered by stimuli. Multivariate logistic regression analysis showed significant associations of SBTs with age at evaluation, tic severity, and palilalia but not with any co-morbid psychiatric disorders. 80% of patients showed at least one stimulus-triggered behavior. Premonitory urges and stimulus sensitization were reported by 60.0 and 40.7% of patients, respectively. No significant correlations between SBTs, premonitory urges and stimulus sensitization were found. Conclusion: SBTs are a part of the tic spectrum and should be taken into account by clinicians who deal with GTS patients. These tics fall at the tic end of the continuum of stimulus induced behaviors. PMID- 29988442 TI - Why does the magnitude of genotype-by-environment interaction vary? AB - Genotype-by-environment interaction (G * E), that is, genetic variation in phenotypic plasticity, is a central concept in ecology and evolutionary biology. G*E has wide-ranging implications for trait development and for understanding how organisms will respond to environmental change. Although G * E has been extensively documented, its presence and magnitude vary dramatically across populations and traits. Despite this, we still know little about why G * E is so evident in some traits and populations, but minimal or absent in others. To encourage synthetic research in this area, we review diverse hypotheses for the underlying biological causes of variation in G * E. We extract common themes from these hypotheses to develop a more synthetic understanding of variation in G * E and suggest some important next steps. PMID- 29988444 TI - Integrative analysis of genome-wide lncRNA and mRNA expression in newly synthesized Brassica hexaploids. AB - Polyploidization, as a significant evolution force, has been considered to facilitate plant diversity. The expression levels of lncRNAs and how they control the expression of protein-coding genes in allopolyploids remain largely unknown. In this study, lncRNA expression profiles were compared between Brassica hexaploid and its parents using a high-throughput sequencing approach. A total of 2,725, 1,672, and 2,810 lncRNAs were discovered in Brassica rapa, Brassica carinata, and Brassica hexaploid, respectively. It was also discovered that 725 lncRNAs were differentially expressed between Brassica hexaploid and its parents, and 379 lncRNAs were nonadditively expressed in this hexaploid. LncRNAs have multiple expression patterns between Brassica hexaploid and its parents and show paternal parent-biased expression. These lncRNAs were found to implement regulatory functions directly in the long-chain form, and acted as precursors or targets of miRNAs. According to the prediction of the targets of differentially expressed lncRNAs, 109 lncRNAs were annotated, and their target genes were involved in the metabolic process, pigmentation, reproduction, exposure to stimulus, biological regulation, and so on. Compared with the paternal parent, differentially expressed lncRNAs between Brassica hexaploid and its maternal parent participated in more regulation pathways. Additionally, 61 lncRNAs were identified as putative targets of known miRNAs, and 15 other lncRNAs worked as precursors of miRNAs. Some conservative motifs of lncRNAs from different groups were detected, which indicated that these motifs could be responsible for their regulatory roles. Our findings may provide a reference for the further study of the function and action mechanisms of lncRNAs during plant evolution. PMID- 29988445 TI - Needle in a haystack? A comparison of eDNA metabarcoding and targeted qPCR for detection of the great crested newt (Triturus cristatus). AB - Environmental DNA (eDNA) analysis is a rapid, cost-effective, non-invasive biodiversity monitoring tool which utilises DNA left behind in the environment by organisms for species detection. The method is used as a species-specific survey tool for rare or invasive species across a broad range of ecosystems. Recently, eDNA and "metabarcoding" have been combined to describe whole communities rather than focusing on single target species. However, whether metabarcoding is as sensitive as targeted approaches for rare species detection remains to be evaluated. The great crested newt Triturus cristatus is a flagship pond species of international conservation concern and the first UK species to be routinely monitored using eDNA. We evaluate whether eDNA metabarcoding has comparable sensitivity to targeted real-time quantitative PCR (qPCR) for T. cristatus detection. Extracted eDNA samples (N = 532) were screened for T. cristatus by qPCR and analysed for all vertebrate species using high-throughput sequencing technology. With qPCR and a detection threshold of 1 of 12 positive qPCR replicates, newts were detected in 50% of ponds. Detection decreased to 32% when the threshold was increased to 4 of 12 positive qPCR replicates. With metabarcoding, newts were detected in 34% of ponds without a detection threshold, and in 28% of ponds when a threshold (0.028%) was applied. Therefore, qPCR provided greater detection than metabarcoding but metabarcoding detection with no threshold was equivalent to qPCR with a stringent detection threshold. The proportion of T. cristatus sequences in each sample was positively associated with the number of positive qPCR replicates (qPCR score) suggesting eDNA metabarcoding may be indicative of eDNA concentration. eDNA metabarcoding holds enormous potential for holistic biodiversity assessment and routine freshwater monitoring. We advocate this community approach to freshwater monitoring to guide management and conservation, whereby entire communities can be initially surveyed to best inform use of funding and time for species-specific surveys. PMID- 29988446 TI - Selection of the sex-linked inhibitor of apoptosis in mountain pine beetle (Dendroctonus ponderosae) driven by enhanced expression during early overwintering. AB - The mountain pine beetle (Dendroctonus ponderosae) is an insect native to western North America; however, its geographical range has recently expanded north in BC and east into Alberta. To understand the population structure in the areas of expansion, 16 gene-linked microsatellites were screened and compared to neutral microsatellites using outlier analyses of Fst and Fct values. One sex-linked gene, inhibitor of apoptosis (IAP), showed a strong signature of positive selection for neo-X alleles and was analyzed for evidence of adaptive variation. Alleles of IAP were sequenced, and differences between the neo-X and neo-Y alleles were consistent with neutral evolution suggesting that the neo-Y allele may not be under functional constraints. Neo-Y alleles were amplified from gDNA, but not effectively from cDNA, suggesting that there was little IAP expression from neo-Y alleles. There were no differences in overall IAP expression between males and females with the common northern neo-X allele suggesting that the neo-X allele in males compensates for the reduced expression of neo-Y alleles. However, males lacking the most common northern neo-X allele thought to be selected for in northern populations had reduced overall IAP expression in early October-at a time when beetles are preparing for overwintering. This suggests that the most common allele may have more rapid upregulation. The reduced function of neo-Y alleles of IAP suggested by both sequence differences and lower levels of expression may foster a highly selective environment for neo-X alleles such as the common northern allele with more efficient upregulation. PMID- 29988448 TI - Plasticity of female reproductive resource allocation depends on the presence or absence of prior environmental sex determination in Ceratopteris richardii. AB - Resource allocation plasticity enables individuals to alter patterns of nutrient use between reproductive and vegetative output to better fit their current environment. In sexually labile plant species, abiotic environmental factors can influence expression of dimorphic gender, resulting in environmental sex determination (ESD), which potentially reduces the need for plasticity of resource allocation by preemptively matching an individual's future nutrient demands to resource availability in its location. Ceratopteris richardii gametophytes exhibit gender-dependent differences in relative carbon and nitrogen content, and ESD in certain nutrient environments. This study examined whether prior ESD in C. richardii gametophyte populations reduced subsequent plasticity of reproductive allocation compared to instances where no ESD occurred, by quantifying phenotypic responses to reduced P, N, or CO 2 availabilities. All three nutrient-limited environments resulted in decreased size of egg-bearing (meristic) gametophytes compared to nonlimited environments, but gametophytes failed to respond to N and CO 2 limitation at the time of sex determination, resulting in no ESD. N limitation resulted in a predictable allometric re allocation of resources based on small gametophyte size, whereas CO 2 limitation caused a change in reproductive output consistent with true plasticity. Withholding exogenous P caused ESD and had no effect on relative reproductive output of resultant meristic gametophytes because the size decrease was minor. Under P limitation, ESD matched the resource demands of gender phenotypes to their environment before the onset of developmental dimorphism, reducing the need for large allocation adjustments after sex determination. PMID- 29988447 TI - Structural Gray Matter Changes in the Hippocampus and the Primary Motor Cortex on An-Hour-to-One- Day Scale Can Predict Arm-Reaching Performance Improvement. AB - Recent studies have revealed rapid (e.g., hours to days) training-induced cortical structural changes using magnetic resonance imaging (MRI). Currently, there is great interest in studying how such a rapid brain structural change affects behavioral improvement. Structural reorganization contributes to memory or enhanced information processing in the brain and may increase its capability of skill learning. If the gray matter (GM) is capable of such rapid structural reorganization upon training, the extent of volume increase may characterize the learning process. To shed light on this issue, we conducted a case series study of 5-day visuomotor learning using neuroanatomical imaging, and analyzed the effect of rapid brain structural change on motor performance improvement via regression analysis. Participants performed an upper-arm reaching task under left right mirror-reversal for five consecutive days; T1-weighted MR imaging was performed before training, after the first and fifth days, and 1 week and 1 month after training. We detected increase in GM volume on the first day (i.e., a few hours after the first training session) in the primary motor cortex (M1), primary sensory cortex (S1), and in the hippocampal areas. Notably, regression analysis revealed that individual differences in such short-term increases were associated with the learning levels after 5 days of training. These results suggest that GM structural changes are not simply a footprint of previous motor learning but have some relationship with future motor learning. In conclusion, the present study provides new insight into the role of structural changes in causing functional changes during motor learning. PMID- 29988449 TI - Integrin alpha2beta1 Expression Regulates Matrix Metalloproteinase-1-Dependent Bronchial Epithelial Repair in Pulmonary Tuberculosis. AB - Pulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the alpha2beta1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin alpha2beta1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which alpha2beta1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB. PMID- 29988451 TI - Association of Interleukin-10 Methylation Levels With Gestational Diabetes in a Taiwanese Population. AB - Objective: Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset during pregnancy, which is also associated with future metabolic diseases in both patients and their offspring. The mechanisms underlying this condition remain largely unknown and may be partly related to epigenetics. The aim of this study was to compare the methylation levels of the cytokine interleukin-10 (IL-10) in pregnant women and their fetuses under both hyperglycemic and euglycemic environments, as those levels may be a clue to the epigenetic mechanisms underlying pathogenesis of GDM. Methods: We analyzed the methylation levels of the IL-10 gene in maternal blood, cord blood, and placental tissue in both a GDM group (n = 8) and a control group (n = 24) using a LightCycler LC480 (Roche, Rotkreuz, Switzerland). IL-10 concentrations in maternal blood and THP-1 cells were measured by enzyme-linked immunosorbent assay (ELISA) using BD OptEIA Human IL-10 ELISA kits (BD Biosciences Pharmingen, San Diego, CA, United States). Results: The maternal blood IL-10 methylation levels in the GDM group and the control group were 0.23 +/- 0.04 and 0.26 +/- 0.04, respectively (p = 0.03), but there were no significant differences between the levels of the two groups in the cord blood or placental tissue. Increased IL-10 plasma concentrations were discovered under hyperglycemic environments and were confirmed via the THP-1 cell line. Conclusion: Hypomethylation of maternal blood and increased plasma IL-10 concentrations before birth were found in the GDM group. PMID- 29988450 TI - Modulation of Amyloidogenesis Controlled by the C-Terminal Domain of Islet Amyloid Polypeptide Shows New Functions on Hepatocyte Cholesterol Metabolism. AB - The islet amyloid polypeptide (IAPP) or amylin maintains a key role in metabolism. This 37-residues-peptide could form pancreatic amyloids, which are a characteristic feature of diabetes mellitus type 2. However, some species do not form amyloid fibril structures. By employing a biomimetic approach, we generated an extensive panel of optimized sequences of IAPP, which could drastically reduce aggregation propensity. A structural and cellular characterization analysis was performed on the C-terminal domain with the highest aggregation propensity. This allowed the observation of an aggregative phenomenon dependent of the lipid environment. Evaluation of the new F23R variant demonstrated inhibition of beta sheet structure and, therefore, amyloid formation on the native C-terminal, phenomenon that was associated with functional optimization in calcium and cholesterol management coupled with the optimization of insulin secretion by beta cells. When F23R variant was evaluated in microglia cells, a model of amyloidosis, cytotoxic conditions were not registered. In addition, it was found that C-terminal sequences of IAPP could modulate cholesterol metabolism in hepatocytes through regulation of SREBP-2, apoA-1, ABCA1, and LDLR, mechanism that may represent a new function of IAPP on the metabolism of cholesterol, increasing the LDL endocytosis in hepatocytes. Optimized sequences with only one residue modification in the C-terminal core aggregation could diminish beta-sheet formation and represent a novel strategy adaptable to other pharmacological targets. Our data suggest a new IAPP function associated with rearrangements on metabolism of cholesterol in hepatocytes. PMID- 29988452 TI - Domain Swap Approach Reveals the Critical Roles of Different Domains of SYMRK in Root Nodule Symbiosis in Lotus japonicus. AB - Symbiosis receptor kinase (SYMRK) is a cell membrane-localized protein kinase containing extracellular malectin-like domain (MLD) and leucine-rich repeat (LRR) domains, which is critically required for both root nodule symbiosis (RNS) and arbuscular mycorrhizal symbiosis (AMS). SYMRK is widely distributed in the genomes of different plant species; however, the contribution of different domains of SYMRK and its homologs from other plant species to RNS is largely unclear. In this study, SYMRK and its homologs from three typical plant species including Medicago truncatula (for both RNS and AMS), Oryza sativa (for AMS but not RNS), and Arabidopsis thaliana (for neither RNS or AMS) were investigated using domain swap approach in response to rhizobia in Lotus japonicus. Full length SYMRK from rice and Medicago but not from Arabidopsis could complement Lotus symrk-409 mutant plants to contribute RNS. The chimeric protein with the extracellular domain (ED) of LjSYMRK and cytoplasmic domains (CD) of SYMRK from both Medicago and rice but not Arabidopsis could contribute to RNS in Lotus, suggesting that the CD of SYMRK is required for symbiotic signaling. The chimeric receptors containing the CD of LjSYMRK (SYMRKCD) and the EDs of MtDMI2 (MtDMI2ED), OsSYMRK (OsSYMRKED), AtSYMRK (AtSYMRKED), NFR1 (NFR1ED), and NFR5 (NFR5ED) could complement Lotus symrk-409 mutant plants to develop nodules. However, MtDMI2 could partially complement Lotus symrk-409 mutants to form both effective nodules and ineffective bumps, which is similar to the complementation results from MtDMI2ED-LjSYMRKCD and LjSYMRKGDLC in Lotus symrk-409 mutants, suggesting that ED of SYMRK has a very fine-tune regulation for RNS in Lotus. The deletion of either MLD or LRR on SYMRKGDLC (a mutant version of SYMRK with GDPC motif replaced by GDLC) could contribute to RNS when overexpressed in Lotus symrk 409 mutants, suggesting that MLD and LRR domains might work together to be involved in symbiotic signaling and the LRR domain might play a negative role in LjSYMRKGDLC-mediated RNS. By mutagenizing the conserved amino acids on LRR domain, five serine residues were found to be required for the function of LjSYMRKGDLC in RNS. These finding precisely refine the molecular mechanisms of SYMRK function in symbiotic signaling in L. japonicus. PMID- 29988453 TI - Automating analysis of vegetation with computer vision: Cover estimates and classification. AB - This study develops an approach to automating the process of vegetation cover estimates using computer vision and pattern recognition algorithms. Visual cover estimation is a key tool for many ecological studies, yet quadrat-based analyses are known to suffer from issues of consistency between people as well as across sites (spatially) and time (temporally). Previous efforts to estimate cover from photograps require considerable manual work. We demonstrate that an automated system can be used to estimate vegetation cover and the type of vegetation cover present using top-down photographs of 1 m by 1 m quadrats. Vegetation cover is estimated by modelling the distribution of color using a multivariate Gaussian. The type of vegetation cover is then classified, using illumination robust local binary pattern features, into two broad groups: graminoids (grasses) and forbs. This system is evaluated on two datasets from the globally distributed experiment, the Nutrient Network (NutNet). These NutNet sites were selected for analyses because repeat photographs were taken over time and these sites are representative of very different grassland ecosystems-a low stature subalpine grassland in an alpine region of Australia and a higher stature and more productive lowland grassland in the Pacific Northwest of the USA. We find that estimates of treatment effects on grass and forb cover did not differ between field and automated estimates for eight of nine experimental treatments. Conclusions about total vegetation cover did not correspond quite as strongly, particularly at the more productive site. A limitation with this automated system is that the total vegetation cover is given as a percentage of pixels considered to contain vegetation, but ecologists can distinguish species with overlapping coverage and thus can estimate total coverage to exceed 100%. Automated approaches such as this offer techniques for estimating vegetation cover that are repeatable, cheaper to use, and likely more reliable for quantifying changes in vegetation over the long-term. These approaches would also enable ecologists to increase the spatial and temporal depth of their coverage estimates with methods that allow for vegetation sampling over large spatial scales quickly. PMID- 29988454 TI - Combining data-derived priors with postrelease monitoring data to predict persistence of reintroduced populations. AB - Monitoring is an essential part of reintroduction programs, but many years of data may be needed to obtain reliable population projections. This duration can potentially be reduced by incorporating prior information on expected vital rates (survival and fecundity) when making inferences from monitoring data. The prior distributions for these parameters can be derived from data for previous reintroductions, but it is important to account for site-to-site variation. We evaluated whether such informative priors improved our ability to estimate the finite rate of increase (lambda) of the North Island robin (Petroica longipes) population reintroduced to Tawharanui Regional Park, New Zealand. We assessed how precision improved with each year of postrelease data added, comparing models that used informative or uninformative priors. The population grew from about 22 to 80 individuals from 2007 to 2016, with lambda estimated to be 1.23 if density dependence was included in the model and 1.13 otherwise. Under either model, 7 years of data were required before the lower 95% credible limit for lambda was > 1, giving confidence that the population would persist. The informative priors did not reduce this requirement. Data-derived priors are useful before reintroduction because they allow lambda to be estimated in advance. However, in the case examined here, the value of the priors was overwhelmed once site specific monitoring data became available. The Bayesian method presented is logical for reintroduced populations. It allows prior information (used to inform prerelease decisions) to be integrated with postrelease monitoring. This makes full use of the data for ongoing management decisions. However, if the priors properly account for site-to-site variation, they may have little predictive value compared with the site-specific data. This value will depend on the degree of site-to-site variation as well as the quality of the data. PMID- 29988455 TI - Age-Dependent Changes in the Propofol-Induced Electroencephalogram in Children With Autism Spectrum Disorder. AB - Patients with autism spectrum disorder (ASD) often require sedation or general anesthesia. ASD is thought to arise from deficits in GABAergic signaling leading to abnormal neurodevelopment. We sought to investigate differences in how ASD patients respond to the GABAergic drug propofol by comparing the propofol-induced electroencephalogram (EEG) of ASD and neurotypical (NT) patients. This investigation was a prospective observational study. Continuous 4-channel frontal EEG was recorded during routine anesthetic care of patients undergoing endoscopic procedures between July 1, 2014 and May 1, 2016. Study patients were defined as those with previously diagnosed ASD by DSM-V criteria, aged 2-30 years old. NT patients were defined as those lacking neurological or psychiatric abnormalities, aged 2-30 years old. The primary outcome was changes in propofol-induced alpha (8 13 Hz) and slow (0.1-1 Hz) oscillation power by age. A post hoc analysis was performed to characterize incidence of burst suppression during propofol anesthesia. The primary risk factor of interest was a prior diagnosis of ASD. Outcomes were compared between ASD and NT patients using Bayesian methods. Compared to NT patients, slow oscillation power was initially higher in ASD patients (17.05 vs. 14.20 dB at 2.33 years), but progressively declined with age (11.56 vs. 13.95 dB at 22.5 years). Frontal alpha power was initially lower in ASD patients (17.65 vs. 18.86 dB at 5.42 years) and continued to decline with age (6.37 vs. 11.89 dB at 22.5 years). The incidence of burst suppression was significantly higher in ASD vs. NT patients (23.0% vs. 12.2%, p < 0.01) despite reduced total propofol dosing in ASD patients. Ultimately, we found that ASD patients respond differently to propofol compared to NT patients. A similar pattern of decreased alpha power and increased sensitivity to burst suppression develops in older NT adults; one interpretation of our data could be that ASD patients undergo a form of accelerated neuronal aging in adolescence. Our results suggest that investigations of the propofol-induced EEG in ASD patients may enable insights into the underlying differences in neural circuitry of ASD and yield safer practices for managing patients with ASD. PMID- 29988457 TI - Reversed predator-prey cycles are driven by the amplitude of prey oscillations. AB - Ecoevolutionary feedbacks in predator-prey systems have been shown to qualitatively alter predator-prey dynamics. As a striking example, defense offense coevolution can reverse predator-prey cycles, so predator peaks precede prey peaks rather than vice versa. However, this has only rarely been shown in either model studies or empirical systems. Here, we investigate whether this rarity is a fundamental feature of reversed cycles by exploring under which conditions they should be found. For this, we first identify potential conditions and parameter ranges most likely to result in reversed cycles by developing a new measure, the effective prey biomass, which combines prey biomass with prey and predator traits, and represents the prey biomass as perceived by the predator. We show that predator dynamics always follow the dynamics of the effective prey biomass with a classic 1/4-phase lag. From this key insight, it follows that in reversed cycles (i.e., 3/4-lag), the dynamics of the actual and the effective prey biomass must be in antiphase with each other, that is, the effective prey biomass must be highest when actual prey biomass is lowest, and vice versa. Based on this, we predict that reversed cycles should be found mainly when oscillations in actual prey biomass are small and thus have limited impact on the dynamics of the effective prey biomass, which are mainly driven by trait changes. We then confirm this prediction using numerical simulations of a coevolutionary predator prey system, varying the amplitude of the oscillations in prey biomass: Reversed cycles are consistently associated with regions of parameter space leading to small-amplitude prey oscillations, offering a specific and highly testable prediction for conditions under which reversed cycles should occur in natural systems. PMID- 29988456 TI - DNA methylation in adults and during development of the self-fertilizing mangrove rivulus, Kryptolebias marmoratus. AB - In addition to genetic variation, epigenetic mechanisms such as DNA methylation might make important contributions to heritable phenotypic diversity in populations. However, it is often difficult to disentangle the contributions of genetic and epigenetic variation to phenotypic diversity. Here, we investigated global DNA methylation and mRNA expression of the methylation-associated enzymes during embryonic development and in adult tissues of one natural isogenic lineage of mangrove rivulus fish, Kryptolebias marmoratus. Being the best-known self fertilizing hermaphroditic vertebrate affords the opportunity to work with genetically identical individuals to examine, explicitly, the phenotypic effects of epigenetic variance. Using the LUminometric Methylation Assay (LUMA), we described variable global DNA methylation at CpG sites in adult tissues, which differed significantly between hermaphrodite ovotestes and male testes (79.6% and 87.2%, respectively). After fertilization, an immediate decrease in DNA methylation occurred to 15.8% in gastrula followed by re-establishment to 70.0% by stage 26 (liver formation). Compared to zebrafish, at the same embryonic stages, this reprogramming event seems later, deeper, and longer. Furthermore, genes putatively encoding DNA methyltransferases (DNMTs), Ten-Eleven Translocation (TET), and MeCP2 proteins showed specific regulation in adult gonad and brain, and also during early embryogenesis. Their conserved domains and expression profiles suggest that these proteins play important roles during reproduction and development. This study raises questions about mangrove rivulus' peculiar reprogramming period in terms of epigenetic transmission and physiological adaptation of individuals to highly variable environments. In accordance with the general-purpose genotype model, epigenetic mechanisms might allow for the expression of diverse phenotypes among genetically identical individuals. Such phenotypes might help to overcome environmental challenges, making the mangrove rivulus a valuable vertebrate model for ecological epigenetic studies. The mangrove rivulus, Kryptolebias marmoratus, is the best-known self fertilizing hermaphroditic vertebrate that allows to work with genetically identical individuals to examine, explicitly, the phenotypic effects of epigenetic variance. The reprogramming event is later, more dramatic and longer than in other described vertebrates. High evolutionary conservation and expression patterns of DNMT, TET, and MeCP2 proteins in K. marmoratus suggest biological roles for each member in gametogenesis and development. PMID- 29988458 TI - Deviant Dynamics of Resting State Electroencephalogram Microstate in Patients With Subjective Tinnitus. AB - Given the importance of central reorganization and tinnitus, we undertook the current study to investigate changes to electroencephalogram (EEG) microstates and their association with the clinical symptoms in tinnitus. High-density (128 channel) EEG was used to explore changes in microstate features in 15 subjects with subjective tinnitus and 17 age-matched controls. Correlations between microstate parameters and subjective tinnitus symptoms were also analyzed. An increased presence of class A microstate and decreased presence of class D microstate were found in coverage and lifespan of microstate parameters in the tinnitus patients. Syntax analysis also demonstrated an aberrant pattern of activity, with reduced transitions from class D to class B in tinnitus patients. Moreover, a significant positive correlation of tinnitus loudness with increased lifespan of microstate class C was found. Significant differences in temporal characteristics and syntax of the EEG microstate classes were found at rest between tinnitus patients and the healthy subjects. Our study indicates that EEG microstates may provide a possible valuable method to study large-scale brain networks, which may in turn be beneficial to investigation of the neurophysiological mechanisms behind tinnitus. PMID- 29988460 TI - Abundance of Bemisia tabaci Gennadius (Hemiptera: Aleyrodidae) and its parasitoids on vegetables and cassava plants in Burkina Faso (West Africa). AB - The whitefly Bemisia tabaci is a pest of many agricultural and ornamental crops worldwide and particularly in Africa. It is a complex of cryptic species, which is extremely polyphagous with hundreds of host plants identified around the world. Previous surveys in western Africa indicated the presence of two biotypes of the invasive MED species (MED-Q1 and MED-Q3) living in sympatry with the African species SSA and ASL. This situation constitutes one of the rare cases of local coexistence of various genetic entities within the B. tabaci complex. In order to study the dynamics of the distribution and abundance of genetic entities within this community and to identify potential factors that could contribute to coexistence, we sampled B. tabaci populations in Burkina Faso in 2015 and 2016 on various plants, and also their parasitoids. All four genetic entities were still recorded, indicating no exclusion of local species by the MED species. While B. tabaci individuals were found on 55 plant species belonging to eighteen (18) families showing the high polyphagy of this pest, some species/biotypes exhibited higher specificity. Two parasitoid species (Eretmocerus mundus and Encarsia vandrieschei) were also recorded with E. mundus being predominant in most localities and on most plants. Our data indicated that whitefly abundance, diversity, and rate of parasitism varied according to areas, plants, and years, but that parasitism rate was globally highly correlated with whitefly abundance suggesting density dependence. Our results also suggest dynamic variation in the local diversity of B. tabaci species/biotypes from 1 year to the other, specifically with MED-Q1 and ASL species. This work provides relevant information on the nature of plant-B. tabaci-parasitoid interactions in West Africa and identifies that coexistence might be stabilized by niche differentiation for some genetic entities. However, MED-Q1 and ASL show extensive niche overlap, which could ultimately lead to competitive exclusion. PMID- 29988459 TI - Fruit-Derived Polysaccharides and Terpenoids: Recent Update on the Gastroprotective Effects and Mechanisms. AB - Ulceration in the stomach develops in peptic ulcer disease when there is a loss of protective mucosal layers, particularly in Helicobacter pylori infection. Antibiotic therapy has failed to eradicate and impede the colonization of H. pylori. Despite given treatment, recurrent bleeding can occur and lead to death in the affected individual. The disease progression is also related to the non steroidal inflammatory drug and stress. There are extensive research efforts to identify the gastroprotective property from various alkaloids, flavonoids, and tannins compounds from plants and marine. These natural products are believed to be safe for consumption. However, not much attention was given to summarize the carbohydrate and terpenoidal anti-ulcer compounds. Hence, this review will cover the possible mechanisms and information about acidic hydroxylans, arabinogalactan and rhamnogalacturon; and limonene, pinene, lupeol, citral, ursolic acid and nomilin to exemplify on the gastroprotective properties of polysaccharides and terpenoid, respectively, obtained from fruits. These compounds could act as a prebiotic to prevent the inhabitation of H. pylori, modulate the inflammation, suppress gastric cancer growth, and capable of stimulating the reparative mechanisms on the affected regions. Finally, this review provides the future research prospects of these natural compounds in an effort to develop new therapy for gastrointestinal tissue healing. PMID- 29988461 TI - Juicy June: a mass-participation snack-swap challenge-results from a mixed methods feasibility study. AB - Background: Improving diet as a means of reducing the development of disease states and obesity is a public health priority. Although a growing number of countries have adopted policies to improve dietary patterns at the population level, as yet there are no established means of successfully bringing about change, suggesting that new approaches are needed. This study aimed to investigate the feasibility and proof of concept of a theoretically informed healthy eating intervention based on the model of successful month-long alcohol reduction or stop smoking campaigns (i.e. a mass-participation 'challenge' format). Methods: The study was a mixed methods feasibility trial and proof of concept of an online intervention. Adults were recruited to take part in a month long 'Juicy June' challenge in which they nominated one unhealthy daily snack and committed to replace this with fruit or vegetables. Behaviour change techniques to promote motivation, increase self-efficacy, promote social support, self regulation and habit formation were integrated into materials provided off- and online to support dietary change. A Facebook group was used to provide information, encouragement and foster social support. Diet quality was assessed before and after the intervention. Reasons for taking part, adherence to the snack swap, use of the intervention materials and experience of taking part were explored using quantitative and qualitative measures. Results: Ninety-one adults of whom 42% were either overweight or obese took part. Over the 4-week intervention period, participants consumed their intended fruit/vegetable snack on average 5 days/week; however, they still consumed their target unhealthy snack on average 2 days/week. Adherence to the snack swap was stable over the 4-week intervention period. The use of specific behaviour change tools (e.g. self monitoring) was low. Sixty-seven percent of participants accessed the online Facebook forum, but there were no user-generated posts or content. Conclusions: The study demonstrated that the concept of a novel snack swap mass participation campaign is acceptable and feasible. Further piloting to explore how to promote greater engagement with men and ethnic minority groups and how to promote social support and maximise engagement with behaviour change techniques would be valuable. PMID- 29988462 TI - Spatiotemporal and gender-specific parasitism in two species of gobiid fish. AB - Parasitism is considered a major selective force in natural host populations. Infections can decrease host condition and vigour, and potentially influence, for example, host population dynamics and behavior such as mate choice. We studied parasite infections of two common marine fish species, the sand goby (Pomatoschistus minutus) and the common goby (Pomatoschistus microps), in the brackish water Northern Baltic Sea. We were particularly interested in the occurrence of parasite taxa located in central sensory organs, such as eyes, potentially affecting fish behavior and mate choice. We found that both fish species harbored parasite communities dominated by taxa transmitted to fish through aquatic invertebrates. Infections also showed significant spatiotemporal variation. Trematodes in the eyes were very few in some locations, but infection levels were higher among females than males, suggesting differences in exposure or resistance between the sexes. To test between these hypotheses, we experimentally exposed male and female sand gobies to infection with the eye fluke Diplostomum pseudospathaceum. These trials showed that the fish became readily infected and females had higher parasite numbers, supporting higher susceptibility of females. Eye fluke infections also caused high cataract intensities among the fish in the wild. Our results demonstrate the potential of these parasites to influence host condition and visual abilities, which may have significant implications for survival and mate choice in goby populations. PMID- 29988464 TI - Should ambulatory appendectomy become the standard treatment for acute appendicitis? AB - Background: Appendectomy is increasingly performed as a 'short stay' or 'ambulatory' procedure, yet there is no consensus for selection of patients with acute appendicitis for ambulatory surgery (AS). We aimed to compare characteristics and outcomes of complicated and uncomplicated appendectomies performed in ambulatory vs. conventional settings, and to determine factors associated with unexpected re-consultations and re-hospitalizations. Methods: The authors reviewed a consecutive series of 185 laparoscopic appendectomies. Whenever possible, patients were offered AS, defined as 'discharge on the same working day.' Multivariable regressions were performed to determine associations of unexpected re-consultations and re-hospitalizations with surgery type (ambulatory or conventional) and patient characteristics (age, gender, obesity, symptoms, appendicolith, perforations, appendix diameter, serologic results, American Society of Anesthesiologists score, and Saint-Antoine score). Results: From the initial cohort, 117 patients (63.2%) were eligible for AS, of which 8 had peri- or post-operative contraindications. Therefore, 109 patients (58.9%) were operated by AS, with median length of stay 8.5 h (range, 3.3-20.5). Ambulatory cases had a lower incidence of complications (11.9%) than conventional cases (25.0%) (p = 0.029). Uni- and multi-variable regressions revealed that unexpected re-consultations were not significantly associated with any of the pre or peri-operative variables but that unexpected re-hospitalizations were 4 times more likely for patients with appendicolith (OR, 4.32; p = 0.04). Conclusions: Ambulatory surgery could be considered as a standard procedure for both complicated and uncomplicated acute appendicitis. Appendicolith was found to be an independent risk factor for unexpected re-hospitalization and should therefore trigger closer monitoring. PMID- 29988463 TI - Botulinum Neurotoxin Detection Methods for Public Health Response and Surveillance. AB - Botulism outbreak due to consumption of food contaminated with botulinum neurotoxins (BoNTs) is a public health emergency. The threat of bioterrorism through deliberate distribution in food sources and/or aerosolization of BoNTs raises global public health and security concerns due to the potential for high mortality and morbidity. Rapid and reliable detection methods are necessary to support clinical diagnosis and surveillance for identifying the source of contamination, performing epidemiological analysis of the outbreak, preventing and responding to botulism outbreaks. This review considers the applicability of various BoNT detection methods and examines their fitness-for-purpose in safeguarding the public health and security goals. PMID- 29988465 TI - Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB 468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB 231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development. PMID- 29988466 TI - Deep Learning: Individual Maize Segmentation From Terrestrial Lidar Data Using Faster R-CNN and Regional Growth Algorithms. AB - The rapid development of light detection and ranging (Lidar) provides a promising way to obtain three-dimensional (3D) phenotype traits with its high ability of recording accurate 3D laser points. Recently, Lidar has been widely used to obtain phenotype data in the greenhouse and field with along other sensors. Individual maize segmentation is the prerequisite for high throughput phenotype data extraction at individual crop or leaf level, which is still a huge challenge. Deep learning, a state-of-the-art machine learning method, has shown high performance in object detection, classification, and segmentation. In this study, we proposed a method to combine deep leaning and regional growth algorithms to segment individual maize from terrestrial Lidar data. The scanned 3D points of the training site were sliced row and row with a fixed 3D window. Points within the window were compressed into deep images, which were used to train the Faster R-CNN (region-based convolutional neural network) model to learn the ability of detecting maize stem. Three sites of different planting densities were used to test the method. Each site was also sliced into many 3D windows, and the testing deep images were generated. The detected stem in the testing images can be mapped into 3D points, which were used as seed points for the regional growth algorithm to grow individual maize from bottom to up. The results showed that the method combing deep leaning and regional growth algorithms was promising in individual maize segmentation, and the values of r, p, and F of the three testing sites with different planting density were all over 0.9. Moreover, the height of the truly segmented maize was highly correlated to the manually measured height (R2> 0.9). This work shows the possibility of using deep leaning to solve the individual maize segmentation problem from Lidar data. PMID- 29988468 TI - The Social Utility of Ambivalence: Being Ambivalent on Controversial Issues Is Recognized as Competence. AB - Research on attitudinal ambivalence is flourishing, but no research has studied how others perceive its expression. We tested the hypothesis that the expression of attitudinal ambivalence could be positively valued if it signals careful consideration of an issue. More specifically, ambivalence should be judged higher on social utility (competence) but not on social desirability (warmth), compared to clear-cut attitudes. This should be the case for controversial (vs. consensual) issues, where ambivalence can signal some competence. The participants in four experiments indeed evaluated ambivalence higher on a measure of social utility, compared to clear-cut (pro-normative and counter-normative) attitudes, when the attitude objects were controversial; they judged pro normative attitudes higher for both social utility and social desirability when the attitude objects were consensual. Attitudinal ambivalence can therefore be positively valued, as it is perceived as competence when the expression of criticism is socially accepted. PMID- 29988467 TI - Sitagliptin and Fractures in Type 2 Diabetes: A Nationwide Population-Based Propensity-Matching Study. AB - Background: Sitagliptin, a dipeptidyl peptidase-4 inhibitor possibly affects bone turnover. We conducted this cohort study to determine whether sitagliptin is associated with an increased risk of fracture. Methods: The sitagliptin cohort included 1,578 patients aged 20 years and above. The nonsitagliptin cohort comprised propensity-score matched patients at a ratio of 1:1. The primary outcome was the incidence of fractures, which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. Results: The mean age of patients in the sitagliptin and nonsitagliptin cohorts was 63.1 and 63.3 years, respectively. The incidence of fractures in the sitagliptin cohort was 46 per 1,000 person-years and that in the nonsitagliptin cohort was 40.8 per 1,000 person-years. Compared with patients in the nonsitagliptin cohort, those in the sitagliptin cohort who received sitagliptin for >=250 days had a higher risk of fracture (aHR = 1.32, 95% CI = 1.06-1.64). Conclusion: Using sitaglipin >=250 days was associated with an increased risk of fracture. PMID- 29988469 TI - Killing Many Birds With Two Stones: Hypoxia and Fibrosis Can Generate Ectopic Beats in a Human Ventricular Model. AB - During cardiac diseases many types of anatomical and functional remodeling of cardiac tissue can occur. In this work, we focus on two conditions: hypoxia and fibrosis, which are part of complex pathological modifications that take place in many cardiac diseases (hypertrophic cardiomyopathy, hypertensive heart disease, and recurrent myocardial infarction) and respiratory diseases (obstructive pulmonary disease, obstructive sleep apnea, and cystic fibrosis). Using computational models of cardiac electrophysiology, we evaluate if the interplay between hypoxia and fibrosis is sufficient to trigger cardiac arrhythmia. We study the mechanisms behind the generation of ectopic beats, an arrhythmic trigger also known as premature ventricular contractions (PVCs), in regions with high hypoxia and fibrosis. First, we modify an electrophysiological model of myocytes of the human left ventricle to include the effects of hypoxia. Second, diffuse fibrosis is modeled by randomly replacing cardiac myocytes by non excitable and non-conducting cells. The Monte Carlo method is used to evaluate the probability of a region to generate ectopic beats with respect to different levels of hypoxia and fibrosis. In addition, we evaluate the minimum size of three-dimensional slabs needed to sustain reentries for different stimulation protocols. The observed mechanism behind the initiation of ectopic beats is unidirectional block, giving rise to sustained micro-reentries inside the region with diffuse fibrosis and hypoxia. In summary, our results suggest that hypoxia and fibrosis are sufficient for the creation of a focal region in the heart that generates PVCs. PMID- 29988471 TI - Biochemical methane potential of microalgae biomass using different microbial inocula. AB - Background: Microalgae biomass is regarded as a potential feedstock for bioenergy purposes through anaerobic digestion (AD). Even though AD is a well-proven technology, the use of new feedstocks requires in-depth studies. A lot of research has been conducted assessing methane yield without paying attention to the anaerobic microbiome and their activities. For such a goal, the present investigation was designed to link methane yield to those two later sludge characteristics. In this sense, different anaerobic sources were tested, namely adapted to microalgae biomass and adapted to sewage sludge. Results: Despite the registered differences for the anaerobic microbiome analysis and specific methane activities towards model substrates, sludge adapted to digest sewage sludge did not affect the methane yield of Chlorella sorokiniana and Scenedesmus sp. Opposite to that, sludge samples adapted to digest microalgae exhibited a concomitant increase in methane yield together with increasing digestion temperatures. More specifically, the values attained were 63.4 +/- 1.5, 79.2 +/- 3.1 and 108.2 +/- 1.9 mL CH4 g COD in-1 for psychrophilic, mesophilic and thermophilic digestions, respectively. While psycro- and mesophilic digestion supported similar yields (most probably linked to their anaerobic microbiome resemblance), the values attained for thermophilic digestion evidenced the usefulness of having a highly specific microbiome. The relative abundance of Firmicutes, particularly Clostridia, and Proteobacteria together with an important abundance of hydrogenotrophic methanogens was highlighted in this inoculum. Conclusion: Overall, this study showed that working with tailored anaerobic microbiome could help avoiding pretreatments devoted to methane yield enhancement. PMID- 29988472 TI - Comparison of flow pressures in different 3-way infusion devices: an in-vitro study. AB - Background: The use of multiple infusions through one cannula is an increasingly common practice in anaesthesia. High pressures in the line often lead to occlusion alarms and pump disconnection. In this study, we aim to determine the pressures generated in common 3-way infusion devices, using simple low-cost equipment available and currently in use in the operating theatre environment. Methods: We compared three different common and commercially available 3-way infusion devices that allowed multiple infusions through one cannula in vitro. One with anti-siphon valves, one without valves, and serial extension sets with side ports connected in series. An invasive blood pressure transducer was used to monitor line pressure. Seven different infusion rates were used to simulate different infusions. Results: 3-way infusion devices with anti-siphon valves have 5.5 times the infusion pressures compared to devices without valves (P < 0.001). The highest pressures obtained across all devices were at the highest flow rate studied (400 ml/hr); this was 243 mmHg in the 3-way device with anti-siphon valves, compared to only 44 mmHg in the 3-way device without valves and 36 mmHg in the serial extension sets. Serial extension sets have the lowest pressures across all flow rates when compared to 3-way devices without valves. (P = 0.0001). Conclusions: The presence of anti-siphon valves generate very high pressures in infusion lines that can contribute to occlusion alarm disconnection of a pump. However, when measured alone and in-vitro, these pressures are not sufficient to trigger occlusion alarms. There are 3-way infusion devices without anti-siphon valves that have lower line pressures, but clinicians should be aware of negative pressure scenarios which can lead to siphoning when using them. PMID- 29988470 TI - Potential Utility of Retinal Imaging for Alzheimer's Disease: A Review. AB - The ensuing upward shift in demographic distribution due to the increase in life expectancy has resulted in a rising prevalence of Alzheimer's disease (AD). The heavy public burden of AD, along with the urgent to prevent and treat the disease before the irreversible damage to the brain, calls for a sensitive and specific screening technology to identify high-risk individuals before cognitive symptoms arise. Even though current modalities, such as positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarker, showed their potential clinical uses in early detection of AD, the high cost, narrow isotope availability of PET probes and invasive characteristics of CSF biomarker limited their broad utility. Therefore, additional tools for detection of AD are needed. As a projection of the central nervous system (CNS), the retina has been described as a "window to the brain" and a novel marker for AD. Low cost, easy accessibility and non invasive features make retina tests suitable for large-scale population screening and investigations of preclinical AD. Furthermore, a number of novel approaches in retina imaging, such as optical coherence tomography (OCT), have been developed and made it possible to visualize changes in the retina at a very fine resolution. In this review, we outline the background for AD to accelerate the adoption of retina imaging for the diagnosis and management of AD in clinical practice. Then, we focus on recent findings on the application of retina imaging to investigate AD and provide suggestions for future research directions. PMID- 29988474 TI - Knowledge of mental health legislation in Ghana: a case of the use of certificate of urgency in mental health care. AB - Introduction: Mental illness can affect anyone irrespective of race, gender or personal characteristics. The study sought to investigate health workers' Knowledge on Mental Health Legislation in Ghana focusing on the Certificate of Urgency. Methods: A descriptive study design was employed for this study. The study population included medical doctors, physician assistants, and nurses/midwives. A simple random sampling technique was used to select 384 respondents for the study. Data was collected through the use of semi-structured questionnaires. Results: Respondents who were psychiatrists were 9.56 times more knowledgeable in the use of Certificate of Urgency than those in other specialties like primary care, obstetrics and gynaecology, surgery and internal medicine; adjusted odds ratio (AOR) = 9.56 [95% confidence interval (CI) 1.57 65.2]. Respondents who had used the Certificate of Urgency before had 4.7 times more knowledge as compared to those who had not used it at all; adjusted odds ratio (AOR) = 4.77 [95% confidence interval (CI) 1.021-14.01]. Conclusion: Knowledge of Certificate of Urgency was generally low. Authorities of the various hospitals should organize regular in-service training to enlighten all healthcare workers on the legislation governing mental healthcare in Ghana. PMID- 29988475 TI - Stop Thinking! I Can't! Do Attentional Mechanisms Underlie Primary Dysfunctional Breathing? PMID- 29988473 TI - DNA methylation of imprinted genes at birth is associated with child weight status at birth, 1 year, and 3 years. AB - Background: This study assessed the associations between nine differentially methylated regions (DMRs) of imprinted genes in DNA derived from umbilical cord blood leukocytes in males and females and (1) birth weight for gestational age z score, (2) weight-for-length (WFL) z score at 1 year, and (3) body mass index (BMI) z score at 3 years. Methods: We conducted multiple linear regression in n = 567 infants at birth, n = 288 children at 1 year, and n = 294 children at 3 years from the Newborn Epigenetics Study (NEST). We stratified by sex and adjusted for race/ethnicity, maternal education, maternal pre-pregnancy BMI, prenatal smoking, maternal age, gestational age, and paternal race. We also conducted analysis restricting to infants not born small for gestational age. Results: We found an association between higher methylation of the sequences regulating paternally expressed gene 10 (PEG10) and anthropometric z scores at 1 year (beta = 0.84; 95% CI = 0.34, 1.33; p = 0.001) and 3 years (beta = 1.03; 95% CI = 0.37, 1.69; p value = 0.003) in males only. Higher methylation of the DMR regulating mesoderm specific transcript (MEST) was associated with lower anthropometric z scores in females at 1 year (beta = - 1.03; 95% CI - 1.60, - 0.45; p value = 0.001) and 3 years (beta = - 1.11; 95% CI - 1.98, - 0.24; p value = 0.01). These associations persisted when we restricted to infants not born small for gestational age. Conclusion: Our data support a sex-specific association between altered methylation and weight status in early life. These methylation marks can contribute to the compendium of epigenetically regulated regions detectable at birth, influencing obesity in childhood. Larger studies are required to confirm these findings. PMID- 29988476 TI - Perceived Statistical Knowledge Level and Self-Reported Statistical Practice Among Academic Psychologists. AB - Introduction: Publications arguing against the null hypothesis significance testing (NHST) procedure and in favor of good statistical practices have increased. The most frequently mentioned alternatives to NHST are effect size statistics (ES), confidence intervals (CIs), and meta-analyses. A recent survey conducted in Spain found that academic psychologists have poor knowledge about effect size statistics, confidence intervals, and graphic displays for meta analyses, which might lead to a misinterpretation of the results. In addition, it also found that, although the use of ES is becoming generalized, the same thing is not true for CIs. Finally, academics with greater knowledge about ES statistics presented a profile closer to good statistical practice and research design. Our main purpose was to analyze the extension of these results to a different geographical area through a replication study. Methods: For this purpose, we elaborated an on-line survey that included the same items as the original research, and we asked academic psychologists to indicate their level of knowledge about ES, their CIs, and meta-analyses, and how they use them. The sample consisted of 159 Italian academic psychologists (54.09% women, mean age of 47.65 years). The mean number of years in the position of professor was 12.90 (SD = 10.21). Results: As in the original research, the results showed that, although the use of effect size estimates is becoming generalized, an under-reporting of CIs for ES persists. The most frequent ES statistics mentioned were Cohen's d and R2/eta2, which can have outliers or show non-normality or violate statistical assumptions. In addition, academics showed poor knowledge about meta-analytic displays (e.g., forest plot and funnel plot) and quality checklists for studies. Finally, academics with higher-level knowledge about ES statistics seem to have a profile closer to good statistical practices. Conclusions: Changing statistical practice is not easy.This change requires statistical training programs for academics, both graduate and undergraduate. PMID- 29988477 TI - Icariin: a Potential Compound for the Recovery of Tibial Dyschondroplasia Affected Chicken Via Up-Regulating BMP-2 Expression. AB - Background: Tibial dyschondroplasia (TD) is a skeletal disease of fast growing chicken and other avian species. It is characterized by an avascular and non mineralized growth plate, which leads to a deformed tibial bone and lameness. Unfortunately, this disease is not only responsible for causing huge economic losses but also raises animal welfare concerns. Icariin is a flavonoid, which is isolated from Epimedium pubescens herb, and it has been used to cure different diseases including bone fractures and osteoporosis. Results: We designed this experiment to use icariin for the treatment of TD affect chickens; for this purpose, a total of 180 chicks were equally divided into three groups: control, TD and icariin. All the three groups were offered ad libitum same normal standard diet with an addition of thiram (50 mg/kg) from 3rd day to 7th day in TD and icariin group in order to induce TD in chickens. After the induction of TD, the chickens in icariin groups were fed standard diet with an addition of icariin at the rate of 10 mg/kg in drinking water to check the therapeutic effect of this flavonoid on TD. Our results showed that the icariin helped in restoring the TD lesion into a normal structure with significantly (P < 0.05) up-regulating the bone morphogenetic protein-2 (BMP-2) expression in the tibial growth plates (GP). Conclusions: Icariin increased the vascular area in the growth plate and decreased the average TD score. In conclusion, this study shows that icariin is a potential compound for the recovery of TD affected chickens via up-regulating the BMP-2 expression without posing a threat of ingestion of toxic veterinary drug residues to human beings upon the consumption of treated chickens. PMID- 29988478 TI - Low-Cytotoxicity Fluorescent Probes Based on Anthracene Derivatives for Hydrogen Sulfide Detection. AB - Owing to the role of H2S in various biochemical processes and diseases, its accurate detection is a major research goal. Three artificial fluorescent probes based on 9-anthracenecarboxaldehyde derivatives were designed and synthesized. Their anion binding capacity was assessed by UV-Vis titration, fluorescence spectroscopy, HRMS, 1HNMR titration, and theoretical investigations. Although the anion-binding ability of compound 1 was insignificant, two compounds 2 and 3, containing benzene rings, were highly sensitive fluorescent probes for HS- among the various anions studied (HS-, F-, Cl-, Br-, I-, AcO-, H2PO4- , SO32- , Cys, GSH, and Hcy). This may be explained by the nucleophilic reaction between HS- and the electron-poor C=C double bond. Due to the presence of a nitro group, compound 3, with a nitrobenzene ring, showed stronger anion binding ability than that of compound 2. In addition, compound 1 had a proliferative effect on cells, and compounds 2 and 3 showed low cytotoxicity against MCF-7 cells in the concentration range of 0-150 MUg.mL-1. Thus, compounds 2 and 3 can be used as biosensors for the detection of H2S in vivo and may be valuable for future applications. PMID- 29988480 TI - Commentary: Mild endoplasmic reticulum stress ameliorates lpopolysaccharide induced neuroinflammation and cognitive impairment via regulation of microglial polarization. PMID- 29988479 TI - Signaling Pathways for Long-Term Memory Formation in the Cricket. AB - Unraveling the molecular mechanisms underlying memory formation in insects and a comparison with those of mammals will contribute to a further understanding of the evolution of higher-brain functions. As it is for mammals, insect memory can be divided into at least two distinct phases: protein-independent short-term memory and protein-dependent long-term memory (LTM). We have been investigating the signaling pathway of LTM formation by behavioral-pharmacological experiments using the cricket Gryllus bimaculatus, whose olfactory learning and memory abilities are among the highest in insect species. Our studies revealed that the NO-cGMP signaling pathway, CaMKII and PKA play crucial roles in LTM formation in crickets. These LTM formation signaling pathways in crickets share a number of attributes with those of mammals, and thus we conclude that insects, with relatively simple brain structures and neural circuitry, will also be beneficial in exploratory experiments to predict the molecular mechanisms underlying memory formation in mammals. PMID- 29988481 TI - Phylogeny of Hepatocystis parasites of Australian flying foxes reveals distinct parasite clade. AB - Hepatocystis parasites are close relatives of mammalian Plasmodium species and infect a range of primates and bats. Here, we present the phylogenetic relationships of Hepatocystis parasites of three Australian flying fox species. Multilocus phylogenetic analysis revealed that Hepatocystis parasites of Pteropus species from Australia and Asia form a distinct clade that is sister to all other Hepatocystis parasites of primates and bats from Africa and Asia. No patterns of host specificity were recovered within the Pteropus-specific parasite clade and the Hepatocystis sequences from all three Australian host species sampled fell into two divergent clades. PMID- 29988482 TI - Effective in Vitro Photokilling by Cell-Adhesive Gold Nanorods. AB - Upon excitation of their localized surface plasmon resonance (LSPR) band, gold nanorods (AuNRs) show a characteristic light-to-heat transduction, a useful and versatile property for a range of biomedical applications such as photothermal therapy, drug delivery, optoacoustic imaging and biosensing, among others. Nanoparticle (NP)-mediated photothermal therapy (PTT) rests on the ability of nanomaterials to convert light energy into heat and can currently be considered as a promising method for selectively destroying tumor cells by (photo) thermoablation. One inherent limitation to NP-mediated PTT is that the nanoparticles must arrive at the site of action to exert their function and this typically involves cellular internalization. Here we report the use of the Keggin type polyoxometalate (POM) phosphotungstic acid (PTA) as an inorganic gelling agent for the encapsulation of plasmonic gold nanorods (AuNRs) inside a biocompatible and cell-adhesive chitosan hydrogel matrix. These functional sub micrometric containers are non-cytotoxic and present the ability to adhere to the cytoplasmic membranes of cells avoiding any need for cellular internalization, rendering them as highly efficient thermoablating agents of eukaryotic cells in vitro. PMID- 29988483 TI - Micro and Nanofabrication methods to control cell-substrate interactions and cell behavior: A review from the tissue engineering perspective. AB - Cell-substrate interactions play a crucial role in the design of better biomaterials and integration of implants with the tissues. Adhesion is the binding process of the cells to the substrate through interactions between the surface molecules of the cell membrane and the substrate. There are several factors that affect cell adhesion including substrate surface chemistry, topography, and stiffness. These factors physically and chemically guide and influence the adhesion strength, spreading, shape and fate of the cell. Recently, technological advances enabled us to precisely engineer the geometry and chemistry of substrate surfaces enabling the control of the interaction cells with the substrate. Some of the most commonly used surface engineering methods for eliciting the desired cellular responses on biomaterials are photolithography, electron beam lithography, microcontact printing, and microfluidics. These methods allow production of nano- and micron level substrate features that can control cell adhesion, migration, differentiation, shape of the cells and the nuclei as well as measurement of the forces involved in such activities. This review aims to summarize the current techniques and associate these techniques with cellular responses in order to emphasize the effect of chemistry, dimensions, density and design of surface patterns on cell-substrate interactions. We conclude with future projections in the field of cell-substrate interactions in the hope of providing an outlook for the future studies. PMID- 29988484 TI - Integration of Metabolomics With Pharmacodynamics to Elucidate the Anti myocardial Ischemia Effects of Combination of Notoginseng Total Saponins and Safflower Total Flavonoids. AB - Notoginseng (Sanqi), the roots and rhizomes of Panax notoginseng and safflower, the flowers of Carthamus tinctorius, are widely used traditional Chinese medicines (TCMs) for the treatment of cardiovascular diseases. Positive evidences have fueled growing acceptance for cardioprotective effects of the combination of the notoginseng total saponins and safflower total flavonoids (CNS) against myocardial ischemia (MI). However, the underlying cardioprotective mechanisms of CNS are still obscured. Metabolomics is a comprehensive tool for investigating biological mechanisms of disease, monitoring therapeutic outcomes, and advancing drug discovery and development. Herein, we investigated the cardioprotective effects of CNS on the isoproterenol (ISO)-induced MI rats by using plasma and urine metabolomics based on ultra-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) and multiple pharmacodynamics approaches. The results showed that pretreatment with CNS could attenuate the cardiac injury resulting from ISO, as evidenced by decreasing the myocardial infarct size, converting the echocardiographic, histopathological, and plasma biochemical abnormalities, and reversing the perturbations of plasma and urine metabolic profiles, particularly for the 55.0 mg/kg dosage group. In addition, 44 metabolites were identified as the potential MI biomarkers, mainly including a range of free fatty acids (FFAs), sphingolipids, and glycerophospholipids. CNS pretreatment group may robustly ameliorate these potential MI-related biomarkers. The accumulation of LysoPCs and FFAs, caused by PLA2, may activate NF-kappaB pathway and increase proinflammatory cytokines. However, our results showed that CNS at 55.0 mg/kg dosage could maximally attenuate the NF-kappaB signaling pathway, depress the expressions of TNF-alpha, IL-6, IL-1beta, and PLA2. The results suggested that the anti-inflammatory property of CNS may contribute to its cardioprotection against MI. Our results demonstrate that the integrating of metabolomics with pharmacodynamics provides a reasonable approach for understanding the therapeutic effects of TCMs and CNS provide a potential candidate for prevention and treatment of MI. PMID- 29988485 TI - Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson's disease. AB - Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease. Methods: In order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype alpha-synuclein (alpha-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse alpha-syn promoter. Results: We observed an age-dependent progressive expression and accumulation of alpha-syn-GFP in the enteric neurons of Meissner's (submucosal) and Auerbach's (myenteric) plexuses of the colon. Additionally, the phosphorylation of alpha-syn at serine 129 also increased with age and the aggregation of alpha-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, alpha-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin. Conclusions: Our results show the development of alpha-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction. PMID- 29988486 TI - Evaluating Established Methods for Rumen 16S rRNA Amplicon Sequencing With Mock Microbial Populations. AB - The rumen microbiome scientific community has utilized amplicon sequencing as an aid in identifying potential community compositional trends that could be used as an estimation of various production and performance traits including methane emission, animal protein production efficiency, and ruminant health status. In order to translate rumen microbiome studies into executable application, there is a need for experimental and analytical concordance within the community. The objective of this study was to assess these factors in relation to selected currently established methods for 16S phylogenetic community analysis on a microbial community standard (MC) and a DNA standard (DS; ZymoBIOMICSTM). DNA was extracted from MC using the RBBC method commonly used for microbial DNA extraction from rumen digesta samples. 16S rRNA amplicon libraries were generated for the MC and DS using primers routinely used for rumen bacterial and archaeal community analysis. The primers targeted the V4 and V3-V4 region of the 16S rRNA gene and samples were subjected to both 20 and 28 polymerase chain reaction (PCR) cycles under identical cycle conditions. Sequencing was conducted using the Illumina MiSeq platform. As the bacteria contained in the microbial mock community were well-classified species, and for ease of explanation, we used the results of the Basic Local Alignment Search Tool classification to assess the DNA, PCR cycle number, and primer type. Sequence classification methodology was assessed independently. Spearman's correlation analysis indicated that utilizing the repeated bead beating and column method for DNA extraction in combination with primers targeting the 16S rRNA gene using 20 first-round PCR cycles was sufficient for amplicon sequencing to generate a relatively accurate depiction of the bacterial communities present in rumen samples. These results also emphasize the requirement to develop and utilize positive mock community controls for all rumen microbiomic studies in order to discern errors which may arise at any step during a next-generation sequencing protocol. PMID- 29988487 TI - Taxonomic Demarcation of Setaria pumila (Poir.) Roem. & Schult., S. verticillata (L.) P. Beauv., and S. viridis (L.) P. Beauv. (Cenchrinae, Paniceae, Panicoideae, Poaceae) From Phytolith Signatures. AB - Background and Aims: The role and significance of phytoliths in taxonomic diagnosis of grass species has been well documented with a focus on the types found in foliar epidermis and the synflorescence. The present paper is an attempt to broaden the scope of phytoliths in species diagnosis of grasses by developing phytolith signatures of some species of the foxtail genus Setaria P. Beauv. through in situ location and physico-chemical analysis of various phytolith morphotypes in different parts of the plant body. Methods: Clearing solution and dry ashing extraction methods were employed for in situ location and isolation of phytolith morphotypes respectively. Ultrastructural details were worked out by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy. Morphometric and frequency data of phytolith morphotypes were also recorded. Biochemical architecture of various phytolith types was worked out through SEM EDX, XRD, and FTIR analysis. Data were analyzed through Principal Component Analysis and Cluster Analysis. Key Results:In situ location of phytoliths revealed species specific epidermal patterns. The presence of cystoliths (calcium oxalate crystals) in the costal regions of adaxial leaf surface of S. verticillata (L.) P. Beauv. is the first report for the genus Setaria. Our results revealed marked variations in epidermal ornamentation and undulation patterns with a novel "Lambda" (Lamda) type of undulated ornamentation reported in S. verticillata. Dry ashing method revealed species specific clusters of phytolith morphotypes. Conclusions: The study revealed that phytoliths can play a significant role in resolution of taxonomic identity of three species of Setaria. Each species was marked out by a unique assemblage of phytolith morphotypes from various parts of the plant body. Apart from in situ location and epidermal patterning, diagnostic shapes, frequency distribution, size dimensions, and biochemical architecture emerged as complementary traits that help in developing robust phytolith signatures for plant species. PMID- 29988488 TI - Naps Do Not Change Delay Discounting Behavior in Young Adults. AB - When offered a choice of $40 today or $50 later, many would choose the immediate reward over the greater delayed reward. Such behavior is a result of future gains being discounted such that their value is rendered less than that of the immediate gain. Extreme discounting behaviors are associated with impulsivity and addiction. Given recent evidence of sleep's role in decision making, we tested the hypothesis that sleep would reduce delayed discounting behavior. Twenty young adults (M = 20.19 years, SD = 0.98 years; 6 males) performed a hypothetical delay discounting task, making a series of choices between an immediate reward (from $0 to $50) or a larger reward ($50) available at a delay of 2, 4, 8, 14, or 22 weeks. Participants performed the task before and after a mid-day nap, and before and after an equivalent interval of wake (within subject, order counterbalanced, wake, and sleep conditions separated by 1 week). As expected, indifference points decreased with longer delays both prior to and following the nap/wake interval. However, the impact of a nap interval on discounting did not differ from the impact of a wake interval. Thus, while sleep has been shown to play an active role in some financial decision-making tasks, a nap is not sufficient to change delay discounting behavior. PMID- 29988489 TI - Exploiting the Genomic Diversity of Rice (Oryza sativa L.): SNP-Typing in 11 Early-Backcross Introgression-Breeding Populations. AB - This study demonstrates genotyping-by-sequencing-based single-nucleotide polymorphism (SNP)-typing in 11 early-backcross introgression populations of rice (at BC1F5), comprising a set of 564 diverse introgression lines and 12 parents. Sequencing using 10 Ion Proton runs generated a total of ~943.4 million raw reads, out of which ~881.6 million reads remained after trimming for low-quality bases. After alignment, 794,297 polymorphic SNPs were identified, and filtering resulted in LMD50 SNPs (low missing data, with each SNP, genotyped in at least 50% of the samples) for each sub-population. Every data point was supported by actual sequencing data without any imputation, eliminating imputation-induced errors in SNP calling. Genotyping substantiated the impacts of novel breeding strategy revealing: (a) the donor introgression patterns in ILs were characteristic with variable introgression frequency in different genomic regions, attributed mainly to stringent selection under abiotic stress and (b) considerably lower heterozygosity was observed in ILs. Functional annotation revealed 426 non-synonymous deleterious SNPs present in 102 loci with a range of 1-4 SNPs per locus and 120 novel SNPs. SNP-typing this diversity panel will further assist in the development of markers supporting genomic applications in molecular breeding programs. PMID- 29988490 TI - On the Reliability of Switching Costs Across Time and Domains. AB - Bilingual speakers are suggested to use control processes to avoid linguistic interference from the unintended language. It is debated whether these bilingual language control (BLC) processes are an instantiation of the more domain-general executive control (EC) processes. Previous studies inconsistently report correlations between measures of linguistic and non-linguistic control in bilinguals. In the present study, we investigate the extent to which there is cross-talk between these two domains of control for two switch costs, namely the n-1 shift cost and the n-2 repetition cost. Also, we address an important problem, namely the reliability of the measures used to investigate cross-talk. If the reliability of a measure is low, then these measures are ill-suited to test cross-talk between domains through correlations. We asked participants to perform both a linguistic- and non-linguistic switching task at two sessions about a week apart. The results show a dissociation between the two types of switch costs. Regarding test-retest reliability, we found a stronger reliability for the n-1 shift cost compared to the n-2 repetition cost within both domains as measured by correlations across sessions. This suggests the n-1 shift cost is more suitable to explore cross-talk of BLC and EC. Next, we do find cross-talk for the n-1 shift cost as demonstrated by a significant cross-domain correlation. This suggests that there are at least some shared processes in the linguistic and non-linguistic task. PMID- 29988492 TI - Editorial: Intraoperative Radiotherapy (IORT)-A New Frontier for Personalized Medicine as Adjuvant Treatment and Treatment of Locally Recurrent Advanced Malignancy. PMID- 29988491 TI - Users' Opinion About a Virtual Reality System as an Adjunct to Psychological Treatment for Stress-Related Disorders: A Quantitative and Qualitative Mixed Methods Study. AB - This study aims to explore patients' and therapists' attitudes about the psychological treatment they received (patients) or applied (therapists). The treatments were standard CBT protocols for post-traumatic stress disorder (PTSD), complicated grief (CG), or adjustment disorders (ADs), depending on each patient diagnosis. The treatments were delivered following a traditional format or supported by a virtual reality (VR) system "EMMA's WORLD" designed for the treatment of stress-related disorders. "EMMA's WORLD" is a VR application in which patients can explore negative experiences using different virtual elements that can be customized to make them more meaningful to the user. The sample was composed of two groups: the "professionals" (N = 10) were all clinical psychologists who applied the same psychological treatment in both the traditional format ("traditional condition") and using the VR system ("EMMA" condition). The second group consisted of a sample of patients (N = 50) who met the criteria for at least one of three different diagnoses: PTSD (N = 15), CG (N = 15), or AD (N = 20). 25 patients received treatment in the traditional format and 25 supported by the VR system. The patients were asked about their expectations (before treatment) and satisfaction (after treatment) with the treatment they received. All the therapists were asked their opinions about both treatment conditions. A mixed-methods approach using quantitative and qualitative methodologies was used. In both conditions, high scores were observed, and the patient's opinions were even better when they have already received the treatments. A more pronounced pre-test-post-test change in the EMMA therapy group than in the traditional group was observed. EMMA's World was well-accepted by both patients and therapists, and it helped to foster motivation in patients, while helping the therapist to apply the treatment. Thus, VR can be useful as an adjunct tool to enhance the treatment. PMID- 29988493 TI - Amelioration of Cognitive Deficit by Embelin in a Scopolamine-Induced Alzheimer's Disease-Like Condition in a Rat Model. AB - Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone) is one of the active components (2.3%) found in Embelia ribes Burm fruits. As determined via in vitro AChE inhibition assay, embelin can inhibit the acetylcholinesterase enzyme. Therefore, embelin can be utilized as a therapeutic compound, after further screening has been conducted for its use in the treatment of Alzheimer's disease (AD). In this study, the nootropic and anti-amnesic effects of embelin on scopolamine-induced amnesia in rats were evaluated. Rats were treated once daily with embelin (0.3 mg/kg, 0.6 mg/kg, 1.2 mg/kg) and donepezil (1 mg/kg) intraperitoneally (i.p.) for 17 days. During the final 9 days of treatment, a daily injection of scopolamine (1 mg/kg) was administered to induce cognitive deficits. Besides that, behavioral analysis was carried out to assess the rats' learning and memory functions. Meanwhile, hippocampal tissues were extracted for gene expression, neurotransmitter, and immunocytochemistry studies. Embelin was found to significantly improve the recognition index and memory retention in the novel object recognition (NOR) and elevated plus maze (EPM) tests, respectively. Furthermore, embelin at certain doses (0.3 mg/kg, 0.6 mg/kg, and 1.2 mg/kg) significantly exhibited a memory-enhancing effect in the absence of scopolamine, besides improving the recognition index when challenged with chronic scopolamine treatment. Moreover, in the EPM test, embelin treated rats (0.6 mg/kg) showed an increase in inflection ratio in nootropic activity. However, the increase was not significant in chronic scopolamine model. In addition, embelin contributed toward the elevated expression of BDNF, CREB1, and scavengers enzymes (SOD1 and CAT) mRNA levels. Next, pretreatment of rats with embelin mitigated scopolamine induced neurochemical and histological changes in a manner comparable to donepezil. These research findings suggest that embelin is a nootropic compound, which also possesses an anti-amnesic ability that is displayed against scopolamine-induced memory impairment in rats. Hence, embelin could be a promising compound to treat AD. PMID- 29988494 TI - The Dimensions of Organizational Character and Its Impacts on Organizational Performance in Chinese Context. AB - As an organic entity, organizations are similar to humans, having unique organizational character which constitutes a source of competitive differentiation. This study aimed to explore the dimensions of organizational character and measure its impacts on organizational performance in a Chinese context. Since several previous studies have developed the definition and constitutions of organizational character in the context of developed countries such as America and England, this indigenous study provides new evidence from the perspective of an emerging economy. A research model using a qualitative analysis method was proposed to define the dimensions of organizational character. The connection between organizational character and organizational performance was empirically tested by a multi-ordered logit regression analysis with a survey of 205 observations in Chinese enterprises. The dimension of organizational character was finally extracted and summarized as six aspects including enterprise, conscientiousness, innovation, agreeableness, democracy, and Boy Scout. The results of the empirical analysis showed that the formation and cultivation of organizational character would directly improve an organizations' business performance as well as their growth potential. It is worth noting that a special part of organizational character, which may depend more on national culture or institutional background than organizational individuals, also has an impact on organizational performance. The findings can provide practical implications for Chinese companies and multinational companies that do or plan to do business in China. Entrepreneurs are suggested to make effective decisions on the cultivation of organizational character, since different types and specific levels of organizational character may have significantly different effects on organizational performance. This paper explored a novel theory to explain the antecedents of organizational performance, and could inspire scholars to expand the sources of organizational competitive advantage in the future. PMID- 29988495 TI - DNA methylation landscapes in the pathogenesis of type 2 diabetes mellitus. AB - Although genetic variations and environmental factors are vital to the development and progression of type 2 diabetes mellitus (T2DM), emerging literature suggest that epigenetics, especially DNA methylation, play a key role in the pathogenesis of T2DM by affecting insulin secretion of pancreatic beta cells and the body's resistance to insulin. Previous studies have elucidated how DNA methylation interacted with various factors in T2DM pathogenesis. This review summarized the role of related methylation genes in insulin-sensitive organs, such as pancreatic islets, skeletal muscle, liver, brain and adipose tissue, as well as peripheral blood cells, comparing the tissue similarity and specificity of methylated genes, aiming at a better understanding of the pathogenesis of T2DM and providing new ideas for the personalized treatment of this metabolism associated disease. PMID- 29988497 TI - Zika Virus Non-structural Protein 4A Blocks the RLR-MAVS Signaling. AB - Flaviviruses have evolved complex mechanisms to evade the mammalian host immune systems including the RIG-I (retinoic acid-inducible gene I) like receptor (RLR) signaling. Zika virus (ZIKV) is a re-emerging flavivirus that is associated with severe neonatal microcephaly and adult Guillain-Barre syndrome. However, the molecular mechanisms underlying ZIKV pathogenesis remain poorly defined. Here we report that ZIKV non-structural protein 4A (NS4A) impairs the RLR-mitochondrial antiviral-signaling protein (MAVS) interaction and subsequent induction of antiviral immune responses. In human trophoblasts, both RIG-I and melanoma differentiation-associated protein 5 (MDA5) contribute to type I interferon (IFN) induction and control ZIKV replication. Type I IFN induction by ZIKV is almost completely abolished in MAVS-/- cells. NS4A represses RLR-, but not Toll-like receptor-mediated immune responses. NS4A specifically binds the N-terminal caspase activation and recruitment domain (CARD) of MAVS and thus blocks its accessibility by RLRs. Our study provides in-depth understanding of the molecular mechanisms of immune evasion by ZIKV and its pathogenesis. PMID- 29988498 TI - Multi-Electrode Alpha tACS During Varying Background Tasks Fails to Modulate Subsequent Alpha Power. AB - Transcranial alternating-current stimulation (tACS) for entraining alpha activity holds potential for influencing mental function, both in laboratory and clinical settings. While initial results of alpha entrainment are promising, questions remain regarding its translational potential-namely if tACS alpha entrainment is sufficiently robust to context and to what extent it can be upscaled to multi electrode arrangements needed to direct currents into precise brain loci. We set out to explore these questions by administering alternating current through a multi-electrode montage (mtACS), while varying background task. A multi-electrode analog of previously employed anterior/posterior stimulation failed to replicate the reported alpha entrainment, suggesting that further work is required to understand the scope of applicability of tACS alpha entrainment. PMID- 29988496 TI - Active Role of the Necrotic Zone in Desensitization of Hypoxic Macrophages and Regulation of CSC-Fate: A hypothesis. AB - Fast-proliferating cancer cells in the hypoxic region face a shortage of oxygen and nutrients, undergo necrotic cell death, and release numerous signaling components. Hypoxia-induced chemo-attractants signal for macrophages/monocytes to clear debris and return the system to steady state. Accordingly, macrophages arrange into pre-necrotic positions, where they are continuously exposed to stress signals. It can thus be hypothesized that gradual alteration of gene expression in macrophages eventually turns off their phagocytic machinery. Uncleared cell corpses within the hypoxic region potentially provide a rich source of building blocks for anaerobic metabolism of cancer stem cells via macropinocytosis, and are conceivably implicated in tumor progression and invasion. PMID- 29988499 TI - Comparison of the Antimicrobial Activities of Four Honeys From Three Countries (New Zealand, Cuba, and Kenya). AB - Skin and chronic wound infections are an increasing and urgent health problem worldwide. Their management is difficult and the development of antibiotic resistance by both planktonic and biofilm-associated bacteria necessitates the use of alternative treatments. The purpose of this study was to compare the antimicrobial activity of four honeys from different floral and geographical origins: Melipona beecheii honey (Cuba) and three Apis mellifera honeys [Manuka honey (New Zealand), A. mellifera honey (Cuba), and African honey (Kenya)]. The physicochemical parameters were within the ranges reported for these honeys and M. beecheii honey stood out due to its acidic character. An agar incorporation technique was used to determine the minimum active dilution of each honey against 52 clinical isolates (34 Gram-positive, 17 Gram-negative, and 1 Candida albicans). The antibiofilm activity of honeys was tested by assessing their ability to inhibit biofilm formation and to disrupt preformed biofilms. Overall, M. beecheii honey had the highest antimicrobial and antibiofilm activity, although a marked disruption in preformed biofilms was shared by all tested honeys. Structural changes induced by M. beecheii honey on Staphylococcus aureus and Pseudomonas aeruginosa cells were observed by transmission electron microscopy suggesting that this honey has a potent antimicrobial action and may be an excellent candidate for the development of topical preparations for the treatment of infected wounds. PMID- 29988500 TI - Role of Hepatic Deposited Immunoglobulin G in the Pathogenesis of Liver Damage in Systemic Lupus Erythematosus. AB - The onset of hepatic disorders in patients with systemic lupus erythematosus (SLE) is frequent; however, the etiology and liver pathogenesis of SLE remain unknown. In the present study, the role of hepatic deposited immunoglobulin G (IgG) in SLE-derived liver damage was investigated. From a retrospective analysis of the medical records of 404 patients with lupus and from experimental studies on mice models, we found that liver dysfunction is common in SLE and liver damage with IgG deposition spontaneously develops in lupus-prone mice. Liver injury was recreated in mice by injecting IgG from lupus serum intrahepatically. The inflammation intensity in the liver decreased with IgG depletion and the lupus IgG-induced liver inflammation in FcgammaRIII-deficient mice was comparatively low; while, inflammation was increased in FcgammaRIIb-deficient mice. Macrophages, Kupffer cells, natural killer cells, and their products, but not lymphocytes, are required for the initiation of SLE-associated liver inflammation. Blocking IgG signaling using a spleen tyrosine kinase (Syk) inhibitor suppressed the liver damage. Our findings provided evidence of spontaneously established liver damage in SLE. They also suggested that hepatic deposited lupus IgG is an important pathological factor in the development of liver injury and that hepatic inflammation is regulated by the Syk signaling pathway. Thus, Syk inhibition might promote the development of a therapeutic strategy to control liver damage in patients with SLE. PMID- 29988502 TI - A Novel Oncolytic Chimeric Orthopoxvirus Encoding Luciferase Enables Real-Time View of Colorectal Cancer Cell Infection. AB - This study hypothesizes that a novel oncolytic chimeric orthopoxvirus CF33-Fluc is imageable and targets colorectal cancer cells (CRCs). A novel chimeric orthopoxvirus (CF33) was constructed. The thymidine kinase locus was replaced with firefly luciferase (Fluc) to yield a recombinant virus-CF33-Fluc. In vitro cytotoxicity and viral replication assays were performed. In vivo CRC flank xenografts received single doses of intratumoral or intravenous CF33-Fluc. Viral biodistribution was analyzed via luciferase imaging and organ titers. CF33-Fluc infects, replicates in, and kills CRCs in vitro in a dose-dependent manner. CF33 has superior secretion of extracellular-enveloped virus versus all but one parental strain. Rapid tumor regression or stabilization occurred in vivo at a low dose over a short time period, regardless of the viral delivery method in the HCT-116 colorectal tumor xenograft model. Rapid luciferase expression in virus infected tumor cells was associated with treatment response. CRC death occurs via necroptotic pathways. CF33-Fluc replicates in and kills colorectal cancer cells in vitro and in vivo regardless of delivery method. Expression of luciferase enables real-time tracking of viral replication. Despite the chimerism, CRC death occurs via standard poxvirus-induced mechanisms. Further studies are warranted in immunocompetent models. PMID- 29988501 TI - TMS Motor Thresholds Correlate With TDCS Electric Field Strengths in Hand Motor Area. AB - Transcranial direct current stimulation (TDCS) modulates cortical activity and influences motor and cognitive functions in both healthy and clinical populations. However, there is large inter-individual variability in the responses to TDCS. Computational studies have suggested that inter-individual differences in cranial and brain anatomy may contribute to this variability via creating varying electric fields in the brain. This implies that the electric fields or their strength and orientation should be considered and incorporated when selecting the TDCS dose. Unfortunately, electric field modeling is difficult to perform; thus, a more-robust and practical method of estimating the strength of TDCS electric fields for experimental use is required. As recent studies have revealed a relationship between the sensitivity to TMS and motor cortical TDCS after-effects, the aim of the present study was to investigate whether the resting motor threshold (RMT), a simple measure of transcranial magnetic stimulation (TMS) sensitivity, would be useful for estimating TDCS electric field strengths in the hand area of primary motor cortex (M1). To achieve this, we measured the RMT in 28 subjects. We also obtained magnetic resonance images from each subject to build individual three-dimensional anatomic models, which were used in solving the TDCS and TMS electric fields using the finite element method (FEM). Then, we calculated the correlation between the measured RMT and the modeled TDCS electric fields. We found that the RMT correlated with the TDCS electric fields in hand M1 (R2 = 0.58), but no obvious correlations were identified in regions outside M1. The found correlation was mainly due to a correlation between the TDCS and TMS electric fields, both of which were affected by individual's anatomic features. In conclusion, the RMT could provide a useful tool for estimating cortical electric fields for motor cortical TDCS. PMID- 29988503 TI - Postural Control in Lowlanders With COPD Traveling to 3100 m: Data From a Randomized Trial Evaluating the Effect of Preventive Dexamethasone Treatment. AB - Objective: To evaluate the effects of acute exposure to high altitude and preventive dexamethasone treatment on postural control in patients with chronic obstructive pulmonary disease (COPD). Methods: In this randomized, double-blind parallel-group trial, 104 lowlanders with COPD GOLD 1-2 age 20-75 years, living near Bishkek (760 m), were randomized to receive either dexamethasone (2 * 4 mg/day p.o.) or placebo on the day before ascent and during a 2-day sojourn at Tuja-Ashu high altitude clinic (3100 m), Kyrgyzstan. Postural control was assessed with a Wii Balance BoardTM at 760 m and 1 day after arrival at 3100 m. Patients were instructed to stand immobile on both legs with eyes open during five tests of 30 s each, while the center of pressure path length (PL) was measured. Results: With ascent from 760 to 3100 m the PL increased in the placebo group from median (quartiles) 29.2 (25.8; 38.2) to 31.5 (27.3; 39.3) cm (P < 0.05); in the dexamethasone group the corresponding increase from 28.8 (22.8; 34.5) to 29.9 (25.2; 37.0) cm was not significant (P = 0.10). The mean difference (95% CI) between dexamethasone and placebo groups in altitude-induced changes (treatment effect) was -0.3 (-3.2 to 2.5) cm, (P = 0.41). Multivariable regression analysis confirmed a significant increase in PL with higher altitude (coefficient 1.6, 95% CI 0.2 to 3.1, P = 0.031) but no effect of dexamethasone was shown (coefficient -0.2, 95% CI -0.4 to 3.6, P = 0.925), even when controlled for several potential confounders. PL changes were related more to antero posterior than lateral sway. Twenty-two of 104 patients had an altitude-related increase in the antero-posterior sway velocity of >25%, what has been associated with an increased risk of falls in previous studies. Conclusion: Lowlanders with COPD travelling from 760 to 3100 m revealed postural instability 24 h after arriving at high altitude, and this was not prevented by dexamethasone. Trial Registration: clinicaltrials.gov Identifier: NCT02450968. PMID- 29988504 TI - Detection of Pulmonary Infectious Pathogens From Lung Biopsy Tissues by Metagenomic Next-Generation Sequencing. AB - Metagenomic next-generation sequencing (mNGS) is a comprehensive approach for sequence-based identification of pathogenic microbes. However, reports on the use of mNGS in pulmonary infection applied to lung biopsy tissues remain scarce. In this study, we applied mNGS to detect the presence of pathogenic microbes in lung biopsy tissues from 20 patients with pulmonary disorders indicating possible infection. We applied a new data management for identifying pathogen species based on mNGS data. We determined the thresholds for the unique reads and relative abundance required to identify the infectious pathogens. Potential pathogens of pulmonary infections in 15 patients were identified by mNGS. The comparison between mNGS and culture method resulted that the sensitivity and specificity were 100.0% (95% CI: 31.0-100.0%) and 76.5% (95% CI: 49.8-92.2%) for bacteria, 57.1% (95% CI: 20.2-88.2%) and 61.5% (95% CI: 32.2-84.9%) for fungi. The positive predictive value (PPV) (42.9% for bacteria, 44.4% for fungi) was much lower than negative predictive value (NPV) (100% for bacteria, 72.7% for fungi) in mNGS vs. culture method. The mNGS showed the highest specificity (100.0 and 94.1%) and PPV (100.0 and 75.0%) in the evaluation of fungi and MTBC respectively, when compared with histopathology method. The study indicated that mNGS of lung biopsy tissues can be used to detect the presence (or absence) of pulmonary pathogens in patients, with potential benefits in speed and sensitivity. However, accurate data management and interpretation of mNGS are required, and should be combined with observations of clinical manifestations and conventional laboratory-based diagnostic methods. PMID- 29988505 TI - Advances in the Characterization of the T-Cell Response to Human Herpesvirus-6. AB - Human herpesvirus (HHV) 6 is thought to remain clinically latent in most individuals after primary infection and to reactivate to cause disease in persons with severe immunosuppression. In allogeneic hematopoietic stem cell transplant recipients, reactivation of HHV-6 species B is a considerable cause of morbidity and mortality. HHV-6B reactivation is the most frequent cause of infectious meningoencephalitis in this setting and has been associated with a variety of other complications such as graft rejection and acute graft versus host disease. This has inspired efforts to develop HHV-6-targeted immunotherapies. Basic knowledge of HHV-6-specific adaptive immunity is crucial for these endeavors, but remains incomplete. Many studies have focused on specific HHV-6 antigens extrapolated from research on human cytomegalovirus, a genetically related betaherpesvirus. Challenges to the study of HHV-6-specific T-cell immunity include the very low frequency of HHV-6-specific memory T cells in chronically infected humans, the large genome size of HHV-6, and the lack of an animal model. This review will focus on emerging techniques and methodological improvements that are beginning to overcome these barriers. Population-prevalent antigens are now becoming clear for the CD4+ T-cell response, while definition and ranking of CD8+ T-cell antigens and epitopes is at an earlier stage. This review will discuss current knowledge of the T-cell response to HHV-6, new research approaches, and translation to clinical practice. PMID- 29988506 TI - Comparison of Infant Gut and Skin Microbiota, Resistome and Virulome Between Neonatal Intensive Care Unit (NICU) Environments. AB - Background: There is a growing move to provide care for premature infants in a single family, private room neonatal intensive care unit (NICU) in place of the traditional shared space, open bay NICU. The resultant effect on the developing neonatal microbiota is unknown. Study Design: Stool and groin skin swabs were collected from infants in a shared-space NICU (old NICU) and a single-family room NICU (new NICU) on the same hospital campus. Metagenomic sequencing was performed and data analyzed by CosmosID bioinformatics software package. Results: There were no significant differences between the cohorts in gestational age, length of stay, and delivery mode; infants in the old NICU received significantly more antibiotics (p = 0.03). Differentially abundant antimicrobial resistance genes and virulence associated genes were found between the cohorts in stool and skin, with more differentially abundant antimicrobial resistance genes in the new NICU. The entire bacterial microbiota analyzed to the genus level significantly differed between cohorts in skin (p = 0.0001) but not in stool samples. There was no difference in alpha diversity between the two cohorts. DNA viruses and fungi were detected but did not differ between cohorts. Conclusion: Differences were seen in the resistome and virulome between the two cohorts with more differentially abundant antimicrobial resistance genes in the new NICU. This highlights the influence that different NICU environments can have on the neonatal microbiota. Whether the differences were due to the new NICU being a single-family NICU or located in a newly constructed building warrants exploration. Long term health outcomes from the differences observed must be followed longitudinally. PMID- 29988507 TI - Toll-Like Receptor-1 Single-Nucleotide Polymorphism 1805T/G Is Associated With Predisposition to Multibacillary Tuberculosis. AB - Tuberculosis (TB), caused by mycobacterial species of the Mycobacterium tuberculosis complex, is a serious global health issue. Brazil is among the 22 countries with the highest number of TB cases, and the state of Amazonas has the highest incidence of TB cases in the country. Toll-like receptors (TLRs) are important pattern recognition receptors of the innate immunity and play a key role in orchestrating an effective immune response. We investigated whether the single-nucleotide polymorphisms (SNPs) 1805T/G TLR1, 2258G/A TLR2, 896A/G and 1196C/T of TLR4, 745T/C TLR6, and -1237A/G and -1486A/G of TLR9 are associated with the predisposition to TB and/or bacillary load. The SNPs genotyping was performed by nucleotide sequencing in 263 TB patients and 232 healthy controls residing in the state of Amazonas. Alleles and genotypes frequencies were similar between patients and healthy individuals for most of the investigated SNPs. Stratification of the TB patients according to their bacillary load showed that the genotype 1805TT TLR1 (rs5743618) was prevalent among paucibacillary patients [odds ratio (OR) = 0.38; 95% confidence interval (CI) = 0.19-0.76; p = 0.009] while the genotype 1805TG was common among multibacillary patients (OR = 3.72; CI = 1.65-8.4; p = 0.004). Comparison of demographic characteristics of patients to controls showed that TB is strongly associated with smoking (OR = 6.55; 95% CI = 3.2-13.6; p < 0.0001); alcohol use disorder (OR = 7.14; 95% CI = 3.7-13.9; p < 0.0001); and male gender (OR = 3.66; 95% CI = 2.52-5.3; p < 0.0001). Multivariate logistic regression demonstrated that alcoholism (OR = 2.93; 95% CI = 1.05-8.16; p = 0.03) and the 1805G allele (OR = 2.75; 95% CI = 1.33-5.7; p = 0.006) are predictive variables for multibacillary TB. Altogether, we suggest that the TLR1 1805G allele may be a relevant immunogenetic factor for the epidemiology of TB together with environmental, sociodemographic, and behavioral factors. PMID- 29988508 TI - Reduced Balance Restoration Capacities Following Unilateral Vestibular Insult in Elderly Mice. AB - Acute vestibular syndrome (AVS) is characterized by severe posturo-locomotor and vestibulo-oculomotor impairment and accompanies several types of peripheral vestibulopathies (PVP). We know very little about its etiology, how its various symptoms are expressed and how it evolves with age. Robust repair capabilities of primary vestibular synapses have recently been shown to restore behavioral functionality. In this study, we used a mouse model of an excitotoxically induced unilateral vestibular lesion to compare the ability to restore balance and posture between old and young adult mice. We compared the temporal evolution of the evoked vestibular syndrome using a battery of behavioral tests to follow the evolution of postural-locomotor alterations and equilibrium. For the first time, we show that young adult (3 months) and elderly (22 months) mice are together able to restore normal postural-locomotor function following transient unilateral excitotoxic vestibular insult, though with different time courses. This animal study paves way for future, more detailed studies of how the early postural and locomotor disturbances following a unilateral insult are compensated for by various plasticity mechanisms, and in particular how age influences these mechanisms. PMID- 29988509 TI - Regional Dominant Frequency: A New Tool for Wave Break Identification During Atrial Fibrillation. AB - Cardiac mapping systems are based on the time/frequency feature analyses of intracardiac electrograms recorded from individual bipolar/unipolar electrodes. Signals from each electrode are processed independently. Such approaches fail to investigate the interrelationship between simultaneously recorded channels of any given mapping catheter during atrial fibrillation (AF). We introduce a novel signal processing technique that reflects regional dominant frequency (RDF) components. We show that RDF can be used to identify and characterize variation and disorganization in wavefront propagation- wave breaks. The intracardiac electrograms from the left atrium of 15 patients were exported to MATLAB and custom software employed to estimate RDF and wave break rate (WBR). We observed a heterogeneous distribution of both RDF and WBR; the two measures were weakly correlated (0.3; p < 0.001). We identified locations of AF or atrial tachycardia (ATach) termination and later compared offline with RDF and WBR maps. We inspected our novel metrics for associations with AF termination sites. Areas associated with AF termination demonstrated high RDF and low WBR (?RDF,?WBR). These sites were present in 14 of 15 patients (mean 2.6 +/- 1.2 sites per patient; range, 1-4 sites), 43% situated within the pulmonary veins. In nine patients where AF terminated to sinus rhythm (6) or ATach (3), post-hoc analysis demonstrated all ?RDF,?WBR sites were ablated and correlated with AF termination sites. The proposed RDF signal processing tools can be used to identify and quantify wave break, and the combined use of these two novel metrics can aid characterization of AF. Further prospective studies are warranted. PMID- 29988510 TI - Cholecystectomy Damages Aging-Associated Intestinal Microbiota Construction. AB - : The intestinal microbiome is essential in humans to maintain physiological balance and nutrition metabolism. Laparoscopic cholecystectomy due to gallstone disease and cholecystitis can cause intestinal microbial dysbiosis, and following bile acid metabolism dysfunction, positions the patient at high risk of colorectal cancer. However, little is known regarding intestinal microbiota characteristics in post-cholecystectomy patients. Here, we compared the microbial composition of cholecystectomy patients with that of a healthy population. We determined that cholecystectomy eliminated aging-associated fecal commensal microbiota and further identified several bile acid metabolism-related bacteria as contributors of colorectal cancer incidence via elevation of secondary bile acids. Significance statement: We identified aging-associated fecal microbiota in a healthy population, which was lost in cholecystectomy patients. Absent intestinal bacteria, such as Bacteroides, were negatively related to secondary bile acids and may be a leading cause of colorectal cancer incidence in cholecystectomy patients. Our study provides novel insight into the connection between cholecystectomy-altered gut microbiota and colorectal carcinoma, which is of value for colorectal cancer diagnosis and management. PMID- 29988511 TI - An investigation of the process of change in psychopathology and exercise during inpatient treatment for adults with longstanding eating disorders. AB - Background: Excessive exercise is recognized as a predictor of poor outcome in eating disorders. However, little is known about how excessive exercise might affect the treatment process. The aim of this study was to describe process of weekly changes in eating disorder psychopathology, general psychopathology and exercise, and the possible interactive effects of excessive exercise on these changes during inpatient treatment of longstanding eating disorders. Methods: Eighty-four patients meeting the DSM-IV criteria for Anorexia Nervosa, Bulimia Nervosa, or Eating Disorders Not Otherwise Specified received inpatient cognitive behavioural therapy including, physical activity and nutritional counselling treatment over 12 weeks. Excessive exercise was defined as having >=6 episodes of driven exercise during week 1 of treatment. Excessive exercisers received one additional session of individual counseling with the clinical exercise physiologist. The study used repeated measurements during treatment and collected measures of eating disorders: psychopathology (EDE-Q), general psychopathology (SCL-5), and frequencies of exercise and body mass index (BMI). Statistical analysis was performed using repeated measures ANOVA. Results: Both eating disorders and general psychopathology were reduced from admission to discharge in excessive exercisers and non-exercisers. There was an overall interaction effect between time (week) and excessive exercise for the process of exercise and eating disorders psychopathology reduction. This interaction effect was also found in week 10 vs 11 regarding general psychopathology. The excessive exercisers showed steep reduction at first, followed by a smaller increase towards the end of treatment in both eating disorder and general psychopathology; this pattern was not found among the non-exercisers. Conclusion: The process of change in exercise and psychopathology during inpatient treatment of longstanding eating disorders differs across excessive and non-excessive exercisers. Although excessive exercisers were given special attention for their exercise cognition and behavior during treatment, it is apparent that this part of treatment must be further developed. PMID- 29988512 TI - Enhanced Control of Oncolytic Measles Virus Using MicroRNA Target Sites. AB - Measles viruses derived from the live-attenuated Edmonton-B vaccine lineage are currently investigated as novel anti-cancer therapeutics. In this context, tumor specificity and oncolytic potency are key determinants of the therapeutic index. Here, we describe a systematic and comprehensive analysis of a recently developed post-entry targeting strategy based on the incorporation of microRNA target sites (miRTS) into the measles virus genome. We have established viruses with target sites for different microRNA species in the 3' untranslated regions of either the N, F, H, or L genes and generated viruses harboring microRNA target sites in multiple genes. We report critical importance of target-site positioning with proximal genomic positions effecting maximum vector control. No relevant additional effect of six versus three miRTS copies for the same microRNA species in terms of regulatory efficiency was observed. Moreover, we demonstrate that, depending on the microRNA species, viral mRNAs containing microRNA target sites are directly cleaved and/or translationally repressed in presence of cognate microRNAs. In conclusion, we report highly efficient control of measles virus replication with various miRTS positions for development of safe and efficient cancer virotherapy and provide insights into the mechanisms underlying microRNA mediated vector control. PMID- 29988515 TI - Cognitive and Affective Perspective-Taking: Evidence for Shared and Dissociable Anatomical Substrates. AB - Perspective-taking refers to the ability to recognize another person's point of view. Crucial to the development of interpersonal relationships and prosocial behavior, perspective-taking is closely linked to human empathy, and like empathy, perspective-taking is commonly subdivided into cognitive and affective components. While the two components of empathy have been frequently compared, the differences between cognitive and affective perspective-taking have been under-investigated in the cognitive neuroscience literature to date. Here, we define cognitive perspective-taking as the ability to infer an agent's thoughts or beliefs, and affective perspective-taking as the ability to infer an agent's feelings or emotions. In this paper, we review data from functional imaging studies in healthy adults as well as behavioral and structural imaging studies in patients with behavioral variant frontotemporal dementia in order to determine if there are distinct neural correlates for cognitive and affective perspective taking. Data suggest that there are both shared and non-shared cognitive and anatomic substrates. For example, while both types of perspective-taking engage regions such as the temporoparietal junction, precuneus, and temporal poles, only affective perspective-taking engages regions within the limbic system and basal ganglia. Differences are also observed in prefrontal cortex: while affective perspective-taking engages ventromedial prefrontal cortex, cognitive perspective taking engages dorsomedial prefrontal cortex and dorsolateral prefrontal cortex (DLPFC). To corroborate these findings, we also examine if cognitive and affective perspective-taking share the same relationship with executive functions. While it is clear that affective perspective-taking requires emotional substrates that are less prominent in cognitive perspective-taking, it remains unknown to what extent executive functions (including working memory, mental set switching, and inhibitory control) may contribute to each process. Overall results indicate that cognitive perspective-taking is dependent on executive functioning (particularly mental set switching), while affective perspective taking is less so. We conclude with a critique of the current literature, with a focus on the different outcome measures used across studies and misconceptions due to imprecise terminology, as well as recommendations for future research. PMID- 29988516 TI - Self-stabilized chitosan and its complexes with carboxymethyl starch as excipients in drug delivery. AB - This study focuses on the behavior of chitosan (CHI) and its polyelectrolyte complexes with carboxymethyl starch (CMS) used as monolithic matrices with acetaminophen as drug tracer. Two different chitosan grades were tested alone or associated in various ratios with CMS as excipients for tablets obtained by direct compression. The degree of deacetylation (DDA) of CHI, estimated from 1H NMR and FTIR data, was correlated with X-ray diffraction and scanning electron microscopy (SEM) to evaluate structural organization of the monolithic matrices. In vitro drug dissolution assays showed major differences in CHI kinetic profiles between tablets exposed to acidic medium for 2h (to mimick gastric passage) prior to dissolution in simulated intestinal fluid (SIF), and those administered directly to SIF. Prior exposure to acidic SGF conducted to longer dissolution profiles (release completed after 16 h) and preservation of tablet shape, whereas tablets directly incubated in SIF were rapidly disintegrated. The improved properties of chitosan matrices exposed to SGF may be related to an outer compact coating layer (visible in SEM). The effect of self-stabilization of chitosan in acidic medium was compared to that due to formation of polyelectrolyte complexes (PEC) in co-processed polymeric systems (CHI:CMS). The self-formed membrane following exposure to gastric acidity appears to help maintaining tablet integrity and allows higher drug loading, recommending CHI and its complexes with CMS as excipients for drug delivery. PMID- 29988514 TI - Adjunct rasagiline to treat Parkinson's disease with motor fluctuations: a randomized, double-blind study in China. AB - Background: The use of adjunct rasagiline in levodopa-treated patients with Parkinson's disease and motor fluctuations is supported by findings from large scale clinical studies. This study is to investigate the efficacy and safety of adjunct rasagiline in Chinese patients with Parkinson's disease, as a product registration study. Methods: This 16-week, randomized, double-blind, parallel group, multicenter, placebo-controlled study of rasagiline 1 mg/day included levodopa-treated patients with Parkinson's disease and motor fluctuations. The primary efficacy endpoint was mean change from baseline in total daily OFF time over 16 weeks. Secondary endpoints were Clinical Global Impressions - Improvement (CGI-I), and change in Unified Parkinson's Disease Rating Scale (UPDRS) Activities of daily living (ADL) and Motor scores. Patient well-being (EQ-5D), and the frequency of adverse events were also assessed. Results: In total, 324 levodopa-treated patients were randomized to rasagiline 1 mg/day (n = 165) or placebo (n = 159). Over 16 weeks, rasagiline statistically significantly reduced the mean [95% confidence interval] total daily OFF time versus placebo (- 0.5 h [ 0.92, - 0.07]; p = 0.023). There were also statistically significant improvements versus placebo in CGI-I (- 0.4 points [- 0.61, - 0.22]; p < 0.001), UPDRS-ADL OFF (- 1.0 points [- 1.75, - 0.27]; p = 0.008), and UPDRS-Motor ON (- 1.6 points [- 3.05, - 0.14]; p = 0.032) scores, as well as the EQ-5D utility index (p < 0.05). Rasagiline was safe and well tolerated. Conclusions: In levodopa-treated Chinese patients with Parkinson's disease and motor fluctuations, adjunct rasagiline 1 mg/day statistically significantly reduced OFF time, and improved daily function and overall well-being, versus placebo. Consistent with findings in other countries, adjunct rasagiline was proven efficacious and well tolerated in Chinese patients. Trial registration number: NCT01479530. Registered 22 November 2011. PMID- 29988513 TI - Neuroendocrine Control of Macrophage Development and Function. AB - Macrophages carry out numerous physiological activities that are essential for both systemic and local homeostasis, as well as innate and adaptive immune responses. Their biology is intricately regulated by hormones, neuropeptides, and neurotransmitters, establishing distinct neuroendocrine axes. The control is pleiotropic, including maturation of bone marrow-derived myeloid precursors, cell differentiation into functional subpopulations, cytotoxic activity, phagocytosis, production of inflammatory mediators, antigen presentation, and activation of effector lymphocytes. Additionally, neuroendocrine components modulate macrophage ability to influence tumor growth and to prevent the spreading of infective agents. Interestingly, macrophage-derived factors enhance glucocorticoid production through the stimulation of the hypothalamic-pituitary-adrenal axis. These bidirectional effects highlight a tightly controlled balance between neuroendocrine stimuli and macrophage function in the development of innate and adaptive immune responses. Herein, we discuss how components of neuroendocrine axes impact on macrophage development and function and may ultimately influence inflammation, tissue repair, infection, or cancer progression. The knowledge of the crosstalk between macrophages and endocrine or brain-derived components may contribute to improve and create new approaches with clinical relevance in homeostatic or pathological conditions. PMID- 29988518 TI - Reno-colic fistula in a tuberculous kidney: About a case report. PMID- 29988517 TI - Animal Models of Vestibular Evoked Myogenic Potentials: The Past, Present, and Future. AB - Vestibular-evoked myogenic potentials (VEMPs) provide a simple and cost-effective means to assess the patency of vestibular reflexes. VEMP testing constitutes a core screening method in a clinical battery that probes vestibular function. The confidence one has in interpreting the results arising from VEMP testing is linked to a fundamental understanding of the underlying functional anatomy and physiology. In this review, we will summarize the key role that studies across a range of animal models have fulfilled in contributing to this understanding, covering key findings regarding the mechanisms of excitation in the sensory periphery, the processing of sensory information in central networks, and the distribution of reflexive output to the motor periphery. Although VEMPs are often touted for their simplicity, work in animals models have emphasized how vestibular reflexes operate within a broader behavioral and functional context, and as such vestibular reflexes are influenced by multisensory integration, governed by task demands, and follow principles of muscle recruitment. We will conclude with considerations of future questions, and the ways in which studies in current and emerging animal models can contribute to further use and refinement of this test for both basic and clinical research purposes. PMID- 29988519 TI - Mindfulness as a Moderator of the Association Between Eating Disorder Cognition and Eating Disorder Behavior Among a Non-clinical Sample of Female College Students: A Role of Ethnicity. AB - The present cross-sectional study examined whether mindfulness moderated the association between eating disorder cognition and eating disorder behaviors among Asian American, Black American, and White American female college students in the United States. Participants (N = 463, age range = 18-25 years) completed self report measures online. Results revealed that mindfulness moderated the association between eating disorder cognition and eating disorder behavior in the White American group, but not in Asian American or Black American samples. Future research should replicate these differential findings across ethnic groups and investigate the factors that may contribute to this group difference. PMID- 29988520 TI - Comparative Pharmacokinetics and Preliminary Pharmacodynamics Evaluation of Piscidin 1 Against PRV and PEDV in Rats. AB - Antimicrobial peptide (Piscidin-1) is an effective natural polypeptide, which has great influence and potential on porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). As an alternative antibiotic substitute, Piscidin-1 was subjected for pharmacokinetics study with three administration routes (i.v, i.m, and p.o) after a single dose of 2 mg/kg in rats and preliminary pharmacodynamics including antiviral activity in cell against PEDV and PRV. Based on 50 percent tissue culture infective dose (TCID50), there were about 2 and 10% virus survived ratios for Piscidin-1 against PRV and PEDV, respectively. The plaque test showed 1 and 2 MUg/ml Piscidin-1 could eliminate 95% PRV and 85% PEDV, respectively. The main pharmacokinetics parameters of Cmax, AUC0-infinity, Ke, t1/2, Tmax, MRT, and Clb in plasma were not applicable value, 25.9 MUg*h/ml, 0.041 h-1, 16.97 h, not available value, 22.77 h, 0.067 L/h*kg after i.v administration, 2.37 MUg/ml, 18.95 MUg*h/ml, 0.029 h-1, 23.50 h, 0.33 h, 30.12 h, 0.095 L/h*kg after i.m administration and 0.73 MUg/ml, 9.63 MUg*h/ml, 0.036 h-1, 19.46 h, 0.50 h, 26.76 h, 0.171 L/h*kg after p.o administration. The bioavailability values after i.m and p.o administrations were calculated as 73.17 and 37.18%, respectively. The i.m administration was selected for pharmacokinetics study in ileum content against PEDV. The main pharmacokinetic parameters of Cmax, AUC0-infinity, Ke, t1/2, Tmax, MRT, and Clb in ileum content were 1.67 MUg/ml, 78.40 MUg*h/ml, 0.034 h-1, 20.16 h, 8.12 h, 36.45 h, 0.026 L/h*kg. The Cmax values in plasma (2.37 MUg/ml) and ileum content (1.67 MUg/ml) were higher than the effective inhibitory concentration determined in the plaque test, and this indicates that Piscidin-1 might have effective inhibition effect against PRV and PEDV after administration of 2 mg/kg i.m. The results of this study represent the first investigations toward the pharmacokinetic characteristics of piscidin-1 in plasma upon three different administration routes, among which i.m. resulted in the highest bioavailability (73.17%). Furthermore, the pharmacokinetics study of ileum content indicated Piscidin-1 might have good effect against PEDV and could be regarded as an alternative antibiotic in clinical veterinary in the future study. PMID- 29988521 TI - Comparison of Autonomic Control of Blood Pressure During Standing and Artificial Gravity Induced via Short-Arm Human Centrifuge. AB - Autonomic control of blood pressure is essential toward maintenance of cerebral perfusion during standing, failure of which could lead to fainting. Long-term exposure to microgravity deteriorates autonomic control of blood pressure. Consequently, astronauts experience orthostatic intolerance on their return to gravitational environment. Ground-based studies suggest sporadic training in artificial hypergravity can mitigate spaceflight deconditioning. In this regard, short-arm human centrifuge (SAHC), capable of creating artificial hypergravity of different g-loads, provides an auspicious training tool. Here, we compare autonomic control of blood pressure during centrifugation creating 1-g and 2-g at feet with standing in natural gravity. Continuous blood pressure was acquired simultaneously from 13 healthy participants during supine baseline, standing, supine recovery, centrifugation of 1-g, and 2-g, from which heart rate (RR) and systolic blood pressure (SBP) were derived. The autonomic blood pressure regulation was assessed via spectral analysis of RR and SBP, spontaneous baroreflex sensitivity, and non-linear heart rate and blood pressure causality (RR<->SBP). While majority of these blood pressure regulatory indices were significantly different (p < 0.05) during standing and 2-g centrifugation compared to baseline, no change (p > 0.05) was observed in the same indices during 2-g centrifugation compared to standing. The findings of the study highlight the capability of artificial gravity (2-g at feet) created via SAHC toward evoking blood pressure regulatory controls analogous to standing, therefore, a potential utility toward mitigating deleterious effects of microgravity on cardiovascular performance and minimizing post-flight orthostatic intolerance in astronauts. PMID- 29988522 TI - Heterogeneity of Ara h Component-Specific CD4 T Cell Responses in Peanut-Allergic Subjects. AB - Understanding the peanut-specific CD4 T cell responses in peanut-allergic (PA) subjects should provide new insights into the development of innovative immunotherapies for the treatment of peanut allergy. Although peanut-specific CD4 T cells have a TH2 profile in PA subjects, the immunogenicity of different Ara h components in eliciting specific CD4 T cell responses and the heterogeneity of these Ara h-reactive TH2 cells remains unclear. In this study, we investigated Ara h 1, 2, 3, 6, and 8-specific T cell responses in PA and sensitized non-peanut allergic (sNPA) subjects, using the CD154 upregulation assay and the class II tetramer technology. In the PA group, T cells directed against Ara h 1, 2, 3, and 6 have a heterogeneous TH2 phenotype characterized by differential expression of CRTH2, CD27, and CCR6. Reactivity toward these different components was also distinct for each PA subject. Two dominant Ara h 2 epitopes associated with DR1501 and DR0901 were also identified. Frequencies of Ara h-specific T cell responses were also linked to the peanut specific-IgE level. Conversely, low peanut-IgE level in sNPA subjects was associated with a weak or an absence of the allergen-specific T cell reactivity. Ara h 8-specific T cell reactivity was weak in both PA and sNPA subjects. Thus, peanut-IgE level was associated with a heterogeneous Ara h (but not Ara h 8)-specific T cell reactivity only in PA patients. This suggests an important immunogenicity of each Ara h 1, 2, 3, and 6 in inducing peanut allergy. Targeting Ara h 1-, 2-, 3-, and 6-specific effector TH2 cells can be the future way to treat peanut allergy. PMID- 29988524 TI - Equipped for Migrations Across High Latitude Regions? Reduced Spur Length and Outcrossing Rate in a Biennial Halenia elliptica (Gentianaceae) With Mixed Mating System Along a Latitude Gradient. AB - Halenia (Gentianaceae) originated from the mountain regions of East Asia, and diversified in America following long migrations via Beringia. While Halenia elliptica, one species of the genus in China, migrated toward high latitudes in China. Spur length of H. elliptica is highly variable. We examined the relationship between spur length and mating pattern along a latitude gradient. Field experiments were performed in two populations of H. elliptica, and we found that this species could produce seeds via both autonomous selfing and the aid of pollinators, suggesting a mixed mating system. In seven populations of H. elliptica along a latitudinal gradient, we found a trend of decrease in spur length with the increase of latitude. Based on molecular data from 11 microsatellite loci, we found that multilocus outcrossing rate decreased with the increase of latitude while the estimated inbreeding depression increased significantly, indicating that a high degree of inbreeding depression might have prevented evolution toward complete selfing in the high latitude populations with short spur length, and thus maintained mixed mating system of H. elliptica. Our results suggest that the mixed mating system of this species might be helpful in overcoming pollinator scarcity in newly colonized populations toward high latitudes after its origination in the mountain regions of China, and the decrease of spur length in the high latitude populations could result from reduced resource allocation to pollinator associated traits. PMID- 29988523 TI - Recent developments in synthetic biology and metabolic engineering in microalgae towards biofuel production. AB - In the wake of the uprising global energy crisis, microalgae have emerged as an alternate feedstock for biofuel production. In addition, microalgae bear immense potential as bio-cell factories in terms of producing key chemicals, recombinant proteins, enzymes, lipid, hydrogen and alcohol. Abstraction of such high-value products (algal biorefinery approach) facilitates to make microalgae-based renewable energy an economically viable option. Synthetic biology is an emerging field that harmoniously blends science and engineering to help design and construct novel biological systems, with an aim to achieve rationally formulated objectives. However, resources and tools used for such nuclear manipulation, construction of synthetic gene network and genome-scale reconstruction of microalgae are limited. Herein, we present recent developments in the upcoming field of microalgae employed as a model system for synthetic biology applications and highlight the importance of genome-scale reconstruction models and kinetic models, to maximize the metabolic output by understanding the intricacies of algal growth. This review also examines the role played by microalgae as biorefineries, microalgal culture conditions and various operating parameters that need to be optimized to yield biofuel that can be economically competitive with fossil fuels. PMID- 29988526 TI - Optimization of Immunofluorescent Detection of Bone Marrow Disseminated Tumor Cells. AB - Background: Cancer metastasis is the primary cause of cancer-related deaths and remains incurable. Current clinical methods for predicting metastatic recurrence are not sensitive enough to detect individual cancer cells in the body; therefore, current efforts are directed toward liquid biopsy-based assays to capture circulating and disseminated tumor cells (CTCs and DTCs) in the blood and bone marrow, respectively. The most promising strategy is fluorescence-based immunostaining using cancer cell-specific markers. However, despite recent efforts to develop robust processing and staining platforms, results from these platforms have been discordant among groups, particularly for DTC detection. While the choice of cancer cell-specific markers is a large factor in this discordance, we have found that marker-independent factors causing false signal are just as critical to consider. Bone marrow is particularly challenging to analyze by immunostaining because endogenous immune cell properties and bone marrow matrix components typically generate false staining. For immunostaining of whole tumor tissue containing ample cancer cells, this background staining can be overcome. Application of fluorescent-based staining for rare cells, however, is easily jeopardized by immune cells and autofluorescence that lead to false signal. Results: We have specifically found two types of background staining in bone marrow samples: autofluorescence of the tissue and non-specific binding of secondary antibodies. We systematically optimized a basic immunofluorescence protocol to eliminate this background using cancer cells spiked into human bone marrow. This enhanced the specificity of automated scanning detection software. Our optimized protocol also outperformed a commercial rare cell detection protocol in detecting candidate DTCs from metastatic patient bone marrow. Conclusions: Robust optimization to increase the signal-to-noise ratio of immunofluorescent staining of bone marrow is required in order to achieve the necessary sensitivity and specificity for rare cell detection. Background immunofluorescent staining in bone marrow causes uncertainty and inconsistency among investigators, which can be overcome by systematically addressing each contributing source. Our optimized assay eliminates sources of background signal, and is adaptable to automated staining platforms for high throughput analysis. PMID- 29988525 TI - Systemically Administered Sindbis Virus in Combination with Immune Checkpoint Blockade Induces Curative Anti-tumor Immunity. AB - Oncolytic viruses represent a promising form of cancer immunotherapy. We investigated the potential of Sindbis virus (SV) for the treatment of solid tumors expressing the human cancer testis antigen NYESO-1. NYESO-1 is an immunogenic antigen frequently expressed in numerous cancers, such as ovarian cancer. We show that SV expressing the tumor-associated antigen NYESO-1 (SV NYESO1) acts as an immunostimulatory agent, inducing systemic and rapid lymphocyte activation, leading to a pro-inflammatory environment. SV-NYESO1 treatment combined with anti-programmed death 1 (anti-PD-1) markedly augmented the anti-tumor immunity in mice over the course of treatment, resulting in an avid systemic and intratumoral immune response. This response involved reduced presence of granulocytic myeloid-derived suppressor cells in tumors and an increase in the activation of splenic and tumor-infiltrating T cells. Combined therapy also induced enhanced cytotoxic activity of T cells against NYESO-1 expressing tumors. These results were in line with an observed inverse correlation between T cell activation and tumor growth. Finally, we show that combined therapy resulted in complete clearance of NYESO-1-expressing tumors in vivo and led to long-term protection against recurrences. These findings provide a rationale for clinical studies of SV-NYESO1 combined with immune checkpoint blockade anti-PD-1 to be used in the treatment of NYESO-1-expressing tumors. PMID- 29988527 TI - Characterization of Plasmodium vivax Proteins in Plasma-Derived Exosomes From Malaria-Infected Liver-Chimeric Humanized Mice. AB - Exosomes are extracellular vesicles of endocytic origin containing molecular signatures implying the cell of origin; thus, they offer a unique opportunity to discover biomarkers of disease. Plasmodium vivax, responsible for more than half of all malaria cases outside Africa, is a major obstacle in the goal of malaria elimination due to the presence of dormant liver stages (hypnozoites), which after the initial infection may reactivate to cause disease. Hypnozoite infection is asymptomatic and there are currently no diagnostic tools to detect their presence. The human liver-chimeric (FRG huHep) mouse is a robust P. vivax infection model for exo-erythrocytic development of liver stages, including hypnozoites. We studied the proteome of plasma-derived exosomes isolated from P. vivax infected FRG huHep mice with the objective of identifying liver-stage expressed parasite proteins indicative of infection. Proteomic analysis of these exosomes showed the presence of 290 and 234 proteins from mouse and human origin, respectively, including canonical exosomal markers. Human proteins include proteins previously detected in liver-derived exosomes, highlighting the potential of this chimeric mouse model to study plasma exosomes derived unequivocally from human hepatocytes. Noticeably, we identified 17 parasite proteins including enzymes, surface proteins, components of the endocytic pathway and translation machinery, as well as uncharacterized proteins. Western blot analysis validated the presence of human arginase-I and an uncharacterized P. vivax protein in plasma-derived exosomes. This study represents a proof-of principle that plasma-derived exosomes from P. vivax infected FRG-huHep mice contain human hepatocyte and P. vivax proteins with the potential to unveil biological features of liver infection and identify biomarkers of hypnozoite infection. PMID- 29988528 TI - Relating Bryophyte Assemblages to a Remotely Sensed Depth-to-Water Index in Boreal Forests. AB - Given the habitat moisture (air humidity or soil moisture) preferences of many forest bryophytes, we explored whether the depth-to-water (DTW) index, derived from remotely sensed Light Detection and Ranging (LiDAR) data, was related to fine-scale patterns of spatial variation in bryophyte abundance, diversity, and composition. The goal was to assess the utility of the topographic DTW index as a tool to decipher trends in bryophyte assemblages along a site wetness gradient in the boreal mixedwood forest. Discrete Airborne Laser Scanning (ALS) data were acquired over the entire Ecosystem Management Emulating Natural Disturbance (EMEND) experimental site located in northwestern Alberta, Canada (56 degrees 46' 13" N, 118 degrees 22' 28" W), based on which we calculated a mathematical index of approximate depth to water at or below the soil surface at 1 m resolution using the Wet-Areas Mapping model. Bryophytes (mosses and liverworts) were sampled in permanent sample plots in unmanaged forest stands of varying dominant canopy tree composition. The relationships between DTW and bryophyte cover, richness, diversity, and composition in broadleaf (deciduous)-, mixed, and conifer-dominated boreal forest stands were analyzed using linear mixed-effect models and multivariate analyses. Bryophyte cover was highest in conifer dominated forest, which occupied the wetter end of the DTW gradient, followed by mixed forest, whereas broadleaf forest, which occupied the drier end of the DTW gradient, had the lowest cover but highest bryophyte diversity. Bryophyte cover in conifer-dominated forests was positively related to site moisture (negatively related to the DTW index). In contrast, bryophyte species richness and diversity were negatively related to site moisture (increased at higher DTW values) in all forest types. DTW explained significant variation in bryophyte species composition in mixed forests, while indicator species analysis identified species with preferences for wet, moist, and dry site conditions in each forest type. Our results corroborate the importance of site moisture as a driver of bryophyte assemblages but, interestingly, there were important differences among forest types, which themselves are distributed across a gradient of site moisture. Our study demonstrates the utility of the topographic DTW index for understanding fine-scale (plot-level) variation in bryophyte assemblages in forested landscapes. PMID- 29988529 TI - Anti-Inflammatory MicroRNAs and Their Potential for Inflammatory Diseases Treatment. AB - Inflammation is a complicated biological and pathophysiological cascade of responses to infections and injuries, and inflammatory mechanisms are closely related to many diseases. The magnitude, the complicated network of pro- and anti inflammatory factors, and the direction of the inflammatory response can impact on the development and progression of various disorders. The currently available treatment strategies often target the symptoms and not the causes of inflammatory disease and may often be ineffective. Since the onset and termination of inflammation are crucial to prevent tissue damage, a range of mechanisms has evolved in nature to regulate the process including negative and positive feedback loops. In this regard, microRNAs (miRNAs) have emerged as key gene regulators to control inflammation, and it is speculated that they are fine-tune signaling regulators to allow for proper resolution and prevent uncontrolled progress of inflammatory reactions. In this review, we discuss recent findings related to significant roles of miRNAs in immune regulation, especially the potential utility of these molecules as novel anti-inflammatory agents to treat inflammatory diseases. Furthermore, we discuss the possibilities of using miRNAs as drugs in the form of miRNA mimics or miRNA antagonists. PMID- 29988530 TI - Kinematic Components of the Reach-to-Target Movement After Stroke for Focused Rehabilitation Interventions: Systematic Review and Meta-Analysis. AB - Background: Better upper limb recovery after stroke could be achieved through tailoring rehabilitation interventions directly at movement deficits. Aim: To identify potential; targets for therapy by synthesizing findings of differences in kinematics and muscle activity between stroke survivors and healthy adults performing reach-to-target tasks. Methods: A systematic review with identification of studies, data extraction, and potential risk of bias was completed independently by two reviewers. Online databases were searched from their inception to November 2017 to find studies of reach-to-target in people with-stroke and healthy adults. Potential risk-of-bias was assessed using the Down's and Black Tool. Synthesis was undertaken via: (a) meta-analysis of kinematic characteristics utilizing the standardized mean difference (SMD) [95% confidence intervals]; and (b), narrative synthesis of muscle activation. Results: Forty-six studies met the review criteria but 14 had insufficient data for extraction. Consequently, 32 studies were included in the meta-analysis. Potential risk-of-bias was low for one study, unclear for 30, and high for one. Reach-to-target was investigated with 618 people-with-stroke and 429 healthy adults. The meta-analysis found, in all areas of workspace, that people-with stroke had: greater movement times (seconds) e.g., SMD 2.57 [0.89, 4.25]; lower peak velocity (millimeters/second) e.g., SMD -1.76 [-2.29, -1.24]; greater trunk displacement (millimeters) e.g. SMD 1.42 [0.90, 1.93]; a more curved reach-path ratio e.g., SMD 0.77 [0.32, 1.22] and reduced movement smoothness e.g., SMD 0.92 [0.32, 1.52]. In the ipsilateral and contralateral workspace, people-with-stroke exhibited: larger errors in target accuracy e.g., SMD 0.70 [0.39, 1.01]. In contralateral workspace, stroke survivors had: reduced elbow extension and shoulder flexion (degrees) e.g., elbow extension SMD -1.10 [-1.62, -0.58] and reduced shoulder flexion SMD -1.91 [-1.96, -0.42]. Narrative synthesis of muscle activation found that people-with-stroke, compared with healthy adults, exhibited: delayed muscle activation; reduced coherence between muscle pairs; and use of a greater percentage of muscle power. Conclusions: This first-ever meta analysis of the kinematic differences between people with stroke and healthy adults performing reach-to-target found statistically significant differences for 21 of the 26 comparisons. The differences identified and values provided are potential foci for tailored rehabilitation interventions to improve upper limb recovery after stroke. PMID- 29988531 TI - Cortical and Subcortical Alterations in Medication Overuse Headache. AB - Medication-overuse headache is an increasing problem in headache clinics and therapy includes drug withdrawal. Although it has been shown that the orbitofrontal cortex is hypo-metabolic and exhibits less gray matter in these patients the functional role of this finding is still unclear as virtually no functional imaging studies exploring withdrawal of medication have been published. We compared structural and functional magnetic resonance images of 18 patients before and after drug withdrawal with age and gender matched controls using a well-established trigeminal, nociceptive fMRI paradigm. We reproduced structural changes in the orbitofrontal cortex of the patients which highly correlated with the clinical outcome of medication withdrawal. The neuronal activity before drug withdrawal in pain related regions (operculum, insula, spinal trigeminal nucleus) was reduced compared to after drug withdrawal and the orbitofrontal cortex showed a reduced functional connectivity to the nociceptive input region (spinal trigeminal nucleus) and the cerebellum which regained after withdrawal. These data suggest the seminal role of the orbitofrontal cortex as a mediator between bottom-up and top-down stream in headache processing. PMID- 29988532 TI - An Interferon Signature Discriminates Pneumococcal From Staphylococcal Pneumonia. AB - Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP). Despite the low prevalence of CAP caused by methicillin-resistant Staphylococcus aureus (MRSA), CAP patients often receive empirical antibiotic therapy providing coverage for MRSA such as vancomycin or linezolid. An early differentiation between S. pneumoniae and S. aureus pneumonia can help to reduce the use of unnecessary antibiotics. The objective of this study was to identify candidate biomarkers that can discriminate pneumococcal from staphylococcal pneumonia. A genome-wide transcriptional analysis of lung and peripheral blood performed in murine models of S. pneumoniae and S. aureus lung infection identified an interferon signature specifically associated with S. pneumoniae infection. Prediction models built using a support vector machine and Monte Carlo cross-validation, identified the combination of the interferon-induced chemokines CXCL9 and CXCL10 serum concentrations as the set of biomarkers with best sensitivity, specificity, and predictive power that enabled an accurate discrimination between S. pneumoniae and S. aureus pneumonia. The predictive performance of these biomarkers was further validated in an independent cohort of mice. This study highlights the potential of serum CXCL9 and CXCL10 biomarkers as an adjunctive diagnostic tool that could facilitate prompt and correct pathogen targeted therapy in CAP patients. PMID- 29988533 TI - Signatures of Selection in the Genomes of Chinese Chestnut (Castanea mollissima Blume): The Roots of Nut Tree Domestication. AB - Chestnuts (Castanea) are major nut crops in East Asia and southern Europe, and are unique among temperate nut crops in that the harvested seeds are starchy rather than oily. Chestnut species have been cultivated for three millennia or more in China, so it is likely that artificial selection has affected the genome of orchard-grown chestnuts. The genetics of Chinese chestnut (Castanea mollissima Blume) domestication are also of interest to breeders of hybrid American chestnut, especially if the low-growing, branching habit of Chinese chestnut, an impediment to American chestnut restoration, is partly the result of artificial selection. We resequenced genomes of wild and orchard-derived Chinese chestnuts and identified selective sweeps based on pooled whole-genome SNP datasets. We present candidate gene loci for chestnut domestication and discuss the potential phenotypic effects of candidate loci, some of which may be useful genes for chestnut improvement in Asia and North America. Selective sweeps included predicted genes potentially related to flower phenology and development, fruit maturation, and secondary metabolism, and included some genes homologous to domestication candidates in other woody plants. PMID- 29988536 TI - Brain Metabolism Alterations Induced by Pregnancy Swimming Decreases Neurological Impairments Following Neonatal Hypoxia-Ischemia in Very Immature Rats. AB - Introduction: Prematurity, through brain injury and altered development is a major cause of neurological impairments and can result in motor, cognitive and behavioral deficits later in life. Presently, there are no well-established effective therapies for preterm brain injury and the search for new strategies is needed. Intra-uterine environment plays a decisive role in brain maturation and interventions using the gestational window have been shown to influence long-term health in the offspring. In this study, we investigated whether pregnancy swimming can prevent the neurochemical metabolic alterations and damage that result from postnatal hypoxic-ischemic brain injury (HI) in very immature rats. Methods: Female pregnant Wistar rats were divided into swimming (SW) or sedentary (SE) groups. Following a period of adaptation before mating, swimming was performed during the entire gestation. At postnatal day (PND3), rat pups from SW and SE dams had right common carotid artery occluded, followed by systemic hypoxia. At PND4 (24 h after HI), the early neurochemical profile was measured by 1H-magnetic resonance spectroscopy. Astrogliosis, apoptosis and neurotrophins protein expression were assessed in the cortex and hippocampus. From PND45, behavioral testing was performed. Diffusion tensor imaging and neurite orientation dispersion and density imaging were used to evaluate brain microstructure and the levels of proteins were quantified. Results: Pregnancy swimming was able to prevent early metabolic changes induced by HI preserving the energetic balance, decreasing apoptotic cell death and astrogliosis as well as maintaining the levels of neurotrophins. At adult age, swimming preserved brain microstructure and improved the performance in the behavioral tests. Conclusion: Our study points out that swimming during gestation in rats could prevent prematurity related brain damage in progeny with high translational potential and possibly interesting cost-benefits. HIGHLIGHTS - Prematurity is a major cause of neurodevelopmental impairments;- Swimming during pregnancy reduces brain damage after HI injury;- Pregnancy is an important but underestimated preventive window. PMID- 29988535 TI - Defining the Species Micromonospora saelicesensis and Micromonospora noduli Under the Framework of Genomics. AB - The type isolates of species Micromonospora saelicesensis and Micromonospora noduli are Gram-stain positive actinobacteria that were originally isolated from nitrogen fixing nodules of the legumes Lupinus angustifolius and Pisum sativum, respectively. These two species are very closely related and questions arise as to whether they should be merged into a single species. To better delineate the relationship of M. saelicesensis and M. noduli, 10 strains isolated from plant tissue (nodules and leaves) and identified by their 16S rRNA gene sequences as either M. saelicensesis or M. noduli, based on a cut-off value of >=99.5% were selected for whole-genome sequencing and compared with the type strains of M. saelicesensis Lupac 09T and M. noduli GUI43T using overall genome relatedness indices (OGRI) which included ANI, OrthoANI and digital DNA-DNA hybridization. Whole- and core-genome phylogenomic analyses were also carried out. These results were compared with the topologies of the 16S rRNA and gyrB gene phylogenies. Good correlation was found between all trees except for the 16S rRNA gene. Overall results also supported the current classification of M. saelicesensis and M. noduli as separate species. Especially useful was the core-genome phylogenetic analyses based on 92 genes and the dDDH results which were highly correlated. The importance of using more than one strain for a better definition of a species was also shown. A series of in vitro phenotypic assays performed at different times were compared with in silico predictions based on genomic data. In vitro phenotypic tests showed discrepancies among the independent studies, confirming the lack of reproducibility even when tests were performed in the same laboratory. On the other hand, the use of in silico predictions proved useful for defining a stable phenotype profile among the strains analyzed. These results provide a working framework for defining Micromonospora species at the genomic and phenotypic level. PMID- 29988537 TI - Development of an Influenza Rapid Diagnostic Kit Specific for the H7 Subtype. AB - Since the spring of 2013, human infections with H7N9 viruses have been detected in China. Some of these viruses have become highly pathogenic. Highly and low pathogenic avian influenza H7N9 viruses are currently co-circulating with the seasonal influenza A viruses H3N2 and H1N1pdm09. Prompt identification and isolation of H7N9 patients is one measure to prevent the spread of H7N9 virus and help prevent a pandemic. The majority of commercially available point-of-care rapid influenza diagnostic kits can differentiate between influenza A and B viruses, but cannot distinguish between H7N9 viruses and seasonal influenza A viruses. Accordingly, we have developed a rapid diagnostic kit specific for the H7 subtype that is accessible, easy to use. Although the detection limit of this H7 kit is one-tenth lower than that of a commercially available rapid influenza A and B diagnostic kit of similar design, except for the specificity of the monoclonal antibodies used, this kit is highly specific, detecting only H7 subtype influenza viruses, including the recent highly pathogenic H7N9 viruses from humans, and does not show any non-specific reactions with other HA subtypes. This H7 kit will be of value for the early detection of H7N9-infected patients. PMID- 29988538 TI - Commentary: Effectiveness of theta burst vs. high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomized non-inferiority trial. PMID- 29988539 TI - The Soliton and the Action Potential - Primary Elements Underlying Sentience. AB - At present the neurological basis of sentience is poorly understood and this problem is exacerbated by only a partial knowledge of how one of the primary elements of sentience, the action potential, actually works. This has consequences for our understanding of how communication within the brain and in artificial brain neural networks (BNNs). Reverse engineering models of brain activity assume processing works like a conventional binary computer and neglects speed of cognition, latencies, error in nerve conduction and the true dynamic structure of neural networks in the brain. Any model of nerve conduction that claims inspiration from nature must include these prerequisite parameters, but current western computer modeling of artificial BNNs assumes that the action potential is binary and binary mathematics has been assumed by force of popular acceptance to mediate computation in the brain. Here we present evidence that the action potential is a temporal compound ternary structure, described as the computational action potential (CAP). The CAP contains the refractory period, an analog third phase capable of phase-ternary computation via colliding action potentials. This would best fit a realistic BNN and provides a plausible mechanism to explain transmission, in preference to Cable Theory. The action potential pulse (APPulse), is made up of the action potential combined with a coupled synchronized soliton pressure pulse in the cell membrane. We describe a model of an ion channel in a membrane where a soliton deforms the channel sufficiently to destroy the electrostatic insulation thereby instigating a mechanical contraction across the membrane by electrostatic forces. Such a contraction has the effect of redistributing the force lengthways thereby increasing the volume of the ion channel in the membrane. Na ions, once attracted to the interior, balance the forces and the channel reforms to its original shape. A refractory period then occurs until the Na ions diffuse from the adjacent interior space. Finally, a computational model of the action potential (the CAP) is proposed with single action potentials significantly including the refractory period as a computational element capable of computation between colliding action potentials. PMID- 29988534 TI - Spinal Control of Locomotion: Individual Neurons, Their Circuits and Functions. AB - Systematic research on the physiological and anatomical characteristics of spinal cord interneurons along with their functional output has evolved for more than one century. Despite significant progress in our understanding of these networks and their role in generating and modulating movement, it has remained a challenge to elucidate the properties of the locomotor rhythm across species. Neurophysiological experimental evidence indicates similarities in the function of interneurons mediating afferent information regarding muscle stretch and loading, being affected by motor axon collaterals and those mediating presynaptic inhibition in animals and humans when their function is assessed at rest. However, significantly different muscle activation profiles are observed during locomotion across species. This difference may potentially be driven by a modified distribution of muscle afferents at multiple segmental levels in humans, resulting in an altered interaction between different classes of spinal interneurons. Further, different classes of spinal interneurons are likely activated or silent to some extent simultaneously in all species. Regardless of these limitations, continuous efforts on the function of spinal interneuronal circuits during mammalian locomotion will assist in delineating the neural mechanisms underlying locomotor control, and help develop novel targeted rehabilitation strategies in cases of impaired bipedal gait in humans. These rehabilitation strategies will include activity-based therapies and targeted neuromodulation of spinal interneuronal circuits via repetitive stimulation delivered to the brain and/or spinal cord. PMID- 29988541 TI - Dual-Task Processing With Identical Stimulus and Response Sets: Assessing the Importance of Task Representation in Dual-Task Interference. AB - Limitations in our ability to produce two responses at the same time - that is, dual-task interference - are typically measured by comparing performance when two stimuli are presented and two responses are made in close temporal proximity to when a single stimulus is presented and a single response is made. While straightforward, this approach leaves open multiple possible sources for observed differences. For example, on dual-task trials, it is typically necessary to identify two stimuli nearly simultaneously, whereas on typical single-task trials, only one stimulus is presented at a time. These processes are different from selecting and producing two distinct responses and complicate the interpretation of dual- and single-task performance differences. Ideally, performance when two tasks are executed should be compared to conditions in which only a single task is executed, while holding constant all other stimuli, response, and control processing. We introduce an alternative dual-task procedure designed to approach this ideal. It holds stimulus processing constant while manipulating the number of "tasks." Participants produced unimanual or bimanual responses to pairs of stimuli. For one set of stimuli (two-task set), the mappings were organized so an image of a face and a building were mapped to particular responses (including no response) on the left or right hands. For the other set of stimuli (one-task set), the stimuli indicated the same set of responses, but there was not a one-to-one mapping between the individual stimuli and responses. Instead, each stimulus pair had to be considered together to determine the appropriate unimanual or bimanual response. While the stimulus pairs were highly similar and the responses identical across the two conditions, performance was strikingly different. For the two-task set condition, bimanual responses were made more slowly than unimanual responses, reflecting typical dual task interference, whereas for the one-task set, unimanual responses were made more slowly than bimanual. These findings indicate that dual-task costs occur, at least in part, because of the interfering effects of task representation rather than simply the additional stimulus, response, or other processing typically required on dual-task trials. PMID- 29988540 TI - An Argument for Amphetamine-Induced Hallucinations in an Invertebrate. AB - Hallucinations - compelling perceptions of stimuli that aren't really there - occur in many psychiatric and neurological disorders, and are triggered by certain drugs of abuse. Despite their clinical importance, the neuronal mechanisms giving rise to hallucinations are poorly understood, in large part due to the absence of animal models in which they can be induced, confirmed to be endogenously generated, and objectively analyzed. In humans, amphetamine (AMPH) and related psychostimulants taken in large or repeated doses can induce hallucinations. Here we present evidence for such phenomena in the marine mollusk Tritonia diomedea. Animals injected with AMPH were found to sporadically launch spontaneous escape swims in the absence of eliciting stimuli. Deafferented isolated brains exposed to AMPH, where real stimuli could play no role, generated sporadic, spontaneous swim motor programs. A neurophysiological search of the swim network traced the origin of these drug-induced spontaneous motor programs to spontaneous bursts of firing in the S-cells, the CNS afferent neurons that normally inform the animal of skin contact with its predators and trigger the animal's escape swim. Further investigation identified AMPH-induced enhanced excitability and plateau potential properties in the S-cells. Taken together, these observations support an argument that Tritonia's spontaneous AMPH-induced swims are triggered by false perceptions of predator contact - i.e., hallucinations-and illuminate potential cellular mechanisms for such phenomena. PMID- 29988542 TI - Whole-Plant Metabolic Allocation Under Water Stress. AB - Trade-offs between plant growth and defense depend on environmental resource availability. Plants are predicted to prioritize growth when environmental resources are abundant and defense when environmental resources are scarce. Nevertheless, such predictions lack a whole-plant perspective-they do not account for potential differences in plant allocation above- and belowground. Such accounting is important because leaves and roots, though both critical to plant survival and fitness, differ in their resource-uptake roles and, often, in their vulnerability to herbivores. Here we aimed to determine how water availability affects plant allocation to multiple metabolic components of growth and defense in both leaves and roots. To do this, we conducted a meta-analysis of data from experimental studies in the literature. We assessed plant metabolic responses to experimentally reduced water availability, including changes in growth, nutrients, physical defenses, primary metabolites, hormones, and other secondary metabolites. Both above- and belowground, reduced water availability reduced plant biomass but increased the concentrations of primary metabolites and hormones. Importantly, however, reduced water had opposite effects in different organs on the concentrations of other secondary metabolites: reduced water increased carbon-based secondary metabolites in leaves but reduced them in roots. In addition, plants suffering from co-occurring drought and herbivory stresses exhibited dampened metabolic responses, suggesting a metabolic cost of multiple stresses. Our study highlights the needs for additional empirical studies of whole-plant metabolic responses under multiple stresses and for refinement of existing plant growth-defense theory in the context of whole plants. PMID- 29988543 TI - Assessing Collaboration in a National Research Partnership in Quality Improvement in Indigenous Primary Health Care: A Network Approach. AB - Background: The ABCD National Research Partnership was formed in mid-2010 as a collaboration to harness the expertise, experiences and resources of Aboriginal and Torres Strait Islander community-controlled peak bodies, government and research organisations to improve the quality of Indigenous primary health care. The aim of this study was to apply social network methods to assess collaboration and functioning of the Partnership at two time-points. Methods: A social network analysis (SNA) survey was conducted in early 2013, with a follow-up survey in mid 2014. In the two survey rounds, online surveys were emailed to one senior person of the organisation participating in the Partnership (2013: 14 organisations; 2014: 11 organisations). The surveys collected data on respondent perceptions of the Partnership as well as social network relationship data. Social network methods were used to apply standardised metrics to assess how well the partnership was functioning as a collaborative three years into its operation, and in its fourth year. Results: Most respondents rated the Partnership as successful in progressing toward its goals. Network density and centrality scores show a well-connected partnership spanning different organisational types and states/territories (Northern Territory, Queensland, Western Australia, South Australia, and Far-West New South Wales). High centrality scores reflect high connectivity between key hubs in the network, contributing toward the shared goal of improved Indigenous primary health care. Network diagrams show key structural positions by organisational type, the frequency and intensity of interactions and the strengths and potential vulnerabilities in the partnership network, with comparisons at two time points for the partnership. Conclusions: The study found that the Partnership was effective in securing collaboration across its partners. Partners' contribution of resources reflected their active involvement. There was a high level of agreement on the achievement of the key goals of the Partnership, showing shared sense-making amongst partners. SNA tools assisted with monitoring the network over time to develop strategies supporting connections between partners for sustaining collaborative learning. Study findings identify successful approaches for a research partnership to improve quality of care in Indigenous primary health care and provide encouragement for wider applications for research partnerships and collaborations in Australia and internationally. PMID- 29988545 TI - A case report: Addison disease caused by adrenal tuberculosis. AB - We report middle age man with skin hyperpigmentation oral and lip mucous membranes, general malaise and depression. Further examinations lead to adrenal insufficiency, Addison's disease. Imaging studies show bilateral adrenal hyperplasia, show negative result for tuberculosis. We perform laparoscopic adrenalectomy. Multiple caseosa necrosis in gross specimen and Langhan's giant cells microscopic appearance ensure patient suffered Addison's disease cause by adrenal gland tuberculosis. PMID- 29988544 TI - Myeloid-Derived Suppressor Cells Induce Podocyte Injury Through Increasing Reactive Oxygen Species in Lupus Nephritis. AB - The expansion of myeloid-derived suppressor cells (MDSCs) has been documented in murine models and patients with lupus nephritis (LN), but the exact role of MDSCs in this process remains largely unknown. In this study, we investigated whether MDSCs are involved in the process of podocyte injury in the development of LN. In toll-like receptor-7 (TLR-7) agonist imiquimod-induced lupus mice, we found the severe podocyte injury in glomeruli of lupus mice and significant expansion of MDSCs in spleens and kidneys of lupus mice. The function of TLR-7 activated MDSCs was enhanced including the increased generation of reactive oxygen species (ROS) in vivo and in vitro. Moreover, the ROS production of MDSCs induced podocyte injury through activating the p-38MAPK and NF-kB signaling. Furthermore, we verified that podocyte injury was indeed correlated with expansion of MDSCs and their ROS secretion in LN of pristane-induced lupus mice. These findings first indicate that the podocyte injury in LN was associated with the increased MDSCs in kidney and MDSCs may be a promising therapeutic target of LN in the future. PMID- 29988546 TI - Childhood Stroke: Awareness, Interest, and Knowledge Among the Pediatric Community. AB - Objective: Acute childhood stroke is an emergency requiring a high level of awareness among first-line healthcare providers. This survey serves as an indicator of the awareness of, the interest in, and knowledge of childhood stroke of German pediatricians. Methods: Thousand six hundred and ninety-seven physicians of pediatric in- and outpatient facilities in Bavaria, Germany, were invited via email to an online-survey about childhood stroke. Results: The overall participation rate was 14%. Forty-six percent of participants considered a diagnosis of childhood stroke at least once during the past year, and 47% provide care for patients who have suffered childhood stroke. The acronym FAST (Face-Arm-Speech-Time-Test) was correctly cited in 27% of the questionnaires. Most commonly quoted symptoms of childhood stroke were hemiparesis (90%), speech disorder (58%), seizure (44%), headache (40%), and impaired consciousness (33%). Migraine (63%), seizure (39%), and infections of the brain (31%) were most frequently named as stroke mimics. Main diagnostic measures indicated were magnetic resonance imaging (MRI) (96%) and computer tomography (CT) (55%). Main therapeutic strategies were thrombolysis (80%), anticoagulation (41%), neuroprotective measures, and thrombectomies (15% each). Thirty-nine percent of participants had taken part in training sessions, 61% studied literature, 37% discussed with colleagues, and 25% performed internet research on childhood stroke. Ninety-three percent of participants approve skill enhancement, favoring training sessions (80%), publications (43%), and web based offers (35%). Consent for offering a flyer on the topic to caregivers in facilities was given in 49%. Conclusion: Childhood stroke constitutes a topic of clinical importance to pediatricians. Participants demonstrate a considerable level of comprehension concerning the subject, but room for improvement remains. A multi-modal approach encompassing an elaborate training program, regular educational publications in professional journals, and web based offers could reach a broad range of health care providers. Paired with a public adult and childhood stroke awareness campaign, these efforts could contribute to optimize the care for children suffering from stroke. PMID- 29988547 TI - Inhibition of Sarco-Endoplasmic Reticulum Ca2+ ATPase Extends the Lifespan in C. elegans Worms. AB - The sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) refills the endoplasmic reticulum (ER) with Ca2+ up to the millimolar range and is therefore the main controller of the ER [Ca2+] level ([Ca2+]ER), which has a key role in the modulation of cytosolic Ca2+ signaling and ER-mitochondria Ca2+ transfer. Given that both cytosolic and mitochondrial Ca2+ dynamics strongly interplay with energy metabolism and nutrient-sensitive pathways, both of them involved in the aging process, we have studied the effect of SERCA inhibitors on lifespan in C. elegans. We have used thapsigargin and 2,5-Di-tert-butylhydroquinone (2,5-BHQ) as SERCA inhibitors, and the inactive analog 2,6-Di-tert-butylhydroquinone (2,6-BHQ) as a control for 2,5-BHQ. Every drug was administered to the worms either directly in the agar or via an inclusion compound with gamma-cyclodextrin. The results show that 2,6-BHQ produced a small but significant increase in survival, perhaps because of its antioxidant properties. However, 2,5-BHQ produced in all the conditions a much higher increase in lifespan, and the potent and specific SERCA inhibitor thapsigargin also extended the lifespan. The effects of 2,5-BHQ and thapsigargin had a bell-shaped concentration dependence, with a maximum effect at a certain dose and smaller or even toxic effects at higher concentrations. Our data show therefore that submaximal inhibition of SERCA pumps has a pro-longevity effect, suggesting that Ca2+ signaling plays an important role in the aging process and that it could be a promising novel target pathway to act on aging. PMID- 29988548 TI - Regulation of the Immune Response by the Inflammatory Metabolic Microenvironment in the Context of Allotransplantation. AB - Antigen challenge induced by allotransplantation results in the activation of T and B cells, followed by their differentiation and proliferation to mount an effective immune response. Metabolic fitness has been shown to be crucial for supporting the major shift from quiescent to active immune cells and for tuning the immune response. Metabolic reprogramming includes regulation of the balance between glycolysis and mitochondrial respiration processes. Recent research has shed new light on the functions served by the end products of metabolism such as lactate, acetate, and ATP. At enhanced local concentrations, these metabolites have complex effects in which they not only induce T and B cell responses, cell mobility, and cytokine secretion but also favor the resolution of inflammation by promoting regulatory functions. Such mechanisms are instrumental in the context of the immune response in transplantation, not only to protect the graft and/or eliminate cells targeting it but also to maintain cell homeostasis per se. Metabolic adaptation thus plays an instrumental role on the outcome of the cellular and humoral responses. This, of course, raises the possibility of drugs that would interfere in these metabolic pathways to control the immune response but also highlights the risk that some drugs may perturb this metabolism and cell homeostasis and be deleterious for graft outcome. This review focuses on how metabolic alterations of the local immune microenvironment regulate the immune response and the impact of metabolic manipulation in allotransplantation. PMID- 29988549 TI - The Effect of Lipopolysaccharide-Induced Experimental Bovine Mastitis on Clinical Parameters, Inflammatory Markers, and the Metabolome: A Kinetic Approach. AB - Mastitis is an inflammatory condition of the mammary tissue and represents a major problem for the dairy industry worldwide. The present study was undertaken to study how experimentally induced acute bovine mastitis affects inflammatory parameters and changes in the metabolome. To this end, we induced experimental mastitis in nine cows by intramammary infusion of 100 ug purified Escherichia coli lipopolysaccharide (LPS) followed by kinetic assessments of cytokine responses (by enzyme-linked immunosorbent assay), changes in the metabolome (assessed by nuclear magnetic resonance), clinical parameters (heat, local pain perception, redness, swelling, rectal temperature, clot formation, and color changes in the milk), and milk somatic cell counts, at several time points post LPS infusion. Intramammary LPS infusion induced clinical signs of mastitis, which started from 2 h post infusion and had returned to normal levels within 24-72 h. Milk changes were seen with a delay compared with the clinical signs and persisted for a longer time. In parallel, induction of IL-6 and TNF-alpha were seen in milk, and there was also a transient elevation of plasma IL-6 whereas plasma TNF-alpha was not significantly elevated. In addition, a robust increase in CCL2 was seen in the milk of LPS-infused cows, whereas G-CSF, CXCL1, and histamine in milk were unaffected. By using a metabolomics approach, a transient increase of plasma lactose was seen in LPS-induced cows. In plasma, significant reductions in ketone bodies (3-hydroxybutyrate and acetoacetate) and decreased levels of short-chain fatty acids, known to be major products released from the gut microbiota, were observed after LPS infusion; a profound reduction of plasma citrate was also seen. Intramammary LPS infusion also caused major changes in the milk metabolome, although with a delay in comparison with plasma, including a reduction of lactose. We conclude that the LPS-induced acute mastitis rapidly affects the plasma metabolome and cytokine induction with similar kinetics as the development of the clinical signs, whereas the corresponding effects in milk occurred with a delay. PMID- 29988550 TI - Sinus computed tomography predicts clinical response to corticosteroids in chronic rhinosinusitis with nasal polyps. AB - Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disease usually characterized by chronic eosinophilia in the sinonasal mucosa, which often requires glucocorticoid (GC) therapy. However, the therapeutic response varies markedly between individuals. The objective of this study was to evaluate the diagnostic values of sinus computed tomography (CT) for GC-sensitivity in patients with CRSwNP. Methods: We conducted a prospective, single-blinded study of 47 consecutive patients with CRSwNP. These patients were given a course of oral prednisone (30 mg daily for 14 days) and subsequently classified into objectively GC-sensitive and -insensitive subgroup according to the change in nasal polyp size score, or subjectively GC-sensitive and insensitive subgroup according to the change in total nasal symptom score. The following parameters were compared between GC-sensitive and GC-insensitive subgroups: Lund-Mackay scores, olfactory cleft (OC) scores, and blood eosinophil counts and ratio (percentage of the total white blood cells). Results: 25/47 (53.2%) and 29/47 (61.7%) patients were objectively and subjectively sensitive to GC therapy, respectively. The OC score and the blood eosinophil counts and ratio in GC-sensitive subgroup were significantly higher than those in GC-insensitive subgroup, defined either objectively or subjectively. Multivariate logistic regression revealed that OC score was independent risk factor for objective or subjective GC-sensitivity. The OC score exhibited comparable accuracy with the blood eosinophil ratio as predictor of objective and subjective GC-sensitivity (the OC score AUC = 0.775 and 0.829, respectively). A OC score of 3.5 could act as a reliable indicator for predicting the clinical response to GC therapy in CRSwNP. Conclusion: Our prospective findings validate the potential value of sinus CT scan in predicting GC-sensitivity in CRSwNP patients. PMID- 29988551 TI - Age-Related Declines in the Ability to Modulate Common Input to Bilateral and Unilateral Plantar Flexors During Forward Postural Lean. AB - Aging can impair an ability to lean the body forward to the edge of the base of support. Here, we investigated, using a coherence analysis, common inputs to bilateral and unilateral plantar flexor muscles to test a hypothesis that the age related impairment would be related to strong synchronous bilateral activation and reduced cortical control of these muscles. Healthy young (n = 14) and elderly adults (n = 19), who were all right-foot dominant, performed quiet standing task and tasks that required the subjects to lean their body forward to 35 and 75% of the maximum lean distance. The electromyogram was recorded from the bilateral medial gastrocnemius (MG) and soleus (SL) muscles. We analyzed delta-band coherence, that reflects comodulation of muscle activity, between the bilateral homologous muscles (MG-MG and SL-SL pairs). The origin of this bilateral comodulation is suggested to be the subcortical system. Also, we examined beta band coherence, that is related to the corticospinal drive, between the unilateral muscles (MG-SL pair) in the right leg. Results indicated that the bilateral delta-band coherence for the MG-MG pair was significantly smaller in the 75% forward lean than quiet standing and 35% forward lean tasks for the young adults (quiet: p = 0.036; 35%: p = 0.0011). The bilateral delta-band coherence for the SL-SL pair was significantly smaller in the 75% forward lean than 35% forward lean task for the young adults (p = 0.027). Furthermore, the unilateral beta-band coherence was larger in the forward lean than quiet standing task for the young adults (35%: p < 0.001; 75%: p = 0.029). Contrarily, the elderly adults did not demonstrate such changes. These findings suggest the importance of decreasing the synchronous bilateral activation and increasing the unilateral cortical control of the plantar flexor muscles for the successful forward postural lean performance, and that aging impairs this modulatory ability. PMID- 29988552 TI - Effect of sequential C-terminal tryptophans on green fluorescent protein fluorescence. AB - The effect of the addition of sequential C-terminal tryptophan residues on the fluorescence intensity of GFP was investigated. Tandem repeats of six tryptophan residues markedly decreased fluorescence intensity. This phenomenon is likely to occur because of the inhibition of GFP folding, resulting in insolubility. Exploiting this phenomenon, we constructed a cloning vector that facilitates the identification of recombinant colonies of Escherichia coli by the activation of GFP. PMID- 29988553 TI - Aquaporin-4 Autoantibodies From Neuromyelitis Optica Spectrum Disorder Patients Induce Complement-Independent Immunopathologies in Mice. AB - Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system inflammatory disorders causing significant morbidities and mortality. The majority of NMOSD patients have autoimmunity against aquaporin-4 (AQP4), evidenced by seropositivity for autoantibodies against aquaporin-4 (AQP4-IgG). AQP4-IgG is pathogenic with neuroinflammation initiated upon binding of AQP4-IgG to astrocytic AQP4. Complement activation contributes to astrocytic cytotoxicity, neuroinflammation, and tissue necrosis in NMOSD, but the role of complement independent mechanisms is uncertain. We studied the complement-independent pathogenic effects of AQP4-IgG by passive transfer of IgG from NMOSD patients to mice with breached blood-brain barrier (BBB). Mice, pretreated with bacterial proteins, received daily intraperitoneal injections of IgG purified from AQP4-IgG seropositive NMOSD patients [IgG(AQP4+)], or IgG from AQP4-IgG-seronegative patients [IgG(AQP4-)] or healthy subjects [IgG(Healthy)] for 8 days. Motor function was tested by walking across narrow beams, and spinal cords were collected for immunofluorescent analysis. We found that human IgG infiltrated into cord parenchyma of mice with breached BBB without deposition of complement activation products. Spinal cord of mice that received IgG(AQP4+) demonstrated loss of AQP4 and glial fibrillary acidic protein (suggestive of astrocyte loss), decrease in excitatory amino acid transporter 2, microglial/macrophage activation, neutrophil infiltration, patchy demyelination, and loss in axonal integrity. Mice that received IgG(AQP4+) required longer time with more paw slips to walk across narrow beams indicative of motor slowing and incoordination. Our findings suggest that AQP4-IgG induces complement-independent cord pathologies, including astrocytopathy, neuroinflammation, demyelination, and axonal injuries/loss, which are associated with subtle motor impairments. These complement-independent pathophysiologies likely contribute to early NMOSD lesion development. PMID- 29988554 TI - Odorants in Fish Feeds: A Potential Source of Malodors in Aquaculture. AB - Although the microbiota is considered to be the primary source of off-flavors in farmed fish, there is a lack of information about the possible contribution of feeds to fish malodor. For this reason, the current study was designed to perform comprehensive sensory and chemo-analytical characterization of fish feed constituents that can impact the quality of farmed fish, and to determine whether feeds cause malodor accumulation in fish. To this aim, odorants in four commercial fish feeds were extracted using solvent assisted flavor evaporation (SAFE) and characterized by comparative aroma extract dilution analysis (cAEDA) and multi-dimensional gas chromatography-mass spectrometry/olfactometry (MD-GC MS/O). The odorants in the fish feed samples were correlated with their respective sensory and fatty acid profiles. The cAEDA studies revealed the presence of 81 odorants of which 55 compounds were common to all the samples. Most of these odorants are identified here for the first time in fish feeds, and include skatole, indole, (E,Z,Z)-2,4,7-tridecatrienal, 4-ethyloctanoic acid, and cresols. Additionally, geosmin and 3-isopropyl-2-methoxypyrazine, known for their contribution to fish taint, and other cyanobacterial by-products, dimethyldisulfide and dimethyltrisulfide, were identified in feed samples. The results suggest that fish feed may contribute to fish malodor. Most of these off flavors were linked to lipid source (fish oil or plant/lard alternatives), unsaturated fatty acids contents, and protein type (plant-based or fishmeal-based sources) in the feed. PMID- 29988555 TI - Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice. AB - The GluA1 subunit of the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R ), expressing the "trafficking compromised" GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory. PMID- 29988556 TI - Lipopolysaccharide-Induced Dephosphorylation of AMPK-Activated Protein Kinase Potentiates Inflammatory Injury via Repression of ULK1-Dependent Autophagy. AB - AMP-activated protein kinase (AMPK) is a crucial metabolic regulator with profound modulatory activities on inflammation. Although the anti-inflammatory benefits of AMPK activators were well documented in experimental studies, the pathological significance of endogenous AMPK in inflammatory disorders largely remains unknown. This study investigated the phosphorylation status of endogenous AMPK and the potential roles of AMPK in mice with lipopolysaccharide (LPS) induced lethal inflammation. The results indicated that LPS dose-dependently decreased the phosphorylation level of AMPK and its target protein acetyl-CoA carboxylase (ACC). Reactivation of AMPK with the AMPK activator A-769662 suppressed LPS-induced elevation of interleukin 6, alleviated histological abnormalities in lung and improved the survival of LPS-challenged mice. Treatment with A-769662 restored LPS-induced suppression of autophagy, inhibition of autophagy by 3-MA reversed the beneficial effects of A-769662. Treatment with A 769662 suppressed LPS-induced activation of mammalian target of rapamycin (mTOR), co-administration of mTOR activator abolished the beneficial effects of A-769662, and the suppressive effects of A-769662 on uncoordinated-51-like kinase 1 (ULK1) phosphorylation. Inhibition of ULK1 removed the beneficial effects of A-769662. These data indicated that LPS-induced dephosphorylation of AMPK could result in weakened inhibition of mTOR and repression of ULK1-dependent autophagy, which might potentiate the development of LPS-induced inflammatory injury. These data suggest that pharmacological restoration of AMPK activation might be a beneficial approach for the intervention of inflammatory disorders. PMID- 29988557 TI - Modeling Hemolytic-Uremic Syndrome: In-Depth Characterization of Distinct Murine Models Reflecting Different Features of Human Disease. AB - Diarrhea-positive hemolytic-uremic syndrome (HUS) is a renal disorder that results from infections with Shiga-toxin (Stx)-producing Escherichia coli. The aim of this study was to establish well-defined refined murine models of HUS that can serve as preclinical tools to elucidate molecular mechanisms of disease development. C57BL/6J mice were subjected to different doses of Stx2 purified from an E. coli O157:H7 patient isolate. Animals received 300 ng/kg Stx2 and were sacrificed on day 3 to establish an acute model with fast disease progression. Alternatively, mice received 25 ng/kg Stx2 on days 0, 3, and 6, and were sacrificed on day 7 to establish a subacute model with moderate disease progression. Indicated by a rise in hematocrit, we observed dehydration despite volume substitution in both models, which was less pronounced in mice that underwent the 7-day regime. Compared with sham-treated animals, mice subjected to Stx2 developed profound weight loss, kidney dysfunction (elevation of plasma urea, creatinine, and neutrophil gelatinase-associated lipocalin), kidney injury (tubular injury and loss of endothelial cells), thrombotic microangiopathy (arteriolar microthrombi), and hemolysis (elevation of plasma bilirubin, lactate dehydrogenase, and free hemoglobin). The degree of complement activation (C3c deposition), immune cell invasion (macrophages and T lymphocytes), apoptosis, and proliferation were significantly increased in kidneys of mice subjected to the 7 day but not in kidneys of mice subjected to the 3-day regime. However, glomerular and kidney volume remained mainly unchanged, as assessed by 3D analysis of whole mount kidneys using CD31 staining with light sheet fluorescence microscopy. Gene expression analysis of kidneys revealed a total of only 91 overlapping genes altered in both Stx2 models. In conclusion, we have developed two refined mouse models with different disease progression, both leading to hemolysis, thrombotic microangiopathy, and acute kidney dysfunction and damage as key clinical features of human HUS. While intrarenal changes (apoptosis, proliferation, complement deposition, and immune cell invasion) mainly contribute to the pathophysiology of the subacute model, prerenal pathomechanisms (hypovolemia) play a predominant role in the acute model. Both models allow the further study of the pathomechanisms of most aspects of human HUS and the testing of distinct novel treatment strategies. PMID- 29988558 TI - Eight Days of Earth Reambulation Worsen Bone Loss Induced by 1-Month Spaceflight in the Major Weight-Bearing Ankle Bones of Mature Mice. AB - Spaceflight induces bone alterations with site-specific rates of bone loss according to the weight-bearing function of the bone. For the first time, this study aimed to characterize bone microarchitecture and density alterations of three ankle bones (calcaneus, navicular, and talus) of mice after spaceflight and to evaluate the impact of 8 days of Earth reambulation. Ten C57BL/6N male 4-month old mice flew on the Bion-M1 biosatellite for 1 month; half were euthanized within 24-h of return and half after 8-days recovery on Earth. Bone microarchitecture and quality was assessed by microtomography (MUCT). Whole calcaneus bone volume fraction decreased in Flight group (-6.4%, p < 0.05), and worsened in the Recovery group (-11.08%, p < 0.01), when compared to Control group. Navicular and talus trabecular bone volume fraction showed trends toward decrease in Flight and differences reached statistical significance in Recovery group (-8.16%; -8.87%, respectively; p < 0.05) when compared to Control group. At calcaneus, cortical thickness decreased in Recovery vs. Control groups (-11.69%; p < 0.01). Bone surface area, reflecting periosteal bone erosion, significantly increased in all bone sites analyzed. Qualitative analyses of 3-D bone reconstruction revealed local sites of cortical thinning and bone erosion, predominantly at articulations, muscle insertions, and ground contact bone sites. Overall, spaceflight-induced bone loss in ankle bones was site and compartment specific whilst the tissue mineral density of the remaining bone was preserved. Eight days after landing, bone status worsened as compared to immediate return. PMID- 29988559 TI - The role of PCNA as a scaffold protein in cellular signaling is functionally conserved between yeast and humans. AB - Proliferating cell nuclear antigen (PCNA), a member of the highly conserved DNA sliding clamp family, is an essential protein for cellular processes including DNA replication and repair. A large number of proteins from higher eukaryotes contain one of two PCNA-interacting motifs: PCNA-interacting protein box (PIP box) and AlkB homologue 2 PCNA-interacting motif (APIM). APIM has been shown to be especially important during cellular stress. PIP box is known to be functionally conserved in yeast, and here, we show that this is also the case for APIM. Several of the 84 APIM-containing yeast proteins are associated with cellular signaling as hub proteins, which are able to interact with a large number of other proteins. Cellular signaling is highly conserved throughout evolution, and we recently suggested a novel role for PCNA as a scaffold protein in cellular signaling in human cells. A cell-penetrating peptide containing the APIM sequence increases the sensitivity toward the chemotherapeutic agent cisplatin in both yeast and human cells, and both yeast and human cells become hypersensitive when the Hog1/p38 MAPK pathway is blocked. These results suggest that the interactions between APIM-containing signaling proteins and PCNA during the DNA damage response is evolutionary conserved between yeast and mammals and that PCNA has a role in cellular signaling also in yeast. PMID- 29988560 TI - Trans-Allelic Model for Prediction of Peptide:MHC-II Interactions. AB - Major histocompatibility complex class two (MHC-II) molecules are trans-membrane proteins and key components of the cellular immune system. Upon recognition of foreign peptides expressed on the MHC-II binding groove, CD4+ T cells mount an immune response against invading pathogens. Therefore, mechanistic identification and knowledge of physicochemical features that govern interactions between peptides and MHC-II molecules is useful for the design of effective epitope-based vaccines, as well as for understanding of immune responses. In this article, we present a comprehensive trans-allelic prediction model, a generalized version of our previous biophysical model, that can predict peptide interactions for all three human MHC-II loci (HLA-DR, HLA-DP, and HLA-DQ), using both peptide sequence data and structural information of MHC-II molecules. The advantage of this approach over other machine learning models is that it offers a simple and plausible physical explanation for peptide-MHC-II interactions. We train the model using a benchmark experimental dataset and measure its predictive performance using novel data. Despite its relative simplicity, we find that the model has comparable performance to the state-of-the-art method, the NetMHCIIpan method. Focusing on the physical basis of peptide-MHC binding, we find support for previous theoretical predictions about the contributions of certain binding pockets to the binding energy. In addition, we find that binding pocket P5 of HLA DP, which was not previously considered as a primary anchor, does make strong contribution to the binding energy. Together, the results indicate that our model can serve as a useful complement to alternative approaches to predicting peptide MHC interactions. PMID- 29988561 TI - Middle Cerebellar Peduncle Width-A Novel MRI Biomarker for FXTAS? AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a severe neurodegenerative movement disorder affecting over 40% of male and 16% of female FMR1 premutation carriers over the age of 50. However, there is a lack of prognostic biomarkers to aid early diagnosis and treatment planning. Therefore, this study aimed to assess the utility of the Magnetic Resonance Parkinson Index (MRPI) as a potential MRI biomarker for FXTAS. The four measurements required for the MRPI were assessed in 45 male premutation carriers at risk of developing FXTAS (Mean age = 59.54 years), 53 male patients with FXTAS (Mean age = 66.16 years) and 61 male controls (Mean age = 60.75 years), of which 73 participants had follow-up visits on average 1.96 years later. Middle cerebellar peduncle (MCP) width as well as midbrain and pons cross-sectional area were reduced in patients with FXTAS compared to both premutation carriers without FXTAS and controls. While these measurements were not found to change over time in the three-group analysis, age was an important predictor of midbrain cross-sectional area and pons/midbrain ratio. MCP width was initially reduced in a subset of premutation carriers who developed FXTAS symptoms between their initial and follow-up visits, which also decreased between visits, compared to age-matched premutation carriers who did not show any FXTAS symptom development over time. Therefore, while the MPRI may not be a useful biomarker for FXTAS, decreased MCP width may be one of the first notable signs of FXTAS, and therefore the first biomarker with the potential to identify those most at risk for the disorder. PMID- 29988562 TI - Effects of Systolic Blood Pressure on Brain Integrity in Multiple Sclerosis. AB - Background: In MS patients, hypertension is associated with a delayed diagnosis and an increased risk of progression. Understanding the mechanisms of this association could potentially lead to improved prevention of disease progression. We aimed to establish whether high blood pressure contributes to white-matter injury and brain atrophy in MS. Methods: Cross-sectional study of 95 patients with RRMS. Estimates of fractional anisotropy, gray-matter volume and lesion load were obtained from 3T MRI. We used fractional anisotropy voxel-based statistics to establish the effect of blood pressure on white matter tracts. Additionally, we used voxel-based morphometry (VBM) to study the effect on gray matter integrity. Results: Only 29.5% had normal blood pressure levels, with 52.6% suffering from prehypertension and 17.9% with hypertension. Increasing systolic blood pressure was associated with damage to posterior white-matter tracts as well as greater levels of gray matter atrophy, in particular in the frontal cortex. Age-adjusted linear regression indicated that neither lesion volume (beta = 0.002, 95%CI: 0.02-0.02; p = 0.85) or lesion number (beta = -0.004, 95%CI: 0.03 0.02; p = 0.74) were associated with systolic blood pressure. Conclusions: Prehypertension and hypertension are frequent in MS. Increased blood pressure is related to white- and gray-matter integrity, both related to MS disability outcomes. These findings suggest attention to the control of blood pressure in MS patients. PMID- 29988563 TI - Efficient CRISPR-based genome editing using tandem guide RNAs and editable surrogate reporters. AB - Cleavage efficiency plays a key role in clustered regularly interspaced short palindromic repeat (CRISPR)-based gene editing, particularly when the given guide RNA exhibits low cleavage activity. Here, we describe the packaging of tandem guide RNAs and single-strand annealing-based surrogate reporter cassettes into the CRISPR/CRISPR-associated protein 9 vector, which increased gene-editing efficiency by 4.94-6.31-fold and simultaneously enriched the proportion of genetically modified cells. This strategy may substantially improve genome editing efficiency for demanding applications. PMID- 29988564 TI - Mitochondrial Calcium Increase Induced by RyR1 and IP3R Channel Activation After Membrane Depolarization Regulates Skeletal Muscle Metabolism. AB - Aim: We hypothesize that both type-1 ryanodine receptor (RyR1) and IP3-receptor (IP3R) calcium channels are necessary for the mitochondrial Ca2+ increase caused by membrane depolarization induced by potassium (or by electrical stimulation) of single skeletal muscle fibers; this calcium increase would couple muscle fiber excitation to an increase in metabolic output from mitochondria (excitation metabolism coupling). Methods: Mitochondria matrix and cytoplasmic Ca2+ levels were evaluated in fibers isolated from flexor digitorium brevis muscle using plasmids for the expression of a mitochondrial Ca2+ sensor (CEPIA3mt) or a cytoplasmic Ca2+ sensor (RCaMP). The role of intracellular Ca2+ channels was evaluated using both specific pharmacological inhibitors (xestospongin B for IP3R and Dantrolene for RyR1) and a genetic approach (shIP3R1-RFP). O2 consumption was detected using Seahorse Extracellular Flux Analyzer. Results: In isolated muscle fibers cell membrane depolarization increased both cytoplasmic and mitochondrial Ca2+ levels. Mitochondrial Ca2+ uptake required functional inositol IP3R and RyR1 channels. Inhibition of either channel decreased basal O2 consumption rate but only RyR1 inhibition decreased ATP-linked O2 consumption. Cell membrane depolarization-induced Ca2+ signals in sub-sarcolemmal mitochondria were accompanied by a reduction in mitochondrial membrane potential; Ca2+ signals propagated toward intermyofibrillar mitochondria, which displayed increased membrane potential. These results are compatible with slow, Ca2+-dependent propagation of mitochondrial membrane potential from the surface toward the center of the fiber. Conclusion: Ca2+-dependent changes in mitochondrial membrane potential have different kinetics in the surface vs. the center of the fiber; these differences are likely to play a critical role in the control of mitochondrial metabolism, both at rest and after membrane depolarization as part of an "excitation-metabolism" coupling process in skeletal muscle fibers. PMID- 29988565 TI - Provision and continuation of antiretroviral therapy during acute conflict: the experience of MSF in Central African Republic and Yemen. AB - Background: Unstable settings present challenges for the effective provision of antiretroviral treatment (ART). In this paper, we summarize the experience and results of providing ART and implementing contingency plans during acute instability in the Central African Republic (CAR) and Yemen. Case presentation: In CAR, MSF has provided HIV care in three conflict-affected rural regions; these were put on hold throughout the acute phase of violence. "Run-away bags" containing 3 or 4 months of ART were distributed to patients at MSF facilities. Among 1820 HIV patients enrolled into care, 1440 (79%) initiated ART. By December 2016, 782 (54%) patients were still under ART, 354 (25%) have been lost to follow up and 182 (13%) had died. In 2013, when violence disrupted services, 683 patients were receiving ART. Between September-December 2013, 594 (87%) patients received runaway bags and by February 2014, 313 (53%) of these patients returned to the clinic.In Yemen, when violence erupted, patients received a health card that included a helpline to call in case of drug shortages in admission to emergency stocks; this was not possible in CAR due to lack of a functioning telephone network. One thousand six hundred fifty-five PLWHA have been enrolled in care and 1470 (89%) initiated ART; 1056 (72%) are still followed on ART, 126 (9%) were lost to follow up, and 288 (20%) died. In January 2011 clashes began and by April 2011 MSF medical activities were interrupted. Of the 363 patients receiving ART, 363 (100%) received emergency bags to cover 9 months and by February 2012, 354 (98%) patients returned to care. In March 2015 a new wave of conflict affected Yemen, forcing HIV activities to revert to contingency planning. Conclusions: This experience provides further evidence that provision of HIV treatment and emergency drug stocks can be successfully provided to most patients in both conflict-affected settings. PMID- 29988566 TI - Suppressor of IKKepsilon forms direct interactions with cytoskeletal proteins, tubulin and alpha-actinin, linking innate immunity to the cytoskeleton. AB - : Suppressor of IKKepsilon (SIKE) is associated with the type I interferon response of the innate immune system through TANK-binding kinase 1 (TBK1). Originally characterized as an endogenous inhibitor of TBK1 when overexpressed in viral infection and pathological cardiac hypertrophic models, a mechanistic study revealed that SIKE acts as a high-affinity substrate of TBK1, but its function remains unknown. In this work, we report that scratch assay analysis of parental and SIKE CRISPR/Cas9 knockout HAP1 cells showed an ~ 20% decrease in cell migration. Investigation of the SIKE interaction network through affinity purification/mass spectrometry showed that SIKE formed interactions with cytoskeletal proteins. In immunofluorescence assays, endogenous SIKE localized to cytosolic puncta in both epithelial and myeloid cells and to nuclear puncta in myeloid cells, while in epithelial cells additional staining occurred in stress fiber-like structures and adjacent to the plasma membrane. Using cellular markers, co-occurrence of SIKE fluorescence with actin, alpha-actinin, and ezrin was detected. Reciprocal immunoprecipitation revealed a SIKE:tubulin interaction sensitive to the phosphorylation state of SIKE, but a SIKE:alpha-actinin interaction was unchanged by SIKE phosphorylation. In vitro precipitation assays confirmed a direct SIKE interaction with tubulin and alpha-actinin. These results indicate that SIKE may promote cell migration by directly associating with the cytoskeleton. In this role, SIKE may mediate cytoskeletal rearrangement necessary in innate immunity, but also link a key catalytic hub, TBK1, to the cytoskeleton. Database: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD007262. PMID- 29988568 TI - Editorial: Cell Stress, Metabolic Reprogramming, and Cancer. PMID- 29988567 TI - Metformin treatment ameliorates diabetes-associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1. AB - Age-related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging- and diabetes-associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle-aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle-aged diabetic mice, it improves hippocampal-dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), atypical protein kinase C zeta (aPKC zeta), and insulin receptor substrate 1 (IRS1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long-term metformin-stimulated phosphorylation of AMPK, aPKC zeta/lambda, and IRS1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect. PMID- 29988569 TI - The IL-33 Receptor ST2 Regulates Pulmonary Inflammation and Fibrosis to Bleomycin. AB - Idiopathic pulmonary fibrosis is a progressive, devastating, and yet untreatable fibrotic disease of unknown origin. Interleukin-33 (IL-33), an IL-1 family member acts as an alarmin with pro-inflammatory properties when released after stress or cell death. Here, we investigated the role of IL-33 in the bleomycin (BLM) induced inflammation and fibrosis model using mice IL-33 receptor [chain suppression of tumorigenicity 2 (ST2)] mice compared with C57BL/6 wild-type mice. Unexpectedly, 24 h post-BLM treatment ST2-deficient mice displayed augmented inflammatory cell recruitment, in particular by neutrophils, together with enhanced levels of chemokines and remodeling factors in the bronchoalveolar space and/or the lungs. At 11 days, lung remodeling and fibrosis were decreased with reduced M2 macrophages in the lung associated with M2-like cytokine profile in ST2-deficient mice, while lung cellular inflammation was decreased but with fluid retention (edema) increased. In vivo magnetic resonance imaging (MRI) analysis demonstrates a rapid development of edema detectable at day 7, which was increased in the absence of ST2. Our results demonstrate that acute neutrophilic pulmonary inflammation leads to the development of an IL-33/ST2-dependent lung fibrosis associated with the production of M2-like polarization. In addition, non invasive MRI revealed enhanced inflammation with lung edema during the development of pulmonary inflammation and fibrosis in absence of ST2. PMID- 29988570 TI - GWAS Reveal Targets in Vessel Wall Pathways to Treat Coronary Artery Disease. AB - Coronary artery disease (CAD) is the leading cause of mortality worldwide and poses a considerable public health burden. Recent genome-wide association studies (GWAS) have revealed >100 genetic loci associated with CAD susceptibility in humans. While a number of these loci harbor gene targets of currently approved therapies, such as statins and PCSK9 inhibitors, the majority of the annotated genes at these loci encode for proteins involved in vessel wall function with no known drugs available. Importantly many of the associated genes linked to vascular (smooth muscle, endothelial, and macrophage) cell processes are now organized into distinct functional pathways, e.g., vasodilation, growth factor responses, extracellular matrix and plaque remodeling, and inflammation. In this mini-review, we highlight the most recently identified loci that have predicted roles in the vessel wall and provide genetic context for pre-existing therapies as well as new drug targets informed from GWAS. With the development of new modalities to target these pathways, (e.g., antisense oligonucleotides, CRISPR/Cas9, and RNA interference) as well as the computational frameworks to prioritize or reposition therapeutics, there is great opportunity to close the gap from initial genetic discovery to clinical translation for many patients affected by this common disease. PMID- 29988571 TI - The Nature and Nurture of Congenital Amusia: A Twin Case Study. AB - In this article, we report the first documented case of congenital amusia in dizygotic twins. The female twin pair was 27 years old at the time of testing, with normal hearing and above average intelligence. Both had formal music lesson from the age of 8-12 and were exposed to music in their childhood. Using the Montreal Battery of Evaluation of Amusia (Peretz et al., 2003), one twin was diagnosed as amusic, with a pitch perception as well as a rhythm perception deficit, while the other twin had normal pitch and rhythm perception. We conducted a large battery of tests assessing the performance of the twins in music, pitch perception and memory, language perception and spatial processing. Both showed an identical albeit low pitch memory span of 3.5 tones and an impaired performance on a beat alignment task, yet the non-amusic twin outperformed the amusic twin in three other musical and all language related tasks. The twins also differed significantly in their performance on one of two spatial tasks (visualization), with the non-amusic twin outperforming the amusic twin (83% vs. 20% correct). The performance of the twins is also compared to normative samples of normal and amusic participants from other studies. This twin case study highlights that congenital amusia is not due to insufficient exposure to music in childhood: The exposure to music of the twin pair was as comparable as it can be for two individuals. This study also indicates that there is an association between amusia and a spatial processing deficit (see Douglas and Bilkey, 2007; contra Tillmann et al., 2010; Williamson et al., 2011) and that more research is needed in this area. PMID- 29988572 TI - Editorial: Parenthood From Biology to Relation. Prevention, Assessment and Interventions for Developmental and Clinical Issues. PMID- 29988574 TI - Anemarrhena asphodeloides Bunge and its constituent timosaponin-AIII induce cell cycle arrest and apoptosis in pancreatic cancer cells. AB - Pancreatic cancer is one of the most recalcitrant and lethal of all cancers. We examined the effects of Anemarrhena asphodeloides (AA) and timosaponin-AIII (TAIII), a steroidal saponin present in AA, on pancreatic cancer cell proliferation and aimed to elucidate their potential apoptotic mechanisms of action. Viability assays and cell cycle analysis revealed that both AA and TAIII significantly inhibited pancreatic cancer cell proliferation and cell cycle progression compared to treatment with gemcitabine, the standard chemotherapeutic agent for advanced pancreatic cancer. We identified a dose-dependent increase in caspase-dependent apoptosis and activation of pro-apoptotic PI3K/Akt pathway proteins, with a subsequent downregulation of pro-survival PI3K/Akt pathway proteins, in pancreatic cancer cells treated with AA or TAIII over those treated with gemcitabine. PMID- 29988573 TI - Impaired Cell Viability and Functionality of Hepatocytes After Incubation With Septic Plasma-Results of a Second Prospective Biosensor Study. AB - Liver dysfunction (LD) and liver failure are associated with poor outcome in critically ill patients. In patients with severe sepsis or septic shock, LD occurred in nearly 19% of patients. An early diagnosis of LD at time of initial damage of the liver can lead to a better prognosis of these patients because an early start of therapy is possible. We performed a second prospective study with septic patients to test a new cell-based cytotoxicity device (biosensor) to evaluate clinical relevance for early diagnosis of LD and prognostic capacity. In the clinical study, 99 intensive care unit patients were included in two groups. From the patients of the septic group (n = 51, SG), and the control (non-septic) group [n = 49, control group (CG)] were drawn 20 ml blood at inclusion, after 3, and 7 days for testing with the biosensor. Patients' data were recorded for hospital survival, organ function, and demographic data, illness severity [acute physiology and chronic health evaluation (APACHE) II-, sepsis-related organ failure assessment (SOFA) scores], cytokines, circulating-free deoxyribonucleic acid/neutrophil-derived extracellular traps (cf-DNA/NETs), microbiological results, and pre-morbidity. For the developed cytotoxicity test, the human liver cell line HepG2/C3A was used. Patients' plasma was incubated in a microtiter plate assay with the test cells and after 6 days incubation the viability (trypan blue staining, XTT-test) and functionality (synthesis of albumin, cytochrome 1A2 activity) was analyzed. An impairment of viability and functionality of test cells was only seen in the SG compared with the CG. The plasma of non-survivors in the SG led to a more pronounced impairment of test cells than the plasma of survivors at inclusion. In addition, the levels of cf-DNA/NETs were significantly higher in the SG at inclusion, after 3, and after 7 days compared with the CG. The SG showed an in-hospital mortality of 24% and the values of bilirubin, APACHE II-, and SOFA scores were markedly higher at inclusion than in the CG. Hepatotoxicity of septic plasma was already detected with the liver cell-based biosensor at inclusion and also in the course of disease. The biosensor may be a tool for early diagnosis of LD in septic patients and may have prognostic relevance. PMID- 29988575 TI - A broader active site in Pyrococcus horikoshii CoA disulfide reductase accommodates larger substrates and reveals evidence of subunit asymmetry. AB - Within the family of pyridine nucleotide disulfide oxidoreductase (PNDOR), enzymes are a group of single-cysteine containing FAD-dependent reductases that utilize a tightly bound coenzyme A to assist in the NAD(P)H-dependent reduction of di-, per-, and polysulfide substrates in bacteria and archaea. For many of these homodimeric enzymes, it has proved difficult to determine the substrate specificity and metabolic function based on sequence and genome analysis alone. Coenzyme A-disulfide reductase (CoADR) isolated from Pyrococcus horikoshii (phCoADR) reduces Co-A per- and polysulfides, but, unlike other highly homologous members of this group, is a poor CoA disulfide reductase. The phCoADR structure has a narrower access channel for CoA substrates, which suggested that this restriction might be responsible for the enzyme's poor activity toward the bulky CoA disulfide substrate. To test this hypothesis, the substrate channel was widened by making four mutations along the channel wall (Y65A, Y66A, P67G, and H367G). The structure of the quadruple mutant shows a widened substrate channel, which is supported by a fourfold increase in kcat for the NAD(P)H-dependent reduction of CoA disulfide and enhanced activity toward the substrate at lower temperatures. Anaerobic titrations of the enzyme with NADH revealed a half-site reactivity not observed with the wild-type enzyme in which one subunit of the enzyme could be fully reduced to an EH4 state, while the other remained in an EH2 or EH2.NADH state. These results suggest that for these closely related enzymes, substrate channel morphology is an important determinant of substrate specificity, and homology modeling will be the preferred technique for predicting function among PNDORs. PMID- 29988576 TI - Inactivation of the Medial-Prefrontal Cortex Impairs Interval Timing Precision, but Not Timing Accuracy or Scalar Timing in a Peak-Interval Procedure in Rats. AB - Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition. PMID- 29988577 TI - Sensilla Morphology and Complex Expression Pattern of Odorant Binding Proteins in the Vetch Aphid Megoura viciae (Hemiptera: Aphididae). AB - Chemoreception in insects is mediated by several components interacting at different levels and including odorant-binding proteins (OBPs). Although recent studies demonstrate that the function of OBPs cannot be restricted to an exclusively olfactory role, and that OBPs have been found also in organs generally not related to chemoreception, their feature of binding molecules remains undisputed. Studying the vetch aphid Megoura viciae (Buckton), we used a transcriptomic approach to identify ten OBPs in the antennae and we examined the ultrastructural morphology of sensilla and their distribution on the antennae, legs, mouthparts and cauda of wingless and winged adults by scanning electron microscopy (SEM). Three types of sensilla, trichoid, coeloconic and placoid, differently localized and distributed on antennae, mouthparts, legs and cauda, were described. The expression analysis of the ten OBPs was performed by RT-qPCR in the antennae and other body parts of the wingless adults and at different developmental stages and morphs. Five of the ten OBPs (MvicOBP1, MvicOBP3, MvicOBP6, MvicOBP7, and MvicOBP8), whose antibodies were already available, were selected for experiments of whole-mount immunolocalization on antennae, mouthparts, cornicles and cauda of adult aphids. Most of the ten OBPs were more expressed in antennae than in other body parts; MvicOBP1, MvicOBP3, MvicOBP6, MvicOBP7 were also immunolocalized in the sensilla on the antennae, suggesting a possible involvement of these proteins in chemoreception. MvicOBP6, MvicOBP7, MvicOBP8, MvicOBP9 were highly expressed in the heads and three of them (MvicOBP6, MvicOBP7, MvicOBP8) were immunolocalized in the sensilla on the mouthparts, supporting the hypothesis that also mouthparts may be involved in chemoreception. MvicOBP2, MvicOBP3, MvicOBP5, MvicOBP8 were highly expressed in the cornicles-cauda and two of them (MvicOBP3, MvicOBP8) were immunolocalized in cornicles and in cauda, suggesting a possible new function not related to chemoreception. Moreover, the response of M. viciae to different components of the alarm pheromone was assessed by behavioral assays on wingless adult morph; ( )-alpha-pinene and (+)-limonene were found to be the components mainly eliciting an alarm response. Taken together, our results represent a road map for subsequent in-depth analyses of the OBPs involved in several physiological functions in M. viciae, including chemoreception. PMID- 29988579 TI - Metal-Adapted Bacteria Isolated From Wastewaters Produce Biofilms by Expressing Proteinaceous Curli Fimbriae and Cellulose Nanofibers. AB - Bacterial biofilm plays a pivotal role in bioremediation of heavy metals from wastewaters. In this study, we isolated and identified different biofilm producing bacteria from wastewaters. We also characterized the biofilm matrix [i.e., extracellular polymeric substances (EPS)] produced by different bacteria. Out of 40 isolates from different wastewaters, only 11 (27.5%) isolates (static condition at 28 degrees C) and 9 (22.5%) isolates (agitate and static conditions at 28 and 37 degrees C) produced air-liquid (AL) and solid-air-liquid (SAL) biofilms, respectively, only on salt-optimized broth plus 2% glycerol (SOBG) but not in other media tested. Biomass biofilms and bacteria coupled with AL biofilms were significantly (P <= 0.001) varied in these isolates. Escherichia coli (isolate ENSD101 and ENST501), Enterobacter asburiae (ENSD102), Enterobacter ludwigii (ENSH201), Pseudomonas fluorescens (ENSH202 and ENSG304), uncultured Vitreoscilla sp. (ENSG301 and ENSG305), Acinetobacter lwoffii (ENSG302), Klebsiella pneumoniae (ENSG303), and Bacillus thuringiensis (ENSW401) were identified based on 16S rRNA gene sequencing. Scanning electron microscope (SEM) images revealed that biofilm matrix produced by E. asburiae ENSD102, uncultured Vitreoscilla sp. ENSG301, A. lwoffii ENSG302, and K. pneumoniae ENSG303 are highly fibrous, compact, and nicely interlinked as compared to the biofilm developed by E. ludwigii ENSH201 and B. thuringiensis ENSW401. X-ray diffraction (XRD) results indicated that biofilm matrix produced by E. asburiae ENSD102, uncultured Vitreoscilla sp. ENSG301, and A. lwoffii ENSG302 are non-crystalline amorphous nature. Fourier transform infrared (FTIR) spectroscopy showed that proteins and polysaccharides are the main components of the biofilms. Congo red binding results suggested that all these bacteria produced proteinaceous curli fimbriae and cellulose-rich polysaccharide. Production of cellulose was also confirmed by Calcofluor binding- and spectrophotometric assays. E. asburiae ENSD102, Vitreoscilla sp. ENSG301, and A. lwoffii ENSG302 were tested for their abilities to form the biofilms exposure to 0 to 2000 mg/L of copper sulfate (for Cu), zinc sulfate (for Zn), lead nitrate (for Pb), nickel chloride (for Ni), and potassium dichromate (for Cr), several concentrations of these metals activated the biofilm formation. The polysaccharides is known to sequester the heavy metals thus, these bacteria might be applied to remove the heavy metals from wastewater. PMID- 29988580 TI - Children's Non-symbolic and Symbolic Numerical Representations and Their Associations With Mathematical Ability. AB - Most empirical evidence supports the view that non-symbolic and symbolic representations are foundations for advanced mathematical ability. However, the detailed development trajectories of these two types of representations in childhood are not very clear, nor are the different effects of non-symbolic and symbolic representations on the development of mathematical ability. We assessed 253 4- to 8-year-old children's non-symbolic and symbolic numerical representations, mapping skills, and mathematical ability, aiming to investigate the developmental trajectories and associations between these skills. Our results showed non-symbolic numerical representation emerged earlier than the symbolic one. Four-year-olds were capable of non-symbolic comparisons but not symbolic comparisons; five-year-olds performed better at non-symbolic comparisons than symbolic comparisons. This performance difference disappeared at age 6. Children at age 6 or older were able to map between symbolic and non-symbolic quantities. However, as children learn more about the symbolic representation system, their advantage in non-symbolic representation disappeared. Path analyses revealed that a direct effect of children's symbolic numerical skills on their math performance, and an indirect effect of non-symbolic numerical skills on math performance via symbolic skills. These results suggest that symbolic numerical skills are a predominant factor affecting math performance in early childhood. However, the influences of symbolic and non-symbolic numerical skills on mathematical performance both declines with age. PMID- 29988581 TI - Independence of Size and Distance in Binocular Vision. AB - For too long, the size distance invariance hypothesis (SDIH) has been the prevalent explanation for size perception. Despite inconclusive evidence, the SDIH has endured, primarily due to lack of suitable information sources for size perception. Because it was derived using the geometry of monocular viewing, another issue is whether the SDIH can encompass binocular vision. A possible alternative to SDIH now exists. The binocular source of size information proposed by Kim (2017) provides metric information about an object's size. Comprised of four angular measures and the interpupillary distance (IPD), with the explicit exclusion of egocentric distance information, Kim's binocular variable demands independence of perceived size and perceived distance, whereas the SDIH assumes interdependence of the two percepts. The validity of Kim's proposed information source was tested in three experiments in which participants viewed a virtual object stereoscopically then judged its size and distance. In Experiments 1 and 2, participants' size judgments were more accurate and less biased than their distance judgments, a finding further reinforced by the results of partial correlation analyses, demonstrating that perceived (stereoscopic) size and distance are independent, rather than interdependent as the SDIH assumes. Experiment 3 manipulated participants' IPDs, one component of Kim's proposed variable. Size and distance judgments were overestimated under a diminished IPD, but underestimated under an enlarged IPD, a result consistent with predictions based on participants' utilization of the proposed information source. Results provide unequivocal evidence against the SDIH as an account of size perception and corroborate the utility of Kim's proposed variable as a viable alternative for the binocular visual system. PMID- 29988578 TI - Application of Light Scattering Techniques to Nanoparticle Characterization and Development. AB - Over the years, the scientific importance of nanoparticles for biomedical applications has increased. The high stability and biocompatibility, together with the low toxicity of the nanoparticles developed lead to their use as targeted drug delivery systems, bioimaging systems, and biosensors. The wide range of nanoparticles size, from 10 nm to 1 MUm, as well as their optical properties, allow them to be studied using microscopy and spectroscopy techniques. In order to be effectively used, the physicochemical properties of nanoparticle formulations need to be taken into account, namely, particle size, surface charge distribution, surface derivatization and/or loading capacity, and related interactions. These properties need to be optimized considering the final nanoparticle intended biodistribution and target. In this review, we cover light scattering based techniques, namely dynamic light scattering and zeta-potential, used for the physicochemical characterization of nanoparticles. Dynamic light scattering is used to measure nanoparticles size, but also to evaluate their stability over time in suspension, at different pH and temperature conditions. Zeta-potential is used to characterize nanoparticles surface charge, obtaining information about their stability and surface interaction with other molecules. In this review, we focus on nanoparticle characterization and application in infection, cancer and cardiovascular diseases. PMID- 29988582 TI - Failure of ceftolozane-tazobactam salvage therapy in complicated pneumonia with lung abscess. AB - Treatment of Pseudomonas aeruginosa remains challenging, despite the availability ceftolozane-tazobactam. We report a treatment failure with ceftolozane-tazobactam salvage therapy for pneumonia complicated by lung abscess. Drug resistance, dose selection, and source control are possible contributing factors. Ceftolozane tazobactam susceptibility testing should precede therapy and consideration should be given to dosing selection. PMID- 29988583 TI - The Games Infants Play: Social Games During Early Mother-Infant Interactions and Their Relationship With Oxytocin. AB - The present study examined early social game routines during natural face-to-face mother-infant interactions and their relationship with oxytocin. Forty-three mother-infant dyads were observed, when infants were 4 months old, during a procedure involving a baseline and a natural interaction, where mothers were instructed to interact with their infants as they would at home. During this procedure four saliva samples from mothers and infants were collected to determine levels of oxytocin at different time points. Social game routines and infant social engagement (gaze, positive, and negative affect) were coded during the natural interaction. Social games were observed in 76.7% of the mother-infant dyads, and 46 different types of games were identified. Mothers initiated games to re-engage infants significantly more often than when infants were already engaged with them. During the games, infants showed more positive affect and less negative affect in comparison to the rest of the interaction. Finally, maternal increase in oxytocin from before to after the natural interaction was positively correlated with game rate and time spent in games, while infant increase in oxytocin from before to after the natural interaction was inversely related to game rate. These results indicate that social games are an inherent part of early mother-infant interactions, and their occurrence is associated with oxytocin of both infants and mothers. PMID- 29988584 TI - The effect of paid maternity leave on early childhood growth in low-income and middle-income countries. AB - Background: Despite recent improvements, low height-for-age, a key indicator of inadequate child nutrition, is an ongoing public health issue in low-income and middle-income countries. Paid maternity leave has the potential to improve child nutrition, but few studies have estimated its impact. Methods: We used data from 583 227 children younger than 5 years in 37 countries surveyed as part of the Demographic and Health Surveys (2000-2014) to compare the change in children's height-for-age z score in five countries that increased their legislated duration of paid maternity leave (Uganda, Zambia, Zimbabwe, Bangladesh and Lesotho) relative to 32 other countries that did not. A quasiexperimental difference-in difference design involving a linear regression of height-for-age z score on the number of weeks of legislated paid maternity leave was used. We included fixed effects for country and birth year to control for, respectively, fixed country characteristics and shared trends in height-for-age, and adjusted for time varying covariates such as gross domestic product per capita and the female labour force participation rate. Results: The mean height-for-age z scores in the pretreatment period were -1.91 (SD=1.44) and -1.47 (SD=1.57) in countries that did and did not change their policies, respectively. The scores increased in treated and control countries over time. A 1-month increase in legislated paid maternity leave was associated with a decrease of 0.08(95% CI -0.20 to 0.04) in child height-for-age z score. Sensitivity analyses did not support a robust association between paid maternity leave policies and height-for-age z score. Conclusion: We found little evidence that recent changes in legislated paid maternity leave have been sufficient to affect child height-for-age z scores. The relatively short durations of leave, the potential for low coverage and the strong increasing trend in children's growth may explain our findings. Future studies considering longer durations or combined interventions may reveal further insight to support policy. PMID- 29988585 TI - Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling. AB - Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world's most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics. PMID- 29988586 TI - Is this really just "fatigue"? A case series of immune-related central adrenal insufficiency secondary to immune checkpoint inhibitors. AB - While immunotherapy with programmed cell death protein 1 (PD1) checkpoint inhibition has shown promising activity against many tumor types, adverse events are common. Hypophysitis is a rare but serious immune-related event known to occur with anti-PD1 inhibition. It will become more prevalent as the usage of checkpoint inhibitors increases. PMID- 29988587 TI - Degradation of histone deacetylase 4 via the TLR4/JAK/STAT1 signaling pathway promotes the acetylation of high mobility group box 1 (HMGB1) in lipopolysaccharide-activated macrophages. AB - High mobility group box 1 (HMGB1) has been proposed as crucial in the pathogenesis of many diseases including sepsis. Acetylation of HMGB1 prevents its entry into the nucleus and leads to its secretion from the cell where it can trigger inflammation. We hypothesized that histone deacetylase 4 (HDAC4) controls the acetylation of HMGB1 in lipopolysaccharide (LPS)-stimulated RAW264.7 cells via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. The results showed that LPS treatment promoted the degradation of HDAC4 in a proteasome-dependent manner, which led to HMGB1 acetylation. In LPS activated RAW264.7 cells, treatment with TAK-242 (a toll like receptor 4 inhibitor) and pyridone 6 (a JAK inhibitor) significantly inhibited HDAC4 degradation and acetylation of HMGB1, and thus prevented secretion of HMGB1. Decreased phosphorylation of STAT1 was also observed. Interestingly, HDAC4 overexpression significantly prevented the acetylation and secretion of HMGB1 in both RAW264.7 cells and isolated murine peritoneal macrophages. We conclude that HDAC4 might be a useful target for the treatment of sepsis. PMID- 29988588 TI - Measurement, Prediction, and Control of Individual Heart Rate Responses to Exercise-Basics and Options for Wearable Devices. AB - The use of wearable devices or "wearables" in the physical activity domain has been increasing in the last years. These devices are used as training tools providing the user with detailed information about individual physiological responses and feedback to the physical training process. Advantages in sensor technology, miniaturization, energy consumption and processing power increased the usability of these wearables. Furthermore, available sensor technologies must be reliable, valid, and usable. Considering the variety of the existing sensors not all of them are suitable to be integrated in wearables. The application and development of wearables has to consider the characteristics of the physical training process to improve the effectiveness and efficiency as training tools. During physical training, it is essential to elicit individual optimal strain to evoke the desired adjustments to training. One important goal is to neither overstrain nor under challenge the user. Many wearables use heart rate as indicator for this individual strain. However, due to a variety of internal and external influencing factors, heart rate kinetics are highly variable making it difficult to control the stress eliciting individually optimal strain. For optimal training control it is essential to model and predict individual responses and adapt the external stress if necessary. Basis for this modeling is the valid and reliable recording of these individual responses. Depending on the heart rate kinetics and the obtained physiological data, different models and techniques are available that can be used for strain or training control. Aim of this review is to give an overview of measurement, prediction, and control of individual heart rate responses. Therefore, available sensor technologies measuring the individual heart rate responses are analyzed and approaches to model and predict these individual responses discussed. Additionally, the feasibility for wearables is analyzed. PMID- 29988589 TI - Characterization of the Sexually Dimorphic fruitless Neurons That Regulate Copulation Duration. AB - Male courtship in Drosophila melanogaster is a sexually dimorphic innate behavior that is hardwired in the nervous system. Understanding the neural mechanism of courtship behavior requires the anatomical and functional characterization of all the neurons involved. Courtship involves a series of distinctive behavioral patterns, culminating in the final copulation step, where sperms from the male are transferred to the female. The duration of this process is tightly controlled by multiple genes. The fruitless (fru) gene is one of the factors that regulate the duration of copulation. Using several intersectional genetic combinations to restrict the labeling of GAL4 lines, we found that a subset of a serotonergic cluster of fru neurons co-express the dopamine-synthesizing enzyme, tyrosine hydroxylase, and provide behavioral and immunological evidence that these neurons are involved in the regulation of copulation duration. PMID- 29988590 TI - An integrated analysis of genome-wide DNA methylation and gene expression data in hepatocellular carcinoma. AB - Despite progress in the treatment of hepatocellular carcinoma (HCC), 5-year survival rates remain low. Thus, a more comprehensive approach to explore the mechanism of HCC is needed to provide new leads for targeted therapy. We performed an integrated analysis to discover the relationship between DNA methylation and gene expression in hepatocellular carcinoma (HCC). DNA methylation and gene expression data for HCC were downloaded from The Cancer Genome Atlas (TCGA) database, and differential analysis was performed. Correlation analysis between DNA methylation and gene expression data was then performed in R language. Finally, we selected several crucial genes and evaluated their potential use as diagnostic biomarkers for HCC. In total, 1135 differentially DNA-methylated CpG sites (DMCs), 377 differentially methylated regions (DMRs), and 1194 differentially expressed genes (DEGs) were identified in HCC. Among the DEGs, 14 genes (ALX3, B4GALNT1,CTHRC1,DLX5,EMX1,IRX3,OTX1,SIX2,TLX1,VASH2,ZIC2,ZIC4,ZIC5, and ZNF695) exhibited changes in DNA methylation in terms of CpG sites or CpG island (CGI) level, of which TLX1 and ZIC4 had the most DMCs (12 and 13, respectively). Further analysis of CTHRC1,ZIC4,SIX2,VASH2,IL17D,TLX1,OTX1, and LART, examining alterations in both DNA methylation and gene expression level in HCC, showed their potential diagnostic value for HCC was better at the gene expression level than that the DNA methylation level. The DNA methylation status of CTHRC1,VASH2, and IL7D was significantly associated with HCC overall survival (P-value <0.05). This systemic analysis identified a group of novel gene signatures (CTHRC1,ZIC4, and OTX1) that may be regulated by DNA hypermethylation, which may be closely associated with HCC. PMID- 29988593 TI - Influence of Sitting Positions and Level of Trunk Control During Reaching Movements in Late Preterm and Full-Term Infants. AB - In order to acquire reaching and independent sitting, refinement of trunk control is needed by gradually and progressively incorporating the head, thoracic, lumbar, and sacral segments. Previous studies have evaluated trunk control in a segmental way, standardizing the level of manual support in the infants' trunk during reaching. The aim of this study was to identify the level of trunk control and to analyze the influence of the difference sitting positions in late preterm and full-term infants between 6 and 8 months of age during reaching. Therefore, 36 infants born full term (control group)-FTG and 20 late preterm infants at a corrected age (experimental group)-PTG were evaluated. Most of the infants started the study at 6 months and they were evaluated monthly until 8 months of age (longitudinal study) in a total of 1-3 visits. The Segmental Assessment of Trunk Control was used to identify the level of trunk control in a segmental way, as well as to verify the capacity of the infant to maintain or regain the vertical position while sitting. Kinematic analysis was used for reaching. The infants were in a ring sitting position and at 90 degrees of flexion. To elicit reaching, an attractive object was presented at the infant's midline and at 45 degrees to the right and left. We found that PTG infants presented lower trunk control scores, i.e., worse control. For both groups, the ring sitting position and at 90 degrees of flexion did not influence most kinematic variables during reaching because accurate manual support was provided for the infants' trunk. The PTG group presented less trunk displacement when at 90 degrees of flexion. Compared to the FTG, even with accurate trunk support, the PTG group presented more immature reaches. These results suggest that accurate manual trunk support favored more stability of the trunk during the reach. Thus, early intervention is suggested for PTG infants and reaching in this age group should be trained in the ring sitting position with their trunk accurately manually supported. SATCo is an effective tool for segmental trunk evaluation. PMID- 29988592 TI - Metabolite Profiles of Sugarcane Culm Reveal the Relationship Among Metabolism and Axillary Bud Outgrowth in Genetically Related Sugarcane Commercial Cultivars. AB - Metabolic composition is known to exert influence on several important agronomic traits, and metabolomics, which represents the chemical composition in a cell, has long been recognized as a powerful tool for bridging phenotype-genotype interactions. In this work, sixteen truly representative sugarcane Brazilian varieties were selected to explore the metabolic networks in buds and culms, the tissues involved in the vegetative propagation of this species. Due to the fact that bud sprouting is a key trait determining crop establishment in the field, the sprouting potential among the genotypes was evaluated. The use of partial least square discriminant analysis indicated only mild differences on bud outgrowth potential under controlled environmental conditions. However, primary metabolite profiling provided information on the variability of metabolic features even under a narrow genetic background, typical for modern sugarcane cultivars. Metabolite-metabolite correlations within and between tissues revealed more complex patterns for culms in relation to buds, and enabled the recognition of key metabolites (e.g., sucrose, putrescine, glutamate, serine, and myo inositol) affecting sprouting ability. Finally, those results were associated with the genetic background of each cultivar, showing that metabolites can be potentially used as indicators for the genetic background. PMID- 29988594 TI - Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts. AB - Background: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-alpha is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy. Methods: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort). Results: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). Conclusion: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation. PMID- 29988591 TI - More Than Skin Deep: Autophagy Is Vital for Skin Barrier Function. AB - The skin is a highly organized first line of defense that stretches up to 1.8 m2 and is home to more than a million commensal bacteria. The microenvironment of skin is driven by factors such as pH, temperature, moisture, sebum level, oxidative stress, diet, resident immune cells, and infectious exposure. The skin has a high turnover of cells as it continually bares itself to environmental stresses. Notwithstanding these limitations, it has devised strategies to adapt as a nutrient-scarce site. To perform its protective function efficiently, it relies on mechanisms to continuously remove dead cells without alarming the immune system, actively purging the dying/senescent cells by immunotolerant efferocytosis. Both canonical (starvation-induced, reactive oxygen species, stress, and environmental insults) and non-canonical (selective) autophagy in the skin have evolved to perform astute due-diligence and housekeeping in a quiescent fashion for survival, cellular functioning, homeostasis, and immune tolerance. The autophagic "homeostatic rheostat" works tirelessly to uphold the delicate balance in immunoregulation and tolerance. If this equilibrium is upset, the immune system can wreak havoc and initiate pathogenesis. Out of all the organs, the skin remains under-studied in the context of autophagy. Here, we touch upon some of the salient features of autophagy active in the skin. PMID- 29988595 TI - Effect of the volatile anesthetic agent isoflurane on lateral diffusion of cell membrane proteins. AB - The volatile anesthetic isoflurane (ISO) has previously been shown to increase the fluidity of artificial lipid membranes, but very few studies have used biological cell membranes. Therefore, to investigate whether ISO affects the mobility of membrane proteins, fluorescence-labeled transferrin receptor (TfR) and glycosylphosphatidylinositol (GPI)-anchored protein were expressed in human embryonic kidney 293T cells and neural cells and lateral diffusion was examined using fluorescence recovery after photobleaching. Lateral diffusion of the TfR increased with ISO treatment. On the other hand, there was no effect on GPI anchored protein. We also used GC/MS to confirm that there was no change in the concentration of ISO due to vaporization during measurement. These results suggest that ISO affects the mobility of transmembrane protein molecules in living cells. PMID- 29988596 TI - A Taxonomy Proposal for Types of Interactions of Language and Place-Value Processing in Multi-Digit Numbers. AB - Research on associations between language and number processing has seen growing interest in the last years - in particular with respect to place-value processing in multi-digit numbers. Recently, Dowker and Nuerk (2016) proposed a taxonomy of linguistic influences on number processing. However, this taxonomy does not address the generality or specificity of linguistic influences across different levels of number processing. In contrast, Nuerk et al. (2015) proposed different levels of place-value processing in multi-digit numbers. However, the authors did not specify if and how linguistic factors influence these levels of place-value processing. The present perspective aims at addressing this conceptual gap by suggesting an integrated taxonomy representing how different linguistic factors may influence different levels of place-value processing. We show that some effects of different linguistic levels have already been observed on different levels of place-value processing. Moreover, while some linguistic influences (e.g., lexical influences) have been studied for all levels of place-value processing, other influences have been studied for only one level or even none. Beyond categorizing existing research, we argue that the explicit consideration of research gaps may inspire new research paradigms complementing the picture of language influences on place-value processing. We conclude by outlining the importance of a differential approach for levels of both linguistic and number processing to evaluate linguistic obstacles and facilitators of different languages and their relevance for numerical development. PMID- 29988597 TI - Application of Antibody-Mediated Therapy for Treatment and Prevention of Clostridium difficile Infection. AB - Clostridium difficile causes antibiotic- and healthcare-associated diarrhea, which is characterized by a high mortality rate (5-15%) and high recurrence rate of 20% or more. Therapeutic alternatives to antibiotics are urgently needed to improve the overall cure rate. Among these, therapeutic antibodies have shown promising results in clinical studies. Herein, the authors review current monoclonal and polyclonal anti- C. difficile antibodies that have entered the clinical development stage, either for systemic administration or by the oral route. The antibodies can be applied as monotherapy or in combination with standard-of-care to treat an infection with C. difficile or to protect from a recurrence. Bezlotoxumab is the first antibody for secondary prevention of recurrence of C. difficile infection approved by the regulatory agencies in US and Europe. The human monoclonal antibody is administered systemically to patients receiving oral standard-of-care antibiotics. Other antibodies are currently in the clinical pipeline, and some are intended for oral use. They show a good safety profile, high efficacy and low production costs, and can be considered promising therapies of the future. The most promising orally administered drug candidate is a bovine antibody from hyperimmune colostral milk, which is in an advanced clinical development stage. Which antibody will enter the market is dependent on its bioavailability at the site of infection as well as its activity against C. difficile toxins, protection against colonization and possible action on spore formation. The antibody must demonstrate a clear benefit in comparison with other available treatment options to be considered for use by clinicians. PMID- 29988598 TI - Fulminant eye infection in a patient with nephrotic syndrome. AB - Endophthalmitis is a bacterial or fungal infection inside the eye, involving the vitreous and/or aqueous humors. High index of suspicion is required for this condition in immunocompromised patients with ocular complaints as it can worsen rapidly and lead to permanent loss of vision. PMID- 29988599 TI - A prenatal case of partial trisomy 21 (q22.2q22.3), resulting from a paternal insertion translocation ins(16;21) and uncovered by QF-PCR, and characterized by array CGH and FISH. AB - In addition to detecting trisomies of whole chromosomes, QF-PCR can also detect partial trisomies of the chromosomes 13, 18, and 21, which can suggest an unbalanced translocation. Additional testing with other techniques, such as microarray or FISH, is recommended when an unbalanced translocation is suspected. PMID- 29988600 TI - Snapshot in surgery: How do you approach this 12-year-old girl? AB - This case open questions about the dimensional limit for a laparoscopic treatment of a giant bezoar. A minimally invasive option should be considered every time a gastric obstruction is suspected, particularly for psychiatric patients, for whom a short hospital stay can be greatly beneficial. PMID- 29988601 TI - Editorial: Optimizing Miscanthus for the Sustainable Bioeconomy: From Genes to Products. PMID- 29988602 TI - The CHARMS pilot study: a multi-method assessment of the feasibility of a sexual counselling implementation intervention in cardiac rehabilitation in Ireland. AB - Background: Many people living with cardiovascular disease (CVD) are affected by sexual problems associated with the condition. International guidelines recommend all patients with CVD should receive sexual counselling, yet this is rarely provided by health professionals. The current study piloted the Cardiac Health and Relationship Management and Sexuality (CHARMS) intervention, a complex multi level intervention designed to increase the implementation of sexual counselling guidelines in hospital-based cardiac rehabilitation (CR) in Ireland. Methods: The CHARMS intervention, consisting of awareness training and skills development for staff, and education and support for patients, was implemented in two CR centres. Following a repeated measures design, quantitative and qualitative feasibility, fidelity, cost, and outcome data were collected from staff and patients at baseline (T1, pre-intervention), at 3 months post-baseline (T2, post intervention), and at 6 months post-baseline (T3, post-intervention). Data were organised according to a 14-point reporting framework of methodological issues that should be examined in pilot and feasibility studies. To inform a future definitive trial, potential solutions to identified feasibility issues were generated using the ADePT process for decision-making after pilot and feasibility trials. Results: Most elements of the study protocol were executed smoothly, and intervention implementation was successful. Patients' (N = 42) responses to the intervention were positive. The reporting framework and the ADePT process facilitated the identification of two overarching feasibility problems, as well as solutions to be implemented in a definitive trial: (1) a high level of patient attrition in the pilot study, to be addressed through the use of financial incentives, reducing the length of the patient questionnaire, and providing a telephone survey option; and (2) negative staff perceptions, to be addressed through an augmented staff intervention, reframing 'sexual counselling' as 'sexual education and support' to fit with professional role perceptions, and reviewing all intervention terminology with a CR staff member to ensure acceptability. Conclusions: This article reports the successful piloting of a novel sexual counselling implementation intervention in cardiac rehabilitation. The utilisation of an extended reporting framework and the ADePT process facilitated the identification of adaptations necessary to ensure the feasibility of a definitive trial, thereby maximising methodological transparency. PMID- 29988603 TI - Effect of Gender on Chronic Intermittent Hypoxic Fosb Expression in Cardiorespiratory-Related Brain Structures in Mice. AB - We aimed to delineate sex-based differences in neuroplasticity that may be associated with previously reported sex-based differences in physiological alterations caused by repetitive succession of hypoxemia-reoxygenation encountered during obstructive sleep apnea (OSA). We examined long-term changes in the activity of brainstem and diencephalic cardiorespiratory neuronal populations induced by chronic intermittent hypoxia (CIH) in male and female mice by analyzing Fosb expression. Whereas the overall baseline and CIH-induced Fosb expression in females was higher than in males, possibly reflecting different neuroplastic dynamics, in contrast, structures responded to CIH by Fosb upregulation in males only. There was a sex-based difference at the level of the rostral ventrolateral reticular nucleus of the medulla, with an increase in the number of FOSB/DeltaFOSB-positive cells induced by CIH in males but not females. This structure contains neurons that generate the sympathetic tone and which are involved in CIH-induced sustained hypertension during waking hours. We suggest that the sex-based difference in neuroplasticity of this structure contributes to the reported sex-based difference in CIH-induced hypertension. Moreover, we highlighted a sex-based dimorphic phenomenon in serotoninergic systems induced by CIH, with increased serotoninergic immunoreactivity in the hypoglossal nucleus and a decreased number of serotoninergic cells in the dorsal raphe nucleus in male but not female mice. We suggest that this dimorphism in the neuroplasticity of serotoninergic systems predisposes males to a greater alteration of neuronal control of the upper respiratory tract associated with the greater collapsibility of upper airways described in male OSA subjects. PMID- 29988605 TI - Systematic re-evaluation of intraoperative motor-evoked potential suppression in scoliosis surgery. AB - Background: Motor- (MEP) and somatosensory-evoked potentials (SSEP) are susceptible to the effects of intraoperative environmental factors. Methods: Over a 5-year period, 250 patients with adolescent idiopathic scoliosis (AIS) who underwent corrective surgery with IOM were retrospectively analyzed for MEP suppression (MEPS). Results: Our results show that four distinct groups of MEPS were encountered over the study period. All 12 patients did not sustain any neurological deficits postoperatively. However, comparison of groups 1 and 2 suggests that neither the duration of anesthesia nor speed of surgical or anesthetic intervention were associated with recovery to a level beyond the criteria for MEPS. For group 3, spontaneous MEPS recovery despite the lack of surgical intervention suggests that anesthetic intervention may play a role in this process. However, spontaneous MEPS recovery was also seen in group 4, suggesting that in certain circumstances, both surgical and anesthetic intervention was not required. In addition, neither the duration of time to the first surgical manoeuver nor the duration of surgical manoeuver to MEPS were related to recovery of MEPS. None of the patients had suppression of SSEPs intraoperatively. Conclusion: This study suggests that in susceptible individuals, MEPS may rarely occur unpredictably, independent of surgical or anesthetic intervention. However, our findings favor anesthetic before surgical intervention as a proposed protocol. Early recognition of MEPS is important to prevent false positives in the course of IOM for spinal surgery. PMID- 29988604 TI - Public health implications of overscreening for carotid artery stenosis, prediabetes, and thyroid cancer. AB - Background: Overscreening occurs when people without symptoms undergo tests for diseases and the results will not improve their health. In this commentary, we examine three examples of how campaigns to screen and treat specific vascular, metabolic, and oncologic diseases in asymptomatic individuals have produced substantial overdiagnosis and may well have contributed to more harm than good. These conditions were chosen because they may not be as well known as other cases such as screening for breast or prostate cancer. Main text: Screening for carotid artery stenosis can be a lucrative business using portable equipment and mobile vans. While this fatty buildup of plaque in the arteries of the neck is one risk factor for ischemic stroke, current evidence does not suggest that performing carotid dopplers to screen for CAS reduces the incidence of stroke or provide long-term benefits. After a positive screening, the follow-up procedures can lead to heart attacks, bleeding, strokes, and even death. Similarly, many organizations have launched campaigns for "prediabetes awareness." Screening for prediabetes with a blood sugar test does not decrease mortality or cardiovascular events. Identifying people with prediabetes could lead to psychological stress and starting medication that may have significant side effects. Finally, palpating people's necks or examining them with ultrasounds for thyroid cancer is common in many countries but ineffective in reducing mortality. Deadly forms of thyroid cancer are rare, and the overall 5-year survival rate is excellent. Interventions from treatment for more prevalent, less aggressive forms of thyroid cancer can lead to surgical complications, radiation side effects, or require lifelong thyroid replacement therapy. Conclusions: Screening for carotid artery stenosis, prediabetes, and thyroid cancer in an asymptomatic population can result in unnecessary, harmful, and costly care. Systemic challenges to lowering overscreening include lack of clinician awareness, examination of conflicts of interests, perverse financial incentives, and communication with the general public. PMID- 29988606 TI - Differential tissue response to growth hormone in mice. AB - Growth hormone (GH) has been shown to act directly on multiple tissues throughout the body. Historically, it was believed that GH acted directly in the liver and only indirectly in other tissues via insulin-like growth hormone 1 (IGF-1). Despite extensive work to describe GH action in individual tissues, a comparative analysis of acute GH signaling in key metabolic tissues has not been performed. Herein, we address this knowledge gap. Acute tissue response to human recombinant GH was assessed in mice by measuring signaling via phospho-STAT5 immunoblotting. STAT5 activation is an easily and reliably detected early marker of GH receptor engagement. We found differential tissue sensitivities; liver and kidney were equally GH-sensitive and more sensitive than white adipose tissue, heart, and muscle (gastrocnemius). Gastrocnemius had the greatest maximal response compared to heart, liver, white adipose tissue, and whole kidney. Differences in maximum responsiveness were positively correlated with tissue STAT5 abundance, while differences in sensitivity were not explained by differences in GH receptor levels. Thus, GH sensitivity and responsiveness of distinct metabolic tissues differ and may impact physiology and disease. PMID- 29988608 TI - The prevalence of the term subluxation in chiropractic degree program curricula throughout the world. AB - Background: The subluxation construct generates debate within and outside the profession. The International Chiropractic Education Collaboration, comprised of 10 chiropractic programs outside of North America, stated they will only teach subluxation in a historical context. This research sought to determine how many chiropractic institutions worldwide still use the term in their curricula and to expand upon the previous work of Mirtz & and Perle. Methods: Forty-six chiropractic programs, 18 United States (US) and 28 non-US, were identified from the World Federation of Chiropractic Educational Institutions list. Websites were searched by multiple researchers for curricular information September 2016 September 2017. Some data were not available on line, so email requests were made for additional information. Two institutions provided additional information. The total number of mentions of subluxation in course titles, technique course (Tech) descriptions, principles and practice (PP) descriptions, and other course descriptions were reported separately for US and non-US institutions. Means for each category were calculated. The number of course titles and descriptions using subluxation was divided by the total number of courses for each institution and reported as percentages. Results: Means for use of subluxation by US institutions were: Total course titles = .44; Tech = 3.83; PP = 1.50; other = 1.16. For non-US institutions, means were: Total course titles = .07; Tech = .27; PP = .44; other = 0. The mean total number of mentions was 6.94 in US vs. 0.83 in non-US institutions. Similarly, the mean course descriptions was 6.50 in US vs. 0.72 in non-US institutions. Conclusions: The term subluxation was found in all but two US course catalogues. The use of subluxation in US courses rose from a mean of 5.53 in 2011 to 6.50 in 2017. US institutions use the term significantly more frequently than non-US. Possible reasons for this were discussed. Unscientific terms and concepts should have no place in modern education, except perhaps in historical context. Unless these outdated concepts are rejected, the chiropractic profession and individual chiropractors will likely continue to face difficulties integrating with established health care systems and attaining cultural authority as experts in conservative neuro-musculoskeletal health care. PMID- 29988607 TI - Ileum terminal antibiotic infusion affects jejunal and colonic specific microbial population and immune status in growing pigs. AB - Background: Compared with oral antibiotics (primarily disrupt foregut microbiota), the present study used antibiotics with ileum terminal infusion to disrupt the hindgut microbiota, and investigated the changes in specific bacterial composition and immune indexes in the jejunum and colon, and serum of growing pigs. Twelve barrows (45 d of age, 12.08 +/- 0.28 kg) fitted with a T cannula at the terminal ileum, were randomly assigned to two groups and infused either saline without antibiotics (Control) or with antibiotics (Antibiotic) at the terminal ileum. After 25 d experiment, all pigs were euthanized for analyzing bacterial composition and immune status. Results: Ileum terminal antibiotic infusion (ITAI) altered dominant bacteria counts, with a decrease in Bifidobacterium, Clostridium cluster IV and Clostridium cluster IV in the colon (P < 0.05), and an increase in Escherichia coli in the jejunum (P < 0.05). ITAI decreased (P < 0.05) short-chain fatty acids concentrations in the colon. ITAI decreased interleukin-8 (IL-8), IL-10 and secretory immunoglobulin A (sIgA) concentrations, and down-regulated IL-10, Mucin-1 (MUC1), Mucin-2 (MUC2) and zonula occludens-1 (ZO-1) mRNA expression in the colonic mucosa (P < 0.05). In the jejunal mucosa, ITAI decreased interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), sIgA and IgG levels together with down-regulation of IFN-gamma, TNF-alpha, MUC2 and ZO-1 mRNA expression (P < 0.05). Furthermore, ITAI decreased IL-10, INF-gamma, TNF-alpha, IgA and IgG concentrations in serum (P < 0.05). Correlation analysis revealed that the change in intestinal microbiota was correlated with alterations of Ig and cytokines. Conclusions: ITAI affected jejunal and colonic specific bacteria counts, and altered some immune markers levels in the jejunal and colonic mucosa and serum. These findings implicate the potential contribution of hindgut bacteria to immune response in the intestinal mucosa and serum of growing pigs. PMID- 29988609 TI - Editorial: School Achievement and Failure in Portuguese and Spanish Speaking Countries. PMID- 29988610 TI - Developing Hierarchical Schemas and Building Schema Chains Through Practice Play Behavior. AB - Examining the different stages of learning through play in humans during early life has been a topic of interest for various scholars. Play evolves from practice to symbolic and then later to play with rules. During practice play, infants go through a process of developing knowledge while they interact with the surrounding objects, facilitating the creation of new knowledge about objects and object related behaviors. Such knowledge is used to form schemas in which the manifestation of sensorimotor experiences is captured. Through subsequent play, certain schemas are further combined to generate chains able to achieve behaviors that require multiple steps. The chains of schemas demonstrate the formation of higher level actions in a hierarchical structure. In this work we present a schema-based play generator for artificial agents, termed Dev-PSchema. With the help of experiments in a simulated environment and with the iCub robot, we demonstrate the ability of our system to create schemas of sensorimotor experiences from playful interaction with the environment. We show the creation of schema chains consisting of a sequence of actions that allow an agent to autonomously perform complex tasks. In addition to demonstrating the ability to learn through playful behavior, we demonstrate the capability of Dev-PSchema to simulate different infants with different preferences toward novel vs. familiar objects. PMID- 29988611 TI - Primary myelofibrosis evolving to an aplastic appearing marrow. AB - Our case highlights a series of bone marrow biopsies from a patient with primary myelofibrosis. Over time, this patient developed an unusual fatty appearance to his marrow, confirmed on multiple biopsies. This finding was supported by a quantitative fat MRI sequence that also shows a fatty appearance to the marrow. PMID- 29988613 TI - Prosthodontic management of a patient with mandibular asymmetry: a case report. AB - This case report outlines a conservative treatment approach utilized in the management of a patient with a transverse left-sided mandibular asymmetry, in an attempt to obtain a functional and esthetic occlusion using removable intraoral prostheses. A positive final result was achieved by maintaining close communication with the on-site dental technician. PMID- 29988612 TI - Flexibility in Language Action Interaction: The Influence of Movement Type. AB - Recent neuropsychological studies in neurological patients and healthy subjects suggest a close functional relationship between the brain systems for language and action. Facilitation and inhibition effects of motor system activity on language processing have been demonstrated as well as causal effects in the reverse direction, from language processes on motor excitability or performance. However, as the documented effects between motor and language systems were sometimes facilitatory and sometimes inhibitory, the "sign" of these effects still remains to be explained. In a previous study, we reported a word-category specific differential impairment of verbal working memory for concordant arm- and leg-related action words brought about by complex sequential movements of the hands and feet. In this article, we seek to determine whether the sign of the functional interaction between language and action systems of the human brain can be changed in a predictable manner by changing movement type. We here report that the sign of the effect of motor movement on action word memory can be reversed from interference to facilitation if, instead of complex movement sequences, simple repetitive movements are performed. Specifically, when engaged in finger tapping, subjects were able to remember relatively more arm-related action words (as compared to control conditions), thus documenting an enhancement of working memory brought about by simple hand movements. In contrast, when performing complex sequences of finger movements, an effector-specific degradation of action word memory was found. By manipulating the sign of the effect in accord with theory-driven predictions, these findings provide support for shared neural bases for motor movement and verbal working memory for action-related words and strengthen the argument that motor systems play a causal and functionally relevant role in language processing semantically related to action. PMID- 29988614 TI - Metronomics: Intrinsic Anakoinosis Modulator? PMID- 29988616 TI - Patterns and epidemiology of acute poisoning in Ethiopia: systematic review of observational studies. AB - Background: Acute poisoning is a common reason for emergency department visit and hospitalization worldwide with major morbidity and mortality. The burden of poisoning exposures in Africa is a significant public health concern, but only 10 of 58 countries have poisons information centers (PICs). Objective: The primary intention of our current review is to explore and summarize the published evidence on the patterns and epidemiology of poisoning in Ethiopia. Method: PubMed and Scopus were searched for primary, case series and human studies for publications from inception to July 2017. A manual search for additional relevant studies using references from retrieved articles was also performed. Only studies that reported acute poisoning in both pediatric and adult patients were included. From the screened articles, data were extracted for baseline characteristics and relevant end points such as case fatality rate, time for health institution presentation and length of hospital stay. Result: Initial entry and search resulted in the retrieval of 332 articles. Finally, 9 studies comprised of 4763 participants were included in this current review. In 78% of the studies included in this review, acute poisoning is reported to be more prevalent in females. Acute poisoning was revealed to be prevalent in less than 30 years old. Organophosphates and household cleaning agents were the predominant agents of acute poisoning. Intentional poisoning was identified responsible for the majority of acute poisoning cases and factors such as psychiatric problems, and quarrel were identified as the underlying reasons for poisoning. Time of presentation to health institution after poisoning, length of hospital stay and case fatality rate were reported and lies in the ranges between 0.2 h-24 h, 0.5 days-17.7 days and 0-14.8%, respectively. Conclusion: The occurrence of acute poisoning was higher in females and common in less than 30 years of age, making this a real public health burden in Ethiopia. Psychiatric problems, quarrel and substance abuse were identified as the most common reasons for acute poisoning. Awareness creation how to handle chemicals and prescribed drugs and psychiatric consultations should be in place for the community. PMID- 29988617 TI - Characteristics distinguishing abusive head trauma from accidental head trauma in infants with traumatic intracranial hemorrhage in Japan. AB - Aim: To identify markers for detecting abusive head trauma (AHT) and its characteristics in the Japanese population. Methods: We retrospectively reviewed the clinical records of 166 infants with traumatic intracranial hemorrhage between 2002 and 2013 in three tertiary institutions in Japan. The infants were classified into AHT (57), suspected AHT (24), and accidental (85) group based on the defined criteria. We compared clinical presentations and computed tomography findings among these three groups and also compared age distribution of infants with AHT in our study to those in the USA. Results: Age distribution of AHT cases is significantly higher in our study than in the USA (P < 0.001). The rates of male sex, bruising, retinal hemorrhage, subdural hematoma, cerebral edema, and neurological sequelae were significantly higher, and those of skull fracture and scalp finding were significantly lower, in the AHT group than in the accidental group (P < 0.05). In the multivariable analysis of the infants with subdural hematoma, absence of skull fracture (odds ratio = 42.1; 95% confidence interval, 3.5-507.7, P = 0.003) was associated with AHT. Conclusions: The age range of AHT in Japan is significantly different from that of countries in Europe and North America because of familial and sociocultural situations. Absence of bruising, and rib or long bone fractures did not reduce the likelihood of AHT. Subdural hematoma without findings of an impact to the head strongly suggested AHT. Abusive head trauma is a global problem, however, diagnosis and defensive measures likely need to be tailored to accommodate cultural risk factors. PMID- 29988618 TI - Gastric mucosal prolapse: A case of proton-pump inhibitor nonresponsive dyspepsia. AB - Gastric mucosal prolapse (GMP) is a rare clinical syndrome that in patients with hiatal hernias and gastroesophageal reflux disease (GERD) may present with typical findings of abdominal pain and reflux symptoms but prove resistant to medical therapy. Physicians should therefore be aware and consider GMP as a differential in such patients in order to make an accurate diagnosis and provide timely treatment. PMID- 29988619 TI - Avoiding exercise mediates the effects of internalized and experienced weight stigma on physical activity in the years following bariatric surgery. AB - Background: People living with severe obesity report high levels of weight related stigma. Theoretically, this stigma undermines weight loss efforts. The objective of this study is to test one proposed mechanism to explain why weight loss is so difficult once an individual becomes obese: that weight-related stigma inhibits physical activity via demotivation to exercise. Methods: The study focused on individuals who had bariatric surgery within the past 5 years (N = 298) and who report a post-surgical body mass index (BMI) ranging from 16 to 70. Exercise avoidance motivation (EAM) and physical activity (PA) were modeled as latent variables using structural equation modeling. Two measures of weight stigma, the Stigmatizing Situations Inventory (SSI) and the Weight Bias Internalization Scale (WBIS) were modified for people with a long history of extreme obesity for use as observed predictors. Results: Exercise avoidance motivation (EAM) significantly mediated the association between both experienced (SSI) and internalized (WBIS) weight stigma and physical activity (PA) in this population. Conclusion: Exercise avoidance motivation, influenced by weight stigma, may be a significant factor explaining the positive relationship between higher body weights with lower levels of physical activity. PMID- 29988615 TI - Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis. AB - Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA. PMID- 29988621 TI - Correction: Developing a globally applicable evidence-informed competency framework to support capacity strengthening in clinical research. AB - [This corrects the article DOI: 10.1136/bmjgh-2016-000229.]. PMID- 29988620 TI - Complete necrosis of graft ureter following renal transplant in a patient with primary antiphospholipid syndrome: A case report. AB - Complete necrosis of the graft ureter is a rare but serious complication following kidney transplant. In a patient with antiphospholipid syndrome, a combination of factors such as arterial thromboembolism, hematoma formation, and surgical collateral damage can cause ischemia of the graft ureter. Preoperative optimization of disease activity and coagulation with meticulous preservation of ureteric perfusion may help in prevention. PMID- 29988622 TI - Cheilitis: An unusual presentation of Mucocutaneous Leishmaniasis. AB - The Mucocutaneous Leishmaniasis (MCL) involving lip is extremely uncommon. A clinical diagnosis of Leishmaniasis of the lips is often challenging to the treating clinician and may result in delayed diagnosis as this case illustrates. MCL should be considered in the differential diagnosis of lip lesions in a Leishmania endemic area. PMID- 29988623 TI - Strategies to improve the growth and homogeneity of growing-finishing pigs: feeder space and feeding management. AB - Background: The aim was to test two strategies to improve the growth rate of the slow-growth pigs and to increase the batch's homogeneity at slaughter. In Trial 1 a total of 264 weaned piglets were distributed into 24 pens (11 piglets/pen) according to sex and initial body weight (BW) for the transition period (T; 28 d to 64 d). During the T period, a commercial lidded feeder hopper was used (3.7 pigs/feeder space). When moving to the growing facilities, the 24 pens were maintained and split into two groups of 12 according to sex, feeder type (HD or 5.5 pigs/feeder space and LD or 2.2 pigs/feeder space). In Trial 2 a total of 1067 piglets were used and classified, when leaving the nursery at 63d of age, as Heavy (Hp, n = 524) and Light (Lp, n = 543) pigs. Along the growing period, Hp and half of the Lp pigs were fed with four consecutive feeds, following a standard feeding program (Std). Alternatively, the other half of the Lp pigs were fed according to a budget approach, changing the first three feeds on the basis of an equivalent feed consumption instead of age (Sp). Results: In Trial 1, higher BW (80.2 kg vs. 82.1 kg; P = 0.02), ADG (704 g/d vs. 725 g/d; P = 0.02) and lower number of lesions were observed for pigs raised in the LD treatment, compared to the HD treatment at d 154 (P < 0.05). The CV of the final BW was numerically lower for the LD treatment. In Trial 2, higher BW and ADG and lower CV were observed for the LSp pigs from 83 d until 163 d (P < 0.001) of age compared to LStd. Moreover, an interaction observed for carcass weight at slaughter (P = 0.016) showed that the Sp pigs had a higher carcass weight than did the Std pigs, and the difference increased as the emptying of the barn facility advanced. Conclusion: It is concluded that feeder space and feeding management may affect the growth of growing-finishing pigs and body-weight homogeneity at the end of the period. PMID- 29988624 TI - Amyloid-beta, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data. AB - We investigated whether amyloid-beta (Abeta) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Abeta status and neuropsychological data available. Linear mixed models were used to assess the associations of Abeta and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Abeta status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Abeta pathology (Abeta- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Abeta- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Abeta and cognition in cognitively normal individuals. The Abeta- norms for memory tests in combination with published norms improve prognostic accuracy of dementia. PMID- 29988625 TI - BHDPC Is a Novel Neuroprotectant That Provides Anti-neuroinflammatory and Neuroprotective Effects by Inactivating NF-kappaB and Activating PKA/CREB. AB - Microglia-mediated neuroinflammatory responses are inevitable and important pathological processes in several kinds of disorder of the central nervous system (CNS). Therefore, alleviating activated microglia-induced inflammatory process might be a valuable therapeutic approach to neuroinflammation-related diseases. In the present study, we investigated BHDPC, a novel neuroprotectant discovered in our previous study that had anti-inflammatory effects under neuroinflammatory conditions. First, we found that BHDPC could inhibit neuroinflammatory responses and promote microglial M2 phenotype polarization in both lipopolysaccharide (LPS) activated BV-2 microglia l cells. Furthermore, BHDPC provided protective actions against neuroinflammation-induced neurotoxicity in HT22 mouse hippocampal cells co-cultured with activated BV-2 microglia. Further experiments demonstrated that BHDPC could suppress LPS-induced activation of transcription factor nuclear factor kappa B (NF-kappaB) via interfering with the degradation of the inhibitor of kappa B (IkappaB) and phosphorylation of IkappaB, the IkappaB kinase (IKK). Moreover, we also found that BHDPC could induce phosphorylation of cAMP-dependent protein kinase A (PKA) and cAMP-response element-binding protein (CREB) in BV-2 microglial cells. Also, using the PKA-specific inhibitor, we found that BHDPC induced CREB phosphorylation was dependent on PKA, which also contributed to BHDPC-mediated anti-inflammation and neuroprotection. PMID- 29988626 TI - 19q13.11 microdeletion: Clinical features overlapping ectrodactyly ectodermal dysplasia-clefting syndrome phenotype. AB - We report a patient who was followed for a long time under an ectrodactyly ectodermal dysplasia-clefting (EEC) syndrome and was subsequently diagnosed with a 19q13.11 microdeletion. After a review of the related literature, we suggest testing patients with EEC for 19q13.11 microdeletion and include WTIP and UBA2 to a minimal overlapping region. PMID- 29988627 TI - Severe allograft rejection in an intestinal transplant patient following oral immunoglobulin treatment for chronic norovirus infection: a case report. AB - In an intestinal transplant patient under triple immunosuppression therapy with tacrolimus levels >10 ng/L, a 2-day oral immunoglobulin therapy given as treatment for chronic norovirus infection was temporally closely associated with the development of severe steroid-resistant acute graft rejection, thus suggesting that oral immunoglobulin might be able to promote a rejection response. PMID- 29988628 TI - Novel use of cutting balloon to manage compressive subintimal hematoma during left main stenting in a patient with spontaneous coronary artery dissection. AB - Spontaneous coronary artery dissection (SCAD) is a common cause of acute coronary syndrome particularly in younger women. Good outcomes with conservative management are generally expected. However, there is uncertainty of how to manage symptomatic or unstable patients. Percutaneous angioplasty may propagate the subintimal hematoma compromising coronary blood flow. Cutting balloon angioplasty can relieve the compressive effects of a propagated subintimal hematoma in SCAD. PMID- 29988629 TI - The case of the unwanted crystal: a case of pediatric pulmonary Actinomyces Odonolyticus. AB - This case report is one of the only known cases of Actinomyces odontolyticus causing thoracic disease in an immunocompetent pediatric patient. This case also exemplifies how bronchoscopy was able to remove the nidus of infection and prevent the potential for significant morbidity associated with a lobectomy. PMID- 29988630 TI - Commentary: Cognitive Behavioral Therapy vs. Eye Movement Desensitization and Reprocessing for Treating Panic Disorder: A Randomized Controlled Trial. PMID- 29988631 TI - A population-based epidemiological study of anaphylaxis using national big data in Korea: trends in age-specific prevalence and epinephrine use in 2010-2014. AB - Background: Previous reports on anaphylaxis in Asia are limited to relatively small-scale studies. We performed this study to identify the nationwide prevalence of anaphylaxis and epinephrine prescription rates by age groups. Methods: The total number of patients, yearly and overall prevalence, percentage of emergency department visits, and epinephrine prescription rates were calculated for patients diagnosed with anaphylaxis based on the Korean National Health Insurance database from 2010 to 2014. Results: The mean prevalence of anaphylaxis in Korea was 26.23 (95% confidence interval, CI 25.78-26.68) per 100,000 person-years during the 5 years. It increased from 20.55 (95% CI 20.15 20.10) in 2010 to 35.33 (95% CI 34.81-35.85) per 100,000 person-years in 2014. The average prevalence was > 35 per 100,000 person-years among 50-69 year-olds, and the mean crude prevalence in children was 22.3 (0-2 years), 17.3 (3-6 years), 12.1 (7-12 years), and 14.9 (13-17 years) per 100,000 person-years, respectively. The overall prevalence increased 1.7-fold, with the highest rate of increase in 0 2 years of age. The overall percentage of emergent anaphylaxis patients was 88.4%, and the prevalence of emergent anaphylaxis increased from 18.63 (95% CI 18.25-19.01) to 31.28 (95% CI 30.79-31.77) per 100,000 person-years. In-hospital epinephrine prescription rate increased from 31.5 to 39.7%. Conclusions: The mean prevalence of anaphylaxis in Korea was 26.2 per 100,000 person-years during the study period. The total number of anaphylaxis patients increased 1.7-fold from 2010 to 2014, with the most noticeable increment being in young children. PMID- 29988632 TI - Giant liver tumor causing dyspnea upon exertion. AB - Asymptomatic elevation of the right hemidiaphragm should always raise suspicion of a silent hepatic tumor. Prompt multimodality imaging plays a critical role in the identification of this entity; high clinical suspicion is the key element for diagnosis of a possible hepatic tumor. PMID- 29988633 TI - Pulmonary pleomorphic carcinoma with pseudoprogression during nivolumab therapy and the usefulness of tumor markers: A case report. AB - Pseudoprogression was reported as one of the unconventional responses during immune checkpoint inhibitor therapy. A 70-year-old man with pulmonary pleomorphic carcinoma received nivolumab therapy. Pleural effusion and pulmonary metastasis increased, however then shrank and serum cytokeratin 19 fragment levels decreased. Serum tumor marker might help to distinguish pseudoprogression. PMID- 29988634 TI - Bartonella endocarditis in a child with tetralogy of Fallot complicated by PR3 ANCA positive serology, autoimmune hemolytic anemia, and acute kidney injury. AB - Although the role of ANCA in infective endocarditis is unclear, Bartonella henselae has been implicated as the culprit in cases of PR3-ANCA positive subacute bacterial endocarditis (SBE) with glomerulonephritis. In this case, a Coombs-positive autoimmune hemolytic anemia and glomerulonephritis accompanied a PR3-ANCA positive SBE caused by Bartonella henselae. PMID- 29988635 TI - Anomalous aortic origin of the right coronary artery with functional ischemia determined with fractional flow reserve derived from computed tomography. AB - A right coronary artery of anomalous origin is rare congenital anatomy that can be fatal. CT angiography is an excellent tool for its anatomical assessment. Noninvasive CT-based fractional flow reserve measurement can additionally evaluate the functional severity of coronary stenosis and is potentially useful for evaluating coronary anomalies. PMID- 29988636 TI - Recovery of muscle weakness and physical function in a patient with severe ICU acquired weakness following pulmonary embolism: A case report. AB - Although ICU-AW is a common condition in critically ill, it is unclear which intervention is best to treat. We applied combined exercise training and nutritional supplementation, and these were effective to recover the skeletal muscle function and exercise capacity. We should recognize necessity of nutritional support in ICU-AW patients. PMID- 29988637 TI - Fitz-Hugh-Curtis syndrome: a diagnostic challenge. AB - Diagnosis of Fitz-Hugh-Curtis is challenging due to its rarity and its similar presentation to common intra-abdominal conditions, such as cholecystitis or appendicitis. In our case, the adherent cecal and omental mass felt on examination were thought to be an appendiceal mass secondary to perforation, hence the patient underwent a diagnostic laparoscopy. PMID- 29988638 TI - Retained surgical sponges: a descriptive study of 319 occurrences and contributing factors from 2012 to 2017. AB - Background: Unintended retention of foreign bodies remain the most frequently reported sentinel events. Surgical sponges account for the majority of these retained items. The purpose of this study was to describe reports of unintentionally retained surgical sponges (RSS): the types of sponges, anatomic locations, accuracy of sponge counts, contributing factors, and harm, in order to make recommendations to improve perioperative safety. Methods: A retrospective review was undertaken of unintentionally RSS voluntarily reported to The Joint Commission Sentinel Event Database by healthcare facilities over a 5-year period (October 1, 2012- September 30, 2017). Event reports involving surgical sponges were reviewed for patients undergoing surgery, invasive procedures, or child birth. Results: A total of 319 events involving RSS were reported. Sponges were most frequently retained in the abdomen or pelvis (50.2%) and the vagina (23.9%). Events occurred in the Operating Room (64.1%), Labor and Delivery (32.7%) and other procedural areas (3.3%). Of the events reported, 318 involved 1 to 12 contributing factors totaling 1430 in 13 different categories, most frequently in human factors and leadership. In 69.6% of reports, the harm was an unexpected additional care or extended stay. Severe temporary harm was associated with 14.7% of the events. One patient died as a result of the retained sponge. Conclusions: Because of the complexity of perioperative patient care, the multitude of contributing factors that are difficult to control, and the potential benefit of radiofrequency sponge detection, we recommend that this technology be considered in areas where surgery is performed and in Labor and Delivery. PMID- 29988639 TI - Co-occurrence of hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia in a neonate with Noonan syndrome, leading to premature death. AB - We report a case of a neonate with Noonan syndrome presenting with concurrent hypertrophic cardiomyopathy and juvenile myelomonocytic leukemia, which resulted in premature death. Cases with Noonan syndrome diagnosed during the neonatal period might not necessarily show mild clinical course, and premature death is a possible outcome to be considered. PMID- 29988641 TI - Ventricular tachycardia revealing drug abuse induced myocarditis: two case reports. AB - Illicit drugs are an uncommon etiology of acute myocarditis but should be evocated in young population. This association may result in further complications, mainly ventricular arrhythmia and therefore increases sudden cardiac deaths among young abusers. Withholding drug intoxication to prevent recurrent events is a major key of management. PMID- 29988640 TI - Comparative Metagenomics Provides Insight Into the Ecosystem Functioning of the Shark Bay Stromatolites, Western Australia. AB - Stromatolites are organosedimentary build-ups that have formed as a result of the sediment trapping, binding and precipitating activities of microbes. Today, extant systems provide an ideal platform for understanding the structure, composition, and interactions between stromatolite-forming microbial communities and their respective environments. In this study, we compared the metagenomes of three prevalent stromatolite-forming microbial mat types in the Spaven Province of Hamelin Pool, Shark Bay located in Western Australia. These stromatolite forming mat types included an intertidal pustular mat as well as a smooth and colloform mat types located in the subtidal zone. Additionally, the metagenomes of an adjacent, non-lithifying mat located in the upper intertidal zone were also sequenced for comparative purposes. Taxonomic and functional gene analyses revealed distinctive differences between the lithifying and non-lithifying mat types, which strongly correlated with water depth. Three distinct populations emerged including the upper intertidal non-lithifying mats, the intertidal pustular mats associated with unlaminated carbonate build-ups, and the subtidal colloform and smooth mat types associated with laminated structures. Functional analysis of metagenomes revealed that amongst stromatolite-forming mats there was an enrichment of photosynthesis pathways in the pustular stromatolite-forming mats. In the colloform and smooth stromatolite-forming mats, however, there was an increase in the abundance of genes associated with those heterotrophic metabolisms typically associated with carbonate mineralization, such as sulfate reduction. The comparative metagenomic analyses suggest that stromatolites of Hamelin Pool may form by two distinctive processes that are highly dependent on water depth. These results provide key insight into the potential adaptive strategies and synergistic interactions between microbes and their environments that may lead to stromatolite formation and accretion. PMID- 29988642 TI - Using kidney size for early detection of contrast-induced nephropathy in the emergency department setting. AB - Aim: We aimed to examine the relationship between kidney size and contrast induced nephropathy (CIN) in patients who underwent contrast-enhanced computed tomography (CT) in the emergency department. Methods: This single-center retrospective observational study was undertaken to evaluate risk factors for CIN at Okayama Saiseikai General Hospital (Okayama, Japan) from January 2014 through to December 2016. Contrast-induced nephropathy was defined as an absolute increase in serum creatinine level of >=0.5 mg/dL or >=25% over the baseline value within 72 h after contrast-enhanced CT. Independent risk factors for CIN were determined by multiple logistic regression analysis. The thickness of the kidney was evaluated as a predictor of CIN using the area under the receiver operating characteristic curve. We also analyzed CIN as an outcome using the Kaplan-Meier method. Results: The incidence of CIN was 26/262 (9.9%). In the multivariate analysis, CIN was associated with renal thickness (odds ratio = 0.65; 95% confidence interval, 0.53-0.81). No patient underwent renal replacement therapy. Conclusion: Renal thickness could be used as a reliable, simple, and easily obtainable marker for identifying CIN in patients undergoing contrast enhanced CT in the emergency department. PMID- 29988643 TI - Pemphigoid gestationis. AB - Pemphigoid gestationis is a rare autoimmune skin disorder emerging exclusively during pregnancy. Topical and oral glucocorticoids as well as oral antihistamines are the standard medications administered during pregnancy, aiming to relieve pruritus and to suppress extensive blister formation. Obstetricians should be able to recognize and treat this rare clinical condition accordingly. PMID- 29988644 TI - Erythema nodosum in an adolescent patient with cryopyrin-associated periodic syndrome. AB - Cryopyrin-associated periodic syndrome (CAPS) is a monogenetic auto-inflammatory disorder with systemic manifestations. Innate immune system aberrance is seen in both CAPS and erythema nodosum and this case may point to a previously unknown association. In pediatric patients with EN and systemic features, the possibility of underlying CAPS should be considered. PMID- 29988645 TI - Acupuncture point injection markedly improved sensory symptoms and motor signs in 2 patients with restless legs syndrome. AB - The acuinjections at acupuncture points (GB41, BL60, ST36, and SP6) provide immediate relief of sensory symptoms and motor signs of restless legs symptom (RLS). An acuinjection can be promising and safe alternative treatment for pharmacotherapy in patients of RLS. PMID- 29988646 TI - Dislodged biliary stent causes lower gastrointestinal hemorrhage four years postendoscopic retrograde cholangiopancreatography. AB - Endoscopic biliary stent placement is an efficient method for the decompression of the biliary system in various benign and malignant causes. Dislocation and stent migration is a well-known complication, with most displaced stents passing through the bowel, uneventfully. Rarely, migrated stents can be accounted for potentially life-threatening complications. PMID- 29988648 TI - Diagnostic exome sequencing identifies GLI2 haploinsufficiency and chromosome 20 uniparental disomy in a patient with developmental anomalies. AB - Clinical diagnostic exome sequencing (DES) is currently infrequently used for detecting uniparental disomy (UPD). We present a patient with a dual diagnosis of GLI2 haploinsufficiency as well as UPD of chromosome 20, both identified through DES. We therefore recommend routine UPD analysis during DES to identify this genetic aberration. PMID- 29988647 TI - Emergency surgeons' perceptions and attitudes towards antibiotic prescribing and resistance: a worldwide cross-sectional survey. AB - Background: Antibiotic resistance (AMR) is a growing public health problem worldwide, in part related to inadequate antibiotic use. A better knowledge of physicians' motivations, attitudes and practice about AMR and prescribing should enable the design and implementation of effective antibiotic stewardship programs (ASPs). The objective of the study was to assess attitudes and perceptions concerning AMR and use of antibiotics among surgeons who regularly perform emergency or trauma surgery. Methods: A cross-sectional web-based survey was conducted contacting 4904 individuals belonging to a mailing list provided by the World Society of Emergency Surgery. Participation was voluntary and anonymous. The survey was open for 5 weeks (from May 3, 2017, to June 6, 2017), within which two reminders were sent. The self-administered questionnaire was developed by a multidisciplinary team; reliability and validity were assessed. Results: The overall response rate was 12.5%. Almost all participants considered AMR an important worldwide problem, but 45.6% of them underrated the problem in their own hospitals. Surgeons provided with periodic reports on local AMR demonstrated a lower underrating in their hospital. Only 66.3% of the surgeons stated to receive periodic reports on local AMR data, and among them, 56.2% had consulted them to select an antibiotic in the previous month. Availability of systematic reports about AMR, availability of guidelines for therapy of infections, and advice from an infectious diseases specialist were considered very helpful measures to improve antibiotic prescribing by 68.0, 65.7, and 64.9%, respectively. Persuasive and restrictive ASPs were both considered helpful measures by 64.5%. Moreover, 86.3% considered locally developed guidelines more useful than national ones. Only 21.9% received formal training in antibiotic prescribing in the previous year; among them, 86.6% declared to be interested in receiving more training. Conclusions: Availability of periodic reports on local AMR data was considered an important tool to guide surgeons in choosing the correct antibiotic and to increase awareness of the problem of AMR. Local guidelines for therapy of infections should be implemented in every emergency surgery setting, and developed by a multidisciplinary team directly involving surgeons, infectious diseases specialists, and microbiologists, and formally established in an ASP. PMID- 29988649 TI - A convenient, reliable, and fast acoustic pressure field measurement method for magnetic resonance-guided high-intensity focused ultrasound systems with phased array transducers. AB - Background: With the expanding applications of magnetic resonance-guided high intensity focused ultrasound (MR-HIFU), there is an urgent need for a convenient, reliable, and fast acoustic pressure field measurement method to aid treatment protocol design, ensure consistent and safe operation of the transducer, and facilitate regulatory approval of new techniques. Herein, we report a method for acoustic pressure field characterization of MR-HIFU systems with multi-element phased array transducers. This method integrates fiber-optic hydrophone measurements and electronic steering of the ultrasound beam with MRI-assisted HIFU focus alignment to the fiber tip. Methods: A clinical MR-HIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) was used to assess the proposed method. A fiber-optic hydrophone was submerged in a degassed water bath, and the fiber tip location was traced using MRI. Subsequently, the nominal transducer focal point indicated on the MR-HIFU therapy planning software was positioned at the fiber tip, and the HIFU focus was electronically steered around the fiber tip within a 3D volume for 3D pressure field mapping, eliminating the need for an additional, expensive, and MRI-compatible 3D positioning stage. The peak positive and negative pressures were measured at the focus and validated using a standard hydrophone measurement setup outside the MRI magnet room. Results: We found that the initial MRI-assisted HIFU focus alignment had an average offset of 2.23 +/- 1.33 mm from the fiber tip as identified by the 3D pressure field mapping. MRI guidance and electronic beam steering allowed 3D focus localization within ~ 1 h, i.e., faster than the typical time required using the standard laboratory setup (~ 3-4 h). Acoustic pressures measured using the proposed method were not significantly different from those obtained with the standard laboratory hydrophone measurements. Conclusions: In conclusion, our method offers a convenient, reliable, and fast acoustic pressure field characterization tool for MR-HIFU systems with phased array transducers. PMID- 29988650 TI - Disparities in caesarean section prevalence and determinants across sub-Saharan Africa countries. AB - Background: Access to safe Cesarean section (C-section) in resource-constrained settings such as sub-Sahara Africa (SSA) region is a foremost approach to reduce maternal mortality. C-section is an obstetric operative procedure used appropriately to improve delivery outcomes. However, errors in the procedure have enormous potential harm that may outweigh the benefits. This study assessed the prevalence and determinants of C-section in several SSA countries. This study examined the prevalence and determinants associated with cesarean delivery in SSA countries. Methods: Secondary data of women of reproductive age (15-49 years) from the current Demographic and Health Survey (DHS) in 34 SSA countries was utilized in this study. The mode of delivery among women was the primary outcome variable. Percentage and descriptive statistics were used to conduct univariate analyses. Furthermore, multivariable multilevel logistic regression was used to investigate correlates of C-section among SSA women. Results: Results showed disparities in the percentage of C-section among women from 34 SSA countries. C section at public healthcare settings ranged from 3% in Burkina Faso to 15.6% in Ghana. However, in private healthcare settings, C-section ranged from 0% in Sao Tome and Principe to 64.2% in Rwanda. Overall, C-section was 7.9% from public healthcare and 12.3% from private healthcare facilities respectively. In the adjusted regression model; women aged 35-49 had increase in the odds of C section, while a unit increase in the number of children ever born had 17 and 20% significant reduction in the odds of C-section in public and private healthcare respectively. Assessing public healthcare settings; women from richer/richest households, male and large size children at birth had increase in the odds of C section, while those from rich neighbourhood had reduction in the odds of C section. In private healthcare settings, women with high decision making power and multiple births had increase in the odds of C-section, while those who attended ANC visits had significant reduction in the odds of C-section. Conclusion: The findings from this study would help formulate health policies and implement actions that would improve the outcome of C-section care. Monitoring of emergency obstetric care services is necessary to address issues connected to poor C-section outcomes in resource-constrained settings. Also training of medical personnel including midwives and nurses in emergency obstetric care, ensuring accessibility to life-saving drugs and supplies should be encouraged in health care system. PMID- 29988651 TI - Pregnancies complicated by maternal osteogenesis imperfecta type III: a case report and review of literature. AB - The restrictive lung disease can be exacerbated by growing fundus in women with osteogenesis imperfecta type III. Regional anesthesia can be performed in these women. Mode of delivery for women with osteogenesis imperfecta type III is generally cesarean delivery. Neonatal outcomes are complicated due to indicated preterm deliveries. PMID- 29988652 TI - Rifaximin as a rare cause of rhabdomyolysis in cirrhosis. AB - Rifaximin has only been rarely reported to cause rhabdomyolysis. When physical and nonphysical etiologies have been excluded, thorough review of the patient's medication list is necessary. In cirrhotics, the potential harm of rifaximin in treatment or prophylaxis of hepatic encephalopathy should be recognized. PMID- 29988653 TI - Genetic variation and relationships in the mitochondrial DNA D-loop region of Qinghai indigenous and commercial pig breeds. AB - Background: Bamei pigs are special germplasm resources in Qinghai. In the specific environment of the Qinghai plateau, local breeds, through long-term natural and artificial selection, have acquired a relatively stable population structure and genetic diversity. This study revealed Bamei pigs' genetic diversity at the molecular level and the degree of introgression of commercial breeds into Bamei pigs. Methods: The mitochondrial DNA D-loop region was amplified and sequenced using the ABI 3130 DNA sequencer. Sequences were collected, edited and aligned using the MEGA 5.0, DNASTAR and ClustalX 1.81 software. Haplotypes of all sequences and genetic diversity were analyzed by DnaSP 5.0 software. Results and conclusions: We identified a total of 73 polymorphic sites in our 489 novel sequences, including 1 single variable site and 72 parsimony informative sites.Genetic diversity was analyzed in this study. The results showed that haplotype diversity, nucleotide diversity and the average number of nucleotide differences of Bamei pigs were lower than those of commercial pigs. Synthetic evaluation of genetic diversity through principal component analysis indicated that Bamei pigs also showed low genetic diversity. In summary, the results of sequence analysis showed that Bamei pigs were low in genetic diversity, and the introgression of commercial pigs into Bamei pigs was serious. PMID- 29988654 TI - Diabetic chorea as a neurological complication. AB - Diabetic chorea accompanies hyperglycemic states or drastic changes in blood glucose levels and involves the acute onset of unilateral or bilateral choreatic movements. Diabetes is sometimes discovered due to diabetic chorea, and thus, diabetic chorea is considered an important neurological complication. PMID- 29988655 TI - Possible associations of personality traits representing harm avoidance and self directedness with medication adherence in Japanese patients with type 2 diabetes. AB - Background: Insufficient medication adherence in diabetes patients, of which numbers continue to increase globally, remains a critical issue. Medication adherence is multifactorial and determined by interactions among factors including socioeconomic status, health care team and system, condition, therapy, and patient-specific factors. On the other hand, personality traits have been studied in adherence other than to medication. Using the instruments of Temperament and Character Inventory (TCI), Harm Avoidance (TCI-HA) and Self directedness (TCI-SD) showed distinguishing associations with adherence of health related programs. However, few studies have been performed to elucidate psychometric properties related to medication adherence. We investigated how TCI HA and TCI-SD of patients with diabetes are related to medication adherence. Method: A cross-sectional survey was conducted among type 2 diabetes patients recruited at medical institutions or via an online research company. Medication adherence was measured using the 8-item Morisky Medication Adherence Scale (MMAS 8). Personality traits were assessed using the established scales of TCI-HA and TCI-SD. Univariate and multivariate regression analyses of the MMAS-8 scores were performed in addition to assessing demographic and disease characteristics and TCI-HA and TCI-SD. Results: A total of 358 responses were analyzed. Multivariate regression analysis of MMAS-8 scores revealed that higher TCI-SD was related to better adherence and experiencing drug-related side effects was related to poor adherence. Aging was significantly associated with better medication adherence in univariate regression analysis but became insignificant in multivariate regression. Conclusions: In diabetes patients, the anxiety reflected in TCI-HA tends to lower and the self-control reflected in TCI-SD tends to promote medication adherence. TCI-SD has a greater effect than TCI-HA. PMID- 29988656 TI - The effect of depression on fracture healing and osteoblast differentiation in rats. AB - Background: Depressive disorder has been proven to be associated with disturbed bone metabolism. However, the effect of depression on fracture healing still lacks evidence. Materials and methods: A rat depressive model was first established by exposing the animals to chronic unpredictable stress, which was assessed using the sucrose preference test, forced swimming test, and open field test. Subsequently, the bone repairing ability was detected by micro-computed tomography and histological analysis of the femoral condyle defect rats with or without depression. To further investigate the potential mechanisms of depression on fracture healing, the osteogenic differentiation and autophagic level were compared between the bone marrow mesenchymal stem cells (BMSCs) derived from depressive and normal rats. Results: Our results showed that rats with depressive disorder significantly slowed the healing process at 4 and 8 weeks postinjury. Furthermore, the osteogenic potential and autophagy remarkably decreased in BMSCs from the depressive rats, suggesting an inherent relationship between autophagy and osteogenic differentiation. Finally, rapamycin, an autophagic agonist, significantly improved osteogenic differentiation of depressive BMSCs through autophagy activation. Conclusion: The present study indicated that depression had a negative effect on fracture healing with low osteoblast differentiation of BMSCs. Also, autophagy activation in BMSCs offers a novel therapeutic target for depressive patients with poor fracture healing. PMID- 29988657 TI - Anaphylactic reaction to gonadotropin-releasing hormone analogues: a pediatric case report. AB - Gonadotropin-releasing hormone (GnRH) analogues represent the gold standard treatment for precocious puberty. Allergic-type reactions in children due to this type of treatment are very rare. However, caregivers should be aware of the potential GnRH analogue systemic reactions. PMID- 29988658 TI - Comparison of clinical practice guidelines for the management of pain, agitation, and delirium in critically ill adult patients. AB - Guideline-based management approaches for pain, agitation, and delirium (PAD) in critically ill adult patients are widely believed to result in good outcomes. However, there are some differences in the recommendations and evidence levels among the management guidelines established for PAD. To identify and compare the current management guidelines, we used the PubMed database. The PAD guidelines and Federacion Panamericana e Iberica de Sociedades de Medicina Critica y Terapia Intensiva (FEPIMCTI) guidelines were identified from our search. We compared the main aspects of these two guidelines as well as the Japanese guidelines for the management of PAD (J-PAD guidelines). The PAD, FEPIMCTI, and J-PAD guidelines contained a total of 4, 12, and 5 sections, having 32, 138, and 37 recommendations, respectively, pertaining to routine monitoring of pain in adult patients in the intensive care unit. Intravenous opioids were recommended as the first-line drug of choice for treating pain. Sedative titrated to maintain a light, rather than deep, level of sedation can be given unless clinically contraindicated. Although neither the PAD nor J-PAD guidelines recommend use of a pharmacologic delirium prevention protocol or treatment with any pharmacological agent to reduce the duration of delirium, the FEPIMCTI guidelines provide such recommendations. The FEPIMCTI guidelines provide suggestions on which analgesics to use for several different cases and present algorithms for sedation and analgesia. The outlines of the three guidelines are similar, and all reinforce the management of PAD to improve patient outcomes. PMID- 29988659 TI - ApoE isoform leading to hypertriglyceridemia in new onset type 1 diabetes. AB - We report a case of pediatric diabetic ketoacidosis (DKA) with significant hypertriglyceridemia. The patient was found to have the e3/ e4 isoform of ApoE, increasing risk of hypertriglyceridemia in DKA. We suggest further genetic investigation for patients presenting with severe hypertriglyceridemia and DKA. PMID- 29988660 TI - Metachronous gastric metastasis from lung primary, with synchronous pancreatic neuroendocrine carcinoma. AB - The finding of gastric metachronous metastasis, several years after the diagnosis of primary lung large cell carcinoma is rare and incidental. Even more extremely rare is the finding of a synchronous primary pancreas cancer. EUS-FNA with immunohistochemistry is useful for diagnosing metastatic lesions and differentiating those from synchronous primary lesions. PMID- 29988661 TI - Cyclic thrombocytopenia with statistically significant neutrophil oscillations. AB - Cyclic thrombocytopenia is often misdiagnosed as immune thrombocytopenia due to similar clinical features, a fact of significance because cyclic thrombocytopenia generally responds poorly to treatments used successfully in immune thrombocytopenia. A precise diagnosis must establish the statistical significance of periodicity of the platelet counts using statistical methods (eg, Lomb-Scargle periodogram). PMID- 29988662 TI - Reversible manifestations of extraparenchymal neurocysticercosis. AB - Movement disorders are uncommon manifestations of neurocysticercosis. When present, most are secondary to parenchymal lesions in the basal ganglia. Rarely, movement disorders can occur in racemose/extraparenchymal neurocysticercosis, an aggressive variant frequently associated with cerebrospinal fluid outflow obstruction and hydrocephalus. Appropriate treatment can reverse neurological manifestations. PMID- 29988663 TI - Sarcoidosis with multiple organ involvement. AB - This is an interesting case that highlights the variability of the clinical course of sarcoidosis and the importance of the knowledge of the clinical and radiologic features of the disease for its diagnosis and management. PMID- 29988666 TI - Ventilator auto-triggering by cardiac electrical activity during noninvasive ventilation with neurally adjusted ventilatory assist. AB - Neurally adjusted ventilatory assist (NAVA), by capturing the electrical activity of the diaphragm, improves patient-ventilator synchrony. It is, however, not completely immune from auto-triggering by cardiac electrical activity as illustrated in this case. Stringent observation of respiratory rate and vigilance for this phenomenon is warranted when using NAVA. PMID- 29988665 TI - Appendix epidermoid cyst: Presenting as an acute appendicitis. AB - We report a rare case of a cystic mass in an appendix in a patient who presented nausea, vomiting, and sharp pain in lower right abdomen and mimicking acute appendicitis. Although this entity is very rare, careful physical observation, imaging, and pathology can be helpful to make an accurate diagnosis. PMID- 29988664 TI - The profile of Japanese Association for Acute Medicine - out-of-hospital cardiac arrest registry in 2014-2015. AB - Aim: To describe the registry design of the Japanese Association for Acute Medicine - out-of-hospital cardiac arrest (JAAM-OHCA) Registry as well as its profile on hospital information, patient and emergency medical service characteristics, and in-hospital procedures and outcomes among patients with OHCA who were transported to the participating institutions. Methods: The special committee aiming to improve the survival after OHCA by providing evidence-based therapeutic strategies and emergency medical systems from the JAAM has launched a multicenter, prospective registry that enrolled OHCA patients who were transported to critical care medical centers or hospitals with an emergency care department. The primary outcome was a favorable neurological status 1 month after OHCA. Results: Between June 2014 and December 2015, a total of 12,024 eligible patients with OHCA were registered in 73 participating institutions. The mean age of the patients was 69.2 years, and 61.0% of them were male. The first documented shockable rhythm on arrival of emergency medical services was 9.0%. After hospital arrival, 9.4% underwent defibrillation, 68.9% tracheal intubation, 3.7% extracorporeal cardiopulmonary resuscitation, 3.0% intra-aortic balloon pumping, 6.4% coronary angiography, 3.0% percutaneous coronary intervention, 6.4% targeted temperature management, and 81.1% adrenaline administration. The proportion of cerebral performance category 1 or 2 at 1 month after OHCA was 3.9% among adult patients and 5.5% among pediatric patients. Conclusions: The special committee of the JAAM launched the JAAM-OHCA Registry in June 2014 and continuously gathers data on OHCA patients. This registry can provide valuable information to establish appropriate therapeutic strategies for OHCA patients in the near future. PMID- 29988667 TI - The current role and future prospectives of functional parameters by diffusion weighted imaging in the assessment of histologic grade of HCC. AB - Hepatocellular carcinoma (HCC) is one of the most common human solid malignancies worldwide. Although the MRI is the technique that is best adapted to characterize HCC, there is not an agreement regarding the study protocol and even what the role of Diffusion-weighted imaging (DWI). The possibility that imaging study can correlate to histologic grade to selecting the therapeutic strategy would be valuable in helping to direct the proper management of HCC. Apparent Diffusion Coefficient (ADC) and IVIM-derived perfusion fraction (fp) and tissue diffusivity (Dt) values of HCC showed significantly better diagnostic performance in differentiating high-grade HCC from low-grade HCC, and significant correlation was observed between ADC, fp, Dt and histological grade. PMID- 29988668 TI - Impact of in-hospital birth weight loss on short and medium term breastfeeding outcomes. AB - Background: The definition for lower limit of safe birthweight loss among exclusively breastfed neonates is arbitrary. Despite this, in cases of great in hospital weight loss, breastfeeding adequacy is immediately questioned. The aim of this study was to examine the relationship between weight loss at discharge from hospital, when babies are ready to go home, and eventual cessation of exclusive breastfeeding since birth. Methods: This is a secondary analysis of a cohort study. Study participants were 788 full term, breastfed and stable babies, born in 2007-2012 consecutively enrolled to primary care pediatric clinics in Majorca, Spain. Data were collected by chart review. The main predictor was birthweight loss at discharge. Extreme weight loss was defined as the 90th and 95th centiles of birthweight loss for babies who were delivered by vaginal delivery and by cesarean section. Main outcomes were cessation of exclusive breastfeeding by 7, 15, 30 and 100 days of life. Multivariate regression analysis was performed to study the relationship of selected variables with exclusive breastfeeding cessation since birth. Results: We observed a median weight loss of 6%. In bivariate analysis, quartiles of birthweight loss at discharge were predictive of exclusive breastfeeding cessation at 15, 30 and 100 days postpartum. In multivariate analysis: in-hospital weight loss above the median did predict exclusive breastfeeding cessation by 15, 30 and 100 days of life, Adjusted Odds Ratios (AORs) (95% Confidence Intervals [CIs]): 1.57 (1.12, 2.19), 1.73 (1.26, 2.38) and 1.69 (1.25, 2.29), respectively. In contrast, we did not find that newborn extreme weight losses were associated with exclusive breastfeeding cessation. Conclusions: We report that extreme birthweight loss does not trigger immediate formula supplementation. We do not identify any cut off values to be used as predictors for the initiation of supplementary feeding, this research question remains unanswered. PMID- 29988670 TI - Ventriculomegaly and cerebellar hypoplasia in a neonate with interstitial 11q 24 deletion in Jacobsen syndrome region. AB - Jacobsen syndrome (JS) is a rare contiguous gene disorder caused by partial deletion of the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. We report a term male neonate with an interstitial deletion of about 12.3 megabase (Mb) of chromosome 11q24.1qter. Our case is the first reported newborn patient with 11q24 deletion. PMID- 29988671 TI - Permanent His-Bundle pacing in a patient with advanced conduction system disease: What is the mechanism of QRS narrowing? AB - QRS narrowing during permanent His-bundle pacing is primarily thought to result from longitudinal dissociation within the His bundle. We present a case with an alternative mechanism, highlighting the likelihood that there are actually multiple explanations for this phenomenon. In addition, this case highlights the utility of His-bundle pacing even in the face of a wide QRS. PMID- 29988669 TI - Edaravone and cyclosporine A as neuroprotective agents for acute ischemic stroke. AB - It is well known that acute ischemic stroke (AIS) and subsequent reperfusion produce lethal levels of reactive oxygen species (ROS) in neuronal cells, which are generated in mitochondria. Mitochondrial ROS production is a self-amplifying process, termed "ROS-induced ROS release". Furthermore, the mitochondrial permeability transition pore (MPTP) is deeply involved in this process, and its opening could cause cell death. Edaravone, a free radical scavenger, is the only neuroprotective agent for AIS used in Japan. It captures and reduces excessive ROS, preventing brain damage. Cyclosporine A (CsA), an immunosuppressive agent, is a potential neuroprotective agent for AIS. It has been investigated that CsA prevents cellular death by suppressing MPTP opening. In this report, we will outline the actions of edaravone and CsA as neuroprotective agents in AIS, focusing on their relationship with ROS and MPTP. PMID- 29988672 TI - Potential role for emergency physicians with endoscopy training in the treatment of upper gastrointestinal hemorrhage: a retrospective observational study. AB - Aim: Urgent endoscopy is essential in gastrointestinal (GI) bleeding. Emergency physicians with endoscopy training treat patients with GI bleeding in our hospital. We compared the management and clinical outcomes of GI bleeding cases between those treated by an emergency physician (EP) and those treated by a non emergency physician (NEP; e.g., gastroenterologist or general surgeon). Methods: We undertook a retrospective chart review of upper GI bleeding cases treated using endoscopy in the emergency department between 2012 and 2014. We examined patients characteristics, endoscopic findings, hemostatic procedures, need for transfusion, rebleeding and adverse events, length of hospital stay, and mortality. Results: The EP group included 33 patients (39%) and the NEP group included 51 (61%). Patient characteristics and diseases did not differ between the groups. The EP group underwent urgent endoscopy more often (100% versus 86%, P = 0.04). Procedure times were not statistically different between the groups. The EP group had fewer hemostatic procedures (42% versus 65%, P = 0.04). Transfusion requirements were lower in the EP group (0.5 U versus 2.1 U, P = 0.006). There were no statistical differences in rebleeding and adverse events. The length of hospital stay was shorter (8 versus 11 days, P = 0.03) and the in hospital mortality rate was lower in the EP group (0% versus 13.7%, P = 0.04). Conclusion: Short-term outcomes in GI bleeding cases managed by emergency physicians with endoscopy training were comparable to those by gastroenterologists and general surgeons. However, the extent of endoscopic training and experience emergency physicians should have remains unclear. PMID- 29988674 TI - A huge asymptomatic pheochromocytoma. AB - Due to their evolution in the retroperitoneal space, pheochromocytomas may grow significantly in size and remain asymptomatic for a long period of time. Normal values of urine catecholamine levels must not preclude the diagnosis of these endocrine lesions. PMID- 29988673 TI - Pathology after a combination of sequential and simultaneous unipolar radiofrequency ablation of ventricular tachycardia in a postmortem heart with cardiac sarcoidosis. AB - This report shows a postmortem examination of a heart performed in a patient with cardiac sarcoidosis undergoing a sequential and simultaneous unipolar radiofrequency ablation. A combination of a sequential and simultaneous unipolar radiofrequency ablation might be useful for creating transmural ablation lesions on the interventricular septum in patients with cardiac sarcoidosis. PMID- 29988675 TI - Resolution of late-onset gastro-colic fistula after laparoscopic sleeve gastrectomy by conservative management: a case report. AB - Nutritional support and Antibiotics treatment can be used as conservative treatment for the resolution of gastro-colic fistula after sleeve gastrectomy in stable patients specially to prevent cumbersome redo surgeries that have higher risks of complications particularly in patients with minimal financial means. PMID- 29988676 TI - Clinical features of stroke mimics in the emergency department. AB - Aim: To clarify the features of stroke mimics. Methods: We retrospectively investigated stroke mimic cases among the suspected stroke cases examined at our emergency department, over the past 9 years, during the tissue-type plasminogen activator treatment time window. Results: Of 1,557 suspected acute stroke cases examined at the emergency department, 137 (8.8%) were stroke mimics. The most common causes were symptomatic epilepsy (28 cases, 20.4%), neuropathy-like symptoms (21 cases, 15.3%), and hypoglycemia (15 cases, 10.9%). Outcomes were survival to hospital discharge for 91.2% and death for 8.8% of the cases. Clinical results were significantly different between stroke mimics and the stroke group for low systolic blood pressure, low National Institutes of Health Stroke Scale score on initial treatment, history of diabetes, and no history of arrhythmia. On multivariate analysis, distinguishing factors for stroke mimics include systolic blood pressure <= 140 mmHg, National Institutes of Health Stroke Scale score <= 5 points, history of diabetes, and no history of arrhythmia. Conclusions: Frequency of stroke mimics in cases of acute stroke suspected cases is 8.8%, and the most common cause is epilepsy. In order to distinguish stroke mimics, it is useful to understand common diseases presenting as stroke mimics and evaluate clinical features different from stroke by medical interview or nerve examination. PMID- 29988677 TI - PIK3CA c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report. AB - We present a patient with suspected Proteus Syndrome, an overgrowth disorder associated with AKT1c.49G>A mutation. NGS analysis detected PIK3CAc.3140A>G mutation in the patient's affected tissue allowing for PROS (PIK3CA-related overgrowth spectrum) diagnosis. The overlapping clinical features in overgrowth disorders highlight the importance of molecular testing for a correct diagnosis. PMID- 29988678 TI - Preliminary experience with a novel Multisensor algorithm for heart failure monitoring: The HeartLogic index. AB - We report the first case of a patient in whom an implantable cardioverter defibrillator (ICD) endowed with HeartLogic, a novel algorithm for heart failure (HF) monitoring, was implanted in clinical practice. The good temporal association between HeartLogic index threshold crossings and HF hospitalizations confirms the high sensitivity in detecting gradual worsening of HF. PMID- 29988680 TI - Step by step full mouth rehabilitation of a class III edentulous patient by implant-supported prosthesis: A case report. AB - Full mouth rehabilitation by dental implants is complex in class III patients. Prediction of the outcome of orthognathic surgery in edentulous patients with no dental index or record is challenging. This report describes rehabilitation of an edentulous patient by placement of dental implants after prediction of the outcome of orthognathic correction. PMID- 29988679 TI - Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease. AB - Background: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. Results: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. Conclusion: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population. PMID- 29988681 TI - Xanthogranulomatous pyelonephritis with psoas abscess and renocolic fistula. AB - Xanthogranulomatous pyelonephritis (XGP) is an uncommon inflammatory disease of the kidney 1. Diffuse XGP is a rare condition which may spread into the pelvic cavity leading to fatal complications from a psoas muscle abscess and/or renocolic fistula 2. In diffuse type, nephrectomy and excision of the fistula is the recommended treatment. PMID- 29988682 TI - Mild manifestation of methanol poisoning half a day after massive ingestion of a fuel alcohol product containing 70% ethanol and 30% methanol: a case report. AB - Case: Is fomepizole necessary after massive ingestion of a mixture of methanol and ethanol? We report the case of a 37-year-old man who was transported to our Poison Center 12 h after ingesting 500 mL of fuel alcohol containing 70% methanol and 30% ethanol in a suicide attempt. On admission, he presented only with somnolence and mild metabolic acidosis. We hypothesized that most of the ethanol had been metabolized. Outcome: As the estimated serum concentration of methanol was lethal (242.6 mg/dL), fomepizole was given i.v. and hemodialysis was carried out twice, resulting in complete recovery. Later, the serum concentrations of both methanol and ethanol on admission were found to be 224.1 and 0.51 mg/dL, respectively. Conclusion: Therapeutic intervention was delayed by half a day after ingestion of a product containing methanol and ethanol in the present case. If the patient had arrived earlier, he may have only been treated with hemodialysis, but not fomepizole. PMID- 29988683 TI - Mass fingerprinting and electrophysiological analysis of the venom from the scorpion Centruroides hirsutipalpus (Scorpiones: Buthidae). AB - Background: Centruroides hirsutipalpus, of the family Buthidae, is a scorpion endemic to the Western Pacific region of Mexico. Although medically important, its venom has not yet been studied. Therefore, this communication aims to identify their venom components and possible functions. Methods: Fingerprinting mass analysis of the soluble venom from this scorpion was achieved by high performance liquid chromatography and electrospray mass spectrometry. Furthermore, the soluble venom and its toxic effects were evaluated extensively via electrophysiological assays in HEK cells expressing human voltage-gated Na+ channels (hNav 1.1 to Nav1.6), CHO cells expressing hNav 1.7, potassium channel hERG 1 (Ether-a-go-go-related-gene) and the human K+-channel hKv1.1. Results: The separation of soluble venom produced 60 fractions from which 83 distinct components were identified. The molecular mass distribution of these components varies from 340 to 21,120 Da. Most of the peptides have a molecular weight between 7001 and 8000 Da (46% components), a range that usually corresponds to peptides known to affect Na+ channels. Peptides with molecular masses from 3000 to 5000 Da (28% of the components) were identified within the range corresponding to K+-channel blocking toxins. Two peptides were obtained in pure format and completely sequenced: one with 29 amino acids, showing sequence similarity to an "orphan peptide" of C. limpidus, and the other with 65 amino acid residues shown to be an arthropod toxin (lethal to crustaceans and toxic to crickets). The electrophysiological results of the whole soluble venom show a beta type modification of the currents of channels Nav1.1, Nav1.2 and Nav1.6. The main effect observed in channels hERG and hKv 1.1 was a reduction of the currents. Conclusion: The venom contains more than 83 distinct components, among which are peptides that affect the function of human Na+-channels and K+-channels. Two new complete amino acid sequences were determined: one an arthropod toxin, the other a peptide of unknown function. PMID- 29988684 TI - A panel of DNA methylation markers for the detection of prostate cancer from FV and DRE urine DNA. AB - Background: Early screening for prostate cancer (PCA) remains controversial because of overdiagnosis and overtreatment of clinically insignificant cancers. Even though a number of diagnostic tests have been developed to improve on PSA testing, there remains a need for a more informative non-invasive test for PCA. The objective of this study is to identify a panel of DNA methylation markers suitable for a non-invasive diagnostic test from urine DNA collected following a digital rectal exam (DRE) and/or from first morning void (FV). A secondary objective is to determine if the cumulative methylation is indicative of biopsy findings. Methods: DRE and FV urine samples were prospectively collected from 94 patients and analyzed using 24 methylation-specific quantitative PCR assays derived from 19 CpG islands. The methylation of individual markers and various combinations of markers was compared to biopsy results. A methylation threshold for cancer classification was determined using a target specificity of 70%. The average methylation and the number of positive markers were also compared to the result of the biopsy, and the area under the receiver operating characteristic curves (AUCs) were calculated. Results: Methylation of all 19 markers was detected in FV and DRE DNAs. Combining the methylation of two or more markers improved on individual marker results. Using 6of19 methylated markers as the threshold for cancer classification yielded a specificity of 71% (95% CI, 0.57 0.86) from both DRE and FV and a sensitivity of 89% (95% CI, 0.79-0.97) from DRE and 94% (95% CI, 0.84-1.0) from FV. The negative predictive value at the 6of19 threshold was >= 90 for both DNA types. Conclusions: PCA-specific methylation was detected in both FV and DRE DNA. There was no significant difference in diagnostic accuracy at the 6of19 threshold between DRE and FV urine DNA. The results support the development of a non-invasive diagnostic test to reduce unnecessary biopsies in men with elevated PSA. The test can also provide patients with personalized recommendations based on their own methylation profile. PMID- 29988685 TI - A case of intestinal obstruction due to inflammatory changes in the small intestine from alkaline ingestion. AB - Case: Alkaline ingestion frequently causes corrosive esophagitis but rarely causes lower digestive tract injury. In this case, a 79-year-old man accidentally drank kitchen detergent. After 3 h, lower abdominal pain occurred and gradually worsened. He was taking a proton pump inhibitor after proximal gastrectomy for gastric cancer. He had local tenderness in the left lower abdomen. Abdominal computed tomography showed expansion of the small intestine, thickening of the intestinal wall, and inflammatory changes. Upper gastrointestinal endoscopy showed no obvious injury to the esophagus or stomach. Outcome: Conservative treatment with an ileus tube was undertaken for intestinal obstruction caused by alkaline ingestion. There were no complications, such as gastrointestinal perforation, and he was discharged on day 17. Conclusion: Alkaline ingestion may cause injuries not only to the upper but also to the lower digestive tract in patients who are taking proton pump inhibitors or have had gastrectomy. PMID- 29988686 TI - Mobilising knowledge between practitioners and researchers to iteratively refine a complex intervention (DAFNEplus) pre-trial: protocol for a structured, collaborative working group process. AB - Background: Randomised controlled trials (RCTs) of complex interventions often begin with a pilot phase to test the proposed methods and refine the intervention before it is trialled. Although the Medical Research Council (MRC) recommends regular communication between the practitioners delivering the intervention and the researchers evaluating it during the pilot phase, there is a lack of practical guidance about how to undertake this aspect of pre-trial work. This paper describes a novel structured process for collaborative working, which we developed to iteratively refine a complex intervention prior to an RCT. We also describe an in-built qualitative study to learn lessons about how this approach could be used by future study teams. Methods: This work forms part of a broader research programme to develop and trial a complex intervention for people with type 1 diabetes, called DAFNEplus. The intervention is being piloted in three National Health Service (NHS) diabetes centres in two waves, with refinements being incrementally implemented between each wave in response to real-time, collective learning (combining practitioner experience, process evaluation data and patient and public involvement via an advisory group). A structured 'Collaborative Working Group' (CWG) process, comprising monthly teleconferences and four strategically timed face-to-face meetings, is being used to identify and respond systematically to emerging implementation challenges and research findings. The group involves 25 members of the study team, including the multi disciplinary practitioners delivering the intervention, the research teams conducting the process evaluation, the study manager and Chief Investigator. An in-built qualitative study comprising documentary analysis of meeting materials, discourse analysis of meeting transcripts, reflexive note taking, and thematic analysis of focus groups and interviews with CWG members is being undertaken to explore how the CWG works and how its processes and procedures might be improved. Discussion: The CWG process offers a potential model for collaborative working in future pre-trial pilot phases and intervention development studies that operationalises MRC guidance to progressively develop a complex intervention and foster shared ownership through genuine collaboration. The findings from the qualitative study will provide insight into how to best support collaborative working to achieve optimal intervention design. PMID- 29988688 TI - Submucosal lipoma of the urinary bladder: Case report and systematic review. PMID- 29988687 TI - Clinical impact of nasal budesonide treatment on COPD patients with coexistent rhinitis. AB - Background: A high percentage of patients with COPD report chronic nasal symptoms. The study aims to evaluate the clinical impact of a 2-month treatment with inhaled nasal budesonide (100 ug per nostril twice daily) in patients affected by COPD with chronic rhinitis comorbidity. Patients and methods: Fifty three stable COPD patients in therapy according to the Global initiative for chronic Obstructive Lung Disease recommendations were enrolled; 49 completed the study. At enrollment (visit 0), patients underwent skin prick test and rhinoscopy. At visit 0 and after 1 month (visit 1) and 2 months (visit 2) of therapy with nasal budesonide, patients underwent spirometry, and COPD assessment test (CAT), Sinonasal Outcome Test (SNOT 22), and modified Medical Research Council dyspnea scale were administered. Differences in continuous variables, after 2 months of treatment with nasal budesonide, were evaluated using a paired t-test or Wilcoxon matched-pairs signed-ranks test. Results: Two months of treatment with nasal budesonide showed a significant statistical improvement in the total scores of CAT, SNOT 22, and modified Medical Research Council (p<0.001). A significant relationship between CAT and SNOT 22 total scores at baseline and after treatment was observed. Conclusion: The results of the present study indicate the importance of careful evaluation of the presence of chronic nasal symptoms in all COPD patients and suggest beneficial clinical effect from treatment with nasal budesonide in terms of COPD symptoms and quality of life. PMID- 29988689 TI - Trends, treatment outcomes, and determinants for attrition among adult patients in care at a large tertiary HIV clinic in Nairobi, Kenya: a 2004-2015 retrospective cohort study. AB - Background: Understanding trends in patient profiles and identifying predictors for adverse outcomes are key to improving the effectiveness of HIV care and treatment programs. Previous work in Kenya has documented findings from a rural setting. This paper describes trends in demographic and clinical characteristics of antiretroviral therapy (ART) treatment cohorts at a large urban, referral HIV clinic and explores treatment outcomes and factors associated with attrition during 12 years of follow-up. Methods: This was a retrospective cohort analysis of HIV-infected adults who started ART between January 1, 2004, and September 30, 2015. ART-experienced patients and those with missing data were excluded. The Cochran-Armitage test was used to determine trends in baseline characteristics over time. Cox proportional hazards models were used to determine the effect of baseline characteristics on attrition. Results: ART uptake among older adolescents (15-19 years), youth, and young adults increased over time (p=0.0001). Independent predictors for attrition included (adjusted hazard ratio [95% CI]) male sex: 1.30 (1.16-1.45), p=0.0001; age: 15-19 years: 1.83 (1.26 2.66), p=0.0014; 20-24 years: 1.93 (1.52-2.44), p=0.0001; and 25-29 years: 1.31 (1.11-1.54), p=0.0012; marital status - single: 1.27 (1.11-1.44), p=0.0005; and divorced/separated: 1.56 (1.30-1.87), p=0.0001; urban residence: 1.40 (1.20 1.64), p=0.0001; entry into HIV care following hospitalization: 1.31 (1.10-1.57), p=0.0026, or transfer from another facility: 1.60 (1.26-2.04), p=0.0001; initiation of ART more than 12 months after the date of HIV diagnosis: 1.36 (1.19 1.55), p=0.0001, and history of a current or past opportunistic infection (OI): 1.15 (1.02-1.30), p=0.0284. Conclusion: Although ART uptake among adolescents and young people increased over time, this group was at increased risk for attrition. Single marital status, urban residence, history of hospitalization or OI, and delayed initiation of ART also predicted attrition. This calls for focused evidence-informed strategies to address attrition and improve outcomes. PMID- 29988690 TI - A novel unbalanced translocation between the short arms of chromosomes 6 and 16 in a newborn girl: Clinical features and management. AB - The reporting of previously undescribed genetic mutations and resulting clinical phenotypes guides management and enables a more accurate prognosis for clinicians treating newborns with similar features. Previous cases of 6p deletions and 16p duplications have been described as separate entities. This patient presents with both and has a unique phenotype. PMID- 29988691 TI - Oral nutrition for left-sided malignant colonic obstruction after decompression with a transanal drainage tube: A case series of 6 patients. AB - Oral nutrition with a low-residue diet for left-sided malignant colonic obstruction after decompression with a transanal drainage tube is safe and can be considered a viable preoperative management option for appropriate patients. PMID- 29988692 TI - Intravenous lipid emulsion therapy for acute clomipramine intoxication in rats. AB - Aim: In this study, to assess the utility of lipid emulsion (ILE) therapy as a treatment option for overdoses of lipophilic drugs, we examined the detoxification effect of ILE therapy in rats that were administered overdoses of the tricyclic antidepressant clomipramine hydrochloride (CMI). Methods: Female Wistar rats were orally administered 50 mg/kg CMI five times in 2-h intervals to examine whether intralipos accelerated the elimination of CMI in the peripheral blood. Rats were divided into the intralipos (i.v. 2 g/kg intralipos) and placebo (i.v. saline) groups. The concentrations of CMI and desmethylclomipramine (DMCMI), a metabolite of CMI, in blood were measured over time by high performance liquid chromatography. We then gave the animals 100 mg/kg CMI orally to examine whether intralipos could inhibit the distribution of CMI. The CMI and DMCMI concentrations in peripheral blood, liver, and brain were measured 60 min after intralipos administration. Results: The blood concentration of CMI was significantly higher in the intralipos group than in the placebo group at 60 and 120 min. After a single administration of 100 mg/kg CMI, the ratio of the concentration of CMI in liver/serum was significantly lower in the intralipos group than in the placebo group. We also found a significantly faster elimination rate for CMI in peripheral blood in the intralipos group than in the placebo group. Conclusion: The distribution of CMI from blood to tissue was suppressed by intralipos. Therefore, ILE therapy is a promising candidate for the treatment of overdoses of lipophilic drugs. PMID- 29988693 TI - Knowledge, attitudes, and practices of breastfeeding among women visiting primary healthcare clinics on the island of Abu Dhabi, United Arab Emirates. AB - Background: The World Health Organization recommends continued breastfeeding up to 2 years of age or beyond. This study assessed breastfeeding knowledge, attitudes, and practices among women residing on the island of Abu Dhabi and identified associated factors. Methods: We conducted a cross-sectional study using a self-administered questionnaire among mothers visiting primary healthcare clinics in Abu Dhabi between November 2014 and 2015. Participants were women aged at least 18 years who had at least one child aged 2 years or younger at the time of the study. Breastfeeding knowledge, attitudes, and practices were assessed on the basis of experience with last child. Selected questions were used to develop a scaled scoring system to categorize these aspects as good, fair, or poor. Exclusive breastfeeding is defined as the act of feeding infants only breast milk since birth, without providing water, formula, or other liquid supplements. Results: The participants were 344 women. Exclusive breastfeeding for 6 months was reported by only 46 (16.9%, 95% CI 0.10, 0.17, n = 272). 79 (28.7%, n = 275) of the participants were breastfeeding and planning to continue after the child was >=24 months. Multivariate logistic regression analysis revealed that the following factors were associated with exclusive breastfeeding: mothers with female children (adjusted OR [AOR] 2.42; 95% CI 1.18, 4.97) and better breastfeeding knowledge scores (AOR 1.25; 95% CI 1.04, 1.50). The following factors were associated with less likelihood of exclusively breastfeeding: working mothers (AOR 0.29; 95% CI 0.12, 0.72), living with relatives (AOR 0.21; 95% CI 0.05, 0.81), no past exclusive breastfeeding experience (AOR 0.23; 95% CI 0.09, 0.58) and being offered readymade liquid formula in hospital (AOR 0.33; 95% CI 0.15, 0.72). The most common reason for stopping breastfeeding was insufficient breast milk production (68/89, 76%), and the most common work related reason was inadequate maternity leave (24/89, 15%). Conclusion: Although breastfeeding knowledge was generally good, breastfeeding practice was still suboptimal. Modifiable factors found to predict exclusive breastfeeding included breastfeeding knowledge and mothers' employment status. PMID- 29988694 TI - Impact of timing of breastfeeding initiation on neonatal mortality in India. AB - Background: Neonatal mortality defined as a death during the first 28 days of life and is the most critical phase of child survival. In spite of the strong evidence supporting immediate and long term health benefits of timely initiation of breastfeeding in India, only two-fifths (44%) of children receive breastfeeding within 1 h of birth. This study aims to examine the role of a behavioral factor i.e., timing of initiation of breastfeeding on neonatal deaths. Methods: Data from India Human Development Survey-II (IHDS-II), 2011-12, a nationally representative, large scale population-based dataset has been used. Sample Registration System (SRS) has been used to examine the rate of change in Neonatal Mortality Rates from the year 2011 to 2015. District Level Household & Facility Survey (DLHS-4), 2012-2013 and Annual Health Survey(AHS), 2012-13 data have been used to show the district wise distribution of women who have breastfed their child within 1 h of birth. Population Attributable fraction has been computed using binary logistic regression model for various scenarios of breastfeeding within first hour of birth. Results: Less than one fourth (21%) of children were breastfed within 1 h of birth across the different districts of India, which varies from the lowest 15% in Sarasvati of Uttar Pradesh state to the highest 94.6% in Thiruvananthapuram of Kerala state. Findings suggest when women did not breastfeed their newborn within the 1 h after his birth, the odds of neonatal deaths were increased by nearly threefold (OR 2.93; 95% CI 1.89, 4.53) in comparison with those neonates who have breastfed within 1 h of birth. Population Attributable Risk estimates that the risk of the neonatal deaths could be reduced to a maximum of 15% when all babies would expose to early breastfeeding from the present level of breastfeeding. Conclusions: We found that timely initiation of breastfeeding is beneficial for child survival within the first 28 days of birth, including all causes of mortality. Therefore, efforts in formulating an effective policy focusing on early initiation of breastfeeding are needed. PMID- 29988695 TI - Anemia and associated factors among children aged 6-23 months in Damot Sore District, Wolaita Zone, South Ethiopia. AB - Background: Anemia affects a significant part of the population in nearly every country in the globe. Iron requirements are greatest at ages 6-23 months when growth is extremely rapid and critically essential in critical times of life. Even though infants and toddlers are highly at risk, they are not considered as separate populations in the estimation of anemia. Despite this, the prevalence of anemia among under 24 months of age is still at its highest point of severity to be a public health problem in Ethiopia. There is no study that documented the magnitude of the problem and associated factors in the study area. The main aim of this study was to assess the prevalence of anemia and to identify associated factors among children 6-23 months of age. Methods: A community-based cross sectional study was carried out among 485 children of Damot Sore, South Ethiopia from March to April 2017. Data on socio-demographic, dietary, blood samples for hemoglobin level and malaria infection were collected. Both descriptive and bivariate analyses were done and all variables having a p-value of 0.25 were selected for multivariable analyses. A multivariable logistic regression model was used to isolate independent predictors of anemia at a p-value less than 0.05. A principal component analysis was used to generate household wealth score, dietary diversity score. Results: Out of 522 sampled children, complete data were captured from 485 giving a response rate of 92.91%. For altitude and persons smoking in the house adjusted prevalence of anemia was 255(52.6%). The larger proportion, 128(26.4%) of children had moderate anemia. On multivariable logistic regression analyses, household food insecurity (AOR = 2.74(95% CI: 1.62-4.65)), poor dietary diversity (AOR = 2.86(95% CI: 1.73-4.7)), early or late initiation of complementary feeding (AOR = 2.0(95% CI: 1.23-3.60)), poor breastfeeding practice (AOR = 2.6(95% CI: 1.41-4.62)), and poor utilization of folic acid by mothers (AOR = 2.75(95% CI: 1.42-5.36)) were significantly associated with anemia. Conclusion: Prevalence of anemia among children (6-23 months) was a severe public health problem in the study area. Most important predictors are suboptimal child feeding practices, household food insecurity, and poor diet. Multi-sectoral efforts are needed to improve health and interventions targeting nutrition security are recommended. PMID- 29988696 TI - The rising tide of opioid use and abuse: the role of the anesthesiologist. AB - Opioid use has risen dramatically in the past three decades. In the USA, opioid overdose has become a leading cause of unintentional death, surpassing motor vehicle accidents. A patient's first exposure to opioids may be during the perioperative period, a time where anesthesiologists have a significant role in pain management. Almost all patients in the USA receive opioids during a surgical encounter. Opioids have many undesirable side effects, including potential for misuse, or opioid use disorder. Anesthesiologists and surgeons employ several methods to decrease unnecessary opioid use, opioid-related adverse events, and side effects in the perioperative period. Multimodal analgesia, enhanced recovery pathways, and regional anesthesia are key tools as we work towards optimal opioid stewardship and the ideal of effective analgesia without undesirable sequelae. PMID- 29988697 TI - Successful treatment of pulmonary embolism-induced cardiac arrest by thrombolysis and targeted temperature management during pregnancy. AB - Background: Thrombolysis for pulmonary embolism and targeted temperature management for cardiac arrest are controversial treatments in pregnancy. Case: A 37-year-old woman at 23 weeks gestation presented with persistent dyspnea. She experienced cardiac arrest soon after arrival at the emergency room. Massive right ventricular dilatation on echocardiography during the transient return of spontaneous circulation suggested pulmonary embolism. We administered recombinant tissue plasminogen activator for suspected pulmonary embolism to successfully resuscitate the patient experiencing refractory cardiac arrest despite heparin infusion. After an additional dose of monteplase for persistent shock with remaining right ventricular dilatation on echocardiography, maternal hemodynamics dramatically improved, but fetal heart rate transiently decreased. Targeted temperature management was initiated for delayed recovery of consciousness. She fully recovered consciousness without neurological deficit. However, the fetus was aborted because of fetal hydrops. Conclusion: Thrombolysis and targeted temperature management should be considered as treatment options for pulmonary embolism-induced cardiac arrest during pregnancy. PMID- 29988698 TI - Successful fluoroless radiofrequency catheter ablation of supraventricular tachycardia during pregnancy. AB - Even in the absence of underlying heart disease, pregnancy is known to increase susceptibility supraventricular tachycardia (SVT). This brings a management challenge, mainly due to concerns about pharmacotherapy and radiation to the fetus. This case highlights the capability of using fluoroless mapping technologies to treat refractory arrhythmia cases safely and successful. PMID- 29988699 TI - Colorectal neoplasia differentially expressed: a long noncoding RNA with an imperative role in cancer. AB - Colorectal neoplasia differentially expressed (CRNDE), as a long noncoding RNA (lncRNA), has attracted increasing attention in recent years and has been documented to be at abnormally high expression in various types of cancer, such as colorectal cancer, glioma, hepatocellular carcinoma, lung cancer, and breast cancer. It could not only be used as a clinical biomarker for the early diagnosis and prognosis evaluation in a variety of cancers but also promote the development and progress of various tumor cells. Moreover, it is involved in the targeting regulation of multiple microRNAs and the activation/inhibition of multiple signaling pathways. In this review, we presented a systematic summary of the potential carcinogenicity and clinical value of CRNDE in the current evidence, so as to provide reference for early diagnosis, prognosis evaluation, and targeted therapy of various clinical cancers. PMID- 29988700 TI - Immunohistochemical assay for neuron-specific enolase, synaptophysin, and RB associated protein as a diagnostic aid in advanced retinoblastomas. AB - Purpose: We evaluated the expression of the neural markers, neuron-specific enolase, and synaptophysin, as a tool to confirm the diagnosis of retinoblastoma (RB) in undifferentiated and advanced tumors. Additionally, we determined whether the extent of RB-associated protein (pRb) expression is helpful in assessing the prognosis in RB patients. Methods: Conventional whole tissue section and tissue microarray immunohistochemistry for neuron-specific enolase, synaptophysin, and pRb were carried out in a series of 22 RBs. Results: Neuron-specific enolase and synaptophysin were expressed in 75%-100% of the tumor cells, and the staining intensity was strong. Two RBs expressed pRb in 75%-100% of the tumor cells, also with strong staining intensity. Concordance between the immunohistochemical outcomes for whole tissue staining and tissue microarray staining was 76.2% for neuron-specific enolase, 85.7% for synaptophysin, and 80.0% for pRb. Conclusion: Neuron-specific enolase and synaptophysin have the potential to be useful markers for the diagnosis of RBs. Extensive and strong pRb staining is not associated with less aggressive tumor behavior according to the pathologic classification of RBs. PMID- 29988701 TI - Multiple effects of CD40-CD40L axis in immunity against infection and cancer. AB - CD8+ cytotoxic T lymphocyte (CTL) protects against infection and cancer cells. Understanding the mechanisms involved in generation and maintenance of effective CTL responses is essential for improving disease therapy and vaccine protocols. During CTL responses, immune cells encounter several tightly regulated signaling pathways; therefore, in such a dynamic process, proper integration of critical signals is necessary to orchestrate an effective immune response. In this review, we have focused on CD40-CD40L interactions (a key signal) in the regulation of dendritic cell (DC)-T cell (CD4+ T and CD8+ T) cross-talk, rescuing CTL exhaustion, and converting DC tolerization. We have also highlighted the knowledge gap and future directions to design immunotherapies. PMID- 29988702 TI - Differences in trophic resources and niches of two juvenile predatory species in three Pangani estuarine zones, Tanzania: stomach contents and stable isotope approaches. AB - Background: Estuaries are primary habitats that serve as feeding and nursery grounds for most juvenile marine fish. However, estuaries have been used as fishing grounds by the artisanal fishers in Tanzania. The slow-growing predatory fish at juvenile and sub-adult stages are among the most frequently caught species that functionally enhance multiple linkages of energy pathways within the food web. Stomach contents and stable isotopes (delta13C and delta15N) were used to describe the nutritional sources and trophic niches between the co-existing benthic, predatory species, Carangoides chrysophrys and Epinephelus malabaricus in the Pangani estuary, Tanzania. Results: The findings indicated significant inter-specific variations in dietary composition (PERMANOVA, p = 0.001, pseudo-F = 15.81). The prey-specific index of relative importance (%PSIRI) indicated that juvenile shrimps (%PSIRI = 51.4) and Teleostei (%PSIRI = 26.5) were the main diets of C. chrysophrys while brachyura (%PSIRI = 38.8), juvenile shrimps (%PSIRI = 25.6) and Teleostei (%PSIRI = 23.3) were important diets of E. malabaricus. The isotope mixing models indicated that the predatory fish species accumulate nutrients derived from similar autotrophic sources, microphytobenthos, seagrass and macro-algae via consumption of small fish, including clupeids and mugilids. Yet, they significantly showed different isotopic niche width with varying degree of niche overlap across the longitudinal estuary gradient. This situation was justified by the presence of basal food sources among the estuarine zones that isotopically were different. Conclusion: The reliance of both predators on clupeids and mugilid preys that are trophically linked with estuarine and marine basal food sources, is an indication of low estuarine food webs' connectivity to the fresh water related food web. This situation is most likely threatening the stability of the estuarine food web structure. Management strategies and plans in place should be cautiously implemented to ensure the balanced anthropogenic freshwater use in the catchment and fishing activities, for the maintenance of the Pangani estuarine ecosystem health. PMID- 29988704 TI - Exploring parental perceptions and knowledge regarding breastfeeding practices in Rajanpur, Punjab Province, Pakistan. AB - Background: Exclusive breastfeeding is significantly associated with strong infant immunity and optimal development. The importance of breastfeeding is underestimated. Parental lack of knowledge and unhealthy practices regarding breastfeeding deprive infants of their basic right to mother's milk. In developing countries, including Pakistan, with high child mortality and malnutrition, healthy breastfeeding practices can bring positive changes in child health status. From this perspective, the present study aims to understand parents' knowledge, attitudes and practical encounters with breastfeeding practices and the factors that prevent them from adopting such practices. Methods: A qualitative study was carried out in both rural and urban settings in Rajanpur District of Punjab Province, Pakistan. We conducted 12 focus-group discussions (FGDs) that involved 38 mothers and 40 fathers with children aged under two years who were being breastfed. A thematic content analysis of data collected through FGDs was performed manually. The themes were both inductive and deductive in nature. Results: The study found that a majority of participants believed that the first thing given to an infant after birth should not be breast milk but honey, rose flower, or goat's milk from the hands of an elder in the family or a religious person. No cleanliness measures were practised in this regard. The participants had misconceptions about the benefits of colostrum, which frequently prevented it being given to newborns. Participants reported many factors, such as: insufficient milk syndrome (slow growth of infants due to insufficient daily breast milk intake), a mother's high workload, lack of social support, the influence of culturally designated advisors, and the promotion and marketing strategies of infant formula companies, that undermined exclusive breastfeeding efforts and encouraged mothers to switch to infant formula. Conclusions: Culturally acceptable and integrated public health interventions are needed to improve the breastfeeding-related health literacy and practices of parents, grandparents and communities. This will ultimately reduce the high infant mortality and malnutrition rates in Pakistan. PMID- 29988705 TI - The characteristics of patients with hypermagnesemia who underwent emergency hemodialysis. AB - Aim: This study aimed to clarify the characteristics of patients who presented with severe hypermagnesemia and subsequently underwent emergency hemodialysis. Methods: We investigated the age, gender, complications, clinical symptoms, causal drugs, electrocardiogram findings, and laboratory data of 15 patients. Results: Magnesium oxide had been administered in all cases and 14 patients were over 65 years old. The male : female ratio was 6:9. Chief complaints included a disturbance of consciousness, hypotension, bradycardia, and respiratory failure. The median serum magnesium value before hemodialysis was 6.0 (3.7-18.6) mg/dL. The daily dosage of magnesium oxide was <= 2.0 g in 12 cases. The median serum creatinine value before hemodialysis was 5.39 (0.54-10.29) mg/dL. However, in two cases, the creatinine value was not elevated. Complications of acute kidney injury exacerbated the hypermagnesemia in nine cases. Conclusions: We recommend that the serum magnesium value should be measured in older patients who are taking magnesium oxide and are showing signs and symptoms of a disturbance of consciousness, hypotension, bradycardia, and respiratory failure of an uncertain etiology, even if the serum creatinine value is not elevated or the dosage of magnesium oxide is within recommended levels. PMID- 29988703 TI - Association of dietary patterns with continuous metabolic syndrome in children and adolescents; a nationwide propensity score-matched analysis: the CASPIAN-V study. AB - Objective: This study aims to determine the association of dietary patterns with metabolic syndrome (MetS) and its components in children and adolescents. Methods: This nationwide study was conducted in 2015 among 4200 students aged 7 18 years, who lived in 30 provinces in Iran. The analysis was conducted based on the propensity score using a matched case-control study design. Three dietary patterns were obtained conducting a principal component analysis with a varimax rotation on 16 dietary groups. Continuous MetS score was computed by standardizing the residuals (z-scores) of MetS components by regressing them according to age and sex. The gold standard diagnosis of MetS was considered based on the International Diabetes Federation criteria. Moreover, for the purpose of data analysis, matched logistics analysis was used. Results: The study participants consisted of 3843 children and adolescents (response rate 91.5%) with mean (SD) age of 12.45 (3.04) years. Totally 49.4% of students were girls and 71.4% lived in urban areas. Three dietary patterns were obtained: Healthy, Western, and Sweet. Prevalence of MetS was 5% (boy 5.5 and girl 4.5%). Results of multivariate analysis show that students with Sweet dietary patterns were at higher risk for abdominal obesity (OR 1.29; 95% CI 1.01-1.66), elevated blood pressure (OR 1.35; 95% CI 1.01-1.81) and MetS (OR 1.33; 95% CI 1.02-1.74). The two other dietary patterns were not associated with MetS and its components. Conclusion: Sweet dietary pattern increase the risk of MetS and some its components in Iranian children and adolescents. This finding provides valuable information for effective preventive strategies of MetS based on diet rather than medication to maintain healthy lifestyle habits. PMID- 29988706 TI - Is black tar heroin use associated with wound botulism? A report of two Hispanic patients. AB - Wound botulism is a potentially lethal condition that can cause paralysis. Its association with black tar heroin is a well-established fact. It is essential to alert clinicians in recognizing the patients with history of injection drug abuse presenting with clinical features of botulism early on admission for prompt diagnosis and treatment. PMID- 29988707 TI - ICEAGE (Incidence of Complications following Emergency Abdominal surgery: Get Exercising): study protocol of a pragmatic, multicentre, randomised controlled trial testing physiotherapy for the prevention of complications and improved physical recovery after emergency abdominal surgery. AB - Background: Postoperative complications and delayed physical recovery are significant problems following emergency abdominal surgery. Physiotherapy aims to aid recovery and prevent complications in the acute phase after surgery and is commonplace in most first-world hospitals. Despite ubiquitous service provision, no well-designed, adequately powered, parallel-group, randomised controlled trial has investigated the effect of physiotherapy on the incidence of respiratory complications, paralytic ileus, rate of physical recovery, ongoing need for formal sub-acute rehabilitation, hospital length of stay, health-related quality of life, and mortality following emergency abdominal surgery. We hypothesise that an enhanced physiotherapy care package of additional education, breathing exercises, and early rehabilitation prevents postoperative complications and improves physical recovery following emergency abdominal surgery compared to standard care alone. Methods: The Incidence of Complications following Emergency Abdominal surgery: Get Exercising (ICEAGE) trial is a pragmatic, investigator initiated, multicentre, patient- and assessor-blinded, parallel-group, active placebo controlled randomised trial, powered for superiority. ICEAGE will compare standard care physiotherapy to an enhanced physiotherapy care package in 288 participants admitted for emergency abdominal surgery at three Australian hospitals. Participants will be randomised using concealed allocation to receive either standard care physiotherapy (education, single session of coached breathing exercises, and daily early ambulation for 15 min) or an enhanced physiotherapy care package (education, twice daily coached breathing exercises for a minimum 2 days, and 30 min of daily supervised early rehabilitation for minimum five postoperative days). The primary outcome is a respiratory complication within the first 14 postoperative hospital days assessed daily with standardised diagnostic criteria. Secondary outcomes include referral for sub acute rehabilitation services, discharge destination, paralytic ileus, hospital length of stay and costs, intensive care unit utilisation, 90-day patient reported complications and health-related quality of life and physical capacity, and mortality at 30 days and at 1 year following surgery. Discussion: The morbidity, mortality, and fiscal burdens following emergency abdominal surgery are some of the worst within surgery. Physiotherapy may be an effective, low cost, minimal harm intervention to improve outcomes and reduce hospital utilisation following this surgery type. ICEAGE will test the benefits of this commonly provided intervention within a methodologically robust, multicentre, double-blinded, active-placebo controlled randomised trial. Trial registration: ACTRN 12615000318583. Registered 8 April 2015. PMID- 29988710 TI - Correction to: Pelagibaca bermudensis promotes biofuel competence of Tetraselmis striata in a broad range of abiotic stressors: dynamics of quorum-sensing precursors and strategic improvement in lipid productivity. AB - [This corrects the article DOI: 10.1186/s13068-018-1097-9.]. PMID- 29988708 TI - New application of anti-TLR monoclonal antibodies: detection, inhibition and protection. AB - Monoclonal antibody (mAb) is an essential tool for the analysis in various fields of biology. In the field of innate immunology, mAbs have been established and used for the study of Toll-like receptors (TLRs), a family of pathogen sensors that induces cytokine production and activate immune responses. TLRs play the role as a frontline of protection against pathogens, whereas excessive activation of TLRs has been implicated in a variety of infectious diseases and inflammatory diseases. For example, TLR7 and TLR9 sense not only pathogen-derived nucleic acids, but also self-derived nucleic acids in noninfectious inflammatory diseases such as systemic lupus erythematosus (SLE) or hepatitis. Consequently, it is important to clarify the molecular mechanisms of TLRs for therapeutic intervention in these diseases. For analysis of the molecular mechanisms of TLRs, mAbs to nucleic acid-sensing TLRs were developed recently. These mAbs revealed that TLR7 and TLR9 are localized also in the plasma membrane, while TLR7 and TLR9 were thought to be localized in endosomes and lysosomes. Among these mAbs, antagonistic mAbs to TLR7 or TLR9 are able to inhibit in vitro responses to synthetic ligands. Furthermore, antagonistic mAbs mitigate inflammatory disorders caused by TLR7 or TLR9 in mice. These results suggest that antagonistic mAbs to nucleic acid-sensing TLRs are a promising tool for therapeutic intervention in inflammatory disorders caused by excessive activation of nucleic acid-sensing TLRs. Here, we summarize the molecular mechanisms of TLRs and recent progresses in the trials targeting TLRs with mAbs to control inflammatory diseases. PMID- 29988709 TI - Could sodium imbalances predispose to postoperative venous thromboembolism? An analysis of the NSQIP database. AB - Background: Hyponatremia is common among patients with pulmonary embolism, while hypernatremia increases the risk of venous thromboembolism (VTE). Our objective was to evaluate the association between sodium imbalances and the incidence of VTE and other selected perioperative outcomes. Methods: We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and identified 1,108,704 patients undergoing major surgery from 2008 to 2012. We evaluated 30-day perioperative outcomes, including mortality and cardiac, respiratory, neurological, urinary, wound, and VTE outcomes. Multivariate logistic regressions were used to estimate the odds of 30-day perioperative outcomes. Results: Compared with the normal sodium group, in which VTE occurred in 1.0% of patients, 1.8% of patients in the hyponatremia group (unadjusted odds ratio (OR) 1.84) and 2.4% of patients in the hypernatremia group (unadjusted OR 2.49) experienced VTE. Crude mortality was 1.3% in the normal sodium group, 4.9% in the hyponatremia group (unadjusted OR 3.93) and 8.4% in the hypernatremia group (unadjusted OR 7.01). Crude composite morbidity was 7.1% for the normal sodium group, 16.7% for the hyponatremia group (unadjusted OR 2.63) and 20.6% for the hypernatremia group (unadjusted OR 3.43). After adjusting for potential confounders, hyponatremia and hypernatremia remained significantly and independently associated with an increased risk of VTE (adjusted OR 1.43 and 1.56, respectively), mortality (adjusted OR 1.39 and 1.39, respectively) and composite morbidity (adjusted OR 2.15 and 3.34, respectively). Conclusions: Pre-operative hyponatremia and hypernatremia are potential prognostic markers for perioperative 30-day morbidity, mortality and VTE. PMID- 29988711 TI - Agitated behaviors among elderly people with dementia living in their home in Taiwan. AB - Background/aims: Limited research has been conducted on agitated behavior in Taiwan and dementia among community-dwelling elderly. Therefore, this study focused on community elderly with dementia and a factor analysis of an inventory of their agitated behaviors was conducted. Patients and methods: Participants (N=221) completed the Chinese Cohen-Mansfield Agitation Inventory, community form. Item analysis and exploratory factor analysis assessed reliability, validity, and the underlying factor structure. Results: Five factors were extracted and accounted for 44.53% of the total variance. This study classified agitated behaviors into 5 main subtypes: physically agitated behaviors, destructive behaviors, verbally agitated behaviors, handling things behavior, and aggressive behaviors. Conclusion: The results indicate that differences in the agitated behavior of elderly with dementia exist with respect to cultural background and setting. This novel research and its findings serve as a reference for assessing the agitated behaviors of elderly with dementia living in their homes. Applications may exist for other countries with Chinese/Taiwanese populations. PMID- 29988712 TI - The mechanism of blood flow during chest compressions for cardiac arrest is probably influenced by the patient's chest configuration. AB - Aim: Mechanical assist devices are sometimes needed during resuscitation efforts of patients with prolonged cardiac arrest. Two such devices, the AutoPulse and the LUCAS, have different mechanisms of action. We propose that the effectiveness of mechanical assist devices is somewhat dependent on the configuration and compliance of the patient's chest wall. Methods: A previous study of patients with out-of-hospital cardiac arrest in Arizona reported that survivors were younger and many were observed to have narrow anterior-posterior chest diameters. These observations suggest that the predominant mechanism of blood flow during cardiopulmonary resuscitation of individuals with primary cardiac arrest is influenced by the patient's anterior-posterior chest diameter and compliance. It is proposed that in older individuals with an increased anterior-posterior chest diameter and decreased chest compliance that the AutoPulse, which works by increasing intrathoracic pressures, may be more effective. In contrast, the LUCAS device, which works predominately by compression of the sternum, is probably more effective in patients with narrower anterior-posterior diameters and a more compliant chest. Results: These hypotheses need to be confirmed by researchers who not only have access to the lateral chest roentgenograms of patients with cardiac arrest, to determine their anterior-posterior chest diameter, but also to the type of mechanical device that was used during resuscitation efforts and their patient's survival. If the observations herein proposed are confirmed, hospitals and paramedics may ideally need to have one of each type of mechanical chest compression unit and select the one to use depending on the patient's age and anterior-posterior chest diameter. Conclusions: The mechanism of blood flow in patients with cardiac arrest is predominantly secondary to cardiac compression in younger patients with narrow anterior chest diameters and predominately secondary to the thoracic pump mechanism in older patients with emphysema. PMID- 29988713 TI - Simulation study of a low-tech and reliable identification coding method for mass casualties. AB - Aim: To evaluate the ease of use, reliability, and duplication risks of a new identification (ID) coding method, which works for mass casualty events such as disaster scenes. Methods: The new ID code consisted of 16 alphanumeric characters: seven characters for the responder's information and nine for the casualty, which can be created in a very low-tech manner without using any electronic devices. A simulated triage was carried out for virtual causalities by students of the same grade at our university's medical school. Each participant was instructed to triage and create IDs for the same 10 virtual casualties. Eighty-nine participants created a total of 890 IDs, which were examined for correct coding and ID duplication rates. Results: Despite situations in which the risk of duplication might be considered high, complete duplication of IDs occurred in only one case (0.2%), and the other 888 IDs (99.8%) were unique. The simulation was done in a reasonable amount of time without any confusion. Conclusions: In the mass casualty incident triage simulation, our new coding method proved easy and useful in creating IDs with an extremely low duplication rate. To develop this method for broader use, further evaluation is needed in more simulations and real disaster situations. PMID- 29988714 TI - Anti-NMDAR encephalitis in a patient with Crohn disease receiving adalimumab. PMID- 29988715 TI - Intake of glucosinolates and risk of coronary heart disease in three large prospective cohorts of US men and women. AB - Importance: Glucosinolates, a group of phytochemicals abundant in cruciferous vegetables, may have cardioprotective properties. However, no prospective study has evaluated the association of intake of glucosinolates with the risk of coronary heart disease (CHD). Objective: The objective of the study was to evaluate the association between the intake of glucosinolates and incident CHD in US men and women. Design: Prospective longitudinal cohort study. Setting: Health professionals in the USA. Participants: We followed 74,241 women in the Nurses' Health Study (NHS; 1984-2012), 94,163 women in the NHSII (1991-2013), and 42,170 men in the Health Professionals Follow-Up Study (1986-2012), who were free of cardiovascular disease and cancer at baseline. Exposure: Glucosinolate intake was assessed using validated semi-quantitative food frequency questionnaires at baseline and updated every 2-4 years during follow-up. Main outcome measures: Incident cases of CHD were confirmed by medical record review. Results: During 4,824,001 person-years of follow-up, 8,010 cases of CHD were identified in the three cohorts. After adjustment for major lifestyle and dietary risk factors of CHD, weak but significantly positive associations were observed for glucosinolates with CHD risk when comparing the top with bottom quintiles (hazard ratio [HR]:1.09; 95% CI: 1.01, 1.17; Ptrend<0.001). Higher intakes of three major subtypes of glucosinolates were consistently associated with a higher CHD risk, although the association for indolylglucosinolate did not achieve statistical significance. Regarding cruciferous vegetable intake, participants who consumed one or more servings per week of Brussels sprouts (HR: 1.16; 95% CI: 1.06, 1.26; P<0.001) and cabbage (HR: 1.09; 95% CI: 1.02, 1.17; P=0.009) had a significantly higher CHD risk than those who consumed these cruciferous vegetables less than once per month. Conclusion and relevance: In these three prospective cohort studies, dietary glucosinolate intake was associated with a slightly higher risk of CHD in US adults. These results warrant replications in further studies including biomarker-based studies. Further studies are needed to confirm these findings and elucidate mechanistic pathways that may underlie these associations. PMID- 29988716 TI - Exploring patients' experiences of the whiplash injury-recovery process - a meta synthesis. AB - Purpose: The aim of this study was to conduct a meta-synthesis to analyze qualitative research findings and thereby understand patients' experiences of whiplash-associated disorders (WAD) and the injury-recovery process. Materials and methods: A qualitative meta-synthesis, which is an interpretive integration of existing qualitative findings, was performed. The databases PubMed, PsychINFO, Scopus, and Web of Science were searched. The Critical Assessment Skills Programme was used to assess the quality of the included studies. Results: Four studies were included. The synthesis resulted in several codes, 6 categories, and 3 themes (distancing from normalcy, self-efficacy in controlling the life situation after the injury, and readjustment and acceptance) that described the participants' pain beliefs, their WAD-related life situation and their future expectations and acceptance. Changes in self-image were difficult to cope with and likely led to perceived stigmatization. Struggling with feelings of loss of control appeared to lead to low confidence and insecurity. Focusing on increasing knowledge and understanding the pain and its consequences were believed to lead to better strategies for handling the situation. Furthermore, recapturing life roles, including returning to work, was challenging, but an optimistic outlook reinforced symptom improvements and contributed to feelings of happiness. Conclusion: The results of the present study provide a comprehensive understanding of patients' complex, multifaceted experiences of WAD, and the injury-recovery process. The findings can guide us in the development of new ways to evaluate and manage WAD. The results also indicate that a more patient centered approach is needed to determine the depth and breadth of each patient's problems. PMID- 29988717 TI - Some reflections on problem-based learning medical curriculum. PMID- 29988719 TI - Tribal Odisha Eye Disease Study (TOES # 2) Rayagada school screening program: efficacy of multistage screening of school teachers in detection of impaired vision and other ocular anomalies. AB - Purpose: To describe program planning and effectiveness of multistage school eye screening and assess accuracy of teachers in vision screening and detection of other ocular anomalies in Rayagada District School Sight Program, Odisha, India. Methods: This multistage screening of students included as follows: stage I: screening for vision and other ocular anomalies by school teachers in the school; stage II: photorefraction, subjective correction and other ocular anomaly confirmation by optometrists in the school; stage III: comprehensive ophthalmologist examination in secondary eye center; and stage IV: pediatric ophthalmologist examination in tertiary eye center. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of teachers for vision screening and other ocular anomaly detection were calculated vis-a-vis optometrist (gold standard). Results: In the study, 216 teachers examined 153,107 (95.7% of enrolled) students aged 5-15 years. Teachers referred 8,363 (5.4% of examined) students and 5,990 (71.6% of referred) were examined in stage II. After prescribing spectacles to 443, optometrists referred 883 students to stage III. The sensitivity (80.51%) and PPV (93.05%) of teachers for vision screening were high, but specificity (53.29%) and NPV (26.02%) were low. The specificity and NPV, in general, were higher in ocular anomaly detection but varied from disease to disease. Conclusion: Multistage school screening is rapid and comprehensive in a resource-limited community. Regular training and periodic reinforcement of teachers for vision assessment and other ocular anomaly identification are required for further success of the strategy. PMID- 29988720 TI - A new species of deep-water spider crab of the genus Paramaya De Haan, 1837 from the Bay of Bengal, India (Crustacea, Brachyura, Majidae). AB - The identity of the majid species of Paramaya De Haan, 1837, in the Indian Ocean is clarified with the collection of fresh specimens from the Bay of Bengal. Previously identified as P. spinigera (De Haan, 1837) which is known only from Japan, Taiwan, and Korea, the material from eastern India is here referred to a new species, P. mullisp. n. The new species can easily be distinguished from all congeners by its relatively shorter pseudorostral and carapace spines, more swollen branchial regions, distinctly granulated male thoracic sternum, and the G1 is not prominently curved with the dorsal projection on the sub distal part short and the tip rounded. PMID- 29988718 TI - High prevalence of bronchiectasis in emphysema-predominant COPD patients. AB - Background: COPD has been identified as an etiology or related disease of bronchiectasis, and bronchiectasis has been classified as a comorbidity of COPD. In this study, we investigated the prevalence of bronchiectasis in different phenotypes of COPD subjects and the correlation between bronchiectasis and different phenotypes, especially emphysema. Methods: COPD patients were recruited from April 2012 to December 2015. The presence of bronchiectasis and related information were statistically analyzed. COPD subjects were separated into subgroups in two ways: COPD with and without bronchiectasis groups and emphysema predominant (emphysema index, EI>=9.9%) and non-emphysema-predominant (EI<9.9%) groups. Results: In total, 1,739 COPD patients were incorporated into the study, among which 140 cases (8.1%) were accompanied with radiological bronchiectasis. COPD patients with concomitant bronchiectasis presented worse pulmonary function (FEV1% predicted, P<0.001), higher EI (15.0% vs 13.4%, P<0.001), and higher proportion of pulmonary hypertension and cor pulmonale (6.4% vs 2.4%, P=0.005 and 23.6% vs 16.1%, P=0.022) than patients without bronchiectasis. Of all the COPD patients, 787 with EI data were divided into emphysema-predominant (n=369) and non-emphysema-predominant groups (n=418). The proportion of bronchiectasis was 16.5% and 10.3% (P=0.01), respectively. Severity of bronchiectasis increased as the degree of airflow limitation (r=-0.371, P<0.001) and emphysema increased (r=0.226, P=0.021). After adjusting confounding factors, FEV1% predicted (OR, 1.636; 95% CI, 1.219-2.197; P=0.001) and EI (OR, 1.993; 95% CI, 1.199-3.313; P=0.008) were significantly related with the presence of bronchiectasis in COPD patients. Conclusion: The proportion of bronchiectasis is higher in emphysema predominant COPD subjects. Emphysema measured by EI and FEV1% predicted are independent predictors for bronchiectasis in COPD subjects, while the underlying mechanism deserves further investigation. PMID- 29988721 TI - Defining the gut microbiota in individuals with periodontal diseases: an exploratory study. AB - Background: This exploratory study aimed to characterize the gut microbiome of individuals with different periodontal conditions, and correlate it with periodontal inflammation and tissue destruction. Methods: Stool samples were obtained from individuals presenting periodontal health (PH = 7), gingivitis (G = 14) and chronic periodontitis (CP = 23). The intestinal microbiome composition was determined by Illumina MiSeq sequencing. Results: A lower alpha-diversity in the gut microbiome of individuals with CP was observed, although no significant difference among groups was found (p > 0.01). Firmicutes, Proteobacteria, Verrucomicrobia and Euryarchaeota were increased, whereas Bacteroidetes were decreased in abundance in patients with periodontitis compared to PH. Prevotella (genus), Comamonadaceae (family) and Lactobacillales (order) were detected in higher numbers in G, while Bacteroidales (order) was predominant in PH (p < 0.01). Significant correlations (rho = 0.337-0.468, p < 0.01) were found between OTUs representative of periodontal pathogens and attachment loss. Mogibacteriaceae, Ruminococcaceae and Prevotella were able to discriminate individuals with periodontal diseases from PH (overall accuracy = 84%). Oral taxa were detected in high numbers in all stool samples. Conclusions: Individuals with periodontal diseases present a less diverse gut microbiome consistent with other systemic inflammatory diseases. High numbers of oral taxa related to periodontal destruction and inflammation were detected in the gut microbiome of individuals regardless of periodontal status. PMID- 29988722 TI - The relationship between sleep disturbance and health status in patients with COPD. AB - Introduction: The detection of insomnia in patients with COPD is assumed to be significantly lower than the actual prevalence. In this study, we investigated the prevalence of insomnia and the relationship between insomnia and health status in patients with COPD using two fairly simple and straightforward questionnaires: COPD assessment test (CAT) and insomnia severity index (ISI). Patients and methods: A cross-sectional study was conducted using data from patients undergoing treatment for COPD at St Paul's Hospital, The Catholic University of Korea, between December 2015 and August 2016. Patients were classified into three groups according to the ISI score: a "clinical insomnia" group (ISI>=15), a "subthreshold insomnia" group (ISI 8-15), and a "non-insomnia" group (ISI<8). Clinical parameters including past medical history, pulmonary function tests, and questionnaire data were collected and analyzed. Results: A total of 192 patients were recruited, of which 25.0% were found to have clinical insomnia (ISI>=8). Insomnia severity was related to all CAT component items except for cough, and patients with higher CAT scores generally had more severe insomnia. Logistic regression analysis revealed that CAT score was significantly associated with insomnia in these patients (odds ratio, 1.23; 95% CI, 1.13-1.34; p<0.0001). CAT score was also a significant predictor of insomnia (area under receiver operating characteristic curve, 0.779; p<0.001). The optimal predictive cutoff value was a CAT score >14, giving a sensitivity and specificity of 66.7% and 71.5%, respectively. Conclusion: CAT score was closely related to insomnia severity in patients with COPD. The use of CAT scores to assess for the presence and severity of insomnia in these patients may allow for better detection and management and improve clinical practice. PMID- 29988724 TI - Effect of teacher's working conditions on voice disorder in Korea: a nationwide survey. AB - Background: Korean teacher's working conditions are deteriorating. There is concern about the deterioration of teachers' health and voice disorder is one of the most common problems. Teacher's vocal health is important for them and their students. The aim of the present study was to investigate working conditions that may affect voice disorders. Methods: In all, 79 primary and secondary schools were randomly selected for a nationwide school system survey (N = 3345). In 64 schools, 1617 (48.3%) teachers participated via a postal self-report questionnaire from June 2016 to August 2016. After applying inclusion and exclusion criteria, data from 1301 teachers' were used for analysis. Multiple logistic regression was used to investigate the associations between general, work-related factors, and frequent voice disorders (fVDs) to estimate the adjusted odds ratio(aOR). Results: Teachers who reported voice symptoms more than once a week (fVD) made up 11.6%. In a multiple logistic regression, fVD was significantly associated with female, difficulty in applying for sick leave as needed, music teachers (primary school), and less than 6 h of sleep per day (primary school). The aOR for fVD was 2.72 (0.83-8.10) in the longest working hours group (> 52 h/wk) among the primary school teachers, and 1.90 (0.80-4.73) in the longest class hour group (>= 20 h/wk), 1.52 (0.90-2.62) in homeroom teachers among the secondary school teachers, but not statistically significant. Conclusions: Korean teachers' working conditions are associated with fVDs. The school health system must take steps to prevent and treat voice disorders of teachers. PMID- 29988723 TI - PathCORE-T: identifying and visualizing globally co-occurring pathways in large transcriptomic compendia. AB - Background: Investigators often interpret genome-wide data by analyzing the expression levels of genes within pathways. While this within-pathway analysis is routine, the products of any one pathway can affect the activity of other pathways. Past efforts to identify relationships between biological processes have evaluated overlap in knowledge bases or evaluated changes that occur after specific treatments. Individual experiments can highlight condition-specific pathway-pathway relationships; however, constructing a complete network of such relationships across many conditions requires analyzing results from many studies. Results: We developed PathCORE-T framework by implementing existing methods to identify pathway-pathway transcriptional relationships evident across a broad data compendium. PathCORE-T is applied to the output of feature construction algorithms; it identifies pairs of pathways observed in features more than expected by chance as functionally co-occurring. We demonstrate PathCORE-T by analyzing an existing eADAGE model of a microbial compendium and building and analyzing NMF features from the TCGA dataset of 33 cancer types. The PathCORE-T framework includes a demonstration web interface, with source code, that users can launch to (1) visualize the network and (2) review the expression levels of associated genes in the original data. PathCORE-T creates and displays the network of globally co-occurring pathways based on features observed in a machine learning analysis of gene expression data. Conclusions: The PathCORE-T framework identifies transcriptionally co-occurring pathways from the results of unsupervised analysis of gene expression data and visualizes the relationships between pathways as a network. PathCORE-T recapitulated previously described pathway-pathway relationships and suggested experimentally testable additional hypotheses that remain to be explored. PMID- 29988725 TI - Availability of right femoral vein as a route for tunneled hemodialysis catheterization. AB - Purpose: This study was performed to investigate the primary patency rate and catheter-related problems associated with use of the femoral vein as a route for tunneled hemodialysis catheterization compared with those of the right internal jugular vein as the first-choice route in patients undergoing maintenance hemodialysis. Patients and methods: Twenty-two patients underwent placement of indwelling tunneled hemodialysis catheters in the right internal jugular vein as the first option for maintenance hemodialysis, and 20 patients underwent placement in the right femoral vein as the second option. The primary patency rate of the catheters and catheter-related problems at 1, 3, 6, and 12 months after placement were investigated. Results: The 1-, 3-, 6-, and 12-month primary patency rates of the tunneled hemodialysis catheters in the right internal jugular vein were 95.5%, 95.5%, 81.3%, and 58.3%. The primary patency rates of the catheters in the right femoral vein were 95.0%, 89.5%, 86.7%, and 66.7%. There were no statistically significant differences in the primary patency rates at 1, 3, 6, and 12 months or in catheter-related problems between the right internal jugular vein and right femoral vein. Conclusion: The primary patency rate and catheter-related problems of indwelling tunneled hemodialysis catheters placed in the right femoral vein were not different from those in the right internal jugular vein in patients undergoing maintenance hemodialysis. These results suggest that the right femoral vein might be a useful option for placement of indwelling tunneled hemodialysis catheters in patients undergoing maintenance hemodialysis. PMID- 29988726 TI - Knowledge and attitude toward anaphylaxis during local anesthesia among dental practitioners in Chennai - a cross-sectional study. AB - Objective: Anaphylaxis is one of the local anesthetic dental emergencies that lead to morbidity and mortality. Hence, this study aimed to assess the knowledge and attitude of dental practitioners in Chennai toward managing anaphylaxis in patients who are given local anesthesia. Participants and methods: Seventeen questions were formulated regarding anaphylaxis reactions and its treatment. The questions were given to a random selection of dentists practicing in private clinics in Chennai. Results: Two hundred dentists responded to the questionnaire. The results indicated that the majority of the participants had knowledge of one or more symptoms relating to anaphylaxis. However, none of the participants demonstrated that they knew about all symptoms relating to anaphylaxis. The results also did not vary with age. Only 62% of the dentists surveyed were equipped with emergency kits in their clinic. Conclusion: The present study has revealed the lack of knowledge among dentists in Chennai in relation to anaphylactic reactions and its management. Knowledge of practicing dentists in this area can be increased by providing continuing education programs consisting of workshops and hands-on courses. PMID- 29988727 TI - Nuclear factor-kappaB p65 regulates glutaminase 1 expression in human hepatocellular carcinoma. AB - Background: Glutaminase (GLS), the key enzyme that catalyzes glutamine catabolism, facilitates the production of energy, building blocks, and factors resisting stresses. Two isoforms of GLS have been identified: GLS1 and GLS2. Elevated GLS1 contributes to tumorigenesis and tumor progression. This study investigates the molecular mechanism by which GLS1 is regulated in human hepatocellular carcinoma (HCC). Methods: Online databases were investigated to search for factors that co-overexpress with GLS1. siRNA knockdown or chemical compounds were utilized to manipulate the activation or inactivation of nuclear factor-kappaB (NF-kappaB) p65 signaling. Both the mRNA and protein levels of GLS1 were detected. The biological and clinical importance of p65-GLS1 in HCC was also demonstrated. Results: NF-kappaB p65 regulates GLS1 expression in HCC cells. Knockdown or suppression of GLS1 compromises HCC cell proliferation. Elevated GLS1 expression correlates with neoplasm histological grade, and the dysregulation of p65-GLS1 is associated with poor prognosis in human HCC patients. Conclusion: GLS1 can be developed as a diagnostic and therapeutic target for human HCC. PMID- 29988728 TI - A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells. AB - Purpose: The combination of oral derived stem cells and 3-D scaffolds is considered advantageous in bone repair. In particular, collagen membranes possess ideal biological properties and can support infiltration and proliferation of osteoblasts, promoting bone regeneration. Our study aimed to develop a new biocompatible osteogenic construct composed of a commercially available collagen membrane (Evolution [Evo]), human periodontal-ligament stem cells (hPDLSCs) enriched with extracellular vesicles (EVs), or polyethylenimine (PEI)-engineered EVs (PEI-EVs). Methods: Osteogenic ability and expression of osteogenic genes were evaluated in vitro in hPDLSCs cultured with or without Evo, with Evo and EVs, or PEI-EVs. In addition, the bone-regeneration capacity of Evo, Evo enriched with hPDLSCs, Evo enriched with hPDLSCs and EVs/PEI-EVs was investigated in rats subjected to calvarial defects. Results: Our results showed that Evo enriched with EVs and PEI-EVs showed high biocompatibility and osteogenic properties in vitro and in vivo. In addition, quantitative reverse-transcription polymerase chain reaction demonstrated the upregulation of osteogenic genes, such as TGFB1, MMP8, TUFT1, TFIP11, BMP2, and BMP4, in the presence of PEI-EVs. Upregulation of BMP2/4 was confirmed for Evo enriched with PEI-EVs and hPDLSCs both in vitro by Western blot and in vivo by immunofluorescence. Conclusion: Our results indicated that Evo enriched with hPDLSCs and PEI-EVs is able to promote a bone-regeneration process for the treatment of calvarium and ossification defects caused by accidental or surgery trauma. In particular, PEI-EVs had a significant role in activation of the osteogenic process. PMID- 29988730 TI - Group-based patient education delivered by nurses to meet a clinical standard for glaucoma information provision: the G-TRAIN feasibility study. AB - Background: Globally, glaucoma is the leading cause of irreversible blindness. However, many patients with glaucoma do not understand their disease which reportedly impacts on their ability to manage their condition successfully. The aim of this feasibility study was to undertake research to inform a future randomised controlled trial of the effectiveness of group-based education for patients to improve adherence to glaucoma eyedrops. Methods: Key objectives were to understand current provision of information during routine nurse-led glaucoma consultations, to investigate if it is possible to deliver patient information in line with a clinical standard by training nurses to deliver group-based education in multiple hospital sites and to explore the acceptability of group-based education to nurses and patients compared with usual information provision in consultations. This study employed quantitative and qualitative research methods situated in a sequential design across three hospitals in England and Wales. Current provision of information given to 112 patients with glaucoma across the three hospitals was observed and compared to that recommended in a clinical standard. Then, six nurses were trained to deliver group-based education. Following which, the level of information was assessed again in line with the clinical standard as the group-based education programme was delivered in the three hospitals to 16 patients in total. All nurses and six patients were interviewed to explore experiences of the group-based education sessions. Results: The main area of information provided during routine nurse-led consultations concerned the management of glaucoma and that least covered was about prognosis of the disease and information about support services. Nurses were trained to implement group-based education for patients. Information was provided more often by the nurses about all the items of the clinical standard when delivering group based education. However, patients' motivation to attend were negatively impacted mainly by delays in delivering the education for the third phase and because the majority were established patients. Nurses and patients who participated found it useful and comprehensive. Conclusion: This feasibility study demonstrates that the proposed intervention for the randomised controlled trial, the group-based education, goes beyond current information provision, is in line with that articulated by a clinical standard and is implementable across several sites. This bodes well for a future randomised trial, but the following needs to be taken into account to ensure success: independent implementation of the research, training and delivery at each site, timely provision of the patient education, inclusion of new patients, and consistently delivered nurse training. Trial registration: International Standard Randomised Controlled Trial number, ISRCTN91188805. PMID- 29988729 TI - IRX-2 natural cytokine biologic for immunotherapy in patients with head and neck cancers. AB - Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive malignancy characterized by tumor-driven immune-system abnormalities that contribute to disease progression. For patients with surgically resectable HNSCC, treatment is often curative surgery followed by irradiation or chemoradiation in high-risk settings to reduce the risk of recurrence. Poor survival and considerable morbidity of current treatments suggest the need for new therapeutic modalities that can improve outcomes. Defects in antitumor immunity of HNSCC patients include suppressed dendritic cell (DC) maturation, deficient antigen-presenting cell function, compromised natural killer (NK)-cell cytotoxicity, increased apoptosis of activated T lymphocytes, and impaired immune-cell migration to tumor sites. Strategies for relieving immunosuppression and restoring antitumor immune functions could benefit HNSCC patients. IRX-2 is a primary cell-derived biologic consisting of physiologic levels of T-helper type 1 cytokines produced by stimulating peripheral blood mononuclear cells of normal donors with phytohemagglutinin. The primary active components in IRX-2 are IL2, IL1beta, IFNgamma, and TNFalpha. In vitro, IRX-2 acts on multiple immune-system cell types, including DCs, T cells, and NK cells, to overcome tumor-mediated immunosuppression. In clinical settings, IRX-2 is administered as part of a 21 day neoadjuvant regimen, which includes additional pharmacologic agents (low-dose cyclophosphamide, indomethacin, and zinc) to promote anticancer immunoresponses. In a Phase IIA trial in 27 patients with surgically resectable, previously untreated HNSCC, neoadjuvant IRX-2 increased infiltration of T cells, B cells, and DCs into tumors and was associated with radiological reductions in tumor size. Event-free survival was 64% at 2 years, and overall 5-year survival was 65%. Follow-up and data analysis are under way in the multicenter, randomized, Phase IIB INSPIRE trial evaluating the IRX-2 regimen as a stand-alone therapy for activating the immune system to recognize and attack tumors. PMID- 29988731 TI - Review of additive manufactured tissue engineering scaffolds: relationship between geometry and performance. AB - Material extrusion additive manufacturing has rapidly grown in use for tissue engineering research since its adoption in the year 2000. It has enabled researchers to produce scaffolds with intricate porous geometries that were not feasible with traditional manufacturing processes. Researchers can control the structural geometry through a wide range of customisable printing parameters and design choices including material, print path, temperature, and many other process parameters. Currently, the impact of these choices is not fully understood. This review focuses on how the position and orientation of extruded filaments, which sometimes referred to as the print path, lay-down pattern, or simply "scaffold design", affect scaffold properties and biological performance. By analysing trends across multiple studies, new understanding was developed on how filament position affects mechanical properties. Biological performance was also found to be affected by filament position, but a lack of consensus between studies indicates a need for further research and understanding. In most research studies, scaffold design was dictated by capabilities of additive manufacturing software rather than free-form design of structural geometry optimised for biological requirements. There is scope for much greater application of engineering innovation to additive manufacture novel geometries. To achieve this, better understanding of biological requirements is needed to enable the effective specification of ideal scaffold geometries. PMID- 29988732 TI - Unilateral anoxic brain injury secondary to strangulation identified on conventional and arterial spin-labeled perfusion imaging. AB - Anoxic brain injury on magnetic resonance imaging classically demonstrates symmetric diffusion restriction involving the highly metabolic structures including the basal ganglia and cortex and global hyperperfusion on arterial spin labeling perfusion. The pattern of injury is classically diffuse and bilateral owing to global oxygen deprivation from systemic causes, most commonly cardiac arrest. In cases of suspected nonaccidental trauma presenting with a unilateral anoxic injury pattern, strangulation with temporary occlusion of a unilateral carotid artery should be considered. We present 2 cases of unilateral anoxic brain injury due to strangulation identified on magnetic resonance imaging and arterial spin labeling perfusion. PMID- 29988734 TI - Surgical excision of a large, verrucous, scrotal mass in a patient with HSV-2 and HIV-1 co-infection. AB - Genital herpes simplex virus (HSV) infection in HIV-positive individuals can result in a unique presentation of symptoms. Instead of small papules or vesicles that recur and heal periodically, certain individuals present with large, chronic, verrucous lesions. We report a case in which a 45 year old male with acyclovir-resistant HSV-2 and positive HIV-1 serology underwent surgical excision of a verrucous mass on his left hemiscrotum. PMID- 29988735 TI - High treatment adherence, satisfaction, motivation, and health-related quality of life with fingolimod in patients with relapsing-remitting multiple sclerosis - results from a 24-month, multicenter, open-label Danish study. AB - Purpose: Treatment adherence is a prerequisite for treatment success and therefore an important consideration to assure that therapeutic goals are achieved both from a patient point of view and for optimal health care resource utilization. Published data on treatment adherence with fingolimod (Gilenya(r)) are limited. Therefore, this study investigated treatment adherence in patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod in Denmark. Patients and methods: This was a 24-month, multicenter, open-label study, investigating treatment adherence, satisfaction, motivation, and health related quality of life (QoL) in RRMS patients treated with fingolimod. In addition, the effect of a motivational interview support program on these measures was evaluated. Treatment adherence was assessed by pill count. Treatment satisfaction, motivation, and QoL were assessed by patient-reported outcomes (PROs). Results: A total of 195 patients were enrolled in the study. A very high treatment adherence was observed during the entire study with no statistically significant difference between study visits before (99%) and after (97%) the motivational interview. In accordance, a high level of treatment satisfaction was found in the Treatment Satisfaction Questionnaire for Medication 9, which was scored high throughout the study with the highest scores seen for the convenience domain (ranging from 94.51 to 95.78). Furthermore, additional PROs demonstrated a high health-related QoL, a self-determined form of motivation for taking medication, and a patient perception of an autonomy supportive approach provided by the health care provider, at all study visits. Conclusion: High levels of treatment adherence, satisfaction, motivation, and QoL were observed in Danish RRMS patients treated with fingolimod. As these positive measures were observed at all study visits and throughout the study, no effect of the motivational interview support program was found. PMID- 29988733 TI - Dual-functional Brij-S20-modified nanocrystal formulation enhances the intestinal transport and oral bioavailability of berberine. AB - Introduction: Berberine (BBR) is a plant-derived benzylisoquinoline alkaloid and has been demonstrated to be a potential treatment for various chronic diseases. The poor water solubility and P-glycoprotein (Pgp)-mediated drug efflux are the main challenges for its further application in a clinical setting. Materials and methods: In this study, a Brij-S20 (BS20)-modified nanocrystal formulation (BBR BS20-NCs) has been developed and investigated with the purpose of improving the intestinal absorption of BBR. The physicochemical properties of the developed BBR BS20-NCs were characterized and the enhancement of the BBR-BS20-NCs on BBR absorption were investigated both in vitro and in vivo. Results: The results indicated that BS20 could significantly enhance the intracellular uptake of BBR in MDCK-MDR1 cells via a short-term and reversible modulation on the Pgp function, accompanied by a marked increase in Pgp mRNA expression but without significant influence on the Pgp protein expression. Moreover, the morphology of the prepared BBR-BS20-NCs was observed to be prism-like, with a smooth surface and an average diameter of 148.0 +/- 3.2 nm. Compared to raw BBR and physical mixture, BBR-BS20-NCs facilitated the dissolution rate and extent of release of BBR in aqueous solution, and further increased the absorption of BBR in MDCK-MDR1 monolayer by overcoming the Pgp-mediated secretory transport (Papp[BL-AP] values of 2.85 +/- 0.04 * 10-6 cm/s, 2.21 +/- 0.14 * 10-6 cm/s, and 2.00 +/- 0.07 * 10-6 cm/s for pure BBR, physical mixture, and BBR-BS20-NCs, respectively). Significant improvements in the maximum concentration observed (Cmax) and area under drug concentration-time curve (AUC0-t) of BBR-BS20-NCs were obtained in pharmacokinetic studies compared to pure BBR, and the relative bioavailability of BBR-BS20-NCs to pure BBR was 404.1%. Conclusion: The developed BBR-BS20-NCs combine the advantages of nanocrystal formulation and functional excipient. The novel pharmaceutical design provides a new strategy to improve the oral bioavailability of those drugs with both poor water solubility and Pgp-mediated efflux. PMID- 29988736 TI - A comparison of psychological well-being and quality of life between spouse and non-spouse caregivers in patients with head and neck cancer: a 6-month follow-up study. AB - Objective: The caregivers of patients with head and neck cancer (HNC) may suffer from impaired psychological well-being and a decreased quality of life (QOL) related to the chronic burden of caring for patients' physical conditions and their mood changes. In this study, we aimed to compare the psychological well being and QOL between spouse caregivers and non-spouse caregivers of patients with HNC over a 6-month follow-up period. Patients and methods: This study was conducted using a prospective design with consecutive sampling. We recruited study subjects from the outpatient combined treatment clinic of HNC at a medical center in Southern Taiwan. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition was carried out by a trained senior psychiatrist to diagnose caregivers. Furthermore, one research assistant collected the caregivers' demographic characteristics, clinical data, and clinical rating scales, including the Short Form 36 (SF-36) Health Survey, Hospital Anxiety and Depression Scale (HADS), and Family Appearance, Pulse, Grimace, Activity, and Respiration index at the patients' pretreatment, as well as their 3- and 6-month follow-up appointments. Results: Of the 143 subjects that successfully completed the study, two-thirds of caregivers were spouses. During the 6-month follow-up period, spouse caregivers demonstrated significantly higher rates of depression diagnosis (p=0.032), higher scores in the depression subscale of HADS (HADS-D) (p=0.010), and lower SF-36 mental component summary (MCS) scores (p=0.007) than non-spouse caregivers. Furthermore, during those 6 months, HADS-D (p=0.007) and the anxiety subscale of HADS scores (p<0.001) significantly decreased, while SF-36 MCS scores significantly increased (p=0.015). Conclusion: The mental health of spouse caregivers of HNC patients was more severely affected than that of non-spouse caregivers during the observed 6-month follow-up period. Therefore, clinicians need to pay more attention to caregivers' psychological distress during patient care, especially for spouse caregivers. PMID- 29988737 TI - Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder. AB - Background: Fluvoxamine therapy is used for treatment of patients with depressive disorder, but it is often ineffective, and some patients suffer from dose dependent undesirable side effects such as vertigo, headache, indigestion, xerostomia, increased anxiety, etc. CYP2D6 is involved in the biotransformation of fluvoxamine. Meanwhile, the genes encoding these isoenzymes have a high level of polymorphism, which may affect the protein synthesis. Objective: The primary objective of our study was to investigate the effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorder, in order to develop the algorithms of optimization of fluvoxamine therapy for reducing the risk of dose dependent undesirable side effects and pharmacoresistance. Methods: The study involved 45 male patients (average age: 36.44+/-9.96 years) with depressive disorder and comorbid alcohol use disorder. A series of psychometric scales was used in the research. Genotyping of CYP2D6 (1846G>A) was performed using real time polymerase chain reaction. Results: According to results of Mann-Whitney U test, statistically significant differences between the efficacy and safety of fluvoxamine were obtained on 9th and 16th days of therapy in patients with GG and GA genotypes (The Hamilton Rating Scale for Depression: 10.0 [10.0; 23.0] vs 25.0 [24.0; 16.0] (P<0.001) on the 9th day and 4.0 [2.0; 5.0] vs 6.0 [6.0; 7.0] on the 16th day; The UKU Side Effect Rating Scale: 6.0 [4.0; 6.0] vs 9.0 [9.0; 10.0] (P<0.001) on the 9th day and 5.0 [1.0; 9.0] vs 19.0 [18.0; 22.0] on the 16th day). Conclusion: This study demonstrated the lower efficacy and safety of fluvoxamine in patients with depressive disorder and comorbid alcohol use disorders with GA genotype in CYP2D6 1846G>A polymorphic marker. PMID- 29988738 TI - High expression of ALDOA and DDX5 are associated with poor prognosis in human colorectal cancer. AB - Purpose: The identification of prognostic markers for colorectal cancer (CRC) is needed for clinical practice. Fructose-bisphosphate aldolase A (ALDOA) and DEAD box p68 RNA helicase (DDX5) are commonly overexpressed in cancer and correlate with tumorigenesis. However, association between expression of ALDOA and DDX5, and CRC outcome has not been reported. Patients and methods: We used 141 formalin fixed paraffin-embedded (FFPE) specimens collected from 105 patients with CRC treated at the Affiliated Hospital of Guilin Medical University and the People's Hospital of Liuzhou. We performed tissue microarray based immunohistochemistry to explore expression features and prognostic value (overall survival, OS; disease free survival, [DFS]) of ALDOA and DDX5 in CRC tissues. The prognostic values were evaluated using Kaplan-Meier analysis, and Cox regression analyses. Results: ALDOA and DDX5 were highly expressed in CRC tissues and liver metastatic CRC tissues compared with normal glandular epithelium tissues (all p<0.05). Interestingly, primary CRC tissues highly expressing ALDOA or DDX5 had poor outcome (p<0.0001 for both OS and DFS for ALDOA; p=0.001 for OS; and p=0.011 for DFS for DDX5) compared with patients who had low expression of those proteins. Furthermore, multivariate Cox analysis showed that ALDOA/DDX5 combination was an independent risk factor for OS and ALDOA was an independent risk factor for DFS. Conclusion: High levels of ALDOA and DDX5 contribute to the aggressiveness and poor prognosis of CRC. ALDOA/DDX5 expression could be a biomarkers for the prognosis of CRC. PMID- 29988740 TI - South African podiatry students' perceptions of feedback given as part of clinical training. AB - Background: As part of their clinical training podiatry students spend time in clinical settings treating patients under the supervision of qualified podiatrists. The role and purpose of feedback during such clinical training is to improve students' knowledge, skills and behaviour. Feedback is an integral part of the learning process that should enhance students' clinical learning experiences. However, there is no data on podiatry students' satisfaction or lack thereof about feedback provided during clinical training. The aim of this study was to determine the perceptions of podiatry students on feedback given or received during clinical training. Methods: Cross-sectional survey design study in which a four-section self-constructed questionnaire was used to collect data from podiatry students in their 2nd to 4th -year of study. Simple descriptive statistics were used to analyse quantitative responses with free text comments yielding qualitative data, which has been used to give more insight into the quantitative findings. Results: Analyses showed that 8% of students were satisfied, 52% were sometimes satisfied and 37% were not satisfied with the feedback. The majority (86%) of students indicated they would prefer to receive feedback in private. Seventy-three percent of students received positive (reinforcing) and negative (corrective) feedback at the same time. Conclusion: Students agree that feedback is an essential component of the clinical learning process and appreciate constructive regular feedback whether negative or positive in nature. Additionally, students understand that feedback regardless of its type has the potential to identify areas of development, reinforce good practice and motivate them to work toward their learning outcome expectations. However, there is a need to consider issues such as setting and timing when giving feedback. PMID- 29988739 TI - Neurotrophic keratitis: current challenges and future prospects. AB - Neurotrophic keratitis (NK) is a degenerative corneal disease caused by damage of trigeminal corneal innervation, which leads to spontaneous epithelial breakdown and corneal ulceration. The impairment of corneal sensory innervation causes the reduction of both protective reflexes and trophic neuromodulators that are essential for the vitality, metabolism, and wound healing of ocular surface tissues. A wide range of ocular and systemic conditions, including herpetic keratitis, ocular chemical burns, corneal surgery, diabetes, multiple sclerosis, and neurosurgical procedures, can cause NK by damaging trigeminal innervation. Diagnosis of NK requires careful investigation of any ocular and systemic condition associated with the disease, complete ocular surface examination, and quantitative measurement of corneal sensitivity. The clinical stages of NK range from corneal epithelial alterations (stage 1) to persistent epithelial defect (stage 2) and ulcer (stage 3), which may progress to corneal perforation. Management of NK is based on clinical severity, and the aim of the therapy is to halt the progression of corneal damage and promote epithelial healing. Although several medical and surgical treatments have been proposed, no therapies are currently available to restore corneal sensitivity, and thus, NK remains difficult and challenging to treat. The purpose of this review is to summarize available evidence on the pathogenesis, diagnosis, and treatment of NK. Novel medical and surgical therapies including the topical administration of nerve growth factor and corneal neurotization are also described. PMID- 29988741 TI - Predicting surgical intervention in patients presenting with carpal tunnel syndrome in primary care. AB - Purpose: Carpal tunnel syndrome (CTS) is a symptomatic compression neuropathy of the median nerve. This study investigated the value of candidate prognostic factors (PFs) in predicting carpal tunnel release surgery. Patients and methods: This is a retrospective cohort study set in the Clinical Practice Research Datalink. Patients >=18 years presenting with an incident episode of CTS were identified between 1989 and 2013. Candidate PF's defined in coded electronic patient records were identified following literature review and consultation with clinicians. Time to first carpal tunnel release surgery was the primary end point. A manual backward stepwise selection procedure was used to obtain an optimal prediction model, which included all the significant PFs. Results: In total, 91,412 patients were included in the cohort. The following PFs were included in an optimal model (C-statistic: 0.588 [95% CI 0.584-0.592]) for predicting surgical intervention: geographical region; deprivation status; age hazard ratio (HR 1.02 per year, 95% CI 1.01-1.02); obesity (HR 1.23, 95% CI 1.19 1.27); alcohol drinker (HR 1.05, 95% CI 1.00-1.10); smoker (HR 1.06, 95% 1.03 1.10); inflammatory condition (HR 1.13, 95% CI 0.98-1.29); neck condition (HR 1.13, 95% CI 1.03-1.23); and multisite pain (HR 1.10, 95% CI 1.05-1.15). Although not included in the multivariable model, pregnancy (if gender female) within 1 year of the index consultation, reduced the risk of surgery (HR 0.24, 95% CI 0.21 0.28). Conclusion: This study shows that patients who are older and who have comorbidities including other pain conditions are more likely to have surgery, whereas patients presenting with CTS during or within a year of pregnancy are less likely to have surgery. This information can help to inform clinicians and patients about the likely outcome of treatment and to be aware of which patients may be less responsive to primary care interventions. PMID- 29988743 TI - Revision of the subterranean genus Spelaeodiscus Brusina, 1886 (Gastropoda, Pulmonata, Spelaeodiscidae). AB - The Balkan genus Spelaeodiscus Brusina, 1886 is revised based on museum collections and newly collected samples from Montenegro and Albania. The following species and subspecies are introduced as new to science: Spelaeodiscus albanicus edentatus Pall-Gergely & P. L. Reischutz, ssp. n. (southern Montenegro and northern Albania), Spelaeodiscus densecostatus Pall-Gergely & A. Reischutz, sp. n., Spelaeodiscus hunyadii Pall-Gergely & Deli, sp. n., Spelaeodiscus latecostatus Pall-Gergely & Eross, sp. n. (all three from southern Montenegro), Spelaeodiscus unidentatus acutus Pall-Gergely & Feher, ssp. n., and Spelaeodiscus virpazarioides Pall-Gergely & Feher, sp. n. (both from northern Albania). For all species and subspecies diagnoses and suggestions for conservation status assessments according to IUCN criteria are provided. An overview is given regarding the habitat preference of Spelaeodiscus species, and the "scratch and flotate" method to collect subterranean gastropods. PMID- 29988742 TI - The increasing prevalence of non-communicable diseases in low-middle income countries: the view from Malawi. AB - Non-communicable diseases (NCDs) are the leading cause of death globally, the majority of these being due to cardiovascular disease, cancer, chronic respiratory diseases, or diabetes. Mortality from many NCDs continues to increase worldwide, with a disproportionately larger impact in low-middle income countries (LMIs), where almost 75% of global deaths occur from these causes. As a low income African country that consistently ranks amongst the world's poorest nations, Malawi as a case study demonstrates how transition due to societal change and increasing urbanization is often accompanied by a rise in the rate of NCDs. Other factors apart from changing lifestyle factors can explain at least some of this increase, such as the complex relationship between communicable and NCD and growing environmental, occupational, and cultural pressures. Malawi and other LMIs are struggling to manage the increasing challenge of NCDs, in addition to an already high communicable disease burden. However, health care policy implementation, specific health promotion campaigns, and further epidemiological research may be key to attenuating this impending health crisis, both in Malawi and elsewhere. This review aims to examine the effects of the major NCDs in Malawi to help inform future public health care policy in the region. PMID- 29988744 TI - Prognostic significance of the long noncoding RNAs in nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - Background and objective: Nasopharyngeal carcinoma (NPC) is a common head and neck malignancy. Despite recent advances in treatment, the prognosis, particularly for those at the advanced stages, remains poor. Moreover, the underlying genetic and molecular events have remained obscure so far. Recently, increasing evidence has demonstrated that long noncoding RNAs (lncRNAs) could act as either oncogenes or tumor suppressor genes in various cancers depending on their targets. And some lncRNAs have been shown to be aberrantly expressed in NPC. In this meta-analysis, we try to elucidate the possible role of lncRNAs and their expression on prognosis in NPC. Methods: We searched the databases of PubMed, Embase, and Web of Science for relevant articles ranging from January 2000 to December 2017. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were used to evaluate the prognostic value of lncRNAs in NPC. Odds ratios (ORs) were used to assess the association between lncRNAs and clinicopathological characteristics. Results: A total of 14 eligible publications including 14 on prognosis and eight on clinicopathological characteristics were identified. Our results demonstrated that the high expression of lncRNAs was related to poor overall survival (OS; HR =1.55; 95% CI =1.01, 2.40; P=0.05) and disease-free survival (DFS; HR =1.83; 95% CI =1.07, 3.13; P=0.03) of NPC. Moreover, the expression of lncRNAs was correlated with male gender (OR =1.42; 95% CI =1.05, 1.91; P=0.02), lymph node status (OR =2.20; 95% CI =1.29, 3.73; P=0.004), and tumor node metastasis (TNM) clinical stage (OR =2.55; 95% CI =1.12, 5.78; P=0.03). Conclusion: This meta-analysis shows that the level of expression of lncRNAs may be a potential prognostic indicator in NPC. PMID- 29988745 TI - Metabolic pairing of aerobic and anaerobic production in a one-pot batch cultivation. AB - Background: The versatility of microbial metabolic pathways enables their utilization in vast number of applications. However, the electron and carbon recovery rates, essentially constrained by limitations of cell energetics, are often too low in terms of process feasibility. Cocultivation of divergent microbial species in a single process broadens the metabolic landscape, and thus, the possibilities for more complete carbon and energy utilization. Results: In this study, we integrated the metabolisms of two bacteria, an obligate anaerobe Clostridium butyricum and an obligate aerobe Acinetobacter baylyi ADP1. In the process, a glucose-negative mutant of A. baylyi ADP1 first deoxidized the culture allowing C. butyricum to grow and produce hydrogen from glucose. In the next phase, ADP1 produced long chain alkyl esters (wax esters) utilizing the by products of C. butyricum, namely acetate and butyrate. The coculture produced 24.5 +/- 0.8 mmol/l hydrogen (1.7 +/- 0.1 mol/mol glucose) and 28 mg/l wax esters (10.8 mg/g glucose). Conclusions: The cocultivation of strictly anaerobic and aerobic bacteria allowed the production of both hydrogen gas and long-chain alkyl esters in a simple one-pot batch process. The study demonstrates the potential of 'metabolic pairing' using designed microbial consortia for more optimal electron and carbon recovery. PMID- 29988747 TI - Species of the subgenus Empis (Xanthempis) from South Korea (Diptera, Empididae). AB - The subgenus Empis (Xanthempis) is newly recorded from South Korea with the following two species: E. (X.) sesquata (Ito, 1961) and E. (X.) suhi sp. n. A key to the known species of Xanthempis from Eastern Asia is presented. The distribution of Xanthempis in eastern Asia is briefly discussed. PMID- 29988746 TI - Comparison of ozone and lidocaine injection efficacy vs dry needling in myofascial pain syndrome patients. AB - Purpose: Myofascial pain syndrome (MPS) is a common musculoskeletal disorder among young adults associated with presence of myofascial trigger points. We aimed to evaluate efficacy of ozone injection (OI) in MPS patients, compared with two currently used methods including lidocaine injection (LI) and dry needling (DN). Patients and methods: In this single-blinded study, a total of 72 eligible patients were included and then randomly divided into three equal groups: DN, OI, and LI. All patients received treatment in three weekly sessions. Visual analog scale (VAS) for pain, cervical lateral flexion, pain pressure threshold (PPT), and neck disability index (NDI) were the main outcome measures, which were evaluated at baseline and at 4 weeks after injections. Analytic results were demonstrated as both within- and between-groups mean difference (MD). Results: Sixty two patients finished the study, 20 participants in both the DN and LI groups, and 22 persons in OI group. Distribution of all demographics and baseline clinical variables were relatively similar among groups. All three interventions were remarkably effective in improving patients' pain and PPT. Significant decrease in VAS (MD=-3.6+/-1.4) and increase in PPT (MD=7.2+/-5.1) within 4 weeks follow-up confirmed this finding. Also, NDI had similar significant improvement (MD=-9.9+/-8.7), but lateral flexion range did not show remarkable increase. There was also a statistically significant difference among three methods' efficacy on VAS, NDI, and PPT, favoring OI and LI. Conclusion: In summary, this data showed that in short-term follow-up, all three methods were significantly effective in MPS treatment; however, OI and LI groups had slightly better results than the DN group, with no remarkable preference between them. PMID- 29988748 TI - The effect of applied voltages on the structure, apatite-inducing ability and antibacterial ability of micro arc oxidation coating formed on titanium surface. AB - The micro arc oxidation (MAO) coatings with different concentrations of Ca, P and Zn elements are successfully formed on the titanium substrate at the different applied voltages. After MAO treatment, the MAO coating exhibits the porous surface structure and composed of anatase and rutile TiO2 phases. Meanwhile, the average size and density of micro-pores on the MAO coatings have been modified via the adjusting the applied voltages. In addition, the contents of the incorporated elements such as Zn, Ca and P elements in the MAO coatings have been optimized. The bonding strength test results reveal that the MAO coating shows higher bonding strength, which is up to 45 +/- 5 MPa. Compared to the pure Ti plate, the MAO coating formed at 350 and 400 V show good apatite-inducing ability. Meanwhile, the MAO coating containing Zn, Ca and P elements have better antibacterial ability for E.coli and S.aureus. Thus, the incorporation of Zn, Ca and P elements was an effective method to improve the antibacterial ability. Moreover, the concentrations of Zn, Ca and P elements could be adjusted with the changing of the applied voltages. As a result, the enhancement of the antibacterial ability on the MAO coating surfaces was depended on the comprehensive effect of the incorporated elements and the surface property of MAO coatings. PMID- 29988749 TI - Periurethral adenocarcinoma of mesonephric origin: A case report and review of the literature. AB - Periurethral mesonephric adenocarcinoma is a rare tumor. To the best of our knowledge, only 13 cases have been reported in the literature to date. We report the case of a 36-year-old lady who presented with periurethral mesonephric adenocarcinoma, treated by surgery followed by adjuvant chemotherapy and pelvic radiotherapy. We demonstrate the unusual histology of mesonephric adenocarcinoma and the necessity to consider this tumor in the differential diagnosis of all unusual genito-urologic tumours. In the present literature, combination of surgery followed by chemotherapy and radiotherapy is the most suitable treatment for locally advanced periurethral mesonephric adenocarcinoma. PMID- 29988750 TI - Frequency of inborn errors of metabolism screening for children with unexplained acute encephalopathy at an emergency department. AB - Objective: Our study aimed to estimate the frequency of inborn errors of metabolism (IEMs) in patients presenting with acute encephalopathy-like picture at an emergency department (ED). Subjects and methods: Our study was a prospective observational study conducted on 30 patients admitted to the pediatric ED with unexplained acute encephalopathy. The study included 30 children with an age ranging from 1 month to 5 years. All patients were subjected to full history taking, thorough clinical examination, and laboratory investigations including serum ammonia, serum lactate, arterial blood gases, tandem mass spectroscopy, organic acid of urine, cerebrospinal fluid examination to exclude central nervous system infection plus the routine laboratory tests (kidney functions, liver functions, random blood glucose, complete blood picture), and brain imaging computed tomography and/or magnetic resonance imaging brain. Results: Thirty children presented with acute encephalopathy at the ED. All were screened for suspected IEMs. Ten (33.3%) of them was positive in the initial screening test. There were four (13.3%) patients with possible mitochondrial diseases, four (13.3%) patients with possible organic acidemia, one (3.3%) patient with possible urea cycle defect, and one (3.3%) patient with possible nonketotic hyperglycinemia. Conclusion: Any case of unexplained acute encephalopathy presenting to the ED should be investigated for suspected IEM, especially in high-risk families, as early interventions will lead to improved outcome. PMID- 29988751 TI - A tailored telephone and email based exercise intervention induced reductions in various measures of body composition in physically inactive adults: A randomized controlled trial. AB - : Obesity prevalence has increased the past decades and has become a serious public health problem. The aim of this six-month assessor-blinded, parallel-group randomized controlled trial was to assess the effect of a tailored telephone and email-based exercise intervention on various measures of body composition in a sample of apparently healthy and physically inactive adults. A total of 111 volunteering adults (40-55 yr) in Southern Norway were randomly assigned to an intervention group (IG; n = 39) or a no-information control group (CG; n = 50), by random allocation numbering. The IG received feedback on their health-related physical fitness, information on guidelines and recommendations for physical activity, a leaflet on national dietary recommendations, prompts and reminders in addition to three tailored exercise programs, one every two months, and fortnightly motivational counselling by email or telephone, alternately. The CG received no follow-up during the intervention period. The main outcome measures: weight, body mass index (BMI), waist circumference (WC) and fat percentage by skinfolds (FPskf) were assessed objectively at baseline and posttest. A one-way ANCOVA analysis, adjusted for baseline scores, gender, age, and educational level, revealed a larger reduction on all body compositional measures in the IG compared to the CG (p <= 0.043), except for BMI when adjusted for baseline scores. Additionally, a significantly higher percentage of the IG (64.1%) achieved a clinically significant reduction in FPskf compared to the CG (36.2%, p = 0.018). This six-month tailored telephone and email-based exercise intervention induced significant reductions on several measures of body composition in physically inactive adults. Trial registration: ClinicalTrials.gov (NCT03164239). PMID- 29988752 TI - Two new species of crayfish of the genus Cherax from Indonesian New Guinea (Crustacea, Decapoda, Parastacidae). AB - Two new species of the genus Cherax are described and illustrated. Cherax mosessalossasp. n., endemic to the Klademak Creek drainage in Sorong, in the western part of the Kepala Burung (Vogelkop) peninsula, West Papua, Indonesia, is described, figured and compared with its closest relatives, Cherax misolicus Holthuis, 1949 and Cherax warsamsonicus. The new species may be easily distinguished from both by the shape of the rostrum, the shape of the chelae, the presence of five cervical spines, the shape of the scaphocerite, and short scattered hairs on the carapace. Cherax alyciaesp. n., endemic to creeks in the Digul River drainage in the eastern part of the Boven Digoel Regency, Papua, Indonesia, is described, figured, and compared with its closest relative, Cherax peknyi Lukhaup & Herbert, 2008. The new species may be easily distinguished from Cherax peknyi by the shape of the chelae, presence of a soft patch on the chelae of the males, and colouration. A molecular phylogeny based on two mitochondrial gene fragments, 16S and COI, supports the morphology-based description of the two new species, which can also be clearly distinguished by sequence differences. PMID- 29988753 TI - Embolization-sclerotherapy of a refractory large volume post-operative pelvic lymphocele. PMID- 29988754 TI - Importance of the identification of Segniliparus species from pulmonary infection. PMID- 29988755 TI - Intravitreal Fluocinolone Acetonide (ILUVIEN) Implant for the Treatment of Refractory Cystoid Macular Oedema After Retinal Detachment Repair. AB - Cystoid macular oedema (CMO) is one of the most frequent postoperative macular complications to cause partial visual recovery after successful retinal detachment (RD) repair. Refractory CMO is difficult to treat and many strategies have been employed with varying degrees of success. We report for the first time the use of ILUVIEN implant to treat refractory CMO after successful RD repair. A 65-year-old female presented with right eye full-thickness macular hole and underwent pars plana vitrectomy, internal limiting membrane peeling and cryotherapy with gas tamponade with 12% C3F8. She subsequently developed right eye macula-on RD and proliferative vitreoretinopathy and required multiple procedures for successful retinal reattachment. Later, she developed CMO that responded to intravitreal triamcinolone injections and intravitreal dexamethasone 0.7-mg implants but recurrence of CMO continued to be a problem. After receiving ILUVIEN intravitreal implant, her visual acuity improved and CMO resolved without recurrence for 13 months. Refractory CMO after RD repair is difficult to treat and in a quarter of cases will not improve without treatment. Our case shows that a single ILUVIEN implant maintained anatomical dry fovea and improved vision. This also demonstrates that ILUVIEN is an effective management strategy to reduce the need for repeated treatments. PMID- 29988756 TI - Comparison of health system responsiveness between HIV and non-HIV patients at infectious disease clinics in Yunnan, China. AB - Background: China is in an epidemiologic transition period. Health system responsiveness (HSR) has become an increasing concern in China. With the burden of increasing human immunodeficiency virus (HIV) infection/acquired immune deficiency syndrome, responsiveness of HIV care is urgently needed. We aimed at comparing the experience of HSR between HIV-positive and non-HIV patients. Methods: A cross-sectional study was carried out in Yunnan, China, from January to February 2015 among two consecutive groups of HIV and non-HIV patients in two hospitals with the largest HIV admissions. Patients' experience and expectation of HSR were measured using a self-reported questionnaire containing items of seven domains and 35 vignettes (five per domain). Each of the items and vignettes was ranked from 1 "very good" to 5 "very bad." For each domain, B-scales were built based on the difference between experience and the vignettes. Ordered probit and censored ordered probit regression models were constructed to compare HSR experience between the two groups adjusted for socioeconomic status (SES) factors. Results: The majority of HIV patients were at clinical stage 1, were infected via unprotected sexual contact, and had a CD4 count <500 cells/uL. After adjustment by SES factors, HIV patients had better experiences of HSR in six of the seven HSR domains, prompt attention being the only domain that non-HIV patients had better experiences. Conclusion: Perceptions of HSR experience were better among HIV patients except for prompt attention, which could not be explained by SES factors and difference in expectations. A reform is needed not to neglect the needs of non-HIV patients in the study area. PMID- 29988757 TI - The Efficiency Index (EFFi), based on volumetric capnography, may allow for simple diagnosis and grading of COPD. AB - Background: Spirometry, the main tool for diagnosis and follow-up of COPD, incompletely describes the disease. Based on volumetric capnography (VCap), an index was developed for the diagnosis and grading of COPD, aimed as a complement or alternative to spirometry. Methods: Nine non-smokers, 10 smokers/former smokers without COPD and 54 smokers/former smokers with COPD were included in the study. Multiple breath washout of N2 and VCap were studied with Exhalyzer D during tidal breathing. VCap was based on signals for flow rate and CO2 and was recorded during one breath preceding N2 washout. Efficiency Index (EFFi) is the quotient between exhaled CO2 volume and the hypothetical CO2 volume exhaled from a completely homogeneous lung over a volume interval equal to 15% of predicted total lung capacity. Results: EFFi increased with increased Global initiative for chronic Obstructive Lung Disease (GOLD) stage and the majority of subjects in GOLD 2 and all subjects in GOLD 3 and 4 could be diagnosed as having COPD using the lower 95% confidence interval of the healthy group. EFFi also correlated with N2 washout (r=-0.73; p<0.001), forced expiratory volume in 1 second (r=0.70; p<0.001) and diffusion capacity for carbon oxide (r=0.69; p<0.001). Conclusion: EFFi measures efficiency of tidal CO2 elimination that is limited by inhomogeneity of peripheral lung function. EFFi allows diagnosis and grading of COPD and, together with FEV1, may explain limitation of physical performance. EFFi offers a simple, effortless and cost-effective complement to spirometry and might serve as an alternative in certain situations. PMID- 29988758 TI - Management of chronic spontaneous urticaria: a worldwide perspective. AB - Background: The approaches to the diagnosis and treatment of chronic spontaneous urticaria (CSU) differ in various parts of the world. We sought to determine the adherence to international and national urticaria guidelines as well as the motives to deviate from the guidelines among physicians worldwide. Methods: A web based questionnaire was created and launched via e-mail by the World Allergy Organization (WAO) to representatives of all WAO Member Societies, the members of the American Academy of Allergy, Asthma & Immunology (AAAAI) and the members of the WAO Junior Members Group (JMG), regardless of the specialty, affiliation, or nationality in March 2017. Results: We received 1140 completed surveys from participating physicians from 99 countries. Virtually all participants (96%) were aware of at least one urticaria guideline and reported that they follow a guideline. However, one in five physicians who follow a guideline (22%) reported to deviate from it. Reliance on own clinical experience is the most frequent reason for deviation from guidelines or not following them (44%). Young (< 40 years) and less experienced physicians more often follow a guideline and less often deviate than older and experienced ones. Physicians who follow a urticaria guideline showed higher rates of routinely ordering a complete blood count, the erythrocyte sedimentation rate, C-reactive protein, anti-thyroid antibodies, and thyroid-stimulating hormone and of performing the autologous serum skin test as compared to those who do not. Physicians who follow a urticaria guideline showed higher rates of using second generation antihistamines as their first-line treatment of CSU (p = 0.001) and more frequently observed higher efficacy of these drugs (or had more confidence that it would work, p < 0.019) as compared to those who do not follow the guidelines. Conclusions: Physicians' characteristics (e.g. age, clinical experience, and specialty) and country specifics and regional features (e.g. availability of drugs for CSU treatment) importantly influence adherence to urticaria guidelines and CSU patient care and should be addressed in more detail in future research. PMID- 29988760 TI - Morphological re-description and molecular identification of Tabanidae (Diptera) in East Africa. AB - Biting flies of the family Tabanidae are important vectors of human and animal diseases across continents. However, records of Africa tabanids are fragmentary and mostly cursory. To improve identification, documentation and description of Tabanidae in East Africa, a baseline survey for the identification and description of Tabanidae in three eastern African countries was conducted. Tabanids from various locations in Uganda (Wakiso District), Tanzania (Tarangire National Park) and Kenya (Shimba Hills National Reserve, Muhaka, Nguruman) were collected. In Uganda, octenol baited F-traps were used to target tabanids, while NG2G traps baited with cow urine and acetone were employed in Kenya and Tanzania. The tabanids were identified using morphological and molecular methods. Morphologically, five genera (Ancala, Tabanus, Atylotus, Chrysops and Haematopota) and fourteen species of the Tabanidae were identified. Among the 14 species identified, six belonged to the genus Tabanus of which two (T. donaldsoni and T. guineensis) had not been described before in East Africa. The greatest diversity of tabanid species were collected from the Shimba Hills National Reserve, while collections from Uganda (around the shores of Lake Victoria) had the fewest number of species. However, the Ancala genus was found in Uganda, but not in Kenya or Tanzania. Maximum likelihood phylogenies of mitochondrial cytochrome c oxidase 1 (COI) genes sequenced in this study show definite concordance with morphological species identifications, except for Atylotus. This survey will be critical to building a complete checklist of Tabanidae prevalent in the region, expanding knowledge of these important vectors of human and animal diseases. PMID- 29988759 TI - Transcranial magnetic stimulation in the treatment of obsessive-compulsive disorder: current perspectives. AB - Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neurostimulation technique receiving increasing attention in the treatment of different psychiatric disorders. Evidence for rTMS use in obsessive-compulsive disorder (OCD) is accumulating and informing further developments in the neurostimulation field, the latest being deep transcranial magnetic stimulation (dTMS). dTMS allows direct stimulation of deeper subcortical structures and larger brain volume than conventional rTMS. Underlying neurobiological mechanisms related to transcranial magnetic stimulation are still under evaluation, but appear to offer a novel "third" way of addressing symptoms via localized electrical stimulation compared to pharmacotherapy and psychotherapy approaches. This systematic review focuses on the effects of rTMS and dTMS stimulation on different brain targets in OCD. Brain areas included are the dorsolateral prefrontal cortex, supplementary motor area, orbitofrontal cortex/medial prefrontal cortex, and anterior cingulate cortex (ACC). Improved understanding of the therapeutic effects of rTMS in OCD will support fine-tuning of the method and help determine how we can best optimize the approach via rTMS or dTMS to achieve clinically relevant results. PMID- 29988761 TI - Lethal disseminated dysembryoplastic neuroepithelial tumor following West Nile virus: Report of a very unusual combination. AB - Dysembryoplastic neuroepithelial tumors (DNETs) are typically benign World Health Organization (WHO) grade I tumors of the cortical or deep gray matter with a favorable prognosis. We encountered a patient with DNET who has been evaluated and treated for West Nile encephalitis 7 months before presentation. Over the course of 2 years, the patient developed diffuse leptomeningeal carcinomatosis. As the disease burden increased, the patient eventually became quadriparetic. The patient elected for hospice care and expired shortly thereafter. Autopsy revealed DNET (WHO grade I) with extensive involvement of the cervical, thoracic, and lumbar spinal cord, bilateral cerebellar hemispheres, brainstem, the cortex of the right frontal and temporal lobes, and meningeal carcinomatosis of the brain and spinal cord. Mortality from DNET is rare, and as per our extensive literature search, there has been only 1 case reported of death attributed to seizures from this diagnosis. To the best of our knowledge, this is the only case of disseminated DNET with meningeal infiltration or carcinomatosis resulting in mortality. PMID- 29988762 TI - A rare complication; retained needle during intracavernosal injection for erectile dysfunction. PMID- 29988763 TI - Dietary trigger factors of migraine and tension-type headache in a South East Asian country. AB - Background: The literature on the dietary trigger factors of headache among the South East Asians is limited. Objective: The objective of the study was to examine the dietary trigger factors of migraine and tension-type headache (TTH) in Malaysian patients, consisting of Malays, Chinese and Indians. Methods: In this prospective cross-sectional study, patients presenting with migraine and TTH to a neurology clinic between April 2010 and June 2017 were recruited. The patients were given a comprehensive dietary list consisting of 25 specified types of food and drink items as well as other unspecified types of food and drink items which were possible dietary triggers. The data on these dietary triggers and missing meals were collected. Results: A total of 684 patients with headache (319 migraine and 365 TTH patients) were recruited. One hundred and fifty-eight (23.1%) patients had missing meals as trigger. Two hundred and fifty-five (37.3%) patients had dietary triggers; 141 (44.2%) patients with migraine and 114 (31.2%) patients with TTH had dietary triggers. Eighty-four (52.8%) Malay, 28 (41.8%) Chinese, 25 (32.5%) Indian migraine patients and five (38.5%) migraine patients from other ethnic groups, had dietary triggers. Some 58 (40.0%) Malay, 27 (25.2%) Chinese, 22 (23.9%) Indian patients and 7 (29.2%) patients from other ethnic groups with TTH had dietary triggers. The most common dietary trigger factors were coffee (19.9%), chocolate (7.5%) and food rich in monosodium glutamate (5.6%). Logistic regression showed that chocolate (OR 2.16, 95% CI 1.06-4.41, p = 0.035) and coffee (OR 1.73, 95% CI 1.12-2.68, p = 0.014) were significantly associated with migraine compared to TTH. Conclusion: Chocolate and coffee significantly triggered migraine compared to TTH. Inter-ethnic differences were observed for dietary trigger factors. PMID- 29988764 TI - Primary effusion lymphoma: current perspectives. AB - Primary effusion lymphoma (PEL) is a rare and aggressive disease, affecting a unique population of patients who are often elderly or immunocompromised. PEL is associated with human herpesvirus type-8 infection and most commonly presents as malignant effusions of the body cavities. Patients diagnosed with PEL often have a compromised immune system from secondary conditions such as HIV. Chemotherapy has traditionally been the cornerstone of treatment for patients with a good performance status and no significant comorbidities. However, an optimal regimen does not exist. Most patients with PEL experience a relapse after frontline therapy within 6-8 months and subsequently require further treatment. In recent years, our understanding of the molecular drivers and environmental factors affecting the pathogenesis of PEL has expanded. This review will discuss the pathogenesis of PEL and various management approaches available in the frontline and relapsed setting as well as targeted agents that have shown promise in this disease. PMID- 29988766 TI - Comparison of Inflammation-Based Prognostic Scores in Patients undergoing Curative Resection for Non-small Cell Lung Cancer. AB - Background: Inflammation-based prognostic scores, including Glasgow prognostic score (GPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), systemic immune-inflammation index (SII) and advance lung cancer inflammation index (ALI) are reported to be associated with survival in patients with non-small cell lung cancer (NSCLC). However, at present, there are no studies that compared these scoring systems for resectable NSCLC. Methods: Three hundred forty-one NSCLC patients who underwent surgery at our institution were included. The optimal cut-off values of SII and ALI were calculated by the Cutoff Finder. The area under the receiver operating characteristics curve (AUC) was calculated to compare the predictive ability of each of the scoring systems. Univariate and multivariate analyses were performed to identify the clinicopathological variables associated with overall survival. Results: The optimal cut-off value of SII and ALI were 471.2 * 109/L and 37.66, respectively. All scores were significantly related to the 5-year cancer-specific survival. The ALI consistently had a higher AUC value in comparison with other inflammation-based prognostic scores. A multivariate analysis showed that GPS and ALI were independently associated with overall cancer-specific survival. Conclusion: To the best of our knowledge, this is the first study to demonstrate that GPS and ALI appear to be superior to other inflammation-based prognostic scores in patients undergoing potentially curative resection for NSCLC. PMID- 29988765 TI - Abnormal degree centrality in chronic users of codeine-containing cough syrups: A resting-state functional magnetic resonance imaging study. AB - Codeine-containing cough syrups (CCS) have become one of the most popular drugs of abuse in young population worldwide. However, the neurobiological mechanisms underlying CCS-dependence are yet ill-defined. Therefore, understanding the brain abnormalities in chronic users of CCS is crucial for developing effective interventions. The present study depicted the intrinsic dysconnectivity pattern of whole-brain functional networks at the voxel level in chronic users of CCS. In addition, the degree centrality (DC) changes were correlated to the Barratt Impulsiveness Scale (BIS-11) total score, dose, duration of CCS use, and the age at first use of cough syrups. The current study included 38 chronic CCS users and 34 matched control subjects. All patients were evaluated using the BIS-11. Next, resting-state functional magnetic resonance imaging (rs-fMRI) datasets were acquired from these CCS users and controls. Whole-brain connectivity was analyzed using a graph theory approach: degree centrality (DC). CCS-dependent individuals exhibited low DC values in the left inferior parietal lobule and the left middle temporal gyrus, while high DC values were noted in the right pallidum and the right hippocampus (P < 0.01, AlphaSim corrected). Also, significant correlations were established between average DC value in the left inferior parietal lobule and attentional impulsivity scores and the age at first CCS use. The rs-fMRI study suggested that the abnormal intrinsic dysconnectivity pattern of whole brain functional networks may provide an insight into the neural substrates of abnormalities in the cognitive control circuit, the reward circuit, and the learning and memory circuit in CCS-dependent individuals. PMID- 29988767 TI - Haematozoa of wild catfishes in northern Australia. AB - Very little is known about the diversity, prevalence, or pathogenicity of haematozoa in Australian freshwater fishes. Blood smears from 189 native catfishes, of six different species, from northern Australia were examined for haematozoa. Haematozoan infections were observed only in fishes from Queensland, at an overall prevalence of 0.191 (95% CI = 0.134-0.265). Intraerythrocytic haemogregarines were present in Neoarius graeffei from the Brisbane River at a prevalence of 0.35 (0.181-0.567). Trypanosomes were present in Tandanus species from four rivers, at prevalences ranging from 0.111 (0.020-0.330) to 1 (0.635-1), and in N. graeffei from one river in Queensland, at a prevalence of 0.063 (0.003 0.305). The haematozoans observed appeared to have little impact on their hosts. Tandanus spp. were significantly more likely to be infected with trypanosomes, suggesting a high parasite-host specificity. This is the first widespread survey of wild Australian freshwater catfishes for haematozoa, resulting in the first report of haemogregarines from Australian freshwater fish, and the first report of trypanosomes from Neoarius graeffei and Tandanus tropicanus. PMID- 29988768 TI - Safety and efficacy of PLGA(Ag-Fe3O4)-coated dental implants in inhibiting bacteria adherence and osteogenic inducement under a magnetic field. AB - Introduction: The placement of dental implants is performed in a contaminated surgical field in the oral cavity, which may lead to implant failure. Bacterial adhesion and proliferation (Streptococcus mutans, Porphyromonas gingivalis) often lead to implant infections. Although Ag nanoparticles hold great promise for a broad spectrum of antibacterial activities, their runoff from dental implants compromises their antibacterial efficacy and potentially impairs osteoblast proliferation. Thus, this aspect remains a primary challenge and should be controlled. Materials and methods: In this study, PLGA(Ag-Fe3O4) was modified on the implanted tooth surface and was characterized by transmission electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The magnetic and antibacterial properties were also determined. Results: Results showed that Ag successfully bonded with Fe3O4, and Ag-Fe3O4 not only exerted superparamagnetism but also exhibited antibacterial activity almost identical to silver nanoparticles (nano-Ag). The PLGA(Ag-Fe3O4) coating could significantly maintain the antibacterial activity and avoid bacterial adhesion to the implant. Compared with the blank control group, PLGA(Ag-Fe3O4) under magnetic field-coated samples had a significantly lower amount of colonized S. mutans (P<0.01). Osteoblast proliferation results showed that the coated samples did not exhibit cytotoxicity and could promote osteoblast proliferation as shown by MTT, alkaline phosphatase, and the nucleolar organizer region count. Conclusion: We developed a novel Ag biologically compatible nanoparticle in this study without compromising the nano-Ag antibacterial activity, which provided continuous antibacterial action. PMID- 29988770 TI - Spontaneous regression of a metastatic melanoma pulmonary deposit following biopsy. AB - Spontaneous complete and partial regression of metastatic melanoma is poorly understood, and is a rare phenomenon with less than 80 cases reported since 1866. Several correlations have been noted such as systemic or local infections, operative trauma, hormonal influences, nutrition and immunologic factors. We present FDG PET and CT findings in a patient with multiple pulmonary metastases of melanoma, one of which underwent regression following biopsy. We suggest immune system modulation, triggered by biopsy, could have played a role, although the precise mechanism remains unknown. PMID- 29988769 TI - The prognostic value of quantitative analysis of CCL5 and collagen IV in luminal B (HER2-) subtype breast cancer by quantum-dot-based molecular imaging. AB - Objective: Breast cancer is the most common malignancy and one of the main causes of death in women. Luminal B (HER2-) breast cancer subtype has been proposed since the 2011 St Gallon consensus. The hormone receptor status in this type of breast cancer is positive; thus, endocrine therapy was performed in all cases, but the treatment was not satisfactory, and a significant number of cases received very little benefit from chemotherapy. Furthermore, there is no effective treatment target for this subtype. Luminal B (HER2-) breast cancer subtype has been proposed since the 2011 St Gallon consensus. Therefore, the study of the key molecules in the microenvironment of breast cancer can help to reveal the biological characteristics. Patients and methods: Luminal B (HER2-) breast cancer is a subtype with higher heterogeneity and poorer prognosis than luminal A. It is known that the development of cancer cells is an active process, and this process needs microenvironment cytokines, including chemokine (C-C motif) ligand 5 (CCL5) and collagen IV. Therefore, CCL5 and collagen IV were imaged and detected by quantum dot, and the CCL5/collagen IV ratio was calculated to investigate the prognostic value of the CCL5/collagen IV ratio in luminal B (HER2-). Results: Quantitative determination showed a statistically significant negative correlation between CCL5 and collagen IV. The 5-year disease-free survival (5-DFS) of the high and low CCL5/collagen IV ratio subgroups was significantly different. The CCL5/collagen IV ratio had a greater prognostic value for 5-DFS. The CCL5/collagen IV ratio was an independent prognostic indicator. Conclusion: Our findings revealed the effective integration of tumor CCL5 and collagen IV, and a new method for predicting the prognosis of luminal B (HER2-) has been developed. PMID- 29988771 TI - Daptomycin: a comparison of two intravenous formulations. AB - Daptomycin is a cyclic lipopeptide antibacterial agent with potent bactericidal activity against a broad range of Gram-positive organisms. In 2003, daptomycin for injection received approval from the US Food and Drug Administration (FDA) for the treatment of patients with complicated skin and skin structure infections (cSSSIs); in 2006, it was approved for the treatment of patients with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates. In 2016, the FDA approved a new formulation of daptomycin for injection (daptomycin RF) for the same indications. The efficacy and safety of daptomycin for injection have been established in pivotal clinical trials, and the findings of nonclinical studies indicate that both formulations of daptomycin for injection are equivalent. Herein we refer to the new daptomycin formulation as daptomycin RF to distinguish it from the original formulation. Daptomycin RF provides clinicians and clinical pharmacists with a product that offers improved stability and more rapid, in-vial reconstitution with either sterile or bacteriostatic water for injection, while maintaining the same antibacterial coverage. Here we discuss the rationale for and the potential value of daptomycin RF, and briefly review the similarities and differences between the original formulation of daptomycin and daptomycin RF. PMID- 29988772 TI - Implementing a novel electronic health record approach to track child sugar sweetened beverage consumption. AB - Sugar-sweetened beverage (SSB) consumption is a risk factor for childhood obesity. Including this measure in electronic health records (EHR) could enhance clinical care and facilitate research on this topic. We implemented a single item, EHR screening question for SSB and 100% fruit juice at 8 pediatric practices affiliated with a North Carolina academic medical center. From March December 2017, we evaluated SSB screening of children 6 months-17 years of age. In a sub-sample of screened patients, we also conducted a telephone-based validation survey, comparing EHR-based responses to a lengthier beverage questionnaire, using Spearman rank coefficients and Kappa statistic. 22,626 children (91% of all seen) were screened for SSB intake. The screened population was diverse - 35% non-Hispanic White, 26% African-American, and 30% Hispanic. Consistent with national estimates, reported intake was typically higher than recommended: 41% (n = 9220) reported consuming SSB or fruit juice >1*/day in the past month, and consumption was higher among race/ethnic minorities. Of 201 validation survey respondents, direct correlation between their beverage survey and EHR screener responses was moderate, with a Spearman's rank correlation coefficient of 0.41 (p < 0.001) and Kappa statistic of 0.42 (95% CI 0.24-0.60). EHR-based screening for SSBs and fruit juice was successfully implemented, generating a large volume of SSB consumption data in a diverse patient population. Inclusion of patient-reported dietary measures in the EHR is feasible and could be useful for clinical care and research. Planned modifications may improve the correlation of such a screener with lengthier dietary instruments. PMID- 29988773 TI - Effect of an educational program on adolescent premenstrual syndrome: lessons from the Great East Japan Earthquake. AB - Background: Catastrophic disasters such as great earthquakes cause tremendous physical and mental damage. We previously reported that the Great East Japan Earthquake worsened premenstrual symptoms among adolescent girls in the disaster stricken area. Objectives: We reanalyzed these data to determine the positive effects of education on premenstrual symptoms. Materials and methods: Annual school-based surveys about premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) have been conducted in Sendai since 2009. The Great East Japan Earthquake occurred on March 11, 2011. First-year students in one school had received education on PMS/PMDD before the earthquake, whereas those in another school had not. We reanalyzed data for 1431 girls (November 2010) and 1489 girls (December 2011) aged 15-18 years. Results: The severity of PMS/PMDD in students who had received the education program showed no changes between before and after the earthquake. However, students who had not received education showed worsening of the severity of PMS/PMDD. Conclusion: This study showed education had a possible beneficial effect for the prevention of stress-induced PMS/PMDD. PMID- 29988774 TI - Kerion and tinea capitis. PMID- 29988775 TI - Hot shoulder PET/CT lesion: Unusual presentation of tenosynovial giant cell tumor. AB - We present a case of a tenosynovial giant cell tumor (TGCT) incidentally discovered at the shoulder on PET/CT, in a patient with history of thyroid cancer. Many documented cases of TGCT have been incidentally imaged by PET/CT and have been found to have varying levels of metabolic activity, however the shoulder location is unusual. This type of musculoskeletal lesion often has MRI characteristics, such as gradient echo blooming, which can render a confident diagnosis without need for biopsy. PMID- 29988777 TI - Dropped gallstones mimicking peritoneal metastasis: A case report. AB - Dropped gallstones is a rare complication after a cholecystectomy. Computed tomography is the modality of choice for diagnosis. Dropped gallstones can be a fortuitous discovery in an asymptomatic patient but it is usually revealed when a complication occurs, most commonly through an abscess. Our case presents a dropped gallstone found during a routine check-up in a patient with a history of small bowel cancer. We will discuss differential diagnosis with others calcified peritoneal nodular patterns, particularly peritoneal carcinomatosis. We will recall the multimodality imaging findings of dropped gallstone and, based on literature, we will review the different sources of calcified peritoneal nodular pattern. The treatment of gallstone drop consequences depends on the clinical aspect. PMID- 29988776 TI - Multidisciplinary recommendations for diagnosis and treatment of foot problems in people with rheumatoid arthritis. AB - Background: Foot problems in people with rheumatoid arthritis (RA) are highly prevalent and have a substantial impact on quality of life. Healthcare professionals from various professions can be involved in the management of these foot problems. There is currently no consensus on optimal management. Therefore, the aim of the present study was to develop multidisciplinary recommendations for the management of foot problems in people with RA in the Netherlands. Methods: The recommendations were based on research evidence and consensus among experts, following published strategies for the development of practice recommendations. The expert group was composed of 2 patients and 22 experienced professionals (rheumatologists, rehabilitation physicians, orthopaedic surgeons, specialized nurses, podiatrists, orthopaedic shoe technicians, pedicurists, and researchers) in the Netherlands. For each developed recommendation i) the level of evidence was determined, and ii) the level of agreement (among the expert group) was set by an anonymous voting procedure using a numeric rating scale. The mean and range of the level of agreement for each recommendation was calculated. A recommendation was approved when >=70% of the expert group voted an NRS-agreement >=7. Results: In total, 41 recommendations were developed. Two recommendations concerned a framework for diagnosis and treatment. Thirty-nine recommendations on foot care were developed: seven on diagnosis (including check-ups of feet and shoes and diagnostic imaging), 27 on treatment (including corticosteroid injections, foot surgery, therapeutic shoes, foot orthoses, exercise therapy, toe orthoses and toenail-braces, treatment of toenails and skin), four on communication, and one on organisation of RA-related footcare. All recommendations were approved by the expert group. The percentage score of NRS agreement >=7 ranged from 80 to 100%. Conclusions: These are the first published multidisciplinary recommendations specific to the management of foot problems in people with RA. Multidisciplinary recommendations can provide guidance in timely referrals and access to adequate footcare. More research is needed to strengthen the evidence on diagnosis and treatment of RA-related foot problems. These national recommendations may be a first step towards developing international multidisciplinary recommendations for the management of foot problems in RA. PMID- 29988778 TI - Next generation sequencing reveals widespread trypanosome diversity and polyparasitism in marsupials from Western Australia. AB - In Western Australia a number of indigenous Trypanosoma spp. infect susceptible native marsupials, such as the woylie (Bettongia penicillata), brushtail possum (Trichosurus vulpecula), and chuditch (Dasyurus geoffroii). Two genotypes of Trypanosoma copemani (identified as G1 and G2) have been found in the woylie, and G2 has been implicated in the decline of this host species, making its presence of particular interest. Here we used targeted amplicon next generation sequencing (NGS) of the Trypanosoma 18S rDNA loci on 70 Trypanosoma-positive marsupial blood samples, to identify T. copemani genotypes and multiple Trypanosoma infections (polyparasitism) in woylies and cohabiting species in Western Australia. Polyparasitism with Trypanosoma spp. was found in 50% of the wildlife sampled, and within species diversity was high, with 85 zero-radius operational taxonomic units (ZOTUs) identified in nine putative parasite species. Trypanosoma copemani was assigned 17 ZOTUs and was identified in 80% of samples. The most abundant ZOTU isolated (63%) differed slightly from the published genotype of G1, and G2 was the second most abundant ZOTU (14%). Trypanosome diversity was significantly greater in woylies than in brushtail possums, and parasite community composition also differed significantly between these host species. One novel Trypanosoma spp. genotype (Trypanosoma sp. ANU2) was found in 20% of samples. A species of Crithidia was detected in a woylie, and two avian trypanosomes (Trypanosoma avium and Trypanosoma sp. AAT) were identified in woylies for the first time. PMID- 29988779 TI - Nontraumatic intradiploic arachnoid cyst of the sphenoid bone. AB - The intradiploic arachnoid cysts are rare radiological entities which are generally post-traumatic in nature and occur mostly in occipital region. We present a rare case of non-traumatic, asymptomatic intradiploic cyst of the greater wing of sphenoid in an elderly patient. The CT and MR imaging confirmed an intraosseous multiloculated cystic lesion which showed communication with the cerebrospinal fluid in anterior temporal fossa, through the small bony defects. PMID- 29988780 TI - Relationship between airway obstruction and incidence of metabolic syndrome in Korea: a community-based cohort study. AB - Background: Although studies have examined the relationship between metabolic syndrome (MetS) and COPD, the incidence of MetS in individuals with COPD has not specifically been investigated. This study aimed to evaluate the incidence of MetS in subjects with airway obstruction using data from a community-based cohort. Patients and methods: Data representing 4 years of follow-up from the Ansung-Ansan cohort were analyzed; a total of 6,184 adults, who were >=40 years of age and underwent spirometry, were enrolled in this study. Airway obstruction was defined as forced expiratory volume in 1 s/forced vital capacity ratio <70%, and MetS was determined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Results: A total of 419 patients were newly diagnosed with MetS, based on the National Cholesterol Education Program Adult Treatment Panel III guidelines, during follow-up. MetS was more frequent in COPD subjects, relative to non-COPD subjects, in both sexes (14.7% vs 11.0% [men] and 14.7% vs 11.8% [women]). In men subjects, the risk for MetS was higher in subjects with airflow obstruction than in subjects without obstruction, after adjusting for age, body mass index, and smoking status. Conclusion: The incidence of MetS was higher in men with airflow obstruction than in healthy subjects. PMID- 29988782 TI - Haemosporidian parasite community in migrating bobolinks on the Galapagos Islands. AB - Bobolinks (Dolichonyx oryzivorus) migrate from their breeding grounds in North America to their wintering grounds in South America during the fall each year. A small number of Bobolinks stop temporarily in Galapagos, and potentially carry parasites. On the North American breeding grounds, Bobolinks carry a least two of the four Plasmodium lineages recently detected in resident Galapagos birds. We hypothesized that Bobolinks carried these parasites to Galapagos, where they were bitten by mosquitoes that then transmitted the parasites to resident birds. The haemosporidian parasite community in 44% of the Bobolinks we captured was consistent with those on their breeding grounds. However, the lineages were not those found in Galapagos birds. Our results provide a parasite community key for future monitoring. PMID- 29988781 TI - Exploring resilience models in a sample of combat-exposed military service members and veterans: a comparison and commentary. AB - Background: The term resilience is applied in numerous ways in the mental health field, leading to different perspectives of what constitutes a resilient response and disparate findings regarding its prevalence following trauma. Objective: illustrate the impact of various definitions on our understanding and prevalence of resilience, we compared various resilience definitions (absence of PTSD, absence of current mental health diagnosis, absence of generalized psychological distress, and an alternative trauma load-resilience discrepancy model of the difference between actual and predicted distress given lifetime trauma exposure) within a combat-exposed military personnel and veteran sample. Method: In this combat-trauma exposed sample (N = 849), of which approximately half were treatment seeking, rates of resilience were determined across all models, the kappa statistic was used to determine the concordance and strength of association across models, and t-tests examined the models in relation to a self-reported resilience measure. Results: Prevalence rates were 43.7%, 30.7%, 87.4%, and 50.1% in each of the four models. Concordance analyses identified 25.7% (n = 218) considered resilient by all four models (kappa = .40, p < .001). Correlations between models and self-reported resilience were strong, but did not fully overlap. Conclusions:The discussion highlights theoretical considerations regarding the impact of various definitions and methodologies on resilience classifications, links current findings to a systems-based perspective, and ends with suggestions for future research approaches on resilience. PMID- 29988783 TI - Comparison of Single Versus Multifraction Radiotherapy in Palliation of Painful Bone Metastases. AB - Background: Bone is a common site of dissemination in advanced cancer accounting for one-third of all distant metastases. Various fractionation schedules of radiotherapy have been used for palliation of bone metastases. The aim of this study was to compare three schedules of external radiation therapy (8 Gy single session versus 20 Gy/5 fractions versus 30 Gy/10 fractions) for palliative management of bone metastases. Methods: In the present study, 60 patients of bone metastases from any primary site were enrolled and randomly divided into three groups of 20 patients each by draw of lots. These patients received palliative external beam radiation therapy to the involved site. Patients were given 8 Gy single session, 20 Gy/5 fractions/1 week and 30 Gy/10 fractions/2 weeks in groups I, II and III, respectively. Results: The percentage of patients with overall pain relief was 80% in group I, 75% in group II and 85% in group III (P = 0.7). The number of patients with complete pain relief was 4 (20%) in each group. Maximum patients got pain relief at 4 weeks post-radiotherapy. The number of patients with improved performance status was 4 (20%) in group II and 2 (10%) each in groups I and III (P = 0.5). Thirteen (65%) patients in each of the groups had decreased analgesic requirement at 2-month follow-up. Retreatment rate was more in the single fraction (20%) compared to only 5% in group II and none in the group III (P = 0.05). Conclusion: From the present study we conclude that 8 Gy single fraction is as effective as multifraction radiotherapy for the palliation of painful bone metastases. However, for a center like ours being the only Government Tertiary Cancer Care Centre in the State, general consensus drawn after this study, recommends external radiation therapy 20 Gy/5 fraction regimen to be an appropriate means of palliation of painful bone metastases. PMID- 29988784 TI - Analysis of Risk Factors for Lymphatic Metastasis in Endometrial Carcinoma and Utility of Three-Dimensional Magnetic Resonance Imaging in Gynecology. AB - Background: The aim of our study was to evaluate the utility of three-dimensional magnetic resonance imaging (3D-MRI) in gynecologic fields. We examined the relation between tumor volume measured with 3D-MRI and lymph node metastasis in patients with endometrial carcinoma. Methods: A retrospective analysis of 84 patients with endometrial carcinoma who underwent hysterectomy, bilateral salpingo-oophorectomy with pelvic/para-aortic lymphadenectomy at our institute was performed. Of these, the tumor volume of 59 patients could be calculated using 3D-MRI. Age, serum CA125 level, histologic type and grade, volume of tumors were examined in relation to pelvic/para-aortic lymph node metastasis as preoperative risk factors. Tumor volume measurements were calculated using 3D-MRI with AqariusNET Server 4G software. Univariate and multivariate associations between the preoperative risk factors and pelvic/para-aortic lymph node metastasis were analyzed. Receiver operating characteristic (ROC) curves were used to determine the best cut-off points for CA125 levels and tumor volume to predict lymph metastasis. Results: The mean age, CA125 value and tumor volume were 61.6 years, 51.6 (IU/L) and 11.6 (cm3), respectively. Lymphatic metastasis occurred in 16.0% (10 of 59) patients. Univariate analysis indicated that a high CA125 level and a tumor volume were risk factors (P = 0.0111, 0.0123 respectively). Multivariate analysis revealed that tumor volume was an independent risk factor for lymphatic metastasis (hazard ratio (HR) 12.7, 95% CI 1.06 - 154). The potential cut-off values of CA-125 level and tumor volume were 29 IU/L (sensitivity: 0.744; specificity: 0.821) and 12.79 cm3 (sensitivity: 0.821; specificity: 0.744), respectively. Conclusions: Our results suggest that tumor volume calculated with 3D-MRI correlates with lymph node metastasis in endometrial carcinoma. PMID- 29988786 TI - Thrombosis of the pampiniform plexus: About a case report. PMID- 29988785 TI - Captive individuals of endangered Philippine raptors maintain native feather mites (Acariformes: Pterolichoidea) species. AB - Endangered species of hosts are coupled with endangered species of parasites, which share the risk of co-extinction. Conservation efforts sometimes include breeding of rare species in captivity. Data on parasites of captive populations of endangered species is scarce and the ability of small numbers of captive host individuals to support the biodiversity of native parasites is limited. Examination of ectosymbionts of the critically endangered Philippine eagles and the endangered Mindanao Hawk-Eagle kept at the Philippine Eagle Center, Philippines, revealed three feather mite species despite regular treatment with insecticide powder. No other ectosymbiont taxa were detected. Studies in morphology and molecular phylogeny of these feather mites based on mitochondrial and nuclear DNA markers indicate that species found were typical for Accipitridae. Three new pterolichoid feather mite species (Acari: Pterolichoidea) were described from two species of eagles (Accipitriformes: Accipitridae) endemic to the Philippines: Hieracolichus philippinensis sp. n. (Gabuciniidae) and Pseudalloptinus pithecophagae sp. n. (Pterolichidae) from the Great Philippine Eagle Pithecophaga jefferyi Ogilvie-Grant, 1896, and Pseudogabucinia nisaeti sp. n. (Kramerellidae) from the Mindanao Hawk-Eagle Nisaetus pinskeri Gould, 1863. The presence of H. philippinensis on P. jefferyi supports the recent finding that the Great Philippine Eagle belongs to the lineage of serpent eagles (Circaetinae) rather than to the Harpy and other eagles. PMID- 29988787 TI - Subcutaneous merocercoids of Clistobothrium sp. in two Cape fur seals (Arctocephalus pusillus pusillus). AB - Fur seals represent intermediate hosts of the cestode Clistobothrium. Large sharks are definitive hosts for these parasites. Two female, 25- and 27-year-old fur seals, caught in the 1980s at the South African coast, were examined pathomorphologically. Both animals showed multifocal, up to 1 cm in diameter large cavities of the thoracic and abdominal subcutaneous adipose tissue containing intraluminal metacestodes of tapeworms, which were surrounded by a locally extensive, pyogranulomatous panniculitis. The metacestodes (merocercoids) of one fur seal were isolated from the subcutaneous adipose tissue and characterized morphologically and for the first time from this host by molecular techniques. The morphometric data corresponded with 'delphini'-morphotype merocercoids, but the sequence of the partial 28S ribosomal RNA gene identified them as conspecific with merocercoids of the morphotype 'grimaldii'. These merocercoid types are morphologically Type XV metacestodes of marine tapeworms and represent different species of Clistobothrium. Sequence data were generated for 18S, ITS1, 5.8S, ITS2, partial 28S ribosomal DNA and partial mitochondrial cox1 gene and phylogenetic analysis of 18S rRNA and partial 28S rRNA genes identified the fur seal merocercoids as Clistobothrium species. However, it cannot yet be assigned to species level because of limited molecular data from adult stages. Most likely, both fur seals were infected as juveniles in their original habitat, the coastal regions of South Africa. The metacestode infection is probably an incidental finding, however, there is a chronic inflammatory reaction next to the subcutaneous merocercoids. It is noteworthy, that the merocercoids remain in a potentially infective stage even after more than 20 years. PMID- 29988788 TI - Post-translational regulation of a Porphyromonas gingivalis regulator. AB - Background: Bacteria use two-component signal transduction systems (among others) to perceive and respond to environmental changes. Within the genus Porphyromonas, we observed degeneration of these systems, as exemplified by the loss of RprX, the sensor kinase partner of the RprY. Objective: The purpose of this study was to investigate modulation of RprY function by acetylation. Design: The transcriptional activity of the rprY-pat genes were measured by RT-PCR and 5' RACE. The acetylation of RprY were detected by western blotting. Electromobility shift and in vitro ChIP assays were used to measure the DNA binding activity of RprY. The expression of RprY target genes was measured by qRT-PCR. Effects of acetylation on phosphorylation of RprY were measured by Phos-tag gels. Results: The rprY gene is cotranscribed with pat. RprY is acetylated in vivo, and autoacetylated in vitro in a reaction that is enhanced by Pat; the CobB sirtuin deacetylates RprY. Acetylation reduced the DNA binding of RprY. Induced oxidative stress decreased production of RprY in vivo, increased its acetylation and increased expression of nqrA. Conclusions: We propose that to compensate for the loss of RprX, P. gingivalis has evolved a novel mechanism to inactivate RprY through acetylation. PMID- 29988789 TI - 'Keep in Mind an Endograft is a Spring!': Re. 'Aorto-enteric Fistula After Endovascular Repair for Behcet's Disease Patient: a Case Report'. PMID- 29988790 TI - Sequence capture phylogenomics of eyeless Cicurina spiders from Texas caves, with emphasis on US federally-endangered species from Bexar County (Araneae, Hahniidae). AB - Morphological, mitochondrial, and nuclear phylogenomic data were combined to address phylogenetic and species delimitation questions in cave-limited Cicurina spiders from central Texas. Special effort was focused on specimens and cave locations in the San Antonio region (Bexar County), home to four eyeless species listed as US Federally Endangered. Sequence capture experiments resulted in the recovery of ~200-400 homologous ultra-conserved element (UCE) nuclear loci across taxa, and nearly complete COI mitochondrial DNA sequences from the same set of individuals. Some of these nuclear and mitochondrial sequences were recovered from "standard" museum specimens without special preservation of DNA material, including museum specimens preserved in the 1990s. Multiple phylogenetic analyses of the UCE data agree in the recovery of two major lineages of eyeless Cicurina in Texas. These lineages also differ in mitochondrial clade membership, female genitalic morphology, degree of troglomorphy (as measured by relative leg length), and are mostly allopatric across much of Texas. Rare sympatry was confirmed in Bexar County, where members of the two major clades sometimes co exist in the same karst feature. Both nuclear phylogenomic and mitochondrial data indicate the existence of undescribed species from the San Antonio region, although further sampling and collection of adult specimens is needed to explicitly test these hypotheses. Our data support the two following species synonymies (Cicurina venii Gertsch, 1992 = Cicurina madla Gertsch, 1992; Cicurina loftini Cokendolpher, 2004 = Cicurina vespera Gertsch, 1992), formally proposed here. Overall, our taxonomy-focused research has many important conservation implications, and again highlights the fundamental importance of robust taxonomy in conservation research. PMID- 29988791 TI - Land snail fauna in Gunung Kuang Limestone Hill, Perak, Malaysia and its conservation implications (Mollusca, Gastropoda). AB - This paper presents the first land snail species checklist for Gunung Kuang (Kuang Hill), a limestone hill located next to Gunung Kanthan that is recognised as one of the most important limestone hills for its diverse land snail fauna in Kinta Valley. Samplings were carried out at five plots in Gunung Kuang. This survey documented 47 land snail species, in which six species were identified as unique to Gunung Kuang. Approximately half of the land snails from Gunung Kanthan were found in Gunung Kuang. In addition, one of six unique species from Gunung Kanthan was also found in Gunung Kuang. These rich land snail species in Gunung Kuang are similar to other hills in Kinta Valley, but it is relatively lesser than the adjacent Gunung Kanthan. In view of Gunung Kuang's unique land snail species, and its location closest to disturbed Gunung Kanthan, Gunung Kuang should be considered in the conservation management plan for Gunung Kanthan. PMID- 29988793 TI - Dilated Virchow-Robin space and Parkinson's disease: A case report of combined MRI and diffusion tensor imaging. AB - In this manuscript we report the case of a 69-year-old female patient, who suffers from Parkinson's disease (PD) with a dilated Virchow-Robin space (dVRS) on the left anterior perforated substance. During a magnetic resonance imaging examination, the presence of a dVRS was discovered on the left anterior perforated substance. Subsequently, the patient has been subjected to further investigation of magnetic resonance imaging and diffusion tensor imaging (DTI). The DTI data of our PD patient showed increased peak frequency of left fractional anisotropy and decreases in the distribution of Mean Diffusivity(MD) with changes in the fiber density compared to the normal contralateral tract. We hypothesize that the DTI changes are due to dVRS. In the text a review of the recent literature on the presence of dVRSs, located in mono and bilateral seat, in patients with PD is reported, explaining its possible implications on disease progression, cognitive decline, and worsening of symptoms. PMID- 29988792 TI - Lurking in the dark: Cryptic Strongyloides in a Bornean slow loris. AB - Within host communities, related species are more likely to share common parasitic agents, and as a result, morphological similarities have led researchers to conclude that parasites infecting closely related hosts within a community represent a single species. However, genetic diversity within parasite genera and host range remain poorly investigated in most systems. Strongyloides is a genus of soil-transmitted nematode that has been reported from several primate species in Africa and Asia, and has been estimated to infect hundreds of millions of people worldwide, although no precise estimates are available. Here we describe a case of infection with a cryptic species of Strongyloides in a Bornean (Philippine) slow loris (Nycticebus menagensis) living within a diverse community of several primate species in the Lower Kinabatangan Wildlife Sanctuary, Malaysian Borneo. Fresh fecal samples were collected from five primate species and nematode larvae cultured from these samples were selected for phylogenetic analyses. Sequences obtained for most larvae were identified as S. fuelleborni, grouping into three different clusters and showing no aggregation within specific hosts or geographic location. In contrast, a set of parasite sequences obtained from a slow loris clustered closely with S. stercoralis into a different group, being genetically distinct to sequences reported from other primate hosts, humans included. Our results suggest that although S. fuelleborni infects all haplorrhines sampled in this primate community, a different species might be infecting the slow loris, the only strepsirrhine in Borneo and one of the least studied primates in the region. Although more data are needed to support this conclusion, we propose that Strongyloides species in primates might be more diverse than previously thought, with potential implications for ecological and evolutionary host-parasite associations, as well as epidemiological dynamics. PMID- 29988794 TI - Major Risk Factors in Head and Neck Cancer: A Retrospective Analysis of 12-Year Experiences. AB - Background: Head and neck cancer (HNC) is the seventh most common type of cancer in the world and constitute 5% of the entire cancers worldwide. The global burden of HNC accounts for 650,000 new cases and 350,000 deaths worldwide every year and a major proportion of regional malignancies in India. More than 70% of squamous cell carcinoma of the head and neck are estimated to be avoidable by lifestyle changes, particularly by effective reduction of exposure to well-known risk factors such as tobacco smoking and alcohol drinking. Methods: A retrospective analysis of 12 years (2001 - 2012) of HNC patients attending RCC, PGIMS Rohtak was done. Total numbers of cancer patients seen were 26,295 and out of these 9,950 patients were of HNCs, which were retrospectively analyzed for their associated risk factors in different HNC subtypes. Most of the patients, i.e. 92.3%, were presented as locally advanced HNC (stages III and IV). Results: It has been observed that smoking and alcohol are the strongest independent risk factors responsible for increased risk of HNC and are further having synergetic correlations. Conclusion: The present study confirms the principal role of alcohol consumption and smoking in HNC carcinogenesis, as well as the differential associations with HNC subtypes, and a significant, positive, multiplicative interaction with different risk factors. PMID- 29988795 TI - TK2-related mitochondrial disorder is not restricted to the skeletal muscle. PMID- 29988796 TI - Systematic review and meta-analysis of the efficacy of liposomal bupivacaine in colorectal resections. AB - Objective: The objective of the study was to systematically investigate the outcomes of Liposomal Bupivacaine following major colorectal resections. Patients and methods: We conducted a comprehensive literature search of PubMed, Medline, Google scholar, Cochrane Central Registry and clinical trials.gov databases through May 2017 for studies published regarding liposomal bupivacaine. Studies were filtered based on relevance to perioperative analgesia in colorectal resections. Data comparing type of study, techniques of resection, mode of administration of liposomal bupivacaine, details of control group, outcomes were collected. Results: A total of 1008 patients from seven studies were included in this systematic review and meta-analysis. The studies were mostly retrospective or prospective cohort studies with one randomized controlled trial (RCT). Meta analysis showed that liposomal bupivacaine was associated with decreased length of stay, standard mean difference in days (SMD) - 0.34, (95% confidence intervals [CI] - 0.56, -0.13, p = .001) and decreased IV opioid use (expressed as intravenous morphine equivalent in milligrams) in the first 48-72 h, SMD -0.49 (95% CI -0.69, -0.28, p < .00001). Pain scores were also significantly low in patients who received liposomal bupivacaine, SMD -0.56 (95% CI -1.07, -0.06, p = .03]. There was no significant difference in hospitalization costs between the two groups. Conclusions: Use of liposomal bupivacaine is associated with decreased IV opioid use, length of stay and lower pain scores. However, our data needs to be interpreted cautiously given the relative paucity of randomized controlled trials. PMID- 29988797 TI - Perforated jejunitis in a child with acute lymphoblastic leukemia treated with pegaspargase. AB - Survival rates of children with acute lymphoblastic leukemia have improved since the incorporation of asparaginase in the treatment protocol, but the medication has potential serious complications, including vascular thrombosis. Here, we describe the case of a 13-year-old boy with pre-T-cell acute lymphoblastic leukemia whose treatment course was complicated by perforated jejunitis requiring resection of a portion of his small bowel. Pathologic assessment showed transmural ischemia, mesenteric venous and arterial thrombi, and scattered cytomegalovirus inclusion bodies. Pediatric mesenteric ischemia is rare, and its consideration in patients treated with asparaginase is discussed. PMID- 29988799 TI - Application of tetracycline hydrochloride loaded-fungal chitosan and Aloe vera extract based composite sponges for wound dressing. AB - Chitosan composite material has been used as an efficient drug carrier for potential drug delivery systems in specific cases of wound dressing management. In the present study, 0.5 g/L of the antibiotic tetracycline hydrochloride (TCH) was loaded into 1% fungal chitosan (FCS) incorporated with 0.2% of Aloe vera extract (AVE). Two types of sponges were prepared, with and without AVE, such as FCS-AVE-TCH and FCS-TCH, respectively. They were characterized by UV-Visible spectrophotometer, attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and scanning electron microscopy (SEM). A constant amount of cumulative TCH release was observed from FCS-AVE-TCH composite sponges at the phosphate buffer saline (pH 7.4), they exhibited good antibacterial activity against both Gram-positive and Gram-negative bacteria. Furthermore, the Vero cells (African green monkey kidney cell line) treated by the composites showed augmented cell viability, which suggests that it could be used as a cost effective, potential wound dressing material. PMID- 29988798 TI - Novel nanocrystal-based solid dispersion with high drug loading, enhanced dissolution, and bioavailability of andrographolide. AB - Objective: The current study sought to design a quickly dissolving, high drug loading nanocrystal-based solid dispersion (NC-SD) in order to improve the dissolution of poorly soluble drugs. Methods: The NC-SD was prepared by means of combination of homogenization and spray-drying. Polymer hydroxypropylmethylcellulose (HPMC) was used as baseline dispersant for NC-SD of the model drug - andrographolide (AG). Three superdisintegrants cohomogenized with HPMC were used as codispersant for AG-NC-SD and compared to common water soluble dispersants - mannitol and lactose. The dissolution characterization and oral bioavailability of AG-NC-SD were evaluated. Results: The AG-NC-SD with the higher concentration of HPMC exhibited fast dissolution due to the enhanced wettability of HPMC. The water-soluble codispersants (mannitol and lactose) did not completely prevent AG-NC from aggregation during spray-drying. To achieve much faster AG release, cohomogenized superdisintegrants at a level of 20% must be used along with 25% HPMC. Compared with water-soluble dispersants like mannitol and lactose, superdisintegrants with high swelling capacity were much more effective dispersants for enhancing fast redispersion/dissolution of AG-NC SD via a swelling-triggered erosion/disintegration mechanism. Surfactant-free AG NC-SD with 15% cohomogenized sodium carboxymethyl starch combined with 15% HPMC and 10% lactose enhanced the dissolution further, without comprising drug loading, exhibited a barely compromised dissolution rate compared to precursor NC suspensions (f2>50), and possessed drug loading up to 67.83%+/-1.26%. The pharmacokinetics results also demonstrated that the AG-NC-SD significantly improved the bioavailability in vivo of AG (P<0.05), compared with to the coarse AG. Conclusion: This study illustrates that a quickly dissolving, high drug load, surfactant-free NC-SD can be prepared by using a superdisintegrant as codispersant, and provides a feasible strategy to improve the oral bioavailability of poorly soluble drugs. PMID- 29988800 TI - Toxocariasis in Carnivora from Argentinean Patagonia: Species molecular identification, hosts, and geographical distribution. AB - Twenty four specimens of seven species belonging to the families Felidae, Mustelidae, and Canidae were obtained in Lanin and Nahuel Huapi National Parks from March 1996 to April 2016. Specimens were processed by necropsy in order to contribute to the knowledge of toxocariasis in wild carnivores of Argentinean Patagonia. The only Puma concolor and the seven Leopardus geoffroyi were positive for Toxocara cati. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) of the ITS-1 region from larval and adult DNA was carried out to confirm parasite species identification. This is the first molecular determination of T. cati from wild felids in Argentina and the study also fill gaps about the spatial distribution and hosts for Toxocara cati. PMID- 29988801 TI - Imaging of blood flow and oxygen state with a multi-segment optoacoustic ultrasound array. AB - Changes in hemodynamic parameters are directly linked to biological function and physiological activity. Characterization of hemodynamics is commonly performed by Doppler ultrasound, which provides accurate measurements of blood flow velocity. Multi-spectral optoacoustic tomography is rapidly undergoing clinical translation fostered by its unique and complementary capacity for label-free mapping of the blood volume and the distribution of oxy- and deoxy-hemoglobin in blood. Here we report on a hybrid optoacoustic and ultrasound imaging approach that enables multi-modal imaging of blood flow and oxygen state using a multi-segment detector array. We further demonstrate rendering of multi-modal pulse-echo ultrasound, multi-spectral optoacoustic tomography, and color Doppler images from carotid artery of a healthy subject. PMID- 29988802 TI - Detecting co-infections of Echinococcus multilocularis and Echinococcus canadensis in coyotes and red foxes in Alberta, Canada using real-time PCR. AB - The continued monitoring of Echinococcus species in intermediate and definitive hosts is essential to understand the eco-epidemiology of these parasites, as well to assess their potential impact on public health. In Canada, co-infections of Echinococcus canadensis and Echinococcus multilocularis based on genetic characterization have been recently reported in wolves, but not yet in other possible hosts such as coyotes and foxes. In this study, we aimed to develop a quantitative real-time PCR assay to detect E. multilocularis and E. canadensis and estimate the occurrence of co-infections while inferring about the relative abundance of the two parasites within hosts. We tested DNA extracted from aliquots of Echinococcus spp. specimens collected from intestinal tracts of 24 coyote and 16 fox carcasses from Alberta, Canada. We found evidence of co infections of E. multilocularis and E. canadensis in 11 out of 40 (27%) samples, with 8 out of 24 (33%) in coyote samples and 3 out of 16 (19%) in red fox samples. DNA concentrations were estimated in three samples with Cq values within the range of the standard curve for both parasites; two of them presented higher DNA concentrations of E. multilocularis than E. canadensis. The use of qPCR aided detection of co-infections when morphological discrimination was difficult and quantification of DNA for samples within the standard curve. This is the first molecularly confirmed record of E. canadensis in coyotes and the first evidence of co-infections of E. multilocularis and E. canadensis in coyotes and red foxes. PMID- 29988803 TI - Occurrence of endoparasites in wild Antillean manatees (Trichechus manatus manatus) in Colombia. AB - The recognized impact of parasites in wildlife populations demands surveillance of endangered species like the Antillean manatees (Trichechus manatus manatus) in Colombia. We conducted a parasitological survey in four rescued sea cows in order to document the parasite diversity of this sirenian in the Caribbean wetland of Colombia and contribute to the molecular characterization of its trematodes. The flukes Chiorchis fabaceus, Nudacotyle undicola and the protozoans Eimeria manatus and E. nodulosa were identified in analysed faecal samples. For C. fabaceus and N. undicola, partial regions of ribosomal RNA genes were amplified and sequenced in order to infer their phylogenetic relations. The current study constitutes a new sirenian host (T. manatus manatus) record for the genus Eimeria and the trematode N. undicola. PMID- 29988804 TI - Failure of Ploidy and Proliferative Fraction to Predict Long-Term Outcome After Prostatectomy. AB - Background: Historically, ploidy and S phase percentage appeared to be promising predictors for prostate cancer recurrence. Lack of uniformity and consistency hampered their development. We evaluated ploidy and S phase for prostate cancer death in a cohort of patients with long-term follow-up. Methods: We identified 127 patients that had ploidy and S phase determined at the time of their radical prostatectomy for prostate cancer. With 15 years of follow-up, we determined the risk of biochemical failure and risk of death from prostate cancer. We correlated the S phase and ploidy findings with standard pathology findings. Results: A total of 107 (84%) had diploid and 20 (16%) had non-diploid cancers. The median S phase was 6.6%. There was no correlation of ploidy (P = 0.472) or S phase with preoperative PSA or Gleason score. On univariate analysis, EPE, margin positivity, seminal vesicle involvement, lymph node involvement, high Gleason score and PSA > 10 ng/mL were all predictive of biochemical failure. Ploidy and S phase were not. For prostate cancer death, only Gleason score was predictive. Conclusions: With long-term follow-up in our cohort, Gleason score was predictive of prostate cancer death. Ploidy and S phase were not predictive for biochemical failure or prostate cancer mortality. PMID- 29988805 TI - Co-infection patterns of intestinal parasites in arboreal primates (proboscis monkeys, Nasalis larvatus) in Borneo. AB - Non-human primates of South-East Asia remain under-studied concerning parasite epidemiology and co-infection patterns. Simultaneously, efforts in conservation demand knowledge of parasite abundance and biodiversity in threatened species. The Endangered proboscis monkey, Nasalis larvatus, a primate flagship species for conservation in Borneo, was investigated in the present study. Habitat loss and fragmentation are among the greatest threats to bachelor and harem groups of this folivorous colobine. Designed as a follow-up study, prevalence and co-infection status of intestinal parasites from N. larvatus in a protected area in Malaysian Borneo were analyzed from fecal samples using a flotation method. For the first time, the intestinal parasite co-infection patterns were examined using quantitative analyses. Overall, 92.3% of fecal samples (N = 652) were positive for helminth eggs. Five helminth groups were detected: (1) trichurids (82.7% prevalence) including Trichuris spp. (82.1%) and Anatrichosoma spp. (1.4%), (2) strongyles (58.9%) including Trichostrongylus spp. (48.5%) and Oesophagostomum/Ternidens spp. (22.8%), (3) Strongyloides fuelleborni (32.7%), (4) Ascaris lumbricoides (8.6%), and (5) Enterobius spp. (5.5%). On average, an individual was co-infected with two different groups. Significant positive associations were found for co-infections of trichurids with strongyles and S. fuelleborni as well as S. fuelleborni with A. lumbricoides and strongyles. This study shows a high prevalence of various gastrointestinal helminths with potential transmission pathways primarily related to soil and with zoonotic relevance in wild proboscis monkeys in their remaining natural habitats. Observed positive associations of trichurids with strongyles and Strongyloides spp. may result from the high prevalence of trichurids. Similarly, positive associations between Strongyloides and Ascaris were found, both of which typically occur predominantly in juvenile hosts. These findings should be considered when proposing conservation actions in altered habitats nearby human settlements and when managing captive populations. PMID- 29988806 TI - Batracobdella leeches, environmental features and Hydromantes salamanders. AB - Leeches can parasitize many vertebrate taxa. In amphibians, leech parasitism often has potential detrimental effects including population decline. Most of studies on the host-parasite interactions involving leeches and amphibians focus on freshwater environments, while they are very scarce for terrestrial amphibians. In this work, we studied the relationship between the leech Batracobdella algira and the European terrestrial salamanders of the genus Hydromantes, identifying environmental features related to the presence of the leeches and their possible effects on the hosts. We performed observation throughout Sardinia (Italy), covering the distribution area of all Hydromantes species endemic to this island. From September 2015 to May 2017, we conducted >150 surveys in 26 underground environments, collecting data on 2629 salamanders and 131 leeches. Water hardness was the only environmental feature correlated with the presence of B. algira, linking this leech to active karstic systems. Leeches were more frequently parasitizing salamanders with large body size. Body Condition Index was not significantly different between parasitized and non parasitized salamanders. Our study shows the importance of abiotic environmental features for host-parasite interactions, and poses new questions on complex interspecific interactions between this ectoparasite and amphibians. PMID- 29988807 TI - Pericardial rupture and cardiac herniation in blunt trauma. AB - Pericardial rupture in blunt trauma is rarely seen on computed tomography (CT) imaging due to its high initial mortality. We report a case of a 53-year-old man who presented to the Emergency Department in hemodynamic shock after intentional fall from height. Chest radiograph, which was taken in the trauma bay as a part of his primary survey, showed abnormal mediastinum contour with pneumopericardium. Pericardial rupture with cardiac herniation, and tamponade secondary to pneumopericardium, was diagnosed on trauma CT scan. The patient underwent emergent surgical management with thoracotomy to reduce the herniation and repair the pericardium. Immediate suspicion for pericardial and cardiac injury on the initial chest radiograph and rapid diagnosis on CT was indispensable for this patient's favorable outcome. PMID- 29988808 TI - A novel quantitative real-time PCR diagnostic assay for seal heartworm (Acanthocheilonema spirocauda) provides evidence for possible infection in the grey seal (Halichoerus grypus). AB - The distinct evolutionary pressures faced by Pinnipeds have likely resulted in strong coevolutionary ties to their parasites (Leidenberger et al., 2007). This study focuses on the phocid seal filarial heartworm species Acanthocheilonema spirocauda. A. spirocauda is known to infect a variety of phocid seals, but does not appear to be restricted to a single host species (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). However, to date, seal heartworm has never been reported in grey seals (Halichoerus grypus) (Measures et al., 1997; Leidenberger et al., 2007; Lehnert et al., 2015). The proposed vector for seal heartworm is Echinophthirius horridus, the seal louse. Seal lice are known to parasitize a wide array of phocid seal species, including the grey seal. With the advent of climate change, disease burden is expected to increase across terrestrial and marine mammals (Harvell et al., 2002). Accordingly, increased prevalence of seal heartworm has recently been reported in harbor seals (Phoca vitulina) (Lehnert et al., 2015). Thus, the need for improved, rapid, and cost effective diagnostics is urgent. Here we present the first A. spirocauda-specific rapid diagnostic test (a quantitative real-time PCR assay), based on a highly repetitive genomic DNA repeat identified using whole genome sequencing and subsequent bioinformatic analysis. The presence of an insect vector provides the opportunity to develop a multifunctional diagnostic tool that can be used not only to detect the parasite directly from blood or tissue specimens, but also as a molecular xenomonitoring (XM) tool that can be used to assess the epidemiological profile of the parasite by screening the arthropod vector. Using this assay, we provide evidence for the first reported case of seal heartworm in a grey seal. PMID- 29988809 TI - Novel ETFDH mutations in four cases of riboflavin responsive multiple acyl-CoA dehydrogenase deficiency. AB - Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism caused by mutations in EFTA, EFTB, or ETFDH. Many MADD patients are responsive to treatment with riboflavin, termed riboflavin-responsive MADD (RR-MADD). Here, we report three novel mutations and one previously reported mutation in ETFDH in four RR-MADD patients who presented at various ages, and characterize the corresponding changes in ETF-QO protein structure. Clinicians should consider MADD in the differential diagnosis when patients present with muscle weakness and biochemical abnormalities. Gene testing plays a critical role in confirming the diagnosis of MADD, and may not only prevent patients from invasive testing, but also allow timely initiation of riboflavin treatment. The novel variants in ETFDH and the corresponding clinical features reported here enrich the allelic heterogeneity of RR-MADD and provide insight into genotype-phenotype relationships. PMID- 29988810 TI - Sarcoptic mange in wild quichua porcupines (Coendou quichua Thomas, 1899) in Colombia. AB - The Quichua porcupine (Coendou quichua) is a neotropical rodent with uncertain taxonomic and conservation status. Two Quichua porcupines with severe hyperkeratosis and alopecia were found in the Magdalena River Basin of Colombia. Sarcoptes scabiei, the mite causing mange, a disease carried mainly by domestic animals, was confirmed via parasitological and molecular methods. This is the first report of mange in neotropical porcupines to date. The population-level impact of mange in Coendou spp., related mammals and predators in Colombia might represent a threat and needs further investigation. PMID- 29988811 TI - Kajal-induced Artefact Simulating a Ciliary Body Tumor on Magnetic Resonance Imaging. PMID- 29988812 TI - Robotic repair of congenital vesicovaginal fistula masquerading as a ureterocele in a 10-year-old girl. PMID- 29988813 TI - Evaluation of Prelaminar Region and Lamina Cribrosa with Enhanced Depth Imaging Optical Coherence Tomography in Pseudoexfoliation Glaucoma. AB - Objectives: To analyze optic nerve head images of pseudoexfoliative glaucoma (PXG) patients and healthy volunteers obtained with enhanced depth imaging spectral domain-optical coherence tomography (SD-OCT). Materials and Methods: Seventy patients with PXG and 68 age- and gender-matched healthy subjects were included in this prospective study. The prelaminar tissue and lamina cribrosa were imaged using spectralis OCT with the enhanced depth imaging technique. PXG disease stage was determined with visual field to evaluate relationships between prelaminar tissue thickness (PTT), lamina cribrosa thickness (LT) and disease severity. Results: There was no significant difference between the PXG group and control group with regard to age, gender, central corneal thickness, or axial length. The mean PTT (93.1+/-44.5 MUm, p<0.05) and LT (206.3+/-33.6 MUm p<0.05) values of the PXG group were significantly lower compared to the control group in enhanced depth imaging OCT measurements. The PXG patients were divided into stages according to visual field defect severity. While a significant difference was not detected in PTT based on disease stage (p>0.05), a statistically significant difference was detected between stages for LT (p<0.05). Conclusion: A thinner PTT was correlated with the presence of PXG but not with the severity of glaucoma. In addition, LT has a stronger relationship with disease severity and progression compared to PTT. PMID- 29988815 TI - Onyx Migration Into the Anterior Spinal Artery During Lumbar Artery Embolisation: an Adverse Event. AB - Introduction: The impact of sequential lumbar and intercostal artery occlusion on the risk of spinal cord ischaemia was evaluated; however, an adverse event (paraplegia) was encountered, which resulted in study interruption. Investigations were carried out to understand the reasons for the paraplegia. Report: To develop a porcine model of spinal cord ischaemic preconditioning prior to extensive thoraco-abdominal aneurysm endovascular aortic repair, the lumbar arteries were selectively embolised with Onyx 5 days prior to an extended thoracic aortic stent graft. Six pigs were used in this preliminary work. Four cases of paraplegia secondary to accidental migration of Onyx to the anterior spinal artery from the lumbar arteries are reported. Histological analysis confirmed severe spinal ischaemic injury and the presence of Onyx particles in the anterior spinal artery. Discussion: Onyx is used for lumbar artery embolisation in type II endoleak treatment after endovascular aortic repair, and while migration in lumbar arteries is frequent, the risk of spinal cord ischaemia has never been described. The current study demonstrates the risk of paraplegia following Onyx migration to the anterior spinal artery from the lumbar artery in an experimental model. Thus, Onyx treatment for type II endoleaks from lumbar arteries should be used cautiously. PMID- 29988814 TI - The identification of Theileria bicornis in captive rhinoceros in Australia. AB - Poaching of both black (Diceros bicornis) and white (Ceratotherium simum) rhinoceros in Africa has increased significantly in recent years. In an effort to ensure the survival of these critically endangered species, breeding programs were established in the 1990s in Australia, where a similar climate and habitat is available. In this study we examined blood samples from two C. simum, including a 16 yr old female (Aluka) who died in captivity, and a 17 yr old asymptomatic male (Umfana). Bloods from seven healthy D. bicornis housed at the zoo were also collected. All samples were tested for the presence of piroplasms via blood smear and PCR. A generic PCR for the 18S rRNA gene of the Piroplasmida revealed the presence of piroplasm infection in both dead and asymptomatic C. simum. Subsequent sequencing of these amplicons revealed the presence of Theileria bicornis. Blood smear indicated that this organism was present at low abundance in both affected and asymptomatic individuals and was not linked to the C. simum mortality. T. bicornis was also detected in the D. bicornis population (n = 7) housed at Taronga Western Plains Zoo using PCR and blood film examination; however only animals imported from Africa (n = 1) tested T. bicornis positive, while captive-born animals bred within Australia (n = 6) tested negative suggesting that transmission within the herd was unlikely. Phylogenetic analysis of the full length T. bicornis 18S rRNA genes classified this organism outside the clade of the transforming and non-transforming Theileria with a new haplotype, H4, identified from D. bicornis. This study revealed the presence of Theileria bicornis in Australian captive populations of both C. simum and D. bicornis and a new haplotype of the parasite was identified. PMID- 29988816 TI - A novel route for synthesis of cross-linked polystyrene copolymer beads with tunable porosity using guar and xanthan gums from bioresources as alternative synthetic suspension stabilizers. AB - Cross-linked polymer beads with different cross-linking agent loading were prepared by carrying out cross-linking suspension copolymerization of styrene divinylbenzene (St- DVB) monomers using guar gum (GG) and xanthan gum (XG) from bioresources as eco-friendly suspension biopolymer stabilizers in the presence of non reactive diluents. The effects of GG and XG as suspension biostabilizers on the characteristics of the styrene copolymer beads were investigated regarding thermal properties, porosity characteristics, solvent swelling ratio, and surface morphologies using TGA, DSC, XRD, SEM, BET analyses. Spherical and regular beads with smooth surface were produced and the average particle size was in the range 170-290 MUm (50-80 mesh size). The porosity characteristics of the produced beads including surface area and pore volume were in range 0.45 m2/g and 32-45 ml/g, respectively. Overall, the present article provided a novel route to prepare cross-linked polystyrene copolymer beads with tunable porosity suitable for catalyst support. PMID- 29988817 TI - Histopathological characterisation of retinal lesions associated to Diplostomum species (Platyhelminthes: Trematoda) infection in polymorphic Arctic charr Salvelinus alpinus. AB - The eye represents an immune privileged organ where parasites can escape host reactions. This study provides the first systematic evidence of the pathology associated with Diplostomum sp. infection in the eye retina of fish (i.e. Arctic charr). Histological sections showed that the trematodes caused mechanical disengagement between the retinal pigmentary epithelium and the neurosensory retina, with damaged cones and rods in the outer segment and epithelium reduced to a single layer of pigmentary cells. The metacercariae were "floating" in possibly fluid-filled vesicles together with several round cells, mostly located in the anterio-dorsal and anterio-ventral areas of the eye near the iris. The round cells may indicate internal retinal damage repair mechanisms, without connections to the general immune system. Metacercariae intestines contained pigmented cellular debris indicating that they feed on retinal epithelium. These retinal lesions may have similar vision effects as focal retinal detachment in vertebrates. Diplostomum metacercaria alters fish visual acuity but may in a lesser degree lead to a severe or total visual impairment because of repairing mechanisms. The pathology in the retina seems thereby to be dependent on fish size, age and dose. PMID- 29988819 TI - Evaluation of Scheimpflug Tomography Parameters in Subclinical Keratoconus, Clinical Keratoconus and Normal Caucasian Eyes. AB - Objectives: To evaluate tomographic and topographic parameters in subclinical and clinical keratoconus eyes by comparing them with normal eyes in a young Caucasian population. Materials and Methods: This cross-sectional study included 88 normal eyes (control group), bilateral data from the preclinical stage of 24 progressive keratoconus eyes (bilateral subclinical keratoconus group), 40 fellow eyes of patients with unilateral keratoconus (fellow eyes group) and 97 eyes with mild keratoconus (clinical keratoconus group). Topographic and tomographic data, data from enhanced elevation maps and keratoconus indices were measured in all study eyes using Scheimpflug tomography. Receiver operating characteristic (ROC) curve analysis was used to assess individual parameters to discriminate eyes of patients with subclinical and clinical keratoconus from control eyes. The sensitivity and specificity of the main effective parameters were evaluated and optimal cut-off points were identified to differentiate subclinical keratoconus and keratoconus from normal corneas. Results: Comparison of all subclinical and clinical keratoconus eyes from the normal group revealed significant differences in most diagnostic parameters. The ROC curve analysis showed high overall predictive accuracy of several Pentacam parameters (overall D value, anterior and posterior elevations and difference elevations, pachymetry progression index, index of surface variance, index of height decentration and keratoconus index) in discriminating ectatic corneas from normal ones. These outcomes were proportionally less pronounced in all subclinical keratoconus eyes than in the clinical keratoconus eyes. Pachymetric readings were progressively lower in the bilateral subclinical keratoconus eyes and sensitivity and specificity of the analyzed tomographic and topographic parameters were higher than the fellow eyes group when differentiating subclinical keratoconus from healthy corneas. Conclusion: Scheimpflug tomography parameters such as D value, elevation parameters, progression index and several surface indices can effectively differentiate keratoconus from normal corneas in a Caucasian population. Nevertheless, a combination of different data is required to distinguish subclinical keratoconus. PMID- 29988818 TI - Ocular Drug, Gene and Cellular Delivery Systems and Advanced Therapy Medicinal Products. AB - Due to recent advances in science and technology, when the products used in therapy are examined, ophthalmology has a priority in terms of research and development, preclinical and clinical studies of innovative drugs, medical devices and drug-medical device combination products. Liposomes, micelles, nanoemulsions, nanoparticles with colloidal structures and intraocular implants as sustained-release drug delivery systems have been developed to overcome the barriers to ocular applications, increase absorption, decrease metabolism and elimination and increase the residence time in ocular tissues and compartments. Studies are also ongoing in the area of advanced therapies using gene or cell based systems which are high-risk products due to their complex structures. In this review, ocular drug, gene and cellular delivery systems and related products and developments in advanced therapy medicinal products are presented in respect to the definition of drug (medicinal product) and current changes in legislation. PMID- 29988820 TI - Applied Machine Learning for the Prediction of Growth of Abdominal Aortic Aneurysm in Humans. AB - Objective: Accurate prediction of abdominal aortic aneurysm (AAA) growth in an individual can allow personalised stratification of surveillance intervals and better inform the timing for surgery. The authors recently described the novel significant association between flow mediated dilatation (FMD) and future AAA growth. The feasibility of predicting future AAA growth was explored in individual patients using a set of benchmark machine learning techniques. Methods: The Oxford Abdominal Aortic Aneurysm Study (OxAAA) prospectively recruited AAA patients undergoing the routine NHS management pathway. In addition to the AAA diameter, FMD was systemically measured in these patients. A benchmark machine learning technique (non-linear Kernel support vector regression) was applied to predict future AAA growth in individual patients, using their baseline FMD and AAA diameter as input variables. Results: Prospective growth data were recorded at 12 months (360 +/- 49 days) in 94 patients. Of these, growth data were further recorded at 24 months (718 +/- 81 days) in 79 patients. The average growth in AAA diameter was 3.4% at 12 months, and 2.8% per year at 24 months. The algorithm predicted the individual's AAA diameter to within 2 mm error in 85% and 71% of patients at 12 and 24 months. Conclusions: The data highlight the utility of FMD as a biomarker for AAA and the value of machine learning techniques for AAA research in the new era of precision medicine. PMID- 29988821 TI - Combined orbital decompression and lower eyelid retraction surgery. AB - Purpose: Orbital decompression and lower eyelid retraction surgery are traditionally performed separately in staged fashion, which may be unnecessary. Herein, we evaluate the safety and efficacy of combined orbital decompression and lower eyelid retraction surgery. Methods: Retrospective analysis of patients undergoing combined orbital decompression and lower eyelid retraction surgery in patients with or without Graves orbitopathy, by one surgeon from 2016 to 2017. Patients with previous orbital or lower eyelid surgery were excluded. Surgical technique for orbital decompression included eyelid crease lateral-wall decompression, transconjunctival inferolateral-wall decompression, or transcaruncular medial-wall decompression, or combination. Surgical technique for lower eyelid retraction surgery described previously. Analysis included 34 surgeries (19 patients). Preoperative and postoperative photographs at longest follow-up visit were standardized and analyzed. Results: Etiologies of lower eyelid retraction included thyroid eye disease (13 patients) and inherited (6 patients). Etiologies of proptosis included thyroid eye disease (13 patients) and inherited with shallow orbits and/or poor maxilla (6 patients). All 34 eyelids demonstrated improvement of lower eyelid position. The mean improvement of marginal reflex distance was 2.4 mm (range, 1.7-2.9 mm). There was one case of mild overcorrection and once case of prolonged chemosis. The average follow-up was 9 months (range, 6 months to 1 year). Conclusions: This study demonstrates improvement of lower lid position in patients undergoing simultaneous orbital decompression and correction of lower eyelid retraction, irrespective of the etiology of lower eyelid retraction and proptosis or orbital decompression technique. Combined procedures may reduce the number of total procedures, patient anxiety, recovery time, and costs, without compromising the results. PMID- 29988823 TI - Challenging Current Conservative Management of Uncomplicated Acute Type B Aortic Dissections. AB - Introduction: Despite weak evidence, current treatment guidelines for uncomplicated acute type B aortic dissection (uATBAD) consistently recommend intensive and rapid lowering of systolic blood pressure and heart rate. Report: The case of a 62 year old man with uATBAD, who was treated according to guidelines, is presented. Owing to an unknown chronic occlusion of the left carotid artery combined with intensive hypotensive treatment, the patient developed a cerebral infarct. Discussion: The case illustrates a severe complication of the widely accepted management of uATBAD. This case, along with scrutiny of guidelines and the evidence behind these guidelines, provoke questions regarding the rationale of current conservative management, and whether it should be challenged with alternative strategies employing a more cautious blood pressure regimen. It also highlights the importance of evaluating the vessels of the supra-aortic trunk when determining the extent of the dissection. PMID- 29988822 TI - Adolescents show differential dysfunctions related to Alcohol and Cannabis Use Disorder severity in emotion and executive attention neuro-circuitries. AB - Alcohol and cannabis are two substances that are commonly abused by adolescents in the United States and which, when abused, are associated with negative medical and psychiatric outcomes across the lifespan. These negative psychiatric outcomes may reflect the detrimental impact of substance abuse on neural systems mediating emotion processing and executive attention. However, work indicative of this has mostly been conducted either in animal models or adults with Alcohol and/or Cannabis Use Disorder (AUD/CUD). Little work has been conducted in adolescent patients. In this study, we used the Affective Stroop task to examine the relationship in 82 adolescents between AUD and/or CUD symptom severity and the functional integrity of neural systems mediating emotional processing and executive attention. We found that AUD symptom severity was positively related to amygdala responsiveness to emotional stimuli and negatively related to responsiveness within regions implicated in executive attention and response control (i.e., dorsolateral prefrontal cortex, anterior cingulate cortex, precuneus) as a function of task performance. In contrast, CUD symptom severity was unrelated to amygdala responsiveness but positively related to responsiveness within regions including precuneus, posterior cingulate cortex, and inferior parietal lobule as a function of task performance. These data suggest differential impacts of alcohol and cannabis abuse on the adolescent brain. PMID- 29988824 TI - Corrigendum to "Community pharmacists' knowledge, behaviors and experiences about adverse drug reaction reporting in Saudi Arabia" [Saudi Pharm. J. 22(5) (2014) 411-418]. AB - [This corrects the article DOI: 10.1016/j.jsps.2013.07.005.]. PMID- 29988825 TI - Hemogregarine and Rickettsial infection in ticks of toads from northeastern Colombia. AB - The toads Rhinella spp. are in constant contact with humans and domestic animals and are commonly parasitized by ticks, which are also potential vectors of pathogenic microorganisms, such as apicomplexans and rickettsia. However, little is known about microorganisms associated with toad ticks. In this work, we molecularly evaluated the presence of Rickettsia spp. and hemogregarines in ticks of Rhinella horribilis and R. humboldti in the Colombian Caribbean, finding two different species of Rickettsia: the colombianensi strain and one close to R. bellii. In the case of hemogregarines, since only 18S gene sequences are available, it is difficult to define species and place them correctly in a phylogeny, but most of our samples show a 99% identity with Hemolivia stellata, while others identical to each other seem to form another clade within this genre. All collected ticks were identified as Amblyomma dissimile, representing the first time that H. stellata was recorded in this tick. The prevalence of both microorganisms was very high, which makes it necessary to generate robust phylogenies to clarify their taxonomic diversity and to correctly define their ecological role and pathogenicity, which should be taken into account in amphibian conservation plans and veterinary medicine. PMID- 29988826 TI - Changes in oral microbiota due to orthodontic appliances: a systematic review. AB - Background: Oral microbiota has been at the center of cultural attention in recent years. In daily clinical practice, orthodontic appliances may be associated with an increased cariogenic risk and a worsening of preexisting periodontal diseases. Objective: The purpose of this review is to investigate the available evidence regarding the association between orthodontic appliances and changes in the quality and quantity of the oral microbiota. Design: The research included every article published up to October 2017 featuring the keywords 'Orthodontic appliance* AND (microbiological colonization OR periodontal pathogen* OR Streptococcus mutans OR Lactobacillus spp. OR Candida OR Tannerella forsythia OR Treponema denticola OR Fusobacterium nucleatum OR Aggregatibacter actinomycetemcomitans OR Prevotella intermedia OR Prevotella nigrescens OR Porphyromonas gingivalis)' and was conducted in the major medical databases. The methodological quality of selected papers was scored using the 'Swedish Council on Technology Assessment in Health Care Criteria for Grading Assessed Studies' (SBU) method. Results: Orthodontic appliances influence the oral microbiota with an increase in the counts of S. mutans and Lactobacillus spp. and in the percentage of potentially pathogenic gram-negative bacteria. Conclusions: There is moderate/high evidence regarding the association between orthodontic appliances and changes in the oral microbiota. PROSPERO registration number CRD42018091589. PMID- 29988827 TI - Validity and Reliability of the Glaucoma Knowledge Level Questionnaire. AB - Objectives: The present study was conducted to develop an instrument for measuring adults' glaucoma knowledge levels and to establish the instrument's validity and reliability. Materials and Methods: The study group consisted of 811 persons aged 40-80 years who presented to primary health care institutions and did not have a glaucoma diagnosis. A 27-item questionnaire measuring level of glaucoma knowledge was created by the study team. Following expert consultation, it was structurally evaluated. The difficulty index and discrimination index were calculated for each item. Factor analysis was used to determine construct validity, Cronbach's alpha internal consistency coefficient and item-total correlations were calculated to determine reliability. Confirmatory factor analysis was used to assess the extent to which the factor structure of the scale fit. We analysed correlation with the National Eye Health Education Program (NEHEP) Eye-Q scale in order to evaluate the validity of the scale. Results: The final glaucoma knowledge level questionnaire comprised 10 items in one dimension. The discrimination index and difficulty index ranged between 0.28 to 0.65 and 33 to 61%, respectively. According to factor analysis, the Kaiser-Meyer-Olkin score was 0.760 and Bartlett's test indicated p<0.001. Confirmatory factor analysis showed acceptable scale fit and fit indices. Validity assessment revealed a positive correlation between the total score of the items of the NEHEP scale and glaucoma knowledge level questionnaire score (r=0.522; p<0.001). Scores were higher in participants who were aged 40-64, living in the city, had education level of high school or above and had previous eye examination or intraocular pressure measurement. Conclusion: The glaucoma knowledge level questionnaire has the distinction of being the first valid and reliable scale for assessing level of glaucoma knowledge in Turkey. PMID- 29988829 TI - Corrigendum to "Exposure of vaccinated and naive cattle to natural challenge from buffalo-derived Theileria parva" [Int. J. Parasitol. Parasites Wildl. 4(2) (2015) 244-251]. AB - [This corrects the article DOI: 10.1016/j.ijppaw.2015.04.006.]. PMID- 29988830 TI - Surveillance of Eimeria species in wild Japanese rock ptarmigans, Lagopus muta japonica, and insight into parasitic seasonal life cycle at timberline regions of the Japanese Alps. AB - The Japanese rock ptarmigan, Lagopus muta japonica, inhabits the alpine zone of mountainous areas at 3000 m above sea level. Since L. m. japonica is endangered due to a decline in the overall population, controlling infectious diseases such as those caused by protozoan parasites is a critical factor in the conservation of this species. Although Eimeria spp. are considered to have a negative impact on Japanese rock ptarmigan populations, the ecological interactions between the parasites and their hosts have not yet been fully clarified. We therefore conducted seasonal surveys of the prevalence of Eimeria spp. in Japanese rock ptarmigan populations. In addition, we recorded the ambient temperature in ptarmigan habitat and characterized the ability of eimerian isolates to acquire infectivity. Eimeria spp. were detected in 217 of 520 (41.7%) Japanese rock ptarmigan fecal samples in 2006 and in 177 of 308 (57.5%) fecal samples in 2007. Specifically, we observed two types of oocysts characteristic of E. uekii and type B. In adult birds and chicks, infection rates increased towards August (summer) and then decreased as the temperature decreased toward November (winter). Oocyst counts per gram (OPG) of feces peaked in August in adults and chicks, and OPG values were markedly higher in chicks than in adults. Isolated Eimeria spp. oocysts sporulated at temperatures as low as 8 degrees C and remained viable after being stored at 4 degrees C for 6 months. Our findings suggest that Eimeria spp. can complete their annual lifecycle in the cold timberline regions inhabited by the host, the Japanese rock ptarmigan, and that Eimeria spp. infection is widespread in the bird populations examined. PMID- 29988828 TI - Wild pigs as sentinels for hard ticks: A case study from south-central Florida. AB - As a result of shifts in the habitable range of ticks due to climate change and the ongoing threat of exotic tick species introductions, efficient surveillance tools for these pests and disease vectors are needed. Wild pigs are habitat generalists, distributed throughout most of the United States, and often hunted recreationally or removed as part of management programs, making them potentially useful sentinel hosts for ticks. We compared ticks collected from captured wild pigs and standard tick dragging methods on a south-central Florida cattle ranch from May 2015-August 2017. Three hundred and sixteen wild pigs were surveyed, and 84 km spanning three habitat types (seminative pasture, improved pasture, and hammock) were dragged. In total, 1023 adults of four species (Amblyomma auricularium, Amblyomma maculatum, Dermacentor variabilis, and Ixodes scapularis) were collected from wild pigs, while 39 adults of three species (A. auricularium, A. maculatum, and I. scapularis) were collected from drags. Only one immature specimen, a nymph, was collected from a pig, while dragging collected 2808 larvae and 150 nymphs. Amblyomma maculatum comprised 96% of adults collected from pigs, while A. maculatum, I. scapularis, and A. auricularium comprised 38%, 33%, and 28% of adults collected from drags, respectively. Adults of all tick species found on drags were found on pigs, and wild pig surveillance detected adults of an additional species not found on drags. Dragging was far superior for collection of immatures but not for adults of most species found in this study. These findings suggest wild pigs could be used as a sentinel for the detection of tick species. When combined with ongoing wild pig research, hunting, or management, wild pig surveillance can provide an effective method to survey for adult tick presence of some species of interest and may assist in tracking the range expansion of some tick species. PMID- 29988831 TI - Contemporary diagnostics and treatment options for female stress urinary incontinence. AB - Stress urinary incontinence is not a deadly disease, but for the large population of women suffering from it, it is a very important issue. Especially in the continuously aging population all over the world, there is more and more need for treatment of this serious medical condition. Treatment of female stress urinary incontinence exists already for ages. In the 20th century invasive treatments like Burch colposuspension and pubovaginal slings were the mainstay of surgical treatments. The introduction of the midurethral sling made the procedure less invasive and accessible for more caregivers. Luckily there are many options available and the field is developing quickly. In recent years many new medical devices have been developed, that increase the number of treatment options available and make it possible to find a suitable solution for the individual patient based on subjective and objective results and the chances of complications. This manuscript provides an introduction to the therapeutical options that are available nowadays for female stress urinary incontinence. PMID- 29988832 TI - The BeGraft Balloon Expandable Covered Stent as a Proximal Extension to an Iliac Branch Device for Endovascular Repair of Isolated Common Iliac Artery Aneurysms. AB - Introduction: Isolated common iliac artery aneurysms (CIAA) are rare and can be treated by endovascular exclusion using iliac branch devices (IBD). The use of a balloon expandable covered stent as a proximal extension to an IBD to allow adequate sealing in the proximal common iliac artery (CIA) for exclusion of isolated CIAA is demonstrated. Report: Two patients with isolated CIAA of >=4.5 cm with a proximal neck length of >=20 mm (patient A: 26 mm; patient B: 24 mm) and a neck diameter of <=20 mm (patient A: 16.4 mm; patient B: 15.6 mm) were treated by combining a Zenith IBD with an aortic BeGraft balloon expandable covered stent. After deploying the BeGraft covered stent at 12 mm a second balloon was used to further dilate the proximal part of the stent outside the IBD to allow adequate sealing in the CIA. Completion angiography and follow up computed tomography angiography 1 month post-operatively showed adequate sealing and no endoleaks. Discussion: The feasibility of the application of a balloon expandable covered stent as a proximal extension to an IBD for isolated CIAA was demonstrated. It is not necessary to insert an aortic bifurcation endograft, thus reducing procedure time, radiation exposure, contrast use, and cost. A patent inferior mesenteric artery and lumbar arteries can be spared and procedures that require crossing over the aortic bifurcation remain possible. Comorbidity, prior interventions, and disease extension can make this endovascular approach preferred over open repair. Isolated CIAA can be efficiently treated combining the BeGraft balloon expandable covered stent and IBD, which allows proximal sealing in the CIA. PMID- 29988833 TI - Not Your Typical Steal Syndrome - Traumatic Superior Mesenteric Arteriovenous Fistula Causing Acute Bowel Ischaemia. PMID- 29988834 TI - Corrigendum to "Periorbital facial rejuvenation; applied anatomy and pre operative assessment" [J. Curr. Ophthalmol. 29 (3), (September 2017) 154-168]. AB - [This corrects the article DOI: 10.1016/j.joco.2017.04.001.]. PMID- 29988835 TI - Assessing nailfold microvascular structure with ultra-wideband raster-scan optoacoustic mesoscopy. AB - Nailfold capillaroscopy, based on bright-field microscopy, is widely used to diagnose systemic sclerosis (SSc). However it cannot reveal information about venules and arterioles lying deep under the nailfold, nor can it provide detailed data about surface microvasculature when the skin around the nail is thick. These limitations reflect the fact that capillaroscopy is based on microscopy methods whose penetration depth is restricted to about 200 MUm. We investigated whether ultra-wideband raster-scan optoacoustic mesoscopy (UWB-RSOM) can resolve small capillaries of the nailfold in healthy volunteers and compared the optoacoustic data to conventional capillaroscopy examinations. We quantified UWB-RSOM-resolved capillary density and capillary diameter as features that relate to SSc biomarkers, and we obtained the first three-dimensional, in vivo images of the deeper arterioles and venules. These results establish the potential of UWB-RSOM for analyzing SSc-relevant markers. PMID- 29988836 TI - Ultrafiltration and size exclusion chromatography combined with asymmetrical-flow field-flow fractionation for the isolation and characterisation of extracellular vesicles from urine. AB - Extracellular vesicles (EVs) have a great potential in clinical applications. However, their isolation from different bodily fluids and their characterisation are currently not optimal or standardised. Here, we report the results of examining the performance of ultrafiltration combined with size exclusion chromatography (UF-SEC) to isolate EVs from urine. The results reveal that UF-SEC is an efficient method and provides high purity. Furthermore, we introduce asymmetrical-flow field-flow fractionation coupled with a UV detector and multi angle light-scattering detector (AF4/UV-MALS) as a characterisation method and compare it with current methods. We demonstrate that AF4/UV-MALS is a straightforward and reproducible method for determining size, amount and purity of isolated urinary EVs. PMID- 29988837 TI - The treatment of complex female urethral pathology. AB - Lower urinary tract symptoms (LUTS) in women produce significant bother. Common conditions causing LUTS in women include urinary tract infections, overactive bladder, and stress incontinence. Urethral diverticulae and female urethral strictures are rare pathologies. They can cause symptoms, which can mimic commoner conditions, leading to delay in diagnosis and unnecessary delay in treatment. In this article, we discuss in detail the definition, symptoms, epidemiology, pathogenesis, diagnosis, and treatment option for these two conditions. Further understanding of these conditions will aid in the proper diagnosis and prevent delay in management. PMID- 29988838 TI - Optical Coherence Tomography Angiography in Branch Retinal Artery Occlusion. AB - Optical coherence tomography angiography (OCTA) is a non-invasive alternative method used in the diagnosis and follow-up of acute branch retinal artery occlusion to show changes secondary to ischemia. We report a case with acute branch retinal artery occlusion. A 52-year-old man presented with a complaint of sudden-onset visual loss in the right lower quadrant of the left eye for the previous three days. Best-corrected visual acuity was 0.4 temporally. Inferonasal visual field deficit was detected with confrontation. Pupillary light reactions were normal in both eyes and there was no relative afferent pupillary defect. Dilated fundus examination revealed retinal lesion suggesting superior temporal branch retinal artery occlusion. He was treated with dextran 40 and pentoxifylline. Follow-up fundus fluorescein angiography could not performed because of chronic renal failure; OCTA demonstrated superficial and deep capillary non-perfusion areas and telangiectases in areas corresponding to the artery occlusion. PMID- 29988839 TI - Molecular investigations of cat fleas (Ctenocephalides felis) provide the first evidence of Rickettsia felis in Malta and Candidatus Rickettsia senegalensis in Israel. AB - Rickettsia felis, the causative agent of flea-borne spotted fever, occurs on all continents except Antarctica, owing to the cosmopolitan distribution of its cat flea vector. In this study, cat fleas were collected in two countries where the occurrence of R. felis was either unknown (Malta) or where accurate prevalence data were lacking (Israel). Altogether 129 fleas were molecularly analysed for the presence of rickettsial DNA. On the basis of three genetic markers, R. felis was identified in 39.5% (15/38) of the cat fleas from Malta. Sequences showed 100% identity to each other and to relevant sequences in GenBank. Among the 91 cat fleas from Israel, two (2.2%) contained the DNA of Candidatus Rickettsia senegalensis. Phylogenetically, the R. felis and Candidatus R. senegalensis identified here clustered separately (with high support) but within one clade, which was a sister group to that formed by the typhus group and spotted fever group rickettsiae. This is the first record of R. felis in Malta and of Candidatus R. senegalensis outside its formerly reported geographical range including Africa, Asia and North America. PMID- 29988840 TI - Parasites in Myodes glareolus and their association with diet assessed by stable isotope analysis. AB - Vertebrates are hosts to numerous parasites, belonging to many different taxa. These parasites differ in transmission, being through either direct contact, a faecal-oral route, ingestion of particular food items, vertical or sexual transmission, or by a vector. Assessing the impact of diet on parasitism can be difficult because analysis of faecal and stomach content are uncertain and labourious; and as with molecular methods, do not provide diet information over a longer period of time. We here explored whether the analysis of stable isotopes in hair provides insight into the impact of diet and the presence of parasites in the rodent Myodes glareolus. Twenty-one animals were examined for parasites and their hair analysed for stable isotopes (C and N). A positive correlation between delta15N and one species of intestinal parasite was observed in females. Furthermore, several ectoparasites were negatively correlated with delta15N, indicating that infections are further associated with foraging habits (size and layout of the home range, length and timing of foraging, interaction with other rodents, etc.) that set the rodents in direct contact with infected hosts. Although a limited number of animals were included, it seemed that the isotope values allowed for identification of the association between diet and parasite occurrence in this rodent. We therefore propose that this method is useful in providing further insight into host biology, feeding preferences and potential exposure to parasites species, contributing to the understanding of the complex relationship between hosts and parasites. PMID- 29988842 TI - Successful Endovascular Management of a Case of Aorto-oesophageal Fistula Presenting as Life Threatening Upper Gastrointestinal Bleed. AB - Introduction: Aorto-oesophageal fistula is a rare but life threatening cause of upper gastrointestinal haemorrhage. Severity of presentation and complexity of subsequent management depends on the size of the defect on both the aortic side and oesophagus. Report: The patient was a 67 year old Chinese man, who presented initially with a Stanford type A dissection with caudal extension to the right common iliac artery. The patient underwent replacement of the ascending aorta and proximal arch with debranching of the right innominate artery and aortic valve replacement. A follow up computed tomography (CT) aortogram done in the post operative period showed a stable appearance of the caudal extension of the aortic dissection. The patient was discharged with a plan for future stenting of the thoracic aorta. Three weeks later the patient re-presented with an upper gastrointestinal bleed from an aorto-oesophageal fistula. The patient underwent endovascular stenting of the descending aorta for management of the fistula. Repeat oesophagogastroduodenoscopy showed a small erosion 35 cm from the incisors where the previous bleeding site had been. No further bleeding was seen. Discussion: The patient recovered uneventfully after the procedure. Follow up CT aortogram done at 6 weeks demonstrated thrombosis of the false lumen of the descending thoracic aorta. Aorto-oesophageal fistula related to chronic type B aortic dissection is an extremely rare clinical entity and presents a challenge to the treating surgeon. This case demonstrates that selected cases can be judiciously managed by thoracic endovascular aneurysm repair alone. PMID- 29988843 TI - Potential of near-infrared fluorescence image-guided debridement in trauma surgery. AB - This case report presents the use of near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) and its potential for the evaluation of soft tissue viability in a traumatic case. Standard implementation of this novel imaging modality might decrease the number of surgical debridement procedures in complex traumatic wounds. PMID- 29988841 TI - A review on pregnancy complicated by ovarian epithelial and non-epithelial malignant tumors: Diagnostic and therapeutic perspectives. AB - The management of gestational ovarian cancer can be challenging because of the risk of fetal wastage, and the possibility of treatment-related complications to the fetus; it is based on insufficient data from retrospective studies and case series. Here, a literature review of the diagnostic and surgical approaches to the gestational ovarian cancer has been performed; moreover, data on safety of chemotherapeutic treatments in pregnancy, including both oncologic and fetal outcomes, have also been reviewed. Up to now, 193 cases of ovarian cancers during pregnancy have been reported in the English literature. Treatment of ovarian malignancies during pregnancy depends on histology, stage, and gestational weeks. When possible, surgical excision is indicated, and fertility-sparing surgery can be offered to stage I epithelial ovarian tumours (EOC), germ cell ovarian, or sex cord stromal ovarian tumours. Neoadjuvant and/or adjuvant chemotherapy for advanced ovarian tumours is indicated as in non-pregnant women. Administration of chemotherapy after the first trimester, can cause fetal growth restriction, while being seemingly safe. The therapeutic approach of ovarian cancer in pregnancy should be individualized and intended in specialized centers. PMID- 29988844 TI - Treatment of posterior urethral distractions defects following pelvic fracture. AB - Posterior urethral injuries typically arise in the context of a pelvic fracture. Retrograde urethrography is the preferred diagnostic test in trauma patients with pelvic fracture where a posterior urethral rupture is suspected. Pelvic fractures however preclude the adequate positioning of the patient on the X-ray table on admission and computed tomography scan with intravenous contrast and delayed films generally performed first. Suprapubic bladder catheter placement under ultrasound guidance should be performed whenever a posterior urethral disruption is suspected. Early diagnosis and proper acute management decrease the associated complications, such as strictures, urinary incontinence and erectile dysfunction. The correct and appropriate initial treatment of associated urethral rupture is critical to the proper healing of the injury. Placing of a suprapubic cystostomy on admission and delayed anastomotic urethroplasty after 3-6 months continues to be the gold standard of treatment. In this paper, we provide a comprehensive review of the literature with a special emphasis on the various treatments available: Open or endoscopic primary realignment, immediate or delayed urethroplasty after suprapubic cystostomy, and delayed optical urethrotomy. PMID- 29988846 TI - Inferior Vena Cava Agenesis: An Unusual Cause of Deep Vein Thrombosis and Pulmonary Embolism in Young Adult Patients. AB - Introduction: Inferior vena cava agenesis (IVCA) is one of the many anomalies of this vessel. It is one of the most uncommon anomalies, with an estimated prevalence of 0.0005-1% in the general population. Around 5% of the patients younger than 30 years with a diagnosis of deep vein thrombosis (DVT) have a total or segmental IVCA. Report: Here two unique cases of young and previously healthy male patients are reported: one with bilateral lower extremity DVT, the second with lower extremity DVT and pulmonary embolism. Both patients were found to have segmental agenesis of the inferior vena cava on computed tomography angiography (CTA). Treatment consisted of ultrasound enhanced thrombolysis (EKOS + alteplase) and venous angioplasty. Both patients were discharged with long-term (up to 24 months) oral anticoagulation and compression stockings. Follow up at 3 and 12 months revealed no new thrombotic episode. Discussion: IVCA can be asymptomatic but the majority of the symptomatic patients present with DVT. IVCA confers a risk factor for DVT. IVCA should be considered and ruled out as a rare but important risk factor and cause of DVT in previously young healthy patients. Once diagnosed, aggressive treatment must be started because of the high risk of post thrombotic syndrome. PMID- 29988845 TI - Magnetic resonance angiography for the primary diagnosis of pulmonary embolism: A review from the international workshop for pulmonary functional imaging. AB - Pulmonary contrast enhanced magnetic resonance angiography (CE-MRA) is useful for the primary diagnosis of pulmonary embolism (PE). Many sites have chosen not to use CE-MRA as a first line of diagnostic tool for PE because of the speed and higher efficacy of computerized tomographic angiography (CTA). In this review, we discuss the strengths and weaknesses of CE-MRA and the appropriate imaging scenarios for the primary diagnosis of PE derived from our unique multi institutional experience in this area. The optimal patient for this test has a low to intermediate suspicion for PE based on clinical decision rules. Patients in extremis are not candidates for this test. Younger women (< 35 years of age) and patients with iodinated contrast allergies are best served by using this modality We discuss the history of the use of this test, recent technical innovations, artifacts, direct and indirect findings for PE, ancillary findings, and the effectiveness (patient outcomes) of CE-MRA for the exclusion of PE. Current outcomes data shows that CE-MRA and NM V/Q scans are effective alternative tests to CTA for the primary diagnosis of PE. PMID- 29988847 TI - Is there a difference in adenoma detection rates between gastroenterologists and surgeons? AB - AIM: To compare the adenoma detection rate (ADR) between gastroenterologists and colorectal surgeons at Box Hill Hospital, Melbourne, Australia. METHODS: A total of 300 colonoscopies performed by gastroenterologists and colorectal surgeons at Box Hill Hospital were retrospectively reviewed from May 2016 to June 2017. Exclusion criteria were: Patients <= 50 years old, colonoscopies with failure of caecal intubation, patients who previously had colon cancer and/or a colonic resection, history of polyposis syndromes or inflammatory bowel disease, or a colonoscopy within the last 10 years. Patient demographics, indications, symptoms and procedural-related outcomes were measured. RESULTS: The ADR was not significantly different between gastroenterologists and colorectal surgeons (34% vs 34.67%; P = 0.90). The adjusted odds ratio correcting for gender, age, 1st degree relative with colorectal cancer, previous colonoscopy, trainee involvement and caecal or terminal ileum intubation rate was 1.19 (0.69-2.05). CONCLUSION: Both specialties at our institution exceed benchmark standards suggested by published Australian and American guidelines. An association between endoscopist specialty and ADR was not observed. PMID- 29988848 TI - Photoacoustic tomography of blood oxygenation: A mini review. AB - Photoacoustic tomography (PAT) is a hybrid imaging modality that combines rich contrast of optical excitation and deep penetration of ultrasound detection. With its unique optical absorption contrast mechanism, PAT is inherently sensitive to the functional and molecular information of biological tissues, and thus has been widely used in preclinical and clinical studies. Among many functional capabilities of PAT, measuring blood oxygenation is arguably one of the most important applications, and has been widely performed in photoacoustic studies of brain functions, tumor hypoxia, wound healing, and cancer therapy. Yet, the complex optical conditions of biological tissues, especially the strong wavelength-dependent optical attenuation, have long hurdled the PAT measurement of blood oxygenation at depths beyond a few millimeters. A variety of PAT methods have been developed to improve the accuracy of blood oxygenation measurement, using novel laser illumination schemes, oxygen-sensitive fluorescent dyes, comprehensive mathematic models, or prior information provided by complementary imaging modalities. These novel methods have made exciting progress, while several challenges remain. This concise review aims to introduce the recent developments in photoacoustic blood oxygenation measurement, compare each method's advantages and limitations, highlight their representative applications, and discuss the remaining challenges for future advances. PMID- 29988849 TI - Does Cataract Surgery Simulation Correlate with Real-life Experience? AB - Objectives: To evaluate the correlation of cataract surgical simulator and real life surgical experience and its contribution to surgical training. Materials and Methods: Sixteen doctors in our department were divided into three groups based on their surgical experience. After being familiarized with the device, the participants were evaluated while performing the navigation, forceps, bimanual practice, anti-tremor and capsulorhexis stages. The capsulorhexis stage was repeated five times. Participants were also assessed while performing capsulorhexis again with their non-dominant hand. The influence of repetition and surgical experience on the recorded points was evaluated. P values below 0.05 were considered statistically significant. Results: There was correlation between the participants' surgical experience and their scores in the capsulorhexis module. Their dominant hand was more successful than the non-dominant hand in capsulorhexis (p=0.004). Capsulorhexis scores increased with repetition (p=0.001). Conclusion: Results achieved with the cataract surgery simulation device correlate with surgical experience. The increase in performance upon repeated practice indicates that the simulator supports surgical training. PMID- 29988850 TI - Corrigendum "Transcriptional modulation of pattern recognition receptors in chronic colitis in mice is accompanied with Th1 and Th17 response" [Biochem. Biophys. Rep. 12 (2017) 29-39]. AB - [This corrects the article DOI: 10.1016/j.bbrep.2017.08.009.]. PMID- 29988852 TI - Gastric endoscopic submucosal dissection via gastrostoma before the second operation for esophageal perforation: A case report. AB - A 69-year-old man with advanced esophageal cancer and 2 early gastric cancers received chemoradiotherapy and was scheduled to undergo subtotal esophagectomy after gastric endoscopic submucosal dissection (ESD). However, left lower esophageal perforation induced by vomiting suddenly occurred, and he urgently underwent esophago-proximal gastrectomy and gastrostomy without reconstruction. The resected specimen showed a complete response of pretreatment for the esophageal cancer and radical resection of one gastric cancer. Radical resection of the other gastric lesion was necessary before reconstruction. The fistula of gastrostoma was gradually dilated from 6.7 to 9.3 mm in order to pass the endoscope. At nine months after emergent operation, gastric ESD was performed via only the gastrostoma. A hemoclip with thread was attached to the specimen, and the thread was pulled out of the gastrostoma. The specimen was able to be removed en bloc, resulting in radical resection. Gastric tube reconstruction through the posterior sternal route was performed at six months after the ESD. He has not developed recurrence of the esophageal or gastric cancer in the two years since the emergent operation. PMID- 29988851 TI - Coagonist of glucagon-like peptide-1 and glucagon receptors ameliorates kidney injury in murine models of obesity and diabetes mellitus. AB - AIM: To investigate the role of glucagon-like peptide-1 (GLP-1)/glucagon receptors coagonist on renal dysfunction associated with diabetes and obesity. METHODS: Chronic high-fat diet fed C57BL/6J mice, streptozotocin-treated high-fat diet fed C57BL/6J mice and diabetic C57BLKS/J db/db mice were used as models of diabetes-induced renal dysfunction. The streptozotocin-treated high-fat diet fed mice and db/db mice were treated with the GLP-1 and glucagon receptors coagonist (Aib2 C24 Chimera2, 150 MUg/kg, sc) for twelve weeks, while in chronic high-fat diet fed mice, coagonist (Aib2 C24 Chimera2, 150 MUg/kg, sc) treatment was continued for forty weeks. Kidney function, histology, fibrosis, inflammation, and plasma biochemistry were assessed at the end of the treatment. RESULTS: Coagonist treatment decreased body weight, plasma lipids, insulin resistance, creatinine, blood urea nitrogen, urinary albumin excretion rate and renal lipids. In kidney, expression of lipogenic genes (SREBP-1C, FAS, and SCD-1) was decreased, and expression of genes involved in beta-oxidation (CPT-1 and PPAR alpha) was increased due to coagonist treatment. In plasma, coagonist treatment increased adiponectin and FGF21 and decreased IL-6 and TNF-alpha. Coagonist treatment reduced expression of inflammatory (TNF-alpha, MCP-1, and MMP-9) and pro-fibrotic (TGF-beta, COL1A1, and alpha-SMA) genes and also improved histological derangement in renal tissue. CONCLUSION: Coagonist of GLP-1 and glucagon receptors alleviated diabetes and obesity-induced renal dysfunction by reducing glucose intolerance, obesity, and hyperlipidemia. PMID- 29988854 TI - Pathogenesis and Classification of Central Nervous System Infection. PMID- 29988853 TI - Molecular surveillance of piroplasms in ticks from small and medium-sized urban and peri-urban mammals in Australia. AB - Natural landscape alterations as a consequence of urbanisation are one of the main drivers in the movements of wildlife into metropolitan and peri-urban areas. Worldwide, these wildlife species are highly adaptable and may be responsible for the transmission of tick-borne pathogens including piroplasms (Babesia, Theileria and Cytauxzoon spp.) that cause piroplasmosis in animals and occasionally in humans. Little is known about piroplasms in the ticks of urban wildlife in Australia. Ticks from long-nosed bandicoots (Perameles nasuta; n = 71), eastern barred bandicoots (Perameles gunnii; n = 41), northern-brown bandicoots (Isoodon macrourus; n = 19), southern-brown bandicoots (Isoodon obesulus; n = 4), bandicoot sp. (n = 2), flying foxes (Pteropus sp.; n = 3), black rats (Rattus rattus; n = 7), bush rats (Rattus fuscipes; n = 4), brushtail possums (Trichosurus vulpecula; n = 19), ringtail possums (Pseudocheirus peregrinus; n = 12), short-eared possums (Trichosurus caninus; n = 6), possum sp. (Trichosurus sp.; n = 8), and red foxes (Vulpes vulpes; n = 12) were analysed using piroplasm specific 18S primers and Sanger sequencing. Seven Ixodes tasmani ticks from long nosed bandicoots and bandicoots sp., three I. tasmani ticks and one Ixodes holocyclus tick from brushtail possums, and one Haemaphysalis longicornis tick from a red fox were positive for piroplasms. New genotypes, with sequences sharing 98% nucleotide similarities with Theileria sp. K1 detected in a burrowing bettong (Bettongia lesueur), were identified from bandicoot ticks. New genotypes were detected in ticks from brushtail possums, which shared 98% similarity with a Babesia sp. (JQ682877) previously identified in marsupials. Theileria orientalis was identified in the H. longicornis tick from the red fox. Babesia and Theileria spp. in the ticks parasitizing bandicoots and brushtail possums clustered closely with respective Babesia and Theileria clades derived from Australian marsupials. This represents the first detection of piroplasms in ticks parasitizing brushtail possums and a red fox in Australia. PMID- 29988856 TI - Geometric morphometric on a new species of Trichodinidae. A tool to discriminate trichodinid species combined with traditional morphology and molecular analysis. AB - This study reports a new Trichodinidae, Trichodina bellottii n. sp., parasitizing the pearly fish Austrolebias bellottii from Buenos Aires, Argentina. Its small subunit ribosomal ribonucleic acid (SSU rDNA) was sequenced for the first time. Based on the results from morphological identification, SSU rDNA sequencing, and Elliptical Fourier analysis, the new species was identified and compared with similar species. Phylogenetic analysis revealed that the genetic distances among the new species and similar species reached interspecific levels, furthermore, the phylogenetic study also validated the identification of T. bellottii n. sp. and its placement in the genus Trichodina. To be able to quantitatively describe the differences in shapes with similar species, this study used the elliptic Fourier analysis by first time in this genus. PMID- 29988855 TI - Novel findings in relation to multiple anti-atherosclerotic effects of XueZhiKang in humans. AB - Background: Previous studies have clearly demonstrated that XueZhiKang (XZK), an extract of cholestin, can decrease low-density lipoprotein cholesterol (LDL-C) and cardiovascular events. However, the mechanism of the effects of XZK on atherosclerosis (AS) in humans has been reported less frequently. In the present study, we investigated the impact of XZK on lipoprotein subfractions, oxidized LDL (oxLDL), and interleukin-6 (IL-6). Methods: From October 2015 to July 2016, 40 subjects were enrolled in this study. Of them, 20 subjects with dyslipidemia received XZK 1200 mg/day for 8 weeks (XZK group); 20 additional healthy subjects who did not receive therapy acted as controls. The plasma lipoprotein subfractions, oxLDL, and IL-6 were examined at baseline and again at 8 weeks. Results: Data showed that XZK could significantly decrease not only plasma LDL-C levels (87.26 +/- 24.45 vs. 123.34 +/- 23.99, P < 0.001), total cholesterol (4.14 +/- 0.87 vs. 5.08 +/- 1.03, P < 0.001), triglycerides (0.95 +/- 0.38 vs. 1.55 +/- 0.61, P < 0.05), and apolipoprotein B (1.70 +/- 0.35 vs. 1.81 +/- 0.72, P < 0.05), but also oxLDL (36.36 +/- 5.31 vs. 49.20 +/- 15.01, P < 0.05) and IL-6 (8.50 +/- 7.40 vs. 10.40 +/- 9.49, P < 0.05). At the same time, XZK reduced the concentration of small LDL-C (1.78 +/- 2.17 vs. 6.33 +/- 7.78, P < 0.05) and the percentage of the small LDL subfraction (1.09 +/- 1.12 vs. 3.07 +/- 3.09, P < 0.05). Conclusions: Treatment with 1200 mg/day XZK for 8 weeks significantly decreased the atherogenic small LDL subfraction and reduced oxidative stress and inflammatory markers, in addition to affecting the lipid profile, suggesting multiple beneficial effects in coronary artery disease. PMID- 29988857 TI - Cellular Diagnostics of CSF. PMID- 29988858 TI - Coil Migration to the Duodenum 1 Year Following Embolisation of a Ruptured Giant Common Hepatic Artery Aneurysm. AB - Introduction: Transcatheter arterial embolisation is often performed for the treatment of visceral artery aneurysms. Here, the case of a patient who developed the rare complication of coil migration into the intestinal tract is reported, and a review of the literature is presented. Case report: A 30 year old woman with a ruptured giant common hepatic artery aneurysm, who had been treated with transarterial coil embolisation 1 year previously, was admitted to hospital complaining of passing the coils on defecation. Abdominal Xray and gastroscopy showed the migration of the coils through a duodenal fistula. Open repair was performed with the coils successfully removed and the duodenal fistula closed with omentopexy. At the 3 year follow up, there were no signs or symptoms of complications. Conclusion: Based on observations from this case, although coil migration to the intestinal tract is exceedingly rare, aneurysm rupture with enteric fistula can lead to coil migration. PMID- 29988859 TI - Salvage of an Exposed Axillo-profunda Bypass Graft and Discussion of Reconstructive Options on the Torso. AB - Introduction: A case of salvage of an exposed axillo-profunda bypass graft is presented. Report: Robust coverage of the graft was achieved with a pedicled latissimus dorsi muscle flap and overlying bi-pedicled cutaneous flap. Discussion: Reconstructive options to salvage an exposed prosthetic graft will depend on the position on the trunk but can be successful if a reconstructive plastic surgery algorithm is followed. The options are discussed within this report. Exposed axillo-profunda graft can be salvaged successfully through a variety of reconstructive techniques. Close cooperation between vascular and plastic surgeons is vital for a successful outcome. PMID- 29988860 TI - Surgical Outcomes in Radiation-induced Cataracts After External-beam Radiotherapy in Retinoblastoma. AB - Objectives: To investigate visual outcomes, surgical complications and tumor recurrence among children with retinoblastoma undergoing phacoemulsification and posterior chamber intraocular lens (PCIOL) implantation for radiation-induced cataract secondary to external beam radiotherapy. Materials and Methods: The medical records of all patients treated by phacoemulsification and PCIOL implantation for radiation-induced cataract after external beam radiotherapy for retinoblastoma at a single institution between 1980 and 2014 were reviewed retrospectively. The study included 6 eyes of 6 children (4 girls, 2 boys). Results: Four patients had bilateral and two patients had unilateral retinoblastoma. The median age at diagnosis of retinoblastoma was 28.3 months (range, 12-96 months). All patients received chemoreduction (OPEC protocol) and external beam radiotherapy with or without local ophthalmic therapies and developed radiation-induced cataracts. The median interval from retinoblastoma diagnosis to cataract surgery was 96.3 months (range, 73-122 months). Time interval between surgery and last retinoblastoma treatment was 67.2 months. Postoperative complications included iridocyclitis in 2 eyes and posterior capsule opacification in all eyes. The mean follow-up after surgery was 105.8 months (range, 59-120 months). Final visual acuity was better in all eyes than preoperative visual acuities. Conclusion: Phacoemulsification and PCIOL implantation is an effective method of managing radiation-induced cataracts in eyes with previously treated retinoblastoma. However, visual acuity was limited by the presence of primary macular tumor. PMID- 29988861 TI - Corrigendum to "Is model of care associated with infant birth outcomes among vulnerable women? A scoping review of midwifery-led versus physician-led care" [SSM - Population Health 2 (2016) 182-193]. AB - [This corrects the article DOI: 10.1016/j.ssmph.2016.01.007.]. PMID- 29988862 TI - Responsibility of hepatitis C virus in the development of hepatocellular carcinoma: From molecular alterations to possible solutions. AB - There are several causes of hepatocellular carcinoma (HCC), but certainly the hepatitis C virus (HCV) is one of the most common. The HCV is able to contribute, both directly and indirectly, to the development of HCC. Determining early HCV clearance before an advanced liver disease develops, is absolutely necessary as this prevents the initiation of the cascade of events induced by HCV that may result in the development of HCC. The early treatment of the infection and the clearance of HCV represents today, in the age of the direct antiviral agents (DAAs), an extraordinary opportunity for true prevention of the development of HCV-related HCC. PMID- 29988863 TI - Repair of a small and crooked vesicovaginal fistula using electrocauterization. PMID- 29988864 TI - Management of acquired rectourethral fistulas in adults. AB - Rectourethral fistula is an uncommon but devastating condition resulting from surgery, radiation, trauma, inflammation, or occasionally anorectal anomaly. Because of involving the urinary and the digestive system, surgical repair can be challenging. More than 40 different surgical approaches were described in the literature. However, no standardized management exists due to the rarity and complexity of the problem. Spontaneous closure of fistula is rare and most cases need reconstructive procedures. Appropriate preoperative assessment is crucial for the decision of operation time and method. Gradually accumulating evidence indicates surgeons should take fistula size, tissue health and vascularity associated with radiation or infection, urethral stricture, and bladder neck sclerosis into consideration and make a proper treatment plan according to the features of various approaches. Accurate preoperative evaluation and proper approach selection would increase success rates. Multiple surgical team corporation, including colorectal, urological and plastic surgeons, would optimize the outcomes. PMID- 29988865 TI - Impairment of retinal function in yellow perch (Perca flavescens) by Diplostomum baeri metacercariae. AB - Histologic studies of fish from Douglas Lake, Cheboygan County, Michigan, USA show that Diplostomum spp. infect the lens of spottail shiners (Notropis hudsonius) and common shiners (Luxilus cornutus). In contrast, infection was confined to the choroidal vasculature of yellow perch (Perca flavescens), and the morphology of the pigment epithelium and retina in regions adjacent to the metacercariae was abnormal. The difference in location of metacercariae within the host suggested that different Diplostomum species may infect shiners and perch in Douglas Lake. Species diversity was investigated by sequencing the barcode region of the cytochrome oxidase I gene of metacercariae. Four species of Diplostomum were identified, all four of which were present in shiner lenses; however, only Diplostomum baeri was present in the perch choroid. To determine whether infection of perch eyes affects the response of the retina to a light stimulus, electroretinograms (ERG) were recorded. The amplitude of the b-wave of the ERG was reduced and the b-wave latency was increased in infected perch, as compared to uninfected eyes, and the flicker-fusion frequency was also reduced. Infection of the yellow perch choroid by Diplostomum baeri, which shows strong host and tissue specificity, has an adverse effect on retinal function, lending support to the hypothesis that parasite-induced impairment of host vision may afford Diplostomum baeri the evolutionary benefit of increasing the likelihood of transmission, via host fish predation, to its definitive avian host. PMID- 29988867 TI - Perioperative glucose management and outcomes in liver transplant recipients: A qualitative systematic review. AB - AIM: To investigate the relationship between post-liver transplantation (LT) glycemic control and LT outcomes. METHODS: A qualitative systematic review on relevant prospective interventions designed to control glucose levels including insulin protocols. Studies investigating an association between glycemic control and post-LT outcomes such as mortality, graft rejection, and infection rate were reviewed. PubMed, EMBASE, and other databases were searched through October 2016. RESULTS: Three thousands, six hundreds and ninety-two patients from 14 studies were included. Higher mortality rate was seen when blood glucose (BG) >= 150 mg/dL (P = 0.05). BG >= 150 mg/dL also led to higher rates of infection. Higher rates of graft rejection were seen at BG > 200 mg/dL (P < 0.001). Mean BG >= 200 mg/dL was associated with more infections (P = 0.002). Nurse-initiated protocols and early screening strategies have shown a reduction in negative post-LT outcomes. CONCLUSION: Hyperglycemia in the perioperative period is associated with poor post-LT outcomes. Only a few prospective studies have designed interventions aimed at managing post-LT hyperglycemia, post-transplant diabetes mellitus (PTDM) and their impact on post-LT outcomes. PMID- 29988866 TI - Applications of stem cells in orthodontics and dentofacial orthopedics: Current trends and future perspectives. AB - A simple overview of daily orthodontic practice involves use of brackets, wires and elastomeric modules. However, investigating the underlying effect of orthodontic forces shows various molecular and cellular changes. Also, orthodontics is in close relation with dentofacial orthopedics which involves bone regeneration. In this review current and future applications of stem cells (SCs) in orthodontics and dentofacial orthopedics have been discussed. For craniofacial anomalies, SCs have been applied to regenerate hard tissue (such as treatment of alveolar cleft) and soft tissue (such as treatment of hemifacial macrosomia). Several attempts have been done to reconstruct impaired temporomandibular joint. Also, SCs with or without bone scaffolds and growth factors have been used to regenerate bone following distraction osteogenesis of mandibular bone or maxillary expansion. Current evidence shows that SCs also have potential to be used to regenerate infrabony alveolar defects and move the teeth into regenerated areas. Future application of SCs in orthodontics could involve accelerating tooth movement, regenerating resorbed roots and expanding tooth movement limitations. However, evidence supporting these roles is weak and further studies are required to evaluate the possibility of these ideas. PMID- 29988868 TI - Intestinal pseudo-obstruction caused by herpes zoster: Case report and pathophysiology. AB - Herpes zoster (HZ) infection occurs in approximately 10% to 30% of individuals. Visceral neuropathies secondary to HZ can cause cystitis and urinary retention. But colonic pseudo-obstruction can also occur. Peripheral neuropathy may reveal segmental motor paresis of either upper or lower limbs, the abdominal muscles or the diaphragm. We report the case of a 62-year-old male patient who presented with abdominal distention and cutaneous vesicular eruption on the left side of the abdominal wall. Plain X-rays and computed tomography scan showed distended small bowel. A diagnosis of intestinal pseudo-obstruction was made secondary to segmental paresis of the small intestine and visceral neuropathy. Conservative management was successful and the patient was discharged uneventfully. Intestinal pseudo-obstruction ought to be considered when dealing with non-obstructive (adynamic) conditions of the digestive tract associated with HZ infection; since early recognition may help to avoid unnecessary surgery. PMID- 29988870 TI - A Challenging Case of Fibromuscular Dysplasia in a Transgender Patient: Is There a Hormonal Link? AB - Introduction: Fibromuscular dysplasia (FMD) and superior mesenteric artery (SMA) aneurysms are rare vascular conditions. An unusual combination of both diseases is reported. Case report: A 54 year old woman presented with symptomatic SMA aneurysm. A diagnosis of FMD was made on the basis of computed tomography angiography (CTA). The patient had undergone gender reassignment surgery 10 years previously and continued to use both topical and oral hormonal therapy. The patient received open anatomical bypass through a retroperitoneal approach using great saphenous vein. Conclusion: Superior mesenteric artery aneurysms are rare and a diagnosis of FMD should be considered as part of the diagnosis process. Anatomical bypass should be considered carefully in relation to a patient's fitness as well as anatomical suitability. PMID- 29988869 TI - Histological and Immunofluorescent Analysis of a Large Tributary of the Great Saphenous Vein Treated with a 1920 nm Endovenous Laser: Preliminary Findings. AB - Objectives: To analyse the biological effects of a 1920 nm endovenous laser (EVL) on extra-fascial great saphenous vein (GSV) in vitro. Methods: A 10 cm length of a large tributary bypassing a hypoplastic segment of the GSV (sometimes called an "extra-fascial GSV") was obtained during routine varicose vein surgery. The length was treated in five sections with different LEEDs (0 (control), 20, 40, 60, and 80 J/cm) with a 1920 nm EVL at 4W power, in a novel in vitro treatment model. The biological effects were assessed by histological staining of the samples for haematoxylin and eosin (HE) and Martius Scarlet Blue (MSB), and by immunofluorescent detection of p-p53 and VCAM-1. Results: Histological analysis showed significant structural damage at LEEDs above 60 J/cm, especially in the intima and media, with the treatment at 80 J/cm causing perforation of the vein wall. In addition, there was a significant increase in p-p53 expression in treated tissue at 60 and 80 J/cm. Conclusions: Using this ex vivo model, the results indicate that in vitro treatment with a 1920 nm EVL, at or above an LEED of 60 J/cm and 4 W power, causes significant vein wall cell death reaching deep into the media by a combination of direct thermal damage and apoptosis. A wavelength of 1920 nm appears to be effective for the endovenous ablation of truncal veins. PMID- 29988871 TI - Candida parapsilosis Infection After Crescentic Lamellar Wedge Resection in Pellucid Marginal Degeneration. AB - Infectious keratitis after corneal lamellar surgery is a rare complication. In this report, we present unexpected complications after crescentic lamellar wedge resection (CLWR) and their treatment in a patient with pellucid marginal degeneration. A 42-year-old male patient developed fungal keratitis due to Candida parapsilosis in the late postoperative period after CLWR. Infection was controlled with medical treatment. However, recurrent intraocular infections and cataract formation occurred, probably due to capsular damage and inoculation of microorganisms into the crystalline lens during antifungal drug injection. Lensectomy was performed due to cataract progression and recurrence of the infection when treatment was discontinued. Amphotericin B was administered to the anterior chamber at the end of the operation. Four months later, an intraocular lens was implanted and corneal cross-linking treatment was performed. At the last visit, visual acuity reached 9/10. This case shows that good visual acuity can be achieved with appropriate treatment of fungal keratitis and all associated complications after CLWR. PMID- 29988872 TI - Functional and reconstructive urology (part two). PMID- 29988873 TI - Endovascular Repair of Superior Mesenteric Arteriovenous Fistula Causing Early Mesenteric Steal Syndrome Following Abdominal Gunshot Injury. AB - Introduction: Superior mesenteric arteriovenous fistulae (SMAVF) are rare, usually secondary to trauma or iatrogenic injury and typically present sometime after the initial insult. Report: A 30 year old male underwent immediate laparotomy for abdominal gunshot injury. The small bowel mesentery contained a large haematoma and a palpable thrill. CT demonstrated a large SMAVF. At re-look laparotomy, small bowel ischaemia was noted and following this endovascular SMA stent graft insertion was performed, with excellent angiographic and clinical results. Conclusion: The first report of immediate traumatic SMAVF leading to acute mesenteric steal syndrome and successful management with endovascular stent insertion is presented. PMID- 29988874 TI - Comparison of simplified and traditional pericardial devascularisation combined with splenectomy for the treatment of portal hypertension. AB - AIM: To compare the clinical outcomes of patients with portal hypertension (PH) who underwent treatment with splenectomy plus simplified pericardial devascularisation (SSPD) or splenectomy plus traditional pericardial devascularisation (STPD). METHODS: We conducted a single-centre retrospective study of 1045 PH patients treated with either SSPD (S Group, 357 patients) or STPD (T Group, 688 patients) between January 2002 and February 2017. In all, 37 clinical indicators were compared to evaluate the efficacy of SSPD. RESULTS: Perioperative indicators in the S Group were significantly better than those in the T Group (P < 0.05). In both groups, the postoperative long-term portal vein diameter and Model for End-Stage Liver Disease score were significantly lower than those in the preoperative and postoperative short-term groups (P < 0.05). The incidence of complications in the S Group was significantly lower than that in the T Group (P < 0.05). Compared to the T Group, postoperative short-term WBC (white blood cell) and platelet counts were significantly lower and the short term Hb (haemoglobin) level was significantly higher in the S Group (P < 0.05). In the S Group, postoperative long-term total bilirubin, direct bilirubin, alanine transaminase, and aspartate transaminase and postoperative serum creatinine and cystatin C levels were significantly lower than those in the T Group (P < 0.05), and postoperative albumin was significantly higher than that in the T Group (P < 0.05). CONCLUSION: Compared to STPD, SSPD is a simple and easy procedure resulting in less tissue damage. Patients recovered smoothly and steadily with fewer complications. Short-term liver and kidney function damage was less severe, and long-term liver function recovery was better. Therefore, SSPD is worthy of clinical promotion and application for the treatment of PH. PMID- 29988875 TI - Molecular characterization and lesions associated with Diomedenema diomedeae (Aproctoidea: Desmidocercidae) from grey-headed albatrosses (Thalassarche chrysostoma) on Subantarctic Marion Island. AB - The Prince Edward Islands are Subantarctic islands in the southwest Indian Ocean that are of global importance as seabird nesting sites, and are breeding grounds for five species of albatrosses (Procellariiformes: Diomedeidae). In March-April 2016 numerous chicks of one of these species, the grey-headed albatross (Thalassarche chrysostoma), were found dead at colonies on Marion Island (46 degrees 57'S 37 degrees 42'E), the larger of the two Prince Edward Islands. Affected chicks were weak, prostrated, apathetic, had drooping wings, and many eventually died while sitting on the nest. Five carcasses were necropsied, and samples were obtained for pathological and parasitological analysis. Four chicks appeared to have died from starvation, and one died due to air-sac helminthiasis, with extensive hemorrhage in the air sacs and multifocal pyogranulomatous air sacculitis. The air sac parasites were identified as Diomedenema diomedeae (Aproctoidea: Desmidocercidae). Phylogenetic analysis of the nuclear 18S rRNA gene and mitochondrial COI gene confirmed that D. diomedeae belongs to the suborder Spirurina and showed that it is most closely related to the Diplotriaenidae (superfamily Diplotriaenoidea), a family of parasites that infect the air sacs and subcutaneous tissues of a variety of bird species. To our knowledge this is the first record of the occurrence of a nematode in the respiratory tract of an albatross and the first study to provide DNA sequences for a species of the superfamily Aproctoidea. PMID- 29988876 TI - The aging bladder insights from animal models. AB - Alterations in bladder function with aging are very common and are very likely to represent an increasing healthcare problem in the years to come with the general aging of the population. In this review the authors describe the prevalence of lower urinary tract symptoms (LUTS) and comment upon potential mechanisms which may be responsible for the increasing prevalence of lower LUTS with increasing age, based on laboratory studies. It is clear that there is a complex interplay between the various components of the neural innervation structure of the bladder in leading to changes with age, which are likely to underpin the LUTS which are seen in the aging bladder. PMID- 29988877 TI - "Thumb's off" for acrometastasis of renal cell carcinoma: Is there a role for acrometastasectomy in the era of targeted therapy? PMID- 29988878 TI - Paracentesis in cirrhotics is associated with increased risk of 30-day readmission. AB - AIM: To determine the readmission rate, its reasons, predictors, and cost of 30-d readmission in patients with cirrhosis and ascites. METHODS: A retrospective analysis of the nationwide readmission database (NRD) was performed during the calendar year 2013. All adults cirrhotics with a diagnosis of ascites, spontaneous bacterial peritonitis, or hepatic encephalopathy were identified by ICD-9 codes. Multivariate analysis was performed to assess predictors of 30-d readmission and cost of readmission. RESULTS: Of the 59597 patients included in this study, 18319 (31%) were readmitted within 30 d. Majority (58%) of readmissions were for liver related reasons. Paracentesis was performed in 29832 (50%) patients on index admission. Independent predictors of 30-d readmission included age < 40 (OR: 1.39; CI: 1.19-1.64), age 40-64 (OR: 1.19; CI: 1.09-1.30), Medicaid (OR: 1.21; CI: 1.04-1.41) and Medicare coverage (OR: 1.13; CI: 1.02 1.26), > 3 Elixhauser comorbidity (OR: 1.13; CI: 1.05-1.22), nonalcoholic cirrhosis (OR: 1.16; CI: 1.10-1.23), paracentesis on index admission (OR: 1.28; CI: 1.21-1.36) and having hepatocellular carcinoma (OR: 1.21; CI: 1.05; 1.39). Cost of index admission was similar in patients readmitted and not readmitted (P value: 0.34); however cost of care was significantly more on 30 d readmission ($30959 +/- 762) as compared to index admission ($12403 +/- 378), P-value: < 0.001. CONCLUSION: Cirrhotic patients with ascites have a 33% chance of readmission within 30-d. Younger patients, with public insurance, nonalcoholic cirrhosis and increased comorbidity who underwent paracentesis are at increased risk of readmission. Risk factors for unplanned readmission should be targeted given these patients have higher healthcare utilization. PMID- 29988879 TI - A Case of Allergic Urticaria After Ophthalmic Nepafenac Use. AB - A 21-year-old male patient with no history of systemic disease or drug use presented to our clinic with redness and pain in the right eye. Best corrected visual acuity was 20/20 in both eyes. Inflamed pinguecula was observed on slit lamp examination and the patient was prescribed ophthalmic nepafenac eye drops. After instilling the drops that day and the next day, the patient presented again due to pruritus and rash. Upon consultation with the dermatology department, the patient was diagnosed with drug-induced allergic urticaria and the nepafenac drops were discontinued. Although urticaria has been reported as a side effect after systemic non-steroidal anti-inflammatory drug (NSAID) use, such a reaction has not been reported with an ophthalmic NSAID and ours is the first reported case of urticaria following ophthalmic nepafenac use. This unique case highlights the fact that ophthalmologists must also keep urticaria in mind as a potential side effect when prescribing this drug. PMID- 29988880 TI - Elusive left ventricular thrombus: Diagnostic role of cardiac magnetic resonance imaging-A case report and review of the literature. AB - Identification of left ventricular mural thrombus (LVT) may be challenging depending on the imaging modality used. We present a case of LVT which was incidentally identified on cine cardiac magnetic resonance imaging (CMR). A sixty four years old female presented with worsening dyspnea on exertion with troponin elevation. Transthoracic echocardiography (TTE) revealed a dilated left ventricle (LV) and ejection fraction (EF 30%) with thinning and akinesis of inferior/inferolateral wall was noted with basal and mid inferior wall aneurysm, and thrombus was not identified. CMR done to ascertain viability of myocardium revealed a mural thrombus within basal inferior aneurysm. This was not visualized on transthoracic echocardiography with and without use of contrast. She underwent coronary artery bypass grafting, bioprosthetic mitral valve replacement, resection and plication of posterior left ventricular aneurysm with removal of mural thrombus, and was started on anticoagulation with warfarin post-operatively for the apical thrombi. Cardiac magnetic resonance is a well suited imaging modality in detecting LVT due to its high resolution images and is more reproducible than TTE. In our patient, conventional TTE despite administration of echo-contrast agents failed to diagnose the presence of LVT in the basal inferior aneurysm as well as the apical thrombi. Delayed-enhancement CMR provides the greatest sensitivity for detection of left ventricular thrombus, superior to standard transthoracic and contrast-enhanced transthoracic echocardiography. PMID- 29988881 TI - Impact of correct anatomical slab segmentation on foveal avascular zone measurements by optical coherence tomography angiography in healthy adults. AB - Purpose: To evaluate the impact of correct anatomical slab segmentation on foveal avascular zone (FAZ) dimensions in the superficial capillary plexus (SCP) and deep capillary plexus (DCP) using optical coherence tomography angiography (OCTA). Methods: Participants with healthy retinas were recruited, and 5 * 5 mm OCTA images were acquired using the Canon HS-100 Angio eXpert module. FAZ size was measured in automatically (AS, manufacturer-based) and manually (MS, anatomical-based) segmented OCTA slabs by two experienced graders. FAZ dimensions, inter-rater agreement, and correlation to demographic and retinal parameters were evaluated. Results: A total of 38 eyes from 20 healthy adult subjects were included in this cross-sectional study. While in AS slabs, the FAZ in the SCP was smaller than in the DCP, in MS images, it was the opposite. MS had a relevant impact on inter-rater agreement of FAZ measurements in the SCP. The FAZ area in both plexus correlated inversely with the central retinal thickness (CRT), irrespective of the segmentation applied. Furthermore, an enlargement of FAZ size in the DCP with increasing age was found. Finally, the FAZ in female participants was significantly larger than in their male counterparts, regardless of the evaluated plexus and chosen segmentation. Conclusions: Correct anatomical slab segmentation has a significant impact on FAZ size measurements. Not adjusting the segmentation boundaries represents a significant source of error for measuring FAZ area and confounds comparisons across studies as well as OCTA devices. PMID- 29988882 TI - Murine models based on acute myeloid leukemia-initiating stem cells xenografting. AB - Acute myeloid leukemia (AML) is an aggressive malignant disease defined by abnormal expansion of myeloid blasts. Despite recent advances in understanding AML pathogenesis and identifying their molecular subtypes based on somatic mutations, AML is still characterized by poor outcomes, with a 5-year survival rate of only 30%-40%, the majority of the patients dying due to AML relapse. Leukemia stem cells (LSC) are considered to be at the root of chemotherapeutic resistance and AML relapse. Although numerous studies have tried to better characterize LSCs in terms of surface and molecular markers, a specific marker of LSC has not been found, and still the most universally accepted phenotypic signature remains the surface antigens CD34+CD38- that is shared with normal hematopoietic stem cells. Animal models provides the means to investigate the factors responsible for leukemic transformation, the intrinsic differences between secondary post-myeloproliferative neoplasm AML and de novo AML, especially the signaling pathways involved in inflammation and hematopoiesis. However, AML proved to be one of the hematological malignancies that is difficult to engraft even in the most immunodeficient mice strains, and numerous ongoing attempts are focused to develop "humanized mice" that can support the engraftment of LSC. This present review is aiming to introduce the field of AML pathogenesis and the concept of LSC, to present the current knowledge on leukemic blasts surface markers and recent attempts to develop best AML animal models. PMID- 29988884 TI - Off label use of lumen-apposing metal stent for persistent gastro-jejunal anastomotic stricture. AB - We are reporting a novel "off-label" use of lumen apposing metal stent (LAMS) for management of refractory gastro-jejunal (GJ) anastomotic stricture after Roux-en y gastric bypass (RYGB). With increasing prevalence of obesity, bariatric surgery is performed more frequently than ever. RYGB is one of the most commonly performed bariatric procedures. GJ anastomotic stricture is a late complication of this procedure. Our patient, seven years after RYGB developed GJ anastomotic ulcer and subsequently a stricture not amendable to repeated pneumatic dilations. Instead of using the conventional fully covered self-expanding metal stent (fcSEMS) we deployed the relatively new LAMS keeping in mind its novel dumbbell shaped design. Our patient's symptoms were controlled successfully and she remained asymptomatic on follow-up. Despite initial approval for pancreatic pseudocyst drainage, LAMS has been used with increased frequency at various locations within gastrointestinal tract including GJ anastomotic strictures. Future randomized control trials are warranted to compare the efficacy of fcSEMS to LAMS. PMID- 29988885 TI - Ocular higher-order aberrations changes after implantable collamer lens implantation for high myopic astigmatism. AB - Purpose: To investigate the changes in higher-order aberrations (HOAs) induced by the implantation of implantable collamer lenses (ICLs) and Toric ICL (TICL) in eyes with high myopia and high myopic astigmatism. Methods: We investigated 33 eyes of 18 consecutive patients (in a prospective, interventional case series study), with spherical equivalent errors of -6.00 to -21.09 diopters (D) and cylindrical errors of -0.5 to -4.75 D, who underwent ICL and TICL implantation. Before and after 5 days, 2 and 6 months of surgery, the uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), defocus and adverse events of the surgery were assessed. Ocular HOAs were also evaluated by Hartmann-Shack aberrometry (Technolas PV, Rochester, New York, USA) before and after 6 months of surgery. Results: At 6.0 months after surgery, the UCVA and BCVA in 40% and 66.7% of eyes were 20/20, respectively. Mean defocus refraction and astigmatism was reduced to -0.66 and 0.65 D from -12.79 and 2.18 at baseline, respectively. For a 6 mm pupil, HOAs were not significantly changed, merely from 0.417 +/- 0.162 MU before surgery to 0.393 +/- 0.119 MU after surgery (P = 0.45). Spherical aberration (Z400) increased significantly (P = 00.0). Surgical induced astigmatism was lower than 0.25 D, and there were no changes in trefoils and coma aberration. No vision-threatening complications occurred during the observation period. Conclusion: This study shows that the ICL and TICL performed well in correcting high myopic astigmatism without significant changes in HOAs during a 6 month observation period, although the spherical aberration (Z400) increased significantly. PMID- 29988886 TI - Iranian healthcare professionals' perspectives about factors influencing the use of telemedicine in diabetes management. AB - AIM: To identify factors influencing the use of telemedicine in diabetes management from the perspectives of healthcare professionals. METHODS: This was a quantitative study that was conducted in 2016. The participants were 240 nurses and 55 physicians from three teaching hospitals as well as from one endocrinology and metabolism research center. No sampling method was used and the data were collected by using a five-point (1 to 5) Likert scale questionnaire, which had 37 questions. Descriptive and inferential statistics (Mann-Whitney U test) were used to analyze the data. RESULTS: The findings showed that both physicians (4.06 +/- 0.69) and nurses (4.02 +/- 0.61) tended to use telemedicine technology for managing diabetes. Overall, the lowest mean value for physicians (3.79 +/- 0.82) was related to the compatibility of telemedicine with other clinical activities in diabetes management. For nurses, the lowest mean value pertained to the usefulness of telemedicine in diabetes management (3.99 +/- 0.53) and their attitude toward using this technology (3.99 +/-0.65). CONCLUSION: Although physicians and nurses agreed on using telemedicine technology in diabetes management, it is necessary to consider their concerns prior to the implementation and deployment of new technologies. This approach will help to improve the level of technology acceptance among the users. PMID- 29988883 TI - Air pollutants and early origins of respiratory diseases. AB - Air pollution is a global health threat and causes millions of human deaths annually. The late onset of respiratory diseases in children and adults due to prenatal or perinatal exposure to air pollutants is emerging as a critical concern in human health. Pregnancy and fetal development stages are highly susceptible to environmental exposure and tend to develop a long-term impact in later life. In this review, we briefly glance at the direct impact of outdoor and indoor air pollutants on lung diseases and pregnancy disorders. We further focus on lung complications in later life with early exposure to air pollutants. Epidemiological evidence is provided to show the association of prenatal or perinatal exposure to air pollutants with various adverse birth outcomes, such as preterm birth, lower birth weight, and lung developmental defects, which further associate with respiratory diseases and reduced lung function in children and adults. Mechanistic evidence is also discussed to support that air pollutants impact various cellular and molecular targets at early life, which link to the pathogenesis and altered immune responses related to abnormal respiratory functions and lung diseases in later life. PMID- 29988887 TI - The choice of surgical approach in the treatment of vesico-vaginal fistulae. AB - Vesico-vaginal fistula is a global healthcare problem that has a high prevalence in sub-Saharan Africa, where obstetric complications lead to the development of this condition. Despite this, comparatively few fistula repairs are performed in well-resourced countries, where iatrogenic injury is the leading aetiological factor. As a consequence, much of our knowledge results from the experience of relatively few fistula surgeons in areas of high prevalence borne out of large case series or retrospective cohorts rather than high level evidence. At present, debate surrounds the exact timing of repair and the most appropriate surgical approach for this condition. Certain fistulae can be selected for conservative management, while those that do not demonstrate factors associated with spontaneous closure can be selected for surgery. Fistula surgeons should be aware of several potential repair options and the principles of contemporary fistula surgery, as the first attempt at repair is likely to be the best opportunity to achieve a successful outcome. We review the available literature and provide evidence on the optimal timing of repair, the appropriate surgical approach and the use of tissue interpositioning in fistula surgery. PMID- 29988888 TI - Compliance to topical anti-glaucoma medications among patients at a tertiary hospital in North India. AB - Purpose: The present study aims to estimate the prevalence of non-compliance and improper drop administration technique among glaucoma patients and describe common obstacles to medication compliance. Methods: A hospital-based cross sectional study, using standardized questionnaire and direct observation by study personnel was conducted among glaucoma patients aged 18 years and above at a tertiary care charitable eye hospital in North India. 151 consecutive glaucoma patients on medical therapy following up at the glaucoma clinics for at least 6 months were recruited. Non-compliance was defined as missing at-least one drop of medication per week and (or) the inability to accurately describe the medication regimen. Study personnel also assessed drop administration technique during application of eye drops by patients treating ophthalmologist-provided information, including measures of disease stability. Factors such as socioeconomic status, presence of caregiver, and number of medications with their effect on compliance were studied using chi-square statistics. Results: Among 151 patients interviewed, around 49% of patients reported problems in using glaucoma medications, with 16% of them reporting total non-compliance. 35% of patients demonstrated improper drop administration technique. Forgetfulness was cited as the main reason for being non-compliant and had a significant association with non-compliance (P = 0.00). Paying patients were more compliant as compared to subsidized patients (P = 0.05). Disease was more stable in compliant patients compared to non-compliant patients (P = 0.05). No other factor had significant association with compliance (P > 0.05). Conclusions: Over 50% of the patients surveyed were non-compliant, and 35% demonstrated improper administration technique. Glaucoma patients should be educated on the importance of compliance and aids that minimize forgetfulness, and delivery systems facilitating the delivery of medications to the eye could be considered to enhance patient adherence. PMID- 29988889 TI - A Recombinant Baculovirus Efficiently Generates Recombinant Adeno-Associated Virus Vectors in Cultured Insect Cells and Larvae. AB - Current large-scale recombinant adeno-associated virus (rAAV) production systems based on the baculovirus expression vector (BEV) remain complicated and cost intensive, and they lack versatility and flexibility. Here we present a novel recombinant baculovirus integrated with all packaging elements for the production of rAAV. To optimize BEV construction, ribosome leaky-scanning mechanism was used to express AAV Rep and Cap proteins downstream of the PH and P10 promoters in the pFast.Bac.Dual vector, respectively, and the rAAV genome was inserted between the two promoters. The yields of rAAV2, rAAV8, and rAAV9 derived from the BEV infected Sf9 cells exceeded 105 vector genomes (VG) per cell. The BEV was shown to be stable and showed no apparent decrease of rAAV yield after at least four serial passages. The rAAVs derived from the new Bac system displayed high-quality and high-transduction activity. Additionally, rAAV2 could be efficiently generated from BEV-infected beet armyworm larvae at a per-larvae yield of 2.75 +/ 1.66 * 1010 VG. The rAAV2 derived from larvae showed a structure similar to the rAAV2 derived from HEK293 cells, and it also displayed high-transduction activity. In summary, the novel BEV is ideally suitable for large-scale rAAV production. Further, this study exploits a potential cost-efficient platform for rAAV production in insect larvae. PMID- 29988890 TI - A light-fluence-independent method for the quantitative analysis of dynamic contrast-enhanced multispectral optoacoustic tomography (DCE MSOT). AB - MultiSpectral Optoacoustic Tomography (MSOT) is an emerging imaging technology that allows for data acquisition at high spatial and temporal resolution. These imaging characteristics are advantageous for Dynamic Contrast Enhanced (DCE) imaging that can assess the combination of vascular flow and permeability. However, the quantitative analysis of DCE MSOT data has not been possible due to complications caused by wavelength-dependent light attenuation and variability in light fluence at different anatomical locations. In this work we present a new method for the quantitative analysis of DCE MSOT data that is not biased by light fluence. We have named this method the two-compartment linear standard model (2C LSM) for DCE MSOT. PMID- 29988892 TI - Exhaled breath analysis for gastric cancer diagnosis in Colombian patients. AB - We present here the first study that directly correlates gastric cancer (GC) with specific biomarkers in the exhaled breath composition on a South American population, which registers one of the highest global incidence rates of gastric affections. Moreover, we demonstrate a novel solid state sensor that predicts correct GC diagnosis with 97% accuracy. Alveolar breath samples of 30 volunteers (patients diagnosed with gastric cancer and a controls group formed of patients diagnosed with other gastric diseases) were collected and analyzed by gas chromatography/mass-spectrometry (GC-MS) and with an innovative chemical gas sensor based on gold nanoparticles (AuNP) functionalized with octadecylamine ligands. Our GC-MS analyses identified 6 volatile organic compounds that showed statistically significant differences between the cancer patients and the controls group. These compounds were different from those identified in previous studied performed on other populations with high incidence rates of this malady, such as China (representative for Eastern Asia region) and Latvia (representative for Baltic States), attributable to lifestyle, alimentation and genetics differences. A classification model based on principal component analysis of our sensor data responses to the breath samples yielded 97% accuracy, 100% sensitivity and 93% specificity. Our results suggest a new and non-intrusive methodology for early diagnosis of gastric cancer that may be deployed in regions lacking well-developed health care systems as a prediagnosis test for selecting the patients that should undergo deeper investigations (e.g., endoscopy and biopsy). PMID- 29988891 TI - Melatonin in drug addiction and addiction management: Exploring an evolving multidimensional relationship. AB - Melatonin is a pleiotropic signalling molecule that regulates several physiological functions, and synchronises biological rhythms. Recent evidences are beginning to reveal that a dysregulation of endogenous melatonin rhythm or action may play a larger role in the aetiology and behavioural expression of drug addiction, than was previously considered. Also, the findings from a number of animal studies suggest that exogenous melatonin supplementation and therapeutic manipulation of melatonin/melatonin receptor interactions may be beneficial in the management of behavioural manifestations of drug addiction. However, repeated exogenous melatonin administration may cause a disruption of its endogenous rhythm and be associated with potential drawbacks that might limit its usefulness. In this review, we examine the roles of melatonin and its receptors in addictive behaviours; discussing how our understanding of melatonin's modulatory effects on the brain rewards system and crucial neurotransmitters such as dopamine has evolved over the years. Possible indications(s) for melatonergic agents in addiction management, and how manipulations of the endogenous melatonin system may be of benefit are also discussed. Finally, the potential impediments to application of melatonin in the management of addictive behaviours are considered. PMID- 29988893 TI - Trans-anal minimally invasive surgery for rectal neoplasia: Experience from single tertiary institution in China. AB - AIM: To evaluate the feasibility and safety of trans-anal minimally invasive surgery (TAMIS) from single institute in China. METHODS: A retrospective review was conducted for patients with rectal neoplasia, who underwent TAMIS using single incision laparoscopic surgery-Port from January 2013 till January 2016 by a group of colorectal surgeons from Gastrointestinal Center Unit III, Peking University Cancer Hospital. Patients' demographic data, surgical related information, post-operational pathology, as well as peri-operative follow-up were all collected. RESULTS: Twenty-five patients with rectal neoplasia were identified consequently. Complete full-thickness excision was achieved in all cases without conversion. 22 (88%) cases had rectal malignancies [6 were adenocarcinomas and 16 were neuroendocrine tumors (NET)], while 3 patients had adenomas. Mean surgical duration was 61.3 min, and mean post-operative stay were 2.7 d. Post-operational examination demonstrated 5 cases had positive resection margin: 2 adenocarcinoma cases and 1 NET case with positive lateral margin, and the other 2 NET cases with positive basal margin. The curve of operation time for TAMIS cases suggested a minimum of 10 cases for a laparoscopic surgeon proficient with this technique. CONCLUSION: TAMIS was demonstrated to be reproducible and safe, with a relatively short learning process for laparoscopic surgeons in selected cases for rectal neoplasia. Long-term oncological outcome needs to be determined by further investigation. PMID- 29988894 TI - Corneal hysteresis and corneal resistance factor in pellucid marginal degeneration. PMID- 29988895 TI - Orbital alveolar echinococcosis: A case report. AB - Purpose: To report a rare case of orbital alveolar echinococcosis in Iran. Methods: A 23-year-old woman with multi-lobular mass lesion in the right orbit underwent excisional biopsy via a deep lateral orbitotomy approach. The pathologic investigation of the lesion was a multilobulated cystic lesion shown where the cyst wall structure was compatible with alveolar Hydatid cyst in histopathology. Clinical course, surgical, and medical management of the disease is noted briefly in the case of orbital involvement of the alveolar echinococcosis. Results: Patient was treated with anti-fungal medication, and the cysts were successfully removed by a surgical excision. Conclusion: Although orbital alveolar echinococcosis is extremely rare, it is noteworthy to study its clinical manifestations and radiological examinations to be able to make a true diagnosis. PMID- 29988896 TI - Kidney exchange transplantation current status, an update and future perspectives. AB - Kidney exchange transplantation is well established modality to increase living donor kidney transplantation. Reasons for joining kidney exchange programs are ABO blood group incompatibility, immunological incompatibility (positive cross match or donor specific antibody), human leukocyte antigen (HLA) incompatibility (poor HLA matching), chronological incompatibility and financial incompatibility. Kidney exchange transplantation has evolved from the traditional simultaneous anonymous 2-way kidney exchange to more complex ways such as 3-way exchange, 4 way exchange, n-way exchange,compatible pair, non-simultaneous kidney exchange,non-simultaneous extended altruistic donor, never ending altruistic donor, kidney exchange combined with desensitization, kidney exchange combined with ABO incompatible kidney transplantation, acceptable mismatch transplant, use of A2 donor to O patients, living donor-deceased donor list exchange, domino chain, non-anonymous kidney exchange, single center, multicenter, regional, National, International and Global kidney exchange. Here we discuss recent advances in kidney exchanges such as International kidney exchange transplantation in a global environment, three categories of advanced donation program, deceased donors as a source of chain initiating kidneys, donor renege myth or reality, pros and cons of anonymity in developed world and (non-) anonymity in developing world, pros and cons of donor travel vs kidney transport, algorithm for management of incompatible donor-recipient pairs and pros and cons of Global kidney exchange. The participating transplant teams and donor-recipient pairs should make the decision by consensus about kidney donor travel vs kidney transport and anonymity vs non-anonymity in allocation as per local resources and logistics. Future of organ transplantation in resource-limited setting will be liver vs kidney exchange, a legitimate hope or utopia? PMID- 29988897 TI - Outcomes of combination MRI-targeted and transperineal template biopsy in restaging low-risk prostate cancer for active surveillance. AB - Objective: Active surveillance (AS) offers a strategy to reduce overtreatment and now is a widely accepted treatment option for low-risk prostate cancer. An ideal tool for risk-stratification would detect aggressive cancers and exclude such men from taking up AS in the first place. We evaluate if a combination of transperineal template biopsy with magnetic resonance imaging (MRI)-targeted biopsy identifies significant prostate cancer amongst men initially diagnosed with low-risk prostate cancer. Methods: This prospective, single-blinded study included men with low-risk prostate cancer (D'Amico's Criteria) diagnosed on conventional transrectal ultrasound-guided biopsy. Patients first underwent multiparametric MRI of the prostate >=6 weeks after initial biopsy. Each suspicious lesion is mapped and assigned a Prostate Imaging Reporting and Data System (PIRADS) score. Template biopsy is first performed with the surgeon blinded to MRI findings followed by MRI-targeted biopsy using a robotic transperineal biopsy platform. Results: The age of the 19 men included is 65.4 +/ 4.9 years (mean +/- SD). Prostate specific antigen (PSA) at diagnosis and at the time of transperineal biopsy were comparable (7.3 +/- 1.7 ng/mL and 7.0 +/- 1.8 ng/mL, p = 0.67), so were prostate volumes (34.2 +/- 8.9 mL and 32.1 +/- 13.4 mL, p = 0.28). MRI-targeted biopsy had a higher percentage of cancer detection per core compared to template biopsy (11.7% vs. 6.5%, p = 0.02), this was more than 3 times superior for Gleason 7 disease (5.9% vs. 1.6%, p < 0.01). Four of 18 (22.2%) patients with MRI lesions had significant disease with MRI-targeted biopsy alone. Three of 19 patients (15.8%) had significant disease with template biopsy alone. In combination, both techniques upclassified five patients (26.3%), all of whom underwent radical prostatectomy. Whole mount histology confirmed tumour location and grade. All six patients with PIRADS 5 lesions had cancer detected (66.6% significant disease). Conclusion: A combination of MRI-targeted and template biopsy may optimally risk-classify "low-risk" patients diagnosed on initial conventional transrectal ultrasonography (TRUS) prostate biopsy. PMID- 29988898 TI - Retroperitoneal laparoscopic non-dismembered pyeloplasty for uretero-pelvic junction obstruction due to crossing vessels: A matched-paired analysis and review of literature. AB - Objective: To compare laparoscopic Anderson-Hynes pyeloplasty (LAHP) and retroperitoneal laparoscopic YV-pyeloplasty (LRYVP) in ureteropelvic junction obstruction (UPJ) in presence of a crossing vessels (CV). Methods: Our database showed 380 UPJO-cases,who underwent laparoscopic retroperitoneal surgery during the last 2 decades including 206 non-dismembered LRYVP, 157 dismembered pyeloplasties LAHP, and 17 cases of laparoscopic ureterolysis. Among them 198 cases were suitable for a matched-pair (2:1) analysis comparing laparoscopic retroperitoneal non-dismembered LRYVP (Group 1, n = 131) and dismembered LAHP (Group 2, n = 67) in presence of a crossing vessel. Patients were matched according to age, gender, kidney functions, and obstruction grade. Complications were graded according to modified Clavien-classification. Results: Comparative data were similar between both groups (LRYVP vs. LAHP) including mean operating time (112 min vs. 114 min), complication rates (4.2% vs. 7.3%) mainly Grade 1-2 according to Clavien classification, and success rates (90% vs. 89%). These results reflected in the reviewed literature indicate that LRYVP provides the advantage of minimal dissection in case of CV with similar outcome. However, redundant pelvis and anteriorly crossing vessels still require a dismembered pyeloplasty LAHP. Conclusion: LRYVP has achieved similar results compared with the previous golden standard of open surgery, especially in case of crossing vessels apart from presence of a redundant pelvis or anteriorly crossing vessel. This can be further improved when using the small access retroperitoneoscopic technique respectively mini-laparoscopy. PMID- 29988899 TI - Treatment outcomes of post cataract surgery endophthalmitis in a tertiary referral center in Iran. AB - Purpose: To evaluate the treatment outcomes of patients with post cataract surgery endophthalmitis in our tertiary referral center. Methods: In this prospective study, patients with presumed post cataract surgery endophthalmitis were treated based on the modified endophthalmitis vitrectomy study (EVS) guidelines and followed for at least three months. Visual and anatomical outcomes were assessed in the last follow-up visit. Results: A total of 46 eyes with presumed post cataract surgery endophthalmitis were admitted to our hospital, of which 3 eyes with initial visual acuity of no light perception (NLP) and severe inflammation underwent primary evisceration. Forty-three patients were included to this study and followed up for at least three months. Culture results were positive in 51.2% of cases and streptococcus viridans was the most frequent isolated organism. Pars plana vitrectomy was performed in 16 eyes as primary treatment, and intravitreal antibiotic injection was done in 27 eyes. Re treatment with pars plana vitrectomy was required in 15 eyes (34.9%). Best corrected visual acuity (BCVA) at final visit was 20/40 or better in 12 eyes (27.9%), between 20/200 to 20/40 in 17 eyes (39.5%), and worse than 20/200 in 14 eyes (32.6%). Evisceration was done in one eye (2.3%), and retinal detachment happened in 4 eyes (9.3%). Conclusions: The visual outcomes of post cataract surgery endophthalmitis are generally poor. Our results in this study were comparable with many previous studies from other referral centers, however, unlike many reports, streptococcus viridans was the most common isolate in our study. PMID- 29988900 TI - Effects of particulate matter on allergic respiratory diseases. AB - The health impact of airborne particulate matter (PM) has long been a concern to clinicians, biologists, and the general public. With many epidemiological studies confirming the association of PM with allergic respiratory diseases, an increasing number of follow-up empirical studies are being conducted to investigate the mechanisms underlying the toxic effects of PM on asthma and allergic rhinitis. In this review, we have briefly introduced the characteristics of PM and discussed its effects on public health. Subsequently, we have focused on recent studies to elucidate the association between PM and the allergic symptoms of human respiratory diseases. Specifically, we have discussed the mechanism of action of PM in allergic respiratory diseases according to different subtypes: coarse PM (PM2.5-10), fine PM (PM2.5), and ultrafine PM. PMID- 29988901 TI - Transient complete visual loss and subsequent cystoid macular edema after intracameral lidocaine injection following uneventful cataract surgery. AB - Purpose: To report a case of transient visual loss following uncomplicated cataract surgery with unpreserved intracameral lidocaine. Methods: A 61-year-old woman with nuclear sclerosis cataract underwent uncomplicated phacoemulsification and in-the-bag intraocular lens (IOL) implantation. Results: After opening the eye patch on the first postoperative day, the patient complained of complete blindness. Her vision was no light perception (NLP) and the Marcus-Gunn was found to be 4+. Eight hours later, the patient's visual acuity improved to count fingers at 1 m. After two days, the vision improved surprisingly to 20/20 without any Marcus-Gunn. After 4 weeks, the vision decreased surprisingly to 20/80 without any Marcus-Gunn. On this day, macular optical coherence tomography (OCT) was performed, and cystoid macular edema was detected. Conclusion: Transient visual loss after intracameral lidocaine has been reported after violation of posterior capsule during cataract surgery, and here, we report a case of transient visual loss despite uncomplicated cataract surgery. PMID- 29988902 TI - T-cell/histiocyte-rich large B-cell lymphoma in a child: A case report and review of literature. AB - T-cell/histiocyte-rich large B-cell lymphoma is uncommon in children population. There were few cases reported in the literature with wide range clinical presentations including advanced stage, and more involvement of liver, spleen and bone marrow. Head and neck lymphadenopathy tends to present in younger children. We report a case of 10-year-old boy who initially presented intermittent fever, headaches and neck lymphadenopathy. Subsequently, he developed diffuse lymphadenopathy and hepatosplenomegaly. T-cell/histiocyte-rich large B-cell lymphoma was diagnosed on a cervical lymph node biopsy. Cervical lymphadenopathy in this age group is most commonly reactive or non-malignant processes. Lymphoma is much less frequent; mainly are non-Hodgkin lymphomas. However, a subset of large B-cell lymphoma called T-cell/histiocyte- rich B-cell lymphoma is rare in children. PMID- 29988903 TI - Posterobasal left ventricular aneurysm after myocardial infarction with normal coronary arteries: Case-report. AB - We present a case of a 64-year-old woman with signs of debilitating condition including anginal chest pain, exertional dyspnea, and depression. The patient had previously suffered from a myocardial infarction after a loss of a close family member. Workup showed a posterobasal left ventricular aneurysm and moderate to severe mitral regurgitation in the absence of coronary atherosclerosis. Routine ultrasonography revealed abdominal aortic aneurysm and intraabdominal aortic deviation. The patient was immediately started on optimal medical treatment. On repeat assessment general condition was satisfactory, vital signs were normal, and investigations showed no signs of progressive heart failure or other significant clinical changes. Although prognosis in patients with myocardial infarction with normal coronary arteries is generally considered favorable, mechanical complications such as posterobasal left ventricular aneurysm with moderate to severe mitral regurgitation are possible. PMID- 29988904 TI - Emerging evidence of the molecular landscape specific for hematogenous metastasis from gastric cancer. AB - Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC. PMID- 29988905 TI - Successful and unsuccessful weight-loss maintainers: strategies to counteract metabolic compensation following weight loss. AB - Adaptive thermogenesis and reduced fat oxidative capacity may accompany weight loss, continuing in weight maintenance. The present study aimed (1) to determine whether weight-reduced and weight-loss relapsed women are at greater metabolic risk for weight gain compared with BMI-matched controls with no weight-loss history, and (2) to identify protective strategies that might attenuate weight loss-associated adaptive thermogenesis and support successful weight-loss maintenance. Four groups of women were recruited: reduced-overweight/obese (RED, n 15), controls (low-weight stable weight; LSW, n 19) BMI <27 kg/m2; relapsed overweight/obese (REL, n 11), controls (overweight/obese stable weight; OSW, n 11) BMI >27 kg/m2. Body composition (bioelectrical impedance), 75 g oral glucose tolerance test, fasting and postprandial metabolic rate (MR) and substrate utilisation (RER) and physical activity (accelerometer (7 d)) were measured. Sociobehavioural questionnaires and 3 * 24 h diet recalls were completed. Fasting and postprandial MR, RER and total daily energy intake (TDEI) were not different between RED and REL v. controls (P > 0.05). RED consumed less carbohydrate (44.8 (sd 10.3) v. 53.4 (sd 10.0) % TDEI, P = 0.020), more protein (19.2 (sd 6.0) v. 15.6 (sd 4.2) % TDEI, P = 0.049) and increased physical activity, but behaviourally reported greater dietary restraint (P = 0.002) compared with controls. TDEI, macronutrient intake and physical activity were similar between OSW and REL. REL reported higher subjective fasting and lower postprandial ratings of prospective food consumption compared with OSW. Weight-reduced women had similar RMR (adjusted for fat-free mass) compared with controls with no weight-loss history. Increased physical activity, higher protein intake and greater lean muscle mass may have counteracted weight loss-associated metabolic compensation and highlights their importance in weight-maintenance programmes. PMID- 29988907 TI - The impact of urological resection and reconstruction on patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - Objective: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly being used to treat peritoneal malignancies. Urological resections and reconstruction (URR) are occasionally performed during the surgery. We aim to evaluate the impact of these procedures on peri-operative outcomes of CRS and HIPEC patients. Methods: A retrospective review of a prospectively maintained database of all patients who underwent CRS HIPEC from April 2001 to February 2016 was performed. Outcomes between patients who had surgery involving, and not involving URR were compared. Primary outcomes were the rate of major complications and the duration of stay in the intensive care unit (ICU) and hospital. Secondary outcomes were that of overall survival (OS) and prognostic factors that would indicate a need for URR. Results: A total of 214 CRS-HIPEC were performed, 21 of which involved a URR. Baseline clinical characteristics did not vary between the groups (URR vs. No URR). Urological resections comprised of 52% bladder resections, 24% ureteric resections, and 24% involving both bladder and ureteric resections. All bladder defects were closed primarily while ureteric reconstructions consisted of two end-to-end anastomoses, one ureto-uretostomy, five direct implantations into the bladder and three boari flaps. URR were more frequently required in patients with colorectal peritoneal disease (p = 0.029), but was not associated with previous pelvic surgery (76% vs. 54%, p = 0.065). Patients with URR did not suffer more serious complications (14% vs. 24%, p = 0.42). ICU (2.2 days vs. 1.4 days, p = 0.51) and hospital stays (18 days vs. 25 days, p = 0.094) were not significantly affected. Undergoing a URR did not affect OS (p = 0.99), but was associated with increased operation time (570 min vs. 490 min, p = 0.046). Conclusion: While concomitant URR were associated with an increase in operation time, there were no significant differences in postoperative complications or OS. Patients with colorectal peritoneal metastases are more likely to require a URR compared to other primary tumours, and needs to be considered during pre-operative planning. PMID- 29988910 TI - Corneal hysteresis and corneal resistance factor in pellucid marginal corneal degeneration. PMID- 29988906 TI - Updates on Managements for Keratoconus. AB - Purpose: Keratoconus is a progressive disease of the cornea which can lead to blindness as irregular astigmatism increases. Currently, a variety of methods are available for the treatment of keratoconus, and in certain cases, it may be difficult to choose the most appropriate option. This article reviews available treatment modalities for keratoconus to provide the practitioner with practical and useful information for selecting the most suitable option for each individual patient. Methods: To review treatment methods for different stages of keratoconus, PubMed (United States National Library of Medicine) and Scopus (Elsevier BV) databases were searched using the keywords "keratoconus", "contact lens", "cross-linking", "Intacs", "keratoplasty", "gene therapy", and "irregular astigmatism", and related articles were reviewed based on disease assessment parameters and treatment methods. Results: Various methods are available for the treatment of keratoconus: eyeglasses and contact lenses in the early stages, cross-linking for stabilizing disease progression, intrastromal corneal ring segments (ICRS) for reducing refractive errors or flattening the cornea, and penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK), conductive keratoplasty, gene therapy and more recently, bowman layer transplantation (BL transplantation) in advanced stages of the disease. To achieve optimum results, it is essential to choose the best option for each individual patient. Conclusions: A commonality of the reviewed papers was the advancement of novel diagnostic and treatment methods in ophthalmology, which can delay the need for corneal grafting. A better understanding of keratoconus treatment options can help enhance visual rehabilitation and prevent blindness in keratoconus patients. PMID- 29988909 TI - Noninvasive hemodynamic monitoring of septic shock in children. AB - Septic shock in children is associated with high mortality and morbidity. Its management is time-sensitive and must be aggressive and target oriented. The use of clinical assessment alone to differentiate between cold and warm shock and to select the appropriate inotropic and vasoactive medications is fraught with errors. Semi-quantitative and quantitative assessment of the preload, contractility and afterload using non-invasive tools has been suggested, in conjunction with clinical and laboratory assessment, to direct shock management and select between vasopressors, vasodilators and inotropes or a combination of these drugs. This review aims to describe non-invasive tools to assess the hemodynamic status in septic shock including echocardiography, trans thoracic/trans-esophageal Doppler and electrical cardiometry. As septic shock is a dynamic condition that changes markedly overtime, frequent or continuous measurement of the cardiac output (CO), systemic vascular resistance (SVR) and other hemodynamic parameters using the above-mentioned tools is essential to personalize the treatment and adapt it over time. The different combinations of blood pressure, CO and SVR serve as a pathophysiological framework to manage fluid therapy and titrate inotropic and vasoactive drugs. Near infrared spectroscopy is introduced as a non-invasive method to measure end organ perfusion and assess the response to treatment. PMID- 29988908 TI - Glutamate transporters, EAAT1 and EAAT2, are potentially important in the pathophysiology and treatment of schizophrenia and affective disorders. AB - Glutamate is the predominant excitatory neurotransmitter in the human brain and it has been shown that prolonged activation of the glutamatergic system leads to nerve damage and cell death. Following release from the pre-synaptic neuron and synaptic transmission, glutamate is either taken up into the pre-synaptic neuron or neighbouring glia by transmembrane glutamate transporters. Excitatory amino acid transporter (EAAT) 1 and EAAT2 are Na+-dependant glutamate transporters expressed predominantly in glia cells of the central nervous system. As the most abundant glutamate transporters, their primary role is to modulate levels of glutamatergic excitability and prevent spill over of glutamate beyond the synapse. This role is facilitated through the binding and transportation of glutamate into astrocytes and microglia. The function of EAAT1 and EAAT2 is heavily regulated at the levels of gene expression, post-transcriptional splicing, glycosylation states and cell-surface trafficking of the protein. Both glutamatergic dysfunction and glial dysfunction have been proposed to be involved in psychiatric disorder. This review will present an overview of the roles that EAAT1 and EAAT2 play in modulating glutamatergic activity in the human brain, and mount an argument that these two transporters could be involved in the aetiologies of schizophrenia and affective disorders as well as represent potential drug targets for novel therapies for those disorders. PMID- 29988911 TI - Adherence to self-care practices, glycemic status and influencing factors in diabetes patients in a tertiary care hospital in Delhi. AB - AIM: To assess the adherence to self-care practices, glycemic status and influencing factors in diabetes patients. METHODS: This was a cross-sectional observational analysis of baseline data from a quasi-experimental study conducted among 375 diabetic patients aged between 18 to 65 years at a major public tertiary care centre in New Delhi, India during February-September' 2016. The Summary of Diabetes Self-care activities measure was used to assess medical adherence in diabetic patients. Open ended questions were used to identify facilitators and inhibitors of medical adherence. RESULTS: Mean age of the study subjects was 49.7 +/- 10.2 years. A total of 201 men and 174 women were enrolled in the study. Three hundred nine (82.4%) subjects were adherent to their intake of anti-diabetic medication. On binary logistic regression, education level below primary school completion and absence of hypertension comorbidity were found to be independent predictors of medication non-adherence. Sociocultural resistance was an important factor impeding outdoor exercise among younger women. Knowledge of diabetes in the study subjects was low with mean score of 3.1 +/- 2 (maximum score = 10). Suboptimal glycemic control was found in 259 (69%) subjects which was significantly more likely in patients on Insulin therapy compared to those on Oral Hypoglycemic agents alone (P < 0.006).DISCUSSIONOur study found a large gap existed between self-reported medication adherence and glycemic control. This suggests the need for enhanced physician focus for diabetic patient management. PMID- 29988912 TI - Pathophysiology and Classification of Neurodegenerative Diseases. PMID- 29988913 TI - Reporting Cerebrospinal Fluid Data: Knowledge Base and Interpretation Software. AB - The compilation of cerebrospinal fluid (CSF) patient data together with a graphic display of immunoglobulin patterns in a single CSF report has two main advantages: analytical and clinical; plausibility control of a complex set of data improves quality assessment and allows improved clinical specificity and sensitivity for recognition of disease-related "typical" data patterns. The widespread use of automated on-line evaluation programs can now be combined with knowledge-based programs for interpretation by clinical chemists and neurologists. These programs are based on knowledge of neuroimmunology, blood-CSF barrier function and dysfunction, influence of CSF flow on concentrations of blood-derived and brain-derived proteins in CSF, specific intrathecal antibody synthesis and relevance of brain proteins for differential diagnosis of degenerative diseases. The relevance of hyperbolic discrimination functions in quotient diagrams for the detection of intrathecal immunoglobu-lin synthesis is compared with earlier, still frequently used, linear interpretation functions. Differences found in commercially available interpretation software are discussed. PMID- 29988914 TI - Endovascular treatment of an unruptured anterior communicating artery aneurysm presenting with acute altitudinal visual field defect: A case report. AB - Purpose: To describe a case of endovascular occlusion of an unruptured anterior communicating artery aneurysm presenting with acute altitudinal visual field defect is presented here. Methods: A 52-year-old man was evaluated and treated for altitudinal visual field defect in the right eye. Results: In ophthalmic and neuro-imaging, an accompanying anterior communication artery aneurysm was detected as a cause of visual field defect. He underwent endovascular procedure, yielding excellent outcome as full recovery of visual field defect was observed one month following the procedure and sustained when followed at month 24. Conclusions: Visual dysfunction is a rare presentation of unruptured anterior communication artery aneurysm. Endovascular procedure may be a safe treatment in these cases. PMID- 29988915 TI - Detection of Oligoclonal Ig Bands: Clinical Significance and Trends in Methodological Improvement. PMID- 29988916 TI - Chronic lung disease, lung regeneration and future therapeutic strategies. AB - Chronic lung diseases have been recognized as one of the world's leading causes of death in recent decades. Lacking effective treatments brings the patients not only bad quality of life but also higher risk for lung cancer development. By increasing the understanding of deeper mechanism of how lung develops and regenerates, researchers now focus on studying lung regenerative medicine, aiming to apply different and more efficient therapies to treat chronic lung diseases. This review will provide a wide picture of both basic lung developmental, regeneration mechanism and different designed strategies for treating chronic lung diseases in the future decades. PMID- 29988917 TI - Pathophysiology and Classification of Cerebrovascular Disorders. PMID- 29988918 TI - The normal distribution of corneal eccentricity and its determinants in two rural areas of north and south of Iran. AB - Purpose: The aim of this study was to determine the distribution of corneal eccentricity (E-value) in a normal population and to examine related factors. Methods: In this cross-sectional study, two villages were selected in Iran using multistage cluster sampling. Selected persons were invited to have a comprehensive eye examination. Examinations in each village were performed at a specific location under standard conditions. After testing for vision and refraction and conducting the slit-lamp exam, E-value was measured with Pentacam. Results: Of the 3851 selected individuals, 3314 participated in the study. After applying the exclusion criteria, data from 2610 subjects was used in the analysis for this report. Mean E-value was 0.53 [95% confidence interval (CI): 0.52 to 0.54]. E-value was not significantly different between males and females. Mean E value reduced with age from 0.60 in subjects aged 6-20 years to 0.47 in subjects older than 70 years. The hyperopic group of participants had significantly lower E-value than myopic and emmetropic ones (P < 0.001). The relationship of E-value with age, gender, and other anterior segment variables and spherical equivalent was examined in a multiple linear regression model. In multiple linear regression model, age (coef = -0.003), spherical equivalent refraction (coef = -0.005), pupil diameter (coef = 0.018), anterior chamber volume (coef = -0.001), and anterior chamber angle (coef = 0.003) significantly correlated with E-value. Conclusions: The results of this study showed that the cornea in normal populations is prolate, and the degree of prolateness varies by age, such that older age is associated with a less prolate cornea. This study showed that factors such as age and refractive errors and anterior chamber indices influence the E-value. PMID- 29988919 TI - Molecular Mechanisms in Alzheimer's Disease. PMID- 29988920 TI - Visual impairment and blindness in a population-based study of Mashhad, Iran. AB - Purpose: To determine the prevalence of visual impairment and blindness and related factors in the 1- to 90-year-old urban population of Mashhad. Methods: In this cross-sectional study of 1- to 90-year-old residents of Mashhad, in northeastern Iran, sampling was done through random stratified cluster sampling (120 clusters). After selecting the samples and their participation in the study, all subjects had vision testing including measurement of visual acuity and refraction, as well as examinations with the slit-lamp and ophthalmoscopy. Visual impairment (primary outcomes) was defined as a visual acuity worse than of 0.5 logMAR (20/60) in the better eye. Results: Of the 4453 selected persons, 3132 (70.4%) participated in the study. The prevalence of visual impairment based on presenting vision and best-corrected vision was 3.95% (95% confidence interval [CI]: 3.13-4.77) and 2.23 (95% CI: 1.54-2.91), respectively. The prevalence of presenting visual impairment increased from 1.59% in children under 5 years of age to 43.59% in people older than 65 years of age; these figures were respectively 1.59% and 42.31% based on corrected visual acuity. In the logistic regression model, older age (OR = 1.06, 95% CI: 1.04-1.07, P < 0.001), higher education (OR = 0.16, 95% CI: 0.06-0.38, P < 0.001), and low income (OR = 1.36, 95% CI: 1.21-1.72, P < 0.001) correlated with impaired sight. Based on presenting vision and best-corrected vision, the prevalence of blindness was 0.86% (95% CI: 0.51-1.22) and 0.32% (95% CI: 0.1-0.55). The most common causes of visual impairment were uncorrected refractive error (41.8%) and cataract (20%). Conclusions: According to our findings, the prevalence of visual impairment was intermediate in comparison with other studies. The prevalence of visual impairment in our study was similar to the global average; however, it was markedly high at older ages. Nonetheless, refractive errors and cataracts remain as the main causes of impaired vision and blindness in this population, while these two conditions are easily treatable with correction or surgery. PMID- 29988923 TI - Foramen tympanicum with symptomatic temporomandibular joint herniation. AB - Foramen tympanicum (FT), or foramen of Huschke, describes an uncommon anatomicvariant of a persistent bony defect connecting the external acoustic meatus to the temporomandibular joint (TMJ). Although rare, it can be associated with significant complications, such as TMJ herniation, salivary gland fistula, infectious or tumoral spread between the external acoustic meatus and the TMJ, or result in inadvertent ear injury during TMJ arthroscopy. To the best of our knowledge, this is the first case report of a symptomatic FT with a full description of computed tomography and magnetic resonance imaging findings. Surgical exploration confirmed the presence of FT with TMJ herniation with subsequent successful closure of the defect obtained. PMID- 29988921 TI - Bortezomib for Reduction of Proteinuria in IgA Nephropathy. AB - Introduction: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria. Methods: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m2 of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day. Results: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease. Conclusion: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function. PMID- 29988924 TI - Women and Kidney Disease: A Twitter Conversation for One and All. PMID- 29988925 TI - Comparison between Betamethasone, Fluorometholone and Loteprednol Etabonate on intraocular pressure in patients after keratorefractive surgery. AB - Purpose: The aim of this study was to compare the ocular hypertensive effect of the commercially available Betamethasone, Fluorometholone in Iran and Loteprednol Etabonate in patients undergoing keratorefractive surgery. Methods: In this prospective randomized clinical trial, 300 eyes of 150 patients were included, and patients were randomly assigned to 3 groups and used one of the 3 steroid drops (Betamethasone 0.1%, Fluorometholone 0.1%, and Loteprednol Etabonate 0.5%) after myopic photorefractive keratectomy (PRK). Intraocular pressure (IOP) was measured 2, 4, and 6 weeks post-surgery. Twenty-two mmHg was set as the threshold IOP for starting anti-glaucoma medication and tapering steroid drops. Results: Of 300 eyes from 150 patients over the first 6 postoperative weeks, 2 eyes in Fluorometholone group (2%), 12 eyes in Betamethasone group (12%), and 16 eyes in Loteprednol group (16%) had IOP equal or more than 22 mmHg. Analysis of variance (ANOVA) test showed that the rise in IOP was significantly different between groups in the 2nd and 4th (P <= 0.001) postoperative weeks but not at 6th week (P = 0.230). An IOP rise equal or more than 10 mmHg was detected in 13 and 15 eyes in Betamethasone and Loteprednol groups, respectively. None of the eyes in Fluorometholone group had such an IOP rise. Conclusions: Loteprednol and Fluorometholone were associated with the most and least increase in IOP, respectively. The highest pressures were detected 4 weeks after surgery in the Betamethasone and Loteprednol groups and 6 weeks after surgery in the Fluorometholone group. Fluorometholone was the safest among the three examined steroid drops in terms of IOP rise. PMID- 29988922 TI - Systematic review of the outcomes of surgical resection for intermediate and advanced Barcelona Clinic Liver Cancer stage hepatocellular carcinoma: A critical appraisal of the evidence. AB - AIM: To perform a systematic review to determine the survival outcomes after curative resection of intermediate and advanced hepatocellular carcinomas (HCC). METHODS: A systematic review of the published literature was performed using the PubMed database from 1st January 1999 to 31st Dec 2014 to identify studies that reported outcomes of liver resection as the primary curative treatment for Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC. The primary end point was to determine the overall survival (OS) and disease free survival (DFS) of liver resection of HCC in BCLC stage B or C in patients with adequate liver reserve (i.e., Child's A or B status). The secondary end points were to assess the morbidity and mortality of liver resection in large HCC (defined as lesions larger than 10 cm in diameter) and to compare the OS and DFS after surgical resection of solitary vs multifocal HCC. RESULTS: We identified 74 articles which met the inclusion criteria and were analyzed in this systematic review. Analysis of the resection outcomes of the included studies were grouped according to (1) BCLC stage B or C HCC, (2) Size of HCC and (3) multifocal tumors. The median 5 year OS of BCLC stage B was 38.7% (range 10.0-57.0); while the median 5-year OS of BCLC stage C was 20.0% (range 0.0-42.0). The collective median 5-year OS of both stages was 27.9% (0.0-57.0). In examining the morbidity and mortality following liver resection in large HCC, the pooled RR for morbidity [RR (95%CI) = 1.00 (0.76-1.31)] and mortality [RR (95%CI) = 1.15 (0.73-1.80)] were not significant. Within the spectrum of BCLC B and C lesions, tumors greater than 10 cm were reported to have median 5-year OS of 33.0% and multifocal lesions 54.0%. CONCLUSION: Indication for surgical resection should be extended to BCLC stage B lesions in selected patients. Further studies are needed to stratify stage C lesions for resection. PMID- 29988926 TI - The Third FESCC Continuous Postgraduate Course in Clinical Chemistry: New Trends in Classification, Monitoring and Management of Neurological Disease. PMID- 29988928 TI - Atherosclerosis and Cerebrovascular Diseases. PMID- 29988927 TI - Evaluating the effect of Brainfood groups for people with mild cognitive impairment and mild dementia: preliminary mixed-methodology study. AB - Background: Brainfood is a 5-week group intervention for people with mild cognitive impairment and mild dementia, promoting cognitive health through a Mediterranean-style diet, exercise, mindfulness and health self-management. Aims: To evaluate Brainfood acceptability and the feasibility of conducting a randomised controlled trial; in a single group study in two National Health Service (NHS) memory services. Method: Participants self-completed quantitative and semi-structured questionnaires. Recruitment, attendance and outcome completion were the primary outcomes. Results: In total, 30 of 59 people invited to Brainfood attended; of the 26 (87%) who completed baseline measures: 25 (96%) completed post-intervention quantitative measures, 16 (67%) qualitative questions and 21 (81%) attended >=3/5 sessions. Compared with baseline, participants reported significantly higher quality of life, Mediterranean diet adherence and exercising more, up to 2 months after the groups. Participants valued the groups and felt enabled to improve their well-being. Conclusions: Brainfood was acceptable and feasible to implement in an NHS setting. Declaration of interest: A.B. and C.C. developed Brainfood - they hold a creative commons license for the manual and make it available to use for free to all. The manual evolves iteratively, but the manual used in this research study is provided in an online supplement. PMID- 29988929 TI - Small bowel intussusception due to inflammatory fibroid polyp: A case report. AB - Inflammatory fibroid polyp (IFP), or Vanek's tumor, is a rare benign lesion of the gastrointestinal tract. According to the location and the size of the lesion, patients present with different clinical manifestations. Our case describes a patient who presented with a picture of a small bowel obstruction. Computed tomography revealed ileoileal intussusception without a clear lead point. The patient underwent resection of the intussuscepted small bowel with primary anastomosis. A polypoid mass was identified as the pathologic lead point. Histopathologic analysis revealed an inflammatory fibroid polyp. PMID- 29988931 TI - Aspirin and Clopidogrel Resistance. PMID- 29988930 TI - Prognostic role of alpha-fetoprotein response after hepatocellular carcinoma resection. AB - AIM: To investigate whether the change in pre-/post-operation serum alpha fetoprotein (AFP) levels is a predictive factor for hepatocellular carcinoma (HCC) outcomes. METHODS: We retrospectively analyzed 334 HCC patients who underwent hepatic resection at our hospital between January 2006 and December 2016. The patients were classified into three groups according to their change in serum AFP levels: (1) the normal group, pre-AFP <= 20 ng/mL and post-AFP <= 20 ng/mL; (2) the response group, pre-AFP > 20 ng/mL and post-AFP decrease of >= 50% of pre-AFP; and (3) the non-response group, pre-AFP level > 20 ng/mL and post-AFP decrease of < 50% or higher than pre-AFP level, or any pre-AFP level < 20 ng/mL but post-AFP >20 ng/mL. RESULTS: Univariate and multivariate analyses revealed that multiple tumors [hazard ratio (HR): 1.646, 95%CI: 1.15-2.35, P < 0.05], microvascular invasion (mVI) (HR: 1.573, 95%CI: 1.05-2.35, P < 0.05), and the non response group (HR: 2.425, 95% CI: 1.42-4.13, P < 0.05) were significant independent risk factors for recurrence-free survival. Similarly, multiple tumors (HR: 1.99, 95%CI: 1.12-3.52, P < 0.05), mVI (HR: 3.24, 95%CI: 1.77-5.90, P < 0.05), and the non-response group (HR: 3.62, 95%CI: 1.59-8.21, P < 0.05) were also significant independent risk factors for overall survival. The non-response group had significantly lower overall survival rates and recurrence-free survival rates than both the normal group and the response group (P < 0.05). Thus, patients with no response regarding post-surgery AFP levels were associated with poor outcomes. CONCLUSION: Serum AFP responses are significant prognostic factors for the surgical outcomes of HCC patients, suggesting post-resection AFP levels can direct the management of HCC patients. PMID- 29988932 TI - Common mental disorders and risk factors in rural India: baseline data from the SMART mental health project. AB - Background: About 10% Indians suffer from stress, depression or substance use disorders. Few receive care for these problems, especially in rural areas. Aims: As part of a broader initiative to deliver technology-enabled mental health services for rural communities (adults >=18 years), information was collected about the prevalence of depression, anxiety and suicide risk. Method: The study was conducted in 12 villages in the West Godavari district of Andhra Pradesh. Depression and anxiety were assessed using the Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7, respectively. Additionally, data were collected about sociodemographic factors and stressful events, among others. Results: Anxiety, depression and suicidal ideation affected 10.8, 14.4 and 3.5% of participants, respectively (N = 22 377). These were more common among women, and among those who were aged 30-59 years, uneducated, or divorced/ separated/ widowed. Stress due to financial loss was significant. Conclusions: The study identified a significant number of people at risk of depression, anxiety and suicide, and needing care. Declaration of interest: None. PMID- 29988933 TI - Vaccination practices in End Stage Renal Failure and Renal Transplantation; Review of current guidelines and recommendations. AB - Due to the increased burden of infectious complications following solid organ transplantation, vaccination against common pathogens is a hugely important area of discussion and application in clinical practice. Reduction in infectious complications will help to reduce morbidity and mortality post-transplantation. Immunisation history is invaluable in the work-up of potential recipients. Knowledge of the available vaccines and their use in transplant recipients, donors and healthcare providers is vital in the delivery of quality care to transplant recipients. This article will serve as an aide-memoire to transplant physicians and health care professionals involved in managing transplant recipients as it provides an overview of different types of vaccines, timing of vaccination, vaccines contraindicated post solid organ transplantation and travel vaccines. PMID- 29988935 TI - Dynamic interfacial tension measurement method using axisymmetric drop shape analysis. AB - The current method describes a simple modification to the dynamic and equilibrium interfacial tension (IFT) measurement in a multiphase system (gas-liquid/liquid liquid) by the Axisymmetric Drop Shape Analysis (ADSA) pendant drop technique. The primary difficulty associated with dynamic IFT measurement by ADSA is providing the appropriate phase densities, especially in a system consisting of gas (CO2, methane, and propane) and liquids (water and hydrocarbon). The density of the phases is calculated using a, considering the solubility og gases in liquids, as a function of time. The calculated densities of the phases are then used as inputs in the experiment to measure the IFT at high pressure and temperature PVT-cell. The method offers benefit such as: *Straightforward and cost effective as it does not require additional experimental setup (like density meter) or a complicated equation of state.*The composition of the binary mixtures (mole and mass) and the density changes of the binary mixture due to mass transfer may be obtained as a function of time at fixed pressure and temperature.*IFT as a function of time is measured by taking into consideration of correct phase density. PMID- 29988934 TI - Criteria for enhancing mucus transport: a systematic scoping review. AB - Background: Uncertainty exists regarding the physiological basis of physiotherapy strategies to facilitate mucus clearance. The aim of this review was to describe the physiological factors and intrinsic conditions that facilitate airway mucus transport. Method: A scoping review was performed. A systematic literature search of six databases was executed. Eligibility criteria were applied by two researchers to reach the aim of the review. Papers were identified independently by two reviewers on title, abstract and full-text level. Any discrepancies were discussed with a third reviewer. Results: The search identified 35 papers published between 1975 and 2015. These differed significantly in terms of outcome measures, measurement techniques and methodologies and included animal studies, laboratory investigations, and the use of small human samples. Nine key factors influencing mucus transport were identified. These include: temperature and humidity, bronchial perfusion, ATP, forced expiratory technique and cough, generation of oscillation, ventilation patterns/airflow, epithelial differences, mucus properties and positioning. Conclusion: This review provides a framework for factors/conditions influencing mucus transport. Existing physiotherapy strategies for augmentation of airway mucus clearance can now be evaluated against the framework and new modalities informed. PMID- 29988936 TI - Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. AB - Purpose: The aim of this study was to review the genetics, epidemiology, clinical findings, and management of BRCA1-associated protein-1 (BAP1) cancer predisposition syndrome, particularly focusing on the development of uveal melanoma (UM). Methods: This is a review article based on eligible studies identified by systematically searching PubMed, Web of Science, and reference lists. Results: UM is the most common primary intraocular malignancy. Most UM cases are sporadic, but a small percentage has been documented with familial tendency. Until recently, there was little information regarding the genetics of this malignant tumor, and we have now begun to understand the pathways of development. BAP1 is a scavenger protein that regulates cell cycle, cellular differentiation, and DNA damage response. Patients and families with germline BAP1 mutation are predisposed to familial cancers including UM, mesothelioma, cutaneous melanoma (CM), renal cell carcinoma (RCC), and others. Clinicians should be aware of the implications of germline BAP1 mutation and advise genetic testing and assessment for BAP1 germline mutation in suspected patients and families. Conclusions: The ability of BAP1 gene mutation to cause multiple tumor types and high penetrance in carriers suggests that this gene has an important role for influencing cancer cell growth. With progress in understanding the molecular landscape of UM and the development of treatments targeted to the pathways involving BAP1 and other gene mutations, it is possible to improve the outcome of this malignant cancer. PMID- 29988937 TI - The impact of common genetic variants in the mitochondrial glycine cleavage system on relevant metabolites. AB - The glycine cleavage system (GCS) is a complex of four enzymes enabling glycine to serve as a source of one-carbon units to the cell. We asked whether concentrations of glycine, dimethylglycine, formate, and serine in blood are influenced by variation within GCS genes in a sample of young, healthy individuals. Fifty-two variants tagging (r2 < 0.9) the four GCS genes were tested; one variant, GLDC rs2297442-G, was significantly associated (p = .0007) with decreased glycine concentrations in serum. PMID- 29988938 TI - Effect of venting incisions on graft attachment in Descemet's stripping automated endothelial keratoplasty. AB - Purpose: To investigate the impact of venting incisions on the adherence of graft to the recipient's stroma in Descemet's stripping automated endothelial keratoplasty (DSAEK). Methods: Fifty-six patients were enrolled in this study. Patients were randomly allocated into two groups. Twenty-eight patients had a DSAEK procedure with venting incisions. The second group was treated by conventional DSAEK with no venting incisions. Slit-lamp examination and anterior segment optical coherence tomography (AS-OCT) were performed in day one and 14 days after surgery to investigate graft attachment. The thickness of cornea and lenticle were also evaluated by AS-OCT. BCVA (logMAR) was measured the day before the surgery and 14 days postoperatively. Results: Subclinical graft detachment in the first day after surgery was significantly lower in patients who had a DSAEK procedure and venting incisions (P = 0.02), but no difference was noted in the rate of clinical graft detachment on day one (P = 0.24) and subclinical and clinical graft detachment on day 14 (P = 0.24, P = 0.50, respectively). The thickness of the cornea and lenticle after the surgery were statistically similar between the two groups (P = 0.903, P = 0.402, respectively). No difference in the improvement of BCVA was observed between the venting and non-venting group (P = 0.143). Conclusions: Routine use of venting incisions may not be necessary in the standard DSAEK procedures. More studies with larger sample sizes are needed to better confirm the results of this study. PMID- 29988939 TI - Pathogenesis of Antiphospholipid Syndrome. PMID- 29988940 TI - Molecular identification of two Eimeria species, E. uekii and E. raichoi as type B, in wild Japanese rock ptarmigans, Lagopus muta japonica. AB - Thus far, two types of Eimeria parasites (E. uekii and type B) have been morphologically identified in wild Japanese rock ptarmigans, Lagopus muta japonica. Although high prevalences were reported for these parasites, genetic analyses have not been conducted. We first clarified the phylogenetic positions of two eimerian isolates using genetic analyses of 18S rRNA and mitochondrial cytochrome c oxidase subunit I gene regions. Consequently, of 61 samples examined, 21 and 11 samples were positive for E. uekii and type B, respectively. Additionally, the infection rate increased in the summer. Molecular analyses revealed both Eimeria isolates formed their own clusters; E. uekii was included in clades of chicken Eimeria and type B was include in clades of turkey Eimeria. Based on our findings in this study and previous data, we herein propose type B as E. raichoi. These genetic data will be helpful to conduct detailed classification and understand the impact of these parasites for conservation of endangered Japanese rock ptarmigans. PMID- 29988941 TI - Utility of central venous pressure measurement in renal transplantation: Is it evidence based? AB - Adequate intravenous fluid therapy is essential in renal transplant recipients to ensure a good allograft perfusion. Central venous pressure (CVP) has been considered the cornerstone to guide the fluid therapy for decades; it was the only available simple tool worldwide. However, the revolutionary advances in assessing the dynamic preload variables together with the availability of new equipment to precisely measure the effect of intravenous fluids on the cardiac output had created a question mark on the future role of CVP. Despite the critical role of fluid therapy in the field of transplantation. There are only a few clinical studies that compared the CVP guided fluid therapy with the other modern techniques and their relation to the outcome in renal transplantation. Our work sheds some light on the available published data in renal transplantation, together with data from other disciplines evaluating the utility of central venous pressure measurement. Although lager well-designed studies are still required to consolidate the role of new techniques in the field of renal transplantation, we can confidently declare that the new techniques have the advantages of providing more accurate haemodynamic assessment, which results in a better patient outcome. PMID- 29988942 TI - Maxwell's demon at work: Mitochondria, the organelles that convert information into energy? PMID- 29988943 TI - Giant retroperitoneal schwannoma in a 52-year-old man. AB - Schwannoma in the retroperitoneal space is rare, and it is extremely rare in patients with no history of neurofibromatosis. We present a case of giant retroperitoneal schwannoma in a 52-year-old man who did not have neurofibromatosis. Because malignant transformation would be extremely rare in this circumstance, close imaging follow-up could avert the necessity for complete resection. The possibility of schwannoma should be considered when evaluating retroperitoneal tumors with the characteristic findings, even if there is no connection between the tumor and the intervertebral foramina. PMID- 29988944 TI - Neuroimmunology: Immunoglobulins and the Intrathecal Polyspecific Immune Response in Acute, Subacute and Chronic Neurological Diseases. PMID- 29988945 TI - Endoscopy in the field of oculo-facial plastic surgery. PMID- 29988946 TI - Foreign body (kidney beans) in urinary bladder: An unusual case report. AB - Introduction: Foreign body in urinary bladder has always been a topic of interest amongst the urologists and surgeon. Foreign body in lower urinary tract is not an unusual finding. Different types of foreign bodies has been retrieved from the lower urinary tract like for example, electric wire, safety pin, hairclip, intrauterine contraceptive device (IUCD), gauze pieces, battery, leech, hairballs and so on.This article presents an unusual case report of the presence of kidney beans in the bladder, self-inflicted by the patient in the middle of the night for the purpose of sexual gratification or autoerotism. A 25 years old male patient, chef by occupation, presented to the outpatient department with history of insertion of 4 kidney beans 3 days back through his penis during the act of masturbation. The patient had complaints of dysuria, one episode, next morning after the act, which was relieved thereafter. Patient came to us only for the purpose of removal of the kidney beans. Attempt was made to remove the beans by non-invasive method by cystoscopy but as the beans were soaked in urine they got swollen and forceps removal was not possible. Hence, the kidney beans were removed by an invasive method by a suprapubic incision. Conclusion: There has been many cases reported in literature about insertion of foreign bodies in bladder but presence of kidney beans in bladder is first of its kind as far as our knowledge is concerned. PMID- 29988948 TI - The Endocrine Brain: Pathophysiological Role of Neuropeptide-Neurotransmitter Interactions. PMID- 29988947 TI - Food offerings on board and dietary intake of European and Kiribati seafarers - cross-sectional data from the seafarer nutrition study. AB - Background: Overweight and cardiovascular risk factors are a common phenomenon in seafarers. According to internal observation particularly crew members from the Pacific Island State of Kiribati are exposed to a high risk. However, in mixed crews, cultural background plays an important role, influencing food choice, and the actual risk. Methods: The Seafarer Nutrition Study (SeaNut study) compared dietary factors in 48 Kiribati and 33 European male seafarers recruited from four merchant ships with a high level of Kiribati manning within a German shipping company. Analysis encompassed the assessment of dietary quality on board, satisfaction with prepared dishes, and individual food intake obtained from 24-h recalls in comparison with nutritional recommendations. Results: The overall supply of meat, fat and eggs was more than double, whereas the proportions of fruits, vegetables, dairy products and cereals were much lower than recommended. Based on the reported food choices, both groups, but notably Kiribati seafarers, did not reach reference values as to macronutrient, micronutrient and fiber intake. In addition, satisfaction with the meals served, food preferences and knowledge about a healthy diet varied markedly between Kiribati and Europeans. Conclusions: The present analysis of the SeaNut study revealed the necessity of future health intervention programs, including the quality of the food supply as well as information about a healthy diet and adequate food selection. In mixed crews, culture-specific differences should be considered, in order to facilitate the long-term success of interventions. Trial registration: German Clinical Trials Registry DRKS00010819 retrospectively. Registered 18 July 2016 (www.germanctr.de). PMID- 29988949 TI - Involvement of anti-tumor miR-124-3p and its targets in the pathogenesis of pancreatic ductal adenocarcinoma: direct regulation of ITGA3 and ITGB1 by miR-124 3p. AB - MicroRNAs (miRNAs) are unique in that a single miRNA molecule regulates a vast number of RNA transcripts. Thus, aberrantly expressed miRNAs disrupt tightly controlled RNA networks in cancer cells. Our functional screening showed that expression of miR-124-3p was downregulated in pancreatic ductal adenocarcinoma (PDAC) tissues. Here, we aimed to investigate the anti-tumor roles of miR-124-3p in PDAC cells and to identify miR-124-3p-mediated oncogenic signaling in this disease. Ectopic expression of miR-124-3p inhibited cancer cell migration and invasion in PDAC cells. Moreover, restoration of miR-124-3p suppressed oncogenic signaling, as demonstrated by reduced phosphorylation of focal adhesion kinase, AKT, and extracellular signal-regulated kinase, in PDAC cells. Our in silico database analyses and luciferase reporter assays showed that two cell-surface matrix receptors, integrin alpha3 (ITGA3) and integrin beta1 (ITGB1), were directly regulated by miR-124-3p in PDAC cells. Overexpression of ITGA3 and ITGB1 was confirmed in PDAC clinical specimens. Interestingly, a large number of cohort analyses from TCGA database showed that high expressions of ITGA3 and ITGB1 were significantly associated with poor prognosis of patients with PDAC. Knockdown of ITGA3 and ITGB1 by siRNAs markedly suppressed the migration and invasion abilities of PDAC cells. Moreover, downstream oncogenic signaling was inhibited by ectopic expression of miR-124-3p or knockdown of the two integrins. The discovery of anti-tumor miRNAs and miRNA-mediated oncogenic signaling may provide novel therapeutic targets for the treatment of PDAC. PMID- 29988950 TI - Genotype-independent Agrobacterium rhizogenes-mediated root transformation of chickpea: a rapid and efficient method for reverse genetics studies. AB - Background: Chickpea (Cicer arietinum L.), an important legume crop is one of the major source of dietary protein. Developing an efficient and reproducible transformation method is imperative to expedite functional genomics studies in this crop. Here, we present an optimized and detailed procedure for Agrobacterium rhizogenes-mediated root transformation of chickpea. Results: Transformation positive roots were obtained on selection medium after two weeks of A. rhizogenes inoculation. Expression of green fluorescent protein further confirmed the success of transformation. We demonstrate that our method adequately transforms chickpea roots at early developmental stage with high efficiency. In addition, root transformation was found to be genotype-independent and the efficacy of our protocol was highest in two (Annigiri and JG-62) of the seven tested chickpea genotypes. Next, we present the functional analysis of chickpea hairy roots by expressing Arabidopsis TRANSPARENT TESTA 2 (AtTT2) gene involved in proanthocyanidins biosynthesis. Overexpression of AtTT2 enhanced the level of proanthocyanidins in hairy roots that led to the decreased colonization of fungal pathogen, Fusarium oxysporum. Furthermore, the induction of transgenic roots does not affect functional studies involving infection of roots by fungal pathogen. Conclusions: Transgenic roots expressing genes of interest will be useful in downstream functional characterization using reverse genetics studies. It requires 1 day to perform the root transformation protocol described in this study and the roots expressing transgene can be maintained for 3-4 weeks, providing sufficient time for further functional studies. Overall, the current methodology will greatly facilitate the functional genomics analyses of candidate genes in root-rhizosphere interaction in this recalcitrant but economically important legume crop. PMID- 29988952 TI - Clinical and Diagnostic Role of Ganglioside Antibody Testing. PMID- 29988951 TI - Microstructure of the superior temporal gyrus and hallucination proneness - a multi-compartment diffusion imaging study. AB - Previous studies reported that the volume of the left superior temporal gyrus (STG) is reduced in patients with schizophrenia and negatively correlated with hallucination severity. Moreover, diffusion-tensor imaging studies suggested a relationship between the brain microstructure in the STG of patients and auditory hallucinations. Hallucinations are also experienced in non-patient groups. This study investigated the relationship between hallucination proneness and the brain structure of the STG. Hallucination proneness was assessed by the Launey Slade Hallucination Scale (LSHS) in 25 healthy individuals who varied in their propensity to hear voices. Brain volume and microstructure of the STG was assessed by magnetic resonance imaging (MRI). Microstructure was examined by conventional diffusion-tensor imaging as well as by neurite orientation dispersion and density imaging (NODDI). The latter decomposes diffusion-based MRI into multiple compartments that characterize the brain microstructure by its neurite complexity known as orientation dispersion (ODI) and by its neurite density (NDI). Hallucination proneness was negatively correlated with the volume and microstructure (fractional anisotropy, neurite complexity) of the left but not the right STG. The strongest relationship (r = -0.563) was observed for neurite complexity (ODI). No correlation was observed for neurite density (NDI). These findings suggest that there is a relationship between the volume and the microstructure of the left STG and hallucination proneness. Dendritic complexity (but not neurite density) is inversely related to hallucination proneness. Metrics based on multi-compartment diffusion models seem to be more sensitive for hallucination-related neural processes than conventional MRI-based metrics. PMID- 29988953 TI - Node-Pore Coded Coincidence Correction: Coulter Counters, Code Design, and Sparse Deconvolution. AB - We present a novel method to perform individual particle (e.g. cells or viruses) coincidence correction through joint channel design and algorithmic methods. Inspired by multiple-user communication theory, we modulate the channel response, with Node-Pore Sensing, to give each particle a binary Barker code signature. When processed with our modified successive interference cancellation method, this signature enables both the separation of coincidence particles and a high sensitivity to small particles. We identify several sources of modeling error and mitigate most effects using a data-driven self-calibration step and robust regression. Additionally, we provide simulation analysis to highlight our robustness, as well as our limitations, to these sources of stochastic system model error. Finally, we conduct experimental validation of our techniques using several encoded devices to screen a heterogeneous sample of several size particles. PMID- 29988955 TI - Novel management of ovarian vein thrombosis: A case report. AB - Ovarian vein thrombosis (OVT) is a rare serious diagnosis especially if extending to inferior vein cava (IVC). We present a case of 36-year- old female who was diagnosed with right OVT reaching the inferior vein cava following a supra cervical hysterectomy that was performed in the postpartum period due to excessive bleeding from uterine fibroids. Using the new generation anti-coagulant "rivaroxaban" for six months followed by maintenance regimen of aspirin and sulodexide, complete resolution of the clot was noticed without any adverse event while using this regimen. This is the first OVT case which is completely treated with rivaroxaban without any adjunct invasive modality. PMID- 29988954 TI - DNA repair capacity correlates with standardized uptake values from 18F fluorodeoxyglucose positron emission tomography/CT in patients with advanced non small-cell lung cancer. AB - Objective: The DNA repair capacity (DRC) of tumor cells is an important contributor to resistance to radiation and platinum-based drugs. Because DRC may be affected by tumor cell metabolism, we measured DRC in lymphocytes from patients with non-small-cell lung cancer (NSCLC) and compared the findings with the maximum standardized uptake value (SUVmax) on18F-fluorodeoxyglucose positron emission tomography (FDG PET) after (chemo)radiation therapy. Methods: This study included 151 patients with stage IA-IV NSCLC who had FDG PET at a single institution and donated blood samples before chemotherapy. We assessed the correlation of DRC, measured in peripheral T lymphocytes by a host-cell reactivation assay with SUVmax and their associations with overall survival (OS) time by hazards ratios calculated with a Cox proportional hazards regression model. Results: SUVmax of the primary tumor at diagnosis was inversely associated with lymphocyte DRC (r = -0.175, P = 0.032), particularly among patients with advanced disease (r = -0.218, P = 0.015). However, DeltaSUVmax of primary tumor was not significantly associated with DRC (r = 0.005, P = 0.968). SUVmax of regional lymph nodes at diagnosis (r = -0.307, P = 0.0008) and after (chemo)radiation treatment (r = -0.329, P = 0.034) and SUVmax of the primary tumor after (chemo)radiation treatment (r = -0.253, P = 0.045) were also inversely associated with OS time. Conclusion: DRC was inversely associated with primary tumor SUVmax before treatment but not with DeltaSUVmax after (chemo)radiation. PMID- 29988956 TI - In-hospital direct costs for thromboembolism and bleeding in Chinese patients with atrial fibrillation. AB - Objective: Limited data are available on the direct costs of hospitalization owing to thromboembolism and bleeding in patients with atrial fibrillation (AF) in China. Such data are essential for policy development, service planning, and cost-effectiveness analysis of new therapeutic strategies. This study aimed to provide detailed data regarding in-hospital direct costs for these patients, compare the costs at different scenarios, and identify independent factors that may predict the costs. Methods: We collected data regarding in-hospital direct costs among patients with AF who were hospitalized owing to ischemic stroke (IS), transient ischemic attack (TIA), intracranial hemorrhage (ICH), or major gastrointestinal bleeding. All data were collected from 7 representative tertiary referral hospitals and 3 secondary care hospitals from December 2009 to October 2014. Results: In total, 312 eligible patients with thromboembolism and 143 patients with major bleeding were identified, and their hospital charts were reviewed. The median in-hospital direct costs were 17,857 Chinese Yuan (CNY) for IS and 16,589 CNY for TIA (equivalent to 2907 US dollars and 2701 US dollars, respectively). For patients with major bleeding, the costs were 27,924 CNY for ICH and 18,196 CNY for major gastrointestinal bleeding (equivalent to 4546 US dollars and 2962 US dollars, respectively). The direct costs were mainly driven by medications, which accounted for approximately 33.4%-36.1% in different groups of patients. The direct costs were highly related to the hospital level and National Institutes of Health Stroke Scale scores in patients with thromboembolism; in patients with ICH, the factors included hospital level, warfarin treatment before admission, and prior hospitalization for stroke. Conclusions: Given the high prevalence, AF-related thromboembolism and bleeding impose considerable economic burden on the Chinese society. Efforts to improve the management of AF may confer substantial economic benefits. PMID- 29988957 TI - Deliberate self-harm among adolescent psychiatric outpatients in Singapore: prevalence, nature and risk factors. AB - Background: Deliberate self-harm (DSH) is a prominent mental health concern among adolescents. Few studies have examined adolescent DSH in non-Western countries. This study examines the prevalence, types and associated risk factors of DSH in a clinical sample of adolescents in Singapore. Methods: Using a retrospective review of medical records, demographic and clinical data were obtained from 398 consecutive adolescent psychiatric outpatients (mean age = 17.5 +/- 1.4 years, range = 13-19 years) who presented at Changi General Hospital from 2013 to 2015. Results: 23.1% (n = 92) of adolescents engaged in at least one type of DSH. Cutting was the most common type of DSH reported. Females were three times more likely to engage in DSH than males. DSH was positively associated with female gender (odds ratio [OR] 5.03), depressive disorders (OR 2.45), alcohol use (OR 3.49) and forensic history (OR 3.66), but not with smoking behaviour, living arrangement, parental marital status, past abuse or family history of psychiatric illness. Conclusion: Interventions targeting adolescent DSH should also alleviate depressive symptoms, alcohol use and delinquent behaviours. PMID- 29988958 TI - Neurotransmitters and Their Receptors - 2003. PMID- 29988959 TI - Bihemispheric alterations in myelination in children following unilateral perinatal stroke. AB - Background: Stroke is a leading cause of perinatal brain injury with variable outcomes including cerebral palsy and epilepsy. The biological processes that underlie these heterogeneous outcomes are poorly understood. Alterations in developmental myelination are recognized as a major determinant of outcome in preterm brain injury but have not been explored in perinatal stroke. We aimed to characterize myelination in hemiparetic children after arterial perinatal stroke, hypothesizing that ipsilesional myelination would be impaired, the degree of which would correlate with poor outcome. Methods: Retrospective, controlled cohort study. Participants were identified through the Alberta Perinatal Stroke Project (APSP), a population-based research cohort (n > 400). Inclusion criteria were: 1) MRI-confirmed, unilateral arterial perinatal stroke, 2) T1-weighted MRI after 6 months of age, 3) absence of other neurological disorders, 4) neurological outcome that included at least one of the following tests - Pediatric Stroke Outcome Measure (PSOM), Assisting Hand Assessment (AHA), Melbourne Assessment (MA), neuropsychological evaluation (NPE), and robotic sensorimotor measurements. FreeSurfer software measured hemispheric asymmetry in myelination intensity (primary outcome). A second method using ImageJ software validated the detection of myelination asymmetry. A repeated measures ANOVA was used to compare perilesional, ipsilesional remote, and contralesional homologous region myelination between stroke cases and typically developing controls. Myelination metrics were compared to clinical outcome measures (t-test, Pearson's correlation). Results: Twenty youth with arterial stroke (mean age: 13.4 +/- 4.2yo) and 27 typically developing controls (mean age: 12.5 +/- 3.7yo) were studied in FreeSurfer. Participants with stroke demonstrated lower myelination in the ipsilesional hemisphere (p < 0.0001). Myelination in perilesional regions had lower intensity compared to ipsilesional remote areas (p < .00001) and contralesional homologous areas (p < 0.00001). Ipsilesional remote regions had decreased myelination compared to homologous regions on the contralesional hemisphere (p = 0.016). Contralesional myelination was decreased compared to controls (p < 0.00001). Myelination metrics were not strongly associated with clinical motor, robotic sensorimotor, or neuropsychological outcomes though some complex tests requiring speeded responses had moderate effect sizes. Conclusion: Myelination of apparently uninjured brain in both the ipsilesional and contralesional hemispheres is decreased after perinatal stroke. Differences appear to radiate outward from the lesion. Further study is needed to determine clinical significance. PMID- 29988961 TI - UNDERSTANDING THE UNIQUE NATURE OF THE ADOLESCENT STUDY ABROAD EXPERIENCE. AB - Despite rising numbers of adolescents traveling abroad each year, the majority of study abroad research focuses on emerging adults. This study represents an effort to expand our understanding of the study abroad experience from the adolescent perspective. Qualitative data were drawn from interviews and focus groups with, and observations of, participants in the program. Results indicate preparing for and then sharing the experience with like-minded peers, coupled with exposure to a new culture and direct interaction with locals, facilitated a process of reflection and growth with both perceived short-term and potential long-term impacts. PMID- 29988960 TI - Comparison of platelet-albumin-bilirubin (PALBI), albumin-bilirubin (ALBI), and child-pugh (CP) score for predicting of survival in advanced hcc patients receiving radiotherapy (RT). AB - Purpose: This work evaluated the prognostic performance of Child-Pugh (CP), albumin-bilirubin (ALBI) and platelet-albumin-bilirubin (PALBI) scores in hepatocellular carcinoma (HCC) patients undergoing radiotherapy (RT). Results: The study included 174 consecutive patients with 63% at CP A5 (n = 110) and 34% at CP A6 (n = 64). The median ALBI score was -2.39 (range: -3.61 to -1.41) with 34.5% at grade A1 (n = 60) and 65.5% at grade A2 (n = 114). The median PALBI score was -2.39 (range -3.39 to -1.24) with 33.3% at grade 1 (n = 58), 41.4% at grade 2 (n = 72) and 25.3% at grade 3 (n = 44). With a median follow-up of 21.7 months, the median OS of the entire cohort was 22.2 months. OS was significantly associated with the PALBI grade (p = 0.002) and for the ALBI grade (p = 0.00495), but not for the CP score (p = 0.46). The PALBI grade has a significantly higher AUC compared than the ALBI grade or CP scores in predicting OS. The PALBI grade was predictive of CP score decline >=2 (20% grade 3 vs. 5.3% grade 1/2 p = 0.05) but the ALBI and CP scores were not. Conclusion: Among CP A HCC patients receiving radiotherapy, the PALBI and ALBI grade maybe a better prognostic tool than the CP score. The role of PALBI in predicting liver toxicity warranted further exploration. Methods: We retrospectively reviewed HCC patients treated with individualized hypo-fractionated radiotherapy (IHRT) using stereotactic technique from 2006 to 2015. We collected CP, ALBI and PALBI scores prior to treatment and analyzed their correlation with overall survival (OS) and liver toxicity. PMID- 29988963 TI - Multiple Sclerosis. PMID- 29988962 TI - Get Going! Self-focused Attention and Sensitivity to Action and Inaction Effort Primes. AB - Implicit action primes and inaction primes can directly affect effort in some circumstances. The present research examined if people high in trait self-focused attention were more strongly affected by action and inaction primes. Past work has found that self-focus makes people more likely to encode implicit primes as self-relevant, thus increasing the effects of primes. As a result, we expected that people high in trait self-focus would be more strongly affected when primed with action and inaction concepts. A group of young adults completed a self-paced parity task in which most trials primed words related to action or inaction. Effort was measured as baseline-to-task change in the cardiac pre-ejection period (PEP), a measure of sympathetic autonomic influence on the heart. Trait self focus significantly interacted with the priming manipulation. People high in self focus were more sensitive to the action primes, shown in greater PEP reactivity, but not to the inaction primes. The findings extend the growing literature on how priming influences effort and support models of how self-focused attention shapes motivational processes. PMID- 29988964 TI - A giant spinal schwannoma mimicking a renal mass: A case report. AB - Spinal schwannomas arise from the cells covering the nerves within the spinal canal. In most cases, they remain confined within the intradural extramedullary space, but occasionally they extend into the extradural space resembling abdominal masses. We present a case of very large spinal schwannoma mimicking a renal mass at ultrasound exam. Using contrast-enhanced computed tomography and magnetic resonance imaging we were able to detect and characterize the lesion and consequently assign a preoperative diagnosis later confirmed by the histopathology report. In this paper, we review computed tomography and magnetic resonance imaging features of spinal schwannomas and attempt a summary of possible differential diagnoses. PMID- 29988965 TI - Osteolytic cancer cells induce vascular/axon guidance processes in the bone/bone marrow stroma. AB - Prostate and breast cancers frequently metastasize to bone. The physiological bone homeostasis is perturbed once cancer cells proliferate at the bone metastatic site. Tumors are complex structures consisting of cancer cells and numerous stroma cells. In this study, we show that osteolytic cancer cells (PC-3 and MDA-MB231) induce transcriptome changes in the bone/bone marrow microenvironment (stroma). This stroma transcriptome differs from the previously reported stroma transcriptome of osteoinductive cancer cells (VCaP). While the biological process "angiogenesis/vasculogenesis" is enriched in both transcriptomes, the "vascular/axon guidance" process is a unique process that characterizes the osteolytic stroma. In osteolytic bone metastasis, angiogenesis is denoted by vessel morphology and marker expression specific for arteries/arterioles. Interestingly, intra-tumoral neurite-like structures were in proximity to arteries. Additionally, we found that increased numbers of mesenchymal stem cells and vascular smooth muscle cells, expressing osteolytic cytokines and inhibitors of bone formation, contribute to the osteolytic bone phenotype. Osteoinductive and osteolytic cancer cells induce different types of vessels, representing functionally different hematopoietic stem cell niches. This finding suggests different growth requirements of osteolytic and osteoinductive cancer cells and the need for a differential anti-angiogenic strategy to inhibit tumor growth in osteolytic and osteoblastic bone metastasis. PMID- 29988967 TI - Long-stay patients with and without intellectual disability in forensic psychiatric settings: comparison of characteristics and needs. AB - Background: In recent years, concerns have been raised that too many patients stay for too long in forensic psychiatric services and that this is a particular problem in those with an intellectual disability. Aims: To compare the characteristics, needs, and care pathways of long-stay patients with and without intellectual disability within forensic psychiatric hospital settings in England. Method: File reviews and questionnaires were completed for all long-stay patients in high secure and a representative sample of those in medium secure settings in England. Between-group analyses comparing patients with and without intellectual disability are reported. Results: Of the 401 long-stay patients, the intellectual disability and non-intellectual disability groups were strikingly similar on many sociodemographic, clinical and forensic variables. The intellectual disability group had significantly lower lengths of stay, fewer criminal sections, restriction orders and prison transfers, and higher levels of behavioural incidents and risk assessment scores. Conclusions: In spite of similar offence histories and higher risk levels, those with intellectual disability appear to be diverted away from the criminal justice system and have shorter lengths of stay. This has implications about the applicability of the Transforming Care programme to this group. PMID- 29988966 TI - V-ATPase-dependent repression of androgen receptor in prostate cancer cells. AB - Prostate Cancer (PCa) is the most commonly diagnosed cancer and the third leading cause of death for men in the United States. Suppression of androgen receptor (AR) expression is a desirable mechanism to manage PCa. Our studies showed that AR expression was reduced in LAPC4 and LNCaP PCa cell lines treated with nanomolar concentrations of the V-ATPase inhibitor concanamycin A (CCA). This treatment decreased PSA mRNA levels, indicative of reduced AR activity. V-ATPase dependent repression of AR expression was linked to defective endo-lysosomal pH regulation and reduced AR expression at the transcriptional level. CCA treatment increased the protein level and nuclear localization of the alpha subunit of the transcription factor HIF-1 (HIF-1alpha) in PCa cells via decreased hydroxylation and degradation of HIF-1alpha. The addition of iron (III) citrate restored HIF 1alpha hydroxylation and decreased total HIF-1alpha levels in PCa cells treated with CCA. Moreover, iron treatment partially rescued CCA-mediated AR repression. Dimethyloxalylglycine (DMOG), which prevents HIF-1alpha degradation independently of V-ATPase, also decreased AR levels, supporting our hypothesis that HIF-1alpha serves as a downstream mediator in the V-ATPase-AR axis. We propose a new V ATPase-dependent mechanism to inhibit androgen receptor expression in prostate cancer cells involving defective endosomal trafficking of iron and the inhibition of HIF-1 alpha-subunit turnover. PMID- 29988968 TI - Marek's disease virus oncoprotein Meq physically interacts with the chicken infectious anemia virus-encoded apoptotic protein apoptin. AB - Marek's disease (MD) is a neoplastic disease of poultry caused by Marek's disease virus (MDV), a highly contagious alphaherpesvirus. Meq, the major MDV oncoprotein, induces neoplastic transformation of T-cells through several mechanisms, including inhibition of apoptosis. In contrast, the chicken anemia virus (CAV)-encoded protein apoptin (VP3) is a powerful inducer of apoptosis of tumor cells, a property that is exploited for anticancer therapeutics. Although the molecular mechanisms of selective induction of tumor cell apoptosis by apoptin are not fully understood, its tumor cell-restricted nuclear translocation is thought to be important. Co-infection with MDV and CAV is common in many countries, CAV antigens are readily detectable in MD lymphomas, and the MDV transformed T-lymphoblastoid cell lines such as MSB-1 is widely used for propagating CAV for vaccine production. As MDV-transformed cell lines express high levels of Meq, we examined here whether CAV-encoded apoptin interacts with Meq in these cells. Using immunofluorescence microscopy, we found that apoptin and Meq co-localize to the nucleus, and biochemical analysis indicated that the two proteins do physically interact. Using a combination of Meq mutagenesis and co-immunoprecipitation, we demonstrate that apoptin interacts with Meq within a region between amino acids 130 and 140. Results from the IncuCyte assay suggested that Meq inhibits apoptin-induced apoptosis activity. In summary, our findings indicate that Meq interacts with and inhibits apoptin. Insights into this novel interaction between Meq and apoptin will relevance for pathogenesis of coinfections of the two viruses and in CAV vaccine production using MDV transformed cell lines. PMID- 29988971 TI - Molecular Diagnosis of Neuromuscular Disease. PMID- 29988969 TI - Chat- and internet-based cognitive-behavioural therapy in treatment of adolescent depression: randomised controlled trial. AB - Background: Depression is a major contributor to the burden of disease in the adolescent population. Internet-based interventions can increase access to treatment. Aims: To evaluate the efficacy of internet-based cognitive-behavioural therapy (iCBT), including therapist chat communication, in treatment of adolescent depression. Method: Seventy adolescents, 15-19 years of age and presenting with depressive symptoms, were randomised to iCBT or attention control. The primary outcome was the Beck Depression Inventory II (BDI-II). Results: Significant reductions in depressive symptoms were found, favouring iCBT over the control condition (F(1,67) = 6.18, P < 0.05). The between-group effect size was Cohen's d = 0.71 (95% CI 0.22-1.19). A significantly higher proportion of iCBT participants (42.4%) than controls (13.5%) showed a 50% decrease in BDI II score post-treatment (P < 0.01). The improvement for the iCBT group was maintained at 6 months. Conclusions: The intervention appears to effectively reduce symptoms of depression in adolescents and may be helpful in overcoming barriers to care among young people. Declaration of interest: N.T. and G.A. designed the programme. N.T. authored the treatment material. The web platform used for treatment is owned by Linkoping University and run on a non-for-profit basis. None of the authors receives any income from the programme. PMID- 29988970 TI - Distinct neural correlates of trait resilience within core neurocognitive networks in at-risk children and adolescents. AB - Background: Most children who are exposed to threat-related adversity (e.g., violence, abuse, neglect) are resilient - that is, they show stable trajectories of healthy psychological development. Despite this, most research on neurodevelopmental changes following adversity has focused on the neural correlates of negative outcomes, such as psychopathology. The neural correlates of trait resilience in pediatric populations are unknown, and it is unclear whether they are distinct from those related to adversity exposure and the absence of negative outcomes (e.g., depressive symptomology). Methods: This functional magnetic resonance imaging (fMRI) study reports on a diverse sample of 55 children and adolescents (ages 6-17 years) recruited from a range of stressful environments (e.g., lower income, threat-related adversity exposure). Participants completed a multi-echo multi-band resting-state fMRI scan and self report measures of trait resilience and emotion-related symptomology (e.g., depressive symptoms). Resting-state data were submitted to an independent component analysis (ICA) to identify core neurocognitive networks (salience and emotion network [SEN], default mode network [DMN], central executive network [CEN]). We tested for links among trait resilience and dynamic (i.e., time varying) as well as conventional static (i.e., averaged across the entire session) resting-state functional connectivity (rsFC) of core neurocognitive networks. Results: Youth with higher trait resilience spent a lower fraction of time in a particular dynamic rsFC state, characterized by heightened rsFC between the anterior DMN and right CEN. Within this state, trait resilience was associated with lower rsFC of the SEN with the right CEN and anterior DMN. There were no associations among trait resilience and conventional static rsFC. Importantly, although more resilient youth reported lower depressive symptoms, the effects of resilience on rsFC were independent of depressive symptoms and adversity exposure. Conclusions: The present study is the first to report on the neural correlates of trait resilience in youth, and offers initial insight into potential adaptive patterns of brain organization in the context of environmental stressors. Understanding the neural dynamics underlying positive adaptation to early adversity will aid in the development of interventions that focus on strengthening resilience rather than mitigating already-present psychological problems. PMID- 29988972 TI - MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma. AB - Purpose: There has been growing interest in using chemoradiation (CRT) for non operative management of rectal cancer, and identifying patients who might benefit most from this approach is crucial. This study identified miRNAs (miRs) associated with clinical outcomes and treatment resistance by evaluating both pre and post-CRT expression profiles. Methods: Forty patients, 9 with pathologic complete response (pCR) and 31 with pathologic incomplete response (pIR) were included. MicroRNA was extracted from 40 pre-therapy tumor samples and 31 post chemoradiation surgical samples with pathologic incomplete response (pIR). A generalized linear model was used to identify miRs associated with pCR. A linear mixed effects model was used to identify miRs differentially expressed before and after treatment. miR expression was dichotomized at the mean and clinical outcomes were evaluated using Cox proportional hazard modeling. Results: Nine miRs were associated with pCR (p<0.05), but none were significant after false discovery rate correction. Among patients with pIR, 68 miRs were differentially expressed between the pre and post-CRT groups (FDR p<0.05). Ingenuity pathway analysis (IPA) demonstrated multiple signaling networks associated with pIR, including p38MAPK, TP53, AKT, IL-6, and RAS. Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p<0.05). Conclusions: No miRs were significantly correlated with pCR. We identified miRs that were differentially expressed between pre- and post-CRT tumor samples, and these miRs implicated multiple signaling pathways that may confer resistance to CRT. In addition, we identified an association between increased let-7b and worse clinical outcomes (DM, DFS, OS). PMID- 29988973 TI - Primary lymphoma of the breast: A case series. AB - Primary breast lymphoma has been defined as localized involvement of one or both breasts with or without ipsilateral axillary nodal involvement, usually as a rare manifestation of extranodal non-Hodgkin's lymphoma. We describe three cases of this uncommon disease seen at our institution. Two of these cases presented as palpable breast lumps and one was screening detected. None of the patients had a prior history of lymphoma; only one reported B symptoms night sweats and weight loss. Diagnosis was established on ultrasound-guided core biopsy and no evidence of metastatic disease was identified. Even though the imaging features are not specific to this diagnosis, the radiologists should be aware of the clinical and imaging presentation of this rare malignancy to recommend appropriate management and establish radiologic-pathologic concordance. PMID- 29988974 TI - Simultaneous characterization of physical, chemical, and thermal properties of polymeric multilayers using infrared spectroscopic ellipsometry. AB - In this study, multilayered films of polyethylenimine/poly (sodium-p-styrene sulfonate) (PEI)/(PSS) and type I collagen/heparin sodium (COL)/(HEP) were fabricated using the layer-by-layer technique, and fully characterized using Infrared Variable Angle Spectroscopic Ellipsometry (IRVASE) to simultaneously analyze the chemistry, thickness, and roughness of the multilayers with respect to changes in pH of the washing solution, and changes in temperature. Film topography and Young's modulus were obtained by atomic force microscopy (AFM) and nanoindentation. Our results show that with IRVASE it is possible to analyze the thickness of the multilayers prepared using a washing solution of pH 5, obtaining values of 71.7 nm and 40.3 nm for three bilayers of PEI/PSS and COL/HEP, respectively. Film roughness varies between multilayer systems, obtaining values of 37.76 nm for three bilayers of PEI/PSS and 33.58 nm for three bilayers of COL/HEP. Increasing the pH of the washing solution for PEI/PSS yielded thinner films that were less susceptible to thermal induced changes in film chemistry in the range of 25 - 150 degrees C. PEI/PSS films decreased in thickness with increasing temperature up to 75 degrees C, whereas above 75 degrees C film thickness increased. Through IRVASE, a transition temperature for the PEI/PSS multilayers was observed at 75 degrees C. Temperatures above 37 degrees C drastically alter the chemistry and the thickness of the COL/HEP multilayers indicating a possible degradation of the polymers. We obtained, through nanoindentation, a Young's modulus of 15000 kPa and 9000 kPa for 12 bilayers of PEI/PSS and COL/HEP, respectively. These results demonstrate that, using IRVASE, we can simultaneously evaluate the physical, chemical, and thermal properties of synthetic and natural multilayered polymeric films. PMID- 29988975 TI - Characteristics of footwear worn by people with systemic lupus erythematosus: a comparison with age- and sex-matched healthy controls: a pilot study. AB - Background: To determine characteristics of footwear worn by people with systematic lupus erythematosus (SLE). Methods: Twenty-two people with SLE and twenty matched healthy controls participated in a cross-sectional study. Objective assessments of footwear included: fit, style, structure, motion control, cushioning, and wear. Footwear was classified as poor, average or good based on a standardised tool. Participants completed 100mm visual analogue scales for foot pain and footwear comfort and suitability. Participants with SLE were asked to indicate which footwear features were important to them using a validated checklist. Results: No differences were observed between groups for footwear fit, age, style, heel height, forefoot flexion or cushioning (all P>0.05). Compared to controls, a greater number of participants with SLE wore shoes with worn tread (65% vs. 91%, P=0.041), wore shoes with a lower motion control scale (median: 5.0 vs. 1.0, P=0.003), and rated their footwear as less comfortable (median: 90mm vs. 78mm, P=0.024) and less suitable (median: 88mm vs. 76mm, P=0.030). Participants with SLE experienced greater foot pain than controls (median: 17mm vs. 0mm, P=0.038). Comfort (95%), fit (95%) and style (86%) were identified as the most important footwear features by people with SLE. Conclusions: Compared to control participants, people with SLE wear shoes that are more worn and lack motion control. They also report greater foot pain and report their shoes to be less comfortable and suitable. These findings highlight the need for a further focus on the role of footwear in the management of foot problems in people with SLE. PMID- 29988977 TI - Differential Diagnosis and Prognostic Markers of Stroke. PMID- 29988976 TI - The 5-HTTLPR genotype, early life adversity and cortisol responsivity to psychosocial stress in women. AB - Background: The serotonin transporter gene-linked polymorphic region (5-HTTLPR) has previously been associated with hypothalamus-pituitary-adrenal axis function. Moreover, it has been suggested that this association is moderated by an interaction with stressful life experiences. Aims: To investigate the moderation of cortisol response to psychosocial stress by 5-HTTLPR genotype, either directly or through an interaction with early life stress. Method: A total of 151 women, 85 of which had personality psychopathology, performed the Trier Social Stress Test while cortisol responsivity was assessed. Results: The results demonstrate a main effect of genotype on cortisol responsivity. Women carrying two copies of the long version of 5-HTTLPR exhibited stronger cortisol responses to psychosocial stress than women with at least one copy of the short allele (P = 0.03). However, the proportion of the variance of stress-induced cortisol responsivity explained by 5-HTTLPR genotype was not further strengthened by including early life adversity as a moderating factor (P = 0.52). Conclusions: Our results highlight the need to clarify gender-specific biological factors influencing the serotonergic system. Furthermore, our results suggest that childhood maltreatment, specifically during the first 15 years of life, is unlikely to exert a moderating influence of large effect on the relationship between the 5-HTTLPR genotype and cortisol responsivity to psychosocial stress. Declaration of interest: None. PMID- 29988978 TI - Real-Time Visual Tracking of Dynamic Surgical Suture Threads. AB - In order to realize many of the potential benefits associated with robotically assisted minimally invasive surgery, the robot must be more than a remote controlled device. Currently, using a surgical robot can be challenging, fatiguing, and time consuming. Teaching the robot to actively assist surgical tasks, such as suturing, has the potential to vastly improve both patient outlook and the surgeon's efficiency. One obstacle to completing surgical sutures autonomously is the difficulty in tracking surgical suture threads. This paper presents novel stereo image processing algorithms for the detection, initialization, and tracking of a surgical suture thread. A Non Uniform Rational B-Spline (NURBS) curve is used to model a thin, deformable, and dynamic length thread. The NURBS model is initialized and grown from a single selected point located on the thread. The NURBS curve is optimized by minimizing the image matching energy between the projected stereo NURBS image and the segmented thread image. The algorithms are evaluated using suture threads, a calibrated test pattern, and a simulated thread image. Additionally, the accuracy of the algorithms presented are validated as they track a suture thread undergoing translation, deformation, and apparent length changes. All of the tracking is in real-time. Note to Practioners: Abstract-The problem of tracking a surgical suture thread was addressed in this work. Since the suture thread is highly deformable, any tracking algorithm must be robust to intersections, occlusions, knot tying, and length changes. The detection algorithm introduced in this paper is capable of distinguishing different threads when they intersect. The tracking algorithm presented here demonstrate that it is possible, using polynomial curves, to track a suture thread as it deforms, becomes occluded, changes length, and even ties a knot in real time. The detection algorithm can enhance directional thin features while the polynomial curve modeling can track any string like structure. Further integration of the polynomial curve with a feed forward thread model could improve the stability and robustness of the thread tracking. PMID- 29988979 TI - Impact of histologic subtypes and treatment modality among patients with primary central nervous system lymphoma: a SEER database analysis. AB - Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal presentation of lymphoma; however, the data for outcomes of patients with subtypes other than diffuse large B-cell lymphoma (DLBCL) are limited. Therefore, we analyzed overall survival (OS) of adult patients diagnosed with PCNSL by histologic subtype between 1998 and 2014 using the Surveillance, Epidemiology and End Results. A total of 4375 patients were identified. The median age of the patients was 64 years (range: 18-96). DLBCL was the most common histology (N=3,091), followed by follicular lymphoma (FL, N=83), peripheral T cell lymphoma (PTCL, N=64), marginal zone lymphoma (MZL, N=63), Burkitt lymphoma (BL, N=27), small lymphocytic lymphoma (SLL, N=22), Hodgkin lymphoma (HL, N=13) and others (N=1,012). The 5-year OS rates were 30% in DLBCL, 66% in FL, 33% in PTCL, 79% in MZL, 42% in BL, 38% in SLL and 45% in HL. Radiation alone showed similar OS compared to no treatment in DLBCL, BL and PTCL, while radiation alone was associated with similar OS to chemotherapy or chemo-radiation in FL and MZL. The outcomes of patients with PCNSL are unfavorable; with the exception of FL and MZL which can potentially show prolonged survival with surgical resection or radiation monotherapy. PMID- 29988981 TI - Acceptability of Ecological Momentary Assessment Among Young Men Who Have Sex with Men. AB - The study evaluated the acceptability of text message- and voice-based ecological momentary assessment (EMA) methods among a sample (n=74) of young men who have sex with men (MSM). We assessed the acceptability of text message- and voice based EMA methods. Almost all participants (96%) reported that they would be willing to accept texts on their smartphone to answer questions about their current mood, surroundings, or feelings. A large majority (89%) also reported being willing to accept phone calls to answer these questions. This work suggests that different EMA methods are acceptable for use among young MSM. PMID- 29988980 TI - Local Adipose-Associated Mediators and Adaptations Following Arteriovenous Fistula Creation. AB - Introduction: Local inflammation is an important regulator of vascular remodeling. We hypothesized that adipose tissue adjacent to hemodialysis arteriovenous fistulae modulates maturation. Methods: During fistula creation, perivenous adipose was collected from 111 participants in the Hemodialysis Fistula Maturation Study. Nine adipose-associated mediators were measured. Duplex ultrasound was performed at 4 time points postoperatively from 1 day to first cannulation (10-26 weeks). Associations between logarithmically transformed biomarker levels and fistula remodeling were evaluated using mixed effects regression. Results: Elevated interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 were associated with a reduction in the fractional vein diameter during the early time frame of 1 day to 2 weeks (diameter change of 26.6% and 20.4% at the 25th and 75th percentile for IL-6, P = 0.01; 27.8% and 21.1% at the 25th and 75th percentile for MCP-1, P = 0.02), but not in later stages of remodeling. Local leptin levels showed a significant negative correlation with fractional venous flow increase between 2 and 6 weeks (percent flow change 31.4% and 11.3% at the 25th and 75th percentile for leptin, P = 0.03). Conclusion: Thus, impaired fistula vein dilation and reduced capacity for flow augmentation associate with specific local adipose phenotypic signatures in a time-dependent manner. In view of adipose tissue plasticity, these findings raise the possibility of novel adipose-based strategies to facilitate fistula maturation. PMID- 29988982 TI - Myelofibrosis-Induced Erythropoietin-Resistant Anemia Due to Severe Refractory Hyperparathyroidism. PMID- 29988983 TI - Real world experience in low-dose ipilimumab in combination with PD-1 blockade in advanced melanoma patients. AB - Dual immune-checkpoint blockade with the anti-PD-1 antibody nivolumab (1 mg/kg) and standard-dose ipilimumab (3 mg/kg) is the mainstay of immunotherapy in advanced melanoma and it is approved since 2016. However, severe side effects (grade 3/4) occur in up to 60% of the patients. Recently, clinical trials have shown similar anti-tumor activity with a more favorable toxicity profile in patients treated with low-dose ipilimumab (1 mg/kg) and standard-dose pembrolizumab (2 mg/kg). In this study we report on the real-world experience of this dosing regime in advanced melanoma patients not eligible for clinical trials. A total of 33 patients with metastatic melanoma (24 with cutaneous and 9 with uveal melanoma) were assessed, retrospectively. Brain metastases were present in 33% of the patients and lactate dehydrogenase was elevated in 70%. Overall response rates were 38% and 0% in cutaneous melanoma and uveal melanoma respectively. Median overall survival was not reached in cutaneous melanoma and was 18 months in uveal melanoma. In 18% of the patients at least one treatment related severe adverse event was observed. Our observation that the combination of standard dose pembrolizumab and low-dose ipilimumab has a favorable toxicity profile yet anti-tumor activity comparable to the approved standard-dose combination regime in advanced patients not suitable for enrollment in clinical trials is encouraging. PMID- 29988985 TI - Rhodium(III)-catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles. AB - The synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles via rhodium(III) catalyzed C-H functionalization of C-alkenyl azoles with sulfoxonium ylides is disclosed. Reactions proceeded in good to high yields for a range of aryl, heteroaryl and alkyl sulfoxonium ylides. In addition, 2-alkenyl imidazoles with different substitution patterns as well as C-alkenyl triazoles were effective inputs. The reaction could also be performed under straightforward bench top conditions. PMID- 29988984 TI - Production of Humanized Mice through Stem Cell Transfer. AB - The development of humanized mice has become a prominent tool for translational animal studies of human diseases. Here we show how immune deficient mice can be "humanized" by injections of human umbilical cord stem cells. The engraftment of these cells and development into human lymphocytes has been possible because of the development of novel severely immune deficient mouse strains. Here we present proven protocols for the generation and analysis of humanized mice on the NSG mouse background. PMID- 29988986 TI - Kidney Transplant Outcomes in 2 Adults With Down Syndrome. PMID- 29988987 TI - Hyperspectral imaging to characterize plant-plant communication in response to insect herbivory. AB - Background: In studies of plant stress signaling, a major challenge is the lack of non-invasive methods to detect physiological plant responses and to characterize plant-plant communication over time and space. Results: We acquired time series of phytocompound and hyperspectral imaging data from maize plants from the following treatments: (1) individual non-infested plants, (2) individual plants experimentally subjected to herbivory by green belly stink bug (no visible symptoms of insect herbivory), (3) one plant subjected to insect herbivory and one control plant in a separate pot but inside the same cage, and (4) one plant subjected to insect herbivory and one control plant together in the same pot. Individual phytocompounds (except indole-3acetic acid) or spectral bands were not reliable indicators of neither insect herbivory nor plant-plant communication. However, using a linear discrimination classification method based on combinations of either phytocompounds or spectral bands, we found clear evidence of maize plant responses. Conclusions: We have provided initial evidence of how hyperspectral imaging may be considered a powerful non-invasive method to increase our current understanding of both direct plant responses to biotic stressors but also to the multiple ways plant communities are able to communicate. We are unaware of any published studies, in which comprehensive phytocompound data have been shown to correlate with leaf reflectance. In addition, we are unaware of published studies, in which plant-plant communication was studied based on leaf reflectance. PMID- 29988989 TI - Wilson's Disease. PMID- 29988988 TI - Understanding for whom, why and in what circumstances payment for performance works in low and middle income countries: protocol for a realist review. AB - Background: Many low and middle income countries (LMIC) are implementing payment for performance (P4P) schemes to strengthen health systems and make progress towards universal health coverage. A number of systematic reviews have considered P4P effectiveness but did not explore how P4P works in different settings to improve outcomes or shed light on pathways or mechanisms of programme effect. This research will undertake a realist review to investigate how, why and in what circumstances P4P leads to intended and unintended outcomes in LMIC. Methods: Our search was guided by an initial programme theory of mechanisms and involved a systematic search of Medline, Embase, Popline, Business Source Premier, Emerald Insight and EconLit databases for studies on P4P and health in LMIC. Inclusion and exclusion criteria identify literature that is relevant to the initial programme theory and the research questions underpinning the review. Retained evidence will be used to test, revise or refine the programme theory and identify knowledge gaps. The evidence will be interrogated by examining the relationship between context, mechanisms and intended and unintended outcomes to establish what works for who, in which contexts and why. Discussion: By synthesising current knowledge on how P4P affects health systems to produce outcomes in different contexts and to what extent the programme design affects this, we will inform more effective P4P programmes to strengthen health systems and achieve sustainable service delivery and health impacts. PMID- 29988990 TI - Phosphorylation of SMC1A promotes hepatocellular carcinoma cell proliferation and migration. AB - Structural maintenance of chromosomes protein 1A (SMC1A) has been implicated in the development of a variety of cancer types. However, its role in hepatocellular carcinoma remains unknown. In this study, we found that phosphorylated SMC1A was highly expressed in HepG2 and Bel7402 cells when compared with other cancer cell lines. Furthermore, SMC1A knockdown dramatically reduced HepG2 and Bel7402 cell proliferation and migration. Re-expressing phosphomimetic mutants S957DS966D significantly enhanced the proliferation and migration of SMC1A knockdown HepG2 and Bel7402 cells. In addition, phosphorylated SMC1A promotes hepatocellular carcinoma cells growth in vivo. Importantly, the expression of phosphorylated SMC1A was significantly higher in human hepatocellular carcinomacells when compared to peri-tumor benign hepatocytes, and its overexpression was significantly associated with worse prognostic outcomes. These observations suggest that phosphorylation of SMC1A is a vital event in tumorigenesis and disease progression in hepatocellular carcinoma thus necessitating further investigation. PMID- 29988991 TI - Measuring Model Misspecification: Application to Propensity Score Methods with Complex Survey Data. AB - Model misspecification is a potential problem for any parametric-model based analysis. However, the measurement and consequences of model misspecification have not been well formalized in the context of causal inference. A measure of model misspecification is proposed, and the consequences of model misspecification in non-experimental causal inference methods are investigated. The metric is then used to explore which estimators are more sensitive to misspecification of the outcome and/or treatment assignment model. Three frequently used estimators of the treatment effect are considered, all of which rely on the propensity score: (1) full matching, (2) 1:1 nearest neighbor matching, and (3) weighting. The performance of these estimators is evaluated under two different sampling designs: (1) simple random sampling (SRS) and (2) a two-stage stratified survey. As the degree of misspecification of either the propensity score or outcome model increases, so does the bias and the root mean square error, while the coverage decreases. Results are similar for the simple random sample and a complex survey design. PMID- 29988992 TI - Emphysematous Pyelonephritis Case Series From South India. AB - Introduction: Emphysematous pyelonephritis (EPN) is a rare, life-threatening necrotizing infection of the kidney. The mortality rate for EPN is as high as 25%. We conducted a retrospective study at MS Ramaiah Hospital between January 2011 and May 2016 to observe the clinical, biochemical, and microbiological patterns of EPN at our institute. Methods: The clinical and laboratory data, imaging findings, and microbiological patterns of 51 patients chosen for the study were recorded. The data were analyzed to identify the prognostic variables that could predict the morbidity and mortality of patients with EPN, and the focus of this study was to determine risk factors for and outcomes of patients who presented with EPN and who required hemodialysis. Primary endpoints were successful treatment and all-cause mortality. Secondary endpoints included need for hemodialysis and the need for a specific treatment. Results: There was an equal incidence among both sexes (median age: 59 years). Common symptoms were abdominal pain (94.11%), fever (83.2%), dysuria (74.5%), vomiting (72.54%), frequency of micturition (68.62%), oliguria, generalized weakness (66.67%), and breathlessness (66.67%); 98.03% (n = 50) of the patients had diabetes. The most common organism cultured was Escherichia coli (37.2%). Nineteen patients (37.2%) required dialysis; their mean age was 60.25 +/- 11.74 years. Male sex, diabetes mellitus, shock, high serum creatinine at presentation, and uremic symptoms showed no statistically significant association. Indefinite hemodialysis was required by 12.5% of patients. The antibiotic-treated group had a 100% success rate, whereas the Double J (DJ) stenting group (Double J stent, Biorad, India) had 96.42% success rate. Conclusion: Early diagnosis and broad spectrum antibiotics, together with an appropriately timed intervention, resulted in decreased mortality. Pain in the abdomen and renal angle tenderness were the most common clinical finding. E coli was the most found organism, and early use of broad spectrum antibiotics decreased mortality. PMID- 29988993 TI - IgM-Positive Tubulointerstitial Nephritis Associated With Asymptomatic Primary Biliary Cirrhosis. PMID- 29988994 TI - Twice-Weekly Hemodialysis and Clinical Outcomes in the China Dialysis Outcomes and Practice Patterns Study. AB - Introduction: In China, a quarter of patients are undergoing 2-times weekly hemodialysis. Using data from the China Dialysis Outcomes and Practice Patterns Study (DOPPS), we tested the hypothesis that whereas survival and hospitalizations would be similar in the presence of residual kidney function (RKF), patients without RKF would fare worse on 2-times weekly hemodialysis. Methods: In our cohort derived from 15 units randomly selected from each of 3 major cities (total N = 45), we generated a propensity score for the probability of dialysis frequency assignment, estimated a survival function by propensity score quintiles, and averaged stratum-specific survival functions to generate mean survival time. We used the proportional rates model to assess hospitalizations. We stratified all analyses by RKF, as reported by patients (urine output <1 vs. >=1 cup/day). Results: Among 1265 patients, 123 and 133 were undergoing 2-times weekly hemodialysis with and without evidence of RKF. Over 2.5 years, adjusted mean survival times were similar for 2- versus 3-times weekly dialysis groups: 2.20 versus 2.23 and 2.20 versus 2.15 for patients with and without RKF (P = 0.65). Hazard ratios for hospitalization rates were similar for 2- versus 3-times weekly groups, with (1.15, 95% confidence interval = 0.66-2.00) and without (1.10, 95% confidence interval 0.68-1.79]) RKF. The normalized protein catabolic rate was lower and intradialytic weight gain was not substantially higher in the 2- versus 3-times weekly dialysis group, suggesting greater restriction of dietary sodium and protein. Conclusion: In our study of patients in China's major cities, we could not detect differences in survival and hospitalization for those undergoing 2- versus 3-times weekly dialysis, regardless of RKF. Our findings indicate the need for pragmatic studies regarding less frequent dialysis with associated nutritional management. PMID- 29988995 TI - Persistent Hepatitis C Virus-Associated Cryoglobulinemic Glomerulonephritis in Patients Successfully Treated With Direct-Acting Antiviral Therapy. PMID- 29988996 TI - A human proteomic dataset from untreated and depleted/enriched serum samples. AB - We present a proteomic dataset generated from a human serum sample and the enriched/depleted fractions obtained by seven commercial products. This report is related to the research article entitled "Comparative evaluation of seven commercial products for human serum enrichment/depletion by shotgun proteomics" [1]. All samples were analyzed by LC-MS/MS, label free quantitation using the spectral counting approach, and Gene Ontology (GO) annotation. Protein relative abundances and functions were reported. PMID- 29988997 TI - Maintenance antipsychotic treatment versus discontinuation strategies following remission from first episode psychosis: systematic review. AB - Background: Understanding the relative risks of maintenance treatment versus discontinuation of antipsychotics following remission in first episode psychosis (FEP) is an important area of practice. Method: A systematic review and meta analysis. Prospective experimental studies including a parallel control group were identified to compare maintenance antipsychotic treatment with total discontinuation or medication discontinuation strategies following remission in FEP. Results: Seven studies were included. Relapse rates were higher in the discontinuation group (53%; 95% CIs: 39%, 68%; N = 290) compared with maintenance treatment group (19%; 95% CIs: 0.05%, 37%; N = 230). In subgroup analyses, risk difference of relapse was lower in studies with a longer follow-up period, a targeted discontinuation strategy, a higher relapse threshold, a larger sample size, and samples with patients excluded for drug or alcohol dependency. Insufficient studies included psychosocial functioning outcomes for a meta analysis. Conclusions: There is a higher risk of relapse for those who undergo total or targeted discontinuation strategies compared with maintenance antipsychotics in FEP samples. The effect size is moderate and the risk difference is lower in trials of targeted discontinuation strategies. Declaration of interest: A.T. has received honoraria and support from Janssen-Cilag and Otsuka Pharmaceuticals for meetings and has been has been an investigator on unrestricted investigator-initiated trials funded by AstraZeneca and Janssen Cilag. He has also previously held a Pfizer Neurosciences Research Grant. S.M. has received sponsorship from Otsuka and Lundbeck to attend an academic congress and owns shares in GlaxoSmithKline and AstraZeneca. J.H. has attended meetings supported by Sunovion Pharmaceuticals. PMID- 29988998 TI - Change in Albuminuria and Risk of Renal and Cardiovascular Outcomes: Natural Variation Should Be Taken into Account. AB - Introduction: Changes in urinary albumin-to-creatinine ratio (UACR) may affect the risk of advanced chronic kidney disease (CKD). How much the association changes after taking account for natural variation in UACR and the length of time taken to observe changes in UACR is unknown. Methods: English Clinical Practice Research Datalink records (2000-2015) with linkage to secondary care and death certification were used to identify prospective cohorts with at least 2 measures of UACR within 1, 2, and 3 years. Adjusted Cox regression assessed the separate relevance of the baseline UACR and the UACR change to the risk of developing stages 4 to 5 CKD and end-stage renal disease (ESRD). Associations were compared before and after accounting for the effects of the natural variation in UACR (i.e., regression to the mean). Results: A total of 212,810 individuals had baseline UACR measurements; 22% had a UACR >=3.4 mg/mmol, and 3% had UACR >=33.9 mg/mmol. During a median 4-year follow-up, 5976 developed stage 4 to 5 CKD, and 1076 developed ESRD. There were strong associations between baseline UACR and stage 4 to 5 CKD or ESRD risk, which doubled in strength after accounting for regression to the mean. Over 3 years, the hazard ratios (95% confidence intervals) for stage 4 to 5 CKD, relative to stable UACR, were 0.62 (0.50-0.77) for at least a halving of UACR and 2.68 (2.29-3.14) for at least a doubling of UACR. Associations were weaker for shorter exposure windows (and for cardiovascular disease or death), but strengthened after allowing for regression to the mean. Conclusion: Baseline values and subsequent medium-term increases in albuminuria are both associated with substantially increased risk of developing advanced CKD. Standard analyses, not allowing for natural variation in UACR, may underestimate these associations. PMID- 29988999 TI - Immunosuppressive Treatment in Children With IgA Nephropathy and the Clinical Value of Podocytopathic Features. AB - Introduction: There is a need for treatment guidelines and prognostic factor identification in children with primary IgA nephropathy. We analyzed the causative effect of steroids and the applicability of the Oxford classification. Methods: A total of 82 consecutive children (mean 10.6 years; median follow-up 3.3 years) were reviewed; 21 patients (25.6%) presented with acute kidney injury, and 6 (7.3%) with nephrotic syndrome. Renal biopsies were scored for Oxford classification and podocytopathic features in 2 groups: a group treated with steroid therapy (some in association with cyclophosphamide) and supportive care (renin angiotensin system blockade) and a group treated by supportive care alone. Results: The 2 groups were not comparable because baseline clinical data were different. Estimated glomerular filtration rate (eGFR) in immunosupressive group significantly improved between M0 (at onset) and M6 (6 months after treatment) from 89.9 [61.2-114.5] to 110.5 [93.7-120] ml/min per 1.73 m2, P < 0.001. Proteinuria also significantly decreased from (1.6 [1-4.3] to 0.3 [0.2-0.7] g/g, P < 0.001). In the supportive care group, eGFR and proteinuria remained stable. Podocytopathic features were predictive of renal function decline by univariable (-4.9 +/- 14.9 ml/min per 1.73 m2, P = 0.0079) and multivariable analysis and of poor renal prognosis to a combined event (renal function impairment more than 10% of the eGFR baseline or chronic kidney disease stage 3 at 6 months) in univariable analysis. MEST-C score failed to prove its prognostic value. Conclusion: Immunosuppressive treatment, especially steroid therapy, seems beneficial in children with glomerular inflammation and proliferation. The Oxford classification does not appear to be entirely appropriate in predicting long-term renal prognosis for children, whereas the characteristics of podocytopathy are strongly predictive of renal prognosis. PMID- 29989000 TI - Rituximab as a front-line therapy for adult-onset minimal change disease with nephrotic syndrome. AB - Minimal change disease (MCD) accounts for 15% of adult nephrotic syndrome (NS) cases. Adult-MCD patients may have more severe clinical features than pediatric patients. In children, Rituximab (RTX) has been used since 2006 to treat frequently relapsing NS. In adults, data about the efficacy of RTX for MCD are limited. We report our experience on the use of RTX in adult biopsy-proven MCD. Our series includes 6 adult patients (2 males and 4 females), age 45-73 years, treated with RTX (4 weekly doses of 375 mg/m2). Proteinuria decreased from 11,2 (23-4.8) g/24 hours to 0.6 (0-2) g/24 hours after 6 months, and to 0.4 (0-1, 4) g/24 h in the 4 pts with the longer follow-up. Creatinine decreased from 1.95 (0.5-5) mg/dl to 0.88 (0.6-1.3) mg/l. Five patients achieved a complete renal remission, while in 1 pt proteinuria decreased by 75%. RTX successfully depleted CD19 lymphocytes in 100% of pts for at least 6 months. No clinically relevant adverse events have been observed. This case series shows a remarkable efficacy of RTX in treatment of MCD. RTX can be an attractive alternative both in recurrent forms and in induction-therapy of MCD. RTX may be preferentially used in patients at a high risk of development of the adverse effects of corticosteroids and should be considered as an alternative option in patients with recurrent NS. Additional data are needed to inform clinical practice on how best to use RTX in this patient population, so that definitive randomized trials can be planned. PMID- 29989001 TI - EGFR overexpression is not common in patients with head and neck cancer. Cell lines are not representative for the clinical situation in this indication. AB - Background: Based on expression data, Epidermal Growth Factor Receptor (EGFR) emerged as therapeutic target in Head and Neck Cancer but clinical efficacy of EGFR inhibitors was very limited. We reinvestigated the EGFR expression and activation status necessary for response in cell lines and compared that to clinical samples. Methods: Clinical samples of head and neck squamous cell carcinoma (HNSCC, n=63), mostly from late stage (IV) and poorly or undifferentiated character and cultured cell lines (n=14) were tested by immunohistochemistry (IHC) (n=55) and sandwich immunoassays (n=63) for expression and phosphorylation of EGFR (Tyrosine-1173). Response of 14 different HNSCC cell lines to Erlotinib was tested in proliferation assays. Results: Most HNSCC cell lines respond to Erlotinib. EGFR is phosphorylated in these cell lines. Resistant cell lines display very low level EGFR expression and phosphorylation. EGFR activity in clinical samples is significantly below that observed in cell lines. In clinical samples, EGFR is not overexpressed on the single cellular level. We show similar levels of EGFR expression in growing keratinocytes and tumor cells. Conclusions: Cell lines are not representative of the clinical situation in HNSCC. Larger studies should investigate whether patient subgroups with activating EGFR mutations or overexpression can be identified. PMID- 29989002 TI - An Exome-wide Association Study for Type 2 Diabetes-Attributed End-Stage Kidney Disease in African Americans. AB - Introduction: Compared with European Americans, African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD). Genome-wide association studies (GWAS) have identified >70 genetic variants associated with kidney function and chronic kidney disease (CKD) in patients with and without diabetes. However, these variants explain a small proportion of disease liability. This study examined the contribution of coding genetic variants for risk of type 2 diabetes (T2D)-attributed ESKD and advanced CKD in AAs. Methods: Exome sequencing was performed in 456 AA T2D-ESKD cases, and 936 AA nondiabetic, non-nephropathy control individuals at the discovery stage. A mixed logistic regression model was used for association analysis. Nominal associations (P < 0.05) were replicated in an additional 2020 T2D-ESKD cases and 1121 nondiabetic, non-nephropathy control individuals. A meta-analysis combining 4533 discovery and replication samples was performed. Putative T2D-ESKD associations were tested in additional 1910 nondiabetic ESKD and 219 T2D-ESKD cases, as well as 912 AA nondiabetic non-nephropathy control individuals. Results: A total of 11 suggestive T2D-ESKD associations (P < 1 x 10-4) from 8 loci (PLEKHN1, NADK, RAD51AP2, RREB1, PEX6, GRM8, PRX, APOL1) were apparent in the meta-analysis. Exclusion of APOL1 renal-risk genotype carriers identified 3 additional suggestive loci (OTUD7B, IFITM3, DLGAP5). Rs41302867 in RREB1 displayed consistent association with T2D-ESKD and nondiabetic ESKD (odds ratio: 0.47; P = 1.2 x 10-6 in 4605 all-cause ESKD and 2969 nondiabetic non-nephropathy control individuals). Conclusion: Our findings suggest that coding genetic variants are implicated in predisposition to T2D-ESKD in AAs. PMID- 29989003 TI - Integrated treatment using intraperitoneal radioimmunotherapy and positron emission tomography-guided surgery with 64Cu-labeled cetuximab to treat early- and late-phase peritoneal dissemination in human gastrointestinal cancer xenografts. AB - Peritoneal dissemination is a common cause of death from gastrointestinal cancers and is difficult to treat using current therapeutic options, particularly late phase disease. Here, we investigated the feasibility of integrated therapy using 64Cu-intraperitoneal radioimmunotherapy (ipRIT), alone or in combination with positron emission tomography (PET)-guided surgery using a theranostic agent (64Cu labeled anti-epidermal growth factor receptor antibody cetuximab) to treat early- and late-phase peritoneal dissemination in mouse models. In this study, we utilized the OpenPET system, which has open space for conducting surgery while monitoring objects at high resolution in real time, as a novel approach to make PET-guided surgery feasible. 64Cu-ipRIT with cetuximab inhibited tumor growth and prolonged survival with little toxicity in mice with early-phase peritoneal dissemination of small lesions. For late-phase peritoneal dissemination, a combination of 64Cu-ipRIT for down-staging and subsequent OpenPET-guided surgery for resecting large tumor masses effectively prolonged survival. OpenPET clearly detected tumors (>=3 mm in size) behind other organs in the peritoneal cavity and was useful for confirming the presence or absence of residual tumors during an operation. These findings suggest that integrated 64Cu therapy can serve as a novel treatment strategy for peritoneal dissemination. PMID- 29989004 TI - Raman Spectroscopy for the Diagnosis of Intratubular Triamterene Crystallization. PMID- 29989005 TI - Targeting CREB-binding protein overrides LPS induced radioresistance in non-small cell lung cancer cell lines. AB - Non-small cell lung cancer (NSCLC) has a very poor prognosis even when treated with the best therapies available today often including radiation. NSCLC is frequently complicated by pulmonary infections which appear to impair prognosis as well as therapy, whereby the underlying mechanisms are still not known. It was investigated here, whether the bacterial lipopolysaccharides (LPS) might alter the tumor cell radiosensitivity. LPS were found to induce a radioresistance but solely in cells with an active TLR-4 pathway. Proteome profiling array revealed that LPS combined with irradiation resulted in a strong phosphorylation of cAMP response element-binding protein (CREB). Inhibition of CREB binding protein (CBP) by the specific inhibitor ICG-001 not only abrogated the LPS-induced radioresistance but even led to an increase in radiosensitivity. The sensitization caused by ICG-001 could be attributed to a reduction of DNA double strand break (DSB) repair. It is shown that in NSCLC cells LPS leads to a CREB dependent radioresistance which is, however, reversible through CBP inhibition by the specific inhibitor ICG-001. These findings indicate that the combined treatment with radiation and CBP inhibition may improve survival of NSCLC patients suffering from pulmonary infections. PMID- 29989006 TI - Multicolor Flow Cytometry and Cytokine Analysis Provides Enhanced Information on Kidney Transplant Biopsies. AB - Introduction: Current processing of renal biopsy samples provides limited information about immune mechanisms causing kidney injury and disease activity. We used flow cytometry with transplanted kidney biopsy samples to provide more information on the immune status of the kidney. Methods: To enhance the information available from a biopsy, we developed a technique for reducing a fraction of a renal biopsy sample to single cells for multicolor flow cytometry and quantitation of secreted cytokines present within the biopsy sample. As proof of concept, we used our technique with transplant kidney biopsy samples to provide examples of clinically relevant immune information obtainable with cytometry. Results: A ratio of CD8+ to CD4+ lymphocytes greater than or equal to 1.2 in transplanted allografts is associated with rejection, even before it is apparent by microscopy. Elevated numbers of CD45 leukocytes and higher levels of interleukin (IL)-6, IL-8, and IL-10 indicate more severe injury. Antibody binding to renal microvascular endothelial cells can be measured and corresponds to antibody-mediated forms of allograft rejection. Eculizumab binding to endothelial cells suggests complement activation, which may be independent of bound antibody. We compared intrarenal leukocyte subsets and activation states to those of peripheral blood from the same donor at the time of biopsy and found significant differences; thus the need for new techniques to evaluate immune responses within the kidney. Conclusion: Assessment of leukocyte subsets, renal microvascular endothelial properties, and measurement of cytokines within a renal biopsy by flow cytometry enhance understanding of pathogenesis, indicate disease activity, and identify potential targets for therapy. PMID- 29989007 TI - A single amino acid substitution in CXCL12 confers functional selectivity at the beta-arrestin level. AB - CXCL12/CXCR4 axis relies on both heterotrimeric Gi protein and beta-arrestin coupling to trigger downstream responses. G protein activation allows for calcium flux, chemotaxis and early extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation, whereas beta-arrestin recruitment leads to late signaling, receptor desensitization and internalization. Together they may regulate the balance between transactivation and transinhibition of epithelial growth factor receptor 1 (HER1). Since we have previously noted significant differences between CXCL12 and its structural variant [N33A]CXCL12 in CXCR4 signaling, we sought to better characterize them by performing cAMP inhibition and beta-arrestin recruitment assays, as well as functional tests that separately investigate G protein and beta-arrestin-induced responses. [N33A]CXCL12 showed reduced potency both in Galphai coupling and beta-arrestin recruitment as compared to the wild type chemokine, acting as an unbiased ligand. While these findings translated into reduced potency within Galphai-dependent functions, beta-arrestin-dependent modules were affected in a more peculiar way. Unlike CXCL12, the mutant analogue did not restore HB-EGF-stimulated HER1 from CXCR4-induced transinhibition, and did not trigger the late wave of ERK1/2 phosphorylation. Instead, CXCR4 internalization was not impaired upon [N33A]CXCL12 stimulation. These differences highlight the novel opportunity to dissect CXCL12 signaling within the beta arrestin layer, in which the mutant chemokine clearly favors the internalization module over the other pathways. Such functional selectivity has an impact on HER1 activation status and may play a relevant part in the crosstalk between tyrosine kinase and seven transmembrane receptors. PMID- 29989008 TI - dACC response to presentation of negative feedback predicts stimulant dependence diagnosis and stimulant use severity. AB - Error-monitoring abnormalities in stimulant-dependent individuals (SDIs) may be due to reduced awareness of committed errors, or to reduced sensitivity upon such awareness. The distinction between these alternatives remains largely undifferentiated, but may have substantial clinical relevance. We sought to better characterize the nature, and clinical relevance, of SDIs' error-monitoring processes by comparing carefully isolated neural responses during the presentation of negative feedback to a) stimulant dependence status and b) lifetime stimulant use. Forty-eight SDIs and twenty-three non-SDIs performed an fMRI-based time-estimation task specifically designed to isolate neural responses associated with the presentation (versus expectation) of contingent negative feedback. SDIs showed reduced dACC response compared to non-SDIs following the presentation of negative feedback, but only when error expectancies were controlled. Moreover, lifetime stimulant use correlated negatively with magnitude of expectancy-controlled dACC attenuation. While this finding was minimized after controlling for age, these results suggest that SDIs may be characterized by a core reduction in neural activity following error feedback, in the context of intact feedback expectancies. Correlations with lifetime stimulant use suggest that this neural attenuation may hold clinical significance. PMID- 29989009 TI - Remote Dwelling Location Is a Risk Factor for CKD Among Indigenous Canadians. AB - Introduction: Rural and remote indigenous individuals have a high burden of chronic kidney disease (CKD) when compared to the general population. However, it has not been previously explored how these rates compare to urban-dwelling indigenous populations. Methods: In a recent cross-sectional screening study, 1346 adults 18 to 80 years of age were screened for CKD and diabetes across 11 communities in rural and remote areas in Manitoba, Canada, as part of the First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis (FINISHED) program. An additional 284 Indigenous adults who resided in low-income areas in the city of Winnipeg, Manitoba, Canada were screened as part of the NorWest Mobile Diabetes and Kidney Disease Screening and Intervention Project. Results: Our findings indicate that a gradient of CKD and diabetes prevalence exists for Indigenous individuals living in different geographic areas. Compared to urban-dwelling Indigenous individuals, rural-dwelling individuals had more than a 2-fold (2.1, 95% CI = 1.4-3.1) increase in diabetes whereas remote dwelling individuals had a 4-fold (4.1, 95% CI = 2.8-6.0) increase, and more than a 3-fold (3.1, 95% CI = 2.2-4.5) increase in CKD prevalence. Conclusion: Although these results highlight the relative importance of geography in determining the prevalence of diabetes and CKD in Indigenous Canadians, geography is but an important surrogate of other determinants, such as poverty and access to care. PMID- 29989010 TI - Hyperactivity precedes conduct problems in preschool children: a longitudinal study. AB - Background: Externalising problems are among the most common symptoms of mental health problems in preschool children. Aims: To investigate the development of externalising problems in preschool children over time, and the way in which conduct problems are linked to hyperactivity problems. Method: In this longitudinal study, 195 preschool children were included. Latent growth modelling of conduct problems was carried out, with gender and hyperactivity at year 1 as time-invariant predictors. Results: Hyperactivity was a significant predictor for the intercept and slope of conduct problems. Children with more hyperactivity at year 1 had more conduct problems and a slower reduction in conduct problems. Gender was a significant predictor for the slope of conduct problems. Conclusions: Children with more initial hyperactivity have less of a reduction in conduct problems over time. It is important to consider the role of hyperactivity in studies of the development of conduct problems. Declaration of interest: None. PMID- 29989011 TI - Inhibition of cytochrome P450 enzymes by thymoquinone in human liver microsomes. AB - The aim of the present study was to investigate the potential effect of thymoquinone (TQ) on the metabolic activity of four major drug metabolizing enzymes in human liver microsomes, namely cytochrome P450 (CYP) 1A2, CYP2C9, CYP2D6 and CYP3A4. The inhibition of CYP enzymatic activities by TQ was evaluated by incubating typical substrates (phenacetin for CYP1A2, tolbutamide for CYP2C9, dextromethorphan for CYP2D6, and testosterone for CYP3A4) with human liver microsomes and NADPH in the absence or presence of TQ (1, 10 and 100 uM). The respective metabolite of the substrate that was formed was measured by HPLC. Results of the presented study presented that the metabolic activities of all the investigated CYP enzymes, viz. CYP1A2, CYP2C9, CYP2D6 and CYP3A4, were inhibited by TQ. At 1 uM TQ, CYP2C9 enzyme activity was maximally inhibited by 46.35%, followed by CYP2D6 (20.26%) > CYP1A2 (13.52%) > CYP3A4 (12.82%). However, at 10 uM TQ, CYP2C9 enzyme activity was maximally inhibited by 69.69%, followed by CYP3A4 (23.59%) > CYP1A2 (23.51%) > CYP2D6 (11.42%). At 100 uM TQ, CYP1A2 enzyme activity was maximally inhibited by 81.92%, followed by CYP3A4 (79.24%) > CYP2C9 (69.22%) > CYP2D6 (28.18%). The IC50 (mean +/- SE) values for CYP1A2, CYP2C9, CYP2D6 and CYP3A4 inhibition were 26.5 +/- 2.9 uM, 0.5 +/- 0.4 uM, >500 uM and 25.2 +/- 3.1 uM, respectively. These findings suggest that there is a high probability of drug interactions resulting from the co-administration of TQ or herbs containing TQ with drugs that are metabolized by the CYP enzymes, particularly CYP2C9. PMID- 29989013 TI - Comparative Efficacy and Safety of Therapies in IgA Nephropathy: A Network Meta analysis of Randomized Controlled Trials. AB - The present study aims to compare the relative efficacy and safety of different interventions for IgA nephropathy (IgAN) with proteinuria more than 1 g/d by using network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for studies compared the rate of clinical remission and/or end-stage renal disease (ESRD) and/or serious adverse events in IgAN patients with proteinuria (>1 g/d). The surface under the cumulative ranking area (SUCRA) was calculated to rank the interventions. A total of 21 randomized controlled trials with 1822 participants were included for the comparisons of 7 interventions. The rank of the most effective treatments to induce clinical remission was renin-angiotensin system inhibitors (RASi) plus urokinase, steroid plus tonsillectomy, and RASi plus steroid with a SUCRA of 0.912, 0.710, and 0.583, respectively. As for the prevention of ESRD or doubling of serum creatinine, RASi plus steroid (SUCRA 0.012) was the most effective, followed by RASi (SUCRA 0.282) and steroid (SUCRA 0.494), leaving mycophenolate mofetil as the least effective (SUCRA 0.644). There was no statistical difference among all interventions in the occurrence of serious adverse events. The current network meta-analysis demonstrated for the first time that RASi plus steroid is probably the best therapeutic choice, not only for reducing proteinuria but also for maintaining long-term renal protection. PMID- 29989012 TI - Beneficial effects of Panax ginseng for the treatment and prevention of neurodegenerative diseases: past findings and future directions. AB - In recent years, several therapeutic drugs have been rationally designed and synthesized based on the novel knowledge gained from investigating the actions of biologically active chemicals derived from foods, plants, and medicinal herbs. One of the major advantages of these naturalistic chemicals is their ability to interact with multiple targets in the body resulting in a combined beneficial effect. Ginseng is a perennial herb (Araliaceae family), a species within the genus Panax, and a highly valued and popular medicinal plant. Evidence for the medicinal and health benefits of Panax ginseng and its components in preventing neurodegeneration has increased significantly in the past decade. The beneficial effects of P. ginseng on neurodegenerative diseases have been attributed primarily to the antioxidative and immunomodulatory activities of its ginsenoside components. Mechanistic studies on the neuroprotective effects of ginsenosides revealed that they act not only as antioxidants but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. The goal of the present paper is to provide a brief review of recent knowledge and developments concerning the beneficial effects as well as the mechanism of action of P. ginseng and its components in the treatment and prevention of neurodegenerative diseases. PMID- 29989015 TI - MiR-98 modulates macrophage polarization and suppresses the effects of tumor associated macrophages on promoting invasion and epithelial-mesenchymal transition of hepatocellular carcinoma. AB - Background: Tumor-associated macrophages (TAMs) are generally recognized as a promoter of tumor progression. miR-98 has been shown to suppress the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. Here, we aim to investigate the role of miR 98-mediated macrophage polarization in HCC progression. Methods: Human blood monocytes were isolated from healthy male donors and incubated with culture medium collected from HepG2 cells for 7 days. The phenotype of the macrophages was detected. The protein expression was detected by Western blot. Levels of cytokines secreted in culture medium were measured using the specific enzyme linked immunosorbent assay kits. To explore the role of miR-98 in HCC-conditioned TAMs, HCC cells HepG2 and SMMC7721 were cultured with conditioned medium from HCC conditioned TAMs that had been transfected with miR-98 mimic/inhibitor. Cell proliferation, migration and invasion assays were performed. Results: HCC conditioned TAMs possessed M2-like phenotype, including increased protein expression of CD163 and TNF-alphalow, IL-1betalow, TGF-betahigh and IL-10high phenotype. HCC-conditioned TAMs also promoted proliferation, migration, invasion and EMT of HepG2 and SMMC7721 cells. Furthermore, miR-98 modulated macrophage polarization from M2 to M1 in HCC-conditioned TAMs, as evidenced by the alteration of M1- or M2-related cytokines. Moreover, miR-98 mimic significantly suppressed the HCC-conditioned TAMs-mediated promotion of cell migration, invasion and EMT in HepG2 and SMMC7721 cells compared with negative control, whereas miR-98 inhibitor exerted reversed effects. Conclusions: miR-98 may play a vital role in regulating macrophage polarization, thereby suppressing the TAMs mediated promotion of invasion and EMT in HCC. PMID- 29989014 TI - Changes With Lanthanum Carbonate, Calcium Acetate, and Phosphorus Restriction in CKD: A Randomized Controlled Trial. AB - Introduction: Abnormal phosphorus homeostasis develops early in chronic kidney disease (CKD). It is unclear if its correction results in improved clinical outcomes in non-dialysis dependent CKD. Methods: We conducted a randomized controlled, parallel design clinical trial in 120 patients with estimated glomerular filtration rate 15 to 59 ml/min per 1.73 m2 and abnormal phosphorus homeostasis (serum phosphorus >4.6 mg/dl, parathyroid hormone [PTH] >70 pg/ml or tubular reabsorption of phosphorus [TRP] <80%). Patients were randomized to open label lanthanum carbonate versus calcium acetate versus dietary intervention over 1 year. The co-primary outcomes were month 12 (vs. baseline) biochemical (serum phosphorus, TRP, PTH, calcium, bone-specific alkaline phosphatase [bALP], and fibroblast growth factor 23 [FGF23]) and vascular parameters (coronary artery calcium score, pulse wave velocity, and endothelial dysfunction) in all patients. Secondary outcomes were between-treatment differences in change for each parameter between month 12 and baseline. All analyses were intention to treat. Results: Baseline characteristics were similar in the 3 groups. A total of 107 patients (89%) completed 12 months of follow-up. Differences were not significant at month 12 (vs. baseline) for any of the outcomes except bALP (median [25th, 75th] percentile at month 12 versus baseline: 13.8 [10.6, 17.6] vs. 15.8 [12.1, 21.1], P < .001) and FGF23 (132 [99, 216] vs. 133 [86, 189], P = .002). Changes for all outcomes were similar in the 3 arms except for PTH, which was suppressed more effectively by calcium acetate (P < .001). Conclusion: A 1-year intervention to limit phosphorus absorption using dietary restriction or 2 different phosphorus binders resulted in decreased bALP suggesting improved bone turnover, but no other significant changes in biochemical or vascular parameters in patients with CKD stage 3/4. (ClinicalTrials.gov: NCT01357317). PMID- 29989016 TI - Current status, and future prospects of pharmaco-epidemiology and post-marketing surveillance in Saudi Arabia: A review of literature. AB - Background: Pharmacoepidemiology is the concept used for evaluating the impact of drugs among a large number of people in the post-marketing phase. The use of this concept makes it increasingly necessary to detect the recurrence of drug-related anomalies that mostly occur through health care professionals or patients themselves. Pharmacoepidemiology is important since it helps to provide the right balance of benefits versus risks of the drug products while remaining an excellent tool to prepare the risk/benefit balance profile. Aim: The objective of this study is to review and explore the current status and future prospects of pharmacoepidemiology and post-marketing surveillance in Saudi Arabia. Methods: A literature review has been conducted using keywords such as pharmacoepidemiology'; 'post-marketing'; 'surveillance'; 'Saudi Arabia'; 'ADRs'; and 'pharmacovigilance'. The study refines its focus on 13 pharmacoepidemiology and post-marketing surveillance research studies conducted in Saudi Arabia using the databases; Embase, PubMed, EBSCOhost, MEDLINE, and AMED. Results: Pharmacoepidemiology and post-marketing surveillance creates a body of research in Saudi Arabia, but within a restricted scope. The studies that were reviewed assessed the challenge from various perspectives. Lack of knowledge, post marketing surveillance, ADR reporting, and increased use of generic products were reported. Conclusion: The current level of research may be widened and increased through improving the process of ADRs reporting system. More research needs to be conducted based on nation-wide observational studies. Collaboration among medical professionals, academics and industries should continue to establish a more efficient and consistent post-marketing surveillance system. PMID- 29989017 TI - Mild Albuminuria Is a Risk Factor for Faster GFR Decline in the Nondiabetic Population. AB - Introduction: A minimal increase in the albumin-to-creatinine ratio (ACR) predicts cardiovascular disease and mortality, but whether it predicts kidney function loss in nondiabetic persons is unclear. We investigated the association between ACR in the optimal or high-normal range and the rate of glomerular filtration rate (GFR) decline in a cohort from the general population without diabetes, cardiovascular, or chronic kidney disease. Methods: In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1567 middle aged nondiabetic individuals with an ACR <3.40 mg/mmol (30.0 mg/g) at baseline. The ACR was measured in unfrozen morning urine samples collected on 3 days before the GFR measurements. A total of 1278 (81%) participants had follow-up with GFR measurements after a median of 5.6 years. Results: The median ACR at baseline was 0.22 mg/mmol (interquartile range: 0.10-0.51 mg/mmol), the mean +/- SD GFR was 104.0 +/- 20.1 ml/min, and the mean +/- SD GFR decline rate was -0.95 +/- 2.23 ml/min per year. Higher baseline ACR levels were associated with a steeper GFR decline in adjusted linear mixed models. Study participants with ACR levels of 0.11 to 0.45 and 0.46 +/- 3.40 mg/mmol had a 0.25 ml/min per year (95% confidence interval [95% CI]: -0.03 to 0.53) and 0.31 ml/min per year (95% CI: 0.02-0.60) steeper rate of decline than those with ACR <=0.10 mg/mmol in multivariable adjusted analyses. Among study participants with an ACR of <1.13 mg/mmol (defined as the optimal range), those with an ACR of 0.11 to 1.12 mg/mmol (n = 812) had a 0.28 ml/min per year (95% CI: 0.04-0.52) steeper rate of GFR decline than those with an ACR of <=0.10 mg/mmol (n = 655). Conclusion: A mildly increased ACR is an independent risk factor for faster GFR decline in nondiabetic individuals. PMID- 29989018 TI - Effect of Korean Red Ginseng extracts on drug-drug interactions. AB - Background: Ginseng has been the subject of many experimental and clinical studies to uncover the diverse biological activities of its constituent compounds. It is a traditional medicine that has been used for its immunostimulatory, antithrombotic, antioxidative, anti-inflammatory, and anticancer effects. Ginseng may interact with concomitant medications and alter metabolism and/or drug transport, which may alter the known efficacy and safety of a drug; thus, the role of ginseng may be controversial when taken with other medications. Methods: We extensively assessed the effects of Korean Red Ginseng (KRG) in rats on the expression of enzymes responsible for drug metabolism [cytochrome p450 (CYP)] and transporters [multiple drug resistance (MDR) and organic anion transporter (OAT)] in vitro and on the pharmacokinetics of two probe drugs, midazolam and fexofenadine, after a 2-wk repeated administration of KRG at different doses. Results: The results showed that 30 mg/kg KRG significantly increased the expression level of CYP3A11 protein in the liver and 100 mg/kg KRG increased both the mRNA and protein expression of OAT1 in the kidney. Additionally, KRG significantly increased the mRNA and protein expression of OAT1, OAT3, and MDR1 in the liver. Although there were no significant changes in the metabolism of midazolam to its major metabolite, 1'-hydroxymidazolam, KRG significantly decreased the systemic exposure of fexofenadine in a dose-dependent manner. Conclusion: Because KRG is used as a health supplement, there is a risk of KRG overdose; thus, a clinical trial of high doses would be useful. The use of KRG in combination with P-glycoprotein substrate drugs should also be carefully monitored. PMID- 29989019 TI - Correction: Intake of red and processed meat and risk of renal cell carcinoma: a meta-analysis of observational studies. AB - [This corrects the article DOI: 10.18632/oncotarget.18549.]. PMID- 29989020 TI - Identifying differentially expressed genes from cross-site integrated data based on relative expression orderings. AB - It is a basic task in high-throughput gene expression profiling studies to identify differentially expressed genes (DEGs) between two phenotypes. But the weakly differential expression signals between two phenotypes are hardly detectable with limited sample sizes. To solve this problem, many researchers tried to combine multiple independent datasets using meta-analysis or batch effect adjustment algorithms. However, these algorithms may distort true biological differences between two phenotypes and introduce unacceptable high false rates, as demonstrated in this study. These problems pose critical obstacles for analyzing the transcriptional data in The Cancer Genome Atlas where there are many small-scale batches of data. Previously, we developed RankComp to detect DEGs for individual disease samples through exploiting the incongruous relative expression orderings between two phenotypes and further improved it here to identify DEGs using multiple independent datasets. We demonstrated the improved RankComp can directly analyze integrated cross-site data to detect DEGs between two phenotypes without the need of batch effect adjustments. Its usage was illustrated in detecting weak differential expression signals of breast cancer drug-response data using combined datasets from multiple experiments. PMID- 29989021 TI - Older adults in phase I clinical trials: a comparative analysis of participation and clinical benefit rate among older adults versus middle age and AYA patients on phase I clinical trials with VEGF/VEGFR inhibitors. AB - Background: Older adults aged 65 years and above remain underrepresented in cancer clinical trials. We hypothesized that older participation in early phase trials with VEGF/VEGFR (VEGF/R) inhibitors was lower than cancer prevalence in this group and lower than other age groups (middle age, adolescent/young adults [AYA]). Results: Of 1489 patients, 278 were older adults (18%, median age 68.9y), 220 AYA (15%, median age 32.6 y), 991 middle age (67%, median age 53.8 y). Common malignancies included gastrointestinal (n = 438, 29%), gynecologic (n = 234, 16%), and thoracic/head/neck (n = 216, 15%). Median time to treatment failure did not vary significantly between the 3 age-based cohorts (3m in older adults, 3.5 m middle age, 3.3 m AYA). OR of achieving clinical benefit in older adults vs middle age (OR 1.10, p 0.19 [two-tailed], p 0.09 [one-tailed]) and AYA vs middle age (OR 0.85, p 0.31 [proportions z-test, two tailed], p 0.15 [one-tailed]) showed no significant differences. Conclusions: Older adults accounted for <20% of participants on phase I clinical trials with VEGF/R inhibitors but those who participated were just as likely to achieve a clinical benefit as AYA and middle age patients. These findings merit further exploration into patient selection for early phase trials. Methods: We identified and separated patients treated on VEGF/R-inhibitor-based phase I trials from 12/1/2004-07/31/2013 into 3 age-based cohorts, AYA (15-39y), middle age (40-64 y), older adults (65 y+). We analyzed clinical/treatment characteristics and response outcomes, calculating the odds ratios (OR) of clinical benefit (defined as SD >= 6months, PR, CR) for older adults and AYAs versus middle age participants. PMID- 29989022 TI - Post-transcriptional regulation of microRNAs in cancer: From prediction to validation. AB - MicroRNA (miRNA) is a small non-coding RNA with an established function to regulate genes at the post-transcriptional level leading to suppression or degradation of its messenger RNA expression (mRNA). Its dysregulation plays a vital role in a variety of biological and pathological processes including cancer. A lot of algorithms have been established to predict the target sites of miRNA, but experimentally identifying and validating its target region is still lacking. Guidance in experimental procedures is really needed to find genuine miRNA targets. Therefore, in this review, we provide an outline on the workflow in predicting and validating the targeted sites of miRNA using several methods as a guideline for the scientists. The final outcome of this type of experiment is essential to explore the major impact of miRNAmRNA interaction involved in the biological processes and to assist miRNA-based drug development in the future. PMID- 29989023 TI - Regenerative Medicine and Immunomodulatory Therapy: Insights From the Kidney, Heart, Brain, and Lung. AB - Regenerative medicine was initially focused on tissue engineering to replace damaged tissues and organs with constructs derived from cells and biomaterials. More recently, this field of inquiry has expanded into exciting areas of translational medicine modulating the body's own endogenous processes, to prevent tissue damage in organs and to repair and regenerate these damaged tissues. This review will focus on recent insights derived from studies in which the manipulation of the innate immunologic system may diminish acute kidney injury and enhance renal repair and recovery without the progression to chronic kidney disease and renal failure. The manner in which these interventions may improve acute and chronic organ dysfunction, including the heart, brain, and lung, will also be reviewed. PMID- 29989024 TI - Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus. AB - As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-MUm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer. PMID- 29989026 TI - Discontinuation of anticoagulant therapy for a month in a patient with HeartMate III continuous-flow left ventricular assist device without thromboembolic events. AB - The recommended anticoagulation regimen for continuous-flow left ventricular assist device (LVAD) systems is warfarin and aspirin with a targeted international normalized ratio (INR) of 2.0-3.0. Our patient is a 58-year-old male who underwent surgical HeartMate III continuous-flow LVAD implantation 3 months ago outside the country. The patient mistakenly stopped taking warfarin for 1 month prior to presenting to our center for a routine visit. Luckily, the patient was doing very well without any complication despite the fact that his INR was 1.0. PMID- 29989025 TI - A computerized exposure system for animal models to optimize nicotine delivery into the brain through inhalation of electronic cigarette vapors or cigarette smoke. AB - Pre-clinical studies investigated the effects of chronic exposure to nicotine on lungs, kidneys and brains using animal models. Most of these studies delivered nicotine into the circulatory and central nervous systems (CNS) through intraperitoneal injection or oral consumption methods. Few studies used inhalation machine system for nicotine delivery into brains in rodents to mimic human exposure to cigarettes. However, finding a more accurate and clinically relevant method of nicotine delivery is critical. A computerized inhalation machine has been designed (SciReq) and is currently employed in several institutions. The computerized machine delivers electronic (e)-cigarette vapor as well as tobacco smoke to rodents using marketed e-cigarette devices or tobacco cigarettes. This provides evidence about clinical effects of nicotine delivery by traditional methods (combustible cigarettes) and new methodologies (e-cigarettes) in physiological systems. Potential neurobiological mechanisms for the development of nicotine dependence have been determined recently in mice exposed to e-cigarette vapors in our laboratory using SciReq system. In this review article, the discussion focuses on the efficiency and practical applicability of using this computerized inhalation exposure system in inducing significant changes in brain protein expression and function as compared to other nicotine delivery methods. The SciReq inhalation system utilized in our laboratory and others is a method of nicotine delivery to the CNS, which has physiological relevance and mimics human inhalant exposures. Translation of the effects of inhaled nicotine on the CNS into clinical settings could provide important health considerations. PMID- 29989027 TI - New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes. AB - Classical hairy cell leukemia (HCL-c) is a rare lymphoid neoplasm. BRAFV600E mutation, detected in more than 80% of the cases, is described as a driver mutation, but additional genetic abnormalities appear to be necessary for the disease progression. For cases of HCL-c harboring a wild-type BRAF gene, the differential diagnosis of the variant form of HCL (HCL-v) or splenic diffuse red pulp lymphoma (SDRPL) is complex. We selected a panel of 21 relevant genes based on a literature review of whole exome sequencing studies (BRAF, MAP2K1, DUSP2, MAPK15, ARID1A, ARID1B, EZH2, KDM6A, CREBBP, TP53, CDKN1B, XPO1, KLF2, CXCR4, NOTH1, NOTCH2, MYD88, ANXA1, U2AF1, BCOR, and ABCA8). We analyzed 20 HCL-c and 4 HCL-v patients. The analysis of diagnostic samples mutations in BRAF (n = 18), KLF2 (n = 4), MAP2K1 (n = 3), KDM6A (n = 2), CDKN1B (n = 2), ARID1A (n = 2), CREBBP (n = 2) NOTCH1 (n = 1) and ARID1B (n = 1). BRAFV600E was found in 90% (18/20) of HCL-c patients. In HCL-c patients with BRAFV600E , other mutations were found in 33% (6/18) of cases. All 4 HCL-v patients had mutations in epigenetic regulatory genes: KDM6A (n = 2), CREBBP (n = 1) or ARID1A (n = 1). The analysis of sequential samples (at diagnosis and relapse) from 5 patients (2 HCL c and 3 HCL-v), showed the presence of 2 new subclonal mutations (BCORE1430X and XPO1E571K ) in one patient and variations of the mutated allele frequency in 2 other cases. In the HCL-v disease, we described new mutations targeting KDM6A that encode a lysine demethylase protein. This opens new perspectives for personalized medicine for this group of patients. PMID- 29989028 TI - GBCK25, fermented ginseng, attenuates cardiac dysfunction in high fat diet induced obese mice. AB - The fermentation of medicinal herbs facilitated by microbes is assumed to exert promising therapeutic efficacy on the absorption, bioavailability, and pharmacological effects by speeding up the making or conversion of active constituents into their metabolites. We examined the cardioprotective potential of fermented ginseng, GBCK25, against high-fat diet (HFD)-induced metabolic and functional illnesses as following the essential analysis such as electrocardiographic parameters, alterations of body and organ weights, and echocardiographic studies. The results exhibited that body weights were significantly reduced and the gain of different organ weights were partly eased by GBCK25 treatment. Echocardiography results proposed the amelioration of heart function through normalized levels of left ventricle systolic pressure, ejection fraction, and fractional shortening. These outcomes deliver straight confirmation that GBCK25 could be a potential nutraceutical source for the relief of HFD induced obesity mediated cardiac dysfunctions. PMID- 29989030 TI - Immunomodulatory activity of curcumin-entrapped poly d,l-lactic-co-glycolic acid nanoparticles in mice. AB - Background: Studies have shown that curcumin from Curcuma longa has a wide range of medicinal and immunomodulatory properties. These activities have, however, been hindered by its low bioavailability. Meanwhile, incorporation of nanoparticles has been shown to increase bioavailability of certain drugs. This study was, therefore, conducted to comparatively evaluate the immunomodulatory activity of free and nanoparticulate curcumin in mice. Methods: Healthy albino mice were sensitized with sheep red blood cells (SRBCs) and thereafter free and nanoparticulate curcumin were administered orally at doses of 5 mg/kg/day and 10 mg/kg/day for 10 days to the mice. The assessment of the immunomodulatory activity was carried out by determining the humoral and cell-mediated immune responses using hemagglutination and delayed-type hypersensitivity assays, respectively. Hematological components and some lymphoid organs of treated mice were further evaluated. Results: The study showed that nanoparticulate curcumin stimulated higher early cell-mediated immune response at 5 mg/kg and 10 mg/kg when compared to control. While nanoparticulate curcumin significantly stimulated primary humoral immune response with 9.00 +/- 1.00 antibody titre (p < 0.05), the free curcumin suppressed the immunity with 3.33 +/- 0.67 antibody titre when compared to control. Similar result was observed with secondary humoral antibody titres. Production of white blood cells and weight of the lymphoid organs were also enhanced in the groups that received 10 mg/kg nanocurcumin. Conclusion: This work showed that poly d,l-lactic-co-glycolic acid entrapped curcumin nanoparticle could increase bioavailability of curcumin for improved immunity. PMID- 29989031 TI - Cardiovascular Risk Factors Accelerate Kidney Function Decline in Post-Myocardial Infarction Patients: The Alpha Omega Cohort Study. AB - Introduction: Impaired kidney function is a robust risk factor for cardiovascular mortality. Age-related annual kidney function decline of 1.0 ml/min per 1.73 m2 after age 40 years is doubled in post-myocardial infarction (MI) patients. Methods: We investigated the impact of the number of cardiovascular risk factors (including unhealthy lifestyle) on annual kidney function decline, in 2426 post MI patients (60-80 years) of the prospective Alpha Omega Cohort study. Glomerular filtration rate was estimated by serum cystatin C (eGFRcysC) and combined creatinine-cystatin C (eGFRcr-cysC), using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations from 2012. Data were analyzed by multivariable linear and logistic regression. Results: At baseline, mean (SD) eGFRcysC and eGFRcr-cysC were 81.5 (19.6) and 78.5 (18.7) ml/min per 1.73 m2, respectively. Of all patients, 79% were men, 19% had diabetes, 56% had high blood pressure (>=140/90 mm Hg), 16% were current smokers, 56% had high serum low density lipoprotein (LDL of >=2.5 mmol/l), and 23% were obese (body mass index of >=30.0 kg/m2). After multivariable adjustment, the additional annual eGFRcysC decline (95% confidence interval) was as follows: in patients with versus without diabetes, -0.90 (-1.23 to -0.57) ml/min per 1.73 m2; in patients with high versus normal blood pressure, -0.50 (-0.76 to -0.24) ml/min per 1.73 m2; in obese versus nonobese patients, -0.31 (-0.61 to 0.01) ml/min per 1.73 m2; and in current smokers versus nonsmokers, -0.19 (-0.54 to 0.16) ml/min per 1.73 m2. High LDL was not associated with accelerated eGFRcysC decline. Similar results were obtained with eGFRcr-cysC. Conclusion: In older, stable post-MI patients without cardiovascular risk factors, the annual kidney function decline was -0.90 (-1.16 to -0.65) ml/min per 1.73 m2. In contrast, in post-MI patients with >=3 cardiovascular risk factors, the annual kidney function decline was 2.5-fold faster, at -2.37 (-2.85 to -1.89) ml/min per 1.73 m2. PMID- 29989029 TI - The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. AB - TROP-2 is a glycoprotein first described as a surface marker of trophoblast cells, but subsequently shown to be increased in many solid cancers, with lower expression in certain normal tissues. It regulates cancer growth, invasion and spread by several signaling pathways, and has a role in stem cell biology and other diseases. This review summarizes TROP-2's properties, especially in cancer, and particularly its role as a target for antibody-drug conjugates (ADC) or immunotherapy. When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers. PMID- 29989032 TI - A juvenile case with nonalcoholic steatohepatitis and traditional Korean medicine based treatment. AB - Nonalcoholic fatty liver disease (NAFLD) has become the common cause leading to chronic liver diseases recently. Unlikely past humankind history, NAFLD is like a new illness especially in developed countries due to decreased number of hepatic virus carriers and increased population with obesity. Among subjects with NAFLD, development of nonalcoholic steatohepatitis (NASH) is a key pathological step which determines the clinical progression. This study reports a case of a boy who has suffered from NASH for 2 years. This study aims to discuss the clinical feature, risk aspect, and treatment strategy of NASH as well as potential of traditional Korean medicine (TKM) therapies. PMID- 29989033 TI - Combining Sensitive Crossmatch Assays With Donor/Recipient Human Leukocyte Antigen Eplet Matching Predicts Living-Donor Kidney Transplant Outcome. AB - Introduction: Despite the different assays available for immune-risk stratification before living-donor kidney transplantation (LDKT), the precise type and number of tests to perform remain uncertain. Methods: In a cohort of 330 consecutive LDKT patients, all of which were complement-dependent cytotoxicity (CDC)-crossmatch negative, we retrospectively analyzed the impact on main clinical outcomes of most sensitive immunoassays (complement-dependent cytotoxicity-panel-reactive antibody [CDC-PRA], flow cytometry crossmatch [FC XM], donor-specific antibodies [DSAs], and their complement-binding capacity DSA C3d]), together with donor/recipient HLA eplet matching. Mean follow-up was 67 months (range 24-190 months). Results: Of 330 patients, 35 (11%) showed a CDC-PRA >20%; 17 (5%) FC-XM+; 30 (9%) DSA+, 18(5%) DSA-C3d+, with low overlapping results (10 patients positive in all donor-specific tests). Unlike HLA allele compatibility, the mean number of HLA class II eplet mismatches was higher in LDKT patients with positive baseline test results. DSA-C3d+ showed higher mean fluorescence intensity (MFI) DSA, with a cut-off MFI of 6192 accurately predicting complement fixation (area under the curve = 0.85, P = 0.008). Although all assays were associated with acute rejection (AR), only DSA-C3d+ (odds ratio [OR] = 6.64, P = 0.038) or high MFI-DSA (OR = 7.54, P = 0.038) independently predicted AR. Likewise, poorly HLA class II eplet-matched patients were at higher risk for AR, particularly patients with negative baseline test results (OR = 1.14, P = 0.019). Finally, previous AR and FC-XM+/DSA+, regardless of C3d positivity, independently predicted graft loss. Conclusion: Combining FC-XM and solid-phase assays with the evaluation of donor/recipient HLA eplet mismatches, are most accurate tools for immune-risk stratification prior LDKT. PMID- 29989034 TI - The case for a global focus on multiple chronic conditions. PMID- 29989035 TI - Characterization of polysaccharides and their antioxidant properties from Plumula nelumbinis. AB - Two novel polysaccharides, Plumula nelumbinis (P. nelumbinis) polysaccharide I (LNP I) and P. nelumbinis polysaccharide II (LNP II), were extracted and purified from P. nelumbinis, and a sulfated polysaccharide, P. nelumbinis polysaccharide III (LNP III), with a substitution degree of 0.62 was prepared from LNPI. The structures of the LNPs were preliminarily characterized using high performance size exclusion chromatography (HPSEC), gas chromatography-mass spectrometry (GC MS), Fourier transformed infrared spectrometry (FT-IR), and nuclear magnetic resonance (NMR) spectrometry. In addition, evaluation of the antioxidant activity of the LNPs showed that they could significantly increase the proliferation of RAW264.7 macrophages (P < 0.05) and improve the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) based on cell model of H2O2-induced oxidative damage. This suggested that these LNPs may be used as potential antioxidants. PMID- 29989036 TI - Measuring progress towards Sustainable Development Goal 3.8 on universal health coverage in Kenya. AB - Background: The inclusion of universal health coverage (UHC) as a health-related Sustainable Development Goal has cemented its position as a key global health priority. We aimed to develop a summary measure of UHC for Kenya and track the country's progress between 2003 and 2013. Methods: We developed a summary index for UHC by computing the geometrical mean of indicators for the two dimensions of UHC, service coverage (SC) and financial risk protection (FRP). The SC indicator was computed as the geometrical mean of preventive and treatment indicators, while the financial protection indicator was computed as a geometrical mean of an indicator for the incidence of catastrophic healthcare expenditure, and the impoverishing effect of healthcare payments. We analysed data from three waves of two nationally representative household surveys. Findings: The weighted summary indicator for SC increased from 27.65% (27.13%-28.14%) in 2003 to 41.73% (41.34% 42.12%) in 2013, while the summary indicator for FRP reduced from 69.82% (69.11% 70.51%) in 2003 to 63.78% (63.55%-63.82%) in 2013. Inequities were observed in both these indicators. The weighted summary measure of UHC increased from 43.94% (95% CI 43.48% to 44.38%) in 2003 to 51.55% (95% CI 51.29% to 51.82%) in 2013. Conclusion: Significant gaps exist in Kenya's quest to achieve UHC. It is imperative that targeted health financing and other health sector reforms are made to achieve this goal. Such reforms should be focused on both, rather than on only either, of the dimensions of UHC. PMID- 29989037 TI - The impact of introduction of Code-STEMI program on the reduction of door-to balloon time in acute ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: A single-center study in Saudi Arabia. AB - Objectives: This study was conducted to evaluate the effect of direct emergency department activation of the catheterization lab on door-to-balloon time (D2BT) and outcomes of acute ST-elevation myocardial infarction (STEMI) patients at a major tertiary care hospital in Riyadh, Saudi Arabia. Methods: This was a retrospective cohort study that enrolled 100 consecutive patients with acute STEMI who underwent primary percutaneous coronary intervention between June 2010 and January 2015. The patients were divided into two groups of 50 patients each. The first group was treated prior to establishing the Code-STEMI protocol. The other group was treated according to the protocol, which was implemented in June 2013. The Code-STEMI protocol is a comprehensive program implementing direct activation of the catheterization lab team using a single call system, data monitoring and feedback, and standardized order forms. Results: The mean age for both groups was 54 +/- 12 years. Males represented 86% (43) and 94% (47) of the patients in the two groups, respectively. In both groups, 90% (90) of patients had one or more comorbidities. The Code-STEMI group had a significantly lower D2BT, with 70% of patients treated within the recommended 90 minutes (median, 76.5 minutes; interquartile range, 63-90 minutes). By contrast, only 26% of pre Code-STEMI patients were treated within this timeframe (median, 107 minutes; interquartile range, 74-149 minutes). In-hospital complications were lower in the Code-STEMI group; however, the only statistically significant reduction was in non-fatal re-infarction (8% vs. 0%, p = 0.043). Conclusion: Implementation of direct emergency department catheterization lab activation protocol was associated with a significant reduction in D2BT. PMID- 29989038 TI - Is Very Low Always Useful? The Case of Very Low-Grade Albuminuria in Kidney Disease. PMID- 29989040 TI - An Exploratory Study of Daprodustat in Erythropoietin-Hyporesponsive Subjects. AB - Introduction: Hyporesponsiveness to recombinant human erythropoietin (rhEPO) is a major problem affecting some patients with chronic kidney disease (CKD), predominantly those on hemodialysis (HD). Daprodustat (GSK1278863) is a hypoxia inducible factor prolyl hydroxylase inhibitor that is being investigated as a treatment for anemia of CKD. Methods: This phase 2a, exploratory, multicenter, single-arm study assessed the ability of daprodustat to increase or maintain hemoglobin concentrations within the target range (10.0-11.5 g/dl) over 16 weeks in subjects with anemia who were on HD and who had a high erythropoietin resistance index (ERI). All included subjects met the criteria for chronic rhEPO hyporesponsiveness (i.e., an ERI based on a series of contiguous strata of patients' hemoglobin-by-epoetin alfa for a minimum of 12 weeks). Eligible adults were on a stable HD regimen 3 to 4 times per week. Markers of iron utilization and safety were also assessed. All subjects initially received oral daprodustat 12 mg once daily. Results: Of the 60 participants screened, 15 were enrolled, and 7 (47%) completed 16 weeks of treatment. At week 16, 2 of 7 subjects (29%) had >1 g/dl increases in hemoglobin from baseline. Daprodustat had minimal effects on markers of iron metabolism and utilization. Fourteen subjects (93%) experienced >=1 adverse event (AE). The most common AEs included nausea, pneumonia, pleural effusion, and urinary tract infection. The majority of on-therapy AEs were mild or moderate in intensity. Conclusion: Daprodustat increased hemoglobin concentrations within the target range in 29% of chronic rhEPO-hyporesponsive subjects. No new safety concerns were identified in this short exploratory study. PMID- 29989039 TI - Direct-Acting Oral Anticoagulants as Prophylaxis Against Thromboembolism in the Nephrotic Syndrome. AB - We report 2 cases of apixaban use as prophylaxis against thromboembolism in the nephrotic syndrome (NS), and review the existing literature on direct-acting oral anticoagulant (DOAC) use in this scenario. Our cases appear to be the first reported use of apixaban as prophylaxis against thromboembolism in NS. We report our systematic review of the existing literature on direct-acting oral anticoagulant (DOAC) use in NS, and discuss theoretical issues relevant to their therapeutic use in this clinical scenario. We searched electronic databases such as OVID, EMBASE, PubMed, and CENTRAL, DARE. The search to identify studies and the application of inclusion and exclusion criteria was performed in duplicate independently. We identified 1 pilot randomized study, 3 case reports, and 3 conference proceedings abstracts relating to DOAC use in NS. These reports all pertain to the treatment of clinically evident thrombosis in NS with rivaroxaban, edoxaban, and dabigatran rather than prophylaxis against thrombosis. Although the existing literature on DOAC use in NS is limited, initial preliminary experience appears promising. PMID- 29989041 TI - Interesting case of narrow QRS tachycardia with atrioventricular dissociation. AB - A 30-year-old man with no structural heart disease has been evaluated for paroxysmal palpitation with documented regular narrow QRS tachycardia that has not responded to intravenous adenosine. Surface electrocardiogram has not shown any pre-excitation. He has been taken for an electrophysiology study after informed consent. Diagnostic catheters were placed at the coronary sinus, His bundle region, and right ventricle. During catheter manipulation a regular narrow QRS tachycardia with incomplete right bundle branch block morphology and normal QRS axis similar to the clinical tachycardia got induced. No other tachycardia was induced. What is the mechanism of tachycardia? PMID- 29989042 TI - Is water carriage associated with the water carrier's health? A systematic review of quantitative and qualitative evidence. AB - Introduction: The work of carrying water falls mainly on women and children, particularly in sub-Saharan Africa and rural areas. While concerns have been raised, how water carriage is associated with health of the water carrier is not clear. The aim of this review is to summarise evidence on whether, and how, water carriage is associated with the water carrier's health. Methods: A systematic review of literature was conducted, searching Embase; Medline; Web of Science Social Sciences Citation Index; Web of Science Arts and Humanities Citation Index; International Initiative for Impact Evaluation website; WHO Virtual Health Sciences Library and WHO African index medicus, from inception to 8 November 2017. Results: Forty-two studies were included. Their ability to demonstrate cause and effect relationships was limited by study design and fair or poor methodological quality. Overall, the studies suggest that water carriage is associated with negative aspects of the water carriers' health. There is moderate quantitative and strong qualitative evidence that water carriage is associated with pain, fatigue, perinatal health problems and violence against vulnerable people, and inconclusive evidence of an association with stress or self-reported mental health and general health status. Conclusion: In many circumstances, water carriage is a potential barrier to Sustainable Development Goal (SDG) 6 target 'universal and equitable access to safe and affordable drinking water for all' and SDG 3 'ensure healthy lives and promote well-being for all at all ages'. Efforts should focus on providing water on premises, and where this is not possible, providing water close to home and reducing risk of gender-based violence. PMID- 29989043 TI - Harnessing RIG-I and intrinsic immunity in the tumor microenvironment for therapeutic cancer treatment. AB - Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum. Approaches aimed at intrinsic cellular immunity in the tumor microenvironment are less understood, but are of intense interest, based on their ability to induce tumor cell apoptosis while orchestrating innate and adaptive immune responses against tumor antigens. The intrinsic immune response is initiated by ancient, highly conserved intracellular proteins that detect viral infection. For example, the RIG-I-like receptors (RLRs), a family of related RNA helicases, detect viral oligonucleotide patterns of certain RNA viruses. RLR activation induces immunogenic cell death of virally infected cells, accompanied by increased inflammatory cytokine production, antigen presentation, and antigen-directed immunity against virus antigens. Approaches aimed at non infectious RIG-I activation in cancers are being tested as a treatment option, with the goal of inducing immunogenic tumor cell death, stimulating production of pro-inflammatory cytokines, enhancing tumor neoantigen presentation, and potently increasing cytotoxic activity of tumor infiltrating lymphocytes. These studies are finding success in several pre-clinical models, and are entering early phases of clinical trial. Here, we review pre-clinical studies of RLR agonists, including the successes and challenges currently faced RLR agonists on the path to clinical translation. PMID- 29989044 TI - Value of three-dimensional echocardiography study of left ventricle function correlated to coronary arterial dominance in predicting the outcome of primary percutaneous coronary intervention. AB - Background: Limited information is available regarding the relationship between coronary vessel dominance and outcome after ST-segment elevation myocardial infarction (STEMI). Objectives: The study was designed to evaluate the prognostic value of coronary arterial dominance after primary percutaneous coronary intervention (PCI) during hospital stay and at 3 months follow-up regarding cardiac mortality, heart failure, nonfatal myocardial infarction, revascularization, and stroke. Patients and methods: The study population consisted of 300 consecutive patients (mean age, 57.35 +/- 13.41 years; 91% men) with STEMI who were admitted to Dallah Hospital (Riyadh, Saudi Arabia) from January 2015 to December 2016. These patients underwent successful primary PCI with thrombolysis in myocardial infarction (TIMI) III flow. They were divided into three groups according to angiographic coronary dominance: 227 (75.7%) in the right coronary dominant group, 40 (13.3%) in the left coronary dominant group, and 33 (11%) in the balanced coronary dominant group. They were evaluated with two- (2D) and three-dimensional (3D) echocardiography within 48 hours of admission and at 3 months follow-up after STEMI. Results: Right dominance was present in 75.6%, left dominance in 13.3%, and balanced dominance was present in 11% of patients. The main finding of this study was that a left dominant system was associated with increased risk of cardiac mortality, heart failure, nonfatal myocardial infarction, revascularization, and stroke shortly after primary PCI, during hospital stay, and at 3 months follow-up after STEMI. Moreover, a significantly lower left ventricular ejection fraction at admission was observed by both 2D and 3D echocardiography in patients with a left dominant system. Conclusion: In patients with STEMI treated with primary PCI, left coronary artery dominance confers a higher risk of various adverse clinical events after primary PCI, during hospital stay, and at 3 months follow-up compared to right and balanced coronary artery dominance. PMID- 29989046 TI - Bullous hemorrhagic dermatosis is an under-recognized side effect of full dose low-molecular weight heparin: a case report and review of the literature. AB - Bullous hemorrhagic dermatosis (BHD) is a systemic side-effect of low molecular weight heparin, characterized by multiple intra-epidermal hemorrhages distant from the site of injection. There have been several small case series and literature reviews on BHD, but none have captured a complete set of reported patients. We sought to describe a case of BHD with late diagnosis and completely summarize the existing English and Spanish literature with searches of Pubmed, Scopus, Ovid Embase and Ovid Medline. After narrowing to 33 relevant reports, we describe 90 reported cases worldwide from 2004 to 2017, in addition to a new case from our institution as a means of comparison. We found that BHD was common in elderly men (mean age 72 +/- 12; male:female, 1.9:1) and typically occurred within 7 days of administration of anticoagulation (median 7 days +/- 6.4) usually with enoxaparin use (66% of cases). Lesions occurred primarily on the extremities only (67.9% of cases). Coagulation testing was most often normal before administration, and the majority of patients had coagulation testing in therapeutic range during treatment. Most practitioners stopped anticoagulation if continued therapeutic intervention was no longer required (57% of cases), or changed therapy to another anticoagulation if continued treatment was required (14.3% of cases). Therapy was continued outright in 23% of patients. The lesions usually resolved within 2 weeks (mean days, 13.0 +/- 7.4). There was no difference in time to resolution between patients who continued the culprit anticoagulant or changed to a different anticoagulant, and those who discontinued anticoagulation altogether (13.9 days vs. 12.1, p = 0.49). Four deaths have been reported in this clinical context, two specified as intracranial hemorrhage. These deaths were unrelated to the occurrence of BHD. Continuation of low molecular weight heparins appeared to be safe in patients with BHD. PMID- 29989045 TI - Perioperative mortality rates in low-income and middle-income countries: a systematic review and meta-analysis. AB - Introduction: The Lancet Commission on Global Surgery proposed the perioperative mortality rate (POMR) as one of the six key indicators of the strength of a country's surgical system. Despite its widespread use in high-income settings, few studies have described procedure-specific POMR across low-income and middle income countries (LMICs). We aimed to estimate POMR across a wide range of surgical procedures in LMICs. We also describe how POMR is defined and reported in the LMIC literature to provide recommendations for future monitoring in resource-constrained settings. Methods: We did a systematic review of studies from LMICs published from 2009 to 2014 reporting POMR for any surgical procedure. We extracted select variables in duplicate from each included study and pooled estimates of POMR by type of procedure using random-effects meta-analysis of proportions and the Freeman-Tukey double arcsine transformation to stabilise variances. Results: We included 985 studies conducted across 83 LMICs, covering 191 types of surgical procedures performed on 1 020 869 patients. Pooled POMR ranged from less than 0.1% for appendectomy, cholecystectomy and caesarean delivery to 20%-27% for typhoid intestinal perforation, intracranial haemorrhage and operative head injury. We found no consistent associations between procedure specific POMR and Human Development Index (HDI) or income-group apart from emergency peripartum hysterectomy POMR, which appeared higher in low-income countries. Inpatient mortality was the most commonly used definition, though only 46.2% of studies explicitly defined the time frame during which deaths accrued. Conclusions: Efforts to improve access to surgical care in LMICs should be accompanied by investment in improving the quality and safety of care. To improve the usefulness of POMR as a safety benchmark, standard reporting items should be included with any POMR estimate. Choosing a basket of procedures for which POMR is tracked may offer institutions and countries the standardisation required to meaningfully compare surgical outcomes across contexts and improve population health outcomes. PMID- 29989047 TI - KDM5B demethylates H3K4 to recruit XRCC1 and promote chemoresistance. AB - Chemotherapy is the main treatment for human cancers including gastric cancer. However, in response to chemotherapeutic drugs, tumor cells can develop drug resistance by reprogramming intracellular metabolic and epigenetic networks to maintain their intrinsic homeostasis. Previously, we have established cisplatin resistant gastric cancer cells as a drug resistant model, and elucidated the XRCC1 as the core DNA repair mechanism of drug resistance. This study investigated the regulation of XRCC1 by lysine demethylase 5B (KDM5B) in drug resistance. We found that the methylation level of H3K4 decreased significantly in drug-resistant cells. The chemical inhibitor of H3K4 demethylases, JIB-04, restored the methylation of H3K4 and blocked the co-localization of XRCC1 and gammaH2AX, eventually improved drug sensitivity. We further found that the expression level of KDM5B increased significantly in drug-resistant cells. Knockdown of KDM5B increased the methylation level of H3K4 and blocked the localization of XRCC1 to the DNA damage site, leads to increased drug sensitivity. In the sensitive cells, overexpression of KDM5B suppressed H3K4 methylation levels, which resulted to resistance to cisplatin. Moreover, we found that the posttranslational modification of KDM5B is responsible for its high expression in drug-resistant cells. Through mass spectrometry screening and co immunoprecipitation validation, we found that the molecular chaperone HSP90 forms a complex with KDM5B in drug resistance cells. Interestingly, HSP90 inhibitor 17 AAG induced KDM5B degradation in a time-and-dose-dependent manner, indicating that HSP90 protected KDM5B from protein degradation. Targeting inhibition of HSP90 and KDM5B reversed drug resistance both in vitro and in vivo. Taken together, molecular chaperon HSP90 interacted with KDM5B to protect it from ubiquitin-dependent proteasomal degradation. Increased KDM5B demethylated H3K4 and facilitated the recruitment of XRCC1 to repair damaged DNA. Therefore, inhibition of HSP90 or KDM5B represented a novel approach to reverse chemoresistance in human cancers. PMID- 29989048 TI - Fear and culture: contextualising mental health impact of the 2014-2016 Ebola epidemic in West Africa. PMID- 29989049 TI - Yokukansan (Kampo medicinal formula) prevents the development of morphine tolerance by inhibiting the secretion of orexin A. AB - Background: Yokukansan (YKS), a traditional herbal (Kampo) medicine consisting of seven herbs, is effective in the treatment of pain disorders, such as headache, postherpetic neuralgia, fibromyalgia, and trigeminal neuralgia, and we have previously shown it to be effective against morphine analgesic tolerance in rats. It has been reported that orexin receptor antagonists prevent the development of morphine tolerance and that YKS inhibits the secretion of orexin A in the hypothalamus. This study examined whether the inhibition of the secretion of orexin A by YKS is one mechanism underlying its effect against morphine analgesic tolerance. Methods: Male Wistar rats were administered a subcutaneous injection of morphine hydrochloride (10 mg/kg/day) for 5 days. One group was preadministered YKS, starting 3 days before the morphine. The withdrawal latency following thermal stimulation was measured daily using a hot plate test. On day 5, the levels of orexin A in the plasma and the midbrain were measured, and the appearance of activated astrocytes in the midbrain was examined by immunofluorescence staining. Results: The preadministration of YKS prevented the development of morphine tolerance. The repeated administration of morphine significantly increased the plasma and midbrain levels of orexin A and the activation of astrocytes. These increases were significantly inhibited by the preadministration of YKS. Conclusion: These results suggest that the preadministration of YKS attenuated the development of antinociceptive morphine tolerance and that the inhibition of orexin A secretion may be one mechanism underlying this phenomenon. PMID- 29989050 TI - Prevalence of CKD, Diabetes, and Hypertension in Rural Tanzania. AB - Introduction: Chronic kidney disease (CKD), diabetes, and hypertension play a disproportionate role in the growing public health challenge posed by noncommunicable diseases (NCDs) in East Africa. The impact of these NCDs may pose the greatest challenge in rural areas with limited screening and treatment facilities, although precise prevalence estimates of these conditions in rural Tanzania are lacking. Methods: The prevalence of CKD, diabetes, and hypertension, were estimated from a probability sample of adults (n = 739) residing in 2 communities within Kisarawe, a rural district of Tanzania. Following consent, participants were studied in their homes. Random point-of-care (POC) measures of glycosylated hemoglobin and blood pressure, were obtained. Serum creatinine, drawn at the POC and measured at Muhimbili National University, was used to calculate estimated glomerular filtration rate with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: The median age was 35 years (interquartile range 25-45 years). Overall the pooled prevalence for CKD stages III, IV, and V was 12.4% (95% confidence interval [CI] = 10.2-14.8). Surprisingly, the prevalence of CKD stage V (3.0%; 95% CI = 2.1-4.4) was high among the youngest age group (18-36 years). The prevalence estimates for prehypertension and hypertension were 38.0% (95% CI = 34.6-41.5) and 19.9% (95% CI = 17.1-22.9), respectively. The prevalence estimates for prediabetes and diabetes were 25.7% (95% CI = 22.6-29.1) and 14.8% (95% CI = 12.4-17.6), respectively. Conclusion: Although this pilot study had a relatively small sample size, the prevalence estimates for CKD, diabetes, and hypertension were higher than we expected based on previous estimates from Tanzania. CKD was not significantly associated with diabetes or hypertension, suggesting the possibility of an alternative causality. PMID- 29989051 TI - Risk factors and health consequences of physical and emotional violence against children in Zimbabwe: a nationally representative survey. AB - Introduction: This study provides, for the first time, comparable national population-based estimates that describe the nature and magnitude of physical and emotional violence during childhood in Zimbabwe. Methods: From August to September 2011, we conducted a national population-based survey of 2410 respondents aged 13-24 years, using a two-stage cluster sampling. Regression models were adjusted for relevant demographics to estimate the ORs for associations between violence, risk factors and various health-related outcomes. Results: Respondents aged 18-24 years report a lifetime prevalence (before the age of 18) of 63.9% (among girls) to 76% (among boys) for physical violence by a parent or adult relative, 12.6% (girls) to 26.4% (boys) for humiliation in front of others, and 17.3% (girls) to 17.5% (boys) for feeling unwanted. Almost 50% of either sex aged 13-17 years experienced physical violence in the 12 months preceding the survey. Significant risk factors for experiencing physical violence for girls are ever experiencing emotional abuse prior to age 13, adult illness in the home, socioeconomic status and age. Boys' risk factors include peer relationships and socioeconomic status, while caring teachers and trusted community members are protective factors. Risk factors for emotional abuse vary, including family relationships, teacher and school-level variables, socioeconomic status, and community trust and security. Emotional abuse is associated with increased suicide attempts for both boys and girls, among other health outcomes. Conclusion: Physical and emotional violence often work in tandem causing poor mental and physical health outcomes. Understanding risk factors for violence within the peer or family context is essential for improved violence prevention. PMID- 29989052 TI - Erratum: Perrone RD, Mouksassi M-S, Romero K, et al. Total kidney volume is a prognostic biomarker of renal function decline and progression to end-stage renal disease in patients with autosomal dominant polycystic kidney disease. Kidney Int Rep. 2017;2:442-450. AB - [This corrects the article DOI: 10.1016/j.ekir.2017.01.003.]. PMID- 29989053 TI - WDR1 Promotes Cell Growth and Migration and Contributes to Malignant Phenotypes of Non-small Cell Lung Cancer through ADF/cofilin-mediated Actin Dynamics. AB - The characteristic of carcinoma is cell migration and invasion, which involve in strong actin dynamics. Regulations of actin dynamics have been implicated in cancer cell migration and tumor progression. WDR1 (WD-repeat domain 1) is a major cofactor of the actin depolymerizing factor (ADF)/cofilin, strongly accelerating ADF/cofilin-mediated actin disassembly. The role of WDR1 in non-small cell lung cancer (NSCLC) progression has been unknown. Here, we show that the expression levels of WDR1 are increased in human NSCLC tissues compared with adjacent non tumor tissues, and high WDR1 level correlates with poor prognosis in NSCLC patients. Knockdown of WDR1 in NSCLC cells significantly inhibits cell migration, invasion, EMT process and tumor cell growth in vitro and in vivo. Otherwise, overexpression of WDR1 promotes NSCLC cell proliferation and migration. Mechanically, our data suggested WDR1 regulated tumor cells proliferation and migration might through actin cytoskeleton-mediated regulation of YAP, and we demonstrated that WDR1 contributes to NSCLC progression through ADF/cofilin mediated actin disassembly. Our findings implicate that the ADF/cofilin-WDR1 actin axis as an activator of malignant phenotype that will be a promising therapeutic target in lung cancer. PMID- 29989054 TI - Transcatheter perforation of atretic pulmonary valve by the stiff end of a coronary wire in neonates with pulmonary atresia with intact ventricular septum: A solution in developing countries. AB - Objectives: To evaluate the safety of using the stiff end of a coronary wire to perforate an atretic pulmonary valve (PV) in patients with pulmonary atresia with intact ventricular septum (PAIVS). Background: Radiofrequency perforation is an accepted modality to perforate the PV in patients PAIVS. However, the high cost precludes its widespread use. Patients and methods: This is a single-center experience that spanned from March 2013 to January 2016 and involved 13 neonates who were severely cyanotic with PAIVS and with ductal-dependent pulmonary circulation. The stiff end of a coronary wire was used to perforate the atretic PV anterogradely, followed by balloon pulmonary valvuloplasty. Results: The mean age of patients was 3.9 +/- 2.7 days and their mean weight was 2.8 +/- 0.19 kg. The mean oxygen saturation was 77.1 +/- 3.2%. All had membranous pulmonary atresia, with patent infundibulum and tripartite right ventricle. The valve was successfully perforated in 11 out of 13 patients. Death occurred in two patients (15.4%) owing to heart failure and sepsis. Patent ductus arteriosus stenting was performed 2 days after the procedure in one patient because of cyanosis followed by one and half ventricle repair at of age 5 months. Two patients (15.4%) had one and a half ventricle repair at age of 5 months and 6 months owing to insufficient anterograde pulmonary flow. Two patients (15.4%) underwent second intervention with balloon dilatation of the valve. The remaining seven patients (53.8%) had no further intervention. Two cases (15.4%) had femoral artery thrombosis treated with streptokinase. The mean duration of follow-up was 13.17 +/- 7 months. There was significant improvement in the degree of tricuspid incompetence. There was a significant growth in the tricuspid valve annulus during the follow-up (the mean Z score increased from -0.8 +/- 0.9 to 0.1 +/- 0.9) (p = 0.003). There was also a significant increase in the tricuspid valve annulus/mitral valve annulus ratio as its mean increased from 0.73 +/- 0.10 to 0.86 +/- 0.11 during follow-up (p < 0.001). Conclusion: Perforation of the atretic PV in selected cases with membranous atresia and patent infundibulum using the stiff end of a coronary wire is an effective alternative to using radiofrequency perforation. PMID- 29989055 TI - Does gentle assisted pushing or giving birth in the upright position reduce the duration of the second stage of labour? A three-arm, open-label, randomised controlled trial in South Africa. AB - Introduction: Gentle assisted pushing (GAP) is an innovative method of applying gentle, steady pressure to a woman's uterine fundus during second stage of labour. This randomised trial evaluated GAP in an upright position, compared with upright position alone or routine practice (recumbent posture). Methods: An open label, hospital-based, randomised trial was conducted in Eastern Cape, South Africa. Randomisation occurred following at least 15 min in second stage of labour. Participants were randomly assigned (1:1:1) using computer-generated block randomisation of variable size using opaque, sealed, numbered envelopes. Primary analysis was intention to treat. Participants were healthy, nulliparous, consenting women with a singleton pregnancy in cephalic presentation where vaginal birth was anticipated. The primary outcome was mean time from randomisation to birth. Results: 1158 participants were randomly allocated to GAP (n=388), upright position (n=386) and routine practice (n=384), with no loss to follow-up. Baseline characteristics were largely similar. In the experimental arm, GAP was applied a median of two times (IQR 1.0-3.0). Women in upright position alone spent a median of 6 min (IQR 3.0-10.0) upright. Mean duration from randomisation to birth was not different across groups (mean (SD) duration: 24.1 (34.9) min in GAP group, 24.6 (30.5) min in upright group, 25.0 (39.3) min in routine practice group). There were no differences in secondary outcomes, except that at two sites maternal discomfort was greater for both GAP and upright position compared with routine practice; at the other sites there were no differences. Conclusion: No benefit was identified from GAP in the second stage; some women found the position uncomfortable. The use of fundal pressure should be limited to further research to determine techniques or settings in which it can safely assist vaginal birth. Women should be encouraged to assume the position they find most comfortable. Trial registration number: PACTR201502001034448. PMID- 29989056 TI - The Nrf2 Signaling in Retinal Ganglion Cells under Oxidative Stress in Ocular Neurodegenerative Diseases. AB - Retinal ganglion cells (RGCs) are one of the important cell types affected in many ocular neurodegenerative diseases. Oxidative stress is considered to be involved in retinal RGCs death in ocular neurodegenerative diseases. More and more attention has been focused on studying the agents that may have neuroprotective effects. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key nuclear transcription factor for the systemic antioxidant defense system. This review elucidates the underlying mechanism of the Nrf2-mediated neuroprotective effects on RGCs in ocular neurodegenerative diseases, such as diabetic retinopathy and retinal ischemia-reperfusion injury. Several Nrf2 inducers that shield RGCs from oxidative stress-induced neurodegeneration via regulating Nrf2 signaling are discussed. PMID- 29989057 TI - Aberrant Levels of Cystatin C in Amyotrophic Lateral Sclerosis: a Systematic Review and Meta Analysis. AB - Evidences suggest that Cystatin C (Cys C) levels might be a biomarker in amyotrophic lateral sclerosis (ALS) diagnosis, but the conclusion is still in doubts. We conducted a systematic review and meta analysis of Cys C levels in cerebrospinal cord fluid (CSF) and peripheral blood of patients with ALS in order to further confirm whether or not Cys C levels is a biomarker in ALS diagnosis. The English relevant studies without year limitation were systematically searched in PubMed, EMBASE, Web of Science databases. The searched term contained "Amyotrophic Lateral Sclerosis" or "Motor Neuron Diseases" and "Cystatin C" and "Cerebrospinal fluid" or "CSF" or "Biomarker" or "Serum" or "Plasma" or "Blood". Observational studies reporting the associations between Cys C levels and ALS patients were selected to conduct a systematic review and meta analysis. Two reviewers performed the selection of this study independently. The Newcastle Ottawa Scale assesses the quality and risk of bias of selected studies. Estimates were pooled using a random-effects model. The Cys C levels of CSF or peripheral blood in ALS patients compared with health controls (HCs) and several relevant neurodegenerative diseases (NDDs). Sixteen studies were included in our systematic review, 9 of them were selected to perform the meta analysis. Of these, eight studies measured Cys C levels in CSF and three studies measured it in blood. Cys C levels in CSF were significantly lower in ALS patients than in HCs (Hedge's g = -1.398, 95%CI: -2.43 to -0.36; p = 0.008), but there was no statistical difference between ALS patients and several relevant NDDs. No statistically significant difference in the Cys C levels of blood in the comparison between ALS and HCs. The correlation meta analysis presented no significant correlation between Cys C levels in CSF and age or disease duration respectively. Cys C levels significantly decrease in the CSF of ALS patients, but are not a specific biomarker for this disease. Cys C levels in CSF might be an auxiliary diagnostic biomarker of ALS. PMID- 29989058 TI - Bioactive constituents from cinnamon, hemp seed and polygonum cuspidatum protect against H2O2 but not rotenone toxicity in a cellular model of Parkinson's disease. AB - Mitochondrial dysfunction and oxidative stress are two factors that are thought to contribute to the pathogenesis of Parkinson's disease (PD), a debilitating progressive neurodegenerative disorder that results in the loss of catecholamine producing cells throughout specific regions of the brain. In this study we aimed to compare the effects of hydrogen peroxide (H2O2) and rotenone (a pesticide and mitochondrial complex 1 inhibitor) on cell viability and the expression of tyrosine hydroxylase (TH) in a cellular model of PD. We also sought to investigate the potential neuroprotective benefits of bioactive constituents from cinnamon, hemp seed and polygonum cuspidatum. To create a model, SH-SY5Y cells transfected with human TH isoform 1 were treated with varying concentrations of H2O2 and rotenone, in the presence or absence of bioactive constituents. The effect of these toxins and constituents on cell viability, apoptosis and protein expression was assessed using MTT viability assays and western blotting. Rotenone treatment caused a significant decrease in cell viability but a significant increase in TH in the remaining cells. H2O2 treatment caused a significant decrease in cell viability but had no significant effect on TH expression. Curcumin, cinnamaldehyde, caffeoyltyramide (hemp seed extract) and piceatannol glucoside (polygonum cuspidatum extract) were unable to attenuate rotenone induced cell death, however they were able to provide protection against H2O2 induced cell death. This is the first study to demonstrate the neuroprotective properties of cinnamaldehyde, caffeoyltyramide and piceatannol glucoside in a dopaminergic cell line in response to H2O2. PMID- 29989059 TI - Acute Renal Failure Following Near-Drowning. AB - Introduction: Acute kidney injury associated with near-drowning (ND-AKI) has rarely been reported and its incidence among survivors is unknown. A patient with AKI and urine biomarkers indicating tubular injury led us to assess the occurrence and clinical characteristics of ND-AKI and to evaluate possible causative mechanisms. Methods: We evaluated medical records of patients rescued from near-drowning in the Mediterranean Sea and treated in a tertiary-level medical center during 2000 to 2017. Results: Ninety-five patients with the diagnosis of near-drowning in seawater were treated. Forty-two of these patients (43%) developed ND-AKI and 17 (18%) were classified as AKI Kidney Disease: Improving Global Outcomes stages 2 to 3. ND-AKI was associated with the need for resuscitation and mechanical ventilation, with the calculated seawater volume ingestion (extrapolated from rising plasma sodium) and with the degree of acidemia, lactemia, and ventilatory failure. This series and 28 additional published cases of ND-AKI in the literature showed an overall male predisposition. Conclusion: AKI is a common complication of near-drowning and is associated with increased in-hospital mortality. Data analysis suggests a predominant role of hypoxic tubular injury due to systemic hypoxemia in ND-AKI, combined with intense sympathetic activity (reflected by tachyarrhythmias, hyperglycemia, and relative hypokalemia) and increased oxygen expenditure for intensified distal tubular sodium transport. Androgen-related reduced renal vasodilatory capacity may explain male gender predominance. PMID- 29989060 TI - Mesenchymal Stem Cells Promote Tumor Progression via Inducing Stroma Remodeling on Rabbit VX2 Bladder Tumor Model. AB - Background and aim: Mesenchymal stem cells (MSCs) are capable of impacting tumor progression but its role in tumor stroma remodeling still remains unclear. This present study was aimed to evaluate the potential function of MSCs on tumor stroma remodeling using rabbits VX2 bladder tumor model. Methods: The VX2 bladder tumor models were established by injecting mixed cell suspensions (106 of VX2 tumor cells and 0/106/107 of autologous MSCs in group A, B, C, respectively) into the bladder mucosa using thirty male New Zealand white rabbits. The tumor volume was measured by ultrasound at the time points of 1st, 2nd, 3rd and 4th week after inoculation. At the end of the fourth week, the tumor tissue expressions of basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGFbeta-1), hepatocyte growth factor (HGF), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) were determined using Real-time quantitative PCR and immunohistochemistry. Masson trichrome staining and Cy3-FITC double-labelled immunofluorescence staining were used to determine the MSCs distribution in tumor tissue in another two rabbits implanted with a cell suspension of 106 VX2 tumor cells and 106 autologous MSCs. Results: MSCs were homogeneously distributed in tumor tissues after 7 days of inoculation, which were not consistent with the distribution of tumor stroma. After 21 days of inoculation, MSCs have been integrated into tumor interstitial tissue and mainly distributed in the mesenchyma around the tumor nest. At the 1st, 2nd, 3rd and 4th week time point, tumor volume in group A < group B < group C, and the difference has statistical significance (all p<0.001).The relative mRNA and protein levels of bFGF, TGFbeta 1 and HGF were significantly higher in group B and C compared with group A (all p<0.05), as well as the mRNA levels of bFGF, HGF were higher in group C than group B (p<0.05), and the protein levels of bFGF, TGFbeta-1 were higher in group C than group B (p<0.05). The mRNA and protein levels of MMP2 were significantly higher in group B, C than group A (p<0.05). MMP9 was increasingly over expressed along with the growing amount of MSCs inoculated within tumor, both at the level of mRNA and protein (all p<0.05). Conclusion: MSCs participate in tumor stroma remodeling via inducing overexpression of some important growth factors and MMPs. PMID- 29989061 TI - Integration of botanicals in contemporary medicine: road blocks, checkpoints and go-ahead signals. AB - The use of botanicals for maintaining good health and preventing diseases is undisputed. The claimed health benefits of natural health products and herbal medicines are based on traditional claims, positive results obtained in preclinical studies and early phase clinical trials that are not backed by safety and efficacy evidences approved by regulatory agencies. Although, the popularity of botanicals is growing, health care practitioners of modern medicine seldom recommend their use because of ill equipped database of their safety and potency. This review discusses problems that preclude botanicals from integrating into the mainstream contemporary therapeutics and cues that provide impetus for their realisation. PMID- 29989062 TI - The role of FGF21 in type 1 diabetes and its complications. AB - Data from the International Diabetes Federation show that 347 million people worldwide have diabetes, and the incidence is still rising. Although the treatment of diabetes has been advanced, the current therapeutic options and outcomes, e.g. complications, are yet far from ideal. Therefore, an urgent need exists for the development of more effective therapies. Numerous studies have been conducted to establish and confirm whether FGF21 exerts beneficial effects on obesity and diabetes along with its complications. However, most of the studies associated with FGF21 were conducted in the patients with type 2 diabetes. Subsequently, the effect of FGF21 in the prevention or treatment of type 1 diabetes and its complications were also increasingly reported. In this review, we summarize the findings available on the function of FGF21 and the status of FGF21's treatment for type 1 diabetes. Based on the available information, we found that FGF21 exerts a hypoglycemic effect, restores the function of brown fat, and inhibits various complications in type 1 diabetes patients. Although these features are predominantly similar to those observed in the studies that showed the beneficial impact of FGF21 on type 2 diabetes and its complications, there are also certain distinct features and findings that may be of provide important and instructive for us to understand mechanistic insights and further promote the prevention and treatment of type 1 diabetes. PMID- 29989064 TI - Improving Prediction of Self-interacting Proteins Using Stacked Sparse Auto Encoder with PSSM profiles. AB - Self-interacting proteins (SIPs) play a significant role in the execution of most important molecular processes in cells, such as signal transduction, gene expression regulation, immune response and enzyme activation. Although the traditional experimental methods can be used to generate SIPs data, it is very expensive and time-consuming based only on biological technique. Therefore, it is important and urgent to develop an efficient computational method for SIPs detection. In this study, we present a novel SIPs identification method based on machine learning technology by combing the Zernike Moments (ZMs) descriptor on Position Specific Scoring Matrix (PSSM) with Probabilistic Classification Vector Machines (PCVM) and Stacked Sparse Auto-Encoder (SSAE). More specifically, an efficient feature extraction technique called ZMs is firstly utilized to generate feature vectors on Position Specific Scoring Matrix (PSSM); Then, Deep neural network is employed for reducing the feature dimensions and noise; Finally, the Probabilistic Classification Vector Machine is used to execute the classification. The prediction performance of the proposed method is evaluated on S.erevisiae and Human SIPs datasets via cross-validation. The experimental results indicate that the proposed method can achieve good accuracies of 92.55% and 97.47%, respectively. To further evaluate the advantage of our scheme for SIPs prediction, we also compared the PCVM classifier with the Support Vector Machine (SVM) and other existing techniques on the same data sets. Comparison results reveal that the proposed strategy is outperforms other methods and could be a used tool for identifying SIPs. PMID- 29989063 TI - Oncograms Visualize Factors Influencing Long-Term Survival of Cancer Patients Treated with Adenoviral Oncolytic Immunotherapy. AB - The first US Food and Drug Administration (FDA)- and EMA-approved oncolytic virus has been available since 2015. However, there are no markers available that would predict benefit for the individual patient. During 2007-2012, we treated 290 patients with advanced chemotherapy-refractory cancers, using 10 different oncolytic adenoviruses. Treatments were given in a Finnish Medicines Agency (FIMEA)-regulated individualized patient treatment program (the Advanced Therapy Access Program [ATAP]), which required long-term follow-up of patients, which is presented here. Focusing on the longest surviving patients, some key clinical and biological features are presented as "oncograms." Some key attributes that could be captured in the oncogram are suggested to predict treatment response and survival after oncolytic adenovirus treatment. The oncogram includes immunological laboratory parameters assessed in peripheral blood (leukocytes, neutrophil-to-lymphocyte ratio, interleukin-8 [IL-8], HMGB1, anti-viral neutralizing antibody status), features of the patient (gender, performance status), tumor features (histological tumor type, tumor load, region of metastases), and oncolytic virus-specific features (arming of the virus). The retrospective approach used here facilitates verification in a prospective controlled trial setting. To our knowledge, the oncogram is the first holistic attempt to identify the patients most likely to benefit from adenoviral oncolytic virotherapy. PMID- 29989065 TI - Sex differences in utilisation of hospital care in a state-sponsored health insurance programme providing access to free services in South India. AB - Background: Universal healthcare coverage provides healthcare and financial protection to all citizens and might help to facilitate gender equity in care. We assessed the utilisation of hospital care services among women and men in a large underprivileged population with access to free hospital care in India. Methods: The Rajiv Aarogyasri Community Health Insurance Scheme, a state-sponsored scheme, provided access to free hospital care for poor households across undivided Andhra Pradesh. Claims data for hospitalisations between 2008 and 2012 were analysed to determine the number of individuals, hospitalisations, bed-days and hospital expenditure for sex-specific and sex-neutral conditions, by sex, disease category and age group. Results: A total of 961 442 individuals (43% women), 1 223 723 hospitalisations (48% women), 7.7 million bed-days (47% women) and hospital expenditure of US$579.3 million (42% women) were recorded. Sex-specific conditions accounted for 27% of hospitalisations, 12% of bed-days and 15% of costs for women, compared with 5%, 4% and 4% in men. Women had a lower share of hospitalisations (42%), bed-days (45%) and costs (39%) for sex-neutral conditions than men. These findings were observed across 14 of 18 disease categories and across all age groups, but especially for older and younger women. Interpretation: In this large underprivileged population in India with access to free hospital care, utilisation of hospital care differed for women and men. For sex-neutral conditions, women accessed a smaller proportion of care than men, suggesting that coverage of hospital care alone is not sufficient to guarantee gender equity in access to healthcare. PMID- 29989067 TI - Exploring Persian Lore in the Hebrew Book of Asaf. AB - The Hebrew medical text referred to as Sefer Refu'ot or Sefer Asaf has long been one of the greatest mysteries of Hebrew science with regards to fundamental questions such as the date and place of its composition and the identity of its author or authors. It has been dated anytime between the third and the eleventh centuries, with its composition located anywhere between Persia and southern Italy. This paper explores some of the Persian lore in Sefer Asaf: the figure of Asaf himself, the similarity with other Persian or Persian-influenced accounts of the origins of the sciences, the appearance of the Indo-Iranian motif of the trees of medicine, the central importance given to Indic medical knowledge, and the form and use of the Persian months in the text. Previous important contributions to the study of Sefer Asaf have argued for a Syriac connection; several other studies have linked the text to a Persian cultural milieu. The information presented here links those two and argues for dependence on material deriving from the Church of the East in Persia. PMID- 29989066 TI - Predicting Potential Drugs for Breast Cancer based on miRNA and Tissue Specificity. AB - Network-based computational method, with the emphasis on biomolecular interactions and biological data integration, has succeeded in drug development and created new directions, such as drug repositioning and drug combination. Drug repositioning, that is finding new uses for existing drugs to treat more patients, offers time, cost and efficiency benefits in drug development, especially when in silico techniques are used. MicroRNAs (miRNAs) play important roles in multiple biological processes and have attracted much scientific attention recently. Moreover, cumulative studies demonstrate that the mature miRNAs as well as their precursors can be targeted by small molecular drugs. At the same time, human diseases result from the disordered interplay of tissue- and cell lineage-specific processes. However, few computational researches predict drug-disease potential relationships based on miRNA data and tissue specificity. Therefore, based on miRNA data and the tissue specificity of diseases, we propose a new method named as miTS to predict the potential treatments for diseases. Firstly, based on miRNAs data, target genes and information of FDA (Food and Drug Administration) approved drugs, we evaluate the relationships between miRNAs and drugs in the tissue-specific PPI (protein-protein) network. Then, we construct a tripartite network: drug-miRNA-disease Finally, we obtain the potential drug disease associations based on the tripartite network. In this paper, we take breast cancer as case study and focus on the top-30 predicted drugs. 25 of them (83.3%) are found having known connections with breast cancer in CTD (Comparative Toxicogenomics Database) benchmark and the other 5 drugs are potential drugs for breast cancer. We further evaluate the 5 newly predicted drugs from clinical records, literature mining, KEGG pathways enrichment analysis and overlapping genes between enriched pathways. For each of the 5 new drugs, strongly supported evidences can be found in three or more aspects. In particular, Regorafenib (DB08896) has 15 overlapping KEGG pathways with breast cancer and their p-values are all very small. In addition, whether in the literature curation or clinical validation, Regorafenib has a strong correlation with breast cancer. All the facts show that Regorafenib is likely to be a truly effective drug, worthy of our further study. It further follows that our method miTS is effective and practical for predicting new drug indications, which will provide potential values for treatments of complex diseases. PMID- 29989068 TI - Endovascular repair of severe aortic coarctation, transcatheter aortic valve replacement for severe aortic stenosis, and percutaneous coronary intervention in an elderly patient with long term follow-up. AB - To the best of our knowledge, there have not been any reports of total transcatheter approach including stenting of severe coarctation of the aorta (CoA), transcatheter aortic valve replacement (TAVR) for concomitant severe aortic valve stenosis, and percutaneous coronary intervention (PCI) to treat significant coronary artery disease in a single patient. We report a 70-year-old female, who presented with uncontrolled hypertension and acute decompensated heart failure (ADHF) and was found to have severe CoA, severe bicuspid aortic valve (BAV) stenosis, and significant proximal left anterior descending (LAD) coronary artery disease. In a multidisciplinary heart team meeting, we decided to perform an endovascular repair of both cardiac and vascular pathologies using a two-stage approach due to the significant comorbidities; mainly uncontrolled hypertension, type 2 diabetes mellitus, chronic obstructive pulmonary disease, and severe calcifications of the ascending aorta. The procedures were successfully performed and the patient was asymptomatic 30 months later at follow up and was without any significant gradients across the coarctation or the aortic valve. PMID- 29989069 TI - An atlas of larval organogenesis in the European shore crab Carcinus maenas L. (Decapoda, Brachyura, Portunidae). AB - Background: The life history stages of brachyuran crustaceans include pelagic larvae of the Zoea type which grow by a series of moults from one instar to the next. Zoeae actively feed and possess a wide range of organ systems necessary for autonomously developing in the plankton. They also display a rich behavioural repertoire that allows for responses to variations in environmental key factors such as light, hydrostatic pressure, tidal currents, and temperature. Brachyuran larvae have served as distinguished models in the field of Ecological Developmental Biology fostering our understanding of diverse ecophysiological aspects such as phenotypic plasticity, carry-over effects on life-history traits, and adaptive mechanisms that enhance tolerance to fluctuations in environmental abiotic factors. In order to link such studies to the level of tissues and organs, this report analyses the internal anatomy of laboratory-reared larvae of the European shore crab Carcinus maenas. This species has a native distribution extending across most European waters and has attracted attention because it has invaded five temperate geographic regions outside of its native range and therefore can serve as a model to analyse thermal tolerance of species affected by rising sea temperatures as an effect of climate change. Results: Here, we used X-ray micro-computed tomography combined with 3D reconstruction to describe organogenesis in brachyuran larvae. We provide a detailed atlas of the larval internal organization to complement existing descriptions of its external morphology. In a multimethodological approach, we also used cuticular autofluorescence and classical histology to analyse the anatomy of selected organ systems. Conclusions: Much of our fascination for the anatomy of brachyuran larvae stems from the opportunity to observe a complex organism on a single microscopic slide and the realization that the entire decapod crustacean bauplan unfolds from organ anlagen compressed into a miniature organism in the sub millimetre range. The combination of imaging techniques used in the present study provides novel insights into the bewildering diversity of organ systems that brachyuran larvae possess. Our analysis may serve as a basis for future studies bridging the fields of evolutionary developmental biology and ecological developmental biology. PMID- 29989070 TI - Ginsenoside Rg1 modulates medial prefrontal cortical firing and suppresses the hippocampo-medial prefrontal cortical long-term potentiation. AB - Background: Panax ginseng is one of the most commonly used medicinal herbs worldwide for a variety of therapeutic properties including neurocognitive effects. Ginsenoside Rg1 is one of the most abundant active chemical constituents of this herb with known neuroprotective, anxiolytic, and cognition improving effects. Methods: We investigated the effects of Rg1 on the medial prefrontal cortex (mPFC), a key brain region involved in cognition, information processing, working memory, and decision making. In this study, the effects of systemic administration of Rg1 (1 mg/kg, 3 mg/kg, or 10 mg/kg) on (1) spontaneous firing of the medial prefrontal cortical neurons and (2) long-term potentiation (LTP) in the hippocampal-medial prefrontal cortical (HP-mPFC) pathway were investigated in male Sprague-Dawley rats. Results: The spontaneous neuronal activity of approximately 50% the recorded pyramidal cells in the mPFC was suppressed by Rg1. In addition, Rg1 attenuated LTP in the HP-mPFC pathway. These effects were not dose-dependent. Conclusion: This report suggests that acute treatment of Rg1 impairs LTP in the HP-mPFC pathway, perhaps by suppressing the firing of a subset of mPFC neurons that may contribute to the neurocognitive effects of Rg1. PMID- 29989071 TI - A Sequential Segment Based Alpha-Helical Transmembrane Protein Alignment Method. AB - Alpha-helical transmembrane protein (alphaTMP) is one of the two major categories of transmembrane protein (TMP). They are abundant existing in eukaryotic cells and involved in many biological processes. The special physicochemical properties, the structures of alphaTMP are hard to be experimentally solved, but alphaTMP's sequential segments are important to determine their conformations, so that TM-specific alignment is necessary to benefit their structure prediction. We used segment information extracted from topology structure and evolutionary information as features to implement a alphaTMP Segment Alignment method (TMSA). The method was trained using one non-redundant dataset and tested using another non-redundant dataset. Comparing the results to a general alignment method HHalign, TMSA achieved higher alignment accuracy, and easier to recognize the fold of alphaTMPs. PMID- 29989072 TI - Corrigendum: ExGUtils: A Python Package for Statistical Analysis With the ex Gaussian Probability Density. AB - [This corrects the article on p. 612 in vol. 9, PMID: 29765345.]. PMID- 29989074 TI - Atypical Noncrescentic Antiglomerular Basement Membrane Disease With Concurrent Thin Basement Membrane Nephropathy. PMID- 29989073 TI - Apoptosis Induction by Iron Radiation via Inhibition of Autophagy in Trp53+/- Mouse Testes: Is Chronic Restraint-Induced Stress a Modifying Factor? AB - We used chronic restraint-induced stress (CRIS) and iron ionizing radiation (IR) to mimic human exposure to psychological stress (PS) and IR in a mouse model, and to investigate the relationship among endoplasmic reticulum stress (ERS), apoptosis and autophagy in testicular toxicity. Male Trp53+/- C57BL/6N mice were restrained for 6 h/day for 28 consecutive days, and total body irradiation with 0.1 or 2 Gy iron ion beam was performed on the day 8. Histopathological observation showed severely damaged spermatogenic cells, increased apoptotic cells, caspase-3 activation and cytochrome c release, indicating that IR and CRIS+IR induced testicular cell apoptosis. Upregulation of GRP78 (78-kDa glucose regulated protein) suggested that IR and CRIS+IR induced ERS in the testes, and further analysis showed that apoptosis was enhanced by ERS through activation of the PERK/eIF2alpha/ATF4/CHOP pathway. Decreased expression of LC3II, Atg5 (autophagy related 5) and Beclin 1, and increased expression of p62, combined with ultrastructural changes seen under transmission electron microscopy, suggest that IR and CRIS+IR inhibit autophagosome formation. This process was related to inhibition of autophagy via activation of the PI3K/AKT/mTOR pathway under ERS. We showed that apoptosis was strengthened and autophagy was inhibited by ERS in mouse testes induced by IR and CRIPS+IR. These results showed that CRIS+IR had no difference in apoptosis induction and autophagy inhibition compared with IR alone. CIRS alone could induce apoptosis only in Leydig cells and its induction of pathological and molecular changes in testicular tissues was only a small extent as compared to those induced by IR. Of note, we showed that 28 consecutive days of CRIS did not exacerbate IR effects (no additive effect with IR). These findings also suggest that studies on the concurrent exposure to PS and IR should be done using different endpoints in both short and long-term CRIS models. PMID- 29989075 TI - GeneFuse: detection and visualization of target gene fusions from DNA sequencing data. AB - In recent years, gene fusion detection for cancer treatment has become increasingly important since more therapeutic agents have been developed to suppress fusion kinases. Although a number of tools have been developed to detect gene fusions from DNA sequencing data, most of them are not sensitive enough for processing the data from the samples with low tumor DNA composition, like cell free tumor DNA. In this paper, we will introduce GeneFuse, a tool to detect and visualize gene fusions with high sensitivity and specificity. GeneFuse focuses on the curated gene fusions, which are available in COSMIC (the Catalogue of Somatic Mutations in Cancer) database. For each detected fusion, GeneFuse reports its genome locus, inferred protein forms, and supporting sequencing reads. The fusion detection results are visualized in an HTML page for cloud-friendly validation. GeneFuse is an open source tool available at GitHub: https://github.com/OpenGene/GeneFuse. PMID- 29989076 TI - Kupffer-derived matrix metalloproteinase-9 contributes to liver fibrosis resolution. AB - Kupffer cells (KCs) contribute to liver fibrosis resolution by production of a large spectrum of matrix metalloproteinases (MMPs). MMP9 is a major MMP expressed by KCs. However, its role in liver fibrosis resolution remains unclear. In this study, rodent liver fibrosis was induced by intraperitoneal thioacetamide (TAA) and the resolution process was initiated by TAA withdrawal. The role of KC derived MMP9 in fibrolysis was investigated by adoptive transfer of KCs with or without MMP9 following their depletion. The levels of serum alanine aminotransferase (ALT) and hepatic cytokines were measured during fibrosis regression. The mRNA levels of MMPs and tissue inhibitor of metalloproteinases (TIMPs) were analyzed as well. It was found that removing KCs delayed fibrosis resolution. Adoptive transfer of KCs from WT animals promoted liver fibrosis resolution, compared with transfer of KCs from MMP9-/- mice. Depletion of KCs also resulted in prolonged liver wound healing, which was reversed partially by transferred KCs from either WT or MMP9-/- mice. Likewise, the absence of KCs led to reduction in MMPs mRNA levels and elevation in TIMPs mRNA levels. The expression patterns of MMPs or TIMPs were restored by adoptive transfer of the wild-type but not MMP9-/- KCs. In addition, liver fibrosis resolution was accelerated in MMP9-/- mice by adoptive transferred KCs from WT animals, compared to the KCs from MMP9-/- mice. Overall, KC-derived MMP9 plays a critical role in fibrosis resolution, which might serve as the foundation for developing anti fibrosis therapy. PMID- 29989078 TI - The magnitude and severity of abortion-related morbidity in settings with limited access to abortion services: a systematic review and meta-regression. AB - Introduction: Defining and accurately measuring abortion-related morbidity is important for understanding the spectrum of risk associated with unsafe abortion and for assessing the impact of changes in abortion-related policy and practices. This systematic review aims to estimate the magnitude and severity of complications associated with abortion in areas where access to abortion is limited, with a particular focus on potentially life-threatening complications. Methods: A previous systematic review covering the literature up to 2010 was updated with studies identified through a systematic search of Medline, Embase, Popline and two WHO regional databases until July 2016. Studies from settings where access to abortion is limited were included if they quantified the percentage of abortion-related hospital admissions that had any of the following complications: mortality, a near-miss event, haemorrhage, sepsis, injury and anaemia. We calculated summary measures of the percentage of abortion-related hospital admissions with each complication by conducting meta-analysis and explored whether these have changed over time. Results: Based on data collected between 1988 and 2014 from 70 studies from 28 countries, we estimate that at least 9% of abortion-related hospital admissions have a near-miss event and approximately 1.5% ends in a death. Haemorrhage was the most common complication reported; the pooled percentage of abortion-related hospital admissions with severe haemorrhage was 23%, with around 9% having near-miss haemorrhage reported. There was strong evidence for between-study heterogeneity across most outcomes. Conclusions: In spite of the challenges on how near miss morbidity has been defined and measured in the included studies, our results suggest that a substantial percentage of abortion-related hospital admissions have potentially life-threatening complications. Estimates that are more reliable will only be obtained with increased use of standard definitions such as the WHO near-miss criteria and/or better reporting of clinical criteria applied in studies. PMID- 29989077 TI - CRISPRMatch: An Automatic Calculation and Visualization Tool for High-throughput CRISPR Genome-editing Data Analysis. AB - Custom-designed nucleases, including CRISPR-Cas9 and CRISPR-Cpf1, are widely used to realize the precise genome editing. The high-coverage, low-cost and quantifiability make high-throughput sequencing (NGS) to be an effective method to assess the efficiency of custom-designed nucleases. However, contrast to standardized transcriptome protocol, the NGS data lacks a user-friendly pipeline connecting different tools that can automatically calculate mutation, evaluate editing efficiency and realize in a more comprehensive dataset that can be visualized. Here, we have developed an automatic stand-alone toolkit based on python script, namely CRISPRMatch, to process the high-throughput genome-editing data of CRISPR nuclease transformed protoplasts by integrating analysis steps like mapping reads and normalizing reads count, calculating mutation frequency (deletion and insertion), evaluating efficiency and accuracy of genome-editing, and visualizing the results (tables and figures). Both of CRISPR-Cas9 and CRISPR Cpf1 nucleases are supported by CRISPRMatch toolkit and the integrated code has been released on GitHub (https://github.com/zhangtaolab/CRISPRMatch). PMID- 29989079 TI - PRWHMDA: Human Microbe-Disease Association Prediction by Random Walk on the Heterogeneous Network with PSO. AB - Microorganisms resided in human body play a vital role in metabolism, immune defense, nutrition absorption, cancer control and protection against pathogen colonization. The changes of microbial communities can cause human diseases. Based on the known microbe-disease association, we presented a novel computational model employing Random Walking with Restart optimized by Particle Swarm Optimization (PSO) on the heterogeneous interlinked network of Human Microbe-Disease Associations (PRWHMDA) (see Figure 1). Based on the known human microbe-disease associations, we constructed the heterogeneous interlinked network with Cosine similarity. The extended random walk with restart (RWR) method was derived to get the potential microbe-disease associations. PSO was utilized to get the optimal parameters of RWR. To evaluate the prediction effectiveness, we performed leave one out cross validation (LOOCV) and 5-fold cross validation (CV), which got the AUC (The area under ROC curve) of 0.915 (LOOCV) and the average AUCs of 0.8875 +/- 0.0046 (5-fold CV). Moreover, we carried out three case studies of asthma, inflammatory bowel disease (IBD) and type 1 diabetes (T1D) for the further evaluation. The result showed that 10, 10 and 9 of top-10 predicted microbes were verified by previously published experimental results, respectively. It is anticipated that PRWHMDA can be effective to identify the disease-related microbes and maybe helpful to disclose the relationship between microorganisms and their human host. PMID- 29989080 TI - Association between trunk pain and lower extremity pain among youth soccer players: a cross-sectional study. AB - Background: Soccer is a high-intensity sport with a high injury rate. Among youth soccer players, lower extremity pain is a major problem that could be associated with trunk function. This study investigated the association between lower extremity pain and trunk pain among youth soccer players. Methods: A cross sectional study involving youth soccer players participating in the Miyagi Amateur Sports Association was conducted using a self-reported questionnaire. A multiple logistic regression analysis was used to examine the association between trunk pain and lower extremity pain. Covariates were sex, age, body mass index, height increase, number of days of training per week, practice time per day on weekdays or weekends, competition levels, frequency of participation in games, and previous injuries. Results: The final study population comprised 1139 youth soccer players (age, 6-15 years; male, 94.2%). Lower extremity pain with concomitant trunk pain occurred in 61.8% (42/68). Trunk pain was significantly associated with lower extremity pain (adjusted odds ratio [OR], 6.82; 95% confidence interval [CI], 3.99-11.67). Back pain and hip pain were significantly associated with knee pain (adjusted OR [95% CI]: 7.63 [3.70-15.76] and 3.84 [1.89 7.83], respectively), ankle pain (adjusted OR [95% CI]: 9.03 [4.42-18.44] and 5.43 [2.77-10.62], respectively), and both knee and ankle pain (adjusted OR [95% CI]: 13.67 [6.01-31.09] and 5.98 [2.56-13.97], respectively). Conclusions: Trunk pain was associated with lower extremity pain among youth soccer players. Clinicians and coaches should consider comorbidities while treating those players. PMID- 29989081 TI - Hyper-dominant left anterior descending coronary artery with continuation as a posterior descending artery-An extended empire. AB - Hyper-dominant left anterior descending artery (LAD) is a rare coronary anomaly where LAD continues as a posterior descending artery. It is a rare coronary anomaly and there are only 19 cases reported so far in 17 case reports in the literature. Its involvement during acute coronary syndrome can be fatal as it leads to ischemia/infarction of a larger area of left and/or right ventricular myocardium. Its early recognition and management is essential with a high index of clinical suspicion. PMID- 29989082 TI - Equity in access to non-communicable disease medicines: a cross-sectional study in Kenya. AB - Introduction: Wealth-based inequity in access to medicines is an impediment to achieving universal health coverage in many low-income and middle-income countries. We explored the relationship between household wealth and access to medicines for non-communicable diseases (NCDs) in Kenya. Methods: We administered a cross-sectional survey to a sample of patients prescribed medicines for hypertension, diabetes or asthma. Data were collected on medicines available in the home, including the location and cost of purchase. Household asset information was used to construct an indicator of wealth. We analysed the relationship between household wealth and various aspects of access, including the probability of having NCD medicines at home and price paid. Results: Among 639 patients interviewed, hypertension was the most prevalent NCD (69.6%), followed by diabetes (22.2%) and asthma (20.2%). There was a positive and statistically significant association between wealth and having medicines for patients with hypertension (p=0.020) and asthma (p=0.016), but not for diabetes (p=0.160). Poorer patients lived farther from their nearest health facility (p=0.050). There was no relationship between household wealth and the probability that the nearest public or non-profit health facility had key NCD medicines in stock, though less poor patients were significantly more likely to purchase medicines at better stocked private outlets. The relationship between wealth and median price paid for metformin by patients with diabetes was strongly u-shaped, with the middle quintile paying the lowest prices and the poorest and least poor paying higher prices. Patients with asthma in the poorest wealth quintile paid more for salbutamol than those in all other quintiles. Conclusion: The poorest in Kenya appear to face increased barriers to accessing NCD medicines as compared with the less poor. To achieve universal health coverage, the country will need to consider pro-poor policies for improving equity in access. PMID- 29989083 TI - iRSpot-Pse6NC: Identifying recombination spots in Saccharomyces cerevisiae by incorporating hexamer composition into general PseKNC. AB - Meiotic recombination caused by meiotic double-strand DNA breaks. In some regions the frequency of DNA recombination is relatively higher, while in other regions the frequency is lower: the former is usually called "recombination hotspot", while the latter the "recombination coldspot". Information of the hot and cold spots may provide important clues for understanding the mechanism of genome revolution. Therefore, it is important to accurately predict these spots. In this study, we rebuilt the benchmark dataset by unifying its samples with a same length (131 bp). Based on such a foundation and using SVM (Support Vector Machine) classifier, a new predictor called "iRSpot-Pse6NC" was developed by incorporating the key hexamer features into the general PseKNC (Pseudo K-tuple Nucleotide Composition) via the binomial distribution approach. It has been observed via rigorous cross-validations that the proposed predictor is superior to its counterparts in overall accuracy, stability, sensitivity and specificity. For the convenience of most experimental scientists, the web-server for iRSpot Pse6NC has been established at http://lin-group.cn/server/iRSpot-Pse6NC, by which users can easily obtain their desired result without the need to go through the detailed mathematical equations involved. PMID- 29989084 TI - Integrated multifactor analysis explores core dysfunctional modules in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disease in early childhood, and growing up to be a major cause of disability in children. However, the underlying molecular mechanism of ASD remains elusive. Hence, we represented integrated multifactor analysis exploring dysfunctional modules based on RNA-Seq data from corpus callosum in 6 patients with ASD and 6 normal individuals. According to protein-protein interactions (PPIs) and WGCNA, we performed co expression modules analysis for ASD-associated genes, and identified 25 modules with differentially expressed genes (DEGs), observing that genes in these modules were significantly involved in various biological processes in nervous system, sensory system, phylogenetic system and variety of signaling pathways. Then, based on transcriptional and post-transcriptional regulations, integrating transcription factor (TF)-target and RNA-associated interactions, significant regulators of co-expression modules were identified as pivot regulators, including 67 pivot TFs, 13 pivot miRNAs and 6 pivot lncRNAs. GO and KEGG pathway enrichment analysis demonstrated that the pivot miRNAs significantly enriched in neural or mental-associated biological progresses. The pivot TFs were mainly involved in various regulation of transcription, immune system and organs development. Finally, our work deciphered a multifactor dysfunctional co expression subnetwork involved in ASD, helps uncover core dysfunctional modules for this disease and improves our understanding of its underlying molecular mechanism. PMID- 29989086 TI - Adoption of paediatric and neonatal pulse oximetry by 12 hospitals in Nigeria: a mixed-methods realist evaluation. AB - Introduction: Pulse oximetry is a life-saving tool for identifying children with hypoxaemia and guiding oxygen therapy. This study aimed to evaluate the adoption of oximetry practices in 12 Nigerian hospitals and identify strategies to improve adoption. Methods: We conducted a mixed-methods realist evaluation to understand how oximetry was adopted in 12 Nigerian hospitals and why it varied in different contexts. We collected quantitative data on oximetry use (from case notes) and user knowledge (pretraining/post-training tests). We collected qualitative data via focus groups with project nurses (n=12) and interviews with hospital staff (n=11). We used the quantitative data to describe the uptake of oximetry practices. We used mixed methods to explain how hospitals adopted oximetry and why it varied between contexts. Results: Between January 2014 and April 2017, 38 525 children (38% aged <=28 days) were admitted to participating hospitals (23 401 pretraining; 15 124 post-training). Prior to our intervention, 3.3% of children and 2.5% of neonates had oximetry documented on admission. In the 18 months of intervention period, all hospitals improved oximetry practices, typically achieving oximetry coverage on >50% of admitted children after 2-3 months and >90% after 6-12 months. However, oximetry adoption varied in different contexts. We identified key mechanisms that influenced oximetry adoption in particular contexts. Conclusion: Pulse oximetry is a simple, life-saving clinical practice, but introducing it into routine clinical practice is challenging. By exploring how oximetry was adopted in different contexts, we identified strategies to enhance institutional adoption of oximetry, which will be relevant for scale-up of oximetry in hospitals globally. Trial registration number: ACTRN12617000341325. PMID- 29989085 TI - HBPred: a tool to identify growth hormone-binding proteins. AB - Hormone-binding protein (HBP) is a kind of soluble carrier protein and can selectively and non-covalently interact with hormone. HBP plays an important role in life growth, but its function is still unclear. Correct recognition of HBPs is the first step to further study their function and understand their biological process. However, it is difficult to correctly recognize HBPs from more and more proteins through traditional biochemical experiments because of high experimental cost and long experimental period. To overcome these disadvantages, we designed a computational method for identifying HBPs accurately in the study. At first, we collected HBP data from UniProt to establish a high-quality benchmark dataset. Based on the dataset, the dipeptide composition was extracted from HBP residue sequences. In order to find out the optimal features to provide key clues for HBP identification, the analysis of various (ANOVA) was performed for feature ranking. The optimal features were selected through the incremental feature selection strategy. Subsequently, the features were inputted into support vector machine (SVM) for prediction model construction. Jackknife cross-validation results showed that 88.6% HBPs and 81.3% non-HBPs were correctly recognized, suggesting that our proposed model was powerful. This study provides a new strategy to identify HBPs. Moreover, based on the proposed model, we established a webserver called HBPred, which could be freely accessed at http://lin group.cn/server/HBPred. PMID- 29989087 TI - Breastfeeding self-efficacy and breastmilk feeding for moderate and late preterm infants in the Family Integrated Care trial: a mixed methods protocol. AB - Background: Breastmilk is the ideal nutrition for preterm infants. Yet, breastmilk feeding rates among preterm infants are substantially lower than those of full-term infants. Barriers incurred through hospital care practices as well as the physical environment of the neonatal intensive care unit (NICU) can result in physical and emotional separation of infants from their parents, posing a substantial risk to establishing and maintaining breastfeeding. Additionally, current practitioner-focused care provision in the NICU can result in decreased breastfeeding self-efficacy (BSE), which is predictive of breastfeeding rates in mothers of preterm infants at 6 weeks postpartum. Methods: Family Integrated Care (FICare) integrates and supports parents to actively participate in the care of their infant while in the NICU. Nested within the broader FICare trial, we will conduct an explanatory sequential mixed methods study to investigate if FICare improves maternal BSE and rates of breastmilk feeding in moderate and late preterm infants at discharge from the NICU. In phase 1, we will calculate the mean difference between admission and discharge BSE scores for the intervention group. Mothers who score in the top and bottom 20th percentile of change scores will be invited to participate in a semi-structured telephone interview exploring maternal experiences with infant feeding in the NICU. We will conduct inductive thematic analysis to identify and describe the facilitators and barriers of FICare on maternal feeding experiences. Once data saturation is achieved and themes have been established, phase 2 will revisit the quantitative data to determine whether FICare was impactful on BSE and breastmilk feeding rates. Findings from the qualitative and quantitative phases will be integrated to determine how infant feeding experiences on FICare units work to improve or detract from maternal BSE and rates of breastmilk feeding. Discussion: FICare may help to improve maternal BSE and rates of breastmilk feeding in moderate and late preterm infants. Improved breastmilk feeding outcomes can have a substantial impact on overall infant health, developmental outcomes, and maternal-infant bonding and will help to improve long-term health outcomes for moderate and late preterm infants. Trial registration: (NCT02879799). Registered May 27, 2016 protocol version June 9, 2016 Version 2. PMID- 29989088 TI - Identification of Inhibitors of MMPS Enzymes via a Novel Computational Approach. AB - Matrix metalloproteases (MMPs) are a family of zinc-dependent proteinases that play complex and diverse roles in metabolism, which are vital for physiological development. In this paper, we present a novel method to identify peptide binding to seven matrix metalloproteases. First, we propose a novel sampling criteria for constructing a training set for each new peptide motif. Then, we select nine physicochemical properties of amino acids and compute their auto-cross covariance to effectively extract features for both natural and non-natural amino acids. Finally, we adopt random forest to predict binding values of each peptide motif respectively with seven MMPs. Our method verifies on 1300 known peptide motifs binding to seven MMPs and achieved preeminent Pearson-product-moment correlation coefficient (PCC) and root mean squared error (RMSE) on all seven MMPs, especially of 0.9181 and 9.3827 on MMP-7. We predict binding values of 4000 peptide motifs and identify peptides preferentially bind to MMP-2 and MMP-7. We herein report 4 novel inhibitor candidates of Asp-Ile-Phe, Asp-Ile-Tyr, Asp-Ile Lys and Hser-Gly-Phe with high potency and selectivity binding to MMP-2, as well as 6 novel inhibitor candidates of Chg-Ile-Ile, Chg-Ile-Leu, Chg-Ile-Glu, Chg-Ile Met, Chg-Val-Ile and Chg-Val-Leu selectively binding to MMP-7. Our findings facilitate the identification of inhibitors with good potency as well as desirable selectivity, providing significant insights of candidate inhibitor drugs. PMID- 29989089 TI - Research on folding diversity in statistical learning methods for RNA secondary structure prediction. AB - How to improve the prediction accuracy of RNA secondary structure is currently a hot topic. The existing prediction methods for a single sequence do not fully consider the folding diversity which may occur among RNAs with different functions or sources. This paper explores the relationship between folding diversity and prediction accuracy, and puts forward a new method to improve the prediction accuracy of RNA secondary structure. Our research investigates the following: 1. The folding feature based on stochastic context-free grammar is proposed. By using dimension reduction and clustering techniques, some public data sets are analyzed. The results show that there is significant folding diversity among different RNA families. 2. To assign folding rules to RNAs without structural information, a classification method based on production probability is proposed. The experimental results show that the classification method proposed in this paper can effectively classify the RNAs of unknown structure. 3. Based on the existing prediction methods of statistical learning models, an RNA secondary structure prediction framework is proposed, namely "Cluster - Training - Parameter Selection - Prediction". The results show that, with information on folding diversity, prediction accuracy can be significantly improved. PMID- 29989091 TI - RicyerDB: A Database For Collecting Rice Yield-related Genes with Biological Analysis. AB - The Rice Yield-related Database (RicyerDB) was created to complement with related research of influence rice (Oryza sativa L.) yield in multiple traits by manually curating the related databases and literature, and genomics and proteomics information that could be useful for comprehensive understanding of the rice biology. RicyerDB provides a more valuable resource in which to efficiently investigate, browse and analyze yield-related genes. The whole data set can be easily queried and downloaded through the webpage. In addition, RicyerDB also constructed a protein-protein interaction network with biological analysis. The combined rice database opens a new path to facilitate researchers achieving information on rice gene in terms of their effects on traits important for rice breeding. The web server is freely available at: http://server.malab.cn/Ricyer/index.html. PMID- 29989090 TI - A comprehensive review of web-based resources of non-coding RNAs for plant science research. AB - Non-coding RNAs (ncRNAs) are transcribed from genome but not translated into proteins. Many ncRNAs are key regulators of plants growth and development, metabolism and stress tolerance. In order to make the web-based ncRNA resources for plant science research be more easily accessible and understandable, we made a comprehensive review for 83 web-based resources of three types, including genome databases containing ncRNA data, microRNA (miRNA) databases and long non coding RNA (lncRNA) databases. To facilitate effective usage of these resources, we also suggested some preferred resources of miRNAs and lncRNAs for performing meaningful analysis. PMID- 29989092 TI - CCL2-SQSTM1 positive feedback loop suppresses autophagy to promote chemoresistance in gastric cancer. AB - Chemotherapy is one of the most important approaches for the treatment of various cancers. However, tumor cells often develop resistance to chemotherapeutic drugs. The tumor microenvironment reconstituted by various cytokines secreted from immune cells was recently found to play important roles in affecting therapeutic response of tumor cells. Herein, we reported that tumor cells can secrete autocrine cytokines to confer chemoresistance by inactivating proapoptotic autophagy. Through cytokine screening, we found that drug resistant cancer cells secreted more CCL2 than drug sensitive cells. Such secreted CCL2 could not only maintain chemoresistance in drug-resistant cancer cells but also confer drug resistance to drug-sensitive cancer cells. CCL2 attenuated drug-induced cytotoxicity by activating PI3K-Akt-mTOR signaling to inhibit proapoptotic autophagy and increase SQSTM1 expression. CCL2 expression in primary carcinoma tissues also correlated well with SQSTM1 expression. Either CCL2 knock-down or autophagy induction successfully reversed drug resistance of tumor cells. Moreover, increased expression of SQSTM1 in turn activated CCL2 transcription via NF-kappaB signal pathway, representing a positive feedback loop to maintain drug resistance. Therefore, our results provided a new insight to understand drug resistance, and indicated the potential value of CCL2 as a biomarker and intervention target for chemotherapy resistance. PMID- 29989094 TI - Qualitative study of Ebola screening at ports of entry to the UK. AB - Introduction: In response to the 2013-2016 West African outbreak of the Ebola virus disease (EVD), Public Health England introduced enhanced screening at major UK ports of entry. Our aim was to explore screeners' and screened travellers' perceptions of screening as part of an evaluation of the screening programme. Methods: We undertook qualitative focus groups and semistructured interviews with screeners and travellers who had returned from affected countries before and after the introduction of screening in England. The study was conducted in two airports: one international rail terminal and one military airport. Research topic guides explored perceptions of the purpose and implementation of the process, potential improvements and reactions to screening. The data were analysed using the framework method. Results: Twenty-four screeners participated in 4 focus groups (one for each port of entry) and 23 travellers participated in interviews. Three themes are presented: 'Context', 'Screeners' experience of the programme' and 'Screening purpose and experiences'. The programme was implemented rapidly, refined over time and adapted to individual ports. Screeners reported diverse experiences of screening including negative impacts on their normal roles, difficult interactions with passengers and pressure to identify positive EVD cases. Screening was considered unlikely to identify individuals with symptoms of EVD, and some participants suggested it was driven by political concerns rather than empirical evidence. The screening process was valued for its provision of information and reassurance. Conclusion: This qualitative study found that the UK EVD screening process was perceived to be acceptable to assess individual risk and provide information and advice to travellers. Future programmes should have clear objectives and streamlined processes to minimise disruption, tailored to the nature of the threat and developed with the needs of humanitarian workers as well as general travellers in mind. PMID- 29989093 TI - An investigation of the distribution and location of mast cells affected by the stiffness of substrates as a mechanical niche. AB - The distribution and location of mast cells are closely related to their physiological and pathological functions, such as allergic responses, immunity, and fibrosis, and are used in acupuncture. In this study, the distribution of mast cells in vivo was observed, and mechanical clues for understanding their distribution based on mechanical niches were explored. By toluidine blue staining and immunohistochemical staining, we examined the distribution and location of mast cells in rat skin and found that mast cells are distributed in a spatially nonuniform manner, preferring to locate at regions in the tissue and extracellular matrix with stiffness changes. In vitro experiments for studying the distribution of rat basophilic leukemia (RBL-2H3) mast cell line on poly-di methyl-siloxane (PDMS) substrates with stiffness variations were performed. It was found that RBL-2H3 cells migrate and tend to remain in the areas with stiffness variations. The present research suggests that changing the stiffness of local tissues may stimulate mast cell recruitment, which may be the method by which some traditional Chinese medicine treatments, such as acupuncture. On the basis of the origin of mast cells and our experimental results, we predict that mast cells exist in tissues that contain permeable capillaries and prefer regions with stiffness changes. We discussed this prediction using examples of specific tissues from some cases. PMID- 29989095 TI - MicroShare: Privacy-Preserved Medical Resource Sharing through MicroService Architecture. AB - This paper takes up the problem of medical resource sharing through MicroService architecture without compromising patient privacy. To achieve this goal, we suggest refactoring the legacy EHR systems into autonomous MicroServices communicating by the unified techniques such as RESTFul web service. This lets us handle clinical data queries directly and far more efficiently for both internal and external queries. The novelty of the proposed approach lies in avoiding the data de-identification process often used as a means of preserving patient privacy. The implemented toolkit combines software engineering technologies such as Java EE, RESTful web services, JSON Web Tokens to allow exchanging medical data in an unidentifiable XML and JSON format as well as restricting users to the need-to-know principle. Our technique also inhibits retrospective processing of data such as attacks by an adversary on a medical dataset using advanced computational methods to reveal Protected Health Information (PHI). The approach is validated on an endoscopic reporting application based on openEHR and MST standards. From the usability perspective, the approach can be used to query datasets by clinical researchers, governmental or non-governmental organizations in monitoring health care and medical record services to improve quality of care and treatment. PMID- 29989096 TI - PTM-ssMP: A Web Server for Predicting Different Types of Post-translational Modification Sites Using Novel Site-specific Modification Profile. AB - Protein post-translational modifications (PTMs) are chemical modifications of a protein after its translation. Owing to its play an important role in deep understanding of various biological processes and the development of effective drugs, PTM site prediction have become a hot topic in bioinformatics. Recently, many online tools are developed to prediction various types of PTM sites, most of which are based on local sequence and some biological information. However, few of existing tools consider the relations between different PTMs for their prediction task. Here, we develop a web server called PTM-ssMP to predict PTM site, which adopts site-specific modification profile (ssMP) to efficiently extract and encode the information of both proximal PTMs and local sequence simultaneously. In PTM-ssMP we provide efficient prediction of multiple types of PTM site including phosphorylation, lysine acetylation, ubiquitination, sumoylation, methylation, O-GalNAc, O-GlcNAc, sulfation and proteolytic cleavage. To assess the performance of PTM-ssMP, a large number of experimentally verified PTM sites are collected from several sources and used to train and test the prediction models. Our results suggest that ssMP consistently contributes to remarkable improvement of prediction performance. In addition, results of independent tests demonstrate that PTM-ssMP compares favorably with other existing tools for different PTM types. PTM-ssMP is implemented as an online web server with user-friendly interface, which is freely available at http://bioinformatics.ustc.edu.cn/PTM-ssMP/index/. PMID- 29989097 TI - Smoke exposure and cardio-metabolic profile in youth with type 1 diabetes. AB - Background: To evaluate the relationship between smoking and metabolic parameters in patients affected by type 1 diabetes (T1D). Patients and methods: We enrolled 104 children and young adults (50 females and 54 males) with T1D (aged 16.4 +/- 8.6 years). The subjects were divided into three groups according to their smoking habits: no smoking (NS), passive smoking (PS), active smoking (AS). The physical examination of the participants included nutritional status assessment by anthropometry and pubertal stage according to Marshall and Tanner as well as blood pressure measurement. In all patients, metabolic blood assays including fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured. Insulin resistance was determined by glucose disposal rate (eGDR). Physical activity was also recorded. Results: Significant differences in biochemical and functional parameters among the three groups were demonstrated, in particular for systolic (p = 0.002) and diastolic pressure (p = 0.02) and eGDR (p = 0.039). No differences in daily insulin dose (p = 0.75) and glycated hemoglobin (p = 0.39) were observed. AS group had significantly higher blood pressure (p < 0.05) and lower eGDR (p <= 0.001) compared to NS and PS. Significant difference was also detected between PS and NS in systolic and diastolic (p = 0.02) pressure and eGDR (p = 0.01). In a multivariable model adjusted for age, gender, BMI and physical activity, smoking habits did not maintain any independent association with metabolic parameters. Conclusion: This is the first study in a Mediterranean population, looking at tobacco smoke and cardio-metabolic factors in youth with T1D. The relationship between smoking and unfavorable metabolic profile was demonstrated. On the basis of these findings, smoking tobacco should be considered an important modifiable risk factor for young patients with diabetes mellitus, highlighting the need for intensified smoking prevention and cessation programs. PMID- 29989098 TI - Genome-wide Analyses on Single Disease Samples for Potential Biomarkers and Biological Features of Molecular Subtypes: A Case Study in Gastric Cancer. AB - Purpose: Based on the previous 3 well-defined subtypes of gastric adenocarcinoma (invasive, proliferative and metabolic), we aimed to find potential biomarkers and biological features of each subtype. Methods: The genome-wide co-expression network of each subtype of gastric cancer was firstly constructed. Then, the functional modules in each genome-wide co-expression network were divided. Next, the key genes were screened from each functional module. Finally, the enrichment analysis was performed on the key genes to mine the biological features of each subtype. Comparative analysis between each pair of subtypes was performed to find the common and unique features among different subtypes. Results: A total of 207 key genes were identified in invasive, 215 key genes in proliferative, and 204 key genes in metabolic subtypes. Most key genes in each subtype were unique and new findings compared with that of the existing related researches. The GO and KEGG enrichment analyses for the key genes of each subtype revealed important biological features of each subtype. Conclusions: For a subtype, most identified key genes and important biological features were unique, which means that the key genes can be used as the potential biomarker of a subtype, and each subtype of gastric cancer might have different occurrence and development mechanisms. Thus, different diagnosis and therapy methods should be applied to the invasive, proliferative and metabolic subtypes of gastric cancer. PMID- 29989099 TI - Non-coding RNA-linked epigenetic regulation in cardiac hypertrophy. AB - Cardiac hypertrophy is an adaptive enlargement of myocardium in response to pressure overload caused various pathological insults, which is accompanied by alteration of a complex cascade of signaling pathways. During the hypertrophy process, many changes occur at cellular level including gene reprogramming by turning off chromatin regulators. Studies from the past decade have demonstrated that the abnormal epigenetic modifications, such as DNA methylation, histone modification, and oxidative modification of nucleic acid, could lead to changes in chromosome structure and cardiac dysfunction. Increasing evidence indicates that non-coding RNAs (ncRNAs) have functional significance in modulating the gene expression during those pathological events in the heart. Emerging evidences have highlighted that ncRNAs might serve as a signal for changing the state of chromatin, however, the knowledge about the ncRNA-linked epigenetic regulatory mechanisms in cardiac pathologies is still largely unexplored. In this review, we summarize the current information on association between ncRNAs and epigenetic modifications in cardiac hypertrophy, and we have discussed their crosstalk. In addition, this review provides insights into their therapeutic and diagnostic potential for treating hypertrophic heart disease. PMID- 29989100 TI - Zika Virus Envelope Protein induces G2/M Cell Cycle Arrest and Apoptosis via an Intrinsic Cell Death Signaling Pathway in Neuroendocrine PC12 Cells. AB - Clinical evidence suggests that there exists a strong correlation between Zika virus (ZIKV) infection and abnormal development of the nervous system. However, the underlying mechanisms remain to be elusive. In this study, recombinant lentiviral vectors coding for ZIKV structural proteins and truncations (prM-Env, M-Env and Env) were transduced into PC12 cells. Envelope (Env) overexpression induced significant inhibition of proliferation and triggered G2/M cell cycle arrest and apoptosis in PC12 cells. Flow cytometry and western blot analysis showed that the apoptosis was associated with up-regulation of both p53 and p21Cip1/Waf1 and down-regulation of cyclin B1. Presence of aberrant nuclei clusters were confirmed by immunofluorescence staining analysis. The data indicate that overexpression of prM-Env, M-Env or Env led to apoptosis via an intrinsic cell death signaling pathway that is dependent on the activation of caspase-9 and caspase-3 and accompanied by an increased ratio of Bax to Bcl-2 in transduced PC12 cells. In summary, our results suggest that ZIKV Env protein causes apoptosis in PC12 cells via an intrinsic cell death signaling pathway, which may contribute to ZIKV-induced abnormal development of the nervous system. PMID- 29989101 TI - Computational Design of Antiangiogenic Peptibody by Fusing Human IgG1 Fc Fragment and HRH Peptide: Structural Modeling, Energetic Analysis, and Dynamics Simulation of Its Binding Potency to VEGF Receptor. AB - Peptibodies represent a new class of biological therapeutics with combination of peptide activity and antibody-like properties. Previously, we discovered a novel peptide HRH that exhibited a dose-dependent angiogenesis-suppressing effect by targeting vascular endothelial growth factor receptors (VEGFRs). Here, we computationally designed an antiangiogenic peptibody, termed as PbHRH, by fusing the HRH peptide to human IgG1 Fc fragment using the first approved peptibody drug Romiplostim as template. The biologically active peptide of Romiplostim is similar with HRH peptide; both of them have close sequence lengths and can fold into a alpha-helical conformation in free state. Molecular dynamics simulations revealed that the HRH functional domain is highly flexible, which is functionally independent of Fc fragment in the designed PbHRH peptibody. Subsequently, the intermolecular interactions between VEGFR-1 domain 2 (D2) and PbHRH were predicted, clustered and refined into three representatives. Conformational analysis and energetic evaluation unraveled that the PbHRH can adopt multiple binding modes to block the native VEGF-A binding site of VEGFR-1 D2 with its HRH functional domain, although the binding effectiveness of HRH segments in peptibody context seems to be moderately decreased relative to that of free HRH peptide. Overall, it is suggested that integrating HRH peptide into PbHRH peptibody does not promote the direct intermolecular interaction between VEGFR-1 D2 and HRH. Instead, the peptibody may indirectly help to improve the pharmacokinetic profile and bioavailability of HRH. PMID- 29989102 TI - Translational Bioinformatics for Cholangiocarcinoma: Opportunities and Challenges. AB - Translational bioinformatics is becoming a driven force and a new scientific paradigm for cancer research in the era of big data. To promote the cross disciplinary communication and research, we take cholangiocarcinoma as an example to review the present status and the future perspectives of the bioinformatics models applied in cancer study. We first summarize the present application of computational methods to the study of cholangiocarcinoma ranged from pattern recognition of biological data, knowledge based data annotation to systems biological level modeling and clinical translation. Then the future opportunities and challenges about database or knowledge base building, novel model developing and molecular mechanism exploring as well as the intelligent decision supporting system construction for the precision diagnosis, prognosis and treatment of cholangiocarcinoma are discussed. PMID- 29989103 TI - Overexpression of Toll-like Receptor 4-linked Mitogen-activated Protein Kinase Signaling Contributes to Internalization of Escherichia coli in Sheep. AB - Escherichia coli is one of the most common causal pathogens of mastitis in milk producing mammals. Toll-like receptor 4 (TLR4) is important for host recognition of this bacteria. Increased activation of TLR4 can markedly enhance the internalization of E. coli. In this study, the relationship between TLR4 and mitogen-activated protein kinase (MAPK) signaling pathways in mediating E. coli internalization was evaluated in sheep monocytes. Using a TLR4-overexpressing transgenic (Tg) sheep model, we explored the bacterial internalization mechanism in sheep. We found that monocytes of Tg sheep could phagocytize more bacteria and exhibited higher adhesive capacity. The specific inhibition of p38 MAPK or c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinases (ERKs) reduced TLR4-dependent internalization of bacteria into sheep monocytes. Furthermore, the inhibition of MAPK signaling down-regulated the adhesive capacity of monocytes and the expression of scavenger receptors and adhesion molecules. Taken together, the overexpression of TLR4 in transgenic sheep enhanced the internalization of E. coli via MAPK signaling. PMID- 29989104 TI - Classification of Sputum Sounds Using Artificial Neural Network and Wavelet Transform. AB - Sputum sounds are biological signals used to evaluate the condition of sputum deposition in a respiratory system. To improve the efficiency of intensive care unit (ICU) staff and achieve timely clearance of secretion in patients with mechanical ventilation, we propose a method consisting of feature extraction of sputum sound signals using the wavelet transform and classification of sputum existence using artificial neural network (ANN). Sputum sound signals were decomposed into the frequency subbands using the wavelet transform. A set of features was extracted from the subbands to represent the distribution of wavelet coefficients. An ANN system, trained using the Back Propagation (BP) algorithm, was implemented to recognize the existence of sputum sounds. The maximum precision rate of automatic recognition in texture of signals was as high as 84.53%. This study can be referred to as the optimization of performance and design in the automatic technology for sputum detection using sputum sound signals. PMID- 29989105 TI - An Inhibitor of Casein Kinase 1epsilon/delta (PF670462) Prevents the Deterioration of Dextran Sodium Sulfate-induced Ulcerative Colitis Caused by UVB Eye Irradiation. AB - Although we previously reported the exacerbation of dextran sodium sulfate (DSS) induced ulcerative colitis by ultraviolet (UV) B eye irradiation, we do not yet understand the mechanism behind this phenomenon. In this study, we examined the relationship between the deterioration of DSS-induced ulcerative colitis and clock genes. We induced a mouse model of ulcerative colitis by administering DSS for 5 days, and administered UVB eye irradiation on each day of the DSS treatment period. The DSS-induced ulcerative colitis was deteriorated by the UVB eye irradiation. The levels of Clock, brain and muscle arnt-like protein 1 (Bmal1), reverse orientation c-erb A gene (Rev-Erb)alpha, RAR-related orphan receptor gamma (RORgammat), and interleukin (IL)-17 in the colon were increased by UVB eye irradiation in the DSS-treated mice (UVB/DSS-treated mice). Conversely, the nuclear factor, interleukin 3 regulated (NFIL-3) levels in the colon were lower after UVB eye irradiation. The Casein Kinase 1epsilon/delta inhibitor (PF670462) administration, which is a Clock/Bmal1 inhibitor (PER2 activator), inhibited the deterioration caused by UVB eye irradiation. These results suggest that the UVB eye irradiation-mediated exacerbation of DSS-induced ulcerative colitis depends on IL-17 produced in response to alterations in clock genes. PMID- 29989106 TI - Special issue on Computational Resources and Methods in Biological Sciences. AB - This special issue covers a wide range of topics in computational biology, such as database construction, sequence analysis and function prediction with machine learning methods, disease-related diagnosis, drug-target and drug discovery, and electronic health record system construction. PMID- 29989107 TI - Can extra-short dental implants serve as alternatives to bone augmentation? A preliminary longitudinal randomized controlled clinical trial. AB - OBJECTIVE: A randomized trial to assess clinical and radiographic outcomes of short versus standard dental implants placed with concomitant vertical bone augmentation. METHOD AND MATERIALS: Patients requiring dental implants were randomized to receive either 6-mm implants (experimental) or 10-mm implants with vertical augmentation (control). Custom load-bearing healing abutments were connected to allow for indirect resonance frequency analysis measurements. Standardized radiographs were taken at implant placement (baseline), and at 3 and 12 months. Implants were restored at 3 to 6 months, and final measurements were taken at 12 months. RESULTS: Fifty patients with 25 implants per group were included. Five implants failed, four experimental and one control (84% and 96% cumulative survival rate, respectively). Short implants required significantly less surgical time (51.6 +/- 23 versus 68.5 +/- 35 minutes, P = .05). Implant stability quotients at baseline (67.9 +/- 8.3 experimental and 70.8 +/- 7.6 control, P = .215) and 12 weeks (70.17 +/- 7.4 and 72.03 +/- 5.9, respectively, P = .513) were similar and unchanged. Positive correlation was found between the two measurement methods (r2 = .6, P = .025). One-year average marginal bone loss was slightly lower for the experimental group (0.6 +/- 0.16 mm) compared to the control group (0.86 +/- 0.19 mm); however, this was not statistically significant (P = .287). CONCLUSION: Short dental implants may offer an alternative for implant placement in an atrophic jaw; however, they are associated with reduced first-year survival rate. Short dental implants should be used judiciously in light of this potential predicament, and alternatives assessed. PMID- 29989108 TI - Short, parallel-walled, conical-connection implants for a broad range of indications in the maxilla and mandible: Retrospective multicenter study with up to 33 months of follow-up. AB - OBJECTIVE: To evaluate the survival and complication rate of 7-mm short, parallel walled, conical-connection implants in daily practice. METHOD AND MATERIALS: This multicenter retrospective study included 219 consecutive patients who received 323 implants. Indication was limited vertical bone height preventing placement of implants longer than 7 mm. Placement and loading protocols were determined on a case-by-case basis and included placement in fresh extraction sockets and healed sites, and loading was either immediate, early, or delayed. Patients were followed for up to 33 months. Outcome measures were implant survival rate and any biologic or technical complications. RESULTS: In total, eight implants in seven patients failed, accounting for the survival rate of 97.3% at implant level and 96.4% at patient level. The mean time to failure was 7.5 months and 10.2 months at the implant and patient level, respectively. The majority of patients (67.1%) received one implant and the placement was predominantly in healed sites (82.7%). Immediate loading was done for 21.4% of implants placed in the extraction site and for 21.3% of implants placed in healed sites. In most of the cases (71.8%) implants were placed in the premolar or molar position in the mandible. No complications were reported. CONCLUSION: These results suggest that in cases of limited vertical bone height, the short, parallel-walled, conical-connection implant can successfully support different prosthesis types in a wide variety of indications and loading protocols. PMID- 29989109 TI - Effect of implant number on the movement of mandibular implant-supported overdentures under biting force: An in-vitro study. AB - OBJECTIVE: Many studies have investigated the effect of implant number on the performance of implant-supported overdentures (ISO), but few have focused on denture movement. This in-vitro study aims to investigate the influence of implant number on the movement of mandibular ISO under biting force. METHOD AND MATERIALS: An edentulous mandibular cast and 12 overdentures (n = 12) were fabricated, and a locator attachment system with blue nylon inserts was chosen for this study. Four implant positions were simulated: anterior midline (1-ISO), bilateral canine regions (2-ISO), anterior midline and bilateral molar regions (3 ISO), and bilateral canine and molar regions (4-ISO). After positioning an overdenture on one of these four casts, vertical loads were applied to the incisor region (40 N), the left canine (55 N), or molar (100 N) regions. The movements at the loading point and the right distal edge were measured. Significance across groups was analyzed using one-way analysis of variance and post hoc Tukey honest significant difference test. P < .05 was considered statistically significant. RESULTS: On incisor loading, the 3-ISO showed the least movement, and no significant movement was detected across the other three groups. Upon canine loading, the largest displacement appeared in the 1-ISO group, at both the loading point and the right distal edge. Additionally, overdentures anchored by three or four implants, especially the 4-ISO, showed significantly smaller movement on molar loading. CONCLUSION: The implant number influences the movement of mandibular ISO, and overdentures retained with three or more implants have minimal movement. PMID- 29989110 TI - Enzymatic hydrolysis-induced degradation of a lactose-coupled supramolecular hydrogel. AB - Amphiphilic urea 1 with a hydrophilic lactose group was prepared as a low molecular-weight hydrogelator, which formed a transparent supramolecular hydrogel. Enzymatic hydrolysis of the lactose moiety using beta-galactosidase allowed a gel-to-sol phase transition of the supramolecular hydrogel. A beta galactosidase inhibitor enables us to control the time course of this phase transition. PMID- 29989111 TI - First complex oxide superconductor by atomic layer deposition. AB - We here report on atomic layer deposition (ALD) of the superconducting complex oxide La2-xSrxCuO4-y and provide details of the structural and electrical properties of such films. This is the first report on a complex oxide thin film with superconducting properties that has been deposited by atomic layer deposition. PMID- 29989112 TI - Peptide nucleic acid mediated inhibition of the bacterial signal recognition particle. AB - We have identified the bacterial signal recognition particle (SRP) as a novel antibacterial target. As a proof of principle, we used an antisense peptide nucleic acid to target a key SRP RNA. The PNA molecules showed efficient inhibition of SRP function and bacterial cell growth, thereby validating our hypothesis. PMID- 29989113 TI - Trifluoromethane modification of thermally activated delayed fluorescence molecules for high-efficiency blue organic light-emitting diodes. AB - Highly efficient blue and green thermally activated delayed fluorescence (TADF) molecules bearing trifluoromethane-modified carbazole groups were developed. The trifluoromethane groups on carbazole induced blue-shifted emission and improved the photoluminescence quantum yield. The photostability of the TADF molecules was strongly related to the modification position of trifluoromethane on carbazole. PMID- 29989114 TI - Vibrational frequencies, structures, and energetics of the highly challenging alkali metal trifluorides MF3 (M = Li, Na, K, Rb, and Cs). AB - Many experimental studies have been reported on alkali metal trifluorides MF3 (M = Li, Na, K, Rb, and Cs), and several controversies remain. In the present research, we systematically study the MF3 systems using both coupled-cluster and multireference methods. New predictions and explanations are provided for some known experimental and theoretical challenges, including identification of the true MF3 minima and global minima, the unclear existence of light alkali metal trifluorides MF3 (M = Li and Na), and assignment of the F-F-F symmetric stretch frequencies for the heavier alkali metal trifluorides MF3 (M = K, Rb, and Cs). With several new structures located, we predict a preference of Cs minima for MF3 (M = Li and Na) and C2v minima for MF3 (M = K, Rb, and Cs). For the species where multiple minima were located, near degeneracies of those minima can be found in most cases. The endothermicities (~3-4 kcal mol-1) for the favored MF3 -> MF + F2 fragmentations suggest that MF3 (M = Li and Na) are weakly bonded complexes. The existence of those species at low temperatures cannot be ruled out, and vibrational frequencies are reported to guide future experiments. Most importantly, significant differences between the coupled-cluster and multireference results were found in predicting the F-F-F symmetric stretch frequencies (nus) of the C2v MF3 (M = K, Rb, and Cs) structures, although both methods show good performance in predicting most structures and antisymmetric stretch frequencies (nuas). The coupled-cluster [CCSD(T), CCSDT, and CCSDT(Q)] results agree with the recent experimental assignment of Redeker, Beckers, and Riedel [389 cm-1, RSC Adv., 2015, 5, 106568] to the nus fundamental of CsF3. In contrast, the multireference (CASPT2, CASPT3, and MRCISD+Q) results support the original experimental assignment of Ault and Andrews [461 cm-1, J. Am. Chem. Soc., 1976, 98, 1591; Inorg. Chem., 1977, 16, 2024]. The F-F-F symmetric stretch frequencies for the MF3 molecules (M = K, Rb, and Cs) continue to provide a great challenge to theory and experiment. PMID- 29989115 TI - NaI-mediated divergent synthesis of isatins and isoindigoes: a new protocol enabled by an oxidation relay strategy. AB - A new approach for the synthesis of isatins and isoindigoes by an inexpensive and environmentally friendly NaI-mediated transformation is disclosed. The selectivity could be switched by simply varying the solvent, and isatins (using THF) and isoindigoes (using DMSO) could be obtained in moderate to excellent yields. PMID- 29989116 TI - Molecular dynamics simulations of ammonium/phosphonium-based protic ionic liquids: influence of alkyl to aryl group. AB - The variation of the center atom in the cation from an N to a P-atom leads to improved physiochemical properties of protic ionic liquids (PILs) which are suitable for electrolyte applications. We present an atomistic simulations study to compare the effect of an alkyl or aryl group on trioctylammonium triflate ([HN(Oct)3][TFO]) and triphenylammonium triflate ([HN(Ph)3][TFO]) with their phosphonium analogues. We have computed the binding energy from quantum chemical calculations and physical properties such as the viscosity and the electrical conductivity of PILs from molecular dynamics simulations. The influence of the aromatic character in PILs is found to be significant to the physical properties. Gas phase quantum chemical calculations on clusters of ion pairs have revealed the presence of C-H/pi interactions in aromatic PILs along with hydrogen bonding. The variation in strength of the ion-pair affinities is examined using electric current correlation and velocity autocorrelation functions. The qualitative differences observed are due to the aromatic rings and change in the central atom of the quaternary cation from an N to a P-atom, substantiated quantitatively by diffusion coefficients and electrical conductivities. The relatively weaker ion pair interactions and low binding energy (-73.34 kcal mol-1) lead to the highest electrical conductivity in [HP(Ph)3][TFO]. PMID- 29989117 TI - Elucidating mysteries of phase-segregated membranes: mobile-lipid recruitment facilitates pores' passage to the fluid phase. AB - Phase segregation of multicomponent lipid bilayers leads to, under phase coexistence conditions, domain formation, featuring delimitation by essentially one-dimensional borders. (Micro-)phase segregation of bilayers is proposed to influence the physiological behaviour of cell membranes and provides the driving force for lipid-raft formation. Experiments show a maximum in the electrical conductivity of membranes at the phase-transition point, which has been conjectured to arise from border-nucleated transmembrane-conducting defects or pores. However, recent electroporation experiments on phase-segregated bilayers demonstrate electro-pore detection in the liquid disordered phase (Ld), wherein they diffuse over macroscopic periods without absorption into the liquid ordered phase (Lo). Here, we scrutinise transmembrane-pore formation via molecular dynamics simulations on a multicomponent phase-segregated bilayer. We find that pores created in Lo domains always migrate spontaneously to the Ld phase, via 'recruitment' of unsaturated lipids to the pore's rim to transport the pore to the fluid phase under a large stress-field driving force. Once in Ld domains, pores migrate towards their centre, never returning or pinning to Lo. These findings are explained by thermodynamics. By comparing the free-energy cost for creating pores in the bulk of Ld and Lo membranes, and in the phase-segregated system, we show that it is always more energetically tractable to create pores in Ld domains, independent of the pore size. PMID- 29989118 TI - Imaging pair-correlated reaction cross sections in F + CH3D(nub = 0, 1) -> CH2D(nu4 = 1) + HF(nu). AB - The title reactions were studied in a crossed-beam experiment at collisional energies (Ec) from 0.5 to 4.7 kcal mol-1. The nub (nu4) vibrational mode denotes the bending (umbrella) motion of the CH3D reactant (CH2D product). Using a time sliced, velocity-map imaging technique, we extracted the state-specific, pair correlated integral and differential cross sections. As with other isotopically analogous ground-state reactions, an inverted vibrational population of the HF coproduct was observed. Both the step-like excitation function near the threshold and the oscillatory forward-backward peakings in the Ec-evolution of the two dominant pair-correlated angular distributions at lower Ec suggest a resonance mediated, time-delay mechanism. As Ec increases, the angular distribution of the HF(nu = 2) product evolves into a smooth and broad swath in the backward hemisphere, indicative of a direct rebound mechanism. One quantum excitation of the bending modes of CH3D(nub = 1) promotes the reaction rate by two- to three fold up to Ec = 2.1 kcal mol-1. Broadly speaking, all major findings are qualitatively in line with previous results in the reactions of the F atom with other isotopologues. However, the rainbow feature recently observed in the CH2D(00) + HF(nu = 3) product channel is entirely absent. A possible rationale is put forward, which reinforces the previous reactive rainbow conjecture and calls for future theoretical investigations. PMID- 29989119 TI - Remarkable multimember-ring configurations in a new family of Na7MIISb5S12 (MII = Zn, Cd, Hg) exhibiting various three-dimensional tunnel structures. AB - A new family of Na7MIISb5S12 (MII = Zn, Cd and Hg) are the first examples exhibiting the unusual 12 + 12 multimember-ring (MR) configuration and an interesting (MII/Sb)3S9 trimer. Moreover, ELF and EDD calculations also reveal that the tetrahedral configurations for the MII/Sb atoms are reasonable and their large birefringences originate from the stereochemically active lone pair effect of the Sb atoms. PMID- 29989120 TI - Unveiling the complex vibronic structure of the canonical adenine cation. AB - Adenine, a DNA base, exists as several tautomers and isomers that are closely lying in energy and that may form a mixture upon vaporization of solid adenine. Indeed, it is challenging to bring adenine into the gas phase, especially as a unique tautomer. The experimental conditions were tuned to prepare a jet-cooled canonical adenine (9H-adenine). This isolated DNA base was ionized by single VUV photons from a synchrotron beamline and the corresponding slow photoelectron spectrum was compared to ab initio computations of the neutral and ionic species. We report the vibronic structure of the X+ 2A'' (D0), A+ 2A' (D1) and B+ 2A'' (D2) electronic states of the 9H adenine cation, from the adiabatic ionization energy (AIE) up to AIE + 1.8 eV. Accurate AIEs are derived for the 9H-adenine (X[combining tilde] 1A') + hnu -> 9H-adenine+ (X+ 2A'', A+ 2A', B+ 2A'') + e- transitions. Close to the AIE, we fully assign the rich vibronic structure solely to the 9H-adenine (X 1A') + hnu -> 9H-adenine+ (X+ 2A'') transition. Importantly, we show that the lowest cationic electronic states of canonical adenine are coupled vibronically. The present findings are important for understanding the effects of ionizing radiation and the charge distribution on this elementary building block of life, at ultrafast, short, and long timescales. PMID- 29989122 TI - Shape-controlled electrodeposition of single Pt nanocrystals onto carbon nanoelectrodes. AB - In this paper, we report the electrosynthesis and characterization of individual, shape-controlled Pt nanocrystals (NCs) electrodeposited on carbon nanoelectrodes (CNEs). Single Pt NCs were deposited onto the CNEs using an empirically developed square-wave potential program. Characterization by scanning electron microscopy indicates that the sizes of Pt NCs are remarkably reproducible (relative standard deviation = 6%). Electrochemically active surface areas, determined by Cu underpotential deposition and H adsorption/desorption analyses, are also reproducible. Selected area electron diffraction indicates that each Pt NC is comprised of just one single crystal (no grain boundaries). Although different square-wave potential programs lead to different types of crystals, the Pt NCs discussed here have a concave hexoctahedral geometry bound primarily by {13 6 2} surface facets. The results in this report represent a first step toward our ultimate goal of studying electrocatalysis at individual, shape-controlled, single-crystal nanoparticles. PMID- 29989126 TI - Conditioned medium from overly excitatory primary astrocytes induced by La3+ increases apoptosis in primary neurons via upregulating the expression of NMDA receptors. AB - Lanthanum (La) can accumulate in the brain and impair learning and memory. However, the underlying mechanism of La-induced neurotoxicity has remained elusive. Under physiological conditions, it has been reported that moderately excitatory astrocytes play an important role in the regulation of neuronal signals and synaptic plasticity. However, under pathological conditions, overly excitatory astrocytes can release excess excitatory transmitters, such as glutamate (Glu) and d-serine, and induce the over-activation of NMDA receptors (NMDAR) in neurons, ultimately leading to neuronal excitotoxicity. To date, limited work has been performed with respect to whether La can induce neuronal excitotoxicity by inducing astrocytes to become overexcited. In this study, in vitro models of primary culture rat cortical astrocytes and neurons were established. First, the astrocytes were treated with 0.125 mM, 0.25 mM and 0.5 mM lanthanum chloride (LaCl3) for 24 h, and the supernatants were collected as a conditioned medium (CM) which is denoted as CM (La3+); then, the neurons were treated with CM (La3+) for 48 h. The results illustrate that LaCl3 treatment significantly upregulated the mRNA and protein expression levels of metabotropic glutamate receptor 5 (mGLUR5), phospholipase C (PLC), connexin 43 (Cx43) and Cx30, increased the concentrations of inositol trisphosphate (IP3) and [Ca2+]i, and promoted the synthesis and release of Glu and d-serine in astrocytes. Moreover, the CM (La3+) could increase the mRNA and protein expression levels of NMDAR subunits (NR1, NR2A, NR2B), the concentration of [Ca2+]i and the rate of apoptosis in neurons. Furthermore, after removal of La, CM (La-free) had a similar effect on neurons which could be antagonized by MK-801, DCKA and DAAO. These results suggest that the neuron apoptosis induced by La is closely related to the excessive release of Glu and d-serine from overly excitatory astrocytes. PMID- 29989127 TI - Influence of outer-layer finite-size effects on the dewetting dynamics of a thin polymer film embedded in an immiscible matrix. AB - In capillary-driven fluid dynamics, simple departures from equilibrium offer the chance to quantitatively model the resulting relaxations. These dynamics in turn provide insight on both practical and fundamental aspects of thin-film hydrodynamics. In this work, we describe a model trilayer dewetting experiment elucidating the effect of solid, no-slip confining boundaries on the bursting of a liquid film in a viscous environment. This experiment was inspired by an industrial polymer processing technique, multilayer coextrusion, in which thousands of alternating layers are stacked atop one another. When pushed to the nanoscale limit, the individual layers are found to break up on time scales shorter than the processing time. To gain insight on this dynamic problem, we here directly observe the growth rate of holes in the middle layer of the trilayer films described above, wherein the distance between the inner film and solid boundary can be orders of magnitude larger than its thickness. Under otherwise identical experimental conditions, thinner films break up faster than thicker ones. This observation is found to agree with a scaling model that balances capillary driving power and viscous dissipation with a no-slip boundary condition at the solid substrate/viscous environment boundary. In particular, even for the thinnest middle-layers, no finite-size effect related to the middle film is needed to explain the data. The dynamics of hole growth is captured by a single master curve over four orders of magnitude in the dimensionless hole radius and time, and is found to agree well with predictions including analytical expressions for the dissipation. PMID- 29989128 TI - Osmotic pressure in polyelectrolyte solutions: cell-model and bulk simulations. AB - The osmotic pressure of polyelectrolyte solutions as a function of concentration has been calculated by Monte Carlo simulations of a spherical cell model and by molecular dynamics simulations with periodic boundary conditions. The results for the coarse-grained polyelectrolyte model are in good agreement with experimental results for sodium polyacrylate and the cell model is validated by the bulk simulations. The cell model offers an alternative perspective on osmotic pressure and also forms a direct link to even simpler models in the form of the Poisson Boltzmann approximation applied to cylindrical and spherical geometries. As a result, the non-monotonic behaviour of the osmotic coefficient seen in simulated salt-free solutions is shown not to rely on a transition between a dilute and semi-dilute regime, as is often suggested when the polyion is modelled as a linear flexible chain. The non-monotonic behaviour is better described as the combination of a finite-size effect and a double-layer effect. Parameters that represent the linear nature of the polyion, including an alternative to monomer concentration, make it possible to display a generalised behaviour of equivalent chains, at least at low concentrations. At high concentrations, local interactions become significant and the exact details of the model become important. The effects of added salt are also discussed and one conclusion is that the empirical additivity rule, treating the contributions from the polyelectrolyte and any salt separately, is a reasonable approximation, which justifies the study of salt-free solutions. PMID- 29989129 TI - Correlation between grafted nanoparticle-matrix polymer interface wettability and slip in polymer nanocomposites. AB - Controlling and understanding the flow properties of polymer nanocomposites (PNC) is very important in realising their potential for various applications. In this study we report molecular dynamics simulation studies of slip between a rotating polymer-grafted nanoparticle and the surrounding free linear matrix chains. By varying the interface wettability between the nanoparticle and matrix chains defined by the parameter f, the ratio of the graft to the matrix chain length, or the graft chain density, Sigma, we were able to tune the interface slip, delta, significantly. Both f and Sigma alter the interface wettability by changing the matrix chain penetration depth, lambda, into the graft chain layer. We observed a large value of delta at smaller f or Sigma which reduces with an increasing value of the respective parameters. Since interface slip is also likely to affect other properies of PNCs, like viscosity and the glass transition, we suggest that these parameters could become useful tools to control the flow and mechanical properties of PNCs made with grafted nanoparticles. PMID- 29989130 TI - TEMPO promoted direct multi-functionalization of terminal alkynes with 2 oxindoles/benzofuran-2(3H)-one. AB - Highly selective and catalyst-free tandem multi-functionalization of terminal alkynes was developed with 2-oxindoles and benzo-furan-2(3H)-one using TEMPO both as a radical promoter and a trapping reagent. This work expands the scope of the radical-cascade addition/trapping process of alkynes for the effective construction of various beta-oxyl carbonyls in moderate to good yields. PMID- 29989132 TI - Computational investigation of actuation mechanisms of droplets on porous air permeable substrates. AB - We study the actuation of droplets on porous substrates by air that permeates through pores. Air pockets are created between the droplets and the substrate which, eventually, incite the droplets to a quasi-moving state. We observe this mechanism computationally and verify it experimentally, using various case studies involving water droplets of different volume that are initially pinned on a porous substrate which has been set to different inclination levels and start to slide down when actuated by permeating air. The computational model employs the continuity equation and the equations of momentum transfer that are coupled with the Volume of Fluid (VOF) method, to track the shape of the droplet. We identify two dominant actuation mechanisms - seen in computations and experiments - that are given the names 'donut' and 'tunnel'. Both of them are characterized by the formation of small air pockets between the droplet and the substrate that coalesce into larger ones that finally escape the droplet, by collapsing its free surface. The two mechanisms differ in the way that the free surface of the droplet collapses. The donut mechanism has the free surface collapsing at its center, thus forming a hole in the middle of the droplet (hence the name, donut), whereas the tunnel mechanism has the free surface collapsing at its rear side, forming a horizontal hole that resembles a tunnel (hence the name). We compare each mechanism in terms of the event (mechanism) occurrence frequency and droplet displacement, and also provide the dependence of the droplet speed with respect to the flow rate of permeating air, substrate inclination and droplet volume. PMID- 29989133 TI - The influence of polyethylene glycol passivation on the surface plasmon resonance induced photothermal properties of gold nanorods. AB - Gold nanorods (AuNRs) possess unique photothermal properties due to their strong plasmonic absorption in the near-infrared region of the electromagnetic spectrum. They have been explored widely as an alternative or a complement to chemotherapy in cancer treatment. However, the use of AuNRs as an injectable medicine is greatly hindered by their stability in biological media. Therefore, studies have been focused on improving the stability of AuNRs by introducing biocompatible surface functionalizations such as polyethylene glycol (PEG) coatings. However, these coatings can affect heat conduction and alter their photothermal behavior. Herein, we studied how functionalization of AuNRs with PEG chains of different molecular weights determined the temperature distribution of suspensions under near-infrared irradiation, cell uptake in vitro, and hyperthermia-induced cytotoxicity. Thermogravimetric analysis of the PEG-conjugated AuNRs exhibited slightly different PEG mass fractions of 12.0%, 12.7%, and 18.5% for PEG chains with molecular weights of 2, 5, and 10 kDa, respectively, implying distinct structures for PEG brushes. When exposed to near-infrared radiation, we found greater temperatures and temperature gradients for longer PEG chains, while rapid aggregation was observed in unmodified (raw) AuNRs. The effect of the PEG coating on heat transport was investigated using molecular dynamics simulations, which revealed the atomic scale structure of the PEG brushes and demonstrated lower thermal conductivity for PEG-coated AuNRs than for unmodified AuNRs. We also characterized the uptake of the AuNRs into mouse melanoma cells in vitro and determined their ability to kill these cells when subjected to near-infrared radiation. For all PEG-coated AuNRs, exposure to 10 s of near-infrared radiation significantly reduced cell viability relative to unirradiated controls, with this viability further decreasing with increasing AuNR doses, indicating potential phototherapeutic effects. The 5 kDa PEG coating appeared to yield the best performance, yielding significant phototoxicity at even the lowest dose considered (0.5 MUg mL-1), while also exhibiting high colloidal stability, which could help in rational design consideration of AuNRs for NIR induced photothermal therapy. PMID- 29989134 TI - Automated crystal characterization with a fast neighborhood graph analysis method. AB - We present a significantly improved, very fast implementation of the Neighborhood Graph Analysis technique for template-free characterization of crystal structures [W. F. Reinhart et al., Soft Matter, 2017, 13, 4733]. By comparing local neighborhoods in terms of their relative graphlet frequencies, we reduce the computational cost by four orders of magnitude compared to the original stochastic method. Furthermore, we present protocols for the detection of topologically important structures and assignment of visually informative colors, providing a fully automated procedure for characterization of crystal structures from particle tracking data. We demonstrate the flexibility of our method on a wide range of crystal structures which have proven difficult to classify by previously available techniques. PMID- 29989135 TI - The role of surface charge in the interaction of nanoparticles with model pulmonary surfactants. AB - Inhaled nanoparticles traveling through the airways are able to reach the respiratory zone of the lungs. In such an event, the incoming particles first come into contact with the liquid lining the alveolar epithelium, the pulmonary surfactant. The pulmonary surfactant is composed of lipids and proteins that are assembled into large vesicular structures. The question of the nature of the biophysicochemical interaction with the pulmonary surfactant is central to understand how the nanoparticles can cross the air-blood barrier. Here we explore the phase behavior of sub-100 nm particles and surfactant substitutes under controlled conditions. Three types of surfactant mimetics, including the exogenous substitute Curosurf(r), a drug administered to infants with respiratory distress syndrome, are tested together with aluminum oxide (Al2O3), silicon dioxide (SiO2) and polymer (latex) nanoparticles. The main result here is the observation of spontaneous nanoparticle-vesicle aggregation induced by coulombic attraction. The role of the surface charges is clearly established. We also evaluate the supported lipid bilayer formation recently predicted and find that in the cases studied these structures do not occur. Pertaining to the aggregate internal structure, fluorescence microscopy shows that the vesicles and particles are intermixed at the nano- to microscale. With particles acting as stickers between vesicles, it is anticipated that the presence of inhaled nanomaterials in the alveolar spaces could significantly modify the interfacial and bulk properties of the pulmonary surfactant and interfere with lung physiology. PMID- 29989136 TI - In silico study of Bombyx mori fibroin enhancement by graphene in acidic environment. AB - Bombyx mori fibroin has been widely used since a long time ago and has become a popular material. Here, we carry out a molecular dynamics simulation-based docking simulation of a small fragment of graphene in order to seek the best binding position on the N-termini domain of Bombyx mori fibroin. We report the best binding position, of which binding free energy falls at -54.8 kJ mol-1, indicating the strong binding. The further analysis of the binding pathway shows that this position is selective for single layered graphene rather than multi layered graphene within our limited simulation times. Via comparing the RAMAN spectra of the corresponding binding pose of atomic clusters, we report the change in the bands compared with free standing graphene fragments, implying the change in molecular orbitals. PMID- 29989138 TI - CS2 capture in the ionic liquid 1-alkyl-3-methylimidazolium acetate: reaction mechanism and free energetics. AB - Reaction pathways for CS2 and COS in the ionic liquid, 1-ethyl-3 methylimidazolium (EMI+) acetate (OAc-), are studied using the ab initio self consistent reaction field theory (SCRF) and molecular dynamics (MD) computer simulations. It is found that while CS2 converts to COS nearly at the 100% level through S/O exchange with acetate, both conversion and capture processes are kinetically possible for COS, yielding CO2/thioacetate and 1-ethyl-3 methylimidazole-2-thiocarboxylate (EMI-COS)/acetic acid as reaction products, respectively. These findings are in excellent agreement with recent experimental observations in the closely related 1-butyl-3-methylimidazolium acetate (BMI+OAc ) ionic liquid system. Constrained ab initio MD indicates that the capture reaction of COS (and CS2 if allowed) proceeds in a concerted fashion; viz., proton transfer from EMI+ to OAc- and carboxylation of EMI+ by COS (and CS2) occur concurrently, analogous to the concerted pathway proposed recently for CO2 capture in the imidazolium acetate ionic liquid family. As N-heterocyclic carbene (NHC) is not required, the concerted mechanism is fully consistent with the experimental fact that NHC has not been detected directly in this ionic liquid family. Computational analysis further predicts that if NHC would be present in the ionic liquid, it would react with CS2 and produce 1-ethyl-3-imidazole-2 dithiocarboxylate, prior to the conversion of CS2 to COS. Since such a dithiocarboxylate compound was not detected experimentally, the present analysis lends support to the view that NHC is not formed in the pure imidazolium acetate ionic liquid family. PMID- 29989139 TI - Defects in orthorhombic LaMnO3 - ionic versus electronic compensation. AB - The ionic and electronic conductivity of orthorhombic LaMnO3 can be modified by introducing lower valence dopants at both the La and Mn sites. Alkaline earth doped perovskites, such as LaMnO3, have a variety of applications in catalysis, for nitrogen storage and reduction, and oxidation of volatile organic compounds, and as the oxygen electrode in solid oxide fuel cells. Here, we investigate doping with the divalent alkaline earth metals Mg, Ca, Sr and Ba, and the charge compensation mechanism. The energies of formation of isolated defects and clustered pairs were investigated at both La and Mn sites to establish the most probable site at which they will be introduced. The charge compensation mechanism for the introduction of alkaline earth dopants was examined by considering both ionic (formation of an oxygen vacancy for every two alkaline earth dopants introduced) and electronic compensation (a hole localised at the Mn site for each dopant introduced). Larger cations (Ca, Sr and Ba) were found to have lower defect formation energies when introduced at the La site, while the smaller Mg defect had lower formation energies when introduced to the Mn site. For all defects introduced, electronic compensation for the defect was found to be more energetically favourable, which will result in improved electronic conductivity of the material. PMID- 29989140 TI - Applicability of a linear diffusion model to determination of the height of the potential barrier at the grain boundaries of Fe-doped SrTiO3. AB - The potential barrier formed at the grain boundaries in Fe-doped SrTiO3 is reported to be one of the main reasons of the exceptionally large grain boundary resistivity of the material. Of particular interest is thus how to accurately quantify the potential barrier height, Psigb, in such electronic conductors. This study aims to expand the applicability of a linear diffusion model (namely I-V model) to electronic conductors. The I-V model has previously proven its success in accurate determination of Psigb in popular ionic conductors. By employing 1 mol% Fe-doped SrTiO3 as a model material, the current-voltage characteristics of the grain boundary investigated demonstrate the power law behavior predicted by the I-V model, verifying the applicability of this model. The Psigb estimated from the I-V model at different temperatures are compared with those from the resistivity ratio of the grain boundary to the bulk. The resistivity ratio has been exclusively used to determine Psigb in various conductors over several decades and yet has limitations in its accuracy. The Psigb determined by the I-V model are found to be substantially lower than those from the resistivity ratio; such discrepancy implies that the potential barrier only partially contributes to the high grain boundary resistivity of a lightly doped electron-hole conducting SrTiO3. PMID- 29989143 TI - Autophagy related markers (Beclin-1 and ATG4B) are strongly expressed in Wilms' tumor and correlate with favorable histology. AB - BACKGROUND: Wilms' tumor treatment has achieved great success in the last decade. Nevertheless, some cases still fail to respond to the current multimodality therapy. These cases fall mainly in the unfavorable histology group with very few belonging to the favorable histology group. In recent years, autophagy manipulation whether inhibition or stimulation has been shown to affect cancer cell behavior and has emerged as a novel mechanism to improve cancer cell response to currently used therapeutic regimens. OBJECTIVE: The current study aimed to investigate the expression of autophagy related markers (ATG4B and Beclin1) in WT, its association with the different clinic-pathological parameters and its impact on patient survival. METHODS: Twenty-one formalin fixed paraffin embedded (FFPE) WT specimens were immunohistochemically stained using autophagy related markers; Beclin-1 and ATG- 4b. All clinical, radiological and follow up data were retrieved from the patient records. RESULTS: All specimens showed positive expression of both Beclin-1 and ATG4B. The staining score for Beclin1 varied between 50 and 300, and its expression was significantly associated with favorable histology (p=0.007). Similarly, ATG-4B expression was significantly higher in favorable histology tumors compared to unfavorable histology (p=0.046). A statistically significant positive correlation between Beclin-1 and ATG4 expression was observed. The cumulative disease-free survival in patients with favorable histology was significantly higher compared to patients with unfavorable histology (p=0.0027). CONCLUSIONS: Beclin-1 and ATG4B expression were both found to be statistically significant discriminators of survival. Collectively these findings suggest that the expression of autophagy-related markers is associated with a favorable histology and could predict better survival in these patients. PMID- 29989144 TI - Association of Anaesthetists guidelines: cell salvage for peri-operative blood conservation 2018. AB - The use of cell salvage is recommended when it can be expected to reduce the likelihood of allogeneic (donor) red cell transfusion and/or severe postoperative anaemia. We support and encourage a continued increase in the appropriate use of peri-operative cell salvage and we recommend that it should be available for immediate use 24 h a day in any hospital undertaking surgery where blood loss is a recognised potential complication (other than minor/day case procedures). PMID- 29989145 TI - Filter-based isolation, enrichment, and characterization of circulating tumor cells. AB - Isolation of circulating tumor cells (CTCs) from blood has long been a challenge due to the rarity and heterogeneity of these cells. Detection technologies have predominantly focused on different molecular or physical properties of CTCs. Size based isolation approach using microfilters have been widely used to capture CTCs because of the difference in size and stiffness of the cells compared to other hemocytes. Isolation of rare cells based on their size was the original CTC enrichment technique and it demonstrated a simple yet rapid method that enhanced the recovery of cells with high throughput. In this review, we highlight key technical aspects of filter-based isolation, detection, and characterization of CTCs, and compare the clinical performance of filter-based devices with the approved platforms and immunoassays used for the analysis of CTCs. We have also discussed future prospective and incorporation of advances in immunochemistry technique into the filter-based platforms for enhancing the utility in clinical settings. PMID- 29989146 TI - PHYLACINE 1.2: The Phylogenetic Atlas of Mammal Macroecology. AB - Data needed for macroecological analyses are difficult to compile and often hidden away in supplementary material under non-standardized formats. Phylogenies, range data, and trait data often use conflicting taxonomies and require ad hoc decisions to synonymize species or fill in large amounts of missing data. Furthermore, most available data sets ignore the large impact that humans have had on species ranges and diversity. Ignoring these impacts can lead to drastic differences in diversity patterns and estimates of the strength of biological rules. To help overcome these issues, we assembled PHYLACINE, The Phylogenetic Atlas of Mammal Macroecology. This taxonomically integrated platform contains phylogenies, range maps, trait data, and threat status for all 5,831 known mammal species that lived since the last interglacial (~130,000 years ago until present). PHYLACINE is ready to use directly, as all taxonomy and metadata are consistent across the different types of data, and files are provided in easy to-use formats. The atlas includes both maps of current species ranges and present natural ranges, which represent estimates of where species would live without anthropogenic pressures. Trait data include body mass and coarse measures of life habit and diet. Data gaps have been minimized through extensive literature searches and clearly labelled imputation of missing values. The PHYLACINE database will be archived here as well as hosted online so that users may easily contribute updates and corrections to continually improve the data. This database will be useful to any researcher who wishes to investigate large scale ecological patterns. Previous versions of the database have already provided valuable information and have, for instance, shown that megafauna extinctions caused substantial changes in vegetation structure and nutrient transfer patterns across the globe. PMID- 29989147 TI - Cortical morphology, epileptiform discharges, and neuropsychological performance in BECTS. AB - OBJECTIVES: The aim of this study was to understand the relationship between cortical morphology, centrotemporal spike (CTS), and neuropsychological functioning in children with BECTS compared to their typically developing peers. MATERIALS AND METHODS: To examine whole-brain differences in cortical thickness between groups, a general linear model approach was applied to T1-weighted structural magnetic resonance imaging (MRI) in children with BECTS and typically developing children. Further region-of-interest (ROI) analyses were performed to examine the effects of frequency and lateralization of CTS. In addition, the relationship between Processing Speed Index (PSI) and cortical thickness was investigated. RESULTS: Twenty-three patients with BECTS and thirty-two controls were included. There was no statistically significant difference in global cortical thickness between groups. With ROI analyses, we found significantly thinner cortex within right pars opercularis when comparing children with right predominant CTS, and with very frequent right CTS (>10/min) to the control group (P = 0.028 and P = 0.026, respectively). A statistically significant interaction of group (controls vs BECTS) and PSI was seen in bilateral frontal and right superior parietal cortices, indicating a positive relationship between cortical thickness and PSI in healthy controls but not BECTS. CONCLUSION: A region of cortex where right CTS may originate was thinner in BECTS compared to children without BECTS. Typically developing children with faster processing speed had thicker cortices in regions supporting visuomotor integration, motor, and executive function, but this relationship was not observed in BECTS. These results suggest that BECTS is associated with atypical cortical morphology that may underlie poorer neuropsychological performance. PMID- 29989148 TI - Bringing the Real World Into Developmental Science: A Commentary on Weber, Fernald, and Diop (2017). AB - This article examines the parent intervention program evaluated by Weber et al. (2017) and argues that there are scientific and ethical problems with such intervention efforts in applied developmental science. Scientifically, these programs rely on data from a small and narrow sample of the world's population; assume the existence of fixed developmental pathways; and pit scientific knowledge against indigenous knowledge. The authors question the critical role of talk as solely providing the rich cognitive stimulation important to school success, and the critical role of primary caregivers as teachers of children's verbal competency. Ethically, these programs do not sufficiently explore how an intervention in one aspect of child care will affect the community's culturally organized patterns of child care. PMID- 29989149 TI - In situ biodistribution and residency of a topical anti-inflammatory using fluorescence lifetime imaging microscopy. AB - BACKGROUND: GSK2894512 is a topically delivered investigational drug being developed for treatment of atopic dermatitis and psoriasis. OBJECTIVES: To investigate, in a phase I clinical trial, the spatial biodistribution and residency of GSK2894512 within the epidermis and dermis of healthy human participants noninvasively using fluorescence lifetime imaging microscopy (FLIM). METHODS: Two topical drug formulations containing GSK2894512 1% were applied to the right and left forearms of six participants for seven consecutive days, followed by seven days of observation for residency. FLIM images were obtained daily throughout the study, approximately every 24 h. During the treatment phase of the study, images were collected from each participant pretreatment, reflecting the residual dose from the previous day. Three punch biopsies from each participant of one formulation was obtained from the treated region during the post-treatment follow-up period between days 8 and 14 for comparison with FLIM results. RESULTS: Cellular and subcellular features associated with different epidermal and dermal layers were visualized noninvasively, down to a depth of 200 MUm. Results yielded three-dimensional maps of GSK2894512 spatial distribution and residency over time. This fluorescence data provided a marker that was used as a monitor for day-to-day variance of drug presence and residency postapplication. CONCLUSIONS: The results suggest FLIM could be a viable alternative to skin biopsies without the usual patient discomfort and limitations, thereby enabling the direct measurement of skin distribution through longitudinal monitoring. These results are the first step in establishing the unique capabilities that multiphoton imaging could provide to patients through noninvasive drug detection. PMID- 29989150 TI - LRRK2 G2019S Parkinson's disease with more benign phenotype than idiopathic. AB - OBJECTIVES: The LRRK2-G2019S mutation is the most common cause of Parkinson's disease (PD) in North Africa. G2019S-PD has been described as similar to idiopathic with minor clinical differences. The aim of this study was to determine the G2019S-related phenotype and to investigate gender and gene dosage effects on clinical features of G2019S carriers. PATIENTS AND METHODS: The G2019S mutation was screened in 250 Tunisian patients with PD. Twenty-four patients carrying mutations in other PD genes were excluded. Logistic regression models were used to compare clinical features between the studied groups. RESULTS: G2019S carriers (107 cases) and non-carriers (119 cases) were similar in disease duration, levodopa doses, and gender and phenotype distributions. However, carriers had a younger age at examination, higher level of education, and were more likely to report family history of PD and to develop PD at earlier age (P = 0.017). Adjusted for age, sex, disease duration, levodopa-equivalent dose and educational level, MMSE scores remained significantly higher (adjust P = 0.019) and UPDRS-III scores were lower (adjust P = 0.012) in the G2019S carriers than non-carriers. Demographic characteristics of men and women with G2019S mutation were similar, but men had higher level of education, better cognition (adjust P value for educational level = 0.042) and less tendency towards depression than females (adjust P = 0.046). Furthermore, PD phenotype did not differ between the homozygous and heterozygous G2019S carriers. CONCLUSION: In this study, G2019S carriers had a more benign phenotype than non-carriers. Cognitive impairment and depression were less common in G2019S male carriers compared with females. In addition, we found that LRRK2 gene dosage does not influence the severity of PD. PMID- 29989151 TI - A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) affects children of all skin types. Most research has focused on light skin types. Studies investigating biomarkers in people with AD with dark skin types are lacking. OBJECTIVES: To explore skin barrier and immune response biomarkers in stratum corneum (SC) tape strips from children with AD with different skin types. METHODS: Tape strips were collected from lesional and nonlesional forearm skin of 53 children with AD and 50 controls. We analysed 28 immunomodulatory mediators, and natural moisturizing factors (NMF) and corneocyte morphology. RESULTS: Interleukin (IL)-1beta, IL-18, C-X-C motif chemokine (CXCL) 8 (CXCL8), C-C motif chemokine ligand (CCL) 22 (CCL22), CCL17, CXCL10 and CCL2 were significantly higher (P < 0.05) in lesional AD skin compared with nonlesional AD skin; the opposite trend was seen for IL 1alpha. CXCL8, CCL2 and CCL17 showed an association with objective SCORing Atopic Dermatitis score. NMF levels showed a gradual decrease from healthy skin to nonlesional and lesional AD skin. This gradual decreasing pattern was observed in skin type II but not in skin type VI. Skin type VI showed higher NMF levels in both nonlesional and lesional AD skin than skin type II. Corneocyte morphology was significantly different in lesional AD skin compared with nonlesional AD and healthy skin. CONCLUSIONS: Minimally invasive tape-stripping is suitable for the determination of many inflammatory mediators and skin barrier biomarkers in children with AD. This study shows differences between children with AD with skin type II and skin type VI in NMF levels, suggesting that some aspects of pathophysiological mechanisms may differ in AD children with light versus dark skin types. PMID- 29989152 TI - Transplantation of photoreceptor precursor cells into the retina of an adult Drosophila. AB - Blindness caused by the disconnection between photoreceptor cells and the brain can be cured by restoring this connection through the transplantation of retinal precursor neurons. However, even after transplanting these cells, it is still unclear how to guide the axons over the long distance from the retina to the brain. To establish a method of guiding the axons of transplanted neurons, we used the Drosophila visual system. By testing different conditions, including the dissociation and preincubation length, we have successfully established a method to transplant photoreceptor precursor cells isolated from the developing eye discs of third-instar larvae into the adult retina. Moreover, we overexpressed N cadherin (CadN) in the transplant, since it is known to be broadly expressed in the optic lobe well after developmental stages, continuing through adult stages. We found that promoting the cell adhesive properties using CadN enhances the axonal length of the grafted photoreceptor neurons and therefore is useful for future transplantation. We tested the overexpression of a CadN::Frazzled chimeric receptor and found that there was no difference in axonal length from our wild type transplants, suggesting that the intracellular domain of CadN is necessary for axonal elongation. Altogether, using the Drosophila visual system, we have established an excellent platform for exploring the molecules required for proper axon extension of transplanted neuronal cells. Future studies building from this platform will be useful for regenerative therapy of the human nervous system based on transplantation. PMID- 29989153 TI - Behavioral treatment of automatically reinforced SIB: 1982 - 2015. AB - Some individuals diagnosed with intellectual and developmental disabilities engage in automatically reinforced self-injurious behavior (SIB). For these individuals, identifying effective treatments may be difficult due to the nature of the reinforcement contingency. The purpose of this study was to review the literature on the treatment of automatically reinforced SIB to determine commonalities in procedures that produced effective and ineffective treatment outcomes, as well as historical trends in the treatment of this class of SIB. Results of this review indicated that there were many high-quality studies on this topic, but also a wide range in the quality of studies. As for effective treatments, noncontingent reinforcement (the most common treatment component) was found to be more effective when informed by a competing stimulus assessment rather than a preference assessment. Suggestions to improve the quality of the published record and areas in which additional research is needed are discussed. PMID- 29989154 TI - Using metabolic and thermal ecology to predict temperature dependent ecosystem activity: a test with prairie ants. AB - As ecosystems warm, ectotherm consumer activity should also change. Here we use principles from metabolic and thermal ecology to explore how seasonal and diel temperature change shapes a prairie ant community's foraging rate and its demand for two fundamental resources: salt and sugar. From April through October 2016 we ran transects of vials filled with solutions of 0.5% NaCl and 1% sucrose. We first confirm a basic prediction rarely tested: the discovery rate of both food resources accelerated with soil temperature, but this increase was typically capped at midday due to extreme surface temperatures. We then tested the novel prediction that sodium demand accelerates with temperature, premised on a key thermal difference between sugar and sodium: sugar is stored in cells, while salt is pumped out of cells proportional to metabolic rate, and hence temperature. We found strong support for the resulting prediction that recruitment to NaCl baits accelerates with temperature more steeply than recruitment to 1% sucrose baits. A follow up experiment in 2017 verified that temperature-dependent recruitment to sucrose concentrations of 20% (mimicking rich extrafloral nectaries), while noisy, was still only half as temperature dependent as recruitment recorded for 0.5% NaCl. These results demonstrate how ecosystem warming accelerates then curtails the work done by a community of ectotherms, and how the demand and use of fundamental nutrients can be differentially temperature dependent. PMID- 29989155 TI - The role of within-class consensus on mastery goal structures in predicting socio emotional outcomes. AB - BACKGROUND: Within-class consensus on mastery goal structures describes the extent to which students agree in their perceptions of mastery goal structures. Research on (work) teams suggests that higher levels of consensus within a group indicate a well-functioning social environment and are thus positively related to beneficial socio-emotional outcomes. However, the potential of within-class consensus to predict socio-emotional outcomes has not yet been explored in research on mastery goal structures. AIMS: This study aimed to test whether within-class consensus on the three mastery goal structures dimensions of task, autonomy, and recognition/evaluation has predictive power for socio-emotional outcomes in terms of classroom climate, negative classmate reactions to errors, and cooperative learning. SAMPLE: A total of 1,455 Austrian secondary school students (65.70% female) in 157 classrooms participated in this study. METHODS: Students responded to items measuring their perceptions of mastery goal structures, classroom climate, error climate, and cooperative learning. Items assessing mastery goal structures, error climate, and cooperative learning referred to the subject of mathematics and items assessing classroom climate referred to positive classmate relations without focusing on a subject. RESULTS: Results from multilevel structural equation models revealed that within-class consensus on all mastery goal structures dimensions predicted a less negative error climate. Additionally, consensus regarding task and autonomy predicted more frequent use of cooperative learning strategies, and consensus regarding task predicted a more positive classroom climate. CONCLUSIONS: Our findings show that higher levels of within-class consensus on mastery goal structures enhance beneficial socio-emotional outcomes. Moreover, the results emphasize the value of expanding the scope of educational research to the study of within-class consensus. PMID- 29989156 TI - Conservative management of placental invasion anomalies with an intracavitary suture technique. AB - OBJECTIVE: To assess the efficacy and safety of a new surgical suture technique for uterine preservation among patients with placental invasion anomalies. METHODS: The present prospective case series included women diagnosed with placental invasion anomalies undergoing cesarean deliveries who desired future fertility at the obstetrics department of a Turkish university hospital between January 10, 2013, and April 20, 2017. Patients were diagnosed with ultrasonography and Doppler ultrasonography; the type of placental invasion anomaly (placenta accreta, increta, or percreta) was confirmed intraoperatively. Surgical management involved an intracavitary suture technique after the proximal branch of the uterine artery was clamped and utero-ovarian anastomoses had been blocked. Outcomes included units of blood transfused, intraoperative and postoperative adverse events, duration of hospital admission, and hysterectomy rate. RESULTS: There were 62 patients included. The mean operative blood loss was 1350 +/- 750 mL (range 600-5000 mL). Blood transfusion required a mean of four units (range 2-15). Bleeding was controlled with the intracavitary sutures in 58 (94%) patients. Three patients experienced postoperative wound infections and two patients developed endometritis that required therapy with broad-spectrum antibiotics. The mean length of hospital stay was 3.6 +/- 1.6 days (range 2-11). None of the patients required reoperation after the initial surgery. CONCLUSION: The novel uterus-sparing suture technique was highly effective among patients with placental invasion anomalies. PMID- 29989157 TI - Detection of Tooth-Colored Restorative Materials for Forensic Purposes Based on Their Optical Properties: An In Vitro Comparative Study. AB - Victim identification using dental records involves antemortem and postmortem comparison of dental charts. Since dental restorations may be part of such records, identifying them accurately is critical. The objective of this study was to compare the diagnostic reliability and validity of two optical methods for identifying tooth-colored restorations (digital imaging fiber optic transillumination (DiFOTI) using near infrared light, and fluorescence-aided identification of restorations (FAIR)) with conventional diagnostic methods. Four examiners identified and charted tooth-colored restorations in three sets of typodonts on the bench using conventional visual and tactile examination, DiFOTI (DIAGNOcamTM) and FAIR. All examinations were repeated after 4 weeks. Both the sensitivity (95%) and specificity (97%) of the FAIR method were significantly higher than those for DiFOTI (82% and 82%) and for conventional inspection (71% and 82%). In conclusion, FAIR method performed better than conventional examination and DiFOTI, and was more reliable for identifying tooth-colored restorations. PMID- 29989159 TI - The cost of deep sleep: Environmental influences on sleep regulation are greater for diurnal lemurs. AB - OBJECTIVES: Primates spend almost half their lives asleep, yet we know little about how evolution has shaped variation in the duration or intensity of sleep (i.e., sleep regulation) across primate species. Our objective was to test hypotheses related to how sleeping site security influences sleep intensity in different lemur species. METHODS: We used actigraphy and infrared videography to generate sleep measures in 100 individuals (males = 51, females = 49) of seven lemur species (genera: Eulemur, Lemur, Propithecus, and Varecia) at the Duke Lemur Center in Durham, NC. We also generated experimental data using sleep deprivation for 16 individuals. This experiment used a pair-wise design for two sets of paired lemurs from each genus, where the experimental pair experienced a sleep deprivation protocol while the control experienced normal sleeping conditions. We calculated a sleep depth composite metric from weighted z scores of three sleep intensity variables. RESULTS: We found that, relative to cathemeral lemurs, diurnal Propithecus was characterized by the deepest sleep and exhibited the most disruptions to normal sleep-wake regulation when sleep deprived. In contrast, Eulemur mongoz was characterized by significantly lighter sleep than Propithecus, and E. mongoz showed the fewest disruptions to normal sleep-wake regulation when sleep deprived. Security of the sleeping site led to greater sleep depth, with access to outdoor housing linked to lighter sleep in all lemurs that were studied. CONCLUSIONS: We propose that sleeping site security was an essential component of sleep regulation throughout primate evolution. This work suggests that sleeping site security may have been an important factor associated with the evolution of sleep in early and later hominins. PMID- 29989158 TI - Nocturnal activity in wild chimpanzees (Pan troglodytes): Evidence for flexible sleeping patterns and insights into human evolution. AB - OBJECTIVES: We investigated occurrences and patterns of terrestrial nocturnal activity in wild chimpanzees (Pan troglodytes) and modelled the influence of various ecological predictors on nocturnal activity. METHODS: Data were extracted from terrestrial camera-trap footage and ecological surveys from 22 chimpanzee study sites participating in the Pan African Programme: The Cultured Chimpanzee. We described videos demonstrating nocturnal activity, and we tested the effects of the percentage of forest, abundance of predators (lions, leopards and hyenas), abundance of large mammals (buffalos and elephants), average daily temperature, rainfall, human activity, and percent illumination on the probability of nocturnal activity. RESULTS: We found terrestrial nocturnal activity to occur at 18 of the 22 study sites, at an overall average proportion of 1.80% of total chimpanzee activity, and to occur during all hours of the night, but more frequently during twilight hours. We found a higher probability of nocturnal activity with lower levels of human activity, higher average daily temperature, and at sites with a larger percentage of forest. We found no effect of the abundance of predators and large mammals, rainfall, or moon illumination. DISCUSSION: Chimpanzee terrestrial nocturnal activity appears widespread yet infrequent, which suggests a consolidated sleeping pattern. Nocturnal activity may be driven by the stress of high daily temperatures and may be enabled at low levels of human activity. Human activity may exert a relatively greater influence on chimpanzee nocturnal behavior than predator presence. We suggest that chimpanzee nocturnal activity is flexible, enabling them to respond to changing environmental factors. PMID- 29989161 TI - Temporal patterns of chimpanzee loud calls in the Issa Valley, Tanzania: Evidence of nocturnal acoustic behavior in wild chimpanzees. AB - OBJECTIVES: Much is known about chimpanzee diurnal call patterns, but far less about night-time vocal behavior. I deployed a passive acoustic monitoring (PAM) system to assess 24-hr temporal acoustic activity of wild, unhabituated chimpanzees that live in a woodland mosaic habitat similar to hominin landscapes from the Plio-Pleistocene. A primary aim was to apply findings to our broader understanding to chimpanzee 24-hr activity patterns, and what implications this may have for reconstructing hominin adaptations to similarly hot, dry, and open landscapes. I also tested whether chimpanzees conform to the acoustic adaptation hypothesis, and produce loud calls during periods of optimal sound transmission. METHODS: Nine custom-made solar-powered acoustic transmission units (SPATUs) recorded continuously for 250 days over 11 months in the Issa Valley, western Tanzania. I complemented acoustic data with environmental data from weather stations as well as behavioral data collected on chimpanzee nest group sizes to assess the relationship between party size and calling. RESULTS: Chimpanzees called at all hours of the day and night in both wet and dry seasons, and night and day calls exhibited parallel rates/month, although twilight calls were produced significantly more in the dry, compared to the wet season. Calls were more likely during warmer temperatures and lower humidity. Call rate was positively associated with (nest) party size and counter-calls exhibited no temporal variation in their origins (similar vs. adjacent valleys). CONCLUSIONS: Chimpanzees were acoustically active throughout the 24-hr cycle, although at low rates compared to diurnal activity, revealing night-time activity in an ape otherwise described as diurnal. Chimpanzee loud calls partially, and weakly, conformed to the acoustic adaptation hypothesis and likely responded to social, rather than environmental factors. Call rates accurately reflect grouping patterns and PAM is demonstrated to be an effective means of remotely assessing activity, especially at times and from places that are difficult to access for researchers. PMID- 29989160 TI - Sleep patterns, daytime predation, and the evolution of diurnal sleep site selection in lorisiforms. AB - OBJECTIVES: Synthesize information on sleep patterns, sleep site use, and daytime predation at sleep sites in lorisiforms of Asia and Africa (10 genera, 36 species), and infer patterns of evolution of sleep site selection. MATERIALS AND METHODS: We conducted fieldwork in 12 African and six Asian countries, collecting data on sleep sites, timing of sleep and predation during daytime. We obtained additional information from literature and through correspondence. Using a phylogenetic approach, we established ancestral states of sleep site selection in lorisiforms and traced their evolution. RESULTS: The ancestral lorisiform was a fur-clinger and used dense tangles and branches/forks as sleep sites. Use of tree holes and nests as sleep sites emerged ~22 Mya (range 17-26 Mya) in Africa, and use of bamboo emerged ~11 (7-14) Mya in Asia and later in Africa. Fur clinging and some sleep sites (e.g., tree holes, nests, but not bamboo or dense tangles) show strong phylogenetic signal. Nests are used by Galagoides, Paragalago, Galago and Otolemur; tree holes by Galago, Paragalago, Sciurocheirus and Perodicticus; tangles by Nycticebus, Loris, Galagoides, Galago, Euoticus, Otolemur, Perodicticus and Arctocebus; all but Sciurocheirus and Otolemur additionally sleep on branches/forks. Daytime predation may affect sleep site selection and sleep patterns in some species of Nycticebus, Galago, Galagoides, Otolemur and Perodicticus. Most lorisiforms enter their sleep sites around sunrise and leave around sunset; several are active during twilight or, briefly, during daytime. CONCLUSION: Variations in sleep behavior, sleep patterns and vulnerability to daytime predation provide a window into the variation that was present in sleep in early primates. Overall, lorisiforms use the daytime for sleeping and no species can be classified as cathemeral or polycyclic. PMID- 29989162 TI - Savanna chimpanzees adjust sleeping nest architecture in response to local weather conditions. AB - OBJECTIVES: Great ape nests are hypothesized to aid safe, secure sleep via providing thermoregulation or protection from predators and vectors. We aimed to describe and investigate variation in chimpanzee nest architecture across two populations in response to local weather conditions. MATERIALS AND METHODS: We experimentally tested whether nests provide insulation by measuring heat loss within and outside nests, and took detailed measurements of the number, size, and type of materials used in nest building across two dry-habitat research sites (Fongoli, Senegal, and Issa, Tanzania). We tested application of principal components analysis (PCA) to extract composite quantitative measures of the key components of shape and architecture, before testing how PCs vary across populations with overnight weather conditions that reflect hypothesized thermoregulatory function. RESULTS: Heat loss is greater and occurs faster outside of nests. PCA allowed meaningful comparison of nests within and between sites. Nest variation at both sites revealed chimpanzees built thicker nests in cooler conditions and used more broken branches and support in moister conditions. Chimpanzees in Fongoli used more lining and mattress material in colder conditions, whilst in Issa nest depth and support branch size were larger in windier conditions. DISCUSSION: Shape and architectural measures reflected insulation and stability of nest structure. Chimpanzees in Fongoli and Issa may achieve the same functional goals by adjusting nest shape and architecture in different ways. These results suggest that wild chimpanzees show flexible building techniques in response to local, overnight weather conditions in making an insulating and stable, supportive platform for sleep. PMID- 29989163 TI - Sleep variability and nighttime activity among Tsimane forager-horticulturalists. AB - OBJECTIVES: A common presumption in sleep research is that "normal" human sleep should show high night-to-night consistency. Yet, intra-individual sleep variation in small-scale subsistence societies has never been studied to test this idea. In this study, we assessed the degree of nightly variation in sleep patterns among Tsimane forager-horticulturalists in Bolivia, and explored possible drivers of the intra-individual variability. METHODS: We actigraphically recorded sleep among 120 Tsimane adults (67 female), aged 18-91, for an average of 4.9 nights per person using the Actigraph GT3X and Philips Respironics Actiwatch 2. We assessed intra-individual variation using intra-class correlations and average deviation from each individual's average sleep duration, onset, and offset times ( E-). RESULTS: Only 31% of total variation in sleep duration was due to differences among different individuals, with the remaining 69% due to nightly differences within the same individuals. We found no statistically significant differences in Tsimane sleep duration by day-of-the week. Nightly variation in sleep duration was driven by highly variable sleep onset, especially for men. Nighttime activities associated with later sleep onset included hunting, fishing, housework, and watching TV. CONCLUSIONS: In contrast to nightly sleep variation in the United States being driven primarily by "sleeping-in" on weekends, Tsimane sleep variation, while comparable to that observed in the United States, was driven by changing "bedtimes," independent of day-of-the-week. We propose that this variation may reflect adaptive responses to changing opportunity costs to sleep/nighttime activity. PMID- 29989165 TI - FIGO-IDF joint statement and declaration on hyperglycemia in pregnancy. PMID- 29989164 TI - Sleep and nesting behavior in primates: A review. AB - Sleep is a universal behavior in vertebrate and invertebrate animals, suggesting it originated in the very first life forms. Given the vital function of sleep, sleeping patterns and sleep architecture follow dynamic and adaptive processes reflecting trade-offs to different selective pressures. Here, we review responses in sleep and sleep-related behavior to environmental constraints across primate species, focusing on the role of great ape nest building in hominid evolution. We summarize and synthesize major hypotheses explaining the proximate and ultimate functions of great ape nest building across all species and subspecies; we draw on 46 original studies published between 2000 and 2017. In addition, we integrate the most recent data brought together by researchers from a complementary range of disciplines in the frame of the symposium "Burning the midnight oil" held at the 26th Congress of the International Primatological Society, Chicago, August 2016, as well as some additional contributors, each of which is included as a "stand-alone" article in this "Primate Sleep" symposium set. In doing so, we present crucial factors to be considered in describing scenarios of human sleep evolution: (a) the implications of nest construction for sleep quality and cognition; (b) the tree-to-ground transition in early hominids; (c) the peculiarities of human sleep. We propose bridging disciplines such as neurobiology, endocrinology, medicine, and evolutionary ecology, so that future research may disentangle the major functions of sleep in human and nonhuman primates, namely its role in energy allocation, health, and cognition. PMID- 29989166 TI - Functional groups differ in trait means, but not in trait plasticity to species richness in local grassland communities. AB - Despite growing interest in incorporating intraspecific variation of functional traits in community-level studies, it remains unclear whether species classified into functional groups based on interspecific trait differences are similar regarding their variation in trait expression in response to varying plant diversity and composition in local communities. In a large biodiversity experiment (Jena Experiment) designed on a trait-based a priori definition of functional groups (grasses, legumes, small herbs, tall herbs), we studied means, extent of variation (coefficient of variation across communities) and plasticity to increased plant diversity (slopes over a logarithmic species richness ranging from 1, 2, 4, 8 and 16 to 60 species) for nine functional traits. Species means and extent of variation in traits related to nitrogen (N) acquisition and N use differed among functional groups and were more similar in phylogenetically closely related species than expected by chance. Species in the same functional group showed a weak phylogenetic signal and varied widely in means and extent of variation in traits related to shoot architecture and to a smaller extent in leaf traits related to carbon acquisition. This indicated that functional groups were less distinguishable in light than in nitrogen acquisition strategies. The direction and degree of trait plasticity to increasing species richness did not show a phylogenetic signal and were not different among functional groups, but varied largely among species within functional groups. Correlation structures in trait means, extent of trait variation and trait plasticity revealed functional tradeoffs in the acquisition of nitrogen and light across species. While correlations between trait means and extent of trait variation varied from trait to trait (positive, negative or unrelated), trait means and trait plasticity were mostly unrelated. Our results suggest that the concept of functional groups is viable, but context-specific trait measurements are required to improve our understanding about the functional significance of intraspecific trait variation and interspecific trait differences in local plant communities. PMID- 29989167 TI - Climate change alterations to ecosystem dominance: how might sponge-dominated reefs function? AB - Anthropogenic stressors are impacting ecological systems across the world. Of particular concern are the recent rapid changes occurring in coral reef systems. With ongoing degradation from both local and global stressors, future reefs are likely to function differently from current coral-dominated ecosystems. Determining key attributes of future reef states is critical to reliably predict outcomes for ecosystem service provision. Here we explore the impacts of changing sponge dominance on coral reefs. Qualitative modelling of reef futures suggests that changing sponge dominance due to increased sponge abundance will have different outcomes for other trophic levels compared with increased sponge dominance as a result of declining coral abundance. By exploring uncertainty in the model outcomes we identify the need to (1) quantify changes in carbon flow through sponges, (2) determine the importance of food limitation for sponges, (3) assess the ubiquity of the recently described "sponge loop," (4) determine the competitive relationships between sponges and other benthic taxa, particularly algae, and (5) understand how changing dominance of other organisms alters trophic pathways and energy flows through ecosystems. Addressing these knowledge gaps will facilitate development of more complex models that assess functional attributes of sponge-dominated reef ecosystems. PMID- 29989168 TI - Stem-cell cardiospheres for myocardial regeneration: advancing cell therapy in myocardial infarction and heart failure. PMID- 29989170 TI - Mechanisms of sarcopenia: motor unit remodelling and muscle fibre type shifts with ageing. PMID- 29989169 TI - Real-time optical manipulation of cardiac conduction in intact hearts. AB - KEY POINTS: Although optogenetics has clearly demonstrated the feasibility of cardiac manipulation, current optical stimulation strategies lack the capability to react acutely to ongoing cardiac wave dynamics. Here, we developed an all optical platform to monitor and control electrical activity in real-time. The methodology was applied to restore normal electrical activity after atrioventricular block and to manipulate the intraventricular propagation of the electrical wavefront. The closed-loop approach was also applied to simulate a re entrant circuit across the ventricle. The development of this innovative optical methodology provides the first proof-of-concept that a real-time all-optical stimulation can control cardiac rhythm in normal and abnormal conditions. ABSTRACT: Optogenetics has provided new insights in cardiovascular research, leading to new methods for cardiac pacing, resynchronization therapy and cardioversion. Although these interventions have clearly demonstrated the feasibility of cardiac manipulation, current optical stimulation strategies do not take into account cardiac wave dynamics in real time. Here, we developed an all-optical platform complemented by integrated, newly developed software to monitor and control electrical activity in intact mouse hearts. The system combined a wide-field mesoscope with a digital projector for optogenetic activation. Cardiac functionality could be manipulated either in free-run mode with submillisecond temporal resolution or in a closed-loop fashion: a tailored hardware and software platform allowed real-time intervention capable of reacting within 2 ms. The methodology was applied to restore normal electrical activity after atrioventricular block, by triggering the ventricle in response to optically mapped atrial activity with appropriate timing. Real-time intraventricular manipulation of the propagating electrical wavefront was also demonstrated, opening the prospect for real-time resynchronization therapy and cardiac defibrillation. Furthermore, the closed-loop approach was applied to simulate a re-entrant circuit across the ventricle demonstrating the capability of our system to manipulate heart conduction with high versatility even in arrhythmogenic conditions. The development of this innovative optical methodology provides the first proof-of-concept that a real-time optically based stimulation can control cardiac rhythm in normal and abnormal conditions, promising a new approach for the investigation of the (patho)physiology of the heart. PMID- 29989172 TI - A BPA Approach to the Shroud of Turin. AB - An investigation into the arm and body position required to obtain the blood pattern visible in the image of the Shroud of Turin was performed using a living volunteer. The two short rivulets on the back of the left hand of the Shroud are only consistent with a standing subject with arms at a ca 45 degrees angle. This angle is different from that necessary for the forearm stains, which require nearly vertical arms for a standing subject. The BPA of blood visible on the frontal side of the chest (the lance wound) shows that the Shroud represents the bleeding in a realistic manner for a standing position while the stains at the back-of a supposed postmortem bleeding from the same wound for a supine corpse are totally unrealistic. Simulation of bleeding from the nail wounds contacting wood surfaces yielded unclear results. PMID- 29989171 TI - Redox-regulation of haemostasis in hypoxic exercising humans: a randomised double blind placebo-controlled antioxidant study. AB - KEY POINTS: In vitro evidence has identified that coagulation is activated by increased oxidative stress, though the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial in healthy participants to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise given their synergistic capacity to promote free radical formation. Systemic free radical formation was shown to increase during hypoxia and was further compounded by exercise, responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation at rest in normoxia, and this was normalised only in the face of prevailing oxidation. Collectively, these findings suggest that human free radical formation is an adaptive phenomenon that serves to maintain vascular haemostasis. ABSTRACT: In vitro evidence suggests that blood coagulation is activated by increased oxidative stress although the link and underlying mechanism in humans have yet to be established. We conducted the first randomised controlled trial to examine if oral antioxidant prophylaxis alters the haemostatic responses to hypoxia and exercise. Healthy males were randomly assigned double-blind to either an antioxidant (n = 20) or placebo group (n = 16). The antioxidant group ingested two capsules/day that each contained 500 mg of l-ascorbic acid and 450 international units (IU) of dl-alpha-tocopherol acetate for 8 weeks. The placebo group ingested capsules of identical external appearance, taste and smell (cellulose). Both groups were subsequently exposed to acute hypoxia and maximal physical exercise with venous blood sampled pre supplementation (normoxia), post-supplementation at rest (normoxia and hypoxia) and following maximal exercise (hypoxia). Systemic free radical formation (electron paramagnetic resonance spectroscopic detection of the ascorbate radical (A*- )) increased during hypoxia (15,152 +/- 1193 AU vs. 14,076 +/- 810 AU at rest, P < 0.05) and was further compounded by exercise (16,569 +/- 1616 AU vs. rest, P < 0.05), responses that were attenuated by antioxidant prophylaxis. In contrast, antioxidant prophylaxis increased thrombin generation as measured by thrombin-antithrombin complex, at rest in normoxia (28.7 +/- 6.4 vs. 4.3 +/- 0.2 MUg mL-1 pre-intervention, P < 0.05) and was restored but only in the face of prevailing oxidation. Collectively, these findings are the first to suggest that human free radical formation likely reflects an adaptive response that serves to maintain vascular haemostasis. PMID- 29989173 TI - Cardiac Ventricular Laceration Due to Child Abuse: Abusive Ventricular Laceration. AB - Traumatic cardiac ventricular ruptures in children are rare. Only a single case of left ventricular rupture due to child abuse has been reported. We report a child who sustained a fatal left ventricular apical rupture. It appeared to have resulted from hydrostatic forces resulting from abusive blunt thoracic injury. That he was being abused was previously missed when he was presented to the emergency department with facial pyoderma. It was not noted that he also had lip and oral mucosal injury, sites not affected by staph toxins. As a result, his underlying, abusive and secondarily infected, facial flow type scald burn was not appreciated. Within a week thereafter his fatal injury occurred, accompanied by extensive and obvious associated abusive injuries. Postmortem high-detail whole body computed tomography scanning aided the autopsy. Although rare, ventricular rupture from abusive blunt thoracic injury can occur. PMID- 29989174 TI - Photophysical and Photoacoustic Properties of pi-Extended Curcumin Dyes. Effects of the Terminal Dimethylamino Electron-donor and the Bridging Aryl Ring. AB - The synthesis, photophysical and photoacoustic characterization for a series of nine pi-extended quadrupolar curcumin dyes is presented. A systematic evaluation of the pi-bridging unit including the p-phenyl, naphth-4-yl, thien-2-yl and hybrid 4-naphthathien-2-yl groups is presented. Furthermore, evaluation of the strongly donating donor-pi-acceptor-pi-donor quadrupolar dimethylamino terminated derivatives is also included. Select dyes exhibit excited state absorption at increased laser fluence which translates to the production of a nonlinear enhanced photoacoustic response. In particular, the bis-4-dimethylaminonaphtha-2 thien-5-yl curcuminBF2 contrast agent DMA-5 exhibits an excellent molar photoacoustics (PA) emission at both low (9.4 * 103 V M-1 ) and high (1.47 * 105 V M-1 ) laser fluence which is confirmed by its strong contrast by photoacoustic tomography (PAT). In summary, the strong absorbance and enhanced photoacoustic properties of naphthyl and thienyl curcuminoids here presented provides great promise for future photoacoustic imaging applications as demonstrated by preliminary PAT studies. PMID- 29989175 TI - Evaluation of left ventricular false tendons in children with idiopathic left ventricular tachycardia. AB - BACKGROUND: Left ventricular false tendons (FT) traverse the ventricular cavity and are thought to have some association with idiopathic left ventricular tachycardia (ILVT). However, reported prevalence of FT varies widely, making correlation difficult. Superior echocardiographic windows of pediatric patients may permit better analysis of FT in ILVT. Our study describes the relationship between FT and ILVT in young patients. METHODS: Retrospective case-control study of 30 ILVT patients with 98 controls compared for FT. Diagnosis of ILVT was made by electrocardiogram and clinical history, and for 25 patients was further confirmed by electrophysiology study (EPS). Presence of FT was identified by one blinded observer and verified by a second blinded observer. Presence of FT was then compared between ILVT patients and controls using Fisher's exact test. RESULTS: Presence of FT did not differ significantly between patients and controls (53% vs 43%, P = 0.40). Twelve FT patients (19%) had multiple FTs detected, though the incidence of ILVT was no higher in the setting of multiple FTs. A total of 25 patients with ILVT underwent EPS for intended ablation therapy, with ultimate success in 22/25 (88%) after one or more ablation sessions. Of the 25 EPS patients, FTs were present in 11, but precise correlation between successful ablation location and FT location was not possible since intraprocedural echocardiography was not performed in this patient group. CONCLUSIONS: Presence of FTs did not differ between ILVT patients and controls. While FTs are not absolutely required for ILVT, they may still play a role in some cases. PMID- 29989176 TI - Dosimetry in a mammography phantom using TLD-300 dosimeters. AB - PURPOSE: The purpose of this study was to evaluate the photon field effective energy (Eeff ) distribution and percentage depth-dose (PDD) within a mammography phantom by the analysis of the CaF2 :Tm (TLD-300) thermoluminescent (TL) glow curve. The experimental procedure involves the use of TLD-300 to determine with single dosimeter exposures both the relative dose and the beam quality. METHODS: TLD-300 chips were exposed to x rays from a GE Senographe 2000D mammography unit at the surface and different depths within a BR12 phantom. X-ray beams were generated with Mo/Mo, Mo/Rh, and Rh/Rh anode/filter combinations and voltages between 25 and 34 kV. Glow curves were deconvoluted into component peaks and the high- to low-temperature ratio (HLTR) was evaluated. The photon field Eeff was obtained from the HLTR values using a calibration curve determined previously. PDD was established from the peak 5 TL signal (TLSP5 ) at depths between 0.0 and 3.5 cm inside the phantom. Taking into account the differences in density and composition between CaF2 :Tm and breast tissue, an energy-dependent correction factor (beta(E)) was applied to TLSP5 . Measurements were compared with radiation transport Monte Carlo (MC) simulations performed with PENELOPE-2008. RESULTS: A typical 5% change in the HLTR from the phantom top surface to 3.5 cm depth was measured, which corresponds to a 2.2 keV increase in photon field Eeff . Values of the beta(E) correction factor were 0.33 and 0.13 for Eeff equal to 15.1 and 22.5 keV, respectively. This strong energy dependence of beta(E) is mostly due to the differences in fluence attenuation between CaF2 and breast tissue. According to PDD measurements, dose decreased to half the surface value at depths between 0.7 and 1.0 cm for Mo/Mo/25 and Rh/Rh/34 beams, respectively. Values of PDD, less than 10% at 3.5 cm depth, would have been overestimated by about 3.5% (a large relative error) if an energy-independent correction factor had been assumed. Mean differences between experiments and MC simulations were 0.8 keV and 1.2% in the determination of Eeff and PDD, respectively. CONCLUSION: The TLD-300 glow curve was used to accurately measure the photon field Eeff and PDD within a mammographic phantom. This work has demonstrated that Eeff and dose can be established simultaneously by using solely TLD-300. PMID- 29989177 TI - Role of implantable loop recorders in patients with postural orthostatic tachycardia syndrome. AB - INTRODUCTION: We previously reported on a subgroup of postural orthostatic tachycardia syndrome (POTS) patients who may also have features of neurocardiogenic syncope as well. In this subgroup of patients, we found syncope and presyncope were predominant clinical features. To understand the mechanism of syncope in this subgroup, we identified 39 patients who underwent loop recorder insertion. METHODS: We reviewed charts of 450 patients who had POTS and syncope seen at the University of Toledo Medical Center from 2003 to 2017. Thirty-nine patients had at least four episodes of syncope in the last 6 months and were included for this study. All of these patients had a prior evaluation with a Holter and an event monitor which were inconclusive. RESULTS: Thirty-nine patients, 33 (85%) women, aged 20-46 years, were included in this study. All patients demonstrated prolonged asystole (>6 seconds) or severe bradycardia (heart rate < 30 beats/min) during their syncope on implantable loop recorder (IRL). Fifteen patients demonstrated an asystole of >10 seconds and also had prolonged and convulsive syncope. All patients had abrupt syncope without any warning sign. All patients underwent dual-chamber pacemaker implantation using a closed loop stimulation algorithm. Syncope were completely eliminated in all patients following pacemaker implantation; however, they continued to have orthostatic tachycardia. CONCLUSION: POTS patients with unusually frequent syncope should be considered for ILR implantation if other monitoring modalities like 48-hour Holter monitor or event recorder are inconclusive. ILR may identify a subgroup of POTS patients who may benefit from pacemaker implantations. PMID- 29989179 TI - Efficacy of omalizumab 150 mg/month as a maintenance dose in patients with severe chronic spontaneous urticaria showing a prompt and complete response to the drug. PMID- 29989178 TI - Risk factors for peripartum blood transfusion in South Africa: a case-control study. AB - BACKGROUND: Obstetric hemorrhage (OH) and access to peripartum blood transfusion remains a global health challenge. The rates of peripartum transfusion in South Africa exceed those in high-income countries despite comparable rates of OH. We sought to evaluate factors associated with peripartum transfusion. STUDY DESIGN AND METHODS: A case-control study was conducted at four large South African hospitals. Transfused peripartum women (cases) and nontransfused controls were stratum matched 1:2 by hospital and delivery date. Data on obstetric, transfusion, and human immunodeficiency virus (HIV) history were abstracted from medical records. Blood was obtained for laboratory evaluation. We calculated unadjusted and adjusted odds ratios (ORs) for transfusion using logistic regression. RESULTS: A total of 1200 transfused cases and 2434 controls were evaluated. Antepartum hemorrhage (OR, 197.95; 95% confidence interval [CI], 104.27-375.78), hemorrhage with vaginal delivery (OR, 136.46; 95% CI, 75.87 245.18), prenatal anemia (OR, 22.76; 95% CI, 12.34-41.93 for prenatal hemoglobin level < 7 g/dL), and failed access to prenatal care (OR, 6.71; 95% CI, 4.32 10.42) were the major risk factors for transfusion. Platelet (PLT) count (ORs, 4.10, 2.66, and 1.77 for <=50 * 109 , 51 * 109 -100 * 109 , and 101 * 109 -150 * 109 cells/L, respectively), HIV infection (OR, 1.29; 95% CI, 1.02-1.62), and admitting hospital (twofold variation) were also associated with transfusion. Mode of delivery, race, age category, gravidity, parity, gestational age, and birthweight were not independently associated with transfusion. CONCLUSION: Major risk factors of peripartum transfusion in South Africa, namely, prenatal anemia and access to prenatal care, may be amenable to intervention. HIV infection and moderately low PLT count are novel risk factors that merit further investigation. PMID- 29989180 TI - Rethinking the Role of the Nervous System: Lessons From the Hydra Holobiont. AB - Here we evaluate our current understanding of the function of the nervous system in Hydra, a non-bilaterian animal which is among the first metazoans that contain neurons. We highlight growing evidence that the nervous system, with its rich repertoire of neuropeptides, is involved in controlling resident beneficial microbes. We also review observations that indicate that microbes affect the animal's behavior by directly interfering with neuronal receptors. These findings provide new insight into the original role of the nervous system, and suggest that it emerged to orchestrate multiple functions including host-microbiome interactions. The excitement of future research in the Hydra model now relies on uncovering the common rules and principles that govern the interaction between neurons and microbes and the extent to which such laws might apply to other and more complex organisms. PMID- 29989181 TI - Endoplasmic reticulum stress and kidney dysfunction. AB - Chronic kidney disease (CKD) affects millions of persons worldwide and constitutes a major public health problem. Therefore, understanding the molecular basis of CKD is a key challenge for the development of preventive and therapeutic strategies. A major contributor to chronic histological damage associated with CKD is acute kidney injury (AKI). At the cellular level, kidney injuries are associated with microenvironmental alterations, forcing cells to activate adaptive biological processes that eliminate the stressor and generate alarm signals. These signalling pathways actively participate in tissue remodelling by promoting inflammation and fibrogenesis, ultimately leading to CKD. Many stresses that are encountered upon kidney injury are prone to trigger endoplasmic reticulum (ER) stress. In the kidney, ER stress both participates in acute and chronic histological damages, but also promotes cellular adaptation and nephroprotection. In this review, we will discuss the implication of ER stress in the pathophysiology of AKI and CKD progression, and we will give a critical analysis of the current experimental and clinical evidence that support ER stress as a mediator of kidney damage. PMID- 29989182 TI - Inflammation and Inflammatory Diseases: How Our Language Influences Our Therapeutic Paradigms. PMID- 29989184 TI - Natural variation in cytokinin maintenance improves salt tolerance in apple rootstocks. AB - Plants experiencing salt-induced stress often reduce cytokinin levels during the early phases of stress-response. Interestingly, we found that the cytokinin content in the apple rootstock "robusta" was maintained at a high level under salt stress. Through screening genes involved in cytokinin biosynthesis and catabolism, we found that the high expression levels of IPT5b in robusta roots were involved in maintaining the high cytokinin content. We identified a 42 bp deletion in the promoter region of IPT5b, which elevated IPT5b expression levels, and this deletion was linked to salt tolerance in robusta*M.9 segregating population. The 42 bp deletion resulted in the deletion of a Proline Response Element (ProRE), and our results suggest that ProRE negatively regulates IPT5b expression in response to proline. Under salt stress, the robusta cultivar maintains high cytokinin levels as IPT5b expression cannot be inhibited by proline due to the deletion of ProRE, leading to improve salt tolerance. PMID- 29989185 TI - Electroanatomic mapping-guided localization of alternative right ventricular septal pacing sites in children. AB - BACKGROUND: Alternative right ventricular (RV) sites (RVAPS) have been proposed to prevent or reduce RV pacing-induced left-ventricular (LV) dysfunction. Nonfluoroscopic 3D electroanatomic mapping systems (EAM) have been developed to guide cardiac catheter navigation and reduce fluoroscopy during electrophysiological procedures or pacemaker implantations. AIM: The aim of the study was to compare the results of EAM-guided permanent pacemaker implantation aiming at RVAPS with conventional fluoroscopic-guided implantation in RV apex (RVA) in children and adolescents. METHODS: A prospective, randomized analysis was performed on children/adolescents with complete atrioventricular block (CAVB) who underwent EAM-guided pacemaker and transvenous leads implantation into RVAPS (EAM-RVAPS) or conventional, fluoroscopic-guided implantation into RV apex (RVA). In EAM-RVAPS, a pacing map guided the implantation of ventricular leads in septal sites with narrower QRS. After implantation, LV contractility (ejection fraction [EF], Global Longitudinal Strain [GLS]) and synchrony were evaluated at 1-12 months. RESULTS: Twenty-one pediatric patients with CAVB, with (six patients) or without structural heart diseases, aged 4-16 (median 10.5) years, were divided in two groups: EAM-RVAPS (11 patients, four dual-chamber/DDD, seven single chamber/VVIR pacemakers) and RVA (10 patients, one DDD/nine VVIR). The two groups did not show significant differences for preoperative parameters. EAM-RVAPS showed: preserved LVEF and synchrony (not significantly different than RVA), significantly lower GLS and radiation doses/exposures, in spite more complex procedures, significantly longer procedure times and narrower paced QRS than RVA. CONCLUSIONS: EAM-guided procedures have been useful to reduce radiation exposure and to localize RVAPS with narrower paced QRS and lower GLS than RVA. PMID- 29989186 TI - Lipidomic reprogramming associated with drought stress priming-enhanced heat tolerance in tall fescue (Festuca arundinacea). AB - Stress priming by exposing plants to a mild or moderate drought could enhance plant tolerance to subsequent heat stress. Lipids play vital roles in stress adaptation, but how lipidomic profiles change, affecting the cross-stress tolerance, is largely unknown. The objectives of this study were to perform lipidomics, to analyse the content, composition, and saturation levels of lipids in leaves of tall fescue (Festuca arundinacea) following drought priming and subsequent heat stress, and to identify major lipids and molecular species associated with priming-enhanced heat tolerance. Plants were initially exposed to drought for 8 days by withholding irrigation and subsequently subjected to 25 days of heat stress (38/33 degrees C day/night) in growth chambers. Drought primed plants maintained significantly higher leaf relative water content, chlorophyll content, photochemical efficiency, and lower electrolyte leakage than nonprimed plants under heat stress. Drought priming enhanced the accumulation of phospholipids and glycolipids involved in membrane stabilization and stress signalling (phosphatidic acid, phosphatidylcholine, phosphatidylinositol, phosphatidylglycerol, and digalactosyl diacylglycerol) during subsequent exposure to heat stress. The reprogramming of lipid metabolism for membrane stabilization and signalling in response to drought priming and subsequent exposure to heat stress could contribute to drought priming-enhanced heat tolerance in cool-season grass species. PMID- 29989183 TI - Chronic, intermittent treatment with a cannabinoid receptor agonist impairs recognition memory and brain network functional connectivity. AB - Elucidating how cannabinoids affect brain function is instrumental for the development of therapeutic tools aiming to mitigate 'on target' side effects of cannabinoid-based therapies. A single treatment with the cannabinoid receptor agonist, WIN 55,212-2, disrupts recognition memory in mice. Here, we evaluate how prolonged, intermittent (30 days) exposure to WIN 55,212-2 (1 mg/kg) alters recognition memory and impacts on brain metabolism and functional connectivity. We show that chronic, intermittent treatment with WIN 55,212-2 disrupts recognition memory (Novel Object Recognition Test) without affecting locomotion and anxiety-like behaviour (Open Field and Elevated Plus Maze). Through 14 C-2 deoxyglucose functional brain imaging we show that chronic, intermittent WIN 55,212-2 exposure induces hypometabolism in the hippocampal dorsal subiculum and in the mediodorsal nucleus of the thalamus, two brain regions directly involved in recognition memory. In addition, WIN 55,212-2 exposure induces hypometabolism in the habenula with a contrasting hypermetabolism in the globus pallidus. Through the application of the Partial Least Squares Regression (PLSR) algorithm to the brain imaging data, we observed that prolonged WIN 55,212-2 administration alters functional connectivity in brain networks that underlie recognition memory, including that between the hippocampus and prefrontal cortex, the thalamus and prefrontal cortex, and between the hippocampus and the perirhinal cortex. In addition, our results support disturbed lateral habenula and serotonin system functional connectivity following WIN 55,212-2 exposure. Overall, this study provides new insight into the functional mechanisms underlying the impact of chronic cannabinoid exposure on memory and highlights the serotonin system as a particularly vulnerable target. PMID- 29989187 TI - Reasonableness: legitimate reasons for illegitimate presentations at the ED. AB - Most studies on gatekeeping at the emergency department (ED) have emphasised the assessment of clients in terms of perceived legitimacy and deservingness, showing that lay considerations lead to exclusionary practices, and the ED contributes to the social reproduction of inequality. Some recent works have challenged this representation, providing compelling evidence of staff's concern for the access to care of the most vulnerable users. I extend this perspective by presenting the criterion of reasonableness of the visit to the ED that nurses in Romania commonly use during the triage admission interview. Reasonableness constitutes an acceptable departure from the mission of the ED that offsets the negative evaluation in terms of legitimacy. Patients deemed to have legitimate reasons for making illegitimate claims for admission escape staff's disciplining efforts. However, the staff-devised understanding of reasonableness is restrictive and does not attend to most cultural and structural barriers in access to quality health care. I argue that reasonableness indexes structural sensitivity, a fragmentary, tacit, and imperfectly consistent orientation to structural deficiencies in the organisation and provision of primary care. PMID- 29989188 TI - Interdisciplinary Approaches to Examining Postdisaster School Recovery. AB - This perspectives article uses a postdisaster school recovery research domain to examine two tenets of interdisciplinary research (IDR): integrative problem formulation and synthesis. Advancing interdisciplinary knowledge requires a "roadmap" of commonalities between disciplinary domains and outcomes of interest. Four school recovery domains-child trauma, educational learning outcomes, school safety, and household and community recovery-are presented to highlight common frameworks for IDR. A case study is also used to illustrate the value of interdisciplinary research and mixed-methods approaches, including statistics, geospatial analysis, and spatial statistics, for answering questions regarding how school contexts and location influence school recovery patterns. PMID- 29989189 TI - Explanatory factors and levels of health-related quality of life among healthy pregnant women at midpregnancy: A cross-sectional study of The PregnActive Project. AB - AIMS: To identify potential explanatory factors and establish health-related quality of life (HRQoL) levels of healthy pregnant women at midpregnancy. BACKGROUND: The HRQoL levels perceived by pregnant women are lower than those perceived by women of similar age and decline during the course of pregnancy. DESIGN: An exploratory cross-sectional design was used. METHODS: One hundred thirty-four healthy women from antenatal clinics completed questionnaires were administered a cardiorespiratory fitness (CRF) test and wore a multisensor body monitor for 7 days at midpregnancy. Data were collected from September 2015 December 2016. RESULTS: Cardiorespiratory fitness, musculoskeletal symptoms, and age were identified as explanatory factors of the physical component summary of HRQoL. Explanatory factors of the mental component summary included musculoskeletal and psychological symptoms and light activity. Significant differences in HRQoL levels were identified among groups of pregnant women stratified by age, occupational status, pregnancy symptoms, and CRF. CONCLUSIONS: Modifiable factors of HRQoL, such as CRF and active lifestyle may be important areas to target in interventions aimed at promoting HRQoL in healthy women at midpregnancy. The identification of the groups of pregnant women with lower levels of HRQoL may help midwives and health professional to focus their advice and conduct interventions on these groups of pregnant women. These modifiable factors should be considered in future longitudinal studies to determine causal effects, will likely help improve multidisciplinary treatments. PMID- 29989190 TI - Management of Pediatric Acute Hematogenous Osteomyelitis, Part II: A Focus on Methicillin-Resistant Staphylococcus aureus, Current and Emerging Therapies. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has become the most prevalent cause of acute hematogenous osteomyelitis (AHO) in pediatric patients. This increase in MRSA is due to the rise in community-acquired MRSA. Therefore, it is important that clinicians are aware of the various and upcoming therapies that cover this bacterium. A literature search of the Medline database was performed from creation through January 2018. Articles chosen for the review emphasize well established MRSA treatment options for pediatric AHO, newer therapies on the horizon, and important pharmacokinetics and pharmacodynamic concepts for treatment. Traditional therapies, including vancomycin and clindamycin, remain effective for the treatment of pediatric AHO. When these agents cannot be used, evidence in AHO has been growing for daptomycin, linezolid, and ceftaroline. Further initial pediatric data with the long-acting lipoglycopeptides show promise and in the future may provide a role in AHO treatment in children. PMID- 29989191 TI - Identification of a glutathione S-transferase gene of Physarum polycephalum as a biomarker for nanosized TiO2 exposure under dark conditions. AB - : In this study, a glutathione S-transferase gene (gst) from sensitive Physarum polycephalum was selected for its ability to detect nanosized TiO2 (nTiO2 ) exposure under dark conditions. The concentration of nTiO2 (25, 40 and 60 nm) for subsequent assays was first determined (5-18 mg ml-1 ) and total GST enzyme activity of P. polycephalum was confirmed to be increased 6-44 fold in groups treated with nTiO2 . Second, an RNA-seq study was performed to identify candidate gst genes before isolation of an optimum gst gene of P. polycephalum (Ppgst), which encoded 223 amino acids. Third, the transcriptional level of the Ppgst gene was further confirmed to be positively correlated with nTiO2 exposure within the concentration range of (5-15 mg ml-1 ) by qPCR. In conclusion, these results indicated that the transcriptional level of Ppgst can reflect nTiO2 exposure, suggesting that it may be employed as a new biomarker for nTiO2 pollution under dark conditions. SIGNIFICANCE AND IMPACT OF THE STUDY: This study identifies a new gst gene for indicating nanosized TiO2 under dark conditions and provides a new option for detection of nanosized TiO2 pollution under dark conditions. PMID- 29989192 TI - Reflections on the Use of Conceptual Research in Risk Analysis. AB - A risk analysis science is developing, characterized by knowledge generation on concepts, principles, theories, frameworks, methods, and models, for understanding, assessing, characterizing, communicating, and managing risk (for short referred to as conceptual knowledge generation in risk analysis), as well as supporting risk knowledge generation of specific activities based on these concepts, principles, theories, frameworks, methods, and models. The scientific knowledge generation is based on different types of research methods. This article provides a discussion of some of these, the main purpose being to demonstrate the central role of conceptual knowledge generation and research in risk analysis. The importance of this type of knowledge generation and research is considered undervalued in risk analysis. Several examples are used to illustrate the discussion, including a risk governance framework and the anti fragility concept. PMID- 29989193 TI - A mixed methods review to develop and confirm a framework for assessing midwifery practice in perinatal mental health. AB - AIM: To ascertain whether a new framework examining midwifery practice in perinatal mental health (PMH) is supported by the research literature. BACKGROUND: The identification and care of women with PMH problems is increasingly considered part of midwifery practice. Research suggests that many midwives lack knowledge, skills and confidence. It would be useful to be able to determine barriers and facilitators to effective clinical practice. The authors propose a framework comprising five potentially measurable domains which have an impact on midwives' ability to identify, assess and care for women with PMH problems. DESIGN: This mixed-methods review uses an innovative qualitative convergent design based on framework synthesis. DATA SOURCES: Relevant electronic databases were searched for the period from January 2007-December 2016; 33 studies from nine countries met the inclusion criteria. REVIEW METHODS: Study quality was assessed using critical appraisal tools. Study findings were mapped onto the five domains of the framework: knowledge, confidence, attitudes, illness perception and infrastructure. Findings were then synthesized for each domain. RESULTS: All five domains are substantially represented in the literature, thus supporting the proposed framework. Several sub-domains and relationships between domains were identified. Varying levels of knowledge, confidence, attitudes and illness perceptions were found; evidence suggests that midwives benefit from further training within these domains. Features of organizational infrastructure act as barriers or facilitators to effective care; these need to be addressed at organizational level. CONCLUSION: The proposed framework was confirmed and can be used to inform practice, policy and research. PMID- 29989194 TI - What is your diagnosis? Conjunctival smear in a dog. PMID- 29989195 TI - "Am I a student or a Healthcare Assistant?" A qualitative evaluation of a programme of prenursing care experience. AB - AIM: To examine the experiences of prenursing healthcare assistants (HCA) during a 6-month programme of prenursing care experience. BACKGROUND: Care experience prior to commencing programmes of nurse education is broadly considered to be advantageous. However, it is not clear how formal care experience prior to nurse education has an impact on the values and behaviours of the aspirant nurse. DESIGN: A longitudinal prospective qualitative study using focus group discussions. METHODS: Data were collected from 23 prenursing HCA during September 2013-February 2014. Three focus groups were held at the beginning, middle, and end of the programme of care experience at each of the participating hospitals. A thematic analysis was used to analyse data sets from each hospital. Findings from each hospital were then compared to reach final themes. RESULTS: Five major themes were identified in the analysis of qualitative data: personal development; positioning of role in the healthcare team; support and supervision; perceived benefits; and advice and recommendations. These themes were underpinned by deep aspirations for better care and better nurses in the future. CONCLUSIONS: Prenursing care experience can positively prepare aspirant nurses for programmes of nurse education. The benefits identified were confirmation of aspiration (or otherwise) to pursue nursing, learning opportunities, and aspiration to improve patient experience. Risks for the programme included poor supervision, role ambiguity or confusion, demotivation through a deteriorating view of nursing, and poor treatment by others. The longer term impact on values and behaviours of this cohort requires further evaluation. PMID- 29989196 TI - Experiences of and satisfaction with care provided by male nurses: A convergent mixed-method study of patients in medical surgical units. AB - AIM: To understand, comprehensively, patients' experiences of and satisfaction with care provided by male nurses in medical surgical units. BACKGROUND: Patients' positive experiences of and satisfaction with care are plausible indicators of nurses' caring attitude. Female nurses are considered more caring than male nurses and knowledge about patient experiences and satisfaction with care by male nurses is minimal. DESIGN: A convergent mixed methods. METHODS: Patients (N = 262) completed an Urdu language-translated version of the Newcastle Satisfaction with Nursing Scale and 15 participated in semi-structured interviews from August - December 2017. Descriptive statistics were used for quantitative analysis and thematic analysis for qualitative analysis. Both quantitative and qualitative data were merged and integrated for mixed-method analysis. RESULTS: High experience and moderate satisfaction scores were reported. Six themes emerged from care experiences: providing support and comfort, respecting privacy, providing information to patients and families, inability to manage workload and rushing too much, responding late and disturbing sleep. Three themes from satisfaction with nursing care: spending time with patients, capability of providing care and respecting autonomy. It was found that patients' actual experiences and satisfaction with the male nurses' care were considerably better than culturally accepted beliefs and perceptions about the role of men and women in the society. CONCLUSION: Male nurses were caring, but patients' views of nurses' caring attitude were influenced by socio-culture perceptions of the men. Male nurses supported and comforted patients and respected their privacy but did not respond to them on time and were perceived to be authoritarian. PMID- 29989197 TI - Pregnancy outcome and management of 25 pregnancies in women with polycythemia vera. PMID- 29989198 TI - HER2 immunohistochemistry in endometrial and ovarian clear cell carcinoma: discordance between antibodies and with in-situ hybridisation. AB - AIMS: Treatment with anti-HER2 therapy could be beneficial for patients with HER2 positive endometrial and ovarian clear cell carcinoma (CCC). We studied HER2 overexpression by immunohistochemistry (IHC) using three different antibodies, including concordance with amplification by in-situ hybridisation (ISH). METHODS AND RESULTS: IHC and ISH were performed on tissue microarrays of 101 tumours: 58 endometrial pure CCC, 19 endometrial mixed carcinomas with a CCC component and 24 ovarian pure CCC. IHC was performed using SP3, 4B5 and HercepTest antibodies, and was scored by two independent observers. ISH was performed using dual-colour silver ISH. Using IHC, agreement was poor between SP3/4B5 (61.4%), poor between SP3/HercepTest (68.3%) and reasonable between 4B5/HercepTest (75.2%). Interobserver agreement was substantial to almost perfect for all antibodies (SP3: linear weighted kappa = 0.89, 4B5: kappa = 0.90, HercepTest: kappa = 0.76). HER2-positivity by ISH was 17.8% (endometrial pure CCC: 24.1%, endometrial mixed: 0%, ovarian pure CCC: 16.7%). IHC/ISH concordance was poor, with a high false negative rate of all three IHC antibodies: sensitivity (38.9-50.0%) and positive predictive value (PPV) (37.5-58.3%) were poor; specificity (81.9-94.0%) and negative predictive value (NPV) (87.1-88.3%) were reasonable. When excluding 2+ cases, sensitivity declined (26.7-43.8%) but PPV (80.0-87.5%) and specificity (98.6-98.7%) improved. CONCLUSIONS: In ovarian and endometrial CCC, there is considerable difference in HER2 overexpression by different IHC antibodies and marked discordance with ISH. As such, no single antibody can be considered conclusive for determining HER2 status in CCC. Based on these results, the lack of predictive value of different HER2 testing methods, as used in other studies, could be explained. PMID- 29989199 TI - The use of metaphors in non-Hodgkin's lymphoma patients undergoing chemotherapy. AB - AIM: The aim of this study was to explore the use of metaphors by non-Hodgkin's lymphoma (NHL) patients undergoing chemotherapy in a haematology ward setting. BACKGROUND: There is a dearth of literature exploring the use of metaphors in people with cancer undergoing aggressive treatment. Hence, this study aims to explore the use of metaphors in NHL patients undergoing chemotherapy and additionally, examining whether the use of such metaphors has an empowering/disempowering effect. DESIGN: A qualitative design was used. METHODS: The participants were six adult patients diagnosed with NHL and undergoing chemotherapy. Data collection was undertaken between July 2016-December 2016. Each participant was interviewed twice using semi-structured interviews. The data were analysed using Pragglejaz method for finding metaphors. FINDINGS: The participants used metaphors 17 times per 1,000 words to describe their experience of undergoing chemotherapy for NHL. The metaphors cited focused on aspects relating to "war", "prison" and a "journey". CONCLUSIONS: The findings demonstrate that certain metaphors used by the study participants, such as those pertaining to "war" or a "journey", concur with those described in narratives of people with cancer in general. However, the use of the "prison" metaphor by NHL patients undergoing chemotherapy relates particularly to their context of being isolated while undergoing treatment for fear of infection. Consequently, there is the need to interpret metaphors in relation to the specific type of illness and context. Furthermore, the findings of this study suggest that the impact of metaphors in empowering/disempowering people with cancer depends on the unique interpretation of the individual patient. PMID- 29989200 TI - Rapid intravenous infusion of velaglucerase-alfa in adults with type 1 Gaucher disease. PMID- 29989201 TI - Improving quality of care for perinatal and newborn care at district and subdistrict hospitals in Haryana, India: Implementation research protocol. AB - AIM: This implementation research aims to improve quality of care for mothers and newborns in three districts of Haryana, India at different public health facilities. BACKGROUND: The decline in key maternal and newborn health indicators in India is relatively slower than expected and missed the millennium development goals. The multifold rise in institutional delivery in last decade has limited impact on neonatal and maternal mortality. Despite investments in infrastructure, equipment, supplies, monitoring tools, and also manpower, suboptimal gains in indicators point towards potential challenge in quality of care. DESIGN: This study adopts pre-post, quasi-experimental study design with repeated observations using mixed research methods to document the impact of the plan-do-study-act implementation cycles. METHODS: The quality improvement interventions shall be implemented at three district hospitals and six-first referral unit hospitals in three districts of Haryana targeting the antenatal, delivery, newborn care services with nurses as the key partners. Formative research, situational analysis, and root-cause analysis shall inform the contextualization, prioritization of interventions. Incremental plan-do-study-act cycles over 15 months shall be implemented. The changes in adherence to protocols, appropriate documentation, reduction in delays, and client satisfaction shall be documented for 16 indicators across delivery, antenatal, and sick newborn care domains. DISCUSSION: The successful implementation of the quality improvement processes has the potential of improving the pregnancy outcomes in terms of stillbirths, maternal, and newborn mortality and sick newborn outcomes. The feasibility and learning of coimplementation in the public health system shall inform integration into standards and scaling up. PMID- 29989204 TI - A retrospective and prospective assessment of the zero-markup drug reform in China from the perspective of policy diffusion. AB - The zero-markup drug policy is an important component of the new round of Chinese health care reform that began in 2009 to promote the separation between medical and pharmaceutical services, reduce patients' medical burden, and improve the medical supply security system. Over the past 8 years, the zero-markup drug reform policy has been carried out in 4 pilot rounds (a policy diffusion model with Chinese characteristics) and has been promoted throughout the mainland China. At this critical point, it is necessary to review this policy systematically. Therefore, based on the literature, government documents, and interview records, this study analyzed the characteristics, progress, achievements, challenges, and recommendations of zero-markup drug reform by using the policy diffusion theory. The study found that zero-markup drug reform has completed its initial diffusion by use of the "policy experiment" method and has reduced drug prices and patients' burden to a certain extent. However, in the next phase of policy diffusion, the reform still requires adjustment and innovative measures to respond to future challenges. Generally speaking, as China's unique health care reform practice, the experience of zero-markup drug reform could be used as a reference for other countries to control drug prices, separate medical and pharmaceutical services, and establish a modern system of hospital operation. PMID- 29989205 TI - Development and implementation of a health education station by community health nursing students. AB - This paper examines the development and implementation of a health literacy/education station at a large free clinic in a metropolitan city in southern California. The station was made possible through a partnership between the leadership team at the clinic and senior nursing students at a large university located in southern California. This paper outlines the importance of health literacy, the partnership between the community health senior nursing students and faculty and a yearly 3-day health clinic, the Core Competencies of Public Health Nursing met by the event, student preparation prior to the event, outcomes, and recommendations for future clinics and for future collaborations. PMID- 29989206 TI - Microbial keratitis following intracorneal ring implantation. AB - BACKGROUND: The aim of this study is to identify predisposing factors, the clinical course and visual outcomes in patients with keratitis after intracorneal ring implantation. METHODS: In a retrospective study, 11 patients with documented keratitis after intracorneal ring implantation and 71 matched controls with uncomplicated surgery were enrolled. Patients were examined for slitlamp findings and corrected distance visual acuity at time of the initial presentation, one month later and six months later. Smears and cultures were provided in all cases. Relevant data in controls were extracted from their medical records, and statistical analysis was done. RESULTS: Keratitis onset time ranged from three to 56 days. The incidence was 2.7 per cent over two years. All pathogens were Gram positive cocci, and the most frequent was Staphylococcus spp. No relationship was found between keratitis occurrence and the ring type or the femtosecond procedure, but the rate of keratitis was higher in patients with the horizontal position of intracorneal ring segments (p = 0.001; Fisher's exact test). All cases were treated with implant explantation and tunnel irrigation with antibiotics. In three cases, amniotic membrane transplantation was performed, and two cases finally underwent penetrating keratoplasty. The final six month corrected distance visual acuity was 0.68 +/- 0.35. Poor corrected distance visual acuity improvement was associated with the ulcer size at the first day of the diagnosis (p = 0.011; Spearman's rho). CONCLUSION: The only predisposing factor was the horizontal position of the ring. A careful evaluation in the early post-operative period for any sign of the infiltration would be helpful. Early diagnosis with proper management including fortified antibiotic therapy specifically against Gram-positive cocci and removal of the intracorneal ring seems to result in acceptable visual outcomes in later follow-up. However, a corneal transplant may be the only choice in advanced infectious complications. PMID- 29989207 TI - Comparison of Enterprise Point-of-Care and Nova Biomedical Critical Care Xpress analyzers for determination of arterial pH, blood gas, and electrolyte values in canine and equine blood. AB - BACKGROUND: Point-of-care analyzers can provide a rapid turnaround time for critical blood test results. Agreement between the Enterprise Point-of-Care (EPOC) and bench-top laboratory analyzers is important to determine the clinical reliability of the EPOC. OBJECTIVES: The aim of the study was (1) to evaluate the precision (repeatability) of blood gas values measured by the EPOC and (2) to determine the level of agreement between the EPOC and Nova Critical Care Express (Nova CCX) for the assessment of arterial pH, blood gases, and electrolyte variables in canine and equine blood. METHODS: Arterial blood samples from dogs were analyzed on the EPOC and Nova CCX analyzers to determine precision and agreement of pH, PaCO2 , PaO2 , and HCT. The same analytes plus Na+ , K- , and Cl were analyzed for agreement using equine blood. Statistical analyses included assessment of precision using the coefficient of variation (CV%), and agreement using the Deming regression, Pearson correlation, and Bland-Altman plots. RESULTS: Both analyzers provided precise results of pH, PaCO2 , PaO2, and HCT, meeting CV% quality requirement values. In both species, Deming regression results were acceptable and correlation values were above 0.93 for arterial pH and blood gases, but lower for sodium and chloride. Bland-Altman plots demonstrated varying degrees of bias, but good agreement between the 2 analyzers was seen when arterial blood gases and electrolytes were measured, except for PaCO2 and Cl-. CONCLUSION: The EPOC analyzer provides consistent, reliable results for canine arterial blood gas values and for equine arterial blood gas and electrolyte values. Cl- results could be acceptable with the application of a correction factor, but the PaCO2 results were more variable. PMID- 29989208 TI - Targeting Wnt signaling pseudokinases in hematological cancers. AB - Recent studies showed that several pseudokinases from the receptor tyrosine kinase family are important players in regulating cancer cell invasion, metastasis, and drug resistance, suggesting that targeting these proteins can play a therapeutic role in cancer treatment. Receptor Tyr kinase-like orphan receptors (RORs), protein Tyr kinase 7 (PTK7) (also called colon carcinoma kinase 4 (CCK4)), and receptor-like Tyr kinase (RYK) are Wnt ligand binding receptors within the non-canonical Wnt signaling, with important roles in development, tissue homeostasis, and organogenesis. At the cellular level, these receptors transduce signals important for cell survival, migration, polarization, and chemotaxis. Considerable progress has been made in the last decade in the field of pseudokinase signaling, improving our understanding of their structure function mechanisms, and intracellular network of transduction components. Consequently, their role in various diseases, including cancer, is now scrutinized for therapeutic interventions to improve treatment outcome. In this article, we review findings regarding molecular mechanisms and targeted therapies for ROR1, PTK7, and RYK in hematological malignancies. PMID- 29989209 TI - Thermoresponsive Amphoteric Metal-Organic Frameworks for Efficient and Reversible Adsorption of Multiple Salts from Water. AB - Regenerable, high-efficiency salt sorption materials are highly desirable for water treatment. Here, a thermoresponsive, amphoteric metal-organic framework (MOF) material is reported that can adsorb multiple salts from saline water at room temperature and effectively release the adsorbed salts into water at elevated temperature (e.g., 80 degrees C). The amphoteric MOF, integrated with both cation-binding carboxylic groups and anion-binding tertiary amine groups, is synthesized by introducing a polymer with tertiary amine groups into the cavities of a water-stable MOF such as MIL-121 with carboxylic groups inside its frameworks. The amphoterized MIL-121 exhibits excellent salt adsorption properties, showing stable adsorption-desorption cycling performances and high LiCl, NaCl, MgCl2 , and CaCl2 adsorption capacities of 0.56, 0.92, 0.25, and 0.39 mmol g-1 , respectively. This work provides a novel, effective strategy for synthesizing new-generation, environmental-friendly, and responsive salt adsorption materials for efficient water desalination and purification. PMID- 29989210 TI - Effectiveness of the proximal optimization technique for longitudinal stent elongation caused by post-balloon dilatation. AB - OBJECTIVES: To evaluate the effectiveness of the proximal optimization technique (POT) to prevent longitudinal stent elongation. BACKGROUND: The mechanism of stent elongation, which occurs after post-balloon dilation, is still unclear. METHODS: A total of 103 lesions treated with optical coherence tomography guided coronary intervention between May 2013 and November 2017 were retrospectively analyzed. Lesions were divided according to the circumferential degree of malapposition at the stent edge immediately after deployment into well-apposed group (<180 degrees ) and malapposed group (>=180 degrees ). Post-dilation was performed from distal to proximal within the stent until August 2016 (non-POT cohort), and POT was applied thereafter (POT cohort). In the POT cohort, post dilation was done at the proximal portion of the stent with sufficiently large balloon to minimize malapposition followed by distal dilatations. Stent elongation length was defined as the change in stent length from stent deployment to after post-dilatation. RESULTS: In the non-POT cohort, 72 lesions, including 54 lesions in the well-apposed group and 18 in the malapposed group were analyzed. Stent elongation length was significantly longer in the malapposed group than in the well-apposed group (1.51 +/- 1.34 mm vs 0.13 +/- 0.84 mm, P < 0.01). In the POT cohort, 31 lesions including 21 in the well-apposed group and 10 in the malapposed group were analyzed. Stent elongation length was not significantly different between the groups (-0.09 +/- 0.91 mm vs 0.30 +/- 0.99 mm, P = 0.29). CONCLUSIONS: Malapposition of the stent edge is responsible for longitudinal stent elongation caused by post-dilatation. POT appeared to effectively prevent longitudinal stent elongation. PMID- 29989211 TI - Traceable Bioinspired Nanoparticle for the Treatment of Metastatic Breast Cancer via NIR-Trigged Intracellular Delivery of Methylene Blue and Cisplatin. AB - Cytotoxic T lymphocyte (CTL) eliminates abnormal cells through target recognition triggered intracellular toxin delivery. Chimeric antigen receptor T-cell improves cancer cell recognition of CTL, but its effectiveness and safety in solid tumor treatment are still hampered by poor tumor infiltration, suppressive tumor microenvironment, and severe on-target off-tumor toxicity. Given the functionality and challenges of CTL in cancer therapy, herein, a CTL-inspired nanovesicle (MPV) with a cell membrane-derived shell and a methylene blue (MB) and cisplatin (Pt) loaded gelatin nanogel core is created. The MPV generates contrast for tumor photoacoustic imaging, and produces hyperthermia upon laser irradiation, enabling photothermal imaging and deep tumor penetration. Meanwhile, it releases MB and Pt, and then delivers them into the cytosol of cancer cells, which process can be visualized by imaging the recovery of MB-derived fluorescence. The localized hyperthermia, photodynamic therapy, and chemotherapy together kill 4T1 breast cancer cells effectively, resulting in primary tumor regression and 97% inhibition of pulmonary metastasis, without significant toxicity to the animals. Taken together, the MPV shows tumor-specific and stimuli triggered intracellular toxin delivery with advantages in traceable accumulation and activation, high tumor penetration, and triple combination therapy, and thus can be an effective nanomedicine for combating metastatic breast cancer. PMID- 29989212 TI - A Highly Efficient Non-Fullerene Organic Solar Cell with a Fill Factor over 0.80 Enabled by a Fine-Tuned Hole-Transporting Layer. AB - With rapid development for tens of years, organic solar cells (OSCs) have attracted much attention for their potential in practical applications. As an important photovoltaic parameter, the fill factor (FF) of OSCs stands for the effectiveness of charge generation and collection, which significantly depends on the properties of the interlayer and active layer. Here, a facile and effective strategy to improve the FF through hole-transporting layer (HTL) modification is demonstrated. By mixing WOx nanoparticles with a poly(3,4 ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) emulsion, the surface free energy of the HTL is improved and the morphology of the active layer is optimized. Benefiting from increased carrier lifetime, a device based on WOx :PEDOT:PSS HTL exhibits a boosted performance with an FF of 80.79% and power conversion efficiency of 14.57% PCE. The results are certified by the National Institute of Metrology (NIM), which, to date, are the highest values in this field with certification. This work offers a simple and viable option of HTL modification to realize highly efficient OSCs. PMID- 29989213 TI - The physiology of uric acid and the impact of end-stage kidney disease and dialysis. AB - Uric acid-mediated biological effects are milieu dependent. In a physiological milieu, serum uric acid serves as an antioxidant; when homeostasis is perturbed, divergent effects are observed depending on the clinical context. Several epidemiologic studies indicated the presence of a direct relationship between higher concentrations of serum uric acid and cardiovascular mortality; yet not all studies support this conclusion. Although high serum levels of uric acid are associated with higher mortality in patients with nondialysis-dependent chronic kidney disease and perhaps in those with end-stage kidney disease receiving peritoneal dialysis, the opposite relationship is seen in patients with end-stage kidney disease on hemodialysis. This review discusses the pathologic mechanisms associated with elevated serum uric acid levels by clinical context; examines the interplay between uric acid metabolism and modality of renal replacement therapy; and presents hypotheses to rationalize the disparate associations between incremental levels of serum uric acid and survival across the continuum of kidney disease and by type of renal replacement therapy. PMID- 29989215 TI - Supratentorial CAPNON associated with WHO grade II meningioma: A case report. AB - Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare benign tumor of uncertain etiology, arising in the craniospinal axis. CAPNON typically arises in isolation, with only two prior reports of a concurrent second neoplasm. Here, we report the case of a male 17-year-old who presented with new-onset seizures. MRIs revealed a 2 cm extra-axial solid-cystic mass, arising at the left temporo occipital junction and abutting the dura with marked surrounding parenchymal vasogenic edema. The solid components demonstrated dense calcification and avid enhancement. Gross total surgical resection was performed. Histopathological examination revealed central regions showing characteristic features of CAPNON. Toward the periphery, the CAPNON was intimately associated with and sharply demarcated from a meningioma, which showed up to five mitoses per 10 high-power fields and had invasion into the adjacent brain parenchyma, warranting a WHO grade II designation. This is the first report of CAPNON arising in association with a meningioma. The coexistence of these two tumors raises the possibility of a reactive/dysplastic etiology for CAPNON. PMID- 29989216 TI - Research on electroencephalogram to measure thermal pleasure in thermal alliesthesia in temperature step-change environment. AB - Thermal pleasure is currently measured along psychological and physiological variables. However, in transient environments where temperatures change, it is hard to correlate psychological and physiological measures, because there is a delay in physiological changes. This study tests a method for correlating both measures using electroencephalogram (EEG), which can capture physiological feedback with a rapid response rate. In this experimental study, thermal pleasure was induced in a temperature step-change environment, one of non-uniform and transient environments. During the experiment, EEG was monitored and psychological responses of thermal sensation and thermal comfort votes were collected via survey questionnaire. A total of 50 males in their twenties participated in a climate chamber experiment. An experimental group of 25 men were exposed to temperature step-change between two different room conditions (32 degrees C, 65% and 25 degrees C, 50%), experiencing thermal pleasure. The control group of the remaining 25 men were exposed to an unchanging condition, experiencing thermal comfort close to thermal neutrality. The EEG spectral analysis demonstrated that EEG frequency band associated with pleasant emotional (theta) increased while frequency band related to pleasantness, satisfaction or relaxation (beta) decreased with thermal pleasure. PMID- 29989217 TI - The skin barrier: Epidermis vs environment. PMID- 29989218 TI - Changes in testicular size, echotexture, and arterial blood flow associated with the attainment of puberty in Dorper rams raised in a subtropical climate. AB - There is a paucity of information on the relationships of testicular morphology, echotextural attributes, and blood flow dynamics with pubertal development of rams raised in a subtropical climate. Forty-five Dorper rams (24 rams aged 8-11 months and 21 rams aged 12-24 months) were examined using a portable ultrasound scanner connected to a 7.5-MHz transducer. Computer-assisted analyses of testicular ultrasonograms utilized commercially available Image ProPlus(r) analytical software. Spectral Doppler scans of testicular arteries were performed immediately after scrotal (B-mode) ultrasonography to determine peak systolic velocity (PSV), end-diastolic velocity (EDV), resistive index (RI = [PSV EDV]/PSV), and pulsatility index (PI = [SPV-EDV]/mean velocity) of the blood vessels. The length of the testes (9.7 +/- 0.3 compared with 9.0 +/- 0.2 cm) and scrotal circumference (33.3 +/- 0.5 compared with 31.8 +/- 0.4 cm) were greater (p < 0.05) but testicular depth (4.9 +/- 0.08 compared with 4.5 +/- 0.1 cm) was less (p < 0.05) in sexually mature compared with peripubertal rams. There were no differences (p > 0.05) between the two age groups of Dorper rams in blood flow indices of testicular arteries. Mean numerical pixel values (100.5 +/- 4.1 compared with 89.2 +/- 4.8) and pixel heterogeneity (25.6 +/- 0.6 compared with 23.6 +/- 0.5) of testicular parenchyma were greater (p < 0.05) in peripubertal than in postpubertal rams. Semen volume was negatively correlated with PI of testicular arteries (r = -0.57, p = 0.04). In summary, the attainment of sexual maturity in the rams of the present study was associated with significant changes in testicular length and depth, scrotal circumference, and parenchymal echogenicity/hetrogeneity but not in testicular volume and blood perfusion rates. Testicular artery PI can be used to predict the volume of ejaculate in rams. PMID- 29989214 TI - Transcatheter mitral valve implantation for degenerated mitral bioprostheses or failed surgical annuloplasty rings: A systematic review and meta-analysis. AB - BACKGROUND: Transcatheter mitral valve-in-valve (TMVIV) and valve-in-ring (TMVIR) implantation for degenerated mitral bioprostheses and failed annuloplasty rings have recently emerged as treatment options for patients deemed unsuitable for repeat surgery. METHODS: A systematic literature review was conducted to summarize the data regarding the baseline characteristics and clinical outcomes of patients undergoing TMVIV and TMVIR procedures. RESULTS: A total of 245 patients (172 patients who underwent TMVIV surgery and 73 patients who underwent TMVIR surgery) were included in the study; 93.5% of patients experienced successful TMVIV or TMVIR implantation. The mortality rates at discharge, 30 days, and 6 months were 5.7%, 8.1%, and 23.4%, respectively. The transapical (TA) access route was used in most procedures (55.2%). The TA and transseptal (TS) access routes resulted in similar outcomes. No significant differences were observed in the short-term outcomes between the patients who developed mitral stenosis versus mitral regurgitation as the mode of failure. CONCLUSIONS: TMVIV and TMVIR implantation for degenerated mitral bioprostheses and failed annuloplasty rings are safe and effective. Both procedures, via TA or TS access, can result in excellent short-term clinical outcomes in patients with mitral stenosis or regurgitation, but long-term follow-up data are currently lacking to determine the durability of these procedures. PMID- 29989219 TI - Air quality in indoor go-kart facilities in Germany. AB - Indoor go-kart driving and viewing is enjoyed by people of all ages. However, it may pose health hazards, especially for children, pregnant women, cardiovascular patients, and elderly individuals. Depending on the race length, for example, high concentrations of various contaminants may result in severe health problems. Therefore, this project investigated the Indoor Air Quality of eight indoor go kart facilities. In general, karts that used regular fuel produced the highest concentrations of CO, benzene, TVOC, and BaP, with maximum levels up to 150 mg/m3 , 170 MUg/m3 , 2690 MUg/m3 , and 8.7 ng/m3 , respectively. As expected, the maximum CO concentrations at go-kart facilities that used liquid gas and electric karts (20 and <6 mg/m3 , respectively) were significantly lower than those at other facilities. The highest 95th percentile values for NO (2680 MUg/m3 ) and NO2 (280 MUg/m3 ) were measured for karts with liquid gas. The alkane, alkene, and cycloalkane groups, as well as benzene and the alkyl benzenes, were the predominant components of the measured TVOCs. Overall, owners of indoor go-kart tracks should ensure that the ventilation with regard to combustion products is optimally adapted in any case to reduce the levels of critical air pollutants. PMID- 29989220 TI - Environmentally Sensitive Fluorescent Nucleoside Analogues for Surveying Dynamic Interconversions of Nucleic Acid Structures. AB - Nucleic acids are characterized by a variety of dynamically interconverting structures that play a major role in transcriptional and translational regulation as well as recombination and repair. To monitor these interconversions, Forster resonance energy transfer (FRET)-based techniques can be used, but require two fluorophores that are typically large and can alter the DNA/RNA structure and protein binding. Additionally, events that do not alter the donor/acceptor distance and/or angular relationship are frequently left undetected. A more benign approach relies on fluorescent nucleobases that can substitute their native counterparts with minimal perturbation, such as the recently developed 2 thienyl-3-hydroxychromone (3HCnt) and thienoguanosine (th G). To demonstrate the potency of 3HCnt and th G in deciphering interconversion mechanisms, we used the conversion of the (-)DNA copy of the HIV-1 primer binding site (-)PBS stem-loop into (+)/(-)PBS duplex, as a model system. When incorporated into the (-)PBS loop, the two probes were found to be highly sensitive to the individual steps both in the absence and the presence of a nucleic acid chaperone, providing the first complete mechanistic description of this critical process in HIV-1 replication. The combination of the two distinct probes appears to be instrumental for characterizing structural transitions of nucleic acids under various stimuli. PMID- 29989221 TI - In silico and in vivo investigation of ferrocene-incorporated acyl ureas and homoleptic cadmium carboxylate derivatives for anticonvulsant, anxiolytic, and sedative potential. AB - In this study different derivatives of ferrocene-incorporated acyl ureas and homoleptic cadmium carboxylates were investigated for potential anticonvulsant, anxiolytic and sedative properties, using in-silico and in-vivo techniques. The molecular docking studies reveled that ferrocene compounds derivative 1-(4 bromobenzoyl)-3-(4-ferrocenylphenyl) urea (PB1) and cadmium compounds derivative bis (diphenylacetato) cadmium (II) (DPAA) exhibit binding affinities against various neurotherapeutic molecular targets involved in epilepsy, anxiety, and sedation. Both PB1 and DPAA showed high binding affinities against protein targets like mammalian shaker voltage dependent potassium channel beta subunit complex, calcium release-activated calcium channel, sodium channel 2A inactivation gate, human sodium/hydrogen exchanger regulatory factor, and gamma amino butyric acid A receptor associated protein. PB1 (2-10 mg/kg) and DPAA (1-5 mg/kg) delayed onset time of pentylenetetrazole-induced myoclonic jerks and tonic clonic seizures in mice while decreased duration of tonic-clonic seizures, determining the anticonvulsant effect of these compounds. PB1 and DPAA (0.5-1 mg/kg) exhibited anxiolytic effect by increasing time spent and number of animals entries into open arms, while decreasing time spent in dark compartment. Furthermore, PB1 (0.5-1 mg/kg) and DPAA (0.1-1 mg/kg) reduced onset time of sleep and increased duration time of sleep in mice, showing sedative effect. Taken together, our results indicate that aforementioned derivatives of ferrocene and cadmium are potent neurotherapeutic agents possessing anticonvulsant, anxiolytic and sedative properties. PMID- 29989222 TI - Evaluation of oral pharmacokinetics, in vitro metabolism, blood partitioning and plasma protein binding of novel antidiabetic agent, S009-0629 in rats. AB - S009-0629 [methyl-8-(methylthio)-2-phenyl-6-p-tolyl-4,5-dihydro-2H benzo[e]indazole-9-carboxylate] is a novel antidiabetic agent with PTP1B inhibitory activity. In this study, we have investigated the in vitro metabolic stability, plasma protein binding, blood partitioning, and oral pharmacokinetic study of S009-0629 in rats. The plasma protein binding, blood partitioning, and metabolic stability were determined by HPLC method. The oral pharmacokinetic study was analyzed by liquid chromatography coupled mass spectrometry (LC-MS/MS) method. The plasma protein binding of S009-0629 using modified charcoal adsorption method at 5 and 10 ug/mL was 80.58 +/- 1.04% and 81.95 +/- 1.15%, respectively. The KRBC/PL of S009-0629 was independent of concentration and time. The in-vitro half-life of S009-0629 at 5 and 10 uM using rat liver microsomes was determined as 273 +/- 24.46 and 281.67 +/- 26.53 min, respectively. After oral administration, S009-0629 exhibited Cmax 55.51 +/- 1.18 ng/mL was observed at 18 hr (tmax ). S009-0629 was found to have the large apparent volume of distribution (1,894.93 +/- 363.67 L/kg). Oral in-vivo t1/2 of S009-0629 was found to be 41.23 +/- 5.96 hr. A rapid and highly sensitive LC-MS/MS method was validated for S009 0629 in rat plasma. S009-0629 has high plasma protein binding and low hepatic extraction. S009-0629 has no affinity with human P-gp and BCRP in ATPase assay. After oral dosing, S009-0629 has slow absorption and elimination in rats. PMID- 29989223 TI - Anti-inflammatory and antinociceptive effects of tilifodiolide, isolated from Salvia tiliifolia Vahl (Lamiaceae). AB - Salvia tiliifolia Vahl (Lamiaceae) is used for the empirical treatment of pain and inflammation. The diterpenoid tilifodiolide (TFD) was isolated from Salvia tiliifolia. The in vitro anti-inflammatory effects of TFD (0.1-200 uM) were assessed using murine macrophages stimulated with LPS and estimating the levels of pro-inflammatory mediators for 48 h. The in vivo anti-inflammatory activity of TFD was assessed using the carrageenan-induced paw edema test for 6 h. The antinociceptive effects of TFD were evaluated using the formalin test and the acetic acid induced-writhing test. The effects of TFD on locomotor activity were assessed using the open field test and the rotarod test. TFD inhibited the production of TNF-alpha (IC50 = 5.66 uM) and IL-6 (IC50 = 1.21 uM) in macrophages. TFD (200 mg/kg) showed anti-inflammatory effects with similar activity compared to 10 mg/kg indomethacin. The administration of TFD induced antinociception in the phase 1 (ED50 = 48.2 mg/kg) and the phase 2 (ED50 = 28.9 mg/kg) of the formalin test. In the acetic acid assay, TFD showed antinociceptive effects (ED50 = 32.3 mg/kg) with similar potency compared to naproxen (ED50 = 36.2 mg/kg). In the presence of different inhibitors in the acetic acid assay, only the co-administration of TFD and naloxone reverted the antinociceptive activity shown by TFD alone. TFD did not affect locomotor activity in mice. TFD exerts in vitro and in vivo anti-inflammatory activity and in vivo antinociceptive effects. PMID- 29989224 TI - Interlayers Self-Generated by Additive-Metal Interactions in Organic Electronic Devices. AB - The fundamental structure of all organic electronic devices is a stack of thin layers sandwiched between electrodes, with precise intralayer morphology and interlayer interactions. Solution processing multilayers with little to no intermixing is, however, technically challenging and often incompatible with continuous roll-to-roll, high-speed manufacturing. Here, an overview of a recently developed methodology for self-generation of interlayers positioned between the active layer and metal contact is presented. The interlayer material is blended as an additive in the active layer and migrates to the organic/metal interface during metal deposition. The driving force for this migration is additive-metal interactions. The generated interlayer positions an interfacial dipole that reduces barriers for charge transfer across the organic/metal interface. This methodology is generic and, as reported here, the self-generated interlayers significantly improve the performance of many devices. Importantly, this approach is compatible with printing and reel-to-reel processing. Directives toward additive selection, processing conditions and integration in future applications are also discussed. PMID- 29989225 TI - Unexpected High Second-Order Nonlinear Optical Activity of Metal Complexes with Three-Branched Hexadentate 2,2'-Bipyridine Ligands. AB - Two hexadentate bipyridine ligands and their RuII and NiII complexes were prepared. The helical alignment of the three electron-donor-pi-bridge-electron acceptor (d-pi-A) single-strands with bundle architecture in cooperation with the metal center can strongly enhance the nonlinear optical (NLO) properties. The complexation of the novel cage-type hexadentate ligands with a paramagnetic NiII core almost doubles the betaHRS values compared with the corresponding diamagnetic RuII complexes. The hyper-Rayleigh scattering (HRS) was performed with a highly sensitive setup for simultaneous discrimination between multi photon fluorescence and the molecular first hyperpolarizability. PMID- 29989226 TI - Reduced vision in a diabetic patient due to incidental leukaemic retinopathy. PMID- 29989227 TI - Triazoles as T2 -Exchange Magnetic Resonance Imaging Contrast Agents for the Detection of Nitrilase Activity. AB - We characterized the T2 -exchange (T2ex ) magnetic resonance imaging (MRI) contrast of azole protons that have large chemical shifts from the water proton resonance as a function of pH, temperature, and chemical modification. Our results showed that 1,2,4-triazoles could be tuned into excellent diamagnetic T2ex contrast agents, with an optimal exchange-based relaxivity r2ex of 0.10 s-1 mm-1 at physiological pH and B0 =9.4 T. A fit of r2ex data to the Swift-Connick equation indicated that imino proton exchange of triazoles is dominated by a base catalyzed process at higher pH values and an acid-catalyzed process at lower pH. The magnitude of r2ex was also found to be heavily dependent on chemical modifications, that is, enhanced by electron-donating groups, such as amines and methyls, or by intramolecular hydrogen bonding between the imino proton and the carboxyl, and weakened by electron-withdrawing groups like bromo, cyano, and nitro. In light of these findings, we applied T2ex MRI to assess the activity of nitrilase, an enzyme catalyzing the hydrolysis of 1,2,4-triazole-3-carbonitrile to 1,2,4-triazole-3-carboxylic acid, resulting in the enhancement of R2ex . Our findings suggest that 1,2,4-triazoles have potential to provide sensitive and tunable diagnostic probes for MRI. PMID- 29989229 TI - Bruxism in dentists' families. PMID- 29989228 TI - Consciousness assessment: A questionnaire of current neuroscience nursing practice in Europe. AB - AIMS AND OBJECTIVES: To study practice in consciousness assessment among neuroscience nurses in Europe. BACKGROUND: Over the years, several instruments have been developed to assess the level of consciousness for patients with brain injury. It is unclear which instrument is being used by nurses in Europe and how they are trained to use these tools adequately. DESIGN/METHODS: A cross-sectional questionnaire, created by the European Association of Neuroscience Nurses Research Committee, was sent to neuroscience nurses in 13 European countries. The countries participated in 2016 with a response period of 3 months for each country. RESULTS: A total of 331 questionnaires were completed by nurses in 11 different countries. Assessment of consciousness was part of the daily routine for a majority of bedside nurses (95%), with an estimated median frequency of six times per shift. The majority uses a standardised instrument, and the Glasgow Coma Scale is the most common. Most participants assess consciousness primarily for clinical decision-making and report both total scores and subscores. The majority was formally trained or educated in use of the instrument, but methods of training were divers. Besides the estimated frequency of assessments and training, no significant difference was found between bedside nurses and other nurse positions, educational level or kind of institution. CONCLUSION: Our study shows that consciousness assessment is part of the daily routine for most nurses working in neurology/neurosurgery/neurorehabilitation wards in Europe. The greatest variation existed in training methods for the use of the instruments, and we recommend standardised practice in the use of assessment scales. RELEVANCE TO CLINICAL PRACTICE: In clinical practice, both managers and staff nurses should focus on formalised training in the use of assessment tools, to ensure reliability and reproducibility. This may also increase the professionalism in the neuroscience nurses' role and performance. PMID- 29989230 TI - A Chinese version of the Patient Perceptions of Patient-Empowering Nurse Behaviours Scale: Reliability and validity assessment in chronically ill patients. AB - AIMS AND OBJECTIVES: To translate the Patient Perceptions of Patient-Empowering Nurse Behaviours Scale (PPPNBS) into Chinese and to psychometrically test the Chinese version of PPPNBS (PPPNBS-C) in chronically ill patients. BACKGROUND: The growing prevalence and burden of chronic illnesses became the driving force for the need of empowerment as an approach to engage patients in self-management. The PPPNBS was developed to assess patient perceptions of the process of empowerment during hospitalisation. Extending its application to different clinical context and ethnicities is worth pursuing. DESIGN: A cross-sectional survey. METHODS: The PPPNBS was translated according to Brislin's translation guidelines and was culturally adapted. A questionnaire survey was carried out to determine the reliability and validity of the PPPNBS-C among a total of 517 hospitalised patients with chronic illnesses. RESULTS: The content validity was found to be good with a content validity index of 0.94. Exploratory factor analysis identified six factors explaining 68.56% of the total variance and confirmatory factor analysis confirmed this six-factor structure. The hypothesised differences were demonstrated through contrasted group comparisons by time since diagnosis and length of hospital stay. The score of the PPPNBS-C was significantly and positively associated with that of the Client Satisfaction Questionnaire, as was the Self-Efficacy for Managing Chronic Disease 6-Item Scale score, providing evidence of convergent validity. The Cronbach's alpha coefficient was 0.960 and the intraclass correlation coefficient was 0.86 for the total scale, explaining good internal consistency and time stability. CONCLUSIONS: The PPPNBS-C has preliminary verification of the validity and reliability and could be useful in measuring patient perceptions of patient-empowering nurse behaviours. RELEVANCE TO CLINICAL PRACTICE: The PPPNBS-C can be applied to chronically ill patients as a metric of the implementation status of patient-empowering nurse behaviours and can be used as a guide to encourage nurse's intentional utilisation of empowering behaviours. PMID- 29989231 TI - Walking on a tightrope-Caring for ambivalent women considering abortions in the first trimester. AB - AIMS AND OBJECTIVES: To improve the understanding and competence of health personnel when caring for ambivalent pregnant women, the aim of this study was to explore the experiences of encountering women who are unsure whether to complete or terminate pregnancy. BACKGROUND: Feelings of ambivalence are present in a significant number of women preparing for abortions and may challenge the provision of health care. Health personnel have reported an ideal to be nonjudgemental and supportive. Insufficient attention has been directed to the experiences of health personnel who prepare women for abortions in gynaecological units. DESIGN: Qualitative design with a hermeneutic-phenomenological approach. METHODS: Focus group interviews were conducted with health personnel from four gynaecological outpatient clinics and wards in Norway (n = 20). RESULTS: The health personnel felt responsible for contributing to patient well-being. This demanded focused attention towards all women being prepared for abortions and meant a consciousness and balancing act towards revealing, handling and being involved in the woman's potential unsureness without influencing her decision. When involved, the health personnel risked being confronted with their own vulnerabilities and values. CONCLUSIONS: The health personnel tried to balance their care and support without influencing the woman's decision. Although they viewed the women as fully autonomous and responsible, they became personally involved, to varying degrees, in the uncertainty and were faced with their own vulnerabilities and values. They lacked a possibility for immediate debriefing and regular counselling after complicated consultations. RELEVANCE TO CLINICAL PRACTICE: Knowledge of the experiences of health personnel can provide input for professional development at gynaecological departments. These findings contribute to discussions about what information should be given and whether the woman's feelings should be discussed in preparation for an abortion. The ability of health personnel to discuss subjects related to ethically challenging encounters with women who are considering abortions should be established, namely, professional education and workshops at the national level and small groups with counselling and case study discussions at hospitals. PMID- 29989232 TI - Mono- and Bisionic Mo- and W-Based Schrock Catalysts for Biphasic Olefin Metathesis Reactions in Ionic Liquids. AB - An extensive series of the first ionic Mo- and W-based Schrock-type catalysts based on pyridinium and phosphonium tagged aryloxide ligands were prepared. Bisionic complexes of the general formula Mo(Imido)(CHR)(OR')2 (OTf)2 and monoionic monoaryloxide pyrrolide (pyr) (MAP-type) catalysts [M(Imido)(CHR)(OR')(pyr)+ ][A- ] were successfully employed and tested in various olefin metathesis benchmark reactions under both, homogeneous and biphasic conditions using pyrrole and, for the first time with Schrock-type catalysts, ionic liquids as the polar phase. Productivities under biphasic conditions up to several thousand turn overs were achieved and are comparable to those obtained in reactions carried out in chlorobenzene or toluene. Metal contamination in the nonpolar product-containing heptane phase was <2 ppm. PMID- 29989233 TI - Caring Interaction with stroke survivors' family members-Family members' and nurses' perspectives. AB - AIMS AND OBJECTIVES: To examine emotional support given by nurses to family members in the acute phase after a working-aged patient's stroke based on nurses' and family members' experiences. BACKGROUND: The number of patients with stroke is increasing globally. There is a lack of knowledge about the emotional support of family members during the acute phase of working-aged stroke victims. To be able to provide high-quality nursing care during this phase, we need information about emotional support from family members' and nurses' perspective. METHOD: Using a Glaserian grounded theory approach, the study was conducted using open interviews with family members and group interviews with nurses. Data were collected between 2012-2013. RESULTS: In this study, emotional support is identified as Caring Interaction. The changed life situation and diverse feelings aroused by the stroke are the starting point of providing emotional support to family members. It is important that the nurses notice family members' need for support at the right time, use their intuition and respond appropriately. CONCLUSIONS: The patient's family members are important when providing holistic nursing care for the whole family. As well as providing emotional support, high quality nursing interventions enhance the care of family members. This study provides an explanation of the interaction process between family members and nurses. It helps family members and nurses to better understand each other. Although the data were collected 5 years ago, it is assumed that the interaction between family members and nurses has not changed during these years remarkably. RELEVANCE TO CLINICAL PRACTICE: According to the experiences of family members and nurses who participated in this research, emotional support manifests in Caring Interaction. Being aware of body language and behaviour of family members, nurses can better interact with them. PMID- 29989234 TI - FDG-PET/CT in the management of lymphomas: current status and future directions. AB - FDG-PET/CT is the current state-of-the-art imaging in lymphoma and plays a central role in treatment decisions. At diagnosis, accurate staging is crucial for appropriate therapy selection: FDG-PET/CT can identify areas of lymphoma missed by CT alone and avoid under-treatment of patients with advanced disease stage who would have been misclassified as having limited stage disease by CT. Particularly in Hodgkin lymphoma, positive interim FDG-PET/CT scans are adversely prognostic for clinical outcomes and can inform PET-adapted treatment strategies, but such data are less consistent in diffuse large B-cell lymphoma. The use of quantitative FDG-PET/CT metrics using metabolic tumour volume, possibly in combination with other biomarkers, may better define prognostic subgroups and thus facilitate better treatment selection. After chemotherapy, FDG-PET/CT response is predictive of outcome and may identify a subgroup who benefit from consolidative radiotherapy. Novel therapies, in particular immunotherapies, exhibit different response patterns than conventional chemotherapy, which has led to modified response criteria that take into account the risk of transient pseudo progression. In relapsed lymphoma, FDG-PET/CT after second-line therapy and prior to high-dose therapy is also strongly associated with outcome and may be used to guide intensity of salvage therapy in relapsed Hodgkin lymphoma. Currently, FDG PET/CT has no role in the routine follow-up after complete metabolic response to therapy, but it remains a powerful tool for excluding relapse if patients develop clinical features suggestive of disease relapse. In conclusion, FDG-PET/CT plays major roles in the various phases of management of lymphoma and constitutes a step towards the pursuit of personalized treatment. PMID- 29989235 TI - Expert in nursing care but sometimes disrespected-Telenurses' reflections on their work environment and nursing care. AB - AIMS AND OBJECTIVES: To describe telenurses' reflections on their work environment and how it impacts on their nursing care. BACKGROUND: Telenursing is one of the largest healthcare settings in Sweden today; approximately 5.5 million care-seekers call the designated number-1177-each year. Telenursing is regarded as highly qualified nursing care, and providing care over the telephone is considered a complex form of nursing. Within other fields of nursing, the work environment has been shown to affect the outcome of care, patient safety, nurse job satisfaction and burnout. DESIGN: The study used a descriptive design and followed the COREQ checklist. METHODS: Twenty-four interviews were performed and analysed using qualitative content analysis. RESULTS: The main theme concerned "feeling like a nursing care expert but sometimes being disrespected." The telenurses reported that their work environment supported their work as nursing care experts via the telephone in some respects, but also hindered them. Appreciation and respect they received from the vast majority of callers positively impacted the work environment and contributed to work satisfaction. However, they also felt disrespected by both their employers and healthcare staff; they sometimes felt like a dumping ground. Receiving support from colleagues seemed invaluable in helping them feel like and be a nursing care expert. CONCLUSION: Work was perceived as cognitively demanding and sometimes exhausting, but appreciation from care-seekers and the feeling of being able to provide qualified nursing care made working as a telenurse worthwhile. RELEVANCE TO CLINICAL PRACTICE: If telenurses are to perform good nursing care over the telephone, managers must provide them with resources, for example, support, education and opportunities for recovery during shifts. It seems that the role of the 1177 service has not been properly implemented and accepted within the healthcare system, and politicians need to anchor its mission within the healthcare organisation. PMID- 29989236 TI - Room service in a public hospital improves nutritional intake and increases patient satisfaction while decreasing food waste and cost. AB - BACKGROUND: Room service (RS) is a hospital foodservice model that is traditionally unique to the private sector. It allows patients to order meals compliant to their nutritional requirements from a single integrated menu at a time that suits them. Meals are prepared and delivered within 45 min of order. Following implementation in a private adult facility in 2013, Mater Group implemented the first RS in a public adult facility in Australia in 2016. In a pre-post study comparing RS with a traditional foodservice model (TM), key outcomes were measured and analysed. METHODS: A retrospective analysis of quality assurance data audits in a pre-post study design was undertaken to assess patient nutritional intake, plate waste, satisfaction and meal costs before and after RS implementation. RESULTS: Comparison of nutritional intake between TM (n = 84) and RS (n = 103) showed statistically significant increases with RS in both energy (5513 kJ day-1 versus 6379 kJ day-1 , P = 0.020) and protein (53 g day-1 versus 74 g day-1 , P < 0.001) intake, as well as energy and protein intake as a percentage of requirements (64% versus 78%, P = 0.002 and 70% versus 99%, P < 0.001, respectively). Total average plate waste decreased from 30% to 17% (P < 0.001). Patient satisfaction indicated an improvement with RS, with 98% of patients scoring the service good to very good, compared to 75% for TM (P < 0.04). Patient food costs decreased by 28% per annum with RS. CONCLUSIONS: This research provides insight into the benefits achievable with RS in the public hospital setting, confirming that a patient-centred food service model can cost effectively improve clinical outcomes. PMID- 29989237 TI - Caregiving experiences, coping strategies and needs of foreign domestic workers caring for older people. AB - BACKGROUND: In societies with ageing populations, foreign domestic workers are essential to provide care for older people in the community. Despite an increasing trend of employing foreign domestic workers as live-in caregivers to older people, limited research has been done to understand their caregiving experiences and coping strategies. AIMS AND OBJECTIVES: To explore the caregiving experiences and coping strategies of foreign domestic workers caring for older people in Singapore. DESIGN: Descriptive qualitative study. METHODS: This study was conducted in a large hospital in Singapore. Purposive sampling was used. Participants had to be able to converse in English and employed as foreign domestic workers to provide care to individuals aged 60 years and above, and needed assistance in at least one activity of daily living. Face-to-face in-depth interviews were conducted until data saturation was achieved. Interviews were audio-recorded and transcribed verbatim. Transcribed data were analysed using thematic analysis. RESULTS: We interviewed 11 participants. Their mean age was 35 years, and they provided caregiving for about 20 hours daily. Eleven subthemes were identified and were organised into four main themes. These themes were "Juggling with Caregiving and Additional Responsibilities," "Facing Challenges," "Coping strategies" and "Seeking support." CONCLUSIONS: Findings showed that many foreign domestic workers lacked the needed physical rest and support for them to recharge, and they were stressed caring for older people with behavioural issues. The findings highlighted the need for more physical rest, social support and caregiver training on behavioural management for foreign domestic workers. RELEVANCE TO CLINICAL PRACTICE: The findings could aid the understanding of the challenges and needs of foreign domestic workers and thereafter assist in development of relevant community nursing, social support and training on disruptive behavioural management for foreign domestic workers for them to effectively care for older people in the community. PMID- 29989238 TI - Spatio-temporal expression dynamics differ between homologues of flowering time genes in the allopolyploid Brassica napus. AB - Polyploidy is a recurrent feature of eukaryotic evolution and has been linked to increases in complexity, adaptive radiation and speciation. Within angiosperms such events have occurred repeatedly in many plant lineages. Here we investigate the retention and spatio-temporal expression dynamics of duplicated genes predicted to regulate the floral transition in Brassica napus (oilseed rape, OSR). We show that flowering time genes are preferentially retained relative to other genes in the OSR genome. Using a transcriptome time series in two tissues (leaf and shoot apex) across development we show that 67% of these retained flowering time genes are expressed. Furthermore, between 64% (leaf) and 74% (shoot apex) of the retained gene homologues show diverged expression patterns relative to each other across development, suggesting neo- or subfunctionalization. A case study of homologues of the shoot meristem identity gene TFL1 reveals differences in cis-regulatory elements that could explain this divergence. Such differences in the expression dynamics of duplicated genes highlight the challenges involved in translating gene regulatory networks from diploid model systems to more complex polyploid crop species. PMID- 29989239 TI - Medical cannabis legalization and opioid prescriptions: evidence on US Medicaid enrollees during 1993-2014. AB - BACKGROUND AND AIMS: While the United States has been experiencing an opioid epidemic, 29 states and Washington DC have legalized cannabis for medical use. This study examined whether state-wide medical cannabis legalization was associated with reduction in opioids received by Medicaid enrollees. DESIGN: Secondary data analysis of state-level opioid prescription records from 1993-2014 Medicaid State Drug Utilization Data. Linear time-series regressions assessed the associations between medical cannabis legalization and opioid prescriptions, controlling for state-level time-varying policy covariates (such as prescription drug monitoring programs) and socio-economic covariates (such as income). SETTING: United States. PARTICIPANTS: Drug prescription records for patients enrolled in fee-for-service Medicaid programs that primarily provide health-care coverage to low-income and disabled people. MEASUREMENTS: The primary outcomes were population-adjusted number, dosage and Medicaid spending on opioid prescriptions. Outcomes for Schedule II opioids (e.g. hydrocodone, oxycodone) and Schedule III opioids (e.g. codeine) were analyzed separately. The primary policy variable of interest was the implementation of state-wide medical cannabis legalization. FINDINGS: For Schedule III opioid prescriptions, medical cannabis legalization was associated with a 29.6% (P = 0.03) reduction in number of prescriptions, 29.9% (P = 0.02) reduction in dosage and 28.8% (P = 0.04) reduction in related Medicaid spending. No evidence was found to support the associations between medical cannabis legalization and Schedule II opioid prescriptions. Permitting medical cannabis dispensaries was not associated with Schedule II or Schedule III opioid prescriptions after controlling for medical cannabis legalization. It was estimated that, if all the states had legalized medical cannabis by 2014, Medicaid annual spending on opioid prescriptions would be reduced by 17.8 million dollars. CONCLUSION: State-wide medical cannabis legalization appears to have been associated with reductions in both prescriptions and dosages of Schedule III (but not Schedule II) opioids received by Medicaid enrollees in the United States. PMID- 29989240 TI - Clinical characteristics and treatment outcomes in IgE multiple myeloma: A case control study. PMID- 29989241 TI - A positive-charged patch and stabilized hydrophobic core are essential for avirulence function of AvrPib in the rice blast fungus. AB - Fungal avirulence effectors, a key weapon utilized by pathogens to promote their infection, are recognized by immune receptors to boost host R gene-mediated resistance. Many avirulence effectors share sparse sequence homology to proteins with known functions, and their molecular and biochemical functions together with the evolutionary relationship among different members remain largely unknown. Here, the crystal structure of AvrPib, an avirulence effector from Magnaporthe oryzae, was determined and showed a high degree of similarity to the M. oryzae Avrs and ToxB (MAX) effectors. Compared with other MAX effectors, AvrPib has a distinct positive-charge patch formed by five positive-charged residues (K29, K30, R50, K52 and K70) on the surface. These five key residues were essential to avirulence function of AvrPib and affected its nuclear localization into host cells. Moreover, residues V39 and V58, which locate in the hydrophobic core of the structure, cause loss of function of AvrPib by single-point mutation in natural isolates. In comparison with the wild-type AvrPib, the V39A or V58A mutations resulted in a partial or entire loss of secondary structure elements. Taken together, our results suggest that differences in the surface charge distribution of avirulence proteins could be one of the major bases for the variation in effector-receptor specificity, and that destabilization of the hydrophobic core is one of the major mechanisms employed by AvrPib for the fungus to evade recognition by resistance factors in the host cell. PMID- 29989242 TI - Editorial Note. PMID- 29989243 TI - "But this is a good cancer:" Patient perceptions of endometrial cancer in Denmark. AB - AIMS AND OBJECTIVES: To explore endometrial cancer patients' perceptions of the disease and the influence of favourable prognoses on their experiences. BACKGROUND: Endometrial cancer is associated with favourable prognoses, which may imply that patients experience distress to a lesser extent than other cancer patients with less positive treatment outcomes. However, most people with cancer report reduced quality of life and, despite endometrial cancer being prevalent worldwide, experiences of the disease have been little explored. DESIGN: Ethnographic fieldwork with participant observations and interviews. METHODS: Observations during clinical consultations at two Danish hospitals and interviews with women with endometrial cancer (n = 18) over a period of 6 months. The article adheres to the COREQ guidelines for reporting qualitative research. RESULTS: We identify how patients consider cancer in general very likely to be fatal, while clinicians in contrast characterise endometrial cancer specifically as "good" because of favourable prognoses. We employ the concept of bricolage to illustrate how bits and pieces of biomedical knowledge and statistical evidence become intertwined with patients' past experiences and subjective ways of knowing, suggesting that patients' perceptions of endometrial cancer as a disease are somewhat dynamic. CONCLUSIONS: Public stories and everyday life experiences of cancer provide a central framework for illness perceptions. As a result, patients retain the idea of a close connection between cancer and death, while also adopting the notion of endometrial cancer as "good". This influenced how women responded to treatment and care. Framing endometrial cancer as "good" is not always helpful, as the impact of a cancer diagnosis per se is rarely favourable. RELEVANCE TO CLINICAL PRACTICE: In providing women with endometrial cancer with optimal support through diagnosis and treatment, clinicians should attend to the complexity of patients' illness understandings and be aware that assuring patients of a good prognosis not always has the expected impact. PMID- 29989244 TI - Management of cytologic material, preanalytic procedures and biobanking in lymph node cytopathology. AB - The range of pathologies that lymph node (LN) fine needle cytology (FNC) may encounter is extremely wide and ancillary techniques, in addition to traditional smears, are generally required to reach reliable cytologic diagnoses. Storing part of the cytologic material may be useful or necessary for molecular testing. The main difficulties concern the generally small size of the sample and the different methods of acquisition of LN-FNC. Therefore, the preanalytic phase is extremely important for LN-FNC. This article outlines the management of LN-FNC material, vials, technical devices (e.g.: additional smears, cytospin slides, LBC slides, cards, resins, etc.) and main ancillary techniques to assess their optimal application, taking into account the different diagnostic needs and cell storage. PMID- 29989245 TI - A calibration framework for the determination of accurate collision cross sections of polyanions using polyoxometalate standards. AB - RATIONALE: Polyoxometalates (POMs) are remarkable oxo-clusters forming compact highly charged anions. We measured their collision cross sections (CCS) in N2 with drift tube ion mobility spectrometry (DTIMS). These values were then used to calibrate a traveling wave ion mobility spectrometry (TWIMS) device and the accuracy of the calibration was tested. METHODS: Six POM standards were analyzed by DTIM-MS (Tofwerk, Thun, Switzerland) at different voltages to determine absolute DT CCS (N2 ) values. Five POM compounds (Lindqvist TBA2 Mo6 O19; decatungstate TBA4 W10 O32; Keggin TBA3 PMo12 O40 ; TBA3 PW12 O40 and Dawson TBA6 P2 W18 O62 ) were used for the calibration of the TWIM-MS instrument (Synapt G2 HDMS, Waters, Manchester, UK) and a sixth Dawson POM, TBA9 P2 Nb3 W15 O62 , was used to compare the accuracy of the calibrations with POM or with polyalanine and dextran reference ions. RESULTS: We determined 45 DT CCS (N2 ) values at 30 degrees C or 60 degrees C. Fourteen DT CCS (N2 ) values at 30 degrees C were used to perform calibration of the TWIMS instrument. Better correlations were observed than when DT CCS values in helium from the literature were used. The accuracy tests on six ions of Dawson POM TBA9 P2 Nb3 W15 O62 led to relative errors below 3.1% while relative errors of 3.6% to 10.1% were observed when calibration was performed with polyalanine and dextran reference ions. CONCLUSIONS: Our novel calibration strategy for determination of CCS values of multiply negatively charged ions on TWIM-MS devices based on DT CCS (N2 ) of standard POM structures covered a wider range of CCS and improved the accuracy to 2.1% relative error on average compared with 6.9% using polyalanine and dextran calibration. PMID- 29989246 TI - Foliar epidermal micromorphology and its taxonomic implications in some selected species of Athyriaceae. AB - For the robust identification of taxonomically complex fern family like Athyriaceae, light and scanning electron microscopy is significance implications. This article present first microscopic investigation of foliar micromorphology of 3 genera and 10 species belonging to Athyriaceae namely, Athyrium, Deparia, and Diplazium were collected from different localities in Malakand Division, Northern Pakistan. In present study we compare foliar micromorphology of all 10 species using standard protocols of light microcopy (LM) and scanning electron microscopy. Qualitative micromorphological variations in shape of epidermal cells, anticlinal wall pattern, stomatal type and shape, stomatal pore shape, guard cells shape, and trichomes types were studied. In addition, some quantitative characters were also studied and data were statistically analyzed in epidermal cell size, stomatal size, stomatal pore size, stomatal density, and stomatal index. The pivotal result of study include; shape of epidermal cell in all species is irregular on both abaxial and adaxial surfaces. The anticlinal walls are sinuous in most of the species but some species have irregular lobed and broadly lobed wall. Leaves are hypostomatic in all studied species. Two main categories of stomatal type were found: polocytic and anomocytic. Unicellular nonglandular trichomes were observed in only one species Athyrium mackinnoni. The variation in foliar micromorphological characters between the genera and within the species was useful in identification and classification and have potential taxonomic significance for species differentiation. An identification key using micromorphological characters are provided to distinguish genera and species. PMID- 29989247 TI - Post-marketing studies of pharmaceutical opioid abuse-deterrent formulations: a framework for research design and reporting. AB - BACKGROUND AND AIMS: Opioid formulations with properties to deter abuse (abuse deterrent formulations; ADFs) have been developed as one response to the prescription opioid 'epidemic'. As for all medicines, ADFs undergo evaluation of safety and efficacy prior to registration for marketing. However, reduced extra medical use (the primary intended outcome of ADFs and reason for their introduction) can only be established in post-marketing observational studies, comparing them to opioid formulations without abuse-deterrent properties. This has implications for various features of study design and analysis. We discuss proposals for the design, conduct, governance and reporting of post-marketing studies on the effectiveness of pharmaceutical and opioid ADFs. METHODS: A review of current guidance documents, public work-shops and forums and our own experience with post-marketing studies of ADFs. RESULTS AND CONCLUSIONS: Research questions for post-marketing studies on ADFs of opioids should reasonably be framed around detecting any probable intended or unintended clinical and/or meaningful changes in specific aspects of extra-medical use (e.g. injection use) and harms. Outcomes reported by prevalence and frequency of occurrence and disaggregated by specific product and route of administration can illustrate the magnitude of ADF impact. We argue that a multi-faceted approach is required, using data from both general population and sentinel high-risk cohorts and from primary and secondary data sources. The comparator (historical non-ADF formulation of that opioid, equivalent current generic or similar opioid product), duration of monitoring and analytical approach require justification and should be sufficient to add weight to conclusions of causality. To maximize transparency, we recommend explicit declarations of funding and conflict of interest, establishment of an advisory committee, publication of study protocol and access to study results. PMID- 29989248 TI - Sham sleep feedback delivered via actigraphy biases daytime symptom reports in people with insomnia: Implications for insomnia disorder and wearable devices. AB - This study investigated whether providing sham feedback about sleep to individuals with insomnia influenced daytime symptom reports, sleep-related attentional bias and psychomotor vigilance. Sixty-three participants meeting DSM 5 criteria for insomnia disorder were recruited from the community. Following baseline assessments and actigraphy briefing, participants were randomised to receive next-day sham feedback on sleep quality ("positive" vs. "negative" sleep efficiency condition). Feedback was delivered at habitual rise-time using an integrated actigraphy-diary watch to simulate wearable device behaviour. Participants completed symptom reports immediately before receiving feedback, and at 12:00 and 15:00 hr, using the experience sampling method. Following this they returned to the laboratory in the evening to complete symptom reports and computerised tests of sleep-related attentional bias and basic psychomotor vigilance. Participants randomised to negative feedback (n = 32) evidenced impaired daytime function (decreased alert cognition [d = 0.79], increased sleepiness/fatigue [d = 0.55]) in the evening compared with those given positive feedback (n = 31). Within-day trajectories revealed that the positive-feedback group, relative to the negative-feedback group, displayed a significantly greater increase in positive mood and alert cognition (from rise-time to 12:00 hr), and significantly greater decrease in sleepiness/fatigue. There were no significant between-group differences on measures of sleep-related attentional bias [d = 0.20] or psychomotor vigilance [d = 0.12]. This controlled experiment shows that sham feedback about sleep biases appraisal of daytime symptoms, highlighting a pathway connecting sleep misperception with daytime features of insomnia. Findings have important implications for wearable devices that claim to measure "objective" sleep yet may provide inaccurate data relative to gold-standard measurement. PMID- 29989249 TI - Investigating the JD-R occupational stress model with Australian direct-care workers: A focus group approach. AB - This study aimed to explore the use of a contemporary workplace stress model, the Job Demands-Resources model, with direct-care workers using a qualitative approach. The JD-R model has successfully been used to predict health outcomes across different occupations using quantitative methods. However, the use of the generic questionnaire developed for this model may not always be appropriate. Direct-care workers (n = 19) attended two focus groups and reported on their job demands, job resources and personal resources. Six themes relating to demands across the two groups: funding insecurity, time pressure, hindrance demands, poor systems, emotional engagement and dealing with client crises were identified. Participants identified clinical supervision, social support and progressive workplace resources as job resources. Finally, the personal resources identified by participants were professional behaviours, disposition and self-care. The JD-R model and its standard questionnaire captures some of these aspects of direct care work, but many were not assessed. As such, future investigations with direct care workers should ensure items related to poor systems, progressive workplace resources, disposition and professional behaviours are included. Alternatively, a qualitative approach should be used as a first step in the development of valid questionnaires when investigating workplace stress with this group to ensure their experience is accurately quantified. PMID- 29989250 TI - Moderating effect of depression on the association between pain and activities of daily living in older adults. AB - BACKGROUND: Maintaining older adults' ability to function independently in the community is a critically important public health concern. One of the most common symptoms threatening that ability is pain. Depression is a common co-occurring symptom in older adults with pain. In the present study, we determined the moderating effect of depression on the association between pain and functional limitations. METHODS: Data were from the Healthy Aging Longitudinal Study in Taiwan, a population-based study of community-dwelling older adults in Taiwan (N = 2680). All data were collected by face-to-face interviews. Sociodemographic and health-related factors along with the location and severity of pain were collected. Functional limitation was assessed using the Barthel Index of Activities of Daily Living, whereas depression was assessed using the Center for Epidemiologic Studies Depression Scale. RESULTS: Pain presence was not significantly associated with functional limitation, but overall pain severity and number of pain sites were. Depressive older adults exhibited a stronger association of pain and functional limitation. CONCLUSION: Depression moderates the relation between pain and functional limitation. This knowledge may be valuable in developing effective public health and clinical management strategies to reduce functional limitation in older adults. PMID- 29989251 TI - Gastrointestinal: A case of hypereosinophilic syndrome with esophageal involvement. PMID- 29989252 TI - Intranasal ovalbumin immunotherapy with mycobacterial adjuvant promotes regulatory T cell accumulation in lung tissues. AB - Allergen-specific immunotherapy to induce T regulatory cells in the periphery has been used to treat allergic diseases. Mycobacteria can be used as an adjuvant for inducing T regulatory cells. However, it is unclear whether intranasal immunotherapy in combination with Mycobacteria adjuvant induces regulatory T cell differentiation and attenuates allergic responses in vivo. To investigate the role of intranasal ovalbumin (OVA) treatment alone and in combination with Mycobacteria vaccae, proportions of FoxP3+ regulatory T cells and anti inflammatory responses were evaluated in a murine model of asthma that was established in three groups of bicistronic Foxp3EGFP reporter BALB/c mice. Before establishment of the asthma model, two groups of mice received intranasal OVA immunotherapy and one also received simultaneous s.c. M. vaccae. Expression of CD4+ CD25+ Foxp3+EGFP+ T cells in the lung and spleen was analyzed by flow cytometry and the cytokine profiles of allergen-stimulated lung and spleen lymphocytes assessed. The intranasal OVA immunotherapy group showed greater expression of CD4+ CD25+ Foxp3+EGFP+ T cells in the spleen whereas in the group that also received M. vaccae such greater expression was demonstrated in the lung. Additionally, the proportion of IL-10 and IFN-gamma-secreting splenocytes was greater in the intranasal OVA + M. vaccae group. CD25 neutralization decreased CD4+ Foxp3+ cells more than other groups. In parallel with this finding, production of IL-10 and IFN-gamma was down-regulated. Mucosal administration of OVA antigen results in a greater proportion of CD4+ Foxp3+ T cells in the spleen. IL-10 and IFN-gamma induced by intranasal OVA immunotherapy and M. vaccae administration is down-regulated after CD25 neutralization. PMID- 29989253 TI - Two Consecutive Magneto-Structural Gas-Solid Transformations in Non-Porous Molecular Materials. AB - Modification of the magnetic properties in a solid-state material upon external stimulus has attracted much attention in the recent years for their potential applications as switches and sensors. Within the field of coordination polymers, gas sorption studies typically focus on porous solids, with the gas molecules accommodating in the channels. Here we present a 1D non-porous coordination polymer capable of incorporating HCl gas molecules, which not only causes a reordering of its atoms in the solid state but also provokes dramatic changes in the magnetic behavior. Subsequently, a further solid-gas transformation can occur with the extrusion of HCl gas molecules causing a second structural rearrangement, which is also accompanied by modification in the magnetic path between the metal centers. Unequivocal evidence of the two-step magnetostructural transformation is provided by X-ray single-crystal diffraction. PMID- 29989255 TI - Tailor-Made Functional Peptide Self-Assembling Nanostructures. AB - Noncovalent interactions are the main driving force in the folding of proteins into a 3D functional structure. Motivated by the wish to reveal the mechanisms of the associated self-assembly processes, scientists are focusing on studying self assembly processes of short protein segments (peptides). While this research has led to major advances in the understanding of biological and pathological process, only in recent years has the applicative potential of the resulting self assembled peptide assemblies started to be explored. Here, major advances in the development of biomimetic supramolecular peptide assemblies as coatings, gels, and as electroactive materials, are highlighted. The guiding lines for the design of helical peptides, beta strand peptides, as well as surface binding monolayer forming peptides that can be utilized for a specific function are highlighted. Examples of their applications in diverse immerging applications in, e.g., ecology, biomedicine, and electronics, are described. Taking into account that, in addition to extraordinary design flexibility, these materials are naturally biocompatible and ecologically friendly, and their production is cost effective, the emergence of devices incorporating these biomimetic materials in the market is envisioned in the near future. PMID- 29989254 TI - Canine urinary bladder transitional cell carcinoma tumor volume is dependent on imaging modality and measurement technique. AB - Transitional cell carcinoma is the most common cancer of the canine urinary tract. The inconsistent appearance of transitional cell carcinoma in patients introduces error if applying mathematic models for extrapolating total tumor volume from linear measurements. Reliable techniques to assess tumor size are important for monitoring treatment response. A method comparison study was performed comparing four techniques for calculating tumor volume were compared: (1 and 2) contoured tracing of tumor margins using serial computed tomography (CT) images using pre-(1) and postintravenous (2) contrast medium studies, (3) longest three linear dimensions using CT, and (4) longest three linear dimensions on abdominal ultrasound. Volumes of the transitional cell carcinoma tumor calculated by CT tracing techniques were significantly smaller than volumes calculated with an ellipsoid mathematic model using the linear measurements (P < 0.01). Intravenous contrast medium did not significantly change the volumes calculated from tracing tumor margins on CT for observer B; however, volumes differed for observer A. The volumes extrapolated from linear measurements using CT and ultrasound did not differ significantly. The interobserver reliability was highest for the precontrast CT contoured technique and was lowest using the ultrasound linear technique. Tumor volumes differed significantly between techniques of contoured tracing of the tumor margins on serial CT images compared to calculation of tumor volume from linear dimensions. The calculated volume of a transitional cell carcinoma depends upon the technique used. Characterizing the response of urinary bladder transitional cell carcinoma tumor size to therapy differs based on the method and modality used. PMID- 29989256 TI - Predictors of potentially harmful behaviour by family caregivers towards patients treated for behavioural and psychological symptoms of dementia in Japan. AB - BACKGROUND: Potentially harmful behaviour (PHB) by caregivers is detrimental to the physical and psychological well-being of care recipients. In Japan, few studies have investigated caregivers' PHB towards dementia patients. This study examined PHB in family caregivers of dementia patients with behavioural and psychological symptoms of dementia (BPSD) and identified factors related to PHB. METHODS: Following primary consultations at an elderly psychiatric patient department, we enrolled 133 pairs of dementia patients and their family caregivers. We assessed PHB using the Japanese version of the modified Conflict Tactics Scale. We defined the presence of PHB as two or more points (PHB frequency of 'sometimes' or more) on at least one indicator of the modified Conflict Tactics Scale. We investigated the prevalence of PHB in relation to the clinical characteristics of the patients and their family caregivers. We evaluated BPSD using the Neuropsychiatric Inventory and caregiver burden using the eight-item Japanese version of the Zarit Caregiver Burden Interview. RESULTS: Of the family caregivers, 48.9% showed PHB. Multivariate analysis identified the following association with PHB: caregiver's Zarit Caregiver Burden Interview total score (odds ratio [OR], 1.09 per unit increase; 95% confidence interval [95%CI], 1.02-1.16), and Neuropsychiatric Inventory scores for patient irritability (OR, 1.22 per unit increase; 95%CI, 1.06-1.40), appetite/eating disorders (OR, 1.41 per unit increase; 95%CI = 1.08-1.84) and daughters-in-law caregivers (OR, 0.17, 95%CI, 0.05-0.57). CONCLUSIONS: Specific BPSD symptoms could contribute to the expression of PHB. In addition to decreasing caregiver burden, more intensive treatment and care strategies are required to manage individual symptoms. PMID- 29989258 TI - Towards an ecological understanding of readiness to engage with interventions for children exposed to domestic violence and abuse: Systematic review and qualitative synthesis of perspectives of children, parents and practitioners. AB - Children who grow up in homes affected by domestic violence and abuse (DVA) are at risk of poor outcomes across the lifespan, yet there is limited evidence on the acceptability and effectiveness of interventions for them. A recent review of child-focused interventions highlighted a gap in understanding the factors influencing the willingness of parents and children to engage with these programmes. We conducted a systematic review of qualitative evidence on the experiences of receiving and delivering interventions with the aim of identifying factors at different levels of the social-ecological context that may influence parent and child readiness to take up interventions. We searched literature till April 2016 and found 12 reports of eight programmes. Two authors independently screened papers for inclusion, extracted data and identified the first- and second-order constructs. The third-order constructs were derived and fitted to the ecological framework to inform a picture of readiness to engage with interventions. Three key findings emerged from this review: (a) parent and child readiness is influenced by a complex interplay of individual, relationship and organisational factors, highlighting that individual readiness to take up child focussed interventions must be viewed in an ecological context; (b) the specific process through which women become ready to engage in or facilitate child focussed interventions may differ from that related to uptake of safety-promoting behaviours and requires parents to be aware of the impact of DVA on children and to focus on children's needs; (c) there are distinct but interlinked processes through which parents and children reach a point of readiness to engage in an interventions aimed at improving child outcomes. We discuss the implications of these findings for both practice and research. PMID- 29989257 TI - Physical comorbidities in older adults receiving antidepressants in Asia. AB - BACKGROUND: The present study explored the patterns of physical comorbidities and their associated demographic and clinical factors in older psychiatric patients prescribed with antidepressants in Asia. METHODS: Demographic and clinical information of 955 older adults were extracted from the database of the Research on Asian Psychotropic Prescription Patterns for Antidepressants (REAP-AD) project. Standardized data collection procedure was used to record demographic and clinical data. RESULTS: Proportion of physical comorbidities in this cohort was 44%. Multiple logistic regression analyses showed that older age (OR = 1.7, P < 0.001), higher number of depressive symptoms (OR = 1.09, P = 0.016), being treated in psychiatric hospital (OR = 0.5, P = 0.002), living in high income countries/territories (OR = 2.4, P = 0.002), use of benzodiazepines (OR = 1.4, P = 0.013) and diagnosis of 'other psychiatric disorders' (except mood, anxiety disorders and schizophrenia) (OR = 2.7, P < 0.001) were significantly associated with physical comorbidities. CONCLUSIONS: Physical comorbidities in older patients prescribed with antidepressants were common in Asia. Integrating physical care into the treatment of older psychiatric patients should be urgently considered. PMID- 29989259 TI - MDP-SPECT Versus Hybrid MDP-SPECT/CT in the Evaluation of Suspected Pars Interarticularis Fracture in Young Athletes. AB - BACKGROUND AND PURPOSE: To assess benefits of hybrid (single photon emission computerized tomography [SPECT]/computed tomography [CT]) imaging over SPECT imaging only in the management of young athletes with low back pain (LBP) due to suspected pars interarticularis fracture. METHODS: Retrospectively reviewed medical records of 163 consecutive patients who had radionuclide SPECT imaging for evaluation of LBP between January 1, 2010 and December 30, 2015. All enrolled patients were divided into two groups (group 1: patients with radionuclide SPECT imaging only and group 2: patients with radionuclide hybrid imaging). Radiation dose, cost benefits, and mean duration of delay in complete diagnosis were assessed and compared using Fisher's exact test. RESULTS: A total of 91 patients were enrolled after applying inclusion and exclusion criteria. The volume CT dose index and dose length product (DLP) estimated for a scan length of 10 cm (DLP 10) were significantly lower for patients in group II (CTDIvol ) (P = .001 and P = .001). Although, there was no significant difference in actual DLP (P = .52). There was a median delay of 7 days (interquartile range 2-10 days) for complete diagnosis in group I patients. Least expensive imaging for early definitive diagnosis required for the treatment decisions was in patients who had a radionuclide Technetium-99m methylene diphosphonate bone scan with limited lumbar spine planar and SPECT imaging followed by a thin slice, limited CT performed only when SPECT imaging was positive for an active pars interarticularis fracture. No significant difference in the management of patients between the groups (P = .47). CONCLUSION: Hybrid imaging should be preferred over SPECT only imaging for initial evaluation of suspected pars interarticularis fracture in young athletes with LBP. PMID- 29989260 TI - Reconceptualization innovative moments as a predictor of symptomatology improvement in treatment for depression. AB - OBJECTIVES: In previous studies, reconceptualization innovative moments were associated with successful psychotherapy. Reconceptualization has two components (a) a positive temporal contrast between the past self and the present self (contrasting self [CS]) and (b) a description of how and/or why this change has occurred (change process [CP])-from the perspective of the client. The aim of this study is to analyse if CS and CP have the same association with outcomes as reconceptualization. METHOD: Sixteen cases of clients with major depression (305 sessions) were analysed. Longitudinal regression models were used to explore if proportions of CS, CP, and reconceptualization predicted outcome measures and if outcome measures predicted CS, CP, and reconceptualization. RESULTS: Reconceptualization is less frequent than CS and CP taken separately, but reconceptualization was a better predictor of treatment outcomes than were its separate components. Moreover, symptom improvement did not predict reconceptualization. CONCLUSION: The construction of new meanings is important in improving depressive symptomatology. Psychotherapists can elicit these new meanings in their regular practice by posing questions that may help clients to conceptualize what is changing in themselves (CS) and questions of how this change is occurring (CP). The construction of an integrative account of these new meanings is associated with psychotherapeutic gains, and thus, reconceptualizing change could improve symptoms of depression. PMID- 29989261 TI - Women prefer proactive support from providers for treatment of heavy menstrual bleeding: A qualitative study in adult women with moderate or severe Von Willebrand disease. AB - OBJECTIVE: To explore key factors for successful support in women with moderate or severe Von Willebrand disease (VWD) who are faced with heavy menstrual bleeding (HMB) and surgery. DESIGN: A qualitative study design with focus-group interviews and thematic analysis of the discussions. SETTINGS AND POPULATION: Eleven VWD women aged 41-68 years (median age 58 years) who had had a hysterectomy or bipolar radiofrequency ablation (BRA) because of HMB participated in this study. Three of the 11 participants had VWD diagnosed before surgery. Two focus groups were conducted in the summer of 2012. Patients were identified through participation in a nationwide study on Von Willebrand disease in the Netherlands (WiN study). Inclusion criteria were at least 18 years of age, fluent in Dutch, diagnosed with VWD (based on Von Willebrand factor (VWF) antigen and/or activity levels < 30 IU/dL) and previous surgical therapy for HMB. FINDINGS: The following key factors were identified during focus-group interviews: receiving information, proactive support from providers and considering bleeding disorders as a cause of HMB. Other topics were as follows: experiences with VWD and/or surgery, how relieved patients were when menses stopped, patients hoped that in future, providers would work better together so that women receive the best care. CONCLUSIONS: In this focus-group study among women with VWD who underwent surgery because of HMB, support by professionals could be improved by considering a bleeding disorder in women with HMB, providing information about different types of surgery and shared decision-making regarding type of interventions. PMID- 29989262 TI - Rapid drinking challenge during high-resolution manometry is complementary to timed barium esophagogram for diagnosis and follow-up of achalasia. AB - BACKGROUND: Esophageal stasis is a hallmark of achalasia. Timed barium esophagogram (TBE) is used to measure stasis but exposes patients to ionizing radiation. It is suggested that esophageal stasis can be objectified on high resolution manometry (HRM) as well using a rapid drinking challenge test (RDC). We aimed to assess esophageal stasis in achalasia by a RDC during HRM and compare this to TBE. METHODS: Thirty healthy subjects (15 male, age 40 [IQR 34-49]) and 90 achalasia patients (53 male, age 47 [36-59], 30 untreated/30 treated symptomatic/30 treated asymptomatic) were prospectively included to undergo HRM with RDC and TBE. RDC was performed by drinking 200 mL of water. Response to RDC was measured by basal and relaxation pressure in the esophagogastric junction (EGJ) and esophageal pressurization during the last 5 seconds. KEY RESULTS: EGJ basal and relaxation pressure during RDC were higher in achalasia compared to healthy subjects (overall P < .01). Esophageal body pressurization was significantly higher in untreated (43 [33-35 mm Hg]) and symptomatic treated patients (25 [16-32] mm Hg) compared to healthy subjects (6 [3-7] mm Hg) and asymptomatic treated patients (11 [8-15] mm Hg, overall P < .01). A strong correlation was observed between esophageal pressurization during RDC and barium column height at 5 minutes on TBE (r = .75, P < .01), comparable to the standard predictor of esophageal stasis, IRP (r = .66, P < .01). CONCLUSIONS & INFERENCES: The RDC can reliably predict esophageal stasis in achalasia and adequately measure treatment response to a degree comparable to TBE. We propose to add this simple test to each HRM study in achalasia patients. PMID- 29989263 TI - Approaches to suicide prevention: Ideas and models presented by Japanese and international early career psychiatrists. PMID- 29989264 TI - Synergistic Catalysis: Highly Enantioselective Acetyl Aza-arene Addition to Enals. AB - A novel catalytic enantioselective methodology based on synergistic catalysis for the synthesis of chiral 2-acyl pyridines and pyrazines is reported. The strategy involves the metal-Lewis acid activation of acetyl aza-arenes and the secondary amine activation of enals. The proposed mechanism is supported by DFT calculations. PMID- 29989265 TI - Developing climate-smart restoration: Can plant microbiomes be hardened against heat waves? AB - Heat waves are increasing in frequency and intensity, presenting a challenge for the already difficult practice of ecological restoration. We investigated whether pre-heating locally sourced rhizosphere soil (inoculum) could acclimatize plants to a field-imposed heat wave in a restoration setting. Soil heating in the laboratory caused a marked shift in rhizosphere bacterial community composition, accompanied by an increase in species evenness. Furthermore, pre-heated rhizosphere soil reduced plant height, number of leaves, and shoot mass of the C4 grass, blue grama (Bouteloua gracilis), and it reduced the shoot mass of the C3 grass, Arizona fescue (Festuca arizonica) in the glasshouse. Following transplantation and the application of a field heat wave, pre-heated inoculum did not influence heat wave survival for either plant species. However, there were strong species-level responses to the field heat wave. For instance, heat wave survivorship was over four times higher in blue grama (92%) than in Arizona fescue (22%). These results suggest that the use of C4 seeds may be preferable for sites exhibiting high heat wave risk. Further research is needed to understand whether inocula are more effective in highly degraded soil in comparison with partially degraded soils. PMID- 29989266 TI - Effective and economical endoscopic resection using a novel multifunctional snare for small-sized gastric neoplasms. PMID- 29989267 TI - Reproducibility of quantitative sensory testing applied to musculoskeletal orofacial region: Site and sex differences. AB - BACKGROUND: This study estimated the inter-rater reliability and agreement of the somatosensory assessment performed at masseter and temporomandibular joint (TMJ) region in a group of healthy female and male participants. METHODS: Forty healthy participants (20 men and 20 women) were evaluated in two sessions by two different examiners. Cold detection threshold (CDT), warm detection threshold (WDT), thermal sensory limen (TSL), cold pain threshold (CPT), heat pain threshold (HPT), mechanical detection threshold (MDT), mechanical pain threshold (MPT), wind-up ratio (WUR) and pressure pain threshold (PPT) were assessed on the skin overlying TMJ and masseter body. Mixed ANOVA, intraclass correlation coefficients (ICC) and standard error of measurement (SEM) were applied to the data (alpha = 5%). Nonoverlapping 95% confidence intervals (95% CI) of ICCs were considered significantly different. RESULTS: The ICCs of 77% of all quantitative sensory testing (QST) measurements were considered fair to excellent (ICCs: 0.47 0.97), and WUR presented the lowest values. The reliability of WDT, TSL and HPT of masseter was significantly higher than TMJ, whereas the MDT reliability of TMJ was higher than masseter. In addition, the following combination of test/sites presented significantly lower ICCs for women: HPT, MDT of TMJ and MPT of both TMJ and masseter. Finally, the highest SEM values were presented for CPT and MPT. CONCLUSION: The overall somatosensory assessment of the masticatory structures performed by two examiners can be considered sufficiently reliable to discriminate participants, except WUR. Possible site and sex influences on the reproducibility parameters should be taken into account for an appropriate interpretation and clinical application of QST. SIGNIFICANCE: The test site and participant's sex can significantly influence the relative reliability and agreement of quantitative sensory testing applied to musculoskeletal orofacial region, which affect the capacity to discriminate participants and to evaluate changes over time. PMID- 29989269 TI - Gas-phase protomers of p-(dimethylamino)chalcone investigated by travelling-wave ion mobility mass spectrometry (TWIMS). AB - Results from ion-mobility (IM) separation experiments demonstrate that O- and N protomers of p-(dimethylamino)chalcone (p-DMAC) can coexist in the gas phase. The relative populations of the two protomers strongly depend on the ion-generating settings and the conditions the precursor ions experience from the point of their gas-phase inception to the time of their detection. Under relatively dry source conditions, the ratio of the gas-phase protomers generated under helium-plasma ionization (HePI) conditions is biased towards the thermodynamically favored O protomer. However, when the humidity of the enclosed ion source was increased, the IM arrival-time distribution profile of the mass-selected protonated precursor of p-DMAC changed rapidly to one dominated by the N-protomer. Under spray-ionization conditions, the formation of the thermodynamically less favored protomer has been generally attributed to a phenomenon called kinetic trapping. Herein, we demonstrate that the population of thermodynamically less favored N protomer can be dramatically increased simply by introducing water vapor to the HePI ion source. PMID- 29989268 TI - Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer. AB - Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ-resistant CRPC. In order to investigate the CBZ-resistant mechanism, the establishment of a CBZ-resistant cell line is urgently needed. We established CBZ-resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G2 /M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP-BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel -resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G2 /M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ resistant CRPC. PMID- 29989270 TI - Living with my small stomach: The experiences of post-bariatric surgery patients within 1 year after discharge. AB - AIMS AND OBJECTIVES: To explore how patients adapt to their changed body and life within the first year of receiving bariatric surgery. BACKGROUND: Bariatric surgery is used to treat severely obese patients. Most studies investigating the postsurgery period are about weight loss related issues. However, few studies have investigated these patients' subjective live experiences within the first year after discharge. DESIGN: A qualitative research using grounded theory method was applied. METHODS: In-depth interviews were conducted with 17 participants with a mean age of 34.5 years. The constant comparative method was used to analyse the interview data. FINDINGS: The core concept of "living with my small stomach" indicates that postbariatric patients are confronted with multidimensional challenges over time in their live experiences. Post-bariatric surgery patients felt "unexpected body discomforts" in the initial period after discharge. Qualitative analysis generated two different types of living processes either in the "life modification" process or a "suffering" process. The associated categories and subcategories delineated the living process after discharge. In the life modification process, five categories were identified: "being forced to change meal habits," "bad feelings due to unsatisfied eating desires," "choosing food for quality rather than quantity," "persisting and confronting" and "getting support from family members." In the suffering process, three categories were identified: "health becoming worse due to loss of albumin," "suffering from bad health" and "emotional disturbances." Finally, most participants would engage in "valuing my changed body" by "doing the right things and maintaining my new life." CONCLUSIONS: How to modify one's life is the main concern of postbariatric patients. These patients need to either engage in the process of making life modifications or suffer from complications. RELEVANCE TO CLINICAL PRACTICE: Patients need support and health education regarding living with their small stomach. In addition, we should be more sensitive about the need to detect malabsorption early. PMID- 29989271 TI - Changes in patterns of neural activity underlie a time-dependent transformation of memory in rats and humans. AB - The dynamic process of memory consolidation involves a reorganization of brain regions that support a memory trace over time, but exactly how the network reorganizes as the memory changes remains unclear. We present novel converging evidence from studies of animals (rats) and humans for the time-dependent reorganization and transformation of different types of memory as measured both by behavior and brain activation. We find that context-specific memories in rats, and naturalistic episodic memories in humans, lose precision over time and activity in the hippocampus decreases. If, however, the retrieved memories retain contextual or perceptual detail, the hippocampus is engaged similarly at recent and remote timepoints. As the interval between the timepoint increases, the medial prefrontal cortex is engaged increasingly during memory retrieval, regardless of the context or the amount of retrieved detail. Moreover, these hippocampal-frontal shifts are accompanied by corresponding changes in a network of cortical structures mediating perceptually-detailed as well as less precise, schematic memories. These findings provide cross-species evidence for the crucial interplay between hippocampus and neocortex that reflects changes in memory representation over time and underlies systems consolidation. PMID- 29989272 TI - Possible effect of maternal safe food preparation behavior on child malnutrition in Benin, Africa. AB - BACKGROUND: In many developing countries, faulty complementary feeding practises and frequently contaminated foods are contributing factors to child malnutrition. The aims of this study were to evaluate the nutrition status of, and clarify the maternal safe food preparation behaviors associated with malnutrition in, children aged <5 years in Cotonou, Benin. METHODS: This study targeted 300 mother child pairs visiting the University Hospital of Mother and Child Cotonou Lagoon. Mothers were interviewed using a structured questionnaire. Child height/length and weight measurements were determined and Z-scores were calculated using the 2006 World Health Organization Child Growth Standards. Children with Z-score < -2 were considered to have stunting or be underweight. On logistic regression analysis, significant variables on bivariate analysis, the associations of which were clarified in previous studies, were established as independent variables. Approximately 80% of the children who participated in this study were aged < 1 year. Being underweight was analyzed as a dependent variable. RESULTS: Regarding nutrition status, 11.0% of the children had stunting and 14.7% were underweight. On logistic regression analysis, underweight was correlated significantly with birthweight. As a remarkable point, food refrigeration was statistically significant. Food refrigeration can possibly be regarded as a maternal safe food preparation behavior. CONCLUSIONS: Maternal safe food preparation behaviors can prevent child malnutrition, even after considering biological and socioeconomic factors. PMID- 29989273 TI - Prophylaxis re-visited: The potential impact of novel factor and non-factor therapies on prophylaxis. PMID- 29989274 TI - A Solvation/Desolvation Indicator Based on van der Waals Interactions between Solvents and Porphyrins. AB - Solvation is a ubiquitous phenomenon associated with molecules in solutions. It often determines the equilibria of molecular systems and the rates of chemical reactions. Van der Waals interactions (a general term) includes weak interactions among noncharged compounds and it contributes significantly to solvation. The distinct observation of van der Waals interaction between solvent and porphyrin derivatives is reported herein. Bis(imidazolylporphyrinatozinc) structures connected through a 1,3-butadiyne moiety give two types of coordination polymers, E (extended) and S (stacked) polymers, exclusively. E polymers have larger solvent-accessible surface areas than the corresponding S polymers. Therefore, E polymers are better solvated than S polymers, providing an indicator of solvation and desolvation for the solvents used. A simple method (like a litmus test) was developed to evaluate the solvation ability of various solvents. Sixty-seven solvents and liquid compounds were tested, under the same conditions, using a conventional UV/Vis spectrometer. The results revealed a new liquid group with high solvation ability towards the porphyrins, and clarified van der Waals interaction assisted by secondary interaction on the substituents. The indicator system should contribute to the solution chemistry of molecules and materials, and to supramolecular chemistry interactions among hetero components. PMID- 29989275 TI - Engaging new refugee in Australian communities at risk for chronic hepatitis B infection into care: A peer-educator intervention. AB - Chronic Hepatitis B (CHB) infection and subsequent liver complications are rising in prevalence in Australia due to increased migration from endemic regions. Nearly 50% of all those living with CHB in Australia are undiagnosed, leading to missed opportunities for liver cancer and cirrhosis prevention. Health literacy around CHB among refugee communities such as Afghan, Rohingyan, and Sudanese populations (all with a high prevalence of CHB) is low, partly due to a paucity of targeted health promotion programmes; despite the release of the Victorian Hepatitis B Strategy (2016-2020). We developed a peer-education intervention in these three communities to deliver CHB focused radio programmes and community forums in their own language, following a needs assessment consisting of semistructured interviews and surveys. Effectiveness of this intervention was measured through paired comparison of disease-knowledge assessment pre and post forum. Community forums were held between 2015 and 2016, with 25 attendees at the Rohingyan forum (68% male), 10 attendees at the Afghan forum (90% male) and 0 attendees at the Sudanese forum. Participants demonstrated a significant improvement in CHB knowledge between pre- and post-forum surveys (p-value < 0.05). A peer-educator approach was a cost-effective health promotion strategy in building CHB knowledge and dispelling misconceptions within the Afghan and Rohingya communities. There were significant barriers in the engagement of the South Sudanese community, which will inform future strategies for health promotion. PMID- 29989276 TI - Lack of association between LTF gene polymorphisms and different caries status in primary dentition. AB - OBJECTIVE: Dental caries is related to cariogenic bacteria, salivary components, oral hygiene and host susceptibility. Lactoferrin is an important antimicrobial glycoprotein in saliva; however, the role of the LTF gene in caries susceptibility is unclear. We investigated the association between LTF polymorphisms and the severity of caries. DESIGN: Our study included 910 healthy paediatric subjects (aged 24-48 months) categorised into three groups: 403 with no caries or white-spot lesions; 230 with moderate caries (8 <= dmft <= 12); and 277 with severe caries (13 <= dmft <= 20). Information regarding the subjects' oral habits was gathered using questionnaires. The LTF rs1126477 and rs1126478 polymorphism alleles were genotyped by Sanger sequencing. RESULTS: The three groups showed no significant differences in LTF polymorphisms alleles, genotypes or haplotypes distribution. Multifactor dimensionality reduction analysis showed that the interactions between breastfeeding for a duration >24 months, night feeding >24 months and high frequency of sweet food intake increased the risk of caries (p = 0.0014); however, we detected no interaction effect between the LTF polymorphisms and oral habits on caries susceptibility. CONCLUSIONS: The LTF rs1126477 and rs1126478 polymorphisms showed no association with the different levels of caries risk in our Chinese paediatric cohort. PMID- 29989277 TI - An in Vitro-Selected DNAzyme Mutant Highly Specific for Na+ under Slightly Acidic Conditions. AB - Sodium is one of the most common metal ions in biology; however, DNA-based sodium probes have only been reported recently. A Na+ -specific RNA-cleaving DNAzyme named NaA43 is active with Na+ alone. In this work, we were using Co(NH3 )63+ as the intended metal cofactor for in vitro selection, but obtained a mutant of the NaA43 DNAzyme. The mutant was named NaH1, and differs from NaA43 by only two nucleotides. NaA43 has an optimal pH of 7.0, whereas the optimal pH for NaH1 is 6.0. This difference might be due to our selection having been performed at pH 6.0. NaH1 also displays an excellent selectivity for sodium relative to other competing monovalent ions, as well as a fast catalytic rate of (0.11+/-0.01) min 1 with 50 mm Na+ . At low Na+ concentrations, the selected DNAzyme exhibited a higher cleavage rate than NaA43 and thus a tighter apparent Kd of (12.0+/-1.6) mm Na+ . Furthermore, the NaH1 DNAzyme was engineered into a fluorescent Na+ biosensor by attaching a fluorophore/quencher pair to the DNAzyme with a detection limit of 223 MUm Na+ . Preliminary work on detection of Na+ in serum was demonstrated as well. This study provides a useful mutant that works in a slightly acidic environment, which might be useful for sensing Na+ in acidic in vivo environments. PMID- 29989278 TI - Characteristics of older people in an inpatient haematology unit: A descriptive study. AB - OBJECTIVE: To characterise older inpatients in a haematology unit. METHODS: Hospital case-mix data of haematology separations of all ages (n = 7419) and more extensive data restricted to older patients (age >=75 years, n = 1025) were evaluated. RESULTS: From 2000 to 2014, there was a 200% increase in those aged >=85 years who were more likely to have a geriatric syndrome as the principal diagnosis (P < 0.05), have delirium (P < 0.05), receive less intensive treatment (P < 0.001) and be discharged to a nursing home (P < 0.001). Compared to younger inpatients, those aged >=75 years were more likely to be emergency admissions (48% vs 37%, P < 0.001) and die during the admission (8% vs 4%, P < 0.001). CONCLUSION: Haematologists care for older inpatients who are complex with multidisciplinary health service needs. There may be value in conducting comprehensive geriatric assessments in this setting. PMID- 29989279 TI - Letermovir successfully used for secondary prophylaxis in a heart transplant recipient with ganciclovir-resistant cytomegalovirus syndrome (UL97 mutation). AB - Letermovir was approved by the Food and Drug Administration (FDA) in November 2017 for use in adult cytomegalovirus (CMV)-seropositive allogeneic stem cell transplant (SCT) recipients for primary prophylaxis of CMV infection and disease. We report off-label use of letermovir for secondary prophylaxis of genotype confirmed ganciclovir-resistant cytomegalovirus (CMV) syndrome (UL 97 mutation [C603W]) in a heart transplant recipient initially treated with intravenous cidofovir followed by foscarnet, both discontinued due to unacceptable toxicities. PMID- 29989280 TI - Functional analysis of superoxide dismutase of Salmonella typhimurium in serum resistance and biofilm formation. AB - AIMS: Further investigations of the novel biological functions of SodA in Salmonella enterica serovar typhimurium (Salm. typhimurium). METHODS AND RESULTS: A deletion mutant of sodA in Salm. typhimurium was constructed and its biological characteristics were analysed. More specifically, the roles of superoxide dismutase (SOD) in resistance to environmental stresses and serum, biofilm formation, epithelial cell adherence and invasion were investigated. Inactivation of sodA gene resulted in a slightly reduced growth rate, low SOD activity and increased susceptibility to reactive oxygen species and chicken serum. However, SodA was not involved in the motility of Salm. typhimurium. In addition, the sodA mutant exhibited a decreased capacity to form biofilm as well as to adhere and invade to HeLa cells, compared to the wild-type and complemented strains. CONCLUSIONS: Salmonella typhimurium SOD appears to play an important role in resistance to serum and oxidative stress, biofilm formation, adherence to and invasion of epithelial cells. SIGNIFICANCE AND IMPACT OF THE STUDY: This study illustrates the novel roles of SodA in serum resistance and biofilm formation in Salm. typhimurium, which may provide a candidate for the biofilm eradication and prevention of infections. PMID- 29989281 TI - Telomere shortening and frailty in Mexican older adults. AB - AIM: Telomere shortening has been associated with several age-related diseases, in addition to being considered a hallmark of aging. Frailty is a clinical syndrome characterized by an accentuated physiological and functional decline that might be a predictor of an adverse condition in older age. The present study evaluated the relationship between frailty and telomere shortening in older adults from Mexico City, Mexico. METHODS: This was a cross-sectional study. Data were collected from 323 frail older adults, including physical and environmental factors, such as body mass index, comorbidities, physical activity and tobacco consumption. Telomere length was measured by real-time polymerase chain reaction. The frailty syndrome was diagnosed using the Fried criteria. RESULTS: An association between frailty and telomere shortening was found in both sexes. Telomere length decreased from 6.05 kb (5.54-6.48 kb) to 4.20 kb (3.80-4.54 kb; P < 0.001). It was also observed that tobacco consumption could be a significant modifying factor in the association between these two variables. Previous reports are contradictory, suggesting that there is no relationship between telomere length and frailty; however, it is possible that there are genetic and/or environmental variables to be elucidated, that might influence this association, particularly in the studied population. CONCLUSIONS: Telomere length is inversely related to frailty in Mexican frail older adults, and tobacco consumption is the main environmental modifying factor. Geriatr Gerontol Int 2018; 18: 1286-1292. PMID- 29989283 TI - Gold(I)-Catalyzed Tandem Cycloisomerization of 1,5-Enyne Ethers by Hydride Transfer. AB - A novel gold-catalyzed tandem protocol, initiated by hydride transfer in the presence of catalytic (C6 F5 )3 PAuCl/AgSbF6 , for the formation of fused polycyclic ring systems has been achieved. This tandem reaction provides rapid access to various fused polycyclic species in a single chemical operation, leading to stereospecific formation of two carbon-carbon bonds and three rings. PMID- 29989282 TI - Competing global statistics on prevalence of injecting drug use: why does it matter and what can be done? PMID- 29989284 TI - Ommochromes in invertebrates: biochemistry and cell biology. AB - Ommochromes are widely occurring coloured molecules of invertebrates, arising from tryptophan catabolism through the so-called Tryptophan -> Ommochrome pathway. They are mainly known to mediate compound eye vision, as well as reversible and irreversible colour patterning. Ommochromes might also be involved in cell homeostasis by detoxifying free tryptophan and buffering oxidative stress. These biological functions are directly linked to their unique chromophore, the phenoxazine/phenothiazine system. The most recent reviews on ommochrome biochemistry were published more than 30 years ago, since when new results on the enzymes of the ommochrome pathway, on ommochrome photochemistry as well as on their antiradical capacities have been obtained. Ommochromasomes are the organelles where ommochromes are synthesised and stored. Hence, they play an important role in mediating ommochrome functions. Ommochromasomes are part of the lysosome-related organelles (LROs) family, which includes other pigmented organelles such as vertebrate melanosomes. Ommochromasomes are unique because they are the only LRO for which a recycling process during reversible colour change has been described. Herein, we provide an update on ommochrome biochemistry, photoreactivity and antiradical capacities to explain their diversity and behaviour both in vivo and in vitro. We also highlight new biochemical techniques, such as quantum chemistry, metabolomics and crystallography, which could lead to major advances in their chemical and functional characterisation. We then focus on ommochromasome structure and formation by drawing parallels with the well-characterised melanosomes of vertebrates. The biochemical, genetic, cellular and microscopic tools that have been applied to melanosomes should provide important information on the ommochromasome life cycle. We propose LRO-based models for ommochromasome biogenesis and recycling that could be tested in the future. Using the context of insect compound eyes, we finally emphasise the importance of an integrated approach in understanding the biological functions of ommochromes. PMID- 29989285 TI - FRET-based Solid-state Luminescent Glyphosate Sensor Using Calixarene-grafted Ruthenium(II)bipyridine Doped Silica Nanoparticles. AB - Calixarene-functionalized luminescent nanoparticles were successfully fabricated for the FRET-based selective and sensitive detection of the organophosphorus pesticide glyphosate (GP). p-Tert-butylcalix[4]arene was grafted on the surface of [Ru(bpy)3 ]2+ incorporated SiNps to produce self-assembled nanosensors (RSC). FRET was switched on in the presence of GP by means of energy transfer due to binding with p-tert-butylcalix[4]arene grafted on the surface of the RSC. The FRET efficiency of the GP-RSC system was increased gradually with the addition of GP. The FRET efficiency was evaluated as 87.69 % and a high binding affinity was established by the binding constant value, 1.16*107 M-1 , using a Langmuir binding isotherm plot. The estimated limit of detection (LOD) was 7.91*10-7 M, which was lower than the Environmental Protection Agency (EPA) recommendation. The probe also effectively responds to real sample analysis. The sensitivity and selectivity was realized due to the efficient FRET towards the fluorescence properties of the [Ru(bpy)3 ]2+ complex. PMID- 29989286 TI - Trends and characteristics of naloxone therapy reported to US poison centers. AB - BACKGROUND AND AIMS: In the United States, access to naloxone has been expanded as a measure to address growing opioid overdose mortality. The study aimed to describe the national trends in naloxone use as reported to the US poison centers (PCs). METHODS: The National Poison Data System (NPDS) was queried for cases reporting naloxone therapy from 1 January 2001 to 31 December 2016. Demographic and clinical characteristics were assessed descriptively. Trends in naloxone reports were evaluated by using generalized linear mixed models that were adjusted for age, gender and random effects of the geographical census region. Cumulative incidence rates (CIR) of naloxone reports at the state- and national level were calculated. RESULTS: There were 304 249 cases reporting naloxone therapy during the study period. The frequency of naloxone reports increased from 9498 in 2000 to 26 826 in 2016. The proportion of cases where naloxone was used prior to PC recommendation increased from 59.8% in 2000 to 81.5% in 2016. The mean number of NPDS naloxone reports per 100 000 human exposures increased from 9.6 [95% confidence interval (CI) = 6.4-14.2] to 31.7 (95% CI = 21.4-46.9, P < 0.001). Among the cases, 52.4% were female and the most frequent age group was 20 39 years (39.1%). The principal reason for a toxic exposure resulting in a naloxone report was suspected suicide (55.0%). Life-threatening symptoms were seen in one-fifth of the cases, with 53.9% cases being admitted to critical care units. Opioids (59.7% cases), were the most commonly reported exposure agents, with hydrocodone being most frequently reported. The national CIR of naloxone reports to the US PCs was 6.3 cases per 100 000 population, with West Virginia demonstrating the highest incidence. CONCLUSIONS: Analysis of calls to the United States poison centers indicates an increasing trend of naloxone use from 2000 to 2016. PMID- 29989287 TI - DNA-Templated [2+2] Photocycloaddition: A Straightforward Entry into the Aplysinopsin Family of Natural Products. AB - Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product. PMID- 29989288 TI - Overcoming Volume Selectivity of Dipolar Recoupling in Biological Solid-State NMR Spectroscopy. AB - Dipolar recoupling in solid-state NMR is an essential method for establishing correlations between nuclei that are close in space. In applications on protein samples, the traditional experiments like ramped and adiabatic DCP suffer from the fact that dipolar recoupling occurs only within a limited volume of the sample. This selection is dictated by the radiofrequency (rf) field inhomogeneity profile of the excitation solenoidal coil. We employ optimal control strategies to design dipolar recoupling sequences with substantially larger responsive volume and increased sensitivity. We show that it is essential to compensate for additional temporal modulations induced by sample rotation in a spatially inhomogeneous rf field. Such modulations interfere with the pulse sequence and decrease its performance. Using large-scale optimizations we developed pulse schemes for magnetization transfer from amide nitrogen to carbonyl (NCO) as well as aliphatic carbons (NCA). Our experiments yield a signal intensity increased by a factor of 1.5 and 2.0 for NCA and NCO transfers, respectively, compared to conventional ramped DCP sequences. Consistent results were obtained using several biological samples and NMR instruments. PMID- 29989290 TI - Post-Synthetic Ligand Exchange in Zirconium-Based Metal-Organic Frameworks: Beware of The Defects! AB - Post-synthetic ligand exchange in the prototypical zirconium-based metal-organic framework (MOF) UiO-66 was investigated by in situ solution 1 H NMR spectroscopy. Samples of UiO-66 having different degrees of defectivity were exchanged using solutions of several terephthalic acid analogues in a range of conditions. Linker exchange only occurred in defect-free UiO-66, whereas monocarboxylates grafted at defect sites were found to be preferentially exchanged with respect to terephthalic acid over the whole range of conditions investigated. A 1:1 exchange ratio between the terephthalic acid analogue and modulator was observed, providing evidence that the defects had missing-cluster nature. Ex situ characterisation of the MOF powders after exchange corroborated these findings and showed that the physical-chemical properties of the MOF depend on whether the functionalisation occurs at defective sites or on the framework. PMID- 29989289 TI - Unveiling epigenetic regulation in cancer, aging, and rejuvenation with in vivo reprogramming technology. AB - Reprogramming technology has enabled the fate conversion of terminally differentiated somatic cells into pluripotent stem cells or into another differentiated state. A dynamic reorganization of epigenetic regulation takes place during cellular reprogramming. Given that reprogramming does not require changes in the underlying genome, the technology can be used to actively modify epigenetic regulation. Although reprogramming has been investigated mostly at the cellular level in vitro, studies have reported that somatic cells are reprogrammable in multicellular organisms in vivo. In vivo reprogramming provides a potential strategy for regenerative medicine. Notably, recent studies using in vivo reprogramming technology to alter epigenetic regulation at organismal levels have revealed unappreciated epigenetic mechanisms in various biological phenomena, including cancer development, tissue regeneration, aging, and rejuvenation in mammals. Moreover, in vivo reprogramming technology can be applied to abrogate epigenetic aberrations associated with aging and cancer, which raises the possibility that the technology could provide a potential strategy to control the fate of detrimental cells such as senescent cells and cancer cells in vivo. Here, we review recent progress and future perspectives of in vivo reprogramming. PMID- 29989292 TI - Summer reading: Medicine, psychoanalysis and the zombie apocalypse in comic books. PMID- 29989291 TI - Acetone clearance of mesocolic or mesorectal fat increases lymph node yield and may improve detection of high-risk Stage II colorectal cancer patients. AB - AIM: Lymph node (LN) status is key to determining the need for adjuvant therapy in colorectal cancer (CRC) and for disease which has progressed to Stage II (T3 T4, N0, M0). A yield of fewer than 12 LNs is considered a risk factor similar to high-grade histology and vascular, lymphatic and perineural invasion. The aim of this retrospective study was to investigate the effect of acetone fat clearance of the mesocolon or mesorectum on LN yield and the identification of patients with high-risk Stage II CRC. METHOD: After conventional LN retrieval, fatty tissue derived from the mesocolon or mesorectum of 80 CRC specimens was incubated in acetone for 24 h. A second dissection was then performed by a trained technician. The total number of LNs as well as tumour involvement (LNpositive and LNnegative) were assessed at each stage. In addition, LN morphology was assessed and clinicopathological data were extracted from existing pathology reports. RESULTS: Eighty CRC specimens were available for study. 1548 (94%) LN were negative and 96 (6%) were positive. The median (range) LN yield per specimen was 12 (3-41) LN increasing to 18 (4-48) LN after fat clearance (P < 0.001). After fat clearance, 534 additional LNs were identified in 75 (94%) of the specimens, and all but 10 were negative. The pN stage did not change in six patients who were found to be LN positive after fat clearance. However, the number of high risk Stage II CRC patients decreased from 11 to 7. Although important for these patients, this downstaging did not reach statistical significance (P = 0.125). CONCLUSION: Acetone clearance of mesocolic or mesorectal fat increases median LN yield and may in a larger study decrease the number of patients classified as having high-risk Stage II CRC. PMID- 29989293 TI - Harnessing the placebo effect: a promising method for curbing the opioid crisis? PMID- 29989294 TI - Cyclophosphamide-induced hemorrhagic cystitis in young patients with solid tumors: A single institution study. AB - AIM: Although hemorrhagic cystitis (HC) is a significant complication in young patients who undergo chemotherapy with cyclophosphamide (CPA), risk factors and supportive care to prevent HC are unclear. This study attempted to identify optimal supportive care to prevent CPA-induced HC. METHODS: Patients (< 30-year old) with malignant solid tumors who had been treated with CPA-containing chemotherapy in inpatient treatment were eligible. Vigorous hydration to increase urine output and intravenous 2-mercaptethane sulfonate (mesna) were used for prophylaxis of CPA-induced HC. We retrospectively analyzed 81 patients who had been treated with CPA-containing chemotherapy over (collectively) 486 cycles, and examined relationships between HC and various factors, especially CPA dosage, use of mesna, and fluid infusion volume/rate. RESULTS: HC occurred in four patients (4.9%) and five cycles (1%). When stratifying by doses and methods of administration of CPA, HC occurred in 3/323 low- and intermediate-dose (< 1500 mg/m2 /day) cycles and mesna was used in all three cycles with HC. Patients who were given mesna had a lower flow rate than those given hydration alone in the low- and intermediate-dose CPA (126 +/- 25 vs 106 +/- 16 mL/m2 /h; P < 0.01). All patients who received high-dose CPA (>=1500 mg/m2 /day) were also given mesna and vigorous hydration (115 +/- 16 mL/m2 /h). CONCLUSIONS: Our supportive care measures may be effective in preventing CPA-induced HC. Patients who receive CPA doses < 1500 mg/m2 /day should get >=125 mL/m2 /h of infused fluid, regardless of mesna usage; those who receive of CPA >=1500 mg/m2 /day should also receive mesna and vigorous hydration. PMID- 29989295 TI - The role of causal models and beliefs in interpreting health claims. AB - OBJECTIVE: Health claims on food packaging are regulated to inform and protect consumers; however, many consumers do not accurately interpret the meaning of the claims. Whilst research has shown different types of misinterpretation, it is not clear how those interpretations are formed. The aim of this study was to elicit the causal beliefs and causal models about food and health held by consumers, that is their understanding of the causal relationships between nutrients, health outcomes, and the causal pathways connecting them, and investigate how well this knowledge explains the variation in inferences they draw about health benefits from health claims. METHOD: A total of 400 participants from Germany, the Netherlands, Spain, Slovenia, and the United Kingdom were presented with seven authorized health claims and drew inferences about the health benefits of consuming nutrients specified in the claim. Then, their personal causal models of health were elicited along with their belief in the truth and familiarity with the claims. RESULTS: The strength of inferences about health benefits that participants drew from the claims was predicted independently by the strength of the relevant causal pathways within the causal model, and belief in the truth of the claim, but not familiarity with the claim. Participants drew inferences about overall health benefits of the nutrients by extrapolating from their causal models of health. CONCLUSION: Consumers' interpretation of claims is associated with their belief in the claim and their causal models of health. This prior knowledge is used to interpret the claim and draw inferences about overall health benefits that go beyond the information in the claim. Therefore, efforts to improve consumers' understanding and interpretation of health claims must address both their wider causal models of health and their knowledge of specific claims. Statement of Contribution What is already known on this subject? Health claims influence the likelihood of buying a product. But consumers do not accurately understand or interpret health claims. What does this study add? Consumers' interpretation of health claims is mediated by their personal causal model of health. Consumers draw inferences that go beyond what is claimed by extrapolating from their personal causal model of health. Consumers are also influenced directly by their belief in the claim, but not frequency of exposure to it. PMID- 29989296 TI - Male factor infertility: an opportunity to investigate individual and family health. PMID- 29989297 TI - Monitoring age-related trends in genomic diversity of Australian lungfish. AB - An important challenge for conservation science is to detect declines in intraspecific diversity so that management action can be guided towards populations or species at risk. The lifespan of Australian lungfish (Neoceratodus forsteri) exceeds 80 years, and human impacts on breeding habitat over the last half century may have impeded recruitment, leaving populations dominated by old postreproductive individuals, potentially resulting in a small and declining breeding population. Here, we conduct a "single-sample" evaluation of genetic erosion within contemporary populations of the Australian lungfish. Genetic erosion is a temporal decline in intraspecific diversity due to factors such as reduced population size and inbreeding. We examined whether young individuals showed signs of reduced genetic diversity and/or inbreeding using a novel bomb radiocarbon dating method to age lungfish nonlethally, based on 14 C ratios of scales. A total of 15,201 single nucleotide polymorphic (SNP) loci were genotyped in 92 individuals ranging in age from 2 to 77 years old. Standardized individual heterozygosity and individual inbreeding coefficients varied widely within and between riverine populations, but neither was associated with age, so perceived problems with recruitment have not translated into genetic erosion that could be considered a proximate threat to lungfish populations. Conservation concern has surrounded Australian lungfish for over a century. However, our results suggest that long-lived threatened species can maintain stable levels of intraspecific variability when sufficient reproductive opportunities exist over the course of a long lifespan. PMID- 29989298 TI - Asparaginase-like protein 1 expression in curettage independently predicts lymph node metastasis in endometrial carcinoma: a multicentre study. AB - OBJECTIVE: Correct preoperative identification of high-risk patients is important to optimise surgical treatment and improve survival. We wanted to explore if asparaginase-like protein 1 (ASRGL1) expression in curettage could predict lymph node metastases and poor outcome, potentially improving preoperative risk stratification. DESIGN: Multicentre study. SETTING: Ten hospitals in Norway, Sweden and Belgium. POPULATION: Women diagnosed with endometrial carcinoma. METHODS: ASRGL1 expression in curettage specimens from 1144 women was determined by immunohistochemistry. MAIN OUTCOME MEASURES: ASRGL1 status related to disease specific survival, lymph node status, preoperative imaging parameters and clinicopathological data. RESULTS: ASRGL1 expression had independent prognostic value in multivariate survival analyses, both in the whole patient population (hazard ratio (HR) 1.63, 95% CI 1.11-2.37, P = 0.012) and in the low-risk curettage histology subgroup (HR 2.54, 95% CI 1.44-4.47, P = 0.001). Lymph node metastases were more frequent in women with low expression of ASRGL1 compared with women with high ASRGL1 levels (23% versus 10%, P < 0.001), and low ASRGL1 level was found to independently predict lymph node metastases (odds ratio 2.07, 95% CI 1.27-3.38, P = 0.003). CONCLUSIONS: Low expression of ASRGL1 in curettage independently predicts lymph node metastases and poor disease-specific survival. TWEETABLE ABSTRACT: Low ASRGL1 expression in curettage predicts lymph node metastasis and poor survival in endometrial carcinoma. PMID- 29989299 TI - Exploitation of Environment-Sensitive Luminophores in the Design of Sydnone-Based Bioorthogonal Imaging Reagents. AB - Although the strain-promoted sydnone-alkyne cycloaddition reaction has been utilized for bioconjugation, its potential applications in bioorthogonal labeling and imaging in live cells have not been explored. This communication reports novel bioorthogonal imaging reagents with environment-sensitive emission properties through the modification of sydnone with cyclometalated iridium(III) polypyridine complexes. These complexes displayed significant emission enhancement and lifetime elongation upon reaction with strained alkyne derivatives, and were utilized to label cyclooctyne-modified proteins and ceramide molecules in live cells. Additionally, the manipulation of the photocytotoxicity of the complexes through the use of a bioorthogonal reagent was demonstrated. PMID- 29989300 TI - Genetic correlations between body weight, scrotal circumference and visual evaluation scores in Bos indicus cattle. AB - The objective was to estimate genetic correlations between body weight (BW), scrotal circumference and visual evaluation scores of body conformation measured at standard ages in Guzerat cattle. All measurements were performed at 205 (weaning age), 365, 450 and 550 days of age; for BW, two additional measurements (at birth and 120 days of age) were realized. The data utilized in this study were retrieved from a database of the Brazilian Association of Zebu Breeders that contained information of registered Guzerat animals born between 1970 and 2013. Genetic parameters were estimated in bi-trait analyses by using Bayesian inference. Genetic correlations between BW at 205 and 450 days of age with other traits were high and positive, whereas the correlations between visual evaluation scores with other traits were moderate. Based on correlations herein obtained, we conclude that selection based on BW results in increased visual scores and scrotal circumference, leading to improvements in productive performance and animals with best body conformation. PMID- 29989301 TI - Impact of patient education on plasma concentrations and effectiveness of posaconazole oral suspension under clinical conditions. AB - Posaconazole prophylaxis is recommended for patients with acute myeloid leukaemia during induction chemotherapy. Although a tablet formulation with better oral bioavailability is available, some patients have to rely on the oral suspension in clinical routine. Therefore, effectiveness of posaconazole oral suspension under real-life clinical conditions and impact of patient education about the correct intake on its plasma concentrations were assessed in this study. Altogether 96 patients receiving 160 cycles of induction chemotherapy were retrospectively (40 patients) and prospectively (56 patients) analysed. Patients were assigned into two groups for each chemotherapy cycle according to the application of antifungal prophylaxis (A: posaconazole oral suspension, 200 mg three times a day >=7 days; B: intake <7 days, fluconazole or no prophylaxis). Antifungal prophylaxis and therapy were analysed for each cycle. Additionally, plasma concentrations were determined from prospectively included subjects of group A who were intensively educated to perform a correct drug intake. Systemic antifungal therapy was statistically started less often in group A (26% vs 53%; P = 0.002). Posaconazole prophylaxis was associated with a lower risk of proven invasive fungal infection (P = 0.003). Median plasma concentration apparently increased between the first and second time of determination effected by an initial intensive on-site patient education. The clinical effectiveness of posaconazole oral suspension was confirmed. A detailed patient education at the beginning of the treatment with posaconazole oral suspensions seems to be of primary importance for efficient plasma concentrations. PMID- 29989302 TI - Elevated Level of miR-551b-5p is Associated With Inflammation and Disease Progression in Patients With Severe Acute Pancreatitis. AB - Circulating microRNAs have the potential to be noninvasive biomarkers for assessing disease progression. MicroRNA-551b-5p (miR-551b-5p) was previously reported to be differentially expressed in pancreatic patients. The serum miR 551b-5p level was measured in patients with mild acute pancreatitis (MAP), severe acute pancreatitis (SAP), and healthy controls using quantitative real-time polymerase chain reaction (RT-PCR) analysis to evaluate its impact on inflammatory response. Acute Physiology and Chronic Health Evaluation II (APACHE II), Multiple Organ Dysfunction Score (MODS), Sequential Organ Assessment Score (SOFA), and Ranson's scores were recorded. Inflammatory cytokines, IL-6, IL-17, IL-1beta, and Tumor Necrosis Factor-alpha (TNF-alpha), were detected in serum samples obtained from MAP and SAP patients on admission day 1, day 3, and day 5 using Enzyme Linked Immunosorbent Assay (ELISA). Inflammatory cytokines were analyzed in peripheral blood mononuclear cells (PBMCs), which were transfected with miR-551b-5p-negative controls and inhibitors. The serum miR-551b-5p level was significantly higher in MAP and SAP patients compared to controls (P < 0.001). An elevated miR-551b-5p level is positively associated with APACHE II, MODS, SOFA, and Ranson's scores (P < 0.001). Serum cytokines levels were significantly elevated in MAP and SAP patients compared to controls (P < 0.05). In addition, the level of these inflammatory cytokines was increased in PBMCs of SAP patients in comparison with those of healthy controls (P < 0.05), and this rise was significantly reduced with the addition of an miR-551b-5p inhibitor. In conclusion, serum miR-551b-5p is elevated in patients with MAP and SAP and is involved in the regulation of inflammatory response. It may be a useful biomarker for assessing the severity of SAP. PMID- 29989303 TI - Diagnostic and therapeutic value of progastrin-releasing peptide on small-cell lung cancer: A Single-Center Experience in China. AB - We aimed to compare the diagnostic efficiency of proGRP and NSE on SCLC and to investigate whether the change of proGRP level would predict therapeutic response. Patients who were firstly diagnosed pathologically in Nanjing Chest Hospital and measured proGRP level consecutively were enrolled in the study. ProGRP level was detected using Elecsys ProGRP Assay. Totally 75 SCLC, 234 NSCLC and 264 benign lung diseases (BLD) were enrolled. Both proGRP and NSE levels in SCLC were significantly higher than those in NSCLC and BLD, and proGRP in extensive stage SCLC was higher than which in limited stage (P <= .001). The diagnostic efficiency of proGRP on SCLC was higher than that of NSE, but when the two biomarkers were bind together, the diagnostic efficiency was the best. When SCLC was differentiated from NSCLC and BLD, the cut-off values were 114.35 pg/mL and 162.55 pg/mL respectively. For treatment responsive patients, proGRP level decreased markedly after the first cycle of therapy and kept a continued momentum of decline during treatment. But for unresponsive patients, no obvious decline was observed. ProGRP had higher diagnostic efficiency on SCLC when compared to NSE, and it could better predict therapeutic response of pulmonary target lesions on chemotherapy. PMID- 29989304 TI - In vivo CYP3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an extended release formulation. AB - The magnitude of interaction between the CYP3A4 substrate tacrolimus and various CYP3A4 inhibitors is highly unpredictable. We investigated whether an individual's baseline in vivo CYP3A4 activity, assessed using the oral midazolam (MDZ) probe, could be used to predict the magnitude of drug-drug interaction between tacrolimus and the potent CYP3A4 inhibitor itraconazole. In a prospective single-arm open-label study, 16 healthy volunteers were administered single doses of MDZ and tacrolimus before and after a 4-day course of itraconazole. Itraconazole treatment resulted in a 9.0-fold decrease in MDZ apparent oral clearance (CL/F) and a 3.3-fold decrease in tacrolimus CL/F (P < 0.001 for each). MDZ CL/F and tacrolimus CL/F were positively correlated both at baseline (r = 0.582, P = 0.018) and after itraconazole (r = 0.811, P < 0.001). Furthermore, baseline MDZ CL/F was positively correlated to the fold change in MDZ CL/F resulting from CYP3A4 inhibition (r = 0.759, P = 0.001). However, no predictors of change in tacrolimus CL/F resulting from CYP3A4 inhibition were identified, including baseline MDZ CL/F (P = 0.453), baseline tacrolimus CL/F (P = 0.759) and fold change in MDZ CL/F between both phases (P = 0.274). In conclusion, baseline oral MDZ clearance does not predict the magnitude of interaction between tacrolimus and itraconazole. PMID- 29989305 TI - Multiple small, rectal neuroendocrine tumors with numerous micronests. PMID- 29989306 TI - Diagnostic accuracy of contrast-enhanced computed tomography for assessment of mandibular and medial retropharyngeal lymph node metastasis in dogs with oral and nasal cancer. AB - The diagnostic accuracy of contrast-enhanced CT for detection of cervical lymph node metastasis in dogs is unknown. The purpose of this retrospective, observational, diagnostic accuracy study was to assess the efficacy of CT for detection of mandibular and medial retropharyngeal lymph node metastasis in dogs. Histopathology of dogs with cancer of the head, CT and bilateral mandibular and medial retropharyngeal lymphadenectomy was reviewed. A single radiologist measured lymph nodes to derive short axis width and long-short axis ratios. Two blinded radiologists separately assessed lymph node margins, attenuation and contrast enhancement and each provided a final subjective interpretation of each node site as benign or neoplastic. Where radiologists' opinions differed, a consensus was reached. Sensitivity, specificity and accuracy were calculated for mandibular and medial retropharyngeal sites. Agreement between radiologists was assessed. Fisher's exact test and the Kruskal-Wallis H-test were used to assess associations between variables. Forty-one primary tumours were recorded in 40 dogs. Metastasis to mandibular or retropharyngeal lymph nodes occurred in 16 out of 40 dogs (43/160 nodes). Agreement between radiologists was almost perfect for margination, attenuation and enhancement, strong for interpretation of mandibular lymph node metastasis, and weak for interpretation of medial retropharyngeal lymph node metastasis. Sensitivity of CT was 12.5% and 10.5%, specificity was 91.1% and 96.7%, and accuracy was 67.5% and 76.3% for mandibular and medial retropharyngeal lymph nodes respectively. No individual CT findings were predictive of nodal metastasis. Given the low sensitivity of CT, this modality cannot be relied upon alone for assessment of cervical lymph node metastasis in dogs. PMID- 29989307 TI - Clinical relevance of 3D gait analysis in patients with haemophilia. AB - Haemophilia is characterized by a congenital deficiency of clotting factor VIII or IX. One of the consequences of haemophilia is joint bleedings. Repetitive haemathroses induce cartilage damage and chronic synovitis leading to joint deterioration, and to definitive haemophilic arthropathy which is source of walking disability. Three-dimension gait analysis (3DGA) appears particularly relevant in the case of haemophilia because it allows an evaluation of several joints in weight-bearing situations. The purpose of this study was to review the interest and the contribution of 3DGA in the management of patients with haemophilia. The greatest interest of gait analysis would be to detect early walking changes with a non-invasive and well-tolerated examination, especially in paediatric population. In adulthood, this technic may be also useful to help detect walking worsening in patients known to have already arthropathy. However, it takes time to realize and needs expensive equipment, which limits its possibility of routine use. Although generalizations of these results remain difficult, especially to compare patients with haemophilia to normal population. Indeed, in the studies, patient groups are small and usually heterogeneous in terms of age and target joints. It certainly results of the rarity of the disease. So, it could be interesting to perform a study with a larger cohort in order to allow subgroup analysis, helping to define clearly the place of 3DGA in the strategy of haemophilia evaluation. PMID- 29989308 TI - Thermodynamics of the Interactions of Aminobisphosphonates and Their Calcium Complexes with Bovine Serum Albumin. AB - Binding of bisphosphonates (BPs) to plasma proteins was investigated in the 1990s as a pharmacokinetic issue in order to fully understand bio-distribution of BP drugs which are successfully used for the treatment of several bone-related diseases. It has been hypothesized that binding to these proteins occurs with low to moderate affinity despite of unfavorable hydrophilicity of BPs, and Ca2+ was identified as a strong catalyst of this binding. However, these studies mainly consisted in the separation and quantification of bound and unbound drug or protein fractions using chromatographic techniques without an outcome on the molecular level. Presented thermodynamic studies analyze the interactions of three N-BPs as well as their Ca2+ complexes with bovine serum albumine (BSA) by means of isothermal calorimetry. The studies reveal spontaneous enthalpy favored interactions of N-BPs (amino-containing BPs) with BSA, which are enhanced by the presence of Ca2+ ions up to ~15-fold, strongly depending on N-BP. Those are low affinity binding events, comparable to Ca2+ -N-BP interactions, which most likely occur at Ca2+ binding site(s). It is a first example of estimation of thermodynamic forces of interactions of free and calcium-bound N-BPs with albumin. PMID- 29989309 TI - Exploration of the Synthetic Potential of Electrophilic Trifluoromethylthiolating and Difluoromethylthiolating Reagents. AB - The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, sN ), using the linear free-energy relationship log k2 =sN (N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido-derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X-SCF3 bonds (Tt+ DA), the cumol-derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O-S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis. PMID- 29989310 TI - Association Between Dialysis Modalities and Risk of Coronary Artery Disease: A Population-Based Cohort Study in Taiwan. AB - The hemodynamic effects of hemodialysis (HD) and peritoneal dialysis (PD) on end stage renal disease (ESRD) patients differ. The influence of dialysis modalities on the cardiovascular system has not been well investigated. We aimed to evaluate the association between dialysis modalities and risk of coronary artery disease (CAD) by using the claim data of Taiwan's Longitudinal Health Insurance Database. This study followed up a cohort of 1624 new onset ESRD patients (>=18 years old), who had started renal replacement therapy during 2000 to 2010; and was followed until 2012. After adjusting for potential confounders, patients who underwent HD had significantly higher risks of incidence of CAD, in comparison with patients who underwent PD (adjusted hazard ratio = 1.47; 95% confidence interval = 1.01 2.11). An increased risk of incident CAD was distinguished in patients receiving HD, compared with those on PD. Further studies are warranted to explore the underlying mechanism and improve dialysis outcomes. PMID- 29989311 TI - High tacrolimus trough level variability is associated with rejections after heart transplant. AB - Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 +/- 3.4 ng/mL vs 12.8 +/- 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability. PMID- 29989312 TI - Phosphate Binders Derived from Natural Ores Contain Many Kinds of Metallic Elements Besides Their Active Ingredient Metals. AB - Most patients undergoing dialysis are required to take many phosphate binder pills to control hyperphosphatemia. Phosphate binders prescribed in Japan are classified into two types: metal-based binders (Ca carbonate, lanthanum carbonate, ferric citrate hydrate, and sucroferric oxyhydroxide) and chemically synthesized polymers (sevelamer hydrochloride and bixalomer). The raw materials of metal-based phosphate binders are natural ores; thus, such binders may contain several other metallic elements. We measured the elemental contents in six metal based phosphate binders using an inductively coupled plasma mass - spectrometry (ICP-MS) method. As a result, despite being in small amounts, ore-derived phosphate binders contained various elements besides their active ingredient metals: Na, Mg, P, Mn, Fe, Sr, Y, Ba, La, Nd, and Pb in three Ca-based products; Mg, P, Se, Ce, and Gd in one La-based product; and Na, Mg, Al, P, Ca, Ti, Cr, Mn, Co, Ni, Ge, Ba, and La in two Fe-based products. These elements are considered to have originated from pharmaceutical bulk and from pharmaceutical additives. It is unlikely these elements are immediately harmful to patients. However, it should be emphasized that patients undergoing dialysis do not have a urinary excretion route and are administered many phosphate binder pills every day over a long period of time. In the future, pharmaceutical companies may have to disclose standard amounts and/or analytical values regarding the type and quantity of metallic elements in the final formulation or pharmaceutical bulk derived from natural ores. PMID- 29989313 TI - The central circadian clock proteins CCA1 and LHY regulate iron homeostasis in Arabidopsis. AB - Circadian clock is the endogenous time-keeping machinery that synchronizes an organism's metabolism, behavior, and physiology to the daily light-dark circles, thereby contributing to organismal fitness. Iron (Fe) is an essential micronutrient for all organisms and it plays important roles in diverse processes of plant growth and development. Here, we show that, in Arabidopsis thaliana, loss of the central clock genes, CIRCADIAN CLOCK ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY), results in both reduced Fe uptake and photosynthetic efficiency, whereas CCA1 overexpression confers the opposite effects. We show that root Fe(III) reduction activity, and expression of FERRIC REDUCTION OXIDASE 2 (FRO2) and IRON-REGULATED TRANSPORTER 1 (IRT1) exhibit circadian oscillations, which are disrupted in the cca1 lhy double mutant. Furthermore, CCA1 directly binds to the specific regulatory regions of multiple Fe homeostasis genes and activates their expression. Thus, this study established that, in plants, CCA1 and LHY function as master regulators that maintain cyclic Fe homeostasis. PMID- 29989314 TI - Comparison of minichromosome maintenance protein 7, Ki67 and mitotic index in the prognosis of intermediate Patnaik grade cutaneous mast cell tumours in dogs. AB - A previous study found that minichromosome maintenance protein 7 (MCM7) score was associated with prognosis in dogs with cutaneous mast cell tumours (MCTs) independent of histological grade. The primary aim of this study was to validate this score in a different cohort of dogs focusing exclusively on patients with Patnaik intermediate grade MCTs treated with surgery alone and followed for a minimum of 1 year. A secondary aim was to evaluate the prognostic performance of MCM7 in relation to Kiupel histological grade, mitotic index (MI) and Ki67 index in the same cohort of dogs. Ninety dogs were identified, 82 were low Kiupel grade and 8 were high Kiupel grade. Seventy-two dogs were alive after a median follow up of 1136 days and 18 dogs died of MCT-related causes after a median of 116 days. A MI threshold of 5 was associated with a sensitivity of 0.39 and a specificity of 0.99 in predicting MCT-related death; for Ki67 a threshold of 0.018 was associated with a sensitivity of 0.78 and a specificity of 0.83; and for MCM7 a threshold of 0.18 gave a sensitivity of 0.83 and a specificity of 0.86. Combining MI, Ki67 and MCM7 showed an improved accuracy of predicting death compared with each individual variable. Therefore, performing Ki67 and MCM7 in dogs with GII MCT, low Kiupel grade and low MI might be a consideration. PMID- 29989315 TI - Posttraumatic stress, uncontrollability, and emotional distress tolerance. AB - BACKGROUND: Although individuals with posttraumatic stress disorder (PTSD) report poor tolerance for distress, the mechanisms underpinning this are unknown. Cognitive models of PTSD propose that appraisals of lacking or losing control impair adaptation to trauma. This study investigated whether avoidance of emotional distress was affected by loss of control in a web-based community sample with and without PTSD symptomatology, expecting that those with PTSD may show more detrimental effects following greater loss of control. METHODS: PTSD symptomatic (N = 104) and nonsymptomatic (N = 102) participants initially had baseline controllability appraisals indexed during a task designed to induce an illusion of control over an unwanted stimulus. Participants were then randomized to be able to delay the onset and also control the termination of interference trials during an effortful visual search task, and separately randomized to receive pretask instructions implying either doubtful or certain controllability. Following the manipulation, participants completed a task indexing delay between selecting and playing a purportedly distressing video at their maximum tolerable distress level. RESULTS: Controlling for age, sex, and instructional condition, those who experienced greater violation of their initial perceptions of control tended to be more avoidant of emotional distress. There was a significant interaction whereby loss of control was more detrimental for those with PTSD symptoms. CONCLUSIONS: These initial data suggest that posttraumatic stress exacerbates sensitivity to loss of control, and this appears to directly impact capacity to approach distressing stimuli. PMID- 29989316 TI - Direct comparison of mastoidal and retrosigmoidal placement of a transcutaneous bone conduction device after canal wall down tympanoplasty. PMID- 29989317 TI - The evolution of sociality in termites from cockroaches: A taxonomic and phylogenetic perspective. AB - Despite multiple studies and advances, sociality still puzzles evolutionary biologists in numerous ways, which might be partly addressed with the advent of sociogenomics. In insects, the majority of sociogenomic studies deal with Hymenoptera, one of the two groups that evolved eusociality with termites. But, to fully grasp the evolution of sociality, studies must obviously not restrict to eusocial lineages. Multiple kinds of social system transitions have been recorded and they all bring complementary insights. For instance, cockroaches, the closest relatives to termites, display a wide range of social interactions and evolved convergently subsocial behaviors (i.e., brood care). In this context, we emphasize the need for natural history, taxonomic, and phylogenetic studies. Natural history studies provide the foundations on which building hypotheses, whereas taxonomy provides the taxa to sample to test these hypotheses, and phylogenetics brings the historical framework necessary to test evolutionary scenarios of sociality evolution. PMID- 29989318 TI - TIMP-1 association with collagen type I overproduction in hereditary gingival fibromatosis. AB - OBJECTIVES: To investigate the processes associated with the excessive production of collagen I in hereditary gingival fibromatosis (HGF). MATERIALS AND METHODS: Three HGF subjects and five controls were enrolled in the study. Histomorphological and immunohistological analyses were performed on gingival tissues. The expression of heat-shock protein 47 (HSP47), collagen I, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) by gingival fibroblasts isolated from HGF and controls was analysed using qRT-PCR, Western blotting and ELISA. RESULTS: Considerable accumulation of fibrotic fibrils and increased synthesis of HSP47 were noted in HGF gingival tissues. The synthesis of collagen I, HSP47, TGF beta1, CTGF and TIMP-1 was significantly elevated in HGF gingival fibroblasts compared with controls, while the production of MMP-1 was decreased. CONCLUSIONS: We report that fibrosis in HGF gingival tissues is associated with increased synthesis of HSP47. This finding was confirmed by an in vitro study, where excessive production of collagen I was associated with increased synthesis of HSP47, TGF-beta1 and CTGF by HGF gingival fibroblasts. Moreover, the shift in the TIMP-1/MMP-1 ratio identifies increased synthesis of TIMP-1 as one of the processes associated with collagen I overproduction in HGF fibroblasts. PMID- 29989319 TI - Investigation before implementation. PMID- 29989320 TI - The Brief Intervention Effect of Metaphorical Cognitive Restructuring on Alleviating Mental Distress: A Randomised Controlled Experiment. AB - BACKGROUND: Metaphors may provide clarity or identify hidden similarities between two ideas, and their use in cognitive restructuring can help maximise the effect of therapy information. This study aimed to determine whether metaphorical cognitive restructuring would produce a greater intervention effect in targeted mood and cognition than non-metaphorical restructuring. METHODS: Eighty-eight participants chose 25 problems of interest and wrote a self-report distress problem and were then randomly divided into a metaphorical restructuring group (N = 29), a literal restructuring group (N = 30), or a no restructuring problem restating group (N = 29). Participants first read a description of psychological distress ("problem") and then read a solution within one micro-counseling scenario. They were asked to evaluate their insightfulness during the intervention and evaluated mental distress and self-efficacy before and after the intervention. RESULTS: The mental distress of the metaphorical restructuring group significantly decreased after the intervention. Further, this group had greater insightfulness during the intervention, and this insightfulness could predict the reduction of negative affect after the intervention. CONCLUSIONS: The use of metaphors can be of great value in eliciting a salient cognitive restructuring process and in alleviating mental distress. PMID- 29989321 TI - A cross-sectional study of non-attendance among patients at a US hemophilia treatment center 2010-2014. AB - INTRODUCTION: Among patients with chronic disease, non-attendance at scheduled healthcare visits is associated with poor outcomes. The impact of non-attendance among patients with bleeding disorders is unknown. METHODS: Scheduling and medical record data over a 5-year period for all individuals with at least one scheduled appointment during 2010-2014 at a US Hemophilia Treatment Center (HTC) were analysed. Non-attendance rates were calculated as the number of non-attended visits divided by the number of years as a patient during the time period. Consistent non-attenders were patients who did not attend more than one scheduled appointment per person-year on average. Logistic regression determined characteristics associated with consistent non-attendance and Poisson regression estimated adjusted incidence rate ratios (aIRRs) describing associations between non-attendance and emergency department (ED) visits and hospitalizations. RESULTS: There were 8028 appointments scheduled for 950 individuals; 12% were not attended. Consistent non-attenders (n = 62; 7% of the HTC patient population) accounted for over one-third of non-attended appointments and over one-quarter of hospitalizations. Characteristics associated with consistent non-attendance included public health insurance and black race. Higher non-attendance rates were associated with more ED visits (aIRR 1.78; 95% CI: 1.37-2.30) and hospitalizations (aIRR 2.73; 95% CI: 2.18-3.42). Consistent non-attenders had more ED visits (aIRR 2.49; 95% CI: 1.56-3.96) and hospitalizations (aIRR 4.73; 95% CI: 2.96-7.57) compared with patients who never missed appointments. CONCLUSIONS: Frequent non-attendance identified a small but at-risk population. Interventions to improve disease management that target them may have an impact on health outcomes and healthcare utilization. PMID- 29989322 TI - To T or not to T: Differences in Testosterone Use and Discontinuation by HIV Serostatus among Men who Have Sex with Men. AB - OBJECTIVES: The aim of the study was to characterize contemporary patterns and correlates of testosterone therapy (TTh) use and discontinuation by HIV serostatus among men in the Multicenter AIDS Cohort Study (MACS). METHODS: Self reported testosterone use data were collected semiannually from 2400 (1286 HIV infected and 1114 HIV-uninfected) men who have sex with men. Multivariable Poisson regression was used to estimate prevalence ratios for TTh use and predictors of TTh discontinuation (2012-2015). RESULTS: Use was higher among HIV infected compared with HIV-uninfected men in all age strata, with an age-adjusted prevalence of 17% vs. 5%, respectively (adjusted prevalence ratio 3.7; P < 0.001). Correlates of use in the multivariable model were similar by HIV serostatus: white race, the Los Angeles (LA) site, more than one recent sexual partner, non-smoking status, and higher American Heart Association/American College of Cardiology (AHA/ACC) cardiovascular disease (CVD) risk score category (approximately 70% of testosterone users were in the high-risk category). Compared with HIV-uninfected men, HIV-infected men more frequently reported building muscle mass as a motivation for testosterone use. The TTh discontinuation rate was 20.9/100 person-years [95% confidence interval (CI) 17.3, 25.0/100 person-years]. Relative to HIV-uninfected men, HIV-infected men were half as likely to discontinue (adjusted incidence rate ratio 0.4; P < 0.001). Discontinuation was 40% higher in the period after the US Food and Drug Administration (FDA) safety communication for testosterone in 2014, independent of co-factors (P = 0.06). CONCLUSIONS: Given the high prevalence of both TTh use and CVD risk among HIV-infected men, the benefits and risks of TTh should be examined in future studies of aging HIV-infected men and monitored routinely in clinical practice. PMID- 29989326 TI - VETERINARY EMERGENCY & CRITICAL CARE SOCIETY 2018 MEMBERSHIP APPLICATION. PMID- 29989328 TI - Alcohol consumption, depressive symptoms, and the incidence of diabetes-related complications. AB - BACKGROUND: Heavy alcohol consumption in individuals with type 2 diabetes mellitus (T2DM) is related to increased risks of diabetes-related micro- and macrovascular complications. Depressive symptoms may be relevant to this relationship, because high depressive symptoms are associated with an increased risk of complications. This study investigated whether the interaction between depressive symptoms and alcohol frequency was positively related to the development of neuropathy, retinopathy, nephropathy, and coronary artery disease (CAD), such that those with high depressive symptoms and high alcohol frequency will be at increased risk of complications. METHODS: Data were from five waves of the Evaluation of Diabetes Treatment annual survey including 1413 adults with T2DM in Quebec. Data on alcohol frequency (number of drinking occasions), depressive symptoms, and complications were collected annually. The development of each complication was investigated using multiple logistic regression analysis with generalized estimating equations. RESULTS: After adjusting for sociodemographic, lifestyle, and diabetes-related covariates, the interaction between alcohol frequency and depressive symptoms was positively related to the incidence of neuropathy and CAD, such that those with high depressive symptoms who drank the most frequently had the highest risk of neuropathy (odds ratio [OR] 1.02, 95% confidence interval [CI] 1.00-1.04; P = 0.04) and CAD (OR 1.02, 95% CI 1.00-1.04; P = 0.04). This interaction was not significantly related to retinopathy or nephropathy. CONCLUSION: Individuals with high depressive symptoms and high alcohol frequency may have a particularly high risk of neuropathy and CAD. Future prevention efforts should examine both alcohol frequency and depressive symptoms when evaluating the risk of complications. PMID- 29989330 TI - Genomic full-length sequence of HLA-A*11:172 was identified by full-length group specific sequencing. AB - Genomic full-length sequence of HLA-A*11:172 was identified by a group-specific sequencing approach from China. PMID- 29989329 TI - Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway. AB - PURPOSE: Macrophages play critical roles in inflammation and wound healing and can be divided into two subtypes: classically activated (M1) and alternatively activated (M2) macrophages. Macrophages also play important roles in regulating iron homeostasis, and intracellular iron accumulation induces M1-type macrophage polarization which provides a potential approach to tumor immunotherapy through M2 tumor-associated macrophage repolarization. However, the mechanisms underlying iron-induced M1 polarization remain unclear. METHODS: Western blotting, qRT-PCR, and flow cytometry were used to detect the polarization indexes in RAW 264.7 murine macrophages treated with iron, and Western bloting and qRT-PCR were used to detect p21 expression. The compound 2,7-dichlorofluorescein diacetate was used to measure reactive oxygen species (ROS) levels in macrophages after iron or N acetyl-l-cysteine (NAC) treatment. The p300/CREB-binding protein (CBP) inhibitor C646 was used to inhibit p53 acetylation, and Western bloting, qRT-PCR, and immunofluorescence were used to detect p53 expression and acetylation. BALB/c mice were subcutaneously injected with H22 hepatoma cells, and macrophage polarization status was investigated after tail intravenous injection of iron. Immunohistochemical staining was used to evaluate the protein expression of cluster of differentiation 86 (CD86) and EGF-like module-containing mucin-like hormone receptor-like 1 (F4/80) in the subcutaneous tumors. RESULTS: Iron overload induced M1 polarization by increasing ROS production and inducing p53 acetylation in RAW cells, and reduction in ROS levels by NAC repressed M1 polarization and p53 acetylation. Inhibition of acetyl-p53 by a p300/CBP inhibitor prevented M1 polarization and inhibited p21 expression. These results showed that high ROS levels induced by iron overload polarized macrophages to the M1 subtype by enhancing p300/CBP acetyltransferase activity and promoting p53 acetylation. PMID- 29989331 TI - Getting Closer to Absolute Molar Masses of Technical Lignins. AB - Determination of molecular weight parameters of native and, in particular, technical lignins are based on size exclusion chromatography (SEC) approaches. However, no matter which approach is used, either conventional SEC with a refractive index detector and calibration with standards or multi-angle light scattering (MALS) detection at 488 nm, 633 nm, 658 nm, or 690 nm, all variants can be severely erroneous. The lack of calibration standards with high structural similarity to lignin impairs the quality of the molar masses determined by conventional SEC, and the typical fluorescence of (technical) lignins renders the corresponding MALS data rather questionable. Application of MALS detection at 785 nm by using an infrared laser largely overcomes those problems and allows for a reliable and reproducible determination of the molar mass distributions of all types of lignins, which has been demonstrated in this study for various and structurally different analytes, such as kraft lignins, milled-wood lignin, lignosulfonates, and biorefinery lignins. The topics of calibration, lignin fluorescence, and lignin UV absorption in connection with MALS detection are critically discussed in detail, and a reliable protocol is presented. Correction factors based on MALS measurements have been determined for commercially available calibration standards, such as pullulan and polystyrene sulfonate, so that now more reliable mass data can be obtained also if no MALS system is available and these conventional calibration standards have to be resorted to. PMID- 29989333 TI - The other facets of family life and their role in the evolution of animal sociality. AB - Family life forms an integral part of the life history of species across the animal kingdom and plays a crucial role in the evolution of animal sociality. Our current understanding of family life, however, is almost exclusively based on studies that (i) focus on parental care and associated family interactions (such as those arising from sibling rivalry and parent-offspring conflict), and (ii) investigate these phenomena in the advanced family systems of mammals, birds, and eusocial insects. Here, we argue that these historical biases have fostered the neglect of key processes shaping social life in ancestral family systems, and thus profoundly hamper our understanding of the (early) evolution of family life. Based on a comprehensive survey of the literature, we first illustrate that the strong focus on parental care in advanced social systems has deflected scrutiny of other important social processes such as sibling cooperation, parent-offspring competition and offspring assistance. We then show that accounting for these neglected processes - and their changing role over time - could profoundly alter our understanding of the origin and subsequent evolution of family life. Finally, we outline how this 'diachronic' perspective on the evolution of family living provides novel insights into general processes driving the evolution of animal sociality. Overall, we infer that the explicit consideration of thus-far neglected facets of family life, together with their study across the whole diversity of family systems, are crucial to advance our understanding of the processes that shape the evolution of social life. PMID- 29989334 TI - Assessing Skewed X-Chromosome Inactivation. AB - We describe a simple and straightforward method for detection and characterization of X-chromosome inactivation in females and/or individuals with more than one X chromosome. The X-chromosome inactivation pattern is visualized on a single-cell level using 5-ethynyl-2-deoxyuridine (EdU) instead of the previously widely applied 5-bromo-2'-deoxyuridine (BUdR). The fluorochrome labeled nucleoside analog EdU is incorporated into late-replication chromosomal regions of living blood cells in vitro; thus, it can also be used to specifically highlight the inactive X chromosome within a cytogenetic preparation. The EdU based test for assessing skewed X-chromosome inactivation can only be meaningfully applied if the X chromosome of the index patient can be cytogenetically distinguished under a microscope from the normal one. (c) 2018 by John Wiley & Sons, Inc. PMID- 29989332 TI - HIV health care providers are ready to introduce pre-exposure prophylaxis in Central and Eastern Europe and neighbouring countries: data from the Euroguidelines in Central and Eastern Europe (ECEE) Network Group. AB - OBJECTIVES: Pre-exposure prophylaxis (PrEP) for HIV infection has been introduced in only a few European countries. We investigated the potential to provide PrEP in the Central and Eastern European region, and in neighbouring countries. METHODS: The Euroguidelines in Central and Eastern Europe (ECEE) Network Group was formed in February 2016 to review standards of care for HIV infection in the region. Information related to PrEP was collected through on-line surveys. Respondents were recruited by ECEE members based on their involvement in HIV care. RESULTS: Seventy-six respondents from 23 countries participated in the survey. Twenty-six (34.2%) respondents reported that PrEP [tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)] was registered by the drug registration authority in their country. Fifty-three (70.7%) respondents reported being aware of 'informal' PrEP use in their country. If they had access to PrEP, 56 (74.7%) would advise its use in their practice. Forty-five (59.2%) respondents had concerns regarding PrEP use, and 10 (13.3%) expressed the need for more training. Most of the respondents (88.2%) would provide PrEP to people with high-risk behaviours. CONCLUSIONS: PrEP is already used informally in some countries in the region. Physicians are keen to use PrEP if and when it is accessible. Obstacles towards implementing PrEP in those countries were mostly related to lack of national guidelines, drug registration and governmental strategy. PMID- 29989335 TI - Comparison of insulin glargine 300 U/mL and insulin degludec using flash glucose monitoring: A randomized cross-over study. AB - AIMS/INTRODUCTION: We compared the efficacy and safety of insulin glargine 300 U/mL (Gla300) and insulin degludec U100 (Deg) using a flash glucose monitoring system. MATERIALS AND METHODS: A total of 24 Japanese patients with type 2 diabetes were randomized to receive once-daily Gla300 (n = 12) or Deg (n = 12) in the morning. The primary end-points were the mean percentage of time in the target glucose range (70-179 mg/dL) and hypoglycemia (<70 mg/dL), as measured using flash glucose monitoring during the last 7 days of each 14-day period. RESULTS: The percentages of time with glucose levels <70 mg/dL were not significantly different between the two insulin treatments. No significant differences were observed in the percentages of time with glucose levels of 70 179 mg/dL or >=180 mg/dL. The percentage of time with nocturnal hypoglycemia with Gla300 was significantly lower than that with Deg treatment (P = 0.021). This difference might be attributable to the difference in the duration of action between the two formulations, and the incidence of nocturnal hypoglycemia with Deg treatment was associated with the concomitant use of metformin (P = 0.035). CONCLUSIONS: The two formulations were comparable in efficacy, whereas the incidence of nocturnal hypoglycemia was significantly lower with Gla300. Thus, the present study suggests that, although Gla300 and Deg are comparable long acting insulin analogs, Gla300 is safer with respect to the incidence of hypoglycemia. PMID- 29989336 TI - Ultrasound-Guided Superficialization of an Arteriovenous Fistula by Minimally Invasive Liposuction Technique. PMID- 29989337 TI - Conversion of Lignin Models by Photoredox Catalysis. AB - One prominent goal of 21st century research is to develop a sustainable carbon neutral biorefinery. Lignin is an important component of lignocellulosic biomass; however, it is currently underutilized owing to its highly cross-linked, complex, and randomly polymerized composition, which poses a significant challenge to its depolymerization and valorization. Chemical catalytic approaches based on transition metals represent the primary research area to drive degradation reactions. Recently, alternative photocatalytic strategies that employ sustainable solar energy to initiate the transformation of lignin have started to emerge. This Concept article examines new developments of photocatalyzed reactions and provides insight into C-O and C-C bond-cleavage reactions of lignin models in both homogeneous and heterogeneous systems. PMID- 29989338 TI - HIV and sexually transmitted infections: responding to the "newest normal". PMID- 29989339 TI - Association of low-density lipoprotein receptor-related protein 1 rs11613352 and angiopoietin-like 3 rs2131925 with hypertension in men-the Tampere adult population cardiovascular risk study. AB - BACKGROUND: We examined the association of three known genome-wide association study loci for blood lipids that have lead traits for triglycerides with hypertension in the Tampere adult population cardiovascular risk study. METHODS: A Finnish cohort of 190 men with diagnosed hypertension and 279 controls were analyzed. Samples were genotyped for low-density lipoprotein receptor-related protein 1 rs11613352 (C>T), angiopoietin-like 3 rs2131925 (T>G), and fatty acid desaturase 1 rs174546 (C>T) polymorphisms using competitive allele-specific polymerase chain reaction technique. RESULTS: At the age of 50, subjects with low density lipoprotein receptor-related protein 1 rs11613352 (C>T) minor genotype TT had significantly more hypertension than those with the C allele (OR 5.17, CI 2.03-12.74, p < 0.001). Subjects with angiopoietin-like 3 rs2131925 (T>G) T allele had more hypertension than those with the minor genotype GG (OR 5.02, CI 1.40-17.98, p = 0.013). Fatty acid desaturase 1 rs174546 (C>T) did not associate with hypertension. CONCLUSION: Association of low-density lipoprotein receptor related protein 1 rs11613352 and angiopoietin-like 3 rs2131925 with hypertension might imply a direct effect at the artery wall. PMID- 29989340 TI - Positionspapier: Diagnostik und Therapie der Xerosis cutis. AB - HINTERGRUND UND RATIONALE: Die Xerosis cutis (Synonym: Xerodermie, trockene Haut, hydrolipidarme Haut) ist mit > 10 Millionen Betroffenen nicht nur eine der haufigsten dermatologischen Diagnosen in Deutschland, sondern auch Leitsymptom vieler dermatologischer, internistischer und neurologischer Erkrankungen. Trotz der medizinischen Relevanz der topischen Basistherapie fur die Xerosis cutis gibt es in Deutschland fur ihr Management bisher keinen wissenschaftlich belegten Diagnostik- und Therapiealgorithmus. ZIEL: Dieses Positionspapier vermittelt Arzten fachubergreifend einen an individuellen Symptomen orientierten, praxisnahen Leitfaden fur die Pravention, Diagnostik und Therapie der Xerosis cutis. METHODIK: Im Rahmen eines strukturierten Entscheidungsprozesses wurden von erfahrenen dermatologischen Experten zunachst praxisrelevante Fragestellungen definiert und systematisch aufgearbeitet. Auf der Basis von Evidenz und Expertenkonsens wurden daraus diagnostische und therapeutische Algorithmen mit Empfehlungen fur die Praxis entwickelt und konsentiert. ERGEBNIS: Die Xerosis cutis kann grundsatzlich klinisch diagnostiziert werden. Ausloser und/oder Grunderkrankungen mussen abgeklart und vermieden bzw. spezifisch behandelt werden. Bei der Wahl der geeigneten Basistherapie ist es wichtig, dass nicht nur die Hauthydratation verbessert, sondern auch die Barrierefunktion der Haut wiederhergestellt wird. Sie sollte daher aus einer Kombination von ruckfeuchtenden und ruckfettenden Inhaltsstoffen bestehen. Je trockener die Haut, desto lipidhaltiger sollte die Hautpflege sein (bevorzugt Wasser-in-Ol Formulierungen). Die individuelle Auswahl der Inhaltsstoffe orientiert sich nach kausaler Prufung an den Symptomen Schuppung (v.a. Urea), Fissuren/Rhagaden (v.a. Urea oder Dexpanthenol), Rotung (v.a. Licochalcone A) und Pruritus (v.a. Polidocanol), sowie an der Lokalisation und dem Alter der Patienten. Inhaltsstoffe bzw. Inhaltsstoffkombinationen mit guter Studienevidenz sind zu bevorzugen. Die mit Abstand beste Evidenz bei der Xerosis cutis weist Urea auf, dessen Wirksamkeit in Kombination mit anderen naturlichen Feuchthalte-Komponenten und Ceramiden noch gesteigert werden kann. Zur Arbeitserleichterung am Patienten und zum besseren Erlernen wurde das Xerosimeter entwickelt, das die praktische Umsetzung der Diagnostik und Verlaufskontrolle, eine Klassifikation der Inhaltsstoffe und einen strukturierten Therapiealgorithmus enthalt. SCHLUSSFOLGERUNG: Das hier vorgeschlagene strukturierte symptom- und evidenzorientierte Vorgehen mit Diagnostik- und Behandlungspfad soll fur die Pravention und fruhzeitige Behandlung der Xerosis cutis sensibilisieren. Damit konnen die Lebensqualitat verbessert und Folgeerkrankungen verhindert werden. PMID- 29989341 TI - Lord of The Crowns: A New Precious in the Kingdom of Clustomesogens. AB - Replacing pure inorganic materials by functional organic-inorganic hybrid ones to lower production costs has become a major challenge, in particular for the optoelectronic industry. Adding nanostructuration abilities meanwhile preserving homogeneity is even more challenging for this class of new materials. Here we show that red-NIR emissive ternary molybdenum cluster salts can be assembled to liquid crystalline 15C5 crown ethers. The resulting hybrids are homogeneous and stable up to high temperature despite the weakness of the supramolecular interactions binding both components. These are illustrated by 133 Cs MAS NMR. All hybrids show hexagonal columnar arrangements and strong red-NIR emission. Surprisingly, when chlorinated clusters are used instead of brominated ones, the mesophase stability is largely enhanced. PMID- 29989342 TI - Correlation between progression-free survival, tumor burden, and circulating tumor DNA in the initial diagnosis of advanced-stage EGFR-mutated non-small cell lung cancer. AB - BACKGROUND: This study was conducted to identify whether the presence of circulating tumor DNA (ctDNA) in plasma before treatment with EGFR-tyrosine kinase inhibitors (TKIs) is associated with clinical outcomes. METHODS: Fifty seven pairs of tissues and plasma samples were obtained from patients with NSCLC adenocarcinoma harboring activating EGFR mutations before the administration of EGFR-TKI treatment. ctDNA mutation was identified using the PANAMutyper EGFR mutation kit. Both qualitative and quantitative analyzes of the data were performed. RESULTS: Concordance rates with tissue biopsy were 40.4% and 59.6% for the qualitative and quantitative methods, respectively. Bone metastasis showed a statistically significant correlation with ctDNA detection (odds ratio 3.985, 95% confidence interval [CI] 1.027-15.457; P = 0.046). Progression-free survival (PFS) was significantly shorter in the group detected with ctDNA than in the undetected ctDNA group (median PFS 9.8 vs. 20.7 months; hazard ratio [HR] 2.30, 95% CI 1.202-4.385; P = 0.012). Detection of ctDNA before treatment with EGFR TKIs (HR 2.388, 95% CI 1.138-5.014; P = 0.021) and extra-thoracic lymph node metastasis (HR 13.533, 95% CI 2.474-68.747; P = 0.002) were independently associated with PFS. Six of 11 patients (45.5%) monitored by serial sampling showed a dynamic change in ctDNA prior to disease progression. CONCLUSION: Quantitative testing can increase the sensitivity of the ctDNA detection test. Patients with detectable ctDNA had significantly shorter PFS after receiving EGFR TKIs than those with undetectable ctDNA. Tumor burden may be associated with plasma ctDNA detection. A shorter PFS was associated with detection of ctDNA and extra-thoracic lymph node metastasis. Dynamic changes in the ctDNA level may help predict clinical outcomes. PMID- 29989343 TI - Regulation of translation initiation factor eIF2B at the hub of the integrated stress response. AB - Phosphorylation of the translation initiation factor eIF2 is one of the most widely used and well-studied mechanisms cells use to respond to diverse cellular stresses. Known as the integrated stress response (ISR), the control pathway uses modulation of protein synthesis to reprogram gene expression and restore homeostasis. Here the current knowledge of the molecular mechanisms of eIF2 activation and its control by phosphorylation at a single-conserved phosphorylation site, serine 51 are discussed with a major focus on the regulatory roles of eIF2B and eIF5 where a current molecular view of ISR control of eIF2B activity is presented. How genetic disorders affect eIF2 or eIF2B is discussed, as are syndromes where excess signaling through the ISR is a component. Finally, studies into the action of recently identified compounds that modulate the ISR in experimental systems are discussed; these suggest that eIF2B is a potential therapeutic target for a wide range of conditions. This article is categorized under: Translation > Translation Regulation. PMID- 29989344 TI - Estimation of an overall standardized mean difference in random-effects meta analysis if the distribution of random effects departs from normal. AB - The random-effects model, applied in most meta-analyses nowadays, typically assumes normality of the distribution of the effect parameters. The purpose of this study was to examine the performance of various random-effects methods (standard method, Hartung's method, profile likelihood method, and bootstrapping) for computing an average effect size estimate and a confidence interval (CI) around it, when the normality assumption is not met. For comparison purposes, we also included the fixed-effect model. We manipulated a wide range of conditions, including conditions with some degree of departure from the normality assumption, using Monte Carlo simulation. To simulate realistic scenarios, we chose the manipulated conditions from a systematic review of meta-analyses on the effectiveness of psychological treatments. We compared the performance of the different methods in terms of bias and mean squared error of the average effect estimators, empirical coverage probability and width of the CIs, and variability of the standard errors. Our results suggest that random-effects methods are largely robust to departures from normality, with Hartung's profile likelihood methods yielding the best performance under suboptimal conditions. PMID- 29989345 TI - Risk of depression in patients with inflammatory bowel disease. AB - OBJECTIVE: Depression is more prevalent in patients with inflammatory bowel disease (IBD) than in the general population. This study evaluated disease related risk factors for depression in Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Altogether 348 patients with IBD (228 with CD, 120 with UC) were included at our Outpatient IBD Clinic. Their characteristics, laboratory results and scores of depression, quality of life and clinical disease activity were retrospectively retrieved from questionnaires and medical records. The patient health questionnaire 9 (PHQ-9) was used as an algorithm for a probable diagnosis of major depression employing a cut-off point >=10. Logistic regression analyses were performed to identify risk factors for depression. RESULTS: Among these patients, 163 (46.8%) had no or minimal depression (PHQ-9 score 0-4), 108 (31.0%) had mild depression (PHQ-9 score 5-9) and 77 (22.1%) were at risk of major depression (PHQ-9 score >=10). Patients with CD had a higher risk of major depression than those with UC (25.4% vs 15.8%, P = 0.040). PHQ-9 scores correlated strongly with clinical disease activity and quality of life scores in both groups but only weakly and solely in the CD group with biochemical disease activity. Clinical disease activity was identified as the only independent risk factor for depression in CD (odds ratio 7.814, 95% CI 2.688-22.717, P < 0.001), while no independent risk factor for depression was detected in UC. CONCLUSION: Achieving clinical remission in patients with IBD seems to be the most important factor to reduce the risk of depression. PMID- 29989346 TI - Effectiveness of submandibular duct relocation in 91 children with excessive drooling: A prospective cohort study. AB - OBJECTIVE: To evaluate the effectiveness of submandibular duct relocation (SMDR) in drooling children with neurological disorders. DESIGN: Prospective cohort study. SETTING: Academic Outpatient Saliva Control Clinic. PARTICIPANTS: Ninety one children suffering from moderate to severe drooling. MAIN OUTCOME MEASURES: Direct observational drooling quotient (DQ; 0-100) and caretaker Visual Analogue Scale (VAS; 0-100). Secondary outcome measures were drooling severity (DS) and frequency rating scales. RESULTS: The DQ at baseline, 8 and 32 weeks postoperatively was 26.4, 12.3 and 10.8, respectively. VAS score decreased from 80.1 at baseline to 28.3 and 37.0 at 8 and 32 weeks after surgery. Median DS at baseline, 8 and 32 weeks was 5, 3 and 4, whereas the drooling frequency median scores were 4, 2 and 2, respectively. Five children required prolonged intubation due to transient floor of the mouth swelling, two of whom developed a ventilator associated pneumonia. Another child developed atelectasis with postoperative pneumonia. Two more children needed tube feeding because of postoperative eating difficulties for 3 days or suprapubic catheterisation for urinary retention. Children aged 12 years or older (OR = 3.41; P = 0.03) and those with adequate stability and position of the head (OR = 2.84; P = 0.09) appeared to benefit most from treatment. CONCLUSIONS: Submandibular duct relocation combined with excision of the sublingual glands appears to be relatively safe and effective in diminishing visible drooling in children with neurological disorders, particularly in children aged 12 years and older and those without a forward head posture. PMID- 29989348 TI - Evaluation on the genetic instability detecting methods for rapid diagnose of Fanconi anemia used in the undeveloped areas of China. AB - INTRODUCTION: Fanconi anemia (FA), as one of the congenital bone marrow failure syndromes, is characterized by severe bone marrow hypocellularity and pancytopenia which is similar with acquired aplastic anemia (AAA). However, patients with FA or AAA need an accurate diagnose, as the two syndromes differ significantly in both treatment and prognosis. FA results from gene mutations of the FA pathway genes specifically required for DNA repair, and the mutation of these genes contributes to the genome instability of FA cells. Based on this feature, chromosome aberration (CA) has been used as a "golden standard" to the auxiliary diagnosis of FA from AAA. However, CA diagnose calls for more technical requirements and a long time for the subsequent statistical analysis. METHODS: In our study, another two genome instability examination tools, cytokinesis-block micronucleus (CBMN) and single-cell gel electrophoresis (SCGE), were used to distinguish FA patients from AAA patients, compared with CA. RESULTS: The results suggested that significant differences were observed in the FA patients compared with the AAA patients and the controls using all of the three genomic instability examination tools. However, CBMN is the most cost-effective method to distinguish FA patients from AAA patients among the three genome instability examination tools, when the time costs, instrument costs, and technical costs were compared. CONCLUSION: In areas with economic and technical limitations, CBMN is an alternative assay to help distinguish FA patients from AAA patients. PMID- 29989347 TI - Serum levels of immunoglobulins in an adult population and their relationship with nonalcoholic fatty liver disease. AB - OBJECTIVES: Few studies have reported the association between nonalcoholic fatty liver disease (NAFLD) and immunoglobulins. In this study, we aimed to investigate the relationship between serum immunoglobulin levels and NAFLD in a Chinese adult population. METHODS: We performed a cross-sectional study including 11 261 Chinese adults. NAFLD was diagnosed based on the Chinese Guidelines for the diagnosis and treatment of fatty liver diseases and an alcohol intake of <70 g/week in women and <140 g/week in men, and serum immunoglobulin (Ig) levels were determined using immune nephelometry. Multiple logistic regression analysis was done to assess relationships between concentrations of serum immunoglobulins and NAFLD. RESULTS: Of the 11 261 adults recruited from January 2010 to December 2015, the prevalence of NAFLD was 40.8% (n = 4598). The geometric mean levels of IgG, IgM, IgE and IgA were 1177.49 mg/dL (95% confidence interval [CI] 1173.07 1181.93), 93.56 mg/dL (95% CI 92.70-94.42), 30.70 IU/mL (95% CI 29.92-31.49) and 216.64 mg/dL (95% CI 214.95-218.34), respectively. Compared with the lowest quintile, the multivariable adjusted odds ratio (95% CI) of NAFLD for the highest quintile of IgG, IgM, IgE, and IgA were 0.78 (0.66-0.92), 0.71 (0.60-0.84), 0.98 (0.84-1.15) and 1.41 (1.21-1.66), respectively. CONCLUSION: Increased IgA and decreased IgG and IgM levels are independently associated with NAFLD prevalence. Further research is needed to explore the causal association between serum immunoglobulins and NAFLD. PMID- 29989349 TI - Rhinology Future Debates 2017 by EUFOREA: Novel treatments and surgical solutions in rhinology. PMID- 29989351 TI - The Virtuous Cycle of Axon Growth: Axonal Transport of Growth-Promoting Machinery as an Intrinsic Determinant of Axon Regeneration. AB - Injury to the brain and spinal cord has devastating consequences because adult central nervous system (CNS) axons fail to regenerate. Injury to the peripheral nervous system (PNS) has a better prognosis, because adult PNS neurons support robust axon regeneration over long distances. CNS axons have some regenerative capacity during development, but this is lost with maturity. Two reasons for the failure of CNS regeneration are extrinsic inhibitory molecules, and a weak intrinsic capacity for growth. Extrinsic inhibitory molecules have been well characterized, but less is known about the neuron-intrinsic mechanisms which prevent axon re-growth. Key signaling pathways and genetic/epigenetic factors have been identified which can enhance regenerative capacity, but the precise cellular mechanisms mediating their actions have not been characterized. Recent studies suggest that an important prerequisite for regeneration is an efficient supply of growth-promoting machinery to the axon; however, this appears to be lacking from non-regenerative axons in the adult CNS. In the first part of this review, we summarize the evidence linking axon transport to axon regeneration. We discuss the developmental decline in axon regeneration capacity in the CNS, and comment on how this is paralleled by a similar decline in the selective axonal transport of regeneration-associated receptors such as integrins and growth factor receptors. In the second part, we discuss the mechanisms regulating selective polarized transport within neurons, how these relate to the intrinsic control of axon regeneration, and whether they can be targeted to enhance regenerative capacity. (c) 2018 Wiley Periodicals, Inc. Develop Neurobiol 00: 000 000, 2018. PMID- 29989350 TI - Chemotaxonomic Considerations of the n-Alkane Composition in Pinus heldreichii, P. nigra, and P. peuce. AB - The n-alkane composition in the leaf cuticular waxes of natural populations of Bosnian pine (Pinus heldreichii), Austrian pine (P. nigra), and Macedonian pine (P. peuce) was compared for the first time. The range of n-alkanes was wider in P. nigra (C16 - C33 ) than in P. heldreichii and P. peuce (C18 - C33 ). Species also diverged in abundance and range of dominant n-alkanes (P. heldreichii: C23 , C27 , and C25 ; P. nigra: C25 , C27 , C29 , and C23 ; P. peuce: C29 , C25 , C27 , and C23 ). Multivariate statistical analyses (PCA, DA, and CA) generally pointed out separation of populations of P. nigra from populations of P. heldreichii and P. peuce (which were, to a greater or lesser extent, separated too). However, position of these species on the basis of n-alkane composition was in accordance neither with infrageneric classification nor with recent molecular and terpene investigations. PMID- 29989352 TI - Identification of an unknown glycoprotein from whole cell lysate using conA and mass spectrometry. AB - Medical laboratory technology major was set up to meet rapid development of science and medical research technology in 2013. Students majoring in medical laboratory had learnt a lot of techniques distributed among different specialized courses. But, they did not understand why they had to learn these techniques and how they were applied in a real-world research setting. In a one-month innovation experimental practice described herein, students had learnt to induce, purify and identify an unknown glycoprotein from whole cell lysate using conA-based affinity chromatography and mass spectrometry. Unlike in a traditional cookbook-style experiment, students chose a research subject on their own and did experiment using their selected variables. Over the one-month laboratory periods, students used sterile technique to cultivate cells, induced glycoprotein expression using LPS and IFN-gamma, purified glycoprotein from cell lysate using agarose-conA beads, identified a glycoprotein via mass spectrometry, and confirmed the result using western blotting. At end of the practice, students were asked to evaluate their experiences via an anonymous survey. All students declared that this experimental practice was interesting and meaningful to them. The process of completing the project was to apply the learnt techniques to real-world biochemistry research, so they became aware of the importance and significance of techniques. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:373-381, 2018. PMID- 29989353 TI - Leaky Expression of the TET-On System Hinders Control of Endogenous miRNA Abundance. AB - With the ability to affect multiple genes and fundamental pathways simultaneously, miRNA engineering of Chinese Hamster Ovary (CHO) cells has significant advantages over single gene expression or repression. Tight control of these molecular triggers is desirable as it could in theory allow on/off or even tunable regulation of desirable cellular phenotypes. The present study investigated the potential of employing a tetracycline inducible (TET-On) system for conditional knockdown of specific miRNAs but encountered several challenges. The authors show a significant reduction in cell proliferation and culture viability when maintained in media supplemented with the TET-On induction agent Doxycycline at concentrations commonly reported. Calculation of a mature miRNA and miRNA sponge mRNA copy number demonstrates that leaky basal transgene expression in the un-induced state, is sufficient for significant miRNA knockdown. This work highlights challenges of the TET-On inducible expression system for controlled manipulation of endogenous miRNAs with two examples; miR 378 and miR-455. The authors suggest a solution involving isolation of highly inducible clones and use a single cell analysis platform to demonstrate the heterogeneity of basal expression and inducibility. Finally, the authors describe numerous strategies to minimize leaky transgene expression and alterations to current miRNA sponge design. PMID- 29989355 TI - Eine ungewohnliche erythematose Plaque am Rucken einer alteren Frau. PMID- 29989356 TI - Aktualisierung der S1-Leitlinie zur Definition und Therapie der primaren Hyperhidrose. PMID- 29989354 TI - Increased Serpina3n release into circulation during glucocorticoid-mediated muscle atrophy. AB - BACKGROUND: Glucocorticoids (GC) play a major role in muscle atrophy. As skeletal muscle is a secretory organ, characterization of the muscle secretome elicited by muscle atrophy should allow to better understand the cellular mechanisms and to identify circulating biomarkers of this condition. Our project aimed to identify the changes in the muscle secretome associated with GC-induced muscle atrophy and susceptible to translate into circulation. METHODS: We have identified the GC induced changes in the secretome of C2 C12 muscle cells by proteomic analysis, and then, we have determined how these changes translate into the circulation of mice or human subjects exposed to high concentrations of GC. RESULTS: This approach led us to identify Serpina3n as one of the most markedly secreted protein in response to GC. Our original in vitro results were confirmed in vivo by an increased expression of Serpina3n in skeletal muscle (3.9-fold; P < 0.01) and in the serum (two-fold; P < 0.01) of mice treated with GC. We also observed increased levels of the human orthologue Serpina3 in the serum of Cushing's syndrome patients compared with healthy controls matched for age and sex (n = 9/group, 2.5-fold; P < 0.01). An increase of Serpina3n was also demonstrated in muscle atrophy models mediated by GC such as cancer cachexia (four-fold; P < 0.01), sepsis (12.5-fold; P < 0.001), or diabetes (two-fold; P < 0.01). In contrast, levels of Serpina3n both in skeletal muscle and in the circulation were reduced in several models of muscle hypertrophy induced by myostatin inhibition (P < 0.01). Furthermore, a cluster of data suggests that the regulation of muscle Serpina3n involves mTOR, an essential determinant of the muscle cell size. CONCLUSIONS: Taken together, these data suggest that Serpina3n may represent a circulating biomarker of muscle atrophy associated to GC and, broadly, a reflection of dynamic changes in muscle mass. PMID- 29989357 TI - Dermatitis durch mesostigmatische Milben (Dermanyssus gallinae, Ornithonyssus [O.] bacoti, O. bursa, O. sylviarum) in Wohngebieten. PMID- 29989358 TI - Correspondence. PMID- 29989360 TI - Tiefe Trichophytie unter dem Bild einer Blepharitis - Tinea ciliaris. PMID- 29989361 TI - Systemic therapies for leg ulcers. AB - Successful management of patients with leg ulcers requires identification of the underlying etiology, with subsequent initiation of causal treatment, if feasible. Supplementary measures of first choice include stage-adjusted wound treatment, usually combined with compression therapy. The significance of systemic drugs has been the subject of controversial debate, depending on the underlying cause of the condition. The present review article is therefore meant to highlight current aspects of systemic drug therapies for the treatment of leg ulcers associated with chronic venous insufficiency, peripheral arterial disease, livedoid vasculopathy, vasculitis, necrobiosis lipoidica, calciphylaxis and pyoderma gangrenosum. In summary, the majority of therapeutic options presented herein are used off-label. While systemic drugs are promising options for the more common types of wounds such as venous, mixed or arterial leg ulcers, they do not represent the current standard of treatment. By contrast, systemic agents play a key role in the management of many of the other disorders presented herein. These agents primarily include immunomodulatory and rheological drugs used to expedite wound healing. PMID- 29989362 TI - Update of the S1 guidelines on the definition and treatment of primary hyperhidrosis. AB - Focal hyperhidrosis can have a considerable impact on social and occupational activities and be associated with significant impairment in quality of life. Primary (idiopathic) hyperhidrosis is neither caused by systemic disorders nor by external factors. It usually occurs in areas characterized by a high density of sweat glands such as the axillae and hands. The diagnosis of focal hyperhidrosis is based on history and clinical findings. Supplementary diagnostic tests include gravimetry (measurement of the amount of sweat) and the iodine starch test (which shows the area of sweating). Treatment options consist of topical agents, botulinum toxin A injections, iontophoresis, treatment with radiofrequency, microwaves, or ultrasound as well as surgical procedures (axillary suction curettage, sympathectomy). Systemic agents such as anticholinergics may also be used. Selection of the most appropriate therapeutic approach depends on the site affected, prior treatment as well as the patient's requests. PMID- 29989363 TI - Patientenakzeptanz und -vertrauen in die automatisierte, computergestutzte Diagnostik des Melanoms mithilfe der Dermatofluoroskopie. PMID- 29989364 TI - Vitiligo und Autoantikorper: Systematischer Review und Metaanalyse. PMID- 29989365 TI - Zwei Gesichter derselben Krankheit. PMID- 29989366 TI - Systemische Therapien des Ulcus cruris. PMID- 29989367 TI - Kongresskalender 2018. PMID- 29989368 TI - Wie schatzen unsere Patienten die Melanomfruherkennung mit Hilfe des Computers und von hochentwickelten technischen Systemen ein? PMID- 29989369 TI - Ixekizumab gegen die Acrodermatitis continua. PMID- 29989370 TI - Kinderwunsch bei Lupus erythematodes - eine medizinische Herausforderung. PMID- 29989371 TI - 34-jahrige Patientin mit schwarzlichen Maculae an Handrucken und Armen. PMID- 29989372 TI - Spontane Besserung einer sekundaren Cutis verticis gyrata bei Akromegalie nach chirurgischer Resektion des Hypophysenadenoms. PMID- 29989373 TI - Anti-Laminin-332-Schleimhautpemphigoid mit laryngealer Beteiligung - adjuvante Behandlung mit Immunadsorption und Rituximab. PMID- 29989374 TI - 45th meeting of the Arbeitsgemeinschaft Dermatologische Forschung. PMID- 29989375 TI - In Memoriam Prof. Dr. Dr. h.c. mult. Otto Braun-Falco. PMID- 29989376 TI - IgG4-assoziierte Erkrankung mit Beteiligung der Haut, des Unterkiefers und der Lunge. PMID- 29989377 TI - Lymphknotenpigmentierung durch Tatowierungsfarbstoffe beeinflusst das Uberleben von Melanompatienten nicht. PMID- 29989378 TI - Psychosoziale Belastung und Unterstutzungswunsch von Hauttumorpatienten - Einfluss des Behandlungs-Settings. PMID- 29989379 TI - Laser-Haarentfernung verandert den Krankheitsverlauf bei leichter Hidradenitis suppurativa. PMID- 29989380 TI - In Memoriam Otto Paul Hornstein 1926 - 2018 PMID- 29989381 TI - Behandlung der erworbenen reaktiven perforierenden Dermatose - eine systematische Ubersicht. PMID- 29989382 TI - Disseminierte exophytische Tumoren bei einer 80-jahrigen Patientin mit chronisch lymphatischer Leukamie. PMID- 29989383 TI - Erythematos-violette Plaques am Stamm und an den Extremitaten eines Kindes. PMID- 29989384 TI - Mixed Ionic-Electronic Conduction in NiFe2 O4 -Ce0.8 Gd0.2 O2-delta Nanocomposite Thin Films for Oxygen Separation. AB - NiFe2 O4 -Ce0.8 Gd0.2 O2-delta (NFO/CGO) nanocomposite thin films were prepared by simultaneously radio-frequency (RF) magnetron sputtering of both NFO and CGO targets. The aim is the growth of a CO2 -stable composite layer that combines the electronic and ionic conduction of the separate NFO and the CGO phases for oxygen separation. The effect of the deposition temperature on the microstructure of the film was studied to obtain high-quality composite thin films. The ratio of both phases was changed by applying different power to each ceramic target. The amount of each deposited phase as well as the different oxidation states of the nanocomposite constituents were analyzed by means of X-ray photoelectron spectroscopy (XPS). The transport properties were studied by conductivity measurements as a function of temperature and pO2 . These analyses enabled (1) selection of the best deposition temperature (400 degrees C), (2) correlation of the p-type electronic behavior of the NFO phase with the hole hopping between Ni3+ -Ni2+ , and (3) following the conductivity behavior of the grown composite layer (prevailing ionic or electronic character) attained by varying the amount of each phase. The sputtered layer exhibited high ambipolar conduction and surfaceexchange activity. A 150 nm-thick nanograined thin film was deposited on a 20 MUm-thick Ba0.5 Sr0.5 Co0.8 Fe0.2 O3-delta asymmetric membrane, resulting in up to 3.8 mL min-1 cm-2 O2 permeation at 1000 degrees C under CO2 atmosphere. PMID- 29989385 TI - The Value of Being Discrete: The Differential and Causal Effects of Positive Affect and Discrete Positive Emotions on Organ Donor Registration Outcomes. AB - BACKGROUND: The current studies examined how positive affect (i.e. the blend of several positive feelings over time) and discrete positive emotions (i.e. a specific set of momentary thoughts and feelings) influence organ donor registration outcomes. METHODS: In Study 1, participants were randomly assigned to a writing task intended to elicit positive or negative affect. In Study 2, participants received a discrete positively valenced emotion induction (i.e. elevation, humor, hubristic pride), or were in a control condition. RESULTS: Study 1 (N = 503) indicated a causal relationship between general positive affect and registration attitudes. An indirect effect beginning with general positive affect, going through attitudes, and then intentions, to influence behavior was also indicated. Study 2a (N = 394) demonstrated that elevation, humor, and hubristic pride can be influenced using an online platform. Study 2b (N = 1,046) indicated a causal relationship between elevation and increased registration intentions and behavior. The humor recall task caused marginally significant greater registration intentions, but no significant behavioral differences. The hubristic pride task did not influence registration outcomes. CONCLUSION: Organ donor practitioners and scholars could benefit from increased focus on the emotional states likely to be experienced at different venues when considering intervention contexts. PMID- 29989387 TI - Rapid Self-Recoverable Hydrogels with High Toughness and Excellent Conductivity. AB - Hydrogels as soft and wet materials have attracted much attention in sensing and flexible electronics. However, traditional hydrogels are fragile or have unsatisfactory recovery capability, which largely limit their applications. Here, a novel hydrogen bond based sulfuric acid-poly(acrylic acid) (PAA)/poly(vinyl alcohol) physical hydrogel is developed for addressing the above drawbacks. Sulfuric acid serves two functions: one is to inhibit the ionization of carboxyl groups from PAA chains to form more hydrogen bonds and the other is to provide conductive ions to promote conductivity of hydrogel. Consequently, the hydrogel obtains comprehensive mechanical properties, including extremely rapid self recovery (strain = 1, instantly self-recover; strain = 20, self-recover within 10 min), high fracture strength (3.1 MPa), and high toughness (18.7 MJ m-3). In addition, we demonstrate this hydrogel as a stretchable ionic cable and pressure sensor to exhibit stable operation after repeated loadings. This work provides a new concept to synthesize physical hydrogels, which will hopefully expand applications of hydrogel in stretchable electronics. PMID- 29989386 TI - In vivo estimation of water diffusivity in occluded human skin using terahertz reflection spectroscopy. AB - Water diffusion and the concentration profile within the skin significantly affect the surrounding chemical absorption and molecular synthesis. Occluding the skin causes water to accumulate in the top layer of the skin (the stratum corneum [SC]) and also affects the water diffusivity. Scar treatments such as silicone gel and silicone sheets make use of occlusion to increase skin hydration. However with existing techniques, it is not possible to quantitatively measure the diffusivity of the water during occlusion: current methods determine water diffusivity by measuring the water evaporated through the skin and thus require the skin to breathe. In this work, we use the high sensitivity of terahertz light to water to study how the water content in the SC changes upon occlusion. From our measurements, we can solve the diffusion equations in the SC to deduce the water concentration profile in occluded skin and subsequently to determine the diffusivity. To our knowledge, this is the first work showing how the diffusivity of human skin can be measured during occlusion and we envisage this paper as being used as a guide for non-invasively determining the diffusivity of occluded human skin in vivo. PMID- 29989388 TI - Self-Assembly of Large DNA Origami with Custom-Designed Scaffolds. AB - As a milestone in DNA self-assembly, DNA origami has demonstrated powerful applications in many fields. However, the scarce availability of long single stranded DNA (ssDNA) limits the size and sequences of DNA origami nanostructures, which in turn impedes the further development. In this study, we present a robust strategy to produce long circular ssDNA scaffold strands with custom-tailored lengths and sequences. These ssDNA products were then used as scaffolds for constructing various DNA origami nanostructures. This scalable method produces ssDNA at low cost with high purity and high yield, which can enable production of custom-designed DNA origami for various applications. PMID- 29989389 TI - Extremely Low Resistance of Li3PO4 Electrolyte/Li(Ni0.5Mn1.5)O4 Electrode Interfaces. AB - Solid-state Li batteries containing Li(Ni0.5Mn1.5)O4 as a 5 V-class positive electrode are expected to revolutionize mobile devices and electric vehicles. However, practical applications of such batteries are hampered by the high resistance at their solid electrolyte/electrode interfaces. Here, we achieved an extremely low electrolyte/electrode interface resistance of 7.6 Omega cm2 in solid-state Li batteries with Li(Ni0.5Mn1.5)O4. Furthermore, we observed spontaneous migration of Li ions from the solid electrolyte to the positive electrode after the formation of the electrolyte/electrode interface. Finally, we demonstrated stable fast charging and discharging of the solid-state Li batteries at a current density of 14 mA/cm2. These results provide a solid foundation to understand and fabricate low-resistance electrolyte/electrode interfaces. PMID- 29989390 TI - Engineered Flumazenil Recognition Site Provides Mechanistic Insight Governing Benzodiazepine Modulation in GABAA Receptors. AB - The anxiolytic, anticonvulsant, muscle-relaxant, and sedative-hypnotic effects of benzodiazepine site ligands are mainly elicited by allosteric modulation of GABAA receptors via their extracellular alphax+/gamma2- ( x = 1, 2, 3, 5) interfaces. In addition, a low affinity binding site at the homologous alpha+/beta- interfaces was reported for some benzodiazepine site ligands. Classical benzodiazepines and pyrazoloquinolinones have been used as molecular probes to develop structure-activity relationship models for benzodiazepine site activity. Considering all possible alpha+/beta- and alpha+/gamma- interfaces, such ligands potentially interact with as many as 36 interfaces, giving rise to undesired side effects. Understanding the binding modes at their binding sites will enable rational strategies to design ligands with desired selectivity profiles. Here, we compared benzodiazepine site ligand interactions in the high affinity alpha1+/gamma2- site with the homologous alpha1+/beta3- site using a successive mutational approach. We incorporated key amino acids known to contribute to high affinity benzodiazepine binding of the gamma2- subunit into the beta3- subunit, resulting in a quadruple mutant beta3(4mut) with high affinity flumazenil (Ro 15 1788) binding properties. Intriguingly, some benzodiazepine site ligands displayed positive allosteric modulation in the tested recombinant alpha1beta3(4mut) constructs while diazepam remained inactive. Consequently, we performed in silico molecular docking in the wildtype receptor and the quadruple mutant. The results led to the conclusion that different benzodiazepine site ligands seem to use distinct binding modes, rather than a common binding mode. These findings provide structural hypotheses for the future optimization of both benzodiazepine site ligands, and ligands that interact with the homologous alpha+/beta- sites. PMID- 29989391 TI - Evolution of Oxyhalide Crystals under Electron Beam Irradiation: An in Situ Method To Understand the Origin of Structural Instability. AB - The oxyhalides have attracted growing interest because of their excellent photocatalytic performance. However, their structural instability hampers further development toward practical applications, a major challenge of current concerns. It is appealing to figure out the origin of structural instability and guide the design of advanced oxyhalide crystals for efficient photocatalysis. In this study, the decomposition of BiOCl crystals, a typical oxyhalide, is triggered by electron beam irradiation and investigated in situ by transmission electron microscopy. The results indicate that the instability originates from the unique layered structure of BiOCl crystals; the interlayer van der Waals bonds are easily broken under electron beam irradiation via the assistance of hydroxyl groups. This facilitates the formation of O/Cl-deficient BiO1- xCl1- y species, Bi metal nanoparticles, and nanobubbles (gaseous substance) that are confined between the adjacent layers. Surface reconstruction would be an effective way to stabilize the oxyhalide crystals. PMID- 29989393 TI - Dual Emitter Nano-Electrospray Ionization Coupled to Differential Ion Mobility Spectrometry-Mass Spectrometry for Shotgun Lipidomics. AB - Current lipidomics workflows are centered around acquisition of large data sets followed by lengthy data processing. A dual nESI-DIMS-MS platform was developed to perform real-time relative quantification between samples, providing data required for biomarker discovery and validation more quickly than traditional ESI MS approaches. Nanosprayer activity and DIMS compensation field settings were controlled by a LabVIEW program synced to the accumulation portion of the ion trap scan function, allowing for full integration of the platform with a commercial mass spectrometer. By comparing samples with short electrospray pulses rather than constant electrospray, the DIMS and MS performance is normalized within an experiment, as signals are compared between individual mass spectra (ms time scale) rather than individual experiments (min-hr time scale). The platform was validated with lipid standards and extracts from nitrogen-deprived microalgae. Dual nESI-DIMS requires minimal system modification and is compatible with all traditional ion activation techniques and mass analyzers, making it a versatile improvement to shotgun lipidomics workflows. PMID- 29989392 TI - Stabilizing Li10SnP2S12/Li Interface via an in Situ Formed Solid Electrolyte Interphase Layer. AB - Despite the extremely high ionic conductivity, the commercialization of Li10GeP2S12-type materials is hindered by the poor stability against Li metal. Herein, to address that issue, a simple strategy is proposed and demonstrated for the first time, i.e., in situ modification of the interface between Li metal and Li10SnP2S12 (LSPS) by pretreatment with specific ionic liquid and salts. X-ray photoelectron spectroscopy and electrochemical impedance spectroscopy results reveal that a stable solid electrolyte interphase (SEI) layer instead of a mixed conducting layer is formed on Li metal by adding 1.5 M lithium bis(trifluoromethanesulfonyl)imide (LiTFSI)/ N-propyl- N-methyl pyrrolidinium bis(trifluoromethanesulfonyl)imide (Pyr13TFSI) ionic liquid, where ionic liquid not only acts as a wetting agent but also improves the stability at the Li/LSPS interface. This stable SEI layer can prevent LSPS from directly contacting the Li metal and further decomposition, and the Li/LSPS/Li symmetric cell with 1.5 M LiTFSI/Pyr13TFSI attains a stable cycle life of over 1000 h with both the charge and discharge voltages reaching about 50 mV at 0.038 mA cm-2. Furthermore, the effects of different Li salts on the interfacial modification is also compared and investigated. It is shown that lithium bis(fluorosulfonyl) imide (LiFSI) salt causes the enrichment of LiF in the SEI layer and results in a higher resistance of the cell upon a long cycling life. PMID- 29989394 TI - Atomic Layer Deposition of Ruthenium Nanoparticles on Electrospun Carbon Nanofibers: A Highly Efficient Nanocatalyst for the Hydrolytic Dehydrogenation of Methylamine Borane. AB - We report the fabrication of a novel and highly active nanocatalyst system comprising electrospun carbon nanofiber (CNF)-supported ruthenium nanoparticles (NPs) (Ru@CNF), which can reproducibly be prepared by the ozone-assisted atomic layer deposition (ALD) of Ru NPs on electrospun CNFs. Polyacrylonitrile (PAN) was electropsun into bead-free one-dimensional (1D) nanofibers by electrospinning. The electrospun PAN nanofibers were converted into well-defined 1D CNFs by a two step carbonization process. We took advantage of an ozone-assisted ALD technique to uniformly decorate the CNF support by highly monodisperse Ru NPs of 3.4 +/- 0.4 nm size. The Ru@CNF nanocatalyst system catalyzes the hydrolytic dehydrogenation of methylamine borane (CH3NH2BH3), which has been considered as one of the attractive materials for the efficient chemical hydrogen storage, with a record turnover frequency of 563 mol H2/mol Ru * min and an excellent conversion (>99%) under air at room temperature with the activation energy ( Ea) of 30.1 kJ/mol. Moreover, Ru@CNF demonstrated remarkable reusability performance and conserved 72% of its inherent catalytic activity even at the fifth recycle. PMID- 29989395 TI - Copper Nanoflower Assembled by Sub-2 nm Rough Nanowires for Efficient Oxygen Reduction Reaction: High Stability and Poison Resistance and Density Functional Calculations. AB - The copper nanoflowers, assembled by sub-2 nm rough nanowires with high catalytic active (200) facets, are prepared by a prompt and simple method with cetyltrimethylammonium bromide (CTAB) as a capping agent. The CTAB plays a vital role in the synthesis process, whereas the copper nanorod arrays assembled by copper nanoparticles are obtained without CTAB. The copper nanoflowers are used as catalysts in oxygen reduction reactions and exhibit excellent electrocatalytic activity, which shows nearly the same activity compared with the commercial Pt/C catalyst, attributing to the nanoflower-exposed higher catalytic active (200) facets. Furthermore, the nanoflowers can avoid methanol-poison effect and show better long-term operation stability. The density functional theory was used to calculate the atom energy of Cu(100) facets and Cu(111) facets. Both of O2 dissociation and H2O activation on the facets are very easy. However, the difference between Cu(100) facets and Cu(111) facets is the adsorption and dissociation energy of O2, and the adsorption and activation of oxygen molecule is much easier on Cu(100) facets than on Cu(111) facets because of the more open nature of (100) facets. PMID- 29989396 TI - One-Pot Catalytic Cleavage of C?S Double Bonds by Pd Catalysts at Room Temperature. AB - The C?S double bonds in CS2 and thioketones were catalytically cleaved by Pd dimeric complexes [(N?N)2Pd2(NO3)2](NO3)2 (N?N, 2,2'-bipyridine, 4,4' dimethylbipyridine or 4,4'-bis(trifluoromethyl)) at room temperature in one pot to afford CO2 and ketones, respectively, for the first time. The mechanisms were fully investigated by kinetic NMR, isotope-labeled experiments, in situ ESI-MS, and DFT calculations. The reaction is involved a hydrolytic desulfurization process to generate C?O double bonds and a trinuclear cluster, which plays a pivotal role in the catalytic cycle to regenerate the dimeric catalysts with HNO3. Furthermore, the electronic properties of catalyst ligands possess significant influence on reaction rates and kinetic parameters. At the same temperature, the reaction rate is consistent with the order of electronegativity of N?N ligands (4,4'-bis(trifluoromethyl) > 2,2'-bipyridine > 4,4' dimethylbipyridine). This homogeneous catalytic reaction features mild conditions, a broad substrate scope, and operational simplicity, affording insight into the mechanism of catalytic activation of carbon sulfur bonds. PMID- 29989397 TI - Solvent-Modulated Emission Properties in a Superhydrophobic Oligo( p phenyleneethynylene)-Based 3D Porous Supramolecular Framework. AB - A chromophoric oligo( p-phenyleneethynylene) (OPE) bola-amphiphile with dioxyoctyl side chains (H2OPE-C8) has been self-assembled with CdII to form a 1D coordination polymer, {Cd(OPE-C8)(DMF)2(H2O)} (1), which is further interdigitated to form a 2D network. Such 2D networks are further interwoven to form a 3D supramolecular framework with surface-projected alkyl chains. The desolvated framework showed permanent porosity, as realized from the CO2 adsorption profile. 1 showed high water contact angles, portraying its superhydrophobic nature. 1 also showed a linker-based cyan luminescence. Solvent removal led to a bathochromic shift in emission into the green region. Resolvation with N, N-dimethylformamide brought back the original cyan emission, whereas for tetrahydrofuran, ethanol, and methanol, it persisted at an intermediate state. Density functional theory calculations unraveled that, twisting of the OPE phenyl rings generated the red shift in emission. PMID- 29989398 TI - Homochiral Metal-Organic Cage for Gas Chromatographic Separations. AB - Metal-organic cages (MOCs) as a new type of porous material with well-defined cavities were extensively pursued because of their relative ease of synthesis and their potential applications in host-guest chemistry, molecular recognition, separation, catalysis, gas storage, and drug delivery. Here, we first reported that a homochiral MOC [Zn3L2] is explored to fabricate [Zn3L2] coated capillary column for high-resolution gas chromatographic separation of a wide range of analytes, including n-alkanes, polycyclic aromatic hydrocarbons, and positional isomers, especially for racemates. Various kinds of racemates such as alcohols, diols, epoxides, ethers, halohydrocarbons, and esters were separated with good enantioselectivity and reproducibility on the [Zn3L2] coated capillary column. The fabricated [Zn3L2] coated capillary column exhibited significant chiral recognition complementary to that of a commercial beta-DEX 120 column and our recently reported homochiral porous organic cage CC3-R coated column. The results show that the homochiral MOCs will be very attractive as a new type of chiral selector in separation science. PMID- 29989399 TI - Mechanistic Insight into the Light-Irradiated Carbon Capsules as an Antibacterial Agent. AB - Infections caused by bacteria are a growing global challenge for public health as bacteria develop resistance, which will cause the failure of anti-infective treatment eventually. An effective alternative strategy to traditional antibacterial therapy is utilizing reactive oxygen species (ROS) to kill bacteria. Here, we report a simple route to prepare PEGylated nitrogen-doped carbon capsules (PEG-N-CCs) as an antibacterial agent. The PEG-N-CCs can translate near-infrared light (NIR) into heat and produce a high concentration of ROS triggered by NIR irradiation. Both heating and ROS are critical to destroy the outer membranes and rupture cell bodies, causing DNA fragmentation and glutathione oxidation both in Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus, and their multidrug-resistant strains. Moreover, PEG-N-CCs plus NIR irradiation can efficiently scavenge the existing biofilms and prevent the formation of new biofilms, killing planktonic bacteria as well as those within the biofilm. Our studies prove that the PEG-N-CCs plus NIR irradiation can provide a simple and effective platform for combating bacteria, employing carbon nanomaterials as an antibacterial alternative for treatment of infectious diseases. PMID- 29989401 TI - Energy-Efficient Elastocaloric Cooling by Flexibly and Reversibly Transferring Interface in Magnetic Shape-Memory Alloys. AB - Elastocaloric cooling is currently under extensive study owing to its great potential to replace the conventional vapor-compression technique. In this work, by employing multiscale characterization approaches, including in situ neutron diffraction in a loading frame, in situ transmission electron microscopy observation at different temperatures, in situ synchrotron X-ray Laue microdiffraction, and high-resolution infrared thermal imaging, we have investigated the thermal and stress-induced martensitic transformation, the stability of superelastic behavior and the associated elastocaloric effect for a Heusler-type Ni50.0Fe19.0Ga27.1Co3.9 single crystal. On the basis of transformation from cubic austenite into monoclinic martensite with a flexibly and reversibly transferring interface, this unique single crystal exhibits a giant elastocaloric effect of 11 K and ultralow fatigue behavior during above 12 000 mechanical cycles. The numerical simulation shows that the Ni50.0Fe19.0Ga27.1Co3.9 alloy offers 18% energy saving potential and 70% cooling capacity enhancement potential compared to the conventional shape-memory nitinol alloy in a single-stage elastocaloric cooling system, making it a great candidate for energy-efficient air conditioner applications. PMID- 29989400 TI - Accelerating DNA-Based Computing on a Supramolecular Polymer. AB - Dynamic DNA-based circuits represent versatile systems to perform complex computing operations at the molecular level. However, the majority of DNA circuits relies on freely diffusing reactants, which slows down their rate of operation substantially. Here we introduce the use of DNA-functionalized benzene 1,3,5-tricarboxamide (BTA) supramolecular polymers as dynamic scaffolds to template DNA-based molecular computing. By selectively recruiting DNA circuit components to a supramolecular BTA polymer functionalized with 10-nucleotide handle strands, the kinetics of strand displacement and strand exchange reactions were accelerated 100-fold. In addition, strand exchange reactions were also favored thermodynamically by bivalent interactions between the reaction product and the supramolecular polymer. The noncovalent assembly of the supramolecular polymers enabled straightforward optimization of the polymer composition to best suit various applications. The ability of supramolecular BTA polymers to increase the efficiency of DNA-based computing was demonstrated for three well-known and practically important DNA-computing operations: multi-input AND gates, Catalytic Hairpin Assembly and Hybridization Chain Reactions. This work thus establishes supramolecular BTA polymers as an efficient platform for DNA-based molecular operations, paving the way for the construction of autonomous bionanomolecular systems that confine and combine molecular sensing, computation, and actuation. PMID- 29989402 TI - Surface Design of Eu-Doped Iron Oxide Nanoparticles for Tuning the Magnetic Relaxivity. AB - Relaxivity tuning of nanomaterials with the intrinsic T1- T2 dual-contrast ability has great potential for MRI applications. Until now, the relaxivity tuning of T1 and T2 dual-modal MRI nanoprobes has been accomplished through the dopant, size, and morphology of the nanoprobes, leaving room for bioapplications. However, a surface engineering method for the relaxivity tuning was seldom reported. Here, we report the novel relaxivity tuning method based on the surface engineering of dual-mode T1- T2 MRI nanoprobes (DMNPs), along with protein interaction monitoring with the DMNPs as a potential biosensor application. Core nanoparticles (NPs) of europium-doped iron oxide (EuIO) are prepared by a thermal decomposition method. As surface materials, citrate (Cit), alendronate (Ale), and poly(maleic anhydride- alt-1-octadecene)/poly(ethylene glycol) (PP) are employed for the relaxivity tuning of the NPs based on surface engineering, resulting in EuIO-Cit, EuIO-Ale, and EuIO-PP, respectively. The key achievement of the current study is that the surface materials of the DMNP have significant impacts on the r1 and r2 relaxivities. The correlation between the hydrophobicity of the surface material and longitudinal relaxivity ( r1) of EuIO NPs presents an exponential decay feature. The r1 relaxivity of EuIO-Cit is 13.2-fold higher than that of EuIO-PP. EuIO can act as T1- T2 dual-modal (EuIO-Cit) or T2-dominated MRI contrast agents (EuIO-PP) depending on the surface engineering. The feasibility of using the resulting nanosystem as a sensor for environmental changes, such as albumin interaction, was also explored. The albumin interaction on the DMNP shows both T1 and T2 relaxation time changes as mutually confirmative information. The relaxivity tuning approach based on the surface engineering may provide an insightful strategy for bioapplications of DMNPs and give a fresh impetus for the development of novel stimuli-responsive MRI nanoplatforms with T1 and T2 dual modality for various biomedical applications. PMID- 29989403 TI - Extracellular Electron Transfer by the Gram-Positive Bacterium Enterococcus faecalis. AB - Extracellular electron transfer (EET) in microbial cells is essential for certain biotechnological applications and contributes to the biogeochemical cycling of elements and syntrophic microbial metabolism in complex natural environments. The Gram-positive lactic acid bacterium Enterococcus faecalis, an opportunistic human pathogen, is shown to be able to transfer electrons generated in fermentation metabolism to electrodes directly and indirectly via mediators. By exploiting E. faecalis wild-type and mutant cells, we demonstrate that reduced demethylmenaquinone in the respiratory chain in the bacterial cytoplasmic membrane is crucial for the EET. Heme proteins are not involved, and cytochrome bd oxidase activity was found to attenuate EET. These results are significant for the mechanistic understanding of EET in bacteria and for the design of microbial electrochemical systems. The basic findings infer that in dense microbial communities, such as in biofilm and in the large intestine, metabolism in E. faecalis and similar Gram-positive lactic acid bacteria might be electrically connected to other microbes. Such a transcellular electron transfer might confer syntrophic metabolism that promotes growth and other activities of bacteria in the microbiota of humans and animals. PMID- 29989404 TI - Controllable Assembly of Flexible Protein Nanotubes for Loading Multifunctional Modules. AB - Viruses with filamentous morphologies, such as tobacco mosaic virus (TMV) and M13 bacteriophage, have long been studied as multivalent nanoscaffolds for loading functional motifs. Structural assembly of the capsid proteins (CPs) of filamentous viruses often requires the presence of DNA or RNA molecules, which has limited their applications. Here, we describe a strategy for controllable assembly of flexible bio-nanotubes consisting of Escherichia coli expressed CP of baculovirus Helicoverpa armigera nucleopolyhedrovirus (HearNPV) in vitro. These protein-only nanotubes were studied as a new structural platform for high-density presentation of multiple active molecules on the exterior surface by direct fusion of the protein of interest to the N-terminus of HearNPV CP (HaCP). Structural characterization using cryoelectron microscopy demonstrated that the HaCP could assemble into two closely related but structurally distinct tube types, suggesting the tunable HaCP interaction network is the major contributor to the flexibility of HaCP nanotubes. Our flexible nanotubes could tolerate larger molecular modifications compared with TMV-based templates and could be used as promising candidates for versatile molecular loading applications. PMID- 29989405 TI - Renal-Clearable Peptide-Functionalized Ba2GdF7 Nanoparticles for Positive Tumor Targeting Dual-Mode Bioimaging. AB - Considering the dilemma between the effective tumor targeting and the avoidance of potential toxicity, it is desired to design nanoprobes with positive tumor targeting and good renal clearance ability. In the present work, we developed epidermal growth factor receptor (EGFR)-targeted peptide-functionalized Ba2GdF7 nanoparticles (termed as pEGFR-targeted Ba2GdF7 NPs) for positive tumor-targeting magnetic resonance imaging and X-ray computed tomography (MRI/CT) dual-mode bioimaging. The positive tumor-targeting ability of pEGFR-targeted Ba2GdF7 NPs is achieved by conjugation of EGFR-targeted peptides on the 6.5 nm Ba2GdF7 NP surface through the formation of Gd-phosphonate coordinate bonds. The pEGFR targeted Ba2GdF7 NPs display desirable cytocompatibility in the test concentration range and high binding affinity with lung cancer cells. In vivo MR and CT imaging results demonstrate that the pEGFR-targeted Ba2GdF7 NPs are able to be accumulated and detained within an engrafted A549 lung carcinoma, which enhances both MR and CT contrast in the tumor tissue. Systematic in vivo experimental results further demonstrate that the pEGFR-targeted Ba2GdF7 NPs have favorable in vivo renal clearance kinetics as well as reasonable in vivo biocompatibility. PMID- 29989406 TI - Reductive Hexachloroethane Degradation by S2O8*- with Thermal Activation of Persulfate under Anaerobic Conditions. AB - Despite that persulfate radical (S2O8*-) is an important radical species formed from the persulfate (PS) activation process, its reactivity toward contaminant degradation has rarely been explored. In this study, we found that S2O8*- efficiently degrades the contaminant hexachloroethane (HCA) under anaerobic conditions, whereas HCA degradation is negligible in the presence of oxygen. We observed dechlorination products such as pentachloroethane, tetrachloroethylene, and Cl- during HCA degradation, which suggest that HCA degradation is mainly a reductive process under anaerobic conditions. Using free radical quenching and electron paramagnetic resonance (EPR) experiments, we confirmed that S2O8*- forms from the reaction between sulfate radical (SO4*-) and S2O82-, which are the dominant reactive species in HCA degradation. Density functional theory (DFT) calculations were used to elucidate the pathways of HCA degradation and S2O8*- radical decomposition. Further investigation showed that S2O8*- can efficiently degrade HCA and DDTs in soil via reduction during the thermal activation of PS under anaerobic conditions. The finding of this study provide a novel strategy for the reductive degradation of contaminant when PS-based in situ chemical oxidation used in the remediation of soil and groundwater, particularly those contaminated with highly halogenated compounds. PMID- 29989407 TI - Hetero-oligomeric Amyloid Assembly and Mechanism: Prion Fragment PrP(106-126) Catalyzes the Islet Amyloid Polypeptide beta-Hairpin. AB - Protein aggregation is typically attributed to the association of homologous amino acid sequences between monomers of the same protein. Coaggregation of heterogeneous peptide species can occur, however, and is implicated in the proliferation of seemingly unrelated protein diseases in the body. The prion protein fragment (PrP106-126) and human islet amyloid polypeptide (hIAPP) serve as an interesting model of nonhomologous protein assembly as they coaggregate, despite a lack of sequence homology. We have applied ion-mobility mass spectrometry, atomic force microscopy, circular dichroism, and high-level molecular modeling to elucidate this important assembly process. We found that the prion fragment not only forms pervasive hetero-oligomeric aggregates with hIAPP but also promotes the transition of hIAPP into its amyloidogenic beta hairpin conformation. Further, when PrP106-126 was combined with non amyloidogenic rIAPP, the two formed nearly identical hetero-oligomers to those seen with hIAPP, despite rIAPP containing beta-sheet breaking proline substitutions. Additionally, while rIAPP does not natively form the amyloidogenic beta-hairpin structure, it did so in the presence of PrP106-126 and underwent a conformational transition to beta-sheet in solution. We also find that PrP106-126 forms hetero-oligomers with the IAPP8-20 fragment but not with the "aggregation hot spot" IAPP20-29 fragment. PrP106-126 apparently induces IAPP into a beta hairpin structure within the PrP:IAPP heterodimer complex and then, through ligand exchange, catalytically creates the amyloidogenic beta-hairpin dimer of IAPP in significantly greater abundance than IAPP does on its own. This is a new mechanistic model that provides a critical foundation for the detailed study of hetero-oligomerization and prion-like proliferation in amyloid systems. PMID- 29989408 TI - Metabolomic Approach for the Authentication of Berry Fruit Juice by Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry Coupled to Chemometrics. AB - Berry fruit juice, which is represented by blueberry and cranberry juice, has become increasingly popular due to its reported nutritional and health benefits. However, in markets, adulteration of berry fruit juice with cheaper substitutes is frequent. In the present study, a metabolomic approach for authentication of berry fruit juices by liquid chromatography coupled with quadrupole time-of flight mass spectrometry (LC-QTOF-MS) was established. The global characterization of the berry fruit metabolome by information dependent acquisition directed LC-MS/MS coupled to a peak mining workflow by isotope pattern matching was reported. Targeted metabolomics analysis of known juice biomarkers, such as flavonoids, anthocyanins, etc. exhibited a good separation of berry fruit juices from adulterant juices. Moreover, untargeted metabolomics analysis was carried out and subjected to chemometrics analysis. Discrimination of blueberry juice, cranberry juice, and its adulterant apple juice and grape juice was obtained by principal component analysis-discriminant analysis. Eighteen characteristic markers discriminating berry fruit juice and its adulterants were selected by comparison of marker abundances in different juice samples. Identification of characteristic markers was accomplished by elemental formula prediction and online database searches based on accurate MS information. These results suggested that the combination of untargeted and targeted metabolomics approach has great potential for authentication of berry fruit juice. PMID- 29989409 TI - Correction to Synthesis of Diaryl Ketones through Oxidative Cleavage of the C-C Double Bonds in N-Sulfonyl Enamides. PMID- 29989410 TI - Enzymatic Synthesis of Polyglycerol Fatty Acid Esters and Their Application as Emulsion Stabilizers. AB - Polyglycerol ester is considered an excellent kind of food emulsifier. The aim of the current study was to synthesize polyglycerol fatty acid esters (PGFEs) with different-sized long-chain fatty acids (i.e. long-carbon fatty acid polyglycerol esters, L-PGFEs; medium-carbon fatty acid polyglycerol esters, M-PGFEs; and short carbon fatty acid polyglycerol esters, S-PGFEs), using Lipozyme 435 as a catalyst in a solvent-free system. Thereafter, the physicochemical properties of the newly synthesized PGFEs and their potential applications as food emulsifiers were investigated. The maximum esterification efficiencies of L-PGFEs, M-PGFEs, and S PGFEs were 69.37, 67.34, and 71.68%, respectively, at the optimum conditions: a reaction temperature of 84.48 degrees C, a reaction time of 6 h, a molar ratio of polyglycerol to fatty acid of 1.35:1, and 1.41 wt % enzyme usage (based on the total substrate mass). A high-performance liquid chromatograph equipped with an evaporative light-scattering detector (HPLC-ELSD) and an electrospray-ionization mass spectrometer (ESI-MS) were employed to identify the synthesized products. The results demonstrated that the main components of these PGFEs were dimeric glycerides (68.3%), triglycerides (13.13%), and a small amount of tetraglycerides (3.18%). The properties of the PGFEs were characterized by physical and chemical methods. Compared with M-PGFEs and S-PGFEs, L-PGFEs had the best physicochemical properties without any obvious odor. Further, the emulsion capabilities of these different long-chain PGFEs were evaluated via examining the particle sizes and storage stabilities and comparing them with those of glycerin monostearate (GMS). The results showed that the emulsions prepared with L-PGFEs had the best stability and the smallest particle sizes (16.8 nm) compared with those of M PGFEs, S-PGFEs, and GMS, and they were not prone to oil-droplet coalescence or the separation of oil and water. From the current study, the newly synthesized PGFEs with long-chain fatty acids showed the best advantages as a food emulsifier compared with M-PGFEs, S-PGFEs, and even glycerin monostearate. PMID- 29989411 TI - Employing Arynes for the Generation of Aryl Anion Equivalents and Subsequent Reaction with Aldehydes. AB - Arynes are highly reactive intermediates, which are utilized for the electrophilic arylation of various X-H bonds (X = O, N, S etc.). Herein, a new synthetic strategy is demonstrated, where arynes are converted into aryl anion equivalents by treatment with phosphines and a base. The addition of phosphines to arynes form the phosphonium salts, which in the presence of a carbonate base generates the aryl anion equivalent. Subsequent addition of the aryl anions with aldehydes afforded the secondary alcohols. PMID- 29989412 TI - Probing Axial Water Bound to Copper in Tutton Salt Using Single Crystal 17O-ESEEM Spectroscopy. AB - Electron spin-echo envelope modulation (ESEEM) signals attributed to axial water bound to Cu2+ have been detected and analyzed in Cu(II)-doped 17O-water-enriched potassium zinc sulfate hexahydrate (Tutton salt) crystals. The magnetic field orientation dependences of low frequency modulations were measured to fit hyperfine and quadrupole coupling tensors of a 17O ( I = 5/2) nucleus. The hyperfine tensor ( A xx, A yy, A zz: 0.13, 0.23, -3.81 MHz) exhibits almost axial symmetry with the largest value directed normal to the metal equatorial plane in the host structure. Comparisons with quantum chemical calculations position this nucleus about 2.3 A from the copper. The isotropic coupling (-1.15 MHz) is small and reflects the weak axial water interaction with a dx2-y2 unshared orbital of copper. The 17O-water quadrupole interaction parameters ( e2 qQ/ h = 6.4 MHz and eta = 0.93) are close to the average of those found in a variety of solid hydrates. In addition, the coupling tensor directions correlate very closely with the O8 water geometry, with the maximum quadrupole direction 3 degrees from the water plane normal, and its minimum coupling about 2 degrees from the H-H direction. In almost all previous magnetic resonance 17O-water studies, the quadrupole tensor orientation was based on theoretical considerations. This work represents one of the few experimental confirmations of its principal axis frame. When Cu2+ dopes into the Tutton salt, a Jahn-Teller distortion interchanges the relative long and intermediate metal O7 and O8 bond lengths of the zinc host. Therefore, only those unit cells containing the impurity conform to the pure copper Tutton structure. This study provides further support for this model. Moreover, coupling interactions from distant H217O such as in the present case have important implications in studies of copper enzymes and proteins where substrates have been proposed to displace weakly bound water in the active site. PMID- 29989413 TI - Reactions of Criegee Intermediates with Benzoic Acid at the Gas/Liquid Interface. AB - Secondary organic aerosol (SOA) found in polluted mega-cities contains benzoic acid (BA) as a major organic acid in addition to a variety of species including alkenes. In polluted air, ozone could be a major oxidizer for SOA and induces subsequent reactions involving Criegee intermediates (CIs, carbonyl oxide, RR'C* O-O*/RR'C?O+-O-) formed by the -C?C- + O3 reaction at the gas/liquid interface. The possibility that abundant BA could be an effective scavenger of CIs at the interface remains to be investigated by direct experiments. Here, we showed that amphiphilic BA is able to compete with water molecules for the CIs produced in the prompt ozonolysis of beta-caryophyllene on the surface of a water/acetonitrile solvent microjet by generating hitherto uncharacterized C22 ester hydroperoxide products. Competition between BA vs octanoic acid vs cis pinonic acid toward CIs reveals that BA is a much less-efficient scavenger of CIs on aqueous organic surfaces. We attribute it to the surface-specific orientation of BA at the gas/liquid interface, where the reactive -C(O)OH group is fully hydrated and not available for CIs generated at the topmost layers. PMID- 29989414 TI - Programming a Biofilm-Mediated Multienzyme-Assembly-Cascade System for the Biocatalytic Production of Glucosamine from Chitin. AB - Chitin is used as an essential raw material for the production of glucosamine (GlcN). In this study, we adopted three key enzymes, isolated from Thermococcus kodakaraensis KOD1, that catalyze the sequential conversion of alpha-chitin into GlcN and developed a multienzyme-assembly-cascade (MAC) system immobilized in a bacterial biofilm, which enabled a multistep one-pot reaction. Specifically, the SpyTag-SpyCatcher and SnoopTag-SnoopCatcher pairs provided covalent and specific binding force to fix enzymes to the biofilm one by one and assemble close enzyme cascades. The MAC system showed great catalytic activity, converting 79.02 +/- 3.61% of alpha-chitin into GlcN with little byproducts, which was 2.09 times that of GlcN catalyzed by a mixture of pure enzymes. The system also exhibited good temperature and pH stability. Notably, 90% of enzyme activity was retained after 6 rounds of reuse, and appreciable activity remained after 17 rounds. PMID- 29989415 TI - Pd-PEPPSI-IPentAn Promoted Deactivated Amination of Aryl Chlorides with Amines under Aerobic Conditions. AB - We report herein a highly efficient Pd-catalyzed amination by "bulky-yet flexible" Pd-PEPPSI-IPentAn complexes. The relationship between the N heterocyclic carbenes (NHCs) structure and catalytic properties was discussed. Sterically hindered (hetero)aryl chlorides and a variety of aliphatic and aromatic amines can be applied in this cross-coupling, which smoothly proceeded to provide desired products. The operationally simple protocol highlights the rapid access to CAr-N bond formation under mild conditions without the exclusion of air and moisture. PMID- 29989416 TI - Correction to Photocatalytic and Chemoselective Transfer Hydrogenation of Diarylimines in Batch and Continuous Flow. PMID- 29989417 TI - Clinical significance of antibodies to antigens in the International Society of Blood Transfusion collections, 700 series of low-incidence antigens, and 901 series of high-incidence antigens. AB - CONCLUSIONS: This article reviews information regarding the clinical significance of antibodies to antigens in the blood group collections, the 700 series of low incidence antigens, and the 901 series of high-incidence antigens. Antibodies to many of the antigens in these groups are rarely encountered, meaning that available information is limited. For a few, the clinical significance-the potential to cause reduced survival of transfused antigen-positive red blood cells, a hemolytic transfusion reaction (e.g., anti-AnWj, anti-Emm), or hemolytic disease of the fetus and newborn (e.g., anti-Kg, anti-HJK)-has been documented. Many other specificities have so far been benign (e.g., anti-Csa, anti-M1). PMID- 29989418 TI - Adsorption of cold agglutinins with rabbit red blood cells. AB - CONCLUSIONS: Cold-reactive autoagglutinins may mask the presence of underlying clinically significant alloantibodies. Adsorption with rabbit red blood cells (RBCs) or stroma can remove cold autoagglutinins found in the patient's plasma/serum that are directed towards antigens expressed on the surface of rabbit RBCs. By removing these cold autoagglutinins, it is then possible to determine whether any underlying alloantibody reactivity is present. Although this method may also unintentionally adsorb alloantibodies directed towards antigens found on rabbit RBCs, it is still a widely used and convenient method to remove cold autoagglutinins. PMID- 29989419 TI - Mixed-field agglutination observed in column agglutination testing is not always associated with the A3 subgroup. AB - CONCLUSIONS: Mixed-field agglutination (MFA) can be observed in forward typing of samples from A3 individuals with serologic ABO typing methods. The results of column agglutination testing (CAT) and tube agglutination testing using different antibody clones can be discordant. In this report, we reveal our experience using polymerase chain reaction-sequence-based typing (PCR-SBT) of ABO exon 7 to clarify serologic method discordance of A subgroup blood typing in Northern Thai donors. A total of 21 group A blood donors with either MFA or weak agglutination on routine ABO CAT were recalled. CAT was repeated with human and monoclonal anti A, and tube agglutination testing with monoclonal anti-A and PCR-SBT of ABO exon 7 was performed. A total of 13 of the 21 donors returned, and ABO CAT with human anti-A was repeated. Eleven samples showed MFA suspected to be the A3 subgroup, and two samples showed 2+ strength suspected to be the Aweak subgroup. When tube agglutination testing using monoclonal antibody was performed, MFA was not observed in 9 of 11 samples with previously observed MFA from routine CAT, which were then interpreted as A2. From PCR-SBT performed in only exon 7 of the ABO gene, 7 of 13 sample results were consistent with ABO*A2 or ABO*AW alleles. Two samples suspected to be A2 or A3 had an ABO*AW allele. In two samples suspected to be Aweak, no mutation was detected in ABO exon 7, suggesting genetic variation elsewhere in the gene. Although other coding exons were not examined, in the alleles that could be assigned, ABO*A3 alleles were found less frequently than would be predicted from the serologic findings. These findings suggest that when MFA in routine CAT is observed, an A3 subgroup cannot be presumed. Caution should be exercised when MFA is noted in routine CAT. PMID- 29989420 TI - Low-ionic-strength saline solution-antiglobulin test (LISS-AGT). AB - CONCLUSIONS: The use of low-ionic-strength saline (LISS) solution as an enhancement for antibody screening and crossmatching was first described by Low and Messeter in 1974. This method allowed for a reduced incubation time while maintaining adequate specificity and sensitivity of the antiglobulin test (AGT). Since then, the LISS-AGT tube method has been widely used in antibody detection and identification, as well as compatibility testing. As initially described, the method used red blood cells suspended in LISS. Modifications of the method led to development of the commercially prepared LISS additive solutions in use today. The LISS-AGT can be used effectively to detect alloantibodies of all major blood groups in antibody detection, antibody identification, and crossmatching procedures. PMID- 29989421 TI - Rh and Kell blood group antigen prevalence in a multi-ethnic cohort in Nigeria: implications for local transfusion service. AB - CONCLUSIONS: Antigens belonging to the Rh and Kell blood group systems are of major clinical significance because of their immunogenicity and the potential of their consequent antibodies to cause in vivo destruction of exogenous red blood cells (RBCs). Despite the wide-spread use of transfusion, there are sparse data on the prevalence of Rh and Kell system antigens and their ethnic variability in Nigeria. The objective of this study was to determine the prevalence of the five major Rh (D, C, c, E, e) and Kell (K) system antigens in Nigeria with the goal of understanding alloimmunization risk in transfusion recipients and improving transfusion safety through the availability of resources, such as antisera for extended RBC typing and antigen panels for alloantibody detection. A multi-ethnic cohort of 302 healthy Nigerian individuals was created to study RBC antigen prevalence. The antigen status of these individuals for Rh and K antigens was determined using commercially prepared antisera and conventional tube agglutination methods. The prevalence of the Rh antigens in the study cohort was found to be: D (92.7%), C (20.5%), c (97.7%), E (19.5%), and e (97.4%). Dce was the most common Rh phenotype (53.3%). The prevalence of K was 0 percent. For all antigens, there was no association between ethnicity and antigen prevalence. This study is the first to document the prevalence of the major Rh and K antigens in the Nigerian population, using a multi-ethnic cohort. Serologic testing demonstrates a zero prevalence of K antigen, which has never been described. C and E pose the higher risks of alloimmunization, hence showing a need for extended RBC typing and matching in at-risk blood recipients. This study demonstrates that phenotyping for major Rh and K antigens within the Nigerian population can potentially improve transfusion safety and prevent alloimmunization. PMID- 29989422 TI - Clinically significant naturally occurring anti-N and anti-S in a blood donor: a rare finding. AB - CONCLUSIONS: To the Editors: Alloimmunization is triggered when an individual whose red blood cells (RBCs) are lacking particular antigens is exposed to these antigens through transfusion or pregnancy, causing the formation of immune antibodies. In addition to these exogenous exposures, underlying inflammatory or autoimmune conditions may lead to formation of unexpected antibodies. Individual factors also play a role, since some people are responders and others are non responders. We report a case of naturally occurring alloanti-N and alloanti-S in a healthy D+ blood donor. Both antibodies were reactive over a wide thermal amplitude and hence were potentially clinically significant. This case highlights the importance of incorporating the indirect antiglobulin test (IAT) to test for unexpected RBC antibodies for all blood units as a routine protocol. PMID- 29989423 TI - Highly effective biosynthesis of N-acetylated human thymosin beta4 (Tbeta4) in Escherichia coli. AB - Thymosin beta4 (Tbeta4) is a multifunctional N-acetylated peptide with distinct activities important at various stages. Due to its potential multiple therapeutic uses in many fields, there is an increasing need of Tbeta4 at lower costs than with the use of chemical synthesis. In this research, we developed a method to produce rhTbeta4 with N-acetylation in E. coli. Firstly, the E. coli strain whose chromosome being integrated by the specific N-terminal acetyltransferase ssArd1 was constructed. Secondly, the rhTbeta4-Intein was constructed, in which rhTbeta4 was fused to the N-terminus of the smallest mini-intein Spl DnaX. The rhTbeta4 could be fully acetylated when the rhTbeta4-Intein was expressed in the engineering strain. After purification, the rhTbeta4-Intein fusion protein was induced with dithiothreitol (DTT) to release rhTbeta4 through intein-mediated N terminal cleavage. Under the optimal conditions, the N-terminal serine residue was shown to be 100% acetylated and the yield of N-acetylated rhTbeta4 can reach 200 mg per litre. The N-acetylated rhTbeta4 could be stable at 2-8 degrees C for 24 months in PBS buffer without protein degradation and concentration change. The N-acetylated rhTbeta4 also showed the activity of binding with actins from different sources and excellent therapeutic effect on the rats with moderate to severe dry eye disease. PMID- 29989424 TI - Fully-automated systems and the need for global approaches should exhort clinical labs to reinvent routine MS analysis? AB - Today, many LC-high-resolution MS instruments have become affordable, easy-to use, sensitive and quantitative. Meanwhile, there is an increased need for more comprehensive approaches. However, omics analyses are still restricted to specialists whereas, in hospitals, routine analyses are targeted and quantitative and represent the main and heavy tasks. But the availability of fully automated LC-MS instruments that can handle independently from sample extraction to result reporting, as well as the increasing biomedical interest for global approaches, clinical analytical workflow should be reorganized. Bioanalysts are now in the position to develop/implement clinical metabolomics or proteomics as routine analyses. In this article, this coming evolution and the reasons to implement global/omics determinations as routine analysis, is described. PMID- 29989425 TI - Enzymatic synthesis of glucuronidated metabolites of two neurological active agents using plant glucuronosyltransferases. AB - Glucuronidation is an important and popular metabolic reaction in vivo of drugs. The further evaluation of biological activity and toxicity of glucuronides is necessary in the course of the drug research and development. However, the synthesis of glucuronides is limited by the lack of efficient approach. Herein, we have developed a new glucuronide synthesis method using plant uridine diphosphate-dependent glucuronosyltransferases (UGTs), UGT88D4, UGT88D7, and EpGT8, enabling the convenient preparation for corresponding O-glucuronide metabolites (1a, 2a, 3a, and 3b) in milligram scale of two neurological active agents, IMM-H004 (1) and FLZ (2). Their structures were characterized by spectroscopic data analyses. PMID- 29989426 TI - Frontal infrared thermography in healthy individuals and chronic migraine patients: Reliability of the method. AB - Background The use of frontal infrared thermography in the diagnosis of primary headaches provided scattering results due to measurement fluctuations and different types of headaches or research protocols. Objective This study aims to assess the reliability of frontal infrared thermography in healthy individuals and provide a preliminary evaluation in chronic migraine patients using a commercial infrared thermal camera. Methods Thermographic images were acquired in 20 controls and 15 patients at three consecutive time-points in two daily sessions. The Side Difference and Asymmetry Index parameters were defined. The reproducibility of the measurements, the correlation of Asymmetry Index and Side Difference with clinical evaluations and patient perceptions, and the ability of the parameters to discriminate between patients and controls were investigated. Results We reported a good reproducibility of the measurements (Inter-class Correlation Coefficient > 0.75 and Coefficient of Variation < 13.4%), independent from external factors. The Side Difference was significantly different between patients and controls ( p < 0.001). The Asymmetry Index showed good correlation with the side of unilateral pain ( p = 0.0056). Conclusions Frontal infrared thermography can be used to quantify the difference between the right and the left side of frontal vascular changes in chronic migraine patients, provided that standardized conditions are satisfied. PMID- 29989427 TI - Current understanding of trigeminal ganglion structure and function in headache. AB - Introduction The trigeminal ganglion is unique among the somatosensory ganglia regarding its topography, structure, composition and possibly some functional properties of its cellular components. Being mainly responsible for the sensory innervation of the anterior regions of the head, it is a major target for headache research. One intriguing question is if the trigeminal ganglion is merely a transition site for sensory information from the periphery to the central nervous system, or if intracellular modulatory mechanisms and intercellular signaling are capable of controlling sensory information relevant for the pathophysiology of headaches. Methods An online search based on PubMed was made using the keyword "trigeminal ganglion" in combination with "anatomy", "headache", "migraine", "neuropeptides", "receptors" and "signaling". From the relevant literature, further references were selected in view of their relevance for headache mechanisms. The essential information was organized based on location and cell types of the trigeminal ganglion, neuropeptides, receptors for signaling molecules, signaling mechanisms, and their possible relevance for headache generation. Results The trigeminal ganglion consists of clusters of sensory neurons and their peripheral and central axon processes, which are arranged according to the three trigeminal partitions V1-V3. The neurons are surrounded by satellite glial cells, the axons by Schwann cells. In addition, macrophage-like cells can be found in the trigeminal ganglion. Neurons express various neuropeptides, among which calcitonin gene-related peptide is the most prominent in terms of its prevalence and its role in primary headaches. The classical calcitonin gene-related peptide receptors are expressed in non calcitonin gene-related peptide neurons and satellite glial cells, although the possibility of a second calcitonin gene-related peptide receptor in calcitonin gene-related peptide neurons remains to be investigated. A variety of other signal molecules like adenosine triphosphate, nitric oxide, cytokines, and neurotrophic factors are released from trigeminal ganglion cells and may act at receptors on adjacent neurons or satellite glial cells. Conclusions The trigeminal ganglion may act as an integrative organ. The morphological and functional arrangement of trigeminal ganglion cells suggests that intercellular and possibly also autocrine signaling mechanisms interact with intracellular mechanisms, including gene expression, to modulate sensory information. Receptors and neurotrophic factors delivered to the periphery or the trigeminal brainstem can contribute to peripheral and central sensitization, as in the case of primary headaches. The trigeminal ganglion as a target of drug action outside the blood brain barrier should therefore be taken into account. PMID- 29989428 TI - Effect of DNA and Histone Methyl Transferase Inhibitors on Outcomes of Buffalo Bovine Interspecies Somatic Cell Nuclear Transfer. AB - Somatic cell nuclear transfer (SCNT) derived embryos suffer from abnormal epigenetic reprogramming, which handicaps pre- and postimplantation development. It was hypothesized that epigenetic modifiers, including zebularine (DNA methyltransferase inhibitors) and BIX-01294 (histone methyltransferase inhibitors), could decrease the respective levels of 5-methylcytosine and H3K9me2 in reconstructed oocytes (RO). Accordingly, we investigated whether treating RO with zebularine and BIX-01294 for 16 hours after activation could improve developmental competence and quality of buffalo-bovine interspecies SCNT (iSCNT) embryos. Treatment of RO with zebularine but not BIX-01294 significantly increased two-cell formation at 16 hours postactivation. Conversely, early cleaved embryos had significantly lower rate of blastocyst formation in zebularine treated RO compared to their counterparts in control and BIX-01294 groups. Treatment of RO with zebularine and BIX-01294 did not improve blastocyst rate of buffalo-bovine iSCNT embryos compared to their control counterparts. However, these two epigenetic drugs might have some beneficial effects on buffalo bovine iSCNT compared to bovine SCNT embryos. The quality of iSCNT blastocysts was improved due to significant expression of OCT4 and CDX2 in BIX-01294 and CDX2 in zebularine treated RO. Furthermore, treatment of RO with zebularine and BIX 01294 did not affect DNA fragmentation in derived blastocysts against control group. In conclusion, treatment with zebularine and BIX-01294 did not enhance developmental competence of iSCNT embryos, but may have some beneficial effects on epigenetic makeup and quality of derived blastocysts. PMID- 29989429 TI - Characterization of Microbial Communities Hosted in Quartzofeldspathic and Serpentinite Lithologies in Jeffrey Mine, Canada. AB - The microbial ecology and activity of serpentine deposits and associated hydrated minerals are largely unknown. Previous research has largely focused on microbial communities in active serpentinizing systems, whereas relatively little research has demonstrated the ability of serpentine deposits to host microbial communities after the cessation of serpentinization. Given the potential role of serpentinization reactions fueling primitive microbial metabolisms on early Earth and the identification of serpentine deposits on Mars, knowledge of these geobiological relationships and potential for serpentine to host extant microbial communities and preserve biosignatures is increasingly important for planetary exploration seeking signs of life. The selection of habitable sites most likely to yield putative biosignatures is crucial to mission success. In this study, we aimed to characterize, on the basis of both metabolic activity and taxonomic composition, the microbial communities hosted in two naturally co-occurring and mineralogically distinct substrates within the serpentine-rich Jeffrey Mine pit igneous quartzofeldspathic intrusives and serpentinite. Detection of heterotrophic activity in both lithologies at 24 degrees C, and in serpentinite at -5 degrees C, demonstrated that each substrate had the ability to host a viable microbial community, at Mars-relevant temperatures. Targeted amplicon sequencing subsequently showed the presence of bacterial, fungal, and photosynthetic microbial communities in both substrates. Here, we have demonstrated the presence of a viable lithic microbial community within two rock types in the Jeffrey Mine and provided evidence that lithologies associated with serpentine deposits and proximal hydrated minerals have the ability to support diverse prokaryotic and eukaryotic microbial colonization. PMID- 29989430 TI - Differences in Step Counts, Motor Competence, and Enjoyment Between an Exergaming Group and a Non-Exergaming Group. AB - OBJECTIVE: The purpose of this study was to examine the effect of an exergaming program on physical activity, motor competence, and enjoyment in preschool children. MATERIALS AND METHODS: A sample of 65 preschool children was recruited from an urban preschool located in the Western United States. Children were randomly assigned to either an exergaming (n = 36) or a free-play group (n = 29). The intervention was 30 min/day, 5 days/week for 12 weeks for both groups, and all outcome variables were measured once during the final week of the intervention. The exergaming program included three active videogames: GoNoodles, Adventure to Fitness, and Cosmic Kids Yoga. Children in the free-play group were offered a variety of sport activities. School-day step counts were recorded using pedometers, motor competence was assessed by the Test for Gross Motor Development Edition 3 (TGMD-3), and enjoyment was accessed using one subscale of the Intrinsic Motivational Inventory. A 2 * 2 multivariate analysis of variance (MANOVA) test was employed to examine the differences between sexes and groups on the outcome variables. RESULTS: The omnibus MANOVA yielded a statistically significant multivariate group main effect (F = 3.71, P = 0.016). Follow-up tests revealed statistically significant differences between groups on average school step counts (mean difference = 785 steps, P = 0.003, d = 0.68) and total TGMD-3 scores (mean difference = 8.7, P = 0.019, d = 0.51), with the exergaming group displaying higher mean scores compared with the free-play group. CONCLUSION: Young children who were randomly assigned to the exergaming group demonstrated higher school-day step counts and higher motor competence levels compared with the free-play group. These results support the use of this modality in childcare settings. PMID- 29989431 TI - Individual risk factors for possible undetected dementia amongst community dwelling older people in New Zealand. AB - There is general acknowledgement of the importance of early diagnosis of dementia, yet there are still high rates of undetected dementia internationally. The aim of this cross-sectional study was to determine the sociodemographic characteristics associated with possible undetected dementia in a large sample of community-dwelling older New Zealanders. The sample consisted of older people (age >= 65) who had received the homecare version of the international Residential Home Care Assessment version 9.1 over a two-year period and who were screened positive for possible dementia on the international Residential Assessment's Cognitive Performance Scale. People with possible alternative explanations for impaired cognitive performance such as depression and other neurological conditions were excluded from analysis. The 5202 eligible individuals were categorized into two groups: (1) those with a recorded diagnosis of dementia (64%) and (2) those without a recorded diagnosis of dementia (i.e. possible undetected dementia group) (36%). Logistic regression was used to evaluate the association between individual characteristics and possible undetected dementia. Significant risk factors for being in the possible undetected dementia group included Asian ethnicity, living alone, not having participated in long-standing social activities recently, major life stressors, and limited accessibility of their house. The knowledge gained from this study could enable targeting of services and resources for the groups at risk of undetected dementia to have a more equitable access to early diagnosis. PMID- 29989432 TI - You, me, us - Creating connection: Report on a program to support and empower couples to navigate the challenges of dementia (innovative practice). AB - Dementia support services have generally been directed either towards the person with dementia or towards the care partner; they rarely address the relational challenges to couplehood. This article describes the philosophy, aims and multimodal processes of the Creating Connection program, a six-session program run in 2017 which aimed to support and empower couples to navigate through the changes and challenges of dementia. The authors recommend this as a model for future programs. Such programs, especially when offered soon after a diagnosis of dementia, may steer couples away from pathways of "disintegration" and onto more positive pathways of "reconstruction". PMID- 29989433 TI - Oral Mucosa-Derived Induced Pluripotent Stem Cells from Patients with Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome. AB - Ectrodactyly-Ectodermal dysplasia-Clefting (EEC) syndrome is a rare monogenic disease with autosomal dominant inheritance caused by mutations in the TP63 gene, leading to progressive corneal keratinocyte loss, limbal stem cell deficiency (LSCD), and eventually blindness. Currently, there is no treatment available to cure or slow down the keratinocyte loss. Human oral mucosal epithelial stem cells (hOMESCs), which are a mixed population of keratinocyte precursor stem cells, are used as source of autologous tissue for treatment of bilateral LSCD. However, hOMESCs from EEC patients have a reduced life span due to TP63 mutations and cannot be used for autologous transplantation. Human induced pluripotent stem cells (hiPSCs) represent a potentially unlimited source of autologous limbal stem cell for EEC patients and can be genetically modified by genome editing technologies to correct the disease ex vivo before transplantation. In this study, we describe for the first time the generation of integration-free EEC hiPSCs from hOMESCs of EEC patients by Sendai virus vector and episomal vector based reprogramming. The generated hiPSC clones expressed pluripotency markers and were successfully differentiated into derivatives of the three germ layers, as well as toward corneal epithelium. These cells may be used for EEC disease modeling and open perspectives for applications in cell therapy of LSCD. PMID- 29989434 TI - Development of emergency food assistance design: a nutritionally balanced, culturally tailored and cost-effective strategy for flood mitigation. AB - Emergency food assistance forms an integral component of flood mitigation in Malaysia. A cross-sectional survey investigating emergency food assistance among 202 flood victims was conducted and alternative food assistance plan was developed using linear programming targeting post-disaster food requirement scenarios. From the study, the receipt of food aid was significantly associated with ethnicity, household income, residential area and evacuation into temporary shelters. Linear programming analysis identified nutritionally appropriate food assistance targeting mass feeding, emergency food basket, and immediate food requirement for as low as MYR 6.07 (1.55 USD), MYR 7.14 (1.82 USD), and MYR 8.00 (2.04 USD), respectively. This study provides nutritional guidelines for disaster food assistance policy. PMID- 29989435 TI - The use of dehydrated amniotic membrane allograft for augmentation of dural closure in craniotomies and endoscopic endonasal transphenoidal surgeries. AB - BACKGROUND: Primary watertight dural closure is the preferred method of postcraniotomy dural repair. However, even when ideal technique is implemented, postoperative infection, cerebrospinal fluid (CSF) leaks, pseudomeningoceles, and dural scarring are possible complications. For this reason, materials that augment the dura's ability to create a watertight seal, prevent disease transmission, and inhibit inflammatory response are sought. Dehydrated amniotic membrane (DAM) allograft appears to fulfil these requirements as it has several beneficial properties that aid wound healing, including promotion of epithelialization, scar tissue prevention, and inhibition of bacterial growth. We provide the literature's first description of the use of DAM allograft to supplement dural closures for craniotomies and transsphenoidal surgeries. METHODS: We conducted a pilot study, retrospectively reviewing our institution's database of craniotomies and transsphenoidal surgeries that utilized DAM to augment dural closure. RESULTS: One hundred fifty-five cases, including 102 new craniotomies for supratentorial lesions, one re-do craniotomy for supratentorial recurrent glioma, 18 craniotomies for infratentorial lesions, 1 craniotomy for anterior skull base schwannoma, 32 transphenoidal surgeries, and 1 combined craniotomy and transnasal endoscopic surgery, used DAM allograft to augment dural closure. Only one complication occurred (0.6% complication rate), which was a superficial wound infection requiring washout without craniectomy. No CSF leaks occurred. CONCLUSIONS: This pilot study demonstrates that dehydrated amniotic membrane allograft can be safely utilized as an adjunct during dural closures for craniotomies and transsphenoidal surgeries. PMID- 29989436 TI - Symptomatology following traumatic brain injury in a multidisciplinary clinic: experiences from a tertiary centre. AB - BACKGROUND: Physical, cognitive and emotional sequelae in patients with traumatic brain injury (TBI) have been identified; some as late as two years post-injury. To aid in the specialist management of such patients, a multidisciplinary neurotrauma clinic was initiated at a tertiary centre. Aim: This study sought to describe the clinical features of patients who attended the clinic. METHODS: Patient data was collected under several categories: basic demographics, mechanism and severity of injury, initial CT findings and management, hospital stay and discharge details, symptoms in clinic and actions performed by clinic staff (medication changes, referrals to other services, etc.). RESULTS: Three hundred and five patients met the inclusion criteria. Mean age was 47.5 and most patients were male (72.1%). Commonest mechanism of injury was falls (53.1%). 17.4% of injuries were classed as mild, 68.2% moderate and 14.1% severe. Commonest injury locations were frontal (21.6%) and temporal (16.1%) with contusions (37.4%) and subdural hematomas (27.9%) the commonest type of injury on initial CT scan. The most frequent physical complaints were headache (47.9%) and memory problems (42.0%). 7.9% complained of new seizures since TBI. 41.6% were referred to further services: most frequently psychology (19.3%) and neuropsychiatry (18.4%). Of 184 known to be employed before their injury, 48.4% of these returned to work before their last appointment. 28.5% were unable to continue driving. CONCLUSION: Our study provides an insight into the reality of long term sequelae of TBI, especially those at the more severe end of the spectrum, who are likely to present to tertiary or specialist services. Information gathered in this study about characteristics of the TBI population and their outcomes allows for better targeting of suitable patients for referral to a multidisciplinary clinic and improved resource planning. PMID- 29989437 TI - Union Rates and Complications After Thumb Metacarpophalangeal Fusion. AB - BACKGROUND: Fusion of the thumb metacarpophalangeal joint (MPJ) can be performed using tension band wiring (TBW) or plate and screw (PS) fixation. This study evaluated results and complications using these techniques. METHODS: A retrospective review of patients who underwent thumb MPJ fusion at our institution from 2010 to 2016 was performed. Patients with >1 year follow-up were included. Demographic information, indication for fusion, time to fusion, and complications were collected. Final radiographs were examined and alignment measured. RESULTS: There were 56 thumbs in 53 patients (42 women and 11 men) including 12 TBW and 44 PS. The mean age was 60.9 years, and follow-up was 32.4 months. Twenty-eight of 44 plates were nonlocking, and 16 were locking. Of the locking plates, 7 of 26 used all locking screws, and 9 of 26 had a combination of locked and nonlocked screws. The mean flexion angle for TBW was 16.5 degrees and PS was 12.8 degrees . The mean coronal angle for TBW patients was 4.0 degrees ulnar and PS was 2.5 degrees ulnar. The overall union rate was 95%. There were 12 complications, 9 in the PS group. The TBW complications were painful hardware requiring removal. Eight complications in the PS group occurred in patients with locked plates. Five of the delayed or nonunions occurred in patients with locked plates and 4 of these were in plates with all screws locked. CONCLUSION: Complications using PS or TBW are not infrequent. Alignment with both techniques is similar, but use of locked plates specifically increases the rate of delayed or nonunions. We do not recommend routine use of locked plates for fusion of the thumb MPJ. PMID- 29989438 TI - Improving Patient-Provider Communication: Evolution of a Tool to Assess Physical Therapist Students' Spanish-Language Proficiency. AB - Communication is at the foundation of safe and effective health care. When patients with limited English proficiency (LEP) have healthcare providers who do not speak their language, the communication barrier can lead to poor outcomes. Responding to the high number of Spanish-speaking individuals with LEP, a Doctor of Physical Therapy (DPT) program has integrated Spanish-language training in the curriculum. This paper describes their development and pilot testing of the Physical Therapy Spanish Proficiency Measure (PT-SPM). The PT-SPM was developed for English-Spanish bilingual faculty or clinicians to assess DPT students' clinically relevant Spanish communication. The PT-SPM has 11 total items with four subscales: verbal proficiency, aural proficiency, written proficiency, and cultural competence. Twenty-three pairs of DPT students and their bilingual clinical instructors were recruited for an interrater agreement study; each used the PT-SPM to independently rate the student's Spanish communication with Spanish speaking patients with LEP in clinical settings. Cohen's weighted kappa was calculated to evaluate interrater agreement between the students and clinicians on item level, using linear incremental weights. The weighted kappa coefficients ranged from 0.35 (fair agreement) to 0.80 (substantial agreement). All weighted kappa coefficients were statistically significant. Two items had fair agreement; four items had moderate agreement, and five items had substantial agreement. These results support that the PT-SPM may have value as an assessment tool for DPT students in clinical settings. Educators in other health professions may consider adapting the PT-SPM. This paper contributes to the broader interprofessional dialogue about how to assess and improve patient-provider communication. PMID- 29989439 TI - Correlation between body image perception and spinopelvic parameters in ankylosing spondylitis. AB - OBJECTIVE: To identify relationships between spinopelvic parameters and body image perception in ankylosing spondylitis (AS). METHODS: The study and control groups comprised 107 AS patients (18 women and 89 men) and 40 controls. All underwent anteroposterior and lateral radiography of whole spine, including hip joints, and completed clinical questionnaires. The radiographic parameters examined were sagittal vertical axis, sacral slope, pelvic tilt, pelvic incidence, lumbar lordosis, thoracic kyphosis, spinosacral angle (SSA), and spinopelvic angle (SPA). The Trunk appearance scale (TAPS), and the Scoliosis Research Society 22 appearance questionnaire (SRSapp) were administered to evaluate body image perception. RESULTS: The patient and control groups were found to differ significantly in terms of sagittal vertical axis, sacral slope, pelvic tilt, pelvic incidence, lumbar lordosis, SSA, and SPA. However, no significant intergroup difference was observed for thoracic kyphosis (p > .05). Correlation analysis revealed significant relationships between radiographic parameters and body image perception. Multiple regression analysis was performed to identify predictors of body image perception scores, and the results obtained revealed age, SSA, and SPA significantly predicted SRSapp scores and that age and SSA predicted TAPS scores. CONCLUSIONS: AS patients and normal controls were found to differ significantly in terms of sagittal spinopelvic parameters. Correlation analysis revealed significant relationships between radiographic parameters and body image perception. In particular, age, SSA, and SPA were found to be significant predictors of body image perception scores in AS patients. PMID- 29989440 TI - Salvage Radiopeptide Therapy of Advanced Castrate-Resistant Prostate Cancer with Lutetium-177-Labeled Prostate-Specific Membrane Antigen: Efficacy and Safety in Routine Practice. AB - BACKGROUND: Prostate-specific membrane antigen (PSMA)-based radiopeptide/radioligand therapy represents a rapidly expanding field in the management of metastatic castrate-resistant prostate cancer (mCRPC). However, there remains concern for the development of significant toxicities in heavily pretreated patients. In this study, the authors present their local experience, with respect to efficacy and toxicity, of 22 consecutive patients treated with lutetium-177-DOTAGA-(I-y)fk(Sub-KuE) or 177Lu-PSMA I&T radioimmunotherapy for progressive mCRPC, followed up over 1 year. MATERIALS AND METHODS: All patients had progressive mCRPC, an European Cooperative Oncology Group (ECOG) <=2 with adequate bone marrow and liver function. 177Lu-PSMA I&T therapy was administered at 8-week intervals with a mean prescribed activity of 5.5 GBq (gigabecquerel) per patient. RESULTS: Twenty patients had evaluable results, median age of 71 years, and median duration of follow-up of 17 months. Three patients (15%) experienced a G1/2 myelotoxicity and four (20%) G3/4. No incidences of myelodysplasia/acute leukemia have been identified. All toxicities were self limiting. Baseline cytopenia was predictive of the development of subsequent G3/4 myelotoxicity (p = 0.0035). Eight patients (40%) experienced an objective PSA response, with a median time to response of 15 weeks. The median time to PSA progression was not reached. Patients receiving three cycles of therapy were statistically more likely to experience a disease response when compared to those treated with one, two, or four cycles (p < 0.0001). CONCLUSIONS: 177Lu-PSMA I&T radioimmunotherapy of progressive mCRPC is safe and effective with three cycles being the potential optimal number for determining long-term disease response. PMID- 29989441 TI - Timing of Intra-Articular Injection of Synovial Mesenchymal Stem Cells Affects Cartilage Restoration in a Partial Thickness Cartilage Defect Model in Rats. AB - Objective We investigated the effect of administration of intra-articular mesenchymal stem cells (MSCs) on cartilage repair at different timings, and the distribution of MSCs in the knee. Design A partial thickness cartilage defect (PTCD) was created on the medial femoral condyle in 14-week-old Sprague-Dawley rats. Intra-articular injection of 1 * 106 MSCs was performed at 3 time points, namely at the time of surgery (0w group), at 1 week after surgery (1w group), and at 2 weeks after surgery (2w group). For the control, 50 MUL phosphate-buffered saline was injected at the time of surgery. The femoral condyles were collected at 6 weeks after creation of PTCD and assessed histologically. To investigate the distribution of MSCs, fluorescent-labeled MSCs were injected into the knee joint. Results In the control group, the cartilage lesion was distinguishable from surrounding cartilage. In the 0w group, hypocellularity and a slight decrease in safranin O stainability were observed around the injured area, but cartilage was restored to a nearly normal condition. In contrast, in the 1w and 2w groups, the cartilage surface was irregular and safranin O stainability in the injured and surrounding areas was poor. Histological score in the 0w group was significantly better than in the control, 1w, and 2w groups. At 1 day postinjection, fluorescent-labeled MSCs were mostly distributed in synovium. However, no migration into the PTCD was observed. Conclusions Early intra-articular injection of MSCs was effective in enhancing cartilage healing in a rat PTCD model. Injected MSCs were distributed in synovium, not in cartilage surrounding the PTCD. PMID- 29989442 TI - A Novel EXT1 Mutation Identified in a Family with Multiple Osteochondromas. AB - AIMS: Multiple exostoses (MO), also referred to as hereditary multiple exostoses (HME), is an autosomal dominant inherited skeletal disorder that has been found to be associated with mutations in the EXT1 and EXT2 genes. In the present study, we report a Chinese family with HME and undertake a mutational analysis of the EXT1 and EXT2 genes in affected and unaffected individuals. METHODS: All exons of the EXT1 and EXT2 genes in seven members of the family were polymerase chain reaction amplified from blood and sequenced. RESULTS: A heterozygous mutation (c.1056G>T) was identified in exon 2 of the EXT1 gene in the proband and other affected family members; this mutation was not found in the unaffected family members. DISCUSSION: This c.1056G>T mutation is located in the exostosin domain of the EXT1 protein and leads to an amino acid change of Glutamine (Gln) to Histidine (His) at position 352. Homology searches reveal that Gln352 is highly conserved in many species and may play an essential role in the normal function of the EXT1 protein. CONCLUSIONS: This study contributes to a better understanding of the genetic basis of HME, expands the known mutational spectrum of EXT1, and provides a reference for genetic counseling and prenatal diagnosis of this family. PMID- 29989443 TI - Tubular carcinomas of the breast: an epidemiologic study. AB - AIM: We explored the clinicopathologic characteristics, prognostic factors and outcomes in tubular carcinoma (TC) of the breast. METHODS: We retrospectively assessed 8091 TC patients using the Surveillance, Epidemiology and End Results database from 2000 to 2013. RESULTS: Most patients were non-Hispanic white, well differentiated disease, tumor size <=2 cm, node-negative, nonmetastatic, hormone receptor-positive and HER2-negative status. The 10-year breast cancer-specific survival and overall survival were 98.1 and 82.0%, respectively. Multivariate analysis indicated that age, ethnicity, surgery procedures, radiotherapy and chemotherapy were independent predictors affecting survival outcomes. There was comparable breast cancer-specific survival between surgery and nonsurgery groups. CONCLUSION: The patients with TC has excellent survival outcomes, which may in part be due to the favorable tumor characteristics. PMID- 29989444 TI - Sustained release of sodium deoxycholate from PLGA-PEG-PLGA thermosensitive polymer. AB - Delivery of the drugs to the target tissue and reducing their side effects on surrounding tissues is still a significant challenge for pharmaceutical scientists. The aim of this study was to investigate the suitability of PLGA-PEG PLGA triblock copolymer as a matrix material for a sustained-release system of sodium deoxycholate (NaDC). The copolymer was synthesized by ring-opening polymerization reaction, using microwave irradiation and characterized by different techniques. It was shown that the introduction of NaDC to the PLGA-PEG PLGA copolymer did not influence its inherent sol-gel transition behaviour, but increased the sol-gel transition. The results showed the appropriate NaDC/polymer interaction and the formation of NaDC/polymer-mixed micelle. The sustained release of NaDC from the copolymer lasted for 2 days. This release can be attributed to the formation of NaDC/polymer-mixed micelles and trapping NaDC in the copolymer matrix. The cytolytic efficacy of NaDC-loaded copolymer and sustained release of NaDC were investigated on human adipocytes. Overall a sustained-release formulation for NaDC can be used to study localized fat dissolution. PMID- 29989445 TI - Second-generation anti-depressants and risk of new-onset seizures in the elderly. AB - BACKGROUND: Anti-depressants are among the most widely-prescribed medications. It is unknown whether the risk of seizure during therapeutic use differs by drug. We ranked the seizure risk of popular anti-depressants. METHODS: We conducted a population-based case-control study between April 2002 and March 2015 in Ontario, Canada. Cases were Ontario residents aged >=65 years hospitalized for a first ever seizure within 60 d of filling a prescription for one of nine second generation anti-depressants, each dispensed more than 1 million times (range: 1,196,810 [fluvoxamine] to 19,849,930 [citalopram]) during the study period. For each case, we identified up to four seizure-free controls receiving a similar anti-depressant, and matched on age, sex, date and a pre-defined seizure-specific disease risk index. RESULTS: We identified 5701 patients hospitalized with a first-ever seizure and matched them with 21,872 controls. Relative to bupropion, the risk of new-onset seizure during therapeutic use was highest for escitalopram (adjusted odds ratio [OR] 1.79; 95% confidence interval [CI] 1.42-2.25) and citalopram (OR 1.67; 95% CI 1.35-2.07), while no incremental risk was found for fluoxetine (OR 1.02; 95%CI 0.78-1.33) and duloxetine (OR 0.94; 95%CI 0.75-1.22). Other anti-depressants were associated with modest increase in seizure risk. CONCLUSIONS: The risk of seizure during therapeutic use among elderly patients varies among second-generation anti-depressants. Escitalopram and citalopram are associated with the highest risk. Prescribers should consider the seizure risk of individual anti-depressants and use discretion when selecting an anti-depressant, especially for patients with other risk factors for seizure. Frontline clinicians should be cognizant of this differential risk. PMID- 29989446 TI - Osthole Delays Tert-Butyl Hydroperoxide-Induced Premature Senescence in Neural Stem Cells. AB - In our previous study, we found that osthole could promote the ability of proliferation and differentiation in normal neural stem cells (NSCs) under normal condition. Then, we used tert-butyl hydroperoxide (t-BHP) to establish the model of senescence NSCs to detect the effects of osthole. Interestingly, the immunofluorescence results showed that osthole (100 MUM) could enhance the ability of proliferation and differentiation, and CCK-8 assay results showed that osthole could also enhance the cell viabilities. Then, SA-beta-gal assay results showed that osthole could decrease the positive of senescence cells. Flow cytometric analysis results showed that osthole could decrease the mixture of G0 and G1 phase. Reverse transcriptase (RT)-polymerase chain reaction results showed that osthole could downregulate the expression of p16 mRNA, and western blot analysis results showed that the expressions of the target protein decreased in p16-pRb signaling pathway with osthole treatment. In conclusion, these results indicated that osthole could probably delay cells senescence through p16-pRb signaling pathway. PMID- 29989447 TI - Tribute to Harvey A. K. Whitney, Jr. PMID- 29989448 TI - Oncogene addicted non-small-cell lung cancer: current standard and hot topics. AB - Lung cancer is the leading cause of cancer mortality worldwide. Activating mutations in the EGFR and rearrangements in the anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) genes have been identified as oncogenic drivers in non-small-cell lung cancer. Development of specific small-molecule tyrosine kinase inhibitors, able to interfere with tumor growth and metastatic spread, dramatically changed the natural history of oncogene-addicted non-small-cell lung cancer. However, despite advances in targeted therapies, all patients inevitably develop acquired resistance to tyrosine kinase inhibitors. Novel promising and effective treatments are under investigations. PMID- 29989449 TI - New options on the horizon for nononcogene addicted non-small-cell lung cancer. AB - The treatment of non-small-cell lung cancer (NSCLC) has historically been based on platinum doublets- and taxan-based chemotherapy in the first- and second-line therapy, respectively. Although new agents have emerged for patients with driver mutations, treatment options for nononcogene addicted NSCLC have not changed for years. However, the last 5 years have seen the approval and introduction of new biological agents, such as immune checkpoint inhibitors and antiangiogenic drugs. The aim of this review is to give readers an update on the news in the treatment of nononcogene addicted NSCLC. As more and more therapeutic options are now available, we will delineate a potential therapeutic algorithm for the optimization of daily life treatment choice of NSCLC patients. PMID- 29989451 TI - Acquired resistance in oncogene-addicted non-small-cell lung cancer. AB - The advance of tyrosine kinase inhibitors has profoundly changed the therapeutic algorithm of non-small-cell lung cancer in molecularly selected patients. However, benefit from these agents is often transient and usually most patients progress within 12 months from treatment. Novel and more potent and selective tyrosine kinase inhibitors have been developed to overcome acquired resistance; however, these agents are once again associated with only temporary benefit and patients frequently develop secondary resistance, a heterogeneous phenomenon that involves different molecular mechanisms simultaneously. The aim of our paper is to provide a comprehensive overview of the mechanisms of acquired resistance in oncogene-addicted non-small-cell lung cancer, focusing on the two most studied target, EGFR mutations and ALK translocation, and reviewing the main challenges in clinical practice. PMID- 29989452 TI - Immunotherapy in non-small-cell lung cancer: a bridge between research and clinical practice. AB - Lung cancer has been historically considered a poorly immunogenic disease because of the few evidence of immune responses in affected patients and the limited efficacy of immunomodulating strategies. Recent understanding of the molecular mechanisms leading to cancer immune evasion has allowed the development of a new class of drugs called immune checkpoint inhibitors, which reactivate host responses with outstanding clinical benefits in a portion of patients with non small-cell lung cancer. In this review, we briefly summarize the basis of immunogenicity and immune escape of cancer, with specific focus on non-small-cell lung cancer, mechanisms underlying immune checkpoint inhibitors efficacy and the most updated results on potential biomarkers, with the final aim of defining current unmet needs of immunotherapy in clinical practice. PMID- 29989453 TI - Emerging targets in advanced non-small-cell lung cancer. AB - New therapeutic options in non-small-cell lung cancer have been available through a great in-depth and genomic research, improving preclinical disease patterns and identifying the specific toxicity of target therapy. The multidisciplinary approach, increasingly practiced among clinicians, researchers, pharmaceutical companies and ethics committees has allowed the emergence of a new generation of translational clinical trials and the adoption of new technologies (e.g., point of-care sequencing), then speeding up the development and trade of these new drugs. Consequently, there is a long list of therapeutic candidates that need to be efficiently evaluated early in the context of Phase I clinical trials. In this review, we discuss some of the key developments and novelties in the main histological groups. PMID- 29989454 TI - Environmental impact on the onset of hypertension-induced end-stage renal disease. AB - This study intends to assess the impact of environmental factors on the onset of hypertension-induced end-stage renal disease (ESRD) and to compare the level of oxidative stress with nonhypertensive diabetic ESRD. ESRD patients were evaluated along with healthy controls through questionnaire for demographic, nutritional and lifestyle variables. Oxidants were measured along with antioxidants. Multiple linear regression (MLR) models were applied to analyze association of studied variables with oxidants and antioxidants. Most of the hypertensive nephrosclerotic patients were residing in locality that was either closer to industrial belt or polluting water bodies, belonging to low socioeconomic status that invariably affected their lifestyle and nutritional status. Hypertensive ESRD patients showed more pronounced oxidative stress than diabetic ESRD. Several of the studied variables were significantly associated with oxidants and antioxidants. Demographic, nutritional and lifestyle variables appeared to have suggestive effect on the onset of hypertensive nephrosclerosis. PMID- 29989455 TI - Reliability of Postural Sway Measures of Standing Balance Tasks. AB - The reliability of balance exercises performance in experimental and clinical studies has typically been confined to a small set of exercises. In order to advance the field of assessing balance exercise intensity, establishing the reliability of performance during a more diverse array of exercises should be undertaken. The purpose of this study was to investigate the test-retest reliability of postural sway produced during performance of 24 different balance tasks, and to evaluate the reliability of different measures of postural sway. Sixty-two healthy subjects between the ages of 18 and 85 years of age (50% female, mean age 55 +/- 20 years) participated. Subjects were tested during two visits one week apart and performed two sets of the 24 randomized standing tasks per visit. The tasks consisted of combinations of the following factors: surface (firm and foam), vision (eyes open and eyes closed), stance (feet apart and semi tandem), and head movement (no movement, yaw, and pitch). Angular position displacement, angular velocity, and linear acceleration postural sway in the pitch and roll planes was recorded via an inertial measurement unit. The postural sway measures demonstrated at fair to good test-retest reliability with few exceptions, and angular velocity measures demonstrated the greatest reliability. The between-visit reliability of two averaged trials was excellent for most tasks. The study indicates that performance of most balance tasks used as part of balance rehabilitation is reliable, and quantitative assessment could be used to document change. PMID- 29989456 TI - Biomechanical Outcomes Due to Impact Loading in Runners While Looking Sideways. AB - A stable gaze is necessary to optimize visual conditions during running. Head accelerations generally remain stable when looking in front, however it is unclear if this response is similar when the head is turned sideways, and whether other adaptive strategies are present to maintain this stability. The purpose of this study, therefore, was to examine whether runners maintained stable head accelerations while gazing at fixed targets in front and to their sides. We collected biomechanical data from thirteen runners as they directed their gaze to visual targets located in front, 45-degree and 90-degree to the sides at a random sequence. Vertical head and tibial accelerations were the primary outcome measures, while vertical loading rate, footstrike angle, contact time, stride length, and stride rate were the secondary measures. A reduction in vertical head accelerations was found in the rightmost direction (p = .040), while an increase in vertical tibial accelerations was found on the same direction (p = .016). No other significant differences were observed for the other variables. The results of this study suggest that the tibia accommodated the increased shock to maintain head stability. PMID- 29989457 TI - Stepping to an Auditory Metronome Improves Weight-Bearing Symmetry in Poststroke Hemiparesis. AB - Asymmetry in weight-bearing is a common feature in poststroke hemiparesis and is related to temporal asymmetry during walking. The aim of this study was to investigate the effect of an auditory cue for stepping in place on measures of temporal and weight-bearing asymmetry. A total of 10 community-dwelling adults (6 males and 4 females) with chronic poststroke hemiparesis performed 5 un-cued stepping trials and 5 stepping trials cued by an auditory metronome cue. A Vicon system was used to collect full body kinematic trajectories. Two force platforms were used to measure ground reaction forces. Step, swing, and stance times were used to calculate temporal symmetry ratios. Weight-bearing was assessed using the vertical component of the ground reaction force and center of mass-center of pressure separation at mid-stance. Weight-bearing asymmetry was significantly reduced during stepping with an auditory cue. Asymmetry values for step, swing, and stance times were also significantly reduced with auditory cueing. These findings show that auditory cueing when stepping in place produces immediate reductions in measures of temporal asymmetry and dynamic weight-bearing asymmetry. PMID- 29989459 TI - Effects of an Exercise and Mental Activity Program for People With Dementia and Their Care Partners. AB - Exercise and mental stimulation may improve cognition, physical function, and well-being of people with dementia (PWD) and older adults more generally. This study evaluated changes in physical function, physical activity, exercise self efficacy, and mental well-being with participation in Minds in Motion(r), a weekly exercise and mental stimulation program for PWD (n = 343) and care partners (n = 318). Most physical function measures improved among PWD and care partners (endurance, upper and lower body strength, upper body flexibility; ps <= .009). Participants also reported a significant increase in weekly frequency, duration, and intensity of physical activity (ps < .001) and in mental well-being (p < .001). Exercise self-efficacy did not change (p = .16). These results suggest that Minds in Motion(r) yields improvements in physical function, which may translate into better functional abilities for PWD and improved ability for their partners to care for people living with dementia. PMID- 29989458 TI - Case Study: Extreme Weight Making Causes Relative Energy Deficiency, Dehydration and Acute Kidney Injury in a Male Mixed Martial Arts Athlete. AB - The aim of the present case study was to quantify the physiological and metabolic impact of extreme weight cutting by an elite male MMA athlete. Throughout an 8 week period, we obtained regular assessments of body composition, resting metabolic rate (RMR), VO2peak and blood clinical chemistry to assess endocrine status, lipid profiles, hydration and kidney function. The athlete adhered to a "phased" weight loss plan consisting of 7 weeks of reduced energy (ranging from 1300 - 1900 kcal.d-1) intake (phase 1), 5 days of water loading with 8 L per day for 4 days followed by 250 ml on day 5 (phase 2), 20 h fasting and dehydration (phase 3) and 32 h of rehydration and refuelling prior to competition (phase 4). Body mass declined by 18.1 % (80.2 to 65.7 kg) corresponding to changes of 4.4, 2.8 and 7.3 kg in phase 1, 2 and 3, respectively. We observed clear indices of relative energy deficiency, as evidenced by reduced RMR (-331 kcal), inability to complete performance tests, alterations to endocrine hormones (testosterone: <3 nmol.L-1) and hypercholesterolemia (>6 mmol.L-1). Moreover, severe dehydration (reducing body mass by 9.3%) in the final 24 hours prior to weigh-in induced hypernatremia (plasma sodium: 148 mmol.L-1) and acute kidney injury (serum creatinine: 177 MUmol.L-1). These data therefore support publicised reports of the harmful (and potentially fatal) effects of extreme weight cutting in MMA athletes and represent a call for action to governing bodies to safeguard the welfare of MMA athletes. PMID- 29989460 TI - Population structure and genetic diversity of hatchery stocks as revealed by combined mtDNA fragment sequences in Indian major carp, Catla catla. AB - Catla catla is the second most important Indian major carp due to high growth rate and acceptance to consumers for food value. It is widely cultured in the Indian subcontinent as monoculture or polyculture. In the present study, genetic diversity among hatchery stocks (total 218 samples of catla) collected from different geographical regions of India was examined using mtDNA fragment sequence of Cyt b (306 bp) and D loop (710 bp). High numbers (57) of population specific haplotypes were observed in the present study. The results revealed significant genetic heterogeneity for the sequence data (FST = 0.27546, p < .05). Analysis of molecular variance revealed significant genetic differentiation among different catla populations. The information generated in present study could be useful to develop broad genetic base populations of catla. PMID- 29989461 TI - Effects of Physical Activity Governmental Programs on Health Status in Independent Older Adults: A Systematic Review. AB - This systematic review analyzes the evidence of the effects of physical activity governmental programs oriented toward the health of independent older adults. Medline, Web of Science, PsycINFO, and Psychology & Behavioral Sciences Collection databases were used for data mining, and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols recommendations were followed. Five studies (n = 2,545 participants) fulfilled the established inclusion criteria. The physical activity programs had beneficial effects on the older adults' quality of life, fall risk, activities of daily living, physical activity levels, nutritional risk, body mass index, arterial pressure, resting heart rate, blood glucose, triglycerides, and/or cholesterol, but did not significantly alter their body fat mass percentage. Programs involving diverse physical capacities seem to be more effective for healthy aging. It is recommended that governments start to disseminate the outcomes of these programs within society and the scientific community. PMID- 29989462 TI - The Effect of Active Physical Training Interventions on Reactive Postural Responses in Older Adults: A Systematic Review. AB - BACKGROUND: A variety of physical interventions have been used to improve reactive balance in older adults. PURPOSE: To summarize the effectiveness of active treatment approaches to improve reactive postural responses in community dwelling older adults. DESIGN: Systematic review guided by PRISMA guidelines. STUDY SELECTION: A literature search included the databases PubMed, OVID, CINAHL, ClinicalTrials.gov, OTseeker, and PEDro up to December 2017. Randomized controlled trials that evaluated quantitative measures of reactive postural responses in healthy adults following participation in an active physical training program were included. DATA SYNTHESIS: Of 4,481 studies initially identified, 11 randomized controlled trials covering 313 participants were selected for analysis. Study designs were heterogeneous, preventing a quantitative analysis. Nine of the 11 studies reported improvements in reactive postural responses. CONCLUSIONS: Several clinically feasible training methods have the potential to improve reactive postural responses in older adults; however, conclusions on the efficacy of treatment methods are limited because of numerous methodological issues and heterogeneity in outcomes and intervention procedures. PMID- 29989463 TI - Severe illness associated with reported use of synthetic cannabinoids: a public health investigation (Mississippi, 2015). AB - STUDY OBJECTIVES: In April 2015, a multistate outbreak of illness linked to synthetic cannabinoid (SC) use was unprecedented in magnitude and severity. We identified Mississippi cases in near-real time, collected information on cases to characterize the outbreak, and identified the causative SC. METHODS: A case was defined as any patient of a Mississippi healthcare facility who was suspected of SC use and presenting with >=2 of the following symptoms: sweating, severe agitation, or psychosis during April 2-May 3, 2015. Clinicians reported cases to the Mississippi Poison Control Center (MPCC). We used MPCC data to identify cases at the University of Mississippi Medical Center (UMMC) to characterize in further detail, including demographics and clinical findings. Biologic samples were tested for known and unknown SCs by liquid chromatography quadrupole time-of flight mass spectrometry (LC-QTOF/MS). RESULTS: Clinicians reported 721 cases (11 deaths) statewide; 119 (17%) were UMMC patients with detailed data for further analysis. Twelve (10%) were admitted to an intensive care unit and 2 (2%) died. Aggression (32%), hypertension (33%), and tachycardia (42%) were common. SCs were identified in serum from 39/56 patients (70%); 33/39 patients (85%) tested positive for MAB-CHMINACA (N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1 (cyclohexylmethyl)-1H-indazole-3-carboxamide) or its metabolites. Compared to all patients tested for SCs, those positive for MAB-CHMINACA were more likely to have altered mental status on examination (OR = 3.3, p = .05). CONCLUSION: SC use can cause severe health effects. MAB-CHMINACA was the most commonly detected SC in this outbreak. As new SCs are created, new strategies to optimize surveillance and patient care are needed to address this evolving public health threat. PMID- 29989464 TI - Individual Step Characteristics During Sprinting in Unilateral Transtibial Amputees. AB - To understand the step characteristics during sprinting in lower-extremity amputees using running-specific prosthesis, each athlete should be investigated individually. Theoretically, sprint performance in a 100-m sprint is determined by both step frequency and step length. The aim of the present study was to investigate how step frequency and step length correlate with sprinting performance in elite unilateral transtibial amputees. By using publicly-available Internet broadcasts, the authors analyzed 88 races from 7 unilateral transtibial amputees. For each sprinter's run, the average step frequency and step length were calculated using the number of steps and official race time. Based on Pearson's correlation coefficients between step frequency, step length, and official race time for each individual, the authors classified each individual into 3 groups: step-frequency reliant, step-length reliant, and hybrid. It was found that 2, 2, and 3 sprinters were classified into step-frequency reliant, step-length reliant, and hybrid, respectively. These results suggest that the step frequency or step length reliance during a 100-m sprint is an individual occurrence in elite unilateral transtibial amputees using running-specific prosthesis. PMID- 29989465 TI - Gut Microbiota Composition Is Related to Cardiorespiratory Fitness in Healthy Young Adults. AB - Bacteria residing in the human gastrointestinal tract has a symbiotic relationship with its host. Animal models have demonstrated a relationship between exercise and gut microbiota composition. This was the first study to explore the relationship between cardiorespiratory fitness (maximal oxygen consumption, VO2max) and relative gut microbiota composition (Firmicutes to Bacteroidetes ratio [F/B]) in healthy young adults in a free-living environment. Twenty males and 17 females (25.7 +/- 2.2 years), who did not take antibiotics in the last 6 months, volunteered for this study. VO2max was measured using a symptom-limited graded treadmill test. Relative microbiota composition was determined by analyzing DNA extracted from stool samples using a quantitative polymerase chain reaction that specifically measured the quantity of a target gene (16S rRNA) found in Firmicutes and Bacteroidetes. Relationships between F/B and potentially related dietary, anthropometric, and fitness variables were assessed using correlation analyses with an appropriate Bonferroni adjustment (p < .004). The average F/B ratio in all participants was 0.94 +/- 0.03. The F/B ratio was significantly correlated to VO2max (r = .48, p < .003), but no other fitness, nutritional intake, or anthropometric variables (p > .004). VO2max explained ~22% of the variance of an individual's relative gut bacteria as determined by the F/B ratio. These data support animal findings, demonstrating a relationship between relative human gut microbiota composition and cardiorespiratory fitness in healthy young adults. Gastrointestinal bacteria is integral in regulating a myriad of physiological processes, and greater insight regarding ramifications of exercise and nutrition on gut microbial composition may help guide therapies to promote human health. PMID- 29989466 TI - Nutritional Intake in Elite Cross-Country Skiers During Two Days of Training and Competition. AB - This study investigated the energy, macronutrient, and fluid intakes, as well as hydration status (urine specific gravity), in elite cross-country skiers during a typical day of training (Day 1) and a sprint skiing competition the following day (Day 2). A total of 31 (18 males and 13 females) national team skiers recorded their food and fluid intakes and urine specific gravity was measured on Days 1 and 2. In addition, the females completed the Low Energy Availability in Females Questionnaire to assess their risk of long-term energy deficiency. Energy intake for males was 65 +/- 9 kcal/kg on Day 1 versus 58 +/- 9 kcal/kg on Day 2 (p = .002) and for females was 57 +/- 10 on Day 1 versus 55 +/- 5 kcal/kg on Day 2 (p = .445). Carbohydrate intake recommendations of 10-12 g.kg-1.day-1 were not met by 89% of males and 92% of females. All males and females had a protein intake above the recommended 1.2-2.0 g/kg on both days and a postexercise protein intake above the recommended 0.3 g/kg. Of the females, 31% were classified as being at risk of long-term energy deficiency. In the morning of Day 1, 50% of males and 46% of females were dehydrated; on Day 2, this was the case for 56% of males and 38% of females. In conclusion, these data suggest that elite cross-country skiers ingested more protein and less carbohydrate than recommended and one third of the females were considered at risk of long-term energy deficiency. Furthermore, many of the athletes were dehydrated prior to training and competition. PMID- 29989467 TI - Impact of Sedentary Time on Chronic Kidney Disease (CKD) and Disability Incidence in Community-Dwelling Japanese Older Adults: A 4-Year Prospective Cohort Study. AB - This study examined the association between the estimated glomerular filtration rate (eGFR) and disability incidence according to sedentary time in community dwelling older Japanese adults. This prospective cohort study sampled 5104 community-dwelling older adults (>= 65 years) enrolled in a health promotion study in a general population. The participants (n = 4457, >= 65 years) were monitored for inclusion in the long-term care insurance (LTCI) system for 4 years. This study used blood samples to assess eGFR. Cox proportional regression analysis was used to determine predictors of disability. In total, 461 participants (10.3%) became newly certified as needing LTCI services. Cox regression models were adjusted for multiple confounders: eGFR < 45 mL/min/1.73 m2 (hazard ratio [HR] = 1.741; 95% confidence interval [CI] [1.193-2.539]) and eGFR < 45 mL/min/1.73 m2 with high sedentary time (>= 8 hours) (HR = 4.367; 95% CI [2.021-9.438]) remained significantly associated with disability incidence. Our findings suggest that in the case of CKD, the disability incidence rate may be affected by sedentary time. PMID- 29989468 TI - Posthospital Falls Prevention Intervention: A Mixed-Methods Study. AB - OBJECTIVE: Posthospital discharge shows increased risk for falls in older people. This pilot study was created to determine feasibility and acceptability of a community-delivered posthospital multifactorial program. METHOD: This mixed method study used randomized controlled design (quantitative component) and interviews (qualitative component). People aged >=65 years, hospitalized for a fall, underwent assessment for quality of life and falls-related outcomes, followed by interviews, randomization into intervention (exercise, medication review, and education) or control group, and follow-up at 6 months. RESULTS: Thirteen people commenced, with 10 people assessed at 6 months. Participants were complex with high degrees of frailty, multimorbidity, polypharmacy, and falls risk. Interview data related to intervention, impacts on quality of life, and fall-related outcomes. CONCLUSION: Preliminary findings suggest suitability of a multifactorial program for older people posthospital discharge following a fall. A social component would be a useful addition to falls prevention strategies, utilizing existing community nursing organizations. PMID- 29989469 TI - Patients with rectal cancer are satisfied with in-hospital communication despite insufficient information regarding treatment alternatives and potential side effects. AB - AIM: Patients with rectal cancer may undergo treatment such as surgery and (chemo)radiotherapy. Before treatment, patients are informed of different options and possible side-effects. The aim of the study was to evaluate the patients' experience of communication with healthcare personnel at time of diagnosis and after one year. METHOD: A total of 1085 patients from Denmark and Sweden were included. They answered a detailed questionnaire at diagnosis and at the one year follow-up. Clinical data were retrieved from national quality registries. RESULTS: Response rates were 87% at baseline and 74% at one year. Overall the patients were very satisfied with the communication with healthcare personnel. However, some patients reported insufficient information regarding treatment options and possible side-effects. Only 32% (335/1050) and 24% (248/1053), respectively, stated that they were informed about possible sexual and urinary dysfunction before treatment. CONCLUSIONS: Even though patients felt that they received insufficient information regarding side-effects on sexual and urinary function, they were generally satisfied with the communication with the healthcare personnel. Since overall satisfaction with the level of information was very high, it is unlikely that further information to patients with rectal cancer in the surgical and oncological settings will improve satisfaction with communication. PMID- 29989470 TI - Concurrent Validity of Depth Sensing Cameras for Non-Contact ACL Injury Screening During Side-Cut Maneuvers in Adolescent Athletes: A Preliminary Study. AB - Anterior cruciate ligament (ACL) injury is one of the most common knee injuries among adolescent athletes. Majority of the ACL injuries occur due to pivoting, sudden deceleration and direction change without contact with any player. Preventive interventions can reduce risks of the ACL injury, thus developing a clinician friendly biomechanical assessment tool to identify athletes with such risk factors is crucial. In this study, we investigated the concurrent validity of a commercially-available depth sensor, Microsoft Kinect, as a cost-effective alternative to the gold standard three-dimensional motion analysis systems in non contact ACL screening for adolescent athletes during side-cut maneuvers. Study participants performed 45 degrees side-cut maneuvers while collecting data from both systems concurrently. The sagittal and frontal plane kinematics were analyzed during the full stance phase and the first 20% of the stance (early deceleration). Absolute agreement (range ICC = 0.767, 0.989) and consistency (range ICC = 0.799, 0.992) were excellent for all measures except early deceleration frontal plane hip angle, which displayed good absolute agreement (ICC = 0.643) and consistency (ICC = 0.625). Findings showed that the Kinect has the potential to be an effective clinical assessment tool for sagittal and frontal plane trunk, hip, and knee kinematics during the side-cut maneuvers. PMID- 29989471 TI - Standing Versus Stepping - Exploring the Relationships Between Postural Steadiness and Dynamic Reactive Balance Control. AB - While the literature has characterized balance control during quasi-static and/or dynamic tasks, comparatively few studies have examined relationships across paradigms. This study investigated whether quiet-stance postural steadiness metrics were associated with reactive control parameters (during both stepping and restabilisation phases) following a lean-and-release perturbation. Forty older adults participated. Postural steadiness (centre of pressure range, root mean square, velocity, and frequency) was evaluated in 'feet together' and 'tandem stance' positions. During the reactive control trials, step length, step width, movement time and reaction time were measured, in addition to the postural steadiness variables measured during the restabilisation phase following the stepping response. Out of 64 comparisons, only ten moderate correlations were observed between postural steadiness and reactive spatio-temporal stepping parameters (p<=0.05, r=-.312 to -.534). However, postural steadiness metrics were associated with centre of pressure velocity and frequency during the restabilisation phase of the reactive control trials (p<=0.015, r= 0.383 to 775 for velocity; p<=0.014, r= 0.386 to 0.550 for frequency). Although some elements of quasi-static centre of pressure control demonstrated moderate associations with dynamic stepping responses, relationships were stronger for restabilisation phase dynamics after foot-contact. Future work should examine the potential association between restabilisation phase control and older adult fall-risk. PMID- 29989472 TI - Active@Home: Investigating the Value of a Home Care Worker-Led Exercise Program for Older Adults With Complex Care Needs. AB - Exercise has proven health benefits for older adults independent of age, disability and disease. However, barriers to exercise participation exist, including travel to, and access to, appropriate facilities and programs. Evidence shows that in-home exercise delivered by allied health professionals can improve physical health and prolong independence among individuals with government supported aged care packages. A less costly alternative is program delivery by home care workers. However, effective training for workers and resources to guide the consumer are required. This project evaluated an exercise training module for home care workers and a consumer resource to promote in-home exercise participation among older Australians with government supported aged care packages. Outcomes included a significant improvement in functional capacity as measured by the Short Physical Performance Battery (mean increase of 1.4 points), a 19% reduction in participants classified as frail and a reduction in healthcare service access of 47% across the intervention. PMID- 29989473 TI - Fertility-related knowledge and perceptions of fertility education among adolescents and emerging adults: a qualitative study. AB - Research shows that young people do not know much about their fertility. In the present study, we examined fertility knowledge and perceptions of a fertility educational brochure (i.e. 'A Guide to Fertility') in five focus groups with adolescents (16-18 years, n = 19) and emerging adults (21-24 years, n = 14) who were childless, not currently pregnant (or for men partner not pregnant) or trying to conceive but intending to have a child in the future. Participants (n = 33) reported having poor knowledge of a range of fertility topics and feelings of surprise, fear and concern in response to the brochure, despite perceiving benefits of the provision of fertility education and feasibility of 'A Guide to Fertility'. Comparison between age groups showed that adolescents lacked confidence in their fertility knowledge and emerging adults more frequently referred to gender and family planning issues when considering the fertility information. The findings show the need and importance of ensuring fertility education is tailored to different age groups for it to be integrated at specific stages of the life course and optimize its benefits over costs. Results point to educators and researchers working together to determine how best to disseminate fertility information to relevant age groups. PMID- 29989474 TI - Ectopic thyroid choroidal mass in linear nevus sebaceous syndrome. PMID- 29989475 TI - Comparison of Body Composition Assessment Methods in Professional Urban Firefighters. AB - Given the importance of body composition in maintaining optimal physical and functional capacities, the use of appropriate, field-based assessment tools should be a priority to assist in maintaining the occupational safety of firefighters and the community. For ease, body mass index has often been used to assess these changes. However, it is limited in its accuracy. The purposes of this study were twofold: (a) to compare the validity of different measures of body composition against dual-energy X-ray absorptiometry (DXA) in urban firefighters and (b) to assess these measures in their ability to provide meaningful interpretation of criteria-driven categories of adiposity. A total of 64 male firefighters (age = 44.0 +/- 9.5 years) underwent full anthropometric profiling (predictor equations used to determine body fat percentage [BF%]), bioelectrical impedance analysis (BIA), and DXA assessments. Participants' body mass index was calculated, and BF% and lean mass were determined along with criteria-driven categorizations of adiposity. Anthropometric (skinfolds) predictor equations (e.g., mean bias = -4.4% for BF%) were typically closer to DXA measures, compared with BIA (9.4% for BF%). However, when determining categories of criteria-driven adiposity, BIA (42.9% overweight or obese) provided closer estimates to the DXA-determined distribution (44.6%) than anthropometric based measures (up to 40%). Body mass index appears an inappropriate measure for accurately determining categories of adiposity with 64.1% classified as overweight or obese. Given the logistical constraints of anthropometric profiling, and the closeness of BIA to DXA in adiposity categories, BIA may be a suitable alternative to DXA for assessing body composition in professional urban firefighters. PMID- 29989476 TI - Development and Assessment of a Low-Cost Clinical Gait Analysis System. AB - Clinically, measuring gait kinematics and ground reaction force (GRF) is useful to determine the effectiveness of treatment. However, it is inconvenient and expensive to maintain a laboratory-grade gait analysis system in most clinics. The purpose of this study was to validate a Wii Balance Board, Kinovea motion tracking software, and a video camera as a portable, low-cost, overground gait analysis system. We validated this low-cost system against a multi-camera Vicon system and AMTI force platform. After validation trials with known weights and angles, five subjects walked across an instrumented walkway multiple times (n=8/subject). We collected vertical GRF and segment angles. Average GRF data from the two systems were similar, with peak GRF errors below 3.5%BW. However, variability in the balance board's sampling rate led to large GRF errors early and late in stance, when the GRF changed rapidly. The thigh, shank and foot angle measurements were similar between the single and multi-camera, but the pelvis angle was far less accurate. The proposed system has the potential to provide accurate segment angles and peak GRF at low cost, but does not match the accuracy of the multi-camera system and force platform, in part because of the Wii Balance Board's variable sampling rate. PMID- 29989477 TI - The Functional Utilization of Propulsive Capacity During Human Walking. AB - Aging and many gait pathologies are characterized by reduced propulsive forces and ankle moment and power generation during trailing leg push-off in walking. Despite those changes, we posit that many individuals retain an underutilized reserve for enhancing push-off intensity during walking that may be missed using conventional dynamometry. By using a maximum ramped impeding force protocol and maximum speed walking, we gained mechanistic insight into the factors that govern push-off intensity and the available capacity thereof during walking in young subjects. We discovered in part that young subjects walking at their preferred speed retain a reserve capacity for exerting larger propulsive forces of 49%, peak ankle power of 43%, and peak ankle moment of 22% during push-off - the latter overlooked by maximum isometric dynamometry. We also provide evidence that these reserve capacities are governed at least in part by the neuromechanical behavior of the plantarflexor muscles, at least with regard to ankle moment generation. We envision that a similar paradigm used to quantify propulsive reserves in older adults or people with gait pathology would empower the more discriminate and personalized prescription of gait interventions seeking to improve push-off intensity and thus walking performance. PMID- 29989478 TI - Molecular identification and phylogenetic assessment of species under genus Parapenaeopsis Alcock, 1901, from Indian waters. AB - Genus Parapenaeopsis constitute an important fishery resource in Indian waters. Parapenaeopsis stylifera, being morphologically very similar to Parapenaeopsis coromandelica, mainly differentiated using telsonic armature and it is subject of controversy regarding the number of armature for the species. The present study was aimed to resolve the taxonomic ambiguity between P. stylifera and P. coromandelica and to study phylogenetic relationship among five species under the genus Parapenaeopsis using partial sequences of mitochondrial 16S ribosomal DNA (rDNA) and cytochrome c oxidase subunit I (COI) genes. Sequence analysis revealed an average genetic divergence value ranging from 7.65 to 20.3% for COI gene and 2.4 to 12.0% for 16S rDNA gene between five species under study. The result shows that P. stylifera and P. coromandelica Alcock, 1906 are genetically a distinct species with average divergence value of 7.6% based on COI sequence and 2.4% based on the 16S rDNA. However, systematic relationship between the P. stylifera and P. coromandelica were closer than other species, thus formed separate clade in phylogenetic tree. The species specific molecular signatures developed in the present study will be helpful in effective fisheries management of the species in Indian waters. PMID- 29989479 TI - Gait Mechanics Differences Between Healthy Controls and Patients With Peripheral Artery Disease After Adjusting for Gait Velocity Stride Length and Step Width. AB - Patients with peripheral artery disease (PAD) experience significant leg dysfunction. The effects of PAD on gait include shortened steps, slower walking velocity, and altered gait kinematics and kinetics, which may confound joint torques and power measurements. Spatiotemporal parameters, joint torques and powers were calculated and compared between 20 patients with PAD and 20 healthy controls using independent t-tests. Separate ANCOVA models were used to evaluate group differences after independently adjusting for gait velocity, stride length and step width. Compared to healthy controls, patients with PAD exhibited reduced peak extensor and flexor torques at the knee, and hip. After adjusting for all covariates combined, differences between groups remained for ankle power generation in late stance, and knee flexor torque. Reduced walking velocity observed in subjects affected by PAD was closely connected with reductions in joint torques and powers during gait. Gait differences remained, at the knee and ankle, after adjusting for the combined effect of spatiotemporal parameters. Improving muscle function through exercise or with the use of assistive devices needs to be a key tool in the development of interventions that aim to enhance the ability of PAD patients to restore spatiotemporal gait parameters. PMID- 29989480 TI - Current Status of the Sari-Dzhas Natural Focus of Plague, Kyrgyzstan: Epizootic Activity and Marmot Population. AB - The Sari-Dzhas natural mountain focus of plague with an area of 5000 sq. km is located mainly in Kyrgyzstan. This enzootic area belongs to a group of Tien-Shan mountain plague foci and crosses the boundaries of Kazakhstan, Kyrgyzstan, and China. After collapse of Soviet Union, this area was not investigated fully, thence we have estimated current status of hosts and vectors comparing to 1977 in the Sari-Dzhas focus. For period 1977-2014, the number of the gray marmot (Marmota baibacina) as main host of plague has decreased twice due to regular chemical suppression of focal area, but now there is a tendency for population recovery. If negative impact of human activity (hunting, livestock, and tourism) will be minimized, the population density should rise in the near future, related to high reproduction score of animals. Significant increase of number of narrow skulled vole (Microtus gregalis) observed on focus area in 1977-2017 can effort a risk of pathogen transmission in cross-populations of marmots provided by recovery of vector number between different hosts. For whole observation period in the Sari-Dzhas focus were described 33 species of marmot fleas with dominated Oropsylla silantiewi (67% from whole amount of fleas) and Radinopsilla li ventricosa (6.5%). Deep dustation of marmot burrows by 10% dichlorodiphenyltrichloroethane (DDT) conducted in 1980s caused significant decrease of ectoparasite abundance: the number of specific fleas is strongly diminished, while recovery of ticks and lice number is faster. At the same time, Yersinia pestis constantly circulates in the focal area, which is comfortable for interacting of human populations and pathogen hosts. Last plague epizootic was recorded in 1983 and recent outbreaks among gray marmot and its vectors with varying intensity are registered again starting from 2012. Thus, the Sari-Dzhas natural plague focus remains active with all links of plague epizootic cycle (marmot-vector-rodent) and needs strong monitoring every year. PMID- 29989481 TI - Understanding and Utilizing the Unmet Needs of Teenagers and Young Adults with Cancer to Determine Priorities for Service Development: The Macmillan On Target Programme. AB - PURPOSE: A systematic attempt to identify and address unmet needs among patients in a large regional teenagers and young adults (TYA) cancer service in the United Kingdom, including perspectives obtained from patients themselves, their families/supporters, and professionals. METHODS: Questionnaires, focus groups, and interviews were undertaken with the following: patients (diagnosed >=16 years, and aged 16-24 years at the time of study)-participation was 42 for questionnaire, 7 for focus group, and 6 for interview; family members/others in patients' lives ("networkers") (participation: 28, 0, and 4); and professionals (participation: 54, 0, and 97). Requirement management methodology was used to specify components for potential service interventions, which were then scored and prioritized. Co-creation was utilized to incorporate a deeper understanding of patient experience. RESULTS: 42/108(39%) patients, 28/177(24%) networkers, and 122/322(38%) professionals participated. For patients, seven themes that "mattered most" (identified by >60% responders) were defined. For many, support was provided both to a lesser extent than needed and was sometimes unsatisfactory. For networkers, results identified the significant support offered by those around the patient and the impact on their own lives. For professionals, consensus was reached on interventions that could be utilized in clinical encounters with TYA to enhance care. A list of prioritized "requirements" was created to drive future service improvement. CONCLUSIONS: Areas identified for development included three specific initiatives applicable to other TYA services: a support website ( www.tyahelp.co.uk ); an electronic, age/developmentally specific, holistic needs assessment tool (the Integrated Assessment Map www.tyaiam.co.uk ); and a portal linking use of the IAM to resources within the Help website (video illustration available at: https://vimeo.com/191019826 ). PMID- 29989482 TI - Longitudinal health and disaster impact in older New Zealand adults in the 2010 2011 Canterbury earthquake series. AB - Pre-existing longitudinal studies of people affected by disasters provide opportunities to examine the effects of these events on health. Data used in the current investigation were provided by participants in the New Zealand Health, Work and Retirement longitudinal surveys conducted in 2010, 2012 and 2014 (n = 428; aged 50-83), who lived in the Canterbury region of New Zealand during the 2010-2011 earthquakes. Latent profile growth analyses were used to identify groups of respondents who had similar pre-post-disaster physical and mental health profiles. These groups were compared in terms of demographic factors, personal impact of the earthquakes assessed in 2012 and the overall negative positive impact of the earthquake assessed in 2014. There was little evidence of change in health status overtime. Groups did not differ in their experiences of threat or disruption, however those in poorest health reported greatest distress and a more negative overall impact of the earthquake. Although results suggest little impact of disasters on health of surviving older adults, pre-disaster vulnerabilities were associated with distress. Social workers and agencies responsible for disaster response can play a key role in pre-disaster planning and assessment of vulnerabilities of older adults to enhance potential for positive outcomes post-disaster. PMID- 29989483 TI - Involvement of prelimbic 5-HT7 receptors in the regulation of anxiety-like behaviors in hemiparkinsonian rats. AB - OBJECTIVE: At present, little is known about the role of serotonin7 (5-HT7) receptor in anxiety, particularly in Parkinson's disease-related anxiety. Here, we tested whether 5-HT7 receptors in the prelimbic (PrL) cortex are involved in the regulation of anxiety-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle (MFB). METHODS: The open field and elevated plus maze (EPM) tests were performed to study the influence of MFB lesion and intra-PrL injection of 5-HT7 agonist AS19 (0.5, 1 or 2 MUg/rat) and antagonist SB269970 (1.5, 3 or 6 MUg/rat) on anxiety like behaviors. Additionally, changes in monoamine levels in limbic and limbic related brain regions were observed after intra-PrL injection of AS19 (2 MUg/rat) and SB269970 (6 MUg/rat). RESULTS: The MFB lesion induced anxiety-like behaviors compared to sham-operated rats. Intra-PrL injection of AS19 showed anxiolytic effects by the open field and EPM tests in two groups of rats, and administration of SB269970 showed anxiogenic responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 increased dopamine, 5-HT and noradrenaline (NA) levels in the medial prefrontal cortex, ventral hippocampus and amygdala in two groups of rats, whereas SB269970 decreased 5-HT and NA levels in these brain regions. DISCUSSION: 5-HT7 receptors in the PrL are involved in the regulation of anxiety-like behaviors, which is attributable to changes in dopamine, 5-HT and NA levels in the limbic and limbic-related brain regions after activation and blockade of 5-HT7 receptors. ABBREVIATIONS: 6-OHDA: 6-hydroxydopamine; DMSO: dimethyl sulfoxide; DA: dopamine; EPM: elevated plus maze; MFB: medial forebrain bundlem; PFC: medial prefrontal cortex; NA: noradrenaline; PD: Pakinson's disease; PrL: prelimbic; 5-HT: serotonin; vHip: ventral hippocampus. PMID- 29989484 TI - Multiplex Polymerase Chain Reaction for Detection of Leishmania Sp. in Sandflies of the Parana River Islands, Southern Brazil. AB - Leishmaniases are classified as tegumentary leishmaniasis (TL) and visceral leishmaniasis (VL). Brazil is among the countries with the highest number of TL and VL cases. This study was undertaken to standardize the multiplex polymerase chain reaction (PCR) for the detection of the genus Leishmania in sandflies of endemic regions, on islands in the Upper Parana River, northwestern Parana. The sandflies were collected on 10 islands, from November 2012 to November 2014, with Falcao light traps, identified and conserved in tubes containing isopropanol, for subsequent DNA extraction. Two pairs of primers were used for multiplex PCR: A1/A2 and 5Llcac/3Llcac. Nyssomyia neivai was the predominant species of the collected specimens. A total of 3870 samples of female sandflies were analyzed and submitted to multiplex PCR, for the validation of the technique. All pools showed the 220 bp fragment for sandfly DNA detection, but no ~120 bp fragment of Leishmania DNA was found. Although no natural infection of Ny. neivai by Leishmania was found in this study, the interaction of sandflies with Leishmania and its natural reservoirs continues in these Parana River islands, despite the low diversity of the sandfly fauna. Some of these islands have permanent residents and are frequented by tourists. PMID- 29989485 TI - Analyzing psychological conditions of field-workers in the construction industry. AB - The Korean construction industry has experienced poor labor productivity and high accident rates. Previous studies have reported that workers' mental health can cause negative impacts on work performance; thus, enhancing workers' psychological conditions would help achieve more productive and safer workplaces. This research aimed to understand the level of psychological conditions of construction field-workers using four categories: (1) stress (occupational stress and stress-coping style), (2) personal temperament, (3) emotional disturbance (depression and trait anxiety), and (4) drinking habits. This research used validated questionnaires commonly used in the field of clinical psychology, surveyed 430 respondents from road, bridge, tunnel, subway, and apartment construction sites in Korea, and analyzed the overall psychological tendency of construction workers with the collaboration of professional clinical psychologists using the Z-test, analysis of variance (ANOVA), and cross tabulation. The research also investigated how the mental conditions differed according to different working conditions, such as demographic information, employment status, work types, work experience, and wage conditions. The results indicated that construction workers suffer from a high level of stress and showed high inclination for problem-focused coping: impulsive, cautious, and dependent on other people. Two out of five construction workers suffer from depression and experience trait anxiety. More seriously, three out of five workers show alcohol use problems that require clinical attention. This study also revealed the particular psychological problems that occur under different working conditions. The findings can be used to promote the awareness of the importance of construction workers' mental well-being and to help in setting targets for improvement. PMID- 29989486 TI - 2000 Steps/Day Does Not Fully Protect Skeletal Muscle Health in Older Adults during Bed Rest. AB - Physical activity in an inpatient setting is often limited to brief periods of walking. For healthy adults, public health agencies recommend a minimum of 150 min/week of moderate intensity exercise. We sought to determine if meeting this activity threshold, in the absence of incidental activities of daily living, could protect skeletal muscle health during bed rest. Healthy older adults (68 +/ 2 y) were randomized to 7-days bed rest with (STEP; n=7) or without (CON; n=10) a 2000 step/day intervention. Performing 2018 +/- 4 steps/day did not prevent the loss of lean leg mass and had no beneficial effect on aerobic capacity, strength or muscle fiber volume. However, the insulin response to an oral glucose challenge was preserved. Performing a block of 2000 steps/day, in the absence of incidental activities of daily living, was insufficient to fully counter the catabolic effects of bed rest in healthy older adults. PMID- 29989487 TI - Promoting well-being through group drumming with mental health service users and their carers. AB - PURPOSE: Music has been linked with well-being across clinical and community settings. Yet, research has focused on assessment of single dimensions of well being and on the typical receiver of support services. Acknowledging the burden that a caring role encompasses and integrating recent proposals for a multifaceted definition of well-being, we explore the extent to which group drumming interventions translate into multidimensional well-being change for both mental health service users and carers. METHOD: Thirty-nine participants engaged in one of a series of community drumming programmes were assessed via semi structured interviews (n = 11) and focus groups (n = 28) at the end of each programme. Data were analysed using IPA. RESULTS AND CONCLUSION: Emotional, psychological and social dimensions of well-being emerged for both patients and carers, accounted for through six themes: (1) hedonia: positive affect and pleasant physical effects of drumming; (2) agency: initiative and sense of control; (3) accomplishment: non-specific and in relation to musical goals; (4) engagement, through focus and flow; (5) a redefinition of self, through self awareness, construction of a positive identity, self-prospection and incorporation of a musical identity; and (6) social well-being, through connectedness and positive relationships. The potential of such interventions for clinical contexts is discussed. PMID- 29989490 TI - Anthropometric analysis of 3D ear scans of Koreans and Caucasians for ear product design. AB - : The present study measured 25 dimensions of the ear including the concha and ear canal for ergonomic design of ear products and compared with existing ear measurement studies. Scanning and casting methods were employed to produce 3D ear images for 230 Koreans and 96 Caucasians and measurements of the ear dimensions were obtained by identifying 21 landmarks on individual ear scan image. The Korean ear measurements were found significantly larger (mean difference [Formula: see text] = 0.4-3.7 mm) and more varied (ratio of SDs =1.01-1.55) than those of Caucasians in most of ear dimensions. The average ear length and ear breadth of male were significantly longer ([Formula: see text] = 1.3-7.0 mm) and wider ([Formula: see text] = 0.8-3.0 mm) than those of female. Use of gender- and ethnicity-composite ear data is recommended in product design due to the much larger intra-population variations (7.5-22.2 mm) than the corresponding inter population variations. Practitioner Summary: The 3D ear measurements of Koreans and Caucasians were collected and compared with those of different ethnic populations. The distinct ear features of the populations identified in this study are applicable to ergonomic design of ear products with better fit and comfort. ABBREVIATIONS: CCW: cavum concha width; CV: coefficient of variation; EB: ear breadth; EL: ear length; SD: standard deviation; SE: sampling error; 3D: 3 dimensional. PMID- 29989491 TI - The dementia caregiver: a guide to caring for someone with Alzheimer's disease and other neurocognitive disorders. PMID- 29989488 TI - The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA induced Parkinson disease-like symptoms in the Drosophila brain. AB - : The autophagy-lysosome pathway plays a fundamental role in the clearance of aggregated proteins and protection against cellular stress and neurodegenerative conditions. Alterations in autophagy processes, including macroautophagy and chaperone-mediated autophagy (CMA), have been described in Parkinson disease (PD). CMA is a selective autophagic process that depends on LAMP2A (lysosomal associated membrane protein 2A), a mammal and bird-specific membrane glycoprotein that translocates cytosolic proteins containing a KFERQ-like peptide motif across the lysosomal membrane. Drosophila reportedly lack CMA and use endosomal microautophagy (eMI) as an alternative selective autophagic process. Here we report that neuronal expression of human LAMP2A protected Drosophila against starvation and oxidative stress, and delayed locomotor decline in aging flies without extending their lifespan. LAMP2A also prevented the progressive locomotor and oxidative defects induced by neuronal expression of PD-associated human SNCA (synuclein alpha) with alanine-to-proline mutation at position 30 (SNCAA30P). Using KFERQ-tagged fluorescent biosensors, we observed that LAMP2A expression stimulated selective autophagy in the adult brain and not in the larval fat body, but did not increase this process under starvation conditions. Noteworthy, we found that neurally expressed LAMP2A markedly upregulated levels of Drosophila Atg5, a key macroautophagy initiation protein, and that it increased the density of Atg8a/LC3-positive puncta, which reflects the formation of autophagosomes. Furthermore, LAMP2A efficiently prevented accumulation of the autophagy defect marker Ref(2)P/p62 in the adult brain under acute oxidative stress. These results indicate that LAMP2A can potentiate autophagic flux in the Drosophila brain, leading to enhanced stress resistance and neuroprotection. ABBREVIATIONS: Act5C: actin 5C; a.E.: after eclosion; Atg5: autophagy-related 5; Atg8a/LC3: autophagy related 8a; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; elav: embryonic lethal abnormal vision; eMI: endosomal microautophagy; ESCRT: endosomal sorting complexes required for transport; GABARAP: GABA typeA receptor-associated protein; Hsc70-4: heat shock protein cognate 4; HSPA8/Hsc70: heat shock protein family A (Hsp70) member 8; LAMP2: lysosomal associated membrane protein 2; MDA: malondialdehyde; PA-mCherry: photoactivable mCherry; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PD: Parkinson disease; Ref(2)P/p62: refractory to sigma P; ROS: reactive oxygen species; RpL32/rp49: ribosomal protein L32; RT-PCR: reverse transcription polymerase chain reaction; SING: startle-induced negative geotaxis; SNCA/alpha-synuclein: synuclein alpha; SQSTM1/p62: sequestosome 1; TBS: Tris-buffered saline; UAS: upstream activating sequence. PMID- 29989493 TI - The surgical care practitioner seeking consent: An appropriate delegate? AB - Surgical care practitioners (SCPs) have become recognised as integral members of the surgical team in many healthcare establishments. Seeking informed consent either as the operating practitioner or on behalf of the surgeon, as their delegate, has becoming routine for many SCPs. Informed consent is a critical step in the patient's care pathway and fundamental in fostering shared decision making and safer surgical practice. The relatively recent case of Montgomery v Lanarkshire Health Board has highlighted a need for those practitioners seeking informed consent to critically examine their practice and revisit the founding principles of the process. PMID- 29989492 TI - Nurses' knowledge about perioperative care of patients with neurological diseases. AB - This study investigated the level of nurses' knowledge regarding the perioperative care of neurological patients. An author-developed questionnaire of 20 items was used in a sample of 94 hospital nurses serving in the neurology, surgery and anesthesiology departments and the intensive care unit. The average percentage of participants with correct answers was 49.2%. The mean value of participants' score was 9.8 +/-3.4. Preexisting experience in the care of cases with multiple sclerosis and Parkinson's disease was positively related to the level of knowledge (p = 0.001 and 0.014 respectively). The ascertained level of nurses' knowledge regarding the perioperative care of neurological patients was moderate, questioning their adequacy to handle such cases. Previous experience in the care of particular diseases had significantly positive impact on knowledge, suggesting potential improvement strategies through targeted education and specialization of nurses. In conclusion, nurse's knowledge regarding perioperative care of neurological patients was insufficient, requiring appropriate improvement interventions. PMID- 29989494 TI - Belongingness: Student ODPs' learning experiences in clinical placements. AB - The aim of this qualitative study is to explore student operating department practitioners' (ODPs') experiences of belongingness in clinical placements. Belongingness has been shown to be significant for learning in clinical placements for student nurses and midwives. This study was designed to look specifically at student ODPs' experiences. Semi-structured interviews were conducted with eight student ODPs. The interviews were transcribed and coded. All student ODPs could describe clinical placement experiences where they felt they belonged and those where they felt they did not belong. Both had a significant impact on students' learning experience. Students also described their own sense of responsibility for belonging while in placement. This study provides qualitative data to help understand how belongingness can positively or negatively affect the learning experiences of student ODPs in clinical placements. PMID- 29989495 TI - How to be a great occupational physician - Lessons from Tar-Ching Aw. PMID- 29989496 TI - Commentary for Phillip Clark mentorship award. PMID- 29989498 TI - Impulsivity Kills Some Who Did Not Plan to Die by Suicide: Evidence From Chinese Rural Youths. AB - This study aimed to compare the mental disorders, psychological factors, and suicidal intent between high- and low-impulsivity Chinese rural young suicides. Rural young women and men aged 15 to 34 years who died by suicide and various risk factors were examined. The data were obtained using psychological autopsy method with instruments as Dysfunctional Impulsivity Scale, the Structured Clinical Interview for DSM-III-R, Beck Hopeless Scale, Social Support Index, Coping Response Inventory, Hamilton Depression Rating Scale, and Beck Suicide Intent Scale. Compared with low-impulsivity suicides, the high-impulsivity suicides were younger, had less mental disorders, owned less social support, scored lower on approach coping and higher on avoidance coping, and scored a lower score on the Suicide Intent Scale. Characteristics of high-impulsivity suicides differed significantly from low-impulsivity suicides in rural China. It was important to develop different prevention and intervention strategies to reduce the suicide rate in China. PMID- 29989497 TI - Providing healthy diets for young children: the experience of parents in a UK inner city. AB - OBJECTIVES: There is a consistent body of evidence to demonstrate that obesity in very early childhood tends to continue into adolescence and through to adulthood. Parental practices in relation to food can have an effect on this trajectory, however existing studies reporting on interventions for treating obesity suggest there is a need to involve populations from demographically diverse backgrounds childhood obesity research. DESIGN/METHODS: A qualitative study was carried out using semi-structured interviews with parents in a deprived inner city area. RESULTS: Although parents had good intentions towards providing a health diet for their chidren, a number of barriers emerged. Findings were reported in relation to the following themes: information and education; barriers (having a child with special needs, children's food preferences and using food to promote desirable behaviour) and techniques (household rules & routines, setting limits and parameters, modelling and food preparation). CONCLUSION: Parents and carers would benefit from targeted interventions based on improving techniques around food parenting practices, with a focus on equipping parents with the skills to overcome barriers encountered not only in early childhood, but as children progress to school age and through to adolescence. PMID- 29989499 TI - "It's Awful When We Get It Wrong": An Exploratory Qualitative Study of Vocational Rehabilitation Counselors' Perspectives on Suicide. AB - Despite the high prevalence of suicide among people with disabilities, little research has explored suicide in the context of the vocational rehabilitation (VR) system. We analyzed the responses of 27 VR counselors who responded to an open-ended qualitative prompt regarding their experiences with suicide training and competency. Key themes included a desire for more training on suicide and the experience of seeking and receiving suicide training and experience outside of VR. Responses also underscored the heavy emotional impact of working with suicidal clients, especially when one feels unprepared to do so. These results suggest that it is important to provide VR counselors with resources and training for addressing suicide in their client populations. PMID- 29989501 TI - To sleep, perchance to dream . . . of better anesthesia for our feline patients. PMID- 29989502 TI - AAFP Feline Anesthesia Guidelines. AB - AIM: The overarching purpose of the AAFP Anesthesia Guidelines (hereafter referred to as the 'Guidelines') is to make anesthesia and sedation safer for the feline patient. Scope and accessibility: It is noteworthy that these are the first exclusively feline anesthesia guidelines authored by an expert panel, making them particularly useful as an extensively referenced, practical resource for veterinary practice teams. Because much of the key content is presented in tabular or visual format, the Guidelines have a high level of accessibility and convenience that invites regular usage. While the recommendations in the Guidelines focus primarily on client-owned cats, the content is also applicable to community-sourced animals with an unknown medical history. PMID- 29989500 TI - Shelter housing for cats: Principles of design for health, welfare and rehoming. AB - : Practical relevance: Shelters and rehoming centres are a valuable tool in the population management and rehoming of cats. However, housing large numbers of a relatively asocial species in close proximity poses significant challenges. Well designed accommodation enables improved standards of husbandry, as well as a better working environment for staff. This can have a significant benefit in expediting rehoming, as cats are healthier, and more likely to display natural behaviors and have positive interactions with potential adopters. Global importance: As cat overpopulation is such a widespread issue, cat shelters are common in many countries. This review will be of interest to those involved in the design and construction of cat shelters, and to those caring for the cats within them. The principles discussed also apply to boarding, breeding, research and hospitalization facilities. Challenges: Shelter housing poses substantial challenges in terms of maintaining positive health and wellbeing while sustaining adoption at an optimum rate. Disease control and biosecurity are typically facilitated by having a relatively barren, easily cleanable environment. However, this must be weighed against the provision of opportunities for cats to perform natural behaviors such as hiding, perching and interacting if they wish. A more enriched environment has also been shown to expedite adoption. AIMS: This review, the first in a two-part series, discusses practical aspects of housing and shelter design for the health, welfare and adoption of shelter cats. Evidence base: There is a relatively small body of empirical evidence to inform shelter design recommendations. The recommendations in this article are based on a careful review of the available evidence, some of which has come from allied fields such as the care of experimental animals. Where evidence is not yet available, recommendations have been based on field experience and collective expert opinion. PMID- 29989503 TI - Shelter housing for cats: Practical aspects of design and construction, and adaptation of existing accommodation. AB - : Practical relevance: Not every cat shelter will have purpose-built accommodation but housing designed with the basic needs of cats in mind, whether purpose-built or adapted from existing housing, will improve the experience of cats passing through the facility. Challenges: Designing and building accommodation for cats in shelters should be a thoughtful process. There is a range of different housing types available. A variety of factors, such as expected length of stay, type of cat, cost and disease risk, will influence which design is most appropriate. AIMS: This review, the second in a two-part series, provides an overview of some of the essential requirements for housing shelter cats, either singly or in groups. Specific practical aspects of housing, including design, space allowances, cage furnishings and suitable construction materials, are discussed, and suggestions made for upgrading existing housing where extensive rebuilding is not feasible or realistic. Evidence base: There is a relatively small body of empirical evidence to inform shelter design recommendations. The recommendations in this article are based on a careful review of the available evidence, some of which has come from allied fields such as the care of experimental animals. Where evidence is not yet available, recommendations have been based on field experience and collective expert opinion. PMID- 29989504 TI - News & Views. PMID- 29989505 TI - The 2017 earthquakes in Mexico and pending issues with older adults. PMID- 29989506 TI - Preventing violence against women and girls in Bihar: challenges for implementation and evaluation. AB - While there are a growing number of interventions and evaluations of programmes aimed at changing gender norms and violence against women and girls, there remains a dearth of documentation outlining the challenges faced in conducting these interventions and evaluations, particularly in traditional and low literacy settings. The Do Kadam Barabari Ki Ore (Two Steps Towards Equality) programme sought to understand what works to prevent violence against women and girls in Bihar, India. This paper draws insights from process evaluation data. It describes promising features and challenges of implementation, and characteristics which weaken the potential effects of complex, community based, social sector programmes that aim to change deeply entrenched gender power hierarchies. We drew on the Medical Research Council framework for process evaluation in analysing our process evaluation data, and focus on mechanisms of impact, and factors inhibiting programme success, including contextual and implementation challenges. The paper also outlines measures that may help overcome observed challenges and areas that require modifications and/or further investigation. The programme experienced several challenges. These included contextual issues, such as the lack of leadership skills of those delivering the intervention and the gap between expected responsibilities and activities of government platforms and reality. Implementation challenges were encountered in reaching men and boys, younger women and the community at large and ensuring their regular attendance; and in maintaining the fidelity of the intervention activities. Our insights call for an evidence-supported dialogue on these challenges and how best to anticipate and address them. PMID- 29989507 TI - Letter from the Editor June 2018. PMID- 29989508 TI - Are Action Sport Cameras Accurate Enough for 3D Motion Analysis? A Comparison With a Commercial Motion Capture System. AB - The aim of this study was to assess the precision and accuracy of an Action Sport Camera (ASC) system (4 GoPro Hero3+ Black) by comparison with a commercial motion capture (MOCAP) system (4 ViconMX40). Both systems were calibrated using the MOCAP protocol and the 3D markers coordinates of a T-shaped tool were reconstructed, concurrently. The 3D precision was evaluated by the differences in the reconstructed position using a Bland-Altman test, while accuracy was assessed by a rigid bar test (Wilcoxon rank sum). To examine the accuracy of the ASC in respect to the knee flexion angles, a jump and gait task were also examined using one subject (Wilcoxon rank sum). The ASC system provided a maximum error of 2.47 mm, about 10 times higher than the MOCAP (0.21 mm). The reconstructed knee flexion angles were highly correlated (r2>0.99) and showed no significant differences between systems (<2.5 degrees ; p>0.05). As expected, the MOCAP obtained better 3D precision and accuracy. However, we show such differences have little practical effect on reconstructed 3D kinematics. PMID- 29989509 TI - Advances in pathological understanding of high-grade B cell lymphomas. AB - INTRODUCTION: The designation high-grade B-cell lymphoma (HGBL) has been incorporated into the 2016 Revision of the WHO classification of lymphoid neoplasms and includes two types: (1) HGBL, not otherwise specified; and (2) HGBL with MYC and BCL2 and/or BCL6 rearrangements, also known as double or triple hit lymphoma (DHL/THL). These categories of lymphomas represent 1-2% of non-Hodgkin lymphomas and a considerable portion of DLBCL patients who are primary refractory to R-CHOP therapy. It corresponds to the designation 'B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma' in the 2008 WHO classification. Areas covered: This paper provides an update of HGBL, focusing on their pathologic features, prognosis, and diagnostic workup. It highlights advances in our understanding of DHL/THL. Expert commentary: The diagnosis relies on FISH testing and the major controversial question is when to perform it to diagnose virtually all DHL/THL cases, but also being cost effective. Currently there is no consensus. Considering the high refractory rate of these patients to standard R-CHOP induction, the authors recommend FISH testing in all newly diagnosed large B-cell lymphoma by using our stepwise test strategy. With the progress of molecular genetics, the prognosis will be further stratified and HGBL-NOS maybe further evolve too. PMID- 29989510 TI - The Visible Heart(r) project and methodologies: novel use for studying cardiac monophasic action potentials and evaluating their underlying mechanisms. AB - INTRODUCTION: This review describes the utilization of Visible Heart(r) methodologies for electrophysiologic studies, specifically in the investigation of monophasic action potential (MAP) recordings, with the aim to facilitate new catheter/device design and development that may lead to earlier diagnosis, treatment, and ultimately a higher quality of life for patients with atrial fibrillation. Areas Covered: We describe the historically proposed mechanisms behind which electrode is responsible for the MAP recording, new catheters for recording these signals, and how Visible Heart methodologies can be utilized to develop and test new technologies for electrophysiologic investigations. Expert Opinion: When compared to traditional electrogram recordings, MAP waveforms provide clinical information vital to the understanding, diagnosis, and treatment of cardiac arrhythmias. New catheters and ablation technologies are routinely being assessed on reanimated large mammalian hearts (swine and human) in our laboratory. These abilities, combined with continued enhancements in imaging modalities and computational systems for electrical mapping, are being applied to the MAP catheter design process. Through this testing we are hopeful that the time from concept to product can be reduced, and that an array of MAP catheters can be placed in the hands of physicians, where they will improve patient outcomes. PMID- 29989511 TI - Lung Deposition of the Dry Powder Fixed Combination Beclometasone Dipropionate Plus Formoterol Fumarate Using NEXThaler(r) Device in Healthy Subjects, Asthmatic Patients, and COPD Patients. AB - BACKGROUND: This study evaluated the lung deposition and the distribution pattern in the airways of a fixed combination of beclometasone dipropionate (BDP) and formoterol fumarate (FF) (100/6 MUg) delivered as an extrafine dry powder formulation (mass median aerodynamic diameter, MMAD (MUm) BDP = 1.5; FF = 1.4) through the NEXThaler(r) device in healthy subjects, asthmatics, and patients with COPD. METHODS: Healthy subjects (n = 10), asthmatic patients (n = 9; 30%<=FEV1 < 80%), and COPD patients (n = 9; FEV1/FVC <=70%, 30%<=FEV1 < 50%) completed this open-label, single administration (inhalation of four actuations) parallel group study. After inhalation of 99mTc-radiolabeled BDP/FF combination (radiolabeled BDP + unlabeled FF), the drug deposition was assessed using a gamma scintigraphy technique. Patients' lung function was assessed. RESULTS: No significant difference in drug deposition was observed between the three study groups. Mean lung deposition, extrathoracic deposition, and amount exhaled ranged, respectively, between 54.9% and 56.2%, between 41.8% and 43.2%, and between 1.6% and 3.3% of BDP emitted dose (71.7 +/- 2.5 MUg) for the three study groups. The central to peripheral ratio (reflecting the lung distribution pattern) ranged between 1.23 and 2.02 for the three study groups, indicating a distribution of the drug throughout the airways, including periphery. The study treatment produced a forced expiratory volume in one second (FEV1) increase over time, reaching a maximum improvement generally within 1-4 hours. CONCLUSIONS: The fixed extrafine dry powder combination BDP/FF (100/6 MUg) administered through the DPI NEXThaler(r) achieved similar intrapulmonary deposition in healthy subjects, in asthmatic patients, and COPD patients (approximately 55% of emitted dose) irrespective of the underlying lung disease with a negligible amount of exhaled particles. The study showed high reliability of the device, reproducible dosing, and distribution throughout the lungs. The results supported the concept of efficient delivery of the combination to the target pulmonary regions, thanks to the extrafine formulation. FEV1 profile confirmed a relevant pharmacodynamic effect of the product. PMID- 29989512 TI - Practical Ethicist: What Is "Understandable" Language? PMID- 29989513 TI - A novel SLC1A4 homozygous mutation causing congenital microcephaly, epileptic encephalopathy and spastic tetraparesis: a video-EEG and tractography - case study. AB - Biallelic mutations in the SLC1A4 gene have been identified as a very rare cause of neurodevelopmental disorders. l-serine transport deficiency has been regarded as the causal molecular mechanism underlying the neurological phenotype of SLC1A4 mutation patients. To date this genetic condition has been reported almost exclusively in a limited number of Ashkenazi-Jewish individuals and as a result the SLC1A4 gene is not routinely included in the majority of the genetic diagnostic panels for neurological diseases. We hereby report a 7-year-old boy from a Southern Italian family, presenting with epileptic encephalopathy, congenital microcephaly, global developmental delay, severe hypotonia, spasticity predominant at the lower limbs, and thin corpus callosum. Whole exome sequencing identified a novel segregating SLC1A4 gene homozygous mutation (c.1141G > A: p.Gly381Arg) as the likely cause of the disease in our family. In order to deeply characterize the electro-clinical and neurological phenotype in our index patient, long-term systematic video-electroencephalograms (EEG) as well as repeated brain imaging studies (which included tractographic reconstructions) were performed on a regular basis during a 7 years follow-up time. In conclusion, we suggest to carefully considering SLC1A4 biallelic mutations in individuals presenting an early onset severe neurodevelopmental disorder with variable spasticity and seizures, regardless the patients' ethnic background. PMID- 29989514 TI - Myocardial Delayed Enhancement CT for the Evaluation of Heart Failure: Comparison to MRI. AB - Purpose To assess the diagnostic performance of dual-energy CT with myocardial delayed enhancement (MDE) in the detection and classification of myocardial scar in patients with heart failure, with late gadolinium enhancement (LGE) MRI as the standard of reference. Materials and Methods MDE CT and LGE MRI were performed in 44 patients with heart failure (30 men; mean patient age, 66 years +/- 14) between 2013 and 2016, and images were retrospectively analyzed. The presence and patterns of MDE on iodine-density and virtual monochromatic (VM) images were assessed by two independent readers. Contrast-to-noise ratio (CNR) and percentage signal intensity increase relative to normal myocardium were measured. Diagnostic performance and area under the receiver operating characteristic curve for MDE CT and kappa values for reader agreement were determined. Results Thirty-five of the 44 patients (80%) demonstrated a focal area of LGE, with a nonischemic pattern in 22 of the 44 patients (50%) and an ischemic pattern in 13 (30%). Iodine-density images demonstrated the highest CNR and percentage signal intensity increase on CT images (P < .05), resulting in the highest diagnostic performance in the detection of any MDE CT abnormality (92% sensitivity [195 of 213 segments] and 98% specificity [481 of 491 segments]). The areas under the receiver operating characteristic curve for iodine-density images and 40-keV VM images in the detection of MDE were 0.97 and 0.95, respectively (P < .001). Kappa values for reader agreement were 0.82 for iodine-density images and 0.72 for 40-keV VM images. Conclusion Myocardial delayed enhancement CT enables accurate detection and localization of scar in patients with heart failure when compared with late gadolinium enhancement MRI, the reference standard. PMID- 29989515 TI - Superior Hypogastric Nerve Block as Post-Uterine Artery Embolization Analgesia: A Randomized and Double-Blind Clinical Trial. AB - Purpose To evaluate the effectiveness of superior hypogastric nerve block (SHNB) in reducing narcotic use after uterine artery embolization (UAE). Materials and Methods This study was a prospective, randomized, double-blind, parallel clinical trial in patients referred to a tertiary care university teaching hospital for UAE. Forty-four participants were enrolled (mean age, 46 years; range, 32-56 years). No consenting patient was excluded. All participants were randomized 1:1 to undergo either a sham procedure or SHNB. There were 22 participants in each group. One participant was lost to follow-up regarding home survey results. Use of narcotics and antiemetics was recorded in-hospital. Pain scores were recorded at home for 10 days with use of a visual analog scale (range, 1-10). Statistical analysis was performed by using the t test and chi2 test, with P < .05 considered indicative of a statistically significant difference. The full study protocol can be found at www.clinicaltrials.gov (NCT02270255). Results Participant demographic characteristics, fibroid volume, symptoms, and perceived sensitivity to pain were similar in both groups. Immediately after embolization, the pain score was lower in the SHNB group than in the sham group (mean, 1.0 +/- 2.1 vs 2.6 +/- 2.0, respectively; P = .01). The total need for fentanyl in the postanesthesia care unit was lower in the SHNB group than in the sham group (mean, 56 MUg +/- 67 vs 124 MUg +/- 91, respectively; P = .009). The morphine-equivalent dose needed was lower in the SHNB group than in the sham group (mean, 5.1 mg +/- 5.8 vs 11.0 mg +/- 9.0, respectively; P = .014). Of the 22 participants in the SHNB group, five (23%) needed antiemetics versus 12 of 22 participants (55%) in the sham group (P = .03). No difference in hospital admissions was observed between the two groups, and no major complications occurred from the SHNB. Conclusion Use of superior hypogastric nerve block reduces the amount of pain-related narcotics and antiemetics after uterine artery embolization. (c) RSNA, 2018. PMID- 29989516 TI - Three-dimensional US as an Optimal Diagnostic Tool for Evaluating Developmental Dysplasia of the Hip. PMID- 29989517 TI - Onco-Cardiology: Value of Cardiac Imaging by Using CT and MRI after Radiation Therapy. PMID- 29989518 TI - Cardiac Dual-Energy CT with Late Iodine Enhancement as an Alternative to Late Gadolinium Enhancement MRI. PMID- 29989519 TI - Quadricuspid Aortic Valve: Cinematic Rendering. PMID- 29989520 TI - Importance of Individualized Decision Making for Lung Cancer Screening. PMID- 29989521 TI - Alain Rahmouni, MD. PMID- 29989522 TI - Importance of Long-term Low-Dose CT Follow-up after Negative Findings at Previous Lung Cancer Screening. AB - Purpose To assess the incidence of lung cancer in a cohort of patients with negative findings at previous lung cancer screening. Materials and Methods In this prospective cohort study, the authors first identified 4782 individuals who had negative screening results as part of the International Early Lung Cancer Action Program (1993-2005). Subjects were assigned a lung cancer risk score by using a validated risk model. Starting with those at highest risk, subjects were interviewed by phone and invited to undergo low-dose CT between March 2013 and October 2016. Subjects with a diagnosis of lung cancer and those who had died of lung cancer were determined. Descriptive statistics were used to summarize data. The independent samples t test and Fisher exact test were used to compare age, sex, and risk scores. Results A total of 327 study participants were contacted, and 200 subjects participated in this study. The average age was 74 years (range, 57-88 years), and the median time since previous CT was 7 years. The incidence rate of developing lung cancer during the next 6 years was estimated at 5.6%. The period prevalence of lung cancer was 20.8% (new and preexisting lung cancer, 68 of total cohort of 327). The detection rate of low-dose CT was 7% (14 of 200 subjects). Of the 14 screening-detected cancers, 12 were stage I or II. Conclusion High-risk individuals have a high incidence of lung cancer after previous negative lung cancer screening. Early-stage lung cancer can be successfully detected in older high-risk individuals. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29989524 TI - Brain Irradiation and Gadobutrol Administration in Pediatric Patients with Brain Tumors: Effect on MRI Brain Signal Intensity. AB - Purpose To determine whether treatment affects MRI signal intensity in pediatric patients with primary brain tumors independent of the administration of macrocyclic gadolinium-based contrast agents (GBCAs). Materials and Methods This retrospective, single-center study included 78 patients (mean age, 7.7 years +/- 5.4) with primary brain tumors who underwent macrocyclic GBCA-enhanced MRI from 2015 to 2018. Three groups were compared: (a) patients who had undergone radiation therapy (37 patients, 26 of whom had undergone concurrent chemotherapy), (b) patients who had undergone chemotherapy only (17 patients), and (c) patients who had received no treatment ("no-treatment group," 24 patients). The signal intensity in the globus pallidus (GP), thalamus, dentate nucleus (DN), and pons was measured on unenhanced T1-weighted images. GP-to thalamus and DN-to-pons signal intensity ratios were compared among groups with analysis of variance by using the Kruskal-Wallis test, followed by post hoc pairwise tests with Tukey adjustment, and were analyzed relative to group, total cumulative doses of GBCA, age, and sex with multivariable linear models. Results The mean number of GBCA-enhanced MRI examinations in the radiation therapy, chemotherapy-only, and no-treatment groups was 7.11, 7.29, and 4.96, respectively (P < .01 for the radiation therapy and chemotherapy groups compared with the no treatment group). The DN-to-pons ratio in the radiation therapy group was higher than that in both the no-treatment group and the chemotherapy-only group (P < .01 for both). There was no significant difference in the DN-to-pons ratios between the chemotherapy-only group and the no-treatment group (P = .99). The GP-to thalamus ratios did not differ among all three groups (P = .09). There was no dose-dependent effect of GBCA on the DN-to-pons and GP-to-thalamus ratios when adjusting for the effects of treatment (P = .21 and P = .38, respectively). Conclusion Brain irradiation contributes to a higher dentate nucleus signal intensity in pediatric patients with brain tumor independent of the administration of macrocyclic gadolinium-based contrast agents. (c) RSNA, 2018. PMID- 29989523 TI - Left Ventricular T1 Mapping during Chemotherapy-Radiation Therapy: Serial Assessment of Participants with Esophageal Cancer. AB - Purpose To assess changes in left ventricular function and tissue composition by using MRI after chemotherapy-radiation therapy in participants with esophageal cancer. Materials and Methods Between January 2013 and April 2015, this prospective study enrolled 24 participants (42% women; mean age, 63 years; range, 49-73 years) scheduled for chemotherapy-radiation therapy. 3.0-T MRI examinations were performed before, at 0.5 year, and at 1.5 years after chemotherapy-radiation therapy. Myocardial native T1, postcontrast T1, and extracellular volume were measured in basal septum (as irradiated areas) and apical lateral wall (as nonirradiated areas). Left ventricular function, prevalence of late gadolinium enhancement, and T1 and extracellular volume values were compared over the follow up period by using Friedman or Cochran Q tests, followed by Dunn test. Results In 14 participants who were followed up for 1.5 years, native T1 and extracellular volume in the septum were elevated at 0.5 year compared with baseline (1183 msec +/- 46 [standard deviation] vs 1257 msec +/- 35; 26% +/- 3 vs 32% +/- 3; adjusted P < .01 for both), but not in the lateral wall. Left ventricular stroke volume index and late gadolinium enhancement changed at 1.5 years compared with baseline (41 mL/m2 +/- 11 vs 36 mL/m2 +/- 9; P = .046; 7% [one of 14] vs 78% [11 of 14]; P < .01). Other measures of left ventricular function did not change during the follow-up period (P > .10 for all). Conclusion Native T1 and extracellular volume could detect early changes in myocardium at 0.5 year after chemotherapy-radiation therapy, whereas left ventricular stroke volume index and late gadolinium enhancement showed abnormality at 1.5 years. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29989525 TI - Nuclear Medicine Procedures in Women: Unappreciated Risks to Reproductive Organs? PMID- 29989526 TI - Bariatric Arterial Embolization: Effect of Microsphere Size on the Suppression of Fundal Ghrelin Expression and Weight Change in a Swine Model. AB - Purpose To determine whether microsphere size effects ghrelin expression and weight gain after selective bariatric arterial embolization (BAE) in swine. Materials and Methods BAE was performed in 10 swine by using smaller (100-300 MUm; n = 5) or larger (300-500 MUm; n = 5) calibrated microspheres into gastric arteries. Nine control pigs underwent a sham procedure. Weight and fasting plasma ghrelin levels were measured at baseline and weekly for 16 weeks. Ghrelin expressing cells (GECs) in the stomach were assessed by using immunohistochemical staining and analyzed by using the Wilcoxon rank-sum test. Results In pigs treated with smaller microspheres, mean weight gain at 16 weeks (106.9% +/- 15.0) was less than in control pigs (131.9% +/- 11.6) (P < .001). Mean GEC density was lower in the gastric fundus (14.8 +/- 6.3 vs 25.0 +/- 6.9, P < .001) and body (27.5 +/- 12.3 vs 37.9 +/- 11.8, P = .004) but was not significantly different in the gastric antrum (28.2 +/- 16.3 vs 24.3 +/- 11.6, P = .84) and duodenum (9.2 +/ 3.8 vs 8.7 +/- 2.9, P = .66) versus in control pigs. BAE with larger microspheres failed to suppress weight gain or GECs in any stomach part compared with results in control swine. Plasma ghrelin levels were similar between BAE pigs and control pigs, regardless of microsphere size. Week 1 endoscopic evaluation for gastric ulcers revealed none in control pigs, five ulcers in five pigs embolized by using smaller microspheres, and three ulcers in five pigs embolized by using larger microspheres. Conclusion In bariatric arterial embolization, smaller microspheres rather than larger microspheres showed greater weight gain suppression and fundal ghrelin expression with more gastric ulceration in a swine model. (c) RSNA, 2018. PMID- 29989527 TI - Developing a program to increase geropsychology competencies of Veterans Health Administration (VHA) psychologists. AB - There is an alarming supply and demand gap for geropsychology expertise within the United States. Health policy experts called for increasing geriatric mental health competencies for all mental health providers, including within Veterans Health Administration (VHA), to address this problematic gap. The VHA Geriatrics Scholar Program (GSP) Psychology Track was developed because there were no commercially available trainings in geropsychology for licensed psychologists. Developing the GSP Psychology Track was based on an evidence-based educational model for the VHA primary care workforce; and included a stepwise curriculum design, pilot implementation, and program evaluation. The educational program was pilot tested with eight VHA psychologists. Evaluation results demonstrated feasibility of implementing an innovative integrated multimodal educational program in geropsychology. Furthermore, this program was associated with reports of increased confidence in geropsychology competencies and self-reported implementation of geropsychology knowledge, indicating the potential for this educational model to improve mental health care for older Veterans. PMID- 29989528 TI - Methylene blue removal by using pectin-based hydrogels extracted from dragon fruit peel waste using gamma and microwave radiation polymerization techniques. AB - This research aims to compare the ability of smart hydrogel in removing the methylene blue prepared by using two different radiation methods. The extracted pectin from the dragon fruit peel (Hylocereus polyrhizus) was used with acrylic acid (AA) to produce a polymerized hydrogel through gamma and microwave radiation. The optimum hydrogel swelling capacity was obtained by varying the dose of radiation, pectin to AA ratio and pH used. From the array of samples, the ideal hydrogel was obtained at pH 8 with a ratio of 2:3 (pectin: AA) using 10 kGy and 400 W radiated gamma and microwave respectively. The performance of both hydrogels namely as Pc/AA(G) (gamma) and Pc/AA(Mw) (microwave) were investigated using methylene blue (MB) adsorption studies. In this study, three variables were manipulated, pH and MB concentration and hydrogel mass in order to find the optimum condition for the adsorption. Results showed that 20 mg of Pc/AA(G) performed the highest MB removal which was about 45% of 20 mg/L MB at pH 8. While 30 mg of Pc/AA(Mw) able to remove up to 35% of 20 mg/L MB at the same pH condition. To describe the adsorption mechanism, both kinetic models pseudo-first order, pseudo-second-order were employed. The results from kinetic data showed that it fitted the pseudo-first-order as compared to pseudo-second-order model equation. This study provides alternative of green, facile and affective biomaterial for dye absorbents that readily available. PMID- 29989529 TI - Transcriptomic analysis of longitudinal Burkholderia pseudomallei infecting the cystic fibrosis lung. AB - The melioidosis bacterium, Burkholderia pseudomallei, is increasingly being recognised as a pathogen in patients with cystic fibrosis (CF). We have recently catalogued genome-wide variation of paired, isogenic B. pseudomallei isolates from seven Australasian CF cases, which were collected between 4 and 55 months apart. Here, we extend this investigation by documenting the transcriptomic changes in B. pseudomallei in five cases. Following growth in an artificial CF sputum medium, four of the five paired isolates exhibited significant differential gene expression (DE) that affected between 32 and 792 genes. The greatest number of DE events was observed between the strains from patient CF9, consistent with the hypermutator status of the latter strain, which is deficient in the DNA mismatch repair protein MutS. Two patient isolates harboured duplications that concomitantly increased expression of the beta-lactamase encoding gene penA, and a 35 kb deletion in another abolished expression of 29 genes. Convergent expression profiles in the chronically-adapted isolates identified two significantly downregulated and 17 significantly upregulated loci, including the resistance-nodulation-division (RND) efflux pump BpeEF-OprC, the quorum-sensing hhqABCDE operon, and a cyanide- and pyocyanin-insensitive cytochrome bd quinol oxidase. These convergent pathoadaptations lead to increased expression of pathways that may suppress competing bacterial and fungal pathogens, and that enhance survival in oxygen-restricted environments, the latter of which may render conventional antibiotics less effective in vivo. Treating chronically adapted B. pseudomallei infections with antibiotics designed to target anaerobic infections, such as the nitroimidazole class of antibiotics, may significantly improve pathogen eradication attempts by exploiting this Achilles heel. PMID- 29989530 TI - Comparative genome and evolution analysis of the locus of enterocyte effacement from enteropathogenic Escherichia coli Deng and its transcriptional response to ciprofloxacin. AB - PURPOSE: In this study, we aimed to investigate the genomic characteristics and evolution of pathogenicity islands of an enteropathogenic Escherichia coli (EPEC) strain, and to obtain a transcriptional profile of EPEC under different concentrations of ciprofloxacin using microarray analysis. METHODOLOGY: The complete EPEC Deng genome was sequenced and compared to genomes of 12 previously sequenced E. coli strains. A 180 min time course experiment was performed in which the effect of ciprofloxacin on EPEC Deng growth was evaluated. Microarray profiling was used to study the effect of varying ciprofloxacin pressure on genome-wide transcriptional expression. Differential expression of the genes identified using microarray data was confirmed using real-time quantitative reverse transcriptase PCR (RTQ). Target gene-defective recombineering strains were created to investigate the influence of the grlA gene on ciprofloxacin susceptibility. RESULTS: Genomic comparisons revealed a close phylogenic relationship between EPEC Deng and E. coli strains O111_H_11128 and O26_H11_11368, with low genetic diversity among their type III secretion system genes and typically genetic variation in the map, tir, eae and espA genes of EPEC. It is noteworthy that 21 genes were down-regulated at all time points examined in the group exposed to 2 ug ml-1 of ciprofloxacin. A grlA-mutant derivative with increased susceptibility to ciprofloxacin was discovered. CONCLUSIONS: The present findings provide an overview of the phylogenetic characteristics of EPEC Deng and its transcriptional response to ciprofloxacin, further suggesting that GrlA may play a clinically important role in EPEC responses to ciprofloxacin. PMID- 29989532 TI - Diagnosis of Haemophilus influenzae Pneumonia by Nanopore 16S Amplicon Sequencing of Sputum. AB - We used deep sequencing of the 16S rRNA gene from sputum to identify Haemophilus influenza in a patient with community-acquired pneumonia. This method may be more effective than conventional diagnostic tests in pneumonia patients because of its speed and sensitivity. PMID- 29989531 TI - Protective Measures for Humans against Avian Influenza A(H5N8) Outbreaks in 22 European Union/European Economic Area Countries and Israel, 2016-17. AB - We sought to better understand national approaches for managing potential human health risks during outbreaks of infection with avian influenza A(H5N8) virus during 2016-17. Twenty-three countries in the Union/European Economic Area and Israel participated in this study. Risk to the general public was assessed as low in 18 countries and medium in 1 country. Of 524 exposed persons identified, 274 were passively monitored and 250 were actively monitored. Of 29 persons tested, all were negative for H5N8 virus. Vaccination and antiviral drug recommendations varied across countries. A high level of personal protection was recommended although a low risk was assessed. No transmission of this virus to humans was identified. PMID- 29989533 TI - Recertification Revisited: A Not So Eleemosynary Tale. PMID- 29989534 TI - Skin Failure. PMID- 29989536 TI - Reticulohistiocytoses: A Unique Nosologic Spectrum of Non-Langerhans Cell Histiocytosiss. PMID- 29989535 TI - Antimicrobial Susceptibility of Cutibacterium acnes Isolated from Ecuadorian Patients with Acne Vulgaris. AB - Antimicrobial resistance to Cutibacterium acnes has become a worldwide problem in the last century, but there are no previous studies on antibiotic susceptibility patterns of this bacterium in Ecuador. A total of 129 skin swabs were collected from patients with acne vulgaris (AV) attending the dermatology department of a hospital in Quito, Ecuador, from July to August 2015. The patients selected had received registered antimicrobial therapy on at least one occasion before sampling. Microbiological procedures were performed according to conventional methods. The species of isolates were identified using a mass spectrometer system (matrix-assisted laser desorption ionization time-offlight [MALDI-TOF]). Antibiotic susceptibility tests on isolated Cutibacterium were performed using an anaerobe-sensitive panel (ANO2; Thermo Fisher; TREK Diagnostic Systems Ltd., West Sussex, UK). PMID- 29989537 TI - Behcet Disease: New Developments in the Etiopathogenesis of an Old Silk Road Disease. AB - Behcet disease (BD) is a systemic inflammatory disorder that affects the skin, mucosa, eyes, joints, blood vessels, brain, and gastrointestinal tract. The etiopathogenesis of BD has not yet been fully elucidated, but disorganized immune responses against the stimuli of environmental triggering factors have been considered to play a major role in the pathogenesis of the disease in individuals with genetic susceptibility. Human leukocyte antigen (HLA)-B*51 is known to be the main factor involved in genetic susceptibility to BD. Among the environmental factors, infectious agents in particular are thought to be important. Immunological abnormalities could thus be the cornerstone in the development of BD. Along with cytokines that play a role in disease pathogenesis, numerous other cytokines have been recently identified or have been the focus of recent studies. This contribution sheds light on the etiopathogenesis and immunology of BD in relation to the current literature. PMID- 29989538 TI - Bavencio(r) (Avelumab)-A Newly Approved Anti-PD-L1 IgG1 Antibody. PMID- 29989540 TI - Picturing in Dermatology-From Wax Models to Teledermatology, Part 2. PMID- 29989539 TI - Nevus Lipomatosus Cutaneous Superficialis on the Nape -A Rare Presentation. PMID- 29989541 TI - Syringocystadenocarcinoma Papilliferum: A Rare Malignant Sweat Gland Tumor. AB - A 73-year-old Hispanic woman presented to the clinic with an erythematous, friable 3.0 cm * 2.7 cm * 0.7 cm mass located on the posterior vertex of the scalp (Figure 1). The lesion had been present since birth but had recently begun to bleed intermittently, prompting evaluation. A biopsy was obtained, revealing a tumor with irregular, complex papillomatous invaginations lined by a two-layered epithelium. Atypical and crowded columnar cells lined the luminal aspect, while cuboidal cells lined the epithelium adjacent to the stroma (Figure 2). Decapitation secretion was noted in several areas on the luminal surface. PMID- 29989542 TI - Reticular Telangiectatic Erythema: A Chronic Hematoma Subsequent to Hip Replacement as an Underlying Cause. AB - A 78-year-old woman with a history of bilateral hip replacements presented with an ill-defined erythematous plaque with foci of reticulated and indurated areas on the left thigh. Initially, a few weeks after her surgery, a small area of erythema appeared overlying the incision site. Over a 6-month period, the erythema slowly expanded before stabilizing in size (Figure 1). There was no pruritus, pain, or warmth. Orthopedic evaluation found no evidence of infection or malfunction of the hip prosthesis. A skin biopsy revealed telangiectasia of the superficial vessels. Based on the clinical and histopathologic findings, a diagnosis of reticular telangiectatic erythema (RTE) was established. An ultrasound scan revealed a greater trochanteric bursa distended by a chronic, organized hematoma measuring 12 cm at greatest dimension, secondary to a full thickness tear of the left gluteus minimus (Figure 2), establishing the underlying cause of the RTE in this patient. PMID- 29989543 TI - Bullous Fixed Drug Eruption Caused by Doxycycline. AB - A 50-year-old woman presented to our dermatology clinic with pruritic lesions on her hands that had appeared 24 hours earlier. The clinical manifestations had started 24 hours after taking 100 mg of doxycycline for acute bronchitis. She had no history of allergic disease or allergic reactions to drugs. The dermatologic examination revealed multiple erythematous, purplish annular patches with overlying bullae with hemorrhagic content on both palms (Figure 1). The patient had no fever, and the rest of the physical examination did not reveal any abnormalities. Results of laboratory tests were within normal limits. A skin biopsy was performed, showing hydrophic degenerations of the basal membrane, a superficial perivascular infiltrate consisting of lymphocytes and eosinophils, and red blood cells in the dermis (Figure 2). A pharmacovigilance investigation was conducted, and doxycycline was confirmed as the agent responsible for the bullous fixed drug eruption (FDE) in our patient. PMID- 29989544 TI - Acrodermatitis Enteropathica Presenting with Recurrent Diarrhea and Vomiting in an Infant Reluctant to Breastfeed, and a Peculiar Erythemato-Eczematous Eruption around the Oral and Anogenital Regions. AB - A 6-month-old, 4-kg, dehydrated girl, an Indian native, was admitted with recurrent episodes of diarrhea that had occurred since age 2 months. She had stopped breastfeeding. She had also had concomitant vomiting and loss of appetite. Later, the mother noticed progressively increasing erythematous eruptions around the anogenital and the oral region. The baby had been born to a short-stature mother and was delivered by lower segment cesarean section. Regular antenatal follow-up was normal. PMID- 29989545 TI - Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans. AB - Mitochondrial dysfunction and subsequent metabolic deregulation is observed in neurodegenerative diseases and aging. Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) cause most cases of familial Alzheimer's disease (AD); however, the underlying mechanism of pathogenesis remains unclear. Here, we show that mutations in the C. elegans gene encoding a PSEN homolog, sel-12 result in mitochondrial metabolic defects that promote neurodegeneration as a result of oxidative stress. In sel-12 mutants, elevated endoplasmic reticulum (ER) mitochondrial Ca2+ signaling leads to an increase in mitochondrial Ca2+ content which stimulates mitochondrial respiration resulting in an increase in mitochondrial superoxide production. By reducing ER Ca2+ release, mitochondrial Ca2+ uptake or mitochondrial superoxides in sel-12 mutants, we demonstrate rescue of the mitochondrial metabolic defects and prevent neurodegeneration. These data suggest that mutations in PSEN alter mitochondrial metabolic function via ER to mitochondrial Ca2+ signaling and provide insight for alternative targets for treating neurodegenerative diseases. PMID- 29989546 TI - BRET-based RAS biosensors that show a novel small molecule is an inhibitor of RAS effector protein-protein interactions. AB - The RAS family of proteins is amongst the most highly mutated in human cancers and has so far eluded drug therapy. Currently, much effort is being made to discover mutant RAS inhibitors and in vitro screening for RAS-binding drugs must be followed by cell-based assays. Here, we have developed a robust set of bioluminescence resonance energy transfer (BRET)-based RAS biosensors that enable monitoring of RAS-effector interaction inhibition in living cells. These include KRAS, HRAS and NRAS and a variety of different mutations that mirror those found in human cancers with the major RAS effectors such as CRAF, PI3K and RALGDS. We highlighted the utility of these RAS biosensors by showing a RAS-binding compound is a potent pan-RAS-effector interactions inhibitor in cells. The RAS biosensors represent a useful tool to investigate and characterize the potency of anti-RAS inhibitors in cells and more generally any RAS protein-protein interaction (PPI) in cells. PMID- 29989547 TI - Variations in HLA-B cell surface expression, half-life and extracellular antigen receptivity. AB - The highly polymorphic human leukocyte antigen (HLA) class I molecules present peptide antigens to CD8+ T cells, inducing immunity against infections and cancers. Quality control mediated by peptide loading complex (PLC) components is expected to ensure the cell surface expression of stable peptide-HLA class I complexes. This is exemplified by HLA-B*08:01 in primary human lymphocytes, with both expression level and half-life at the high end of the measured HLA-B expression and stability hierarchies. Conversely, low expression on lymphocytes is measured for three HLA-B allotypes that bind peptides with proline at position 2, which are disfavored by the transporter associated with antigen processing. Surprisingly, these lymphocyte-specific expression and stability differences become reversed or altered in monocytes, which display larger intracellular pools of HLA class I than lymphocytes. Together, the findings indicate that allele and cell-dependent variations in antigen acquisition pathways influence HLA-B surface expression levels, half-lives and receptivity to exogenous antigens. PMID- 29989548 TI - CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia. AB - Throughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Gamete formation ultimately requires bridge closure, yet how bridges are reactivated to close is not known. The most conserved bridge component is centralspindlin, a complex of the Rho family GTPase activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin 6. Here, we show that oocyte production by the syncytial Caenorhabditis elegans germline requires CYK-4 but not ZEN-4, which contrasts with cytokinesis, where both are essential. Longitudinal imaging after conditional inactivation revealed that CYK-4 activity is important for oocyte cellularization, but not for the cytokinesis-like events that generate syncytial compartments. CYK-4's lipid binding C1 domain and the GTPase-binding interface of its GAP domain were both required to target CYK-4 to intercellular bridges and to cellularize oocytes. These results suggest that the conserved C1-GAP region of CYK-4 constitutes a targeting module required for closure of intercellular bridges in germline syncytia. PMID- 29989549 TI - Characterization of developmental and molecular factors underlying release heterogeneity at Drosophila synapses. AB - Neurons communicate through neurotransmitter release at specialized synaptic regions known as active zones (AZs). Using biosensors to visualize single synaptic vesicle fusion events at Drosophila neuromuscular junctions, we analyzed the developmental and molecular determinants of release probability (Pr) for a defined connection with ~300 AZs. Pr was heterogeneous but represented a stable feature of each AZ. Pr remained stable during high frequency stimulation and retained heterogeneity in mutants lacking the Ca2+ sensor Synaptotagmin 1. Pr correlated with both presynaptic Ca2+ channel abundance and Ca2+ influx at individual release sites. Pr heterogeneity also correlated with glutamate receptor abundance, with high Pr connections developing receptor subtype segregation. Intravital imaging throughout development revealed that AZs acquire high Pr during a multi-day maturation period, with Pr heterogeneity largely reflecting AZ age. The rate of synapse maturation was activity-dependent, as both increases and decreases in neuronal activity modulated glutamate receptor field size and segregation. PMID- 29989552 TI - Wild boar and infectious diseases: evaluation of the current risk to human and domestic animal health in Switzerland: A review. AB - INTRODUCTION: The Eurasian wild boar is widely distributed in Europe and hunting bags reveal a massive increase in the population. Since wild boar and domestic pigs are susceptible to the same pathogens and can infect each other, free ranging wild boar populations are increasingly considered to be a threat to the pig industry. Switzerland has an outstanding veterinary health situation due to its official free-of-disease status for many diseases, and the role that wildlife could play as a source of infection for domestic animals is of particular concern. This article provides an overview of the current knowledge on wild boar health in Switzerland and discusses the health risk to domestic animals and humans currently posed by wild boar. It places the data in the context of the situation in neighbouring countries. The risk currently posed by wild boar within Switzerland is largely limited to swine brucellosis. The major threat coming from abroad originates from the expansion of African swine fever. To prevent pathogen introduction and transmission between wild boar and domestic pigs, it is essential to pursue efforts in 4 areas: disease surveillance in domestic pigs, biosecurity on pig farms, disease surveillance in wild boar, and sustainable wild boar management. PMID- 29989550 TI - Down regulation of vestibular balance stabilizing mechanisms to enable transition between motor states. AB - The neural control of transition between posture and movement encompasses the regulation of reflex-stabilizing mechanisms to enable motion. Optimal feedback theory suggests that such transitions require the disengagement of one motor control policy before the implementation of another. To test this possibility, we investigated the continuity of the vestibular control of balance during transitions between quiet standing and locomotion and between two standing postures. Healthy subjects initiated and terminated locomotion or shifted the distribution of their weight between their feet, while exposed to electrical vestibular stimuli (EVS). The relationship between EVS and ground reaction forces was quantified using time-frequency analyses. Discontinuities corresponding to null coherence periods were observed preceding the onset of movement initiation and during the step preceding locomotion termination. These results show humans interrupt the vestibular balance stabilizing mechanisms to transition between motor states, suggesting a discrete change between motor control policies, as predicted by optimal feedback theory. PMID- 29989553 TI - Optimization of analgesia for piglet castration under isoflurane anaesthesia with parenteral butorphanol, meloxicam or intratesticular lidocaine. AB - INTRODUCTION: This blinded prospective study investigated analgesic effects of intramuscular (IM) butorphanol, meloxicam or intratesticular (IT) lidocaine for castration of 7-14 days old piglets under isoflurane anaesthesia. 66 piglets were randomly injected with: meloxicam IM (0.4 mg/kg; group M), butorphanol IM (0.2 mg/kg; group B), or both (group BM) 20 minutes prior to castration, or lidocaine IT (4 mg/kg (group ML4) or 8 mg/kg (group ML8)) together with meloxicam IM (0.4 mg/kg) under anaesthesia with 1.8% end-tidal isoflurane. Heart rate, respiratory rate, mean arterial blood pressure and end-tidal carbon dioxide were recorded. Anaesthesia quality was scored and postoperative behaviour assessed. As butorphanol caused unacceptable side effects, its use was stopped. Group M showed worse anaesthesia quality than ML4 and ML8 (higher incidence of movements: 11/17, 3/18 and 4/17, respectively). There were no significant differences between groups regarding parameters measured during castration. Postoperative behaviour did not differ between groups. For castration of 7-14 days old piglets under isoflurane anaesthesia, IT lidocaine provides an additional side effect free analgesia. PMID- 29989551 TI - Long-Term Air Pollution Exposure and Amyotrophic Lateral Sclerosis in Netherlands: A Population-based Case-control Study. AB - BACKGROUND: Recently, there has been increasing evidence that exposure to air pollution is linked to neurodegenerative diseases, but little is known about the association with amyotrophic lateral sclerosis (ALS). OBJECTIVES: We investigated the association between long-term exposure to air pollution and risk of developing ALS. METHODS: A population-based case-control study was conducted in Netherlands from 1 January 2006 to 1 January 2013. Data from 917 ALS patients and 2,662 controls were analyzed. Annual mean air pollution concentrations were assessed by land use regression (LUR) models developed as part of the European Study of Cohorts for Air Pollution Effects (ESCAPE). Exposure estimates included nitrogen oxides (NO2, NOx), particulate matter (PM) with diameters of <2.5 MUm (PM2.5), <10 MUm (PM10), between 10 MUm and 2.5 MUm (PMcoarse), and PM2.5 absorbance. We performed conditional logistic regression analysis using two different multivariate models (model 1 adjusted for age, gender, education, smoking status, alcohol use, body mass index, and socioeconomic status; model 2 additionally adjusted for urbanization degree). RESULTS: Risk of ALS was significantly increased for individuals in the upper exposure quartile of PM2.5 absorbance [OR=1.67; 95% confidence interval (CI): 1.27, 2.18], NO2 (OR=1.74; 95% CI: 1.32, 2.30), and NOx concentrations (OR=1.38; 95% CI: 1.07, 1.77). These results, except for NOx, remained significant after adjusting additionally for urbanization degree. CONCLUSIONS: Based on a large population-based case-control study, we report evidence for the association between long-term exposure to traffic-related air pollution and increased susceptibility to ALS. Our findings further support the necessity for regulatory public health interventions to combat air pollution levels and provide additional insight into the potential pathophysiology of ALS. https://doi.org/10.1289/EHP1115. PMID- 29989554 TI - [Evaluation of a field-suitable injection anesthesia protocol for the castration of 8 to 14 days old piglets]. AB - INTRODUCTION: The aim of this study was to find an intramuscularly (IM) injectable anaesthetic combination for 8 to 14-days old piglets, that guarantees a calm induction and sufficient quality of anaesthesia without excitations with a maximum of two hours long lasting recovery. In preliminary dose finding trials, different combinations of -ketamine, azaperone and romifidine were compared. A constant dose of 0.2 mg/kg of butorphanol was added to each combination and all piglets received 0.4 mg/kg meloxicam. Subsequently a dosage algorithm for the main trial was developed. In case of insufficient analgesia, lidocaine 2% (0.25 ml) was injected intratesticular. If two piglets showed an insufficient anaesthetic induction phase, depth of anaesthesia or recovery, the next dosage in the algorithm was tried. With the combination of 3 mg/kg azaperone, 0.2 mg/kg romifidine, 15 mg/kg ketamine and 0.2 mg/kg butorphanol the requirement of a smooth anaesthesia induction, sufficient anaesthesia and a recovery without excitation was fulfilled but the recovery lasted more than 120 minutes. PMID- 29989556 TI - ? PMID- 29989555 TI - [Diagnostic procedure after abortions in sows after simultaneous infection with leptospira and chlamydia]. AB - INTRODUCTION: In a farrowing farm 2 first parity sows aborted on day 95 and day 110 of gestation due to an infection with leptospira and chlamydia. The double infection was diagnosed by PCR examination of abortion material. Serum samples of both sows and additional 8 sows taken three weeks after abortions were sent to two different labs for serological examination for antibodies against leptospira and chlamydia using a microagglutination test and a complement fixation test, respectively. In both labs the tests for antibodies against chlamydia were negative. Titers against diverse leptospira serovars varied between both labs and were low, so that they were not indicative for the involvement of the two pathogens regarding abortion. This case report indicates the diagnostic difficulties of direct and indirect detection methods for leptospira and chlamydia to assess the impact of these pathogens on observed reproductive failure. PMID- 29989557 TI - Bacteriotherapy for preventing recurrent upper respiratory infections in children: a real-world experience. AB - Background Recurrent upper respiratory infections (RURI) constitute a social problem for both their pharmaco-economic impact and the burden for the family. Bacteriotherapy could be an interesting preventive option. Objective The aim of this study was to evaluate the preventive effects of RURI in children. Design The study was designed as spontaneous, and was conducted in real-life seting. Globally, 80 children (40 males, mean age 5.26 (2.52) years) with RURI were enrolled. Children were treated with Streptococcus salivarius 24SMB and Streptococcus oralis 89a: nasal spray 2 puffs per nostril twice/day for a week for 3 monthly courses. Number of URI, and school and work absences were evaluated and compared with the past year. Results Bacteriotherapy significantly halved the mean number of URI episodes being 5.98 (2.30) in the past year and 2.75 (2.43) after the treatment (p<0.0001). Bacteriotherapy also induced an over 35% reduction both in the number of school days and in the number of working days missed per month from 4.50 (2.81) to 2.80 (3.42) and from 2.33 (2.36) to 1.48 (2.16) respectively (p<0.0001). Conclusions This and real-life study provides the first evidence that Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray could be effective in preventing RURI in children. PMID- 29989558 TI - The usefulness of the NBI - narrow band imaging for the larynx assessment. AB - Narrow band imaging (NBI) by enhancing the contrast between the mucosal epithelium and submucosal vessels facilitates diagnosis of precancerous and cancerous lesions, as well as hypertrophic lesions such as laryngeal papillomatosis. Narrow band imaging (NBI) is an optical technique based on the modification of white light by the use of special optical filters. Every change in the microvascular architecture of the mucosa is classified according to Ni's classification (2011). The use of NBI improves sensitivity and specificity of assessment of laryngeal lesions and allows more precise assessment of the status of surgical margins of early-stage and locally-advanced laryngeal cancers managed in endoscopic laser cordectomy. PMID- 29989559 TI - Posturography studies in patients with central and mixed vertigo Summary. AB - INTRODUCTION: The aim of the study was to compare the results of posturography in patients with central and mixed vertigo. MATERIAL AND METHODS: 50 patients (40 female and 10 male) aged between 26-47 complaining of vertigo were examined during their hospitalization in the Department of Otolaryngology, Laryngological Oncology, Audiology and Phoniatrics, Medical University of Lodz in 2014. The subjects were divided into two groups: I - 26 patients (23 female and 3 male) with central vertigo, II - 24 patients (17 female and 7 male) with mixed vertigo. The control group (III) consisted of 26 subjects, students and graduates of Lodz Universities, aged from 19 to 30, that did not complain of vertigo. The subjects were qualified to particular groups based on videonystagmography results. The examinations were conducted with "BioSway portable balance system" by Biodex. RESULTS: In tests on a stable surface, with both closed and opened eyes, subjects with mixed vertigo coped slightly better. In tests on a sponge surface, subjects with central vertigo coped better. CONCLUSIONS: Based on the conducted research, it may be concluded that the ability to keep balance in subjects with central and mixed vertigo is on average three times lower than in population not suffering from vertigo episodes. PMID- 29989560 TI - Indications and Long-term Outcomes of Open Augmentation Rhinoplasty with Autogenous L-shaped Costal Cartilage Strut Grafts - A Single Plastic Surgeon's Experience. AB - Introduction We present a single surgeon's experience of open augmentation rhinoplasty with autogenous L-shaped costal cartilage grafts, with long-term patient-reported outcome data. We highlight the salient operative steps and outline the peri-operative care required to optimise outcomes. Materials and Methods A retrospective review of eleven such augmentation rhinoplasties performed between 2008 and 2016 was undertaken. Indications included saddle nose deformity [granulomatosis with polyangiitis (n=7) and relapsing polychondritis (n=1)], post-traumatic nasal collapse (n=1) and advanced cosmetic westernisation of the nose (n=2). Long-term patient-reported outcome was assessed with a patient questionnaire. Results All patients achieved marked improvement in nasal position, shape and function. There was no cartilage exposure, warping or resorption and no recurrent deformities. One patient's dorsal graft was fractured two years later during an ophthalmological procedure and the deformity was re corrected successfully, again with the above technique. Average follow up was 5.2 years. Of the nine patients who responded to the follow-up questionnaire, 100% were satisfied with their nasal appearance. 100% of responders at follow-up reported that they have had no problems relating to their nose (n=9). Discussion L-shaped costal cartilage grafts provided a reliable, reproducible approach in augmentation rhinoplasty for disparate indications (inflammatory, traumatic and cosmetic) in the hands of a low-volume operator. With careful patient selection and planning, this technique can provide pleasing aesthetic outcomes and high patient satisfaction, with good long-term outcomes. PMID- 29989561 TI - Analysis of diagnostic-therapeutic results after the first year of life in children of hearing disturbance risk groups. AB - INTRODUCTION: It is assumed that the critical period for diagnosis of hearing disorders is the baby's first three months of life and that appropriate course and implementation of treatment and/or rehabilitation should begin before a child is six months old. However various kinds of problems may occur during auditory screening of a child may exceed this interval. AIM: The aim of this study was an evaluation of auditory screening results for children over 12 months old with congenital hearing loss. MATERIAL AND METHODS: Results from 250 children were analyzed retrospectively. The study group consisted of children between one and three months old observed between 2015-2016. For the purpose of this analysis we divided the patients into four groups: children with Down Syndrome, children with nervous system disorders , children with cleft palate or both cleft palate and lip and children with congenital CMV. To discuss performed diagnostics and treatment two groups of children were esteblished: * with implementation of appropriate course of treatment * without instituted treatment Results: 250 children were examined in Level III NICUs in the years 2015 - 2016. The highest proportion of children with the implemented course of proceedings, was in groups with children with congenital CMV (71.1%). The highest proportion of children substituted with a hearing prosthesis was observed in the group of children with Down Syndrome. The lowest proportion of children with the implemented course of proceedings, was in groups with children with cleft palate or both cleft palate and lip (41.6%). CONCLUSIONS: * Early implementation of treatment and/or rehabilitation in children with hearing disorders is crucial to prevent depression of speech and psychological development. I t is important in children with cleft palate or both cleft palate and lip even if surgical correction is discussed. * The highest proportion of children with the implemented course of proceedings, was in groups with children with congenital CMV. This children should be observed despite of right results of hearing tests. * In children with nervous system disorders 1 year period of observation is too short to exclude problems with hearing. PMID- 29989562 TI - External auditory meatus and/or conchal bowl reconstruction with postauricular island flap in patients with Basal Cell Carcinoma or Squamous Cell Carcinoma. AB - AIMS: Presenting our clinical experience with the postauricular island flap (pif) and estimation of the results following partial external auditory canal (eac) and/or auricular conchal bowl reconstructions with the pif in patients after carcinoma resections. METHODS: We have analyzed postoperative results of 19 patients after auricular conchal bowl (11), or auricular conchal bowl and eac (8) reconstructions with pif, following malignant tumor resections, between 2000 2015. The patients were followed-up and evaluated in respect of early and long term results after surgical treatment considering plastic surgeon's and patient's opinion. RESULTS: The cancers were completely excised in all patients, and there were no recurrences within at least 2 years of follow-up. The observed complications after reconstructions comprised venous congestion in five cases (26.3 %), pinning of the operated ear in four patients (21 %), prominent earlobe in three (15.8 %), and eac constriction in three cases (15.8 %). Postoperative result was very good in all cases (both in the opinion of plastic surgeon and patients), except patients with pinning of the operated ear, prominent earlobe (moderately satisfied). Conclusions 1. Combined operations involving postauricular island flap reconstructions after partial (external auditory meatus and/or auricular conchal bowl) resections allowed for complete removal of malignant tumors with no evidence of recurrence, and also preservation of proper conchal shape in the reconstructed ear. 2. Retroauricular approach in cases with cancer involvement of the external auditory meatus allowed for proper visualization and estimation of lesions extent, as well as adequate surgical access. PMID- 29989563 TI - Automated gas extraction system for the handling of radioactive waste gases from routine carbon-11 production. AB - Radiopharmaceutical production processes have the ability to produce radioactive waste in both liquid and gases forms. Control of radioactive waste gas emissions continues to be a significant issue for radiochemistry laboratories. As these facilities are often situated within urban areas emissions must be controlled to ensure the public's safety. Various methods have been employed but most of these methods use a passive gas capture bag which is often located within the hotcell where the work is being conducted. Here we report on an active system that completely removes the waste gas from the hotcell and stores the gases for decay in a safe location. This system is not only cost effective but helps to protect the operators from dose that they would otherwise receive due to working around the radioactive waste gas bag. This gas extraction system is now in continuous use and forms an integral part of the carbon-11 production process at National Research Cyclotron Facility. PMID- 29989564 TI - Interaction between interstitial carbon atoms and a 1/2 <1 1 1> self-interstitial atoms loop in an iron matrix: a combined DFT, off lattice KMC and MD study. AB - A static and kinetic study of the interaction between a 19 1/2 <1 1 1> self interstitial atoms loop and C atoms in body-centred cubic iron is presented in this work. An empirical potential matching the density functional theory calculations is used to study the static properties of the system. The usual kinetic Monte-Carlo (KMC) on-lattice restriction is not valid when the material is highly distorted, especially in the presence of a dislocation loop. Therefore, the dynamics of the system are investigated using both molecular dynamics simulations and k-ART, a self-learning/off-lattice atomic kinetic monte-carlo. The presented work is thus a full study of the C-loop and the C2-loop systems. A good agreement is observed between the statics and the kinetics (e.g. the discovery of a zone of stability of the C atom around the Fe cluster where the C can almost freely move), even though the kinetics show some unexpected behaviours of the studied systems. The pinning time of the loop induced by the C atoms is also estimated. PMID- 29989565 TI - Assembling fullerene into nanostructures over micrometer scale with atomic precision. AB - Assembling large organic molecules into predesigned structures for nanoscale devices is a long-standing challenge. Here, we present the atom-scale precise repositions of individual fullerene molecules and molecule transportation over the micrometer scale on a Si(111) surface via reproducible and reversible vertical manipulation by a scanning tunneling microscopy tip. A two-rod abacus consisting of ten fullerene molecules was used to perform arithmetic operations with double digits. This opens the door for the use of larger organic molecules displaying intrinsic characteristics as complex molecular devices with novel functions. PMID- 29989566 TI - Giant conductance anisotropy in black phosphorene tuned by external electric field. AB - Based on the non-equilibrium Green's function method, the conductance anisotropy of black phosphorene has been studied under chemical potential and/or external electric field. The direction and magnitude of the conductance anisotropy strongly depend on the chemical potential, which are in good agreement with experimental observations. Furthermore, the magnitude of conductance anisotropy can be largely modulated by external electric field, which is one order of magnitude larger than previously reported. The directions of the maximum and minimum conductance can be reversed by external electric field, which shows that the former jumps from 24 degrees to 90 degrees and the latter jumps from 90 degrees to 0 degrees respectively. The results are fundamentally interesting and technologically promising in nano-electronics. PMID- 29989567 TI - Vibration analysis of hydrogen, deuterium and tritium in metals: consequences on the isotope effect. AB - The present study focuses on the impact of the vibrational frequencies on the thermodynamic behavior of hydrides, deuterides and tritides, using high scale harmonic phonon calculations based on first-principle calculations. 115 MH y hydrides were considered, for [Formula: see text] with M among 30 metallic elements. The results were found to be in good agreement with the available experimental data and pointed out trends on the evolution of the hydride zero point energy as a function of the crystal structure and the host metal nature. Based on this information, the vibration contribution to the formation enthalpy was deduced. This contribution is responsible for the differences between the enthalpies and therefore pressures of formation of the hydride, deuteride and tritide compounds. This so-called 'isotope effect' is experimentally observed but has never been studied by large scale calculations. A straightforward method has been developed allowing to quantify the isotope effect at non zero temperature. It explains the experimentally observed relative stability of hydride, deuteride and tritide compounds. As a major achievement, a new phenomenon was highlighted, which has never been anticipated, consisting in an inversion of the isotope effect when the temperature increases. PMID- 29989568 TI - Quasi-periodic magnetization reversal of ferromagnetic nanoparticles induced by torsional oscillations in static magnetic fields. AB - In order to reverse the magnetization of small ferromagnetic particles it is necessary to overcome an energy barrier, which is mainly defined by the magnetic anisotropy. Usual reversal stimuli include the application of static or time dependent external magnetic fields, thermal activation, spin transfer torque, or combinations thereof. Here, we report on repeated, quasi-periodic magnetization reversal in single-domain particles that are exposed to a constant magnetic field perpendicular to the magnet's easy axis. The continuous sequence of reversals is induced by torsional oscillations of the magnet's anisotropy landscape, which are caused by angular oscillations of the magnet's body. In our experiments, a nickel nanowire constitutes both a mechanical resonator and a nanomagnetic sample with uniaxial anisotropy. We measure the transient flexural vibration behavior by electron beam based methods and find strong signatures of periodic magnetization switching between two magnetic states of the nanowire. Our system can be modeled as a driven damped harmonic oscillator under the influence of switchable magnetostatic interactions. PMID- 29989569 TI - A poly(hydroxyethyl methacrylate)-Ag nanoparticle porous hydrogel for simultaneous in vivo prevention of the foreign-body reaction and bacterial infection. AB - The use of implants or indwelling medical devices has greatly enhanced the quality and efficacy of health care. However, foreign-body reactions (FBRs) and infections can lead to potential failure or removal of the devices, or increased morbidity and mortality of patients. Herein, we develop a silver nanoparticle (AgNP) loaded poly(hydroxyethyl methacrylate) hydrogel with spherical, interconnected 40 MUm pores. The resulting hydrogels displayed good antibacterial properties regarding both gram positive bacteria (Staphylococcus aureus) and gram negative bacteria (Escherichia coli (E. coli)) in vitro and were highly efficient at inhibiting bacterial cell growth. Moreover, they exhibited an in vivo resistance to FBRs by reducing the immune responses, and completely prevented the formation of collagen capsules. Finally, in vivo studies of the E. coli infected mouse model demonstrated that the AgNP loaded porous hydrogels were highly efficient at resisting the bacterial FBRs and infections, while they promoted cell mitigation and infiltration. Findings from this work suggest that AgNP loaded porous hydrogels hold promise in various biomedical applications including in the new generation of implantable biomedical devices and tissue engineering scaffolds. PMID- 29989570 TI - [Perhydroxyl Radical (HO2^(*)) as Inducer of the Isoprostane Lipid Peroxidation in Mitochondria]. AB - The nonenzymatic isoprostane pathway of lipid peroxidation of polyunsaturated fatty acids results in formation of products, termed isoprostanes, which have very large positional and stereo isomerism, possess various biological activities, produce adducts with proteins, and thus contribute to pathogeneses of the age-dependent diseases. However, it was unclear what mechanism drives this type of lipid autoxidation, and why the products have very large isomerism. We propose a mechanism when perhydroxyl radicals (HO2^(*)) react with polyunsaturated fatty acids in the hydrophobic milieu of membranes. In the membrane HO2^(*) initiates a chain of reactions with formation first H2O2, which undergoes homolytic fission producing two ^(*)OH radicals, thus very rapidly abstracting three H atoms from a polyunsaturated fatty acid. As a result, the HO2^(*) molecule is converted to two molecules of water, and the molecule of a polyunsaturated fatty acid loses two double bonds, becomes highly unstable and undergoes peroxidation and random intramolecular re-arrangements causing a very large isomerism of the final products. The extremely high reactivity of ^(*)HO2 with polyunsaturated fatty acids is the cause of very subtle and slow accumulation of damages in the membrane and membrane associated proteins, even though the concentration of ^(*)HO2 relative to superoxide radical may be very low. PMID- 29989571 TI - [Oncolytic Paramyxoviruses: Mechanism of Action, Preclinical and Clinical Studies]. AB - Preclinical studies demonstrate that a broad spectrum of human and animal malignant cells can be killed by oncolytic paramyxoviruses, which includes cells of ecto-, endo- and mesodermal origin. In clinical trials, significant reduction or even complete elimination of primary tumors and established metastases has been reported. Different routes of virus administration (intratumoral, intravenous, intradermal, intraperito-neal, or intrapleural) and single- vs. multiple-dose administration schemes have been explored. The reported side effects were grades 1 and 2, with the most common among them being mild fever. There are certain advantages in using paramyxoviruses as oncolytic agents compared to members of other virus families exist. Thanks to cytoplasmic replication, paramyxoviruses do not integrate the host genome or engage in recombination, which makes them safer and more attractive candidates for widely used therapeutic oncolysis than ret-roviruses or some DNA viruses. The list of oncolytic Paramyxoviridae members includes the attenuated measles virus, mumps virus, low pathogenic Newcastle disease, and Sendai viruses. Metastatic cancer cells frequently overexpress certain surface molecules that can serve as receptors for oncolytic paramyxoviruses. This promotes specific viral attachment to these malignant cells. Paramyxoviruses are capable of inducing efficient syncytium-mediated lysis of cancer cells and elicit strong immune stimulation, which dramatically enforces anticancer immune surveillance. In general, preclinical studies and phases I-III of clinical trials yield very encouraging results and warrant continued research of oncolytic paramyxoviruses as a particularly valuable addition to the existing panel of cancer-fighting approaches. PMID- 29989572 TI - [Bispecific Antibodies: Formats and Areas of Application]. AB - Bispecific antibodies capable of simultaneously binding two targets have been studied for many years with a view to their implementation in clinical practice. Unique biological and pharmacological properties, as well as the diversity of their formats, make it possible to consider bispecific antibodies as promising agents for use in various procedures: from visualization of intracellular processes to targeted anticancer therapy. Bispecific antibodies help to determine more precisely the therapeutic target, thereby increasing the efficiency of therapy and reducing the probability of side effects. The present review describes the main formats of bispecific antibodies, methods for their generation, and possibilities for practical application. PMID- 29989573 TI - [Proteoforms: Methods of Analysis and Clinical Prospects]. AB - A critical analysis of proteomes provides a basis for understanding the operation of complex biochemical systems. A personalized approach to therapy takes into account biological uniqueness of each patient at genome, transcriptome, and proteome levels, and is a priority area in molecular medicine. The identification of proteoforms, which have dramatic impact on the phenotype of a disease, is a fundamental task of personal molecular profiling. Considerable progress of proteomic approaches presented new avenues for accurate, specific, and high performance protein analysis. Thus, the identification of new efficient bio markers can be expected based on studies of aberrant proteoforms associated with various diseases. PMID- 29989574 TI - [Laminins in Metastatic Cancer]. AB - Laminins are a family of extracellular heterotrimeric glycoproteins that are the main structural component of basement membranes (BMs), perform a barrier function, and are important for adhesion, differentiation, migration, and resistance to apoptosis of various cells, including cancer cells. The review summarizes the current knowledge of how laminins produced by cancer and normal cells influence the key stages of carcinogenesis. Laminin 332 (LN-332) and LN-111 enhance proliferation of certain cancer cells and increase the tumour growth. LN 111 increases resistance to apoptosis, induces differentiation, and inhibits the epithelial-mesenchymal transition (EMT) of cancer cells. LN-332 is associated with higher adhesion and higher migration potential of cancer cells. LN-411 and LN-421 significantly increase motility of cancer cells. LN-332 and LN-511 facilitate cell-cell adhesion and affect the efficacy of cell-cell interactions. The laminin chains alpha4 and alpha5 are important for the development and function of blood and lymphatic vessels. The expression ratio of the alpha4 and alpha5 laminin chains defines the BM permeability to leukocytes and, presumably, cancer cells in blood and lymphatic vessels. Interactions between LN-511 and alpha2-containing laminins enhance self-renewal and survival of circulating cancer stem cells. Moreover, laminins are involved in the formation of premetastatic niches and new colonies. Endogenous expression of the alpha4 laminin chain stimulates proliferation of individualised circulating cancer cells in vitro and in vivo and facilitates micrometastasis. PMID- 29989575 TI - [Molecular Mechanisms of Drug Tolerance in Mycobacterium tuberculosis]. AB - A dramatic increase in drug-resistant forms of tuberculosis (TB) stimulates a search for novel anti-TB drugs and studies of the drug resistance acquisition. One of the possible causes is a phenotypic resistance or drug tolerance which is not associated with genomic changes. The majority of anti-TB drugs eliminate 99% of MTB cells in 3-5 days, but the remaining subpopulation becomes unsusceptible to treatment and capable for long-term persistence with ability to resuscitate once the external adverse factor is removed. This evasion of the stress factor facilitates selection of resistant forms, thus warranting long-term treatment with at least four antibacterial drugs in TB. The review considers the main mechanisms of bacterial tolerance that are due to alterations in the cell wall, activation of efflux pumps, induction of transcriptional regulons, changes in metabolic flows, and modification of molecular machineries. PMID- 29989576 TI - [Transcription Factor SAP30 Is Involved in the Activation of NETO2 Gene Expression in Clear Cell Renal Cell Carcinoma]. AB - Clear cell renal cell carcinoma (ccRCC) is a common oncourological disease with a high mortality level. The incidence of this type of cancer is constantly increasing, while molecular mechanisms involved in the disease initiation and progression remain far from being fully understood. A problem of the search for novel markers is crucial for improvement of diagnosis and therapy of ccRCC. We have previously found that the disease is characterized by increased expression of the NETO2 gene. In the present study, we showed that isoform 1 (NM_018092.4) makes the main contribution to the upregulation of this gene. Using original CrossHub software, "The Cancer Genome Atlas" (TCGA) project data were analyzed to identify possible mechanisms of NETO2 gene activation in ccRCC. The absence of significant contribution of methylation to the increase of mRNA level of the gene was observed. At the same time, a number of genes encoding transcription factors, which could potentially regulate the expression of NETO2 in ccRCC, were identified. Three such genes (MYCBP, JMY, and SAP30) were selected for the further analysis of their mRNA levels in a set of ccRCC samples with quantitative PCR. We showed a significant increase in mRNA level of one of the examined genes, SAP30, and revealed its positive correlation with NETO2 gene expression. Thus, upregulation of NETO2 gene is first stipulated by the isoform 1 (NM_018092.4), and the probable mechanism of its activation is associated with the increased expression of SAP30 transcription factor. PMID- 29989577 TI - [Mutation Frequencies in HIV-1 Genome in Regions Containing Efficient RNAi Targets As Calculated from Ultra-Deep Sequencing Data]. AB - HIV-1 is one of the most variable viruses. The development of gene therapy technology using RNAi for AIDS/HIV-1 treatment is a potential alternative for traditional anti-retroviral therapy. Anti-HIV-1 siRNA should aim to exploit the most conserved viral targets. Using the deep sequencing of potential RNAi targets in 100-nt HIV-1 genome fragments from the clinical HIV-1 subtype A isolates in Russia, we found that the frequencies of all possible transversions and transitions in certain RNAi targets are 3-38 times lower than in adjacent sequences. Therefore, these targets are conserved. We propose the development of these RNAi targets for AIDS/HIV-1 treatment. Deep sequencing also enables the detection of the characteristic mutational bias of RT during the replication of viral RNA. PMID- 29989578 TI - [Inactivation of Receptor Tyrosine Kinases Overcomes Resistance to Targeted B-RAF Inhibitors in Melanoma Cell Lines]. AB - The discovery of B-RAF activating mutations in malignant melanoma cells has led to the development of a number of targeted drugs, which block exclusively the mutant B-RAF protein. Tumor cells often acquire resistance to B-RAF inhibitors via activation of alternative signaling pathways. One of the resistance mechanisms is activation of PDGF, VEGF, c-KIT, and certain other tyrosine kinases. The possibility of overcoming the resistance to the B-RAF inhibitor Vemurafenib by inactivating receptor tyrosine kinases (RTKs) was studied in metastatic melanoma cell lines differing in B-RAF mutations and RTK activity. It was found that RTK inactivation may help to overcome resistance to B-RAF inhibitors via inhibition of tyrosine kinase phosphorylation and a subsequent blocking of the PI3K-AKT-mTOR and MEK-ERK1/2 downstream signaling pathways. The changes eventually mitigated the cell growth and enhanced the Vemurafenib dependent cell cycle arrest. PMID- 29989579 TI - [Inhibition of Histone Deacetylases Reverses Epithelial-Mesenchymal Transition in Triple-Negative Breast Cancer Cells through a Slug Mediated Mechanism]. AB - High metastatic ability and poor clinical outcome are the most known clinical features of the triple-negative breast tumors. Given that the tumor cells undergoing epithelial-mesenchymal transition (EMT) often gain malignant and invasive features, we have investigated the possibility of EMT reversal in triple negative breast cancer cells by targeting the epigenetic-modifying enzymatic complexes named histone deacetylases (HDACs) and examined the possible mechanism underlying the HDACs-based inversion in model MDA-MB-231 cells. Cells were treated with a maximal tolerable 200 nM concentrations of classical HDACs inhibitor Trichostatin A (TSA) for 48 h and afterwards the invasiveness and immigration of the cells were evaluated in TransWell Invasion Scratch Wound Healing assays. Then, in treated and control cells, quantitative real time-PCR reacions were performed for assessing the gene expression of EMT biomarkers E cadherin, Vimentin and transcriptional factor Slug. After TSA treatment, the invasion and migration properties MDA-MB-231 cells significantly decreased, gene expression of E-cadherin was significantly up-regulated, while the levels of Slug and Vimentin encoding mRNAs were suppressed. We conclude that inhibition of HDACs in triple-negative breast cancer cells may lead to inversion of EMT and the decrease of invasiveness by down-regulating the gene expression of Slug. Since EMT is known as a pre-metastatic process, triple-negative breast tumors, the EMT reversal effects of HDACs inhibition may reduce tumor cell metastasis. PMID- 29989580 TI - [Suppression of NR0B2 gene in Clear Cell Renal Cell Carcinoma Is Associated with Hypermethylation of Its Promoter]. AB - Clear cell renal cell carcinoma (ccRCC) is a common urologic malignancy. Understanding of the transcriptional regulation of oncogenes and tumor suppressor genes involved is critical for the development of the treatments for renal tumors. Using ccRCC subdivision of the TCGA dataset, we identified NR0B2 encoding orphan nuclear receptor as a tumor suppressor candidate in renal tissue. In independent cohort of primary renal tumors, quantitative PCR experiments confirmed significant suppression of NR0B2 mRNA in 86% of ccRCC samples studied. In 80% of these cases, we detected the hypermethylation of the NR0B2 pro-moter region. These results suggest that NR0B2 is a tumor suppressor gene in ccRCC, and that the hypermethylation of promoter region is the main mechanism of its downregulation. PMID- 29989581 TI - [AICAR-Dependent Activation of AMPK Kinase Is Not Accompanied by G1/S Block in Mouse Embryonic Stem Cells]. AB - Embryonic stem cells (ESCs) have the capacity for self-renewal and pluripotency. Due to high proliferative activity, ESCs use a specific pathway of the formation of ATP molecules, which can lead to the development of the adaptive metabolic response under the conditions of energy deficiency (which is different from the response of differentiated cells). It is known that metabolic signals are integrated with the cell cycle progression; however, the signaling pathways that connect the availability of nutrients with the regulation of cell cycle in ESCs are insufficiently studied. We have studied the effect of the AICAR agent, which imitates an increase in AMP level and induces the activation of the metabolic sensor AMPK, on proliferation, cell cycle distribution, and pluripotency of mouse ESCs (mESCs). It has been demonstrated that cells treated with AICAR do not stop at the control G1/S point of the cell cycle, since they do not accumulate P21/WAF1 (G1/S checkpoint regulator), despite P53 activation. On the contrary, AICAR increases the rate of mESC proliferation, which correlates with increased expression of pluripotency marker genes (OCT3/4, NANOG, SOX2, KLF4, ESRRB, PRDM14). In addition, an increase in the transcription of the HIFlalpha gene (a key regulator of the cell proliferation and viability, as well as glucose metabolism under stress) was detected. An increase in the expression of glycolytic enzyme genes (LDHA, ALDOA, PCK2, GLUT4) under the effect of AICAR indicates a change in mESC metabolism towards increased glycolysis. Thus, AICAR dependent AMPK activation as one of possible mechanisms of the mESC adaptive response to the emergence of energetic imbalance is not accompanied by a cell cycle arrest at the G1/S checkpoint, but involves the processes of increasing glycolytic activity. PMID- 29989582 TI - [Insertion of Multiple Artificial Introns of Universal Design into cDNA during Minigene Construction Assures Correct Transgene Splicing]. AB - The presence of introns is often required for efficient transgene expression. The use of full-length genes for transgenesis is associated with technical difficulties due to the large size of the genetic construct. To solve this problem, we recently suggested a universal design of small artificial introns that ensures efficient splicing. However, the insertion of more than one intron into cDNA might result in the aberrant splicing of the minigene with exon skipping. Here, we showed that the insertion of two artificial introns of universal design into cDNA resulted in a splicing pattern that corresponds to the excision of each intron with an exon between them remaining in the transcript. No transcript formation with exon skipping was detected. Therefore, the developed design of small artificial introns assures splicing solely between the donor and the acceptor splice sites of each single intron and results in the generation of a correct transcript from minigene pre-mRNA. These findings enable the construction of minigenes for transgenesis with more than one artificial intron, with no additional cis-elements required to prevent aberrant splicing. PMID- 29989584 TI - [Effect of Sodium Selenite on Gene Expression of SELF, SELW, and TGR Selenoproteins in Adenocarcinoma Cells of the Human Prostate]. AB - Selenium is an essential trace element, the deficiency of which leads to the development of several serious diseases, including male infertility, prostate cancer, etc. It has been shown that oxidative stress contributes to the progression of prostate cancer, and antioxidants such as selenium and vitamin E can significantly reduce the risk of this disease. Sodium selenite, one of the selenium compounds that induce the formation of reactive oxygen species, is considered as a potential anticancer agent. The SS concentrations that lead to a decrease in the viability of human prostate adenocarcinoma cells (line Du-145) have been selected, and the effect of sodium selenite on the expression of mRNA of the SELV, SELW, and TGR selenocysteine proteins in these cells has been analyzed. PMID- 29989583 TI - [The Novel Short Isoform of Securin Stimulates the Expression of Cyclin D3 and Angiogenesis Factors VEGFA and FGF2, but Does Not Affect the Expression of MYC Transcription Factor]. AB - Pituitary tumor-transforming gene-1 (PTTG1) encodes securin, a multifunctional protein involved in development of various types of cancer. Securin participates in the regulation of sister chromatids separation and the expression of multiple genes involved in the control of the cell cycle, metabolism, and angiogenesis. In several human cell lines, we have found a novel short isoform of securin mRNA, which does not contain exons 3 and 4. After the translation of this new mRNA, a shortened protein is produced that, like the full-size form, is able to activate the transcription of cyclin D3 gene (CCND3), which controls the G1/S transition and angiogenesis factors VEGFA (vascular endothelial growth factor), and FGF2 (fibroblast growth factor 2) in HEK293 cells. However, unlike the full-size protein, the short isoform of PTTG1 does not affect the MYC gene expression because it lacks the DNA-binding domain, which is needed for its interactions with the MYC promoter. Furthermore, the short form of securin does not influence the expression of MYC transcriptional targets, such as TP53 and IL-8. Thus, we found a novel isoform of securin which is able to activate a more restricted repertoire of genes compared to the full-size protein. PMID- 29989585 TI - [A DNA Construct That Encodes the Rabies Virus Consensus Glycoprotein with a Proteasome Degradation Signal Induces Antibody Production with IgG2A Subtype Predominance]. AB - The possibility of enhancing the immunogenicity of the rabies virus glycoprotein antigen encoded by a DNA vaccine has been investigated. Ubiquitin-like protein FAT10 has been attached to the N-terminus of the glycoprotein to target it to the proteasome and stimulate its presentation by MHC class I. Two forms of the protein, chimeric and original, have been detected in cells transfected with the DNA construct encoding the chimeric protein. The presence of the glycoprotein on the cell surface has been detected by immunostaining of transfected cells. The production of IgG and IgG2a antibodies has been more efficiently induced in mice immunized with the plasmid that encodes the chimeric protein than in those immunized with the plas-mid that encodes unmodified glycoprotein. Moreover, the level of IgG2a antibodies exceeded the level of IgG1 antibodies, which indicates a preferential increase in the Th1 component of the immune response. The proposed DNA construct that encodes a modified glycoprotein with a proteasome degradation signal maybe a promising DNA vaccine immunogen for post-exposure prophylaxis of rabies. PMID- 29989586 TI - [Substrate Properties of New Fluorescently Labeled Deoxycytidine Triphosphates in Enzymatic Synthesis of DNA with Polymerases of Families A and B]. AB - The efficiency of the incorporation of fluorescently labeled derivatives of 2' deoxycytidine in DNA synthesized de novo has been studied using PCR with Taq and Tth polymerases of family A and Vent (exo-) and Deep Vent (exo-) polymerases of family B. Four derivatives of 5'-triphosphate-2'-deoxycytidine (dCTP) have different chemical structures of the indodicarbocyanine dye and Cy5 analogue attached to position 5 of cytosine. The kinetics of the accumulation of the PCR products and the intensity of the fluorescent signals in the hybridization analysis with immobilized DNA probes depend on the modification of the fluorescently labeled dCTP counterpart, its concentration, and the type of DNA polymerase. All labeled triphosphates showed some inhibitory effects on PCR. The best balance between the efficiency of incorporating labeled cytidine derivatives and the negative effect on the PCR kinetics has been shown in the case of Hot Taq polymerase in combination with the Cy5-dCTP analogue, which contains containing electrically neutral chro-mophore, the axis of which is a continuation of the linker between the chromophore and the pyrimidine base. PMID- 29989587 TI - [Efficiency of the miRNA- mRNA Interaction Prediction Programs]. AB - miRNAs play a key role in regulation of gene expression. Nowadays it is known more than 2500 human miRNAs, while a majority of miRNA-mRNA interactions remains unidentified. The recent development of a high-throughput CLASH (crosslinking, ligation and sequencing of hybrids) technique for discerning miRNA-mRNA interactions allowed an experimental analysis of the human miRNA-mRNA interactome. Therefore, it allowed us, for the first time, make an experimental analysis of the human miRNA-mRNA interactome as a whole and an evaluation of the quality of most commonly used miRNA prediction tools (TargetScan, PicTar, PITA, RNA22 and miRanda). To estimate efficiency of the miRNA-mRNA prediction tools, we used next parameters: sensitivity, positive predicted value, predictions in different mRNA regions (3' UTR, CDS, 5' UTR), predictions for different types of interactions (5 classes), predictions of "canonical" and "nocanonical" interactions, similarity with the random generated data. The analysis revealed low efficiency of all prediction programs in comparison with the CLASH data in terms of the all examined parameters. PMID- 29989588 TI - [Determination of Amino Acid Residues Responsible for Specific Interaction of Protein Kinases with Small Molecule Inhibitors]. AB - Identifying amino acid positions that determine the specific interaction of proteins with small molecule ligands, is required for search of pharmaceutical targets, drug design, and solution of other biotechnology problems. We studied applicability of an original method SPrOS (specificity projection on sequence) developed to recognize functionally significant positions in amino acid sequences. The method allows residues specific to functional subgroups to be determined within the protein family based on their local surroundings in amino acid sequences. The efficiency of the method has been estimated on the protein kinase family. The residues associated with the protein specificity to inhibitors have been predicted. The results have been verified using 3D structures of protein-ligand complexes. Three small molecule inhibitors have been tested. Residues predicted with SPrOS either in contacted the inhibitor or influenced the conformation of the ligand-binding area. Excluding close homologues from the studied set makes it possible to decrease the number of difficult to interpret positions. The expediency of this procedure was determined by the relationship between an inhibitory spectrum and phylogenic partition. Thus, the method efficiency has been confirmed by matching the prediction results with the protein 3D structures. PMID- 29989589 TI - FRY, a global database of fire patch functional traits derived from space-borne burned area products. AB - Vegetation fires are intrinsic ecosystem disturbances of the Earth system. Global burned area products have been delivered from several space-borne instruments, and have recently provided pixel-level information underpinning fire spread processes. Here we present FRY, a global database of fire patches with morphology based functional traits reconstructed from pixel-based burned areas derived from the MODIS and MERIS imagery using a flood-fill algorithm. Each fire patch is characterized by the geo-location of its center, area, perimeter, the features of the ellipse fitted over its pixel's spatial distribution, and different indices of patch complexity. We obtained a consistent spatial distribution of global fire patch functional traits between the MCD64A1 Collection 6 and the MERIS fire_cci v4.1 datasets during their overlap period (2005-2011), confirming the robustness of the applied algorithm and the consistency between both products. This database is relevant to a broad spectrum of fire-related applications such as local to global functional pyrodiversity, fire emissions quantification, and the benchmarking of fire modules embedded in dynamic global vegetation models. PMID- 29989590 TI - A functional trait database for Mediterranean Basin plants. AB - Functional trait databases are emerging as crucial tools for a wide range of ecological studies across the world. Here, we provide a database of functional traits for vascular plant species of the Mediterranean Basin. The database includes 25,764 individual records of 44 traits from 2,457 plant taxa distributed in 119 taxonomic families. This database (BROT 2.0) is an updated and enlarged version of a previous database (BROT 1.0; 8,263 records, 14 traits, 952 taxa). Trait data were obtained from a comprehensive literature review, plus some field and experimental observations. All records are fully referenced and, in many cases, include geographic coordinates. The database is structured to include different levels of accuracy of trait information for each entry. BROT 2.0 should facilitate testing hypotheses on plant functional ecology within the Mediterranean Basin, and comparing this region with other ecosystems worldwide. The BROT 2.0 database and its trait definitions can be used as a template for creating similar trait databases in other regions of the world. PMID- 29989591 TI - Full body mobile brain-body imaging data during unconstrained locomotion on stairs, ramps, and level ground. AB - Human locomotion is a complex process that requires the integration of central and peripheral nervous signalling. Understanding the brain's involvement in locomotion is challenging and is traditionally investigated during locomotor imagination or observation. However, stationary imaging methods lack the ability to infer information about the peripheral and central signalling during actual task execution. In this report, we present a dataset containing simultaneously recorded electroencephalography (EEG), lower-limb electromyography (EMG), and full body motion capture recorded from ten able-bodied individuals. The subjects completed an average of twenty trials on an experimental gait course containing level-ground, ramps, and stairs. We recorded 60-channel EEG from the scalp and 4 channel EOG from the face and temples. Surface EMG was recorded from six muscle sites bilaterally on the thigh and shank. The motion capture system consisted of seventeen wireless IMUs, allowing for unconstrained ambulation in the experimental space. In this report, we present the rationale for collecting these data, a detailed explanation of the experimental setup, and a brief validation of the data quality. PMID- 29989592 TI - A global dataset of river network geometry. AB - The plan-form structure of the world's river basins contains extensive information regarding tectonic, paleo-geographic and paleo-climate conditions, but interpretation of this structure is complicated by the need to disentangle these processes from the autogenic behavior of fluvial processes. One method of interpreting this structure is by integrating channel length and drainage area as characterized by the scaling relationship between slope and area, resulting in a characteristic length parameter, referred to in recent studies as chi. In this paper, we apply this methodology at a continental scale by calculating chi for the world's river networks. Mapping of chi', a modified version of chi including the influence of precipitation distribution on river discharge and correction of base level for chi' in closed basins, illustrates the geometric structure of global river networks, thus highlighting where tectonics or changing climate have resulted in an apparent disequilibrium of the river channel geometry. Our global chi maps quantify a dynamic view of Earth's river networks and help to identify past and ongoing evolution of Earth's landscape. PMID- 29989593 TI - The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products. AB - Quantitative data on product chemical composition is a necessary parameter for characterizing near-field exposure. This data set comprises reported and predicted information on more than 75,000 chemicals and more than 15,000 consumer products. The data's primary intended use is for exposure, risk, and safety assessments. The data set includes specific products with quantitative or qualitative ingredient information, which has been publicly disclosed through material safety data sheets (MSDS) and ingredient lists. A single product category from a refined and harmonized set of categories has been assigned to each product. The data set also contains information on the functional role of chemicals in products, which can inform predictions of the concentrations in which they occur. These data will be useful to exposure and risk assessors evaluating chemical and product safety. PMID- 29989594 TI - A decade after the metabolomics standards initiative it's time for a revision. PMID- 29989595 TI - Transcriptome sequencing and molecular markers discovery in the gonads of Portunus sanguinolentus. AB - Crab culture has gained prominence in the last decade due to the large global market demand for live crabs and crab products. Portunus sanguinolentus is one of the economically important crab species in the Indo-Pacific region, with distinct differences in growth and size between male and female crabs, thus, leading to huge difference in their market values. The culture of P. sanguinolentus is still in its infancy, with crab supplies heavily dependent on wild catch. In order to unravel the molecular differences between male and female crabs, we generated a comprehensive transcriptomic dataset for P. sanguinolentus by sequencing the gonads of both sexes using the Illumina Hiseq 2500 system. Transcriptomes were assembled using Trinity de novo assembly followed by annotation. This transcriptomic data set for P. sanguinolentus would serve as an important reference data for genomic and genetic studies in this crab and related species. PMID- 29989596 TI - ? PMID- 29989597 TI - [2017 ESC guidelines on valvular heart disease: what's new?] PMID- 29989598 TI - [Ten questions about constrictive pericarditis]. AB - Constrictive pericarditis is one of the most feared complications of patients with pericarditis, especially if recurrent. The common perception is that the higher the number of recurrences, the higher the risk of constriction. However, the risk of constriction is related to the etiology and not to the number of recurrences. Constriction has never been reported as a complication of idiopathic recurrent pericarditis, while the risk is low (<1%) after a first attack of idiopathic or viral pericarditis, intermediate for immune-mediated etiologies (2 5%, e.g. systemic inflammatory diseases, post-pericardiotomy syndromes) and cancer, and high especially for bacterial etiologies (20.30%, e.g. tuberculosis, purulent pericarditis). Constriction may be reversible in the setting of pericarditis and about 7-10% of patients with acute pericarditis may have transient constriction during the acute phase of inflammation, due to increased pericardial stiffness. Empiric anti-inflammatory therapy may prevent pericardiectomy in one half of cases.The clinical diagnosis is not easy but feasible with prompt recognition of the clinical symptoms and signs that may mimic heart failure and chronic hepatic disease (e.g. jugular vein distention, peripheral edema, ascites), the echocardiographic signs (e.g. septal bounce, respiratory variations of transmitral and tricuspid flows, annulus reversus, inferior vena cava plethora), and other imaging features (e.g. pericardial thickening in about 80% of cases, pericardial calcifications).In this paper, we will try to give an answer to common clinical doubts for assessing the risk of constriction, making the diagnosis, and addressing the therapy of these patients also underlying the possible outcomes. PMID- 29989600 TI - [Surgical indications for thoracic aortic disease: beyond the "magic numbers" of aortic diameter]. AB - Thoracic aortic aneurysm (TAA) is a silent disease that can become rapidly lethal once dissection or rupture occurs. To prevent aortic catastrophe, prophylactic aortic replacement is the mainstay of therapy in patients with TAA. Currently, surgical indications for TAA repair are predominantly based on the aortic size. However, the effectiveness of the diameter criterion to predict aortic rupture and dissection has been largely questioned over the last years. Growing evidence suggests that aortic size alone may not be sufficient to predict the risk in all TAAs. In this setting, other predictors such as genetic, environmental, biochemical and hemodynamic factors have been proposed. The aim of this paper is to review and discuss on current evidence, controversies and future directions for the treatment of patients with TAA. PMID- 29989599 TI - [Dual antiplatelet therapy in elderly patients with acute coronary syndrome: does age make the difference?] AB - The appropriate use of dual antiplatelet therapy (DAPT) in elderly patients with acute coronary syndrome (ACS) remains a highly debated subject. In fact, achieving the correct balance between the reduction of ischemic risk and the increase in hemorrhagic events is more difficult in this population than in younger subjects, especially in the case of very potent drug therapy. As a consequence of this, despite guideline recommendations, antiplatelet therapy is currently underutilized in elderly patients with ACS.In current clinical practice, the antiplatelet drugs that can be used in combination with aspirin are clopidogrel, prasugrel and ticagrelor. The efficacy of these molecules is supported by randomized clinical trials, which gave variable results in terms of the extent of reduction in ischemic events and increase in hemorrhagic complications. The purpose of this article is to identify, based on the results of a consensus meeting, common elements in the use of DAPT in the elderly and to identify areas where further scientific evidence is required to better define the role of the individual antiplatelet agents. PMID- 29989601 TI - [Ambulatory dynamic Holter monitoring: a practical guide to appropriate use and reporting in clinical cardiology]. AB - Ambulatory electrocardiographic monitoring is still a useful tool in the hands of the clinical cardiologist, for both the diagnosis of many pathologies and the management of long-term therapy. The evolution of the instrumentation, which has become sophisticated but at the same time more manageable and easy to use, has made it possible to evaluate many parameters and data. The aim of this review is to provide a general overview of this old, but not obsolete tool, to describe the main indications for its use in the light of new scientific evidence and to offer a practical guide for its appropriate use and reporting. PMID- 29989602 TI - [Wearable cardioverter-defibrillators: clinical experience and future perspectives]. AB - Sudden cardiac death (SCD) can affect patients with ischemic or non-ischemic left ventricular dysfunction. Automatic implantable cardioverter-defibrillator (ICD) implantation is the most effective option for the treatment of malignant ventricular tachyarrhythmias; however, the procedure is burdened with known significant risks, even in the long term.In patients at high risk of SCD, either real or perceived, without a definite indication to ICD implantation, wearable cardioverter-defibrillators have been shown to offer effective temporary protection in different clinical settings, for patients with recent high-risk myocardial infarction with left ventricular dysfunction, even after myocardial revascularization procedures, heart failure with reduced ejection fraction, newly diagnosed dilated cardiomyopathy, ICD post-explant phase for infection, and bridge to cardiac transplantation.The purpose of this review is to describe the technical aspects and clinical results available in the literature on the use of wearable cardioverter-defibrillators, with particular reference to safety, efficacy, costs and patient selection, together with current and unconventional indications.The authors also report the first data related to their personal experience. PMID- 29989603 TI - [Medical intensive care unit patients with hyperglycemia: is it possible a hypoglycemic risk close to zero?] AB - BACKGROUND: In patients with diabetic or stress hyperglycemia hospitalized for acute cardiovascular disease, the occurrence of hypoglycemia increases the risk of mortality and morbidity without this being counterbalanced by a reduction in events related to a tighter glycemic control. The guidelines on this topic agree in excluding intensive treatment, but are very discordant in recommending a conventional (<180 mg/dl) or milder (<200 mg/dl) blood glucose control. METHODS: In 1256 hyperglycemic patients (mean age 74 +/- 12 years) admitted to the medical intensive care unit (MICU) for acute coronary syndrome or acute heart failure, we adopted a nurse-led protocol of mild blood glucose control with subcutaneous administration of insulin, called "BBC200" (basal-bolus correction insulin regimen with glycemic target <200 mg/dl), with the aim at maintaining average blood glucose <200 mg/dl and an indication for intravenous insulin only for blood glucose >350 mg/dl. A retrospective analysis was carried out for assessing the occurrence of hypoglycemic episodes (blood glucose <70 mg/dl) and therapeutic failure (persistent hyperglycemia with values >240 mg/dl). RESULTS: Mean blood glucose was 261 +/- 72 mg/dl on admission and 173 +/- 50 mg/dl during treatment. Five patients (0.2%) required intravenous insulin infusion. There was only one case of severe hypoglycemia (<=40 mg/dl) due to an error of administration, and 2 cases of moderate hypoglycemia (41-70 mg/dl), with a total hypoglycemia rate of 0.24%. Transient therapeutic failure occurred in 27% of cases. CONCLUSIONS: In MICU hyperglycemic patients, the simple, intuitive and economical "BBC200" protocol could lead to a hypoglycemic risk very close to zero (0.24%), with a significant reduction in hypoglycemia-related clinical events and a modest increase in persistent hyperglycemic phenomena. PMID- 29989604 TI - [Left main stent avulsion during percutaneous coronary intervention for chronic total occlusion]. AB - We report the case of a chronic total occlusion in the left circumflex coronary artery due to the struts of a stent previously placed on the left main artery. The procedure was complicated by detachment of the stent advanced into the culprit lesion within the struts of the previously implanted stent in the left main artery. The extraction of the lost stent was performed using the twisting wire technique, but this operation resulted in a further complication, i.e. avulsion of the previously implanted stent on the left main artery. The case was resolved favorably with the implantation of a new stent on the left main artery and surgical extraction of the retracted stent from the brachial artery. PMID- 29989605 TI - [Presentation]. PMID- 29989606 TI - [How to choose between intra-aortic balloon pump, Impella and extracorporeal membrane oxygenation]. AB - The use of percutaneous mechanical circulatory support systems in the setting of both high-risk percutaneous coronary intervention (PCI) and cardiogenic shock is an emerging, controversial issue in contemporary clinical cardiology. The most common devices are the intra-aortic balloon pump (IABP), the Impella and the extracorporeal membrane oxygenator (ECMO). Technical progress, equipment improvement and growing cath-lab team expertise are allowing to offer critical patients different levels of assistance according to the selected device. Indeed, they are extremely different and the selection of the proper device for each clinical scenario might be tricky. In high-risk PCI, mechanical hemodynamic support serves the purpose of preventing hemodynamic collapse during the procedure. According to baseline risk stratification, IABP or Impella are usually considered whereas ECMO is seldom considered as a third option for highly selected patients.Cardiogenic shock and cardiac arrest are still associated with high mortality rates. In these conditions mechanical support may be promising. The lack of benefit observed with the systematic use of the IABP (combined with the increased mortality associated with higher number of inotropic drugs) is actually prompting to increasingly consider Impella and ECMO use in critically ill patients. The development of multidisciplinary local protocols is considered pivotal to improve management and outcome of those patients requiring percutaneous circulatory support devices. PMID- 29989607 TI - [Tips and tricks for using extracorporeal life support devices in the intensive cardiac care unit]. AB - In patients with severe cardiac dysfunction refractory to conventional therapies, extracorporeal membrane oxygenation used in veno-arterious modality can provide temporary circulatory assistance (extracorporeal life support, ECLS). Since it is an invasive and complex technique, its use is potentially burdened by severe complications, thus requiring careful nursing and medical care during intensive cardiac care unit stay. The use of ECLS requires specific skills such as knowledge of protective mechanical invasive ventilation, specific echocardiographic evaluation, accurate monitoring of hemodynamics and laboratory tests. A patient on ECLS is at high risk of thrombotic and hemorrhagic complications that could be fatal, hence specific pro- and anti-hemostatic therapy is needed. Moreover, the knowledge of some peculiar aspects of ECLS system and management can help doctors to avoid several complications such as limb ischemia, left ventricular overload and regional perfusion discrepancy. In conclusion, careful management by adequately trained personnel is required. PMID- 29989608 TI - [Percutaneous mechanical circulatory support devices: a new treatment option for refractory right ventricular failure]. AB - Right ventricular (RV) failure refractory to medical therapy is associated with a poor prognosis in cardiogenic shock. Because of the RV remarkable properties to rapidly recover under favorable hemodynamic conditions, the use of RV acute mechanical circulatory support (AMCS) devices may represent a new option to promptly stabilize the patient and change prognosis. If giant leaps forward have been made in left ventricle AMCS technology and clinical use, devices to support the right ventricle are still moving their first steps in the clinical arena. While surgically implanted RV assist devices may provide durable, long-term support when this need is anticipated, percutaneous RV-AMCS (RV-pAMCS) devices are emerging as a minimally invasive alternative, able to guarantee faster decision-making and early intervention, and with the potential to lower complications and improve survival.In this review, after summarizing the epidemiology and the pathophysiology of acute RV failure, we focus on the mechanisms of action, characteristics and clinical evidence relating to the currently available RV-pAMCS devices. We further provide an algorithm embedding relevant aspects of clinical decision-making, when RV-AMCS is considered. PMID- 29989609 TI - [High-risk ST-elevation acute coronary syndrome in a patient with multivessel coronary artery disease complicated by refractory cardiogenic shock undergoing complex percutaneous coronary revascularization: role and timing of mechanical circulatory support devices]. AB - Cardiogenic shock (CS) following acute myocardial infarction complicated by severe ventricular dysfunction remains the leading cause of death despite customized pharmacological therapy and optimal revascularization. The use of temporary mechanical circulatory support (MCS) devices during refractory CS might represent the only chance of survival to address the underlying systemic inflammatory response preventing the development of multiorgan failure. We report the case of a patient with a very-high-risk non-ST-elevation acute coronary syndrome and multivessel calcific coronary artery disease complicated by refractory CS undergoing complex percutaneous coronary revascularization. We show a gradual and complementary use of MCS devices tailored on hemodynamic monitoring, clinical and laboratory variables and multidisciplinary collaboration to early recognize the downward spiral that may ensue with multiorgan dysfunction or potential complications leading to death. PMID- 29989610 TI - Blood pressure targets: How low should you go (and for whom)? AB - The ACC/AHA's lower BP goals are supported by previously unavailable evidence, the strongest of which is for patients with CVD. But others can benefit, too. PMID- 29989611 TI - Diabetes in the elderly: Matching meds to needs. AB - Elderly patients, whose insulin resistance is complicated by age-related loss of beta-cell function and concomitant diseases, require personalized Tx considerations. PMID- 29989612 TI - The problem with blood pressure guidelines. PMID- 29989613 TI - Gun addiction. PMID- 29989614 TI - Dietary recommendations for patients with diabetes. AB - A new UK guideline bolsters recommendations from the American Diabetes Association and cites newer evidence of diabetes remission through weight loss. PMID- 29989615 TI - PURL: First-time, mild diverticulitis: Antibiotics or watchful waiting? AB - Don't jump to antibiotic Tx for mild, uncomplicated diverticulitis, a recent RCT says. Observation may be just as effective. PMID- 29989616 TI - Body-wide, pruritic, papular rash . scalp lesion . excoriation . Dx? PMID- 29989617 TI - Photo Rounds: Pain in right shoulder. AB - This patient's joint pain kept her out of work for several years. While x-rays of her hands appeared normal, an x-ray of her shoulder exposed the underlying problem. PMID- 29989618 TI - Clinical Inquiries: Can CBT effectively treat adult insomnia disorder? AB - Yes. Cognitive behavioral therapy (CBT) administered individually, in a group setting, or on the internet is effective for treating insomnia in adults compared with control (strength of recommendation [SOR]: A, meta-analyses). CBT is comparable to pharmacotherapy for improving measures of sleep (SOR: A, comparative meta-analysis). CBT produces sustainable improvements in subjective sleep quality for adults with comorbid insomnia (SOR: A, meta-analysis). PMID- 29989619 TI - Clinical Inquiries: What are the benefits/risks of giving betamethasone to women at risk of late preterm labor? AB - Giving betamethasone to women at risk for delivery between 34 weeks 0 days and 36 weeks 6 days can lower by almost 40% the incidence of transient tachypnea of the newborn, severe respiratory distress syndrome, and the use of surfactant (strength of recommendation [SOR]: A, systematic review of randomized controlled trials [RCTs]). Betamethasone may increase neonatal hypoglycemia, but the hypoglycemia isn't associated with a prolonged hospital stay or other negative outcomes. PMID- 29989620 TI - How best to manage chronic cholestasis. AB - Here's how to maximize your use of lab work and imaging techniques to identify the source of your patient's cholestasis and provide prompt treatment. PMID- 29989621 TI - Thrombocytopenia and neutropenia: A structured approach to evaluation. AB - These algorithms and tables will help you quickly assess the severity of the 2 blood abnormalities and delineate between life-threatening and benign causes. PMID- 29989622 TI - Ultrastrong Al0.1CoCrFeNi high-entropy alloys at small scales: effects of stacking faults vs. nanotwins. AB - Metastability engineering opens a new avenue to design high-entropy alloys (HEAs) originally proposed to benefit from phase stabilization. Meanwhile, boundary engineering via embedding planar defects such as stacking faults and nanotwins into the matrix of metals provides them with unique mechanical properties. In this work, for the first time, we combine the above two strategies to prepare Al0.1CoCrFeNi HEA pillars populated with a high density of stacking faults and nanotwins. It is uncovered that the stacking faulted (SF) Al0.1CoCrFeNi HEA pillars manifest ultrahigh strength exceeding 4.0 GPa and considerable compressive plasticity over 15%, much superior to their nanotwinned (NT) counterparts. Compared with the nanotwins undergoing detwinning during plastic deformation, the stacking faults in Al0.1CoCrFeNi high-entropy alloy thin films (HEAFs) are quite stable to hinder dislocation motion. Our findings not only endow the Al0.1CoCrFeNi HEAs with a predominant combination of strength and compression deformability, but also shed light on a new perspective for overcoming the strength and ductility trade-off in structural materials. PMID- 29989623 TI - A sinusoidal alternating output of a triboelectric nanogenerator array with asymmetric-layer-based units. AB - A triboelectric nanogenerator (TENG) shows great promise for the energy of the new era. In this study, we present a triboelectric nanogenerator array assembled with multiple asymmetric-layer-based triboelectric units with a sinusoidal alternating output. It raises the possibility that large-scale triboelectric energy may be developed as an alternative energy source. Moreover, we systematically analyzed the device operation to show that the internal capacitance effect controlled the output waveforms. Finally, by tuning the internal capacitance, a TENG array with performances of both stable sinusoidal alternating output and high power density is obtained based on the quantitative evaluations. The optimized TENG array can produce a maximum conversion efficiency of 60% and a load power density of 1.53 kW m-3. PMID- 29989624 TI - Wearable glove sensor for non-invasive organophosphorus pesticide detection based on a double-signal fluorescence strategy. AB - A wearable glove-based sensor has been developed for non-invasive organophosphorus pesticide (OP) monitoring via the fluorescent detection technology. The new "lab-on-a-glove" device integrates a flexible host material (CMC aerogel) and two fluorescent centers (EuMOFs for red and nanosized CDs for blue emissons). After characterizing the performance and stability of the sensor, qualitative and quantitative OP detections are successfully conducted on the surfaces of different agricultural products using swipe collection. The real-time detection system offers considerable advantages such as rapid response (30 s) due to the porous structures of CMC aerogel and MOFs, detection with the naked eye (the red to blue emission transition corresponds to an increase in the OP concentration) and high sensitivity (R2 = 0.99529, LOD = 89 nM) owing to the double-signal sensing strategy in which EuMOFs are the working fluorescence center and CDs are the reference fluorescence center. Compared with other OP detection methods, our strategy of using wearable device with the ratiometric fluorescence method leads to a convenient and reliable detection process for OP analysis. Also, considering its cost advantage, the glove-based sensor holds promise for practical applications in food safety and security. PMID- 29989625 TI - A multi-shelled CoP nanosphere modified separator for highly efficient Li-S batteries. AB - Lithium-sulfur batteries are considered to be one of the most promising energy storage systems because of their high theoretical energy density, as well as low cost, nontoxicity and natural abundance of sulfur. However, their poor cycling stability mostly originates from the shuttling of polysulfides which hinders their future practical applications. Here, multi-shelled CoP nanospheres are designed as a coated separator material for Li-S batteries for the first time. Conductive CoP can efficiently anchor polysulfides not only owing to its polar character but also its partial natural surface oxidation feature as evidenced by XPS results, which further activates Co sites for chemically trapping polysulfides via strong Co-S bonding. Furthermore, the unique multi-shelled structure can capture polysulfides to alleviate the "shuttle effect". Consequently, the battery using a CoP coated separator exhibits outstanding cycling stability with a capacity degradation of 0.078% per cycle over 500 cycles at a current density of 1 C and excellent rate performance (725 mA h g-1 at 5 C). It is also worth noting that a high areal capacity of 3.2 mA h cm-2 can be achieved even with a sulfur loading of 3.24 mg cm-2. Our approach demonstrates the convenient fabrication and application potential for a multi-shelled CoP nanosphere modified separator for highly efficient Li-S batteries. PMID- 29989626 TI - Hyperpolarised NMR to follow water proton transport through membrane channels via exchange with biomolecules. AB - Water uptake in vesicles and the subsequent exchange between water protons and amide -NH protons in amino acids can be followed by a new, highly sensitive, type of magnetic resonance spectroscopy: dynamic nuclear polarisation (DNP)-enhanced NMR in the liquid state. Water hydrogen atoms are detected prior to and after their transfer to molecular sites in peptides and proteins featuring highly accessible proton-exchangeable groups, as is the case for the -NH groups of intrinsically disordered proteins. The detected rates for amide proton-water proton exchange can be modulated by membrane-crossing rates, when a membrane channel is interposed. We hyperpolarised water proton spins via dynamic nuclear polarisation followed by sample dissolution (d-DNP) and transferred the created polarisation to -NH groups with high solvent accessibility in an intrinsically disordered protein domain. This domain is the membrane anchor of c-Src kinase, whose activity controls cell proliferation. The hindrance of effective water proton transfer rate constants observed in free solvent when a membrane-crossing step is involved is discussed. This study aims to assess the feasibility of recently-introduced hyperpolarised (DNP-enhanced) NMR to assess water membrane crossing dynamics. PMID- 29989627 TI - An automated microfluidic gene-editing platform for deciphering cancer genes. AB - Gene-editing techniques such as RNA-guided endonuclease systems are becoming increasingly popular for phenotypic screening. Such screens are normally conducted in arrayed or pooled formats. There has been considerable interest in recent years to find new technological methods for conducting these gene-editing assays. We report here the first digital microfluidic method that can automate arrayed gene-editing in mammalian cells. Specifically, this method was useful in culturing lung cancer cells for up to six days, as well as implementing automated gene transfection and knockout procedures. In addition, a standardized imaging pipeline to analyse fluorescently labelled cells was also designed and implemented during these procedures. A gene editing assay for interrogating the MAPK/ERK pathway was performed to show the utility of our platform and to determine the effects of knocking out the RAF1 gene in lung cancer cells. In addition to gene knockout, we also treated the cells with an inhibitor, Sorafenib Tosylate, to determine the effects of enzymatic inhibition. The combination of enzymatic inhibition and guide targeting on device resulted in lower drug concentrations for achieving half-inhibitory effects (IC50) compared to cells treated only with the inhibitor, confirming that lung cancer cells are being successfully edited on the device. We propose that this system will be useful for other types of gene-editing assays and applications related to personalized medicine. PMID- 29989628 TI - Cyclometalated Ir(iii) complexes [Ir(tpy)(bbibH2)Cl][PF6] and [Ir(tpy)(bmbib)Cl][PF6]: intramolecular pipi interactions leading to facile synthesis and enhanced luminescence. AB - Cyclometalated Ir(iii) complexes [Ir(tpy)(bbibH2)Cl][PF6] (1.PF6) and [Ir(tpy)(bmbib)Cl][PF6] (2.PF6), and the control complex [Ir(tpy)(mbib)Cl][PF6] (3.PF6) were synthesized at 135 degrees C for 10 hours for the former two complexes, while at 190 degrees C for 24 hours for the latter complex, in which the cyclometalated ligands bbibH2-, bmbib- and mbib- incorporate one or two N methylbenzoimidazole/benzimidazole units in order to explore the influence of the molecular structures of these complexes on their synthesis conditions and luminescence behaviors. The 1H NMR and crystal structure measurements indicate that both 1.PF6 and 2.PF6 contain intramolecular pipi stacking interactions between the non-coordinated N-methylbenzoimidazole/benzimidazole unit and the tpy ligand, but there are no such pipi interactions in 3.PF6. At room temperature, these complexes in CH3CN reveal an emission with a combination of 3MLCT and 3LC characteristics, occurring at 534 nm with a quantum yield Phi = 39.5% and a lifetime tau = 2.39 MUs for 1.PF6, 536 nm with Phi = 66.4% and tau = 2.94 MUs for 2.PF6, and 558 nm with Phi = 27.0% and tau = 1.75 MUs for 3.PF6. Moreover, both 1.PF6 and 2.PF6 exhibit a TFA-induced luminescence decrease. Based on the comparison among 1.PF6, 2.PF6 and 3.PF6, we discuss the influence of intramolecular pipi interactions and Nimidazole-H/Nimidazole-CH3 units in 1.PF6 and 2.PF6 on their syntheses and luminescence. PMID- 29989629 TI - Electrochemical quantification of transmitter concentration in single nanoscale vesicles isolated from PC12 cells. AB - We use an electrochemical platform, nanoparticle tracking analysis, and differential centrifugation of single catecholamine vesicles to study the properties of nanometer transmitter vesicles, including the number of molecules, size, and catecholamine concentration inside. Vesicle impact electrochemical cytometry (VIEC) was used to quantify the catecholamine content of single vesicles in different batches isolated from pheochromocytoma (PC12) cells with different ultracentrifugation speeds. We show that, vesicles containing less catecholamine are obtained at subsequent centrifugation steps with higher speed (force). Important to quantification, the cumulative content after subsequent centrifugation steps is equivalent to that of one-step centrifugation at the highest speed, 70 000g. Moreover, as we count molecules in the vesicles, we compared molecular numbers from VIEC, flow VIEC, and intracellular VIEC to corresponding vesicle size measured by nanoparticle tracking analysis to evaluate catecholamine concentration in vesicles. The data suggest that vesicular catecholamine concentration is relatively constant and independent of the vesicular size, indicating vesicular transmitter content as a main factor regulating the vesicle size. PMID- 29989631 TI - Inhibition of alpha-glucosidase and alpha-amylase by flavonoid glycosides from Lu'an GuaPian tea: molecular docking and interaction mechanism. AB - Green tea may favorably modulate blood glucose homeostasis, and regular consumption of green tea can prevent the development of type 2 diabetes mellitus. In this study, alpha-glucosidase and alpha-amylase inhibitory effects of the novel acylated flavonol tetraglycoside (camellikaempferoside C, 1) and 14 other flavone and flavone glycosides (FGs) isolated from Lu'an GuaPian (Camellia sinensis L.O. Kuntze) were evaluated. The kaempferol monoglycoside (15) showed inhibitory activity against alpha-glucosidase with IC50 at 40.02 +/- 4.61 MUM, and kaempferol diglycoside (13) showed alpha-amylase inhibition with IC50 at 0.09 +/- 0.02 MUM. Further, inhibitory mechanisms of FGs 15 and 13 were studied by molecular docking analysis and fluorescence spectrometry. Molecular docking suggested that FG 15 interacted with alpha-glucosidase mainly by hydrogen bonding, which was the same interaction force between FG 13 and alpha-amylase. Intrinsic fluorescence of alpha-glucosidase and alpha-amylase was quenched by 15 and 13, respectively, through a static quenching mechanism. The spontaneous formation of 15-alpha-glucosidase and 13-alpha-amylase complexes was driven by van der Waals forces and hydrogen bonding. The present study provides new insight into the potential application of Lu'an GuaPian green tea as a functional food ingredient to regulate postprandial hyperglycemia through inhibition of alpha glucosidase/alpha-amylase by FGs, particularly the mono- and di- glycosides of kaempferol. PMID- 29989630 TI - Putative metal binding site in the transmembrane domain of the manganese transporter SLC30A10 is different from that of related zinc transporters. AB - SLC30 proteins belong to the cation diffusion facilitator (CDF) superfamily of metal transporters. SLC30A10 mediates manganese efflux, while other SLC30 members transport zinc. Metal specificity of CDFs may be conferred by amino acids that form a transmembrane metal binding site (Site A). Site A of zinc-transporting CDFs, such as SLC30A1/ZnT1, have a HXXXD motif, but manganese transporters, such as SLC30A10, harbor a NXXXD motif. This critical histidine-to-asparagine substitution, at residue 43, was proposed to underlie manganese transport specificity of SLC30A10. However, we recently discovered that asparagine-43 was dispensable for manganese efflux in HeLa cells; instead, glutamate-25, aspartate 40, asparagine-127, and aspartate-248 were required. In contrast, another group reported that asparagine-43 was required in a chicken cell line. The goal of this study was to resolve the divergent results about the requirement of the crucial asparagine-43 residue. For this, we compared the manganese efflux activity of four cell types that stably over-expressed SLC30A10wild-type (WT), SLC30A10N43A or SLC30A10E25A: physiologically-relevant hepatic HepG2 and neuronal AF5 cells, HEK cells, and embryonic fibroblasts from Slc30a10-/- mice. In all cell types, manganese efflux activity of SLC30A10N43A was comparable to WT, while SLC30A10E25A lacked activity. Importantly, unlike SLC30A10, the histidine residue of the HXXXD motif of SLC30A1/ZnT1 was required for zinc transport. These results imply that the mechanisms of ion coordination within the transmembrane domain of SLC30A10 substantially differ from previously-studied CDFs, suggest that factors beyond Site A residues may confer metal specificity to CDFs, and improve understanding of the pathobiology of manganese toxicity due to mutations in SLC30A10. PMID- 29989632 TI - High-rate potassium ion and sodium ion batteries by co-intercalation anodes and open framework cathodes. AB - Here we demonstrate a full-cell battery design that bridges the energy density and rate capability between that of supercapacitors or pseudocapacitors with that of traditional lithium-ion batteries. This is accomplished by pairing an anode that enables ultrafast ion co-intercalation, an open framework cathode that allows rapid ion diffusion, and linear ether based electrolyte that sustains cell level stability and high rate performance. We show this platform to be suitable for both sodium and potassium batteries using graphite as the co-intercalation anode, and Prussian blue as the open framework cathode. Our devices exhibit active material energy densities >100 W h kg-1 with power density >1000 W kg-1 with cycling durability approaching ~80% energy density retention over 2000 cycles. This work brings together state-of-the-art concepts for fast-charging batteries into a full-cell configuration. PMID- 29989633 TI - Fe-Catalyzed tandem cyclization for the synthesis of 3-nitrofurans from homopropargylic alcohols and Al(NO3)3.9H2O. AB - Al(NO3)3.9H2O as a nitro source for the synthesis of 3-nitrofurans from homopropargylic alcohols through Fe-catalyzed tandem cyclization is described. In this transformation, the substituted nitrofurans are obtained through nitration and cyclization. The substrate homopropargylic alcohols with different groups participate smoothly in this process and the desired substituted nitrofurans were obtained in moderate yields. PMID- 29989634 TI - Predictive modelling of the water contact angle of surfaces using attenuated total reflection - Fourier transform infrared (ATR-FTIR) chemical imaging and partial least squares regression (PLSR). AB - The static water contact angle (CA) quantifies the degree of wetting that occurs when a surface encounters a liquid, e.g. water. This property is a result of factors such as surface chemistry and local roughness and is an important analytical parameter linked to the suitability of a surface for a given bioanalytical process. Monitoring the spatial variation in wettability over surfaces is increasingly critical to analysts and manufacturers for improved quality control. However, CA acquisition is often time-consuming because it involves measurements over multiple spatial locations, independent sampling and the need for a single instrument operator. Furthermore, surfaces exposed to local environments specific to an intended application may affect the surface chemistry thereby modifying the surface properties. In this study, Attenuated Total Reflection-Fourier Transform Infrared (ATR-FTIR) chemical imaging data acquired from wet and dry polymer surfaces were used to develop multivariate predictive models for CA prediction. Partial Least Squares Regression (PLSR) models were built using IR spectra from surfaces presenting differences in the experimentally measured CA in the range 16 degrees -141 degrees . The best performing PLSR models were locally developed and combined to make a global model utilising wet IR spectra which performed well (R2p = 0.98, RMSECV ~ 5 degrees ) when tested on an independent experimental set. This model was subsequently applied to IR spectra acquired from a surface exhibiting spatial differences in surface chemistry and the CA with a reasonable confidence and precision (prediction error within 10 degrees ), demonstrating the potential of this method for prediction of the spatially varying CA as a non-destructive in-line process monitoring technique. PMID- 29989635 TI - Photocatalytic H2 production by dirhodium(ii,ii) photosensitizers with red light. AB - Photocatalytic proton reduction to generate H2 was achieved with the photosensitizers Rh2(DTolF)2(npCOO)2 (DTolF = p-ditolylformamidinate; npCOO- = 2 carboxylate-1,8-naphthyridine; 1) and [Rh2(DTolF)2(qnnp)2][BF4]2 (qnnp = 2 (quinolin-2-yl)-1,8-naphthyridine; 2) using a relay system containing the sacrificial donor BNAH (1-benzyl-1,4-dihydronicotinamide), electron acceptor MV2+ (methylviologen), and Pt nanoparticles as the catalyst with 655 nm irradiation. Comparison of the H2 evolution under similar experimental conditions show comparable activity of the Rh2(ii,ii) complexes (lambdairr = 655 nm) to that of the prototypical [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine; 3) with lambdairr = 447 nm. This work demonstrates the ability of the new panchromatic Rh2(ii,ii) complexes to achieve photocatalysis with red light. PMID- 29989636 TI - Flow chemistry-enabled studies of rhodium-catalyzed hydroformylation reactions. AB - We present an automated microscale flow chemistry platform for rapid performance evaluation of continuous and discrete reaction parameters in homogeneous hydroformylation reactions. We demonstrate the versatility of the developed microfluidic platform through a systematic study of the effects of a library of phosphine-based ligands on catalytic activity and regioselectivity. PMID- 29989637 TI - Chemical and in silico tuning of the magnetisation reversal barrier in pentagonal bipyramidal Dy(iii) single-ion magnets. AB - Two new air-stable axial Dy(iii) single-ion magnets, [Dy(H2O)5(HMPA)2]Cl3.HMPA.H2O (1) and [Dy(H2O)5(HMPA)2]I3.2HMPA (2) (HMPA = hexamethylphosphoramide), exhibit magnetic hysteresis which remains open up to 9 K for 1@Y and 10 K for 2@Y, respectively. Ab initio calculations, using step-by step elimination of fragments to generate a series of model complexes, reveal that the secondary coordination sphere plays a key role in controlling the magnetisation reversal barrier and predict that the removal of outer-sphere molecules and anions will enhance the barrier further. PMID- 29989638 TI - In situ construction of hierarchical Co/MnO@graphite carbon composites for highly supercapacitive and OER electrocatalytic performances. AB - The development of new electrode materials with high specific capacity for excellent supercapacitive storage and energy conversion is highly desirable. The combination of metal and metal oxide with carbon is an effective strategy to achieve active bimetallic nanocatalysts. Herein, we developed a facile method to synthesize CoxMn1-xO@GC and Co/MnO@GC nanocomposites by an in situ conversion of Co-Mn PBAs. The as-prepared carbon hybrids, especially the resulting Co/MnO@GC carbonized under 700 degrees C (Co/MnO@GC-700), preserve the nanocubic morphology of Co-Mn PBAs and show excellent supercapacitance and OER performance. Specifically, an outstanding specific capacitance of 2275 F g-1 can be obtained with Co/MnO@GC-700 as the electrode material at a current density of 4 A g-1. When used as OER catalysts, Co/MnO@GC-700 shows a low overpotential of only 358 mV at 10 mA cm-2 in 1 M KOH. Moreover, a fabricated asymmetric supercapacitor device (ASC device), in combination with active carbon, shows a high cell voltage of 1.7 V and a considerably high specific capacitance of 246 F g-1 at 2 A g-1. Our nanoarchitecture design derived from PBAs provides a new opportunity for future applications in high-performance energy storage and transformation systems. PMID- 29989640 TI - Chitosan-templated Pt nanocatalyst loaded mesoporous SnO2 nanofibers: a superior chemiresistor toward acetone molecules. AB - In this work, we introduce a chitosan-Pt complex (CS-Pt) as an effective template for catalytic Pt sensitization and creation of abundant mesopores in SnO2 nanofibers (NFs). The Pt particles encapsulated by the CS exhibit ultrasmall size (~2.6 nm) and high dispersion characteristics due to repulsion between CS molecules. By combining CS-Pt with electrospinning, mesoporous SnO2 NFs uniformly functionalized with the Pt catalyst (CS-Pt@SnO2 NFs) are synthesized. Particularly, numerous mesopores with diameters of ~20 nm form through the decomposition of CS, while a small SnO2 grain size (14.32 nm) is achieved by the pinning effect of CS. It is observed that CS-Pt@SnO2 NFs exhibit outstanding response (Rair/Rgas = 141.92 at 5 ppm), excellent selectivity, stability, and fast response (12 s)/recovery (44 s) speed toward 1 ppm of acetone at 350 degrees C and high humidity (90% RH). In addition, by applying an exponential fitting tool to experimental response values toward 0.1-5 ppm of acetone, it is estimated that CS-Pt@SnO2 NFs can detect 5 ppb of acetone with a notable response (Rair/Rgas = 2.9). Furthermore, the sensor array based on CS-Pt@SnO2 NFs, CS driven SnO2 NFs, polyol-Pt loaded SnO2 NFs, and dense SnO2 NFs obviously classifies simulated diabetic breath and healthy human breath by using a pattern recognition tool. These results clearly demonstrate that mesoporous SnO2 NFs, particularly functionalized with CS-Pt templated nanocatalysts, open up a new class of sensing layers offering high sensitivity and selectivity. PMID- 29989639 TI - Synthesis, characterization and photocatalytic activity of mixed-metal oxides derived from NiCoFe ternary layered double hydroxides. AB - Ternary NiCoFe mixed-metal oxides (NCF-MMOs) with different Ni/Co/Fe ratios were successfully synthesized through a hydrotalcite-like precursor route by co precipitation of appropriate amounts of metal salts from homogeneous solution, followed by calcination at 600 degrees C. X-ray diffraction (XRD) patterns revealed the formation of well crystalline layered double hydroxides (LDHs), particularly at the M2+/M3+ ratio of 3 : 1. Brunauer-Emmett-Teller (BET) analysis revealed that the resulting NiCoFe LDHs possessed large specific surface areas (66.9-93.8 m2 g-1). The NCF-MMO (1 : 2 : 1) samples were demonstrated to be formed by the aggregation of regular cubes with an edge length of about 2 MUm, and each cube was accumulated with many fine particles with a size of ~130 nm. UV vis diffuse reflection spectroscopy (DRS) confirmed that the samples showed a broad absorption in the visible-light region (450-750 nm), with a low band gap of 2.33-2.77 eV. The calcined samples with a Ni/Co/Fe molar ratio of 1 : 2 : 1 possessed the best photocatalytic activity with 96.8% degradation of methylene blue (MB) dye under visible light irradiation for 4 h, which exceeded those of commercial P25 TiO2, binary NiFe mixed-metal oxides and pure Fe2O3, CoO and NiO particles under the same conditions. NCF-MMO (1 : 2 : 1) also had a strong degradation effect on the non-dye pollutant phenol as well. Kinetic studies suggested that the degradation of MB followed a pseudo-first-order kinetic behavior. The photodegradation mechanism of NCF-MMOs was also discussed. PMID- 29989642 TI - Total synthesis of the proposed structure of talarolide A. AB - The proposed structure of talarolide A, a cycloheptapeptide featuring a hydroxamate moiety within the peptide backbone, was successfully synthesized. An initial attempt to synthesize a linear peptide precursor containing a C-terminal N-benzyloxy glycine residue was problematic due to an unreported on-resin reduction of N-benzyloxy glycine to glycine. After repositioning the peptide cyclization point, a new linear peptide sequence was successfully prepared using Fmoc-solid-phase peptide synthesis. Subsequent solution-phase cyclization and removal of protecting groups furnished the synthetic talarolide A in good yield. Despite the mismatch of the NMR data between the synthetic talarolide A and the natural product, a detailed structural analysis using 2D NMR spectroscopy, together with re-synthesis of the same synthetic material using two additional cyclization sites, confirmed that our synthetic product has the reported structure of talarolide A. PMID- 29989641 TI - In situ fluorescence monitoring of diagnosis and treatment: a versatile nanoprobe combining tumor targeting based on MUC1 and controllable DOX release by telomerase. AB - We have constructed versatile drug-loaded nanoprobes capable of responding to both MUC1 and telomerase and achieving intracellular drug release. Besides, the synthesized drug-loaded nanoprobes can realize the in situ imaging observation of the whole process of nanoprobes targeting the tumor cell membrane, the transmembrane entering the cytoplasm and the release of DOX into the cell nucleus. PMID- 29989643 TI - Culturally and Linguistically Diverse Older Adults and Mainstream Long-Term Care Facilities: Integrative Review of Views and Experiences. AB - Older adults from culturally and linguistically diverse (CALD) backgrounds are increasingly identified within mainstream aging populations. However, few studies have focused on CALD older adults' views and experiences in long-term care facilities (LTCFs). The current integrative review aimed to achieve a contemporary understanding through synthesized evidence from studies focusing on CALD older adults in mainstream LTCFs. Two major categories were identified-Views About LTCFs, which included two subcategories: (a) the last stop and no other choice and (b) reasons for admission or transfer; and Experiences of Living in LTCFs, which also included two subcategories: (a) desire to remain connected to personal routines and (b) maintaining identity through native language. CALD older adults have differing perspectives about LTCFs, which are influenced by their cultural backgrounds and values. Future research should evaluate the effectiveness of ethno-specific LTCFs. Establishing culturally appropriate services for CALD older adults in LTCFs, particularly in mainstream facilities, should emphasize cultural accommodation among residents, health care providers, and staff. [Res Gerontol Nurs. 2018; 11(5):265-276.]. PMID- 29989644 TI - Service Use, Participation, Experiences, and Outcomes Among Older Adult Immigrants in American Adult Day Service Centers: An Integrative Review of the Literature. AB - Older adult immigrants are often socially isolated and vulnerable to poor health. Adult day service (ADS) centers could potentially facilitate social integration and address their long-term health care needs. The current review (a) identifies barriers to and facilitators of ADS use among immigrants, (b) explores how ADS programs impact older adult immigrants' health and well-being, and (c) isolates the most effective culturally based components of ADS programs. An integrative review was conducted using Whittemore and Knafl's methodology. Four databases were searched. Articles were critically appraised and data were organized within an ADS-specific framework. Functional impairment, race, gender, and degree of loneliness were all predictors of ADS use. ADS enhanced immigrants' quality of life and provided fulfillment. Transportation, bilingual nurses, peer support, and cultural activities were deemed essential by participants. ADS can provide support to older adult immigrants by adding cultural elements to existing services and using nurses as cultural liaisons. More research is needed to assess the impact of ADS on disease outcomes, including dementia, and on immigrants in multi-ethnic settings. [Res Gerontol Nurs. 2018; 11(6):317-328.]. PMID- 29989645 TI - MicroRNA-320a suppresses tumor cell growth and invasion of human breast cancer by targeting insulin-like growth factor 1 receptor. AB - The present study was performed to investigate the biological functions of microRNA-320a in human breast cancer and the underlying mechanisms. MicroRNA-320a expression was downregulated in human breast cancer, compared with the normal control. Overexpression of microRNA-320a induced apoptosis, and inhibited cell viability and invasion in MDA-MB-231cells while downregulation of microRNA-320a reduced apoptosis, and increased cell viability and invasion in MDA-MB-231 cells. Then, overexpression of microRNA-320a suppressed insulin-like growth factor 1 receptor (IGF-1R), p-AKt and cyclin D1 protein expression in MDA-MB-231cells. In addition, the downregulation of microRNA-320a induced IGF-1R, p-Akt and cyclin D1 protein expression in MDA-MB-231cells. Furthermore, the IGF-1R inhibitor increased the effects of microRNA-320a on the apoptosis of MDA-MB-231 cells. The p-Akt inhibitor (MK 2206 dihydrochloride, 2.5 nM) increased the effects of microRNA-320a on the apoptosis of MDA-MB-231 cells. These results revealed that microRNA-320a suppresses tumor cell growth and invasion of human breast cancer by targeting IGF-1R. PMID- 29989646 TI - Insulin-like growth factor-1 induces epithelial-mesenchymal transition in hepatocellular carcinoma by activating survivin. AB - Insulin-like growth factor-1 (IGF-1), a small polypeptide hormone similar to insulin in protein structures, has been identified as an activator of epithelial mesenchymal transition (EMT) pathways in several types of cancers. As a member of the inhibitor of apoptosis protein (IAP) family, survivin is implicated in the EMT of some cancers. However, the role of survivin on IGF-1-mediated EMT of hepatocellular carcinoma (HCC) has not been clarified. In the present study, we demonstrated that survivin was involved in the EMT process induced by IGF-1 in HCC cell line SMMC7721. With administration of different concentrations of IGF-1, survivin mRNA and protein expression were significantly increased and stimulated EMT in the tested cell line, while the increased invasive and migratory abilities of HCC cells and activation of the EMT process induced by IGF-1 were reversed after silencing of survivin expression by transfecting small interfering RNA. This was further confirmed by the observation of morphological changes, the decrease of invasive and migratory abilities and the downregulation of EMT markers, N-cadherin, vimentin and Snail, and the upregulation of E-cadherin. In conclusion, survivin may play a vital role in the IGF-1 signaling pathway by mediating EMT in HCC through the upregulation of the expression of EMT markers, and the knockdown of survivin expression may suppress the metastasis of HCC, which may provide new insights for the molecular therapy of HCC patients in clinical treatment. PMID- 29989647 TI - Proliferative role of BDNF/TrkB signaling is associated with anoikis resistance in cervical cancer. AB - Brain-derived neurotrophic factor (BDNF) is known as one of the members of the neurotropin family. BDNF-induced activation of its receptor tyrosine kinase B (TrkB) is associated with anoikis tolerance, tumor progression and poor prognosis in many types of malignancy. However, to the best of our knowledge, there are no reports describing the contribution of the BDNF/TrkB axis to cervical cancer. BDNF and TrKB expression in cervical cancer (CC) tissues and adjacent normal tissues from 87 patients were analyzed by immunohistochemistry, western blot analysis and quantitative PCR assays and the results showed that they were significantly higher in cancer tissues than that in normal adjacent tissues, respectively. Higher expression rates of BDNF and TrKB were observed in stage IIB or higher and BDNF expression was positively associated with lymph node metastasis. Notably, a high expression of TrKB may be contributed to poor survival time, which confirmed by Kaplan-Meier analysis. Compared to the corresponding CC cell lines, HeLa, SiHa, CASKI, C4-1 and C-33a, BDNF and TrKB expression was enhanced in anoikis-like apoptotic tolerance (AAT), a cell model established from cervical cancer cell lines. AAT cells showed a higher proliferation activity compared with CC cell lines, which was confirmed by a shorter G0/G1 phase, elevated cyclin A, cyclin D1 and c-myc, decreased caspase-3 and Bax, and increased Bcl-2. By contrast, the knockdown of TrKB expression reversed these changes in AAT cells, induced G0/G1 arrest and suppressed proliferation activity. The results of the present study show that PI3K/Akt signaling is involved in the BDNF/TrKB-induced proliferation of AAT cells in cervical cancer. These findings indicate that BDNF/TrKB pathway is a potential target for the treatment of cervical cancer. PMID- 29989648 TI - LC-MS/MS metabolome analysis detects the changes in the lipid metabolic profiles of dMMR and pMMR cells. AB - The DNA mismatch repair (MMR) system plays an important role in the initiation, diagnosis and treatments of colorectal cancer (CRC). Compared to CRC patients deficient in DNA MMR (dMMR), CRC patients proficient in DNA MMR (pMMR) have higher metastasis, short survival and poor response to chemotherapy and immunotherapy. It is well-known that a high-fat diet can cause CRC, and lipid metabolism is closely related to the development and metastasis of CRC. However, there have been few studies that address the difference in lipid metabolism between dMMR and pMMR CRC. Liquid chromatography-tandem mass spectrometry (LC/MS) is an advanced technique that can perform the analysis of lipid metabolites and the roles of lipids present in low abundance in cell signaling and membrane stability. In the present study, we used the LC/MS technique to analyze the difference in the lipid metabolic profiles between dMMR cell lines (HCT116, DLD1, LoVo and HCT15) and pMMR cell lines (SW480, SW620, HT29 and NCM460). The results revealed that, among the 19 classes and 157 intact lipid species identified by the LC/MS analysis, the levels of most phospholipids were lower in dMMR cells than pMMR cells. Higher levels of phosphatidylcholine (PC; 16:0/18:1) and phosphatidic acid (PA; 18:0/18:0) were observed in pMMR cells than in dMMR cells. Furthermore, our results revealed that SCD1 and PLD1, the key enzymes involved in lipid metabolism associated with metastasis, are higher in pMMR cells than dMMR cells. To the best of our knowledge, we are the first to reveal that the levels of metastasis-associated lipids and key enzymes in lipid metabolism were higher in the CRC patients with pMMR compared with the CRC patients with dMMR. This study identified potential anti-metastatic targets in the therapy of patients with pMMR, and also personalized therapy for the patients with pMMR. PMID- 29989649 TI - Systems biology analysis of the lung cancer-related secretome. AB - Tumorigenesis is closely and highly associated with developmental biology. The present study aimed to discover and identify marker proteins strongly associated with the occurrence and development of non-small cell lung cancer (NSCLC) in humans and to provide new ideas for investigating lung cancer markers by combining biological analyses of embryonic development. We established primary cultures for samples of tumor and control tissues from 9 patients with NSCLC and collected conditioned medium (CM). Subsequently, we used liquid chromatography and linear ion trap (LTQ) mass spectrometry to isolate and identify proteins in CM samples. Data mining of free proteins was conducted using the analogous analysis strategy in systems biology to obtain important lung cancer-associated proteins (plasma markers). Proteins with significant plasma enrichment in lung cancer patients were detected via enzyme-linked immunosorbent assay (ELISA). We identified 987 high-confidence proteins and established a primary database of free proteins associated with lung cancer. Furthermore, 511 high-confidence proteins were present in CM from primary tissue cultures from at least 2 of the 9 examined cases of lung cancer. Analysis using Gene Set Enrichment Analysis (GSEA) software revealed significant enrichment for 197 proteins from the CM of lung cancer samples in maternal-placental interface expression profiles for a mid-term placenta with strong invasiveness relative to RNA expression profiles for a human full-term placenta after delivery. ELISA results demonstrated that hypoxanthine phosphoribosyltransferase 1 (HPRT1) was associated with worse rates of disease free survival (DFS) and overall survival (OS). The biological behaviors of embryonic implantation are similar to those of tumor invasion and metastasis, and the information obtained regarding developmental biology could facilitate the interpretation of tumor invasion and metastasis. Therefore, similar biological behaviors combined with analyses at different molecular levels from the perspective of systems biology will provide new ideas for tumor research. PMID- 29989650 TI - Salinomycin induces apoptosis and differentiation in human acute promyelocytic leukemia cells. AB - At present, acute promyelocytic leukemia (APL) is the most curable form of acute myeloid leukemia and can be treated using all-trans retinoic acid and arsenic trioxide. However, the current treatment of APL is associated with some issues such as drug toxicity, resistance and relapse. Therefore, other strategies are necessary for APL treatment. In the present study, we investigated the effects of salinomycin (SAL) on APL cell lines NB4 and HL-60 and determined its possible mechanisms. We observed that SAL inhibited cell proliferation, as determined by performing Cell Counting Kit-8 (CCK-8) assay, promoted cell apoptosis, as determined based on morphological changes, and increased Annexin V/propidium iodide (PI)-positive apoptotic cell percentage. Treatment with SAL increased Bax/Bcl-2 and cytochrome c expression and activated caspase-3 and -9, thus leading to poly(ADP-ribose) polymerase (PARP) cleavage and resulting in cell apoptosis. These results revealed that SAL induced cell apoptosis through activation of the intrinsic apoptosis pathway. The present study is the first to show that SAL induced the differentiation of APL cells, as determined based on mature morphological changes, increased NBT-positive cell and CD11b-positive cell percentages and increased CD11b and C/EBPbeta levels. Furthermore, SAL decreased the expression of beta-catenin and its targets cyclin D1 and C-myc. Results of immunofluorescence analysis revealed that SAL markedly decreased the beta-catenin level in both the nucleus and cytoplasm. Combination treatment with SAL and IWR 1, an inhibitor of Wnt signaling, synergistically triggered SAL-induced differentiation of APL cells. These findings demonstrated that SAL effectively inhibited cell proliferation accompanied by induction of apoptosis and promotion of cell differentiation by inhibiting Wnt/beta-catenin signaling. Collectively, these data revealed that SAL is a potential drug for treatment of APL. PMID- 29989654 TI - ? PMID- 29989652 TI - Oxymatrine induces cell cycle arrest and apoptosis and suppresses the invasion of human glioblastoma cells through the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3. AB - Oxymatrine (OM), a natural quinolizidine alkaloid extracted from the traditional Chinese herb Sophora flavescens, has been revealed to produce antitumor activities in various cancer cell lines, including glioblastoma lines, in vitro. However, the mechanisms by which OM exerts its antitumor effect against glioma are poorly understood. The aim of this study was to investigate the role of OM in the proliferation, apoptosis and invasion of glioma cells and to reveal the underlying mechanisms. The effects of OM on U251MG cells in vitro were determined using a Cell Counting Kit-8 (CCK-8) assay, flow cytometric analysis, Annexin V FITC/PI staining, DAPI staining, a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay, a Transwell assay and western blotting. Our data indicated that OM inhibited proliferation, arrested the cell cycle at the G0/G1 phase, decreased the expression levels of G1 cell cycle regulatory proteins (cyclin D1, CDK4 and CDK6), inhibited invasion and induced apoptosis in glioma cells. Additional investigations revealed that the expression levels of p-STAT3 and key proteins in the EGFR/PI3K/Akt/mTOR signaling pathway, such as p-EGFR, p Akt and p-mTOR, were markedly decreased after OM treatment, while the total STAT3, EGFR, Akt and mTOR levels were not affected. These findings indicated that the EGFR/PI3K/Akt/mTOR signaling pathway and STAT3 suppression may be a potential mechanism of the OM-mediated antitumor effect in glioblastoma cells and that EGFR may be a target of OM. Hence, OM may be a promising drug and may offer a novel therapeutic strategy for malignant gliomas in the future. PMID- 29989651 TI - Osthole enhances antitumor activity and irradiation sensitivity of cervical cancer cells by suppressing ATM/NF-kappaB signaling. AB - Osthole (7-methoxy-8-isopentenoxycoumarin) is an O-methylated coumarin, originally extracted from Chinese herbal medicine. It has been demonstrated that osthole has antitumor effects in various cancer cells in vitro. The present study assessed the effects of osthole on the regulation of cervical cancer cell viability, apoptosis, and radiation sensitization. HeLa, SiHa, C-33A and CaSki cervical cancer cell lines were cultured and treated with osthole and/or irradiation and then subjected to 3-(4,5-dimethylthiazol-2-yl)-2,5--diphenyl tetrazolium bromide cell viability, colony formation, apoptosis, acridine orange/ethidium bromide fluorescence staining, wound-healing, Transwell migration and invasion, immunofluorescence, Comet and western blot assays. The data showed that osthole dose-dependently reduced cervical cancer cell viability, proliferation, and migration and invasion, but induced apoptosis. At the protein level, osthole affected the expression of cervical cancer cell epithelial mesenchymal transition markers, which showed that the expression of E-cadherin was increased, whereas that of vimentin was decreased. Osthole treatment also sensitized cervical cancer cells to irradiation, showing increased DNA damage as assessed by the Comet assay, and inhibited nuclear factor-kappaB signaling. In conclusion, osthole is an herbal agent that may offer potential for used as an adjuvant treatment for cervical cancer. PMID- 29989655 TI - ? PMID- 29989653 TI - Silencing of Girdin suppresses the malignant behavior of colorectal carcinoma cells. AB - The aim of the present study was to investigate the effect of the actin-binding protein Girdin on the proliferation, invasion and migration of colorectal cancer (CRC) cells. Cultured CRC cells (LoVo cell line) were transfected by Girdin specific and control shRNA constructs and analyzed for proliferation, invasion and migration by the MTT, Transwell and wound-healing assays, respectively. The activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and expression of proinflammatory cytokines was examined by western blotting and ELISA assay, respectively. The effect of Girdin silencing on CRC growth was also evaluated in a xenograft model using nude mice, which were subcutaneously injected with Girdin-deficient and negative control LoVo cells and analyzed for tumor volume and weight. Transfection of LoVo cells with Girdin-specific shRNA inhibited Girdin mRNA expression to 27.5% and protein expression to 36.7% when compared with expression levels in the control cells (P<0.001) and significantly demonstrated suppression of LoVo cell proliferation (P<0.05), invasion (P<0.01) and migration (P<0.01). Furthermore, Girdin silencing downregulated the phosphorylation of the signaling proteins JAK (by 42%, P<0.001) and STAT3 (by 34%, P<0.01) and the content of IFN (by 28%, P<0.001) and IL-6 (by 44%, P<0.001) compared to the control. Notably, inhibition of Girdin expression effectively suppressed tumorigenicity of LoVo cells in vivo as evidenced by the reduced volume (P<0.05) and weight (P<0.05) of the tumors derived from Girdin shRNA-transfected LoVo cells compared to those from the control cells. In conclusion, the silencing of Girdin expression inhibited the malignant behavior of CRC cells via the downregulation of the JAK/STAT signaling pathway, indicating Girdin as a potential therapeutic target in CRC. In the present study, we revealed, for the first time, that the malignant behavior of CRC cells depended on the expression of an actin-binding protein, Girdin. Silencing of Girdin expression by specific shRNA suppressed the proliferation, invasion, and migration of CRC cells through the decrease in proinflammatory cytokines IFN and IL-6 and the downregulation of the JAK/STAT signaling pathway. Our findings indicated that Girdin expression may be a potential novel therapeutic target in CRC. PMID- 29989656 TI - Hypoxia adaptation in termites: hypoxic conditions enhance survival and reproductive activity in royals. AB - Termite royals (queen and king) exhibit extraordinary longevity without sacrificing reproductive performance, unlike most animals, in whom lifespan is generally negatively associated with reproduction. Therefore, the regulatory mechanisms underlying longevity have attracted much attention. Although the ageing process is influenced by environmental factors in many insects during their life cycle, it remains unclear whether any factors have an effect on the extended survival and high reproductive capacity of termite royals. Here, we show that hypoxia, possibly an important environmental factor in the nests, enhances survival and reproductive activity in incipient royals of the subterranean termite Reticulitermes speratus compared with those in control conditions. Quantitative real-time PCR analysis revealed that the expression levels of the vitellogenin gene in queens are maintained to a greater extent under hypoxic conditions than under control conditions. The expression levels of the antioxidant enzyme genes RsCAT1 and RsPHGPX are also significantly promoted by hypoxia in queens and kings respectively. These results suggest that hypoxic exposure can contribute in part to achieving high reproductive output by altering gene expression after founding of colonies in the royals. Our study provides novel insights into the effect of a nest environment on the reproductive characteristics in termite royals. PMID- 29989657 TI - Wolbachia-induced apoptosis associated with increased fecundity in Laodelphax striatellus (Hemiptera: Delphacidae). AB - Wolbachia influence the fitness of their invertebrate hosts. They have effects on reproductive incompatibility and egg production. Although the former are well characterized, the mechanistic basis of the latter is unclear. Here, we investigate whether apoptosis, which has been implicated in fecundity in model insects, influences the interaction between fecundity and Wolbachia in the planthopper Laodelphax striatellus. Wolbachia-infected females produced about 30% more eggs than uninfected females. We used the terminal deoxyribonucleotidyl transferase (TDT)-mediated dUTP-digoxigenin nick end labeling staining to visualize apoptosis. Microscopic observations indicated that the Wolbachia strain wStri increased the number of ovarioles that contained apoptotic nurse cells in both young and aged adult females. The frequency of apoptosis was much higher in the infected females. The increased fecundity appeared to be a result of apoptosis of nurse cells, which provide nutrients to the growing oocytes. In addition, cell apoptosis inhibition by caspase messenger RNA interference in Wolbachia-infected L. striatellus markedly decreased egg numbers. Together, these data suggest that wStri might enhance fecundity by increasing the number of apoptotic cells in the ovaries in a caspase-dependent manner. Our findings establish a link between Wolbachia-induced apoptosis and egg production effects mediated by Wolbachia, although the way in which the endosymbiont influences caspase levels remains to be determined. PMID- 29989658 TI - Autoantibodies reactive to PEP08 are clinically related with morbidity and severity of interstitial lung disease in connective tissue diseases. AB - Anti-Ro52 autoantibodies (Ro52-autoAbs) appear in the sera of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Studies using patient sera have shown a correlation between the generation of Ro52-autoAbs and the clinical morbidity and severity of CTD with ILD. In this study, we used a single B-cell manipulating technology and obtained 12 different monoclonal Ro52 autoAbs (mRo52-autoAbs) from the selected four patients suffering from severe ILD with a high titer of Ro52-autoAbs in their sera. Western blot analysis revealed that 11 of 12 mRo52-autoAbs bound to the coiled-coil domain of Ro52. Competitive ELISA demonstrated that mRo52-autoAbs competed with each other to bind to Ro52. Epitope mapping showed that two of them specifically bound to a peptide (PEP08) in the coiled-coil domain. We then examined the titer of Ro52-autoAbs in the sera of 192 CTD patients and assessed the relationship between the serum levels of Ro52-autoAbs that were reactive to PEP08 peptide and the clinical morbidity and severity of ILD. Statistical analysis revealed that the production of PEP08 reactive Ro52-autoAbs correlated with the morbidity and severity of ILD in CTD. Assessment of the production of PEP08-reactive Ro52-autoAbs in autoimmune diseases is useful for predicting the clinical morbidity of ILD. PMID- 29989659 TI - Exploration into the Syntheses of Gallium- and Indiumborates under Extreme Conditions: M5 B12 O25 (OH): Structure, Luminescence, and Surprising Photocatalytic Properties. AB - Explorative solid-state chemistry led to the discovery of the two new compounds Ga5 B12 O25 (OH) and In5 B12 O25 (OH). Extreme synthetic conditions within the range of 12 GPa and a temperature of 1450 degrees C realized in a Walker-type multianvil apparatus resulted in the formation of an unprecedented tetragonal structure with the exclusive presence of condensed BO4 tetrahedra, forming cuboctahedral cavities. Doping of these cavities with Eu3+ in In5 B12 O25 (OH) yielded in an orange-red luminescence. Photocatalytic tests of In5 B12 O25 (OH) revealed a hydrogen production rate comparable to TiO2 but completely co-catalyst free. PMID- 29989660 TI - Selective separation and determination of quercetin from red wine by molecularly imprinted nanoparticles coupled with HPLC and ultraviolet detection. AB - In this study, a highly sensitive and selective sample pretreatment procedure using molecularly imprinted silica nanoparticles was developed for the extraction and determination of quercetin in red wine samples coupled with high-performance liquid chromatography with ultraviolet detection. The imprinted silica nanoparticles were prepared in the presence of N-acryoyl-l-aspartic acid (functional monomer), quercetin (template), azobisisobutyronitrile (initiator) and methylene bisacrylamide (cross-linker) and methanol/water (porogen) via surface-initiated reversible addition-fragmentation chain transfer polymerization. Surface characterization was performed and several imprinting parameters were investigated, and the results indicated that adsorption of quercetin on the imprinted silica nanoparticles followed a pseudo-first-order adsorption isotherm with a maximum adsorption capacity at 26.4 mg/g within 60 min. The imprinted silica nanoparticles also showed satisfactory selectivity towards quercetin as compared with its structural analogues. Moreover, the imprinted nanoparticles preserved their recognition ability even after five adsorption-desorption cycles. Meanwhile, the nanoparticles were successfully applied to selective extraction of quercetin from red wine with a high recovery (99.7-100.4%). The limit of detection was calculated to be 0.058 MUg/mL with a correlation coefficient 0.9996 in the range of 0.2-50 MUg/mL. As a result, the developed selective extraction method using molecular imprinting technology simplifies the sample pretreatment procedure before determination of quercetin in real samples. PMID- 29989661 TI - Infant wake after sleep onset serves as a marker for different trajectories in cognitive development. AB - BACKGROUND: Sleep variables have been linked to improved functioning of learning and memory throughout life, with most studies focusing on older children and adults. Since infancy is a time of outstanding plasticity, sleep variables could be particularly important for cognitive development in that age group. METHODS: This is a longitudinal study collecting data from 40 infants at four different time points of 4, 6, 8 and 10 months. Sleep variables were assessed using actigraphy for a week, as well as a sleep questionnaire. Eye-tracking was employed to examine developmental cognitive trajectories. Infants had to remember the location of a toy that had previously been linked to a sound and an eye tracker recorded whether they were searching the correct location upon hearing the sound. RESULTS: Based on their trajectories between 4 and 10 months, infants were divided into two groups who shifted their response strategies at different time points. Those two groups also differed in other aspects of their looking patterns and scored increasingly differently in the Ages & Stages Questionnaire over time. Time spent awake in the night early in life was reduced in the group who changed their strategy earlier. CONCLUSIONS: While previous research examined the relation of infant sleep and cognitive functioning measured once, this paper provides first evidence that night wake time can serve as a marker for different cognitive trajectories. PMID- 29989662 TI - Head-to-head trials of systemic psoriasis therapies: a systematic review of study design and maximum acceptable treatment differences. AB - There is increasing use of head-to-head clinical trials in dermatology when establishing the efficacy of a new treatment. Active comparator trials (ACTs) can be classified into three distinct study trial designs: non-inferiority, equivalence and superiority. A better understanding of the statistical parameters, such as acceptable treatment differences (also known as the margin or delta), is necessary to properly design and interpret findings of active comparator trials (ACTs) in the field of dermatology. Therefore, the objective of this study was to summarize the maximum acceptable treatment differences in clinical trials that examine the efficacy of an oral or biologic psoriasis therapy with an active comparator. We conducted a systematic search using MEDLINE, Scopus, EMBASE, Cochrane Central Register of Controlled Trials, LILACS, Web of Science and ClinicalTrials.gov from inception to 31 August 2017. All ACTs with adult participants that had a primary outcome of the Psoriasis Area and Severity Index score were included. Bibliographies of articles were further reviewed. Two investigators independently assessed for article inclusion and separately completed data extraction of predefined data points. When there was a disagreement, a third investigator was consulted. Of the 49 ACTs included, there were 13 superiority, eight non-inferiority and seven equivalence trials. Another 21 studies had inadequate information for classification. All of the non inferiority trials reported the margin, one of the superiority and six of the equivalence trials stated the treatment difference explicitly. For superiority trials, acceptable treatment differences ranged from 14% to 20%. The non inferiority studies reported lower bound margins ranging from -20% to -10%. The equivalence trials reported upper and lower bound margins ranging from +/-12.5% to +/-18%. The results demonstrate the need for harmonization in the conduct of dermatological clinical trials and in the approaches of reporting research parameters. PMID- 29989663 TI - Extracardiac ice formation during CoolLoop cryoablation of atrial fibrillation. AB - A 75-year-old male patient was referred for longstanding atrial fibrillation ablation. We performed this procedure combining an epicardial and endocardial approach. Under general anesthesia and via a left-sided thoracoscopic approach, we isolated the pulmonary veins (PVs) and the roofline and inferior line were created using a radiofrequency tool. To isolate the endocardial PVs, a transseptal puncture was performed via the groin, and a cryoablation CoolLoop catheter (AFreeze GmbH, Innsbruck, Austria) was advanced into the left atrium. Ice crystals started to appear on the epicardial surface of the left inferior PV antrum after 121 seconds later, those crystals had formed an ice plaque. For the first time in humans, we were able to visualize the transmural effects of cryothermal energy ablation via a CoolLoop catheter on the epicardial surface of the ostium of the PV. PMID- 29989664 TI - Childhood high-frequency EEG activity during sleep is associated with incident insomnia symptoms in adolescence. AB - BACKGROUND: Insomnia has been associated in cross-sectional studies with increased beta (15-35 Hz) electroencephalogram (EEG) power during nonrapid eye movement (NREM) sleep, an index of cortical hyperarousal. However, it is unknown whether this cortical hyperarousal is present before individuals with insomnia develop the disorder. To fill this gap, we examined the association of childhood sleep high-frequency EEG activity with incident insomnia symptoms (i.e., absence of insomnia symptoms in childhood but presence in adolescence). METHODS: We studied a case-control subsample of 45 children (6-11 years) from the Penn State Child Cohort, a population-based random sample of 421 children, who were followed up after 8 years as adolescents (13-20 years). We examined low-beta (15-25 Hz) and high-beta (25-35 Hz) relative power at central EEG derivations during NREM sleep and, in secondary analyses, during sleep onset latency, sleep onset, and REM sleep. Incident insomnia symptoms were defined as the absence of parent reported difficulty falling and/or staying asleep during childhood and a self report of these insomnia symptoms during adolescence. RESULTS: Childhood high beta power during NREM sleep was significantly increased in children who developed insomnia symptoms in adolescence (n = 25) as compared to normal sleeping controls (n = 20; p = .03). Multivariable-adjusted logistic regression models showed that increased childhood high-beta EEG power during NREM sleep was associated with a threefold increased odds (95% CI = 1.12-7.98) of incident insomnia symptoms in adolescence. No other significant relationships were observed for other sleep/wake states or EEG frequency bands. CONCLUSIONS: Increased childhood high-frequency EEG power during NREM sleep is associated with incident insomnia symptoms in adolescence. This study indicates that cortical hyperarousal during sleep may be a premorbid neurophysiological sign of insomnia, which may mediate the increased risk of psychiatric disorders associated with insomnia. PMID- 29989665 TI - Focusing on the Science: JBMR Manuscript Types. PMID- 29989666 TI - Deletion of the Fanconi Anemia C Gene in Mice Leads to Skeletal Anomalies and Defective Bone Mineralization and Microarchitecture. AB - Fanconi anemia (FA) is a rare genetic disorder associated with a progressive decline in hematopoietic stem cells leading to bone marrow failure. FA is also characterized by a variety of developmental defects including short stature and skeletal malformations. More than half of children affected with FA have radial ray abnormalities, and many patients have early onset osteopenia/osteoporosis. Although many Fanconi anemia genes have been identified and a molecular pathway defined, the underlying mechanism leading to bone defects remains elusive. To understand the role of FA genes in skeletal development and bone microarchitecture, we evaluated bone physiology during embryogenesis and in adult FancA- and FancC-deficient mice. We found that both FancA-/- and FancC-/- embryos have abnormal skeletal development shown by skeletal malformations, growth delay, and reduced bone mineralization. FancC-/- adult mice present altered bone morphology and microarchitecture with a significant decrease in cortical bone mineral density in a sex-specific manner. Mechanical testing revealed that male but not female FancC-/- mice show reduced bone strength compared with their wild type littermates. Ex vivo cultures showed that FancA-/- and FancC-/- bone marrow derived mesenchymal stem cells (BM MSC) have impaired differentiation capabilities together with altered gene expression profiles. Our results suggest that defective bone physiology in FA occurs in utero and possibly results from altered BM MSC function. These results provide valuable insights into the mechanism involved in FA skeletal defects. (c) 2018 American Society for Bone and Mineral Research. PMID- 29989667 TI - Dynamic Behavior of Covalent Organic Cages. AB - Discrete, large, covalent organic cages have recently been constructed by utilizing various types of dynamic covalent bond formation. The reversibility of bond formation can provide an opportunity to exhibit unique dynamic behavior; however, the transformation of such rigid cages to other structures remains challenging. To clarify the current status of this emerging research field, this Concept article gives an overview of recent progress of the dynamic behavior of covalent organic cages by classifying them into four types of transformation, namely, dimerization into the interlocked cages, transformation into different cage structures, exchange of components, and disassembly. The driving forces of such dynamic behavior and problems to be solved are also highlighted. PMID- 29989668 TI - Burosumab: At Long Last, an Effective Treatment for FGF23-Associated Hypophosphatemia. PMID- 29989669 TI - Preparation of Dimethyl Disulfide Adducts from the Mono-Trans Octadecadienoic Acid Methyl Esters. AB - The dimethyl disulfide (DMDS) adduct method is one of the more effective methods for determining double bond positions of dienoic acid. The DMDS method can be simply used to obtain the characteristic ions in which cleavage occurs between the methylthio group-added double-bond carbons as can be seen in the mass spectrum obtained using gas chromatography/electron ionization-mass spectrometry. In the case of the methylene-interrupted di-cis type and di-trans type dienoic acid, the DMDS addition reaction only occurs at one double-bond position, and cannot occur at the remaining double-bond position due to steric hindrance. As a result, two types of adducts are produced in the addition reaction. However, in the case of the methylene-interrupted mono-trans (mono-cis) type dienoic acid, the DMDS addition reaction only occurs at the cis-double bond. As a result, one type of adduct is produced in the addition reaction. In this report, we investigate the cause of the reaction selectivity by focusing on the addition reaction time. PMID- 29989670 TI - Organellar genomics: a useful tool to study evolutionary relationships and molecular evolution in Gracilariaceae (Rhodophyta). AB - Gracilariaceae has a worldwide distribution including numerous economically important species. We applied high-throughput sequencing to obtain organellar genomes (mitochondria and chloroplast) from 10 species of Gracilariaceae and, combined with published genomes, to infer phylogenies and compare genome architecture among species representing main lineages. We obtained similar topologies between chloroplast and mitochondrial genomes phylogenies. However, the chloroplast phylogeny was better resolved with full support. In this phylogeny, Melanthalia intermedia is sister to a monophyletic clade including Gracilaria and Gracilariopsis, which were both resolved as monophyletic genera. Mitochondrial and chloroplast genomes were highly conserved in gene synteny, and variation mainly occurred in regions where insertions of plasmid-derived sequences (PDS) were found. In mitochondrial genomes, PDS insertions were observed in two regions where the transcription direction changes: between the genes cob and trnL, and trnA and trnN. In chloroplast genomes, PDS insertions were in different positions, but generally found between psdD and rrs genes. Gracilariaceae is a good model system to study the impact of PDS in genome evolution due to the frequent presence of these insertions in organellar genomes. Furthermore, the bacterial leuC/leuD operon was found in chloroplast genomes of Gracilaria tenuistipitata, G. chilensis, and M. intermedia, and in extrachromosomal plasmid of G. vermiculophylla. Phylogenetic trees show two different origins of leuC/leuD: genes found in chloroplast and plasmid were placed with proteobacteria, and genes encoded in the nucleus were close to Viridiplantae and cyanobacteria. PMID- 29989671 TI - Highly Stretchable and Tough Hydrogels below Water Freezing Temperature. AB - Hydrogels consist of hydrophilic polymer networks dispersed in water. Many applications of hydrogels rely on their unique combination of solid-like mechanical behavior and water-like transport properties. If the temperature is lowered below 0 degrees C, however, hydrogels freeze and become rigid, brittle, and non-conductive. Here, a general class of hydrogels that do not freeze at temperatures far below 0 degrees C, while retaining high stretchability and fracture toughness, is demonstrated. These hydrogels are synthesized by adding a suitable amount of an ionic compound to the hydrogel. The present study focuses on tough polyacrylamide-alginate double network hydrogels equilibrated with aqueous solutions of calcium chloride. The resulting hydrogels can be cooled to temperatures as low as -57 degrees C without freezing. In this temperature range, the hydrogels can still be stretched more than four times their initial length and have a fracture toughness of 5000 J m-2 . It is anticipated that this new class of hydrogels will prove useful in developing new applications operating under a broad range of environmental and atmospheric conditions. PMID- 29989672 TI - Physicians' challenges under El Salvador's criminal abortion prohibition. AB - El Salvador's criminal abortion law-one of the few in the world that prohibits all abortions and that is actively enforced against women-harms women's health and undermines the ethical duties of Salvadoran physicians and the standing of the medical profession. Under the criminal abortion regime, physicians are incentivized to disclose their patients' confidential medical information, in violation of their ethical duties, and public healthcare facilities have become sites of criminal investigation. These investigations target women not only for illegal abortions, but also for miscarriages and obstetric emergencies. The ban further prevents physicians from providing medical care that is often necessary to preserve a woman's life or health. Finally, by criminalizing women's pregnancy outcomes, the regime undermines the country's recent public health improvement efforts and compounds the marginalization of women and girls from its most vulnerable communities, in violation of the state's international human rights obligations. PMID- 29989673 TI - Novel approaches for the management of primary hyperparathyroidism during pregnancy. PMID- 29989674 TI - Staphylococcus aureus haem biosynthesis and acquisition pathways are linked through haem monooxygenase IsdG. AB - Haem is an essential cofactor in central metabolic pathways in the vast majority of living systems. Prokaryotes acquire haem via haem biosynthesis pathways, and some also utilize haem uptake systems, yet it remains unclear how they balance haem requirements with the paradox that free haem is toxic. Here, using the model pathogen Staphylococcus aureus, we report that IsdG, one of two haem oxygenase enzymes in the haem uptake system, inhibits the formation of haem via the internal haem biosynthesis route. More specifically, we show that IsdG decreases the activity of ferrochelatase and that the two proteins interact both in vitro and in vivo. Further, a bioinformatics analysis reveals that a significant number of haem biosynthesis pathway containing organisms possess an IsdG-homologue and that those with both biosynthesis and uptake systems have at least two haem oxygenases. We conclude that IsdG-like proteins control intracellular haem levels by coupling the two pathways. IsdG is thus a target for the treatment of S. aureusinfections. PMID- 29989676 TI - Efficacy of ivabradine to control ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal hereditary disease characterized by complex ventricular arrhythmias provoked by exercise or emotional stress and by a high mortality rate in young individuals. Nadolol alone or in combination with flecainide is the most effective therapy. However, compliance to treatment is often low due to side effects. We report two patients with CPVT in whom side effects of treatment prompted discontinuation of flecainide or nadolol and in whom ivabradine was successfully added to therapy. In these two patients, ivabradine in combination with nadolol or flecainide was well tolerated and successfully suppressed nonsustained polymorphic ventricular tachycardia and couplets. Thus, ivabradine could limit the use of implantable cardioverter-defibrillators or left cardiac sympathetic denervation in CPVT patients with uncontrollable ventricular arrhythmias. PMID- 29989675 TI - The Impact of Alcohol and Social Context on the Startle Eyeblink Reflex. AB - BACKGROUND: Researchers have long sought to understand how individuals respond to alcohol in social settings with the aim of elucidating pathways of risk for alcohol use disorder (AUD). But studies that incorporate a social context are still outnumbered by those that examine alcohol's subjective effects among participants drinking alcohol in isolation. Further, perhaps due to the challenges of capturing automatic affective processes in these settings, prior studies of alcohol response in social context have relied mainly on self-report measures, and so relatively little is known about alcohol's psychophysiological effects in social settings. METHODS: Using a novel paradigm that integrated alcohol-administration procedures, startle methodology, and social context, this study examined the impact of alcohol and social context on startle eyeblink reflex among 40 social drinkers. RESULTS: Results indicated that there was a significant effect of group presence, indicating that startle magnitude was larger when people were alone than with others. There was a significant group presence-by-alcoholic beverage interaction, with the effect of alcohol being significantly larger when people were alone versus with others. These effects were found both for the startle habituation data and during the picture-viewing task. CONCLUSIONS: Results of this study highlight the importance of considering the presence of other individuals for understanding alcohol response and mechanisms of AUD risk. Findings are discussed in light of both emotional and cognitive correlates of startle reflex magnitude. Future research should examine these effects within larger samples of participants and further explore mechanisms that might underlie these effects. PMID- 29989677 TI - Dysregulated growth hormone-insulin-like growth factor-1 axis in adult type 1 diabetes with long duration. AB - CONTEXT: In type 1 diabetes (T1D), dysregulation of the GH-IGF-1 axis has been reported. Whether this is related to upper extremity impairments (UEI) is unknown. OBJECTIVE: Examine differences in GH-IGF-1 axis between T1D on subcutaneous insulin treatment and matched controls without diabetes and possible associations between GH-IGF-1 axis and UEI. DESIGN: Cross-sectional population based study. Patients with T1D, onset <35 years, duration >= 20 years, <67 years old and controls were invited to answer questionnaires and take blood samples. SUBJECTS: A total of 605 patients with T1D and 533 controls accepted to participate. OUTCOMES: Fasting levels of IGF-1, IGF-1 Z-score, IGFBP-1, IGFBP-3, C-peptide, GH and UEI. RESULTS: Patients with T1D had lower IGF-1 and IGFBP-3 and higher IGFBP-1 and GH than controls. The difference in IGF-1 persisted with age. Insulin dose was associated with increasing IGF-1 Z-score but even at a very high insulin dose (>1U/kg) IGF-1 Z-score was subnormal compared to controls. IGF-1 Z score was unaffected by glycaemic control (HbA1c) but increased with residual insulin secretion, (C-peptide 1-99 pmol/L). IGFBP-1 was associated with fasting blood glucose, negatively in controls and positively in patients with T1D probably reflecting insulin resistance and insulin deficiency, respectively. There was no association between lower IGF-1 Z-score and UEI in T1D. CONCLUSION: In adult T1D with fair glycaemic control, the GH-IGF-1 axis is dysregulated exhibiting GH resistance, low IGF-1 and elevated IGFBP-1. Subcutaneous insulin cannot normalize these changes while endogenous insulin secretion has marked effects on IGF-1 pointing to a role of portal insulin. PMID- 29989678 TI - Plant sn-Glycerol-3-Phosphate Acyltransferases: Biocatalysts Involved in the Biosynthesis of Intracellular and Extracellular Lipids. AB - Acyl-lipids such as intracellular phospholipids, galactolipids, sphingolipids, and surface lipids play a crucial role in plant cells by serving as major components of cellular membranes, seed storage oils, and extracellular lipids such as cutin and suberin. Plant lipids are also widely used to make food, renewable biomaterials, and fuels. As such, enormous efforts have been made to uncover the specific roles of different genes and enzymes involved in lipid biosynthetic pathways over the last few decades. sn-Glycerol-3-phosphate acyltransferases (GPAT) are a group of important enzymes catalyzing the acylation of sn-glycerol-3-phosphate at the sn-1 or sn-2 position to produce lysophosphatidic acids. This reaction constitutes the first step of storage-lipid assembly and is also important in polar- and extracellular-lipid biosynthesis. Ten GPAT have been identified in Arabidopsis, and many homologs have also been reported in other plant species. These enzymes differentially localize to plastids, mitochondria, and the endoplasmic reticulum, where they have different biological functions, resulting in distinct metabolic fate(s) for lysophosphatidic acid. Although studies in recent years have led to new discoveries about plant GPAT, many gaps still exist in our understanding of this group of enzymes. In this article, we highlight current biochemical and molecular knowledge regarding plant GPAT, and also discuss deficiencies in our understanding of their functions in the context of plant acyl-lipid biosynthesis. PMID- 29989680 TI - The effect of neuraminidase inhibitors on household transmission in Japanese patients with influenza A and B infection: a prospective, observational study. AB - BACKGROUND: The relative ability of neuraminidase inhibitors (NAIs) to reduce household influenza transmission when given to index patients is not established. OBJECTIVES: To compare daily secondary infection rates (SIR) of influenza A (A/H1pdm and A/H3) and B in households of index patients treated with oseltamivir, zanamivir, laninamivir, or peramivir. PATIENTS/METHODS: This Japanese, single-center, prospective, observational study (UMIN-CTR: UMIN000024650) enrolled index patients with confirmed influenza who were treated with an NAI during 6 influenza seasons (2010-2016). Secondary infection patients were household members diagnosed with the same influenza subtype 1-7 days after onset in the index patient. Daily SIR was calculated using a modified Reed-Frost model. The rate of household members with secondary infection and proportion of households with any secondary infection were also calculated. RESULTS: Index patients with influenza A (n=1146) or B (n=661) were enrolled (~3400 total index and secondary patients). Daily SIR for all virus subtypes was highest when oseltamivir was used (eg, unadjusted estimate: type A, 1.47% vs 0.71%-1.13%; type B, 1.30% vs 0.59%-0.88%). Pairwise comparisons revealed significant differences in daily SIR between NAIs for influenza type A, type B, and subtype A/H3; eg, for type A, SIR was significantly higher with oseltamivir than with peramivir or zanamivir. The rate of household members with secondary infection and proportion of households with any secondary infection also varied between NAIs. CONCLUSIONS: NAIs differed in their ability to reduce household influenza transmission; transmission was highest with oseltamivir. Physicians may consider effects on household transmission when deciding which NAI to prescribe. This article is protected by copyright. All rights reserved. PMID- 29989679 TI - H9N2 influenza viruses from Bangladesh: Transmission in chicken and New World quail. AB - The H9N2 influenza viruses that have become established in Bangladeshi live poultry markets possess five gene segments of the highly pathogenic H7N3 avian influenza virus. We assessed the replication, transmission, and disease potential of three H9N2 viruses in chickens and New World quail. Each virus replicated to high titers and transmitted by the airborne route to contacts in both species. Infected chickens showed no disease signs, and the viruses differed in their disease potential in New World quail. New World quail were more susceptible than chickens to H9N2 viruses and shed virus after airborne transmission for 10 days. Consequently, New World quail are a potential threat in the maintenance and spread of influenza virus in live poultry markets. PMID- 29989681 TI - Safety of adipose-derived cell (stromal vascular fraction - SVF) augmentation for surgical breast reconstruction in cancer patients. AB - BACKGROUND: Progress in breast cancer surgery results in a decreased frequency of mastectomy, in the early phases of cancer replaced by breast conserving therapy (lumpectomy). Increased popularity of breast reconstruction by fat or adipose stem cells (ASC)-enriched fat transfer raised uncertainty about the possible risk of increased cancer recurrence. In vitro studies suggest that locally secreted cytokines and reconstructed local blood vessels may stimulate cancer expansion or cancer de novo induction from glandular tissue remaining after lumpectomy. OBJECTIVES: The purpose of the study was to evaluate the risk of cancer recurrence in breast cancer patients related to the stromal vascular fraction (SVF) augmentation during autologous fat grafting for breast reconstruction. MATERIAL AND METHODS: The tumor recurrence ratio in 56 patients having the breast reconstructed with autologous ASC (transplanted as the subpopulation present in SVF) was compared with the frequency of tumor recurrence in 252 matched patients treated in clinics without subsequent breast reconstruction. Adipose tissue was collected by the Coleman technique and split into 2 portions: one was used for breast reconstruction, the other was enzymatically digested, and isolated cells were used for the augmentation of fat implanted into the breast area. Cancer recurrence in the experimental and matched control group was evaluated following 3-year-long observation time, and the statistical significance of difference in cancer recurrence between the experimental and control group was evaluated. RESULTS: Cancer recurrence in the group of patients treated with ASC-enriched fat for breast reconstruction was 3.7% and did not differ significantly from the control group data (4.13%). No adverse effects of therapy were observed. CONCLUSIONS: Our study does not produce any data suggesting increased cancer risk following breast reconstruction after a mastectomy or a lumpectomy combined with local radiotherapy. It may be concluded that an autologous transplantation of fat augmented with ASC is a safe and efficient procedure. Longer observation time and the observation of larger numbers of patients would be useful for strengthening the conclusion. PMID- 29989683 TI - High Initial-dose Dependency of Cerebrovascular Disease Mortality among Female Survivors of the Hiroshima Atomic Bomb Exposed in Teens: A Cohort Study, 1970 2010. AB - Several studies have been conducted on cerebrovascular disease mortality in Atomic bomb survivors. Previous studies have investigated the relationship between mortality and initial radiation dose after adjusting for the effects of sex and age at the time of the bombing (ATB), and detected a weak (but statistically significant) dose-response relationship was detected. The objective of the present study was to examine whether the sex- and age ATB-specific cerebrovascular disease mortality among Hiroshima atomic bomb survivors can be explained by the initial radiation dose. At Hiroshima University, a cohort study has been conducted with Hiroshima Atomic Bomb Survivors (ABS) since 1970. We selected 30,378 subjects from the ABS who were exposed at 3.5 km or less from the hypocenter and still alive on January 1, 1970. These subjects were followed up until December 31, 2010. The cohort data were stratified with respect to sex and age ATB into 10-year age groups. For each stratum, using Cox regression, we performed survival analyses of the risk of cerebrovascular mortality using the initial radiation dose and the exposure distance (the ground distance between the exposure location and the hypocenter) as explanatory variables. The results indicated that the risks to females exposed at 10 to 19 years old were highly dependent on the initial radiation dose (hazard ratio: 1.51, p < 0.001), while the risks to males were not. There might exist some radiation exposure effects limited to women who were in their teens at the time of exposure. However, the background mechanisms remain unclear, necessitating further study. PMID- 29989682 TI - Assessment of Outcome of Hepatic Arterial Infusion Chemotherapy in Patients with Advanced Hepatocellular Carcinoma by the Combination of RECIST and Tumor Markers. AB - To assess the outcome of stable disease (SD) patients with advanced hepatocellular carcinoma (HCC) by tumor markers after the first course of hepatic arterial infusion chemotherapy (HAIC). The study subjects were 156 HCC patients treated with HAIC and classified as Child Pugh A, with no extrahepatic metastasis, and no history of sorafenib treatment. In the study and validation cohorts, the AFP and DCP ratios of patients who were considered SD to the first course of HAIC were analyzed by AUROC for a prediction of response to the second course of HAIC. The imaging response to the first course of HAIC was classified as partial response (PR), SD and progressive disease (PD) in 29 (18.8%), 80 (51.9%), and 44 (28.6%) patients respectively. For SD patients, the a-fetoprotein (AFP) and des-y-carboxy prothrombin (DCP) ratios of patients who were considered SD to the first course of HAIC were analyzed by the receiver operating characteristic curve for prediction of response to the second course of HAIC in the study cohorts. The area under the curve of AFP ratio was 0.743. The area under the curve of DCP ratio was 0.695. The cut-off values of AFP and DCP ratios were 1.3 and 1.0, respectively. In the validation cohort, the accuracy of the prediction of response in this validation cohort (71.4%) showed no significant difference compared to that in the study cohort (72.4%) (p = 1.0). The results suggested that patients with a high tumor marker ratio could be switched to alternative therapeutic regimens despite the SD response to HAIC. PMID- 29989685 TI - STPs: a ticking time bomb? PMID- 29989684 TI - High Excess Risk of Heart Disease Mortality among Hiroshima Atomic Bomb Male Survivors Exposed Near the Hypocenter. AB - Heart disease (HD) mortality is the second leading cause of death in Japan. The HD mortality risk among Atomic bomb survivors is slightly positive but shows a statistically significant dose-response relationship with initial radiation dose, as reported by the Radiation Effects Research Foundation. In that report, dosimetry was based on initial radiation only, with the effect of indirect radiation dose not taken into consideration. The atomic bomb radiation, however, consisted of both initial and residual radiation. We reevaluated the dose response relationship for HD mortality using exposure distance (ground distance between the location where exposed and the hypocenter) as a surrogate indicator of radiation dose. At Hiroshima University, a cohort study has been conducted with Hiroshima Atomic Bomb Survivors (ABS) since 1970. We selected 29605 subjects from the ABS who were exposed at 3.5 km or less from the hypocenter and alive on January 1, 1970. These subjects, referred to as "Hiroshima hibakusha" in this paper, were followed until December 31, 2010. We stratified the cohort data with respect to sex and age at the time of bombing (ATB) into 10-year age groups. For each stratum, by applying an extended Cox regression model with time-dependent covariates, we analyzed the risk of HD mortality using either initial radiation dose or exposure distance as an explanatory variable. The results indicate a high excess risk in males and older age ATB females who were exposed near the hypocenter. This difference may be explained by the effect of female sex hormone on the circulatory system among young age ATB females. Some unknown risk factor related to exposure distance was also implicated in the elevated risk of HD among the Hiroshima hibakusha, especially in males. This necessitates further study. PMID- 29989686 TI - Standing up and SPEAKING OUT. PMID- 29989687 TI - Preventive measures. PMID- 29989688 TI - Spreading smiles. PMID- 29989689 TI - Bridging the gap?. PMID- 29989690 TI - BE BOLD! PMID- 29989691 TI - Rise to the challenge. PMID- 29989692 TI - Breaking through the TABOO. PMID- 29989693 TI - Tackling a dark reality. PMID- 29989694 TI - Lessons from abroad. PMID- 29989695 TI - Fighting poverty head on. PMID- 29989696 TI - Making food waste the main course. PMID- 29989698 TI - LEADING THE WAY FROM THE FRONT LINES AND INTO THE FUTURE. PMID- 29989697 TI - Spreading telehealth know-how to other hospitals. PMID- 29989699 TI - A 30/30/30 SOLUTION TO SET QUALITY GOALS AND KEEP THE MOMENTUM GOING. PMID- 29989700 TI - 'ITS AMAZING WHAT YOU FIND OUT WHEN YOU MAKE ROUNDS'. PMID- 29989701 TI - TRIUMPH OVER TURMOIL. PMID- 29989702 TI - REACHING THE COMMUNITY OUTSIDE HOSPITAL WALLS. PMID- 29989703 TI - CREATING AN ACCESS POINT FOR WELLNESS. PMID- 29989704 TI - PAVING THE WAY FOR FUTURE GENERATIONS. PMID- 29989705 TI - DENTAL CARE ON WHEELS GIVES KIDS NEW HOPE. PMID- 29989706 TI - A COMMITMENT THAT IS LONG-TERM. PMID- 29989707 TI - BRINGING CARE AND COMFORT ACROSS THE CONTINUUM. PMID- 29989708 TI - BON SECOURS RICHMOND HEALTH SYSTEM, RICHMOND, VA. PMID- 29989709 TI - CAMBIA PALLIATIVE CARE CENTER OF EXCELLENCE, SEATTLE. PMID- 29989711 TI - HOSPITAL & PHYSICIAN LEADERS MAKE THE MOST OF THEIR COMBINED STRENGTHS. PMID- 29989710 TI - HELPING HOSPITALS ACROSS THE STATE SHARE DATA AND BEST PRACTICES TO PIONEER VALUE. PMID- 29989712 TI - A CENTURY OF FOSTERING COLLABORATION FOR PATIENT SAFETY & QUALITY. PMID- 29989714 TI - Can I Dismiss a Very Obese Patient from My Practice?. PMID- 29989713 TI - THREE INNOVATIVE, BUT PRACTICAL WAYS TO USE HEALTH IT. PMID- 29989716 TI - The Problem with an After-Hours Prophy Appointment. PMID- 29989715 TI - Addressing Repeated Injuries in the Workplace. PMID- 29989717 TI - CBCT Diagnosis of a Stafne Bone Defect. AB - The Stafne bone defect, also known as the Stafne bone cyst, or Stafne bone cavity, is an asymptomatic, static depression of the lingual aspect of the mandible that often appears as a radiolucent area near the angle of the mandible. It noted as an incidental finding during routine dental imaging. The purpose of this article is to present a case that was diagnosed as a Stafne bone defect using Cone Beam Computed Tomography (CBCT). This diagnosis is based on radiographic characteristics, which are described as a well-defined, round to ovoid radiolucent lesion in the lower left mandible, located below the inferior alveolar nerve canal and anterior to the angle of the mandible. Radiographic confirmation should preclude further surgical exploration. PMID- 29989718 TI - Segmenting Full-mouth Reconstruction to Enable Financial Feasibility. PMID- 29989719 TI - What Are OIG Requirements? And What Do You Need to Know?. PMID- 29989720 TI - Clinical Significance of Pharmacological Prophylaxis based on the Original Risk Classification of Venous Thromboembolism after Lower Abdominal Surgery. AB - Pharmacological prophylaxis was not routinely administrated following gastroenterological surgery because of concerns about bleeding complications. We tried to establish the original risk classification to determine the indication for pharmacological prophylaxis for selected patients at high risk of venous thromboembolism (VTE). One hundred and fifty-six consecutive patients who underwent lower abdominal elective surgery were divided into three groups (highest, high, and low risk groups) based on the original risk classification. Pharmacological prophylaxis was indicated for patients in the highest and high risk groups. We investigated safety and efficacy of the pharmacological prophylaxis based on this classification. Sixteen patients were classified in the highest, 50 in the high, and 90 in the low risk groups. Pharmacological prophylaxis was used for 59 cases (37.8%). There was no symptomatic pulmonary embolism or major bleeding complications. There were no significant differences in the occurrence of postoperative complications, analgesia use, and median postoperative pain scores for the three groups. In the highest and high risk groups administrated pharmacological prophylaxis, fibrin degradation products (FDP) and D-dimer did not change between postoperative day 1 and day 7. These data suggested the clinical significance of the pharmacological prophylaxis based on the original risk classification. PMID- 29989721 TI - Ganglioneuroma of Spinal Nerve Root: A Rare Case Mimicking Herniated Lumbar Disc and Lumbar Radiculopathy. AB - Ganglioneuromas are rare benign tumors arising from neuroepithelial cells. Even more rarely they involve lumbar spinal nerve roots. We report a 34-year-old male patient who presented with typical lumbar radiculopathy. He had low back pain radiating to the right lower leg with numbness. His MRI revealed a herniated disc at L5-S1 compressing the right nerve root. Surgery was planned for microdiscectomy and nerve root decompression. Right L5 hemilaminotomy was performed and the nerve root was identified. Surprisingly the nerve root was markedly inflamed and there was no obvious disc tissue herniation. Considering it to be a spinal nerve root tumor, the dura of the nerve root was opened and nerve root mass exposed. Subtotal resection was performed. Biopsy showed Ganglioneuroma. The main purpose of this article is to report such a rare case and also to review the literature. PMID- 29989722 TI - A Case of Spontaneously Reduced Ileoileal Intussusception Caused by a Lipoma. AB - Intussusception in adulthood is unusual. We describe herein a rare case of adult ileoileal intussusception caused by an ileal lipoma, which was diagnosed preoperatively and was confirmed at the operation to have reduced spontaneously. A 68-year-old woman experienced sudden-onset colicky pain in the upper abdomen accompanied by vomiting and was brought to our hospital by ambulance. Physical examination revealed a distended abdomen and tenderness in the upper abdomen. Laboratory findings showed slightly elevated inflammatory parameters. Abdominal computed tomography (CT) showed a target sign in the ileum, which is a typical sign of intussusception. Additional caudal-side scans showed a homogenous and fatty mass measuring 2.5 cm that was considered to be the leading point for the invagination. These findings led to a pre-operative diagnosis of intussusception induced by a lipoma. The patient underwent emergency surgery. Laparotomy revealed a yellowish, soft ileal tumor measuring 2.5 cm in diameter and that the intussusception had already been reduced at laparotomy. Approximately 15 cm of the ileum's length, including the tumor, was resected, and an end-to-end anastomosis was performed. Adult intussusception caused by an ileal lipoma is a rare condition. However, CT is the most useful tool for making a definite preoperative diagnosis based on its typical findings. PMID- 29989723 TI - Russell Body Gastritis Concurrent with Eosinophilia: a case report. AB - A 64-year-old male patient with a histological diagnosis of Russell body gastritis and with eosinophilic infiltrate in biopsy specimens is reported. The patient continued hemodialysis and pseudomembranous enteritis was contracted. Upper gastrointestinal endoscopy was performed due to poor appetite and blood eosinophilia. During endoscopy, a flare, swollen mucous membrane, and multiple verrucous erosions were noted in the gastric antrum. Biopsy and histopathological examination of gastric mucosa showed infiltration of plasma cells containing Russell bodies and eosinophils. Plasma cells containing Russell bodies were positive for CD138, immunoglobulin A (IgA) and kappa-light chain. Giemsa stained biopsy specimen revealed that the patient was negative for Helicobacter pylori. The patient was diagnosed with Russell body gastritis with eosinophilia. This is the first report of Russell body gastritis concurrent with eosinophilia. We discussed the possible correlation between the presence of plasma cells containing Russell bodies and gastric eosinophilia. PMID- 29989724 TI - Venturing Into Murky Waters: New Economic Models for EMS Alternative payment setups are coming-start your basic understanding here. PMID- 29989725 TI - Pediatric Education in EMS A qualitative study looks at how it might be improved. PMID- 29989726 TI - Special Protocols for Special Patients. PMID- 29989727 TI - ExDS is characterized by extreme agitation and aggression in a patient with altered mental status. PMID- 29989728 TI - Beyond Eduation Regurgitation The secret recipe for 100% competence (and first time exam pass rates) revealed. PMID- 29989729 TI - Simulation Technology Improves Training Quality. PMID- 29989730 TI - How to use to Enhance EMS Education It can inspire both new students and experienced practitioners to think differently and act decisively. PMID- 29989731 TI - Curriculum Matching For a credible and valid educational experience, make sure these three key elements are aligned. PMID- 29989732 TI - A FIELD GUIDE TO Mixed-Methods Research and Its Applications in EMS. PMID- 29989733 TI - Breeding of new Rehmannia glutinosa variety. AB - Huaidi 81, a new variety of Rehmannia glutinosa with excellent comprehensive characters, was screened by space mutation of hybrid seeds of 85-5 and Beijing No.1. The fresh weight, index composition, resistance, chlorophyll, anthocyanin and photosynthetic characteristics of Huaidi 81 and the main cultivars were determined. The results showed that: the per plant fresh weight of Rehmannia ranked in the order as follows: Huaidi 81 > 85-5 > Golden Nine >Huaifeng >Qinhuai>Beijing No.3, there was extremely significant difference between Huaidi 81 and others. The catalpol content ranked in the following order: Beijing No.3 (1.601%)> Qinhuai (1.588%)> Huaidi 81 (1.314%)> Golden Nine > 85-5 (1.073%)> Huaifeng (0.924%). There was no significant difference between Huaidi 81 and Golden Nine, but extremely significant difference between was found in Huaidi 81 and other varieties; The acteoside content ranked in the following following order: Huaidi 81 (0.096%) > Qin Huai (0.069%) >85-5 (0.047%) > Beijing No.3 (0.035%) > Huaifeng (0.023%) > Golden Nine (0.022%). There was significant difference between Huaidi 81 and other varieties. Huaidi 81 showed high resistance to Septoris digitalis Pass and middle resistance against leaf ring rot, which indicated that Huaidi 81 had good resistance to leaf diseases. Huaidi 81 with highest chlorophyll content and moderate anthocyanin content showed the highest photosynthetic rate. All these results indicated that the new variety Huaidi 81 with best comprehensive properties was suitable for popularizing as a new Rehmannia glutinosa variety. PMID- 29989734 TI - Construction of a genetic linkage map and identification of QTL associated with growth traits in Malus sieversii. AB - 110 F(1) individuals of apple were obtained by crossing between a good quality cultivar'Red Fuji'ofMalus domestica and an accession'Hongrou Apple'ofMalus sieversi. Using Joinmap3.0, a molecular genetic linkage map of Malus sieversii was constructed by 175 SSR and 105 SRAP markers which were integrated into 17 linkage groups and spanned 1299.67cM in genome with an average distance of 4.6cM between the markers. By using interval mapping method,17 QTLs for eight growth traits of Malus sieversii were detected, including 2 QTLs for tree height on cl and c16, 2 QTLs for stem height on c7, 2 QTLs for stem thickness on c3, 2 QTLs for new shoot length on c15 and c16, 2 QTLs for new shoot diameter on c2, 3 QTLs for internode number on c1, c2 and c2, 2 QTLs for internode length on c 1 and c2, 2 QTLs for lenticel density on c17, respectively. The phenotypic variations explained by each QTL ranged from 10.15% to 41.66%, and their LOD values varied from 2.54 to 4.53, of which five QTLs were major effect genes (LOD>=3.5). PMID- 29989735 TI - Extrication process of chlorogenic acid in Crofton weed and antibacterial mechanism of chlorogenic acid on Escherichia coli. AB - Crofton weed is a perennial herb and a biological intruding species. The present study firstly used the orthogonal test to compare the differences in extraction of chlorogenic acid in leaves and stems of Crofton weed by using three kinds of solvents, namely water, ethanol and ethyl acetate. The best effect was found by using ethonolic extraction of chlorogenic acid in Crofton weed. Further, by choosing Escherichia coli as test object, in-vitro antibacterial test was conducted to study the antimicrobial activities of chlorogenic acid by testing a series of indexes before and after the interaction between chlorogenic acid and Escherichia coli, to clarify the antibacterial mechanism of chlorogenic acid on Escherichia coli. Finally, by comparing the antibacterial activities of isochlorogenic acid A on Escherichia coli, it was concluded that both chlorogenic acid and isochlorogenic acid A showed antibacterial activities against Escherichia coli, wherein chlorogenic acid had a better antibacterial effect on Escherichia coli than isochlorogenic acid A. PMID- 29989736 TI - Rapid propidium monoazide cPCR assay for exclusive quantification of viable Salmonella spp. cells. AB - Combination of pretreatment with propidium monoazide by competitive polymerase chain reaction (cPCR) was evaluated to enumerate the viability of Salmonella spp. The results showed that PMA treatment was effective in preventing the cPCR detection of target sequences from non- viable cells. In less than 5 hrs, this method generated a signal from viable but nonculturable (VBNC) Salmonella spp. The standard culture method gave approximately 1-2 log(10)cfu ml(-1) less as compared to the PMA-cPCR results. These results provided evidence to support the VBNC state, whereas, the viable cells failed to be cultured by SCM. The proposed method did not detect DNA from dead Salmonella spp. but recognizes the infectious potential of the VBNC state and is thereby, able to assess the effect of control strategies and provide trustworthy data for risk assessment. PMID- 29989737 TI - in vitro polysaccharide extraction from Cipangopaludina cathayensis and its pharmacological potential. AB - Cipangopaludina cathayensis (mudsnails) is a snail-like animal. This study intends to reveal pharmacological potential of polysaccharide extracted from mudsnails. Crude soluble polysaccharide of mudsnails was extracted using hot water extraction and ethanol precipitation method. The crude polysaccharide was purified successively using Sevag method. Applying Fenton reactions, it was found that antioxidant potential efficiency of polysaccharide extracted from mudsnail was dose-dependent and reached up to 44.29% at 4 mg ml(-1) concentration. Most significantly, polysaccharide extracted from mudsnail could efficiently inhibit lung cancer cell line A-549 proliferation in vitro and over 50% cells were killed on applying 300 mg ml(-1) of polysaccharide after 24 hrs of post treatment. It implies that mudsnail polysaccharide is a potential anti-tumor agent. PMID- 29989738 TI - Seasonal characteristics of chlorophyll-a and its relationship with environmental factors in Yunmeng Lake of China. AB - Sampling was carried out according to the season, in order to analyze the seasonal characteristics of chlorophyll-a and its relationship with environmental factors in Yunmeng Lake on 1st May, 12th August, 1st October and 14th December of 2013. The results showed that the average annual water temperature, pH, TP, TN and chlorophyll-a concentration in Yunmeng Lake was 15.9 degrees C, 7.12, 0.07 mg l(-1), 1.58 mg l(-1) C and 30.60 MUg 1(1) respectively. The water quality was Class IV water or eutrophic type. Water chlorophyll-a was significantly positive with pH and TP(R(2)=0.6077 p<0.01; R(2)=0.5855 p<0.01), low correlation with water temperature (R(2)=0.0566 p>0.05). lg (Y(Chl a)was significantly positive with lg(X(TP))(R(2)=0.5176 p<0.01), N/P was 22 and P may be restricted. PMID- 29989739 TI - Study on CH(4) and N(2)O emissions from water-saving irrigation in Phaeozem paddy fields in cold areas. AB - Increasing greenhouse gas emissions and water shortage are two main problems associated with cultivation of rice. Soil moisture control is not only a core technology in water-saving irrigation, but also a decisive factor of greenhouse gas emissions. The CH(4) and N(2)0 emission fluxes from intermittent irrigation and flooding irrigation in Phaeozem paddy fields in cold area were measured in situ to provide a theoretical basis for studying the regulation of CH(4) and N(2)O emissions and comprehensive assessing the effect of intermittent irrigation on the environment and control of greenhouse gas emissions. During the rice growing period, CH(4) emissions peaked at the tillering stage, whilst N(2)0 emissions peaked twice at the tillering and milky ripening stages. The accumulated emission of N(2)O from the implementation of flooding irrigation in paddy fields was 6.46 gm(-2), whilst that from intermittent irrigation was 5.47 gm(-2). The accumulated emission of N(2)0 from the implementation of flooding irrigation in paddy fields was 36.88 mgm(-2), whilst that from intermittent irrigation was 68.47 mgm(-2). The global warming potential of CH(4) and N(2)0 was 1362.7lkgCO(2)ha(-1) from intermittent irrigation in paddy fields, a value 108.12 kgCO(2)ha(-1) lower than that from flooding irrigation. Intermittent irrigation can thus be used to effectively decrease and control the combined greenhouse effect of CH4 and N20 emissions from rice paddy fields. PMID- 29989740 TI - Sorption of tetracycline, oxytetracycline and tylosin to eight surface sediments of Taihu Lake. AB - The objective of the present study is to investigate the mechanism of tetracyclines and macrolieds absorption on Taihu Lake sediments. In the study, batch technique was used to study the adsorptive behavior of three pharmaceutical antibiotics (tetracycline, oxytetracycline and tylosin) from several sediments of Taihu Lake, Zhushan Bay, Western Lakeshore, Lake Center, Southern Lakeshore, East Tai Lake, Eastern Lakeshore, Gonghu Bay and Meiliang Bay. The eight sediments showed extraordinarily high absorption affinity for all the tested antibiotics. However, especially the sediments of East Tai Lake was exceptional. The observed sorbent to solution distribution coefficient (K(d), 1 kg(-1)) was 10(2)-10(4) . The sediment of East Tai Lake showed highest organic carbon content and cation exchange capacity. A remarkably strong sorption of antibiotics to the sediment of East Tai Lake can be attributed to the cation exchange and complexation reactions between the functional groups of antibiotics and the respective charged and polar sites of the sorbents. The sorption affinity of tetracycline and oxytetracycline from the eight sediments was higher than tylosin. Tetracycline and oxytetracycline had multiple polar and ionizable functional groups. In the study within the tested pH, the zwitterion speciation is predominated; therefore, the sorption interaction (cation exchange and surface complexation) between tetracycline and sediments was expected stronger than tylosin. PMID- 29989741 TI - Bera Lake water quality, past and present situation. AB - Bera Lake is the largest natural fresh water reservoir in Malaysia. It has vital environmental and ecological importance for human and wild life. Nevertheless, water quality of this lake has been degraded during the last few decades due to land development projects at catchment area. Therefore, a comprehensive water quality assessment of Bera Lake was implemented in order to compare current water quality with the implementation of land development projects. In situ water quality surveying was implemented using calibrated full option Hydrolab DS 5. Eleven parameters viz., temperature, depth of sampling, salinity, Turbidity, total dried solid, pH, NH4(+), N03(-), Cl(-), saturation percentage of dissolved oxygen, specific conductivity were recorded in fifty one stations at 0.2h, 0.5h, and 0.8h depth. National Water Quality Standards for Malaysia (NWQS) and Water Quality were used to evaluate Bera Lake quality based on previous and resultant data. Vertical water quality analysis revealed a clear stratification in Bera Lake water profile in terms of temperature, dissolved oxygen, chloride (Cl(-)), nitrate (NO(3)), pH and specific conductivity (EC) parameters. Results clearly demonstrate the important role of land use changes since 1972 in the physico chemical condition of water quality at Bera Lake. Classifications of water quality before and after land development project were calculated as class II and class V, respectively. A long-term and comprehensive monitoring of water quality assessment is recommended in order to reach plan of sustainable water resources use with conservation approach. PMID- 29989742 TI - Hydrodynamic analysis of rigid and flexible pectoral fins. AB - Numerical study on unsteady hydrodynamic characteristics of rigid and flexible pectoral fins in viscous flow-field was performed in the present study. The effect of key kinematical parameters on the propulsion performance was analyzed. The propulsion mechanism was explored by evolution of wake vortices. Computational results revealed that optimal combination for investigated parameters was U = 4C, Phi(FLA) = 45 degrees , DeltaPhi(FL) = 60 degrees and alpha(0) = 0.2. Wake vortices were shed from two edges of fin and fin tip and convect downstream as well as laterally. For flexible pectoral fin, the shedding time was delayed and shed wake vortices keep longer time near the fin that led to difference in variation amplitude of hydrodynamics as compared to rigid fin. The hydrodynamic performance of flexible fin was superior to that of rigid fin for low incoming velocity. However, the opposite situation occured for high incoming velocity. PMID- 29989743 TI - Effect of COD/SO(4)(2-) ratio and alkalinity on COD removal and sulfate reduction in two-phase expanded granular sludge bed. AB - In the present study, a bench-scale two-phase expanded granular sludge bed (EGSB) reactor was applied for treatment of high-sulfate wastewater. The reactor was operated continuously at 35 degrees C. The EGSB 1, as sulfate-reducing phase, and EGSB2, as methane-producing phase, were combined after successful start-up. The treatment characteristics, including the effect of influent COD/SO(4)(2-) ratio and alkalinity in reactor have been discussed for EGSB1 and EGSB2 respectively. When total COD removal was 85%, the influent COD/S0(4)(2-) ratio was 2.8. When the ratio was less than 2.8, the COD removal descended quickly. The total sulfate removal then raised to 90% and the ratio exceeded 4.4. When influent alkalinity was kept at 8-10 mmol l(-1), the total COD and SO(4)(2-)removal reached 93.3% and 94.0% respectively. The results presented in the study provide some useful information for optimization of COD removal and SO(4)(2-) reduction process in wastewater treatment. PMID- 29989744 TI - Geographical distribution of persistent organic pollutants in the environment: A review. AB - The sources, distribution, transformation, toxicity and accumulation of persistent organic pollutants (POPs) in aquatic and terrestrial ecosystems have attracted global concern and attention over the last several decades. Although, POPs are toxic, degrade slowly and have a tendency to accumulate in the food chain, they are still widely used worldwide in many fields, such as industrial and agricultural activities. In addition, discharge of POPs into waterways may lead to serious health-related and environmental problems. This review provides an overview of the continental distributions of many types of POPs and the health risks associated with the exposure to POPs in daily life. This review also discusses the distribution of POPs in Malaysia, and the future work that will be conducted in the Klang River, one of the basins subjected to pollution due to development and urbanization. PMID- 29989745 TI - A new mathematical model of the dynamic of psychotherapy. AB - The aim of the present study is to construct a mathematical model skilled in creating hard estimates about the dynamic of psychotherapy with a purpose of using it for better sequence therapists. The outcome of the calculations envisages a new viewpoint on the therapeutic relationship and a number of suitable visions. The proposed model is based on a class of fractional differential equations. This type of class was a generalized neutral differential equation of first order. Certain sufficient conditions for the existence of periodic outcomes have been imposed. PMID- 29989746 TI - Generalized population dynamic operator with delay based on fractional calculus. AB - In population dynamics, a growing population consumes more food than a matured one that depends upon condition of individual species. This hints to neutral equations. In the present study, certain sufficient conditions for the existence of periodic solutions to a generalized Rayleigh-type equation with state dependent delay, based on fractional calculus concept was investigated. PMID- 29989747 TI - Impact of treated wastewater on soil hydraulic properties and vegetable crop under irrigation with treated wastewater, field study and statistical analysis. AB - Due to aridity, scarcity and unsustainably of natural water resources many developing countries tend to utilize wastewater for crop production. The use of treated wastewater in irrigation has many advantages and disadvantages to soil, crop and environment. The objective of the study was to investigate the effect of irrigation with wastewater on soil physical and hydraulic properties of soil, as well as the effect on yield, yield components and irrigation water use efficiency (IWUE) of vegetable crop grown under surface and subsurface drip irrigation systems. Field experiments were carried out over two consecutive seasons (2011 and 2012) at an agricultural field site in Saudi Arabia. A strip plot design (split block) was constructed to maintain six wastewater qualities. Crop water requirement was calculated by Penman Monteith equation for dry land condition. Physical and hydraulic properties of soil were analyzed at pre-season and post season to quantify the impact of wastewater treatment. Results were statistically analyzed by analysis of variance and mean separation by LSD test. Post-season analysis indicates that the second layer of soil profile was affected. The saturated hydraulic conductivity decreased by 43%, alpha value increased by 6%, and n value decreased by 2%. Accordingly simulation results a reduction of cumulative flow through soil profile was observed. On the other hand, the response ofvegetable crop to wastewater qualities, irrigation systems and growing seasons was different. The fruit yield and IWUE under subsurface irrigation system were significant as compared to surface irrigation system using two seasons. However, the local groundwater (LGW) practice produced highest yield and maximum IWUE; followed by qualities containing less percentage of wastewater. The statistical approach was successful in the analysis of designed experiment. PMID- 29989748 TI - Robust reverse logistics network design for the waste of electrical and electronic equipment (WEEE) under recovery uncertainty. AB - The recovery of waste electrical and electronic equipment (WEEE) has become a major issue for solid waste management. Exploring new ways to dispose of WEEE has become mandatory in most of the countries in the world. Reverse logistics which is the backward flows of used product from consumers to producers is an important stage dealing with the WEEE. The reverse logistics network design for WEEE plays an important role in the total cost of recovery system. With this study, taking into account the uncertainty of reverse logistics network operation for WEEE, a robust mixed integer linear programming model for WEEE reverse logistics network was established for handling problem, which was affected by the uncertainty of recovery based on the risk preference coefficient and penalty coefficient deviated from the constraints, that could allow decision-makers to adjust the robust level of the operation system and risk preferences. The calculation and simulation of the model is used for lingo 11.0. The result showed that the robust mixed integer linear programming model was better than the classic model, which had a lower operational risk and could give consideration to the cycles of different circumstances that is effective in inhibiting the uncertainty ofreverse logistics system for WEEE. PMID- 29989749 TI - Determining efficient delivery routes in specific time-frames using Geographic Information System. AB - Perishable products must be transported quickly from its production area to the markets due to the climatic conditions of Malaysia. Deterioration of fresh produce is affected by temperature and delivery time. The cost to achieve such timely delivery of perishable food can affect the revenue of suppliers and retailers. Choosing an efficient delivery route at right time can reduce the total transportation cost. However, insufficient attention has been given to transportation issues with regards to fresh food delivery of greater Kuala Lumpur. The present study involves adoption of the Geographic Information System (GIS) modelling approach to determine the fastest delivery routes for fresh products to several hypermarkets. For this purpose, ArcGIS software was adopted for solving the problem of a complex road networks. With a goal of realizing the shortest time for delivery route planning, impedance function would be integrated by taking into account the time emphasized in the study. The main findings of this study include determination of efficient routes for delivery of fresh vegetables based on minimal drive time. It has been proposed that the fastest route model for delivery of fresh products is based on comparing two time frames within a day. The final output of this research was a map of quickest routes with best delivery time based on two time frames. PMID- 29989750 TI - Study on temporary resolution for offshore marine oil spill emergencies based on remote sensing system. AB - Time is particularly critical for an oil spill occurring in the ocean as wind and current can rapidly spread the oil over a large area in a short time. Using the features of sensor surveillance system and mathematical trajectory models, the cooperation of surveillance and trajectory under oil spill emergency response is presented in this paper. Based on integration of equation simulating an oil spill trajectory, the method for remote-sensing application time (Te) has been described, and optimization of processing time described in the application time equation has been proposed. This contribution, which is integrated with remote sensing and mathematical models, is expected to be a powerful tool for real-time contingency planning in the Dalian Xingang oil spill. According to these findings, the method allowed spills emergency alerts to make the best decision for choosing remote-sensing data, considering effective temporary resolution. PMID- 29989751 TI - Analysis of heavy metals as a key indicator to predict shallow slope failure. AB - Degradation or decline of soil quality that cause shallow slope failure may occur due to physical or chemical processes. It can be triggered off by natural phenomena, or induced by human activity through misuse of land resources, excessive development and urbanization leading to deforestation and erosion of covered soil masses causing serious threat to slopes. The extent of damage of the slopes can be minimized if a long-term early warning system is predicted in the landslide prone areas. The aim of the study was to characterize chemical properties of stable and unstable slope along selected highways of Malaysia which can be manipulated as indicator to forecast shallow slope failure. The elements in soil chemical properties contributed to each other as binding agents that affected the existing soil structure. It could make the soil structure strong or weak. Indicators that can be used to predict shallow slope failure were low content in iron, lead, aluminum, chromium, zinc, low content of organic carbon and CEC. PMID- 29989752 TI - Evaluation of carbon reduction through integration of vertical and horizontal landscape design for hotel premises. AB - Hotel premises is a fundamental component of the tourism and hospitality. The design, construction, operation and end-of-life-cycle processes of hotel premises built the environment by which it exerts both positive and negative impacts on the guest and surrounding environment. Carbon emission from hotel premises are one of the major sources for greenhouse effect in urban areas. To counteract these tendencies, it is therefore necessary to identify green building practices that can be implemented over the hotel building's carbon emission in order to reduce its environmental impact as minimize the operational cost while maximizing economic and social opportunities. This study proved that through a substantial integration of spatial landscape design in combination with the right selection of plant materials based on its characteristics, carbon sequestration rate in a hotel premise can be optimized. Consequently, the role of these plants and trees in sequestering carbon emission will be best understood and the greatest opportunity as a carbon sink may be explored. This study aimed to predict carbon sequestration rate by plant materials through integration of vertical and horizontal landscape design. The decisive outcome of this study is a green practice applied in monitoring carbon toxicity and a cost effective environmental friendly carbon neutralization. PMID- 29989753 TI - Start-up of a bench-scale UASB reactor treating real substitute natural gas wastewater with glucose addition. AB - Investigation on a up-flow anaerobic sludge blanket (UASB) treating real substitute natural gas wastewater (SNGW) with glucose addition was conducted. The UASB was analyzed and addition of glucose remained as co-substrate during the whole start-up period. Excellent treatment performance was achieved when SNGW was treated with 500-mg 1(-1) glucose. The anaerobic reactor was operated continuously at 35 degrees C for 125 days. After increasing the organic loading rate, fluctuations in removal efficiencies were observed, which were partly reversible. At the end of the reactor operation, removal of chemical oxygen demand was 60% and 44% respectively. The organic loading rate and hydraulic retention time was 1.2 kg COD/(m(3).day) and 72 hrs. Gas chromatography-mass spectrometry (GC/MS) analysis showed that the phenolic compounds decreased to a low level at this condition. The main phenols in the anaerobic effluent were phenol, m-cresol, o-cresol and 2-methyl-Naphthalene. The biodegradation process of microorganisms showed the effect on toxic organic compounds of SNGW with the glucose addition. On the whole, the system exhibited good stability in terms of COD and phenols, and was found to be efficient and convenient method for SNGW. PMID- 29989755 TI - Application of bioenzymatic soil stabilization in comparison to macadam in the construction of transport infrastructure. AB - uver ninety percent or roaas anc nignways are pavea witn aspnait as it is less expensive, iexime and easy to construct and repair in comparison to concrete. The increasing effect of climatic change and cost of construction materials have forced to consider environment friendly methods to build roads. One economically feasible solution for achieving these objectives is use of enzyme soil stabilization. Use of bioenzymes is known to improve the stability of aggregates and soil materials in the roadways and other pavement structures. The present study was designed to introduce environment friendly TerraZyme to increase engineering qualities of soil for road construction. Soil classification and earth work characteristics were analyzed for two soil types representing pulverized local and transported soil with and without TerraZyme. Obtained results confirmed that treatment with TerraZyme increased engineering characteristics as indicated by increase in CBR values from 10.47 to 16.28 with 55 % improvement, increase of 4.28 % and 2.20 % in dry density and decrease of 18.13 % and 6.17 % in moisture content for untreated and treated soils, respectively. TerraZyme constructed roads will be effective for cost saving upto 15-20 % and maintenance cost reduction of60 % as compared to normal water bound Macadam road. PMID- 29989754 TI - Analysis on pollutant accidental discharge in Zhoushan Islands, China. AB - The water quality diffusion and transport around archipelago have their own uniqueness and complexity. On the basis of multinest 2D mathematical model for currents around Zhoushan Islands, model for water quality prediction was built. The pollutants discharge of Xiaogan Island was taken into consideration and mathematical model for pollutant diffusion and transport in accident discharge was studied. The influence on water quality in different discharge intensity was calculated, which provided scientific basis for the control results. It was observed that the concentration contours of COD(Mn) at 0.03 km(2) in three conditions corresponded to standard discharge at 0.90 mg l(-1), accidental discharge at 1.02 mg l(-1)and extreme discharge at 1.42 mg l(-1), respectively. Although discharge point locates between the archipelago, diffusion of pollutants is rapid for the fast-flowing waters ofZhoushan Islands, that provides good diffusion conditions. PMID- 29989756 TI - Depression internal solitary wave interaction with submerged obstacle. AB - The process of depression internal solitary wave interaction with submerged plate has been successfully stimulated in the present study. The characteristics of internal solitary wave interact with submerged plate have been reported. The results showed that both transformation and reflection were found in the wave plate interaction. For reflected wave, the wave amplitude and wave energy obeyed logarithmic law with no dimensional blocking parameter. For transmitted wave, wave amplitude and wave energy followed exponential rule with the blocking parameter. The reflected and transmitted waves showed the same wave amplitude and wave energy, while the blocking parameter was nearly 0.8. PMID- 29989758 TI - Identity and Narrative: Turning Oppression Into Client Empowerment in Social Security Disability Cases. PMID- 29989757 TI - Accuracy of Intraoral Scanners: A Systematic Review of Influencing Factors. AB - Digital impressions by intraoral scanning (IOS) have become an increasingly popular alternative to conventional impressions. This systematic review aimed to evaluate the accuracy of the available IOS systems for dental impression, and identify the influencing factors on accuracy. The literature search was completed to retrieve all the studies that investigated the IOS accuracy when used to scan teeth. A total of 2305 studies were initially obtained. After applying the inclusion criteria, 32 studies were suitable for the analysis. The following systems were included in the review: Cerec Bluecam, Cerec Omnicam, Cadent iTero, Lava C.O.S, Lava True Definition, TRIOS, TRIOS Color, E4D, Planscan, MHT, Carestream 3500 and Zfx IntraScan. In comparison to conventional impressions, the IOS systems can be reliably used for diagnostic purposes and short-span scanning. However, for whole arch scanning, the IOS is susceptible for more deviation. The studies indicated variable outcome of the different IOS systems. While the accuracy of IOS systems appears to be promising and comparable to conventional methods, they are still vulnerable to inaccuracies. For prosthesis fabrication, the IOS accuracy is enhanced by reducing the span of scanning, and ensuring the scanned surfaces exhibit minimal irregularities. PMID- 29989759 TI - Gender, Victimization, and Evolving State Standards: a Study of New York and Michigan Sexual Assault Legislation. PMID- 29989770 TI - Nursing Home Abuse of Agents: Creditor Misuse of New York's Revised Durable Power of Attorney. PMID- 29989771 TI - The Immigrant Paradox: Protecting Immigrants Through Better Mental Health Care. PMID- 29989772 TI - Screening for Social Determinants of Health: An Opportunity or Unreasonable Burden? PMID- 29989774 TI - It's Not Hard to Be Humble: The Role of Humility in Leadership. PMID- 29989773 TI - Deprescribing Unnecessary Medications: A Four-Part Process. PMID- 29989775 TI - How to Be Happy in Practice for 30-Plus Years. PMID- 29989776 TI - Developing Standing Orders to Help Your Team Work to the Highest Level. PMID- 29989777 TI - A Practical Approach to Screening for Social Determinants of Health. PMID- 29989778 TI - What Needs to Change to Make Deprescribing Doable. PMID- 29989779 TI - Quality Measures: How to Get Them Right. PMID- 29989780 TI - Teach-Back: A Simple Technique to Enhance Patients' Understanding. PMID- 29989781 TI - Quality Measurement: A Long Way to Go. PMID- 29989782 TI - Patient Inducements: The New Dos and Don'ts. PMID- 29989783 TI - How to Create a Culture of Well-Being in Your Practice. PMID- 29989784 TI - Five Ways to Cultivate Resilience. PMID- 29989785 TI - 99213 or 99214? Three Tips for Navigating the Coding Conundrum. PMID- 29989787 TI - Oxygen-Insensitive Aggregates of Pt(II) Complexes as Phosphorescent Labels of Proteins with Luminescence Lifetime-Based Readouts. AB - The synthesis and photophysical properties of a tailored Pt(II) complex are presented. The phosphorescence of its monomeric species in homogeneous solutions is quenched by interaction with the solvent and therefore absent even upon deoxygenation. However, aggregation-induced shielding from the environment and suppression of rotovibrational degrees of freedom trigger a phosphorescence turn on that is not suppressed by molecular oxygen, despite possessing an excited state lifetime ranging in the microsecond scale. Thus, the photoinduced production of reactive oxygen species is avoided by the suppression of diffusion controlled Dexter-type energy transfer to triplet molecular oxygen. These aggregates emit with the characteristic green luminescence profile of monomeric complexes, indicating that Pt-Pt or excimeric interactions are negligible. Herein, we show that these aggregates can be used to label a model biomolecule (bovine serum albumin) with a microsecond-range luminescence. The protein stabilizes the aggregates, acting as a carrier in aqueous environments. Despite spectral overlaps, the green phosphorescence can be separated by time-gated detection from the dominant autofluorescence of the protein arising from a covalently bound green fluorophore that emits in the nanosecond range. Interestingly, the aggregates also acted as energy donors able to sensitize the emission of a fraction of the fluorophores bound to the protein. This resulted in a microsecond-range luminescence of the fluorescent acceptors and a shortening of the excited-state lifetime of the phosphorescent aggregates. The process that can be traced by a 1000-fold increase in the acceptor's lifetime mirrors the donor's triplet character. The implications for phosphorescence lifetime imaging are discussed. PMID- 29989788 TI - High-Performance Identification of Human Bladder Cancer Using a Signal Self Amplifiable Photoacoustic Nanoprobe. AB - Cancer diagnostics has been an important research field, and identification of small lesions that are less noticeable plays a vital role in thoroughly removing the tumor, thereby reducing the recurrence rate of cancer. Herein, we synthesized a signal self-amplifiable photoacoustic (PA) liposomal nanoprobe composed by ammonium hydrogen carbonate (AHC) payload and aggregated purpurin-18 (P18) within the bilayer. Under PA laser irradiation, P18 aggregates efficiently generated local heat, leading to the launch of wide-band ultrasonic emission. In parallel, the heat also triggered the decomposition of AHC and production of CO2 bubbles, which consequently dramatically amplified the acoustic signal. For clinical translation, by decorating bladder cancer (BC) specific CD44v6 antibody onto nanoprobe, we were capable of utilizing this high sensitive and specific PA probe for human BC tissue imaging. The results indicated that small tumor lesion (<5 mm) was identified and the tumor-to-normal tissue ratio was ~18 folds enhancement by using this PA probe, which rendered the tumor boundary distinct. All together, we developed a new strategy for exploring high-performance imaging probes, which might potentially benefit for the imaging-guided surgery in clinics. PMID- 29989789 TI - NeuroSystematics and Periodic System of Neurons: Model vs Reference Species at Single-Cell Resolution. AB - There is more than one way to develop neuronal complexity, and animals frequently use different molecular toolkits to achieve similar functional outcomes (=convergent evolution). Neurons are different not only because they have different functions, but also because neurons and circuits have different genealogies, and perhaps independent origins at the broadest scale from ctenophores and cnidarians to cephalopods and primates. By combining modern phylogenomics, single-neuron sequencing (scRNA-seq), machine learning, single cell proteomics, and metabolomic across Metazoa, it is possible to reconstruct the evolutionary histories of neurons tracing them to ancestral secretory cells. Comparative data suggest that neurons, and perhaps synapses, evolved at least 2-3 times (in ctenophore, cnidarian and bilateral lineages) during ~600 million years of animal evolution. There were also several independent events of the nervous system centralization either from a common bilateral/cnidarian ancestor without the bona fide neurons or from the urbilaterian with diffuse, nerve-net type nervous system. From the evolutionary standpoint, (i) a neuron should be viewed as a functional rather than a genetic character, and (ii) any given neural system might be chimeric and composed of different cell lineages with distinct origins and evolutionary histories. The identification of distant neural homologies or examples of convergent evolution among 34 phyla will not only allow the reconstruction of neural systems' evolution but together with single-cell "omic" approaches the proposed synthesis would lead to the "Periodic System of Neurons" with predictive power for neuronal phenotypes and plasticity. Such a phylogenetic classification framework of Neuronal Systematics (NeuroSystematics) might be a conceptual analog of the Periodic System of Chemical Elements. scRNA-seq profiling of all neurons in an entire brain or Brain-seq is now fully achievable in many nontraditional reference species across the entire animal kingdom. Arguably, marine animals are the most suitable for the proposed tasks because the world oceans represent the greatest taxonomic and body-plan diversity. PMID- 29989790 TI - Porous Scandia-Stabilized Zirconia Layer for Enhanced Performance of Reversible Solid Oxide Cells. AB - Reversible solid oxide cells (RSOCs) developed so far display short-term stability during solid oxide electrolysis cell (SOEC) mode. This is due to the delamination of the strontium-doped lanthanum manganite (LSM) air electrode when tested for a long time. Here, we report a highly stable RSOC operation of LSM for 5 cycles using half and full cells. A scandia-stabilized zirconia (SSZ) porous layer was applied between the dense SSZ electrolyte and the porous LSM electrode. The half-cells were tested under +/-0.5 A cm-2, whereas the full cells were tested at +0.5 and -0.25 A cm-2 at 800 degrees C. It was found that the cells with a porous SSZ layer are stable and show a performance increase after five RSOC cycles. The ohmic and polarization resistance of both the half and full cells decreased after each cycle. Also, the maximum power density of the full cell increased from 425 to 550 mW cm-2, whereas the electrolysis current density increased from 294 to 407 mA cm-2 after 5 cycles at 1.3 V in 10% H2O/90% H2, at 800 degrees C. This performance enhancement can be ascribed to the creation of oxygen vacancies in LSM under applied current, the alleviation of oxygen partial pressure from the interface and the introduction of electronic conductivity in the electrolyte near the interface. The cell without the SSZ porous layer experienced the zirconate formation, high oxygen partial pressure at the interface as well as the silver deposition at the electrode-electrolyte interface. Therefore, an increase in the polarization resistance for the half cell and a decrease in the electrolysis current density for the full cell were observed. PMID- 29989791 TI - Honokiol Alleviates Oxidative Stress-Induced Neurotoxicity via Activation of Nrf2. AB - Honokiol (Hon), a polyphenol and main active ingredient from the bark of Magnolia officinalis, has been documented as having multiple pharmacological functions, including neuroprotection. However, the mechanisms underlying its neuroprotective effects are not well-defined. In this study, we reported that Hon attenuates the H2O2- or 6-hydroxydopamine (6-OHDA)-induced apoptosis of PC12 cells by increasing the glutathione level and upregulating a multitude of cytoprotective proteins, including heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, thioredoxin 1, and thioredoxin reductase 1. Further studies reveal that Hon promotes transcription factor Nrf2 nuclear translocation and activation. Moreover, the cytoprotection of Hon was antagonized by silence of Nrf2 expression, highlighting the fact that Nrf2 is critically engaged in the cellular functions of Hon. Taken together, our study identified that Hon is an effective agonist of Nrf2 in the neuronal system and displays potent neuroprotection against oxidative stress-mediated PC12 cell damage. These findings indicate that Hon is promising for further development as a therapeutic drug against oxidative stress-related neurodegenerative disorders. PMID- 29989792 TI - Flexible Polydimethylsilane Nanocomposites Enhanced with a Three-Dimensional Graphene/Carbon Nanotube Bicontinuous Framework for High-Performance Electromagnetic Interference Shielding. AB - High-performance electromagnetic interference (EMI)-shielding materials featuring lightweight, flexibility, excellent conductivity, and shielding properties, as well as superior mechanical robustness, are highly required, yet their development still remains a daunting challenge. Here, a flexible and exceptional EMI-shielding polydimethylsilane/reduced graphene oxide/single-wall carbon nanotube (PDMS/rGO/SWCNT) nanocomposite was developed by a facile backfilling approach utilizing a preformed rGO/SWCNT aerogel as the three-dimensional (3D) conducting and reinforcement skeleton. Pristine SWCNTs acting as secondary conductive fillers showed intriguing advantages, whose intrinsically high conductivity could be well preserved in the composites because of no surface acidification treatment. The robust and interconnected 3D network can not only serve as fast channels for electron transport but also effectively transfer external load. Accordingly, a prominent electrical conductivity of 1.2 S cm-1 and an outstanding EMI-shielding effectiveness of around 31 dB over the X-band frequency range were achieved for the resultant composite with an ultralow loading of 0.28 wt %, which is among the best results for currently reported conductive polymer nanocomposites. Moreover, the composite displayed excellent mechanical properties and bending stability; for example, a 233% increment in the compression strength was obtained compared with that of neat PDMS. These observations indicate the unrivalled effectiveness of 3D rGO/SWCNT aerogel as a reinforcement to endow the polymer composites with outstanding conductive and mechanical properties toward high-performance EMI-shielding application. PMID- 29989793 TI - Surface-Bound Gradient Deposition of Protein Nanoparticles for Cell Motility Studies. AB - A versatile evaporation-assisted methodology based on the coffee-drop effect is described to deposit nanoparticles on surfaces, obtaining for the first time patterned gradients of protein nanoparticles (pNPs) by using a simple custom-made device. Fully controllable patterns with specific periodicities consisting of stripes with different widths and distinct nanoparticle concentration as well as gradients can be produced over large areas (~10 cm2) in a fast (up to 10 mm2/min), reproducible, and cost-effective manner using an operational protocol optimized by an evolutionary algorithm. The developed method opens the possibility to decorate surfaces "a-la-carte" with pNPs enabling different categories of high-throughput studies on cell motility. PMID- 29989794 TI - A Dimethyl-Labeling-Based Strategy for Site-Specifically Quantitative Chemical Proteomics. AB - Activity-based protein profiling (ABPP) has emerged as a powerful functional chemoproteomic strategy which enables global profiling of proteome reactivity toward bioactive small molecules in complex biological and/or pathological processes. To quantify the degree of reactivity in a site-specific manner, an isotopic tandem orthogonal proteolysis (isoTOP)-ABPP strategy has been developed; however, the high cost and long workflow associated with the synthesis of isotopically labeled cleavable tags limit its wide use. Herein, we combined reductive dimethyl labeling with TOP-ABPP to develop a fast, affordable, and efficient method, termed "rdTOP-ABPP", for quantitative chemical proteomics with site-specific precision and triplex quantification. The rdTOP-ABPP method shows high accuracy and precision, good reproducibility, and better capacity for site identification and quantification and is highly compatible with many commercially available cleavable tags. We demonstrated the power of rdTOP-ABPP by profiling the target of (1 S,3 R)-RSL3, a canonical inducer for cell ferroptosis, and provided the first global portrait of its proteome reactivity in a quantitative and site-specific manner. PMID- 29989795 TI - Sensor Array for Detection of Early Stage Parkinson's Disease before Medication. AB - Early diagnosis of Parkinson's disease (PD) is important because it affects the choice of therapy and is subject to a relatively high degree of error. In addition, early detection of PD can potentially enable the start of neuroprotective therapy before extensive loss of dopaminergic neurons of the substantia nigra occurs. However, until now, studies for early detection of PD using volatile biomarkers sampled only treated and medicated patients. Therefore, there is a great need to evaluate untreated patients for establishing a real world screening and diagnostic technology. Here we describe for the first time a clinical trial to distinguish between de novo PD and control subjects using an electronic system for detection of volatile molecules in exhaled breath (sensor array). We further determine for the first time the association to other common tests for PD diagnostics as smell, ultrasound, and nonmotor symptoms. The test group consisted of 29 PD patients after initial diagnosis by an experienced neurologist, compared with 19 control subjects of similar age. The sensitivity, specificity, and accuracy values of the sensor array to detect PD from controls were 79%, 84%, and 81% respectively, in comparison with midbrain ultrasonography (93%, 90%, 92%) and smell detection (62%, 89%, 73%). The results confirm previous data showing the potential of sensor arrays to detect PD. PMID- 29989796 TI - DIA-SIFT: A Precursor and Product Ion Filter for Accurate Stable Isotope Data Independent Acquisition Proteomics. AB - Quantitative mass spectrometry-based protein profiling is widely used to measure protein levels across different treatments or disease states, yet current mass spectrometry acquisition methods present distinct limitations. While data independent acquisition (DIA) bypasses the stochastic nature of data-dependent acquisition (DDA), fragment spectra derived from DIA are often complex and challenging to deconvolve. In-line ion mobility separation (IMS) adds an additional dimension to increase peak capacity for more efficient product ion assignment. As a similar strategy to sequential window acquisition methods (SWATH), IMS-enabled DIA methods rival DDA methods for protein annotation. Here we evaluate IMS-DIA quantitative accuracy using stable isotope labeling by amino acids in cell culture (SILAC). Since SILAC analysis doubles the sample complexity, we find that IMS-DIA analysis is not sufficiently accurate for sensitive quantitation. However, SILAC precursor pairs share common retention and drift times, and both species cofragment to yield multiple quantifiable isotopic y-ion peak pairs. Since y-ion SILAC ratios are intrinsic for each quantified precursor, combined MS1 and y-ion ratio analysis significantly increases the total number of measurements. With increased sampling, we present DIA-SIFT ( SILAC Intrinsic Filtering Tool), a simple statistical algorithm to identify and eliminate poorly quantified MS1 and/or MS2 events. DIA-SIFT combines both MS1 and y-ion ratios, removes outliers, and provides more accurate and precise quantitation (<15% CV) without removing any proteins from the final analysis. Overall, pooled MS1 and MS2 quantitation increases sampling in IMS-DIA SILAC analyses for accurate and precise quantitation. PMID- 29989797 TI - Mechanistic Basis of the Fast Dark Recovery of the Short LOV Protein DsLOV from Dinoroseobacter shibae. AB - Light, oxygen, voltage (LOV) proteins, a ubiquitously distributed class of photoreceptors, regulate a wide variety of light-dependent physiological responses. Because of their modular architecture, LOV domains, i.e., the sensory domains of LOV photoreceptors, have been widely used for the construction of optogenetic tools. We recently described the structure and function of a short LOV protein (DsLOV) from the marine phototropic bacterium Dinoroseobacter shibae, for which, in contrast to other LOV photoreceptors, the dark state represents the physiologically relevant signaling state. Among bacterial LOV photoreceptors, DsLOV possesses an exceptionally fast dark recovery, corroborating its function as a "dark" sensor. To address the mechanistic basis of this unusual characteristic, we performed a comprehensive mutational, kinetic, thermodynamic, and structural characterization of DsLOV. The mechanistic basis of the fast dark recovery of the protein was revealed by mutation of the previously noted uncommon residue substitution at position 49 found in DsLOV. The substitution of M49 with different residues that are naturally conserved in LOV domains tuned the dark recovery time of DsLOV over 3 orders of magnitude, without grossly affecting its overall structure or the light-dependent structural change observed for the wild type protein. Our study thus provides a striking example of how nature can achieve LOV photocycle tuning by subtle structural alterations in the LOV domain active site, highlighting the easy evolutionary adaptability of the light sensory function. At the same time, our data provide guidance for the mutational photocycle tuning of LOV domains, with relevance for the growing field of optogenetics. PMID- 29989798 TI - Controlling Ligand Surface Density on Streptavidin-Magnetic Particles by a Simple, Rapid, and Reliable Chemiluminescent Test. AB - The use of functionalized magnetic particles is increasing because they simplify the analytical process and yield promising results in a wide range of applications. Particularly, streptavidin-coated magnetic beads offer the possibility of rapid and very efficient grafting of biomolecules. Unfortunately, current methods to monitor and compute this grafting process are cumbersome and scarce. We describe herein a simple, rapid, and reliable chemiluminescent assay we have developed to check the grafting rate of functionalized magnetic beads. The power of the assay also relies on its ability to predict the amount of ligands required to obtain a precise grafting rate. In addition, results were correlated with a more general parameter in material functionalization characterization like surface ligand density. Finally, the assay was validated for a wide variety of biotinylated biomolecule sizes, ranging from small molecules (around 200 Da) to antibodies (around 150 kDa). This approach will allow a precise quantification and prediction of the functionalization of magnetic particles that is of enormous importance for quality control in many applications. PMID- 29989799 TI - Farnesylated Glycol Chitosan as a Platform for Drug Delivery: Synthesis, Characterization, and Investigation of Mucus-Particle Interactions. AB - Amphiphilic polymer-based drug delivery systems hold potential in enhancing pharmacokinetics and therapeutic efficacy due to their ability to simultaneously codeliver different drugs in a controlled manner. We propose here a facile method for synthesizing a new amphiphilic polymer, farnesylated glycol chitosan (FGC), which self-assembles into nanoparticles upon being dispersed in aqueous media. The characteristics of FGC nanoparticles, in particular the size, could be tuned in a range from 200 to 500 nm by modulating the degree of farnesylation and the pH and polymer concentration during particle preparation. Carrier capacity, release kinetics, and surface modification of the established system were investigated using different model compounds. The colloids were biocompatible and stable at biologically relevant pH values. The interactions between the carriers and human mucus were examined by multiple particle tracking, which revealed that ~80% of the particles remain immobilized within the mucus matrix. These results postulate FGC as a versatile drug delivery platform. PMID- 29989800 TI - Luminescent Vapochromism Due to a Change of the Ligand Field in a One-Dimensional Manganese(II) Coordination Polymer. AB - The reactions of MnBr2 and ethane-1,2-diylbis(diphenylphosphine oxide) (dppeO2) in dichloromethane-methanol solutions gave colorless crystals with the general chemical formulas [MnBr2(dppeO2)] n (1), [MnBr2(dppeO2)(DMF)] n (1a), [Mn(dppeO2)3][MnBr4] (2), and Mn2Br4(dppeO2)2 (3) depending on the crystallization conditions. Compounds 1 and 1a display one-dimensional chain structures composed of Mn(II) ions linked by bridging dppeO2 to exhibit tetrahedral (1) or trigonal-bipyramidal (1a) coordination geometry, whereas 3 exhibits a cyclic dinuclear structure with two Mn(II) centers bridged by double dppeO2 to adopt tetrahedral geometry. Compound 2 consists of octahedrally coordinated cation [Mn(dppeO2)3]2+ and tetrahedrally arranged anion [MnBr4]2-. While 1 and 3 in crystalline and powder states are highly luminescent with green emission bands centered at ca. 510 nm, 2 shows intense orange luminescence peaking at 594 nm. Upon exposure of 1 to N, N-dimethylformamide vapor, the green emission centered at 510 nm is converted to red luminescence peaking at 630 nm, ascribed to the formation of DMF-coordinated compound 1a with a trigonal bipyramidal ligand field, as demonstrated by X-ray crystallography. Red-emitting 1a could be reverted to the original green-emitting 1 with a tetrahedral ligand field upon heat at 160 degrees C, and such a reversible conversion could be perfectly repeated for several cycles. A new mechanism of luminescent vapochromism is thus proposed because of the reversible conversion of ligand fields in manganese(II) complexes. PMID- 29989802 TI - Enantioselective Copper-Catalyzed Defluoroalkylation Using Arylboronate-Activated Alkyl Grignard Reagents. AB - A copper-catalyzed system has been introduced for the enantioselective defluoroalkylation of linear 1-(trifluoromethyl)alkenes through C-F activation to synthesize various gem-difluoroalkenes as carbonyl mimics. For the first time, arylboronate-activated alkyl Grignard reagents were uncovered in this cross coupling reaction. Mechanistic studies confirmed that the tetraorganoborate complexes generated in situ were the key reactive species for this transformation. PMID- 29989801 TI - H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals. AB - An acyclic hexadentate oxine-derived chelating ligand, H2hox, was investigated as an alternative to current chelators for 68Ga. The straightforward preparation of H2hox, involving only one or two steps, obviates the synthetic challenges associated with many reported 68Ga chelators; it forms a Ga3+ complex of great stability (log K = 34.4) with a remarkably high gallium scavenging ability (pGa3+ = -log[Ga3+free] = 28.3, ([Ga3+] = 1 MUM; [L x-] = 10 MUM; pH 7.4, and 25 degrees C)). Moreover, H2hox coordinates 68Ga quantitatively in 5 min at room temperature in ligand concentrations as low as 1 * 10-7 M, achieving an unprecedented high molar activity of 11 +/- 1 mCi/nmol (407 +/- 3.7 MBq/nmol) without purification, suggesting prospective kit-based convenience. [68Ga(hox)]+ showed no decomposition in a plasma challenge. Good in vivo stability and fast renal and hepatic clearance of the [68Ga(hox)]+ complex were demonstrated using dynamic positron emission tomography/computed tomography imaging. The intrinsic fluorescence of [Ga(hox)]+ allowed for direct fluorescence imaging of cellular uptake and distribution, demonstrating the dual-channel detectability and intracellular stability of the metal complex. PMID- 29989804 TI - Aerial Interyear Comparison and Quantification of Methane Emissions Persistence in the Bakken Formation of North Dakota, USA. AB - We performed an infrared optical gas imaging (OGI) survey by helicopter of hydrocarbon emissions in the Bakken formation of North Dakota. One year after an earlier survey of 682 well pads in September of 2014, the same helicopter crew resurveyed 353 well pads in 2015 to examine the persistence of emissions. Twenty one newly producing well pads were added in the same sampling blocks. An instrumented aircraft was also used to quantify emissions from 33 plumes identified by aerial OGI. Well pads emitting methane and ethane in 2014 were far more likely to be emitting in 2015 than would be expected by chance; Monte Carlo simulations suggest >5sigma deviation ( p < 0.0001) from random assignment of detectable emissions between survey years. Scaled up using basin-wide leakage estimates, the emissions quantified by aircraft are sufficient to explain previously observed basin-wide emissions of methane and ethane. PMID- 29989803 TI - Hydroamination versus Allylic Amination in Iridium-Catalyzed Reactions of Allylic Acetates with Amines: 1,3-Aminoalcohols via Ester-Directed Regioselectivity. AB - In the presence of a neutral dppf-modified iridium catalyst and Cs2CO3, linear allylic acetates react with primary amines to form products of hydroamination with complete 1,3-regioselectivity. The collective data, including deuterium labeling studies, corroborate a catalytic mechanism involving rapid, reversible acetate-directed aminoiridation with inner-sphere/outer-sphere crossover followed by turnover-limiting proto-demetalation mediated by amine. PMID- 29989805 TI - Phenylsulfinyl Radical: Gas-Phase Generation, Photoisomerization, and Oxidation. AB - Arylsulfinyl radicals are key intermediates in sulfoxide chemistry. The parent molecule, phenylsulfinyl radical PhSO*, has been generated for the first time in the gas phase through high-vacuum flash pyrolysis of PhS(O)R (R = CF3 and Cl) at about 1000 K. Upon UV light irradiation (365 nm), PhSO* isomerizes to novel oxathiyl radical PhOS* in cryogenic matrices (2.8 K). Prolonged irradiation causes further isomerization of PhOS* to 2-hydroxyphenylthiyl radical, the formation of which has been also observed in the 193 nm laser photolysis of matrix-isolated 2-hydroxybenzenethiol. Concomitantly, ring-opening occurs during the UV photolysis of PhOS* and 2-hydroxybenzenethiol and forms an acyclic thioketoketene radical. Phenylsulfinyl radical reacts partially with molecular oxygen in the gas phase and yields phenyl radical Ph* and OSOO. Upon irradiation (365 nm), the isomeric oxathiyl radical also combines O2 with immediate dissociation to phenoxy radical PhO* and SO2. The identification of the intermediates with IR and UV-vis spectroscopy is supported by quantum chemical computations at the B3LYP/def2-TZVPP and UCCSD(T)/aug-cc-pV(D+d)Z levels of theory. The isomerization of PhSO* has been discussed based on the computed potential energy profile and the comparison with the intensively explored photochemistry of phenylperoxy radical PhOO*. PMID- 29989806 TI - Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark. AB - Computer-aided protein-ligand binding predictions are a valuable help in drug discovery. Protein-ligand docking programs generally consist of two main components: a scoring function and a search algorithm. It is of interest to evaluate the intrinsic performance of scoring functions, independently of conformational exploration, to understand their strengths and weaknesses and suggest improvements. The comparative assessment of scoring functions (CASF) provides such an evaluation. Here we add the AutoDock and Vina scoring functions to the CASF-2013 benchmark. We find that these popular, free software docking programs are generally in the first half (AutoDock) and first quarter (Vina) among all methods tested in CASF-2013. Vina is the best of all methods in terms of docking power. We also find that ligand minimization has an important impact, reducing the performance difference between AutoDock and Vina. PMID- 29989807 TI - DNA-Encoded Protein Janus Nanoparticles. AB - Asymmetric functionality and directional interactions, which are characteristic of noncentrosymmetric particles, such as Janus particles, present an opportunity to encode particles with properties, but also a great synthetic challenge. Here, we exploit the chemical anisotropy of proteins, and the versatile chemistry of DNA to synthesize a protein-based Janus nanoparticle comprised of two proteins encoded with sequence-specific nucleic acid domains, tethered together by an interprotein "DNA bond". We use these novel nanoparticles to realize a new class of three-dimensional superlattice, only possible when two sides of the particle are modified with orthogonal oligonucleotide sequences. The low symmetry, intrinsic to Janus particles, enables the realization of unprecedented multicomponent nanoparticle superlattices with unique, hexagonal layered architectures. In addition, the interprotein "DNA bond" can be modulated to selectively expand the lattice in a single direction. The results presented herein not only emphasize the power of rationally designing nanoscale building blocks to create highly engineered colloidal crystals, but also establish a precedent for applications of multidomain DNA-encoded nanoparticles, especially in the field of colloidal crystallization. PMID- 29989808 TI - Metal-Organic Frameworks as Efficient Oral Detoxifying Agents. AB - Poisoning and accidental oral intoxication are major health problems worldwide. Considering the insufficient efficacy of the currently available detoxification treatments, a pioneering oral detoxifying adsorbent agent based on a single biocompatible metal-organic framework (MOF) is here proposed for the efficient decontamination of drugs commonly implicated in accidental or voluntary poisoning. Furthermore, the in vivo toxicity and biodistribution of a MOF via oral administration have been investigated for the first time. Orally administered upon a salicylate overdose, this MOF is able to reduce the salicylate gastrointestinal absorption and toxicity more than 40-fold (avoiding histological damage) while exhibiting exceptional gastrointestinal stability (<9% degradation), poor intestinal permeation, and safety. PMID- 29989809 TI - Photosensitized Membrane Permeabilization Requires Contact-Dependent Reactions between Photosensitizer and Lipids. AB - Although the general mechanisms of lipid oxidation are known, the chemical steps through which photosensitizers and light permeabilize lipid membranes are still poorly understood. Herein we characterized the products of lipid photooxidation and their effects on lipid bilayers, also giving insight into their formation pathways. Our experimental system was designed to allow two phenothiazinium-based photosensitizers (methylene blue, MB, and DO15) to deliver the same amount of singlet oxygen molecules per second to 1-palmitoyl-2-oleoyl- sn-glycero-3 phosphocholine liposome membranes, but with a substantial difference in terms of the extent of direct physical contact with lipid double bonds; that is, DO15 has a 27-times higher colocalization with omega-9 lipid double bonds than MB. Under this condition, DO15 permeabilizes membranes at least 1 order of magnitude more efficiently than MB, a result that was also valid for liposomes made of polyunsaturated lipids. Quantification of reaction products uncovered a mixture of phospholipid hydroperoxides, alcohols, ketones, and aldehydes. Although both photosensitizers allowed the formation of hydroperoxides, the oxidized products that require direct reactions between photosensitizer and lipids were more prevalent in liposomes oxidized by DO15. Membrane permeabilization was always connected with the presence of lipid aldehydes, which cause a substantial decrease in the Gibbs free energy barrier for water permeation. Processes depending on direct contact between photosensitizers and lipids were revealed to be essential for the progress of lipid oxidation and consequently for aldehyde formation, providing a molecular-level explanation of why membrane binding correlates so well with the cell-killing efficiency of photosensitizers. PMID- 29989810 TI - Pharmacokinetic Characteristics of Steamed Notoginseng by an Efficient LC-MS/MS Method for Simultaneously Quantifying Twenty-three Triterpenoids. AB - Steamed Panax notoginseng (SNG) has been widely used as a restorative medicine instead of the raw one, but its pharmacokinetic profile is entirely unknown. To address this, we've developed an LC-MS/MS method with high efficiency and sensitivity for simultaneous quantification of 23 triterpenoids (notoginsenosides Fa, Fc, R1, 20( S)-R2, 20( R)-R2, ginsenosides F4, Rb1, Rg1, Rd, Re, Rb2, 20( S) Rh1, 20( R)-Rh1, Rh4, R k1, R k3, 20( S)-Rg2, 20( S)-Rg3, 20( R)-Rg3, Rg5, C-K, 20( S)-PPT, 20( S)-PPD) from SNG in rat plasma. This validated approach exhibits great linearity, precision, accuracy, recovery, and stability for all analytes. Furthermore, we, for the first time, applied this method to the pharmacokinetic study of SNG and proposed Rb1, Fa, Rd, R k1, Rg5, R k3, Rh4, and 20( S)-PPD to be suitable pharmacokinetic markers of SNG due to their high exposure levels of systemic plasma. Hence, this developed approach would be a powerful tool for future in vivo investigation of various sources of notoginseng-related samples. PMID- 29989811 TI - Swinhoeisterols from the South China Sea Sponge Theonella swinhoei. AB - Swinhoeisterols C-F (1-4), four new steroids having a rearranged 6/6/5/7 ring system, were isolated from the Xisha sponge Theonella swinhoei, together with the known analogue swinhoeisterol A (5). Their structures were determined based on spectroscopic analysis, TDDFT-ECD and optical rotation calculations, and biogenetic correlations. In an in vitro assay, compound 1 showed an inhibitory effect on (h)p300 with an IC50 value of 8.8 MUM, whereas compounds 2-4 were not active. PMID- 29989812 TI - 3-Boryl-2,1-borazaronaphthalene: Umpolung Reagents for Diversifying Naphthalene Isosteres. AB - A Pd-catalyzed Miyaura borylation of 3-bromo-2,1-borazaronaphthalenes is reported. This method allows the formation of umpolung reagents for subsequent Pd mediated cross-coupling. Coupling of this nucleophilic partner with a variety of commercially available aryl- and heteroaryl halides allows facile and rapid diversification of these cores. PMID- 29989813 TI - Cu-Catalyzed Aerobic Oxidative N-N Coupling of Carbazoles and Diarylamines Including Selective Cross-Coupling. AB - A Cu-catalyzed method has been identified for aerobic oxidative dimerization of carbazoles and diarylamines to the corresponding N-N coupled bicarbazoles and tetraarylhydrazines. The reactions proceed under mild conditions (1 atm O2, 60-80 degrees C) with a catalyst composed of CuBr.dimethylsulfide and N, N dimethylaminopyridine. Reactions between carbazole and diarylamines show unusually selective cross-coupling, even with a 1:1 ratio of the two substrates. This behavior was found to arise from reversible formation of the tetraarylhydrazine. Formation of this species is kinetically favored, but cleavage of the N-N bond under the reaction conditions leads to selective formation of the thermodynamically favored cross-coupling product. PMID- 29989814 TI - Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis. AB - Small-molecule natural products (NPs) have a long and successful track record of providing first-in-class drugs and pharmacophore (scaffolds) in all therapeutic areas, serving as a bridge between modern and traditional medicine. This trajectory has been remarkably successful in three key areas of modern therapeutics: cancers, infections, and CNS diseases. Beginning with the discovery of morphine 200 years ago, natural products have remained the primary source of new drugs/scaffolds for CNS diseases. In this perspective, we address the question: why are the majority of active compounds in the CNS domain natural products? Our analysis indicates that ~84% approved drugs for CNS diseases are NPs or NP-inspired, and interestingly, 20 natural products provided more than 400 clinically approved CNS drugs. We have discussed unique physicochemical properties of NPs and NP-inspired vis-a-vis synthetic drugs, isoform selectivity, and evolutionary relationship, providing a rationale for increasing focus on natural product driven discovery for next-generation drugs for neurodegenerative diseases. PMID- 29989815 TI - Effects of Hydration on Structure and Phase Behavior of Pig Gastric Mucin Elucidated by SAXS. AB - In this work small-angle X-ray scattering (SAXS) was used to study hydration and temperature-induced changes of pig gastric mucin (PGM) within the entire concentration range. The scattering is interpreted as originating from PGM fiber like structures that adopt rod-like bottle-brush conformation in dilute solutions. On the basis of the knowledge about molecular structure of mucins and SAXS data for dilute solutions, we propose a theoretical model for predicting mucin conformation in solution and calculate the corresponding scattering profile. This bottle-brush model comprises a protein backbone with carbohydrate side chains and corresponding structural parameters, such as grafting distance and lengths of the backbone and side chains. It describes the experimental PGM data from dilute solutions in the full q range very well. It furthermore suggests that the carbohydrate side chains are grafted with a regular separation of around 5 nm and a length of 14 nm. The cross-section size with a radius of about 1 nm is also in accordance with the size of the carbohydrate units. Structuring of PGM solutions at higher concentrations was investigated by analyzing semidilute and concentrated PGM samples. Starting at about 20 wt %, Bragg peaks become clearly visible indicating a more ordered mucin system. In very dehydrated and fully dry mucin samples these peaks are not present indicating lack of long-range order. The SAXS data show that the structural change occurring at about 80 wt % mucin and 25 degrees C corresponds to a glass transition in agreement with our previous calorimetric results. Temperature also has an effect on the phase behavior of mucin. At intermediate levels of hydration, a phase transition is observed at about 60-70 degrees C. The main Bragg peak appears to split in two, indicating formation of a different structure at elevated temperatures. These findings are used to improve the PGM-water phase diagram. PMID- 29989816 TI - Use of XtalFluor-E as an Alternative to POCl3 in the Vilsmeier-Haack Formylation of C-2-Glycals. AB - We report the use of XtalFluor-E ([Et2NSF2]BF4) as an alternative to POCl3 in the Vilsmeier-Haack formylation reaction of C-2-glycals. Employing a XtalFluor-E/DMF combination allowed the desired C-2-formyl glycals to be isolated in 11-90% yield. This method was extended to the synthesis of a C-2 -formylated disaccharide glycal. PMID- 29989817 TI - 25 S-Adamantyl-23-yne-26,27-dinor-1alpha,25-dihydroxyvitamin D3: Synthesis, Tissue Selective Biological Activities, and X-ray Crystal Structural Analysis of Its Vitamin D Receptor Complex. AB - Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1alpha,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1alpha,25-dihydroxyvitamin D3, 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%), and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells. The X-ray crystal structural analysis of 4b in complex with rat VDR-ligand binding domain (LBD) showed the highest Calpha positional shift from the 1/VDR-LBD complex at helix 11. Helix 11 of the 4b and 1 VDR-LBD complexes also showed significant differences in surface properties. These results suggest that 4b should be examined further as another candidate for a mild preventive osteoporosis agent. PMID- 29989818 TI - Self-Assembly of Quantum Dot-Gold Heterodimer Nanocrystals with Orientational Order. AB - The self-assembly of nanocrystals into ordered superlattices is a powerful strategy for the production of functional nanomaterials. The assembly of well ordered target structures, however, requires control over the building blocks' size and shape as well as their interactions. While nanocrystals with homogeneous composition are now routinely synthesized with high precision and assembled into various ordered structures, high-quality multicomponent nanocrystals and their ordered assemblies are rarely reported. In this paper, we demonstrate the synthesis of quantum dot-gold (QD-Au) heterodimers. These heterodimers possess a uniform shape and narrow size distribution and are capped with oleylamine and dodecyltrimethylammonium bromide (DTAB). Assembly of the heterodimers results in a superlattice with long-range orientational alignment of dimers. Using synchrotron-based X-ray measurements, we characterize the complex superstructure formed from the dimers. Molecular dynamics simulations of a coarse-grained model suggest that anisotropic interactions between the quantum dot and gold components of the dimer drive superlattice formation. The high degree of orientational order demonstrated in this work is a potential route to nanomaterials with useful optoelectronic properties. PMID- 29989819 TI - Tough Photocrosslinked Silk Fibroin/Graphene Oxide Nanocomposite Hydrogels. AB - The development of protein-based hydrogels for tissue engineering applications is often limited by their mechanical properties. Herein, we present the facile fabrication of tough regenerated silk fibroin (RSF)/graphene oxide (GO) nanocomposite hydrogels by a photochemical cross-linking method. The RSF/GO composite hydrogels demonstrated soft and adhesive properties during initial stages of photocrosslinking (<2 min), which is not observed for the pristine RSF hydrogel, and rendered a tough and nonadhesive hydrogel upon complete cross linking (10 min). The composite hydrogels exhibited superior tensile mechanical properties, increased beta-sheet content, and decreased chain mobility compared to that of the pristine RSF hydrogels. The composite hydrogels demonstrated Young's modulus as high as ~8 MPa, which is significantly higher than native cartilage (~1.5 MPa), and tensile toughness as high as ~2.4 MJ/m3, which is greater than that of electroactive polymer muscles and at par with RSF/GO composite membranes fabricated by layer-by-layer assembly. Small-angle scattering study reveals the hierarchical structure of photocrosslinked RSF hydrogels to comprise randomly distributed water-poor (hydrophobic) and water-rich (hydrophilic) regions at the nanoscale, whereas water pores and channels exhibiting fractal-like characteristics at the microscale. The size of hydrophobic domain (containing beta-sheets) was observed to increase slightly with GO incorporation and/or alcohol post-treatment, whereas the size of the hydrophilic domain (intersheet distance containing random coils) was observed to increase significantly, which influences/affects water uptake capacity, cross link density, and mechanical properties of hydrogels. The presented results have implications for both fundamental understanding of the structure-property relationship of RSF-based hydrogels and their technological applications. PMID- 29989820 TI - Heat Treatment of Poloxamer-Stabilized Triglyceride Nanodispersions: Effects and Underlying Mechanism. AB - Lipid nanoemulsions are being investigated for the parenteral administration of poorly soluble drugs. A narrow particle size distribution in these formulations is a prerequisite for meaningful research and safe administration to patients. Autoclaving a poloxamer-stabilized trimyristin nanoemulsion resulted in moderate particle growth and a strong decrease in particle size distribution width ( Goke , K. ; Roese , E. ; Arnold , A. ; Kuntsche , J. ; Bunjes , H. Mol. Pharmaceutics 2016 , 13 , 3187 . ). In this work, the critical parameters for such a change upon autoclaving poloxamer 188-stabilized lipid nanodispersions were investigated to elucidate the underlying mechanism. Nanodispersions of triglycerides with esterified fatty acid chain lengths from C8 to C18 were treated at different temperatures and for varying durations. The influence of a decrease in poloxamer 188's cloud point was tested by adding potassium chloride to the dispersions prior to autoclaving. The influence of poloxamer 188 concentration and of the type of emulsifier was investigated. The change in particle size and particle size distribution width upon heat treatment was analyzed by dynamic or static light scattering or differential scanning calorimetry. A short esterified fatty acid chain length of the triglycerides, high temperatures, and the addition of potassium chloride were key factors for particle growth up to emulsion break up, whereas the cloud point of poloxamer 188 was irrelevant. Sodium dodecyl sulfate and sucrose laurate had negative effects on emulsion stability during autoclaving. It was concluded that the increase in particle size and the decrease in particle size distribution widths upon heat treatment resulted from heat accelerated Ostwald ripening and not from a coalescence-based process. PMID- 29989821 TI - Multiscale Dynamic Growth and Energy Transport of Droplets during Condensation. AB - Condensation is an important physical process and has direct relevance for a range of engineering applications, including heat transfer, antifrosting, and self-cleaning. Understanding the mechanism of droplet growth during condensation is an important aspect, but past works have not typically considered the dynamics of the multiscale process. In this paper, we developed a dynamic growth model, which considers the continuous and multiscale nature of the droplet growth process from several nanometers to hundreds of microns. This model couples the transient phase change heat transfer and two-phase flow both inside and outside the droplet. Accordingly, the energy transport is distinct from the classical pure conduction model. We show that convection near the liquid-vapor interface and inside the droplets plays an increasingly important role as droplets grow and finally dominates the energy transport process. Driven by strong convection, the droplets mix well and the discrete layers of temperature observed in the pure conduction model disappear at the microscale. This model that considers convection can lead to over 4 times higher predicted overall heat transfer than that obtained with the pure conduction model. The interfacial mass flow through the liquid-vapor interface is the dominant factor responsible for the strong convection. We studied the critical radius where convection starts to have a significant influence on droplet growth under different subcooling temperatures and contact angles. Droplets have smaller critical radii under larger subcooling temperatures or larger contact angles, ranging from 0.5 to 20 MUm. This work identifies the modes of energy transport in condensation at different scales, which not only enhances our fundamental understanding of individual droplet growth but provides design guidelines for various dropwise and jumping-droplet condensation research. PMID- 29989822 TI - Controlling the Quality Factor of a Single Acoustic Nanoresonator by Tuning its Morphology. AB - The mechanical vibrations of individual gold nanodisks nanopatterned on a sapphire substrate are investigated using ultrafast time-resolved optical spectroscopy. The number and characteristics of the detected acoustic modes are found to vary with nanodisk geometry. In particular, their quality factors strongly depend on nanodisk aspect ratio (i.e., diameter over height ratio), reaching a maximal value of ~70, higher than those previously measured for substrate-supported nano-objects. The peculiarities of the detected acoustic vibrations are confirmed by finite-element simulations, and interpreted as the result of substrate-induced hybridization between the vibrational modes of a nanodisk. The present findings demonstrate novel possibilities for engineering the vibrational modes of nano-objects. PMID- 29989823 TI - In Silico, in Vitro, and in Vivo Evaluation of New Candidates for alpha-Synuclein PET Imaging. AB - Accumulation of alpha-synuclein (alpha-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective alpha-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific alpha-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting alpha-syn binding characteristics was used as a starting point. Bioinformatics modeling of alpha-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the alpha-syn binding characteristics. Two compounds exhibited a good brain availability and bound to alpha-syn and Abeta fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results. PMID- 29989825 TI - Molecular Dynamics Simulation of Ice Crystal Growth Inhibition by Hexadecyl trimethyl-ammonium Bromide. AB - Recent experiments have found hexadecyl-trimethyl-ammonium bromide (CTAB) to have superior ice nucleation inhibition properties [ J. Phys. Chem. B 121, 6580]. The mechanism of how the inhibition takes place remains unclear. Therefore, molecular dynamics was used to simulate ice crystallization of a water/CTAB/ice system. The ice crystallization rate for a pure water system was compared for the basal [0001], first prism [1010], and secondary prism plane [1120], where the basal plane grew the slowest followed by the first prism plane. When CTAB was added to the ice-liquid water system, crystallization was clearly impeded. Even when ice starts growing away from the CTAB molecule, the hydrophilic head would at some point protrude and get caught in the water/ice interface. Once the head of the CTAB was encapsulated in the advancing interface, the hydrophobic body would wriggle around and disrupt the formation of hydrogen bond networks that are essential for ice growth. When the interface clears the length of the body of the CTAB molecule, ice crystallization resumes at its normal pace. In summary, the inhibition of ice growth is a combination of the hydrophilic head acting as an anchor and the dynamic motion of the hydrophobic tail hindering stable hydrogen bonding for ice growth. PMID- 29989824 TI - Hierarchical Assembly of DNA Nanostructures Based on Four-Way Toehold-Mediated Strand Displacement. AB - Because of its attractive cost and yield, hierarchical assembly, in which constituent structures of lower hierarchy share a majority of components, is an appealing approach to scale up DNA self-assembly. A few strategies have already been investigated to combine preformed DNA nanostructures. In this study, we present a new hierarchical assembly method based on four-way toehold-mediated strand displacement to facilitate the combination of preformed DNA structural units. Employing such a method, we have constructed a series of higher-order structures composed of 5, 7, 9, 11, 13, and 15 preformed units respectively. PMID- 29989826 TI - Three-Dimensional Cell Culture Conditions Affect the Proteome of Cancer Associated Fibroblasts. AB - In vitro cell culture systems are an invaluable tool for cell biological research to study molecular pathways and to characterize processes critical in human pathophysiology. However, the experimental conditions in two-dimensional (2D) cell cultures often differ substantially from the in vivo situation, which continuously raises concerns about the reliability and conferrability of the obtained results. Three-dimensional (3D) cell cultures have been shown to closer mimic in vivo conditions and are commonly employed, for example, in pharmacological screens. Here, we introduce a 3D cell culture system based on a mixture of collagen I and matrigel amenable to stable isotope labeling by amino acids in cell culture (SILAC) and quantitative mass spectrometry-based proteomics analyses. We study the extra- and intracellular proteomic response of skin fibroblast isolated from healthy volunteers in comparison to cancer-associated fibroblasts (CAF) on 3D culture conditions. Both, control cells and CAF, change their proteomic composition based on the culture conditions. Critically, cell type differences observed in 2D are often not preserved in 3D, which commonly closer resemble phenotypes observed in vivo. Especially, extracellular matrix and plasma membrane proteins are differentially regulated in 2D versus 3D. PMID- 29989827 TI - Detecting Ultrasound Vibrations with Graphene Resonators. AB - Ultrasound detection is one of the most-important nondestructive subsurface characterization tools for materials, the goal of which is to laterally resolve the subsurface structure with nanometer or even atomic resolution. In recent years, graphene resonators have attracted attention for their use in loudspeakers and ultrasound radios, showing their potential for realizing communication systems with air-carried ultrasound. Here, we show a graphene resonator that detects ultrasound vibrations propagating through the substrate on which it was fabricated. We ultimately achieve a resolution of ~7 pm/[Formula: see text] in ultrasound amplitude at frequencies up to 100 MHz. Thanks to an extremely high nonlinearity in the mechanical restoring force, the resonance frequency itself can also be used for ultrasound detection. We observe a shift of 120 kHz at a resonance frequency of 65 MHz for an induced vibration amplitude of 100 pm with a resolution of 25 pm. Remarkably, the nonlinearity also explains the generally observed asymmetry in the resonance frequency tuning of the resonator when it is pulled upon with an electrostatic gate. This work puts forward a sensor design that fits onto an atomic force microscope cantilever and therefore promises direct ultrasound detection at the nanoscale for nondestructive subsurface characterization. PMID- 29989828 TI - Tunable Polymer Microcapsules for Controlled Release of Therapeutic Gases. AB - Encapsulation and delivery of oxygen, carbon dioxide, and other therapeutic gases, using polymeric microcapsules (PMCs) is an emerging strategy to deliver gas as an injectable therapeutic. The gas cargo is stored within the PMC core and its release is mediated by the physiochemical properties of the capsule shell. Although use of PMCs for the rapid delivery of gases has been well described, methods which tune the material properties of PMCs for sustained release of gas are lacking. In this work, we describe a simple method for the high-yield production of gas-in-oil-filled PMCs with tunable sizes and core gas content from preformed polymers using the sequential phase separation and self-emulsification of emulsion-based templates. We demonstrate that prolonged gas release occurs from gas-in-oil PMCs loaded with oxygen and carbon dioxide gas, each of which could have significant clinical applications. PMID- 29989829 TI - Enzymatic Synthesis of Highly Electroactive Oligoanilines from a p Aminodiphenylamine/Aniline Mixture with Anionic Vesicles as Templates. AB - Oligoanilines with characteristic properties of the electrically conductive emeraldine salt form of polyaniline (PANI-ES) are promising molecules for various applications. A mixture of such oligoanilines can be obtained, for example, enzymatically under mild conditions from the linear aniline dimer p aminodiphenylamine (PADPA) with hydrogen peroxide (H2O2) and low amounts of horseradish peroxidase (HRP) in an aqueous pH = 4.3 suspension of anionic vesicles formed from AOT, the sodium salt of bis(2-ethylhexyl)sulfosuccinate. However, the simultaneous formation of undesired side products containing phenazine-type units or oxygen atoms is unsatisfactory. We have found that this situation can be improved considerably by using a mixture of PADPA and aniline instead of PADPA only but otherwise nearly identical conditions. The PANI-ES-like oligoaniline products that are obtained from the PADPA and aniline mixture were not only found to have much lower contents of phenazine-type units and not contain oxygen atoms but also were shown to be more electroactive in cyclic voltammetry measurements than the PANI-ES-like products obtained from PADPA only. The AOT vesicle suspension remained stable without product precipitation during and after the entire reaction so that it could be analyzed by in situ UV/visible/near-infrared, in situ electron paramagnetic resonance, and in situ Raman spectroscopy measurements. These measurements were complemented with ex situ high-performance liquid chromatography analyses of the deprotonated and reduced products formed from mixtures of PADPA and either fully or partially deuterated aniline. On the basis of the results obtained, a reaction mechanism is proposed for explaining this improved HRP-triggered, vesicle-assisted synthesis of electroactive PANI-ES-like products. The oligomeric products obtained can be further used, without additional special workup, for example, to coat electrodes for their possible application in biosensor devices. PMID- 29989830 TI - 4-Cyanoindole-2'-deoxyribonucleoside (4CIN): A Universal Fluorescent Nucleoside Analogue. AB - The synthesis and characterization of a universal and fluorescent nucleoside, 4 cyanoindole-2'-deoxyribonucleoside (4CIN), and its incorporation into DNA is described. 4CIN is a highly efficient fluorophore with quantum yields >0.90 in water. When incorporated into duplex DNA, 4CIN pairs equivalently with native nucleobases and has uniquely high quantum yields ranging from 0.15 to 0.31 depending on sequence and hybridization contexts, surpassing that of 2 aminopurine, the prototypical nucleoside fluorophore. 4CIN constitutes a new isomorphic nucleoside for diverse applications. PMID- 29989831 TI - Correction to Direct Synthesis of 4-Quinolones via Copper-Catalyzed Intermolecular Cyclization of Anilines and Alkynes. PMID- 29989832 TI - Catalytic Double [2 + 2] Cycloaddition Relay Enabled C-C Triple Bond Cleavage of Yne-Allenones. AB - An unusual catalytic double [2 + 2] cycloaddition relay reaction of yne-allenones with unactivated alkenes and alkynes has been achieved, which enabled C-C triple bond cleavage to access more than 60 examples of functionalized phenanthren-9-ols with generally good yields. This reaction provides a regioselective and practical method for the construction of carbocyclic ring systems with a high degree of functional group compatibility. Aside from surveying the scope of this transformation, mechanistic details of this process are provided by conducting systematic theoretical calculations. PMID- 29989833 TI - Deceleration Capacity of Heart Rate After Acute Altitude Exposure. AB - : Hamm, Wolfgang, Lukas von Stulpnagel, Mathias Klemm, Monika Baylacher, Konstantinos D. Rizas, Axel Bauer, and Stefan Brunner. Deceleration capacity of heart rate after acute altitude exposure. High Alt Med Biol 19:299-302, 2018. BACKGROUND: The autonomic nervous system plays a crucial role in adaptive changes after high-altitude exposure. Deceleration capacity (DC) of heart rate is an advanced marker of heart rate variability (HRV) that predominantly reflects the vagal activity of the cardiac autonomic nervous system. The impact of high altitude exposure on DC has not been investigated yet. METHODS: In eight healthy individuals we performed a high-resolution digital 30-min electrocardiography in Frank leads configuration at baseline (521 m altitude), immediately after ascent to the Environmental Research Station Schneefernerhaus (UFS) at Zugspitze (2650 m altitude) and after a sojourn of 24 hours at this altitude. DC of heart rate was assessed using customized software. In addition, standard parameters of HRV were assessed. RESULTS: DC decreased significantly from 10.2 +/- 0.8 ms to 8.9 +/- 1.0 ms (p < 0.05) after acute altitude exposure. After a sojourn of 24 hours at high altitude, DC remained low at 8.6 +/- 1.2 ms. There were no significant changes in standard parameters of HRV. CONCLUSION: Our findings show for the first time a decrease of DC of heart rate providing a novel insight into the dysbalance of autonomic nervous system at high altitude. PMID- 29989834 TI - The Triad of Risk-Related Behaviors (TriRB): A Three-Dimensional Model of Cyber Risk Taking. AB - OBJECTIVE:: We identify three risk-related behaviors in coping with cyber threats the exposure to risk a person chooses, use of security features, and responses to security indications. The combinations of behaviors that users choose determine how well they cope with threats and the severity of adverse events they experience. BACKGROUND:: End users' coping with risks is a major factor in cybersecurity. This behavior results from a combination of risk-related behaviors rather than from a single risk-taking tendency. METHOD:: In two experiments, participants played a Tetris-like game, attempting to maximize their gains, while exogenous occasional attacks could diminish earnings. An alerting system provided indications about possible attacks, and participants could take protective actions to limit the losses from attacks. RESULTS:: Variables such as the costs of protective actions, reliability of the alerting system, and attack severity affected the three behaviors differently. Also, users dynamically adjusted each of the three risk-related behaviors after gaining experience with the system. CONCLUSION:: The results demonstrate that users' risk taking is the complex combination of three behaviors rather than the expression of a general risk taking tendency. The use of security features, exposure to risk, and responses to security indications reflect long-term strategy, short-term tactical decisions, and immediate maneuvering in coping with risks in dynamic environments. APPLICATION:: The results have implications for the analysis of cybersecurity related decisions and actions as well as for the evaluation and design of systems and targeted interventions in other domains. PMID- 29989835 TI - Outcomes of Closed Versus Open Technique of Rhinoplasty During Primary Repair of Unilateral Cleft Lip: A Systematic Review. AB - OBJECTIVE: Primary cleft rhinoplasty has almost become the norm in cleft practice. Although various closed and open rhinoplasty techniques are in use, there is no consensus as to which technique is superior in terms of outcome. The authors hypothesized that the long-term outcomes of open rhinoplasty during primary cleft lip repair in unilateral cleft is better than that of the closed method. This systematic review has been done to evaluate the hypothesis by a review and analysis of literature. METHODS: Protocol was registered on the PROSPERO register of systematic reviews. PRISMA-P guidelines for the conduct of systematic review were followed. Literature search was done in various databases. The inclusion criteria were patients with nonsyndromic unilateral cleft lip undergoing rhinoplasty with primary cleft lip repair and preference given to studies comparing the 2 procedures. RESULTS: Sixteen articles were selected based on inclusion criteria after screening 522 articles-1 randomized controlled trial, 2 retrospective cohorts, and 13 case series. Both closed and open techniques have achieved good symmetry of nostrils with no impairment of growth. No advantage of one technique over the other was noted. CONCLUSIONS: There is a paucity of randomized controlled trials and prospective studies on the subject to arrive at an evidence-based recommendation as to whether open or closed rhinoplasty during primary cleft lip repair gives better long-term outcomes. Due to insufficient evidence, the authors are not able to support or refute the hypothesis put forward in the review. PMID- 29989836 TI - Description of Mandibular Improvements in a Series of Infants With Congenital Muscular Torticollis and Deformational Plagiocephaly Treated With Physical Therapy. AB - BACKGROUND: Many infants with congenital muscular torticollis (CMT) have deformational plagiocephaly (DP), and a small cohort also demonstrate mandibular asymmetry (MA). The aim of this retrospective study was to evaluate mandibular changes in these infants with previous computed tomography (CT) scans who underwent physical therapy (PT) to treat CMT. METHODS: A retrospective study included patients presenting to a pediatric plastic surgery clinic from December 2010 to June 2012 with CMT, DP, and MA. A small subset of these patients initially received a 3D CT scan due to concern for craniosynostosis. An even smaller subset of these patients subsequently received a second 3D CT scan to evaluate for late-onset craniosynostosis. Patients were treated with PT for at least 4 months for CMT. Initial CT scans were retrospectively compared to subsequent CT scans to determine ramal height asymmetry changes. Clinical documentation was reviewed for evidence of MA changes, CMT improvement, and duration of PT. RESULTS: Ten patients met inclusion criteria. Ramal height ratio (affected/unaffected) on initial CT was 0.87, which significantly improved on subsequent CT to 0.93 ( P < .05). None of the patients were diagnosed with craniosynostosis on initial CT. One patient was diagnosed with late-onset coronal craniosynostosis on subsequent CT. CONCLUSIONS: We identified a small cohort of infants with MA, CMT, and DP. These patients uniformly demonstrated decreased ramal height ipsilateral to the affected sternocleidomastoid muscle. Ramal asymmetry measured by ramal height ratios improved in all infants undergoing PT. PMID- 29989837 TI - Ewing Sarcoma Presenting as a Congenital Scalp Mass. AB - Ewing sarcoma is a locally aggressive, highly malignant tumor most commonly seen in the skeletal system. The "Ewing family of tumors" also includes other tissue types that are not common, such as soft tissue origin classified as extraosseous Ewing sarcoma (EES) or primitive neuroendocrine origin. Age of onset most often occurs within the first 2 decades of life. Congenital presentation of EES is exceedingly rare. We report the first described case to our knowledge of congenital EES originating from the scalp. PMID- 29989838 TI - Long Noncoding RNA SNHG7 Promotes the Tumor Growth and Epithelial-to-Mesenchymal Transition via Regulation of miR-34a Signals in Osteosarcoma. AB - The long noncoding RNA (LncRNA) SNHG7 (small nuclear RNA host gene 7) is a novel LncRNA and functions as an oncogene to promote tumor proliferation and inhibits apoptosis in many cancers. However, the role of SNHG7 in osteosarcoma (OS) remains to be further investigated. In this study, OS tissues and corresponding relative normal tissues (n = 30) were collected to determine the expression of SNHG7 in OS. The results indicated that high SNHG7 level in OS correlated with high Enneking stage, distant metastasis, and short overall survival time of OS patients. Moreover, miRNA-34a (miR-34a) is a classic tumor suppressor. Bioinformatic analysis predicted that SNHG7 harbored miR-34a binding sites, and the authors found that SNHG7 negatively correlated with miR-34a in OS tissues and the SNHG7 inhibition induced the restoration of miR-34a in OS cell lines MG63 and SaOS2, leading to the reactivation of miR-34a-mediated tumor suppression. Knockdown of SNHG7 in tumor cells significantly impaired the cell vitality, migration and invasion or TGF-beta-induced epithelial-mesenchymal transition (EMT), induced apoptosis, and G1/S arrest via miR-34a. Mechanistically, the targets of miR-34a could be upregulated by SNHG7, including proliferation-related Notch1, apoptosis-related BCL-2, cell cycle-related CDK6, and EMT-related SMAD4. The oncogene role of SNHG7 in vivo was also confirmed and found that knockdown of SNHG7 delayed the tumor growth with increased miR-34a level and Ki-67 level in OS tissues. These findings demonstrated that the LncRNA SNHG7 is upregulated during the development of OS via inhibition of tumor suppressor miR-34s signals. PMID- 29989839 TI - Systemic Therapy for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update Summary. PMID- 29989840 TI - Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update Summary. PMID- 29989842 TI - How little is known about the role of human FOXP3+ Tregs in tumors. PMID- 29989841 TI - Novel Surgical and Radiologic Classification of the Subtympanic Sinus: Implications for Endoscopic Ear Surgery. AB - Objective The aim of this study is to describe the endoscopic anatomy of the subtympanic sinus (STS), establish a classification according to its extension regarding the level of the facial nerve (FN), and assess the feasibility of the transcanal endoscopic approach to the STS. Study Design Experimental anatomic research. Setting Temporal bone laboratory. Methods We performed endoscopic dissection of 34 human whole head and ear block specimens. Of those, 29 underwent high-resolution computed tomography. The STS was classified according to its extension regarding the level of the FN: type A, no extension medial to the FN; type B, extension to the medial limit of the FN; type C, extension of the sinus medially and posteriorly from the FN into the mastoid cavity. Results The majority of cases (n = 21, 72%) showed a shallow type A STS. We observed a deep type B configuration in 6 cases (21%) and a type C in 2 cases (7%). The STS was completely exposable with a 0 degrees endoscope in 44% of the specimens. Using a 45 degrees endoscope, we gained complete insight in 79%. However, in 21% of the cases, the posteromedial extension of the STS was too deep to be completely explored by an endoscopic transcanal approach. Conclusion The majority of the STS is shallow and does not extend medially from the FN. This morphologic variant allows complete transcanal endoscopic visualization. In more excavated STS, a complete endoscopic exploration is not achievable, and a retrofacial approach may be adopted to completely access the STS. PMID- 29989843 TI - Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys. AB - PURPOSE: To investigate the mechanism of the intraocular pressure (IOP)-lowering effect of a novel selective prostaglandin E2 receptor 2 (EP2) receptor agonist, omidenepag isopropyl (OMDI). METHODS: The effect of OMDI on IOP and aqueous humor dynamics was evaluated in cynomolgus monkeys with unilateral laser-induced ocular hypertension. In a crossover manner, the hypertensive eye of each monkey was dosed once daily with 20 MUL of either 0.002% OMDI or vehicle. On day 7 of dosing, IOP was measured by pneumatonometry, aqueous humor flow and outflow facility were evaluated by fluorophotometry, and uveoscleral outflow was calculated mathematically. Treatments were compared by paired t-tests. RESULTS: OMDI at 0.002% significantly lowered IOP by 27%, 35%, and 44% at 0.5, 1.5, and 4 h after the last dosing, respectively. There was no difference in aqueous humor flow between vehicle and OMDI treatments. When comparing OMDI to the vehicle treatment, outflow facility and uveoscleral outflow were significantly (P < 0.05) increased by 71% and 176%, respectively. CONCLUSIONS: OMDI, a novel IOP-lowering compound, reduced IOP by increasing outflow facility and uveoscleral outflow in nonhuman primates. PMID- 29989845 TI - Association Between Serum CK-18 Levels and the Degree of Liver Damage in Fructose Induced Metabolic Syndrome. AB - BACKGROUND: The pathogenesis of nonalcoholic fatty liver disease as a component of metabolic syndrome (MetS) involves the activation of apoptosis in steatotic hepatocytes. Caspase-generated fragments such as cytokeratin-18 (CK-18) in patients with various hepatic impairments are investigated as markers for diagnosis and assessment of disease severity. The goal of the study was to capture early biomarkers of apoptosis and elucidate their role in assessing the presence and extent of hepatic damage in a MetS model. MATERIALS AND METHODS: We used male Wistar rats, divided into two groups (n = 7): control and high-fructose drinking (HFD) (35% fructose corn syrup for 16 weeks). Metabolic disorders and liver damage were studied by histochemistry (hematoxylin and eosin), immunohistochemical, immunological, and biochemical testing. RESULTS: Our results showed significant increase in liver and serum levels of CK-18 and pro/antiapoptotic Bax/Bcl2 ratio, and decreased levels of HMGB1 (marker of necrosis) in the HFD group when compared with the control. All HFD rats developed obesity, hyperglycemia, hepatomegaly, microvesicular steatosis, an imbalance in hepatic antioxidative defense by measuring malondialdehyde and sulfhydryl groups (SH) with no inflammation and fibrosis, elevated serum levels of triglycerides, tumor necrosis factor alpha (TNF-alpha), and C-reactive protein without changes in serum aminotransferase levels relative to the control group. As a result of the applied regression analysis, we have determined that the variables TNF-alpha (0.92) and SH (0.659) have a strong complex effect on hepatic CK-18 levels with predicted value of the model R = 0.9. CONCLUSION: The elevated CK-18 serum levels in the HFD group and their association with the histological changes in the liver and biochemical indicators demonstrate the key role of apoptosis in the pathogenesis of HFD-induced liver damage and the reliability of CK-18 as a biomarker for noninvasive assessment of liver damages in MetS. PMID- 29989844 TI - Polydatin suppresses VEGF-induced angiogenesis through binding with VEGF and inhibiting its receptor signaling. AB - Polydatin, also called piceid, is a stilbenoid glucoside of a resveratrol derivative. It derives mainly from the root and rhizome of Polygonum cuspidatum Sieb. et Zucc. Although the role of P. cuspidatum root in angiogenesis has been reported, the active chemical or chemicals responsible for such function is not known. Here, polydatin was proposed to bind VEGF, which therefore altered the functions of VEGF in angiogenesis. Several lines of evidence supported the pharmaceutical effects of polydatin in VEGF-induced angiogenesis. In human umbilical vein endothelial cells, polydatin inhibited VEGF-stimulated cell proliferation, cell migration, and tube formation. Moreover, polydatin showed suppressive effects on the subintestinal vessel formation in zebrafish embryos. In signaling cascades, polydatin application attenuated VEGF-induced phosphorylations of VEGF receptor 2 and JNK. Moreover, the VEGF-induced phosphorylations of Akt, eNOS, and Erk were significantly decreased in the presence of polydatin. In parallel, the formation of reactive oxygen species, triggered by VEGF, was markedly decreased under polydatin application. Thus, our results supported the angiogenic roles of polydatin, as well as its signaling mechanism in blocking VEGF-mediated responses. The current study provides support for the possible development of polydatin as a potential therapeutic agent for treatment and prevention of angiogenesis-related diseases.-Hu, W.-H., Wang, H. Y., Kong, X.-P., Xiong, Q.-P., Poon, K. K.-M., Xu, L., Duan, R., Chan, G. K.-L., Dong, T. T.-X., Tsim, K. W.-K. Polydatin suppresses VEGF-induced angiogenesis through binding with VEGF and inhibiting its receptor signaling. PMID- 29989846 TI - Dissecting Symptomatology and Fumonisin Contamination Produced by Fusarium verticillioides in Maize Ears. AB - The fungus Fusarium verticillioides can infect maize ears, contaminating the grain with mycotoxins, including fumonisins. This global public health threat can be managed by breeding maize varieties that are resistant to colonization by F. verticillioides and by sorting grain after harvest to reduce fumonisin levels in food systems. Here, we employed two F. verticillioides inoculation techniques representing distinct infection pathways to dissect ear symptomatology and morphological resistance mechanisms in a diverse panel of maize inbred lines. The "point" method involved penetrating the ear with a spore-coated toothpick and the "inundative" method introduced a liquid spore suspension under the husk of the ear. We evaluated quantitative and qualitative indicators of external and internal symptom severity as low-cost proxies for fumonisin contamination, and found that kernel bulk density was predictive of fumonisin levels (78 to 84% sensitivity; 97 to 99% specificity). Inundative inoculation resulted in greater disease severity and fumonisin contamination than point inoculation. We also found that the two inoculation methods implicated different ear tissues in defense, with cob morphology being a more important component of resistance under point inoculation. Across both inoculation methods, traits related to cob size were positively associated with disease severity and fumonisin content. Our work demonstrates that (i) the use of diverse modes of inoculation is necessary for combining complementary mechanisms of genetic resistance, (ii) kernel bulk density can be used effectively as a proxy for fumonisin levels, and (iii) trade offs may exist between yield potential and resistance to fumonisin contamination. PMID- 29989847 TI - Evidence for Sexual Recombination in Didymella tanaceti Populations, and Their Evolution Over Spring Production in Australian Pyrethrum Fields. AB - Tan spot, caused by Didymella tanaceti, is one of the most important foliar diseases affecting pyrethrum in Tasmania, Australia. Population dynamics, including mating-type ratios and genetic diversity of D. tanaceti, was characterized within four geographically separated fields in both late winter and spring 2012. A set of 10 microsatellite markers was developed and used to genotype 774 D. tanaceti isolates. Isolates were genotypically diverse, with 123 multilocus genotypes (MLG) identified across the four fields. Fifty-eight MLG contained single isolates and Psex analysis estimated that, within many of the recurrent MLG, there were multiple clonal lineages derived from recombination. Isolates of both mating types were at a 1:1 ratio following clone correction in each field at each sampling period, which was suggestive of sexual recombination. No evidence of genetic divergence of isolates of each mating type was identified, indicating admixture within the population. Linkage equilibrium in two of the four field populations sampled in late winter could not be discounted following clone correction. Evaluation of temporal changes in gene and genotypic diversity identified that they were both similar for the two sampling periods despite an increased D. tanaceti isolation frequency in spring. Genetic differentiation was similar in populations sampled between the two sampling periods within fields or between fields. These results indicated that sexual reproduction may have contributed to tan spot epidemics within Australian pyrethrum fields and has contributed to a genetically diverse D. tanaceti population. PMID- 29989848 TI - When LC-HRMS metabolomics gets ISO17025 accredited and ready for official controls - application to the screening of forbidden compounds in livestock. AB - Within the particular context of controlling chemical residues in food, an alternative to targeted approaches has emerged; it consists in the characterisation of physiological perturbations induced upon exposure of animals to a given chemical substance/class of substances to highlight suitable biomarkers addressing safety and/or regulatory issues. Metabolomics in particular has been investigated in the hope of identifying such biomarkers, and a range of studies have demonstrated the efficiency of the strategy. Until very recently, steps remained to be taken towards official or commercial implementation of corresponding tools. In particular, the lack of guidelines and criteria to validate such methods that do not target specific chemical species per se, constituted a bottleneck. In the present work, a metabolomics model dedicated to the detection of beta-agonist administration in bovines has been developed and fully validated; criteria (selectivity, robustness, stability, suspicion threshold definition, false positive and false negative rates) have been proposed in agreement with EU expectations (Dec 2002/657), enabling demonstration that performances comply with screening requirements. Although some of the biomarkers involved in the prediction model remain un-elucidated, the corresponding LC-HRMS method has recently been ISO17025 accredited, allowing for the very first official implementation of a metabolomics based strategy within French National Monitoring Plans. PMID- 29989849 TI - Systematic Review of Voice Outcomes for Injection Laryngoplasty Performed under Local vs General Anesthesia. AB - Objective To assist otolaryngologists in counseling patients with hoarseness who would benefit from injection laryngoplasty on whether or not to perform the procedure in the office vs the operating room. Data Sources Cochrane library, CINAHL, PubMed, and EMBASE. Review Methods Systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting standards of English-language articles that compared voice outcomes for in-office and in the operating room injection laryngoplasty. Two independent investigators assessed study eligibility, rated the quality using Methodological Index for Non Randomized Studies (MINORS), and abstracted data for comparative analysis. Results Of 689 initial studies, 4 observational, comparative studies met inclusion criteria, with follow-up of 2 weeks to 12 months postinjection. Laryngoplasty was most commonly performed for vocal fold immobility with varied injectable materials (micronized dermis, hyaluronic acid, and calcium hydroxyapatite). Follow-up ranged from 2 weeks to 12 months. Voice outcomes improved in all studies, with comparable improvement for patients injected in the office vs the operating room ( P = .42 to P = .88). Meta-analysis of 3 studies showed no difference in Voice Handicap Index-10 voice outcomes by treatment setting (standardized mean difference -0.11, P = .441), with the 95% confidence interval (-0.405 to 0.176), making it unlikely that anything larger than a small or trivial difference was missed. Conclusion Our systematic review makes it unlikely that meaningful clinical differences exist in postprocedure voice outcomes for injection laryngoplasty in the office vs the operating room. PMID- 29989850 TI - TRPC1 regulates brown adipose tissue activity in a PPARgamma-dependent manner. AB - Brown adipose tissue (BAT) has the unique ability of converting energy stored in the form of triglycerides into heat. This property makes BAT a target tissue to increase energy expenditure and improve systemic metabolic control. TRPC1 is a founding member of the TRP protein family that also includes several temperature sensitive channels. We show that TRPC1 is highly expressed in all adipocyte depots, including BAT, and that Trpc1-deficient mice are prone to weight gain and manifest reduced metabolic control. We also demonstrate that knockdown of TRPC1 in cultured brown adipocytes leads to a downregulation of several metabolic genes, including UCP1 and PPARgamma, as well as upregulation of the BAT-specific thermosensitive channel TRPV2, ultimately resulting in impaired respiratory function. We also show that TRPC1 is a possible target of PPARgamma, suggesting that TRPC1 is a downstream component of a mechanism that translates metabolic or environmental stimuli into output in the form of BAT activity. Better understanding of the possible role of TRPC1 and other TRP channels in body temperature regulation and BAT function may help us to develop obesity therapies based on BAT activation. PMID- 29989851 TI - Saturated Fatty Acid Combined with Lipopolysaccharide Stimulates a Strong Inflammatory Response in Hepatocytes in vivo and in vitro. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and consumption of high-fat diet (HFD) is a risk factor for NAFLD. The HFD not only increases intake of saturated fatty acid (SFA), but also induces metabolic endotoxemia, a HFD-associated increase in circulating lipopolysaccharide (LPS). Although it is known that SFA or LPS promotes hepatic inflammation, a hallmark of NAFLD, it remains unclear how SFA in combination with LPS stimulates host inflammatory response in hepatocytes. In this study, we performed both in vivo and in vitro experiments to investigate the effect of SFA in combination with LPS on proinflammatory gene expression in hepatocytes. Our animal study showed that feeding low-density lipoprotein-deficient mice HFD enriched with SFA and injection of low dose LPS cooperatively stimulated IL-6 expression in livers. To understand how SFA and LPS interact to promote IL-6 expression, our in vitro studies showed that palmitic acid (PA), a major SFA, and LPS exerted synergistic effect on the expression of IL-6 in hepatocytes. Furthermore, co-culture of hepatocytes with macrophages resulted in a greater IL 6 expression than culture of hepatocytes without macrophages in response to the combination of PA and LPS. Finally, we observed that LPS and PA increased ceramide production by cooperatively stimulating ceramide de novo synthesis, which played an essential role in the synergistic stimulation of proinflammatory gene expression by LPS and PA. Taken together, this study showed that SFA in combination with LPS stimulated a strong inflammatory response in hepatocytes in vivo and in vitro. PMID- 29989852 TI - Expression of miR-206 in human islets and its role in glucokinase regulation. AB - Inappropriate insulin secretion from beta-cells is considered as an early sign of impaired glucose tolerance and type 2 diabetes (T2D). Glucokinase (GCK) is an important enzyme that regulates glucose metabolism and ensures that the normal circulating glucose concentrations are maintained. GCK expression is induced by glucose and regulated via transcription factors and regulatory proteins. Recently, microRNA-206 (miR-206) was reported to regulate GCK and alter glucose tolerance in normal and high-fat diet-fed mice. Although the study findings have implications for human diabetes, studies in human islets are lacking. Here, we analyze human islets from individuals without or with T2D, using TaqMan-based real-time qPCR at the tissue (isolated islet) level as well as at single cell resolution, to assess the relationship between miR-206 and GCK expression in normal and T2D human islets. Our data suggest that, unlike mouse islets, human islets do not exhibit any correlation between miR-206 and GCK transcripts. These data implicate the need for further studies aimed toward exploring its potential role(s) in human islets. PMID- 29989853 TI - Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice. AB - Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation induced glucose intolerance using C57BL/6J male mice. A single 6-hr sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and determine the molecular mechanisms of sleep deprivation induced hepatic steatosis. Hepatic metabolites, such as acetyl CoA, 3beta hydroxybutyric acid, and certain acylcarnitines were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of Elovl3, Lpin1, Plin4, Plin5 and Acot1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes. PMID- 29989854 TI - Ado-Trastuzumab Emtansine for Patients With HER2-Mutant Lung Cancers: Results From a Phase II Basket Trial. AB - Purpose Human epidermal growth factor receptor 2 ( HER2, ERBB2)-activating mutations occur in 2% of lung cancers. We assessed the activity of ado trastuzumab emtansine, a HER2-targeted antibody-drug conjugate, in a cohort of patients with HER2-mutant lung cancers as part of a phase II basket trial. Patients and Methods Patients received ado-trastuzumab emtansine at 3.6 mg/kg intravenously every 3 weeks until progression. The primary end point was overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A Simon two-stage optimal design was used. Other end points included progression-free survival and toxicity. HER2 testing was performed on tumor tissue by next generation sequencing, fluorescence in situ hybridization, immunohistochemistry, and protein mass spectrometry. Results We treated 18 patients with advanced HER2-mutant lung adenocarcinomas. The median number of prior systemic therapies was two (range, zero to four prior therapies). The partial response rate was 44% (95% CI, 22% to 69%), meeting the primary end point. Responses were seen in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane, and extracellular domains. Concurrent HER2 amplification was observed in two patients. HER2 immunohistochemistry ranged from 0 to 2+ and did not predict response, and responders had low HER2 protein expression measured by mass spectrometry. The median progression-free survival was 5 months (95% CI, 3 to 9 months). Toxicities included grade 1 or 2 infusion reactions, thrombocytopenia, and elevated hepatic transaminases. No patient stopped therapy as a result of toxicity or died on study. Conclusion Ado trastuzumab emtansine is an active agent in patients with HER2-mutant lung cancers. This is the first positive trial in this molecular subset of lung cancers. Further use and study of this agent are warranted. PMID- 29989855 TI - Outcome of Patients With Early-Stage Infradiaphragmatic Hodgkin Lymphoma: A Comprehensive Analysis From the German Hodgkin Study Group. AB - Purpose The prognostic effect of isolated infradiaphragmatic involvement in Hodgkin lymphoma (HL) is controversial, and there are little data about patients treated with current therapies. Therefore, we performed a risk factor analysis to focus on isolated nodal infradiaphragmatic disease in patients treated within the German Hodgkin Study Group trials HD13 (clinical trial information: ISRCTN63474366) and HD14 (clinical trial information: ISRCTN04761296) for early stage HL. Patients and Methods Characteristics and outcomes of patients who had infradiaphragmatic HL were compared with patients who had supradiaphragmatic disease. Progression-free survival (PFS) and overall survival (OS) were estimated according to Kaplan-Meier methods and were compared between groups using the log rank test and Cox proportional hazards regression, which was also applied for multivariable analyses that adjusted for relevant baseline characteristics. Results Of 2,903 qualified patients, 223 (7.7%) were diagnosed with isolated nodal infradiaphragmatic disease. In general, these patients were older, had a poorer performance status, were more often male, and had the nodular sclerosis subtype less often than those with supradiaphragmatic disease. After a median follow-up time of 51 months, PFS and OS were significantly worse in patients with infradiaphragmatic disease (5-year PFS and OS, 80.1% and 91.5% v 91.2% and 97.6% in patients with supradiaphragmatic disease; each P < .001). In multivariable analyses, infradiaphragmatic HL remained a significant risk factor in terms of PFS (hazard ratio [HR], 1.5; 95% CI, 1.04 to 2.2; P = .03) and OS (HR, 2.0; 95% CI, 1.2 to 3.5; P = .01). However, inferior PFS and OS could not be observed among those patients treated with the more intensive chemotherapy (two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] in HD13, and two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPPescalated] plus two cycles of ABVD in HD14; all patients received 30 Gy of involved-field radiotherapy). Conclusion Early-stage HL that presents with infradiaphragmatic disease only represents a distinct patient group with an inferior outcome. However, this adverse outcome can be outweighed by appropriate combined modality treatment. PMID- 29989856 TI - Risk of Solid Cancer After Treatment of Testicular Germ Cell Cancer in the Platinum Era. AB - Purpose Testicular cancer (TC) treatment increases risk of subsequent malignant neoplasms (SMNs). It is unknown whether changes in TC treatment over time have affected SMN risk. Methods Solid SMN risk was evaluated in a multicenter cohort comprising 5,848 1-year survivors treated for TC before age 50 years between 1976 and 2007. SMN incidence was compared with cancer incidence in the general population. Treatment-specific risks were assessed using multivariable regression in a case-cohort design. Results After a median follow-up of 14.1 years, 350 solid SMNs were observed, translating into a 1.8-fold (95% CI, 1.6-2.0) increased risk compared with general population rates. Solid SMN risk was increased in patients with seminoma and those with nonseminoma (standardized incidence ratio, 1.52 and 2.21, respectively). Patients with nonseminoma experienced increased risk of SMNs of the thyroid, lung, stomach, pancreas, colon, and bladder and of melanoma and soft tissue sarcoma, whereas those with seminoma experienced increased risk of SMNs of the small intestine, pancreas, and urinary bladder. The 25-year cumulative incidence of solid SMNs was 10.3% (95% CI, 9.0% to 11.6%). In multivariable analysis, platinum-based chemotherapy was associated with increased risk of a solid SMN (hazard ratio [HR], 2.40; 95% CI, 1.58 to 3.62), colorectal SMN (HR, 3.85; 95% CI, 1.67 to 8.92), and noncolorectal GI SMN (HR, 5.00; 95% CI, 2.28 to 10.95). Receipt of platinum 400 to 499 and >= 500 mg/m2 increased solid SMN risk compared with surgery only (HR, 2.43; 95% CI, 1.40 to 4.23 and HR, 2.42; 95% CI, 1.50 to 3.90, respectively), whereas risk was not significantly increased with lower doses (HR, 1.75; 95% CI, 0.90 to 3.43). The HR of a GI SMN increased by 53% (95% CI, 26% to 80%) per 100 mg/m2 of platinum-containing chemotherapy. The HR of an infradiaphragmatic SMN increased by 8% per Gray of radiation dose administered (95% CI, 6% to 9%; P < .001). Conclusion Radiotherapy and platinum containing chemotherapy are associated with increased solid SMN risk, specifically with GI SMNs. PMID- 29989857 TI - Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203. AB - Purpose NRG Oncology/RTOG 1203 was designed to compare patient-reported acute toxicity and health-related quality of life during treatment with standard pelvic radiation or intensity-modulated radiation therapy (IMRT) in women with cervical and endometrial cancer. Methods Patients were randomly assigned to standard four field radiation therapy (RT) or IMRT radiation treatment. The primary end point was change in patient-reported acute GI toxicity from baseline to the end of RT, measured with the bowel domain of the Expanded Prostate Cancer Index Composite (EPIC). Secondary end points included change in patient-reported urinary toxicity, change in GI toxicity measured with the Patient-Reported Outcome Common Terminology Criteria for Adverse Events, and quality of life measured with the Trial Outcome Index. Results From 2012 to 2015, 289 patients were enrolled, of whom 278 were eligible. Between baseline and end of RT, the mean EPIC bowel score declined 23.6 points in the standard RT group and 18.6 points in the IMRT group ( P = .048), the mean EPIC urinary score declined 10.4 points in the standard RT group and 5.6 points in the IMRT group ( P = .03), and the mean Trial Outcome Index score declined 12.8 points in the standard RT group and 8.8 points in the IMRT group ( P = .06). At the end of RT, 51.9% of women who received standard RT and 33.7% who received IMRT reported frequent or almost constant diarrhea ( P = .01), and more patients who received standard RT were taking antidiarrheal medications four or more times daily (20.4% v 7.8%; P = .04). Conclusion Pelvic IMRT was associated with significantly less GI and urinary toxicity than standard RT from the patient's perspective. PMID- 29989858 TI - Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial. AB - Purpose The contribution of adjuvant chemotherapy after chemoradiation therapy (CRT) in nasopharyngeal cancer (NPC) remains controversial. Plasma Epstein-Barr virus (EBV) DNA is a potential biomarker of subclinical residual disease in NPC. In this prospective, multicenter, randomized controlled trial, we used plasma EBV DNA to identify patients with NPC at a higher risk of relapse for adjuvant chemotherapy. Patients and Methods Eligible patients with histologically confirmed NPC of Union for International Cancer Control stage IIB to IVB, adequate organ function, and no locoregional disease or distant metastasis were screened by plasma EBV DNA at 6 to 8 weeks after radiotherapy (RT). Patients with undetectable plasma EBV DNA underwent standard surveillance. Patients with detectable plasma EBV DNA were randomly assigned to either adjuvant chemotherapy with cisplatin and gemcitabine for six cycles (arm 1) or observation (arm 2). Patients were stratified for primary treatment (RT v CRT) and stage (II/III v IV). The primary end point was relapse-free survival (RFS). Results Seven hundred eighty-nine patients underwent EBV DNA screening. Plasma EBV DNA was undetectable in 573 (72.6%) and detectable in 216 (27.4%); 104 (13.2%) with detectable EBV DNA were randomly assigned to arms 1 (n = 52) and 2 (n = 52). After a median follow up of 6.6 years, no significant difference was found in 5-year RFS rate between arms 1 and 2 (49.3% v 54.7%; P = .75; hazard ratio for relapse or death, 1.09; 95% CI, 0.63 to 1.89). The level of post-RT plasma EBV DNA correlated significantly with the hazards of locoregional failure, distant metastasis, and death. Conclusion In patients with NPC with detectable post-RT plasma EBV DNA, adjuvant chemotherapy with cisplatin and gemcitabine did not improve RFS. Post-RT plasma EBV DNA level should be incorporated as the selection factor in future clinical trials of adjuvant therapy in NPC. PMID- 29989860 TI - Corrigendum. PMID- 29989859 TI - Association Between Inflammatory Biomarker C-Reactive Protein and Radiotherapy Induced Early Adverse Skin Reactions in a Multiracial/Ethnic Breast Cancer Population. AB - Purpose This study examined an inflammatory biomarker, high-sensitivity C reactive protein (hsCRP), in radiotherapy (RT)-induced early adverse skin reactions or toxicities in breast cancer. Patients and Methods Between 2011 and 2013, 1,000 patients with breast cancer who underwent RT were evaluated prospectively for skin toxicities through the National Cancer Institute-funded Wake Forest University Community Clinical Oncology Program Research Base. Pre- and post-RT plasma hsCRP levels and Oncology Nursing Society skin toxicity criteria (0 to 6) were used to assess RT-induced skin toxicities. Multivariable logistic regression analyses were applied to ascertain the associations between hsCRP and RT-induced skin toxicities after adjusting for potential confounders. Results The study comprised 623 white, 280 African American, 64 Asian/Pacific Islander, and 33 other race patients; 24% of the patients were Hispanic, and 47% were obese. Approximately 42% and 15% of patients developed RT-induced grade 3+ and 4+ skin toxicities, respectively. The hsCRP levels differed significantly by race and body mass index but not by ethnicity. In multivariable analysis, grade 4+ skin toxicity was significantly associated with obesity (odds ratio [OR], 2.17; 95% CI, 1.41 to 3.34], post-RT hsCRP >= 4.11 mg/L (OR, 1.61; 95% CI, 1.07 to 2.44), and both factors combined (OR, 3.65; 95% CI, 2.18 to 6.14). Above median post-RT hsCRP (OR, 1.93; 95% CI, 1.03 to 3.63), and change in hsCRP (OR, 2.80; 95% CI, 1.42 to 5.54) were significantly associated with grade 4+ skin toxicity in nonobese patients. Conclusion This large prospective study is the first to our knowledge of hsCRP as an inflammatory biomarker in RT-induced skin toxicities in breast cancer. We demonstrate that nonobese patients with elevated RT-related change in hsCRP levels have a significantly increased risk of grade 4+ skin toxicity. The outcomes may help to predict RT responses and guide decision making. PMID- 29989861 TI - Comparative Histopathologic Analysis of "Radiogenic" and "Sporadic" Papillary Thyroid Carcinoma: Patients Born Before and After the Chernobyl Accident. AB - BACKGROUND: The issue of whether radiation-induced thyroid cancer is pathologically different from sporadic remains not fully answered. This study compared structural characteristics and invasive features of papillary thyroid carcinoma (PTC) in two age-matched groups: patients who were children (<=4 years old) at the time of the Chernobyl accident and who lived in three regions of Ukraine most contaminated by radioactive iodine 131I ("radiogenic" cancer), and those who lived in the same regions but who were born after 1987 and were not exposed to 131I ("sporadic" cancer). Further, the histopathologic features of PTC were analyzed in relation to age and individual 131I thyroid dose. METHODS: The study included 301 radiogenic and 194 sporadic PTCs. According to age at surgery, patients were subdivided into children (<=14 years old), adolescents (15-18 years old), and adults (19-28 years old). Statistical analyses included univariate tests and multivariable logistic regression within and across the age subgroups. Analyses of morphological features related to 131I doses were conducted among exposed patients on categorical and continuous scales controlling for sex and age. RESULTS: Among children, radiogenic PTC displayed a significantly higher frequency of tumors with a dominant solid growth pattern, intrathyroidal spread, extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adolescents more frequently displayed extrathyroidal extension, lymphatic/vascular invasion, and distant metastases. Exposed adults more frequently had intrathyroidal spread and extrathyroidal extension. The frequency of PTC with dominant papillary pattern and oxyphilic cell metaplasia was significantly lower in radiogenic compared to sporadic tumors for all age groups. Manifestations of tumor aggressiveness were most frequent in children compared to adolescents and adults regardless of etiology. CONCLUSIONS: Radiogenic PTC is less likely to demonstrate a dominant papillary growth pattern and more likely to display more aggressive tumor behavior than sporadic PTC. Histopathologic tumor aggressiveness declines with patient age in both radiogenic and sporadic cases. PMID- 29989863 TI - Salivary and Serum Anti-Desmoglein 1 and 3 ELISA and Indirect Immunofluorescence in Pemphigus Vulgaris: Correlations with Serum ELISA, Indirect Immunofluorescence and Disease Severity. AB - Anti-desmoglein (anti-Dsg) ELISA and indirect immunofluorescence (IIF) are used for the diagnosis of pemphigus vulgaris (PV). The value of salivary ELISA, serum ELISA, and IIF in the diagnosis of PV, and the correlation of salivary anti-Dsg1 and anti-Dsg3 ELISA with serum ELISA, serum and salivary IIF titers, and disease severity in patients with PV were evaluated. Fifty newly diagnosed patients with PV were enrolled in the study. Demographic data and disease-severity scores were recorded for each patient. Anti-Dsg1 and anti-Dsg3 ELISA and IIF were performed on both serum and salivary samples. Given the cut-off value of 20 RU/mL for Dsg1 and Dsg3, serum Dsg1 and Dsg3 ELISA were positive in 41 (82%) and 40 (80%) patients, and saliva Dsg1 and the Dsg3 ELISA were positive in 2 (4%) and 3 (6%) patients, respectively. Using the cut-off value of 13.4 RU/mL and 7.7 RU/mL for Dsg3 and Dsg1 salivary ELISA, 25 (50%) and 23 (46%) patients tested positive for Dsg3 and Dsg1, respectively. Serum IIF results were positive in 35 (70%) patients, and salivary IIF results were positive in 16 (32%) patients. Salivary anti-Dsg1 and anti-Dsg3 showed moderate correlations with the total pemphigus disease area index (PDAI) score (r=0.466, P<0.001), (r=0.459, P<0.001), respectively. A moderate correlation between serum IIF and salivary IIF was also detected (r=0.413, P<0.001). Salivary anti-Dsg1 and anti-Dsg3 ELISA could be used as a safe and noninvasive method for the diagnosis of PV under certain circumstances, especially in children or elderly patients. Salivary ELISA is superior to salivary IIF. PMID- 29989864 TI - Evaluation of the Importance of Immunological Profile for Pemphigus Vulgaris in the Light of Necessity to Modify Compensation Theory. AB - According to the "desmoglein compensation theory," anti-Dsg1 and anti-Dsg3 profiles are crucial for the clinical outcome of pemphigus vulgaris. However, recent studies have highlighted several cases with an incompatibility between the antibody profile and clinical manifestation. Data of 37 patients who had been diagnosed pemphigus vulgaris in our Department between January 2014-June 2016 were retrieved from our clinical database. Patients with ABSIS skin involvement scores, oral mucosa extent and severity scores, anti-Dsg1 and Dsg3 antibody profile were included in this retrospective study. Patients with discordance between clinical manifestations and immunological profile were considered as atypical clinical phenotype. Patients with missing data were excluded. In all 37 patients, Dsg1 and Dsg3 antibody titers at the baseline did not correlate with the concurrent ABSIS scores. At follow up, we detected statistically significant correlations between anti Dsg-1 profile and ABSIS skin involvement scores (p=0.006; r=0.588) and between anti-Dsg3 and ABSIS mucosal extent and severity scores (p=0.058; r=0.431). After treatment, the reduction of Dsg-1 antibody titers was statistically significant in remittent patients (p=0.027). We did not detect statistically significant reduction of Dsg-3 antibodies. Four subjects had incompatible antibody profile and clinical activity. Discordance between phenotype-antibody profile and clinical activity-Dsg titers support the idea that non-Dsg antigens may also be the target for pemphigus autoimmunity. PMID- 29989865 TI - The Usage of Hypoallergenic Cosmetics in Patients with Atopic Dermatitis. AB - The aim of this study was to investigate how many patients with atopic dermatitis applied hypoallergenic cosmetics compared with topical corticosteroids. The study included 41 patients with atopic dermatitis (AD) who were treated from June 1 to July 1, 2017 at the Department of Dermatology and Venerology, Clinical Hospital Mostar. According to the data analyzed, 46.34% of patients used hypoallergenic cosmetics while 24.39% used them periodically. 32.7% patients used topical corticosteroids and 17.07 % used them periodically. 19.51 % of the patients with atopic dermatitis used alternative products, while 17.07% used them periodically. Out of the total number of patients, most of the patients used neutral products. 78.05% used neutral cosmetic products, and 19.51 % used them periodically. 65.85 % patients used sunscreens and 24.40 % used them periodically. The majority of patients used neutral cosmetic products and sunscreens. There was no statistically significant difference in the frequency of the use hypoallergenic cosmetics compared with topical corticosteroids (chi2 = 1.802; df = 2; P=0.405). Women used sunscreens more often (chi2 = 16,02; df = 1; p = <0,05). PMID- 29989866 TI - General Characteristics and Comorbidities in Patients with Palmoplantar Pustulosis. AB - The aim of this prospective study was to analyze comorbidities in patients with palmoplantar pustulosis (PPP). The current study comprised 63 consecutive patients with palmoplantar pustulosis. The control group consisted of 37 patients with psoriasis vulgaris (PSV). The study included a standardized anamnesis, a clinical examination, blood tests for thyroid hormones, as well as calcium, magnesium, antiendomysial antibody, and patch tests. Hypertension was observed in 28/63 (44.44%) patients with PPP. Eight (12.7%) had ischaemic heart disease, and 7/63 (11.11%) had type 2 diabetes mellitus. There was no statistically significant difference between the patients with PPP and those in the control group. Metabolic syndrome was diagnosed in 19/63 (30.16%) patients with PPP and in 12/37 (32.43%) patients with PSV. Thyroid disease was more prevalent among patients with PPP in comparison to patients with PSV (31.75% vs. 13.51%; p=0.0421). Body mass index was statistically significantly higher in patients with PSV (28.25 vs. 25.86 kg/m2, p=0.0144). BMI was higher than 25 kg/m2 in 18.03% patients with PPP and 26.47% patients with PSV (p=0.333). Positive patch tests were observed in 12/39 (30.77%) patients with PPP. The most common allergens were nickel chloride (5/12, 41.67%) and fragrances (5/12, 41.67%). In the control group, patch tests were positive in 2/11 (18.18%) cases (p<0.05). Patients with PPP, like patients with PSV, often presented with hypertension and metabolic syndrome. Given that many studies have focused on cardiovascular risk in PSV, there is a need for further research on the association between PPP and cardiovascular risk. In addition, patients resistant to PPP treatment should be screened for contact allergies. PMID- 29989867 TI - Clinical and Demographic Characteristics of Pemphigus Vulgaris Patients. AB - Pemphigus is an autoimmune disease characterized by intraepithelial bullae and erosions in the skin and mucosa. We aimed to evaluate the clinical and demographic characteristics of pemphigus vulgaris (PV) patients who presented to our Department. Patients who presented to our Department between May 2013 and May 2014, were examined dermatologically and diagnosed with PV based on clinical, histological and direct immunofluorescent findings. Name, family name, and gender of the patients, their complaint at presentation, onset time and location of the lesions, the number of lesions, systemic treatments received by patients and patients' medication histories were recorded. Forty-nine PV patients were included in our study. Among these, 22 (44.9%) were female and 27 (55.1%) male. The mean age of the patients was 53.28+/-14.70 (range 23 to 79) years. The mean duration of the disease was 44.45+/-45.68 (range 1 to 180) months. The most common complaints at presentation were lesion in the mouth (47/49) and lesion/blister in the skin (39/49). The onset locations of the lesions were the oropharynx (63.3%), the skin and oropharynx combined (16.3%), the skin (18.4%) and the anus (2%). The chronological order for the sites of involvement were as follows: first the oropharynx then the skin (42.9%), first the skin then the oropharynx (18.4%), and the oropharynx and the skin combined (16.3%). Ten patients (20.4%) had mucosal involvement and one (2%) had skin involvement alone, whereas both mucosal and skin involvements were observed in 38 patients (77.6%). Forty-seven patients (95.9%) had not used any medications that could have led to pemphigus. One patient had a history of beta-blocker use and another had a history of ACE inhibitor prior to the emergence of the pemphigus lesions. The clinical and demographic results of the PV patients in our region were consistent with those from other studies. PMID- 29989868 TI - The Effect of Zinc Gluconate Supplementation on Symptoms and Tongue Epithelium Regeneration in Non-psoriatic Patients with Migratory Glossitis. AB - The aim of this study was to evaluate zinc gluconate as a treatment option in patients with symptomatic migratory glossitis (MG). Using simple random sampling, 28 non-psoriatic patients with symptomatic MG were divided into a test and control group. The test group took 20 mg/day of chelated zinc gluconate for one month, and was put on a diet rich in zinc. The control group was only put on a diet rich in zinc. Changes in the size of red atrophied areas (width and length) and the intensity of symptoms were evaluated as primary and secondary outcomes, respectively, at baseline, after therapy, and one month later. In the test group, the mean value of the red atrophy area width and length displayed some significant reduction as a primary outcome. There were no significant changes in the size of red patches in the control group. Secondary outcome showed that the intensity of subjective symptoms in the test group significantly decreased (P=0.042) compared with controls. The filiform papillae had partially or completely regenerated in 85.7% of cases in the test group and in 23.1% of the controls (P=0.001). Red patches with raised keratotic rims may have healed spontaneously and reappeared in constantly changing patterns that are typical for MG. This phenomenon was not observed in patients supplemented with zinc, and new atrophy areas occurred in only one case. Low-dose zinc gluconate. PMID- 29989869 TI - The Value of Type IV Collagen Immunohistochemical Staining in the Differential Diagnosis of Autoimmune Subepidermal Bullous Diseases. AB - Autoimmune subepidermal bullous diseases (AISBDs) exhibit various clinical presentations, histological appearances, prognoses, and responses to treatment. Many diagnostic techniques, such as direct immunofluorescence (IF), indirect salt split skin IF, and enzyme-linked immunosorbent assays, are used in the differential diagnoses of AISBDs. However, these techniques require fresh frozen tissue, expensive laboratory equipment, and sophisticated laboratory techniques. The purpose of this study was to evaluate the value of type IV collagen immunohistochemical (IHC) staining for the differential diagnosis of AISBDs. Paraffin-embedded blocks of skin biopsies were selected from 28 patients with autoimmune subepidermal bullous diseases. Among these 28 cases, 24 patients exhibited bullous pemphigoid (BP), 2 exhibited epidermolysis bullosa acquisita (EBA), 1 exhibited linear immunoglobulin A dermatosis (LAD), and 1 exhibited bullous systemic lupus erythematosus (BSLE). Sections were stained for type IV collagen and examined to determine the location of type IV collagen in the subepidermal blister. Type IV collagen positivity was observed on the base of the subepidermal blister in patients with BP (24 of 24 cases) and LAD (1 of 1 case). Staining was observed on the roof of the blister in patients with EBA (2 of 2 cases) and BSLE (1 of 1 case), and irregular staining was also observed on the base in patients with EBA. In conclusion, type IV collagen IHC staining is a simple and useful diagnostic technique for the differential diagnosis of AISBDs. PMID- 29989870 TI - Quality of Life of School and University Students with Acne. AB - Acne may have severe negative impact on different aspects of patient health related quality of life (HRQoL). Prevalence of acne in university and school students is high, and the HRQoL of students with acne from different countries was studied. There is a lack of studies on direct comparison of HRQoL impairment of university and school students with acne. The Cardiff Acne Disability Index (CADI) was used to assess the HRQOL in university and school students with self assessed acne. The CADI results from 159 university and 99 school students with self-reported acne were obtained. Mean age of university and school students was 20.99+/-1.47 (mean +/- Standard Deviation) and 14.10+/-0.51 years, respectively. Reported impact on QoL of university students was significantly higher (3.33+/ 2.26 and 2.76+/-2.42, P<0.05). Total CADI scores negatively correlated with the age of university students (r=-0.16; P<0.05). Analysis of gender differences of university students showed that negative correlation of HRQoL with age was present in women (r=-0.22; P<0.05) but absent in male students (r=0.05; P=0.77). Female university students reported more severe impact of acne on their life (2.55+/-2.31 in male and 3.59+/-2.20 in female students, P<0.01). Our results showed that university students experience higher impact of acne on their life than school students. The highest is the impact on young female university students. We recommend paying more attention to the psychological aspects of young female students with acne during consultations. PMID- 29989871 TI - Serological Diagnosis of Syphilis: Preliminary Study Searching for an Algorhitm in Turkey. AB - Different algorithms have been proposed to increase the diagnostic capacity of syphilis. We analyzed three common algorithms for detecting suspected syphilis cases in low prevelance Turkish population. The study included a total of 340 clinical serum samples from adults throughout Turkey, who had syphilis as a clinical preliminary diagnosis and were positive on at least one of the following tests: Rapid Plasma Reagin (RPR), Treponema pallidum Haemagglutination test (TPHA) and FTA-abs Ig. In adittion to percent agreement, kappa coefficients were calculated to compare the conformity between the three algorithms. Both the reverse and the ECDC algorithms had higher diagnostic efficacy than the conventional algorithm. The sensitivity/specificity/ accuracy of conventional, reverse and ECDC algorithms were 51.3%/86.1%/55%; 80.9%/86.1%/81.4% and 80.9%/100%/82.9% respectively. The interrater reliability was moderate for conventional-reverse algorithm (73.53%; k=0.484; 95%CI=0.41-0.56; p=0.001) and conventional-ECDC algorithm (72.06%; k=0.454; 95% CI= 0.37-0.54; p=0.001), and near perfect for reverse-ECDC algorithm (98.53%; k=0.963; 95% CI=0.93-0.99; p=0.0001). Our data support the use of ECDC algorithm in serological diagnosis of syphilis. It may increase the diagnostic capacity if treponemal tests are used for screening, and then positive results are confirmed with a different and second treponemal test. PMID- 29989872 TI - Skin Barrier Function in Patients with Primary and Secondary Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is a systemic autoimmune disease. A large percentage of patients with SS suffer from dry skin, the cause and pathogenesis of which in this group of patients remains obscure. The aim of the present study was to investigate skin barrier function in patients with SS. Measurements of transepidermal water loss (TEWL) and hydration of stratum corneum (corneometry, CM) were performed in 30 female patients with SS (17 with primary SS and 13 with secondary SS), 20 patients with atopic dermatitis (AD) and 14 healthy controls. There were no statistically significant differences in TEWL values between the three investigated groups, while CM values were significantly decreased in patients with AD when compared with patients with SS and the healthy controls. Based on the obtained results, skin barrier function and hydration in patients with SS showed no functional alterations. PMID- 29989873 TI - Bowen's Disease in Dermoscopy. AB - Bowen's disease, named after John Templeton Bowen, also known as squamous cell carcinoma in situ is a type of non-melanocytic intraepidermal malignancy. It is estimated that in general population around 3% to 5% of Bowen's disease transform into invasive squamous cell cancer. Dermoscopy aims in the identification of the Bowen's disease. The most typical dermoscopic features of Bowen's disease include glomerular vessels and scaly surface. Although dermoscopy of Bowen's disease has been well established other skin lesions may present similar or identical structures in dermoscpic images leading to differential diagnosis dilemmas. Histopathological confirmation should be obtained prior the treatment of suspected cases of Bowen's disease in order to avoid a misdiagnosis. PMID- 29989874 TI - Trichoepithelioma: A Comprehensive Review. AB - Trichoepithelioma is an uncommon benign adnexal neoplasm. It can present as a solitary non-familial or multiple familial form. Trichoepithelioma usually develops in early childhood or puberty. Females are more affected. It is attributed to two genetic mutations on chromosomes 9p21 and 16q12-q13. Multiple familial trichoepithelioma is an autosomal-dominant disorder, characterized by numerous nodules and papules, predominantly on the face and occasionally on the scalp, neck, or upper trunk, positive family history, and histopathological findings. The lesions gradually increase in both size and number over time; however, they remain mostly asymptomatic. Although it is rare, trichoepithelioma lesions can undergo malignant transformation to trichoblastic carcinoma or basal cell carcinoma. Patients mainly seek treatment because the lesions are usually disfiguring and can lead to psycho-social issues. Non-pharmacologic approaches (e.g., excisional surgery, laser resurfacing), as the current mainstay of management, suffer from several drawbacks. New treatment techniques such as pharmacotherapy with potentially effective agents deserve more attention and investigation. PMID- 29989875 TI - The First Reported Case of Trichothiodystrophy in Hungary: A Young Male Patient with Mutations in the ERCC2 Gene. AB - Trichothiodystrophy, also called sulphur-deficient brittle hair syndrome, is a rare autosomal recessive genetic disorder of DNA repair and transcription. Trichothiodysthrophy is characterised by dry, thin, easily broken hair, showing alternating light and dark pattern called 'tiger tail' banding under polarizing light microscopy. According to our knowledge, our report is the first one on this rare disorder from Hungary: a case of a 9-year-old boy showing clinical features typical of trichotiodystrophy. Sequence analysis of the ERCC2 gene identified two recurrent trichothidodystrophy missense heterozygous mutations - c.934G/A p.Asp312Asn (CM015299) and c.2251A/C p.Lys751Gln (CM004814) - suggesting compound heterozygous state of the patient and confirming the clinically suspected diagnosis of trichothiodystrophy. PMID- 29989876 TI - Tumor Necrosis Factor Antagonists in the Treatment of Pyoderma Gangrenosum, Acne, and Suppurative Hidradenitis (PASH) Syndrome. AB - The clinical triad of pyoderma gangrenosum (PG), acne and suppurative hidradenitis (HS) has been described under the acronym PASH syndrome and is considered to represent a distinct entity in the group of autoinflammatory diseases. It is a fairly new, only recently recognized disorder with a limited number of reported cases and without defined treatment recommendations. We aimed to summarize currently available data on the use of tumor necrosis factor (TNF) antagonists in the management of PASH syndrome and report on our own experience with the use of adalimumab in a patient presenting with this specific constellation of clinical signs and symptoms. Among the 11 cases identified in the literature, infliximab and adalimumab were the most commonly used agents, both exhibiting favorable effects in the majority of, but not all, patients. This was particularly evident in terms of relatively rapid remission of PG whereas HS lesions seemed to be more resistant to treatment. In our patient, adalimumab monotherapy resulted in a remarkable and sustained remission, although significant improvement of HS lesions was observed only from week 16 of therapy onwards. In summary, TNF antagonists are a promising treatment for PASH; however, conclusions regarding the choice of a specific agent, optimal dosing or use in combination with other treatment modalities cannot yet be drawn. PMID- 29989877 TI - Bullous Pemphigoid Associated with Ischemic Cerebrovascular Accident and Dementia: Exclusive Blistering Lesions on the Upper Hemiparetic Limb. AB - Bullous pemphigoid (BP) has been associated with neurological disorders (NDs), which has led to the hypothesis that molecular mimicry exists between hemidesmosomal proteins and neuronal peptides. A 79-year-old hemiparetic woman presented with tense bullae affecting exclusively her right paretic upper limb for three months. Histopathology, taken from the perilesional area, revealed an inflammatory infiltrate with predominant eosinophils. IIF evidenced linear IgG deposition in the epidermal side of the cleavage. ELISA detected circulating anti BP180 and anti-BP230 autoantibodies. Immunoblotting exhibited unspecific reactivity against the 190-kDa periplakin in normal human epidermal extract. The immunocompromised cutaneous district concept may explain the possible mechanism for the exclusive involvement of the autoimmune blistering disease in lymphedematous hemiparetic upper limb. PMID- 29989878 TI - Atypical Nevi in a Patient After Toxic Epidermal Necrolysis. AB - Dear Editor, There are few literature data about nevi in patients with a history of toxic epidermal necrolysis (TEN) and little recommendations for follow-up and risks of melanoma (MM). Eruptive melanocytic nevi (EMN) is a rare phenomenon that has been associated with bullous disorders, immunosuppression, and immunodeficiency, but in some cases can occur without precipitating factors (1). The etiology is largely unknown, but there is evidence that immunosuppression might play a crucial role in nevogenesis, probably due to the inability of the immune system to inhibit melanocytic (MC) proliferation (2,3). We report the follow-up of a patient with a history of TEN who later developed atypical nevi. A 17-year-old man with a history of severe TEN two years earlier, most probably due to valproic acid and diclofenac, was referred to our Department due to atypical nevi. The patient presented with scars, scattered pigmentation (Fig. 1), and symblepharon as a consequence of TEN (Fig. 2). Most of his nevi developed in following two years after TEN. During the first visit in 2009, clinical and dermoscopic photodocumentation was performed. The patient presented with a moderate number of nevi (Fig. 3), dermoscopically subclassified as globular. One atypical MN was found on the back, with dermoscopic findings of reticular pattern and presence of suspected areas of regression (Fig. 4. a, b), and it was excised to rule out melanoma (Fig. 4, Fig. 5). The patient did not come to regular follow up from 2009 to 2014, and presented in 2014 which was when comparative photo documentation was made. As this visit another, speckled type of newly-occurred nevus was excised. Both excised nevi were histopathologically characterized as dysplastic. Only a few references are available on nevi development after TEN. Anticonvulsives and NSAIDs, as in our case, are often involved in the etiopathogenesis of TEN (4,5). Survivors may experience a variety of long-term complications; authors reported that 19% of their patients developed new nevi after TEN (6,7). EMN develop several years after TEN as a suddenly arising large number of nevi that may resemble speckled lentiginous nevi (8). Histologically. EMN demonstrate a proliferation of MC at the dermo-epidermal junction and, if compound, in the papillary dermis, arranged mostly in nests. Junctional MC may appear slightly pleomorphic, but no significant cytological atypia or prominent pagetoid spread of MC was reported (9). EMN have been associated with a specific dermoscopic finding of a symmetrical peripheral rim of globules which represent pigmented junctional nests of MC in the periphery and are a specific feature of rapidly enlarging MC nevi (10,11). The pathogenesis of EMN is not known. The microenvironment of epidermal regeneration may have some effects on MC because MC hyperplasia develops after cutaneous trauma (observed in recurrent nevi). The cytokines and growth factors produced and secreted during epidermal regeneration might contribute to the proliferation of residual epidermal MC and subsequent nevus formation (12). Because most of the bullous disorders associated with EMN are transient, the authors believe that changes in local growth factors may also be temporary and MN remain stable without a propensity to malignant degeneration without further stimuli (13). This is corroborated by the fact that no reports of malignant change of EMN in patients with bullous disorders have been described. It is likely that the etiology and natural course of EMN differs between two main populations of patients, with EMN arising after bullous disorders being more likely to remain benign compared with those with ongoing immunosuppression, but this hypothesis has yet to be proven. The actual risk of MM in patients with EMN remains unknown. Since our patient did not have many nevi, he does not fit into the EMN category. Due to the atypical appearance of his nevi, long-term follow-up on 6-month basis is recommended. PMID- 29989879 TI - Unusual Manifestations of Secondary Syphilis: Case Presentations. AB - Dear Editor, Syphilis is an infection caused by Treponema pallidum. Without treatment, it goes through the following stages: primary, secondary, latent, and tertiary (1). The clinical picture of secondary syphilis is very variable (2,3). We present two rare cases of secondary syphilis, one with nodular lesions initially considered to be lymphoma and second with periostitis, which was initially interpreted as an osteoma. To date, only 15 cases with nodular lesions and 10 cases with periostitis in secondary syphilis have been reported in the literature. The first patient was a 59 year old man who presented in a private practice with nodular lesions on the face and axillary and inguinal folds (Figure 1, a, b). The initial diagnostic consideration was lymphoma. A biopsy specimen was taken, and the histopathological features revealed epidermal hyperplasia with papillomatosis, minimal spongiosis with many neutrophils and with a marked inflammatory infiltrate in dermis, consisting of lymphocytes, plasma cells, and neutrophils; the diagnosis of interfaced dermatitis was established (Figure 1, d, e). After one month, the patient presented to our clinic with numerous nodular lesions, some of them painful, located on the trunk and intertriginous folds, including the intergluteal cleft - the lesions in this area being suggestive of condylomata lata (Figure 1, c). The diagnosis of secondary syphilis was taken into consideration, and screening serum tests were performed and found reactive: a Venereal Diseases Research Laboratory (VDRL) titer of 1:64 and Treponema pallidum Hemaglutination Assay (TPHA) titer of 1:80. Hepatitis and anti-human immunodeficiency virus (HIV) antibodies serology was negative. The biopsy was repeated and showed the same histopathological changes. In addition, Warthin Starry staining was performed, revealing the presence of some spiral micro organisms in the dermis corresponding to Treponema pallidum (Figure 1, f). A diagnosis of secondary syphilis was established, and the patient was treated with benzathine penicillin G 2.4 million units by intramuscular injection once a week for 2 consecutive weeks. The skin lesions regressed within 1 month, and serological tests showed a VDRL titer of 1:8 3 months after treatment. The second patient was a homosexual male, 35 years old, diagnosed with HIV infection, stage B2. He presented with bone pain in the calves and forearms, with insidious onset. He also presented with an associated erythematous maculo-papular rash on the trunk and limbs and generalized lymphadenopathy (Figure 2, a, b). The tibial crest and radius were sensitive to palpation. A right leg radiography was performed, raising suspicion of osteoid osteoma. The CT scan excluded the diagnosis of osteoma; taking into account the epidemiological context, the diagnosis of syphilis was suspected. The diagnosis was confirmed by leg ultrasound examination (2D US) which showed thickening of the compact tibial bone associated with subperiosteal destructive and proliferative changes (Figure 2, c, d) and by serology for syphilis: the VDRL titer was 1:32 and the TPHA titer was 1:80. The patient was treated with benzathine penicillin 2.4 million units, once a week, for 2 consecutive weeks, with clinical improvement. Syphilis continues to be a serious public health problem worldwide, even if it is a controllable disease due to diagnostic tests and effective and accessible treatment. According to the World Health Organization in 2008, the estimated number of new cases of sexually transmitted diseases in adults with syphilis is 10.6 million cases (4). The cases presented in this paper were characterized by unusual manifestations, requiring good collaboration between the dermatologist and other specialties. In the first case, the diagnosis of secondary syphilis was confirmed by positive serological, clinical, and histopathological findings. The main differential diagnosis of nodular syphilis includes lymphoma, sarcoidosis, Kaposi's sarcoma, atypical mycobacteriosis, deep fungal infections, leprosy, tuberculosis, leishmaniasis, and lymphomatoid papulosis (5). Another important differential diagnosis is between secondary and tertiary syphilis, especially when ulcerating nodules are present. Tertiary syphilis is characterized by unilateral, deep ulcerating nodules with necrotizing granulomas (6). Bone involvement during syphilis is mainly represented by polyarthritis, synovitis, osteitis, and periostitis (7,8). Syphilitic periostitis is characterized by localized or diffuse pain, particularly during the night, which is relieved by movement. The skull, the shoulder girdle, and the long bones are the most common sites of involvement (9). In conclusion, we presented two different cases of secondary syphilis that contribute to the clinical experience of rare cases presented in the literature, raising the awareness of dermatologists and other specialists about less specific clinical aspects of syphilis. PMID- 29989880 TI - Comparison of three different antibiotic protocols in transurethral resection of bladder tumour and the possible infectious risk factors: A non-randomized, prospective study. AB - INTRODUCTION: We sought to investigate three different antibiotic protocols in transurethral resection of a bladder tumour (TURBT), and the possible infectious risk factors of this surgery. METHODS: We conducted a non-randomized, prospective study, gathering cases of patients in whom TURBT had been performed. The sample was divided into three groups based on those who received antibiotics as: a single preoperative dose (Group A); a preoperative dose, plus a long protocol during the hospitalization (Group B); a preoperative dose, plus a long protocol during the hospitalization, plus five days at home (Group C). Intra- and postoperative data that could be relevant to infections was gathered. RESULTS: A total of 219 patients were included. In the multivariate analysis, it was observed that the patients in Group A were more prone to re-hospitalization due to fever than were those from Group C (odds ratio [OR] 11.13; p=0.03). Furthermore, the cases with tumour necrosis and those who entered surgery with a urinary catheter were more prone to have a temperature above 37.5 degrees C (OR6.74; p=0.02 and OR6.4; p=0.04, respectively), as well as have an increased risk per every additional tumour in the cystoscopy (OR 1.32; p=0.01). Those who received mitomycin had a lower chance of a positive urine culture (OR 0.29; p=0.01), contrary to those patients with over two days of hospitalization (OR 4.11; p<0.01) and those who entered surgery with a urinary catheter (OR 12.35; p=0.02). CONCLUSIONS: Those patients that only received a single dose of antibiotic before TURBT may have an increased risk of re-hospitalization due to fever in comparison to those who received prolonged antibiotic protocols. In addition, there are perioperative factors in this surgery that predict the risk of infectious complications. PMID- 29989881 TI - Case: Causation vs. correlation: Naturopathic medicine vs. natural history of a disease. PMID- 29989882 TI - Bladder neck placement of a synthetic polypropylene sling for the treatment of stress urinary incontinence. AB - INTRODUCTION: Pubo-vaginal sling placed at the bladder neck is the gold standard treatment for stress urinary incontinence (SUI). The synthetic mid-urethral sling (MUS) is now widely used, as morbidity rates with this technique are substantially reduced. This is an initial report on long-term outcomes of a polypropylene sling (PPS) placed in the traditional bladder neck location. METHODS: A retrospective analysis of all patients who underwent PPS insertion at our institution between 2006 and 2014 was conducted. Patient and urodynamic demographics were recorded. Subjective and objective measures of success were determined by postoperative pad usage and validated incontinence questionnaires. RESULTS: A total of 170 patients were followed for a median of four years (range 1-8). The mean age was 51 years (+/-10). Subjective response was assessed in 57% of patients; the overall subjective cure rate was 85.3% (n=145), subjective improvement rate was 4.1% (n=7), and the subjective failure rate was 10.6% (n=18). The mean Urogenital Distress Inventory (UDI)-6 score was 6.5 (+/-5.6) out of a maximum score of 24 and the Incontinence Impact Questionnaire (IIQ)-7 score was 5.5 (+/-6.3) out of a maximum score of 28. There was no significant difference in objective outcome measures in those with an abdominal leak-point pressure (ALPP) < or >60 cmH2O. CONCLUSIONS: Bladder neck placement of a PPS resulted in cure rates of 85% in this series. SUI secondary to intrinsic sphincter deficiency (ISD) and urethral hypermobility were treated with equal success. Bladder neck PPS placement has a role in the treatment of SUI. Our data may well reassure rectus fascia sling (RFS) surgeons who wish to take advantage of faster postoperative recovery using the less invasive PPS placed at the bladder neck. PMID- 29989883 TI - Overnight continuous saline irrigation after transurethral resection for non muscle-invasive bladder cancer is helpful in prevention of early recurrence. AB - INTRODUCTION: It has been reported that many methods prevent recurrence after transurethral resection of bladder tumour (TURBT) for non-muscle-invasive bladder cancer (NMIBC), but it has rarely been reported that overnight continuous saline irrigation is effective in preventing recurrence. The purpose of this study was to evaluate the efficacy of overnight continuous saline irrigation in preventing recurrence after TURBT. METHODS: We retrospectively studied patients with NMIBC who underwent TURBT from January 2010 to May 2015 at our institution. Patients who underwent cystoscopy every 12 weeks during the first year after surgery were included. Patients with cancer stage >=pT2, lymph node metastasis, or distant metastasis were excluded. The overnight continuous saline irrigation (OCSI) group and the no irrigation group were compared and analyzed. RESULTS: A total of 332 patients were included in the study. There were no differences in the basic characteristics of the patients between the two groups. In the OCSI group, the recurrence-free survival rate was higher than that in the no irrigation group, indicating that there was a significant difference between the two groups (p=0.032). CONCLUSIONS: After TURBT surgery, OCSI may help prevent early recurrence of NMIBC. PMID- 29989884 TI - Images: Ruptured intratesticular arteriovenous malformation. PMID- 29989885 TI - Relevance of open magnetic resonance imaging position (sitting and standing) to quantify pelvic organ prolapse in women. AB - INTRODUCTION: In pelvic organ prolapse (POP), posture and gravity impact organ position and symptom severity. The advanced magnet configuration in open magnetic resonance imaging (MRO) allows patients to be imaged when sitting and standing, as well in a conventional supine position. This study evaluated if sitting and standing MRO images are relevant as a means of improving quantification of POP because they allow differences in organ position not seen on supine imaging to be identified. METHODS: Forty women recruited from a university urogynecology clinic had MRO imaging (0.5 T scanner) with axial and sagittal T2-weighted pelvic scans obtained when sitting, standing, and supine. Pelvic reference lines were used to quantify the degree of POP, and the relevance of imaging position on the detection of POP compared. RESULTS: Images from 40 participants were evaluated (20 with POP and 20 asymptomatic controls). Our results indicate that the maximal extent of prolapse is best evaluated in the standing position using H line, M line, mid-pubic line, and perineal line as reference lines to determine POP. CONCLUSIONS: MRO imaging of symptomatic patients in a standing position is relevant in the quantification of POP. Compared with supine images, standing imaging identifies that greater levels of downward movement in the anterior and posterior compartments occur, presumably under the influence of posture and gravity. In contrast, no appreciable benefit was afforded by imaging in the sitting position, which precluded use of some reference lines due to upward movement of the anorectal junction. PMID- 29989886 TI - Case - Azoospermia with bilateral varicocele and normal folliclestimulating hormone. PMID- 29989887 TI - First Canadian experience with robotic laparoendoscopic single-site vs. standard laparoscopic living-donor nephrectomy: A prospective comparative study. AB - INTRODUCTION: We aimed to compare the outcomes of robotic laparoendoscopic single site living donor nephrectomy (R-LESS LDN) vs. standard laparoscopic living donor nephrectomy (LLDN). METHODS: Between October 2013 and November 2015, 39 patients were allocated to either standard LLDN (n=25) or R-LESS LDN (n=14). Patient demographics, perioperative outcomes, analgesic requirement, visual analogue scale of pain at postoperative days 1, 3, 7, and 30, and a health-related quality of life and body image questionnaire were prospectively collected. RESULTS: There were no significant differences in demographics and intraoperative outcomes between the two cohorts. The R-LESS LDN cohort had lower analgesic requirement (p=0.002) and lower visual pain scores on days 1 and 3 (p=0.001). Additionally, body image and satisfaction scores in the R-LESS group were also superior compared to the LLDN cohort (p=0.008). There was no significant difference in the postoperative complications according to the Clavien-Dindo system. Recipient graft functional outcomes were equivalent. CONCLUSIONS: This is the first evidence that R-LESS LDN is safe and associated with comparable surgical and early functional outcomes compared to LLDN, while pain, donor body image, and satisfaction scores were improved compared to LLDN. PMID- 29989888 TI - Prospective evaluation of kidney displacement during supine mini-percutaneous nephrolithotomy: Incidence, significance, and analysis of predictive factors. AB - INTRODUCTION: Kidney displacement may alter the quality of renal puncture during percutaneous nephrolithotomy (PCNL). The aim of this study was to identify the rate of kidney displacement and parameters associated with kidney displacement in patients who underwent supine mini-PCNL. METHODS: Data of 98 consecutive patients who underwent mini-PCNL was collected prospectively. The patients were grouped as displacement-positive vs. -negative. The parameters collected were age, gender, body mass index, side of the kidney, punctured calyx, fluoroscopy time to successful puncture and tract dilation, stone-free and complication rates, stone diameter, length of the renal artery, and quantity of peri-renal and abdominal fat. Groups were compared for the above listed parameters and logistic regression analysis was performed to identify factors associated with kidney displacement. RESULTS: There were 34 and 64 patients in the displacement-positive and -negative groups, respectively. Groups were similar for stone-free and complication rates. Fluoroscopy time to puncture and tract dilation were longer in the displacement positive group. Groups were different for renal artery length and peri-renal fat measurements. In multivariate analysis, lower pole puncture, renal artery length, and peri-renal fat measurement were found to be independent predictors of kidney displacement. CONCLUSIONS: Kidney displacement does not alter the success and complication rates, but is associated with longer fluoroscopy times during supine PCNL. In the current study, parameters in preoperative non-contrast computerized tomography (NCCT) associated with kidney displacement were identified. We recommend surgeons evaluate and take into account these parameters during preoperative planning to establish better outcomes and diminish fluoroscopy times. PMID- 29989889 TI - Prevalence estimates for lower urinary tract symptom severity among men in Uganda and sub-Saharan Africa based on regional prevalence data. AB - INTRODUCTION: In the absence of specific regional data, the prevalence of urinary symptoms in the developing world is currently estimated. Regional prevalence data and estimates based on them have relevance for accurate planning/provision of future healthcare. We sought to extrapolate prevalence estimates for lower urinary tract symptom (LUTS) severity and associated sexual dysfunction for Uganda as a whole and sub-Saharan Africa (SSA) using newly available regional data from a community-based cohort of men in Uganda. METHODS: Global Burden of Disease Study (GBDS) population statistics were applied to a regional dataset to provide prevalence estimates for Uganda and SSA; 415 men >55 years from five rural Ugandan communities had completed the International Prostate Symptom Scale (IPSS) and Epstein inventory to grade their LUTS severity and satisfaction with sexual function. RESULTS: Prevalence rates for moderate and severe LUTS were 40.5% and 20%, respectively, in men >55 in the Ugandan regional data; associated scores for all four Epstein sexual satisfaction measures were low. GBDS population figures (2016) for men >55 years are 942 115 (Uganda) and 33.9 million (SSA); hence, scaling up from regional prevalence data suggests 381 557 and 188 423 men >55 years in Uganda, and 13 729 500 and 6 780 000 in SSA have moderate and severe LUTS, respectively, and the majority will have compromise of elements of their sexual function. CONCLUSIONS: Extrapolation from a small regional dataset (for which we have no guarantee of national or SSA representability) provides the first prevalence estimates for LUTS severity based on African data, and suggests a large proportion of men >55 years are troubled with LUTS and associated sexual dysfunction. PMID- 29989890 TI - Trying to Sidestep Off-Label Dance-Around. AB - After years of court challenges, agency-imposed fines, and drugmaker lobbying, those restrictions on off-label marketing are loosening up. The agency is working on revisions to rules that govern how drug companies and their sales representatives can communicate with doctors and payers about off-label use. PMID- 29989891 TI - Fred Hutchinson Report Plots The Nexus of Cost and Quality. AB - A report from the Hutchinson Institute for Cancer Outcomes Research is remarkable. Committing to transparency as a catalyst for improvement, 27 hospital systems and cancer centers across Washington State bare all in the first public report to integrate clinic level quality and cost data in oncology. PMID- 29989892 TI - Aimovig for Migraine Prevention: The New Kid May Have Trouble Fitting in. AB - Aimovig (erenumab-aooe), codeveloped by Amgen and Novartis, has been recently approved for the prevention of migraines. Its mechanism of action is different than other migraine medications. But perhaps more interestingly, it is the first drug recently developed specifically for migraine prevention. PMID- 29989893 TI - Taming the Gene Genie. AB - Genetic tests are all the rage, but insurers are well aware of the downside. Genomics is complicated, and test results are often couched in uncertainty and loaded with caveats. The tests available to consumers may not be clinical quality, so if something questionable pops up, the tests need to be redone anyway. A positive result could also lead to a cascade of additional, expensive, and potentially risky diagnostic tests. PMID- 29989894 TI - Must Sky-High Prices 'Come on Down' Before the Price Is Right? AB - The pipeline for gene therapies is flush. Clinical-Trials.gov lists 721 gene therapy trials. Last year, the FDA received 106 new drug applications for gene therapies, up 34% from 2016. There is no shortage of diseases for gene therapies to target. But the costs of these therapies will break the bank. PMID- 29989895 TI - Polishing the Crystal Ball. How Far Have We Really Come in 2018? AB - Zachary Hafner: "For the December 2017 issue of Managed Care, I wrote a piece titled, 'Better for Patients, or Better for Business-Do We Really Have To Choose'? I put forward several predictions related to key trends for 2018. Now that we have reached the midpoint of the year, it is a fitting time to check in and see how accurate those predictions have been." PMID- 29989896 TI - Continuous Glucose Monitors: The Long and Winding Road To Acceptance, Coverage. AB - The time may finally be here for standalone continuous glucose monitors. It's been a long road. Medicare and consumer health plans were slow to cover them, but now the FDA has approved four such devices. Experts expect that nearly 3 million Americans will be able to use the devices. PMID- 29989897 TI - Health Care Needs the Real Triple Aim. AB - Price transparency, payment reform, and consumerism are needed to bring market forces to health care. Too many managed care organizations are comfortable with the status quo. PMID- 29989898 TI - Small Changes or Big Ones? The Case of Limits on Prescription Drug Copayments in California. AB - Despite standardization, advocates for various industries and certain patient needs continue to propose changes in coverage rules. Much of the advocacy is occurring at the state level with a focus on pharmaceutical coverage, such as equalizing cost sharing between oral and infused oncology drugs or setting limits on cost sharing for prescriptions. PMID- 29989899 TI - Geisinger: All-in and Thumbs-up On Electronic Payment to Providers. AB - Now that Geisinger is confident in the payment process for providers, it will continue to innovate new ways to improve the member experience. The goal is to be not just one of the top companies for members and not just one of the top health care organizations, but one of top organizations among all the companies in the United States. PMID- 29989900 TI - A Review of the Utility and Cost Effectiveness of Monitoring Fractional Exhaled Nitric Oxide (FeNO) in Asthma Management. AB - : Asthma is a common chronic respiratory disease affecting nearly 8% of the U.S. POPULATION: It results in substantially higher direct and indirect costs as well as an increased mortality risk and poorer quality of life, particularly among patients with difficult-to-control asthma. While several physiologic tests, including spirometry, are typically used to diagnose and characterize asthma, they do not provide the sensitivity and specificity required to accurately reflect the underlying heterogeneous inflammatory pathways. Fractional exhaled nitric oxide (FeNO) is a validated, noninvasive biomarker for T2-driven (i.e., allergic) airway inflammation that correlates with sputum eosinophils at or greater than 3% across various asthma phenotypes. Its use as a biomarker in asthma is well supported by numerous peer-reviewed articles and guidelines. There is also evidence that its use in clinical settings for patients with uncontrolled asthma is cost effective, given its ability to improve the accurate diagnosis of asthma, monitor treatment response, optimize inhaled corticosteroid dosing, and identify patient nonadherence. It may also have a role in identifying patients who are possible candidates for treatment with biologics. PMID- 29989901 TI - Cost-Effectiveness Analysis of Monitoring Fractional Exhaled Nitric Oxide (FeNO) in the Management of Asthma. AB - PURPOSE: Current asthma guidelines combine treatment, follow-up, and reevaluation to manage asthma control, reduce impairment, and decrease risk of morbidity in patients. Clinical use of biomarkers, such as fractional exhaled nitric oxide (FeNO), along with standard management can provide clinicians with improved ability to recognize airway inflammation, optimize drug therapy, and potentially increase asthma control. Our objective is to examine the impact of FeNO monitoring on the cost effectiveness of asthma management compared with management without FeNO. Sensitivity analyses further examine the impact of FeNO monitoring on patients with varying levels of severity and exacerbations. DESIGN AND METHODS: A decision-tree analysis of estimated outcomes and costs associated with annual management of asthma was utilized to simulate asthma management and treatment cost scenarios, comparing estimated 12-month costs and outcomes using the following treatment alternatives: (1) current standard of care (SOC) or (2) FeNO utilized in conjunction with the current SOC. Costs were estimated from the perspective of the health care payer; cost effectiveness was estimated as cost per quality-adjusted life year (QALY). RESULTS: FeNO in conjunction with SOC guidelines has decreased expected per-patient annual expenditure ($2,228) and increased expected per-patient annual QALYs (0.844) compared with SOC alone ($2,637 and 0.767). FeNO monitoring with SOC resulted in decreased annual costs and increased annual QALYs compared with SOC alone, and this difference was consistent through all one-way sensitivity analyses. CONCLUSION: Our analysis revealed that FeNO monitoring to guide asthma management is cost effective and could result in increased QALYs and decreased health care costs associated with asthma management. PMID- 29989902 TI - If You Make Them Build It, They Still May Not Come. AB - State laws that make meaningful price information available-e.g., paid claims, not charges, or prices for episode level bundles, and make these prices broadly available to the public-are an important step in enhancing price transparency. But the jury is still out on whether these efforts will make people buy health care based on quality. PMID- 29989903 TI - HDHPs: Cost Shift But No Swing to High-Value Care. AB - Employers and health insurers are asking consumers to put "more skin in the game" with high deductible health plans, but don't provide incentives for them to choose high-value care. A recent study in the American Journal of Managed Care found no change in spending on 26 commonly used, low-profile services. PMID- 29989904 TI - When the Cost of Medications Keeps Patients From Taking Them. AB - Even the most effective drug is useless if its cost prevents people from using it. Today's high drug prices are pushing more patients into nonadherence. This can impair or shorten life, and that's toxic for a system that has trouble controlling costs as it is. PMID- 29989906 TI - PBMs: Maligned as Middlemen, They're Hearing Wedding Bells. AB - The PBM industry is under fire these days for what critics call its lack of transparency and its knotty contract language, secretive pricing schemes, and an inscrutable assortment of rebates, discounts, side deals, and administrative fees. Some see partnerships with insurers and retailers as a possible solution. Opponents see a risk of even higher drug prices. PMID- 29989905 TI - Nevada Pushes For Transparency On Diabetes Drug Prices. AB - A state senator who describes insulin prices as "outrageous" introduced a transparency bill that requires drugmakers to report pricing, costs, and rebates. Other states might make similar moves, and the pharmaceutical industry is suddenly on edge, with PhRMA and BIO fighting the law in court. PMID- 29989907 TI - Make Paying for Health Care More Like Paying for a Haircut. AB - Health care is increasingly becoming like other retail encounters-a transaction between buyers and sellers. Patients, providers, payers-everybody needs to adjust. With the right technology and the will to change, the process of paying for health care can become as simple-and as painless-as getting a haircut. PMID- 29989908 TI - Blood Sugar Control Limbo: How Low To Go? AB - The stakes are particularly high when interpretations differ on evidence for treating diabetes, a condition affecting 30 million Americans and costing $245 billion annually. New guidelines from the American College of Physicians recommend less stringent blood sugar targets for most people with diabetes. Other professional groups think that's a terrible idea. PMID- 29989909 TI - Dividing Diabetes by Cluster Instead of Types. AB - Breaking up type 2 diabetes into subtypes has been something that clinicians and researchers have discussed and debated for years. Swedish researchers have proposed a new taxonomy to do just that. If it takes, the trick will be to come up with treatment plans that fit individual patients based on these more precise diagnostic categories. PMID- 29989910 TI - Multidrug Resistant HIV Drug Lauded, But Clinical Foundation Not Very Deep. AB - Trogarzo (ibalizumab-uiyk) is a CD4-directed post-attachment HIV-1 inhibitor, indicated for use with other antiretroviral inhibitors in adults with multidrug resistant HIV-1 infection who aren't responding to their antiretroviral regimen. It is considered an advance. But FDA approval was based on a study of only 40 people-and it had no control group. PMID- 29989911 TI - Economic Outcomes of a Precision Medicine Blood Test To Assess Obstructive Coronary Artery Disease: Results from the PRESET Registry. AB - PURPOSE: The evaluation of obstructive coronary artery disease (CAD) is inefficient and costly. Previous studies of an age/sex/gene expression score (ASGES) in this diagnostic workup have shown a 96% negative predictive value, as well as an 85% decreased likelihood of cardiac referral among low-score outpatients at 45 days. The objective was to explore the one-year cost implications of ASGES use among symptomatic outpatients. DESIGN: A prospective PRESET Registry (NCT01677156) enrolled stable, nonacute adult patients presenting with symptoms suggestive of obstructive CAD at 21 U.S. primary care practices. METHODOLOGY: Demographics, clinical factors, and ASGES (defined as low <=15 or elevated >15), as well as management plans post-ASGES, were collected. The economic endpoint analysis was based on the cost of cardiovascular-related tests, procedures, office visits, emergency room visits, and hospitalizations during one year after testing. RESULTS: The analysis included 566 patients, 51% of whom were women and the median age was 56. Forty-five percent had a low ASGES. The mean cost of cardiovascular care for patients in the year following ASGES was $1,647 for patients with a low ASGES versus $2,709 for those with an elevated score (39% reduction, P=.03 by Wilcoxon rank test). This relationship remained after multivariate analysis that adjusted for patient demographics and clinical covariates (P<.001). CONCLUSION: The ASGES helped identify patients with low current likelihood of obstructive CAD. These patients had lower costs of cardiovascular care during one year of follow-up. Early reductions in cardiac referrals at 45 days among these patients persisted at one year. PMID- 29989912 TI - Making their decisions for prostate cancer treatment: Patients' experiences and preferences related to process. AB - INTRODUCTION: We sought to determine the experiences and preferences of prostate cancer patients related to the process of making their treatment decisions, and to the use of decision support. METHODS: Population surveys were conducted in four Canadian provinces in 2014-2015. Each provincial cancer registry mailed surveys to a random sample of their prostate cancer patients diagnosed in late 2012. Three registries' response rates were 46-55%; the fourth used a different recruiting strategy, producing a response rate of 13% (total n=1366). RESULTS: Overall, 90% (n=1113) of respondents reported that they were involved in their treatment decisions. Twenty-three percent (n=247) of respondents wanted more help with the decision than they received and 52% of them (n=128) reported feeling well-informed. Only 51% (n=653) of all respondents reported receiving any decision support, but an additional 34% (n=437) would want to if they were aware of its existence. A quarter (25%, n=316) of respondents found it helpful to use a decision aid, a type of decision support that provides assistance to decision processes and provides information, but 64% (n=828) reported never having heard of decision aids; 26% (n=176) of those who had never heard of decision aids wanted more help with the decision than they received compared to 13% (n=36) of those who had used a decision aid. CONCLUSIONS: The majority of respondents wanted to participate in their treatment decisions, but a portion wanted more help than they received. Half of those who wanted more help felt well-informed, thus, needed support beyond information. Decision aids have potential to provide information and support to the decision process. PMID- 29989913 TI - Dual usage of a stone basket: Stone capture and retropulsion prevention. AB - INTRODUCTION: Stone migration during ureteroscopy (URS) for proximal ureteric calculi is a constant challenge. Several retropulsion prevention devices have been developed to optimize URS outcomes. Our technique involves capturing the stone within a four-wire Nitinol stone basket and then performing laser lithotripsy to dust the stone while it is engaged in the basket. The dusted fragments wash out with the irrigation fluid and once small enough, the remaining stone is removed intact. METHODS: A retrospective chart review was performed of all proximal semi-rigid URS procedures for a solitary calculus (2000-2016). We compared our new technique introduced in 2010 to URS control procedures that did not use retropulsion prevention techniques or devices. RESULTS: One hundred and forty patients underwent URS for proximal ureteric calculi. Mean stone diameter was 9.3+/-3.4 mm, with similar impaction rate between both groups (44.1% vs. 43.1% control; p=n/s). The mean surgical procedure time was 53.3+/-17.9 minutes for the new technique and 65.2+/-29.2 minutes for the control group (p=0.005). Compared to the new technique, the control group had a higher rate of retropulsion (33.3% vs. 14.7%; p=0.01) and required flexible URS more often to exclude or remove residual fragments (24.1% vs. 59.1%; p=0.001). Using the new technique, stone-free rates were higher (79.1% vs. 69.4%; p=n/s) and there was a lower likelihood of leaving residual fragments both <3 mm and >=3 mm (p=0.001). CONCLUSIONS: Our novel technique results in shorter operative times, lower retropulsion rates, and decreases postoperative residual stone fragments. PMID- 29989914 TI - Investigating the effect of early bladder management in patients with chronic kidney disease and diabetes: Lessons learned from a failed pilot study. PMID- 29989915 TI - Efficacy and patient satisfaction of pelvic organ prolapse reduction using transvaginal mesh: A Canadian perspective. AB - INTRODUCTION: Due to U.S Food and Drud Administration warnings and class-action lawsuits, the use of transvaginal mesh for pelvic organ prolapse surgery is controversial. We report data from two Canadian centres, focusing on recurrence and reoperation rates, complication rates, and patient satisfaction. METHODS: A retrospective medical chart review was performed. Patients were also invited to a long-term followup clinic for a complete questionnaire and gynecological exam. Patients unable to present to clinic for followup had the option to answer the questionnaire via telephone. RESULTS: A total of 334 patients were operated between 2000 and 2013. Median followup was 38 months for questionnaire and 36 months for physical exam. Thirty-seven patients (11.1%) required repeat operation, including 17 for recurrent prolapse and 10 for mesh exposure; 98.8% of patients reported feeling subjectively improved by their prolapse surgery. CONCLUSIONS: Midterm results are satisfactory and patient subjective satisfaction is high following transvaginal mesh repair of pelvic organ prolapse. PMID- 29989916 TI - Radiotherapy with radical cystectomy for bladder cancer: A systematic review and meta-analysis. AB - INTRODUCTION: Muscle-invasive bladder cancer (MIBC) is associated with high recurrence and mortality rates. The role of radiotherapy as an adjunct to radical cystectomy is not well-defined. We sought to evaluate the efficacy and safety of radiotherapy preoperatively or postoperatively for patients with MIBC receiving cystectomy compared to cystectomy alone. The primary outcome was overall survival. The secondary outcome was adverse effects. METHODS: MEDLINE, EMBASE, and CENTRAL were searched on August 30, 2016 for randomized controlled trials (RCTs) of patients undergoing cystectomy for bladder cancer. A control group receiving cystectomy alone and an intervention group with radiotherapy and cystectomy were required. The Jadad score was used to assess for bias. Fifteen studies representing 10 RCTs met eligibility criteria. RESULTS: A total of 996 patients were randomized in seven trials included in a meta-analysis of neoadjuvant radiotherapy. Insufficient data were available to complete a pooled analysis for adjuvant radiotherapy. There was a non-statistically significant improvement in overall survival for patients who received neo-adjuvant radiotherapy and cystectomy. At three years and five years, the odds ratios were 1.23 (95% confidence interval [CI] 0.72-2.09) and 1.26 (95% CI 0.76-2.09), respectively, in favour of neoadjuvant radiotherapy. Subgroup analyses including higher doses of radiotherapy showed greater effect on survival. CONCLUSIONS: These data suggest that radiotherapy prior to cystectomy may improve overall survival. This review was limited by old studies, heterogeneous patient populations, and radiotherapy treatment techniques that may not meet current standards. There is a need for current RCTs to further evaluate this effect. PMID- 29989917 TI - Metabolic evaluation guidelines in patients with nephrolithiasis: Are they being followed? Results of a national, multi-institutional, quality-assessment study. AB - INTRODUCTION: The significant cost burden of kidney stones underscores the importance of best clinical practice in kidney stone management. We evaluated adherence to kidney stone metabolic evaluation guidelines in a Canadian population and the interest of patients with regard to prevention. METHODS: A questionnaire based on Canadian Urological Association (CUA) best practice guidelines was designed. Patients presenting for extracorporeal shockwave lithotripsy treatment (ESWL) were administered this questionnaire to evaluate risk factors of stone disease and assess the use of metabolic evaluations. Patients were asked if they received explanations about their results and if they were interested in kidney stone prevention. RESULTS: We identified 530 patients at five academic institutions; 79.4% had at least one indication to receive a metabolic evaluation (high-risk stone formers), which increased to 96.6% if first time stone formers whom reported an interest in metabolic evaluation were included. However, only 41.1 % of these patients had a metabolic evaluation. Endourologists ordered metabolic evaluation more often than other referring urologists (63.6% vs. 36.5%; p<0.001). Furthermore, urologists ordered metabolic evaluations more often than other prescribing physicians (68.9% vs. 31.1%; p<0.001). Sixty-two percent of patients received explanations about their metabolic evaluation results and 77.5% understood them. Regarding prevention, 84.1% and 83.8% were interested in more explanations and in following a diet or taking a medication, respectively. CONCLUSIONS: Adherence to CUA metabolic evaluation guidelines is suboptimal and could be improved by urologists referring patients for ESWL. Communication between physician and patient may not be adequate. The majority of stone formers are interested in kidney stone prevention. PMID- 29989918 TI - Malignant websites? Analyzing the quality of prostate cancer education web resources. AB - INTRODUCTION: Prostate cancer patients are using more web resources to inform themselves about their cancer. However, patients may receive out-of-date or inaccurate information due to lack of regulation. The current study looks to systematically analyze the quality of websites accessed by patients with prostate cancer. METHODS: The term "prostate cancer" was searched in Google and the metasearch engines, Yippy and Dogpile, and the top 100 hits related to patient information were compiled from over 32 million hits. A standardized tool was used to examine 100 sites with respect to attribution, currency, usability, and content. RESULTS: Of the top 100 websites relating to prostate cancer information, only 27% identified an author, of which 16% had their credentials displayed. The majority of websites disclosed ownership (97%). Over half of the websites did not include the date of the last update and of those that did, only 66% were current within two years. According to the Flesch Kincaid grade level tool for readability, the majority (87%) of sites were found to be at a high school level, while 6% were at university level. Finally, content varied among websites; 90% of sites provided information on detection and workup and treatments, but only 14% of sites included information on prognosis. CONCLUSIONS: The reliability of websites presenting prostate cancer information is questionable. There were noted deficiencies in attribution, currency, and readability. While information on detection and treatment is well-covered, information related to prognosis is lacking. PMID- 29989919 TI - Exposure to radiation and medical oncology training: A survey of Canadian urology residents and fellows. AB - INTRODUCTION: Residency experiences and teaching in oncology among urology residents are variable across Canada. We sought to identify how radiation and medical oncology concepts, as they pertain to genitourinary malignancies, are taught to urology residents. METHODS: A total of 190 trainees enrolled in Canadian urology residency training programs were invited to participate in the study from January 2016 to June 2016. Participants completed an online questionnaire addressing the training they received. RESULTS: The overall response rate was 32%. Twenty-three percent of respondents were in their fellowship year; 17%, 20%, 10%, 17%, and 12% were first-, second-, third-, fourth , and fifth-year residents, respectively, with a median of four (range 1-9) respondents from each training program. Ninety-five percent of respondents had academic half-day (AHD) as part of their training that included radiotherapy (61%) and chemotherapy (51%) teaching. Most respondents indicated their main exposure to chemotherapy and radiation came from informal teaching in urology clinics. Twenty-nine percent and 41%, of participants had mandatory rotations in radiation and medical oncology, respectively. Only 6% of respondents used their voluntary elective time in these disciplines and most voluntary electives were of 1-2-week duration. Despite this, 90% of respondents preferred some mandatory radiation and medical oncology training. CONCLUSIONS: Most of the limited exposure that urology residents have to medical and radiation oncology is through AHD or informal urology clinics, despite a desire among current urology trainees to have clinical exposure in these areas. Moving forward, urology residency programs should consider integrating medical and radiation oncology rotations into the residency program curriculum. PMID- 29989920 TI - Noninvasive Assessment of Jugular Venous Pressure via Force-Coupled Single Crystal Ultrasound. AB - OBJECTIVE: we have developed a handheld device for noninvasive quantitative assessment of jugular venous pressure (JVP). METHODS: we used a single crystal ultrasound coupled to a force-sensing load cell to measure JVP based on the force necessary to collapse the internal jugular vein (IJV) walls. We used a gelatin based model system of the IJV to test the ability of single crystal ultrasound to identify the IJV and verified the cross-sectional position and diameter of the vessels with conventional imaging ultrasound. We also tested our prototype device on healthy human volunteers. RESULTS: experiments on model system demonstrated that vessel diameters determined with single crystal ultrasound were in close agreement with the diameters derived from conventional 2-D ultrasound. Proof-of concept human experiments demonstrate that single crystal ultrasound can detect the IJV in basal and collapsed states, as compared to gold-standard sonography (insert stats). Assessment of JVP in human volunteers was physiologically consistent with and sensitive to postural changes (supine JVP 6.6 +/- 2.4 mmHg; standing JVP 4.2 +/- 1.9 mmHg (p < 0.0001). CONCLUSION: noninvasive assessment of JVP could prove valuable in informing rapid clinical decision-making across various pathologies and conditions leading to derangements in intravascular volume status. PMID- 29989921 TI - Skull Modeling Effects in Conductivity Estimates Using Parametric Electrical Impedance Tomography. AB - OBJECTIVE: To estimate scalp, skull, compact bone, and marrow bone electrical conductivity values based on electrical impedance tomography (EIT) measurements, and to determine the influence of skull modeling details on the estimates. METHODS: We collected EIT data with 62 current injection pairs and built five 6-8 million finite element (FE) head models with different grades of skull simplifications for four subjects, including three whose head models serve as Atlases in the scientific literature and in commercial equipment (Colin27 and EGI's Geosource atlases). We estimated electrical conductivity of the scalp, skull, marrow bone, and compact bone tissues for each current injection pair, each model, and each subject. RESULTS: Closure of skull holes in FE models, use of simplified four-layer boundary element method-like models, and neglecting the CSF layer produce an overestimation of the skull conductivity of 10%, 10%-20%, and 20%-30%, respectively (accumulated overestimation of 50%-70%). The average extracted conductivities are 288 +/- 53 (the scalp), 4.3 +/- 0.08 (the compact bone), and 5.5 +/- 1.25 (the whole skull) mS/m. The marrow bone estimates showed large dispersion. CONCLUSION: Present EIT estimates for the skull conductivity are lower than typical literature reference values, but previous in vivo EIT results are likely overestimated due to the use of simpler models. SIGNIFICANCE: Typical literature values of 7-10 mS/m for skull conductivity should be replaced by the present estimated values when using detailed skull head models. We also provide subject specific conductivity estimates for widely used Atlas head models. PMID- 29989922 TI - Stochastic Modeling of Temporal Enhanced Ultrasound: Impact of Temporal Properties on Prostate Cancer Characterization. AB - OBJECTIVES: Temporal enhanced ultrasound (TeUS) is a new ultrasound-based imaging technique that provides tissue-specific information. Recent studies have shown the potential of TeUS for improving tissue characterization in prostate cancer diagnosis. We study the temporal properties of TeUS-temporal order and length-and present a new framework to assess their impact on tissue information. METHODS: We utilize a probabilistic modeling approach using hidden Markov models (HMMs) to capture the temporal signatures of malignant and benign tissues from TeUS signals of nine patients. We model signals of benign and malignant tissues (284 and 286 signals, respectively) in their original temporal order as well as under order permutations. We then compare the resulting models using the Kullback-Liebler divergence and assess their performance differences in characterization. Moreover, we train HMMs using TeUS signals of different durations and compare their model performance when differentiating tissue types. RESULTS: Our findings demonstrate that models of order-preserved signals perform statistically significantly better (85% accuracy) in tissue characterization compared to models of order-altered signals (62% accuracy). The performance degrades as more changes in signal order are introduced. Additionally, models trained on shorter sequences perform as accurately as models of longer sequences. CONCLUSION: The work presented here strongly indicates that temporal order has substantial impact on TeUS performance; thus, it plays a significant role in conveying tissue-specific information. Furthermore, shorter TeUS signals can relay sufficient information to accurately distinguish between tissue types. SIGNIFICANCE: Understanding the impact of TeUS properties facilitates the process of its adopting in diagnostic procedures and provides insights on improving its acquisition. PMID- 29989923 TI - A Methodology for Non-Invasive 3-D Surveillance of Arteriovenous Fistulae Using Freehand Ultrasound. AB - OBJECTIVE: Surveillance techniques for arteriovenous fistulae are required to maintain functional vascular access, with two-dimensional duplex ultrasound the most widely used imaging modality. This paper presents a surveillance method for an arteriovenous fistula using a freehand three-dimensional (3-D) ultrasound system. A patient-case study highlights the applicability in a clinical environment. METHODS: The freehand ultrasound system uses optical tracking to determine the vascular probe location, and as the probe is swept down a patient's arm, each B-mode slice is spatially arranged to be post-processed as a volume. The volume is segmented to obtain the 3-D vasculature for high detail analysis. RESULTS: The results follow a patient with stenosis, undergoing surgery to have a stent placement. A surveillance scan was taken pre-surgery, postsurgery, and at a two-month follow-up. Vasculature changes are quantified using detailed analysis, and the benefits of using 3-D imaging are shown through 3-D printing and visualization. CONCLUSION AND SIGNIFICANCE: Non-invasive 3-D surveillance of arteriovenous fistulae is possible, and a patient-specific geometry was created using ultrasound and optical tracking. Access to this non-invasive 3-D surveillance technique will enable future studies to determine patient-specific remodeling behavior, in terms of geometry and hemodynamics over time. PMID- 29989924 TI - Procedure-Specific Validation of Artificial Vertebrae. AB - OBJECTIVE: The development of a novel hybrid patient simulator was initiated to provide a safe training possibility for novice surgeons. Integrated artificial vertebrae should be able to realistically mimic the haptics of transpedicular vertebroplasty instrument insertion and pedicle screw placement. Therefore, new open-celled material compositions were developed, tested, and validated with reference to elderly human vertebrae. METHODS: Vertebroplasty tool insertion force and pedicle screw torque measurements were performed. To validate the new bone surrogates for transpedicular tool insertion, a novel parametric model of the procedure was developed identifying three characteristic insertion parameters (weighting factors, cutting, and clamping forces). Furthermore, the slope of the insertion torque was used to validate the new materials against the human vertebrae for pedicle screw placement. RESULTS: A relative error less than 6% confirmed the suitability of the parametric model for validation. The weighting factors () and the clamping forces ( ) of the human reference were met by the bone surrogate with 1.25% of blowing agent ( and , respectively). However, no material was able to reflect the instrument cutting forces. The slope obtained during pedicle screw placement in human vertebrae was Nm/m. The material composition with 1% blowing agent achieved similar results ( N m/m). CONCLUSION: Two suitable materials that deliver realistic haptics during both instrument insertions were validated. The parametric model suitably modeled the transpedicular instrument insertion. SIGNIFICANCE: These newly developed models provide a realistic haptic feedback during transpe-dicular instrument insertions with the potential of cement application during surgical skill training. PMID- 29989925 TI - Extremum Seeking Control for Personalized Zone Adaptation in Model Predictive Control for Type 1 Diabetes. AB - Zone model predictive control has proven to be an effective closed-loop method to regulate blood glucose for people with type 1 diabetes (T1D). In this paper, we present a universal model-free optimization scheme for adapting the zone for T1D patients individually. The adaptation is based on a clinical glycemic risk index named relative regularized glycemic penalty index (rrGPI), which is calculated from glucose measurements by a continuous glucose monitor. The scheme's objective is to minimize rrGPI by simultaneously modulating a controller's blood glucose target zone's upper bound and lower bound. The adaptation mechanism is based on extremum seeking control, in which the zone boundaries are driven by gradient estimation obtained by continuously sinusoidally modulating and demodulating the rrGPI readings. To improve the adaptation method's robustness against uncertainties, a decaying feedback gain and a vanishing dither signal are employed. in-silico trials suggested that the personalized optimized zone can be reached within a week of adaptation. Both for announced and unannounced meals, the proposed method outperforms the fixed zone [80, 140] mg/dL, which has been employed in the authors' clinical trials. It is also shown that the developed method has strong robustness against real-life uncertainties. PMID- 29989926 TI - Learning Based Segmentation of CT Brain Images: Application to Postoperative Hydrocephalic Scans. AB - OBJECTIVE: Hydrocephalus is a medical condition in which there is an abnormal accumulation of cerebrospinal fluid (CSF) in the brain. Segmentation of brain imagery into brain tissue and CSF [before and after surgery, i.e., preoperative (pre-op) versus postoperative (post-op)] plays a crucial role in evaluating surgical treatment. Segmentation of pre-op images is often a relatively straightforward problem and has been well researched. However, segmenting post-op computational tomographic (CT) scans becomes more challenging due to distorted anatomy and subdural hematoma collections pressing on the brain. Most intensity- and feature-based segmentation methods fail to separate subdurals from brain and CSF as subdural geometry varies greatly across different patients and their intensity varies with time. We combat this problem by a learning approach that treats segmentation as supervised classification at the pixel level, i.e., a training set of CT scans with labeled pixel identities is employed. METHODS: Our contributions include: 1) a dictionary learning framework that learns class (segment) specific dictionaries that can efficiently represent test samples from the same class while poorly represent corresponding samples from other classes; 2) quantification of associated computation and memory footprint; and 3) a customized training and test procedure for segmenting post-op hydrocephalic CT images. RESULTS: Experiments performed on infant CT brain images acquired from the CURE Children's Hospital of Uganda reveal the success of our method against the state-of-the-art alternatives. We also demonstrate that the proposed algorithm is computationally less burdensome and exhibits a graceful degradation against a number of training samples, enhancing its deployment potential. PMID- 29989928 TI - Modeling Subcutaneous Absorption of Fast-Acting Insulin in Type 1 Diabetes. AB - OBJECTIVE: Subcutaneous (sc) administration of fast-acting insulin analogues is the key in conventional therapy of type 1 diabetes (T1D). A model of sc insulin absorption would be helpful for optimizing insulin therapy and test new open- and closed-loop treatment strategies in in silico platforms. Some models have been published in the literature, but none was assessed on a frequently-sampled large dataset of T1D subjects. The aim here is to propose a model of sc absorption of fast-acting insulin, which is able to describe the data and precisely estimate model parameters with a clear physiological interpretation. METHODS: Three candidate models were identified on 116 T1D subjects, who underwent a single sc injection of fast-acting insulin and were compared on the basis of their ability to describe the data and their numerical identifiability. RESULTS: A linear two compartment model including a subject-specific delay in sc insulin absorption is proposed. On average, a delay of 7.6 min in insulin appearance in the first compartment is detected, then the insulin is slowly absorbed into plasma (in 23% of the subjects) with a rate of 0.0034 min-1, while the remaining diffuses into the second compartment, with a rate constant of 0.028 min-1, and then finally absorbed into plasma with a rate constant of 0.014 min-1. CONCLUSION: Among the three tested models, the one proposed here is the only one able to both accurately describe plasma insulin data after a single sc injection and precisely estimate physiologically plausible parameters. The model needs to be further tested in case of variable sc insulin delivery and/or multiple insulin doses. SIGNIFICANCE: Results are expected to help the development of new open- and closed-loop insulin treatment strategies. PMID- 29989930 TI - Fusing Partial Camera Signals for Noncontact Pulse Rate Variability Measurement. AB - Remote camera-based measurement of physiology has great potential for healthcare and affective computing. Recent advances in computer vision and signal processing have enabled photoplethysmography (PPG) measurement using commercially available cameras. However, there remain challenges in recovering accurate noncontact PPG measurements in the presence of rigid head motion. When a subject is moving, their face may be turned away from one camera, be obscured by an object, or move out of the frame resulting in missing observations. As the calculation of pulse rate variability (PRV) requires analysis over a time window of several minutes, the effect of missing observations on such features is deleterious. We present an approach for fusing partial color-channel signals from an array of cameras that enable physiology measurements to be made from moving subjects, even if they leave the frame of one or more cameras, which would not otherwise be possible with only a single camera. We systematically test our method on subjects ( N=25) using a set of six, 5-min tasks (each repeated twice) involving different levels of head motion. This results in validation across 25 h of measurement. We evaluate pulse rate and PRV parameter estimation including statistical, geometric, and frequency-based measures. The median absolute error in pulse rate measurements was 0.57 beats-per-minute (BPM). In all but two tasks with the greatest motion, the median error was within 0.4 BPM of that from a contact PPG device. PRV estimates were significantly improved using our proposed approach compared to an alternative not designed to handle missing values and multiple camera signals; the error was reduced by over 50%. Without our proposed method, errors in pulse rate would be very high, and estimation of PRV parameters would not be feasible due to significant data loss. PMID- 29989927 TI - A Comparison of Intention Estimation Methods for Decoder Calibration in Intracortical Brain-Computer Interfaces. AB - OBJECTIVE: Recent reports indicate that making better assumptions about the user's intended movement can improve the accuracy of decoder calibration for intracortical brain-computer interfaces. Several methods now exist for estimating user intent, including an optimal feedback control model, a piecewise-linear feedback control model, ReFIT, and other heuristics. Which of these methods yields the best decoding performance? METHODS: Using data from the BrainGate2 pilot clinical trial, we measured how a steady-state velocity Kalman filter decoder was affected by the choice of intention estimation method. We examined three separate components of the Kalman filter: dimensionality reduction, temporal smoothing, and output gain (speed scaling). RESULTS: The decoder's dimensionality reduction properties were largely unaffected by the intention estimation method. Decoded velocity vectors differed by <5% in terms of angular error and speed vs. target distance curves across methods. In contrast, the smoothing and gain properties of the decoder were greatly affected (> 50% difference in average values). Since the optimal gain and smoothing properties are task-specific (e.g. lower gains are better for smaller targets but worse for larger targets), no one method was better for all tasks. CONCLUSION: Our results show that, when gain and smoothing differences are accounted for, current intention estimation methods yield nearly equivalent decoders and that simple models of user intent, such as a position error vector (target position minus cursor position), perform comparably to more elaborate models. Our results also highlight that simple differences in gain and smoothing properties have a large effect on online performance and can confound decoder comparisons. PMID- 29989931 TI - Feasibility of Automatic Error Detect-and-Undo System in Human Intracortical Brain-Computer Interfaces. AB - OBJECTIVE: Brain-computer interfaces (BCIs) aim to help people with impaired movement ability by directly translating their movement intentions into command signals for assistive technologies. Despite large performance improvements over the last two decades, BCI systems still make errors that need to be corrected manually by the user. This decreases system performance and is also frustrating for the user. The deleterious effects of errors could be mitigated if the system automatically detected when the user perceives that an error was made and automatically intervened with a corrective action; thus, sparing users from having to make the correction themselves. Our previous preclinical work with monkeys demonstrated that task-outcome correlates exist in motor cortical spiking activity and can be utilized to improve BCI performance. Here, we asked if these signals also exist in the human hand area of motor cortex, and whether they can be decoded with high accuracy. METHODS: We analyzed posthoc the intracortical neural activity of two BrainGate2 clinical trial participants who were neurally controlling a computer cursor to perform a grid target selection task and a keyboard-typing task. RESULTS: Our key findings are that: 1) there exists a putative outcome error signal reflected in both the action potentials and local field potentials of the human hand area of motor cortex, and 2) target selection outcomes can be classified with high accuracy (70-85%) of errors successfully detected with minimal (0-3%) misclassifications of success trials, based on neural activity alone. SIGNIFICANCE: These offline results suggest that it will be possible to improve the performance of clinical intracortical BCIs by incorporating a real-time error detect-and-undo system alongside the decoding of movement intention. PMID- 29989932 TI - Characterization of Conductivity Changes During High-Frequency Irreversible Electroporation for Treatment Planning. AB - : For irreversible-electroporation (IRE)-based therapies, the underlying electric field distribution in the target tissue is influenced by the electroporation induced conductivity changes and is important for predicting the treatment zone. OBJECTIVE: In this study, we characterized the liver tissue conductivity changes during high-frequency irreversible electroporation (H-FIRE) treatments of widths 5 and 10 MUs and proposed a method for predicting the ablation zones. METHODS: To achieve this, we created a finite-element model of the tissue treated with H-FIRE and IRE pulses based on experiments conducted in an in-vivo rabbit liver study. We performed a parametric sweep on a Heaviside function that captured the tissue conductivity versus electric field behavior to yield a model current close to the experimental current during the first burst/pulse. A temperature module was added to account for the current increase in subsequent bursts/pulses. The evolution of the electric field at the end of the treatment was overlaid on the experimental ablation zones determined from hematoxylin and eosin staining to find the field thresholds of ablation. RESULTS: Dynamic conductivity curves that provided a statistically significant relation between the model and experimental results were determined for H-FIRE. In addition, the field thresholds of ablation were obtained for the tested H-FIRE parameters. CONCLUSION: The proposed numerical model can simulate the electroporation process during H-FIRE. SIGNIFICANCE: The treatment planning method developed in this study can be translated to H-FIRE treatments of different widths and for different tissue types. PMID- 29989933 TI - Evaluation of an Integrated System of Wearable Physiological Sensors for Stress Monitoring in Working Environments by Using Biological Markers. AB - OBJECTIVE: The objectives of this paper are to develop and test the ability of a wearable physiological sensors system, based on ECG, EDA, and EEG, to capture human stress and to assess whether the detected changes in physiological signals correlate with changes in salivary cortisol level, which is a reliable, objective biomarker of stress. METHODS: 15 healthy participants, eight males and seven females, mean age 40.8 +/- 9.5 years, wore a set of three commercial sensors to record physiological signals during the Maastricht Acute Stress Test, an experimental protocol known to elicit robust physical and mental stress in humans. Salivary samples were collected throughout the different phases of the test. Statistical analysis was performed using a support vector machine (SVM) classification algorithm. A correlation analysis between extracted physiological features and salivary cortisol levels was also performed. RESULTS: 15 features extracted from heart rate variability, electrodermal, and electroencephalography signals showed a high degree of significance in disentangling stress from a relaxed state. The classification algorithm, based on significant features, provided satisfactory outcomes with 86% accuracy. Furthermore, correlation analysis showed that the observed changes in physiological features were consistent with the trend of salivary cortisol levels (R2 = 0.714). CONCLUSION: The tested set of wearable sensors was able to successfully capture human stress and quantify stress level. SIGNIFICANCE: The results of this pilot study may be useful in designing portable and remote control systems, such as medical devices used to turn on interventions and prevent stress consequences. PMID- 29989934 TI - A Novel Accelerometer-Based Technique for Robust Detection of Walking Direction. AB - OBJECTIVE: Distance estimation in pedestrian dead reckoning is acquired using vector norm of accelerations, which results in positive values. However, anteroposterior acceleration is negative when a step is taken backward, which must be detected for accurate localization. This paper proposes a novel approach for the detection of walking direction, which uses a dominant trend duration. METHODS: The approach evaluates anteroposterior acceleration out of a foot-worn accelerometer for temporal dominance of acceleration trends during swing phase of the walk. The approach is tested for forward and backward walks with speed variations on a straight path as well as for forward walk at normal speed on a turning path. To validate the detection accuracy, success rates per participant per walk trial are calculated and then overall success rate for all the trials are reported. Moreover, metrics precision, recall and F1 scores are calculated for detection reliability in both directions. RESULTS: Overall 98 +/- 2% detection accuracy is achieved on linear path considering both directions and all speed variations, whereas 93 +/- 7% on turning path including left and right turns. In comparison with the state-of-the-art bidirectional detection approach, the proposed approach delivers accurate detection with speed variations without requiring prior training and relies on a single sensory feature. CONCLUSION: Dominant trend duration is a novel and reliable feature to detect directional changes during communal walk with speed variation. SIGNIFICANCE: The approach can be employed in different contexts, such as enabling pedestrian localization approaches to accommodate back stepping or any application that requires knowledge of changing directions while walking. PMID- 29989935 TI - The HF-CGM Study: An Analysis of Cardiogoniometric Axes in Patients With Cardiac Resynchronization Therapy. AB - GOAL: The HF-CGM is a proof-of-principle study to investigate whether cardiogoniometry (CGM), a three-dimensional electrocardiographic method, can differentiate between pacing modes in patients with cardiac resynchronization therapy (CRT). METHODS: At a tertiary cardiology center, CGM recordings were performed using four pacing modes: no pacing; right ventricular (RV) pacing; left ventricular (LV) pacing, and biventricular (BIV) pacing. Three orthogonal CGM planes orientated to the long axis (XY), the frontal plane (YZ), and the short axis (XZ) of the heart were constructed, and the direction of the QRS-axis was calculated for each pacing mode in each plane. During BIV pacing, the direction of CGM QRS-axis was compared between patients with optimal and nonoptimal 12-lead pacing variables. RESULTS: Twenty-two participants (aged 71.5 +/- 10.8; 77.3% male, LVEF 29 +/- 7%) were consecutively recruited. Only QRS-axis measured in the XY plane could significantly distinguish between all three pacing modes versus no pacing. Mean QRS-axis in the XY plane with pacing off and during RV pacing was leftward and basal; LV pacing was apical; and BIV pacing was rightward and basal. There was a statistically significant difference in the direction of the QRS-axis between patients with optimal versus nonoptimal paced QRS morphology in the XY plane (rightward and basal versus inconsistent). SIGNIFICANCE: CGM recorded in the XY plane can accurately detect differences between ventricular pacing sites. It may also be able to identify patients with a CRT device in situ who have optimal response. PMID- 29989936 TI - Accelerated Cardiac Diffusion Tensor Imaging Using Joint Low-Rank and Sparsity Constraints. AB - OBJECTIVE: The purpose of this paper is to accelerate cardiac diffusion tensor imaging (CDTI) by integrating low-rankness and compressed sensing. METHODS: Diffusion-weighted images exhibit both transform sparsity and low-rankness. These properties can jointly be exploited to accelerate CDTI, especially when a phase map is applied to correct for the phase inconsistency across diffusion directions, thereby enhancing low-rankness. The proposed method is evaluated both ex vivo and in vivo, and is compared to methods using either a low-rank or sparsity constraint alone. RESULTS: Compared to using a low-rank or sparsity constraint alone, the proposed method preserves more accurate helix angle features, the transmural continuum across the myocardium wall, and mean diffusivity at higher acceleration, while yielding significantly lower bias and higher intraclass correlation coefficient. CONCLUSION: Low-rankness and compressed sensing together facilitate acceleration for both ex vivo and in vivo CDTI, improving reconstruction accuracy compared to employing either constraint alone. SIGNIFICANCE: Compared to previous methods for accelerating CDTI, the proposed method has the potential to reach higher acceleration while preserving myofiber architecture features, which may allow more spatial coverage, higher spatial resolution, and shorter temporal footprint in the future. PMID- 29989937 TI - Closed-Loop Control for Precision Antimicrobial Delivery: An In Silico Proof-of Concept. AB - OBJECTIVE: Inappropriate dosing of patients with antibiotics is a driver of antimicrobial resistance, toxicity, and poor outcomes of therapy. In this paper, we investigate, in silico, the hypothesis that the use of a closed-loop control system could improve the attainment of pharmacokinetic-pharmacodynamic targets for antimicrobial therapy, where wide variations in target attainment have been reported. This includes patients in critical care, patients with renal disease, and patients with obesity. METHODS: The presented in silico study focuses on vancomycin delivery, a first line therapy for Methicillin-resistant Staphylococcus aureus (MRSA) that has serious side effects, including nephrotoxicity. For this purpose, an in silico platform for the simulation of pharmacokinetics of vancomycin agents was developed including 24 virtual noncritically ill-adult subjects obtained from routinely collected data from two prospective audits of vancomycin therapy. Intraday variability on renal clearance, sensor error, and infusion constraints were taken into account. Proportional integral derivative (PID) controller was chosen because of its simplicity of implementation and satisfactory performance. RESULTS: Even though significant intraday variability and sensor error were considered in the simulations, by assuming a minimum inhibitory concentration of 1 mg/l for MRSA, the proposed controller was able to reach the well-established therapeutic target of 24-h area under curve to minimum inhibitory concentration ratio equal to 400 $?text{mg} ?cdot ?text{h}?text{/}?text{l}$ for all the studied subjects, while staying significantly below toxic levels. CONCLUSION: A PID controller has the potential to precisely deliver a vancomycin therapy in a noncritically ill-adult population. SIGNIFICANCE: Closed-loop control for precision Vancomycin delivery can potentially reduce toxicity and poor therapeutic outcomes, as well as reduce antimicrobial resistance. PMID- 29989938 TI - Automated In Vivo Sub-Hertz Analysis of Viscoelasticity (SAVE) for Evaluation of Breast Lesions. AB - We present an automated method for acquiring images and contrast parameters based on mechanical properties of breast lesions and surrounding tissue at load frequencies less than 1 Hz. The method called sub-Hertz analysis of viscoelasticity (SAVE) uses a compression device integrated with ultrasound imaging to perform in vivo ramp-and-hold uniaxial creep-like test on human breast in vivo. It models the internal deformations of tissues under constant surface stress as a linear viscoelastic response. We first discuss different aspects of our unique measurement approach and the expected variability of the viscoelastic parameters estimated based on a simplified one-dimensional reconstruction model. Finite-element numerical analysis is used to justify the advantages of using imaging contrast over viscoelasticity values. We then present the results of SAVE applied to a group of patients with breast masses undergoing biopsy. PMID- 29989939 TI - A Robust Fusion Model for Estimating Respiratory Rate From Photoplethysmography and Electrocardiography. AB - OBJECTIVE: Respiratory rate (RR) estimation algorithms based on the photoplethymogram (PPG) and electrocardiogram (ECG) lack clinical robustness. This is because the PPG and ECG respiratory modulations are dependent on patient physiology, regardless of general signal quality. The present work describes an RR estimation algorithm using respiratory quality indices (RQIs) that assess the presence or absence of the PPG- and ECG-derived respiratory modulations. METHODS: Six respiratory waveforms are derived from the amplitude modulation, frequency modulation, and baseline wander of the PPG and ECG. The respiratory quality of each modulation is assessed by using RQIs based on the fast Fourier transform, autoregression, and autocorrelation. The individual RQIs are fused to obtain a single RQI per modulation per time window. Based on a tunable threshold, the RQIs are used to discard poor modulations and weight the remaining modulations to provide a single RR estimation per time window. RESULTS: The proposed method was tested on two independent datasets and found that using a conservative threshold, the mean absolute error was 0.71 $?pm$ 0.89 and 3.12 $?pm$ 4.39 brpm while discarding only 1.3% and 23.2% of all time windows, for each dataset, respectively. CONCLUSION: These errors are either better than or comparable to current methods, and the number of windows discarded is far lower demonstrating improved robustness. SIGNIFICANCE: This work describes a novel preprocessing algorithm that can be implemented in conjunction with other RR estimation techniques to improve robustness by specifically considering the quality of the respiratory information. PMID- 29989940 TI - Visible Illumination Enhanced Nonenzymatic Glucose Photobiosensor Based on TiO2 Nanorods Decorated With Au Nanoparticles. AB - A nonenzymatic glucose photobiosensor was developed based on Au-nanoparticle decorated TiO2 nanorods (NRs) under visible illumination. Au nanoparticles (NPs) absorbed the visible illumination, resulting in surface plasmon resonance (SPR). The SPR of the Au NPs indicated that there was a strong electric field around them, which promoted the transport of more electrons to the TiO2 NRs and enhanced the glucose sensing properties. The sensing current under visible illumination was five times higher than in the dark when in 0.1 M NaOH solution at a potential of 0.17 V. Moreover, the Michaelis-Menten constant (Km) of the Au NPs/TiO2 NRs/FTO under visible illumination was 0.52 mM, which is much smaller than that reported previously. Moreover, these results indicate that the Au NPs/TiO2 NRs/FTO under visible illumination feature outstanding properties as a nonenzymatic glucose photobiosensor. PMID- 29989941 TI - Prediction of Hemorrhagic Transformation Severity in Acute Stroke From Source Perfusion MRI. AB - OBJECTIVE: Hemorrhagic transformation (HT) is the most severe complication of reperfusion therapy in acute ischemic stroke (AIS) patients. Management of AIS patients could benefit from accurate prediction of upcoming HT. While prediction of HT occurrence has recently provided encouraging results, the prediction of the severity and territory of the HT could bring valuable insights that are beyond current methods. METHODS: This study tackles these issues and aims to predict the spatial occurrence of HT in AIS from perfusion-weighted magnetic resonance imaging (PWI) combined with diffusion weighted imaging. In all, 165 patients were included in this study and analyzed retrospectively from a cohort of AIS patients treated with reperfusion therapy in a single stroke center. RESULTS: Machine learning models are compared within our framework; support vector machines, linear regression, decision trees, neural networks, and kernel spectral regression were applied to the dataset. Kernel spectral regression performed best with an accuracy of $?text{83.7} ?pm ?text{2.6}?%$. CONCLUSION: The key contribution of our framework formalize HT prediction as a machine learning problem. Specifically, the model learns to extract imaging markers of HT directly from source PWI images rather than from pre-established metrics. SIGNIFICANCE: Predictions visualized in terms of spatial likelihood of HT in various territories of the brain were evaluated against follow-up gradient recalled echo and provide novel insights for neurointerventionalists prior to endovascular therapy. PMID- 29989942 TI - PMN-PT Single Crystal Ultrasonic Transducer With Half-Concave Geometric Design for IVUS Imaging. AB - As the key component of intravascular ultrasound (IVUS) imaging systems, traditional commercial side-looking IVUS transducers are flat and unfocused, which limits their lateral resolution. We propose a PMN-PT single crystal IVUS transducer with a half-concave geometry. This unique configuration makes it possible to conduct geometric focusing at a desired depth. To compare performances, the proposed and the traditional flat transducer with similar dimensions were fabricated. We determined that the half-concave transducer has a slightly higher center frequency (35 MHz), significantly broader -6 dB bandwidth (54%) but a higher insertion loss (-22.4 dB) compared to the flat transducer (32 MHz, 28%, and -19.3 dB, respectively). A significant enhancement of the lateral resolution was also confirmed. The experimental results are in agreement with the finite element simulation results. This preliminary investigation suggests that the half-concave geometry design is a promising approach in the development of focused IVUS transducers with broad bandwidth and high lateral resolution. PMID- 29989944 TI - EEG for Current With Two-Dimensional Support. AB - OBJECTIVE: The inverse problem of computing the neuronal current density from scalp EEG is highly ill-posed. In part, this is due to the nonuniqueness of the mapping between current sources and scalp potentials. We develop an explicit formula for the scalp EEG for sources constrained to the cortical surface in terms only of the components of the current that affect the EEG signal. METHODS: Starting from the quasi-static form of Maxwell's equations, we develop a formula that involves only the "visible" part of the current (i.e., the part of the current that affects the EEG measurements), as well as certain auxiliary functions that depend on the topology and conductivity of the 3-D domains $?Omega _c$ , $?Omega _f$, $?Omega _b$, and $?Omega _s$, which model the spaces occupied by the cerebrum, cerebrospinal fluid, bone, and scalp, respectively. RESULTS: we derive expressions for the scalp potential for a general nested topology, as well as for the special case of spherical and ellipsoidal surfaces. We verify that the resulting scalp potential, in the case that the current resides in a spherical shell in the cerebrum of thickness $2?delta$, agrees with the potential obtained via the 3-D formulation for $?delta =10^{-8}?text{m}$. CONCLUSION: The "visible" part of the current can be explicitly characterized and consists of a combination of its component normal to the surface and of a certain function generating the remaining tangential components of the current. SIGNIFICANCE: The resulting ability to restrict the source space greatly reduces the degree of ambiguity in the inverse solutions, offering the potential for more stable inverse solutions, since the auxiliary functions that define the mapping can be computed efficiently using standard numerical methods. PMID- 29989943 TI - Effect of Low-Field High-Frequency nsPEFs on the Biological Behaviors of Human A375 Melanoma Cells. AB - OBJECTIVE: To evaluate the effect of low-field high-frequency nanosecond pulsed electric fields (nsPEFs) on multiple biological behaviors of human A375 melanoma cells and to optimize suitable parameters for further study and clinical use. METHODS: An nsPEF generator was developed to generate appropriate pulses. Cell apoptosis and the cell cycle were evaluated by flow cytometry. The CCK-8 assay was performed to explore the effect of nsPEFs on the viability of A375 melanoma cells. Cell migration was assessed using a Transwell Boyden Chamber. The proliferation of A375 melanoma cells was determined by the cloning efficacy test. Furthermore, the nude mouse tumorigenicity assay was used to detect the effectiveness of nsPEFs in vivo. RESULTS: The nsPEFs with our tested parameters failed to induce apoptosis of A375 melanoma cells, though nsPEFs with high pulse duration (500 ns) induced necrosis. However, the viability and migration of A375 melanoma cells were significantly inhibited by nsPEFs. nsPEFs also suppressed the proliferation of A375 melanoma cells by restricting cells in G0/G1 phase. Moreover, animal experiments demonstrated that nsPEFs inhibited the growth of melanoma in vivo. CONCLUSION: Low-field high-frequency nsPEFs failed to induce apoptosis but effectively inhibited the growth of melanoma via affecting other biological behaviors of melanoma cells, such as cell viability, proliferation, and migration. SIGNIFICANCE: This study investigated the influence of low-field high-frequency nsPEFs on melanoma through evaluating their effects on multiple biological behaviors and is helpful in the treatment of melanoma and other tumors. PMID- 29989945 TI - Generalized Adaptive Gaussian Markov Random Field for X-Ray Luminescence Computed Tomography. AB - OBJECTIVE: X-ray luminescence computed tomography (XLCT) is an emerging and promising modality, but suffers from inferior reconstructions and smoothed target shapes. This work aims to improve the image quality with new mathematical framework. METHODS: We present a Bayesian local regularization framework to tackle the ill-conditioness of XLCT. Different from traditional overall regularization strategies, the proposed method utilizes correlations of neighboring voxels to regularize the solution locally based on generalized adaptive Gaussian Markov random field (GAGMRF), and provides an adjustable parameter to facilitate the edge-preserving property. RESULTS: Numerical simulations and phantom experiments show that the GAGMRF method yields both high image quality and accurate target shapes. CONCLUSION: Compared to conventional L2 and L1 regularizations, GAGMRF provides a new and efficient model for high quality imaging based on the Bayesian framework. SIGNIFICANCE: The GAGMRF method offers a flexible regularization framework to adapt to a wide range of biomedical applications. PMID- 29989946 TI - Asynchronous Brain-Computer Interfacing Based on Mixed-Coded Visual Stimuli. AB - OBJECTIVE: One of the challenges in the area of brain-computer interfacing (BCI) is to develop an asynchronous BCI or a self-paced BCI that detects whether a user intends to pass messages. This paper proposes a novel asynchronous BCI that uses mixed frequency and phase-coded visual stimuli, which can provide high-speed and accurate command entries. METHODS: The mixed-coded visual stimuli were presented as flickers with a following blank interval to synchronize the recorder of electroencephalogram (EEG) with the stimuli, which was aimed to detect the phase in an asynchronous situation. For decoding from the measured EEG, multiset canonical correlation analysis (MCCA) was efficiently exploited for recognizing the intentional state and the intending command. The proposed asynchronous BCI was tested on 11 healthy subjects. RESULTS: The proposed decoder was capable of discriminating between the intentional control/noncontrol state and determining the command faster and more accurately than the contrast methods, achieving area under the curve of 0.9191 $?pm$ 0.1206 and command recognition accuracy of 91.08 $?pm$ 13.97 $?%$ with data lengths of 3.0 s. CONCLUSION: The BCI based on mixed coded visual stimuli was able to be implemented in an asynchronous manner, and the MCCA-based decoder outperformed the conventional ones in terms of discriminability of intentional states and command recognition accuracy. SIGNIFICANCE: The present study showed that an asynchronous BCI can be implemented with mixed-coded visual stimuli for the first time, which enables a large increase in the number of choices/commands. PMID- 29989947 TI - Methods for Improved Discrimination Between Ventricular Fibrillation and Tachycardia. AB - Differentiating between ventricular tachycardia and ventricular fibrillation in clinical and preclinical research is based on subjective definitions that have yet to be validated using objective criteria. This is partly due to shortcomings in the discrimination ability of current objective approaches, typified by the algorithms that perform cardiac rhythm classification using low-dimensional feature representations of electrocardiogram (ECG) signals. These identify ventricular tachyarrhythmias, but do not discriminate between ventricular tachycardia and ventricular fibrillation. In order to address this limitation, we have tested the utility of high-dimensional feature vectors, in particular, magnitude spectra and classifier ensembles that take into account local context information from ECG signals. Using these approaches, we categorized rhythms into three classes: ventricular tachycardia, ventricular fibrillation, and any other possible rhythm, defined here as "nonventricular rhythms." The high-dimensional spectral features achieved a substantial improvement in the discrimination between ventricular tachycardia and ventricular fibrillation, but exhibited a decreased sensitivity to nonventricular rhythms. In order to deal with the reduced sensitivity for the detection of nonventricular rhythms, methods were elaborated for combining the strengths of different feature spaces, and this substantially improved the identification sensitivities of all three classes. PMID- 29989948 TI - Modeling, Detecting, and Tracking Freezing of Gait in Parkinson Disease Using Inertial Sensors. AB - In this paper, we develop new methods to automatically detect the onset and duration of freezing of gait (FOG) in people with Parkinson disease (PD) in real time, using inertial sensors. We first build a physical model that describes the trembling motion during the FOG events. Then, we design a generalized likelihood ratio test framework to develop a two-stage detector for determining the zero velocity and trembling events during gait. Thereafter, to filter out falsely detected FOG events, we develop a point-process filter that combines the output of the detectors with information about the speed of the foot, provided by a foot mounted inertial navigation system. We computed the probability of FOG by using the point-process filter to determine the onset and duration of the FOG event. Finally, we validate the performance of the proposed system design using real data obtained from people with PD who performed a set of gait tasks. We compare our FOG detection results with an existing method that only uses accelerometer data. The results indicate that our method yields 81.03% accuracy in detecting FOG events and a threefold decrease in the false-alarm rate relative to the existing method. PMID- 29989949 TI - Visual Limit-Push Training Alters Movement Variability. AB - : In both movement training and neurorehabilitation, there have been numerous examples of how average performance can be manipulated through practice using enhanced visual feedback. OBJECTIVE: Rather than just influencing the mean, our objective was to use a novel feedback technique called limit-push to influence the trial-to-trial variability of motion by distorting vision. METHOD: Limit-push was previously done using robotic forces; the present study employed only visual distortions that imitated the limit-push approach. RESULTS: Like the robotic force treatment, our results showed how subjects significantly shifted the distributions of their motions. This effect was even greater than that of the original limit-push experiment that used robotic forces. SIGNIFICANCE: Such visual distortion interventions do not require a robot for enhanced training. CONCLUSION: The visual limit-push technique appears to be able to selectively alter both the central tendency and variability in performance training applications. PMID- 29989950 TI - User-Independent Intent Recognition for Lower Limb Prostheses Using Depth Sensing. AB - OBJECTIVE: The intent recognizers of advanced lower limb prostheses utilize mechanical sensors on the prosthesis and/or electromyographic measurements from the residual limb. Besides the delay caused by these signals, such systems require user-specific databases to train the recognizers. In this paper, our objective is the development and validation of a user-independent intent recognition framework utilizing depth sensing. METHODS: We collected a depth image dataset from 12 healthy subjects engaging in a variety of routine activities. After filtering the depth images, we extracted simple features employing a recursive strategy. The feature vectors were classified using a support vector machine. For robust activity mode switching, we implemented a voting filter scheme. RESULTS: The model selection showed that the support vector machine classifier with no dimension reduction has the highest classification accuracy. Specifically, it reached 94.1% accuracy on the testing data from four subjects. We also observed a positive trend in the accuracy of classifiers trained with data from increasing the number of subjects. Activity mode switching using a voting filter detected 732 out of 778 activity mode transitions of the four users while initiating 70 erroneous transitions during steady-state activities. CONCLUSION: The intent recognizer trained on multiple subjects can be used for any other subject, providing a promising solution for supervisory control of powered lower limb prostheses. SIGNIFICANCE: A user-independent intent recognition framework has the potential to decrease or eliminate the time required for extensive data collection regiments for intent recognizer training. This could accelerate the introduction of robotic lower limb prostheses to the market. PMID- 29989951 TI - Tensor Decomposition of Gait Dynamics in Parkinson's Disease. AB - OBJECTIVE: The study of gait in Parkinson's disease is important because it can provide insights into the complex neural system and physiological behaviors of the disease, of which understanding can help improve treatment and lead to effective developments of alternative neural rehabilitation programs. This paper aims to introduce an effective computational method for multichannel or multisensor data analysis of gait dynamics in Parkinson's disease. METHOD: A model of tensor decomposition, which is a generalization of matrix-based analysis for higher dimensional analysis, is designed for differentiating multisensor time series of gait force between Parkinson's disease and healthy control cohorts. RESULTS: Experimental results obtained from the tensor decomposition model using a PhysioNet database show several discriminating characteristics of the two cohorts, and the achievement of 100% sensitivity and 100% specificity under various cross validations. CONCLUSION: Tensor decomposition is a useful method for the modeling and analysis of multisensor time series in patients with Parkinson's disease. SIGNIFICANCE: Tensor-decomposition factors can be potentially used as physiological markers for Parkinson's disease, and effective features for machine learning that can provide early prediction of the disease progression. PMID- 29989952 TI - Focal Onset Seizure Prediction Using Convolutional Networks. AB - OBJECTIVE: This paper investigates the hypothesis that focal seizures can be predicted using scalp electroencephalogram (EEG) data. Our first aim is to learn features that distinguish between the interictal and preictal regions. The second aim is to define a prediction horizon in which the prediction is as accurate and as early as possible, clearly two competing objectives. METHODS: Convolutional filters on the wavelet transformation of the EEG signal are used to define and learn quantitative signatures for each period: interictal, preictal, and ictal. The optimal seizure prediction horizon is also learned from the data as opposed to making an a priori assumption. RESULTS: Computational solutions to the optimization problem indicate a 10-min seizure prediction horizon. This result is verified by measuring Kullback-Leibler divergence on the distributions of the automatically extracted features. CONCLUSION: The results on the EEG database of 204 recordings demonstrate that (i) the preictal phase transition occurs approximately ten minutes before seizure onset, and (ii) the prediction results on the test set are promising, with a sensitivity of 87.8% and a low false prediction rate of 0.142 FP/h. Our results significantly outperform a random predictor and other seizure prediction algorithms. SIGNIFICANCE: We demonstrate that a robust set of features can be learned from scalp EEG that characterize the preictal state of focal seizures. PMID- 29989954 TI - Magnet-Assisted Hydraulic Bougienage for Correction of Long-Gap Esophageal Atresia. AB - OBJECTIVE: An infant born with long-gap esophageal atresia has its esophagus separated into two pouches, and typically undergoes multiple open-chest surgeries for esophageal reconstruction. In this paper, we study a possible approach for less invasive correction of long-gap esophageal atresia. METHODS: Our technique utilizes a magnet-tipped catheter with a piston on the end to push the esophageal pouch from the inside. The attractive magnetic force helps the catheter stretch the esophageal pouches, while the hydraulic piston prevents the magnet from applying too large force. The piston also enables estimation of the esophageal tension based on the hydraulic pressure measurement. RESULTS: We have built a prototype system and performed bench-level tests on an esophageal mock-up. A hydraulic dither is applied to the piston to average out seal friction, thereby improving the tension estimation performance. CONCLUSION: The bench-level tests demonstrate that the prototype bougienage system gives a reliable low-frequency estimate of the esophageal tension in real-time, and also enables longitudinal bougienage by a desired amount of load, e.g., 2N, for various gap sizes. SIGNIFICANCE: This study provides a foundation for the next step of designing a system for use on actual patients. PMID- 29989953 TI - Multiclass Classification of Word Imagination Speech with Hybrid Connectivity Features. AB - OBJECTIVE: In this study, electroencephalography data of imagined words were classified using four different feature extraction approaches. Eight subjects were recruited for the recording of imagination with five different words, namely; 'go', 'back', 'left', 'right', and 'stop'. PMID- 29989955 TI - Characterization of Nonlinearity and Dispersion in Tissue Impedance During High Frequency Electroporation. AB - OBJECTIVE: The use of high-voltage, high-frequency bipolar pulses (HFBPs) is an emerging electroporation-based therapy for the treatment of solid tumors. In this study, we quantify the extent of nonlinearity and dispersion during the HFBP treatment. METHODS: We utilize flat-plate electrodes to capture the impedance of the porcine liver tissue during the delivery of a burst of HFBPs of widths 1 and 2 $?mu$s at different pulse amplitudes. Next, we fit the impedance data to a frequency-dependent parallel RC network to determine the conductivity and permittivity of the tissue as a function of frequency, for different applied electric fields. Finally, we present a simple model to approximate the field distribution in the tissue using the conductivity function at a frequency that could minimize the errors due to approximation with a nondispersive model. RESULTS: The conductivity/permittivity of the tissue was plotted as a function of frequency for different electric fields. It was found that the extent of dispersion reduces with higher applied electric field magnitudes. CONCLUSION: This is the first study to quantify dispersion and nonlinearity in the tissue during the HFBP treatment. The data have been used to predict the field distribution in a numerical model of the liver tissue utilizing two needle electrodes. SIGNIFICANCE: The data and technique developed in this study to monitor the electrical properties of tissue during treatment can be used to generate treatment-planning models for future high-frequency electroporation therapies as well as provide insights regarding treatment effect. PMID- 29989956 TI - Effects of Ablation (Radio Frequency, Cryo, Microwave) on Physiologic Properties of the Human Vastus Lateralis. AB - OBJECTIVE: Ablative treatments can sometimes cause collateral injury to surrounding muscular tissue, with important clinical implications. In this study, we investigated the changes in muscle physiology of the human vastus lateralis when exposed to three different ablation modalities: radiofrequency ablation, cryoablation, and microwave ablation. METHODS: We obtained fresh vastus lateralis tissue biopsy specimens from nine patients (age range: 29-73 years) who were undergoing in vitro contracture testing for malignant hyperthermia. Using leftover waste tissue, we prepared 46 muscle bundles that were utilized in tissue baths before and after ablation. RESULTS: After ablation with all the three modalities, we noted dose-dependent sustained reductions in peak force (strength of contraction), as well as transient increases in baseline force (resting muscle tension). But, over the subsequent 3-h recovery period, peak force improved and the baseline force consistently recovered to below its preablation levels. CONCLUSION: The novel in vitro methodologies we developed to investigate changes in muscle physiology after ablation can be used to study a spectrum of ablation modalities and also to make head-to-head comparisons of different ablation modalities. SIGNIFICANCE: As the role of ablative treatments continues to expand, our findings provide unique insights into the resulting changes in muscle physiology. These insights could enhance the safety and efficacy of ablations and help individuals design and develop novel medical devices. PMID- 29989957 TI - Semiblind Spectral Factorization Approach for Magnetic Resonance Spectroscopy Quantification. AB - An observed magnetic resonance (MR) spectrum is composed of a set of metabolites spectrum, baseline, and noise. Quantification of metabolites of interest in the MR spectrum provides great opportunity for early diagnosis of dangerous disease such as brain tumors. In this paper, a novel spectral factorization approach based on singular spectrum analysis (SSA) is proposed to quantify magnetic resonance spectroscopy (MRS). In addition, baseline removal is performed in this study. The proposed method is a semiblind spectral factorization algorithm that jointly uses observed signal and prior knowledge about metabolites of interest to improve metabolite separation. In order to incorporate prior knowledge about metabolites of interest, a new covariance matrix is suggested that exploits correlation between the observed nuclear magnetic resonance signal and prior knowledge. The objectives of the proposed method are 1) removing baseline in frequency domain using SSA; 2) extracting the underlying components of MRS signal based on the suggested novel covariance matrix; and 3) reconstructing metabolite of interest by combining some of the extracted components using a novel cost function. Performance of the proposed method is evaluated using both synthetic and real MRS signals. The obtained results show the effectiveness of the proposed technique to accurately remove baseline and extract metabolites of MRS signal. PMID- 29989958 TI - Coded-Aperture Compressed Sensing X-Ray Luminescence Tomography. AB - OBJECTIVE: The purpose of this work is to introduce and study a novel imaging geometry for X-ray luminescence computed tomography (XLCT), termed coded aperture compressive X-ray luminescence tomography (CAC-XLCT). METHODS: CAC-XLCT is studied through simulations of X-ray and diffuse light propagation and the implementation of a compressed sensing image reconstruction algorithm. RESULTS: CAC-XLCT is compared against cone beam XLCT considering simulated targets with varying complexity, and it is found to offer a remarkable enhancement in spatial resolution and image quality with only a small overhead in image acquisition time. CONCLUSIONS AND SIGNIFICANCE: XLCT has been mainly investigated so far in pencil beam and cone beam excitation geometries which suffer from either very long image acquisition time or low spatial resolution and accuracy. CAC-XLCT presents a very promising alternative, which can offer simultaneously high spatial resolution, high image quality, and fast image acquisition, appropriate for in vivo imaging. PMID- 29989959 TI - Adaptive Estimation of the Neural Activation Extent in Computational Volume Conductor Models of Deep Brain Stimulation. AB - OBJECTIVE: The aim of this study is to propose an adaptive scheme embedded into an open-source environment for the estimation of the neural activation extent during deep brain stimulation and to investigate the feasibility of approximating the neural activation extent by thresholds of the field solution. METHODS: Open source solutions for solving the field equation in volume conductor models of deep brain stimulation and computing the neural activation are embedded into a Python package to estimate the neural activation dependent on the dielectric tissue properties and axon parameters by employing a spatially adaptive scheme. Feasibility of the approximation of the neural activation extent by field thresholds is investigated to further reduce the computational expense. RESULTS: The varying extents of neural activation for different patient-specific dielectric properties were estimated with the adaptive scheme. The results revealed the strong influence of the dielectric properties of the encapsulation layer in the acute and chronic phase after surgery. The computational time required to determine the neural activation extent in each studied model case was substantially reduced. CONCLUSION: The neural activation extent is altered by patient-specific parameters. Threshold values of the electric potential and electric field norm facilitate a computationally efficient method to estimate the neural activation extent. SIGNIFICANCE: The presented adaptive scheme is able to robustly determine neural activation extents and field threshold estimates for varying dielectric tissue properties and axon diameters while substantially reducing the computational expense. PMID- 29989960 TI - Super-Resolution Axial Localization of Ultrasound Scatter Using Multi-Focal Imaging. AB - OBJECTIVE: This paper aims to develop a method for achieving micrometre axial scatterer localization for medical ultrasound, surpassing the inherent, pulse length dependence limiting ultrasound imaging. METHODS: The method, directly translated from cellular microscopy, is based on multi-focal imaging and the simple, aberration-dependent, image sharpness metric of a single point scatterer. The localization of a point scatterer relies on the generation of multiple overlapping sharpness curves, created by deploying three foci during receive processing, and by assessing the sharpness values after each acquisition as a function of depth. Each derived curve peaks around the receive focus and the unique position of the scatterer is identified by combining the data from all curves using a maximum likelihood algorithm with a calibration standard. RESULTS: Simulated and experimental ultrasound point scatter data show that the sharpness method can provide scatterer axial localization with an average accuracy down to 10.21 m ( 21) and with up to 11.4 times increased precision compared to conventional localization. The improvements depend on the rate of change of sharpness using each focus, and the signal to noise ratio in each image. CONCLUSION: Super-resolution axial imaging from optical microscopy has been successfully translated into ultrasound imaging by using raw ultrasound data and standard beamforming. SIGNIFICANCE: The normalized sharpness method has the potential to be used in scatterer localization applications and contribute in current super-resolution ultrasound imaging techniques. PMID- 29989961 TI - An Adjustable-Length Dipole Using Forced-Current Excitation for 7T MR. AB - Ultrahigh field imaging of the body and the spine is challenging due to the large field-of-view (FOV) required. It is especially difficult for RF transmission due to its requirement on both the length and the depth of the ${?rm{B}}_{1}^{{?rm + }}$ field. One solution is to use a long dipole to provide continuous current distribution. The drawback is the natural falloff of the ${?rm{B}}_{1}$ field toward the ends of the dipole, therefore the ${?rm{B}}_{1}^{{?rm + }}$ per unit square root of maximum specific absorption rate ${?rm{(B}}_{1}^{{?rm + }}{?rm{/ ?surd SAR}}_{{?rm{max}}})$ performance is particularly poor toward the end of the dipole. In this study, a segmented element design using forced-current excitation and a switching circuit is presented. The design provides long FOV when desired and allows flexible FOV switching and power distribution without additional power amplifiers. Different element types and arrangements were explored and a segmented dipole design was chosen as the best design. The segmented dipole was implemented and tested on the bench and with a phantom on a 7T whole body scanner. The switchable mode dipole enabled a large FOV in the long mode and improved ${?rm{B}}_{1}^{{?rm + }}{?rm{/ ?surd SAR}}_{{?rm{max}}}$ efficiency in a smaller FOV in the short mode. PMID- 29989962 TI - Hand-Object Contact Force Estimation from Markerless Visual Tracking. AB - We consider the problem of estimating realistic contact forces during manipulation, backed with ground-truth measurements, using vision alone. Interaction forces are usually measured by mounting force transducers onto the manipulated objects or the hands. Those are costly, cumbersome, and alter the objects' physical properties and their perception by the human sense of touch. Our work establishes that interaction forces can be estimated in a cost effective, reliable, non-intrusive way using vision. This is a complex and challenging problem. Indeed, in multi-contact, a given motion can generally be caused by an infinity of possible force distributions. To alleviate the limitations of traditional models based on inverse optimization, we collect and release the first large-scale dataset on manipulation kinodynamics as 3.2 hours of synchronized force and motion measurements under 193 object-grasp configurations. We learn a mapping between high-level kinematic features based on the equations of motion and the underlying manipulation forces using recurrent neural networks (RNN). The RNN predictions are consistently refined using physics based optimization through second-order cone programming (SOCP). We show that our method can successfully capture interaction forces compatible with both the observations and the way humans intuitively manipulate objects, using a single RGB-D camera. PMID- 29989963 TI - Person Re-Identification by Cross-View Multi-Level Dictionary Learning. AB - Person re-identification plays an important role in many safety-critical applications. Existing works mainly focus on extracting patch-level features or learning distance metrics. However, the representation power of extracted features might be limited, due to the various viewing conditions of pedestrian images in complex real-world scenarios. To improve the representation power of features, we learn discriminative and robust representations via dictionary learning in this paper. First, we propose a Cross-view Dictionary Learning (CDL) model, which is a general solution to the multi-view learning problem. Inspired by the dictionary learning based domain adaptation, CDL learns a pair of dictionaries from two views. In particular, CDL adopts a projective learning strategy, which is more efficient than the optimization in traditional dictionary learning. Second, we propose a Cross-view Multi-level Dictionary Learning (CMDL) approach based on CDL. CMDL contains dictionary learning models at different representation levels, including image-level, horizontal part-level, and patch level. The proposed models take advantages of the view-consistency information, and adaptively learn pairs of dictionaries to generate robust and compact representations for pedestrian images. Third, we incorporate a discriminative regularization term to CMDL, and propose a CMDL-Dis approach which learns pairs of discriminative dictionaries in image-level and part-level. We devise efficient optimization algorithms to solve the proposed models. Finally, a fusion strategy is utilized to generate the similarity scores for test images. Experiments on the public VIPeR, CUHK Campus, iLIDS, GRID and PRID450S datasets show that our approach achieves the state-of-the-art performance. PMID- 29989964 TI - Continuous 3D Label Stereo Matching Using Local Expansion Moves. AB - We present an accurate stereo matching method using local expansion moves based on graph cuts. This new move-making scheme is used to efficiently infer per-pixel 3D plane labels on a pairwise Markov random field (MRF) that effectively combines recently proposed slanted patch matching and curvature regularization terms. The local expansion moves are presented as many -expansions defined for small grid regions. The local expansion moves extend traditional expansion moves by two ways: localization and spatial propagation. By localization, we use different candidate -labels according to the locations of local -expansions. By spatial propagation, we design our local -expansions to propagate currently assigned labels for nearby regions. With this localization and spatial propagation, our method can efficiently infer MRF models with a continuous label space using randomized search. Our method has several advantages over previous approaches that are based on fusion moves or belief propagation; it produces submodular moves deriving a subproblem optimality; it helps find good, smooth, piecewise linear disparity maps; it is suitable for parallelization; it can use cost-volume filtering techniques for accelerating the matching cost computations. Even using a simple pairwise MRF, our method is shown to have best performance in the Middlebury stereo benchmark V2 and V3. PMID- 29989965 TI - Max-Margin Deep Generative Models for (Semi-)Supervised Learning. AB - Deep generative models (DGMs) can effectively capture the underlying distributions of complex data by learning multilayered representations and performing inference. However, it is relatively insufficient to boost the discriminative ability of DGMs. This paper presents max-margin deep generative models (mmDGMs) and a class-conditional variant (mmDCGMs), which explore the strongly discriminative principle of max-margin learning to improve the predictive performance of DGMs in both supervised and semi-supervised learning, while retaining the generative capability. In semi-supervised learning, we use the predictions of a max-margin classifier as the missing labels instead of performing full posterior inference for efficiency; we also introduce additional max-margin and label-balance regularization terms of unlabeled data for effectiveness. We develop an efficient doubly stochastic subgradient algorithm for the piecewise linear objectives in different settings. Empirical results on various datasets demonstrate that: (1) max-margin learning can significantly improve the prediction performance of DGMs and meanwhile retain the generative ability; (2) in supervised learning, mmDGMs are competitive to the best fully discriminative networks when employing convolutional neural networks as the generative and recognition models; and (3) in semi-supervised learning, mmDCGMs can perform efficient inference and achieve state-of-the-art classification results on several benchmarks. PMID- 29989966 TI - Graph Matching with Adaptive and Branching Path Following. AB - Graph matching aims at establishing correspondences between graph elements, and is widely used in many computer vision tasks. Among recently proposed graph matching algorithms, those utilizing the path following strategy have attracted special research attentions due to their exhibition of state-of-the-art performances. However, the paths computed in these algorithms often contain singular points, which could hurt the matching performance if not dealt properly. To deal with this issue, we propose a novel path following strategy, named branching path following (BPF), to improve graph matching accuracy. In particular, we first propose a singular point detector by solving a KKT system, and then design a branch switching method to seek for better paths at singular points. Moreover, to reduce the computational burden of the BPF strategy, an adaptive path estimation (APE) strategy is integrated into BPF to accelerate the convergence of searching along each path. A new graph matching algorithm named ABPF-G is developed by applying APE and BPF to a recently proposed path following algorithm named GNCCP (Liu & Qiao 2014). Experimental results reveal how our approach consistently outperforms state-of-the-art algorithms for graph matching on five public benchmark datasets. PMID- 29989968 TI - Visual Representation and Classification by Learning Group Sparse Deep Stacking Network. AB - Deep stacking networks (DSNs) have been successfully applied in classification tasks. Its architecture builds upon blocks of simplified neural network modules (SNNM). The hidden units are assumed to be independent in the SNNM module. However, this assumption prevents SNNM from learning the local dependencies between hidden units to better capture the information in the input data for the classification task. In addition, the hidden representations of input data in each class can be expectantly split into a group in real-world classification applications. Therefore, we propose two kinds of group sparse SNNM modules by mixing -norm and -norm. The first module learns the local dependencies among hidden units by dividing them into non-overlapping groups. The second module splits the representations of samples in different classes into separate groups to cluster the samples in each class. A group sparse DSN (GS-DSN) is constructed by stacking the group sparse SNNM modules. Experimental results further verify that our GS-DSN model outperforms the relevant classification methods. Particularly, GS-DSN achieves the state-of-the-art performance (99.1%) on 15 Scene. PMID- 29989969 TI - Toward Support-free 3D Printing: A Skeletal Approach for Partitioning Models. AB - Minimizing support structures is crucial in reducing 3D printing material and time. Partition-based methods are efficient means in realizing this objective. Although some algorithms exist for support-free fabrication of solid models, no algorithm ever considers the problem of support-free fabrication for shell models (i.e., hollowed meshes). In this paper, we present a skeleton-based algorithm for partitioning a 3D surface model into the least number of parts for 3D printing without using any support structure. To achieve support-free fabrication while minimizing the effect of the seams and cracks that are inevitably induced by the partition, which affect the aesthetics and strength of the final assembled surface, we put forward an optimization system with the minimization of the number of partitions and the total length of the cuts, under the constraints of support-free printing angle. Our approach is particularly tailored for shell models, and it can be applicable to solid models as well. We first rigorously show that the optimization problem is NP-hard and then propose a stochastic method to find an optimal solution to the objectives. We propose a polynomial time algorithm for a special case when the skeleton graph satisfies the requirement that the number of partitioned parts and the degree of each node are bounded by a small constant. We evaluate our partition method on a number of 3D models and validate our method by 3D printing experiments. PMID- 29989970 TI - Structured Penalized Logistic Regression for Gene Selection in Gene Expression Data Analysis. AB - In gene expression data analysis, the problems of cancer classification and gene selection are closely related. Successfully selecting informative genes significantly improve the classification performance. To identify informative genes from a large number of candidate genes, various methods have been proposed. However, the gene expression data may include some important correlation structures, and some of the genes can be divided into different groups based on their biological pathways. Many existing methods do not take into consideration the exact correlation structure within the data. Therefore, from both the knowledge discovery and biological perspectives, an ideal gene selection method should take this structural information into account. Moreover, the better generalization performance can be obtained by discovering correlation structure within data. In order to discover structure information among data and improve learning performance, we propose a structured penalized logistic regression model which simultaneously performs feature selection and model learning for gene expression data analysis. An efficient coordinate descent algorithm has been developed to optimize the model. The numerical simulation studies demonstrate that our method is able to select the highly correlated features. In addition, the results from real gene expression datasets show that the proposed method performs competitively with respect to previous approaches. PMID- 29989971 TI - Stability Analysis of Quaternion-Valued Neural Networks: Decomposition and Direct Approaches. AB - In this paper, we investigate the global stability of quaternion-valued neural networks (QVNNs) with time-varying delays. On one hand, in order to avoid the noncommutativity of quaternion multiplication, the QVNN is decomposed into four real-valued systems based on Hamilton rules: $ij=-ji=k,~jk=-kj=i$ , $ki=-ik=j$ , $i^{2}=j^{2}=k^{2}=ijk=-1$ . With the Lyapunov function method, some criteria are, respectively, presented to ensure the global $?mu $ -stability and power stability of the delayed QVNN. On the other hand, by considering the noncommutativity of quaternion multiplication and time-varying delays, the QVNN is investigated directly by the techniques of the Lyapunov-Krasovskii functional and the linear matrix inequality (LMI) where quaternion self-conjugate matrices and quaternion positive definite matrices are used. Some new sufficient conditions in the form of quaternion-valued LMI are, respectively, established for the global $?mu $ -stability and exponential stability of the considered QVNN. Besides, some assumptions are presented for the two different methods, which can help to choose quaternion-valued activation functions. Finally, two numerical examples are given to show the feasibility and the effectiveness of the main results. PMID- 29989972 TI - Sequential Labeling With Structural SVM Under Nondecomposable Losses. AB - Sequential labeling addresses the classification of sequential data, which are widespread in fields as diverse as computer vision, finance, and genomics. The model traditionally used for sequential labeling is the hidden Markov model (HMM), where the sequence of class labels to be predicted is encoded as a Markov chain. In recent years, HMMs have benefited from minimum-loss training approaches, such as the structural support vector machine (SSVM), which, in many cases, has reported higher classification accuracy. However, the loss functions available for training are restricted to decomposable cases, such as the 0-1 loss and the Hamming loss. In many practical cases, other loss functions, such as those based on the $F_{1}$ measure, the precision/recall break-even point, and the average precision (AP), can describe desirable performance more effectively. For this reason, in this paper, we propose a training algorithm for SSVM that can minimize any loss based on the classification contingency table, and we present a training algorithm that minimizes an AP loss. Experimental results over a set of diverse and challenging data sets (TUM Kitchen, CMU Multimodal Activity, and Ozone Level Detection) show that the proposed training algorithms achieve significant improvements of the $F_{1}$ measure and AP compared with the conventional SSVM, and their performance is in line with or above that of other state-of-the-art sequential labeling approaches. PMID- 29989973 TI - The Stability of Stochastic Coupled Systems With Time-Varying Coupling and General Topology Structure. AB - We introduce a class of novel stochastic coupled systems in which the coupling structure is time-varying and the topology structure is not strongly connected, and first establish the system on a digraph with a time-varying weight matrix. Motivated by Du and Li (2014), we give a hierarchical method to deal with digraphs without strong connectivity and establish the corresponding hierarchical algorithm to realize this approach. Also, an example is given to illustrate our hierarchical algorithm and its feasibility. In the sequel, based on the theory of asymptotically autonomous systems, Kirchhoff's matrix tree theorem, and Lyapunov method, several moment exponential stability criteria are presented, including a Lyapunov-type theorem and a coefficient-type criterion. Furthermore, theoretical results are applied to stochastic coupled oscillators with time-varying coupling structure (SCTCS), and the stability criterion of SCTCS is obtained. Finally, the effectiveness of theoretical results is illustrated by two numerical examples. PMID- 29989974 TI - Event-Driven Stereo Visual Tracking Algorithm to Solve Object Occlusion. AB - Object tracking is a major problem for many computer vision applications, but it continues to be computationally expensive. The use of bio-inspired neuromorphic event-driven dynamic vision sensors (DVSs) has heralded new methods for vision processing, exploiting reduced amount of data and very precise timing resolutions. Previous studies have shown these neural spiking sensors to be well suited to implementing single-sensor object tracking systems, although they experience difficulties when solving ambiguities caused by object occlusion. DVSs have also performed well in 3-D reconstruction in which event matching techniques are applied in stereo setups. In this paper, we propose a new event-driven stereo object tracking algorithm that simultaneously integrates 3-D reconstruction and cluster tracking, introducing feedback information in both tasks to improve their respective performances. This algorithm, inspired by human vision, identifies objects and learns their position and size in order to solve ambiguities. This strategy has been validated in four different experiments where the 3-D positions of two objects were tracked in a stereo setup even when occlusion occurred. The objects studied in the experiments were: 1) two swinging pens, the distance between which during movement was measured with an error of less than 0.5%; 2) a pen and a box, to confirm the correctness of the results obtained with a more complex object; 3) two straws attached to a fan and rotating at 6 revolutions per second, to demonstrate the high-speed capabilities of this approach; and 4) two people walking in a real-world environment. PMID- 29989975 TI - On Wang $k$ WTA With Input Noise, Output Node Stochastic, and Recurrent State Noise. AB - In this paper, the effect of input noise, output node stochastic, and recurrent state noise on the Wang $k$ WTA is analyzed. Here, we assume that noise exists at the recurrent state $y(t)$ and it can either be additive or multiplicative. Besides, its dynamical change (i.e., $dy/dt$ ) is corrupted by noise as well. In sequel, we model the dynamics of $y(t)$ as a stochastic differential equation and show that the stochastic behavior of $y(t)$ is equivalent to an Ito diffusion. Its stationary distribution is a Gibbs distribution, whose modality depends on the noise condition. With moderate input noise and very small recurrent state noise, the distribution is single modal and hence $y(?infty )$ has high probability varying within the input values of the $k$ and $k+1$ winners (i.e., correct output). With small input noise and large recurrent state noise, the distribution could be multimodal and hence $y(?infty )$ could have probability varying outside the input values of the $k$ and $k+1$ winners (i.e., incorrect output). In this regard, we further derive the conditions that the $k$ WTA has high probability giving correct output. Our results reveal that recurrent state noise could have severe effect on Wang $k$ WTA. But, input noise and output node stochastic could alleviate such an effect. PMID- 29989977 TI - Deep EHR: A Survey of Recent Advances in Deep Learning Techniques for Electronic Health Record (EHR) Analysis. AB - The past decade has seen an explosion in the amount of digital information stored in electronic health records (EHRs). While primarily designed for archiving patient information and performing administrative healthcare tasks like billing, many researchers have found secondary use of these records for various clinical informatics applications. Over the same period, the machine learning community has seen widespread advances in the field of deep learning. In this review, we survey the current research on applying deep learning to clinical tasks based on EHR data, where we find a variety of deep learning techniques and frameworks being applied to several types of clinical applications including information extraction, representation learning, outcome prediction, phenotyping, and deidentification. We identify several limitations of current research involving topics such as model interpretability, data heterogeneity, and lack of universal benchmarks. We conclude by summarizing the state of the field and identifying avenues of future deep EHR research. PMID- 29989978 TI - Optimal Robust Output Containment of Unknown Heterogeneous Multiagent System Using Off-Policy Reinforcement Learning. AB - This paper investigates optimal robust output containment problem of general linear heterogeneous multiagent systems (MAS) with completely unknown dynamics. A model-based algorithm using offline policy iteration (PI) is first developed, where the -copy internal model principle is utilized to address the system parameter variations. This offline PI algorithm requires the nominal model of each agent, which may not be available in most real-world applications. To address this issue, a discounted performance function is introduced to express the optimal robust output containment problem as an optimal output-feedback design problem with bounded -gain. To solve this problem online in real time, a Bellman equation is first developed to evaluate a certain control policy and find the updated control policies, simultaneously, using only the state/output information measured online. Then, using this Bellman equation, a model-free off policy integral reinforcement learning algorithm is proposed to solve the optimal robust output containment problem of heterogeneous MAS, in real time, without requiring any knowledge of the system dynamics. Simulation results are provided to verify the effectiveness of the proposed method. PMID- 29989979 TI - Adaptive Semi-Supervised Classifier Ensemble for High Dimensional Data Classification. AB - High dimensional data classification with very limited labeled training data is a challenging task in the area of data mining. In order to tackle this task, we first propose a feature selection-based semi-supervised classifier ensemble framework (FSCE) to perform high dimensional data classification. Then, we design an adaptive semi-supervised classifier ensemble framework (ASCE) to improve the performance of FSCE. When compared with FSCE, ASCE is characterized by an adaptive feature selection process, an adaptive weighting process (AWP), and an auxiliary training set generation process (ATSGP). The adaptive feature selection process generates a set of compact subspaces based on the selected attributes obtained by the feature selection algorithms, while the AWP associates each basic semi-supervised classifier in the ensemble with a weight value. The ATSGP enlarges the training set with unlabeled samples. In addition, a set of nonparametric tests are adopted to compare multiple semi-supervised classifier ensemble (SSCE)approaches over different datasets. The experiments on 20 high dimensional real-world datasets show that: 1) the two adaptive processes in ASCE are useful for improving the performance of the SSCE approach and 2) ASCE works well on high dimensional datasets with very limited labeled training data, and outperforms most state-of-the-art SSCE approaches. PMID- 29989980 TI - Quasi-Synchronization of Delayed Chaotic Memristive Neural Networks. AB - We study the problem of master-slave synchronization of two delayed memristive neural networks (MNNs). Different from most previous papers, memristors are regarded as uncertain continuous time-varying parameters, and MNNs are modeled by neural networks (NNs) with continuous time-varying parameters and polytopic uncertainty. Thus, synchronization of two delayed MNNs is converted into synchronization of delayed NNs with uncertain parameter mismatches. Quasi synchronization criteria are derived by Lyapunov function and inequality technique. It is shown that, given a predetermined error bound, quasi synchronization of two delayed chaotic MNNs can be achieved provided that the pinning strength is larger than a threshold. In the end, a numerical example is provided to illustrate the effectiveness of the derived results. PMID- 29989981 TI - Ensembles of Lasso Screening Rules. AB - In order to solve large-scale lasso problems, screening algorithms have been developed that discard features with zero coefficients based on a computationally efficient screening rule. Most existing screening rules were developed from a spherical constraint and half-space constraints on a dual optimal solution. However, existing rules admit at most two half-space constraints due to the computational cost incurred by the half-spaces, even though additional constraints may be useful to discard more features. In this paper, we present AdaScreen, an adaptive lasso screening rule ensemble, which allows to combine any one sphere with multiple half-space constraints on a dual optimal solution. Thanks to geometrical considerations that lead to a simple closed form solution for AdaScreen, we can incorporate multiple half-space constraints at small computational cost. In our experiments, we show that AdaScreen with multiple half space constraints simultaneously improves screening performance and speeds up lasso solvers. PMID- 29989982 TI - Learning Kinematic Structure Correspondences Using Multi-Order Similarities. AB - In this paper, we present a novel framework for finding the kinematic structure correspondences between two articulated objects in videos via hypergraph matching. In contrast to appearance and graph alignment based matching methods, which have been applied among two similar static images, the proposed method finds correspondences between two dynamic kinematic structures of heterogeneous objects in videos. Thus our method allows matching the structure of objects which have similar topologies or motions, or a combination of the two. Our main contributions can be summarised as follows: (i) casting the kinematic structure correspondence problem into a hypergraph matching problem by incorporating multi order similarities with normalising weights, (ii) introducing a structural topology similarity measure by aggregating topology constrained subgraph isomorphisms, (iii) measuring kinematic correlations between pairwise nodes, and (iv) proposing a combinatorial local motion similarity measure using geodesic distance on the Riemannian manifold. We demonstrate the robustness and accuracy of our method through a number of experiments on synthetic and real data, outperforming various other state of the art methods. Our method is not limited to a specific application nor sensor, and can be used as building block in applications such as action recognition, human motion retargeting to robots, and articulated object manipulation amongst others. PMID- 29989983 TI - Clickstream Analysis for Crowd-Based Object Segmentation with Confidence. AB - With the rapidly increasing interest in machine learning based solutions for automatic image annotation, the availability of reference annotations for algorithm training is one of the major bottlenecks in the field. Crowdsourcing has evolved as a valuable option for low-cost and large-scale data annotation; however, quality control remains a major issue which needs to be addressed. To our knowledge, we are the first to analyze the annotation process to improve crowd-sourced image segmentation. Our method involves training a regressor to estimate the quality of a segmentation from the annotator's clickstream data. The quality estimation can be used to identify spam and weight individual annotations by their (estimated) quality when merging multiple segmentations of one image. Using a total of 29,000 crowd annotations performed on publicly available data of different object classes, we show that (1) our method is highly accurate in estimating the segmentation quality based on clickstream data, (2) outperforms state-of-the-art methods for merging multiple annotations. As the regressor does not need to be trained on the object class that it is applied to it can be regarded as a low-cost option for quality control and confidence analysis in the context of crowd-based image annotation. PMID- 29989984 TI - Monte-Carlo Acceleration of Bilateral Filter and Non-Local Means. AB - We propose stochastic bilateral filter (SBF) and stochastic non-local means (SNLM), efficient randomized processes that agree with conventional bilateral filter (BF) and non-local means (NLM) on average, respectively. By Monte-Carlo, we repeat this process a few times with different random instantiations so that they can be averaged to attain the correct BF/NLM output. The computational bottleneck of the SBF and SNLM are constant with respect to the window size and the color dimension of the edge image, meaning the execution times for color and hyperspectral images are nearly the same as for the grayscale images. In addition, for SNLM, the complexity is constant with respect to the block size. The proposed stochastic filter implementations are considerably faster than the conventional and existing "fast" implementations for high dimensional image data. PMID- 29989985 TI - Learning Common and Feature-Specific Patterns: A Novel Multiple-Sparse Representation-Based Tracker. AB - The use of multiple features has been shown to be an effective strategy for visual tracking because of their complementary contributions to appearance modeling. The key problem is how to learn a fused representation from multiple features for appearance modeling. Different features extracted from the same object should share some commonalities in their representations while each feature should also have some feature-specific representation patterns which reflect its complementarity in appearance modeling. Different from existing multi feature sparse trackers which only consider the commonalities among the sparsity patterns of multiple features, this paper proposes a novel multiple sparse representation framework for visual tracking which jointly exploits the shared and feature-specific properties of different features by decomposing multiple sparsity patterns. Moreover, we introduce a novel online multiple metric learning to efficiently and adaptively incorporate the appearance proximity constraint, which ensures that the learned commonalities of multiple features are more representative. Experimental results on tracking benchmark videos and other challenging videos demonstrate the effectiveness of the proposed tracker. PMID- 29989986 TI - $?ell _{2,p}$ -Norm Based PCA for Image Recognition. AB - Recently, many l1-norm-based PCA approaches have been developed to improve the robustness of PCA. However, most existing approaches solve the optimal projection matrix by maximizing l1-norm-based variance and do not best minimize the reconstruction error, which is the true goal of PCA. Moreover, they do not have rotational invariance. To handle these problems, we propose a generalized robust metric learning for PCA, namely, l2,p-PCA, which employs l2,p -norm as the distance metric for reconstruction error. The proposed method not only is robust to outliers but also retains PCA's desirable properties. For example, the solutions are the principal eigenvectors of a robust covariance matrix and the low-dimensional representation have rotational invariance. These properties are not shared by l1-norm-based PCA methods. A new iteration algorithm is presented to solve l2,p-PCA efficiently. Experimental results illustrate that the proposed method is more effective and robust than PCA, PCA-L1 greedy, PCA-L1 nongreedy, and HQ-PCA. PMID- 29989987 TI - Volumetric Feature-Based Classification and Visibility Analysis for Transfer Function Design. AB - Transfer function (TF) design is a central topic in direct volume rendering. The TF fundamentally translates data values into optical properties to reveal relevant features present in the volumetric data. We propose a semi-automatic TF design scheme which consists of two steps: First, we present a clustering process within 1D/2D TF domain based on the proximities of the respective volumetric features in the spatial domain. The presented approach provides an interactive tool that aids users in exploring clusters and identifying features of interest (FOI). Second, our method automatically generates a TF by iteratively refining the optical properties for the selected features using a novel feature visibility measurement. The proposed visibility measurement leverages the similarities of features to enhance their visibilities in DVR images. Compared to the conventional visibility measurement, the proposed feature visibility is able to efficiently sense opacity changes and precisely evaluate the impact of selected features on resulting visualizations. Our experiments validate the effectiveness of the proposed approach by demonstrating the advantages of integrating feature similarity into the visibility computations. We examine a number of datasets to establish the utility of our approach for semi-automatic TF design. PMID- 29989988 TI - Statistical Framework for Uncertainty Quantification in Computational Molecular Modeling. AB - As computational modeling, simulation, and predictions are becoming integral parts of biomedical pipelines, it behooves us to emphasize the reliability of the computational protocol. For any reported quantity of interest (QOI), one must also compute and report a measure of the uncertainty or error associated with the QOI. This is especially important in molecular modeling, since in most practical applications the inputs to the computational protocol are often noisy, incomplete, or low-resolution. Unfortunately, currently available modeling tools do not account for uncertainties and their effect on the final QOIs with sufficient rigor. We have developed a statistical framework that expresses the uncertainty of the QOI as the probability that the reported value deviates from the true value by more than some user-defined threshold. First, we provide a theoretical approach where this probability can be bounded using Azuma-Hoeffding like inequalities. Second, we approximate this probability empirically by sampling the space of uncertainties of the input and provide applications of our framework to bound uncertainties of several QOIs commonly used in molecular modeling. Finally, we also present several visualization techniques to effectively and quantitavely visualize the uncertainties: in the input, final QOIs, and also intermediate states. PMID- 29989989 TI - Early Diagnosis of Alzheimer's Disease Based on Resting-State Brain Networks and Deep Learning. AB - Computerized healthcare has undergone rapid development thanks to the advances in medical imaging and machine learning technologies. Especially, recent progress on deep learning opens a new era for multimedia based clinical decision support. In this paper, we use deep learning with brain network and clinical relevant text information to make early diagnosis of Alzheimer's Disease (AD). The clinical relevant text information includes age, gender and ApoE gene of the subject. The brain network is constructed by computing functional connectivity of brain regions using resting-state functional magnetic resonance imaging (R-fMRI) data. A targeted autoencoder network is built to distinguish normal aging from mild cognitive impairment, an early stage of AD. The proposed method reveals discriminative brain network features effectively and provides a reliable classifier for AD detection. Compared to traditional classifiers based on R-fMRI time series data, 31.21% improvement of the prediction accuracy on average is achieved by the proposed deep learning method, and standard deviation reduces by 51.23% on average that means our prediction model is more stable and reliable compared to traditional methods. Our work excavates deep learning's advantages of classifying high-dimensional multimedia data in medical services, and could help predict and prevent AD at an early stage. PMID- 29989990 TI - Protein-protein interaction identification using a similarity-constrained graph model. AB - Protein-protein interaction (PPI) identification is an important task in text mining. Most PPI detection systems make predictions solely based on evidence within a single sentence and often suffer from the heavy burden of manual annotation. This paper approaches PPI detection task from a different paradigm by investigating the context of protein pairs collected from a large corpus and their relations. Firstly, crucial cues in the context are exploited to make the predictions. Then, relational similarity between protein pairs is calculated. Finally, evidence from the two views is integrated in the framework of minimum cuts algorithm. Experimental results show that the graph model achieves better performance than standard supervised approaches. Using 10% data as the training set, our algorithm achieves higher accuracy than support vector machine (SVM) using 80% data as training data. Moreover, the semi-supervised settings reveal promising directions for PPI identification exploiting unlabeled data. PMID- 29989991 TI - Computing Minimum Reaction Modifications in a Boolean Metabolic Network. AB - In metabolic network modification, we newly add enzymes or/and knock-out genes to maximize the biomass production with minimum side-effect. Although this problem has been studied for various problem settings via mathematical models including flux balance analysis, elementary mode, and Boolean models, some important problem settings still remain to be studied. In this paper, we consider Boolean Reaction Modification (BRM) problem, where a host metabolic network and a reference metabolic network are given in the Boolean model, the host network initially produces some toxic compounds and cannot produce some necessary compounds, but the reference network can produce the necessary compounds, and we should minimize the total number of removed reactions from the host network and added reactions from the reference network so that the toxic compounds are not producible, but the necessary compounds are producible in the resulting host network. We developed integer linear programming (ILP)-based methods for BRM, and compared with OptStrain and SimOptStrain. The results show that our method performed better for reducing the total number of added and removed reactions, while OptStrain and SimOptStrain performed better for optimizing the production of the target compound. Our developed software is freely available at "http://sunflower.kuicr.kyoto-u.ac.jp/~rogi/solBRM/solBRM.html". PMID- 29989992 TI - A Review of Automated Pain Assessment in Infants: Features, Classification Tasks, and Databases. AB - Bedside caregivers assess infants' pain at constant intervals by observing specific behavioral and physiological signs of pain. This standard has two main limitations. The first limitation is the intermittent assessment of pain, which might lead to missing pain when the infants are left unattended. Second, it is inconsistent since it depends on the observer's subjective judgment and differs between observers. Intermittent and inconsistent assessment can induce poor treatment and, therefore, cause serious long-term consequences. To mitigate these limitations, the current standard can be augmented by an automated system that monitors infants continuously and provides quantitative and consistent assessment of pain. Several automated methods have been introduced to assess infants' pain automatically based on analysis of behavioral or physiological pain indicators. This paper comprehensively reviews the automated approaches (i.e., approaches to feature extraction) for analyzing infants' pain and the current efforts in automatic pain recognition. In addition, it reviews the databases available to the research community and discusses the current limitations of the automated pain assessment. PMID- 29989993 TI - Design of Distributed Observers in the Presence of Arbitrarily Large Communication Delays. AB - This paper focuses on the construction of distributed observers in the presence of arbitrarily large communication time delays. In contrast with the traditional centralized observer with the ability to acquire full output of the plant, we design a set of distributed observers, each having access to partial output of the plant through a distributed sensor network. More specifically, each observer obtains partial plant output and communicates with its neighboring observers through consensus protocols. The communication among the network is subject to arbitrarily large time delays. We consider three representative network topologies and for each topology establish conditions to guarantee the observation error systems be exponentially stable. We also consider the design of a pinning synchronization problem as a dual problem of the design of distributed observers. Numerical simulation is carried out to verify the effectiveness of our theoretical analysis. PMID- 29989994 TI - Deep Learning in Microscopy Image Analysis: A Survey. AB - Computerized microscopy image analysis plays an important role in computer aided diagnosis and prognosis. Machine learning techniques have powered many aspects of medical investigation and clinical practice. Recently, deep learning is emerging as a leading machine learning tool in computer vision and has attracted considerable attention in biomedical image analysis. In this paper, we provide a snapshot of this fast-growing field, specifically for microscopy image analysis. We briefly introduce the popular deep neural networks and summarize current deep learning achievements in various tasks, such as detection, segmentation, and classification in microscopy image analysis. In particular, we explain the architectures and the principles of convolutional neural networks, fully convolutional networks, recurrent neural networks, stacked autoencoders, and deep belief networks, and interpret their formulations or modelings for specific tasks on various microscopy images. In addition, we discuss the open challenges and the potential trends of future research in microscopy image analysis using deep learning. PMID- 29989995 TI - Home Monitoring of Blood Pressure: Short-Term Changes During Serial Measurements for 56398 Subjects. AB - Hypertension is one of the greatest contributors to premature morbidity and mortality worldwide. It has been demonstrated that lowering blood pressure (BP) by just a few mmHg can bring substantial clinical benefits, reducing the risk of stroke and ischemic heart disease. Properly managing high BP is one of the most pressing global health issues, but accurate methods to continuously monitoring BP at home are still under discussion. Indeed, the BP for any given individual can fluctuate significantly during intervals as short as a few minutes. In clinical settings, the guidelines suggest to wait for 5 or 10 minutes in seated rest before taking the measure, in order to alleviate the effect of the stress induced by the clinical environment. Alternatively, BP measured in the home environment is thought to provide a more accurate measure free of the stress of a clinical environment, but there is currently a lack of extensive studies on the trajectory of serial BP measurements over minutes in the home setting. In this paper, we aim at filling this gap by analyzing a large dataset of more than 16 million BP measurements taken at home with commercial BP monitoring devices. In particular, we propose new techniques to analyze this dataset, taking into account the limitations due to the uncontrolled data collection, and we study the characteristics of the BP trajectory for consecutive measures over several minutes. We show that the BP values significantly decrease after 10 minutes minutes from the initial measurement (4.1 and 6.6 mmHg for the diastolic and systolic BP, respectively), and continue to decrease for about 25 minutes. We also describe statistically the clinical relevance of this change, observing more than 50% misclassifications for measurements in the hypertension region. We then propose a model to study the inter-subject variability, showing significant variations in the expected decrease in systolic BP. These results may provide the initial evidence for future large clinical studies using participant-monitored BP. PMID- 29989996 TI - A Treatment-Response Index From Wearable Sensors for Quantifying Parkinson's Disease Motor States. AB - The goal of this study was to develop an algorithm that automatically quantifies motor states (off, on, dyskinesia) in Parkinson's disease (PD), based on accelerometry during a hand pronation-supination test. Clinician's ratings using the Treatment Response Scale (TRS), ranging from -3 (very Off) to 0 (On) to +3 (very dyskinetic), were used as target. For that purpose, 19 participants with advanced PD and 22 healthy persons were recruited in a single center open label clinical trial in Uppsala, Sweden. The trial consisted of single levodopa dose experiments for the people with PD (PwP), where participants were asked to perform standardized wrist rotation tests, using each hand, before and at prespecified time points after the dose. The participants used wrist sensors containing a three-dimensional accelerometer and gyroscope. Features to quantify the level, variation, and asymmetry of the sensor signals, three-level discrete wavelet transform features, and approximate entropy measures were extracted from the sensors data. At the time of the tests, the PwP were video recorded. Three movement disorder specialists rated the participants' state on the TRS. A Treatment Response Index from Sensors (TRIS) was constructed to quantify the motor states based on the wrist rotation tests. Different machine learning algorithms were evaluated to map the features derived from the sensor data to the ratings provided by the three specialists. Results from cross validation, both in tenfold and a leave-one-individual out setting, showed good predictive power of a support vector machine model and high correlation to the TRS. Values at the end tails of the TRS were under and over predicted due to the lack of observations at those values but the model managed to accurately capture the dose-effect profiles of the patients. In addition, the TRIS had good test-retest reliability on the baseline levels of the PD participants (Intraclass correlation coefficient of 0.83) and reasonable sensitivity to levodopa treatment (0.33 for the TRIS). For a series of test occasions, the proposed algorithms provided dose-effect time profiles for participants with PD, which could be useful during therapy individualization of people suffering from advanced PD. PMID- 29989997 TI - Locally Weighted Fusion of Structural and Attribute Information in Graph Clustering. AB - Attributed graphs have attracted much attention in recent years. Different from conventional graphs, attributed graphs involve two different types of heterogeneous information, i.e., structural information, which represents the links between the nodes, and attribute information on each of the nodes. Clustering on attributed graphs usually requires the fusion of both types of information in order to identify meaningful clusters. However, most of existing works implement the combination of these two types of information in a ''global'' manner by treating all nodes equally and learning a global weight for the information fusion. To address this issue, this paper proposed a novel weighted K means algorithm with ''local'' learning for attributed graph clustering, called adaptive fusion of structural and attribute information (Adapt-SA) and analyzed the convergence property of the algorithm. The key advantage of this model is to automatically balance the structural connections and attribute information of each node to learn a fusion weight, and get densely connected clusters with high attribute semantic similarity. Experimental study of weights on both synthetic and real-world data sets showed that the weights learned by Adapt-SA were reasonable, and they reflected which one of these two types of information was more important to decide the membership of a node. We also compared Adapt-SA with the state-of-the-art algorithms on the real-world networks with varieties of characteristics. The experimental results demonstrated that our method outperformed the other algorithms in partitioning an attributed graph into a community structure or other general structures. PMID- 29989998 TI - Marginalized Denoising Dictionary Learning With Locality Constraint. AB - Learning good representation for images is always a hot topic in machine learning and pattern recognition fields. Among the numerous algorithms, dictionary learning is a well-known strategy for effective feature extraction. Recently, more discriminative sub-dictionaries have been built by Fisher discriminative dictionary learning with specific class labels. Different types of constraints, such as sparsity, low rankness, and locality, are also exploited to make use of global and local information. On the other hand, as the basic building block of deep structure, the auto-encoder has demonstrated its promising performance in extracting new feature representation. To this end, we develop a unified feature learning framework by incorporating the marginalized denoising auto-encoder into a locality-constrained dictionary learning scheme, named marginalized denoising dictionary learning. Overall, we deploy low-rank constraint on each sub dictionary and locality constraint instead of sparsity on coefficients, in order to learn a more concise and pure feature spaces meanwhile inheriting the discrimination from sub-dictionary learning. Finally, we evaluate our algorithm on several face and object data sets. Experimental results have demonstrated the effectiveness and efficiency of our proposed algorithm by comparing with several state-of-the-art methods. PMID- 29989999 TI - Discriminative Multiple Canonical Correlation Analysis for Information Fusion. AB - In this paper, we propose the discriminative multiple canonical correlation analysis (DMCCA) for multimodal information analysis and fusion. DMCCA is capable of extracting more discriminative characteristics from multimodal information representations. Specifically, it finds the projected directions, which simultaneously maximize the within-class correlation and minimize the between class correlation, leading to better utilization of the multimodal information. In the process, we analytically demonstrate that the optimally projected dimension by DMCCA can be quite accurately predicted, leading to both superior performance and substantial reduction in computational cost. We further verify that canonical correlation analysis (CCA), multiple canonical correlation analysis (MCCA) and discriminative canonical correlation analysis (DCCA) are special cases of DMCCA, thus establishing a unified framework for canonical correlation analysis. We implement a prototype of DMCCA to demonstrate its performance in handwritten digit recognition and human emotion recognition. Extensive experiments show that DMCCA outperforms the traditional methods of serial fusion, CCA, MCCA, and DCCA. PMID- 29990000 TI - On Space-Time Filtering Framework for Matching Human Actions Across Different Viewpoints. AB - Space-time template matching is considered as a promising approach for human action recognition. However, a major drawback of template-based methods is computational overhead due to matching in spatial domain. Recently, space-time correlation-based action filters have been proposed for recognizing human actions in frequency domain. These action filters present reduction in time complexity as Fourier transform-based matching is faster than spatial template matching. However, the utility of such action filters is challenged due to a number of factors: 1) inability to deal with view variations due to implicit lack of support for view-invariance; 2) these filters can be trained only for one action class at a time, and separate filters are required for each action class with increased computational overhead; 3) these filters simply take average of similar action instances and behave no better than average filters; and 4) slightly misaligned action data sets create problems as these filters are not shift invariant. In this paper, we try to address these shortcomings by proposing an advanced space-time filtering framework for recognizing human actions despite large viewpoint variations. Rather than using crude intensity values, we use 3D tensor structure at each pixel, which characterizes the most common local motion in action sequences. Discrete tensor Fourier transform is then applied to achieve frequency domain representations. Then, we form view clusters from multiple view action data and use space-time correlation filtering to achieve discriminative view representations. These representations are used in an innovative way to achieve action recognition despite viewpoint variations. Extensive experimentation is performed on well-known multiple view action data sets, including IXMAS, WVU, and N-UCLA action data set. A detailed performance comparison with the existing view-invariant action recognition techniques indicates that our approach works equally well for RGB and RGB-D video data with increased accuracy and efficiency. PMID- 29990001 TI - PhotoRecomposer: Interactive Photo Recomposition by Cropping. AB - We present a visual analysis method for interactively recomposing a large number of photos based on example photos with high-quality composition. The recomposition method is formulated as a matching problem between photos. The key to this formulation is a new metric for accurately measuring the composition distance between photos. We have also developed an earth-mover-distance-based online metric learning algorithm to support the interactive adjustment of the composition distance based on user preferences. To better convey the compositions of a large number of example photos, we have developed a multi-level, example photo layout method to balance multiple factors such as compactness, aspect ratio, composition distance, stability, and overlaps. By introducing an EulerSmooth-based straightening method, the composition of each photos is clearly displayed. The effectiveness and usefulness of the method has been demonstrated by the experimental results, user study, and case studies. PMID- 29990002 TI - Cartogram Visualization for Bivariate Geo-Statistical Data. AB - We describe bivariate cartograms, a technique specifically designed to allow for the simultaneous comparison of two geo-statistical variables. Traditional cartograms are designed to show only a single statistical variable, but in practice, it is often useful to show two variables (e.g., the total sales for two competing companies) simultaneously. We illustrate bivariate cartograms using Dorling-style cartograms, yet the technique is simple and generalizable to other cartogram types, such as contiguous cartograms, rectangular cartograms, and non contiguous cartograms. An interactive feature makes it possible to switch between bivariate cartograms, and the traditional (monovariate) cartograms. Bivariate cartograms make it easy to find more geographic patterns and outliers in a pre attentive way than previous approaches, as shown in Fig. 2 . They are most effective for showing two variables from the same domain (e.g., population in two different years, sales for two different companies), although they can also be used for variables from different domains (e.g., population and income). We also describe a small-scale evaluation of the proposed techniques that indicates bivariate cartograms are especially effective for finding geo-statistical patterns, trends and outliers. PMID- 29990003 TI - Switched latent force models for reverse-engineering transcriptional regulation in gene expression data. AB - To survive environmental conditions, cells transcribe their response activities into encoded mRNA sequences in order to produce certain amounts of protein concentrations. The external conditions are mapped into the cell through the activation of special proteins called transcription factors (TFs). Due to the difficult task to measure experimentally TF behaviours, and the challenges to capture their quick-time dynamics, different types of models based on differential equations have been proposed. However, those approaches usually incur in costly procedures, and they present problems to describe sudden changes in TF regulators. In this paper, we present a switched dynamical latent force model for reverse-engineering transcriptional regulation in gene expression data which allows the exact inference over latent TF activities driving some observed gene expressions through a linear differential equation. To deal with discontinuities in the dynamics, we introduce an approach that switches between different TF activities and different dynamical systems. This creates a versatile representation of transcription networks that can capture discrete changes and non-linearities We evaluate our model on both simulated data and real-data (e.g. microaerobic shift in E. coli, yeast respiration), concluding that our framework allows for the fitting of the expression data while being able to infer continuous-time TF profiles. PMID- 29990004 TI - Protein remote homology detection and fold recognition based on Sequence-Order Frequency Matrix. AB - Protein remote homology detection and fold recognition are two critical tasks for the studies of protein structures and functions. Currently, the profile-based methods achieve the state-of-the-art performance in these fields. However, the widely used sequence profiles, like Position-Specific Frequency Matrix (PSFM) and Position-Specific Scoring Matrix (PSSM), ignore the sequence-order effects along protein sequence. In this study, we have proposed a novel profile, called Sequence-Order Frequency Matrix (SOFM), to extract the sequence-order information of neighboring residues from Multiple Sequence Alignment (MSA). Combined with two profile feature extraction approaches: Top-n-grams and Smith-Waterman algorithm, the SOFMs are applied to protein remote homology detection and fold recognition, and two predictors called SOFM-Top and SOFM-SW are proposed. Experimental results show that SOFM contains more information content than other profiles, and these two predictors outperform other state-of-the-art methods. It is anticipated that SOFM will become a very useful profile in the studies of protein structures and functions. PMID- 29990005 TI - An Integrated Approach for Identification of Functionally Similar MicroRNAs in Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the most prevalent cancers around the globe. However, the molecular reasons for pathogenesis of CRC is still poorly understood. Recently, role of microRNAs or miRNAs in the initiation and progression of CRC has been studied. MicroRNAs are small, endogenous non-coding RNAs found in plants, animals, and some viruses, which function in RNA silencing and post-transcriptional regulation of gene expression. Their role in CRC development is studied and are found to be potential biomarkers in diagnosis and treatment of CRC. Therefore, identification of functionally similar CRC related miRNAs may help in the development of prognostic tool. In this regard, this paper presents a new algorithm, called Sim. It is an integrative approach for identification of functionally similar miRNAs associated with CRC. It integrates judiciously the information of miRNA expression data and miRNA-miRNA functionally synergistic network data. The functional similarity is calculated based on both miRNA expression data and miRNA-miRNA functionally synergistic network data. The effectiveness of the proposed method in comparison to other related methods are shown on four CRC miRNA data sets. The proposed method selected more significant miRNAs related to CRC as compared to other related methods. PMID- 29990006 TI - Combined Seismo- and Gyro-Cardiography: A More Comprehensive Evaluation of Heart Induced Chest Vibrations. AB - This paper reports on the combined analysis of seismocardiogram (SCG) and gyrocardiogram (GCG) recordings. An inertial measurement unit (IMU) consisting of a three-axis micro-electromechanical (MEMS) accelerometer and a three-axis MEMS gyroscope is used to record heart-induced mechanical vibrations from the chest wall of the subjects. An electrocardiogram and an impedance cardiogram (ICG) sensor are also used as references for segmenting the cardiac cycles and recording the aortic valve opening and closure (AO and AC) events, respectively. A simplified model is proposed to explain the mechanical coupling of the chest wall to the IMU. Correlations and time differences are analyzed for the annotation of GCG and its first derivative with respect to ICG and SCG as references. Experimental results indicate a precise identification of systolic points such as the AO and AC events. The left ventricular ejection time and pre ejection period metrics calculated from gyroscope recordings are also shown to accurately track their corresponding trends acquired from ICG signals. Waveform similarity analyses indicate that the first derivative of GCG has a better similarity with SCG than the GCG signal itself. Experimental results also suggest that interdevice differences in GCG recordings would need to be addressed before this technology can gain widespread application. PMID- 29990007 TI - Comparison of Machine Learning Approaches Toward Assessing the Risk of Developing Cardiovascular Disease as a Long-Term Diabetes Complication. AB - The estimation of long-term diabetes complications risk is essential in the process of medical decision making. Guidelines for the management of Type 2 Diabetes Mellitus (T2DM) advocate calculating the Cardiovascular Disease (CVD) risk to initiate appropriate treatment. The objective of this study is to investigate the use of sophisticated machine learning techniques toward the development of personalized models able to predict the risk of fatal or nonfatal CVD incidence in T2DM patients. The important challenge of handling the unbalanced nature of the available dataset is addressed by applying novel ensemble strategies. Hybrid Wavelet Neural Networks (HWNNs) and Self-Organizing Maps (SOMs) constitute the primary models for building ensembles following a subsampling approach. Different methods for combining the decisions of the primary models are applied and comparatively assessed. Data from the 5-year follow up of 560 patients with T2DM are used for development and evaluation purposes. The highest discrimination performance (Area Under the Curve (AUC): 71.48%) is achieved by taking into account both the HWNN- and SOM- based primary models' outputs. The proposed method is superior to the Binomial Linear Regression (BLR) model justifying the need to apply more sophisticated techniques in order to produce reliable CVD risk scores. PMID- 29990008 TI - Carotid Arterial Pulse Waveform Measurements Using Fiber Bragg Grating Pulse Probe. AB - Arterial pulse is an established source of information for the clinical assessment of cardiovascular health. The central aortic pressure is known to be a better predictor of cardiovascular status than the peripheral pressure. The carotid arterial pulse is considered to be the best indicator of the central aortic pressure. The present work deals with the development of a novel noninvasive probe based on fiber Bragg grating (FBG) sensor for the real-time acquisition of the pulse waveform in the carotid arterial site. The fiber Bragg grating pulse probe (FBGPP) developed is used to obtain the carotid arterial pulse waveform (CAPW) of individual subjects, in the form of beat-to-beat carotid pulse. The FBGPP developed comprises of an elastic rubber diaphragm that comes into contact with the skin below, which the carotid artery is pulsating, creating strain variations over it. Effectively, the carotid arterial pulse is tranduced into the strain variations over a rubber diaphragm, which is acquired by the FBG sensor bonded over it. The FBGPP is designed such that the positioning and the access for the device to the carotid arterial site can be carried out with ease. Furthermore, the recorded CAPW is subjected to the pulse wave analysis in order to evaluate vital cardiovascular parameters like heart rate, left ventricular ejection time, carotid augmentation index, and ejection duration index, which are indicators of the cardiac health of the subject and the performance of the heart. Also, the linearity between these cardiovascular parameters is explored for a sample size of 55. PMID- 29990010 TI - Revisiting Superquadric Fitting: A numerically stable formulation. AB - Superquadric surfaces play an important role in many different research fields due to their ability to model a variety of shapes with a small number of parameters. One of their core applications is the estimation of object shape characteristics from a set of discrete samples from the surface of an object. However, the corresponding optimization problem is prone to numerical instabilities in some regions of the parameter space. To mitigate this problem, lower bound constraints to the shape parameters are applied during the optimization thus limiting the range of shapes which can be accurately represented by superquadrics. Therefore, the exact modeling of very common shapes like cuboids and cylinders is error-prone in practice. In this article we investigate this problem and provide a numerically stable formulation for the evaluation of the superquadric surface function and for its gradient. This new formulation enables numerically stable fitting of superquadrics in the previously constrained region, i.e., in its full range including cuboids and cylinders. In addition, the new formulation also leads to faster convergence speed. The theoretical contributions are substantiated by experiments on synthetic as well as real data. PMID- 29990011 TI - Multi-Scale Deep Reinforcement Learning for Real-Time 3D-Landmark Detection in CT Scans. AB - Robust and fast detection of anatomical structures is a prerequisite for medical image analysis. Current solutions for anatomy detection are typically based on machine learning and are subject to several limitations, including the use of suboptimal feature engineering techniques and most importantly the use of computationally suboptimal search-schemes. To address these issues, we propose a method that follows a new paradigm by reformulating the detection problem as a behavior learning task for an artificial agent. We couple the modeling of the anatomy appearance and the object search in a unified behavioral framework, using the capabilities of deep reinforcement learning and multi-scale image analysis. In other words, an artificial agent is trained not only to distinguish the target anatomical object from the rest of the body but also how to find the object by learning and following an optimal navigation path to the target object in the imaged volumetric space. We evaluate our approach on 1487 3D-CT volumes from 532 patients and show that we significantly outperform state-of-the-art solutions on detecting several anatomical structures with no failed cases, while also improving the detection accuracy by 20-30%. Most importantly, we improve the detection-speed of the reference methods by 2-3 orders of magnitude, achieving unmatched real-time performance on large 3D-CT scans. PMID- 29990012 TI - Panoptic Studio: A Massively Multiview System for Social Interaction Capture. AB - We present an approach to capture the 3D motion of a group of people engaged in a social interaction, where inter-occlusions are frequent and functional. The Panoptic Studio is a system organized around the thesis that social interactions should be measured through the integration of perceptual analyses over a large variety of viewpoints. We present a modularized system designed around this principle, consisting of integrated structural, hardware, and software innovations. The system takes, as input, 480 synchronized video streams of multiple people engaged in social activities, and produces, as output, the labeled time-varying 3D structure of anatomical landmarks on individuals in the space. Our algorithm is designed to fuse the "weak" perceptual processes in the large number of views by progressively generating skeletal proposals from low level appearance cues, and a framework for temporal refinement is also presented by associating body parts to reconstructed dense 3D trajectory stream. Our system and method are the first in reconstructing full body motion of more than five people engaged in social interactions without using markers. We also empirically demonstrate the impact of the number of views in achieving this goal. PMID- 29990013 TI - From Images to 3D Shape Attributes. AB - Our goal in this paper is to investigate properties of 3D shape that can be determined from a single image. We define 3D shape attributes -- generic properties of the shape that capture curvature, contact and occupied space. Our first objective is to infer these 3D shape attributes from a single image. A second objective is to infer a 3D shape embedding -- a low dimensional vector representing the 3D shape. PMID- 29990014 TI - Tracking Gaze and Visual Focus of Attention of People Involved in Social Interaction. AB - The visual focus of attention (VFOA) has been recognized as a prominent conversational cue. We are interested in estimating and tracking the VFOAs associated with multi-party social interactions. We note that in this type of situations the participants either look at each other or at an object of interest; therefore their eyes are not always visible. Consequently both gaze and VFOA estimation cannot be based on eye detection and tracking. We propose a method that exploits the correlation between eye gaze and head movements. Both VFOA and gaze are modeled as latent variables in a Bayesian switching state-space model (also referred switching Kalman filter). The proposed formulation leads to a tractable learning method and to an efficient online inference procedure that simultaneously tracks gaze and visual focus. The method is tested and benchmarked using two publicly available datasets, Vernissage and LAEO, that contain typical multi-party human-robot and human-human interactions. PMID- 29990015 TI - TV: A Sparse Optimization Method for Impulse Noise Image Restoration. AB - Total Variation (TV) is an effective and popular prior model in the field of regularization-based image processing. This paper focuses on total variation for removing impulse noise in image restoration. This type of noise frequently arises in data acquisition and transmission due to many reasons, e.g. a faulty sensor or analog-to-digital converter errors. Removing this noise is an important task in image restoration. State-of-the-art methods such as Adaptive Outlier Pursuit(AOP), which is based on TV with -norm data fidelity, only give sub optimal performance. In this paper, we propose a new sparse optimization method, called TV-PADMM, which solves the TV-based restoration problem with -norm data fidelity. To effectively deal with the resulting non-convex non-smooth optimization problem, we first reformulate it as an equivalent biconvex Mathematical Program with Equilibrium Constraints (MPEC), and then solve it using a proximal Alternating Direction Method of Multipliers (PADMM). Our TV-PADMM method finds a desirable solution to the original -norm optimization problem and is proven to be convergent under mild conditions. We apply TV-PADMM to the problems of image denoising and deblurring in the presence of impulse noise. Our extensive experiments demonstrate that TV-PADMM outperforms state-of-the-art image restoration methods. PMID- 29990016 TI - Disentangling the Modes of Variation in Unlabelled Data. AB - Statistical methods are of paramount importance in discovering the modes of variation in visual data. The Principal Component Analysis (PCA) is probably the most prominent method for extracting a single mode of variation in the data. However, in practice, several factors contribute to the appearance of visual objects including pose, illumination, and deformation, to mention a few. To extract these modes of variations from visual data, several supervised methods, such as the TensorFaces relying on multilinear (tensor) decomposition have been developed. The main drawbacks of such methods is that they require both labels regarding the modes of variations and the same number of samples under all modes of variations (e.g., the same face under different expressions, poses etc.). Therefore, their applicability is limited to well-organised data, usually captured in well-controlled conditions. In this paper, we propose a novel general multilinear matrix decomposition method that discovers the multilinear structure of possibly incomplete sets of visual data in unsupervised setting (i.e., without the presence of labels). We also propose extensions of the method with sparsity and low-rank constraints in order to handle noisy data, captured in unconstrained conditions. Besides that, a graph-regularised variant of the method is also developed in order to exploit available geometric or label information for some modes of variations. We demonstrate the applicability of the proposed method in several computer vision tasks, including Shape from Shading (SfS) (in the wild and with occlusion removal), expression transfer, and estimation of surface normals from images captured in the wild. PMID- 29990018 TI - Support-Free Hollowing. AB - Offsetting-based hollowing is a solid modeling operation widely used in 3D printing, which can change the model's physical properties and reduce the weight by generating voids inside a model. However, a hollowing operation can lead to additional supporting structures for fabrication in interior voids, which cannot be removed. As a consequence, the result of a hollowing operation is affected by these additional supporting structures when applying the operation to optimize physical properties of different models. This paper proposes a support-free hollowing framework to overcome the difficulty of fabricating voids inside a solid. The challenge of computing a support-free hollowing is decomposed into a sequence of shape optimization steps, which are repeatedly applied to interior mesh surfaces. The optimization of physical properties in different applications can be easily integrated into our framework. Comparing to prior approaches that can generate support-free inner structures, our hollowing operation can reduce more volume of material and thus provide a larger solution space for physical optimization. Experimental tests are taken on a number of 3D models to demonstrate the effectiveness of this framework. PMID- 29990017 TI - Fast and Accurate Detection of Complex Imaging Genetics Associations Based on Greedy Projected Distance Correlation. AB - Recent advances in imaging genetics produce large amounts of data including functional MRI images, single nucleotide polymorphisms (SNPs), and cognitive assessments. Understanding the complex interactions among these heterogeneous and complementary data has the potential to help with diagnosis and prevention of mental disorders. However, limited efforts have been made due to the high dimensionality, group structure, and mixed type of these data. In this paper we present a novel method to detect conditional associations between imaging genetics data. We use projected distance correlation to build a conditional dependency graph among high-dimensional mixed data, then use multiple testing to detect significant group level associations (e.g., ROI-gene). In addition, we introduce a scalable algorithm based on orthogonal greedy algorithm, yielding the greedy projected distance correlation (G-PDC). This can reduce the computational cost, which is critical for analyzing large-volume of imaging genomics data. The results from our simulations demonstrate a higher degree of accuracy with GPDC than distance correlation, Pearson's correlation and partial correlation, especially when the correlation is nonlinear. Finally, we apply our method to the Philadelphia Neurodevelopmental data cohort with 866 samples including fMRI images and SNP profiles. The results uncover several statistically significant and biologically interesting interactions, which are further validated with many existing studies. The Matlab code is available at https://sites.google.com/site/jianfang86/gPDC. PMID- 29990019 TI - Physics-Based Quadratic Deformation Using Elastic Weighting. AB - This paper presents a spatial reduction framework for simulating nonlinear deformable objects interactively. This reduced model is built using a small number of overlapping quadratic domains as we notice that incorporating high order degrees of freedom (DOFs) is important for the simulation quality. Departing from existing multi-domain methods in graphics, our method interprets deformed shapes as blended quadratic transformations from nearby domains. Doing so avoids expensive safeguards against the domain coupling and improves the numerical robustness under large deformations. We present an algorithm that efficiently computes weight functions for reduced DOFs in a physics-aware manner. Inspired by the well-known multi-weight enveloping technique, our framework also allows subspace tweaking based on a few representative deformation poses. Such elastic weighting mechanism significantly extends the expressivity of the reduced model with light-weight computational efforts. Our simulator is versatile and can be well interfaced with many existing techniques. It also supports local DOF adaption to incorporate novel deformations (i.e., induced by the collision). The proposed algorithm complements state-of-the-art model reduction and domain decomposition methods by seeking for good trade-offs among animation quality, numerical robustness, pre-computation complexity, and simulation efficiency from an alternative perspective. PMID- 29990020 TI - Bayesian Network Construction and Genotype-Phenotype Inference Using GWAS Statistics. AB - Genome-wide association studies (GWASs) have received an increasing attention to understand how genetic variation affects different human traits. In this paper, we study whether and to what extend exploiting the GWAS statistics can be used for inferring private information about a human individual. We first provide a method to construct a three-layered Bayesian network explicitly revealing the conditional dependency between single-nucleotide polymorphisms (SNPs) and traits from public GWAS catalog. The key challenge in building a Bayesian network from GWAS statistics is the specification of the conditional probability table of a variable with multiple parent variables. We employ the models of independence of causal influences which assume that the causal mechanism of each parent variable is mutually independent. We then formulate three inference problems based on the dependency relationship captured in the Bayesian network, namely trait inference given SNP genotype, genotype inference given trait, and trait inference given known traits, and develop efficient formulas and algorithms. Different from previous work, the possible target of these inference problems we study may be any individual, not limited to GWAS participants. Empirical evaluations show the effectiveness of our proposed methods. In summary, our work implies that meaningful information can be inferred from modeling GWAS statistics, and appropriate privacy protection mechanisms need to be developed to protect genetic privacy not only of GWAS participants but also regular individuals. PMID- 29990021 TI - Incremental Design of Simplex Basis Function Model for Dynamic System Identification. AB - In this paper, we propose a novel adaptive piecewise linear model for dynamic system identification. It has four unique features. First, the model designs a new kind of basis function for function approximation. It maintains the uniform shape for each basis function, so as to achieve a satisfactory tradeoff between generalization ability and model complexity. Second, the model takes the structure of basis functions as decision variables to optimize the formulated identification problems instead of taking expansion coefficients as decision variables as proposed by many existing approaches. Third, we establish an incremental design strategy to solve the system identification problems. In each step of the identification, the selection of optimal basis function is a Lipschitz continuous optimization problem that is likely to be easily handled with some mature toolboxes. This incremental design strategy greatly reduces the estimation cost. Fourth, we introduce a smoothing mechanism to avoid overfitting, when the output of dynamic systems is disturbed by noise. Tests on several benchmark dynamic systems demonstrate the potential of the proposed model. PMID- 29990022 TI - Predicting High-Cost Patients at Point of Admission Using Network Science. AB - Data mining models for high-cost patient encounter prediction at the point-of admission (HPEPP) in inpatient wards are scarce in the literature. This is due to the lack of availability of relevant features at such an early stage of treatment. In this study, we create a disease co-occurrence network (DCN) using a subset of the state inpatient database of Arizona. We explore this network for community formation and structural properties to create new input features for HPEPP models. Tree-based data mining models are trained using input feature sets including these new network features, and distinct disease communities in the DCN are identified. We propose community membership and high-cost propensity scores as two network-based features for HPEPP modeling. We compare the performance of models with different input feature sets and find that the new features significantly improve the accuracy sensitivity and specificity of prediction models. This model has the potential to improve targeted care management and reduce health care expenditure. PMID- 29990023 TI - Particle Filtering and Sensor Fusion for Robust Heart Rate Monitoring Using Wearable Sensors. AB - This paper describes a novel methodology leveraging particle filters for the application of robust heart rate monitoring in the presence of motion artifacts. Motion is a key source of noise that confounds traditional heart rate estimation algorithms for wearable sensors due to the introduction of spurious artifacts in the signals. In contrast to previous particle filtering approaches, we formulate the heart rate itself as the only state to be estimated, and do not rely on multiple specific signal features. Instead, we design observation mechanisms to leverage the known steady, consistent nature of heart rate variations to meet the objective of continuous monitoring of heart rate using wearable sensors. Furthermore, this independence from specific signal features also allows us to fuse information from multiple sensors and signal modalities to further improve estimation accuracy. The signal processing methods described in this work were tested on real motion artifact affected electrocardiogram and photoplethysmogram data with concurrent accelerometer readings. Results show promising average error rates less than 2 beats/min for data collected during intense running activities. Furthermore, a comparison with contemporary signal processing techniques for the same objective shows how the proposed implementation is also computationally more efficient for comparable performance. PMID- 29990024 TI - Weighted-Cumulated S-EMG Muscle Fatigue Estimator. AB - This paper addresses a new approach to objectively evaluate muscle fatigue in isometric and dynamic physical exertions using surface electromyography (S-EMG). The emphasis of this proposal is to preserve the spectral signature of the muscle fatigue phenomenon while reducing the spatial effects of electrode localization, and decreasing the disparity of results obtained by the same experimental protocol at different times. A cumulated and normalized modeling was sought to make evident the nonstationary characteristics of muscle fatigue that is gradually identified with its inertia and intensity. A metric involving the proposal of temporal, frequency, and time-frequency weighted-cumulated indicators is presented. Results based on real signals are shown for isometric and dynamic experimental protocols. Performance comparison of the various proposed weighted cumulated indexes is shown and discussed. The presented approach for the objective cumulative evaluation of muscle fatigue with S-EMG signals has shown to be promising. PMID- 29990025 TI - Full Impedance Cardiography measurement device using Raspberry PI3 and System-on Chip biomedical Instrumentation Solutions. AB - Impedance Cardiography (ICG) is a non-invasive method for monitoring cardiac dynamics using Electrical Bioimpedance (EBI) measurements. Since its appearance more than 40 years ago, ICG has been used for assessing hemodynamic parameters. This paper present a measurement system based on two System on Chip (SoC) solutions and Raspberry PI, implementing both a full 3-lead ECG recorder and an impedance cardiographer, for educational and research development purposes. Raspberry PI is a platform supporting Do-It-Yourself project and education applications across the world. The development is part of Biosignal PI, an open hardware platform focusing in quick prototyping of physiological measurement instrumentation. The SoC used for sensing cardiac biopotential is the ADAS1000, and for the EBI measurement is the AD5933. The recording were wirelessly transmitted through Bluetooth to a PC, where the waveforms were displayed, and hemodynamic parameters such as heart rate, stroke volume, ejection time and cardiac output were extracted from the ICG and ECG recordings. These results show how Raspberry PI can be used for quick prototyping using relatively widely available and affordable components, for supporting developers in research and engineering education. The design and development documents, will be available on www.BiosignalPI.com, for open access under a Non Commercial-Share A like 4.0 International License. PMID- 29990026 TI - Breathing Rate Estimation From the Electrocardiogram and Photoplethysmogram: A Review. AB - Breathing rate (BR) is a key physiological parameter used in a range of clinical settings. Despite its diagnostic and prognostic value, it is still widely measured by counting breaths manually. A plethora of algorithms have been proposed to estimate BR from the electrocardiogram (ECG) and pulse oximetry (photoplethysmogram, PPG) signals. These BR algorithms provide opportunity for automated, electronic, and unobtrusive measurement of BR in both healthcare and fitness monitoring. This paper presents a review of the literature on BR estimation from the ECG and PPG. First, the structure of BR algorithms and the mathematical techniques used at each stage are described. Second, the experimental methodologies that have been used to assess the performance of BR algorithms are reviewed, and a methodological framework for the assessment of BR algorithms is presented. Third, we outline the most pressing directions for future research, including the steps required to use BR algorithms in wearable sensors, remote video monitoring, and clinical practice. PMID- 29990027 TI - A Distance-Based Weighted Undersampling Scheme for Support Vector Machines and its Application to Imbalanced Classification. AB - A support vector machine (SVM) plays a prominent role in classic machine learning, especially classification and regression. Through its structural risk minimization, it has enjoyed a good reputation in effectively reducing overfitting, avoiding dimensional disaster, and not falling into local minima. Nevertheless, existing SVMs do not perform well when facing class imbalance and large-scale samples. Undersampling is a plausible alternative to solve imbalanced problems in some way, but suffers from soaring computational complexity and reduced accuracy because of its enormous iterations and random sampling process. To improve their classification performance in dealing with data imbalance problems, this work proposes a weighted undersampling (WU) scheme for SVM based on space geometry distance, and thus produces an improved algorithm named WU-SVM. In WU-SVM, majority samples are grouped into some subregions (SRs) and assigned different weights according to their Euclidean distance to the hyper plane. The samples in an SR with higher weight have more chance to be sampled and put to use in each learning iteration, so as to retain the data distribution information of original data sets as much as possible. Comprehensive experiments are performed to test WU-SVM via 21 binary-class and six multiclass publically available data sets. The results show that it well outperforms the state-of-the-art methods in terms of three popular metrics for imbalanced classification, i.e., area under the curve, F-Measure, and G-Mean. PMID- 29990028 TI - Symmetric Predictive Estimator for Biologically Plausible Neural Learning. AB - In a real brain, the act of perception is a bidirectional process, depending on both feedforward sensory pathways and feedback pathways that carry expectations. We are interested in how such a neural network might emerge from a biologically plausible learning rule. Other neural network learning methods either only apply to feedforward networks, or employ assumptions (such as weight copying) that render them unlikely in a real brain. Predictive estimators (PEs) offer a better solution to this bidirectional learning scenario. However, PEs also depend on weight copying. In this paper, we propose the symmetric PE (SPE), an architecture that can learn both feedforward and feedback connection weights individually using only locally available information. We demonstrate that the SPE can learn complicated mappings without the use of weight copying. The SPE networks also show promise in deeper architectures. PMID- 29990029 TI - Learning With Coefficient-Based Regularized Regression on Markov Resampling. AB - Big data research has become a globally hot topic in recent years. One of the core problems in big data learning is how to extract effective information from the huge data. In this paper, we propose a Markov resampling algorithm to draw useful samples for handling coefficient-based regularized regression (CBRR) problem. The proposed Markov resampling algorithm is a selective sampling method, which can automatically select uniformly ergodic Markov chain (u.e.M.c.) samples according to transition probabilities. Based on u.e.M.c. samples, we analyze the theoretical performance of CBRR algorithm and generalize the existing results on independent and identically distributed observations. To be specific, when the kernel is infinitely differentiable, the learning rate depending on the sample size $m$ can be arbitrarily close to $?mathcal {O}(m^{-1})$ under a mild regularity condition on the regression function. The good generalization ability of the proposed method is validated by experiments on simulated and real data sets. PMID- 29990030 TI - Object Categorization Using Class-Specific Representations. AB - Object categorization refers to the task of automatically classifying objects based on the visual content. Existing approaches simply represent each image with the visual features without considering the specific characters of images within the same class. However, objects of the same class may exhibit unique characters, which should be represented accordingly. In this brief, we propose a novel class specific representation strategy for object categorization. For each class, we first model the characters of images within the same class using Gaussian mixture model (GMM). We then represent each image by calculating the Euclidean distance and relative Euclidean distance between the image and the GMM model for each class. We concatenate the representations of each class for joint representation. In this way, we can represent an image by not only considering the visual contents but also combining the class-specific characters. Experiments on several public available data sets validate the superiority of the proposed class specific representation method over well-established algorithms for object category predictions. PMID- 29990031 TI - Ultrasound-Based Sensing Models for Finger Motion Classification. AB - Motions of the fingers are complex since hand grasping and manipulation are conducted by spatial and temporal coordination of forearm muscles and tendons. The dominant methods based on surface electromyography (sEMG) could not offer satisfactory solutions for finger motion classification due to its inherent nature of measuring the electrical activity of motor units at the skin's surface. In order to recognize morphological changes of forearm muscles for accurate hand motion prediction, ultrasound imaging is employed to investigate the feasibility of detecting mechanical deformation of deep muscle compartments in potential clinical applications. In this study, finger motion classification has been represented as subproblems: recognizing the discrete finger motions and predicting the continuous finger angles. Predefined 14 finger motions are presented in both sEMG signals and ultrasound images and captured simultaneously. Linear discriminant analysis classifier shows the ultrasound has better average accuracy (95.88%) than the sEMG (90.14%). On the other hand, the study of predicting the metacarpophalangeal (MCP) joint angle of each finger in nonperiod movements also confirms that classification method based on ultrasound achieves better results (average correlation 0.89 $?pm$ 0.07 and NRMSE 0.15 $?pm$ 0.05) than sEMG (0.81 $?pm$ 0.09 and 0.19 $?pm$ 0.05). The research outcomes evidently demonstrate that the ultrasound can be a feasible solution for muscle-driven machine interface, such as accurate finger motion control of prostheses and wearable robotic devices. PMID- 29990032 TI - Video Saliency Detection Using Object Proposals. AB - In this paper, we introduce a novel approach to identify salient object regions in videos via object proposals. The core idea is to solve the saliency detection problem by ranking and selecting the salient proposals based on object-level saliency cues. Object proposals offer a more complete and high-level representation, which naturally caters to the needs of salient object detection. As well as introducing this novel solution for video salient object detection, we reorganize various discriminative saliency cues and traditional saliency assumptions on object proposals. With object candidates, a proposal ranking and voting scheme, based on various object-level saliency cues, is designed to screen out nonsalient parts, select salient object regions, and to infer an initial saliency estimate. Then a saliency optimization process that considers temporal consistency and appearance differences between salient and nonsalient regions is used to refine the initial saliency estimates. Our experiments on public datasets (SegTrackV2, Freiburg-Berkeley Motion Segmentation Dataset, and Densely Annotated Video Segmentation) validate the effectiveness, and the proposed method produces significant improvements over state-of-the-art algorithms. PMID- 29990033 TI - Real-Time Multimedia Social Event Detection in Microblog. AB - Detecting events from massive social media data in social networks can facilitate browsing, search, and monitoring of real-time events by corporations, governments, and users. The short, conversational, heterogeneous, and real-time characteristics of social media data bring great challenges for event detection. The existing event detection approaches rely mainly on textual information, while the visual content of microblogs and the intrinsic correlation among the heterogeneous data are scarcely explored. To deal with the above challenges, we propose a novel real-time event detection method by generating an intermediate semantic level from social multimedia data, named microblog clique (MC), which is able to explore the high correlations among different microblogs. Specifically, the proposed method comprises three stages. First, the heterogeneous data in microblogs is formulated in a hypergraph structure. Hypergraph cut is conducted to group the highly correlated microblogs with the same topics as the MCs, which can address the information inadequateness and data sparseness issues. Second, a bipartite graph is constructed based on the generated MCs and the transfer cut partition is performed to detect the events. Finally, for new incoming microblogs, incremental hypergraph is constructed based on the latest MCs to generate new MCs, which are classified by bipartite graph partition into existing events or new ones. Extensive experiments are conducted on the events in the Brand-Social-Net dataset and the results demonstrate the superiority of the proposed method, as compared to the state-of-the-art approaches. PMID- 29990034 TI - An Efficient Second-Order Algorithm for Self-Organizing Fuzzy Neural Networks. AB - Intelligent computing technologies are useful and important for online data modeling, where system dynamics may be nonstationary with some uncertainties. In this paper, an efficient learning mechanism is developed for building self organizing fuzzy neural networks (SOFNNs), where a second-order algorithm (SOA) with adaptive learning rate is employed, the network size and the parameters can be determined simultaneously in the learning process. First, all parameters of SOFNN are adjusted by using the SOA strategy to achieve fast convergence through a powerful search scheme. Second, the structure of SOFNN can be self-organized using the relative importance index of each rule. The fuzzy rules used in SOFNN with SOA (SOA-SOFNN) are generated or pruned automatically to reduce the computational complexity and potentially improve the generalization power. Finally, a theoretical analysis on the learning convergence of the proposed SOA SOFNN is given to show the computational efficiency. To demonstrate the merits of our proposed approach for data modeling, several benchmark datasets, and a real world application associated with nonlinear systems modeling problems are examined with comparisons against other existing methods. The results indicate that our proposed SOA-SOFNN performs favorably in terms of both learning speed and prediction accuracy for online data modeling. PMID- 29990035 TI - The Atlas Structure of Images. AB - Many operations of vision require image regions to be isolated and inter-related. This is challenging when they are different in detail and extent. Practical methods of Computer Vision approach this through the tools of downsampling, pyramids, cropping and patches. In this paper we develop an ideal geometric structure for this, compatible with the existing scale space model of image measurement. Its elements are apertures which view the image like fuzzy-edged portholes of frosted glass. We establish containment and cause/effect relations between apertures, and show that these link them into cross-scale atlases. Atlases formed of Gaussian apertures are shown to be a continuous version of the image pyramid used in Computer Vision, and allow various types of image description to naturally be expressed within their framework. We show that views through Gaussian apertures are approximately equivalent to the jets of derivative of Gaussian filter responses that form part of standard Scale Space theory. This supports a view of the simple cells of mammalian V1 as implementing a system of local views of the retinal image of varying extent and resolution. As a worked example we develop a keypoint descriptor scheme that outperforms previous schemes that do not make use of learning. PMID- 29990036 TI - Recovering Joint and Individual Components in Facial Data. AB - A set of images depicting faces with different expressions or in various ages consists of components that are shared across all images (i.e., joint components) imparting to the depicted object the properties of human faces as well as individual components that are related to different expressions or age groups. Discovering the common (joint) and individual components in facial images is crucial for applications such as facial expression transfer and age progression. The problem is rather challenging when dealing with images captured in unconstrained conditions in the presence of sparse non-Gaussian errors of large magnitude (i.e., sparse gross errors or outliers) and contain missing data. In this paper, we investigate the use of a method recently introduced in statistics, the so-called Joint and Individual Variance Explained (JIVE) method, for the robust recovery of joint and individual components in visual facial data consisting of an arbitrary number of views. Since the JIVE is not robust to sparse gross errors, we propose alternatives, which are (1) robust to sparse gross, non-Gaussian noise, (2) able to automatically find the individual components rank, and (3) can handle missing data. We demonstrate the effectiveness of the proposed methods to several computer vision applications, namely facial expression synthesis and 2D and 3D face age progression 'in-the wild'. PMID- 29990037 TI - Head and Body Orientation Estimation Using Convolutional Random Projection Forests. AB - In this paper, we consider the problem of estimating the head pose and body orientation of a person from a low-resolution image. Under this setting, it is difficult to reliably extract facial features or detect body parts. We propose a convolutional random projection forest (CRPforest) algorithm for these tasks. A convolutional random projection network (CRPnet) is used at each node of the forest. It maps an input image to a high-dimensional feature space using a rich filter bank. The filter bank is designed to generate sparse responses so that they can be efficiently computed by compressive sensing. A sparse random projection matrix can capture most essential information contained in the filter bank without using all the filters in it. Therefore, the CRPnet is fast, e.g., it requires to process an image of pixels, due to the small number of convolutions (e.g., 0.01% of a layer of a neural network) at the expense of less than 2% accuracy. The overall forest estimates head and body pose well on benchmark datasets, e.g., over 98% on the HIIT dataset, while requiring at without using a GPU. Extensive experiments on challenging datasets show that the proposed algorithm performs favorably against the state-of-the-art methods in low resolution images. PMID- 29990038 TI - CROification: Accurate Kernel Classification with the Efficiency of Sparse Linear SVM. AB - Kernel methods have been shown to be effective for many machine learning tasks such as classification and regression. In particular, support vector machines with the Gaussian kernel have proved to be powerful classification tools. The standard way to apply kernel methods is to use the kernel trick, where the inner product of the vectors in the feature space is computed via the kernel function. Using the kernel trick for SVMs, however, leads to training that is quadratic in the number of input vectors and classification that is linear with the number of support vectors. PMID- 29990039 TI - Probabilistic Dimensionality Reduction via Structure Learning. AB - We propose an alternative probabilistic dimensionality reduction framework that can naturally integrate the generative model and the locality information of data. Based on this framework, we present a new model, which is able to learn a set of embedding points in a low-dimensional space by retaining the inherent structure from high-dimensional data. The objective function of this new model can be equivalently interpreted as two coupled learning problem, i.e., structure learning and the learning of projection matrix. Inspired by this interesting interpretation, we propose another model, which finds a set of embedding points that can directly form an explicit graph structure. We proved that the model by learning explicit graphs generalizes the reversed graph embedding method, but leads to a natural interpretation from Bayesian perspective. This can greatly facilitate data visualization and scientific discovery in downstream analysis. Extensive experiments are performed that demonstrate that the proposed framework is able to retain the inherent structure of datasets and achieve competitive quantitative results in terms of various performance evaluation criteria. PMID- 29990041 TI - Robust Virtual Unrolling of Historical Parchment XMT Images. AB - We develop a framework to virtually unroll fragile historical parchment scrolls, which cannot be physically unfolded via a sequence of X-ray tomographic slices, thus providing easy access to those parchments whose contents have remained hidden for centuries. The first step is to produce a topologically correct segmentation, which is challenging as the parchment layers vary significantly in thickness, contain substantial interior textures and can often stick together in places. For this purpose, our method starts with linking the broken layers in a slice using the topological structure propagated from its previous processed slice. To ensure topological correctness, we identify fused regions by detecting junction sections, and then match them using global optimization efficiently solved by the blossom algorithm, taking into account the shape energy of curves separating fused layers. The fused layers are then separated using as-parallel-as possible curves connecting junction section pairs. To flatten the segmented parchment, pixels in different frames need to be put into alignment. This is achieved via a dynamic programming-based global optimization, which minimizes the total matching distances and penalizes stretches. Eventually, the text of the parchment is revealed by ink projection. We demonstrate the effectiveness of our approach using challenging real-world data sets, including the water damaged fifteenth century Bressingham scroll. PMID- 29990043 TI - Multi-Material Volume Rendering with a Physically-Based Surface Reflection Model. AB - Rendering techniques that increase realism in volume visualization help enhance perception of the 3D features in the volume data. While techniques focusing on high-quality global illumination have been extensively studied, few works handle the interaction of light with materials in the volume. Existing techniques for light-material interaction are limited in their ability to handle high-frequency real-world material data, and the current treatment of volume data poorly supports the correct integration of surface materials. In this paper, we introduce an alternative definition for the transfer function which supports surface-like behavior at the boundaries between volume components and volume-like behavior within. We show that this definition enables multi-material rendering with high-quality, real-world material data. We also show that this approach offers an efficient alternative to pre-integrated rendering through isosurface techniques. We introduce arbitrary spatially-varying materials to achieve better multi-material support for scanned volume data. Finally, we show that it is possible to map an arbitrary set of parameters directly to a material representation for the more intuitive creation of novel materials. PMID- 29990042 TI - Chunked Bounding Volume Hierarchies for Fast Digital Prototyping Using Volumetric Meshes. AB - We present a novel approach to using Bounding Volume Hierarchies (BVHs) for collision detection of volumetric meshes for digital prototyping based on accurate simulation. In general, volumetric meshes contain more primitives than surface meshes, which in turn means larger BVHs. To manage these larger BVHs, we propose an algorithm for splitting meshes into smaller chunks with a limited-size BVH each. Limited-height BVHs make guided, all-pairs testing of two chunked meshes well-suited for GPU implementation. This is because the dynamically generated work during BVH traversal becomes bounded. Chunking is simple to implement compared to dynamic load balancing methods and can result in an overall two orders of magnitude speedup on GPUs. This indicates that dynamic load balancing may not be a well suited scheme for the GPU. The overall application timings showed that data transfers were not the bottleneck. Instead, the conversion to and from OpenCL friendly data structures was causing serious performance impediments. Still, a simple OpenMP acceleration of the conversion allowed the GPU solution to beat the CPU solution by 20 percent. We demonstrate our results using rigid and deformable body scenes of varying complexities on a variety of GPUs. PMID- 29990044 TI - ATOM: A Grammar for Unit Visualizations. AB - Unit visualizations are a family of visualizations where every data item is represented by a unique visual mark-a visual unit-during visual encoding. For certain datasets and tasks, unit visualizations can provide more information, better match the user's mental model, and enable novel interactions compared to traditional aggregated visualizations. Current visualization grammars cannot fully describe the unit visualization family. In this paper, we characterize the design space of unit visualizations to derive a grammar that can express them. The resulting grammar is called ATOM, and is based on passing data through a series of layout operations that divide the output of previous operations recursively until the size and position of every data point can be determined. We evaluate the expressive power of the grammar by both using it to describe existing unit visualizations, as well as to suggest new unit visualizations. PMID- 29990045 TI - Chemical Transformation Motifs --- Modelling Pathways as Integer Hyperflows. AB - We present an elaborate framework for formally modelling pathways in chemical reaction networks on a mechanistic level. Networks are modelled mathematically as directed multi-hypergraphs, with vertices corresponding to molecules and hyperedges to reactions. Pathways are modelled as integer hyperflows and we expand the network model by detailed routing constraints. In contrast to the more traditional approaches like Flux Balance Analysis or Elementary Mode analysis we insist on integer-valued flows. While this choice makes it necessary to solve possibly hard integer linear programs, it has the advantage that more detailed mechanistic questions can be formulated. It is thus possible to query networks for general transformation motifs, and to automatically enumerate optimal and near-optimal pathways. Similarities and differences between our work and traditional approaches in metabolic network analysis are discussed in detail. To demonstrate the applicability of the mathematical framework to real-life problems we first explore the design space of possible non-oxidative glycolysis pathways and show that recent manually designed pathways can be further optimised. We then use a model of sugar chemistry to investigate pathways in the autocatalytic formose process. A graph transformation-based approach is used to automatically generate the reaction networks of interest. PMID- 29990046 TI - New Deep Learning Methods for Protein Loop Modeling. AB - Computational protein structure prediction is a long-standing challenge in bioinformatics. In the process of predicting protein 3D structures, it is common that parts of an experimental structure are missing or parts of a predicted structure need to be remodeled. The process of predicting local protein structures of particular regions is called loop modeling. In this paper, five new loop modeling methods based on machine learning techniques, called NearLooper, ConLooper, ResLooper, HyLooper1 and HyLooper2 are proposed. NearLooper is based on the nearest neighbor technique; ConLooper applies deep convolutional neural networks to predict Calpha atoms distance matrix as an orientation-independent representation of protein structure; ResLooper uses residual neural networks instead of deep convolutional neural networks; HyLooper1 combines the results of NearLooper and ConLooper while HyLooper2 combines NearLooper and ResLooper. Three commonly used benchmarks for loop modeling are used to compare the performance between these methods and existing state-of-the-art methods. The experiment results show promising performance in which our best method improves existing state-of-the-art methods by 28% and 54% of average RMSD on two datasets while being comparable on the other one. PMID- 29990047 TI - Bayesian Optimisation of Personalised Models for Patient Vital-Sign Monitoring. AB - Gaussian process regression (GPR) provides a means to generate flexible personalised models of timeseries of patient vital signs. These models can perform useful clinical inference in ways that population-based models cannot. A challenge for the use of personalised models is that they must be amenable to a wide range of parameterisations, to accommodate the plausible physiology of any patient in the population. Additionally, optimal performance is typically achieved when models are regularised in light of knowledge of the physiology of the individual patient. In this paper, we describe a method to build GP models with varying complexity (via covariance kernels) and regularisation (via fixed priors over hyperparameters) on a patient-specific level, for the purpose of robust vitalsign forecasting. To this end, our results present evidence in support of two main hypotheses: (i) the use of patientspecific models can out perform population-based models for useful clinical tasks, such as vital-sign forecasting; and (ii) the optimal values of (hyper)parameters of these models are best determined by sophisticated methods of optimisation, due to high correlation between dimensions of the search space. The resulting models are sufficiently robust to inform clinicians of a patient's vital-sign trajectory, and warn of imminent deterioration. PMID- 29990048 TI - Frequency Network Analysis of Heart Rate Variability for Obstructive Apnea Patient Detection. AB - Obstructive sleep apnea (OSA) is a popular sleep disorder. Traditional OSA diagnosis methods are cumbersome and expensive, which bring inconvenience for patient diagnosis and heavy workload for physician. Automatically identifying OSA patients from electrocardiogram (ECG) records is important for clinical diagnosis and treatment. In this paper, a new method based on the frequency and network domains is proposed to automatically recognize OSA patients with nocturnal ECG records. First, each RR-interval (beat to beat heart rate) series was divided into segments. By calculating the power spectral density (PSD) of heart rate variability segment with Lomb-Scargle method, the dynamic time warping (DTW) distance was used to evaluate the similarity (dissimilarity) of the lower frequency in the PSD series, then the DTW distance matrix was transformed to a binary matrix, and then network metrics were calculated to discriminate OSA patients with healthy subjects. The new method was tested with data of 389 subjects collected from two public databases that consist of normal subjects without OSA (apnea-hypopnea index, AHI 5) and OSA patients (AHI 5). Results show that a single network metric (local clustering coefficient) can recognize OSA patients with 90.1% accuracy, 88.29% sensitivity, and 90.5% specificity, and confirm the potential of using the ECG records for OSA patients recognition. PMID- 29990049 TI - Joint Detection of Associations between DNA Methylation and Gene Expression from Multiple Cancers. AB - DNA methylation plays an important role in the development of various cancers mainly through the regulation on gene expression. Hence, the study on the relation between DNA methylation and gene expression is of particular interest to understand cancers. Recently, an increasing number of datasets are available from multiple cancers, which makes it possible to study both the similarity and difference of genomic alterations across multiple tumor types. However, most of the existing pan-cancer analysis methods perform simple aggregations, which may overlook the heterogeneity of the interactions. In this paper, we propose a novel method to jointly detect complex associations between DNA methylation and gene expression levels from multiple cancers. The main idea is to apply joint sparse canonical correlation analysis to detect a small set of methylated sites, which are associated with another set of genes either shared across cancers or specific to a particular group (group-specific) of cancers. These methylated sites and genes form a complex module with strong multivariate correlations. We further introduced a joint sparse precision matrix estimation method to identify driver methylation-gene pairs in the module. These pairs are characterized by significant partial correlations, which may imply high functional impacts and contribute to complementary information to the main step. We apply our method to The Cancer Genome Atlas(TCGA) datasets with 1166 samples from four cancers. The results reveal significant shared and groupspecific interactions between DNA methylation and gene expression levels. To promote reproducible research, the Matlab code is available at https://sites.google.com/site/jianfang86/jointTCGA. PMID- 29990050 TI - Simultaneous Clustering and Feature Weighting Using Multiobjective Optimization for Identifying Functionally Similar miRNAs. AB - MicroRNAs (miRNAs) are a type of RNAs, which are responsible for monitoring the gene expression values. Recent research asserts that miRNAs form some clustering on chromosomes. The miRNAs belonging to a particular cluster are highly similar in terms of their activity and they are termed as "coregulated" miRNAs. The current paper presents an approach that simultaneously performs two tasks: i) clustering of miRNAs into different categories based on some similarity measures ii) identification of proper weight values for different time points with respect to which expression values are available. In general, a large number of expression values are available for a given miRNA data set. All these values may not be suitable to be used equally to measure the similarity between two miRNAs. In the current study, the problem of proper selection of weight values for different time points and then determining the proper partitioning from the given miRNA data set utilizing the similarity computed using the new set of weight values is formulated as an optimization problem where several cluster validity indices are optimized as the goodness measures. To that end, a multiobjective differential evolution based optimization technique is utilized. The supremacy of the proposed technique is tested on three miRNA data sets in comparison to some recent approaches in terms of some popular performance measures like Silhouette index and DB-index. The observations are further supported by statistical and biological significance tests. Supplementary information is available at https://www.iitp.ac.in/~sriparna/journals.html. PMID- 29990051 TI - 3D Feature-Enhanced Network for Automatic Femur Segmentation. AB - Automatic femur segmentation from computed tomography volume is a crucial but challenging task for computer-aided diagnosis in orthopedic surgeries. The main obstacles are weak bone boundaries, narrowness of joint space, variations in femur density and shape, as well as diverse leg postures. In this paper, we presented a novel 3D feature-enhanced network to address these challenges. The novelty of our approach lies in two feature enhancement modules, including the edge detection task and the multi-scale features fusion. First, the edge detection task was embedded into femur segmentation from computed tomography volume to solve the problems of narrow joint space and weak femur boundary. Crucially, a task-specific edge detector was used to optimize the performance of femur segmentation in an end-to-end trainable system. Second, the multi-scale features fusion provided both local and global contexts to handle the problems of large variations in leg postures as well as femur shape and density. The results demonstrated that accurate 3D femur segmentation with a high Dice similarity coefficient of 96.88% was achieved using the developed method, and the segmentation of computed tomography volume took 0.93 s on an average. PMID- 29990052 TI - Automatic Classification of Functional Gait Disorders. AB - This paper proposes a comprehensive investigation of the automatic classification of functional gait disorders (GDs) based solely on ground reaction force (GRF) measurements. The aim of this study is twofold: first, to investigate the suitability of the state-of-the-art GRF parameterization techniques (representations) for the discrimination of functional GDs; and second, to provide a first performance baseline for the automated classification of functional GDs for a large-scale dataset. The utilized database comprises GRF measurements from 279 patients with GDs and data from 161 healthy controls (N). Patients were manually classified into four classes with different functional impairments associated with the "hip", "knee", "ankle", and "calcaneus". Different parameterizations are investigated: GRF parameters, global principal component analysis (PCA) based representations, and a combined representation applying PCA on GRF parameters. The discriminative power of each parameterization for different classes is investigated by linear discriminant analysis. Based on this analysis, two classification experiments are pursued: distinction between healthy and impaired gait (N versus GD) and multiclass classification between healthy gait and all four GD classes. Experiments show promising results and reveal among others that several factors, such as imbalanced class cardinalities and varying numbers of measurement sessions per patient, have a strong impact on the classification accuracy and therefore need to be taken into account. The results represent a promising first step toward the automated classification of GDs and a first performance baseline for future developments in this direction. PMID- 29990053 TI - Robust Fuzzy Adaptive Tracking Control for Nonaffine Stochastic Nonlinear Switching Systems. AB - This paper is concerned with the trajectory tracking control problem of a class of nonaffine stochastic nonlinear switched systems with the nonlower triangular form under arbitrary switching. Fuzzy systems are employed to tackle the problem from packaged unknown nonlinearities, and the backstepping and robust adaptive control techniques are applied to design the controller by adopting the structural characteristics of fuzzy systems and the common Lyapunov function approach. By using Lyapunov stability theory, the semiglobally uniformly ultimate boundness in the fourth-moment of all closed-loop signals is guaranteed, and the system output is ensured to converge to a small neighborhood of the given trajectory. The main advantages of this paper lie in the fact that both the completely nonaffine form and nonlower triangular structure are taken into account for the controlled systems, and the increasing property of whole state functions is removed by using the structural characteristics of fuzzy systems. The developed control method is verified through a numerical example. PMID- 29990054 TI - Distributed Formation Control of Multiple Quadrotor Aircraft Based on Nonsmooth Consensus Algorithms. AB - The problem of distributed formation control for multiple quadrotor aircraft in the form of leader-follower structure is considered in this paper. Based on a nonsmooth backstepping design, a novel consensus formation control algorithm is proposed and utilized. First, for the position control subsystem, based on the linear quadratic regulator optimal design method, a formation control law for multiple quadrotor aircraft is designed such that the positions of all the quadrotor aircraft converge to the desired formation pattern. The designed formation control law for position systems will generate the desired attitude for the attitude control systems. Second, for the attitude control subsystem described by unit quaternion, by employing the technique of finite-time control and switch control, a global bounded finite-time attitude tracking controller is designed such that the desired attitude can be tracked by the multiple quadrotor aircraft in finite time. Finally, numerical example is performed to demonstrate that all quadrotor aircraft converge to the desired formation pattern in the 3-D space. PMID- 29990055 TI - Estimation of the Volume of the Left Ventricle From MRI Images Using Deep Neural Networks. AB - Segmenting human left ventricle (LV) in magnetic resonance imaging images and calculating its volume are important for diagnosing cardiac diseases. The latter task became the topic of the Second Annual Data Science Bowl organized by Kaggle. The dataset consisted of a large number of cases with only systole and diastole volume labels. We designed a system based on neural networks to solve this problem. It began with a detector to detect the regions of interest (ROI) containing LV chambers. Then a deep neural network named hypercolumns fully convolutional network was used to segment LV in ROI. The 2-D segmentation results were integrated across different images to estimate the volume. With ground-truth volume labels, this model was trained end-to-end. To improve the result, an additional dataset with only segmentation labels was used. The model was trained alternately on these two tasks. We also proposed a variance estimation method for the final prediction. Our algorithm ranked the fourth on the test set in this competition. PMID- 29990056 TI - Truncated Cauchy Non-negative Matrix Factorization for Robust Subspace Learning. AB - Non-negative matrix factorization (NMF) minimizes the Euclidean distance between the data matrix and its low rank approximation, and it fails when applied to corrupted data because the loss function is sensitive to outliers. In this paper, we propose a Truncated Cauchy loss that handle outliers by truncating large errors, and develop a Truncated CauchyNMF to robustly learn the subspace on noisy datasets contaminated by outliers. We theoretically analyze the robustness of Truncated CauchyNMF comparing with the competing models and theoretically prove that Truncated CauchyNMF has a generalization bound which converges at a rate of order , where is the sample size. We evaluate Truncated CauchyNMF by image clustering on both simulated and real datasets. The experimental results on the datasets containing gross corruptions validate the effectiveness and robustness of Truncated CauchyNMF for learning robust subspaces. PMID- 29990057 TI - MPIIGaze: Real-World Dataset and Deep Appearance-Based Gaze Estimation. AB - Learning-based methods are believed to work well for unconstrained gaze estimation, i.e. gaze estimation from a monocular RGB camera without assumptions regarding user, environment, or camera. However, current gaze datasets were collected under laboratory conditions and methods were not evaluated across multiple datasets. Our work makes three contributions towards addressing these limitations. First, we present the MPIIGazedataset that contains 213,659 full face images and corresponding ground-truth gaze positions collected from 15 users during everyday laptop use over several months. An experience sampling approach ensured continuous gaze and head poses and realistic variation in eye appearance and illumination. To facilitate cross-dataset evaluations, 37,667 images were manually annotated with eye corners, mouth corners, and pupil centres. Second, we present an extensive evaluation of state-of-the-art gaze estimation methods on three current datasets, including MPIIGaze. We study key challenges including target gaze range, illumination conditions, and facial appearance variation. We show that image resolution and the use of both eyes affect gaze estimation performance while head pose and pupil centre information are less informative. Finally, we propose GazeNet, the first deep appearance-based gaze estimation method. GazeNet improves the state of the art by 22% percent (from a mean error of 13.9 degrees to 10.8 degrees) for the most challenging cross-dataset evaluation. PMID- 29990058 TI - Face Alignment In Full Pose Range: A 3D Total Solution. AB - Face alignment, which fits a face model to an image and extracts the semantic meanings of facial pixels, has been an important topic in the computer vision community. However, most algorithms are designed for faces in small to medium poses (yaw angle is smaller than ), which lack the ability to align faces in large poses up to . The challenges are three-fold. Firstly, the commonly used landmark face model assumes that all the landmarks are visible and is therefore not suitable for large poses. Secondly, the face appearance varies more drastically across large poses, from the frontal view to the profile view. Thirdly, labelling landmarks in large poses is extremely challenging since the invisible landmarks have to be guessed. In this paper, we propose to tackle these three challenges in an new alignment framework termed 3D Dense Face Alignment (3DDFA), in which a dense 3D Morphable Model (3DMM) is fitted to the image via Cascaded Convolutional Neural Networks. We also utilize 3D information to synthesize face images in profile views to provide abundant samples for training. Experiments on the challenging AFLW database show that the proposed approach achieves significant improvements over the state-of-the-art methods. PMID- 29990060 TI - Contextual Bag-of-Words for Robust Visual Tracking. AB - An appearance model is critical for most modern trackers. While numerous novel appearance models have been proposed with demonstrated success, challenges such as occlusion and drifting are still not well addressed. In this paper, we propose a novel contextual bag-of-words (CBOW) discriminative appearance model that appropriately handles drifting and occlusion. Specifically, a contextual region containing both the target and its surroundings is explored to construct a compact representation with two bags-of-words. Each word carries discriminative appearance information that is learned by Bayesian inference. An adaptive updating approach, where the background BOWs of the CBOW model acts as a "sentinel" to prevent the integration of the background appearance with the object model, is introduced to alleviate the drifting problem. Based on CBOW, visual tracking is posed within a Bayesian framework. Moreover, an explicit detection method is employed to handle severe occlusions, which further reduces drifting. Two trackers based on the same CBOW model are implemented using either handcrafted color/texture or deep convolutional features. Our trackers are evaluated based on the popular OTB50 and VOT2015 benchmarks and perform competitively against the current state of the art. In addition, they outperform two recent BOWs trackers by a large margin using the currently available figures of merit. To take into account a tracking breakdown, we propose a new figure of merit called the mean maximum-tracked-frame ratio (MTFR) that evaluates a tracker's temporal persistence without any interruption. Experiments with OTB50 demonstrate the superior robustness of our tracker compared with all other evaluated trackers on the basis of MTFR. PMID- 29990061 TI - Recurrent Spatial-Temporal Attention Network for Action Recognition in Videos. AB - Recent years have witnessed the popularity of using recurrent neural network (RNN) for action recognition in videos. However, videos are of high dimensionality and contain rich human dynamics with various motion scales, which makes the traditional RNNs difficult to capture complex action information. In this paper, we propose a novel recurrent spatial-temporal attention network (RSTAN) to address this challenge, where we introduce a spatial-temporal attention mechanism to adaptively identify key features from the global video context for every time-step prediction of RNN. More specifically, we make three main contributions from the following aspects. First, we reinforce the classical long short-term memory (LSTM) with a novel spatial-temporal attention module. At each time step, our module can automatically learn a spatial-temporal action representation from all sampled video frames, which is compact and highly relevant to the prediction at the current step. Second, we design an attention driven appearance-motion fusion strategy to integrate appearance and motion LSTMs into a unified framework, where LSTMs with their spatial-temporal attention modules in two streams can be jointly trained in an end-to-end fashion. Third, we develop actor-attention regularization for RSTAN, which can guide our attention mechanism to focus on the important action regions around actors. We evaluate the proposed RSTAN on the benchmark UCF101, HMDB51 and JHMDB data sets. The experimental results show that, our RSTAN outperforms other recent RNN-based approaches on UCF101 and HMDB51 as well as achieves the state-of-the-art on JHMDB. PMID- 29990062 TI - Probabilistic Decision Based Block Partitioning for Future Video Coding. AB - In the latest Joint Video Exploration Team development, the quadtree plus binary tree (QTBT) block partitioning structure has been proposed for future video coding. Compared to the traditional quadtree structure of High Efficiency Video coding (HEVC) standard, QTBT provides more flexible patterns for splitting the blocks, which results in dramatically increased combinations of block partitions and high computational complexity. In view of this, a confidence interval based early termination (CIET) scheme is proposed for QTBT to identify the unnecessary partition modes in the sense of rate-distortion (RD) optimization. In particular, a RD model is established to predict the RD cost of each partition pattern without the full encoding process. Subsequently, the mode decision problem is casted into a probabilistic framework to select the final partition based on the confidence interval decision strategy. Experimental results show that the proposed CIET algorithm can speed up QTBT block partitioning structure by reducing 54.7% encoding time with only 1.12% increase in terms of bit rate. Moreover, the proposed scheme performs consistently well for the high resolution sequences, of which the video coding efficiency is crucial in real applications. PMID- 29990063 TI - Differential Evolutionary Superpixel Segmentation. AB - Superpixel segmentation has been of increasing importance in many computer vision applications recently. To handle the problem, most state-of-the-art algorithms either adopt a local color variance model or a local optimization algorithm. This paper develops a new approach, named differential evolutionary superpixels, which is able to optimize the global properties of segmentation by means of a global optimizer. We design a comprehensive objective function aggregating within superpixel error, boundary gradient, and a regularization term. Minimizing the within-superpixel error enforces the homogeneity of superpixels. In addition, the introduction of boundary gradient drives the superpixel boundaries to capture the natural image boundaries, so as to make each superpixel overlaps with a single object. The regularizer further encourages producing similarly sized superpixels that are friendly to human vision. The optimization is then accomplished by a powerful global optimizer-differential evolution. The algorithm constantly evolves the superpixels by mimicking the process of natural evolution, while using a linear complexity to the image size. Experimental results and comparisons with eleven state-of-the-art peer algorithms verify the promising performance of our algorithm. PMID- 29990064 TI - Blind Quality Estimation by Disentangling Perceptual and Noisy Features in High Dynamic Range Images. AB - High dynamic range (HDR) image visual quality assessment in the absence of a reference image is challenging. This research topic has not been adequately studied largely due to the high cost of HDR display devices. Nevertheless, HDR imaging technology has attracted increasing attention, because it provides more realistic content, consistent to what the human visual system perceives. We propose a new no-reference image quality assessment (NR-IQA) model for HDR data based on convolutional neural networks. The proposed model is able to detect visual artifacts, taking into consideration perceptual masking effects, in a distorted HDR image without any reference. The error and perceptual masking values are measured separately, yet sequentially, and then processed by a mixing function to predict the perceived quality of the distorted image. Instead of using simple stimuli and psychovisual experiments, perceptual masking effects are computed from a set of annotated HDR images during our training process. Experimental results demonstrate that our proposed NR-IQA model can predict HDR image quality as accurately as state-of-the-art full-reference IQA methods. PMID- 29990065 TI - Efficient VR and AR Navigation Through Multiperspective Occlusion Management. AB - Immersive navigation in virtual reality (VR) and augmented reality (AR) leverages physical locomotion through pose tracking of the head-mounted display. While this navigation modality is intuitive, regions of interest in the scene may suffer from occlusion and require significant viewpoint translation. Moreover, limited physical space and user mobility need to be taken into consideration. Some regions of interest may require viewpoints that are physically unreachable without less intuitive methods such as walking in-place or redirected walking. We propose a novel approach for increasing navigation efficiency in VR and AR using multiperspective visualization. Our approach samples occluded regions of interest from additional perspectives, which are integrated seamlessly into the user's perspective. This approach improves navigation efficiency by bringing simultaneously into view multiple regions of interest, allowing the user to explore more while moving less. We have conducted a user study that shows that our method brings significant performance improvement in VR and AR environments, on tasks that include tracking, matching, searching, and ambushing objects of interest. PMID- 29990066 TI - Constructing Pathway-based Priors Within a Gaussian Mixture Model for Bayesian Regression and Classification. AB - Gene-expression-based classification and regression are major concerns in translational genomics. If the feature-label distribution is known, then an optimal classifier can be derived. If the regressor-target distribution is known, then an optimal regression function can be derived. In practice, neither is known, data must be employed, and, for small samples, prior knowledge concerning the feature-label or regressor-target distribution can be used in the learning process. Optimal Bayesian classification and optimal Bayesian regression provide optimality under uncertainty. With optimal Bayesian classification (or regression), uncertainty is treated directly on the feature-label (or regressor target) distribution. The fundamental engineering problem is prior construction. The Regularized Expected Mean Log-Likelihood Prior (REML) utilizes pathway information and provides viable priors for the feature-label distribution, assuming that the training data contain labels. In practice, the labels may not be observed. This paper extends the REML methodology to a Gaussian mixture model (GMM) when the labels are unknown. Prior construction bundled with prior update via Bayesian sampling results in Monte Carlo approximations to the optimal Bayesian regression function and optimal Bayesian classifier. Simulations demonstrate that the GMM REML prior yields better performance than the EM algorithm for small data sets. We apply it to phenotype classification when the prior knowledge consists of colon cancer pathways. PMID- 29990067 TI - Vectorial Dimension Reduction for Tensors Based on Bayesian Inference. AB - Dimension reduction for high-order tensors is a challenging problem. In conventional approaches, dimension reduction for higher order tensors is implemented via Tucker decomposition to obtain lower dimensional tensors. This paper introduces a probabilistic vectorial dimension reduction model for tensorial data. The model represents a tensor by using a linear combination of the same order basis tensors, thus it offers a learning approach to directly reduce a tensor to a vector. Under this expression, the projection base of the model is based on the tensor CandeComp/PARAFAC (CP) decomposition and the number of free parameters in the model only grows linearly with the number of modes rather than exponentially. A Bayesian inference has been established via the variational Expectation Maximization (EM) approach. A criterion to set the parameters (a factor number of CP decomposition and the number of extracted features) is empirically given. The model outperforms several existing principal component analysis-based methods and CP decomposition on several publicly available databases in terms of classification and clustering accuracy. PMID- 29990068 TI - An Algorithm for Clustering Categorical Data With Set-Valued Features. AB - In data mining, objects are often represented by a set of features, where each feature of an object has only one value. However, in reality, some features can take on multiple values, for instance, a person with several job titles, hobbies, and email addresses. These features can be referred to as set-valued features and are often treated with dummy features when using existing data mining algorithms to analyze data with set-valued features. In this paper, we propose an SV- $k$ modes algorithm that clusters categorical data with set-valued features. In this algorithm, a distance function is defined between two objects with set-valued features, and a set-valued mode representation of cluster centers is proposed. We develop a heuristic method to update cluster centers in the iterative clustering process and an initialization algorithm to select the initial cluster centers. The convergence and complexity of the SV- $k$ -modes algorithm are analyzed. Experiments are conducted on both synthetic data and real data from five different applications. The experimental results have shown that the SV- $k$ modes algorithm performs better when clustering real data than do three other categorical clustering algorithms and that the algorithm is scalable to large data. PMID- 29990069 TI - A Solution Path Algorithm for General Parametric Quadratic Programming Problem. AB - Parameter in learning problems (usually arising from the tradeoff between training error minimization and regularization) is often tuned by cross validation (CV). A solution path provides a compact representation of all optimal solutions, which can be used to determine the parameter with the global minimum CV error, without solving original optimization problems multiple times based on grid search. However, existing solution path algorithms do not provide a unified implementation to various learning problems. In this paper, we first introduce a general parametric quadratic programming (PQP) problem that can be instantiated to an extensive number of learning problems. Then, we propose a generalized solution path (GSP) for the general PQP problem. Particularly, we use the $QR$ decomposition to handle singularities in GSP. Finally, we analyze the finite convergence and the time complexity of GSP. Our experimental results on a variety of data sets not only confirm the identicality between GSP and several existing solution path algorithms but also show the superiority of our GSP over the existing solution path algorithms on both generalization and robustness. Finally, we provide a practical guild of using the GSP to solve two important learning problems, i.e., generalized error path and Ivanov SVM. PMID- 29990070 TI - 40-Hz ASSR for Measuring Depth of Anaesthesia During Induction Phase. AB - This paper proposes an anaesthesia monitoring system that accurately measures the depth of anaesthesia through 40-Hz auditory steady-state response. With accurate and fast depth of anaesthesia measuring, the monitor can reduce the incidence of awareness during surgical operation. The proposed denoising method for extracting 40-Hz auditory steady-state cycles, adaptive multilevel wavelet denoising, enabled the system to extract auditory steady-state response cycles from fewer epochs and over short periods of time which is of crucial importance in monitoring anaesthesia. The noise estimation scheme, adaptive threshold levels, rearranging, and multilevel denoising of frames increase the accuracy and signal to noise ratio of the extracted cycles. The modified fuzzy c-means clustering scheme, proposed to improve clustering performance in noisy data bases where no prior information about the level of noise and signal energy is available, is used for clustering the auditory steady-state cycles. Weighting the features with a novel algorithm and based on their differentiating role in clustering, the modified fuzzy c-means improves fuzziness in cluster partitions and the geometrical structure of the data. An index called depth of anaesthesia index is defined and determined at each cycle based on the clustering information of the cycle and the previous ones. The algorithm is applied to auditory steady-state response signals recorded from 20 human subjects during surgical operations with Propofol-induced general anaesthesia. The accuracy of the depth of anaesthesia index is validated through the subjects' medical markers, clinical parameters, and the recorded bispectral index during the induction phase. Depth of anaesthesia index is verified to be accurate and able to detect fast transitions between different levels of anaesthesia. The computed depth of anaesthesia indices detected the induction of anaesthesia on average 55 s faster than bispectral index and 17 s earlier than loss of eyelash reflex. PMID- 29990071 TI - Understanding the Bioinformatics Challenges of Integrating Genomics into Healthcare. AB - Genomic data is paving the way towards personalized healthcare. By unveiling genetic disease-contributing factors, genomic data can aid in the detection, diagnosis, and treatment of a wide range of complex diseases. Integrating genomic data into healthcare is riddled with a wide range of challenges spanning social, ethical, legal, educational, economic, and technical aspects. Bioinformatics is a core integration aspect presenting an overwhelming number of unaddressed challenges. In this paper we tackle the fundamental bioinformatics integration concerns including: genomic data generation, storage, representation, and utilization in conjunction with clinical data. We divide the bioinformatics challenges into a series of seven intertwined integration aspects spanning the areas of informatics, knowledge management, and communication. For each aspect, we provide a detailed discussion of the current research directions, outstanding challenges, and possible resolutions. This paper seeks to help narrow the gap between the genomic applications, which are being predominantly utilized in research settings, and the clinical adoption of these applications. PMID- 29990072 TI - A Low-Power Fall Detector Balancing Sensitivity and False Alarm Rate. AB - Falls in older people are a major challenge to public health. A wearable fall detector can detect falls automatically based on kinematic information of the human body, allowing help to arrive sooner. To date, most studies have focused on the accuracy of an offline algorithm to distinguish real-world or simulated falls from activities of daily living, while neglecting the false alarm rate and battery life of a real device. To address these two important metrics, which significantly influence user compliance, this paper proposes a low-power fall detector using triaxial accelerometry and barometric pressure sensing. This fall detector minimizes power consumption using both hardware- and firmware-based techniques. Additionally, the fall detection algorithm used in this device is optimized to achieve a balance between sensitivity and false alarm rate, while minimizing the power consumption due to algorithm execution. The fall detector achieved a high sensitivity (91%) with a low false alarm rate (0.1149 alarms per hour), and a commercially-viable battery life (1125 days). PMID- 29990074 TI - Better Dense Trajectories by Motion in Videos. AB - Currently, the most widely used point trajectories generation methods estimate the trajectories from the dense optical flow, by using a consistency check strategy to detect the occluded regions. However, these methods will miss some important trajectories, thus resulting in breaking smooth areas without any structure especially around the motion boundaries (MBs). We suggest exploring MBs in video to generate more accurate dense point trajectories. Estimating MBs from the video improves the point trajectory accuracy of the discontinuity or occluded areas. Then, we obtain trajectories by tracking the initial feature points through all frames. The experimental results demonstrate that our method outperforms the state-of-the-art methods on the challenging benchmark. PMID- 29990073 TI - Sparse Bayesian Learning-Based Kernel Poisson Regression. AB - In this paper, we introduce a closed-form sparse Bayesian kernel Poisson regression (SBKPR) model for count data regression problems based on the sparse Bayesian learning (SBL) approach. In Bayesian setting, a Gaussian prior is given to the model parameter, which is not the conjugate distribution of Poisson regression. Hence, the model parameters cannot be integrated analytically, which leads to the inference intractable problem. In this paper, the log-gamma Gaussian approximation method is proposed to solve this analytically intractable problem, which can give out the closed-form solutions. Furthermore, an individual Gaussian prior is given to the model parameters, which can enhance the flexibility of the proposed method. Finally, sparse solutions can be obtained by applying SBL, which can benefit the learning efficiency and reduce the computational time in practical applications. Experimental results demonstrate that the proposed SBKPR model can outperform some state-of-the-art count data regression models on both toy data and real-world data. PMID- 29990075 TI - A Decomposition-Based Many-Objective Artificial Bee Colony Algorithm. AB - In this paper, a decomposition-based artificial bee colony (ABC) algorithm is proposed to handle many-objective optimization problems (MaOPs). In the proposed algorithm, an MaOP is converted into a number of subproblems which are simultaneously optimized by a modified ABC algorithm. The hybrid of the decomposition-based algorithm and the ABC algorithm can make full use of the advantages of both algorithms. The former, with the help of a set of weight vectors, is able to maintain a good diversity among solutions, while the latter, with a fast convergence speed, is highly effective when solving a scalar optimization problem. Therefore, the convergence and diversity would be well balanced in the new algorithm. Moreover, subproblems in the proposed algorithm are handled unequally, and computational resources are dynamically allocated through specially designed onlooker bees and scout bees. The proposed algorithm is compared with five state-of-the-art many-objective evolutionary algorithms on 13 test problems with up to 50 objectives. It is shown by the experimental results that the proposed algorithm performs better than or comparably to other algorithms in terms of both quality of the final solution set and efficiency of the algorithms. Finally, as shown by the Wilcoxon signed-rank test results, the onlooker bees and scout bees indeed contribute to performance improvements of the algorithm. Given the high quality of solutions and the rapid running speed, the proposed algorithm could be a promising tool when approximating a set of well converged and properly distributed nondominated solutions for MaOPs. PMID- 29990076 TI - Fuzzy Rule-Based Design of Evolutionary Algorithm for Optimization. AB - During the last two decades, many multioperator- and multimethod-based evolutionary algorithms for solving optimization problems have been proposed. Although, in general terms, they outperform single-operator-based traditional ones, they do not perform consistently for all the problems tested in the literature. The designs of such algorithms usually follow a trial and error approach that can be improved by using a rule-based approach. In this paper, we propose a new way for two algorithms to cooperate as an effective team, in which a heuristic is applied using fuzzy rules of two complementary characteristics, the quality of solutions and diversity in the population. In this process, two subpopulations are used, one for each algorithm, with greater emphasis placed on the better-performing one. Inferior algorithms learn from trusted ones and a fine tuning procedure is applied in the later stages of the evolutionary process. The proposed algorithm was analyzed on the CEC2014 unconstrained problems and then tested on other three sets (CEC2013, CEC2005, and 12 classical problems), with its results showing a high success rate and that it outperformed both single operator-based and different state-of-the-art algorithms. PMID- 29990077 TI - Dynamic Cluster Formation Game for Attributed Graph Clustering. AB - Besides the topological structure, there are additional information, i.e., node attributes, on top of the plain graphs. Usually, these systems can be well modeled by attributed graphs, where nodes represent component actors, a set of attributes describe users' portraits and edges indicate their connections. An elusive question associated with attributed graphs is to study how clusters with common internal properties form and evolve in real-world networked systems with great individual diversity, which leads to the so-called problem of attributed graph clustering (AGC). In this paper, we comprehended AGC naturally as a dynamic cluster formation game (DCFG), where each node's feasible action set can be constrained by every cluster in a discrete-time dynamical system. Specifically, we carried out a deep research on a special case of finite dynamic games, named dynamic social game (DSG), the convergence of the finite Nash equilibrium sequence in a DSG was also proved strictly. By carefully defining the feasible action set and the utility function associated with each node, the proposed DCFG can be well related to a DSG; and we showed that a balanced solution of AGC could be found by solving a finite set of coupled static Nash equilibrium problems in the related DCFG. We, finally, proposed a self-learning algorithm, which can start from any arbitrary initial cluster configuration, and, finally, find the corresponding balanced solution of AGC, where all nodes and clusters are satisfied with the final cluster configuration. Extensive experiments were applied on real-world social networks to demonstrate both effectiveness and scalability of the proposed approach by comparing with the state-of-the-art graph clustering methods in the literature. PMID- 29990078 TI - Deblurring Low-Light Images with Light Streaks. AB - Images acquired in low-light conditions with handheld cameras are often blurry, so steady poses and long exposure time are required to alleviate this problem. Although significant advances have been made in image deblurring, state-of-the art approaches often fail on low-light images, as a sufficient number of salient features cannot be extracted for blur kernel estimation. On the other hand, light streaks are common phenomena in low-light images that have not been extensively explored in existing approaches. In this work, we propose an algorithm that utilizes light streaks to facilitate deblurring low-light images. The light streaks, which commonly exist in the low-light blurry images, contain rich information regarding camera motion and blur kernels. A method is developed in this work to detect light streaks for kernel estimation. We introduce a non linear blur model that explicitly takes light streaks and corresponding light sources into account, and pose them as constraints for estimating the blur kernel in an optimization framework. For practical applications, the proposed algorithm is extended to handle images undergoing non-uniform blur. Experimental results show that the proposed algorithm performs favorably against the state-of-the-art methods on deblurring real-world low-light images. PMID- 29990079 TI - One-Pass Learning with Incremental and Decremental Features. AB - In many real tasks the features are evolving, with some features vanished and some other features being augmented. For example, in environment monitoring some sensors expired whereas some new ones were deployed; in mobile game recommendation some games dropped whereas some new ones were added. Learning with such incremental and decremental features is crucial but rarely studied, particularly when the data comes like a stream and thus it is infeasible to keep the whole data for optimization. In this paper, we study this challenging problem and present the OPID approach. Our approach attempts to compress important information of vanished features into functions of survived features, and then expand to include the augmented features. It is an one-pass learning approach, which only needs to scan each instance once and does not need to store the whole data, and thus satisfies the evolving streaming data nature. After tackling this problem in one-shot scenario, we then extend it to multi-shot case. Empirical study on a broad range of data sets shows that our approach can address this problem effectively. PMID- 29990080 TI - Action Recognition with Dynamic Image Networks. AB - We introduce the concept of dynamic image, a novel compact representation of videos useful for video analysis, particularly in combination with convolutional neural networks (CNNs). A dynamic image encodes temporal data such as RGB or optical flow videos by using the concept of 'rank pooling'. The idea is to learn a ranking machine that captures the temporal evolution of the data and to use the parameters of the latter as a representation. We call the resulting representation dynamic image because it summarizes the video dynamics in addition to appearance. This powerful idea allows to convert any video to an image so that existing CNN models pre-trained with still images can be immediately extended to videos. We also present an efficient approximate rank pooling operator that runs two orders of magnitude faster than the standard ones with any loss in ranking performance and can be formulated as a CNN layer. To demonstrate the power of the representation, we introduce a novel four stream CNN architecture which can learn from RGB and optical flow frames as well as from their dynamic image representations. We show that the proposed network achieves state-of-the-art performance, 95.5 and 72.5 percent accuracy, in the UCF101 and HMDB51, respectively. PMID- 29990081 TI - Tele-Immersion Concepts. AB - Tele-immersive systems development is always driven as well as restricted by the available immersive technology. Hence, existing such systems are described mainly from a technological point of view; their conceptual description is usually limited to the description of a scenario that is implementable with or circumvents the limitations of the chosen technology. This focus on technology makes it difficult to compare systems' concepts; moreover, it has led to different views on tele-immersion in different fields, such as remotely controlled robots, immersive video conferencing, and tele-collaboration. In this work, we give a general, structured principle to describe the conceptual part of any tele-immersion system. This principle naturally unifies the different views on tele-immersion. Our idea is based on the insight that, in order to be general, immersion must be described separately for each direction of communication. We characterize communication between locations using a graph; for each directed edge of this graph, we describe immersion as operations on volumes. Using this principle, we define a typology, which enables the comparison and enumeration of tele-immersion concepts. We apply this typology to survey the concepts of existing tele-immersion systems and thereby demonstrate how three well-known tele immersive scenarios-Marvin Minsky's tele-operated robot, the Office of the Future, and the asymmetric Beaming scenario-integrate naturally. We show how the general principle can be utilized conveniently to grasp conceptual ideas in tele immersion, such as direct interaction, locational presence, spatial consistency, symmetries, and self-inclusion. PMID- 29990082 TI - Point-Based Rendering for Homogeneous Participating Media with Refractive Boundaries. AB - Illumination effects in translucent materials are a combination of several physical phenomena: refraction at the surface, absorption and scattering inside the material. Because refraction can focus light deep inside the material, where it will be scattered, practical illumination simulation inside translucent materials is difficult. In this paper, we present an a Point-Based Global Illumination method for light transport on homogeneous translucent materials with refractive boundaries. We start by placing light samples inside the translucent material and organizing them into a spatial hierarchy. At rendering, we gather light from these samples for each camera ray. We compute separately the sample contributions for single, double and multiple scattering, and add them. We present two implementations of our algorithm: an offline version for high-quality rendering and an interactive GPU implementation. The offline version provides significant speed-ups and reduced memory footprints compared to state-of-the-art algorithms, with no visible impact on quality. The GPU version yields interactive frame rates: 30 fps when moving the viewpoint, 25 fps when editing the light position or the material parameters. PMID- 29990083 TI - Exponential Rosenbrock-Euler Integrators for Elastodynamic Simulation. AB - High quality simulations of the dynamics of soft flexible objects can be rather costly, because the assembly of internal forces through an often nonlinear stiffness at each time step is expensive. Many standard implicit integrators introduce significant, time-step dependent artificial damping. Here we propose and demonstrate the effectiveness of an exponential Rosenbrock-Euler (ERE) method which avoids discretization-dependent artificial damping. The method is relatively inexpensive and works well with the large time steps used in computer graphics. It retains correct qualitative behaviour even in challenging circumstances involving non-convex elastic energies. Our integrator is designed to handle and perform well even in the important cases where the symmetric stiffness matrix is not positive definite at all times. Thus we are able to address a wider range of practical situations than other related solvers. We show that our system performs efficiently for a wide range of soft materials. PMID- 29990084 TI - Transformation of the Multivariate Generalized Gaussian Distribution for Image Editing. AB - Multivariate generalized Gaussian distributions (MGGDs) have aroused a great interest in the image processing community thanks to their ability to describe accurately various image features, such as image gradient fields. However, so far their applicability has been limited by the lack of a transformation between two of these parametric distributions. In this paper, we propose a novel transformation between MGGDs, consisting of an optimal transportation of the second-order statistics and a stochastic-based shape parameter transformation. We employ the proposed transformation between MGGDs for a color transfer and a gradient transfer between images. We also propose a new simultaneous transfer of color and gradient, which we apply for image color correction. PMID- 29990085 TI - Neural-Network-Based Adaptive Backstepping Control With Application to Spacecraft Attitude Regulation. AB - This paper investigates the neural-network-based adaptive control problem for a class of continuous-time nonlinear systems with actuator faults and external disturbances. The model uncertainties in the system are not required to satisfy the norm-bounded assumption, and the exact information for components faults and external disturbance is totally unknown, which represents more general cases in practical systems. An indirect adaptive backstepping control strategy is proposed to cope with the stabilization problem, where the unknown nonlinearity is approximated by the adaptive neural-network scheme, and the loss of effectiveness of actuators faults and the norm bounds of exogenous disturbances are estimated via designed online adaptive updating laws. The developed adaptive backstepping control law can ensure the asymptotic stability of the fault closed-loop system despite of unknown nonlinear function, actuator faults, and disturbances. Finally, an application example based on spacecraft attitude regulation is provided to demonstrate the effectiveness and the potential of the developed new neural adaptive control approach. PMID- 29990086 TI - Neural Observer and Adaptive Neural Control Design for a Class of Nonlinear Systems. AB - This paper addresses the problem of adaptive neural tracking control for nonlinear nonstrict-feedback systems. The state variables are immeasurable and only the system output is available. A neural observer is constructed to estimate these unknown system state variables. An observer-based adaptive neural tracking control scheme is developed via backstepping approach. It is shown that the designed controller guarantees that the system output well follows the desired reference signal, and meanwhile, other closed-loop signals remain bounded. Finally, two simulation examples are used to test our results. PMID- 29990087 TI - Stability Analysis of Neural Networks With Time-Varying Delay by Constructing Novel Lyapunov Functionals. AB - This paper presents two novel Lyapunov functionals for analyzing the stability of neural networks with time-varying delay. Based on our newly proposed Lyapunov functionals and a relaxed Wirtinger-based integral inequality, new stability criteria are derived in the form of linear matrix inequalities. A comprehensive comparison of results is given to illustrate the newly proposed stability criteria from both the conservative and computational complexity point of views. PMID- 29990088 TI - Online Supervised Learning for Hardware-Based Multilayer Spiking Neural Networks Through the Modulation of Weight-Dependent Spike-Timing-Dependent Plasticity. AB - In this paper, we propose an online learning algorithm for supervised learning in multilayer spiking neural networks (SNNs). It is found that the spike timings of neurons in an SNN can be exploited to estimate the gradients that are associated with each synapse. With the proposed method of estimating gradients, learning similar to the stochastic gradient descent process employed in a conventional artificial neural network (ANN) can be achieved. In addition to the conventional layer-by-layer backpropagation, a one-pass direct backpropagation is possible using the proposed learning algorithm. Two neural networks, with one and two hidden layers, are employed as examples to demonstrate the effectiveness of the proposed learning algorithms. Several techniques for more effective learning are discussed, including utilizing a random refractory period to avoid saturation of spikes, employing a quantization noise injection technique and pseudorandom initial conditions to decorrelate spike timings, in addition to leveraging the progressive precision in an SNN to reduce the inference latency and energy. Extensive parametric simulations are conducted to examine the aforementioned techniques. The learning algorithm is developed with the considerations of ease of hardware implementation and relative compatibility with the classic ANN-based learning. Therefore, the proposed algorithm not only enjoys the high energy efficiency and good scalability of an SNN in its specialized hardware but also benefits from the well-developed theory and techniques of conventional ANN-based learning. The Modified National Institute of Standards and Technology database benchmark test is conducted to verify the newly proposed learning algorithm. Classification correct rates of 97.2% and 97.8% are achieved for the one-hidden layer and two-hidden-layer neural networks, respectively. Moreover, a brief discussion of the hardware implementations is presented for two mainstream architectures. PMID- 29990089 TI - Shared Autoencoder Gaussian Process Latent Variable Model for Visual Classification. AB - Multiview learning reveals the latent correlation among different modalities and utilizes the complementary information to achieve a better performance in many applications. In this paper, we propose a novel multiview learning model based on the Gaussian process latent variable model (GPLVM) to learn a set of nonlinear and nonparametric mapping functions and obtain a shared latent variable in the manifold space. Different from the previous work on the GPLVM, the proposed shared autoencoder Gaussian process (SAGP) latent variable model assumes that there is an additional mapping from the observed data to the shared manifold space. Due to the introduction of the autoencoder framework, both nonlinear projections from and to the observation are considered simultaneously. Additionally, instead of fully connecting used in the conventional autoencoder, the SAGP achieves the mappings utilizing the GP, which remarkably reduces the number of estimated parameters and avoids the phenomenon of overfitting. To make the proposed method adaptive for classification, a discriminative regularization is embedded into the proposed method. In the optimization process, an efficient algorithm based on the alternating direction method and gradient decent techniques is designed to solve the encoder and decoder parts alternatively. Experimental results on three real-world data sets substantiate the effectiveness and superiority of the proposed approach as compared with the state of the art. PMID- 29990090 TI - Design, Analysis, and Representation of Novel Five-Step DTZD Algorithm for Time Varying Nonlinear Optimization. AB - Continuous-time and discrete-time forms of Zhang dynamics (ZD) for time-varying nonlinear optimization have been developed recently. In this paper, a novel discrete-time ZD (DTZD) algorithm is proposed and investigated based on the previous research. Specifically, the DTZD algorithm for time-varying nonlinear optimization is developed by adopting a new Taylor-type difference rule. This algorithm is a five-step iteration process, and thus, is referred to as the five step DTZD algorithm in this paper. Theoretical analysis and results of the proposed five-step DTZD algorithm are presented to highlight its excellent computational performance. The geometric representation of the proposed algorithm for time-varying nonlinear optimization is also provided. Comparative numerical results are illustrated with four examples to substantiate the efficacy and superiority of the proposed five-step DTZD algorithm for time-varying nonlinear optimization compared with the previous DTZD algorithms. PMID- 29990091 TI - Characterizing the Location and Extent of Myocardial Infarctions With Inverse ECG Modeling and Spatiotemporal Regularization. AB - Myocardial infarction (MI) is among the leading causes of death in the United States. It is imperative to identify and characterize MIs for timely delivery of life-saving medical interventions. Cardiac electrical activity propagates in space and evolves over time. Traditional works focus on the analysis of time domain ECG (e.g., 12-lead ECG) on the body surface for the detection of MIs, but tend to overlook spatiotemporal dynamics in the heart. Body surface potential mappings (BSPMs) provide high-resolution distribution of electric potentials over the entire torso, and therefore provide richer information than 12-lead ECG. However, BSPM are available on the body surface. Clinicians are in need of a closer look of the electric potentials in the heart to investigate cardiac pathology and optimize treatment strategies. In this paper, we applied the method of spatiotemporal inverse ECG (ST-iECG) modeling to map electrical potentials from the body surface to the heart, and then characterize the location and extent of MIs by investigating the reconstructed heart-surface electrograms. First, we investigate the impact of mesh resolution on the inverse ECG modeling. Second, we solve the inverse ECG problem and reconstruct heart-surface electrograms using the ST-iECG model. Finally, we propose a wavelet-clustering method to investigate the pathological behaviors of heart-surface electrograms, and thereby characterize the extent and location of MIs. The proposed methodology is evaluated and validated with real data of MIs from human subjects. Experimental results show that negative QRS waves in heart-surface electrograms indicate potential regions of MI, and the proposed ST-iECG model yields superior characterization results of MIs on the heart surface over existing methods. PMID- 29990092 TI - CNNs-Based RGB-D Saliency Detection via Cross-View Transfer and Multiview Fusion. AB - Salient object detection from RGB-D images aims to utilize both the depth view and RGB view to automatically localize objects of human interest in the scene. Although a few earlier efforts have been devoted to the study of this paper in recent years, two major challenges still remain: 1) how to leverage the depth view effectively to model the depth-induced saliency and 2) how to implement an optimal combination of the RGB view and depth view, which can make full use of complementary information among them. To address these two challenges, this paper proposes a novel framework based on convolutional neural networks (CNNs), which transfers the structure of the RGB-based deep neural network to be applicable for depth view and fuses the deep representations of both views automatically to obtain the final saliency map. In the proposed framework, the first challenge is modeled as a cross-view transfer problem and addressed by using the task-relevant initialization and adding deep supervision in hidden layer. The second challenge is addressed by a multiview CNN fusion model through a combination layer connecting the representation layers of RGB view and depth view. Comprehensive experiments on four benchmark datasets demonstrate the significant and consistent improvements of the proposed approach over other state-of-the-art methods. PMID- 29990093 TI - On the Definiteness of Earth Mover's Distance and Its Relation to Set Intersection. AB - Positive definite (PD) kernels are an important tool in machine learning that enable efficient solutions to otherwise difficult or intractable problems by implicitly linearizing the problem geometry. In this paper, we develop a set theoretic interpretation of the earth mover's distance (EMD) and propose earth mover's intersection (EMI), a PD analog to EMD for sets of different sizes. We provide conditions under which EMD or certain approximations to EMD are negative definite. We also present a PD-preserving transformation that can be applied to any kernel and can also be used to derive PD EMD-based kernels and show that the Jaccard index is simply the result of this transformation. Finally, we evaluate kernels based on EMI and the proposed transformation versus EMD in various computer vision tasks and show that EMD is generally inferior even with indefinite kernel techniques. PMID- 29990094 TI - Estimating Graph Robustness Through the Randic Index. AB - Graph robustness-the ability of a graph to preserve its connectivity after the loss of nodes and edges-has been extensively studied to quantify how social, biological, physical, and technical systems withstand to external damages. In this paper, we prove that graph robustness can be quickly estimated through the Randic index, a parameter introduced in chemistry to study organic compounds. We prove that Erdos-Renyj (ER) graphs are a good specimen of robust graphs because they lack of a clear modular structure; we derive an analytical expression for the Randic index of ER graphs and use ER graphs as an effective term of comparison to decide about graph robustness. Experiments on real datasets from different domains (scientific collaboration networks, content-sharing systems, co purchase networks from an e-commerce platform, and a road network) show that real life large graphs are more robust than ER ones with the same number of nodes and edges. We also observe that if node degree distribution closely follows a power law, then few edges contribute for more than half of the Randic index, thus indicating that the selective removal of those edges has devastating impact on graph robustness. Finally, we describe sampling-based algorithms to efficiently but accurately approximate the Randic index. PMID- 29990095 TI - Collision-Free Path Planning and Delivery Sequence Optimization in Noncoplanar Radiation Therapy. AB - Radiation therapy is among the top three cancer treatments in current medical services. The novel noncoplanar radiation therapy which claimed the best characteristics in almost all dosimetric properties encountered the challenges of the potential collision and the long time delivering. In this paper, we proposed a brand new scheme which uses a combined method of the collision avoidance path planning based on an improved probability roadmap method (PRM) and the delivery sequence optimization based on a modified genetic algorithm (GA) to solve the problems in noncoplanar radiation therapy. A uniform sampling strategy, an improved connection strategy, and an efficient local planner are introduced to optimize the roadmap result and accelerate the roadmap construction. The GA is improved by the elitist selection, the local search strategy, and the similar substitution strategy to achieve a better performance both in convergence rate and optimal solution. Experiments are carried out on the simulation platform with typical therapy system models. The results show that our proposed methods work well with the radiation therapy system in a compact working area. Collision is avoided and time consumption is reduced. We believe that our proposed algorithms could solve the problems in current radiation therapy and promote their clinic applications. PMID- 29990096 TI - Distributed Nash Equilibrium Seeking in Multiagent Games Under Switching Communication Topologies. AB - This paper investigates distributed Nash equilibrium seeking in multiagent games under switching communication topologies. To be specific, the communication topology is supposed to be switching among a set of strongly connected digraphs, which might suffer from occasional loss of communication due to sensor failure, packet loss, etc. The synthesis of the leader-following consensus protocol and the gradient play is exploited to achieve the distributed Nash equilibrium seeking under the switching communication topologies. Switching topology without loss of communication is firstly considered, followed by switching topology subject to missing communication within some time slots. For both situations, nonquadratic and quadratic games are addressed separately. Local convergence results are presented for nonquadratic games and nonlocal convergence results are provided for quadratic games. The theoretical results are verified by numerical examples. PMID- 29990097 TI - Self-Organizing RBF Neural Network Using an Adaptive Gradient Multiobjective Particle Swarm Optimization. AB - One of the major obstacles in using radial basis function (RBF) neural networks is the convergence toward local minima instead of the global minima. For this reason, an adaptive gradient multiobjective particle swarm optimization (AGMOPSO) algorithm is designed to optimize both the structure and parameters of RBF neural networks in this paper. First, the AGMOPSO algorithm, based on a multiobjective gradient method and a self-adaptive flight parameters mechanism, is developed to improve the computation performance. Second, the AGMOPSO-based self-organizing RBF neural network (AGMOPSO-SORBF) can optimize the parameters (centers, widths, and weights), as well as determine the network size. The goal of AGMOPSO-SORBF is to find a tradeoff between the accuracy and the complexity of RBF neural networks. Third, the convergence analysis of AGMOPSO-SORBF is detailed to ensure the prerequisite of any successful applications. Finally, the merits of our proposed approach are verified on multiple numerical examples. The results indicate that the proposed AGMOPSO-SORBF achieves much better generalization capability and compact network structure than some other existing methods. PMID- 29990098 TI - Exploring Web Images to Enhance Skin Disease Analysis Under A Computer Vision Framework. AB - To benefit the skin care, this paper aims to design an automatic and effective visual analysis framework, with the expectation of recognizing the skin disease from a given image conveying the disease affected surface. This task is nontrivial, since it is hard to collect sufficient well-labeled samples. To address such problem, we present a novel transfer learning model, which is able to incorporate external knowledge obtained from the rich and relevant Web images contributed by grassroots. In particular, we first construct a target domain by crawling a small set of images from vertical and professional dermatological websites. We then construct a source domain by collecting a large set of skin disease related images from commercial search engines. To reinforce the learning performance in the target domain, we initially build a learning model in the target domain, and then seamlessly leverage the training samples in the source domain to enhance this learning model. The distribution gap between these two domains are bridged by a linear combination of Gaussian kernels. Instead of training models with low-level features, we resort to deep models to learn the succinct, invariant, and high-level image representations. Different from previous efforts that focus on a few types of skin diseases with a small and confidential set of images generated from hospitals, this paper targets at thousands of commonly seen skin diseases with publicly accessible Web images. Hence the proposed model is easily repeatable by other researchers and extendable to other disease types. Extensive experiments on a real-world dataset have demonstrated the superiority of our proposed method over the state-of-the-art competitors. PMID- 29990099 TI - Learning Consensus Representation for Weak Style Classification. AB - Style classification (e.g., Baroque and Gothic architecture style) is grabbing increasing attention in many fields such as fashion, architecture, and manga. Most existing methods focus on extracting discriminative features from local patches or patterns. However, the spread out phenomenon in style classification has not been recognized yet. It means that visually less representative images in a style class are usually very diverse and easily getting misclassified. We name them weak style images. Another issue when employing multiple visual features towards effective weak style classification is lack of consensus among different features. That is, weights for different visual features in the local patch should have been allocated similar values. To address these issues, we propose a Consensus Style Centralizing Auto-Encoder (CSCAE) for learning robust style features representation, especially for weak style classification. First, we propose a Style Centralizing Auto-Encoder (SCAE) which centralizes weak style features in a progressive way. Then, based on SCAE, we propose both the non linear and linear version CSCAE which adaptively allocate weights for different features during the progressive centralization process. Consensus constraints are added based on the assumption that the weights of different features of the same patch should be similar. Specifically, the proposed linear counterpart of CSCAE motivated by the "shared weights" idea as well as group sparsity improves both efficacy and efficiency. For evaluations, we experiment extensively on fashion, manga and architecture style classification problems. In addition, we collect a new dataset-Online Shopping, for fashion style classification, which will be publicly available for vision based fashion style research. Experiments demonstrate the effectiveness of the SCAE and CSCAE on both public and newly collected datasets when compared with the most recent state-of-the-art works. PMID- 29990100 TI - A Simple, Fast and Highly-Accurate Algorithm to Recover 3D Shape from 2D Landmarks on a Single Image. AB - Three-dimensional shape reconstruction of 2D landmark points on a single image is a hallmark of human vision, but is a task that has been proven difficult for computer vision algorithms. We define a feed-forward deep neural network algorithm that can reconstruct 3D shapes from 2D landmark points almost perfectly (i.e., with extremely small reconstruction errors), even when these 2D landmarks are from a single image. Our experimental results show an improvement of up to two-fold over state-of-the-art computer vision algorithms; 3D shape reconstruction error (measured as the Procrustes distance between the reconstructed shape and the ground-truth) of human faces is , cars is .0022, human bodies is .022, and highly-deformable flags is .0004. Our algorithm was also a top performer at the 2016 3D Face Alignment in the Wild Challenge competition (done in conjunction with the European Conference on Computer Vision, ECCV) that required the reconstruction of 3D face shape from a single image. The derived algorithm can be trained in a couple hours and testing runs at more than 1,000 frames/s on an i7 desktop. We also present an innovative data augmentation approach that allows us to train the system efficiently with small number of samples. And the system is robust to noise (e.g., imprecise landmark points) and missing data (e.g., occluded or undetected landmark points). PMID- 29990101 TI - Learning without Forgetting. AB - When building a unified vision system or gradually adding new apabilities to a system, the usual assumption is that training data for all tasks is always available. However, as the number of tasks grows, storing and retraining on such data becomes infeasible. A new problem arises where we add new capabilities to a Convolutional Neural Network (CNN), but the training data for its existing capabilities are unavailable. We propose our Learning without Forgetting method, which uses only new task data to train the network while preserving the original capabilities. Our method performs favorably compared to commonly used feature extraction and fine-tuning adaption techniques and performs similarly to multitask learning that uses original task data we assume unavailable. A more surprising observation is that Learning without Forgetting may be able to replace fine-tuning with similar old and new task datasets for improved new task performance. PMID- 29990102 TI - Copula Based Classifier Fusion Under Statistical Dependence. AB - We consider the problem of fusing probability scores from a set of classifiers to estimate a final fused probability score. Our interest is in scenarios where the classifiers are statistically dependent. To that end, we propose a new classifier fusion approach that is data driven and founded on the statistical theory of copulas. Numerical results with both simulated and real data show that our copula based classifier fusion approach produces better probability scores than individual classifiers and outperforms existing probability score fusion approaches. PMID- 29990103 TI - Latent Constrained Correlation Filter. AB - Correlation filters are special classifiers designed for shift-invariant object recognition, which are robust to pattern distortions. The recent literature shows that combining a set of sub-filters trained based on a single or a small group of images obtains the best performance. The idea is equivalent to estimating variable distribution based on the data sampling (bagging), which can be interpreted as finding solutions (variable distribution approximation) directly from sampled data space. However, this methodology fails to account for the variations existed in the data. In this paper, we introduce an intermediate step solution sampling-after the data sampling step to form a subspace, in which an optimal solution can be estimated. More specifically, we propose a new method, named latent constrained correlation filters (LCCF), by mapping the correlation filters to a given latent subspace, and develop a new learning framework in the latent subspace that embeds distribution-related constraints into the original problem. To solve the optimization problem, we introduce a subspace-based alternating direction method of multipliers, which is proven to converge at the saddle point. Our approach is successfully applied to three different tasks, including eye localization, car detection, and object tracking. Extensive experiments demonstrate that LCCF outperforms the state-of-the-art methods.11 . PMID- 29990104 TI - A Robust 3D-2D Interactive Tool for Scene Segmentation and Annotation. AB - Recent advances of 3D acquisition devices have enabled large-scale acquisition of 3D scene data. Such data, if completely and well annotated, can serve as useful ingredients for a wide spectrum of computer vision and graphics works such as data-driven modeling and scene understanding, object detection and recognition. However, annotating a vast amount of 3D scene data remains challenging due to the lack of an effective tool and/or the complexity of 3D scenes (e.g. clutter, varying illumination conditions). This paper aims to build a robust annotation tool that effectively and conveniently enables the segmentation and annotation of massive 3D data. Our tool works by coupling 2D and 3D information via an interactive framework, through which users can provide high-level semantic annotation for objects. We have experimented our tool and found that a typical indoor scene could be well segmented and annotated in less than 30 minutes by using the tool, as opposed to a few hours if done manually. Along with the tool, we created a dataset of over a hundred 3D scenes associated with complete annotations using our tool. Both the tool and dataset will be available at http://scenenn.net. PMID- 29990106 TI - Time Interval Ray Tracing for Motion Blur. AB - We introduce a new motion blur computation method for ray tracing that provides an analytical approximation of motion blurred visibility per ray. Rather than relying on timestamped rays and Monte Carlo sampling to resolve the motion blur, we associate a time interval with rays and directly evaluate when and where each ray intersects with animated object faces. Based on our simplifications, the volume swept by each animated face is represented using a triangulation of the surface of this volume. Thus, we can resolve motion blur through ray intersections with stationary triangles, and we can use any standard ray tracing acceleration structure without modifications to account for the time dimension. Rays are intersected with these triangles to analytically determine the time interval and positions of the intersections with the moving objects. Furthermore, we explain an adaptive strategy to efficiently shade the intersection intervals. As a result, we can produce noise-free motion blur for both primary and secondary rays. We also provide a general framework for emulating various camera shutter mechanisms and an artistic modification that amplifies the visibility of moving objects for emphasizing the motion in videos or static images. PMID- 29990105 TI - Animated Construction of Chinese Brush Paintings. AB - In this paper, we present a method for reconstructing the drawing process of Chinese brush paintings. We demonstrate the possibility of computing an artistically reasonable drawing order from a static brush painting that is consistent with the rules of art. We map the key principles of drawing composition to our computational framework, which first organizes the strokes in three stages and then optimizes stroke ordering with natural evolution strategies. Our system produces reasonable animated constructions of Chinese brush paintings with minimal or no user intervention. We test our algorithm on a range of input paintings with varying degrees of complexity and structure and then evaluate the results via a user study. We discuss the applications of the proposed system to painting instruction, painting animation, and image stylization, especially in the context of art teaching. PMID- 29990107 TI - Human pathway-based disease network. AB - Constructing disease-disease similarity network is important in elucidating the associations between the origin and molecular mechanism of diseases, and in researching disease function and medical research. In this paper, we use a high quality protein interaction network and a collection of pathway databases to construct a Human Pathway-based Disease Network (HPDN) to explore the relationship between diseases and their intrinsic interactions. We find that the similarity of two diseases has a strong correlation with the number of their shared functional pathways and the interaction between their related gene sets. Comparing HPDN with disease networks based on genes and symptoms respectively, we find the three networks have high overlap rates. Additionally, HPDN can predict new disease-disease correlations, which are supported by Comparative Toxicogenomics Database (CTD) benchmark and large-scale biomedical literature database. The comprehensive, high-quality relations between diseases based on pathways can further be applied to study important matters in systems medicine, for instance, drug repurposing. Based on a dense subgraph in our network, we find two drugs, prednisone and folic acid, may have new indications, which will provide potential directions for the treatments of complex diseases. PMID- 29990108 TI - Moment-Based Parameter Estimation for Stochastic Reaction Networks in Equilibrium. AB - Calibrating parameters is a crucial problem within quantitative modeling approaches to reaction networks. Existing methods for stochastic models rely either on statistical sampling or can only be applied to small systems. Here, we present an inference procedure for stochastic models in equilibrium that is based on a moment matching scheme with optimal weighting and that can be used with high throughput data like the one collected by flow cytometry. Our method does not require an approximation of the underlying equilibrium probability distribution and, if reaction rate constants have to be learned, the optimal values can be computed by solving a linear system of equations. We discuss important practical issues such as the selection of the moments and evaluate the effectiveness of the proposed approach on three case studies. PMID- 29990109 TI - Engineering Approaches to Assessing Hydration Status. AB - Dehydration is a common condition characterized by a decrease in total body water. Acute dehydration can cause physical and cognitive impairment, heat stroke and exhaustion, and, if severe and uncorrected, even death. The health effects of chronic mild dehydration are less well studied with urolithiasis (kidney stones) the only condition consistently associated with it. Aside from infants and those with particular medical conditions, athletes, military personnel, manual workers, and older adults are at particular risk of dehydration due to their physical activity, environmental exposure, and/or challenges in maintaining fluid homeostasis. This review describes the different approaches that have been explored for hydration assessment in adults. These include clinical indicators perceived by the patient or detected by a practitioner and routine laboratory analyses of blood and urine. These techniques have variable accuracy and practicality outside of controlled environments, creating a need for simple, portable, and rapid hydration monitoring devices. We review the wide array of devices proposed for hydration assessment based on optical, electromagnetic, chemical, and acoustical properties of tissue and bodily fluids. However, none of these approaches has yet emerged as a reliable indicator in diverse populations across various settings, motivating efforts to develop new methods of hydration assessment. PMID- 29990110 TI - Early Classification of Time Series by Simultaneously Optimizing the Accuracy and Earliness. AB - The problem of early classification of time series appears naturally in contexts where the data, of temporal nature, are collected over time, and early class predictions are interesting or even required. The objective is to classify the incoming sequence as soon as possible, while maintaining suitable levels of accuracy in the predictions. Thus, we can say that the problem of early classification consists of optimizing two objectives simultaneously: accuracy and earliness. In this context, we present a method for early classification based on combining a set of probabilistic classifiers together with a stopping rule (SR). This SR will act as a trigger and will tell us when to output a prediction or when to wait for more data, and its main novelty lies in the fact that it is built by explicitly optimizing a cost function based on accuracy and earliness. We have selected a large set of benchmark data sets and four other state-of-the art early classification methods, and we have evaluated and compared our framework obtaining superior results in terms of both earliness and accuracy. PMID- 29990111 TI - Lagrangean-Based Combinatorial Optimization for Large-Scale S3VMs. AB - The process of manually labeling instances, essential to a supervised classifier, can be expensive and time-consuming. In such a scenario the semisupervised approach, which makes the use of unlabeled patterns when building the decision function, is a more appealing choice. Indeed, large amounts of unlabeled samples often can be easily obtained. Many optimization techniques have been developed in the last decade to include the unlabeled patterns in the support vector machines formulation. Two broad strategies are followed: continuous and combinatorial. The approach presented in this paper belongs to the latter family and is especially suitable when a fair estimation of the proportion of positive and negative samples is available. Our method is very simple and requires a very light parameter selection. Several medium- and large-scale experiments on both artificial and real-world data sets have been carried out proving the effectiveness and the efficiency of the proposed algorithm. PMID- 29990112 TI - Automated EEG Artifact Handling With Application in Driver Monitoring. AB - Automated analyses of electroencephalographic (EEG) signals acquired in naturalistic environments are becoming increasingly important in areas such as brain-computer interfaces and behavior science. However, the recorded EEG in such environments is often heavily contaminated by motion artifacts and eye movements. This poses new requirements on artifact handling. The objective of this paper is to present an automated EEG artifacts handling algorithm, which will be used as a preprocessing step in a driver monitoring application. The algorithm, named Automated aRTifacts handling in EEG (ARTE), is based on wavelets, independent component analysis, and hierarchical clustering. The algorithm is tested on a dataset obtained from a driver sleepiness study including 30 drivers and 540 30 min 30-channel EEG recordings. The algorithm is evaluated by a clinical neurophysiologist, by quantitative criteria (signal quality index, mean square error, relative error, and mean absolute error), and by demonstrating its usefulness as a preprocessing step in driver monitoring, here exemplified with driver sleepiness classification. All results are compared with a state-of-the art algorithm called FORCe. The quantitative and expert evaluation results show that the two algorithms are comparable, and that both algorithms significantly reduce the impact of artifacts in recorded EEG signals. When artifact handling is used as a preprocessing step in driver sleepiness classification, the classification accuracy increased by 5% when using ARTE and by 2% when using FORCe. The advantage with ARTE is that it is data driven and does not rely on additional reference signals or manually defined thresholds, making it well suited for use in dynamic settings where unforeseen and rare artifacts are commonly encountered. PMID- 29990113 TI - Nocturnal Heart Rate Variability Spectrum Characterization in Preschool Children With Asthmatic Symptoms. AB - Asthma is a chronic lung disease that usually develops during childhood. Despite that symptoms can almost be controlled with medication, early diagnosis is desirable in order to reduce permanent airway obstruction risk. It has been suggested that abnormal parasympathetic nervous system (PSNS) activity might be closely related with the pathogenesis of asthma, and that this PSNS activity could be reflected in cardiac vagal control. In this work, an index to characterize the spectral distribution of the high frequency (HF) component of heart rate variability (HRV), named peakness ($?wp$), is proposed. Three different implementations of $?wp$, based on electrocardiogram (ECG) recordings, impedance pneumography (IP) recordings and a combination of both, were employed in the characterization of a group of preschool children classified attending to their risk of developing asthma. Peakier components were observed in the HF band of those children classified as high-risk ( $p < 0.005$), who also presented reduced sympathvoagal balance. Results suggest that high-risk of developing asthma might be related with a lack of adaptability of PSNS. PMID- 29990115 TI - Classification of Medical Images in the Biomedical Literature by Jointly Using Deep and Handcrafted Visual Features. AB - The classification of medical images and illustrations from the biomedical literature is important for automated literature review, retrieval, and mining. Although deep learning is effective for large-scale image classification, it may not be the optimal choice for this task as there is only a small training dataset. We propose a combined deep and handcrafted visual feature (CDHVF) based algorithm that uses features learned by three fine-tuned and pretrained deep convolutional neural networks (DCNNs) and two handcrafted descriptors in a joint approach. We evaluated the CDHVF algorithm on the ImageCLEF 2016 Subfigure Classification dataset and it achieved an accuracy of 85.47%, which is higher than the best performance of other purely visual approaches listed in the challenge leaderboard. Our results indicate that handcrafted features complement the image representation learned by DCNNs on small training datasets and improve accuracy in certain medical image classification problems. PMID- 29990114 TI - Sinusoidal Signal Assisted Multivariate Empirical Mode Decomposition for Brain Computer Interfaces. AB - A brain-computer interface (BCI) is a communication approach that permits cerebral activity to control computers or external devices. Brain electrical activity recorded with electroencephalography (EEG) is most commonly used for BCI. Noise-assisted multivariate empirical mode decomposition (NA-MEMD) is a data driven time-frequency analysis method that can be applied to nonlinear and nonstationary EEG signals for BCI data processing. However, because white Gaussian noise occupies a broad range of frequencies, some redundant components are introduced. To solve this leakage problem, in this study, we propose using a sinusoidal assisted signal that occupies the same frequency ranges as the original signals to improve MEMD performance. To verify the effectiveness of the proposed sinusoidal signal assisted MEMD (SA-MEMD) method, we compared the decomposition performances of MEMD, NA-MEMD, and the proposed SA-MEMD using synthetic signals and a real-world BCI dataset. The spectral decomposition results indicate that the proposed SA-MEMD can avoid the generation of redundant components and over decomposition, thus, substantially reduce the mode mixing and misalignment that occurs in MEMD and NA-MEMD. Moreover, using SA-MEMD as a signal preprocessing method instead of MEMD or NA-MEMD can significantly improve BCI classification accuracy and reduce calculation time, which indicates that SA-MEMD is a powerful spectral decomposition method for BCI. PMID- 29990116 TI - DECAL: Decomposition-Based Coevolutionary Algorithm for Many-Objective Optimization. AB - This paper develops a decomposition-based coevolutionary algorithm for many objective optimization, which evolves a number of subpopulations in parallel for approaching the set of Pareto optimal solutions. The many-objective problem is decomposed into a number of subproblems using a set of well-distributed weight vectors. Accordingly, each subpopulation of the algorithm is associated with a weight vector and is responsible for solving the corresponding subproblem. The exploration ability of the algorithm is improved by using a mating pool that collects elite individuals from the cooperative subpopulations for breeding the offspring. In the subsequent environmental selection, the top-ranked individuals in each subpopulation, which are appraised by aggregation functions, survive for the next iteration. Two new aggregation functions with distinct characteristics are designed in this paper to enhance the population diversity and accelerate the convergence speed. The proposed algorithm is compared with several state-of-the art many-objective evolutionary algorithms on a large number of benchmark instances, as well as on a real-world design problem. Experimental results show that the proposed algorithm is very competitive. PMID- 29990117 TI - A Dynamic Event-Triggered Transmission Scheme for Distributed Set-Membership Estimation Over Wireless Sensor Networks. AB - This paper is concerned with the distributed set-membership estimation for a discrete-time linear time-varying system over a resource-constrained wireless sensor network under the influence of unknown-but-bounded (UBB) process and measurement noise. Sensors collaborate among themselves by exchanging local measurements with only neighboring sensors in their sensing ranges. First, a new dynamic event-triggered transmission scheme (ETS) is developed to schedule the transmission of each sensor's local measurement. In contrast with the majority of existing static ETSs, the newly proposed dynamic ETS can result in larger average interevent times and thus less totally released data packets. Second, a criterion for designing desired event-triggered set-membership estimators is derived such that the system's true state always resides in each sensor's bounding ellipsoidal estimation set regardless of the simultaneous presence of UBB process and measurement noise. Third, a recursive convex optimization algorithm is presented to determine optimal ellipsoids as well as the estimator gain parameters and the event triggering weighting matrix parameter. Furthermore, the proposed dynamic ETS is applied to address the distributed set-membership estimation problem for a discrete-time linear time-varying system with a nonlinearity satisfying a sector constraint. Finally, an illustrative example is given to show the effectiveness and advantage of the developed approach. PMID- 29990118 TI - Evolutionary Multiobjective Blocking Lot-Streaming Flow Shop Scheduling With Machine Breakdowns. AB - In various flow shop scheduling problems, it is very common that a machine suffers from breakdowns. Under this situation, a robust and stable suboptimal scheduling solution is of more practical interest than a global optimal solution that is sensitive to environmental changes. However, blocking lot-streaming flow shop (BLSFS) scheduling problems with machine breakdowns have not yet been well studied up to date. This paper presents, for the first time, a multiobjective model of the above problem including robustness and stability criteria. Based on this model, an evolutionary multiobjective robust scheduling algorithm is suggested, in which solutions obtained by a variant of single-objective heuristic are incorporated into population initialization and two novel crossover operators are proposed to take advantage of nondominated solutions. In addition, a rescheduling strategy based on the local search is presented to further reduce the negative influence resulted from machine breakdowns.The proposed algorithm is applied to 22 test sets, and compared with the state-of-the-art algorithms without machine breakdowns. Our empirical results demonstrate that the proposed algorithm can effectively tackle BLSFS scheduling problems in the presence of machine breakdowns by obtaining scheduling strategies that are robust and stable. PMID- 29990119 TI - Uncertainty Propagation in Fuzzy Grey Cognitive Maps With Hebbian-Like Learning Algorithms. AB - This paper is focused on an innovative fuzzy cognitive maps extension called fuzzy grey cognitive maps (FGCMs). FGCMs are a mixture of fuzzy cognitive maps and grey systems theory. These have become a useful framework for facing problems with high uncertainty, under discrete small and incomplete datasets. This paper deals with the problem of uncertainty propagation in FGCM dynamics with Hebbian learning. In addition, this paper applies differential Hebbian learning (DHL) and balanced DHL to FGCMs for the first time. We analyze the uncertainty propagation in eight different scenarios in a classical chemical control problem. The results give insight into the propagation of the uncertainty or greyness in the iterations of the FGCMs. The results show that the nonlinear Hebbian learning is the choice with less uncertainty in steady final grey states for Hebbian learning algorithms. PMID- 29990120 TI - Fault Tolerant Sliding Mode Predictive Control for Uncertain Steer-by-Wire System. AB - The Steer-by-Wire (SbW) system is an electronically controlled steering system that is able to improve steering capability without mechanical links between the steering wheel and the front wheels. However, failure of the SbW system actuator may lead to steering performance degradation and result in instability. In this paper, a fault tolerant sliding mode predictive control (SMPC) strategy for an SbW system is proposed. The sliding mode control is applied to improve the robustness of the model predictive control (MPC) in the presence of modeling uncertainties and disturbances, while the MPC is applied to enhance the fault tolerant capability of the steering control processes. The chaos particle swarm optimization (CPSO) algorithm is introduced to optimize the MPC and a two-stage Kalman filter is introduced to simultaneously provide fault information and state estimation. The performance of the proposed approach is validated through computer simulation. The results demonstrate that the proposed SMPC-CPSO controller is more robust and provides better tracking performance in the presence of model uncertainties, disturbance, and actuator faults than SCMP-PSOs (heterogeneous comprehensive learning particle swarm optimization, evolutionary particle swarm optimizer, etc), SMPC-differential evolution, MPC, SMPC, and MPC PSO. PMID- 29990122 TI - Guaranteed Outlier Removal for Point Cloud Registration with Correspondences. AB - An established approach for 3D point cloud registration is to estimate the registration function from 3D keypoint correspondences. Typically, a robust technique is required to conduct the estimation, since there are false correspondences or outliers. Current 3D keypoint techniques are much less accurate than their 2D counterparts, thus they tend to produce extremely high outlier rates. A large number of putative correspondences must thus be extracted to ensure that sufficient good correspondences are available. Both factors (high outlier rates, large data sizes) however cause existing robust techniques to require very high computational cost. In this paper, we present a novel preprocessing method called guaranteed outlier removal for point cloud registration. Our method reduces the input to a smaller set, in a way that any rejected correspondence is guaranteed to not exist in the globally optimal solution. The reduction is performed using purely geometric operations which are deterministic and fast. Our method significantly reduces the population of outliers, such that further optimization can be performed quickly. Further, since only true outliers are removed, the globally optimal solution is preserved. On various synthetic and real data experiments, we demonstrate the effectiveness of our preprocessing method. Demo code is available as supplementary material, which can be found on the Computer Society Digital Library at http://doi.ieeecomputersociety.org/10.1109/TPAMI.2017.2773482. PMID- 29990121 TI - Event-Based, 6-DOF Camera Tracking from Photometric Depth Maps. AB - Event cameras are bio-inspired vision sensors that output pixel-level brightness changes instead of standard intensity frames. These cameras do not suffer from motion blur and have a very high dynamic range, which enables them to provide reliable visual information during high-speed motions or in scenes characterized by high dynamic range. These features, along with a very low power consumption, make event cameras an ideal complement to standard cameras for VR/AR and video game applications. With these applications in mind, this paper tackles the problem of accurate, low-latency tracking of an event camera from an existing photometric depth map (i.e., intensity plus depth information) built via classic dense reconstruction pipelines. Our approach tracks the 6-DOF pose of the event camera upon the arrival of each event, thus virtually eliminating latency. We successfully evaluate the method in both indoor and outdoor scenes and show that because of the technological advantages of the event camera-our pipeline works in scenes characterized by high-speed motion, which are still inaccessible to standard cameras. PMID- 29990123 TI - Object-Part Attention Model for Fine-Grained Image Classification. AB - Fine-grained image classification is to recognize hundreds of subcategories belonging to the same basic-level category, such as 200 subcategories belonging to the bird, which is highly challenging due to large variance in the same subcategory and small variance among different subcategories. Existing methods generally first locate the objects or parts and then discriminate which subcategory the image belongs to. However, they mainly have two limitations: 1) relying on object or part annotations which are heavily labor consuming; and 2) ignoring the spatial relationships between the object and its parts as well as among these parts, both of which are significantly helpful for finding discriminative parts. Therefore, this paper proposes the object-part attention model (OPAM) for weakly supervised fine-grained image classification and the main novelties are: 1) object-part attention model integrates two level attentions: object-level attention localizes objects of images, and part-level attention selects discriminative parts of object. Both are jointly employed to learn multi view and multi-scale features to enhance their mutual promotion; and 2) Object part spatial constraint model combines two spatial constraints: object spatial constraint ensures selected parts highly representative and part spatial constraint eliminates redundancy and enhances discrimination of selected parts. Both are jointly employed to exploit the subtle and local differences for distinguishing the subcategories. Importantly, neither object nor part annotations are used in our proposed approach, which avoids the heavy labor consumption of labeling. Compared with more than ten state-of-the-art methods on four widely-used datasets, our OPAM approach achieves the best performance. PMID- 29990124 TI - LMap: Shape-Preserving Local Mappings for Biomedical Visualization. AB - Visualization of medical organs and biological structures is a challenging task because of their complex geometry and the resultant occlusions. Global spherical and planar mapping techniques simplify the complex geometry and resolve the occlusions to aid in visualization. However, while resolving the occlusions these techniques do not preserve the geometric context, making them less suitable for mission-critical biomedical visualization tasks. In this paper, we present a shape-preserving local mapping technique for resolving occlusions locally while preserving the overall geometric context. More specifically, we present a novel visualization algorithm, LMap, for conformally parameterizing and deforming a selected local region-of-interest (ROI) on an arbitrary surface. The resultant shape-preserving local mappings help to visualize complex surfaces while preserving the overall geometric context. The algorithm is based on the robust and efficient extrinsic Ricci flow technique, and uses the dynamic Ricci flow algorithm to guarantee the existence of a local map for a selected ROI on an arbitrary surface. We show the effectiveness and efficacy of our method in three challenging use cases: (1) multimodal brain visualization, (2) optimal coverage of virtual colonoscopy centerline flythrough, and (3) molecular surface visualization. PMID- 29990125 TI - RF-NR: Random forest based approach for improved classification of Nuclear Receptors. AB - The Nuclear Receptor (NR) superfamily plays an important role in key biological, developmental and physiological processes. Developing a method for the classification of NR proteins is an important step towards understanding the structure and functions of the newly discovered NR protein. The recent studies on NR classification are either unable to achieve optimum accuracy or are not designed for all the known NR subfamilies. In this study we developed RF-NR, which is a Random Forest based approach for improved classification of nuclear receptors. The RF-NR can predict whether a query protein sequence belongs to one of the eight NR subfamilies or it is a non-NR sequence. The RF-NR uses spectrum like features namely: Amino Acid Composition, Di-peptide Composition and Tripeptide Composition. Benchmarking on two independent datasets with varying sequence redundancy reduction criteria, the RF-NR achieves better (or comparable) accuracy than other existing methods. The added advantage of our approach is that we can also obtain biological insights about the important features that are required to classify NR subfamilies. PMID- 29990126 TI - Sequence-based prediction of putative transcription factor binding sites in DNA sequences of any length. AB - A transcription factor (TF) is a protein that regulates gene expression by binding to specific DNA sequences. Despite the recent advances in experimental techniques for identifying transcription factor binding sites (TFBS) in DNA sequences, a large number of TFBS are to be unveiled in many species. Several computational methods developed for predicting TFBS in DNA are tissue- or species specific methods, so cannot be used without prior knowledge of tissue or species. Some computational methods are applicable to finding TFBS in short DNA sequences only. In this paper we propose a new learning method for predicting TFBS in DNA of any length using the composition, transition and distribution of nucleotides and amino acids in DNA and TF sequences. In independent testing of the method on datasets that were not used in training the method, its accuracy and MCC were as high as 81.84% and 0.634, respectively. The proposed method can be a useful aid for selecting potential TFBS in a large amount of DNA sequences before conducting biochemical experiments to empirically determine TFBS. The program and data sets are available at http://bclab.inha.ac.kr/TFbinding. PMID- 29990127 TI - Quasi-Newton Stochastic Optimization Algorithm for Parameter Estimation of a Stochastic Model of the Budding Yeast Cell Cycle. AB - Parameter estimation in discrete or continuous deterministic cell cycle models is challenging for several reasons, including the nature of what can be observed, and the accuracy and quantity of those observations. The challenge is even greater for stochastic models, where the number of simulations and amount of empirical data must be even larger to obtain statistically valid parameter estimates. The two main contributions of this work are (1) stochastic model parameter estimation based on directly matching multivariate probability distributions, and (2) a new quasi-Newton algorithm class QNSTOP for stochastic optimization problems. QNSTOP directly uses the random objective function value samples rather than creating ensemble statistics. QNSTOP is used here to directly match empirical and simulated joint probability distributions rather than matching summary statistics. Results are given for a current state-of-the-art stochastic cell cycle model of budding yeast, whose predictions match well some summary statistics and one-dimensional distributions from empirical data, but do not match well the empirical joint distributions. The nature of the mismatch provides insight into the weakness in the stochastic model. PMID- 29990128 TI - ASSA-PBN: A Toolbox for Probabilistic Boolean Networks. AB - As a well-established computational framework, probabilistic Boolean networks (PBNs) are widely used for modelling, simulation, and analysis of biological systems. To analyze the steady-state dynamics of PBNs is of crucial importance to explore the characteristics of biological systems. However, the analysis of large PBNs, which often arise in systems biology, is prone to the infamous state-space explosion problem. Therefore, the employment of statistical methods often remains the only feasible solution. We present ${?mathsf{ASSA-PBN}}$ , a software toolbox for modelling, simulation, and analysis of PBNs. ${?mathsf{ASSA-PBN}}$ provides efficient statistical methods with three parallel techniques to speed up the computation of steady-state probabilities. Moreover, particle swarm optimisation (PSO) and differential evolution (DE) are implemented for the estimation of PBN parameters. Additionally, we implement in-depth analyses of PBNs, including long run influence analysis, long-run sensitivity analysis, computation of one parameter profile likelihoods, and the visualization of one-parameter profile likelihoods. A PBN model of apoptosis is used as a case study to illustrate the main functionalities of ${?mathsf{ASSA-PBN}}$ and to demonstrate the capabilities of ${?mathsf{ASSA-PBN}}$ to effectively analyse biological systems modelled as PBNs. PMID- 29990129 TI - Deformable Models for Surgical Simulation: A Survey. AB - This paper presents a survey of the state-of-the-art deformable models studied in the literature, with regard to soft tissue deformable modeling for interactive surgical simulation. It first introduces the challenges of surgical simulation, followed by discussions and analyses on the deformable models, which are classified into three categories: the heuristic modeling methodology, continuum mechanical methodology, and other methodologies. It also examines linear and nonlinear deformable modeling, model internal forces, and numerical time integrations, together with modeling of soft tissue anisotropy, viscoelasticity, and compressibility. Finally, various issues in the existing deformable models are discussed to outline the remaining challenges of deformable models in surgical simulation. PMID- 29990130 TI - Sensory integration of apparent motion speed and vibration magnitude. AB - Tactile apparent motion can display directional information in an intuitive way. It can for example be used to give directions to visually impaired individuals, or for waypoint navigation while cycling on busy streets, when vision or audition should not be loaded further. However, although humans can detect very short tactile patterns, discriminating between similar motion speeds has been shown to be difficult. Here we develop and investigate a method where the speed of tactile apparent motion around the user's wrist is coupled with vibration magnitude. This redundant coupling is used to produce tactile patterns from slow&weak to fast&strong. We compared the just noticeable difference (JND) of the coupled and the individual variables. The results show that the perception of the coupled variable can be characterised by JND smaller than JNDs of the individual variables. This allowed us to create short tactile pattens (tactons) for display of direction and speed, which can be distinguished significantly better than tactons based on motion alone. Additionally, most subjects were also able to identify the coupled-variable tactons better than the magnitude-based tactons. PMID- 29990131 TI - Neuroadaptive Control With Given Performance Specifications for MIMO Strict Feedback Systems Under Nonsmooth Actuation and Output Constraints. AB - This paper studies the prescribed performance tracking control problem for a class of multi-input multi-output strict-feedback systems with asymmetric nonsmooth actuator characteristics and output constraints as well as unexpected external disturbances. By combining a novel speed transformation with barrier Lyapunov function, a neural adaptive control scheme is developed that is able to achieve given tracking precision within preassigned finite time at prespecified converging mode. At each of the first $n-1$ steps of backstepping design, we make use of the radial basis function neural networks to cope with the uncertainties arising from unknown and time-varying virtual control gains, and in the last step, we introduce a matrix factorization technique to remove the restrictive requirement on the unknown control gain matrix and its NN-approximation, simplifying control design. Furthermore, to reduce the number of parameters to be online updated, we introduce a virtual parameter to handle the lumped uncertainties, resulting in a control scheme with low complexity and inexpensive computations. The effectiveness of the proposed control strategy is validated by systematic stability analysis and numerical simulation. PMID- 29990132 TI - Multiple-Instance Ordinal Regression. AB - Ordinal regression (OR) is a paradigm in supervised learning, which aims at learning a prediction model for ordered classes. The existing studies mainly focus on single-instance OR, and the multi-instance OR problem has not been explicitly addressed. In many real-world applications, considering the OR problem from a multiple-instance aspect can yield better classification performance than from a single-instance aspect. For example, in image retrieval, an image may contain multiple and possibly heterogeneous objects. The user is usually interested in only a small part of the objects. If we represent the whole image as a global feature vector, the useful information from the targeted objects that the user is of interest may be overridden by the noisy information from irrelevant objects. However, this problem fits in the multiple-instance setting well. Each image is considered as a bag, and each object region is treated as an instance. The image is considered as of the user interest if it contains at least one targeted object region. In this paper, we address the multi-instance OR where the OR classifier is learned on multiple-instance data, instead of single instance data. To solve this problem, we present a novel multiple-instance ordinal regression (MIOR) method. In MIOR, a set of parallel hyperplanes is used to separate the classes, and the label ordering information is incorporated into learning the classifier by imputing the parallel hyperplanes with an order. Moreover, considering that a bag may contain instances not belonging to its class, for each bag, the instance which is nearest to the middle of the corresponding class is selected to learn the classifier. Compared with the existing single-instance OR work, MIOR is able to learn a more accurate OR classifier on multiple-instance data where only the bag label is available and the instance label is unknown. Extensive experiments show that MIOR outperforms the existing single-instance OR methods. PMID- 29990133 TI - Removal of Eye Blink Artifacts From EEG Signals Using Sparsity. AB - Neural activities recorded using electroencephalography (EEG) are mostly contaminated with eye blink (EB) artifact. This results in undesired activation of brain-computer interface (BCI) systems. Hence, removal of EB artifact is an important issue in EEG signal analysis. Of late, several artifact removal methods have been reported in the literature and they are based on independent component analysis (ICA), thresholding, wavelet transformation, etc. These methods are computationally expensive and result in information loss which makes them unsuitable for online BCI system development. To address the above problems, we have investigated sparsity-based EB artifact removal methods. Two sparsity-based techniques namely morphological component analysis (MCA) and K-SVD-based artifact removal method have been evaluated in our work. MCA-based algorithm exploits the morphological characteristics of EEG and EB using predefined Dirac and discrete cosine transform (DCT) dictionaries. Next, in K-SVD-based algorithm an overcomplete dictionary is learned from the EEG data itself and is designed to model EB characteristics. To substantiate the efficacy of the two algorithms, we have carried out our experiments with both synthetic and real EEG data. We observe that the K-SVD algorithm, which uses a learned dictionary, delivers superior performance for suppressing EB artifacts when compared to MCA technique. Finally, the results of both the techniques are compared with the recent state-of the-art FORCe method. We demonstrate that the proposed sparsity-based algorithms perform equal to the state-of-the-art technique. It is shown that without using any computationally expensive algorithms, only with the use of over-complete dictionaries the proposed sparsity-based algorithms eliminate EB artifacts accurately from the EEG signals. PMID- 29990134 TI - Automatic Side Branch Ostium Detection and Main Vascular Segmentation in Intravascular Optical Coherence Tomography Images. AB - Intravascular optical coherence tomography is the state-of-the-art imaging modality in percutaneous coronary intervention planning and evaluation, in which side branch ostium and main vascular measurements play critical roles. However, manual measurement is time consuming and labor intensive. In this paper, we propose a fully automatic method for side branch ostium detection and main vascular segmentation to make up manual deficiency. In our method, side branch ostium points are first detected and subsequently used to divide the lumen contour into side branch and main vascular regions. Based on the division, main vascular contour is then smoothly fitted for segmentation. In side branch ostium detection, our algorithm creatively converts the definition of curvature into the calculation of the signed included angles in global view, and originally applies a differential filter to highlight the feature of side branch ostium points. A total of 4618 images from 22 pullback runs were used to evaluate the performance of the presented method. The validation results of side branch detection were TPR = 82.8 $?%$, TNR = 98.7$?%$ , PPV = 86.8$?%$, NPV = 98.7$?%$. The average ostial distance error (ODE) was 0.22 mm, and the DSC of main vascular segmentation was 0.96. In conclusion, the qualitative and quantitative evaluation indicated that the presented method is effective and accurate. PMID- 29990135 TI - A Speed- and Power-Efficient SPIHT Design for Wearable Quality-On-Demand ECG Applications. AB - In this paper, a speed and power-efficient set partitioning in hierarchical trees (SPIHT) design is introduced for one-dimensional (1-D) wavelet-based electrocardiography (ECG) compression systems with quality guarantee. To achieve real-time and low-power design objectives toward wearable quality-on-demand (QoD) ECG applications, we first propose a coding-time- and computation-efficient SPIHT algorithm using various types of coding status register files to overcome the disadvantages of low coding speeds and complicated hardware architectures characterizing prior SPIHT algorithms resulting from the necessity of dynamic computation and arrangement in the sorting and refinement processing phase. Second, a highly pipelined and power-efficient very large scale integration (VLSI) architecture is developed to implement a high-performance and low-power SPIHT design based on the proposed algorithm. The final simulation results demonstrate that our proposed algorithm can speed up the average coding time 1.52 to 2.74 times compared to prior work with an identical compression ratio for an 11-level $1024?times 1?,1-{?rm{D}}$ discrete wavelet transform at diverse target percentage root-mean-square differences (PRDT) on various MIT-BIH arrhythmia datasets. Applied to wearable wavelet-based QoD ECG applications, our proposed VLSI architecture attains a working frequency of 740 MHz and consumes an average of $?text{23}? ?mu {?text{W}}$ of power with Taiwan Semiconductor Manufacturing Company 90-nm CMOS technology, which shows the effectiveness of speed and power over the state-of-the-art designs. PMID- 29990136 TI - Online Scale Adaptive Visual Tracking Based on Multilayer Convolutional Features. AB - Convolutional neural networks can efficiently exploit sophisticated hierarchical features which have different properties for visual tracking problem. In this paper, by using multilayer convolutional features jointly and constructing a scale pyramid, we propose an online scale adaptive tracking method. We construct two separate correlation filters for translation and scale estimations. The translation filters improve the accuracy of target localization by a weighted fusion of multiple convolutional layers. Meanwhile, the separate scale filters achieve the optimal and fast scale estimation by a scale pyramid. This design decreases the mutual errors of translation and scale estimations, and reduces computational complexity efficiently. Moreover, in order to solve the problem of tracking drifts due to the severe occlusion or serious appearance changes of the target, we present a new adaptive and selective update mechanism to update the translation filters effectively. Extensive experimental results show that our proposed method achieves the excellent overall performance compared with the state-of-the-art methods. PMID- 29990137 TI - Disambiguating Visual Verbs. AB - In this article, we introduce a new task, visual sense disambiguation for verbs: given an image and a verb, assign the correct sense of the verb, i.e., the one that describes the action depicted in the image. Just as textual word sense disambiguation is useful for a wide range of NLP tasks, visual sense disambiguation can be useful for multimodal tasks such as image retrieval, image description, and text illustration. We introduce a new dataset, which we call VerSe (short for Verb Sense) that augments existing multimodal datasets (COCO and TUHOI) with verb and sense labels. We explore supervised and unsupervised models for the sense disambiguation task using textual, visual, and multimodal embeddings. We also consider a scenario in which we must detect the verb depicted in an image prior to predicting its sense (i.e., there is no verbal information associated with the image). We find that textual embeddings perform well when gold-standard annotations (object labels and image descriptions) are available, while multimodal embeddings perform well on unannotated images. VerSe is publicly available at https://github.com/spandanagella/verse. PMID- 29990138 TI - Facial Landmark Detection with Tweaked Convolutional Neural Networks. AB - This paper concerns the problem of facial landmark detection. We provide a unique new analysis of the features produced at intermediate layers of a convolutional neural network (CNN) trained to regress facial landmark coordinates. This analysis shows that while being processed by the CNN, face images can be partitioned in an unsupervised manner into subsets containing faces in similar poses (i.e., 3D views) and facial properties (e.g., presence or absence of eye wear). Based on this finding, we describe a novel CNN architecture, specialized to regress the facial landmark coordinates of faces in specific poses and appearances. To address the shortage of training data, particularly in extreme profile poses, we additionally present data augmentation techniques designed to provide sufficient training examples for each of these specialized sub-networks. The proposed Tweaked CNN (TCNN) architecture is shown to outperform existing landmark detection methods in an extensive battery of tests on the AFW, ALFW, and 300W benchmarks. Finally, to promote reproducibility of our results, we make code and trained models publicly available through our project webpage. PMID- 29990140 TI - Deep Visual Attention Prediction. AB - In this paper, we aim to predict human eye fixation with view-free scenes based on an end-to-end deep learning architecture. Although convolutional neural networks (CNNs) have made substantial improvement on human attention prediction, it is still needed to improve the CNN-based attention models by efficiently leveraging multi-scale features. Our visual attention network is proposed to capture hierarchical saliency information from deep, coarse layers with global saliency information to shallow, fine layers with local saliency response. Our model is based on a skip-layer network structure, which predicts human attention from multiple convolutional layers with various reception fields. Final saliency prediction is achieved via the cooperation of those global and local predictions. Our model is learned in a deep supervision manner, where supervision is directly fed into multi-level layers, instead of previous approaches of providing supervision only at the output layer and propagating this supervision back to earlier layers. Our model thus incorporates multi-level saliency predictions within a single network, which significantly decreases the redundancy of previous approaches of learning multiple network streams with different input scales. Extensive experimental analysis on various challenging benchmark data sets demonstrate our method yields the state-of-the-art performance with competitive inference time. PMID- 29990139 TI - Multi-Channel Acquisition for Isotropic Resolution in Magnetic Particle Imaging. AB - Magnetic Particle Imaging (MPI), a molecular imaging modality that images biocompatible superparamagnetic iron oxide tracers, is well-suited for clinical angiography, in vivo cell tracking, cancer detection, and inflammation imaging. MPI is sensitive and quantitative to tracer concentration, with a positive contrast that is not attenuated or corrupted by tissue background. Like other clinical imaging techniques, such as computed tomography, magnetic resonance imaging, and nuclear medicine, MPI can be modeled as a linear and shift-invariant system with a well-defined point spread function (PSF) capturing the system blur. The key difference, as we show here, is that the MPI PSF is highly dependent on scanning parameters and is anisotropic using only a single-imaging trajectory. This anisotropic resolution poses a major challenge for clear and accurate clinical diagnosis. In this paper, we generalize a tensor imaging theory for multidimensional x-space MPI to explore the physical source of this anisotropy, present a multi-channel scanning algorithm to enable isotropic resolution, and experimentally demonstrate isotropic MPI resolution through the construction and the use of two orthogonal excitation and detector coil pairs. PMID- 29990141 TI - MixedFusion: Real-Time Reconstruction of an Indoor Scene with Dynamic Objects. AB - Real-time indoor scene reconstruction aims to recover the 3D geometry of an indoor scene in real time with a sensor scanning the scene. Previous works of this topic consider pure static scenes, but in this paper, we focus on more challenging cases that the scene contains dynamic objects, for example, moving people and floating curtains, which are quite common in reality and thus are eagerly required to be handled. We develop an end-to-end system using a depth sensor to scan a scene on the fly. By proposing a Sigmoid-based Iterative Closest Point (S-ICP) method, we decouple the camera motion and the scene motion from the input sequence and segment the scene into static and dynamic parts accordingly. The static part is used to estimate the camera rigid motion, while for the dynamic part, graph node-based motion representation and model-to-depth fitting are applied to reconstruct the scene motions. With the camera and scene motions reconstructed, we further propose a novel mixed voxel allocation scheme to handle static and dynamic scene parts with different mechanisms, which helps to gradually fuse a large scene with both static and dynamic objects. Experiments show that our technique successfully fuses the geometry of both the static and dynamic objects in a scene in real time, which extends the usage of the current techniques for indoor scene reconstruction. PMID- 29990142 TI - Is There a Robust Technique for Selecting Aspect Ratios in Line Charts? AB - The aspect ratio of a line chart heavily influences the perception of the underlying data. Different methods explore different criteria in choosing aspect ratios, but so far, it was still unclear how to select aspect ratios appropriately for any given data. This paper provides a guideline for the user to choose aspect ratios for any input 1D curves by conducting an in-depth analysis of aspect ratio selection methods both theoretically and experimentally. By formulating several existing methods as line integrals, we explain their parameterization invariance. Moreover, we derive a new and improved aspect ratio selection method, namely the -LOR (local orientation resolution), with a certain degree of parameterization invariance. Furthermore, we connect different methods, including AL (arc length based method), the banking to 45 principle, RV (resultant vector) and AS (average absolute slope), as well as -LOR and AO (average absolute orientation). We verify these connections by a comparative evaluation involving various data sets, and show that the selections by RV and LOR are complementary to each other for most data. Accordingly, we propose the dual-scale banking technique that combines the strengths of RV and -LOR, and demonstrate its practicability using multiple real-world data sets. PMID- 29990143 TI - Identifying Important Attributes for Early Detection of Chronic Kidney Disease. AB - Individuals with chronic kidney disease (CKD) are often not aware that the medical tests they take for other purposes may contain useful information about CKD, and that this information is sometimes not used effectively to tackle the identification of the disease. Therefore, attributes of different medical tests are investigated to identify which attributes may contain useful information about CKD. A database with several attributes of healthy subjects and subjects with CKD are analyzed using different techniques. Common spatial pattern (CSP) filter and linear discriminant analysis are first used to identify the dominant attributes that could contribute in detecting CKD. Here, the CSP filter is applied to optimize a separation between CKD and nonCKD subjects. Then, classification methods are also used to identify the dominant attributes. These analyses suggest that hemoglobin, albumin, specific gravity, hypertension, and diabetes mellitus, together with serum creatinine, are the most important attributes in the early detection of CKD. Further, it suggests that in the absence of information on hypertension and diabetes mellitus, random blood glucose and blood pressure attributes may be used. PMID- 29990144 TI - Modified Primal-Dual Neural Networks for Motion Control of Redundant Manipulators With Dynamic Rejection of Harmonic Noises. AB - In recent decades, primal-dual neural networks, as a special type of recurrent neural networks, have received great success in real-time manipulator control. However, noises are usually ignored when neural controllers are designed based on them, and thus, they may fail to perform well in the presence of intensive noises. Harmonic noises widely exist in real applications and can severely affect the control accuracy. This work proposes a novel primal-dual neural network design that directly takes noise control into account. By taking advantage of the fact that the unknown amplitude and phase information of a harmonic signal can be eliminated from its dynamics, our deliberately designed neural controller is able to reach the accurate tracking of reference trajectories in a noisy environment. Theoretical analysis and extensive simulations show that the proposed controller stabilizes the control system polluted by harmonic noises and converges the position tracking error to zero. Comparisons show that our proposed solution consistently and significantly outperforms the existing primal-dual neural solutions as well as feedforward neural one and adaptive neural one for redundancy resolution of manipulators. PMID- 29990145 TI - Editorial: Growth and Success - Looking Forward to 2018 and Beyond. PMID- 29990146 TI - Improving Dermoscopic Image Segmentation with Enhanced Convolutional Deconvolutional Networks. AB - Automatic skin lesion segmentation on dermoscopic images is an essential step in computer-aided diagnosis of melanoma. However, this task is challenging due to significant variations of lesion appearances across different patients. This challenge is further exacerbated when dealing with a large amount of image data. In this paper, we extended our previous work by developing a deeper network architecture with smaller kernels to enhance its discriminant capacity. In addition, we explicitly included color information from multiple color spaces to facilitate network training and thus to further improve the segmentation performance. We participated and extensively evaluated our method on the ISBI 2017 skin lesion segmentation challenge. By training with the 2000 challenge training images, our method achieved an average Jaccard Index (JA) of 0:765 on the 600 challenge testing images, which ranked itself in the first place among 21 final submissions in the challenge. PMID- 29990148 TI - Consensus of Discrete-Time Multiagent Systems With Input Delays by Truncated Pseudo-Predictor Feedback. AB - The consensus problem for multiagent systems (MASs) described by discrete-time linear systems with multiple input delays is investigated. Under two reasonable assumptions, a truncated pseudo-predictor feedback (TPPF) approach is established to solve the consensus problem. The proposed TPPF protocols allow arbitrarily large yet bounded delays and are easy to implement in practice since they are finite dimensional and only use the relative current state information of neighboring agents. Moreover, the proposed protocols can also achieve semi-global consensus of MASs if the actuators are subject to saturations. A numerical example is given to illustrate the effectiveness of the proposed approaches. PMID- 29990147 TI - Wandering Pattern Sensing at S-Band. AB - Increasing prevalence of dementia has posed several challenges for care-givers. Patients suffering from dementia often display wandering behavior due to boredom or memory loss. It is considered to be one of the challenging conditions to manage and understand. Traits of dementia patients can compromise their safety causing serious injuries. This paper presents investigation into the design and evaluation of wandering scenarios with patients suffering from dementia using an S-band sensing technique. This frequency band is the wireless channel commonly used to monitor and characterize different scenarios including random, lapping, and pacing movements in an indoor environment. Wandering patterns are characterized depending on the received amplitude and phase information of that measures the disturbance caused in the ideal radio signal. A secondary analysis using support vector machine is used to classify the three patterns. The results show that the proposed technique carries high classification accuracy up to 90% and has good potential for healthcare applications. PMID- 29990149 TI - Feature-Related Searching Control Model for Curve Detection. AB - In this paper, a novel method is proposed for curve detection in images using a feature-related searching control model. It is composed of three parts: 1) prediction; 2) searching; and 3) updating. First, curve related features are modeled to a three order array. Then, equations of the prediction, searching, and curve parameter updating are deduced. Third, an optimal model for curve parameter estimation during iterations is given. Based on the proposed model, a curve detection algorithm is designed. Experiments on thousands of images demonstrate the effectiveness and advantages of the proposed method. Comparison experiments with state-of-the-art methods show that the proposed method outperforms the existing methods on most indexes. Our method can describe the contents of original images more completely with fewer curves. The contour evaluation framework and the Berkeley segmentation dataset are used to evaluate the performances of different curve detection methods. The proposed method can also detect curves in the order relates to their importance, which has been validated in experiments. PMID- 29990150 TI - PD2T: Person-Specific Detection, Deformable Tracking. AB - Face detection/alignment methods have reached a satisfactory state in static images captured under arbitrary conditions. Such methods typically perform (joint) fitting for each frame and are used in commercial applications; however in the majority of the real-world scenarios the dynamic scenes are of interest. We argue that generic fitting per frame is suboptimal (it discards the informative correlation of sequential frames) and propose to learn person specific statistics from the video to improve the generic results. To that end, we introduce a meticulously studied pipeline, which we name PD2T, that performs person-specific detection and landmark localisation. We carry out extensive experimentation with a diverse set of i) generic fitting results, ii) different objects (human faces, animal faces) that illustrate the powerful properties of our proposed pipeline and experimentally verify that PD2T outperforms all the compared methods. PMID- 29990151 TI - Ego-Surfing: Person Localization in First-Person Videos Using Ego-Motion Signatures. AB - We envision a future time when wearable cameras are worn by the masses and recording first-person point-of-view videos of everyday life. While these cameras can enable new assistive technologies and novel research challenges, they also raise serious privacy concerns. For example, first-person videos passively recorded by wearable cameras will necessarily include anyone who comes into the view of a camera-with or without consent. Motivated by these benefits and risks, we developed a self-search technique tailored to first-person videos. The key observation of our work is that the egocentric head motion of a target person (i.e., the self) is observed both in the point-of-view video of the target and observer. The motion correlation between the target person's video and the observer's video can then be used to identify instances of the self uniquely. We incorporate this feature into the proposed approach that computes the motion correlation over densely-sampled trajectories to search for a target individual in observer videos. Our approach significantly improves self-search performance over several well-known face detectors and recognizers. Furthermore, we show how our approach can enable several practical applications such as privacy filtering, target video retrieval, and social group clustering. PMID- 29990152 TI - Visual and Semantic Knowledge Transfer for Large Scale Semi-Supervised Object Detection. AB - Deep CNN-based object detection systems have achieved remarkable success on several large-scale object detection benchmarks. However, training such detectors requires a large number of labeled bounding boxes, which are more difficult to obtain than image-level annotations. Previous work addresses this issue by transforming image-level classifiers into object detectors. This is done by modeling the differences between the two on categories with both image-level and bounding box annotations, and transferring this information to convert classifiers to detectors for categories without bounding box annotations. We improve this previous work by incorporating knowledge about object similarities from visual and semantic domains during the transfer process. The intuition behind our proposed method is that visually and semantically similar categories should exhibit more common transferable properties than dissimilar categories, e.g. a better detector would result by transforming the differences between a dog classifier and a dog detector onto the cat class, than would by transforming from the violin class. Experimental results on the challenging ILSVRC2013 detection dataset demonstrate that each of our proposed object similarity based knowledge transfer methods outperforms the baseline methods. We found strong evidence that visual similarity and semantic relatedness are complementary for the task, and when combined notably improve detection, achieving state-of-the-art detection performance in a semi-supervised setting. PMID- 29990153 TI - Linear Maximum Margin Classifier for Learning from Uncertain Data. AB - In this paper, we propose a maximum margin classifier that deals with uncertainty in data input. More specifically, we reformulate the SVM framework such that each training example can be modeled by a multi-dimensional Gaussian distribution described by its mean vector and its covariance matrix-the latter modeling the uncertainty. We address the classification problem and define a cost function that is the expected value of the classical SVM cost when data samples are drawn from the multi-dimensional Gaussian distributions that form the set of the training examples. Our formulation approximates the classical SVM formulation when the training examples are isotropic Gaussians with variance tending to zero. We arrive at a convex optimization problem, which we solve efficiently in the primal form using a stochastic gradient descent approach. The resulting classifier, which we name SVM with Gaussian Sample Uncertainty (SVM-GSU), is tested on synthetic data and five publicly available and popular datasets; namely, the MNIST, WDBC, DEAP, TV News Channel Commercial Detection, and TRECVID MED datasets. Experimental results verify the effectiveness of the proposed method. PMID- 29990155 TI - Sparse and Low-Rank Decomposition of a Hankel Structured Matrix for Impulse Noise Removal. AB - Recently, the annihilating filter-based low-rank Hankel matrix (ALOHA) approach was proposed as a powerful image inpainting method. Based on the observation that smoothness or textures within an image patch correspond to sparse spectral components in the frequency domain, ALOHA exploits the existence of annihilating filters and the associated rank-deficient Hankel matrices in an image domain to estimate any missing pixels. By extending this idea, we propose a novel impulse noise removal algorithm that uses the sparse and low-rank decomposition of a Hankel structured matrix. This method, referred to as the robust ALOHA, is based on the observation that an image corrupted with the impulse noise has intact pixels; consequently, the impulse noise can be modeled as sparse components, whereas the underlying image can still be modeled using a low-rank Hankel structured matrix. To solve the sparse and low-rank matrix decomposition problem, we propose an alternating direction method of multiplier approach, with initial factorized matrices coming from a low-rank matrix-fitting algorithm. To adapt local image statistics that have distinct spectral distributions, the robust ALOHA is applied in a patch-by-patch manner. Experimental results from impulse noise for both single-channel and multichannel color images demonstrate that the robust ALOHA is superior to existing approaches, especially during the reconstruction of complex texture patterns. PMID- 29990154 TI - Statistical Models of Signal and Noise and Fundamental Limits of Segmentation Accuracy in Retinal Optical Coherence Tomography. AB - Optical coherence tomography (OCT) has revolutionized diagnosis and prognosis of ophthalmic diseases by visualization and measurement of retinal layers. To speed up the quantitative analysis of disease biomarkers, an increasing number of automatic segmentation algorithms have been proposed to estimate the boundary locations of retinal layers. While the performance of these algorithms has significantly improved in recent years, a critical question to ask is how far we are from a theoretical limit to OCT segmentation performance. In this paper, we present the Cramer-Rao lower bounds (CRLBs) for the problem of OCT layer segmentation. In deriving the CRLBs, we address the important problem of defining statistical models that best represent the intensity distribution in each layer of the retina. Additionally, we calculate the bounds under an optimal affine bias, reflecting the use of prior knowledge in many segmentation algorithms. Experiments using in vivo images of human retina from a commercial spectral domain OCT system are presented, showing potential for improvement of automated segmentation accuracy. Our general mathematical model can be easily adapted for virtually any OCT system. Furthermore, the statistical models of signal and noise developed in this paper can be utilized for the future improvements of OCT image denoising, reconstruction, and many other applications. PMID- 29990156 TI - Semi-Supervised Deep Learning Using Pseudo Labels for Hyperspectral Image Classification. AB - Deep learning has gained popularity in a variety of computer vision tasks. Recently, it has also been successfully applied for hyperspectral image classification tasks. Training deep neural networks, such as a convolutional neural network for classification requires a large number of labeled samples. However, in remote sensing applications, we usually only have a small amount of labeled data for training because they are expensive to collect, although we still have abundant unlabeled data. In this paper, we propose semi-supervised deep learning for hyperspectral image classification-our approach uses limited labeled data and abundant unlabeled data to train a deep neural network. More specifically, we use deep convolutional recurrent neural networks (CRNN) for hyperspectral image classification by treating each hyperspectral pixel as a spectral sequence. In the proposed semi-supervised learning framework, the abundant unlabeled data are utilized with their pseudo labels (cluster labels). We propose to use all the training data together with their pseudo labels to pre train a deep CRNN, and then fine-tune using the limited available labeled data. Further, to utilize spatial information in the hyperspectral images, we propose a constrained Dirichlet process mixture model (C-DPMM), a non-parametric Bayesian clustering algorithm, for semi-supervised clustering which includes pairwise must link and cannot-link constraints-this produces high-quality pseudo-labels, resulting in improved initialization of the deep neural network. We also derived a variational inference model for the C-DPMM for efficient inference. Experimental results with real hyperspectral image data sets demonstrate that the proposed semi-supervised method outperforms state-of-the-art supervised and semi supervised learning methods for hyperspectral classification. PMID- 29990158 TI - Analyses of Gait Parameters of Younger and Older Adults During (Non-)Isometric Virtual Walking. AB - Understanding real walking in virtual environments (VEs) is important for immersive experiences, allowing users to move through VEs in the most natural way. Previous studies have shown that basic implementations of real walking in virtual spaces, in which head-tracked movements are mapped isometrically to a VE, are not estimated as entirely natural. Instead, users estimate a virtual walking velocity as more natural when it is slightly increased compared to the user's physical locomotion. However, these findings have been reported in most cases only for young persons, e.g., students, whereas older adults are clearly underrepresented in such studies. Recently, virtual reality (VR) has received significant public and media attention. Therefore, it appears reasonable to assume that people at different ages will have access to VR, and might use this technology more and more in application scenarios such as rehabilitation or training. To better understand how people at different ages walk and perceive locomotion in VR, we have performed a study to investigate the effects of (non )isometric mappings between physical movements and virtual motions in the VE on the walking biomechanics across generations, i.e., younger and older adults. Three primary domains (pace, base of support and phase) of spatio-temporal parameters were identified to evaluate gait performance. The results show that the older adults walked very similar in the real and VE in the pace and phasic domains, which differs from results found in younger adults. In contrast, the results indicate differences in terms of base of support domain parameters for both groups while walking within a VE and the real world. For non-isometric mappings, we found in both younger and older adults an increased divergence of gait parameters in all domains correlating with the up- or down-scaled velocity of visual self-motion feedback. The results provide important insights into the design of future VR applications for older adults in domains ranging from medicine and psychology to rehabilitation. PMID- 29990159 TI - Magnetic Levitation Haptic Augmentation for Virtual Tissue Stiffness Perception. AB - Haptic-based tissue stiffness perception is essential for palpation training system, which can provide the surgeon haptic cues for improving the diagnostic abilities. However, current haptic devices, such as Geomagic Touch, fail to provide immersive and natural haptic interaction in virtual surgery due to the inherent mechanical friction, inertia, limited workspace and flawed haptic feedback. To tackle this issue, we design a novel magnetic levitation haptic device based on electromagnetic principles to augment the tissue stiffness perception in virtual environment. Users can naturally interact with the virtual tissue by tracking the motion of magnetic stylus using stereoscopic vision so that they can accurately sense the stiffness by the magnetic stylus, which moves in the magnetic field generated by our device. We propose the idea that the effective magnetic field (EMF) is closely related to the coil attitude for the first time. To fully harness the magnetic field and flexibly generate the specific magnetic field for obtaining required haptic perception, we adopt probability clouds to describe the requirement of interactive applications and put forward an algorithm to calculate the best coil attitude. Moreover, we design a control interface circuit and present a self-adaptive fuzzy proportion integration differentiation (PID) algorithm to precisely control the coil current. We evaluate our haptic device via a series of quantitative experiments which show the high consistency of the experimental and simulated magnetic flux density, the high accuracy (0.28 mm) of real-time 3D positioning and tracking of the magnetic stylus, the low power consumption of the adjustable coil configuration, and the tissue stiffness perception accuracy improvement by 2.38 percent with the self-adaptive fuzzy PID algorithm. We conduct a user study with 22 participants, and the results suggest most of the users can clearly and immersively perceive different tissue stiffness and easily detect the tissue abnormality. Experimental results demonstrate that our magnetic levitation haptic device can provide accurate tissue stiffness perception augmentation with natural and immersive haptic interaction. PMID- 29990160 TI - ToBio: Global Pathway Similarity Search based on Topological and Biological Features. AB - Pathway similarity search plays a vital role in the post-genomics era. Unfortunately, pathway similarity search involves the graph isomorphism problem which is NP-complete. Therefore, efficient search algorithms are desirable. In this work, we propose a novel global pathway similarity search approach named ToBio, which considers both topological and biological features for effective global pathway similarity search. Specifically, as motivated from nature, various topological and biological features including subgraph signature similarities, sequence similarities, and gene ontology similarities are considered in ToBio. Since different features carry different functional importance and dependences, we report three schemes of ToBio using different sets of features. In addition, to enhance the existing search algorithms for rigorous comparisons, post processing pipelines are also proposed to investigate how different features can contribute to the search performance. ToBio and other state-of-the-art methods are benchmarked on the gold-standard pathway datasets from three species; the results demonstrate the competitive edges of ToBio over the state-of-the-arts ranging from the topological aspects to the biological aspects. Case studies have been conducted to reveal mechanistic insights into the unique search performance of ToBio. PMID- 29990161 TI - Connectivity-Preserving Consensus Tracking of Uncertain Nonlinear Strict-Feedback Multiagent Systems: An Error Transformation Approach. AB - This brief addresses a distributed connectivity-preserving adaptive consensus tracking problem of uncertain nonlinear strict-feedback multiagent systems with limited communication ranges. Compared with existing consensus results for uncertain nonlinear lower triangular multiagent systems, the main contribution of this brief is to present an error-transformation-based design methodology to preserve initial connectivity patterns in the consensus tracking field, namely, both connectivity preservation and consensus tracking problems are considered for uncertain nonlinear lower triangular multiagent systems. A dynamic surface design based on nonlinearly transformed errors and neural network function approximators is established to construct the local controller of each follower. In addition, a technical lemma is derived to analyze the stability of the proposed connectivity preserving consensus scheme in the Lyapunov sense. PMID- 29990162 TI - Multiobjective Patient Stratification Using Evolutionary Multiobjective Optimization. AB - One of the main challenges in modern medic-ine is to stratify patients for personalized care. Many different clustering methods have been proposed to solve the problem in both quantitative and biologically meaningful manners. However, existing clustering algorithms suffer from numerous restrictions such as experimental noises, high dimensionality, and poor interpretability. To overcome those limitations altogether, we propose and formulate a multiobjective framework based on evolutionary multiobjective optimization to balance the feature relevance and redundancy for patient stratification. To demonstrate the effectiveness of our proposed algorithms, we benchmark our algorithms across 55 synthetic datasets based on a real human transcription regulation network model, 35 real cancer gene expression datasets, and two case studies. Experimental results suggest that the proposed algorithms perform better than the recent state of-the-arts. In addition, time complexity analysis, convergence analysis, and parameter analysis are conducted to demonstrate the robustness of the proposed methods from different perspectives. Finally, the t-Distributed Stochastic Neighbor Embedding (t-SNE) is applied to project the selected feature subsets onto two or three dimensions to visualize the high-dimensional patient stratification data. PMID- 29990163 TI - 3-D Tracking for Augmented Reality Using Combined Region and Dense Cues in Endoscopic Surgery. AB - An augmented reality (AR) technique has recently gained its popularity in minimally invasive surgery. Tracking is a crucial step to achieve precise AR. Besides optical tracking in traditional medical AR, visual tracking attracts a lot of attention due to its generality. Moreover, when the target organ's 3-D model can be obtained from preoperative images and under the model rigidity assumption, tracking is then converted into a problem of computing the six-degree of-freedom pose of the 3-D model. In this paper, we introduce a robust tracking algorithm in our endoscopic AR system, where we combine the benefits of both region and dense cues in a unified framework. Each kind of cues alone may not be adequate for tracking in endoscopic surgery. However, they have complementary characteristics, with region cues being more robust to motion blur and fast motion, and dense cues being more accurate when motion is not large. We also propose an appearance model adaption method and an occlusion processing method to effectively handle occlusions. Experiments on both synthetic dataset and simulated surgical environment show the effectiveness and robustness of our proposed method. This work presents a novel tracking strategy in medical AR applications. PMID- 29990164 TI - Real-Time Multilead Convolutional Neural Network for Myocardial Infarction Detection. AB - In this paper, a novel algorithm based on a convolutional neural network (CNN) is proposed for myocardial infarction detection via multilead electrocardiogram (ECG). A beat segmentation algorithm utilizing multilead ECG is designed to obtain multilead beats, and fuzzy information granulation is adopted for preprocessing. Then, the beats are input into our multilead-CNN (ML-CNN), a novel model that includes sub two-dimensional (2-D) convolutional layers and lead asymmetric pooling (LAP) layers. As different leads represent various angles of the same heart, LAP can capture multiscale features of different leads, exploiting the individual characteristics of each lead. In addition, sub 2-D convolution can utilize the holistic characters of all the leads. It uses 1-D kernels shared among the different leads to generate local optimal features. These strategies make the ML-CNN suitable for multilead ECG processing. To evaluate our algorithm, actual ECG datasets from the PTB diagnostic database are used. The sensitivity of our algorithm is 95.40%, the specificity is 97.37%, and the accuracy is 96.00% in the experiments. Targeting lightweight mobile healthcare applications, real-time analyses are performed on both MATLAB and ARM Cortex-A9 platforms. The average processing times for each heartbeat are approximately 17.10 and 26.75 ms, respectively, which indicate that this method has good potential for mobile healthcare applications. PMID- 29990165 TI - Hierarchical Bayesian Inference and Learning in Spiking Neural Networks. AB - Numerous experimental data from neuroscience and psychological science suggest that human brain utilizes Bayesian principles to deal the complex environment. Furthermore, hierarchical Bayesian inference has been proposed as an appropriate theoretical framework for modeling cortical processing. However, it remains unknown how such a computation is organized in the network of biologically plausible spiking neurons. In this paper, we propose a hierarchical network of winner-take-all circuits which can carry out hierarchical Bayesian inference and learning through a spike-based variational expectation maximization (EM) algorithm. Particularly, we show how the firing activities of spiking neurons in response to the input stimuli and the spike-timing-dependent plasticity rule can be understood, respectively, as variational E-step and M-step of variational EM. Finally, we demonstrate the utility of this spiking neural network on the MNIST benchmark for unsupervised classification of handwritten digits. PMID- 29990166 TI - Tetrahedron Based Fast 3D Fingerprint Identification Using Colored LEDs Illumination. AB - Emerging 3D fingerprint recognition technologies have attracted growing attention in addressing the limitations from contact-based fingerprint acquisition and improve recognition accuracy. However, the complex 3D imaging setups employed in these systems typically require structured lighting with scanners or multiple cameras which are bulky with higher cost. This paper presents a more accurate and efficient 3D fingerprint identification approach using a single 2D camera with multiple colored LED illumination. A 3D minutiae tetrahedron based algorithm is developed to more efficiently match recovered minutiae features in 3D space and address the limitations of 3D minutiae matching approach in the literature. This algorithm significantly improves the matching time to about 15 times than the state-of-art in the reference. A hierarchical tetrahedron matching scheme is also developed to further improve the matching accuracy with faster speed. The 2D images acquired to reconstruct the 3D fingerprints are also used to recover 2D minutiae and further improve matching performance for 3D fingerprints. A new two session database acquiring from 300 different clients consists of 2760 3D fingerprints reconstructed from 5520 colored 2D fingerprints is also developed and shared in public domain to further advance much needed research in this area. Extensive experimental results presented in this paper validate our approach and demonstrate the effectiveness of proposed algorithms. PMID- 29990167 TI - Skeleton-Based Action Recognition Using Spatio-Temporal LSTM Network with Trust Gates. AB - Skeleton-based human action recognition has attracted a lot of research attention during the past few years. Recent works attempted to utilize recurrent neural networks to model the temporal dependencies between the 3D positional configurations of human body joints for better analysis of human activities in the skeletal data. The proposed work extends this idea to spatial domain as well as temporal domain to better analyze the hidden sources of action-related information within the human skeleton sequences in both of these domains simultaneously. Based on the pictorial structure of Kinect's skeletal data, an effective tree-structure based traversal framework is also proposed. In order to deal with the noise in the skeletal data, a new gating mechanism within LSTM module is introduced, with which the network can learn the reliability of the sequential data and accordingly adjust the effect of the input data on the updating procedure of the long-term context representation stored in the unit's memory cell. Moreover, we introduce a novel multi-modal feature fusion strategy within the LSTM unit in this paper. The comprehensive experimental results on seven challenging benchmark datasets for human action recognition demonstrate the effectiveness of the proposed method. PMID- 29990168 TI - Multiresolution Volume Filtering in the Tensor Compressed Domain. AB - Signal processing and filter operations are important tools for visual data processing and analysis. Due to GPU memory and bandwidth limitations, it is challenging to apply complex filter operators to large-scale volume data interactively. We propose a novel and fast multiscale compression-domain volume filtering approach integrated into an interactive multiresolution volume visualization framework. In our approach, the raw volume data is decomposed offline into a compact hierarchical multiresolution tensor approximation model. We then demonstrate how convolution filter operators can effectively be applied in the compressed tensor approximation domain. To prevent aliasing due to multiresolution filtering, our solution (a) filters accurately at the full spatial volume resolution at a very low cost in the compressed domain, and (b) reconstructs and displays the filtered result at variable level-of-detail. The proposed system is scalable, allowing interactive display and filtering of large volume datasets that may exceed the available GPU memory. The desired filter kernel mask and size can be modified online, producing immediate visual results. PMID- 29990169 TI - Evaluating Quality of Screen Content Images Via Structural Variation Analysis. AB - With the quick development and popularity of computers, computer-generated signals have drastically invaded into our daily lives. Screen content image is a typical example, since it also includes graphic and textual images as components as compared with natural scene images which have been deeply explored, and thus screen content image has posed novel challenges to current researches, such as compression, transmission, display, quality assessment, and more. In this paper, we focus our attention on evaluating the quality of screen content images based on the analysis of structural variation, which is caused by compression, transmission, and more. We classify structures into global and local structures, which correspond to basic and detailed perceptions of humans, respectively. The characteristics of graphic and textual images, e.g., limited color variations, and the human visual system are taken into consideration. Based on these concerns, we systematically combine the measurements of variations in the above stated two types of structures to yield the final quality estimation of screen content images. Thorough experiments are conducted on three screen content image quality databases, in which the images are corrupted during capturing, compression, transmission, etc. Results demonstrate the superiority of our proposed quality model as compared with state-of-the-art relevant methods. PMID- 29990170 TI - A Bi-objective RNN Model to Reconstruct Gene Regulatory Network: A Modified Multi objective Simulated Annealing Approach. AB - Gene Regulatory Network (GRN) is a virtual network in a cellular context of an organism, comprising a set of genes and their internal relationships to regulate protein production rate (gene expression level) of each other through coded proteins. Computational Reconstruction of GRN from gene expression data is a widely-applied research area. Recurrent Neural Network (RNN) is a useful modeling scheme for GRN reconstruction. In this research, the RNN formulation of GRN reconstruction having single objective function has been modified to incorporate a new objective function. An existing multi-objective meta-heuristic algorithm, Archived Multi Objective Simulated Annealing (AMOSA) has been modified and applied to this bi-objective RNN formulation. Executing the resulting algorithm (called AMOSA-GRN) on a gene expression dataset, a collection (termed as Archive) of non-dominated GRNs has been obtained. Ensemble averaging has been applied on the archives, obtained through a sequence of executions of AMOSA-GRN. Accuracy of GRNs in the averaged archive, with respect to gold standard GRN, varies in the range 0.875 1.0 (87.5% - 100%). PMID- 29990171 TI - Improved Stability Analysis for Delayed Neural Networks. AB - In this brief, by constructing an augmented Lyapunov-Krasovskii functional in a triple integral form, the stability analysis of delayed neural networks is investigated. In order to exploit more accurate bounds for the derivatives of triple integrals, new double integral inequalities are developed, which include some recently introduced estimation techniques as special cases. The information on the activation function is taken into full consideration. Taking advantages of the proposed inequalities, the stability criteria with less conservatism are derived. The improvement of the obtained approaches is verified by numerical examples. PMID- 29990172 TI - Recursive Adaptive Sparse Exponential Functional Link Neural Network for Nonlinear AEC in Impulsive Noise Environment. AB - Recently, an adaptive exponential trigonometric functional link neural network (AETFLN) architecture has been introduced to enhance the nonlinear processing capability of the trigonometric functional link neural network (TFLN). However, it suffers from slow convergence speed, heavy computational burden, and poor robustness to noise in nonlinear acoustic echo cancellation, especially in the double-talk scenario. To reduce its computational complexity and improve its robustness against impulsive noise, this paper develops a recursive adaptive sparse exponential TFLN (RASETFLN). Based on sparse representations of functional links, the robust proportionate adaptive algorithm is deduced from the robust cost function over the RASETFLN in impulsive noise environments. Theoretical analysis shows that the proposed RASETFLN is stable under certain conditions. Finally, computer simulations illustrate that the proposed RASETFLN achieves much improved performance over the AETFLN in several nonlinear scenarios in terms of convergence rate, steady-state error, and robustness against noise. PMID- 29990173 TI - Large-Scale Metric Learning: A Voyage From Shallow to Deep. AB - Despite its attractive properties, the performance of the recently introduced Keep It Simple and Straightforward MEtric learning (KISSME) method is greatly dependent on principal component analysis as a preprocessing step. This dependence can lead to difficulties, e.g., when the dimensionality is not meticulously set. To address this issue, we devise a unified formulation for joint dimensionality reduction and metric learning based on the KISSME algorithm. Our joint formulation is expressed as an optimization problem on the Grassmann manifold, and hence enjoys the properties of Riemannian optimization techniques. Following the success of deep learning in recent years, we also devise end-to-end learning of a generic deep network for metric learning using our derivation. PMID- 29990174 TI - Distributed Event-Triggered Adaptive Control for Cooperative Output Regulation of Heterogeneous Multiagent Systems Under Switching Topology. AB - This paper investigates the cooperative output regulation problem for heterogeneous multiagent systems (MASs) under switching topology. Two novel distributed event-triggered adaptive control strategies based on state feedback and output feedback are developed, which can avoid using the minimal nonzero eigenvalue of Laplacian matrix associated with global system topologies. It is shown that under the proposed control protocols, MASs could achieve asymptotic tracking and disturbance rejection, and meanwhile, the amount of transmission data and communication cost among agents can be reduced. Then, the leader following consensus problem of MASs is given as an application of our main results. Finally, an example is presented to verify the effectiveness of the proposed control schemes. PMID- 29990175 TI - Multilabel Prediction via Cross-View Search. AB - Embedding methods have shown promising performance in multilabel prediction, as they are able to discover the label dependence. However, most methods ignore the correlations between the input and output, such that their learned embeddings are not well aligned, which leads to degradation in prediction performance. This paper presents a formulation for multilabel learning, from the perspective of cross-view learning, that explores the correlations between the input and the output. The proposed method, called Co-Embedding (CoE), jointly learns a semantic common subspace and view-specific mappings within one framework. The semantic similarity structure among the embeddings is further preserved, ensuring that close embeddings share similar labels. Additionally, CoE conducts multilabel prediction through the cross-view $k$ nearest neighborhood ( $k$ NN) search among the learned embeddings, which significantly reduces computational costs compared with conventional decoding schemes. A hashing-based model, i.e., Co-Hashing (CoH), is further proposed. CoH is based on CoE, and imposes the binary constraint on continuous latent embeddings. CoH aims to generate compact binary representations to improve the prediction efficiency by benefiting from the efficient $k$ NN search of multiple labels in the Hamming space. Extensive experiments on various real-world data sets demonstrate the superiority of the proposed methods over the state of the arts in terms of both prediction accuracy and efficiency. PMID- 29990176 TI - Dynamic Analysis of Hybrid Impulsive Delayed Neural Networks With Uncertainties. AB - Neural networks (NNs) have emerged as a powerful illustrative diagram for the brain. Unveiling the mechanism of neural-dynamic evolution is one of the crucial steps toward understanding how the brain works and evolves. Inspired by the universal existence of impulses in many real systems, this paper formulates a type of hybrid NNs (HNNs) with impulses, time delays, and interval uncertainties, and studies its global dynamic evolution by a robust interval analysis. The HNNs incorporate both continuous-time implementation and impulsive jump in mutual activations, where time delays and interval uncertainties are represented simultaneously. By constructing a Banach contraction mapping, the existence and uniqueness of the equilibrium of the HNN model are proved and analyzed in detail. Based on nonsmooth Lyapunov functions and delayed impulsive differential equations, new criteria are derived for ensuring the global robust exponential stability of the HNNs. Convergence analysis together with illustrative examples show the effectiveness of the theoretical results. PMID- 29990177 TI - Robust Zeroing Neural-Dynamics and Its Time-Varying Disturbances Suppression Model Applied to Mobile Robot Manipulators. AB - This paper proposes a novel robust zeroing neural-dynamics (RZND) approach as well as its associated model for solving the inverse kinematics problem of mobile robot manipulators. Unlike existing works based on the assumption that neural network models are free of external disturbances, four common forms of time varying disturbances suppressed by the proposed RZND model are investigated in this paper. In addition, theoretical analyses on the antidisturbance performance are presented in detail to prove the effectiveness and robustness of the proposed RZND model with time-varying disturbances suppressed for solving the inverse kinematics problem of mobile robot manipulators. That is, the RZND model converges toward the exact solution of the inverse kinematics problem of mobile robot manipulators with bounded or zero-oriented steady-state position error. Moreover, simulation studies and comprehensive comparisons with existing neural network models, e.g., the conventional Zhang neural network model and the gradient-based recurrent neural network model, together with extensive tests with four common forms of time-varying disturbances substantiate the efficacy, robustness, and superiority of the proposed RZND approach as well as its time varying disturbances suppression model for solving the inverse kinematics problem of mobile robot manipulators. PMID- 29990178 TI - Event-Based Adaptive NN Tracking Control of Nonlinear Discrete-Time Systems. AB - This paper is concerned with the simultaneous design of a neural network (NN) based adaptive control law and an event-triggering condition for a class of strict feedback nonlinear discrete-time systems. The stability and tracking performance of the closed-loop network control system under the event-triggering strategy is formally proven based on the Lyapunov theory in a hybrid framework. The proposed Lyapunov formulation yields an event-triggered algorithm to update the control input and NN weights based on conditions involving the closed-loop state. Different from the existing traditional NN control schemes where the feedback signals are transmitted and executed periodically, the feedback signals are transmitted and executed only when the event-trigger error exceeds the specified threshold, which can largely reduce the communication load. The effectiveness of the approach is evaluated through a simulation example. PMID- 29990179 TI - Computer-Aided Medical Image Annotation: Preliminary Results With Liver Lesions in CT. AB - The increasing volume of medical image data, as well as the need for multicenter data consolidation for big data analytics, require computer-aided medical image annotation (CMIA). Majority of the methods proposed so far do not exploit interdependencies between annotations explicitly. They further limit their annotations at a higher level than diagnostics and/or do not consider a standardized lexicon. A radiologist-in-the-loop semi-automatic CMIA system is proposed. It is based on a Bayesian tree structured model, linked to RadLex, and present preliminary results with liver lesions in computed tomography images. The proposed system guides the radiologist to input the most critical information in each iteration and uses a network model to update the full annotation online. The effectiveness of the system using this model-based interactive annotation scheme is shown by contrasting the domain-blind and domain-aware models. Preliminary results show that on average 7.50 (out of 29) manual annotations are sufficient for ${?text{95}}?%$ accuracy, which is ${?text{32.8}}?%$ less than the required manual effort when there is no guidance. The results also suggest that the domain aware models perform better than the domain-blind models learned from data. Further analysis with larger datasets and in domains other than the liver lesions is needed. PMID- 29990180 TI - Regularizing Knowledge Transfer in Recommendation With Tag-Inferred Correlation. AB - Traditional recommender systems suffer from the data sparsity problem. However, user knowledge acquired in one domain can be transferred and exploited in several other relevant domains. In this context, cross-domain recommender systems have been proposed to create a new and effective recommendation paradigm in which to exploit rich data from auxiliary domains to assist recommendations in a target domain. Before knowledge transfer takes place, building reliable and concrete domain correlation is the key ensuring that only relevant knowledge will be transferred. Social tags are used to explicitly link different domains, especially when neither users nor items overlap. However, existing models only exploit a subset of tags that are shared by heterogeneous domains. In this paper, we propose a complete tag-induced cross-domain recommendation (CTagCDR) model, which infers interdomain and intradomain correlations from tagging history and applies the learned structural constraints to regularize joint matrix factorization. Compared to similar models, CTagCDR is able to fully explore knowledge encoded in both shared and domain-specific tags. We demonstrate the performance of our proposed model on three public datasets and compare it with five state-of-the-art single and cross-domain recommendation approaches. The results show that CTagCDR works well in both rating prediction and item recommendation tasks, and can effectively improve recommendation performance. PMID- 29990181 TI - Pricing Mechanism With Noncooperative Game and Revenue Sharing Contract in Electricity Market. AB - In this paper, a pricing mechanism is proposed for the electricity supply chain, which is consisting of one generation company (GC), multiple consumers, and competing utility companies (UCs). The UC participates in electricity supply chain management by a revenue sharing contract (RSC). In the electricity supply chain, the electricity real-time balance has an important role in the stable operation of the power system. Therefore, we introduce the demand response into the electricity supply chain to match supply with demand under forecast errors. Hence, we formulate a noncooperative game to characterize the interactions among the multiple competing UCs, which set the retail prices to maximize their profits. Besides, the UCs select their preferred contractual terms offered by the GC to maximize its profits and coordinate the electricity supply chain simultaneously. The existence and uniqueness of the Nash equilibrium (NE) are examined, and an iterative algorithm is developed to obtain the NE. Furthermore, we analyze the RSC that can coordinate the electricity supply chain and align the NE with the cooperative optimum under the RSC. Finally, numerical results demonstrate the superiority of the proposed model and the influence of market demand disruptions on the profits of the UCs, GC, and supply chain. PMID- 29990182 TI - Pareto Optimal Decision Making in a Distributed Opportunistic Sensing Problem. AB - We extend prior results on a single decision maker opportunistic sensing problem to a distributed, multidecision maker setting. The original formulation of the problem considers how to opportunistically use ''in-flight'' sensors to maximize target coverage. In that paper, the authors show that this problem is NP-hard with a strong polynomial heuristic for a single decision maker. This paper extends this by considering a distributed decision making scenario in which multiple independent parties attempt to simultaneously engage in opportunistic sensor assignment while managing interassignment conflict. Specifically, we develop an algorithm that: 1) produces a Pareto optimal opportunistic sensor allocation; 2) requires fewer bits of communicated information than a completely centralized deconfliction approach; and 3) runs in distributed polynomial time once the individual decision makers identify their preferred (optimal) sensor allocations. We validate these claims using appropriate simulations. PMID- 29990183 TI - Distributed Optimization for Multiagent Systems: An Edge-Based Fixed-Time Consensus Approach. AB - This paper deals with the problem of distributed optimization for multiagent systems by using an edge-based fixed-time consensus approach. In the case of time invariant cost functions, a new distributed protocol is proposed to achieve the state agreement in a fixed time while the sum of local convex functions known to individual agents is minimized. In the case of time-varying cost functions, based on the new distributed protocol in the case of time-invariant cost functions, a distributed protocol is provided by taking the Hessian matrix into account. In both cases, stability conditions are derived to ensure that the distributed optimization problem is solved under both fixed and switching communication topologies. A distinctive feature of the results in this paper is that an upper bound of settling time for consensus can be estimated without dependence on initial states of agents, and thus can be made arbitrarily small through adjusting system parameters. Therefore, the results in this paper can be applicable in an unknown environment such as drone rendezvous within a required time for military purpose while optimizing local objectives. Case studies of a power output agreement for battery packages are provided to demonstrate the effectiveness of the theoretical results. PMID- 29990184 TI - Color Homography: theory and applications. AB - Images of co-planar points in 3-dimensional space taken from different camera positions are a homography apart. Homographies are at the heart of geometric methods in computer vision and are used in geometric camera calibration, 3D reconstruction, stereo vision and image mosaicking among other tasks. In this paper we show the surprising result that homographies are the apposite tool for relating image colors of the same scene when the capture conditions - illumination color, shading and device - change. PMID- 29990185 TI - Cross Euclidean-to-Riemannian Metric Learning with Application to Face Recognition from Video. AB - Riemannian manifolds have been widely employed for video representations in visual classification tasks including video-based face recognition. The success mainly derives from learning a discriminant Riemannian metric which encodes the non-linear geometry of the underlying Riemannian manifolds. In this paper, we propose a novel metric learning framework to learn a distance metric across a Euclidean space and a Riemannian manifold to fuse average appearance and pattern variation of faces within one video. The proposed metric learning framework can handle three typical tasks of video-based face recognition: Video-to-Still, Still to-Video and Video-to-Video settings. To accomplish this new framework, by exploiting typical Riemannian geometries for kernel embedding, we map the source Euclidean space and Riemannian manifold into a common Euclidean subspace, each through a corresponding high-dimensional Reproducing Kernel Hilbert Space (RKHS). With this mapping, the problem of learning a cross-view metric between the two source heterogeneous spaces can be converted to learning a single-view Euclidean distance metric in the target common Euclidean space. By learning information on heterogeneous data with the shared label, the discriminant metric in the common space improves face recognition from videos. Extensive experiments on four challenging video face databases demonstrate that the proposed framework has a clear advantage over the state-of-the-art methods in the three classical video based face recognition scenarios. PMID- 29990186 TI - Safe Feature Screening for Generalized LASSO. AB - Solving Generalized LASSO (GL) problems is challenging, particularly when analyzing many features with a complex interacting structure. Recent developments have found effective ways to identify inactive features so that they can be removed or aggregated to reduce the problem size before applying optimization solvers for learning. However, existing methods are mostly devoted to special cases of GL problems with special structures for feature interactions, such as chains or trees. Developing screening rules, particularly, safe screening rules to remove or aggregate features with general interaction structures, calls for a very different screening approach for GL problems. To tackle this challenge, we formulate the GL screening problem as a bound estimation problem in a large linear inequality system when solving them in the dual space. We propose a novel bound propagation algorithm for efficient safe screening for general GL problems, which can be further enhanced by developing novel transformation methods that can effectively decouple interactions among features. The proposed propagation and transformation methods are applicable with dynamic screening that can easily initiate the screening process while existing screening methods require the knowledge of the solution under a desirable regularization parameter. Experiments on both synthetic and real-world data demonstrate the effectiveness of the proposed screening method. PMID- 29990187 TI - Efficient Group-n Encoding and Decoding for Facial Age Estimation. AB - Different ages are closely related especially among the adjacent ages because aging is a slow and extremely non-stationary process with much randomness. To explore the relationship between the real age and its adjacent ages, an age group n encoding (AGEn) method is proposed in this paper. In our model, adjacent ages are grouped into the same group and each age corresponds to n groups. The ages grouped into the same group would be regarded as an independent class in the training stage. On this basis, the original age estimation problem can be transformed into a series of binary classification sub-problems. And a deep Convolutional Neural Networks (CNN) with multiple classifiers is designed to cope with such sub-problems. Later, a Local Age Decoding (LAD) strategy is further presented to accelerate the prediction process, which locally decodes the estimated age value from ordinal classifiers. Besides, to alleviate the imbalance data learning problem of each classifier, a penalty factor is inserted into the unified objective function to favor the minority class. To compare with state-of the-art methods, we evaluate the proposed method on FG-NET, MORPH II, CACD and Chalearn LAP 2015 databases and it achieves the best performance. PMID- 29990188 TI - Single Image Super-Resolution Based on Wiener Filter in Similarity Domain. AB - Single image super-resolution (SISR) is an ill-posed problem aiming at estimating a plausible high-resolution (HR) image from a single low-resolution image. Current state-of-the-art SISR methods are patch-based. They use either external data or internal self-similarity to learn a prior for an HR image. External data based methods utilize a large number of patches from the training data, while self-similarity-based approaches leverage one or more similar patches from the input image. In this paper, we propose a self-similarity-based approach that is able to use large groups of similar patches extracted from the input image to solve the SISR problem. We introduce a novel prior leading to the collaborative filtering of patch groups in a 1D similarity domain and couple it with an iterative back-projection framework. The performance of the proposed algorithm is evaluated on a number of SISR benchmark data sets. Without using any external data, the proposed approach outperforms the current non-convolutional neural network-based methods on the tested data sets for various scaling factors. On certain data sets, the gain is over 1 dB, when compared with the recent method A+. For high sampling rate (x4), the proposed method performs similarly to very recent state-of-the-art deep convolutional network-based approaches. PMID- 29990189 TI - Exploiting Target Data to Learn Deep Convolutional Networks for Scene-Adapted Human Detection. AB - The difference between sample distributions of public data sets and specific scenes can be very significant. As a result, the deployment of generic human detectors in real-world scenes most often leads to sub-optimal detection performance. To avoid the labor-intensive task of manual annotations, we propose a semi-supervised approach for training deep convolutional networks on partially labeled data. To exploit a large amount of unlabeled target data, the knowledge learnt from public data sets is transferred to new model training by adapting an auxiliary detector to the target scene. We hypothesize that the components of the auxiliary detector capture essential human characteristics useful for constructing a scene-adapted detector. A selective ensemble algorithm is proposed to select a subset of the components relevant to the target scene for recombination. The resulting model is applied for collecting high-confidence samples from unlabeled target data. Furthermore, a deep convolutional network is trained by progressively labeling and selecting new training samples in a self paced way. The detailed experimental evaluation verifies the effectiveness and superiority of the proposed approach in scene-specific human detection. PMID- 29990190 TI - Robust Multi-Focus Image Fusion Using Edge Model and Multi-Matting. AB - An effective multi-focus image fusion method is proposed to generate an all-in focus image with all objects in focus by merging multiple images. The proposed method first estimates focus maps using a novel combination of edge model and a traditional block-based focus measure. Then, a propagation process is conducted to obtain accurate weight maps based on a novel multi-matting model that makes full use of the spatial information. The fused all-in-focus image is finally generated based on a weighted-sum strategy. Experimental results demonstrate that the proposed method has state-of-the-art performance for multi-focus image fusion under various situations encountered in practice, even in cases with obvious misregistration. PMID- 29990191 TI - Exploiting Spatial-Temporal Locality of Tracking via Structured Dictionary Learning. AB - In this paper, a novel spatial-temporal locality is proposed and unified via a discriminative dictionary learning framework for visual tracking. By exploring the strong local correlations between temporally obtained target and their spatially distributed nearby background neighbors, a spatial-temporal locality is obtained. The locality is formulated as a subspace model and exploited under a unified structure of discriminative dictionary learning with a subspace structure. Using the learned dictionary, the target and its background can be described and distinguished effectively through their sparse codes. As a result, the target is localized by integrating both the descriptive and the discriminative qualities. Extensive experiments on various challenging video sequences demonstrate the superior performance of proposed algorithm over the other state-of-the-art approaches. PMID- 29990192 TI - 3-D Shape Matching and Non-Rigid Correspondence for Hippocampi Based on Markov Random Fields. AB - The purpose of this paper is to recover dense correspondence between non-rigid shapes for anatomical objects, which is a key element of disease diagnosis and analysis. We proposed a shape matching framework based on Markov random fields to obtain non-rigid correspondence. We constructed an energy function by summing up two terms where one was a unary term and the other was a binary term. By using this formulation, shape matching was represented as an energy function minimisation problem. Loopy belief propagation (LBP) was then used to minimize the energy function. We adopted a new sparse update technique for LBP update to increase computational efficiency. At the same time, we also proposed to use a novel clamping technique, an expectation-maximization (EM) like approach, to enhance matching accuracy. Experiments with the hippocampal data from OASIS and PATH showed that the sparse update was 160 times faster than standard BP. By iteratively running the EM-like clamping procedure, we were able to obtain high quality non-rigid correspondence results to achieve 97% matching rate between two hippocampi. Our shape matching based approach overcomes the flip problem of first order ellipsoid and does not assume pre-alignment unlike iterative closest point. PMID- 29990193 TI - Joint Hand Detection and Rotation Estimation Using CNN. AB - Hand detection is essential for many hand related tasks, e.g., recovering hand pose and understanding gesture. However, hand detection in uncontrolled environments is challenging due to the flexibility of wrist joint and cluttered background. We propose a convolutional neural network (CNN), which formulates in plane rotation explicitly to solve hand detection and rotation estimation jointly. Our network architecture adopts the backbone of faster R-CNN to generate rectangular region proposals and extract local features. The rotation network takes the feature as input and estimates an in-plane rotation which manages to align the hand, if any in the proposal, to the upward direction. A derotation layer is then designed to explicitly rotate the local spatial feature map according to the rotation network and feed aligned feature map for detection. Experiments show that our method outperforms the state-of-the-art detection models on widely-used benchmarks, such as Oxford and Egohands database. Further analysis show that rotation estimation and classification can mutually benefit each other. PMID- 29990194 TI - A Fractional-Order Variational Framework for Retinex: Fractional-Order Partial Differential Equation-Based Formulation for Multi-Scale Nonlocal Contrast Enhancement with Texture Preserving. AB - This paper discusses a novel conceptual formulation of the fractional-order variational framework for retinex, which is a fractional-order partial differential equation (FPDE) formulation of retinex for the multi-scale nonlocal contrast enhancement with texture preserving. The well-known shortcomings of traditional integer-order computation-based contrast-enhancement algorithms, such as ringing artefacts and staircase effects, are still in great need of special research attention. Fractional calculus has potentially received prominence in applications in the domain of signal processing and image processing mainly because of its strengths like long-term memory, nonlocality, and weak singularity, and because of the ability of a fractional differential to enhance the complex textural details of an image in a nonlinear manner. Therefore, in an attempt to address the aforementioned problems associated with traditional integer-order computation-based contrast-enhancement algorithms, we have studied here, as an interesting theoretical problem, whether it will be possible to hybridize the capabilities of preserving the edges and the textural details of fractional calculus with texture image multi-scale nonlocal contrast enhancement. Motivated by this need, in this paper, we introduce a novel conceptual formulation of the fractional-order variational framework for retinex. First, we implement the FPDE by means of the fractional-order steepest descent method. Second, we discuss the implementation of the restrictive fractional-order optimization algorithm and the fractional-order Courant-Friedrichs-Lewy condition. Third, we perform experiments to analyze the capability of the FPDE to preserve edges and textural details, while enhancing the contrast. The capability of the FPDE to preserve edges and textural details is a fundamental important advantage, which makes our proposed algorithm superior to the traditional integer order computation-based contrast enhancement algorithms, especially for images rich in textural details. PMID- 29990195 TI - Multiple Pedestrian Tracking From Monocular Videos in an Interacting Multiple Model Framework. AB - We present a multiple pedestrian tracking method for monocular videos captured by a fixed camera in an interacting multiple model (IMM) framework. Our tracking method involves multiple IMM trackers running in parallel, which are tied together by a robust data association component. We investigate two data association strategies which take into account both the target appearance and motion errors. We use a 4D color histogram as the appearance model for each pedestrian returned by a people detector that is based on the histogram of oriented gradients features. Short-term occlusion problems and false negative errors from the detector are dealt with using a sliding window of video frames, where tracking persists in the absence of observations. Our method has been evaluated, and compared both qualitatively and quantitatively with four state-of the-art visual tracking methods using benchmark video databases. The experiments demonstrate that, on average, our tracking method outperforms these four methods. PMID- 29990196 TI - Visualization in Meteorology-A Survey of Techniques and Tools for Data Analysis Tasks. AB - This article surveys the history and current state of the art of visualization in meteorology, focusing on visualization techniques and tools used for meteorological data analysis. We examine characteristics of meteorological data and analysis tasks, describe the development of computer graphics methods for visualization in meteorology from the 1960s to today, and visit the state of the art of visualization techniques and tools in operational weather forecasting and atmospheric research. We approach the topic from both the visualization and the meteorological side, showing visualization techniques commonly used in meteorological practice, and surveying recent studies in visualization research aimed at meteorological applications. Our overview covers visualization techniques from the fields of display design, 3D visualization, flow dynamics, feature-based visualization, comparative visualization and data fusion, uncertainty and ensemble visualization, interactive visual analysis, efficient rendering, and scalability and reproducibility. We discuss demands and challenges for visualization research targeting meteorological data analysis, highlighting aspects in demonstration of benefit, interactive visual analysis, seamless visualization, ensemble visualization, 3D visualization, and technical issues. PMID- 29990197 TI - Computer Simulation and Generation of Moving Sand Pictures. AB - Moving sand pictures are interesting devices that can be used to generate an infinite number of unique scenes when repeatedly being flipped over. However, little work has been done on attempting to simulate the process of picture formulation. In this paper, we present an approach capable of generating images in the style of moving sand pictures. Our system defines moving sand pictures in a few steps, such as initialization, segmentation and physical simulation, so that a variety of moving sand pictures including mountain ridges, desert, clouds and even regular patterns can be generated by either automatic or semi-automatic via interaction during initialization and segmentation. Potential applications of our approach range from advertisements, posters, post cards, packaging, to digital arts. PMID- 29990198 TI - An RJMCMC-Based Method for Tracking and Resolving Collisions of Drosophila Larvae. AB - Drosophila melanogaster is an important model organism for ongoing research in neuro- and behavioral biology. Especially the locomotion analysis has become an integral part of such studies and thus elaborated automated tracking systems have been proposed in the past. However, most of these approaches share the inability to precisely segment the contours of colliding animals leading to the absence of model and motion-related features during collisions. Here, we translate the task of tracking and resolving colliding animals into a filtering problem solvable by Markov Chain Monte Carlo methods and elaborate an adequate larva model. By comparing our method with state-of-the-art approaches we demonstrate that our algorithm produces significantly better results in a fraction of time and facilitates the analysis of animal behavior during interaction in more detail. PMID- 29990199 TI - A Feature Sampling Strategy for Analysis of High Dimensional Genomic Data. AB - With the development of high throughput technology, it has become feasible and common to profile tens of thousands of gene activities simultaneously. These genomic data typically have sample size of hundreds or fewer, which is much less than the feature size (number of genes). In addition, the genes, in particular the ones from the same pathway, are often highly correlated. These issues impose great challenge for selecting meaningful genes from a large number of (correlated) candidates in many genomic studies. Quite a few methods have been proposed to attack this challenge. Among them, regularization-based techniques, e.g. lasso, become much more appealing, because they can do model fitting and variable selection at the same time. However, the lasso regression has its known limitations. One is that the number of genes selected by the lasso couldn't exceed the number of samples. Another limitation is that, if causal genes are highly correlated, the lasso tends to select only one or few genes from them. Biologists, however, desire to identify them all. To overcome these limitations, we present here a novel, robust and stable variable selection method. Through simulation studies and a real application to the transcriptome data, we demonstrate the superiority of the proposed method in selecting highly correlated causal genes. We also provide some theoretical justifications for this feature sampling strategy based on the mean and variance analyses. PMID- 29990200 TI - Estrogenic active stilbene derivatives as anti-cancer agents: A DFT and QSAR study. AB - Exploring different quantum chemical quantities for lead compounds is ongoing approach in identifying crucial structural features in their biological activities. Herein, quantum chemical calculations are reported for selected estrogenic stilbene derivatives using density functional theory (DFT) with B3LYP functional and 6-311++G** basis set. In addition, specific activity-related geometry-independent drug-like properties are discussed for these derivatives. To obtain the mathematical model that correlates the chemical descriptors with their measured estrogenic activities, quantitative structure activity relationship (QSAR) is established using multiple linear regression (MLR) and support vector regression (SVR) methods. Satisfactory fit with a reasonable regression correlation coefficient () between predicted and experimental values is observed using MLR method. The present study identifies the essential physicochemical descriptors that effectively contribute in the estrogenic activity. The applied approach provides helpful insight into the designing novel estrogenic agents with improved anticancer activities. PMID- 29990201 TI - Theory and A Heuristic for the Minimum Path Flow Decomposition Problem. AB - Motivated by multiple genome assembly problems and other applications, we study the following minimum path flow decomposition problem: given a directed acyclic graph with source and sink and a flow , compute a set of paths and assign weight for such that , and is minimized. We develop some fundamental theory for this problem, upon which we design an efficient heuristic. Specifically, we prove that the gap between the optimal number of paths and a known upper bound is determined by the nontrivial equations within the flow values. This result gives rise to the framework of our heuristic: to iteratively reduce the gap through identifying such equations. We also define an operation on certain independent substructures of the graph, and prove that this operation does not affect the optimality but can transform the graph into one with desired property that facilitates reducing the gap. We apply and test our algorithm on both simulated random instances and perfect splice graph instances, and also compare it with the existing state-of art algorithm for flow decomposition. The results illustrate that our algorithm can achieve very high accuracy on these instances, and also that our algorithm significantly improves on the previous algorithms. An implementation of our algorithm is freely available at https://github.com/Kingsford-Group/catfish. PMID- 29990202 TI - The Robust Classification Model Based on Combinatorial Features. AB - Analyzing the disease data from the view of combinatorial features may better characterize the disease phenotype. In this study, a novel method is proposed to construct feature combinations and a classification model (CFC-CM) by mining key feature relationships. CFC-CM iteratively tests for differences in the feature relationship between different groups. To do this, it uses a modified -top scoring pair () algorithm and then selects the most discriminative feature pairs in the current feature set to infer the combinatorial features and build the classification model. Compared with support vector machines, random forests, least absolute shrinkage and selection operator, elastic net and , the superior performance of CFC-CM on nine public gene expression datasets validates its potential for more precise identification of complex diseases. Subsequently, CFC CM was applied to two metabolomics datasets, it obtained accuracy rates of and in distinguishing between hepatocellular carcinoma and hepatic cirrhosis groups and between acute kidney injury (AKI) and non-AKI samples, results superior to those of the other five methods. In summary, the better results of CFC-CM show that in contrast to molecules and combinations constituted by just two features, the combinations inferred by appropriate number of features could better identify the complex diseases. PMID- 29990203 TI - Probabilistic Guaranteed Gradient Learning-Based Spark Advance Self-Optimizing Control for Spark-Ignited Engines. AB - In spark-ignited (SI) engines, the spark advance (SA) controls the combustion phase that has a significant impact on the efficiency. Online self-optimizing control (SOC) of SA to maximize the indicated fuel conversion efficiency (IFCE) forms a stochastic optimization problem for a static map due to the stochasticity of combustion. Gradient-based optimization algorithms using periodic dithers are effective methods of dealing with such problems. However, decision sequences corrupted by periodic dithers are undesirable in SA online SOC. To choose a proper decision sequence for this problem, a gradient descent-based dither-free SOC scheme iteratively updates the decision based on probabilistic guaranteed gradient learning (PGGL). The PGGL approach uses the statistical distribution of the past samples to approximate the gradient on which the sample size can be adaptively adjusted to achieve the probabilistic target. The proposed scheme not only guarantees the accuracy of gradient learning but also adaptively adjusts the sample size in the learning process, achieving a tradeoff between a rapid response and a stable decision sequence. Moreover, the convergence performance of the obtained decision sequence is analyzed with respect to the probability distribution. Finally, experimental validations performed on an SI engine test bench show that the proposed PGGL-based SOC scheme successfully manages engine operation around the optimal IFCE with a fast response and stable SA behavior, under both steady and mild transient conditions. PMID- 29990204 TI - Parallelized Tensor Train Learning of Polynomial Classifiers. AB - In pattern classification, polynomial classifiers are well-studied methods as they are capable of generating complex decision surfaces. Unfortunately, the use of multivariate polynomials is limited to kernels as in support-vector machines, because polynomials quickly become impractical for high-dimensional problems. In this paper, we effectively overcome the curse of dimensionality by employing the tensor train (TT) format to represent a polynomial classifier. Based on the structure of TTs, two learning algorithms are proposed, which involve solving different optimization problems of low computational complexity. Furthermore, we show how both regularization to prevent overfitting and parallelization, which enables the use of large training sets, are incorporated into these methods. The efficiency and efficacy of our tensor-based polynomial classifier are then demonstrated on the two popular data sets U.S. Postal Service and Modified NIST. PMID- 29990205 TI - Tracking Control for Linear Discrete-Time Networked Control Systems With Unknown Dynamics and Dropout. AB - This paper develops a new method for solving the optimal control tracking problem for networked control systems (NCSs), where network-induced dropout can occur and the system dynamics are unknown. First, a novel dropout Smith predictor is designed to predict the current state based on historical data measurements over the communication network. Then, it is shown that the quadratic form of the performance index is preserved even with dropout, and the optimal tracker solution with dropout is given based on a novel dropout generalized algebraic Riccati equation. New algorithms for off-line policy iteration (PI), online PI, and Q-learning PI are presented for NCS with dropout. The Q-learning algorithm adaptively learns the optimal control online using data measured over the communication network based on reinforcement learning, including dropout, without requiring any knowledge of the system dynamics. Simulation results are provided to show that the proposed approaches give proper optimal tracking performance for the NCS with unknown dynamics and dropout. PMID- 29990206 TI - Complete Stability Analysis With Respect to Delay for Neural Networks. AB - The stability property of delayed neural networks (NNs) along the whole delay axis is studied in this paper. Such a complete stability problem with respect to the delay parameter has not been addressed in the community of NNs. Most of the existing studies focus on the stability interval of delay starting from zero and are not applicable for the complete stability problem. In this paper, we will present some examples to show that there are various types of stability intervals for NNs, demonstrating the necessity of the complete stability analysis. We will adopt a frequency-sweeping approach to study delayed NNs in this paper. As a result, the complete stability problem with respect to delay for NNs can be systematically solved. The approach is applicable in the general case and simple to implement. Finally, some representative examples illustrate the approach. PMID- 29990207 TI - Learning With Kernels: A Local Rademacher Complexity-Based Analysis With Application to Graph Kernels. AB - When dealing with kernel methods, one has to decide which kernel and which values for the hyperparameters to use. Resampling techniques can address this issue but these procedures are time-consuming. This problem is particularly challenging when dealing with structured data, in particular with graphs, since several kernels for graph data have been proposed in literature, but no clear relationship among them in terms of learning properties is defined. In these cases, exhaustive search seems to be the only reasonable approach. Recently, the global Rademacher complexity (RC) and local Rademacher complexity (LRC), two powerful measures of the complexity of a hypothesis space, have shown to be suited for studying kernels properties. In particular, the LRC is able to bound the generalization error of an hypothesis chosen in a space by disregarding those ones which will not be taken into account by any learning procedure because of their high error. In this paper, we show a new approach to efficiently bound the RC of the space induced by a kernel, since its exact computation is an NP-Hard problem. Then we show for the first time that RC can be used to estimate the accuracy and expressivity of different graph kernels under different parameter configurations. The authors' claims are supported by experimental results on several real-world graph data sets. PMID- 29990208 TI - Spoofing Detection in Automatic Speaker Verification Systems Using DNN Classifiers and Dynamic Acoustic Features. AB - With the development of speech synthesis technology, automatic speaker verification (ASV) systems have encountered the serious challenge of spoofing attacks. In order to improve the security of ASV systems, many antispoofing countermeasures have been developed. In the front-end domain, much research has been conducted on finding effective features which can distinguish spoofed speech from genuine speech and the published results show that dynamic acoustic features work more effectively than static ones. In the back-end domain, Gaussian mixture model (GMM) and deep neural networks (DNNs) are the two most popular types of classifiers used for spoofing detection. The log-likelihood ratios (LLRs) generated by the difference of human and spoofing log-likelihoods are used as spoofing detection scores. In this paper, we train a five-layer DNN spoofing detection classifier using dynamic acoustic features and propose a novel, simple scoring method only using human log-likelihoods (HLLs) for spoofing detection. We mathematically prove that the new HLL scoring method is more suitable for the spoofing detection task than the classical LLR scoring method, especially when the spoofing speech is very similar to the human speech. We extensively investigate the performance of five different dynamic filter bank-based cepstral features and constant Q cepstral coefficients (CQCC) in conjunction with the DNN HLL method. The experimental results show that, compared to the GMM-LLR method, the DNN-HLL method is able to significantly improve the spoofing detection accuracy. Compared with the CQCC-based GMM-LLR baseline, the proposed DNN-HLL model reduces the average equal error rate of all attack types to 0.045%, thus exceeding the performance of previously published approaches for the ASVspoof 2015 Challenge task. Fusing the CQCC-based DNN-HLL spoofing detection system with ASV systems, the false acceptance rate on spoofing attacks can be reduced significantly. PMID- 29990209 TI - Marginal Representation Learning With Graph Structure Self-Adaptation. AB - Learning discriminative feature representations has shown remarkable importance due to its promising performance for machine learning problems. This paper presents a discriminative data representation learning framework by employing a simple yet powerful marginal regression function with probabilistic graphical structure adaptation. A marginally structured representation learning (MSRL) method is proposed by seamlessly incorporating distinguishable regression targets analysis, graph structure adaptation, and robust linear structural learning into a joint framework. Specifically, MSRL learns marginal regression targets from data rather than exploiting the conventional zero-one matrix that greatly hinders the freedom of regression fitness and degrades the performance of regression results. Meanwhile, an optimized graph regularization term with self-improving adaptation is constructed based on probabilistic connection knowledge to improve the compactness of the learned representation. Additionally, the regression targets are further predicted by utilizing the explanatory factors from the latent subspace of data, which can uncover the underlying feature correlations to enhance the reliability. The resulting optimization problem can be elegantly solved by an efficient iterative algorithm. Finally, the proposed method is evaluated by eight diverse but related tasks, including object, face, texture, and scene, categorization data sets. The encouraging experimental results and the explicit theoretical analysis demonstrate the efficacy of the proposed representation learning method in comparison with state-of-the-art algorithms. PMID- 29990210 TI - A Piecewise-Markovian Lyapunov Approach to Reliable Output Feedback Control for Fuzzy-Affine Systems With Time-Delays and Actuator Faults. AB - This paper addresses the problem of delay-dependent robust and reliable $?mathscr {H}_{?infty }$ static output feedback (SOF) control for a class of uncertain discrete-time Takagi-Sugeno fuzzy-affine (FA) systems with time-varying delay and actuator faults in a singular system framework. The Markov chain is employed to describe the actuator faults behaviors. In particular, by utilizing a system augmentation approach, the conventional closed-loop system is converted into a singular FA system. By constructing a piecewise-Markovian Lyapunov-Krasovskii functional, a new $?mathscr {H}_{?infty }$ performance analysis criterion is then presented, where a novel summation inequality and S-procedure are succeedingly employed. Subsequently, thanks to the special structure of the singular system formulation, the piecewise-affine SOF controller design is proposed via a convex program. Lastly, illustrative examples are given to show the efficacy and less conservatism of the presented approach. PMID- 29990211 TI - An Improved Mixture of Probabilistic PCA for Nonlinear Data-Driven Process Monitoring. AB - An improved mixture of probabilistic principal component analysis (PPCA) has been introduced for nonlinear data-driven process monitoring in this paper. To realize this purpose, the technique of a mixture of probabilistic principal component analyzers is utilized to establish the model of the underlying nonlinear process with local PPCA models, where a novel composite monitoring statistic is proposed based on the integration of two monitoring statistics in modified PPCA-based fault detection approach. Besides, the weighted mean of the monitoring statistics aforementioned is utilized as a metrics to detect potential abnormalities. The virtues of the proposed algorithm are discussed in comparison with several unsupervised algorithms. Finally, Tennessee Eastman process and an autosuspension model are employed to demonstrate the effectiveness of the proposed scheme further. PMID- 29990212 TI - Norm Discriminant Eigenspace Transform for Pattern Classification. AB - Most of the supervised dimensionality reduction (DR) methods design interclass scatter as the separability between the class means, which may force to assume unimodal Gaussian likelihoods and their projection space trends toward the class means. This paper presents a novel DR approach, norm discriminant eigenspace transform (NDET), in which average norms (l2) of classes have been utilized to characterize the interclass separability and the within-class distance characterizes the intraclass compactness. NDET is intended to accommodate data distributions that may be multimodal and non-Gaussian. We derive an upper bound for NDET, and a specific solution space to attain this bound. Existence of the specific solution is very unwonted, thereby we have considered the solution space of upper bound to achieve better reduction of dimensionality and discrimination of classes. Also, a nonlinear version of NDET (kernel NDET) is developed to model nonlinear relationships between the features. We show, experimentally (on synthetic data) that NDET effectively overcomes the limitations, which arise due to unimodal and data distribution assumptions of the traditional algorithms. Extensive empirical studies are made; and the proposed method is compared with closely related state-of-the-art schemes on UCI machine learning repository and face recognition data sets, to establish its novelty. PMID- 29990213 TI - Design of a Wireless Control System With Unreliable Nodes and Communication Links. AB - Unlike a traditional topology of a control system with feedback connected plant and controller systems, this paper discusses a new topology that uses an intermediate network system between the plant and controller systems. More specifically, this paper presents modeling frameworks as well as computational procedures for the design of the closed-loop control system when the nodes of the plant, controller, and network systems fail to operate and the communication links fail to transfer information between communicating nodes. It also discusses conditions required for the synthesis of the controller and network systems, and characterizes the maximum number of unavailable nodes and the maximum probability of unavailable communication links. The aim of the presented results is to provide a more practical approach to the design of the new topology. Also, a four tank process system is used to demonstrate details of the presented modeling frameworks and computational procedures. PMID- 29990214 TI - Ensemble Teaching for Hybrid Label Propagation. AB - Label propagation aims to iteratively diffuse the label information from labeled examples to unlabeled examples over a similarity graph. Current label propagation algorithms cannot consistently yield satisfactory performance due to two reasons: one is the instability of single propagation method in dealing with various practical data, and the other one is the improper propagation sequence ignoring the labeling difficulties of different examples. To remedy above defects, this paper proposes a novel propagation algorithm called hybrid diffusion under ensemble teaching (HyDEnT). Specifically, HyDEnT integrates multiple propagation methods as base ''learners'' to fully exploit their individual wisdom, which helps HyDEnT to be stable and obtain consistent encouraging results. More importantly, HyDEnT conducts propagation under the guidance of an ensemble of ''teachers''. That is to say, in every propagation round the simplest curriculum examples are wisely designated by a teaching algorithm, so that their labels can be reliably and accurately decided by the learners. To optimally choose these simplest examples, every teacher in the ensemble should comprehensively consider the examples' difficulties from its own viewpoint, as well as the common knowledge shared by all the teachers. This is accomplished by a designed optimization problem, which can be efficiently solved via the block coordinate descent method. Thanks to the efforts of the teachers, all the unlabeled examples are logically propagated from simple to difficult, leading to better propagation quality of HyDEnT than the existing methods. Experiments on six popular datasets reveal that HyDEnT achieves the highest classification accuracy when compared with six state-of-the-art propagation methodologies such as harmonic functions, Fick's law assisted propagation, linear neighborhood propagation, semisupervised ensemble learning, bipartite graph-based consensus maximization, and teaching-to learn and learning-to-teach. PMID- 29990215 TI - Hybrid Incremental Ensemble Learning for Noisy Real-World Data Classification. AB - Traditional ensemble learning approaches explore the feature space and the sample space, respectively, which will prevent them to construct more powerful learning models for noisy real-world dataset classification. The random subspace method only search for the selection of features. Meanwhile, the bagging approach only search for the selection of samples. To overcome these limitations, we propose the hybrid incremental ensemble learning (HIEL) approach which takes into consideration the feature space and the sample space simultaneously to handle noisy dataset. Specifically, HIEL first adopts the bagging technique and linear discriminant analysis to remove noisy attributes, and generates a set of bootstraps and the corresponding ensemble members in the subspaces. Then, the classifiers are selected incrementally based on a classifier-specific criterion function and an ensemble criterion function. The corresponding weights for the classifiers are assigned during the same process. Finally, the final label is summarized by a weighted voting scheme, which serves as the final result of the classification. We also explore various classifier-specific criterion functions based on different newly proposed similarity measures, which will alleviate the effect of noisy samples on the distance functions. In addition, the computational cost of HIEL is analyzed theoretically. A set of nonparametric tests are adopted to compare HIEL and other algorithms over several datasets. The experiment results show that HIEL performs well on the noisy datasets. HIEL outperforms most of the compared classifier ensemble methods on 14 out of 24 noisy real-world UCI and KEEL datasets. PMID- 29990216 TI - Modeling and Control of Single-Cell Migration Induced by a Chemoattractant-Loaded Microbead. AB - Cell migration plays an essential role in cancer cell study. Investigation of a novel method for controlling cell migration movement can help develop new therapeutic strategies. In this paper, a chemoattractant-loaded microbead, which is controlled by optical tweezers, is used to stimulate a target cell to accomplish automated migration along a desired path while avoiding obstacles. Models of both tweezers-bead and bead-cell interactions are investigated. A dual closed-loop control strategy is proposed, which includes an inner tweezers-bead control loop and an outer bead-cell control loop. A proportional-integral feedback plus feedforward controller is used to control the inner loop, and an active disturbance rejection controller is used for the outer loop, which can address the cell migration modeling errors and unknown external disturbances. A traffic rule based on interference-clearing mechanism is also proposed to reduce external disturbances on the system by preventing other particles from interfering with the migration process. The effectiveness of the proposed control approach is verified by simulations and experiments on migrating leukemia cancer cells. PMID- 29990217 TI - A Mixed-norm Laplacian Regularized Low-Rank Representation Method for Tumor Samples Clustering. AB - Tumor samples clustering based on biomolecular data is a hot issue of cancer classifications discovery. How to extract the valuable information from high dimensional genomic data is becoming an urgent problem in tumor samples clustering. In this paper, we introduce manifold regularization into low-rank representation model and present a novel method named Mixed-norm Laplacian regularized Low-Rank Representation (MLLRR) to identify the differentially expressed genes for tumor clustering based on gene expression data. Then, in order to advance the accuracy and stability of tumor clustering, we establish the clustering model based on Penalized Matrix Decomposition (PMD) and propose a novel cluster method named MLLRR-PMD. In this method, the cancer clustering research includes three steps. Firstly, the matrix of gene expression data is decomposed into a low rank representation matrix and a sparse matrix by MLLRR. Secondly, the differentially expressed genes are identified based on the sparse matrix. Finally, the PMD is applied to cluster the samples based on the differentially expressed genes. The experiment results on simulation data and real genomic data illustrate that MLLRR method enhances the robustness to outliers and achieves remarkable performance in the extraction of differentially expressed genes. PMID- 29990218 TI - Disease Gene Prediction by Integrating PPI Networks, Clinical RNA-Seq Data and OMIM Data. AB - Disease gene prediction is a challenging task that has a variety of applications such as early diagnosis and drug development. The existing machine learning methods suffer from the imbalanced sample issue because the number of known disease genes (positive samples) is much less than that of unknown genes which are typically considered to be negative samples. In addition, most methods have not utilized clinical data from patients with a specific disease to predict disease genes. In this study, we propose a disease gene prediction algorithm (called dgSeq) by combining protein-protein interaction (PPI) network, clinical RNA-Seq data, and Online Mendelian Inheritance in Man (OMIN) data. Our dgSeq constructs differential networks based on rewiring information calculated from clinical RNA-Seq data. To select balanced sets of non-disease genes (negative samples), a disease-gene network is also constructed from OMIM data. After features are extracted from the PPI networks and differential networks, the logistic regression classifiers are trained. Our dgSeq obtains AUC values of 0.88, 0.83 and 0.80 for identifying breast cancer genes, thyroid cancer genes and Alzheimer's disease genes, respectively, which indicates its superiority to other three competing methods. Both gene set enrichment analysis and predicted results demonstrate that dgSeq can effectively predict new disease genes. PMID- 29990219 TI - Efficient k-NN Implementation for Real-Time Detection of Cough Events in Smartphones. AB - The potential of telemedicine in respiratory health care has not been completely unveiled in part due to the inexistence of reliable objective measurements of symptoms such as cough. Currently available cough detectors are uncomfortable and expensive at a time when generic smartphones can perform this task. However, two major challenges preclude smartphone-based cough detectors from effective deployment namely, the need to deal with noisy environments and computational cost. This paper focuses on the latter, since complex machine learning algorithms are too slow for real-time use and kill the battery in a few hours unless specific actions are taken. In this paper, we present a robust and efficient implementation of a smartphone-based cough detector. The audio signal acquired from the device's microphone is processed by computing local Hu moments as a robust feature set in the presence of background noise. We previously demonstrated that pairing Hu moments and a standard k-NN classifier achieved accurate cough detection at the expense of computation time. To speed-up k-NN search, many tree structures have been proposed. Our cough detector uses an improved vantage point (vp)-tree with optimized construction methods and a distance function that results in faster searches. We achieve 18* speed-up over classic vp-trees, and 560* over standard implementations of k-NN in state-of-the art machine learning libraries, with classification accuracies over 93%, enabling real-time performance on low-end smartphones. PMID- 29990220 TI - Transfer Learning for Multicenter Classification of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a lung disease that can be quantified using chest computed tomography scans. Recent studies have shown that COPD can be automatically diagnosed using weakly supervised learning of intensity and texture distributions. However, up till now such classifiers have only been evaluated on scans from a single domain, and it is unclear whether they would generalize across domains, such as different scanners or scanning protocols. To address this problem, we investigate classification of COPD in a multicenter dataset with a total of 803 scans from three different centers, four different scanners, with heterogenous subject distributions. Our method is based on Gaussian texture features, and a weighted logistic classifier, which increases the weights of samples similar to the test data. We show that Gaussian texture features outperform intensity features previously used in multicenter classification tasks. We also show that a weighting strategy based on a classifier that is trained to discriminate between scans from different domains can further improve the results. To encourage further research into transfer learning methods for the classification of COPD, upon acceptance of this paper we will release two feature datasets used in this study on http://bigr.nl/research/projects/copd. PMID- 29990221 TI - Cost-Sensitive Feature Selection by Optimizing F-Measures. AB - Feature selection is beneficial for improving the performance of general machine learning tasks by extracting an informative subset from the high-dimensional features. Conventional feature selection methods usually ignore the class imbalance problem, thus the selected features will be biased towards the majority class. Considering that F-measure is a more reasonable performance measure than accuracy for imbalanced data, this paper presents an effective feature selection algorithm that explores the class imbalance issue by optimizing F-measures. Since F-measure optimization can be decomposed into a series of cost-sensitive classification problems, we investigate the cost-sensitive feature selection by generating and assigning different costs to each class with rigorous theory guidance. After solving a series of cost-sensitive feature selection problems, features corresponding to the best F-measure will be selected. In this way, the selected features will fully represent the properties of all classes. Experimental results on popular benchmarks and challenging real-world data sets demonstrate the significance of cost-sensitive feature selection for the imbalanced data setting and validate the effectiveness of the proposed method. PMID- 29990222 TI - Robust Distance Metric Learning via Bayesian Inference. AB - Distance metric learning (DML) has achieved great success in many computer vision tasks. However, most existing DML algorithms are based on point estimation, and thus are sensitive to the choice of training examples and tend to be over-fitting in the presence of label noise. In this paper, we present a robust DML algorithm based on Bayesian inference. In particular, our method is essentially a Bayesian extension to a previous classic DML method-large margin nearest neighbor classification and we use stochastic variational inference to estimate the posterior distribution of the transformation matrix. Furthermore, we theoretically show that the proposed algorithm is robust against label noise in the sense that an arbitrary point with label noise has bounded influence on the learnt model. With some reasonable assumptions, we derive a generalization error bound of this method in the presence of label noise. We also show that the DML hypothesis class in which our model lies is probably approximately correct learnable and give the sample complexity. The effectiveness of the proposed method1 is demonstrated with state of the art performance on three popular data sets with different types of label noise.1 A MATLAB implementation of this method is made available at http://parnec.nuaa.edu.cn/xtan/Publication.htm. PMID- 29990223 TI - Detection and Recognition for Life State of Cell Cancer Using Two-Stage Cascade CNNs. AB - Cancer cell detection and its stages recognition of life cycle are an important step to analyze cellular dynamics in the automation of cell based-experiments. In this work, a two-stage hierarchical method is proposed to detect and recognize different life stages of bladder cells by using two cascade Convolutional Neural Networks (CNNs). Initially, a hybrid object proposal algorithm (called EdgeSelective) by combining EdgeBoxes and Selective Search is proposed to generate candidate object proposals instead of a single Selective Search method in Region-CNN (R-CNN), and it can exploit the advantages of different mechanisms for generating proposals so that each cell in the image can be fully contained by at least one proposed region during the detection process. Then the obtained cells from the previous step are used to train and extract features by employing CNNs for the purpose of cell life stage recognition. Finally, a series of comparison experiments are implemented. The results show that the proposed method can obtain better performance than traditional methods either in the stage of cell detection or cell life stage recognition, and it encourages and suggests the application in the development of new anticancer drug and cytopathology analysis of cancer patients in the near future. PMID- 29990224 TI - SPF-CellTracker: Tracking multiple cells with strongly-correlated moves using a spatial particle filter. AB - Tracking many cells in time-lapse 3D image sequences is an important challenging task of bioimage informatics. Motivated by a study of brain-wide 4D imaging of neural activity in C. elegans, we present a new method of multi-cell tracking. Data types to which the method is applicable are characterized as follows: (i) cells are imaged as globular-like objects, (ii) it is difficult to distinguish cells based only on shape and size, (iii) the number of imaged cells ranges in several hundreds, (iv) moves of nearly-located cells are strongly correlated and (v) cells do not divide. We developed a tracking software suite which we call SPF CellTracker. Incorporating dependency on cells moves into prediction model is the key to reduce the tracking errors: cell-switching and coalescence of tracked positions. We model target cells correlated moves as a Markov random field and we also derive a fast computation algorithm, which we call spatial particle filter. With the live-imaging data of nuclei of C. elegans neurons in which approximately 120 nuclei of neurons are imaged, we demonstrate an advantage of the proposed method over the standard particle filter and a method developed by Tokunaga et al. (2014). PMID- 29990225 TI - Rank-One Matrix Completion With Automatic Rank Estimation via L1-Norm Regularization. AB - Completing a matrix from a small subset of its entries, i.e., matrix completion is a challenging problem arising from many real-world applications, such as machine learning and computer vision. One popular approach to solve the matrix completion problem is based on low-rank decomposition/factorization. Low-rank matrix decomposition-based methods often require a prespecified rank, which is difficult to determine in practice. In this paper, we propose a novel low-rank decomposition-based matrix completion method with automatic rank estimation. Our method is based on rank-one approximation, where a matrix is represented as a weighted summation of a set of rank-one matrices. To automatically determine the rank of an incomplete matrix, we impose L1-norm regularization on the weight vector and simultaneously minimize the reconstruction error. After obtaining the rank, we further remove the L1-norm regularizer and refine recovery results. With a correctly estimated rank, we can obtain the optimal solution under certain conditions. Experimental results on both synthetic and real-world data demonstrate that the proposed method not only has good performance in rank estimation, but also achieves better recovery accuracy than competing methods. PMID- 29990226 TI - Quantized CNN: A Unified Approach to Accelerate and Compress Convolutional Networks. AB - We are witnessing an explosive development and widespread application of deep neural networks (DNNs) in various fields. However, DNN models, especially a convolutional neural network (CNN), usually involve massive parameters and are computationally expensive, making them extremely dependent on high-performance hardware. This prohibits their further extensions, e.g., applications on mobile devices. In this paper, we present a quantized CNN, a unified approach to accelerate and compress convolutional networks. Guided by minimizing the approximation error of individual layer's response, both fully connected and convolutional layers are carefully quantized. The inference computation can be effectively carried out on the quantized network, with much lower memory and storage consumption. Quantitative evaluation on two publicly available benchmarks demonstrates the promising performance of our approach: with comparable classification accuracy, it achieves 4 to $6 ?times $ acceleration and 15 to $20?times $ compression. With our method, accurate image classification can even be directly carried out on mobile devices within 1 s. PMID- 29990227 TI - Hidden Markov Model-Based Fall Detection With Motion Sensor Orientation Calibration: A Case for Real-Life Home Monitoring. AB - Falls are a major threat for senior citizens' independent living. Motion sensor technologies and automatic fall detection systems have emerged as a reliable low cost solution to this challenge. We develop a hidden Markov model (HMM) based fall detection system to detect falls automatically using a single motion sensor for real-life home monitoring scenarios. We propose a new representation for acceleration signals in HMMs to avoid feature engineering and developed a sensor orientation calibration algorithm to resolve sensor misplacement issues (misplaced sensor location and misaligned sensor orientation) in real-world scenarios. HMM classifiers are trained to detect falls based on acceleration signal data collected from motion sensors. We collect a dataset from experiments of simulated falls and normal activities and acquired a dataset from a real-world fall repository (FARSEEING) to evaluate our system. Our system achieves positive predictive value of 0.981 and sensitivity of 0.992 on the experiment dataset with 200 fall events and 385 normal activities, and positive predictive value of 0.786 and sensitivity of 1.000 on the real-world fall dataset with 22 fall events and 2618 normal activities. Our system's results significantly outperform benchmark systems, which shows the advantage of our HMM-based fall detection system with sensor orientation calibration. Our fall detection system is able to precisely detect falls in real-life home scenarios with a reasonably low false alarm ratet. PMID- 29990228 TI - Evaluation of an mHealth-Based Adjunct to Outpatient Cardiac Rehabilitation. AB - A pilot study was conducted to determine if a smartphone-based adjunct to standard care could increase the completion rate of a cardiac rehabilitation program (CRP). Based on historical completion rates, 66 participants who were about to commence a hospital-based CRP were randomized so that half received three devices embedded with near-field communication, namely, a smartphone [pre installed with an application (app) designed specifically for cardiac rehabilitation], portable blood pressure monitor, and weight scale while completing the CRP. The completion rate among participants who were randomized to the intervention group was 88%, compared to 67% in the control group ( = 0.038). This combined with the week-to-week frequency with which participants in the intervention group measured their blood pressure ( 5/week) demonstrated the ability of the intervention to increase the proportion of patients who completed the CRP. No significant differences were found between the treatment groups for the measurements taken at baseline and prior to discharge from the CRP. A statistically significant correlation ( = 0.472; = 0.013) was found between the average time participants walked each day (as estimated via the smartphone app) and participants' six minute walking distance (6MWD) before they were discharged from the CRP (a clinically validated measurement). PMID- 29990229 TI - Improving Health Outcomes Sooner Rather Than Later via an Interactive Website and Virtual Specialist. AB - Nonlife threatening chronic health conditions can significantly reduce the quality of life for the patient and their family. Given pressure on specialist services and lengthy wait times, we propose a novel approach that involves a website and virtual specialist for patients while they are awaiting their specialist appointment. To capture patient history and provide tailored treatment advice, an interactive website was developed. To increase adherence, the website was enhanced with an empathic embodied conversational agent to allow discussion of the suggested treatment. A six-month trial with 74 children with urinary incontinence showed an overall improvement in 74% of patients, with 38% those who used the program reporting a resolution of their wetting without needing a specialist appointment. Capturing the expertise of medical specialists to provide online tailored treatment advice and use of humanlike face-to-face conversations to educate and build rapport with the patient appeared to increase treatment adherence compared to an earlier text-based version without the empathic agent. PMID- 29990230 TI - Adaptive Neural Network Control for Robotic Manipulators With Unknown Deadzone. AB - This paper addresses the problem of robotic manipulators with unknown deadzone. In order to tackle the uncertainty and the unknown deadzone effect, we introduce adaptive neural network (NN) control for robotic manipulators. State-feedback control is introduced first and a high-gain observer is then designed to make the proposed control scheme more practical. One radial basis function NN (RBFNN) is used to tackle the deadzone effect, and the other RBFNN is also proposed to estimate the unknown dynamics of robot. The proposed control is then verified on a two-joint rigid manipulator via numerical simulations and experiments. PMID- 29990231 TI - Engineering Deep Representations for Modeling Aesthetic Perception. AB - Many aesthetic models in multimedia and computer vision suffer from two shortcomings: 1) the low descriptiveness and interpretability 1 of the hand crafted aesthetic criteria (i.e., fail to indicate region-level aesthetics) and 2) the difficulty of engineering aesthetic features adaptively and automatically toward different image sets. To remedy these problems, we develop a deep architecture to learn aesthetically relevant visual attributes from Flickr, 2 which are localized by multiple textual attributes in a weakly supervised setting. More specifically, using a bag-of-words representation of the frequent Flickr image tags, a sparsity-constrained subspace algorithm discovers a compact set of textual attributes (i.e., each textual attribute is a sparse and linear representation of those frequent image tags) for each Flickr image. Then, a weakly supervised learning algorithm projects the textual attributes at image level to the highly-responsive image patches. These patches indicate where humans look at appealing regions with respect to each textual attribute, which are employed to learn the visual attributes. Psychological and anatomical studies have demonstrated that humans perceive visual concepts in a hierarchical way. Therefore, we normalize these patches and further feed them into a five-layer convolutional neural network to mimic the hierarchy of human perceiving the visual attributes. We apply the learned deep features onto applications like image retargeting, aesthetics ranking, and retrieval. Both subjective and objective experimental results thoroughly demonstrate the superiority of our approach.1 In this paper, "describing" and "interpretability" means the ability of seeking region-level representation of each mined textual attribute, i.e., a sparse and linear representation of those frequent image tags. 2 https://www.flickr.com/. PMID- 29990232 TI - Trajectory Optimization of Space Maneuver Vehicle Using a Hybrid Optimal Control Solver. AB - In this paper, a constrained space maneuver vehicles trajectory optimization problem is formulated and solved using a new three-layer-hybrid optimal control solver. To decrease the sensitivity of the initial guess and enhance the stability of the algorithm, an initial guess generator based on a specific stochastic algorithm is applied. In addition, an improved gradient-based algorithm is used as the inner solver, which can offer the user more flexibility to control the optimization process. Furthermore, in order to analyze the quality of the solution, the optimality verification conditions are derived. Numerical simulations were carried out by using the proposed hybrid solver and the results indicate that the proposed strategy can have better performance in terms of convergence speed and convergence ability when compared with other typical optimal control solvers. A Monte-Carlo simulation was performed and the results show a robust performance of the proposed algorithm in dispersed conditions. PMID- 29990233 TI - Atomic Representation-based Classification: Theory, Algorithm and Applications. AB - Representation-based classification (RC) methods such as sparse RC (SRC) have attracted great interest in pattern recognition recently. Despite their empirical success, few theoretical results are reported to justify their effectiveness. In this paper, we establish the theoretical guarantees for a general unified framework termed as atomic representation-based classification (ARC), which includes most RC methods as special cases. We introduce a new condition called atomic classification condition (ACC), which reveals important geometric insights for the theory of ARC. We show that under such condition ARC is provably effective in correctly recognizing any new test sample, even corrupted with noise. Our theoretical analysis significantly broadens the range of conditions under which RC methods succeed for classification in the following two aspects: (1) prior theoretical advances of RC are mainly concerned with the single SRC method while our theory can apply to the general unified ARC framework, including SRC and many other RC methods; (2) previous works are confined to the analysis of noiseless test data while we provide theoretical guarantees for ARC using both noiseless and noisy test data. Numerical results are provided to validate and complement our theoretical analysis of ARC and its important special cases for both noiseless and noisy test data. PMID- 29990234 TI - Directional 3D Wavelet Transform Based on Gaussian Mixtures for the Analysis of 3D Ultrasound Ovarian Volumes. AB - The success of in-vitro fertilization can be predicted by a correct quantitative and qualitative assessment of ovarian follicles. Several ovarian follicle detection and recognition algorithms have been published. Their effectiveness is inferior to human follicle annotations due to various kinds of noise, degradations, and artefacts in ultrasonic images. This paper deals with an approach to recognize antral follicles from 2 mm in diameter in 3D ultrasound data. Its detection phase looks for candidate follicular regions, while the recognition phase assesses the likelihood of a region to correspond to a follicle. Three innovative definitions underpin the detection: Laplacian-of Gaussian-based directional 3D wavelet transform, adaptive multiscale search based on Gaussian mixtures, and recursive convexity-based region splitting. A likelihood index is also introduced to support follicle recognition. The proposed approach was tested on 30 ultrasound ovarian volumes generated by different sonographic machines in stimulated and non-stimulated examination cycles. The obtained follicle recognition rates exceed those of the best 3D approaches known by about 10%, while qualitative assessments yield comparable values. PMID- 29990235 TI - HyperFace: A Deep Multi-task Learning Framework for Face Detection, Landmark Localization, Pose Estimation, and Gender Recognition. AB - We present an algorithm for simultaneous face detection, landmarks localization, pose estimation and gender recognition using deep convolutional neural networks (CNN). The proposed method called, HyperFace, fuses the intermediate layers of a deep CNN using a separate CNN followed by a multi-task learning algorithm that operates on the fused features. It exploits the synergy among the tasks which boosts up their individual performances. Additionally, we propose two variants of HyperFace. PMID- 29990238 TI - Detecting Population-differentiation Copy Number Variants in Human Population Tree by Sparse Group Selection. AB - Copy-number variants (CNVs) account for a substantial proportion of human genetic variations. Understanding the CNV diversities across populations is a computational challenge because CNV patterns are often present in several related populations and only occur in a subgroup of individuals within each of the population. This paper introduces a tree-guided sparse group selection algorithm (treeSGS) to detect population-differentiation CNV markers of subgroups across populations organized by a phylogenetic tree of human populations. The treeSGS algorithm detects CNV markers of populations associated with nodes from all levels of the tree such that the evolutionary relations among the populations are incorporated for more accurate detection of population-differentiation CNVs. We applied treeSGS algorithm to study the 1179 samples from the 11 populations in Hapmap3 CNV data. The treeSGS algorithm accurately identifies CNV markers of each population and the collection of populations organized under the branches of the human population tree, validated by consistency among family trios and SNP characterizations of the CNV regions. Further comparison between the detected CNV markers and other population-differentiation CNVs reported in 1000 genome data and other recent studies also shows that treeSGS can significantly improve the current annotations of population-differentiation CNV markers. TreeSGS package is available at http://compbio.cs.umn.edu/treesgs. PMID- 29990237 TI - Semantic Flow Graph: A Framework for Discovering Object Relationships in Flow Fields. AB - Visual exploration of flow fields is important for studying dynamic systems. We introduce semantic flow graph (SFG), a novel graph representation and interaction framework that enables users to explore the relationships among key objects (i.e., field lines, features, and spatiotemporal regions) of both steady and unsteady flow fields. The objects and their relationships are organized as a heterogeneous graph. We assign each object a set of attributes, based on which a semantic abstraction of the heterogeneous graph is generated. This semantic abstraction is SFG. We design a suite of operations to explore the underlying flow fields based on this graph representation and abstraction mechanism. Users can flexibly reconfigure SFG to examine the relationships among groups of objects at different abstraction levels. Three linked views are developed to display SFG, its node split criteria and history, and the objects in the spatial volume. For simplicity, we introduce SFG construction and exploration for steady flow fields with critical points being the only features. Then we demonstrate that SFG can be naturally extended to deal with unsteady flow fields and multiple types of features. We experiment with multiple data sets and conduct an expert evaluation to demonstrate the effectiveness of our approach. PMID- 29990239 TI - Bi-level error correction for PacBio long reads. AB - The latest sequencing technologies such as the Pacific Biosciences (PacBio) and Oxford Nanopore machines can generate long reads at the length of thousands of nucleic bases which is much longer than the reads at the length of hundreds generated by Illumina machines. However, these long reads are prone to much higher error rates, for example 15%, making downstream analysis and applications very difficult. Error correction is a process to improve the quality of sequencing data. Hybrid correction strategies have been recently proposed to combine Illumina reads of low error rates to fix sequencing errors in the noisy long reads with good performance. In this paper, we propose a new method named Bicolor, a bi-level framework of hybrid error correction for further improving the quality of PacBio long reads. At the first level, our method uses a de Bruijn graph-based error correction idea to search paths in pairs of solid -mers iteratively with an increasing length of -mer. At the second level, we combine the processed results under different parameters from the first level. In particular, a multiple sequence alignment algorithm is used to align those similar long reads, followed by a voting algorithm which determines the final base at each position of the reads. We compare the superior performance of Bicolor with three state-of-the-art methods on three real data sets. Results demonstrate that Bicolor always achieves the highest identity ratio. Bicolor also achieves a higher alignment ratio () and a higher number of aligned reads than the current methods on two data sets. On the third data set, our method is closely competitive to the current methods in terms of number of aligned reads and genome coverage. The C++ source codes of our algorithm are freely available at https://github.com/yuansliu/Bicolor. PMID- 29990240 TI - Brain-Inspired Wireless Communications: Where Reservoir Computing Meets MIMO OFDM. AB - Reservoir computing (RC) is a class of neuromorphic computing approaches that deals particularly well with time-series prediction tasks. It significantly reduces the training complexity of recurrent neural networks and is also suitable for hardware implementation whereby device physics are utilized in performing data processing. In this paper, the RC concept is applied to detecting a transmitted symbol in multiple-input multiple-output orthogonal frequency division multiplexing (MIMO-OFDM) systems. Due to wireless propagation, the transmitted signal may undergo severe distortion before reaching the receiver. The nonlinear distortion introduced by the power amplifier at the transmitter may further complicate this process. Therefore, an efficient symbol detection strategy becomes critical. The conventional approach for symbol detection at the receiver requires accurate channel estimation of the underlying MIMO-OFDM system. However, in this paper, we introduce a novel symbol detection scheme where the estimation of the MIMO-OFDM channel becomes unnecessary. The introduced scheme utilizes an echo state network (ESN), which is a special class of RC. The ESN acts as a black box for system modeling purposes and can predict nonlinear dynamic systems in an efficient way. Simulation results for the uncoded bit error rate of nonlinear MIMO-OFDM systems show that the introduced scheme outperforms conventional symbol detection methods. PMID- 29990241 TI - Online Training of LSTM Networks in Distributed Systems for Variable Length Data Sequences. AB - In this brief, we investigate online training of long short term memory (LSTM) architectures in a distributed network of nodes, where each node employs an LSTM based structure for online regression. In particular, each node sequentially receives a variable length data sequence with its label and can only exchange information with its neighbors to train the LSTM architecture. We first provide a generic LSTM-based regression structure for each node. In order to train this structure, we put the LSTM equations in a nonlinear state-space form for each node and then introduce a highly effective and efficient distributed particle filtering (DPF)-based training algorithm. We also introduce a distributed extended Kalman filtering-based training algorithm for comparison. Here, our DPF based training algorithm guarantees convergence to the performance of the optimal LSTM coefficients in the mean square error sense under certain conditions. We achieve this performance with communication and computational complexity in the order of the first-order gradient-based methods. Through both simulated and real life examples, we illustrate significant performance improvements with respect to the state-of-the-art methods. PMID- 29990242 TI - GCRNN: Group-Constrained Convolutional Recurrent Neural Network. AB - In this paper, we propose a new end-to-end deep neural network model for time series classification (TSC) with emphasis on both the accuracy and the interpretation. The proposed model contains a convolutional network component to extract high-level features and a recurrent network component to enhance the modeling of the temporal characteristics of TS data. In addition, a feedforward fully connected network with the sparse group lasso (SGL) regularization is used to generate the final classification. The proposed architecture not only achieves satisfying classification accuracy, but also obtains good interpretability through the SGL regularization. All these networks are connected and jointly trained in an end-to-end framework, and it can be generally applied to TSC tasks across different domains without the efforts of feature engineering. Our experiments in various TS data sets show that the proposed model outperforms the traditional convolutional neural network model for the classification accuracy, and also demonstrate how the SGL contributes to a better model interpretation. PMID- 29990243 TI - Reinforcement Learning-Based Differential Evolution With Cooperative Coevolution for a Compensatory Neuro-Fuzzy Controller. AB - This paper presents the integration of reinforcement learning-based differential evolution (DE) with the cooperative coevolution (R-CCDE) method in a compensatory neuro-fuzzy controller (CNFC). The CNFC model employs compensatory fuzzy operations, which increase the adaptability and effectiveness of the controller. The R-CCDE method was used to determine an adequate control policy for nonlinear system problems. The evolution of a population involved the use of DE with cooperative coevolution to adjust CNFC parameters, and the fitness function of the R-CCDE method is used by a reinforcement signal to determine the controller that can be used to solve the control problem. This paper identified the best performing controller to solve nonlinear system problems. The simulation results of the proposed R-CCDE method were compared with those of various DE methods and the performance of the proposed R-CCDE method was superior to that of the other methods. PMID- 29990244 TI - Feature Extraction of Galvanic Skin Responses by Nonnegative Sparse Deconvolution. AB - Wearable sensors are increasingly taking part in daily activities, not only because of the recent society health concern, but also due to their relevance in the medical industry. In this paper, a galvanic skin response (GSR) extraction technique has been developed in order to interpret electrodermal activity (EDA) records, which can be useful both for ambulatory and health applications. The core of the proposed approach is a novel feature extraction scheme that is based on a nonnegative sparse deconvolution of the observed GSR signals. Unlike previous approaches, the resulting SparsEDA algorithm is fast (immediately extracting the skin conductance level and response), efficient (being able to work with any sampling rate and signal length), and highly interpretable (due to the sparsity of the extracted phasic component of the GSR). Results on real data from 100 different subjects confirm the good performance of the method, which has been released through a free web-based code repository. PMID- 29990245 TI - Smartphone Orientation Estimation Algorithm Combining Kalman Filter With Gradient Descent. AB - Availability and all-in-one functionality of smartphones have become a multipurpose personal tool to improve our daily life. Recent advancements in hardware and accessibility of smartphones have spawn huge potential for assistive healthcare, in particular telerehabilitation. However, using smartphone sensors face certain challenges, in particular, accurate orientation estimation, which is usually less of a problem in specialized motion tracking sensor devices. Drift is one of the challenges. We first propose a simple feedback loop complementary filter (CFF) to reduce the error caused by the integration of the gyroscope's data in the orientation estimation. Next, we propose a new and better orientation estimation algorithm which combines quaternion-based kalman filter with corrector estimates using gradient descent (KFGD). We then evaluate CFF's and KFGD's performance on two early-stage rehabilitation exercises. The results show that CFF is capable of fast motion tracking and confirm that the feedback loop can correct the error caused by the integration of gyroscope data. The KFGD orientation estimation is comparable to XSENS Awinda and has shown itself to be stable than and outperforms CFF. KFGD also outperforms the prominent Madgwick algorithm using mobile data. Thus, KFGD is suitable for low-cost motion sensors or mobile inertial sensors, especially during early recovery stage of sport injuries and exercise for the elderly. PMID- 29990246 TI - Asthmatic Wheeze Detection From Compressively Sensed Respiratory Sound Spectra. AB - Quantification of wheezing by a sensor system consisting of a wearable wireless acoustic sensor and smartphone performing respiratory sound classification may contribute to the diagnosis, long-term control, and lowering treatment costs of asthma. In such battery-powered sensor system, compressive sensing (CS) was verified as a method for simultaneously cutting down power cost of signal acquisition, compression, and communication on the wearable sensor. Matching real time CS reconstruction algorithms, such as orthogonal matching pursuit (OMP), have been demonstrated on the smartphone. However, their lossy performance limits the accuracy of wheeze detection from CS-recovered short-term Fourier spectra (STFT), when using existing respiratory sound classification algorithms. Thus, here we present a novel, robust algorithm tailored specifically for wheeze detection from the CS-recovered STFT. The proposed algorithm identifies occurrence and tracks multiple individual wheeze frequency lines using hidden Markov model. The algorithm yields 89.34% of sensitivity, 96.28% of specificity, and 94.91% of accuracy on Nyquist-rate sampled respiratory sounds STFT. It enables for less than 2% loss of classification accuracy when operating over STFT reconstructed by OMP, at the signal compression ratio of up to 4 $?times$ (classification from only 25% signal samples). It features execution speed comparable to referent algorithms, and offers good prospects for parallelism. PMID- 29990247 TI - Feature Distilled Tracking. AB - Feature extraction and representation is one of the most important components for fast, accurate, and robust visual tracking. Very deep convolutional neural networks (CNNs) provide effective tools for feature extraction with good generalization ability. However, extracting features using very deep CNN models needs high performance hardware due to its large computation complexity, which prohibits its extensions in real-time applications. To alleviate this problem, we aim at obtaining small and fast-to-execute shallow models based on model compression for visual tracking. Specifically, we propose a small feature distilled network (FDN) for tracking by imitating the intermediate representations of a much deeper network. The FDN extracts rich visual features with higher speed than the original deeper network. To further speed-up, we introduce a shift-and-stitch method to reduce the arithmetic operations, while preserving the spatial resolution of the distilled feature maps unchanged. Finally, a scale adaptive discriminative correlation filter is learned on the distilled feature for visual tracking to handle scale variation of the target. Comprehensive experimental results on object tracking benchmark datasets show that the proposed approach achieves 5x speed-up with competitive performance to the state-of-the-art deep trackers. PMID- 29990248 TI - Proposal-Free Network for Instance-Level Object Segmentation. AB - Instance-level object segmentation is an important yet under-explored task. Most of state-of-the-art methods rely on region proposal methods to extract candidate segments and then utilize object classification to produce final results. Nonetheless, generating reliable region proposals itself is a quite challenging and unsolved task. In this work, we propose a Proposal-Free Network (PFN) to address the instance-level object segmentation problem, which outputs the numbers of instances of different categories and the pixel-level information on i) the coordinates of the instance bounding box each pixel belongs to, and ii) the confidences of different categories for each pixel, based on pixel-to-pixel deep convolutional neural network. All the outputs together, by using any off-the shelf clustering method for simple post-processing, can naturally generate the ultimate instance-level object segmentation results. The whole PFN can be easily trained without the requirement of a proposal generation stage. Extensive evaluations on the challenging PASCAL VOC 2012 semantic segmentation benchmark demonstrate the effectiveness of the proposed PFN solution without relying on any proposal generation methods. PMID- 29990249 TI - A Background Modeling and Foreground Detection Algorithm Using Scaling Coefficients Defined With a Color Model Called Lightness-Red-Green-Blue. AB - This paper presents an algorithm for background modeling and foreground detection that uses scaling coefficients, which are defined with a new color model called lightness-red-green-blue (LRGB). They are employed to compare two images by finding pixels with scaled lightness. Three backgrounds are used: 1) verified background with pixels that are considered as background; 2) testing background with pixels that are tested several times to check if they belong to the background; and 3) final background that is a combination of the testing and verified background (the testing background is used in places, where the verified background is not defined). If a testing background pixel matches pixels from previous frames (the match is tested using scaling coefficients), it is copied to the verified background, otherwise the pixel is set as the weighted average of the corresponding pixels of the last input images. After the background is computed, foreground objects are detected by using the scaling coefficients and additional criteria. The algorithm was evaluated using the SABS data set, Wallflower data set and a subset of the CDnet 2014 data set. The average F measure and sensitivity with the SABS Data set were 0.7109 and 0.8725, respectively. In the Wallflower data set, the total number of errors was 5280 and the total F-measure was 0.9089. In the CDnet 2014 data set, the F-measure for the baseline test case was 0.8887 and for the shadow test case was 0.8300. PMID- 29990250 TI - Semantic Neighbor Graph Hashing for Multimodal Retrieval. AB - Hashing methods have been widely used for approximate nearest neighbor search in recent years due to its computational and storage effectiveness. Most existing multimodal hashing methods try to preserve the similarity relationship based on either metric distances or semantic labels in a procrustean way, while ignoring the intra-class and inter-class variations inherent in the metric space. In this paper, we propose a novel multimodal hashing method, termed as semantic neighbor graph hashing (SNGH), which aims to preserve the fine-grained similarity metric based on the semantic graph that is constructed by jointly pursuing the semantic supervision and the local neighborhood structure. Specifically, the semantic graph is constructed to capture the local similarity structure for the image modality and the text modality, respectively. Furthermore, we define a function based on the local similarity in particular to adaptively calculate multi-level similarities by encoding the intra-class and inter-class variations. After obtaining the unified hash codes, the logistic regression with kernel trick is employed to learn view-specific hash functions independently for each modality. Extensive experiments are conducted on four widely used multimodal data sets. The experimental results demonstrate the superiority of the proposed SNGH method compared with the state-of-the-art multimodal hashing methods. PMID- 29990251 TI - Normalized Total Gradient: A New Measure for Multispectral Image Registration. AB - Image registration is a fundamental issue in multispectral image processing, and is challenged by two main characteristics of multispectral images. First, the regional intensities can be essentially different between band images. Second, the local contrasts of two difference band images are inconsistent or even reversed. Conventional measures can align images with different regional intensity levels, but may fail in the circumstance of severe local intensity variation. In this paper, a new measure called normalized total gradient is proposed for multispectral image registration. The measure is based on the key assumption (observation) that the gradient of the difference between two aligned band images is sparser than that between two misaligned ones. A registration framework, which incorporates image pyramid and global/local optimization, is further introduced for affine transform. Experimental results validate that the proposed method is not only effective for multispectral image registration, but also applicable to general unimodal/multimodal image registration tasks. It performs better than or comparable to the existing methods, both quantitatively and qualitatively. PMID- 29990252 TI - Efficient Detection of Communities in Biological Bipartite Networks. AB - Methods to efficiently uncover community structures are required in a number of biological applications where observing tightly-knit groups of vertices ("communities") can offer insights into the structural and functional building blocks. Classical applications of community detection have largely focused on unipartite networks. However, due to increased availability of biological data from various sources, there is now a need for handling heterogeneous networks which are built out of multiple types of objects. In this paper, we address the problem of identifying communities from biological bipartite networks---i.e., networks where interactions are observed between two different types of objects. Toward detecting communities in such bipartite networks, we make the following contributions: i) (metric) we propose a variant of bipartite modularity; ii) (algorithms) we present an efficient algorithm called biLouvain that implements a set of heuristics toward fast and precise community detection in bipartite networks (https://github.com/paolapesantez/biLouvain); and iii) (experiments) we present a thorough experimental evaluation of our algorithm including comparison to other state-of-the-art methods to identify communities in bipartite networks. Experimental results show that biLouvain identifies communities that have a comparable or better quality (as measured by bipartite modularity) than existing methods, while significantly reducing the time-to-solution between one and four orders of magnitude. PMID- 29990253 TI - DNRLMF-MDA:Predicting microRNA-disease associations based on similarities of microRNAs and diseases. AB - Discovering miRNA-disease associations is beneficial to understanding disease mechanisms, developing drugs, and treating complex diseases. We all know that discovering the miRNA-disease associations via biological experiments is a time consuming and expensive process. Alternatively, computational models could provide a low-cost and high-efficiency way for predicting miRNA-disease associations. In this study, we propose a method (called DNRLMF-MDA) to predict miRNA-disease associations. DNRLMF-MDA integrates known miRNA-disease associations, functional similarity and GIP kernel similarity of miRNAs, and functional similarity and GIP kernel similarity of diseases. DNRLMF-MDA models the association probability for each miRNA-disease pair by logistic matrix factorization. Positive observations are assigned higher importance levels than negative observations. Furthermore, DNRLMF-MDA further improves the prediction performance by dynamic neighborhood regularized. Through 5-fold cross validation and predicting potential diseases for new miRNAs on three datasets, the performance of DNRLMF-MDA usually outperformed other three methods in terms of the area under ROC curve (AUC). DNRLMF-MDA can predict potential diseases for new miRNAs and the computation time are shorter than PBMDAs computation time on three datasets .In addition, case studies further illustrate the practical ability of DNRLMF-MDA. It provides the basis for understanding disease mechanisms, developing drugs, and treating complex diseases. PMID- 29990254 TI - Elucidating Genome-Wide Protein-RNA Interactions using Differential Evolution. AB - RNA-binding proteins (RBPs) play an important role in the post-transcriptional control of RNAs, such as splicing, polyadenylation, mRNA stabilization, mRNA localization, and translation. Thanks to the recent breakthrough, non-negative matrix factorization (NMF) has been developed to combine multiple data sources to discover non-overlapping and class-specific RNA binding patterns. However, several challenges still exist in determining the number of latent dimensions in the factorization steps. In most circumstances, it is often assumed that the number of latent dimensions (or components) is given. Such trial-and-error procedures can be tedious in practice. In order to address this problem, differential evolution algorithm is proposed as the model selection method to choose the suitable number of ranks via differential evolution, which can adaptively decompose the input protein-RNA data matrix into different nonnegative components. Experimental results demonstrate that the proposed algorithms can improve the factorization quality over the recent state-of-the-arts. The effectiveness of the proposed algorithms are supported by comprehensive performance benchmarking on 31 genome-wide cross-linking immunoprecipitation (CLIP) coupled with high-throughput sequencing (CLIP-seq) datasets. In addition, time complexity analysis and parameter analysis are conducted to demonstrate the robustness of the proposed methods. PMID- 29990255 TI - Meta-path methods for prioritizing candidate disease miRNAs. AB - MicroRNAs (miRNAs) play critical roles in regulating gene expression at post transcriptional levels. Predicting potential miRNAdisease association is beneficial not only to explore the pathogenesis of diseases, but also to understand biological processes. In this work, we propose two methods that can effectively predict potential miRNAdisease associations using our reconstructed miRNA and disease similarity networks, which are based on the latest experimental data. We reconstruct a miRNA functional similarity network using the following biological information: the miRNA family information, miRNA cluster information, experimentally valid miRNA target association and disease miRNA information. We also reconstruct a disease similarity network using disease functional information and disease semantic information. We present Katz with specific weights and Katz with machine learning, on the comprehensive heterogeneous network. These methods, which achieve corresponding AUC values of 0.897 and 0.919, exhibit performance superior to the existing methods. Comprehensive data networks and reasonable considerations guarantee the high performance of our methods. Contrary to several methods, which cannot work in such situations, the proposed methods also predict associations for diseases without any known related miRNAs. A web service for the download and prediction of relationships between diseases and miRNAs is available at http://lab.malab.cn/soft/MDPredict/. PMID- 29990257 TI - Automatic Estimation of Fetal Abdominal Circumference From Ultrasound Images. AB - Ultrasound diagnosis is routinely used in obstetrics and gynecology for fetal biometry, and owing to its time-consuming process, there has been a great demand for automatic estimation. However, the automated analysis of ultrasound images is complicated because they are patient specific, operator dependent, and machine specific. Among various types of fetal biometry, the accurate estimation of abdominal circumference (AC) is especially difficult to perform automatically because the abdomen has low contrast against surroundings, nonuniform contrast, and irregular shape compared to other parameters. We propose a method for the automatic estimation of the fetal AC from two-dimensional ultrasound data through a specially designed convolutional neural network (CNN), which takes account of doctors' decision process, anatomical structure, and the characteristics of the ultrasound image. The proposed method uses CNN to classify ultrasound images (stomach bubble, amniotic fluid, and umbilical vein) and Hough transformation for measuring AC. We test the proposed method using clinical ultrasound data acquired from 56 pregnant women. Experimental results show that, with relatively small training samples, the proposed CNN provides sufficient classification results for AC estimation through the Hough transformation. The proposed method automatically estimates AC from ultrasound images. The method is quantitatively evaluated and shows stable performance in most cases and even for ultrasound images deteriorated by shadowing artifacts. As a result of experiments for our acceptance check, the accuracies are 0.809 and 0.771 with expert 1 and expert 2, respectively, whereas the accuracy between the two experts is 0.905. However, for cases of oversized fetus, when the amniotic fluid is not observed or the abdominal area is distorted, it could not correctly estimate AC. PMID- 29990256 TI - Adaptive Fault-Tolerant Control for Nonlinear Systems With Multiple Sensor Faults and Unknown Control Directions. AB - This paper investigates the problem of adaptive fault-tolerant control for a class of nonlinear parametric strict-feedback systems with multiple unknown control directions. Multiple sensor faults are first considered such that all real state variables are unavailable. Then, a constructive design method for the problem is set up by exploiting a parameter separation and regrouping technique. To circumvent the main obstacle caused by the coupling effects of multiple unknown control directions and sensor faults, a region-dependent segmentation analysis method is proposed. It is proven that the closed-loop system is globally exponentially stable. Simulation results are presented to illustrate the effectiveness of the proposed scheme. PMID- 29990258 TI - Robust Segmentation of Intima-Media Borders With Different Morphologies and Dynamics During the Cardiac Cycle. AB - Segmentation of carotid intima-media (IM) borders from ultrasound sequences is challenging because of unknown image noise and varying IM border morphologies and/or dynamics. In this paper, we have developed a state-space framework to sequentially segment the carotid IM borders in each image throughout the cardiac cycle. In this framework, an ${?mathrm{H}}_{?mathrm{?infty }}$ filter is used to solve the state-space equations, and a grayscale-derivative constraint snake is used to provide accurate measurements for the ${?mathrm{H}}_{?mathrm{?infty }}$ filter. We have evaluated the performance of our approach by comparing our segmentation results to the manually traced contours of ultrasound image sequences of three synthetic models and 156 real subjects from four medical centers. The results show that our method has a small segmentation error (lumen intima, LI: 53 $?pm?, 67?;{?mathrm{?mu }}$m; media-adventitia, MA: 57 $?pm?, 63?;{?mathrm{?mu }}$m) for synthetic and real sequences of different image characteristics, and also agrees well with the manual segmentation (LI: bias = 1.44 ${?mathrm{?mu }}$m; MA: bias = $-$3.38 ${?mathrm{?mu }}$m). Our approach can robustly segment the carotid ultrasound sequences with various IM border morphologies, dynamics, and unknown image noise. These results indicate the potential of our framework to segment IM borders for clinical diagnosis. PMID- 29990260 TI - Learning Stylometric Representations for Authorship Analysis. AB - Authorship analysis (AA) is the study of unveiling the hidden properties of authors from textual data. It extracts an author's identity and sociolinguistic characteristics based on the reflected writing styles in the text. The process is essential for various areas, such as cybercrime investigation, psycholinguistics, political socialization, etc. However, most of the previous techniques critically depend on the manual feature engineering process. Consequently, the choice of feature set has been shown to be scenario- or dataset-dependent. In this paper, to mimic the human sentence composition process using a neural network approach, we propose to incorporate different categories of linguistic features into distributed representation of words in order to learn simultaneously the writing style representations based on unlabeled texts for AA. In particular, the proposed models allow topical, lexical, syntactical, and character-level feature vectors of each document to be extracted as stylometrics. We evaluate the performance of our approach on the problems of authorship characterization, authorship identification and authorship verification with the Twitter, blog, review, novel, and essay datasets. The experiments suggest that our proposed text representation outperforms the static stylometrics, dynamic n-grams, latent Dirichlet allocation, latent semantic analysis, distributed memory model of paragraph vectors, distributed bag of words version of paragraph vector, word2vec representations, and other baselines. PMID- 29990259 TI - IoT-Based Remote Pain Monitoring System: From Device to Cloud Platform. AB - Facial expressions are among behavioral signs of pain that can be employed as an entry point to develop an automatic human pain assessment tool. Such a tool can be an alternative to the self-report method and particularly serve patients who are unable to self-report like patients in the intensive care unit and minors. In this paper, a wearable device with a biosensing facial mask is proposed to monitor pain intensity of a patient by utilizing facial surface electromyogram (sEMG). The wearable device works as a wireless sensor node and is integrated into an Internet of Things (IoT) system for remote pain monitoring. In the sensor node, up to eight channels of sEMG can be each sampled at 1000 Hz, to cover its full frequency range, and transmitted to the cloud server via the gateway in real time. In addition, both low energy consumption and wearing comfort are considered throughout the wearable device design for long-term monitoring. To remotely illustrate real-time pain data to caregivers, a mobile web application is developed for real-time streaming of high-volume sEMG data, digital signal processing, interpreting, and visualization. The cloud platform in the system acts as a bridge between the sensor node and web browser, managing wireless communication between the server and the web application. In summary, this study proposes a scalable IoT system for real-time biopotential monitoring and a wearable solution for automatic pain assessment via facial expressions. PMID- 29990261 TI - An Iterative Co-Saliency Framework for RGBD Images. AB - As a newly emerging and significant topic in computer vision community, co saliency detection aims at discovering the common salient objects in multiple related images. The existing methods often generate the co-saliency map through a direct forward pipeline which is based on the designed cues or initialization, but lack the refinement-cycle scheme. Moreover, they mainly focus on RGB image and ignore the depth information for RGBD images. In this paper, we propose an iterative RGBD co-saliency framework, which utilizes the existing single saliency maps as the initialization, and generates the final RGBD co-saliency map by using a refinement-cycle model. Three schemes are employed in the proposed RGBD co saliency framework, which include the addition scheme, deletion scheme, and iteration scheme. The addition scheme is used to highlight the salient regions based on intra-image depth propagation and saliency propagation, while the deletion scheme filters the saliency regions and removes the non-common salient regions based on interimage constraint. The iteration scheme is proposed to obtain more homogeneous and consistent co-saliency map. Furthermore, a novel descriptor, named depth shape prior, is proposed in the addition scheme to introduce the depth information to enhance identification of co-salient objects. The proposed method can effectively exploit any existing 2-D saliency model to work well in RGBD co-saliency scenarios. The experiments on two RGBD co-saliency datasets demonstrate the effectiveness of our proposed framework. PMID- 29990263 TI - High Frame Rate Ultrasound Particle Image Velocimetry for Estimating High Velocity Flow Patterns in the Left Ventricle. AB - Echocardiographic determination of multi-component blood flow dynamics in the left ventricle remains a challenge. In this study we compare contrast enhanced, high frame rate (1000 fps) echo particle image velocimetry (ePIV) against optical particle image velocimetry (oPIV, gold standard), in a realistic left ventricular phantom. We find that ePIV compares well to oPIV, even for the high velocity inflow jet (normalized RMSE = 9 +/-1%). Additionally, we perform the method of Proper Orthogonal Decomposition, to better qualify and quantify the differences between the two modalities. We show that ePIV and oPIV resolve very similar flow structures, especially for the lowest order mode with a cosine similarity index of 86%. The coarser resolution of ePIV does result in increased variance and blurring of smaller flow structures when compared to oPIV. However, both modalities are in good agreement with each other for the modes that constitute the bulk of the kinetic energy. We conclude that high frame rate ePIV can accurately estimate the high velocity diastolic inflow jet and the high energy flow structures in a left ventricular setting. PMID- 29990264 TI - Statistical Association Mapping of Population-Structured Genetic Data. AB - Association mapping of genetic diseases has attracted extensive research interest during the recent years. However, most of the methodologies introduced so far suffer from spurious inference of the associated sites due to population inhomogeneities. In this paper, we introduce a statistical framework to compensate for this shortcoming by equipping the current methodologies with a state-of-the-art clustering algorithm being widely used in population genetics applications. The proposed framework jointly infers the disease-associated factors and the hidden population structures. In this regard, a Markov Chain Monte Carlo (MCMC) procedure has been employed to assess the posterior probability distribution of the model parameters. We have implemented our proposed framework on a software package whose performance is extensively evaluated on a number of synthetic datasets, and compared to some of the well known existing methods such as STRUCTURE. It has been shown that in extreme scenarios, up to of improvement in the inference accuracy is achieved with a moderate increase in computational complexity. PMID- 29990265 TI - Unsupervised Discovery of Geometrically Common Structural Motifs and Long-Range Contacts in Protein 3D Structures. AB - The essential role of small evolutionarily conserved structural units in proteins has been extensively researched and validated. A popular example are serine proteases, where the peptide cleavage reaction is realized by a configuration of only three residues. Brought to close spatial proximity during the protein folding process, such structural motifs are often long-range contacts and usually hard to grasp at sequence level. Due to the constantly increasing resource of protein 3D structure data, the computational identification of structural motifs can contribute significantly to the understanding of protein fold and function. Thus, we propose a method to unveil structural motifs of high geometrical similarity and desired sequence separation in protein 3D structure data. By utilizing methods originated from data mining, no a priori knowledge is required. The applicability of the method is demonstrated by the identification of the catalytic unit of serine proteases and the ion-coordination center of cupredoxins. Furthermore, large-scale screening of the entire Protein Data Bank points towards the presence of ubiquitous structural motifs, independent of any specific fold or function. We envision that our method is suitable to uncover functional mechanisms and to derive fingerprint libraries of naturally observed structural motifs, which could be used to assess protein family association. PMID- 29990266 TI - Robust Object Tracking by Nonlinear Learning. AB - We propose a method that obtains a discriminative visual dictionary and a nonlinear classifier for visual tracking tasks in a sparse coding manner based on the globally linear approximation for a nonlinear learning theory. Traditional discriminative tracking methods based on sparse representation learn a dictionary in an unsupervised way and then train a classifier, which may not generate both descriptive and discriminative models for targets by treating dictionary learning and classifier learning separately. In contrast, the proposed tracking approach can construct a dictionary that fully reflects the intrinsic manifold structure of visual data and introduces more discriminative ability in a unified learning framework. Finally, an iterative optimization approach, which computes the optimal dictionary, the associated sparse coding, and a classifier, is introduced. Experiments on two benchmarks show that our tracker achieves a better performance compared with some popular tracking algorithms. PMID- 29990267 TI - High-Performance Mixed-Signal Neurocomputing With Nanoscale Floating-Gate Memory Cell Arrays. AB - Potential advantages of analog- and mixed-signal nanoelectronic circuits, based on floating-gate devices with adjustable conductance, for neuromorphic computing had been realized long time ago. However, practical realizations of this approach suffered from using rudimentary floating-gate cells of relatively large area. Here, we report a prototype $28?times28$ binary-input, ten-output, three-layer neuromorphic network based on arrays of highly optimized embedded nonvolatile floating-gate cells, redesigned from a commercial 180-nm nor flash memory. All active blocks of the circuit, including 101 780 floating-gate cells, have a total area below 1 mm2. The network has shown a 94.7% classification fidelity on the common Modified National Institute of Standards and Technology benchmark, close to the 96.2% obtained in simulation. The classification of one pattern takes a sub-1- $?mu ?text{s}$ time and a sub-20-nJ energy-both numbers much better than in the best reported digital implementations of the same task. Estimates show that a straightforward optimization of the hardware and its transfer to the already available 55-nm technology may increase this advantage to more than $10^{2}?times $ in speed and $10^{4}?times $ in energy efficiency. PMID- 29990268 TI - Medication Episode Construction Framework for Retrospective Database Analyses of Patients With Chronic Diseases. AB - OBJECTIVE: For chronic diseases, medical history reconstruction is essential for retrospective database analyses. One important aspect is determining which prescriptions belong to the same episode. However, a standard framework for this task is still lacking, particularly for multitherapy datasets. This paper presents a medication episode construction framework for the medical history of patients with chronic diseases. METHODS: Allen's relaxed temporal relations (i.e., temporal relations with time constraints relaxed by ) is used to define the consecutive prescription relations considering the patients' behavior. For example, patients occasionally arrive earlier or later than their appointment. RESULTS: influences the generation of stable periods (i.e., periods of time, at least three months, in which a medication is continuously taken by a patient). When using the lowest selected value (7 days), considerably fewer shorter stable periods (for durations less than 300 days) are produced and more longer stable periods are produced compared to cases without using . Furthermore, the results show that by using , regarding the number of events, where a stable period continues the previous stable period, decreases and the number of medication transition events available to be observed increases. CONCLUSION: Using in medication episode construction from multitherapy prescription datasets enables the longer expression of short-duration fragmented prescriptions and pruning repetitive prescriptions. SIGNIFICANCE: Our proposed framework is designed for multitherapy datasets, which has not been addressed by previous studies. The concept of relaxes the prescription relation against noise caused by the patient behavior and consequently provides a compact, but informative search space for observing medication transition events in a longitudinal analysis. PMID- 29990269 TI - Camera-Assisted Video Saliency Prediction and Its Applications. AB - Video saliency prediction is an indispensable yet challenging technique which can facilitate various applications, such as video surveillance, autonomous driving, and realistic rendering. Based on the popularity of embedded cameras, we in this paper predict region-level saliency from videos by leveraging human gaze locations recorded using a camera, (e.g., those equipped on an iMAC and laptop PC). Our proposed camera-assisted mechanism improves saliency prediction by discovering human attended regions inside a video clip. It is orthogonal to the current saliency models, i.e., any existing video/image saliency model can be boosted by our mechanism. First of all, the spatial-and temporal-level visual features are exploited collaboratively for calculating an initial saliency map. We notice that the current saliency models are not sufficiently adaptable to the variations in lighting, different view angles, and complicated backgrounds. Therefore, assisted by a camera tracking human gaze movements, a non-negative matrix factorization algorithm is designed to accurately localize the semantically/visually salient video regions perceived by humans. Finally, the learned human gaze locations as well as the initial saliency map are integrated to optimize video saliency calculation. Empirical results thoroughly demonstrated that: 1) our approach achieves the state-of-the-art video saliency prediction accuracy by outperforming 11 mainstream algorithms considerably and 2) our method can conveniently and successfully enhance video retargeting, quality estimation, and summarization. PMID- 29990270 TI - Dynamic Coverage Control in a Time-Varying Environment Using Bayesian Prediction. AB - This paper investigates the dynamic coverage control problem for a group of agents with unknown density function. A cost function, depending on a certain metric and the density function, is defined to describe the performance of coverage network. Since the optimal deployment of agents is closely depending on the density function, we employ the Bayesian prediction approaches to estimate the density function. Moreover, a novel coverage-control-customized algorithm is proposed to acquire the Bayesian parameters. The merits of this Bayesian-based spatial estimation algorithm are the consideration of measurement noise and the capability of dealing time-varying density function. However, the estimated density function from Bayesian framework follows normal distribution, which leads the cost function to a stochastic process. To deal with this type of cost function, a discrete control scheme is proposed to steer the agents approaching to a near-optimal deployment. The mean-square stability of the proposed coverage system is further analyzed. Finally, numerical simulations are provided to verify the effectiveness of the proposed approaches. PMID- 29990271 TI - Multiplicative Update Methods for Incremental Quantile Estimation. AB - We present a novel lightweight incremental quantile estimator which possesses far less complexity than the Tierney's estimator and its extensions. Notably, our algorithm relies only on tuning one single parameter which is a plausible property which we could only find in the discretized quantile estimator Frugal. This makes our algorithm easy to tune for better performance. Furthermore, our algorithm is multiplicative which makes it highly suitable to handle quantile estimation in systems in which the underlying distribution varies with time. Unlike Frugal and our legacy work which are randomized algorithms, we suggest deterministic updates where the step size is adjusted in a subtle manner to ensure the convergence. The deterministic algorithm is more efficient since the estimate is updated at every iteration. The convergence of the proposed estimator is proven using the theory of stochastic learning. Extensive experimental results show that our estimator clearly outperforms legacy works. PMID- 29990272 TI - MOEA/HD: A Multiobjective Evolutionary Algorithm Based on Hierarchical Decomposition. AB - Recently, numerous multiobjective evolutionary algorithms (MOEAs) have been proposed to solve the multiobjective optimization problems (MOPs). One of the most widely studied MOEAs is that based on decomposition (MOEA/D), which decomposes an MOP into a series of scalar optimization subproblems, via a set of uniformly distributed weight vectors. MOEA/D shows excellent performance on most mild MOPs, but may face difficulties on ill MOPs, with complex Pareto fronts, which are pointed, long tailed, disconnected, or degenerate. That is because the weight vectors used in decomposition are all preset and invariant. To overcome it, a new MOEA based on hierarchical decomposition (MOEA/HD) is proposed in this paper. In MOEA/HD, subproblems are layered into different hierarchies, and the search directions of lower-hierarchy subproblems are adaptively adjusted, according to the higher-hierarchy search results. In the experiments, MOEA/HD is compared with four state-of-the-art MOEAs, in terms of two widely used performance metrics. According to the empirical results, MOEA/HD shows promising performance on all the test problems. PMID- 29990273 TI - Hough Forest With Optimized Leaves for Global Hand Pose Estimation With Arbitrary Postures. AB - Vision-based hand pose estimation is important in human-computer interaction. While many recent works focus on full degree-of-freedom hand pose estimation, robust estimation of global hand pose remains a challenging problem. This paper presents a novel algorithm to optimize the leaf weights in a Hough forest to assist global hand pose estimation with a single depth camera. Different from traditional Hough forest, we propose to learn the vote weights stored at the leaf nodes of a forest in a principled way to minimize average pose prediction error, so that ambiguous votes are largely suppressed during prediction fusion. Experiments show that the proposed method largely improves pose estimation accuracy with optimized leaf weights on both synthesis and real datasets and performs favorably compared to state-of-the-art convolutional neural network based methods. On real-world depth videos, the proposed method demonstrates improved robustness compared to several other recent hand tracking systems from both industry and academy. Moreover, we utilize the proposed method to build virtual/augmented reality applications to allow users to manipulate and examine virtual objects with bare hands. PMID- 29990274 TI - Improving Metaheuristic Algorithms With Information Feedback Models. AB - In most metaheuristic algorithms, the updating process fails to make use of information available from individuals in previous iterations. If this useful information could be exploited fully and used in the later optimization process, the quality of the succeeding solutions would be improved significantly. This paper presents our method for reusing the valuable information available from previous individuals to guide later search. In our approach, previous useful information was fed back to the updating process. We proposed six information feedback models. In these models, individuals from previous iterations were selected in either a fixed or random manner. Their useful information was incorporated into the updating process. Accordingly, an individual at the current iteration was updated based on the basic algorithm plus some selected previous individuals by using a simple fitness weighting method. By incorporating six different information feedback models into ten metaheuristic algorithms, this approach provided a number of variants of the basic algorithms. We demonstrated experimentally that the variants outperformed the basic algorithms significantly on 14 standard test functions and 10 CEC 2011 real world problems, thereby, establishing the value of the information feedback models. PMID- 29990275 TI - Sampled-Data-Based Event-Triggered Active Disturbance Rejection Control for Disturbed Systems in Networked Environment. AB - This paper develops a methodology on sampled-data-based event-triggered active disturbance rejection control (ET-ADRC) for disturbed systems in networked environment when only using measurable outputs. By using disturbance/uncertainty estimation and attenuation technique, an event-based sampled-data composite controller is proposed together with a discrete-time extended state observer. Under the presented new framework, the newest state and disturbance estimates as well as the control signals are not transmitted via the common sensor-controller network, but instead communicated and calculated until a discrete-time event triggering condition is violated. Compared with the periodic updates in the traditional time-triggered active disturbance rejection control, the proposed ET ADRC scheme can remarkably reduce the communication frequency while maintaining a satisfactory closed-loop system performance. The proposed discrete-time control scheme provides the engineers with a manner of direct and easier implementation via networked digital computers. It is shown that the bounded stability of the closed-loop system can be guaranteed. Finally, an application design example of a dc-dc buck converter with experimental results is conducted to illustrate the efficiency of the proposed control scheme. PMID- 29990276 TI - A Control-Theoretic Assessment of Interventions During Drinking Events. AB - This paper employs control-theoretic tools to provide guidelines for in-situ interventions aimed at reducing high-risk alcohol consumption at drinking events. A dynamical directed network model of a drinking event with external intervention, suitable for mathematical analysis and parameter estimation using field data is proposed, with insights from pharmacokinetics and psychology. Later, a characterization of a bound on blood alcohol content (BAC) trajectories is obtained via Lyapunov stability analysis, and structural controllability guarantees are obtained via a graph-theoretic method. We use the degree of controllability, given to be the trace of the system's controllability Gramian, as a metric to compare the viability of network nodes for intervention based on theoretic and heuristic centrality measures. Results of numerical examples of bars and parties, informed by field data, and the stability and controllability results, suggest that intervening in the environment in wet bars, while targeting influential individuals with high alcohol consumption motivations in private parties efficiently yield lower peak BAC levels in individuals at the drinking events. PMID- 29990277 TI - Dependence models for searching text in document images. AB - The main goal of existing word spotting approaches for searching document images has been the identification of visually similar word images in the absence of high quality text recognition output. Searching for a piece of arbitrary text is not possible unless the user identifies a sample word image from the document collection or generates the query word image synthetically. To address this problem, a Markov Random Field (MRF) framework is proposed for searching document images and shown to be effective for searching arbitrary text in real time for books printed in English (Latin script), Telugu and Ottoman scripts. The English experiments demonstrate that the dependencies between the visual terms and letter bigrams can be automatically learned using noisy OCR output. It is also shown that OCR text search accuracy can be significantly improved if it is combined with the proposed approach. No commercial OCR engine is available for Telugu or Ottoman script. In these cases the dependencies are trained using manually annotated document images. It is demonstrated that the trained model can be directly used to resolve arbitrary text queries across books despite font type and size differences. The proposed approach outperforms a state-of-the-art BLSTM baseline in these contexts. PMID- 29990278 TI - Kernel clustering: density biases and solutions. AB - Clustering is widely used in data analysis where kernel methods are particularly popular due to their generality and discriminating power. However, kernel clustering has a practically significant bias to small dense clusters, e.g. empirically observed in [1]. Its causes have never been analyzed and understood theoretically, even though many attempts were made to improve the results. We provide conditions and formally prove this bias in kernel clustering. Previously, Breiman [2] proved a bias to histogram mode isolation in discrete Gini criterion for decision tree learning. We found that kernel clustering reduces to a continuous generalization of Gini criterion for a common class of kernels where we prove a bias to density mode isolation and call it Breiman's bias. These theoretical findings suggest that a principled solution for the bias should directly address data density inhomogeneity. In particular, we show that density equalization can be implicitly achieved using either locally adaptive weights or a general class of Riemannian (geodesic) kernels. Our density equalization principle unifies many popular kernel clustering criteria including normalized cut, which we show has a bias to sparse subsets inversely related to Breiman's bias. Our synthetic and real data experiments illustrate these density biases and proposed solutions. We anticipate that theoretical understanding of kernel clustering limitations and their principled solutions will be important for a broad spectrum of data analysis applications across the disciplines. PMID- 29990279 TI - A Sparse Regression Method for Group-Wise Feature Selection with False Discovery Rate Control. AB - The method of Sorted L-One Penalized Estimation, or SLOPE, is a sparse regression method recently introduced by Bogdan et. al. [1] . It can be used to identify significant predictor variables in a linear model that may have more unknown parameters than observations. When the correlations between predictor variables are small, the SLOPE method is shown to successfully control the false discovery rate (the expected proportion of the irrelevant among all selected predictors) at a user specified level. However, the requirement for nearly uncorrelated predictors is too restrictive for genomic data, as demonstrated in our recent study [2] by an application of SLOPE to realistic simulated DNA sequence data. A possible solution is to divide the predictor variables into nearly uncorrelated groups, and to modify the procedure to select entire groups with an overall significant group effect, rather than individual predictors. Following this motivation, we extend SLOPE in the spirit of Group LASSO to Group SLOPE, a method that can handle group structures between the predictor variables, which are ubiquitous in real genomic data. Our theoretical results show that Group SLOPE controls the group-wise false discovery rate (gFDR), when groups are orthogonal to each other. For use in non-orthogonal settings, we propose two types of Monte Carlo based heuristics, which lead to gFDR control with Group SLOPE in simulations based on real SNP data. As an illustration of the merits of this method, an application of Group SLOPE to a dataset from the Framingham Heart Study results in the identification of some known DNA sequence regions associated with bone health, as well as some new candidate regions. The novel methods are implemented in the R package grpSLOPEMC , which is publicly available at https://github.com/agisga/grpSLOPEMC. PMID- 29990280 TI - Robotic-Assisted Needle Steering Around Anatomical Obstacles Using Notched Steerable Needles. AB - Robotic-assisted needle steering can enhance the accuracy of needle-based interventions. Application of current needle steering techniques are restricted by the limited deflection curvature of needles. Here, a novel steerable needle with improved curvature is developed and used with an online motion planner to steer the needle along curved paths inside tissue. The needle is developed by carving series of small notches on the shaft of a standard needle. The notches decrease the needle flexural stiffness, allowing the needle to follow tightly curved paths with small radius of curvature. In this paper, first, a finite element model of the notched needle deflection in tissue is presented. Next, the model is used to estimate the optimal location for the notches on needle's shaft for achieving a desired curvature. Finally, an ultrasound-guided motion planner for needle steering inside tissue is developed and used to demonstrate the capability of the notched needle in achieving high curvature and maneuvering around obstacles in tissue. We simulated a clinical scenario in brachytherapy, where the target is obstructed by the pubic bone and cannot be reached using regular needles. Experimental results show that the target can be reached using the notched needle with a mean accuracy of 1.2 mm. Thus, the proposed needle enables future research on needle steering toward deeper or more difficult-to reach targets. PMID- 29990281 TI - Large-scale Image Geo-Localization Using Dominant Sets. AB - This paper presents a new approach for the challenging problem of geo-locating an image using image matching in a structured database of city-wide reference images with known GPS coordinates. We cast the geo-localization as a clustering problem on local image features. Akin to existing approaches on the problem, our framework builds on low-level features which allow partial matching between images. For each local feature in the query image, we find its approximate nearest neighbors in the reference set. Next, we cluster the features from reference images using Dominant Set clustering, which affords several advantages over existing approaches. First, it permits variable number of nodes in the cluster which we use to dynamically select the number of nearest neighbors (typically coming from multiple reference images) for each query feature based on its discrimination value. Second, as we also quantify in our experiments, this approach is several orders of magnitude faster than existing approaches. Thus, we obtain multiple clusters (different local maximizers) and obtain a robust final solution to the problem using multiple weak solutions through constrained Dominant Set clustering on global image features, where we enforce the constraint that the query image must be included in the cluster. This second level of clustering also bypasses heuristic approaches to voting and selecting the reference image that matches to the query. We evaluate the proposed framework on an existing dataset of 102k street view images as well as a new larger dataset of 300k images, and show that it outperforms the state-of-the-art by 20% and 7%, respectively, on the two datasets. PMID- 29990282 TI - Upper and Lower Tight Error Bounds for Feature Omission with an Extension to Context Reduction. AB - In this work, fundamental analytic results in the form of error bounds are presented that quantify the effect of feature omission and selection for pattern classification in general, as well as the effect of context reduction in string classification, like automatic speech recognition, printed/handwritten character recognition, or statistical machine translation. A general simulation framework is introduced that supports discovery and proof of error bounds, which lead to the error bounds presented here. Initially derived tight lower and upper bounds for feature omission are generalized to feature selection, followed by another extension to context reduction of string class priors (aka language models) in string classification. For string classification, the quantitative effect of string class prior context reduction on symbol-level Bayes error is presented. The tightness of the original feature omission bounds seems lost in this case, as further simulations indicate. However, combining both feature omission and context reduction, the tightness of the bounds is retained. A central result of this work is the proof of the existence, and the amount of a statistical threshold w.r.t. the introduction of additional features in general pattern classification, or the increase of context in string classification beyond which a decrease in Bayes error is guaranteed. PMID- 29990283 TI - Exploiting Negative Evidence for Deep Latent Structured Models. AB - The abundance of image-level labels and the lack of large scale detailed annotations (e.g. bounding boxes, segmentation masks) promotes the development of weakly supervised learning (WSL) models. In this work, we propose a novel framework for WSL of deep convolutional neural networks dedicated to learn localized features from global image-level annotations. The core of the approach is a new latent structured output model equipped with a pooling function which explicitly models negative evidence, e.g. a cow detector should strongly penalize the prediction of the bedroom class. We show that our model can be trained end-to end for different visual recognition tasks: multi-class and multi-label classification, and also structured average precision (AP) ranking. Extensive experiments highlight the relevance of the proposed method: our model outperforms state-of-the art results on six datasets. We also show that our framework can be used to improve the performance of state-of-the-art deep models for large scale image classification on ImageNet. Finally, we evaluate our model for weakly supervised tasks: in particular, a direct adaptation for weakly supervised segmentation provides a very competitive model. PMID- 29990284 TI - Camera Shutter-Independent Registration and Rectification. AB - Inevitable camera motion during exposure does not augur well for free-hand photography. Distortions introduced in images can be of different types and mainly depend on the structure of the scene, the nature of camera motion, and the shutter mechanism of the camera. In this paper, we address the problem of registering images taken from global shutter and rolling shutter cameras and reveal the constraints on camera motion that admit registration, change detection, and rectification. Our analysis encompasses degradations arising from camera motion during exposure and differences in shutter mechanisms. We also investigate conditions under which camera motions causing distortions in reference and target image can be decoupled to yield the underlying latent image through RS rectification. We validate our approach using several synthetic and real examples. PMID- 29990285 TI - Matching Contactless and Contact-based Conventional Fingerprint Images for Biometrics Identification. AB - Vast databases of billions of contact-based fingerprints have been developed to protect national borders and support e-governance programs. Emerging contactless fingerprint sensors offer better hygiene, security and accuracy. However the adoption/success of such contactless fingerprint technologies largely depends on advanced capability to match contactless 2D fingerprints with legacy contact based fingerprint databases. This paper investigates such problem and develops a new approach to accurately match such fingerprint images. Robust thin-plate spline (RTPS) is developed to more accurately model elastic fingerprint deformations using splines. In order to correct such deformations on the contact based fingerprints, RTPS based generalized fingerprint deformation correction model (DCM) is proposed. The usage of DCM results in accurate alignment of key minutiae features observed on the contactless and contactbased fingerprints. Further improvement in such cross-matching performance is investigated by incorporating minutiae related ridges. We also develop a new database of 1800 contactless 2D fingerprints and the corresponding contact-based fingerprints acquired from 300 clients which is made publicly accessible for further research. The experimental results presented in this paper, using two publicly available databases, validate our approach and achieve outperforming results for matching contactless 2D and contact-based fingerprint images. PMID- 29990286 TI - An Integrated Framework for Identifying Mutated Driver Pathway and Cancer Progression. AB - Next-generation sequencing (NGS) technologies provide amount of somatic mutation data in a large number of patients. The identification of mutated driver pathway and cancer progression from these data is a challenging task because of the heterogeneity of interpatient. In addition, cancer progression at the pathway level has been proved to be more reasonable than at the gene level. In this paper, we introduce an integrated framework to identify mutated driver pathways and cancer progression (iMDPCP) at the pathway level from somatic mutation data. First, we use uncertainty coefficient to quantify mutual exclusivity on gene driver pathways and develop a computational framework to identify mutated driver pathways based on the adaptive discrete differential evolution algorithm. Then, we construct cancer progression model for driver pathways based on the Bayesian Network. Finally, we evaluate the performance of iMDPCP on real cancer somatic mutation datasets. The experimental results indicate that iMDPCP is more accurate than state-of-the-art methods according to the enrichment of KEGG pathways, and it also provides new insights on identifying cancer progression at the pathway level. PMID- 29990287 TI - Credibility of Evolutionary Events in Gene Trees. AB - Based on the classical non-parametric bootstrapping for phylogenetic trees, we propose a novel bootstrap method to define support for gene duplication and speciation events. By comparing bootstrap gene trees to the original gene tree, we calculate support for evolutionary events. While this approach can be used to annotate orthology and paralogy, we show how it can be used to verify the reliability of tree reconciliation. We propose a linear time algorithm for the computation of bootstrap values, and we show the correspondence of our method with the classical non-parametric bootstrapping. Finally, we present two computational experiments. In the first one, based on simulated data and nine yeast genomes, we show a comparative study of several tree rooting methods and evaluation of their performance by using our bootstrapping method. In the second experiment, using data from the TreeFam database, we tested how the reliability of the gene trees influence the inferred supertree. We found out that species trees inferred from gene trees having highly supported events are more biologically consistent. PMID- 29990288 TI - Unsupervised Learning of 3-D Local Features From Raw Voxels Based on a Novel Permutation Voxelization Strategy. AB - Effective 3-D local features are significant elements for 3-D shape analysis. Existing hand-crafted 3-D local descriptors are effective but usually involve intensive human intervention and prior knowledge, which burdens the subsequent processing procedures. An alternative resorts to the unsupervised learning of features from raw 3-D representations via popular deep learning models. However, this alternative suffers from several significant unresolved issues, such as irregular vertex topology, arbitrary mesh resolution, orientation ambiguity on the 3-D surface, and rigid and slightly nonrigid transformation invariance. To tackle these issues, we propose an unsupervised 3-D local feature learning framework based on a novel permutation voxelization strategy to learn high-level and hierarchical 3-D local features from raw 3-D voxels. Specifically, the proposed strategy first applies a novel voxelization which discretizes each 3-D local region with irregular vertex topology and arbitrary mesh resolution into regular voxels, and then, a novel permutation is applied to permute the voxels to simultaneously eliminate the effect of rotation transformation and orientation ambiguity on the surface. Based on the proposed strategy, the permuted voxels can fully encode the geometry and structure of each local region in regular, sparse, and binary vectors. These voxel vectors are highly suitable for the learning of hierarchical common surface patterns by stacked sparse autoencoder with hierarchical abstraction and sparse constraint. Experiments are conducted on three aspects for evaluating the learned local features: 1) global shape retrieval; 2) partial shape retrieval; and 3) shape correspondence. The experimental results show that the learned local features outperform the other state-of-the-art 3-D shape descriptors. PMID- 29990289 TI - MOO-MDP: An Object-Oriented Representation for Cooperative Multiagent Reinforcement Learning. AB - Reinforcement learning (RL) is a widely known technique to enable autonomous learning. Even though RL methods achieved successes in increasingly large and complex problems, scaling solutions remains a challenge. One way to simplify (and consequently accelerate) learning is to exploit regularities in a domain, which allows generalization and reduction of the learning space. While object-oriented Markov decision processes (OO-MDPs) provide such generalization opportunities, we argue that the learning process may be further simplified by dividing the workload of tasks amongst multiple agents, solving problems as multiagent systems (MAS). In this paper, we propose a novel combination of OO-MDP and MAS, called multiagent OO-MDP (MOO-MDP). Our proposal accrues the benefits of both OO-MDP and MAS, better addressing scalability issues. We formalize the general model MOO-MDP and present an algorithm to solve deterministic cooperative MOO-MDPs. We show that our algorithm learns optimal policies while reducing the learning space by exploiting state abstractions. We experimentally compare our results with earlier approaches in three domains and evaluate the advantages of our approach in sample efficiency and memory requirements. PMID- 29990290 TI - Consensus in Self-Similar Hierarchical Graphs and Sierpinski Graphs: Convergence Speed, Delay Robustness, and Coherence. AB - The hierarchical graphs and Sierpinski graphs are constructed iteratively, which have the same number of vertices and edges at any iteration, but exhibit quite different structural properties: the hierarchical graphs are nonfractal and small world, while the Sierpinski graphs are fractal and ''large-world.'' Both graphs have found broad applications. In this paper, we study consensus problems in hierarchical graphs and Sierpinski graphs, focusing on three important quantities of consensus problems, that is, convergence speed, delay robustness, and coherence for first-order (and second-order) dynamics, which are, respectively, determined by algebraic connectivity, maximum eigenvalue, and sum of reciprocal (and square of reciprocal) of each nonzero eigenvalue of Laplacian matrix. For both graphs, based on the explicit recursive relation of eigenvalues at two successive iterations, we evaluate the second smallest eigenvalue, as well as the largest eigenvalue, and obtain the closed-form solutions to the sum of reciprocals (and square of reciprocals) of all nonzero eigenvalues. We also compare our obtained results for consensus problems on both graphs and show that they differ in all quantities concerned, which is due to the marked difference of their topological structures. PMID- 29990291 TI - "It's a Race Against the Clock": A Qualitative Analysis of Barriers to Legal Abortion in Bogota, Colombia. AB - CONTEXT: In 2006, the Colombian Constitutional Court issued a decision largely decriminalizing abortion; however, illegal abortion persists. Understanding the barriers that cause women to resort to unsafe, illegal abortions could help improve access to legal services. METHODS: In-depth interviews were conducted in 2014 with 17 women aged 18 or older who had had legal abortions in the past year in Bogota, Colombia, to identify barriers to abortion access and elucidate the ways in which these barriers affect women's decision making regarding abortion. Interview transcripts were coded and analyzed using standard techniques to find patterns, parallels and differences; a phenomenological approach guided the thematic analysis. RESULTS: Barriers related to knowledge and information, along with logistic, emotional, financial, cultural and religious barriers culminated in delays in obtaining comprehensive abortion services. Religion influenced social stigma, which manifested most powerfully in the obstructive behavior of health care providers and health insurance companies. Lack of understanding of current laws on abortion and conscientious objection was evident on the part of patients, health care providers and insurers. CONCLUSION: Dissemination of accurate information regarding the availability of clinical and legal abortion is needed. Better training may help physicians, nurses and insurance company personnel understand their roles and legal responsibilities in abortion care and reduce delays in women's access to services. PMID- 29990292 TI - Imidacloprid as reproductive toxicant and endocrine disruptor: investigations in laboratory animals. AB - Imidacloprid, a neonicotinoid insecticide, has been used worldwide due to its selective toxicity for insects. Its residues may enter the food chain, which is why it is important to investigate the potential adverse effects of imidacloprid exposure. This review summarises current knowledge of the reproductive toxicity and disruptive endocrine effects of imidacloprid in laboratory animals. Investigations, conducted mostly on laboratory rats, have shown adverse effects of imidacloprid on the reproductive ability in both parental and offspring generation as well as on the development of the offspring. Like many pesticides, imidacloprid may also act as endocrine disrupting chemical (EDC). It may disrupt the metabolic homeostasis, contribute to obesity, and disrupt steroidogenesis by inhibiting cytochrome P450 (CYP) enzyme activities. All these adverse effects of imidacloprid may pose a serious risk for reproduction and development with long term consequences in adulthood. PMID- 29990294 TI - Redox imbalance caused by pesticides: a review of OPENTOX-related research. AB - Pesticides are a highly diverse group of compounds and the most important chemical stressors in the environment. Mechanisms that could explain pesticide toxicity are constantly being studied and their interactions at the cellular level are often observed in well-controlled in vitro studies. Several pesticide groups have been found to impair the redox balance in the cell, but the mechanisms leading to oxidative stress for certain pesticides are only partly understood. As our scientific project "Organic pollutants in environment - markers and biomarkers of toxicity (OPENTOX)" is dedicated to studying toxic effects of selected insecticides and herbicides, this review is focused on reporting the knowledge regarding oxidative stress-related phenomena at the cellular level. We wanted to single out the most important facts relevant to the evaluation of our own findings from studies conducted on in vitro cell models. PMID- 29990293 TI - Oxidative stress, cholinesterase activity, and DNA damage in the liver, whole blood, and plasma of Wistar rats following a 28-day exposure to glyphosate. AB - In this 28 day-study, we evaluated the effects of herbicide glyphosate administered by gavage to Wistar rats at daily doses equivalent to 0.1 of the acceptable operator exposure level (AOEL), 0.5 of the consumer acceptable daily intake (ADI), 1.75 (corresponding to the chronic population-adjusted dose, cPAD), and 10 mg kg-1 body weight (bw) (corresponding to 100 times the AOEL). At the end of each treatment, the body and liver weights were measured and compared with their baseline values. DNA damage in leukocytes and liver tissue was estimated with the alkaline comet assay. Oxidative stress was evaluated using a battery of endpoints to establish lipid peroxidation via thiobarbituric reactive substances (TBARS) level, level of reactive oxygen species (ROS), glutathione (GSH) level, and the activity of glutathione peroxidase (GSH-Px). Total cholinesterase activity and the activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were also measured. The exposed animals gained less weight than control. Treatment resulted in significantly higher primary DNA damage in the liver cells and leukocytes. Glyphosate exposure significantly lowered TBARS in the liver of the AOEL, ADI, and cPAD groups, and in plasma in the AOEL and cPAD group. AChE was inhibited with all treatments, but the AOEL and ADI groups significantly differed from control. Total ChE and plasma/liver ROS/GSH levels did not significantly differ from control, except for the 35 % decrease in ChE in the AOEL and ADI groups and a significant drop in liver GSH in the cPAD and 100xAOEL groups. AOEL and ADI blood GSH-Px activity dropped significantly, but in the liver it significantly increased in the ADI, cPAD, and 100xAOEL groups vs. control. All these findings show that even exposure to low glyphosate levels can have serious adverse effects and points to a need to change the approach to risk assessment of low-level chronic/sub-chronic glyphosate exposure, where oxidative stress is not necessarily related to the genetic damage and AChE inhibition. PMID- 29990295 TI - A case of synthetic cannabinoid poisoning in Croatia. AB - The number of new psychoactive substances (NPS), synthetic cannabinoids (SCs) in particular, is growing constantly. Because of the insufficiently explored effects on consumer health, they have become a major problem in the emergency departments. They are difficult to identify, and there are no antidotes that could reverse their detrimental effects. We report a case of poisoning of a young man who used SCs. The patient was admitted to the emergency department of the Clinical Hospital Merkur, Zagreb (Croatia) after sniffing and smoking a herbal product bought on the street. He presented with severe cognitive difficulties and visible eye redness. Other symptoms included somnolence, disorientation, loss of coordination, unsteady gait, hyporeflexia, stiffness, cramps and cold limbs, blurred vision, teeth grinding, dry mouth, tinnitus, fear, suicidal thoughts, impaired focus, memory, and speech, sedation, fatigue, depression, thought blocking, and autistic behaviour. His skin was dry, and his mucosa dry and irritated. Herbal products "Rainbow Special" and "Luminated Aroma" used by the patient were qualitatively analysed with gas chromatography / mass spectrometry (GC/MS) after direct extraction with an organic solvent. Solid-phase extraction method was used to analyse serum and urine samples. Despite the negative findings of biological samples, mostly due to the limitations of GC/MS, the clinical picture infallibly pointed to the poisoning with SCs. This was confirmed by the findings of 5-fluoro AMB (methyl 2-(1-(5-fluoropentyl)-1H-indazole-3-carboxamido) 3-methylbutanoate) in the herbal products. PMID- 29990296 TI - New insights into the organophosphate-induced intermediate syndrome. AB - Acute organophosphate (OP) poisoning can be deadlier than any other type of chemical poisoning. So far, only a few cases have been described that include extensive neurological complications. We present an outstanding case of severe oral OP poisoning with intermediate syndrome developed on the fourth day after hospital admission. The clinical picture involved weakness of the proximal upper and lower limb muscles and several muscles supplied by motor cranial nerves, but, what is peculiar, the distal upper and lower limb muscles were also affected (forearms, hands, legs, and feet). To our knowledge, this is a unique presentation, as lower limb muscle weakness was reported only in the context of delayed polyneuropathy. Another remarkable feature was the involvement of six of the twelve cranial nerves, which makes this case of intermediate syndrome the first with such a spread of muscle weakness and provides new insights into the polymorphic clinical manifestations of acute OP poisoning. PMID- 29990297 TI - Clinical and analytical experience of the National Poison Control Centre with synthetic cannabinoids. AB - A rising number of patients are being treated for overdosing with new psychoactive substances (NPS) available at the illegal drug market in Serbia. The aim of this study was to report clinical and analytical experience of the National Poison Control Centre of Serbia (NPCC) with synthetic cannabinoids (SCs) and point to the NPS available at the illegal drug market in our country. From January 2013 to December 2016, 58 patients (aged between 14 and 25) were treated for the effects of synthetic cannabinoids at the NPCC. Tachycardia was established in 53, mydriasis in 31, somnolence, nausea, vomiting, and agitation in 16, dizziness in 10, disorientation in 9, dyspnoea and chest pain in 4, and loss of consciousness, pallor, paraesthesia, muscle twitches, and short-term memory impairment in 2 patients. After receiving symptomatic and supportive treatment in the emergency ward, all patients had fully recovered within 8 h and were discharged shortly afterwards. Another part of the study was focused on the analysis of the products known under their local street names as "Biljni tamjan" (herbal incense), "Beli slez", and "Rainbow Special" and the analysis of urine sampled from the patients with gas chromatography - mass spectrometry and high performance liquid chromatography. The detected synthetic cannabinoids were AB PINACA, JWH-018, JWH-122, JWH-210, 5F-AKB48, and MDMB-CHMICA in herbal products and AB-FUBINACA, AB-CHMINACA, and MDMB-CHMICA in the urine samples. Our findings have shown the great capacity of NPCC to I) monitor NPS abuse in Serbia, II) reliably detect SCs in illicit products and biological samples, and III) clinically manage the adverse effects in their users. Future commitments of the NPCC will include systematic collection of relevant data on SCs and their adverse effects, detection of changes in purity and composition of the controlled NPS based products, and raising the public awareness of NPS to improve the effectiveness of the national Early Warning System. PMID- 29990298 TI - Dihydroxyacetone as a definitive treatment for aluminium phosphide poisoning in rats. AB - Aluminium phosphide (AlP), a very toxic pesticide also known as the rice tablet, releases phosphine gas upon contact with water, moisture, or gastric acid. Its mortality rate in humans is 70-100 % due to cardiogenic shock and refractory hypotension. Dihydroxyacetone (DHA) is a simple ketonic carbohydrate, mainly used for sunless skin tanning. It also plays a beneficial role in the treatment of hypotension and cardiogenic shock by restoring blood volume and cellular respiration. The aim of this study was to investigate the its effect on the haemodynamics and electrocardiogram (ECG) in male rats poisoned with AlP. The animals were divided into the following groups: control (received 1 mL corn oil, orally), AlP (received 15 mg kg-1 AlP solved in corn oil, orally), AlP plus DHA (treated with 50 mg kg-1 of DHA 30 min after receiving AlP), and AlP plus N acetyl cysteine (NAC) (treated with 200 mg kg-1 of NAC 30 min after receiving AlP). The animals were then anaesthetised and ECG, blood pressure, and heart rate were recorded for 120 min. Treatment with AlP alone and in combination with NAC was associated with progressive hypotension, tachycardia, and ECG disturbances in rats, resulting in 100 % mortality 3 h after poisoning. However, DHA achieved 100 % survival in the poisoned rats and prevented AlP-induced ECG and haemodynamic abnormalities. The main mechanism of DHA in the treatment of AlP poisoning is unclear, but the findings suggest the promising therapeutic potential of DHA against AlP poisoning. PMID- 29990299 TI - Levels of polychlorinated biphenyls in human milk samples in European countries. AB - Polychlorinated biphenyls (PCBs) are persistent pollutants, harmful to human health, which enter the human body mainly through food and bind to body fat. For these reasons their use in most countries is prohibited. Human milk has an advantage over other types of human samples in measuring human exposure to PCBs, as it is obtained with non-invasive sampling methods. In Europe, including Croatia, PCB levels have been monitored for many years. This review summarises PCB trends in human milk across Europe. The trend is generally downward, with higher levels prevailing in urban areas near industrial plants. The highest PCB levels were reported in the Czech Republic and Slovakia. PMID- 29990300 TI - Oxidative stress in triazine pesticide toxicity: a review of the main biomarker findings. AB - This review article provides a summary of the studies relying on oxidative stress biomarkers (lipid peroxidation and antioxidant enzymes in particular) to investigate the effects of atrazine and terbuthylazine exposure in experimental animals and humans published since 2010. In general, experimental animals showed that atrazine and terbuthylazine exposure mostly affected their antioxidant defences and, to a lesser extent, lipid peroxidation, but the effects varied by the species, sex, age, herbicide concentration, and duration of exposure. Most of the studies involved aquatic organisms as useful and sensitive bio-indicators of environmental pollution and important part of the food chain. In laboratory mice and rats changes in oxidative stress markers were visible only with exposure to high doses of atrazine. Recently, our group reported that low-dose terbuthylazine could also induce oxidative stress in Wistar rats. It is evident that any experimental assessment of pesticide toxic effects should take into account a combination of several oxidative stress and antioxidant defence biomarkers in various tissues and cell compartments. The identified effects in experimental models should then be complemented and validated by epidemiological studies. This is important if we wish to understand the impact of pesticides on human health and to establish safe limits. PMID- 29990301 TI - Non-target toxicity of novel insecticides. AB - Humans have used insecticides since ancient times. The spectrum and potency of available insecticidal substances has greatly expanded since the industrial revolution, resulting in widespread use and unforeseen levels of synthetic chemicals in the environment. Concerns about the toxic effects of these new chemicals on non-target species became public soon after their appearance, which eventually led to the restrictions of use. At the same time, new, more environmentally-friendly insecticides have been developed, based on naturally occurring chemicals, such as pyrethroids (derivatives of pyrethrin), neonicotinoids (derivatives of nicotine), and insecticides based on the neem tree vegetable oil (Azadirachta indica), predominantly azadirachtin. Although these new substances are more selective toward pest insects, they can still target other organisms. Neonicotinoids, for example, have been implicated in the decline of the bee population worldwide. This review summarises recent literature published on non-target toxicity of neonicotinoids, pyrethroids, and neem-based insecticidal substances, with a special emphasis on neonicotinoid toxicity in honeybees. We also touch upon the effects of pesticide combinations and documented human exposure to these substances. PMID- 29990302 TI - MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells. AB - Down-regulation of the meningioma-associated protein (MAC30) gene has been found in many solid cancers. This study was carried out to determine the roles and the mechanisms of MAC30 in breast cancer. We used our own data and a public database to analyze the MAC30 mRNA and protein levels in breast cancer tissues. In addition, we established MAC30 knockdown breast cancer cells using MAC30 siRNA. The roles of MAC30 were detected by using the Soft agar assay, Annexin-V-FITC/PI double staining and the Transwell assay. Western blotting was used to analyze the potential mechanism(s) of MAC30 in these cells. We found that MAC30 mRNA and protein were higher in the cancer tissues compared to the matched normal tissues. MAC30 expression was associated with tumor size, tumor differentiation and estrogen receptor (ER) status. Overall survival rate of the patients with low MAC30 expression was obviously higher than the ones with high expression. The apoptotic ratio was lower in MDA-MB-231 and MDA-MB-157 cells with MAC30 expression. By Western blot analysis, we found that increased levels of phosphorylated YAP1, MST1 and LATS1 after MAC30 siRNA transfection in these two cells. In summary, we demonstrate that MAC30 knockdown is involved in the activation of the Hippo signaling pathway. PMID- 29990303 TI - Assessment of Architect cSystems Abbott(r) for the colorimetric measurement of lithium in urines and dyalisates. PMID- 29990304 TI - Personalized laboratory medicine: a patient-centered future approach. AB - In contrast to population-based medical decision making, which emphasizes the use of evidence-based treatment strategies for groups of patients, personalized medicine is based on optimizing treatment at the level of the individual patient. The creation of molecular profiles of individual patients was made possible by the advent of "omics" technologies, based on high throughput instrumental techniques in combination with biostatistics tools and artificial intelligence. The goal of personalized laboratory medicine is to use advanced technologies in the process of preventive, curative or palliative patient management. Personalized medicine does not rely on changes in concentration of a single molecular marker to make a therapeutic decision, but rather on changes of a profile of markers characterizing an individual patient's status, taking into account not only the expected response to treatment of the disease but also the expected response of the patient. Such medical approach promises a more effective diagnostics with more effective and safer treatment, as well as faster recovery and restoration of health and improved cost effectiveness. The laboratory medicine profession is aware of its key role in personalized medicine, but to empower the laboratories, at least an enhancement in cooperation between disciplines within laboratory medicine will be necessary. PMID- 29990305 TI - Undetected paraganglioma by functional imaging techniques: case report. PMID- 29990306 TI - Diagnostic stewardship and the 2017 update of the IDSA-SHEA Clinical Practice Guidelines for Clostridium difficile Infection. PMID- 29990307 TI - Pain assessment in native and non-native language: difficulties in reporting the affective dimensions of pain. AB - Background and aims The language in assessing intensity or quality of pain has been studied but the results have been inconsistent. The physicians' language skills might affect the estimation of the severity of pain possibly leading to insufficient use of analgesics. Several interfering cultural factors have complicated studies aimed at exploring the language used to detect the quality of pain. We aimed to compare native and non-native language related qualitative aspects of pain chosen by Swedish speaking patients with diabetes. Methods In the study participated 10 Finnish and 51 Swedish speaking patients with diabetes. The Pain Detect-questionnaire was used for clarifying the patients' pain and the mechanism of their pain (neuropathic or not) and for assessing the intensity and quality of pain. In addition, the patients completed the short-form McGill Pain Questionnaire (sfMPQ) in Finnish (test I). After 30 min the subjects completed the sfMPQ a second time in their native language (test II). The Swedish speakers estimated their second language, Finnish, proficiency on a 5-graded scale. Results There were significantly more discrepancies between sfMPQ test I and test II among the Swedish speaking respondents who reported poor (hardly none) Finnish language proficiency compared with those with good Finnish proficiency. Discrepancies occurred especially between the affective qualities of pain. Conclusions Poor second language proficiency exposes Swedish speakers to pain communication difficulties related to the affective aspects of pain. Consequently, discordant language communication could cause underestimation of the severity of pain and pain undertreatment. Implications To ensure adequate pain treatment measuring the affective dimension of pain in the patient's native language is crucial. PMID- 29990308 TI - Towards nanoscale electrical measurements in liquid by advanced KPFM techniques: a review. AB - Fundamental mechanisms of energy storage, corrosion, sensing, and multiple biological functionalities are directly coupled to electrical processes and ionic dynamics at solid-liquid interfaces. In many cases, these processes are spatially inhomogeneous taking place at grain boundaries, step edges, point defects, ion channels, etc and possess complex time and voltage dependent dynamics. This necessitates time-resolved and real-space probing of these phenomena. In this review, we discuss the applications of force-sensitive voltage modulated scanning probe microscopy (SPM) for probing electrical phenomena at solid-liquid interfaces. We first describe the working principles behind electrostatic and Kelvin probe force microscopies (EFM & KPFM) at the gas-solid interface, review the state of the art in advanced KPFM methods and developments to (i) overcome limitations of classical KPFM, (ii) expand the information accessible from KPFM, and (iii) extend KPFM operation to liquid environments. We briefly discuss the theoretical framework of electrical double layer (EDL) forces and dynamics, the implications and breakdown of classical EDL models for highly charged interfaces or under high ion concentrations, and describe recent modifications of the classical EDL theory relevant for understanding nanoscale electrical measurements at the solid-liquid interface. We further review the latest achievements in mapping surface charge, dielectric constants, and electrodynamic and electrochemical processes in liquids. Finally, we outline the key challenges and opportunities that exist in the field of nanoscale electrical measurements in liquid as well as providing a roadmap for the future development of liquid KPFM. PMID- 29990309 TI - Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers. AB - Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors. PMID- 29990310 TI - Selective disruption of TLR2-MyD88 interaction inhibits inflammation and attenuates Alzheimer's pathology. AB - Induction of TLR2 activation depends on its association with the adapter protein MyD88. We have found that TLR2 and MyD88 levels are elevated in the hippocampus and cortex of patients with Alzheimer's disease (AD) and in a 5XFAD mouse model of AD. Since there is no specific inhibitor of TLR2, to target induced TLR2 from a therapeutic angle, we engineered a peptide corresponding to the TLR2 interacting domain of MyD88 (TIDM) that binds to the BB loop of only TLR2, and not other TLRs. Interestingly, WT TIDM peptide inhibited microglial activation induced by fibrillar Abeta1-42 and lipoteichoic acid, but not 1-methyl-4 phenylpyridinium, dsRNA, bacterial lipopolysaccharide, flagellin, or CpG DNA. After intranasal administration, WT TIDM peptide reached the hippocampus, reduced hippocampal glial activation, lowered Abeta burden, attenuated neuronal apoptosis, and improved memory and learning in 5XFAD mice. However, WT TIDM peptide was not effective in 5XFAD mice lacking TLR2. In addition to its effects in 5XFAD mice, WT TIDM peptide also suppressed the disease process in mice with experimental allergic encephalomyelitis and collagen-induced arthritis. Therefore, selective targeting of the activated status of 1 component of the innate immune system by WT TIDM peptide may be beneficial in AD as well as other disorders in which TLR2/MyD88 signaling plays a role in disease pathogenesis. PMID- 29990312 TI - Effect of Serum Potassium on Residual-specific Mortality: Interaction Evaluation by Physical Activity. PMID- 29990313 TI - Automated Deterioration Detection Using Electronic Medical Record Data in Intensive Care Unit Patients: A Systematic Review. AB - Timely detection of deterioration in status for intensive care unit patients can be problematic due to variation in data availability and the necessity of integrating data from multiple sources. This can lead to opaqueness of clinical trends and failure to rescue. Automated deterioration detection using electronic medical record data can reduce the risk of failure to rescue. This review describes the automated use of electronic medical record data in identifying deterioration in intensive care unit patients. PubMed and Google Scholar were used to retrieve publications between January 1, 2006, and March 31, 2016. Six studies met inclusion criteria: intensive care unit patient focus, description of electronic medical record data use in automated patient deterioration detection, and presence of predictive, sensitivity, and/or specificity values. Detection focused on specific clinical events such as infection; data sources were electronic medical record-populated databases. Detection algorithms incorporated laboratory results, vital signs, medication orders, and respiratory therapy and radiology documentation. Positive and negative predictive values and sensitivity and specificity measures varied across studies. Three systems generated clinician alerts. Automated deterioration detection using electronic medical record data may be an important aid in caring for intensive care unit patients, but its usefulness is limited by variable electronic medical record detection approaches and performance. PMID- 29990311 TI - Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neoplasms. AB - Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors. PMID- 29990314 TI - Clinical Outcomes in Children With Orbital Cellulitis and Radiographic Globe Tenting. AB - PURPOSE: Axial displacement of the globe with tenting centered on the optic nerve globe junction is a predictor of visual loss in adults. The purpose of this study was to determine the visual outcomes of children with orbital cellulitis and globe tenting. METHODS: The records of 46 consecutive children with orbital cellulitis at a single tertiary children's hospital were reviewed retrospectively. Initial and final visual acuities were available for 34 of 46 patients (74%). Globe tenting was defined by an angle of 130 degrees or less at the optic nerve-globe junction as derived from sagittal CT or MRI. Visual acuities of 4 children with globe tenting (mean age, 10.3 +/- 3.3 years) were compared with those of 30 children without globe tenting (mean age, 10.8 +/- 3.5 years). Final logarithm of the minimum angle of resolution visual acuities were analyzed. RESULTS: The mean posterior globe angle was 124.5 degrees +/- 8.0 degrees in patients with globe tenting, compared with 145.6 degrees +/- 7.4 degrees in the affected eye of the patients without globe tenting (p = 0.002). Final visual acuity was logarithm of the minimum angle of resolution = 0 following treatment in patients with globe tenting and logarithm of the minimum angle of resolution = 0.02 in patients without tenting (p = 0.70). DISCUSSION: We propose that the increased elastic compliance of the optic nerve sheath and sclera in children may contribute to better visual outcomes. CONCLUSIONS: Pediatric orbital cellulitis with globe tenting may not lead to devastating vision loss as previously seen in adults. PMID- 29990315 TI - Overexpression of Rho-Associated Coiled-Coil Containing Protein Kinase 2 Is Correlated with Clinical Progression and Poor Prognosis in Breast Cancer. AB - BACKGROUND Rho-associated coiled-coil containing protein kinases 2 (ROCK2) is one of the best characterized targets for the small GTPase Rho. It has been reported that ROCK2 is critical for cancer cell migration and invasion. The objective of this study was to investigate the association of ROCK2 expression with clinicopathological features and overall survival of breast cancer patients. MATERIAL AND METHODS The expression of ROCK2 in breast cancer and paired adjacent normal tissues was detected and compared by immunohistochemical staining of tissue array. ROCK2 mRNA expression and clinicopathological information was extracted from the TCGA breast cancer dataset. The association of ROCK2 expression with the clinicopathological characteristics of patients with breast cancer was evaluated using univariate and multivariate Cox proportional hazards models. Overall survival was analyzed using the Kaplan-Meier method. RESULTS Immunohistochemistry showed that ROCK2 expression was significantly higher in tumor tissues than in paired adjacent normal tissues [immunoreactivity score (IRS): tumor, 5.25+/-2.10, n=40 vs. adjacent normal 3.83+/-1.06, n=40, P<0.01]. The IRS was correlated to breast cancer staging. Similarly, the mRNA level of ROCK2 was correlated to tumor stage. Notably, ROCK2 mRNA expression (hazard ratio [HR] 1.665 and 95% confidence interval [CI] 1.115-2.488, P=0.013) were also associated with overall survival in a multivariate analysis. CONCLUSIONS Upregulation of ROCK2 was associated with the progression of breast cancer. High expression of ROCK2 may predict poor overall survival rates for breast cancer patients. PMID- 29990316 TI - Schiff bases containing a furoxan moiety as potential nitric oxide donors in plant tissues. AB - Stable Schiff bases containing a furoxan moiety are synthesized as single regioisomers by the reaction of 3-methyl-2-oxy-furazan-4-carbaldehydewith various amino compounds at room temperature. The structures of synthesized compounds were fully characterized by multinuclear NMR spectroscopy and X-ray crystallography. The effect of synthesized Schiff bases containing a furoxan moiety on biological generation of reactive oxygen species and nitric oxide in plant tissues was investigated for the first time by fluorescence microscopy and the released NO identified as nitrite with Griess reagent. There is a good correlation between the biological generation of NO determined by fluorescence microscopy and with Griess reagent. Some of the synthesized compounds exhibited both nitric oxide and reactive oxygen species generation abilities and represent potential NO donors in plant tissues. PMID- 29990317 TI - Assessment of acoustic pulse therapy (APT), a non-antibiotic treatment for dairy cows with clinical and subclinical mastitis. AB - Clinical and subclinical mastitis affects 30% of cows and is regarded as the most significant economic burden on the dairy farm reducing milk yield and quality and increasing culling rate. A proprietary Acoustic Pulse Therapy (APT) device was developed specifically for treating dairy cows. The APT device was designed to produce deep penetrating acoustic pulses that are distributed over a large treated area at a therapeutic level. This paper presents findings from a clinical assessment of this technology for the treatment of dairy cows with subclinical and clinical mastitis. In subclinical mastitis, a group of 116 cows from 3 herds were identified with subclinical intramammary infection and enrolled in the study; 78 cows were assigned to the treatment group and 38 cows to the control group. Significant differences (P<0.001) were found where 70.5% of the cows in the treatment group returned to normal milk production, compared with only 18.4% of the control group. Daily milk yields of the treated cows increased significantly (P<0.05) and the percentage of cows with log somatic cell count under 5.6 cells/mL was significantly higher (P<0.001). Milk of the infected quarters appeared normal with lactose greater than 4.8%, but this difference was not significant. Of the treated cows with identified bacteria, 52.6% of the quarters were cured, while in the control group only 25.0% (P<0.001). Specifically, all cows identified with Escherichia coli in the treatment group were cured, with 66.6% cured with no intervention in the control. Spontaneous cure of glands infected with coagulase negative staphylococci (CNS) and Streptococci was low while treatment successfully increased the cure of CNS from 13.3% to 53.8% and that of Streptococci from 18.2% to 36.4%. Of the 4 cows identified with Staphylococcus aureus, 3 were cured. The clinical mastitis study group included 29 infected cows that were submitted either to a gold standard antibiotic treatment subgroup of 16 cows (n = 16) or to an APT treatment subgroup of 13 cows (n = 13). A cure of 18.7% was shown for the antibiotic treatment, of which logSCC returned to <5.6 cell/mL and 56.2% were culled. A cure of 76.9% was shown for the APT treatment with only one cow culled (7.7%). PMID- 29990319 TI - Carotenoids moderate the effectiveness of a Bt gene against the European corn borer, Ostrinia nubilalis. AB - We assessed the effectiveness of a biofortified maize line (4BtxHC) which accumulates high levels of antioxidant carotenoids that also expressed the insecticidal Cry1Ac Bacillus thuringiensis (Bt) gene against the European corn borer Ostrinia nubilalis. This line had been previously engineered to accumulate carotenoids specifically in the seed endosperm, whereas the Bt gene was expressed constitutively. The concentrations of Bt toxin (Cry 1Ac) in the leaves of the 4Bt and 4BtxHC lines were not significantly different at 47+/-6 MUg/g of fresh weight (FW); neither were they in the kernels of both lines (35+/-3 MUg/g FW). The kernels and leaves were toxic to the larvae of O. nubilalis. However, the insecticidal activity was substantially lower (ca. 20%) than that of lines that expressed only Bt in spite that the two lines showed a quantity of toxin not significantly different in kernels or in leaves. Although the reduced effectiveness of Cry1Ac in kernels may not be entirely surprising, the observation of the same phenomenon in vegetative tissues was unexpected. When semi-artificial diets containing kernels from 4Bt supplemented with different levels of beta-carotene were used in insect bioassays, the beta-carotene moderated the effectiveness of the Bt similarly to the plant material with carotenoid enrichment. To elucidate the biochemical basis of the reduced effectiveness of Bt toxin in the carotenoid-enriched plants, we measured the activity of three enzymes known to be implicated in the detoxification defence, namely, catalase, superoxide dismutase and glutathione S-transferase. Whereas Cry1Ac expression significantly increased SOD and CAT enzymatic activity in the absence of carotenoids, carotenoids, either in 4BtxHC or in artificial diets enriched with beta-carotene, significantly lowered CAT activity. Carotenoids can therefore moderate the susceptibility of the maize borer O. nubilalis to Cry1Ac, and we hypothesize that their role as antioxidants could explain this phenomenon via their scavenging of reactive oxygen species produced during Cry1Ac detoxification in the larvae. The involvement of this mechanism in the decreased mortality caused by Cry1Ac when carotenoids are present in the diet is discussed. PMID- 29990318 TI - An amyloidogenic hexapeptide derived from amylin attenuates inflammation and acute lung injury in murine sepsis. AB - Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 MUg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-alpha, IFN gamma) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL 10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury. PMID- 29990320 TI - Creative decision making and visual search behavior in skilled soccer players. AB - The ability to produce creative solutions is a key part of expert performance. The aim of this study was to identify the visual search behaviors that underpin superior creative performance of skilled soccer players during simulated 11-a side match play. Players (N = 44) were required to interact with a representative life-size video-based simulation of attacking situations whilst in possession of the ball. Clips were occluded at a key moment and they were required to play the ball in response to each situation presented. Moreover, they were required to name other additional actions they could execute for each situation. Creative performance on the task was measured using the three criteria of originality, flexibility, and fluency of decisions. Visual search behaviors were examined using a portable eye-movement registration system. Players were classified as most- (n = 11) or least-creative (n = 11) based on their performance on the representative task. The most-creative players produced more appropriate, original, flexible, and fluid decisions compared to least-creative players. The creativity-based differences in judgment were underpinned by differences in visual search strategy. Most-creative players employed a broader attentional focus including more fixations of shorter duration and towards more informative locations of the display compared with least-creative players. Moreover, most creative players detected teammates in threatening positions earlier in the attacking play. Creative performance is underpinned by different underlying visual processes when compared to less-creative performance, which appears to be crucial in facilitating more creative solutions. PMID- 29990321 TI - Influence of factor XIII activity on post-operative transfusion in congenital cardiac surgery-A retrospective analysis. AB - OBJECTIVES: Coagulation factor XIII (FXIII) plays a key role in fibrin clot stabilization-an essential process for wound healing following cardiothoracic surgery. However, FXIII deficiency as a risk for post-operative bleeding in pediatric cardiac surgery involving cardiopulmonary bypass (CPB) for congenital heart disease (CHD) is controversially discussed. Thus, as primary outcome measures, we analyzed the association of pre-operative FXIII activity and post operative chest tube drainage (CTD) loss with transfusion requirements post operatively. Secondary outcomes included the influence of cyanosis and sex on transfusion. METHODS: Our retrospective analysis (2009-2010) encompassed a single center series of 76 cardio-surgical cases with CPB (0-17 years, mean age 5.61 years) that were post-operatively admitted to our pediatric intensive care unit (PICU). The observational period was 48 hours after cardiac surgery. Blood cell counts and coagulation status, including FXIII activity were routinely performed pre- and post-operatively. The administered amount of blood products and volume expanders was recorded electronically, along with the amount of CTD loss. Uni- and multivariate logistic regression analysis was performed to calculate the associations (odds ratios) of variables with post-operative transfusion needs. RESULTS: FXIII activities remained stable following CPB surgery. There was no association of pre- and post-operative FXIII activities and transfusion of blood products or volume expanders in the first 48 hours after surgery. Similarly, FXIII showed no association with CTD loss. Cyanosis and female sex were associated with transfusion rates. CONCLUSIONS: Although essentially involved in wound healing and clotting after surgery, FXIII activity does not serve as a valid predictor of post-operative transfusion need. PMID- 29990322 TI - Intra-cavity stem cell therapy inhibits tumor progression in a novel murine model of medulloblastoma surgical resection. AB - BACKGROUND: Cytotoxic neural stem cells (NSCs) have emerged as a promising treatment for Medulloblastoma (MB), the most common malignant primary pediatric brain tumor. The lack of accurate pre-clinical models incorporating surgical resection and tumor recurrence limits advancement in post-surgical MB treatments. Using cell lines from two of the 5 distinct MB molecular sub-groups, in this study, we developed an image-guided mouse model of MB surgical resection and investigate intra-cavity NSC therapy for post-operative MB. METHODS: Using D283 and Daoy human MB cells engineered to express multi-modality optical reporters, we created the first image-guided resection model of orthotopic MB. Brain-derived NSCs and novel induced NSCs (iNSCs) generated from pediatric skin were engineered to express the pro-drug/enzyme therapy thymidine kinase/ganciclovir, seeded into the post-operative cavity, and used to investigate intra-cavity therapy for post surgical MB. RESULTS: We found that surgery reduced MB volumes by 92%, and the rate of post-operative MB regrowth increased 3-fold compared to pre-resection growth. Real-time imaging showed NSCs rapidly homed to MB, migrating 1.6-fold faster and 2-fold farther in the presence of tumors, and co-localized with MB present in the contra-lateral hemisphere. Seeding of cytotoxic NSCs into the post operative surgical cavity decreased MB volumes 15-fold and extended median survival 133%. As an initial step towards novel autologous therapy in human MB patients, we found skin-derived iNSCs homed to MB cells, while intra-cavity iNSC therapy suppressed post-surgical tumor growth and prolonged survival of MB bearing mice by 123%. CONCLUSIONS: We report a novel image-guided model of MB resection/recurrence and provide new evidence of cytotoxic NSCs/iNSCs delivered into the surgical cavity effectively target residual MB foci. PMID- 29990323 TI - A scheme for 3-dimensional morphological reconstruction and force inference in the early C. elegans embryo. AB - In this study, we present a scheme for the reconstruction of cellular morphology and the inference of mechanical forces in the early C. elegans embryo. We have developed and bench-marked a morphological reconstruction scheme that transforms flourescence-based in vivo images of membranes into a point cloud of smoothed surface patches, which facilitates an accurate estimation of membrane curvatures and the angles between membranes. Assuming an isotropic and homogeneous distribution of tensions along individual membranes, we infer a pattern of forces that are 7% deviated from force balance at edges, and 10% deviated from the Young Laplace relation across membranes. We demonstrate the stability of our inference scheme via a sensitivity analysis, and the reproducibility of our image-analysis and force inference pipelines. PMID- 29990324 TI - Scaling behavior of drug transport and absorption in in silico cerebral capillary networks. AB - Drug delivery to the brain is challenging due to the presence of the blood-brain barrier. Mathematical modeling and simulation are essential tools for the deeper understanding of transport processes in the blood, across the blood-brain barrier and within the tissue. Here we present a mathematical model for drug delivery through capillary networks with increasingly complex topologies with the goal to understand the scaling behavior of model predictions on a coarse-to-fine sequence of grids. We apply our model to the delivery of L-Dopa, the primary drug used in the therapy of Parkinson's Disease. Our model replicates observed blood flow rates and ratios between plasma and tissue concentrations. We propose an optimal network grain size for the simulation of tissue volumes of 1 cm3 that allows to make reliable predictions with reasonable computational costs. PMID- 29990325 TI - Chronic debilitation in stranded loggerhead sea turtles (Caretta caretta) in the southeastern United States: Morphometrics and clinicopathological findings. AB - Chronically debilitated loggerhead sea turtles (Caretta caretta) (DT) are characterized by emaciation, lethargy, and heavy barnacle coverage. Although histopathological findings associated with this condition have been reported, only limited data is available on health variables with clinical application. The objectives of this study were to 1) to compare morphometrics, clinicopathological variables, and immune functions of DTs to a group of apparently healthy loggerhead turtles to better understand the pathophysiology of the condition and 2) to assess health parameters in live debilitated turtles as they recovered during rehabilitation in order to identify potential prognostic indicators. We examined and sampled 43 DTs stranded from North Carolina to Florida for 47 health variables using standardized protocols to further characterize the condition. DTs were grouped into categories of severity of the condition, and those that survived were sampled at four time points through rehabilitation. All groups and time points were compared among DTs and to clinically healthy loggerhead turtles. Compared to healthy turtles, DTs had significantly lower body condition index, packed cell volume (PCV), total white blood cell (WBC) count, lymphocytes, glucose (Glc), total protein, all protein fractions as determined by electrophoresis, calcium (Ca), phosphorus (P), Ca:P ratio, potassium (K), lymphocyte proliferation, and greater heterophil toxicity and left-shifting, uric acid (UA), aspartate aminotransferase, creatine kinase, lysozyme, and respiratory burst. From admission to recovery, hematology and plasma chemistry data improved as expected. The most informative prognostic indicators, as determined by correlations with a novel severity indicator (based on survival times), were plastron concavity, P, albumin, total solids, UA, lymphocyte proliferation, WBC, K, Glc, Ca:P, and PCV. The results of this study document the wide range and extent of morphometric and metabolic derangements in chronically debilitated turtles. Monitoring morphometrics and clinicopathological variables of these animals is essential for diagnosis, treatment, and prognosis during rehabilitation. PMID- 29990326 TI - Prevalence of extraintestinal manifestations in Korean inflammatory bowel disease patients. AB - BACKGROUND: The prevalence of inflammatory bowel disease (IBD) in South Korea is increasing. Although extraintestinal manifestations (EIMs) are an important factor in the clinical outcomes of IBD patients, EIMs have not yet been investigated in Korea. Thus, we conducted a cross-sectional study to assess the prevalence of EIMs in Korean IBD patients. METHODS: The 2014 claims data from the National Health Insurance System (NHIS) of Korea were used. IBD patients were identified by codes for Crohn disease (CD) and ulcerative colitis (UC) in the NHIS registration system for rare or intractable diseases. International Classification of Diseases, Tenth Edition codes were used to identify EIM cases. To estimate the prevalence of EIMs in the general population of Korea, we used national sample data. Standardized prevalence ratios (SPRs) were calculated to compare the prevalence rates of EIMs among IBD patients to those among the general population of Korea. RESULTS: A total of 13,925 CD patients and 29,356 UC patients were identified. CD and UC patients were different in terms of demographics and utilization of medication. Among the 17 EIMs investigated, pyoderma gangrenosum, osteomalacia, Sweet syndrome, and scleritis were observed in very few patients. The SPRs were greater than 1 for all EIMs. Aphthous stomatitis, rheumatoid arthritis, and osteoporosis were highly prevalent in both CD and UC patients, but the SPRs of the EIMs were not high. CONCLUSION: The study confirmed that EIMs are more prevalent among IBD patients than among the general population of Korea. The prevalence of EIMs in IBD patients suggests the need for greater attention and effort in clinical practice. PMID- 29990327 TI - Flavonoid compound icariin enhances BMP-2 induced differentiation and signalling by targeting to connective tissue growth factor (CTGF) in SAMP6 osteoblasts. AB - BACKGROUND: Icariin, a major active flavonoid glucoside, is widely used for the treatment of bone injury and rebuilding in the clinic because of its roles in suppressing osteoblastogenesis and promoting osteogenesis. The senescence accelerated mouse SAMP6 was accepted as a useful murine model to reveal the mechanism of senile osteoporosis and the therapeutic mechanism of drug activity. However, little is known about the characteristics of SAMP6 osteoblasts and the associated regulatory roles of icariin. METHODS: We isolated and cultured osteoblasts from SAMP6 or SAMR1 mice and compared their proliferation, migration, and differentiation by performing the CCK-8 assay, cell counting assay, EdU staining, cell cycle analysis, ALP staining and activity measurement, Alizarin red staining, and RT-qPCR analysis to measure the levels of osteoblast markers, including RUNX2, Colla1 and Oc. To assess the effects of icariin on BMP-2-induced osteoblast differentiation, after BMP-2 treatment, osteoblast markers were analyzed by RT-qPCR and semi-quantitative Western blotting. The effects of icariin on connective tissue growth factor (CTGF) were measured by RT-qPCR. shRNA targeting CTGF mRNA was employed to knockdown its expression level in osteoblasts. RESULTS: The SAMP6 osteoblasts presented decreased the development and differentiation activity compared with SAMR1 osteoblasts, indicating that they are the potential mechanisms underlying age-associated disease. Moreover, SAMP6 osteoblasts presented upregulated CTGF compared with SAMR1 osteoblasts. Icariin enhanced BMP-2-induced osteoblast differentiation by downregulating CTGF expression, which tightly regulates osteoblast differentiation. By downregulating CTGF, icariin treatment upregulated phosphate-Smad1/5/8, indicating its activating effects on the BMP signaling pathway. CONCLUSION: These results suggest that decreased osteoblast development and function potentially contributes to age-associated disease. Icariin exerts enhancing effects on BMP-2 mediated osteoblast development via downregulating CTGF. PMID- 29990328 TI - Glycerol-3-phosphate dehydrogenase (GPDH) gene family in Zea mays L.: Identification, subcellular localization, and transcriptional responses to abiotic stresses. AB - Glycerol-3-phosphate dehydrogenase (GPDH) catalyzes the formation of glycerol-3 phosphate, and plays an essential role in glycerolipid metabolism and in response to various stresses in different species. In this study, six ZmGPDH genes were obtained by a thorough search against maize genome, and designated as ZmGPDH1-6, respectively. The structural and evolutionary analyses showed that the ZmGPDHs family had typical conserved domains and similar protein structures as the known GPDHs from other plant species. ZmGPDHs were divided into NAD+-dependent type A form (ZmGPDH1-5) and FAD-dependent type B form (ZmGPDH6) based on their N terminal sequences. Four full length ZmGPDHs were fused with GFP fusion proteins, and their subcellular localization was determined. ZmGPDH1 and ZmGPDH3 were located to the cytosol and mainly recruited to the surface of endoplasmic reticulum (ER), whereas ZmGPDH4 and ZmGPDH5 were located in the chloroplast. The transcriptional analysis of the ZmGPDHs in different maize tissues revealed relatively high level of transcripts accumulation of ZmGPDHs in roots and early stage developing seeds. Furthermore, we examined the transcriptional responses of the six GPDH genes in maize under various abiotic stresses, including salt, drought, alkali and cold, and significant induction of ZmGPDHs under osmotic stresses was observed. Together, this work will provide useful information for deciphering the roles of GPDHs in plant development and abiotic stress responses. PMID- 29990329 TI - The oligosaccharides 6'-sialyllactose, 2'-fucosyllactose or galactooligosaccharides do not directly modulate human dendritic cell differentiation or maturation. AB - Breast milk plays an important role in immune development in early life and protects against diseases later in life. A wide range of the beneficial effects of breast milk are attributed to human milk oligosaccharides (HMOs) as well as components such as vitamin D3 (VitD3) or TGFbeta. One mechanism by which HMOs might contribute to immune homeostasis and protection against disease is the induction of a local tolerogenic milieu. In this study we investigated the effect of the HMOs 6'-sialyllactose (6'SL) and 2'-fucosyllactose (2'FL) as well as prebiotic galactooligosaccharides (GOS) on DC differentiation and maturation. Isolated CD14+ monocytes were cultured for six days in the presence of GM-CSF and IL-4 with or without 6'SL, 2'FL, GOS, VitD3 or TGFbeta. Additionally, immature VitD3DC, TGFbetaDC and moDC were used as different DC types to investigate the effect of 6'SL, 2'FL and GOS on DC maturation. Surface marker expression and cytokine production was measured by flow cytometry and cytometric bead array, respectively. Unlike TGFbeta and vitD3, the oligosaccharides 6'SL, 2'FL and GOS did not influence DC differentiation. Next, we studied the effect of 6'SL, 2'FL and GOS on maturation of moDC, VitD3DC and TGFbetaDC that showed different profiles of HMO-binding receptors. 6'SL, 2'FL and GOS did not modulate LPS induced maturation, even though their putative receptors were present on the different DCs types. Thus, whereas VitD3 and TGFbeta halt DC differentiation, which results in phenotypically distinct tolerogenic DCs, 6'SL, 2'FL and GOS do not alter DC differentiation or maturation of in vitro differentiated DC types. PMID- 29990330 TI - Sperm traits on in vitro production (IVP) of bovine embryos: Too much of anything is good for nothing. AB - Sperm samples used on fertilization strongly influence the in vitro production (IVP) rates. However, sperm traits behind this effect are not stated consistently until now. This study aimed to evaluate the isolated and combined effect of some sperm traits (MB: total motility before Percoll(r) gradient, MA: total motility after Percoll(r) gradient, AI: acrosome integrity, MI: membrane integrity, MP: mitochondrial membrane potential, and CR: chromatin resistance) on IVP rates. This is the first study focusing on the isolated effect of distinct traits. For this purpose, the experiment was divided in three steps. In first step, to study behavior of traits sperm samples (n = 63 batches) were analyzed and ranked based on each trait. In second step, samples ranked were selected from target ranks regions and allocated in groups of four to five batches, creating Higher and Lower groups, according to two different approaches. One aimed to form groups that differed to all sperm traits simultaneously (effect of combined traits). The other aimed to form groups that differed only to a single sperm trait while no differences were observed for the remaining traits (effect of each isolated trait). In third step, for each group successfully formed in step 2, sperm samples were individually and prospectively used for IVP. Cleavage, embryo development and blastocyst rates were recorded and compared between Higher and Lower of respective trait groups. Surprisingly, evaluation of isolated effects revealed that lower levels of MB, AI and MP resulted in higher embryo development and blastocyst rates (p<0.05), which was not observed on cleavage rate. We conclude that sperm traits strongly influence embryo development after in vitro fertilization (IVF), affecting the zygote competence to achieve blastocyst stage. Individually, levels of MB, AI or MP could be some of the key traits that may define IVP efficiency on current systems of embryo production. PMID- 29990331 TI - The golden hour of sepsis: An in-depth analysis of sepsis-related maternal mortality in middle-income country Suriname. AB - BACKGROUND: Sepsis was the main cause of maternal mortality in Suriname, a middle income country. Objective of this study was to perform a qualitative analysis of the clinical and management aspects of sepsis-related maternal deaths with a focus on the 'golden hour' principle of antibiotic therapy. METHODS: A nationwide reproductive age mortality survey was performed from 2010 to 2014 to identify and audit all maternal deaths in Suriname. All sepsis-related deaths were reviewed by a local expert committee to assess socio-demographic characteristics, clinical aspects and substandard care. RESULTS: Of all 65 maternal deaths in Suriname 29 (45%) were sepsis-related. These women were mostly of low socio-economic class (n = 23, 82%), of Maroon ethnicity (n = 14, 48%) and most deaths occurred postpartum (n = 21, 72%). Underlying causes were pneumonia (n = 14, 48%), wound infections (n = 3, 10%) and endometritis (n = 3, 10%). Bacterial growth was detected in 10 (50%) of the 20 available blood cultures. None of the women with sepsis as underlying cause of death received antibiotic treatment within the first hour, although most women fulfilled the diagnostic criteria of sepsis upon admission. In 27 (93%) of the 29 women from which sufficient information was available, substandard care factors were identified: delay in monitoring in 16 (59%) women, in diagnosis in 17 (63%) and in treatment in 21 (78%). CONCLUSION: In Suriname, a middle-income country, maternal mortality could be reduced by improving early recognition and timely diagnosis of sepsis, vital signs monitoring and immediate antibiotic infusion (within the golden hour). PMID- 29990332 TI - Grain zinc concentrations differ among Brazilian wheat genotypes and respond to zinc and nitrogen supply. AB - The combined application of nitrogen (N) and zinc (Zn) fertilizers is a promising agronomic strategy for the biofortification of wheat grain with Zn for human nutrition. A glasshouse experiment was carried out to assess the effects of supplying N on the uptake, translocation and accumulation of Zn in tissues of two wheat genotypes (Quartzo and BRS Parrudo) with contrasting potential for grain Zn biofortification. Winter wheat genotypes were grown to maturity in 5 cm diameter, 100 cm length tubes filled with a mixture of sand, grit and gravel (40:40:20 v/v/v) over a layer of 0.1 m3 of gravel, and supplied a full nutrient solution with low Zn (0.15 MUM) or high Zn (2.25 MUM) and low N (0.4 mM) or high N (4.0 mM) concentrations. High N supply increased biomass production, Zn concentration and Zn content of straw and grain in both Quartzo and BRS Parrudo. Grain Zn content more than doubled when the supplies of Zn and N were both increased from low to high in both genotypes. Quartzo had a greater grain yield than BRS Parrudo. BRS Parrudo had greater grain Zn concentration and Zn content than Quartzo. A greater N supply promoted better uptake, translocation to the shoot and accumulation of Zn within the grain. Quartzo and BRS Parrudo differed in their partitioning of biomass and Zn between tissues. It might be possible to combine the greater grain yield of Quartzo with the greater grain Zn accumulation of BRS Parrudo to deliver a greatly improved genotype for human food security. PMID- 29990333 TI - CT predicts liver fibrosis: Prospective evaluation of morphology- and attenuation based quantitative scores in routine portal venous abdominal scans. AB - OBJECTIVES: Our aim was to prospectively determine whether quantitative computed tomography (CT) scores, consisting of simplified indices for liver remodeling and attenuation, may predict liver fibrosis in abdominal CT scans. MATERIALS AND METHODS: This cross-sectional, prospective study was approved by the local IRB (Kantonale Ethikkommission Bern). Written informed consent was given from all patients undergoing study-MR exams. Between 02/16 and 05/17, four different liver fibrosis scores (CRL-R = caudate-right-lobe ratio, LIMV-, LIMA- and LIMVA fibrosis score, with "LIM" for liver imaging morphology, "V" for liver vein diameter and "A" for attenuation) were calculated in 1534 consecutive abdominal CT scans, excluding patients with prior liver surgery and liver metastasis. Patients were invited to undergo magnetic resonance (MR) elastography as the non invasive gold standard to evaluate liver fibrosis. MR elastography shear modulus >=2.8 kPa was defined as beginning liver fibrosis, while >=3.5 kPa was defined as significant liver fibrosis (which would correspond to fibrosis stage F2 or higher in histology). Cutoff values, sensitivities and specificities obtained from the receiver operating characteristics (ROC) analysis were then calculated in 141 patients who followed the invitation for MR elastography. To mitigate selection bias, prevalence was estimated in the screened total population (n = 1534) by applying the cutoff values with sensitivities and specificities calculated in the MR elastography sub-group. Positive predictive values (PPV) and negative predictive values (NPV) were then calculated. RESULTS: Fibrosis scores including liver vein attenuation LIMA-FS and LIMVA-FS showed higher areas under the ROC curves (0.96-0.97) than CRL-R (0.82) to detect significant liver fibrosis, while LIMV-FS showed good performance as well (0.92). The prevalence-corrected PPV were 29% for CRL-R, 70% for LIMV-FS, 76% for LIMA-FS and 82% for LIMVA-FS. CONCLUSION: CT fibrosis scores, notably LIMA-FS and LIMVA-FS, may predict significant liver fibrosis on routine abdominal CT scans. PMID- 29990334 TI - SeRUN(r) study: Development of running profiles using a mixed methods analysis. AB - OBJECTIVE: To determine profiles of urban runners based on socio-demographic, health, motivational, training characteristics and running-related beliefs and behaviours. METHODS: Mixed, exploratory, sequential study with two stages: 1) quantitative, using an online survey; and 2) qualitative, using semi-structured interviews with runners from the previous stage. Participants were recruited via: running routes commonly attended by runners, eight races, previous databases and social media networks. The survey collected information on six dimensions: (1) socio-demographic; (2) health; (3) motivations; (4) training characteristics; (5) running-related behaviour; and (6) beliefs and perceptions about health. Profiles were identified using a two-step hierarchical clustering analysis. Subsequently, 15 interviews were conducted with participating runners across each of the identified profiles. Qualitative analysis complemented the profiles characterization, explaining motivations to start and continue running, beliefs about risk factors and injury prevention, and the physical therapist's role in rehabilitation. Statistical analysis from stage one was conducted using SPSS 22 with a confidence level of 5%. Qualitative data were analysed using thematic and content analyses. RESULTS: A total of 821 surveys were analysed (46% female), mean aged 36.6+/-10.0 years. Cluster analysis delineated four profiles (n = 752) according to years of running experience, weekly running volume and hours of weekly training. Profiles were named "Beginner" (n = 163); "Basic" (n = 164); "Middle" (n = 160) and "Advanced" (n = 265). Profiles were statistically different according to sex, age, years of running experience, training characteristics, previous injuries and use of technological devices (p<0.05). There were identified motivations to start and continue running. Beliefs about risk factors vary among stretching, footwear, training surface and overload. Runners identified the physical therapist as a specialist, involved in the rehabilitation process and showing empathy towards the patient. The identification of these profiles allows the generation of future prospective studies and clinical trials to evaluate risk and prognostic factors targeting specific populations of runners, with the ultimate aim of reducing running related injury. PMID- 29990335 TI - Predictors of participation in risk-based prostate cancer screening. AB - BACKGROUND: Implementation of risk-based prostate cancer screening has been proposed as a means to reduce the harms of PSA screening. Little is known, however, about the factors influencing men's decision to attend a prostate cancer screening based on a risk assessment. METHOD: We sent postal invitations with a login to a survey to 10.000 men, three months before invitation to a risk-based prostate cancer screening. Prostate cancer specific worry, prostate cancer related knowledge, health behaviour, and health related quality of life were used as predictors of subsequent participation. Participation to risk-based prostate cancer screening was defined as providing a blood sample for the STHLM3 trial, a study evaluating a risk-based model that predicts the risk for aggressive prostate cancer. RESULTS: With a response rate of 20%, 1.347 men (70%) participated in ensuing risk-based prostate cancer screening three months later whereas 568 men (30%) declined participation in the STHLM3-study. These decliners reported less worry and feeling less vulnerable to prostate cancer and responded "Do not know" more often than participants when asked questions about prostate cancer knowledge. Participants reported greater benefits of prostate testing (p = 0.0005), less barriers to prostate testing (p<0.0001), and higher intention to attend prostate cancer testing (p<0.0001) than decliners. Finally, participants reported better overall health than decliners (p<0.0001). CONCLUSION: Prostate cancer worry, PC knowledge, health behaviour and quality of life were identified as predictors of participation in risk-based prostate cancer screening. Targeting these predictors may improve the participation rates. These results can inform policymaking for future population-based prostate cancer screening programs that should address potential worry in men and lack of knowledge about prostate cancer. PMID- 29990336 TI - Clinic-based evaluation study of the diagnostic accuracy of a dual rapid test for the screening of HIV and syphilis in pregnant women in Nigeria. AB - BACKGROUND: Screening pregnant women for HIV and syphilis is recommended by WHO in order to reduce mother-to-child transmission. We evaluated the field performance, feasibility, and acceptability of a dual rapid diagnostic test (RDT) for HIV and syphilis test in antenatal clinic settings in Nigeria. METHODS AND FINDINGS: Participants were recruited at 12 antenatal clinic sites in three states of Nigeria. All consenting individuals were tested according to the national HIV testing algorithm, as well as a dual RDT, the SD BIOLINE HIV/Syphilis Duo Test (Alere, USA), in the clinic. To determine sensitivity, specificity and concordance, whole blood samples were obtained for repeat RDT performance in the laboratory, as well as reference tests for HIV and syphilis. Dual test acceptability and operational characteristics were assessed among participants and clinic staff. The prevalence of HIV among the 4,551 enrollees was 3.0% (138/4551) using the national clinic-based HIV testing algorithm. Positive and negative percent agreement of the HIV component of the dual RDT were 100.0% (95% CI 99.7-100.0) and 99.9% (95% CI 99.7-100.0) respectively, when compared with the national rapid testing algorithm. The prevalence of syphilis, using TPHA as the reference test, was low at 0.09% (4/4550). The sensitivity of the syphilis component of the dual RDT could not be calculated as no positive results were observed for patients that were positive for syphilis by TPHA. Each of the only four TPHA-positive specimens had RPR titers of 1:1 (neat), indicative of non-active syphilis. The specificity of the syphilis component of the dual RDT was 99.9% (95% CI 99.8-100.0). The dual RDT received favorable feasibility ratings among antenatal care clinic staff. Acceptability among study participants was high with most women reporting preference for rapid dual HIV/syphilis testing. CONCLUSIONS: The SD BIOLINE HIV/Syphilis Duo Test showed a high overall diagnostic accuracy for HIV and a high specificity for syphilis diagnosis in antenatal clinic settings. This study adds to a growing body of evidence that supports the clinic-based use of dual tests for HIV and syphilis among pregnant women. PMID- 29990337 TI - Global meta-analysis reveals agro-grassland productivity varies based on species diversity over time. AB - Ecological research suggests increased diversity may improve ecosystem services, as well as yield stability; however, such theories are sometimes disproven by agronomic research, particularly at higher diversity levels. We conducted a meta analysis on 2,753 studies in 48 articles published over the last 53 years to test: if biological N2 fixation (BNF) supplies adequate nitrogen (N) for plant growth relative to synthetic fertilizers; how crop physiological traits affect legume-grass symbiosis; and, how cultural practices affect BNF over a range of soils and climates overtime (in polycultures versus sole grasslands). Globally, net primary productivity (NPP; total aboveground production response of grass and legume in higher-diversity treatments) increased 44% via legume associations relative to sole grass controls (including both with and without N fertilizer). Several moderating variables affected NPP including: (i) plant photosynthetic pathway (mixtures of C3 grasses resulted in a 57% increase in NPP, whereas mixtures of C4 grasses resulted in a 31% increase; similarly cool-season legumes increased NPP 52% compared to a 27% increase for warm-season legumes relative to grasslands without diversity); (ii) legume life cycle [NPP response for perennial legume mixtures was 50% greater than sole grass controls, followed by a 28% increase for biennial, and a 0% increase for annual legumes)]; and, (iii) species richness (one leguminous species in a grassland agroecosystem resulted in 52% increase in NPP, whereas >2 legumes resulted in only 6% increases). Temporal and spatial effect sizes also influenced facilitation, considering facilitation was greatest (114% change) in Mediterranean climates followed by oceanic (84%), and tropical savanna (65%) environments; conversely, semiarid and subarctic systems had lowest Rhizobium-induced changes (5 and 0% change, respectively). Facilitation of grass production by legumes was also affected by soil texture. For example, a 122% NPP increase was observed in silt clay soils compared to 14% for silt loam soils. Niche complementarity effects were greatest prior to 1971 (61% change), compared to recent studies (2011-2016; -7% change), likely owing to reduced global sulfur deposition and increased ambient temperatures overtime. These historical trends suggest potential for legume intercrops to displace inorganic-N fertilizer and sustainably intensify global NPP. Results herein provide a framework for ecologists and agronomists to improve crop diversification systems, refine research goals, and heighten BNF capacities in agro-grasslands. PMID- 29990338 TI - How (not) to increase older adults' tendency to anthropomorphise in serious games. AB - Among elderly, the use of serious games steadily increases. Research shows that anthropomorphising digital agents (i.e., ascribing human characteristics to them) has positive short-term consequences on interactions with digital agents. However, whether these effects can also be observed over a long-term period and in a real-life setting is unknown. In two studies, we investigated the important long-term consequences of anthropomorphism among older adults (age > 50) to increase involvement in serious games. Participants read either a story that highly anthropomorphized the digital agent of a training game, or a low anthropomorphism story about that agent. To investigate long-term effect, they played the training game for three weeks, and gaming data was assessed (number of games played, time of playing, points gained). While on the short-term, the anthropomorphic story increased the humanness of the agent (Study 1), no long term effects where found (Study 2). Furthermore, an anthropomorphic story had no influence on the gaming outcome. Our results inform app developers about which techniques are useful to humanise digital agents. PMID- 29990339 TI - Phase-lags in large scale brain synchronization: Methodological considerations and in-silico analysis. AB - : Architecture of phase relationships among neural oscillations is central for their functional significance but has remained theoretically poorly understood. We use phenomenological model of delay-coupled oscillators with increasing degree of topological complexity to identify underlying principles by which the spatio temporal structure of the brain governs the phase lags between oscillatory activity at distant regions. Phase relations and their regions of stability are derived and numerically confirmed for two oscillators and for networks with randomly distributed or clustered bimodal delays, as a first approximation for the brain structural connectivity. Besides in-phase, clustered delays can induce anti-phase synchronization for certain frequencies, while the sign of the lags is determined by the natural frequencies and by the inhomogeneous network interactions. For in-phase synchronization faster oscillators always phase lead, while stronger connected nodes lag behind the weaker during frequency depression, which consistently arises for in-silico results. If nodes are in anti-phase regime, then a distance pi is added to the in-phase trends. The statistics of the phases is calculated from the phase locking values (PLV), as in many empirical studies, and we scrutinize the method's impact. The choice of surrogates do not affects the mean of the observed phase lags, but higher significance levels that are generated by some surrogates, cause decreased variance and might fail to detect the generally weaker coherence of the interhemispheric links. These links are also affected by the non-stationary and intermittent synchronization, which causes multimodal phase lags that can be misleading if averaged. Taken together, the results describe quantitatively the impact of the spatio-temporal connectivity of the brain to the synchronization patterns between brain regions, and to uncover mechanisms through which the spatio-temporal structure of the brain renders phases to be distributed around 0 and pi. TRIAL REGISTRATION: South African Clinical Trials Register: http://www.sanctr.gov.za/SAClinicalbrnbspTrials/tabid/169/Default.aspx, then link to respiratory tract then link to tuberculosis, pulmonary; and TASK Applied Sciences Clinical Trials, AP-TB-201-16 (ALOPEXX): https://task.org.za/clinical trials/. PMID- 29990340 TI - Visualization and quantification of the cellular and extracellular components of Salmonella Agona biofilms at different stages of development. AB - Salmonella is a major food-borne pathogen able to persist in food processing environments because of its ability to form biofilms. A Salmonella enterica serotype Agona isolate from poultry (S24) was grown at 37 degrees C in biofilms for up to 144 hours (H144) in attachment to polystyrene surfaces. Biofilm structures were examined at different stages in their development (H3, H24, H48, H72, H96 and H144) using confocal laser scanning microscopy (CLSM) in conjunction with fluorescent dyes for live cells (SYTO 9), dead cells (propidium iodide), proteins (fluorescein isothiocyanate isomer I), lipids (DiD'oil), alpha polysaccharides (concanavalin A, tetramethylrhodamine conjugate), and beta polysaccharides (calcofluor white M2R). Strain S24 developed a robust biofilm at H72 (biovolume of 166,852.5 +/- 13,681.8 MUm3 in the observation field of 16,078.2 MUm2). The largest biovolume of live cells was also detected at H72 (128,110.3 +/- 4,969.1 MUm3), decreasing thereafter, which was probably owing to the detachment of cells prior to a new phase of colonization. The percentage of dead cells with regard to total cells in the biofilms increased throughout the incubation, ranging from 2.3 +/- 1.1% (H24) to 44.2 +/- 11.0% (H144). Proteins showed the greatest biovolume among the extracellular components within the biofilms, with values ranging from 1,295.1 +/- 1,294.9 MUm3 (H3) to 19,186.2 +/- 8,536.0 MUm3 (H96). Maximum biovolume values of 15,171.9 +/- 660.7 MUm3 (H48), 7,055.3 +/- 4,415.2 MUm3 (H144), and 2,548.6 +/- 1,597.5 MUm3 (H72) were observed for beta-polysaccharides, alpha-polysaccharides and lipids, respectively. A strong (P < 0.01) positive correlation was found between the total biovolume of biofilm and the biovolume of live cells, proteins and beta-polysaccharides, which may serve as useful markers of biofilm formation. The present work provides new insights into the formation of S. Agona biofilms. Our findings may contribute to the designing of reliable strategies for preventing and removing these bacterial communities. PMID- 29990341 TI - Detection of 4-formylaminooxyvinylglycine in culture filtrates of Pseudomonas fluorescens WH6 and Pantoea ananatis BRT175 by laser ablation electrospray ionization-mass spectrometry. AB - The oxyvinylglycine 4-formylaminooxyvinylglycine (FVG) arrests the germination of weedy grasses and inhibits the growth of the bacterial plant pathogen Erwinia amylovora. Both biological and analytical methods have previously been used to detect the presence of FVG in crude and extracted culture filtrates of several Pseudomonas fluorescens strains. Although a combination of these techniques is adequate to detect FVG, none is amenable to high-throughput analysis. Likewise, filtrates often contain complex metabolite mixtures that prevent the detection of FVG using established chromatographic techniques. Here, we report the development of a new method that directly detects FVG in crude filtrates using laser ablation electrospray ionization-mass spectrometry (LAESI-MS). This approach overcomes limitations with our existing methodology and allows for the rapid analysis of complex crude culture filtrates. To validate the utility of the LAESI-MS method, we examined crude filtrates from Pantoea ananatis BRT175 and found that this strain also produces FVG. These findings are consistent with the antimicrobial activity of P. ananatis BRT175 and indicate that the spectrum of bacteria that produce FVG stretches beyond rhizosphere-associated Pseudomonas fluorescens. PMID- 29990342 TI - The Predictive Value of SPECT/CT imaging in colorectal liver metastases response after 90Y-radioembolization. AB - CONCLUSION: The mT/N1 ratio, PAD, and AAD can be used as predictors of tumor response to SIRT treatment, and SPECT/CT imaging can be used for dosimetric assessment of radioembolization. PMID- 29990343 TI - Climate change and women's health: Impacts and policy directions. AB - In a Policy Forum, Cecilia Sorensen and colleagues discuss the implications of climate change for women's health. PMID- 29990344 TI - Scaling properties of food flow networks. AB - Food flows underpin the complex food supply chains that are prevalent in our increasingly globalized world. Recently, much effort has been devoted to evaluating the resources (e.g. water, carbon, nutrients) embodied in food trade. Now, research is needed to understand the scientific principles of the food commodity flows that underpin these virtual resource transfers. How do food flows vary with spatial scale? To address this question, we present an empirical analysis of food commodity flow networks across the full spectrum of spatial scales: global, national, and village. We discover properties of both scale invariance and scale dependence in food flow networks. The statistical distribution of node connectivity and mass flux are consistent across scales. Node connectivity follows a generalized exponential distribution, while node mass flux follows a Gamma distribution across scales. Similarly, the relationship between node connectivity and mass flux follows a power law across scales. However, the parameters of the distributions change with spatial scale. Mean node connectivity and mass flux increase with increasing scale. A core group of nodes exists at all scales, but node centrality increases as the spatial scale decreases, indicating that some households are more critical to village food exchanges than countries are to global trade. Remarkably, the structural network properties of food flows are consistent across spatial scales, indicating that a universal mechanism may underpin food exchange systems. In future research, this understanding can be used to develop theoretical models of food flow networks and to model food flows at resolutions for which empirical information is not available. PMID- 29990346 TI - Simulating optical coherence tomography for observing nerve activity: A finite difference time domain bi-dimensional model. AB - We present a finite difference time domain (FDTD) model for computation of A line scans in time domain optical coherence tomography (OCT). The OCT output signal is created using two different simulations for the reference and sample arms, with a successive computation of the interference signal with external software. In this paper we present the model applied to two different samples: a glass rod filled with water-sucrose solution at different concentrations and a peripheral nerve. This work aims to understand to what extent time domain OCT can be used for non invasive, direct optical monitoring of peripheral nerve activity. PMID- 29990345 TI - What speech and language therapy do community dwelling stroke survivors with aphasia receive in the UK? AB - BACKGROUND: Speech and language therapy provision for aphasia (a language disorder) post stroke has been studied over time through surveys completed by speech and language therapists. This paper revisits provision based on what was received by 278 patients in 21 UK speech and language therapy departments in 2014 2016. AIMS: To explore the speech and language therapy received by community dwelling people with post stroke aphasia in the UK. METHODS AND PROCEDURES: A quantitative content analysis was conducted by two speech and language therapist researchers. Therapy goals recorded were coded into categories and subcategories. Descriptive statistics were used to identify the frequency with which goal categories were targeted, average therapy time received, length and frequency of therapy sessions, personnel involved and mode of delivery. OUTCOMES AND RESULTS: Forty-five percent of participants were in receipt of therapy in the three month window observed. Six goal categories were identified. Rehabilitation was the most frequent (60%) followed by enabling (17.2%), review (4.3%), assessment (3.6%), supportive (3.5%) and activity to support therapy (2.8%). The median amount of therapy received in three months was 6.3 hours at an average of one 60-minute session every two weeks. Seventy-seven percent of therapy sessions were delivered by qualified speech and language therapists and 23% by assistants. Ninety percent of sessions were one to one, face to face sessions whilst 9.5% were group sessions. DISCUSSION: In line with previous reports, speech and language therapy for community dwelling stroke survivors with aphasia is restricted. Rehabilitation is a large focus of therapy but the intensity and dose with which it is provided is substantially lower than that required for an effective outcome. Despite this, one to one face to face therapy is favoured. More efficient methods to support more therapeutic doses of therapy are not commonly used in routine clinical services. PMID- 29990347 TI - Correction: Influenza A Virus NS1 Protein Inhibits the NLRP3 Inflammasome. AB - [This corrects the article DOI: 10.1371/journal.pone.0126456.]. PMID- 29990348 TI - Adaptation of the Autism Spectrum Screening Questionnaire (ASSQ) to preschool children. AB - The Autism Spectrum Screening Questionnaire (ASSQ) is equipped with good properties for screening the broader phenotype of autistic traits, but it is standardized for a limited age range-from 7 to 16 years. To contribute to the early detection of Autism Spectrum Disorder (ASD), particularly in high functioning children with ASD, likely to cause maladjustments during school age, the present study examined psychometric properties to apply the ASSQ to a younger age. We tested parents' ASSQ ratings for preschool children in clinical (N = 154, average age 60.77 months, range 55-72 months) and community settings (N = 1390, average age 60.53 months, range 57-68 months) in Japan. The results showed, just as in school-aged children, the ASSQ had reliability and validity as a screening instrument for preschool children in community settings. A cut-off of 7 with sensitivity of 0.93 and specificity of 0.84 is recommended for community screening. Still, based on the current study with a clinical group, an optimal cut-off score with high sensitivity and high specificity for parents' ASSQ ratings could not be established. The clinicians should be reminded that the ASSQ is a screening instrument, not a diagnosing instrument. Also, this result suggest multi-faceted evaluation is necessary in clinical settings, for example, the addition of teachers' ratings. PMID- 29990349 TI - Self-regulation of emotional responses to Zika: Spiral of fear. AB - Fear of infectious disease can create a variety of problems not the least of which is fear itself. An important question is how individuals attempt to manage their fear. The appearance of Zika in the U.S. presented an opportunity to examine this issue in a consequential natural context. Beginning nine days after the W.H.O. declared Zika a world health crisis, two-waves of survey data were collected from women ages 18-35 who were living in the Southern U.S. (N = 561). Most respondents (71%) used one or more emotion regulation strategies and a plurality (41%) utilized multiple strategies. Fear of Zika showed no demonstrable effect on avoidance, reappraisal, or contesting and none of these three strategies were effective at down-regulating fear. Fear and suppression, however, showed a self-reinforcing cycle in which fear increased use of suppression and suppression increased intensity of the fear response. Although the observed associations were small, even modest effects can be consequential when cumulated over time or across large numbers of individuals. PMID- 29990350 TI - Relationship between weight and linear dimensions of Bluefin tuna (Thunnus thynnus) following fattening on western Mediterranean farms. AB - This study presents various models based on formulae relating weight and dimensions (length, height and width) of Bluefin tuna, Thunnus thynnus (L.), fattened in captivity. The main aim of establishing these expressions is to design tools for indirectly predicting the weight of a Bluefin tuna from measurements of one or more dimensions obtained using non-invasive methods such as stereoscopic cameras. Measurements of maximum length, height and width following slaughter were taken of fish fattened in captivity (n = 2078). Different relationships drawn from the dimensions of the tuna against their weight are fitted with part of the data collection and later checked against a reserved sample set. The resulting formulae are compared with the formulae most commonly used in the case of wild tuna. The results of this study confirm that, for tuna fattened in cages, the availability of more than one dimension to estimate weight improves the predictive power of the model and reduces error in the estimate. PMID- 29990351 TI - Bayesian validation of grammar productions for the language of thought. AB - Probabilistic proposals of Language of Thoughts (LoTs) can explain learning across different domains as statistical inference over a compositionally structured hypothesis space. While frameworks may differ on how a LoT may be implemented computationally, they all share the property that they are built from a set of atomic symbols and rules by which these symbols can be combined. In this work we propose an extra validation step for the set of atomic productions defined by the experimenter. It starts by expanding the defined LoT grammar for the cognitive domain with a broader set of arbitrary productions and then uses Bayesian inference to prune the productions from the experimental data. The result allows the researcher to validate that the resulting grammar still matches the intuitive grammar chosen for the domain. We then test this method in the language of geometry, a specific LoT model for geometrical sequence learning. Finally, despite the fact of the geometrical LoT not being a universal (i.e. Turing-complete) language, we show an empirical relation between a sequence's probability and its complexity consistent with the theoretical relationship for universal languages described by Levin's Coding Theorem. PMID- 29990352 TI - Study of specific nanoenvironments containing alpha-helices in all-alpha and (alpha+beta)+(alpha/beta) proteins. AB - Protein secondary structure elements (PSSEs) such as alpha-helices, beta-strands, and turns are the primary building blocks of the tertiary protein structure. Our primary interest here is to reveal the characteristics of the nanoenvironment formed by both PSSEs and their surrounding amino acid residues (AARs), which might contribute to the general understanding of how proteins fold. The characteristics of such nanoenvironments must be specific to each secondary structure element, and we have set our goal here to gather the fullest possible description of the alpha-helical nanoenvironment. In general, this postulate (the existence of specific nanoenvironments for specific protein substructures/neighbourhoods/regions with distinct functionality) was already successfully explored and confirmed for some protein regions, such as protein protein interfaces and enzyme catalytic sites. Consequently, PSSEs were the obvious next choice for additional work for further evidence showing that specific nanoenvironments (having characteristics fully describable by means of structural and physical chemical descriptors) do exist for the corresponding and determined intraprotein regions. The nanoenvironment of alpha-helices (nEoalphaH) is defined as any region of the protein where this secondary structure element type is detected. The nEoalphaH, therefore, includes not only the alpha-helix amino acid residues but also the residues immediately around the alpha-helix. The hypothesis that motivated this work is that it might in fact be possible to detect a postulated "signal" or "signature" that distinguishes the specific location of alpha-helices. This "signal" must be discernible by tracking differences in the values of physical, chemical, physicochemical, structural and geometric descriptors immediately before (or after) the PSSE from those in the region along the alpha-helices. The search for this specific nanoenvironment "signal" was made possible by aligning previously selected alpha-helices of equal length. Afterward, we calculated the average value, standard deviation and mean square error at each aligned residue position for each selected descriptor. We applied Student's t-test, the Kolmogorov-Smirnov test and MANOVA statistical tests to the dataset constructed as described above, and the results confirmed that the hypothesized "signal"/"signature" is both existing/identifiable and capable of distinguishing the presence of an alpha-helix inside the specific nanoenvironment, contextualized as a specific region within the whole protein. However, such conclusion might rarely be reached if only one descriptor is considered at a time. A more accurate signal with broader coverage is achieved only if one applies multivariate analysis, which means that several descriptors (usually approximately 10 descriptors) should be considered at the same time. To a limited extent (up to a maximum of 15% of cases), such conclusion is also possible with only a single descriptor, and the conclusion is also possible in general for up to 50-80% of cases when no less than 5 nonlinear descriptors are selected and considered. Using all the descriptors considered in this work, provided all assumptions about data characteristics for this analysis are met, multivariate analysis regularly reached a coverage and accuracy above 90%. Understanding how secondary structure elements are formed and maintained within a protein structure could enable a more detailed understanding of how proteins reach their final 3D structure and consequently, their function. Likewise, this knowledge may also improve the tools used to determine how good a structure is by means of comparing the "signal" around a selected PSSE with the one obtained from the best (resolution and quality wise) protein structures available. PMID- 29990353 TI - Carbon trading, co-pollutants, and environmental equity: Evidence from California's cap-and-trade program (2011-2015). AB - BACKGROUND: Policies to mitigate climate change by reducing greenhouse gas (GHG) emissions can yield public health benefits by also reducing emissions of hazardous co-pollutants, such as air toxics and particulate matter. Socioeconomically disadvantaged communities are typically disproportionately exposed to air pollutants, and therefore climate policy could also potentially reduce these environmental inequities. We sought to explore potential social disparities in GHG and co-pollutant emissions under an existing carbon trading program-the dominant approach to GHG regulation in the US and globally. METHODS AND FINDINGS: We examined the relationship between multiple measures of neighborhood disadvantage and the location of GHG and co-pollutant emissions from facilities regulated under California's cap-and-trade program-the world's fourth largest operational carbon trading program. We examined temporal patterns in annual average emissions of GHGs, particulate matter (PM2.5), nitrogen oxides, sulfur oxides, volatile organic compounds, and air toxics before (January 1, 2011 December 31, 2012) and after (January 1, 2013-December 31, 2015) the initiation of carbon trading. We found that facilities regulated under California's cap-and trade program are disproportionately located in economically disadvantaged neighborhoods with higher proportions of residents of color, and that the quantities of co-pollutant emissions from these facilities were correlated with GHG emissions through time. Moreover, the majority (52%) of regulated facilities reported higher annual average local (in-state) GHG emissions since the initiation of trading. Neighborhoods that experienced increases in annual average GHG and co-pollutant emissions from regulated facilities nearby after trading began had higher proportions of people of color and poor, less educated, and linguistically isolated residents, compared to neighborhoods that experienced decreases in GHGs. These study results reflect preliminary emissions and social equity patterns of the first 3 years of California's cap-and-trade program for which data are available. Due to data limitations, this analysis did not assess the emissions and equity implications of GHG reductions from transportation related emission sources. Future emission patterns may shift, due to changes in industrial production decisions and policy initiatives that further incentivize local GHG and co-pollutant reductions in disadvantaged communities. CONCLUSIONS: To our knowledge, this is the first study to examine social disparities in GHG and co-pollutant emissions under an existing carbon trading program. Our results indicate that, thus far, California's cap-and-trade program has not yielded improvements in environmental equity with respect to health-damaging co-pollutant emissions. This could change, however, as the cap on GHG emissions is gradually lowered in the future. The incorporation of additional policy and regulatory elements that incentivize more local emission reductions in disadvantaged communities could enhance the local air quality and environmental equity benefits of California's climate change mitigation efforts. PMID- 29990354 TI - Progesterone-associated arginine decline at luteal phase of menstrual cycle and associations with related amino acids and nuclear factor kB activation. AB - BACKGROUND/OBJECTIVES: Given their role in female reproduction, the effects of progesterone on arginine and related amino acids, polyamines and NF-kappaB p65 activation were studied across the menstrual cycle. METHODS: Arginine, ornithine and citrulline as well as putrescine, spermidine, spermine, and N-acetyl putrescine were determined in plasma, NF-kappaB p65 activation in peripheral blood mononuclear cells and progesterone in serum of 28 women at early (T1) and late follicular (T2) and mid (T3) and late (T4) luteal phase. RESULTS: Arginine and related amino acids declined from T1 and T2 to T3 and T4, while progesterone increased. At T3, arginine, ornithine, and citrulline were inversely related with progesterone. Changes (DeltaT3-T2) in arginine, ornithine, and citrulline were inversely related with changes (DeltaT3-T2) in progesterone. Ornithine and citrulline were positively related with arginine, as were changes (DeltaT3-T2) in ornithine and citrulline with changes (DeltaT3-T2) in arginine. At T2, NF-kappaB p65 activation was positively related with arginine. Polyamines did not change and were not related to progesterone. All results described were significant at P < 0.001. CONCLUSIONS: This study for the first time provides data, at the plasma and PBMC level, supporting a proposed regulatory node of arginine and related amino acids, progesterone and NF-kappaB p65 at luteal phase of the menstrual cycle, aimed at successful preparation of pregnancy. PMID- 29990357 TI - A novel bibliometric index with a simple geometric interpretation. AB - We propose the chi-index as a bibliometric indicator that generalises the h index. While the h-index is determined by the maximum square that fits under the citation curve of an author when plotting the number of citations in decreasing order, the chi-index is determined by the maximum area rectangle that fits under the curve. The height of the maximum rectangle is the number of citations ck to the kth most-cited publication, where k is the width of the rectangle. The chi index is then defined as [Formula: see text], for convenience of comparison with the h-index and other similar indices. We present a comprehensive empirical comparison between the chi-index and other bibliometric indices, focusing on a comparison with the h-index, by analysing two datasets-a large set of Google Scholar profiles and a small set of Nobel prize winners. Our results show that, although the chi and h indices are strongly correlated, they do exhibit significant differences. In particular, we show that, for these data sets, there are a substantial number of profiles for which chi is significantly larger than h. Furthermore, restricting these profiles to the cases when ck > k or ck < k corresponds to, respectively, classifying researchers as either tending to influential, i.e. having many more than h citations, or tending to prolific, i.e. having many more than h publications. PMID- 29990355 TI - Riociguat prevents hyperoxia-induced lung injury and pulmonary hypertension in neonatal rats without effects on long bone growth. AB - Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates. PMID- 29990358 TI - Estimating the costs of air pollution to the National Health Service and social care: An assessment and forecast up to 2035. AB - BACKGROUND: Air pollution damages health by promoting the onset of some non communicable diseases (NCDs), putting additional strain on the National Health Service (NHS) and social care. This study quantifies the total health and related NHS and social care cost burden due to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) in England. METHOD AND FINDINGS: Air pollutant concentration surfaces from land use regression models and cost data from hospital admissions data and a literature review were fed into a microsimulation model, that was run from 2015 to 2035. Different scenarios were modelled: (1) baseline 'no change' scenario; (2) individuals' pollutant exposure is reduced to natural (non-anthropogenic) levels to compute the disease cases attributable to PM2.5 and NO2; (3) PM2.5 and NO2 concentrations reduced by 1 MUg/m3; and (4) NO2 annual European Union limit values reached (40 MUg/m3). For the 18 years after baseline, the total cumulative cost to the NHS and social care is estimated at L5.37 billion for PM2.5 and NO2 combined, rising to L18.57 billion when costs for diseases for which there is less robust evidence are included. These costs are due to the cumulative incidence of air-pollution-related NCDs, such as 348,878 coronary heart disease cases estimated to be attributable to PM2.5 and 573,363 diabetes cases estimated to be attributable to NO2 by 2035. Findings from modelling studies are limited by the conceptual model, assumptions, and the availability and quality of input data. CONCLUSIONS: Approximately 2.5 million cases of NCDs attributable to air pollution are predicted by 2035 if PM2.5 and NO2 stay at current levels, making air pollution an important public health priority. In future work, the modelling framework should be updated to include multi-pollutant exposure-response functions, as well as to disaggregate results by socioeconomic status. PMID- 29990356 TI - Prevalence of chronic comorbidities in dengue fever and West Nile virus: A systematic review and meta-analysis. AB - BACKGROUND: Flavivirus diseases such as dengue fever (DENV), West Nile virus (WNV), Zika and yellow fever represent a substantial global public health concern. Preexisting chronic conditions such as cardiovascular diseases, diabetes, obesity, and asthma were thought to predict risk of progression to severe infections. OBJECTIVE: We aimed to quantify the frequency of chronic comorbidities in flavivirus diseases to provide an estimate for their prevalence in severe and non-severe infections and examine whether chronic diseases contribute to the increased risk of severe viral expression. METHODS: We conducted a comprehensive search in PubMed, Ovid MEDLINE(R), Embase and Embase Classic and grey literature databases to identify studies reporting prevalence estimates of comorbidities in flavivirus diseases. Study quality was assessed with the risk of bias tool. Age-adjusted odds ratios (ORs) were estimated for severe infection in the presence of chronic comorbidities. RESULTS: We identified 65 studies as eligible for inclusion for DENV (47 studies) and WNV (18 studies). Obesity and overweight (i.e., BMI> 25 kg/m2, prevalence: 24.5%, 95% CI: 18.6 31.6%), hypertension (17.1%, 13.3-21.8%) and diabetes (13.3%, 9.3-18.8%) were the most prevalent comorbidities in DENV. However, hypertension (45.0%, 39.1-51.0%), diabetes (24.7%, 20.2-29.8%) and heart diseases (25.6%, 19.5-32.7%) were the most prevalent in WNV. ORs of severe flavivirus diseases were about 2 to 4 in infected patients with comorbidities such as diabetes, hypertension and heart diseases. The small number of studies in JEV, YFV and Zika did not permit estimating the prevalence of comorbidities in these infections. CONCLUSION: Higher prevalence of chronic comorbidities was found in severe cases of flavivirus diseases compared to non-severe cases. Findings of the present study may guide public health practitioners and clinicians to evaluate infection severity based on the presence of comorbidity, a critical public health measure that may avert severe disease outcome given the current dearth of clear prevention practices for some flavivirus diseases. PMID- 29990359 TI - Reduced cognitive function during a heat wave among residents of non-air conditioned buildings: An observational study of young adults in the summer of 2016. AB - BACKGROUND: In many regions globally, buildings designed for harnessing heat during the cold exacerbate thermal exposures during heat waves (HWs) by maintaining elevated indoor temperatures even when high ambient temperatures have subdued. While previous experimental studies have documented the effects of ambient temperatures on cognitive function, few have observed HW effects on indoor temperatures following subjects' habitual conditions. The objective was to evaluate the differential impact of having air conditioning (AC) on cognitive function during a HW among residents of AC and non-AC buildings using a prospective observational cohort study. METHODS: We followed 44 students (mean age = 20.2 years; SD = 1.8 years) from a university in the Greater Boston area, Massachusetts in the United States living in AC (n = 24) and non-AC (n = 20) buildings before, during, and after a HW. Two cognition tests were self administered daily for a period of 12 days (July 9-July 20, 2016), the Stroop color-word test (STROOP) to assess selective attention/processing speed and a 2 digit, visual addition/subtraction test (ADD) to evaluate cognitive speed and working memory. The effect of the HW on cognitive function was evaluated using difference-in-differences (DiD) modelling. FINDINGS: Mean indoor temperatures in the non-AC group (mean = 26.3 degrees C; SD = 2.5 degrees C; range = 19.6-30.4 degrees C) were significantly higher (p < 0.001) than in the AC group (mean = 21.4 degrees C; SD = 1.9 degrees C; range = 17.5-25.0 degrees C). DiD estimates show an increase in reaction time (STROOP = 13.4%, p < 0001; ADD = 13.3%, p < 0.001) and reduction in throughput (STROOP = -9.9%, p < 0.001; ADD = -6.3%, p = 0.08) during HWs among non-AC residents relative to AC residents at baseline. While ADD showed a linear relationship with indoor temperatures, STROOP was described by a U-shaped curve with linear effects below and above an optimum range (indoor temperature = 22 degrees C-23 degrees C), with an increase in reaction time of 16 ms/ degrees C and 24 ms/ degrees C for STROOP and ADD, respectively. Cognitive tests occurred right after waking, so the study is limited in that it cannot assess whether the observed effects extended during the rest of the day. Although the range of students' ages also represents a limitation of the study, the consistent findings in this young, healthy population might indicate that greater portions of the population are susceptible to the effects of extreme heat. CONCLUSIONS: Cognitive function deficits resulting from indoor thermal conditions during HWs extend beyond vulnerable populations. Our findings highlight the importance of incorporating sustainable adaptation measures in buildings to preserve educational attainment, economic productivity, and safety in light of a changing climate. PMID- 29990360 TI - Climate change could threaten cocoa production: Effects of 2015-16 El Nino related drought on cocoa agroforests in Bahia, Brazil. AB - Climate models predict a possible increase in the frequency of strong climate events such as El Nino-Southern Oscillation (ENSO), which in parts of the tropics are the cause of exceptional droughts, these threaten global food production. Agroforestry systems are often suggested as promising diversification options to increase farmers' resilience to extreme climatic events. In the Northeastern state of Bahia, where most Brazilian cocoa is grown in wildlife-friendly agroforests, ENSOs cause severe droughts which negatively affect forest and agriculture. Cocoa (Theobroma cacao) is described as being sensitive to drought but there are no field-studies of the effect of ENSO-related drought on adult cocoa trees in the America's; there is one study of an experimentally-imposed drought in Indonesia which resulted in 10 to 46% yield loss. In our study, in randomly chosen farms in Bahia, Brazil, we measured the effect of the 2015-16 severe ENSO, which caused an unprecedented drought in cocoa agroforests. We show that drought caused high cocoa tree mortality (15%) and severely decreased cocoa yield (89%); the drought also increased infection rate of the chronic fungal disease witches' broom (Moniliophthora perniciosa). Ours findings showed that Brazilian cocoa agroforests are at risk and that increasing frequency of strong droughts are likely to cause decreased cocoa yields in the coming decades. Furthermore, because cocoa, like many crops, is grown somewhat beyond its climatic limits, it and other crops could be the 'canaries in the coalmine' warning of forthcoming major drought effects on semi-natural and natural vegetation. PMID- 29990361 TI - Correction: Broadening understanding of accountability ecosystems in sexual and reproductive health and rights: A systematic review. AB - [This corrects the article DOI: 10.1371/journal.pone.0196788.]. PMID- 29990362 TI - The San Diego 2007 wildfires and Medi-Cal emergency department presentations, inpatient hospitalizations, and outpatient visits: An observational study of smoke exposure periods and a bidirectional case-crossover analysis. AB - BACKGROUND: The frequency and intensity of wildfires is anticipated to increase as climate change creates longer, warmer, and drier seasons. Particulate matter (PM) from wildfire smoke has been linked to adverse respiratory and possibly cardiovascular outcomes. Children, older adults, and persons with underlying respiratory and cardiovascular conditions are thought to be particularly vulnerable. This study examines the healthcare utilization of Medi-Cal recipients during the fall 2007 San Diego wildfires, which exposed millions of persons to wildfire smoke. METHODS AND FINDINGS: Respiratory and cardiovascular International Classification of Diseases (ICD)-9 codes were identified from Medi Cal fee-for-service claims for emergency department presentations, inpatient hospitalizations, and outpatient visits. For a respiratory index and a cardiovascular index of key diagnoses and individual diagnoses, we calculated rate ratios (RRs) for the study population and different age groups for 3 consecutive 5-day exposure periods (P1 [October 22-26], P2 [October 27-31], and P3 [November 1-5]) versus pre-fire comparison periods matched on day of week (5 day periods starting 3, 4, 5, 6, 8, and 9 weeks before each exposed period). We used a bidirectional symmetric case-crossover design to examine emergency department presentations with any respiratory diagnosis and asthma specifically, with exposure based on modeled wildfire-derived fine inhalable particles that are 2.5 micrometers and smaller (PM2.5). We used conditional logistic regression to estimate odds ratios (ORs), adjusting for temperature and relative humidity, to assess same-day and moving averages. We also evaluated the United States Environmental Protection Agency (EPA)'s Air Quality Index (AQI) with this conditional logistic regression method. We identified 21,353 inpatient hospitalizations, 25,922 emergency department presentations, and 297,698 outpatient visits between August 16 and December 15, 2007. During P1, total emergency department presentations were no different than the reference periods (1,071 versus 1,062.2; RR 1.01; 95% confidence interval [CI] 0.95-1.08), those for respiratory diagnoses increased by 34% (288 versus 215.3; RR 1.34; 95% CI 1.18-1.52), and those for asthma increased by 112% (58 versus 27.3; RR 2.12; 95% CI 1.57-2.86). Some visit types continued to be elevated in later time frames, e.g., a 72% increase in outpatient visits for acute bronchitis in P2. Among children aged 0-4, emergency department presentations for respiratory diagnoses increased by 70% in P1, and very young children (0-1) experienced a 243% increase for asthma diagnoses. Associated with a 10 MUg/m3 increase in PM2.5 (72-hour moving average), we found 1.08 (95% CI 1.04-1.13) times greater odds of an emergency department presentation for asthma. The AQI level "unhealthy for sensitive groups" was associated with significantly elevated odds of an emergency department presentation for respiratory conditions the day following exposure, compared to the AQI level "good" (OR 1.73; 95% CI 1.18-2.53). Study limitations include the use of patient home address to estimate exposures and demographic differences between Medi-Cal beneficiaries and the general population. CONCLUSIONS: Respiratory diagnoses, especially asthma, were elevated during the wildfires in the vulnerable population of Medi-Cal beneficiaries. Wildfire related healthcare utilization appeared to persist beyond the initial high exposure period. Increased adverse health events were apparent even at mildly degraded AQI levels. Significant increases in health events, especially for respiratory conditions and among young children, are expected based on projected climate scenarios of wildfire frequency in California and globally. PMID- 29990363 TI - Modeling collisions in laying hens as a tool to identify causative factors for keel bone fractures and means to reduce their occurrence and severity. AB - Keel fractures represent a major productivity and welfare issue for the laying hen industry with greater than 50% of birds in recent surveys across various commercial operations and nations exhibiting some form of damage by end of lay. While the causes are likely multifactorial and influenced by age, diet, genetic line, and other factors, high energy collisions with house furnishings and conspecifics in the barn are believed to be a major contribution to the frequency and severity of factures. The current study applies a previously described ex vivo impact testing protocol to quantify susceptibility to keel bone damage across an extensive range of collision energies and ages. We also link fracture susceptibility with bone and physiological measures likely to influence skeletal resilience. Further, we applied the impact testing protocol to evaluate the benefit of an omega-3 enriched diet to improve bone health and reduce fracture susceptibility. Our results indicated that fracture susceptibility increased rapidly from 23 weeks of age, peaking at 49.5 weeks of age and thereafter decreasing. Fracture susceptibility also varied with multiple natural characteristics of bone, including mineral density, though the nature of that relationship was dependent on whether an old fracture was present. Severity of the experimental fracture demonstrated considerable variation with collision energy and biomechanical properties. An omega-3 enhanced diet provided a protective effect against fractures, though only in terms of collision energies that were relatively low. In conclusion, the impact testing protocol provided a unique means to assess fracture susceptibility and quantify the role of likely influencing bird-level biological factors, both those that vary naturally as well as when altered through specific interventions. PMID- 29990364 TI - Seismic collapse assessment of bridge piers constructed with steel fibers reinforced concrete. AB - Steel fiber is one of the most widely used reinforcements to improve the performance of concrete members. However, few studies have been proposed to study the seismic performance of bridge piers constructed with steel fiber reinforced concrete. This paper presents the collapse vulnerability assessment of typical single bridge piers constructed with steel fibers. Fiber element models of RC bridge piers with and without steel fibers are firstly built by selecting suitable cyclic constitutive laws of steel fiber reinforced concrete, and then calibrated using the experimental results. The seismic capacity and inelastic demand of RC piers with steel fibers are quantified using both nonlinear static pushover analyses and nonlinear incremental dynamic analyses (IDA). In order to conduct the IDA, a suite of 20 earthquake ground motions are selected and scaled to different levels of peak ground acceleration (PGA). Collapse fragility curves are then generated using the maximum drift ratio of piers as the engineering demand parameter (EDP). In order to investigate the impact of various parameters on the collapse fragility curves, six parameters are considered in the parametric study: peak compressive strength of concrete, yield strength of steel, longitudinal reinforcement ratio, axial load ratio, transverse hoops ratio and steel fiber content. It was observed that the concrete strength, longitudinal reinforcement ratio and steel fiber content could significantly affect the collapse fragility curve of the bridge piers with steel fibers. PMID- 29990365 TI - Information-theoretic analysis of realistic odor plumes: What cues are useful for determining location? AB - Many species rely on olfaction to navigate towards food sources or mates. Olfactory navigation is a challenging task since odor environments are typically turbulent. While time-averaged odor concentration varies smoothly with the distance to the source, instaneous concentrations are intermittent and obtaining stable averages takes longer than the typical intervals between animals' navigation decisions. How to effectively sample from the odor distribution to determine sampling location is the focus in this article. To investigate which sampling strategies are most informative about the location of an odor source, we recorded three naturalistic stimuli with planar lased-induced fluorescence and used an information-theoretic approach to quantify the information that different sampling strategies provide about sampling location. Specifically, we compared multiple sampling strategies based on a fixed number of coding bits for encoding the olfactory stimulus. When the coding bits were all allocated to representing odor concentration at a single sensor, information rapidly saturated. Using the same number of coding bits in two sensors provides more information, as does coding multiple samples at different times. When accumulating multiple samples at a fixed location, the temporal sequence does not yield a large amount of information and can be averaged with minimal loss. Furthermore, we show that histogram-equalization is not the most efficient way to use coding bits when using the olfactory sample to determine location. PMID- 29990367 TI - Robust and automatic motion-capture data recovery using soft skeleton constraints and model averaging. AB - Motion capture allows accurate recording of human motion, with applications in many fields, including entertainment, medicine, sports science and human computer interaction. A common difficulty with this technology is the occurrence of missing data, due to occlusions, or recording conditions. Various models have been proposed to estimate missing data. Some are based on interpolation, low-rank properties or inter-correlations. Others involve dataset matching or skeleton constraints. While the latter have the advantage of promoting a realistic motion estimation, they require prior knowledge of skeleton constraints, or the availability of a prerecorded dataset. In this article, we propose a probabilistic averaging method of several recovery models (referred to as Probabilistic Model Averaging (PMA) in this paper), based on the likelihoods of the distances between body points. This method has the advantage of being automatic, while allowing an efficient gap data recovery. To support and validate the proposed method, we use a set of four individual recovery models, based on linear/nonlinear regression in local coordinate systems. Finally, we propose two heuristic algorithms to enforce skeleton constraints in the reconstructed motion, which can be used on any individual recovery model. For validation purposes, random gaps were introduced into motion-capture sequences, and the effects of factors such as the number of simultaneous gaps, gap length and sequence duration were analyzed. Results show that the proposed probabilistic averaging method yields better recovery than (i) each of the four individual models and (ii) two recent state-of-the-art models, regardless of gap length, sequence duration and number of simultaneous gaps. Moreover, both of our heuristic skeleton-constraint algorithms significantly improve the recovery for 7 out of 8 tested motion capture sequences (p < 0.05), for 10 simultaneous gaps of 5 seconds. The code is available for free download at: https://github.com/numediart/MocapRecovery. PMID- 29990366 TI - Center volume and the outcomes of percutaneous transluminal angioplasty and stenting in patients with symptomatic intracranial vertebrobasilar stenoses: A meta-analysis. AB - BACKGROUND: Evidence for the preventative effects of percutaneous transluminal angioplasty and stenting (PTAS) on the recurrence of stroke in patients with severe intracranial vertebrobasilar stenoses (IVBS) varies, and the influence of study characteristics on the study outcomes have not been determined. METHODS: A study level based meta-analysis was performed to investigate the influence of baseline characteristics on the 30-day and follow-up stroke recurrence or death in symptomatic IVBS patients receiving PTAS. Relevant single center studies were retrieved by searching PubMed and Embase. A random effect model was applied to synthesize the outcomes. Meta-regression and subgroup analyses were performed to evaluate the potential influence of study characteristics on outcomes. RESULTS: Fifteen cohort studies comprising 554 symptomatic IVBS patients were included. PTAS was associated with an 8% incidence of stroke recurrence or death (95% CI: 5% to 12%) in IVBS patients within 30 days, and 8 per 100 person-years (95% CI: 5 to 11 per 100 person-years) of cumulative stroke recurrence or death during follow-up. Meta-regression indicated that the center volume, as defined by the numbers of cases per year, was negatively correlated with 30-day (regression coefficient = -0.09, p = 0.02) and follow-up (regression coefficient = -0.60, p = 0.01) stroke recurrence or death. Age, gender, or comorbidities have no significant effect on the outcomes. CONCLUSIONS: Centers of higher procedural volume may be associated with better clinical outcomes for symptomatic IVBS patients receiving PTAS. PMID- 29990369 TI - Identification and annotation of newly conserved microRNAs and their targets in wheat (Triticum aestivum L.). AB - MicroRNAs (miRNAs) are small, non-coding and regulatory RNAs produce by cell endogenously. They are 18-26 nucleotides in length and play important roles at the post-transcriptional stage of gene regulation. Evolutionarily, miRNAs are conserved and their conservation plays an important role in the prediction of new miRNAs in different plants. Wheat (Triticum aestivum L.) is an important diet and consumed as second major crop in the world. This significant cereal crop was focused here through comparative genomics-based approach to identify new conserved miRNAs and their targeted genes. This resulted into a total of 212 new conserved precursor miRNAs (pre-miRNAs) belonging to 185 miRNA families. These newly profiled wheat's miRNAs are also annotated for stem-loop secondary structures, length distribution, organ of expression, sense/antisense orientation and characterization from their expressed sequence tags (ESTs). Moreover, fifteen miRNAs along with housekeeping gene were randomly selected and subjected to RT PCR expressional validation. A total of 32927 targets are also predicted and annotated for these newly profiled wheat miRNAs. These targets are found to involve in 50 gene ontology (GO) enrichment terms and significant processes. Some of the significant targets are RNA-dependent DNA replication (GO:0006278), RNA binding (GO:0003723), nucleic acid binding (GO:0003676), DNA-directed RNA polymerase activity (GO:0003899), magnesium ion transmembrane transporter activity (GO:0015095), antiporter activity (GO:0015297), solute:hydrogen antiporter activity (GO:0015299), protein kinase activity (GO:0004672), ATP binding (GO:0005524), regulation of Rab GTPase activity (GO:0032313) Rab GTPase activator activity (GO:0005097), regulation of signal transduction (GO:0009966) and phosphoprotein phosphatase inhibitor activity (GO:0004864). These findings will be helpful to manage this economically important grain plant for desirable traits through miRNAs regulation. PMID- 29990368 TI - Development and pilot of a decision-aid for patients with bipolar II disorder and their families making decisions about treatment options to prevent relapse. AB - INTRODUCTION: Treatment decisions in bipolar II disorder (BPII) are finely balanced and sensitive to patient preferences. This pilot study evaluated a decision-aid booklet (DA) for patients with BPII (and their family) to obtain evidence on its acceptability, feasibility, safety, and usefulness in potential end-users. METHODS: The DA booklet was developed according to International Patient Decision-Aid Standards. Thirty-one patients diagnosed with BPII and their families (n = 11), who were currently making or had previously made treatment decisions, participated. Participants read the DA and completed validated and purpose-designed questionnaires. A follow-up semi-structured telephone interview elicited more in-depth DA feedback (n = 40). RESULTS: Patients and family endorsed the DA booklet as: easy-to-use (100% agree), useful in treatment decision-making (100%), presenting balanced (patients = 96.8%, family = 100%), up to-date (93.5%, 100%) and trustworthy information (93.5%, 100%) that did not provoke anxiety (93.5%, 90.9%). All participants stated that they would recommend the DA to others. Following DA use, all except one participant (97.6%) demonstrated adequate treatment knowledge (> 50% score). Patients reported low decisional conflict (M = 18.90/100) following DA use and felt well-prepared to make treatment decisions (M = 4.28/5). Most patients (90.3%) indicated uptake of treatments consistent with the best available clinical evidence. Additionally, a large proportion of patients made an informed choice about medication (65.5%) with adjunctive psychological treatment (50.0%), based on adequate knowledge and their treatment values. Interview findings further supported the DA's acceptability among participants. DISCUSSION: Pilot findings indicate that patients with BPII and their family consider this DA booklet highly acceptable and useful in making evidence-based treatment decisions that align with their treatment preferences. PMID- 29990370 TI - Caenorhabditis elegans respond to high-glucose diets through a network of stress responsive transcription factors. AB - High-glycemic-index diets, as well as a sedentary lifestyle are considered as determinant factors for the development of obesity, type 2 diabetes, and cardiovascular diseases in humans. These diets have been shown to shorten the life span of C. elegans in a manner that is dependent on insulin signaling, but the participation of other signaling pathways have not been addressed. In this study, we have determined that worms fed with high-glucose diets show alterations in glucose content and uptake, triglyceride content, body size, number of eggs laid, egg-laying defects, and signs of oxidative stress and accelerated aging. Additionally, we analyzed the participation of different key regulators of carbohydrate and lipid metabolism, oxidative stress and longevity such as SKN 1/NRF2, HIF-1/HIF1alpha, SBP-1/SREBP, CRH-1/CREB, CEP-1/p53, and DAF-16/FOXO, in the reduction of lifespan in glucose-fed worms. PMID- 29990371 TI - All-oral direct antiviral treatment for hepatitis C chronic infection in a real life cohort: The role of cirrhosis and comorbidities in treatment response. AB - BACKGROUND: Hepatitis C virus (HCV) infection is the major cause of end-stage liver disease (LD) worldwide. The aim of this study was to assess sustained virological response (SVR) rates in a real-world cohort of patients with HCV infection treated with interferon-free direct antiviral agents (DAA). PATIENTS AND METHODS: All patients with genotypes 1, 2 or 3 HCV infection who started interferon-free treatment at a university hospital from December 2015 through July 2017 were included. The primary outcome was SVR at post-treatment week 12 by intention-to-treat (ITT) and modified ITT (mITT) analysis. RESULTS: Five hundred twenty seven patients were enrolled, 51.6% with cirrhosis. Most patients received sofosbuvir + daclatasvir + ribavirin (60.7%) and sofosbuvir + simeprevir (25.6%). Overall SVR rates were 90.5% for ITT and 96% for mITT. SVR rates were higher in non-cirrhotic (94.2% in ITT and 96.8% in mITT) versus cirrhotic patients (87.1% in ITT and 95.2% in mITT). In ITT and mITT assessments, SVR rates were higher in patients with Child-Pugh A (n = 222, 88.7% and 95.7%, respectively) versus Child Pugh B or C (n = 40, 80% and 90%, respectively); SVR rates were higher in patients with genotype 1 (n = 405, 92.1% and 98.2%), followed by genotype 2 (n = 13, 84.6% and 92.7%) and genotype 3 (n = 109, 84.4% and 88.4%). Lower comorbidity index (p = 0.0014) and absence of cirrhosis (p = 0.0071) were associated with SVR. Among cirrhotic patients, lower Model for End-Stage Liver Disease (p = 0.0258), higher albumin (p = 0.0015), and higher glomerular filtration rate (p = 0.0366) were related to SVR. Twenty-two cirrhotic patients (8%) had clinical liver decompensation during treatment. Complications of advanced LD were responsible for discontinuation of treatment and death in 12 and 7 patients, respectively. CONCLUSION: Treatment with all-oral DAA achieved high SVR rates, particularly in patients without cirrhosis and few comorbidities. Advanced LD is associated to poor outcome, such as treatment failure and death. PMID- 29990372 TI - Adolescent and nurse perspectives of psychotherapeutic interventions for PTSD delivered through task-shifting in a low resource setting. AB - BACKGROUND: This investigation compared the perceived effectiveness of supportive counselling (SC) and prolonged exposure for adolescents (PE-A) by treatment users (adolescents with PTSD) and non-specialist treatment providers (supervised nurses). METHOD: Adolescent participants and nurse providers were purposively recruited to share their experiences of trial participation through face to face semi-structured in-depth interviews and treatment-specific focus groups (all recorded). Twelve adolescent participant transcripts (ten interviews and two focus groups) and three nurse provider transcripts were doubly transcribed. Thematic content analysis was applied using Atlas.ti software. Two emerging themes are presented in this paper: 1) Perceptions of the intervention and 2) Usefulness of the intervention. RESULTS: Regardless of treatment arm, adolescents experienced warm counselling relationships and described the process of extending trust to the counselor. Adolescents in the PE-A arm provided clear descriptions of session structure and treatment rationale compared with adolescents receiving SC. The most helpful tools were breathing retraining and imaginal exposure for PE A and creation of distraction strategies during non-directive SC. Adolescents in both arms continued to use the techniques acquired during treatment and reported symptom improvement. Participants who received SC acknowledged ongoing reexperiencing. Nurses perceived SC to be an immediately transferable skill, but feedback on their preference for one intervention over the other was inconclusive. CONCLUSION: Both PTSD treatment strategies, implemented by non specialists, were perceived as helpful. Overall, adolescents reported warm therapeutic relationships and a reduction in PTSD symptoms. Nurses stated that they would require institutional support to ensure delivery of these interventions in a scalable and sustainable manner. PMID- 29990373 TI - Correction: Reduced Topological Efficiency in Cortical-Basal Ganglia Motor Network of Parkinson's Disease: A Resting State fMRI Study. AB - [This corrects the article DOI: 10.1371/journal.pone.0108124.]. PMID- 29990374 TI - Methylation dynamics during the maternal-to-zygotic genome transition in dioecious species. AB - The starting point of a new generation in sexually reproducing species is fertilization. In many species, fertilization is followed by cell divisions controlled primarily by maternal transcripts, with little to no zygotic transcription. The activation of the zygotic genome (ZGA) is part of a process called maternal-to-zygotic transition (MZT), during which transcripts from the zygotic genome take control of development, setting the conditions for cellular specialization. While we know that epigenetic processes (e.g. methylation) are involved in the MZT, their roles and interplay in the transition are largely unknown. I developed a model and used simulations to elucidate the interaction between possible epigenetic processes, namely methylation processes, involved in the MZT. The model focuses on the dynamics of global methylation levels and how these interact with factors such as a parental repressor and the nucleocytoplasmic ratio to trigger the ZGA, followed by development from fertilization to adulthood. In addition, I included transgenerational effects transmitted to the zygote from both parents through their gametes to show that these may set the stage for plastic developmental processes. I demonstrate that the rates of maintenance methylation and demethylation, which are important for the achievement of the final methylation levels of an individual, exhibit a certain level of flexibility in terms of parameter values. I find that high final methylation levels require more restricted combinations of parameter values. The model is discussed in the context of the current empirical knowledge and provide suggestions for directions of future empirical and theoretical studies. PMID- 29990375 TI - Preliminary validation of a Urinary Symptom Questionnaire for individuals with Neuropathic Bladder using Intermittent Catheterization (USQNB-IC): A patient centered patient reported outcome. AB - BACKGROUND: We developed a Urinary Symptom Questionnaire for individuals with neurogenic bladder due to spinal cord injury (SCI) and spina bifida (SB) who manage their bladders with intermittent catheterization, the USQNB-IC. This project followed an approach to patient-centered patient reported outcomes development that we created and published in 2017, specifically to ensure the primacy of the patient's perspective and experience. PARTICIPANTS: Two sets of responses were collected from individuals with neurogenic bladder due to either SCI (n = 336) and SB (patients, n = 179; and caregivers of patients with NB, n = 66), and three sets of "controls", individuals with neurogenic bladder who do not have a history of UTIs (n = 49) individuals with chronic mobility impairments (neither SCI nor SB) and without neurogenic bladder (n = 46), and those with no mobility impairment, no neurogenic bladder, and no history of UTIs (n = 64). METHOD: Data were collected from all respondents to estimate these psychometric or measurement domains characterizing a health related PRO: Reliability (minimization of measurement error; internal consistency or interrelatedness of the items; and maximization of variability that is due to "true" difference between levels of the symptoms across patients), and validity (content, reflection of the construct to be measured; face, recognizability of the contents as representing the construct to be measured; structural, the extent to which the instrument captures recognizable dimensions of the construct to be measured; and criterion, association with a gold standard). RESULTS: Evidence from these five groups of respondents suggest the instrument has face, content, criterion, convergent, and divergent validity, as well as reliability. The items were all more descriptive of our patient (focus) groups and were only weakly endorsed by the control groups. CONCLUSIONS: The instrument is unique in its emphasis on, and origination from, the lived experiences of patients with neurogenic bladder who use intermittent catheterization; this preliminary psychometric evidence suggests the instrument could be useful for research and in the clinic. These results justify further development of the instrument, including formal exploration of the scoring and estimation of responsivity of these items to clinical interventions as well as patient-directed self care. PMID- 29990376 TI - Correction: Implementation and outcomes of guideline revisions for the prevention of mother-to-child HIV transmission in Mother Support Programme, Addis Ababa, Ethiopia. AB - [This corrects the article DOI: 10.1371/journal.pone.0198438.]. PMID- 29990377 TI - Cell fate decisions of human iPSC-derived bipotential hepatoblasts depend on cell density. AB - During embryonic development bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes- the two main cell types within the liver. Cell fate decision depends on elaborate interactions between distinct signalling pathways, namely Notch, WNT, TGFbeta, and Hedgehog. Several in vitro protocols have been established to differentiate human pluripotent stem cells into either hepatocyte or cholangiocyte like cells (HLC/CLC) to enable disease modelling or drug screening. During HLC differentiation we observed the occurrence of epithelial cells with a phenotype divergent from the typical hepatic polygonal shape- we refer to these as endoderm derived epithelial cells (EDECs). These cells do not express the mature hepatocyte marker ALB or the progenitor marker AFP. However they express the cholangiocyte markers SOX9, OPN, CFTR as well as HNF4alpha, CK18 and CK19. Interestingly, they express both E Cadherin and Vimentin, two markers that are mutually exclusive, except for cancer cells. EDECs grow spontaneously under low density cell culture conditions and their occurrence was unaffected by interfering with the above mentioned signalling pathways. PMID- 29990378 TI - Genome analysis of new Blattabacterium spp., obligatory endosymbionts of Periplaneta fuliginosa and P. japonica. AB - The successful adaptation of cockroaches is, in part, dependent of the activity of their obligatory endosymbionts, Blattabacterium spp., which are involved in uric acid degradation, nitrogen assimilation and nutrient provisioning. Their strategic localization, within bacteriocytes in the proximities of uric acid storage cells (urocytes), highlights their importance in the recycling of nitrogen from urea and ammonia, end-products not secreted by their host insects. In this study, we present the complete genome sequence of two new Blattabacterium spp. from Periplaneta fuliginosa (BPfu) and P. japonica (BPja), and detailed comparison with other Blattabacterium strains from different cockroach species. The genomes of BPfu and BPja show a high degree of stability as showed with for other Blattabacterium representatives, only presenting a 19-kb fragment inversion between BPja and BPfu. In fact, the phylogenomics showed BPja as an ancestor species of BPfu, BPLAN (P. americana) and BBor (Blatta orientalis), in congruence with their host cockroach phylogeny. Their functional profile is similar and closest to the omnivorous strain BBge (Blattella germanica). Interesting, BPja possesses the complete set of enzymes involved sulfate assimilatory pathway only found in BBge and BMda (Mastotermes darwiniensis). The newly sequenced genomes of BPja and BPfu emphasise the remarkable stability of Blattabacterium genomes supported by their long-term coevolution and obligatory lifestyle in their host insect. PMID- 29990380 TI - Effect of cowpea flour processing on the chemical properties and acceptability of a novel cowpea blended maize porridge. AB - Childhood growth stunting is a pervasive problem in Malawi and is in large part due to low quality complementary foods and chronic gut inflammation. Introducing legumes such as cowpea (Vigna unguiculata) into the complementary diet has the potential to improve childhood growth by improving diet quality through improvements in macro- and micronutrients and also by reducing gut inflammation. However, cowpea is relatively underutilized in complementary feeding in Malawi due to its strong taste, long processing time, and high energy requirements for processing. Effective utilization of cowpea in complementary feeding requires processing which may affect chemical composition as well as sensory quality. The present study evaluated the effect of processing on the retention of zinc, crude fibre, and flavonoid in roasted, boiled, and dehulled cowpea flours, and assessed the acceptability of maize porridge (70%) enriched with one of the three cowpea flours (30%). Roasting, dehulling, and boiling did not have any effect on zinc content. Crude fibre content increased after processing by all methods. Processing had no effect on measurable flavonoids. Roasted, boiled, and dehulled cowpea blended maize porridges were acceptable to children with mean quantities of leftover food of less than 3g from the given 100g. Caregivers also rated the blended flours to be highly acceptable to them as well, with maize porridge blended with dehulled cowpea flour the most acceptable to both children and caregivers. These results demonstrate that cowpea flour, processed by any of these three different methods, could serve as a useful addition to maize porridge for complementary feeding of children in sub-Saharan Africa. PMID- 29990379 TI - CD177-mediated nanoparticle targeting of human and mouse neutrophils. AB - Neutrophils are the most abundant white blood cells, with a vital role in innate immune defense against bacterial and fungal pathogens. Although mostly associated with pathological processes directly related to immune defense, they can also play a detrimental role in inflammatory conditions and have been found to have a pro-metastatic role in the spread of cancer cells. Here, we explore ways to temporarily suppress these detrimental activities. We first examined the possibility of using siRNA and antisense oligonucleotides (ASOs) for transient knockdown of the human and mouse C5a receptor, an important chemoattractant receptor involved in neutrophil-mediated injury that is associated with myocardial infarction, sepsis, and neurodegenerative diseases. We found that siRNAs and ASOs transfected into cultured cell lines can eliminate 70-90% of C5a receptor mRNA and protein within 72 h of administration, a clinically relevant time frame after a cardiovascular event. Targeted drug delivery to specific cells or tissues of interest in a mammalian host, however, remains a major challenge. Here, using phage display technology, we have identified peptides that bind specifically to CD177, a neutrophil-specific surface molecule. We have attached these peptides to fluorescent, lipid-based nanoparticles and confirmed targeting and delivery to cultured cells ectopically presenting either human or mouse CD177. In addition, we have shown peptide-nanoparticle binding specifically to neutrophils in human and mouse blood. We anticipate that these or related tagged nanoparticles may be therapeutically useful for delivery of siRNAs or ASOs to neutrophils for transient knockdown of pro-inflammatory proteins such as the C5a receptor. PMID- 29990382 TI - Isolation and purification of antibacterial compound from Streptomyces levis collected from soil sample of north India. AB - During the screening programme for microbial cultures producing antimicrobial agents, an active microbial strain of Streptomyces was isolated from the agricultural soil of Narnaul, Haryana India. Physiological, biochemical characteristics and 16S ribosomal RNA sequence homology studies revealed that it was similar to Streptomyces levis (sequence similarity 100%). The microbial strain was submitted to Genomebio Technologies Pvt. Ltd., Pune, Maharashtra, India under Accession No. EU124569. The isolated strain was found to produce extracellular active compound showing strong antimicrobial activity against Klebsiella pneumoniae MTCC 109, Pseudomonas aeruginosa MTCC 741 and Staphylococcus aureus MTCC 96. The antibacterial compound was successfully isolated and purified. Structure elucidation of antibacterial metabolite with EI MS/ HRMS showed molecular ion peak at m/z 686 [M+H]+. Whereas, elemental analysis of the said compound showed C = 61.31, H = 8.61, N = 2.04 and O = 28.02, and indicated a molecular formula of C35H59NO12. The presence of 'chromone' nucleus in the compound's chemical structure was confirmed by using 1HNMR studies. The present study reports the purification of potential antibacterial compound from Streptomyces levis isolated from the unexplored soil of north India and warrants for further characterization of this potential compound for optimum utilization for antimicrobial purposes. PMID- 29990381 TI - Gouty arthritis: Can we avoid unnecessary dual-energy CT examinations using prior radiographs? AB - OBJECTIVE: The dual-energy CT (DECT) algorithm for urate detection is feasible only if hyperdense deposits are present. Based on our experience, around half of the performed DECT examinations show no such deposits and thus were useless for this indication. Our diagnostic accuracy study investigates whether conventional radiographs can serve as gatekeeper test prior to DECT for reliable exclusion of such radiopaque deposits. MATERIALS AND METHODS: In this retrospective study, 77 clinically indicated DECT examinations of the hand (n = 29), foot (n = 36) and ankle (n = 12) of 55 patients (13 female, mean age 62+/-15 years) with suspected gouty arthritis were included. Two blinded readers independently evaluated DECT, gray-scale CT images (reference standard) and corresponding standardized radiographs for the presence/location of dense soft tissue deposits. RESULTS: Interreader agreement for detection of soft tissue deposits with DECT and radiographs was excellent (DECT: both readers, kappa = 1; radiographs: both readers, kappa = 0.94). DECT showed soft tissue deposits in 54/77 DECT (70%) scans. 30/54 scans (56%) showed deposits on the corresponding radiographs, while in 24 scans (44%) no deposits were seen on radiographs. Test performance of radiographs for soft tissue deposit detection: sensitivity 56%, specificity 100%, PPV 100%, NPV 48.9%, and accuracy 69%. Low density of the deposits was the main reasons for false-negative radiographs (19 cases, 79%), followed by superimposition of deposits by osseous structures (5 cases, 21%). CONCLUSION: Conventional radiographs of the hand, foot and ankle cannot serve as a gatekeeper test for reliable exclusion of radiopaque soft tissue deposits prior to DECT. PMID- 29990384 TI - Optic nerve changes in chronic sinusitis patients: Correlation with disease severity and relevant sinus location. AB - PURPOSE: This study was to evaluate whether optic nerve damage occurs in eyes with adjacent chronic sinusitis. METHODS: Data were collected from eighty-eight eyes of 46 chronic sinusitis patients and 93 eyes of 57 normal controls. Visual sensitivity using standard automated perimetry (SAP) and inner retinal thickness using optical coherence tomography (OCT) were measured. The Lund-Mackay system was used to quantify radiographic findings on the ostiomeatal unit CT scan with a numerical score representing the severity of sinusitis. RESULTS: There was a significant positive correlation between the pattern standard deviation (dB) and Lund-Mackay score (P = 0.031). Nasal retinal nerve fiber layer (RNFL) thickness, average, minimum, superotemporal, superior, superonasal, and inferonasal ganglion cell-inner plexiform layer (GCIPL) thickness were negatively correlated significantly with Lund-Mackay score (all, P < 0.05). Eyes with grade 2 opacification of the posterior ethmoid sinus showed a significantly lower mean deviation (dB) and higher pattern standard deviation (dB) than those with clear respective sinuses (P = 0.007 and <0.001, respectively). Eyes with grades 1,2 and 3 opacification of the sphenoid sinus had a significantly less average RNFL thickness (P = 0.004, <0.001, and <0.001, respectively) and a significantly less average GCIPL thickness (P = 0.004, 0.003, and 0.003, respectively) than those with a clear sphenoid sinus. CONCLUSIONS: Structural and functional optic nerve changes were correlated with the severity of chronic sinusitis. Inflammation of the posterior ethmoid and sphenoid sinuses was associated with optic nerve changes to a greater extent than that of the other paranasal sinuses. PMID- 29990383 TI - Substitutions for arginine at position 780 in triple helical domain of the alpha1(I) chain alter folding of the type I procollagen molecule and cause osteogenesis imperfecta. AB - OI is a clinically and genetically heterogeneous disorder characterized by bone fragility. More than 90% of patients are heterozygous for mutations in type I collagen genes, COL1A1 and COL1A2, and a common mutation is substitution for an obligatory glycine in the triple helical Gly-X-Y repeats. Few non-glycine substitutions in the triple helical domain have been reported; most result in Y position substitutions of arginine by cysteine. Here, we investigated leucine and cysteine substitutions for one Y-position arginine, p.Arg958 (Arg780 in the triple helical domain) of proalpha1(I) chains that cause mild OI. We compared their effects with two substitutions for glycine located in close proximity. Like substitutions for glycine, those for arginine reduced the denaturation temperature of the whole molecule and caused asymmetric posttranslational overmodification of the chains. Circular dichroism and increased susceptibility to cleavage by MMP1, MMP2 and catalytic domain of MMP1 revealed significant destabilization of the triple helix near the collagenase cleavage site. On a cellular level, we observed slower triple helix folding and intracellular collagen retention, which disturbed the Endoplasmic Reticulum function and affected matrix deposition. Molecular dynamic modeling suggested that Arg780 substitutions disrupt the triple helix structure and folding by eliminating hydrogen bonds of arginine side chains, in addition to preventing HSP47 binding. The pathogenic effects of these non-glycine substitutions in bone are probably caused mostly by procollagen misfolding and its downstream effects. PMID- 29990385 TI - Activity of ceftolozane-tazobactam against Escherichia coli isolates from U.S. veterans (2011) in relation to co-resistance and sequence type 131 (ST131) H30 and H30Rx status. AB - BACKGROUND: Escherichia coli sequence type 131 (ST131), with its multidrug resistance-associated H30R1 and H30Rx clonal subsets, causes most antimicrobial resistant E. coli infections in the U.S., especially among veterans. The activity of ceftolozane-tazobactam (C/T), a new beta-lactamase inhibitor agent, against ST131 strains, and E. coli isolates from veterans, is undefined. METHODS: We determined broth microdilution MICs for C/T and five comparators-piperacillin tazobactam (TZP) levofloxacin (LVX), gentamicin (GEN), ceftazidime (CAZ), and meropenem (MEM)-for 595 clinical E. coli isolates, collected in 2011 from 24 Veterans Affairs Medical Centers across the U.S. Categorical resistance and MICs were compared statistically with resistance category (fluoroquinolone susceptible, fluoroquinolone-resistant, and extended-spectrum beta-lactamase [ESBL]-producing) and with PCR-defined ST131, H30R1, and H30Rx status. RESULTS: Resistance prevalence was <= 6% for C/T (6%) and MEM (0%), vs. from 8.0% (TZP) to 59% (LVX) for the other comparators. MICs generally increased by resistance category, from fluoroquinolone-susceptible through fluoroquinolone-resistant to ESBL, and by clonal subgroup, from non-ST131-H30 through H30R1 to H30Rx. For each comparator agent except MEM, although a significantly greater fraction of resistant than susceptible isolates were C/T-resistant, only a minority of comparator-resistant isolates were C/T-resistant (i.e., 9% if LEV-resistant, 12% if GEN-resistant, 21% if CAZ-resistant, 38% if TZP-resistant). CONCLUSIONS: C/T was broadly active against E. coli clinical isolates from veterans, notwithstanding significant variation by resistance category and ST131 H30R1/H30Rx status, outperforming all non-carbapenem comparators. C/T should prove useful as a carbapenem-sparing therapy for multidrug-resistant E. coli ST131 infections, including in veterans. PMID- 29990392 TI - How to Run a Successful Orthodontic Practice- Part V. PMID- 29990393 TI - Current Perspectives on Craniofacial Pain and Temporomandibular Disorders. AB - This is the first in a series of articles addressing current issues in the diagnosis and treatment of CFP-TMD. PMID- 29990391 TI - Injectable local anaesthetic agents for dental anaesthesia. AB - BACKGROUND: Pain during dental treatment, which is a common fear of patients, can be controlled successfully by local anaesthetic. Several different local anaesthetic formulations and techniques are available to dentists. OBJECTIVES: Our primary objectives were to compare the success of anaesthesia, the speed of onset and duration of anaesthesia, and systemic and local adverse effects amongst different local anaesthetic formulations for dental anaesthesia. We define success of anaesthesia as absence of pain during a dental procedure, or a negative response to electric pulp testing or other simulated scenario tests. We define dental anaesthesia as anaesthesia given at the time of any dental intervention.Our secondary objective was to report on patients' experience of the procedures carried out. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2018, Issue 1), MEDLINE (OVID SP), Embase, CINAHL PLUS, WEB OF SCIENCE, and other resources up to 31 January 2018. Other resources included trial registries, handsearched journals, conference proceedings, bibliographies/reference lists, and unpublished research. SELECTION CRITERIA: We included randomized controlled trials (RCTs) testing different formulations of local anaesthetic used for clinical procedures or simulated scenarios. Studies could apply a parallel or cross-over design. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological approaches for data collection and analysis. MAIN RESULTS: We included 123 studies (19,223 participants) in the review. We pooled data from 68 studies (6615 participants) for meta-analysis, yielding 23 comparisons of local anaesthetic and 57 outcomes with 14 different formulations. Only 10 outcomes from eight comparisons involved clinical testing.We assessed the included studies as having low risk of bias in most domains. Seventy-three studies had at least one domain with unclear risk of bias. Fifteen studies had at least one domain with high risk of bias due to inadequate sequence generation, allocation concealment, masking of local anaesthetic cartridges for administrators or outcome assessors, or participant dropout or exclusion.We reported results for the eight most important comparisons.Success of anaesthesiaWhen the success of anaesthesia in posterior teeth with irreversible pulpitis requiring root canal treatment is tested, 4% articaine, 1:100,000 epinephrine, may be superior to 2% lidocaine, 1:100,000 epinephrine (31% with 2% lidocaine vs 49% with 4% articaine; risk ratio (RR) 1.60, 95% confidence interval (CI) 1.10 to 2.32; 4 parallel studies; 203 participants; low-quality evidence).When the success of anaesthesia for teeth/dental tissues requiring surgical procedures and surgical procedures/periodontal treatment, respectively, was tested, 3% prilocaine, 0.03 IU felypressin (66% with 3% prilocaine vs 76% with 2% lidocaine; RR 0.86, 95% CI 0.79 to 0.95; 2 parallel studies; 907 participants; moderate-quality evidence), and 4% prilocaine plain (71% with 4% prilocaine vs 83% with 2% lidocaine; RR 0.86, 95% CI 0.75 to 0.99; 2 parallel studies; 228 participants; low-quality evidence) were inferior to 2% lidocaine, 1:100,000 epinephrine.Comparative effects of 4% articaine, 1:100,000 epinephrine and 4% articaine, 1:200,000 epinephrine on success of anaesthesia for teeth/dental tissues requiring surgical procedures are uncertain (RR 0.85, 95% CI 0.71 to 1.02; 3 parallel studies; 930 participants; very low-quality evidence).Comparative effects of 0.5% bupivacaine, 1:200,000 epinephrine and both 4% articaine, 1:200,000 epinephrine (odds ratio (OR) 0.87, 95% CI 0.27 to 2.83; 2 cross-over studies; 37 participants; low quality evidence) and 2% lidocaine, 1:100,000 epinephrine (OR 0.58, 95% CI 0.07 to 5.12; 2 cross-over studies; 31 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction are uncertain.Comparative effects of 2% mepivacaine, 1:100,000 epinephrine and both 4% articaine, 1:100,000 epinephrine (OR 3.82, 95% CI 0.61 to 23.82; 1 parallel and 1 cross-over study; 110 participants; low-quality evidence) and 2% lidocaine, 1:100,000 epinephrine (RR 1.16, 95% CI 0.25 to 5.45; 2 parallel studies; 68 participants; low-quality evidence) on success of anaesthesia for teeth requiring extraction and teeth with irreversible pulpitis requiring endodontic access and instrumentation, respectively, are uncertain.For remaining outcomes, assessing success of dental local anaesthesia via meta-analyses was not possible.Onset and duration of anaesthesiaFor comparisons assessing onset and duration, no clinical studies met our outcome definitions.Adverse effects (continuous pain measured on 170-mm Heft Parker visual analogue scale (VAS))Differences in post-injection pain between 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine are small, as measured on a VAS (mean difference (MD) 4.74 mm, 95% CI -1.98 to 11.46 mm; 3 cross-over studies; 314 interventions; moderate-quality evidence). Lidocaine probably resulted in slightly less post-injection pain than articaine (MD 6.41 mm, 95% CI 1.01 to 11.80 mm; 3 cross-over studies; 309 interventions; moderate-quality evidence) on the same VAS.For remaining comparisons assessing local and systemic adverse effects, meta-analyses were not possible. Other adverse effects were rare and minor.Patients' experiencePatients' experience of procedures was not assessed owing to lack of data. AUTHORS' CONCLUSIONS: For success (absence of pain), low-quality evidence suggests that 4% articaine, 1:100,000 epinephrine was superior to 2% lidocaine, 1:100,000 epinephrine for root treating of posterior teeth with irreversible pulpitis, and 2% lidocaine, 1:100,000 epinephrine was superior to 4% prilocaine plain when surgical procedures/periodontal treatment was provided. Moderate-quality evidence shows that 2% lidocaine, 1:100,000 epinephrine was superior to 3% prilocaine, 0.03 IU felypressin when surgical procedures were performed.Adverse events were rare. Moderate-quality evidence shows no difference in pain on injection when 4% articaine, 1:100,000 epinephrine and 2% lidocaine, 1:100,000 epinephrine were compared, although lidocaine resulted in slightly less pain following injection.Many outcomes tested our primary objectives in simulated scenarios, although clinical alternatives may not be possible.Further studies are needed to increase the strength of the evidence. These studies should be clearly reported, have low risk of bias with adequate sample size, and provide data in a format that will allow meta-analysis. Once assessed, results of the 34 'Studies awaiting classification (full text unavailable)' may alter the conclusions of the review. PMID- 29990394 TI - Anchorage Reinforcement Post Molar Distalization. AB - After distalization of maxillary molars, retaining it in the new position is of utmost importance. There are various methods available to avoid taxing freshly distilized molars. We have discussed various methods to reinforce anchorage post molar ditalization. We have introduced a new appliance that is a modified Nance palatal button for continuous distally directed force on the molars. PMID- 29990395 TI - Class II Division I Treated with Twin Block Appliance: A Case Report. AB - A 10-yearfemale presented a skeletal Class II relation with 7mm of overet, 40% overbite, and bilateral posterior lingual crossbite. Two phase therapy was planned to correct Class II skeletal relation, overjet, overbite, and achieve lip competency. Phase I therapy was done with Twin Block appliance to advance the retrognathic mandible. Phase II therapy was accomplished with fixed appliance for arch coordination, to correct minor displacement, and to finalize occlusion. Post treatment skeletal Class I relation was achieved. Incisors inclination was improved, ideal overjet and overbite with bilateral class I molar relationship was achieved. As the mandible advanced, lip competency, facial convexity, and mentolabial sulcus improved. PMID- 29990396 TI - Correlation of Dental age and Cervical Vertebral Maturation and Chronological Age in an Iranian Population Based on Radiography. AB - This study aims to evaluate the association of dental and skeletal maturity and chronological age. Demerjien and Baccetti systems were used for measurements. CVM and dental age showed a significant association in females(OR=1. 05, 95% CI:1. 01 1.07). Teeth calcification can be used as simple predictors for CVM status and chronological age. PMID- 29990397 TI - Effect of Diameter on Stability of Mini-Screws Used as Skeletal Anchorage for Maxillary Canine Retraction Using Two Force Magnitudes. AB - This study investigated the effect of diameter on stability of mini-screws used as skeletal anchorage for maxillary canine retraction utilizing two different force magnitudes. Findings revealed that increasing the diameter of the mini screws increases their stability. However, utilization of a high retraction force negatively affects stability especially with small diameters mini-screws. PMID- 29990398 TI - A Technique for Utilizing Ankylosed Teeth for Anchorage. AB - We present a novel method of reinforcing anchorage by utilizing ankylosed teeth. This technique provides simple solutions in otherwise challenging and complex cases. PMID- 29990399 TI - Correlation of Crown Angulation and Inclination Based on Occlusal, Camper's, and Frankfurt Planes Using Digital Models. AB - This study provided the measures of crown angulations and inclinations which were evaluated using 3D cephalometry. This study was conducted to demonstrate the relationship between the main planes : Camper's, Frankfurt, and occlusalplanes for guiding the positioning ofthe skull and orthodontic planning. PMID- 29990400 TI - Facile Stabilizer for Lingual Retainer Wires. AB - To overcome the challenge of maintaining the perfect adaptation of the retainer wire to the lingual surfaces of an anterior tooth while bonding, we have designed a facile method which will aid in accurate and precise placement of lingual retainer wire to ensure longterm stability ofan orthodontic treatment result. PMID- 29990401 TI - Simple Elastomeric Chain Ligation Method for Palatally / Linguall Placed Lateral or Canines. AB - Palataly-displaced incisors or canines are typically extruded. The crossbite must be corrected without occlusal interference during alignment. Occlusal interference associated with such extrusion can prevent proper tooth positioning, and therefore, the temporary use of a bite plate may be necessary' However, unnecessary bite raising may occur when a bite plate is used in adults, and the patient's discomfort due to such an appliance cannot be ignored. Most of the time, conventional ligation fails and also ends with debonding of the bracket. A slin shot use ofan elastic chain forfaster correction of instanding tooth is suggested. PMID- 29990402 TI - Timing of Surgical Removal of Odontoma in a Growing Orthodontic Patient: A Case Report. AB - In patients with skeletal malocclusion and odontoma, the prioritization of treatment is ofgreat importance. Ifsurgical removal of odontoma is postponed, the probability of adjacent teeth impaction increases. In this case, skeletal treatment was performed before odontoma rgery due to concerns about facial appearance and the patient's fear of surgery, and therefore adjacent tooth failed to erupt. PMID- 29990403 TI - Customized Lingual Orthodontic Treatment of Skeletal Class II Malocclusion with Bilateral Maxillary First Premolar Extraction: Case Report. AB - This report describes the orthodontic camouflage treatment for a 52-year-old Chinese man using eBrace customized lingual appliance with bilateral maxillary first premolar extraction. The treatment results showed that using the eBrace customized lingual appliance can achieve expected effects and has a high level of safety for periodontal health. PMID- 29990404 TI - Surgical Orthodontic Approach for the Retreatment of a High Angle Skeletal Class III Patient: Case Report. AB - The aim of this article is to describe the retreatment ofa high angle skeletal Class II patient with a moderate anterior crossbite who had previous mandibular orthognathic surgery. A traditional orthodontics/orthognathic surgery approach was selected for treatment. Facial balance was improved, and the final occlusal relationships were good. PMID- 29990405 TI - A Proposed Method for Covering a Mini-Screw Head While Maintaining Space for Ligation. AB - The use of mini-screws, also known as temporary anchorage devices (TADs), to obtain absolute anchorage has become very popular in orthodontics. Nevertheless, potential complications, including traumatic soft tissue lesions, accompany their use. We propose a method to cover the mini-screw head to prevent traumatic soft tissue lesions and promote patient comfort, while maintaining some separation between the composite resin and the peri-implant tissue. PMID- 29990407 TI - Class I Correction Using a Combination of an Upper Lingual and Lower Labial Appliance. AB - No orthodontic system combines aesthetics and comfort which delivers optimal treatment outcomes. This case report outlines how combining an upper lingual and a lower ceramic appliance can provide the best combination ofaesthetics whilst maintaining patien comfort, when undertaking class II camouflage treatment involving extraction of the upper first premolars. PMID- 29990406 TI - Two-Year Follow-up of Multidisciplinary Treatment Using Digital Smile Design as a Planning Tool for Esthetic Restorations on Maxillary Midline Diastema. AB - One of the challenges posed by diastema closure treatment in the presence of tooth size discrepancy is to achieve adequate distribution of the spaces between the teeth. The use of the Digital Smile Design can assist the clinician in visualizing and measuring dentogingival discrepancies with maximum predictability. The present clinical case describes an approach to space distribution with assistance of the digital tool, allowing adequate restorative procedures. The protocol used was shown to be efficient, achieving the esthetics desired by the patient both during and after multidisciplinary treatment, as well as having adequate stability. PMID- 29990409 TI - Costs. PMID- 29990408 TI - A New Approach to Maxillary Protrusion with an Unstable Mandibular Position Accompanied with Unidentified Complaints: Case Report. AB - This case report describes the importance of combining morphological and functional examination with psychological examination in the establishment ofstable mandibular position in the treatment of maxillary protrusion with unstable mandibular position accompanied by unidentified complaints, which ensures safe orthodontic treatment. PMID- 29990410 TI - A Masquerader of Disease: An Incomplete Presentation of Kawasaki Disease. AB - Kawasaki disease (KD) is a systemic pediatric vasculitis that most commonly affects children between the ages of 6 months and 4 years. The diagnosis of KD requires a high degree of clinical suspicion. In younger patients (less than 6 months) the diagnosis is exceedingly difficult as these patients typically do not meet the criteria to diagnosis KD clinically. Oftentimes, these younger patients do not meet enough of the criteria to warrant ordering an echocardiogram. We report a case of a 6-month-old Caucasian female who presented with high fevers originally thought to be due to a urinary tract infection. The patient required multiple echocardiograms in order to be diagnosed with incomplete KD. The patient was treated with IVIG and aspirin per standard of care, and experienced resolution of fevers and illness. PMID- 29990411 TI - Robotic-Assisted Percutaneous Coronary Intervention of a Saphenous Vein Graft Stenosis using a FilterWire EZ Embolic Protection. AB - Robotic-assisted coronary angioplasty has been utilized to decrease radiation exposure to cardiologists, and to diminish risk of orthopedic and ergonomic injuries caused by wearing heavy lead during long procedures. The efficacy and safety of robotic-assisted percutaneous coronary intervention for relatively low risk lesions was demonstrated in the PRECISE study. Successful percutaneous coronary interventions using robotic system for treatment of complex high-risk lesions have been reported in few case series so far. We describe a successful robotic-assisted coronary angioplasty for a complex lesion of saphenous vein graft using a FilterWire EZ embolic protection. This case illustrates the feasibility to use robotic-assisted angioplasty for complex cases. PMID- 29990412 TI - Successful Resolution of a Large Left Ventricular Thrombus with Rivaroxaban Therapy after Acute Myocardial Infarction. AB - Left ventricular (LV) thrombus is a major complication of acute systolic cardiomyopathy especially after a large anterior myocardial infarction (AMI), and it poses a significant embolic risk, up to five times higher than the general population. Current guidelines for LV thrombi recommend vitamin K antagonist for anticoagulation in contrast to novel oral anticoagulants (NOACs) which have not been studied well in cases of LV thrombus. We present a case of patient with AMI, who was noted to have severe systolic dysfunction and a large LV thrombus which was successfully treated with rivaroxaban therapy with complete resolution of LV thrombus on two months follow-up. PMID- 29990413 TI - Primum Non Nocere: Origin of a Principle. PMID- 29990414 TI - An Analysis of the Financial Burden Associated with the Residency Match at the University of South Dakota Sanford School of Medicine. AB - OBJECTIVE: The application process for residency positions is a costly endeavor. This study aims to quantify the financial expenses incurred by University of South Dakota Sanford School of Medicine (USD SSOM) class of 2016. Our hope is that this study will prepare future students of USD and other smaller programs for the financial burdens associated with the match. This data should be used to guide financial decision making by medical students from USD or by regional students from medical programs that desire to apply to residency programs not offered at their home institution. METHODS: A 10-item online survey was administered in April of 2016 via the USD Sanford School of Medicine email listserv to the graduating MD class of 2016. The survey asked respondents about the number and cost of away-rotations completed, interviews attended, second-look days attended after the interview, preferences for interviewing during an away rotation, the specialty the applicant matched into, and number on each applicant's rank list that he/she matched. RESULTS: The survey had a 68.3 percent response rate. The mean number of away-rotations completed, interviews attended, and second-look days attended were 1.3, 12.1, and 0.1 per applicant respectively. The mean costs of attendance to away-rotations, interviews, and second-look days were $1,690.63, $4,881.88, and $24 per applicant, respectively. The total mean collective cost of away-rotations, interviews, and second-look days was $6,596.51 per applicant. CONCLUSIONS: The process of applying to residencies among the graduating MD class of 2016 is a costly endeavor. Attendance of interviews for residency positions is the most costly part of the residency application process. Although the financial burden associated with applying to residency programs is high, increasing competition for graduate medical education positions may only drive the cost further. PMID- 29990415 TI - Radiation Therapy Induced Esophageal Ulcer. PMID- 29990416 TI - Using Data Science to Provide Preliminary Estimates of Out-of-Hospital Cardiac Arrest in Rural South Dakota. AB - BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is the cessation of electric or mechanical activity of the heart, confirmed by absence of circulation. Survival to hospital dismissal rates have remained low nationwide despite considerable effort to improve treatment. Current initiatives seek systems approaches that optimize care at each point along the "chain of survival." Systems approaches rely on the availability of robust data sets to understand and control variables that can be highly interdependent. The current report seeks to provide a source of reliable data of OHCA for South Dakota. METHODS: Using the "Utstein" guidelines for reviewing and reporting OHCA resuscitations issued by the American Heart Association in 2014, we analyzed the EMS data that were captured by ePCR between January 1, 2013 and December 31, 2015. Inclusion criteria were 911 calls in 2013-2015, where first impression of the call was cardiac arrest. Exclusion criteria were inconsistent and missing data. RESULTS: There were 1,781 OHCA in the ePCR, and 1,280 cases had survival information, with 378 victims surviving to ED. Overall, SD OHCA rates were lower than those reported nationally. Survival was the highest in patients with a shockable rhythm and when victim received bystander CPR. The odds for survival were greater if the arrest took place in an urban setting compared to a rural setting and if the victim received care from an EMS unit that did not have a "hardship" designation. DISCUSSION: Recommendations for future efforts include: (1) Develop and employ quality improvement methodologies for data collection and utilization to minimize the impact of poor or missing data, (2) Assess the educational and training needs of the EMS staff to properly collect, analyze, and develop actionable outputs, (3) Provide public training to include hands-only CPR and PulsePoint. PMID- 29990417 TI - Radiation Therapy Induced Esophageal Ulcer. AB - Dysproteinemia is excessive production of immunoglobulins from clonal proliferation of plasma or B cells. Cryoglobulins are a special group of immunoglobulins that precipitate below 37 degrees C. Type 1 cryoglobulinemia consists mostly of IgM and IgG that infrequently leads to glomerulonephritis. In these situations, an underlying malignancy is even rare with only 21 cases described so far with only four having chronic lymphocytic leukemia (CLL). We present a case of a 68-year-old male admitted with hypertension and kidney dysfunction who upon work up was found to have CLL. Kidney biopsy was performed that showed capillary loops thickening with massive intraluminal cryoglobulin deposition in the glomeruli on periodic acid-Schiff (PAS) stain and "tram tracking" on silver stains. The patient was started on chemotherapy with rituximab, cyclophosphamide, vincristine, and prednisone. After his fourth and final cycle of treatment, the patient's serum creatinine and Glomerular filtration rate improved to 1.2 mg/dL and 85 mL/min from 3 mg/dL and 29 mL/min respectively. One month later, his renal function remained mostly unchanged. The rare association of type 1 cryoglobulinemia with underlying CLL makes it a unique and intriguing case. PMID- 29990418 TI - Which Vaccine Should I Get to Prevent Herpes Zoster? PMID- 29990419 TI - Quality Focus: Hypertension: The Challenges of Appropriate Diagnosis and Treatment Continue. PMID- 29990420 TI - Bottom-Up Synthesis of Heteroatom-Doped Chiral Graphene Nanoribbons. AB - Bottom-up synthesis of graphene nanoribbons (GNRs) has significantly advanced during the past decade, providing various GNR structures with tunable properties. The synthesis of chiral GNRs, however, has been underexplored and only limited to (3,1)-GNRs. We report herein the surface-assisted synthesis of the first heteroatom-doped chiral (4,1)-GNRs from the rationally designed precursor 6,16 dibromo-9,10,19,20-tetraoxa-9a,19a-diboratetrabenzo[ a, f, j, o]perylene. The structure of the chiral GNRs has been verified by scanning tunneling microscopy, noncontact atomic force microscopy, and Raman spectroscopy in combination with theoretical modeling. Due to the presence of oxygen-boron-oxygen (OBO) segments on the edges, lateral self-assembly of the GNRs has been observed, realizing well aligned GNR arrays with different modes of homochiral and heterochiral inter ribbon assemblies. PMID- 29990421 TI - Structural Coupling Throughout the Active Site Hydrogen Bond Networks of Ketosteroid Isomerase and Photoactive Yellow Protein. AB - Hydrogen bonds are fundamental to biological systems and are regularly found in networks implicated in folding, molecular recognition, catalysis, and allostery. Given their ubiquity, we asked the fundamental questions of whether, and to what extent, hydrogen bonds within networks are structurally coupled. To address these questions, we turned to three protein systems, two variants of ketosteroid isomerase and one of photoactive yellow protein. We perturbed their hydrogen bond networks via a combination of site-directed mutagenesis and unnatural amino acid substitution, and we used 1H NMR and high-resolution X-ray crystallography to determine the effects of these perturbations on the lengths of the two oxyanion hole hydrogen bonds that are donated to negatively charged transition state analogs. Perturbations that lengthened or shortened one of the oxyanion hole hydrogen bonds had the opposite effect on the other. The oxyanion hole hydrogen bonds were also affected by distal hydrogen bonds in the network, with smaller perturbations for more remote hydrogen bonds. Across 19 measurements in three systems, the length change in one oxyanion hole hydrogen bond was propagated to the other, by a factor of -0.30 +/- 0.03. This common effect suggests that hydrogen bond coupling is minimally influenced by the remaining protein scaffold. The observed coupling is reproduced by molecular mechanics and quantum mechanics/molecular mechanics (QM/MM) calculations for changes to a proximal oxyanion hole hydrogen bond. However, effects from distal hydrogen bonds are reproduced only by QM/MM, suggesting the importance of polarization in hydrogen bond coupling. These results deepen our understanding of hydrogen bonds and their networks, providing strong evidence for long-range coupling and for the extent of this coupling. We provide a broadly predictive quantitative relationship that can be applied to and can be further tested in new systems. PMID- 29990422 TI - Hybrid Liquid Crystal Nanocarriers for Enhanced Zinc Phthalocyanine-Mediated Photodynamic Therapy. AB - Current challenges in photodynamic therapy (PDT) include both the targeted delivery of the photosensitizer (PS) to the desired cellular location and the maintenance of PS efficacy. Zinc phthalocyanine (ZnPc), a macrocyclic porphyrin and a potent PS for PDT, undergoes photoexcitation to generate reactive singlet oxygen that kills cells efficiently, particularly when delivered to the plasma membrane. Like other commonly employed PS, ZnPc is highly hydrophobic and prone to self-aggregation in aqueous biological media. Further, it lacks innate subcellular targeting specificity. Cumulatively, these attributes pose significant challenges for delivery via traditional systemic drug delivery modalities. Here, we report the development and characterization of a liquid crystal nanoparticle (LCNP)-based formulation for the encapsulation and targeted tethering of ZnPc to the plasma membrane bilayer. ZnPc was coloaded with the organic fluorophore, perylene (PY), in the hydrophobic polymeric matrix of the LCNP core. PY facilitated the fluorescence-based tracking of the LCNP carrier while also serving as a Forster resonance energy transfer (FRET) donor to the ZnPc acceptor. This configuration availed efficient singlet oxygen generation via enhanced excitation of ZnPc from multiple surrounding PY energy donors. When excited in a FRET configuration, cuvette-based assays revealed that singlet oxygen generation from the ZnPc was ~1.8-fold greater and kinetically 12 times faster compared to when the ZnPc was excited directly. The specific tethering of the LCNPs to the plasma membrane of HEK 293 T/17 and HeLa cells was achieved by surface functionalization of the NPs with PEGylated cholesterol. In HeLa cells, LCNPs coloaded with PY and ZnPc, when photoexcited in a FRET configuration, mediated 70% greater cell killing compared to LCNPs containing ZnPc alone (direct excitation of ZnPc). This was attributed to a significant increase of the oxidative stress in the cells during the PDT. Overall, this work details the ability of the LCNP platform to facilitate (1) the specific tethering of the PY ZnPc FRET pair to the plasma membrane and (2) the FRET-mediated, augmented singlet oxygen generation for enhanced PDT relative to the direct excitation of ZnPc alone. PMID- 29990423 TI - Conjugate Addition of Perfluoroarenes to alpha,beta-Unsaturated Carbonyls Enabled by an Alkoxide-Hydrosilane System: Implication of a Radical Pathway. AB - Conjugate addition of organometallic reagents to alpha,beta-unsaturated carbonyls is a key strategy for the construction of carbon-carbon bond in organic synthesis. Although direct C-H addition to unsaturated bonds via transition metal catalysis is explored in recent years, electron-deficient arenes that do not bear directing groups continue to be challenging. Herein we disclose the first example of a conjugate addition of perfluoroarenes to alpha,beta-unsaturated carbonyls enabled by an alkoxide-hydrosilane system. The reaction is convenient to carry out at room temperature over a broad range of substrates and reactants to furnish synthetically versatile products in high to excellent yields. Mechanistic experiments in combination with computational studies suggest that a radical pathway is most likely operative in this transformation. The hypervalent silicate and silanide species, which are relevant to the proposed mechanism, were observed experimentally by NMR and single crystal X-ray diffraction analyses. PMID- 29990424 TI - Discovery of the Polyamine Conjugate with Benzo[ cd]indol-2(1 H)-one as a Lysosome-Targeted Antimetastatic Agent. AB - Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative that can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo[ cd]indol-2(1 H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome. Mechanistic investigations demonstrated the interdependence of 5e-triggered apoptosis and autophagy. Compound 5e modulated the expression of LC3-II, p62, cathepsins, and the expression of capases 3, caspase 8, Bcl-2, and p53. The SSAT mediated Akt/beta-catenin pathways were also inhibited by 5e. The dual features of 5e make it a worthwhile lead compound for further structural optimization. PMID- 29990425 TI - Integrating Metal-Catalyzed C-H and C-O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation. AB - One major goal of organometallic chemists is the direct functionalization of the bonds most recurrent in organic molecules: C-H, C-C, C-O, and C-N. An even grander challenge is C-C bond formation when both precursors are of this category. Parallel to this is the synthetic goal of achieving reaction selectivity that contrasts with conventional methods. Electrophilic aromatic substitution (EAS) via Friedel-Crafts acylation is the most renowned method for the synthesis of aryl ketones, a common structural motif of many pharmaceuticals, agrochemicals, fragrances, dyes, and other commodity chemicals. However, an EAS synthetic strategy is only effective if the desired site for acylation is in accordance with the electronic-controlled regioselectivity of the reaction. Herein we report steric-controlled regioselective arene acylation with salicylate esters via iridium catalysis to access distinctly substituted benzophenones. Experimental and computational data indicate a unique reaction mechanism that integrates C-O activation and C-H activation with a single iridium catalyst without an exogenous oxidant or base. We disclose an extensive exploration of the synthetic scope of both the arene and the ester components, culminating in the concise synthesis of the potent anticancer agent hydroxyphenstatin. PMID- 29990426 TI - Light or Thermally Powered Autonomous Rolling of an Elastomer Rod. AB - Specially arranged external stimuli or carefully designed geometry are often essential for realizing continuous autonomous motion of active structures without self-carried power. As a consequence, it is usually very challenging to further integrate those structures as active building blocks into a system with a complex form and multiple functions. In this letter, we report an autonomous motion of a surprisingly simple setup: a cylindrical elastomer rod on a flat hot surface or under homogeneous illumination of visible light. We further show that the rod can roll continuously without any sign of a pause after 6 h, if an obstacle is put in front of it. We demonstrate that such nonintuitive autonomous rolling results from a combination of large thermal actuation of the elastomer and heat transfer between the rod and its surroundings. Quantitative predictions of the rolling speed from the developed thermomechanics model agree reasonably well with experimental measurements. Using the autonomous rolling rods as main building blocks, we further design and fabricate a light-powered vehicle and a thermally powered conveyor for mass transport in both air and water environments. PMID- 29990427 TI - Modeling Small-Molecule Reactivity Identifies Promiscuous Bioactive Compounds. AB - Scientists rely on high-throughput screening tools to identify promising small molecule compounds for the development of biochemical probes and drugs. This study focuses on the identification of promiscuous bioactive compounds, which are compounds that appear active in many high-throughput screening experiments against diverse targets but are often false-positives which may not be easily developed into successful probes. These compounds can exhibit bioactivity due to nonspecific, intractable mechanisms of action and/or by interference with specific assay technology readouts. Such "frequent hitters" are now commonly identified using substructure filters, including pan assay interference compounds (PAINS). Herein, we show that mechanistic modeling of small-molecule reactivity using deep learning can improve upon PAINS filters when modeling promiscuous bioactivity in PubChem assays. Without training on high-throughput screening data, a deep learning model of small-molecule reactivity achieves a sensitivity and specificity of 18.5% and 95.5%, respectively, in identifying promiscuous bioactive compounds. This performance is similar to PAINS filters, which achieve a sensitivity of 20.3% at the same specificity. Importantly, such reactivity modeling is complementary to PAINS filters. When PAINS filters and reactivity models are combined, the resulting model outperforms either method alone, achieving a sensitivity of 24% at the same specificity. However, as a probabilistic model, the sensitivity and specificity of the deep learning model can be tuned by adjusting the threshold. Moreover, for a subset of PAINS filters, this reactivity model can help discriminate between promiscuous and nonpromiscuous bioactive compounds even among compounds matching those filters. Critically, the reactivity model provides mechanistic hypotheses for assay interference by predicting the precise atoms involved in compound reactivity. Overall, our analysis suggests that deep learning approaches to modeling promiscuous compound bioactivity may provide a complementary approach to current methods for identifying promiscuous compounds. PMID- 29990428 TI - Identification of the First Synthetic Allosteric Modulator of the CB2 Receptors and Evidence of Its Efficacy for Neuropathic Pain Relief. AB - The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects; therefore several CBRs ligands have been synthesized and tested in vitro and in vivo. However, none of them reached an advanced phase of clinical development due mainly to side effects on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands. Here we identify the first ever synthesized positive allosteric modulator (PAM) that targets CB2Rs. The evidence for this was obtained using [3H]CP55940 and [35S]GTPgammaS binding assays. This finding will be useful for the characterization of allosteric binding site(s) on CB2Rs which will be essential for the further development of CB2R allosteric modulators. Moreover, the new CB2R PAM displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain, raising the possibility that it might be a good candidate for clinical development. PMID- 29990429 TI - Self-Assembled Nanofibers for Strong Underwater Adhesion: The Trick of Barnacles. AB - Developing adhesives that can function underwater remains a major challenge for bioengineering, yet many marine creatures, exemplified as mussels and barnacles, have evolved their unique proteinaceous adhesives for strong wet adhesion. The mechanisms underlying the strong adhesion of these natural adhesive proteins provide rich information for biomimetic efforts. Here, combining atomic force microscopy (AFM) imaging and force spectroscopy, we examine the effects of pH on the self-assembly and adhesive properties of cp19k, a key barnacle underwater adhesive protein. For the first time, we confirm that the bacterial recombinant Balanus albicostatus cp19k (rBalcp19k), which contains no 3,4 dihydroxyphenylalanine (DOPA) or any other amino acids with post-translational modifications, can self-assemble into aggregated nanofibers at acidic pHs. Under moderately acidic conditions, the adhesion strength of unassembled monomeric rBalcp19k on mica is only slightly lower than that of a commercially available mussel adhesive protein mixture, yet the adhesion ability of rBalcp19k monomers decreases significantly at increased pH. In contrast, upon preassembly at acidic and low-salinity conditions, rBalcp19k nanofibers keep stable in basic and high salinity seawater and display much stronger adhesion and thus show resistance to its adverse impacts. Besides, we find that the adhesion ability of Balcp19k is not impaired when it is combined with an N-terminal Thioredoxin (Trx) tag, yet whether the self-assembly property will be disrupted is not determined. Collectively, the self-assembly-enhanced adhesion presents a previously unexplored mechanism for the strong wet adhesion of barnacle cement proteins and may lead to the design of barnacle-inspired adhesive materials. PMID- 29990430 TI - Structure-Activity Relationships of the Competence Stimulating Peptide in Streptococcus mutans Reveal Motifs Critical for Membrane Protease SepM Recognition and ComD Receptor Activation. AB - Streptococcus mutans ( S. mutans) is a Gram-positive human pathogen that is one of the major contributors to dental caries, a condition with an economic cost of over $100 billion per year in the United States. S. mutans secretes a 21-amino acid peptide termed the competence stimulating peptide (21-CSP) to assess its population density in a process termed quorum sensing (QS) and to initiate a variety of phenotypes such as biofilm formation and bacteriocin production. 21 CSP is processed by a membrane bound protease SepM into active 18-CSP, which then binds to the ComD receptor. This study seeks to determine the molecular mechanism that ties 21-CSP:SepM recognition and 18-CSP:ComD receptor binding and to identify QS modulators with distinct activity profiles. To this end, we conducted systematic replacement of the amino acid residues in both 21-CSP and 18-CSP and assessed the ability of the mutated analogs to modulate QS. We identified residues that are important to SepM recognition and ComD receptor binding. Our results shed light on the S. mutans competence QS pathway at the molecular level. Moreover, our structural insights of the CSP signal can be used to design QS based anti-infective therapeutics against S. mutans. PMID- 29990432 TI - White and Brightly Colored 3D Printing Based on Resonant Photothermal Sensitizers. AB - The use of photothermal sensitizers to facilitate the sintering of polymer powders is rapidly becoming a pivotal additive manufacturing technology, impacting multiple sectors of industry. However, conventional carbon-based sensitizers can only produce black or gray objects. To create white or colorful prints with this method, visibly transparent equivalents are needed. Here, we address this problem by designing resonant photothermal sensitizers made of plasmonic nanoparticles that strongly absorb in the near-infrared, while only minimally interacting with visible light. Gold nanorods were coated with silica before being mixed with polyamide powders to create stable colorful nanocomposite powders. At resonance, these composites showed greatly improved light-to-heat conversion compared with equivalent composites using the industry standard carbon black as a sensitizer and could be sintered using low-power light sources. Furthermore, they appear much whiter and can produce brightly colored 3D objects when mixed with dyes. Our results open a new route to utilize plasmonic nanoparticles to produce colorful and functional 3D-printed objects. PMID- 29990431 TI - Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets. AB - To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, kappa-opioid receptor ligands were sought with selectivity versus the MU-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2A ligand with 21-fold selectivity versus the H1 receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field. PMID- 29990433 TI - Complete Coupled Binding-Folding Pathway of the Intrinsically Disordered Transcription Factor Protein Brinker Revealed by Molecular Dynamics Simulations and Markov State Modeling. AB - Intrinsically disordered proteins (IDPs) make up a large class of proteins that lack stable structures in solution, existing instead as dynamic conformational ensembles. To perform their biological functions, many IDPs bind to other proteins or nucleic acids. Although IDPs are unstructured in solution, when they interact with binding partners, they fold into defined three-dimensional structures via coupled binding-folding processes. Because they frequently underlie IDP function, the mechanisms of this coupled binding-folding process are of great interest. However, given the flexibility inherent to IDPs and the sparse populations of intermediate states, it is difficult to reveal binding-folding pathways at atomic resolution using experimental methods. Computer simulations are another tool for studying these pathways at high resolution. Accordingly, we have applied 40 MUs of unbiased molecular dynamics simulations and Markov state modeling to map the complete binding-folding pathway of a model IDP, the 59 residue C-terminal portion of the DNA binding domain of Drosophila melanogaster transcription factor Brinker (BrkDBD). Our modeling indicates that BrkDBD binds to its cognate DNA and folds in ~50 MUs by an induced fit mechanism, acquiring most of its stable secondary and tertiary structure only after it reaches the final binding site on the DNA. The protein follows numerous pathways en route to its bound and folded conformation, occasionally becoming stuck in kinetic traps. Each binding-folding pathway involves weakly bound, increasingly folded intermediate states located at different sites on the DNA surface. These findings agree with experimental data and provide additional insight into the BrkDBD folding mechanism and kinetics. PMID- 29990434 TI - Optimizing a Weakly Binding Fragment into a Potent RORgammat Inverse Agonist with Efficacy in an in Vivo Inflammation Model. AB - The transcription factor RORgammat is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORgammat inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism. In contrast to other reported inverse agonists, there is no direct interaction or displacement of helix 12 observed in the crystal structure. Nevertheless, compound 9 proved to be efficacious in a delayed-type hypersensitivity (DTH) inflammation model in rats. PMID- 29990435 TI - Boosting Tunable Blue Luminescence of Halide Perovskite Nanoplatelets through Postsynthetic Surface Trap Repair. AB - The easily tunable emission of halide perovskite nanocrystals throughout the visible spectrum makes them an extremely promising material for light-emitting applications. Whereas high quantum yields and long-term colloidal stability have already been achieved for nanocrystals emitting in the red and green spectral range, the blue region currently lags behind with low quantum yields, broad emission profiles, and insufficient colloidal stability. In this work, we present a facile synthetic approach for obtaining two-dimensional CsPbBr3 nanoplatelets with monolayer-precise control over their thickness, resulting in sharp photoluminescence and electroluminescence peaks with a tunable emission wavelength between 432 and 497 nm due to quantum confinement. Subsequent addition of a PbBr2-ligand solution repairs surface defects likely stemming from bromide and lead vacancies in a subensemble of weakly emissive nanoplatelets. The overall photoluminescence quantum yield of the blue-emissive colloidal dispersions is consequently enhanced up to a value of 73 +/- 2%. Transient optical spectroscopy measurements focusing on the excitonic resonances further confirm the proposed repair process. Additionally, the high stability of these nanoplatelets in films and to prolonged ultraviolet light exposure is shown. PMID- 29990436 TI - Growth of Cuprous Oxide Particles in Liquid-Phase Synthesis Investigated by X-ray Laser Diffraction. AB - Cuprous oxide (Cu2O) particles obtained by surfactant-assisted liquid-phase synthesis have cuboid shapes but the internal structures are difficult to be visualized by electron microscopy. Herein, we investigated the internal structures of numerous individual Cu2O particles with submicrometer dimensions by X-ray diffraction imaging (XDI) using X-ray free-electron laser (XFEL) pulses. The reconstructed two-dimensional electron density maps, which displayed inhomogeneous internal structures, were divided into five classes characterized by the positions and shapes of high and low electron density areas. Further analysis of the maps in each class by a manifold learning algorithm revealed that the internal structures of Cu2O particles varied in correlation with total electron density while retaining the characteristics within each class. On the basis of the analyses, we proposed a growth mechanism to yield the inhomogeneity in the internal structures of Cu2O particles in surfactant-mediated liquid-phase synthesis. PMID- 29990437 TI - Electronic Origin of Optically-Induced Sub-Picosecond Lattice Dynamics in MoSe2 Monolayer. AB - Atomically thin layers of transition metal dichalcogenide (TMDC) semiconductors exhibit outstanding electronic and optical properties, with numerous applications such as valleytronics. While unusually rapid and efficient transfer of photoexcitation energy to atomic vibrations was found in recent experiments, its electronic origin remains unknown. Here, we study the lattice dynamics induced by electronic excitation in a model TMDC monolayer, MoSe2, using nonadiabatic quantum molecular dynamics simulations. Simulation results show sub-picosecond disordering of the lattice upon photoexcitation, as measured by the Debye-Waller factor, as well as increasing disorder for higher densities of photogenerated electron-hole pairs. Detailed analysis shows that the rapid, photoinduced lattice dynamics are due to phonon-mode softening, which in turn arises from electronic Fermi surface nesting. Such mechanistic understanding can help guide optical control of material properties for functionalizing TMDC layers, enabling emerging applications such as phase change memories and neuromorphic computing. PMID- 29990438 TI - Diabetes Technology Use Among Pregnant and Nonpregnant Women with T1D in the T1D Exchange. AB - BACKGROUND: Gestational tight glycemic control is critical for women with type 1 diabetes (T1D). Limited data exist on the adoption and retention of diabetes technologies among women in different parity strata. METHODS: We compared T1D management between T1D Exchange clinic registry participants (mean age 28 +/- 9 years, 84% white non-Hispanic, and median T1D duration 13 years) who were pregnant at enrollment or year 1 follow-up ("recently pregnant" between 2010 and 2013, n = 214), ever (but not recently) pregnant (n = 1540), and never pregnant (n = 2586). We examined self-reported maternal and fetal outcomes in 130 women who delivered a baby within the last year. RESULTS: Recently pregnant women had the lowest hemoglobin A1c (6.5% pregnant vs. 7.8% ever pregnant vs. 8.0% never pregnant, P < 0.001). Recently pregnant women reported the highest use of continuous subcutaneous insulin infusion (74% vs. 60% vs. 58%, adjusted P < 0.001) and continuous glucose monitor (CGM) (36% vs.17% vs. 12%, adjusted P < 0.001) therapies compared with ever or never pregnant women, respectively, after adjusting for age, diabetes duration, and socioeconomic status. Among women 18-25 years old, CGM use was highest among recently pregnant women (adjusted P = 0.0022). Never pregnant women 26-45 years old had a higher use of CGM compared with younger counterparts (adjusted P < 0.001). Adverse maternal and fetal outcomes were common. CONCLUSIONS: Despite high uptake levels of advanced diabetes technologies among pregnant women, rates of adverse maternal and fetal outcomes remain high. More studies are needed to determine how these technologies could be best used in pregnancy and postpartum to improve health outcomes among women with T1D. PMID- 29990440 TI - EFFECTS OF ISOKINETIC ECCENTRIC VERSUS TRADITIONAL LOWER BODY RESISTANCE TRAINING ON MUSCLE FUNCTION: EXAMINING A MULTIPLE-JOINT SHORT TERM TRAINING MODEL. AB - Early adaptations of eccentric training show several advantages over concentric training. The purpose of this study was to quantify the effects of 4-weeks of multi-joint eccentric versus traditional leg press (TLP) training on muscle strength, rate of torque development (RTD) and jump and sprint performance adaptations. Twenty-six resistance trained adults performed either an eccentric or a TLP resistance training program twice per week for 4-weeks. Single-joint isometric maximum and rapid strength (peak torque and RTD, respectively) and isokinetic strength of the knee extensors and flexors, multi-joint eccentric strength, leg press strength (1-RM), 40-m sprint, and vertical and long jump were measured before (Pre), at the midpoint (Mid), and after (Post) a 4-week training period. Four weeks of isokinetic multi-joint eccentric training elicited greater test-specific strength gains (ES=1.06) compared to TLP (ES=0.11). The eccentric group (ES=0.51 and 0.54) also yielded moderate improvements in the early-middle phase RTD (RTD100-200) whereas the TLP group showed small-moderate improvements (ES=0.37). The majority of the single-joint strength variables showed negligible improvements. Performance tests showed no (broad jump) to small (vertical jump; sprint for the leg press) improvements. Eccentric multi-joint training induced significant improvements for lower body strength in a short amount of time in a trained population. These accelerated adaptations and also the lowered energy requirements of eccentric exercise may be useful for clinicians or practitioners when prescribing training programs for those who are injured, sedentary, or elderly, who are in need of time efficient muscle function improvements. PMID- 29990439 TI - Association Between Polymorphisms in CMTM Family Genes and Hepatocellular Carcinoma in Guangxi of China. AB - Polymorphisms in genes may affect its expression and alter individual susceptibility to cancer. In this study, we investigate associations between CMTM family gene polymorphisms and hepatocellular carcinoma (HCC) in a southern Chinese population. Ten selected single-nucleotide polymorphisms (SNPs) in CMTM family genes were genotyped in 315 HCC patients and 315 cancer-free controls using Sequenom MassARRAY platform and the associations of the selected SNPs with HCC risk were evaluated. We found individuals with the rs164207 AA genotypes had a significantly increased risk of HCC than those with CC genotypes (adjusted OR = 2.794, 95% CI = 1.143-6.828). Also, individuals with the rs3811178 GG genotypes showed a significant association with increased risk of HCC when compared with the AA genotypes (adjusted OR = 2.578, 95% CI = 1.114-5.969). Furthermore, there was also a significantly increased risk of HCC when combined risk genotypes of these loci, i.e., rs164207 AA, CA and rs3811178 GG, GA. Compared with the low risk group (0 risk genotypes), the high-risk group (2 risk genotypes) was at significantly increased risk of HCC (adjusted OR = 3.339, 95% CI = 1.119-9.964, p = 0.031). Our results suggest that polymorphisms of rs3811178 in CMTM5 and rs164207 in CMTM6 might contribute to the genetic susceptibility of HCC in the southern Chinese population. Further well-designed studies with larger sample sizes are needed to confirm our findings. PMID- 29990441 TI - Parasitological and Molecular Detection of Canine Trypanosomiasis From Riyadh Province, Saudi Arabia. AB - Trypanosoma evansi is the most widespread of the pathogenic salivarian trypanosomes; it causes a serious disease called surra that affects domestic animals such as camels, horses, and dogs, and often leads to reduced productivity and economic losses. Therefore, the objectives of the present study were to determine the prevalence rates of trypanosomiasis using 3 parasitological tests (wet blood film, Giemsa staining, and microhematocrit centrifugation technique) and polymerase chain reaction (PCR) among stray dogs from Riyadh Province, Saudi Arabia. In the current study, 117 dog blood samples collected from certain districts of Riyadh Province showed that 5 of 117 dogs (4.3%) were positive for the genus Trypanosoma. In addition, the findings indicated no effect of dog gender or age on parasite infection. For a more specific diagnosis, PCR amplification of the RoTat 1.2 VSG gene in 5 internal transcribed spacer1 positive samples diagnosed with Trypanosoma indicated that 2 were positive for RoTat 1.2 T. evansi. The absence of the RoTat 1.2 VSG gene in 3 of the 5 T. evansi-positive samples could be explained by the circulation of T. evansi type B in dogs from Saudi Arabia. Thus, this is the first study demonstrating T. evansi type B outside of Africa. PMID- 29990442 TI - Pentraxin3 increases in adult overweight and obese men after weight-loss by dietary modification with exercise training. AB - The circulatory level of pentraxin3 (PTX3), an anti-inflammatory cardio protective protein, has been known to be lower in obese individuals than in those with normal weight. However, reports on the effects of different weight-loss methods on PTX3 were limited. The present study aimed to investigate the effect of weight loss on the circulating PTX3 levels in overweight and obese men and to examine the combined effect of dietary modification and exercise training on PTX3 levels. Forty-eight overweight and obese men were assigned to two groups: the dietary modification (group D) or exercise training and dietary modification (group DE). Groups D and DE were composed of 27 and 21 participants, respectively. We observed a significant independent relationship between the changes of PTX3 and body mass index (BMI) in all participants (beta=-0.617, p<0.01). Subsequently, we compared the effect of two other types of weight loss on plasma PTX3 in groups D and DE. The magnitude of increase in plasma PTX3 levels was similar in the two groups. Interestingly, we observed that PTX3 levels in group DE increased significantly more than those in group D in subjects who achieved normal weight, as defined based on BMI, after interventions. Our present study suggested that weight reduction after lifestyle modification significantly increased PTX3 levels in overweight and obese men, and the addition of habitual exercise to dietary modification enhanced the magnitude of increasing of PTX3 levels in obese individuals achieving normal weight after weight loss. PMID- 29990443 TI - Arsenic-hypertolerant and arsenic-reducing bacteria isolated from wells in Tucuman, Argentina. AB - Arsenic-hypertolerant bacteria were isolated from arsenic-contaminated well water from the village of Los Pereyra in Tucuman province, Argentina. Microorganisms that biotransform arsenic are a major factor in arsenic mobilization in contaminated aquifers. Groundwater analyses showed a level of arsenic contamination (mean concentration of 978 MUg.L-1) that exceeds the safe drinking water limit of 10 MUg.L-1 recommended by the World Health Organization and the Argentine Food Code. There was considerable spatial variability in the concentration of arsenic in each of the wells analyzed and in the distribution of the major anions HCO3-, SO42-, and Cl-. Eighteen bacterial strains were characterized. Six strains belonging to the Actinobacteria phylum were able to grow in media with 20 mmol.L-1 As(III) or 200 mmol.L-1 As(V) and were also highly resistant to Cr, Cd, and Cu. Their ability to biotransform arsenic was examined by speciation of the products by high-performance liquid chromatography inductively coupled plasma mass spectrometry. In addition, two strains, Brevibacterium sp. strain AE038-4 and Microbacterium sp. strain AE038-20, were capable of aerobic arsenate reduction, which suggests that these strains could increase the mobility of arsenic by formation of more mobile As(III). PMID- 29990444 TI - Three Salmonella enterica serovar Enteritidis bacteriophages from the Siphoviridae family are promising candidates for phage therapy. AB - Salmonella is a common and widely distributed foodborne pathogen that is frequently implicated in gastrointestinal infections. The emergence and spread of Salmonella strains resistant to multiple antibiotics poses a significant health threat, highlighting the urgent need for early and effective therapeutic strategies. We isolated a total of 32 phages from water samples and anal swabs from pigs. Of these, three phages that produced large, clear plaques were selected for further study using the following methods: electron microscopy, analysis of the life cycle parameters, genetic analysis, inhibition of bacterial growth, and activity against biofilms. The three Salmonella phages (vB_SenS_CSP01, vB_SenS_PHB06, and vB_SenS_PHB07) were assigned to the family Siphoviridae on the basis of their morphology. All showed polyvalent infectivity, and individual phages or phage cocktails could inhibit the growth of host Salmonella enterica serovar Enteritidis strains or reduce biofilm formation by Salmonella enterica serovar Typhimurium. In summary, these three phages merit further research as biocontrol agents for Salmonella infection. PMID- 29990445 TI - Are Canadian protein and physical activity guidelines optimal for sarcopenia prevention in older adults? AB - Aging is characterized by physiological and morphological changes that affect body composition, strength, and function, ultimately leading to sarcopenia. This condition results in physical disability, falls, fractures, poor quality of life, and increased health care costs. Evidence suggests that increased consumption of dietary protein and physical activity levels, especially resistance exercise, can counteract the trajectory of sarcopenia. Canadian guidelines for protein intake and physical activity were last updated in 2005 and 2011, respectively, and new evidence on sarcopenia diagnosis, prevention, and treatment is rapidly evolving. Protein recommendations are set as "one-size-fits-all" for both young and older adults. Recent evidence demonstrates that current recommendations are insufficient to meet the minimum protein requirement to counteract muscle loss and to stimulate hypertrophy in healthy older adults. Beyond quantity, protein quality is also essential to benefit muscle anabolism in older adults. In terms of physical activity, resistance exercise training is a potential strategy to counteract age-related effects, as it can elicit muscle hypertrophic response in addition to increases in muscle strength and function in older adults. Canadian physical activity guidelines lack details on how this modality of training should be performed. Current guidelines for protein intake and physical activity do not reflect recent knowledge on sarcopenia prevention. The gap between guidelines and the latest evidence on the maintenance and promotion of older adult's health highlight the need for updated protein and physical activity recommendations. PMID- 29990446 TI - Hitting the Target: Mathematical Attainment in Children Is Related to Interceptive-Timing Ability. AB - Interceptive timing is a fundamental ability underpinning numerous actions (e.g., ball catching), but its development and relationship with other cognitive functions remain poorly understood. Piaget suggested that children need to learn the physical rules that govern their environment before they can represent abstract concepts such as number and time. Thus, learning how objects move in space and time may underpin the development of related abstract representations (i.e., mathematics). To test this hypothesis, we captured objective measures of interceptive timing in 309 primary school children (5-11 years old), alongside scores for general motor skill and national standardized academic attainment. Bayesian estimation showed that interceptive timing (but not general motor capability) uniquely predicted mathematical ability even after we controlled for age, reading, and writing attainment. This finding demonstrates that interceptive timing is distinct from other motor skills with specificity in predicting childhood mathematical ability independently of other forms of attainment and motor capability. PMID- 29990447 TI - Phylogenetic Position of Pseudosellacotyla lutzi (Freitas, 1941) (Digenea: Cryptogonimidae), A Parasite of Hoplias malabaricus (Bloch) in South America, through 28S rDNA Sequences, and New Observations of the Ultrastructure of Their Tegument. AB - The freshwater fish digenean Pseudosellacotyla lutzi ( Freitas, 1941 ) Yamaguti, 1954 has had an unsettled taxonomic history, and has at various times been classified as a member of Nanophyetidae, Heterophyidae, Microphallidae, Faustulidae, and Cryptogonimidae. Nine individual specimens of the trahira, Hoplias malabaricus (Bloch, 1794), were sampled in the Parana River basin, Parana State, Brazil; 22 specimens of P. lutzi were collected. One specimen of P. lutzi was used to obtain a sequence of the domains D1-D3 of the 28S rRNA gene, and to perform a phylogenetic analysis to assess their position and classification within Plagiorchiida. The resulting tree unequivocally shows that the species, along with acanthostomines, belong to the Cryptogonimidae, corroborating recent findings based on the morphology of the cercariae, and in the characteristics of the life cycle. In addition, the study of the ultrastructure of the tegumental spines through scanning electron microscopy allowed us to characterize them as pectinate spines possessing 3 to 8 digitiform projections at their distal end and extending from the anterior to the posterior extremity of the body. This study also provides the first molecular data for a cryptogonimid from South America. PMID- 29990448 TI - Phylogenomics, Diversification Dynamics, and Comparative Transcriptomics across the Spider Tree of Life. PMID- 29990450 TI - Fuxianhuiids. AB - Ortega-Hernandez et al. introduce fuxianhuiids, Cambrian arthropods that are important for our understaindg how the largest animal phylum evolved. PMID- 29990449 TI - Widespread vulnerability of Malagasy predators to the toxins of an introduced toad. PMID- 29990451 TI - Methanogenesis. AB - Methanogenesis is an anaerobic respiration that generates methane as the final product of metabolism. In aerobic respiration, organic matter such as glucose is oxidized to CO2, and O2 is reduced to H2O. In contrast, during hydrogenotrophic methanogenesis, H2 is oxidized to H+, and CO2 is reduced to CH4. Although similar in principle to other types of respiration, methanogenesis has some distinctive features: the energy yield is very low, <=1 ATP per methane generated, and only methanogens - organisms capable of this specialized metabolism - carry out biological methane production. Methanogens, like the process they catalyze, are similarly distinctive. Methanogens are comprised exclusively of archaea. They are obligate methane producers, that is, they do not grow using fermentation or alternative electron acceptors for respiration. Finally, methanogens are strict anaerobes and do not grow in the presence of O2. Historically, methanogenesis has been viewed as a highly specialized metabolism restricted to a narrow group of prokaryotes. However, recent developments have revealed enormous diversity within the methanogens and suggest that this metabolism is one of the most ancient on earth. PMID- 29990452 TI - How does the insect central complex use mushroom body output for steering? AB - Research on central brain areas in Drosophila and other insects is revealing the highly conserved neural circuitries in the central complex that are responsible for course control using visual, ideothetic and compass cues [1,2], and in the mushroom bodies that hold long-term visual and olfactory memories [3,4]. Interactions between these areas are likely to be particularly important for navigation in which long-term memories determine an insect's course. Many ants, for example, use long-term visual memories for guidance along routes between their nest and food sites. But the interactions remain a puzzle: both because there are no known direct connections between mushroom body and central complex, and because the output from the mushroom body, where the route memories are probably stored [5], may simply signal whether a sensory input is attractive or aversive [4]. Extrapolating from a recent behavioural finding [6], we propose one way that the long-term memories in the mushroom body may be transformed into central complex steering commands. This answer, if correct, may reconcile two apparently conflicting ways of thinking about route following - suggesting how steering along a route can use a feedback controller based on a few prominent features [7], while the route memories themselves are holistic memories of the entire panorama [5]. It also suggests how visual navigation is related to (and possibly evolved from) visual targeting and olfactory-based guidance. PMID- 29990453 TI - Strengthening functionally specific neural pathways with transcranial brain stimulation. AB - Cortico-cortical paired associative stimulation (ccPAS) is a recently established offline dual-coil transcranial magnetic stimulation (TMS) protocol [1-3] based on the Hebbian principle of associative plasticity and designed to transiently enhance synaptic efficiency in neural pathways linking two interconnected (targeted) brain regions [4,5]. Here, we present a new 'function-tuning ccPAS' paradigm in which, by pairing ccPAS with the presentation of a specific visual feature, for example a specific motion direction, we can selectively target and enhance the synaptic efficiency of functionally specific, but spatially overlapping, pathways. We report that ccPAS applied in a state-dependent manner and at a low intensity selectively enhanced detection of the specific motion direction primed during the combined visual-TMS manipulations. This paradigm significantly enhances the specificity of TMS-induced plasticity, by allowing the targeting of cortico-cortical pathways associated with specific functions. PMID- 29990455 TI - Auditory Perception: Laurel and Yanny Together at Last. AB - An auditory illusion caught the world's attention recently. For the same noisy speech utterance, different people reported hearing either 'Laurel' or 'Yanny'. The dichotomy highlights how perceptions are inferences from inherently ambiguous sensory information, even though ambiguity is often unnoticed. PMID- 29990454 TI - Sensory Biology: How to Structure a Tailor-Made Retina. AB - A new study of the zebrafish retina using sophisticated imaging has revealed how anisotropic properties of the retina are closely matched to the statistics of the natural visual world that the fish experiences. PMID- 29990456 TI - Cell Competition: How to Take Over the Space Left by Your Neighbours. AB - Fast-growing cells can expand in a tissue by eliminating and replacing the neighbouring wild-type cells. A new study provides an elegant explanation for how cell elimination contributes to the preferential expansion of the invading population. PMID- 29990457 TI - Communication: Potassium Channels Define the Dialect. AB - Weakly electric fishes use electric pulses to interact with conspecifics, but the molecular origin of species-specific communication is unknown. A new study shows that some properties of the electric fish 'language' are dictated by the activity of a voltage-gated potassium channel in electrocytes. PMID- 29990458 TI - Social Behavior: How the Brain Thinks like a Mom. AB - Becoming a parent changes our choices and actions. Identifying the underlying neural circuits is necessary to understand the transformation of an animal's behavior post-parenthood. Multiple nodes of the 'parenting circuit' have now been identified to reveal the workings of a single brain region key to the orchestration of parent-specific behaviors. PMID- 29990459 TI - Neuroscience: The Key to Consciousness May Not Be under the Streetlight. AB - Key theories of consciousness predict that the prefrontal cortex (PFC) plays important roles, but there has been relatively little causal evidence showing that manipulation of activity in the region can broadly affect conscious experiences. A new study provides crucial findings to help resolve this issue, showing that direct pharmacological stimulation of PFC restores wakefulness in anesthetized rats. PMID- 29990460 TI - Social Evolution: Selection on Multiple Cooperative Traits Optimizes Cost-Benefit Relationships. AB - Cooperation is potentially risky in a population where non-producing cheats can reap benefits from and gain a fitness advantage over cooperators. A new study shows that cooperation can be safeguarded by selection on multiple traits. PMID- 29990461 TI - Developmental Biology: Morphogen in a Dish. AB - Reconstitution of a Hedgehog morphogen gradient in vitro and in silico reveals the architectural features of the signal transduction pathway that ensure rapid formation of a robust signalling gradient. PMID- 29990462 TI - Decision Making: How Fruit Flies Integrate Olfactory Evidence. AB - New studies show that, as in mammals, perceptual decision-making behavior in fruit flies involves the integration of sensory information that accumulates over time; this involves a process of dendritic integration that depends on the transcription factor FoxP. PMID- 29990463 TI - Clinical and Radiologic Follow-Up of Zimmer Biomet Stock Total Temporomandibular Joint Replacement After Surgical Modifications. AB - PURPOSE: The aim of this study was to evaluate the clinical and radiologic results of Zimmer Biomet stock prostheses (Jacksonville, FL) in temporomandibular joint replacement after surgical modifications during at least 1 year of follow up. PATIENTS AND METHODS: We recruited patients treated by Zimmer Biomet stock prostheses after technical modifications, including digital templates, autogenous ipsilateral bone grafting from the mandible to the fossa, salvaging of the disc remnant and suturing it to the medial aspect of the prosthesis, and fat grafts from a retromandibular incision, between 2010 and 2016. Clinical examination findings including maximal incisal opening; visual analog scale scores for pain, diet, and mandibular movement; and quality of life were compared before the operation and at least 1 year postoperatively. The status of the fossa bone graft was evaluated by computed tomography examination. RESULTS: The study comprised 38 joints in 33 patients with diagnoses including osteoarthritis, ankylosis, and neoplasm. Compared with before the operation, maximal incisal opening and visual analog scale scores for diet, function, and pain level, as well as the quality-of life survey score, were considerably improved during the last follow-up. Computed tomography scans showed all bone grafts were completely healed within the fossa 1 year after surgery. There was no ectopic bone formation, screw loosening, or component displacement or breakage. CONCLUSIONS: Our surgical modifications of Zimmer Biomet stock prostheses showed good results for at least 1 year of follow up. PMID- 29990464 TI - Radiologic scales as a tool for the etiologic diagnosis of pediatric community acquired pneumonia. PMID- 29990465 TI - Label-free and enzyme-free sensitive fluorescent method for detection of viable Escherichia coli O157:H7. AB - We have developed a label-free, enzyme-free, modification-free and DNA extraction free fluorescent aptasensing (LEFA) method for detection of E. coli O157:H7 based on G-quadruplex formation using two ingeniously designed hairpin probes (GHP1 and GHP2). In the presence of E. coli O157:H7, it released the single stranded initiation sequence (IS) resulting in the toehold strand displacement between GHP1 and GHP2, which in turn led to the cyclic reuse of the production of DNA assemblies with numerous G-quadruplex structures and initiation sequences. Then these G-quadruplex structures can be recognized quickly by N-methyl mesoporphyrin IX (NMM) resulting in significantly enhanced fluorescence. The LEFA method was successfully implemented for detecting E. coli O157:H7 with a detection limit of 66 CFU/mL in pure culture, 10 CFU/mL and 1 CFU/mL after pre-incubation of the milk and tap water for 4 and 8 h, respectively. Moreover, the strategy could distinguish viable E. coli O157:H7 from dead E. coli O157:H7 and other species of pathogen cells. Furthermore, the whole process of the strategy is accomplished within 100 min. The results indicated that the approach may be used to effectively control potential microbial hazards in human health, food safety, and animal husbandry. PMID- 29990466 TI - Beyond replicator dynamics: From frequency to density dependent models of evolutionary games. AB - Game theoretic models of evolution such as the Hawk-Dove game assume that individuals gain fitness (which is a proxy of the per capita population growth rate) in pair-wise contests only. These models assume that the equilibrium distribution of phenotypes involved (e.g., Hawks and Doves) in the population is given by the Hardy-Weinberg law, which is based on instantaneous, random pair formation. On the other hand, models of population dynamics do not consider pairs, newborns are produced by singles, and interactions between phenotypes or species are described by the mass action principle. This article links game theoretic and population approaches. It shows that combining distribution dynamics with population dynamics can lead to stable coexistence of Hawk and Dove population numbers in models that do not assume a priori that fitness is negative density dependent. Our analysis shows clearly that the interior Nash equilibrium of the Hawk and Dove model depends both on population size and on interaction times between different phenotypes in the population. This raises the question of the applicability of classic evolutionary game theory that requires all interactions take the same amount of time and that all single individuals have the same payoff per unit of time, to real populations. Furthermore, by separating individual fitness into birth and death effects on singles and pairs, it is shown that stable coexistence in these models depends on the time-scale of the distribution dynamics relative to the population dynamics. When explicit density dependent fitness is included through competition over a limited resource, the combined dynamics of the Hawk-Dove model often lead to Dove extinction no matter how costly fighting is for Hawk pairs. PMID- 29990467 TI - Symptom Based Clustering of Women in the LURN Observational Cohort Study. AB - PURPOSE: Women with lower urinary tract symptoms are often diagnosed based on a predefined symptom complex or a predominant symptom. There are many limitations to this paradigm as often patients present with multiple urinary symptoms which do not perfectly fit the preestablished diagnoses. We used cluster analysis to identify novel, symptom based subtypes of women with lower urinary tract symptoms. MATERIALS AND METHODS: We analyzed baseline urinary symptom questionnaire data obtained from 545 care seeking female participants enrolled in the LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Observational Cohort Study. Symptoms were measured with the LUTS (lower urinary tract symptoms) Tool and the AUA SI (American Urological Association Symptom Index), and analyzed using a probability based consensus clustering algorithm. RESULTS: Four clusters were identified. The 138 women in cluster F1 did not report incontinence but experienced post-void dribbling, frequency and voiding symptoms. The 80 women in cluster F2 reported urgency incontinence as well as urgency and frequency but minimal voiding symptoms or stress incontinence. Cluster F3 included 244 women who reported all types of incontinence, urgency, frequency and mild voiding symptoms. The 83 women in cluster F4 reported all lower urinary tract symptoms at uniformly high levels. All but 2 of 44 LUTS Tool and 8 AUA SI questions significantly differed between at least 2 clusters (p <0.05). All clusters contained at least 1 member from each conventional group, including continence, and stress, urgency, mixed and other incontinence. CONCLUSIONS: Women seeking care for lower urinary tract symptoms cluster into 4 distinct symptom groups which differ from conventional clinical diagnostic groups. Further validation is needed to determine whether management improves using this new classification. PMID- 29990469 TI - Direct Detection of Membrane-Inserting Fragments Defines the Translocation Pores of a Family of Pathogenic Toxins. AB - Large clostridial toxins (LCTs) are a family of homologous proteins toxins that are directly responsible for the symptoms associated with a number of clostridial infections that cause disease in humans and in other animals. LCTs damage tissues by delivering a glucosyltransferase domain, which inactivates small GTPases, across the endosomal membrane and into the cytosol of target cells. Elucidating the mechanism of translocation for LCTs has been hampered by difficulties associated with identifying marginally hydrophobic segments that insert into the bounding membrane to form the translocation pore. Here, we directly measured the membrane-insertion partitioning propensity for segments spanning the putative pore-forming region using a translocon-mediated insertion assay and synthetic peptides. We identified membrane-inserting segments, as well as a conserved and functionally important negatively charged residue that requires protonation for efficient membrane insertion. We provide a model of the LCT pore, which provides insights into translocation for this enigmatic family of alpha-helical translocases. PMID- 29990468 TI - Connecting the nutrient composition of seasonal pollens with changing nutritional needs of honey bee (Apis mellifera L.) colonies. AB - Free-ranging herbivores have yearly life cycles that generate dynamic resource needs. Honey bee colonies also have a yearly life cycle that might generate nutritional requirements that differ between times of brood rearing and colony expansion in the spring and population contraction and preparation for overwintering in the fall. To test this, we analyzed polyfloral mixes of spring and fall pollens to determine if the nutrient composition differed with season. Next, we fed both types of seasonal pollens to bees reared in spring and fall. We compared the development of brood food glands (i.e., hypopharyngeal glands - HPG), and the expression of genes in the fat body between bees fed pollen from the same (in-season) or different season (out-of-season) when they were reared. Because pathogen challenges often heighten the effects of nutritional stress, we infected a subset of bees with Nosema to determine if bees responded differently to the infection depending on the seasonal pollen they consumed. We found that spring and fall pollens were similar in total protein and lipid concentrations, but spring pollens had higher concentrations of amino and fatty acids that support HPG growth and brood production. Bees responded differently when fed in vs. out of season pollen. The HPG of both uninfected and Nosema-infected spring bees were larger when they were fed spring (in-season) compared to fall pollen. Spring bees differentially regulated more than 200 genes when fed in- vs. out-of season pollen. When infected with Nosema, approximately 400 genes showed different infection-induced expression patterns in spring bees depending on pollen type. In contrast, HPG size in fall bees was not affected by pollen type, though HPG were smaller in those infected with Nosema. Very few genes were differentially expressed with pollen type in uninfected (4 genes) and infected fall bees (5 genes). Pollen type did not affect patterns of infection-induced expression in fall bees. Our data suggest that physiological responses to seasonal pollens differ between bees reared in the spring and fall with spring bees being significantly more sensitive to pollen type especially when infected with Nosema. This study provides evidence that seasonal pollens may provide levels of nutrients that align with the activities of honey bees during their yearly colony cycle. The findings are important for the planning and establishment of forage plantings to sustain honey bees, and in the development of seasonal nutritional supplements fed to colonies when pollen is unavailable. PMID- 29990470 TI - Mechanisms of Gasdermin Family Members in Inflammasome Signaling and Cell Death. AB - The Gasdermin (GSDM) family consists of Gasdermin A (GSDMA), Gasdermin B (GSDMB), Gasdermin C (GSDMC), Gasdermin D (GSDMD), Gasdermin E (GSDME) and Pejvakin (PJVK). GSDMD is activated by inflammasome-associated inflammatory caspases. Cleavage of GSDMD by human or mouse caspase-1, human caspase-4, human caspase-5, and mouse caspase-11 liberates the N-terminal effector domain from the C-terminal inhibitory domain. The N-terminal domain oligomerizes in the cell membrane and forms a pore of 10-16 nm in diameter, through which substrates of a smaller diameter, such as interleukin-1beta and interleukin-18, are secreted. The increasing abundance of membrane pores ultimately leads to membrane rupture and pyroptosis, releasing the entire cellular content. Other than GSDMD, the N terminal domain of all GSDMs, with the exception of PJVK, have the ability to form pores. There is evidence to suggest that GSDMB and GSDME are cleaved by apoptotic caspases. Here, we review the mechanistic functions of GSDM proteins with respect to their expression and signaling profile in the cell, with more focused discussions on inflammasome activation and cell death. PMID- 29990471 TI - Transdifferentiation of Melanoma Cells by the Reprogramming Factors Attenuates Malignant Nature In Vitro and In Vivo. PMID- 29990472 TI - Methotrexate causes persistent deficits in memory and executive function in a juvenile animal model. AB - Methotrexate is a dihydrofolate reductase inhibitor widely employed in curative treatment for children with acute lymphoblastic leukemia (ALL). However, methotrexate administration is also associated with persistent cognitive deficits among long-term childhood cancer survivors. Animal models of methotrexate-induced cognitive deficits have primarily utilized adult animals. The purpose of present study is to investigate the neurotoxicity of methotrexate in juvenile rats and its relevant mechanisms. The doses and schedule of systemic and intrathecal methotrexate, given from post-natal age 3-7 weeks, were chosen to model the effects of repeated methotrexate dosing on the developing brains of young children with ALL. This methotrexate regimen had no visible acute toxicity and no effect on growth. At 15 weeks of age (8 weeks after the last methotrexate dose) both spatial pattern memory and visual recognition memory were impaired. In addition, methotrexate-treated animals demonstrated impaired performance in the set-shifting assay, indicating decreased cognitive flexibility. Histopathological analysis demonstrated decreased cell proliferation in methotrexate-treated animals compared to controls, as well as changes in length and thickness of the corpus callosum. Moreover, methotrexate suppressed microglia activation and RANTES production. In conclusion, our study demonstrated that a clinically relevant regimen of systemic and intrathecal methotrexate induces persistent deficits in spatial pattern memory, visual recognition memory and executive function, lasting at least 8 weeks after the last injection. The mechanisms behind methotrexate-induced deficits are likely multifactorial and may relate to suppression of neurogenesis, alterations in neuroinflammation and microglial activation, and structural changes in the corpus callosum. PMID- 29990473 TI - The effects of alpha-lipoic acid supplementation on glucose control and lipid profiles among patients with metabolic diseases: A systematic review and meta analysis of randomized controlled trials. AB - OBJECTIVE: This systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to summarize the effect of alpha-lipoic acid (ALA) supplementation on glycemic control and lipid profiles among patients with metabolic diseases. METHODS: We searched the following databases till October 2017: MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials. The relevant data were extracted and assessed for quality of the studies according to the Cochrane risk of bias tool. Data were pooled using the inverse variance method and expressed as standardized mean difference (SMD) with 95% confidence intervals (95% CI). Heterogeneity between studies was assessed by the Cochran Q statistic and I-squared tests (I2). Twenty-four studies were included in the meta-analyses. RESULTS: The findings of this meta-analysis showed that ALA supplementation among patients with metabolic diseases significantly decreased fasting glucose (SMD -0.54; 95% CI, -0.89, -0.19; P = 0.003), insulin (SMD -1.01; 95% CI, -1.70, -0.31; P = 0.006), homeostasis model assessment of insulin resistance (SMD -0.76; 95% CI, -1.15, -0.36; P < 0.001) and hemoglobin A1c (SMD 1.22; 95% CI, -2.01, -0.44; P = 0.002), triglycerides (SMD -0.58; 95% CI, -1.00, 0.16; P = 0.006), total- (SMD -0.64; 95% CI, -1.01, -0.27; P = 0.001), low density lipoprotein-cholesterol (SMD -0.44; 95% CI, -0.76, -0.11; P = 0.008). We found no detrimental effect of ALA supplementation on high density lipoprotein cholesterol (HDL-cholesterol) levels (SMD 0.57; 95% CI, -0.14, 1.29; P = 0.11). CONCLUSIONS: Overall, the current meta-analysis demonstrated that ALA administration may lead to an improvement in glucose homeostasis parameters and lipid profiles except HDL-cholesterol levels. PMID- 29990474 TI - TPC2 mediates autophagy progression and extracellular vesicle secretion in cancer cells. AB - Autophagy is an evolutionarily conserved lysosomal degradation process, and is involved in various cellular processes. Here we studied the role of two pore channel 2 (TPC2), a lysosomal non-selective Na+/Ca2+ channel, in autophagy progression. We found that TPC overexpression in 4T1 mouse breast cancer cell line or in HeLa human cervical cancer cell line inhibited the fusion between autophagosome and lysosome, resulting in the accumulation of autophagosomes accompanied with increased lysosomal pH and TFEB nuclear localization. Interestingly, we also found that extracellular vesicle (EV) secretion was markedly decreased in TPC2 overexpressing cells but was induced in TPC2 knockdown cells. In addition, migration of TPC2 knockdown cells, not TPC2 overexpressing cells, was inhibited. Taken together, these results support a role of TPC2 in autophagy progression and EV trafficking in cancer cells. PMID- 29990476 TI - Administrator Perspectives of Patient-Centered and Culturally Appropriate Reproductive Health Care for Women From Somalia. AB - OBJECTIVE: To explore health care administrators' perspectives on (a) institutional values, practices, and policies on the provision of patient- and family-centered and culturally appropriate reproductive health care for women from Somalia; (b) limitations imposed by these institutional values, practices, and policies; and (c) strategies to address these limitations. DESIGN: An exploratory single case study with in-person interviews and institutional document analysis guided by critical theory. SETTING: A Level 4 academic medical center on the West Coast of the United States. PARTICIPANTS: Eleven health care administrators employed at the study site. METHODS: Administrators participated in semistructured interviews after reading a prototypical vignette to contextualize the clinical encounter of a Somali woman with health care providers. Data from interviews were analyzed using a deductive structural coding process. Institutional documents were analyzed to identify values, policies, and practices regarding patient- and family-centered and culturally appropriate care for women from Somalia. RESULTS: The overarching theme was Our institution respects diversity and patient- and family-centered care. The subthemes that emerged were Current practices are important but difficult to institute, Current institutional policies are good but too nonspecific to follow, and Engagement between the provider and woman is of value but difficult to enact. Recommendations to address these contrasts fell into two categories: pragmatic planning and changing the paradigm of care. CONCLUSION: Cultural barriers, limitations caused by structural factors, and competing provider-patient paradigms contribute to challenges for many providers when caring for Somali women in some U.S. health care systems. Specific policies and training to provide culturally appropriate reproductive care for Somali women are imperative. PMID- 29990477 TI - Assessment of Fasciola hepatica glutathione S-transferase as an antigen for serodiagnosis of human chronic fascioliasis. AB - Due to the unsatisfactory performance of parasitological diagnosis of human fascioliasis; the use of immunodiagnosis based on the detection of anti-Fasciola antibodies is traditionally used as a diagnostic alternative using total or purified parasite excretory-secretory products (ESPs). Glutathione S-transferase (GST) protein, one of the F. hepatica ESP components, possesses well-known roles in the detoxification of xenobiotic and endogenously derived toxins within the host bile environment. GST has shown to be a good target for vaccine or drug development against fascioliasis. The current study aimed to evaluate the potential of GST protein purified from a soluble crude extract of adult flukes as an antigen for serodiagnosis of chronic human fascioliasis by indirect ELISA. The study included a panel of 116 serum samples collected from individuals with confirmed fascioliasis, individuals carrying heterologous parasitic infections and healthy subjects. The parasitological examination was used as gold standard and a previously optimized ESP-ELISA was used to compare the performance of the GST-ELISA method. Results demonstrated that GST-ELISA is 94.3% sensitive, 80.2% specific and exhibits a moderate positive correlation (r = 0.555) and substantial agreement (k = 0.786) with the results obtained with the ESP-ELISA method. Moreover, because no sera from patients with early F. hepatica infection were available, GST-ELISA was then tested with sera from rabbits experimentally infected with F. hepatica metacercariae. The assay was able to detect anti Fasciola antibodies as early as the 3rd week of infection (p < 0.0001) with peaks at 4th and 10th week post-infection. PMID- 29990475 TI - Gsx transcription factors control neuronal versus glial specification in ventricular zone progenitors of the mouse lateral ganglionic eminence. AB - The homeobox gene Gsx2 has previously been shown to inhibit oligodendroglial specification in dorsal lateral ganglionic eminence (dLGE) progenitors of the ventral telencephalon. The precocious specification of oligodendrocyte progenitor cells (OPCs) observed in Gsx2 mutants, however, is transient and begins to normalize by late stages of embryogenesis. Interestingly, this normalization correlates with the expansion of Gsx1, a close homolog of Gsx2, in a subset of progenitors in the Gsx2 mutant LGE. Here, we interrogated the mechanisms underlying oligodendroglial specification in Gsx2 mutants in relation to Gsx1. We found that Gsx1/2 double mutant embryos exhibit a more robust expansion of Olig2+ cells (i.e. OPCs) in the subventricular zone (SVZ) of the dLGE than Gsx2 mutants. Moreover, misexpression of Gsx1 throughout telencephalic VZ progenitors from E15 and onward resulted in a significant reduction of cortical OPCs. These results demonstrate redundant roles of Gsx1 and Gsx2 in suppressing early OPC specification in LGE VZ progenitors. However, Gsx1/2 mutants did not show a significant increase in adjacent cortical OPCs at later stages compared to Gsx2 mutants. This is likely due to reduced proliferation of OPCs within the SVZ of the Gsx1/2 double mutant LGE, suggesting a novel role for Gsx1 in expansion of migrating OPCs in the ventral telencephalon. We further investigated the glial specification mechanisms downstream of Gsx2 by generating Olig2/Gsx2 double mutants. Consistent with the known essential role for Olig2 in OPC specification, ectopic production of cortical OPCs observed in Gsx2 mutants disappeared in Olig2/Gsx2 double mutants. These mutants, however, maintained the expanded expression of gliogenic markers Zbtb20 and Bcan in the VZ of the LGE similarly to Gsx2 single mutants, suggesting that Gsx2 suppresses gliogenesis via Olig2 dependent and -independent mechanisms. PMID- 29990478 TI - Respiratory Failure in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis is a progressive neuromuscular disease characterized by both lower motor neuron and upper motor neuron dysfunction. Although clinical presentations can vary, there is no cure for ALS, and the disease is universally terminal, with most patients dying of respiratory complications. Patients die, on average, within 3 to 5 years of diagnosis, unless they choose to undergo tracheostomy, in which case, they may live, on average, 2 additional years. Up to 95% of patients with ALS in the United States choose not to undergo tracheostomy; management of respiratory failure is therefore aimed at both prolonging survival as well as improving quality of life. Standard of care for patients with ALS includes treatment from multidisciplinary teams, but many patients do not have consistent access to a pulmonary physician who regularly sees patients with this disease. The goal of this review was to serve as an overview of respiratory considerations in the management of ALS. This article discusses noninvasive ventilation in the management of respiratory muscle weakness, mechanical insufflation/exsufflation devices for airway clearance, and treatment of aspiration, including timing of placement of a percutaneous endoscopic gastrostomy tube, as well as secretion management. In addition, it is important for physicians to consider end-of-life issues such as advanced directives, hospice referral, and ventilator withdrawal. PMID- 29990479 TI - Indwelling Pleural Catheters in Hepatic Hydrothorax: A Single-Center Series of Outcomes and Complications. AB - BACKGROUND: Treatment of hepatic hydrothorax (HH) generally involves sodium restriction, diuretics, and serial thoracentesis. In more advanced cases, transjugular intrahepatic portosystemic shunt and liver transplantation may be required. Previously, indwelling tube drainage has been avoided due to concerns regarding high complication rates and overall poor outcomes. Recently, indwelling pleural catheters (IPCs) have been proposed as a novel treatment option for HH. METHODS: This study was a retrospective review of patients who had undergone IPC placement for HH over a 10-year period at a large liver transplant referral center. We tracked outcomes, including complication rates and liver transplantation, as well as biomarkers of nutritional status. RESULTS: Sixty-two patients underwent IPC placement between 2007 and 2017, with 33 IPCs (53%) placed as a bridge to liver transplantation. Complications were recorded in 22 patients (36%); empyema was the most common, diagnosed in 10 patients (16.1%). Ten patients evaluated for liver transplantation underwent successful transplantation following IPC placement. There were statistically significant decreases in both BMI and serum albumin levels following IPC placement. CONCLUSIONS: IPCs represent a potential treatment for refractory HH and should be used with caution in patients eligible for liver transplantation. Ideally, IPC use for these patients would be evaluated by a multidisciplinary team. IPC use may lead to small decreases in BMI and serum albumin levels in patients over time. PMID- 29990480 TI - Transformation of naturally occurring (3R,3'R,6'R)-lutein and its fatty acid esters to (3 R)-beta-cryptoxanthin and (3R,6'R)-alpha-cryptoxanthin. AB - The objective of this study was to develop straightforward processes that could be applied to the large-scale production of beta-cryptoxanthin in an attempt to facilitate investigation of its biological activity. An oleoresin obtained from crude extracts of marigold flowers (Tagetes erecta) with approximately 24% total lutein fatty acid ester content was directly used as starting material for partial synthesis of (3 R)-beta-cryptoxanthin under mild reaction conditions at ambient temperature. Therefore, acid-catalyzed deoxygenation of lutein esters from marigold oleoresin followed by hydrogenation in the presence of catalytic amount of platinum (Pt) supported on alumina (5%) at ambient temperature gave a mixture of (3 R)-beta-cryptoxanthin fatty acid esters (major) and (3 R,6'R)-alpha cryptoxanthin fatty acid esters (minor). Saponification and Z-to-E isomerization of the product followed by crystallization gave a mixture of (3 R)-beta cryptoxanthin as the major product. Similarly, acid-catalyzed hydrogenation of unesterified (3 R,3'R,6'R)-lutein with Pt/alumina in ethyl acetate gave a mixture of (3 R,6'R)-alpha-cryptoxanthin acetate (minor) in a one-pot reaction. Alkaline hydrolysis and Z-to-E isomerization of the mixture followed by crystallization provided (3 R)-beta-cryptoxanthin. PMID- 29990481 TI - Catalytic bioscavengers as countermeasures against organophosphate nerve agents. AB - Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures against OPNA intoxications are aimed at mitigating their symptoms, but are unable to effectively prevent them. In addition, they may fail to prevent the onset of a cholinergic crisis in the brain and its secondary toxic manifestations. The need for improved medical countermeasures has led to the development of bioscavengers; proteins and enzymes that may prevent intoxication by binding and inactivating OPNAs before they can reach their target organs. Non-catalytic bioscavengers such as butyrylcholinesterase, can rapidly bind OPNA molecules in a stoichiometric and irreversible manner, but require the administration of large protein doses to prevent intoxication. Thus, many efforts have been made to develop catalytic bioscavengers that could rapidly detoxify OPNAs without being inactivated in the process. Such enzymes may provide effective prophylactic protection and improve post-exposure treatments using much lower protein doses. Here we review attempts to develop catalytic bioscavengers using molecular biology, directed evolution and enzyme engineering techniques; and natural or computationally designed enzymes. These include both stoichiometric scavengers and enzymes that can hydrolyze OPNAs with low catalytic efficiencies. We discuss the catalytic parameters of evolved and engineered enzymes and the results of in-vivo protection and post-exposure experiments performed using OPNAs and bioscavengers. Finally, we briefly address some of the challenges that need to be met in order to transition these enzymes into clinically approved drugs. PMID- 29990482 TI - Peripapillary fluorescence lifetime reveals age-dependent changes using fluorescence lifetime imaging ophthalmoscopy in rats. AB - Many fundus diseases accompany fundus autofluorescence change. Fluorescence lifetime imaging ophthalmoscope (FLIO) is a latest technique in imaging fundus autofluorescence. With FLIO, the fundus fluorescence lifetime (FLT) is recorded topographically, assisting to diagnose and monitor multiple fundus diseases. The purpose of this study was to evaluate the repeatability of FLT using FLIO on adult rats and to analyze the age-dependency of the peripapillary FLT of the fundus in a short spectral channel (498-560 nm) and a long spectral channel (560 720 nm). Sprague Dawley rats (n of eyes = 10) were used for repeatability experiments. Age-dependent changes were investigated in young (two months old, n of eyes = 20) and old (eight months old, n of eyes = 10) rats. Repeatability experiments showed highly corresponding data for all segments in both spectral channel, with higher repeatability in the short spectral channel. FLT decreased significantly in all areas in the short (young: 991 +/- 29 ps; old: 547 +/- 42 ps) and long (young: 382 +/- 28 ps; old: 261 +/- 16 ps) spectral channels, indicating an overall metabolic change of the fundus in old animals. FLT of veins increased in the short spectral channel (young: 385 +/- 43 ps; old: 424 +/- 25 ps) and no change was observed in the long spectral channel (young: 274 +/- 9 ps; old: 269 +/- 24 ps). FLIO represents a highly repeatable and sensitive method to detect changes of the FLT in aged eyes for monitoring the degeneration of the rodent retinae. PMID- 29990483 TI - Sini decoction alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis. AB - AIMS: Acute respiratory distress syndrome (ARDS), one of the serious form of acute lung injury (ALI), is the primary cause of death in patients with ALI. Sini decoction (SND) is a widely used Traditional Chinese Medicine (TCM). However, the application of SND in ALI is rarely reported. Previous studies have found that renin-angiotensin-aldosterone system (RAAS) played vital and bidirectional roles in ALI. Therefore, the aim of the present study was to investigate protective effect of SND on ALI model induced by E. coli, as well as to further explore relations between RAAS and SND. MATERIALS AND METHODS: The ALI model was evaluated by morphological observations and biochemical assays. The expression levels of angiotensin converting enzyme (ACE), Angiotensin II type 1 receptor (AT1R) and angiotensin converting enzyme 2 (ACE2) were examined by Western blotting. The expression levels of angiotensinII (AngII) and angiotensin-(1-7) (Ang-(1-7)) were measured through ELISA. MasR, IL-6, IL-1beta and TNFalpha were all measured using qRT-PCR. KEY FINDINGS: SND significantly ameliorated E. coli induced ALI, including reducing inflammatory factors in lung tissue and the activity of MPO in serum. Furthermore, SND could obviously decrease the expression of ACE, AngII and AT1R, which were induced by E. coli. On the other hand, SND could markedly activate ACE2-Ang-(1-7)-Mas pathway. SIGNIFICANCE: In this paper, we demonstrated that SND alleviates E. coli induced acute lung injury in mice via equilibrating ACE-AngII-AT1R and ACE2-Ang-(1-7)-Mas axis. PMID- 29990484 TI - COX inhibitors and bone: A safer impact on osteoblasts by NO-releasing NSAIDs. AB - : Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of pain and inflammation. Although it is well known that NSAIDs can suppress bone growth, remodelling and repair, they are largely used post operatively and post-traumatically to achieve analgesia and reduce inflammation in bone tissue. AIMS: The impact of two NO-releasing, non-selective NSAIDs, NCX 4016 and HCT-3012 (NO-derivatives of Aspirin and Naproxen, respectively) on osteoblasts were evaluated and compared to the non-selective, parent chemicals and to the COX-2-selective inhibitor Celecoxib. MAIN METHODS: Using MG-63 osteoblast-like cells, we considered proliferation, the early and late stage of differentiation, and the activity of proteinases thought to be involved in osteoid degradation, a preliminary fundamental event of bone remodelling. KEY FINDINGS: Unlike Aspirin, Naproxen and Celecoxib, the two NO-NSAIDs did not alter proliferation and differentiation of osteoblasts. They also reduced the activity of plasminogen activator, metalloproteinases, and cathepsin B. Similar inhibitory effects against these proteinases were recapitulated by the NO-donor sodium nitroprusside, thereby suggesting a NO-mediated mechanism. SIGNIFICANCE: Due to a differential effect on cell proliferation and differentiation, the two NO-NSAIDs exhibit a safer impact on osteoblast metabolism compared to Celecoxib and their parent compounds. This suggests an advantageous option for these drugs in individuals with a need of COX-inhibiting treatment, in general. In addition, their capability of modulating the proteinases involved in osteoid degradation may specifically suggest an additional safer use in comorbidity conditions of inflammation or pain with bone disorders characterized by high rate of remodelling, such as high-turnover osteoporosis in post-menopausal women. PMID- 29990485 TI - Multiparametric radiomics improve prediction of lymph node metastasis of rectal cancer compared with conventional radiomics. AB - AIMS: To establish multiparametric radiomics of rectal tumor for the preoperative prediction of lymph node (LN) metastasis. MATERIALS AND METHODS: This prospective study consisted of 115 consecutive patients with rectal carcinoma between April 2015 and April 2017. The multiparametric radiomics scores were extracted from the endorectal ultrasound (ERUS), computed tomography (CT) and shear-wave elastography (SWE) features of the rectal tumor, LN, and peripheral tissues. The three radiomics scores were generated. Further validation as an independent predictor was performed using multivariate logistic regression together with clinical data, and a nomogram was subsequently developed. The predictive performance of the multiparametric radiomics nomogram was compared with that of conventional radiomics. KEY FINDINGS: All three scores (ERUS, CT, and SWE) were significantly higher in patients with LN metastasis than in patients with negative LN metastasis (all P < 0.05) in both training and validation set. Multivariate analysis indicated that CT and SWE scores were independent risk variables (odds ratio, OR = 6.764 and 5.482, respectively). In validation cohort, the multiparametric radiomics nomogram showed the highest predictive accuracy for LN metastasis, with a concordance index (C-index) of 0.857 compared with the conventional radiomics nomogram (C-index, 0.703, P = 0.100), resulting in a significantly improved net reclassification index (NRI) (P < 0.05) and integrated discriminatory improvement (IDI) (P = 0.002). Decision curve analysis showed that the multiparametric radiomics nomogram had a higher overall net benefit. SIGNIFICANCE: Multiparametric radiomics of rectal cancer, which captures blood supply and stiffness phenotypes, is a useful tool for predicting LN metastasis preoperatively and has marked discrimination accuracy compared to conventional radiomics. PMID- 29990486 TI - Melatonin restrains angiogenic factors in triple-negative breast cancer by targeting miR-152-3p: In vivo and in vitro studies. AB - AIMS: Breast cancer represents the second most prevalent tumor-related cause of death among women. Although studies have already been published regarding the association between breast tumors and miRNAs, this field remains unclear. MicroRNAs (miRNAs) are defined as non-coding RNA molecules, and are known to be involved in cell pathways through the regulation of gene expression. Melatonin can regulate miRNAs and genes related with angiogenesis. This hormone is produced naturally by the pineal gland and presents several antitumor effects. The aim of this study was to understand the action of melatonin in the regulation of miRNA 152-3p in vivo and in vitro. MAIN METHODS: In order to standardize the melatonin treatment in the MDA-MB-468 cells, we carried out the cell viability assay at different concentrations. PCR Array plates were used to identify the differentiated expression of miRNAs after the treatment with melatonin. The relative quantification of the target gene expression (IGF-IR, HIF-1alpha and VEGF) was performed by real-time PCR. For the tumor development, MDA-MB-468 cells were implanted in female BALB/c mice, and treated or not treated with melatonin. Moreover, the quantification of the target genes protein expression was performed by immunocytochemistry and immunohistochemistry. KEY FINDINGS: Relative quantification shows that the melatonin treatment increases the gene expression of miR-152-3p and the target genes, and decreased protein levels of the genes both in vitro and in vivo. SIGNIFICANCE: Our results confirm the action of melatonin on the miR-152-3p regulation known to be involved in the progression of breast cancer. PMID- 29990487 TI - Prevalence of Antibiotic Resistance in Helicobacter pylori: A Systematic Review and Meta-analysis in World Health Organization Regions. AB - BACKGROUND & AIMS: In 2017, the World Health Organization (WHO) designated clarithromycin-resistant Helicobacter pylori a high priority for antibiotic research and development. However, there are no clear data on the global distribution of resistance or its clinical effects. We performed a systematic review and meta-analysis to assess the distribution of H pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure. METHODS: We searched publication databases for studies that assessed rates of H pylori resistance to clarithromycin, metronidazole, levofloxacin, amoxicillin, or tetracycline. Pooled estimates of primary and secondary resistance and 95% confidence intervals (CIs) were grouped by WHO region. The association between antibiotic resistance and treatment failure was measured by extracting data on treatment efficacy in patients with resistant and susceptible isolates and pooling odds ratios with 95% CIs. RESULTS: We identified 178 studies, comprising 66,142 isolates from 65 countries. Primary and secondary resistance rates to clarithromycin, metronidazole, and levofloxacin were >=15% in all WHO regions, except primary clarithromycin resistance in the Americas (10%; 95% CI, 4%-16%) and South-East Asia region (10%; 95% CI, 5%-16%) and primary levofloxacin resistance in the European region (11%; 95% CI, 9%-13%). There was considerable heterogeneity (I2 > 75%) among all analyses-this might have resulted from the grouping of resistance rates by country. Increasing antibiotic resistance was observed in most WHO regions. Resistance to clarithromycin was significantly associated with failure of clarithromycin containing regimens (odds ratio, 6.97; 95% CI, 5.23-9.28; P < .001). CONCLUSIONS: Resistance of H pylori to antibiotics has reached alarming levels worldwide, which has a great effect on efficacy of treatment. Local surveillance networks are required to select appropriate eradication regimens for each region. PMID- 29990489 TI - WITHDRAWN: Physical aggression and attentional bias to angry faces: An event related potential study. AB - This article has been withdrawn at the request of the authors. The authors have opted to update their article and have resubmitted it to the journal as a new submission. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29990490 TI - Distributed performance of white matter properties in chess players: A DWI study using automated fiber quantification. AB - The aim of this study is to verify whether anatomical changes occur in the brains of chess players. Besides, it is a potential attempt to evaluate diffusion properties along the tracts due to the diverse situations at anatomical level in different locations; moreover, conventional voxel-based analysis (VBA) has already been used to calculate the average values within the voxels in the investigated regions as analysis data. In this study, we used automated fiber quantification (AFQ) to automatically identify the major tracts that are related to functional domains of the human brain. AFQ can quantify pointwise white matter (WM) properties to detect specific local differences. We selected chess players with superior logical cognition abilities as the carrier to conduct our AFQ experiments. The diffusion properties of the 20 major tracts of professional chess players (n = 28) and matched controls (n = 29) were calculated using diffusion weighted imaging (DWI) data. We noted significant differences (p < 0.05) in the diffusion properties of some successive locations among 100 equidistant points in several tracts, especially in the left superior longitudinal fasciculus(SLF) and right inferior fronto-occipital fasciculus (IFOF). Professional chess players exhibited increase levels in the studied diffusion metrics with Pearson results paralleled the findings. Afterwards, considering the starting and terminating regions of SLF, IFOF, and thalamic radiation, the connectivity of gray matter (GM) where connections are active in the frontal lobe, temporal lobe, and thalamus was assessed to help with the further experiment. The results confirmed the tendency in which anatomical alterations generated different performances along the tracts; furthermore, long term cognitive activities, such as chess, may systematically influence the WM properties of early memory, attention, and visual pathways. PMID- 29990488 TI - Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. AB - BACKGROUND & AIMS: Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. METHODS: We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. RESULTS: The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis-including those given placebo-had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (-0.2%, 95% confidence interval [CI] -1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (-0.4%, 95% CI -1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI -1.2 to 1.5, P = .84 for 200 mg; 95% CI -1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups. CONCLUSION: In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879. PMID- 29990491 TI - Evolution of cerebral perfusion in the peri-contusional cortex in mice revealed by in vivo laser speckle imaging after traumatic brain injury. AB - The role of the cerebrovascular network during the acute and chronic phases after traumatic brain injury (TBI) is poorly defined and emerging evidence suggests that cerebral perfusion is altered. The purpose of this study is to explore how the cortical blood flow is pathologically altered following TBI using a newly developed technique, laser speckle imaging. The controlled cortical impact (CCI) model was established in mice. Then, cerebral blood flow was monitored in vivo laser speckle imaging and vessel painting was labeled by Lectin in the peri contusional cortex. Lastly, mice were assessed for lesion size and neurological functions. Our results indicated that: 1) In the acute phase of TBI, cerebral blood flow and microvessel counts decreased significantly (P < 0.05) 2) In the chronic phase of TBI, cerebral blood flow and microvessel counts recovered gradually (P < 0.05) 3) Cortical lesion volume reduced significantly in the chronic phase of TBI (P < 0.05) 4) Spontaneous neurocognitive recovery occurred following CCI in mice (P < 0.05). In the acute phase of TBI, there is a reduction in cerebral perfusion at the lesion site. However, this reduction recovers in the chronic phase of TBI ultimately, followed by an improvement of ameliorated neurobehavioral functions and a decrease in the lesion size. The novel approach for cerebral blood flow monitoring by laser speckle imaging can be extended from bench to bedside and provide potential therapeutic strategies for TBI patients. PMID- 29990492 TI - Sex determination in Neotropical fish: Implications ranging from aquaculture technology to ecological assessment. AB - The high biodiversity of fish in the Neotropical region contrasts with scarce or biased studies on the mechanisms involved in the sex determination in members of this fauna. In this review, we attempted to compile the information available on determination, differentiation, and manipulation of sex for Neotropical species, with special focus on silversides and other two speciose groups, known as characins (Characiformes) and catfishes (Siluriformes). Currently, there is plenty of information available on chromosomal sex determination systems, which includes both male and female heterogamety with many variations, and sex chromosomes evolution at the macro chromosomal level. However, there is hitherto a blank in information at micro, gene/molecule levels and in research related to the effects of environmental cues on sex determination; most of reported studies are limited to silversides and guppies. In view of such a high diversity, it is critically necessary to establish key model species for relevant Neotropical fish taxa and also multi-disciplinary research groups in order to uncover the main patterns and trends that dictate the mechanisms of sex determination and gonadal differentiation in this icthyofauna. By increasing our knowledge on sex determination/differentiation with the identification of sex chromosome-linked markers or sex-determining genes, characterization of the onset timing of morphological gonadal differentiation, and determination of the environmental hormonal labile period of gonadal sex determination in reference species, it will be possible to use those information as guidelines for application in other related groups. Overall, the strategic advance in this research field will be crucial for the development of biotechnological tools for aquaculture industry and for conservation of fish fauna from the Neotropical Region. PMID- 29990493 TI - Tales of testosterone: Advancing our understanding of environmental endocrinology through studies of neotropical birds. AB - Studies of birds have greatly advanced our understanding of how testosterone modulates complex phenotypes, specifically its role in mediating male reproductive and associated behaviors. Yet most of the foundational studies have been limited to northern latitude breeding species despite the fact that they represent only a small fraction of worldwide avian diversity. In contrast, phylogenetic, life-history, and mating system diversity all reach their apex in neotropical avifauna and yet these birds, along with more southern latitude species, remain very poorly understood from an endocrine perspective. Despite the relatively limited previous work on taxa breeding in Central and South America, empirical findings have had a disproportionately large impact on our understanding of testosterone's role in everything from geographic variation to behavioral roles and neuroplasticity. Here, we synthesize how studies of neotropical breeding avifauna have advanced our understanding of how testosterone's actions can and are associated with the broad patterns of phenotypic diversity that we see in birds. In addition, we outline how these studies can be used individually or in a comparative context to address fundamental questions about the environmental endocrinology of testosterone and to understand the diversity of roles that testosterone plays in mediating behavioral variation, reproductive strategies, and associated life-history trade offs. PMID- 29990494 TI - Thyroid hormones and androgens differentially regulate gene expression in testes and ovaries of sexually mature Silurana tropicalis. AB - A series of ex vivo exposures using testicular and ovarian tissues of sexually mature Western clawed frogs (Silurana tropicalis) were designed to examine molecular mechanisms of thyroid hormone (TH) and androgen crosstalk sans hypophyseal feedback as well as investigate potential sex-specific differences. Tissues were exposed ex vivo to either triiodothyronine (T3), iopanoic acid (IOP), one co-treatment of IOP + 5alpha-dihydrotestosterone (5alpha-DHT), 5alpha DHT, 5beta-dihydrotestosterone (5beta-DHT), or testosterone (T). Direct exposure to different androgens led to androgen specific increases in thyroid receptor and deiodinase transcripts in testes (trbeta and dio1) but a decrease in expression in ovaries (trbeta and dio3), suggesting that male and female frogs can be differently affected by androgenic compounds. Moreover, exposure to select androgens differentially increased estrogen-related transcription (estrogen receptor alpha (eralpha) and aromatase (cyp19)) and production (estradiol) in ovaries and testes indicating the activation of alternate metabolic pathways yielding estrogenic metabolites. Sex-steroid-related transcription (i.e., steroid 5alpha-reductase type 2 (srd5alpha2) and eralpha) and production (i.e., 5alpha DHT) were also differentially regulated by THs. The presence and frequency of transcription factor binding sites in the putative promoter regions of TH- and sex steroid-related genes were also examined in S. tropicalis, rodent, and fish models using in silico analysis. In summary, this study provides an improved mechanistic understanding of TH- and androgen-mediated actions and reveals differential transcriptional effects as a function of sex in frogs. PMID- 29990495 TI - BRN 2 Invade. AB - One of the remaining challenges in treating melanoma is its strong propensity to metastasize. Thus, there is considerable interest in understanding the alterations that drive progression of the disease. In this issue of Cancer Cell, Shain et al. and Zheng et al. provide insights implicating p16INK4A in melanoma invasiveness. PMID- 29990496 TI - Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia. AB - Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies. PMID- 29990497 TI - Radiologic and Genomic Evolution of Individual Metastases during HER2 Blockade in Colorectal Cancer. AB - Targeting HER2 is effective in 24% of ERBB2 amplified metastatic colorectal cancer; however, secondary resistance occurs in most of the cases. We studied the evolution of individual metastases during treatment to discover spatially resolved determinants of resistance. Circulating tumor DNA (ctDNA) analysis identified alterations associated with resistance in the majority of refractory patients. ctDNA profiles and lesion-specific radiographic reports revealed organ- or metastasis-private evolutionary patterns. When radiologic assessments documented progressive disease in target lesions, response to HER2 blockade was retained in other metastases. Genomic and functional analyses on samples and cell models from eight metastases of a patient co-recruited to a postmortem study unveiled lesion-specific evolutionary trees and pharmacologic vulnerabilities. Lesion size and contribution of distinct metastases to plasma ctDNA were correlated. PMID- 29990499 TI - EZH2 Inactivates Primary Cilia to Activate Wnt and Drive Melanoma. AB - EZH2 is frequently amplified in human melanomas. In this issue of Cancer Cell, Zingg et al. find that EZH2 overexpression silences genes for the primary cilium, causing deciliation, Wnt pathway activation, and progression of BrafV600E- or NrasQ61N-driven melanomas, thus defining a tumor-suppressor role for cilia in cancer. PMID- 29990498 TI - Epidermal Growth Factor Receptor Extracellular Domain Mutations in Glioblastoma Present Opportunities for Clinical Imaging and Therapeutic Development. AB - We explored the clinical and pathological impact of epidermal growth factor receptor (EGFR) extracellular domain missense mutations. Retrospective assessment of 260 de novo glioblastoma patients revealed a significant reduction in overall survival of patients having tumors with EGFR mutations at alanine 289 (EGFRA289D/T/V). Quantitative multi-parametric magnetic resonance imaging analyses indicated increased tumor invasion for EGFRA289D/T/V mutants, corroborated in mice bearing intracranial tumors expressing EGFRA289V and dependent on ERK-mediated expression of matrix metalloproteinase-1. EGFRA289V tumor growth was attenuated with an antibody against a cryptic epitope, based on in silico simulation. The findings of this study indicate a highly invasive phenotype associated with the EGFRA289V mutation in glioblastoma, postulating EGFRA289V as a molecular marker for responsiveness to therapy with EGFR-targeting antibodies. PMID- 29990500 TI - Genomic and Transcriptomic Analysis Reveals Incremental Disruption of Key Signaling Pathways during Melanoma Evolution. AB - We elucidated genomic and transcriptomic changes that accompany the evolution of melanoma from pre-malignant lesions by sequencing DNA and RNA from primary melanomas and their adjacent precursors, as well as matched primary tumors and regional metastases. In total, we analyzed 230 histopathologically distinct areas of melanocytic neoplasia from 82 patients. Somatic alterations sequentially induced mitogen-activated protein kinase (MAPK) pathway activation, upregulation of telomerase, modulation of the chromatin landscape, G1/S checkpoint override, ramp-up of MAPK signaling, disruption of the p53 pathway, and activation of the PI3K pathway; no mutations were specifically associated with metastatic progression, as these pathways were perturbed during the evolution of primary melanomas. UV radiation-induced point mutations steadily increased until melanoma invasion, at which point copy-number alterations also became prevalent. PMID- 29990502 TI - UnSASPing Senescence: Unmasking Tumor Suppression? AB - Cellular senescence serves as a barrier to tumor development and a principle effector of anti-cancer therapy, but the largely pro-inflammatory senescence associated secretory phenotype (SASP) may drive tumor promotion and contribute to age-related pathologies. In this issue of Cancer Cell, Georgilis et al. present SASP-deprived senescence as a potential therapeutic perspective. PMID- 29990501 TI - Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation. AB - Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression. Loss of the CDKN2A protein product p16INK4A permitted metastatic dissemination of human melanoma lines in mice, a phenotype rescued by inhibition of BRN2. These results demonstrate a mechanism by which CDKN2A suppresses the initiation of melanoma invasion through inhibition of BRN2. PMID- 29990504 TI - Food intake and addictive-like eating behaviors: Time to think about the circadian clock(s). AB - Compulsive feeding has been considered as an addicted-like behavior with similarities to drug addiction. Food intake is brain controlled involving a balance between metabolic and hedonic pathways that modulate respectively how much and what is eaten. Pathological conditions such as compulsive feeding or an eating addiction can interfere with this balance and obesity may develop. Daily feeding times are also centrally controlled by the circadian clock in the suprachiasmatic nucleus. Disruptions of this body clock (e.g., social jet-lag, shift work) lead to eating and metabolic disorders. The circadian pacemaker is intricately connected with the metabolic and hedonic centers controlling feeding, and most importantly, some of these nuclei have clock activity. When the brain circadian system is compromised in eating disorders, such perturbations may be in part the causes of compulsive feeding, night eating and addictive-like eating behavior. Therefore, food intake is regulated by the central circadian-metabolic hedonic network, which is functionally interconnected to avoid perturbing the eating behavior physiology. PMID- 29990503 TI - PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells. AB - Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer. PMID- 29990506 TI - The potential colonization histories of Opsariichthys bidens (Cyprinidae) in China using Bayesian binary MCMC analysis. AB - Vicariance and/or long-distance dispersal shape the distribution patterns of many extant taxa, and orogenesis and/or climate fluctuations are key factors that drive the events of vicariance and/or dispersal. In this study, we yielded biogeographical inferences from Bayesian binary MCMC (BBM) analysis to explore the potential colonization histories of Opsariichthys bidens in China and to identify potential factors responsible for the colonization histories. Many vicariance and dispersal events were identified. The results suggested that O. bidens seemed to have originated from the Yangtze River and/or the Pearl River and experienced a Yangtze River-Pearl River split at 7.04 million years ago (Ma). BBM analysis revealed that the Pearl River populations had undergone expansions to the Hainan drainages, the Lancangjiang River (upper Mekong) and the Nanpanjiang River (upper branch of the Pearl River) at 0.74 Ma. Meanwhile, the Yangtze River populations expanded to the northeastern drainages during the Early Pleistocene. Subsequently, the northeastern drainages dispersed to the Yellow River during the Middle Pleistocene. More recently, the northeastern drainage populations also dispersed to the Huaihe River and back to the Yangtze River. A portion of the Pearl River populations originated from the Yangtze River dispersed to the Jiulongjiang River during the Middle Pleistocene. These time scales fit well with the uplift of the Qinghai-Tibet Plateau and Pleistocene glacial cycles, indicating the two factors played vital roles in shaping the colonization histories of O. bidens. PMID- 29990505 TI - Osteoglycin post-transcriptional regulation by miR-155 induces cellular architecture changes in H9c2 cardiomyoblasts. AB - Several studies have demonstrated dysregulated cardiac microRNAs (miRNAs) following cardiac stress and development of cardiac hypertrophy and failure. miRNAs are also differentially expressed in the inflammation that occurs in heart failure and, among these inflammatory-related miRNAs, the miR-155 has been implicated in the regulation of cardiac hypertrophy. Despite these data showing the role of miRNA-155 in cardiomyocyte hypertrophy under a hypertrophic stimulus, it is also important to understand the endogenous regulation of this miRNA without a hypertrophic stimulus to fully appreciate its function in this cell type. The first aim of the present study was to determine whether, without a hypertrophic stimulus, miR-155 overexpression induces H9c2 cardiac cells hypertrophy in vitro. The second objective was to determine whether osteoglycin (Ogn), a key regulator of heart mass in rats, mice, and humans, is post transcriptionally regulated by miR-155 with a potential role in inducing H9c2 cells hypertrophy. Here, we show that, without a hypertrophic stimulus, miR-155 significantly repressed Ogn protein levels, but induce neither alteration in morphological phenotype nor in the expression of the molecular markers that fully characterize pathological hypertrophy of H9c2 cells. However, most importantly, Ogn silencing in H9c2 cells mimicked the effects of miR-155 overexpression in inducing cellular architecture changes that were characterized by a transition of the cell shape from fusiform to rounded. This is a new role of the post transcriptional regulation of Ogn by miR-155 in the maintenance of the cardiac cell morphology in physiological and pathological conditions. PMID- 29990508 TI - Adult dyslexic readers benefit less from visual input during audiovisual speech processing: fMRI evidence. AB - The aim of the present fMRI study was to investigate whether typical and dyslexic adult readers differed in the neural correlates of audiovisual speech processing. We tested for Blood Oxygen-Level Dependent (BOLD) activity differences between these two groups in a 1-back task, as they processed written (word, illegal consonant strings) and spoken (auditory, visual and audiovisual) stimuli. When processing written stimuli, dyslexic readers showed reduced activity in the supramarginal gyrus, a region suggested to play an important role in phonological processing, but only when they processed strings of consonants, not when they read words. During the speech perception tasks, dyslexic readers were only slower than typical readers in their behavioral responses in the visual speech condition. Additionally, dyslexic readers presented reduced neural activation in the auditory, the visual, and the audiovisual speech conditions. The groups also differed in terms of superadditivity, with dyslexic readers showing decreased neural activation in the regions of interest. An additional analysis focusing on vision-related processing during the audiovisual condition showed diminished activation for the dyslexic readers in a fusiform gyrus cluster. Our results thus suggest that there are differences in audiovisual speech processing between dyslexic and normal readers. These differences might be explained by difficulties in processing the unisensory components of audiovisual speech, more specifically, dyslexic readers may benefit less from visual information during audiovisual speech processing than typical readers. Given that visual speech processing supports the development of phonological skills fundamental in reading, differences in processing of visual speech could contribute to differences in reading ability between typical and dyslexic readers. PMID- 29990507 TI - Identification and analysis of differentially expressed microRNAs in rainbow trout (Oncorhynchus mykiss) responding to infectious hematopoietic necrosis virus infection. AB - MicroRNAs (miRNAs) are a class of regulators essential for numerous biological processes. Infectious hematopoietic necrosis virus (IHNV) is one of the most important viral pathogens in salmon and trout. In this study, the miRNA expression profiles of rainbow trout upon IHNV infection were explored. In total, 392 known miRNAs and 936 novel miRNAs were identified. Twelve known and 13 novel miRNAs were differentially expressed between infected and uninfected fish. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that certain miRNA target genes were associated with biological regulation, the immune system, and signal transduction. In addition, over- and suppressed expression of miR-146a-3p, miR-155-5p, miR-216a-5p, and miR-499b-5p could respectively increase and decrease viral gene expression in cells and viral titers. MiR-146a-3p and miR 216a-5p inhibited the expression of type-I IFN and the Mx1 gene induced by IHNV. These results provide preliminary insights into the IHNV-host interactions mediated by miRNAs. PMID- 29990509 TI - Task switching in autism: An EEG study on intentions and actions. AB - One of the main symptoms of Autism Spectrum Conditions (ASC) is experiencing cognitive inflexibility when adjustments of behaviour are required. While this so called behavioural rigidity is broadly recognised in ASC, finding evidence for the underlying neurocognitive mechanisms remains challenging. In this electroencephalographic (EEG) study, participants with ASC and matched controls were instructed to choose between two cognitive tasks in each trial, and to respond to the subsequently presented target stimulus according to their task choice. While doing so, we tracked the frontally distributed contingent negative variation (CNV) during the task preparation interval as a measure of intentional control, and the posteriorly measured P3 during the task execution interval to monitor the translation of intentions into actions. The results support the notion of intentional control difficulties in ASC, where the CNV was attenuated in the ASC group compared to the control group. Furthermore, the CNV was differentiated between the tasks and transition types in the control group only, suggesting that the ASC group was less fine-tuning the required amount of intentional control to contextual circumstances. In contrast, the P3 showed no significant differences between the groups. Together, these findings highlight the importance of intentional control mechanisms as a crucial future route for a better understanding of cognitive flexibility and behavioural rigidity in ASC. PMID- 29990510 TI - Evolutionary and phylodynamic analyses of Dengue virus serotype I in Guangdong Province, China, between 1985 and 2015. AB - To determine the evolutionary and phylodynamic history of DENV-1 in Guangdong, the strains detected between 1985 and 2015 were determined with phylogenetic and Bayesian analyses of the E gene. Three DENV-1 genotypes (I, V, and VI) were circulating in Guangdong, and genotype I was detected most frequently. The evolutionary rate of DENV-1 was estimated to be 1.03 * 10-3 nucleotide substitutions/site/year. The most recent ancestor of the viruses existed approximately 141 years ago. The observed epidemiological dynamics correlated with similar fluctuations in diversity, and the epidemiological dynamics of DENV 1 transmission reflect dramatic changes in the viral population sizes. Two recombination events were identified in those strains. The selection pressures were estimated and revealed an abundance of negatively selected sites but few positively selected sites. These data improve our understanding of the evolution and molecular epidemiology of DENV-1 and provide insights that will facilitate the surveillance and control of DENV-1. PMID- 29990511 TI - Implications of uterine NK cells and regulatory T cells in the endometrium of infertile women. AB - A range of studies have shown that the complex process of implantation and an establishment of a pregnancy also involves immune factors. Disturbances in these underlying immune mechanisms might lead to implantation and pregnancy failure and may be involved in the pathogenesis of unexplained infertility. Several studies have reported that imbalances in uterine NK (uNK) cell abundance are associated with infertility; however, controversies exist. An increased amount of CD56+ uNK cells along with a decrease in CD16+ uNK cells have been associated with normal fertility in some studies. Very few studies of FoxP3+ regulatory T cells (Tregs) in the pre-implantation endometrium have been performed. Results are sparse and controversial, studies reporting both increased and decreased numbers of Tregs, respectively, in women suffering from infertility. In conclusion, studies imply that uNK cells, Tregs and HLA-G carry pivotal roles regarding the establishment of a healthy pregnancy, and that abnormal immune mechanisms involving these parameters may be associated with infertility. However, more research in early phases of the reproductive cycle, such as investigating the conditions in the endometrium before implantation, is needed to further clarify the underlying mechanisms. PMID- 29990512 TI - Recombinant and native TviCATL from Trypanosoma vivax: Enzymatic characterisation and evaluation as a diagnostic target for animal African trypanosomosis. AB - African animal trypanosomosis (nagana) is caused by tsetse-transmitted protozoan parasites. Their cysteine proteases are potential chemotherapeutic and diagnostic targets. The N-glycosylated catalytic domain of Trypanosoma vivax cathepsin L like cysteine protease, rTviCATLcat, was recombinantly expressed and purified from culture supernatants while native TviCATL was purified from T. vivax Y486 parasite lysates. Typical of Clan CA, family C1 proteases, TviCATL activity is sensitive to E-64 and cystatin and substrate specificity is defined by the S2 pocket. Leucine was preferred in P2 and basic and non-bulky, hydrophobic residues accepted in P1 and P3 respectively. Reversible aldehyde inhibitors, antipain, chymostatin and leupeptin, with Arg in P1 and irreversible peptidyl chloromethylketone inhibitors with hydrophobic residues in P2 inhibited TviCATL activity. TviCATL digested host proteins: bovine haemoglobin, serum albumin, fibrinogen and denatured collagen (gelatine) over a wide pH range, including neutral to slightly acidic pH. The recombinant catalytic domain of TviCATL showed promise as a diagnostic target for detecting T. vivax infection in cattle in an indirect antibody detection ELISA. PMID- 29990513 TI - Optimising genetic transformation of Trypanosoma cruzi using hydroxyurea-induced cell-cycle synchronisation. AB - The limited flexibility and time-consuming nature of the genetic manipulation procedures applicable to Trypanosoma cruzi continue to restrict the functional dissection of this parasite. We hypothesised that transformation efficiency could be enhanced if electroporation was timed to coincide with DNA replication. To test this, we generated epimastigote cultures enriched at the G1/S boundary using hydroxyurea-induced cell-cycle synchronisation, and then electroporated parasites at various time points after release from the cell-cycle block. We found a significant increase in transformation efficiency, with both episomal and integrative constructs, when cultures were electroporated 1 h after hydroxyurea removal. It was possible to generate genetically modified populations in less than 2 weeks, compared to the normal 4-6 weeks, with a 5 to 8-fold increase in the number of stably transformed clones. This straightforward optimisation step can be widely applied and should help streamline functional studies in T. cruzi. PMID- 29990514 TI - Cooperation of intrathymic T15 idiotype-bearing B and complementary T cells in ontogeny of natural Treg cells involved in establishment of T15 clonal dominance. AB - The mechanisms for dominant T15 idiotype selection are not well understood, yet the significance of idiotypic regulation has been suggested. We proposed that to become dominant V regions of a given subset of B-1a cell must establish a functional idiotypic network with complementary T cells. Features required for the cells involved in immune network and steps preceding the establishment of clonal dominance are suggested. PMID- 29990515 TI - Evaluation of SOCS1 methylation in patients with Behcet's disease. AB - INTRODUCTION: Epigenetic discusses to inherited changes in mitosis and meiosis in the gene expression pattern which is independent of primary DNA sequence. Since, SOCS1 hyper-methylation can activate JAK / STAT signaling pathway and activation of this pathway can directly affect the impact of different cytokines on cell function and subsequently lead to pathophysiology of diseases, in particular autoimmune diseases that interact directly with the amount of cytokines and due to the fact that the cause and pathology of Behcet's disease (BD) have not ever been completely determined. So, the purpose of this study was to evaluate the methylation pattern of SOCS1 gene in patients with BD and compare them with healthy group. METHODOLOGY: This study was a case-control study in which 50 patients with BD and 60 subjects as healthy group participated. Blood samples were collected from all participants and then Peripheral Blood Mononuclear Cells (PBMCs) were isolated through Ficoll method. After extraction of DNA by Salting out method and its analysis with Nano-drop, the methylation level of SOCS1 was examined using qMS-PCR technique. RESULTS: Findings about methylation and gene expression in SOCS1 gene showed that the level of SOCS1 methylation was increased in patient groups compared with healthy subjects (control group) which the increase was statistically significant (p-value<0.05). Also, the results of gene expression revealed that the fold change of SOCS1 gene expression was decreased in patient group compared with healthy subjects which the decrease was statistically significant (p-value<0.05). DISCUSSION AND CONCLUSION: According to the results of this study, it can be suggested that the DNA methylation of SOCS1 gene is likely to affect the gene expression and thereby contribute to the pathogenesis of Behcet's disease. PMID- 29990517 TI - The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression. AB - Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent. PMID- 29990516 TI - Vaccination with RSV M209-223 peptide promotes a protective immune response associated with reduced pulmonary inflammation. AB - Respiratory syncytial virus (RSV) is the most common etiologic agent in severe infections of the lower respiratory tract in children with a high mortality rate. However, there are still no licensed vaccines for RSV. In this study, we investigated a putative vaccine based on M209-223 peptide. Mice vaccinated with M209-223 peptide expanded M209-223-specific effector CD4+ T cells upon infection. Vaccination resulted in increased numbers of regulatory T cells (Treg) and Th1 cells, and decreased numbers of Th2 cells. In addition, vaccination with M209-223 peptide, protected mice from infection and prevented lung inflammation, leading to increase in IL-10 and IFN-gamma production by lung CD4+ T cells. Treg depletion with anti-CTLA4 antibodies abrogated protection induced by peptide vaccination. Our results support vaccination with M209-223 peptide as an important strategy to generate protection, both systemic and local, by memory RSV specific CD4+ T cells in mice. Contrarily to inactivated RSV particles, M209-223 peptide vaccination is capable of not only promoting viral clearance, but also reducing inflammatory processes in lungs upon infection. PMID- 29990518 TI - Low-expressional IGF1 mediated methimazole-induced liver developmental toxicity in fetal mice. AB - Anti-thyroid drugs (ATDs) therapy is necessary for pregnant women with hyperthyroidism. However, there is a lack of studies on developmental toxicity of ATDs. In this study, we observed the developmental toxicity of fetal liver induced by prenatal methimazole exposure (PME) in mice, and explored the potential mechanism. Pregnant Kunming mice were administered intragastrically with 4.5 or 18 mg/kg.d methimazole from gestational day (GD) 9~18. After PME, the birth weights of the offspring mice were decreased, and the liver morphology, development indexes and metabolic function were all altered in different degree in the PME fetuses. Meanwhile, PME decreased the levels of serum and hepatic insulin-like growth factor 1 (IGF1), and reduced the gene expression of IGF1 downstream signaling pathway. Furthermore, the protein levels of phosphorylated extracellular regulated protein kinases (p-ERK) and serine-threonine protein kinase (p-Akt) were also reduced. Furthermore, methimazole disturb hepatocyte differentiation, maturation and metabolic function through suppressing IGF1 signaling pathway in HepG2 cells. These results demonstrated that PME could induce fetal liver developmental toxicity, and the underlying mechanism was related to low-expression of hepatic IGF1 caused by methimazole, which mediated abnormal liver morphology and metabolic function. PMID- 29990519 TI - Could male reproductive system be the main target of subchronic exposure to manganese in adult animals? AB - Manganese (Mn) is one of the most common chemical elements on Earth and an essential micronutrient in animal organism. However, in supraphysiological levels and long-term exposures, it is a potential toxicant. Although nervous system is the most studied in relation to Mn toxicity, other tissues can have their function impaired by Mn in high doses. The present study investigated the possible adverse effects of subchronic exposure to supraphysiologic level of Mn (5 mg/kg or 15 mg/kg, intraperitoneally) on reproductive, neurobehavioral, renal and hepatic parameters of male rats. For the first time, the vulnerability of these parameters to Mn was concomitantly investigated. While our results demonstrate that Mn treatments were not sufficient to produce a marked effect of neurotoxic, hepatotoxic or renal toxicity in adult rats, we found typical indicators of reproductive toxicity such as histopathological changes (major in testes and epididymis) and impaired sperm concentration and quality. Mn, under these experimental conditions, seems to exert reproductive toxicity by different testicular mechanisms, i.e. direct and indirect action on germ cells. On the other hand, exposure to Mn did not change the pattern of cognitive and emotional behaviors and the histological organization of kidneys of experimental rats. The liver showed a weight increasement and hidropic degeneration, probable due to the detoxification overload. In summary, for the first time it was demonstrated that adult male reproductive system was more sensitive to Mn toxicity than nervous, hepatic and renal systems, although nervous system is known as the main target tissue of this metal. PMID- 29990520 TI - A possible social relative reward effect: Influences of outcome inequity between rats during operant responding. AB - Social interactions/situations have dramatic influences on motivation. Creating animal models examining these influences promotes a better understanding of the psychological and biological underpinnings of social motivation. Rodents are sensitive to social history/experience during associative conditioning and food sharing tasks. Would reward-oriented operant behavior be sensitive to social influences by showing a negative contrast-like effect when another organism obtains a greater value outcome? We used a side-by-side arrangement of operant response chambers wherein one animal obtained consistently high reward signaled by a discrete cue. The neighboring, experimental rat experienced different combinations of high and low reward trial sequences. Control conditions included distraction from a conspecific in the neighboring chamber (rat distractor) or cue/food dispenser operating without a conspecific (program distractor) in addition to testing subjects alone. Results support an influence of the other animal actively performing the task on the experimental subject's behavior. Primarily, responding was significantly slower for the low reward trials while the neighboring rat was receiving the higher magnitude reward. The lever-press and not food-cup retrieval latency was significantly slower during exposure to a conspecific neighbor performing the operant task. The effect was not obtained in all session sequences and was more pronounced using longer series of consecutive low reward trials. The slowing effect was also obtained with the program distractor experience in a different trial sequence. These findings suggest a social-induced negative incentive contrast effect in rats possibly mediated by an outcome inequity process that could have key similarities to complex situational affective effects on motivation involving frustration or jealously. PMID- 29990521 TI - Aqueous extract of Sedum oxypetalum induces mineralization and osteogenic differentiation by human Periodontal Ligament-Derived cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal plant Sedum oxypetalum Kunth (Crassulaceae), locally known as Jiote or in general Siempreviva (always alive) has been traditionally used by people of the Mexican community of Tenango del Valle as a home remedy to treat periodontal diseases, inducing teeth strengthening. Consequently, the aim of this work was to investigate its capacity directed to mineralized tissues regeneration. MATERIALS AND METHODS: The aerial parts of the plant were processed and its aqueous extract (AE) was chemically characterized. The AE and its components sedoheptulose and syngenite were tested for either osteogenic differentiation or mineral-nucleation induction respectively. RESULTS: The AE and one of its components (sedoheptulose) were shown to promote the proliferation and/or osteogenic differentiation by Human Periodontal Ligament-Derived Cells (hPDLs), while inducing the mineralization process. The AE also promoted the nucleation of octacalcium phosphate and its component syngenite, the hydroxyapatite crystals formation in vitro. CONCLUSION: The findings reported herein support the traditional use of S. oxypetalum due to its potential capacity to promote the regeneration of mineralized tissues. PMID- 29990522 TI - A review on the effects of verbal instructions in human fear conditioning: Empirical findings, theoretical considerations, and future directions. AB - Fear learning reflects the adaptive ability to learn to anticipate aversive events and to display preparatory fear reactions based on prior experiences. Usually, these learning experiences are modeled in the lab with pairings between a neutral conditioned stimulus (CS) and an aversive unconditioned stimulus (US) (i.e., fear conditioning via CS-US pairings). Nevertheless, for humans, fear learning can also be based on verbal instructions. In this review, we consider the role of verbal instructions in laboratory fear learning. Specifically, we consider both the effects of verbal instructions on fear responses in the absence of CS-US pairings as well as the way in which verbal instructions moderate fear established via CS-US pairings. We first focus on the available empirical findings about both types of effects. More specifically, we consider how these effects are moderated by elements of the fear conditioning procedure (i.e., the stimuli, the outcome measures, the relationship between the stimuli, the participants, and the broader context). Thereafter, we discuss how well different mental-process models of fear learning account for these empirical findings. Finally, we conclude the review with a discussion of open questions and opportunities for future research. PMID- 29990523 TI - A contextual identification of home-living older adults' positive mealtime practices: A honeycomb model as a framework for joyful aging and the importance of social factors. AB - In this study, we outlined contextual identifications within positive mealtime practices among home-living older adults in Denmark. We aimed to understand and facilitate optimal dietary intake and to promote well-being for older adults who live at home. We used data from 22 participants, who wrote diary entries and took photos of their meal experiences over a 6-day period. We followed this with in depth interviews, using the photos as mediators within a photo-elicitation framework. The results revealed that social factors play a major role in positive mealtime practices and that the types of commensal eating vary based on the contextual setting. Furthermore, we found that, in the new generation of older adults, some men have extremely good cooking skills and are interested in contextual food matters. Meeting older adults' needs for adequate nutrition requires in-depth knowledge, including a complex understanding of individual preferences and contextual everyday practices. PMID- 29990525 TI - A preclinical evaluation of a programmable CNT membrane device for transdermal nicotine delivery in hairless Guinea pigs. AB - Nicotine replacement therapy in the form of transdermal nicotine patches and nicotine gums combined with behavioral counseling still has a low smoking cessation rate of 25%. A promising approach to smoking cessation is to remotely program variable transdermal nicotine delivery rates, with inputs from counselor and patient through a smartphone counseling application. A switchable carbon nanotube (CNT) membrane device has been developed for transdermal nicotine delivery that can be programmed to deliver variable doses matching those of nicotine patches (7, 14 and 21 mg/24 h) and nicotine gums (2 mg /4 mg). The performance of switchable devices was evaluated in vitro on flow-cell geometry and in vivo on the skin of hairless guinea pig (HGP). In vitro, CNT membrane devices successfully switched between therapeutically useful nicotine fluxes of 1.3-1.8 MUmoles/cm2/h (ON, -1.5 V) and 0.17-0.23 MUmoles/cm2/h (OFF, 0 V), corresponded to the higher doses of gum and nicotine patch fluxes. In vivo, a microdialysis membrane probe was implanted in skin of HGP to directly detect nicotine fluxes through the skin barriers into dialysate with high temporal resolution. The CNT membrane device on HGP skin resulted in an ON/OFF nicotine flux ratio 6.4 +/- 2.5 as detected in microdialysis membrane probe in skin. Compared to commercial nicotine patches, the device in ON state was approximately 2-2.4 times the commercial nicotine patch dose as measured by dialysate nicotine fluxes. These results enable smartphone-controlled, battery operated transdermal delivery devices that can be coupled to remote counseling apps for personalized smoking cessation therapy. PMID- 29990524 TI - Doggy bags and downsizing: Packaging uneaten food to go after a meal attenuates the portion size effect in women. AB - Serving larger portions leads to increased food and energy intake, but little is known about strategies to moderate this response. This study tested how the effect of portion size on meal intake was influenced by providing the option to take away uneaten food in a "doggy bag" (to-go container). Women were randomly assigned to one of two subject groups: a To-Go Group (n = 27) that was informed before each meal that their leftover food would be packaged to take away after the meal, and a Control Group (n = 26) that was not given this option. In a crossover design, subjects came to the lab once a week for four weeks to eat a dinner composed of five foods. Across meals, the portion size of all foods was varied (100%, 125%, 150%, and 175% of baseline). Results showed that the portion size effect, defined as the trajectory of intake across the weight of food served, differed significantly by subject group (P <= 0.025). In the Control Group, increasing the portion size of all foods led to substantial increases in intake (P < 0.0001); for every 100 g added to the baseline portion, women in this group consumed an additional mean (+/-SEM) of 64 +/- 12 g of food and 90 +/- 19 kcal, until intake leveled off. In contrast, intake of women in the To-Go Group increased by only 17 +/- 12 g and 19 +/- 18 kcal for every additional 100 g served; these increases did not differ significantly from zero (P > 0.15). Thus, the effect of portion size on intake was attenuated in the To-Go Group compared to the Control Group. These data indicate that packaging uneaten food after a meal could be an effective strategy to reduce overconsumption from large portions. PMID- 29990526 TI - Hydrogel-forming microneedles enhance transdermal delivery of metformin hydrochloride. AB - We investigated, for the first time, the potential for a hydrogel-forming microneedle (MN) patch to deliver the high-dose drug metformin HCl transdermally in a sustained manner. This may minimize some gastrointestinal side effects and small intestine absorption variations associated with oral delivery. Patches (two layers) were assembled from a lyophilised drug reservoir layer, with the MN layer made from aqueous blend of 20% w/w poly (methylvinylether-co-maleic acid) crosslinked by esterification with 7.5% w/w poly (ethylene glycol) 10,000 Da. >90% of metformin was recovered from homogeneous drug reservoirs. Drug reservoir dissolution time in PBS (pH 7.4) was <10 min. MN penetrated a validated skin model Parafilm(r) M consistently. Permeation of metformin HCl across dermatomed neonatal porcine skin in vitro was enhanced by using MN. The combined MN and metformin HCl reservoir patch (containing 75 mg or 50 mg metformin HCl, respectively) delivered 9.71 +/- 2.22 mg and 10.04 +/- 1.92 mg at 6 h, respectively, and 28.15 +/- 2.37 mg and 23.25 +/- 3.58 mg at 24 h, respectively.In comparison, 0.34 +/- 0.39 mg and 0.85 +/- 0.68 mg was delivered at 6 h, respectively, and 0.39 +/- 0.39 mg and 1.01 +/- 0.84 mg was delivered at 24 h, respectively, from a control set-up employing only the drug reservoirs. In vivo, metformin HCl was detected in rat plasma at 1 h post MN application at a concentration of 0.62 +/- 0.51 MUg/mL, increasing to 3.76 +/- 2.58 MUg/ml at 3 h. A maximal concentration of 3.77 +/- 2.09 MUg/ml was achieved at 24 h. Css was 3.2 MUg/mL. Metformin transdermal bioavailability using MNs was estimated as 30%.Hydrogel-forming MN are a promising technology that has demonstrated successful transdermal delivery of metformin HCl. Potential clearly exists for administration of other high-dose drugs using this system. PMID- 29990527 TI - Modeling of adsorption isotherms of reactive red RR-120 on spirulina platensis by statistical physics formalism involving interaction effect between adsorbate molecules. AB - In this study, the formalism of statistical physics is used to describe and interpret the adsorption mechanism by applying the law of real gas which takes into account the interaction between the reactive red 120 dye (RR-120) molecules due to its very large size (approximately 2.11 nm). Modeling of the RR-120 dye adsorption isotherms on Spirulina platensis sp. is performed. Five models based on statistical physics formalism are developed: Hill model with one adsorbed site energy, Hill model with two energies, Hill model with three energies, double layer model with one energy and double layer model with two energies. These five models are treated alternatively with the ideal gas law (IG) and with the law of Ven Der Waals (VDW) real gas (RG).Fitting of six adsorption isotherms at different temperatures (298K, 303K,308K, 313K, 318K and 328K) is performed with, the pH fixed to 2. According to values of correlation coefficient, the Hill model with one energy and a VDW real gas interaction has been chosen as the adequate model to best fit the experimental data. PMID- 29990528 TI - Novel formononetin-7-sal ester ameliorates pulmonary fibrosis via MEF2c signaling pathway. AB - Pulmonary fibrosis is a progressive disorder with poor prognosis and limited treatment options. Therefore, novel therapeutic drugs should be developed in preclinical studies. In this study, we designed and synthesized a novel compound named formononetin-7-sal ester (FS). We also investigated its anti-pulmonary fibrosis ability on transforming growth factor beta 1 (TGF-beta1)-stimulated pulmonary epithelial cells and fibroblasts in vitro and on bleomycin (BLM) induced pulmonary fibrosis in vivo. FS strongly blocked cell proliferation and migration, which were activated by TGF-beta1, thereby reducing the expression of lung fibrosis markers, such as vimentin, alpha-smooth muscle actin (alpha-SMA), Snail, and collagen I and III, and increasing the expression of the epithelial cell marker E-cadherin. FS ameliorated BLM-induced pulmonary fibrosis in mice and decreased histopathologic fibrosis scores and collagen deposition. A low expression of hydroxyproline, vimentin, alpha-SMA, and Snail and a high expression of E-cadherin were found in FS-treated lungs compared with BLM instilled lungs. Using the Cignal Finder 45-Pathway Reporter Array, we tested the regulation of FS in pulmonary fibrosis-associated signaling pathways and observed that FS significantly inhibited the myocyte enhancer factor-2c (MEF2c) signaling pathway. Gain- and loss-of-function studies, rescue experiments and promoter activity testing were designed to further confirm this result in vivo and in vitro. Collectively, our results demonstrated that FS prevents pulmonary fibrosis via the MEF2c signaling pathway. PMID- 29990530 TI - Rapid ligand fishing for identification of acetylcholinesterase-binding peptides in snake venom reveals new properties of dendrotoxins. AB - Acetylcholinesterase (AChE) from Electrophorus electricus (eel) was immobilized on the surface of amino-modified paramagnetic beads to serve as a model for the development, validation and application of a new affinity-based ligand-fishing assay for the discovery of bioactive peptides from complex protein mixtures such as venoms. Nano liquid chromatography-mass spectrometry (nanoLC-MS) was used for the analysis of trapped peptides. Using enzyme-functionalized beads, the ligand fishing assay was evaluated and optimized using a peptide reference mixture composed of one acetylcholinesterase binder (fasciculin-II) and five non-binders (mambalgin-1, angiotensin-II, bradykinin, cardiotoxin and alpha-bungarotoxin). As proof of concept, snake venom samples spiked with fasciculin-II demonstrated assay selectivity and sensitivity, fishing the peptide binder from complex venom solutions at concentrations as low as 1.0 MUg/mL. As negative controls for method validation, venoms of four different snake species, not known to harbor AChE binding peptides, were screened and no AChE binders were detected. The applicability of the ligand fishing assay was subsequently demonstrated with venom from the black mamba, Jameson's mamba and western green mamba (Dendroaspis spp.), which have previously been reported to contain the AChE binding fasciculins. Unknown peptides (i.e. not fasciculins) with affinity to AChE were recovered from all mamba venoms tested. Tryptic digestion followed by nano-LC-MS analysis of the material recovered from black mamba venom identified the peptide with highest AChE-binding affinity as dendrotoxin-I, a pre-synaptic neurotoxin previously not known to interact with AChE. Co-incubation of AChE with various dendrotoxins in vitro revealed reduced inactivation of AChE activity over time, thus demonstrating that these toxins stabilize AChE. PMID- 29990529 TI - Embryoid body test with morphological and molecular endpoints implicates potential developmental toxicity of trans-resveratrol. AB - Developmental toxicity of compounds, which women of reproductive age are exposed to, should be assessed to minimize the incidence of miscarriage and birth defects. The present study examined the potential developmental toxicity of resveratrol, a dietary supplement widely marketed with various health claims, using the P19C5 embryoid body (EB) morphogenesis assay, which evaluates adverse effects of chemical exposures on tissue growth and axial elongation. Resveratrol (trans isoform) impaired morphogenesis at 4 MUM and higher, creating smaller and rounder EBs, whereas cis isoform, and glucuronated and sulfonated metabolites did not. Trans-resveratrol also altered expression levels of developmental regulator genes involved in embryonic patterning, such as Wnt3a, Tbx6, and Cyp26a1. To investigate the mechanisms of trans-resveratrol action, the roles of estrogen receptor, sirtuin 1 (SIRT1), and DNA replication in EB morphogenesis were examined. Neither activators of estrogen receptors (diethylstilbestrol [18 MUM] and raloxifene [8 MUM]) nor activator of SIRT1 (SRT1720 [2.4-3.2 MUM]) caused morphological and molecular alterations that are comparable to trans-resveratrol (10 MUM). By contrast, a reduction in the DNA replication rate with aphidicolin (0.4 MUM) or hydroxyurea (40 MUM) created smaller and rounder EBs and altered the expression levels of Wnt3a, Tbx6, and Cyp26a1 in a manner similar to trans resveratrol. Consistently, trans-resveratrol significantly reduced the rate of EdU incorporation in P19C5 cells. These results suggest that a reduction in the DNA replication rate is one of the mechanisms by which trans-resveratrol impacts EB development. This study provides mechanistic insight for further investigations on the developmental toxicity of trans-resveratrol. PMID- 29990531 TI - Evaluation of colorimetric indices for the assessment of tooth whiteness. AB - OBJECTIVES: To evaluate the performance of existing equations that measure perceptual whiteness of teeth. METHODS: Three new psychophysical experiments were conducted and combined with two previously published experiments to form a large set of data to test performance of whiteness indices. Three whiteness indices (WIC, WIO, WID,) were compared with regard to their ability to measure perceived whiteness. Coefficient of determination (r2) and '% wrong decisions' were used as measures of performance. One of the new experiments involved 500 participants across five different countries to explore the effect of gender, age and culture on whiteness perception. RESULTS: Equations (WIO and WID) that have been optimized for use with tooth whiteness better correlated with visual perceptions of changes in tooth whiteness than the more general CIE whiteness index (WIC). The best performance was given by WIO (in terms of both r2 and % wrong decisions). No effect of age, gender or culture was found on whiteness perception. CONCLUSIONS: WIO is a robust method for assessing whiteness of human teeth. PMID- 29990532 TI - "The vestibular system, body temperature and sense of body ownership: a potential link? Insights from a single case study". AB - The vestibular system plays a pivotal role in behavioural and physiological aspects of body representation. If on the one hand, the stimulation of the vestibular system in healthy subjects provokes body representation distortions, accompanied by a decrease of body temperature, on the other hand, in brain damaged patients it transiently restores body representation disorders. So far, the physiological counterpart of such behavioural amelioration on patients has never been explored. Here we aimed at investigating body temperature variations following Caloric Vestibular Stimulation (CVS), in a patient affected by somatoparaphrenia who regained the sense of body part ownership after the stimulation. Results showed an increase in body temperature after CVS, which also correlated with the temporary restored sense of limb ownership. Our results support the idea that physiological signals are fundamental to maintain a coherent mental representation of the body. PMID- 29990533 TI - Obesity and Cardiac Remodeling in Adults: Mechanisms and Clinical Implications. AB - Obesity, particularly severe obesity is capable of producing hemodynamic alterations that contribute to changes in cardiac morphology which may predispose to impairment of ventricular function and heart failure. These include a high cardiac output state in most, left ventricular (LV) hypertrophy, and LV diastolic dysfunction. Right heart involvement may result from LV failure, the hypercirculatory state, and sleep disordered breathing. In recent years experimental studies and some studies in humans suggest that certain neurohormonal and metabolic alterations that occur commonly in obesity may contribute to alterations in cardiac structure and function. These include activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, hyperleptinemia due to leptin resistance, low circulating adiponectin levels, insulin resistance with hyperinsulinemia, and possibly cardiac lipotoxicity. This review will describe the ways in which these factors weave together to promote adaptations and maladaptations that result in alterations in cardiac structure and function which may contribute to the development of heart failure. PMID- 29990534 TI - Obesity Paradox in Aging: From Prevalence to Pathophysiology. AB - Recent advances in medical technology and health care have greatly improved the management for chronic diseases and prolonged human lifespan. Unfortunately, increased lifespan and the aging population impose a major challenge on the ever rising prevalence of chronic diseases, in particular cardiometabolic stress associated with the pandemic obesity in our modern society. Although overweight and obesity are associated with incident cardiovascular diseases (CVD), including heart failure (HF), it paradoxically leads to a more favorable prognosis in patients with chronic HF, a phenomenon commonly defined as "obesity paradox". Numerous population-based and clinical studies have suggested possible explanations such as better metabolic reserve, smoking and disease-associated weight loss for obesity paradox. Recent evidence noticed a shift in obesity paradox with aging. While some studies have reported a more pronounced "obesity paradox" in the older patients, others have seen diminished cardiac benefits with overweight and obesity in the elderly patients with CVD. These findings suggested that a complex relationship among aging, metabolism, and HF severity/chronicity, which may explain the shift in obesity paradox in the elderly. Aging negatively affects body metabolism and cardiac function although its precise impact on obesity paradox remains elusive. To develop new strategies for cardiovascular health in the elderly, it is imperative to understand the precise role for aging on obesity-related CVD. PMID- 29990535 TI - Stabilization of unilamellar catanionic vesicles induced by beta-cyclodextrins: A strategy for a tunable drug delivery depot. AB - The limited stability of catanionic vesicles has discouraged their wide use for encapsulation and controlled release of active substances. Their structure can easily break down to form lamellar phases, micelles or rearrange into multilamellar vesicles, as a consequence of small changes in their composition. However, despite the limited stability, catanionic vesicles possess an attractive architecture, which is able to efficiently encapsulate both hydrophobic and hydrophilic molecules. Therefore, improving the stability of the vesicles, as well as the control on unilamellar structures, are prerequisites for their wider application range. This study focuses on the impact of beta-cyclodextrins for the stabilization of SDS/CTAB catanionic vesicles. Molar ratio and sample preparation procedures have been investigated to evaluate the temperature stability of catanionic vesicles. Diffusion and spectroscopic techniques evidenced that when beta-cyclodextrins are added, unilamellar structures are stabilized above the multilamellar-unilamellar vesicles critical temperature. The results evidence encouraging perspectives for the use of vesicular nanoreservoirs for drug depot applications. PMID- 29990536 TI - Fluorescent probes for the detection of catalytic Fe(II) ion. AB - Iron (Fe) is the most abundant redox-active metal ion in the human body, and its redox-active inter-convertible multiple oxidation states contributes to numerous essential biological processes. Moreover, iron overload can potentially cause cellular damage and death, as wel as numerous diseases through the aberrant production of highly reactive oxidative species (hROS). Protein-free or weakly protein-bound Fe ions play a pivotal role as catalytic reactants of the Fenton reaction. In this reaction, hROS, such as hydroxyl radicals and high valent-iron oxo species, are generated by a reaction between hydrogen peroxide and Fe(II), which is re-generated through reduction using abundant intracellular reductants, such as glutathione. This results in the catalytic evolution of hROS. Thus, selective detection of the catalytic Fe(II) in the living systems can explain both of the pathological and physiological functions of Fe(II). Written from the perspective of their modes of actions, this paper presents recent advances in the development of fluorescent and bioluminescent probes that can selectively detect catalytic Fe(II) together with their biological applications. PMID- 29990537 TI - Laparoscopic cervico-isthmic cerclage: About 25 cases. AB - INTRODUCTION: The purpose of this study is to report on our experience of laparoscopic cervico-isthmic cerclage. MATERIAL AND METHOD: A monocentric retrospective study covering a 13-year period during which 25 cases of laparoscopic cerclage outside of pregnancy were performed, using the technique described by Dubuisson, at the University Hospital of Clermont-Ferrand. Individual patient data included pregnancy outcomes before and after cerclage and the characteristics of surgery. RESULTS: The mean age of the patients was 33.9 (+/-4.6) years. A total of 68 pregnancies were recorded before cerclage, including 31 late miscarriages, 11 premature deliveries, with only 9 pregnancies attaining full-term. The average time of surgery was 54 (+/-17.5) minutes with a hospital stay of 24h. 3 minor intraoperative complications (12%) with hemorrhage <300cc were noted and managed intraoperatively. In some cases laparoscopy allowed treatment of associated pathologies (septum resection, adhesiolysis, endometriosis, ovarian drilling, tube assessment). 21 pregnancies (68% of patients) were recorded post cerclage including 5 early miscarriages and 16 cesarean deliveries with an average time taken to conceive of 11.8 months. The overall neonatal survival rate after cerclage was 76.2% versus 16.20% before surgery (p<0.0001), with a 100% neonatal survival rate beyond the 1st trimester as compared to 21.6% before cerclage (p<0.0001). PMID- 29990538 TI - Effects of mitochondrial disease/dysfunction on pregnancy: A retrospective study. AB - A retrospective survey assessed the gynecologic, obstetric and fertility history of 103 women with mitochondrial disease (MD)/dysfunction (Md) aged 16 to 75 who had previously been pregnant. Most participants (34%) had a mitochondrial myopathy and there were 248 combined pregnancies with live deliveries (average 3.6 pregnancies/woman). In general, pregnancy in those with MD/Md appears to exacerbate some constitutional and neurological symptoms and may be more frequently associated with common obstetric complications, but this did not appear to result in worse pregnancy outcomes. Most women carried their pregnancy to term, but their neonates tended to have more congenital anomalies than expected. PMID- 29990539 TI - Understanding the 3D genome: Emerging impacts on human disease. AB - Recent burst of new technologies that allow for quantitatively delineating chromatin structure has greatly expanded our understanding of how the genome is organized in the three-dimensional (3D) space of the nucleus. It is now clear that the hierarchical organization of the eukaryotic genome critically impacts nuclear activities such as transcription, replication, as well as cellular and developmental events such as cell cycle, cell fate decision and embryonic development. In this review, we discuss new insights into how the structural features of the 3D genome hierarchy are established and maintained, how this hierarchy undergoes dynamic rearrangement during normal development and how its perturbation will lead to human disease, highlighting the accumulating evidence that links the diverse 3D genome architecture components to a multitude of human diseases and the emerging mechanisms by which 3D genome derangement causes disease phenotypes. PMID- 29990540 TI - Epidemiology and ARIMA model of positive-rate of influenza viruses among children in Wuhan, China: A nine-year retrospective study. AB - OBJECTIVE: Influenza is a common childhood disease and protecting children by predicting the positive rate of influenza virus is important as vaccines are not routinely administered in China. Our study aims to describe the epidemiology of influenza viruses among children in Wuhan, China during the past nine influenza seasons (2007-2015) and to predict the positive rate of different types of influenza virus in the future. METHODS: During the last nine influenza seasons (2007-2015), a total of 10,232 nasopharyngeal swabs collected from pediatric outpatients (age <15years) with influenza-like illness (ILI) infections in two sentinel children's hospitals were examined for influenza A and B by real-time one step RT-PCR. An autoregressive integrated moving average (ARIMA) model was used to fit the time series and to predict the future (first half of 2016) positive rates of different types of influenza virus. RESULTS: A total of 1,341 specimens were positive for influenza A and 490 for influenza B. The majority of infected patients were 1-11 years old (87.7%). The ARIMA model could effectively predict the positive rate of influenza virus in a short time. ARIMA(0,0,11), SARIMA(1,0,0)(0,1,1)12, ARIMA(0,0,1) and SARIMA(0,0,1)(1,0,1)12 were suitable for B(Victoria), B(Yamagata), A(H1N1)pdm09, and A(H3N2), respectively. CONCLUSION: Additional policies must be formulated to prevent and control influenza. The wide use of influenza vaccines, especially for influenza B, especially for influenza B(Yamagata) and B(Victoria), can potentially reduce the effects of influenza on children of China. PMID- 29990541 TI - Giant left atrium: Adaptive or maladaptive? PMID- 29990542 TI - Pleiotropic effects of antiplatelet treatment in patients with coronary artery disease. PMID- 29990543 TI - Administration of donor splenocytes via the respiratory tract generates CD8alpha+ regulatory dendritic cells and induces hyporesponsiveness to fully allogeneic cardiac grafts. AB - BACKGROUND: We previously showed that pretreatment with intratracheal delivery (ITD) of alloantigen induced prolonged cardiac allograft survival and generated regulatory T cells (Tregs) in mice. In this study, we examined the role of splenic dendritic cells (DCs) in the ITD model. METHODS: CBA mice were treated with ITD from C57BL/10 splenocytes and 7 days later received transplantation of C57BL/10 hearts. In adoptive transfer studies, splenic DCs from ITD-treated mice were transferred into naive CBA recipients that received C57BL/10 hearts immediately after the transfer. In addition, to determine the role of splenic DCs isolated from ITD-treated mice, the cells were incubated under stimulation with lipopolysaccharide (LPS). RESULTS: ITD-treated CBA recipients had markedly prolonged allograft survival (median survival time [MST], 67 days) while naive recipients rejected allografts acutely (MST, 8 days). In adoptive transfer studies, CBA recipients of the transfer of splenic DCs from ITD-treated mice had prolonged allograft survival (MST, 85 days), while CBA recipients of the transfer of splenic DCs from naive mice did not have prolonged allograft survival (MST, 8 days). In another transfer study, CBA recipients of the transfer of splenic CD8alpha+ DCs from ITD-treated mice had prolonged allograft survival (MST, 79 days), while those receiving splenic CD8alpha- DCs from ITD-treated mice did not have prolonged allograft survival (MST, 8 days). In vitro studies showed that ITD treated splenic DCs produced more IL-10 and less IL-12 than naive splenic DCs under stimulation with LPS. CONCLUSIONS: ITD pretreatment induces regulatory DCs, which produce high amounts of IL-10 resulting in the prolongation of graft survival in our model. PMID- 29990544 TI - Diet induced obesity modifies vitamin D metabolism and adipose tissue storage in mice. AB - Low circulating levels of total and free 25-hydroxyvitamin D (25(OH)D) indicative of vitamin D status have been associated with obesity in humans. Moreover, obesity is thought to play a causal role in the reduction of 25(OH)D levels, and several theories have been put forward to explain this relationship. Here we tested the hypothesis that obesity disrupts vitamin D homeostasis in key organs of vitamin D metabolism. Male C57BL6 mice were fed for 7 or 11 weeks on either a control diet (control, 10% energy from fat) or a high-fat diet (HF, 60% energy from fat) formulated to provide equivalent vitamin D3 intake in both groups. After 7 weeks, there was a transient increase of total 25(OH)D together with a significant decrease of plasma vitamin D3 that could be related to the induction of hepatic genes involved in 25-hydroxylation. After 11 weeks, there was no change in total 25(OH)D but a significant decrease of free 25(OH)D and plasma vitamin D3 levels. We also quantified an increase of 25(OH)D in adipose tissue that was inversely correlated to the free 25(OH)D. Interestingly, this accumulation of 25(OH)D in adipose tissue was highly correlated to the induction of Cyp2r1, which could actively participate in vitamin D3 trapping and subsequent conversion to 25(OH)D in adipose tissue. Taken together, our data strongly suggest that the enzymes involved in vitamin D metabolism, notably in adipose tissue, are transcriptionally modified under high-fat diet, thus contributing to the obesity-related reduction of free 25(OH)D. PMID- 29990545 TI - PPARgamma regulates meibocyte differentiation and lipid synthesis of cultured human meibomian gland epithelial cells (hMGEC). AB - PURPOSE: To evaluate the role of PPARgamma in regulating meibocyte differentiation and lipid synthesis in a human meibomian gland epithelial cell line (hMGEC). METHODS: HMGEC were exposed to the PPARgamma agonist, Rosiglitazone, from 10-50 MUM. Cultures were also exposed to specific PPARgamma antagonist, T0070907, to block PPARgamma receptor signaling. Cells were then stained with Ki-67 and LipidTox to determine the effects on cell cycling and lipid synthesis, respectively. Expression of meibocyte differentiation related proteins, ADFP, PPARgamma, ELOVL4, and FABP4, were evaluated by quantitative PCR and western blotting. A human corneal epithelial cell line (hTCEpi) was used as a control. RESULT: Rosiglitazone significantly decreased Ki-67 staining within 2 days in a dose-dependent manner (P = 0.003) and increased lipid accumulation in hMGEC in a dose dependent manner. T0070907 suppressed both lipid droplet synthesis and cell cycle exit. Rosiglitazone significantly upregulated expression of ADFP, PPARgamma, ELOVL4, and FABP4 by 9.6, 2.7, 2.6, and 3.3 fold on average (all P < 0.05 except for FABP4, P = 0.057) in hMGEC. T0070907 significantly abrogated rosiglitazone-induced upregulation of these genes when treated prior to rosiglitazone treatment (all P < 0.05). The observed lipogenic differentiation response was not duplicated in hTCEpi after exposure to rosiglitazone. CONCLUSION: Rosiglitazone induced cell cycle exit and upregulation of lipogenic gene expression leading to lipid accumulation in hMGEC. These effects were suppressed by PPARgamma antagonist indicating that PPARgamma signaling specifically directs lipogenesis in hMGEC. These findings suggest that PPARgamma plays a critical role in meibocyte differentiation. PMID- 29990546 TI - Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation. AB - Candida albicans is a commensal yeast of the human body, able to form biofilms on solid surfaces such as implanted medical devices, and contributes to nosocomial infections. Biofilms have the capacity to resist higher levels of antifungals compared with planktonic cells, and can develop tolerance to commonly used treatments. The necessity to overcome acquired drug resistance and identify new active molecules with low toxicity is a significant problem. It has been reported that some antidepressants have antibacterial properties, but little is known regarding the effect of these drugs on fungi. This study demonstrated the capacity of three tricyclic antidepressants (doxepin, imipramine and nortriptyline) to inhibit the growth and biofilm formation of Candida spp. The antimicrobial potential of the drugs was assessed by studying gene expression, hyphae formation, biofilm growth and maturation. Their negative impact on the growth of C. albicans and other Candida spp. is shown in vitro and with the hepatic S9 system, which is preliminary to any in-vivo test. This study found that the antidepressants considered can inhibit not only hyphae and biofilm formation, but also kill cells in a mature biofilm. Moreover, cell lysis by nortriptyline was observed, along with its synergistic activity with amphotericin B. These findings suggest that tricyclic antidepressants, particularly nortriptyline, should be studied further in drug repositioning programmes to assess their antimycotic capacity in full. PMID- 29990547 TI - Significance of catalase-peroxidase (KatG) mutations in mediating isoniazid resistance in clinical strains of Mycobacterium tuberculosis. AB - OBJECTIVES: Isoniazid (INH) is still the most important first-line antitubercular drug. INH resistance is regarded as a major impediment to the tuberculosis (TB) control programme and contributes to the emergence of multidrug-resistant strains. Mutation at position 315 in the katG gene, encoding the catalase peroxidase (KatG) enzyme, is the major cause of INH resistance in Mycobacterium tuberculosis. Therefore, investigation of the molecular mechanisms of INH resistance is the need of the hour. METHODS: To understand the clinical importance of KatG mutants (MTs) leading to INH resistance, in this study five MTs (S315T, S315I, S315R, S315N and S315G) were modelled, docked and interacted with INH in dynamic state. RESULTS: The binding affinity based on docking was found to be higher for MTs than for wild-type (WT) isolates, except for MT-S315R, indicating rigid binding of INH with MT proteins compared with the flexible binding seen in the WT. Analysis of molecular dynamics (MD) experiments suggested that fluctuations and deviations were higher at the INH binding residues for MTs than for the WT. Reduction in the hydrogen bond network after MD in all KatG enzymes implies an increase in the flexibility and stability of protein structures. Superimposition of MTs upon the WT structure showed a significant deviation that varies for the different MTs. CONCLUSIONS: It can be inferred that the five KatG MTs affect enzyme activity in different ways, which could be attributed to conformational changes in MT KatG that result in altered binding affinity to INH and eventually to INH resistance. PMID- 29990548 TI - Unilateral Labial Edema in a Female Adolescent: A Gynecologic Presentation of Rhabdomyolysis. AB - BACKGROUND: Rhabdomyolysis can be the result of vigorous physical activity. Typical signs and symptoms at presentation are muscle pain, weakness, or dark colored urine. There is no scientific literature associating rhabdomyolysis with gynecologic signs and symptoms. CASE: We present a case of a 16-year-old girl who presented to our pediatric emergency department with complaints of progressive left vulvar swelling. The patient underwent magnetic resonance imaging, which showed polymyositis in the rectus abdominus, external and internal obliques, and bilateral vastus lateralis muscles. Laboratory evaluation showed elevated liver transaminases, creatine kinase, and myoglobin serum levels. SUMMARY AND CONCLUSION: Exertional rhabdomyolysis is associated with muscular damage after vigorous exercise. This case is an example of a patient with rhabdomyolysis presenting with an unusual external gynecological manifestation, as unilateral labial edema. PMID- 29990549 TI - Peritoneal Nodules in a Pediatric Patient with Benign Teratoma. A Case Report and Review of Literature. AB - BACKGROUND: Mature ovarian teratomas are common in children. These well differentiated tumors are typically confined to the ovary. In rare cases, they can rupture leading to granulomatous peritonitis that mimics carcinomatosis. Ovarian tumors with peritoneal/omental implants suggest malignant pathology with a different prognosis. CASE: A 15-year-old girl presented with 5 months of abdominal pain, and weight loss. Computed tomography (CT) imaging of the abdomen revealed a large mass filling the abdomen. Slightly elevated lactate dehydrogenase (LDH) and carcinoma antigen 125 (CA125). On laparotomy an ovarian tumor with peritoneal and omental implants was identified. Left salpingo oophorectomy, omentectomy, and peritoneal washing were performed. Pathology revealed a benign cystic teratoma. SUMMARY AND CONCLUSION: Although ovarian teratomas are typically benign, they might mimic carcinomatosis. In patients with unexpected finding of peritoneal implants, histologic diagnosis is recommended before proceeding with a full oncologic ovarian resection. PMID- 29990550 TI - Medical Child Abuse: A Case Presenting as Anogenital Bleeding of Unknown Origin in an Older Child. AB - BACKGROUND: Medical child abuse is a challenging diagnosis to make, particularly in older children with unusual presenting symptoms. CASE: A 7-year-old child with complex medical history presented with anogenital bleeding of unknown origin. Extensive laboratory testing, imaging studies, and diagnostic procedures were negative for any etiology. Forensic testing confirmed the blood in her underwear was a genetic match to the patient. Trial separation from the mother was diagnostic and therapeutic in this case. SUMMARY AND CONCLUSION: Older children who are victims of medical child abuse might present in a variety of ways, and might even collaborate with the perpetrator in falsifying symptoms. It is important to keep medical child abuse on the differential when the patient's symptoms and work-up do not match. PMID- 29990551 TI - Animal models of NAFLD from a hepatologist's point of view. AB - Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disorder closely linked to obesity, hyperlipidemia and type 2 diabetes and is increasingly recognized as a major health problem in many parts of the world. While early stages of NAFLD are characterized by a bland accumulation of fat (steatosis) in hepatocytes, the disease can progress to non-alcoholic steatohepatitis (NASH) which involves chronic liver inflammation, tissue damage and fibrosis and can ultimately lead to end-stage liver disease including cirrhosis and cancer. As no approved pharmacological treatment for NAFLD exists today, there is an urgent need to identify promising pharmacological targets and develop future therapies. For this purpose, basic and translational research in NAFLD animal models is indispensable. While a large number of diverse animal models are currently used in the field, there is an ongoing challenge to identify those models that mirror human pathology the closest to allow good translation of obtained results into further clinical development. This review is meant to provide a concise overview of the most relevant NAFLD animal models currently available and will discuss the strengths and weaknesses of these models with regard to their comparability to human disease conditions. PMID- 29990552 TI - Post-transcriptional Regulation of MicroRNA Accumulation and Function: New Insights from Plants. PMID- 29990553 TI - Mediator, known as a coactivator, can act in transcription initiation in an activator-independent manner in vivo. AB - Mediator is an evolutionarily conserved complex best known for its role as a coactivator responsible for transducing regulatory signals from DNA-bound activators to the basal RNA polymerase II (Pol II) machinery that initiates transcription from promoters of protein-encoding genes. By exploiting our in vivo activator-independent transcription assay in Saccharomyces cerevisiae, in combination with new temperature sensitive (ts) mutants of Med14 N-terminal half exhibiting widespread transcriptional defects, and existing ts mutants of Kin28 and Med17, we show that, in the absence of activator: (i) Mediator can associate with a promoter as a form devoid of the Cyclin-dependent kinase 8 (CDK8) module, and this association remains regulated by Kin28; (ii) Mediator can stimulate the assembly of the entire Pol II initiation machinery. Although the literature emphasizes the role of the interaction between activators and Mediator, together our results support the view that Mediator is able to act through a dual mechanism in vivo, activator-dependent but also activator-independent, therefore not always as a coactivator. PMID- 29990554 TI - Synthesis of starch functionalized sulfonic acid co-imidazolium/silica composite for improving oil recovery through chemical flooding technologies. AB - Polymer flooding in HPHT reservoirs using modified biopolymers and their composites acquire incremental attention nowadays. Some literature reported about limitations of native starch through enhanced oil recovery applications regarding bacterial degradation, thermal and ionic stability under severe reservoir environment. In the present study, functionalization of the starch biopolymer with thiol derivative then oxidation of thiol to sulfonic acid by environmentally friendly oxidants has been prepared and confirmed, after that starch derivative copolymerized with vinyl-containing monomers by free radical/redox emulsion polymerization in presence of silica seeds. Spectroscopic characterization and structure determination carried out by different spectroscopic techniques comprising FTIR, 1H NMR, while particles size measured through DLS and TEM, and thermal analysis determined by TGA analysis. Evaluation of the prepared composite as a novel enhanced oil recovery (EOR) candidate as well as the precursors conducted at simulated reservoir condition, where the oil recovery factor and water cut percentage calculated relevant to injected pore volume. The flooding data indicate that the prepared starch functionalized sulfonic acid co imidazolium/silica composite is favorable for enhanced oil recovery applications as it can withstand high temperature and salinity conditions and the recovery factor reaches 39% of residual oil saturation. PMID- 29990555 TI - Auricularia auriculajudae polysaccharide-cisplatin complexes conjugated with folic acid as new tumor targeting agents. AB - The Auricularia auriculajudae polysaccharide-cisplatin complex (AAP-CDDP) was synthesized and characterized. The drug release, hemocompatibility, anti-tumor activity, and targeting ability of the complex were studied. The results of cell assay showed that the FA-AAP-CDDP complex showed better anti-tumor activity (IC50 lower 49.5%), and displayed higher uptake rate (higher 2-11-fold) than the AAP CDDP complex. In vivo experiments showed that the FA-AAP-CDDP complex had the same ability as free cisplatin to decrease subcutaneous tumor growth and reduce the level of serum tumor markers in nude mice. Meanwhile, western blotting analysis showed that the FA-AAP-CDDP complex induced apoptosis by activating Bax, Cytochrome-c, and Caspase-3, and downregulating Bcl-2, which suggested that the FA-AAP-CDDP complex may induce apoptosis through the endogenetic-mitochondrion signaling apoptosis pathways and intrinsic apoptotic pathways. In addition, the organ weights of FA-AAP-CDDP complex treated mice were significant higher than the cisplatin; and these mice had higher superoxide dismutase, catalase, and glutathione peroxidase activities, and less malondialdehyde in the serum. Thus, the FA-AAP-CDDP complex seems to be an effective, potential, and clinically feasible tumor cell-targeted preparation which shows a better clinical efficacy in treatment of cervical cancer, with improved quality of life, immune function and survival rate. PMID- 29990556 TI - Conformational and dynamical basis for cross-reactivity observed between anti HIV 1 protease antibody with protease and an epitope peptide from it. AB - F11.2.32 is a monoclonal antibody raised against HIV-1 protease and it inhibits protease activity. While the structure of the epitope peptide in complex with the antibody is known, how protease interacts with the antibody is not known. In this study, we model the conformational features of the free and bound epitope peptide and protease-antibody interactions. We find through our simulations, that the free epitope peptide P36-46 samples conformations akin to the bound conformation of the peptide in complex with the Ab, with a beta-turn conformation sampled by the 38LPGR41 sequence highlighting the role of inherent conformational preferences of the peptide. Further, to determine the interactions present between the protease and antibody, we docked the protease in its conformation observed in the crystal structure, onto the antibody and simulated the dynamics of the complex in explicit water. We have identified the key residues involved in hydrogen-bond interactions and salt-bridges in Ag-Ab complex and examined the role of CDR flexibility in binding different conformations of the same epitope sequence in peptide and protein antigens. Thus, our results provide the basis for understanding the cross-reactivity observed between the antibody with protease and the epitope peptide from it. PMID- 29990557 TI - Mass spectrometry-assisted venom profiling of Hypnale hypnale found in the Western Ghats of India incorporating de novo sequencing approaches. AB - Hypnale hypnale (hump-nosed pit viper) is considered to be one among the medically important venomous snake species of India and Sri Lanka. In the present study, venom proteome profiling of a single Hypnale hypnale from Western Ghats of India was achieved using SDS-PAGE based protein separation followed by LC-MS/MS analysis. The identities of the proteins that were not established using the Mascot search were determined through de novo sequencing tools such as Novor followed by MS-BLAST based sequence similarity search algorithm and PEAKS proteomics software. The combined proteomics analysis revealed a total of 37 proteins belonging to nine different snake venom families, in which 7 proteins were exclusively identified through de novo strategies. The enzymatic and non enzymatic venom protein families identified include serine proteases, metalloproteases, phospholipase A2, thrombin-like enzymes, phospholipase B, C type lectins/snaclecs, disintegrins, cysteine rich secretory proteins and nerve growth factor. Among these, disintegrins, nerve growth factor, phospholipase B and cysteine rich secretory protein families were identified for the first time in HPV venom. This could possibly explain the regiospecific venom variation seen across snake species. Taken together, the venom proteome profiling on Indian Hypnale hypnale venom correlates with the clinical manifestations often seen in the envenomed victims. PMID- 29990558 TI - Cyclosomatostatin- and haloperidol-induced catalepsy in Wistar rats: Differential responsiveness to sleep deprivation. AB - Total sleep deprivation (SD) has been found to mitigate motor dysfunctions in Parkinson's disease. Apparently, the similar sensitivity of an animal model for parkinsonism would support the model's validity. Recently, we described catalepsy induced in Wistar rats by somatostatin antagonist, cyclosomatostatin (cSST); this model simulates such a disease-associated abnormality as a fall in brain somatostatin levels. To evaluate the similarity between the cSST model and Parkinson's disease, we assessed here the responsiveness of cSST-induced catalepsy to 1-h and 3-h SD. In parallel, the influence of SD on catalepsy induced by a dopamine receptor antagonist, haloperidol, was examined. It was found that the short-term SD failed to influence cataleptic responses of both types (sleep deprived rats and undisturbed ones displayed a similar duration of immobility, p > 0.05). By contrast, 3-h SD suppressed (p < 0.01) cSST-induced catalepsy, however, enhanced (p < 0.01) cataleptic response to haloperidol. Thus, the anti-cataleptic effect of SD appears to be cSST-specific. These findings support the validity of the cSST-induced catalepsy in Wistar rats as a model for parkinsonian motor dysfunctions. PMID- 29990559 TI - Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene as risk factors for Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a complex aetiology. The epsilon4 allel of the apolipoprotein E gene (APOE) is the only confirmed genetic risk factor for the development of AD. In addition, polymorphisms at the promoter region of the APOE gene are assumed to modulate the susceptibility to AD by their different affinity to the transcription factors thus affecting the expression of the gene. In the presented study, we investigated the association between -491 A/T (rs449647), -427C/T, (rs769446) and -219 T/G (rs405509) single nucleotide polymorphisms (SNPs) of APOE gene and AD risk in the Polish population. We found that only the -491 T allele and -491 A/T genotype acted as protective factors against AD, whereas the -219 T/G heterozygosity increased risk for AD in APOE epsilon4 carriers but not in APOE epsilon4 non-carriers. What is more, haplotype frequency estimation showed significant positive for A-T-T-C-C and A-T-G-C-C haplotypes or negative for A-T-T T-C and T-T-T-T-C haplotypes associations with AD. These results contribute to the evidence that APOE promoter polymorphisms modulate risk for AD. PMID- 29990560 TI - Neural activation in response to the two sides of emotion. AB - Emotions are at the core of human cognition and behavior. Traditionally, emotions have been classified dichotomously as being either positive or negative. However, recent behavioral research (An et al., 2017) suggests that emotions contain both positivity and negativity. The current work investigated neural correlates of experiencing positive and negative emotions in response to happy and sad photos. Functional MRI revealed the precuneus and posterior cingulate cortex showed stronger activation when experiencing positivity compared to negativity of sadness, but not happiness, whereas the bilateral cerebellum showed greater response to positivity than negativity regardless of emotion. Results suggest that there are similarities and differences in the neural activation of positivity and negativity of happiness and sadness, consistent with previous findings (An et al., 2017). Emotion from both the neural and psychological perspectives were investigated. Further implications are discussed. PMID- 29990561 TI - Response of intestinal HT-29 cells to the trichothecene mycotoxin deoxynivalenol and its sulfated conjugates. AB - The sulfated forms of the Fusarium toxin deoxynivalenol (DON), deoxynivalenol-3 sulfate (DON-3-Sulf) and deoxynivalenol-15-sulfate (DON-15-Sulf) were recently described, however little is known about their mechanism of action in mammalian cells. DON-3-Sulf and DON-15-Sulf were taken up by HT-29 colon carcinoma cells, although to a lesser extent compared to DON. All three compounds were found to enhance the intracellular ROS level in the dichlorofluorescein assay (>= 1MUM), even though substantial differences were observed in their cytotoxic potential. In silico modelling highlighted that DON-sulfates do not share the classical mechanism of action of DON, being unable to fit into the ribosomal pocket and trigger the classical ribotoxic stress response. However, DON-3-Sulf and DON-15 Sulf sustained a distinctive proliferative stimulus in HT-29 and activated autophagy. The mechanisms of action of DON-3-Sulf and DON-15-Sulf suggest a potential interplay between the onset of ribosomal inhibition and autophagy activation as an alternative and/or complementary mode of action for DON and its sulfated analogues. PMID- 29990562 TI - Chronic iron overload induces vascular dysfunction in resistance pulmonary arteries associated with right ventricular remodeling in rats. AB - Although iron excess is toxic to the vasculature and even that pulmonary hypertension has been reported in this scenario, the role of iron overload per se remains to be clarified. This study aimed to test the effects of chronic iron overload in rats on the morphophysiology of resistance pulmonary arteries (RPA) and right ventricle (RV) remodeling. Rats were injected with saline or iron dextran (10, 100 and 200 mg/kg/day i.p.) for 28 days. Our results indicated increased circulating iron with significant lung deposits. Moreover, rats treated with the highest dose exhibited RV dysfunction and hypertrophy; inward remodeling and increased vasoconstriction of the RPA. Vascular hyperreactivity was accompanied by reduced nitric oxide (NO), and was reversed by incubation with Dimethylsulfoxide, Catalase and Tempol. The NADPH oxidase subunit gp91phox was increased due to iron-overload, and incubation with angiotensin II type-1 receptor (AT1) antagonist losartan not only reduced oxidative stress but also restored vascular function. Thus, we concluded that AT1 pathway plays a role in pulmonary vascular dysfunction by increasing oxidative stress and reducing NO bioavailability, thereby contributing to vascular remodeling and pulmonary hypertension of iron-overload. This finding should instigate future studies on the beneficial impacts of in vivo blockade of AT1 receptor under iron overload. PMID- 29990563 TI - Suitability of several naphthalene metabolites for their application in biomonitoring studies. AB - Naphthalene occurs together with polycyclic aromatic hydrocarbons (PAHs) at industrial workplaces and is ubiquitous in the environment. For biological monitoring of naphthalene exposures, up to now mainly 1- and 2-naphthol in urine have been used. Recently, we proposed 1,2-dihydroxynaphthalene (1,2-DHN) and the 1- and 2-naphthylmercapturic acid (1- and 2-NMA) as new urinary biomarkers to characterise a naphthalene exposure. In this study, in a collective of nine occupationally exposed workers handling with creosote the naphthalene metabolites 1,2-DHN, 1- and 2-NMA as well as 1- and 2-naphthol were analysed in order to evaluate the suitability of the different parameters for their application in biomonitoring studies. Additionally, air sampling was conducted to characterise the exposure in task related exposure situations at different workplaces. In the analysed 51 urine samples, 1,2-DHN was the main metabolite with concentrations ranging from 2.3 to 886 MUg/g creatinine (crea) (median 34 MUg/g crea). For the sum of 1- and 2-naphthol, concentrations in the range of 2.6-174 MUg/g crea (median 15 MUg/g crea) were observed. 1-NMA concentrations were in the range of < LOD-2.4 MUg/g crea (61% > LOD), while 2-NMA was not detected in the analysed urine samples. The biomarkers 1,2-DHN, 1- and 2-naphthol as well as 1-NMA showed significant correlations, which pointed out to naphthalene as the common exposure source. The poor correlations between naphthalene in the air and the biomarkers in urine may be a result of the varying exposure situations and may indicate not solely inhalative, but additional dermal uptake. 1,2-DHN was the most sensitive and, together with 1-NMA, the most specific parameter of the biological monitoring of naphthalene exposure at workplaces. Further studies with this parameter are needed for individuals at different workplaces as well as for persons of the general population without occupational PAH exposure to characterise 1,2-DHN levels as well as to establish their relationship with the naphthalene exposure. PMID- 29990564 TI - Clinical usefulness of the body muscle-to-fat ratio for screening obstructive sleep apnea syndrome in patients with inadequately controlled type 2 diabetes mellitus. AB - AIMS: To investigate whether body composition measures can be used for screening obstructive sleep apnea syndrome (OSAS) in patients with type 2 diabetes mellitus (T2DM) suspected of having OSAS. METHODS: Subjects were 186 hospital inpatients with inadequately controlled T2DM. We measured the respiratory disturbance index (RDI) as an indicator of OSAS using a sheet-type breath detection monitor, defining OSAS as an RDI >= 19 events/hour. Elementary body composition was measured by bioelectrical impedance analysis using InBody770. RESULTS: Simple logistic regression analysis identified body weight, body mass index (BMI), waist circumference, total body fat mass, body fat percentage, and body muscle-to-fat ratio (BMFR) as significantly associated with OSAS. The Nagelkerke R2 test showed that the BMFR was the most suitable measure for screening OSAS. Multivariate logistic regression analysis demonstrated that BMFR was significantly and independently associated with OSAS. In receiver operating characteristic curve analysis, the area under the BMFR curve was 0.70 (P < 0.001), indicating that BMFR was significantly predictive of OSAS. Furthermore, BMFR was the most suitable measure for screening OSAS in a sub-group analysis of non-obese patients with relatively low BMI (<27.5 kg/m2). CONCLUSIONS: In patients with T2DM, the BMFR is useful for screening OSAS in daily clinical practice. PMID- 29990565 TI - Impact of treatment with glibenclamide or vildagliptin on glucose variability after aerobic exercise in type 2 diabetes: A randomized controlled trial. AB - AIMS: To evaluate the glucose variability, oxidative stress, metabolic and cardiovascular responses after an aerobic exercise session in diabetic patients on treatment with metformin plus vildagliptin or glibenclamide. METHODS: Parallel clinical trial including patients with type 2 diabetes treated with metformin plus vildagliptin or glibenclamide for 12 weeks. Glucose variability, oxidative stress, metabolic (plasma glucose, insulin and glucagon-like-peptide-1) and cardiovascular responses were evaluated at rest, during and after a 30 min aerobic exercise session (70% of the peak heart rate). RESULTS: Thirteen patients were included, seven in vildagliptin group (METV) and six in glibenclamide group (METG), baseline glycated hemoglobin (HbA1c) 8.8 +/- 0.3%. Treatment reduced HbA1c (1.2% and 1.5% for METV and METG, respectively). The aerobic exercise session did not change glucose variability in both groups. A decrease in glucose during exercise recovery was found, with area under the curve lower in the METG vs. METV (p = 0.04). After the intervention, systolic blood pressure (SBP) decreased in both groups. Patients treated with vildagliptin showed lower SBP variability compared to those treated with glibenclamide. CONCLUSIONS: Besides improvement in glucose control and reduction of SBP obtained by both treatments, lower blood pressure variability was observed in patients receiving vildagliptin. Glucose variability remained unaffected by both interventions and the exercise session. PMID- 29990566 TI - The association of self-efficacy and hospitalization rates in people with type-2 diabetes: A prospective cohort study. AB - AIMS: Self-efficacy is presumed important in chronic disease management; we assessed the association between self-efficacy and risk of hospitalization in adults with type-2 diabetes. METHODS: A prospective cohort was assembled between December 2011 to December 2013. Participants completed an extensive survey, including a previously validated 6-item assessment of chronic disease management self-efficacy. The association between self-efficacy (low, medium, high) and all cause hospitalization within 1 year of the survey was assessed using multivariable logistic regression, after adjustment for sociodemographic characteristics, physical, behavioral and psychosocial factors. RESULTS: Among the cohort (n = 1915), the average age was 64.5 (SD 10.7) years, 45.3% were women and 199 (10.4%), 459 (24.0%) and 1257 (65.6%) participants reported low, medium and high self-efficacy, respectively. Participants with low self-efficacy were younger, had more comorbidities, and followed less healthy behaviors compared to those with high self-efficacy. In unadjusted analyses, low self-efficacy was associated with increased risk of hospitalization (23.6% vs 9.6%; odds ratio (OR) 2.90: 95% confidence interval (95%CI 1.99, 4.23)) compared to those with high self-efficacy, while no significant association was observed for medium self efficacy level (OR 1.28: 95%CI 0.91, 1.79). After adjustment, there was no difference in hospitalization risk for participants with low (OR 0.99; 95%CI 0.59, 1.67) or medium (OR 0.67; 95%CI 0.44, 1.01) self-efficacy compared to high self-efficacy. CONCLUSIONS: Our results suggest that self-efficacy is not independently associated with lower all-cause hospitalization in this population. Focus on additional heath aspects are likely required to improve overall health outcomes in people with type-2 diabetes. PMID- 29990567 TI - Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress. AB - The commensal microbiota affects brain functioning, emotional behavior and ACTH and corticosterone responses to acute stress. However, little is known about the role of the microbiota in shaping the chronic stress response in the peripheral components of the hypothalamus-pituitary-adrenocortical (HPA) axis and in the colon. Here, we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids. Using specific pathogen-free (SPF) and germ-free (GF) BALB/c mice, we showed that the microbiota modulates emotional behavior in social conflicts and the response of the HPA axis, colon and mesenteric lymph nodes (MLN) to chronic psychosocial stress. In the pituitary gland, microbiota attenuated the expression of Fkbp5, a gene regulating glucocorticoid receptor sensitivity, while in the adrenal gland, it attenuated the expression of genes encoding steroidogenesis (MC2R, StaR, Cyp11a1) and catecholamine synthesis (TH, PNMT). The pituitary expression of CRH receptor type 1 (CRHR1) and of proopiomelanocortin was not influenced by microbiota. In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFalpha, IFNgamma, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1beta. Compared to GF mice, chronic stress upregulated in SPF animals the expression of pituitary Fkbp5 and colonic CRH and UCN2 and downregulated the expression of colonic cytokines. Differences in the stress responses of both GF and SPF animals were also observed when immunophenotype of MLN cells and their secretion of cytokines were analyzed. The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling. PMID- 29990568 TI - Synthesis of butyl oleate catalyzed by cross-linked enzyme aggregates with magnetic nanoparticles in rotating magneto-micro-reactor. AB - In order to increase application of cross-linked enzyme aggregates (CLEAs) in industry production, a novel micro-reactor system that included a rotating magnetic field (RMF), a micro-reactor and CLEAs with magnetic nanoparticles (M CLEAs) was designed to synthesize butyl oleate. Result showed that the presence of RMF significantly increased the yield of butyl oleate and the maximum increment was 23%. The yield of butyl oleate was impacted by the dosage and distribution of M-CLEAs in micro-reactor. M-CLEAs showed good reusability, since the morphology and the second structure of protein of M-CLEAs did not show evident change after 4 operative cycles. Although the three-dimensional fluorescence of M-CLEAs showed shift in fluorescence intensity and the maximum emission wavelengths, the yield of butyl oleate was not affected. This study provides a novel design that realized efficient, convenient and continuous application of CLEAs in biosynthesis, and M-CLEAs also show good promises in industry production. PMID- 29990569 TI - Influence of hydraulic retention time and carbon loading rate on the production of algae. AB - This paper is focused on the assessment of the production of algae in batch bioreactors. Hydraulic retention time, carbon loading rate and light color were the inputs of the study and algae production the main output. Bioreactors were operated in semi-continuous mode and tests lasted two months, more than two times the period required to meet a steady-state response. This steady-state was verified with plateau responses in both, soluble parameters and suspended solids. Results points out the great relevance of temperature. Likewise, they show that green light improves the production of algae, as well as long HRT and high CLR. Maximum production rates attained were in the range 4-14 mg d-1 L-1. The ratio COD /TSS for this biofuel was almost constant (3.13 mg COD mg-1 TSS) but the quality of the product obtained in terms of the Mean Oxidation State of Carbon is completely different. Longer HRT leads to lower MOSC and hence to potentially more valuable fuels. PMID- 29990570 TI - Deciphering molecular consequences of the proprotein convertase 1/3 inhibition in macrophages for application in anti-tumour immunotherapy. AB - During tumour development, macrophages are recruited to the tumour site and orientated towards an anti-inflammatory phenotype. Due to their immunosuppressive function, tumour associated macrophages (TAMs) are recognized as major components in tumour progression. Changing these macrophages to a pro-inflammatory phenotype is thus extensively studied as a potential means for developing novel anti-tumour therapy. In this context, we found that the Proprotein convertase 1/3 (PC1/3) is a relevant target. Proteomic analysis reveals that PC1/3 knockdown (KD) macrophages present all the characteristic of activated pro-inflammatory macrophages. Moreover, in PC1/3 KD macrophages, TLR4 and TLR9 signaling pathways can be enhanced leading to the secretion of pro-inflammatory factors and anti tumour factors. To develop an efficient anti-tumour immunotherapy, we may (i) target TAMs directly inside the tumour site for PC1/3 inhibition and TLR activation and used them as "Trojan macrophages" or (ii) directly take advantage of PC1/3 inhibited macrophages and use them as "drone macrophages" by activating them "at distance" with a TLR ligand. Therefore, PC1/3 inhibited macrophages constitute an innovative cell therapy to treat tumours efficiently. PMID- 29990571 TI - Outpatient Microureteroscopy for Distal Ureteral Stone-A True Minimally Invasive Procedure. AB - INTRODUCTION: To describe microureteroscopy, a novel minimally invasive approach for treating distal ureteral lithiasis. TECHNICAL CONSIDERATIONS: Seven female patients with distal ureteral stones <= 10 mm were operated by microureteroscopy. The microureteroscope consist on a 4.85 Fr (16-gauge) sheath, a 0.9 mm diameter flexible optic system, and a 3-arm Luer-lock adapter to connect the sheath and insert the optics. Patients are placed in lithotomy position. Under sedative anesthesia and antimicrobial coverage, we performed microureteroscopy in patients with distal ureteral stones, describing key steps and perioperative and postoperative outcomes. Stone clearance was assessed using X-ray plain abdominal film of KUB at 15 days. Mean patients age was 54.5 years, and mean stone size was 7.98 mm. Stone-free rate was 100%. Patients were discharged 2-4 hours after the procedure without intraoperative or major perioperative complications. CONCLUSION: Microureteroscopy was developed to reduce dilation and ureteral wall damage and, thus, to decrease postoperative stenting and hospital stay. PMID- 29990572 TI - Tailoring Medication for Lower Urinary Tract Symptoms in Men Based on International Prostate Symptom Score Voiding to Storage Ratio. AB - OBJECTIVE: To investigate therapeutic results of tailoring medication for lower urinary tract symptoms (LUTS) in men according to initial treatment results and International Prostate Symptom Score (IPSS)-voiding to storage subscore (V/S) ratio. METHODS: Men with mild-to-moderate LUTS were initially treated for 1 month with doxazosin 4 mg daily for IPSS-V/S >1 or tolterodine 4 mg daily for IPSS-V/S <=1. They then underwent the Global Response Assessment (GRA) to tailor their medication by changes in IPSS-V/S, uroflow, and GRA, which were compared at baseline, 1, and 3 months post-treatment. RESULTS: Upon baseline, 162/374 men had IPSS-V/S <=1, and 212/374 had an IPSS-V/S >1. Both groups had significant improvement in IPSS-T, IPSS-S, and IPSS-V/S 1 month post-treatment. Of the 162 men initially receiving tolterodine, 102 (63.0%) continued monotherapy; 20 (12.3%) had IPSS-V/S >1.5 and were shifted to doxazosin monotherapy, and 40 (24.7%) had IPSS-V/S >1 but <=1.5 and added doxazosin. Among the 212 men initially receiving doxazosin, 171 (80.7%) continued monotherapy; 9 with IPSS-V/S <1.5 were switched to tolterodine, and 32 had IPSS-V/S <2 but >1.5 and added tolterodine. Improvement in GRA was remarkable in all subgroups with tailoring the medication to patient symptomatology. CONCLUSION: This study reveals that treatment customization according to IPSS-V/S after initial medical therapy provided satisfactory outcomes for men with mild-to-moderate LUTS. PMID- 29990573 TI - National Trends in Active Surveillance for Prostate Cancer: Validation of Medicare Claims-based Algorithms. AB - OBJECTIVE: To better describe the real-world use of active surveillance. Active surveillance is a preferred management option for low-risk prostate cancer, yet its use outside of high-volume institutions is poorly understood. We created multiple claims-based algorithms, validated them using a robust clinical registry, and applied them to Medicare claims to describe national utilization. MATERIALS AND METHODS: We identified men with prostate cancer from 2012-2014 in a 100% sample of Michigan Medicare data and linked them with the Michigan Urologic Surgery Improvement Collaborative (MUSIC) registry. Using MUSIC treatment assignment as the standard, we determined the performance of 8 claims-based algorithms to identify men on active surveillance. We selected 3 algorithms (the most sensitive, the most specific, and a balanced algorithm incorporating age and comorbidity) and applied them to a 20% national Medicare sample to describe national trends. RESULTS: We identified 1186 men with incident prostate cancer and completely linked data. Eight algorithms were tested with sensitivity ranging from 23.5% to 88.2% and specificity ranging from 93.5% to 99.1%. We found that the use of surveillance for men with incident prostate cancer increased from 2007 to 2014, nationally. However, among all men in the population, there was a large decrease in the rate of prostate cancer diagnosis and an increased or stable rate in the use of active surveillance, depending on the algorithm used. Less than 25% of men on active surveillance underwent a confirmatory prostate biopsy. CONCLUSION: We describe the performance of claims-based algorithms to identify active surveillance. PMID- 29990574 TI - Comparative Effectiveness of Local and Systemic Therapy for T4 Prostate Cancer. AB - OBJECTIVE: To evaluate the comparative effectiveness of local vs systemic therapy among patients diagnosed with nonmetastatic clinical T4 prostate cancer. METHODS: Using the National Cancer Database men with clinical T4N0-1M0 prostate cancer from 2004 to 2013 were identified. Local therapy was defined as radiation (RT with androgen deprivation therapy [ADT]), surgery (radical prostatectomy with ADT), or combined radiation plus surgery (radical prostatectomy plus RT with ADT). Systemic therapy was defined as ADT or chemotherapy alone. The primary outcome of overall survival was estimated using the Kaplan-Meier method. Factors associated with overall survival were determined by Cox proportional hazards models. RESULTS: A total of 1914 patients were included in our analysis, 1559 received local therapy and 355 received systemic therapy. Median 5-year survival for local vs systemic therapy was 41.5 and 28.2 months, respectively. On multivariable analysis, local therapy was associated with increased overall survival compared to systemic therapy (hazard ratio [HR] = 0.52; 95% confidence interval [CI] 0.44-0.62, P < .001). Comparing local therapy treatment modalities, both radiation (HR = 0.44; 95% CI 0.36-0.53, P < .001) and surgery (HR = 0.67; 95% CI 0.55-0.82, P < .001) were associated with increased overall survival compared to systemic therapy. Among those receiving local therapy, more patients were treated with radiation (n = 709/1559 or 45.5%) compared to surgery (n = 560/1559 or 35.9%) or combined radiation plus surgery (n = 290/1559 or 18.6%) with 5-year overall survival by treatment type being 61%, 51.4%, and 62.2%, respectively. CONCLUSION: Local therapy for clinical T4 prostate cancer is associated with improved overall survival. Due to the retrospective, nonrandomized nature of the study design, a clinical trial is needed to better define the efficacy of local therapy in this high-risk patient population. PMID- 29990575 TI - Molecular mechanism and inhibitory targets of dioscin in HepG2 cells. AB - Dioscin has been known for its anti-cancer activity; however, its detailed molecular mechanisms have not been studied so far. Herein, we evaluated the anti cancer activity of dioscin for proliferation inhibition and apoptosis in HepG2 cancer cells. Initially, dioscin was purified and identified from Polygonatum sibiricum by HPLC, MS, and NMR analysis, respectively. Dioscin inhibited the cell multiplication at IC50 of 8.34 MUM, altered the cell morphology, arrested the cell cycle in G2/M phase and led to considerable programmed cell death. Furthermore, it has efficiently promoted the mitochondrial pathway and death receptor pathway. The inhibition of Caspase-8 and Caspase-9 proteins in these pathways abolished the dioscin induced apoptosis significantly; while dioscin inhibited the PI3K/Akt/mTOR pathway. Moreover, dioscin exposure led to enhanced intracellular ROS generation and the mRNA expression of JNK gene which emphasized their involvement in the apoptosis process in HepG2 cells. PMID- 29990576 TI - Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems. AB - Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs. PMID- 29990577 TI - Role of food-derived antioxidants against cisplatin induced-nephrotoxicity. AB - Cancer is a relevant public health problem that represents the second leading cause of global death. In this regard, cisplatin is a highly effective antineoplastic drug used in treatment of several types of cancer, such as head and neck, testicular, ovarian, gastric, lung and breast cancer. Nevertheless, treatment with this compound leads to nephrotoxicity, which limits its use. Oxidative stress plays a pivotal role in cisplatin-induced renal damage and several dietary antioxidants have been reported to ameliorate this secondary effect. Relevant findings on the protective effects of these antioxidant agents in cisplatin-induced nephrotoxicity are summarized in this paper. Further, limitations of animal models used in these studies are discussed. Additionally, clinical studies on the protective effect of these antioxidants, as well as future directions for these kind of trials are also considered. PMID- 29990578 TI - 3D bioprinting of tissues and organs for regenerative medicine. AB - 3D bioprinting is a pioneering technology that enables fabrication of biomimetic, multiscale, multi-cellular tissues with highly complex tissue microenvironment, intricate cytoarchitecture, structure-function hierarchy, and tissue-specific compositional and mechanical heterogeneity. Given the huge demand for organ transplantation, coupled with limited organ donors, bioprinting is a potential technology that could solve this crisis of organ shortage by fabrication of fully functional whole organs. Though organ bioprinting is a far-fetched goal, there has been a considerable and commendable progress in the field of bioprinting that could be used as transplantable tissues in regenerative medicine. This paper presents a first-time review of 3D bioprinting in regenerative medicine, where the current status and contemporary issues of 3D bioprinting pertaining to the eleven organ systems of the human body including skeletal, muscular, nervous, lymphatic, endocrine, reproductive, integumentary, respiratory, digestive, urinary, and circulatory systems were critically reviewed. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro drug testing models, and personalized medicine. While there is a substantial progress in the field of bioprinting in the recent past, there is still a long way to go to fully realize the translational potential of this technology. Computational studies for study of tissue growth or tissue fusion post-printing, improving the scalability of this technology to fabricate human-scale tissues, development of hybrid systems with integration of different bioprinting modalities, formulation of new bioinks with tuneable mechanical and rheological properties, mechanobiological studies on cell-bioink interaction, 4D bioprinting with smart (stimuli-responsive) hydrogels, and addressing the ethical, social, and regulatory issues concerning bioprinting are potential futuristic focus areas that would aid in successful clinical translation of this technology. PMID- 29990579 TI - Associations between body size and outcomes of adult in-hospital cardiac arrest: A retrospective cohort study. AB - AIM: Animal studies have demonstrated that hemodynamic-directed cardiopulmonary resuscitation (CPR) improves outcomes following cardiac arrest compared with the "one-size-fits-all" algorithm. We investigated whether body size of patients is correlated with outcomes of in-hospital cardiac arrest (IHCA). METHODS: A retrospective study in a single centre was conducted. Adult patients experiencing IHCA between 2006 and 2015 were screened. Body mass index (BMI) was calculated using body weight and height measured at hospital admission. Thoracic anteroposterior diameter (APD) was measured by analysing computed tomography images. Multivariate logistic regression analysis was used to study the associations between independent variables and outcomes. Generalised additive models were used to identify cut-off points for continuous variables. RESULTS: A total of 766 patients were included, and 60.4% were male. Their mean age was 62.8 years. Mean BMI was 22.9 kg/m2, and the mean thoracic APD was 21.4 cm. BMI > 23.2 kg/m2 was inversely associated with a favourable neurological outcome (odds ratio [OR]: 0.30, 95% confidence interval [CI]: 0.13-0.68; p-value = 0.004), while thoracic APD was not. When the interaction term was analysed, BMI > 23.2 (kg/m2) * thoracic APD > 18.5 (cm) was inversely associated with both a favourable neurological outcome (OR: 0.33, 95% CI: 0.16-0.69; p-value = 0.003) and survival to hospital discharge (OR: 0.46, 95% CI: 0.26-0.81; p-value = 0.007). CONCLUSION: Higher BMI and thoracic APD was correlated with worse outcomes following IHCA. For those patients, it might be better to perform CPR under guidance of physiological parameters rather than a "one-size-fits-all" resuscitation algorithm to improve outcomes. PMID- 29990580 TI - Unresponsive wakefulness or coma after cardiac arrest-A long-term follow-up study. AB - OBJECTIVE: To investigate the clinical course and early prognostic markers in cardiac arrest (CA) patients discharged from the intensive care unit (ICU) in an unresponsive wakefulness syndrome (UWS) or coma. METHODS: 89 patients were identified from a prospective CA database. Follow-up was conducted by telephone interviews with legal guardians, evaluation of re-admission and rehabilitation reports assessing core elements of the coma recovery scale-revised (CRS-R). Somatosensory evoked potential (SSEP) and electroencephalography (EEG) original recordings were re-analyzed, the gray-white-matter ratio (GWR) was determined from brain computed tomography (CT) and neuron-specific enolase (NSE) serum concentrations were retrieved. RESULTS: Follow-up was successful for 32/50 (64%) patients admitted between 2001-2009 and 31/39 (79%) between 2009-2015. Median ICU stay was 27 days (IQR 20-36). Neurological improvement beyond UWS was found in 2 of 63 patients. Among 61 patients with successful follow-up and no improvement, NSE serum concentrations within the reference range, SSEP amplitudes above 2.5 MUV or continuous reactive EEG were found in 5%, 3% and 2% of those tested. NSE > 90 MUg/L, SSEP <= 0.3 MUV, highly malignant EEG or GWR < 1.10 were found in 44%, 49%, 35% and 22% of those tested. CONCLUSIONS: Neurological recovery was rare in CA patients discharged in UWS after prolonged ICU treatment. Status epilepticus requiring prolonged deep sedation is one potential reason for delayed awakening. Sensitivity for established poor outcome parameters to predict persistent UWS early after CA was moderate. SSEP, EEG and NSE may indicate absence of severe HIE early after CA. PMID- 29990581 TI - Resting-state functional MRI studies on infant brains: A decade of gap-filling efforts. AB - Resting-state functional MRI (rs-fMRI) is one of the most prevalent brain functional imaging modalities. Previous rs-fMRI studies have mainly focused on adults and elderly subjects. Recently, infant rs-fMRI studies have become an area of active research. After a decade of gap filling studies, many facets of the brain functional development from early infancy to toddler has been uncovered. However, infant rs-fMRI is still in its infancy. The image analysis tools for neonates and young infants can be quite different from those for adults. From data analysis to result interpretation, more questions and issues have been raised, and new hypotheses have been formed. With the anticipated availability of unprecedented high-resolution rs-fMRI and dedicated analysis pipelines from the Baby Connectome Project (BCP), it is important now to revisit previous findings and hypotheses, discuss and comment existing issues and problems, and make a "to do-list" for the future studies. This review article aims to comprehensively review a decade of the findings, unveiling hidden jewels of the fields of developmental neuroscience and neuroimage computing. Emphases will be given to early infancy, particularly the first few years of life. In this review, an end to-end summary, from infant rs-fMRI experimental design to data processing, and from the development of individual functional systems to large-scale brain functional networks, is provided. A comprehensive summary of the rs-fMRI findings in developmental patterns is highlighted. Furthermore, an extensive summary of the neurodevelopmental disorders and the effects of other hazardous factors is provided. Finally, future research trends focusing on emerging dynamic functional connectivity and state-of-the-art functional connectome analysis are summarized. In next decade, early infant rs-fMRI and developmental connectome study could be one of the shining research topics. PMID- 29990582 TI - Interactions between frontal and posterior oscillatory dynamics support adjustment of stimulus processing during reinforcement learning. AB - Reinforcement learning (RL) in humans is subserved by a network of striatal and frontal brain areas. The electrophysiological signatures of feedback evaluation are increasingly well understood, but how those signatures relate to the use of feedback to guide subsequent behavioral adjustment remains unclear. One mechanism for post-feedback behavioral optimization is the modulation of sensory processing. We used source-reconstructed MEG to test whether feedback affects the interactions between sources of oscillatory activity in the learning network and task-relevant stimulus-processing areas. Participants performed a probabilistic RL task in which they learned associations between colored faces and response buttons using trial-and-error feedback. Delta-band (2-4 Hz) and theta-band (4-8 Hz) power in multiple frontal regions were sensitive to feedback valence. Low and high beta-band power (12-20 and 20-30 Hz) in occipital, parietal, and temporal regions differentiated between color and face information. Consistent with our hypothesis, single-trial power-power correlations between frontal and posterior sensory areas were modulated by the interaction between feedback valence and the relevant stimulus characteristic (color versus identity). These results suggest that long-range oscillatory coupling supports post-feedback updating of stimulus processing. PMID- 29990583 TI - Decoding neuropathic pain severity using distinct patterns of corticolimbic metabotropic glutamate receptor 5. AB - Susceptibility to neuropathic pain and the degree of pain amplification vary among individuals. However, methods for objective evaluation of pain status have not been well established. Using an animal model, we identified the brain signature of neuropathic pain, and developed a method for the objective evaluation of pain degree. We analyzed paw withdrawal thresholds from rats that were subjected to right L5 spinal nerve ligation (SNL) surgery, and regressed them to the metabotropic glutamate receptor 5 (mGluR5) availability levels in the brain using [11C] ABP688 PET image data from our previous research. We found clusters with a significant correlation to paw withdrawal threshold localized in brain areas involved in sensory, cognitive, and affective aspects of pain processing. Strikingly, mGluR5 availability levels in the identified brain regions showed distinct patterns in the neuropathic pain group but not in the control group. We successfully elucidated the degree of pain-sensing behavior using the neuropathic pain-specific pattern of the mGluR5 availability. Our study provides new insight into the signature of neuropathic pain in the brain, and offers a novel diagnostic method for objectively decoding the status of individual neuropathic pain. PMID- 29990584 TI - Impact of short- and long-term mindfulness meditation training on amygdala reactivity to emotional stimuli. AB - Meditation training can improve mood and emotion regulation, yet the neural mechanisms of these affective changes have yet to be fully elucidated. We evaluated the impact of long- and short-term mindfulness meditation training on the amygdala response to emotional pictures in a healthy, non-clinical population of adults using blood-oxygen level dependent functional magnetic resonance imaging. Long-term meditators (N = 30, 16 female) had 9081 h of lifetime practice on average, primarily in mindfulness meditation. Short-term training consisted of an 8-week Mindfulness- Based Stress Reduction course (N = 32, 22 female), which was compared to an active control condition (N = 35, 19 female) in a randomized controlled trial. Meditation training was associated with less amygdala reactivity to positive pictures relative to controls, but there were no group differences in response to negative pictures. Reductions in reactivity to negative stimuli may require more practice experience or concentrated practice, as hours of retreat practice in long-term meditators was associated with lower amygdala reactivity to negative pictures - yet we did not see this relationship for practice time with MBSR. Short-term training, compared to the control intervention, also led to increased functional connectivity between the amygdala and a region implicated in emotion regulation - ventromedial prefrontal cortex (VMPFC) - during affective pictures. Thus, meditation training may improve affective responding through reduced amygdala reactivity, and heightened amygdala VMPFC connectivity during affective stimuli may reflect a potential mechanism by which MBSR exerts salutary effects on emotion regulation ability. PMID- 29990585 TI - Exploring the potential of tocotrienol from Bixa orellana as a single agent targeting metabolic syndrome and bone loss. AB - Metabolic syndrome (MetS) is associated with osteoporosis due to the underlying inflammatory and hormonal changes. Annatto tocotrienol has been shown to improve medical complications associated with MetS or bone loss in animal studies. This study aimed to investigate the effects of annatto tocotrienol as a single treatment for MetS and osteoporosis in high-carbohydrate high-fat (HCHF) diet induced MetS animals. Three-month-old male Wistar rats were randomly divided into five groups. The baseline group was euthanized at the onset of the study. The normal group received standard rat chow and tap water. The remaining groups received HCHF diet and treated with three different regimens orally daily: (a) tocopherol-stripped corn oil (the vehicle of tocotrienol), (b) 60 mg/kg annatto tocotrienol, and (c) 100 mg/kg annatto tocotrienol. At the end of the study, measurements of MetS parameters, body compositions, and bone mineral density were performed in animals before sacrifice. Upon euthanasia, blood and femur of the rats were harvested for the evaluations of bone microstructure, biomechanical strength, remodelling activities, hormonal changes, and inflammatory response. Treatment with annatto tocotrienol improved all MetS parameters (except abdominal obesity), trabecular bone microstructure, bone strength, increased osteoclast number, normalized hormonal changes and inflammatory response in the HCHF animals. In conclusion, annatto tocotrienol is a potential agent for managing MetS and osteoporosis concurrently. The beneficial effects of annatto tocotrienol may be attributed to its ability to prevent the hormonal changes and pro inflammatory state in animals with MetS. PMID- 29990586 TI - Effect of Acupressure on Preoperative Cesarean Section Anxiety. AB - Anxiety is a common preoperative problem in cesarean section candidates. Non pharmacologic anxiety control has been demonstrated to be more suitable in pregnant women. The current study was a randomized, single-blind clinical trial which evaluated the effect of acupressure on preoperative C-section anxiety. In this study, 60 patients facing surgery were randomly divided into two groups of 30 patients each. Those patients in the intervention group received simultaneous acupressure at the Yintang and HE-7 acupoints for 5 minutes before surgery, and patients in the control group received intervention at a sham acupoint. The anxiety level of patients was preoperatively assessed twice using the Spielberger's State-Trait Anxiety Inventory [STAI]. The mean anxiety scores of the two groups were shown to be insignificantly different before the intervention [p=0.859], whereas a significant difference between the mean anxiety scores of the two groups was observed after the intervention [p=0.001], suggesting that acupressure reduced the anxiety of patients before surgery. PMID- 29990587 TI - Development and application of a HPLC-MS/MS method for quantitation of fucosylated chondroitin sulfate and fucoidan in sea cucumbers. AB - Fucosylated chondroitin sulfate (FCS) and fucoidan (FUC) are two main bioactive polysaccharides in sea cucumbers. A novel method for quantitation of FCS and FUC was developed by detecting chondroitin disaccharide and fucose produced through acid hydrolysis using HPLC-MS/MS. The present method showed satisfactory performance for both saccharides. It was applied to assay sea cucumbers (Stichopus japonicus) reared in pond grow-out or bottom sowing, and the results were compared with those obtained by traditional HPLC method and 1,9 dimethylmethylene blue test, which could only provide the total sea cucumber polysaccharide (SCP) contents. No difference of total SCP content was observed between sea cucumbers reared through different ways, while a higher ratio of FCS to FUC of sea cucumbers of pond grow-out was revealed by the present method. Thus, this novel method is potential to quantify the two polysaccharides and could be a powerful tool for quality evaluation of sea cucumbers. PMID- 29990589 TI - Symmetry of root anatomy and root canal morphology in maxillary premolars analyzed using cone-beam computed tomography. AB - OBJECTIVE: This study aimed to use cone-beam computed tomography (CBCT) to evaluate the root anatomy and canal morphology of maxillary premolars in a Chinese population and determine their degree of bilateral symmetry. DESIGN: 774 CBCT images were retrospectively analyzed, representing 1387 maxillary first premolars and 1403 second premolars. The number of roots and canals were recorded. The morphology of root canal systems was determined according to Vertucci's classification. The symmetry of root and canal anatomies between maxillary contralateral premolars was further evaluated. RESULTS: The most common anatomy of maxillary first and second premolars was one-rooted with two canals (58.0%) and one-rooted with one canal (50.3%), respectively. The typical canal morphology was type IV (42.7%) in maxillary first premolars and type I (50.3%) in maxillary second premolars. One-rooted maxillary premolars exhibited a higher variability in the canal morphology, compared to two-rooted or three-rooted teeth. Maxillary second premolars exhibited greater anatomic symmetry than first premolars. The root and canal numbers showed bilateral symmetry between 80.2% of maxillary first premolar pairs and 81.8% of second premolar pairs. Bilateral symmetry in both number and morphology of roots and canals was observed for 72.3% of maxillary first premolar pairs and 73.2% of second premolar pairs. CONCLUSION: The root anatomy and canal morphology of maxillary premolars in a Chinese population were quite diversified. Maxillary contralateral premolars demonstrated a high degree of symmetry in root and canal anatomies, which enables practitioners to better determine the nature of the root canal system during treatment of opposite homonymous teeth. PMID- 29990588 TI - Investigation on the relationship of dimensions of the maxillary sinus drainage system with the presence of sinusopathies: a cone beam computed tomography study. AB - OBJECTIVE: This study sought to assess the relationship between the dimensions of the maxillary sinus drainage system with the content of sinuses. DESIGN: Three hundred cone beam computed tomography images were selected from a database (105 males and 195 females). The images were assessed by a single investigator, trained and calibrated, performing image analysis. The length of the infundibulum and the ostium height in both maxillary sinuses were measured. The data were analyzed using Minitab 16, using 5% as a critical p-value. RESULTS: A significant gender difference was also found for presence in the normal content of sinus for females and presence of antral pseudocyst for males (p < 0.05). Subjects with normal content in the maxillary sinus present lower ostium height values. There were statistically significant with presence of and higher ostium height values and antral pseudocyst (p < 0.01). CONCLUSION: The current study results demonstrated that some sinusopathies were significantly related to dimensions of maxillary sinus drainage. PMID- 29990590 TI - Novel minor HLA DR associated antigens in type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease leading to insulin deficiency. Autoantibodies to beta cell proteins are already present in the asymptomatic phase of type 1 diabetes. Recent findings have suggested a number of additional minor autoantigens in patients with type 1 diabetes. We have established luciferase immunoprecipitation systems (LIPS) for anti-MTIF3, anti-PPIL2, anti NUP50 and anti-MLH1 and analyzed samples from 500 patients with type 1 diabetes at onset of clinical disease and 200 healthy individuals who had a family history of type 1 diabetes but no evidence of beta cell autoantibodies. We show significantly higher frequencies of anti-MTIF3, anti-PPIL2 and anti-MLH1 in recent onset type 1 diabetes patients in comparison to controls. In addition, antibodies to NUP50 were associated with HLA-DRB1*03 and antibodies to MLH1 were associated with HLA-DRB1*04 genotypes. PMID- 29990591 TI - Lymphatic lacunae of the mucosal folds of human uterine tubes - A rediscovery of forgotten structures and their possible role in reproduction. AB - The mucosa of uterine tube forms multiple and branched longitudinal mucosal folds and takes part in many reproduction events, such as oocyte pick-up, gamete transport, sperm capacitation, fertilization, and early embryonic development. In the habilitation thesis of German physician Paul Kroemer (1904) was the first to describe the lymphatic lacunae inside the tubal folds (by injection of Indian ink), which the author named the oLymphbahnen" (olymphatic channels"). Despite the fact that this first description has existed for 110 years, there is no mention of these lacunae in most of the current literature. In this article we present a rediscovery of completely overlooked morphological structures of uterine tubes - the lymphatic lacunae in their mucosal folds. The specimens from the uterine tubes were taken from 72 women (mean age 46.25 years) who underwent transabdominal or laparoscopic salpingectomy. The tissue samples from anatomically different parts of the uterine tubes were used for hematoxylin and eosin staining and for immunohistochemistry. Primary antibodies were used to label and detect podoplanin D2-40, a selective marker of lymphatic endothelia, CD34 antigen, and von Willebrand factor (Factor VIII). In the histological slides of the uterine tubes, there were noticeable slits or gaps within the loose connective tissue of the lamina propria of the mucosal folds. They were lined with one layer of squamous endothelial cells. These oempty spaces" were most prominent in the fimbriae, but were still well recognizable in mucosal folds of the ampulla. They always run through the central part of the fold. As a results of immunohistochemistry, we confirmed that in the centre of every mucosal fold, as well as in the fimbriae of the uterine tubes, dilated lymphatic spaces were situated and were lined with a simple layer of lymphatic endothelial cells (positive for podoplanin and CD34, and negative for Factor VIII). As there is no mention on them in the current Terminologia Histologica, we proposed the term olymphatic lacunae of tubal mucosal folds and fimbriae" in English and olacunae lymphaticae plicae mucosae et fimbriae" in Latin. According to our hypothesis, these lymphatic lacunae may be responsible for the thickening of the fimbriae during the oocyte pick-up and the maintenance of the tubal fluid. PMID- 29990592 TI - Adding Value to the Conversation About Colorectal Cancer Screening: Practical Pearls For Gastroenterologists. PMID- 29990593 TI - Multisite pacing: Have we reached the tipping point of managing cardiac resynchronization therapy nonresponders? PMID- 29990594 TI - What is the most accurate radiographic criterion to determine anterior cervical fusion? AB - BACKGROUND CONTEXT: The accuracy of radiographic criteria for determining anterior cervical fusion remains controversial, and inconsistency in the literature makes a comparison of published clinical results problematic. The descriptions of bridging bone are still lacking and subjective, and the interpretation of images can be influenced by the type of graft or cage used. PURPOSE: To assess and validate the diagnostic accuracies of four radiographic fusion criteria using the results of surgical exploration. STUDY DESIGN: Retrospective, radiographic, and comparative study. PATIENT SAMPLE: This study included patients who required anterior or posterior exploration of a previous anterior cervical arthrodesis level(s) ranging from C3-C4 to C7-T1 for suspected pseudarthrosis or adjacent-segment pathologies. They underwent radiologic examinations to determine the four fusion criteria. We included patients whose images were taken at least 1 year after the index surgery, and 82 patients with 151 cervical segments were enrolled. OUTCOME MEASURES: The inter- and intra-rater reliabilities and validity that correlated with the results of surgical exploration for the four fusion criteria were assessed using data (fusion or not) that were collected by two raters. METHODS: The four published radiographic fusion criteria were interspinous motion (ISM) < 1 mm and superjacent ISM >= 4 mm, seen on dynamic radiographs; conventional bridging bone, as seen on computed tomography (CT) scans; and extra-graft bridging bone (ExGBB) and intragraft bridging bone (InGBB), observed on multi-axial reconstructed CT scans. The criteria were evaluated by two raters (spine surgeons with 5 and 7 years of experience). The raters evaluated each criterion twice at two different time points, 3 to 4 weeks apart. First, ISM and conventional bridging bone on CT scans were evaluated, followed by ExGBB and InGBB, with a time interval of 4 months. This Research was supported by the Chung-Ang University Research Grants (less than 5,000 US dollars) in 2016. RESULTS: The inter- and intra-rater reliability values of the ExGBB (0.887-0.933) criteria were the highest, followed by those for the ISM (0.860-0.906), bridging bone (0.755-0.907), and InGBB (0.656-0.695) criteria. The validity values that correlated with the exploration results were the highest for the ExGBB criteria (k=0.889), followed by the ISM (k=0.776), bridging bone (k=0.757), and InGBB (k=0.656) criteria and ExGBB showed the highest sensitivity (91.7%) and specificity (98.4%). Regarding the graft materials that were used, all criteria had the highest values in the auto cortical group and lowest values in the cage group. Of note, sensitivity and specificity of ExGBB were 100% in autocortical group. In the cage group, the validity values for the ExGBB (k=0.663) and ISM (k=0.666) criteria were higher than those for the bridging bone (k=0.504) and InGBB (k=0.308) criteria CONCLUSION: The presence of ExGBB (anterior, posterior, or lateral to the graft or cage) correlated the best with surgical exploration. The ISM criteria demonstrated a similar accuracy to that of conventional bridging bone criteria on CT scans. In arthrodesed segments with auto-cortical bone, criteria showed the highest validity values. In cage group, ISM and ExGBB had acceptable accuracy, but the conventional bridging bone and InGBB were worse than guessing. We recommend that ISM and ExGBB criteria should be used to increase accuracy in patients who undergo arthrodesis with cages. PMID- 29990595 TI - The biomechanical influence of anterior vertebral body osteophytes on the lumbar spine: A finite element study. AB - BACKGROUND CONTEXT: Anterior vertebral body osteophytes are common with degeneration but their biomechanical influence on the whole lumbar spine remains unclear. PURPOSE: To investigate the biomechanical influence of anterior vertebral body osteophytes on the whole lumbar spine. STUDY DESIGN/SETTING: This is a study using finite element analysis. OUTCOME MEASURES: Intersegmental rotation, maximum Mises stress, and intradiscal pressure on the intervertebral discs of different lumbar levels were calculated. METHODS: A finite element model of an intact lumbar spine was constructed and validated against in vitro studies. The modified models, which had different degrees of anterior vertebral body osteophyte formation (OF) in combination with disc space narrowing, were applied with physiological loadings. RESULTS: The lumbar levels with various degrees of OF altered the kinematics of these levels, which also affected the whole lumbar spine. In flexion and lateral bending, the segment that was one level inferior to the vertebra with OF showed a trend towards increased range of motion. On the intervertebral discs that were one level inferior to the OF level, a trend towards increase in the maximum von Mises stress was found on the annulus. CONCLUSIONS: Segments adjacent to levels with anterior vertebral body osteophytes showed increased intersegmental rotation and maximum stress. Further clinical observation should be performed to verify the results in vivo. PMID- 29990596 TI - Electrode plate-culture methods for colony isolation of exoelectrogens from anode microbiomes. AB - Exoelectrogens play central roles in microbial fuel cells and other bioelectrochemical systems (BESs), yet their physiological diversity remains largely elusive due to the lack of efficient methods for the isolation from naturally occurring microbiomes. The present study developed an electrode plate culture (EPC) method that facilitates selective colony formation by exoelectrogens and used it for isolating them from an exoelectrogenic microbiome enriched from paddy-field soil. In an EPC device, the surface of solidified agarose medium was spread with a suspension of a microbiome and covered with a transparent fluorine doped tin oxide (FTO) electrode (poised at 0 V vs. the standard hydrogen electrode) that served as the sole electron acceptor. The medium contained acetate as the major growth substrate and Coomassie Brilliant Blue as a dye for visualizing colonies under FTO. It was shown that colonies successfully appeared under FTO in association with current generation. Analyses of 16S rRNA gene sequences of colonies indicated that they were affiliated with genera Citrobacter, Geobacter and others. Among them, Citrobacter and Geobacter isolates were found to be exoelectrogenic in pure-culture BESs. These results demonstrate the utility of the EPC method for colony isolation of exoelectrogens. PMID- 29990597 TI - Impact of the protein myristoylation on the structure of a model cell membrane in a protein bound state. AB - The neuronal calcium sensor protein recoverin is expressed in retinal rod and cone cells and is involved in the calcium-dependent control of receptor (rhodopsin) phosphorylation and receptor inactivation. In its Ca2+-saturated form recoverin is attached to membranes by an exposed myristoyl group and responds to oscillating changes of intracellular Ca2+-concentration by performing a so-called Ca2+-myristoyl switch. In this work we analyze changes in a liquid lipid bilayer interacting with myristoylated and non-myristoylated recoverin by employing polarization modulation infrared reflection absorption spectroscopy (PM IRRAS) with electrochemical control. The lipid bilayer is transferred onto a polycrystalline gold electrode using Langmuir-Blodgett Langmuir-Schaefer transfer at the surface pressure pi = 30 mN m-1 which ensures, necessary for the lipid protein interaction, liquid state of the hydrocarbon chains of phospholipids. The model lipid bilayers are adsorbed directly on the Au electrode surface at transmembrane potentials -0.2 < ?phiM|S < 0.25 V. The interaction with recoverin leads to a stabilization of the adsorbed state of the lipid bilayer at positive transmembrane potentials. The interaction leads to a decrease in the surface charge density that accumulates on the membrane covered electrode surface, indicating changes in the lateral interactions in the lipid membrane. In situ spectroelectrochemical studies confirm orientation changes in the hydrophobic environment of the model membrane. Insertion of the myristoyl group of recoverin into the membrane is connected with an increase in the tilt of the hydrocarbon chains with respect to the surface normal and decrease in the bilayer thickness. Potential-induced pore formation and desorption of the lipid bilayer from the membrane surface is accompanied by the removal of the acyl chains of recoverin from the membrane. PMID- 29990598 TI - Evaluating the efficiency of a photoelectrochemical electrode constructed with photosystem II-enriched thylakoid membrane fragments. AB - The photoelectrochemical electrode has been intensively studied in recent years as a means of generating electricity from light through the use of intact thylakoid membranes or highly purified photosystem II. PSII-enriched thylakoid membrane fragments (PSII-BBY), also have the potential to construct the photoelectrochemical anode. In this study, we examined the feasibility of utilizing PSII-BBY preparations to construct a relatively inexpensive photoelectrochemical anode with a comparable current density and a reasonable stability. Intact thylakoid membrane based photoelectrochemical electrode was also constructed to compare with the PSII-BBY based photoelectrochemical electrode with respect to the protein activity and current density. In addition, the practicability of replacing the popular gold nanoparticle modified gold slide with multi-walled carbon nanotube modified indium tin oxide coated slides was tested. In order to understand the surface change during slide surface modification, an atomic force microscope (AFM) was used to image the topography of the slide. Above all, we observed a current density of 20.44 +/- 1.58 MUA/cm2 when PSII-BBY was used to construct the photoelectrochemical anode. Moreover, the PSII-BBY based photoelectrochemical anode showed high stability over time with the current decreasing at a rate of 0.78%/h. PMID- 29990599 TI - Cell membrane electroporation modeling: A multiphysics approach. AB - Electroporation-based techniques, i.e. techniques based on the perturbation of the cell membrane through the application of electric pulses, are widely used at present in medicine and biotechnology. However, the electric pulse - cell membrane interaction is not yet completely understood neither explicitly formalized. Here we introduce a Multiphysics (MP) model describing electric pulse - cell membrane interaction consisting on the Poisson equation for the electric field, the Nernst-Planck equations for ion transport (protons, hydroxides, sodium or calcium, and chloride), the Maxwell tensor and mechanical equilibrium equation for membrane deformations (with an explicit discretization of the cell membrane), and the Smoluchowski equation for membrane permeabilization. The MP model predicts that during the application of an electric pulse to a spherical cell an elastic deformation of its membrane takes place affecting the induced transmembrane potential, the pore creation dynamics and the ionic transport. Moreover, the coincidence among maximum membrane deformation, maximum pore aperture, and maximum ion uptake is predicted. Such behavior has been corroborated experimentally by previously published results in red blood and CHO cells as well as in supramolecular lipid vesicles. PMID- 29990600 TI - Nanosecond pulsed electric field induces calcium mobilization in osteoblasts. AB - Nanosecond pulsed electric field (nsPEF) has the ability to induce a host of intracellular biochemical processes in living cells as a function of parameter setting. In vitro experiments proved that nsPEF stimulation could remarkably promote biomineralization processes and new bone formation. However, the impact of nsPEF parameter settings on the calcium flux of osteoblasts, as well as the intracellular mechanisms underlying those observations have yet to be elucidated. In this study, live osteoblast-like MG63 cells were loaded with fluorescence indicator dye fluo-4 AM. nsPEF stimulation could induce intracellular calcium mobilization in MG63 cells with no refractory period. We confirmed that moderate output voltage (4-8 KV) and large pulse number (25) were required for efficient nsPEF irritation of MG63 cells. Additionally, nsPEF stimulation-induced calcium flux in MG63 cells was dramatically reduced with the treatment by ethylene glycol tetraacetic acid (EGTA), proving that the intake of extracellular calcium ions is crucial for increasing intracellular calcium concentration of nsPEF-treated MG63 cells. Our preliminary study investigated the mechanisms underlying nsPEF stimulation-induced calcium mobilization in osteoblast-like cells, and it has the potential to accelerate the application of nsPEF stimulation in new bone formation. PMID- 29990601 TI - Ultrasonography for the Orthopaedic Surgeon. AB - The recent development of high-frequency ultrasonography transducers has provided better accuracy and improved the ability to image more superficial body structures. Ultrasonography is a widely available, inexpensive, comparative, and dynamic imaging technique that involves no radiation exposure and has no other adverse effects. Ultrasonography must always be combined with a medical history, physical examination, and radiographic assessment. What is ultrasound-assisted orthopaedic surgery? This approach consists in the use of ultrasonography by orthopaedic surgeons during patient visits and/or in the operating room. Similar to arthroscopy, ultrasonography is used as a complementary technique by physicians involved in the management of musculoskeletal disease (e.g., radiologists, rheumatologists, and sports physicians). What knowledge of biophysics is needed to use ultrasonography? The surgeon must be familiar with the mechanisms by which the ultrasound waves are generated and received during B mode and Doppler ultrasonography and with possible types of image artefacts. What is the procedure for examining a structure by ultrasonography? Each anatomic component must be assessed along two perpendicular planes in scanning mode. What does ultrasonography contribute during patient visits? Ultrasonography provides additional diagnostic information and helps to explain the pathological process to the patient. How does the contribution of ultrasonography vary across body sites and pathological processes? Ultrasonographic imaging is easier at some body sites than at others. Ultrasonography can provide useful information in patients with joint disease, sports injuries, osteo-articular infections, peripheral neuropathy, or tumours. What is interventional ultrasonography in orthopaedic surgery? Ultrasound-guided orthopaedic interventions include injections, aspirations, and minimally invasive surgical procedures. How can orthopaedic surgeons incorporate ultrasonography into their practice? The surgeon must purchase an ultrasound machine dedicated to the musculoskeletal system and follow the necessary training courses. PMID- 29990602 TI - Patellar complications after total knee arthroplasty. AB - : Patellar complications are a source of poor total knee arthroplasty (TKA) outcomes that can require re-operation or prosthetic revision. Complications can occur with or without patellar resurfacing. The objective of this work is to answer six questions. (1) Have risk factors been identified, and can they help to prevent patellar complications? Patellar complications are associated with valgus, obesity, lateral retinacular release, and a thin patella. Selecting a prosthetic trochlea that will ensure proper patellar tracking is important. Resurfacing is an option if patellar thickness is greater than 12mm. (2) What is the best management of patellar fracture? The answer depends on two factors: (a) is the extensor apparatus disrupted? and (b) is the patellar implant loose? When either factor is present, revision surgery is needed (extensor apparatus reconstruction, prosthetic implant removal). When neither factor is present, non operative treatment is the rule. (3) What is the best management of patellar instability? Rotational malalignment should be sought. In the event of femoral and/or tibial rotational malalignment, revision surgery should be considered. If not performed, options consist of medial patello-femoral ligament reconstruction and/or medialization tibial tuberosity osteotomy. (4) What is the best management of patellar clunk syndrome? When physiotherapy fails, arthroscopic resection can be considered. Recurrence can be treated by open resection, despite the higher risk of complications with this method. (5) What is the best management of anterior knee pain? The patient should be evaluated for causes amenable to treatment (fracture, instability, clunk, osteonecrosis, bony impingement on the prosthetic trochlea). If patellar resurfacing was performed, loosening should be considered. Otherwise, secondary resurfacing is appropriate only after convincingly ruling out other causes of pain. A painstaking evaluation is mandatory before repeat surgery for anterior knee pain: surgery is not in order in the 10% to 15% of cases that have no identifiable explanation. (6) What can be done to treat patellar defects? Available options include re-implantation (with bone grafting, cement, a biconvex implant, or a metallic frame), bone grafting without re-implantation, patellar reconstruction, patellectomy (best avoided due to the resulting loss of strength), osteotomy, and extensor apparatus allograft reconstruction. LEVEL OF EVIDENCE: V, expert opinion. PMID- 29990603 TI - Extraocular Pressure Measurements to Avoid Orbital Compartment Syndrome in Aneurysm Surgery. AB - BACKGROUND: Orbital compartment syndrome (OCS) is a rare but devastating complication following pterional craniotomy. Although the causes of OCS are unclear, external compression of the orbit by a myocutaneous flap is commonly mentioned as a major factor. We evaluated the ocular influence of external compression using an extraocular pressure monitor. METHODS: We measured extraocular pressure in 86 patients who underwent surgery for cerebral aneurysm via a pterional approach. Clinical information and radiologic parameters, including the area of the medial rectus muscle (MRM) and the craniotomy height from the bottom of the anterior skull base, were collected. As a control group, 117 patients who underwent surgery without pressure monitoring were also evaluated. RESULTS: Extraocular pressure reached a maximum during craniotomy (mean, 22.0 mm Hg; range, 18.4-51.0 mm Hg) and decreased after myocutaneous flap adjustment (mean, 7.9 mm Hg; range, 5.4-17.5 mm Hg). Pressure before myocutaneous flap manipulation differed between patients with anterior communicating artery (Acomm) aneurysms and other patients (mean, 16.5 mm Hg vs. 9.4 mm Hg; P = 0.003). Among Acomm aneurysm cases, the monitored group showed a significantly lower MRM swelling ratio (postoperative MRM area/preoperative MRM area) compared with the control group (1.03 +/- 0.10 vs. 1.17 +/- 0.15; P = 0.036). CONCLUSIONS: Myocutaneous flaps can produce unnoticed overpressure on the orbit, resulting in OCS-related blindness during aneurysm clipping surgery, especially in cases involving mandatory lower craniotomy. The continuous extraocular compressive pressure monitoring technique is a simple and effective approach to prevent such a serious complication. PMID- 29990604 TI - Factors of Delayed Hyperperfusion and the Importance of Repeated Cerebral Blood Flow Evaluation for Hyperperfusion After Direct Bypass for Moyamoya Disease. AB - OBJECTIVE: Postoperative hyperperfusion is an important complication after direct bypass for moyamoya disease, which sometimes occurs late after initial postoperative cerebral blood flow (CBF) measurement. This study aimed to clarify the incidence of hyperperfusion with management using postoperative continuous sedation and repeated postoperative CBF measurement and to identify factors associated with delayed hyperperfusion. METHODS: This retrospective study evaluated 72 consecutive hemispheres in 56 adult Japanese patients with moyamoya disease who underwent direct bypass. Postoperative continuous sedation was routinely administered based on CBF evaluation. First, the incidence of symptomatic hyperperfusion was investigated. Second, radiologic hyperperfusion (RHP), which was strictly defined as >30% increase in CBF compared with the contralateral side, and factors associated with delayed RHP were statistically analyzed. RESULTS: Postoperative symptomatic hyperperfusion occurred in 3 hemispheres (4.2%), including subarachnoid hemorrhage in 1 hemisphere (1.4%). RHP immediately after surgery was identified in 16 hemispheres (22.2%). In 8 hemispheres (11.1%), RHP appeared or worsened several days after initial CBF study. In univariate logistic regression analysis, decreased preoperative cerebral vasoreactivity was significantly associated with delayed RHP. CONCLUSIONS: The incidence of symptomatic hyperperfusion was 4.2% with management. Delayed hyperperfusion was significantly associated with decreased cerebral vasoreactivity. Therefore, repeated CBF measurements evaluating preoperative cerebral vasoreactivity may decrease complications. PMID- 29990605 TI - Surgical Treatment of Intramedullary Spinal Metastasis in Medulloblastoma: Case Report and Review of the Literature. AB - BACKGROUND: Medulloblastomas are common childhood central nervous system tumors that are prone to leptomeningeal spread. Intramedullary dissemination is rare with very few case reports existing in the available literature. CASE DESCRIPTION: The authors here present a case of a 14-year-old boy with Li Fraumeni syndrome and medulloblastoma who underwent surgical resection of spinal intramedullary spread. Histopathology revealed the tumor to be anaplastic medulloblastoma, same as the intracranial lesions. Genetic testing of the metastatic deposit revealed loss of functions mutations in SUFU, NOTCH3, and TP53 and TERC amplification. An improvement in ambulatory function at short-term follow-up was noted before the patient died of disseminated disease. CONCLUSIONS: Intramedullary metastasis of medulloblastoma remains a rare disease. Surgical resection might play a possible role in management in addition to radiation and chemotherapy. PMID- 29990606 TI - The Use of Flow Diversion in Vessels <=2.5 mm in Diameter-A Single-Center Experience. AB - BACKGROUND: Flow diversion has become an accepted treatment strategy for aneurysms; however, there are limited data on the use of these devices in small vessels <=2.5 mm in diameter. METHODS: We performed a retrospective review of our prospectively maintained database to identify all patients treated with flow diversion between September 2009 and January 2018. We identified all patients in whom the average parent artery was <=2.5 mm in diameter. Ruptured aneurysms were excluded from the analysis as were patients who had adjunctive coiling at the time of flow diversion. RESULTS: We identified 29 patients (22 female, 76%) with average age 56.2 +/- 15.9 years (range, 21-83 years). Most aneurysms were classified as saccular (n = 21, 72.4%), with 7 fusiform aneurysms (24.2%) and 1 presumed dissecting aneurysm (3.4%). The average parent artery diameter was 2.1 +/- 0.37 mm (range, 1.3-2.5 mm). Delayed angiographic follow-up was available for 18 patients at an average of 19.4 months after treatment. Fifteen patients showed Raymond-Roy classification grade 1 occlusion (94%) and 1 patient with complete filling showed Raymond-Roy classification grade 3 (6%). Four patients (13.7%) underwent repeat treatment with implantation of another flow-diverting stent in a telescoping manner. At 90 days, 2 patients had a modified Rankin Scale (mRS) score of 6, 1 from an unrelated cause and 1 from the enlarging compressive dissecting aneurysm and intraparenchymal hemorrhage. All the remaining patients had an mRS score <=2 at 90 days, with 24 patients (83%) with an mRS score of 0. CONCLUSIONS: Flow diverters can be implanted into small vessels with a high rate of technical success and good rates of aneurysm occlusion. Dedicated devices to target these vessels should be developed. PMID- 29990608 TI - Total En Bloc Spondylectomy for Solitary Metastatic Tumors of the Fourth Lumbar Spine in a Posterior-Only Approach. AB - BACKGROUND: Total en bloc spondylectomy (TES) significantly decreases the rate of local recurrence and provides long-term survival in patients with malignant tumor of the spine. This procedure can be performed through a posterior-only approach. However, TES for lower lumbar spine through a posterior-only approach is technically challenging. METHODS: We retrospectively reviewed 9 patients with solitary metastatic tumors of the fourth lumbar spine who underwent TES in a posterior-only approach from June 2012 to December 2015. This series included 5 female and 4 male patients, with a mean age of 54.1 years. Endpoints included length of surgery, estimated blood loss, visual analogue scale for pain, instrumentation failure, perioperative complications, local control rate, and overall survival. RESULTS: All patients underwent TES and circumferential reconstruction of the involved level. Average operative time and estimated blood loss were 282 minutes and 2421 mL, respectively. The mean follow-up time was 41.2 months. We encountered nerve roots stretches in all patients during the surgeries. Three patients experienced acute lower-extremity neurologic dysfunction, but the symptoms were significantly alleviated in 4 weeks postoperatively and fully resolved within 6 months. Five patients showed no evidence of disease at the latest follow-up. Three patients died of metastasis and systemic failure. One patient developed new metastases and was alive with disease. Titanium mesh cage subsidence was observed in 3 patients, but no implant failures or related clinical symptoms were found. CONCLUSIONS: TES for the fourth lumbar spine in a posterior-only approach is feasible. Although the surgery is challenging, long-term oncologic and neurologic outcomes are satisfying. PMID- 29990607 TI - Dynamic Changes in Toll-Like Receptor 4 in Human Perihematoma Tissue after Intracerebral Hemorrhage. AB - BACKGROUND: With the increase in the aging population and unhealthy lifestyles, the prevalence of intracerebral hemorrhage (ICH) continues to increase. The secondary injury to brain tissue after ICH might play a significant role in the prognosis of the patient; however, the underlying mechanisms of this process are unclear. This study aimed to explore the function of the toll-like receptor 4 (TLR4)-mediated myeloid differentiation primary response 88 (MyD88)-dependent pathway in inflammatory injury and apoptosis in the perihematoma tissues of patients with ICH. METHODS: We included 24 patients who were diagnosed with hypertensive supratentorial ICH and collected perihematoma tissue samples from them. We explored the pathologic changes and the expression of TLR4, MYD88, nuclear factor kappaB, and CASPASE-3 in these tissues. RESULTS: In patients with ICH, the pathologic changes appeared within 6 hours of the onset of disease, peaked (maximum damage) at 24-72 hours, and the damage subsided after 72 hours. The expression of TLR4, MYD88, nuclear factor kappaB, and CASPASE-3 began to increase within 6 hours after ICH, peaked during 24-72 hours after ICH, and decreased after 72 hours. CONCLUSIONS: The TLR4-mediated MyD88-dependent pathway plays a significant role in the mechanism of tissue injury after ICH in human tissues. Our study sheds light on the regulation of inflammation and apoptosis as potential novel targets to prevent secondary injury after ICH. Moreover, our results indicate that the optimal window for antiinflammation and antiapoptosis treatment is within 6 hours after ICH. PMID- 29990609 TI - Navigation-Supported Stereotaxy by Applying Intraoperative Computed Tomography. AB - OBJECTIVE: To investigate how frameless navigational techniques can be implemented to support standard frame-based stereotactic procedures. METHODS: In 25 patients (18 deep brain stimulation procedures, 3 stereotactic biopsies, and 4 stereoencephalography procedures), 57 trajectories were planned. A navigation reference array was attached to the stereotactic frame for automatic registration applying intraoperative computed tomography. RESULTS: User-independent automatic registration resulted in a low navigation registration error (0.76 +/- 0.30 mm). Because the stereotactic scan is performed intraoperatively, it can also be used for automatic navigation registration without additional patient radiation exposure. Low-dose intraoperative computed tomography protocols allowed the effective radiation dose to be reduced to 0.39 mSv (i.e., by a factor of 7.7) compared with standard head protocols without impeding navigational accuracy with a registration error of 0.65 +/- 0.05 mm. Additional use of navigation facilitated surgery, in which entry points and alignments of trajectory paths could be easily checked, provided additional safety. Visualizing the depth of a biopsy needle or electrode during the procedure in relation to target and risk structures greatly enhanced the understanding of the procedure. CONCLUSIONS: In a setting with intraoperative imaging, the combination of frameless and frame-based techniques offers new possibilities. Because of the high registration accuracy, the additional navigation provides improved safety and redundancy. Furthermore, the stereotactic procedure is supported by enhanced intuitive intraoperative visualization during the advancement of a biopsy needle or electrode. However, further technical refinements are necessary, such as possibilities to track microelectrodes during the advancement with a microdrive. PMID- 29990610 TI - Investigation of flashing and intensity characteristics for vehicle-mounted warning beacons. AB - Reducing the potential for crashes involving front line service workers and passing vehicles is important for increasing worker safety in work zones and similar locations. Flashing yellow warning beacons are often used to protect, delineate, and provide visual information to drivers within and approaching work zones. A nighttime field study using simulated workers, with and without reflective vests, present outside trucks was conducted to evaluate the effects of different warning beacon intensities and flash frequencies. Interactions between intensity and flash frequency were also analyzed. This study determined that intensitiesof 25/2.5 cd and 150/15 cd (peak/trough intensity) provided the farthest detection distances of the simulated worker. Mean detection distances in response to a flash frequency of 1 Hz were not statistically different from those in response to 4 Hz flashing. Simulated workers wearing reflective vests were seen the farthest distances away from the trucks for all combinations of intensity and flash frequency. PMID- 29990611 TI - Road anger expression-Changes over time and attributed reasons. AB - Based on the results from three independent surveys conducted in Denmark in 2005, 2008 and 2016, this paper provides an overview of the development of road anger expression in general and in demographic sub-groups of road users. In addition, it investigates how people explain own and other people's road anger expression and if attributed reasons are related to demographic factors and level of anger expression measured based on the short form of the driving anger expression inventory (DAX-short). From 2005 to 2016 the percentage of people involved in anger expression incidents increased particularly in the densely populated Capital Region of Denmark. The increase was most pronounced for "yelling" and "threatening". Men were more often involved than women both as aggressor and as victim, but the gender difference decreased from 2008 to 2016. Generally, own anger expression was more often explained with getting frightened (non-hostile attribution), while anger expression by other road users was more often explained by not being able to control own anger or by wanting to show that one made a mistake (hostile attribution). However, people scoring high in aggressive anger expression often explained own anger expression by "not being able to control anger", thereby indicating self-reflection and a potential for behavioural change. Behavioural reactions to being frightened are to some extend mistakenly interpreted as expressions of anger by other road users. Results indicate that cognitive and behavioural interventions, possibly as part of the driver education, are relevant to reduce aggressive anger expression in traffic. PMID- 29990612 TI - Selecting anti-speeding messages for roadside application. AB - PURPOSE: Analyze qualitative and quantitative data to determine the relative effectiveness of theoretically-developed anti-speeding messages, as judged by relatively inexperienced and experienced drivers, both for themselves as a driver, and for drivers in general. METHOD: Eight focus groups and three individual interviews were conducted. Participants initially completed a questionnaire, ranking sets of three anti-speeding messages representing each of the six components of protection motivation theory (PMT). Participants were encouraged to write down the reasons for their rankings. During group and individual facilitation sessions, the rankings and reasons for them were discussed to identify salient reasons for participants' judgments. The ranking data were analyzed quantitatively, with individual and group-based comments being analyzed thematically. RESULTS: Quantitative analyses of message pairs revealed five third-person effects (TPEs). Three messages were perceived as more relevant to drivers in general than to the participant-as-driver while two were associated with reverse TPEs, which participants perceived as more relevant to themselves-as driver than for drivers in general. For four PMT components (rewards, self efficacy, response efficacy, response costs), one or more messages received significantly higher rankings than one or more other messages representing the same component. Substantial variation was found within the individual and group discussion comments in respect of nearly all the messages, reflecting different driver perspectives and demographics. DISCUSSION: A general preference for shorter messages was evident, leading to a revision of most of the messages comprising the stimuli for this study. On the basis of the focus group and interview responses, consideration was given as to which messages would be recommended for a pilot field study. PMID- 29990613 TI - The impact of booster seat use on child injury and mortality: Systematic review and meta-analysis of observational studies of booster seat effectiveness. AB - OBJECTIVE: To determine through systematic review and meta-analysis of observational studies if booster seats, compared to seatbelts alone, reduce injury and mortality from motor vehicle collisions among child passengers four to eight years of age. METHODS: A comprehensive search of several data sources (including Medline, Embase, and PsycINFO) was conducted from inception to December 2016, to retrieve relevant publications in any language and from any geographic region. Data extraction was completed by two independent reviewers, capturing: study details, population characteristics, exposure (booster seat compared to seat belt use), outcomes (injury and fatality), and all associations reported between the exposure and outcomes. Risk of bias assessment was completed by two reviewers using the QUIPS tool. Meta-analysis of sufficiently similar studies was conducted using random effects models. RESULTS: Eleven observational studies were included in qualitative syntheses. The systematic review and meta analysis found no association between booster seat use, compared to seatbelts, and reduced injury (4 studies, OR 1.03; 95% CI 0.53-1.99) or fatality (2 studies, OR 0.91; 95% CI 0.73-1.13). CONCLUSIONS: Evidence on booster seat effectiveness to protect against injury and mortality in real-world conditions is limited. This review identified the need for high quality studies assessing the effects of different models of booster seats on children of varying ages and weights. PMID- 29990614 TI - Likelihood estimation of secondary crashes using Bayesian complementary log-log model. AB - Secondary crashes (SCs) occur within the spatial and temporal impact range of a primary incident. They are non-recurring events and are major contributors to increased traffic delay, and reduced safety, particularly in urban areas. However, the limited knowledge on the nature of SCs has largely impeded their mitigation strategies. The primary objective of this study was to develop a reliable SC risk prediction model using real-time traffic flow conditions. The study data were collected on a 35-mile I-95 freeway section for three years in Jacksonville, Florida. SCs were identified based on travel speed data archived by the Bluetooth detectors. Bayesian random effect complementary log-log model was used to link the probability of SCs with real-time traffic flow characteristics, primary incident characteristics, environmental conditions, and geometric characteristics. Random forests technique was used to select the important variables. The results indicated that the following variables significantly affect the likelihood of SCs: average occupancy, incident severity, percent of lanes closed, incident type, incident clearance duration, incident impact duration, and incident occurrence time. The study results have the potential to proactively prevent SCs. PMID- 29990615 TI - A systematic review of interventions to increase physical activity among South Asian adults. AB - OBJECTIVES: To identify interventions aimed at increasing physical activity (PA) levels among South Asian (SA) adults and identify the specific changes in the content and delivery mode of interventions designed to increase PA levels among SA people aged >=18 years. DESIGN: A systematic review of quantitative studies. DATA SYNTHESIS: Extracted data were synthesized using a narrative approach. DATA SOURCES: ASSIA, CINHAL, EMBASE, Medline, SPORTDiscus and PsychINFO were searched. Included articles met the following criteria: (1) population: community-dwelling SA adults aged >=18 years and (2) outcome: reporting determinants of PA, exercise, or a combination of the two, measured objectively or using self-report. The search was restricted to articles published in the English language up to 31 January 2017. RESULTS: Fifteen trials/programmes (16 articles) met the review criteria. The findings show that involving the target community in developing culturally appropriate interventions appears to be important in their acceptability, delivery and uptake. Using community-based participation in intervention planning, evaluation and research appears to produce culturally and linguistically tailored interventions that address core values, attitudes, beliefs and norms, and encourage participation in PA. Furthermore, the use of community health workers and underpinning the interventions with a psychological theory show promise in increasing PA uptake. CONCLUSIONS: This systematic review suggests that making cultural adaptations to PA interventions shows promise, but the evidence base presented is not strong. This does not mean that adopting such an approach is ineffective but that the evidence base is currently lacking. PMID- 29990616 TI - Spatiotemporal distribution and determinants of gonorrhea infections in mainland China: a panel data analysis. AB - OBJECTIVES: Gonorrhea remains a major public health concern worldwide. This study aims to explore the spatiotemporal distribution and sociodemographic determinants of gonorrhea rates during 2004-2014 in mainland China. STUDY DESIGN: Space-time scan statistics and spatial panel regression model. METHODS: The gonorrhea infection data and sociodemographic data during 2004-2014 at the provincial level in mainland China were extracted from the China Public Health Science Data Center and China Statistical Yearbooks, respectively. The space-time scan statistics were used to identify the high-risk clusters of gonorrhea, and the spatial panel regression model was adopted to examine the sociodemographic determinants. RESULTS: One most likely and five secondary high-risk clusters of gonorrhea rates were identified, which were mainly located in southern and eastern China. The regions with higher GDP per capita, larger floating population, less access to healthcare, higher male-female ratio, and higher divorce rate were more likely to become high-risk areas of gonorrhea. CONCLUSIONS: Gonorrhea rates were distributed unevenly through space and time and affected by various sociodemographic variables. The space-time scan statistics and spatial panel regression are viable tools for identifying clusters and examining determinants of gonorrhea rates. The findings provide valuable implications for developing targeted prevention and control programs in public health practice. PMID- 29990617 TI - Challenges for prison governors and staff in implementing the Healthy Prisons Agenda in English prisons. AB - OBJECTIVES: In the two decades that have passed since the World Health Organisation established the Healthy Prisons Agenda, there has been no research conducted to investigate barriers and challenges prison managerial and operational staff encounter in implementing the Agenda in the English prison context. This article debates sectoral, institutional and occupational challenges perceived to hinder effective implementation of the Agenda, based on a qualitative study involving prison governors and operational staff. STUDY DESIGN: Qualitative study taking a grounded theory approach. METHODS: Semistructured interviews were conducted with 30 participants comprising prison governors, prison officers and external stakeholders with key strategic and operational roles across the prison estate. The interviews were analysed and coded into themes using constant comparative method. RESULTS: The research identified a range of managerial and operational factors that impeded recognition, acceptance and successful implementation of the Healthy Prisons Agenda. These were found to be associated with scarcity of resources, low prioritisation, perceived low importance, and pressures at operational, managerial and strategic levels to adhere to standard operating procedures. Security, control and discipline tended to supersede other imperatives considered of secondary importance to the effective running of prisons. CONCLUSIONS: Sustainability of the Healthy Prisons Agenda can only be assured by raising its significance and importance across prison hierarchies and within policies and practices through which operational and strategic objectives are realised. This means achieving wholesale commitment by prisons-among staff at all levels-towards public health goals that are fundamental to a successful and effective criminal justice system. PMID- 29990618 TI - Outbreaks of influenza-like illness in care homes in the East of England: impact of variations in neuraminidase inhibitor provision. AB - OBJECTIVES: To examine the differences in outcomes related to variable provision of antivirals in care home respiratory outbreaks. STUDY DESIGN: This is a retrospective observational study. METHODS: Routinely collected outbreak surveillance data reported from care home staff was recorded using a standard template and extracted from the Public Health England health protection electronic records. Data included numbers of people affected, provision of oseltamivir, hospitalization, and deaths during the outbreak in the care home. Oseltamivir provision was categorized by proportion of eligible residents prescribed it on advice. Additional data on microbiological diagnoses were obtained directly from the hospital laboratories. Logistic regression was used to examine associations between oseltamivir provision and hospitalizations and deaths in care homes. RESULTS: One hundred and sixty-eight outbreaks were reported from 28th July 2016 until 27th March 2017, affecting 1459 residents and 347 staff. There were 76 hospital admissions and 37 deaths overall. Although deaths and hospital admissions also occurred in outbreaks caused by other respiratory viruses, outbreaks caused by influenza had the highest median number of people affected and a greater proportion of hospital admissions and deaths. Of the 56 outbreaks caused by influenza, there was a significant increase in the odds of the care home reporting deaths when oseltamivir was not used (odds ratio = 8.15, 95% confidence interval = 1.38-48.20, P = 0.02). There were also non significant reductions in duration of outbreak and hospital admissions in care home outbreaks with oseltamivir treatment. CONCLUSIONS: Partial or no provision of oseltamivir was associated with poorer outcomes in laboratory-confirmed influenza outbreaks. PMID- 29990619 TI - Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen on the surface of vascular endothelial and smooth muscle cells. AB - Lipoprotein(a) [Lp(a)] is an enigmatic lipoprotein which has been identified as a causal risk factor for coronary heart disease and calcific aortic valve disease. Lp(a) consists of a low-density lipoprotein (LDL) moiety covalently linked to the unique glycoprotein apolipoprotein(a) [apo(a)]. Apo(a) is homologous to the fibrinolytic zymogen plasminogen and thus may interfere with plasminogen activation. Conversion of native Glu-plasminogen by plasmin to the more readily activatable Lys-plasminogen greatly accelerates plasminogen activation and is necessary for optimal stimulation of plasminogen activation on endothelial cells. Lp(a)/apo(a) has been previously shown to inhibit pericellular plasminogen activation on vascular cells, but the mechanism underling these observations is unknown. We therefore explored whether apo(a) can inhibit pericellular Glu- to Lys-plasminogen conversion on cell surfaces. A physiologically relevant recombinant version of apo(a) (17K) significantly inhibits plasmin-mediated Glu- to Lys-plasminogen conversion on human umbilical vein endothelial cells (HUVECs) and smooth muscle cells (SMCs). All isoforms of apo(a) that were analyzed, ranging in size from 3 to 21 kringle IV type 2 repeats, were able to inhibit conversion to a similar extent. Removal of the kringle V and protease domain of apo(a) strongly reduces the ability of apo(a) to inhibit conversion on HUVECs and SMCs. Removing the strong lysine binding site in KIV10 of apo(a) abolishes its ability to inhibit conversion on HUVECs and, to a lesser extent, on SMCs. These results indicate a novel mechanism in which apo(a) inhibits the positive feedback mechanism that accelerates plasmin formation on vascular cells. PMID- 29990620 TI - Activated platelets and leukocyte activations in young patients with beta thalassemia/HbE following bone marrow transplantation. AB - Bone marrow transplantation (BMT) is the only curable option for thalassemia major, beta-thalassemia/HbE. However, some patients still have the risk of hypercoagulable complications. We used a whole blood flow cytometric analysis to measure the circulating microparticle (MP) levels, activated platelets, and leukocyte-platelet aggregates in 59 young beta-thalassemia/HbE patients compared with 20- and 28-matched healthy and patients receiving regular blood transfusion (RT), respectively. Results from the studies showed that blood samples from BMT group contained a significantly higher numbers of circulating MPs originated from platelets (ann-V+CD41a+), leukocyte (ann-V+CD45+) and endothelial cells (ann V+CD146+) when compared to samples from healthy subjects and RT patients. In contrast, the percentages of activated/procoagulant platelets (CD62P and CD142 expressing platelets) were decreased in BMT group. In addition, monocytes forming microaggregates were the major population among other leukocyte-platelet complexes. Different patterns of CD11b, CD62P and CD142 expression on platelet leukocyte microaggregate surface were also found. These data suggest that circulating MPs together with leukocyte-platelet aggregates may be responsible, in part, in pathogenesis of hypercoagulable state in beta-thalassemia/HbE patients who undergone BMT. PMID- 29990621 TI - Introduction: Epigenetics in cancer. PMID- 29990622 TI - Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning. AB - The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics. PMID- 29990623 TI - Modifying exosome release in cancer therapy: How can it help? AB - The reciprocal interactions of cancer cells with their microenvironment constitute an inevitable aspect of tumor development, progression and response to treatment in all cancers. Such bilateral transactions also serve as the key scenario underlying the development of drug resistance in many cases finally determining the fate of the disease and survival. In this view, a class of extracellular vesicles (EV) known as exosomes (EX) have been shown in the past few years to be important mediators of local and remote cell-to-cell contact changing the activity of their target cells by introducing their content of proteins, non-coding RNAs, and membrane-associated small molecules. In addition to the direct targeting of cancer cells, which has been routinely undertaken by different means to date, parallel attempts to change the signaling network governed by tumor-derived exosomes (TDE) may offer a promising potential to be utilized in cancer therapy. TDE drive diverse functions in the body, most of which have been shown to act to the advantage of tumor progression; however, there are also several studies that report the good aspects of TDE the interruption of which may result in undesirable outcomes. In the present paper, we made an effort to address this important issue by reviewing the very recent literature on different aspects of EX biogenesis and regulation and the various bodily effects of TDE which have been uncovered to date. Moreover, we have reviewed the possible interventions that can be made in TDE release as an important stage of EX biogenesis. Finally, keeping a criticizing view, the advantages and disadvantages of such interventions have been discussed and the future prospect in the field has been outlined. PMID- 29990624 TI - The anti-inflammatory peptide Ac-SDKP: Synthesis, role in ACE inhibition, and its therapeutic potential in hypertension and cardiovascular diseases. AB - Cardiovascular diseases (CVDs) represent ~31% of all global deaths, and hypertension alone accounts for ~50% of these cases. Inflammation and subsequent fibrosis in heart, kidney and brain are associated with increased morbidity and mortality in CVD patients. N-Acetyl-Seryl-Aspartyl-Proline (Ac-SDKP) is a naturally occurring immunomodulatory and pro-angiogenic peptide mainly released from its precursor thymosin beta4 (Tbeta4) via enzymatic hydrolysis involving meprin-alpha and prolyl-oligopeptidase, while Ac-SDKP degradation is primarily carried out by angiotensin converting enzyme (ACE). Keeping its immunomodulatory and angiogenic properties in view, numerous studies have focused on its beneficial effects in cardiovascular diseases. Research in the past 20 years involving heart, kidney and brain injury show that, treatment with Ac-SDKP ameliorates end-organ damage in part, by reducing inflammation, fibrosis and by promoting angiogenesis. Clinical studies involving ACE inhibitor therapy have shown increased plasma and tissue Ac-SDKP concentration, and some of the beneficial effects of ACE inhibitors in hypertension are partly due to increased Ac-SDKP content. Interestingly, these protective effects of Ac-SDKP are independent of blood-pressure regulation. This review discusses the Ac-SDKP biology in health and disease conditions, identifying its possible mechanisms of action, and explore potential use of Ac-SDKP as a novel treatment for CVDs. PMID- 29990625 TI - Targeting mTORs by omega-3 fatty acids: A possible novel therapeutic strategy for neurodegeneration? AB - Neurodegenerative diseases (NDs) such as Parkinson's (PD), Alzheimer's (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) cause significant world-wide morbidity and mortality. To date, there is no drug of cure for these, mostly age-related diseases, although approaches in delaying the pathology and/or giving patients some symptomatic relief have been adopted for the last few decades. Various studies in recent years have shown the beneficial effects of omega-3 poly unsaturated fatty acids (PUFAs) through diverse mechanisms including anti-inflammatory effects. This review now assesses the potential of this class of compounds in NDs therapy through specific action against the mammalian target of rapamycin (mTOR) signaling pathway. The role of mTOR in neurodegenerative diseases and targeted therapies by PUFAs are discussed. PMID- 29990626 TI - State of midwifery research in France. AB - OBJECTIVE: We describe French midwives' experience and perception of research and publication as well as their publications in scientific and professional journals. DESIGN: We conducted an online cross sectional survey of midwives from June to November 2016; complemented by a bibliometric analysis of their publications in any language. SETTING: This study was conducted in France, where it is necessary to question some midwifery and obstetrical practices. PARTICIPANTS: 146 midwives working/residing in France or holding/studying in France for a PhD or a Masters' degree at the time of the study; or having already published articles in any scientific or professional journal. FINDINGS: Of the 146 eligible midwives, 91.8% were female; 15 (10.3%) had a PhD degree, 26 (17.8%) and 80 (54.8%) were preparing a PhD and a Master's degree, respectively. A total of 140 midwives (95.8%) were working in midwifery and 54 (37.0%) respondents reported having already participated in midwifery research programs. Publication experience was reported by 73 midwives, including 26 (17.8%) who have published at least one article on midwifery in a journal accessible online and peerreviewed. 97.2% of midwives with publication experience consider it useful to publish but 75.7% consider that it is a difficult process. Lack of time, not mastering scientific writing and English language are their main barriers to publication. We identified 218 articles published by these midwives before January 2016, including 180 (82.6%) on maternal and perinatal health. Of their 134 unique articles on midwifery accessible online, 77 (57.5%) dealt with bio medical topics, 49 (36.6%) with health system issues, and 17 (12.7%) used human and social sciences approaches. Pregnancy and birth were the two most studied reproductive life phases. Eighty-nine (28.4%) of these 314 articles were about midwifery practices or interventions. Since 1990, 93 articles have been published on midwifery in peer-reviewed journals, including 32 in the French language. The number of publications increased significantly with time with a progression coefficient at +1.18% per year, in particular in scientific journals (+0.78% per year). KEY CONCLUSIONS AND IMPLICATION: We evidenced that even though midwives in France have a still limited experience of research, and few of them have completed a PhD degree, or receive a salary for doing research, they publish an increasing number of scientific articles on midwifery topics. However, very few research programs in France examine aspects of midwifery. This scarcity is a major barrier to the involvement of midwives in research. Scientific publications about midwifery in French language are limited mainly due to the lack of adequate and specialized journal in French. However, publishing in French would facilitate the access to knowledge and evidence of midwifery practitioners in Frenchspeaking countries, including French-speaking Africa, where maternal mortality ratios can be very high. We suggest and discuss a number of approaches to increase access to scientific knowledge on midwifery in France and French-speaking countries. PMID- 29990628 TI - Threatened preterm labour: Women's experiences of risk and care management: A qualitative study. AB - BACKGROUND: Preterm birth is a major cause of neonatal death and severe morbidity, so pregnant women experiencing symptoms of threatened preterm labour may be very anxious. The risk assessment and management that follows recognition of threatened preterm labour has the potential to either increase or decrease this anxiety. The aim of this study was to explore women's experience of threatened preterm labour, risk assessment and management in order to identify potential improvements in practice. DESIGN: One-to-one semi-structured interviews with 19 women who experienced assessment for threatened preterm labour took place between March 2015 and January 2017. A purposive sample approach was employed to ensure participants from different risk and demographic backgrounds were recruited at an inner city UK NHS hospital. Interviews were recorded and transcribed. Data was managed with NVivo software and analysed using the Framework Approach. A public and patient involvement panel contributed to the design, analysis and interpretation of the findings. FINDINGS: Data saturation was achieved after 19 interviews. 11 women were low risk and 8 were high risk for preterm birth. All high risk women had experience of being supported by a specialist preterm team. Four main themes emerged: (i) coping with uncertainty; (ii) dealing with conflicts; (iii) aspects of care and (iv) interactions with professionals. Both low and high risk women experiencing TPTL struggle to cope with the uncertainty of this unpredictable state. The healthcare management they receive can both help and hinder their ability to cope with this extremely stressful experience. High risk women were less likely to receive conflicting advice. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Clinicians should acknowledge uncertainty, minimize conflicting information and advice, and promote continuity of care models for all women, including those attending high risk clinics and in the ward environment. PMID- 29990627 TI - Lack of partner impacts newborn health through maternal depression: A pilot study of low-income immigrant Latina women. AB - INTRODUCTION: Latina women have a high burden of depression and other mental health issues, particularly in the perinatal period. Suboptimal maternal mental health can have adverse developmental and physiological impacts on child growth. The present study examines the impact of unplanned pregnancy and pregnancy relationship status on prenatal maternal depression in a sample of low-income Latina women. We hypothesized that the association between these prenatal stressors and newborn health would be mediated through prenatal depression. METHOD: The present study included a sample 201 Latina mothers and their children recruited from prenatal clinics during their second or third trimesters. Depression symptomology, relationship status were collected prenatally. At birth, several indices of newborn health were examined, including head circumference percentile and birthweight. Finally, planned pregnancy status was retrospectively collected when the child was between 1 and 2 years old. RESULTS: Structural equation modelling revealed that single women, compared to partnered women, had higher levels of depression. Higher levels of depression, in turn, predicted poorer newborn health. Unplanned pregnancy was not significantly associated with newborn health. DISCUSSION: These results suggest that relationship status may be an important screening question for medical examiners to ask to pregnant Latina women during prenatal visits. These results are consistent with past research investigating the effects of maternal mental health on adverse birth outcomes that propose that stressful early environments shape developmental trajectories. PMID- 29990629 TI - Women's decision making regarding prenatal screening for fetal aneuploidy: A qualitative comparison between 2003 and 2016. AB - OBJECTIVE: Situational factors of prenatal screening have changed in recent decades. To explore the effect of a changing context on women's decision making, differences and similarities in the decision-making process of pregnant women regarding prenatal screening for fetal aneuploidy between two periods in time were studied. DESIGN: A qualitative comparison was made between a dataset of 22 semi-structured interviews with pregnant women from 2003 and a newly collected dataset with 19 semi-structured interviews from 2016. FINDINGS: Overall, women reported similar considerations in their decision-making process in 2003 and 2016, suggesting that decision making has not essentially changed. In 2016, women were still making a deliberate decision, however for some women costs and societal views as to what is acceptable did appear to impact the decision-making process. Moreover, new screening possibilities (e.g. improved test characteristics and including more conditions to be screened) seemed to impact the decision outcome. CONCLUSIONS: Since most women based their decisions mainly on their personal values and personal experiences rather than on situational factors, the results suggest that the changing context with regard to prenatal screening had no major effect on women's decision making. It therefore seems unlikely that future changes in the field of prenatal screening will drastically change the decision-making process of pregnant women as long as informed and deliberate decision making is safeguarded. PMID- 29990631 TI - Exercise, diet and educational interventions for metabolic syndrome in persons with schizophrenia: A systematic review. AB - INTRODUCTION: Individuals with major psychotic disorders such as schizophrenia are at increased risk for developing metabolic syndrome due to lifestyle- and treatment-related factors. Numerous interventions have been tested in inpatient and outpatient mental health settings to decrease risk factors. Diet and exercise represent the mainstay of weight loss treatment. With this background the review aimed to evaluate the effects of psychoeducation, diet and physical activity interventions on reduction of metabolic syndrome risk factors such as BMI, Body weight, biochemical profiles in schizophrenia. METHODS: The authors conducted database searches of PsychINFO, MEDLINE, Pubmed, Proquest, EBSCO and the Cochrane Database of Systematic Reviews, and manual searches from 1968 to 2017. Search indentified 11 studies that met the inclusion criteria. Study quality was critically appraised by 2 reviewers using established criteria. The outcome measures were body mass index, body weight, waist circumference, lipid profile, fasting glucose. RESULTS: Interventions led to significant weight reduction (8 studies), reduced body mass index (5 studies), decreased waist circumference (4 studies) and lower blood glucose levels (5 studies). Dietician and nurse led interventions (6 studies). The studies showed non pharmacological interventions were effective in reducing risk factors. CONCLUSION: This review was able to demonstrate effectiveness of peychoeducation, diet and physical activity interventions were helpful to decrease and manage antipsychotic-induced weight gain. Results showed lifestyle interventions are safer and effective for promoting decrease or maintenance of weight and it can be delivered at low cost, safe and improves quality of life. PMID- 29990630 TI - A case of sibutramine causing recurrent episodes of catatonia. PMID- 29990632 TI - Sequential type schizoaffective disorder: A concept missed in the classificatory system. PMID- 29990633 TI - The role of differentiation of self and schema modes in prediction of rumination and compulsive behaviors in adolescents. PMID- 29990634 TI - Effect of yeast volatile organic compounds on ochratoxin A-producing Aspergillus carbonarius and A. ochraceus. AB - Many foods and beverages in temperate and tropical regions are prone to contamination by ochratoxin A (OTA), one of the most harmful mycotoxins for human and animal health. Aspergillus ochraceus and Aspergillus carbonarius are considered among the main responsible for OTA contamination. We have previously demonstrated that four low or non- fermenting yeasts are able to control the growth and sporulation of OTA-producing Aspergilli both in vitro and on detached grape berries: the biocontrol effect was partly due to the release of volatile organic compounds (VOCs). Aiming to further characterise the effect of VOCs produced by biocontrol yeast strains, we observed that, beside vegetative growth and sporulation, the volatile compounds significantly reduced the production of OTA by two A. carbonarius and A. ochraceus isolates. Exposure to yeast VOCs also affected gene expression in both species, as confirmed by downregulation of polyketide synthase, non-ribosomal peptide synthase, monooxygenase, and the regulatory genes laeA and veA. The main compound of yeast VOCs was 2 phenylethanol, as detected by Headspace-Solid Phase Microextraction-Gas Chromatography-Tandem Mass Spectrometry (HS-SPME-GC-MS) analysis. Yeast VOCs represent a promising tool for the containment of growth and development of mycotoxigenic fungi, and a valuable aid to guarantee food safety and quality. PMID- 29990635 TI - Insight into the global regulation of laeA in Aspergillus flavus based on proteomic profiling. AB - In Aspergillus flavus, laeA affects cell morphology and contributes to the production of secondary metabolites (SMs) production including aflatoxin, cyclopiazonic acid, and aflatrem. Here, we investigated the function of this transcription factor by performing proteomics analysis of the wild-type (WT) and DeltalaeA mutant growing on corn. Notably, our proteomics profile confirmed the functions of extracellular hydrolases, conidial hydrophobin, and response to oxidative stress during the induction of aflatoxin biosynthesis regulated by laeA. Unexpectedly, deletion of laeA resulted in the significant upregulation of the NAD+-dependent histone deacetylase sirA involved in silencing SM clusters via chromatin remodeling. Accompanying the chromatin modification, enzymes participating in SM, including aflatoxin and cyclopiazonic acid biosynthesis, were drastically decreased. Another unexpected finding was that enzymes in the recently identified ustiloxin B biosynthesis pathway might be regulated by laeA. These data provided novel insights into the complex regulation of laeA and suggested a potential link between laeA deletion, NAD+-dependent histone deacetylation, and SM production in A. flavus. PMID- 29990636 TI - Use of Saccharomyces cerevisiae var. boulardii in co-fermentations with S. cerevisiae for the production of craft beers with potential healthy value-added. AB - In recent years, the awareness of consumers about the impact of food on health is constantly increasing. A high amount of dietary antioxidant intake can be supplied by beverages widely consumed, such as wine, coffee, beer. Recently, an increase in the consumer interest was observed for beer, in consequence of the high phenolic antioxidants and low ethanol content present in this beverage. Among all beer types, in recent years, consumption of craft beers has gained popularity. Being an unpasteurized and unfiltered, craft beer is potentially a new vehicle for delivering health effects. While health benefits of lactic acid bacteria as probiotics are well known, few data are available on probiotic yeasts in fermented food. Therefore, this study was aimed to analyse the effect of integrating the well-known probiotic yeast strain of S. cerevisiae var. boulardii (S.b) in mixed cultures with S. cerevisiae strains for production of beers with increased healthy benefits. The probiotic strain of S.b was tested in mixed cultures with selected S. cerevisiae strains, during wort fermentation. As the viability during processing operations is one of the criteria for selecting suitable strains of probiotic microorganisms, the survival of probiotic yeast during the fermentation and the presence of highly viable cells at the end of fermentations were evaluated. In almost all the mixed fermentations, at the end of the process the probiotic yeast was predominant on S. cerevisiae strain, and the experimental beers contained a high number of viable cells of S.b strain (ranging between 8 * 106 and 7.0 * 107/mL). The analysis of experimental beers for the content of main volatile compounds showed that the inclusion of S.b strain in mixed starter did not affect negatively beer aroma. Moreover, the inclusion of S.b strain in mixed starters determined an increase in the antioxidant activity and polyphenols content, in comparison to beers from single starter fermentations, indicating the influence of S.b strain on these parameters. Some mixed starter cultures tested in this study resulted a very promising tool to increase the healthy quality of the product, such as the improve the antioxidant activity and polyphenols content of beer. PMID- 29990638 TI - Efficacy of activated persulfate in inactivating Escherichia coli O157:H7 and Listeria monocytogenes. AB - Concerns have been on the rise regarding the use of chlorine-based sanitizers for fresh produce sanitation due to the production of toxic disinfection by-products (DBPs). This study was undertaken to evaluate the efficacy of activated persulfate in inactivating Escherichia coli O157:H7 and Listeria monocytogenes in pure culture. The objectives were to study the effect of persulfate to activator ratios and determine the major contributing radical in pathogen inactivation. A five-strain cocktail of each pathogen was treated with sodium persulfate activated by ferrous sulfate or sodium hydroxide for 60 s or 120 s. Non-selective agars supplemented with sodium pyruvate were used for pathogen enumeration. The steady-state concentrations of free radicals were quantified using HPLC-DAD. Radical scavengers (tert-butanol, isopropanol, and benzoquinone) were used to determine the major contributing radical in pathogen inactivation. The results showed more than 7 log CFU/mL reductions can be achieved in 120 s for both pathogens at appropriate activation conditions. For ferrous activation, the persulfate to ferrous ratio played an important role in the overall inactivation efficacy. The maximum pathogen reduction (7.77 log CFU/mL for E. coli O157:H7 and 7.25 log CFU/mL for L. monocytogenes) was achieved at persulfate to ferrous molar ratio of 1:0.33 when the initial persulfate concentration was set at 40 mmol/L. Further increase or decrease of ferrous ratio always leads to lower pathogen reductions. For alkaline activation, the inactivation efficacy increased with more initial sodium hydroxide. The maximum reduction was achieved at 40 mmol/L persulfate with 30 mmol/L sodium hydroxide for E. coli O157:H7 (6.21 log CFU/mL reduction) and at 500 mmol/L persulfate with 350 mmol/L sodium hydroxide for L. monocytogenes (8.64 log CFU/mL reduction). Also, persulfate activated by sodium hydroxide always achieved significantly (P < 0.05) higher microbial reductions than sodium hydroxide or persulfate alone. L. monocytogenes was generally more resistant against the activated persulfate treatment compared with E. coli O157:H7, which might be due to the different cell envelop structures between Gram positive and Gram-negative bacteria. Hydroxyl radical was demonstrated to be the major radical to inactivate both pathogens in ferrous activation while superoxide radical was demonstrated to be the major radical to inactivate both pathogens in alkaline activation. PMID- 29990637 TI - Analysis of enterotoxigenic Bacillus cereus strains from dried foods using whole genome sequencing, multi-locus sequence analysis and toxin gene prevalence and distribution using endpoint PCR analysis. AB - Bacillus cereus strains were isolated from dried foods, which included international brands of spices from South East Asia, Mexico and India purchased from several retail stores, samples of powdered infant formula (PIF), medicated fish feed and dietary supplements. The genetic diversity of 64 strains from spices and PIF was determined using a multiplex endpoint PCR assay designed to identify hemolysin BL, nonhemolytic enterotoxin, cytotoxin K, and enterotoxin FM toxin genes. Thirteen different B. cereus toxigenic gene patterns or profiles were identified among the strains. Randomly selected B. cereus strains were sequenced and compared with reference Genomic Groups from National Center Biotechnology Information using bioinformatics tools. A comprehensive multi-loci sequence analysis (MLSA) was designed using alleles from 25 known MLST genes specifically tailored for use with whole genome assemblies. A cohort of representative genomes of strains from a few FDA regulated commodities like dry foods and medicated fish feed was used to demonstrate the utility of the 25-MLSA approach for rapid clustering and identification of Genome Groups. The analysis clustered the strains from medicated fish feed, dry foods, and dietary supplements into phylogenetically-related groups. 25-MLSA also pointed to a greater diversity of B. cereus strains from foods and feed than previously recognized. Our integrated approach of toxin gene PCR, and to our knowledge, whole genome sequencing (WGS) based sequence analysis, may be the first of its kind that demonstrates enterotoxigenic potential and genomic diversity in parallel. PMID- 29990639 TI - Weekly variations in norovirus genogroup II genotypes in Japanese oysters. AB - Increased levels of norovirus contamination in oysters were reportedly associated with a gastroenteritis epidemic occurring upstream of an oyster farming area. In this study, we monitored the norovirus concentration in oysters weekly between November 2014 and March 2015 and investigated the statistical relationship between norovirus genogroup II (GII) concentrations in oyster and sewage samples and the number of gastroenteritis cases in the area using cross-correlation analysis. A peak correlation coefficient (R = 0.76) at a time lag of +1 week was observed between the number of gastroenteritis cases and norovirus GII concentrations in oysters, indicating that oyster contamination is correlated with the number of gastroenteritis cases with a 1-week delay. Moreover, weekly variations in norovirus GII genotypes in oysters were evaluated using pyrosequencing. Only GII.3 was detected in November and December 2014, whereas GII.17 and GII.4 were present from January to March 2015. GII.17 Kawasaki 2014 strains were detected more frequently than GII.4 Sydney 2012 strains in oyster samples, as previously observed in stool and sewage samples collected during the same study period in Miyagi, Japan. Our observations indicate that there is a time lag between the circulation of norovirus genotypes in the human population and the detection of those genotypes in oysters. PMID- 29990640 TI - Synergistic effect of ultrasonic waves under pressure at mild temperatures (MTS) in yeast inactivation. AB - Ultrasonic treatments are one of the new technologies for microbial inactivation that could serve as an alternative for food preservation. However, decimal reduction times for most of microbial species generally exceed 1 min. Therefore, combined processes have been designed, based on the simultaneous application of ultrasonic waves under pressure at moderate temperatures (mano-thermo-sonication process, MTS). The aim of this study was mathematically quantify the synergism of MTS treatments on S. bayanus and different microbial groups including vegetative cells and bacterial spores and compare them. Results show that the lethal effect of MTS treatments may have both, additive (A. hydrophila, Y. enterocolitica) or synergistic effect (S. bayanus, L. monocytogenes, Salmonella spp., Bacillus spp.). The synergistic effect increases with temperature until reaching a maximum and then descending. A big synergistic effect was observed in yeasts and bacterial spores while lower synergy was observed in bacterial vegetative cells. The more heat resistant bacterial species showed higher synergistic effect of the MTS treatments. PMID- 29990641 TI - Biofilms of Candida albicans and Streptococcus sanguinis and their susceptibility to antimicrobial effects of photodynamic inactivation. AB - This study evaluated the effects of photodynamic inactivation (PDI) on single and multi-species biofilms, compounds by Candida albicans and Streptococcus sanguinis. Biofilms were formed, on microplate of 96 wells, by suspensions of C. albicans (ATCC 18804) and S. sanguinis (ATCC 7073) adjusted in 107 cells/mL, followed by incubation of 48 h (with 5% CO2). The effects of the photosensitizer erythrosine (ER) at 400 MUM for 5 min and green light-emitting diode (LED - 532 +/- 10 nm) for 3 min, alone and conjugated, were evaluated. After normality test, results was analysed by Tukey's test (P < 0.05). PDI group promoted reductions of 1.07 and 0.39 log10, respectively, in biofilms of C. albicans alone and in association with S. sanguinis. Biofilms of S. sanguinis alone were more sensitive, with reduction of 4.48 log10. When in association with the yeast, S. sanguinis have a decrease of 2.67 log10. SEM analysis revealed a decrease in bacterial and fungal structures of biofilms treated with PDI. In conclusion PDI promoted significant microbial reductions in both species of microorganisms grown on mixed biofilms. This study is one of the pioneers to evaluate the antimicrobial action of PDI on biofilms of S. sanguinis and C. albicans, demonstrating a way to control these microorganisms of clinical importance. PMID- 29990642 TI - 5-Aminolevulinic acid-mediated photodynamic therapy can target human glioma stem like cells refractory to antineoplastic agents. AB - BACKGROUND: Glioblastoma (GBM) is a highly malignant lethal brain cancer. Accumulated evidence suggests that elevated resistance of GBM to both chemo- and radio-therapy is, at least in part, due to the presence of a small population of glioma stem cells (GSC). In the present study, we aimed to determine the sensitivity of GSCs to 5-aminolevulinic acid-mediated photodynamic therapy (ALA PDT). METHODS: For this purpose, we established GSC-enriched cell cultures (termed glioma stem-like cells or GSLCs) from A172 human GBM cell line. Under our cultivation conditions, GSLCs formed floating spheroid clusters that contained increased population of CD133/Sox2 expressing cells. Firstly, to compare the activity of protoporphyrin IX (PpIX) biosynthesis in the GSLCs and the parental A172 glioma cells, we examined the expression levels of biosynthesis enzymes and transporters for PpIX using qRT-PCR, and investigated the intracellular levels of PpIX with use of flow cytometry analysis. Then, we evaluated the sensitivity of these cells to ALA-PDT in vitro. Finally, to confirm the therapeutic impact of ALA-PDT on GSLCs with more clinically relevant model, we performed the same experiment using three different patient-derived glioma sphere lines, which cultivated them either in stem cell media or under differentiation conditions in the presence of serum. RESULTS AND CONCLUSION: GSLCs expressed higher mRNA levels of PpIX biosynthesis enzymes and its transporters PEPT1/2 and ABCB6, when compared to the parental A172 glioma cells. Consistently, flow cytometry analysis revealed that upon incubation with ALA, GSLCs accumulate a higher level of PpIX. Finally, we showed that GSLCs were more sensitive to ALA-PDT than the original A172 cells, and confirmed that all patient-derived glioma sphere lines also showed significantly increased sensitivity to ALA-PDT if cultivated under the pro stem cell condition. Our data indicate that ALA-PDT has potential as a novel clinically useful treatment that might eliminate GBM stem cells that are highly resistant to current chemo- and radio-therapy. PMID- 29990643 TI - Application of an optimal class of antisymmetric wavelet filter banks for obstructive sleep apnea diagnosis using ECG signals. AB - Obstructive sleep apnea (OSA) is a sleep disorder caused due to interruption of breathing resulting in insufficient oxygen to the human body and brain. If the OSA is detected and treated at an early stage the possibility of severe health impairment can be mitigated. Therefore, an accurate automated OSA detection system is indispensable. Generally, OSA based computer-aided diagnosis (CAD) system employs multi-channel, multi-signal physiological signals. However, there is a great need for single-channel bio-signal based low-power, a portable OSA-CAD system which can be used at home. In this study, we propose single-channel electrocardiogram (ECG) based OSA-CAD system using a new class of optimal biorthogonal antisymmetric wavelet filter bank (BAWFB). In this class of filter bank, all filters are of even length. The filter bank design problem is transformed into a constrained optimization problem wherein the objective is to minimize either frequency-spread for the given time-spread or time-spread for the given frequency-spread. The optimization problem is formulated as a semi-definite programming (SDP) problem. In the SDP problem, the objective function (time spread or frequency-spread), constraints of perfect reconstruction (PR) and zero moment (ZM) are incorporated in their time domain matrix formulations. The global solution for SDP is obtained using interior point algorithm. The newly designed BAWFB is used for the classification of OSA using ECG signals taken from the physionet's Apnea-ECG database. The ECG segments of 1 min duration are decomposed into six wavelet subbands (WSBs) by employing the proposed BAWFB. Then, the fuzzy entropy (FE) and log-energy (LE) features are computed from all six WSBs. The FE and LE features are classified into normal and OSA groups using least squares support vector machine (LS-SVM) with 35-fold cross-validation strategy. The proposed OSA detection model achieved the average classification accuracy, sensitivity, specificity and F-score of 90.11%, 90.87% 88.88% and 0.92, respectively. The performance of the model is found to be better than the existing works in detecting OSA using the same database. Thus, the proposed automated OSA detection system is accurate, cost-effective and ready to be tested with a huge database. PMID- 29990644 TI - Conformity, reliability and validity of digital dental models created by clinical intraoral scanning and extraoral plaster model digitization workflows. AB - BACKGROUND: In dentistry, digitization of dental arches with intraoral scanners could one day replace impressions and plaster model digitization processes, if accuracy is clinically sufficient. This study aimed to assess the reliability, validity and conformity of an intraoral scanning procedure (Lythos(c), Ormco) and of two extraoral digitization workflows via alginate impression and plaster model scanning with the D810(c) (3shape) or the Atos II Triple Scan(c) (GOM) under clinical conditions. METHODS: In 20 subjects three consecutive intraoral scans, three alginate and one reference polyether impression were taken of both the upper and lower dental arch, respectively. The digital models created from the corresponding plaster models and the intraoral scans were superimposed with the polyether reference standard by both a global and a local best-fit algorithm. Reliability, validity and conformity of the three digital workflows were assessed via intraclass (ICC) and Lin's concordance correlation coefficients (CCC) as well as analyses according to Bland-Altman. RESULTS: The digital models created from the intraoral scanning procedure were less in agreement with the polyether reference (validity) than those from the extraoral procedures with reduced conformity and reliability. Local numerical deviations from the reference standard were approximately twice as high compared to the extraoral procedures, which showed high conformity and were equivalent and clinically acceptable in terms of reliability and validity. CONCLUSIONS: Although the intraoral scanning method with Lythos(c) seems to have drawbacks in terms of reliability, validity and conformity to the indirect alginate methods, all procedures proved to be clinically equivalent for diagnostic purposes. PMID- 29990645 TI - Real-time apnea-hypopnea event detection during sleep by convolutional neural networks. AB - Sleep apnea-hypopnea event detection has been widely studied using various biosignals and algorithms. However, most minute-by-minute analysis techniques have difficulty detecting accurate event start/end positions. Furthermore, they require hand-engineered feature extraction and selection processes. In this paper, we propose a new approach for real-time apnea-hypopnea event detection using convolutional neural networks and a single-channel nasal pressure signal. From 179 polysomnographic recordings, 50 were used for training, 25 for validation, and 104 for testing. Nasal pressure signals were adaptively normalized, and then segmented by sliding a 10-s window at 1-s intervals. The convolutional neural networks were trained with the data, which consisted of class-balanced segments, and were then tested to evaluate their event detection performance. According to a segment-by-segment analysis, the proposed method exhibited performance results with a Cohen's kappa coefficient of 0.82, a sensitivity of 81.1%, a specificity of 98.5%, and an accuracy of 96.6%. In addition, the Pearson's correlation coefficient between estimated apnea-hypopnea index (AHI) and reference AHI was 0.99, and the average accuracy of sleep apnea and hypopnea syndrome (SAHS) diagnosis was 94.9% for AHI cutoff values of >=5, 15, and 30 events/h. Our approach could potentially be used as a supportive method to reduce event detection time in sleep laboratories. In addition, it can be applied to screen SAHS severity before polysomnography. PMID- 29990646 TI - A study of time-frequency features for CNN-based automatic heart sound classification for pathology detection. AB - This study concerns the task of automatic structural heart abnormality risk detection from digital phonocardiogram (PCG) signals aiming at pediatric heart disease screening applications. Recently, various systems based on convolutional neural networks trained on time-frequency representations of segmental PCG frames have been presented that outperform systems using hand-crafted features. This study focuses on the segmentation and time-frequency representation components of the CNN-based designs. We consider the most commonly used features (MFCC and Mel Spectrogram) used in state-of-the-art systems and a time-frequency representation influenced by domain-knowledge, namely sub-band envelopes as an alternative feature. Via tests carried on two high quality databases with a large set of possible settings, we show that sub-band envelopes are preferable to the most commonly used features and period synchronous windowing is preferable over asynchronous windowing. PMID- 29990647 TI - Machine learning models to predict the progression from early to late stages of papillary renal cell carcinoma. AB - Papillary Renal Cell Carcinoma (PRCC) is a heterogeneous disease with variations in disease progression and clinical outcomes. The advent of next generation sequencing techniques (NGS) has generated data from patients that can be analysed to develop a predictive model. In this study, we have adopted a machine learning approach to identify biomarkers and build classifiers to discriminate between early and late stages of PRCC from gene expression profiles. A machine learning pipeline incorporating different feature selection algorithms and classification models is developed to analyse RNA sequencing dataset (RNASeq). Further, to get a reliable feature set, we extracted features from different partitions of the training dataset and aggregated them into feature sets for classification. We evaluated the performance of different algorithms on the basis of 10-fold cross validation and independent test dataset. 10-fold cross validation was also performed on a microarray dataset of PRCC. A random forest based feature selection (varSelRF) yielded minimum number of features (104) and a best performance with area under Precision Recall curve (PR-AUC) of 0.804, MCC (Matthews Correlation Coefficient) of 0.711 and accuracy of 88% with Shrunken Centroid classifier on a test dataset. We identified 80 genes that are consistently altered between stages by different feature selection algorithms. The extracted features are related to cellular components - centromere, kinetochore and spindle, and biological process mitotic cell cycle. These observations reveal potential mechanisms for an increase in chromosome instability in the late stage of PRCC. Our study demonstrates that the gene expression profiles can be used to classify stages of PRCC. PMID- 29990648 TI - Assessment of barrier severity and willingness to enter opioid agonist treatment among people who inject drugs in Ukraine. AB - BACKGROUND: Opioid agonist therapies (OAT) in Ukraine were first introduced in 2004 not as addiction treatment, but for HIV prevention. Numerous obstacles have thwarted OAT scale-up, including individual constraints and structural barriers. METHODS: A cross-sectional survey of 1613 opioid dependent people who inject drugs (PWID) were recruited in 2014-2015 using stratified sampling in Kyiv, Odesa, Mykolayiv, Dnipro and Lviv. Analysis was restricted to a subset of 811 PWID who never received OAT. Barriers to OAT were assessed based on reasons why study participants were reluctant to enroll into OAT. A Rasch model from the Item Response Theory was applied to 24 potential barriers, used to score their severity and estimate a latent composite measure for each person's willingness and ability to participate in OAT. RESULTS: The Rasch model confirmed the cumulative nature of barriers with concerns over treatment efficacy, safety and tolerability being more prevalent than barriers related to logistical constraints, opportunity costs and social stigma. If barriers related to treatment perception and logistics were eliminated, the average barrier number would decrease from 10 to 2.2. Participants were more likely to have a higher resistance to OAT entry if they experienced fewer overdoses, did not attain higher education, were not previously incarcerated and if their peers did not have a higher level of resistance to OAT. CONCLUSIONS: Understanding the interdependence of various barriers and attitudes toward OAT can improve the rate of OAT expansion and ameliorate entry into substance abuse treatment programs in Ukraine. PMID- 29990649 TI - Nicotine metabolite ratio predicts smoking topography: The Pennsylvania Adult Smoking Study. AB - BACKGROUND: The nicotine metabolite ratio (NMR) as measured by the ratio of 3'hydroxycotinine to cotinine has been examined in relation to tobacco use patterns including cigarettes per day and quit success to determine its role in nicotine dependence. We examined the NMR in relation to smoking topography and tested the hypothesis that normal metabolizers have a greater total daily puff volume than slow metabolizers. METHODS: The Pennsylvania Adult Smoking Study (PASS) is a longitudinal study of 352 adults who smoked, on average, 17 cigarettes per day. Subjects used a portable smoking topography device over a two day period at home and at work. We measured the ratio of 3'hydroxycotinine to cotinine in the saliva of the subjects. RESULTS: In multiple linear regression analyses, a higher rate of nicotine metabolism was significantly associated with increased daily puffs and total daily puff volume. In a mediation analysis, a significant, indirect effect of race on the relationship between NMR and puff volume was observed, with 22% of the effect mediated by white race. A higher NMR was also associated with female gender, white race, cigarettes per day and nicotine dependence measures. CONCLUSION: The NMR was associated with tobacco use patterns including smoking topography. Faster nicotine metabolism was associated with greater total daily puffs and puff volume. PMID- 29990650 TI - Effects of a non-eating confederate on food intake do not persist for everyone over time when people are left alone: An exploratory study. AB - An extensive body of research has established that eating with others can have inhibitory effects on food intake. Recent findings suggest that these effects may (partly) persist over time when the eating norm is no longer enforced. To gain more insights into the persistence of effects of a live non-eating stranger, the main aim of the present study is to explore how food intake of young women changes as a result of previous exposure to a non-eating confederate (i.e., adult stranger). To address this aim, an experiment was conducted in which 64 young women, aged 17 to 26 (M = 19.81, SD = 1.95), were given access to chocolates at two different time points. First, participants were all paired with a non-eating stranger (i.e., confederate). Afterwards, half of the participants remained with the non-eating stranger (i.e., together-together condition), while the other half was left alone with the food (i.e., together-alone condition). Results indicated that participants who were left alone increased their intake on average, although raw data revealed interesting individual differences. In contrast, most of the participants who remained with the non-eating stranger did not increase intake. Participants in an ad hoc added control condition (i.e., no exposure to a non eating confederate; alone-alone condition; n = 26) showed food intake similar to participants in the together-alone condition after they were left alone. Our findings suggest that if intake behaviors are too extreme and divergent from the desire to eat as much as possible, women may, on average, only adhere to these behaviors in the presence of others. PMID- 29990652 TI - Men who engage in both subjective and objective binge eating have the highest psychological and medical comorbidities. AB - Data suggest that assessing for the presence of loss of control (LOC) while eating is more useful in identifying risk for excess weight gain and psychosocial comorbidities than focusing on the amount of food consumed during episodes of perceived overeating. Yet, most of this research has included children and women. The current study examined whether perceived overeating patterns with and without LOC were uniquely associated with eating- and weight-related comorbidities in a community sample of young men. Participants (N = 1114; 18-30 y) completed a brief online survey assessing body mass index (BMI); perceived overeating habits, including overeating without LOC (OEs), and subjective (SBEs) and objective binge eating episodes (OBEs); weight-related medical comorbidities; and disordered eating pathology. After adjusting for BMI and race/ethnicity, men who reported engaging in both OBE(s) and SBE(s) were the most likely to have a weight-related medical comorbidity, and reported the highest levels of dietary restraint, concerns about body fat, and excessive exercise pathology. Group differences remained even after adjusting for frequency of disordered eating episodes, a common indicator of severity of comorbid pathology. The current study's findings suggest that young men who engage in both OBE(s) and SBE(s) may be at the highest risk for chronic disease and psychological concerns, although additional studies with prospective data are necessary to confirm this hypothesis. PMID- 29990653 TI - Using participant feedback to improve two selective eating disorder and obesity prevention programs. AB - OBJECTIVE: To examine qualitative feedback from participants of Healthy Weight and Project Health eating disorder/obesity prevention programs to guide refinements to increase program efficacy. METHOD: Feedback was collected from college students with weight concerns randomly assigned to one of these interventions (N = 364, 72% female). RESULTS: Healthy Weight participants reported greater program satisfaction (p = 0.02); no other quantitative differences emerged in opinions of the program or leaders. Project Health participants most valued goal setting (27%), the group setting (23%), and the provided information (16%). Healthy Weight participants most valued the group setting (21%), goal setting (19%), and accountability for behavior change (18%). Project Health participants reported home exercises most frequently as least valuable (22%), followed by role-plays (13%). Healthy Weight participants most frequently reported "nothing" as least valuable (24%), followed by food/exercise logs (9%). The top suggestion from participants from both groups was to add interactive activities. CONCLUSIONS: Weight gain preventive effects of Project Health were stronger, but Healthy Weight participants were more satisfied, perhaps because Project Health incorporates dissonance-induction strategies which produce psychological discomfort that promotes internalization of health lifestyle goals. Both interventions could be made more interactive by adding group exercises, encouraging group connection via social media, and adding icebreakers. PMID- 29990654 TI - Body mass index as a moderator of the association between weight status misperception and disordered eating behaviors. AB - Weight status under-perception is protective against disordered eating behaviors and weight gain; however, it is unclear whether under-perception may confer protection across all weight classes. This work explored body mass index as a moderator of the association between weight status perception accuracy and disordered eating behaviors among adults with overweight or obesity. A total of 572 adults (58.7% female; age M = 39.50, SD = 11.57) with overweight or obesity (body mass index M = 31.50, SD = 6.24) completed a series of online questionnaires assessing uncontrolled, emotional, and restrained eating, eating disorder symptoms, weight status perception, and demographics. Controlling for race/ethnicity, age, and sex, linear and negative binomial regressions were used to test hypotheses. Compared to accurate weight status perception, under perception was associated with less uncontrolled (p = .003) and restrained eating (p = .002). Under-perception was particularly protective against emotional eating (p = .022) and eating disorder symptoms (p = .017) for individuals of overweight or Class I obesity. In general, weight status under-perception was associated with fewer disordered eating behaviors. The protective effects of under perception of weight status may be maximized for individuals of overweight or Class I obesity statuses. PMID- 29990651 TI - An examination of the associations between pediatric loss of control eating, anxiety, and body composition in children and adolescents. AB - BACKGROUND: Data on the link between anxiety and body composition in youth are mixed. Yet, anxiety and disordered eating are highly correlated. One pathway between anxiety and excess body weight and fat mass may be through loss of control (LOC) eating. We examined whether LOC eating mediated the relationship between anxiety and body composition in youth with and without overweight. METHOD: Non-treatment-seeking youth (8-17 years) participated in studies examining weight and eating behaviors. Anxiety (child- and parent-report of child) and LOC eating were assessed by self-report questionnaires and interviews, respectively. Fat mass was assessed by dual-energy x-ray absorptiometry or air displacement plethysmography. Cross-sectional mediation models with bias corrected bootstrap confidence intervals (CI) were conducted. RESULTS: 257 youth (12.91 +/- 2.76 years; 52.5% female; BMI-z 0.93 +/- 1.07) were studied. There was a significant indirect path between child-reported anxiety and both BMI-z (ab = .005, SE = 0.003, 95% CI = 0.001-0.01) and body fat mass (ab = 0.001, SE = 0.001, 95% CI <=0.001-0.003) through the number of LOC episodes in the past month. No significant indirect paths through the number of LOC episodes was observed for parent-report of child anxiety on BMI-z (ab = 0.004, SE = 0.01, 95% CI = -0.01 0.03) or body fat mass (ab = 0.001, SE = 0.002, 95% CI = -0.002-0.01). No direct paths were observed between anxiety and body composition regardless of the informant. DISCUSSION: LOC eating appears to mediate the relationship of child reported anxiety with body composition in non-treatment seeking boys and girls. Prospective data are needed to determine if anxiety promotes LOC eating that results in increased risk for excess body weight and fat gain. PMID- 29990655 TI - Can social support and physical activity buffer cognitive impairment in individuals with depressive symptoms? Results from a representative sample of young to older adults. AB - BACKGROUND: Previous study results on associations between depressive symptoms and cognitive functioning, mainly based on clinical samples and explanatory mechanisms including potential protective factors, are yet to be clarified. To this end, we investigated relations between depressive symptoms and executive functioning as well as episodic memory in a representative population sample. Furthermore, we determined the role of social support and physical activity in the explanation of cognitive performance differences in individuals with depressive symptoms. METHODS: A total of N = 3661 participants (52% female) from the German Health and Examination Interview for Adults (18-79 years; M = 52.71, SD = 16.06) were included in the present study. Within a larger assessment protocol, participants answered a depressive symptom questionnaire and completed a neuropsychological test battery including executive functioning and episodic memory. RESULTS: Depressive symptoms significantly predicted executive functioning and episodic memory scores with small effects of beta = -0.04. Social support and physical activity mediated the relationships between depressive symptoms and cognitive functioning. LIMITATIONS: As the present study is cross sectional, future research is warranted to provide more insight into causality by following individuals with depressive symptoms over time. CONCLUSIONS: The present findings indicate that effects from depressive symptoms on cognitive functioning (a) have been overestimated and do not generalize to non-clinical populations and (b) vary owing to behavioral lifestyle factors such as social support and physical activity. Thereby, the present results highlight opportunities for buffering cognitive decline in individuals with depressive symptoms in the general population. PMID- 29990656 TI - State and trait hopelessness in a prospective five-year study of patients with depressive disorders. AB - BACKGROUND: Hopelessness is a common experience of patients with depressive disorders (DD) and an important predictor of suicidal behaviour. However, stability and factors explaining state and trait variation of hopelessness in patients with DD over time are poorly known. METHODS: Patients with DD (n = 406) from the Vantaa Depression Study and the Vantaa Primary Care Depression Study filled in the Beck Hopelessness Scale (BHS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Social Support Scale-Revised (PSSS-R), and Eysenck Personality Inventory-Q (EPI-Q) at baseline, at six and eighteen months, and at five years. We conducted a multilevel linear regression analyses predicting BHS with these covariates. RESULTS: During the five-year follow-up half of the variance in BHS was attributable to between-patient variance (50.6%, CI = 41.2-61.5%), and the rest arose from within-patient variance and measurement errors. BDI and BAI explained 5.6% of within-patient and 28.4% of between-patient variance of BHS. High Neuroticism and low Extraversion explained 2.6% of the between-patient variance of BHS. PSSS-R explained 5% of between-patient variance and 1.7% of within-patient variance of BHS. LIMITATIONS: No treatment effects were controlled. CONCLUSIONS: Hopelessness varies markedly over time both within and between patients with depression; it is both state- and trait-related. Concurrent depressive and anxiety symptoms and low social support explain both state and trait variance, whereas high Neuroticism and low Extraversion explain only trait variance of hopelessness. These variations influence the utility of hopelessness as an indicator of suicide risk. PMID- 29990657 TI - A research agenda for bipolar disorder developed from a patients' perspective. AB - BACKGROUND: Diagnosis and treatment of bipolar disorder is complex. Health care is supported by clinical guidelines, which are highly based on scientific evidence. However, such care does not necessarily correspond to preferred care according to patients. In order to narrow the gap between scientifically based guidelines and the patient's perceptions of the best clinical practice, additional research is needed. The aim of this study was to create a patient based research agenda for bipolar disorder to enhance the alignment between patients' needs and care system. METHODS: A mixed method study design was employed consisting of two phases: consultation and prioritization. In the consultation phase, six focus group discussions with patients (n = 35) were conducted to explore research needs according to patients, resulting in 23 research topics. Subsequently, these topics were prioritized by means of a questionnaire with patients (n = 219). RESULTS: Patients with bipolar disorder mentioned a variety of research topics covered by the following five themes: causes of disorder; pharmacotherapy; non-pharmacological treatment; diagnosis; and recovery & recovery oriented care. 'Etiology' was the topic with highest priority. DISCUSSION: The theme 'causes of disorder' is prioritized highest. We argue that this can be explained by the added value of an explanatory framework for appropriate treatment and recovery. The theme 'recovery & recovery oriented care' is currently underrepresented in actual research. It is argued that in order to bridge the knowledge and implementation gap, social science and health system research is needed in addition to biomedical research. PMID- 29990659 TI - Response letter: Retinal changes in patients with major depressive disorder - a controlled optical coherence tomography study. PMID- 29990658 TI - Prevalence and incidence of probable perinatal depression among women enrolled in Option B+ antenatal HIV care in Malawi. AB - BACKGROUND: Perinatal depression is a common condition of pregnancy and the postpartum period. Depression negatively affects engagement in HIV care, but systematic screening for perinatal depression is not done in most sub-Saharan African countries. Estimating the burden and timing of perinatal depression can help inform medical programs with the current scale-up of HIV care for pregnant women. METHODS: Women (n = 299) initiating antiretroviral therapy for HIV were recruited from a government antenatal clinic in Malawi in 2015-2016 into a cohort study. Probable perinatal depression was assessed at enrollment and at 6 weeks and 3, 6, and 12 months postpartum with the Edinburgh Postnatal Depression Scale (EPDS) and Patient Health Questionnaire-9 (PHQ-9). We estimated point prevalence and incidence of depression as well as concordance between EPDS and PHQ-9 scores. RESULTS: One in ten women screened positive for probable antenatal depression, whereas 1-6% screened positive postpartum. Sensitivity analyses to account for loss to follow-up suggested that postpartum depression prevalence could have ranged from 1-11%. At postpartum time points, 0-3% of participants screened positive for incident probable depression. EPDS and PHQ-9 scores were concordant for 96% of assessments during antenatal and postpartum visits. LIMITATIONS: Lack of diagnostic psychiatric evaluation precludes actual diagnosis of major depression, and social desirability bias may have contributed to low postpartum scores. CONCLUSIONS: Probable depression was more common during the antenatal period than postpartum among our participants. Given the association between depression and negative HIV outcomes, screening for depression during pregnancy should be integrated into antenatal HIV care. PMID- 29990660 TI - What are the effects of preventative interventions on major depressive disorder (MDD) in young adults? A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Depression is a prevalent disorder with a peak rate of onset in young adulthood from 18 to 25 years. To date, no review has systematically assessed the effectiveness of programs that aim to reduce depressive symptoms or diagnosis of depression in young adults. METHOD: A systematic search was performed in Cochrane, PubMed, PsycINFO and EMBASE. We performed a random-effects meta analysis of the randomized controlled studies that compared an intervention for young adults (aged 18-25) without a diagnosis or history of depression and a control condition. Comparisons between intervention and control group outcomes were carried out at the post-intervention time point. We also compared intervention and control group outcomes at later follow-up time points where data were available. RESULTS: Twenty-six randomized controlled trials among 2865 young adults were included in the analysis. The pooled effect size of the interventions versus control at post-intervention was g = 0.37 (95% CI: 0.28-0.47, NNT = 9) and heterogeneity was moderate I2 = 36 (95% CI: 11-64). There were no significant effects in terms of the type of delivery, focus of study, type of control, or type of support within the interventions. LIMITATIONS: The authors were unable to assess the effects of interventions on the onset of depression as none of the included studies measured incidence. The risk of bias was high in most studies (81%). Only one study included a follow-up of more than a year. Demographic factors were inconsistently reported in the included articles. CONCLUSION: While it was not possible to investigate the effects of interventions on depression incidence, some evidence was found for the effectiveness of preventative interventions in reducing depressive symptoms in young adults. Future research should address limitations of the current evidence base to allow stronger conclusions to be drawn. PMID- 29990661 TI - Efficacy of narrative reformulation during cognitive analytic therapy for depression: Randomized dismantling trial. AB - BACKGROUND: Narrative reformulation (NR) is a component of cognitive analytic therapy (CAT) that is assumed to increase client engagement and improve clinical outcomes. This study set out to test these claims. METHODS: A single-blind randomized and controlled dismantling trial investigated treatment outcomes for moderate to severely depressed patients receiving CAT in Primary Care. Ninety five participants were randomized to either full-CAT (n = 52) or CAT minus narrative reformulation (CAT-NR, n = 43). Treatment duration in both arms was 8 sessions and was matched apart from the omission of the NR in the CAT-NR arm. The primary outcome measure was the Patient Health Questionnaire (PHQ-9), with secondary outcome measures of anxiety, functioning, helpfulness and the therapeutic alliance. Outcomes were assessed at screening, every treatment session and at 8-weeks follow-up. RESULTS: Growth curve modelling found that NR did not enhance the efficacy of CAT for depression. There were no significant differences between groups in terms of attendance, adverse events, anxiety, functioning, helpfulness or therapeutic alliance. There were large within-group effect sizes (d+ > 1.5), as CAT with or without NR produced significant reductions in depression (p < .01). LIMITATIONS: The primary outcome were assessed via self-report and the follow-up period was brief. CONCLUSIONS: These results suggest that NR may be redundant when treating depression with CAT. Whilst a brief 8-session version of the CAT model appears suitable for treating depression in Primary Care, further research regarding the need for NR is indicated. PMID- 29990662 TI - Employment predictors and outcomes of U.S. state-federal vocational rehabilitation consumers with affective disorders: A CHAID analysis. AB - BACKGROUND: This study examined the demographic and rehabilitation service variables affecting employment outcomes of people with affective disorders receiving services from U.S. state-federal vocational rehabilitation (VR) agencies. METHODS: An ex post facto design, using data mining as a statistical analysis strategy, was used to analyze the Rehabilitation Services Administration Case Service Report (RSA-911) for the fiscal year 2011. The sample included 44,960 customers with affective disorders who were closed either as successfully employed (Status 26) or not employed (Status 28) by their VR agency. The dependent variable is employment outcome. The predictor variables include a set of personal characteristic variables and rehabilitation service variables. RESULTS: The chi-squared automatic interaction detector (CHAID) data mining analysis results indicated that job placement services, on-the-job supports, and job search assistance services were significant predictors of successful employment outcomes for individuals with affective disorders. LIMITATIONS: The study used data from the RSA-911 database. Causality cannot be inferred due to the use of archival data. CONCLUSIONS: Employment should be viewed as a viable treatment outcome for individuals with affective disorders. Rehabilitation professionals should advocate for their clients to receive VR services, including job placement services, on-the-job supports, and job search assistance services in order to maximize their employment and mental health outcomes. PMID- 29990663 TI - Socio-demographic, mental health and childhood adversity risk factors for self harm and suicidal behaviour in College students in Northern Ireland. AB - BACKGROUND: Prevalence estimates of suicidal behaviour in the college student population are consistently higher than rates for the general adult population. This study examines mental health disorders and childhood adversities as predictors of self-harm and suicidal behaviours. METHODS: The Ulster University Student Wellbeing study commenced in September 2015 as part of the WHO World Mental Health Surveys International College Student Project. In Northern Ireland (NI) 739 students participated (462 female, 274 male and 3 other specified), with the WMH-CIDI used to examine psychopathology. Mean age was 21 years old. RESULTS: Thirty-one percent endorsed suicidal ideation (24.3% of males and 36.9% of females) with almost 1 in 5 students having made a plan for suicide in the 12 months prior to the survey. Latent profile analysis revealed three profiles of childhood adversity (high, moderate, and low risk). Logistic regression analyses showed that there was an increased likelihood of all queried self-harm and suicidal behaviours in those who were not heterosexual orientation, and among those with either moderate or high levels of childhood adversities. Probable alcohol dependence was associated with a significantly increased likelihood of suicide attempt or self-harm with either a suicide plan or a suicide attempt. LIMITATIONS: Influences of self-report measures and the generalizability of the sample are discussed. CONCLUSIONS: Policies and strategies for early identification of those with mental illnesses or adversities that increase their risk, should be prioritised. It would also be useful to identify individuals at risk in secondary schools to allow for additional support to be offered to them during the key time of transitioning into higher education. PMID- 29990664 TI - Availability and use of mental health services in European countries: Influence on national suicide rates. AB - BACKGROUND: Previous research suggests significant increases in suicide mortality rates in European countries following the economic crisis of 2008. However, the relationship between national differences in availability and use of mental health services and suicide rates has not been extensively examined yet. MATERIALS AND METHODS: Data on mental health services and socioeconomic variables were derived from Eurostat for the years 2000-2013 for ten European countries. The national health care variables consisted of suicide mortality rate (SMR), average length of hospital stay and number of hospitalizations due to affective disorder or any psychiatric disorder, number of psychiatric beds and number of prescribed antidepressants. Economic variables included the gross domestic product (GDP), the gross domestic product per 1000 inhabitants (Real GDP), the rate of unemployment and the GINI-coefficient as a measurement for the equality of wealth distribution. Mixed models were used to investigate the potential influence of the onset of the economic crisis in 2008 on each of the psychiatric variables. Multivariable regression analyses were used to assess the influence on suicide mortality rates. RESULTS: In this study, a significant change in slope starting from 2008 was revealed for the number of psychiatric beds, hospitalizations due to affective disorder or any psychiatric disorder and for prescribed antidepressants. Furthermore, a significant step change for hospitalizations due to affective disorder was observed in 2008. SMR exhibited a significant step change in 2008 for males and females as well as a significant change in slope from 2008 onwards for males only. Contrary to our hypothesis, most variables showed no statistically significant influence on SMR. Only a higher number of available psychiatric beds was significantly associated with higher suicide mortality rates. This effect, however, was only significant for females and did not remain significant after correcting for economic variables. Less than 10% of suicide mortality rate variability could be explained by a model including all variables, further corroborating the multifactorial etiology of suicide. LIMITATIONS: Since administrative registry data was used, the results should be interpreted with caution. Results might not be applicable to countries not included. CONCLUSION: While significant changes in the psychiatric variables, as well as SMR, were observed, no statistically significant influence on SMR remained after correcting for country, time and economic variables. Our study suggests the necessity of a more comprehensive international data gathering effort. Further research is needed to identify populations at risk of suicide. PMID- 29990665 TI - Affective instability predicts the course of depression in late middle-age and older adulthood. AB - BACKGROUND: Affective instability is a facet of emotion dysregulation that characterizes various mental disorders, including Major Depressive Disorder (MDD). However, it is unclear as to how affective instability predicts the course of MDD. It is also unknown whether affective instability is a relevant predictor of MDD in later adulthood, a period when there is a decrease in both affective instability and MDD prevalence. Thus, we investigated the role of affective instability in the course of MDD in a sample of late middle-age and older adults. METHODS: Using a longitudinal design over five years, 1,630 adults aged 55-64 years (M = 59.60, SD = 2.70) completed a baseline assessment of affective instability (self-report, informant-report, interviewer-report), three assessments of MDD (computerized interview), and eight assessments of depressive symptoms (self-report). RESULTS: Baseline affective instability positively predicted the likelihood of having lifetime major depressive episodes (MDE) and first-time MDEs, as well as depressive symptoms up to five years later. However, affective instability did not predict remission or having more depressive symptoms over time. These findings held when controlling for neuroticism. LIMITATIONS: We only assessed affective instability at the baseline, did not investigate specific mechanisms or recurrence, and focused on middle-age and older adults. CONCLUSIONS: Our findings replicate and extend prior work by showing that affective instability is differentially related to multiple aspects of MDD's course and remains an important predictor of MDD even in older age. We discuss implications for the role of affective instability in MDD across the lifespan. PMID- 29990666 TI - Determinants of antidepressant response: Implications for practice and future clinical trials. AB - BACKGROUND: Response to antidepressants in major depressive disorder is variable and determinants are not well understood or used to design clinical trials. We aimed to understand these determinants. METHODS: Supported by Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from industry sponsored randomized placebo-controlled trials of antidepressant drugs in adults with MDD. We examined patient and trial-design-related determinants of outcome as measured by change on Hamilton Depression Scale or Montgomery-Asberg Depression Rating Scale in 34 placebo-controlled trials (drug, n = 8260; placebo, n = 3957). RESULTS: While it is conventional for trials to be 6-8 weeks long, drug-placebo differences were nearly the same at week 4 as at week 6 and with lower dropout rates. At the multivariate level, having any of these attributes was significantly associated with greater drug vs. placebo differences on symptom improvement: female, increasing proportion of patients on placebo, centers located outside of North America, centers with low placebo response (regardless of active treatment response) and using randomized withdrawal designs. LIMITATIONS: Data on compounds that failed were not available to us. Findings may not be relevant for new mechanisms of action. CONCLUSIONS: Proof of concept trials can be shorter and efficiency improved by selecting enriched populations based on clinical and demographic variables, ensuring adequate balance of placebo patients, and carefully selecting and monitoring centers. In addition to improving drug discovery, patient exposure to placebo and experimental treatments can be reduced. PMID- 29990667 TI - Association between sexual minority status and suicidal behavior among Chinese adolescents: A moderated mediation model. AB - BACKGROUND: Evidence shows sexual minority adolescents have a higher risk of suicidality than their heterosexual peers due to minority stressors or lack of social support, but it remains unclear how the combined effects of these influence factors impact suicidality in this population. In this study, we examine whether school victimization mediates association between sexual minority status and suicidal behavior of adolescents and explore whether such mediation is moderated by interpersonal relationships. METHODS: We sampled a large nationally representative dataset comprising data collected from 7th to 12th graders (the 2015 School-based Chinese Adolescents Health Survey) using a multistage, stratified-cluster, random-sampling method. Our sample consisted of 123,459 students who completed questionnaires regarding their sexual minority status, suicidal ideation, suicide attempts, school victimization, classmate relations, and teacher-classmate relations. RESULTS: Using a moderated mediation model, we found that school victimization mediated the effects of sexual minority status on suicidal ideation (indirect effect = 0.0296, 95% confidence intervals (CI) = 0.0259-0.0333) and suicide attempts (indirect effect = 0.0086, 95% CI = 0.0074 0.0100). These indirect effects were moderated by interpersonal relationships, and a greater effect was seen among sexual minority students with poor classmate or teacher-classmate relations. LIMITATIONS: Our study sample included only students attending school, and interpretation of the direction of the observed associations is limited due to the cross-sectional design. CONCLUSIONS: Interpersonal relationships moderate the indirect effects of school victimization on association between sexual minority status and suicidal behavior. Early intervention addressing school violence combined with improving the quality of relationships with school peers would help prevent suicidality in sexual minority adolescents. PMID- 29990668 TI - Interpersonal styles in major and chronic depression: A systematic review and meta-analysis. AB - BACKGROUND: McCullough's (2000) theory of chronic depression posits that a hostile-submissive interpersonal style distinguishes chronically depressed individuals from those with Major Depressive Disorder (MDD). This study sought to determine to what extent hostility and submissiveness feature in MDD, and whether there is evidence for a stronger effect in chronic depression. METHODS: A systematic literature search was conducted for research measuring the relationship between depression and hostility and/or submissiveness. A meta analysis was carried out to determine the strength of the relationship. Separate analyses were conducted for the effects of hostility, submissiveness, and hostile submissiveness. Subgroup analyses were performed comparing the effect sizes of chronic depression and MDD. RESULTS: Twelve studies met criteria for inclusion. Subgroup analyses revealed large effect sizes for submissiveness (d = 0.86) and hostile-submissiveness (d = 0.93) in chronic depression, and a medium effect for hostility (d = 0.72). MDD was associated with medium effects for hostility (d = 0.58) and hostile-submissiveness (d = 0.63), and a small effect for submissiveness (d = 0.40). LIMITATIONS: The review yielded a small number of papers, particularly in relation to chronic depression. The majority reported secondary analyses using baseline samples of intervention trials, with normative data as controls. Quality scores were generally low, and analyses revealed high heterogeneity, which may indicate differences between clinical populations studied. CONCLUSIONS: The review provides preliminary evidence that individuals with chronic depression are more hostile-submissive than those with MDD. Results highlight the limited research into interpersonal correlates of chronic depression. PMID- 29990669 TI - The influence of family factors on time to suicidal ideation onsets during the adolescent developmental period. AB - Family factors are associated with suicidal behavior in youth, but little is known about how the joint influence of multiple family factors prospectively predicts onsets of suicidal ideation (SI) in adolescence, a developmental period characterized by increases in SI and risk for suicide. This study investigated whether parent history of SI interacted with either positive or negative parent child relationship quality to longitudinally predict time to SI onsets during the transition into and across adolescence. Specifically, we used a longitudinal, multi-wave design and survival analyses to examine whether the interaction between these family factors prospectively predicted time to emergence of SI onsets (assessed at 6 month intervals over 3 years) in a community sample of youth ages 8 to 15 (N = 238; 57% girls). Results supported an interaction effect, such that more negative relationship quality with parents predicted earlier emergence of SI among those youth whose parents had no history of SI. However, negative parent relationship quality did not amplify risk among youth with parent history of SI; all youth with a parent history of SI were more likely to experience earlier emergence of SI regardless of level of negative relationship quality. Findings did not support an interaction between low levels of parent child positive relationship quality and parent history of ideation. Implications for the role of family factors in the etiology and prevention of SI are discussed. PMID- 29990670 TI - Tuning the chain length of new pyrene derivatives for site-selective photocleavage of avidin. AB - Rational design of photoreagents with systematic modifications of their structures can provide valuable information for a better understanding of the protein photocleavage mechanism by these reagents. Variation of the length of the linker connecting the photoactive moiety with the protein anchoring-group allowed us to investigate the control of the protein photocleavage site. A series of new photochemical reagents (PMA-1A, PMA-2A and PMA-3A) with increasing chain lengths is examined in the current study. Using avidin as a model system, we examined the interaction of these probes by UV-Vis, fluorescence spectroscopic methods, photocleavage and computational docking studies. Hypochromism of the absorption spectrum was observed for the binding of these new photochemical reagents with estimated binding constants (Kb) of 6.2 * 105, 6.7 * 105 and 4.6 * 105 M-1, respectively. No significant changes of Stern-Volmer quenching constant (Ksv) with Co(NH3)6Cl3 has been noted and the data indicated that the probes bind near the surface of the protein with sufficient exposure to the solvent. Photoexcitation of the probe-avidin complex, in the presence of Co(NH3)6Cl3, resulted in protein fragmentation, and the cleavage yield decreased with the increase in the linker length, and paralleled with the observed Ksv values. Amino acid sequencing of the photofragments indicated that avidin is cleaved between Thr77 and Val78, as a major cleavage site for all the three photoreagents. This site is proximate to the biotin binding site on avidin, and molecular docking studies indicated that the H-bonding interactions between the polar end-group of the photoreagents and hydrophilic amino acids of avidin were important in positioning the reagent on the protein. The major cleavage site, at residues 77 78, was within 5 A of the pyrenyl moiety of the probe, and hence, molecular tuning of the linker provided a simple approach to position the photoreagent along the potential photocleavage site. PMID- 29990671 TI - The effects of culturally targeted patient decision aids on medical consultation preparation for Hispanic women in the U.S.: Results from four randomized experiments. AB - RATIONALE: Do culturally targeted patient decision aids (DAs) better prepare lower-middle and middle-class Hispanic American women for medical decision making compared to DAs designed for the general population? Health promotion evidence indicates that inclusion of cultural values, imagery, linguistics, and health data in a DA will improve ethnic patients' preparation relative to a generic DA; yet, this hypothesis remains untested. METHOD: Four experiments examined consultation preparation effects of culturally targeted versus generic DAs for Hispanic women living in the United States. Drawing on highly rated online DAs, an experienced Hispanic content developer and Hispanic focus groups worked with researchers to develop culturally targeted digital DAs. Online panels of self identified Hispanic women in the U.S. were randomly assigned to a targeted or generic DA as part of a scenario-based physician consultation for advanced diabetes (Study 1) or early stage breast cancer (Studies 2-4). RESULTS: Manipulation checks showed high awareness of cultural information in the targeted DA group. Despite efforts to rule out confounds that could account for null effects, DA cultural targeting did not increase knowledge, decision preparedness, or empowerment or reduce decision conflict in the four randomized experiments. Only individual difference variables (e.g., group interdependence) consistently predicted enhanced DA consultation preparation effects. Related research indicates that culture at the group level may exert less influence when individuals think deliberatively, feel less constrained by limited resources such as time, understand processing objectives, and/or are primed with task-specific schema/norms. CONCLUSION: Given deeper deliberation and clearly primed processing objectives, personal experiences and task-related schema/norms may have significantly reduced the effects of cultural targeting. Consistent findings from four studies suggest that culturally targeted DAs may not better prepare Hispanic women in the U.S. for medical decision making than generic versions designed for the broader population. PMID- 29990672 TI - Two distinct transcriptional controls triggered by nuclear Piwi-piRISCs in the Drosophila piRNA pathway. AB - Transposons occupy a large proportion of eukaryotic genomes. Spontaneous movement of transposons within the genome leads to genomic mutations that are often life threatening. To avoid such outcomes, host species have acquired an elaborate molecular pathway during evolution, in which PIWI proteins and PIWI-interacting RNAs (piRNAs) collaboratively control transposons to maintain germline genome integrity. Studies of PIWI-piRNA-based transposon silencing have uncovered the molecular mechanisms underlying piRNA biogenesis and the silencing mode-of-action in the pathway. Interestingly, the bilateral events require transcriptional controls triggered by nuclear PIWI-piRNA complexes in positive and negative manners, respectively. This review summarizes the mechanisms of PIWI-piRNA mediated transcriptional controls in Drosophila ovaries. PMID- 29990673 TI - FAN1 protects against repeat expansions in a Fragile X mouse model. AB - The Fragile X-related disorders (FXDs) are members of a large group of human neurological or neurodevelopmental conditions known as the Repeat Expansion Diseases. The mutation responsible for all of these diseases is an expansion in the size of a disease-specific tandem repeat tract. However, the underlying cause of this unusual mutation is unknown. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in the vicinity of the FAN1 (MIM* 613534) gene that are associated with variations in the age at onset of a number of Repeat Expansion Diseases. FAN1 is a nuclease that has both 5'-3' exonuclease and 5' flap endonuclease activities. Here we show in a model for the FXDs that Fan1-/- mice have expansions that, in some tissues including brain, are 2-3 times as extensive as they are in Fan1+/+ mice. However, no effect of the loss of FAN1 was apparent for germ line expansions. Thus, FAN1 plays an important role in protecting against somatic expansions but is either not involved in protecting against intergenerational repeat expansions or is redundant with other related enzymes. However, since loss of FAN1 results in increased expansions in brain and other somatic tissue, FAN1 polymorphisms may be important disease modifiers in those Repeat Expansion Diseases in which somatic expansion contributes to age at onset or disease severity. PMID- 29990674 TI - Health care in a multi-payer system: Spillovers of health care service demand among adults under 65 on utilization and outcomes in medicare. AB - This paper examines, theoretically and empirically, how changes in the demand for health insurance and medical services in the non-Medicare population - coverage eligibility changes for parents and the firm size composition of employment - spill over and affect health insurance coverage and how these factors affect per beneficiary Medicare spending. We find that factors that increase coverage and hence demand for medical services in the non-Medicare population generate contemporaneous decreases in per beneficiary Medicare spending and utilization, particularly for high variation services. Moreover, these increases in the demand for medical services in the non-Medicare population are not associated with increases in the total quantity of physician services supplied. Finally, we find that the higher Medicare spending associated with lower insurance coverage rates in the non-Medicare population does not generate improvements in measures of Medicare patients' well-being, such as patient experience of care, ambulatory care sensitive admissions, and mortality. PMID- 29990675 TI - The role of health insurance on treatment for opioid use disorders: Evidence from the Affordable Care Act Medicaid expansion. AB - We estimate the effect of health insurance coverage on opioid use disorder treatment utilization and availability by exploiting cross-state variation in effective dates of Medicaid expansions under the Affordable Care Act. Using a difference-in-differences design, we find that aggregate opioid admissions to specialty treatment facilities increased 18% in expansion states, most of which involved outpatient medication-assisted treatment (MAT). Opioid admissions from Medicaid beneficiaries increased 113% without crowding out admissions from individuals with other health insurance. These effects appeared to be driven by market entry of select MAT providers and by greater acceptance of Medicaid payments among existing MAT providers. Moreover, effects were largest in expansion states with comprehensive MAT coverage. Our findings suggest that Medicaid expansions resulted in substantial utilization and availability gains to clinically efficacious and cost-effective pharmacological treatments, implying potential benefits of expanding Medicaid to non-expansion states and extending MAT coverage. PMID- 29990676 TI - Ultrasound imaging and on-demand therapy of peripheral arterial diseases using H2O2-Activated bubble generating anti-inflammatory polymer particles. AB - Muscles of peripheral artery disease (PAD) patients are under oxidative stress associated with a significantly elevated level of reactive oxygen species (ROS) including hydrogen peroxide (H2O2). Curcumin is a major active constituent of turmeric and is well known for its highly potent antioxidant, anti-inflammatory and angiogenic effects. We previously reported antioxidant vanillyl alcohol incorporated copolyoxalate (PVAX) which is designed to rapidly scavenge H2O2 and release bioactive vanillyl alcohol and CO2 in a H2O2-triggered manner. In this work, we developed curcumin-loaded PVAX (CUR-PVAX) nanoparticles as contrast enhanced ultrasound imaging agents as well as on-demand therapeutic agents for ischemic injuries based on the hypothesis that PVAX nanoparticles generate echogenic CO2 bubbles through H2O2-triggered oxidation of peroxalate esters and the merger of curcumin and PVAX exerts H2O2-activatable synergistic therapeutic actions. CUR-PVAX nanoparticles also displayed the drastic ultrasound signal in ischemic areas by generating CO2 bubbles. CUR-PVAX nanoparticles exhibited significantly higher antioxidant and anti-inflammatory activities than empty PVAX nanoparticles and equivalent curcumin in vascular endothelial cells. A mouse model of ischemic injury was used to evaluate the potential of CUR-PVAX nanoparticles as ultrasound imaging agents and on-demand therapeutic agents. CUR PVAX nanoparticles significantly suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta). Moreover, CUR-PVAX nanoparticles significantly enhanced the level of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31), leading to blood perfusion into ischemic tissues. We, therefore, believe that CUR-PVAX nanoparticles hold great translational potential as novel theranostic agents for ischemic diseases such as PAD. PMID- 29990677 TI - Alterations in the metabolism of tryptophan in patients with chronic hepatitis C six months after pegylated interferon-alpha 2a treatment. AB - BACKGROUND: Risk of depression and suicide in patients on interferon remains also after the treatment, the pathogenesis of which is still unclear. We aimed to determine the influence of the PEG-IFN-alpha2a on tryptophan metabolism along the kynurenine pathway during treatment and up to 6 months after the end of treatment. METHODS: We evaluated 101 patients with chronic hepatitis C treated with PEG-IFN-alpha2a, and 40 controls, so as to determine the activation of indolamine 2,3-dioxygenase (IDO) and tryptophan (TRP) and their metabolites' concentrations/levels: kynurenine (KYN), kynurenic acid (KYNA) and anthranilic acid (AA). The subjects were evaluated before and after weeks 2, 4, 8, 12, 24, 48, as well as 6 months after the end of the treatment. RESULTS: In the group of patients treated 24 weeks, six months after the end of treatment IDO activity was significantly higher compared to baseline (69.5 vs 57.2 beta = 0.21 P = 0.000); TRP concentration was significantly lower compared to baseline (30.0 vs 35.6 beta=-0.21 P = 0.001); KYNA concentration was significantly higher compared to baseline (37.2 nmol/L vs 29.4 nmol/L beta = 0.22 P = 0.02), and AA concentration was significantly higher compered to baseline (51.0 nmol/L vs 38.4 nmol/L beta = 0.22 P = 0.05) In the group of patients treated 48 weeks six months, after the end of treatment both the IDO activity and KYNA concentration were significantly higher compared to baseline (respective values - IDO: 78.8 vs 56.2 beta = 0.14 P = 0.02; KYNA: 39.2 nmol/L vs 27.0 nmol/L beta = 0.26 P = 0.000). CONCLUSIONS: This is the first report of a prolonged activation of IDO six months after the end of PEG-IFN-alpha2a treatment. The clinical significance of the finding can be implicated in the pathophysiology of depressive episodes. PMID- 29990678 TI - Interactive effects of prenatal alcohol exposure and chronic stress in adulthood on anxiety-like behavior and central stress-related receptor mRNA expression: Sex and time-dependent effects. AB - Children and adults prenatally exposed to alcohol show higher rates of mental health problems than unexposed individuals, with depression and anxiety being among the more commonly encountered disorders. Previous studies in rats showed that prenatal alcohol exposure (PAE) can indeed increase depressive- and anxiety like behavior in adulthood; however, depression and anxiety are often observed in the context of stress and/or a dysregulated stress response system (the hypothalamic-pituitary-adrenal [HPA] axis). PAE can dysregulate the HPA axis, resulting in hyperresponsivity to stress. In turn, this may predispose individuals prenatally exposed to alcohol to the adverse effects of stress compared to unexposed individuals. We have shown previously that PAE animals may be more sensitive to the effects of chronic stress on behavior, showing increased anxiety- and depressive-like behavior following chronic unpredictable stress (CUS) exposure. Here, we investigated the independent and interactive effects of PAE and adult CUS on anxiety-like behavior and receptor systems (corticotropin releasing hormone receptor type 1 [CRHR1], mineralocorticoid receptor [MR], and glucocorticoid receptor [GR]), and underlying stress and emotional regulation, and whether exposure to CUS differentially results in immediate or delayed effects. Adult male and female offspring from PAE, pair-fed (PF), and ad libitum fed control (C) dams were exposed to either 10 days of CUS or left undisturbed. Behavioral testing began 1 or 14 days post-CUS, and brains were collected following testing. Anxiety-like behaviors were evaluated using the open field, elevated plus maze and dark-light emergence tests. CRHR1, MR, and GR mRNA expression were assessed in the medial prefrontal cortex (mPFC), amygdala, and hippocampal formation, brain areas key to both stress and emotional regulation. We found that PAE differentially increased anxiety-like behavior and altered GR mRNA in males and females compared to their control counterparts. Furthermore, depending on the timing of testing, CUS unmasked alterations in GR and CRHR1 mRNA expression in the mPFC and amygdala in PAE males, and MR mRNA in the hippocampal formation in PAE females compared to their C counterparts. Overall, the changes observed in these receptor systems may underlie the increase in anxiety-like behavior following PAE and CUS exposure in adulthood. That CUS differentially affected brain and behavioral outcome of PAE and C animals, and did so in a sexually-dimorphic manner, has important implications for understanding the etiology of psychopathology in individuals prenatally exposed to alcohol. PMID- 29990679 TI - Video-based CBT-E improves eating patterns in obese patients with eating disorder: A single case multiple baseline study. AB - BACKGROUND AND OBJECTIVES: Cognitive Behavioral Therapy (CBT) is effective for treating eating disorders but it may be difficult to reach patients living far from urban centers. Mobile video-based psychotherapy may potentially improve service reach but has not yet been evaluated. The purpose of this study was to investigate the effects of mobile video-based CBT for eating disorder and to explore the feasibility to use this technology in clinical care. METHODS: A controlled single case multiple baseline design was used which allowed for statistical analyses with randomization tests and non-overlap of all pairs (NAP). Five patients in the first stage of eating disorder treatment were included and the main outcome variable was daily meal frequency. Secondary outcome variables included eating disorder symptoms, psychological distress and treatment satisfaction. RESULTS: The treatment resulted in a significant (p < .01) increase in daily meal frequency with medium to large effect sizes (combined NAP = .89). Four participants reported reliable improvements in eating disorder symptoms and three reported improvements in mood. The participants reported high satisfaction with the treatment and with the mobile video-application despite some technical problems. LIMITATIONS: Self-reported data on eating behavior is prone to be biased and the results of single case studies may have limited generalizability. CONCLUSION: CBT can be delivered effectively via a mobile video application and, despite some technological issues, can be well received by patients. All participants in this study had previous low access to mental health services and reported high satisfaction with the treatment format. PMID- 29990680 TI - Anxiety sensitivity and post-traumatic stress reactions: Effects of time-varying intrusive thoughts and associated distress. AB - BACKGROUND AND OBJECTIVES: The present study examines the extent to which intrusive thoughts and associated distress explains the association between anxiety sensitivity (AS) and post-traumatic stress (PTS) using the "trauma film paradigm". METHODS: Participants high and low in AS viewed a 10-min film of graphic scenes of fatal traffic accidents and then underwent a 10-min thought suppression period where intrusive thoughts and associated distress about the film was assessed. Participants also kept a diary of intrusions and associated distress about the film for one-week and post-traumatic stress reactions about the film were assessed after the one-week period. RESULTS: The high AS group reported greater post-traumatic stress reactions about the film a week later than the low AS group. Although the high AS group also reported more intrusion distress than the low AS group during thought suppression in the laboratory, this difference did not mediate group differences in subsequent post-traumatic stress reactions. Furthermore, the intercept and slope of intrusions and associated distress about the film during the week generally did not differentiate those high in AS from those low in AS. However, the intercept of distress during the week mediated the association between intrusion distress during thought suppression in the laboratory and post-traumatic stress reactions at the end of the week. LIMITATIONS: The present study is limited by use of an analogue sample as well as modeling trauma exposure with a film. CONCLUSIONS: Distress about intrusive thoughts in proximity to the trauma and over time may be an important determinant of PTS. PMID- 29990681 TI - The relation between generalized anxiety disorder symptoms and content-specific interpretation biases for auditory stimuli in children. AB - BACKGROUND AND OBJECTIVES: Cognitive theories of fear suggest that biases in interpretation are content-specific: Fearful children should only interpret materials negatively if they are specifically related to the content of their fear. So far, there are only a few studies available that report on this postulated content-specificity of interpretation processes in childhood fear. The goal of this study was to examine interpretation bias and its content-specificity in children with varying levels of Generalized Anxiety Disorder (GAD) symptoms. METHODS: In an Auditory Interpretation Task (AIT), two words that differ by one phoneme are acoustically blended so that one can hear only one of the words. In the current AIT, we included GAD-related blends, negatively-valenced fear-related blends and positive blends. Multiple-choice (n = 371) or open-ended (n = 295) responses were collected from 666 nonclinical children between 7 and 13 years of age. RESULTS: Children with higher levels of self-reported GAD showed significantly more negative interpretations of ambiguous GAD-related blends in the multiple-choice version than children with lower levels of GAD. There were no differences when interpreting the other ambiguous blends. This result was not found with the open-ended version. LIMITATIONS: Effects were relatively small, some GAD-stimuli were sub-optimal, and the task was administered in a classroom setting. Even though we ensured that all children were able to hear all words clearly, this may have impacted the results. CONCLUSIONS: The findings only partly support the idea that fearful children display cognitive biases specific for fear-relevant stimuli, and more research is needed to replicate the results and test the usability of the AIT. PMID- 29990682 TI - The influence of positive and negative affect on emotional attention. AB - BACKGROUND AND OBJECTIVES: Mechanisms of engagement and disengagement of attention to emotional information are thought to contribute to the onset and maintenance of anxiety and depression, a conclusion based largely on findings in analogue subclinical samples. However, we argue that traditionally defined analogue samples can be misleading. Firstly, research has challenged the adequacy of conventional measures of subclinical traits by illustrating that supposedly distinct scales are highly inter-correlated and do not therefore measure independent constructs. Secondly, recent research in clinical groups has revealed results opposite to those expected from the analogue literature, suggesting speeded, rather than impaired, disengagement from threat. METHODS: We present analogue findings, from a sample of 70 healthy participants, allowing a purer distinction between the phenomenology of anxiety versus depression using the orthogonal traits of positive and negative affect to classify individuals. RESULTS: Using emotional peripheral cueing we found that, at short cue durations, dysphoric individuals' (those with low positive and high negative affect) attention to facial expressions was slowed by emotional compared to neutral invalid cues. LIMITATIONS: Limitations included a small sample size and limited generalisability due to sampling from a student population. CONCLUSIONS: The data suggest that, in line with the previous subclinical literature, dysphoric individuals are slow to disengage attention from emotional information at early stages of processing and are consistent with the possibility that patterns of orienting of attention might be qualitatively different in subclinical versus clinical populations. PMID- 29990683 TI - My Child's thoughts frighten me: Maladaptive effects associated with parents' interpretation and management of children's intrusive thoughts. AB - BACKGROUND AND OBJECTIVES: Environmental factors explain substantial variance in youth's obsessive-compulsive symptoms (OCS) and much of this research has focused upon overt parenting behaviors (e.g., accommodation). No work, however, has examined how parents' internal processes (e.g., perception of children's intrusions) influence youth's OCS. Based upon the cognitive theory of obsessions, we propose that parents' misappraisal of children's intrusions as threatening will be positively associated with (a) the number of maladaptive intrusion management strategies recommended by the parent, as well as (b) children's obsessive beliefs, (c) interpretation biases, and (d) OCS severity. METHODS: Twenty-seven children (M = 12.81; SD = 3.43) and the parent most involved in childcare completed diagnostic interviews and self-report questionnaires. In the laboratory, we induced obsessional anxiety in youth through a standardized in vivo paradigm (e.g., think about a personalized harm-related negative event occurring). Parents rated how they interpreted their children's unwanted thought and the intrusion management strategies they would recommend. RESULTS: Parents who interpreted their children's intrusions as threatening recommended more maladaptive intrusion management strategies and their misappraisal positively and significantly correlated with the severity of children's obsessive beliefs, interpretation biases, and OCS, even after controlling for co-occurring internalizing symptoms. LIMITATIONS: Small sample and cross-sectional design precludes causal conclusions. CONCLUSIONS: Parents' misinterpretation of children's intrusions may operate as a mechanism by which OCS are generationally transmitted. Results can inform OC prevention programs that target parents' cognitive biases in their own psychotherapy. PMID- 29990684 TI - Attention bias for appearance words can be reduced in women: Results from a single-session attention bias modification task. AB - BACKGROUND AND OBJECTIVES: We tested whether a single-session of attention bias modification (ABM) could change bias towards appearance-related words and improve body satisfaction. METHODS: Females (N = 102; Mage = 33 years) completed an ABM session where attention was trained towards positive appearance-related information (n = 31), away from negative appearance-related information (n = 37), or a non-training session (n = 34). Importance of appearance and shape concern were examined as moderators. RESULTS: ABM was effective in women high on appearance importance, trained to direct attention away from negative appearance words. LIMITATIONS: No long-term follow up of attention biases or body image challenge were conducted. CONCLUSIONS: These findings suggest that certain types of attention biases are amenable to change within a single session. PMID- 29990685 TI - An educator-administered measure of language development in young children. AB - An increasing number of infants and toddlers in many countries are enrolled in early childhood education (ECE) programs, and educators thus play a central role in stimulating language development in these young children. A valid, brief educator-completed measure of language development in young children has important uses both for the identification and monitoring of language development and for the guidance and evaluation of intentional instruction and targeted interventions for children who need it. We present such a measure here for Danish, the CDI: Educator (CDI-Edu) version, which is based on well-developed and validated parent report measures, adapted for the early childhood education setting. It requires approximately 10 min per child on the part of the educator. It includes a 70-item vocabulary checklist, as well as questions concerning the child's use of decontextualized language with respect to objects and actions distant from the here and now. The test has been standardized on a total of 5097 children aged 18-34 months. Test-retest and internal consistency measures demonstrate reliability. Validation is established through correlations with age, maternal education, the Danish One-Word Picture Vocabulary Test, and the Social Emotional Assessment Measure. PMID- 29990686 TI - Synchronization of mother-infant feeding behavior. AB - In the weaning period, infants are introduced to solid food after being fed solely on milk, which involves a deliberate reorganization of the infant caregiver feeding interaction. This multiple case study, involving 5 dyads with 10 repeated observations, analyzed its dynamical structure using Cross-Recurrence Quantification Analysis. The results showed that an optimal interaction occurs when the caregiver is leading by roughly 1-2 seconds. During the weaning period, all dyads showed signs of increased synchronization, although there are interesting differences between dyads. These findings indicate that infant caregiver dyads co-regulate their behavior within a relatively short period. PMID- 29990688 TI - Deep learning and conditional random fields-based depth estimation and topographical reconstruction from conventional endoscopy. AB - Colorectal cancer is the fourth leading cause of cancer deaths worldwide and the second leading cause in the United States. The risk of colorectal cancer can be mitigated by the identification and removal of premalignant lesions through optical colonoscopy. Unfortunately, conventional colonoscopy misses more than 20% of the polyps that should be removed, due in part to poor contrast of lesion topography. Imaging depth and tissue topography during a colonoscopy is difficult because of the size constraints of the endoscope and the deforming mucosa. Most existing methods make unrealistic assumptions which limits accuracy and sensitivity. In this paper, we present a method that avoids these restrictions, using a joint deep convolutional neural network-conditional random field (CNN CRF) framework for monocular endoscopy depth estimation. Estimated depth is used to reconstruct the topography of the surface of the colon from a single image. We train the unary and pairwise potential functions of a CRF in a CNN on synthetic data, generated by developing an endoscope camera model and rendering over 200,000 images of an anatomically-realistic colon.We validate our approach with real endoscopy images from a porcine colon, transferred to a synthetic-like domain via adversarial training, with ground truth from registered computed tomography measurements. The CNN-CRF approach estimates depths with a relative error of 0.152 for synthetic endoscopy images and 0.242 for real endoscopy images. We show that the estimated depth maps can be used for reconstructing the topography of the mucosa from conventional colonoscopy images. This approach can easily be integrated into existing endoscopy systems and provides a foundation for improving computer-aided detection algorithms for detection, segmentation and classification of lesions. PMID- 29990687 TI - Preparation and characterization of MnO2- SiO2 composite resin for 226Ra pre concentration in water samples. AB - The presented work describes an effective method for 226Ra determination using laboratory- prepared MnO2-SiO2 composite resin. Samples were traced with 133Ba for radium radiochemical recoveries monitoring which were in the range of (77 - 100%). MnO2- SiO2 composite resin was used to collect for 226Ra from water samples (pH = 6.5-7.0). Radium was eluted from the column with 50 mL of 4 mol L-1 HNO3 at a flow rate of 1.5 mL min-1. Alpha-spectrometric counting of Ba(Ra)SO4 microprecipitate was used for 226Ra determination. The new developed method was used to the 226Ra determination in samples of natural mineral, mountain spring, drinking and natural healing waters from Slovakia and Czech Republic. PMID- 29990689 TI - A cortical shape-adaptive approach to local gyrification index. AB - The amount of cortical folding, or gyrification, is typically measured within local cortical regions covered by an equidistant geodesic or nearest neighborhood ring kernel. However, without careful design, such a kernel can easily cover multiple sulcal and gyral regions that may not be functionally related. Furthermore, this can result in smoothing out details of cortical folding, which consequently blurs local gyrification measurements. In this paper, we propose a novel kernel shape to locally quantify cortical gyrification within sulcal and gyral regions. We adapt wavefront propagation to generate a spatially varying kernel shape that encodes cortical folding patterns: neighboring gyral crowns, sulcal fundi, and sulcal banks. For this purpose, we perform anisotropic wavefront propagation that runs fast along gyral crowns and sulcal fundi by solving a static Hamilton-Jacobi partial differential equation. The resulting kernel adaptively elongates along gyral crowns and sulcal fundi, while keeping a uniform shape over flat regions like sulcal banks. We then measure local gyrification within the proposed spatially varying kernel. The experimental results show that the proposed kernel-based gyrification measure achieves a higher reproducibility than the conventional method in a multi-scan dataset. We further apply the proposed kernel to a brain development study in the early postnatal phase from neonate to 2 years of age. In this study we find that our kernel yields both positive and negative associations of gyrification with age, whereas the conventional method only captures positive associations. In general, our method yields sharper and more detailed statistical maps that associate cortical folding with sex and gestational age. PMID- 29990690 TI - Neutralizing antibody production against Rebif(r) and ReciGen(r) in Relapsing Remitting Multiple Sclerosis (RRMS) patients and its association with patient's disability. AB - INTRODUCTION: Human recombinant interferon beta (IFN-beta) is one of the first line treatments for Relapsing-Remitting Multiple Sclerosis (RRMS). However, the production of neutralizing antibodies (NAb) can impair its function. The aim of this study was to investigate the production of neutralizing antibodies against Rebif(r) and ReciGen(r) (two brands of IFN-beta-1a) and to evaluate its correlation with Expanded Disability Status Scale (EDSS). MATERIALS AND METHODS: Serum samples of 71 RRMS patients (34 in ReciGen(r), 37 in Rebif(r) group) were collected. Neutralizing antibody was measured by Myxo-virus resistance protein A (MxA) assay using A549 cell line. The MxA concentration was measured by enzyme linked immunosorbent assay (ELISA) kit. RESULTS: The median period of treatment with IFN-beta-1a was 18 months in ReciGen(r) and 24 months in Rebif(r) arms. The percentage of patients with positive titer of neutralizing antibody (NAb+) had no statistically significant difference between groups (P = 0.6). In both ReciGen(r) and Rebif(r) groups, the increase in EDSS score was significantly higher in NAb+ patients compared to NAb- patients (p <= 0.05). The duration of using ReciGen(r) or Rebif(r) for >24 months was influential in the NAb positivity (OR = 3.78). CONCLUSION: Receiving interferon beta-1a for >24 months is correlated with higher possibility of NAb production. The type of IFN-beta used in the study had no significant impact on NAb positivity. In addition, both groups had comparable EDSS score changes, and NAb status of patients was correlated with their EDSS score. PMID- 29990691 TI - Melatonin attenuates airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1beta in rats with COPD. AB - Chronic airway inflammation is a characteristic feature of chronic obstructive pulmonary disease (COPD). Previous studies demonstrated that melatonin had a protective effect against COPD. In addition, silent information regulator 1 (SIRT1) was reported to be beneficial in COPD. However, whether SIRT1 is involved in the protective effect of melatonin against COPD remains unclear. In this study, we investigated the effect of melatonin on a rat model of COPD and explored the potential mechanisms. Twenty eight male Wistar rats were randomly assigned to four groups: control group, COPD group, COPD+Mel group and COPD+Mel+EX527 group. Rats were challenged with cigarette smoke and lipopolysaccharide (LPS) for 28 days with or without melatonin or EX527. The pulmonary function, lung histopathology, inflammatory cells count and the concentration of IL-1beta in the BALF as well as the protein expressions of SIRT1, NLRP3, cleaved caspase-1 and ASC in the lung tissues were measured. The results demonstrated that melatonin prevented the development of COPD, which was attributed to the inhibition of airway inflammation by attenuating NLRP3 inflammasome and IL-1beta. Furthermore, melatonin increased the expression of SIRT1 in lung tissues of rats with COPD, while inhibition of SIRT1 by EX527 abolished the protective effect of melatonin against COPD. In conclusion, these findings suggested that melatonin attenuated airway inflammation via SIRT1 dependent inhibition of NLRP3 inflammasome and IL-1beta in rats with COPD. PMID- 29990692 TI - Immune checkpoint blockade therapy for cancer: An overview of FDA-approved immune checkpoint inhibitors. AB - Although T lymphocytes have long been appreciated for their role in the immunosurveillance of cancer, it has been the realization that cancer cells may ultimately escape a response from tumor-reactive T cells that has ignited efforts to enhance the efficacy of anti-tumor immune responses. Recent advances in our understanding of T cell immunobiology have been particularly instrumental in informing therapeutic strategies to overcome mechanisms of tumor immune escape, and immune checkpoint blockade has emerged as one of the most promising therapeutic options for patients in the history of cancer treatment. Designed to interfere with inhibitory pathways that naturally constrain T cell reactivity, immune checkpoint blockade releases inherent limits on the activation and maintenance of T cell effector function. In the context of cancer, where negative T cell regulatory pathways are often overactive, immune checkpoint blockade has proven to be an effective strategy for enhancing the effector activity and clinical impact of anti-tumor T cells. Checkpoint inhibitors targeting CTLA-4, PD 1, and PD-L1 have yielded unprecedented and durable responses in a significant percentage of cancer patients in recent years, leading to U.S. FDA approval of six checkpoint inhibitors for numerous cancer indications since 2011. In this review, we highlight the clinical success of these FDA-approved immune checkpoint inhibitors and discuss current challenges and future strategies that must be considered going forward to maximize the efficacy of immune checkpoint blockade therapy for cancer. PMID- 29990693 TI - A novel CXCL8-IP10 hybrid protein is effective in blocking pulmonary pathology in a mouse model of Klebsiella pneumoniae infection. AB - Klebsiella pneumoniae (K. pneumoniae) is a hospital-acquired infectious agent that causes a range of diseases. Herein we have developed a novel CXCL8-IP10 hybrid protein and evaluated its efficacy in an animal model of K. pneumoniae infection. Neutrophil chemotaxis data revealed that CXCL8-IP10 could inhibit human neutrophil chemotactic responses induced by the ELR-CXC chemokine CXCL8. To evaluate the effect of CXCL8-IP10 on K. pneumoniae infection, C57BL/6 mice were challenged with K. pneumoniae followed by treatment with CXCL8-IP10 (500 MUg/kg, i.p.), or dexamethasone (0.8 mg/kg, s.c.), or ceftazidime (200 mg/kg, s.c.) individually. CXCL8-IP10, dexamethasone or ceftazidime markedly inhibit Klebsiella-induced pulmonary inflammation as assessed by gross examination and histopathology. Moreover, the chemotactic responses of neutrophils was blocked by CXCL8-IP10 rather than dexamethasone or ceftazidime. Furthermore, the levels of inflammatory factors IL-1beta, IFN-gamma and TNF-alpha were decreased after CXCL8 IP10, dexamethasone or ceftazidime treatment. Together, these results suggest that CXCL8-IP10 may provide a novel strategy for treating K. pneumoniae infection. PMID- 29990694 TI - Efficacy and safety of biologics targeting IL-17 and IL-23 in the treatment of moderate-to-severe plaque psoriasis: A systematic review and meta-analysis of randomized controlled trials. AB - Numerous biologics are currently licensed for the treatment of psoriasis, including new drugs targeting interleukin-17 (IL-17) and interleukin-23 (IL-23). This meta-analysis evaluated the short-term (12-16 weeks) efficacy and safety of biologics targeting IL-17 and IL-23 in the treatment of moderate-to-severe plaque psoriasis. Twenty-one randomized clinical trials met the defined inclusion criteria. Our results showed that Ixekizumab (160 mg wk0 + 80 mg q2w) had the greatest probability of achieving both PASI 75 (RR 21.32, 95% CI 15.48-29.36, P < 0.00001) and PASI 90 response (RR 59.76, 95% CI 32.41-110.19, P < 0.00001) at the primary endpoint times, followed by Ustekinumab and Secukinumab. Regarding the safety profile, Tildtakizumab (200 mg, q4w) was safest (RR 0.88, 95% CI 0.78 0.99, P = 0.04), while Ixekizumab (160 mg wk0 + 80 mg q2w) showed highest risk for one or more AE (RR 1.26, 95% CI 1.15-1.38, P < 0.00001). However, there was no significant difference between the two biologics regarding one or more SAEs. Comparing to the biologics targeting IL-23, the pooled effect size favored the biological agents targeting IL-17 in terms of the PASI 75 (PASI 75: RR 17.28, 95% CI 14.51-20.58, P < 0.00001) and PASI 90 (RR 37.19, 95% CI 26.91-51.41, P < 0.00001). The rate of overall AEs was significantly higher (P < 0.00001) in biologics targeting the IL-17 (RR 1.18, 95% CI 1.12-1.24, P < 0.00001) compared to biologics targeting IL-23 (RR 0.97, 95% CI 0.91-1.04, P = 0.44), and with respect to one or more SAEs, no difference was seen between biologics targeting IL-17 and IL-23. This meta-analysis found that Ixekizumab was the most effective short-term treatment, but was ranked as the most risk therapeutic choice among the biologics involved in this study, while Tildtakizumab was the best alternative in the case of safety. Furthermore, it demonstrated that biologics inhibiting IL-17 were superior to biologics targeting IL-23 in terms of the efficacy, but posed higher risk at the same time. This study might help the clinicians and guideline developers to choose the optimal one among these biologics for the treatment of moderate-to-severe plaque psoriasis. PMID- 29990695 TI - Recovery of circulating CD56dim NK cells and the balance of Th17/Treg after nucleoside analog therapy in patients with chronic hepatitis B and low levels of HBsAg. AB - BACKGROUND AND AIMS: Much evidence indicates that the soluble antigens secreted by hepatitis B virus (HBV) inhibit the function of the immune system. The aim of this study is to investigate, after treatment with nucleoside (acid) analogs (NAs) and the inhibition of viral replication, whether the immune systems of patients with a peripheral blood HBV-DNA level <1000 IU/mL, hepatitis B e antigen (HBeAg) disappearance, and a decrease in hepatitis B surface antigen (HBsAg) levels could be reconstructed. METHODS: The frequency and phenotype of circulating natural killer (NK) cells, dendritic cells (DCs), T-helper (Th) cells, regulatory T (Treg) cells, CD4+, CD8+ T cells, T follicular helper (Tfh) cells and B cells subtypes were tested by flow cytometry in chronic hepatitis B (CHB) patients and healthy controls (HCs). The levels of HBV-related serum HBsAg, HBeAg, HBV-DNA load, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. RESULTS: Regarding the innate immune system, an increased frequency of CD56dim NK cells was found in the therapeutic response (TR) group compared with that in the immune-active phase (IA) group. Additionally, regarding the adaptive immune system, the Th17/CD4+CD25+CD127dimTreg ratio was reduced in the TR group. Additionally, the frequency of CD40L+CXCR5+CD4+T cells and CD40+CD19+CD27+CD38+B cells was significantly higher than that of HCs, while that of PDL1+CD19+ B cells was lower. Furthermore, the frequencies of CTLA4+CD4+T cells and CTLA4+CD8+T cells in patients with CHB were significantly higher than those in HCs. CONCLUSION: After NA treatment and the inhibition of viral replication, circulating CD56dim NK cells and the balance of Th17/Treg can be recovered. Restoring circulating CD56dim NK cells and the Th17/Treg balance may help reduce HBsAg levels in patients. PMID- 29990696 TI - A systematic investigation on animal models of cyclosporine A combined with Escherichia coli to simulate the immunosuppressive status of sepsis patients before onset. AB - Immunosuppression is an important mechanism for the development of sepsis pathology, and is the key to the high mortality of sepsis. However, patients appear to be immunocompromised before sepsis onset due to lack of enough attention. Present sepsis models cannot fully mimic the onset of sepsis in patients. Hence, effective treatments in animal experiments could not be transformed into clinical application. In the present study, we improved the animal model of sepsis and used cyclosporine A immunosuppressive mice to make it closer to immune status before the onset of sepsis, followed by the intraperitoneal injection of Escherichia coli (E. coli) CMCC (B) 44,102 standard strain to produce the immunocompromised sepsis model. This trial systematically evaluates the new immunosuppressive sepsis model. Compared with routine sepsis models, the release of inflammatory factors in the new sepsis model was insufficient, blood bacteria were more cultured, diffuse intravascular coagulation (DIC) was more severe, lung, liver and kidney damage were heavier, and mortality rate was higher. In conclusion, the new sepsis model can mimic the patient's pre-onset immunocompromised state, is suitable for the development and evaluation of new methods of sepsis, and solves the controversy of sepsis treatment, providing new ideas and direction. PMID- 29990698 TI - Genistein reduces proliferation of EP3-expressing melanoma cells through inhibition of PGE2-induced IL-8 expression. AB - Genistein, a natural isoflavone found in soybean products, is considered as a powerful anti-cancer agent, although the involved mechanisms are not fully understood. There is a growing body of evidence that, among the genes inhibited by genistein and responsible for cell cycle progression, invasion, metastasis, and angiogenesis, IL-8 occupies a relevant place. On the other hand, it is equally well documented that IL-8 is upregulated by prostaglandin E2 (PGE2) in different pathological conditions, particularly in neoplastic disease. Here we investigated whether genistein could affect cell growth in a panel of oral, uveal and cutaneous melanoma cell lines by interfering with basal or PGE2-induced IL-8 production. To this end, experiments were performed to evaluate the effect of PGE2 treatment on IL-8 levels, the expression and the role of PGE2 receptors and whether genistein could be able to interfere with these events. Finally, it was evaluated whether the inhibition of oral, uveal and cutaneous melanoma cell proliferation in the presence of genistein could be related to a reduction of IL 8 levels. We show that PGE2 enhances IL-8 synthesis via the EP3 receptor and that genistein is able to down-regulate the latter, as well as to decrease IL-8 mRNA and protein expression, thereby inhibiting oral, uveal and cutaneous melanoma cell proliferation. Taken together, our data provide new insights into the anti cancer properties of genistein by showing that this flavonoid may affect the development and growth of melanoma at oral, uveal and cutaneous sites. Moreover, these results provide evidence that genistein may exert its therapeutic activity through its ability to prevent PGE2-mediated IL-8 induction. PMID- 29990697 TI - Nootkatone, a neuroprotective agent from Alpiniae Oxyphyllae Fructus, improves cognitive impairment in lipopolysaccharide-induced mouse model of Alzheimer's disease. AB - Neuroinflammatory responses play a crucial role in the pathogenesis of Alzheimer's disease (AD). Our previous study demonstrated that petroleum ether extracts from Alpiniae Oxyphyllae Fructus(AOF) could attenuate lipopolysaccharide (LPS)-induced learning and memory impairment in mice, which could be associated with its inhibitory effect on neuroinflammation. Therefore, our present study is to investigate the potential therapeutic neuroprotective effects of nootkatone (NKT) on an AD mouse model induced by intracerebroventricular injection of LPS. We found that NKT (10 mg/kg) group showed good performance in behavior experiments including Y-maze test and Morris water maze test. The results of histopathological examination and immunohistochemical analysis showed that LPS induced degeneration of neurons and activation of microglia particularly in hippocampus and NKT (10 mg/kg) reversed these changes. Enzyme linked immunosorbent assay and western blot analysis also demonstrated that the model group had increased expression of IL-1beta, IL-6, TNF-alpha, NLRP3 and NF-kappaB p65, especially in hippocampus relative to sham-operated group, and NKT (10 mg/kg) decreased the high expression of these inflammatory cytokines. Collectively, these data indicated that LPS-induced learning and memory impairments in mice could be improved by NKT, which was associated with attenuating neuroinflammatory responses. Our study indicated that NKT could act as a potential therapeutic agent for the treatment of neuroinflammation and AD. PMID- 29990699 TI - Neutrophils contribute to the pathogenesis of hemorrhagic cystitis induced by ifosfamide. AB - Ifosfamide (IFO) is an antineoplastic drug that is commonly used to treat gynecological and breast cancers. Hemorrhagic cystitis (HC) is a common side effect associated with IFO injection, which courses with neutrophil accumulation and affects 6-50% of patients depending on dose intensity. Here, we investigated the role of neutrophils in this inflammatory process. Female Swiss mice (n = 8/group) were injected with saline, IFO (400 mg/kg, i.p.), fucoidan (a P- and L selectins inhibitor, 100 mg/kg, i.v.) or IFO + fucoidan (1-100 mg/kg) alone or combined with mesna (80 mg/kg i.p.). Another group of mice received anti-Ly6G antibody (500 MUg/mouse, once daily for 2 days) for neutrophil depletion before IFO injection. In another experimental setting, animals received granulocyte colony-stimulating factor (G-CSF, 400 MUg/kg), IFO (200 mg/kg), G-CSF (25-400 MUg/kg, for 5 days) + IFO (200 mg/kg, i.p.) or fucoidan + G-CSF + IFO. Bladder injury was evaluated 12 h after IFO injection. IFO 400 mg/kg significantly increased visceral hyperalgesia, bladder edema, hemorrhage, vascular permeability, MPO, IL-1beta and IL-6 tissue levels, and COX-2 immunostaining and expression versus the saline group (P < 0.05). Conversely, fucoidan (100 mg/kg) significantly attenuated these parameters compared to IFO-injected mice (P < 0.05). Additionally, fucoidan potentiated mesna protective effect when compared with IFO + mesna group (P < 0.05). Accordingly, neutrophil depletion with anti Ly6G reduced inflammatory parameters and bladder injury compared to IFO (P < 0.05). In contrast, G-CSF enhanced IFO (200 mg/kg)-induced HC, which was significantly attenuated by treatment with fucoidan (P < 0.05). Therefore, neutrophils contribute to the pathogenesis of HC. PMID- 29990700 TI - Spatial selective attention biases are shaped by long-term musical experience and short-term exposure to tones. AB - Selective attention is a dynamic process that rapidly shifts processing resources to information that is most relevant to our goals. Although individuals often show spatial biases in attention, these biases can be modified by both long-term factors, such as musical training, or by momentary changes in the auditory context. The present study used a visual search task to examine the influence of these factors on spatial attention biases while increasing demands on selective attention. Experiment 1 examined the effects of musical experience on baseline spatial selective attention biases during search. Individuals with little musical experience showed a typical leftward response bias that became stronger as the number of distractors increased. However, those with more musical experience showed similar responses to targets on the left and right sides, indicating an attenuation of the typical leftward spatial attention bias. Experiment 2 examined whether the addition of low- and high-frequency tones dynamically influenced participants' spatial attention biases during visual search. Participants showed increased orienting to and scanning of left-side distractor locations in response to low-frequency tones regardless of musical experience. The present results demonstrate that spatial attention biases are dynamic and can be shaped by both long-term experiences and momentary contextual effects. PMID- 29990701 TI - Neuroplasticity across the lifespan and aging effects in bilinguals and monolinguals. AB - Evidence that bilingualism protects against age-related neurocognitive decline is mixed. One relatively consistent finding is that bilingual seniors have greater grey matter volume (GMV) in regions implicated in executive control (EC) and language processing. Here, we compare the neuroplastic effects of bilingual experience on the EC network of young and aging populations directly, and for the first time we evaluate the extent to which such effects may predict executive control performance across age. We used GMV as an index of neural reserve and response time (RT) performance on the Flanker task for measuring EC efficiency. In the presence of age-related widespread GM deterioration, bilinguals had greater GMV than monolinguals in key regions of interest across age. Moreover, whereas EC performance in monolingual seniors was strictly related to GMV, this was not observed for bilingual seniors or younger participants in either group. Interactions between expected effects-of-age and language group on the relationships between GMV and RT suggested that bilingualism affords differential benefits across the lifespan. In younger participants, greater GMV offered no behavioral benefit on EC performance, whilst it did for seniors. It thus appears that age-related cognitive decline following GMV loss in the EC network is delayed in bilinguals. PMID- 29990702 TI - Higher cardiovascular fitness level is associated to better cognitive dual-task performance in Master Athletes: Mediation by cardiac autonomic control. AB - INTRODUCTION/PURPOSE: This study compared cognitive performances and cardiac autonomic measures of higher fit and lower fit middle-aged and older highly active adults. The working hypotheses were that higher fit (master athletes) would show cognitive benefits in executive control conditions due to a high level of fitness compared to lower fit people and that this effect would be mediated by better cardiac autonomic adaptations in athletes. METHODS: We recruited 39 highly active middle aged and older adults from Master Athletes' organizations. All participants performed a Rockport walking test and a computerized dual-task. Cardiac autonomic control was assessed with a measure of heart rate variability. Based on the VO2max estimated by the Rockport test, a median split was performed to assess the influence of fitness level on cognitive performance and the link with heart rate variability. Those with the highest fitness level were considered Master Athletes. RESULTS: Master Athletes showed better dual-task performances than lower fit individuals. A positive relationship between the VO2max and dual task performances was also observed. Master Athletes demonstrated a lower resting HR and higher RR interval than lower fit individuals, and this index was specifically related to the executive conditions of the dual task. CONCLUSION: Our results highlight the role of fitness level on executive function in highly active middle aged and older adults and suggest that the better performances observed in highly fit individuals is mediated by cardiac autonomic control. PMID- 29990703 TI - Cerebral blood flow modulations during proactive control in chronic hypotension. AB - In addition to complaints including fatigue, mood disturbance, dizziness or cold limbs, chronic low blood pressure (hypotension) is associated with reduced cognitive performance. Deficiencies in cerebral blood flow regulation may contribute to this impairment. This study investigated cerebral blood flow modulations during proactive control in hypotension. Proactive control refers to cognitive processes during anticipation of a behaviourally relevant event that allow optimization of readiness to react. Using functional transcranial Doppler sonography, bilateral blood flow velocities in the middle cerebral arteries were recorded in 40 hypotensive and 40 normotensive participants during a precued Stroop task. Hypotensive participants exhibited smaller bilateral blood flow increases during response preparation and longer response time. The group differences in blood flow and response time did not vary by executive function load, i.e. congruent vs. incongruent trials. Over the total sample, the flow increase correlated negatively with response time in trials with a higher executive function load. The findings indicate reduced cerebral blood flow adjustment during both the basic and more complex requirements of proactive control in hypotension. They also suggest a general deficit in attentional function and processing speed due to low blood pressure and cerebral hemodynamic dysregulations rather than particular impairments in executive functions. PMID- 29990704 TI - The role of the cerebellum for feedback processing and behavioral switching in a reversal-learning task. AB - Previous studies have reported cerebellar activations during error and reward processing. The present study investigated if the cerebellum differentially processes feedback depending on changes in response strategy during reversal learning, as is conceivable given its internal models for movement and thought. Negative relative to positive feedback in an fMRI-based reversal learning task was hypothesized to be associated with increased cerebellar activations. Moreover, increased activations were expected for negative feedback followed by a change in response strategy compared to negative feedback not followed by such a change, and for first positive feedback after compared to final negative feedback before a change, due to updating of internal models. As predicted, activation in lobules VI and VIIa/Crus I was increased for negative relative to positive feedback, and for final negative feedback before a change in response strategy relative to negative feedback not associated with a change. Moreover, activation was increased for first positive feedback after relative to final negative feedback before a change. These findings are consistent with updating of cerebellar internal models to accommodate new behavioral strategies. Recruitment of posterior regions in reversal learning is in line with the cerebellar functional topography, with posterior regions involved in complex motor and cognitive functions. PMID- 29990705 TI - Telling a truth to deceive: Examining executive control and reward-related processes underlying interpersonal deception. AB - Does deception necessarily involve false statements that are incompatible with the truth? In some cases, people choose truthful statements in order to mislead others. This type of deception has been investigated less. The current study employed event-related brain potentials (ERPs) to investigate the neurocognitive processes when both truthful and false statements were used to deceive others. We focused our ERP analysis on two stages: a decision making stage during which participants decided whether to tell a false or a truthful statement, and an outcome evaluation stage during which participants evaluated whether their deception had succeeded or not. Results showed that in the decision making stage, intentions to deceive elicited larger N200s and smaller P300s than an honest control condition. During the outcome evaluation stage, success/failure feedback in the deception condition elicited larger Reward positivity (RewP) and feedback P300 than feedback after honest responses. Importantly, whether participants chose to tell false or true statements, did not further modulate executive control or reward-related processes. Taken together, these results suggest that during interpersonal deception, having deceptive intentions engages executive control and reward-related processes regardless of the veracity of statements. PMID- 29990706 TI - Modulation of epileptiform EEG discharges in patients with JME. AB - PURPOSE: To study modulation of epileptiform EEG discharges in patients with JME. METHOD: 50 subjects with JME underwent a sleep deprived EEG recording along with conventional provocative methods and testing with cognitive tasks (CTs). Both categories of tests were evaluated for their effect on occurrence of IEDs. Number of IEDs per unit time was calculated at baseline as well as with each task. Statistical and arbitrary methods were used to assess modulation. By arbitrary method if frequency of IEDs was more than twice that of baseline, it was considered as provocation and if less than half, it was considered as inhibition. To account for spontaneous fluctuation of IEDs, 95% CI was calculated for baseline IEDs in each patient and provocation/inhibition was considered if frequency of IEDs exceeded/remained below limits of CI respectively. RESULTS: There was no significant difference in rates of provocation of IEDs by conventional or CTs. However there was exclusive provocation of IEDs by CTs in 4 patients, 3 of whom were already on AEDs. There was a significant inhibitory effect of CTs as mean baseline discharge frequency was 0.4 +/- 1.16 IEDS/min and during CTs was 0.1 +/- 0.38 IEDs/min. However when spontaneous fluctuation was accounted for, inhibition was seen in only 22.23% patients by statistical method as compared to 90.91% by arbitrary method. CONCLUSIONS: Inclusion of CTs may assist in provocation of IEDs, thereby increasing yield of routine EEG. Spontaneous fluctuation of IEDs accounts for much observed inhibition by CTs in JME patients. PMID- 29990707 TI - Prospective study of the efficacy of a ketogenic diet in 20 patients with Dravet syndrome. AB - PURPOSE: We evaluated the efficacy and tolerability of the ketogenic diet (KD) on generalised convulsions and status epilepticus (SE) in patients with Dravet syndrome (DS). METHODS: Patients with DS having >=2 generalised convulsions/month despite drug treatment were included in this study and placed on a KD for 6 months. From 3 months before (baseline) to 6 months after KD initiation, caregivers recorded patients' seizure activity, antiepileptic drug use, and adverse events. The KD efficacy was determined by examining the frequency and duration of seizures at 3 and 6 months vs. baseline. Responders were defined as individuals whose generalised convulsions decreased in frequency by >=50% vs. baseline. Seizures lasting >=5 min and SE were specifically evaluated. Patients' cognition was also assessed at 3 and 6 months via questionnaire. RESULTS: Twenty patients continued the KD for at least 3 months. Of the 17 responders identified at month 3, seizures decreased by 50-89% and 90-99% in nine and two patients, respectively; six patients were seizure free. The KD was ineffective in three patients, who discontinued the diet. By month 6, seizures decreased by 50-89% and 90-99% in six and one patient(s), respectively; 10 patients were seizure free. The frequency of other seizure types also improved. During all 6 months, neither generalised convulsions lasting >=5 min nor SE was detected in the 17 responders. The KD also improved patients' cognition. CONCLUSION: The KD is a good treatment option for medically intractable epilepsy. PMID- 29990708 TI - Are epilepsy patients bypassing primary care? A cross-sectional study from India. AB - PURPOSE: Lack of epilepsy primary and secondary care and an arbitrary referral system causes many epilepsy patients to seek tertiary care even when they may not need it. This causes overcrowding, increased waiting times and also compromises the quality of tertiary care. We conducted this study to identify what proportion of epilepsy patients presenting to tertiary care actually needed it. METHODS: To test appropriateness of candidacy for tertiary care, we formulated Modified NICE criteria (MNC) based on NICE criteria. Modified NICE criteria were used to dichotomize participants into two groups: a) those who needed tertiary care and b) those who did not need tertiary care. We also looked at agreement between MNC and original NICE criteria. RESULTS: Four hundred and twenty two patients were recruited. According to the MNC, 240 patients (57%) qualified for tertiary care while 182 (43%) did not. The agreement between MNC and original NICE criteria was 86.7%, kappa 0.73(95% CI 0.66-0.79, p < 0.001). The most frequently cited reason for seeking tertiary care was 'Unsatisfactory response to treatment', although; many of these patients were actually non-adherent to treatment. Amongst variables that predicted non-eligibility for tertiary care, the most important was not having been referred. CONCLUSION: Many epilepsy patients seeking tertiary care do not need it. Access and quality of epilepsy care can be improved if there is a rational and need-based distribution of patients between primary, secondary and tertiary care. Referral systems also need to be developed and used to transition patients from one level of care to another. PMID- 29990710 TI - Derivation and molecular characterization of pancreatic differentiated MODY1 iPSCs. AB - Maturity onset diabetes of the young (MODY) is a hereditary form of diabetes mellitus presenting at childhood or adolescence, which eventually leads to pancreatic beta-cells dysfunction. The underlying genetic basis of MODY disorders is haploinsufficiency, where loss-of-function mutations in a single allele cause the diabetic phenotype in heterozygous patients. MODY1 is a type of MODY disorder resulting from a mutation in the transcription factor hepatocyte nuclear factor 4 alpha (HNF4alpha). In order to establish a human based model to study MODY1, we generated patient-derived induced pluripotent stem cells (iPSCs). Differentiation of these pluripotent cells towards the pancreatic lineage enabled to evaluate the effects of the MODY1 mutation and its impact on endodermal and pancreatic cells. Analyzing the gene expression profiles of differentiated MODY1 cells, revealed the outcome of HNF4alpha haploinsufficiency on its targets. This molecular analysis suggests that the differential expression of HNF4alpha target genes in MODY1 is affected by the number of HNF4alpha binding sites, their distance from the transcription start site, and the number of other transcription factor binding sites. These features may help explain the molecular manifestations of haploinsufficiency in MODY1 disease. PMID- 29990709 TI - Valproate free serum concentrations: More complex than simple formulas. PMID- 29990711 TI - Isolation and identification of a novel algicidal peptide from mackerel muscle hydrolysate. AB - To help remedy damage from harmful algal blooms, an attempt was made to isolate an algicidal substance previously observed to be present in mackerel muscle hydrolysate. Crude extract was obtained by cold acetone precipitation, and it dissolved best in water. Through molecular weight cut-off determination and tricine-SDS PAGE, the algicidal substance was determined to be a peptide of <1 kDa. Based on this result, purification was first performed using size exclusion chromatography and preparative reverse phase high-performance liquid chromatography. Then, the active algicidal fraction was applied to an ultra performance liquid chromatography-electrospray ionization-mass spectrometry system, followed by MS/MS analysis. The algicidal peptide had linear structure consisting of amino acids with sequence NH-KMNF-COOH. Its calculated properties were: molecular weight 538.66 g/mol; isoelectric point 9.91; net charge +1 at pH 7.0; and 50% hydrophobicity. Algicidal ability of the identified peptide was confirmed using synthesized peptide. The LC50 values toward four harmful algal blooming species were 0.69, 0.83, 0.85 and 1.24 mg/ml for Alexandrium fundyense, A. catenella, Heterocapsa triquetra, and Prorocentrum minimum, respectively. There was no coincidence in the sequence of the identified peptide with those of known metabolites in the APD, Norine, CAMP, UniProt and METLIN databases. Consequently, this algicidal substance originating from mackerel protein was deduced to be a novel peptide that can usefully be applied to relieve harmful algal blooms. PMID- 29990712 TI - Application of a simple methodology to analyze Hydroxypropyl-beta-Cyclodextrin in urine using HPLC-LS in early Niemann-Pick disease type C patient. AB - A new methodology, based on high resolution liquid chromatography with light scatterin detector, is applied to analyze Hydroxypropyl-beta-Cyclodextrin (HPbetaCD) in urine samples of a child affected by Niemann-Pick Type C disease. The treatment not only stopped disease progression, but has also increased the life expectancy and quality of our patient. The pharmacokinetic of HPbetaCD in the patient was studied with a 92.8% of HPbetaCD recovered. At 88 h, no HPbetaCD was found in the urine. During the treatment, HPbetaCD has not shown toxicity. Before application of the new treatment, injections were given every two weeks but, we have demonstrated that this can be increased to every four days. PMID- 29990713 TI - Rapid analysis of neomycin in cochlear perilymph of guinea pigs using disposable SPE cartridges and high performance liquid chromatography-tandem mass spectrometry. AB - Irreversible hearing loss induced by aminoglycoside in human through local or systemic administration route negatively impacts quality of life. The aim of this work was to develop and validate an analytical method suitable for the detection and quantification of neomycin in cochlear perilymph of guinea pig after local application. The SupelMIP SPE column was used for the pre-treatment of matrix. Chromatographic separation was conducted by a reversed phase ODS column (100 * 2.1 mm, 3 MUm) at 40 degrees C in gradient mode with 0.20/00 (v/v) HFBA in water and 0.20/00 (v/v) HFBA in acetonitrile as mobile phase, at a flow rate of 0.30 mL/min, with retention time of 3.50 and 3.62 min for internal standard tobramycin and analyte neomycin, respectively. The MS was performed with positive ionization mode, with data acquisition in Multi Reaction Monitor (MRM) mode. This method was proved to be specific, accurate (97.1-115% of nominal values) and precise (CV% < 15%). Calibration curves for matrix matched standard of neomycin ranged from 1.25 to 200 MUg/mL, with LOD and LLOQ of 0.625 and 1.25 MUg/mL in blank matrix. The matrix effect was corrected to (-0.1) - 1.33 by adding internal standard. The relative SPE recovery values were >=98.9% in low, medium and high QC samples. Neomycin in matrix proved to be stable under room temperature - and -20 degrees C, or under three freeze-thawing cycles, or under processing as well. Finally, the proposed method was successfully applied to a toxicokinetics study of neomycin in perilymph after round window membrane (RWM) administration, which was in accordance with threshold shift of auditory brainstem response (ABR) test related to hearing loss. PMID- 29990714 TI - Dry Blood Spot sample collection for post-exposure monitoring of chemical warfare agents - In vivo determination of phosphonic acids using LC-MS/MS. AB - Phosphonic acids are the direct and immediate metabolites of organophosphorus chemical warfare agents (OP-CWAs). Accordingly, their detection serves for evaluating exposure to OP-CWAs in a terror or war scenario. After exposure, phosphonic acids are present in the blood; however, blood drawing must be carried out by medical personnel, hence the number of samples that can be drawn in a mass casualty event is limited. Herein, we describe a new approach developed for the determination of phosphonic acids in blood using Dry Blood Spots (DBSs) on a filter paper. The method is based on a simple sample preparation protocol, followed by LC-MS-MS targeted (MRM) analysis. The detection limits of Soman (GD), Cyclosarin (GF) and VX metabolites in whole blood were as low as 1 ng/ml, while the detection limits were 0.3 ng/ml for the GF metabolite and 0.5 ng/ml for the Sarin (GB) metabolite. Good recoveries were obtained in the range of 1-100 ng/ml for GB and GD metabolites, and 3-100 ng/ml for GF, VX and RVX metabolites, with a linear response (R2 = 0.99). The method has proven to be reliable even with DBS samples stored up to 35 days at room temperature before analysis. This method was implemented in a 24 h time-course determination of the Sarin metabolite in an in vivo experiment, after rat exposure to 1 LD50 of Sarin. This technique is simple, rapid, sensitive, robust, long lasting and compatible with field collection and storage; hence, it can serve for large-scale sampling and reliable monitoring of potential OP-CWAs casualties. Since DBS sampling is amenable to nonprofessionals, including self-sampling, this technique is highly suitable for mass-casualty incidents. PMID- 29990715 TI - Validation of analytical methods for chlordecone and its metabolites in the urine and feces of ewes. AB - Chlordecone (CLD) is a Persistent Organic Pollutant used between 1972 until 1993 in the French West Indies (FWI). Due to its persistence and extensive application, a quarter of the total local agricultural acreage is still moderate to heavily polluted. In consequence, livestock may be contaminated at various levels. This is a major public health concern, particularly for local consumers. In order to better understand the fate of CLD in livestock organisms, in vivo studies are required. There is no information available about its metabolism and elimination in ruminants, common livestock in the FWI. To be able to monitor the fate of chlordecone and its metabolites in livestock and to assess if the compounds could be released in the environment, urinary and fecal samples were logically targeted. In order to reach this goal, robust and validated analytical methods are required. For this purpose, Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction methods were validated to analyze CLD and its metabolites in the urine and feces. The analysis was carried using liquid phase chromatography with tandem mass spectrometry and validated according to French standard NF V03-110 and SANTE guidelines. Matrix effect, Accuracy, within laboratory repeatability, specificity, Q/q relative ion intensities and uncertainty were reported. Recoveries between 70% and 120% were obtained from urine and feces. The limits of quantification (LOQ) in urine samples were 0.1 MUg CLD L-1, 0.1 MUg total CLD (CLD and its conjugates).L-1, 1.3 MUg CLDOH L-1 and 2.4 MUg total CLD (chlordecol and its conjugates) L-1 of urine. LOQ in fresh feces were 3.2 MUg CLD kg-1 and 5.8 MUg CLDOH kg-1. Contaminated urinary and fecal samples from ewes were analyzed to confirm the relevance of the methods. In urine, CLD and conjugated CLDOH could be quantified whereas only free CLD and free CLDOH were found in feces. These methods are essential for future toxicokinetic studies and also to estimate the environmental contamination. PMID- 29990716 TI - Inter-laboratory study of the skin distribution of 4-n-butyl resorcinol in ex vivo pig and human skin. AB - 4-n-butyl resorcinol (4-nBR) is a highly effective tyrosinase inhibitor, and can be used in cosmetic product for depigmentation purpose. Its efficacy correlates with 4-nBR that absorbed by skin. In this study, skin distribution of 4-nBR within either human or pig skin ex vivo was studied and compared by three independent laboratories. Good agreement was observed in each compartment considering usual inter-lab variability. This study supports the use of pig skin as an alternative source of skin when the availability of human skin is a limiting factor. PMID- 29990717 TI - Bioanalytical method validation of endogenous substances according to guidelines by the FDA and other organizations: Basic need to specify concentration ranges. PMID- 29990718 TI - Recent development of chromatographic methods to determine parabens in breast milk samples: A review. AB - Parabens have been widely used as antimicrobial preservatives in food, drugs, and cosmetics for over 60 years. These endocrine disruptors can alter both the wildlife and the human hormone function. Determining these compounds in human milk is important because breast milk plays an important role in infant growth and in neurocognitive development. This article summarizes the current state-of the-art of chromatographic methods to determine parabens in breast milk samples. Apart from the conventional and modern microextraction sample preparation techniques described herein, the authors discuss the chromatographic systems, primarily LC-MS/MS, and the concentration ranges at which parabens have been detected in milk samples obtained from lactating women over the past few years. PMID- 29990719 TI - Morpho-syntactic complexity modulates brain activation in Persian-English bilinguals: An fMRI study. AB - The Persian language can be considered to have a relatively more complex and combinatorial morpho-syntax than languages like Chinese and English. For example, the Persian verbal system is largely constituted of light verb constructions, in which light verbs are combined with specific items coming from other grammatical classes to generate entirely new verbal entities. This study was designed to examine the mediating effect of language-inherent properties related to morpho syntax on activation of the left inferior frontal gyrus (LIFG), a brain area involved in morpho-syntactic processing. To this end, 20 late Persian-English bilinguals were required to covertly generate verbs and nouns from object and action pictures, within a cued grammatical context. Consistent with predictions, the results of an ROI analysis revealed an interaction between task and language in BA 44 of the LIFG and its right homologue, with greater activation of this region during the production of Persian compared to English verbs. In contrast, there was greater activation of the BA 44 during the production of English compared to Persian nouns, consistent with the more effortful processing of their less proficient second language (English). The findings suggest that language specific properties such as morpho-syntactic complexity can modulate the recruitment of Broca's area, over and above the more well-documented effects of language proficiency. PMID- 29990720 TI - Intact perception of coherent motion, dynamic rigid form, and biological motion in chronic schizophrenia. AB - BACKGROUND: Prior studies have documented biological motion perception deficits in schizophrenia, but it remains unclear whether the impairments arise from poor social cognition, perceptual organization, basic motion processing, or sustained attention/motivation. To address the issue, we had 24 chronic schizophrenia patients and 27 healthy controls perform three tasks: coherent motion, where subjects indicated whether a cloud of dots drifted leftward or rightward; dynamic rigid form, where subjects determined the tilt direction of a translating, point light rectangle; and biological motion, where subjects judged whether a human point-light figure walked leftward or rightward. Task difficulty was staircase controlled and depended on the directional variability of the background dot motion. Catch trials were added to verify task attentiveness and engagement. RESULTS: Patients and controls demonstrated similar performance thresholds and near-ceiling catch trial accuracy for each task (uncorrected ps > 0.1; ds < 0.35). In all but the coherent motion task, higher IQ correlated with better performance (ps < 0.001). CONCLUSION: Schizophrenia patients have intact perception of motion coherence, dynamic rigid form, and biological motion at least for our sample and set-up. We speculate that previously documented biological motion perception deficits arose from task or stimulus differences or from group differences in IQ, attention, or motivation. PMID- 29990721 TI - Immobilization of Sphingomonas sp. GY2B in polyvinyl alcohol-alginate-kaolin beads for efficient degradation of phenol against unfavorable environmental factors. AB - In this study, batch experiments were carried out to evaluate the biodegradation of phenol by Sphingomonas sp. GY2B, which were immobilized in polyvinyl alcohol (PVA)-sodium alginate-kaolin beads under different conditions. The optimal degradation performance was achieved by GY2B immobilized in beads containing 1.0% (w/v) of kaolin, 10% (w/v) of PVA, 0.3% (w/v) of sodium alginate, 10% (v/v) of biomass dosage, and exposed to an initial phenol concentration of 100 mg/L. The experimental results indicated that PVA-sodium alginate-kaolin beads can accelerate the degradation rate of phenol by reducing the degradation time and also improve degradation rate. The biodegradation rate of phenol by immobilized cells (16.79 +/- 0.81 mg/(L.h)) was significantly higher than that of free cells (11.49 +/- 1.29 mg/(L.h)) under the above optimal conditions. GY2B immobilized on beads was more competent than free GY2B in degradation under conditions with high phenol concentrations (up to 300 mg/L) and in strong acidic (pH = 1) and alkaline (pH = 12) environments. Higher phenol concentrations inhibit the biomass and reduce the biodegradation rate, while the lower biodegradation rate at low initial phenol concentrations is attributed to mass transfer limitations. The Haldane inhibitory model was in agreement with the experimental data well, revealing that phenol showed a considerable inhibitory effect on the biodegradation by Sphingomonas sp. GY2B, especially at concentrations higher than 90 mg/L. Intra-particle diffusion model analysis suggests that adsorption of phenol by immobilized beads was controlled by both rapid surface adsorption as well as pore diffusion mechanism. It's worth noting that the presence of 1 mg/L Cr(VI) enhanced the biodegradation of phenol by free cells, while Cr(VI) showed no obvious impact on the removal of phenol by immobilized cells. In addition, immobilized cells were reused 16 times and removed 99.5% phenol, and when stored at 4 degrees C for 90 days, more than 99% phenol was removed. These results showed that immobilized cells can significantly improve the microbial degradation performance, and protect microorganisms against unfavorable environment. It is implied that PVA -sodium alginate-kaolin beads have great potential to be applied in a practical and economical phenolic wastewater treatment system. PMID- 29990722 TI - Human exposure to trace elements in central Cambodia: Influence of seasonal hydrology and food-chain bioaccumulation behaviour. AB - Exposure to mercury and other trace elements remains an important public health concern, worldwide. The present study involved a comprehensive field study to determine concentrations of fourteen trace elements (Al, As, Cr, Co, Cd, Cu, Fe, Hg, Mn, Ni, Pb, Se, V and Zn) in surface water and different fish species from Tonle Sap Lake in central Cambodia, during both the dry and wet seasons. Total arsenic (tAs) and Mn in surface water during the dry season exceeded WHO drinking water guidelines. Total mercury (tHg) concentrations (ug/g wet wt.) in fish during the wet season (GM = 0.055; CI95 = 0.01-0.26) were approximately 15 times higher (P < 0.05) compared to those during the dry season (GM = 0.0035; CI95 = 0.0004-0.033). Mean target hazard quotients (THQs) for inorganic arsenic (iAs), methyl mercury (MeHg), Mn and Pb were > 1, with estimated maximum values greatly exceeding 1. Mean THQs of Zn, Cd, Ni and Se were very near 1, with estimated maximum values exceeding 1. The MeHg THQ (min-max range: 0.16-9.09) during the wet season was 7 times higher than in the dry season (min-max range: 0.05-1.35). Concentrations of Hg and other trace elements varied widely between fish species. The findings suggest that exposure of some trace elements via water and food is of concern in this region. High consumption rates of fish and rice key factors related to trace element exposure. Seasonal hydrology and species-specific bioaccumulation behaviour in the Tonle Sap Lake watershed also play an important role. The generated information will be useful to better mitigate trace element exposure in this region. PMID- 29990723 TI - Biomarkers of oxidative stress in blood of workers exposed to non-cholinesterase inhibiting pesticides. AB - In occupational settings workers are often exposed to pesticides at relatively high doses compared to environmental exposures. Long-term exposure to pesticides has been associated with numerous adverse health effects in epidemiological studies, and oxidative stress is often claimed as one of the underlying mechanisms. In fact, different pesticides have been reported to induce oxidative stress due to the generation of free radicals and/or alteration in antioxidant defense enzymes. The present study examined greenhouse workers regularly exposed to diverse pesticides under integrated production system, and a group of controls of the same geographic area without any chemical exposure. Two different periods of the same crop season were assessed, one of high exposure (with greater use of pesticides) and other of low exposure (in which a less use of these compounds was made). Non-specific biomarkers of oxidative stress, e.g. thiobarbituric acid reactive substances (TBARS), ferric reducing ability of serum (FRAS), total thiol groups (SHT), gamma-glutamyl transpeptidase (GGT) and paraoxonase-1 (PON1) were measured in serum samples from all study subjects, alongside erythrocyte acetylcholinesterase (AChE). Results are suggestive of a mild increase in oxidative stress associated with pesticide exposure, which was compensated by an adaptive response to raise the antioxidant defenses and thus counter the detrimental effects of sustained oxidative stress. This response led to significantly increased levels of FRAS, SHT and PON1 in greenhouse workers relative to controls. Furthermore, AChE was decreased likely as a result of oxidative stress as workers did not use organophosphate insecticides. PMID- 29990724 TI - Mining alfalfa (Medicago sativa L.) nodules for salinity tolerant non-rhizobial bacteria to improve growth of alfalfa under salinity stress. AB - There are fewer reports on plant growth promoting (PGP) bacteria living in nodules as helper to tolerance to abiotic stress such as salinity and drought. The study was conducted to isolate rhizobial and non-rhizobial drought and salinity tolerant bacteria from the surface sterilized root nodules of alfalfa, grown in saline soils, and evaluate the effects of effective isolates on plant growth under salt stress. Based on drought and salinity tolerance of bacterial isolates and having multiple PGP traits, two non-rhizobial endophytic isolates and one rhizobial endophytic isolate were selected for further identification and characterization. Based on partial sequences of 16 S rRNA genes, non-rhizobial isolates and rhizobial isolate were closely related to Klebsiella sp., Kosakonia cowanii, and Sinorhizobium meliloti, respectively. None of the two non-rhizobial strains were able to form nodules on alfalfa roots under greenhouse and in vitro conditions. Co-inoculation of alfalfa plant with Klebsiella sp. A36, K. cowanii A37, and rhizobial strain S. meliloti ARh29 had a positive effect on plant growth indices under salinity stress. In addition, the single inoculation of non rhizobial strains without rhizobial strain resulted in an increase in alfalfa growth indices compared to the plants non-inoculated and the ones inoculated with S. meliloti ARh29 alone under salinity stress, indicating that nodule non rhizobial strains have PGP potentials and may be a promising way for improving effectiveness of Rhizobium bio-fertilizers in salt-affected soils. PMID- 29990725 TI - Discerning three novel chromate reduce and transport genes of highly efficient Pannonibacter phragmitetus BB: From genome to gene and protein. AB - Here, Pannonibacter phragmitetus BB was investigated at genomic, genetic and protein levels to explore molecular mechanisms of chromium biotransformation, respectively. The results of Miseq sequencing uncovered that a high-qualified bacterial genome draft was achieved with 5.07 Mb in length. Three novel genes involved in chromate reduce and transport, named nitR, chrA1 and chrA2, were identified by alignment, annotation and phylogenetic tree analyses, which encode a chromate reductase (NitR) and two chromate transporters (ChrA1 and ChrA2). Reverse transcription real-time polymerase chain reaction (RT-qPCR) analyses showed that the relative quantitative transcription of the three genes as the maximum reduction rate of Cr(VI) were significantly up-regulated with the increasing initial Cr(VI) concentrations. However, at the maximum cell growth points nitR was in a low transcription level, while the transcription of chrA1 and chrA2 were hold at a relatively high level and decreased with the increasing initial Cr(VI) concentrations. The ex-situ chromate reducing activity of NitR was revealed a Vmax of 34.46 umol/min/mg enzyme and Km of 14.55 umol/L, suggesting feasibility of the reaction with Cr(VI) as substrate. The multiple alignment demonstrates that NitR is potentially a nicotinamide adenine dinucleotide phosphate (NADPH) dependent flavin mononucleotide (FMN) reductase of Class I chromate reductases. Our results will prompt a large-scaled bioremediation on the contaminated soils and water by Pannonibacter phragmitetus BB, taking advantage of uncovering its molecular mechanisms of chromium biotransformation. PMID- 29990726 TI - Bioaccumulation, cytotoxicity and oxidative stress of the acute exposure selenium in Oreochromis mossambicus. AB - Selenium (Se) is an essential trace-element that becomes toxic when present at high concentrations for aquatic organisms. The knowledge about the mechanism of Se toxicity in freshwater ecosystem is still poorly studied. Thus the aim of the present study was to assess the impact of environmentally relevant concentrations of Se toxicity: 5, 10, 25, 50 and 100 ug/L or water only (control) for periods of 96 hour (h) to test for Se accumulation (gill, liver and brain), its effects on enzymatic and non-enzymatic antioxidant defenses (gill and liver), oxidative stress effects on lipid, protein (gill and liver), DNA (liver) and inhibition of AchE (brain) activity were measured in Mozambique tilapia, Oreochromis mossambicus. Our result showed that Se accumulation was observed in the gill, liver and brain tissues of fish exposed to different concentrations and accumulation varied upon different tissues. Enzymatic (SOD, CAT, GPx and GST) and non-enzymatic (GSH and MT) antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-s-transferase (GST) were significantly increased after 96 h exposure of higher concentrations Se in the gill and liver tissue with the exception of GST activity was significantly inhibited in liver after 96 h exposure of higher concentrations of Se. In contrast, catalase (CAT) activities were inhibited for both tissues of Se exposure at 96 h. Reduced glutathione (GSH) and Metallothionein (MT) levels were increased in the gill and liver tissues after exposure to Se for 96 h. We also observed that Se affected antioxidant defense, increasing oxidative stress indicator of lipid peroxidation (LPO) and protein carbonyl (PCO) in gill and liver tissues of fish exposed to Se for 96 h at the concentration dependent manner. Increased DNA damage scores observed in liver tissue of fish exposed to Se for concentrations dependent manner, indicating potential of Se on fish. We also observed inhibition of acetylcholine esterase (AchE) activity in brain tissue of fish exposed to Se for higher concentrations. The changes in these parameters can be used as suitable biomarkers for monitoring the toxicity of Se in the aquatic environment. PMID- 29990728 TI - Correlation of pesticide exposure from dietary intake and bio-monitoring: The different sex and socio-economic study of children. AB - Exposure to organophosphorus pesticides was assessed though bio-monitoring of urinary dialkyl phosphate metabolites to characterize children's exposure to pesticides. No reports have been found which evaluate exposure of pesticides among adolescents of different sexes. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine the metabolite concentrations. Related objective was to determine any significant changes of pesticide exposure among the adolescents of different sexes. The primary objective was to develop a coupled exposure-dose modeling approach to determine the metabolites concentrations to keep children's urine metabolites levels below specified values considering exposures from water, and the food related objective was to determine any significant changes of pesticide exposure among the adolescents of different sexes. We recruited a sample of 377 children (188 boys, 189 girls) ages 6-10 and 11-15 years from Hyderabad, India for urine collection. Results showed that the mean concentrations of dialkyl phosphate metabolites in first morning first urine samples (3.05 umol L-1) were strongly correlated with concentrations of the same-day 24-h samples (1.7 umol L-1) ( r = 0.997, model R2 ~ 0.994, p < 0.00) with 99.4% accuracy. Irrespective of similar amounts of conventional food consumption, girls showed 87.5% of detection frequency of DAP metabolites which was higher than the 74% detection frequency of DAP metabolites among boys. The female group showed (87%) higher pesticide metabolite levels than boys. This report may help to focus on new studies of the connection between adolescents of different sex and organophosphorus metabolite exposure and to develop an exposure database to facilitate health risk assessment in our day-to-day environment. PMID- 29990727 TI - TiO2 nanoparticles enhance bioaccumulation and toxicity of heavy metals in Caenorhabditis elegans via modification of local concentrations during the sedimentation process. AB - Unintentionally released titanium dioxide nanoparticles (TiO2 NPs) may co-occur with pre-existing heavy metal pollutants in aquatic environments. However, the interactions between NPs and heavy metals (HMs) and their co-effects in living organisms are largely unknown. The aim of this investigation was to illustrate the influence of TiO2 NPs (5 and 15 nm) on the bioaccumulation and toxicity of cadmium (Cd), arsenate (As(III)), and nickel (Ni) in Caenorhabditis elegans (C. elegans) during the process of sedimentation in aquatic environment. Our data showed that HMs accelerated the aggregation of TiO2 NPs. The rapid aggregation and sedimentation of TiO2 NPs changed the vertical distribution of HMs through adsorption and induced increased and prolonged exposure of benthic species. Aggregate particle size along with ionic strength were the major factors affecting the rate of sedimentation. TiO2 NPs at non-toxic concentrations efficiently enhanced the bioaccumulation and reproductive toxicity of HMs to C. elegans in a dose- and size-dependent manner; however, the effect of TiO2 NPs on As(III) was obviously lower than that on two valence metals. These data provided clear evidence that TiO2 NPs could serve as environmental regulators to significantly facilitate the toxicity and the accumulation of HMs in C. elegans, indicating that the interaction and fate of TiO2 NPs and HMs on their co-toxic responses during the sedimentation should be considered as a necessary and integral part of risk assessment in the ecological system. PMID- 29990729 TI - Screening of native plants from wasteland surrounding a Zn smelter in Feng County China, for phytoremediation. AB - Phytoremediation is regarded as one of the most cost-effective and environmentally friendly strategies for potentially toxical metals (PTMs) contaminated soil remediation. Despite that, continuous studies are conducting to explore the potential plant species in order to achieve enhanced remediation efficiencies. Therefore, in this study, a field investigation was conducted to screen the potential phytoremediation plants from a contaminated site in the surrounding area of a Zn smelter in Feng Country, China. Results indicated that soils in the studied area were severely contaminated with Cd and Zn, while the contents of other metals (Cu, Pb, and Ni) were below the allowanced threshold. Moreover, the contamination was more serious in areas closer to the smelter. The elevated level of contamination had great impacts on plant diversity and abundance. Fifty-nine plant species belonging to 28 families were identified in the studied area, of which plants from the Asteraceae family and herbs were most frequently observed. Plants demonstrated differentiated potential on metal accumulation and translocation, and the total Cd, Cu, Pb, and Zn contents in the aerial parts of plants ranged from 5.57 to 268.5, 14.34 to 140.90, 10.43 to 570.3, and 110.3 to 1350 mg kg-1, respectively. Symphytum officinale Linn. distinguished itself from the various plants as a promising plant candidate for soil remediation, due to its great capacities for absorbing Cd, Pb, and Zn. Specifically, an individual Symphytum officinale Linn. plant can accumulate up to 5.54, 21.0, and 52.9 mg Cd, Pb, and Zn in its aboveground parts (20.67 g dry weight). Results from this study can provide a reference for the phytoremediation of PTMs contaminated soil in this area or other places with similar soil and climate conditions. PMID- 29990730 TI - Investigating organic matter properties affecting the binding behavior of heavy metals in the rhizosphere of wetlands. AB - Soil organic matter (SOM) is a crucial factor affecting the immobilization of heavy metal in wetlands. Recent studies have shown that the rhizosphere SOM has great ability to immobilize heavy metals. However, there existed few works on studying molecular characteristics of SOM to explore the mechanisms. Electrospray ionization-Fourier transform ion cyclotron resonance-mass spectrometry (ESI-FTICR MS) combined with FTIR spectroscopy were applied to investigate the characteristics of SOM in rhizosphere and nonrhizosphere samples and to find out what characteristics the rhizosphere SOM embodies conducive to metal binding in this paper. The rhizosphere contained higher C, P, Mn, and other metal concentrations. The adsorption of Cr on rhizosphere SOM was greater than that on nonrhizosphere SOM. Compared to nonrhizosphere SOM, rhizosphere SOM contained less saturated and more oxidized compounds, greater overall molecular weights (MW), more condensed aromatic structures (56.59% VS 51.56% by peak intensity), less carboxylate and N-containing COO functional groups (25.98% VS 56.63% by peak intensity), more hydrophilicity, and the latter four are conducive to metal binding. This study showed that the rhizosphere SOM had unique compositional and structural characteristics. These results provided evidence for the phytoremediation technologies of heavy metal contaminated wetlands. PMID- 29990731 TI - Eco-friendly profile of pegylated nano-graphene oxide at different levels of an aquatic trophic chain. AB - Nanographene oxide (nGO) has been recently proposed as a new antitumoral therapeutic agent, drug delivery carrier and gene transfection vehicle, among others. Treatment is carried out by hyperthermia induced by infrared irradiation. After treatment, the nanosystems will be inevitably excreted and released to the environment. To understand the potential impacts of pegylated nGO (nGO-PEG), three key species from different trophic levels were used: the green micro-algae Raphidocelis subcapitata (growth inhibition test), the cladocera Daphnia magna (acute and chronic tests), and the fish Danio rerio (fish embryo test). Besides a regular standard procedure to assess toxicity, and considering the mode of action of nGO-PEG in cancer treatment, a simultaneous infrared lamp exposure was carried out for D. magna and D. rerio. Additionally, and taking advantage of the phenotypic transparency of D. magna, nGO-PEG was fluorescently tagged to evaluate the potential uptake of nGO-PEG. The R. subcapitata growth inhibition test showed effects during the first 48 h, recovering till the end of the test (96 h). No acute or chronic effects were observed for D. magna, under standard or infrared light exposures although confocal microscope images showed nGO-PEG uptake. Very small percentages of mortality and abnormalities were observed in D. rerio exposed with and without the infrared lamp. Although low hazard may be expected for nGO-PEG in aquatic ecosystems, further studies with species with different life traits should be accomplished, in order to derive more accurate conclusions. PMID- 29990732 TI - Toxicity induced by glyphosate and glyphosate-based herbicides in the zebrafish hepatocyte cell line (ZF-L). AB - Glyphosate is the active component of many commonly used herbicides; it can reach bodies of water through irrigated rice plantations. In the present study, we evaluated the effect of glyphosate and Roundup(r) (a glyphosate-based herbicide) in established culture of the zebrafish hepatocyte cell line ZF-L after 24 and 48 h of exposure to concentrations of 650 and 3250 ug/L. We observed a reduction in metabolic activity and lysosomal integrity, and an increase in cell number after 24 h of Roundup(r) exposure at the highest concentration. An increase in active mitochondria and apoptotic cells was observed following 24 h exposure to glyphosate and Roundup(r), while only exposure to Roundup(r) induced an increase in necrotic cells. Rhodamine B accumulation decreased after 48 h exposure to 650 ug/L of Roundup(r); this reduction is indicative of increased activity of ABC pumps. Overall, the present findings highlighted the hazard of glyphosate exposure not only in the commercial formulation but also glyphosate alone, since both can induce damage in the ZF-L cell line primarily through the induction of apoptosis. PMID- 29990733 TI - Mechanism and effects of Zearalenone on mouse T lymphocytes activation in vitro. AB - Zearalenone (ZEA) is particularly toxic to the female reproductive system. Nevertheless, the effect of ZEA on the immune system is still not fully understood. The following study investigates the effects and mechanism of ZEA on mouse T cell activation in vitro. Briefly, T lymphocytes were extracted from primary splenic lymphocyte in mice, activated by concanavalin A, and then were exposed to different concentrations of ZEA for a certain period of time. Flow cytometry was used to detect the expression of activating and co-stimulatory molecules, and the secretion of cytokines in T cells at various stages. The expression of initiation regulatory protein in T cell activation, nuclear factor protein and co-stimulatory molecule related PI3K-Akt-mTOR signaling pathway proteins were detected by western blot. Our data showed that ZEA exposure inhibits the activity of T cell, and inhibits the expression of different activation signals in T cell. Additionally, ZEA exposure reduces the expression of initiative regulatory protein, i.e. LAT, Lck, Zap-70 during the activation of T cells. Thus, the results showed that ZEA exposure inhibits the formation and transmission of activated signal in T cells, interferes with signal pathway of T cell activation nuclear factor NFAT and NFkappaB, and decreases the secretion of cytokines after activation. Moreover, ZEA exposure interferes with co-stimulatory molecule CD28 during T cell activation, and with the activity of the PI3K-Akt mTOR signaling pathway downstream of CD28. To conclude, our results indicated that ZEA toxin interferes with the activation of mouse T lymphocytes by affecting TCR signal and co-stimulatory signal, thus playing an essential role in immune toxicity. PMID- 29990734 TI - Environmental toxicants impair liver and kidney function and sperm quality of captive pandas. AB - Captive pandas are exposed to higher concentrations of environmental toxins in their food source and from atmospheric pollution than wild pandas. Moreover, the Qinling panda subspecies had significantly higher concentrations of toxic chemicals in its feces. To determine whether these toxicants also accumulate in panda's blood and impair its health, concentrations of persistent organic pollutants (POPs) and heavy metals were measured in blood samples. Four heavy metals (As, Cd, Cr and Pb), PCDD/Fs and PCBs were detected in blood drawn from captive Qinling pandas. Time spent in captivity was a better predictor of toxicant concentration accumulation than was panda age. More than 50% of the studied pandas were outside the normal levels for 11 health parameters, and five (ALT, LDH, Ca, Cl, TB) of the 11 parameters classified as abnormal were correlated with blood pollutant concentrations. The proportion of live sperm was significantly lower and the aberrance ratio of sperm was significantly greater for captive pandas than for wild ones. A short-term solution to reduce the health impacts of pollution and toxicant exposure of Qinling pandas is to relocate breeding centers to less contaminated areas and to strictly control the quality of their food provided. A longer term solution depends on improving air quality by reducing toxic emissions. PMID- 29990735 TI - Toxicity of carbon nanotubes to white rot fungus Phanerochaete chrysosporium. AB - Carbon nanotubes (CNTs) are widely used in diverse areas with increasing annual production, thus the environmental impact of CNTs needs thorough investigation. In this study, we evaluated the effect of pristine multi-walled CNTs (p-MWCNTs) and oxidized multi-walled CNTs (o-MWCNTs) on white rot fungus Phanerochaete chrysosporium, which is the decomposer in carbon cycle and also has many applications in environmental remediation. Both p-MWCNTs and o-MWCNTs had no influence on the dry weight increase of P. chrysosporium and the pH value of culture system. The fibrous structure of P. chrysosporium was disturbed by p MWCNTs seriously, while o-MWCNTs had litter influence. The ultrastructural changes were more evident for P. chrysosporium exposed to p-MWCNTs and only p MWCNTs could penetrate into the cell plasma. The chemical composition of P. chrysosporium was nearly unchanged according to the infrared spectra. The laccase activity was suppressed by p-MWCNTs, while o-MWCNTs showed stimulating effect. The decoloration of reactive brilliant red X-3B was not affected by both CNT samples. However, serious inhibition of wood degradation was observed in the p MWCNTs exposed groups, suggesting the potential threat of CNTs to the decomposition of carbon cycle. The implication to the environmental risks and safe applications of carbon nanomaterials is discussed. PMID- 29990736 TI - Differential susceptibility of kidneys and livers to proliferative processes and transcriptional level of the genes encoding desmin, vimentin, connexin 43, and nestin in rats exposed to furan. AB - In this study, we aimed to assess the differential toxic impact, induced by furan exposure, on the liver and kidney tissues by estimating reactive oxygen species (ROS) level, total antioxidant capacity (TAC), oxidative damage, and the tissue injury markers in a male rat model. To explain such impacts, 20 rats were assigned into two groups: a control group, where rats were administered corn oil as a vehicle, and a furan-administered group, where furan was orally administered to rats at a dose of 16 mg/kg b wt/day (five days per week over eight weeks). The transcriptional levels of intermediate filament proteins (desmin, vimentin, nestin, and connexin 43) were assessed by using quantitative real-time polymerase chain reaction (PCR), and the cell proliferation markers (proliferating cell nuclear antigen [PCNA] and proliferation-associated nuclear antigen [Ki-67]) were recognized by immunohistochemical analysis. Furthermore, the ultrastructural changes of liver and kidney were monitored using electron microscopy. Our findings showed that furan exposure could induce hepatic and renal damage to different extents. Furan can increase the ROS content, oxidative damage indices, and liver tissue injury indices but not kidney injury indices. Furthermore, it decreases the TAC in the serum of exposed rats. In addition, furan exposure was associated with changes in the mRNA expression pattern of intermediate filament proteins in both kidney and liver tissues. Moreover, furan enhances the expression of PCNA and Ki-67 in the liver tissues but not in the kidney tissues. The ultrastructure evaluation revealed the incidence of glomerular podocyte degeneration and hepatocyte injury. These results conclusively demonstrate that the deleterious effects of furan are caused by promoting fibrosis and hepatocyte proliferation in liver tissues and triggering podocyte injury in the kidney tissues. PMID- 29990737 TI - Synthesis of novel magnetic nano-sorbent functionalized with N-methyl-D-glucamine by click chemistry and removal of boron with magnetic separation method. AB - Click chemistry refers to a group of reactions that are fast, simple to use, easy to purify, versatile, regiospecific, and give high product yields. Therefore, a novel, efficient magnetic nano-sorbent based on N-methyl-D-glucamine attached to magnetic nanoparticles was prepared using click coupling method. Its boron sorption capacity was compared with N-methyl-D-glucamine direct attached nano sorbent. The characterization of the magnetic sorbents was investigated by several techniques such as X-ray diffraction, scanning electron microscope, transmission electron microscope, dynamic light scattering, thermogravimetric analysis, Fourier transform infrared spectrophotometer, and vibrating sample magnetometer. The boron sorption capacity of sorbents was compared by studying various essential factors influencing the sorption, like sorbate concentration, sorbents dosage, pH of the solution, and contact time. Langmuir and Freundlich and Dubinin-Radushkevich adsorption isotherms models were applied. Percent removal and sorption capacities efficiencies of sorbents obtained with direct and click coupling are found to be 49.5%, 98.7% and 6.68 mg/g, 13.44 mg/g respectively. Both sorbents have been found to be compatible with Langmuir isotherm, and the boron sorption kinetics conforms to the pseudo second order kinetics. The reusability study of sorbents was carried out five times for boron sorption and desorption. PMID- 29990738 TI - Removal of Cd(II) and Fe(III) from DMSO by silica gel supported PAMAM dendrimers: Equilibrium, thermodynamics, kinetics and mechanism. AB - A series of silica gel supported amino-terminated PAMAM dendrimers (SG-G1.0 - SG G3.0) were used for the removal of Cd(II) and Fe(III) from dimethylsulfoxide (DMSO). Various parameters that influence adsorption behaviors including temperature, contact time, and initial metal ion concentration were studied. The adsorption mechanism was revealed by combining the results of experiment and density functional theory (DFT) calculation. It indicates that the adsorption capacities for Cd(II) and Fe(III) are largest among the metal ions tested. The adsorption capacity of SG-G1.0 - SG-3.0 for Cd(II) and Fe(III) follows the order of SG-G2.0 > SG-3.0 > SG-G1.0. The adsorption isotherm shows the adsorption capacities for both metal ions increases with raising the temperature and initial metal ion concentration. The adsorption isotherm is consistent with Langmuir model and the adsorption process is dominated by chemical adsorption mechanism. Thermodynamic parameters indicates that the adsorption for both Cd(II) and Fe(III) is spontaneous and endothermic. Kinetic adsorption indicates that the adsorption equilibrium times for Cd(II) and Fe(III) is about 200 and 350 min, respectively, which can be described by a pseudo-second-order model and controlled by film diffusion process. FTIR analysis and theoretical calculation revealed that the carbonyl O atoms, secondary amine N atoms, and primary amine N atoms are the primary factor responsible for PAMAM adsorption by forming tetra- and penta-coordinated chelates with metal ions. PMID- 29990739 TI - Enhanced photocatalytic removal of Safranin-T dye under sunlight within minute time intervals using heulandite/polyaniline@ nickel oxide composite as a novel photocatalyst. AB - Natural zeolite heulandite/polyaniline composite (Hu/PANI) was synthesized for the first time as catalyst support for nickel oxide photocatalyst (Hu/PANI@Ni2O3). The structural, chemical, morphological, textural and optical properties were investigated using different techniques. The synthetic Ni2O3 crystals showed well developed flaky habits with diameter range 200-400 nm and length range 1-4 um. The estimated band gap energies of Hu/PANI composite and Hu/PANI@Ni2O3 composite are 1.8 eV and 1.46 eV, respectively, which are remarkably smaller than the recorded value for pure nickel oxide. The photocatalytic properties of Hu/PANI@Ni2O3 composite for efficient degradation of safranin-T dye were evaluated under sunlight as a function of irradiation time, initial dye concentration, catalyst mass, solution pH, and the catalyst stability. Hu/PANI@Ni2O3 composite exhibits amazing photocatalytic degradation efficiency for safranin dye, whereas 80%, 98%, and ~ 100% of 5 mg/l dye were removed after only 1 min of solar irradiation using 0.025, 0.03, and 0.035 g of Hu/PANI@Ni2O3, respectively. The higher concentrations of the dye (10-50 mg/L) can be fully removed within minutes by increasing the solution pH or using higher doses from the Hu/PANI@Ni2O3 catalyst. The removal percentage achieved the maximum value at the alkaline conditions. Also, the Hu/PANI@Ni2O3 displayed high stability and remain 84.5% of the initial photocatalytic efficiency after 5 runs. Additionally, the composite can be used effectively in the removal of different types of dyes and mixed dyes within the same time intervals. Thus, loading of nickel oxide onto hybrid Hu/PANI composite as a catalyst support achieved amazing photocatalytic degradation capacity. PMID- 29990740 TI - Photolytic and photocatalytic transformation of an antipsychotic drug asenapine: Comparison of kinetics, identification of transformation products, and in silico estimation of their properties. AB - The photolytic and photocatalytic transformation of an antipsychotic drug asenapine with the use of H2O2 and TiO2 was studied. A method employing irradiation with a simulated full solar spectrum in the photostability chamber was applied, then the reverse-phase ultra high performance liquid chromatography with diode array detector, coupled with electrospray quadrupole time-of-flight mass spectrometer (RP-UHPLC-DAD - ESI-Q-TOF) was used for the quantitative and qualitative analysis of the processes. The developed quantitative method was fully validated, according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines, and the kinetic parameters of asenapine photodecomposition were compared. Nineteen phototransformation products were detected, and their probable structures - mainly hydroxylated and oxidized asenapine derivatives - were suggested. On the basis of the elucidated structures the computational prediction of their toxicity at the various endpoints, as well as bioconcentration factors and biodegradability was performed. The obtained results were then subjected to the principal component analysis (PCA). This chemometric technique facilitated comparison of the applied models, calculated properties of the TPs, and enabled visualization of relationships between them. PMID- 29990741 TI - Effect of combined application of lead, cadmium, chromium and copper on grain, leaf and stem heavy metal contents at different growth stages in rice. AB - Most studies on plants' response to heavy metal toxicity have been focusing on single metals. However, soils are always contaminated by several kinds of heavy metals. In this study, pot experiments were carried out to investigate the effects of combined toxicity on two rice genotypes differing in Cd accumulation (Xiushui817, a low-grain-Cd-accumulation and Zheda821, a high-grain-Cd accumulation genotype). Yield, heavy metal concentrations of grain and leaf/stem at different growth stages were measured under combined application of Cd, Cr, Pb and Cu. Yield was significantly decreased under higher Pb and Cd treatment in both genotypes with Xiushui817 showing greater reduction. Increasing soil Cu level showed no significant effect on grain yield. Zheda821 consistently showed a higher grain Cd content than Xiushui817. The application of Pb, Cd, Cr and Cu significantly affected grain Cd, Cr and Cu accumulations. Similar trends were also observed in leaves and stems at harvest stage. The critical levels of leaf/stem Cd and Cr for safe rice production were also estimated. Alleviation measures should be taken to decrease Cd or Cr accumulations in grain of rice if leaf or stem Cd or Cr concentrations at different growth stages exceed the critical levels. PMID- 29990742 TI - Agrochemicals: Effect on genetic resistance in yeasts colonizing winter wheat kernels. AB - Crop protection agents are widely used in modern agriculture and exert direct effects on non-target microorganisms such as yeasts. Yeasts abundantly colonize wheat grain and affect its chemical composition. They can also limit pathogen growth. This study evaluated the sensitivity of yeast communities colonizing winter wheat kernels to benzimidazole, strobilurin, triazole and morpholine fungicides, trinexapac-ethyl, a commercial mixture of o-nitrophenol+p nitrophenol+5-nitroguaiacol, and chitosan applied during the growing season of winter wheat and in vitro in a diffusion test. A molecular identification analysis of yeasts isolated from winter wheat kernels was performed, and nucleotide polymorphisms in the CYTb gene (G143A) conferring resistance to strobilurin fungicides in yeast cells were identified. The size of yeast communities increased during grain storage, and the total counts of endophytic yeasts were significantly (85%) reduced following intensive fungicide treatment (fenpropimorph, a commercial mixture of pyraclostrobin, epoxiconazole and thiophanate-methyl). This study demonstrated that agrochemical residues in wheat grain can drive selection of yeast communities for reduced sensitivity to xenobiotics. A mutation in the CYTb gene (G143A) was observed in all analyzed isolates of the following azoxystrobin-resistant species: Aureobasidium pullulans, Debaryomyces hansenii, Candida albicans and C. sake. Agrochemicals tested in vitro were divided into four classes of toxicity to yeasts: (1) tebuconazole and a commercial mixture of flusilazole and carbendazim - most toxic to yeasts; (2) fenpropimorph and a commercial mixture of pyraclostrobin and epoxyconazole; (3) propiconazole, chitosan, thiophanate-methyl and a commercial mixture of o-nitrophenol, p-nitrophenol and 5-nitroguaiacol; (4) trinexapac-ethyl and azoxystrobin - least toxic to yeasts. It was found that agrochemicals can have an adverse effect on yeast abundance and the composition of yeast communities, mostly due to differences in fungicide resistance between yeast species, including the clinically significant C. albicans. PMID- 29990743 TI - Effects of parabens on antioxidant system and oxidative damages in Nile tilapia (Oreochromis niloticus). AB - In this study, effects of parabens on antioxidant defenses and oxidative damages in gills and liver of Nile tilapia (Oreochromis niloticus) were evaluated. Adult Nile tilapia were exposed to methyl, ethyl, propyl, butyl and benzylparaben and a mixture of methyl and propylparaben for 6 and 12 days. The biomarkers analyzed were superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), total glutathione (GSH-t) and lipid peroxidation measured by malondialdehyde (MDA) content. Results indicated that exposure to parabens caused biochemical changes in gill and liver cells, which in turn modulated enzymatic and non-enzymatic antioxidants in Nile tilapia. SOD, GPx and GR activity significantly increased in gills and liver after exposure to most parabens. CAT activity had little (liver) or no alteration (gills) in this fish species after treatment with parabens. GSH-t content in liver decreased after 6 days of exposure to parabens, but after 12 days, GSH-t levels increased in liver in all treatments, indicating an antioxidant adaptation to exposure to sublethal doses of parabens. Regarding the MDA levels, no alterations were observed in gills compared to control and in liver the MDA content was reduced after 12d of exposure to ethylparaben, butylparaben and paraben mixture, indicating no lipid peroxidation in the analyzed tissues. Our results demonstrate parabens-induced adaptive responses in fish, which were important in the protection against oxidative damages. PMID- 29990744 TI - Mechanisms involved in the impact of engineered nanomaterials on the joint toxicity with environmental pollutants. AB - Emerging nanoscience and nanotechnology inevitably facilitate discharge of engineered nanomaterials (ENMs) into the environment. Owing to their versatile physicochemical properties, ENMs invariably come across and interact with various pollutants already existing in the environment, leading to considerable uncertainty regarding the risk assessment of pollutants. Nevertheless, the underlying mechanisms of the complicated joint toxicity are still largely unexplored. This review aims to aid in understanding the interaction of ENMs and pollutants from the perspective of ecological and environmental health risk assessment. Based on related research published from 2005 to 2018, this review focuses on summarizing the effect of ENMs on the toxicity of pollutants both in vivo and in vitro. Physicochemical interaction appears as a main factor affecting ENMs-pollutants joint toxicity, with the mechanisms and the resultants for ENM pollutant adsorption been illustrated. Cellular and molecular mechanisms involved in the joint toxicity of ENMs and pollutants are discussed, including the effect of ENMs on the bioaccumulation, biodistribution, and metabolism of pollutants, as well as the defense responses of organisms against such pollutants. Future in depth investigation are suggested to focus on further exploring biological mechanisms (especially for the antagonized effect of ENMs against pollutants), using more advanced mammalian models, and paying more attention to the realistic exposure scenarios. PMID- 29990745 TI - Influence of mixing on anaerobic digestion efficiency in stirred tank digesters: A review. AB - A comprehensive review was carried out on the influence of mixing on anaerobic digestion (AD) efficiency in stirred tank anaerobic digesters. Though traditionally, stirred tank digesters operated as continuous stirred tank reactors (CSTRs), this review revealed that there is no motivation to continue to operate stirred tank anaerobic digesters as CSTRs if AD energy efficiency is to be improved. AD energy production efficiency can be achieved with optimized intermittent mixing. AD efficiency should include an assessment of the net energy production efficiency and should be the criteria in determining the mixing mode, mixing intensity, mixing time and mixing interval for every anaerobic digestion operating plan. PMID- 29990747 TI - MicroRNA-193b-3p regulates hepatocyte apoptosis in selenium-deficient broilers by targeting MAML1. AB - Selenium (Se) is an important nutritional element in the diet. Apoptosis is one of the characteristic pathological changes in liver tissue resulting from Se deficiency. MicroRNA (miRNA) plays an important role in cell proliferation, differentiation, apoptosis and tumorigenesis. However, why apoptosis occurs during Se deficiency and how miRNA regulates hepatocyte apoptosis in broilers requires further study. We used a dual luciferase reporter assay system and quantitative real-time PCR (qPCR) to screen hepatocytes in Se-deficient broilers for the specificity of hepatocyte apoptosis miRNA and its target protein. We tested the apoptosis of Se-deficient broiler livers and microRNA-193b-transfected primary hepatocytes using qPCR, western blot (WB) and flow cytometry. Our studies revealed that Se deficiency led to microRNA-193b-3p (miR-193b-3p) overexpression and increased apoptosis-related gene expression, resulting in broiler hepatocyte apoptosis. Mastermind-like protein 1 (MAML1) was one of the miR-193b-3p targets, and its expression was down-regulated in miR-193b-3p-overexpressing hepatocytes. Further studies have shown that miR-193b-3p overexpression induced changes of apoptosis-related gene expression by inhibiting the release of MAML1. Interestingly, when we overexpressed miR-193b-3p, which was added to the Signal transducers and activators of transcription-1 (STAT1) inhibitor fludarabine (Flu), hepatocyte apoptosis was significantly reduced. When these results were combined, they indicated that miR-193b-3p is involved in broiler hepatocyte apoptosis in Se deficiency by regulating the target protein MAML1. This finding may provide new ideas for studying the mechanism of hepatocyte injury due to Se deficiency. PMID- 29990746 TI - The relationships between cytochromes P450 and H2O2: Production, reaction, and inhibition. AB - In this review we address the relationship between cytochromes P450 (P450) and H2O2. This association can affect biology in three distinct ways. First, P450s produce H2O2 as a byproduct either during catalysis or when no substrate is present. This reaction, known as uncoupling, releases reactive oxygen species that may have implications in disease. Second, H2O2 is used as an oxygen-donating co-substrate in peroxygenase and peroxidase reactions catalyzed by P450s. This activity has proven to be important mainly in reactions involving prokaryotic P450s, and investigators have harnessed this reaction with the aim of adaptation for industrial use. Third, H2O2-dependent inhibition of human P450s has been studied in our laboratory, demonstrating heme destruction and also the inactivating oxidation of the heme-thiolate ligand to a sulfenic acid (-SOH). This reversible oxidative modification of P450s may have implications in the prevention of uncoupling and may give new insights into the oxidative regulation of these enzymes. Research has elucidated many of the chemical mechanisms involved in the relationship between P450 and H2O2, but the application to biology is difficult to evaluate. Further studies are needed reveal both the harmful and protective natures of reactive oxygen species in an organismal context. PMID- 29990748 TI - Cytotoxicity, dual-targeting apoptosis induction evaluation of multinuclear cu complexes based on pyrazine-benzimidazole derivative. AB - To investigate the cytotoxicity and mechanism of action of multinuclear Cu complexes against tumor cell lines, two complexes, Cu6(bpbib)4Br8 (1) and Cu2(bpbib)2(BF4)2Cl2 (2) (bpbib = 1,4-bis((2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1 yl)methyl)benzene) were synthesized and characterized. Both Cu complexes showed high selectivity toward cancer and not normal cells, and the SMMC7721 cell line showed most sensitivity toward both complexes. Complex 1 exhibited more potent cytotoxicity and enhanced cellular uptake, and therefore, was comprehensively investigated. Complex 1 exhibited dual effects in the inhibition of tumor cell proliferation of SMMC7721 cells, causing nuclear DNA damage and mitochondrial dysfunction involving simultaneous reactive oxygen species (ROS) generation and Ca2+ increase. DNA binding studies suggest that intercalation might be the most probable binding mode. Fluorescence spectrometry also detected a medium affinity of complex 1 to bovine serum albumin (BSA) at distinct temperatures and resulted in BSA fluorescence static quenching. PMID- 29990749 TI - Integrin alphavbeta3 receptor targeting PET/MRI dual-modal imaging probe based on the 64Cu labeled manganese ferrite nanoparticles. AB - With the advent of positron emission tomography/magnetic resonance imaging (PET/MRI) scanner, PET/MRI dual-modal imaging will play more and more important role in the diagnosis of cancers and other diseases. Until now, there is no an approved PET/MRI dual-modal imaging probe. The goal of this work is to design and synthesize potential PET/MRI dual-modal imaging probe based on superparamagnetic manganese ferrite nanoparticles. We have developed superparamagnetic nanoparticles that have uniform size with 5 nm and can be further functionalized through surface coating with dopamine and polyethylene glycol derivatives, which provide functional groups for conjugating tumor-targeting biomolecules and bifunctional chelators. The nanoparticles conjugated with integrin alphavbeta3 over-expressed targeting cyclic arginine-glycine-aspartic acid (RGD)-peptide and labeled with positron radionuclide copper-64 were intravenously injected into glioblastoma xenograft nude mice. In vivo MRI and PET imaging of mice implied that the PET/MRI dual-modal imaging probe can precisely locate the tumor site with alphavbeta3 over expression. PMID- 29990750 TI - Future perception in P450 research. AB - Cytochrome P450 (P450) of eukaryotes and prokaryotes diversified remarkably during the long course of their evolution. Since the diversification of P450 was the consequence of the adaptation of various living organisms to diverse environmental changes, the catalytic activities and physiological functions of the P450s of different taxa can be significantly different. It is likely that many P450s with novel physiological functions will be found in future when we further identify and examine the P450s of various eukaryotes and prokaryotes. The whole-genome sequences of a few thousand species are now available. The genome data will be helpful for the search of novel P450s in the eukaryotic and prokaryotic organisms that have not been studied so far. Discovery of new P450s with unique catalytic activities will expand the scope of biochemical and biophysical research on P450. PMID- 29990751 TI - Coordination environment changes of the vanadium in vanadium-dependent haloperoxidase enzymes. AB - Vanadium-dependent haloperoxidases are a class of enzymes that catalyze oxidation reactions with halides to form halogenated organic products and water. These enzymes include chloroperoxidase and bromoperoxidase, which have very different protein sequences and sizes, but regardless the coordination environment of the active sites is surprisingly constant. In this manuscript, the comparison of the coordination chemistry of V-containing-haloperoxidases of the trigonal bipyramidal geometry was done by data mining. The catalytic cycle imposes changes in the coordination geometry of the vanadium to accommodate the peroxidovanadium(V) intermediate in an environment we describe as a distorted square pyramidal geometry. During the catalytic cycle, this intermediate converts to a trigonal bipyramidal intermediate before losing the halogen and forming a tetrahedral vanadium-protein intermediate. Importantly, the catalysis is facilitated by a proton-relay system supplied by the second sphere coordination environment and the changes in the coordination environment of the vanadium(V) making this process unique among protein catalyzed processes. The analysis of the coordination chemistry shows that the active site is very tightly regulated with only minor changes in the coordination geometry. The coordination geometry in the protein structures deviates from that found for both small molecules crystalized in the absence of protein and the reported functional small molecule model compounds. At this time there are no examples reported of a structurally similar small molecule with the geometry observed for the peroxidovanadium(V) in the active site of the vanadium-containing haloperoxidases. PMID- 29990752 TI - Inhibitory effect of melittin on endonuclease-like activity of centrin. AB - The xeroderma pigmentosum group C protein (XPC) and centrin2 are the primary initiators of global genome nucleotide excision repair (NER). Centrin, acts as a member of the EF-hand super family of calcium-binding proteins, playing roles in reconstitution of the vitro NER reaction. To understand the possible molecular and structural properties of the multiprotein process, the interactions of Euplotes octocarinatus centrin (EoCen), melittin, and DNA are described. EoCen shares a sequence identity of 66% with centrin2. Melittin possesses inverse direction hydrophobic triads-leucine-leucine-tryptophan (LLW) which are responsible for centrin binding. It is applied as a natural peptide to mimic centrin target peptide. As a result, it is proved that the integrated protein shows an endonuclease-like activity to DNA. Melittin is capable of interaction with both EoCen and DNA. More importantly, it is found that melittin displays an inhibitory effect on the endonuclease-like activity of centrin when it co-exists with EoCen and DNA in solution. Meanwhile, the DNA-melittin-EoCen ternary complex forms in the process. Quantitative analyses demonstrated by extensive biophysical assays reveal that binding of the peptide to DNA or centrin modulates the binding properties of it to another component. Furthermore, a possible positioning model of DNA and EoCen on melittin is proposed. This finding may constitute a model for that existing between centrin and its target peptide in NER process. PMID- 29990753 TI - Environmental risk assessment of perfluoroalkyl substances and halogenated flame retardants released from biosolids-amended soils. AB - Biosolid application is considered a sustainable management tool as it positively contributes to recycle nutrients and to improve soil properties and fertility. Nevertheless, this waste management technique involves an important input source of emerging organic pollutants in soil. To evaluate the environmental potential risk related to perfluoroalkyl substances (PFASs) and halogenated flame retardants (HFRs) due to the biosolid application to soil, a quantitative ecotoxicological risk assessment was conducted. The analyte concentrations were employed to perform an estimation of the exposure levels to contaminants in the receiving media, defining predicted environmental concentrations (PECs) for terrestrial and aquatic compartments (PECsoil, PECwater, PECsed) and for secondary poisoning via the terrestrial and aquatic food chain (PECoral, predator (T), PECoral, predator (Aq)). The risk characterization ratios (RCRs) were calculated based in the comparison of the PEC values obtained with concentrations with no effect (PNECs) on terrestrial and aquatic ecosystems. Based on the chosen scenarios and experimental conditions, no environmental risk of PFASs and HFRs released from biosolid amended soils to different environmental compartments was detected (RCRsoil, RCRoral, worm, RCRwater, RCRsed and RCRoral, fish were below 1 in all cases). Besides, the potential health risk of PFASs and HFRs to local people who live in the scenario studied and are fed on horticultural crops grown in biosolid amended soil was also below 1, indicating that the risk is not considered significant to human health in the conditions studied. This approach provides a first insight of the risks relative to biosolid amendments to further research based on fieldwork risk assessment. PMID- 29990754 TI - Polymer reaction engineering tools to design multifunctional polymer flocculants. AB - A series of multifunctional terpolymers, poly(N-isopropyl acrylamide/2 (methacryloyloxy) ethyl trimethyl ammonium chloride/N-tert-butylacrylamide) [P(NIPAM-MATMAC-BAAM)], were designed to flocculate and dewater oil sands mature fine tailings (MFT). The hydrophobic BAAM comonomer helped in expelling water from the sediments, while the cationic MATMAC comonomer promoted the charge neutralization of negatively charged particles suspended in MFT. The chemical composition distributions of these terpolymers were designed based on the knowledge of the reactivity ratios of all comonomers, instead of by trial and error, as usually done for most polymer flocculants. The binary reactivity ratios of the comonomers were estimated by synthesizing the binary copolymers with various mole fractions of each comonomer in the feed and experimentally measuring the corresponding fraction of comonomer in the copolymers. Polymer reaction engineering tools were used to minimize compositional drift and guarantee the synthesis of terpolymers with narrow chemical composition distributions suitable for MFT dewatering. Focused beam reflectance measurement (FBRM) experiments showed that terpolymers promoted the formation of large MFT flocs (120 MUm). The initial settling rate decreased with the increase in flocculant hydrophobicity, likely because the hydrophobic terpolymer segments did not take part in the bridging of the MFT particles. In contrast, the sediment dewaterability increased with the increase in terpolymer hydrophobicity. This study provides guidelines to design a polymer flocculant from first principles and demonstrates the potential of using hydrophobically modified cationic polymers to flocculate MFT effectively. PMID- 29990755 TI - Variability in responses of soil nematodes to trace element contamination. AB - Free-living soil nematodes and plant parasites were previously repeatedly tested for their use as bioindicators of soil contamination. We investigated soil nematode communities from grasslands in four different industrial areas in Slovakia to estimate their responses to heavy metals. We considered differences or similarities in behavioural reactions of nematodes to different quantities of selected heavy metals in the soil. Using the CCA analysis and t-value biplot diagrams with van Dobben circles, we split individual nematode genera by their tolerance/intolerance to the particular heavy metal into several clusters. Our results showed that (a) representatives of nematode genera showed concurrently positive and negative associations with two or more heavy metals, (b) most nematode genera expressed a strong positive relation with Ni and to a lesser extend with Cr and Zn, (c) taxonomically closely related nematodes did not demonstrated similar responses to the same pollutant. We assume that nematode genera with a higher level of tolerance to trace elements should be prioritized in the heavy metal bioindication instead of sensitive species, due to their longer persistence in the stressed environment and better indicative ability. We pointed nematode genera, which according to received results may serve as suitable sentinels for specific soil pollutants. PMID- 29990756 TI - Metals and arsenic in sediment and fish from Cau Hai lagoon in Vietnam: Ecological and human health risks. AB - Concentrations of Al, As, Bi, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, U, V and Zn were quantified in surface sediments collected from 13 different sampling sites from Cau Hai lagoon in Central Vietnam, and in 8 wild and farmed-fishes involving both pelagic and benthic species. Multivariate analysis shows that these trace elements are mainly associated with lithogenic matter, and are most likely the result of alteration and erosion processes in the lagoon. Enrichment factors and geo-accumulation indices reveal substantial sediment enrichments for both As and Bi with respect to the mean composition in the upper continental crust. As is enriched in the edible portion of fish tissue with values up to 10 times higher than the allowed limits set up by Health Canada. Target hazard quotient and target carcinogenic risk for As were assessed through fish diet and were greater than 1 and 10-4, respectively, indicating potential health risks for fish consumers in Cau Hai lagoon. PMID- 29990757 TI - Silica nanoparticles induced endothelial apoptosis via endoplasmic reticulum stress-mitochondrial apoptotic signaling pathway. AB - Along with their extensively application, human exposure to amorphous silica nanoparticles (SiNPs) has highly increased. Accumulative toxicological researches have provided the scientific correlation between SiNPs exposure and cardiovascular diseases. Endothelial apoptosis is vital in the initiation and progression of atherosclerosis. However, molecular details between SiNPs and endothelial apoptosis remain unidentified. Here, we investigated the uptake and toxic mechanism of SiNPs using HUVECs (Human umbilical vein endothelial cells). Consequently, at 24-h exposure, SiNPs were located freely or within membrane bound agglomerates in the cytosol, especially in mitochondrial and endoplasmic reticulum (ER) regions with swelled mitochondria, cristae rupture or aggregated ER. Further, we demonstrated that SiNPs induced endothelial apoptosis as evidenced by the Annexin V/PI staining and flow cytometry determination. In line with the ultrastructure alterations, SiNPs triggered mitochondrial ROS generation, DeltaPsim collapse, cytosolic Ca2+ overload, as well as ER stress confirmed by enhanced ER staining, up-regulated GRP78/BiP and XBP1 splicing. More notably, in line with the induction of apoptosis, SiNPs-induced ER stress associated activation of CHOP, caspase-12, and IRE1alpha/JNK pathways, which may regulate the BCL2 family member as evidenced by a increased proapoptotic BAX while a decline of anti-apoptotic Bcl-2, ultimately facilitate the mitochondria mediated apoptotic caspase cascade as confirmed by the upregulated expressions of cytochrome c, Caspase-9 and -3. Altogether, our results indicated the activation of ER stress-mitochondria cascade-mediated apoptotic pathways may be a key mechanism among the SiNPs-induced endothelial apoptosis. PMID- 29990758 TI - New conditions for global stability of neutral-type delayed Cohen-Grossberg neural networks. AB - This paper carries out a theoretical investigation of the class of neutral-type delayed Cohen-Grossberg neural networks by using the Lyapunov stability theory. By employing a suitable Lyapunov functional candidate, we derive some new delay independent sufficient conditions for the global asymptotic stability of the equilibrium point for the neutral-type Cohen-Grossberg neural networks with time delays. The obtained stability conditions can be completely characterized by the networks parameters of the neutral systems under consideration. Therefore, it is easy to verify the applicability of our results by simply using some algebraic manipulations of the conditions. Some numerical examples are also given to show the effectiveness of the derived analytical results. A detailed comparison between our proposed results and recently reported corresponding stability results is also made, revealing that the conditions given in this paper establish a new set of stability criteria for Neutral-Type Cohen-Grossberg Neural Networks. PMID- 29990759 TI - High-efficiency second generation ethanol from the hemicellulosic fraction of softwood chips mixed with construction and demolition residues. AB - Using lignocellulosic residues for bioethanol production could provide an alternative solution to current approaches at competitive costs once challenges related to substrate recalcitrance, process complexity and limited knowledge are overcome. Thus, the impact of different process variables on the ethanol production by Saccharomyces cerevisiae using the hemicellulosic fraction extracted through the steam-treatment of softwood chips mixed with construction and demolition residues was assessed. A statistical design of experiments approach was developed and implemented in order to identify the influencing factors (various nutrient addition sources as well as yeast inoculum growth conditions and inoculation strategies) relevant for enhancing the ethanol production potential and substrate uptake. Ethanol yields of 74.12% and monomeric sugar uptakes of 82.12 g/L were predicted and experimentally confirmed in bench and bioreactor systems. This innovative approach revealed the factors impacting the ethanol yields and carbohydrate consumption allowing powerful behavioral predictions spanning different process inputs and outputs. PMID- 29990760 TI - Active biocatalyst for biodiesel production from spent coffee ground. AB - Physical adsorption preserving activity and support reusability was used to directly bond lipase from Thermomyces lanuginosus on citric acid (CA) modified Fe3O4/Au magnetic nanoparticles. A new faster approach has been used for CA ligand exchange, which ensures an high payload of stable enzyme. The immobilized lipase was tested for the biodiesel production from spent coffee ground in a solvent free system. It retains, after 60 days, more than 90% of its initial activity. Biodiesel yield of 51.7%, after 3 h of synthesis, which increases up to ~100% after 24 h indicating an enzymatic fast kinetic, was measured. No significant decrease, during the first three cycles of use, of the lipase activity occurs. The biodiesel presents an ester content of 98.4 +/- 0.23 in agreement with the EN14214. The iodine value of 76.67 (g iodine/100 g) is in agreement with the European standard. PMID- 29990761 TI - Enhanced sulfate and metal removal by reduced graphene oxide self-assembled Enterococcus avium sulfate-reducing bacteria particles. AB - Graphene oxide (GO) was introduced to Enterococcus avium strain BY7 sulfate reducing bacteria culture as a carrier, GO was partially reduced by SRB to reduced graphene oxide (rGO). The rGO could further self-assemble Enterococcus avium strain BY7 sulfate-reducing bacteria to form BY-rGO particles. Growth and sulfate reduction activity of strain BY7 was promoted by rGO, which probably due to the protective effect of rGO, and enhanced electron transfer by rGO as electron shuttle. Effects of pH and temperature variance on strain BY-rGO were remarkably weakened, growth and sulfate reduction were observed from pH 2.0 to 12.0, and from 10 to 45 degrees C, respectively. Metal toxicity to BY7 strain SRB was sharply decreased in BY-rGO particles and heavy metal removal was remarkably accelerated (up to 50%). The immobilization methods established in this study might open a new way for the application of SRBs, especially under extreme environmental conditions. PMID- 29990762 TI - Influence of carrier media physical properties on start-up of moving attached growth systems. AB - Five carrier media with different shapes (spherical and cylindrical), sizes, voidage and protected surface areas (112-610 m2/m3) were studied in a pilot scale moving bed biofilm reactor (MBBR). This study aimed at assessing start-up duration using biofilm formation rates. Results indicated that the spherical media required shorter periods to achieve stable biofilm formation rates associated with chemical oxygen demand (COD) (15-17 days), compared to cylindrical high surface area media (23-24 days). Protected surface area presented weaker correlations with the biofilm formation rate for COD (R2 = 0.83) and ammonia removal (R2 = 0.76). However, good correlations were observed with a combination of the media physical factors: dimensionality (Di), voidage (Voi), and hydraulic efficiency (HE) strongly correlated with biofilm formation rates for heterotrophic (R2 = 0.95) and nitrifying bacteria (R2 = 0.92). This study proposes that the media physical properties can contribute to shortening start up, contributing to improved removal rates and fast commissioning of MBBRs. PMID- 29990763 TI - Detoxification of chromium-rich tannery industry sludge by Eudrillus eugeniae: Insight on compost quality fortification and microbial enrichment. AB - Chromium-rich tannery sludge (TS) is a hazardous industrial waste. Although vermicomposting can be an effective remediation pathway; but, the unique waste degrading efficiency of Eudrillus eugeniae is least explored. The present work showcases an efficient earthworm-mediated protocol for TS sanitization deploying E. eugeniae. Changes in pH, TOC (%), nutrients (NPK), metals (Cr, Cd etc.) and microbial diversity were monitored in various E. eugeniae mediated TS based vermibed. Total N, P, and K availability increased by 2-5 folds upon vermicomposting with 3-4 folds reduction in C/N ratio. Moreover, substantial removal of Cr (89%), Cd (88%), and Zn (79%) was recorded in the substrate. Bioaccumulation of these metals in the gut significantly reduced the pollution load in the finished products. The corresponding augmentation of microbial density and low respiratory CO2 release from the vermibeds substantiated the environmental proficiency of vermitechnology. PMID- 29990764 TI - Development of a method for the valorization of fermentation wastewater and algal residue extract in docosahexaenoic acid production by Schizochytrium sp. AB - Fermentation wastewater (FW) and algal residue are major by-products of docosahexaenoic acid (DHA) fermentations utilizing Schizochytrium sp. In order to reduce production costs and environmental pollution, we explored the application of FW and algal-residue extract (AE) for DHA production. Components analysis showed that FW and AE contained some mineral elements and protein residues, respectively. When they were used for DHA fermentation, results showed that 20% replacement of fresh water by FW and 80% replacement of yeast extract nitrogen by AE reached DHA content of 22.23 g/L and 27.10 g/L, respectively. Furthermore, a novel medium that utilizes a mixture of FW and AE was applied for DHA fermentation, whereby the final DHA yield reached 28.45 g/L, 24.56% higher than conventional medium. The strategy of valorizing fermentation waste provides a new method for reducing the costs and reducing environmental pollution of microbial fermentations. PMID- 29990765 TI - Vortex fluidic mediated direct transesterification of wet microalgae biomass to biodiesel. AB - A bottleneck in the production of biodiesel from microalgae is the dewatering and lipid extraction process which is the dominant energy penalty and cost. A novel biodiesel production platform based on vortex fluidic device (VFD)-assisted direct transesterification (DT) of wet microalgal biomass of Chloroparva pannonica was developed and evaluated. Fatty acid extraction and fatty acid to FAME conversion efficiencies were used at different parameter settings to evaluate performance of the processing technology in confined and continuous mode. A response surface method based on Box-Behnken experimental design was used to determine the effects of water content, the ratio of biomass to methanol and residence time in the VFD. Average extraction efficiencies were 41% and conversion efficiencies >90% with the processing technology showing a broad tolerance to parameter settings. The findings suggest that VFD-assisted DT is a simple and effective way to produce biodiesel directly from wet microalgae biomass at room temperature. PMID- 29990766 TI - Impact of surface tension of wastewater on biofilm formation of microalgae Chlorella sp. AB - The organic matter and surfactants in wastewater may cause variations in the surface tension of wastewater (STW) ranging between ~40 and ~70 mJ.m-2. This study focused on the influence of STW on microalgae biofilm formation. A theoretical analysis was first conducted, and then microalgae biofilm formation on hydrophilic and hydrophobic substrata in liquid and real wastewater with different surface tensions was studied. The results demonstrated that STW affected microalgae biofilm formation remarkably. When the surface tension of liquid medium (gammalv) was approximately equal to the average value of surface free energy of microalgae and substrata, biofilm formation reached the minimum. Microalgae biofilm formation on a hydrophilic surface first decreased (from ~2200 to ~1500 cells/mm2) and then increased (from ~1500 to 3100 cells/mm2) with the decrease in gammalv (from ~70 to ~40 mJ.m-2), whereas biofilm on a hydrophobic surface continued to decrease (from ~2500 to 1000 cells/mm2). PMID- 29990767 TI - Comparison of microRNA transcriptomes reveals differential regulation of microRNAs in different-aged boars. AB - To elucidate the role of microRNA (miRNA) during early testicular development, we constructed three small RNA libraries from boar testes at three timepoints. Utilizing Solexa deep sequencing technology, over 12 million reads were measured. Of a total of 263 known miRNAs, 159 were co-expressed in all libraries. Read counts of the top 20 most abundant miRNAs accounted for more than 75% of total known miRNAs, and in all libraries, miR-10b was the most abundant. Analysis of higher fold changes in miRNAs (|log2_fold changes| > 4) revealed seven miRNAs that were involved in testes development (miR-381, miR-205, miR-217, miR-146a-5p, miR-187, miR-215, and miR-195). Among these, miR-146a-5p and miR-195 played an important role in 0-day-old (N0) and 28-day-old (N28) boars; miR-187 and miR-205 primarily regulated reproductive processes in N28 and 120-day-old (N120) boars; and miR-381, miR-217, and miR-215 participated in the modulation of testes development during all three timepoints. These miRNAs regulated testes cell proliferation and apoptosis at different stages. Furthermore, the predicted miRNA targets from the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that these differentially expressed miRNAs likely regulated developmental processes via PI3K-AKT, mitogen-activated protein kinase, and other related signaling pathways. Our results present a genome-wide miRNA profile from the testes of different-aged boars and provide a useful theoretical basis for further studies on the role of miRNA regulation in testes development during early life. PMID- 29990768 TI - Expression of alpha and beta adrenergic receptors in the pig uterus during inflammation. AB - Under physiological conditions, noradrenaline (NA) and adrenergic receptors (ARs) are implicated in the function of the uterus. The role of NA and the expression of ARs in the inflamed uterus is not fully understood. The aim of the present study was to determine the effect of inflammation on the levels of alpha1 (A, B, D)-, alpha2 (A, B, C)- and beta (1, 2, 3)-ARs mRNA and protein expression and the localization of these receptors in the porcine uterus. On Day 3 of the estrous cycle (Day 0 of the study), 50 ml of either saline (group SAL) or E. coli suspension (109 colony-forming units/ml, group E. coli) were injected into each uterine horn. In the control pigs (group CON), only laparotomy was performed. Eight days later, alpha1D-ARs mRNA (P < 0.001) and protein (P < 0.05) levels and alpha2A-ARs protein level (P < 0.05) were increased in the inflamed endometrium, while the alpha2C-ARs protein level (P < 0.001) was lowered, as compared to the SAL and CON groups. In the inflamed endometrium, beta2-ARs mRNA (P < 0.01) and protein (CON: P < 0.01, SAL: P < 0.001) expression was lower than in the other two groups, and beta1-ARs mRNA (P < 0.001) and protein (P < 0.01) expression was higher compared to the SAL group. After bacterial treatment, alpha2A- (P < 0.001) and alpha2B (P < 0.05) -ARs protein levels and beta2-ARs mRNA (CON: P < 0.01, SAL: P < 0.05) and protein (CON: P < 0.01, SAL: P < 0.05) expression in myometrium were found to be increased compared to both groups. In turn, in myometrium following E. coli infusion, the alpha2C-ARs protein level was lower (P < 0.01) than in the CON group. All studied receptors were present in the luminal and glandular epithelium, blood vessels and myometrial muscular cells of the gilt uteri in the E. coli, SAL and CON groups. The data show that inflammation changes the ARs expression in porcine uterus, suggesting their importance in the course/consequences of uterine inflammation. Those affected ARs may constitute a therapeutic target in an inflamed uterus. PMID- 29990769 TI - Title: Enhanced salt tolerance and photosynthetic performance: Implication of ? amino butyric acid application in salt-exposed lettuce (Lactuca sativa L.) plants. AB - Gamma-Amino Butyric Acid (GABA) is a substantial component of the free amino acid pool with low concentration in plant tissues. Enhanced GABA content occurs during plant growth and developmental processes like seed germination. GABA level, basically, alters in response to many endogenous and exogenous stimuli. In the current study, GABA effects were studied on germination, photosynthetic performance and oxidative damages in salt-exposed lettuce plants. Three NaCl (0, 40 and 80 mM) and two GABA (0 and 25 MUM) concentrations were applied on lettuce during two different developmental (seed germination and seedlings growth) stages. Negative effects of salinity on germination and plant growth were removed by GABA application. GABA significantly reduced mean germination time (MGT) in salt-exposed lettuce seeds. Although, salinity caused a significant decline in maximum quantum yield of photosystem II (Fv/Fm) during distinct steps of plant growth, GABA application improved Fv/Fm particularly on high salinity level. GABA decreased specific energy fluxes per reaction center (RC) for energy absorption and dissipation, while enhanced-electron transport flux in photosynthetic apparatus of lettuce plants was observed in GABA-supplemented plants. Moreover, decline in non-photochemical quenching (NPQ) and quenching coefficients (qP, qL, qN) by salt stress were recovered by GABA application. Elevated electrolyte leakage considerably decreased by GABA exposure on salt-treated plants. Although, proline level increased by NaCl treatments in a concentration dependent manner, combined application of salt with GABA caused a significant reduction in proline content. Catalase; EC 1.11.1.6 (CAT), l-ascorbate peroxidase; EC 1.11.1.11 (APX), and superoxide dismutase; EC 1.15.1.1 (SOD) activities were increased by GABA exposure in salt-supplemented plants that resulted in regulated hydrogen peroxide level. In conclusion, a multifaceted role for GABA is suggested for minimizing detrimental effects of salinity on lettuce through improvement of photosynthetic functionality and regulation of oxidative stress. PMID- 29990770 TI - Comparative phosphoproteome analysis upon ethylene and abscisic acid treatment in Glycine max leaves. AB - Abscisic acid (ABA) and ethylene play key roles in growth and development of plants. Several attempts have been made to investigate the ABA and ethylene induced signaling in plants, however, the involvement of phosphorylation and dephosphorylation in fine-tuning of the induced response has not been investigated much. Here, a phosphoproteomic analysis was carried out to identify the phosphoproteins in response to ABA, ethylene (ET) and combined ABA + ET treatments in soybean leaves. Phosphoproteome analysis led to the identification of 802 phosphopeptides, representing 422 unique protein groups. A comparative analysis led to the identification of 40 phosphosites that significantly changed in response to given hormone treatments. Functional annotation of the identified phosphoproteins showed that these were majorly involved in nucleic acid binding, signaling, transport and stress response. Localization prediction showed that 67% of the identified phosphoproteins were nuclear, indicating their potential involvement in gene regulation. Taken together, these results provide an overview of the ABA, ET and combined ABA + ET signaling in soybean leaves at phosphoproteome level. PMID- 29990771 TI - Chlorophytum comosum-bacteria interactions for airborne benzene remediation: Effect of native endophytic Enterobacter sp. EN2 inoculation and blue-red LED light. AB - This study was performed to determine the effect of plant-endophytic Enterobacter sp. EN2 interactions and blue-red LED light conditions on gaseous benzene removal by plants. It was found that under consecutive benzene fumigation for three cycles (18 days), inoculation of the strain EN2 into sterilized and non sterilized native C. comosum resulted in significantly increased gaseous benzene removal compared to that in non-inoculated groups under the same light conditions (P < 0.05). Remarkably, EN2 colonization in inoculated plants under LED conditions was higher than under fluorescence conditions as the EN2 could grow better under LED conditions. Strain EN2 possesses NADPH that is used to facilitate benzene degradation and modulate plant growth under benzene stress by bacterial IAA production and ACC deaminase activity; higher IAA and lower ethylene levels were found in inoculated plants compared to non-inoculated ones. These contributed to better benzene removal efficiency. Interestingly, under fumigation for 16 cycles (67 days), there was no difference in gaseous benzene removal between inoculated plants and non-inoculated plants under the same light conditions at initial benzene concentrations of 5 ppm. This is probably due to EN2 reaching maximum growth under all treatments. However, C. comosum exhibited better benzene removal under LED conditions than under fluorescence conditions during 16 cycles, possibly due to better photosynthetic performance and plant growth, leading to more NADPH, and eventually enhanced benzene removal efficiency. Hence, the most efficient acceleration of benzene removal was provided by inoculation of strain EN2 onto C. comosum under blue-red LED light conditions. PMID- 29990772 TI - The molecular events of IAA inhibiting citrus fruitlet abscission revealed by digital gene expression profiling. AB - Citrus fruits possess two abscission zones (AZ), AZ A and AZ C located at the pedicel and calyx, respectively. Early citrus fruitlet abscission (CFA) exclusively occurs at AZ A. Previous data have shown that indole-3-acetic acid (IAA) could inhibit fruitlet abscission. However, its role in CFA remains vague. In this study, we first removed the ovaries of fruitlets in order to exclude their interferences. Then, the calyxes were treated with IAA, gibberellin 3 (GA3) and 6-benzylaminopurine (6-BA), respectively. The results have shown that IAA could prevent CFA from taking place, while either GA3 or 6-BA could not. When IAA concentration decreased to a value between 30 mg/L and 40 mg/L, CFA occurred, showing a concentration-dependent manner. Digital gene expression analysis revealed that 2317 corresponded to IAA treatment, of which 1226 genes were closely related to CFA. The most affected genes included those related to biosynthesis, transport and signaling of phytohormones, primarily ethylene (ET), abscisic acid (ABA) and auxin as well as protein ubiquitination, ROS response, calcium signal transduction, cell wall and transcription factors (TFs). The results obtained in this study suggested that the IAA in AZ A could suppress ethylene biosynthesis and signaling, and then inhibit abscission signaling. To our knowledge, it is the first time to reveal the key role of IAA in CFA, which will contribute to a better understanding for the mechanism underlying CFA. PMID- 29990773 TI - Contribution of abscisic acid to aromatic volatiles in cherry tomato (Solanum lycopersicum L.) fruit during postharvest ripening. AB - Fruit aroma development depends on ripening. Abscisic acid (ABA) has been reported to be involved in the regulation of tomato fruit ripening. In the present study, the effects of exogenous ABA on aromatic volatiles in tomato fruit during postharvest ripening were studied. The results showed that exogenous ABA accelerated color development and ethylene production as well as the accumulation of carotenoids, total phenolics and linoleic acid in tomato fruit during ripening. Moreover, exogenous ABA increased the accumulation of volatile compounds such as 1-peten-3-one (2.06-fold), beta-damascenone (1.64-fold), benzaldehyde (3.29-fold) and benzyl cyanide (4.15-fold); induced the expression of key genes implicated in the biosynthesis pathways of aromatic volatiles, including TomloxC, HPL, ADH2, LeCCD1B and SlBCAT1 (the values of the log2 fold changes ranged from -3.02 to 2.97); and promoted the activities of lipoxygenase (LOX), hydroperoxide lyase (HPL) and alcohol dehydrogenase (ADH). In addition, the results of promoter analyses revealed that cis-acting elements involved in ABA responsiveness (ABREs) exist in 8 of the 12 key genes involved in volatile biosynthesis, suggesting that ABA potentially affects aromatic volatile emissions via the regulation of gene expression profiles. PMID- 29990774 TI - Spatial relationship between the field-measured ambient gamma dose equivalent rate and geological conditions in a granitic area, Velence Hills, Hungary: An application of digital spatial analysis methods. AB - In order to estimate the annual dose that the public receive from natural radioactivity, the identification of the potential risk areas is required which, in turn, necessitates understanding the relationship between the spatial distribution of natural radioactivity and the geogenic risk factors (e.g., rock types, presence of dikes, faults, physical conditions of soil, etc.). A detailed spatial analysis of outdoor ambient gamma dose equivalent rate was performed in the western side of Velence Hills, the largest outcropped granitic area in Hungary. In order to assess the role of local geology in the spatial distribution of gamma dose rates, field measurements were carried out at ground level at 300 sites along a 250 m x 250 m regular grid in a total surface of 19.8 km2. Digital image processing methods were applied to identify anomalies, heterogeneities and spatial patterns in the measured gamma dose rates, including local maxima and minima determination, digital cross sections, gradient magnitude and gradient direction, second derivative profile curvature, local variability, lineament density, 2D autocorrelation and directional variogram analyses. Statistical inference shows that different gamma dose rate levels are associated with the geological formations, with the highest level on the Carboniferous granite including outlying values. Moreover, digital image processing reveales that linear gamma dose rate spatial features are parallel to the SW-NE dike system and to the NW-SE main fractures. The results of this study underline the importance of understanding the role of geogenic risk factors influencing the ambient gamma dose equivalent rate received by public. The study also demonstrates the power of the image processing techniques for the identification of spatial pattern in field-measured geogenic radiation. PMID- 29990775 TI - Behaviour of carbon-14 containing low molecular weight organic compounds in contaminated groundwater under aerobic conditions. AB - Short chain carbon-14 (14C) containing organic compounds can be formed by abiotic oxidation of carbides and impurities within nuclear fuel cladding. During fuel reprocessing and subsequent waste storage there is potential for these organic compounds to enter shallow subsurface environments due to accidental discharges. Currently there is little data on the persistence of these compounds in such environments. Four 14C-labelled compounds (acetate; formate; formaldehyde and methanol) were added to aerobic microcosm experiments that contained glacial outwash sediments and groundwater simulant representative of the Sellafield nuclear reprocessing site, UK. Two concentrations of each electron donor were used, low concentration (10-5 M) to replicate predicted concentrations from an accidental release and high concentration (10-2 M) to study the impact of the individual electron donor on the indigenous microbial community in the sediment. In the low concentration system only ~5% of initial 14C remained in solution at the end of experiments in contact with atmosphere (250-350 h). The production of 14CO2(g) (measured after 48 h) suggests microbially mediated breakdown is the primary removal mechanism for these organic compounds, although methanol loss may have been partially by volatilisation. Highest retention of 14C by the solid fractions was found in the acetate experiment, with 12% being associated with the inorganic fraction, suggesting modest precipitation as solid carbonate. In the high concentration systems only ~5% of initial 14C remains in solution at the end of the experiments for acetate, formate and methanol. In the formaldehyde experiment only limited loss from solution was observed (76% remained in solution). The microbial populations of unaltered sediment and those in the low concentration experiments were broadly similar, with highly diverse bacterial phyla present. Under high concentrations of the organic compounds the abundance of common operational taxonomic units was reduced by 66% and the community structure was dominated by Proteobacteria (particularly Betaproteobacteria) signifying a shift in community structure in response to the electron donor available. The results of this study suggest that many bacterial phyla that are ubiquitous in near surface soils are able to utilise a range of 14C-containing low molecular weight organic substances very rapidly, and thus such substances are unlikely to persist in aerobic shallow subsurface environments. PMID- 29990776 TI - Facile synthesis of flexible mesoporous aerogel with superhydrophobicity for efficient removal of layered and emulsified oil from water. AB - Aerogel with porous structure and ultra-light weight is a potential sorbent for solving oils or organic solvents pollution. Herein, a type of flexible mesoporous aerogel was fabricated though a simple ambient pressure drying using methyltrimethoxysilane/dodecyltrimethoxysilane (MTMS/DTMS) as precursors and distilled water as solvent. The as-synthesized aerogel exhibits superhydrophobicity with water contact angle of 163 degrees and low density of 0.102 g/cm3. Moreover, the aerogel can selectively separate oils and water insoluble organic solvents on and under water, and the sorption capacities can reach up to 7.98-13.4 times its own weight. More importantly, the obtained aerogel is capable of separate surfactant-free and surfactant-stabilized oil-in water emulsions with high separation efficiency of greater than 98.4%. In addition, the aerogel is highly resistant toward corrosive aqueous solutions (acidic, alkaline, salty solutions), harsh temperature environments (-30 and 160 degrees C), and mechanical abrasion. Due to eco-friendly fabrication process, low cost, and outstanding oil/water separation performance, the developed aerogel have potential application in oils or organic pollutants sorption and water purification. PMID- 29990777 TI - Facile co-precursor sol-gel synthesis of a novel amine-modified silica aerogel for high efficiency carbon dioxide capture. AB - Massive amount of CO2 emission, which could cause climate change, has been recognized as a serious environmental issue. Chemical adsorption is generally considered as a promising technology for CO2 capture in low CO2 partial pressure. Physical properties and chemical components of the adsorbent are important to CO2 adsorption performance. To address structure limitation and complicated preparation process of the conventional adsorbent, herein, we reported a rapid and simple route to synthesis amine-modified silica aerogel monolith by co precursor sol-gel method. Microstructure and the surface functional groups of the amine-modified silica aerogel could be easily manipulated. The products were characterized by SEM, XPS, NMR, in situ DRIFT and CNS elemental analyzer. The amine-modified silica aerogel exhibited good physical properties and demonstrated excellent CO2 adsorption performance. The density, porosity and BJH pore volume of the amine-modified silica aerogel were 0.12 g/cm3, 94.5% and 2.39 cm3/g, respectively. The maximum static and dynamic adsorption capacities of CO2 on the amine-modified silica aerogel were 2.2 mmol/g and 5.59 mmol/g under anhydrous and humid mixed gas conditions, respectively. The as-prepared aerogel also showed good cyclic ability for CO2 adsorption and desorption. The CO2 adsorption on the amine-modified silica aerogel is by the formation of carbamate through a two-step zwitterion mechanism. This easily prepared amine-modified silica aerogel could be a promising adsorbent for CO2 capture. PMID- 29990778 TI - Silver iodide nanowires grown within tubular J-aggregates. AB - Silver iodide nanowires have been grown within tubular J-aggregates of the cyanine dye 3,3'-bis(2-sulfopropyl)-5,5',6,6'-tetrachloro-1,1'-dioctylbenzimida carbo-cyanine (C8S3) from aqueous AgNO3 solutions. Crystal structure analysis by selected area electron diffraction (SAED), high resolution transmission electron microscopy (HRTEM) and energy-dispersive X-ray spectroscopy (EDXS) of single nanowires revealed that they are of silver iodide (AgI), while previously they were presumed to be of metallic silver. Iodine has not been added intentionally, but it is a remnant from the chemical synthesis of the dye and present in a dye:iodine ratio of almost 2:1, as revealed by inductively coupled plasma mass spectrometry (ICP-MS). The AgI wires grow as single crystals with lengths of several 10-100 nm and width of 6.5 +/- 0.5 nm. The width and the orientation of the crystal relative to the aggregate axis are defined by the tubular structure of the templating dye aggregate. Caused by the nucleation at the tube wall the main growth is not along the usually preferred [0 0 0 1] direction but along the extension of the basal plane, which is furthermore tilted by an angle of 6 degrees +/- 2 degrees against the main axis of the aggregate. This self assembled system represents an organic-inorganic hybrid system with a well defined semiconductor nanowire, AgI, that is strictly oriented with respect to the aggregated phase of conjugated molecules. PMID- 29990779 TI - Three-dimensional cellulose based silver-functionalized ZnO nanocomposite with controlled geometry: Synthesis, characterization and properties. AB - Cellulose based Ag-functionalized ZnO nanocomposite (AZC) films were prepared using a green and easy scale-up strategy. Firstly, ZnO embedded cellulose (ZC) nanocomposite was synthesized from a cellulose-NaOH/zincate/urea solution through a biomimetic approach. Secondly, Ag nanoparticles (NPs) with a mean diameter of 53.2 nm were efficiently deposited onto the surface of embedded ZnO in cellulose matrix under UV irradiation (16 w), yielding the multi-hybrid AZC film. Owing to the porous structure of cellulose substrate and its rich hydroxyl group, the NPs in the ACZ films displayed good stability. Because of the formation of Schottky barriers in the Ag-ZnO regions, the catalytic activity of ACZ films increased by 20 times when compared to that of ZC sample. Furthermore, the AZC films could completely inhibit both S. aureus and E. coli growth. This facile and eco friendly approach is expected to pave the way for constructing multifunctional cellulose material for various niche applications. PMID- 29990780 TI - Colloidal characteristics and functionality of rationally designed esculin-loaded hydrogel microcapsules. AB - This work reports the development of different types of alginate hydrogel microparticles designed specifically for the esculin (ESC) payload. Negatively charged alginate (ALG) microspheres were prepared by the ionotropic gelation technique, and an oppositely charged polyelectrolyte (PE) shell as a compatible polycation (chitosan (CHIT) or gelatin (GEL)) or a synthetic PEs (poly(allylamine hydrochloride) (PAH) and poly(4-styrenesulfonate) (PSS)) were adsorbed using electrostatic complexation. Thorough characterization of microparticles was performed with advanced microscopic techniques (scanning electron, fluorescence and confocal), followed by stability studies, ESC encapsulation efficacy determination and in vitro release kinetics measurements. We provide an in-depth investigation of the relationships between the properties (thickness, viscosity, areal mass, zeta potential) of the outer shell and the retaining and release abilities of the fabricated microcarriers, using quartz crystal microbalance with dissipation monitoring technique (QCM-D), spectroscopic ellipsometry and streaming potential measurements, combined in a new approach that was not attempted before for micrometric particles. The PAH-PSS and GEL coatings provided sufficient protection against ESC release under simulated gastric conditions that followed a two-stage Corrigan-Gallagher model with a marginal release rate in the first (lag) stage. This seems to be an interesting outcome, since it is rather peculiar for a low-molecular weight hydrophilic compound encapsulated in a highly porous microhydrogel to be released in such a manner. PMID- 29990781 TI - Rhodium(0) nanoparticles supported on ceria as catalysts in hydrogenation of neat benzene at room temperature. AB - Rhodium(0) nanoparticles supported on ceria (Rh NPs/CeO2) were prepared from the reduction of Rh3+ ions on the surface of ceria in aqueous medium. Rh NPs/CeO2 catalyst was found to be highly active in hydrogenation of benzene under mild conditions. It provided a TOF value of 495 h-1 in hydrogenation of solventless benzene under ~3 bar pressure of H2 gas at 25.0 +/- 0.1 degrees C. Rh NPs/CeO2 shows superior catalytic activity over titania, zirconia and hafnia supported Rh NPs in this reaction. PMID- 29990782 TI - Three-dimensional poly(lactic-co-glycolic acid)/silica colloidal crystal microparticles for sustained drug release and visualized monitoring. AB - In this paper, a three-dimensional (3D) poly(lactic-co-glycolic acid) (PLGA)/silica colloidal crystal drug delivery system with sustained drug release and visualized release monitoring was developed. This system had employed silica colloidal crystal microparticles as template skeleton, PLGA as drug carrier and dexamethasone (DEX) as therapeutic agent. The fabrication of the microparticle based system included droplet formation based-on microfluidics, silica nanoparticle self-assembly and layer-by-layer deposition of PLGA containing DEX. In 370 MUm droplets, the silica colloidal nanoparticles could self-assemble orderly into microparticles with a diameter of 187 MUm, featuring red structure color. During the deposition of PLGA with the drug into the voids of the template microparticles, the reflection peak red-shifted and weakened until the voids were completely filled. Owing to the gradual degradation of PLGA, the release of DEX was triggered and sustained for 4 weeks with a cumulative release of 94.9%, while the structure color of the microparticles recovered during the release process. The color change could be recognized by the naked eyes, which would benefit the non-invasive monitoring of the drug release. The in vitro cytotoxicity and long term inhibiting proliferation were investigated on retinal pigment epithelial cells. The inhibition effect of DEX released from the microparticles showed concentration-dependence from 40 to 200 MUg mL-1 and time-dependence within 7 days. As a sustained drug delivery system with self-reporting drug release, the particles have potential applications in treatment of intraocular diseases. PMID- 29990783 TI - Calcium molybdate nanoparticles formation in egg phosphatidyl choline based liposome caused by liposome fusion. AB - In order to achieve the highly efficient 99mTc production from 100MoO3 by the 100Mo(n, 2n)99Mo reaction, we have developed a new protocol to synthesize nano sized Mo particles, of which the size was controlled by the inner space of the liposomes. Calcium and molybdate ions were encapsulated into ~100 nm size liposomes. The liposome suspensions were then mixed and heated to promote the membrane fusion. As a result, the insoluble CaMoO4 nanoparticles precipitated inside the liposomes. The median particle diameter of 168 nm and average diameter of 169 +/- 56 nm (n = 109) were obtained from an SEM image, and the particles have a powellite-structure. The formation process of the particles was then examined. The formation of nano-sized CaMoO4 was observed by the high resolution TEM image and TEM image of negative-stained liposome. At the room temperature, the fusion of liposome did not occur significantly. These results suggest that nanocrystals of the CaMoO4 were likely formed in the liposomes because of the liposome fusion and aggregated during the drying processes of reaction solution. PMID- 29990784 TI - Modified stannous sulfide nanoparticles with metal-organic framework: Toward efficient and enhanced photocatalytic reduction of chromium (VI) under visible light. AB - Novel metal-organic framework/stannous sulfide (MIL-53(Fe)/SnS) nanocomposite photocatalysts were successfully synthesized by a one-step deposition process. The structure, composition and optical properties of the MIL-53(Fe)/SnS composite were systematically characterized by the X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy, Fourier transform-infrared spectroscopy, UV-vis diffuse reflection spectroscopy and photoluminescence analysis. The photocatalytic performance of MIL-53(Fe)/SnS composite has been evaluated in the reduction of chromium (VI) under visible light irradiation. Compared with pure MIL-53(Fe) and SnS, the MIL-53(Fe)/SnS composite exhibited enhanced photoreduction capability of chromium (VI) due to the strengthened absorption in the visible region, higher electron-hole separation rate and larger specific area. The MIL-53(Fe)/SnS composite with MIL 53(Fe) adding of 15 mg displayed optimal chromium (VI) reduction rate of 0.01878 min-1, which was about 7.5 and 5.2 times than pure MIL-53(Fe) and SnS, respectively. The active species superoxide radical (O2-), electron(e-) and hole(h+) are essential toward chromium (VI) reduction. Lastly, a possible photocatalytic mechanism is proposed. PMID- 29990785 TI - Insight on the plasmonic Z-scheme mechanism underlying the highly efficient photocatalytic activity of silver molybdate/silver vanadate composite in rhodamine B degradation. AB - A facile deposition-precipitation method was applied to synthesize novel plasmonic Z-scheme Ag2MoO4/Ag3VO4 photocatalysts with different molar ratios of Ag2MoO4. The morphological, structural, and spectroscopic properties of the as obtained samples were characterized through X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X-ray photoelectron spectroscopy, and UV-vis diffuse reflectance spectral analysis. The photocatalytic performance of the synthesized photocatalysts in rhodamine B (RhB) degradation under visible light irradiation was evaluated. The 5% Ag2MoO4/Ag3VO4 composite displayed the highest photocatalytic activity among all samples and the RhB removal rate of 93% within 6 min. The RhB removal rate of 5% Ag2MoO4/Ag3VO4 composite was higher than that of precursor Ag2MoO4 and Ag3VO4 compounds. The formation of Ag nanoparticles (Ag NPs) on the surface of Ag2MoO4/Ag3VO4 during photocatalysis resulted in the transformation of the Ag2MoO4/Ag3VO4 heterojunction to the Ag2MoO4/Ag/Ag3VO4 Z scheme system, thus enhancing photocatalytic activity. Z-scheme Ag2MoO4/Ag/Ag3VO4 composites could efficiently facilitate charge transfer, promote redox ability, and restrain Ag3VO4 photocorrosion. The produced active species O2-, h+, and OH are vital for RhB degradation. The present work could benefit the development of advanced visible-light photocatalytic materials with future applications in environmental remediation. PMID- 29990786 TI - Enhancement of the particle stabilization of water-in-water emulsions by modulating the phase preference of the particles. AB - HYPOTHESIS: The stability of particle stabilized water-in-water (W/W) emulsions depends on the position of the particles at the interface, which in turn depends on their preference for each phase. The surface properties of the particles determine their preference and it should therefore be possible to enhance the stability of W/W emulsions by modulating the surface of particles, for instance by adsorption of small molecules on their surface. EXPERIMENTS: Polystyrene latex particles were covered with proteins to varying extents by adding different amounts of whey proteins. The effect on the efficacy of the particles to stabilize W/W emulsions formed by mixing dextran and poly(ethylene oxide) (PEO) was studied using confocal laser scanning microscopy and visual observations. Both emulsions with droplets of the PEO rich phase in a continuous dextran rich phase (P/D) and the inverse (D/P) were investigated. FINDINGS: The preference of the particles could be modulated from strongly preferring the PEO phase in the absence of protein to preferring dextran phase in excess protein. It was found that the particles stabilized emulsions best when they preferred the continuous phase, i.e. protruded outward from the droplets. Both D/P emulsions and P/D could be stabilized at intermediate coverage. PMID- 29990787 TI - A graphene oxide-based switch-on fluorescent probe for glutathione detection and cancer diagnosis. AB - Reduced glutathione (GSH) is a crucial endogenous antioxidant that plays a central role in maintaining cell activity by involving in cellular defense against reactive oxygen species (ROS). Therefore, the detection of intracellular GSH is essential to monitor the cellular state. Herein, graphene oxide-MnO2 fluorescein (GO-MnO2-FL) nanocomposite was synthesized and used for GSH detection. GSH could reduce MnO2 to Mn2+ and block the energy transfer between FL and GO-MnO2, leading to the significant fluorescence enhancement of FL. The fluorescence-based GSH sensing has a limit of detection of 1.53 MUM and a wide detection range of 10 MUM-2 mM. Moreover, the GO-MnO2-FL nanocomposite was found to selectively image the cancer cells since the GSH content of cancer cells is higher than that of normal cells. In vivo experiments also confirmed the normal/cancer cell differentiation capability and excellent tumor-targeting ability of the GO-MnO2-FL nanocomposite. These properties make the GO-MnO2-FL nanocomposite an excellent fluorescent probe for GSH detection both in vitro and in vivo, and we believe it may hold great potential for GSH-mediated cancer diagnosis. PMID- 29990788 TI - Interfacial self-assembly of functional bilayer templates comprising porphyrin arrays and graphene oxide. AB - Fabricating of solid-supported hybrid nanostructures remains a challenging problem because it is difficult to control all interfacial interactions influencing the structure and stability of these systems. The most widely used approach to solving this problem is a bottom-up assembly on the surface templates such as self-assembled monolayers (SAMs). Herein we suggest an alternative approach to tailoring solid surfaces by a formation of an interlayer anchoring the nanostructured film to the solid substrate. We formed a multifunctional bilayer template (MBT), comprising an adhesive monolayer of graphene oxide and a functional ordered monolayer of metal organic compound (Zinc-tetra(4 pyridyl)porphyrin) directing further bottom-up growth of the nanostructures. The one-step assembly of MBT proceeded spontaneously at the air/water interface and was monitored by an in-situ fiber optic absorption and fluorescence spectroscopy in a Langmuir trough. Dilatation surface rheology was applied to study the evolution of molecular organization of the monolayers upon adding the zinc ions, GO and their mixture into the subphase. The MBT templates were used for the assembly of porphyrin-based SURMOFs with two different structures. Our strategy makes it possible to assemble surface-anchored nanostructures avoiding the use of SAMs and it can be extended to other types of ultrathin hybrid systems. PMID- 29990789 TI - Investigation of sedimentation process of soluble spherical particles in a non Newtonian medium. AB - In this work, transient movement of a vertically falling soluble spherical particle in a non-Newtonian medium is perused. It is supposed that the particle mass diminishes owing to its solubility in the fluid, and thus particle size will be diminished by a linear function. The governing nonlinear differential equation is solved analytically using Collocation Method (CM). The impacts of the effective parameters of this study are examined on the velocity and acceleration. Further, the positions of the particle are portrayed graphically at every 1 s time trend. Also, the limiting cases are gained and are found to be in good compromise with the numerical and literature results. The outcomes portray that the particle with a larger rate of diameter diminution moving with larger velocity rather than smaller diameter particle. PMID- 29990790 TI - Putative dual inhibitors of Janus kinase 1 and 3 (JAK1/3): Pharmacophore based hierarchical virtual screening. AB - Janus kinase 1 and 3 are non-receptor protein tyrosine kinases, involved in the regulation of various cytokines implicated in the pathogenesis of autoimmune and inflammatory disease conditions. Thus, they serve as therapeutic targets for the designing of multi-targeted agents for the treatment of inflammatory-mediated pathological conditions. In the present study, diverse inhibitors of JAK1 and JAK3 were considered for the development of ligand-based pharmacophore models, followed by docking analysis to design putative dual inhibitors. The pharmacophore models were generated in PHASE 3.4, and top five models for each target were selected on the basis of survival minus inactive score. The best model for JAK1 (AAADH.25) and JAK3 (ADDRR.142) were selected corresponding to the highest value of Q2test. Both models were employed for the screening of a PHASE database, and subsequently, the retrieved hits were filtered employing molecular docking in JAK1 and JAK3 proteins. The stable interactions between retrieved hits and proteins were confirmed using molecular dynamics simulations. Finally, ADME properties of screened dual inhibitors displaying essential interactions with both proteins were calculated. Thus, the new leads obtained in this way may be prioritized for experimental validation as potential novel therapeutic agents in the treatment of various autoimmune and inflammatory disorders related to JAK1 and JAK3. PMID- 29990791 TI - A novel feature selection method to predict protein structural class. AB - Integrating various features from different protein properties helps to improve the prediction accuracy of protein structural class but need to deal with the corresponding integrated high-dimensional data. Thus, the feature selection process used to select the informative features from the integrated features also becomes an indispensable key step. This paper proposes a novel feature selection method, Partial-Maximum-Correlation-Information based Recursive Feature Elimination (PMCI-RFE), to quickly select the best feature subset from the integrated high-dimensional protein features set to improve the prediction performance of protein structural class. PMCI-RFE can also be used to find different types of informative features to further analyze some biological relationships. The proposed PMCI-RFE method uses the correlation information between the feature space and class encoding space to select informative features based on the idea of orthogonal component projection in the feature space. The experimental results on six widely used benchmark datasets show that PMCI-RFE is a fast and effective method compare to other four state-of-the-art feature selection methods, which indeed can make full use of different protein property information and improve the predictability of protein structural class. PMID- 29990792 TI - A modified Delphi process to identify, rank and prioritize quality indicators for continuous renal replacement therapy (CRRT) care in critically ill patients. AB - BACKGROUND: Continuous renal replacement therapy (CRRT) is a complex and life sustaining therapy, reserved for our most acutely ill patients, and should be delivered in a safe, consistent and high-quality manner. However valid evidence based quality indicators (QIs) for CRRT care are lacking. The objective of this study was to develop a prioritized list of QIs for CRRT care that may be used in any CRRT program. METHOD: We conducted a modified three stage Delphi process. This consisted of two web-based rounds followed by an in-person meeting. We recruited an interdisciplinary panel of critical care nephrology experts and knowledge users. In each stage of the Delphi process panelists responded on whether a QI should be included in our final list. In the third round, any QI for which there was uncertainty to include was discussed and a final decision on whether to include was made. RESULTS: Forty-one panelists participated (18 from nephrology, 11 from intensive care, 7 educators, 2 decision-makers, 2 industry representatives and 1 pharmacist) from North America, Europe, Australasia and South America. Following the third Delphi round, 13 QIs for CRRT care were identified; 10 QIs were identified with a high level of agreement for face validity while 3 QIs were identified with a moderate level of agreement for face validity among panelists. CONCLUSIONS: We developed a prioritized list of 13 QIs for CRRT care. Future work should focus on developing validated benchmarks for these QIs and implementing them into CRRT programs. PMID- 29990793 TI - Early enteral nutrition is associated with reduced in-hospital mortality from sepsis in patients with sarcopenia. AB - PURPOSE: To determine whether the association of early enteral nutrition (EEN) with mortality from sepsis differs between patients with and without sarcopenia. MATERIALS AND METHODS: We retrospectively reviewed septic patients treated at our centre between January 2010 and August 2017. The skeletal muscle area (SMA) at the level of the third lumbar vertebra was measured with CT on admission, and sarcopenia was defined as SMA < 80% of the predicted value. Patients were divided into two subgroups (sarcopenic and non-sarcopenic patients), and in-hospital mortality was compared in patients treated with and without EEN within each subgroup. We used logistic regression to examine factors associated with in hospital mortality in each subgroup. RESULTS: EEN was administered to 35/91 sarcopenic patients and 43/100 non-sarcopenic patients. In-hospital mortality did not differ between non-sarcopenic patients with EEN and those without EEN (16% vs 16%, P = 0.947), but was significantly lower in sarcopenic patients with EEN than in those without EEN (9% vs 34%, P = 0.005). Logistic regression showed that EEN was independently associated with reduced in-hospital mortality in sarcopenic patients (OR 0.18, 95% CI 0.05-0.71, P = 0.014), but not in non-sarcopenic patients. CONCLUSIONS: EEN may be more beneficial in sarcopenic patients. PMID- 29990795 TI - Epidemiological surveillance of mesothelioma mortality in Italy. AB - BACKGROUND: Malignant mesothelioma (MM) is causally linked to asbestos exposure with an estimated etiological fraction of 80% or more. METHODS: Standardized rates of all mesothelioma (C45, ICD-10) and malignant pleural mesothelioma (C45.0, ICD-10) mortality in Italy were computed at national and regional levels, for the period 2003-2014. Standardized Mortality Ratios (SMRs, with 95% Confidence Intervals) were calculated for each of the 8047 Italian municipalities, for both diseases, with respect to Regional figures. A geographical clustering analysis at municipal level was performed, applying SatScan methods. RESULTS: In Italy, 16,086 persons (about 1,340/year) died for MM, in analysed period. National Standardized rates of MM mortality are 3.65/100,000 in men and 1.09/100,000 in women, with an increasing annual trend, among male population. The highest rates were found in men from Northern Regions. Significant clusters (p < 0.10) were found corresponding to areas that hosted major asbestos-cement plants, naval shipyards, petrochemical plants and refineries. Furthermore, excesses were found corresponding to chemical and textile industries; the latter involving, particularly, female population. Excesses were found also in areas near the chrysotile mine of Balangero, and in Biancavilla, a town with a stone quarry contaminated by fluoro-edenitic fibres; an excess of MM mortality was observed among male population living in a minor island where a Navy shipyard is located. CONCLUSIONS: Mortality for mesothelioma in Italy is still increasing, twenty-six years after the asbestos ban. Epidemiological surveillance of mesothelioma mortality allows to detect the temporal trend of the disease and highlights previously unknown or underestimated sources of asbestos exposure. PMID- 29990796 TI - Foetal-neonatal exposure of Di (2-ethylhexyl) phthalate disrupts ovarian development in mice by inducing autophagy. AB - The female reproductive lifespan is largely determined by the size of the primordial follicle pool, which is established early in life. We previously reported that Di (2-ethylhexyl) phthalate (DEHP), an environmental endocrine disruptor and a widely-spreading plasticizer, impairs primordial folliculogenesis. In the present study, we found DEHP significantly altered the number and sex ratio of the offspring of neonatal-exposed mice. Furthermore, by a neonatal exposure model and an ovary culture model, it showed that DEHP activated autophagy in the ovary, with increased autophagy-related gene expression and recognizable autophagosomes, while inhibition of autophagy by 3-MA attenuated the adverse impact of DEHP on primordial folliculogenesis. Moreover, key components of AMPK-SKP2-CARM1 signalling were up-regulated by DEHP in the ovary, and AMPK inhibitor Compound C reduced autophagy-related gene expression and partially recovered primordial follicle assembly. Collectively, this study demonstrates that DEHP induces autophagy by activating AMPK-SKP2-CARM1 signalling in mice perinatal ovaries, which results in disrupted primordial folliculogenesis and reduced female fertility. PMID- 29990794 TI - Intake of folate and other nutrients related to one-carbon metabolism and risk of cutaneous melanoma among US women and men. AB - BACKGROUND: Nutrients involved in one-carbon metabolism - folate, vitamins B6 and B12, methionine, choline, and betaine - have been inversely associated with multiple cancer sites and may be related to skin cancer. However, there is a lack of research on the association between intake of these nutrients and cutaneous melanoma risk. The aim of this study was to examine the associations between intake of one-carbon metabolism nutrients and cutaneous melanoma risk in two large prospective cohorts. METHODS: The cohorts included 75,311 white women and 48,523 white men. Nutrient intake was assessed repeatedly by food frequency questionnaires and self-reported supplement use. We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) and then pooled HRs using a random-effects model. RESULTS: Over 24-26 years of follow-up, we documented 1328 melanoma cases (648 men and 680 women). Higher intake of folate from food only, but not total folate, was associated with increased melanoma risk (pooled HR for top versus bottom quintile: 1.36; 95% CI: 1.13-1.64; P for trend = 0.001). The association was significant in men, but attenuated in women. Higher intake of vitamins B6 and B12, choline, betaine, and methionine were not associated with melanoma risk, although there was modest increasing trend of risk for vitamin B6 from food only (pooled HR for top versus bottom quintile: 1.18; 95% CI: 0.99-1.41; P for trend = 0.03). CONCLUSIONS: We found some evidence that higher intake of folate from food only was associated with a modest increased risk of cutaneous melanoma. However, since other factors related to dietary folate intake may account for the observed association, our findings warrant further investigation. PMID- 29990797 TI - Significant enhancement in hydrolytic degradation of sulfur mustard promoted by silver nanoparticles in the Ag NPs@HKUST-1 composites. AB - The Ag NPs@HKUST-1 composites have been successfully prepared with different loading amounts of silver nanoparticles in HKUST-1 featuring a three-dimensional system of channels constructed by benzene-1,3,5-tricarboxylate and dimeric cupric units by a simple one-pot hydrothermal method, and characterized by various microscopy and spectroscopy analysis techniques. The average particle size of Ag NPs increased with the increase of the loading amount of Ag NPs. The experimental results showed that the degradation of sulfur mustard (HD) under ambient conditions followed pseudo-first order reaction kinetics. Additionally, the optimized Ag NPs@HKUST-1 (wherein Ag is l6.67 wt%) exhibited the highest degradation efficacy with an equilibrium rate constant and half-life for HD of 0.0450 min-1 and 15.34 min, respectively. These values were significantly higher than those for pure HKUST-1 with an equilibrium rate constant and half-life for HD of 0.0168 min-1 and 41.29 min, under the same experimental conditions. Gas chromatography-mass spectrometry (GC-MS) analysis on the product of 2 chloroethylethyl sulfide (2-CEES) degraded by Ag NPs@HKUST-1 showed that 2 hydroxyethyl ethyl sulfide (2-HEES) is the sole product, indicating that the remarkable enhancement of the degradation of HD must be due to the Ag NPs, which can promote hydrolysis of the chemical war agent in the composite. PMID- 29990798 TI - Pilot trial of detoxification of chromium slag in cyclone furnace and production of slag wool fibres. AB - The pilot trial of detoxification of chromium slag in cyclone furnace and production of slag wool fibres were investigated in a power plant in China. 10-30 wt.% chromium slag was mixed with pulverized coal and 0-10 wt.% limestone as the raw materials of the cyclone furnace. Cr(VI) in chromium slag was reduced to Cr2O3 inside the cyclone furnace at high temperature. The melt was then produced into slag wool fibres through high-speed centrifugation. Optimal fibres with shot content of 4.5%, average diameter of 4.8 MUm and acidity coefficient of 1.6 were produced with 15 wt.% chromium slag and 5 wt.% limestone in the mixture. Leaching toxicity test showed Cr(VI) of 0.016 mg/L of the produced fibres, which is far below the national standard of China. The total energy consumption could be significantly decreased compared to traditional cupola furnace method. This technique provides an effective and comprehensive technique for the detoxification and utilization of chromium slag at low cost and large-scale. PMID- 29990799 TI - Application of a ceramic membrane contacting process for ozone and peroxone treatment of micropollutant contaminated surface water. AB - This study investigates the performance of membrane-based ozonation and peroxone processes, regarding the transformation of carbamazepine (CBZ), benzotriazole (BZT), p-chlorobenzoic acid (pCBA) and atrazine (ATZ) in natural surface waters, as well as the formation of bromates. Ozonation, performed with the use of ceramic membrane contactor, was able to diminish CBZ concentration below 0.1 MUM at 0.4 mg O3/mg DOC, i.e. presenting >90% removal rate, whereas the transformation of BZT, pCBA and ATZ was not exceeded 70%, 57% and 49%, respectively, under the same experimental conditions. The addition of H2O2 reduced the removal efficiency of CBZ, since up to -8% transformation values were observed at 0.1 mg O3/mg DOC. In contrast, the transformation of ozone-resistant compounds pCBA and ATZ was slightly improved by approximately 5-10%, at 0.8 mg O3/mg DOC. Membrane-based oxidative treatment of surface water resulted to high bromate concentrations (49 MUg/L and 28 MUg/L for ozone and peroxone process, respectively, at 0.8 mg O3/mg DOC). The results obtained by using the membrane contactor were also compared with the corresponding from conventional batch experiments. These results suggest that the implementation of membrane contactors with the highest possible inner surface per volume along with the use of low ozone gas concentration are required to improve the removal of micropollutants and diminish bromate formation. PMID- 29990800 TI - Three-dimensional hierarchical porous sludge-derived carbon supported on silicon carbide foams as effective and stable Fenton-like catalyst for odorous methyl mercaptan elimination. AB - The poor reusability of catalysts and secondary pollution are critical issues for sulfur-containing volatile organic compounds (S-VOCs) removal. In this paper, a three-dimensional (3D) hierarchical porous sludge-derived carbon supported on silicon carbide foams (SiC) has been fabricated for deep decomposition of S-VOCs under ambient conditions. The sludge-derived Fenton-like catalyst has been confirmed to be hierarchical 3D porous structure based on detailed characterization by scanning electron microscopy (SEM), X-ray diffraction (XRD), Nitrogen adsorption-desorption measurements and Raman spectroscopy. Significantly, the catalyst after KOH activation (SCFeK-SiC) shows excellent catalytic decomposition of methyl mercaptan (CH3SH) with almost complete CH3SH oxidation into sulfate using hydrogen peroxide as an oxidant under ambient conditions. This catalyst also possesses relative low iron dissolution and excellent cycling performance. The efficient catalytic ability of SCFeK-SiC can be attributed to SiC foam functioned as a stable 3D macroporous skeleton, in which the porous sludge-derived carbon immobilizes the active iron species and promotes the efficient capture of gaseous CH3SH, thus facilitating the decomposition of CH3SH by generating reactive species, specifically .OH. The reaction mechanism was systematically investigated. Herein, the design of the porous sludge-derived carbonaceous Fenton-like catalyst paves an avenue for efficient VOCs treatment and rational sludge disposal. PMID- 29990801 TI - Multifunctional photoactive and selective adsorbent for arsenite and arsenate: Evaluation of nano titanium dioxide-enabled chitosan cross-linked with copper. AB - A novel multifunctional sorbent material of nano-titanium dioxide-enabled chitosan beads cross-linked with copper (CuTICB) is capable of photo-oxidation of As(III) to the less-toxic and more easily adsorbed As(V) in UV light and selective adsorption of arsenite (As(III)) and arsenate (As(V)) in the presence of phosphate, a strong adsorptive competitor and inhibitor of arsenic removal performance. CuTICB is an attractive sorbent as simultaneous photo-oxidation and adsorption reduces treatment time and cost while selective adsorption improves removal efficiency of arsenic in typical environmental conditions where competitive ions are predominant. In CuTICB, nano-titanium dioxide (n-TiO2) anatase photo-oxidizes As(III) to As(V) through generation of reactive oxygen species. Additionally, Cu-chitosan bidentate crosslinkers form through Lewis acid base coordinate bonding between Cu(II) and chitosan amine groups resulting in cationic behavior that electrostatically favors As(V) chelation even when phosphate concentrations are orders of magnitude higher. The influence of copper and n-TiO2 loading on arsenic photo-oxidation and selective removal over phosphate was explored to optimize CuTICB design using batch experiments under varying systems conditions. For a system requiring both photo-oxidation and selective adsorption, it was found that copper and n-TiO2 act non-linearly and synergistically, where maximum loadings of both does not yield the optimal selectivity or removal efficacy. PMID- 29990802 TI - The plasticity of indigenous microbial community in a full-scale heavy oil produced water treatment plant. AB - Indigenous microbial communities are main and promising performers for bioremediation due to their excellent adaptability, degradation capability, and inherent plasticity. Treating heavy oil-produced water (HOPW) is a challenge owing to the high recalcitrance and heterogeneity of chemicals it contains. A full-scale HOPW treatment plant was built at a capacity of 10,000 m3/d with the indigenous microbial community. After the treatment, the outlet water reached the design standard. The microbial community structures in all treatment stages were analyzed by using Illumina MiSeq 16S rRNA gene sequencing. The composition of microbial community changed greatly with the changes in environmental conditions, especially with the only artificially regulated parameter of dissolved oxygen. In the anaerobic stage, the community converted the recalcitrant chemical oxygen demand to biological oxygen demand (BOD), and played a major role in enhancing the biodegradability of HOPW. During the aerobic stage, the community mainly mineralized BOD. These results suggest that the structures of indigenous microbial community differed in different treatment stages to accomplish the corresponding functions. Based on these findings, it is proposed that exploiting the plasticity of microbial communities for bioremediation is feasible, especially treating wastewater with varied components. PMID- 29990803 TI - Regulation of clay particles charge for design of protective electrokinetic barriers. AB - Coupled electrokinetic protective reactive barriers (PRB) are considered as a perspective technology for the treatment of contaminated groundwater. Design of PRB is directly connected with a problem of barrier material choice. Clays can be considered as an appropriate material due to high adsorptive properties and relative cheapness. The barrier internals are formed by clay surface charge properties. We revealed that acidic and alkaline treatment of clay is an effective way to affect its protective properties so that clay can be used to treat various pollutants. Surface charge and electrokinetic properties of clays were characterized by point of zero charge (p.z.c.), point of zero net proton charge (p.z.n.p.c.) and zeta-potential at different pH. Suspensions of 3 main clay types were studied by microelectrophoresis and potentiometric titration methods. At pH > p.z.n.p.c. clayey barrier adsorbs predominantly cationic toxicants and at pH < p.z.c. - anionic ones. The barrier is seemed to be the least effective in pH range between p.z.c. and p.z.n.p.c. Given the physicochemical and electrokinetic parameters, the most efficient clays for barrier design are Cambrian illite and all montmorillonite clays. PMID- 29990804 TI - Transient reactive transport model for physico-chemical transformation by electrochemical reactive barriers. AB - A comprehensive model that integrates coupled effects of chemical, physical, and electrochemical processes, is necessary for design, analysis, and implementation of the electro-remediation of groundwater under flow conditions. A coupled system of equations to solve for transport and multiple reactions in an electrochemical reactor is numerically intensive due to highly stiff nature of reaction model formulation. In this study, the focus is to develop an efficient model for reactions associated with the transport and physico-chemical transformation in an electrochemical reactor. The model incorporates effects of transport mechanisms as well as chemical and electrochemical reactions. Model verification is provided for pH profiles under different electrolyte compositions in two sets of reactors; a batch and a flow-through reactor. The model is able to predict the concentration of species during the electrochemical remediation process with a close correlation to experimental data (R2 = 0.99 for batch and R2 = 0.78 for flow-through reactor.) Imposing polarity reversal to the system will cause fluctuation of pH, however, the trend stays the same as if no polarity were applied. Ultimately, volumetric charge flow is introduced as a unique parameter characterizing the electroremediation reactor for operating purposes. PMID- 29990805 TI - Self-mediated pH changes in culture medium affecting biosorption and biomineralization of Cd2+ by Bacillus cereus Cd01. AB - Biomineralization is an interesting naturally occurring process of forming minerals by microorganisms, which offers an efficient way to sequester heavy metal ions within relatively stable solid phases. In this study, Bacillus cereus Cd01 was selected to investigate effects of self-mediated pH on biosorption and biomineralization of Cd2+ in whole 72h cultivation period. Results revealed that strain Cd01-mediated pH decrease of the cultivation medium from 7.0 to 6.1 inhibited biosorption of Cd2+ on Cd01 cells at the initial cultivation period, while an increased pH from 6.1 to 7.4 facilitated biosorption of Cd2+ on Cd01 cells at the middle and late cultivation period. The reasons were mainly that self-mediated pH altered cell surface hydrophobicity and cell membrane fluidity of strain Cd01. Moreover, biosorption and bioaccumulation of Cd2+ on Cd01 cells in the period of increased pH promoted biomineralization of Cd2+ observed by the transmission and scanning electron microscopes. The analyses of energy dispersive spectroscopy, X-ray photoelectron spectroscopy and select area electron diffraction demonstrated that Cd2+ loaded on Cd01 cells was biomineralized into polycrystalline and/ or amorphous cadmium sulfide and cadmium phosphate. These results suggest that strain Cd01 may play a potential role in biomineralization remediation of heavy metal contaminated soils. PMID- 29990806 TI - Electrochemical treatment of flutriafol wastewater using a novel 3D macroporous PbO2 filter: Operating parameters, mechanism and toxicity assessment. AB - In order to break the high operating cost bottleneck of electrochemical treatment of aqueous flutriafol (FTF), an emerging fungicide, a novel three-dimensional ordered macroporous PbO2 (3DOM-PbO2) filter was designed to facilitate mass transfer. The effects of operating parameters, including current density, flow rate and initial concentration on FTF electrooxidation performance were investigated using conventional flat Ti/PbO2 (F-Ti/PbO2) and 3DOM-PbO2 filters, with primary objective being the development of appropriate parameters for FTF treatment. The results indicated that the FTF removal efficiency on 3DOM-PbO2 filter was improved by 2.8 times compared to that on F-Ti/PbO2 at 5 mA cm-2, 10 ml s-1 and 100 mg L-1 FTF. The corresponding electrical energy consumption was reduced by 2.7 times, ' TOC removal and mineralization current efficiency were enhanced by 4.9 and 4.8 times, respectively. Furthermore, aromatic intermediates, nitrogenous compounds and carboxylic acids were identified as main byproducts using experimental method combined with quantum chemical calculations. Then, a possible pathway of FTF degradation on 3DOM-PbO2 was proposed. Finally, the acute toxicity results showed that toxicity of the byproducts first increases and then decreases through the proposed route. LC50,48 h value of FTF wastewater increased 35%-70% on the 3DOM-PbO2 filter, indicating a significant biodegradability enhancement. PMID- 29990807 TI - Catalytic removal of mercury from waste carbonaceous catalyst by microwave heating. AB - Waste carbonaceous catalyst (WCC) from vinyl chloride monomer (VCM) production is a potential environmental threat due to the mercury toxicity. Microwave heating (MWH) was used to decontaminate WCC. Treatment temperature had a stronger influence on mercury removal than that of treatment time while mercury removal was highly depended on treatment time at lower temperature. When WCC was treated at 350 degrees C for 60 min, 400 degrees C for 30 min and 450 degrees C or more for 10 min, leaching toxicity of mercury conformed to the US EPA standard. 99.98% of total mercury was removed and residual mercury concentration was only 4.5 mg kg-1 when treated at 500 degrees C for 30 min. Soluble and exchangeable Hg and Hg combined with labile organics were more easily to be removed than that of Hg bound to crystalline Fe/Al oxides, Hg combined with non-labile organics and HgS. The removal limit for different mercury species may be achieved at 500 degrees C. Evaporation removal of mercury followed exponential decay model. Activation energy for mercury removal was reduced due to the catalytic effect of MWH. Removal mechanisms of mercury included thermal evaporation, breakdown of molecular bonds, selective stripping of carbonaceous impurities. PMID- 29990808 TI - Preparation and characterization of nanosilica copper (II) complexes of amino acids. AB - The frequent use of traditional copper-based microbicides has led to the growing risk of toxicity to non-target organisms in the environment. In this work, nanosilica was conjugated with copper(II) complexes of L-glutamate (or glycine) to develop novel copper-based microbicides with good microbicidal activity, systemicity and desired safety to plant, and the obtained nanosilica-L-glutamate copper complexes (Silica-Glu-Cu) and nanosilica-glycine copper complexes (Silica Gly-Cu) were characterized and evaluated by FT-IR, SEM, TEM, and XPS. The results showed that Silica-Glu-Cu and Silica-Gly-Cu exhibited satisfactory activities and long effective periods against Phytophthora capsica and Botrytis cinereal and could move upward and downward freely in cucumber seedlings. Moreover, Silica-Glu Cu increased the fresh weights of cucumber and wheat seedlings by 0.4-6.4% at the concentrations of 50-200 mg/L of copper. Thus, the novel copper-based microbicides can reduce the frequency of using copper-based bactericides and phytotoxicity to plants. PMID- 29990809 TI - Unveiling the important roles of coexisting contaminants on photochemical transformations of pharmaceuticals: Fibrate drugs as a case study. AB - Pharmaceuticals are a group of ubiquitous emerging pollutants, many of which have been shown to undergo efficient photolysis in the environment. Photochemically produced reactive intermediates (PPRIs) sensitized by the pharmaceuticals in sunlit natural waters may induce photodegradation of coexisting compounds. In this study, the roles of coexisting contaminants on the phototransformation of pharmaceuticals were unveiled with the fibrate drugs gemfibrozil (GMF), fenofibrate (FNF), and fenofibric acid (FNFA) as model compounds. GMF undergoes initial concentration dependent photodegradation due to the involvement of singlet oxygen (1O2) initiated self-sensitized photolysis, and undergoes pH dependent photodegradation due to dissociation and hydroxyl radical (OH) generation. The decarboxylated intermediates of GMF and coexisting FNFA significantly accelerated the photodegradation of GMF. The promotional effects of the decarboxylated intermediates are attributed to generation of PPRIs, e.g. 1O2, superoxide (O2-), that subsequently react with GMF. Besides, FNFA can also promote the photodegradation of GMF through the electron transfer reaction from ground state GMF to excited state FNFA, leading to the formation of decarboxylated intermediates. The formed intermediates can subsequently also facilitate GMF photodegradation. The results presented here provided valuable novel insights into the effects of coexisting contaminants on the photodegradation of pharmaceuticals in polluted waters. PMID- 29990810 TI - Studies on mass production and highly solar light photocatalytic properties of gray hydrogenated-TiO2 sphere photocatalysts. AB - In this paper, it is first reported that gray hydrogenated TiO2 sphere photocatalysts (H-TiO2) with high reactivity to solar light are mass produced within a few minutes using an underwater discharge plasma modified sol-gel method at room temperature and atmospheric pressure. This plasma modified system is an easy one-step in-situ synthetic process and the crystallinity, hydrogenation, and spherical structure of H-TiO2 are achieved by the synergy effect between the continuous reaction of highly energetic atomic and molecular species generated from the underwater plasma and surface tension of water. The resultant H-TiO2 demonstrated high anatase/rutile bicrystallinity and extended optical absorption spectrum from the ultraviolet (UV) to visible range. Furthermore, various defects including oxygen vacancies and hydroxyl species on the TiO2 surface permitted the enhancement of the photocatalytic performance. It was demonstrated that H-TiO2 photocatalysts showed significant degradation efficiencies for reactive black 5 (RB 5), rhodamine B (Rho B), and phenol (Ph) under solar light irradiation, up to approximately 5 times higher than that of commercial anatase TiO2 (C-TiO2), which resulted in good water purification. Notably, it was also possible to cultivate HepG2 cells using such well-purified water (to degrees up to 76%), with minimal cytotoxicity. Considering all these results, we believe that this novel plasma technology is promising for important environmental applications. PMID- 29990811 TI - New shape-selectivity discovered on graphene-based materials in catching tobacco specific nitrosamines. AB - New shape-selectivity of graphene-based materials was discovered on this article. To explore the new selectivity, the structure and surface state of graphene and carbon nanotube were examined firstly, and their specific selectivity was verified and was compared with that of ZSM-5 zeolite in aqueous solutions of tobacco specific nitrosamines (TSNA) along with dyes. These two adsorbents trapped about 55% and 70% of 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK) but only 3% of N'-nitrosonornicotine (NNN) in solution, having an obvious selectivity for the former, due to its stronger interaction with graphene. NNK on graphene sheet obtained more electrons (0.015 e) and owned larger adsorption energy (15.63 kcal mol-1) than that of NNN (0.003 e, 9.19 kcal mol-1), according to theoretical calculation and FTIR results. More 95 or 136 mg g -1 acid red 88 than methyl orange was captured by graphene or carbon nanotube, demonstrating this special and abnormal selectivity again. With new selectivity, graphene showed a higher capacity (6.9%) and shorter adorption equilibrium time (5 min) for TSNA than the typical selecive sorbent ZSM-5 zeolite (1.7% and 20 min) in tobacco solution but kept the similar selctivity to NNK, paving a new way to control the carcinogens like TSNA in environment. PMID- 29990812 TI - Polyvinyl acetate processing wastewater treatment using combined Fenton's reagent and fungal consortium: Application of central composite design for conditions optimization. AB - The Fenton reaction as an oxidative degradation process was used for industrial chemical wastewater (ICW) pretreatment. The biodegradation of pretreated ICW was performed, in aqueous environment under aerobic condition, by a defined fungal consortium. The central composite design (CCD) was used to study the effect of nitrogen and phosphorus addition and the concentration of the pollution on the removal of polyvinyl alcohol (PVA) and organic compounds. The interaction between parameters was modeled using the response surface methodology (RSM). Results of optimization showed COD, PVA and color removal yields of 97.8%, 98.5% and 99.75%, respectively with a supplementof 1.4 gL-1 of (NH4)2SO4, 1.2 gL-1 of KH2PO4 and 75% of concentrated ICW. Enzymatic analysis proved that laccase and lignin peroxidase were involved in the biodegradation with 45 UIL-1 and 450 UIL-1, respectively. Furthermore, the analysis of metabolic products using Fourier transforms infrared spectroscopy (FTIR) and nuclear magnetic resonance (1HNMR) showed clearly the mineralization of organic compounds and the formation of formic acid and ethanol. Therefore, the effective treatment of ICW was achieved by developing an integrated chemical and biological process which met the requirement for a safety effluent respectful for environment without risks for public health. PMID- 29990813 TI - Subchronic reproductive effects of 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFAES), an alternative to PFOS, on adult male mice. AB - With a similar structure to perfluorooctane sulfonate (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFAES) has been widely used as a mist suppressant in the chromium plating industry in China since the 1970s. After being disregarded for the past 30 years, 6:2 Cl-PFAES has now been detected in environmental matrices and human sera, suggesting potential health concerns. We carried out a subchronic exposure study to investigate the reproductive toxicity of 6:2 Cl-PFAES exposure (0, 0.04, 0.2, and 1.0 mg/kg/d body weight, 56 d) in adult male BALB/c mice. Results showed that relative epididymis and testis weights decreased in the 1.0 mg/kg/d group compared with the control. However, no changes were observed in the serum levels of testosterone, estradiol, follicle stimulating hormone (FSH), or luteinizing hormone (LH), nor in the histopathological structure of the epididymis and testis and sperm count. In addition, 56 d of consecutive gavage of 1.0 mg/kg/d of 6:2 Cl-PFAES did not affect male mouse fertility. RNA sequencing showed that no genes were significantly altered in the testes after 6:2 Cl-PFAES exposure. Several testicular genes, which are sensitive to PFOS exposure, were also detected using Western blotting, and included steroidogenic proteins, STAR, CYP11A1, CYP17A1, and 3beta-HSD and cell junction proteins, occludin, beta-catenin, and connexin 43; however, none were changed after 6:2 Cl-PFAES exposure. Except for a decrease in the relative epididymis and testis weights in the 1.0 mg/kg/d group, 6:2 Cl PFAES exposure for 56 d exerted no significant effect on the serum levels of reproductive hormones or the testicular mRNA profilesin adult male mice, implying a relative weak reproductive injury potential compared with that of PFOS. PMID- 29990814 TI - EDDS enhanced PCB degradation and heavy metals stabilization in co-contaminated soils by ZVI under aerobic condition. AB - In the present study, biodegradable ligand EDDS was employed to assist ZVI on simultaneous remediation of PCB and heavy metals co-contaminated soils under aerobic condition. With addition of 4 mmol L-1 EDDS and 5 g L-1 ZVI, the total removal ratio of PCB reached 75.3%, and the stabilization ratio of Pb and Cu attained 97.1% and 91.9% respectively. EDDS played two key roles during the process. Firstly, the addition of EDDS could enhance hydroxyl radical generation by ZVI and oxygen for the oxidation of PCB including distribution in the soil phase and dissolved form in the aqueous phase. Secondly, free EDDS could accelerate the release of Cu and Pb from the soil phase to the aqueous phase. As the oxidation of EDDS and the increase of pH value during the process, the dissolved Cu and Pb could be efficiently stabilized by iron oxyhydroxide through coprecipitation. Compared with ZVI/Air, ZVI/EDDS/Air treatment could significantly enhance the stabilization of Pb and Cu. The reason was the dissolution of Cu and Pb by EDDS extraction could reduce the mass transfer limitations between heavy metals and iron oxyhydroxide. Therefore, our study suggests a promising alternative for remediation of organic compounds and heavy metals co-contaminated soil. PMID- 29990815 TI - Graphene-synergized 2D covalent organic framework for adsorption: A mutual promotion strategy to achieve stabilization and functionalization simultaneously. AB - Most of current absorbents are difficult to hold favorable stability and functionality simultaneously when used in condition of high acidity and strong radiation existing in nuclear industry. Herein, a new graphene-synergized 2D covalent organic framework (GS-COF) was obtained via an in-situ loading of a covalent organic framework (TDCOF) on graphene sheets based on a mutual promotion strategy proposed in this work. The corresponding oximation products, o-GS-COF, and also o-TDCOF as a reference object, were respectively prepared subsequently. The results of experiments confirmed that o-GS-COF possesses better acid and irradiation stability than that of o-TDCOF. Adsorption experiments showed that the adsorption capacity of o-GS-COF for uranium is 144.2 mg g-1, higher than that of GO (92.5 mg g-1) and o-TDCOF (105.0 mg g-1), and the maximum adsorption capacity reaches 220.1 mg g-1. In the multi-ions system, o-GS-COF also displayed good selective adsorption property for uranium with SFU/M 35-100 for 5 coexisting divalent metal ions and 14-18 for 5 coexisting trivalent lanthanide ions. The proposed strategy successfully achieved the synergistic improvement of both stability and functionality for the desired adsorbing materials and is of considerable practical utility in the field of design and preparation of reliable high-performance absorbents. PMID- 29990816 TI - Ecotoxicological effects prior to and after the ozonation of tamoxifen. AB - The endocrine disrupting micropollutant tamoxifen can induce several effects on aquatic organisms. It is introduced into the environment mainly by wastewater treatment plant effluents. To reduce the discharge of micropollutants into surface waters, ozonation can be used as additional wastewater treatment option. For only few transformation products (TPs) formed by ozonation ecotoxicological data are available. To enable an initial estimation of ecotoxicological potentials of the TPs formed after the ozonation of tamoxifen, acute toxicity (immobilization) to Daphnia magna and green algae growth inhibition using Desmodesmus subspicatus were determined for several ozone doses spiked at pH 3 and pH 7. The initial immobilization of D. magna by tamoxifen was not further observed after ozonation. In contrast, the green algae growth inhibition increased due to ozonation of tamoxifen. Overall, five transformation products were observed. For three TPs, positive correlations of green algae growth inhibition and peak area were determined, whereas two TPs do not induce the residual effects. Based on our observations, TP 270 can be assumed as most potent of the formed TPs concerning green algae growth inhibition. Since the effect is not induced by formed N-oxides, green algae growth inhibition could be reduced by sufficient ozone exposure during wastewater treatment. PMID- 29990817 TI - Electrocatalytic dechlorination of halogenated antibiotics via synergistic effect of chlorine-cobalt bond and atomic H. AB - Although noble metal electrocatalysts are highly efficient in the dehalogenation of halogenated antibiotics, the prohibitive cost hinders their practical applications. In this study, a cobalt-phosphorous/oxide (CoP/O) composite prepared via a one-step electrodeposition was for the first time applied in electroreductive dechlorination of halogenated antibiotics (HA), including chloramphenicol (CAP), florfenicol (FLO) and thiamphenicol (TAP). CoP/O had a higher FLO dechlorination efficiency (91%) than Pd/C (69.3%) (t = 60 min, C0 = 20 mg L-1, applied voltage of -1.2 V vs. saturated calomel electrode (SCE)). Furthermore, the dechlorination efficiencies of CoP/O for CAP and TAP reached to 98.7 and 74.2%, respectively. The electron spin resonance and in situ Raman characterizations confirmed that atomic H* was produced via the CoP and the formation of CoCl bonds occurred on the CoO in CoP/O. The CoCl bond formation could trap HA molecules onto CoP/O and weaken the CCl bond strength. The synergistic effect of H* attack and CoCl bond was responsible for the high dechlorination efficiency. This study offers new insights into the interface mechanism of electroreductive dehalogenation process, and shows a great potential for the remediation of halogenated antibiotics contaminated wastewater. PMID- 29990818 TI - Analysis of air photocatalytic purification using a total hazard index: Effect of the composite TiO2/zeolite photocatalyst. AB - The TiO2 and composite TiO2/zeolite catalysts were investigated in the photocatalytic oxidation of model volatile organic compounds. The photocatalytic experiments were performed in a batch reactor using an FTIR in situ method for the detailed analysis of the reaction components in the gas phase. The kinetic data for the TiO2 and composite TiO2/zeolite photocatalysts were compared. A focus on the analysis of the total hazard of gas mixture during the process by using the total hazard index, which includes the contribution of all the gas phase components, was made. The effect of composite TiO2/zeolite photocatalyst on the total hazard during the photocatalytic oxidation of different VOCs is studied and discussed. The composite TiO2/zeolite photocatalyst allows for suppressing the secondary pollution with harmful intermediates formed during the process that increases the efficiency of air purification compared to TiO2 alone. PMID- 29990819 TI - Insights on sulfamethoxazole bio-transformation by environmental Proteobacteria isolates. AB - Although sulfonamide residues are frequently reported as freshwaters contaminants, information on the ability of native bacteria to modify these synthetic antibiotics is scarce. Our purpose was to investigate the potential of bacteria from different aquatic environments to cleave or transform sulfamethoxazole (SMX) and infer on their ability to reduce the toxicity of this antibiotic. From a collection of about 100 Proteobacteria, 47 strains previously isolated from drinking water, surface water, and wastewater grew in the presence of 200 MUMSMX, and were further studied. Out of these, 14 strains, mostly from mineral drinking water, transformed SMX into equimolar amounts of the lesser toxic derivative N4-acetyl-sulfamethoxazole. The highest percentage of SMX transformation was recorded for two strains affiliated to Pseudomonas mandelii. For P. mandelii McBPA4 higher SMX transformation rate and extent were observed in fed-batch (~8 MUMSMX/h, 81%) than in batch conditions (~5 MUMSMX/h, 25%), but similar specific transformation rates were found in both cultivation modes (~20 MUmolSMX/gcell dry weight/h), indicating the dependence of the process on the microbial load. These results evidence that the capacity to transform synthetic antibiotics may be common among bacteria and highlight the potential of environmental bacteria in attenuating the potential adverse effects of pollution with sulfonamides. PMID- 29990820 TI - Fe(III)-oxalate complex mediated phosphate released from diazinon photodegradation: Pathway signatures based on oxygen isotopes. AB - The photodegradation of organophosphorus pesticides has an important influence on their fate and bioavailability in the water environment. In this study, the kinetics and mechanisms of diazinon photodegradation by Fe(III)-oxalate complex have been determined. Special attention was given to the pathway by which phosphate is released following diazinon photodegradation, as assessed by HPLC ESI-Q/TOF-MS coupled with oxygen isotope. The results showed that diazinon was stable under dark treatment. However, the degradation of diazinon was observed in the UV-only, UV-Fe(III), and UV-Fe(III)-oxalate treatments. The degradation rate constant is the largest in the UV-Fe(III)-oxalate treatment and clearly influenced by the pH and Fe(III) / oxalate ratio. The hydroxyl radical (OH) was the main reactive oxygen species (ROS) in the UV-Fe(III)-oxalate complex treatment and the steady-state concentration of OH was 5.75 * 10-14 M. The products analysis revealed that phosphate could be released during the photodegradation of diazinon; the intermediate products were diazonon, 2 hydroxydiazonon, hydroxydiazonon, hydrogen phosphorothioate, O,O-diethyl thiophosphate (DETP), diethyl phosphate (DEP) and pyrimidinol (IMP). Compound stable oxygen isotope analysis coupled to Q-TOF/MS revealed that the degradation of diazinon initiated by the P-O bond cleavage. PMID- 29990821 TI - Contributions of the microbial community and environmental variables to antibiotic resistance genes during co-composting with swine manure and cotton stalks. AB - Understanding the main drivers that affect the spread of antibiotic resistance genes (ARGs) during the composting process is important for the removal of ARGs. In this study, three levels of tylosin (25, 50, and 75 mg kg-1 on a dry weight basis) were added to swine manure plus a control, which was composted with cotton stalks. Each treatment was repeated in triplicate and the ARG profiles were determined with different levels of tylosin. The top 35 genera and ARGs profiles were clustered together based on the composting time. Combined composting parameters (temperature, pH, NH4+-N, NO3-N, and moisture content) accounted for 78.4% of the total variation in the changes in the potential host bacteria. In addition, the selected five composting parameters and six phyla (including 25 potential host bacterial genera) explained 46.9% and 30.7% of the variation in the ARG profiles according to redundancy analysis, respectively. The variations in ARGs during the composting process were mainly affected by the dynamics of potential host bacteria rather than integrons and the selective pressure due to bio-Cu and bio-Zn. PMID- 29990822 TI - Biomimetic strategies to design metallic proteins for detoxification of hazardous heavy metal. AB - Discharge of hazardous heavy metals in to the environment poses a serious threat to the ecosystem owing to its non-degradability and indestructability. Physical and chemical techniques for the removal of heavy metals from industrial effluent is expensive and causes secondary pollution. On the other hand, biological processes using microorganisms play a vital role due to their large surface area to volume ratio, which increases the interactions with metal ions present in the environment. Here, we developed a third generation biological tool for the removal of heavy metal (copper) from the effluent through the biosynthesis of intracellular and surface displayed metallic proteins with novel metal co ordination chemistry. We evaluated the cell viability for maximum heavy metal adsorption and metal tolerance of synthesized congener metallic proteins. Finally, to eliminate the cost associated with incorporation of metal binding aminoacid, we have introduced a genetic circuit in order to evolve a novel magnetotactic bacterium. The bioreactor studies of the consortia of metallic protein expressing cells immobilized on functionalized granular activated carbon revealed that 97% of copper was adsorbed from the industrial effluent. It is evident that the use of congener metallic proteins will be a futuristic approach for the treatment of wastewater facilitating environmental detoxification. PMID- 29990823 TI - The information gain from peak height data in DNA mixtures. AB - We present the results of a comparison of likelihood ratios obtained from DNA mixture data, obtained either by a peak height model (EuroForMix) and by a discrete model, using probabilities of dropout and integrating over them (MixKin). We use the mixture data that have been published in [1] and were made publicly available. We show that, for mixtures for which replicate analyses were available in this set, there is almost no difference in weight of evidence, suggesting that the additional information in the peak heights is limited. On the other hand, for mixtures for which only a single replicate is available, the weight of evidence for true donors can be substantially higher with the peak height model, especially so for major donors and also for minor donors provided they are the only minor contributor to the mixture. False positive rates were very low with both methods, but for related non-contributors the risk of a false positive is much higher with the discrete method unless kinship is taken into account in the likelihood ratio calculation. PMID- 29990824 TI - In-field collection and preservation of decomposing human tissues to facilitate rapid purification and STR typing. AB - Short tandem repeats (STR) are currently the gold standard in human identification for forensic casework purposes, and successful STR typing is dependent on sufficient quantity and quality DNA. In the aftermath of a mass disaster and some forensic cases, human remains are recovered for identification in various stages of decomposition, and ideally these remains are transported to a refrigerated facility in order to halt the decomposition process and preserve the integrity of DNA within the tissue. However, in situations where refrigeration is not available (e.g., after a mass disaster or in rural forensic casework), remains continue to be exposed to environmental insults after collection, causing further DNA damage and degradation. Therefore, successful STR typing is dependent on the time of collection and preservation of the DNA sample. This study aims to test two simple in-field collection and preservation methods for decomposing human tissues that are subsequently stored at room temperature for up to six months either in a tissue preservative solution (modified TENT buffer) or on an FTA(r) Elute Card. In addition, these collection and preservation methods were tested for their ability to facilitate more direct and faster processing of DNA from preserved tissues or DNA leached into the surrounding TENT preservative solution for STR typing. Pre-PCR methods tested in this study include a quick lysis of FTA(r) Elute Cards, silica-based purification (QIAquick(r)), enzyme-based extractions (PDQeX), and simple dilution of liquid preservative. The traditional DNA analysis pipeline, which includes DNA extraction and quantification, will be compared to an alternate direct PCR method, thereby allowing the elimination of these two time-consuming and costly steps. The results indicate that modified TENT preservative and FTA(r) Elute Cards both preserved DNA from relatively fresh tissue for up to six months at room temperature. However, mostly partial profiles were produced from decomposed tissues (day 6 - day 14 in this study) when stored for up to six months compared to when tissues were processed immediately following collection. Overall, the modified TENT preservative produced higher DNA concentrations and more successful STR results than FTA(r) Elute Cards. In addition, a rapid DNA extraction platform (PDQeX) generated the most successful STR typing results from the decomposed tissues stored in TENT for up to six months at room temperature. The direct PCR method used in this study generated comparable STR results to the traditional DNA analysis approach, warranting further investigation of direct PCR methods for forensic casework type samples. PMID- 29990825 TI - Old meets new: Comparative examination of conventional and innovative RNA-based methods for body fluid identification of laundered seminal fluid stains after modular extraction of DNA and RNA. AB - The knowledge about the type of the body fluid/tissue that contributed to a trace can provide contextual insight into crime scene reconstruction and connect a suspect or a victim to a crime scene. Especially in sexual assault cases, it is important to verify the presence of spermatozoa. Victims often tend to clean their underwear/bedding after a sexual assault. If they later decide to report the crime to the police, in our experience, investigators usually do not send laundered items for DNA examination, since they believe that analysis after washing is no longer promising. As not only the individualization of traces on laundered items could be important in court, but also the type of biological material, we compared the potential of modular DNA and RNA extraction from the same specimen for simultaneous body fluid identification (BFI) and STR profiling of laundered items. BFI included the comparison of a broad range of conventional approaches, as wells as new molecular mRNA- and miRNA-based methods. The examination comprises the assessment of different fabrics and washing temperatures and multiple washing steps. Our results indicate that although conventional enzymatic and immunochromatographical approaches show limitations for BFI of laundered stains, the RSID test was sensitive enough to detect seminal fluid in 80% of all tested samples. Furthermore, the HY-Liter fluorescence analysis successfully detected spermatozoa, even in cloths that were washed twice. For the first time, it could be shown that a marker set of mRNAs can be applied for the identification of seminal fluid stained cotton and synthetic fiber fabrics that have been washed at 40 degrees C. Our experiments demonstrate that analysis of DNA and RNA of laundered items is feasible, giving the possibility to identify the perpetrator as well as the biological properties of the same laundered (seminal) stain under certain conditions. PMID- 29990826 TI - Evaluating DNA evidence in a genetically complex population. AB - In forensic genetics, the likelihood ratio (LR), measuring the value of DNA profile evidence, is computed from a database of allele frequencies. Here, we address the choice of database and adjustments for population structure and sample size in the context of Brazil. The Brazilian population underwent a complex process of colonization, migration and mating, which created an admixed genetic composition that makes it difficult to obtain an appropriate database for a given case. National databases are now available, as well as databases for many Brazilian states. However, those databases are not statistically random samples, and state boundaries may not accurately reflect the sub-structuring of genetic diversity. We compared the LR calculated using the relevant state-specific database with the statistics calculated when a national database and when international databases were used. We evaluated two methods of adjustment for population structure, due to Wright [13] and Balding and Nichols [14]. We also considered two adjustments for database sample size: the Balding size bias correction [15] and a minimum allele frequency [16]. Our results show that the use of a national database with the Balding and Nichols adjustment and theta = 0.002 generated lower LR values than did the state-specific database in more than 50% of the profiles simulated using the state-based allele frequencies, while theta = 0.01 produced lower LRs for more than 90% of the profiles. We conclude that the utilization of a national database for Brazilian cases can be justified in association with the appropriate adjustment for population structure. PMID- 29990827 TI - What women want? Results from a prospective multicenter study on women's preference about pain management during labour. AB - OBJECTIVE: The aim of this study was to assess women preference about pain and duration of labour applying a standardized questionnaire. STUDY DESIGN: A prospective multicentre large cohort study was carried out in two different University Hospitals. A standardized questionnaire was proposed before active labour and the day after delivery in order to investigate whether women preferred low pain intensity for a longer labour duration or greater pain intensity for a shorter labour duration. The studied population was divided and analysed in two groups according to Epidural Analgesia (EA) administration. A multivariable linear regression analysis was performed to assess which variables were able to influence the opinion about the pain perception after birth. RESULTS: EA group showed an increased risk of episiotomy (p = 0.004), of longer duration of labour (Stage I, p < 0.001; Stage II, p = 0.002) and of oxytocin augmentation (P = 0.030). No statistical differences were found about the route of delivery between the two groups. Rates of pre-labour scores significantly differed from rates of post labour scores (p < 0.001). In the multivariable linear regression analysis, pre-labour score was directly related to post-labour score (p = 0.013). The EA was indirectly related to higher pain levels for a longer duration preference (p = 0.001), whereas oxytocic infusion in labour was directly related with preference for higher pain for a shorter duration (p = 0.011). CONCLUSIONS: Patients' preferences about labour are focused on both pain relief and labour duration. The standardized questionnaire could be a useful tool to screen patients eligible for EA. PMID- 29990829 TI - Astragaloside IV reduces the hypoxia-induced injury in PC-12 cells by inhibiting expression of miR-124. AB - BACKGROUND: Astragalus membranaceus has been clinically used in cerebral ischemia treatment in China and its main component, Astragaloside IV (Ast IV) shows anti hypoxia activity, but the underlying mechanism has not been clearly clarified. This study was aimed to investigate the effects of Ast IV on hypoxia-induced injury in PC-12 cells as well as the underlying mechanism. METHODS: Relative miR 124 expression was detected by qRT-PCR. Hic-5 expression was analyzed by qRT-PCR and Western blot. To alter miR-124 and Hic-5 expressions, cells were respectively transfected with miR-124 mimic and pEX-Hic-5. Cell proliferation and apoptosis were measured by BrdU assay and Annexin V-fluorescein isothiocynate (FITC)/propidium iodide (PI) double staining method, respectively. Besides, apoptotic proteins and cell proliferation-associated factors were analyzed by Western blot. RESULTS: Ast IV alleviated hypoxia-induced injury in PC-12 cells by decreasing apoptosis (P < 0.01). Ast IV inhibited up-regulation of miR-124 induced by hypoxia (P < 0.01). miR-124 mimic impaired the anti-apoptotic effect of Ast IV on PC-12 cells (P < 0.01). Hic-5 expression was significantly down regulated in miR-124 overexpressed cells (P < 0.001) and Hic-5 overexpression activated Sp1/Survivin signaling pathway (P < 0.001). CONCLUSION: Ast IV could ameliorate hypoxia-induced injury in PC-12 cells by decreasing miR-124 expression and then up-regulating Hic-5 expression. PMID- 29990828 TI - Cell type-dependent effects of ellagic acid on cellular metabolism. AB - Ellagic acid is a botanical polyphenol which has been shown to have numerous effects on cellular function. Ellagic acid can induce apoptosis and inhibit the proliferation of various cancer cell types in vitro and in vivo. As such, ellagic acid has attracted significant interest as a potential chemotherapeutic compound. One mechanism by which ellagic acid has been proposed to affect cellular physiology is by regulating metabolic pathways. Here we show the dose-dependent effects of ellagic acid on cellular energy production and downstream induction of the apoptotic program in HEK293, HeLa, MCF7, and HepG2 cells. At physiologically relevant doses, ellagic acid has pleiotropic and cell-type specific effects on mitochondrial function. At high doses ellagic acid can also influence glycolytic pathways and induce cell death. Our results demonstrate that ellagic acid can influence mitochondrial function at therapeutically relevant concentrations. The observed effects of ellagic acid on cellular respiration are complex and cell type-specific, which may limit the chemotherapeutic utility of this compound. PMID- 29990831 TI - Research on the pharmacodynamics and mechanism of Fraxini Cortex on hyperuricemia based on the regulation of URAT1 and GLUT9. AB - Fraxini Cortex (also known as Qinpi, QP) has been used for the treatment of hyperuricemia with a significant difference on efficacy of QP from different regions. However, it's still unknown whether proportion of components is the key and why same kind of herbs have different therapeutic effects. In this study, different sources of QP were collected from Shaanxi Qinpi extracts (SQPE), Henan Qinpi extracts (HQPE), Hebei Qinpi extracts (GQPE) provinces in China. Rat model of hyperuricemia with hypoxanthine combined with potassium oxonate were established to determine the levels of blood urea nitrogen (BUN), serum uric acid (SUA), urine uric acid (UUA) and creatinine (Cr). Hematoxylin-eosin staining (H&E) and Periodic Acid-Schiff staining (PAS) were performed for renal pathology while Western blot analysis and real-time PCR analysis for proteins and mRNA expression levels. High-performance liquid chromatograph (HPLC) was used for components and composition analysis. Our results demonstrated that QPE from different regions could alleviate hyperuricemia via increasing significantly the SCr and BUN levels whereas decreasing markedly UCr, SUA and UUA levels. Additionally, QPE could also improve the pathological changes of the kidneys. The protein and mRNA levels of urate reabsorption transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were down-regulated by QPE treatment. SQPE hold a better activity on improving hyperuricemia and regulating URAT1 and GLUT9. HPLC analysis showed that the proportion of four components aesculin, aesculetin, fraxin, fraxetin were 9.002: 0.350: 8.980: 0.154 (SQPE); 0.526: 0.164: 7.938: 0.102 (HQPE); 12.022: 1.65: 0.878: 1.064 (GQPE). These data indicate that this proportion of effective components may be an important factor for efficacy of QP and had implications for the treatment of hyperuricemia. PMID- 29990830 TI - Flavonoid-rich Scabiosa comosa inflorescence extract attenuates CCl4-induced hepatic fibrosis by modulating TGF-beta-induced Smad3 phosphorylation. AB - Scabiosa comosa inflorescence is a traditional Mongolian medicine in the treatment of liver diseases. In the study, we investigated the anti-fibrotic efficacy of flavonoid-rich Scabiosa comosa inflorescence extract (TF-SC) in a rat model of CCl4-induced hepatic fibrosis and explored its underlying mechanism in vitro and in vivo. Rats (Wistar, Male, weight 200-250 g) were injected intraperitoneally with CCl4 (1:1v/v in peanut oil, 2 mL/kg body weight) to induce liver fibrosis, followed by treatment with TF-SC or vehicle. In addition, transforming growth factor-beta1 (TGF-beta1)-activated hepatic stellate cells (HSCs) were used for measuring Smad3 phosphorylation. We found decrease in liver function and liver fibrosis markers in serums. Also, TF-SC decreased hydroxyproline content and collagen deposition in liver tissues. TF-SC also decreased the expression of alpha-SMA, collagen I and fibronectin in CCl4-induced hepatic fibrosis rats. Mechanistically, TF-SC attenuated liver fibrosis by selectively inhibiting Smad3 phosphorylation. In TGF-beta1-stimulated HSCs, TF-SC blocked the interaction between Smad3 and TGF-beta type I receptor (TbetaRI), suppressed subsequent phosphorylation and nuclear translocation of Smad3, and down-regulated the transcription of fibrotic genes. In conclusion, the study demonstrated that TF-SC was an effective therapeutic agent for treatment of hepatic fibrosis, and provided a molecular basis through which TF-SC exerts its anti-fibrotic effects. PMID- 29990833 TI - An ellagic acid isolated from Clerodendrum viscosum leaves ameliorates iron overload induced hepatotoxicity in Swiss albino mice through inhibition of oxidative stress and the apoptotic pathway. AB - Iron is a vital element required for normal cellular physiology in animal systems, but excess iron accumulation in the biological system accelerates oxidative stress, cellular toxicity, tissue injury and organ fibrosis, which ultimately leads to the generation of chronic liver diseases including cancer. A natural antioxidant, ellagic acid (EA) has been previously reported for its pharmacological properties; however, there is no significant evidence available that could illustrate its protective potential against iron-overload induced hepatotoxicity. In the present work, EA was evaluated for its in vitro free radical scavenging and iron chelation potentials. Further, EA was tested in vivo for its protective activity against iron overload-induced hepatotoxicity in Swiss albino mice by evaluating liver iron content, reactive oxygen species (ROS), liver antioxidant enzymes, serum marker levels, liver damage and fibrosis, histopathological study and finally western blotting analysis. EA treatment significantly decreased liver iron and serum ferritin levels. Elevated ROS levels, decreased antioxidant parameters and elevated serum markers were normalized upon treatment with EA. Cellular morphology, iron -overload and liver fibrosis were found to be effectively ameliorated. Finally, the protective effect of EA against iron overload-induced apoptosis was confirmed by western blotting when its treatment upregulated the expressions of caspase-3 and poly(ADP-ribose) polymerase (PARP) proteins. EA revealed hepatoprotective activity against iron overload-induced toxicity through scavenging free radicals, inhibiting excess ROS production, normalizing liver damage parameters and upregulating caspase-3, PARP expression. Collectively, our findings support the possible use of the natural antioxidant EA as a promising candidate against iron-overloaded diseases. PMID- 29990832 TI - Morin attenuates doxorubicin-induced heart and brain damage by reducing oxidative stress, inflammation and apoptosis. AB - Doxorubicin (DOX) is an effective antineoplastic agent of the anthracycline group. However, as with most anticancer drugs, they cause some toxic effects, including major cardiotoxicity and cognitive impairment. In this study, protective effects of morin against DOX-induced cardiotoxicity and neurotoxicity in rats were investigated. Morin was orally administered to rats at a dose of 50 and 100 mg/kg body weight for 10 days. DOX was administered 40 mg/kg body weight by single dose intraperitoneal injection on the 8th day of the study. Both the levels of glutathione (GSH) and malondialdehyde (MDA) were assessed and enzyme activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were assessed to determine the protective effect of morin against oxidative stress. To determine the anti-inflammatory effect, the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), nuclear factor kappa B (NF-kappaB) were assessed in the heart and brain tissues. Lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB (CKMB) activities, which are cardiac function markers, and cardiac troponin-I (cTn-I) levels were also determined. Anti-apoptotic effect was determined by anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) and pro-apoptotic protein cysteine aspartate specific protease 3 (caspase-3) changes. The regulatory role of morin in signal transduction in the brain tissue was assigned with the determination of amount of acetylcholinesterase (AChE), and its healing effect on the central nervous system was determined with imuinohistochemical detection of glial fibrillar acidic protein (GFAP) level. Histopathological evaluation of heart and brain tissues was performed in all groups. PMID- 29990834 TI - Dexmedetomidine protects high-glucose induced apoptosis in human retinal pigment epithelial cells through inhibition on p75(NTR). AB - BACKGROUND: In both human patients and animals, diabetic condition of high blood glucose induced significant apoptotic responses in retinal pigment epithelial (RPE) cells. In this work, we used an in vitro culture model of human ARPE-19 cells to evaluate whether dexmedetomidine (DEX) may protect high d-glucose (DG) induced diabetic apoptosis. METHODS: ARPE-19 cells were incubated with DG in vitro to induce apoptosis. Cells were also pre-incubated with different concentrations of DEX prior to DG treatment. The apoptotic injury by DG, and possible protection by DEX were evaluated using a TUNEL assay. Western blot assay was used to evaluate DEX-associated signaling pathway proteins, including Casp-3, precursor of the nerve growth factor (proNGF) and p75 neurotrophin receptor (p75(NTR)). Moreover, p75(NTR) was overexpressed in ARPE-19 cells, to assess its mechanistic role in DEX-mediated protection on DG-induced apoptosis. RESULTS: In ARPE-19 culture, DG induced significant apoptosis, which was protected by pre incubation of DEX, in a concentration-dependent manner. DG-induce apoptosis was associated with protein upregulation of Casp-3, proNGF and p75(NTR). Among them, Casp-3 and p75(NTR) were inversely reduced by DEX pre-incubation, but not proNGF. In ARPE-19 cells, p75(NTR) overexpression was shown to reverse the protective effect of DEX on DG-induced apoptosis. CONCLUSION: DEX was proven to have protective effect on DG-induced RPE apoptosis, possible through inhibition on p75(NTR) and its associated signaling pathways. PMID- 29990835 TI - Expression kinetics reveal the self-adaptive role of beta cells during the progression of diabetes. AB - OBJECTIVE: To determine the histopathological and molecular changes in beta-cells at different time intervals following streptozotocin (STZ)-induced diabetes. METHODS: STZ (65 mg/kg body weight) was given to overnight fasted rats that were sacrificed after 1, 3, and 10 days of injection. Changes in islet morphology and in the expression of various factors involved in beta-cell proliferation, inflammation and apoptosis were analyzed. RESULTS: Superoxide dismutase (Sod) expression was completely reduced and that of NF-kB and iNOS were significantly increased, along with lymphocytic infiltration in the islets within 24 h of STZ injection. In addition, the beta-cell protective markers Bcl-2, IL-6, Ki67, Hif 1alpha, VEGF and insulin were also enhanced, indicating a compensatory response of the beta-cells to the initial damaging effects. Lymphocytic infiltration decreased after 3 days of injection, accompanied by enhanced expression of both GLP-1R and GIP R. The unresponsiveness of the incretin ligands after STZ administration further suggested a compensatory approach by the incretin receptors independent of glucose regulation. After 10 days, lymphocytic infiltration and inflammatory markers again increased, along with a concomitant reduction in the expression of incretin receptors, and upregulation of the protective markers. Furthermore, the saturation peak of blood glucose indicated progressive diabetes. CONCLUSIONS: The beta-cells follow a biphasic pattern of expression of certain factors in order to achieve a balance between apoptosis, autophagy, neo-genesis, hypoxia and proliferation, and achieve homeostatic protection before the onset of diabetes. The drug interventions at an early stage, which are specific to these pathways, could be beneficial in preventing the progression of diabetes pathogenesis. PMID- 29990836 TI - MicroRNA-298 represses hepatocellular carcinoma progression by inhibiting CTNND1 mediated Wnt/beta-catenin signaling. AB - MicroRNAs (miRNAs) are solid factors involved in the initiation and progression of hepatocellular carcinoma (HCC). Recently, miR-298 is recognized as a cancer associated miRNA in breast, gastric and ovarian cancer. However, the functional role of miR-298 and its underlying mechanism are rarely reported in HCC. Herein, we found that the expression of miR-298 was down-regulated in HCC tissues and cell lines. The in vitro experiments showed that miR-298 overexpression inhibited cell proliferation, migration and invasion, and induced G1 arrest and apoptosis of HCC cells. miR-298 knockdown exerted an opposite effect on these cellular behaviors of HCC cells. Moreover, miR-298 restoration suppressed HCC tumor growth and metastasis in vivo. Additionally, catenin delta 1 (CTNND1) was demonstrated to be a direct target of miR-298 in HCC cells. CTNND1 knockdown led to similar effects with miR-298 overexpression on HCC cell proliferation, cell cycle progression, apoptosis and mobility. CTNND1 restoration reversed miR-298-induced inhibitory effects on HCC cells. Mechanistically, both miR-298 overexpression and CTNND1 knockdown repressed Wnt/beta-catenin signaling and resulted in reduced expression of beta-catenin, WNT11, Cyclin D1 and MMP7 in HCCLM3 cells. While, CTNND1 restoration abolished miR-298-induced inactivation of Wnt/beta-catenin signaling. In conclusion, our findings provide the first evidence that miR-298 suppresses HCC progression at least partially by targeting CTNND1-mediated Wnt/beta-catenin signaling. MiR-298 may be a target for new therapies in HCC patients. PMID- 29990837 TI - Vascular endothelial growth factor over-expressed mesenchymal stem cells conditioned media ameliorate palmitate-induced diabetic endothelial dysfunction through PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathway. AB - In the pathogenesis of diabetes mellitus (DM), islet microvasculares are severely damaged due to glucolipotoxicity and other reasons. Vascular endothelial growth factor (VEGF) is an indispensable and specific angiogenic factor in the pathogenesis and treatment of diabetic islet microvascular disease. Mesenchymal stem cells (MSCs) are regarded as a promising treatment of diabetes because of their immunosuppressive effect and multipotential differentiation potency. In this study, we tested whether MSCs over-expressing VEGF conditioned medium (MSC VEGF-CM) could ameliorate pancreatic islet endothelial cells (MS-1) dysfunction induced by a common diabetic inducer palmitate (PA). We found that cell survival and migration were restrained by PA and partly repaired by the pro-protected of MSC-VEGF-CM. Meanwhile, PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways were also up-regulated. Though apoptosis-related proteins, caspase-3 and caspase-9, had no significantly suppressed between MSC-VEGF-CM and MSC-CM alone, the expression levels of vascular surface factors such as CD31, VE-cadherin, occludin and ICAM-1, were remarkably up-regulated by the pro-protected of MSC-VEGF-CM. Our data suggested that MSC-VEGF-CM had therapeutic effect on the PA-induced dysfunction through the re-activation of PI-3K/AKT/m-TOR/eNOS and p38/MAPK signaling pathways. PMID- 29990838 TI - Commiphora molmol protects against methotrexate-induced nephrotoxicity by up regulating Nrf2/ARE/HO-1 signaling. AB - Commiphora molmol possesses multiple therapeutic benefits against various diseases; however, its protective role against methotrexate (MTX) renal toxicity has not been previously investigated. MTX is a dihydrofolate reductase inhibitor that can induce acute kidney injury (AKI). This study evaluated the in vitro antioxidant activity and the protective effect of C. molmol resin extract against MTX-induced oxidative stress, inflammation and renal injury. Male Wistar rats received 125 and 250 mg/kg C. molmol resin extract for 15 days and a single injection of MTX at day 16. C. molmol showed a radical scavenging activity against DPPH, superoxide and nitric oxide (NO) radicals. Rats received MTX showed renal injury evidenced by the significantly elevated serum creatinine and urea, and the histological alterations. The kidney of MTX-induced rats exhibited increased lipid peroxidation, NO, NF-kappaB and pro-inflammatory cytokines. Pre treatment with C. molmol prevented MTX-induced kidney injury and attenuated oxidative stress and inflammation. C. molmol down-regulated Bax and enhanced the activity and expression of the antioxidant defenses. Furthermore, the expression of Bcl-2, Nrf2, NQO-1 and HO-1 was down-regulated in the kidney of MTX-induced rats. Pre-treatment with C. molmol resin up-regulated Bcl-2 and activated Nrf2/HO 1 signaling in the kidney of MTX-induced rats. In conclusion, C. molmol resin provided protection against MTX-induced AKI via activation of Nrf2 signaling and mitigation of oxidative stress. PMID- 29990839 TI - Pharmacological and toxicological activity of RSD921, a novel sodium channel blocker. AB - BACKGROUND: RSD921, the R,R enantiomer of the kappa (k) agonist PD117,302, lacks significant activity on opioid receptors. METHODS: The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. RESULTS: In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (ito) and sustained (IKsus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. CONCLUSIONS: RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity. PMID- 29990840 TI - miR-125a-3p is responsible for chemosensitivity in PDAC by inhibiting epithelial mesenchymal transition via Fyn. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and resistance to cytotoxic chemotherapy is the major cause of mortality in PDAC patients. miR-125a-3p was found to be down-regulated in PDAC cells; however, the function of miR-125a-3p in PDAC has been elusive. Here, we explored the role of miR-125a-3p in chemosensitivity in PDAC cells. METHODS: We used qRT PCR to detect miR-125a-3p expression in two PDAC cell lines. And we measured cell viability and apoptosis by MTT assay and flow cytometry, respectively. Scratch wound healing assay and transwell invasion assay were used to test the effects of miR-125a-3p and Fyn on cell EMT process. In addition, we validated the interaction of miR-125a-3p and Fyn by dual luciferase reporter assay. qRT-PCR and western blot were used to detect the mRNA and protein expressions of E-cadhrein, N-cadhrein, Snail and Fyn. RESULTS: We found that miR-125a-3p was down-regulated in a time-dependent manner following treatment with gemcitabine in PDAC cells. Meanwhile, we found that overexpression of miR-125a-3p significantly increased chemosensitivity to gemcitabine and suppressed epithelial-mesenchymal transition (EMT) of PDAC cells. Mechanistically, miR-125a-3p directly targeted Fyn and decreased the expression of Fyn that functions to promote EMT process in PDAC. Furthermore, overexpression of Fyn could partially reverse the effects of miR 125a-3p on chemosensitivity to gemcitabine. CONCLUSION: Our study is the first to show that miR-125a-3p is responsible for chemosensitivity in PDAC and could inhibit epithelial-mesenchymal transition by directly targeting Fyn. This provides a novel potential therapeutic strategy to overcome chemoresistance in PDAC. PMID- 29990841 TI - C-phycocyanin to overcome the multidrug resistance phenotype in human erythroleukemias with or without interaction with ABC transporters. AB - The phenotype of multidrug resistance (MDR) is one of the main causes of chemotherapy failure. Our study investigated the effect of C-phycocyanin (C-PC) in three human erythroleukemia cell lines with or without the MDR phenotype: K562 (non-MDR; no overexpression of drug efflux proteins), K562-Lucena (MDR; overexpression of ATP-binding cassette, sub-family B/ABCB1), and FEPS (MDR; overexpression of ABCB1 and ATP-binding cassette, sub-family C/ABCC1). Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we showed that 20 and 200 MUg/mL C-PC decreased K562 viable cells after 24 h and 200 MUg/mL C-PC decreased K562-Lucena cell proliferation after 48 h. C-PC did not decrease viable cells of FEPS cells. On the other hand, the MTT assay showed that exposure of 2, 20, and 200 MUg/mL C-PC for 24 or 48 h was not cytotoxic to peritoneal macrophages. At 72 h, the trypan blue exclusion assay showed that 20 MUg/mL C-PC decreased K562 and K562-Lucena cell proliferation and in FEPS cells, only 200 MUg/mL C-PC decreased proliferation. In addition, protein-protein docking showed differences in energy and binding sites of ABCB1 and ABCC1 for C PC, and these results were confirmed by the efflux protein activity assay. Only ABCC1 activity was altered in the presence of C-PC and FEPS cells showed lower C PC accumulation, suggesting C-PC extrusion by ABCC1, conferring C-PC resistance. In combination with chemotherapy (vincristine [VCR] and daunorubicin [DNR]), the sensitivity of K562-Lucena cells for C-PC + VCR did not increase, whereas FEPS cell sensitivity for C-PC + DNR was increased. In molecular docking experiments, the estimated free energies of binding for C-PC associated with chemotherapy were similar (VCR: -6.9 kcal/mol and DNR: -7.2 kcal/mol) and these drugs were located within the C-PC cavity. However, C-PC exhibited specificity for tumor cells and K562 cells were more sensitive than K562-Lucena cells, followed by FEPS cells. Thus, C-PC is a possible chemotherapeutic agent for cells with the MDR phenotype, both alone in K562-Lucena cells (resistance due to ABCB1), or in combination with other drugs for cells similar to FEPS (resistance due to ABCC1). Moreover, C-PC did not damage healthy cells (peritoneal macrophages of Mus musculus). PMID- 29990842 TI - LncRNA-NR_033515 promotes proliferation, fibrogenesis and epithelial-to mesenchymal transition by targeting miR-743b-5p in diabetic nephropathy. AB - Diabetic nephropathy (DN) is a crucial microvascular complication of diabetes. Long non-coding RNAs (lncRNAs) participate in the occurrence and development of various diseases, but the function and regular mechanism of lncRNA-NR_033515 in DN is still unclear. In the present study, we demonstrated that the expression of NR_033515 was significantly increased in the serum of DN patients and was related to the different stages of DN. NR_033515 was also positively associated with diagnostic markers of DN (KIM-1 and NGAL). Overexpression of NR_033515 promoted proliferation, and inhibited apoptosis of MMC cells and increased the expression levels of proliferation-related genes. NR_033515 also accelerated the expression levels of fibrogenesis-related genes. TGF-beta1 enhanced NR_033515-induced Epithelial-mesenchymal transition (EMT), while NR_033515 over-expression accelerated TGF-beta1-induced EMT. Furthermore, we found that NR_033515 promoted cell proliferation and regulated P38, ASK1, Fibronectin, alpha-SMA, E-cadherin, and Vimentin expressions by miR-743b-5p. Therefore, our data indicated the potential role of NR_033515 in the proliferation, fibrogenesis and EMT in DN. NR_033515 could be a pivotal potential diagnostic and therapeutic target for the treatment of DN. PMID- 29990843 TI - A molecular approach in drug development for Alzheimer's disease. AB - An increase in dementia numbers and global trends in population aging across the world prompts the need for new medications to treat the complex biological dysfunctions, such as neurodegeneration associated with dementia. Alzheimer's disease (AD) is the most common form of dementia. Cholinergic signaling, which is important in cognition, is slowly lost in AD, so the first line therapy is to treat symptoms with acetylcholinesterase inhibitors to increase levels of acetylcholine. Out of five available FDA-approved AD medications, donepezil, galantamine and rivastigmine are cholinesterase inhibitors while memantine, a N methyl d-aspartate (NMDA) receptor antagonist, blocks the effects of high glutamate levels. The fifth medication consists of a combination of donepezil and memantine. Although these medications can reduce and temporarily slow down the symptoms of AD, they cannot stop the damage to the brain from progressing. For a superior therapeutic effect, multi-target drugs are required. Thus, a Multi Target-Directed Ligand (MTDL) strategy has received more attention by scientists who are attempting to develop hybrid molecules that simultaneously modulate multiple biological targets. This review highlights recent examples of the MTDL approach and fragment based strategy in the rational design of new potential AD medications. PMID- 29990844 TI - Effects of amlodipine and valsartan on glibenclamide-treated streptozotocin induced diabetic rats. AB - Diabetes mellitus (DM) is a spectrum of metabolic disorders, arising from pathologic mechanisms, resulting in hyperglycaemia. Diabetes and hypertension frequently occur together and are leading risk factors for cardiovascular complications. This study examined the effects of amlodipine and valsartan on glibenclamide-treated streptozotocin-induced diabetic rats. Male albino rats (200 350 g) were fasted overnight and DM was induced by a single dose 40 mg/kg of streptozotocin (i.p.). After 48 h, DM was confirmed (blood sugar >=200 mg/dl) and the animals were grouped into normal rats with no drug treatment, untreated diabetic animals and groups treated with glibenclamide, glibenclamide plus amlodipine, and glibenclamide plus valsartan. After six weeks treatment, animals were sacrificed under chloroform anaesthesia. Kidney, liver, lung, heart and blood were collected for histology, haematological and biochemical analyses. Untreated diabetic rats had 100% mortality before 6 weeks but addition of valsartan to glibenclamide improved survival rate (71.4% compared with 57.4% in glibenclamide-treated) and blood glucose control but this was not so with glibenclamide plus amlodipine-treated group with 50% survival rate. Treatment ameliorated pathologic changes and there was histologic evidence of organ protection among the various treatment groups when compared with the untreated diabetic group. Addition of valsartan to glibenclamide improved treatment outcome compared to when glibenclamide was used alone but this was not so with the addition of amlodipine to glibenclamide. PMID- 29990845 TI - Amelioration of neurodegeneration and cognitive impairment by Lemon oil in experimental model of Stressed mice. AB - Citrous lemon (Rutaceae) an Indian folk medicine has been used for the treatment of various pathological diseases viz., diabetes, cardiovascular, inflammation, hepatobiliary dysfunction and neurodegenerative disorder. Can lemon oil altered the memory of unstressed and stressed mice, a basic question for which the present work was put on trial. The present investigation was intended to assess the impact of Lemon oil on memory of unstressed and Stressed Swiss young Albino mice. Lemon oil (50 and 100 mg/kg o.r.) and donepezil (10 mg/kg) were guided for three weeks to different groups of stressed and unstressed mice. The nootropic movement was assessed utilizing elevated plus maze and Hebbs Williams Maze. Cerebrum acetylcholinesterase (AChE), plasmacorticosterone, decreased glutathione, lipid per oxidation alongside superoxide dismutase and catalase was surveyed as marker for disease. Histopathology was performed for estimation of drug effects. Acute immobilized stress was induce, lemon oil (100 mg/kg) and donepezil together indicated memory enhancing movement both in stressed and unstressed mice. Lemon oil significantly (p < 0.001) altered and lowered brain AChE activity both in stressed and unstressed mice. Scopolamine induced amnesia was also significantly altered and reversed both in stressed and unstressed mice by lemon oil at a dose of 50 and 100 mg/kg. Lemon oil (50 and 100 mg/kg) was further able to control the corticosterone level in plasma for stressed mice. Lemon oil significantly (p < 0.001) elevated the level of catalase, superoxide dismutase and reduced glutathione levels both in stressed and unstressed animals with respect to controlled group along with TBARS both in stressed and unstressed compared with control group. Hence it can be concluded that memory enhancing activity might be related to reduction in AChE and TBARS activity and by elevated GSH, SOD and catalase through decrease in raised plasma corticosterone levels. PMID- 29990846 TI - Emerging role of lncRNAs in systemic lupus erythematosus. AB - Long non-coding RNAs (lncRNAs), defined as >=200 base pairs in length but have little translation potential, play a key role in imprinting control, immune cell differentiation, apoptosis and immune responses. Recently, many potential lncRNAs have been revealed to contribute to a new layer of molecular regulation of systemic lupus erythematosus (SLE). Immune-related functional lncRNAs may serve as novel therapeutic targets and disease biomarkers to provide potential support for clinic treatment in this disease. In this review, we will briefly introduce the identification, biogenesis and functions of lncRNAs, and summarize recent advance in the role of lncRNAs in SLE. PMID- 29990847 TI - Wogonoside induces apoptosis in human non-small cell lung cancer A549 cells by promoting mitochondria dysfunction. AB - Non-small cell lung cancer (NSCLC) is one of the most prevailing malignancies worldwide. It has been previously shown that wogonoside exerts anti-tumor activities in various kinds of human cancers. But its role in NSCLC remains elusive. In the present study, we determined the anti-tumor effect of wogonoside in human NSCLC A549 cells. We found that wogonoside effectively inhibits A549 cell viability through inducing cell cycle arrest and apoptosis. Moreover, administration of wogonoside by intraperitoneal injection inhibits the growth of A549 cell xenografts in athymic nude mice. Additionally, mitochondrial membrane potential was disrupted and cytochrome c was released to cytosol in the wogonoside-treated A549 cells. Finally, we found that AMPK/mTOR signaling might be implicated in the anti-NSCLC efficacy of wogonoside. Therefore, we may assume that wogonoside may be considered as a potential therapeutic agent for the treatment of NSCLC. PMID- 29990848 TI - Gamma irradiation of Toxoplasma gondii protein extract improve immune response and protection in mice models. AB - Gamma radiation induces protein changes that enhance immunogenicity for venoms, used in antivenin production. Coccidian parasites exposed to gamma radiation elicit immune response with protection in mice and man, but without studies on the effect of gamma radiation in soluble acellular extracts or isolated proteins. Toxoplasmosis is a highly prevalent coccidian disease with only one vaccine for veterinary use but with remaining tissue cysts. Total parasite extracts or recombinant proteins used as immunogen induce usually low protection. Here, we study gamma radiation effect on T. gondii extracts proteins (STAG) and its induced immunity in experimental mice models. By SDS-PAGE, protein degradation is seen at high radiation doses, but at ideal dose (1500 Gy), there are preservation of the antigenicity and immunogenicity, detected by specific antibody recognition or production after mice immunization. Immunization with STAG irradiated at 1500 Gy induced significant protection in mice immunized and challenged with distinct T. gondii strains. In their blood, higher levels of specific CD19+, CD3+CD4+ and CD3+CD8+ activated cells were found when compared to mice immunized with STAG. Irradiated T. gondii tachyzoites extracts induce immune response and protection in mice in addition, could be a feasible alternative for Toxoplasma vaccine. PMID- 29990849 TI - Plasma concentrations of the trace elements copper, zinc and selenium in Brazilian children with autism spectrum disorder. AB - The association between the plasma levels of trace elements, such as copper (Cu), zinc (Zn) and selenium (Se), in people with autism spectrum disorder (ASD), has attracted the interest of many physicians in the very recent years, because the impaired homeostatic regulation of trace elements, including their levels in the bloodstream and their potential neurotoxicity, contribute to the onset and exacerbation of ASD. In this study, we investigated 23 pediatric subjects (<= 18 yrs old, both sexes) with ASD, all residents in the city of Campo Grande in Brazil, by searching for their micronutrient levels in plasma in relation with metabolic and nutrition biomarkers. Aside for the few evidence reported, generally, the Brazilian cohort of ASD children here examined did not show a marked difference in micro-nutrient intake in relation with their resident geographical area and their dietary habit or metabolic state, although a slight difference in the levels of magnesium and phosphorus was retrieved due to sex difference. PMID- 29990850 TI - Appraisal of mechanisms of radioprotection and therapeutic approaches of radiation countermeasures. AB - Radiation countermeasures are radioprotective agents that reduce the harmful effects of ionizing radiation. They have wide range of applications extending from protection of normal tissues of cancer patients during radiotherapy to safeguard people aftermath of radiologic or nuclear accidents. Despite the screening of thousands of natural and synthetic compounds, only few found place in clinic with limited tolerance. Therefore, mechanistic understanding is essential in the development of more suitable and customized radiation countermeasure agents. This review focuses on the mechanisms of radioprotection imparted by these agents. Radioprotectors are diverse and act through widely varying mechanisms that can be classified in 10 categories: 1) scavenging of free radicals; 2) enhancing DNA repair; 3) synchronizing of cells; 4) modulating redox sensitive genes; 5) modulating growth factors and cytokines; 6) inhibiting apoptosis; 7) repurposing of drug; 8) interacting and chelating of radionuclides; and therapeutic methods of tissue regeneration such as 9) gene therapy; and 10) stem cell therapy. The most common mechanism of radioprotection is the scavenging of free radicals whereas, modulation of growth factors, cytokines and redox genes emerge as effective strategies. Gene and stem cell therapies as therapeutic radiation countermeasures are being developed and can be applied in the near future to minimize the side effects of radiation exposure through tissues regenerations. Thus, the management of radiation exposure may require a holistic multi-mechanistic approaches to achieve optimal radiation protection during radiotherapy of cancer patients and in cases of nuclear eventualities. PMID- 29990851 TI - Characterization of cardiovascular depression effect for propofol during anesthesia induction period on morbidly obese patients. AB - This study aims to determine the pharmacodynamics (PD) effect (measured by cardiovascular depression) of propofol during anesthesia induction period on morbidly obese (MO) patients. Four hemodynamics indexes [i.e., three indexes about blood pressure and cardiac output (CO)] representing cardiovascular function were measured. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed by population analysis to obtain PD parameters. Two propofol dosing scalars, namely, dosing based on total body weight (TBW) or lean body weight (LBW), were used for MO subjects. The PD data were well described by a PK/PD model. Blood pressure and CO were rapidly decreased within one minute after intravenous injection of propofol (2 mg/kg). TBW group showed significantly lower blood pressure and CO values at and 1 min after propofol administration compared with the control group, whereas the control and LBW groups had similar PD profiles. In addition, the propofol EC50 value was significantly decreased in MO patients, whereas all other PD parameters were similar between control and MO subjects. This change indicated that propofol potency and/or sensitivity was increased in MO subjects. For MO patients, dosing of propofol based on LBW rather than TBW would be a safer choice due to a less cardiovascular depression effect. PMID- 29990852 TI - Increased lipid peroxidation, apoptosis and selective cytotoxicity in colon cancer cell line LoVo and its doxorubicin-resistant subline LoVo/Dx in the presence of newly synthesized phenothiazine derivatives. AB - Cancer cells often develop the resistance to pro-apoptotic signaling that makes them invulnerable to conventional treatment. Therapeutic strategies that make cancer cells enter the path of apoptosis are desirable due to the avoidance of inflammatory reaction that usually accompanies necrosis. In the present study phenothiazines (fluphenazine and four recently synthesized derivatives) were investigated in order to identify compounds with a potent anticancer activity. Since phenothiazines are known as multidrug resistance modulators the sensitive human colorectal adenocarcinoma cell line (LoVo) and its doxorubicin-resistant, ABCB1 overexpressing, subline (LoVo/Dx) have been employed as a model system. In studied cancer cells cytotoxic effect of the phenothiazine derivatives was accompanied by apoptosis and autophagy induction as well as by the increase of cellular lipid peroxidation and intracellular reactive oxygen species generation. Molecular modelling revealed that reactivity of phenothazines (manifested by their low energy gap) but not lipophilicity was positively correlated with their anticancer potency, pro-oxidant properties and apoptosis induction ability. Additionally, some of the studied compounds turned out to be more potent cytotoxic and pro-apoptotic agents in doxorubicin-resistant (LoVo/Dx) cells than in sensitive ones (LoVo). The hypothesis was assumed that studied phenothiazine derivatives induced apoptotic cell death by increasing the production of reactive oxygen species. PMID- 29990853 TI - Evaluation of the effect of andrographolide and methotrexate combined therapy in complete Freund's adjuvant induced arthritis with reduced hepatotoxicity. AB - OBJECTIVE: Methotrexate is one of the most widely used disease-modifying anti rheumatic drugs. The hepatotoxicity of methotrexate resulted in poor compliance with therapy. The current study was designed to analyse the combined therapy of andrographolide (AD) and methotrexate (MTX) for complete Freund's adjuvant (CFA) induced arthritis, focusing on hepatoprotective effects, oxidative stress and arthritic-related cytokines. METHOD: Wistar rats were injected with CFA into the right hind paw. Ten days post-CFA injection, the Wistar rats were administered with 1% CMC-Na solution, methotrexate (2 mg/kg/week), AD (50 mg/kg/d) and combined therapy for 35 days. The anti-arthritic effect was assessed by paw volume, X-ray and serum tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta levels. Serum samples were also analysed for glutamic oxaloacetic transaminases (GOT), serum glutamic pyruvic transaminase (GPT), alkaline phosphatase (AKP) and lactate dehydrogenase (LDH). Liver tissue samples were used to examine the cellular antioxidant defence activities using catalase activity (CAT) and GSH as well as GSH-Px and MDA. Histopathology analysis was conducted to evaluate liver damage. RESULTS: AD treatment strengthened the anti-arthritic capacity of MTX. AD and MTX-combined therapy additively reduced the inflammatory symptoms in CFA rats. The combined therapy of AD and MTX showed hepatoprotective effect indicated by an improvement in the serum marker, possibly due to antioxidant action and confirmed by liver histopathological changes. Furthermore, the combined therapy significantly reduced serum TNF-alpha, IL-6 and IL-1beta levels. CONCLUSIONS: A combined therapy of AD and methotrexate significantly alleviated MTX-induced hepatocellular injury and strengthened the anti-arthritic effect. Further clinical studies should be done to further verify the possibility of combined its clinical usage. PMID- 29990854 TI - Downregulation of miR-218-5p promotes invasion of oral squamous cell carcinoma cells via activation of CD44-ROCK signaling. AB - The invasion front of oral squamous cell carcinoma (OSCC) harbors the most aggressive cells of the tumor and is critical for cancer invasion and metastasis. MicroRNAs (miRNAs) play important roles in OSCC progression. In this study, we modelled the OSCC invasion front on a microfluidic chip, and investigated differences in miRNA profiles between cells in the invasion front and those in the tumor mass by small RNA sequencing. We found that miR-218-5p was downregulated in invasion front cells and negatively regulates OSCC invasiveness by targeting the CD44-ROCK pathway. Thus, miR-218-5p may serve as a useful therapeutic target for OSCC. Moreover, invasion front cell isolation based-on microfluidic technology provided a useful strategy for cancer invasion study. PMID- 29990855 TI - beta-asarone induces cell apoptosis, inhibits cell proliferation and decreases migration and invasion of glioma cells. AB - Glioma is the most common primary brain tumor Despite the availability of adjuvant therapies, malignant glioma grows fast and metastasizes via cerebrospinal fluid after tumorectomy or cerebrospinal fluid shunt placement, and the prognosis for patients with glioma remains poor. Our previous study demonstrated that beta-asarone has anti-tumor effects on several kinds of cancer cells, especially for glioma cells. In this study, human glioma U251 cells and rat glioma C6 cells were treated with different concentrations of beta-asarone. Cultured them for 24 h, 48 h, 72 h and evaluated the IC50 with the results of Counting Kit-8 assay. Then, cell apoptosis and cell DNA cycles were evaluated with flow cytometry. Apoptosis related mRNA and protein were analyzed In addition, cell migration and invasion were also detected with wound healing and transwell assays, respectively. What is more, glioma specific proteins: GFAP, NRP 1 and NSE an enzyme-linked immunosorbent assay. The corresponding CCK-8 results showed that beta-asarone altered cell morphology and inhibited cell proliferation. beta-asarone can also induced cell apoptosis, decreased the expression of BCL-2 mRNA and blocked the DNA cycle at the G0/G1 phase for all the two cells. In addition, beta-asarone inhibited cell migration and invasion by reducing the expression of GFAP, NRP-1 and NSE. Co-administration with TMZ showed a more pronounced effect. In summary, beta-asarone induces cell death and inhibits cell migration and invasion in Glioma U251 and C6 cells. PMID- 29990856 TI - MicroRNA-1469, a p53-responsive microRNA promotes Genistein induced apoptosis by targeting Mcl1 in human laryngeal cancer cells. AB - Genistein, a plant isoflavone, is reported to have therapeutic potentials in multiple cancers, However, the molecular mechanism underlying promoting cell apoptosis in laryngeal cancer remains unclear. In this study, we report that miR 1469 was induced by genistein in laryngeal cancer. Elevated miR-1469 promoted cell apoptosis and inhibited Mcl1 expression. In addition, we also observed that tumor suppressor p53 was increased under genistein treatment. Elevation of p53 promoted miR-1469 expression, leading to miR-1469 increase and Mcl1 decrease. Therefore, our findings suggest that genistein can suppress laryngeal cancer cell survival through p53 -miR-1469-Mcl1pathway. PMID- 29990857 TI - KLF15 suppresses cell growth and predicts prognosis in lung adenocarcinoma. AB - Kruppel-like factors (KLFs) are transcription factors containing three different C2H2-type zinc finger domains in their carboxy-terminal regions which have been identified to play important roles in a variety of cancers. However, little is known about KLF15 in lung adenocarcinoma (LAUD). Our study demonstrated that the expression levels of KLF15 were observably down-regulated in LAUD tissues compared to paired adjacent normal tissues. LUAD patients with low expression levels of KLF15 have worse prognosis than those with high expression levels of KLF15. KLF15 could suppress cell growth, which was partly via up-regulating CDKN1 A/p21 and CDKN2A/p15. Our findings suggested that KLF15 showed a significant role in LAUD progression and may shed light on a promising novel therapeutic target for blocking progression of LAUD. PMID- 29990858 TI - Repression of Dok7 expression mediated by DNMT1 promotes glioma cells proliferation. AB - Malignant glioma is one of the most common primary human tumors in the central nervous system. The molecular mechanisms of the progression and development of glioma have been largely unexplored. In this study, we illustrated that the expression of Dok7 was downregulation in human glioma tissues. Dok7 overexpression significantly inhibits proliferation and colony formation in vitro, and the xenograft tumor formation in vivo. In addition, 5-Aza-2' deoxycytidine (5-Aza), a DNA methylation inhibitor, preventing the loss of Dok7 expression by decreasing aberrant hypermethylation of Dok7 promoter in glioma cells. More importantly, DNMT1 knockdown induced the demethylation of Dok7 promoter, and enhanced the expression of Dok7 in gliomas. These results suggest that epigenetic silencing of Dok7 may provide a novel glioma treatment strategy. PMID- 29990859 TI - Alkyl-glycerophosphate-mediated C-C motif chemokine 2 secretion induces oxidative stress via increased PPARgamma activation in human umbilical vein endothelial cells. AB - We previously showed that an alkyl-ether analog of lysophosphatidic acid, AGP (alkyl-glycerophosphate), accumulates in human atherosclerotic plaques and is a potent agonist of peroxisome proliferator-activated receptor-gamma (PPARgamma). On the other hand, cyclic phosphatidic acid (cPA), similar in structure to AGP, can negatively regulate PPARgamma. However, in this study, cPA had no effect on the expression and secretion of C-C motif chemokine 2 (CCL-2), a chemokine that is also linked to inflammatory responses and atherosclerosis. We showed that AGP enhances CCL-2 mRNA expression and secretion in a dose-dependent manner. Furthermore, oxidative stress plays a major role in the pathology of cardiovascular diseases; we showed that AGP triggers ROS generation and lipid peroxidation and that ROS and 8-isoprostane generation can be suppressed by a PPARgamma antagonist. These results suggest that an imbalance of the PPARgamma agonist-antagonist equilibrium is involved in changes in cellular functions, including ROS generation and lipid peroxidation. PMID- 29990860 TI - Sulfur dioxide attenuates hypoxia-induced pulmonary arteriolar remodeling via Dkk1/Wnt signaling pathway. AB - OBJECTIVE: This study investigated the impact of SO2 on rats with hypoxic pulmonary vascular structural remodeling and its possible mechanisms. MATERIALS AND METHODS: Pulmonary vascular morphological change was examined by HE staining. RNA-based high-throughput sequencing (RNA-seq) was performed to detect differential expression of mRNAs in Normal and Hypoxia-induced Pulmonary hypertension (HPH) rats. The Real-time quantitative RT-PCR (q RT-PCR) was used for validation of wnt7b, sfrp2, cacna1f, DKK1, CaSR and vimentin mRNA expression levels. Protein levels of CaSR, Vimentin, Caspase3, E-cadherin and P-Akt1/2/3 were detected by Western blot and immunohistochemistry. RESULTS: This study showed that SO2 significantly attenuated the interstitial thickening and prominent media hypertrophy of pulmonary arteries. SO2 downregulated p-Akt1/2/3 protein level and upregulated E-cadherin protein level in lung tissues, which inhibited the proliferation and epithelial-to-mesenchymal transition (EMT) in HPH rats. RNA-seq and PCR validation results showed that levels of Wnt7b, Sfrp2 and Cacna1f mRNAs decreased and Dkk1 mRNA level increased obviously in HPH rats. Moreover, SO2 attenuated the mRNA and protein level of CaSR, which was activated in HPH rats and resulted in the proliferation of PASMCs. Besides, the mRNA and protein expression of vimentin in PASMCs significantly reduced after SO2 treatment. CONCLUSION: Together, these findings indicate that SO2 could attenuate hypoxia-induced pulmonary arteriolar remodeling and may suppress the proliferation and migration of PASMCs at least in part through the Dkk1/Wnt signaling pathway. PMID- 29990861 TI - Non-toxic and non teratogenic extract of Thuja orientalis L. inhibited angiogenesis in zebra fish and suppressed the growth of human lung cancer cell line. AB - Lung cancer is a malignant tumour with minimal survival rate and the current treatments are not showing complete remission of tumour and have many side effects. Thus a natural herbal medicine with good anti-cancer properties is highly demanded. Thuja orientalis L. is a traditionally used medicine to cure cough, bronchitis, excessive menstruation, asthma, skin infection and premature baldness. In addition, recent studies have revealed that it has anti proliferative and anti-cancer activity. Angiogenesis is the main reason for the propagation and metastasis of cancers. We therefore intended to study the effects of the leaf extract of Thuja orientalis L. on angiogenesis as well as lung cancer cell growth. We have tested the anti-angiogenesis efficiency by alkaline phosphatase assay and also analysed the in vivo toxicity and teratogenic effects of various concentration of Thuja orientalis L. extract by establishing an in vivo zebra fish (Danio rerio), a promising model for cancer research which share genetic structure similarity to that of human beings. Also we demonstrated an anti-cancer effect of leaf extract from Thuja orientalis L. on human lung cancer cell line (A549) by MTT and trypan blue assay. The results revealed that the Thuja orientalis L. extract is efficient in repressing lung tumour cell growth significantly (p <= 0.01) in all treatments (2.4 mg/ml to 0.3 mg/ml) except 0.15 mg/ml compared to the control. The in vivo toxicity assay has proven that it is non-toxic at concentrations 0.6 mg/ml, 0.3 mg/ml and 0.15 mg/ml in zebrafish. The teratogenic assays revealed the therapeutic index (TI) as 0.808 with 0.7029 mg/ml as LC50 concentration at 24 h which is within the desirable value (below 1) for drug administration. Noticeable inhibition of angiogenesis also was observed in treatment with 2.4 mg/ml to 0.3 mg/ml. Overall we found that Thuja orientalis L. plant leaf extract exhibits better anti-cancer properties as we have validated by in vitro and in vivo analysis. PMID- 29990862 TI - Emerging landscape in psoriasis management: From topical application to targeting biomolecules. AB - Psoriasis is a chronic autoimmune skin disorder affecting 2-3% of the world population. It has characteristic features such as increased keratinocyte proliferation and production of inflammatory mediators. The treatment involves various strategies including topical, systemic, phototherapy and biologics. Topical therapies are preferred for mild to moderate psoriasis conditions over the systemic therapies which are ideal in severe disease conditions. The systemic therapies include immunosuppressants, biological agents and recently approved phosphodiesterase-4 (PDE4) inhibitors. There are various limitations associated with the existing therapies where the new findings in the pathogenesis of psoriasis are paving a path for newer therapeutics to target at the molecular level. Various small molecules, PDE-4 inhibitors, biologics, and immunomodulator proved efficacious including the new molecules targeting Janus kinases (JAK) inhibitors that are under investigation. Furthermore, the role of genetic and miRNAs in psoriasis is still not completely explored and may further help in improving the treatment efficacy. This review provides an insight into various emerging therapies along with currently approved treatments for psoriasis. PMID- 29990863 TI - Role of oxidative stress in pathology of chronic prostatitis/chronic pelvic pain syndrome and male infertility and antioxidants function in ameliorating oxidative stress. AB - Oxidative stress (OS) is a result of the imbalance between reactive oxygen species (ROS) and antioxidants in the body that can cause tissue damage. Oxidative stress has a significant involvement in the pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and male infertility. CP/CPPS is a major risk factor for male infertility due to generation of excessive ROS that damage sperm DNA, lipids, and proteins, resulting in compromised vitality and decreased sperm motility. Here we present a comprehensive review of oxidative stress relevance in CP/CPPS and male infertility, and embody the protective effects of antioxidants against ROS. An online literature was searched using the following keywords/terms: oxidative stress, ROS, Oxidative stress and chronic prostatitis, oxidative stress and male infertility and antioxidants. Original and review articles, clinical trials, and case reports of human and animal studies published till 2017 were searched using the PubMed and MEDLINE. PMID- 29990864 TI - Immunomodulatory effect of Arabinosylated lipoarabinomannan restrict the progression of visceral leishmaniasis through NOD2 inflammatory pathway: Functional regulation of T cell subsets. AB - NOD like receptors (NLR) are essential pathogen associated molecular pattern receptors of cytoplasmic origin. During several intracellular parasitic infections NLR played vital role for host protective immune response against the pathogen. Amongst various classes of NLR, NOD1 and NOD2 had been extensively studied and were found to be the most active member of the NLR family. Therefore, we wanted to study the role of NOD1/NOD2 during Leishmania donovani infection and the mechanism behind the utilization of this pathway as a therapeutic approach. Using the infected model of macrophage and BALB/c mice the expression of NOD1 and NOD2 were analysed. Our study showed that NOD2 but not NOD1 has been exploited during experimental VL, leading to the imbalance between Th-1/Th-2 cytokines profile. Over-expression of NOD2 and stimulation with its ligand muramyl dipeptide leads to successful clearance of parasite. During in vivo experiments we found that arabinosylated lipoarabinomannan helps in the restoration of NOD2 and with MDP in combination leads to effective clearance of parasite which rescued host protective immunity and comparatively more effective than Mw and MDP combination resulting in increase T cell response. Consequently, our study highlighted the significance of NOD2 during infection the immune-modulations of which can be used as a therapeutic target. PMID- 29990865 TI - Tangganjian decoction ameliorates type 2 diabetes mellitus and nonalcoholic fatty liver disease in rats by activating the IRS/PI3K/AKT signaling pathway. AB - AIM: Previous clinical studies have demonstrated that tangganjian (TGJ), a modern Chinese prescribed medicine, has a clinical effect in the treatment of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD). Our study aimed to investigate whether the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is involved in this therapeutic effect. MATERIALS AND METHODS: T2DM and NAFLD rat models were constructed and treated with three different concentrations of TGJ. Pioglitazone was used as a positive control, along with the model and normal groups. For analyses, blood and livers were collected. Levels of glucose and lipid metabolism indicators, including fasting insulin and total cholesterol, were determined. The expression levels of insulin receptor substrate (IRS), PI3K, and AKT were also determined by western blotting and immunohistochemistry. Liver tissues were stained with hematoxylin & eosin. RESULTS: In the high-dose TGJ-treated and positive groups, there was a significant increase in the HDL-C level and decreases in the levels of the fasting blood glucose, 2 h postprandial blood glucose, fasting insulin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol, along with a significant increase in the expression of IRS, PI3K, and AKT in the liver. TGJ could also attenuate or counteract the effects of T2DM and NAFLD in the liver lobules. CONCLUSION: A high concentration of TGJ can improve glucose and lipid metabolism by activating the IRS/PI3K/AKT signaling pathway. PMID- 29990866 TI - Knockdown of lncRNA MALAT1 attenuates acute myocardial infarction through miR-320 Pten axis. AB - BACKGROUND: Long noncoding RNA (LncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in the development of acute myocardial infarction (AMI). However, the molecular mechanism and biological function of MALAT1 in AMI remained unclear. METHODS: The expression levels of MALAT1, miR-320 and phosphatase and tensin homolog deleted on chromosome 10 (Pten) in a mouse model of AMI and sham-operated mice were determined by quantitative real-time PCR (qRT-PCR) and western blotting, respectively. The relationships between miR-320 and MALAT1, Pten were confirmed by luciferase reporter assay. The roles of MALAT1, miR-320 and Pten in myocardial apoptosis were evaluated using Annexin V FITC/PI double-labeled flow cytometry. Echocardiographic evaluation, serum creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH), myocardial infarct size and myocardial apoptosis using terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were used to examine the impact of MALAT1 on myocardial injury. RESULTS: MALAT1 and Pten were highly expressed, while miR-320 was suppressed in MI group. Mechanistically, MALAT1 may serve as a sponge for miR 320 to upregulate Pten, a direct target of miR-320. Moreover, MALAT1 knockdown overturned the pro-apoptotic effect of miR-320 in vitro and in vivo. CONCLUSION: MALAT1 knockdown attenuated myocardial apoptosis through suppressing Pten expression by sponging miR-320 in mouse AMI. PMID- 29990867 TI - Role of PI3K/Akt/NF-kappaB and GSK-3beta pathways in the rat model of cardiopulmonary bypass-related lung injury. AB - BACKGROUND: Apoptosis is a cellular mechanism contributing to cardiac surgery using cardiopulmonary bypass (CPB)-induced lung injury. The ubiquitous PI3K/Akt pathway regulates proliferation, apoptosis and differentiation by controlling a broad range of target proteins including NF-kappaB and GSK-3beta. The roles of the PI3K/Akt/NF-kappaB and PI3K/Akt/GSK-3beta pathways in CPB-related lung injury are unclear. METHODS: Seventy-two male Sprague-Dawley rats were assigned into sham, CPB, Wortmannin (Wtn) and insulin-like growth factor-I (IGF-I) groups (n = 18, each). Six subjects per group were evaluated at each of three time points: Prior to CPB (T1); opening of the left hilus pulmonis (T2); and 90 min after CPB (T3). Arterial blood specimens were obtained at each time point to test respiratory and oxygenation indices. Left lung tissues were processed for H&E and TUNEL staining. Western blot was employed to evaluate protein levels and activities of Akt, phospho-Akt (p-Akt), GSK-3beta, phospho-GSK-3beta (p-GSK 3beta) and nuclear NF-kappaB. RESULTS: Lung ischemia/reperfusion and CPB caused notable lung injury, as evidenced by lung functional decline and pathological deterioration, accompanied by increases in apoptosis and expression levels of p Akt, p-GSK-3beta and nuclear NF-kappaB in lungs (all P < 0.05 vs. Sham). At T3, Wtn-treated CPB subjects showed worsened lung function and pathological lung structures, as well as apoptosis in lungs (all P < 0.05 vs. CPB); additionally, Wtn inhibited Akt phosphorylation and slightly, but significantly increased expression of nuclear NF-kappaB (both P < 0.001 vs. CPB). Conversely, treatment of subjects with IGF-I increased Akt phosphorylation (P < 0.001 vs. CPB), inhibited expression of nuclear NF-kappaB (P = 0.008 vs. CPB), improved lung function and tissue morphology (both P < 0.05 vs. CPB), and reduced apoptosis in lungs (P < 0.001 vs. CPB). Neither Wtn nor IGF-I did alter GSK-3beta phosphorylation levels (P = 0.836 and P = 0.669 vs. CPB, respectively). CONCLUSION: The PI3K/Akt/NF-kappaB pathway played a role in CPB-related lung injury, possibly through mediating apoptosis in lungs. GSK-3beta, a signaling effector that also participated in CPB-induced apoptosis in lungs, but was not regulated by the PI3K/Akt pathway in this context. PMID- 29990868 TI - Long non-coding RNA LINC00222 regulates GSK3beta activity and promotes cell apoptosis in lung adenocarcinoma. AB - Recent evidence indicates that long noncoding RNAs (lncRNAs) play a critical role in the regulating cellular processes such as differentiation, proliferation, metastasis and apoptosis. These lncRNAs are found to be dysregulated in a variety of cancers. However, the underlying mechanisms of lncRNAs action in lung adenocarcinoma remain unclear. We investigated expression of the lncRNA LINC00222 in 76 lung adenocarcinoma tissues and paired normal lung tissues and found that LINC00222 is downregulated in lung adenocarcinoma tissues. Enforced expression of LINC00222 significantly inhibited the proliferation, migration and invasive ability of lung adenocarcinoma cells, and also induced apoptosis. Furthermore, overexpression of LINC00222 enhanced the activity of glycogen synthase kinase 3beta (GSK3beta), which is a key element of the Wnt signaling pathway. Taken together, our findings suggest that LINC00222 acts as a tumor suppressor in lung adenocarcinoma and, therefore, could serve as a valuable prognostic biomarker and therapeutic target for lung adenocarcinoma patients. PMID- 29990869 TI - MiR-185 enhances radiosensitivity of colorectal cancer cells by targeting IGF1R and IGF2. AB - OBJECTIVE: Radioresistance is a significant obstacle for effective treatment of colorectal cancer (CRC). Recent studies have indicated that miR-185 inhibits proliferation, survival, and invasion of CRC; however, the role of this miRNA in radioresistance of CRC has not been identified yet. The aim of this study is to investigate the role of miR-185 in radiosensitivity of CRC. METHODS: After transfecting the cells with mimic miR-185, expressions of IGF1R and IGF2 were evaluated by real-time PCR and western blot. The radiation response of transfected cells was also examined by colony forming assay. Sub-G1 fraction analysis through flow cytometry and caspase 3 activity was used to evaluate apoptosis. RESULTS: The results of real-time PCR and western blot indicated that IGF1R and IGF2 are downregulated in the transfected cells. Colony forming assay revealed that transfected cells were more radiosensitive than other cells. On the other hand,following irradiation the rate of apoptosis was significantly higher in the transfected cells than in the other cells. CONCLUSION: In summary, our study is the first to show that upregulation of miR-185 enhances the sensitivity of CRC cells to ionizing radiation. miR-185 may act as a novel biomarker of radioresistance and may clinically enhance the radiation response of CRC. PMID- 29990870 TI - Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels. AB - In this study, we investigated the potential effects of naringenin on the motility of MAT-LyLu cells, which overexpress voltage-gated sodium channels and whose metastatic behaviours are associated with these channels. We first determined the concentration of naringenin that did not show toxic effects or block cell growth. Then, the effects of naringenin on cell motility in the lateral and vertical directions were tested by wound healing assays and transwell invasion assays, respectively. Finally, to determine the suppressive effects of naringenin on cell movement in both directions, the expression of the SCN9A gene, which encodes Nav1.7 voltage-gated sodium channel, was determined by real-time quantitative polymerase chain reaction. The data revealed that high concentrations of naringenin (75 MUM) inhibited cell proliferation, whereas low concentrations (5 and 10 MUM) decreased the movement of MAT-LyLu cells. Moreover, 10 MUM naringenin displayed inhibitory effects on cell movement by reducing the expression of the SCN9A gene at the mRNA level. In conclusion, naringenin was found to have direct or indirect blocking activity on voltage-gated sodium channels encoded by the SCN9A gene. PMID- 29990871 TI - Role of TLR4/MyD88/NF-kappaB signaling pathway in coronary microembolization induced myocardial injury prevented and treated with nicorandil. AB - Coronary microembolization (CME) is a common complication during the treatment of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Nicorandil can be used to prevent myocardial injury after PCI to reduce the incidence of coronary no-reflow and slow flow, and play a role in myocardial protection, suggesting that its mechanism may be related to the inhibition of CME induced inflammation of cardiomyocytes. However, the specific mechanism remains unclear. This study investigated the myocardial protective effects of nicorandil pretreatment on CME-induced myocardial injury and the specific mechanism of its inhibition of myocardial inflammation. An CME rat model exhibited CME-induced myocardial inflammation and the elevation of serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta based on echocardiography, myocardial enzyme detection, hematoxylin and eosin (HE) and hematoxylin-basic fuchsin-picric acid (HBFP) stainings, ELISA, quantitative real-time PCR, and western blotting. Nicorandil treatment seven days before CME induction effectively inhibited myocardial inflammation, ameliorated myocardial injury, and improved cardiac function, mainly by inhibiting Toll-like receptor 4 (TLR4)-mediated myeloid differentiation primary response protein 88 (MyD88)-dependent nuclear factor kappa B (NF-kappaB) signaling. Rat neonatal cardiomyocyte experiments further confirmed that nicorandil ameliorated lipopolysaccharide (LPS)-induced myocardial inflammation and improved cardiomyocyte survival. The specific mechanisms mainly involved the inhibition of TLR4/MyD88/NF-kappaB signaling and the reduction of the inflammatory cytokines TNF-alpha and IL-1beta released from cardiomyocytes. In summary, nicorandil significantly protected cardiomyocytes from CME-induced myocardial injury mainly by inhibiting TLR4/MyD88/NF-kappaB signaling, thereby reducing the onset of CME-induced myocardial inflammation. This could be one of the important mechanisms for reducing postoperative myocardial injury via PCI preoperative prophylactic treatment with nicorandil. PMID- 29990872 TI - Plumbagin ameliorates hepatic ischemia-reperfusion injury in rats: Role of high mobility group box 1 in inflammation, oxidative stress and apoptosis. AB - Ischemia-reperfusion (I/R) injury is a pathological process which magnifies with the ensuing inflammatory response and endures with the increase of oxidants especially during reperfusion. The present study was conducted to assess the possible modulatory effects of plumbagin, the active constituent extracted from the roots of traditional medicinal plant Plumbago zeylanica L., on the dire role of high mobility group box 1 (HMGB1) as well as the associated inflammation, oxidative stress and apoptotic cell death following hepatic I/R. Four groups of rats were included: sham-operated, sham-operated treated with plumbagin, I/R (30 min ischemia and 1 h reperfusion) and I/R treated with plumbagin. Pretreatment with plumbagin markedly improved hepatic function and structural integrity compared to the I/R group, as manifested by depressed plasma transaminases and lactate dehydrogenase (LDH) activities as well as alleviated tissue pathological lesions. Plumbagin prominently hampered HMGB1 expression and subsequently quelled inflammatory cascades, as nuclear factor kappaB (NF-kappaB), tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO) activity. It also interrupted reactive oxygen species (ROS)-HMGB1loop as evident by restored liver reduced glutathione (GSH), elevated glutathione peroxidase (GPx) activity, along with decreased liver lipid peroxidation. Simultaneously, plumbagin significantly ameliorated apoptosis by amending the mRNA expressions of both anti-apoptotic (Bcl-2) and pro-apoptotic (Bax). The present results revealed that plumbagin is endowed with hepatoprotective activity ascribed to its antioxidant, anti inflammatory and anti-apoptotic properties which are partially mediated through dampening of HMGB1 expression. PMID- 29990873 TI - A novel synthesized 3', 5'-diprenylated chalcone mediates the proliferation of human leukemia cells by regulating apoptosis and autophagy pathways. AB - Leukemia is a hematologic malignancy with poor prognosis in humans and chemotherapy is the main strategy for treating leukemia patients. Novel drugs with better selectivity and lower toxicity are required for the treatment of patients. A novel 3',5'-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5 diprenyl) phenyl-3-(3- pyridinyl)-propene-1-one (C10) is a potential new anti leukemia agent. In this study, we investigated the molecular mechanisms of the anti-leukemia effects of C10 on different leukemia cells in vitro. C10 showed strong inhibition of proliferation of the human erythroleukemia cell line HEL and human myeloid leukemia cell line K562, and several cell and flow cytometer assays showed that inhibition by C10 was due to the regulation of gene expression or phosphorylation in the apoptosis and autophagy pathways. The results showed that C10 regulated the expression of Bax, c-Myc, Bcl-2, P38/AMPK and ERK 1/2, activated the expression of Caspase-3, -8, and PARP at the protein level in the apoptosis pathway of the two leukemia cell types, and inhibited the expression of erythroleukemia carcinogene Fli-1 in the human erythroleukemia cell line HEL. Additionally,treatment with the compound induced a time-dependent increase in expression of LC 3A/B via inhibiting the AKT-mTOR pathway, which is associated with cell autophagy. Taken together, the above results suggest that the novel synthesized 3',5'-diprenylated chalcone can prevent the growth of leukemia cells by inducing apoptosis and autophagy. PMID- 29990874 TI - Therapeutic effects of JLX001 on cerebral ischemia through inhibiting platelet activation and thrombus formation in rats. AB - (3beta,5alpha,16alpha,20S)-4,4,14-trimethyl-3,20-bis(methylamino)-9,19 cyclopregnan-16-ol-dihydrochloride (JLX001), a derivative of cyclovirobuxine D (CVB-D), is a novel compound from synthesis. This study aims to confirm the therapeutic effect of JLX001 on cerebral ischemia and researchits antiplatelet and antithrombosis activities via thromboxane (TXA2)/phospholipase C-beta 3(PLCbeta3)/protein kinase C (PKC) pathway suppression. The therapeutic effects of JLX001 was evaluated by infarct sizes, brain edema and neurological scores in Sprague-Dawley (SD) rats with middle cerebral artery occlusion (MCAO). Brain TXA2 and prostacyclin (PGI2) were measured by enzyme-linked immunosorbentassay (ELISA). P-PLCbeta3and activated PKC were detected by immunohistochemical method. Adenosine diphosphate (ADP) or 9, 11-dieoxy-11alpha, 9alpha epoxymethanoeprostaglandin F2alpha (U46619) was used as platelet agonist in the in vivo and in vitro platelet aggregation experiments. Clotting time and bleeding time were determined. Besides, two whole-animal experiments including arteriovenous shunt thrombosis and pulmonary thromboembolism model were conducted. Results showed that JLX001 treatment markedly alleviated cerebral infarcts, edema, and neurological scores in permanent middle cerebral artery occlusion (pMCAO) rats. Brain TXA2 level, p-PLCbeta3and activated PKC were decreased, while PGI2level had no significant change. Besides, JLX001 inhibited platelet aggregation induced by ADP or U46619 and exhibited anti-coagulation effects with a minor bleeding risk. In the two whole-animal experiments, JLX001 inhibited thrombus formation. In summary, JLX001 attenuates cerebral ischemia injury and the underlying mechanisms relate to inhibiting platelet activation and thrombus formation via TXA2/PLCbeta3/PKC pathway suppression. PMID- 29990875 TI - Study on the efficacy and mechanism of triptolide on treating TNF transgenic mice with rheumatoid arthritis. AB - OBJECTIVE: To discuss the curative effect and security of triptolide (TPL) on TNF transgenic (TNF-Tg) mice with rheumatoid arthritis (RA), and to explore the mechanism primarily. METHOD: 40 TNF-Tg RA mice were randomlydivided into five groups averagely: the control group, low-dose group (3.3 MUg/kg/d TPL), middle dose group (10 MUg/kg/d TPL), high-dose group (33 MUg/kg/d TPL) and MTX group (0.1 mg/kg/d MTX). Mice were administrated five days a week for six weeks. The arthritis deformation index, arthritis detumescencepercentage and the level of inflammatory factor in each group were recorded during theadministration. After administration, body weight, liver and renal function indexes, the apoptosis rates of osteoclast precursors (OCP), T and B lymphocytes in the peripheral blood and the number of osteoclast (OC) were detected and compared. MUCT scanning and HE staining methods were taken to observethebone histomorphometry and bony erosion. RESULT: After administration, the arthritis deformation indexes were lower and arthritis detumescence percentageswere higher in TPL groups thanthe control group (P < 0.05), and the arthritis detumescence percentage in the high dose group was higher than the MTX group (P < 0.05). The liver function index ALT increased after administrationin the high-dose group but was lower than that in the MTX group (P < 0.05). The level of IL-1alpha, IL-1beta, and TNF-alpha decreased in the TPL groups and MTX group after administration;The apoptosis rates of OCP and T lymphocytes in middle and high dose TPL groups and MTX group were higher than other groups, and that in the high-dose group was higher than the MTX group (P < 0.05). Compared with the other groups, the bony erosion degree was lower and the number of OC was less and the parameters of bone histomorphometry were better in the high-dose group. CONCLUSION: TPL could improvearthritic of TNF-Tg mice by decreasing the levels of pro-inflammatory cytokines, promoting the apoptosis of OCP, inhibiting the generation of OC and bone resorption. There was some toxic and side effect on liver for high-dose TPL which was weaker than the MTX. PMID- 29990876 TI - beta-Asarone suppresses Wnt/beta-catenin signaling to reduce viability, inhibit migration/invasion/adhesion and induce mitochondria-related apoptosis in lung cancer cells. AB - Lung cancer is the leading cause of cancer death worldwide. Chemotherapy is one of the most effective strategies for lung cancer treatment. However, the side effects of chemotherapy limit the application of chemotherapeutic agents. The beta-Asarone, a low-toxicity natural compound from a traditional Chinese medicinal herb, has been demonstrated to display anticancer activities in multiple cancer types. However, the anticancer activities of beta-Asarone in lung cancer have not been shown, and the underlying molecular mechanisms are still unclear. In the current study, we show that beta-Asarone displays a dose dependent inhibitory effect on the viability of lung cancer cells. Additionally, beta-Asarone significantly suppresses the cell migration, invasion, and adhesion of lung cancer cells. Moreover, beta-Asarone induces apoptosis associated with the activation of caspase-9 and caspase-3, the upregulation of XAF1, Puma, Bax (Ser184) and Bad (Ser112), the downregulation of XIAP, Bcl-2 and Survivin, the translocation of Bax, Bad, phospho-Bax (Ser184), phospho-Bad (Ser112) and cytochrome C and the reduction of the mitochondrial membrane potential. Mechanistically, our study shows that beta-Asarone inhibits Wnt/beta-catenin signaling. Rescuing the activation of Wnt/beta-catenin signaling overcomes beta Asarone-induced anticancer effects. Taken together, our data provide the first evidence of the anticancer effects of beta-Asarone in lung cancer, demonstrates that the inhibition of Wnt/beta-catenin signaling could be critical for beta Asarone-induced anticancer effects. Our study thus suggests a potential application of beta-Asarone as an anticancer agent in the clinical treatment of lung cancer. PMID- 29990877 TI - Degradation of antibiotic ampicillin on boron-doped diamond anode using the combined electrochemical oxidation - Sodium persulfate process. AB - In this work, the electrochemical oxidation of antibiotic ampicillin (AMP) on a boron-doped diamond anode in the presence of sodium persulfate (SPS) was investigated (EO/SPS process). Experiments were conducted at AMP concentrations between 0.8 and 3 mg/L, SPS concentrations between 100 and 500 mg/L, current densities between 5 and 110 mA/cm2, in three water matrices (ultrapure water, bottled water and secondary treated wastewater), using 0.1 M Na2SO4 as the supporting electrolyte. AMP degradation follows a pseudo-first order kinetic expression with the apparent rate constant increasing with (i) increasing SPS concentration (from 0.08 min-1 to 0.36 min-1 at 0 and 500 mg/L SPS, respectively, 1.1 mg/L AMP, 25 mA/cm2), (ii) increasing current (from 0.08 min-1 to 0.6 min-1 at 5 and 110 mA/cm2, respectively, 1.1 mg/L AMP, 250 mg/L SPS), and (iii) decreasing AMP concentration (from 0.16 min-1 to 0.31 min-1 at 3 and 0.8 mg/L, respectively, 250 mg/L SPS, 25 mA/cm2). The presence of various anions (mainly bicarbonates) in bottled water did not impact AMP degradation. The observed kinetic constant decreased by 40% in the presence of 10 mg/L humic acid. On the other hand, process efficiency was enhanced almost 3.5 times in secondary effluent due to the electrogeneration of active chlorine species that promote indirect oxidation reactions in the bulk solution. The efficacy of the EO/SPS process was compared to and found to be considerably greater than a process where SPS was activated by simulated solar irradiation at an intensity of 7.3 * 10-7 E/(L.s) (SLR/SPS process). Coupling the two processes (EO/SLR/SPS) resulted in a cumulative, in terms of AMP degradation, effect. The combined process was tested for AMP degradation, mineralization and inhibition to Vibrio fischeri in wastewater; fast AMP removal was accompanied by low mineralization and incomplete toxicity removal. PMID- 29990878 TI - Insights on the transport of tamoxifen by gold nanoparticles for MCF-7 breast cancer cells based on SERS spectroscopy. AB - Gold nanoparticles (AuNP) were synthesized and modified with anti-folate receptor antibody (AB), folic acid (FA), crystal violet (CV), poly (ethyleneglycol) methyl ether thiol and the antineoplastic drug tamoxifen (TAM). Such a preparation was incubated in vitro with MCF-7 human breast cancer cells, showing a decrease in the TAM dosage for the reduction of cell viability. The adsorption of TAM on gold surface was investigated by surface-enhanced Raman scattering (SERS) spectroscopy and the assignment based on Density Functional Theory calculations showed that the ether moiety was involved in the interactions with the metal. Such a chemical affinity was correlated with the carrying of TAM in the biological media. CV was included in the preparation as a molecular probe for SERS spectroscopy, whose signal was monitored to analyse the efficiency of the modified AuNP in the target of neoplastic cells. The results showed AB, FA and TAM components had complementary roles in the cell recognition and, therefore, in the efficiency of the drug carrier nanosystem. PMID- 29990879 TI - High selective and sensitive detection of Zn(II) using tetrapeptide-based dansyl fluorescent chemosensor and its application in cell imaging. AB - The zinc ions (Zn2+) play extremely irreplaceable role in the organism and the environment, the design and synthesis of a biomolecule-based fluorescence chemosensor for the detection of Zn2+ with high sensitivity is very important. Herein, a novel tetrapeptide-based dansyl fluorescent "turn-on" response chemosensor (L) has been designed and synthesized by solid phase peptide synthesis (SPPS). As designed, L can detect Zn2+ ions with specifically and sensitively based on photo-induced electron transfer (PET) mechanism in 100% aqueous solutions, and other metal ions do not interfere with Zn2+ ions recognition. The stoichiometric ratio of L with Zn2+ ions was 2:1, which matches with fluorescence titration and Job-plot assay. In addition, the reversibility and circularly process of the detection of L was confirmed by adding bonding agent Na2EDTA. Moreover, L exhibits excellent biocompatibility and low biotoxicity with the limit of detection (LOD) for Zn2+ about 18 nM, and has been successfully utilized for fluorescence imaging of Zn2+ ions in living HeLa cells under physiological conditions. PMID- 29990880 TI - Smart spectrophotometric methods based on normalized spectra for simultaneous determination of alogliptin and metformin in their combined tablets. AB - Alogliptin (ALO) and metformin (MET) are coformulated for the treatment of type II diabetes mellitus. ALO is estimated at its lambdamax 277 nm (0D), while MET was determined accurately by four spectrophotometric methods with minimum manipulation steps based on normalized division spectrum namely; ratio difference, advanced amplitude modulation, first derivative ratio (1DD) and mean centering of the ratio spectra spectrophotometric methods. Linearity was acceptable over the concentration ranges of 5-40 and 2-16 MUg/mL for ALO and MET, respectively. Accuracy and precision of the suggested methods were found to be within the acceptable limit. The specificity was inspected by analyzing laboratory prepared mixtures of the above drugs and their pharmaceutical preparation. The results of proposed and reported methods were statistically compared showing no significant difference regarding accuracy and precision. The developed methods could be applied for routine analysis of the cited drugs in quality control laboratories. PMID- 29990881 TI - Development and validation of a UFLC-MS/MS method for simultaneous quantification of sixty-six saponins and their six aglycones: Application to comparative analysis of red ginseng and white ginseng. AB - A new and sensitive ultra fast liquid chromatography coupled with electrospray ionization triple quadrupole tandem mass spectrometry (UFLC-MS/MS) method was developed to evaluate the quality of Red ginseng (RG) and to find out its chemical markers by comparing with multi-batches of RG and white ginseng (WG). This innovative method could quantify sixty-six saponins and their six aglycones including 10 pairs of 20(S) and 20(R) epimers within 35 min simultaneously. All compounds could be determined in individual multiple-reaction monitoring channel without interference, and the optimized method was rapid, accurate, precise, reproducible and efficient. Using the orthogonal partial least squared discriminant analysis, ginsenosides Rg5, Rh4, Rk1, Rs4, F4, and 20(S)-Rg3 were found to be the characteristic components of RG, the six compounds should be suggested as quality control markers to distinguish RG from WG. These findings will be significant for standardizing the processing procedures of RG and ensuring the consistent quality, as well as consequently the efficacy of RG in clinical applications. Results will be helpful in providing crucial chemical profiles of RG. PMID- 29990882 TI - 27Al and 31P NMR spectroscopy method development to quantify aluminum phosphate in adjuvanted vaccine formulations. AB - A novel qNMR method is described for the quantitative determination of total aluminum and phosphate in aluminum phosphate (AlPO4) adjuvanted vaccine samples using solution 27Al and 31P nuclear magnetic resonance (NMR) spectroscopy. External standard calibrations of AlPO4 solutions established excellent linearity in the range of 15-40 * 10-3 M and additional studies determined the level of detection for both nuclei. A commercialized combination vaccine product (Quadracel(r)), along with several individual adsorbed antigen components used in the vaccine were employed as model systems for method development. The developed method is also capable of quantitating the free phosphate (i.e. the fraction not bound to AlPO4 particles) in adjuvanted vaccines. This study is the first demonstration of a solution NMR method that is suitable for measuring total aluminum, and free and total phosphate concentrations in vaccine formulations consisting of antigen(s) adsorbed to aluminum adjuvant, in a single analytical workflow. PMID- 29990883 TI - A high crosslinking grade of hyaluronic acid found in a dermal filler causing adverse effects. AB - Facial treatments with dermal fillers for medical or esthetic purposes occasionally give rise to adverse effects, ranging from temporary effects such as reddening of the skin, to long term effects such as hardening of tissue. There appears to be a relationship between the lifetime of the filler product and the risk for adverse effects. The lifetime of hyaluronic acid-based fillers is dependent on the presence and amount of crosslinking agents such as 1,4 butanediol diglycidyl ether (BDDE). It would therefore make sense to establish methodology to analyze the crosslinking grade of HA-based filler products on a routine basis. To this end, an analytical method was developed and validated to identify HA-BDDE-based fillers and to quantify their modification and crosslinking grade. The method was subsequently applied to products from the legal supply chain and the illegal market. It was found that the product Hyacorp H 1000, previously taken from the market, indeed contains a high modification grade and crosslinking grade, as was the assumed reason for the increased risk for adverse effects of this product. However, it was also shown that the Hyacorp products are highly unreliable in relation to their product composition in general. In this study, authentic products could not be distinguished from the illegal market products based on their modification and crosslinking grade. PMID- 29990884 TI - Study on the compatibility interactions of formula Ding-Zhi-Xiao-Wan based on their main components transport characteristics across Caco-2 monolayers model. AB - Influencing the absorption of effective components in the intestines is one of the important compatibility mechanisms of the traditional Chinese medicine. Simulation of drug absorption through an in vitro intestinal epithelial cell line is an important method to study the interaction of drug compatibility and bioavailability of drugs. In this study, the compatibility mechanism of Ding-Zhi Xiao-Wan (DZXW) was investigated by using the in vitro Caco-2 cell monolayers model. Decomposing the formula into single herb and drug-pair to clarify the compatibility mechanism was firstly used. The transport characteristics of 20 major bioactive compounds including 8 ginsenosides, 6 poria triterpenes, 3 onjisaponins, one polygala oligosaccharide and two essential oils were selected as the main evaluation factor, and the absorption of these compounds by Caco-2 cells in the single herb group, drug-pair group and DZXW group were detected by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS). The results showed that the absorption of ginsenosides and polysaponins were related to the numbers of glycosyl groups, and the uptaken of poria triterpenes was dominated by lipophilicity. Polygala radix played a critical role in the permeability of gensenosides, and acorus tatarinowii rhizome dominated permeability of poria triterpenes. The apparent permeability coefficients of ginsenosides and poria triterpenes were greater than 14.0 * 10-6 cm s-1, indicating they could be absorbed well, and the ginseng and poria cocos might played the crucial role in the efficacy of DZXW. Herbal combination could remarkable improve the absorption of 18 compounds and the scientific rationality compatibility of DZXW formula was proved. PMID- 29990885 TI - Simultaneous quantification of Schisandrin B enantiomers in rat plasma by chiral LC-MS/MS: Application in a stereoselective pharmacokinetic study. AB - Schisandrin B (Sch B) has received much attention owing to its various biological activities. Schisandrin B exists as a racemate in "wuweizi", a traditional Chinese medicine in China. In the present study, a novel chiral LC-MS/MS method was developed for enantioselective separation and determination of Schisandrin B in rat plasma. The plasma samples were prepared by liquid-liquid extraction (LLE). Schisandrol B was used as internal standard. Chiral separation was obtained on a Chiralpak IC column using 0.1% (v/v) formic acid in mixture of methanol and water (90:10, v/v) as a mobile phase. Parameters including the selectivity, linearity, precision, accuracy, extraction recovery, matrix effect and stability were evaluated. The method described here is simple and reproducible. The lower limit of quantification of 5.0 ng/mL for each Sch B enantiomer permits the use of the method in investigating the stereoselective pharmacokinetics of Sch B. Following racemic Sch B and "wuweizi" extracts, the area under the curve of (8R, 8'S)-Sch B was statistically higher than the one of (8S, 8' R)-Sch B, with a ratio of 1.16-1.40 in three cases. This study firstly reports the development and validation of enantioselective behavior of Sch B in vivo, and provides a reference for clinical practice and encourages further research into Sch B enantioselective metabolism and drug interactions. PMID- 29990886 TI - Simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in rat plasma by using high performance liquid chromatography-diode array detector. AB - In this manuscript we aimed at the simultaneous separation and quantification of Gemcitabine and Irinotecan hydrochloride (injected both as single components and in combination) from Sprague Dawley rat plasma by using a validated method obtained through the use of a High Performance Liquid Chromatography (HPLC)-diode array detector (DAD). Gemcitabine and Irinotecan hydrochloride were detected and quantified using a Zorbax Extend C-18 column (250 mm * 4.6 mm; 5 MUm particle size) in gradient elution mode. The chromatographic analyses were carried out in 15 min. The analytical mode was calibrated and validated in the concentration range from 0.1 to 18 MUg/mL both for Gemcitabine and Irinotecan hydrochloride. Sprague Dawley rat plasma was used to perform the analysis. 3-methylxanthine was the internal standard. The weighted-matrix matched standard curves of Gemcitabine and Irinotecan hydrochloride showed a good linearity up to 18 MUg/mL. Parallelism tests were also performed to evaluate whether the over-range samples could be analyzed after dilution without affecting the analytical performance. The intra- and inter-day precision (RSD%) values of Gemcitabine and Irinotecan hydrochloride were <=7.14% and <=11.5%, respectively. The intra- and inter-day trueness (Bias%) values were in the range from -11.5% to 1.70% for both drugs. The analytical mode performance was further tested after collecting Sprague Dawley rat plasma following a single-dose administration of chemotherapeutics or their association. The validated HPLC-DAD method allowed the simultaneous quantification of Gemcitabine and Irinotecan hydrochloride in the rat plasma, besides the evaluation of the pharmacokinetic parameters and drug delivery. PMID- 29990887 TI - Identification and structural characterization of in vivo metabolites of balofloxacin in rat plasma, urine and feces samples using Q-TOF/LC/ESI/MS/MS : In silico toxicity studies. AB - Balofloxacin is a fluroquinolone antibiotic drug which has been used for the treatment of urinary tract infections (UTIs). Identification and structural characterization of metabolites is a critical component of both drug discovery and drug development research. In vivo metabolites of balofloxacin have been identified and characterized by using liquid chromatography positive ion electrospray ionization high resolution tandem mass spectrometry (LC/ESI-HR MS/MS) experiments. To identify in vivo metabolites, blood, urine and feces samples were collected after oral administration of the drug to the female Sprague-Dawley rats (n = 3 per group). Protein precipitation, freeze liquid separation followed by solid-phase extraction methods were used for sample preparation. The extracted samples were subjected to LC-ESI/HRMS/MS analysis. The chromatographic separation of the drug and its metabolites were achieved on a XDB, C18 (50, 4.6 mm, 5 mm) column using gradient elution method in combination with 0.1% formic acid and acetonitrile at a flow rate of 0.4 mL/min. A total of 13 phase I and phase II metabolites of balofloxacin have been identified in plasma, urine and feces samples. Most of metabolites were observed in plasma and urine samples including dealkylated, desmethylated, decarbonylated, decarboxylated, hydroxylated, methylated, carboxylated, cysteine conjugated metabolites and high abundance glucuronidated metabolite. The structures of metabolites have been elucidated based on fragmentation patterns, accurate mass measurements and LC/MS/MS experiments. The main phase I metabolites of balofloxacin, decarbonylated, decarboxylated and desmethylated metabolites and phase II methylated metabolite undergo subsequent phase II glucuronidation pathways. In silico toxicity of the drug and its metabolites was determined using ProTox-II. Metabolites B-1, B-2, B-5, B-6, B-7, and B-8 to B-13 were predicted to possess immunotoxicity with high probability score. Additionally, Amine Oxidase A and Prostaglandin G/H Synthase 1 are predicted for metabolites B-1, B-3 to B-6 as toxicity targets with binding probability. PMID- 29990888 TI - Enantioselective analysis for L-pidolic acid in ertugliflozin drug substance and drug product by chiral gas chromatography with derivatization. AB - L-pidolic acid is being used as a coformer for ertugliflozin, a sodium-glucose cotransport 2 inhibitor. A sensitive and rapid two-step achiral derivatization combined with gas chromatography with flame ionization detection or gas chromatography with mass spectroscopic detection was developed and validated for the enantiomeric purity determination of L-pidolic acid in the drug substance and drug product, respectively. The method was used to analyze ertugliflozin drug substance forced degradation samples and showed no racemization of pidolic acid in any of the solid or solution stress samples. Analysis of ertugliflozin drug product stability samples showed no significant levels of D-pidolic acid in the drug product indicating that no significant racemization of pidolic acid occurs in the drug product under normal storage conditions. Based on the data generated, a chiral control for pidolic acid is not necessary for drug substance or drug product, but rather can be controlled in the purchase of L-pidolic acid. PMID- 29990889 TI - Stressed degradation studies of domiphen bromide by LC-ESI-MS/MS identify a novel promising antimicrobial agent. AB - Nowadays, parabens have been replaced by domiphen bromide, which is widely used in pharmaceutical and cosmetic products. The main aim of this study was to investigate stressed degradation products of domiphen bromide by mean of a rapid, specific and reliable LC-ESI MS/MS since phenyl bromination may occur due to the oxidation of bromide counter ion under oxidative conditions. LC-ESI-MS/MS have characterized a new compound, p-bromodomiphen, as the only degradation product and structure elucidation was also confirmed by the synthesis of the standard. Notably, the resulting p-bromodomiphen bromide is more stable then domiphen bromide in oxidizing conditions since no di-bromoderivatives were detected by MS studies; both domiphen and its p-bromo derivative were tested for antibacterial activity and were more effective on Gram positive (Staphylococcus aureus ATCC25923 and Bacillus cereus DSM31) compared to Gram negative bacteria (Escherichia coli ATCC25922 and Pseudomonas aeruginosa DSM22644). In conclusion, stressed degradation studies by LC-ESI-MS/MS have characterized a new compound that comprises an alternative to domiphen bromide since its antimicrobial activity is comparable to, if not better than, the parental compound. PMID- 29990890 TI - A study of low-molecular-weight organic acid urinary profiles in prostate cancer by a new liquid chromatography-tandem mass spectrometry method. AB - Metabolomic studies constantly require high throughput screenings, and this drives development and optimization of methods that include more analytes in a single run, shorten the analysis time and simplify sample preparation. The aim of the study was to develop a new simple and fast liquid chromatography-tandem mass spectrometry-based methodology for quantitative analysis of a panel of ten organic acids in urine. The metabolites selected for the study include ten molecules potentially associated with cancer development. Chromatographic separation involved a Phenomenex Synergi Hydro-RP column under gradient conditions. Quantitation of the analytes was performed in multiple reaction monitoring mode under negative ionization. Validation parameters were satisfactory and in line with the international guidelines. The methodology enabled us to analyze urine samples collected from prostate cancer (PC) (n = 49) and benign prostate hyperplasia (BPH) (n = 49) patients. The obtained concentrations were normalized with urinary specific gravity (USG) prior to statistical analysis. Five analytes were quantified in all urine samples and we observed the following USG-normalized concentration ranges: citric acid (146.5 6339.8), 3-hydroxyisobutyric acid (22.5-431.7), 2-ketoglutaric acid (4.4-334.4), lactic acid (10.1-786.3), succinic acid (4.1-500.5). 3-hydroxyisobutyric acid significantly decreased between two groups of prostate cancer patients: >=7 Gleason patients and <7 Gleason patients. Quick sample preparation limited to "dilute and shoot" makes the developed methodology a great tool for future metabolomic studies, especially for detecting disturbances in energy metabolism (Krebs cycle) and amino acids metabolism. The research also broadens our knowledge on the alteration of selected organic acids in PC and BPH patients. PMID- 29990891 TI - On-line coupling of achiral Reversed Phase Liquid Chromatography and chiral Supercritical Fluid Chromatography for the analysis of pharmaceutical compounds. AB - On-line selective comprehensive two-dimensional chromatography combining Reversed Phase Liquid Chromatography and Supercritical Fluid Chromatography (sRPLCxSFC) was investigated for the analysis of chiral pharmaceutical compounds. Preliminary studies were carried out with the aim of overcoming instrumental constraints which are related to such 2D-coupling. The impact of both injection solvent and injection volume on the chiral SFC second separation was assessed with a view to limiting injection effects due to mobile phase compatibility issues between both dimensions. The resulting on-line sRPLCxSFC system was applied to the achiral x chiral analysis of a pharmaceutical sample. Using an Acquity BEH C18 column in the first dimension and a Chiralpak IC column in the second one, both chemical (achiral) and enantiomeric (chiral) purities could be evaluated in less than 50 min within a single run. Under such conditions, a detection limit of about 0.5% for R-enantiomer could be obtained with UV detection. The results obtained in sRPLCxSFC were compared to those obtained in conventional chiral 1D-SFC. Baseline resolution was obtained in both cases and the linearity in the detector response was on the same order of magnitude (R2 > 0.99). Finally, despite current instrumental limitations (no commercially available system for sLCxSFC, large dwell volume and large extra-column volume in SFC), the on-line coupling of RPLC and SFC appears to be attractive and promising for rapid achiral/chiral analysis of complex pharmaceutical samples. PMID- 29990892 TI - 68Ga-NOTA-ubiquicidin fragment for PET imaging of infection: From bench to bedside. AB - This study explores the possibility of formulation of a cold kit for fast and easy preparation of a PET radiopharmaceutical, 68Ga-NOTA-UBI (29-41) for clinical translation. In this study, Circular dichroism (CD) spectroscopy to study conformation of NOTA-UBI (29-41) and its comparison with conformation of UBI (29 41) was done. Pharmaceutical grade cold kits of NOTA-UBI (29-41) were formulated for radiolabeling with 68Ga and necessary quality control tests were carried out. 68Ga-NOTA-UBI (29-41) could be prepared in >90% radiochemical yield and radiochemical purity using cold kits of NOTA-UBI (29-41). In vitro and in vivo evaluation of 68Ga-NOTA-UBI (29-41) was done to demonstrate specificity of the agent for imaging infection. Kits were utilized for preparation of patient dose of 68Ga-NOTA-UBI (29-41). Simple instant thin layer chromatography (ITLC) method for estimating radiolabeling yield of 68Ga-NOTA-UBI (29-41) at hospital radiopharmacy was demonstrated. Clinical evaluation was done in patients with suspected infection. 148-185 MBq of 68Ga-NOTA-UBI (29-41) was injected intravenously in three patients. 68Ga-NOTA-UBI (29-41) uptake could clearly delineate infection foci from non target normal tissues. This is the first report on formulation of a cold kit of NOTA-UBI (29-41) for preparation of 68Ga labeled NOTA-UBI(29-41) at hospital radiopharmacy for infection imaging. Initial clinical evaluation reveal it to be a prospective agent for imaging infection. PMID- 29990893 TI - Investigation of the hepatoprotective effect of Corydalis saxicola Bunting on carbon tetrachloride-induced liver fibrosis in rats by 1H-NMR-based metabonomics and network pharmacology approaches. AB - Liver fibrosis is a common consequence of chronic liver diseases resulting from multiple etiologies. Furthermore, prolonged unresolved liver fibrosis may gradually progress to cirrhosis, and eventually evolve into hepatocellular carcinoma (HCC). Corydalis saxicola Bunting (CS), a type of traditional Chinese folk medicine, has been reported to have hepatoprotective effects on the liver. However, the exact mechanism of how it cures liver fibrosis requires further elucidation. In this work, an integrated approach combining proton nuclear magnetic resonance (1H-NMR)-based metabonomics and network pharmacology was adopted to elucidate the anti-fibrosis mechanism of CS. Metabonomic study of serum biochemical changes by carbon tetrachloride (CCl4)-induced liver fibrosis in rats after CS treatment were performed using 1H-NMR analysis. Metabolic profiling by means of partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation caused by CCl4 was reduced after CS treatment. As a result, lipids, leucine, alanine, acetate, O-acetyl-glycoprotein and creatine were significantly restored after CS treatment, which regulated valine, leucine and isoleucine metabolism; arginine and proline metabolism; lipid metabolism and pyruvate metabolism. Additionally, 157 potential targets of CS and 265 targets of liver fibrosis were identified by means of network pharmacology. Subsequently, 5 target proteins, which are the intersection of potential CS targets and liver fibrosis targets, indicated that CS has potential anti-fibrosis effects through regulating alanine aminotransferase (ALT) activity, the farnesoid X receptor (FXR), cyclooxygenase-2 (COX-2), matrix metalloproteinase-1 (MMP-1) and angiotensinogen. Chelerythrine and sanguinarine were the potential active compounds in CS for treating liver fibrosis through regulating ALT activity. This study is the first report to study the anti-fibrosis effects of CS on the basis of combining a metabonomics and network pharmacology approaches, and it may be a potentially powerful tool to study the efficacy and mechanisms of traditional Chinese folk medicines. PMID- 29990894 TI - A phase II baseline versus treatment study to determine the efficacy of raltegravir (Isentress) in preventing progression of relapsing remitting multiple sclerosis as determined by gadolinium-enhanced MRI: The INSPIRE study. AB - BACKGROUND: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. OBJECTIVES: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. METHODS: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. RESULTS: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1beta, IL-6, IL 10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. CONCLUSIONS: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found. PMID- 29990895 TI - Synthesis, biological activities, and molecular docking studies of 2 mercaptobenzimidazole based derivatives. AB - A new series of N-acylhydrazone derivatives of 2-mercaptobenzimidazole (2-MBI) has been synthesized through S-alkylation with 1-bromotetradecane and N alkylation with ethyl-2-chloroacetate. The resulting ester was synthetically modified through hydrazine hydrate to acyl hydrazide which was condensed with aromatic aldehydes to afford the title N-acylhydrazones (4-17). Chemical structures of the newly synthesized compounds have been confirmed through mass, FT-IR and 1HNMR techniques. In vitro free radical scavenging and alpha glucosidase inhibition activities of the compounds were investigated with reference to the standard ascorbic acid and acarbose, respectively. Amongst the target compounds, 13 showed the highest inhibition in DPPH scavenging assay (IC50 = 131.50 uM) and alpha-glucosidase inhibition potential (IC50 = 352 ug/ml). We extended our investigations to explore the mechanism of enzyme inhibition and conducted docking analysis by using Molecular Operating Environment (MOE 2016.08). A homology model for alpha-glucosidase was constructed and validated using Ramachandran plot. Docking studies were also carried out on human intestinal alpha-glucosidases. In view of the importance of the nucleus involved, the synthesized compounds might find extensive medicinal applications as reported in the literature. PMID- 29990896 TI - Synthesis and dopaminergic activity of a series of new 1-aryl tetrahydroisoquinolines and 2-substituted 1-aryl-3-tetrahydrobenzazepines. AB - A series of new 1-aryl-6,7-dihydroxy tetrahydroisoquinolines with several substitution patterns in the 1-aryl group at C-1 were prepared in good yields. The influence of each substituent on the affinity and selectivity for D1 and D2 dopaminergic receptors was studied. Moreover, N-alkyl salts of these tetrahydroisoquinolines were used as starting material to synthesize a series of new 1-aryl-7,8-dihydroxy 3-tetrahydrobenzazepines derivatives with electron withdrawing substituents at C-2 position by the diastereoselective Stevens rearrangement. The structure-activity relationship of these compounds was explored to evaluate the effect of the functional group at C-2 in benzazepines and the modification in the aryl group at the isoquinoline C-1 position towards the affinity and selectivity for the mentioned receptors. The 1-aryl-6,7 dihydroxy tetrahydroisoquinoline 4c shows significant affinity towards D2 receptor, with Ki value of 31 nM. This significant affinity can be attributed to the presence of a thiomethyl group, and it is the most active 1-aryl-6,7 dihydroxy tetrahydroisoquinoline derivative reported to date. PMID- 29990897 TI - Design, synthesis and activity of light deactivatable microRNA inhibitor. AB - miRNAs are key cellular regulators and their dysregulation is associated with many human diseases. They are usually produced locally in a spatiotemporally controlled manner to target mRNAs and regulate gene expression. Thus, developing chemical tools for manipulating miRNA with spatiotemporal precise is critical for studying miRNA. Herein, we designed a strategy to control miRNA biogenesis with light controllable inhibitor targeting the pre-miRNA processing by Dicer. By conjugating two non-inhibiting units, a low affinity Dicer inhibitor and a pre miRNA binder, through a photocleavable linker, the bifunctional molecule obtained could inhibit miRNA production. Taking advantage of the photocleavable property of the linker, the bifunctional inhibitor can be fragmented into separate non inhibiting units and therefore be deactivated by light. We expect that this strategy could be applied to generate chemical biological tools that allow light mediated spatiotemporal control of miRNA maturation and contribute to the study of miRNA function. PMID- 29990898 TI - Clomazone influence soil microbial community and soil nitrogen cycling. AB - We designed an indoor mesocosm experiment to investigate the long-term effects of exposure to clomazone, a widely used herbicide, on soil microbial communities and their nitrogen (N) cycling functions. Clomazone was applied to two typical soils from China at three concentrations: 0.8 (the recommended dosage), 8 and 80 mg kg 1 soil dry weight, and the mix was incubated for 90 days. Samples were removed periodically for assay with several techniques. The half-lives of clomazone in this experiment were 11-126 d. Results were significant only for the highest clomazone concentration. Next-generation sequencing of the 16S and 18S rDNA genes revealed that bacterial diversity significantly decreased whereas fungal abundance increased after day 60 but with no detectable effect on the microbial community. Hierarchical cluster and principal coordinates analysis revealed that the bacterial community structure was negatively impacted. Linear discriminant analysis of effect size identified Sphingomonas and Arthrobacter as the predominant bacterial species. Finally, we measured soil NH4+ and NO3- concentrations and used real-time PCR to analyze the abundance of the N-cycling genes, nifH and amoA. In the first 30 days, the NO3--N content and the number of ammonia-oxidizing bacteria increased. N2-fixing bacteria were inhibited after 60 days, but the NH4+-N concentration remained unchanged and was likely provided by ammoniation. PMID- 29990899 TI - Different bacterial species and their extracellular polymeric substances (EPSs) significantly affected reverse osmosis (RO) membrane fouling potentials in wastewater reclamation. AB - Biofouling represents the "Achilles' heel" for reverse osmosis (RO) processes due to the growth of bacteria and their production of extracellular polymeric substances (EPSs). Although the microbial community structure on the RO membrane has been analysed previously, the bacterial species with a high potential of causing RO membrane fouling have not yet been identified clearly. The key components in EPSs causing RO membrane fouling have not been revealed either. In this study, seven different bacterial species were isolated from fouled RO membranes, and their EPSs were analysed in terms of the content of polysaccharides and proteins, fluorescence characteristics and molecular weight (MW) distributions. The membrane fouling potentials of these bacterial species and EPSs were evaluated based on normalized flux decline. Generally, under the same growth conditions, bacterial species with higher EPS concentrations, rather than higher cell numbers, resulted in more severe flux decline. The flux decline showed an apparent positive correlation with the EPS concentration, indicating that the concentration of EPS rather than the bacterial number mainly contributed to biofouling. Furthermore, it was found that the MW distribution was the key factor affecting the RO membrane fouling potential of EPSs from different bacterial species. With the increase in the percentage of the high-MW fraction (>10 kDa) in the EPSs from 12.6% to 74.4%, the normalized flux decline increased from 0.4 to 0.59. The components in EPSs with a MW over 10 kDa were also separated by the ultrafiltration membrane and were proven to have a higher membrane fouling potential. PMID- 29990900 TI - Changes of quinolone resistance genes and their relations with microbial profiles during vermicomposting of municipal excess sludge. AB - Antibiotic resistance genes abundant in municipal excess sludge reduce the agricultural value of vermicompost. However, little attention has been paid on the fate and behavior of the problem-causing agents in vermicomposting. In this study, the fate and behavior of quinolone resistance genes in excess activated sludge during vermicomposting were studied with reactors introduced with Eisenia fetida for three different densities. The substrate pile without earthworms was operated as control in parallel. The results showed that earthworms could significantly reduce the absolute abundance of quinolone resistance genes in the excess sludge, with a reduction ratio of 85.6-100% for qnr A and 92.3-95.3% for qnr S, respectively (p < 0.05). For microbial profiles, both the dehydrogenase activity and the abundance of microbes (16S rDNA) revealed a distinct decreasing trend after 7 days from the start of the experiment; however, the bacterial diversity in the final products seemed to be enriched with the emergence of the uncultured Flavobacteriales bacterium and uncultured Anaerolineaceae bacterium. Redundancy analysis revealed clearly that the qnr genes had positive correlations with the targeted indexes of microbial profiles, with the correlations with the bacterial abundance and dehydrogenase activity being more statistically significant than the bacterial diversity (p < 0.05). The results of this study suggested that earthworms could promote the attenuation of quinolone resistance genes in the excess sludge through lowering the bacterial abundance and activity, and the promotion effect could be enhanced by increasing the density of earthworms. PMID- 29990901 TI - Prediction of land use changes based on Land Change Modeler and attribution of changes in the water balance of Ganga basin to land use change using the SWAT model. AB - Conflicts between increasing irrigated agricultural area, commercial crops, shifting cultivation and ever increasing domestic and industrial demand has already been a cause of tension in the society over water in the Ganga River Basin, India. For the development of sustainable water resource strategies, it is essential to establish interaction between landuse changes and local hydrology through proper assessment. Precisely, seeing how change in each LULC affects hydrologic regimes, or conversely evaluating which LULC shall be appropriate for the local hydrological regime can help decision makers to incorporate in the policy instruments. In this study, hydrologic regimes of the Ganga River basin have been assessed with landuse change. Catchment hydrologic responses were simulated using Soil and Water Assessment Tool (SWAT). Meteorological data from IMD of 0.25 degrees * 0.25 degrees spatial resolution were taken as the climate inputs. Simulated stream flow was compared at different gauge stations distributed across the Gang River and its tributaries. Urbanization has been the topmost contributor to the increase in surface runoff and water yield. While increased irrigation demands were the dominant contributor to the water consumption and also added to the increased evapotranspiration. This study can be important tool in quantifying the changes in hydrological components in response to changes made in landuse in especially basins undergoing rapid commercialization. This shall provide substantive information to the decision makers required to develop ameliorative strategies. PMID- 29990902 TI - Multi-dimensional assessment of drought vulnerability in Africa: 1960-2100. AB - Drought vulnerability is a complex concept that identifies the capacity to cope with drought, and reveals the susceptibility of a system to the adverse impacts of drought. In this study, a multi-dimensional modeling framework is carried out to investigate drought vulnerability at a national level across the African continent. Data from 28 factors in six different components (i.e. economy, energy and infrastructure, health, land use, society, and water resources) are collected for 46 African countries during 1960-2015, and a composite Drought Vulnerability Index (DVI) is calculated for each country. Various analyses are conducted to assess the reliability and accuracy of the proposed DVI, and the index is evaluated against historical observed drought impacts. Then, regression models are fitted to the historical time-series of DVI for each country, and the models are extrapolated for the period of 2020-2100 to provide three future scenarios of DVI projection (low, medium, and high) based on historical variations and trends. Results show that Egypt, Tunisia, and Algeria are the least drought vulnerable countries, and Chad, Niger, and Malawi are the most drought vulnerable countries in Africa. Future DVI projections indicate that the difference between low- and high-vulnerable countries will increase in future, with most of the southern and northern African countries becoming less vulnerable to drought, whereas the majority of central African countries indicate increasing drought vulnerability. The projected DVIs can be utilized for long-term drought risk analysis as well as strategic adaptation planning purposes. PMID- 29990904 TI - Fermentation liquor of CaO2 treated chemically enhanced primary sedimentation (CEPS) sludge for bioplastic biosynthesis. AB - Chemically enhanced primary sedimentation (CEPS) technology has been widely applied in Hong Kong, exhibiting excellent performance in contaminants removal from sewage. The generated CEPS sludge contains abundance of organics which could be recovered as volatile fatty acids (VFAs) by fermentation for further utilization. In this work, the effect of calcium peroxide (CaO2) on the fermentation of FeCl3 based CEPS sludge was investigated. The feasibility of utilizing the fermentation liquor as substrate for polyhydroxyalkanoates (PHAs) biosynthesis was also evaluated. Results demonstrated that CaO2 addition facilitated the disintegration of CEPS sludge and enhanced VFAs production. The maximum VFAs yield of 455.8 mg COD/g VSS was obtained with the dosage of 0.1 g CaO2/g SS, improving by 44.7% compared with the control sludge. Acetic and propionic acid were the predominant components of the VFAs. Microbial analysis indicated that CaO2 induced microbial reduction of Fe(III), accelerating the initial disintegration of FeCl3 based CEPS sludge. Microbial communities with hydrolysis and acidogenesis functions were enriched effectively. CaO2 treatment had no significant influence on the release of ammonia nitrogen (NH4+-N), while reduced the concentration of orthophosphate (PO43--P) and ferrous (Fe2+) in fermentation liquor, that was beneficial to the further utilization as substrate for PHAs biosynthesis. The VFA-rich fermentation liquor was proved to be a suitable substrate for PHAs biosynthesis. After cultivation, the PHAs content in activated sludge reached 22.3%, which was comparable to those obtained using waste materials as carbon source. This integrated technology could be a superior alternative of realizing sludge disposal and bioplastic production simultaneously. PMID- 29990903 TI - Treatment of rural domestic wastewater using multi-soil-layering systems: Performance evaluation, factorial analysis and numerical modeling. AB - The discharge of wastewater in rural areas without effective treatment may result in contamination of surrounding surface water and groundwater resources. This study explored the wastewater treatment performance of multi-soil-layering (MSL) systems through interactive factorial analysis. MSL systems showed good performances under various operating conditions. The COD and BOD5 removal rates in MSL systems could reach 98.53 and 93.66%, respectively. The performances of MSL systems in TP removal stayed at high levels ranged from 97.97 to 100% throughout the experiments. The NH4+ - N removal rates of the well performed MSL systems reached highest levels ranging from 89.96 to 100%. The TN removal rates of aerated MSL systems ranged from 51.11 to 64.44% after 72 days of operation. The independent effects of bottom submersion, microbial amendment and aeration, as well as most interactions were significant. The performance of MSL systems was mainly affected by bottom submersion and aeration as well as their interactions. Aeration was the most positive factor for the removal of organic matter, TP and NH4+ - N. However, oxygenated environment was unfavorable for NO3- - N removal. In the submerged area with limited oxygen, the microbial transformation of NO3- - N still occurred. A stepwise-cluster inference model was developed for tackling the multivariate nonlinear relationships in contaminant removal processes. The results can help obtain a better understanding of the complicated processes among contaminant removal in MSL systems. PMID- 29990905 TI - Influence of land use change on the ecosystem service trade-offs in the ecological restoration area: Dynamics and scenarios in the Yanhe watershed, China. AB - Land use change can result in variations in ecosystem services (ESs) and their relationships. Studying the temporal dynamics of ESs and their relationships can support scenario analyses that provide the theoretical basis for policy decisions and regional ecosystem management. Previous studies have revealed the trade-offs between two ESs on multiple scales, while the trade-offs between multiple ESs require further analysis. Furthermore, trade-offs are rarely considered in scenario constructions, which weakens the ability of scenarios to inform land use policy. In this study, the InVEST model was applied to assess carbon sequestration, habitat quality, nutrient retention, sediment retention and seasonal water yield at five-year intervals from 1990 to 2015 and to construct five simulated scenarios that represented different ecological restoration and land reclamation policies. The results indicated that the Grain for Green Project (GFGP) increased all ESs, with seasonal water yield increasing by approximately 1.29 times above the initial stage. However, decreasing cropland area reduced the correlations between ESs both in trade-offs and synergies. Among all scenarios studied, the Returning Cropland to Grassland trade-off scenario had the maximum effect, while the natural succession to shrubland scenario had a minimum effect at the pixel level. Except for the land reclamation scenario, the overall ES benefits in the other scenarios exceeded the benefits received in 2015. Given the extent of watershed areas impacted by different overall ES benefit and trade-off situations, the Returning Cropland to Grassland scenario appears to best reduce the impacts of the worst situation compared to 2015, reducing the negative impacts by 22.6%. We suggest that scenarios that combine both overall ESs values and their trade-offs can support more effective and efficient land use decisions. PMID- 29990907 TI - A review of urban wildlife management from the animal personality perspective: The case of urban deer. AB - Wildlife living around urbanized areas is often a cause of crucial issues such as zoonosis and wildlife-vehicle collisions. Despite this, residents hold positive views on the presence of urban wildlife primarily due to aesthetic reasons. This accepting attitude towards our coexistence with urban wildlife has made it difficult for wildlife managers to come to a consensus concerning the importance of human-urban wildlife conflicts. Although countermeasures such as lethal force and/or fencing are commonly used to control human-wildlife conflicts, these approaches are rarely applied in the case of urban wildlife. It is essential to recognize the gap between the current state of urban wildlife management and advanced scientific knowledge of urban wildlife behavior in order to mitigate urban deer conflicts. Fortunately, behavioral ecologists have been attempting to apply the perspective of individual differences, such as animal personality, to wildlife management. Studies have shown how the personalities of wildlife contribute to their adaptation to urban habitats. In order to prevent human-urban wildlife conflicts, recognizing the personalities of wildlife and selective culling of bold individuals should be conducted for deliberate selection for shyness when developing wildlife management plans. Making wildlife shy away from humans is essential to urban wildlife management. The aim of this study is to review observed measures against human-urban wildlife conflicts in Japan and to propose a new direction for innovative and effective approaches that takes animals personality into account to mitigate urban-wildlife conflicts. For this review we will target deer as a model species because deer are among the most serious of problem-causing urban wildlife. PMID- 29990906 TI - Abiotic hydroxylamine nitrification involving manganese- and iron-bearing minerals. AB - Hydroxylamine (NH2OH) undergoes biotic and abiotic transformation processes in soil, producing nitrous oxide gas (N2O(g)). Little is known about the magnitude of the abiotic chemical processes in the global N cycle, and the role of abiotic nitrification is still neglected in most current nitrogen trace gas studies. The abiotic fate of NH2OH in soil systems is often focused on transition metals including manganese (Mn) and iron (Fe), and empirical correlations of nitrogen residual species including nitrite (NO2-), nitrate (NO3-), and N2O(g). In this study, abiotic NH2OH nitrification by well-characterized manganese (Mn)- and iron (Fe)-bearing minerals (pyrolusite, amorphous MnO2(s), goethite, amorphous FeOOH(s)) was investigated. A nitrogen mass balance analysis involving NH2OH, and the abiotic nitrification residuals, N2O(g), N2O(aq), NO2-, NO3-, was used, and specific reactions and mechanisms were investigated. Rapid and complete NH2OH nitrification occurred (4-5 h) in the presence of pyrolusite and amorphous MnO2(s), achieving a 95-96% mass balance of N byproducts. Conversely, NH2OH nitrification was considerably slower by amorphous FeOOH(s) (14.5%) and goethite (1.1%). Direct reactions between the Mn- and Fe-bearing mineral species and NO2- and NO3- were not detected. Brunauer-Emmett-Teller surface area and energy dispersive X-ray measurements for elemental composition were used to determine the specific concentrations of Mn and Fe. Despite similar specific concentrations of Mn and Fe in crystalline and amorphous minerals, the rate of NH2OH nitrification was much greater in the Mn-bearing minerals. Results underscore the intrinsically faster NH2OH nitrification by Mn minerals than Fe minerals. PMID- 29990908 TI - Effects of prescribed burning for pasture reclamation on soil chemical properties in subalpine shrublands of the Central Pyrenees (NE-Spain). AB - The abandonment of the traditional pastoral activities in the subalpine grasslands of the Central Pyrenees (NE-Spain) has resulted in shrub encroachment processes that are dominated by species such as the Echinospartum horridum. Therefore, prescribed burning has been recently readopted in this region as a management tool to stop the spread of shrubs and recover grasslands. We aimed to assess the effect that this practice may have on soil chemical properties such as SOC, N, pH, EC, water-extractable and exchangeable cations (Ca2+, Mg2+ and K+), cation exchange capacity, inorganic N forms (N-NH4+ and N-NO3-) and available P. We studied two prescribed burnings conducted at the subalpine level of the Central Pyrenees in the municipalities of Tella-Sin (April 2015) and Buisan (November 2015). At each site, the topsoil was sampled in triplicate at soil depths of 0-1, 1-2 and 2-3 cm immediately before (U), immediately after (B0) and one year after (B12) burning, and litter and/or ashes were removed prior to sampling. The results indicate that in the B0 samples, burning significantly reduced the SOC and N contents as well as the exchangeable Ca2+ and Mg2+ at 0-1 cm, whereas the rest of the studied properties remained virtually unchanged. However, in the B12 samples we detected a decrease of nutrient content that was probably related to leaching and/or erosion processes. PMID- 29990909 TI - Seasonal and spatial variations of stream insect emergence in an intensive agricultural landscape. AB - A growing amount of literature exists on reciprocal fluxes of matter and energy between ecosystems. Aquatic subsidies of winged aquatic insects can affect terrestrial ecosystems significantly, but this issue is rarely addressed in agroecosystems. By altering the production of benthic macroinvertebrates, agricultural practices could increase or decrease the strength of aquatic subsidies and subsequently the provision of several ecosystem services to agriculture. Effects of seasons and environmental variables on aquatic insect emergence were investigated in third-order agricultural streams in northwestern France. Most emerging dry mass (DM) of caught insects belonged to Trichoptera (56%), Chironomidae (25%) and Ephemeroptera (19%). We estimated that annual emerging dry mass of aquatic insects ranged between 1445 and 7374 mg/m2/y depending on the stream. Seasonal variations were taxon-specific, with Ephemeroptera emerging only in spring, Trichoptera emerging in spring and early summer, and Chironomidae emerging throughout the year. The percentage of watershed area covered by agriculture, ammonium concentration and hypoxia positively influenced emerging DM of Chironomidae but negatively influenced Ephemeroptera. Emerging DM of Trichoptera and Ephemeroptera increased significantly as water conductivity and temperature increased. Channel openness increased the emerging DM of all taxonomic groups, but Chironomidae were more abundant in narrow, incised streams. Assuming that the biomass of aquatic invertebrates ultimately disperse toward terrestrial habitats, nutrient accumulations on land near streams were estimated to reach 0.5-2.3 kg C ha-1 y-1, 0.1-0.5 kg N ha-1 y-1 and 0.005-0.03 kg P ha-1 y-1, depending on the stream. This suggests a significant flux of aquatic nutrients to agroecosystems and the need for future studies of its potential influence on the ecosystem services provided to agriculture. PMID- 29990910 TI - Selenium reduces cadmium uptake into rice suspension cells by regulating the expression of lignin synthesis and cadmium-related genes. AB - Although previous studies have indicated that selenium (Se) can reduce cadmium (Cd) uptake into rice, the mechanism at the cellular level has not been reported. Here, rice suspension cells exposed to Cd treatment in the presence or absence of Se were characterized. Compared with treatment with alone, pretreatment with Se increased the proportion of live cells by 83.1%. The levels of reactive oxygen species and mitochondrial membrane potential in the Se-pretreated rice cells were decreased by 86.6% and 76.0%, respectively. In addition, non-invasive micro-test technology suggested that the mean values of Cd2+ influx decreased significantly in the Se-pretreated rice cells in a concentration-dependent manner. The results of inductively coupled plasma-mass spectrometry (ICP-MS) showed that 67.4%-78.8% Cd accumulated onto the cell walls of the pretreated-Se rice cells. The addition of Se increased the lignin content and thickness of the cell walls, leading to an improved mechanical force of the cell walls, as determined by atomic force microscopy (AFM). Furthermore, Se pretreatment decreased the expression of genes involved in Cd uptake (OsNramp5) and transport (OsLCT1) but activated the expression of genes involved in Cd transport into vacuoles (OsHMA3) and lignin synthesis (OsPAL, OsCoMT and Os4CL3). These results indicated that supplying Se alleviates Cd toxicity by regulating the express of lignin synthesis and Cd related genes. The present findings provide new insights on a plausible explanation of the Se-reduced Cd uptake into rice. PMID- 29990911 TI - Carbon footprint and agricultural sustainability nexus in an intensively cultivated region of Indo-Gangetic Plains. AB - Green Revolution led to an unprecedented increase in world food production but with a significant carbon footprint raising concerns about its sustainability. With the rising global population and the need to produce more food, the farming systems will have to be sustainable. To identify farming practices that increase yield with minimum environmental cost, it is imperative to quantify the environment footprint of different technologies. The present study quantified the impact of Green Revolution technologies on the carbon footprint of intensive crop production systems, mainly rice-wheat in an agriculturally important region of Indo-Gangetic Plains. The results revealed the overriding importance of groundwater irrigation and fertilizer use in determining the carbon footprint of crop production, and underpin the opportunities for their mitigation. Intensification of agriculture resulted in ~2.5 fold increase in food grain production and 3-fold increase in emission of greenhouse gases (GHGs) during 1980 to 2015. Carbon sustainability of food grain production declined with time indicating that energy use efficiency is decreasing; the greatest decline being in rice followed by wheat and negligible in maize. Options for mitigating environment footprint of food grain production included partially replacing area under rice with other less water requiring crops, improving irrigation water productivity and pumping efficiency, and increasing fertilizer use efficiency. Maize with low global warming potential and high C sustainability appeared a viable option for diversification. The implementation of these mitigation measures can reduce environment footprint by 46%. Preventing crop residue burning will not only offset the associated GHG emissions (6266 Gg yr-1) but can also improve soil health if returned to the soil. Intensification of agriculture has co-benefit of C sequestration in soil, which besides offsetting emissions by ~10% is an important determinant of soil quality and sustainability. PMID- 29990912 TI - Geochemical cadmium anomaly and bioaccumulation of cadmium and lead by rapeseed (Brassica napus L.) from noncalcareous soils in the Guizhou Plateau. AB - The cruciferous crop, oil rapeseed (Brassica napus L.), may bioaccumulate excessive cadmium (Cd) and lead (Pb) as well, from Cd-enriched noncalcareous soils in Guizhou province of southwestern China. Field paired soil-rapeseed sampling and greenhouse experiment were performed to characterize the Cd anomaly in rapeseed-planting soils and to predict the bioaccumulation of Cd and Pb in raw seeds using soil variables. The results indicated that total soil-Cd concentrations averaged 0.43 mg kg-1 (range 0.11-1.41 mg kg-1) from field investigation; and a soil type dependent Cd anomaly was observed. Besides, cumulative frequency of total soil-Cd was plotted to be helpful in delimitation of regional Cd anomalies. Rapeseeds readily bioaccumulated Cd from soils as validated by greenhouse experiment and field data. Contrary results were observed in relation to rapeseed Pb levels measured from greenhouse experiment (very low) and field (very high) which was likely due to soil particle contamination as indicated by the considerably higher ratio of Pb to Cd level in seeds harvested from fields. Based on multiple stepwise regression analysis, reliable Cd soil rapeseed relationships, but less reliable for Pb, were derived using either total or (bio)available metal concentrations and were further inversely used to derive local soil Cd criteria (e.g., total soil-Cd based, 2.5 mg kg-1) based on Hygienic Standard for Feeds (GB13082-2001). Although seed Cd levels ( Zn > Cr > Cu > Pb, Cd > Zn > Pb > Cr > Cu, Cd > Cr > Cu > Zn > Pb, Cd > Cu > Pb > Cr > Zn, and Cd > Pb > Cr > Zn > Cu, respectively. The different pollution assessment methods outputted the differentiated conclusions to some extent except the judgment for Cd. Results based on ISFPAM indicated that metal pollution degrees decreased in the order of Cd (5.91, Grade 6) > Cu (2.81, Grade 3) > Pb (2.66, Grade 3) > Cr (1.58, Grade 2) > Zn (0.69, Grade 1). By detailed comparison analysis, the double weight system and stochastic-fuzzy theory made ISFPAM better resolving ability to find out priority heavy metals and areas with relatively higher enrichment, ecotoxicity and bioaccessibility under efficient parameter uncertainty control. Cd, Cu and Pb were regarded as the priority control metals, especially Cd. Simultaneously, the reliabilities of heavy metal pollution corresponding to adjacent pollution grades were quite close in some sites, which recommend recheck for avoid misleading the decision-makers. PMID- 29990914 TI - Meta-analysis of non-reactive phosphorus in water, wastewater, and sludge, and strategies to convert it for enhanced phosphorus removal and recovery. AB - Current and future trends indicate that mining of natural phosphorus (P) reserves is occurring faster than natural geologic replenishment. This mobilization has not only led to P supply concerns, but has also polluted many of the world's freshwater bodies and oceans. Recovery and reuse of this nuisance P offers a long term solution simultaneously addressing mineral P accessibility and P-based pollution. Available physical, chemical, and biological P removal/recovery processes can achieve low total P (TP) concentrations (<=100 MUg/L) and some processes can also recover P for direct reuse as fertilizers (e.g., struvite). However, as shown by our meta-analysis of over 20,000 data points on P quantity and P form, the P in water matrices is not always present in the reactive P (RP) form that is most amenable to recovery for direct reuse. Thus, strategies for removing and recovering other P fractions in water/wastewater are essential to provide environmental protection via P removal and also advance the circular P economy via P recovery. Specifically, conversion of non-reactive P (NRP) to the more readily removable/recoverable RP form may offer a feasible approach; however, extremely limited data on such applications currently exist. This review investigates the role of NRP in various water matrices; identifies NRP conversion mechanisms; and evaluates biological, physical, thermal, and chemical processes with potential to enhance P removal and recovery by converting the NRP to RP. This information provides critical insights into future research needs and technology advancements to enhance P removal and recovery. PMID- 29990915 TI - Polycyclic Aromatic Hydrocarbons (PAHs) and nitrated analogs associated to particulate matter emission from a Euro V-SCR engine fuelled with diesel/biodiesel blends. AB - Among the new technologies developed for the heavy-duty fleet, the use of Selective Catalytic Reduction (SCR) aftertreatment system in standard Diesel engines associated with biodiesel/diesel mixtures is an alternative in use to control the legislated pollutants emission. Nevertheless, there is an absence of knowledge about the synergic behaviour of these devices and biodiesel blends regarding the emissions of unregulated substances as the Polycyclic Aromatic Hydrocarbons (PAHs) and Nitro-PAHs, both recognized for their carcinogenic and mutagenic effects on humans. Therefore, the goal of this study is the quantification of PAHs and Nitro-PAHs present to total particulate matter (PM) emitted from the Euro V engine fuelled with ultra-low sulphur diesel and soybean biodiesel in different percentages, B5 and B20. PM sampling was performed using a Euro V - SCR engine operating in European Stationary Cycle (ESC). The PAHs and Nitro-PAHs were extracted from PM using an Accelerated Solvent Extractor and quantified by GC-MS. The results indicated that the use of SCR and the largest fraction of biodiesel studied may suppress the emission of total PAHs. The Toxic Equivalent (TEQ) was lower when using 20% biodiesel, in comparison with 5% biodiesel on the SCR system, reaffirming the low toxicity emission using higher percentage biodiesel. The data also reveal that use of SCR, on its own, suppress the Nitro-PAHs compounds. In general, the use of larger fractions of biodiesel (B20) coupled with the SCR aftertreatment showed the lowest PAHs and Nitro-PAHs emissions, meaning lower toxicity and, consequently, a potential lower risk to human health. From the emission point of view, the results of this work also demonstrated the viability of the Biodiesel programs, in combination with the SCR systems, which does not require any engine adaptation and is an economical alternative for the countries (Brazil, China, Russia, India) that have not adopted Euro VI emission standards. PMID- 29990916 TI - A systematic review on Asian's farmers' adaptation practices towards climate change. AB - Climate change in Asia is affecting farmers' daily routines. Much of the focus surrounding climate change has targeted the economic and environmental repercussions on farming. Few systematic reviews have been carried out on the social impacts of climate change among farmers in Asia. The present article set out to analyse the existing literature on Asian farmers' adaptation practices towards the impacts of climate change. Guided by the PRISMA Statement (Preferred Reporting Items for Systematic reviews and Meta-Analyses) review method, a systematic review of the Scopus and Web of Science databases identified 38 related studies. Further review of these articles resulted in six main themes - crop management, irrigation and water management, farm management, financial management, physical infrastructure management and social activities. These six themes further produced a total of 35 sub-themes. Several recommendations are highlighted related to conducting more qualitative studies, to have specific and a standard systematic review method for guide research synthesis in context of climate change adaptation and to practice complimentary searching techniques such as citation tracking, reference searching, snowballing and contacting experts. PMID- 29990917 TI - Identification of meteorological factors associated with human infection with avian influenza A H7N9 virus in Zhejiang Province, China. AB - BACKGROUND: Since the first reported human infection with an avian-origin influenza A (H7N9) virus in China in early 2013, there have been recurrent outbreaks of the virus in the country. Previous studies have shown that meteorological factors are associated with the risk of human infection with the virus; however, their possible nonlinear and lagged effects were not commonly taken into account. METHOD: To quantify the effect of meteorological factors on the risk of human H7N9 infection, daily laboratory-confirmed cases of human H7N9 infection and meteorological factors including total rainfall, average wind speed, average temperature, average relative humidity, and sunshine duration of the 11 sub-provincial/prefecture cities in Zhejiang during the first four outbreaks (13 March 2013-30 June 2016) were analyzed. Separate models were built for the 6 sub-provincial/prefecture cities with the greatest number of reported cases using a combination of logistic generalized additive model and distributed lag nonlinear models, which were then pooled by a multivariate meta-regression model to determine their overall effects. RESULTS: According to the meta regression model, for rainfall, the log adjusted overall cumulative odds ratio was statistically significant when log of rainfall was >4.0, peaked at 5.3 with a value of 12.42 (95% confidence intervals (CI): [3.23, 21.62]). On the other hand, when wind speed was 2.1-3.0 m/s or 6.3-7.1 m/s, the log adjusted overall cumulative odds ratio was statistically significant, peaked at 7.1 m/s with a value of 6.75 (95% CI: [0.03, 13.47]). There were signs of nonlinearity and lag effects in their associations with the risk of infection. CONCLUSION: As rainfall and wind speed were found to be associated with the risk of human H7N9 infection, weather conditions should be taken into account when it comes to disease surveillance, allowing prompt actions when an outbreak takes place. PMID- 29990918 TI - Increased salinity improves the thermotolerance of mesophilic anammox consortia. AB - While the application of anammox-based process for mesophilic sidestream treatment is at present the state of the art and mainstream treatment at ambient temperature is also in development, the feasibility of thermophilic anammox process is still unclear. This study investigated the effects of salinity on the thermotolerance of mesophilic anammox sludge. In batch activity tests, 45 degrees C seems to be the critical temperature for the tolerance of mesophilic anammox consortia without acclimatization or amendments. The optimal anammox activity at 40, 42.5, and 45 degrees C can be achieved with the amendment of salt at 5-8, 8-10, and ~12 g NaCl L-1, respectively. However, this improvement effect was limited at 50 degrees C or when the shock duration was longer than 24 h even at 45 degrees C. In continuous-flow bioreactors, mesophilic anammox consortia could gradually adapt to 40-50 degrees C under a transition of 2.5 degrees C, and the performance was enhanced by an increase in salinity, which may be associated with the increase in extracellular polymeric substances. A nitrogen removal rate of 0.53 kgN m-3 d-1 was finally obtained at 50 degrees C. Overall, these interesting results facilitate further opportunities for thermophilic anammox process. PMID- 29990919 TI - The role of dead standing biomass of Calamagrostis epigejos in nutrient turnover during spontaneous succession. AB - Here we explore the idea that keeping dead standing (marcescent) biomass plants can reduce its nutrient (N, P) content. Later after biomass falling to ground this may result in substantial changes in nutrient turnover with consequences for plant competitive interactions. To explore the effects standing dead biomass we used Calamagrostis epigejos as a model species. It is a common expansive grass, which after senescence retain a large proportion of the plant remains as dead standing biomass. We determined the biomass, N and P concentrations of living biomass, standing dead biomass, and lying dead biomass at young and old successional sites on the post-mining heap near Sokolov. Further, we analyzed nutrient budget in dead biomass during decomposition and we compared it with nutrient budget in decomposing cellulose. Concentrations of N and P in living biomass were highest in April and decreased during season. Lying dead biomass had a higher N concentration than N concentration contained in standing dead biomass. A litterbag experiment revealed that N was released from lying dead biomass but accumulated in standing dead biomass during decomposition. Similarly the N was accumulated in decomposing cellulose. This accumulation was highest in sites with low decomposition rate. In late summer and autumn lying biomass was derived from senescence plants, came to soil and N was released during decomposition potentially usable for C. epigejos. Standing dead biomass turned to lying biomass during winter and spring and then during its decomposition N was immobilized from soil. This mechanism could reduce availability of N for other plants and increase competitive advantage of C. epigejos regrowing from belowground organs during spring. PMID- 29990920 TI - Characterization and source identification of PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in different seasons from Shanghai, China. AB - PM2.5 samples in four representative periods were collected from a highly industrialized district in Shanghai, China. The concentrations of PM2.5 and PM2.5 bound PAHs were analyzed. Positive matrix factorization (PMF) model was used to identify the potential sources. Relationship between PAHs distribution and meteorological parameters was assessed meanwhile. The incremental lifetime cancer risks (ILCRs) model was applied to quantitatively evaluate the exposure risk of PAHs. Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLT) model was used to track the potential pollution area of PM2.5 along with a Potential Source Contribution Function (PSCF) and Concentration Weighted Trajectory (CWT) methods. The results showed concentrations of PM2.5 and PAHs ranged from 14.83 to 185.58 MUg/m3, 2.58 to 123.62 ng/m3, respectively. The source apportionment model indicated that traffic emissions were the most important sources in each sampling season, which accounted for 38.44%, 34.48%, 39.04% and 45.03%, respectively. Spearman correlation coefficient showed that PAHs had negative correlation with ambient temperature and relative humidity in some periods, while had no significant correlation with atmospheric pressure and visibility. The average estimated lifetime cancer risk for total PAHs reached 4.7 * 10-5, 4.5 * 10-5 and 4.1 * 10-5, 4.0 * 10-5 to exposed children and adults in winter and autumn, respectively, meaning that PM2.5-bound PAHs had high potential risk. HYSPLIT model suggested that monsoon greatly influenced the air quality in both winter and autumn. PMID- 29990921 TI - Tissue distribution of Ag and oxidative stress responses in the freshwater snail Bellamya aeruginosa exposed to sediment-associated Ag nanoparticles. AB - Silver nanoparticles (AgNPs) are among the most widely used engineered nanomaterials and may eventually accumulate in sediments. Limited information is currently available regarding the toxicity, bioaccumulation and distribution of sediment-associated AgNPs in aquatic organisms. In the present study, a freshwater snail Bellamya aeruginosa was exposed via sediment to commercial Ag particles of four nominal sizes: 20 nm (AgNPs-20), 40 nm (AgNPs-40), 80 nm (AgNPs 80), and < 10 MUm (bulk Ag), and to silver nitrate at sub-lethal concentrations (1, 10 and 100 MUg Ag/g sediment). Ag burden and biomarkers of oxidative stress were assessed in different tissues of B. aeruginosa: hepatopancreas, gonad, foot and digestive tracts. All five Ag types were available for uptake by B. aeruginosa when spiked into sediment, and Ag accumulation in different tissues presented the following pattern: hepatopancreas > gonad ~ digestive tracts > foot. Snails accumulated higher levels of Ag from aqueous Ag than from particulate Ag. In contrast, AgNPs-40 and AgNPs-80 treatments occasionally induced higher oxidative stress than aqueous Ag, indicating the significant role of nanoparticle itself in exerting toxicity. Size-dependent toxicity of AgNPs in sediment was also found, with AgNPs-20 showing lower toxicity than other Ag particles. Overall, this study demonstrated that the toxicity of sediment associated AgNPs to B. aeruginosa varies with size and differs from aqueous Ag. PMID- 29990922 TI - Phosphate oxygen isotope evidence for methylphosphonate sources of methane and dissolved inorganic phosphate. AB - The ocean is an important source of methane, however, the sources of oceanic methane and mechanisms of its release to the atmosphere have only recently begun to be understood. Recent studies have identified methylphosphonate (MPn) as a previously unknown and likely source of methane in the aerobic ocean (Karl et al., 2008), as well as shown the biosynthesis of methylphosphonic acid to be a widespread trait in marine microbes (Metcalf et al., 2012). The mechanisms and reaction pathways from MPn to free methane, however, have not been well studied. Here we present results of laboratory studies on the photo-degradation of MPn, a likely mechanism of methane release to the atmosphere and phosphate release to the surface oceans. Phosphonoacetic acid was also studied as an additional model compound for comparison. We used the multi-labeled water isotope probing (MLWIP) approach, involving 18O-labeled waters to probe the photolytic mechanism of CP bond cleavage in phosphates through analysis of P released from MPn as PO4. These studies identified distinct reaction pathways involving phosphates compared with other common organophosphorus compounds (e.g., phosphoesters), as well as suggest the involvement of both ambient water and atmospheric oxygen in CP bond cleavage. There is only a small amount of water oxygen incorporated into product PO4 after cleavage of the CP bond in MPn, suggesting atmospheric O2 or radicals formed from O2 under Ultra Violet Radiation (UVR), as the primary source of O that replaces C in the CP bond of MPn. Model calculations suggest that the delta18OP signature of phosphate released via UV-degradation of phosphates is largely (75%) inherited from the original phosphate substrate. This opens up the possibility of tracing and differentiating specific phosphate sources of dissolved phosphate from other organophosphorus (Porg) sources (e.g., phosphoesters) used in primary production, as well as for tracing specific MPn sources of atmospheric methane. PMID- 29990923 TI - Concentrations and fate of parabens and their metabolites in two typical wastewater treatment plants in northeastern China. AB - Parabens are widely used in food, pharmaceuticals, and personal care products because they are excellent preservatives. Recently, the environmental fate of parabens has attracted attention owing to their similarity to some endocrine disrupters. Wastewater treatment plants (WWTPs) are both important sinks of parabens discharged from our daily activities and key pollution sources for the environment if the parabens are not completely removed. However, research in this area is scarce, especially in Asia. In this study, 6 commonly used parabens and 4 metabolites were analyzed in wastewater and sludge samples from two typical WWTPs with different treatment processes (the anaerobic-oxic (A/O) and cyclic activated sludge technology (CAST) treatment processes). The average concentrations of parabens in the A/O and CAST treatment processes were 1510 ng/L and 2180 ng/L, respectively, in the influent, and 70.5 ng/L and 19.7 ng/L, respectively, in the effluent. The paraben removal efficiencies in the A/O treatment process were between 56.8% and 100%, which is lower than the efficiencies for the CAST treatment process (97.7% to 100%). The average concentrations of metabolites in the A/O treatment process, which were much higher than paraben concentrations, were 35,200 ng/L in the influent, 334 ng/L in the effluent, and 146 ng/g in the sludge samples. The removal efficiencies for the 4 metabolites were >92% for the A/O treatment process. In total, for the A/O treatment process, 5.07 kg and 16.8 kg of parabens, and 24.4 kg and 16.0 kg of metabolites, were discharged into the environment annually via effluent and sludge, respectively. Overall, the results of this study indicate that the A/O and CAST treatment processes are both effective at removing parabens and their metabolites. PMID- 29990924 TI - Changing rainfall frequency affects soil organic carbon concentrations by altering non-labile soil organic carbon concentrations in a tropical monsoon forest. AB - Soil stores a substantial proportion of carbon (C), making it the greatest terrestrial C pool and pivotal to stabilizing the global climate system. Rainfall amounts and regimes have been changing in many places, but effects of precipitation changes on soil organic C (SOC) stabilization are not completely understood. Considerable attention has been focused on the consequences of changes in rainfall amounts, with rainfall regimes having been less studied. This study was conducted in a tropical climax forest to clarify the effects of rainfall changes on SOC fractions, with permanganate oxidation and density fractionations employed to divide the labile and non-labile SOC fractions. Two rainfall manipulation treatments, i.e., increased rainfall frequency with the total rainfall amount unchanged (IRF) and decreased rainfall amount by 50% with rainfall frequency unaltered (DRA), were conducted for two years, with ambient rainfall (AR) as the control. As a result, the IRF treatment increased the SOC concentration that mainly originated from increases in the non-labile SOC content. Relative to the AR control, the DRA treatment did not change the total SOC concentration although the labile SOC concentration increased. This typically is due to a small proportion of the labile fraction to the total SOC content. Our results suggest that this water-rich mature forest is resistant to rainfall amount changes to a great extent (e.g., decrease of 50% as in the present study) from the SOC stabilization perspective, while changes in rainfall frequency could exert more notable effects. PMID- 29990925 TI - Comparative study of the phytotoxicity of ZnO nanoparticles and Zn accumulation in nine crops grown in a calcareous soil and an acidic soil. AB - The increasing use of zinc oxide nanoparticles (ZnO NPs) in agriculture and consumer products has created the need to evaluate their impact on crops. Nine crops were investigated: wheat, maize, radish, bean, lettuce, tomato, pea, cucumber, and beet. The toxic effects of ZnO NPs on seed germination, plant growth, and biochemical parameters, including photosynthetic pigments, protein and malondialdehyde (MDA) content, reactive oxygen species (ROS), enzymes of the antioxidant defence system, as well as the Zn translocation in the plants were investigated using pots containing non-contaminated or ZnO NP-contaminated soil at concentrations of 20, 225, 450, and 900 mg Zn kg-1. Two soils with different physicochemical properties, namely a calcareous soil and an acidic soil, were used. The total and available Zn in the soils were correlated with the Zn in the plants (roots and shoots) and the observed effects. In the calcareous soil, the available Zn was very low and the phytotoxicity was limited to a slight reduction in the biomass for wheat, cucumber, and beet at the highest concentration. Only beet showed an increase in photosynthetic pigments. The parameters related to oxidative stress were affected to different degrees depending on the crop, with the exceptions of maize, lettuce, pea, and beet. In the acidic soil, the available Zn was high, and the germination of bean, tomato, lettuce, and beet, and the growth of most of the crops were seriously affected. The calculated EC50 values (growth) in the acidic soil ranged from 110 to 520 mg Zn kg-1. The photosynthetic pigments and most of the markers of oxidative stress were negatively affected in maize, wheat, bean, and pea. However, these changes were not always associated with a decrease in plant weight. In summary, soil pH and plant species are key factors affecting the Zn availability and phytotoxicity of ZnO NPs. PMID- 29990926 TI - Linking ecosystem services and circuit theory to identify ecological security patterns. AB - The rapid process of urbanization, accompanied by the sharp increase of urban population and expansion of artificial surface, has resulted in the loss of natural ecosystems and the degradation of ecosystem services. Identifying and protecting key places that have high importance for ecological sustainability are great challenges. Ecological security patterns are such an integrated approach to protecting regional ecological sustainability. In this study, taking Yunnan Province, China as a case study area, ecological sources were identified through ecosystem services, and circuit theory was used to model ecosystem processes in heterogeneous landscapes via calculating the 'resistance' or 'current', and thus to identify ecological corridors and key ecological nodes. The results showed that, ecological security patterns included 66 ecological sources, 186 ecological corridors, 24 pinch-points and 10 barriers. In details, the ecological sources were mainly distributed in the southwest and northwest of Yunnan Province, with the ecological corridors locating along the high mountains, and both ecological sources and corridors were mostly covered with forest land. Pinch-points covered by forest land and cultivated land, were distributed in the middle of Yunnan Province along the rivers. Approximately 75.9% nature reserves were located in the identified ecological sources, and the remainings were mainly distributed in eastern Yunnan Province with small area, showing the effectiveness in identifying ecological security patterns. Among 81 projects of low-slope hill development carried out in Yunnan Province, 46.9% showed potential human stress on regional ecological security. Based on ecosystem services and circuit theory, this study provides a new approach to identifying the spatial range of ecological corridors and the specific location of key nodes for effective ecological conservation and restoration. PMID- 29990927 TI - Distinct large-scale biogeographic patterns of fungal communities in bulk soil and soybean rhizosphere in China. AB - Fungi play a crucial role in the agroecological system; however, little is known about their large-scale biogeographical patterns and how various ecological processes contribute to community assembly, especially in the crop rhizosphere. In this study, we investigated the spatial distribution and community assembly of fungi in the bulk soil and rhizosphere of soybean collected from 43 sites across China using high-throughput sequencing. The alpha diversity of the rhizosphere was lower than that of bulk soil. The fungal community structures of the two soil compartments were distinct. Fungal communities in the rhizosphere had a steeper distance-decay relationship slope between sampled sites than those in bulk soil, suggesting a greater influence of historical processes (geographical separation) in the rhizosphere. The relative importance of dispersal limitation and environmental filtering for the fungal community composition differed between bulk soil and rhizosphere. Sloan neutral model analysis suggested that niche based processes dominated the assemblage of fungal communities in the two soil compartments, while neutral processes had a weaker influence in the rhizosphere than in bulk soil. Additionally, we analyzed the structures of abundant and rare fungal sub-communities in each soil compartment. Rare sub-communities were more strongly influenced by dispersal limitation than abundant sub-communities. These results expand the current understanding of root-associated fungal community biogeography in agricultural soils on a large scale. PMID- 29990928 TI - Full moon and traffic accident-related emergency ambulance transport: A nationwide case-crossover study. AB - BACKGROUND: Several studies have examined the association between environmental factors and traffic accidents. However, the role of a full moon in triggering emergency ambulance transport due to road traffic casualties is unclear. Thus, we aimed to examine whether a full moon contributes to the incidence of emergency transport due to road traffic crashes. METHODS: We acquired nationwide data on daily emergency transport due to road traffic crashes from all 47 prefectures of Japan from 2010 to 2014. We conducted a time-stratified case-crossover study using conditional Poisson regression to examine the relationship between the occurrence of a full moon and emergency transport due to road traffic crashes for each prefecture. Prefecture-level results were combined using a random-effects meta-analysis to evaluate nation-level estimates. RESULTS: There were 842,554 cases of emergency transport due to road traffic crashes across 1826 nights (62 full moon nights: n = 29,584; 1764 control nights: n = 812,970). On days with a full moon, the pooled adjusted relative risk (RR) of emergency transport due to traffic accidents was 1.042 (95% confidence interval [CI], 1.021-1.063). Overall, 4.03% (95% CI: 2.06-5.93) of the cases (1192 cases) were attributable to full moon nights. Stratified analyses revealed a significant increase in emergency transport due to traffic accidents on full moon nights for males, people aged >=40 years, and before midnight. CONCLUSIONS: Full moon nights are associated with an increase in the incidence of emergency transport due to road traffic crashes. These results indicate that public health strategies should account for full moon nights to decrease emergency transport due to traffic accidents. PMID- 29990929 TI - Intensive land-use drives regional-scale homogenization of plant communities. AB - Intensive anthropogenic land-use causes habitat loss and landscape homogenization, which leads to the decrease of biodiversity and ecosystem degradation. Therefore, it is important to study the influence of landscape heterogeneity on biodiversity. In this study, vegetation surveys conducted at 53 sites in the Tabu River basin, located at the agro-pastoral ecotone of Inner Mongolia of China, revealed 146 species. Species diversity was evaluated at three scales: species richness within patches (alpha diversity), between patches (beta diversity) and at the landscape scale (gamma diversity). We analyzed landscape heterogeneity (LHtotal) and its driving factors including environmental variables (LHDFenv-var, such as precipitation and altitude), environmental heterogeneity (LHDFenv-het) and human activities (LHDFhum). We used structural equation modeling (SEM) to evaluate the response of species richness to landscape heterogeneity at three scales and determined the relative contribution of driving factors in explaining species diversity at these scales. The results of the study are summarized as follows: 1) Alpha diversity was the dominant component of gamma diversity in the Tabu River basin in Inner Mongolia. 2) There is no significant correlation (P = 0.512) between alpha diversity and LHtotal; with the increase of LHtotal beta and gamma diversities showed hump-shaped relationships. 3) LHDFenv het was the primary factor in maintaining alpha diversity, with heterogeneity of mean annual precipitation (MAP), temperature (MAT) and altitude (ALT) acting as three largest contributors. LHDFhum primarily contributed to the maintenance of beta diversity. 4) LHDFhum was the primary contributor to gamma diversity, and human activity exceeded threshold values for positive effects. Based on our findings we suggest liming agricultural use along the river to prevent reductions in species diversity. PMID- 29990930 TI - Nutritional status affects the bioaccessibility and speciation of arsenic from soils in a simulator of the human intestinal microbial ecosystem. AB - Arsenic (As) is a highly toxic contaminant in food and soil. In this study, we investigated the effects of four nutritional states (including a fed state with vitamin C, a fed state with protein powder, a fed state with glucose and a fasted state) on the variability of soil As bioaccessibility and biotransformation using the physiologically based extraction test (PBET) combined with a simulator of the human intestinal microbial ecosystem model (SHIME). The results indicated that the vitamin C and protein powder increased As bioaccessibility in gastric digests. In the colon phase, As bioaccessibility was observably enhanced by protein powder, and it varied under the vitamin C and glucose conditions. Additionally, the order of As methylation percentages in the four nutritional states was protein powder > vitamin C > fasted state > glucose (except S2); As bioaccessibility increased 1.3-13.7% and 15.8-35.4% in treatments of the vitamin C and protein powder, respectively. Meanwhile, large amounts of monomethylarsonic acid (MMAV) were observed in the colon digest in the protein powder condition. In contrast, As methylation was significantly decreased with the addition of glucose, with a decline of 25.9-45.5%. Additionally, glucose enhanced the reduction of As(V). Therefore, nutritional status is a crucial parameter for the prediction of bioaccessibility and speciation of As when assessing health risks from As following oral exposure. PMID- 29990931 TI - Temporal dynamics of SO2 and NOX pollution and contributions of driving forces in urban areas in China. AB - SO2 and NOX pollution have significantly reduced the air quality in China in past decades. Haze and acid rain have negatively affected the health of animals, plants, and human beings. Documented studies have shown that air pollution is influenced by multiple socioeconomic driving forces. However, the relative contributions of these driving forces are not well understood. In this study, using the structural equation model (SEM), we quantified the contributing effects of various forces driving air pollution in 2015 in prefecture-level cities of China. Our results showed that there has been significant control of SO2 pollution in the past 20 years. The annual average SO2 concentration has dropped from 83 MUg/m3 in 1996 to 21 MUg/m3 in 2015, while the annual average NOX concentration has increased from 47 MUg/m3 in 1996 to 58 MUg/m3 in 2015. We evaluated data on the annual average concentrations of SO2, which in some cities may mask the differences of SO2 concentrations between different months. Hence, SO2 pollution should continue to be controlled in accordance with existing policies and regulations. However, we suggest that NOX should become the new focus of air pollution prevention and treatment. The SEM results showed that industrial scale, city size, and residents' activities have a significant impact on NOX pollution. Among these, industrial scale had the highest contribution. The findings from our study can provide a theoretical basis for the formulation of NOX pollution control policy in China. PMID- 29990932 TI - Enhancement of synchronous bio-reductions of vanadium (V) and chromium (VI) by mixed anaerobic culture. AB - The co-occurrence of toxic vanadium (V) and chromium (VI) in groundwater receives incremental attention while knowledge on their interactions in biogeochemical processes is limited, with lack of efficient removal means. This study is the first to realize synchronous bio-reductions of V(V) and Cr(VI) with high efficiency by mixed anaerobic culture. After 72-h operation, 97.0 +/- 1.0% of V(V) and 99.1 +/- 0.7% of Cr(VI) were removed, respectively, with initial concentration of 1 mM for both V(V) and Cr(VI). Cr(VI) bio-reduction took priority while V(V) detoxification was inhibited. V(IV) and Cr(III) were the identified reduction products, both of which could precipitate naturally. Initial Cr(VI) and acetate concentrations as well as pH affected this process significantly. High-throughput 16S rRNA gene sequencing analysis indicated the accumulation of Anaerolineaceae, Spirochaeta and Spirochaetaceae, which could contribute to V(V) and Cr(VI) bio-reductions. The new knowledge obtained in this study will facilitate understanding the biogeochemical fate of co-existing V(V) and Cr(VI) in groundwater and development of bioremediation strategy for their induced combined pollution. PMID- 29990933 TI - Soil degassing during watering: An overlooked soil N2O emission process. AB - Pulse diffusive nitrous oxide (N2O) emission following water application is well documented, whereas N2O emission caused by soil water-air displacement during the watering process (termed as soil degassing) has been largely overlooked. Watering induced N2O emissions from ten different soils in China were quantified, and found to range from 74.4 +/- 6.7 to 678.1 +/- 36.6 MUg N2O m-2 h-1 in surface watered (SW) soils, and from 45.6 +/- 4.4 to 358.1 +/- 23.6 MUg N2O m-2 h-1 in subsurface watered (SUW) soils. These N2O fluxes were much larger than the diffusive N2O flux from the same soil either under dry (7.9%-9.6% water filled pore space, WFPS) or wet (85.1%-93.6% WFPS) conditions. The watering process (the water infiltration process upon irrigation/rainfall or the process of shallow groundwater uplifting) resulted in massive N2O emissions. PMID- 29990934 TI - Long term metal release and acid generation in abandoned mine wastes containing metal-sulphides. AB - The sulphide-rich mine wastes accumulated in tailing dumps of La Concordia Mine (Puna of Argentina) have been exposed to the weathering action for more than 30 years. Since then, a series of redox reactions have triggered the generation of a highly acidic drainage -rich in dissolved metals-that drains into the La Concordia creek. The extent of metal and acid release in the site was analysed through field surveys and laboratory experiments. Static tests were conducted in order to predict the potential of the sulphidic wastes to produce acid, while Cu , Zn-, Fe- and Pb-bearing phases present in the wastes were identified by XRD, SEM/EDS analysis and sequential extraction procedures. Finally, the release of these metals during sediment-water interaction was assessed in batch experiments carried out in a period of nearly two years. Field surveys indicate that the prolonged alteration of the mine wastes led to elevated electrical conductivity, pH values lower than 4 and metal concentrations that exceed the guide values for drinking water in the La Concordia stream regardless of the dominating hydrological conditions. The highly soluble Fe and Mg (hydrous)sulphates that form salt crusts on the tailings surfaces and the riverbed sediments play an important role in the control of metal mobility, as they rapidly dissolve in contact with water releasing Fe, but also Cu and Zn which are scavenged by such minerals. Another important proportion of the analysed metals is adsorbed onto Fe (hydr)oxides or form less soluble hydroxysulfates. Metals present in these phases are released to water more slowly, thus representing a potential long term source of heavy metal pollution. The obtained results are a contribution to the understanding of long term metal transformations and mobility in mine waste impacted sites. PMID- 29990935 TI - Effects of phenanthrene on different levels of biological organization in larvae of the sediment-dwelling invertebrate Chironomus sancticaroli (Diptera: Chironomidae). AB - The hydrocarbon phenanthrene is an organic compound commonly found in the environment. In aquatic ecosystems, it is highly toxic to organisms, although little is known about its effects on sediment-dwelling organisms. The purpose of this study was to evaluate phenanthrene effects on biochemical, histological, and ontogenetic levels in larvae of the sediment-dwelling invertebrate Chironomus sancticaroli at acute and chronic exposure. Lethal concentrations were estimated and toxicity (acute-96 h and chronic- 8 d) tests were performed at phenanthrene concentrations from 0.12 to 1.2 mg L-1. At acute and chronic exposure, we evaluated acetylcholinesterase (AChE), alpha esterase (EST-alpha), and beta esterase (EST-beta) activities as well as histological alterations. In the assays with chronic exposure, effects on larval development were estimated using antennae length (instar estimative) and body length (growth estimative). The EST alpha showed a significantly increased activity after 48 h at acute exposure to high concentrations of phenanthrene, while EST-beta activity was increased after 48 and 72 h at acute exposure at higher concentrations and at 0.12 mg L-1 at chronic exposure. At acute exposure, the midgut showed alterations such as brush border disruption, gastric caeca regression, and lumen area reduction; the fat body showed nuclear alteration in the trophocytes, while the Malpighian tubules showed brush border reduction and the salivary glands were subject to cytoplasm vacuolation. At chronic exposure, the same alterations were observed, in addition to vacuolar coalescence in the trophocytes of the fat body. Regarding larval development, a reduction of body length was observed with increasing phenanthrene concentrations. Similarly, molting was delayed; in the control group, all larvae were in the fourth instar, while at higher phenanthrene concentrations, larvae were predominantly in the third instar. Phenanthrene had toxic effects on this chironomid, indicating risks for natural populations. PMID- 29990936 TI - Integrated regional ecological risk assessment of multiple metals in the soils: A case in the region around the Bohai Sea and the Yellow Sea. AB - Methodology to quantify and distinguish the spatial distribution of the risks from multiple pollutants within the region was developed in this paper. An integrated quantitative risk assessment was conducted by utilizing a large amount of information available to explore spatial distribution of risk by single and multiple pollutants, and the magnitude of the overall risk from multiple pollutants based on the current concentrations of pollutants and toxicity data. Two target criteria levels - level I (NOEC/LOEC based) and level II (LC/EC/IC50 based) - were employed, and thus, the regional and sub-regional risks were evaluated according to these two levels. The risk of multiple toxic metals (As, Cd, Cr, Hg and Pb) to a terrestrial ecosystem for the region around the Bohai Sea and the Yellow Sea were evaluated as a case. The total overall ecological risks from heavy metals in the region for level I and level II were 21.73% and 12.53%, respectively. The risks were ranked in the order of Cr > As > Pb > Cd > Hg with Cr posing the greatest ecological risk, which was 61.12% for level I. The top three cities according to the level II ecological risk were Cangzhou > Lianyungang > Panjin, while the top three cities of level I ecological risk were Cangzhou > Panjin > Lianyungang. This method provides a quantitative risk assessment with multiple and clear protection levels for risk management. PMID- 29990937 TI - Influence of humic acid on transport, deposition and activity of lysozyme in quartz sand. AB - Interaction with natural organic matter (NOM) is hypothesized to impact the fate and bioavailability of enzymes and some hazardous proteins in terrestrial and aquatic environments. By using saturated column transport experiments the transport and deposition of the model enzyme lysozyme (LSZ), in the absence and presence of purified Aldrich humic acid (PAHA), was investigated at a series of mass ratios PAHA/LSZ at pH 5 and 8 and two ionic strength values (0.5 mM and 50 mM KCl solution). PAHA decreased LSZ transport under all conditions. The shapes of breakthrough curves (BTCs) and retention profiles (RPs) during cotransport of both colloids evolved from symmetrical to blocking with time and from flat to hyper-exponential with depth, respectively, in response to increases in mass ratio PAHA/LSZ. The results indicated that the "size-selective retention" and concurrent homo- and hetero-aggregation induced straining, which resulted in preferential retention of relatively large PAHA-LSZ aggregates in the column and elution of relatively small ones. Due to differences in aggregate size, in general, the enzyme activity of LSZ in the effluent was larger and that of the retained LSZ was smaller than that of the influent. Therefore, protein transport process could partially increase the enzyme activity and bring potential environmental hazards. PMID- 29990938 TI - A meta-analysis of the distribution, sources and health risks of arsenic contaminated groundwater in Pakistan. AB - Globally, millions of people who rely on groundwater for potable purposes and agriculture have been inadvertently exposed to toxic arsenic (As) because of its natural occurrence in groundwater in several countries of Asia, Europe and America. While the presence of As in groundwater and its impacts on human health have been documented in many countries, there is little information on As contamination in Pakistan. This review highlights, for the first time, the extent and severity of As-induced problems in Pakistan based on relevant published papers; discusses possible sources of As contamination of aquifers; and estimates As-induced potential health hazards in the country in relation to global data. Data from 43 studies (>9882 groundwater samples) were used to describe As variability in groundwater of Pakistan and for comparison with global data. The mean groundwater As content reported in these studies was 120 MUg/L (range: 0.1 2090 MUg/L; SD: +/-307). About 73% of the values for mean As contents in the 43 studies were higher than the World Health Organization (WHO) permissible limit (10 MUg/L) for drinking water, while 41% were higher than the permissible limit of As in Pakistan (50 MUg/L). It was observed that groundwater samples in some areas of Punjab and Sindh provinces contained high As concentrations which were almost equal to concentrations reported in the most contaminated areas of the world. We predicted that the mean values of ADD, HQ and CR were 4.4 MUg kg-1day-1 (range: 0-77 MUg kg-1day-1), 14.7 (range: 0-256) and 0.0029 (range: 0-0.0512), respectively, based on mean As concentrations reported in Pakistan. In addition, this article proposes some integrated sustainable solutions and future perspectives keeping in view the regional and global context, as well as the on ground reality of the population drinking As-contaminated water, planning issues, awareness among civil society and role of the government bodies. Based on available data, it is predicted that almost 47 million people in Pakistan are residing in areas where more than 50% of groundwater wells contain As concentrations above the WHO recommended limit of As in drinking water. PMID- 29990939 TI - Tree rings reveal the reduction of Cd, Cu, Ni and Pb pollution in the central region of Sao Paulo, Brazil. AB - The concern about environmental pollution has risen in the last decades because of its effects on human's health. However, evaluation of the exposure to certain pollutants is currently hampered by the availability of past environmental data. Tree rings are an alternative to reconstruct environmental variability of pre instrumental periods. Nevertheless, this approach has some reported limitations including migration of chemical elements in the tree rings. The aim of this study was to evaluate the distribution of Cd, Cu, Hg, Na, Ni, Pb, Zn in the tree rings of Tipuana tipu (Fabaceae) to aid the reconstruction of past environmental pollution. We sampled trees in the central region of the city of Sao Paulo, Brazil, and scanned their tree rings using LA-ICP-MS. We used these data to evaluate the temporal trends of chemical elements under investigation. Results show a non-random distribution of these chemical elements within the tree rings, with higher content in the cell-walls of vessels and lower content in the fibers. Sodium was the only element intimately related to the axial parenchyma cells. Due to differences in elemental composition of xylem cells, temporal trends where evaluated using distinct quartiles of data distribution in each tree ring. The first quartile represents the lower content found in fibers and parenchyma, while the third quartile corresponds to the higher content found in vessels. Data from vessels better represent the decreasing trend of Cd, Cu, Pb, and Ni in the last three decades. This reduction is less significant for Na and Zn. Our results highlight the potential to improve the records of environmental pollution using data from different cells. Pronounced reduction in Pb may be attributed to the lead phase-out in gasoline, while the decreasing trend of Cd, Cu, Ni pollution is probably related to increasing efficiency of vehicles and the deindustrialization of Sao Paulo. Chemical elements are non-randomly distributed in tree rings. Chemical content of vessels cell-walls is a reliable record of metal pollution, which is decreasing in Sao Paulo. PMID- 29990940 TI - Influence of persistent organic pollutants on the endocrine stress response in free-living and captive red kites (Milvus milvus). AB - Persistent organic pollutants (POPs) have the potential to impair the endocrine regulation of organisms and alter their ability to respond to environmental changes. We studied whether polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) affected the endocrine regulation of free-living and captive red kites (Milvus milvus) through studying the dynamics of corticosterone (CORT) and dehydroepiandrosterone (DHEA). We sampled migratory free-living kites coming from northern Europe and captive kites born in a rehabilitation center in Spain. We used body feathers from the interscapular region as a minimally-invasive and integrative matrix. The most abundant compound detected in free-living kites was 4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE; 6.10 +/- 1.56 ng g-1 dw feather) followed by CB-153 (3.10 +/- 0.63 ng g-1 dw feather) and CB-180 (2.43 +/- 1.08 ng g-1 dw feather). In captive kites, the most abundant compounds were 4,4' dichlorodyphenyltrichloroethane (4,4'-DDT; 2.38 +/- 1.30 ng g-1 dw feather), CB 153 (2.15 +/- 0.47 ng g-1 dw feather) and hexachlorobenzene (HCB; 2.03 +/- 0.45 ng g-1 dw feather) at similar concentrations. Free-living kites showed higher levels of 4,4'-DDE and CB-180 in comparison to captive kites. Age influenced HCB and CB-101 levels, whereas body mass was inversely related to CB-180 and 4,4' DDT. Interestingly, captive kites showed a ratio DDT/DDE higher than 1 suggesting a relatively recent exposure of DDT, in contrast to free-living kites. Regarding hormonal levels, free-living kites showed higher levels of CORT (3.30 +/- 0.22 pg mm-1 feather) than captive (2.40 +/- 0.16 pg mm-1 feather), reflecting higher allostatic load. In addition, a positive association between PCBs and DDTs and adrenal hormones was found in free-living kites, suggesting an increase of CORT as a response of the endocrine system to cope with stressors and a subsequent elevation of DHEA to ameliorate the potential negative effects that high CORT levels could cause to the organism. PMID- 29990941 TI - Influence of microplastic addition on glyphosate decay and soil microbial activities in Chinese loess soil. AB - The intensive use of pesticide and plastic mulches has considerably enhanced crop growth and yield. Pesticide residues and plastic debris, however, have caused serious environmental problems. This study investigated the effects of the commonly used herbicide glyphosate and micrometre-sized plastic debris, referred as microplastics, on glyphosate decay and soil microbial activities in Chinese loess soil by a microcosm experiment over 30 days incubation. Results showed that glyphosate decay was gradual and followed a single first-order decay kinetics model. In different treatments (with/without microplastic addition), glyphosate showed similar half-lives (32.8 days). The soil content of aminomethylphosphonic acid (AMPA), the main metabolite of glyphosate, steadily increased without reaching plateau and declining phases throughout the experiment. Soil microbial respiration significantly changed throughout the entirety of the experiment, particularly in the treatments with higher microplastic addition. The dynamics of soil beta-glucosidase, urease and phosphatase varied, especially in the treatments with high microplastic addition. Particles that were considerably smaller than the initially added microplastic particles were observed after 30 days incubation. This result thus implied that microplastic would hardly affect glyphosate decay but smaller plastic particles accumulated in soils which potentially threaten soil quality would be further concerned especially in the regions with intensive plastic mulching application. PMID- 29990942 TI - The hidden threat of heavy metal pollution in high sedimentation and highly dynamic environment: Assessment of metal accumulation rates in the Thi Vai Estuary, Southern Vietnam. AB - Paleoecological assessment is challenging in highly dynamic environments such as estuaries, where sedimentation of material derived from the catchment interferes with marine processes. In this study we analyzed sedimentary heavy metal contents of the last decades to assess the impact of recent industrialization and changes in land use of the Thi Vai Estuary in Southern Vietnam. Two sediment cores (upstream and downstream) were dated using 210Pb, allowing the environmental reconstruction of the last three decades. Considering the recent and fast economic growth of this region these results are suitable for the evaluation of anthropogenic impacts. Mean sedimentation rates (9.2 cm yr-1 upstream, 4.7 cm yr 1 downstream) indicate high land erosion likely due to deforestation and dumping of dredged material. Sediment quality guidelines (SQG's) showed that Cr and Cu levels exceed threshold values (TEL) in both cores. Upstream Ni is above the probable effect level (PEL) suggesting risk of potential adverse biological effects. Geo-accumulation (I-geo), enrichment factor (EF) and contamination factor (CF) indices were calculated based on geogenic background values. Most indices show only moderate contamination for different elements, particularly by Cr and Pb. However, considering the historical land use impacts (such as discharge of untreated wastewater, intense agricultural practices, tanning operations, etc.), pollutant concentrations are lower than expected, presumably due to dilution by high sedimentation rates and tidal hydrodynamics. Nonetheless, heavy metal indices and SQG's indicate the ecological condition in the area is of concern, particularly upstream as corroborated by high metal fluxes, highlighting severe impacts in the region. PMID- 29990943 TI - Effect of erythromycin and modulating effect of CeO2 NPs on the toxicity exerted by the antibiotic on the microalgae Chlamydomonas reinhardtii and Phaeodactylum tricornutum. AB - Erythromycin is an antibiotic employed in the treatment of infections caused by Gram positive microorganisms and the increasing use has made it a contaminant of emerging concern in aqueous ecosystems. Cerium oxide nanoparticles (CeO2 NPs), which are known to have catalytic and antioxidant properties, have also become contaminants of emerging concern. Due to the high reactivity of CeO2 NPs, they can interact with erythromycin magnifying their effects or on the other hand, considering the redox potential of CeO2 NPs, it can alleviate the toxicity of erythromycin. The present study was carried out to assess the toxicity of both single compounds as well as mixed on Chlamydomonas reinhardtii and Phaeodactylum tricornutum (freshwater and marine microalgae respectively) employed as target species in ecotoxicological tests. Mechanisms of oxidative damage and those harmful to the photosynthetic apparatus were studied in order to know the toxic mechanisms of erythromycin and the joint effects with CeO2 NPs. Results showed that erythromycin inhibited the microalgae population growth and effective quantum yield of PSII (E.Q.Y.) in both microalgae. However, the freshwater microalgae Chlamydomonas reinhardtii was more sensitive than the marine diatom Phaeodactylum tricornutum. Responses related to the photosynthetic apparatus such as E.Q.Y. was affected by the exposure to erythromycin of both microalgae, as chloroplasts are target organelle for this antibiotic. Mixed experiments (CeO2 NPs + erythromycin) showed the protective role of CeO2 NPs in both microalgae preventing erythromycin toxicity in toxicological responses such as the growth of the microalgae population and E.Q.Y. PMID- 29990944 TI - Experimental addition of nitrogen to a whole forest ecosystem at Gardsjon, Sweden (NITREX): Nitrate leaching during 26 years of treatment. AB - Chronic high deposition of nitrogen (N) to forest ecosystems can lead to increased leaching of inorganic N to surface waters, enhancing acidification and eutrophication. For 26 years nitrogen has been added as ammonium nitrate (NH4NO3) at 40 kg N ha-1 yr-1 to a whole forested catchment ecosystem at Gardsjon, Sweden, to experimentally simulate the transition from a N-limited to N-rich state. Over the first 10 years of treatment there was an increasing amount of nitrate (NO3-) and to a lesser extent ammonium (NH4+) lost in runoff, but then N leaching stabilised, and for the subsequent 16 years the fraction of N added lost in runoff remained at 9%. NO3- concentrations in runoff were low in the summer during the first years of treatment, but now are high throughout the year. High frequency sampling showed that peaks in NO3- concentrations generally occurred with high discharge, and were enhanced if high discharge coincided with occasions of N addition. Approximately 50% of the added N has gone to the soil. The added N is equivalent to 140 years of ambient N deposition. At current ambient levels of N deposition there thus appears to be no immediate risk of N saturation at this coniferous forest ecosystem, and by inference to other such N-limited forests in Scandinavia. PMID- 29990945 TI - Multiple trace element accumulation in the mussel Septifer virgatus: Counteracting effects of salinity on uptake and elimination. AB - Salinity effects on the bioaccumulation and biokinetic processes of eight trace elements (Cu, Cr, Pb, Ni, Zn, Cd, Se, and As) in the black mussel Septifer virgatus were explored in the present study. A 6-week laboratory waterborne exposure first showed that salinity (15, 20, 25, and 30) had relatively weak or even no significant influence on trace element accumulation in the black mussels. Biokinetics including uptake and efflux was then quantified in the mussels at different salinities. Uptake rates of Ni and Zn were negatively correlated with the salinity, while the uptake of Cd was not significantly influenced by salinity. The efflux rates of Ni and Zn also exhibited an inverse relationship with salinity, whereas the case of Cd was on the contrary. Biokinetic modeling showed that the salinity effects on uptake and elimination of Ni and Zn counteracted with each other, thus weakening the combined effects on accumulation. Overall, the response of uptake to salinity could weakened, removed, or even overturned by elimination, depending on the relative magnitude of the change of the two processes. The combined effects of uptake and elimination further led to negative, no, or positive relationship between trace element accumulation and salinity. PMID- 29990946 TI - Cadmium, copper and lead levels in different cultivars of lettuce and soil from urban agriculture. AB - Urban agriculture plays an important role in sustainable food supply. However, because of the atmospheric pollution and soil contamination associated with urban areas, this activity may be of concern. In fact, contamination of soil with metals and the transference of contaminants to vegetables can represent health and safety risks associated with urban agriculture. The objective of this study was to evaluate the concentrations of selected trace metals (cadmium, copper and lead) in three lettuce cultivars produced in three different urban gardens in the metropolitan region of Belo Horizonte, Brazil and their respective soils. Samples of lettuce and soil were analyzed by inductively coupled plasma mass spectrometry (ICP-MS) and graphite furnace atomic absorption spectrometry (AAS-GF), respectively, and their transfer coefficients were calculated. The methods were optimized and were fit for the purpose. Copper was the prevalent metal found in soils and lettuce, with an average of 27.9 +/- 13.9 and 0.608 +/- 0.157 mg kg-1 respectively, followed by lead (19.4 +/- 7.7 and 0.037 +/- 0.039 mg kg-1), and cadmium (0.16 +/- 0.03 and 0.009 +/- 0.005 mg kg-1). Cadmium presented the largest transfer coefficients, ranging from 0.34 to 1.84 with an average of 0.92 +/- 0.45, which may indicate a potential risk of accumulation in vegetables in the case of high soil contamination. A significant positive correlation was observed (p < 0.01) between cadmium in lettuce and in soil. Even though lead concentrations varied in the soils from the different urban areas, ranging from 11.88 to 30.01 mg kg-1, no significant difference (p < 0.05) was found among the lettuce, probably due to its low mobility (transfer coefficient = 0.02). The copper and cadmium levels found in lettuce indicate safe lettuce production in the three urban gardens. PMID- 29990947 TI - Do progestins contribute to (anti-)androgenic activities in aquatic environments? AB - Unknown compounds with (anti-)androgenic activities enter the aquatic environment via municipal wastewater treatment plants (WWTPs). Progestins are well-known environmental contaminants capable of interfering with androgen receptor (AR) signaling pathway. The aim of the present study was to determine if 15 selected progestins have potential to contribute to (anti-)androgenic activities in municipal wastewaters and the respective recipient surface waters. AR-specific Chemically Activated LUciferase gene eXpression bioassay in agonistic (AR-CALUX) and antagonistic (anti-AR-CALUX) modes and liquid chromatography tandem atmospheric pressure chemical ionization/atmospheric photoionization with hybrid quadrupole/orbital trap mass spectrometry operated in high resolution product scan mode (LC-APCI/APPI-HRPS) methods were used to assess (anti-)androgenic activity and to detect the target compounds, respectively. The contribution of progestins to (anti-)androgenic activities was evaluated by means of a biologically and chemically derived toxicity equivalent approach. Androgenic (0.08-59 ng/L dihydrotestosterone equivalents - DHT EQs) and anti-androgenic (2.4 26 MUg/L flutamide equivalents - FLU EQs) activities and progestins (0.19-75 ng/L) were detected in selected aquatic environments. Progestins displayed androgenic potencies (0.01-0.22 fold of dihydrotestosterone) and strong anti androgenic potencies (9-62 fold of flutamide). Although they accounted to some extent for androgenic (0.3-29%) and anti-androgenic (4.6-27%) activities in influents, the progestins' contribution to (anti-)androgenic activities was negligible (<=2.1%) in effluents and surface waters. We also tested joint effect of equimolar mixtures of target compounds and the results indicate that compounds interact in an additive manner. Even if progestins possess relatively strong (anti-)androgenic activities, when considering their low concentrations (sub-ng/L to ng/L) it seems unlikely that they would be the drivers of (anti-)androgenic effects in Czech aquatic environments. PMID- 29990948 TI - Traffic noise, noise annoyance and psychotropic medication use. AB - BACKGROUND: Road-traffic noise can induce stress, which may contribute to mental health disorders. Mental health problems have not received much attention in noise research. People perceive noise differently, which may affect the extent to which noise contributes to poor mental health at the individual level. This paper aims to assess the relationships between outdoor traffic noise and noise annoyance and the use of psychotropic medication. METHODS: We conducted a survey to assess noise annoyance and psychotropic medication among residents of the Helsinki Capital Region of Finland. We also assessed the associations of annoyance and road-traffic noise with sleep disorders, anxiety and depression. Respondents were randomly sampled from the Finnish Population registry, and data was collected using a self-administered questionnaire. Outdoor traffic noise was modelled using the Nordic prediction model. Associations between annoyance and modelled facade-noise levels with mental health outcome indicators were assessed using a binary logistic regression while controlling for socioeconomic, lifestyle and exposure-related factors. RESULTS: A total of 7321 respondents returned completed questionnaires. Among the study respondents, 15%, 7% and 7% used sleep medication, anxiolytic and antidepressant medications, respectively, in the year preceding the study. Noise annoyance was associated with anxiolytic drug use, OR = 1.41 (95% CI: 1.02-1.95), but not with sedative or antidepressant use. There was suggestive association between modelled noise at levels higher than 60 dB and anxiolytic or antidepressant use. In respondents whose bedroom windows faced the street, modelled noise was definitively associated with antidepressant use. Noise sensitivity did not modify the effect of noise but was associated with an increased use of psychotropic medication. CONCLUSION: We observed suggestive associations between high levels of road-traffic noise and psychotropic medication use. Noise sensitivity was associated with psychotropic medication use. PMID- 29990950 TI - Carbapenem resistance exposures via wastewaters across New Delhi. AB - Antimicrobial resistance (AMR) is a major global concern, especially in India where the burden of infectious diseases is high and health care spending is low. Here we quantified total coliform, faecal coliforms (FC), carbapenem-resistant enteric bacteria (CRE), blaNDM-1, and three integron genes in samples collected from wastewater effluent of 12 hospitals, 12 sewage treatment plants (STPs), 20 sewer drains, and five locations along the Yamuna River in New Delhi over two seasons. Significant correlations were found between FC levels, CRE (r = 0.903, p = 0.004, n = 49) and blaNDM-1 (r = 0.787, p = 0.003, n = 49) concentrations across all samples. Concentrations of coliforms, CRE, blaNDM-1, int1, and int3 were highest in hospital effluents compared to other locations in both seasons. Although absolute concentration data indicate greater abundances of CRE and blaNDM-1 in the winter, normalised data indicates greater carriage of blaNDM-1 per cell in summer samples. In general, observed CRE levels were highest in surface water downstream of areas with higher population densities. Among CRE isolates (n = 4077), 82%, 75%, 71% and 43% of the strains from hospitals, sewer drains, river samples, and STPs, respectively, contained blaNDM-1, implying STPs have relatively fewer blaNDM-1 positive CRE in their effluents. The most common CRE isolates in the drains were Pseudomonas putida (39%) followed by Acinetobacter baumanni (20%) and Pseudomonas montelli (19%). The present scenario in New Delhi highlights the urgent need for increased coverage of appropriate waste treatment facilities across the city to reduce CRE exposures from polluted surface waters. PMID- 29990949 TI - Environmental grass pollen levels in utero and at birth and cord blood IgE: Analysis of three birth cohorts. AB - BACKGROUND: Early life factors are associated with allergic respiratory diseases, but the role of high grass pollen concentrations during pregnancy and shortly after birth is not known. OBJECTIVE: To assess outdoor levels of grass pollen during the intrauterine period and at birth during peak pollen season on cord blood IgE in birth cohorts. METHODS: Three birth cohorts were included: MACS (n = 429), Australia; COPSAC2000 (n = 200), Denmark; and LISA (n = 1968), Germany. Cord blood IgE was categorized (<0.5 kU/L, 0.5-1 kU/L, >1 kU/L) and dichotomized (high IgE >= 0.5 kU/L). Birth during the grass pollen season months and cumulative exposure to outdoor grass pollen counts during pregnancy with cord blood IgE were analysed using multinomial regression and analysed in meta analysis using binomial regression adjusted for potential confounders. RESULTS: Birth during the grass pollen season had higher pooled odds of cord blood IgE >0.5 kU/L 1.37 (95% CI 1.06, 1.77) in a meta-analysis with little heterogeneity between the three cohorts. Cumulative exposure to outdoor grass pollen counts during the entire pregnancy was associated with slightly lower pooled odds but significant (OR = 0.98, 95% CI: 0.96 to 0.99). CONCLUSIONS: Birth during grass pollen seasons were associated with increased risk of high cord blood IgE in cities from both hemispheres, but high pollen loads in the environment during the entire pregnancy appeared protective. As IgE responses develop during the first months of life, our study findings provide new insights into the mechanisms of grass pollen exposure at birth and shortly after on possible allergic respiratory diseases. PMID- 29990951 TI - Co-benefits of climate mitigation on air quality and human health in Asian countries. AB - Climate change mitigation involves reducing fossil fuel consumption and greenhouse gas emissions, which is expensive, particularly under stringent mitigation targets. The co-benefits of reducing air pollutants and improving human health are often ignored, but can play significant roles in decision making. In this study, we quantified the co-benefits of climate change mitigation on ambient air quality and human health in both physical and monetary terms with a particular focus on Asia, where air quality will likely be degraded in the next few decades if mitigation measures are not undertaken. We used an integrated assessment framework that incorporated economic, air chemistry transport, and health assessment models. Air pollution reduction through climate change mitigation under the 2 degrees C goal could reduce premature deaths in Asia by 0.79 million (95% confidence interval: 0.75-1.8 million) by 2050. This co-benefit is equivalent to a life value savings of approximately 2.8 trillion United States dollars (USD) (6% of the gross domestic product [GDP]), which is decidedly more than the climate mitigation cost (840 billion USD, 2% of GDP). At the national level, India has the highest potential net benefit of 1.4 trillion USD, followed by China (330 billion USD) and Japan (68 billion USD). Furthermore, in most Asian countries, per capita GDP gain and life value savings would increase with per capita GDP increasing. We robustly confirmed this qualitative conclusion under several socioeconomic and exposure-response function assumptions. PMID- 29990952 TI - Exposure and dietary sources of bisphenol A (BPA) and BPA-alternatives among mothers in the APrON cohort study. AB - Diet is regarded as the main source of bisphenol A (BPA) exposure, but comparatively little is known about dietary sources of BPA-alternatives. Here we measured exposure of BPA and BPA-alternatives among pregnant women in Canada, estimated their 24-h intakes and examined the importance of various dietary sources. Free and total BPA, bisphenol S (BPS) and bisphenol F (BPF) were measured in 467 second trimester maternal urine samples, and in 455 paired samples collected at three months postpartum. Linear regression was used to evaluate associations between urinary concentrations of bisphenols and 24-h dietary recall data. The geometric means of total BPA in second trimester and postpartum urine (1.2 and 0.95 ng/mL, respectively) were 5-7 times higher than corresponding total BPS (0.16 and 0.17 ng/mL). The detection frequency of BPF was only 9% (i.e. >1.0 ng/mL). However, at both time points 95th percentiles of total BPF (7.3 and 4.2 ng/mL, respectively) were similar to total BPA (8.2 and 5.0 ng/mL). Free BPS and BPF were detected in <2% of samples, but were detectable when total BPS or BPF concentrations were highest, always at <1% of the total concentration. The tolerable daily intake for total BPA (i.e. 18 nmol/kg BW/d) was not exceeded, but for BPS the estimated 24-h intake was as high as 14 nmol/kg BW/d (95th percentile: 0.12 nmol/kg BW/d), and for BPF was even higher among the highest centile of exposure (maximum and 95th percentile: 30, 0.81 nmol/kg BW/d). Canned food consumption was associated with higher total BPA, but was not associated with BPS. For BPF, mustard consumption may be an important exposure source, particularly among the highest exposed. Relatively high exposure to BPS and BPF in a minority of pregnant women highlights the need to better understand the associated health risks and exposure sources of BPA-alternatives. PMID- 29990953 TI - Persistence and spatial variation of antibiotic resistance genes and bacterial populations change in reared shrimp in South China. AB - More attention has been paid to the abundance and diversity of antibiotic resistance genes (ARGs) in aquatic environments. However, few studies have investigated the persistence and spatial variation of ARGs in aquatic organisms. This study investigated the occurrence and abundance of ARGs and the bacterial populations in shrimp intestinal tracts during the rearing period in different regions of Guangdong, South China. The results showed that sul1, sul2, qnrD, and floR were the predominant ARGs. Compared with those of juvenile shrimp, the total concentrations of ARGs in the intestinal tract of adult shrimp in three shrimp farms were 2.45-3.92 times higher (p < 0.05), and the bacterial populations in the adult shrimp intestinal tract changed considerably. Redundancy analysis (RDA) showed that the abundance of Proteobacteria, Firmicutes, and Verrucomicrobia in Farms A, B, and C, respectively, were strongly positively correlated with the most abundant and predominant genes (sul1 and qnrD for Farm A; floR and sul2 for Farm B; floR and sul2 for Farm C) in the shrimp intestinal tract. The results of this study indicated that ARGs gained persistence in the developmental stages of the reared shrimp. Different phyla of predominant bacteria were responsible for the increase of ARGs abundance in the shrimp intestinal tract in different regions. This study represents a case study of the persistence and spatial variation of ARGs in aquaculture and can be a reference for the determination of harmful impacts of ARGs on food safety and human health. PMID- 29990955 TI - Impact of European chemicals regulation on the industrial use of plasticizers and patterns of substitution in Scandinavia. AB - REACH aims at promoting the safe use of chemicals in Europe, inter alia by identification and regulation of substances of very high concern (SVHCs). Once identified, SVHCs need to be substituted by safer alternatives. However, substitutes are frequently not safer than the substances that they replace but rather show similar hazard profiles, resulting in regrettable substitution. This paper investigates the impact of chemicals regulation on substitution of chemicals by analyzing time trends in the industrial use of chemicals from 2000 to 2014 in Scandinavia. It is shown that the use of ten water-relevant SVHCs decreased by about 90% in the considered period in Sweden as compared to a control group of unregulated substances which decreased by only 20%. A closer inspection of the use of 23 highly used plasticizers revealed that the use of regulated phthalate plasticizers decreased while the use of non-phthalate plasticizers increased. A first comparison of hazardous properties showed that during the 15-years period chemical substitution drastically reduced the chemical hazard burden of plasticizers in Scandinavia for both, the environment and human health. This study shows that regulation and the related discussion on chemicals safety have significantly reduced the chemical hazard burden from plasticizers in Scandinavia since the year 2000. It is assumed that similar trends can be found for the whole European Union. To combat regrettable substitution, mitigation options are suggested, including information-based tools for the identification of safer alternatives and an improved accessibility of information on production volumes and uses of chemicals to allow for an improved assessment of chemical's risk. PMID- 29990954 TI - Perturbation of metabolic pathways mediates the association of air pollutants with asthma and cardiovascular diseases. AB - BACKGROUND: Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratory and cardiovascular diseases, suggesting the involvement of common altered molecular pathways. OBJECTIVES: The goal was to find intermediate metabolites or metabolic pathways that could be associated with both air pollutants and health outcomes ("meeting-in-the-middle"), thus shedding light on mechanisms and reinforcing causality. METHODS: We applied a statistical approach named 'meet-in-the-middle' to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio cerebrovascular diseases (CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways. RESULTS: A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26, 2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentially mediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolism pathway was associated with air pollution exposure, AOA and CCVD. CONCLUSIONS: Our results suggest common pathway perturbations may occur as a consequence of chronic exposure to air pollution leading to increased risk for both AOA and CCVD. PMID- 29990957 TI - Advanced cellular systems to study tuberculosis treatment. AB - Mycobacterium tuberculosis (Mtb) kills more humans than any other infection and drug resistant strains are progressively emerging. Whilst the successful development of new agents for multi-drug resistant Mtb represents a major step forward, this progress must be balanced against recent disappointments in treatment-shortening trials. Consequently, there is a pressing need to strengthen the pipeline of drugs to treat tuberculosis (TB) and develop innovative therapeutic regimes. Approaches that bridge diverse disciplines are likely to be required to provide systems that address the limitations of current experimental models. Mtb is an obligate human pathogen that has undergone extensive co evolution, resulting in a complex interplay between the host and pathogen. This chronic interaction involves multiple micro-environments, which may underlie some of the challenges in developing new drugs. The authors propose that advanced cell culture models of TB are likely to be an important addition to the experimental armamentarium in developing new approaches to TB, and here we review recent progress in this area and discuss the principal challenges. PMID- 29990956 TI - Unconscious influence over executive control: Absence of conflict detection and adaptation. AB - Executive control and its modulation of attentional mechanisms allow us to detect and adapt to conflicting information. According to recent studies, executive control functions may be modulated by unconsciously perceived information, although the available evidence is not consistent. In this study, we used a Flanker Task and employed Chromatic Flicker Fusion, a suppression technique that has been proposed as more adequate to elicit executive control functions, to assess conflict and conflict adaptation effects. Our results showed that, when suppressed, flankers did not evoke conflict related effects on performance. However, in trials where most flankers were incongruent, longer response times in congruent trials were observed, consistent with orienting responses. Our results help to support earlier theories regarding the inherent limitations of unconsciously perceived information, though future studies should further investigate why and under which conditions is the executive control system modulated by unconscious information. PMID- 29990958 TI - Anteromedial GPi deep brain stimulation in Tourette syndrome: The first case series from Iran. AB - OBJECTIVES: Tourette syndrome (TS) is a neuropsychiatric disorder characterized by childhood onset motor and phonic tics. In refractory cases, deep brain stimulation (DBS) with different targets including anteromedial Globus pallidus (AM-GPi) looks promising. PATIENTS AND METHODS: Patients with TS diagnosed according to DSM-IV TR criteria with severe medication-recalcitrant disease referred to our DBS clinic, were recruited for this study. They underwent bilateral AM-GPi DBS with Model 3389, Medtronic electrodes. Patients were assessed using Yale Global Tic Severity Scale (YGTSS) and Gilles de la Touretts syndrome-quality of life (GTS-QOL) questionnaire before and one year after DBS. RESULTS: Six patients (four men and two women) with severe medication recalcitrant TS, mean age of 26.33 +/- 7.25 years fulfilled the follow up visits. All patients revealed significant improvement in tics severity one year after surgery. Based on YGTSS, total tic severity score decreased from 75.66 +/- 16.54 to 28.33 +/- 13.95, P-value:0.005. Quality of life improved significantly after DBS (26.66 +/- 20.65 before and 70.00 +/- 17.88 one year after surgery, P value:0.02). CONCLUSIONS: Results of our study in accordance to previous ones suggest AM-GPi DBS as an effective and well-tolerated therapeutic modality for patients with medication refractory TS. PMID- 29990959 TI - Recurrent posterior reversible encephalopathy syndrome with cerebellar involvement leading to acute hydrocephalus. AB - Posterior reversible encephalopathy syndrome or PRES is a proposed cliniconeuroradiological entity that is characterized by headache, confusion, seizure, cortical visual disturbances or even blindness and, to a lesser extent, focal neurological signs. The etiology of this entity includes a sudden increase in blood pressure, renal failure, immunosuppressive drugs, infections, and intravenous immunoglobulin (IVIG). Classically, magnetic resonance imaging (MRI) findings show a symmetric reversible vasogenic edema in the parietooccipital lobes. PRES can involve the brainstem and cerebellum and sometimes can leave irreversible lesions but it can also recur, which is a very rare presentation. In this article, we report a case of recurrent PRES with cerebellar involvement associated with non-communicating hydrocephalus in a 2-year-old child with renal failure on peritoneal dialysis after receiving Etoposide for macrophage activation syndrome. PMID- 29990960 TI - Peripheral facial paralysis associated with HIV infection: A case series and literature review. AB - OBJECTIVE: The association between peripheral facial paralysis (PFP) and HIV infection has been scarcely explained. The authors aimed to describe the association between PFP and HIV infection status, along with the related co morbidities and the outcomes of PFP, as well as the literature review on this topic. PATIENTS AND METHODS: All HIV-infected patients who experienced PFP, both before and after a positive HIV serology test, between January 2002 and June 2015 were retrospectively reviewed. The patients' demographic data, clinical characteristics, HIV co-morbidities and outcomes of PFP were summarized. A literature review of PFP in HIV infection was also performed. Descriptive statistics were used in the data analysis. The Mann-Whitney U test was performed to compare the parameters between the current case series and cases from literature review to determine statistical significant differences (p < 0.05). RESULTS: Sixteen patients (6 males and 10 females) were enrolled. Their median age was significantly higher than that of the cases in the literature review [46 (38, 49.75) vs. 33 (26, 41) years (p = 0.004)]. Nonetheless, a non-significant lower median CD4 count was observed [274 (134.5, 425.5) vs. 373 (265, 718) cells/MUL (p = 0.058)]. In our series, unilateral PFP (UFP) was the most frequent, and it typically occurred long after a positive HIV serology test. However, bilateral PFP (BFP) was commonly found in the literature, and a simultaneous positive HIV serology test was reported in almost all cases. Consequently, most of our cases, except for those with HIV-related complications or co-morbidities, experienced a satisfactory recovery from PFP regardless of treatments received. CONCLUSIONS: Most of the cases in our series were UPF with a higher median age and a lower median CD4 count. Moreover, facial paralysis presented later in our series than in the previously reported cases in the literature. Most of our cases experienced satisfactory recovery of facial weakness. PMID- 29990961 TI - Health-related quality of life outcomes from botulinumtoxin treatment in blepharospasm. AB - OBJECTIVE: Blepharospasm associates with impairment in generic health-related quality of life (HR-QoL). Albeit botulinum toxin is widely used to alleviate the motor symptoms of blepharospasm, its effect on generic health-related quality of life (HR-QoL) is heterogeneous. PATIENTS AND METHODS: In this open-label clinical observational study, we characterized outcomes on HR-QoL in terms of the EuroQol (EQ-5D-5 L) from botulinum toxin (BoNT) injection in a prospective cohort of patients with blepharospasm (n = 55). Additionally, we characterized motor and non-motor signs of blepharospasm including motor symptom improvement, life satisfaction, depressive symptoms, pain and sleep quality. Patients were assessed at the end of a regular three-month period from last injection (Timepoint1) and four weeks after the re-injection of BoNT (Timepoint2). RESULTS: There was no improvement of generic HR-QoL on group-level. Individual findings were heterogeneous, dividing patients in three groups of responders (RESP), unchanged outcomes (UNCHN), and worsening (WORSE). We identified, that these subgroups differed at Timepoint 1 with respect to EQ-5D-5 L, EQ-VAS, life satisfaction (health and movement disorders domains), Beck's Depression inventory, and sleep quality (One-way ANOVAs, P < 0.05, adjusted for multiple comparisons). In post hoc Tuckey tests, RESP or WORSE showed distinct differences from UNCHN that might help to separate the subgroups in future. As such, RESP showed higher impairment in EQ-5D-5L, EQ-VAS, and Beck's Depression Inventory compared to UNCHN (unlike WORSE), whereas WORSE showed higher impairment in life satisfaction 'movement disorders' domain (unlike RESP). CONCLUSION: Our study suggests, that several dependent non-motor, life satisfaction and generic HR-QoL measures associate to individual patient outcomes. The variables identified in this study may be validated in future studies to predict HR-QoL outcomes in patients with blepharospasm. PMID- 29990962 TI - Vascular Access Differences in Men and Women: Time to Solve the Problem? PMID- 29990963 TI - Amyotrophic Lateral Sclerosis Mortality in the United States, 2011-2014. AB - BACKGROUND: The International Classification of Disease, 10th Revision (ICD-10) did not include a code specific for Amyotrophic lateral sclerosis (ALS) until 2017. Instead, code G12.2 included both ALS and other motor neuron diseases (MND). Our objective was to determine US mortality rates for ALS exclusively by excluding other MND and progressive supranuclear palsy. METHODS: All mortality data coded as G12.2 under the pre-2017 rubric were obtained for 2011-2014. Deaths without ALS listed in one of the un-coded cause-of-death fields were excluded. ALS death rates per 100,000 persons were age-adjusted to the 2000 US standard population using the direct method. RESULTS: The proportion of excluded records coded G12.2 but not ALS was 0.21, resulting in 24,328 ALS deaths. The overall age adjusted mortality rate was 1.70 (95% CI 1.68-1.72). The rate among males was 2.09 (95% CI 2.05-2.12) and females was 1.37 (95% CI 1.35-1.40). The overall rate among whites was 1.84, blacks 1.03, and other races 0.70. For both sexes and all races, the rate increased with age and peaked among 75-79 year-olds. Rates tended to be greater in states at higher latitudes. CONCLUSIONS: Previous reports of ALS mortality in the United States showed similar age, sex, and race distributions but with greater age-adjusted mortality rates due to the inclusion of other diseases in the case definition. When using ICD-10 data collected prior to 2017, additional review of multiple-cause of death data is required for the accurate estimation of ALS deaths. PMID- 29990964 TI - Significance of High-Risk Human Papillomavirus Testing for Atypical Glandular Cells on Cervical Cytology. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic significance of high-risk human papillomavirus (hrHPV) testing for managing women with atypical glandular cells (AGC) and to explore the distribution of hrHPV genotypes. METHODS: We analyzed cytologic and histopathologic diagnoses in patients referred to our institution due to AGC or atypical squamous cells of undetermined significance (ASC-US). All patients underwent hrHPV testing and genotyping, and positive (PPV) and negative predictive values (NPV) for cervical intraepithelial neoplasia (CIN) 2 or worse [CIN2+/adenocarcinoma in situ (AIS)+] were calculated. RESULTS: Among 41 cases previously diagnosed with AGC, 22 (53%) were classified as CIN2+ (2 squamous cell carcinomas), whereas only 2 were AIS or adenocarcinoma. Twenty-seven (65.8%) cases in the AGC group were hrHPV positive. The most frequent genotypes in both the ASC-US and AGC groups were HPV16 and HPV52. The PPV of hrHPV testing for CIN2+/AIS+ was significantly higher in the AGC than in the ASC-US group (74.1 vs. 35.0%; p = 0.0005). The NPV for CIN2+/AIS+ was significantly lower in the AGC than in the ASC-US group (74.4 vs. 100%; p = 0.0441). CONCLUSION: In patients with AGC, both glandular and squamous lesions must be monitored. hrHPV testing is useful for detecting CIN2+/AIS+ in AGC. PMID- 29990965 TI - Ultralow Anterior Resection and Coloanal Anastomosis for Low-Lying Rectal Cancer: An Appraisal Based on Bowel Function. AB - BACKGROUNDS/AIMS: On the basis of acceptable oncologic results, ultralow anterior resection (ULAR) and colo-anal anastomosis plus hand-sewn coloanal anastomosis have been performed for treating very low-lying rectal cancer. However, many patients experience bowel dysfunction after ULAR. Studies have provided inadequate data on bowel dysfunctions and only a few functional studies have focused on low rectal cancer. Therefore, we aimed to elucidate the severity of bowel dysfunction after ULAR in a single-surgeon cohort. METHODS: In this prospective observational study, we analyzed data of 203 patients who underwent sphincter-preserving surgery for low-lying rectal cancer (tumor located within 5 cm from the anus) between January 2011 and December 2014. During routine follow up, examinations (3-6 months interval) after ileostomy closure, patients were asked about their bowel functions based on the Wexner incontinence and LAR syndrome (LARS) scores. Patients were divided into 2 groups: LAR group (LAR with double-stapled anastomosis) and ULAR group (ULAR with coloanal anastomosis), and functional scores were compared between 6 and 36 months. Seven risk factors for major LARS were analyzed. RESULTS: At 36 months after surgery, 94.2 and 70.6% of patients in the ULAR group still had moderate to severe incontinence and major LARS respectively. Fecal incontinence improved significantly over time (ULAR group, 14.4 vs. 7.2, p = 0.045; LAR group, 13.9 vs. 5.4, p < 0.05). However, improvement in LARS over time was observed in the LAR group only (26.5 vs. 19.7, p = 0.045). In the ULAR group, the difference did not reach a statistical significance (33.6 vs. 26.0, p = 0.10). Major LARS and moderate incontinence were significantly higher in the ULAR group than in the LAR group (70.6 vs. 47.6%, p = 0.001; 82.4 vs. 32.0%, p = 0.012 respectively). Among the 7 factors evaluated in multivariable analysis, old age (> 70), male sex, ULAR per se, and chemoradiation therapy were found to be meaningful risk factors for major LARS. CONCLUSION: In patients with low rectal cancers undergoing ULAR plus coloanal anastomosis, bowel dysfunctions were severe. Bowel dysfunctions improved over time, but most patients still experienced major bowel dysfunctions even 36 months after surgery. Risk factors for bowel dysfunctions were old age, male sex, adjuvant chemoradiation therapy, and ULAR. Therefore, ULAR should be performed in carefully selected patients with low-lying rectal cancer. PMID- 29990966 TI - Clinical Outcome of Twice-Weekly Hemodialysis Patients with Long-Term Dialysis Vintage. AB - BACKGROUND/AIMS: Twice-weekly hemodialysis(HD) is prevalent in the developing countries, scarce data are available for this treatment in patients with long term dialysis vintage. METHODS: 106 patients with more than 5 years HD vintage undergoing twice-weekly HD or thrice-weekly HD in a hemodialysis center in Shanghai between December 1, 2013 and December 31, 2013 were enrolled into the cohort study with 3 years follow-up. Kaplan-Meier analysis and Cox proportional hazards models were used to compare patient survival between the two groups. Subgroup analysis of 62 patients more than 10 years HD vintage was also performed according to their different dialysis frequency. RESULTS: Compared with patients on thrice-weekly HD, twice-weekly HD patients had significantly longer HD session time and higher single-pool Kt/V (spKt/V) (session time, 4.59+/-0.45 vs 4.14+/ 0.31 hours/per session, P< 0.001; spKt/V, 2.12+/-0.31 vs 1.83+/-0.30, P< 0.001). Kaplan-Meier survival analysis indicated that the two groups had similar survival (P=0.983). Multivariate Cox regression analysis showed that age and time dependent serum albumin were predictors of patient mortality. Subgroup analysis of 62 patients more than 10 years HD vintage also indicated that the two groups had similar survival. During the follow-up, 4 patients dropped out from the twice weekly HD group and transferred to thrice-weekly HD. CONCLUSION: The similar survival between twice-weekly HD and thrice-weekly HD in patients with long-term dialysis vintage is likely relating to patient selection, individualized treatment for dialysis patients based on clinical features and socioeconomic factors remains a tough task for the clinicians. PMID- 29990968 TI - Reply. PMID- 29990967 TI - Re-Evaluation of Total CO2 Concentration in Apparently Healthy Younger Adults. AB - The initial assessment of acid-base status is usually based on the measurement of total CO2 concentration ([TCO2]) in venous blood, a surrogate for [HCO3-]. Previously, we posited that the reference limits of serum [TCO2] in current use are too wide. Based on studies on the acid-base composition of normal subjects, we suggested that the reference limits of serum [TCO2] at sea level be set at 23 30 mEq/L. To validate this proposal, we queried the University of California at Los Angeles (UCLA's) Integrated Clinical and Research Data Repository, a database containing information on 4.5 million patients seen at UCLA from 2006 to the present. Criteria for inclusion included adults (18-40 years of age), who were free of disorders that could affect acid-base balance, were not taking medications that could affect acid-base balance, and were seen for a routine medical examination or immunization in the outpatient setting. The number of individuals who met the inclusion criteria (52% female and 48% male) was 28,480, with a mean age of 28.9 +/- 5.1 years. The mean serum [TCO2] level was slightly higher in males than females, 26.6 +/- 2.16 mEq/L vs. 25.0 +/- 2.11 mEq/L (p < 0.05). Ninety-one percent of patient values were within the proposed 23-30 mEq/L range and 61.7% were within the 24-27 mEq/L range. These findings validate our proposal that the reference range of serum [TCO2] in venous blood at sea level be narrowed to 23-30 mEq/L. Subjects with serum [TCO2] outside this range might require assessment with a venous blood gas to exclude the presence of clinically important acid-base disorders. PMID- 29990970 TI - Laser-Induced Interstitial Thermotherapy of Gliomas. AB - Laser-induced interstitial thermotherapy (LITT) is a modern minimally invasive treatment modality applied for management of a variety of diseases. Recent developments of techniques for precise targeting of the lesion, accurate delivery of the prescribed therapeutically effective thermal doses, and real-time visualization of the induced tissue damage during the procedure by means of intraoperative MR thermometry have stimulated a number of clinical studies testing LITT in cases of different brain pathologies, including gliomas. This modality is particularly attractive in patients with recurrent, deep-seated, and/or critically located neoplasms refractory to other treatments, where it can effectively demonstrate improvement of prognosis providing high quality of life and eliminating the risks of open tumor resection. Low morbidity rates associated with LITT and short hospital stay result in decreased cost of hospitalization. The effectiveness of thermal therapies, particularly after long-term follow-up, still needs evaluation in carefully planned randomized clinical trials, whereas elucidating the effects of laser treatment at the molecular, cellular, and organic levels will continue to expand the boundaries of its clinical applicability in neuro-oncology. PMID- 29990969 TI - Photodynamic Therapy of Malignant Gliomas. AB - Recently, the clinical applications of photodynamic therapy (PDT) in the management of malignant brain tumors have attracted significant attention. Meta analysis of the observational studies on this treatment in high-grade gliomas (Eljamel, 2010) included more than 1,000 patients and reported median survival in cases of newly diagnosed and recurrent glioblastoma multiforme (GBM) of 16.1 and 10.3 months, respectively. In some series, increase in the long-term survival rates was also observed. Few controlled trials demonstrated statistically significant impact of PDT on prolongation of survival in patients with GBM in comparison to conventional management. The main treatment-related adverse event is short-lasting excessive photosensitivity of the skin and retina after photosensitizer administration, but its negative consequences can be easily avoided with appropriate protective measures. Overall, PDT may be considered to be a safe and effective adjuvant therapeutic option for patients with newly diagnosed and recurrent malignant gliomas. Aggressive tumor resection seems to be an important prerequisite to maximize treatment efficacy. PMID- 29990971 TI - Stereotactic Cryodestruction of Gliomas. AB - Surgical resection of gliomas affecting functionally important brain structures is associated with high risk of permanent postoperative neurological deficit and deterioration of the patient's quality of life. The availability of modern neuroimaging and neuronavigation permits the application of minimally invasive stereotactic cryodestruction of the tumor in such cases. The authors used this treatment in 88 patients with supratentorial gliomas of various WHO histopathological grades not suitable for microsurgical resection. Postoperative mortality (1.1%) and rate of surgical complications (11.4%) were comparable to reported results of stereotactic brain tumor biopsy, whereas the rate of neurological morbidity (42%) was comparable to outcome after resection of gliomas within eloquent brain areas. The majority of complications were temporary, and permanent deterioration of neurological function was noted in 8% of cases only. The median survival after treatment in patients with glioblastoma and anaplastic astrocytoma was 12.4 and 46.9 months, respectively, and was not reached in cases of diffuse astrocytoma, which compared favorably both with historical controls and literature data. Therefore, it seems reasonable to consider stereotactic cryodestruction in multimodality management strategies of "unresectable" intracranial gliomas, and further studies directed at evaluation of its efficacy are definitely needed. PMID- 29990972 TI - High-Intensity Focused Ultrasound Ablation Therapy of Gliomas. AB - Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of biological effects, including thermal ablation of brain tumors. Therapeutic ultrasound has been studied for many years, but only within the last decade has the technology reached a point where it is safe and practical for clinical adoption. Using large, multi-element arrays, ultrasound can be focused through the skull, and combined with MRI for image guidance and real-time thermometry, to create lesions in the brain with millimeter accuracy. Using this technology, true non-invasive surgery can be accomplished with immediate tumor killing. Combining the ablative capabilities of focused ultrasound with its other unique effects, such as blood-brain barrier disruption and radiosensitization, may eventually result in change of the current glioma treatment paradigm. PMID- 29990973 TI - Boron Neutron Capture Therapy of Malignant Gliomas. AB - Boron neutron capture therapy (BNCT) is a promising modality for biochemically targeted, highly selective radiation treatment of various cancers, including malignant gliomas. Currently available results demonstrate the beneficial effect of such therapy on survival of patients with both recurrent and newly diagnosed glioblastomas. The main drawback of BNCT in cases of previously irradiated neoplasms is high rates of symptomatic pseudoprogression and radiation necrosis. For prevention of these complications, concurrent administration of bevacizumab may be helpful. Further studies are needed to establish the optimal therapeutic protocols and to define the exact role of this management option in multimodality treatment strategies. Recent technological developments of accelerator-based neutron sources may simplify placement of the device for BNCT within clinical facilities and lead to wider application of this technique in cases of various cancers. PMID- 29990974 TI - Proton and Carbon Ion Therapy of Intracranial Gliomas. AB - In comparison to photon irradiation, particle therapy of cancer performed either with protons or with carbon ions, offers the advantage of their distinct physical characteristics, and through delivery of high linear energy transfer (LET) particles, exploits greater relative biological effectiveness (RBE). There is strong rationale for applying such treatment in patients with intracranial gliomas. In cases of low-grade tumors, the main benefits may be related to potential decrease of long-term morbidity, whereas in cases of high-grade neoplasms, the use of modalities with greater RBE may lead to better tumor control and improve patient survival. Nevertheless, to date, there are no convincing data that confirm the superior effects of particle therapy (either with protons or carbon ions) in comparison to advanced photon fractionated radiotherapy (FRT) in patients with either newly diagnosed or recurrent intracranial gliomas. Therefore, the real clinical benefit of such treatment should be evaluated further in prospective clinical trials. PMID- 29990975 TI - Novel and Prospective Molecular Targets for Therapy of Intracranial Gliomas. AB - Multiple alterations in the expression levels of genes or proteins have been identified in gliomas, including activation of oncogenes and silencing of tumor suppressor genes. Illuminating these molecular mechanisms of tumorigenesis and treatment resistance is necessary for the development of new therapies. With the promise of better effectiveness and less toxicity, the emphasis in drug development has moved from cytotoxic, non-specific chemotherapies to molecular targeted agents. However, despite progress in other areas of oncology, targeted therapy success stories in cases of brain tumors remain all but absent. Nonetheless, experiences from previous clinical trials suggest that a small number of unselected patients may benefit from such treatment. An increasing knowledge about related factors and prospective enrichment strategies now shape research and clinical trial design in neuro-oncology and may lead to improved outcomes after molecular targeted therapies of gliomas. PMID- 29990976 TI - Cytokine Therapy of Gliomas. AB - Cytokines are a heterogeneous group of soluble small polypeptides or glycoproteins, which exert pleiotropic and redundant effects that promote growth, differentiation, and activation of cells. Cytokine production plays a profound role in the modulation of the tumor microenvironment, including the host of heterogeneous neoplastic cells, immune cells, and extracellular matrix, which is essential for progression of the neoplasm. Depending on specific conditions, the cytokines can either upregulate or downregulate anti-inflammatory and immunosuppressive activities. The crosstalk between cytokines and their receptors in the tumor microenvironment constitutes the target for various types of cytokine therapies that have been tested until now for treatment of patients with intracranial glioma. PMID- 29990977 TI - Cell-Based Immunotherapy of Gliomas. AB - Current cell-based immunotherapeutic strategies attempt to produce and maintain an immune response against glioma cells by artificially stimulating the immune system using passive and/or active approaches. Cellular immunotherapy is taken to mean the administration of live immune cells that either have immune effector capabilities themselves (passive immunotherapy) or engender a downstream antitumor response (active immunotherapy). Passive cellular immunotherapy most often takes the form of the adoptive transfer of a range of cell types, whereby antitumor immune cells from a patient (or allogeneic donor) are created, activated, and/or expanded ex vivo and subsequently administered back to the patient to directly attack the neoplasm. Active cellular immunotherapy approaches for the treatment of malignant gliomas have most often taken the form of dendritic cell (DC)-based vaccines. PMID- 29990978 TI - Vaccine Therapy of High-Grade Gliomas. AB - Multiple phase II clinical trials on the use of tumor vaccines in cases of high grade gliomas (HGG), in particular autologous formalin-fixed tumor vaccine (AFTV), demonstrated the safety and potential efficacy of such therapy. There is evidence that maximal resection of neoplasm provides optimal conditions for enhancement of the tumor-specific immune reactions induced by vaccine administration, and thus aggressive surgery may be an important prerequisite for treatment success. Irradiation and chemotherapy may also enhance the effectiveness of vaccines, particularly through modulation of the tumor microenvironment. Nevertheless, the most effective combinations of vaccine therapies with surgery, irradiation, chemotherapy, antiangiogenic therapy, or other modes of immunotherapy in cases of HGG are still unclear and likely to be an active area of research in the future. PMID- 29990979 TI - Gene Therapy and Virotherapy of Gliomas. AB - Despite many recent advances in the management of gliomas, such as aggressive surgical resection, chemoradiotherapy, antiangiogenic therapy, and molecular targeted therapy, the survival of patients with high-grade neoplasms remains dismal. Gene therapy and oncolytic virotherapy have emerged as highly promising strategies for treatment of malignant brain tumors due to recent progress in understanding of the underlying cancer biology as well as improved techniques for genetic modification of potential therapeutics. PMID- 29990980 TI - Stem Cell Therapy of Gliomas. AB - Stem cells (SC) are the seeds of tissue repair and regeneration that have been extensively investigated as tumor-tropic vectors for gene delivery to solid cancers. SC have an inherent glioma tropism that supports their use as reliable vehicles to deliver therapeutic gene products to brain neoplasms. Several types of adult SC (ASC) have been used to carry antiglioma agents, and neural SC (NSC) and mesenchymal SC (MSC) are the most studied. The therapeutic cargoes that have been tested include secreted proteins, converting enzyme/prodrug suicide combinations, oncolytic viruses, antibodies, and nanoparticles. Some of these preclinical studies have advanced to phase I clinical trials. Use of SC as carriers to deliver various antitumor agents could become a valuable therapeutic option for glioma patients in the future. PMID- 29990981 TI - Convection-Enhanced Delivery for Management of Malignant Gliomas. AB - Convection-enhanced delivery (CED) is a novel method of bypassing the blood-brain barrier for administration of therapeutic agents directly into brain with a potential to provide concentrations that cannot be achieved with systemic drug delivery. This technique has grown significantly over the last 20 years with better understanding of the biomechanics of infusion and of the delivery process. Though clinical trials of CED in malignant brain tumors have not yielded the desired results, a number of new biologically active compounds and pharmaceutical preparations, their carriers, modes of delivery, and improved catheter designs are continually being tested, which hold promise for the future. PMID- 29990982 TI - Targeted Local Therapy for Management of Intracranial High-Grade Gliomas. AB - Systemic chemotherapy of malignant brain tumors has failed to achieve sufficient drug concentrations at the neoplasm site and frequently results in severe toxicities. Therefore, the local application of several anticancer agents, oncolytic viruses and vectors for gene therapy, immune-modifying preparations, and angiogenesis inhibitors has been investigated widely. Various modes of their administration were introduced, including intratumoral injections, implantation of reservoirs or pumps, convection-enhanced delivery, and use of nanocarriers, thermoreversible gels, microchips, and drug-loaded polymers. Many of these therapeutic approaches have shown promising results in management of high-grade gliomas. PMID- 29990983 TI - Extracellular Vesicles as a Platform for Glioma Therapeutic Development. AB - Normal and pathologic cells secrete extracellular vesicles (EV), which are defined as 30-2,000 nm spherical organelles. It has been found that EV mediate various biological functions including cellular remodeling and export of biomolecules, extracellular communication, immune stimulation and suppression, and modulation of the cellular microenvironment. EV secreted by human glioma cells contain a wealth of tumor-specific proteins and nucleic acids that can be isolated from patients with these neoplasms. Thus, EV contribute to the development of biomarkers, and additionally have certain therapeutic potential for possible use in neuro-oncology and neurosurgery. PMID- 29990984 TI - Alternating Electric Fields Therapy for Malignant Gliomas: From Bench Observation to Clinical Reality. AB - Alternating electric fields of intermediate frequencies, also known as Tumor Treating Fields (TTFields or TTF) is a novel anticancer treatment modality that disrupts tumor cell mitosis at the metaphase-anaphase transition, leading to mitotic catastrophe, aberrant mitotic exit, and/or cell death. It is realized through alteration of the cytokinetic cleavage furrow by interference of proteins possessing large dipole moments, like septin heterotrimer complex and alpha/beta tubulin, and that results in disordered membrane contraction and failed cytokinesis. Aberrant mitotic exit also elicits immunogenic cell death, which may potentiate an immune response against treated tumors. Notably, in patients with recurrent glioblastoma multiforme (GBM) a prospective clinical trial demonstrated comparable overall survival and progression-free survival after TTFields therapy and best physician's choice chemotherapy. Moreover, it was shown that in patients with newly diagnosed GBM initially treated with standard chemoradiotherapy with daily temozolomide (TMZ), adjuvant TTFields combined with TMZ offered better survival than adjuvant TMZ alone. Therefore, TTFields therapy can be appreciated as a standard treatment option in cases of intracranial malignant gliomas, whereas future studies should establish its optimal combination with other existing anticancer modalities, which may offer additional survival benefits for patients. PMID- 29990985 TI - Perspectives of Nanotechnology in the Management of Gliomas. AB - Significant advances in the design and understanding of the materials and systems of 1-100 nm have provided unprecedented tools to probe, diagnose, and treat diseases at the molecular level with greater efficiency and accuracy. In particular, optical and chemical properties of nanomaterials are being exploited to improve the effectiveness of neuro-oncological and neurosurgical interventions. Modern nanotechnology-driven clinical applications may have significant impact on management of brain tumors. PMID- 29990986 TI - Severe Solute Depletion in Patients with Hyponatremia Due to Diuretics Despite Biochemical Pictures Similar Than Those Observed in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone. AB - BACKGROUND/AIMS: Hyponatremia secondary to distal diuretics intake could have a biochemical picture similar to the one observed in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In these patients, water retention is considered to be the main causal factor and solute depletion a secondary one. METHODS: We compared the level of cation (Na + K) depletion and water balance in patients with high or low uric acid levels (< 4 mg/dL or 238 umol/L) or with high or low (< 30 mg/dL or 5 mmol/L) urea levels. Data were collected from 15 consecutive patients treated in a similar way by a daily infusion of 2 L isotonic saline with potassium chloride until SNa reached at least 132 mmol/L. The same procedure was performed in 6 patients with hyponatremia due to salt depletion not related to diuretic intake. RESULTS: Hyponatremia, associated with low or high uric acid level is mainly due to severe cation depletion (around 600 mmol) and not due to water retention, since body weight did not change significantly (SNa 122 +/- 2.0 mEq/L). If patients were classified according to serum urea levels those with higher urea levels (>=30 mg/dL) presented with a mild increase in BW (0.84 +/- 0.37 kg). In patients with salt depletion and hyponatremia not related to diuretic intake, we observe as expected an increase in BW (1.5 +/- 0.3 kg) and similar cation retention with the treatment. CONCLUSION: We therefore suggest that diuretic induced hyponatremia with an SIADH-like biochemical profile, should be treated mainly by solute -repletion. PMID- 29990987 TI - Somatostatin Octapeptide Inhibits Cell Invasion and Metastasis in Hepatocellular Carcinoma Through PEBP1. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a major threat to human health. The condition carries a high risk of death; 45% of new cases occur in China. Surgical resection is the first choice for treatment of HCC, but 30.9% of patients experience recurrence within 6 months after the operation. To improve patient survival, we must determine how to reduce the probability of recurrence and metastasis and elucidate the underlying mechanism of disease. We therefore studied the effect of somatostatin octapeptide (octreotide) on the invasion and metastasis of HCC. METHODS: The migration and invasion cytological tests were used to detect the effect of octreotide on liver cancer cells (SK-Hep-1 and HepG2). PEBP1 RNAi was used to knockdown expression. Invasion and metastasis were measured with transwell migration and wound-healing assays. Western blotting was used to detect changes in levels of PEBP1 and invasion pathway proteins after octreotide treatment. The effect of octreotide was studied in vivo by establishing a pulmonary metastasis model using SK-Hep-1 cells in nude mice. In vivo bioluminescence imaging and hematoxylin and eosin staining of lung tissue were used to verify the results. RESULTS: Increasing concentrations of octreotide were progressively more effective in halting the invasion and metastasis of liver cancer cells. Octreotide may upregulate PEBP1, TIMP-2, and E-cadherin while downregulating MMP-2 and Twist to inhibit cell invasion and metastasis. And downregulation of PEBP1 would also change the expression of MMP-2, TIMP-2 and Twist. The in-vivo experiments showed no cancer cell metastasis in 4 of the 6 mice in the octreotide-treatment group, while all of the mice in the control group displayed pulmonary metastasis of human HCC cells. And the survival period of the mice in the octreotide-treatment group was significantly prolonged. CONCLUSIONS: Octreotide may weaken invasion and metastasis through the upregulation of PEBP1. Octreotide may reduce the risk of recurrence and metastasis after surgery for liver cancer. PMID- 29990988 TI - Proteomic Analysis for Identification of Biomarkers that Predict Severe Acute Kidney Injury. AB - The search for acute kidney injury (AKI) biomarkers has identified a number of urine proteins that can be used to predict the presence of AKI but has struggled to identify proteins that are prognostic for severe AKI. In this review, we discuss 2 currently available biomarkers and the designs of the studies in which they were identified and relate this to the AKI characteristics they predict clinically. We discuss recent advances in mass spectrometry and sample preparation, which have improved the ability to identify low abundance proteins as well as the ability to characterize more of the protein by mass spectrometry. We show how these changes can lead to a deeper and more thorough analysis of the urine proteome. Finally, we highlight 2 important issues that can help in the identification of these biomarkers, appropriate study design and adequate technical characteristics in the analysis. PMID- 29990989 TI - A Direct Interaction Between P53-Binding Protein 1 and Minichromosome Maintenance Complex in Hepg2 Cells. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. DNA damage repair in cancer cells is a promising approach for the treatment of cancers. We aimed to explore the potential interaction between p53-binding protein 1 (53BP1) and minichromosome maintenance (MCMs) proteins during DNA damage in human hepatoma HepG2 cells. METHODS: The recombinant vectors of 53BP1 and MCMs with tags were constructed and transfected into HepG2 cells. Immunoprecipitation (IP) and mass spectrometry (MS) were performed to identify the possible interactions between 53BP1 and MCMs, and glutathione S-transferase (GST) pull-down assay was carried out to detect the direct interaction. Moreover, the expressions of MCM2 and MCM6 were suppressed by specific short hairpin RNAs (shRNAs), and then the chromatin fraction and foci formation of 53BP1 were examined under the condition of DNA damage. RESULTS: The results showed that MCM2/3/5/6 was immunoprecipitated against the hemaglutinin (HA)-tagged 53BP1 in HepG2 cell nuclei. GST results revealed that there was a direct interaction between 53BP1 and MCMs complex. Moreover, the non-chromatin level of 53BP1 was significantly increased by down-regulation of MCM2 or MCM6, but was statistically decreased the chromatin level. Furthermore, we observed that knockdown of MCM2 or MCM6 could statistically inhibit the foci formation of 53BP1 in HepG2 cell nuclei upon bleomycin-induced DNA damage (P < 0.01). CONCLUSION: Our results suggest that there is a direct interaction between 53BP1 and MCMs, which is essential for 53BP1 chromatin fraction and foci formation in hepatoma HepG2 cells. PMID- 29990990 TI - Identification and Characterization of CircRNAs of Two Pig Breeds as a New Biomarker in Metabolism-Related Diseases. AB - BACKGROUND/AIMS: CircRNAs, as miRNA sponges, participate in many important biological processes. However, it remains unclear whether circRNAs can regulate lipid metabolism. This paper aims to study the molecular mechanism of fat deposition and provide useful information for the prevention and therapy of lipid metabolism-related diseases. METHODS: CircRNA sequencing was performed to investigate the expression of circRNAs in the subcutaneous adipose tissues of Large White pig and Laiwu pig. The expression of circRNAs was further validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Furthermore, circRNA-microRNAs (miRNA)-mRNA interaction networks were constructed using bioinformatics tools. In addition, GO and KEGG enrichment analyses were performed for the target genes of circRNAs. RESULTS: In the subcutaneous adipose tissue of Laiwu pig, 70 up-regulated circRNAs and 205 down-regulated circRNAs were identified. Two circRNAs (up-regulated circRNA_26852 and down-regulated circRNA_11897), the expressions of which were confirmed by qRT-PCR, were selected for subsequent analysis. CircRNA-miRNA-mRNA interaction networks were constructed for circRNA_26852 and its target genes as well as circRNA_11897 and its target genes. GO and KEGG enrichment analyses reveal that the target genes of circRNA_26852 and circRNA_11897 are enriched in pathways related to adipocyte differentiation and lipid metabolism, as well as in disease-related pathways. CONCLUSIONS: In this study, circRNA sequencing and bioinformatics technique were used to analyze, for the first time, the expression of circRNAs in the subcutaneous adipose tissues of Large White pig and Laiwu pig. It is inferred that circRNAs might regulate adipogenic differentiation and lipid metabolism. The results provide a theoretical basis for further study on fat deposition mechanism and provide potential therapy targets for metabolism-related diseases. PMID- 29990991 TI - Optogenetics in Understanding Mechanisms of Acute Kidney Injury. AB - BACKGROUND: No approved pharmacological agents are available for the treatment and prevention of acute kidney injury (AKI). The nervous system has been reported to play an important role, directly or indirectly via the immune system, in the pathophysiology of AKI. Neuromodulation, such as vagus nerve stimulation and pulsed ultrasound, is emerging as an innovative therapeutic treatment for various diseases including AKI. However, lack of effective methods to selectively stimulate or inhibit neurons has hampered the complete understanding of the roles of the nervous system in AKI because electrical stimulation is nonspecific for cell types. SUMMARY: A novel technique called optogenetics optically controls cells in living tissues, typically neurons, which have been genetically modified to express light-sensitive opsins. For example, channelrhodopsin-2 (ChR2), an opsin, is a nonselective cation channel residing in a cell membrane, which rapidly opens its gate after exposing to monochromatic light in the "blue" wavelength. Unlike electrodes, blue light can selectively depolarize ChR2 expressing neurons, mainly via the Na+ entry, evoking an action potential. Optogenetics that use ChR2 and several variants to modulate kinetic properties and inhibitory opsins help in understanding the roles of the nervous system in AKI, thus leading to a clinical application of neuromodulation to AKI treatment. PMID- 29990992 TI - Differential Effects of 3,5-Diiodo-L-Thyronine and 3,5,3'-Triiodo-L-Thyronine On Mitochondrial Respiratory Pathways in Liver from Hypothyroid Rats. AB - BACKGROUND/AIMS: Both 3,5-diiodo-L-thyronine (3,5-T2) and 3,5,3'-triiodo-L tyronine (T3) affect energy metabolism having mitochondria as a major target. However, the underlying mechanisms are poorly understood. Here, using a model of chemically induced hypothyroidism in male Wistar rats, we investigated the effect of administration of either 3,5-T2 or T3 on liver oxidative capacity through their influence on mitochondrial processes including: proton-leak across the mitochondrial inner membrane; complex I-, complex II- and glycerol-3-phosphate linked respiratory pathways; respiratory complex abundance and activities as well as individual complex aggregation into supercomplexes. METHODS: Hypothyroidism was induced by propylthiouracil and iopanoic acid; 3,5-T2 and T3 were intraperitoneally administered at 25 and 15 ug/100 g BW for 1 week, respectively. Resulting alterations in mitochondrial function were studied by combining respirometry, Blue Native-PAGE followed by in-gel activity, and Western blot analyses. RESULTS: Administration of 3,5-T2 and T3 to hypothyroid (hypo) rats enhanced mitochondrial respiration rate with only T3 effectively stimulating proton-leak (450% vs. Hypo). T3 significantly enhanced complex I (+145% vs. Hypo), complex II (+66% vs. Hypo), and glycerol-3 phosphate dehydrogenase (G3PDH) linked oxygen consumptions (about 6- fold those obtained in Hypo), while 3,5-T2 administration selectively restored Euthyroid values of complex II- and increased G3PDH- linked respiratory pathways (+165% vs. Hypo). The mitochondrial abundance of all respiratory complexes and of G3PDH was increased by T3 administration whereas 3,5-T2 only increased complex V and G3PDH abundance. 3,5-T2 enhanced complex I and complex II in gel activities with less intensity than did T3, and T3 also enhanced the activity of all other respiratory complexes tested. In addition, only T3 enhanced individual respiratory component complex assembly into supercomplexes. CONCLUSIONS: The reported data highlight novel molecular mechanisms underlying the effect elicited by iodothyronine administration to hypothyroid rats on mitochondrial processes related to alteration in oxidative capacity in the liver. The differential effects elicited by the two iodothyronines indicate that 3,5-T2, by influencing the kinetic properties of specific mitochondrial respiratory pathways, would promote a rapid response of the organelle, while T3, by enhancing the abundance of respiratory chain component and favoring the organization of respiratory chain complex in supercomplexes, would induce a slower and prolonged response of the organelle. PMID- 29990993 TI - Golgi Phosphoprotein 3 Promotes Wls Recycling and Wnt Secretion in Glioma Progression. AB - BACKGROUND/AIMS: Golgi phosphoprotein 3 (GOLPH3) plays pro-malignancy roles in several types of cancer. However, the molecular mechanism underlying GOLPH3 promoting tumor progression remains poorly understood. METHODS: The expression of GOLPH3 and Wntless (Wls) in glioma tissues was examined by western blotting and immunohistochemistry. EdU incorporation assay and colony formation assay was used to examine the cell growth ability. The effect of GOLPH3 on Wls recycling, Wnt secretion and beta-catenin activity was detected using western blotting, immunofluorescence, RT-PCR, ELISA or luciferase assay. RESULTS: The protein levels of GOLPH3 and Wls were upregulated and positively correlated with each other in human glioma tissues. The promoting effect of GOLPH3 on glioma cell proliferation was partially mediated by Wls. In addition, GOLPH3 interacted with Wls and GOLPH3 down-regulation drove Wls into lysosome for degradation, inhibiting its recycling to golgi and the plasma membrane. Importantly, GOLPH3 down-regulation inhibited Wnt2b secretion and decreased beta-catenin level and transcription activity. CONCLUSIONS: This study provides a brand new evidence that GOLPH3 promotes glioma cell proliferation by facilitating Wls recycling and Wnt/beta-catenin signaling. Our findings suggest a rationale for targeting the GOLPH3-Wls-Wnt axis as a promising therapeutic approach for glioblastoma. PMID- 29990994 TI - Gender and Racial Disparities in Initial Hemodialysis Access and Outcomes in Incident End-Stage Renal Disease Patients. AB - BACKGROUND: Arteriovenous (AV) access confers survival benefits over central venous catheters (CVC) in hemodialysis patients. Although chronic kidney disease disproportionately affects women and racial minorities, disparities in the utilization of hemodialysis access across Asians, Native Americans, Hispanics, blacks, and whites among males and females after accounting for pre-dialysis health are not well studied. METHODS: We evaluated 885,699 patients with end stage renal disease who initiated hemodialysis between January 1, 2004 and December 31, 2014 using the US Renal Data System. Multivariable logistic regression models -adjusted for pre-dialysis health were used to test the associations between gender and race on type of vascular access (AV access vs. CVC, and AV fistula vs. AV graft) at hemodialysis initiation as primary outcome, and on 1-year mortality as a secondary outcome. RESULTS: Mean age was 65 +/- 14 years. Females were less likely to use AV access for hemodialysis initiation than were males (OR 0.85; 95% CI 0.84-0.86). Compared to whites, adjusted odds of AV access for hemodialysis initiation were higher in blacks (OR 1.08; 95% CI 1.07 1.70), Asians (OR 1.11; 95% CI 1.07-1.14); and lower in Hispanics (OR 0.89; 95% CI 0.87-0.90). There was no -significant difference in mortality between males and females. Compared to whites, 1-year adjusted mortality was lower in Asians (OR 0.55; 95% CI 0.53-0.56), blacks (OR 0.67; 95% CI 0.66-0.68), Hispanics (OR 0.62; 95% CI 0.61-0.63), and Native Americans (OR 0.62; 95% CI 0.58-0.66). CONCLUSION: Females had lower odds of using AV access than do males for hemodialysis initiation. As compared to whites, blacks and Asians were more likely, and Hispanics were less likely to use AV access for first outpatient hemodialysis. Further investigation of biological and process of care factors may help in developing ways to reduce these disparities. PMID- 29990995 TI - Interferon Lambda Family along with HTLV-1 Proviral Load, Tax, and HBZ Implicated in the Pathogenesis of Myelopathy/Tropical Spastic Paraparesis. AB - HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neuroinflammatory disease related to human T lymphotropic virus type 1 (HTLV-1) infection. Interferon type III (IFN-lambda), which includes IL28, IL29, and IL28R, and affects the outcome of viral infections, might be complicated in the progression of HAM/TSP. Here, we investigated the host-virus interactions in the manifestation of HAM/TSP, using IL28B, IL29, IL28R, HTLV-1 Tax, HTLV-1 basic leucine zipper factor (HBZ), and proviral load (PVL). The study groups consisted of 20 patients with HAM/TSP, 20 asymptomatic HTLV-1 carriers (ACs), and 20 healthy controls (HCs). The means of PVL, Tax, and HBZ gene expressions in the HAM/TSP group (p = 0.004, 0.006, and < 0.0001, respectively) were significantly higher than in the AC group. The comparison of IL28B, IL29, and IL28R expression in the HAM/TSP, AC, and HC groups revealed no significant difference between the first 2, but lower concentrations in the HCs (IL28B: p = 0.03, 0.01; IL29: p = 0.07, 0.01; and IL28R: p < 0.0001, respectively). In the HAM/TSP group, correlations were seen between Tax and HBZ (R = 0.61, p = 0.004) and between Tax and IL29 (R = 0.45, p = 0.04). Negative correlations were observed between Tax and IL28B (R = -0.49, p = 0.02) and between HBZ and IL28R (R = -0.43, p = 0.06). In the ACs, an inverse correlation was found between Tax and IL28B (R = -0.42, p = 0.06). These findings suggest that IL29, IL28B, and IL28R interfere in the infection of HAM/TSP, mainly via Tax activation. PMID- 29990996 TI - UK Renal Registry 20th Annual Report: Introduction. PMID- 29990997 TI - Chapter 1 UK Renal Replacement Therapy Adult Incidence in 2016: National and Centre-specific Analyses. PMID- 29990998 TI - Chapter 2 UK Renal Replacement Therapy Adult Prevalence in 2016: National and Centre-specific Analyses. PMID- 29990999 TI - Chapter 3 Demographic and Biochemistry Profile of Kidney Transplant Recipients in the UK in 2016. PMID- 29991001 TI - Chapter 5 Survival and Cause of Death in UK Adult Patients on Renal Replacement Therapy in 2016. PMID- 29991000 TI - Chapter 4 Demography of the UK Paediatric Renal Replacement Therapy Population in 2016. PMID- 29991002 TI - Chapter 6 Adequacy of Haemodialysis in UK Adult Patients in 2016: National and Centre-specific Analyses. PMID- 29991003 TI - Chapter 7 Haemoglobin, Ferritin and Erythropoietin in UK Adult Dialysis Patients in 2016: National and. PMID- 29991004 TI - Chapter 8 Biochemical Variables in UK Adult Dialysis Patients in 2016: National and Centre-specific. PMID- 29991005 TI - Chapter 9 Centre Variation in Access to Kidney Transplantation (2011-2013 incident cohort). PMID- 29991006 TI - Chapter 10 Multisite Dialysis Access Audit in England, Northern Ireland and Wales and 2015 Peritoneal. PMID- 29991007 TI - Chapter 11 Clinical, Haematological and Biochemical Parameters in Patients on Renal Replacement Therapy. PMID- 29991009 TI - Appendix B Definitions and Analysis Criteria. PMID- 29991008 TI - Appendix A The UK Renal Registry Statement of Purpose. PMID- 29991010 TI - Appendix C Renal Services Described for Non-physicians. PMID- 29991011 TI - Appendix D Methodology for Analyses of CCG/HB Incidence and Prevalence Rates and of Standardised Ratios. PMID- 29991013 TI - Appendix F Additional Data Tables for 2016 Incident and Prevalent Patients. PMID- 29991012 TI - Appendix E Methodology for Estimating Catchment Populations of Renal Centres in the UK for Dialysis. PMID- 29991014 TI - Appendix G UK Renal Registry dataset specification. PMID- 29991015 TI - Appendix H Coding: Ethnicity, EDTA Primary Renal Diagnoses, EDTA Causes of Death. PMID- 29991017 TI - Appendix K Renal Centre Names and Abbreviations used in the Figures and Data Tables. PMID- 29991016 TI - Appendix I Acronyms and Abbreviations used in the Annual Report. PMID- 29991018 TI - The Role of RhoA in Neovascular-Related Functions of Endothelial Progenitor Cells Induced by AngiotensinII. AB - BACKGROUND/AIMS: Interference with endothelial progenitor cell (EPC) neovascularization is a novel therapeutic target for neovascular-related diseases. Angiotensin II (Ang II) was found to enhance new vessel formation and aggravated neovascular-related diseases. In this study, we investigated the effects of Ang II on EPC neovascular-related functions and explored the underlying mechanisms. METHODS: EPCs were cultured from bone marrow derived mononuclear cells. The effects of Ang II on EPC proliferation, adhesion, migration, and in vitro tube formation were investigated using the MTT assay, adhesion assay, transwell chamber assay, and in vitro tube formation assay respectively. The underlying mechanisms were explored using Western blotting assay. RESULTS: EPC adhesion, migration and in vitro tube formation were promoted by Ang II, and the effects were reversed by RhoA/Rho-associated kinases (ROCK) signaling pathway inhibitors including C3 exoenzyme, GGTI-286 and Y-27632. The active form of RhoA was up-regulated by Ang II and this effect was abolished by C3 exoenzyme. Moreover, RhoA silencing resulted in a notable inhibition of EPC adhesion, migration and in vitro tube formation, suggesting that RhoA activation played a pivotal role in Ang II angiogenic effect. The results also demonstrated that phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun-NH2 kinase was elevated by Ang II and attenuated by C3 exoenzyme, GGTI-286 and Y 27632. The enhancing effects of Ang II on EPC adhesion, migration and in vitro vasculogenesis were reversed by p38 inhibitor SB202190 and JNK inhibitor SP600125. CONCLUSION: Ang II may enhance EPC neovascular-related functions through activating RhoA/ ROCK and MAPK signaling pathway. PMID- 29991019 TI - Prenatal Evaluation and Postnatal Follow-Up of Ureteral Ectopic Insertion in Multicystic Dysplastic Kidneys. AB - OBJECTIVE: To emphasize the need for analyzing the pelvis when a unilateral multicystic dysplastic kidney (MCDK) is observed at prenatal ultrasonography (US) because of possible associated ectopic ureteral insertion. METHODS: We performed a retrospective study including prenatal US diagnosis of unilateral MCDK and retrovesical cyst. The following data were recorded: pre- and postnatal US, magnetic resonance imaging (MRI), and voiding cystourethrography (VCUG) findings. The shape of the pelvic cyst was analyzed as well as the visibility of the ureteral insertion into the cyst. RESULTS: Fourteen patients were included (7 females). At prenatal US, the cyst wall was smooth in 8 cases (6 females) and lobulated in 5 cases (4 males). In 1 case it protruded into the bladder. Ectopic ureteral insertion was observed in 2 cases. Prenatal MRI (n = 6) depicted ureteral insertion in 2 more cases. Postnatal US (n = 14) showed the same cyst patterns as prenatally, ectopic ureteral insertion (n = 8), and duplicated uterus (n = 4). Postnatal MRI (n = 7) always depicted the ureteral ectopic insertion into the cyst. VCUG (n = 5) showed indirect findings of ectopic ureteral insertion (n = 3). CONCLUSION: Unilateral MCDK should lead to search for a retrovesical cyst corresponding most commonly to a distended hemivagina or a seminal vesicle. Early diagnosis of this condition leads to better clinical management. PMID- 29991020 TI - Trace Albumin in the Urine Dipstick Test is Associated with Coronary Artery Calcification in Korean Adults. AB - BACKGROUND/AIMS: Albuminuria is a risk factor for coronary artery calcification (CAC) and cardiovascular disease (CVD). Although the urine dipstick test is widely used to screen albuminuria, little is known about the association between low-grade urine dipstick albumin and CAC. The aim of this study is to investigate the relationship between the trace of urine dipstick albumin and CAC in Korean adults. METHODS: This cross-sectional study analyzed 45,006 participants without previous CVD, who underwent coronary computed tomography and urine dipstick test from 2012 to 2014 as part of a health examination program in Korea. CAC was defined as coronary artery calcium score > 100. Participants were divided into 3 groups based on urine dipstick albumin results as follows: negative (-), trace (+/-), and positive (+1 to +4). RESULTS: The numbers of participants with CAC were 800 (2.0%), 111 (2.8%), and 33 (4.9%) for the negative, trace, and positive groups respectively. Based on multivariate analysis, albuminuria determined with urine dipstick test was associated with CAC after adjustment for various cardiovascular risk factors. Compared with the negative group, the OR for CAC was 1.62 (1.08-2.42) in the positive group and 1.34 (1.07-1.66) in the trace group. CONCLUSION: Even a trace level of albumin in the urine dipstick test was associated with subclinical CAC in Korean adults. Low-grade dipstick albuminuria should not be overlooked. PMID- 29991021 TI - Is HERV-K and HERV-W Expression Regulated by miR-155 in Kidney Transplant Patients with Human Cytomegalovirus Infection? AB - According to the latest update, 2,578 unique mature micro-RNAs (miRNAs) are currently annotated in the human genome and participate in the regulation of multiple events, such as cellular proliferation or apoptosis. A previous study analyzing global miRNA expression patterns in GH cells (high human endogenous retrovirus, HERV, K vs. low) showed that 2 miRNAs (miR-663 and miR-638) are differentially regulated and exhibit expression parallel to that of HERV-K. The aim of this study was to evaluate HERV-K and -W pol gene and miR-155 expression in kidney transplant recipients and the possible relationship between them. The comparison between kidney transplant patients negative for human cytomegalovirus (HCMV) infection and positive patients showed a significant difference in terms of miR-155 expression (p = 0.0111). We demonstrated that HERV-K and -W pol gene expression was significantly higher in CMV-infected kidney transplant recipients versus those not infected as previously reported by our groups. Our correlation data suggest that miR-155 are not directly involved in regulating the HERV notwithstanding that we together observed increased expression of HERV-K and -W and diminished expression of miR-155 in HCMV-infected human kidney transplant recipients. PMID- 29991022 TI - CSN6 and Rab34 Are Involved in Androgen Receptor Trafficking in Mouse Testicular Sertoli Cells. AB - BACKGROUND/AIMS: Androgen and its receptor (AR) play an important role in maintaining spermatogenesis and male fertility. Our previous studies showed that testosterone at a physiological concentration induces cytoplasmic AR translocation to the Sertoli cell plasma membrane of within 5 minutes. METHODS: In this study, mass spectrometry (MS) and bioinformatic analyses were applied to identify candidate proteins mediating AR trafficking. The candidate proteins were knocked down by shRNA transfection. RESULTS: Nine candidate proteins were identified by MS. The data was verified by co-immunoprecipitation and Western blot. Of the candidates, CSN6 regulated AR transport through the phosphorylation signaling pathway and Rab34 affected AR trafficking by regulating Ras activity. CONCLUSIONS: CSN6 and Rab34 are involved in AR trafficking by regulating the phosphorylation signaling pathway. These findings provide new insights into the testosterone signaling pathway in Sertoli cells that mediates spermatogenesis. PMID- 29991023 TI - Identification of Circular RNAs Altered in Mouse Jejuna After Radiation. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) make up a large class of non-coding RNAs and play important roles in a variety of diseases, including nervous system diseases and cancers. The intestinal epithelium is sensitive to ionizing radiation, radiotherapy of abdominal or pelvic tumors or nuclear accident exposure can lead to high radiation toxicity, which can result in radiation induced intestinal injury. The goal of this present study was to analyze the potential roles of circRNAs in radiation-induced intestinal injury. METHODS: Mice were divided into two groups: control group and irradiated group. Irradiated group was 3.5 days after 14Gy abdominal irradiation (ABI) group. We started with RNA-seq of circRNA changes in mouse jejuna after radiation and validated by RT PCR in the following experimental. miRNAs targeted mRNAs were predicted using proprietary software based on target scan and Miranda. The network of circRNA miRNA-mRNA was illustrated by cytoscape software. RESULTS: 2751 circRNAs were detected in the two groups. At day 3.5 post-radiation, 42 and 48 circRNAs were found to be significantly upregulated and downregulated, respectively, compared to the control (p<=0.05, Fold Change >=2). Further, the altered expression of 10 circRNAs (chr18: 35610871-35613502+, chr15: 95864225-95894541+, chr3: 96041338 96042928-, chr5: 64096979-64108263+, chr19: 16705875-16710941-, chr5: 134491893 134500149-, chr19: 42562552-42564341+, chr5: 32640331-32664400+, chr3: 72958113 72960367- and chr8: 79343654-79372364-) were verified by RT-PCR. Compared the miRNA-targeted mRNAs with our mRNAs sequencing data, we found 14 upregulated circRNA-targeted mRNAs were also unregulated and 22 downregulated circRNAs targeted mRNAs were also downregulated. Gene ontology and KEGG pathway analyses indicated the predicted genes were mainly involved in the MAPK signaling pathway. CONCLUSIONS: This study reveals that expression of circRNAs was altered in the jejuna of mice post-irradiation and provides a resource for the study of circRNAs in radiation-induced intestinal injury and repair. PMID- 29991024 TI - Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours. AB - BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib. PMID- 29991025 TI - Lentivirus-Mediated Silencing of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase 2 Inhibits Release of Inflammatory Cytokines and Apoptosis in Renal Tubular Epithelial Cells Via Inhibition of the TLR4/NF-kB Pathway in Renal Ischemia-Reperfusion Injury. AB - BACKGROUND/AIMS: Renal reperfusion injury occurs after the blood flow to the ischemic kidney is re-established under various clinical conditions, such as organ transplantation, renal artery stenosis, embolic disease, and the repair of descending aortic. The current study aims to explore the effects of src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP-2) on the release of inflammatory cytokines and the apoptosis of renal tubular epithelial cells by regulating the TLR4/NF-kappaB signaling pathway in rats with renal ischemia reperfusion (I/R) injury. METHODS: A total of 60 normal clean Sprague Dawley (SD) (WT) rats were used in this study. The levels of creatinine (Cr) and blood urea nitrogen (BUN) were determined using an automatic biochemical analyzer. The apoptosis in renal tissue was detected by TUNEL assay. The renal tubular epithelial cells of rats were cultured, infected and treated with different lentivirus vectors. The serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), IL-1beta and SHP27 were measured. Reverse transcription quantitative polymerases chain reaction and Western blot analysis were performed to measure the expression of relevant genes and proteins. Furthermore, the effect of SHP-2 on the proliferation, cell cycle and apoptosis of renal tubular epithelial cells was also investigated. RESULTS: In the serum of rats with renal I/R injury and prolonged reperfusion time, the contents of Cr and BUN were increased, the positive expression of SHP-2 was higher, the level of apoptosis was promoted, IL-6, TNF-alpha, IL-1beta and SHP27 expression in the serum was increased, the expression of SHP2, TLR4, NF-kappaB, IL-6, TNF-alpha and Bax was up-regulated, and the expression of Bcl-2 was down-regulated. Lentivirus-mediated silencing of SHP-2 promoted the proliferation of renal tubular epithelial cells, inhibited their apoptosis, and reduced the expression of inflammatory factors in these cells by functionally suppressing the TLR4/NF-kappaB signaling pathway. CONCLUSION: The results indicated that lentivirus-mediated silencing of SHP-2 inhibited the release of inflammatory cytokines and the apoptosis of renal tubular epithelial cells, and promoted the proliferation of these cells by inhibiting the TLR4/NF-kappaB signaling pathway in rats with renal I/R injury. PMID- 29991027 TI - Implications of Growth as a Time-Specific Event. AB - Nutritional influences on human growth are commonly assessed as weight or length/height outcomes, and adequacy is determined by reference to population based growth charts. These approaches estimate gross effects only and are insensitive proxies for the dynamic processes by which nutritional components affect tissue accrual. Weight provides information about calorie balance and/or hydration status, while offering little insight into functional physiology. Height is often attributed meaning in accordance with growth charts, a static group level statistical summary unrelated to individual skeletal dynamics. Evidence accumulates that the lifelong health consequences of early growth necessitate a better understanding of individual-level body composition and its developmental determinants. Empirical evidence documents that children's skeletal and head circumference growth occurs in time-specific saltations separated by intervals of no growth. These saltation events are accompanied by discrete increases and decreases in subcutaneous fat implying pulsatile metabolic changes that may or may not be reflected in weight. The mechanisms determining the timing of these saltatory growth events to emerge from stasis, as well as the required energy and chemical building blocks to fuel and support them, remain to be clarified. Their occurrence suggests that the present understanding of nutritional needs for growth is incomplete. PMID- 29991026 TI - Renal Mesangial Cells Isolated from Sphingosine Kinase 2 Transgenic Mice Show Reduced Proliferation and are More Sensitive to Stress-Induced Apoptosis. AB - BACKGROUND/AIMS: Sphingosine 1-phosphate (S1P) is considered as a key molecule regulating various cell functions including cell growth and death. It is produced by two sphingosine kinases (SK) denoted as SK-1 and SK-2. Whereas SK-1 has been extensively studied and has been appointed a role in promoting cell growth, the function of SK-2 is controversial, and both pro-proliferative and pro-apoptotic functions have been suggested. In this study we investigated whether renal mesangial cells isolated from transgenic mice overexpressing the human Sphk2 gene (hSK2-tg) showed an altered cell response towards growth-inducing and apoptotic stimuli. METHODS: hSK2-tg mice were generated by using a Quick KnockinR strategy. Renal mesangial cells were isolated by a differential sieving method and further cultivated in vitro. Lipids were quantified by mass spectrometry. Protein expression was determined by Western blot analysis, cell proliferation was determined by 3H-thymidine incorporation, and apoptosis was determined by a DNA fragmentation ELISA. RESULTS: We show here that kidneys and mesangial cells from hSK2-tg mice express the hSK2 as well as the endogenous mouse mSK2. hSK2 and mSK2 predominantly resided in the cytosol of quiescent transgenic cells. However, S1P accumulated strongly in the nucleus and only minimally in the cytosol of transgenic cells. Functionally, hSK2-tg cells proliferated less than control cells under normal growth conditions and were also more sensitive towards stress induced apoptosis. On the molecular level, this was reflected by reduced ERK and Akt/PKB activation, and upon staurosporine treatment, by a sensitized mitochondrial pathway as manifested by reduced anti-apoptotic Bcl-XL expression and increased cleavage of caspase-9, downstream caspase-3 and PARP-1. CONCLUSION: Altogether, these data demonstrate that SK-2 exerts an antiproliferative and apoptosis-sensitizing effect in renal mesangial cells which suggests that selective inhibitors of SK-2 may promote proliferation and reduce apoptosis and this may have impact on the outcome of proliferation-associated diseases such as mesangioproliferative glomerulonephritis. PMID- 29991028 TI - Elongation of the Long Bones in Humans by the Growth Plates. AB - The disk of hyaline cartilage that is interposed between the epiphysis and the metaphysis of each of the long bones is responsible for its elongation, and, thus, when the lower limbs are concerned, for increases in bodily height. This so called growth plate is avascular, aneural, and alymphatic. It consists solely of chondrocytes and an extracellular matrix which the cells elaborate. The growth plate is architectonically striking in so far as the chondrocytes are aligned in strictly vertical columns, which represent the functional units of longitudinal bone growth. The growth process begins with the slow division of chondrocytes in the resting ("stem cell") zone and proceeds with their rapid proliferation in the adjacent zone. These cells then undergo a process of progressive enlargement, which culminates in the zone of terminal hypertrophy. The life history of any given cell is recapitulated in a vertical column. The neoformation of cartilage in the axial direction is synchronized with its destruction at the vascular invasion front of the metaphysis and results in an elongation of the bony trabeculae. The mechanism that governs the highly coordinated sequence of events that underlies the growth of the long bones is complex; it is subject to influence by genetic, hormonal, nutritional, environmental, and pathological factors. PMID- 29991029 TI - Critical Windows for the Programming Effects of Early-Life Nutrition on Skeletal Muscle Mass. AB - Skeletal myogenesis begins in the embryo with proliferation and differentiation of muscle progenitor cells that ultimately fuse to form multinucleated myofibers. After midgestation, muscle growth occurs through hypertrophy of these myofibers. The most rapid growth phase occurs in the perinatal period, resulting in the expansion of muscle mass from 25% of lean mass at birth to 40-45% at maturity. These 2 phases of muscle growth are regulated by distinct molecular mechanisms engaged by extracellular cues and intracellular signaling pathways and regulatory networks they activate. Nutrients influence muscle growth by both providing the necessary substrates and eliciting extracellular cues which regulate the signal transduction pathways that control the anabolic processes of the fibers. The uniquely large capacity of immature myofibers for hypertrophy is enabled by a heightened capacity and sensitivity of protein synthesis to feeding-induced changes in plasma insulin and amino acids, and the ability to expand their myonuclear population through proliferation of muscle precursor cells (satellite cells). With maturation, satellite cells become quiescent, limiting myonuclear accretion, and the capacity of the muscles for protein anabolism progressively diminishes. Therefore, the early developmental phases represent critical windows for muscle growth which, if disrupted, result in muscle mass deficits that are unlikely to be entirely recoverable. PMID- 29991030 TI - Fat Tissue Growth and Development in Humans. AB - Lipid storage and release from fat cells in adipose tissue are key factors in the regulation of the energy balance. During infancy and adolescence, adipose tissue is growing by a combination of increase in fat cell size (to a lesser extent) and (above all) the number of these cells. In adults, fat cell number is constant over time in spite of a large turnover (about 10% of the fat cells per year) when body weight is stable. A decrease in body weight only changes fat cell size (becoming smaller), whereas an increase in body weight causes elevation of both fat cell size and number in adults. An important source of renewal of fat cells during the entire life span is the bone marrow. This is most apparent in obesity when ~20% of all fat cells are derived from the bone marrow. Fat cell turnover is also important for the size of fat cells. Low turnover may cause large fat cells which, in turn, is linked to cardiovascular disease and type 2 diabetes. There is also a rapid turnover of fat cell lipids, which constitute a single active pool and are renewed about 6 times during the life span of individual fat cells. Overweight and obesity are associated with decreased lipid turnover due to high input in combination with low output of lipids from the fat cells. Low fat cell lipid turnover is associated with insulin resistance and dyslipidemia. Thus, changes in the turnover of fat cells and their lipid content are important for the development of adipose tissue mass and its cellularity (fat cell size and number) and, in turn, for metabolic disturbances. PMID- 29991031 TI - Osteoblast Bioenergetics and Global Energy Homeostasis. AB - The emergence of the endochondral skeleton in terrestrial animals enabled ambulation against increased gravitational forces and provided a storage site for scarce minerals essential for life. This skeletal upgrade increased overall fuel requirements and altered global energy balance, prompting the evolution of endocrine networks to coordinate energy expenditure. Bone-forming osteoblasts require a large and constant supply of energy substrates to fuel bone matrix production and mineralization. When fuel demands are unmet, bone quality and strength are compromised. Recent studies suggest that key developmental signaling pathways are coupled to bioenergetic programs, accommodating changes in energy requirements at different stages of the osteoblast life cycle. Studies in genetically altered mice have confirmed a link between bone cells and global metabolism and have led to the identification of hormonal interactions between the skeleton and other tissues. These observations have prompted new questions regarding the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis. Answers to such questions should advance our understanding of metabolic diseases and may ultimately improve treatments for patients with diabetes and osteoporosis. PMID- 29991032 TI - Summary on a Systems Perspective on Growth. PMID- 29991033 TI - Breastfeeding, Breast Milk Composition, and Growth Outcomes. AB - Breastfed infants have a growth pattern that is different from formula-fed infants, which is regarded as the optimal growth pattern. Breastfed infants increase more in weight, length, and BMI during the first 2-3 months of life and then have a slower growth velocity up to 12 months. They also have a higher accumulation of fat during early infancy. Breastfed infants have lower levels of circulating IGF-I and insulin, which could be part of the explanation of their growth pattern. Many studies and meta-analyses have examined the association between breastfeeding and later obesity. Most find a moderate reduction in the risk of later obesity, but it has been argued that this could be biased due to residual confounding and reverse causation. From studies in low- and middle income countries randomizing women to breastfeeding promotion, there was only little effect on early growth. Recent studies have found associations between breast milk composition (total fat, protein, human milk oligosaccharides, adiponectin, leptin, and insulin) and growth. However, the studies are few, and the results are inconsistent. More studies, including studies of maternal factors influencing breast milk composition, are needed to better understand how breastfeeding influences current and later growth and thereby short- and long term health. PMID- 29991034 TI - Metabolic Regulation of Pre- and Postnatal Growth. AB - Growth characteristics during periods of early developmental plasticity are linked with later health outcomes and with disease risks. Infant growth is modulated by genetic and exogenous factors including nutrition. We try to explore their underlying mechanisms using targeted metabolomic profiling of small molecules in biological samples using high-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) to quantify hundreds of molecules in small biosamples, e.g., 50 uL plasma. In the large German LISA birth cohort study, cord blood lysophosphatidylcholines and fatty acids were closely associated with infant birth weight, with a nonsignificant trend towards an association with infant weight gain and later BMI. Studies in infants randomized to different protein intakes in the European CHOP Study show conventional high protein intakes to markedly increase plasma-indispensable amino acids (AA), particularly branched-chain AA (BCAA), while exceeding the infant's capacity of BCAA breakdown, and an increase in the dispensable AA tyrosine previously associated with insulin resistance. In a path model analysis of the relationship of infant plasma AA, growth factors, and infant growth, AA were generally found to induce a stronger response of insulin than IGF-I although effects of individual AA were very different. We conclude that targeted improvement in nutrient supply in pregnancy and infancy may offer large opportunities for promoting desirable child growth patterns and long-term health. PMID- 29991035 TI - Complementary Feeding, Infant Growth, and Obesity Risk: Timing, Composition, and Mode of Feeding. AB - The complementary feeding period is a short transitional period from breastfeeding and formula feeding to family foods. Timing, quantity, and quality are implied to impact growth and obesity risk. We summarized the literature and analyzed data of monthly 3-day food diaries of >1,000 children from 5 European countries in the first 2 years of life, which were collected as part of the prospective European Childhood Obesity Project (CHOP Study). Formula-fed children started complementary food approximately 2 weeks earlier than breastfed children, and almost 40% of them at or before 4 months of age. While introduction of solids between 4 and 6 months or after 6 months does not seem to impact growth and later obesity risk, solids before 4 months of age increased the risk. There are indications that this is especially problematic for formula-fed children. During the complementary feeding period, fat intake decreases, and protein and carbohydrate intakes increase. Protein intake often exceeds European recommendations from 9 months onwards. However, the role of macronutrients during complementary feeding in growth and metabolism needs further clarification. Findings on the role of responsive feeding or baby-led feeding during complementary feeding in growth are not conclusive. In summary, while introduction of complementary foods before 4 months of age should be avoided, the impact of the quality of complementary food on short-term growth and later obesity risk has to be elucidated further. PMID- 29991036 TI - Causes of Stunting and Preventive Dietary Interventions in Pregnancy and Early Childhood. AB - Stunting of linear growth, a highly prevalent problem in children of low- and middle-income countries, is the result of the exposure of the fetus and/or young child to nutritional deficiencies and infectious diseases. Maternal undernutrition results in fetal growth restriction, and infectious diseases in pregnancy can result in preterm delivery. Both of these conditions are important contributors to stunting in early childhood, albeit their relative contribution varies by world region. After birth, growth faltering may begin at 3-5 months of life and becomes more prominent from 6 to 18 months. During this time, the young child is exposed to many infectious diseases, such as diarrhea, that have an adverse effect on growth. There is also increasing evidence that frequent ingestion of microorganisms results in damage to the small intestine. The resulting condition, referred to as environmental enteric dysfunction, even without clinical symptoms, may cause growth faltering. The complementary foods that the child receives in addition to breast milk are often inadequate in nutrients and energy, negatively affecting growth. Harmful exposure during pregnancy and the first 2 years of life, a critical period for growth and development, has led to a programmatic focus on this "1,000 days" in the life cycle. Dietary interventions, including nutrition education and for undernourished women provision of food supplements during pregnancy, result in improvements in fetal growth that position the newborn for healthier growth. Interventions in the first 2 years of life include promotion of exclusive breastfeeding for the first 6 months of life and continued breastfeeding for at least the first 2 years, nutritional counseling to assure adequate complementary feeding, and, if necessary in food insecure areas, the provision of supplemental food to be given to the child. Evidence shows that each of the interventions has a beneficial effect on the growth of the young child, yet that the effect is modest in relation to the degree of stunting observed in these underprivileged populations. Nevertheless, in recent years, reductions in the prevalence of stunting in some low-income countries show that substantial improvements are possible as a result of socioeconomic changes along with specific infection control and dietary interventions. PMID- 29991037 TI - Summary on Dietary Modulation of Growth and Body Composition. PMID- 29991038 TI - A Nutritionist's Perspective on Behavioral Assessment. AB - The perspective shared here is that of a nutritionist who has been collaborating with a behavioral scientist for 20 years. Examples will be related to long-chain polyunsaturated fatty acids, the subject of our collaboration. While it is well accepted that nutrition is key to optimal human health and development, nutrition intervention trials in populations and randomized controlled trials of specific nutrients that have measured these outcomes have occurred relatively recently. Studies of nutrition and behavior are even less common - the first appears to have been a protein intervention that began in 1969 in Guatemala that involved developmental follow-up to adulthood. When results of multiple trials are available, findings of individual trials frequently range from no effect to benefit, making it difficult to make decisions about policy and practice. A meta analysis that combines the results of all randomized trials of a nutrient is considered the highest level of evidence for drug trials. For studies of nutrient supplementation, however, meta-analyses can err on the side of no effect and lead to assumptions that a nutrient is adequate in populations with deficient or marginal status. In studies that assess behavior, collaboration with a behavioral scientist is necessary to determine the behavioral outcome(s) to assess, ensure the proper administration of the outcome, and analyze and interpret the results. The goal of the paper is to offer insight into issues common to all nutrition research, but especially issues unique to studies that assess behavior. As noted, industry, governments, health organizations, journals, as well as scientists have roles to play. PMID- 29991039 TI - Assessing Neurocognitive Development in Studies of Nutrition. AB - As research on clinical nutrition has become more concerned with the effects of macro- and micronutrients on cognitive and brain development, success in evaluating and interpreting those effects is critically dependent on how human cognitive development is conceptualized and measured. The body of research on neurocognitive development from the past 50 years indicates that various cognitive components are relatively independent of one another and develop at different times during infancy and early childhood. For many studies in this area, however, the choice of measures of cognitive development for inclusion in clinical trials has not been guided by a particular theory of cognition or on the hypothesized effect of the nutrient. This practice is potentially disadvantageous for the interpretation of studies in the field; studies may choose neurocognitive assessments which may either obscure the specific effects of a particular nutrient or miss such specific effects altogether because the appropriate domain was not assessed. In developmental studies, this complex scenario is further compounded by the consideration of age-appropriate assessments and domains. This chapter will describe the difficulties in choosing and interpreting cognitive assessments for this field and make recommendations for best practices in addressing this issue. PMID- 29991040 TI - Neuroimaging of the Developing Brain and Impact of Nutrition. AB - The first 1,000 days of life are increasingly viewed as laying the essential foundations for lifelong physical and mental health. Extending this age range to include childhood, that is up to 10 years of age, these early-life periods encompass the peak period of brain growth, coincide with the emergence of nearly all fundamental cognitive and behavioral skills and abilities, and overlap with the earliest onset and symptoms of a wide breadth of developmental, intellectual, and psychiatric disorders. It is increasingly recognized that altered brain development throughout this sensitive period can negatively affect cognitive and behavioral outcomes. The development of safe and noninvasive neuroimaging techniques, such as magnetic resonance imaging, has provided important new insights into patterns of early structural and functional neurodevelopment, the relationships between brain growth and emerging brain function, and the influence of environmental, genetic, and nutritional factors on shaping these brain function relationships. In particular, nutrition is a critical and readily modifiable influence that can profoundly impact early brain maturation. Here, we overview the current understanding of early-life nutrition and its effects on the developing brain as detailed through neuroimaging. PMID- 29991041 TI - Effects of Nutrition on the Development of Higher-Order Cognition. AB - The long-chain polyunsaturated fatty acids (LC-PUFAs) docosahexaenoic acid (DHA) and arachidonic acid (ARA) occur in high levels in the brain and play a key role in brain growth and the operation of neurotransmitters. Infants supplemented with DHA show improved language and communication skills, and there is accumulating evidence that the early development of executive functions such as planning, working memory, and attention control are influenced by LC-PUFAs, especially DHA. Several studies have found significantly improved means-end problem solving at 9 and 10 months in infants given DHA-/ARA-supplemented formula, and similar results were shown for infants whose mothers were supplemented with DHA during pregnancy and breastfeeding. Long-term benefits of LC-PUFA supplementation in infancy have been reported in children aged 3-6 years. Follow-up studies of infants given DHA /ARA-supplemented versus control formula have shown better performance on tests of impulsivity and attention control in the supplemented children, with indications of a dose-response relationship for DHA. LC-PUFAs (especially DHA) in postnatal infant diet influence the development of executive functions and other higher-order cognitive abilities, and have a long-term influence on the development of attention and information processing in later childhood. PMID- 29991043 TI - Summary on Nutrition, Brain Function, and Cognitive Development. PMID- 29991042 TI - Impact of Nutrition on Growth, Brain, and Cognition. AB - Brain development begins shortly after conception and continues throughout early childhood and into adolescence and early adulthood. During the first 1,000 days (conception to age 2), brain development is rapid, with nutrition playing an important role in the expression of the genetic code. Recent animal and human findings have illustrated that the timing, chronicity, and severity of nutritional deficiencies has differential effects on brain development and on subsequent cognitive and emotional processes. Evidence from intervention trials and longitudinal studies has shown the interactive nature of environmental influences on brain functioning and cognition over time, opening new opportunities for interventions to prevent or overcome potential adversities, including nutritional deficiencies. Strategies to enhance early brain development and promote children's cognitive functioning are based on integrated multisectoral interventions that prevent or alleviate nutritional deficiencies, while promoting developmental opportunities and responsive caregiving. Investing in early intervention based on evidence from brain development and ensuring nutritional adequacy throughout the first 1,000 days are effective means to ensure that children have the necessary health, cognition, creativity, and commitment to achieve the Sustainable Development Goals. PMID- 29991044 TI - Acute Respiratory Distress Syndrome Induced by White Smoke Inhalation: a Potential Animal Model For Evaluating Pathological Changes and Underlying Mechanisms. AB - BACKGROUND/AIMS: White smoke inhalation (WSI) is an uncommon but potentially deadly cause of acute respiratory distress syndrome (ARDS). However, no clinical treatment protocol has been established for the treatment of WSI-induced ARDS. Therefore, it is necessary to investigate the effects of WSI in ARDS and the mechanisms underlying the effects of WSI to determine a novel therapeutic target. METHODS: On the basis of the duration of continued inhalation of white smoke (3 min, 5 min, and 7 min), rats were divided into three groups (WSI-3 min, WSI-5 min, and WSI-7 min). The survival rate, pathological change, and computed tomography (CT) score were evaluated to determine the modeling conditions. In the established WSI-5 min models, evaluations were performed to evaluate the following: arterial blood gas levels, lung wet/dry weight ratio, the expression of inflammatory cytokines, and the effect of NF-kappaB signaling pathway. RESULTS: The survival rate of rats at 72 h post-WSI in the WSI-3 min, WSI-5 min, and WSI-7 min groups was 83.33%, 75%, and 25%, respectively. Results from evaluation of H&E staining, CT scan, arterial blood gas levels, and lung wet/dry weight ratio suggest that the pathological changes in the rat in the WSI-5 min and WSI-7 min groups are very similar to those in patients with ARDS induced by WSI. Additionally, the expression of INF-gamma, TGF-beta1, TNF-alpha, and IL 1beta were increased, and the NF-kappaB signaling pathway was activated in the WSI-5 min group. CONCLUSION: The rat model of WSI-5 min can be used as a WSI induced ALI model for further experiments. The NF-kappaB signaling pathway may be a potential therapeutic target for the treatment of WSI- induced ARDS. PMID- 29991045 TI - Expanding Phenotype of Nephronophthisis-Related Ciliopathy: an Elderly Patient with Homozygous RPGRIP1L Mutation. AB - Nephronophthisis-related ciliopathies (NPHP-RC) are autosomal recessive disorders characterized by renal corticomedullary cysts with the extrarenal symptoms. Typically, patients with NPHP-RC reach end-stage kidney disease (ESKD) before the age of 30 years. We herein report a Japanese woman with NPHP-RC who had unusually delayed progression to ESKD after 6 decades. She exhibited liver dysfunction at the age of 23 years. She also showed mild renal dysfunction at the age of 43 years. Ultrasonography revealed bilateral multiple renal cysts with loss of corticomedullary differentiation. Her liver and renal functions gradually deteriorated. She was diagnosed with liver fibrosis as a result of biopsy, and initiated the maintenance hemodiafiltration therapy for ESKD at the age of 61 years. Because of a unique combination of multiple renal cysts and liver fibrosis, ciliopathy was suspected and medical exome analysis was performed. A novel homozygous missense mutation was identified in RPGRIP1L (c.1810G>A p.Glu604Lys), a causative gene for NPHP-RC. To the best of our knowledge, this patient is the oldest one who progressed to ESKD in NPHP-RC. Our case illustrates that NPHP-RC should be included in the differential diagnosis of the patient with corticomedullary polycystic kidneys accompanied by the extrarenal organ involvements, even if the patient is elderly. PMID- 29991046 TI - Repeat Thoracentesis in Hepatic Hydrothorax and Non-Hepatic Hydrothorax Effusions: A Case-Control Study. AB - BACKGROUND: Repeat thoracentesis for symptom control is offered to patients with refractory hepatic hydrothorax (HH) but the risk profile for this management strategy remains unclear. OBJECTIVES: This study aimed to compare complication frequency and nature during repeat thoracentesis in patients with and without HH. METHODS: Complication rates in patients undergoing repeat thoracentesis for symptom relief was compared between patients with HH and a control group (non-HH group) at a single center from 2010 to 2015. Records were reviewed for demographics, laboratory values, number of thoracentesis, and associated complications with each procedure. RESULTS: 82 patients with HH (274 thoracenteses) and 100 control patients (188 thoracenteses) were included. A complication was noted in 17/462 (0.03%) procedures in the entire cohort. There was a higher overall complication rate with repeat thoracentesis in the HH group (8 vs. 0%, p = 0.016, 95% CI = 1.5-14.6). In the HH group, the cumulative risk of complications increased with sequential thoracenteses; a complication occurring in the preceding intervention was the strongest predictor for subsequent complication (OR = 17.1, p = 0.0013) and more than 1 previous complication was associated with a 15-fold increased risk of a subsequent complication (p < 0.001). In multivariate analysis within the HH group, the Model for End-Stage Liver Disease (MELD) score was an independent predictor of hemothorax (OR = 1.19, 95% CI = 1.03-1.36, p = 0.012). CONCLUSIONS: Repeat thoracentesis is an overall low-risk procedure, although a higher complication rate is observed in HH compared with non-HH patients. The presence of a previous complication significantly increases the risk of future complications in the HH population. PMID- 29991047 TI - U-Shaped Relationship Between Functional Outcome and Serum Uric Acid in Ischemic Stroke. AB - BACKGROUND/AIMS: We sought to assess a consecutive number of patients with first ever acute ischemic stroke (AIS), the clinical relevance in regard to functional outcome of the serum uric acid (SUA) measured at admission. METHODS: In 2 prospective centers for observational study, serum concentrations of SUA were measured on admission in the serum of 710 consecutive patients with AIS. SUA concentrations were determined by high-performance liquid chromatography. SUA, NIH stroke scale (NIHSS), and conventional risk factors were evaluated to determine their value to predict functional outcome within 3 months. RESULTS: During the follow-up, an unfavorable functional outcome (defined as a mRS score > 2) was found in 219 (30.8%) patients. The unfavorable functional outcome distribution across the SUA quartiles ranged between 12.4% (third quartile) and 50.6% (first quartile). After adjusting for all other significant outcome predictors, SUA concentration remained an independent unfavorable outcome predictor with an adjusted OR of 0.996 (95% CI, 0.993-0.998; P< 0.001). CONCLUSIONS: The data show that the U-shaped nature of the exposure-risk relationship was more prominent when the data were assessed in deciles (based on the SUA values). This model predicted the lowest relative risk of unfavorable outcome in the 67th percentile (corresponding to 309 umol/L). SUA was significantly associated with the risk of poor functional outcomes in Chinese patients with stroke. PMID- 29991048 TI - Long Non-Coding RNA RP11-789C1.1 Suppresses Epithelial to Mesenchymal Transition in Gastric Cancer Through the RP11-789C1.1/MiR-5003/E-Cadherin Axis. AB - BACKGROUND/AIMS: Gastric cancer (GC) is a common malignancy with a global incidence that ranks fourth among all tumor types. Epithelial-to-mesenchymal transition (EMT) is a tumor biological process with a role in GC cell metastasis. Long non-coding RNAs (lncRNAs) and microRNAs possess important regulatory functions at the cellular level and in diverse pathophysiological processes. This study was conducted to investigate whether lncRNA RP11-789C1.1 regulates EMT in GC by mediating the miR-5003/E-cadherin pathway. METHODS: RP11-789C1.1 and miR 5003 expression was detected in GC specimens and cell lines by quantitative real time PCR. Western blotting and immunohistochemistry were performed to detect EMT markers in GC. Cell Counting Kit 8 assays were carried out to explore cell proliferation. Wound healing and Transwell assays were conducted to determine the migration and invasion of GC cells. To clarify the correlation between RP11 789C1.1, miR-5003, and E-cadherin, dual-luciferase reporter assays were applied. RESULTS: LncRNA RP11-789C1.1 was significantly down-regulated in GC patients and cell lines, along with the concomitant up-regulation of miR-5003. Silencing RP11 789C1.1 and over-expressing miR-5003 significantly promoted the tumor behavior of GC cells. Dual-luciferase reporter assays confirmed that miR-5003 was the target of both RP11-789C1.1 and E-cadherin. Furthermore, at both the mRNA and protein level, silencing RP11-789C1.1 remarkably reduced the expression of E-cadherin and promoted EMT, which were reversed by knocking down miR-5003. CONCLUSIONS: LncRNA RP11-789C1.1 inhibited EMT in GC through the RP11-789C1.1/miR-5003/E-cadherin axis, which could be a promising therapeutic target for GC. PMID- 29991049 TI - Where Do You Look? Visual Attention to Human Bodies across the Weight Spectrum in Individuals with Normal Weight or with Obesity. AB - OBJECTIVE: We investigated how individuals with normal weight (NW) versus individuals with obesity (OB) visually explore human bodies varying in BMI. METHODS: 16 OB (BMI 37.5 +/- 7.7 kg/m2) and 35 NW (BMI 21.5 +/- 1.6 kg/m2) visually explored 35 natural photographs and 25 avatars depicting male and female bodies ranging from normal weight to obesity. Gaze behaviour was assessed using eye tracking technology. Additionally, participants rated the attractiveness of all body stimuli. RESULTS: A comparison of the displayed gaze behaviour shown by both participant weight classes indicates that regarding visual stimuli of obese natural bodies, all participants (OB + NW) looked at the waist longer, whereas regarding visual stimuli of normal-weight bodies, all participants viewed the head longer. Overall, OB spent less time looking at the bodies than NW. All participants rated normal-weight bodies as more attractive than obese bodies. However, the NW sample rated the depicted obese bodies as even less attractive than the OB sample did. CONCLUSIONS: The BMI of the explored body, but not the observer's BMI, produces differences in the visual exploration of human bodies. The displayed exploration pattern of obese bodies can cautiously be interpreted as a 'de-individualised' and 'obesity-focused' perception. This tendency may prove in close relationship with the negative cultural views on obesity. PMID- 29991050 TI - Contrasting Rates of LINE-1 Amplification among New World Primates of the Atelidae Family. AB - LINE-1 (L1) retrotransposons constitute the dominant category of transposons in mammalian genomes. L1 elements are active in the vast majority of mammals, and only a few cases of L1 extinction have been documented. The only possible case of extinction in primates was suggested for South American spider monkeys. However, these previous studies were based on a single species. We revisited this question with a larger phylogenetic sample, covering all 4 genera of Atelidae and 3 species of spider monkeys. We used an enrichment method to clone recently inserted L1 elements and performed an evolutionary analysis of the sequences. We were able to identify young L1 elements in all taxa, suggesting that L1 is probably still active in all Atelidae examined. However, we also detected considerable variations in the proportion of recent elements indicating that the rate of L1 amplification varies among Atelidae by a 3-fold factor. The extent of L1 amplification in Atelidae remains overall lower than in other New World monkeys. Multiple factors can affect the amplification of L1, such as the demography of the host and the control of transposition. These factors are discussed in the context of host life history. PMID- 29991051 TI - 5'-AMP-Activated Protein Kinase Regulates Goat Sperm Functions via Energy Metabolism In Vitro. AB - BACKGROUND/AIMS: ATP is essential for mammalian sperm to survive and maintain fertilizing capacity. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The aims of the present study were to explore the localization of AMPK in goat sperm and to investigate whether and how AMPK regulates sperm functions in vitro. METHODS: Sperm were treated with AMPK modulators (AICAR, metformin and Compound C) during incubation. Sperm motility was assessed with a computer-assisted spermatozoa analysis system (CASA). Membrane integrity, acrosome reaction and mitochondrial membrane potentials were detected by SYBR 14/PI, FITC-PNA and JC-1 staining, respectively. And the lactate content, ATP content, AMPK activity, activity of pyruvate kinase (PK) and lactate dehydrogenase (LDH) were also measured with the commercial assay kits. Immunofluorescence staining was used to analyze the distribution of PK, LDH, AMPK and phospho-Thr172-AMPK in sperm. The role of AMPK was further studied during induction of capacitation and acrosome reaction. RESULTS: We found that AMPKalpha was localized in the entire acrosomal region, the midpiece and the flagellum, while the phospho-Thr172-AMPK was distributed in the head, the midpiece and flagellum. Activation of AMPK by AICAR and metformin significantly improved sperm motility, membrane integrity and acrosome reaction, largely maintained sperm mitochondrial membrane potentials, lactate content and ATP content, and enhanced the activity of AMPK, PK and LDH, whereas inhibition by Compound C triggered the converse effects. Moreover, PK was localized in the acrosomal area and the midpiece, while LDH was distributed in the tail. Induction of capacitation and acrosome reaction led to AMPK phosphorylation. AMPK phosphorylation regulated the activity of energetic enzymes. CONCLUSION: This study for the first time provides evidence that AMPK governs goat sperm functions through energy metabolism in vitro. This finding will help to improve assisted reproductive techniques in goats and the other species. PMID- 29991052 TI - A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome. AB - BACKGROUND/AIMS: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder classically characterized by distinctive facies, growth retardation, intellectual disability, feeding difficulties, and multiple organ system anomalies. Previously, the diagnosis of CdLS was based mainly on identifying the typical phenotype in patients. However, with the advances in clinical molecular genetic diagnostic techniques, more patients, especially patients with milder phenotypes, are being diagnosed from detecting pathogenic mutation. METHODS: Pathogenic mutation in a female patient with a milder phenotype was detected using whole exome sequencing (WES), and was further characterized using bioinformatic analysis and in vitro functional experiments, including X-chromosome inactivation analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and enzyme activity assay. RESULTS: This patient was found to harbor a novel missense mutation (c.806T>G, p.I269R) in the coding region of the HDAC8 gene, which was predicted to be pathogenic. Compared with other CdLS patients with HDAC8 mutation, the patient lacked typical facies, including synophrys and arched eyebrows. In vitro functional experiments showed the presence of skewed X chromosome inactivation. Furthermore, the novel mutation decreased the dissolubility and enzymatic activity of HDAC8 protein. CONCLUSIONS: The present study identified a novel missense mutation (c.806T>G, p.I269R) in the HDAC8 gene leading to CdLS, which not only provided strong evidence for diagnosis in this present patient, but also expanded the spectrum of pathogenic mutations for CdLS. PMID- 29991053 TI - Effect of Sucroferric Oxyhydroxide on Fibroblast Growth Factor 23 Levels in Hemodialysis Patients. AB - OBJECTIVE: This study investigated the effects of sucroferric oxyhydroxide on fibroblast growth factor (FGF)-23 and dose reduction of erythropoiesis stimulating agents (ESA) and intravenous saccharated ferric oxide in hemodialysis patients. METHODS: In this prospective, open-label, parallel-group, multicenter trial involving patients receiving lanthanum carbonate hydrate, eligible patients were randomized to a sucroferric oxyhydroxide group or a control group. Hemoglobin, serum phosphate, FGF-23, iron, and ferritin levels, as well as transferrin saturation, doses of intravenous saccharated ferric oxide and ESA administered, and the erythropoietin responsiveness index (ERI) were monitored for 24 weeks. RESULTS: Sixty-eight eligible patients were allocated to receive sucroferric oxyhydroxide (n = 34) or serve as controls (n = 34). Data for 31 patients in the sucroferric oxyhydroxide group and 32 in the control group were analyzed. Serum phosphate was equally well controlled in both groups. In the sucroferric oxyhydroxide group, intact FGF-23 levels decreased significantly from baseline at the end of the study (p = 0.01) and there was a significant difference compared with the control group (p = 0.035). Required doses of ESA and ERI were significantly reduced in the sucroferric oxyhydroxide group decreased significantly. The dose of intravenous saccharated ferric oxide required in the sucroferric oxyhydroxide group was significantly lower than that at baseline (p = 0.006) and in the control group (p = 0.003). CONCLUSIONS: Treatment of hyperphosphatemia with sucroferric oxyhydroxide was effective in patients on hemodialysis, resulting in decreased serum FGF-23 levels and a reduction in the required dose of saccharated ferric oxide. PMID- 29991054 TI - The Effect of Mecp2 on Heart Failure. AB - BACKGROUND/AIMS: Heart failure is the end result of various kinds of cardiovascular diseases. It has a high rate of morbidity and mortality. This article aims to determine the effect of MeCP2, a key epigenetic regulator, on heart failure. METHODS: The genes associated with heart failure were selected and analyzed using Gene Ontology (GO) term analysis and protein-protein interaction (PPI) network analysis. Significantly up- or downregulated genes in a heart failure animal model were identified, and the genes that had the same or opposite alteration trends as MeCP2 were also recognized. Eighteen hub genes were picked based on topological parameters, and then aberrantly expressed genes with MeCP2 overexpression or knockout were analyzed by GO term, KEGG pathway and PPI analyses. RESULTS: MeCP2 was downregulated in the heart failure animal model. Through comparison and alignment, 10 dysregulated genes were selected from the 18 hub genes (JAK1, SETD1B, HRC, TTN, LYZ2, TPM3, MYH11, MYH6, ALOX5AP, DECR1). These genes were mainly enriched in cytoskeletal regulation mediated by Rho GTPase and inflammation mediated by chemokine and cytokine signaling pathways. CONCLUSIONS: These dysregulated genes provide a better understanding of the underlying mechanisms of the effect of MeCP2 on heart failure and might be used as targets and prognostic markers of heart failure. PMID- 29991055 TI - SKP2 Promotes Hepatocellular Carcinoma Progression Through Nuclear AMPK-SKP2 CARM1 Signaling Transcriptionally Regulating Nutrient-Deprived Autophagy Induction. AB - BACKGROUND/AIMS: SKP2 overexpression has been associated with poor prognosis in numerous cancers. The mechanisms of autophagy in the tumor pathogenesis have been a research focus recently. How the SKP2 involved in autophagy expresses oncogenic characteristics, especially in HCC, are largely unclear. METHODS: The expression of SKP2 was detected by qPCR, Western blot, Immunohistochemical (IHC) and Immunofluorescence (IF) techniques. SKP2 was knocked down or overexpressed by lentivirus transfection in HCC cells. Functional assays such as CCK8 assays, transwell migration and invasion assays, and colony formation assays were performed to determine the role of SKP2 in HCC. Furthermore, autophagy was induced by glucose deprivation in HCC cells followed by monitoring of the levels and distributions of SKP2, CARM1 and AMPK. RESULTS: Our data showed that SKP2 levels were significantly increased in HCC cell lines and HCC tissues rather than corresponding normal liver tissues, and augmented SKP2 levels were statistically correlated with tumor grade, size and metastases. By up-regulation or down regulation of SKP2 in HCC cells, we confirmed that SKP2 encourages proliferation, migration, invasion, and colony formation. We then found that SKP2 was inhibited, CARM1 increased and AMPKalpha2 became activated in the nucleus under glucose deprivation induced autophagy. Moreover, we discovered that SKP2 was repressing CARM1 in the nucleus under nutrient-sufficient conditions in HCC. CONCLUSIONS: We show that SKP2 promotes HCC progression and its nuclear functions of autophagy induction with CARM1 and AMPK, which may provide a potential target for HCC therapy. PMID- 29991056 TI - Body Mass Index Categories and Attained Height in Portuguese Adults. AB - OBJECTIVE: To analyze the associations between height and BMI categories in a Portuguese representative sample. METHODS: This is a cross-sectional study with a representative sample of 32,644 Portuguese adults (52.4% females). Sociodemographic and lifestyle characteristics were obtained along with self reported height and weight. We performed generalized linear models to assess the differences in attained height across BMI categories; analyses were adjusted for age, gender, education, family income per month, proxy reporting information, dietary patterns, and smoking. RESULTS: BMI categories included underweight and normal weight (46.4%), overweight (37.6%), obese class I and II (15.2%), and obese class III (0.8%). Adults with normal weight had a significantly higher height (females +7 cm and males +5 cm) when compared to obese class III. As BMI categories increased, height decreased. In females and males, after adjusting for confounders, estimates of attained height decreased when compared to the unadjusted model (beta = -0.049, 95% CI = -0.050; -0.049 and beta = -0.030, 95% CI = -0.031; -0.029, respectively), although they remained still significant. CONCLUSION: Our results suggest a significant difference in attained height between BMI categories. Future intervention programs aiming at preventing overweight and obesity should monitor sociodemographic, health and environmental conditions that affect attained height potential. PMID- 29991057 TI - Salivary Circular RNAs Hsa_Circ_0001874 and Hsa_Circ_0001971 as Novel Biomarkers for the Diagnosis of Oral Squamous Cell Carcinoma. AB - BACKGROUND/AIMS: Recent studies have demonstrated that circular RNAs (circRNAs) can serve as potential molecular markers for disease diagnosis. However, little is known about their diagnostic potential for oral squamous cell carcinoma (OSCC). This study aimed to determine the expression of circRNAs in the saliva of OSCC patients to identify novel biomarkers for OSCC screening. METHODS: Microarray screening of circRNA was performed to identify differentially expressed circRNAs in saliva from 3 OSCC patients compared with 3 healthy controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate the results, and the association between these confirmed salivary circRNAs and clinicopathological features was analyzed using the chi squared test. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of the circRNAs identified. Preoperative expression and postoperative expression (1 month after the surgery) of hsa_circ_0001874 and hsa_circ_0001971 was also determined. RESULTS: Our results indicated 12 upregulated and 20 downregulated circRNAs in the saliva from the OSCC patients compared with that from the healthy controls. Among the differentially expressed circRNAs, hsa_circ_0001874, hsa_circ_0001971, and hsa_circ_0008068 were upregulated and hsa_circ_0000140, hsa_circ_0002632, and hsa_circ_0008792 were downregulated in the OSCC group versus the healthy group. Clinical data indicated that salivary hsa_circ_0001874 was correlated with TNM stage (P=0.006) and tumor grade (P=0.023) and that hsa_circ_0001971 was correlated with TNM stage (P=0.019). The combination of hsa_circ_0001874 and hsa_circ_0001971 showed an area under the ROC curve of 0.922 (95% confidence interval, 0.883-0.961; P< 0.001). The risk score based on the combination of hsa_circ_0001874 and hsa_circ_0001971 also discriminated patients with OSCC from patients with oral leukoplakia (P< 0.001). Moreover, the expression levels of salivary hsa_circ_0001874 and hsa_circ_0001971 were clearly decreased in the postoperative samples compared with preoperative samples (P< 0.001). CONCLUSIONS: This is the first study to demonstrate the potential of salivary hsa_circ_0001874 and hsa_circ_0001971 as biomarkers for the diagnosis of OSCC. PMID- 29991058 TI - Interleukin-35 Suppresses the Antitumor Activity of T Cells in Patients with Non Small Cell Lung Cancer. AB - BACKGROUND/AIMS: Interleukin (IL)-35 has immunosuppressive functions in autoimmune diseases, infectious diseases, and certain cancers. However, few studies have focused on its immunoregulatory activity in non-small cell lung cancer (NSCLC). Thus, we investigated the role of IL-35 in the pathogenesis of this disease. METHODS: A total of 66 NSCLC patients and 21 healthy individuals were enrolled. IL-35 expression in peripheral blood and bronchoalveolar lavage fluid (BALF) was measured. The modulatory functions of IL-35 on purified CD4+ and CD8+ T cells from NSCLC patients were investigated in direct and indirect coculture systems with NSCLC cell lines. RESULTS: IL-35 expression was significantly increased in BALF from the tumor site, but not in the peripheral blood of NSCLC patients. IL-35 did not affect the bioactivity including proliferation, cytokine production, cell cycle, and cellular invasion of NSCLC cells. It suppressed responses from type 1 T helper (Th1) and Th17 cells but elevated the regulatory T cell response in cultured CD4+ T cells from NSCLC patients, and reduced cytokine-mediated CD4+ T cells cytotoxicity to NSCLC cells. Moreover, IL-35 also inhibited cytotoxic gene expression in CD8+ T cells from NSCLC, reducing their cytolytic and noncytolytic functions. CONCLUSION: The results of this study suggest that IL-35 contributes to the dysfunction/exhaustion of T cells and limited antitumor immune responses in NSCLC. PMID- 29991059 TI - Placental Growth Factor Mediates Crosstalk Between Lung Cancer Cells and Tumor Associated Macrophages in Controlling Cancer Vascularization and Growth. AB - BACKGROUND/AIMS: Assistance with tumor-associated vascularization is needed for the growth and invasion of non-small cell lung cancer (NSCLC). Recently, it was shown that placental growth factor (PLGF) expressed by NSCLC cells had a critical role in promoting the metastasis of NSCLC cells. However, the underlying molecular mechanisms remain elusive. METHODS: Here, we first established a NSCLC model in mice that allows us not only to isolate tumor cells from non-tumor cells in the tumor, but also to trace tumor cells in living animals. Levels of PLGF, its unique receptor Flt-1, as well as transforming growth factor beta1 (TGFbeta1) was examined in tumor cells and tumor-associated macrophages (TAM) by RT-qPCR. A transwell well co-culture system and HUVEC assay were applied to study the crosstalk between NSCLC cells and TAM. RESULTS: NSCLC cells produced and secreted PLGF to signal to tumor-associated macrophages (TAM) through surface expression of Flt-1 on macrophages. In a transwell co-culture system, PLGF secreted by NSCLC cells triggered macrophage polarization to a TAM subtype that promote growth of NSCLC cells. Moreover, polarized TAM seemed to secrete TGFbeta1 to enhance the growth of endothelial cells in a HUVEC assay. CONCLUSION: The cross-talk between TAM and NSCLC cells via PLGF/Flt-1 and TGFbeta receptor signaling may promote the growth and vascularization of NSCLC. PMID- 29991060 TI - Endobronchial Coils for Endoscopic Lung Volume Reduction: Best Practice Recommendations from an Expert Panel. AB - Endobronchial coils are an additional treatment option for lung volume reduction in patients with severe emphysema. Patient selection should be focused on patients with severe emphysema on optimal medical therapy and with evidence of severe hyperinflation. The technique is suitable in a broad range of patients with emphysema; however, patients with paraseptal emphysema, large focal (giant) bullae, significant co-morbidity and airway-predominant disease should be avoided. Treatment involves placing between 10 and 14 coils by bronchoscopy in the selected treatment lobe, with 2 lobes being treated sequentially. Lobe selection for treatment should be based on quantitative computed tomography, and the lobes with the greatest destruction should be targeted (excluding the right middle lobe). The treatment results in an improvement in pulmonary function, exercise performance and quality of life, particularly in patients with severe hyperinflation (residual volume > 200% predicted) and upper-lobe heterogeneous emphysema, but will also be of benefit in lower-lobe predominant and homogeneous emphysema. Finally, it has an acceptable safety profile, although special attention has to be paid to coil-associated opacity which is an inflammatory response that occurs in some patients treated with endobronchial coils. PMID- 29991070 TI - Outcome of Neonates with Vein of Galen Malformation Presenting with Severe Heart Failure: A Case Series. AB - BACKGROUND: Neonatal presentation of vein of Galen aneurysmal malformations (VGAMs) complicated by cardiac failure and pulmonary hypertension is frequently associated with a poor prognosis. Interventional neuroradiology with embolization can offer a chance for survival, although neurological damage can represent a limitation. OBJECTIVE: This article determines if aggressive intensive care and drug management of cardiac failure before urgent embolization can influence morbidity and mortality. PATIENTS AND METHODS: Twelve infants (7 boys, 5 girls) were diagnosed with symptomatic vein of Galen malformations in the neonatal period during the period 2000 to 2014. Due to high output cardiac failure, endovascular treatment was attempted as soon as stabilization was achieved. RESULTS: Endovascular procedures successfully reverted cardiac failure in 5 patients who survived without significant neurological damage, while in 7 patients the causes of death were refractory cardiac failure, multiorgan failure, and severe brain damage. Bidimensional echocardiography assessment was performed at presentation and after early embolization procedures. CONCLUSION: Aggressive intensive care approach to heart failure and pulmonary hypertension leading to early neurointervention results in good survival rates with low morbidity even in cases of high-risk neonatal VGAM. Combined hemodynamic treatment can improve outcome in neonates with cardiac failure secondary to VGAM, although there is the risk of precipitating systemic hypoperfusion and renal failure. A moderate prematurity may not prevent both interventional approach and good outcome. PMID- 29991071 TI - Self-expandable metal stent placement for malignant esophageal strictures - changes in clinical outcomes over time. AB - BACKGROUND: Self-expandable metal stents (SEMSs) are effective for improving dysphagia in patients with incurable esophageal cancer but are also associated with recurrent dysphagia and adverse events. In the past decades, new SEMSs have been introduced, but also patients' risk profiles have altered. It is unknown if these changes have affected SEMS outcomes. METHODS: This retrospective cohort study was conducted in a tertiary referral center in the Netherlands. Patients who underwent palliative esophageal SEMS placement for malignant dysphagia between 1994 and 2017 were included. The primary outcome was to assess shifts over time with respect to recurrent dysphagia and adverse events after SEMS placement. RESULTS: 997 patients who underwent SEMS placement were included. Recurrent dysphagia occurred in 309 patients (31 %) and remained stable, although with a trend towards an increase over time (hazard ratio [HR] 1.02 per 1-year increase; P = 0.05). Migration rate significantly increased over time (HR 1.04 per 1-year increase; P = 0.01). SEMS-related complications occurred in 461 patients (46.2 %), with 207 (20.7 %) major and 336 (33.7 %) minor complications. Prior chemoradiotherapy was significantly associated with major complications (HR 1.69; P < 0.001). Pain was the most common adverse event and showed a significant increase over time (P < 0.01). Factors associated with pain were prior chemoradiotherapy, absence of a fistula, axial and radial forces, and squamous cell carcinoma. CONCLUSIONS: Despite the introduction of novel esophageal SEMS designs, recurrent dysphagia has not declined over the years. Stent-related complications have increased in recent years, which seems to be mainly associated with more frequent use of chemoradiotherapy prior to SEMS placement. PMID- 29991074 TI - Value of Preoperative MRI and Examination under Anesthesia for Differentiating Complete from Partial Anterior Cruciate Ligament Tears. AB - Partial tears of the anterior cruciate ligament (ACL) recently regained attention due to a better understanding of the two distinct bundles of the ligament and the possibility of single-bundle reconstruction procedures. An accurate diagnosis is important as it influences treatment options and patient prognosis. The aim of this study was to evaluate the value of examination under anesthesia (EUA) and magnetic resonance imaging (MRI) for differentiating partial from complete ACL tears. For this purpose, this prospective case series included 95 consecutive patients undergoing primary ACL reconstruction surgeries. MRI, EUA, and MRI combined with EUA were performed preoperatively, and results were compared with arthroscopy. Our data showed that ACL lesions were diagnosed as partial tears in 42.1% (n = 40) of EUA, 23.2% (n = 22) of MRI, and 11.6% (n = 11) of arthroscopies. EUA and MRI demonstrated sensitivity of 100 and 90.1%, and specificity of 65.5 and 85.6%, respectively. Combined EUA and MRI demonstrated sensitivity of 100% and specificity of 83.1%. Our study revealed that preoperatively MRI and EUA may help surgeons early identify partial ACL tears and influence treatment decisions. PMID- 29991072 TI - A systematic review of advanced endoscopy-assisted lithotripsy for retained biliary tract stones: laser, electrohydraulic or extracorporeal shock wave. AB - BACKGROUND: When conventional endoscopic treatment of bile duct stones is impossible or fails, advanced endoscopy-assisted lithotripsy can be performed by electrohydraulic lithotripsy (EHL), laser lithotripsy, or extracorporeal shock wave lithotripsy (ESWL). No systematic review has compared efficacy and safety between these techniques. METHODS: A systematic search was performed in PubMed, the Cochrane Library, and EMBASE for studies investigating EHL, laser lithotripsy, and ESWL in patients with retained biliary tract stones. RESULTS: After screening 795 studies, 32 studies with 1969 patients undergoing EHL (n = 277), laser lithotripsy (n = 426) or ESWL (n = 1266) were included. No randomized studies were available. Although each advanced lithotripsy technique appeared to be highly effective, laser lithotripsy had a higher complete ductal clearance rate (95.1 %) than EHL (88.4 %) and ESWL (84.5 %; P < 0.001). In addition, a higher stone fragmentation rate was reported for laser lithotripsy (92.5 %) than for EHL (75.5 %) and ESWL (89.3 %; P < 0.001). The post-procedural complication rate was significantly higher for patients treated with EHL (13.8 %) than for patients treated with ESWL (8.4 %) or laser lithotripsy (9.6 %; P = 0.04). Data on the recurrence rate of the biliary tract stones were lacking. CONCLUSION: This systematic review revealed that laser lithotripsy appeared to be the most successful advanced endoscopy-assisted lithotripsy technique for retained biliary tract stones, although randomized studies are lacking. PMID- 29991075 TI - Preoperative Opioid Use in Knee Surgery Patients. AB - A cross-sectional analysis of data derived from patients undergoing knee surgery at a single institution was conducted. The objectives of the study were to determine the demographic, diagnostic, and psychologic factors associated with opioid use; and to determine the clinical correlates of opioid use. We hypothesized that preoperative opioid use would be associated with worse patient reported outcome (PRO) measures. The sample consisted of 383 patients undergoing knee surgery. The patients were classified as either opioid or nonopioid users on the basis of medical record review. All participants completed a battery of clinical assessments, including the Patient-Reported Outcomes Measurement Information System computer adaptive testing in six domains: Physical Function, Pain Interference, Fatigue, Social Satisfaction, Anxiety, and Depression. Analyses were conducted to examine clinical variables as a function of opioid use. The results indicated that opioid use was associated with female gender, unemployment, smoking, higher American Society of Anesthesiologists scores, greater number of previous surgeries, depression or anxiety, and worse expectation of surgery (p < 0.05). Multivariable analysis found opioid use to be a significant independent predictor of multiple PRO measures in patients undergoing knee surgery. Potential explanations for these findings are presented, and clinical implications are discussed. PMID- 29991076 TI - The Role of Surgical Closure Position in Total Knee Arthroplasty: Flexion versus Extension-A Randomized Prospective Study. AB - We aimed to investigate the effect of the knee position during the surgical closure on isokinetic muscle strength, clinical score, and range of motion in total knee arthroplasty. Seventy-five eligible patients were enrolled in the study and randomly divided into two groups; wound closure was performed with the knee flexed at 90 degrees in group 1 and knee extended in group 2. All the surgeries were performed by the same surgeon and by the same prosthesis type. All the patients received the same rehabilitation program postoperatively. The primary outcomes were the knee flexion degrees and the American Knee Society Score values at preoperative and postoperative 6 weeks, 3, and 6 months. The secondary outcome was the isokinetic muscle strength measurements of both knees before the surgery and after 6 months. There were no significant differences in the American Knee Society Scores and knee flexion degrees between the flexion and extension groups. However, a significant decrease was found in the extensor muscle strength in the extension group after 6 months of the surgery. The findings of our study are that the closing of the knee in flexion or extension does not affect the postoperative knee flexion degrees and scores in total knee arthroplasty. However, quadriceps strength recovers early if the knee closure is performed in flexion position. PMID- 29991077 TI - Primary Allograft ACL Reconstruction in Skeletally Immature Patients-A Systematic Review of Surgical Techniques, Outcomes, and Complications. AB - The purpose of this systematic review is to ascertain the risk profile of allografts in primary anterior cruciate ligament reconstruction (ACLR) of skeletally immature patients. Three databases (PubMed, EMBASE, and MEDLINE) were searched for articles addressing primary ACLR in skeletally immature patients (i.e., open femoral and tibial physes). Inclusion criteria encompassed the use of allograft tissue with available postoperative outcomes data. The methodological index for non-randomized studies (MINORS) was used to assess all studies. Descriptive statistics such as means, 95% confidence intervals and standard deviations are presented where applicable. A total of 3,852 studies were screened, with 9 studies of a total of 406 skeletally immature patients (mean age 14.9 +/- 1.2 years) satisfying inclusion criteria. The majority (98%) of included patients underwent complete transphyseal ACLR. Where specified, allograft options included Achilles tendon (AT) (66.5%), tibialis anterior tendon (7.6%), bone patellar tendon (2.5%), and fascia lata (1.0%). The use of a bone block for the AT was reported in one patient (0.2%). Postoperatively, and where specified, patients achieved full range of motion (12.1%), had good Lysholm scores of 94 to 100 (8.1%), and a return to preinjury level athletic participation of 82.9% (8.4%). Complications (13.3%) included graft failures (7.9%), nonrevision reoperation (4.7%), and a combined leg length discrepancy and angular (valgus and extension) deformity (0.2%). There were no reported incidences of disease transmission. Although failure rates of primary allograft ACL reconstruction are acceptable compared with other studies of mainly autograft use in this young, high-risk population, there was a very low rate of clinically significant physeal damage. However, the relatively low quality of the included studies limits the ability to recommend routine use of allograft for ACLR in the skeletally immature patient. More robust studies with long-term follow-up data are necessary to better ascertain the influence of allograft choice on postoperative outcomes for these young patients. This is a Level IV study, systematic review of Levels III and IV studies. PMID- 29991078 TI - The Pellegrini-Stieda Lesion of the Knee: An Anatomical and Radiological Review. AB - The Pellegrini-Stieda lesion is a calcification on the medial side of the knee. The origin of this tissue is controversial. The purpose of our study is to investigate the origin of the Pellegrini-Stieda lesion using conventional radiography as to recreate the circumstances in which Pellegrini and Stieda had to study this pathology. Six nonpaired fresh-frozen cadaveric knees were used. A surgical approach to the medial side of the knee was performed using the layered approach. The origin of the gastrocnemius muscle (GM) (n = 3) or the superficial medial collateral ligament (sMCL) (n = 3) were marked with a radio-opaque fluid. X-ray analysis was performed by measuring the distance from the proximal part of the marking to the medial tibial plateau, multilayer views, and comparison to the original X-rays by Pellegrini-Stieda. Two out of three markings in both the GM and sMCL group were matched with the correct structure. The images were digitally processed so that the osseous structures became partly transparent. After overlaying the images, we found a random distribution of the markings. The Stieda/GM group had no overlap of the markings at all. Compared with the original images from the publications by Pellegrini and Stieda, no comparable position could be found between the original lesions and the markings in our specimens. Conventional X-ray of the knee could not reproduce a distinction between the sMCL and GM as origins for the Pellegrini-Stieda lesion as suggested by Pellegrini and Stieda. PMID- 29991079 TI - Predicting the Outcome of Total Knee Arthroplasty Using the WOMAC Score: A Review of the Literature. AB - It is estimated that up to a third of recipients of total knee arthroplasty (TKA) experience chronic pain postoperatively. However, there are no clear indications within the literature that predict which patients are at higher risk of being dissatisfied with their TKA. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC) is one of the most commonly used, patient-reported outcome measures in patients with lower limb osteoarthritis. This review discusses the available evidence surrounding the predictability of the outcome of TKA using the WOMAC score as well as considering further patient factors that have been implicated in the level of improvement post TKA. It may be concluded from the available literature that a combination of knee scores and patient factors would be the most accurate way of predicting those patients most likely to have a good outcome from their TKA. There is some disparity within the literature about which patient factors and reported outcome measure scores lead to a positive postoperative outcome. Patient expectations following the procedure also need to be evaluated, as objective measures on a scoring system do not necessarily equate with the subjective patient experience. PMID- 29991080 TI - Isolated Tibial Component Failure in Total Knee Arthroplasty: A Case Series Evaluating Inflammatory Response versus Mechanical Failure. AB - Total knee prostheses are routinely redesigned to improve performance, longevity, and to closer mimic the native kinematics of the knee. Despite continued improvements, all knee implants, even those with proven design features, have failures. We identified a cohort of patients with isolated tibial component failures that occurred in a popular and successful knee system. Our purpose was to (1) characterize the observed radiographic failure pattern; (2) investigate the biologic response that may have contributed to the failure; and (3) to determine if the failure mechanism was of a biological or a mechanical nature. Twenty-one knees from 19 patients met the inclusion criteria of isolated tibial component failure in a single knee implant system. Radiographs from the primary and revision knee surgery were analyzed for implant positioning and the failure pattern. Inflammatory biomarkers interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha were available in 16/21 knees and peripheral CD14+/16+ monocytes were measured in 14 of the aforementioned 16 knee revisions. Serum CD3, CD4, and CD19 were measured in 10 of the aforementioned 14 knees. Additionally, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) were measured to rule out infection as a cause of the cytokine upregulation. Radiographic findings demonstrated that all of the 21 tibial components were implanted in either neutral or 2 to 3 degrees varus in the coronal plane, and none of the revisions was implanted in valgus. All tibias showed obvious radiographic loosening and the implant failed into varus. The inflammatory biomarkers IL-1beta, IL-6, and TNF-alpha were negative. WBC, ESR, and CRP were normal. Serum CD3, CD4, and CD19 flow cytometry analyses were found to be in the normal range. Peripheral CD14+/16+ and total CD16+ monocytes measurements were consistent with previous findings of patients with osteoarthritis, rather than particulate-induced inflammatory loosening. The findings support the implant failure observed in our study occurred by a different mechanism than the wear debris-induced aseptic loosening. We believe that a mechanical failure can occur based on our findings. The loosening, collapse, and debonding from the cement may have been related to the implantation technique, stresses due to favorable rotational freedoms of the implant, or patient characteristics/behavior. Continued exploration into implant failure mechanisms and particularly into the biologic response associated with failure is ongoing. PMID- 29991081 TI - Antimicrobial Dialkylresorcins from Marine-Derived Microorganisms: Insights into Their Mode of Action and Putative Ecological Relevance. AB - Zobellia galactanivorans has been reported as a seaweed-associated or marine derived species with largely unknown secondary metabolites. The combination of bioinformatic analysis and MS- and bioactivity guided separation led to the isolation of a new antibiotically active dialkylresorcin from the marine bacterium Z. galactanivorans. The antibiotic profile of the new dialkylresorcin zobelliphol (1: ) was investigated and compared with related and naturally occurring dialkyresorcins (i.e., stemphol (2: ) and 4-butyl-3,5-dihydroxybenzoic acid (3: )) from the marine-derived fungus Stemphylium globuliferum. Bacterial reporter strain assays provided insights into the mode of action of this antibiotic compound class. We identified an interference with bacterial DNA biosynthesis for the dialkylresorcin derivative 1: . In addition, the putative biosynthetic gene cluster corresponding to production of 1: was identified and a biosynthetic hypothesis was deduced. PMID- 29991082 TI - Association of Serum Leptin with All-Cause and Disease Specific Mortality: A Meta Analysis of Prospective Observational Studies. AB - Leptin levels may affect mortality through its link to inflammation and obesity. However, data are inconclusive. This meta-analysis was performed to investigate the association of leptin with mortality. The PubMed, Scopus, Google scholar, and reference lists of the included studies were searched for all published prospective observational studies that described the associations of serum leptin and mortality up to August 2017. Two reviewers independently assessed all potentially relevant studies for inclusion and methodological quality using standardized abstraction forms. Of 518 studies identified, 19 studies considered the association of leptin with all-cause mortality (16 208 subjects) and 12 studies evaluated the association of leptin with disease-specific mortality (13 680 subjects). In the overall analysis, no significant association was found between leptin and all-cause mortality (HR=1.028; 95% CI: 0.908-1.165; p=0.659), with a high between study heterogeneity (p?0.001, I2=61). Subgroup analysis found that high leptin is associated with increased all-cause mortality in healthy people (HR=1.159 (95% CI, 1.032, 1.302), p=0.012), in men (HR=1.162; 95% CI: 1.036-1.302; p=0.010), and in subjects with >=60 years old (HR=1.129; 95% CI: 1.030-1.238; p=0.010); whereas, increased leptin levels was related to the decreased cancer-specific mortality ((HR=0.550; 95% CI: 0.418-0.724), p?0.001). Higher leptin levels in healthy people, old people, and males were associated with increased all-cause mortality, while increased leptin level was related to the reduced risk of death among patients with cancer. PMID- 29991083 TI - Correlation Between Resistin Level and Metabolic Syndrome Component: A Review. AB - Metabolic syndrome (MetS) has a collection of some abnormal and pathological conditions that cause many critical diseases. Resistin is one of the possible candidates for these pathologies but there are not enough data to prove if resistin has positive, neutral, or negative effects on one or some components of MetS. This review summarizes data about comparing the effects and contribution of resistin in initiation and progression of MetS components and also its different actions between human and other mammalians. This summarized data about the relationship of resistin and MetS components have been obtained from clinical researches and in some cases even animal studies. To find the relevant studies, the search in PubMed, Science Direct, and Scopus were performed. Human and animal studies on relationships between resistin and MetS (initiation and progression of components) were included in our search. In experiments reported among different human genetic groups as well as the patients with various disease such as diabetes, no significant correlation is shown between FBG and resistin level. Furthermore, this review shows that the results of correlation between resistin and TG, HDL, and central or abdominal obesity were inconsistent. These inconsistencies can arise from different sample size or genetic groups, gender, and also from experimental studies. Therefore, to obtain precise results systematic review and meta-analyses are required. PMID- 29991084 TI - Thyroid Autoantibodies do not Impair the Ovarian Reserve in Euthyroid Infertile Women: A Cross-Sectional Study. AB - Patients with primary ovarian insufficiency (POI) have a high prevalence of thyroid autoimmune disorders. However, the extent of the contribution of thyroid autoantibodies or elevated thyroid-stimulating hormone (TSH) levels to decreased ovarian reserve is unclear. Therefore, we evaluated the serum levels of anti Mullerian hormone (AMH) and thyroid autoantibodies [antithyroperoxidase antibody (TPOAb), and antithyroglobulin antibody (TgAb)] in euthyroid infertile women. One hundred and fifty-three women with normal menstrual cycles were recruited for this retrospective study. Serum levels of AMH were compared between patients with positive and negative thyroid autoantibodies. The correlation between serum levels of AMH and each thyroid autoantibody was also evaluated. Participants were observed to be either TPOAb or TgAb positive (n=27), only TPOAb positive (n=8), only TgAb positive (n=7), TPOAb and TgAb positive (double positive; n=12), and TPOAb and TgAb negative (double negative; n=126). No significant differences were found in serum AMH levels between the TPOAb- or TgAb-positive women and the antibody-double negative women. Serum AMH levels did not show a significant correlation with the concentration of TgAb or TPOAb. On the other hand, serum AMH levels negatively correlated with TSH levels in patients who were either positive for TPOAb or TgAb. Thyroid autoantibodies are not likely to influence ovarian reserve in euthyroid women whose TSH levels fall within the normal range although elevated TSH levels may be involved in the decline of serum AMH levels. PMID- 29991085 TI - Could Lipid Profile be Used as a Marker of Autonomous Cortisol Secretion in Patients with Adrenal Incidentalomas? AB - Adrenal incidentalomas (AIs) have been associated with an increased risk of metabolic syndrome and dyslipidemia, though evidence regarding the latter is limited. Lipid abnormalities in patients with AIs have been associated with subclinical hypercortisolism. The current study aims to test whether lipid profile in patients with AIs predicts "autonomous cortisol secretion" (ACS). Patients with AIs found on either computerized tomography (CT) or magnetic resonance imaging (MRI), were included in a prospective cohort study. All patients were followed up for at least three years. Alterations in their hormonal and lipid profiles were recorded. Ninety-four patients (69 women) harboring 111 AIs were included. There were no differences between patients with ACS and those without, with respect to their baseline lipid profile [total cholesterol, low density-lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C) and non-HDL-C] and blood pressure (systolic and diastolic). Non-HDL-C concentrations decreased over time (Repeated Measures ANOVA, p=0.013), despite patients' body mass index (BMI) remaining unchanged. Logistic regression analysis revealed that the only predictor of ACS was the size of AIs, as calculated by CT or MRI. The current study demonstrated that lipid profile at baseline or during follow-up cannot predict ACS in patients with AIs. However, larger AIs may have a greater probability of ACS. PMID- 29991086 TI - Diabetes Mellitus and Autoimmune Hepatitis: Demographical and Clinical Description of a Relatively Rare Phenotype. AB - We studied demographic, metabolic, and clinical characteristics of patients with diabetes and autoimmune hepatitis (AIH) from the German/Austrian DPV registry. A total of 139 patients with diabetes and AIH were analyzed and compared to 437 728 patients with diabetes without AIH. The prevalence of AIH in patients with T1DM (44.8/100 000) seems higher than in the general population, the prevalence of AIH in patients with T2DM (23.6/100 000) does not seem to be increased. Patients with T2DM and AIH had a shorter duration of diabetes (p=0.007) and a higher proportion of females (p<0.001) compared to T2DM without AIH. Patients with diabetes (T1DM or T2DM) and AIH required higher insulin doses (p<0.001 and p=0.03, respectively) and showed increased liver enzymes (aspartate transaminase, alanine transaminase, gamma-glutamyltransferase) compared to diabetes patients without (all p<0.001). We detected a lower percentage of patients treated with oral antidiabetic drugs (p=0.01) and a higher percentage of patients treated by insulin in patients with T2DM and AIH (p<0.001) compared to patients with T2DM alone. We observed a higher incidence of autoimmune thyroid disease (AIT) in patients with diabetes (T1DM or T2DM) and AIH (p<0.001) compared to diabetes patients without AIH. AIH seems more frequent in patients with T1DM. Patients with diabetes and AIH require intensification of antidiabetic therapy and seem to have a higher prevalence of AIT. PMID- 29991087 TI - Pharmacokinetics of Riluzole in Beagle Dogs. AB - BACKGROUND: Riluzole is a benzothiazole anticonvulsant used in the treatment of patients with amyotrophic lateral sclerosis and it is being investigated for clinical use in patients with spinal cord injury. The present study evaluated the pharmacokinetics of riluzole in beagle dogs after oral dose administration. METHODS: The oral doses (1.5, 5, 15 and 50 mg/kg) of riluzole were administered to beagle dogs and blood samples were collected from 0 h to 24 h post drug administration. Riluzole was quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). RESULTS: The method was sensitive, precise, accurate and selective to riluzole quantification in plasma of beagle dogs. The pharmacokinetics following oral administration was linear from 1.5 to 15 mg/kg and the t1/2 was 2.16, 1.5, 1.8 and 3.0 h after oral administration of 1.5, 5.0, 15 and 50 mg/kg riluzole. CONCLUSION: The riluzole pharmacokinetics was linear up to 15 mg/kg and had a significantlyshorter t1/2 in beagle dogs than in humans. PMID- 29991088 TI - Value of Systemic Staging in Asymptomatic Early Breast Cancer. AB - OBJECTIVE: Metastases are rare in early breast cancer (EBC), and international guidelines recommend against routine systemic staging for asymptomatic patients. However, imaging exams remain widely employed in the clinical practice. The aim of the present study is to evaluate the value of imaging for systemic staging in EBC. METHODS: A retrospective analysis of newly-diagnosed breast cancer (BC) patients was performed. Clinical data including BC subtype, stage, presence of symptoms at diagnosis and instrumental procedures performed for staging were recorded. RESULTS: A total of 753 patients were included, with a median age of 57 years. The majority of the patients underwent at least 1 imaging procedure (91%); had invasive ductal carcinoma (83.5%); histological grade 2 (51.4%); stage II (61.8%); and luminal subtype (67.9%). Among the 685 (91%) patients who underwent any radiologic staging, distant metastases (DMs) were detected in 32 (4.7%). In the univariate analyses, stage IIb and pathological lymph node involvement (pN1) showed a statistically significant association with the presence of DMs, versus only a trend for triple negative and human epidermal growth factor receptor 2 (Her2) positive subtype. In an exploratory analysis performed in this same subgroup, when unfavorable biology (triple negative or Her2 positive) was present, patients had a DM rate of 14.4%, one of the highest reported at this stage of the disease. CONCLUSION: Early breast cancer has a low prevalence of DM at the initial evaluation, and systemic staging of asymptomatic, unselected patients is not warranted as a routine practice. However, we have identified subgroups of patients to whom a full staging could be indicated. PMID- 29991089 TI - [Influence of a structured follow-up on CPAP adherence in patients with an OSAS]. AB - OBJECTIVE: Continuous positive airway pressure (CPAP) therapy is the reference therapy for moderate and severe obstructive sleep apnea syndrome (OSAS). However, CPAP adherence is dissatisfying. We analyzed influencing factors on CPAP adherence and we evaluated if a structured follow-up enhances its adherence. MATERIAL AND METHODS: In this study all patients (n = 237) with a newly adjusted CPAP therapy due to the diagnosis of mild to severe OSAS between 2011 and 2013 were investigated. Follow-up took place every 1593.7 +/- 77.4 CPAP operation hours. RESULTS: AHI (Apnea-hypopnea index) decreased significantly during therapy (5.6 +/- 8.5/h; p < 0.001). 79 % fulfilled the criteria of CPAP adherence (at least 4 operation hours at 7 days a week). There were no significant influences on CPAP adherence seen in patients' demographic, clinical and pharmacological characteristics. The most common problems of patients receiving a CPAP therapy were dryness of the mucous membranes (43.7 %) and pressure marks (22.4 %). Considering the changes in Epworth Sleepiness Scale there were no significant relations to CPAP adherence. Satisfaction with our follow-up significantly correlated with CPAP adherence (r = 0.185; p = 0.032), whereas therapy pressure did not have any significant influence on CPAP adherence (r = -0.072; p = 0.383). CONCLUSION: A structured and individually adapted follow-up is important. In future, apart from control of therapy success, greater attention in the follow-up of CPAP therapy should be given to aspects of problem solution, feedback, education, and motivation. PMID- 29991090 TI - Erratum: Economic Analysis of Using Free Fat Graft or Acellular Dermis to Prevent Post-parotidectomy Frey Syndrome. PMID- 29991091 TI - Searching for a Cell-Based Therapeutic Tool for Haemophilia A within the Embryonic/Foetal Liver and the Aorta-Gonads-Mesonephros Region. AB - The development of new strategies based on cell therapy approaches to correct haemophilia A (HA) requires further insights into new cell populations capable of producing coagulation factor VIII (FVIII) and presenting stable engraftment potential. The major producers of FVIII in the adult are liver sinusoidal endothelial cells (LSECs) and in a lesser degree bone marrow-derived cells, both of which have been shown to ameliorate the bleeding phenotype in adult HA mice after transplantation. We have previously shown that cells from the foetal liver (FL) and the aorta-gonads-mesonephros (AGM) haematopoietic locations possess higher LSEC engraftment potential in newborn mice compared with adult-derived LSECs, constituting likely therapeutic targets for the treatment of HA in neonates. However, less is known about the production of FVIII in embryonic locations. Quantitative polymerase chain reaction and Western blot analysis were performed to assess the relative level of FVIII production in different embryonic tissues and at various developmental stages, identifying the FL and AGM region from day 12 (E12) as prominent sources of FVIII. Furthermore, FL-derived VE cad+CD45-Lyve1+/- endothelial/endothelial progenitor cells, presenting vascular engraftment potential, produced high levels of F8 ribonucleic acid compared with CD45+ blood progenitors or Dlk1+ hepatoblasts. In addition, we show that the E11 AGM explant cultures expanded cells with LSEC repopulation activity, instrumental to further understand signals for in vitro generation of LSECs. Taking into account the capacity for FVIII expression, culture expansion and newborn engraftment potential, these results support the use of cells with foetal characteristics for correction of FVIII deficiency in young individuals. PMID- 29991092 TI - Inflammasome, T Lymphocytes and Innate-Adaptive Immunity Crosstalk: Role in Cardiovascular Disease and Therapeutic Perspectives. AB - Over the past few decades, lot of evidences have shown atherosclerosis as a chronic progressive disease with an exquisite inflammatory feature. More recently, the role of innate immune response in the onset and progression of coronary artery disease (CAD) and an adaptive immunity imbalance, mostly involving T cell sub-sets, have been documented. Therefore, like in many other inflammatory and autoimmune disorders, an altered innate-adaptive immunity crosstalk could represent the key of the inflammatory burden leading to atherosclerotic plaque formation and progression and to the breakdown of plaque stability. In this review, we will address the role of inflammasome in innate immunity and in the imbalance of adaptive immunity. We will discuss how this altered immune crosstalk is related to CAD onset and progression. We will also discuss how unravelling the key molecular mechanisms is of paramount importance in the development of therapeutic tools to delay the chronic progression and prevent the acute destabilization of atherosclerotic plaque. PMID- 29991094 TI - Case Reports. PMID- 29991093 TI - Enhancing the Performance of the Half Tin and Half Lead Perovskite Solar Cells by Suppression of the Bulk and Interfacial Charge Recombination. AB - In this article it is investigated how the hole extraction layer (HEL) influence the charge recombination and performance in half tin and half lead (FASn0.5 Pb0.5 I3 ) based solar cells (HPSCs). FASn0.5 Pb0.5 I3 film grown on PEDOT:PSS displays a large number of pin-holes and open grain boundaries, resulting in a high defect density and shunts in the perovskite film causing significant bulk and interfacial charge recombination in the HPSCs. By contrast, FASn0.5 Pb0.5 I3 films grown on PCP-Na, an anionic conjugated polymer, show compact and pin-hole free morphology over a large area, which effectively eliminates the shunts and trap states. Moreover, PCP-Na is characterized by a higher work function, which determines a favorable energy alignment at the anode interface, enhancing the charge extraction. Consequently, both the interfacial and bulk charge recombination in devices using PCP-Na HEL are considerably reduced giving rise to an overall improvement of all the device parameters. The HPSCs fabricated with this HEL display power conversion efficiency up to 16.27%, which is 40% higher than the efficiency of the control devices using PEDOT:PSS HEL (11.60%). Furthermore, PCP-Na as HEL offers superior performance in larger area devices compared to PEDOT:PSS. PMID- 29991095 TI - Progressive Multifocal Leukoencephalopathy versus Brain Metastasis in a Patient with Locally-Advanced Non-Small Cell Lung Cancer. AB - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease affecting the white matter of the brain. This condition is caused by the John Cunningham virus and leads to progressive neuropsychological deficits. Though the infection is typically seen in association with HIV or AIDS, other immune compromised states may predispose patients as well. This report discusses a patient who developed PML following standard chemo-radiotherapy for non-small cell lung cancer in whom presentation was initially more convincing for brain metastasis; thus, highlighting the importance of accurate diagnosis of new brain lesions in this setting. PMID- 29991096 TI - A Very Rare Case of Sarcoid-Lymphoma Syndrome Imposing an Intriguing Diagnostic Challenge. AB - An enigmatic association between sarcoidosis and lymphoma has been proposed in the past. This poses a significant diagnostic challenge, especially when the time interval is less than one year between the two diagnoses. A 54-year-old male patient presented to his primary care physician with worsening acute kidney injury and hypercalcemia. His chest x-ray showed bilateral interstitial nodular thickening and mild bilateral hilar fullness. After a diagnostic workup, the patient was diagnosed with sarcoidosis and started on prednisone. He initially improved, but returned with acute kidney injury, hypercalcemia, and generalized lymphadenopathy. An excisional lymph node biopsy was positive for diffuse large B cell lymphoma. Our case illustrates the sarcoidosis-lymphoma syndrome. Although there is no recommendation to screen patients with sarcoidosis for malignancy, it is crucial to be aware of this association and to evaluate any new or enlarging lymphadenopathy with a biopsy. It is essential to assess response to prednisone in patients with sarcoidosis. PMID- 29991097 TI - Multiple Myeloma Light Chain Amyloidosis Presenting as Hepatic Failure. AB - Amyloidosis is characterized by abnormal deposition of aggregations of amyloid fibril proteins. Systemic amyloidosis usually involves multiple organs, with kidneys being the most common organ involved, followed by the heart. In general, the presentation of hepatic amyloidosis varies with minimal or no symptoms commonly seen. Hepatic amyloidosis is rarely associated with multiple myeloma. We report here a case of portal hypertension, ascites, and severe intrahepatic cholestasis as the initial presentation of hepatic amyloidosis and multiple myeloma, which followed a rapidly progressive clinical course. PMID- 29991098 TI - A Review of Extrapulmonary Tuberculosis. AB - Mycobacterium tuberculosis is an aerobic, non-spore-forming, non-motile bacillus that causes tuberculosis of both pulmonary and extrapulmonary sites. Though nationwide 66 percent of reported tuberculosis cases occur in foreign-born individuals, these individuals only contributed to 29 percent of the cases in South Dakota in 2015, whereas most of our cases were found in citizens born in the U.S.1 The South Dakota Department of Health also reported 317 cases of latent tuberculosis in South Dakota in 20151, making reactivation tuberculosis a major concern for U.S.-born residents. During the five years spanning 2011-2015, we have seen varying presentations of tuberculosis in South Dakota, many of which included extrapulmonary sites. We report a recent case involving of a 62-year-old Native American female with extrapulmonary tuberculosis cystitis. PMID- 29991099 TI - Sporadic Meningioangiomatosis: Bystander or Curious Culprit. AB - In this report, we describe two cases of sporadic meningioangiomatosis (MA) - a rare condition of the central nervous system known to cause headaches, seizures and other focal neurologic deficits. Both patients presented with headache and vision change, somewhat suggestive of migraine. The combination of magnetic resonance imaging (MRI) and computerized tomography (CT) can establish the diagnosis of MA. PMID- 29991100 TI - Coexistent Alpha-1 Antitrypsin Deficiency and Hereditary Hemochromatosis. AB - Alpha-1 antitrypsin (AAT) deficiency and hereditary hemochromatosis are systemic diseases inherited in an autosomal recessive fashion. The primary manifestation of AAT is early-onset pulmonary disease, while hemochromatosis primarily affects function of the liver, heart, and pancreas through excess iron deposition. No clear association between the two diseases has been delineated. We present a case in which a 34-year old female patient presenting with elevated liver enzymes during a visit for an unrelated acute illness was found to be a homozygous variant for AAT deficiency and hereditary hemochromatosis. A description of her presentation and clinical work up is included, along with a discussion of the epidemiology and clinical characteristics of each disease. PMID- 29991101 TI - Single Coronary Artery Arising from the Right Sinus of Valsalva and the Role of Coronary Computed Tomography Angiography. AB - There are many variations of coronary anatomy encountered during coronary angiogram. Anatomy demonstrating a single coronary artery is a rare congenital coronary artery anomaly. The entire heart is supplied solely by a coronary artery with single coronary ostium. We present a rare case of single coronary artery arising from the right sinus of Valsalva. The patient had presented with atypical chest pain and a stress test was performed, which was abnormal. We proceeded with coronary angiography which showed a common ostium of the right and left coronary artery coming from the right coronary cusp. The coronary computed tomography angiography revealed the left main had a pre-pulmonic course, crossing the base of the heart and passing anterior to the pulmonary artery and then branching into the left anterior descending artery and left circumflex artery. Patients with single coronary artery usually has benign prognosis; however, a specific coronary anomaly may result in myocardial ischemia and sudden cardiac death if the anomalous coronary artery takes an intra-arterial course, running between the aorta and the pulmonary artery. Coronary computed tomography angiography is a useful imaging modality to identify anatomical course of coronary anomaly. PMID- 29991103 TI - Quality Focus: Early Diagnosis Using Colorectal Cancer Screening Impacts Incidence and Mortality. PMID- 29991102 TI - Value-Based Pricing of Disease-Modifying Therapies for Multiple Sclerosis: Is This Mission Possible? PMID- 29991104 TI - Competition and Premium Costs in Single-Insurer Marketplaces: A Study of Five Rural States. AB - Issue: In 2017, five states--Alabama, Alaska, Oklahoma, South Carolina, and Wyoming--had only one issuer participating in their health care marketplaces, limiting consumer choice and competition among insurers. Goal: Examine the history of participation in the individual market from 2010 (before the Affordable Care Act was enacted) to 2017, and analyze premium changes among marketplace plans. Methods: Robert Wood Johnson Foundation's HIX Compare, which provides national data on the marketplaces from 2014 to 2017. Findings and Conclusions: In 2010, the individual insurance market was already concentrated in the five study states, with Blue Cross and Blue Shield (BCBS) plans covering the majority of enrollees. By 2015, with the marketplaces in full swing, more issuers were competing in the five states. But by 2016, co-ops were facing bankruptcy and left the marketplaces in these states; and in 2017, citing large financial losses, national issuers UnitedHealthcare, Aetna, and Humana also exited, leaving only a single BCBS plan in each state. Three of the five states experienced substantially higher annual premium increases than the national average. Policy options with bipartisan support, such as resuming cost-sharing reduction payments and reestablishing reinsurance and risk corridors, could help attract new or returning issuers to marketplaces in these states. PMID- 29991105 TI - Do Medicare Advantage Plans Respond to Payment Changes? A Look at the Data from 2009 to 2014. AB - Issue: Medicare Advantage (MA) enrollment has grown significantly since 2009, despite legislation that reduced what Medicare pays these plans to provide care to enrollees. MA payments, on average, now approach parity with costs in traditional Medicare. Goal: Examine changes in per enrollee costs between 2009 and 2014 to better understand how MA plans have continued to thrive even as payments decreased. Methods: Analysis of Medicare data on MA plan bids, net of rebates. Findings: While spending per beneficiary in traditional Medicare rose 5.0 percent between 2009 and 2014, MA payment benchmarks rose 1.5 percent and payment to plans decreased by 0.7 percent. Plans' expected per enrollee costs grew 2.6 percent. Plans where payment rates decreased generally had slower growth in their expected costs. HMOs, which saw their payments decline the most, had the slowest expected cost growth. Conclusions: In general, MA plans responded to lower payment by containing costs. By preserving most of the margin between Medicare payments and their bids in the form of rebates, they could continue to offer additional benefits to attract enrollees. The magnitude of this response varied by geographic area and plan type. Despite this slower growth in expected per enrollee costs, greater efficiencies by MA plans may still be achievable. PMID- 29991106 TI - Evolution of Quality Improvement for the Journal of Korean Neurosurgical Society. PMID- 29991107 TI - Nerve Growth Factor Stimulates Glioblastoma Proliferation through Notch1 Receptor Signaling. AB - Objective: Notch receptors are heterodimeric transmembrane proteins that regulate cell fate, such as differentiation, proliferation, and apoptosis. Dysregulated Notch pathway signaling has been observed in glioblastomas, as well as in other human malignancies. Nerve growth factor (NGF) is essential for cell growth and differentiation in the nervous system. Recent reports suggest that NGF stimulates glioblastoma proliferation. However, the relationship between NGF and Notch1 in glioblastomas remains unknown. Therefore, we investigated expression of Notch1 in a glioblastoma cell line (U87-MG), and examined the relationship between NGF and Notch1 signaling. Methods: We evaluated expression of Notch1 in human glioblastomas and normal brain tissues by immunohistochemical staining. The effect of NGF on glioblastoma cell line (U87-MG) was evaluated by 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. To evaluate the relationship between NGF and Notch1 signaling, Notch1 and Hes1 expression were evaluated by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. To confirm the effects of NGF on Notch1 signaling, Notch1 and Hes1 small interfering RNAs (siRNAs) were used. Results: In immunohistochemistry, Notch1 expression was higher in glioblastoma than in normal brain tissue. MTT assay showed that NGF stimulates U87-MG cells in a dose dependent manner. RT-PCR and Western blot analysis demonstrated that Notch1 and Hes1 expression were increased by NGF in a dose-dependent manner. After transfection with Notch1 and Hes1 siRNAs, there was no significant difference between controls and 100 nM NGF-beta, which means that U87-MG cell proliferation was suppressed by Notch1 and Hes1 siRNAs. Conclusion: These results indicate that NGF stimulates glioblastoma cell proliferation via Notch1 signaling through Hes 1. PMID- 29991108 TI - Clinical Outcome of Nonfistulous Cerebral Varices: the Analysis of 39 Lesions. AB - Objective: Cerebral varices (CVs) without an arteriovenous shunt, so called nonfistulous CVs, are very rare, and their etiology and natural course are not well understood. The aim of this study is to evaluate the clinical outcomes of nonfistulous CVs by the analysis of 39 cases. Methods: From 2000 to 2015, 22 patients with 39 nonfistulous CVs (>=5 mm) were found by searching the medical and radiologic records of our institute. Clinical data and radiological data including numbers, sizes and locations of CVs and associated anomalies were retrospectively collected and analyzed. Previously reported cases in literature were reviewed as well. Results: The mean age of the patients was 21 years (range, 0-78 years). On average, 1.8+/-1.2 CVs were found per patient. CVs were categorized as either fusiform or saccular depending on their shapes. Two patients had saccular type CVs, seventeen patients had fusiform types, and three patients had both fusiform and saccular CVs. Eight patients had associated compromise of the vein of Galen and the straight sinus. Four of those patients had sinus pericranii, as well. Five patients had CVs that were distal draining veins of large developmental venous anomalies. One patient had associated migration anomaly, and two patients had Sturge- Weber syndrome. Six patients with an isolated cerebral varix were observed. Of the 39 CVs in 22 patients, 20 lesions in 14 patients were followed up in outpatient clinics with imaging studies. The average follow-up duration was 6.6 years. During this period, no neurological events occurred, and all the lesions were managed conservatively. Conclusion: Nonfistulous CVs seemed to be asymptomatic in most cases and remained clinically silent. Hence, we suggest conservative management. PMID- 29991110 TI - Anatomical Variants of "Short Head of Biceps Femoris Muscle" Associated with Common Peroneal Neuropathy in Korean Populations : An MRI Based Study. AB - Objective: In Asians, kneeling and squatting are the postures that are most often induce common peroneal neuropathy. However, we could not identify a compatible compression site of the common peroneal nerve (CPN) during hyper-flexion of knees. To evaluate the course of the CPN at the popliteal area related with compressive neuropathy using magnetic resonance imaging (MRI) scans of healthy Koreans. Methods: 1.5-Tesla knee MRI scans were obtained from enrolled patients and were retrospectively reviewed. The normal populations were divided into two groups according to the anatomical course of the CPN. Type I included subjects with the CPN situated superficial to the lateral gastocnemius muscle (LGCM). Type II included subjects with the CPN between the short head of biceps femoris muscle (SHBFM) and the LGCM. We calculated the thickness of the SHBFM and posterior elongation of this muscle, and the LGCM at the level of femoral condyles. In type II, the length of popliteal tunnel where the CPN passes was measured. Results: The 93 normal subjects were included in this study. The CPN passed through the "popliteal tunnel" formed between the SHBFM and the LGCM in 36 subjects (38.7% type II). The thicknesses of SHBFM and posterior portions of this muscle were statistically significantly increased in type II subjects. The LGCM thickness was comparable in both groups. In 78.8% of the "popliteal tunnel", a length of 21 mm to <40 mm was measured. Conclusion: In Korean population, the course of the CPN through the "popliteal tunnel" was about 40%, which is higher than the Western results. This anatomical characteristic may be helpful for understanding the mechanism of the CPNe by posture. PMID- 29991109 TI - Safe Margin beyond Dens Tips to Ventral Dura in Anterior Odontoid Screw Fixation : Analysis of Three-Dimensional Computed Tomography Scan of Odontoid Process. AB - Objective: Anterior odontoid screw fixation is a safe and effective method for the treatment of odontoid fractures. The surgical technique is recommended for perforation of the apical cortex of the dens by the lag screw. However, overpenetration of the apical cortex may lead to potentially serious complications such as damages of adjacent vascular and neural structures. The purpose of this study was to assess the role of three-dimensional computed tomography (CT) scan to evaluate the safe margin beyond dens tip to ventral dura for anterior odontoid screw fixation. Methods: We retrospectively analyzed the three-dimensional CT scans of the cervical spines in 55 consecutive patients at our trauma center. The patients included 38 males and 17 females aged between 22 and 73 years (mean age+/-standard deviation, 45.8+/-14.2 years). Using sagittal images of 3-dimensional CT scan, the safe margins beyond dens tip to ventral dura as well as the appropriate screw length were measured. Results: The mean width of the apical dens tip was 9.6+/-1.1 mm. The mean lengths from the screw entry point to the apical dens tip and posterior end of dens tip were 39.2+/-2.6 mm and 36.6+/-2.4 mm. The safe margin beyond apical dens tip to ventral dura was 7.7+/ 1.7 mm. However, the safe margin beyond the posterior end of dens tip to ventral dura was decreased to 2.1+/-3.2 mm, which was statistically significant (p<0.01). There were no significant differences of safe margins beyond dens tip to ventral dura with patient gender and age. Conclusion: Extension by several millimeters beyond the dens tip is safe, if the trajectory of anterior odontoid screw is targeted at the apical dens tip. However, if the trajectory of the screw is targeted to the posterior end of dens tip, extension beyond dens tip may lead to damage immediately adjacent to the vental dura mater. PMID- 29991111 TI - Efficacy of Gamma Knife Radiosurgery for Recurrent High-Grade Gliomas with Limited Tumor Volume. AB - Objective: This study aims to determine whether gamma knife radiosurgery (GKR) improves survival in patients with recurrent highgrade gliomas. Methods: Twenty nine patients with recurrent high-grade glioma underwent 38 GKR. The male-to female ratio was 10 : 19, and the median age was 53.8 years (range, 20-75). GKR was performed in 11 cases of recurrent anaplastic oligodendrogliomas, five anaplastic astrocytomas, and 22 glioblastomas. The median prescription dose was 16 Gy (range, 10-24), and the median target volume was 7.0 mL (range, 1.1-15.7). Of the 29 patients, 13 (44.8%) received concurrent chemotherapy. We retrospectively analyzed the progression-free survival (PFS) and overall survival (OS) after GKR depending on the Eastern Cooperative Oncology Group (ECOG) performance status (PS), pathology, concurrent chemotherapy, radiation dose, and target tumor volume. Results: Starting from when the patients underwent GKR, the median PFS and OS were 5.0 months (range, 1.1-28.1) and 13.0 months (range, 1.1 75.1), respectively. On univariate analysis, the median PFS was significantly long in patients with anaplastic oligodendroglioma, ECOG PS 1, and target tumor volume less than 10 mL (p<0.05). Meanwhile, on multivariate analysis, patients with ECOG PS 1 and target tumor volume less than 10 mL showed improved PFS (p=0.043 and p=0.007, respectively). The median OS was significantly increased in patients with ECOG PS 1 and tumor volume less than 10 mL on univariate and multivariate analyses (p<0.05). Conclusion: GKR could be an additional treatment option in recurrent high-grade glioma, particularly in patients with good PS and limited tumor volume. PMID- 29991113 TI - Corrigendum to "Microsurgical Foraminotomy via Wiltse Paraspinal Approach for Foraminal or Extraforaminal Stenosis at L5-S1 Level : Risk Factor Analysis for Poor Outcome" by Cho SI, et al. (J Korean Neurosurg Soc 59 : 610-614, 2016). PMID- 29991114 TI - Experimental Feline Infectious Enteritis in the Germfree Cat. AB - In the absence of other microorganisms the virus of feline infectious enteritis produced a mild, non-fatal clinical disease in germfree cats. A biphasic temperature rise occurred on post inoculation day (PID) 2 and 4. All of the germfree cats began to recover by PID 7. Absolute lymphopenia occurred on the first day followed by absolute neutropenia on PID 4. The leucocyte counts were within the normal range by PID 10. Severe atrophy of the thymus was the only macroscopic lesion produced. Depletion of mature lymphocytes and reticuloendothelial cell hyperplasia occurred in all other lymphocytic tissue. No inclusion body considered to be of diagnostic significance could be demonstrated. There was no evidence of enteritis grossly or microscopically in germfree cats. PMID- 29991115 TI - Neoplasms in the Adenohypophysis of Dogs: A Clinical and Pathologic Study. AB - Twenty-six neoplasms of the adenohypophysis were classified either as chromophobe adenomas (20 dogs) or adenomas of the pars intermedia (6 dogs). In 62% of the dogs the neoplasms were functionally active (14 chromophobe adenomas, 2 adenomas of the pars intermedia) and associated with a syndrome of hyperadrenocorticism (Cushing's-like disease). The adrenal cortical hypertrophy and hyperplasia, muscular weakness and wasting, leukocytosis with a neutrophilia, eosinopenia and lymphopenia, deposition of fat in the liver, increased serum corticosteroid, and increased urinary 17-hydroxycorticosteroids all suggested the neoplasms were producing ACTH. Mineralization of the lungs and other tissues was consistently present in dogs with functional neoplasms. Adenomas of the pars intermedia appeared to arise from the lining epithelium of the residual hypophysial lumen covering the infundibular process. They were sharply demarcated from the compressed pars distalis. PMID- 29991112 TI - Fractionated Stereotactic Radiosurgery for Brain Metastases Using the Novalis Tx(r) System. AB - Objective: To evaluate the efficacy of fractionated stereotactic radiosurgery (FSRS) performed using the Novalis Tx(r) system (BrainLAB AG, Feldkirchen, Germany; Varian Medical Systems, Palo Alto, CA, USA) for brain metastases. Methods: Between March 2013 and July 2016, 23 brain metastases patients were admitted at a single institute. Twenty-nine lesions too large for single session stereotactic radiosurgery or located in the vicinity of eloquent structures were treated by FSRS. Based on the results obtained, we reviewed the efficacy and toxicity of FSRS for the treatment of brain metastases. Results: The most common lesion origin was lung (55%) followed by breast (21%). Median overall survival was 10.0 months (95% confidence interval [CI], 4.9-15.0), and median progression free survival was 10.0 months (95% CI, 2.1-13.9). Overall survival rates at 1 and 2 years were 58.6% and 36.0%, respectively. Local recurrence and neurological complications affecting morbidity each occurred in two cases. Conclusion: FSRS using the Novalis-Tx(r) system would appear to be an effective, safe noninvasive treatment modality for large and eloquently situated brain metastases. Further investigation is required on a larger number of patients. PMID- 29991116 TI - Functional Chromophobe Adenomas of the Canine Adenohypophysis: An Ultrastructural Evaluation of a Neoplasm of Pituitary Corticotrophs. AB - Chromophobe adenomas from 8 dogs with clinical signs and lesions of hyperadrenocorticism (Cushing's-like disease) were selected for electron microscopic study in order to establish a morphologic basis for active secretion by the neoplastic cells. At the level of ultrastructure there was definite evidence of secretory activity and the organelles concerned with protein synthesis (endoplasmic reticulum) and packaging of secretory products (Golgi apparatus) were well developed. Although the numerous secretory granules present varied in electron density and in size, the most frequently encountered granule measured 170 m MU in diameter. The secretory granules of the neoplastic cells differed from those found within acidophils and basophils of the canine hypophysis. Based on these findings it was concluded that the cells comprising these chromophobe adenomas were actively secreting corticotrophs of the pituitary gland. PMID- 29991117 TI - The Production of Cytopathic Changes in Canine Cell Lines by Infectious Agents: Cell Lines Derived from Melanoma and Thyroidal Carcinoma. AB - The cytopathic effect of more than 30 viruses and Toxoplasma gondii and Histoplasma capsulatum was determined in established canine thyroid adenocarcinoma and canine melanoma cell lines. Marked effect was observed with the viruses of canine hepatitis, pseudorabies, and canine distemper, and reo type 1 and vaccinia viruses in both cell lines. Moderate effect was found with human adenovirus type 1, swine adenovirus and the viruses of swine influenza and Newcastle disease. Cytopathic changes were produced with the virus of herpes simplex in the thyroid adenocarcinoma cells. A transient giant cell formation was produced by the virus of measles in the thyroid cell line. Hemadsorption was demonstrated in both cell lines with vaccinia virus. Toxoplasma gondii multiplied in both cell lines and produced cellular degeneration and necrosis. Histoplasma capsulatum grew in the thyroid adenocarcinoma cell line with little cellular degeneration. PMID- 29991118 TI - The Ultrastructure and Histopathology of an Acidophil Adenoma of the Canine Adenohypophysis. AB - An acidophil adenoma in a 12-year-old spayed boxer dog resulted in clinical signs related to a space-occupying lesion of the hypophysis. There were two types of acidophils, as determined ultrastructurally, within the adenoma. The predominating type was interpreted to be in the storage phase of the secretory cycle as the cytoplasm was densely granulated and the organelles concerned with protein synthesis and packaging of secretory products were poorly developed. The second, less common type contained few secretory granules, had a well developed endoplasmic reticulum and Golgi apparatus, and was interpreted to be secretorily active. The secretory granules of the neoplastic acidophils were large (420 m MU), uniformly electron-dense, and had a narrow submembranous space. An adenoma of the pancreatic islets was also present. PMID- 29991119 TI - Infraglomerular Epithelial Reflux as a Postmortem Phenomenon in the Kidneys of Dog and Rat. AB - The significance of postmortem renal changes for the pathogenesis of infraglomerular epithelial reflux (IER) was examined in a number of experiments with kidneys of the dog and rat. The reflux can develop after death in both species. Intravital circumstances (e.g., ischemia) may stimulate the postmortem development of IER. The development of IER was accompanied by swelling of tubular epithelial cells and could be provoked by palpation at autopsy. The type of fixative can also influence the degree of the phenomenon, which was more pronounced in ethanol-fixed than in formalin-fixed kidney. IER has to be considered primarily a postmortem phenomenon and a correct evaluation of IER is only possible if the postmortem treatment of the kidney be exactly known and, in appropriate investigations, has been very well standardized for control and experimental animals. PMID- 29991120 TI - A Useful marker in the assessment of remission and activation of disease in patients with rheumatoid arthritis: Serum human neutrophil peptides 1-3. AB - AIM: Rheumatoid arthritis (RA) is a chronic disease of unknown etiology. Various cellular and molecular immunological factors are involved in the pathophysiology of RA. Recent studies suggest that neutrophils and alpha-defensins released from the neutrophils assume significant roles in the pathogenesis of RA. The aim of this study was to investigate the potential association between serum alpha defensin levels and disease activity, functional status, radiological damage and several laboratory parameters in patients with RA. MATERIAL AND METHOD: A total of 42 patients with established RA who presented to the outpatient clinics of rheumatology of Dicle University Hospital and 38 healthy control subjects were included in this study. Disease activity was assessed by using the Disease Activity Scale 28 (DAS28). Quality of life was assessed by using the Rheumatoid Arthritis Quality of Life (RAQoL) Questionnaire and the Nottingham Health Profile (NHP). Functional status was assessed by using the Stanford Health Assessment Questionnaire (HAQ). Laboratory examinations included the following tests: CBC, ESH, CRP, and HNP 1-3. RESULTS: Patients with an active disease exhibited higher HNP 1-3 levels compared to patients in remission. At a cut off value of 708 pg/ml, sensitivity and specificity of the tests for HNP 1-3 were 72% and 70.6%, respectively. CONCLUSION: In the present study, patients with an active disease had significantly higher serum HNP 1-3 levels compared to patients in remission. In this respect, serum HNP 1-3 can be a useful marker in the assessment of disease activity and remission in patients with RA. PMID- 29991121 TI - Effectiveness of an innovative mattress overlay for improving rehabilitation in low back pain: A pilot randomized controlled study. AB - BACKGROUND AND OBJECTIVE: Sleep disorders should be routinely evaluated and treated in low back pain (LBP) patients because they represent an important contributor to pain. However, no study thus far has investigated the potential benefit to LBP management of a device improving the sleep quality. Therefore, aim of this study was to assess the effectiveness of an innovative mattress overlay as add-on treatment to LBP rehabilitation. METHODS: Thirty eight LBP patients were randomized to standard rehabilitation plus mattress overlay use (cases) or standard rehabilitation only (controls). The intervention duration was 2 months and the following assessments were performed before and after: pain intensity; level of perceived back disability and sleep health; spine mobility; thickness and echo intensity of the lumbar multifidus. RESULTS: Significant pre-post intervention improvements were observed in cases for resting and movement pain, perceived back disability, sleep, fingertip-to-floor distance, multifidus thickness (~ 6% increase) and echo intensity (~ 13% decrease). On the contrary, all these variables remained constant between the two experimental phases in controls. CONCLUSIONS: A combination of rehabilitation and mattress overlay use seems an effective approach for improvement of pain, perceived back disability, sleep, spine mobility, and lumbar multifidus size and structure of LBP patients. PMID- 29991122 TI - New approach for evaluating the effectiveness of whole-body magnetic field therapy in the rehabilitation of patients with lumbar discectomy. AB - OBJECTIVE: Magnetic field therapy involves the application of low-intensity magnetic fields (1-3.5 mT) to a patient's whole body. The purpose of this study was to assess the effectiveness of whole-body magnetic field (WBMF) therapy in the early rehabilitation of patients after lumbar discectomy. METHODS: A convenience sample of 73 patients who underwent lumbar discectomy within 1 month previously participated in the study. All patients were randomly assigned to one of two groups and received either a course of conventional rehabilitation (control group) or conventional rehabilitation together with 10 sessions of WBMF therapy (WBMF group). Participants were evaluated before and after the rehabilitation course by using the Visual Analog Scale for Pain (VAS) and thermal infrared imaging. The latter was used to detect pathological changes in temperature (hyperthermia and thermal asymmetry) of the surface of the skin overlying the lumbar spine and lower extremities. RESULTS: The VAS score of the WBMF group decreased from 6.2 +/- 0.3 cm before to 3.2 +/- 0.2 cm after rehabilitation (p< 0.01), compared to 6.1 +/- 0.4 cm before to 4.3 +/- 0.2 cm after rehabilitation for the control group (p< 0.05). Reduction of the area of lumbar hyperthermia was observed in 88% of WBMF and 35% of control group patients. CONCLUSIONS: When combined with conventional rehabilitation, WBMF therapy was effective in reducing lumbar pain, temperature, and, possibly, inflammation. Results of this study will be used for designing a large-scale clinical trial. PMID- 29991123 TI - Effects of ankle dorsiflexion limitation on lower limb kinematic patterns during a forward step-down test. AB - BACKGROUND: Altered lower limb movement patterns (LLMP) during the forward step down (FSD) test have been studied in people suffering from knee instability. However, ankle dorsiflexion range of motion (ADROM) seems to be related to LLMP but no causal inference has been defined between those variables. OBJECTIVE: Our goals were to evaluate (1) psychometric quality of the FSD test in healthy people and (2) the influence of experimental restricted ADROM on LLMP. METHODS: Kinematics were measured by a motion capture system. Angular displacement and speed were calculated as well as center of mass (COM) and knee linear displacement. Forty-two healthy participants; firstly, performed the test three times to assess reliability, and secondly the same test in an experimental condition limiting the ADROM. RESULTS: Reliability was excellent for all parameters (ICC: 0.75-0.99, SEM%: 2.0-34.0%). ADROM limitation significantly decreased Knee flexion range of motion (ROM) (-3.8?), increased Hip flexion ROM (6?), Hip adduction ROM (6.1?), Pelvis drop ROM (3.5?), Pelvic rotation ROM (3.1?). No significant effect was found for Hip rotation ROM. CONCLUSIONS: LLMP was affected by this experimental ADROM limitation in healthy people. As this limitation is often encountered in post-traumatic ankle sprain patients, clinicians should consider this point during FSD assessment test. PMID- 29991124 TI - Overexpression of GBP1 predicts poor prognosis and promotes tumor growth in human glioblastoma multiforme. AB - OBJECTIVE: Guanylate binding protein-1 (GBP1) is highly associated with cell proliferation, and can modulate growth and invasiveness of gliomas. The relationship between GBP1 expression and the prognosis of glioma patients is further evaluated for the purpose of investigating whether GBP1 can serve as an predictor for evaluating prognosis of glioma patients. METHODS: GBP1 expression in 528 glioblastoma multiforme (GBM) patients of The Cancer Genome Atlas (TCGA) database were investigated, then 103 surgical specimens from glioma patients in our center were further evaluated. The effect of GBP1 on proliferation, invasion and migration of glioma cells in vitro was analyzed, and the effects of GBP1 on sensitivity of radiotherapy and chemotherapy on glioma cells in vitro were also analyzed. GBP1 associated signaling pathways were identified with Gene Set Enrichment Analysis (GSEA). Besides, the effect of GBP1 expression on proliferation of glioma cells in vivo was analyzed. RESULTS: In both TCGA database and our clinical data, GBM tissues exhibited increased mRNA expression of GBP1 gene, its expression level was co-related to PETN deletion and EGFR amplification, and was associated with prognosis of GBM patients. GBP1 overexpression can enhance migration and invasion ability of tumor cells in vitro, and in vivo studies showed that GBP1 can promote tumor proliferation, decrease survival in tumor-bearing mice. GSEA analysis predicted that GBP1 may play its biological roles via toll-like receptor pathway. CONCLUSION: This study provides new insights and evidences that high level expression of GBP1 is significantly correlated with progression and prognosis in GBMs. Furthermore, transfection of GBP1 revealed its regulation on migration and invasiveness of glioma cells, decreasing sensitivity of chemotherapeutic agent, shortening survival of tumor-bearing animals. These data demonstrate that GBP1 may serve as a novel prognostic biomarker and a potential therapeutic target for gliomas. PMID- 29991125 TI - Activation of PI3K/AKT is involved in TINAG-mediated promotion of proliferation, invasion and migration of hepatocellular carcinoma. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy that has a poor prognosis. Through the literatures, TINAG significantly participated in the processes of the renal-associated diseases, but there were no studies about the roles of TINAG in the HCC development. Hence, we attempted to use the HCC samples collected by ourselves to reveal the clinical significance and prognostic impact of TINAG in HCC. METHODS: We first measured the expression level of TINAG in HCC on the basis of TCGA database. Then, real time quantitative reverse transcription PCR (RT-qPCR) was used to examine the expression level of TINAG in 100 pairs of HCC tissues and corresponding adjacent non-tumor tissues, as well as HCC cell lines (HepG2, HB611, HHCC, and Hep3B). Moreover, Kaplan-Meier method and COX's proportional hazards model were utilized to perform the survival and prognosis analyses using the clinical data collected by ourselves. After knockdown of TINAG, the cell proliferation, invasion and migration capacities of HepG2 and Hep3B cells were evaluate by counting kit-8 (CCK-8) assay (24 h, 48 h, 72 h, and 96 h post-cultivation), clone formation experiment, would-healing, and invasion as well as migration assays. To further explore whether the dys regulated TINAG expression regulates the HCC progression and prognosis, protein biomarkers of PI3K signaling pathway, including AKT, p-AKT, PI3K, p-PI3K, p70S6K, and p-p70S6K were measured based on western blotting analysis. RESULTS: According to the data of TCGA database, clinical patients, and HCC cell lines, TINAG was highly expressed in HCC compared with normal. Relationship of TINAG expression level with the clinicopathological factors implicated that the high expression of TINAG was significantly associated with pathologic stage, pathologic-node, and pathologic-metastasis. Univariate as well as multivariate COX analysis indicated that TINAG expression and pathologic metastasis can serve as the independent prognostic factor for overall survival of HCC. After TINAG knockdown in HepG2 and Hep3B cells, cell proliferation rate, the colony numbers, and the invasive and migratory capacity were found to be suppressed. Remarkably, western blot results showed that reduction of TINAG remarkably decreased p-AKT, p-PI3K, and p-p70S6K expression level in HepG2 and Hep3B cells. CONCLUSION: Collectively, our results underscore the significance of TINAG in HCC progression and prognosis, and TINAG might be a novel candidate oncogene in HCC. These results propose that targeting TINAG might offer future clinical utility in HCC. PMID- 29991126 TI - Investigation of IL-33 serum levels in patients with benign and malignant salivary gland tumors. AB - BACKGROUND: Interleukin-33 (IL-33) has been recently discovered as an influential factor in the process of tumor immunity, and is presented in cancer pathogenesis. OBJECTIVE: This study aimed to determine the serum levels of IL-33 in patients with benign and malignant Salivary gland tumors (SGTs). METHODS: This descriptive cross-sectional study was performed on 47 samples of malignant SGTs including 18 mucoepidermoid carcinoma (MEC), 8 adenoid cystic carcinoma (ADCC), 21 malignant mixed tumor (MMT), and 14 benign pleomorphic adenoma (PA). A control group was considered consisting of 28 healthy subjects. The serum level of IL-33 was measured by using sandwich ELISA method. The data were statistically analyzed through Kruskal-Wallis and Mann-Whitney tests. RESULTS: The median concentration of IL-33 was 6.91 in malignant, 5.14 in benign, and 5.01 in healthy cases, with a statistically significant difference (P= 0.001). The median serum levels of IL-33 increased significantly in ADCC (7.15), MEC (7.03), and MMT (6.91) compared with the control group (5.01) (P< 0.05). The mean rank of MEC was significantly higher than PA (P= 0.01). IL-33 concentration was positively and significantly correlated with the tumor stage (P= 0.02) and tumor size (P= 0.03). CONCLUSIONS: IL-33 could be suggested as a novel biomarker to distinguish different types of SGTs. PMID- 29991127 TI - An eight-miRNA signature expression-based risk scoring system for prediction of survival in pancreatic adenocarcinoma. AB - PURPOSE: The purpose of this study was to establish a risk scoring system based on miRNAs to evaluate the prognosis in pancreatic adenocarcinoma. METHODS: Using a miRNA microarray dataset (179 pancreatic adenocarcinoma specimens and 4 normal control specimens) from TCGA, differentially expressed miRNAs were identified. Cox proportional hazards regression analysis was used to identify significant prognostic miRNAs, with which a risk scoring system was established and tested on a validation set. Cox regression analysis was performed to identify independent predictors of survival from clinical characteristics. Stratified Cox regression analyses were conducted to unravel the associations of clinical characteristics with survival. Differentially expressed genes (DEGs) were screened followed by functional annotation of the DEGs. RESULTS: Eight miRNAs (miR-1301, miR-598, miR 1180, miR-155, miR-496, miR-203, miR-193b, miR-135b) were independent predictors for survival. A risk scoring system was established with the 8 signature miRNAs. Upon Cox multivariate regression analysis, risk score, new tumor and targeted molecular therapy were independent predictors of prognosis. Stratified Cox regression analyses found that targeted molecular therapy and new tumor are associated with survival of patients. Survival-related DEGs were significantly enriched with regulation of transforming growth factor beta receptor, potassium ion transport and MAPK signaling pathway. CONCLUSIONS: The study proposes 8-miRNA expression-based risk scoring system to predict prognosis in pancreatic adenocarcinoma. New tumor and targeted molecular therapy were independent predictors of prognosis. Transforming growth factor beta receptor, potassium ion transport and MAPK signaling pathway may be related to prognosis in pancreatic adenocarcinoma. PMID- 29991128 TI - Identification of long noncoding RNAs biomarkers in patients with hepatitis B virus-associated hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancer worldwide and chronic infection of hepatitis B virus (HBV) serve as one of leading causes of HCC. OBJECTIVE: This study aimed to identify the novel long noncoding RNAs (lncRNAs) biomarkers for HBV-associated HCC. METHODS: The lncRNA and mRNA expression profiles of HCC patients with HBV infection were downloaded from The Cancer Genome Atlas. The differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) between HCC and adjacent tissues were identified. The optimal diagnostic and prognostic lncRNA biomarkers for HCC were identified by using feature selection procedure and classification model. Functional annotation of DEmRNAs co-expressed with these lncRNAs biomarkers were performed. Receiver operating characteristic (ROC) curve and survival analysis of these lncRNAs biomarkers were performed. qRT-PCR validation was performed. RESULTS: A total of 82 DElncRNAs and 805 DEmRNAs between HBV associated HCC and normal tissues were identified. CAPN10-AS1, LINC01093, RP5 890E16.2, FENDRR and C17orf82 were selected as optimal diagnostic and prognostic lncRNA biomarkers for HBV-associated HCC that were co-expressed with 105, 86, 70, 30 and 1 DEmRNAs, respectively. Based on the DEmRNAs co-expressed with these five lncRNAs biomarkers, Jak-STAT signaling pathway and retinol metabolism were two significantly enriched pathways. The result in qRT-PCR validation were consistent with our analysis based on TCGA, generally. CONCLUSIONS: This study identified five potential lncRNAs biomarkers for HBV-associated HCC with great diagnostic and prognostic value and provided clues for their functions in HBV-associated HCC. PMID- 29991129 TI - MicroRNA-185 inhibits cell proliferation while promoting apoptosis and autophagy through negative regulation of TGF-beta1/mTOR axis and HOXC6 in nasopharyngeal carcinoma. AB - OBJECTIVE: Accumulating studies have revealed that microRNAs (miRs) play a critical role in the development and progression of nasopharyngeal carcinoma (NPC), which is a disease with a remarkable racial and geographical distribution. In our study, through the alteration in the expression of microRNA-185 (miR-185) in NPC cells by microarray-based gene expression profiling, we subsequently evaluated its ability to influence NPC cells and associated mechanism. METHODS: The expressions of miR-185 and HOXC6 in NPC and paracancerous tissues collected from patients with NPC were detected. The CNE-2 cells with the lowest miR-185 among the five NPC cell lines (CNE-1, CNE-2, HNE-1, HNE-2, and 5-8F) were selected and transfected with a series of mimic or inhibitor of miR-185, or shRNA against HOXC6. The Kaplan-Meier method was used to analyze the survival of patients. Besides, the reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to determine the levels of related genes/proteins. By means of cell counting kit-8 (CCK-8) assay, transwell assay, flow cytometry, and AO staining, the influences miR-185 has on the processes associated with NPC, including cell proliferation, invasion, apoptosis and autophagy were evaluated. RESULTS: NPC was observed to decrease miR-185 but increase HOXC6. Dual luciferase reporter gene assay demonstrated that HOXC6 is a target gene of miR-185. Increased mRNA and protein levels of Bax, caspase-3, LC3 and Beclin1 and reduced levels of HOXC6, TGF-beta1, mTOR, Cyclin D1, PCNA, Bcl-2 were found by overexpression of miR-185. High expression of miR-185 and low expression of HOXC6 had longer survival time of NPC patients. Overexpressed miR 185 enhanced cell apoptosis and autophagy, and reduced cell proliferation and invasion, while miR-185 inhibitor was observed to have induced effects on the CNE 2 cells. CONCLUSION: Overall, the data show that miR-185 could negatively target HOXC6 to suppress cell proliferation, promotes apoptosis and autophagy through inhibiting TGF-beta1/mTOR axis in NPC. Thus, miR-185 is useful strategy for the treatment of NPC. PMID- 29991130 TI - Aberrant methylation of PCDH17 gene in high-grade serous ovarian carcinoma. AB - BACKGROUND: Aberrant DNA methylation of protocadherins (PCDHs) has been associated with development and progression of various types of cancer. It could represent possible direction in the search for critically needed tumor biomarkers for ovarian cancer. OBJECTIVE: To investigate methylation of delta2 group of non clustered PCDHs in high-grade serous ovarian carcinoma (HGSOC) tissue in comparison with control tissue. METHODS: We used next-generation sequencing for detecting regions with the most altered methylation. For further confirmation of discovered alterations we used methylation-sensitive high-resolution melting analysis. RESULTS: PCDH17 methylation was detected in almost 70% of HGSOC patients without any methylation in the group of control samples and was found both in the late stage tumors as well as in the early stage ones. Other selected PCDHs did not show any relevant changes in methylation. Subsequent gene expression analysis of PCDH17 revealed decreased expression in all of the tumor samples in comparison to the control ones. Statistically significant negative correlation was found between methylation and levels of expression suggesting potentially methylation-based silencing. CONCLUSIONS: Methylation of PCDH17 could play an important role in development and progression of HGSOC and has potential to become a target in the search for new clinical biomarkers. PMID- 29991131 TI - The Effects of Music Therapy on Cognition, Psychiatric Symptoms, and Activities of Daily Living in Patients with Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is the most common type of dementia, affecting millions of older people worldwide. However, pharmacological therapies have not achieved desirable clinical efficacy in the past decades. Non pharmacological therapies have been receiving increased attention to treat dementia in recent years. OBJECTIVE: This study explores the effects of music therapy on cognitive function and mental wellbeing of patients with AD. METHODS: A total number of 298 AD patients with mild, moderate, or severe dementia participated in the study. The participants with each grade of severity were randomly divided into three groups, which were a singing group, a lyric reading group, and a control group. These three groups received different interventions for three months. All participants underwent a series of tests on cognitive functions, neuropsychological symptoms, and activities of daily living at baseline, three months, and six months. RESULTS: The analysis shows that music therapy is more effective for improving verbal fluency and for alleviating the psychiatric symptoms and caregiver distress than lyrics reading in patients with AD. Stratified analysis shows that music therapy is effective for enhancing memory and language ability in patients with mild AD and reducing the psychiatric symptoms and caregiver distress in patients with moderate or severe AD. However, no significant effect was found for activities of daily living in patients with mild, moderate, or severe AD. CONCLUSION: This study suggests that music therapy is effective in enhancing cognitive function and mental wellbeing and can be recommended as an alternative approach to manage AD associated symptoms. PMID- 29991132 TI - Age-Dependent Changes in the Sarkosyl-Insoluble Proteome of APPSWE/PS1DeltaE9 Transgenic Mice Implicate Dysfunctional Mitochondria in the Pathogenesis of Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-beta (Abeta) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity. OBJECTIVE: This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE/PS1DeltaE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD. METHODS: Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ). RESULTS: The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype induced effects. In addition to Abeta and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function. CONCLUSION: The results of this study implicate dysfunctional mitochondria as playing a key role of Abeta- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD. PMID- 29991133 TI - The Use of Mobile Games to Assess Cognitive Function of Elderly with and without Cognitive Impairment. AB - BACKGROUND: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients. OBJECTIVE: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly. METHODS: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20- 24]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with MMSE and the Addenbrooke's Cognitive Evaluation revised (ACE-R). RESULTS: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively). CONCLUSION: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30. PMID- 29991135 TI - EEG Theta Power Is an Early Marker of Cognitive Decline in Dementia due to Alzheimer's Disease. AB - BACKGROUND: Quantitative EEG (qEEG) power could potentially be used as a diagnostic tool for Alzheimer's disease (AD) and may further our understanding of the pathophysiology. However, the early qEEG power changes of AD are not well understood. OBJECTIVE: To investigate the early changes in qEEG power and the possible correlation with memory function and cerebrospinal fluid biomarkers. In addition, whether qEEG power could discriminate between AD, mild cognitive impairment (MCI), and older healthy controls (HC) at the individual level. METHODS: Standard EEGs from 138 HC, 117 MCI, and 117 AD patients were included from six Nordic memory clinics. All EEGs were recorded consecutively before the diagnosis and were not used for the consensus diagnosis. Absolute and relative power was calculated for both eyes closed and open condition. RESULTS: At group level using relative power, we found significant increases globally in the theta band and decreases in high frequency power in the temporal regions for eyes closed for AD and, to a lesser extent, for MCI compared to HC. Relative theta power was significantly correlated with multiple neuropsychological measures and had the largest correlation coefficient with total tau. At the individual level, the classification rate for AD and HC was 72.9% for relative power with eyes closed. CONCLUSION: Our findings suggest that the increase in relative theta power may be the first change in patients with dementia due to AD. At the individual level, we found a moderate classification rate for AD and HC when using EEGs alone. PMID- 29991134 TI - Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576. AB - BACKGROUND: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. OBJECTIVE: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. METHODS: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. RESULTS: Both the APP/PS1 model at 8 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. CONCLUSION: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition. PMID- 29991136 TI - What Factors Predict Family Caregivers' Attendance at Dementia Cafes? AB - BACKGROUND: Dementia Cafes are community support groups which provide post diagnostic support for families affected by dementia. However, little is known about the characteristics of caregivers who attend Cafes. OBJECTIVES: To describe the demographic and psychosocial characteristics of caregivers who attend Dementia Cafes, and to identify which of those factors may influence the likelihood of family caregivers attending Dementia Cafes. METHODS: A cross sectional study on caregivers (n = 80; July 2016- July 2017). Resilience (Brief Resilient Coping Scale), Subjective Wellbeing (Personal Wellbeing Index), and Social Support (MOS-Social Support Survey) were measured. Cafe attendees and non attendees were compared in regards to demographic characteristics (Chi-Square tests), resilience, subjective wellbeing and social support (independent t tests). Bivariate and multivariate regression analyses were run to detect associations between predictor variables and cafe attendance. RESULTS: Caregivers who attended Cafes reported higher resilience (OR: 1.26; 95% CI 1.10-1.45; p = 0.001) and subjective wellbeing (OR: 1.63; 95% CI 1.24-2.142; p = 0.001); no significant difference in social support was detected. Female caregivers were more likely to attend a Cafe (OR: 3.23; 95% CI 1.14-9.10; p = 0.03). However, only higher subjective wellbeing (OR: 1.63; 95% CI 1.10-24.2; p = 0.02) and fewer years formal education (OR: 4.99; 95% CI 1.12-21.36; p = 0.03) predicted attendance at a cafe. CONCLUSION: Dementia Cafes may bring about benefits in resilience and subjective wellbeing, or may be best suited to those with higher resilience and wellbeing. Cafes are not being accessed by all caregiver groups. Alternative models of post-diagnostic support should be considered to increase equity of care. PMID- 29991137 TI - The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-beta Neurotoxicity in CB2R-/- Mice. AB - Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-beta (Abeta) plays a pivotal role in Abeta accumulation and type-2 cannabinoid receptor (CB2R) participates in Abeta processing in the brain; however, the underlying mechanisms remain unclear. We determined that Abeta degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Abeta level is significantly enhanced in CB2R-/ -Abeta1 - 42 mice compared with that of WT-Abeta1 - 42 mice. Furthermore, Abeta mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Abeta1 - 42 mice than that in WT-Abeta1 - 42 mice. CB2R activation could decrease Abeta1 - 40 and Abeta1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AbetaPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Abeta degradation and aggravates the toxicity of Abeta via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD. PMID- 29991138 TI - Neuroepigenetics and Alzheimer's Disease: An Update. AB - Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence-a change in phenotype without a change in genotype-which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA) associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer's disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely, non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD. PMID- 29991139 TI - BON CONFERENCE ABSTRACTS, 11-13 July 2018, Downing College, Cambridge University, UK. PMID- 29991140 TI - Virtual Reality Computer Gaming with Dynamic Arm Support in Boys with Duchenne Muscular Dystrophy. AB - BACKGROUND: In boys with Duchenne muscular dystrophy (DMD), loss of upper limb function becomes more evident after the onset of wheelchair-dependency, because of the inability to lift the arms against gravity. With an increasing population of older wheelchair-dependent boys with DMD it is worthwhile to know whether training can delay the loss of upper limb functions. Dynamic arm supports may enable boys with impaired arm function to train their muscles without becoming exhausted by providing external mechanical compensation for muscle weakness. OBJECTIVE: This study investigated the effect of gravity-compensated 3D-training for the arms on the functional abilities in boys with DMD. METHODS: An explorative RCT was conducted among boys with DMD with impaired arm function (n = 16). Boys in the intervention group (n = 7) trained their arms by playing virtual reality games while using dynamic arm support during 20 weeks. The primary endpoint was the difference in change in Performance of the Upper Limb (PUL) score between the intervention and control group (n = 9) after 20 weeks. Secondary outcome measures were at the different ICF-CY levels. RESULTS: No significant group differences were found for the PUL. Elbow range of motion (p = 0.018) and extension strength (p = 0.038) improved in the intervention group and worsened in the control group. CONCLUSIONS: Although this study did not show a significant effect of training on the primary outcome measure, there are indications that training may decline the loss of range of motion and strength. This may prolong the functional abilities on long-term. TRIAL REGISTRATION: Netherlands Trial Register 3857. PMID- 29991142 TI - Coexistence of Kasabach-Merritt Syndrome and placental chorioangioma in a premature infant. AB - Kasabach-Merritt syndrome is a rare life-threatening clinical presentation in neonatal period. it is characterized by giant hemangioma and serious thrombocytopenia. The diagnostic criteria include: 1) hemangiomas on skin, 2) thrombocytopenia or coagulopathy, 3) hemangioma on internal organs diagnosed by ultrasonography, computed tomography or magnetic resonance imaging, and 4) excluding reasons, such as idiopathic thrombocytopenic purpura or hypersplenism.Placental chorioangiomas are the most widespread non-trophoblastic benign tumor-like lesions of placenta. The clinical signs are associated with tumor size. Chorioangiomas larger than 4-5 cm may lead to various maternal and fetal complications.Here, a female premature infant was diagnosed with placental chorioangioma and liver hemangioma during antenatal period. She developed heart failure secondary to non-immune hydrops fetalis in the neonatal period. The atypical giant hemangioma and coagulopathy suggested the diagnosis of Kasabach Merritt syndrome. The macroscopic and histopathological examination of the placenta confirmed the diagnosis of chorioangioma. The patient died due to purpura fulminans despite the treatment with prednisolone and propranolol that was started on the second day of life. We are presenting this rare case where placental chorioangioma leading to non-immune hydrops fetalis co-existed with Kasabach-Merritt syndrome. PMID- 29991143 TI - Severity of hypoxic ischemic encephalopathy correlates with increased expression of angiogenin in neonates. AB - BACKGROUND: Angiogenin is a small protein encoded by the ANG gene. It is activated by tissue hypoxia, and is known to be a potent stimulator of angiogenesis. The role of angiogenic factors in the pathogenesis of HIE is poorly understood, yet, angiogenin may be part of the molecular mechanisms underlying HIE. OBJECTIVE: Our objective was to explore the predictive value of angiogenin as a biochemical marker in early hypoxic ischemic encephalopathy staging. STUDY DESIGN: We prospectively studied 36 full term HIE neonates and 20 non- asphyxia neonates. Cord blood samples from all subjects immediately at delivery were withdrawn. Neurological examination and grading of HIE were performed during the first day of life. RESULTS: Concentrations of cord blood angiogenin were increased in infants with asphyxia when compared txht o controls (P = 0). Within the asphyxia group, the median cord blood angiogenin was significantly higher in stage III encephalopathy patient compared to stage I and stage II (p = 0). There was a negative correlation between pH, HCo3 level and angiogenin in stage II and stage III. CONCLUSION: Angiogenin helps in assessing the severity of HIE in neonates and is promising marker predicting the stage of hypoxia-ischemia so treatment may be initiated earlier. PMID- 29991141 TI - Parkinson's Disease and Melanoma: Co-Occurrence and Mechanisms. AB - Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa. PMID- 29991145 TI - Abstracts of the 26th European Workshop on Neonatology, September 2-5, 2018, Cappadocia, Turkey. PMID- 29991144 TI - Distribution, antimicrobial resistance and predictors of mortality in neonatal sepsis. AB - OBJECTIVE: The aim of this study is to investigate etiological agents, patterns of antimicrobial resistance and predictors of mortality in culture proven neonatal sepsis. METHOD: This is a twenty-four month retrospective cohort study of infants with culture proven sepsis. Demographic data, type of isolates and its sensitivity pattern were recorded. Multidrug resistant gram-negative isolates were defined as resistance to any three of five antibiotic classes: extended spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones and piperacillin-tazobactam. RESULT: A total of 183 case with culture positive sepsis were identified. Early onset sepsis occurred in 59% of cases. The majority of isolates (56.2%) were gram-positive but the most common individual isolates were klebsiella spp. (31.1%), Staphylococcus aureus (24.5%) and coagulase-negative staphylococci (CONS) (22.9%). The pathogen mix in early-onset did not differ from late-onset sepsis. High rates of multidrug resistance were observed in klebsiella spp. (49.1%), Escherichia coli (50%), citrobacter spp (50%), acinetobacter spp. (28.5%), pseudomonas spp. (100%) isolates. Methicillin resistance prevailed in 16.6% of coagulase-negative staphylococci, 24.4% of Staphylococcus aureus and 62.5% of enterococcus spp. Multivariate analysis revealed invasive ventilation and early onset sepsis to be independently associated with increased risk of mortality in contrast to breast milk feeding which is associated with decreased risk of mortality. CONCLUSION: A high degree of antimicrobial resistance underscores the need to understand the pathogenesis of resistance, curtail the irrational prescription of antibiotics in neonates and the requirement for measures to prevent it in low-income and middle-income countries. PMID- 29991146 TI - Been there, done that, so what's next for arm and hand rehabilitation in stroke? AB - BACKGROUND: The extraordinary advances in technology such as body-worn sensors, health information technologies, technological advances in neuroimaging, and computational approaches to predictive modelling using biomarkers offers considerable promise to literally transform our thinking, our approach to the problem, and the design of future clinical trials about arm and hand rehabilitation after stroke. OBJECTIVE: To provide a focused review that considers the past, present and future of arm and hand rehabilitation in stroke. METHOD: We organized this perspective into three parts: 1) Past- we summarize the past decade of the clinical trial enterprise in neurorehabilitation, 2) Present- we provide a brief review of three research areas where mechanistic studies that rely on uniquely human neural circuits provide a basis for promising intervention tools, and 3) Future-we highlight three unique research domains that are likely to provide the biggest impact on the future of post-stroke arm and hand recovery. RESULTS: The past has not been a complete failure- in particular, the EXCITE RCT put arm and hand rehabilitation on the map. Unfortunately, the majority of clinical trials that followed were based on an immature science of neurorehabilitation. We got drawn in by the seductive preclinical animal model work which suggested that dose and intensity of task-oriented training was the most important ingredient for fostering recovery in humans. While dose, and intensity are clearly important, they are of little value unless the stroke survivor is engaged, motivated, and the neural infrastructure provides enough resource to allow the recovery process. Recently, we noticed an increase in mechanistic and theory-driven studies, findings from which will not only advance our understanding of critical brain-behavior mechanisms, but will provide a more mature science moving into the future. CONCLUSIONS: The good news is that there is evidence that we learned from the past and have invented a future that appears to be much more exciting and promising than the past. PMID- 29991147 TI - Brain network topology influences response to intensive comprehensive aphasia treatment. AB - BACKGROUND: Recent imaging studies indicate that aphasia is associated with large scale reorganization of brain networks. Today, neuroimaging studies show that various brain connectivity properties, as measured by resting state fMRI, can partially explain different behavioral symptoms in and across various patient groups. Despite these observations, the neural networks underlying the progress and recovery of aphasia following intensive treatment remains relatively obscure. OBJECTIVE: To examine the role of brain network properties in determining recovery of aphasia following intensive therapy in stroke patients. METHODS: We studied eight patients with left hemispheric lesions who completed an intensive comprehensive aphasia program (ICAP). Language and cognition were assessed before and after four weeks of intensive treatment. In addition, all patients underwent resting state fMRI prior to and after treatment. We used graph theory analysis to evaluate relationships of baseline brain network properties, such as efficiency, modularity, and connectivity to clinical improvements. RESULTS: We found global properties such as efficiency and interhemispheric connectivity could partially explain recovery. More importantly, we identified two unique brain networks that are significantly associated with improvement in language and attention related behavior. CONCLUSIONS: These results suggest baseline brain functional properties play a key role in determining responsiveness of patients with aphasia to intensive comprehensive aphasia treatment. Furthermore, these results indicate that brain mechanisms underlying language comprehension and processes are different from those involved in spatial attention. PMID- 29991148 TI - Low variable rate stimulation strategy for cochlear implants using temporal cues and electrophysiological factors. AB - BACKGROUND: The performance of a cochlear implant (CI), especially in conveying pitch depends on its electrical stimulation strategy. OBJECTIVE: The present study proposes a variable-rate stimulation algorithm which improves speech emotion perception by using temporal fine-structure cues and electrophysiological parameters of the patient. METHODS: This method is based on the coding of the phase information at the peak time intervals of the band-passed signals. The stimulation pulse is generated at the time of peak occurrence, which is able to excite the number of fibers with a discharge probability above a threshold. Calculating the discharge probability is based on the excitable fiber model and taking into account the biological characteristics of the patient, such as the fiber threshold and the distribution of remaining intact fibers. RESULTS: The results of the emotion detection test on selective reconstructed sentences from the Persian emotional speech database (Persian ESD) indicated that the listeners have been able to detect the emotion by an average of 83.82% using the proposed stimulation algorithm while it was 75% and 48.03% for the zero-crossing and the continuous interleaved sampling (CIS), respectively. Furthermore, the number of pulses compared to the zero-crossing and the CIS has decreased by 76.3% and 75.4%, respectively. CONCLUSIONS: In this paper, a stimulation method was proposed for cochlear implants by considering the patient's biological parameters. It has been successful in transmitting speech emotion despite the reduction of stimulating pulses. This has some advantages such as reducing the interaction of current fields between electrodes during stimulation and reducing battery usage. PMID- 29991149 TI - Diagnosing periprosthetic hip joint low-grade infection via arthroscopic neo synovium biopsies. AB - BACKGROUND: There is currently a lack of consensus regarding the most effective diagnostic algorithm for cases of supposed low-grade infection after total hip arthoplasty (THA). OBJECTIVE: The aim of this study was to assess reliability in the use of biopsies, obtained by hip arthroscopy, to detect a periprosthetic hip joint infection (PJI). METHODS: From 2012 to 2016, diagnostic arthroscopy of the hip joint was performed in 20 patients with a supposed PJI following THA. In 10 of these patients, the THA was revised for various reasons after diagnostic arthroscopy. The microbiological and histological findings of the biopsies obtained by arthroscopy were compared to findings from intraoperative samples of the revision arthroplasty. RESULTS: For arthroscopic biopsies, we detected a sensitivity of 1.00 (95% confidence interval [CI] 0.40-1.00), a specificity of 0.83 (95% CI 0.36-1.00), a positive predictive value of 0.80 (95% CI 0.28-1.00), and a negative predictive value of 1.00 (95% CI 0.48-1.00). The accuracy was 0.90. CONCLUSIONS: The analysis of arthroscopic biopsies represents a helpful tool to verify or rule out a PJI in selected patients. Nevertheless, minimally invasive diagnostic tools (e.g., laboratory analysis and aspiration) should be utilized beforehand. PMID- 29991150 TI - Changes in trunk sway and impairment during sitting and standing in children with cerebral palsy. AB - BACKGROUND: Poor postural control constitutes a major impairment in children with cerebral palsy (CP), compromising everyday activities such as sitting- and standing-position. PURPOSE: In this study, we measured trunk sway during sitting- and standing-position. Additionally, we assessed trunk control ability using the trunk impairment scale (TIS), trunk control measurement scale (TCMS), and sitting assessment test for children with neuromotor dysfunction (SACND), in children with CP. METHODS: Fifteen children (10 boys and 5 girls) were recruited for this study. Trunk sway was measured using a triaxial accelerometer that recorded variation in movement acceleration during quiet sitting- and standing-position. RESULTS: Anterior-posterior (AP) acceleration was significantly greater in the standing position than the sitting position (p= 0.001). Medio-lateral (ML) acceleration was significantly greater in the standing position than in the sitting position (p= 0.012). The TIS total score showed a moderate negative relationship with AP acceleration (r=-0.635, p= 0.011). The TCMS total score moderately and negatively correlated with AP acceleration (r=-0.582, p= 0.023). The SACND total score moderately and positively correlated with AP acceleration (r= 0.670, p= 0.006). CONCLUSION: Measurement of trunk sway using a triaxial accelerometer revealed a moderate correlation with trunk control test data and excellent reliability. Our findings suggest that measurement of trunk sway using a triaxial accelerometer is not time-consuming, and is simple and easy. Our approach can be applied in clinical settings to gain information on trunk control in children with CP. PMID- 29991151 TI - A support vector machine approach to detect trans-tibial prosthetic misalignment using 3-Dimensional ground reaction force features: A proof of concept. AB - BACKGROUND: Prosthetists conventionally evaluate alignment based on visual interpretation of patients' gait, which is convenient, but largely subjective and depends on prosthetists' experience. OBJECTIVE: In this paper, we explore the feasibility of using a support vector machine (SVM) approach to automatically detect misalignment of trans-tibial prostheses through ground reaction force (GRF). METHODS: Alternate classification algorithms with varying kernels and feature sets were compared to assess the suitability for detection of a representative misalignment (six degrees of ankle plantar flexion) from normal alignment. A classical feature selection algorithm, Fisher Score, was further introduced to identify valuable features and reduce the dimension of feature sets. RESULTS: The SVMs achieved a detection accuracy of 96.67% at best within the same subject and 88.89%, respectively, for inter-subject. Combined horizontal and vertical components of GRF features provided the maximum detection accuracies. Propulsion peak force was identified as key variable of gait for misalignment prediction. CONCLUSIONS: As a proof of concept, the results demonstrate potential in applying this approach to detect prosthetic misalignment based on gait patterns, and is a step towards future developments of tools for early prevention of misalignment in clinical. PMID- 29991152 TI - Analytical expressions for the reconstructed image of a homogeneous cylindrical sample exhibiting a beam hardening artifact in X-ray computed tomography. AB - BACKGROUND: Cylindrical phantoms are often imaged by X-ray computed tomography (CT) to evaluate the extent of beam hardening (or cupping artifact) resulting from a polychromatic X-ray source. OBJECTIVE: Our goal was to derive analytical expressions for the reconstructed image of a homogeneous cylindrical phantom exhibiting a cupping artifact, to permit a quantitative comparison with experimental cupping data. METHODS: A filtered backprojection method was employed to obtain the analytical cupping profile for the phantom, assuming that the projection data could be approximated as a power series with respect to the sample penetration thickness. RESULTS: The cupping profile was obtained analytically as a series of functions by employing Ramachandran filtering with an infinite Nyquist wavenumber. The quantitative relationship between the power series of the projection and the nth moment of the linear attenuation coefficient spectrum of the phantom was also determined. Application of the obtained cupping profile to the evaluation of the practical reconstruction filters with a finite Nyquist wavenumber and to the best choice of the contrast agent was demonstrated. CONCLUSIONS: The set of exact solutions derived in this work should be applicable to the analysis of cylindrical phantom experiments intended to evaluate CT systems. PMID- 29991153 TI - Joint regularization-based image reconstruction by combining data-driven tight frame and total variation for low-dose computed tomography. AB - Since the excessive radiation dose may induce potential body lesion, the low-dose computed tomography (LDCT) is widely applied for clinical diagnosis and treatment. However, the dose reduction will inevitably cause severe noise and degrade image quality. Most state-of-the-art methods utilize a pre-determined regularizer to account for the prior images, which may be insufficient for the most images acquired in the clinical practice. This study proposed and investigated a joint regularization method combining a data-driven tight frame and total variation (DDTF-TV) to solve this problem. Unlike the existing methods that designed pre-determined sparse transform for image domain, data-driven regularizer introduced a learning strategy to adaptively and iteratively update the framelets of DDTF, which can preferably recover the detailed image structures. The other regularizer, TV term can reconstruct strong edges and suppress noise. The joint term, DDTF-TV, collaboratively affect detail preservation and noise suppression. The proposed new model was efficiently solved by alternating the direction method of the multipliers. Qualitative and quantitative evaluations were carried out in simulation and real data experiments to demonstrate superiority of the proposed DDTF-TV method. Both visual inspection and numerical accuracy analysis show the potential of the proposed method for improving image quality of the LDCT. PMID- 29991154 TI - Increased separability of K-edge nanoparticles by photon-counting detectors for spectral micro-CT. AB - BACKGROUND: X-ray CT/micro-CT methods with photon-counting detectors (PCDs) and high Z materials are a hot research topic. One method using PCDs allows for spectral imaging in 5 energy windows while conventional X-ray detectors only collect energy-integrating data. OBJECTIVE: To demonstrate the enhanced separation of contrast materials by using PCDs, multivariate analysis, and linear discriminant methods. METHODS: Phantoms containing iodine and aqueous nanomaterials were scanned on a MARS spectral micro-CT. Image volumes were segmented into separate material-specific populations. Contrast comparisons were made by calculating T2 test statistics in the univariate, pseudo-conventional and multivariate, spectral CT data sets. Separability after Fisher discriminant analysis (FDA) was also assessed. RESULTS: The T2 values calculated for material comparisons increased as a result of the spectral expansion. The majority of the tested contrast agents showed increased T2 values by a factor of ~2 -3. The total significant T2 statistics in the pure and mixed lanthanide image sets increased in the spectral data set. CONCLUSION: This work consolidates the groundwork for photon-counting-based material decomposition with micro-CT, facilitating future development of novel nanomaterials and their preclinical applications. PMID- 29991155 TI - The effects of dentoalveolar distraction extraction on alveolar ridge preservation: Cone-beam computed tomography and X-ray analysis in canine model. AB - OBJECTIVE: This study aims to evaluate the effect of dentoalveolar distraction extraction (DDE) on site preservation, and to evaluate how the technique keeps the height and width of alveolar bones to a greater extent. METHODS: 12 beagle dogs, randomly divided into three groups (DDE group, NH group, BOG group), were used. In the dogs of three groups, the root of the left or right third mandibular premolars were respectively extracted by three methods namely, DDE, traditional extraction with natural healing, and traditional extraction with Bio-Oss bone dust implanted and guided bone regeneration (GBR). Cone-beam computed tomography (CBCT) scans and X-rays were taken immediately and three months after the tooth extraction. The height and width of the alveolar ridges were compared among different groups. RESULTS: Three months after tooth extraction, at the 1 mm level below the alveolar ridge crest, the amount and degree of buccal alveolar ridge width resorption in DDE group were significantly lower than that of NH and BOG group (P < 0.05). At the 2 mm and 3 mm level below the alveolar ridge crest, the amount and degree of buccal alveolar ridge width resorption in DDE group and BOG had no significant difference, and both were significant lower than that of NH group (P < 0.05). The height resorption of alveolar ridge in DDE group was significantly lower than NH and BOG groups (P < 0.05), while NH and BOG group had no statistically significant. CONCLUSIONS: To a greater extent, the alveolar ridge preservation through DDE could preserve the height and width of alveolar ridge crest. PMID- 29991156 TI - A study on the characteristics of mobile X-ray device using supercapacitor as internal power. AB - Mobile X-ray device is widely employed because it is useful for diagnosis in patients having mobility difficulties and in medical emergencies. As various devices for X-ray generation have continued to be developed, X-ray devices can now be used more safely and effectively. However, mobile X-ray devices generate relatively low X-ray doses due to the limitation of the power input. Therefore, the use of mobile X-ray devices is limited to thin parts of body. In this study, a new device was designed in order to increase the usefulness of mobile X-ray devices by offsetting the weaknesses of the existing mobile X-ray devices, rendering them useable independently. A supercapacitor and battery were used as the internal power source for the X-ray generation in the manufactured device. The pulse width modulation (PWM) method is applied to control the tube voltage and current required for generating the X-ray, and the pulse frequency modulation (PFM) method is applied to the control to generate the high voltage in order to enhance the precision and efficiency. The manufactured X-ray device was used to evaluate the control signal, frequency, and output characteristics according to changes in tube voltage and current. Based on the results of X-ray generation, it is confirmed that precise control was achieved by X-ray generation increases linearly with increasing tube voltage and tube current. This means that precise control of the manufactured mobile X-ray device is passible. In addition, the study confirmed that stable output was achieved by checking the tube voltage, tube current and exposure rate during the exposure times by high power condition. PMID- 29991157 TI - Stocking success of Scottish Atlantic salmon in two Spanish rivers. AB - A previous analysis of proportions of stocked and wild Atlantic salmon among angled fish in the Rivers Ason and Nansa in northern Spain based on the analysis of MEP-2* genotypes is extended. The results reinforce the initial conclusion that returns of stocked Scottish salmon are significantly lower than returns for wild fish. PMID- 29991158 TI - Reproductive biology, species status and taxonomic relationships of four recently discovered galaxiid fishes in a New Zealand river. AB - The reproductive biology of four recently discovered, largely allopatric non migratory Galaxias species in the Taieri River, New Zealand, was compared with the closely related Galaxias vulgaris. Timing of spawning was similar (late winter/spring) but spawning habitat, spawning behaviour and nest structure differed among the Taieri species and G. vulgaris. Patterns of fecundity also differed among the Taieri species but, with G. vulgaris, they form a distinct group of galaxiids with maxima of 800-1500 eggs having diameters of 2.3-2.8 MUn. The different spawning behaviours of the Taieri galaxiids, in particular the differences in spawning orientation, provide evidence for prezygotic isolating mechanisms and support their status as separate species. In cladistics terms, the results indicate that Galaxias anomalus, G. eldoni and G. vulgaris are sister taxa, while G. depressiceps and Galaxias sp. form a second cluster. PMID- 29991159 TI - On the life history of the lesser gurnard (Scorpaeniformes: Triglidae) inhabiting the Agulhas Bank, South Africa. AB - Growth analysis based on sectioned sagittal otoliths revealed the lesser gurnard Chelidonichthys queketti on the Agulhas Bank to be relatively fast growing and long lived, with ages of up to 7 years being recorded. Total length at age (mm) was described best by the specialized von Bertalanffy growth model as LT =306.1 (1 - e0.53(t+0.18) ). First approximations of total, natural and fishing mortality rates were determined at 0.73, 0.38 and 0.35 year-1 respectively. The adult population was male dominated with a sex ratio of 1 female: 1.2 males with the mean size of males and females being similar. The lesser gurnard is an iteroparous species with females maturing by the end of the first year of life (195 mm LT ), thereafter spawning throughout the year with reproductive activity peaking over spring and late summer. The lesser gurnard appears to exhibit similar life-history patterns to other triglid species in that it can be classified as a generalist. Generalistic life-history characteristics such as a fast growth rate, early sexual maturity at a relatively large size, a non seasonal spawning pattern, feeding on a variety of prey organisms and the ability to inhabit various substrata could all contribute to it maintaining a high biomass on the Agulhas Bank. PMID- 29991160 TI - Population dynamics of Gila trout in the Gila River drainage of the south-western United States. AB - In some small, often unstable, streams of the Gila River drainage, New Mexico, Gila trout Oncorhynchus gilae populations fluctuated numerically seasonally and annually. Few differences were noted in length-weight and size-structure comparisons, but Fulton condition index varied significantly. Time of sample and time since disturbance (natural or human-caused) were often associated with differences in condition. Other factors may include availability of prey, cannibalism, and reproductive condition. The repeatedly sampled McKnight Creek population illustrated the resilience of Gila trout populations to natural disturbances. A scouring flood in 1988 caused a >90% reduction in numbers, but, by 1992, population structure was not substantially different from that of other streams. Likewise, juvenile/adult ratio, density, and per cent large specimens (>= 200 mm total length) of most other samples were within the ranges for the McKnight Creek population. Gila trout density (no. fish min-1 electrofishing) tended to increase with higher elevation and greater drainage density (stream km catchment-1 km-2 ) but decreased with larger catchments. Information gained in this study demonstrates that a variety of factors must be considered when evaluating the relative well-being of Gila trout populations and illustrates the importance of larger, more hydrologically complex drainages to the long-term survival of Gila trout populations. PMID- 29991161 TI - Temporal patterns of resource partitioning among Cichla species in a Venezuelan blackwater river. AB - In channel and floodplain habitats of the Cinaruco River, Venezuela, Cichla temensis was more abundant and larger than C. intermedia and C. orinocensis. Seasonal variation in hydrology influenced habitat use, spawning, and predator prey interactions. The three piscivores partitioned habitat, with C. intermedia showing a strong affinity for structured habitats in the main channel during all water level fluctuations. C. orinocensis was most abundant in shallow areas with submerged structure in lagoons and, to a lesser extent, in low velocity regions of the channel, and C. temensis occupied a wide range of lotic and lentic habitats. During the low-water period, the feeding frequency and body condition of all three species declined, and this was related, in part, to preparation for spawning near the end of the low-water season. The diet of C. intermedia was least similar to its two congeners during falling and rising water. C. orinocensis and C. temensis had lowest diet overlap during the low-water conditions, the period when many individuals of these two species move into lagoons for nesting. Prey in stomachs were significantly larger during the falling-water than the rising-water period, and predation by Cichla and other large piscivores during the falling-water period may have reduced the abundance of large prey, particularly Semaprochilodus kneri. These migratory detritivorous fish were important prey for C. temensis during the falling-water period and probably contributed a substantial fraction of the annual energy intake for this species. Together, the three Cichla species consume a wide spectrum of prey from a diverse fish assemblage, but prey are subdivided based on habitat, prey type, and season. PMID- 29991162 TI - Distribution of four recently discovered galaxiid species in the Taieri River, New Zealand: the role of macrohabitat. AB - The physical features of 20 streams inhabited by four recently discovered species of allopatric, non-migratory galaxiid fishes in the Taieri River, South Island, New Zealand were examined. Significant differences in particle size frequencies, combined waterfall frequency, channel depth variation and stream width: flood channel width ratios, indicated that Galaxias anomalus lived in low gradient shallow streams whereas G. depressiceps and G. eldoni occupied low to high gradient streams with more variability in depth. Climbing ability differed significantly among the species. Their allopatric patterns of distribution were, in part, the probable consequence of the abilities of G. depressiceps and G. eldoni to colonize areas that G. anomalus could not penetrate. Historical factors and reproductive biology of the four species are hypothesized also to be causal determinants of their current distributions. PMID- 29991163 TI - Cloning and sequencing of cDNAs of the beta-globin gene family in carp. AB - A total blood cell cDNA library was constructed using a 3-year-old carp Cyprinus carpio. A beta-globin cDNA (CbetaG1) was identified from the library by the polymerase chain reaction using a beta-globin-specific primer deduced from the carp beta-globin-A amino acid sequence. Also, five additional types of beta globin cDNAs (CbetaG2~6) were isolated by colony hybridization using CbetaG1 as a probe. Sequence analysis revealed that these CbetaGs encoded 147 amino acids, and the deduced amino acid sequences showed high identity (89.1-95.2%) to previously reported carp beta-globin amino acid sequences. The nucleotide sequences of the CbetaGs were very similar (identity 96.0-99.6%) and the expression levels of CbetaG1~6 were 28.6, 28.6, 21.4, 14.3, 3.6 and 3.6% of the total number of cloned CbetaGs, respectively. Although the complete amino acid sequence identities between the CbetaGs and the beta-globin of higher vertebrates were low, functionally important regions such as the alpha-betacontact region and haem contact region were well conserved. These data showed that, as in higher vertebrates, the adult carp has a multiple beta-globin gene family (at least six members). However, transcripts encoding four types of peptides (CbetaG1 type, CbetaG2 and 3 type, CbetaG5 type, and CbetaG4 and 6 type) were expressed at relatively high levels, this being a unique character of the carp haemoglobin system. PMID- 29991164 TI - Chromosomal inheritance patterns of intergeneric hybrids of ictalurid catfishes: odd diploid numbers with equal parental contributions. AB - Hybrid chromosomal compositions of channel catfish Ictalurus punctatus* black bullhead Ameiurus melas and channel catfish * flathead catfish Pylodictis olivaris were analysed by a computer-based method. The karyotype of each hybrid was highly asymmetric, and the diploid numbers and arm numbers were intermediate to the parental types. The hybrid offspring of channel catfish * black bullhead possessed a diploid number of 59 chromosomes, with an arm number estimate of 87. The hybrid offspring of the channel catfish * flathead catfish cross possessed a diploid number of 57 chromosomes, also with an arm number estimate of 87. Nucleolus organizer regions (NORs) were located on a single pair of chromosomes with symmetric staining intensity in channel catfish and in black bullhead, and on a single pair of chromosomes with asymmetric staining intensity in flathead catfish. The channel catfish * black bullhead hybrid had two unpaired chromosomes that stained positively for NORs. The channel catfish * flathead catfish had three unpaired chromosomes that stained positively for NORs. Specific marker chromosomes were identified in each hybrid. There was no evidence of androgenesis, gynogenesis, polyploidy or aneuploidy in the hybrids. Results of this study, plus information reported previously, indicate that chromosomes of ictalurid catfishes are inherited stably in a haploid pattern with an equal contribution to the genomes of F1 hybrids, even in intergeneric crosses involving divergent numbers of parental chromosomes. PMID- 29991165 TI - Seasonal variation in trypsin activity in juvenile Atlantic salmon upper and lower modal groups. AB - Juvenile salmon in their first year of growth showed a bimodal distribution of body lengths by December. For experimental purposes samples of fish from the upper 2% of body lengths were taken as representing the upper modal group (UMG), whilst fish from the bottom 5% of body lengths were taken to represent the lower modal group (LMG). The population of fish from which the samples were taken were fed ad libitum from December to July. During the winter months to March, neither group increased in weight. Growth resumed between March and July. The LMG fish had a very low food intake, as indicated by the relative weight of digesta in the stomach, in the winter months. However, following resumption of feeding, the relative weight of stomach digesta of the LMG fish exceeded that of the UMG fish between May and July. The activity of trypsin in the intestinal digesta followed a similar pattern, the LMG fish showing a higher trypsin activity in the spring months. Starvation of UMG fish for 5 days in winter resulted in accumulation of trypsin in the pancreatic tissues, whilst injection of the trypsin releasing hormone cholecystokinin (CCK) into starving UMG fish resulted in reduction of trypsin in the secretory tissues. CCK also caused reduction of trypsin in the pancreatic tissues of LMG fish, suggesting that the pancreas of this group is potentially fully functional during the winter period. Ultrastructure studies of the pancreatic acinar cells showed evidence for lower secretory activity in the LMG fish, as indicated by smaller numbers of zymogen granules, less well developed Golgi systems and a smaller number of active secreting cells. It appears that trypsin secretion by the pancreas in LMG fish is at a low level during the winter, in response to the reduced amounts of food passing through the gut, which is ultimately controlled by changes in food intake, lowered metabolic level and lowered appetite levels. PMID- 29991166 TI - Presence of dentition in the premaxilla of juvenile Mullus barbatus and M. surmuletus. AB - The genus Mullus is usually described as lacking teeth in the premaxilla. Contrary to generic descriptions (based on adult specimens), the juveniles of M. barbatus and M. surmuletus have teeth in the premaxilla; however, the teeth are not visible in specimens >50 mm total length, because they are covered by lip tissue. The number of teeth decrease with juvenile growth and disappears after c. 100 mm total length is attained. PMID- 29991167 TI - The biosynthesis of docosahexaenoic acid [22:6(n-3)] from linolenic acid in primary hepatocytes isolated from wild northern pike. AB - Primary hepatocytes from wild northern pike Esox lucius were incubated with radiolabelled linolenic acid ([l-14 C]-18:3(n-3)) to assess their ability to synthesize docosahexaenoic acid [22:6(n-3)]. The distribution of radioactivity in lipid classes and hepatocyte polyunsaturated fatty acids (PUFA) was measured over the time-course of 24h. The majority of radioactivity from [l-14 C]-18:3(n-3) was recovered in hepatocyte triacylglycerols (TAG) and phosphatidylcholine (PC). The levels of radioactivity in TAG and in most of phospholipids, including PC, increased significantly over the incubation period. Radioactivity from [1-14 C] 18:3(n-3) was recovered in several hepatocyte PUFA, including 22:6(n-3), and the Delta6 and Delta5-desaturation products 18:4(n-3) and 20:5(n-3). The presence of radioactivity in C24 (n-3) PUFA may be evidence that the biosynthesis of 22:6(n 3) in pike proceeds via a pathway independent of Delta4-desaturation. Analysis by radio gas chromatography revealed that radiolabelled 24:6(n-3) was present among the desaturation and elongation products of [l-14 C]-18:3(n-3). The results establish that, under the in vitro conditions employed, pike hepatocytes are able to convert linolenic acid to 20:5(n-3) and 22:6(n-3). PMID- 29991168 TI - Caelorinchus abditilux Merrett, 1980, a junior synonym of Caelorinchus caudani (Koehler, 1896) (Teleostei: Macrouridae). AB - Comparisons between the holotype of Macrurus caudani Koehler, 1896 and the type series of Caelorinchus abditilux Merrett, 1980, show that the latter is a junior synonym of the former. Caelorinchus caudani (Koehler, 1896) is the correct scientific name for this valid species. PMID- 29991169 TI - How to quantify embryo survival in nest-building fishes, exemplified with three spined sticklebacks. AB - Egg survival in manipulated nests of three-spined sticklebacks Gasterosteus aculeatus in the field was not significantly different from that in unmanipulated nests. PMID- 29991170 TI - Importance of ontogenetic habitat shifts to juvenile output and life history of Atlantic salmon in a large subarctic river: an approach based on analysis of scale characteristics. AB - Juvenile and adult scale characteristics were used to compare two juvenile groups of Atlantic salmon in a large subarctic river in northern Scandinavia: individuals that have migrated from the main stem into small tributaries and those which remain in the main stem. Body size and scale measurements indicated enhanced growth in migratory parr as compared to their resident main stem counterparts. Analysis of adult salmon scale characteristics using maximum likelihood estimators revealed that 20% of the adults had been in the tributaries before the end of their second year of life, and more than 30% more had moved into the tributaries in the third year. Tributary fish matured at a smaller size and younger age (one-sea-winter salmon) than those rearing in the main stem which included a higher proportion of multi-sea-winter salmon. In addition, when smolt ages and ages at maturity were compared, older female smolts often resulted in smaller spawners and younger smolts, larger spawners. Small female spawners were more likely to survive to become repeat spawners. PMID- 29991171 TI - A review of the biology and ecology of the whale shark. AB - The information available on the biology and ecology of the whale shark is reviewed, and is updated from material published since 1986. Research work carried out on the seasonal aggregation of whale sharks at the Ningaloo Reef in Western Australia is summarized. Future research studies on whale sharks in the Ningaloo Marine Park are discussed in the context of management of sustainable whale shark interaction tourism. PMID- 29991172 TI - Feeding strategy and growth of cyprinids in the littoral zone of Lake Balaton. AB - The growth, diet and feeding strategy of five phytophil or phytolithophil species of Cyprinidae from the littoral habitats of Lake Balaton were investigated by examining their scales and foregut contents. The relationships between the total anterior radii of scales and the standard lengths were represented best by a power function for white bream Blicca bjoerkna, and linear functions for common bream Abramis brama, roach Rutilus rutilus and wild goldfish Carassius auratus gibelio, respectively. The backcalculated mean lengths for the first age groups of common bream, white bream and roach did not differ statistically from those obtained by direct observation on 0 group fish in late November 1995. Compared to other waters, common bream grows slowly, wild goldfish and roach rapidly, while the growth rate of white bream can be considered of medium speed in Lake Balaton. Common bream showed a generalized feeding pattern, consuming mainly chironomid larvae, detritus and Corophium curvispinun. Roach showed a clear shift between specialization for Dreissena and algae. Despite the dense population of D. polymorpha in the lake, the significance of the herbivorous adaptation of roach has not yet been made clear. Wild goldfish consumed mainly detritus but, in the open water region, it shifted to zooplankton. White bream preyed chiefly on D. polymorpha, but showed a mixed feeding pattern and utilized most of the available food resources. Carp had the most specialized feeding strategy and preyed mainly on D. polymorpha. According to the discriminant analysis, the five cyprinids exhibited significant food resource partitioning. PMID- 29991173 TI - A Numerical Model Study of Ground-Water Contamination from Price's Landfill, New Jersey- I. Data Base and Flow Simulation. AB - Toxic waste contamination is currently threatening the Atlantic City, New Jersey public water-supply wells. The geohydrologic data for this region are presented and organized into a format suitable for a numerical model study of the contamination problem. Presentation of the data in light of numerical work reveals the importance of good estimates of boundary conditions, historical pumping records, reliable water-quality data, accurate well logs, and reasonable parameter estimates. One set of measured head data is simulated. PMID- 29991174 TI - A Computer Program for a Trilinear Diagram Plot and Analysis of Water Mixing Systemsa. AB - The Piper (1953) trilinear diagram has been widely used to graphically represent the dissolved constituents of natural waters and to test for apparent mixtures of waters from different sources. Because of the time required to plot points and calculate the proportional values of mixing, this treatment of data was often quite tedious, particularly in studies involving large numbers of chemical analyses. The PIPER program was written in BASIC to be run on a Hewlett-Packard desktop computer with an X-Y plotter. Data input is in ppm units. The program plots points in all three fields of the trilinear diagram, draws at each point within the central diamond field a circle with a radius correspondent to the concentrations expressed in meq/1, checks for points that fall on a straight line (or within a predetermined tolerance of a straight line) representing postulated mixtures with two end members, and/or within a triangle representing mixtures of three end members. Finally, the program does a numerical analysis of the mixing ratios of the constituents for postulated mixing systems according to the methodology as presented by Piper (1953). PMID- 29991175 TI - The Rainfall/Water-Table Level Relationship of an Unconfined Aquifer. AB - The soil parameters that determine the infiltration rates of a shallow unconfined coastal aquifer due to rainfall were obtained using the recursive least squares method. The parameters were predicted by minimizing the mean square error between the estimated and measured water-table levels in a bore hole. The parameters lambdat , a drainage factor, betat , a parameter which accounts for external disturbances, and alphat , a set of parameters which determine the infiltration rates due to rainfall, were all treated as time-dependent variables. Their variation is traced by introducing a "forgetting factor" in the algorithm used to determine the parameters. The parameters were determined using rainfall and water table levels for the year 1979 at a bore hole. The parameters betat and alphat varied considerably over the period of time and lambdat remained constant. From the parameters obtained, it appears that most of the recharge due to rainfall takes place within the first two days of the event. After two days there is very little variation in the water-table level due to rainfall although there is a slight drop on the third, fourth and fifth day, presumably due to the escape of entrapped air beneath the water-table level. PMID- 29991176 TI - LAND-USE CONTROL: AN IMPORTANT PIECE OF THE GROUND-WATER PROTECTION PUZZLE. PMID- 29991177 TI - Field Determination of Aquifer Thermal Energy Storage Parametersa. AB - Determination of the potential of a specific confined aquifer as an effective thermal energy storage medium requires thorough knowledge of the geochemical, thermodynamic, and hydraulic properties of the aquifer and its confining layers. A series of laboratory and field studies must be performed in order to determine the fundamental parameters. Procedures and analyses of a series of tests for a confined aquifer near Mobile, Alabama were completed prior to an aquifer thermal energy storage experiment. Parameters determined were: the regional gradient; vertical and horizontal permeabilities of the storage aquifer; horizontal dispersivity of the storage aquifer; vertical permeability of the confining layers; and thermal conductivities, heat capacities, and chemical characteristics of the aquifer matrix and native ground water. PMID- 29991178 TI - AQUIFER MODELING WITH A HANDHELD CALCULATOR - AQMODL. AB - AQMODL is an analytical mathematical aquifer modeling program for the HP-41C handheld programmable calculator. It does not require any written instructions for its use. It guides the operator through its use and prevents operator error. It is designed so that it can be used by anyone only basically familiar with the operation of the HP-41C calculator, and with aquifer modeling. There are no special key assignments, and no special data preparation or storage operations or any other prior preparation necessary before running AQMODL, simply XEQ AQMODL and follow the calculator'guidance. AQMODL can be used to model simple or complex single aquifer situations. It considers any regional change (rising or falling) in water level not necessarily associated with the development being modeled. It also models the aquifer's water-level gradient. Sixty pumping and/or recharge wells can be entered into the model, and the resultant change in water level and water-level elevation determined at an unlimited number of observation points in the aquifer. PMID- 29991179 TI - A Numerical Model Study of Ground-Water Contamination from Price's Landfill, New Jersey - II. Sensitivity Analysis and Contaminant Plume Simulation. AB - A numerical model of flow and transport in the vicinity of Price's Landfill and the Atlantic City public water-supply wells is used to estimate the extent of the existing contamination problem. Model parameters such as boundary conditions, pumping rates, permeability, and dispersivity are varied to demonstrate the sensitivity of the model to these quantities. A historical simulation of the past ten years of contamination is obtained and two schemes for remediation of the contamination problem are compared. In the light of this work, additional data requirements are revealed. PMID- 29991180 TI - REPLY TO the preceding Discussion by Adrian P. Visocky, Ellis W. Sanderson, James P. Gibb, Richard J. Schicht, and Robert T. Sasman, of "Shades of Immortality (Where Do We Hang the Plaque?)". PMID- 29991181 TI - A New Method for Simultaneous Measurement of Cl- , Br- , NO3- , SCN- , and I- at Sub-ppm Levels in Ground Water. AB - Ion-exchange high performance liquid chromatography coupled with ultraviolet absorption detection is shown to be a rapid and sensitive method for analysis of some common anions in water. Sensitivity of measurement is approximately 50 ppb for NO-2 , NO-3 , Br- , I- , and SCN- while Cl- has a detection limit in the one to ten ppm range. Chromatograms require 8 to 13 minutes to complete. Analyses are performed on either of two stationary phases (Whatman SAX 10 MUm or Brownlee anion exchange) depending on the anions of interest in the analysis and their interferences. PMID- 29991182 TI - A Quantitative Model to Predict a Safe Yield for Well Fields in Kufra and Sarir Basins, Libya. AB - The Kufra and Sarir basins of Libya have huge ground-water resources. Three well fields-Sarir, Kufra, and Jalo-have been constructed for irrigation purposes. The Tazerbo and West Sarir well fields are under construction. Wells in these well fields have tapped only a small portion of the total ground water available. The hydrological behavior of the Sarir well field (determined by using analytical and numerical models) indicated a leaky artesian aquifer and a significant partial penetration effect. Long and short-term pump tests did not provide true estimates of the values of transmissivity and the coefficient of storage. A steady-state model of the Kufra and Sarir basins indicated a minimum of 80 m3 /s of underflow entering from Tibesti, Chad and Sudan. A transient model was constructed to pump a total of 120 m3 /s from 14 well fields. The simulation indicated that sufficient drawdown was available to last at least 50 years. PMID- 29991183 TI - DISCUSSION OF "Shades of Immortality (Where Do We Hang the Plaque?)" by Truman Bennett, July-August 1982 issue, v. 20, no. 4, pp. 390-392. PMID- 29991184 TI - Application of Resistivity Surveys to Regional Hydrogeologic Reconnaissance. AB - Vertical electrical soundings using DC resistivity methods have been completed along over 60 miles of survey lines in southwest Florida. The resistivity soundings were obtained in order to outline major hydrogeologic features as part of a regional hydrogeologic investigation covering approximately 400 square miles. The two significant hydrogeologic features which can be effectively mapped on a regional scale by DC methods are the presence of shallow, high resistivity limestones associated with late Tertiary reef complexes, and the approximate depth to waters with TDS concentrations well above the potable water limits. The reef limestones commonly exhibit very high transmissivities and are potential sites for ground-water development. The approximate thickness of potable waters allows resource investigations to be limited to the most promising areas and a rough assessment of the total resource to be made for long-term planning. The interpretation and mapping of the resistivity section is accomplished through published resistivity inversion and computer graphics programs. This automated data processing produces resistivity maps and sections without requiring extensive geophysical training of the interpreter. The automatic interpretations compare well with more traditional master curve interpretation procedures, and have the same limitations with equivalence of solutions and geologic correlation, but are produced with considerably less effort. PMID- 29991185 TI - THE APPLICATION OF A MICROCOMPUTER IN THE ANALYSIS OF PUMPING TEST DATA IN CONFINED AQUIFERS. AB - With an Apple II microcomputer it is possible to rapidly generate and graphically compare theoretical time-drawdown curves with field data from pumping tests in confined aquifers. This technique has the advantage over standard curve-matching methods in that any solution can be tested over the complete range of field data. PMID- 29991186 TI - Muscle system organization in the echinoderms: III. Fine structure of the contractile apparatus of the arm flexor muscles of the comatulids (Antedon mediterranea). AB - The crinoid arm muscles consist of obliquely striated fibers with striking differences in function and in ultrastructural features. These fibers can be distinguished mainly on the basis of different myofilament arrangements (A- and B type patterns) and are variously combined at different levels (proximal, intermediate, and distal portions) of the arm. Some rare smooth fibers (C-type) are irregularly distributed in the periphery and in the core of the bundle. The characteristic features of the A- and B-type obliquely striated fibers are (1) a continuous and homogeneous structure of the Z line and (2) a very heterogeneous arrangement of myosin filaments which vary widely in size, number, and distribution from section to section. The significance of such an atypical, obliquely striated muscle may be related to the double skeletal system combination (endoskeleton and hydroskeleton) of the crinoid arms. PMID- 29991187 TI - Placentation in the lizard Gerrhonotus coeruleus with a comparison to the extraembryonic membranes of the oviparous Gerrhonotus multicarinatus (Sauria, Anguidae). AB - Paraffin sections of an ontogenetic series of embryos of the viviparous lizard Gerrhonotus coeruleus and the oviparous congener G. multicarinatus reveal that although general features of the development of the chorioallantoic and yolk sac membranes are similar, differences are evident in the distribution of the chorioallantoic membrane in late stage embryos. An acellular shell membrane surrounds the egg throughout gestation in both species although the thickness of this structure is much reduced in G. coeruleus over that of G. multicarinatus. The initial vascular membrane to contact the shell membrane in both species is a trilaminar omphalopleure (choriovitelline membrane) composed of ectoderm, mesoderm of the area vasculosa, and endoderm. This transitory membrane is replaced by the vascularized chorioallantois as the allantois expands to contact the inner surface of the chorion. Prior to the establishment of the chorioallantois at the embryonic pole, a membrane begins to form within the yolk ventral to the sinus terminalis. This membrane, which becomes vascularized, extends across the entire width of the abembryonic region and isolates a mass of yolk ventral to the yolk mass proper. The outer membrane of the yolk pole is a nonvascular bilaminar omphalopleure (chorionic ectoderm and yolk endoderm). In G. multicarinatus the bilaminar omphalopleure is supported internally by the vascularized allantoic membrane, whereas in G. coeruleus the allantois does not extend beyond the margin of the isolated yolk mass and the bilaminar omphalopleure is supported by the vascularized intravitelline membrane. Both the chorioallantoic placenta (uterine epithelium, chorionic ectoderm and mesoderm, and allantoic mesoderm and endoderm) and the yolk sac placenta at the abembryonic pole (uterine epithelium, chorionic ectoderm, and yolk sac endoderm) persist to the end of gestation in G. coeruleus. PMID- 29991188 TI - Muscle system organization in the echinoderms: II. Microscopic anatomy and functional significance of the muscle-ligament-skeleton system in the arm of the comatulids (Antedon mediterranea). AB - Comatulids are able to perform quick and complex movements of the arms which are used to swim, creep, walk, and also form a rigid, feeding-filtration fan. To perform such versatile movements, the arms of these animals are equipped with a classical endoskeletal system, with joints, muscles, ligaments, and a hydroskeleton of three different coelomic channels. Light microscopic study of the detailed anatomical organization of the arm clarifies both the complex relations between the parts involved in the movements and their functional responsibilities. In particular, (1) the ventral muscle bundles show a heterogeneous structure that consists of different and variously arranged populations of fibers, which allows the different flexing movements of the arms (i.e., flexion and maintaining the flexed state); (2) the ligaments (both dorsal and interarticular) consist only of collagen fibrils and, therefore, have a passive function in binding the skeletal pieces together: their possible active engagement in the extending movements of the arms is thus excluded; (3) owing to the absence of other suitable antagonists to the flexor muscles, the only efficient antagonist system seems to be the coelomic cavities, which are well separated from each other and are also provided with muscular valves. They thus function as typical hydraulic systems, which allows the arm to perform both simple extensions and very complex combined movements and to maintain some rigid straight or twisted positions. PMID- 29991189 TI - Morphology, ultrastructure, and germ cell cluster formation in ovarioles of aphids. AB - The structure of aphid ovaries, including ovipare and virginopare morphs of five species, was investigated by light and electron microscopy. Aphids contain telotrophic meroistic ovarioles. The amount and distribution of cytoplasmic components of nurse cells, nutritive cords, and young oocytes are nearly identical to those known from scale insects and heteropterans. Each ovariole has a constant number of nurse cells and oocytes. In ovaries of ovipare morphs, the nurse cell nuclei enlarge by endomitosis (n = 28 n-210 n), whereas in virginopare morphs the nurse cell nuclei remain small (n = 22 n-24 n). Furthermore, in virginoparae the previtellogenic growth of oocytes is highly reduced, and vitellogenesis and chorionogenesis are blocked totally. Embryogenesis starts immediately after the shortened previtellogenic growth. In each ovariole, all germ cell descendants belong to one germ cell cluster that follows the 2n rule. The cluster normally contains 25 = (32) cells, but other mostly smaller numbers also occur. In contrast to polytrophic meroistic ovarioles, more than one cell of each cluster will develop into an oocyte. In Drepanosiphum platanoides, 16 (2n-1 ) nurse cells and 16 (2n-1 ) oocytes exist in each cluster, whereas, in Metopolophium dirhodum, 8 (2n-2 ) oocytes and 24 (2n-1 + 2n-2 ) nurse cells are normally found. In many ovarioles of Macrosiphum rosae, 21 nurse cells nourish 11 oocytes. Models of germ cell cluster formation in aphid ovaries are discussed. PMID- 29991190 TI - Ovarian, oviductal, and placental morphology of the reproductively bimodal lizard, Sceloporus aeneus. AB - Sceloporus aeneus exhibits reproductive bimodality. That is, one taxon (Sceloporus aeneus bicanthalis) is viviparous whereas the other (Sceloporus aeneus aeneus) is oviparous. Morphological differences in luteal and oviductal structure were examined. Oviparous and viviparous females have distinct corpora lutea that form immediately after ovulation and remain active until just prior to oviposition or parturition. Luteal activity is correlated positively with follicular atresia. The oviduct of both subspecies is divided into three distinct morphological regions: an anterior infundibulum, a median uterus, and a posterior vagina. The infundibulum and vagina of females exhibiting either parity type are similar, whereas distinct differences in utering morphology are apparent. Primarily, these differences include the loss of uterine glands and a reduction in epithelial cell height in the viviparous form. Moreover, viviparous females possess a simple but well-developed chorioallantoic placenta and a simple choriovitelline placenta. Chorioallantoic placentation is associated with a significant increase in uterine vascularity, indicating a role in gas and/or water exchange. The evolution of viviparity and placentation are discussed in relation to these observations. PMID- 29991191 TI - New data on the structure and the growth of the osteoderms in the reptile Anguis fragilis L. (Anguidae, Squamata). AB - Light and electron microscopy shows the osteoderms of Anguis fragilis to be small, flat disks located in the dermis along the adult trunk: microradiography established the extent of the mineralization. Each osteoderm coincides exactly with an epidermal fold forming the keratinized scales characteristic of the skin of reptiles. Sections perpendicular to the surface show two mineralized layers differing in histological and histochemical characteristics and in fine structure, although both contain collagen fibrils. The structure of each layer can be related to that of the surrounding dermis. The outer superficial layer located in the loose dermis contains few collagen bundles that form a discontinuous sheet at the upper surface of the osteoderms. This superficial layer appears to be constituted of units separated by furrows and is composed of woven fibered bone. The basal plate comprises stratified lamellae formed of parallel-oriented collagen fibrils; the fibrils of successive lamellae lie at right angles. The densely packed collagen fibrils of the basal plate are distributed similarly to those of the dense dermis within which it lies. This layer exhibits structural and histochemical characteristics of a lamellar bone. The presence of two different layers in the osteoderms of Anguis fragilis may reflect their mode of formation, which consists of the deposit of mineral crystals in the preexisting dermal tissue. This mineralization process, considered as a "metaplastic ossification," may reflect the potentiality retained by the dermis of reptiles to form mineralized structures. PMID- 29991192 TI - Ovarian cycle in the frog Rana cyanophlyctis: A quantitative study of follicular kinetics in relation to body mass, oviduct, and fat body cycles. AB - In Rana cyanophlyctis, all stages of oocyte development are present throughout the year owing to continuous and asynchronous gametogenetic activity, but quantitative differences occur in the frequency distribution of the first growth phase (FGP) and second growth phase (SGP) oocytes. The number of SGP oocytes influences ovarian weight; therefore, seasonal changes in the number of SGP oocytes and ovarian mass are correlated. Mean ovarian weight and gonadosomatic index follow comparable changes during the annual cycle. The body mass of the frog undergoes only minor seasonal variations. Also, the body mass does not influence the number of oocytes in the frog. Small FGP oocytes always formed the dominant type in the ovary. Only 20-0% of FGP oocytes were recruited to SGP stage during the prebreeding months (March-April). The breeding season extends over 2- months (July-September) and an adult R. cyanophlyctis spawns 3,000-,500 eggs of 1,300-1,350 MUm diameter in size. The breeding is not followed by any resting period, and therefore oogonial proliferation and recruitment of FGP oocytes start soon after the breeding months (October-December). Atretic oocytes are present in all months but their number is greatest during prebreeding and breeding months. The frequency distribution of oocytes in the right and the left ovaries is identical. The oviducts undergo seasonal changes that are correlated with ovarian weight, whereas the fat body cycle is inversely related to ovarian weight. PMID- 29991193 TI - Ontogeny of hemopoietic and lymphopoietic tissues in the lizard Chalcides ocellatus (Reptilia, Sauna, Scincidae). AB - The first and major blood-forming organ to develop in the viviparous lizard Chalcides ocellatus is the yolk sac, which exhibits prominent erythropoietic activity from as early as stage 21 through birth (stage 41). Myeloid cells and megakaryocytes are produced in the yolk sac from stage 23 onward. During lizard embryogenesis hemopoietic activity is also observed in spleen and bone marrow but in neither kidney nor liver. Cells capable of giving rise to lymphocytes both in vivo and in vitro are first found in the thymus at stage 35. Active lymphopolesis in thymus and spleen begins at stages 36 and 39, respectively. In contrast, the gut-associated lymphoid aggregates are not evident before birth. PMID- 29991194 TI - Oogenesis in the terrestrial hermit crab Coenobita clypeatus (decapoda, anomura). I. Previtellogenic oocytes. AB - Ultrastructural study of previtellogenic oocytes found in cystlike clusters scattered throughout the length of the bilobed ovary of the hermit crab Coenobita clypeatus shows a high nuclear:cytoplasm ratio. Large, round nuclei containing synaptinemal complexes serve as good temporal markers for identification of previtellogenic oocytes. The cytoplasm contains many smooth-membraned vesicles filled with granules and probably of nuclear origin. In addition to its complement of Golgi complexes, endoplasmic reticulum, mitochondria, and free ribosomes, the cytoplasm also contains stacks of annulate lamellae, a feature not previously described for decapod oocytes. Typically, the previtellogenic oocyte with its accumulation of ribosomes has the appearance of a nonsynthetic cell preparing to go through a metabolic transition. PMID- 29991195 TI - Patterns of cells and extracellular material of the sea urchin Lytechinus variegatus (Echinodermata; Echinoidea) embryo, from hatched blastula to late gastrula. AB - Scanning electron microscopy of six stages of Lytechinus variegatus embryos from hatching through gastrulation reveals changes in the shapes of the ectodermal cells and morphological changes in the extracellular material (ECM) in relation to the locations and migratory activities of mesenchyme cells. The classical optical patterns in the blastular wall (Okazaki patterns) are due to differential orientations of the cells, which bend and extend sheet-like lamellipodia over adjoining cells toward the eventual location of the primary mesenchymal ring. The blastocoelic surfaces of the blastomeres become covered with a thin basal lamina (BL) composed of fibers and nonfibrous material. During primary mesenchyme cell (PMC) ingression, a web-like ECM is located in the blastocoel overlying the amassed PMCs. This ECM becomes sparse in migratory mesenchyme blastulae, and is confined to the animal hemisphere. Localized regions of intertwining basal cell processes in the blastular wall are also present during PMC migration. While a distinct BL is present during early and midgastrulation, blastocoelic ECM is absent. Late gastrulae, on the other hand, have an abundance of blastocoelic ECM concentrated near secondary mesenchyme cell protrusive activity. ECM appearing at both the early mesenchyme and late gastrula stages are probably remnants of degraded BL and intercellular matrix preserved by fixation for SEM. Thus, early mesenchyme ECM is formed of BL material whose degradation is necessary for entry of PMCs into the blastocoel. Late gastrula ECM is apparently a degradation product of BL and intercellular material whose destruction is required for fusion of the gut with oral ectoderm in formation of the mouth. PMID- 29991197 TI - The Effect of Education Based on the Theory of Planned Behavior on Iron Supplementation among Pregnant Women. AB - BACKGROUND: Iron is an essential element for women of reproductive age, especially in the period before and during the pregnancy. This study investigates the consumption of iron to prevent iron deficiency anemia among pregnant women visiting Neyshabur healthcare centers based on the theory of planned behavior. METHODS: In this experimental study, data were collected through a questionnaire survey. It included 160 pregnant women who were receiving maternity services at twelve healthcare centers in the city of Neyshabur in Iran between 2015 and 2017. The participants' demographic and anthropometric characteristics, Using the theory of planned behavior, and blood lab examination results, including ferritin levels were measured and the data were analyzed using IBM SPSS ver. 22.0 (IBM Corp., Armonk, NY, USA). RESULTS: The average scores of knowledge, attitude, perceived behavioral control, subjective norms, and intention categories for the intervention group were meaningfully increased after the participants received education on iron supplementation (P<0.05). However, these changes were not found to be significant in the control group (P>0.05). No statistically significant difference was obtained in the subjective norms category between the two groups after the education intervention (P=0.92). CONCLUSION: Based on the experimental effects of education encouraging iron supplementation in pregnant women, it is suggested that workshops promoting iron supplementation should be conducted in health centers with the aim of preventing widespread iron deficiency anemia. PMID- 29991198 TI - Selection of Adjuvant Treatment Without Neoadjuvant Chemoradiotherapy for Patients With Rectal Cancer: Room for Further Investigation. PMID- 29991199 TI - Colorectal Surgery Training in the Hong Kong Special Administrative Region and China. AB - Until 1st July 1997, Hong Kong was under the governance of the British Government; therefore, the British system of education was followed. After internship, 7 years of general surgical training is required to obtain registration and fellowship qualifications of the College of Surgeon of Hong Kong and Edinburg. After having become a specialist in general surgery, the surgeon could choose to specialize in colorectal surgery with an additional 3 to 5 years of specialist training in an accredited centre and 6 months of overseas training with subsidies. On the contrary, China has more than 600 medical schools, and students can enroll in different programs to become a medical practitioner. Despite a great discrepancy exists in the quality of teaching and supervision but there are comprehensive regulations governing the accreditation of hospitals, credentialing of operations, medical records, etc. to ensure medical and patient safety. Vast amounts of resources are being invested to strengthen the quality and to advance the technology used in patient care, not only by supporting basic and clinical research but also by providing extra resources to "import" experts and help develop services with clinical excellence. To accomplish this, the aim of the "three fames project" with a 5-year funding of 3 million United States dollar is to invite overseas experts to help build medical teams in specific areas. Due to its huge population (more than 1.3 billion people), China is a country full of potential for development in clinical research, collaboration, knowledge exchange, and the provision of premier medical services. PMID- 29991200 TI - Laparoscopic Posterolateral Rectopexy for the Treatment of Patients With a Full Thickness Rectal Prolapse: Experience With 63 Patients and Short-term Outcomes. AB - PURPOSE: Although numerous procedures have been proposed for the treatment of patients with a rectal prolapse, the most effective operation has not yet been established. Minimal rectal mobilization can prevent constipation; however, it is associated with increased recurrence rates. We describe our novel method for a laparoscopic posterolateral rectopexy, which includes rectal mobilization with a posterior-right unilateral dissection, suture fixation to the sacral promontory with a polypropylene mesh (Optilene), and a mesorectal fascia propria that is as wide as possible. The present report describes our novel method and assesses the short-term outcomes of patients. METHODS: Between June 2014 and June 2017, 63 patients (28 males and 35 females) with a full-thickness rectal prolapse underwent a laparoscopic posterolateral (LPL) rectopexy. We retrospectively analyzed the clinical characteristics and postoperative complications in those patients. The outcome of surgery was determined by evaluating the answers on fecal incontinence questionnaires, the results of anal manometry preoperatively and 3 months postoperatively, the patients' satisfaction scores (0-10), and the occurrence of constipation. RESULTS: No recurrence was reported during follow-up (3.26 months), and 3 patients reported postoperative complications (wound infection, postoperative sepsis, which was successfully treated with conservative management, and retrograde ejaculation). Compared to the preoperative baseline, fecal incontinence at three months postoperatively showed an overall improvement. The mean patient satisfaction score was 9.55 +/- 0.10, and 8 patients complained of persistent constipation. CONCLUSION: LPL rectopexy is a safe, effective method showing good functional outcomes by providing firm, solid fixation for patients with a full-thickness rectal prolapse. PMID- 29991201 TI - Effects of Intraoperative Insufflation With Warmed, Humidified CO2 during Abdominal Surgery: A Review. AB - PURPOSE: During a laparotomy, the peritoneum is exposed to the cold, dry ambient air of the operating room (20 degrees C, 0%-5% relative humidity). The aim of this review is to determine whether the use of humidified and/or warmed CO2 in the intraperitoneal environment during open or laparoscopic operations influences postoperative outcomes. METHODS: A review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, OVID MEDLINE, Cochrane Central Register of Controlled Trials and Embase databases were searched for articles published between 1980 and 2016 (October). Comparative studies on humans or nonhuman animals that involved randomized controlled trials (RCTs) or prospective cohort studies were included. Both laparotomy and laparoscopic studies were included. The primary outcomes identified were peritoneal inflammation, core body temperature, and postoperative pain. RESULTS: The literature search identified 37 articles for analysis, including 30 RCTs, 7 prospective cohort studies, 23 human studies, and 14 animal studies. Four studies found that compared with warmed/humidified CO2, cold, dry CO2 resulted in significant peritoneal injury, with greater lymphocytic infiltration, higher proinflammatory cytokine levels and peritoneal adhesion formation. Seven of 15 human RCTs reported a significantly higher core body temperature in the warmed, humidified CO2 group than in the cold, dry CO2 group. Seven human RCTs found lower postoperative pain with the use of humidified, warmed CO2. CONCLUSION: While evidence supporting the benefits of using humidified and warmed CO2 can be found in the literature, a large human RCT is required to validate these findings. PMID- 29991196 TI - KASL clinical practice guidelines for liver cirrhosis: Ascites and related complications. PMID- 29991202 TI - Clinical Characteristics and Incidence of Perianal Diseases in Patients With Ulcerative Colitis. AB - PURPOSE: While perianal disease (PAD) is a characteristic of patients with Crohn disease, it has been overlooked in patients with ulcerative colitis (UC). Thus, our study aimed to analyze the incidence and the clinical features of PAD in patients with UC. METHODS: We reviewed the data on 944 patients with an initial diagnosis of UC from October 2003 to October 2015. PAD was categorized as hemorrhoids, anal fissures, abscesses, and fistulae after anoscopic examination by experienced proctologists. Data on patients' demographics, incidence and types of PAD, medications, surgical therapies, and clinical course were analyzed. RESULTS: The median follow-up period was 58 months (range, 12-142 months). Of the 944 UC patients, the cumulative incidence rates of PAD were 8.1% and 16.0% at 5 and 10 years, respectively. The incidence rates of bleeding hemorrhoids, anal fissures, abscesses, and fistulae at 10 years were 6.7%, 5.3%, 2.6%, and 3.4%, respectively. The cumulative incidence rates of perianal sepsis (abscess or fistula) were 2.2% and 4.5% at 5 and 10 years, respectively. In the multivariate analyses, male sex (risk ratio [RR], 4.6; 95% confidence interval [CI], 1.7-12.5) and extensive disease (RR, 4.2; 95% CI, 1.6-10.9) were significantly associated with the development of perianal sepsis. CONCLUSION: Although the clinical course of PAD in patients with UC is not serious, in clinical practice, PAD is not rare in such patients. Therefore, careful examination and appropriate management for PAD is needed if the quality of life for patients with UC is to be improved. PMID- 29991203 TI - Impact of Adjuvant Therapy Type on Survival in Stage II/III Rectal Cancer Without Preoperative Chemoradiation: A Korean Multicenter Retrospective Study. AB - PURPOSE: This study compared the oncologic impact of postoperative chemotherapy and chemoradiotherapy on patients with rectal cancer without preoperative chemoradiation. METHODS: This retrospective study analyzed 713 patients with a mean follow-up of 58 months who had undergone radical resection for stage II/III rectal cancer without preoperative treatment in nine hospitals from January 2004 to December 2009. The study population was categorized a chemotherapy group (CG, n = 460) and a chemoradiotherapy group (CRG, n = 253). Five-year overall survival (OS) and disease-free survival (DFS) were analyzed, and independent factors predicting survival were identified. RESULTS: The patients in the CRG were significantly younger (P < 0.001) and had greater incidences of low rectal cancer (P < 0.001) and stage III disease (P < 0.001). Five-year OS (P = 0.024) and DFS (P = 0.012) were significantly higher in the CG for stage II disease; however, they were not significantly different for stage III disease. In the multivariate analysis, independent predictive factors were male sex, low rectal cancer and stage III disease for OS and male sex, abdominoperineal resection, stage III disease and tumor-positive circumferential margin for DFS. However, adjuvant therapy type did not independently affect OS (hazard ratio [HR], 1.243; 95% confidence interval [CI], 0.794-1.945; P = 0.341) and DFS (HR, 1.091; 95% CI, 0.810-1.470; P = 0.566). CONCLUSION: Adjuvant therapy type did not affect survival of stage II/III rectal cancer patients without neoadjuvant chemoradiotherapy. These results suggest that adjuvant therapy can be chosen based on the patient's condition and the policies of the surgeons and hospital facilities. PMID- 29991204 TI - Diagnosis and Management of a Cryptoglandular Actinomycotic Fistula-in-Ano: An Update on 7 New Cases and a Review of the Literature. AB - PURPOSE: Primary anal actinomycosis of cryptoglandular origin, a rare cause of anal suppurative disease, requires specific management to be cured. The aims of this retrospective study were to describe clinical, morphological, and microbiological features of this entity and to evaluate management practices for new cases observed since 2001. METHODS: This was a retrospective case series conducted at the Diaconesses-Croix Saint-Simon Hospital in Paris. RESULTS: From January 2001 to July 2016, 7 patients, 6 males and 1 female (median, 49 years), presenting with an actinomycotic abscess with a cryptoglandular anal fistula were included for study. The main symptom was an acute painful ischioanal abscess. One patient exhibited macroscopic small yellow granules ("sulfur granules"), another "watery pus" and a third subcutaneous gluteal septic metastasis. All patients were overweight (body mass index >= 25 kg/m2). Histological study of surgically excised tissue established the diagnosis. All the patients were managed with a combination of classical surgical treatment and prolonged antibiotic therapy. No recurrence was observed during follow-up, the median follow-up being 3 years. CONCLUSION: Actinomycosis should be suspected particularly when sulfur granules are present in the pus, patients have undergone multiple surgeries or suppuration has an unusual aspect. Careful histological examination and appropriate cultures of pus are needed to achieve complete eradication of this rare, but easily curable, disease. PMID- 29991205 TI - Toothpick Colon Injury Mimicking Colonic Diverticulitis. AB - Although toothpick ingestion is rare, it can lead to fatal complications in the gastrointestinal tract. Diagnosing toothpick ingestion is difficult because most patients do not recall swallowing one. We report 2 cases of toothpick-ingestion induced colon injury, mimicking diverticulitis. The first patient was a 47-year old male who had received conservative treatment under the impression of his having diverticulitis in the cecum. Ultrasonography revealed a linear foreign body in the right lower abdomen; a subsequent laparoscopic examination revealed inflammation around the cecum, but no evidence of bowel perforation. A thorough investigation revealed a toothpick embedded in the subcutaneous fat and muscle layer of the lower abdominal wall; we removed it. The second patient was a 56 year-old male who had received conservative treatment under the impression of his having diverticulitis in the sigmoid colon. An explorative laparotomy revealed a toothpick piercing the sigmoid colon; we performed an anterior resection. Both patients were discharged without postoperative complications. PMID- 29991206 TI - Toxocara canis Mimicking a Metastatic Omental Mass from Sigmoid Colon Cancer: A Case Report. AB - Toxocara canis is an important roundworm of canids and a fearsome animal parasite of humans. Human infections can lead to syndromes called visceral larva migrans (VLM), ocular larva migrans, neurotoxocariasis, and covert toxocariasis. VLM is most commonly diagnosed in children younger than 8 years of age, but adult cases are relatively frequent among those infected by ingesting the raw tissue of paratenic hosts in East Asia. This research reports the case of a 59-year-old man with sigmoid colon cancer, who visited our institution for surgery. An intraperitoneal mass was found on preoperative computed tomography, and it was thought to be a metastatic mass from sigmoid colon cancer. A postoperative histologic examination and serum test showed eosinophilic granuloma due to toxocariasis. Diagnosis of VLM is often difficult and highly suspicious in adults. Researchers suggest, although rarely, that VLM be included in the differential diagnosis as a cause of intraperitoneal tumors. PMID- 29991207 TI - Testosterone and male rejuvenation. AB - Testosterone has long been touted as the panacea for men wishing to restore their vitality, sexuality, and masculinity to that of their youth. While the benefits of testosterone are not mythical, they are definite. In this article we will review the various benefits of testosterone as it pertains to men's health and male infertility. PMID- 29991208 TI - Hepatitis C virus, alcohol use disorders and hepatocellular carcinoma. PMID- 29991210 TI - Clinical diagnosis of endocrine diseases. PMID- 29991209 TI - Role in depression of a multi-fractionated versus a conventional Hypericum perforatum extract. AB - BACKGROUND: Hypericum perforatum is used as medicinal plant for mild to moderately severe depression. Several trials have found hypericum to be more effective than placebo or some antidepressant drugs, but the exact mechanism and most relevant compounds are still unclear. A possible hypothesis is that the antidepressant activity might be due to its multiplicity of bioactive compounds. Aim is to test if greater chemical complexity could result in a greater hypericum antidepressant action. METHODS: A retrospective, 12-month, open-label, observational, controlled trial was conducted to compare the antidepressant clinical activity of a conventional Hypericum perforatum (C-Hp) versus a multi fractionated (M-Hp) one (IperiPlex(r)). RESULTS: Treatment with C-Hp demonstrated no efficacy after 6 months and partial (P<0.05) efficacy after 12 months. Treatment with MF-Hp demonstrated highly (P<0.01) significant results at both 6 and 12 months. Analysis of the monthly reduction coefficient demonstrated that treatment with MF- Hp was twice as effective as treatment with C-Hp (0.96 versus 0.48). No side effects were reported. CONCLUSIONS: A multi-fractionated hypericum extract has better clinical outcomes in subjects with depression without determining an increased risk of toxicity or reduced tolerability. PMID- 29991211 TI - Obesity and breast cancer risk: implications of MiR-126. PMID- 29991212 TI - Weight gain increase plasma levels of uric acid in adults in China. PMID- 29991213 TI - Polycystic ovary syndrome and vitamin D serum levels. PMID- 29991214 TI - Sports therapy and recreation exercise program in type 2 diabetes: randomized controlled trial, 3-month follow-up. AB - BACKGROUND: A sports therapy program in type 2 diabetes helps in glucose control, but little is known how a long-term structured exercise intervention affects the parameters in this disease. Our aim was to measure the impact of a 24-week long sports therapy program in type 2 diabetes on the concentration of glucose in blood, body composition, and physical fitness level. METHODS: In this prospective longitudinal study, 208 type II diabetic patient (80 male, 128 female, aged: 61+/ 6,86 years) were selected and randomly assigned to a control or an intervention group. The intervention group took part in a sports therapy and recreation sports program for 6 months. Taking into account the rules of training theory and physiotherapy, fitness material of exercising (aerobics, resistance training, muscle strengthening, stretching) and outdoor elements were used during the 3 month sports program, after which it became a 3-month recreation exercise program. In the control group, there was no intervention. RESULTS: The intervention group showed significant decrease in concentration of glucose in blood (Mean Differences (MD):-3.23; [Confidence Interval (CI) lowest: -3.50; CI highest: - 2.95]; p<0.01), weight (MD: -1.68; [-0.82, -0.52] p=0.01), BMI (MD: 0.37; [-0.82; 0.08]; p=0.01), body fat percentage (MD:-1.74; [-2.15, -1.34]; p=0.05) and visceral fat (MD:-0.37; [-0.67, -0.07; p=0.01); right (MD: 5.33; [4.98, 5.68]; p<0.01) and left arm curl (MD: 5.23; [4.87, 5.60]; p<0.01) test, chair stand test (MD: 2.95; [2.65, 3.25]; p=0.00) and the 6- minute walk test (MD: 111.21; [101.12; 121.31]; p<0.01) showed significant improvement. CONCLUSIONS: A 24-week long sports therapy program is a successful intervention for improving parameters affected by type 2 diabetes. PMID- 29991215 TI - Post-exercise hypotension in central aortic pressures following walking and its relation to cardiorespiratory fitness. AB - BACKGROUND: Central aortic blood pressure (BP) is reduced after exercise. The aim of this study was to determine whether cardiorespiratory fitness relates to post exercise reductions in aortic BP. METHODS: Sixteen young adults completed maximal exercise testing for peak oxygen uptake (VO2). Participants walked at a slow (80 steps/min, ~47% maxHR) and fast (125 steps/min, ~65% maxHR) stepping cadence for 3,000 steps on two nonconsecutive days. Before and after each walking condition, radial tonometry was used to derive aortic pressures. Measurements after walking were taken after 30 and 60 min of supine recovery. RESULTS: The change in aortic BP was similar between walking cadences. Aortic systolic BP (-2.3 mmHg, p=0.03) and pulse pressure (-3.2 mmHg, p<0.001) were significantly reduced after 60 min of recovery as compared to baseline. The reduction in aortic pulse pressure was associated with decreased forward (r=0.69, p<0.001) and backward wave pressure (r=0.70, p<0.001). Peak VO2 was not associated (p>0.05) with these changes, but was strongly associated with non-significant changes in aortic systolic BP (30min: r= -0.54, p=0.03) and diastolic BP (30min: r= -0.64, 60min: r= -0.77; both p<0.01) after slow walking only. CONCLUSIONS: These results indicate that cardiorespiratory fitness associates with aortic pressure reductions after walking dependent on exercise intensity. PMID- 29991216 TI - Low- and high-intensity one-week occlusion training improve muscle oxygen consumption and reduce muscle fatigue. AB - BACKGROUND: Low-intensity resistance exercises with blood flow restriction have been shown is effective to increase muscular strength and hypertrophy. However, the effects of combined training: one-week occlusion training with various exercise intensities by using less occlusion pressure on muscle strength improvement, fatigability and their work capacity are not clear. METHODS: Participants (n = 24) were middle-distance runners with 4-6 years of training experience. A control group without blood flow restriction (n = 12, age 23+/-1 years) and an experimental group with blood flow restriction (n = 12, age 22+/-1 years). In this study, the calf muscles were impacted by the training with occlusion 120 mmHg. We used intensive one-week daily training, whereby exercise intensity was gradually increased daily from 20 to 80 % of maximal voluntary contraction (MVC) and then decreased to 60% by the end of the week. RESULTS: MVC of foot flexion muscles after the one-week occlusion training in the experimental group and control group increased (p < 0.05) by 5.6 +/- 1.3% and 5.3 +/- 1.2% accordingly. Meanwhile in experimental group work capacity improved only 2.4 +/- 3.5% (p > 0.05) and in control group it significantly decreased 11.8 +/- 2.5% (p < 0.05). StO2 decreased during exercise test from the baseline 100% to 45.2 +/- 4.3% before occlusion training and to 34.6 +/- 6.2% after the week of occlusion training (p < 0.05). CONCLUSIONS: Intensive one-week training with occlusion with varying intensity improves resistance to fatigue and recovery after training. This kind of training improves oxygen consumption while exercising. PMID- 29991217 TI - The effects of rapid weight loss and 3-h recovery on energy expenditure, carbohydrate, and fat oxidation in boxing athletes. AB - BACKGROUND: Boxers need to consider energy metabolism during rapid weight loss (RWL) followed by rapid weight regain. We examined the effects of RWL and a 3-h acute weight recovery on energy expenditure, carbohydrate oxidation, and fat oxidation in boxing athletes. METHODS: The analysis was based on the data of seven healthy young male athletes who underwent rapid weight loss followed by acute weight recovery. Energy expenditure was evaluated at three time points: one week prior to the acute weight loss (baseline); after the 1- week weight loss period; after a 3-h acute weight recovery period. This 3-compartment model was used to estimate body composition. Sleeping metabolic rate and diet-induced thermogenesis (DIT) were measured in an indirect calorimetry room over a 17-h period. After an overnight fast, a prescribed meal was provided and the DIT was measured over a 3- h period. This was followed by a three-step treadmill running protocol. RESULTS: Weight loss produced a significant decrease in fat mass, fat free mass, and body mass, with recovery of body mass within 3 h (1.7 +/- 0.3 kg). Postprandial carbohydrate oxidation was significantly lower during the recovery period than at baseline, while fat oxidation was higher, although there was no change in the DIT. CONCLUSIONS: RWL, followed by a short-term of acute weight recovery, produces an increase in fat oxidation and a decrease in carbohydrate oxidation, with the increase in fat oxidation being maintained through an overnight sleep period, as well as in the postprandial and exercise periods. PMID- 29991218 TI - Coaches' perceptions of the quality of care provided by athletic trainers. AB - BACKGROUND: The coach's perception of the quality of care provided by the athletic trainer (AT) is essential in providing the best care for the athlete given the coaches' influential role on the sports medicine team. The purpose of this study was to examine National Collegiate Athletic Association (NCAA) coaches' perceptions of the quality of care provided by the athletic trainer (AT). METHODS: A survey was used to assess NCAA coaches' perceptions in both 1998 and 2016 in order to provide an analysis of change over time. RESULTS: A total of 261 NCAA coaches (129 in 1998 and 132 in 2016) participated. There was a significant difference between the perception scores of coaches from high-profile sports (74.9+/-13.6) and low-profile sports (72.0+/-13.2; p=0.01) and between coaches surveyed in 1998 (75.9+/-11.7) and 2016 (70.2+/-14.3; p<0.01). However, there was no significant difference between the perception scores of coaches from Division I (74.3+/-13.3), II (70.1+/-13.9), or III (74.2+/-12.7; p=0.11) institutions. CONCLUSIONS: The perceptions of coaches from high-profile sports are greater than those from low-profile sports. The perceptions of coaches surveyed in 1998 are greater than those surveyed in 2016. The factors that appear to influence the perceptions of coaches include equality for all athletes regardless of sport, adequate staffing of the athletic training room, and effective communication between the coach and AT. PMID- 29991220 TI - Prediction of extubation failure in intensive care unit: systematic review of parameters investigated. AB - INTRODUCTION: Extubation failure (EF) refers to the inability to maintain spontaneous breathing after removal of endotracheal tube. The aim of this review is to identify the best parameter to predict EF in adult intensive care patients. EVIDENCE ACQUISITION: We searched for publications in PubMed (2000-2016). Studies of patients intubated and mechanically ventilated for more than 24 hours were included and divided in groups basing on the extubation method. 2x2 tables were performed to evaluate the sensitivity, specificity and the predictive values only for those parameters investigated in more than three studies. Studies were divided in groups, basing on time required to define EF (<24 hours, <72 or >72 hours), and EF percentage was calculated for each group. EVIDENCE SYNTHESIS: On 443 potentially studies, 26 were included. Rapid Shallow Breathing Index (RSBI) and cough strength parameters were found in more than three studies. RSBI or cough strenght parameter showed a sensitivity of 20-88.8% or 55.5-85.2%, a specificity of 68.5-94.8% or 24-49%, a positive predictive value of 39.5-66.6% or 24-49% and a negative predictive value of 98-82% or 89.5-96.4%, respectively. EF rate was 12.5%, 15.3% and 22% in patients evaluated within 24 hours, 72 hours and over 72 hours, respectively. CONCLUSIONS: This review shows that all parameters used to predict EF have a low PPV. Therefore, the limitation of use of such predictive tests may prolong unnecessary the intubation and increase the unfavorable outcome. A prospective study involving all variables could be useful to predict the EF in ICU. PMID- 29991219 TI - Determination of 1,3-beta-D-glucan in the peritoneal fluid for the diagnosis of intra-abdominal candidiasis in critically ill patients: a pilot study. AB - BACKGROUND: Decision to start an anti-fungal therapy in intra-abdominal candidiasis (IAC) is complex. Yeast culture, considered the gold standard, suffers from a delayed response time and exposes the patient to delayed introduction of anti-fungal therapy. We sought to evaluate the performance and feasibility of measuring 1,3-beta-D-glucan (1,3-BDG) in the peritoneal fluid (PF) for the diagnosis of IAC. METHODS: We analyzed retrospectively all PF obtained during abdominal surgery for critically ill adult patients presenting intra abdominal infections. For each PF sample, direct examination, bacterial and fungal culture, fungal PCR and 1,3-BDG measurements were performed. The diagnostic performance of each technique and the Peritonitis score were calculated considering the positive yeast culture as the reference. The levels of 1,3-BDG were compared between IAC and non-IAC patients. RESULTS: During an 8 month period in 2016, 33 PF samples were recovered. Median (interquartile range) SAPS 2 and SOFA scores were 44 (9-94) and 9 (4-15), respectively. There were seven cases of IAC, 14 of bacterial peritonitis and 12 of undocumented peritonitis. All IAC cases were secondary peritonitis, with a 1,3-BDG level of 1461 (325-5000) versus 224 (68-1357) pg/mL in the non-IAC group (P=0.03). When the 1,3-BDG level was <=310 pg/mL, its negative predictive value was 100%. CONCLUSIONS: In secondary peritonitis, a peritoneal measurement of 1,3-BDG <=310 pg/mL could rule out IAC. PMID- 29991221 TI - Choosing wisely: what's the actual role of antimicrobial stewardship in intensive care units? AB - More than two-thirds of critically ill patients receive an antimicrobial therapy with a percentage between 30 and 50% of all prescribed antibiotics reported to be unnecessary, inappropriate or misused. Since inappropriate prescription of antibiotic drugs concurs to dissemination of the multi-drug resistant organisms, a reasoned antibiotics use is crucial especially in Intensive Care Unit (ICU), where up to 60% of the admitted patients develops an infection during their ICU stay. Even if the concept of Antimicrobial Stewardship (AS) has been clearly described as a series of coordinated interventions designed to improve antimicrobial agents use, few studies are reporting about its effectiveness to improve outcomes, reduce adverse events and costs and decrease resistance rate spread. Moreover, although it is recognized that AS programs are particularly indicated in the critical setting due to the huge number of antimicrobial drugs used, the optimal characteristics of these interventions and the best system to evaluate their effectiveness are still unclear. Specific interventions, designed tacking into account the peculiarities of the ICU setting, are hence necessary to set-up an 'in-ICU-stewardship', including prompt identification of infected patients, selection of appropriate empiric treatments, optimization of dosing and route of administration, improvement of diagnostic techniques, early de escalation to achieve shorter duration and avoid unnecessary therapies. The present narrative review summarizes the "state of art" about AS programmes and discusses the effects of the interventions possibly applied in ICU setting to optimize the patient's treatment, reduce the micro-organisms resistance and contain the hospital resources utilization. PMID- 29991222 TI - Interscalenic versus suprascapular nerve block: can the type of block influence short- and long-term outcomes? An observational study. AB - BACKGROUND: While interscalenic nerve block (INB) is still considered the 'gold standard' for shoulder arthroscopy, its postoperative analgesic effectiveness has recently been called into question. Meanwhile, in light of its high-quality postoperative pain relief, a renewed interest has emerged in suprascapular nerve block (SNB). The first aim of our study was to compare the postoperative analgesia effects of these two types of block at 2, 4 and 6 hours after surgery. We also assessed shoulder functional recovery over a six-month follow-up period. METHODS: All patients requiring arthroscopic shoulder surgery for rotator cuff repair during the study period were enrolled. INB or SNB was performed under ultrasound guidance. The patients underwent general anaesthesia. Numerical rate scores (NRS) at rest and in motion at 2, 4 and 6 postoperative hours were recorded. RESULTS: Over two years, 280 patients were screened. Of these, 136 were excluded. Pain scores after surgery were lower at 2 hours in INB at rest (0.70+/ 1.50 versus 2.1+/-2.2; p<0.0067) and after movement (1.0 +/- 2.2 versus 2.5 +/- 2.3; p=0.01). A significant difference in terms of arm extrarotation degrees at week 6 and month 2 (p <0.01) in SNB was found. CONCLUSIONS: INB showed better analgesic efficacy in the immediate postoperative period. Both types of block showed similar results in terms of functional recovery over the six-month follow up. SNB without motor block seems matched better with ambulatory surgery and with an early rehabilitation program. PMID- 29991223 TI - Analgesia Nociception Index-guided intraoperative fentanyl consumption and postoperative analgesia in patients receiving scalp block versus incision-site infiltration for craniotomy. AB - BACKGROUND: Scalp block or local anesthetic infiltration for craniotomy blunts hemodynamic response to noxious stimuli, reduces opioid requirement and decreases postoperative pain. Analgesia Nociception Index (ANI) provides objective information about the magnitude of pain (rated from 0 to 100 with 0 indicating extreme nociception and 100 indicating absence of nociception) and adequacy of intra-operative analgesia. This study compared intra-operative fentanyl consumption guided by ANI and postoperative pain in patients who receive scalp block with those who receive incision-site local anesthetic infiltration for craniotomy. METHODS: Sixty adult patients undergoing elective supra-tentorial tumor surgery were randomly allocated to receive scalp block or incision-site infiltration after induction of anesthesia. Throughout the intra-operative period, patients received fentanyl 0.5 ug/kg/h and ANI was continuously monitored. Fentanyl 1 ug/kg bolus was administered when ANI decreased to <50. Intraoperative fentanyl consumption was compared using unpaired t-test. Correlation between ANI and postoperative numerical rating scale (NRS) pain score was done using Spearman's rho. RESULTS: The fentanyl consumption (ug/kg/h) was less with scalp block when compared to incision-site infiltration (median [interquartile range]; 1.04 [0.92-1.34] vs. 1.34 [1.18-1.59], P=0.001). Postoperative pain scores were similar [median (interquartile range); 1.5 (0-4) vs. 3 (0-4), P=0.840]. No correlation was observed between postoperative NRS Score and ANI (correlation coefficient = 0.072; P=0.617). CONCLUSIONS: ANI-guided analgesic administration during craniotomy demonstrated lower intra-operative fentanyl consumption in patients receiving scalp block as compared to incision site local anesthetic infiltration. No correlation was seen between postoperative NRS and ANI. PMID- 29991224 TI - More than catherization guidance, ultrasound also can reposition the cephalad malposition in real-time. PMID- 29991225 TI - The combination of erector spinae plane block and pectoralis blocks could avoid general anesthesia for radical mastectomy in high risk patients. PMID- 29991226 TI - The Oxygen Reserve Index in anesthesiology: a superfluous toy or a tool to individualize oxygen therapy? PMID- 29991227 TI - The Afferent Sensory Pathway: The Unsung Hero of Neural Interactions Controlling Detrusor Contractions. PMID- 29991228 TI - Overactive Bladder is a Distress Symptom in Heart Failure. AB - The prevalence of Heart failure (HF) is expected to increase worldwide with the aging population trend. The numerous symptoms of and repeated hospitalizations for HF negatively affect the patient's quality of life and increase the patient's economic burden. Up to 50% of patients with HF suffer from urinary incontinence (UI) and an overactive bladder (OAB). However, there are limited data about the relationship between UI, OAB, and HF. The association between HF and urinary symptoms may be directly attributable to worsening HF pathophysiology. A comprehensive literature review was conducted for all publications between January 2000 and November 2017 using the PubMed, Embase, and Cochrane databases. HF represents a major and growing public health problem, with an increased risk of UI and an OAB as comorbidities. Possible effects of HF on urinary problems may be mediated by the prescription of medications for symptomatic relief. Although diuretics are typically used to relieve congestion, and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers improve survival, these classes of drugs have been suggested to worsen urinary symptoms in the presence of HF. Further research is required to understand the impact of UI and an OAB on the HF illness trajectory. PMID- 29991229 TI - Capsaicin-Sensitive Sensory Nerves Indirectly Modulate Motor Function of the Urinary Bladder. AB - PURPOSE: The urinary bladder (UB) is innervated by both sensory and autonomic nerves. Recent studies have shown that sensory neuropeptides induced contractions in the detrusor muscle. Therefore, in a mouse model, we investigated the presence of interactions between the submucosal sensory nerves and the autonomic nerves that regulate the motor function of the detrusor muscle. METHODS: UB samples from male C57BL/6 mice were isolated, cut into strips, and mounted in an organ bath. Dose-response curves to norepinephrine and phenylephrine were studied in UB strips with and without mucosa, and the effects of preincubation with a receptor antagonist and various drugs on relaxation were also studied using tissue bath myography. RESULTS: Phenylephrine-induced relaxation of the UB strips showed concentration-related effects. This relaxation appeared in both mucosa-intact and mucosa-denuded UB strips, and was significantly inhibited by lidocaine, silodosin, and guanethidine (an adrenergic neuronal blocker). Meanwhile, phenylephrine-induced relaxation was inhibited by pretreatment with propranolol and calcitonin gene-related peptide (CGRP)-depletory capsaicin in UB strips with and without mucosa. Conclusions: The present study suggests that phenylephrine activates the alpha-1A adrenergic receptor (AR) of the sensory nerve, and then activates capsaicin-sensitive sensory nerves to release an unknown substance that facilitates the release of norepinephrine from adrenergic nerves. Subsequently, norepinephrine stimulates beta-ARs in the detrusor muscle in mice, leading to neurogenic relaxation of the UB. Further animal and human studies are required to prove this concept and to validate its clinical usefulness. PMID- 29991230 TI - Neurologic Mechanisms Underlying Voiding Dysfunction due to Prostatitis in a Rat Model of Nonbacterial Prostatic Inflammation. AB - PURPOSE: The neurological molecular mechanisms underlying the voiding dysfunction associated with nonbacterial chronic prostatitis/chronic pelvic pain syndrome remain poorly understood. In this study, we assessed whether prostate inflammation activated bladder afferent neurons, leading to bladder dysfunction, and sought to elucidate the underlying mechanisms. METHODS: Thirty male Sprague Dawley rats were divided into 3 groups: sham-saline, formalin-injected, and capsaicin-pretreated and formalin-injected. Chemical prostatitis was induced by 0.1 mL of 10% buffered formalin injected into the ventral prostate. Capsaicin was injected subcutaneously to desensitize capsaicin-sensitive nerves. In each group, conscious cystometry was performed, and c-fos expression within the spinal cord was determined immunocytochemically. Double immunofluorescent staining with c-fos and choline acetyltransferase (ChAT) was performed. On the third day after pseudorabies virus (PRV) infection, c-fos and PRV double-staining was performed. RESULTS: Intraprostatic formalin significantly increased the maximal voiding pressure and decreased the intercontraction interval, compared with controls. Pretreatment with capsaicin significantly reversed these effects. More c-fos positive cells were observed in the sacral parasympathetic nucleus (SPN) and dorsal gray commissure (DCM) in the prostatitis group than in the sham group. c fos-positive cells decreased in the capsaicin-pretreated group. Preganglionic neurons labeled by c-fos and ChAT were observed in the SPN in rats with prostatitis. Interneurons labeled by c-fos and PRV were identified in the DCM after PRV infection. Conclusions: Our results suggest that prostate inflammation activates afferent nerve fibers projecting to the lumbosacral spinal cord, producing reflex activation of spinal neurons innervating the bladder and bladder hyperreflexia. This is mediated by capsaicin-sensitive prostate afferent neurons. PMID- 29991231 TI - The Overactive Bladder Symptom Score, International Prostate Symptom Score Storage Subscore, and Urgency Severity Score in Patients With Overactive Bladder and Hypersensitive Bladder: Which Scoring System is Best? AB - PURPOSE: To evaluate the correlations among the Overactive Bladder Symptom Score (OABSS), International Prostate Symptom Score-Storage Subscore (IPSS-S), and the modified Urgency Severity Scale (USS) in patients with overactive bladder (OAB) and hypersensitive bladder (HSB) and to identify the most useful diagnostic tool for classifying the severity of OAB. METHODS: We retrospectively reviewed the charts of consecutive patients with OAB who visited our urologic clinics for treatment. All patients underwent a detailed history, physical examination, urinalysis, uroflowmetry, and postvoid residual volume measurement, and completed a 3-day voiding diary. All patients answered the Chinese versions of the IPSS, OABSS, and USS, according to which they were classified as having wet or dry OAB based on whether their chief complaint was urgency urinary incontinence or urgency without incontinence. HSB was defined as a functional bladder capacity <350 mL and a USS of 0 or 1. RESULTS: The records of 325 OAB patients (99 women and 226 men) were reviewed. The OAB subgroups included HSB (n=31), OAB-dry (n=74), and OAB-wet (n=220). One-way analysis of variance showed significant differences among the OAB subgroups evaluated using each scoring system. Each scoring system was significantly correlated with the OAB subgroups. The Spearman rho was 0.983 for the USS, 0.651 for the OABSS, and 0.428 for the IPSS-S. Conclusions: The IPSS-S, OABSS, and USS showed good correlations with the OAB subgroups. Their ranking in terms of discriminant ability for classifying OAB severity as HSB, OAB-dry, and OAB-wet was USS>OABSS>IPSS-S. The simplest survey, the USS, with a single item scored from 0 to 4, had the strongest correlation with the OAB severity subgroups. PMID- 29991232 TI - Time Course of Treatment for Primary Enuresis With Overactive Bladder. AB - PURPOSE: To characterize the course of treatment for nonmonosymptomatic enuresis with overactive bladder (OAB) in a real clinical setting. METHODS: Data from 111 OAB patients with moderate to severe enuresis were analyzed. The baseline analysis included a questionnaire, voiding diary, uroflowmetry with postvoid residual urine measurement, and plain abdominal radiography of the kidneys, ureters, and bladder (KUB). Following standard urotherapy for 1 month, anticholinergic medication was administered with or without laxatives. Desmopressin was added if there was a partial response to OAB. Patients were followed every 3 months to evaluate the status of OAB and enuresis. Multivariate analysis was performed to identify predictors associated with the lack of complete response (CR) in enuresis at 12 months. RESULTS: Following 12 months of treatment, 64% and 88% of patients experienced at least partial response in enuresis and OAB, respectively. Urgency improved more quickly than enuresis, supporting the need to address daytime symptoms before enuresis. Seventy-nine patients (71%) had fecal impaction on KUB and/or subjective constipation. The combination of anticholinergics with either laxatives or desmopressin fared better than anticholinergics alone. Daytime incontinence and anticholinergics- only treatment were associated with a lack of CR during 12 months of treatment. Conclusions: The data confirmed the validity of addressing OAB before treating enuresis. The results of this study also highlight the need to address fecal impaction. Patients should be counseled about the need for a prolonged course of treatment before starting treatment. Anticholinergics should be accompanied with either desmopressin or laxatives for better control of enuresis. PMID- 29991233 TI - The Role of Preoperative Puborectal Muscle Function Assessed by Transperineal Ultrasound in Urinary Continence Outcomes at 3, 6, and 12 Months After Robotic Assisted Radical Prostatectomy. AB - PURPOSE: The efficacy of pelvic floor muscle training (PFMT) for men with postprostatectomy incontinence (PPI) after robotic-assisted radical prostatectomy (RARP) is controversial and the mechanism for its possible effect remains unclear. The aim of this study was to investigate the relationship between bladder neck (BN) displacement, as a proxy for puborectal muscle activation, and continence outcomes after RARP. METHODS: Data were extracted from the South Australian Prostate Cancer Clinical Outcomes Collaborative database for men undergoing RARP by high volume surgeons who attended preoperative pelvic floor physiotherapy for pelvic floor muscle (PFM) training between 2012 and 2015. Instructions were to contract the PFM as if stopping the flow of urine. BN displacement was measured with 2-dimensional transperineal ultrasound, without digital rectal examination. Urinary continence status was assessed preoperatively and at 3, 6, and 12 months using the Expanded Prostate Cancer Index Composite 26. Data were analysed using logistic regression and mixed effects linear modelling. Confounding variables considered were baseline continence, age at diagnosis, margin status, nerve sparing procedures and pathological stage. RESULTS: Of 671 eligible men, 358 met the inclusion criteria and were available for analysis, with 136 complete datasets at 12-month follow-up. While BN movement was associated with preoperative continence, there was no significant effect of BN displacement on the change in urinary continence at 12 months postprostatectomy (P=0.81) or on the influence of time on continence over 3-12 months. Conclusions: Continence outcomes were not associated with BN displacement, produced by activity of the puborectal portion of the levator ani muscle, at 3, 6, or 12 months after RARP. These results suggest that the puborectal muscle does not play a role in the recovery of continence after RARP and may help to explain the negative findings of many studies of PFMT for PPI. PMID- 29991234 TI - A Prospective Analysis of the Effects of Nerve-Sparing Radical Prostatectomy on Urinary Continence Based on Expanded Prostate Cancer Index Composite and International Index of Erectile Function Scoring Systems. AB - PURPOSE: This study aims to objectively characterize the effect of successful nerve sparing (NS) during radical prostatectomy (RP) on postoperative urinary continence (UC) using International Index of Erectile Function (IIEF)-scores and a previously described Expanded Prostate Cancer Index Composite (EPIC) score cutoff value (COV) for UC. Several notable studies on this topic present conflicting outcomes. This is largely due to a lack of clear definitions and consensus regarding preserved erectile function (EF) and UC. METHODS: This study is comprised of all patients who underwent RP at the Kantonsspital Baden, Switzerland, between 2004 and 2013. Patients completed self-assessment questionnaires for UC (EPIC) and EF (IIEF) pre- and postoperatively (3, 6, 9, 12, 18, and 24 months; yearly thereafter). We used a previously described EPIC subscore COV, with "satisfactory continence" signified by a score >85. Statistical analysis was performed using Kaplan-Meier and Cox regression analyses for "surgeon-" and "IIEF-defined" NS definitions. RESULTS: Of 236 men with a median age of 63 years (interquartile range [IQR], 59-66 years) and median follow up time of 48 months (IQR, 30-78 months), 176 underwent unilateral (n=33) or bilateral (n=143) NS RP. Fifty-four underwent non-NS (NNS) RP. Kaplan-Meier analyses identified the following risk factors for UC: age, prostate volume, cancer risk group, and NS status. In surgeon-defined NS RP cases, multivariate analysis for regaining continence demonstrated no significant difference (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.48-1.25; P=0.3). With successful IIEF-defined NS RPs, regression analysis demonstrated no significant difference (HR, 0.89; 95% CI, 0.59-1.35; P=0.58). Conclusions: In our population, analysis and comparison of surgeon- and IIEF-defined NS and NNS cohorts revealed that NS RP did not improve postoperative UC. The conservation of UC alone should not motivate surgeons or patients to pursue NS RP. PMID- 29991235 TI - Adherence to Anticholinergic Therapy and Clean Intermittent Self-Catheterization in Patients With Multiple Sclerosis. AB - PURPOSE: To evaluate adherence to anticholinergic therapy (AT) and clean intermittent self-catheterization (CISC) in patients with multiple sclerosis (MS) and to identify factors associated with poor adherence. METHODS: This single center study prospectively included 49 patients suffering from MS who had been prescribed AT and/or CISC. Adherence was evaluated using a self-report questionnaire. The Expanded Disability Status Scale (EDSS), Patient Global Impression of Improvement, Mini-Mental State Examination, Urinary Symptom Profile, and Hospital Anxiety and Depression (HAD) instruments were administered, and the number of daily anticholinergic pills and/or catheterizations was noted. Whether patients were receiving concomitant intradetrusor botulinum toxin injections was assessed, as were barriers to treatment, side effects, number of spontaneous micturitions, reasons for the prescription, satisfaction, and difficulties. RESULTS: Only 38% of patients were adherent to AT. Experiencing side effects was related to nonadherence (P=0.02). Only 29% of patients were adherent to CISC. More intense voiding dysfunction (P<0.001), a higher frequency of CISC (P=0.03), and a higher EDSS score (P=0.02) were associated with better adherence. Conversely, the HAD score (P<0.001), depression (P<0.001), the persistence of spontaneous micturition (P<0.001), a blocking sensation during catheterization (P=0.04), and the need to adapt one's posture or gesture to perform catheterization (P=0.04) were associated with poorer adherence. Conclusions: Adherence to AT and CISC was poor in patients with MS suffering from bladder dysfunction. Several factors related to nonadherence were identified in this study, and addressing these factors might help to improve treatment adherence. PMID- 29991236 TI - Potential Epigenetic Biomarkers for Prostate Cancer Screening. PMID- 29991238 TI - War, Peace, and Neurospine. PMID- 29991237 TI - Is It Possible to Prevent Symptom Recurrence After Transurethral Resection for Hunner Lesion? PMID- 29991239 TI - Development of Neurospine Surgery in North Korea: The Contribution of Korean American Neurosurgeons. PMID- 29991240 TI - Spinal Epidermoid Tumors: Case Report and Review of the Literature. AB - Spinal epidermoid tumors are rare, benign tumors that are either acquired from trauma, surgery, or lumbar puncture or arise as congenital lesions, particularly spinal dysraphisms. We report a case of a massive spinal epidermoid tumor and review the literature with a focus on the surgical outcomes. A 71-year-old female patient presented after a fall with subsequent symptoms of severe back and hip pain, as well as loss of motor strength in the left leg. Her magnetic resonance imaging demonstrated a T2/short tau inversion recovery hyperintense mass extending from the level of the T10-11 disc caudally through S2. A biopsy was recommended to determine whether the tumor was radio- or chemo-sensitive. The patient underwent a L4 laminectomy and a pearly-white tumor was encountered, with a subsequent biopsy confirming it to be an epidermoid tumor. The following conclusions can be drawn from a review of the literature. Spinal epidermoid tumors are more common in women and tend to present in younger patients (median age of 23). The majority of patients had acquired lesions (46%). In terms of surgical outcomes for adherent tumors, gross total resection was found to provide optimal outcomes, with 90% of patients improving clinically after surgery. PMID- 29991241 TI - Choice of Rods in Surgical Treatment of Adolescent Idiopathic Scoliosis: What Are the Clinical Implications of Biomechanical Properties? - A Review of the Literature. AB - The surgical treatment of adolescent idiopathic scoliosis (AIS) involves 3 dimensional curve correction with multisegmental pedicle screws attached to contoured bilateral rods. The substantial corrective forces exert a high level of stress on the rods, and the ability of the rod to withstand these forces without undergoing permanent deformation relies on its biomechanical properties. These properties, in turn, are dependent on the material, diameter, and shape of the rod. The surgical treatment of AIS is characterized by the requirement for a special biomechanical profile that may differ substantially from what is needed for adult deformity surgery. This overview summarizes the current knowledge of rod biomechanics in frequently used rod constructs, with a particular focus on translational research between biomechanical studies and clinical applicability in AIS patients. PMID- 29991242 TI - Feasibility of Full Endoscopic Spine Surgery in Patients Over the Age of 70 Years With Degenerative Lumbar Spine Disease. AB - Objective: Degenerative spine disease, encompassing disc prolapse and stenosis, is a common ailment in old age. This prospective study was undertaken to evaluate the role of endoscopic spine surgery in elderly patients (above 70 years of age) with clinical and radiological follow-up. Methods: In this study, a prospective analysis was conducted of 53 patients with lumbar disc prolapse or spinal stenosis who were treated with percutaneous endoscopic discectomy or decompression from November 2015 to June 2017. Clinical follow-up was done at 1 week, 3 months, and 1 year, and at yearly intervals thereafter. The outcomes were assessed using the modified Macnab criteria, a visual analogue scale, and the Oswestry Disability Index. Results: Of the 53 patients, 21 were men and 32 were women. Their mean age was 76+/-4 years. The mean follow-up period was 17 months. Percutaneous endoscopic discectomy was performed in 24 patients and endoscopic decompression in 24 patients, while 5 patients underwent combined surgery. An excellent outcome in terms of the MacNab criteria was observed in 9 patients (16.98%), a good outcome in 38 patients (71.7%), and a poor outcome in 6 patients (11.3%). Of the 6 patients with a poor outcome, 5 (9.4%, 5 of 53) developed recurrent disc prolapse, and 1 developed hematoma with motor weakness. All 6 of these cases required revision surgery. Conclusion: Managing degenerative spine disease in elderly patients with multiple comorbidities is a challenging task. Percutaneous endoscopic spine surgery is pivotal for addressing this concern. The authors have shown that optimal results can be achieved with various types of disc prolapse and stenosis with favorable long-term outcomes. PMID- 29991243 TI - The Characteristics and Incidence of Posterior Apophyseal Ring Fracture in Patients in Their Early Twenties With Herniated Lumbar Disc. AB - Objective: Posterior apophyseal ring fracture (PARF) is a common disorder that may be accompanied by herniated lumbar disc (HLD) in patients in their early twenties. However, there are very few reports on PARF in this clinical context. The objective of this study was to identify the incidence and characteristics of PARF with HLD in this age group. Methods: We surveyed patients who visited Armed Forces Busan Hospital between May 2017 and October 2017 and included those aged between 19 and 25 years who had HLD accompanied by PARF. We retrospectively collected their demographic characteristics, clinical manifestations, and radiological findings on computed tomography (CT) scans. We categorized the PARF lesions according to Takata's classification. Results: Of 140 HLD patients, 43 (30.7%) had PARF lesions with HLD. We found that the presence of a PARF lesion was significantly related to a severe pain score on the visual analogue scale for lower back pain and/or lower leg radiating pain (p=0.001). The most common level and location of PARF were L5/S1 (n=25, 56.8%) and the superior endplate of the S1 vertebra, respectively. Type 1, according to Takata's classification, was the most common type of PARF in the patients (n=34, 77.2%). Conclusion: We recommend that spinal surgeons perform CT scans to check for PARF lesions in all young patients in their 20s who present with severe radiating and lower back pain. PMID- 29991244 TI - The Impact of Surgical Treatment on Survival in Patients With Cervical Spine Metastases. AB - Objective: To compare overall survival (OS) in patients with cervical spine metastases between initial radiotherapy followed by surgery and initial surgery followed by radiotherapy. Methods: The medical records of 36 patients with cervical spine metastases from January 2007 to December 2015 were retrospectively analyzed. These patients were divided into 2 groups. Group 1 included patients who underwent initial radiotherapy followed by surgery, while group 2 included patients who underwent initial surgery followed by radiotherapy. Clinical outcomes, OS, OS after cervical spine metastasis, and OS after surgery were analyzed in both groups. We evaluated whether primary tumor type, initial treatment modality, the modified Tomita score, Eastern Cooperative Oncology Group performance status, Karnofsky performance status, Japanese Orthopedic Association (JOA) score, Nurick grade, Frankel classification, and preoperative symptoms were associated with OS after cervical spine metastasis. Results: Both groups exhibited improvement in the postoperative visual analogue scale, but only group 2 showed a significant improvement in postoperative JOA score (p=0.03). OS did not differ significantly between groups. However, OS after cervical spine metastasis was only 7.0 months (95% confidence interval [CI], 4.8-9.3) in group 1 versus 15.8 months (95% CI, 8.8-24.0) in group 2, which represented a significant difference (p<0.05). Factors related to OS after cervical spine metastasis were primary tumor type, initial treatment modality, and preoperative symptoms (p<0.05). Patients who presented with only preoperative pain had approximately 3 fold longer OS after cervical spine metastasis than patients with preoperative motor weakness, even in group 2 (p<0.05). Conclusion: Surgical treatment prior to the onset of motor weakness or radiotherapy may be a good decision in case of cervical spine metastasis. PMID- 29991245 TI - Postoperative Fever Evaluation Following Lumbar Fusion Procedures. AB - Objective: This study aimed to determine the incidence of postoperative fever, the workup conducted for postoperative fever, the rate of subsequent fever related diagnoses or complications, and the risk factors associated with fever following lumbar fusion. Methods: A retrospective review of patients undergoing lumbar fusion was performed. For patients in whom fever (>=38.6 degrees C) was documented, charts were reviewed for any fever workup or diagnosis. Multivariate regression was used to identify independent risk factors for the development of postoperative fever. Results: A total of 868 patients met the inclusion criteria, of whom 105 exhibited at least 1 episode of fever during hospitalization. The first documentation of fever occurred during the first 24 hours in 43.8% of cases, during postoperative hours 24-48 in 53.3%, and later than 48 hours postoperatively in 2.9%. At least 1 component of a fever workup was conducted in 47 of the 105 patients who had fever, resulting in fever-associated diagnoses in 4 patients prior to discharge. Three patients who had fever during the inpatient stay developed complications after discharge. On multivariate analysis, operations longer than 150 minutes (relative risk [RR], 1.66; p=0.015) and narcotic consumption greater than 85 oral morphine equivalents on postoperative day 0 (RR, 1.53; p=0.038) were independently associated with an increased risk of developing postoperative fever. Conclusion: The results of this study suggest that inpatient fever occurred in roughly 1 in 8 patients following lumbar fusion surgery. In most cases where a fever workup was performed, no cause of fever was detected. Longer operative time and increased early postoperative narcotic use may increase the risk of developing postoperative fever. PMID- 29991246 TI - Study of the Transverse Foramen in the Subaxial Cervical Spine in Korean Patients With Degenerative Changes: An Anatomical Note. AB - Objective: The purpose of this study was to provide anatomical data on the dimensions and location of the subaxial transverse foramen (TF) in relation to surgical landmarks routinely used during anterior cervical procedures. Methods: A total of 116 patients who underwent preoperative computed tomography (CT) evaluations for degenerative cervical disease were enrolled. Axial and coronal CT images of the cervical vertebrae from C3 to C6 were analyzed to measure interforaminal distance, the TF distance from the anterior and posterior vertebral body margin, TF dimensions, and the TF medial margin from the tip and medial margin of the uncus. Comparative and correlative analyses were also performed according to age, body mass index (BMI), and sex. Results: All measurement values in male patients were larger than those in their female counterparts. The interforaminal distance gradually increased from C3 to C6. The distance of the TF medial margin from the tip of the uncus was found be above approximately 3 mm in all vertebrae except C6. Correlation analysis revealed that age had a significant negative relationship with the transverse diameter of TF. In contrast, BMI had a significant positive correlation with interforaminal distance. Moreover, the distances of the TF medial margin from the tip and medial margin of the uncus showed strong negative correlations with age. Conclusion: Useful morphometric data were obtained that may help the operating surgeon to avoid vertebral artery injury. The safe distance from the tip of the uncus to the TF medial margin was found to be approximately 3 mm, and this distance should not be violated during lateral decompression. In addition, this value may decrease with age. PMID- 29991247 TI - Highly Accurate Analysis of the Cervical Neural Tract of the Elderly Using ZOOM DTI. AB - Objective: To investigate the fractional anisotropy (FA) values of the cervical spinal cord in elderly individuals using zonally magnified oblique multislice (ZOOM) diffusion tensor imaging (DTI). Methods: Fourteen healthy elderly volunteers (group E) and 10 young volunteers (group Y) were enrolled. We assessed the FA, apparent diffusion coefficient (ADC), and lambda1-lambda3 values using 3 T magnetic resonance imaging. The region of interest was contoured entirely inside the spinal cord, with no gray/white matter distinction, in order to avoid including the cerebrospinal fluid. Results: As lower cervical levels were approached, the FA values gradually decreased, while the ADC values increased. The mean FA values at each cervical level were as follows in groups E and Y: 0.71 and 0.70 at the C2/3 level, 0.66 and 0.66 at the C3/4 level, 0.63 and 0.62 at the C4/5 level, 0.57 and 0.57 at the C5/6 level, and 0.58 and 0.57 at the C6/7 level, respectively. The mean ADC values in groups E and Y were 1.06 and 0.99 at the C2/3 level, 1.05 and 1.06 at the C3/4 level, 1.14 and 1.06 at the C4/5 level, 1.18 and 1.21 at the C5/6 level, and 1.39 and 1.46 at the C6/7 level, respectively. There were no significant differences between the elderly and young participants. Conclusion: In both asymptomatic elderly and young individuals, the FA values gradually decreased and the ADC values increased moving towards lower cervical levels. Age did not affect the FA values, even though mild cord compression was evident due to spondylotic changes. ZOOM DTI has the potential to provide more information than conventional DTI. PMID- 29991248 TI - Intra- and Interrater Reliability of Sagittal Spinopelvic Parameters on Full Spine Radiographs in Adults With Symptomatic Spinal Disorders. AB - Objective: To evaluate the intra- and interrater reliability (I-IR) of sagittal spinopelvic parameters from digital full-spine plain radiographs with basic software tools in an unselected adult population with degenerative spinal complaints who were evaluated for surgery. Methods: Forty-nine adult full-spine digital radiographs were measured twice by 3 independent observers, including an experienced spine surgeon, an experienced radiologist, and a resident orthopedic surgeon. Clinical picture archiving and communication system workstations and software tools were used and landmarks were set manually. The I-IR of the sagittal vertical axis (SVA), pelvic tilt (PT), pelvic incidence (PI), sacral slope (SS), and thoracic kyphosis in T4-T12 (TK) were assessed. Results: The intrarater intraclass correlation coefficient (ICC) scores varied from 0.82 to 0.99. The interrater ICC scores ranged from 0.78 to 0.99. The intrarater standard error of measurement (SEM) values for SS, PT, PI, and TK varied from 0.8 degrees to 5.0 degrees , and the interrater SEM values ranged from 2.5 degrees to 6.2 degrees , depending on the parameter and the reading round. The I-IR SEM values for SVA varied from 2.2 to 5.7 mm and from 4.6 to 5.0 mm, respectively. Kappa values were >0.88 for all readers. The intrarater variability was the smallest for the most experienced rater. Conclusion: The I-IR of measuring sagittal spinopelvic parameters on digital full-spine images with basic software tools was high. Parameters consisting of several anatomic landmarks were more liable to error. Rater experience had a positive influence on reliability and repeatability. Reader experience should be assessed before accepting measurements for surgical planning and the interpretation of surgical correction during postoperative follow-up. PMID- 29991249 TI - Monostotic Paget Disease of the Lumbar Vertebrae: A Pathological Mimicker. AB - Paget disease is a metabolic disorder involving abnormal bone turnover that consists of 3 phases: the initial lytic phase, the intermediate mixed phase, and the chronic sclerotic phase. Paget disease mostly presents as polyostotic or monostotic lesions of the spine, and is rare on the Indian subcontinent. We present a case of isolated Paget disease of the lumbar third vertebra, which was confirmed only at biopsy. The patient presented with chronic low backache with a developing neurological deficit. We managed the patient with posterior spinal stabilisation, using pedicular screws and vertebroplasty of the collapsed vertebrae to regain the height. Upon the diagnosis of Paget disease, the patient was treated with calcitonin and bisphosphonates for 3 months, along with regular monitoring of alkaline phosphatase levels. Through this case, we hope to emphasize that Paget disease should be considered in the differential diagnosis of lytic lesions. Additionally, the alkaline phosphatase level in this patient was high-normal, which was an aspect of the role of Paget disease as a mimicker. Confirmatory biopsy is mandatory in all lesions. PMID- 29991250 TI - Oxidation States, Stability, and Reactivity of Organoferrate Complexes. AB - We have applied a combination of electrospray-ionization mass spectrometry, electrical conductivity measurements, and Mossbauer spectroscopy to identify and characterize the organoferrate species R nFe m- formed upon the transmetalation of iron precursors (Fe(acac)3, FeCl3, FeCl2, Fe(OAc)2) with Grignard reagents RMgX (R = Me, Et, Bu, Hex, Oct, Dec, Me3SiCH2, Bn, Ph, Mes, 3,5-(CF3)2-C6H3; X = Cl, Br) in tetrahydrofuran. The observed organoferrates show a large variety in their aggregation (1 <= m <= 8) and oxidation states (I to IV), which are chiefly determined by the nature of their organyl groups R. In numerous cases, the addition of a bidentate amine or phosphine changes the distributions of organoferrates and affects their stability. Besides undergoing efficient intermolecular exchange processes, several of the probed organoferrates react with organyl (pseudo)halides R'X (R' = Et, iPr, Bu, Ph, p-Tol; X = Cl, Br, I, OTf) to afford heteroleptic complexes of the type R3FeR'-. Gas-phase fragmentation of most of these complexes results in reductive eliminations of the coupling products RR' (or, alternatively, of R2). This finding indicates that iron-catalyzed cross-coupling reactions may proceed via such heteroleptic organoferrates R3FeR'- as intermediates. Gas-phase fragmentation of other organoferrate complexes leads to beta-hydrogen eliminations, the loss of arenes, and the expulsion of organyl radicals. The operation of both one- and two electron processes is consistent with previous observations and contributes to the formidable complexity of organoiron chemistry. PMID- 29991251 TI - Catalytic Asymmetric [3 + 2] Cycloaddition Reaction between Aurones and Isocyanoacetates: Access to Spiropyrrolines via Silver Catalysis. AB - The first enantioselective formal [3 + 2] cycloaddition of aurone analogues with isocyanoacetates was developed via chiral Ag-complex catalysis. A variety of optically enriched spiro-1-pyrrolines were obtained in excellent yields, diastero and enantioselectivities (up to 99% yield, >20:1 dr, >99% ee). This synthetic approach represents an extremely simple, efficient, and atom-economical method for spiro-1-pyrrolines synthesis. PMID- 29991253 TI - Structural Rearrangement by Isomer-Specific Infrared Excitation in the Neutral Isolated Dihydrated Cluster of 3-Hydroxyflavone. AB - Isomer-specific, IR-induced reactions in the electronic ground state (S0) can be of great interest to control reaction pathways. Here we show a first example of these reactions with isomer-specific excitation and formation of a new isomer under isolated conditions in a molecular beam experiment. The investigated dihydrated cluster of 3-hydroxyflavone forms two isomers, I and D, in the S0 state. We show that only a mode-specific excitation of isomer I leads to a structural rearrangement yielding an isomer that has not been identified so far. This isomer is assigned in comparison to quantum chemical calculations. The experiments are performed by applying an IR/IR method in combination with a mass selective resonant two-photon ionization (R2PI) process. Usually these kinds of IR/IR/R2PI methods are chosen to discriminate isomers; here it is demonstrated that this powerful method can also be applied for analysis of IR-induced reactions probed by an IR/R2PI process. PMID- 29991252 TI - Visualization and Quantification of Radiochemical Purity by Cerenkov Luminescence Imaging. AB - Determination of radiochemical purity is essential for characterization of all radioactive compounds, including clinical radiopharmaceuticals. Radio-thin layer chromatography (radio-TLC) has been used as the gold standard for measurement of radiochemical purity; however, this method has several limitations in terms of sensitivity, spatial resolution, two-dimensional scanning, and quantification accuracy. Here, we report a new analytical technique for determination of radiochemical purity based on Cerenkov luminescence imaging (CLI), whereby entire TLC plates are visualized by detection of Cerenkov radiation. Sixteen routinely used TLC plates were tested in combination with three different radioisotopes (131I, 124I, and 32P). All TLC plates doped with a fluorescent indicator showed excellent detection sensitivity with scanning times of less than 1 min. The new CLI method was superior to the traditional radio-TLC scanning method in terms of sensitivity, scanning time, spatial resolution, and two-dimensional scanning. The CLI method also showed better quantification features across a wider range of radioactivity values compared with radio-TLC and classical zonal analysis, especially for beta--emitters such as 131I and 32P. PMID- 29991254 TI - Truly Immobilization-Free Diffusivity-Mediated Photoelectrochemical Biosensing Strategy for Facile and Highly Sensitive MicroRNA Assay. AB - In conventional photoelectrochemical (PEC) analysis, photoactive materials are usually immobilized on electrode surfaces, and such immobilization procedures are tedious and time-consuming, and it is also difficult to prepare electrodes with good reproducibility. To circumvent such limitations, we propose here a truly immobilization-free diffusivity-mediated PEC bionsensing strategy for microRNA assay, using methylene blue (MB) in solution as the photoactive probe, and nonmodified indium tin oxide (ITO) glass as the working electrode. The hybridization between the target microRNA and the MB-labeled single-stranded DNA probe (MB-DNA) triggers the digestion of MB-DNA by T7 exonuclease (T7 Exo), thus to generate MB-labeled mononucleotide, and then the released target microRNA initiates the subsequent cycling processes and generates a large amount of MB labeled mononucleotides. Due to the diffusivity difference between MB-DNAs and MB labeled mononucleotides, significantly increased photocurrent signal is observed for MB-labeled mononucleotides as compared to that of MB-DNAs. Therefore, via this "signal-on" mode and the T7 Exo facilitated signal amplification, a facile and highly sensitive immobilization-free PEC microRNA assay is readily realized, with a detection limit down to 27 aM. Moreover, this strategy exhibits excellent specificity and is successfully applied in detecting microRNA spiked in serum samples. Since all the reactions take place in homogeneous solutions and no electrode modification is needed, this PEC biosensing strategy exhibits the advantages of simplicity, rapidness, and good reproducibility. More significantly, it provides a novel concept to design truly immobilization-free PEC biosensing systems, and shows potential to be applied in bioanalysis and biochemical research. PMID- 29991255 TI - Decoding Oxyanion Aqueous Solvation Structure: A Potassium Nitrate Example at Saturation. AB - The ability to probe the structure of a salt solution at the atomic scale is fundamentally important for our understanding of many chemical reactions and their mechanisms. The capability of neutron diffraction to "see" hydrogen (or deuterium) and other light isotopes is exceptional for resolving the structural complexity around the dissolved solutes in aqueous electrolytes. We have made measurements using oxygen isotopes on aqueous nitrate to reveal a small hydrogen bonded water coordination number (3.9 +/- 1.2) around a nitrate oxyanion. This is compared to estimates made using the existing method of nitrogen isotope substitution and those of computational simulations (>5-6 water molecules). The low water coordination number, combined with a comparison to classical molecular dynamics simulations, suggests that ion-pair formation is significant. This insight demonstrates the utility of experimental diffraction data for benchmarking atomistic computer simulations, enabling the development of more accurate intermolecular potentials. PMID- 29991256 TI - Spectroscopy of Surface-State p-Doped CdSe/CdS Quantum Dots. AB - Transient absorption (TA) and time-resolved photoluminescence (PL) spectroscopies have been used to provide direct spectroscopic evidence for the recently reported phenomenon of thermal "surface charging" in II-VI quantum dots (QDs). In these studies, zincblende CdSe cores are synthesized by standard methods, and a thin CdS shell deposited by the decomposition of Cd(DDTC)2, resulting in core/shell QDs with chalcogenide-rich surfaces. Following ligand exchange with oleylamine, these QDs have empty low-lying surface states that can be thermally populated from the valence band. At room temperature, the surface charging equilibrium results in some fraction of the particles having a hole in the valence band, i.e., the surface acceptor states make the particle p-type. Photoexcitation of the surface charged state results in what is essentially a positive trion, which can undergo a fast Auger recombination. Both PL and TA (bleach recovery) kinetics of the CdSe/CdS QDs show a 70 ps decay component, which is assigned to Auger recombination. The empty nonbonding surface orbitals are passivated by ligation with a trialkylphosphine, and the fast decay component is absent when tributylphosphine is present. The comparison of the TA and PL kinetics shows that the relative amplitude of the 70 ps component is a factor of about 1.5 greater in the TA than in the PL. They also show that the fast component in the PL spectrum is shifted about 6 nm to the blue of the exciton luminescence. The above observations can be understood in terms of the trion versus exciton spectroscopy and strongly support the assignment of the 70 ps transient to the decay of a trion formed from the surface charged state. PMID- 29991257 TI - Super Bright Luminescent Metallic Nanoparticles. AB - It is found that, by curing the surface defects that quench photoexcited carriers, luminescence efficiency of metallic nanoparticles can be dramatically increased. For Ag nanoparticles, as much as 300 times increase in photoexcitation induced luminescence is observed upon surface adsorption of ethanethiol. The same treatment increases Au nanoparticle luminescence efficiency by a factor of 3. A model based on the elimination of surface defects by the sulfur-metal bond formed upon thiol adsorption can quantitatively account for the observations, which also indicate that nanoparticles without proper surface treatment typically have low luminescence quantum yields. PMID- 29991258 TI - Emission Recovery and Stability Enhancement of Inorganic Perovskite Quantum Dots. AB - Inorganic lead halide perovskite quantum dots (PQDs), especially red emission PQDs, are well-known to easily lose their luminescence emission with time, which shows from strong emission of fresh PQDs to no emission of aged PQDs. Here, we demonstrate that trioctylphosphine (TOP) can effectively and instantly recover the luminescence emission of aged red PQDs, making the "dead" PQDs "reborn". Furthermore, TOP also works to improve the emission intensity of freshly synthesized PQDs. In this process, TOP does not make any detectable structural changes to PQDs. Besides, TOP can effectively enhance the stability of PQDs against long-term storage, temperature, UV irradiation, and polar solvents. This unusual emission recovery and stability enhancement by TOP shall promote the understanding of particle surface conditions and the development of PQD devices. PMID- 29991259 TI - Pressure-Induced Phase Transformation and Band-Gap Engineering of Formamidinium Lead Iodide Perovskite Nanocrystals. AB - Formamidinium lead halide (FAPbX3, X = Cl, Br, I) perovskite materials have recently drawn an increased amount of attention owing to their superior optoelectronic properties and enhanced material stability as compared with their methylammonium-based (MA-based) analogues. Herein, we report a study of the pressure-induced structural and optical evolutions of FAPbI3 hybrid organic inorganic perovskite nanocrystals (NCs) using a synchrotron-based X-ray scattering technique coupled to in situ absorption and photoluminescence spectroscopies. As a result of their unique structural stability and soft nature, FAPbI3 NCs exhibit a wide range of band-gap tunability (1.44-2.17 eV) as a function of pressure (0-13.4 GPa). The study presented here not only provides an efficient and chemically orthogonal means to controllably engineer the band gap of FAPbI3 NCs using pressure but more importantly sheds light on how to strategically design the band gaps of FA-based hybrid organic-inorganic perovskites for various optoelectronic applications. PMID- 29991260 TI - Resolving Deep Quantum-Well States in Atomically Thin 2H-MoTe2 Flakes by Nanospot Angle-Resolved Photoemission Spectroscopy. AB - Transition-metal dichalcogenides exhibit strong quantum confinement effects, and their electronic structure is strongly dependent on the number of layers. Resolving the thickness-dependent electronic structure is important. While the electronic structure of atomically thin 2H-MoSe2 or 2H-MoS2 have been explored, information on the experimental electronic structure of 2H-MoTe2 is still missing. Here, by using nanospot angle-resolved photoemission spectroscopy (nanoARPES), we reveal the experimental electronic structure of exfoliated 2H MoTe2 thin flakes with different thickness (three, five, and seven monolayers). Well-separated quantum-well states are clearly observed in thin 2H-MoTe2 flakes at deep valence bands at energies between -3 to -5 eV, while those at the top of the valence band between -1 and -2 eV are much more closely spaced compared with those from 2H-MoSe2 and 2H-MoS2. First-principles calculation shows that the main difference is attributed to the weaker hybridization and smaller energy difference between Mo 4d z2 and Te 5p z orbitals as compared with Se 4p z and S 3p z orbitals. Our work demonstrates the power of nanoARPES in resolving the electronic structure of atomically thin exfoliated flakes. PMID- 29991261 TI - A Processive Protein Chimera Introduces Mutations across Defined DNA Regions In Vivo. AB - Laboratory time scale evolution in vivo relies on the generation of large, mutationally diverse gene libraries to rapidly explore biomolecule sequence landscapes. Traditional global mutagenesis methods are problematic because they introduce many off-target mutations that are often lethal and can engender false positives. We report the development and application of the MutaT7 chimera, a potent and highly targeted in vivo mutagenesis agent. MutaT7 utilizes a DNA damaging cytidine deaminase fused to a processive RNA polymerase to continuously direct mutations to specific, well-defined DNA regions of any relevant length. MutaT7 thus provides a mechanism for in vivo targeted mutagenesis across multi-kb DNA sequences. MutaT7 should prove useful in diverse organisms, opening the door to new types of in vivo evolution experiments. PMID- 29991262 TI - Hydrazide Mimics for Protein Lysine Acylation To Assess Nucleosome Dynamics and Deubiquitinase Action. AB - A range of acyl-lysine (acyl-Lys) modifications on histones and other proteins have been mapped over the past decade but for most, their functional and structural significance remains poorly characterized. One limitation in the study of acyl-Lys containing proteins is the challenge of producing them or their mimics in site-specifically modified forms. We describe a cysteine alkylation based method to install hydrazide mimics of acyl-Lys post-translational modifications (PTMs) on proteins. We have applied this method to install mimics of acetyl-Lys, 2-hydroxyisobutyryl-Lys, and ubiquityl-Lys that could be recognized selectively by relevant acyl-Lys modification antibodies. The acyl-Lys modified histone H3 proteins were reconstituted into nucleosomes to study nucleosome dynamics and stability as a function of modification type and site. We also installed a ubiquityl-Lys mimic in histone H2B and generated a diubiquitin analog, both of which could be cleaved by deubiquitinating enzymes. Nucleosomes containing the H2B ubiquityl-Lys mimic were used to study the SAGA deubiquitinating module's molecular recognition. These results suggest that acyl Lys mimics offer a relatively simple and promising strategy to study the role of acyl-Lys modifications in the function, structure, and regulation of proteins and protein complexes. PMID- 29991263 TI - Impedance Analysis of Polyaniline in Comparison with Some Conventional Solid Electrolytes. AB - Doped polyaniline (PANI) is well-known as an electronic (polaronic) conductor and mostly is used as semiconductor in various applications. However, in the literature there are examples of employment of the acid doped form of PANI as electrolytic filler in proton exchange membranes. In order to distinguish between two types of conduction, in the present study powdered samples of polyaniline, either in the form of emeraldine base (PANI-EB) or in the form doped with camphorsulfonic acid (PANI-CSA), were investigated using impedance spectroscopy both in the dry state and in contact with liquid water. The obtained spectra were compared with the spectra of such conventional solid electrolytes, as zeolites X and ZSM5 and a strong electrolyte boron orthophosphate, acquired in identical conditions. The most important dissimilarity between conventional electrolytes and PANI was that ion diffusion dominates in the impedance response of the formers, whereas the behavior of PANI is under control of electron/hole displacement and the diffusion part is quite inessential. This corroborates the results of analysis of temperature dependence of PANI conductivity, which revealed values of activation energy twice as large as typical solid electrolytes. Equivalent circuits, simulating the impedance responses of all materials, were built up and used to estimate a possible diffusion coefficient of cations in the comparable solids. It was found that the diffusion in a strong electrolyte such as BPO4 is ~2 orders of magnitude faster than evaluated for zeolites and ~4 orders higher than what was PANI estimation. A conclusion was made that the slow cation diffusion both in protonated and in base form of PANI makes them less efficient solid electrolytes than conventional materials. PMID- 29991264 TI - Ultrafast Ground-State Intramolecular Proton Transfer in Diethylaminohydroxyflavone Resolved with Pump-Dump-Probe Spectroscopy. AB - 4'- N, N-Diethylamino-3-hydroxyflavone (DEAHF), due to excited-state intramolecular proton transfer (ESIPT) reaction, exhibits two solvent-dependent emission bands. Because of the slow formation and fast decay of the ground-state tautomer, its population does not accumulate enough for its detection during the normal photocycle. As a result, the details of the ground-state intramolecular proton-transfer (GSIPT) reaction have remained unknown. The present work uses femtosecond pump-dump-probe spectroscopy to prepare the short-lived ground-state tautomer and track this GSIPT process in solution. By simultaneously measuring femtosecond pump-probe and pump-dump-probe spectra, ultrafast kinetics of the ESIPT and GSIPT reactions are obtained. The GSIPT reaction is shown to be a solvent-dependent irreversible two-state process in two solvents, with estimated time constants of 1.7 ps in toluene and 10 ps in the more polar tetrahydrofuran. These results are of great value in both fully describing the photocycle of this four-level proton transfer molecule and for providing a deeper understanding of dynamical solvent effects on tautomerization. PMID- 29991265 TI - Coherent Control of the Rotation Axis of Molecular Superrotors. AB - The control of ultrafast molecular rotational motion has benefited from the development of innovative techniques in strong-field laser physics. Here, we theoretically demonstrate a novel type of coherent control by inducing rotation of an asymmetric-top molecule about two different molecular axes. An optical centrifuge is applied to the hydrogen sulfide (H2S) molecule to create a molecular superrotor, an object performing ultrafast rotation about a well defined axis. Using two distinct pulse envelopes for the optical centrifuge, we show that H2S can be excited along separate pathways of rotational states. This leads to stable rotation about two entirely different molecular axes while ensuring rotation is about the propagation direction of the centrifuge, i.e., the laboratory-fixed Z-axis. The presented scheme to control the angular momentum alignment of a molecule will, for instance, be useful in studies of molecule molecule or molecule-surface scattering, especially due to the large amounts of energy associated with superrotors, which can even be controlled by changing the duration of the optical centrifuge pulse. PMID- 29991266 TI - Disentangling Magnetic Hardening and Molecular Spin Chain Contributions to Exchange Bias in Ferromagnet/Molecule Bilayers. AB - We performed ferromagnetic resonance and magnetometry experiments to clarify the relationship between two reported magnetic exchange effects arising from interfacial spin-polarized charge transfer in ferromagnetic metal (FM)/molecule bilayers: the magnetic hardening effect and spinterface-stabilized molecular spin chains. To disentangle these effects, we tuned the metal phthalocyanine molecule central site's magnetic moment to enhance or suppress the formation of spin chains in the molecular film. We find that both effects are distinct, and additive. In the process, we extend the list of FM/molecule candidate pairs that are known to generate magnetic exchange effects, experimentally confirm the predicted increase in anisotropy upon molecular adsorption, and show that spin chains within the molecular film can enhance magnetic exchange. Our results confirm, as an echo to progress regarding inorganic spintronic tunnelling, that spintronic tunnelling across structurally ordered organic barriers has been reached through previous magnetotransport experiments. PMID- 29991267 TI - Introduction: 2D Materials Chemistry. PMID- 29991269 TI - Does Ticagrelor Improve Endothelial Function? AB - Ticagrelor is a P2Y12 receptor antagonist with proven clinical benefit in patients with acute coronary syndrome. Apart from its principal antiplatelet action, pleiotropic effects have been implicated in the clinical profile of ticagrelor, including a potentially beneficial impact on endothelial function. In light of the common presence and prognostic value of endothelial dysfunction in patients with coronary artery disease, several clinical studies have investigated the postulated effect of ticagrelor on endothelial function, yielding conflicting results. Limitations of the relevant studies as well as substantial differences in patient population, study design, and methods may account for these controversial findings. Most of these studies, however, support a beneficial impact of ticagrelor on endothelial function, which seems to be significant in the higher risk patients. In order to elucidate this effect, further research efforts should aim to clarify how quickly does endothelial function respond to ticagrelor, how sustained this response is during the dosing intervals and in the long term, which mechanisms are implicated, and whether this pleiotropic action is clinically significant. Future studies should include larger and diverse populations of patients, assess endothelial function at several time points after treatment initiation, and use multiple methods of endothelial function measurement, while implementing strict methodology. Nevertheless, the extent of the clinical benefit of ticagrelor attributable to actions beyond its potent and consistent antiplatelet effect remains uncertain. PMID- 29991270 TI - Effects of diacutaneous fibrolysis in patients with mild to moderate symptomatic carpal tunnel syndrome: a randomized controlled trial. AB - OBJECTIVE:: To compare the effects of diacutaneous fibrolysis with sham in patients with mild to moderate carpal tunnel syndrome. DESIGN:: Double-blind (patient and evaluator) randomized controlled trial. SETTING:: Miguel Servet University Hospital, Zaragoza, Spain. SUBJECTS:: A total of 52 patients (72 wrists) with carpal tunnel syndrome, 41 women and 11 men, mean age was 46.9 (8.8) years. They were divided into two groups: diacutaneous fibrolysis group and sham group. INTERVENTIONS:: Real diacutaneous fibrolysis in diacutaneous fibrolysis group and sham diacutaneous fibrolysis in sham group. Both groups received five sessions in the forearm, wrist and hand. MAIN MEASURES:: Neurophysiological parameters assessed at baseline and at the end of the treatment. Intensity of nocturnal symptoms (visual analogue scale (VAS)) and upper limb functional capacity (Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire) at baseline, at the end of the treatment and one month after treatment. RESULTS:: Diacutaneous fibrolysis group (n = 30 wrists) improved in nerve conduction distal motor latency (mean difference: -0.26, 95% confidence interval (CI): -0.49/ 0.26), sensory conduction velocity (mean difference: 6.52, 95% CI: 3.52/9.51), intensity of nocturnal symptoms (mean difference: -2.24, 95% CI: -4.08/-2.04) and upper limb functional capacity (mean difference: -19, 95% CI: -26.1/-11.9) compared to the sham group (n = 30 wrists) ( P < 0.02, P < 0.01, P < 0.01 and P < 0.01, respectively). At one-month follow-up, improvements in the nocturnal symptoms and upper limb functional capacity were maintained compared to the sham group ( P < 0.01). CONCLUSION:: Diacutaneous fibrolysis provides short-term and one-month follow-up, improvements in sensory conduction velocity, motor distal latency, symptoms and functional capacity in patients with mild to moderate carpal tunnel syndrome. PMID- 29991272 TI - Effect of Nicorandil Administration on Preventing Contrast-Induced Nephropathy: A Meta-Analysis. PMID- 29991271 TI - Prevalence and Incidence of Statin Use and 3-Year Adherence and Discontinuation Rates Among Older Adults With Dementia. AB - OBJECTIVE:: To examine the patterns of statin use and determine the 3-year adherence and discontinuation rates among a cohort of Australians aged >=65 years with dementia. METHODS:: The yearly prevalence and incidence of statin use were compared via Poisson regression modeling using 2007 as the reference year. People with dementia were identified according to dispensing of antidementia medications. A cohort of 589 new statin users was followed longitudinally. Adherence was estimated via the proportion of days covered (PDC). Discontinuation was defined as >=90 days without statin coverage. RESULTS:: The annual prevalence of statin use among older Australians with dementia increased from 20.6% in 2007 to 31.7% in 2016 (aged-sex adjusted rate ratio: 1.51, 95% confidence interval: 1.35-1.69). Among the new users, the proportion adherent (PDC >= 0.80) decreased from 60.3% at 6 months to 31.0% at 3 years. During the 3-year follow-up, 58.7% discontinued their statin. CONCLUSIONS:: Despite increased use of statins among older Australians with dementia, adherence is low and discontinuation is high, which may point to intentional cessation. PMID- 29991273 TI - Stuck Between Two Lives: The Paradox of Eliminating and Welcoming Errors. PMID- 29991274 TI - Secret intake of antiretroviral treatment and HIV-1 viremia in a public routine clinic in Burkina Faso: a surprising relationship. AB - In sub-Saharan Africa, where people living with HIV are frequently stigmatized, the intake of antiretroviral treatment (ART) remains a critical issue for many patients. Although the secret intake of ART may hinder the adherence to treatment, data on its specific impact on therapeutic effectiveness are lacking. We therefore assessed the association between secret intake of ART (i.e., hidden from family) and HIV-1 viremia among patients treated in a public routine clinic in Burkina Faso. We performed a cross-sectional study from December 2012 to September 2013 among patients on ART at the Day Care Unit in Bobo Dioulasso. Patients were eligible for the study if they were 15 years old or over, infected with HIV-1 or HIV-1 + 2, and on ART for at least six months. HIV-1 viral load was measured using Biocentric or Abbott Real Time assay. Study-specific data were collected by social workers using face-to-face interviews, and medical data using the routine electronic database. The association between secret intake of ART and viral load >300 copies/mL was assessed using a multivariate logistic regression. Of 771 patients (women 81.4%; median age 41 years; median time on ART 51 months), 408 reported secret intake of ART and 363 declared open intake. Compared to the latter, patients who hid their intake were younger, more likely to be women and to be involved in a polygamist or in a non-cohabiting union. Viremia was observed in 4.4% of patients hiding ART intake and 9.4% of those taking it openly. By multivariate analysis, secret intake of ART was significantly associated with a lower risk of viremia (adjusted odds ratio 0.41, 95% confidence interval 0.22 0.76). The unexpected relation between secret intake of ART and viremia found in this study requires further investigations. Quantitative and qualitative studies need to be performed. PMID- 29991275 TI - Death of the Swiss Cheese Model of Medical Error. PMID- 29991276 TI - Statistical Practices of Safety Monitoring: An Industry Survey. AB - The Biopharmaceutical Section of the American Statistical Association (ASA) formed a Safety Monitoring Working Group to strengthen collaborations between biostatisticians and safety scientists. The task began by surveying current needs and practices regarding available statistical safety tools and methods, regulatory guidance, and processes needed to support their implementation. The goal is for biostatisticians to become fully engaged safety team members by having the necessary safety skill set including appropriate methodology, regulatory guidance and access to appropriate tools. In this publication, we will discuss our survey results that reveal current practices at 22 pharmaceutical companies and demonstrate how the survey instrument can be used to map an action plan for meeting the demand for improved quantitative safety monitoring. PMID- 29991277 TI - A Retrospective Review of Patients With Acute Stroke With and Without Palliative Care Consultations. AB - Despite advances in stroke care, patients continue to incur significant disability, are at risk for future events, and are inconsistently comanaged with palliative care (PC) specialty teams. The purpose of this study was to review patients with stroke admitted to our institution, comparing patients with and without PC consultation. We retrospectively reviewed medical record data of all patients with stroke admitted to our neurosciences ICU (NICU) in July 2014 to June 2015 with and without PC consultation. Review focused on stroke type, patient demographics, median days to discharge and death, and posthospitalization discharge. Of 463 patients admitted to the NICU with a stroke diagnosis, 27% (125/463) had (PC) consultation. A higher percentage of the patients with PC consult presented with hemorrhagic stroke than those without PC consult (38% vs 21%, P < .001). Patients with PC consult had longer median days to discharge and death ( P < .001) and a higher percentage of mortality (32% vs 11%). Of the 301 patients without PC consult who discharged (89.1%), 36.5% discharged to inpatient rehab while 10% discharged to a skilled nursing facility. In comparison, of the patients with PC consultation who discharged alive (41.1%), 15.7% discharged to inpatient rehab whereas 39% discharged to skilled nursing ( P < .001). The uncertainty of which patients with stroke benefit most from specialty PC is highlighted in that although sicker patients are referred to PC, a substantial portion (41%) of these patients discharge alive, of which 39.2% discharged to skilled nursing. Future research should focus on which patients with stroke would benefit from specialty PC. PMID- 29991278 TI - Novel Bivalent and D-Peptide Ligands of CXCR4 Mobilize Hematopoietic Progenitor Cells to the Blood in C3H/HeJ Mice. AB - The interaction of SDF-1alpha (also known as CXCL12) with the CXCR4 receptor plays a critical role in the retention of hematopoietic stem cells (HSCs) in bone marrow. The viral macrophage inflammatory protein-II (vMIP-II), a human herpesvirus-8 (HHV-8)-encoded viral chemokine, can bind the CXCR4 receptor and inhibit endogenous ligand-induced calcium responses and cell migration. Previously, we used the bivalent ligand approach to link synthetically two unnatural D-amino acid peptides derived from the N-terminus of vMIP-II (DV1 and DV3, respectively) to generate a dimeric peptide, DV1-K-(DV3) (also named HC4319), which shows very high affinity for CXCR4. Here, we studied the biological effects of this dimeric peptide, HC4319, and its monomeric counterpart, DV1, on SDF-1alpha-induced signaling in CXCR4- or CXCR7-transfected Chinese hamster ovary cells and mobilization of hematopoietic progenitor cells (HPCs) in C3H/HeJ mice using an HPC assay. HC4319 and DV1 inhibited significantly the phosphorylation of Akt and Erk, known to be downstream signaling events of CXCR4. This in vivo study in C3H/HeJ mice showed that HC4319 and DV-1 strongly induced rapid mobilization of granulocyte-macrophage colony-forming units (CFUs), erythrocyte burst-forming units, and granulocyte-erythrocyte-monocyte megakaryocyte CFUs from the bone marrow to the blood. These results provide the first reported experimental evidence that bivalent and D-amino acid peptides derived from the N-terminus of vMIP-II are potent mobilizers of HPCs in C3H/HeJ mice and support the further development of such agents for clinical application. PMID- 29991279 TI - Mesenchymal Stem Cell Therapy of Pulmonary Fibrosis: Improvement with Target Combination. AB - Although the clinical application of new drugs has been shown to be effective in slowing disease progression and improving the quality of life in patients with pulmonary fibrosis, the damaged lung tissue does not recover with these drugs. Thus, there is an urgent need to establish regenerative therapy, such as stem cell therapy or tissue engineering. Moreover, the clinical application of mesenchymal stem cell (MSC) therapy has been shown to be safe in humans with idiopathic pulmonary fibrosis (IPF). It seems that a combination of MSC transplantation and pharmaceutical therapy might have additional benefits; however, the experimental design for its efficacy is still lacking. In this review, we provide an overview of the mechanisms that were identified when IPF was treated with MSC transplantation or new drugs. To maximize the therapeutic effect, we suggest that MSC transplantation is combined with drug application for synergistic effects. This review provides clinicians and scientists with the most efficient medical options, in the hope that this will spur on future research and lead to an eventual cure for this disease. PMID- 29991280 TI - Characteristics of Female Germline Stem Cells from Porcine Ovaries at Sexual Maturity. AB - Pigs share many anatomical and physiological features with humans, offering a unique and viable model for biomedical research. Although porcine female germline stem cells (FGSCs) were identified in the juvenile ovary, no reports described the isolation and purification of FGSCs from the pig at sexual maturity. Here, we isolated, purified, and cultured FGSCs from porcine ovaries at sexual maturity. Furthermore, we established and characterized the porcine FGSC (pFGSC) lines. In addition, we found that pFGSC lines could differentiate into oocytes when injection into tissue grafts, including human ovarian tissues. The results show that FGSCs exist in ovaries of Banna mini-pigs at juvenile and sexually maturity. These findings have implications in animal biotechnology applications and regeneration medicine. PMID- 29991281 TI - Using Cluster Analysis to Understand Clinician Readiness to Promote Continuous Glucose Monitoring Adoption. AB - BACKGROUND:: Many people with type 1 diabetes (T1D) report barriers to using continuous glucose monitoring (CGM). Diabetes care providers may have their own barriers to promoting CGM uptake. The goal of this study was to develop clinician "personas" with regard to readiness to promote CGM uptake. METHODS:: Diabetes care providers who treat people with T1D (N = 209) completed a survey on perceived patient barriers to device uptake, technology attitudes, and characteristics and barriers specific to their clinical practice. K-means cluster analyses grouped the sample by CGM barriers and attitudes. ANOVAs and chi-square tests assessed group differences on provider and patient characteristics. The authors assigned descriptive names for each persona. RESULTS:: Analyses yielded three clinician personas regarding readiness to promote CGM uptake. Ready clinicians (20% of sample; 24% physicians, 38% certified diabetes educators/CDEs) had positive technology attitudes, had clinic time to work with patients using CGM, and found it easy to keep up with technology advances. In comparison, Cautious clinicians (41% of sample; 17% physicians, 53% CDEs) perceived that their patients had many barriers to adopting CGM and had less time than the Ready group to work with patients using CGM data. Not Yet Ready clinicians (40% of sample; 9% physicians; 79% CDEs) had negative technology attitudes and the least clinic time to work with CGM data. They found it difficult to keep up with technology advances. CONCLUSION:: Some diabetes clinicians may benefit from tailored interventions and additional time and resources to empower them to help facilitate increased uptake of CGM technology. PMID- 29991282 TI - Evaluating Twitter as a complementary data source for pharmacovigilance. AB - BACKGROUND: Social media are currently considered as a potential complementary source of knowledge for drug safety surveillance. Our primary objective was to estimate the frequency of adverse drug reactions (ADRs) experienced by Twitter users. Our secondary objective was to determine whether tweets constitute a valuable and informative source of data for pharmacovigilance purposes, despite limitations on character number per tweet. RESEARCH DESIGN AND METHODS: We selected a list of 33 drugs subject to careful monitoring due to safety concern in France and Europe, and extracted tweets using the streaming API from 30 September 2014 to 5 April 2015. Two pharmacovigilance centers classified these tweets manually as potential ADR case reports. RESULTS: Among 10,534 tweets, 848 (8.05%) implied or mentioned an ADR without meeting the four FDA criteria required for reporting an ADR, and 289 (2.74%) tweets were classified as 'case reports.' Among them 20 (7.27%) tweets mentioned an unexpected ADR and 33 (11.42%) tweets mentioned a serious ADR. CONCLUSIONS: With the use of dedicated tools, Twitter could become a complementary source of information for pharmacovigilance, despite a major limitation regarding causality assessment of ADRs in individual tweets, which may improve with the new limitation to 280 characters per tweet. PMID- 29991283 TI - Listening in noise training in children with auditory processing disorder: exploring group and individual data. AB - PURPOSE: The purpose of this study was to examine the impact of auditory training in noise on auditory behaviors and life habits in children with auditory processing disorder. METHODS: Ten children with auditory processing disorder underwent an auditory training program in noise and six children with auditory processing disorder comprised a control group. Before and after training, participants were tested on sentence identification in noise and auditory evoked late latency responses. Participants teachers completed two questionnaires on children's auditory behaviors and life habits. RESULTS: Participants were more tolerant to noise as the training sessions progressed. Significant between-group differences were found in P1 and N2 latency measures, independent of measurement time. The observed data trends suggest that some participants improved their performance on the sentence identification task in noise as well as on some electrophysiological parameters. No significant differences in questionnaire scores were found between groups or measurement times. However, one questionnaire showed significant between-group differences for certain questions. CONCLUSIONS: Listening in noise can improve with training for children with auditory processing disorder. However, this training program might be beneficial for some, but not all, children with auditory processing disorder. More data are needed to verify individual data trends. Implication for rehabilitation A structured program was developed to improve the ability of children with auditory processing disorder to listen in noise. Intervention can be beneficial for improving auditory behaviors in some children with auditory processing disorder. A limited number of questions on children's auditory behaviors asked to teachers appears to be more sensitive to intervention-related improvement compared to questions on life habits. PMID- 29991284 TI - Optic coherence tomography appearances of retinal astrocytic hamartoma and systemic features in tuberous sclerosis of Japanese patients. AB - PURPOSE: To describe the optical coherence tomography findings of retinal astrocytic hamartoma of tuberous sclerosis and to confirm the association between the type of retinal astrocytic hamartoma and systemic manifestations in Japanese patients. STUDY DESIGN: A retrospective observational case series. METHODS: The medical records of 35 patients with tuberous sclerosis who underwent ophthalmological examination were reviewed. The retinal astrocytic hamartomas were classified into four types based on the optical coherence tomography findings, and their association with systemic disease was evaluated. RESULTS: A total of 40 retinal astrocytic hamartomas in 13 eyes of eight patients aged 4-28 years were identified. Optical coherence tomography images were obtained for 23 lesions in 10 eyes of seven patients. Retinal astrocytic hamartomas were seen as protruding lesions of varying heights (maximum thickness, range between 221 to 1043 MUm). Of the 23, 15 lesions showed homogeneous reflectivity; in six lesions, hyper-reflective spots that presumably represented intratumoral calcification were noted. Vitreous changes were noted in 13 lesions; vitreous seeding by retinal astrocytic hamartoma was observed in seven eyes. There were no significant differences in the rates of each systemic feature among the optical coherence tomography types. CONCLUSION: Retinal astrocytic hamartomas were classified into four types according to the previous reports; however, this classification may be worthless because the extent of protrusion did not correspond to the intratumoral characteristics, and the involved depth of the retina was not same even in the same type. An association between the type of retinal astrocytic hamartoma and systemic manifestations was not confirmed in this small case series. We considered that the classification of retinal astrocytic hamartoma and its association with systemic manifestations need further study. PMID- 29991285 TI - Immunolocalization of transforming growth factor-beta1, connective tissue growth factor, phosphorylated-SMAD2/3, and phosphorylated-ERK1/2 during mouse incisor development. AB - BACKGROUND/AIMS: Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta 1 (TGF-beta1) and TGF-beta1-induced CTGF expression is regulated through SMAD and mitogen-activated protein kinase (MAPK) signaling pathways. However, little is known about the localization of CTGF and TGF-beta1 signaling cascades during incisor development. Therefore, we aimed to investigate the distribution pattern of TGF-beta1, CTGF, phosphorylated-SMAD2/3 (p-SMAD2/3), and phosphorylated-ERK1/2 (p-ERK1/2) in the developing mouse incisors. MATERIALS AND METHODS: ICR mice heads of embryonic (E) day 16.5, postnatal (PN) day 0.5 and PN3.5 were processed for immunohistochemistry. RESULTS: From E16.5 to PN3.5, moderate to strong staining for TGF-beta1 and CTGF was localized in stellate reticulum (SR), transit amplifying (TA) cells, outer enamel epithelium (OEE), preameloblasts (PA), preodontoblasts (PO), and dental papilla (DP). p-SMAD2/3 was weakly positive in SR and OEE at E16.5 and PN0.5 but was strongly positive in SR and OEE at PN3.5. Particularly, in the stem cell niche, p-SMAD2/3 was only localized in SR cells adjacent to OEE. There was no staining for p-SMAD2/3 in TA cells, PA and PO, although weak to moderate staining for p-SMAD2/3 was seen in DP. From E16.5 to PN3.5, p-ERK1/2 was negative in TA cells, OEE, PA and PO, whereas weak to moderate staining for p-ERK1/2 was observed in SR. DP was moderately stained for p-ERK1/2. CONCLUSIONS: TGF-beta1 and CTGF show a similar expression, while p-SMAD2/3 and p-ERK1/2 exhibit differential distribution pattern, which indicates that CTGF and TGF-beta1 signaling cascades might play a regulatory role in incisor development. PMID- 29991286 TI - Comparison of 2-Octyl Cyanoacrylate Topical Skin Adhesive and Simple Interrupted Nylon Sutures for Wound Closure in Ankle Fracture Surgery. AB - BACKGROUND:: Multiple options are available for closure of incisions in ankle fracture surgery. The aim of our study was to compare postoperative outcomes between conventional simple interrupted nylon sutures and 2-octyl cyanoacrylate as a topical skin adhesive to close the incision after ankle fracture surgery. METHODS:: We retrospectively reviewed the records of 367 consecutive patients (174 simple interrupted nylon suture patients and 193 topical skin adhesive patients) who underwent operative treatment for ankle fracture between 2010 and 2015. Development of wound complications, operative time, Olerud-Molander Ankle Score (OMAS), and patient satisfaction with the wound were compared. The demographics between the 2 groups were not different. RESULTS:: There were no differences in complication rates ( P = .861), OMAS at 3 months or 12 months following surgery ( P = .897 and .646, respectively) between the 2 types of wound closure. Operative time was 9 minutes shorter when topical skin adhesive was used compared to nylon sutures ( P = .003). Patient satisfaction with their wound was significantly higher in the topical skin adhesive group than the nylon skin suture group ( P = .012). CONCLUSIONS:: The use of 2-octyl cyanoacrylate topical skin adhesive for wound closure following ankle fracture surgery was effective, safe, and showed higher patient satisfaction compared to simple interrupted nylon sutures. Although caution should be taken because of the insufficient statistical power of complications, this method was an additional safe option for wound closure in ankle fracture surgery. LEVEL OF EVIDENCE:: Level III, retrospective comparative study. PMID- 29991287 TI - Epidermal growth factor receptor based active targeting: a paradigm shift towards advance tumor therapy. AB - The epidermal growth factor receptor (EGFR) is a cell surface receptor belonging to erythroblastic leukemia viral oncogene homologue (ErbB) family of tyrosine kinase. It plays critical role in the regulation of cell proliferation, survival and differentiation. The EGFR receptor is crucial in a variety of tumor development due to unlikely triggered by receptor overexpression, chromosomal mutation and or ligand-dependent receptor dimerization. The EGFR inhibition established a major therapeutic target in cancer therapy. The signal transduction pathway of EGFR is directly involved in tumor pathogenesis and progression. The combinatorial approach with EGFR inhibitors bring novel therapeutic regime with proved clinical efficacy. This critique briefly addressed EGFR receptor characteristics, worldwide report on various cancers and EGFR based potential targeting modalities in skin, breast, ovary, brain, lungs, pancreas, gastric and colorectal tumors and molecular pathways involved in EGFR targeting. PMID- 29991288 TI - Assuring Health Access and Culturally Competent Health Services Through the Latino Health for All Coalition. AB - Although the importance of health care access is widely acknowledged, less is known about how partnerships can help assure access to quality health services for those experiencing health inequities. This report describes implementation of collaborative efforts through the Health Access Committee of the Latino Health for All Coalition (Wyandotte County/Kansas City, Kansas) to address its three goal areas (1) improving cultural competence through organizational change, (2) improving access to quality health services through access to diabetes prevention services, and (3) improving access and linkage to care via enrollment in health insurance. Using community-based participatory approaches, we documented and reflected on the pattern of activities facilitated by the coalition and its partners for each goal area over a 1-year period. This case report outlines strategies, activities, and lessons learned by coalition partners. This article offers practical guidance about how to structure and implement a coalition that provides technical support for increasing health care access and cultural competency. PMID- 29991289 TI - Resveratrol attenuates iron-induced toxicity in a chronic post-treatment paradigm in Caenorhabditis elegans. AB - There is an increase in the number of studies indicating that a disturbance in iron homeostasis is involved in the pathogenesis of neurodegenerative diseases, in which oxidative stress plays an important role. Oxidative stress can be counteracted by bioactive molecules like the flavonoid resveratrol, which acts as scavenging agent, or by modulating enzymes and metabolic signalling pathways, thus depicting the neuroprotective potential. On the other hand, flavonoids, resveratrol included, have been reported to induce an increase in the reactive species production. In this study we aimed to evaluate in vivo the protective potential of resveratrol against iron imbalance using the Caenorhabditis elegans model. We acutely exposed C. elegans to iron and administered resveratrol pre- or post-iron treatment. Iron-treated worms demonstrated a significant decrease in the survival, neuronal change, decreased dehydrogenases activity and ATP levels, and a significant increase in the oxidative stress. Acute pre-exposure to resveratrol potentiated the toxic effect of the metal by reducing ATP levels, while post-iron chronic resveratrol treatment following the iron exposure increased the worms' survival and reduced the generation of reactive species and neuronal damage. In conclusion, our results demonstrated that resveratrol has various protective effects depending on the duration and order of administration, whereby chronic post-iron treatment to resveratrol as an antidote appeared to be a more effective approach. PMID- 29991290 TI - Optical coherence tomography angiography in myopic choroidal neovascularization after intravitreal ranibizumab. AB - PURPOSE: To describe the optical coherence tomography angiography characteristics of myopic patients with choroidal neovascularization secondary to pathologic myopia during ranibizumab therapy. METHODS: Nineteen patients were enrolled in this prospective study (13 females, 6 males, mean age 55.25 +/- 9.63 years) for a total of 20 eyes examined (14 right eyes, 6 left eyes). Images were analyzed independently by two examiners. RESULTS: Mean follow-up was 5.75 +/- 1.88 months, with a mean intravitreal injections of 1.90 +/- 0.44. Mean best-corrected visual acuity at baseline was 0.39 +/- 0.18 logMAR versus 0.26 +/- 0.16 logMAR 6 months after treatment. The neovascular area (Z = -2.091, p = 0.037) was significantly reduced after treatment, whereas vessel density was not (Z = -1.848, p = 0.065). Moreover, the best-corrected visual acuity was increased (Z = -3.055, p = 0.002). Neovascular area was significantly correlated with best-corrected visual acuity, at both baseline and follow-up (p < 0.05). CONCLUSION: Our data suggest that optical coherence tomography angiography is a reproducible non-invasive examination with which to monitor changes in the neovascular area in patients with pathologic myopia treated with ranibizumab. PMID- 29991291 TI - Can we predict the refractive outcome after triple Descemet membrane endothelial keratoplasty? AB - PURPOSE: To analyze and correlate corneal parameters with refractive shift after Descemet membrane endothelial keratoplasty combined with cataract surgery (triple Descemet membrane endothelial keratoplasty). METHODS: This single-center retrospective observational case series included 152 eyes of 152 consecutive patients undergoing triple Descemet membrane endothelial keratoplasty in the first eye for Fuchs endothelial corneal dystrophy. Patients were examined preoperatively, as well as at 3, 6, and 12 months after surgery. The main outcome measures were: refractive shift (predicted refractive outcome based on intraocular lens calculation compared to actual postoperative refractive outcome), central corneal thickness, corneal volume, anterior and posterior corneal curvature, and corneal densitometry. These parameters were analyzed and correlated with the refractive shift after surgery. RESULTS: After 3 months from surgery, a mean refractive shift of +1.12 +/- 1.10 D was observed and remained stable until the last follow-up at 12 months (+1.24 +/- 1.07 D). Correlation analysis showed a weak but significant positive correlation between refractive shift and preoperative posterior curvature (rho = 0.314; p = 0.002) or preoperative posterior densitometry (rho = 0.227; p = 0.008). No correlation was found between refractive shift and preoperative central corneal thickness, corneal volume, anterior curvature, or anterior/mid-cornea densitometry. CONCLUSION: Changes of the posterior cornea may have an influence on the refractive shift. Patients with flatter posterior corneal curvature or higher posterior corneal density seem to exhibit a higher hyperopic shift. The weak correlations indicate a poor predictive value of any preoperative parameter used in our study. PMID- 29991292 TI - Synthesis and evaluation of coumarin/1,2,4-oxadiazole hybrids as selective BChE inhibitors with neuroprotective activity. AB - A series of new coumarin/1,2,4-oxadiazole hybrids were synthesized and evaluated for cholinesterase inhibitory and neuroprotective activities. Among them, enantiomers 5u and 5v showed potent hBChE inhibitory activity with IC50 values of 8.17 and 9.56 MUM, respectively, and also exhibited good selectivity for hBChE over hAChE by 9.49- and 7.58-fold, respectively. In addition, both compounds could protect SH-SY5Y cells against Abeta25-35-induced neurotoxicity. The preliminary bioassay results provided a new chemotype for multifunctional anti Alzheimer's disease agents and continuing investigation into compounds 5u and 5v is warranted. PMID- 29991293 TI - IGFBP7 is associated to prognosis and could suppress cell survival in cholangiocarcinoma. AB - Insulin-like growth factor-binding protein 7 (IGFBP7) is a secreted protein and its expression was restrained in varied solid tumours, but there was no report about biological role of IGFBP7 in cholangiocarcinoma (CCA). Here, we found that high expression of IGFBP7 correlated to a better overall survival in CCA patients. To investigate the hypothetic antineoplastic activity of IGFBP7 in CCA, we induced overexpression of IGFBP7 in QBC939 and RBE cells, as well as knockdown in HCCC9810 cells. And the biological functions triggered by level changes of IGFBP7 were assessed, including proliferation, cell cycle distribution, apoptosis and invasion evaluation. Cell growth assessment showed that enhanced IGFBP7 expression significantly retarded proliferation rates of QBC939 and RBE cells while an enhancement was observed in IGFBP7-inhibited HCCC9810 cells. The inhibition of cell viability was induced via G2/M phase arrest and apoptosis. Both QBC939 and RBE cells possess highly invasive ability, and IGFBP7 overexpression attenuated their serious invasiveness by reversing their mesenchymal phenotype to endothelial signature. We next investigated the potential mechanism involving in IGFBP7-induced tumour suppression and found that increased expression of IGFBP7 resulted in decrease of IGF-IR, IRS-1 and phosphor AKT protein levels, accompanied with elevation of phorsphor-p38MAPK. These results suggest that IGFBP7 might be related to CCA carcinogenesis and metastasis, which further implicates that IGFBP7 might become a prospective benchmark for CCA diagnosis and therapy. PMID- 29991294 TI - Assessing Levels and Correlates of Implementation of Evidence-Based Approaches for Colorectal Cancer Screening: A Cross-Sectional Study With Federally Qualified Health Centers. AB - Multiple evidence-based approaches (EBAs) exist to improve colorectal cancer screening in health clinics. The success of these approaches is tied to effective implementation. Therefore, the purpose of this study was to assess the implementation of EBAs for colorectal cancer screening and clinic-level correlates of implementation in federally qualified health centers (FQHCs). We conducted descriptive and cross-sectional analyses using data collected from FQHC clinics across seven states ( n = 51). A clinic representative completed electronic surveys about clinic characteristics (e.g., size, patient characteristics, and medical record system characteristics) and the implementation of Community Guide recommended EBAs (e.g., client reminders, small media, and provider assessment and feedback). We used bivariate Spearman correlations to assess clinic-level correlates with implementation outcomes. Most clinics were planning to implement, in the early implementation stages, or inconsistently implementing EBAs. No EBA was fully implemented by more than nine (17.6%) clinics. Clinic size variables were inversely related to implementation levels of one-on-one education; medical record variables were directly related to implementation levels of client and provider reminders as well as provider assessment and feedback; and rapid and timely feedback from clinic leaders was directly associated with implementation levels of four out of six EBAs. Given the varying levels of implementation, clinics need to assess current use of implementation strategies and improve effective program delivery to increase colorectal cancer screening among their patients. In addition, clinics should also consider how their characteristics may support or serve as a barrier to implementation in their respective settings. PMID- 29991295 TI - A comparative clinical study on the generation of nitrosative stress in cataractous lenses of smokers and non-smoker tobacco patients. AB - AIM: To quantify the levels of nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine in cataractous lenses of smokers and smokers who chewed tobacco in comparison with non-smokers and non-smokers who chewed tobacco. STUDY DESIGN: A total of 80 cataractous lenses from smokers, non-smokers, smokers with tobacco chewing habit, and non-smokers with tobacco chewing habit were collected from the patients who had enrolled in the Department of Ophthalmology, Mahatma Gandhi Medical College & Research Institute, Puducherry. METHODS: Levels of nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine were quantified using commercially available enzyme-linked immunosorbent assay kits. RESULTS: The mean concentrations of lens nitric oxide, inducible nitric oxide synthase, and 3 nitrotyrosine are as follows: (a) smokers-112.01, 59.57, and 88.91 umol/L; (b) smokers who chewed tobacco-175.15, 93.95, and 128.72 umol/L; (c) non-smokers 76.15, 40.65, and 70.20 umol/L; and (d) non-smokers who chewed tobacco-96.56, 52.87, and 83.88 umol/L, respectively. CONCLUSION: Nitric oxide, inducible nitric oxide synthase, and 3-nitrotyrosine at high levels are the major causative agents for cataractogenesis. The results of this study suggest that smoking and tobacco chewing habit generate nitrosative stress that could enhance the pathogenesis for early cataractogenesis. PMID- 29991296 TI - Effects of rehabilitation exercise on coronary artery after percutaneous coronary intervention in patients with coronary heart disease: a systematic review and meta-analysis. AB - PURPOSE: The purpose of this study is to evaluate the effects of rehabilitation exercise on coronary artery of the patients with coronary heart disease (CHD) after percutaneous coronary intervention (PCI). METHODS: We searched Medline, EMBASE, Cochrane CENTRAL databases, ISI Web of Science databases, Chinese Biological Medicine Data Base, Chinese knowledge resources, and Wan Fang database. Two researchers independently screened the literature databases, and assessed methodological qualities using the Physiotherapy Evidence Database scale and extracted data. RESULTS: The coronary restenosis rate in rehabilitation exercise group was 10.8% (23/212), and that in the control group was 21% (48/229). Patients with rehabilitation exercise showed a significant reduction in restenosis rate, compared to the control group ((pooled OR: 0.46, 95% CI: 0.26 0.82, p < 0.01); heterogeneity: Chi2=3.86, df =5 (p = 0.57); I2=0%). In addition, the late luminal loss per stent in the rehabilitation exercise group was significantly smaller than that in the control group ((pooled MD: -0.33, 95% CI: 0.52 to -0.13, p < 0.01); heterogeneity: Chi2=0.27, df =1 (p = 0.60); I2=0%). CONCLUSIONS: Appropriate rehabilitation exercise reduces the incidence of coronary restenosis after PCI in patients with CHD and contributes to a significant reduction in late luminal loss in the stented coronary segment. Implications for Rehabilitation Appropriate rehabilitation exercise can reduce the incidence of coronary restenosis after percutaneous coronary intervention in patients with coronary heart disease. Appropriate rehabilitation exercise contributes to a reduction in late luminal loss in the stented coronary segment. PMID- 29991297 TI - Reduction of Insulin Requirement After Starting Treatment With Sacubitril/Valsartan in a Patient with Diabetes Treated With Continuous Subcutaneous Insulin Infusion (CSII): A case report. PMID- 29991298 TI - Structure, evolution and phylogenetic informativeness of eelpouts (Cottoidei: Zoarcales) mitochondrial control region sequences. AB - Control region (CR) is a major non-coding domain of mitochondrial DNA in vertebrates which contains the promoters for replication and transcription of mitochondrial genome along with the binding sites for metabolic machinery and, hence, is a vital element for the integrity of mitochondrial genome as a biological replicator. The origin and diversity of structural elements within CR have been intensively studied in recent years with the involvement of new diverse taxa. In this paper, we provide new data on the nucleotide and structural patterns of CR evolution and phylogenetic suitability among eelpouts (Cottoidei: Zoarcales). To achieve this, we carried out a comparative phylogenetic and structural analysis of 29 CR sequences belonging to the long shanny Stichaeus grigorjewi together with nine sequences of other eelpouts taxa representing four families in contrast to mitochondrial protein-coding fragments. The CR organization within S. grigorjewi, as well as in all other eelpouts, is consistent with the common three-domain structure known from most vertebrates. We found a hidden CR variation constrains on the landscape level and a lack of nucleotide saturation. Finally, our results demonstrate the advantage of the length variation in CR sequences for phylogenetic reconstructions among eelpouts. PMID- 29991299 TI - 2016 American Society of Biomechanics Hay Award Lecture: Preparing for Impact Biomechanical Inspirations From Olympic Sports. PMID- 29991300 TI - Concomitant Use of Psychotropic Medication With Stimulants for the Treatment of ADHD in Children and Adolescents: A Retrospective Insurance Claims Study in the United States. AB - OBJECTIVE: To evaluate annual concomitant psychotropic medication use among stimulant-treated children/adolescents with ADHD. METHOD: Children/adolescents with >=1 primary ADHD diagnosis who had received >=30 days of stimulant medication were identified from insurance claims for each calendar year (2011 2014). Use of 15 psychotropic medications concomitantly with stimulants was evaluated and their prevalence in each year was calculated overall and by medication category for children (6-12 years) and adolescents (13-17 years). RESULTS: Each year 133,354 to 157,303 children and 95,632 to 111,280 adolescents were included. Annual period prevalence of any concomitant psychotropic medication use was 22.9% to 25.0% for children and 25.2% to 28.2% for adolescents. The most common medication categories included selective serotonin reuptake inhibitors (children: 6.8%-7.9%; adolescents: 12.7%-14.9%), atypical antipsychotics (4.2%-5.4%; 5.3%-6.3%), and guanfacine extended release (5.1% 7.0%; 2.3%-3.6%). CONCLUSION: Around a quarter of children/adolescents with ADHD were prescribed psychotropic medication concomitant to stimulant treatment, although only 2 of the 15 medication classes studied were Food and Drug Administration (FDA)-approved for adjunctive use. PMID- 29991301 TI - Development of a High-Throughput Biochemical Assay to Screen for Inhibitors of Aerobactin Synthetase IucA. AB - Acquiring sufficient quantities of iron to support survival is often a critical limitation for pathogenic bacteria. To meet this demand, bacteria have evolved unique strategies to scavenge iron and circumvent the nutritional immunity exerted by their hosts. One common strategy, which is often a key virulence factor for bacterial pathogens, involves the synthesis, secretion, and reuptake of iron chelators known as siderophores. In vitro and in vivo studies have demonstrated that the siderophore aerobactin is critical for virulence in the hypervirulent pathotype of Klebsiella pneumoniae (hvKP). Given the high rate of multidrug resistance in K. pneumoniae, and in light of the ever-increasing demand for novel Gram-negative therapeutic targets, we identified aerobactin production as a promising antivirulence target in hvKP. Herein, we describe the development of a high-throughput biochemical assay for identifying inhibitors of the aerobactin synthetase IucA. The assay was employed to screen ~110,000 compounds across several commercially available small-molecule libraries. IucA inhibitors with activity at micromolar concentrations were identified in our screening campaigns and confirmed using secondary orthogonal assays. However, the most potent compounds also exhibited some properties commonly observed with promiscuous/nonspecific inhibitors, including incubation time and target enzyme concentration dependence, as well as the potential to antagonize unrelated enzymes. PMID- 29991303 TI - Menopause - a new beginning. PMID- 29991302 TI - Assay for Detecting Galphai-Mediated Decreases in cAMP in Living Cells. AB - Cell-based assays to detect Galphai signaling are often indirect, frequently involve complex pharmacological interventions, and are usually blind to the kinetics of the signaling. Our goal was to develop a simple, direct measure of Galphai signaling in living cells. We previously reported our fluorescent cADDis assay and showed that it reliably detects Galphas-mediated increases in cAMP levels. Agonists that stimulate a Gs-coupled receptor produce changes in the intensity of bright green or red fluorescent protein sensors that can be followed over time using automated fluorescence plate readers or fluorescence imaging systems. Since the cADDis sensors can monitor Galphas-mediated increases in adenylyl cyclase activity, in theory they should also be capable of detecting Galphai-mediated decreases. Here we apply our green fluorescent cADDis sensor to the detection of Galphai-mediated inhibition of adenylyl cyclase activity. We validated and optimized the assay in living HEK 293T cells using several known Galphai-coupled receptors and agonists, and we report robust Z' statistics and consistent EC50 responses. PMID- 29991304 TI - Progesterone. PMID- 29991305 TI - Human breast milk-derived exosomes attenuate cell death in intestinal epithelial cells. AB - Human breast milk has been shown to reduce the incidence of necrotizing enterocolitis (NEC). Breast milk has many components (immunoglobulins, proteins, fat, and, of recent interest, exosomes), but the specific component that affords protection against NEC is not known. Exosomes are small-nanometer vesicles that are rich in protein, lipid, and microRNA. Here, we hypothesized that human breast milk-derived exosomes can protect intestinal epithelial cells (IECs) from cell death. Human breast milk was collected, separated using ultracentrifugation, and quantified using NanoSight tracking analysis. Purified exosomes were added to IECs that had been treated with varying concentrations of H2O2. Cells were then incubated overnight with the human breast milk-derived exosomes and assessed for cell viability. Western blot analysis showed that both clathrin and CD81 were present in the purified sample. Oxidative stress using H2O2 caused a 50% decrease in cell viability and human breast milk-derived exosomes had a protective effect in IECs. In the presence of H2O2, exosomes had a statistically significant protective effect. The protection seen by human breast milk-derived exosomes was not attenuated by cycloheximide. Thus, human breast milk-derived exosomes allow IECs to be protected from oxidative stress, but the mechanism is still not clear. Exosomes derived from human breast milk are an attractive treatment concept for children with intestinal injury. PMID- 29991306 TI - A Socioecological Model of Risk Associated With Campus Sexual Assault in a Representative Sample of Liberal Arts College Students. AB - Campus sexual assault (CSA) is a growing area of research and public health concern, yet little research has considered the sociocultural context in which CSA occurs or the effect of sociocultural factors on the posttraumatic stress disorder (PTSD) symptoms of CSA survivors. This study describes the results of a web-based census survey administered to students at a liberal arts college. Of the 1,611 students who completed the survey (74% female; 71.4% White, 4.3% African American, 12% Hispanic), 13.5% reported experiencing at least one type of completed or attempted CSA. Female students, participants in Greek life, and students who reported victimization prior to college were more likely to report having experienced CSA. CSA was positively correlated with PTSD symptoms, and this relationship was stronger for racial/ethnic minorities, those who reported less sense of community, and those who were more aware of campus services to address CSA. This study demonstrates multiple levels of sociocultural influence on the mental health of college students who have experienced CSA and may suggest ways for improving prevention and intervention strategies to address CSA and its consequences. PMID- 29991307 TI - Modification of the Ti15Mo alloy surface through TiO2 nanotube growth-an in vitro study. AB - In this study, ordered and uniform TiO2 nanotubular structures were obtained on the surface of the Ti15Mo alloy by anodic oxidation. The amorphous state of TiO2 nanotubes formed under different anodization conditions was investigated. Crystallization of TiO2 into anatase phase occurs during annealing at temperatures of around 400 degrees C, whereas anatase to rutile transformation starts around 500 degrees C and is completed at 800 degrees C. Phase transformations in annealed samples led to morphological changes of tubular nanostructures, suggesting that the oxide layer formed at the nanotube/substrate interface serves as nucleation sites for more stable phases of TiO2. The proliferation of fibroblasts cells under annealing conditions of 450 degrees C, and of untreated samples (control group), was evaluated after 1, 4, and 7 days in cell culture using fluorescence microscopy images. A gradual increase in the number and size of cells was observed, indicating a non-toxic alloy. There was also better surface coverage on anodized samples compared with the untreated group; as well as increased development of the cytoskeleton in samples after anodization. The results of this study showed that the growth of TiO2 nanotubular structures associated with annealing allow better cell adhesion on the Ti15Mo alloy surface. PMID- 29991309 TI - NIHSS sub-item scores predict collateral flow in acute middle cerebral artery infarction. AB - BACKGROUND AND PURPOSE: The status of collateral vessels has important clinical implications in acute ischemic stroke. To evaluate which components of ischemic symptoms were predictive of pretreatment collateral status, we tested the hypothesis that sub-item scores from the National Institutes of Health Stroke Scale (NIHSS) are associated with leptomeningeal collateral status in acute ischemic stroke with middle cerebral artery (MCA) occlusion. METHODS: This study included consecutive patients with acute M1 occlusion who underwent revascularization treatment for acute MCA infarction. We evaluated clinical factors and the NIHSS score according to the collateral status assessed by multiphase perfusion computed tomography. RESULTS: Eighty-six patients were included (48 good collateral status, 38 poor collateral status). The patients with poor collateral status were more likely to have a higher total NIHSS score (18 versus 11, p < 0.001) and atrial fibrillation (65.8% versus 41.7%, p = 0.026) than patients with good collateral flow. In a multiple logistic regression, the NIHSS sub-items such as profound "facial palsy" (score 2 versus 0-1) and "visual field defect" (score 2 versus 0-1) were independently associated with poor collateral status. CONCLUSION: Among the NIHSS sub-items, severe facial palsy and visual field defect were associated with poor collateral status in acute MCA stroke with M1 occlusion. Decision on whether to treat these patients endovascularly should be made more cautiously due to the possibility of a poor outcome. PMID- 29991308 TI - Binders alternative to Portland cement and waste management for sustainable construction - Part 2. AB - The paper represents the "state of the art" on sustainability in construction materials. In Part 1 of the paper, issues related to production, microstructures, chemical nature, engineering properties, and durability of mixtures based on binders alternative to Portland cement were presented. This second part of the paper concerns the use of traditional and innovative Portland-free lime-based mortars in the conservation of cultural heritage, and the recycling and management of wastes to reduce consumption of natural resources in the production of construction materials. The latter is one of the main concerns in terms of sustainability since nowadays more than 75% of wastes are disposed of in landfills. PMID- 29991310 TI - Recurrent periventricular hemorrhage in cerebral proliferative angiopathy: Case report. AB - Cerebral proliferative angiopathy (CPA) is a rare vascular lesion. Bleeding from CPA is uncommon, but the risk of rebleeding is high once it bleeds. We describe a case of CPA with multiple intra- and periventricular hemorrhages during 30-year follow-up. Recurrent bleeding in these areas are common in moyamoya disease. These lesions may share the cause of bleeding: proliferation of the periventricular vessels functioning as collateral pathways. Revascularization surgery for CPA may attenuate the vascular proliferation in the vicinity of the ventricle, which may prevent rebleeding. PMID- 29991311 TI - Balloon-expandable stents for treatment of symptomatic middle cerebral artery stenosis: Clinical outcomes during long-term follow-up. AB - BACKGROUND: Insertion of a balloon-expandable stent (BES) in patients with symptomatic intracranial atherosclerosis is a treatment option for reperfusion therapy. In this study, we retrospectively reviewed clinical outcomes during long term follow-up after insertion of balloon-expandable stents in patients with symptomatic middle cerebral artery (MCA) stenosis. METHODS: Institutional review board approval was obtained for retrospective review of patient data. Thirty-four patients (15 men, 19 women; median age, 67.5 years) with symptomatic MCA stenosis underwent balloon-expandable stent insertion between June 2008 and December 2010. Patient records were reviewed for angiographic findings and clinical outcomes during long-term follow-up. RESULTS: Of these patients, 22 presented with acute ischemic stroke with underlying MCA atherosclerosis and had good clinical outcomes (modified Rankin Scale score (mRS): 0-2) after reperfusion therapy. Indications for stenting for the remaining 12 patients were recurrent transient ischemic attacks (TIAs) refractory to medical therapy and MCA stenosis greater than 70%. During the poststenting follow-up period, which ranged from 61 to 108 months (median, 67.5 months), a TIA occurred in five patients. Of these five patients, one experienced a complete reocclusion of the MCA stent, and three had symptomatic restenosis. The remaining 29 patients did not experience any further ischemic events or restenosis during the follow-up period. CONCLUSIONS: In our study, treatment with balloon-expandable stents in patients with symptomatic MCA stenosis resulted in low recurrence rates for both ischemic events and restenosis during long-term follow-up. PMID- 29991312 TI - Patterns of Intimate Partner Violence Victimization Among South African Women and Their Relation to Emotional Distress During Pregnancy and Postpartum. AB - Although numerous studies have established a link between intimate partner violence (IPV) victimization and maternal mental health, extant research examining this association has not considered heterogeneity in the forms of IPV that women experience. This is an important gap given that typological perspectives suggest that mental health consequences of IPV victimization may depend on the particular pattern of IPV that is experienced. The current study used latent class analysis to (a) identify and characterize distinct patterns of physical, psychological, and sexual IPV and male controlling behavior in a sample of pregnant South African women ( n = 1,480) and (b) examine associations between IPV patterns and emotional distress during pregnancy (baseline) and 9 months postpartum (follow-up). Latent class analysis identified a three-class solution wherein the largest class demonstrated a low probability of IPV victimization across all indicators ( nonvictims; 72% of the sample) and the smallest class demonstrated high probabilities of having experienced moderate and severe forms of IPV victimization as well as male controlling behavior ( multiform severe controlling IPV; 4% of the sample). A third class ( moderate IPV) was identified for which there was a high probability of experiencing moderate, but not severe, physical and psychological IPV (24% of the sample). Age, education, cohabitation status, experience of childhood abuse, and forced first sex were associated with class membership. Multiform severe controlling IPV victims reported significantly greater emotional distress than moderate IPV victims and nonvictims at baseline and follow-up. The results contribute to understanding heterogeneity in the patterns of IPV that women experience that may reflect distinct etiological processes and warrant distinct prevention and treatment approaches. PMID- 29991313 TI - Recruiting Older Adults With Functional Difficulties Into a Community-Based Research Study: Approaches and Costs. AB - The CAPABLE (Community Aging in Place, Advancing Better Living for Elders) trial in Baltimore City tested whether an interdisciplinary team of occupational therapists, nurses, and handymen reduces disability and health expenditures in community-dwelling older adults with functional difficulties. This study describes methods and associated costs of recruiting 300 low-income, cognitively intact, older adults with functional difficulties into this study. Sources of participant enrollment included direct mailings (35%), government program referrals (19%), community-based organizations (16%), ambassador referrals (15%), and media (4%). Fifty six (30%) of 187 older adults referred through government organizations were enrolled, while 49 (7.6%) of 648 referred from community-based organizations were enrolled. Total recruitment costs were US$81,453.12. Costs per participant for mailings, media, ambassadors, and community-based organizations were respectively US$745.10, US$256.82, US$22.28, and US$1.00. Direct mailings yielded the most participants but was the most costly method per participant. Ambassadors were least expensive and may offer a low-cost addition to community outreach for recruitment of older adults into research. PMID- 29991314 TI - Whole-Genome mRNA Gene Expression Differs Between Patients With and Without Delirium. AB - OBJECTIVE: To identify differences in gene expression between patients with in hospital delirium from a known etiology (urinary tract infection [UTI]) and patients with delirium from an unknown etiology, as well as from nondelirious patients. METHODS: Thirty patients with delirium (8 with UTI) and 21 nondelirious patients (11 with UTI) were included in this prospective case-control study. Transcriptomic profiles from messenger RNA sequencing of peripheral blood were analyzed for gene expression and disease-specific pathway enrichment patterns, correcting for systemic inflammatory response syndrome. Genes and pathways with significant differential activity based on Fisher exact test ( P < .05, |Z score| >2) are reported. RESULTS: Patients with delirium with UTI, compared to patients with delirium without UTI, exhibited significant activation of interferon signaling, upstream cytokines, and transcription regulators, as well as significant inhibition of actin cytoskeleton, integrin, paxillin, glioma invasiveness signaling, and upstream growth factors. All patients with delirium, compared to nondelirious patients, had significant complement system activation. Among patients with delirium without UTI, compared to nondelirious patients without UTI, there was significant activation of elF4 and p7056 K signaling. CONCLUSIONS: Differences exist in gene expression between delirious patients due to UTI presence, as well as due to the presence of delirium alone. Transcriptional profiling may help develop etiology-specific biomarkers for patients with delirium. PMID- 29991315 TI - Electronic consultation impact from the primary care clinician perspective: Outcomes from a national sample. AB - Introduction Electronic consultations (eConsults) provide asynchronous, store-and forward communication between primary care clinicians (PCCs) and specialists using web-based platforms, electronic health records or mobile applications. eConsults have demonstrated benefits in many areas of the Quadruple Aim, including educational value for PCCs. In this study, we explored the connection between eConsults and the Quadruple Aim using a unique national dataset of PCC reported eConsult outcomes. Methods We conducted a retrospective study analysing registry data from the RubiconMD electronic consultation platform used by PCCs in 34 US states. We analysed PCC-reported outcomes from eConsults that took place between March 2017 and January 2018. PCCs were asked to select one or more of the following options after each eConsult: improved care plan, educational, avoided unnecessary diagnostics/procedures, avoided referral altogether or to wrong specialty, or no effect. Results PCCs reported an outcome for 3872 eConsults. eConsults for dermatology, endocrinology, and haematology-oncology were most common. Over one in four PCCs reported that the eConsult avoided a referral altogether or to the wrong specialty (26.3%) and avoided unnecessary diagnostics/procedures (26.1%). In 75% of eConsults, PCCs reported an improved care plan. Fifty percent reported that the eConsult was educational. Discussion PCCs in diverse practice settings reported substantial benefits from eConsults. In over half of eConsults, PCCs reported that the eConsult avoided unnecessary diagnostics/procedures, avoided a referral altogether or avoided a referral to the wrong specialty. Findings suggest that eConsults demonstrate important educational benefits, but may also influence PCC decision-making in a way that yields tremendous cost-saving potential and improved patient experience. PMID- 29991317 TI - Perceptions of slow codes by nurses working on internal medicine wards. AB - BACKGROUND: Cardio-pulmonary resuscitation is the default procedure during cardio pulmonary arrest. If a patient does not want cardio-pulmonary resuscitation, then a do not attempt resuscitation order must be documented. Often, this order is not given; even if thought to be appropriate. This situation can lead to a slow code, defined as an ineffective resuscitation, where all resuscitation procedures are not performed or done slowly. RESEARCH OBJECTIVES: To describe the perceptions of nurses working on internal medicine wards of slow codes, including the factors associated with its implementation. RESEARCH DESIGN: This was a cross-sectional, descriptive study. Participants completed a personal characteristics questionnaire and the Perceptions and Factors of Slow Codes questionnaire designed for this study. Participants and research context: The sample was a convenience sample of nurses working on internal medicine wards in two Israeli hospitals. Ethical considerations: The study received ethical approval from both institutions, where data were collected and stored according to institutional policy. FINDINGS: Most reported that resuscitations were conducted according to protocol (n = 90, 76.2%). Some took their time calling the code (n = 22, 18.3%), or waited by the bedside and did not perform cardio-pulmonary resuscitation (n = 45, 37.5%). Factors most associated with slow codes were poor patient prognosis (mean = 3.52/5, standard deviation = 1.27) and a low chance of patient survival (mean = 3.37/5, standard deviation = 1.21). Two-thirds (n = 76, 66.8%) reported that slow codes were done on their unit and the majority (n = 80, 69%) perceived slow codes as ethical. DISCUSSION: This study confirms that slow codes are part of medical care on internal medicine wards, where most nurses perceive them as an ethical alternative. These perceptions are in contrast to most legal and ethical opinions expressed in the literature. CONCLUSION: Nurses should be educated about the legal and ethical implications of slow codes, and qualitative and quantitative studies should be conducted that further investigate its implementation. PMID- 29991316 TI - Evaluation of an innovative tele-education intervention in chronic pain management for primary care clinicians practicing in underserved areas. AB - Introduction Inadequate knowledge and training of healthcare providers are obstacles to effective chronic pain management. ECHO (extension for community healthcare outcomes) uses case-based learning and videoconferencing to connect specialists with providers in underserved areas. ECHO aims to increase capacity in managing complex cases in areas with poor access to specialists. Methods A pre post study was conducted to evaluate the impact of ECHO on healthcare providers' self-efficacy, knowledge and satisfaction. Type of profession, presenting a case, and number of sessions attended were examined as potential factors that may influence the outcomes Results From June 2014 to March 2017, 296 primary care healthcare providers attended ECHO, 264 were eligible for the study, 170 (64%) completed the pre-ECHO questionnaire and 119 completed post-ECHO questionnaires. Participants were physicians (34%), nurse practitioners (21%), pharmacists (13%) and allied health professionals (32%). Participants attended a mean of 15 +/- 9.19 sessions. There was a significant increase in self-efficacy ( p < 0.0001) and knowledge ( p < 0.0001). Self-efficacy improvement was significantly higher among physicians, physician assistants and nurse practitioners than the non prescribers group ( p = 0.03). On average, 96% of participants were satisfied with ECHO. Satisfaction was higher among those who presented cases and attended more sessions. Discussion This study shows that ECHO improved providers' self efficacy and knowledge. We evaluated outcomes from a multidisciplinary group of providers practicing in Ontario. This diversity supports the generalisability of our findings. Therefore, we suggest that this project may be used as a template for creating other educational programs on other medical topics. PMID- 29991318 TI - Not Just an Undergraduate Issue: Campus Climate and Sexual Violence Among Graduate Students. AB - The lack of research on graduate students' experiences with campus sexual violence and the campus climate is a glaring gap in the literature (Bonistall Postel, 2017). Thus, the current exploratory study examines the experience of graduate students at one university to determine their victimization rates and the number of disclosures they receive from peers. In addition, we compare graduate and undergraduate students' awareness of resources on campus and their confidence in knowing where to seek assistance for their peers or themselves. Finally, we compare key influential factors related to the campus climate such as sense of community and perceptions of the university's responsiveness to incidents of sexual violence among graduate and undergraduate students. An online survey was administered to a sample of 9,546 students, with 79.9% undergraduates and 20.1% graduates. A total of 5.2% of graduate students reported experiences of sexual violence since attending the university, with 13% receiving disclosures from peers. MANCOVA revealed that compared with undergraduate students, graduate students had significantly less awareness of campus resources, less confidence in knowing where to seek assistance, and less of a sense of community. There were no differences in perceptions of the university's handling of sexual violence. The findings highlight the importance of including and targeting graduate students in sexual violence awareness and prevention programming on college campuses. PMID- 29991319 TI - Saving the Perruchet effect: A role for the strength of the association in associative learning. AB - In a partial reinforcement schedule where a cue repeatedly predicts the occurrence of a target in consecutive trials, reaction times to the target tend to decrease in a monotonic fashion, while participants' expectancies for the target decrease at the same time. This dissociation between reaction times and expectancies-the so-called Perruchet effect-challenges the propositional view of learning, which posits that human conditioned responses result from conscious inferences about the relationships between events. However, whether the reaction time pattern reflects the strength of a putative cue-target link, or only non associative processes, such as motor priming, remains unclear. To address this issue, we implemented the Perruchet procedure in a two-choice reaction time task and compared reaction time patterns in an Experimental condition, in which a tone systematically preceded a visual target, and in a Control condition, in which the onset of the two stimuli were uncoupled. Participants' expectancies regarding the target were recorded separately in an initial block. Reaction times decreased with the succession of identical trials in both conditions, reflecting the impact of motor priming. Importantly, reaction time slopes were steeper in the Experimental than in the Control condition, indicating an additional influence of the associative strength between the two stimuli. Interestingly, slopes were less steep for participants who showed the gambler's fallacy in the initial block. In sum, our results suggest the mutual influences of motor priming, associative strength, and expectancies on performance. They are in line with a dual-process model of learning involving both a propositional reasoning process and an automatic link-formation mechanism. PMID- 29991321 TI - Comparisons of Sexual Victimization Experiences among Sexual Minority and Heterosexual Women. AB - This study examined the associations among heterosexual women (HW) and sexual minority women (SMW; for example, lesbian and bisexual), adolescent and adult sexual victimization experiences, childhood experiences of abuse, coping strategies, and mental health symptoms. Participants were 177 women recruited across the United States via the Internet to complete an online survey. Participants first completed the Sexual Experiences Survey and then described qualitatively their most distressing and/or severe sexual victimization experience. They were asked to include situational (e.g., location, alcohol, and drug use) and interpersonal features (e.g., relationship to perpetrator) of their experience. They then completed self-report questionnaires on childhood sexual abuse, coping with substances, coping through self-blame, social reactions to their assault disclosure, and symptoms of anxiety, depression, and somatization. Nonparametric tests were used to examine associations among the variables. There were no significant differences between SMW and HW in terms of the contextual features (i.e., situational, interpersonal) of their most distressing (i.e., severe) sexual victimization experiences or their postassault experiences. However, results revealed significant associations between sexual minority status and both victimization severity and sexual revictimization, with SMW reporting more severe victimization histories and higher rates of sexual revictimization relative to HW. In addition, there was a significant difference between SMW and HW with respect to coping through substances, with SMW reporting more substance use relative to HW. Future work should endeavor to identify the reasons for these important differences and seek to develop appropriate interventions for SMW who have experienced sexual violence. PMID- 29991320 TI - Non-insulin pharmacological therapies for treating type 1 diabetes. AB - INTRODUCTION: Despite intensified insulin treatment, many persons with type 1 diabetes (T1D) do not achieve glycemic and metabolic targets. Consequently, non insulin chemical therapies that improve glycemic control and metabolic parameters without increasing the risk of adverse events (including hypoglycemia) are of interest as adjunct therapies to insulin. Areas covered: In this review, the authors discuss the efficacy and safety of non-insulin therapies, including pramlintide, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP-4), sodium-glucose cotransporter (SGLT1 and SGLT2) inhibitors, metformin, sulfonylureas, and thiazolidinediones as add-on therapies to insulin in T1D. Expert opinion: The current evidence shows that the efficacy of non-insulin therapies as add-on therapies to insulin is minimal or modest with an average HbA1c reduction of 0.2-0.5% (2-6 mmol/mol). Indeed, the current focus is on the development of SGLT inhibitors as adjuncts to insulin in type 1 diabetes. Studies of subgroups with obesity, residual beta-cell function (including newly diagnosed patients) and patients prone to hypoglycemia could be areas of future research. PMID- 29991322 TI - Left Off the Route: A Qualitative Examination of Urban Bus Drivers Wanting to be Players in the Bully Prevention Solution. AB - Every school day millions of children board the bus from home and school oftentimes with 90 others including a bus driver. Perhaps not found in a bus drivers' job description are the details to monitor and respond to all suspected bullying behaviors. Being bullied can have long-term negative consequences for both bullies and victims. The school bus has been identified as a potential hot spot for student bullying, wherein bus drivers may see, hear, and respond to several types of bullying on a daily basis that often require support from school officials. However, a bus driver's ability to intercede effectively in cases of school bus bullying may be limited. This qualitative study used a nonprobability, purposeful sample to examine 18 urban African American school bus drivers' and bus attendants'experiences in addressing school bus bullying within the context of their riders and school officials. Using focus groups, a definition of school bullying was read aloud to provide context to six questions from a semistructured interview guide that related bus drivers' experiences in responding to acts of bullying. An interpretive phenomenology method was used throughout the data analysis process. Several key themes and practices emerged. Results suggest bus drivers' reports were mostly passified and not taken seriously. Furthermore, these bus drivers' experiences overwhelmingly reflected a lack of both being taken seriously and being included in decision making. This led to a key stakeholder: bus drivers, being left out of the process. From these drivers' interviews, a model was developed to illustrate their lived experiences from behind the wheel to working with the school in responding to bullying. PMID- 29991323 TI - Decolorization of mordant yellow 1 using Aspergillus sp. TS-A CGMCC 12964 by biosorption and biodegradation. AB - In this report, the decolorization features of extracellular enzymes and mycelia separately prepared from Aspergillus sp. TS-A CGMCC 12,964 (120 h) were investigated. The fermentation broth of TS-A degraded 98.6% of Mordant Yellow 1 (50 mg/L) at an initial pH 6 within 1 h with over 70% of the dye (50 mg/L) degraded by extracellular enzymes and 18.8% removed by live mycelia. The degradation products of the dye were analyzed by UV-Vis and FTIR spectra. The decolorization rates of extracellular enzymes and mycelia were examined under different contact periods, dye concentrations and pH values. The extracellular enzymes exhibited excellent degradation activity under weak acidic conditions. In addition, biosorption models of mycelia fitted well the Langmuir isotherm model and the pseudo-second-order kinetic equation. Although the decolorization process was achieved through the synergistic effects of mycelia and extracellular enzymes, decolorization was dominated by the biodegradation activity of the extracellular enzymes from TS-A. PMID- 29991324 TI - Monocyte/granulocyte to lymphocyte ratio and the MELD score as predictors for early recurrence of hepatocellular carcinoma after trans-arterial chemoembolization. AB - BACKGROUND: The first-line treatment option for intermediate-stage hepatocellular carcinoma is trans-arterial chemoembolization (TACE). Blood indices, such as lymphocyte/monocyte ratio (LMR), lymphocyte count, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte-granulocyte/lymphocyte ratio (MGLR) and red blood cell distribution width (RDW), are prognostic biomarkers in certain diseases. The model for end-stage liver disease (MELD) and Child-Turcotte Pugh (CTP) scores have been designed for patients with cirrhosis waiting for liver transplantation and in patients with hepatocellular carcinoma. We hypothesized possible roles for these blood indices, and the MELD and CTP scores as predictors for early recurrence of hepatocellular carcinoma after TACE. METHODS: Routine laboratory indices determined the NLR, LMR, MGLR, RDW, PLR, as well as MELD and CTP scores in 147 patients. Sensitivity and specificity of the indices for hepatocellular carcinoma recurrence 36 months after TACE were estimated by receiver operator characteristic curve. RESULTS: In multivariate regression analysis, only male sex, the lymphocyte count, CTP, the MGLR and the MELD score significantly (P < 0.01) predicted recurrence. The area under curve (AUC) for detection of recurrence for MGLR at a cut-off value 2.75 was 0.63 (95% CI 0.54-0.72) with sensitivity 70.7%, specificity 59.2% and accuracy 63%. The MELD score at cut-off value 9.5 had diagnostic performance with AUC 0.71 (0.63 0.79), sensitivity 80% and specificity 55.8% and accuracy 71.3%. CONCLUSIONS: High MGLR and MELD scores are linked to increasing frequency of hepatocellular carcinoma recurrence after TACE and could be used as novel, simple, non-invasive prognostic tests. PMID- 29991325 TI - Recent developments in vaccines and biological therapies against Japanese encephalitis virus. AB - INTRODUCTION: Japanese encephalitis is the most common vaccine-preventable encephalitis in the Asia-Pacific region. Areas covered: We provide an overview on Japanese encephalitis virus and associated disease, review the results of studies on the immunogenicity and efficacy of the licensed vaccines, and describe the new vaccines that are under development. We also discuss data on candidate anti Japanese encephalitis drugs that have shown promising results in experimental models. Expert opinion: The global burden of the Japanese encephalitis and associated mortality is still high, thus emphasizing the need to achieve the highest vaccination coverage in endemic areas. Clinical trials exhaustively demonstrated the safety and efficacy of current Japanese encephalitis vaccines. In addition, several new vaccine candidates, characterized by high immunogenicity and broad cross-protection, have been developed and evaluated in experimental models, warranting further clinical testing. No licensed anti-Japanese encephalitis drugs are available, notwithstanding intense research efforts. Some candidate antiviral agents that inhibit viral entry and replication have been identified, including compounds with broad-spectrum antiviral activity. Further research is needed to refine candidate compounds into drugs suitable for clinical evaluation, characterized by low toxicity, ability to penetrate the blood-brain barrier, activity during the late phase of infection, and high genetic barrier to resistance. PMID- 29991326 TI - The Common Time Course of Memory Processes Revealed. AB - Magnetoencephalography (MEG) was used to compare memory processes in two experiments, one involving recognition of word pairs and the other involving recall of newly learned arithmetic facts. A combination of hidden semi-Markov models and multivariate pattern analysis was used to locate brief "bumps" in the sensor data that marked the onset of different stages of cognitive processing. These bumps identified a separation between a retrieval stage that identified relevant information in memory and a decision stage that determined what response was implied by that information. The encoding, retrieval, decision, and response stages displayed striking similarities across the two experiments in their duration and brain activation patterns. Retrieval and decision processes involve distinct brain activation patterns. We conclude that memory processes for two different tasks, associative recognition versus arithmetic retrieval, follow a common spatiotemporal neural pattern and that both tasks have distinct retrieval and decision stages. PMID- 29991327 TI - Elevated cardiac biomarkers and echocardiographic left ventricular dysfunction at admission in patients with dengue fever: report from a tertiary care center in Northwest India. AB - Cardiac involvement is not an uncommon manifestation in dengue fever and diagnosing it has always been a challenge to physicians owing to its constellation of clinical features and lack of standard screening methods. We studied the prevalence of cardiac involvement among fifty sequential adult patients of dengue fever admitted in our emergency department, PGIMER, Chandigarh, India, who were assessed clinically and classified based on the severity. They were studied for possible cardiac involvement by means of point-of care testing for serum cardiac biomarkers (quantitative troponin-I, creatinine kinase - MB Isoform and cardiac myoglobin) and two-dimensional transthoracic echocardiogram (2D-echo). Evidence of myocardial involvement was present in 16% and 30% patients based on 2D-echo and biomarker testing respectively. On univariate analysis, the presence of cardiac symptoms (p = 0.009) and of shock (p = 0.003) showed statistically significant association with biomarker elevation. However, this and evidence of myocardial dysfunction by 2-D echo showed poor inter-correlation. PMID- 29991328 TI - CYP3A5 and ABCB1 polymorphisms in living donors do not impact clinical outcome after kidney transplantation. AB - AIM: To investigate the association between donor CYP3A5 and ABCB1 polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients. METHODS: The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors. RESULTS: There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis. CONCLUSION: A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes. PMID- 29991329 TI - Clinical outcome of kidney transplantation in HIV-infected recipients: a retrospective study. AB - Kidney transplantation is a safe and effective option for HIV-positive (HIV+) patients. We conducted a retrospective study on HIV+ kidney transplant recipients who underwent transplantation from March 2008 to September 2016. Inclusion criteria for transplantation were CD4+ T-cell count >=200 per mm3 and undetectable HIV load. The current study reports the outcome of 19 HIV+ recipients, mostly of Caucasian origin (79%) with a median age of 50 years (interquartile range [IQR], 42-52), who were followed up for a median period of 2.4 years (IQR, 1.2-4.6) after transplantation. Compared with HIV-negative (HIV-) controls, HIV+ recipients had similar one- and three-year graft and patient survival, but significantly lower five-year patient survival (P = 0.03). The differences in graft outcome became less evident with the analysis of death censored graft survival rates. Cumulative incidence of allograft rejection at one year was 32.9%. Rates of infections were not particularly elevated and HIV replication remained well controlled in all but one patient. A high prevalence of metabolic and endocrine complications (68%) was reported after transplantation. Further studies are needed to evaluate long-term outcomes of HIV+ recipients who underwent kidney transplantation. PMID- 29991330 TI - On adaptive propensity score truncation in causal inference. AB - The positivity assumption, or the experimental treatment assignment (ETA) assumption, is important for identifiability in causal inference. Even if the positivity assumption holds, practical violations of this assumption may jeopardize the finite sample performance of the causal estimator. One of the consequences of practical violations of the positivity assumption is extreme values in the estimated propensity score (PS). A common practice to address this issue is truncating the PS estimate when constructing PS-based estimators. In this study, we propose a novel adaptive truncation method, Positivity-C-TMLE, based on the collaborative targeted maximum likelihood estimation (C-TMLE) methodology. We demonstrate the outstanding performance of our novel approach in a variety of simulations by comparing it with other commonly studied estimators. Results show that by adaptively truncating the estimated PS with a more targeted objective function, the Positivity-C-TMLE estimator achieves the best performance for both point estimation and confidence interval coverage among all estimators considered. PMID- 29991331 TI - Is There Full or Proportional Somatosensory Recovery in the Upper Limb After Stroke? Investigating Behavioral Outcome and Neural Correlates. AB - BACKGROUND: Proportional motor recovery in the upper limb has been investigated, indicating about 70% of the potential for recovery of motor impairment within the first months poststroke. OBJECTIVE: To investigate whether the proportional recovery rule is applicable for upper-limb somatosensory impairment and to study underlying neural correlates of impairment and outcome at 6 months. METHODS: A total of 32 patients were evaluated at 4 to 7 days and 6 months using the Erasmus MC modification of the revised Nottingham Sensory Assessment (NSA) for impairment of (1) somatosensory perception (exteroception) and (2) passive somatosensory processing (sharp/blunt discrimination and proprioception); (3) active somatosensory processing was evaluated using the stereognosis component of the NSA. Magnetic resonance imaging scans were obtained within 1 week poststroke, from which lesion load (LL) was calculated for key somatosensory tracts. RESULTS: Somatosensory perception fully recovered within 6 months. Passive and active somatosensory processing showed proportional recovery of 86% (95% CI = 79%-93%) and 69% (95% CI = 49%-89%), respectively. Patients with somatosensory impairment at 4 to 7 days showed significantly greater thalamocortical and insulo-opercular tracts (TCT and IOT) LL ( P < .05) in comparison to patients without impairment. Sensorimotor tract disruption at 4 to 7 days did not provide significant contribution above somatosensory processing score at 4 to 7 days when predicting somatosensory processing outcome at 6 months. CONCLUSIONS: Our sample of stroke patients assessed early showed full somatosensory perception but proportional passive and active somatosensory processing recovery. Disruption of both the TCT and IOT early after stroke appears to be a factor associated with somatosensory impairment but not outcome. PMID- 29991332 TI - Drug transporters and anthracycline-induced cardiotoxicity. AB - The solute carrier superfamily comprises of uptake transporters that can contribute to the absorption and elimination of a broad array of clinically important drugs. Recent studies have suggested that the tissue-specific expression of these transporters may have important consequences for an individual's susceptibility to drug-induced organ damage or to drug-drug interactions. Polymorphic variants have been identified in genes encoded by this family, and some of these have been associated with functional changes in transport function and response to anthracycline-induced toxicity and efficacy. Here, we review recent advances in the role solute carrier transporters play in anthracycline-induced cardiotoxicity, highlight potential implications of genetic variants that may contribute to drug response and discuss novel technologies to study mechanisms of anthracycline transport. PMID- 29991333 TI - Caregiver Strategies to Enhance Participation in Children With Autism Spectrum Disorder. AB - Participation is necessary for childhood development, however, children with disabilities participate in fewer activities than their nondisabled peers. This study identified strategies caregivers use to increase participation in home- and community-based activities for children with autism spectrum disorder. Survey responses of 44 caregivers were analyzed through open and axial coding to develop a central theme and five broad themes. Caregiver strategies which produce a participation outcome fell into five themes: (a) adapters/facilitators, (b) pragmatic considerations, (c) social reframing, (d) sensory adjustments, and (e) desperate measures. Nonproductive strategies were identified where the child did not participate in the activity. Adaptations/facilitators were more likely used in the home, whereas community-based strategies were more often pragmatic considerations. Nonproductive strategies occurred more frequently in the community. When evaluating a child's participation, occupational therapy (OT) practitioners should take into consideration the context of the activity to identify appropriate and helpful strategies. PMID- 29991334 TI - Merits and Pitfalls in the Characterization of Covalent Inhibitors of Bruton's Tyrosine Kinase. AB - In vitro analysis of covalent inhibitors requires special consideration, due to the time-dependent and typically irreversible nature of their target interaction. While many analyses are reported for the characterization of a final candidate, it is less clear which are most useful in the lead optimization phase of drug discovery. In the context of identifying covalent inhibitors of Bruton's tyrosine kinase (BTK), we evaluated multiple techniques for characterizing covalent inhibitors. Several methods qualitatively support the covalent mechanism of action or support a particular aspect of interaction but were not otherwise informative to differentiate inhibitors. These include the time dependence of IC50, substrate competition, mass spectrometry, and recovery of function after inhibitor removal at the biochemical and cellular level. A change in IC50 upon mutation of the targeted BTK C481 nucleophile or upon removal of the electrophilic moiety of the inhibitor was not always a reliable indicator of covalent inhibition. Determination of kinact and KI provides a quantitative description of covalent interactions but was challenging at scale and frequently failed to provide more than the ratio of the two values, kinact/KI. Overall, a combination of approaches is required to assess time-dependent, covalent, and irreversible inhibitors in a manner suitable to reliably advance drug candidates. PMID- 29991335 TI - Adult Children's Perceptions of Maternal Favoritism During Caregiving: Comparisons Between Turkey and the United States. AB - This study explores cross-cultural variations in adult children's perceptions of maternal favoritism during caregiving in Turkey and the United States. Qualitative analysis of interview data from two siblings in each of 14 Turkish and 14 American families revealed differences in adult children's perceptions of and explanations for maternal favoritism. Most Turkish children perceived that their mothers favored sons because of higher filial expectations from sons. Conversely, most American children perceived that their mothers favored daughters and explained mothers' preferences as based on socioemotional factors. Furthermore, perceptions of maternal favoritism had detrimental consequences for sibling relationships in both contexts but differently. Turkish daughters reported conflicts over their favored brothers' lack of cooperation. American daughters perceived themselves as favored and felt obligated to undertake most of the caregiving burden which fueled sibling conflict. Taken together, this study highlights the importance of cultural context for understanding the within-family differences in sibling relationships during caregiving. PMID- 29991336 TI - Development of a multiplex two-gene real-time PCR assay for accurate detection of Klebsiella pneumoniae. PMID- 29991337 TI - The Influence of Culture on Healthy Relationship Formation and Teen Dating Violence: A Qualitative Analysis of South Asian Female Youth Residing in the United States. AB - Teen dating violence (TDV) has well-documented detrimental health effects. Scant research has examined the perspectives of ethnically diverse youth about the impact of culture on TDV. We sought to explore the intersection between culture and TDV specifically for South Asian youth residing in the United States. We conducted semi-structured interviews with South Asian youth aged 16 to 21 years. Interviews included three aims: (a) exploring participants' perspectives on TDV and healthy relationships within the South Asian community, (b) examining how different components of their cultural identity affect their romantic relationships, and (c) understanding ideas for TDV prevention programs for South Asian youth. Interview transcripts were coded using thematic analysis. Twenty five adolescent females participated; the majority (76%) trace their heritage to India, were born abroad (62%), and are in college (80%). The majority believed that dating was stigmatized within the South Asian community, forcing youth to hide relationships from their parents. Participants described aspects of culture that may negatively impact relationships (e.g., patriarchal attitudes and fear of stigma), as well as those that may protect teens (e.g., close-knit community). Conflicts about dating due to generational differences were also discussed. Participants suggested programs for South Asian youth focused on engaging parents in conversations about TDV and promoting gender equity. About half thought TDV prevention programs should be culturally tailored for South Asian youth, while others believed multicultural programs would be more effective. Although South Asian culture may confer some protection for youth experiencing TDV, stigma against dating and generational differences may create unique challenges. Future work should examine how to mediate parent-adolescent cultural conflicts around dating. PMID- 29991338 TI - Perceptions of Same-Gender and Different-Gender Intimate Partner Cyber Monitoring. AB - There is a paucity of research comparing perceptions of technology-facilitated partner monitoring or stalking between same-gender and different-gender relationships. As such, a randomized vignette study was conducted with 738 undergraduate students at a large Midwestern university, who read one of four stories of intimate partner cyber-monitoring (IPCM): same-gender IPCM with physical violence, same-gender IPCM without physical violence, different-gender IPCM with physical violence, and different-gender IPCM without physical violence. Results show that participants were significantly less likely to recommend the survivor break up with the abuser if the story described a same-gender relationship. If the story involved IPCM alone rather than also physical violence, participants were significantly less likely to label the abuse as "domestic violence," more likely to recommend doing nothing, and less likely to recommend most of the assessed protective actions-including being less likely to recommend asking the survivor to break up with the abuser, seeking help from friends and family, calling a domestic violence hotline, or calling the police. Results also indicate that IPCM is largely perceived to be less serious and less deserving of survivor support than physical intimate partner violence (IPV), for both same-gender and different-gender relationships. Implications for prevention education programming as well as research are discussed. PMID- 29991339 TI - Thumb carpometacarpal arthritis in patients with Ehlers-Danlos Syndrome: non operative and operative experiences. AB - : Ehlers-Danlos Syndrome is a connective tissue disorder that results in joint and generalized tissue hyperlaxity, predisposing patients to early onset arthritis. An institutional database spanning 1999-2016 was reviewed for all patients with symptomatic carpometacarpal arthritis and coexisting Ehlers-Danlos Syndrome, resulting in 14 thumbs amongst nine patients followed clinically for a median of 5.9 years (range 1-15). Patients managed non-operatively demonstrated stable subjective pain and trended towards decreased range of motion over time, whereas patients managed operatively had significant improvements in pain and trended towards increased grip strength. Our findings suggest that patients with Ehlers-Danlos-associated carpometacarpal arthritis can be successfully managed both operatively and non-operatively and that patients with pain refractory to conservative therapy may benefit from relief and increased hand strength following surgical intervention. LEVEL OF EVIDENCE: IV. PMID- 29991340 TI - Breast Tumor Analysis Using Shifted-Excitation Raman Difference Spectroscopy (SERDS). AB - We used a shifted-excitation Raman difference spectroscopy method for the ex vivo classification of resected and formalin-fixed breast tissue samples as normal (healthy) tissue, fibroadenoma, or invasive carcinoma. We analyzed 8 tissue samples containing invasive carcinoma that were surrounded by normal tissue and 3 tissue samples with fibroadenoma only. We made various measurement sites on various tissue samples, in total 240 measurements for each type of tissue. Although the acquired raw spectra contain enough information to clearly differentiate between normal and tumor (fibroadenoma and invasive carcinoma) tissue, the differentiation between fibroadenoma and invasive carcinoma was possible only after the shifted-excitation Raman difference spectroscopy isolation of pure Raman spectra from the heavily fluorescence interfered raw spectra. We used 784 and 785 nm as excitation wavelengths for the shifted excitation Raman difference spectroscopy method. The differences in the obtained pure Raman spectra are assigned to the different chemical compositions of normal breast tissue, fibroadenoma, and invasive breast carcinoma. Principal component analysis and linear discriminant analysis showed excellent classification results in the Raman shift range between 1000 and 1800 cm-1. Invasive breast carcinoma was identified with 99.15% sensitivity, and the absence of invasive carcinoma was identified with 90.40% specificity. Tumor tissue in tumor-containing tissue was identified with 100% sensitivity, and the absence of tumor in no-tumor containing tissue was identified with 100% specificity. As gold standard for the determination of the sensitivity and the specificity, we considered the conventional histopathological classification. In summary, shifted-excitation Raman difference spectroscopy could be potentially very useful to support histopathological diagnosis in breast pathology. PMID- 29991342 TI - Author's reply. PMID- 29991341 TI - N,N-dimethyltryptamine facts and myths. PMID- 29991343 TI - The Deferred Consent Model in a Prospective Observational Study Evaluating Myocardial Injury in the Intensive Care Unit. AB - BACKGROUND: Informed consent is a hallmark of ethical clinical research. An inherent challenge in critical care research is obtaining consent when patients lack decision-making capacity. One solution is deferred consent, which is often used for studies that are low risk or involve emergency interventions. Our objective was to describe a deferred consent model in a low-risk critical care study. METHODS: Prognostic Value of Elevated Troponins in Critical Illness Study was a prospective, pilot observational study of critically ill patients in 3 intensive care units, involving serial electrocardiograms and cardiac biomarkers. Newly admitted patients were enrolled over 1 month. When possible, informed consent was obtained a priori from the patient or substitute decision maker (SDM); otherwise, consent was deferred until the patient regained consent capacity or until their SDM was available. Logistic regression analysis was used to determine the association between patient's sex, Acute Physiology and Chronic Health Evaluation II score, study center, person providing consent (patient vs SDM), method of consent (telephone vs in person), and the provision or not of informed consent. RESULTS: The overall consent rate was 80.1% (213 of 266 persons approached). Of the 53 persons declining consent, 37 (69.8%) agreed to the use of data collected up until that point. Over half of all consent encounters were with patients rather than SDMs. Median interval delay between enrollment and the consent encounter was 1 day. On multivariate analysis, the only variable associated with consent was male sex of the patient (odds ratio for males 2.59, confidence interval: 1.19-5.63). CONCLUSION: Deferred consent facilitates implementation of time-sensitive research protocols until a consent encounter is possible. As a feasible alternative to exclusive a priori consent, the deferred consent model can be useful in low-risk studies in critically ill patients. PMID- 29991344 TI - Let's talk about standards: a commentary on standards of practice in empirical bioethics. AB - This commentary welcomes the work of Ives et al. on Standards of practice in Empirical Bioethics, and especially the dialogical spirit in which the standards have been constructed and offered. It also raises some questions about the consistent interpretation and use of such standards. PMID- 29991345 TI - Greater vegetable variety and amount are associated with lower prevalence of coronary heart disease: National Health and Nutrition Examination Survey, 1999 2014. AB - BACKGROUND: The 2015-2020 Dietary Guidelines for Americans (DGA) provides specific intake recommendations for vegetable variety and amount in order to protect against chronic disease. However, to the best of our knowledge, no studies have examined the link between DGA recommended vegetable variety and cardiometabolic disease. To address this research gap, our aim was to estimate the relationship between vegetable variety, vegetable amount, and prevalent cardiometabolic disease subtypes, and to assess potential determinants of vegetable variety. METHODS: Data on food intake and reported cardiometabolic disease status were acquired for 38,981 adults from the National Health and Nutrition Examination Survey (1999-2014). Vegetable variety was measured using a modified dietary diversity index that was adjusted for the potential confounding effects of vegetable amount. Temporal trends in vegetable variety and amount were assessed using univariate linear regression models. Multivariate logistic regression models were used to estimate the relationship between vegetable variety and prevalent disease, and between vegetable amount and prevalent disease. Multivariate ordered logistic regression models were used to assess the relationship between vegetable variety and explanatory variables. RESULTS: Overall, vegetable variety decreased (P = 0.035) from 1999 to 2014, but vegetable amount did not (P = 0.864). Intake of starchy vegetables decreased (P < 0.001), and intake of dark green vegetables increased (P < 0.001) over this 16-year period, but no trends were observed for other subgroups. An inverse linear relationship was observed between vegetable variety and prevalent coronary heart disease (P-trend = 0.032) but not other prevalent diseases; and between vegetable amount and coronary heart disease (P-trend = 0.026) but not other prevalent diseases. Individuals who reported consuming dark green vegetables had lower odds of having cardiovascular disease (0.86, 95% CI: 0.74-0.99) and coronary heart disease (0.78, 0.65-0.94) compared to individuals who reported not consuming any green vegetables. Living with a domestic partner was associated with greater vegetable variety (P = < 0.001), and currently smoking was associated with lower vegetable variety (P = < 0.001). Vegetable variety and amount were positively associated (P < 0.001). CONCLUSIONS: Vegetable variety and amount were inversely associated with prevalent coronary heart disease. Vegetable variety was strongly associated with vegetable amount, likely mediated by reduced habituation and increased liking. Increasing vegetable variety and amount are still important messages for the public. PMID- 29991346 TI - Potential mechanisms responsible for cardioprotective effects of sodium-glucose co-transporter 2 inhibitors. AB - Diabetes mellitus currently affects over 350 million patients worldwide and is associated with many deaths from cardiovascular complications. Sodium-glucose co transporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs with cardiovascular benefits beyond other antidiabetic drugs. In the EMPA-REG OUTCOME trial, empagliflozin significantly decreases the mortality rate from cardiovascular causes [38% relative risk reduction (RRR)], the mortality rate from all-causes (32% RRR) and the rate of heart failure hospitalization (35% RRR) in diabetic patients with established cardiovascular diseases. The possible mechanisms of SGLT-2 inhibitors are proposed to be systemic effects by hemodynamic and metabolic actions. However, the direct mechanisms are not fully understood. In this review, reports concerning the effects of SGLT-2 inhibitors in models of diabetic cardiomyopathy, heart failure and myocardial ischemia from in vitro, in vivo as well as clinical reports are comprehensively summarized and discussed. By current evidences, it may be concluded that the direct effects of SGLT-2 inhibitors are potentially mediated through their ability to reduce cardiac inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ionic dyshomeostasis. PMID- 29991348 TI - Walking hyponatremia syndrome of inappropriate antidiuretic hormone secretion secondary to carbamazepine use: a case report. AB - BACKGROUND: Severe hyponatremia is rare when carbamazepine is used as monotherapy. It is common to encounter this imbalance in the hospital setting, but rare in the ambulatory one. Here, we present a case of hyponatremia secondary to carbamazepine use in an otherwise asymptomatic patient. CASE PRESENTATION: A 44-year-old Guatemalan woman presented to our outpatient clinic with a chief complaint of left knee pain. One month prior, our patient had previously consulted with an outside physician, who prescribed her with 300 mg of carbamazepine, 5 mg of prednisone every 24 hours, and ibuprofen every 8 hours as needed. The symptoms did not resolve and our patient had increased the dose to 600 mg of carbamazepine and 20 mg of prednisone 7 days prior. Our patient complained of left knee pain, fatigue, and bilateral lower limb cramps. No pertinent medical history was recorded and her vital signs were within normal limits. A physical examination was non-contributory, only multiple port-wine stains in the upper and lower extremities associated with mild hypertrophy of the calves, more prominent on the right side. Laboratory studies revealed: a serum sodium level of 119 mmol/L, potassium level of 2.9 mmol/L, thyroid-secreting hormone of 1.76 mIU/m, thyroxine of 14.5 ng/dL, and serum osmolality at 247 mmol/kg. No neurologic or physical disabilities were recorded. In the emergency department, her electrolyte imbalance was corrected and other diagnostic studies revealed: a urinary sodium level of 164 mmol/L and osmolality at 328 mmol/kg. Our patient was diagnosed with syndrome of inappropriate antidiuretic hormone secretion secondary to carbamazepine use, hypokalemia secondary to corticosteroid therapy, and Klippel-Trenaunay-Weber syndrome. Carbamazepine was discontinued, fluid restriction ordered, and hypokalemia was corrected. One week after discharge, our patient no longer felt fatigued, the cramps were not present, and her left knee pain had mildly improved with acetaminophen use and local nonsteroidal anti-inflammatory cream. Electrolyte studies revealed a sodium level of 138 mmol/L, potassium level of 4.6 mmol/L, and serum osmolality at 276 mmol/L. CONCLUSIONS: Hyponatremia can be misdiagnosed if not recognized promptly; suspicion should be high when risk factors are present and the patient has been prescribed antiepileptic drugs. Presence of mild symptoms such as fatigue or dizziness should lead to suspicion and subsequent laboratory testing. Patients can suffer from neurologic complications if the imbalance is not corrected. PMID- 29991347 TI - Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN?D study: a pragmatic, multi-centre, assessor blinded randomised controlled trial. AB - BACKGROUND: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. METHODS: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. RESULTS: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. CONCLUSIONS: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010. PMID- 29991351 TI - Correction to: The impact of nasal aspiration with an automatic device on upper and lower respiratory symptoms in wheezing children: a pilot case-control study. AB - The original article [1] contained a typesetting error in Table 5; this has now been corrected. PMID- 29991349 TI - Untangling the Tauopathy for Alzheimer's disease and parkinsonism. AB - Tau is a microtubule-associated protein that mainly localizes to the axon to stabilize axonal microtubule structure and neuronal connectivity. Tau pathology is one of the most common proteinopathies that associates with age-dependent neurodegenerative diseases including Alzheimer's disease (AD), and various Parkinsonism. Tau protein undergoes a plethora of intra-molecular modifications and some altered forms promote the production of toxic oligomeric tau and paired helical filaments, and through which further assemble into neurofibrillary tangles, also known as tauopathy. In this review, we will discuss the recent advances of the tauopathy research, primarily focusing on its association with the early axonal manifestation of axonal transport defect, axonal mitochondrial stress, autophagic vesicle accumulation and the proceeding of axon destruction, and the pathogenic Tau spreading across the synapse. Two alternative strategies either by targeting tau protein itself or by improving the age-related physiological decline are currently racing to find the hopeful treatment for tauopathy. Undoubtedly, more studies are needed to combat this devastating condition that has already affected millions of people in our aging population. PMID- 29991350 TI - Fine metagenomic profile of the Mediterranean stratified and mixed water columns revealed by assembly and recruitment. AB - BACKGROUND: The photic zone of aquatic habitats is subjected to strong physicochemical gradients. To analyze the fine-scale variations in the marine microbiome, we collected seven samples from a single offshore location in the Mediterranean at 15 m depth intervals during a period of strong stratification, as well as two more samples during the winter when the photic water column was mixed. We were able to recover 94 new metagenome-assembled genomes (MAGs) from these metagenomes and examine the distribution of key marine microbes within the photic zone using metagenomic recruitment. RESULTS: Our results showed significant differences in the microbial composition of different layers within the stratified photic water column. The majority of microorganisms were confined to discreet horizontal layers of no more than 30 m (stenobathic). Only a few such as members of the SAR11 clade appeared at all depths (eurybathic). During the winter mixing period, only some groups of bloomers such as Pseudomonas were favored. Although most microbes appeared in both seasons, some groups like the SAR116 clade and some Bacteroidetes and Verrucomicrobia seemed to disappear during the mixing period. Furthermore, we found that some microbes previously considered seasonal (e.g., Archaea or Actinobacteria) were living in deeper layers within the photic zone during the stratification period. A strong depth related specialization was detected, not only at the taxonomic level but also at the functional level, even within the different clades, for the manipulation and uptake of specific polysaccharides. Rhodopsin sequences (green or blue) also showed narrow depth distributions that correlated with the taxonomy of the microbe in which they were found but not with depth. CONCLUSIONS: Although limited to a single location in the Mediterranean, this study has profound implications for our understanding of how marine microbial communities vary with depth within the photic zone when stratified. Our results highlight the importance of collecting samples at different depths in the water column when comparing seasonal variations and have important ramifications for global marine studies that most often take samples from only one single depth. Furthermore, our perspective and approaches (metagenomic assembly and recruitment) are broadly applicable to other metagenomic studies. PMID- 29991353 TI - Transcutaneous bilirubin estimation in extremely low birth weight infants receiving phototherapy: a prospective observational study. AB - BACKGROUND: Measurement of transcutaneous bilirubin (TcB) is a quick, reliable and painless method to guide management of hyperbilirubinemia. Studies in term and late preterm infants have found that TcB measurements from covered areas (TcB C) during phototherapy (PHT) co-relate well with serum bilirubin levels. Limited data exists in extremely low birth weight (ELBW) infants. METHODS: In this prospective observational study, an opaque patch was placed on the back of an ELBW infant prior to initiation of PHT. TcB-C and TcB-E (TcB from exposed area) levels were measured at birth and at 24-h intervals for 5 days. Total serum bilirubin (TSB) levels were also measured within 30 min of obtaining TcB levels. A Wilcoxon signed rank test was used for data analysis. A mixed effect model was used to adjust for repeated measurements over time. The p value < 0.05 was considered significant. RESULTS: A total of 19 infants were enrolled in the study, with a mean gestational age of 26 +/- 2 weeks and mean weight 827 +/- 127 g. The difference between TcB-C and TSB was 2.68 +/- 2.41 mg/dl (mean +/- SD, p < 0.001). In contrast, the difference between TcB-E and TSB was - 0.51 +/- 1.74 mg/dl (p = 0.02). TcB-C consistently overestimates TSB, while TcB-E consistently underestimates TSB. CONCLUSIONS: During PHT exposure, TcB-C does not correlate with TSB values in ELBW infants. TcB-C levels cannot be used as a surrogate for TSB measurement in ELBW infants. PMID- 29991352 TI - The evolutionary signal in metagenome phyletic profiles predicts many gene functions. AB - BACKGROUND: The function of many genes is still not known even in model organisms. An increasing availability of microbiome DNA sequencing data provides an opportunity to infer gene function in a systematic manner. RESULTS: We evaluated if the evolutionary signal contained in metagenome phyletic profiles (MPP) is predictive of a broad array of gene functions. The MPPs are an encoding of environmental DNA sequencing data that consists of relative abundances of gene families across metagenomes. We find that such MPPs can accurately predict 826 Gene Ontology functional categories, while drawing on human gut microbiomes, ocean metagenomes, and DNA sequences from various other engineered and natural environments. Overall, in this task, the MPPs are highly accurate, and moreover they provide coverage for a set of Gene Ontology terms largely complementary to standard phylogenetic profiles, derived from fully sequenced genomes. We also find that metagenomes approximated from taxon relative abundance obtained via 16S rRNA gene sequencing may provide surprisingly useful predictive models. Crucially, the MPPs derived from different types of environments can infer distinct, non-overlapping sets of gene functions and therefore complement each other. Consistently, simulations on > 5000 metagenomes indicate that the amount of data is not in itself critical for maximizing predictive accuracy, while the diversity of sampled environments appears to be the critical factor for obtaining robust models. CONCLUSIONS: In past work, metagenomics has provided invaluable insight into ecology of various habitats, into diversity of microbial life and also into human health and disease mechanisms. We propose that environmental DNA sequencing additionally constitutes a useful tool to predict biological roles of genes, yielding inferences out of reach for existing comparative genomics approaches. PMID- 29991354 TI - Births and induced abortions among women of Russian, Somali and Kurdish origin, and the general population in Finland -comparison of self-reported and register data. AB - BACKGROUND: Since reproductive health is often considered a highly sensitive topic, underreporting in surveys and under coverage of register data occurs frequently. This may lead to inaccurate information about the reproductive health. This study compares the proportion of women having births and induced abortions among migrant women of Russian, Somali and Kurdish origin in Finland to women in the general Finnish population and examines the agreement between survey and register-based data. METHODS: The survey data from the Migrant Health and Wellbeing Study conducted in 2010-2012 and data from the Health 2011 Survey with corresponding information on women in the general population were used in this study. The respondents were women aged 18-64: 341 Russian, 176 Somali and 228 Kurdish origin women and 630 women in the general population. The survey data were linked to the Finnish Medical Birth Register and the Register of Induced Abortions. RESULTS: In the combined (survey and register) data, migrant groups aged 30-64 had a higher proportion (89-96%) compared to the general population (69%) of women with at least one birth. Under-coverage of registered births was observed in all study groups. Among women aged 18-64, 36% of the Russian group and 24% of the Kurdish group reported more births in the survey than in the register data. In the combined data, the proportions of Russian origin (69%) and Kurdish origin (38%) women who have had at least one induced abortion in their lifetime are higher than in the general population (21%). Under-reporting of induced abortions in survey was observed among Somali origin women aged 18-29 (1% vs. 18%). The level of agreement between survey and register data was the lowest for induced abortions among the Somali and Russian groups (- 0.01 and 0.27). CONCLUSION: Both survey- and register-based information are needed in studies on reproductive health, especially when comparing women with foreign origin with women in the general population. Culturally sensitive survey protocols need to be developed to reduce reporting bias. PMID- 29991355 TI - Quality of life of women who practice dance: a systematic review protocol. AB - BACKGROUND: As general population life expectancy has increased, the need to investigate the quality of life has arisen, especially because it is important that people have a healthy long life and with good quality. Studies are done with specific populations, and in the case of this investigation, the target studies are the ones done with women. Female population is growing demographically and professionally. Women have shown increased levels of stress and higher number of illness. It is known that many practices can be used to improve the level of quality of life and that one of them is the dance. Dance is an activity which combines physical and psychosocial aspects. Moreover, it promotes self expression, self-esteem, and self-confidence. It relieves women of stress. And it also helps in a variety of aspects such as group interaction, motivation, and positive emotions. In this systematic review, the main objective is to assess the effect of dance on quality of life of adult women. METHODS: Only quantitative studies will be included. Studies will be accepted with any amount of dance practice time. They will have been published in the following bibliographic databases: Scientific Electronic Library Online (SciELO), Biblioteca Virtual em Saude (BVS), Portal da Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), MEDLINE, Embase, and Cochrane from inception until June 30, 2018. There will be no restrictions for geographical location. It will be included studies published in Portuguese, English, and Spanish. Only published ones will be included in the review. DISCUSSION: There is a variety of systematic review studies with men and women on quality of life and dance, but this is the first one focused exclusively on adult female audience. It is expected that this review will be useful to promote the discussion about quality of life of adult women and the interest of this population for dance practice. In order to summarize and to explain the characteristics and findings of those studies, tables and information from texts will be used in a systematic narrative synthesis. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016039961. PMID- 29991356 TI - Visit-to-visit HbA1c variability is inversely related to baroreflex sensitivity independently of HbA1c value in type 2 diabetes. AB - BACKGROUND: The relationship between long-term glycemic variability (GV) represented by visit-to-visit HbA1c variability and baroreflex sensitivity (BRS) in type 2 diabetes mellitus (T2DM) has not been clarified by previous literature. The present study is the first to examine the relationships between visit-to visit HbA1c variability and BRS. METHODS: This retrospective study initially analyzed data on 94 patients with T2DM. Visit-to-visit HbA1c variability was evaluated using the intrapersonal coefficient of variation (CV), standard deviation (SD), and adjusted SD of 8 or more serial measurements of HbA1c during a 2-year period. The BRS was analyzed using the sequence method. Short-term GV was assessed by measuring the glucose CV during 24-h continuous glucose monitoring (CGM). The primary objective was to determine if there was a relationship between visit-to-visit HbA1c variability (HbA1c CV) and BRS. Secondary objectives were to examine the relationship between other variables and BRS and the respective and combined effects of long-term GV (HbA1c CV) and short term GV (CGM CV) on BRS. RESULTS: A total of 57 patients (mean age 67.2 +/- 7.7 years, mean HbA1c 7.3 +/- 1.0%) who met this study's inclusion criteria were finally analyzed. In the univariate analysis, HbA1c CV (r = - 0.354, p = 0.007), HbA1c SD (r = - 0.384, p = 0.003), and adjusted HbA1c SD (r = - 0.391, p = 0.003) were significantly related to low levels of BRS. Multiple regression analysis showed that HbA1c CV, HbA1c SD, and adjusted HbA1c SD were inversely related to BRS. Furthermore, although the increase in either long-term GV (HbA1c CV) or short-term GV (CGM CV) as determined by 24-h CGM was inversely correlated with BRS, additional reductions in BRS were not shown in participants with both HbA1c CV and CGM CV values above the median. CONCLUSIONS: Visit-to-visit HbA1c variability was inversely related to BRS independently of the mean HbA1c in patients with T2DM. Therefore, visit-to-visit HbA1c variability might be a marker of reduced BRS in T2DM. PMID- 29991357 TI - VALUE AND PERFORMANCE OF ACCOUNTABLE CARE ORGANIZATIONS: A COST-MINIMIZATION ANALYSIS. AB - OBJECTIVES: Determine the relationship between quality of an accountable care organization (ACO) and its long-term reduction in healthcare costs. METHODS: We conducted a cost minimization analysis. Using Centers for Medicare and Medicaid cost and quality data, we calculated weighted composite quality scores for each ACO and organization-level cost savings. We used Markov modeling to compute the probability that an ACO transitioned between different quality levels in successive years. Considering a health-systems perspective with costs discounted at 3 percent, we conducted 10,000 Monte Carlo simulations to project long-term cost savings by quality level over a 10-year period. We compared the change in per-member expenditures of Pioneer (early-adopters) ACOs versus Medicare Shared Savings Program (MSSP) ACOs to assess the impact of coordination of care, the main mechanism for cost savings. RESULTS: Overall, Pioneer ACOs saved USD 641.24 per beneficiary and MSSP ACOs saved USD 535.59 per beneficiary. By quality level: (a) high quality organizations saved the most money (Pioneer: USD 459; MSSP: USD 816); (b) medium quality saved some money (Pioneer: USD 222; MSSP: USD 105); and (c) low quality suffered financial losses (Pioneer: USD -40; MSSP: USD -386). CONCLUSIONS: Within the existing fee-for-service healthcare model, ACOs are a mechanism for decreasing costs by improving quality of care. Higher quality organizations incorporate greater levels of coordination of care, which is associated with greater cost savings. Pioneer ACOs have the highest level of integration of services; hence, they save the most money. PMID- 29991358 TI - Prolonged exposure therapy and supportive counselling for post-traumatic stress disorder in adolescents: task-shifting randomised controlled trial. AB - BACKGROUND: Empirical evidence on the effectiveness of evidence-based treatments for adolescents with post-traumatic stress disorder (PTSD) in low-resource settings is needed.AimsTo evaluate the comparative effectiveness of prolonged exposure and supportive counselling in adolescents with PTSD. METHOD: Sixty-three adolescents (13-18 years) with PTSD were randomly assigned to receive either of the interventions comprising 7-14 sessions of treatment (trial registration in the Pan African Clinical Trials Registry: PACTR201511001345372). The primary outcome measure was PTSD symptom severity, as independently assessed on the Child PTSD Symptom Scale at pre-treatment, post-treatment, and at 3- and 6-month follow up. RESULTS: Participants receiving prolonged exposure experienced greater improvement on the PTSD symptom severity scale than those receiving supportive counselling (between group differences at post-intervention, mean 12.49, 95% CI 6.82-18.17, P<0.001; d = 1.22). A similar effect size was maintained at 3-month (d = 0.85) and 6-month (d = 1.02) follow-up assessments. CONCLUSIONS: Adolescents with PTSD experienced greater benefit from prolonged exposure treatment when provided by non-specialist health workers (nurses) in a community setting.Declaration of interestNone. PMID- 29991359 TI - Hepatitis delta virus and hepatocellular carcinoma: an update. AB - Hepatitis delta virus (HDV) is a defective RNA virus that depends on the presence of hepatitis B virus (HBV) for the creation of new virions and propagation of the infection to hepatocytes. Chronic infection with HDV is usually associated with a worsening of HBV infection, leading more frequently to cirrhosis, increased risk of liver decompensation and hepatocellular carcinoma (HCC) occurrence. In spite of a progressive declining prevalence of both acute and chronic HDV infection observed over several years, mainly due to increased global health policies and mass vaccination against HBV, several European countries have more recently observed stable HDV prevalence mainly due to migrants from non-European countries. Persistent HDV replication has been widely demonstrated as associated with cirrhosis development and, as a consequence, development of liver decompensation and occurrence of HCC. Several treatment options have been attempted with poor results in terms of HDV eradication and improvement of long term prognosis. A global effort is deemed urgent to enhance the models already existing as well as to learn more about HDV infection and correlated tumourigenesis mechanisms. PMID- 29991360 TI - Visual analogue mood scale scores in healthy young versus older adults. AB - : ABSTRACTBackground:The current research sought to characterize current mood state profiles in healthy young versus older adults using 100-point visual analogue mood scales (VAMS), provide within-sample and new sample replication of age-group differences, assess sex differences, and compare with commonly used standardized symptom measures. METHODS: In two studies, six word-only VAMS (happy, sad, calm, tense, energetic, and sleepy) were administered in a laboratory setting. In Study 1, 22 young and 29 older males completed the VAMS six times (twice per day at weekly intervals). In Study 2, 60 young (30 males) and 60 older (30 males) adults completed on one occasion the VAMS, Beck Depression Inventory-II, State-Trait Anxiety Inventory, and Pittsburgh Sleep Quality Index. RESULTS: VAMS scores showed that older adults had a tendency to indicate feeling happier, less sad, calmer, less tense, more energetic, and less sleepy than young adults. This pattern occurred across assessment points and irrespective of sex, except for the tense VAMS, which showed higher scores in females than males in young but not older adults. The standardized measures showed significant age-group differences for Trait Anxiety only (lower in older than young adults). CONCLUSIONS: These findings establish current mood state differences in young versus older adults. The absence of age-group differences in past studies may relate to the limited precision of the scales (only 7 points, in contrast to the 100-point scales used here). PMID- 29991361 TI - Is there association between human development index and tuberculosis mortality risk? Evidence from a spatial analysis study in the south of Brazil. AB - The goal of this study was to analyse the spatial pattern of tuberculosis (TB) mortality using different approaches, namely: mortality rates (MR), spatial relative risks (RR) and Bayesian rates (Global and Local) and their association with human development index (HDI), Global and its three dimensions: education, longevity and income. An ecological study was developed in Curitiba, Brazil based on data from Mortality Information System (2008-2014). Spatial scan statistics were used to compute RR and identify high-risk clusters. Bivariate Local Indicator of Spatial Associations was used to assess associations. MR ranged between 0 and 25.24/100.000 with a mean (standard deviation) of 1.07 (2.66). Corresponding values for spatial RR were 0-27.46, 1.2 (2.99) and for Bayesian rates (Global and Local) were 0.49-1.66, 0.90 (0.19) and 0-6.59, 0.98 (0.80). High-risk clusters were identified for all variables, except for HDI-income and Global Bayesian rate. Significant negative spatial relations were found between MR and income; between RR and HDI global, longevity and income; and Bayesian rates with all variables. Some areas presented different patterns: low social development/low risk and high risk/high development. These results demonstrate that social development variables should be considered, in mortality due TB. PMID- 29991362 TI - Trends in prescription of cardiovascular drugs to children in relation to prevalence of CHD from 1999 to 2016. AB - : IntroductionOwing to massive improvements in the diagnostics and surgery of children with CHD, fatality has decreased substantially. As more children with CHD survive from infancy into later childhood, more will need medication for chronic heart failure. However, surprisingly little is actually known about which drugs are being used to treat children with CHD, and whether prescription rates and CHD prevalence have changed over time. OBJECTIVE: The objective of this study was to assess the total prescription of cardiovascular drugs to children during an 18-year period and to assess concomitant CHD prevalence. METHODS: All prescription data of cardiovascular drugs to children aged 0-19 years were extracted from publicly available databases in Norway and Denmark from 1999 to 2016. This was coupled with data on CHD prevalence and birth rates. RESULTS: The number of defined daily doses of cardiovascular drugs prescribed to children doubled in the study period. This was because of an increased use of beta blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, and anti-arrhythmic agents. The use of some classes of drugs was significantly reduced over time. The prevalence of CHD remained constant in both countries - 80 per 10,000 births. CONCLUSION: We show that there is an increase in the overall prescription of cardiovascular drugs to children. Beta blockers, angiotensin converting enzyme/angiotensin receptor blockers, and anti-arrhythmics account for the largest increase. Birth rates decreased or remained constant together with CHD prevalence, suggesting that the increased use of cardiovascular drugs reflected increased prescription per patient, rather than more patients receiving a constant amount of drugs. PMID- 29991363 TI - Human fascioliasis infection sources, their diversity, incidence factors, analytical methods and prevention measures. AB - Human fascioliasis infection sources are analysed for the first time in front of the new worldwide scenario of this disease. These infection sources include foods, water and combinations of both. Ingestion of freshwater wild plants is the main source, with watercress and secondarily other vegetables involved. The problem of vegetables sold in uncontrolled urban markets is discussed. Distinction between infection sources by freshwater cultivated plants, terrestrial wild plants, and terrestrial cultivated plants is made. The risks by traditional local dishes made from sylvatic plants and raw liver ingestion are considered. Drinking of contaminated water, beverages and juices, ingestion of dishes and soups and washing of vegetables, fruits, tubercles and kitchen utensils with contaminated water are increasingly involved. Three methods to assess infection sources are noted: detection of metacercariae attached to plants or floating in freshwater, anamnesis in individual patients, and questionnaire surveys in endemic areas. The infectivity of metacercariae is reviewed both under field conditions and experimentally under the effects of physicochemical agents. Individual and general preventive measures appear to be more complicated than those considered in the past. The high diversity of infection sources and their heterogeneity in different countries underlie the large epidemiological heterogeneity of human fascioliasis throughout. PMID- 29991364 TI - Gene expression of matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 13 (MMP13), vascular endothelial growth factor (VEGF) and fibroblast growth factor 23 (FGF23) in femur and vertebra tissues of the hypovitaminosis D kyphotic pig model. AB - The hypovitaminosis D kyphotic pig provides a reliable model to study the initiation of bone lesions caused by maternal vitamin D (D) deficiencies. Matrix metalloproteinases (MMP; specifically, MMP9 and MMP13) and vascular endothelial growth factor (VEGF) are important in endochondral ossification and are potentially regulated by D. Fibroblast growth factor 23 (FGF23) is interrelated with D homoeostasis and bone mineralisation. Relative mRNA expression of MMP9, MMP13, VEGF and FGF23 was measured in pig femur and vertebra. Sows (n 37) were fed diets with 0 (-D), 8.125 (+D) or 43.750 (++D) ug D3/kg throughout gestation and lactation. At weaning (3 weeks), pigs were fed diets with 0 (-D) or 7.0 (+D) ug D3/kg, each with 75 and 95 % (LCaP) or 150 and 120 % (HCaP) of the Ca and P requirements. Pigs at birth (n 27), 3 weeks (n 27) and after the nursery period (7 weeks; n 72) were euthanised for analysis. At 3 weeks, femur MMP9 expression of pigs produced by +D or ++D sows was reduced (P<0.05) to 0.5-fold and VEGF expression to 0.4-fold compared with pigs from -D sows. At 7 weeks, MMP9 expression was reduced (P<0.05) to 0.45-fold in femur and 0.58-fold in vertebra from pigs produced by +D or ++D sows compared with pigs from -D sows. Pig femur VEGF expression was reduced to 0.75-fold in pigs produced by ++D sows. MMP9 and VEGF mRNA expression offer potential markers for the initiation of bone lesions in the hypovitaminosis D kyphotic pig model. PMID- 29991365 TI - Interventions that support major life transitions in older adulthood: a systematic review. AB - : ABSTRACTBackground:Major life transitions can negatively impact the emotional well-being of older people. This study examined the effectiveness of interventions that target the three most common transitions in later life, namely bereavement, retirement, and relocation. METHODS: A systematic search was performed via MEDLINE, EMBASE, CINAHL, Cochrane Library, PsycINFO, and reference lists of retrieved non-randomized and randomized controlled trials (RCTs) in English that studied the effectiveness of interventions addressing the three transitions in those >50 years of age. Two researchers independently selected the publications, piloted the data extraction form, and critically appraised studies specific to transition type and study design. RESULTS: A total of 11 studies (bereavement: 7; retirement: 2; relocation: 2) of 8 unique interventions met the inclusion criteria of which nine were RCTs and two were of quasi-experimental designs were reviewed. Six studies were group-based interventions, three studies used individualized sessions, and one intervention used a combination of group and individualized programming. Group size varied (20-32 participants), as did qualifications of those administering the interventions. The methodological quality of included studies was weak. Findings suggest that group-based approaches provided by trained personnel can mitigate the negative health-related consequences associated with major transitions in later life. CONCLUSION: Evidence concerning interventions that address mental health challenges associated with these major transitions is limited. Future research should better characterize participants at study outset and use validated measures to capture effectiveness. Use of peer mentorship to navigate such transitions is promising, but given the small number of studies and their methodological weaknesses, further research on effectiveness is warranted. PMID- 29991366 TI - Amoebiasis in Iran: a systematic review and meta-analysis. AB - A comprehensive meta-analysis study was performed to estimate the reliable national prevalence and molecular epidemiology of amoebiasis in Iran. Nine English and Persian databases were searched to achieve the relevant studies. Pooled estimates were generated and meta-regression was performed. We identified 71 eligible articles involving 330 930 subjects from 25 provinces to be included in the final analysis. Moreover, 17 studies compromising 462 polymerase chain reaction (PCR)-positive isolates performed molecular analysis to inter-species differentiation. The pooled prevalence of Entamoeba infection among Iranian population was about 1% (95% CI 0.8-2.0%). Moreover, regarding Human Development Index (HDI), a higher prevalence was observed in undeveloped provinces. Out of 462 PCR-positive isolates, 83% (95% CI 69-94%) and 12% (95% CI 3-24%) were Entamoeba dispar, Entamoeba histolytica, respectively. In subgroup analysis based on molecular results, in general, population prevalence of Entamoeba dispar and E. histolytica were 91% (95% CI 80-99%) and 7%, (95% CI 0-19%), respectively, while prevalence of these species in patients with gastrointestinal disorders were 75% (95% CI 45-96%) and 18% (95% CI 1-43%), respectively. Our findings indicate the low burden of amoebiasis in Iran. E. dispar, that is mostly non pathogenic, was identified as most prevalent species. Nevertheless, we suggest more public health interventions in areas with lower HDI. PMID- 29991367 TI - Epidemiology and risk factors associated with surgical site infection following surgery on thoracic aorta. AB - Surgical site infection (SSI) following cardiovascular surgery has been well documented, possibly owing to its highly invasive nature, but SSI following surgery on the thoracic aorta has not. This study aimed to describe the epidemiology and assess risk factors associated with the latter in Japan using a national database for SSI. Data on surgery on thoracic aorta performed between 2012 and 2014 were extracted from the Japan Nosocomial Infections Surveillance (JANIS) database. Risk factors were assessed initially by univariate analysis, and then entered into a logistic regression model for final evaluation. The cumulative incidence of SSI was 4.1% (146/3538) and staphylococci were the most frequent pathogens isolated. Factors such as the duration of operation, emergency surgery and male gender were significantly associated with SSI. These findings differ from previous studies on open heart and coronary artery bypass surgery, in which the American Society of Anesthesiologists (ASA) score was significantly associated with SSI, but gender was not. This study suggests that risk stratification in the JANIS system might be improved by incorporating additionally identified factors for risk adjustment, when comparing the incidence of SSI between hospitals. PMID- 29991368 TI - Environmental factors influencing the link between APOE epsilon4 and Alzheimer's disease (AD) risk. AB - While APOE epsilon4 allele is considered a genetic risk factor for Alzheimer's disease (AD), no relation existed between APOE epsilon4 and AD in the Yoruba in Nigeria among cohorts included in early prevalence waves. The authors' explanation that other disease susceptibilities may provoke earlier mortality is inconsistent with the Yoruba having a lower incidence of disease risk factors. Cohort enrichment in 2001 has altered the authors' conclusions; Yorba participants homozygous, and not heterozygous, for the epsilon4 allele had significantly increased risk for AD (HR = 2.95, p = 0.0002) (Hendrie et al., 2014). This is a critical revelation, yet it is not clear why such a temporal relationship exists between risk genotypes and AD among the Yoruba. This letter proposes an explanation. PMID- 29991370 TI - Successful simultaneous transcatheter treatment for a secundum atrial septal defect complicated by valvular pulmonary stenosis in an infant. AB - Only few reports have described successful simultaneous transcatheter intervention for CHD in infants. We present an infant with secundum atrial septal defect complicated by valvular pulmonary stenosis. Percutaneous transcatheter pulmonary valvuloplasty was performed first, followed by transcatheter closure of the secundum atrial septal defect uneventfully. Simultaneous transcatheter correction is an effective therapeutic option even in infants. PMID- 29991369 TI - Parental stress and resilience in CHD: a new frontier for health disparities research. AB - Parental stress is a universal experience for parents who have children diagnosed with CHD and has been studied within the context of the child's illness, but not through a broader health disparity lens. This paper provides a thorough synthesis of the current literature on parental stress addressing disparities in parents of children with CHD. Several theories and models from within this literature are described and a new comprehensive framework, the Parental Stress and Resilience in CHD Model, is presented. Future research and clinical implications are discussed. PMID- 29991371 TI - Meandering pulmonary veins mimicking scimitar syndrome. AB - Scimitar or pulmonary venolobar syndrome, a rare pulmonary anomaly, consists basically of anomalous pulmonary venous drainage of the right lung to the inferior caval vein, anomalous systemic arterial supply to the right lower lobe from the descending aorta, hypoplasia of the right lung, and dextroposed heart. We present a rare case with constellation of all these findings of scimitar syndrome, but with the aberrant pulmonary vein draining into the left atrium. PMID- 29991372 TI - Perinatal exposures to phthalates and phthalate mixtures result in sex-specific effects on body weight, organ weights and intracisternal A-particle (IAP) DNA methylation in weanling mice. AB - Developmental exposure to phthalates has been implicated as a risk for obesity; however, epidemiological studies have yielded conflicting results and mechanisms are poorly understood. An additional layer of complexity in epidemiological studies is that humans are exposed to mixtures of many different phthalates. Here, we utilize an established mouse model of perinatal exposure to investigate the effects of three phthalates, diethylhexyl phthalate (DEHP), diisononyl phthalate (DINP) and dibutyl phthalate (DBP), on body weight and organ weights in weanling mice. In addition to individual phthalate exposures, we employed two mixture exposures: DEHP+DINP and DEHP+DINP+DBP. Phthalates were administered through phytoestrogen-free chow at the following exposure levels: 25 mg DEHP/kg chow, 25 mg DBP/kg chow and 75 mg DINP/kg chow. The viable yellow agouti (A vy ) mouse strain, along with measurement of tail DNA methylation, was used as a biosensor to examine effects of phthalates and phthalate mixtures on the DNA methylome. We found that female and male mice perinatally exposed to DINP alone had increased body weights at postnatal day 21 (PND21), and that exposure to mixtures did not exaggerate these effects. Females exposed to DINP and DEHP+DINP had increased relative liver weights at PND21, and females exposed to a mixture of DEHP+DINP+DBP had increased relative gonadal fat weight. Phthalate-exposed A vy /a offspring exhibited altered coat color distributions and altered DNA methylation at intracisternal A-particles (IAPs), repetitive elements in the mouse genome. These findings provide evidence that developmental exposures to phthalates influence body weight and organ weight changes in early life, and are associated with altered DNA methylation at IAPs. PMID- 29991373 TI - Effect of cow replacement strategy on cow and calf performance in the beef herd. AB - Two contrasting replacement strategies are used by Irish beef farmers to select replacement females - animals sourced from within the suckler beef herd and sourced from the dairy herd. The objective of this study was to investigate the effect of replacement strategy (i.e. beef v. beef*dairy (BDX)) on cow and calf performance using data from the national beef database across a range of beef and dairy breeds. The association between replacement strategy and calving difficulty score, calving interval, weaning weight, weaning price and all carcass traits was investigated using a mixed model. The effect of replacement strategy on cow survival, calving dystocia and calf perinatal mortality was quantified using logistic regression. Beef cows were older (10.92 days; P<0.001) at their first calving, but were 1.15 times (P<0.01) more likely to survive to a subsequent lactation compared with BDX cows. Calving interval was 1.53 days shorter (P<0.001) for BDX compared with beef cows. Greater calving difficulty and calving dystocia was associated with beef cows (P<0.001) relative to BDX. However, BDX were 1.36 times (P<0.001) more likely to have a dead calf at birth relative to beef cows. Calves weaned from BDX were heavier (18.49 kg; P<0.001) at weaning, reached slaughter 12.8 days earlier (P<0.001), had 7.99 kg heavier carcass (P<0.001) and a greater fat score (P<0.001) compared with the progeny of beef cows. Beef cow progeny had a superior conformation score (0.5; P<0.001) and achieved a greater price per kilogram (P<0.001) compared with progeny from BDX. Beef cull cows had a heavier carcass (5.58 kg), superior carcass conformation, greater carcass price per kilogram and greater overall carcass value (P<0.001) than BDX. Results from this study show that replacement strategy is of fundamental importance depending on the type of system implemented by farmers and consideration must be given to the traits of importance within the context of the individual production system. PMID- 29991374 TI - Clinical pharmacology considerations for children supported with ventricular assist devices. AB - The ventricular assist device is being increasingly used as a "bridge-to transplant" option in children with heart failure who have failed medical management. Care for this medically complex population must be optimised, including through concomitant pharmacotherapy. Pharmacokinetic/pharmacodynamic alterations affecting pharmacotherapy are increasingly discovered in children supported with extracorporeal membrane oxygenation, another form of mechanical circulatory support. Similarities between extracorporeal membrane oxygenation and ventricular assist devices support the hypothesis that similar alterations may exist in ventricular assist device-supported patients. We conducted a literature review to assess the current data available on pharmacokinetics/pharmacodynamics in children with ventricular assist devices. We found two adult and no paediatric pharmacokinetic/pharmacodynamic studies in ventricular assist device-supported patients. While mechanisms may be partially extrapolated from children supported with extracorporeal membrane oxygenation, dedicated investigation of the paediatric ventricular assist device population is crucial given the inherent differences between the two forms of mechanical circulatory support, and pathophysiology that is unique to these patients. Commonly used drugs such as anticoagulants and antibiotics have narrow therapeutic windows with devastating consequences if under-dosed or over-dosed. Clinical studies are urgently needed to improve outcomes and maximise the potential of ventricular assist devices in this vulnerable population. PMID- 29991375 TI - The perceived influence of cost-offset community-supported agriculture on food access among low-income families. AB - OBJECTIVE: To examine perspectives on food access among low-income families participating in a cost-offset community-supported agriculture (CO-CSA) programme. DESIGN: Farm Fresh Foods for Healthy Kids (F3HK) is a multicentre randomized intervention trial assessing the effect of CO-CSA on dietary intake and quality among children from low-income families. Focus groups were conducted at the end of the first CO-CSA season. Participants were interviewed about programme experiences, framed by five dimensions of food access: availability, accessibility, affordability, acceptability and accommodation. Transcribed data were coded on these dimensions plus emergent themes. SETTING: Nine communities in the US states of New York, North Carolina, Washington and Vermont. SUBJECTS: Fifty-three F3HK adults with children. RESULTS: CSA models were structured by partner farms. Produce quantity was abundant; however, availability was enhanced for participants who were able to select their own produce items. Flexible CSA pick-up times and locations made produce pick-up more accessible. Despite being affordable to most, payment timing was a barrier for some. Unfamiliar foods and quick spoilage hindered acceptability through challenging meal planning, despite accommodations that included preparation advice. CONCLUSIONS: Although CO-CSA may facilitate increased access to fruits and vegetables for low-income families, perceptions of positive diet change may be limited by the ability to incorporate share pick-up into regular travel patterns and meal planning. Food waste concerns may be particularly acute for families with constrained resources. Future research should examine whether CO-CSA with flexible logistics and produce self selection are sustainable for low-income families and CSA farms. PMID- 29991376 TI - Successful preoperative bridge with extracorporeal membrane oxygenation in three neonates with D-transposition of the great vessels and pulmonary hypertension. AB - Pulmonary hypertension with transposition of the great arteries is associated with significant morbidity and mortality. At the worst end of the spectrum are patients who undergo extracorporeal support perioperatively. We describe our experience with three patients who received preoperative extracorporeal support and separated from cardiopulmonary bypass successfully on conventional postoperative care, with no significant deficits on follow-up. PMID- 29991377 TI - Nurse sow strategies in the domestic pig: II. Consequences for piglet growth, suckling behaviour and sow nursing behaviour. AB - Nurse sow strategies are used to manage large litters on commercial pig farms. However, new-born piglets transferred to nurse sows in late lactation might be compromised in terms of growth and survival. We investigated the effects of two nurse sow strategies on piglet growth, suckling behaviour and sow nursing behaviour. At 1-day post-farrowing, the four heaviest piglets from large litters were transferred to a nurse sow either 21 (1STEP21, n=9 litters) or 7 (2STEP7, n=10 litters) days into lactation. The remainder of the litter remained with their mother and was either kept intact (remain intact (RI), n=10 litters) or had some piglets cross-fostered to equalise birth weights (remain equalised (RE), n=9 litters). The 7-day-old piglets from 2STEP7 were transferred onto a sow 21 days into lactation (2STEP21, n=10 litters). The growth of new-born piglets on 1STEP21 and 2STEP7 nurse sows was initially lower than in RI litters (F 3,33.8=4.61; P<0.01), but weaning weights did not significantly differ (F 4,32.7=0.78; P>0.5). After the 1st week of lactation, the weights and growth rates did not differ between treatments. Fighting behaviour during nursing bouts decreased over time. The frequency of fights was higher in 1STEP21 and 2STEP21 litters compared with RI litters (t 122=3.06 and t 123=3.00, respectively, P<0.05). The 2STEP21 litters had shorter nursing bouts than RI and 1STEP21 litters (t 107=-2.81 and t 81.7=2.8, respectively, P<0.05), which were more frequently terminated by 2STEP21 than RI sows (t 595=2.93; P<0.05). Transferring heaviest piglets from RI and RE litters to nurse sows reduced the percentage of teat changes during nursing bouts (RI: F 1,275=16.61; RE: F 1,308=43.59; P<0.001). In conclusion, nurse sow strategies do not appear to compromise piglet growth. However, new-born piglets transferred onto sows in late lactation experienced more competition at the udder, suggesting that the sows' stage of lactation is of importance to how achievable nurse sow strategies are. Thus, the two-step nurse sow strategy is likely the best option (in relation to growth and suckling behaviour), as it minimises the difference between piglet age and sow stage of lactation. PMID- 29991378 TI - Static balloon atrial septostomy for the purpose of left heart intervention in postoperative adult CHD. AB - : Background and purposeStatic balloon atrial septostomy is a widely accepted intervention for children with CHD. Successful surgical palliation is creating increasing numbers of adult CHD patients who need subsequent left heart intervention requiring transseptal access. In these patients, the interatrial septum is usually thick and fibrotic because of a previous open heart surgery or catheter intervention, and conventional transseptal puncture may be unsuccessful. Static balloon atrial septostomy to access the left atrium may facilitate intervention via the interatrial septum in such situations. The purpose of this study was to investigate the usefulness and the safety of static balloon atrial septostomy, and the evolution of an iatrogenic atrial septal defect post procedure in adult CHD. METHODS: We retrospectively reviewed six procedures in five adults with CHD and collected demographic characteristics, details of the procedures, clinical outcome, and size changes of the iatrogenic atrial septal defect. RESULTS: The mean age at the time of the procedure was 35 years. The intended primary interventions were pulmonary vein isolation, stenting for pulmonary vein obstruction, and catheter ablation for focal atrial tachycardia. All static balloon atrial septostomies were effective, and the left heart interventions were successfully achieved via transseptal sheaths. There were no major complications associated with the static balloon atrial septostomy. There were no adverse clinical outcomes related to iatrogenic atrial septal defect, and the size of the defects regressed over time in all cases. CONCLUSIONS: Static balloon atrial septostomy can be a safe and useful technique in adult CHD patients needing left heart procedures. The thick interatrial septum found in postoperative patients may reduce the risk of persistent iatrogenic atrial septal defect. PMID- 29991379 TI - Prayer Requests, Generous Love, and A Patient's Wish to Die. PMID- 29991380 TI - Dilated cardiomyopathy due to premature ductus arteriosus constriction. AB - Herein, we present the first case of dilated cardiomyopathy due to premature constriction of the ductus arteriosus. A fetal echocardiography showed narrowing in the ductus arteriosus, and colour Doppler flow mapping could not identify blood flow through the ductus. Neonatal echocardiography revealed a left ventricular dilated cardiomyopathy, and the cardiomyopathy had fully resolved at 6 months of age. PMID- 29991382 TI - Letter to the editor: Applying incidence-based disability-adjusted life years (DALYs) disease burden estimates to foster change in national vaccination policy, Slovenia, 2017 to 2018. PMID- 29991381 TI - Two concurrent outbreaks of hepatitis A highlight the risk of infection for non immune travellers to Morocco, January to June 2018. AB - From January to June 2018, two ongoing hepatitis A outbreaks affected travellers returning from Morocco and cases in Europe without travel history, resulting in 163 patients in eight European countries. Most interviewed travel-related cases were unaware of the hepatitis A risk in Morocco. Molecular analysis revealed two distinct hepatitis A virus (HAV) strains (subgenotype IA DK2018_231; subgenotype IB V18-16428). Vaccination recommendations should be emphasised to increase awareness among non-immune travellers to Morocco and HAV-endemic countries. PMID- 29991383 TI - Gonorrhoea treatment failure caused by a Neisseria gonorrhoeae strain with combined ceftriaxone and high-level azithromycin resistance, England, February 2018. AB - We describe a gonorrhoea case with combined high-level azithromycin resistance and ceftriaxone resistance. In February 2018, a heterosexual male was diagnosed with gonorrhoea in the United Kingdom following sexual intercourse with a locally resident female in Thailand and failed treatment with ceftriaxone plus doxycycline and subsequently spectinomycin. Resistance arose from two mechanisms combining for the first time in a genetic background similar to a commonly circulating strain. Urgent action is essential to prevent further spread. PMID- 29991385 TI - Inclusion of TB diagnostics on the WHO Essential Diagnostics List. PMID- 29991384 TI - Sharing more than friendship - transmission of NDM-5 ST167 and CTX-M-9 ST69 Escherichia coli between dogs and humans in a family, Finland, 2015. AB - IntroductionCarbapenemase-producing Enterobacteriaceae (CPE) have rarely been reported in dogs, and never in animals in Finland. However, in April 2015, two meropenem-resistant Escherichia coli were identified from two dogs in one family. Both dogs suffered from chronic otitis externa. Methods: Epidemiological and molecular investigations (pulsed-field gel electrophoresis (PFGE), multilocus sequence typing) were conducted to investigate the source of infection and transmission routes. Results: In both dogs and one family member New Delhi metallo-beta-lactamase (NDM-5)-producing multidrug-resistant ST167 E. coli was found. Whole genome sequencing confirmed that the isolates were identical or only had one or two allelic differences. Additionally, the dogs and humans of the family carried an identical extended-spectrum beta-lactamase (ESBL) CTX-M-group 9 E. coli ST69 strain, indicating interspecies transmission. While the original source remains unclear, human-to-canine transmission is possible. No carbapenems had been administered to the dogs, but exposure to numerous other antimicrobials likely sustained the bacteria and supported its propagation in the canine host. Conclusion: To our knowledge, canine clinical NDM-5 E. coli in Europe, and confirmed CPE transmission between dogs and humans have not been previously reported. The screening of veterinary Enterobacteriaceae isolates for carbapenem resistance is highly recommended. PMID- 29991386 TI - Reflections on the State of the Art series on TB and migration, and the way forward. PMID- 29991387 TI - Gaps in understanding factors influencing tuberculosis recurrence. PMID- 29991388 TI - The economic burden of multidrug-resistant tuberculosis. PMID- 29991389 TI - Long-acting injectables for tuberculosis prophylaxis and treatment: is now the time? PMID- 29991390 TI - Defining a migrant-inclusive tuberculosis research agenda to end TB. AB - BACKGROUND: Pillar 3 of the End TB Strategy calls for the promotion of research and innovation at the country level to facilitate improved implementation of existing and novel interventions to end tuberculosis (TB). In an era of increasing cross-border migration, there is a specific need to integrate migration-related issues into national TB research agendas. The objective of the present review is to provide a conceptual framework to guide countries in the development and operationalization of a migrant-inclusive TB research agenda. METHODS: We conducted a literature review, complemented by expert opinion and the previous articles in this State of the Art series, to identify important themes central to migration-related TB. We categorized these themes into a framework for a migration-inclusive global TB research agenda across a comprehensive spectrum of research. We developed this conceptual framework taking into account: 1) the biomedical, social and structural determinants of TB; 2) the epidemiologic impact of the migration pathway; and 3) the feasibility of various types of research based on a country's capacity. DISCUSSION: The conceptual framework presented here is based on the key principle that migrants are not inherently different from other populations in terms of susceptibility to known TB determinants, but that they often have exacerbated or additional risks related to their country of origin and the migration process, which must be accounted for in developing comprehensive TB prevention and care strategies. A migrant-inclusive research agenda should systematically consider this wider context to have the highest impact. PMID- 29991391 TI - Value of chest X-ray in TB diagnosis in HIV-infected children living in resource limited countries: the ANRS 12229-PAANTHER 01 study. AB - OBJECTIVE: To evaluate inter-reader agreement and diagnostic accuracy of chest radiography (CXR) in the diagnosis of tuberculosis (TB) in children with human immunodeficiency virus (HIV) infection. DESIGN: HIV-infected children with clinically suspected TB were enrolled in a prospective study conducted in Burkina Faso, Cambodia, Cameroon and Viet Nam from April 2010 to December 2014. Three readers-a local radiologist, a paediatric pulmonologist and a paediatric radiologist-independently reviewed the CXRs. Inter-reader agreement was then assessed using the kappa coefficient. Diagnostic accuracy of CXR was assessed in culture-confirmed cases and controls. RESULTS: A total of 403 children (median age 7.3 years, interquartile range 3.5-9.7; 49.6% males) were enrolled. Inter reader agreement was as follows: between local radiologist and paediatric pulmonologist, kappa = 0.36 (95%CI 0.27-0.45); local radiologist and paediatric radiologist, kappa = 0.16 (95%CI 0.08-0.24); and paediatric pulmonologist and paediatric radiologist, kappa = 0.30 (95%CI 0.21-0.40). Among 51 cases and 151 controls, after a consensus, CXR had a sensitivity of 71.4% (95%CI 58.8-84.1) and a specificity of 50.0% (95%CI 41.9-58.1). Alveolar opacities and enlarged lymph nodes on CXR had limited specificity for TB (64.7% and 70.2%, respectively). Miliary and/or nodular opacities patterns on CXR were more specific to TB (specificity 94.3%). CONCLUSION: CXR showed poor-to-fair inter-reader agreement and limited diagnostic accuracy for TB in HIV-infected children, likely due to comorbidities. Radiological criteria for this specific population require further investigation. PMID- 29991392 TI - Improving childhood tuberculosis detection and treatment through facility-based screening in rural Pakistan. AB - SETTING: Many children with tuberculosis (TB) remain undiagnosed due to the absence of services, lack of child-friendly diagnostics and underappreciation of TB as a common cause of childhood illness. OBJECTIVE: To show the impact of systematic verbal screening and contact tracing with appropriate management services on TB case finding in pediatric populations. DESIGN: Between October 2014 and March 2016, children were verbally screened at the pediatric out-patient departments of four public hospitals in Jamshoro District, Pakistan. Children with symptoms or risk of TB were referred for clinical evaluation and free chest X-ray and bacteriological tests. Children with TB were started on treatment and their care givers asked to bring household members to the hospital for screening. RESULTS: Over 105 000 children were verbally screened and 5880 presumptive childhood TB patients were identified; 1417 children (prevalence 1.3%) were diagnosed with TB; 43% were female. The median age was 5 years; 82% had pulmonary TB. An additional 390 children with TB were diagnosed through contact tracing. These activities resulted in a three-fold increase in pediatric TB case notifications. CONCLUSION: Systematic verbal screening with clinical evaluation and free diagnostics can identify children with TB who may otherwise be missed in rural health settings. PMID- 29991393 TI - Tuberculosis preventive treatment preferences among care givers of children in Lesotho: a pilot study. AB - BACKGROUND: Shorter-duration regimens for preventing drug-susceptible tuberculosis (TB) have been shown to be safe and efficacious in children, and may improve acceptability, adherence, and treatment completion. While these regimens have been used in children in low TB burden countries, they are not yet widely used in high TB burden countries. SETTING: Five health facilities in one district in Lesotho, a high TB burden country. OBJECTIVE: Assess the preventive treatment preferences of care givers of child TB contacts. DESIGN: Qualitative data were collected using in-depth interviews with 12 care givers whose children completed preventive treatment, and analyzed using grounded theory. FINDINGS: Care givers were interested in being involved in the children's treatment decisions. Pill burden, treatment duration and related frequency of dosing were identified as important factors that influenced preventive treatment preferences among care givers. CONCLUSION: Understanding care giver preferences and involving them in treatment decisions may facilitate efforts to implement successful preventive treatment for TB among children in high TB burden countries. PMID- 29991394 TI - Daily cough frequency in tuberculosis and association with household infection. AB - SETTING: Although cough in tuberculosis (TB) is presumed to be important for transmission, there is little objective supporting evidence. OBJECTIVE: To describe 24-h cough frequency in a group with TB, and investigate associations with household rates of infection. DESIGN: Patients with a new diagnosis of pulmonary TB underwent 24-h cough frequency measurement at or just before initiation of anti-tuberculosis treatment. A group with latent Mycobacterium tuberculosis infection (LTBI) acted as controls. Rates of infection among household contacts of sputum smear-positive TB were measured using the interferon gamma release assay and the tuberculin skin test, and compared with variables relating to the contacts themselves, and to the index case, including cough frequency. RESULTS: Daily cough frequency in TB patients (n = 44) was variable (geometric mean [GM] 174, interquartile range [IQR] 68-475 coughs/24 h), higher than in LTBI (n = 17; GM 19 coughs/24 h, IQR 8-53; P < 0.001), and higher during the day than overnight (GM 8.9 coughs/h, IQR 4.1-19.0 vs. GM 2.9 coughs/h, IQR 0.7-13.4; P < 0.0001). Also, 24-h cough frequency in TB was associated with sputum smear status (P = 0.040), but not smoking (P = 0.475). Multivariable logistic regression confirmed that infection in contacts was independently associated with index case sputum smear grade (P = 0.014) and cough frequency (P = 0.022). CONCLUSION: Measurement of 24-h cough frequency in pulmonary TB helps predict infectiousness and transmission patterns. PMID- 29991395 TI - Older age at first tuberculosis diagnosis is associated with tuberculosis recurrence in HIV-negative persons. AB - SETTING: Tuberculosis (TB) clinic in Durban, South Africa. OBJECTIVE: To assess the factors associated with TB recurrence among human immunodeficiency virus (HIV) negative adults and children. DESIGN: We conducted a retrospective longitudinal study from January 2000 to December 2012. We defined recurrence as a TB episode occurring within the study period after treatment completion or cure of a previous episode. We used a multivariable Poisson regression model to assess the factors associated with the number of recurrences among HIV-negative patients. RESULTS: Among 17 941 patients with known HIV status, 3653 (20%) were HIV-negative; of these, 235 (6%) had one recurrence, 21 (1%) had two recurrences and 4 (0.1%) had three recurrences. The median follow-up time from the end of treatment for the first episode was 3.0 years (interquartile range 1.9-4.2). Age at the first TB episode was significantly associated with the number of TB recurrences: younger patients had the lowest rate of recurrence, with a steady increase in rates until age 40 years, after which rates stabilized. CONCLUSIONS: TB recurrence rates among HIV-negative patients were higher at increased age at the first TB episode. Further translational studies are needed to clarify the factors that drive multiple TB recurrences in older age, including impaired immunity, the results of which have implications for TB vaccine development. PMID- 29991396 TI - Strain diversity and relative transmission of Mycobacterium tuberculosis in south coastal Karnataka, India. AB - BACKGROUND: There are no published reports on the strain diversity and relative transmission of Mycobacterium tuberculosis isolates circulating in Karnataka State, India. OBJECTIVE: To explore the strain diversity of M. tuberculosis isolates and their relative transmission in south coastal Karnataka using spoligotyping and mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) typing. DESIGN: A total of 108 clinical isolates of M. tuberculosis were processed for spoligotyping, and 12-locus MIRU-VNTR typing and cluster analysis was performed. RESULTS: Spoligotyping data of 108 isolates revealed 63 spoligotype patterns: 36 (80 isolates, 74.1%) patterns corresponded to spoligotype international types (SITs), whereas 27 (28 isolates, 25.9%) patterns were orphans. A further 57 (52.8%) isolates were clustered into 12 clusters; 51 (47.2%) isolates were unique. The largest spoligotype cluster comprised SIT 48 (L1.2.2), followed by SIT 1942 (L3) and SIT 11 (L1.1.2). Combined MIRU-VNTR typing and spoligotyping analysis further differentiated these 108 isolates into five clusters of two isolates each and 98 individual patterns. CONCLUSIONS: Combined use of spoligotyping and MIRU-VNTR typing is best suited for genotyping studies in this region. Very high genetic diversity was observed among the clinical isolates. Further elaborate studies are required for a better understanding of the genetic diversity and transmission dynamics of the strains circulating in this region. PMID- 29991397 TI - P2X7 receptor polymorphisms and susceptibility to tuberculosis in a North Indian Punjabi population. AB - BACKGROUND: Genetic elements are known to influence susceptibility to tuberculosis (TB). P2X7R is a candidate gene with multiple single-nucleotide polymorphisms (SNPs) that has the potential to influence an individual's ability to kill the intracellular pathogen Mycobacterium tuberculosis. OBJECTIVE: To explore the role of five functional polymorphisms of P2X7R in susceptibility or resistance to TB in a North Indian Punjabi population. DESIGN: A case-control study was conducted among 245 TB patients (145 pulmonary TB [PTB] and 100 extra pulmonary TB [EPTB]) and 247 healthy controls. DNA extracted from samples of peripheral blood was analysed for five SNPs of P2X7R using amplification refractory mutation system-polymerase chain reaction (PCR) [-762(T/C), +1513(A/C), DNA sequencing +1729(T/A)] and PCR-restriction fragment length polymorphism [+489(G/A), +946(G/A)] methods. RESULTS: Of the three loss-in function polymorphisms, +1513(A/C) showed a statistically significant association with TB susceptibility, while the other two (+946 and +1729) sites were found to be monomorphic in our population. The only gain-in-function polymorphism (+489), and -762 promoter polymorphisms failed to reveal differences in genotypic or allelic distributions. CONCLUSION: The C allele at the +1513 site was identified as a risk factor for TB in this North Indian Punjabi population; the +1729 site was found to be monomorphic, unlike its polymorphic distribution in a South Indian TB patient population. PMID- 29991398 TI - Improving rifampicin-resistant tuberculosis diagnosis using Xpert(r) MTB/RIF: modelling interventions and costs. AB - SETTING: Cape Town, South Africa. OBJECTIVE: To model the diagnosis of rifampicin resistant tuberculosis (RR-TB) and laboratory costs of smear/culture and Xpert based algorithms and the effect of varying adherence and human immunodeficiency virus (HIV) testing in the Xpert-based algorithm. METHODS: We used a validated operational model (100 000 population) and published laboratory cost data. We estimated the number and cost of RR-TB cases identified using the smear/culture- and Xpert-based algorithms. We modelled varying adherence and different levels of known HIV status against the Xpert-based algorithm. RESULTS: The number of RR-TB cases identified increased from 603 with smear/culture to 1178 with the Xpert based algorithm (100% adherence; 60% knew their HIV status). The overall laboratory cost increased from US$1 073 858 to US$2 430 050 and the cost per RR TB case identified increased from US$1781 to US$2063 in the respective algorithms. When adherence to the Xpert-based algorithm was increased from 50% to 100% (60% knew their HIV status), the number of RR-TB cases identified increased from 721 to 1178. CONCLUSION: The Xpert-based algorithm is efficient in identifying RR-TB, as the increase in costs is offset by the increase in the number of cases identified. Adherence to the Xpert-based algorithm is important to ensure that all presumptive TB cases receive the benefit of simultaneous TB and RR-TB testing. PMID- 29991399 TI - Impact of scaling up Xpert(r) MTB/RIF testing for the detection of rifampicin resistant TB cases in Karachi, Pakistan. AB - SETTING: Pakistan ranks fourth among the countries with a high burden of multidrug-resistant tuberculosis (MDR-TB), with only 19.2% of the 15 000 estimated incident cases being notified. Increasing treatment coverage for MDR-TB is a key priority for Pakistan's National Tuberculosis Programme. The World Health Organization recommends the use of the Xpert(r) MTB/RIF assay as the first line diagnostic test for individuals with presumed TB. OBJECTIVE: To describe a multifaceted case-finding intervention targeting public and private sector health care facilities that used the Xpert assay as a frontline diagnostic test for individuals with presumptive TB, in Karachi, Pakistan, and its impact on case notifications of MDR-TB. DESIGN: Cross-sectional study. RESULTS: A total of 51 168 individuals were tested using Xpert, of whom respectively 7581 and 1534 people were diagnosed with TB in the public sector (reverse public-private mix) and private sector (social business model) arms; 574 (6.3% of all TB cases) were identified as having rifampicin (RMP) resistance. A total of 517 (90.1%) people with RMP-resistant TB (RR-TB) identified through the project were initiated on second-line treatment. The intervention resulted in 194 additional cases of RR TB, an increase of 43% over the baseline. CONCLUSION: This project, one of the largest Xpert testing programmes conducted at city level, resulted in significantly increased detection and treatment of MDR-TB. PMID- 29991400 TI - Can patients afford the cost of treatment for multidrug-resistant tuberculosis in Ethiopia? AB - SETTING: Ethiopia has a high prevalence of tuberculosis (TB) and is one of the countries with the highest burden of multidrug-resistant TB (MDR-TB). OBJECTIVE: To understand the costs that patients incur in obtaining diagnosis and treatment for MDR-TB. DESIGN: In March 2013, interviews were conducted with 169 MDR-TB patients at three hospitals in Ethiopia to identify the cost to patients and the impact on employment and family income. RESULTS: The average MDR-TB patient incurred a total cost of US$1378, which represented 25 months of a mid-treatment household income of US$54. The impact on the patient's employment and on overall patient and family income was generally catastrophic: 74% of all respondents reported losing their jobs, 66% of patients lost household income, and household income was reduced by 38%. To help cover the costs, 38% of patients sold some type of property, while 7% leased out property and 41% took out loans, any of which could jeopardize their future financial situation even further. CONCLUSION: Despite services being officially free of charge, most patients incurred catastrophic costs and suffered significant income loss as a result of obtaining diagnosis and treatment for MDR-TB. PMID- 29991401 TI - Economic burden of multidrug-resistant tuberculosis: a multicenter study across Vietnamese regions. AB - SETTING: Multidrug-resistant tuberculosis (MDR-TB) has become a major worldwide health problem. Various studies have been conducted on the cost of MDR-TB treatment; however, this has remained largely unexplored in Viet Nam. OBJECTIVE: To estimate the total cost of MDR-TB treatment at several health care facilities in Viet Nam. DESIGN: A prospective, prevalence-based study was conducted at three selected centers from March to June 2016 in 204 patients, 102 of whom were treated for 9 months and 102 for 20 months. Direct medical costs were calculated using electronic hospital databases, while a questionnaire was used to interview participants for evaluating direct non-medical and indirect costs. Total costs were estimated from a societal perspective in 2017 USD. RESULTS: Patients were mostly males aged 25-44 years. The average length of hospitalization in the 9 month treatment group was 168 +/- 127 days; in the 20-month group, it was 671 +/- 119 days. The average treatment cost for MDR-TB was respectively US$1480.34 +/- 211.61 and US$2695.58 +/- 294.98 for the 9- and 20-month treatment groups. Direct medical costs generally accounted for the highest proportion of the total costs, while the cost of pharmaceuticals and materials comprised the highest direct cost. CONCLUSION: There was a significant difference in total costs among the three hospitals in the 9- and 20-month treatment groups. PMID- 29991402 TI - Impact of adverse drug reactions on the incremental cost-effectiveness of bedaquiline for drug-resistant tuberculosis. AB - BACKGROUND: Adverse drug reactions (ADRs) are common during standard, long-course treatment for multidrug-resistant and rifampicin-resistant tuberculosis (MDR-/RR TB). In particular, second-line injectables (SLIs) are associated with permanent hearing loss, acute renal injury and electrolyte imbalance. We adapted an established Markov model for ambulatory treatment to estimate the impact of the toxicity profile on the incremental cost-effectiveness ratio (ICER) for a proposed MDR-/RR-TB regimen replacing the SLI with bedaquiline (BDQ). METHODS: Treatment effectiveness was evaluated in disability-adjusted life-years (DALYs). Clinical outcomes and ingredient costs from a provider perspective were derived from the South African public-sector treatment program or extracted from the literature. Costs and effectiveness were discounted at 3% per year over 10 years. RESULTS: A BDQ-based MDR-/RR-TB regimen compared with the SLI regimen had a mean ICER of US$516 per DALY averted using the standard Markov model. Costs for both regimens increased and effectiveness decreased for the SLI regimen once adjusted for toxicity. The resulting ICER for the BDQ-based regimen was cost saving (US$96/patient) and more effective (0.96 DALYs averted) after adjusting for ADRs. CONCLUSION: Decision-analysis models of treatment for MDR-/RR-TB, including new drug regimens, should consider the costs of managing ADRs and their sequelae. PMID- 29991403 TI - Effect of lidocaine on kanamycin injection-site pain in patients with multidrug resistant tuberculosis. AB - SETTING: Reducing pain from intramuscular injection of kanamycin (KM) could improve the tolerability of multidrug-resistant tuberculosis (MDR-TB) treatment. Lidocaine has been shown to be an effective anaesthetic diluent for some intramuscular injections, but has not been investigated with KM in the treatment of adult patients with MDR-TB. OBJECTIVE AND DESIGN: We performed a randomised single-blinded crossover study to determine if lidocaine reduces KM injection site pain. We recruited patients aged ?18 years on MDR-TB treatment at two TB hospitals in Cape Town, South Africa. KM pharmacokinetic parameters and a validated numeric pain scale were used at intervals over 10 h following the injection of KM with and without lidocaine on two separate occasions. RESULTS: Twenty participants completed the study: 11 were males, the median age was 36 years, 11 were HIV-infected, and the median body mass index was 17.5 kg/m2. The highest pain scores occurred early, and the median pain score was 0 by 30 min. The use of lidocaine with KM significantly reduced pain at the time of injection and 15 min post-dose. On multiple regression analysis, lidocaine halved pain scores (adjusted OR 0.5, 95%CI 0.3-0.9). The area under the curve at 0-10 h of KM with and without lidocaine was respectively 147.7 and 143.6 MUg.h/ml. CONCLUSION: Lidocaine significantly reduces early injection-site pain and has no effect on KM pharmacokinetics. PMID- 29991404 TI - Therapeutic drug monitoring of cycloserine and linezolid during anti-tuberculosis treatment in Beijing, China. AB - SETTING: Plasma concentrations of cycloserine (CS) and linezolid (LZD) in tuberculosis (TB) patients are largely unknown. OBJECTIVE: To measure the plasma concentrations of CS and LZD after drug ingestion in drug-resistant TB patients. DESIGN: Patients who received CS and LZD as part of their treatment between 1 July 2012 and 1 July 2016 were studied retrospectively. CS and LZD plasma levels were determined using high-pressure liquid chromatography-tandem mass spectrometry. Plasma drug concentration, age, sex, liver disease, renal disease, administered doses and diabetes mellitus status were recorded. RESULTS: Based on 390 samples, CS plasma concentrations were below the lower limit of normal (54.87%, 214/390). There was a statistically significant difference between the low concentration group (14.0 +/- 3.71 MUg/ml) and the target concentration group (25.2 +/- 3.73 MUg/ml, P < 0.01). The mean plasma concentration of LZD was 15.6 +/- 4.91 MUg/ml, which was within the target concentration (12-26 MUg/ml) in 65 patients. Variables that correlated with CS and LZD concentrations were not found in this retrospective study. CONCLUSION: Low plasma CS concentrations were common, while 83.1% (54/65) of plasma LZD concentrations were within the target range. Therapeutic drug monitoring is essential to maintain appropriate plasma drug concentrations in the era of precision medicine. PMID- 29991406 TI - Evaluation of OMNIgene(r)*SPUTUM reagent for mycobacterial culture. AB - SETTING: National Mycobacterium Reference Laboratory, Borstel, Germany. OBJECTIVE: To evaluate the effectiveness of OMNIgene(r)*SPUTUM (OM-S) reagent in comparison with a method using N-acetyl-L-cysteine-sodium hydroxide (NALC-NaOH) with regard to mycobacterial recovery and contamination of broth and solid cultures. DESIGN: Sputum samples from patients with tuberculosis and other respiratory diseases underwent decontamination with NALC-NaOH-based (MycoDDRTM) or OM-S reagent. The decontamination procedure was assigned by block randomisation. Samples were inoculated on Lowenstein-Jensen, Stonebrink and MGITTM (Mycobacterial Growth Indicator Tubes). Mycobacterial recovery from samples spiked with Mycobacterium tuberculosis following decontamination was determined. RESULTS: Eighty-five samples were randomised to NALC-NaOH and 84 to OM-S reagent. Mycobacterial recovery was significantly lower for samples processed with OM-S reagent compared with the NALC-NaOH method across all media types. Culture contamination was lower with NALC-NaOH reagent on solid media (9.4 12.9% vs. 28.6-29.8%). Growth was not observed in MGIT among samples spiked with 10 600-16 800 colony-forming units of M. tuberculosis following decontamination with OM-S reagent. CONCLUSION: Low mycobacterial recovery, especially in MGIT, observed in the present study suggests that OM-S reagent might not be compatible with the MGIT system. More extensive field evaluations of the OM-S reagent are warranted to demonstrate a significant benefit over currently used methods. PMID- 29991405 TI - Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. AB - SETTING: Anti-tuberculosis formulations necessitate uninterrupted treatment to cure tuberculosis (TB), but are characterised by suboptimal adherence, which jeopardises therapeutic efficacy. Long-acting injectable (LAI) formulations or implants could address these associated issues. OBJECTIVE: niazid, rifapentine, bedaquiline and delamanid-in adults for treatment for latent tuberculous infection (LTBI). DESIGN: PBPK models were developed and qualified against available clinical data by integrating drug physicochemical properties and in vitro and population pharmacokinetic data into a mechanistic description of drug distribution. Combinations of optimal dose and release rates were simulated such that plasma concentrations were maintained over the epidemiological cut-off or minimum inhibitory concentration for the dosing interval. RESULTS: The PBPK model identified 1500 mg of delamanid and 250 mg of rifapentine as sufficient doses for monthly intramuscular administration, if a formulation or device can deliver the required release kinetics of 0.001-0.0025 h-1 and 0.0015-0.0025 h-1, respectively. Bedaquiline and isoniazid would require weekly to biweekly intramuscular dosing. CONCLUSION: We identified the theoretical doses and release rates of LAI anti-tuberculosis formulations. Such a strategy could ease the problem of suboptimal adherence provided the associated technological complexities for LTBI treatment are addressed. PMID- 29991407 TI - Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum. AB - BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert(r) MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment. PMID- 29991408 TI - Evaluation of panels of Mycobacterium tuberculosis antigens for serodiagnosis of tuberculosis. AB - OBJECTIVE: To evaluate antibody responses to panels of Mycobacterium tuberculosis antigens for serological diagnosis of active tuberculosis (TB). DESIGN: We cloned, expressed and purified 10 M. tuberculosis recombinant proteins 38KD, MPT32 (M. tuberculosis protein 32), MPT64, EspC (ESX-1 secretion-associated protein), Mtb81, Rv3881, Rv3425, Rv0222, Rv3872 and CFP21 (culture filtrate protein 21), and obtained lipoarabinomannan (LAM) polysaccharide antigen from BEI Resources. The plasma immunoglobulin (Ig)G titre responses to the 11 antigens based on 45 patients with pulmonary TB (PTB) and 30 healthy controls (HCs) were first evaluated using enzyme-linked immunosorbent assays. Antigens with high sensitivities were then selected for further investigation in 200 PTB patients (121 smear- or culture-positive patients, 79 smear- or culture-negative patients) and 152 HCs. RESULTS: LAM, 38KD, MPT32, MPT64, EspC and Mtb81 were chosen. The LAM, 38KD, MPT32 and EspC IgG titres were significantly higher in Bacterium negative TB patients than in HCs, except for MPT64 and Mtb81. The sensitivity of the individual antigens for detecting antibodies ranged from 21.5% to 67.0%, with 74.3-98.0% specificity. The sensitivity of MPT32 was higher than that of 38KD at a high level of specificity. The six-antigen combination reached a sensitivity of 69.6% in bacterium-negative TB patients, with 77.0% specificity. CONCLUSION: The combination panel had markedly improved sensitivity, but specificity requires further enhancement. PMID- 29991410 TI - Thin body habitus is a risk factor for active pulmonary tuberculosis, but not for infection. PMID- 29991409 TI - Multidrug-resistant tuberculosis in Ukraine: what is hidden behind the numbers? PMID- 29991411 TI - In reply. PMID- 29991413 TI - Patterns of Zolpidem Use in Male and Female Veterans Following Revised FDA Dosing Guidelines. PMID- 29991414 TI - Quantitative Analysis of Thoracoabdominal Asynchrony in Pediatric Polysomnography. AB - STUDY OBJECTIVES: Objective measurements of thoracoabdominal asynchrony (TAA), such as average phase angle (thetaavg), can quantify airway obstruction. This study demonstrates and evaluates use of thetaavg for predicting obstructive sleep apnea (OSA) in pediatric polysomnography (PSG). METHODS: This prospective observational study recruited otherwise healthy 3- to 8-year-old children presenting for PSG due to snoring, behavioral problems, difficulty sleeping, and/or enlarged tonsils. Respiratory inductance plethysmography (RIP) was directly monitored and data were collected during each PSG. thetaavg and average labored breathing index (LBIavg) were calculated for earliest acceptable 5-minute periods of stage N3 sleep and stage R sleep. Associations between thetaavg and obstructive apnea index (OAI) and obstructive apnea-hypopnea index (OAHI), as well as between LBIavg and OAI and OAHI, were examined. RESULTS: Forty patients undergoing PSG were analyzed. Thirty percent of patients had OSA, 57.5% had enlarged tonsils, and 17.5% were obese. thetaavg during stage N3 sleep and stage R sleep had significant positive correlations with OAI (Spearman r = .35 [P = .03] and .40 [P = .01], respectively) and thetaavg during stage N3 sleep with OAHI (r = .35 [P = .03]). LBIavg showed lower correlations. Median thetaavg during stage R sleep (33.1) was significantly greater than during stage N3 sleep (13.7, P = .0005). CONCLUSIONS: Association of thetaavg with OAI and OAHI shows that thetaavg reflects airway obstruction and has potential use as a quantitative indicator of OSA. RIP provides valuable information that is readily available in PSG. The significant difference between thetaavg in stage N3 sleep and stage R sleep confirms the clinical observation that there is more asynchrony during rapid eye movement sleep than non-rapid eye movement sleep. PMID- 29991416 TI - A Case of Non-24-Hour Sleep-Wake Rhythm Disorder Treated With a Low Dose of Ramelteon and Behavioral Education. AB - ABSTRACT: Non-24-hour sleep-wake rhythm disorder (N24SWD) occurs when the intrinsic circadian pacemaker does not entrain (synchronize) to the 24-hour light/dark cycle. There is currently no established treatment for sighted patients with N24SWD. To the best of our knowledge, there have been very few reports on the efficacy of ramelteon administered to sighted patients with N24SWD. We report the case of a sighted patient with N24SWD whose free-running sleep-wake pattern recorded by actigraphy was stopped after the administration of a low dose of ramelteon combined with behavioral education. PMID- 29991415 TI - Obstructive Sleep Apnea in Cardiac Rehabilitation Patients. AB - STUDY OBJECTIVES: Although regular physical activity improves obstructive sleep apnea (OSA) in the general population, this finding has not been assessed in postmyocardial infarction (MI) patients in a rehabilitation setting (coronary artery disease, CAD). We aimed to determine whether cardiac rehabilitation may benefit post-MI patients in terms of OSA disease and associated autonomic nervous system (ANS) activity. METHODS: Consecutive post-MI patients participating in the ambulatory cardiac rehabilitation program of St-Etienne University Hospital were included in this study. The apnea-hypopnea index calculated from electrocardiogram (ECG)-derived respiration (AHIEDR) was obtained through nocturnal Holter ECG recordings. According to AHIEDR, patients were classified as normal, mild, moderate, or severe OSA (< 5, 5-14, 15-29, >= 30, respectively). Physiological performance (peak VO2) was established via cardiopulmonary exercise testing. ANS activity was evaluated through spontaneous baroreflex sensibility as well as heart rate variability analysis. RESULTS: Of the 105 patients with CAD and OSA included (95 men, 55.2 +/- 12.4 years), 100 had at least 1 cardiovascular risk factor (98%) and 52 patients (50%) had an ANS dysfunction. Surprisingly, 68 of these patients with OSA (65%) were free of classical diurnal symptoms usually associated with sleep apnea. In response to cardiac rehabilitation, AHIEDR decreased significantly (-9.3 +/- 9.5, P < .0001) only in patients with severe OSA, and the decrease was even greater when peak VO2 and baroreflex sensibility improved beyond 20% compared to basal values (-11.6 +/- 9.1, P < .001). CONCLUSIONS: Severe OSA in patients with CAD is significantly improved after 2 months of cardiopulmonary rehabilitation. Reviving ANS activity through physical activity might be a target for complementary therapy of OSA in patients with CAD. PMID- 29991417 TI - A Pilot Study of Impulse Radio Ultra Wideband Radar Technology as a New Tool for Sleep Assessment. AB - STUDY OBJECTIVES: To validate Impulse radio ultra wideband pulse-doppler radar technology against polysomnography (PSG) for sleep assessment. METHODS: In all, 12 participants were recruited and their overnight sleep was assessed both by a Novelda XeThru radar and PSG. Two subjects had two nightly recordings, whereas 10 had one recording. Epoch by epoch (30 seconds) comparisons from bedtime to rise time were conducted. Concordance was estimated in terms of the mean difference between the radar and the PSG estimates regarding sleep onset latency, wake time after sleep onset and total sleep time. In addition, accuracy, sensitivity, specificity and Cohen kappa were calculated. RESULTS: The mean difference (minutes) between the radar and the PSG registrations was -5.7 minutes (standard deviation [SD] = 22.1 minutes) for sleep onset latency, 6.4 minutes (SD = 32.5 minutes) for wake after sleep onset, and 1.5 minutes (SD = 24.6 minutes) for total sleep time. The mean values obtained for accuracy, sensitivity, specificity and Cohen kappa were 0.931, 0.961, 0.695 and 0.670, respectively. CONCLUSION: Impulse radio ultra wideband radar technology is a promising tool in terms of affordable and practical objective sleep assessment. Further technical development and more validation studies are needed in order to conclude about the utility potential of this device. PMID- 29991418 TI - Changes in Sleep Characteristics and Breathing Parameters During Sleep in Early and Late Pregnancy. AB - STUDY OBJECTIVES: Few studies have objectively evaluated sleep characteristics during pregnancy or investigated the relationship between altered spectral electroencephalogram (EEG) bands and sleep-disordered breathing (SDB). The study aimed to describe changes in sleep as measured by polysomnography (PSG) and spectral EEG bands during pregnancy and to examine the relationship between delta power in non-rapid eye movement (NREM) sleep and SDB. METHODS: This is a secondary analysis of a prospective study. One hundred twenty-three women underwent full PSG in early pregnancy, and 97 repeated PSG in late pregnancy. Spectral analysis of the EEG in NREM sleep was performed. We used linear and logistic mixed-model regression to analyze the sleep measures and linear regression to explore the association between delta power and apnea-hypopnea index (AHI) changes during pregnancy. RESULTS: In late pregnancy, women had shorter sleep duration, poorer sleep efficiency, more awakenings, more stage N2 sleep, less slow wave sleep, less REM sleep, higher AHI, and higher periodic limb movement index compared to early pregnancy. The percentage of stage N1 sleep, sleep latency, REM sleep latency, and arousal index frequency did not change. Regarding EEG-spectra, delta and theta powers decreased, but beta-2 power increased during pregnancy. In multivariable analyses, greater reduction of delta power was associated with larger increases in AHI (beta [95% confidence interval] = -0.038 [-0.073, -0.002], P = .040). Estimates suggest that each one-unit increase in AHI reduces delta power by 4% in late pregnancy. CONCLUSIONS: PSG measured sleep characteristics change during pregnancy. Delta power decreases when the severity of SDB increases during pregnancy. COMMENTARY: A commentary on this article appears in this issue on page 1095. PMID- 29991419 TI - Simplifying the Screening of Obstructive Sleep Apnea With a 2-Item Model, No Apnea: A Cross-Sectional Study. AB - STUDY OBJECTIVES: To develop and validate a practical model for obstructive sleep apnea (OSA) screening in adults based on objectively assessed criteria, and then compare it with two widely used tools, namely STOP-BANG and NoSAS. METHODS: This is a retrospective study of an existing database of consecutive outpatients who were referred for polysomnography for suspected sleep-disordered breathing by their primary care physicians. Area under the curve (AUC) and 2 * 2 contingency tables were employed to obtain the performance of the new instrument. RESULTS: A total of 4,072 subjects were randomly allocated into two independent cohorts: one for derivation (n = 2,037) and one for validation (n = 2,035). A mnemonic model, named No-Apnea, with two variables (neck circumference and age) was developed (total score: 0-9 points). We used the cutoff >= 3 to classify patients at high risk of having OSA. OSA severity was categorized by apnea-hypopnea index (AHI): any OSA (AHI 5 >= events/h; OSA-5), moderate/ severe OSA (AHI 15 >= events/h; OSA 15); and severe OSA (AHI 30 >= events/h; OSA-30). In the derivation cohort, the AUCs for screening of OSA-5, OSA-15, and OSA-30 were: 0.784, 0.758, and 0.754; respectively. The rate of subjects correctly screened was 78.1%, 68.8%, and 54.4%, respectively for OSA-5, OSA-15, and OSA-30. Subsequently, the model was validated confirming its reproducibility. In both cohorts, No-Apnea discrimination was similar to STOP-BANG or NoSAS. CONCLUSIONS: The No-Apnea, a 2 item model, appears to be a useful and practical tool for OSA screening, mainly when limited resources constrain referral evaluation. Despite its simplicity when compared to previously validated tools (STOP-BANG and NoSAS), the instrument exhibits similar performance characteristics. PMID- 29991420 TI - Responsiveness of Veterans Affairs Health Care System to Zolpidem Safety Warnings. AB - STUDY OBJECTIVES: Sedative hypnotic medications are routinely prescribed for insomnia treatment, but have been associated with significant risks of morning after impairment. We evaluated responsiveness in the Veterans Health Administration (VHA) facilities to two drug safety warnings recommending against high-dose zolpidem use-a 2007 Veterans Administration Pharmacy Benefits Management Service warning and a 2013 Food and Drug Administration (FDA) warning. METHODS: We used interrupted time-series design to assess how the two warnings influenced prescribing within the VHA in outpatients from 2005 to 2014. We assessed two outcomes: monthly outpatient use of (1) higher-than-recommended dose of zolpidem among zolpidem users and (2) any-dose zolpidem among all VHA users. In sensitivity analyses, we compared zolpidem prescribing to prescribing other sleep medications not subject to safety warnings. RESULTS: After the 2007 VHA warning, high-dose zolpidem use decreased significantly among both sexes from approximately 10% to 2%. Following the 2013 FDA warning, high-dose zolpidem use declined again; however, approximately half of women Veterans remained on high doses. Overall zolpidem use nearly quadrupled between the 2007 VHA and 2013 FDA warnings, but the overall use declined after the 2013 FDA warning. Increase in sedating antidepressant use was seen after the FDA warning, suggesting potential substitution. CONCLUSIONS: Higher than recommended dose use within the VHA decreased after each zolpidem high dose warning. Although overall use also decreased after the FDA warning, almost 50% of high-dose use among women Veterans is concerning. Different strategies to communicate the warnings should be examined. COMMENTARY: A commentary on this article appears in this issue on page 1093. PMID- 29991421 TI - Sleep Disturbances in Midlife Women at the Cusp of the Menopausal Transition. AB - STUDY OBJECTIVES: To compare causes of sleep disturbance and to compare self reported sleep duration among groups of late premenopausal women and early perimenopausal women. METHODS: In a longitudinal study of a community-based sample of healthy women 40 to 50 years of age, menstrual cycle and symptom data were collected every 2 months; anthropometric measures, a urine sample for follicle stimulating hormone (FSH), and the Pittsburgh Sleep Quality Index (PSQI) measures were collected every 6 months. RESULTS: At 12 to 18 months, 206 women remained premenopausal and 69 women became perimenopausal. Poor sleep quality (PSQI score > 5) was experienced by 42% of the total cohort. Awakening to use the bathroom was the most frequent reason (81%) for sleep disturbance in the entire cohort, followed by feeling too hot (26%). However, premenopausal women were significantly more likely to awaken to use the bathroom than perimenopausal women (P = .047), and perimenopausal women were more likely than premenopausal women to awaken because of feeling too hot (P = .002). Women in early perimenopause reported shorter sleep duration (P = .007) and worse sleep quality (P = .05) than premenopausal women of similar age. CONCLUSIONS: Sleep disturbance is a significant issue for midlife women regardless of age or reproductive stage. Identification of salient factors that disrupt sleep, such as nocturia prior to menopausal transition or feeling too hot early in menopausal transition, will provide direction for developing tailored intervention strategies to improve sleep and quality of life. COMMENTARY: A commentary on this article appears in this issue on page 1095. PMID- 29991422 TI - Adropin and Inflammation Biomarker Levels in Male Patients With Obstructive Sleep Apnea: A Link With Glucose Metabolism and Sleep Parameters. AB - STUDY OBJECTIVES: The main objectives of the study were to determine plasma adropin, systemic inflammation biomarker levels, and glucose metabolism parameters in patients with moderate and severe obstructive sleep apnea (OSA) compared to healthy controls. METHODS: In this study, we included 50 male patients with OSA (25 moderate and 25 severe) and 25 age- and sex-matched control subjects. All subjects underwent fasting sampling of peripheral blood for laboratory analyses. RESULTS: Adropin plasma levels were significantly lower in the severe OSA group in comparison with the moderate and control groups (4.50 +/- 1.45 versus 6.55 +/- 1.68 versus 8.15 +/- 1.79 ng/mL, P < .001). Plasma biomarkers of systemic inflammation were significantly increased in patients with moderate OSA (interleukin [IL]-6 and tumor necrosis factor alpha [TNF-alpha]) and severe OSA (IL-6, TNF-alpha, high-sensitivity C-reactive protein) when compared with controls (P < .001). Adropin levels showed a significant negative correlation with IL-6 (r = -.419, P < .001), TNF-alpha (r = -.540, P < .001), fasting glucose (r = -.331, P = .004), hemoglobin A1c (r = -.438, P < .001), homeostatic model assessment insulin resistance index (r = -.213, P = .046), and polysomnographic parameters including apnea-hypopnea index (r = -.615, P < .001) and oxygen desaturation index (r = -.573, P < .001). A multivariate regression analysis showed that plasma adropin remained as a significant negative predictor of severe OSA status, when adjusted for age and body mass index and computed along with other inflammatory biomarkers in the regression model (odds ratio 0.069, 95% confidence interval 0.009-0.517, P = .009). CONCLUSIONS: Plasma adropin concentrations significantly correlate with indices of disease severity in patients with OSA, suggesting that adropin potentially plays an important role in the complex pathophysiology of the disease. PMID- 29991423 TI - Craniofacial Phenotyping in Chinese and Caucasian Patients With Sleep Apnea: Influence of Ethnicity and Sex. AB - STUDY OBJECTIVES: Craniofacial abnormalities are a risk factor for obstructive sleep apnea (OSA). We have previously shown that phenotypic information derived from craniofacial photographs predict OSA in sleep clinic populations. However, there are likely ethnic and sex differences in craniofacial phenotypes related to OSA. We aimed to assess the use of craniofacial photography to identify interactions between OSA, ethnicity, and sex in craniofacial phenotype. METHODS: Frontal and profile craniofacial photographs were analyzed from two sleep clinic populations of different ethnicity (Hong Kong Chinese, Australian Caucasians). OSA was defined as apnea-hypopnea index (AHI) > 10 events/h. Ten craniofacial measurements (three angles relating to jaw position and seven ratios describing proportions of the face) were examined for interactions between OSA status and sex or ethnicity) using factorial analysis of variance. RESULTS: A total of 363 subjects (25% female) were included (n = 200 Chinese, n = 163 Caucasian), of which 33% were controls. There were two-way interactions for OSA with both sex (mandibular plane angle [F = 7.0, P = .009], face / eye width ratio [F = 4.7, P = .032], maxillary / mandibular volume ratio [F = 9.2, P = .003]) and ethnicity (face / nose width ratio [F = 4.0, P = .045], mandibular width / length ratio [F = 5.1, P = .024], maxillary / mandibular volume ratio [F = 11.0, P = .001]). CONCLUSIONS: We provide evidence of ethnic and sex differences in facial phenotype related to OSA. Furthermore, we demonstrate that craniofacial photography can be used as a phenotypic tool to assess these differences and allow investigation of OSA phenotypes in large samples. This has relevance to personalizing OSA recognition strategies across different populations. PMID- 29991424 TI - Accuracy of Patient Perception of Supine Sleep. AB - STUDY OBJECTIVES: For clinicians involved in investigating and treating sleep disorders, understanding the accuracy of patient recall of supine sleep would allow informed comparisons between polysomnography (PSG) and patient-reported sleep in patients with supine-predominant obstructive sleep apnea. This study aims to assess the accuracy of patient perception of supine sleep. METHODS: Prospective observational cohort study, assessing patient perception of total sleep and supine sleep, including duration. Data were analyzed utilizing descriptive statistics, bias-plot (Bland-Altman) analysis, and Spearman correlation (rs) to analyze relationships among continuous data. RESULTS: Total number of patients who underwent PSG was 518, with data from 368 of these patients analyzed. Most of these patients underwent diagnostic PSG (49.2%). Patients were excluded because of missing or incomplete data (n = 133) or immobility (n = 17). Some patients (n = 97, 26%) did not perceive supine sleep, with 34 (35% of those with unperceived supine sleep or 9% of whole group) of these having more than 60 minutes of PSG supine sleep (range 0-305.5 minutes). All "unsure" patients (n = 8, 2.2%) had significant supine sleep recorded (31.5 257.5 minutes). For the presence of any PSG supine sleep, questioning had a sensitivity of 77.9%, specificity 72.7% with positive predictive value of 96.7% and negative predictive value of 24.5%. There was a significant correlation (rs = 0.63, P < .0001) between perceived and PSG supine sleep, but wide limits of agreement (-246.9 to 194.2 minutes). CONCLUSIONS: In patients undergoing in laboratory PSG, the perception of supine sleep predicts the presence of PSG supine sleep. However, questioning patients has a poor negative predictive value and patient estimates of supine sleep duration are inaccurate. PMID- 29991425 TI - Sleep-Related Eating Disorder (SRED): Paradoxical Effect of Clonazepam. AB - ABSTRACT: A 9-year-old boy with primary myoclonus dystonia with comorbid severe attention deficit hyperactive disorder (ADHD) also had sleep onset and maintenance insomnia. Polysomnography showed features of non-rapid eye movement parasomnia. Daily bedtime clonidine helped sleep and hyperactivity. ADHD symptoms improved with 40 mg daily lisdexamphetamine mesylate. As the myoclonus and dystonia symptoms progressed, clonazepam was initiated at a dose of 0.5 mg daily at bedtime. It was anticipated that clonazepam would also improve parasomnia. Concomitant with the initiation of clonazepam, he developed a sleep-related eating disorder (SRED) continuing almost throughout the night. The symptoms went away upon stopping clonazepam. This is the first description of clonazepam producing SRED though it is the treatment of choice for this disorder. PMID- 29991426 TI - Positive Airway Pressure Therapy Is Challenging for Patients With Epilepsy. AB - STUDY OBJECTIVES: To investigate whether patients with epilepsy and comorbid obstructive sleep apnea (OSA) are more likely to be nonadherent to positive airway pressure (PAP) therapy than adults with OSA but without epilepsy. METHODS: This retrospective study included patients with epilepsy diagnosed with OSA and age-, sex-, and apnea-hypopnea index (AHI)-matched controls with OSA but without epilepsy who started PAP treatment between February 2014 and August 2017. Subjects' adherence to PAP therapy was continuously recorded electronically, and comparisons were made at 1 month, 3 months, and 1 year following PAP initiation. Predictors to poor adherence were also evaluated. RESULTS: Patients with epilepsy (n = 23) were less adherent to PAP than controls (n = 23) during the first month of treatment (13% versus 78%, P = .03). During this first month, average PAP use was lower in patients with epilepsy (4.7 +/- 2.1 hours) relative to controls (6.1 +/- 1.2 hours, P = .03). Despite sustained PAP treatment, patients with epilepsy had a greater residual AHI and were five times more likely than controls to have residual apnea events above normal range at 3-month and 1-year follow-up. However, no clinical characteristics could significantly predict poor adherence in patients. CONCLUSIONS: Patients with epilepsy are less likely to be adherent to PAP therapy during the first month of treatment, as compared to adults with OSA but no epilepsy. Moreover, PAP therapy could not sufficiently reduce AHI in up to 72% of patients. These findings highlight the need for careful monitoring of PAP treatment in patients with epilepsy, as untreated OSA may worsen seizure burden. PMID- 29991427 TI - Continued Presence of Period Limb Movements During REM Sleep in Patients With Chronic Static Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). AB - STUDY OBJECTIVES: A major component of pediatric acute-onset neuropsychiatric syndrome (PANS) is disruption of sleep. These disturbances have been reported in the acute phase of diagnosis but it is unknown if these sleep disruptions persist, especially in patients with chronic static symptoms. This retrospective chart review sought to review polysomnography (PSG) tests of patients in whom PANS has been clinically diagnosed in order to assess sleep architecture, periodic limb movements, and presence of rapid eye movement (REM) sleep without atonia (RSWA) after a chronic static course of symptoms, which were refractory to immunomodulatory interventions. METHODS: Patients were retrospectively identified through the PANS clinic at our institution and had to have fully completed a PSG study and be younger than 18 years. PSG with video were reviewed and scored based on established criteria. RESULTS: We identified 9 patients who met inclusion criteria. The median time from presentation to PSG was 4 years. This study identified PSG-measured periodic limb movement index (PLMI) > 5 events/h in REM sleep in 7 of 9 patients. Two patients with elevated PLMI also demonstrated RSWA, although neither fit a clinical diagnosis of REM sleep behavior disorder. This cohort also demonstrated increased onset of REM sleep (median 134 minutes), insomnia (median total sleep time of 389 minutes), and decreased sleep efficiency (77%). CONCLUSIONS: This study identifies continued sleep disturbances in patients with refractory PANS symptoms several years after diagnosis and treatment. Continued sleep disturbances after presentation and treatment in patients with chronic static PANS may be a contributing factor in prolonged symptomatology of this disease process. PMID- 29991429 TI - Abnormal Pulse Oximetry Signal. PMID- 29991428 TI - Cognitive Behavioral Therapy for Insomnia Reduces Fear of Sleep in Individuals With Posttraumatic Stress Disorder. AB - STUDY OBJECTIVES: Our study aims were to examine (1) the association between fear of sleep and posttraumatic stress disorder (PTSD) symptoms, (2) the association between fear of sleep and subjective and objective insomnia symptoms and disruptive behaviors during sleep, and (3) whether fear of sleep decreases following cognitive behavioral therapy for insomnia (CBT-I). METHODS: Forty-five adults with PTSD and insomnia participated in the study. Fear of sleep was assessed using the Fear of Sleep Inventory; PTSD symptoms were assessed using the Clinician Administered PTSD Scale; and sleep disturbance symptoms were assessed using the Insomnia Severity Index, polysomnography, sleep diaries, and the Pittsburgh Sleep Quality Index Addendum for PTSD. Participants were randomly assigned to 8 weeks of CBT-I (n = 29) or a waitlist control condition (n = 16). RESULTS: Greater fear of sleep was associated with greater PTSD symptom severity, greater nightmare frequency, and greater hypervigilance intensity. Greater fear of sleep was associated with decreased wake after sleep onset (WASO), reduced total sleep time, and greater disruptive nocturnal behaviors. Following CBT-I, there was a significant reduction in fear of sleep compared to the waitlist condition. These improvements persisted 6 months later. CONCLUSIONS: Fear of sleep was related to sleep disturbances specific to trauma rather than "classic" insomnia symptoms. Unexpectedly, greater fear of sleep was associated with reduced WASO. These results may be related to having a truncated sleep period and thus more consolidated sleep. Fear of sleep deceased following CBT-I despite not being a permissible target for this research protocol and not being related to insomnia symptoms. CLINICAL TRIAL REGISTRATION: Registry: CinicalTrials.gov; Name: Treating People with Post-traumatic Stress Disorder with Cognitive Behavioral Therapy for Insomnia; Identifier: NCT00881647; URL: https://clinicaltrials.gov/ct2/show/NCT00881647. PMID- 29991430 TI - Sleep Disturbances in Traumatic Brain Injury: Associations With Sensory Sensitivity. AB - STUDY OBJECTIVES: Sleep disturbances following traumatic brain injury (TBI) in Veterans are very common and often persist as chronic sequelae. In addition, sensory sensitivity, ie, discomfort upon exposure to light and noise, is common after TBI. However, the relationship between sleep disturbances and sensory sensitivity in Veterans following TBI has not yet been examined, yet both are established early markers of neurodegeneration. METHODS: Veterans (n = 95) in the chronic phase of recovery from TBI at the VA Portland Health Care System completed an overnight polysomnography and provided self-report data on sensory (eg, light and noise) sensitivity, and sleep disturbances. Participants were categorized into four sensory sensitivity groups: (1) "neither," neither light nor noise sensitivity (n = 36); (2) "light," only light sensitivity (n = 12); (3) "noise," only noise sensitivity (n = 24); and (4) "both," light and noise sensitivity (n = 23). RESULTS: Veterans with TBI reported sleep disturbances that were significantly correlated with the severity of their sensory sensitivity and associated with posttraumatic stress disorder (PTSD). Multiple linear regression revealed insomnia severity to be the strongest predictor of the relationship between sleep disturbances and sensory sensitivity. Furthermore, sensory sensitivity was associated with a higher mean heart rate during sleep, even after controlling for PTSD status. CONCLUSIONS: These data are the first to report the prevalence and association between sensory sensitivity and sleep disturbances in Veterans with TBI. These data also suggest that the underlying mechanism of the sleep-sensory relationship could be due in part to comorbid PTSD and autonomic nervous system hyperarousal. PMID- 29991432 TI - Measurement of Mefloquine Exposure in Studies of Veterans' Sleep Disorders. PMID- 29991431 TI - Severe Chronic Abuse of Zolpidem in Refractory Insomnia. AB - ABSTRACT: Zolpidem is an imidazopyridine nonbenzodiazepine hypnotic drug with a high affinity to the alpha1 subunit of the gamma amino butyric acid A receptor It is the first pharmacological option in the short-term management of sleep-onset insomnia. Initially considered a safer drug compared to benzodiazepines because of lower liability for abuse and dependence, recently, an increasing body of reports has questioned zolpidem's proneness to misuse. In this report, we describe a case of serious zolpidem abuse requiring pharmacological washout during hospitalization because of previous withdrawal seizures in a patient with chronic sleep-onset and maintenance insomnia. PMID- 29991433 TI - Sleep Education for College Students: The Time Is Now. PMID- 29991434 TI - Evaluation of Clinical Tools to Screen and Assess for Obstructive Sleep Apnea. AB - ABSTRACT: Obstructive sleep apnea (OSA) is a globally recognized medical condition, associated with development of long-term adverse health consequences, including cardiovascular disease, cerebrovascular disease, neurocognitive deficiencies, and vehicular and occupational accidents. OSA can be screened effectively, because it can be identified well before the manifestation of the aforementioned poor health and public safety consequences. Additionally, appropriate management of OSA includes an assessment of outcomes before and after therapeutic intervention initiation. OSA clinical screening and outcome assessment tools exist; however, a key existing knowledge gap is identifying which tools are most clinically relevant and efficient to use in clinical practice models. The American Academy of Sleep Medicine (AASM) commissioned a task force (TF) of sleep medicine experts to identify and evaluate current OSA screening and assessment tools for adult patients and determine if they are reliable, effective, and feasible for use in clinical settings. No single tool met all the TF's objective criteria and subjective evaluation for clinical validity and feasibility to be recommended by the AASM. The TF provides several suggestions for the development of new tools or modifications to existing tools that would enhance their functionality in adults. PMID- 29991435 TI - Sleep Education for College Students. PMID- 29991436 TI - Nightmares in United States Military Personnel Are Multifactorial and Require Further Study. PMID- 29991437 TI - Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Clinical Practice Guideline. AB - INTRODUCTION: The purpose of this guideline is to establish clinical practice recommendations for the use of actigraphy in adult and pediatric patients with suspected or diagnosed sleep disorders or circadian rhythm sleep-wake disorders. METHODS: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assigned strengths based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended as a guide for clinicians using actigraphy in evaluating patients with sleep disorders and circadian rhythm sleep-wake disorders, and only apply to the use of FDA-approved devices. Each recommendation statement is assigned a strength ("Strong" or "Conditional"). A "Strong" recommendation (ie, "We recommend...") is one that clinicians should follow under most circumstances. A "Conditional" recommendation (ie, "We suggest...") reflects a lower degree of certainty regarding the outcome and appropriateness of the patient-care strategy for all patients. The ultimate judgment regarding any specific care must be made by the treating clinician and the patient, taking into consideration the individual circumstances of the patient, available treatment options, and resources. We suggest that clinicians use actigraphy to estimate sleep parameters in adult patients with insomnia disorder. (Conditional). We suggest that clinicians use actigraphy in the assessment of pediatric patients with insomnia disorder. (Conditional). We suggest that clinicians use actigraphy in the assessment of adult patients with circadian rhythm sleep-wake disorder. (Conditional). We suggest that clinicians use actigraphy in the assessment of pediatric patients with circadian rhythm sleep-wake disorder. (Conditional). We suggest that clinicians use actigraphy integrated with home sleep apnea test devices to estimate total sleep time during recording (in the absence of alternative objective measurements of total sleep time) in adult patients suspected of sleep-disordered breathing. (Conditional). We suggest that clinicians use actigraphy to monitor total sleep time prior to testing with the Multiple Sleep Latency Test in adult and pediatric patients with suspected central disorders of hypersomnolence. (Conditional). We suggest that clinicians use actigraphy to estimate total sleep time in adult patients with suspected insufficient sleep syndrome. (Conditional). We recommend that clinicians not use actigraphy in place of electromyography for the diagnosis of periodic limb movement disorder in adult and pediatric patients. (Strong). PMID- 29991439 TI - Polysomnography for Obstructive Sleep Apnea Should Include Arousal-Based Scoring: An American Academy of Sleep Medicine Position Statement. AB - ABSTRACT: The diagnostic criteria for obstructive sleep apnea (OSA) in adults, as defined in the International Classification of Sleep Disorders, Third Edition, requires an increased frequency of obstructive respiratory events demonstrated by in-laboratory, attended polysomnography (PSG) or a home sleep apnea test (HSAT). However, there are currently two hypopnea scoring criteria in The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications (AASM Scoring Manual). This dichotomy results in differences among laboratory reports, patient treatments and payer policies. Confusion occurs regarding recognizing and scoring "arousal-based respiratory events" during OSA testing. "Arousal-based scoring" recognizes hypopneas associated with electroencephalography-based arousals, with or without significant oxygen desaturation, when calculating an apnea-hypopnea index (AHI), or it includes respiratory effort-related arousals (RERAs), in addition to hypopneas and apneas, when calculating a respiratory disturbance index (RDI). Respiratory events associated with arousals, even without oxygen desaturation, cause significant, and potentially dangerous, sleep apnea symptoms. During PSG, arousal-based respiratory scoring should be performed in the clinical evaluation of patients with suspected OSA, especially in those patients with symptoms of excessive daytime sleepiness, fatigue, insomnia, or other neurocognitive symptoms. Therefore, it is the position of the AASM that the RECOMMENDED AASM Scoring Manual scoring criteria for hypopneas, which includes diminished airflow accompanied by either an arousal or >= 3% oxygen desaturation, should be used to calculate the AHI. If the ACCEPTABLE AASM Scoring Manual criteria for scoring hypopneas, which includes only diminished airflow plus >= 4% oxygen desaturation (and does not allow for arousal-based scoring alone), must be utilized due to payer policy requirements, then hypopneas as defined by the RECOMMENDED AASM Scoring Manual criteria should also be scored. Alternatively, the AASM Scoring Manual includes an option to report an RDI which also provides an assessment of the sleep-disordered breathing that results in arousal from sleep. Furthermore, given the inability of most HSAT devices to capture arousals, a PSG should be performed in any patient with an increased risk for OSA whose HSAT is negative. If the PSG yields an AHI of 5 or more events/h, or if the RDI is greater than or equal to 5 events/h, then treatment of symptomatic patients is recommended to improve quality of life, limit neurocognitive symptoms, and reduce accident risk. PMID- 29991438 TI - Use of Actigraphy for the Evaluation of Sleep Disorders and Circadian Rhythm Sleep-Wake Disorders: An American Academy of Sleep Medicine Systematic Review, Meta-Analysis, and GRADE Assessment. AB - INTRODUCTION: The purpose of this systematic review is to provide supporting evidence for a clinical practice guideline on the use of actigraphy. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine. A systematic review was conducted to identify studies that compared the use of actigraphy, sleep logs, and/or polysomnography. Statistical analyses were performed to determine the clinical significance of using actigraphy as an objective measure of sleep and circadian parameters. Finally, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. RESULTS: The literature search resulted in 81 studies that met inclusion criteria; all 81 studies provided data suitable for statistical analyses. These data demonstrate that actigraphy provides consistent objective data that is often unique from patient-reported sleep logs for some sleep parameters in adult and pediatric patients with suspected or diagnosed insomnia, circadian rhythm sleep-wake disorders, sleep disordered breathing, central disorders of hypersomnolence, and adults with insufficient sleep syndrome. These data also demonstrate that actigraphy is not a reliable measure of periodic limb movements in adult and pediatric patients. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. PMID- 29991440 TI - Women's Sleep Across the Reproductive Life Span. PMID- 29991441 TI - Differential inhibitory effect of a pyrazolopyran compound on human serine hydroxymethyltransferase-amino acid complexes. AB - Serine hydroxymethyltransferase (SHMT) is a pivotal enzyme in one-carbon metabolism that catalyses the reversible conversion of serine and tetrahydrofolate into glycine and methylenetetrahydrofolate. It exists in cytosolic (SHMT1) and mitochondrial (SHMT2) isoforms. Research on one-carbon metabolism in cancer cell lines has shown that SHMT1 preferentially catalyses serine synthesis, whereas in mitochondria SHMT2 is involved in serine breakdown. Recent research has focused on the identification of inhibitors that bind at the folate pocket. We have previously found that a representative derivative of the pyrazolopyran scaffold, namely 2.12, inhibits both SHMT isoforms, with a preference for SHMT1, causing apoptosis in lung cancer cell lines. Here we show that the affinity of 2.12 for SHMT depends on the identity of the amino acid substrate bound to the enzyme. The dissociation constant of 2.12 is 50-fold lower when it binds to SHMT1 enzyme-serine complex, as compared to the enzyme-glycine complex. Evidence is presented for a similar behaviour of compound 2.12 in the cellular environment. These findings suggest that the presence and identity of the amino acid substrate should be considered when designing SHMT inhibitors. Moreover, our data provide the proof-of-concept that SHMT inhibitors selectively targeting the directionality of one-carbon metabolism flux could be designed. PMID- 29991442 TI - Coffee consumption and purchasing behavior review: Insights for further research. AB - This paper presents a systematic literature review of consumer research towards coffee with the objective to identify and categorize motives, preferences and attributes of coffee consumption and purchasing behavior. Research papers were analyzed in terms of main characteristics and components (study type, research methodology, sampling, and product type). The review gives a systematic overview of the heterogeneous group of concepts and approaches that have been used so far to examine consumer behavior towards coffee. Results provide a model of key determinants for coffee consumption that can be grouped into the categories, (1) personal preferences, (2) economic attributes, (3) product attributes, (4) context of consumption, and (5) socio-demographics. The findings also show that there is a strong focus on coffee sustainability. PMID- 29991443 TI - Regional glucose metabolism due to the presence of cerebral amyloidopathy in older adults with depression and mild cognitive impairment. AB - BACKGROUND: Depression is a risk factor for mild cognitive impairment (MCI) and for the conversion from MCI to Alzheimer's disease (AD). This study investigated regional cerebral glucose metabolism (rCMglc) in older adults with depression and MCI, either with or without amyloidopathy. METHODS: We recruited 31 older adults diagnosed with depression and MCI, and 21 older adults with normal cognition (NC). All participants completed demographic questionnaires and were examined with a standardized neuropsychological battery, F-18 fluorodeoxyglucose positron emission tomography (PET), and F-18 florbetaben PET. We classified subjects with depression and MCI into amyloid-beta-positive (CDAP; n = 16) and amyloid-beta negative (CDAN; n = 15) groups. Pairwise rCMglc analyses were conducted between all three groups (CDAP vs. NC, CDAN vs. NC, and CDAP vs. CDAN). RESULTS: In comparison with the NC group, the CDAP group showed reduced rCMglc predominantly in temporoparietal regions, whereas the CDAN group showed lower rCMglc in regions of the frontal lobe, in addition to the temporoparietal regions. The CDAN group also showed lower rCMglc in right anterior cingulate and left inferior orbitofrontal regions, in a comparison between the CDAP and CDAN groups. LIMITATIONS: The generalizability of the findings is limited because this study has a relatively small number of participants. In addition, this study used cross sectional design rather than longitudinal design. CONCLUSIONS: Our findings may provide a reference to assess the risk of future cognitive deterioration. Consequently, this study is expected to contribute to prevention and early identification of dementia associated with AD. PMID- 29991444 TI - Food derived respiratory complex I inhibitors modify the effect of Leber hereditary optic neuropathy mutations. AB - Mitochondrial DNA mutations in genes encoding respiratory complex I polypeptides can cause Leber hereditary optic neuropathy. Toxics affecting oxidative phosphorylation system can also cause mitochondrial optic neuropathy. Some complex I inhibitors found in edible plants might differentially interact with these pathologic mutations and modify their penetrance. To analyze this interaction, we have compared the effect of rotenone, capsaicin and rolliniastatin-1 on cybrids harboring the most frequent Leber hereditary optic neuropathy mutations and found that m.3460G > A mutation increases rotenone resistance but capsaicin and rolliniastatin-1 susceptibility. Thus, to explain the pathogenicity of mitochondrial diseases due to mitochondrial DNA mutations, their potential interactions with environment factors will have to be considered. PMID- 29991445 TI - Decoding selective attention to context memory: An aging study. AB - Emerging evidence has suggested that the tendency for older adults to bind too much contextual information during encoding (i.e., hyper-binding) may contribute to poorer memory for relevant contextual information during retrieval. While these findings are consistent with theories of age-related declines in selective attention and inhibitory control, the degree to which older adults are able to selectively attend to relevant contextual information during encoding is unknown. To better understand the neural dynamics associated with selective attention during encoding, the current study applied multivariate pattern analyses (MVPA) to oscillatory EEG in order to track moment-to-moment shifts of attention between relevant and irrelevant contextual information during encoding. Young and older adults studied pictures of objects in the presence of two contextual features: a color and a scene, and their attention was directed to the object's relationship with one of those contexts (i.e., target context). Results showed that patterns of oscillatory power successfully predicted whether selective attention was directed to a scene or color, across age groups. Individual differences in overall classification performance were associated with individual differences in target context memory accuracy during retrieval. However, changes in classification performance within a trial, suggestive of fluctuations in selective attention, predicted individual differences in hyper-binding. To the best of our knowledge, this is the first study to use MPVA techniques to decode attention during episodic encoding and the impact of attentional shifts toward distracting information on age-related context memory impairments and hyper binding. These results are consistent with the as-of-yet unsubstantiated theory that age-related declines in context memory may be attributable to poorer selective attention and/or greater inhibitory deficits in older adults. PMID- 29991446 TI - Cell surface vimentin-targeted monoclonal antibody 86C increases sensitivity to temozolomide in glioma stem cells. AB - Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor. The current standard therapy, which includes radiation and chemotherapy, is frequently ineffective partially because of drug resistance and poor penetration of the blood-brain barrier. Reducing resistance and increasing sensitivity to chemotherapy may improve outcomes. Glioma stem cells (GSCs) are a source of relapse and chemoresistance in GBM; sensitization of GSCs to temozoliomide (TMZ), the primary chemotherapeutic agent used to treat GBM, is therefore integral for therapeutic efficacy. We previously discovered a unique tumor-specific target, cell surface vimentin (CSV), on patient-derived GSCs. In this study, we found that the anti-CSV monoclonal antibody 86C efficiently increased GSC sensitivity to TMZ. The combination TMZ+86C induced significantly greater antitumor effects than TMZ alone in eight of 12 GSC lines. TMZ+86C-sensitive GSCs had higher CSV expression overall and faster CSV resurfacing among CSV- GSCs compared with TMZ+86C-resistant GSCs. Finally, TMZ+86C increased apoptosis of tumor cells and prolonged survival compared with either drug alone in GBM mouse models. The combination of TMZ+86C represents a promising strategy to reverse GSC chemoresistance. PMID- 29991447 TI - Resting cerebral blood flow alterations specific to the comitant exophoria patients revealed by arterial spin labeling perfusion magnetic resonance imaging. AB - PURPOSE: It has been shown in many previous studies that there were significant changes of the brain anatomy and function in strabismus. However, the significance of the alterations of resting cerebral blood flow (CBF) in comitant exophoria (CE) remains obscure. Arterial spin labeling (ASL) MRI, which is a noninvasive method, could be applied to detect the cerebral blood flow quantitatively. Our study aimed to compare the resting CBF between the comitant exophoria and health controls using pseudo-continuous arterial spin labeling (pCASL) perfusion MRI method. METHODS: 32 patients (25 males and 7 females) with CE (study group), and 32 (25 males and 7 females) healthy individuals with matched age and sex status (control group) underwent a whole-brain pCASL magnetic resonance (MR) examination at the resting state. The resting CBF were voxel-wise compared between the two groups using an analysis of variance designed in a statistical parametric mapping program. The CE patients were distinguishable from the healthy controls (HCs) by receiver operating characteristic (ROC) curves. RESULTS: Compared with the control group, the CE group showed significantly increased resting CBF values in the right parahippocampal regions, bilateral medial frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal gyrus, left superior frontal gyrus, bilateral medial cingulate cortex, right middle frontal gyrus, and right paracentral lobule. CONCLUSION: Comitant exophoria showed increased resting CBF in eye movement related brain areas including supplementary eye field, cingulate eye field and frontal eye field, which could be an explanation of the brain function compensation for the ocular motility disorders in the CE patients. PMID- 29991448 TI - The effects of hydrogen sulfide on microvascular circulation in the axial pattern flap ear model in hairless mice. PMID- 29991449 TI - Protostemonine attenuates alternatively activated macrophage and DRA-induced asthmatic inflammation. AB - Asthma is one of the most common pulmonary diseases that threatens human life because of lack of effective medicines. Protostemonine (PSN), an active alkaloid extracted from the roots of Stemona sesslifolia, has anti-inflammatory effects on acute lung injury and acute liver failure. However, it has not been defined whether PSN alleviates asthmatic inflammation. Here, we reported that PSN inhibits pulmonary eosinophil infiltration, goblet cell hyperplasia, mucus secretion, IgE and Th2 cytokine (IL-4, IL-5, IL-13 and IL-33) production by using DRA (dust mites, ragweed and aspergillus)-induced murine asthma model. Moreover, PSN also attenuated the expression of Arginase-1 (Arg-1), Ym-1 and Fizz-1, markers of AAM (alternatively activated macrophage) polarization, in lung tissues. In addition, PSN attenuated IL-4-induced expression of Arg-1, Ym-1 and Fizz-1 in bone marrow derived macrophages (BMDMs). Treatment with PSN decreased IL-4-induced STAT6 phosphorylation, KLF4 and IRF4 expression in BMDMs. Collectively, our results indicated that PSN ameliorates AAM polarization and asthmatic inflammation and might be a potential agent for treating asthma. PMID- 29991450 TI - Surface-dependent endocytosis of poly(isobutylcyanoacrylate) nanoparticles by Trichomonas vaginalis. AB - Previous data from our research group showed that chitosan-coated poly(isobutylcyanoacrylate) nanoparticles (NPs) (denoted PIBCA/Chito20) exhibited intrinsic anti-Trichomonas vaginalis activity, while PIBCA/pluronic(r) F68 without chitosan (PIBCA/F68) were inactive. However, the mechanism of anti-T. vaginalis activity of chitosan-coated PIBCA NPs is still unknown. Our hypothesis is that chitosan-coated NPs are internalized by the parasite, contrarily to PIBCA/F68. In this investigation, the impact of NP surface on their internalization by the protozoan was studied using flow cytometry and parasite morphological changes after different incubation times with PIBCA/Chito20 NPs were monitored by electron microscopy. Flow-cytometry revealed that PIBCA/Chito20 NPs were uptaken by T. vaginalis as early as 10-min-incubation. Drastic cell morphological transformations were observed from scanning electron microscopy and transmission electron microscopy after incubation with PIBCA/Chito20 NPs. Numerous pits were seen on cell membrane since 10 min. Gradual increase in contact time increased NP endocytosis and induced proportional damages to T. vaginalis membrane. Then, investigation of whether PIBCA/Chito20 NPs can improve MTZ anti-T. vaginalis activity was studied using checkerboard experiment. Calculation of fractional inhibitory concentration index (FICI = 3.53) showed an additive effect between NPs and MTZ. PMID- 29991451 TI - Deciphering magnesium stearate thermotropic behavior. AB - Magnesium stearate (MgSt) is the most commonly used excipient for oral solid dosage forms, yet there is significant commercial physicochemical variability that can lead to variable performance of critical product attributes. Differential scanning calorimetry (DSC) is often used as a quality control tool to characterize MgSt, but little data is available regarding the physicochemical relevance for the DSC thermograms. The main aim of this study was to decipher MgSt's complex thermotropic behavior using DSC, thermogravimetric analysis, capillary melting point, polarized hot-stage microscopy, and temperature dependent small-angle X-ray scattering (SAXS) and assign physicochemical relevance to the DSC thermograms. Several DSC thermal transitions are irreversible after the first heating cycle of a heat-cool-heat-cool-heat cycle. Interestingly, after the first heat cycle, the complex cool-heat-cool-heat DSC thermograms were highly reproducible and exhibited 6 reversible exothermic endothermic conjugate pairs. SAXS identified 5 distinct mesophases at different temperatures with Phase C' persisting to 250 degrees C. MgSt maintained molecular ordering beyond 276 degrees C and did not undergo a simple melting phenomena reported elsewhere. This research serves as a starting point to design heat-treatment strategies to create more uniform MgSt starting material. PMID- 29991452 TI - Challenges for pulmonary delivery of high powder doses. AB - In recent years there is an increasing interest in the pulmonary delivery of large cohesive powder doses, i.e. drugs with a low potency such as antibiotics or drugs with a high potency that need a substantial fraction of excipient(s) such as vaccines stabilized in sugar glasses. The pulmonary delivery of high powder doses comes with unique challenges. For low potency drugs, the use of excipients should be minimized to limit the powder mass to be inhaled as much as possible. To achieve this objective the inhaler design should be adapted to the properties of the API in order to achieve a compatible combination of the drug formulation and inhaler device. The inhaler should have an appropriate powder dosing principle for which prefilled compartments seem most appropriate. The drug formulation should not only allow for accurate filling of these compartments but also enable efficient compartment emptying during inhalation. The dispersion principle must have the capacity to disperse considerable amounts of powder in a short time frame that allows the powder to reach the deep lung. Last, but not least, the inhaler should be simple and intuitive in use, be cost-effective and exhibit accurate and consistent, preferably patient independent, pulmonary delivery performance. PMID- 29991453 TI - Development of customised 3D printed biodegradable projectile for administrating extended-release contraceptive to wildlife. AB - Customisation of sustained and controlled release of contraceptives plays a key role in veterinary applications. A biodegradable projectile containing different doses of contraceptive progesterone was prepared using fused deposition modelling 3D printing. Three concentrations of progesterone (2, 5 and 10% w/w) with polylactic acid was prepared as a 1.75 mm filament by hot melt extrusion. Solvent dissolution tests confirmed the successful incorporation of progesterone in the polymer while microscopic (SEM) studies indicated the drug was melted and thoroughly mixed with the polymer matrix and pore-formation after dissolution. A significant suppression of melting temperature of polymer from 166 to 145 degrees C was noted by thermal analysis (DSC) studies of the drug loaded systems. Interaction between the contraceptive drug and the polymer via hydrogen bonding was revealed from the spectroscopic (FTIR) studies. In vitro release behaviour was assessed over a five-month period, for 2% and 5% progesterone loaded projectiles release profiles fitted zero order whereas 10% loaded projectiles fitted the Higuchi model. Penetration assessment confirmed the drug loaded PLA projectiles provided sufficient specific kinetic energy required to penetrate thin and medium-thickness skins. This work demonstrates the feasibility of fused deposition modelling 3D printing as suitable process for manufacturing ballistic customised drug delivery devices. PMID- 29991454 TI - Preparation of novel phospholipid-based sonocomplexes for improved intestinal permeability of rosuvastatin: In vitro characterization, dynamic simulation, Caco 2 cell line permeation and in vivo assessment studies. AB - The study aimed to fabricate innovative drug-phospholipid complexes termed "sonocomplexes" adopting ultrasound irradiation to increase the liposolubility and to enhance the intestinal absorption of rosuvastatin as a model drug for BCS class III active pharmaceutical ingredients (APIs). A 22 full factorial design was fashioned to investigate the influence of phosphatidylcholine content in the phospholipid (~30 and 60%) and molar ratio of phospholipid to rosuvastatin (1:1 and 2:1) on physicochemical properties of sonocomplexes. In comparison to pure drug, sonocomplexes showed a minimum of about 2 folds and a maximum of about 15 folds increase in lipophilicity (expressed in terms of partition coefficient, P). Results of molecular docking, dynamic simulations, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) confirmed the strong interactions between rosuvastatin and the phospholipid via hydrogen bonding interaction, van der Waals forces and hydrophobic interaction. The complexation efficiency reached around 99% and transmission electron microscopy (TEM) of the aqueous dispersion of the optimal sonocomplex showed spherical nanosized vesicles. The optimal sonocomplex showed significantly superior Caco-2 cells permeability and markedly better oral bioavailability compared to the pure drug. In summary, sonocomplexes can be considered as effective approach for enhancing the liposolubility and consequently the intestinal permeability of BCS class III drugs. PMID- 29991455 TI - The effects of random taxa sampling schemes in Bayesian virus phylogeography. AB - Public health researchers are often tasked with accurately and quickly identifying the location and time when an epidemic originated from a representative sample of nucleotide sequences. In this paper, we investigate multiple approaches to subsampling the sequence set when employing a Bayesian phylogeographic generalized linear model. Our results indicate that near categorical posterior MCC estimates on the root can be obtained with replicate runs using 25-50% of the sequence data, and that including 90% of sequences does not necessarily entail more accurate inferences. We present the first analysis of predictor signal suppression and show how the ability to detect the influence of predictor variables is limited when sample size predictors are included in the models. PMID- 29991456 TI - First phenotypic and genotypic description of Fasciola hepatica infecting highland cattle in the state of Mexico, Mexico. AB - Fascioliasis is a plantborne and zoonotic parasitic disease caused by fasciolid liver flukes. Fasciola hepatica is the only fasciolid species described in the Americas. Human fascioliasis endemic areas are mainly located in high altitude areas of the Americas. Given the necessity to characterize F. hepatica populations involved, the phenotypic and genotypic features of fasciolid adults infecting cattle in the highland area of Toluca, State of Mexico, Mexico, were analyzed and compared to fasciolid materials from the Northern Bolivian Altiplano, representing the altiplanic transmission pattern in a hyperendemic scenario. A computer image analysis system (CIAS) was applied on the basis of standardized measurements. The aforementioned F. hepatica highland populations were compared to standard lowland natural populations of European origin (Spain and France) and F. gigantica of African origin (Burkina Faso). Liver-fluke size was studied by principal component analysis (PCA). Two phenotypic patterns could be distinguished in the F. hepatica material analyzed from the Americas: the valley pattern (Toluca, Mexico) and the altiplanic pattern (Northern Altiplano, Bolivia). PCA showed that the Altiplano population presented a large body size range with a pronouncedly lower minimum size. Mahalanobis distances demonstrated that American populations are very close to European populations. Genetic haplotyping was performed using the ribosomal DNA intergenic region, including ITS-1, 5.8S and ITS-2. The intergenic region was 951 bp-long, providing 2 combined haplotypes due to one mutation appearing in the ITS-2 sequence. Molecular results showed that Fh-1A and Fh-2A, the most frequent haplotypes of F. hepatica from southern Europe, are present in Mexican cattle. Nuclear rDNA biomarkers correlated with adult fluke phenotypic characteristics. Results showed that the Mexican population analyzed and European standard populations presented a phenotypic and genotypic homogeneity, suggesting an introduction with livestock transported during the early colonization period. Results are moreover analyzed in terms of altitude and permanent/seasonal transmission characteristics. PMID- 29991457 TI - Children with myelomeningocele do not exhibit normal remodeling of tibia roundness with physical development. AB - Skeletal loading through daily movement is an important factor in the normal development of bones. This loading is affected by the neurological and muscle deficits that result from myelominingocele (MM). While children with MM have been shown to have atypical gait, decreased bone accrual, and increased fracture risk, it is still unclear what morphological bone differences exist and to what extent they relate to physical developmental and ambulation level. This study analyzed computed tomography images of the tibia from 77 children with MM and 124 typically developing (TD) children between the ages of 6 and 16 years. Differences in cross-sectional roundness along the length of the tibia diaphysis were observed across developmental stages (pre-pubertal, pubertal, post-pubertal) and ambulation level (MM non-ambulatory, MM assistive devices, MM independent, and TD). The results showed that tibia cross-sectional morphology becomes less round with development in TD children (p < 0.017). In children with MM, however, roundness is maintained throughout adolescence (p > 0.017), with greater roundness in less ambulatory children (p < 0.0083). These in vivo results align with mechanobiological modeling studies suggesting that intracortical loads (caused by joint loading) as well as periosteal loads (imposed by surrounding muscles) are critical in promoting non-circular cross-sectional bone shape remodeling. PMID- 29991458 TI - Genetic predisposition score predicts the increases of knee strength and muscle mass after one-year exercise in healthy elderly. AB - This study aims to identify a genetic predisposition score from a set of candidate gene variants that predicts the response to a one-year exercise intervention. 200 participants (aged 60-83 years) were randomly assigned to a fitness (FIT), whole-body vibration (WBV) and control group. Participants in the exercise (FIT and WBV) groups performed a one-year intervention program. Whole body skeletal muscle mass (SMM) and isometric knee extension strength (PTIM60) were measured before and after the intervention. A set of 170 muscle-related single nucleotide polymorphisms (SNPs) were genotyped. Stepwise regression analysis was applied to select significantly contributing SNPs for baseline and relative change parameters. A data-driven genetic predisposition score (GPS) was calculated by adding up predisposing alleles for each of the phenotypes. GPS was calculated based on 4 to 8 SNPs which were significantly related to the corresponding phenotypes. These SNPs belong to genes that are involved in myoblast differentiation, muscle and bone growth, myofiber contraction, cytokines and DNA methylation. GPS was related to baseline PTIM60 and relative changes of SMM and PTIM60 in the exercise groups, explaining the variance of the corresponding parameter by 3.2%, 14% and 27%, respectively. Adding one increasing allele in the GPS increased baseline PTIM60 by 4.73 Nm, and exercise-induced relative changes of SMM and PTIM60 by 1.78% and 3.86% respectively. The identified genetic predisposition scores were positively related to baseline knee extension strength and muscle adaptations to exercise in healthy elderly. These findings provide supportive genetic explanations for high and low responders in exercise-induced muscle adaptations. PMID- 29991459 TI - Altered monocyte phenotypes but not impaired peripheral T cell immunity may explain susceptibility of the elderly to develop tuberculosis. AB - Tuberculosis (TB) is the leading killer due to a single infectious disease worldwide. With the aging of the global population, the case rate and deaths due to TB are highest in the elderly population. While general immunosenescence associated with old age is thought to contribute to the susceptibility of the elderly to develop active TB disease, very few studies of immune function in elderly individuals with Mycobacterium tuberculosis (M.tb) infection or disease have been performed. In particular, impaired adaptive T cell immunity to M.tb is one proposed mechanism for the elderly's increased susceptibility primarily on the basis of the decreased delayed type hypersensitivity response to tuberculin purified protein derivative in the skin of elderly individuals. To investigate immunological reasons why the elderly are susceptible to develop active TB disease, we performed a cross-sectional observational study over a five year period (2012-2016) enrolling participants from 2 age groups (adults: 25-44 years; elderly: 65 and older) and 3 M.tb infection statuses (active TB, latent TB infection, and healthy controls without history of M.tb infection). We hypothesized that impaired peripheral T cell immunity plays a role in the biological susceptibility of the elderly to TB. Contrary to our hypothesis, we observed no evidence of impaired M.tb specific T cell frequency or altered production of cytokines implicated in M.tb control (IFN-gamma, IL-10) in peripheral blood in the elderly. Instead, we observed alterations in monocyte proportion and phenotype with age and M.tb infection that suggest their potential role in the susceptibility of the elderly to develop active TB. Our results suggest a potential link between the known widespread low-grade systemic inflammation of old age, termed "inflammaging," with the elderly's specific susceptibility to developing active TB. Moreover, our results highlight the need for further research into the biological reasons why the elderly are more susceptible to disease and death from TB, so that public health systems can be better equipped to face the present and future problem of TB in an aging global population. PMID- 29991460 TI - Assessment of immunoturbidimetric DiAgam kit for plasma albumin measurement: a comparative study. PMID- 29991461 TI - Down-regulation of magnesium transporting molecule, claudin-16, as a possible cause of hypermagnesiuria with the development of tubulo-interstitial nephropathy. AB - Tubulo-interstitial nephropathy (TIN) is a critical pathological setting for the renal prognosis, and an increase in the urine magnesium excretion is a well-known characteristic feature as one of clinical parametets for the assessment of TIN. We examined the correlation between the development of TIN and the changes in the mRNA expression of renal magnesium-transporting molecules in rats with unilateral ureter obstruction (UUO). Ureter-ligated kidney was sampled at day-0 (control), day-1 (early phase) and day-7 (late phase). The development of TIN was assessed by immunohistochemistry and the real-time PCR of fibrosis-related genes (MCP-1: 105.1 +/- 14.8% on day-0, 132.9 +/- 25.7% on day-1, 302.7 +/- 32.7% on day-7, TGF beta: 101.1 +/- 7.6% on day-0, 93.6 +/- 4.1% on day-1, 338.9 +/- 20.7% on day-7) . The respective expressions of claudin-10, 14, 16, 19, and transient receptor potential (TRP) M6 as magnesium-transporting molecules were also studied. The expression of calcium sensing receptor (CaSR) as an inhibitory regulator of claudin-14 was additionally studied. The gene expression of claudin-16 was decreased in the late phase of UUO (100.2 +/- 2.9% at day-0, 90.3 +/- 6.3% at day 1, 36.4 +/- 1.6% at day-7) which was consistent with the increased urine magnesium excretion. Immunohistochemistry showed an apparent reduction of the immunoreactivity of claudin-16 in the late phase. The expression of TRPM6 was reduced even in the early phase. The immunohistochemistry and gene expression of MCP-1 and TGF-beta showed that TIN was not apparent in the early phase but was significant in the late phase of UUO. The density of peritubular capillaries was diminished in the late phase but not in the early phase. Expression of claudin-14 and CaSR was up- and down-regulated, respectively. Our findings may indicate that the characteristic hypermagnesiuria in TIN is principally caused by the dysfunction of magnesium reabsorption in the thick ascending limb of Henle resulting from a significant decrease in the claudin-16 expression. The down regulation might be closely related to the development of TIN. PMID- 29991462 TI - Factitious hypoglycemia : "a never-ending story"? AB - Our team of diabetologist is challenged by the case of a 41 year-old woman with recurrent hypoglycaemic episodes. Her clinical background was complex with, among others, a neuroendocrine tumor, a nonalcoholic steatohepatitis and an adrenal insufficiency; these conditions require the exploration of several potential causes. After excluding an endogenous etiology, a factitious hypoglycemia was quicky suspected by clinicians. However, several venous samples showed normal insulinemia and a moderately decreased C-peptide. After multidisciplinary team discussion and facing a strong clinical suspicion, samples were sent to another laboratory to confirm the insulin results. Substantially supratherapeutics insulin concentrations were highlighted. This confirms the previous suspicion of surreptitious insulin administration with a recombinant form unrecognized by our routinely used analyzer. This observation leads us to briefly discuss the lack of cross-reactivities observed with many different insulin assays. PMID- 29991463 TI - A single dose of magnesium, as well as chronic administration, enhances long-term memory in novel object recognition test, in healthy and ACTH-treated rats. AB - Although a magnesium-mediated attenuation of memory deficits was reported in animal models of ageing and traumatic brain injury, a possible memory enhancement in healthy subjects has not been investigated yet. We used novel object recognition test (NORT) to examine the effects of acute (30 mg/kg) and chronic (50 mg/kg, 28 days) Mg-sulfate treatment on the long-term memory (LTM) in healthy adult male rats, and to test the sustainability of magnesium effects in the models of acute and chronic (21 days) ACTH administration (10 MUg/animal), mimicking the stress- and depression-like conditions. A single dose of Mg-sulfate enhanced the LTM retrieval in the 24 h inter-trial NORT protocol, in healthy, as well as in rats acutely treated with ACTH. Memory enhancement was also detected after 4-week long Mg-sulfate intake, in both healthy and rats chronically treated with ACTH. While the present findings on procognitive effects of chronic Mg sulfate treatment corroborate with those from studies on the therapeutic potential of Mg-threonate, the current study is the first to report on memory enhancement induced by a single dose of magnesium. PMID- 29991465 TI - Severe Neonatal Cholestasis as an Early Presentation of McCune Albright Syndrome. AB - McCune-Albright syndrome (MAS) is a rare genetic disorder characterized by cafe au-lait macules, polyostotic fibrous dysplasia and multiple endocrinopathies. Liver involvement, although described, is a rare complication. We review the case of a child with MAS whose initial presentation was characterized by severe neonatal cholestasis. The case demonstrates a severe phenotype of persistent cholestasis in MAS requiring liver transplantation, which has been previously considered to be a more benign feature. This case highlights the importance of consideration of MAS as an uncommon but important etiology of neonatal cholestasis. Early diagnosis may allow for prompt recognition and treatment of other endocrinopathies. PMID- 29991464 TI - A Novel Mutation in the AVPR2 Gene Causing Congenital Nephrogenic Diabetes Insipidus AB - Objective: Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by a renal insensitivity to arginine vasopressin (AVP). In the majority of the cases, CNDI is caused by mutations in the arginine vasopressin receptor 2 (AVPR2) gene. Our objective is to report a novel mutation in the AVPR2 gene causing CNDI in a 6-year-old boy, presenting with growth failure and dull normal cognitive functions. Methods: The proband was the third off-spring of non-consanguineous parents and had polyuria (4.3 L/day), polydipsia (5 L/day). The diagnosis of CNDI was established by a water-deprivation test and a desmopressin challenge test. Genetic studies were also carried out in the mother, siblings and affected family members, since excessive fluid intake and diuresis were also reported in these individuals. All exons of the AVPR2 gene for all participants were amplified and sequenced. Bioinformatics analysis for wild type and mutant AVPR2 were obtained with Swiss-Model and UCSF Chimera 1.10.2. Results: A novel, hemizygous, missense mutation was identified at the position 80th in exon 2 (p.H80Y) of AVPR2 in the proband. The proband's mother, maternal aunt and grandmother were heterozygous and his maternal uncle was hemizygous for this mutation. Bioinformatic analysis indicates this mutation would cause significant conformational changes in protein structure. Conclusion: p.H80Y mutation will cause inappropriate folding of the protein compromising water homeostasis via AVPR2 and AVP and leading to diabetes insipidus. We suggest that future functional investigations of the H80Y mutation may provide a basis for understanding the pathophysiology of the NDI in patients with this variant. PMID- 29991466 TI - Pathogenesis of Thalassemia Major-Associated Osteoporosis: Review of the Literature and Our Experience. AB - Due to increasing life expectancy in thalassemia major (TM), osteoporosis is emerging as a significant problem. Its aetiology is multifactorial, culminating in increased bone resorption and remodelling. Hypogonadism and marrow expansion seem to play an important role, but iron overload, deferoxamine toxicity, a defective GH-IGF-1 axis and multiple endocrinopathies may represent additional causes of bone damage. Many of these patients, though under appropriate treatment programs, do not achieve normal peak bone mass. The RANK/RANKL/OPG and the Wnt/betaCatenin systems work as major mediators of imbalanced bone turnover and bone loss. Additional genetic factors, such as collagen type I alpha 1 and vitamin D receptor gene polymorphisms, may exert some influence on the enhanced fracture risk observed in TM. To date, in spite of adequate hormone replacement, chelating therapy, and acceptable haemoglobin levels, subjects with TM display impaired bone density and imbalanced bone turnover, so the puzzle of the pathogenesis of thalassemia major-induced osteoporosis remains far from being solved. PMID- 29991467 TI - What is your diagnosis? PMID- 29991468 TI - A Decade of Veteran Voices: Examining Patient Portal Enhancements Through the Lens of User-Centered Design. AB - BACKGROUND: Health care systems have entered a new era focused on patient engagement. Patient portals linked to electronic health records are recognized as a promising multifaceted tool to help achieve patient engagement goals. Achieving significant growth in adoption and use requires agile evaluation methods to complement periodic formal research efforts. OBJECTIVE: This paper describes one of the implementation strategies that the Department of Veterans Affairs (VA) has used to foster the adoption and sustained use of its patient portal, My HealtheVet, over the last decade: an ongoing focus on user-centered design (UCD). This strategy entails understanding the users and their tasks and goals and optimizing portal design and functionality accordingly. Using a case study approach, we present a comparison of early user demographics and preferences with more recent data and several examples to illustrate how a UCD can serve as an effective implementation strategy for a patient portal within a large integrated health care system. METHODS: VA has employed a customer experience analytics (CXA) survey on its patient portal since 2007 to enable ongoing direct user feedback. In a continuous cycle, a random sample of site visitors is invited to participate in the Web-based survey. CXA model questions are used to track and trend satisfaction, while custom questions collect data about users' characteristics, needs, and preferences. In this case study, we performed analyses of descriptive statistics comparing user characteristics and preferences from FY2008 (wherein "FY" means "fiscal year") to FY2017 and user trends regarding satisfaction with and utilization of specific portal functions over the last decade, as well as qualitative content analysis of user's open-ended survey comments. RESULTS: User feedback has guided the development of enhancements to core components of the My HealtheVet portal including available features, content, interface design, prospective functional design, and related policies. Ten-year data regarding user characteristics and portal utilization demonstrate trends toward greater patient engagement and satisfaction. Administration of a continuous voluntary Web-based survey is an efficient and effective way to capture veterans' voices about who they are, how they use the patient portal, needed system improvements, and desired additional services. CONCLUSIONS: Leveraging "voice-of-the-customer" techniques as part of patient portal implementation can ensure that such systems meet users' needs in ways that are agile and most effective. Through this strategy, VA has fostered significant adoption and use of My HealtheVet to engage patients in managing their health. PMID- 29991469 TI - A Text Message-Based Intervention Targeting Alcohol Consumption Among University Students: User Satisfaction and Acceptability Study. AB - BACKGROUND: Heavy consumption of alcohol among university students is a global problem, with excessive drinking being the social norm. Students can be a difficult target group to reach, and only a minority seek alcohol-related support. It is important to develop interventions that can reach university students in a way that does not further stretch the resources of the health services. Text messaging (short message service, SMS)-based interventions can enable continuous, real-time, cost-effective, brief support in a real-world setting, but there is a limited amount of evidence for effective interventions on alcohol consumption among young people based on text messaging. To address this, a text messaging-based alcohol consumption intervention, the Amadeus 3 intervention, was developed. OBJECTIVE: This study explored self-reported changes in drinking habits in an intervention group and a control group. Additionally, user satisfaction among the intervention group and the experience of being allocated to a control group were explored. METHODS: Students allocated to the intervention group (n=460) were asked about their drinking habits and offered the opportunity to give their opinion on the structure and content of the intervention. Students in the control group (n=436) were asked about their drinking habits and their experience in being allocated to the control group. Participants received an email containing an electronic link to a short questionnaire. Descriptive analyses of the distribution of the responses to the 12 questions for the intervention group and 5 questions for the control group were performed. RESULTS: The response rate for the user feedback questionnaire of the intervention group was 38% (176/460) and of the control group was 30% (129/436). The variation in the content of the text messages from facts to motivational and practical advice was appreciated by 77% (135/176) participants, and 55% (97/176) found the number of messages per week to be adequate. Overall, 81% (142/176) participants stated that they had read all or nearly all the messages, and 52% (91/176) participants stated that they were drinking less, and increased awareness regarding negative consequences was expressed as the main reason for reduced alcohol consumption. Among the participants in the control group, 40% (52/129) stated that it did not matter that they had to wait for access to the intervention. Regarding actions taken while waiting for access, 48% (62/129) participants claimed that they continued to drink as before, whereas 35% (45/129) tried to reduce their consumption without any support. CONCLUSIONS: Although the main randomized controlled trial was not able to detect a statistically significant effect of the intervention, most participants in this qualitative follow-up study stated that participation in the study helped them reflect upon their consumption, leading to altered drinking habits and reduced alcohol consumption. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number ISRCTN95054707; http://www.isrctn.com/ISRCTN95054707 (Archived by WebCite at http://www.webcitation.org/705putNZT). PMID- 29991471 TI - Clinically effective implementation of intravenous paracetamol as primary analgesia after major surgery in neonates and young infants. PMID- 29991472 TI - Recognising the role of South Asian doctors in UK general practice. PMID- 29991470 TI - Reducing HIV Vulnerability Through a Multilevel Life Skills Intervention for Adolescent Men (The iREACH Project): Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Few HIV interventions have demonstrated efficacy in reducing HIV risk among adolescent men who have sex with men (AMSM), and fewer still have recognized the unique needs of AMSM based on race/ethnicity or geographical setting. Recognizing that youths' HIV vulnerability is intricately tied to their development and social context, delivering life skills training during adolescence might delay the onset or reduce the consequences of risk factors for HIV acquisition and equip AMSM with the skills to navigate HIV prevention. This protocol describes the development and testing of iREACH, an online multilevel life skills intervention for AMSM. OBJECTIVE: This randomized controlled trial (RCT) aims to test the efficacy of an online-delivered life skills intervention, iREACH, on cognitive and behavioral HIV-related outcomes for AMSM. METHODS: iREACH is a prospective RCT of approximately 600 cisgender adolescent males aged 13 to 18 years who report same-sex attractions. The intervention will be tested with a racial/ethnically diverse sample (>=50% racial/ethnic minority) of AMSM living in four regions in the United States: (1) Chicago to Detroit, (2) Washington, DC to Atlanta, (3) San Francisco to San Diego, and (4) Memphis to New Orleans. RESULTS: This project is currently recruiting participants. Recruitment began in March 2018. CONCLUSIONS: iREACH represents a significant innovation in the development and testing of a tailored life skills-focused intervention for AMSM, and has the potential to fill a significant gap in HIV prevention intervention programming and research for AMSM. REGISTERED REPORT IDENTIFIER: RR1 10.2196/10174. PMID- 29991474 TI - Response to: 'Inconsistency between supplement and article?' by Babaoglu H. PMID- 29991473 TI - Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. AB - OBJECTIVES: To investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA). METHODS: Synovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA. RESULTS: M1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of beta catenin signalling in chondrocytes. CONCLUSIONS: Synovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment. PMID- 29991475 TI - Scale of research misconduct is unknown because of poor reporting by universities, say MPs. PMID- 29991477 TI - Fecal Microbiota and Screening for Colorectal Cancer. PMID- 29991476 TI - Getting leaves into shape: a molecular, cellular, environmental and evolutionary view. AB - Leaves arise from groups of undifferentiated cells as small primordia that go through overlapping phases of morphogenesis, growth and differentiation. These phases are genetically controlled and modulated by environmental cues to generate a stereotyped, yet plastic, mature organ. Over the past couple of decades, studies have revealed that hormonal signals, transcription factors and miRNAs play major roles during leaf development, and more recent findings have highlighted the contribution of mechanical signals to leaf growth. In this Review, we discuss how modulating the activity of some of these regulators can generate diverse leaf shapes during development, in response to a varying environment, or between species during evolution. PMID- 29991478 TI - Genomic Privacy. AB - BACKGROUND: Genetic information is unique among all laboratory data because it not only informs the current health of the specific person tested but may also be predictive of the future health of the individual and, to varying degrees, all biological relatives. CONTENT: As DNA sequencing has become ubiquitous with decreasing cost, large repositories of genomic data have emerged from the domains of research, healthcare, law enforcement, international security, and recreational consumer interest (i.e., genealogy). Broadly shared genomic data are believed to be a key element for future discoveries in human disease. For example, the National Cancer Institute's Genomic Data Commons is designed to promote cancer research discoveries by providing free access to the genome data sets of 12000 cancer patients. However, in parallel with the promise of curing diseases, genomic data also have the potential for harm. Genomic data that are deidentified by standard healthcare practices (e.g., removal of name, date of birth) can be reidentified by methods that combine genomic software with publicly available demographic databases (e.g., phone book). Recent law enforcement cases (i.e., Bear Brook Murders, Golden State Killer) in the US have demonstrated the power of combining DNA profiles with genealogy databases. SUMMARY: We examine the current environment of genomic privacy and confidentiality in the US and describe current and future risks to genomic privacy. Reidentification and inference of genetic information of biological relatives will become more important as larger databases of clinical, criminal, and recreational genomic information are developed over the next decade. PMID- 29991480 TI - A physiologist observing and reporting supraphysiologic dobutamine stress testing. AB - In a study, published in this issue of Echo Research and Practice, Ntoskas et al. retrospectively analyzed the safety of a cardiac physiologist performing, and interpreting, DSEs in of 300 patients undergoing DSE for the detection of inducible reversible ischemia, myocardial viability, and valvular heart disease. While safety during the tests themselves did not appear to be compromised with this unsupervised approach, the interpretation of these DSEs causes concerns regarding broad patient safety relative to misread results. PMID- 29991479 TI - Fetal articular cartilage regeneration versus adult fibrocartilaginous repair: secretome proteomics unravels molecular mechanisms in an ovine model. AB - Osteoarthritis (OA), a degenerative joint disease characterized by progressive cartilage degeneration, is one of the leading causes of disability worldwide owing to the limited regenerative capacity of adult articular cartilage. Currently, there are no disease-modifying pharmacological or surgical therapies for OA. Fetal mammals, in contrast to adults, are capable of regenerating injured cartilage in the first two trimesters of gestation. A deeper understanding of the properties intrinsic to the response of fetal tissue to injury would allow us to modulate the way in which adult tissue responds to injury. In this study, we employed secretome proteomics to compare fetal and adult protein regulation in response to cartilage injury using an ovine cartilage defect model. The most relevant events comprised proteins associated with the immune response and inflammation, proteins specific for cartilage tissue and cartilage development, and proteins involved in cell growth and proliferation. Alarmins S100A8, S100A9 and S100A12 and coiled-coil domain containing 88A (CCDC88A), which are associated with inflammatory processes, were found to be significantly upregulated following injury in adult, but not in fetal animals. By contrast, cartilage-specific proteins like proteoglycan 4 were upregulated in response to injury only in fetal sheep postinjury. Our results demonstrate the power and relevance of the ovine fetal cartilage regeneration model presented here for the first time. The identification of previously unrecognized modulatory proteins that plausibly affect the healing process holds great promise for potential therapeutic interventions. PMID- 29991481 TI - Honokiol Ameliorates Amyloidosis and Neuroinflammation and Improves Cognitive Impairment in Alzheimer's Disease Transgenic Mice. AB - The present study examined the effects of honokiol on amyloid-beta (Abeta) induced cognitive impairment and the underlying mechanisms in APPswe/PS1dE9 transgenic mice. The results showed that honokiol administration (20 mg/kg per day, intraperitoneally) for 6 weeks effectively improved spatial memory deficits in APPswe/PS1dE9 transgenic mice. Honokiol significantly lowered Abeta production and senile plaque deposition by downregulating beta-site amyloid precursor protein cleavage enzyme 1 and enhancing Abeta phagocytosis by microglia. Honokiol reduced glial cell activation and the production of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6). Honokiol increased the transcriptional activity and protein levels of peroxisome proliferator-activated receptor-gamma (PPARgamma) However, all of the beneficial effects of honokiol on pathologic changes, including biochemistry and cognitive function, could be blocked by GW9662, a specific PPARgamma inhibitor. These findings suggested that honokiol may be a natural PPARgamma agonist, acting to attenuate Abeta generation and neuroinflammation. Therefore, honokiol may be a potential therapeutic approach for Alzheimer's disease. PMID- 29991482 TI - Lessons from Frankenstein: narrative myth as ethical model. AB - As Frankenstein's 200th anniversary nears, its use as a shorthand for ethical critique only increases. This article argues, though, that its lessons inhere in its unique structure, which enacts an interpretive process that models the multiplicity and uncertainty constitutive of ethical decision-making. Frankenstein deliberately functions as a modern myth, rewriting classical and Christian mythology to challenge the straightforward moral lessons often ascribed to the text. Complex portrayals of the creature and of Victor Frankenstein in the context of contemporary science make it impossible to read Victor as villain, victim or hero, or to take a consequentialist or nature-based stance in which the outcome of his research dictates its wrongness. The use of Paradise Lost insists on the creature's fundamental humanity. Indeed, the creature's voice frames the entire novel and serves as its structural centrepiece. His experience counters Victor's and vividly expresses the harm in a narrow focus on discovery and in the denial of responsibility for scientific work as it moves beyond the laboratory. Both the creature's and Captain Walton's stories stress the need to hear other voices and honour their distinct lived experiences. While Frankenstein-as-myth (re)produces science as the fundamental explanatory paradigm, it presents a vision of science as passionately personal and societally situated. Repeated disruptions of narrative cohesion question accuracy and causality, producing instead an acute awareness of perspective. Frankenstein argues for a reflective and dialogical narrative ethics: choices must be made and evaluated not according to a priori abstract rules, but within the attached stories. PMID- 29991483 TI - Genetic engineering, synthetic biology and the light reactions of photosynthesis. PMID- 29991484 TI - Consensus Coexpression Network Analysis Identifies Key Regulators of Flower and Fruit Development in Wild Strawberry. AB - The diploid strawberry, Fragaria vesca, is a developing model system for the economically important Rosaceae family. Strawberry fleshy fruit develops from the floral receptacle and its ripening is nonclimacteric. The external seed configuration of strawberry fruit facilitates the study of seed-to-fruit cross tissue communication, particularly phytohormone biosynthesis and transport. To investigate strawberry fruit development, we previously generated spatial and temporal transcriptome data profiling F. vesca flower and fruit development pre- and postfertilization. In this study, we combined 46 of our existing RNA-seq libraries to generate coexpression networks using the Weighted Gene Co-Expression Network Analysis package in R. We then applied a post-hoc consensus clustering approach and used bootstrapping to demonstrate consensus clustering's ability to produce robust and reproducible clusters. Further, we experimentally tested hypotheses based on the networks, including increased iron transport from the receptacle to the seed postfertilization and characterized a F. vesca floral mutant and its candidate gene. To increase their utility, the networks are presented in a web interface (www.fv.rosaceaefruits.org) for easy exploration and identification of coexpressed genes. Together, the work reported here illustrates ways to generate robust networks optimized for the mining of large transcriptome data sets, thereby providing a useful resource for hypothesis generation and experimental design in strawberry and related Rosaceae fruit crops. PMID- 29991486 TI - Genetic Lineage Tracing of Sca-1+ Cells Reveals Endothelial but Not Myogenic Contribution to the Murine Heart. AB - Background -The adult mammalian heart displays a cardiomyocyte turnover rate of ~1% per year throughout postnatal life and after injuries such as myocardial infarction (MI), but the question of which cell types drive this low level of new cardiomyocyte formation remains contentious. Cardiac-resident stem cells marked by stem cell antigen-1 (Sca-1, gene name Ly6a) have been proposed as an important source of cardiomyocyte renewal. However, the in vivo contribution of endogenous Sca-1+ cells to the heart at baseline or after MI has not been investigated. Methods -Here we generated Ly6a gene-targeted mice containing either a constitutive or inducible Cre recombinase to perform genetic lineage tracing of Sca-1+ cells in vivoResults -We observed that the contribution of endogenous Sca 1+ cells to the cardiomyocyte population in the heart was <0.005% throughout all of cardiac development, aging or after MI. In contrast, Sca-1+ cells abundantly contributed to the cardiac vasculature in mice during physiological growth and in the post-MI heart during cardiac remodeling. Specifically, Sca-1 lineage-traced endothelial cells expanded postnatally in the mouse heart after birth and into adulthood. Moreover, pulse-labeling of Sca-1+ cells using an inducible Ly6a MerCreMer allele also revealed a preferential expansion of Sca-1 lineage-traced endothelial cells following MI injury in the mouse. Conclusions -Cardiac-resident Sca-1+ cells are not significant contributors to cardiomyocyte renewal in vivo However, cardiac Sca-1+ cells represent a subset of vascular endothelial cells that expand postnatally with enhanced responsiveness to pathological stress in vivo. PMID- 29991485 TI - Arabidopsis Leaf Flatness Is Regulated by PPD2 and NINJA through Repression of CYCLIN D3 Genes. AB - In Arabidopsis (Arabidopsis thaliana), reduced expression of the transcriptional regulator PEAPOD2 (PPD2) results in propeller-like rosettes with enlarged and dome-shaped leaves. However, the molecular and cellular processes underlying this peculiar phenotype remain elusive. Here, we studied the interaction between PPD2 and NOVEL INTERACTOR OF JAZ (NINJA) and demonstrated that ninja loss-of-function plants produce rosettes with dome-shaped leaves similar to those of ppd mutants but without the increase in size. We showed that ninja mutants have a convex shaped primary cell cycle arrest front, putatively leading to excessive cell division in the central leaf blade region. Furthermore, ppd and ninja mutants have a similar increase in the expression of CYCLIN D3;2 (CYCD3;2), and ectopic overexpression of CYCD3;2 phenocopies the ppd and ninja rosette and leaf shape phenotypes without affecting the size. Our results reveal a pivotal contribution of NINJA in leaf development, in addition to its well-studied function in jasmonate signaling, and imply a new function for D3-type cyclins in, at least partially, uncoupling the size and shape phenotypes of ppd leaves. PMID- 29991487 TI - PKCtheta via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6Chi Cells Contributes to Atherosclerosis. AB - Background -Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known. Methods -Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor (GPCR) signaling in diet-induced atherosclerosis. Results -In exploring the role of GPCR signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression and these events require Par1-mediated Galpha12-Pyk2-Gab1-PKCtheta-dependent ATF2 activation. Genetic deletion of PKCtheta in ApoE-/- mice reduced western diet (WD)-induced plaque formation. Furthermore, thrombin induced Pyk2, Gab1, PKCtheta and ATF2 phosphorylation, CD36 expression and foam cell formation in peritoneal macrophages of ApoE-/- mice. On the other hand, thrombin only stimulated Pyk2 and Gab1 but not ATF2 phosphorylation or its target gene CD36 expression in the peritoneal macrophages of ApoE-/-:PKCtheta-/- mice and it had no effect on foam cell formation. In addition, the aortic root cross sections of WD-fed ApoE-/- mice showed increased Pyk2, Gab1, PKCtheta and ATF2 phosphorylation and CD36 expression as compared to ApoE-/-:PKCtheta-/- mice. Furthermore, while the monocytes from peripheral blood and aorta of WD-fed ApoE-/- mice were found to contain more of Ly6Chi cells than Ly6Clo cells, the monocytes from WD-fed ApoE-/ :PKCtheta-/- mice were found to contain more of Ly6Clo cells than Ly6Chi cells. Interestingly, the Ly6Chi cells showed higher CD36 expression with enhanced capacity to form foam cells as compared to Ly6Clo cells. Conclusions -The above findings reveal for the first time that thrombin-mediated Par1-Galpha12 signaling via targeting Pyk2-Gab1-PKCtheta-ATF2-dependent CD36 expression might be playing a crucial role in diet-induced atherogenesis. PMID- 29991488 TI - Left Ventricular Mass Change After Anthracycline Chemotherapy. AB - BACKGROUND: Myocardial atrophy and left ventricular (LV) mass reductions are associated with fatigue and exercise intolerance. The relationships between the receipt of anthracycline-based chemotherapy (Anth-bC) and changes in LV mass and heart failure (HF) symptomatology are unknown, as is their relationship to LV ejection fraction (LVEF), a widely used measurement performed in surveillance strategies designed to avert symptomatic HF associated with cancer treatment. METHODS AND RESULTS: We performed blinded, serial assessments of body weight, LVEF and mass, LV-arterial coupling, aortic stiffness, and Minnesota Living with Heart Failure Questionnaire measures before and 6 months after initiating Anth-bC (n=61) and non-Anth-bC (n=15), and in 24 cancer-free controls using paired t and chi2 tests and multivariable linear models. Participants averaged 51+/-12 years, and 70% were women. Cancer diagnoses included breast cancer (53%), hematologic malignancy (42%), and soft tissue sarcoma (5%). We observed a 5% decline in both LVEF (P<0.0001) and LV mass (P=0.03) in the setting of increased aortic stiffness and disrupted ventricular-arterial coupling in those receiving Anth-bC but not other groups (P=0.11-0.92). A worsening of the Minnesota Living with Heart Failure Questionnaire score in Anth-bC recipients was associated with myocardial mass declines (r=-0.27; P<0.01) but not with LVEF declines (r=0.11; P=0.45). Moreover, this finding was independent of LVEF changes and body weight. CONCLUSIONS: Early after Anth-bC, LV mass reductions associate with worsening HF symptomatology independent of LVEF. These data suggest an alternative mechanism whereby anthracyclines may contribute to HF symptomatology and raise the possibility that surveillance strategies during Anth-bC should also assess LV mass. PMID- 29991489 TI - Anthracycline Cardiomyopathy: The Plot Gets Thinner. PMID- 29991490 TI - Cladribine: mechanisms and mysteries in multiple sclerosis. AB - OBJECTIVES: The aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which cladribine acts as a disease-modifying therapy in MS. METHODS: This is a narrative review of the available clinical and preclinical data on the use of cladribine in MS. RESULTS: Clinical trial data argue strongly that cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that cladribine also exerts immunomodulatory influences over innate and adaptive immunity. CONCLUSIONS: Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine's action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications. PMID- 29991492 TI - Sixty seconds on . . . exercise. PMID- 29991491 TI - ABCC6 Deficiency Promotes Development of Randall Plaque. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disease caused by mutations in the ABCC6 gene that result in low pyrophosphate levels and subsequent progressive soft tissue calcifications. PXE mainly affects the skin, retina, and arteries. However, many patients with PXE experience kidney stones. We determined the prevalence of this pathology in patients with PXE and examined the possible underlying mechanisms in murine models. METHODS: We conducted a retrospective study in a large cohort of patients with PXE and analyzed urine samples and kidneys from Abcc6-/- mice at various ages. We used Yasue staining, scanning electron microscopy, electron microscopy coupled to electron energy loss spectroscopy, and Fourier transform infrared microspectroscopy to characterize kidney calcifications. RESULTS: Among 113 patients with PXE, 45 (40%) had a past medical history of kidney stones. Five of six computed tomography scans performed showed evidence of massive papillary calcifications (Randall plaques). Abcc6-/- mice spontaneously developed kidney interstitial apatite calcifications with aging. These calcifications appeared specifically at the tip of the papilla and formed Randall plaques similar to those observed in human kidneys. Compared with controls, Abcc6-/- mice had low urinary excretion of pyrophosphate. CONCLUSIONS: The frequency of kidney stones and probably, Randall plaque is extremely high in patients with PXE, and Abcc6-/- mice provide a new and useful model in which to study Randall plaque formation. Our findings also suggest that pyrophosphate administration should be evaluated for the prevention of Randall plaque and kidney stones. PMID- 29991494 TI - Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials. AB - Carfilzomib is a selective proteasome inhibitor approved for the treatment of relapsed and/or refractory multiple myeloma (RRMM). It has significantly improved outcomes, including overall survival (OS), and shown superiority vs standard treatment with lenalidomide plus dexamethasone and bortezomib plus dexamethasone. The incidence rate of cardiovascular (CV) events with carfilzomib treatment has varied across trials. This analysis evaluated phase 1-3 trials with >2000 RRMM patients exposed to carfilzomib to describe the incidence of CV adverse events (AEs). In addition, the individual CV safety data of >1000 patients enrolled in the carfilzomib arm of phase 3 studies were compared with the control arms to assess the benefit-risk profile of carfilzomib. Pooling data across carfilzomib trials, the CV AEs (grade >=3) noted included hypertension (5.9%), dyspnea (4.5%), and cardiac failure (4.4%). Although patients receiving carfilzomib had a numeric increase in the rates of any-grade and grade >=3 cardiac failure, dyspnea, and hypertension, the frequency of discontinuation or death due to these cardiac events was low and comparable between the carfilzomib and control arms. Serial echocardiography in a blinded cardiac substudy showed no objective evidence of cardiac dysfunction in the carfilzomib and control arms. Moreover, carfilzomib had no significant effect on cardiac repolarization. Our results, including the OS benefit, showed that the benefit of carfilzomib treatment in terms of reducing progression or death outweighed the risk for developing cardiac failure or hypertension in most patients. Appropriate carfilzomib administration and risk factor management are recommended for elderly patients and patients with underlying risk factors. PMID- 29991493 TI - Hidden features: exploring the non-canonical functions of metabolic enzymes. AB - The study of cellular metabolism has been rigorously revisited over the past decade, especially in the field of cancer research, revealing new insights that expand our understanding of malignancy. Among these insights is the discovery that various metabolic enzymes have surprising activities outside of their established metabolic roles, including in the regulation of gene expression, DNA damage repair, cell cycle progression and apoptosis. Many of these newly identified functions are activated in response to growth factor signaling, nutrient and oxygen availability, and external stress. As such, multifaceted enzymes directly link metabolism to gene transcription and diverse physiological and pathological processes to maintain cell homeostasis. In this Review, we summarize the current understanding of non-canonical functions of multifaceted metabolic enzymes in disease settings, especially cancer, and discuss specific circumstances in which they are employed. We also highlight the important role of subcellular localization in activating these novel functions. Understanding their non-canonical properties should enhance the development of new therapeutic strategies for cancer treatment. PMID- 29991495 TI - Ten-year outcome of patients with acute myeloid leukemia not treated with allogeneic transplantation in first complete remission. AB - The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged <60 years, and 944 aged >=60 years) enrolled in Cancer and Leukemia Group B treatment protocols and the cytogenetics companion protocol 8461 between 1983 and 2004. At 10 years, 267 (16.6%) of patients aged <60 years and 23 (2.4%) of those aged >=60 years were alive and disease-free. This disease-free AML group consisted predominantly of patients with core-binding factor AML with t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) and those with a normal karyotype. Occurrences of AML beyond 10 years were infrequent and associated with cytogenetic findings different from those at diagnosis. These data provide evidence that the frequency of long-term cure of AML is low among younger and especially older patients in the absence of Allo-HCT in CR1. In older patients not appropriate for Allo-HCT, these data provide further justification for early use of alternative treatments outside of intensive chemotherapy. PMID- 29991496 TI - Gastrointestinal microbiota contributes to the development of murine transfusion related acute lung injury. AB - Transfusion-related acute lung injury (TRALI) is a syndrome of respiratory distress upon blood transfusion and is the leading cause of transfusion-related fatalities. Whether the gut microbiota plays any role in the development of TRALI is currently unknown. We observed that untreated barrier-free (BF) mice suffered from severe antibody-mediated acute lung injury, whereas the more sterile housed specific pathogen-free (SPF) mice and gut flora-depleted BF mice were both protected from lung injury. The prevention of TRALI in the SPF mice and gut flora depleted BF mice was associated with decreased plasma macrophage inflammatory protein-2 levels as well as decreased pulmonary neutrophil accumulation. DNA sequencing of amplicons of the 16S ribosomal RNA gene revealed a varying gastrointestinal bacterial composition between BF and SPF mice. BF fecal matter transferred into SPF mice significantly restored TRALI susceptibility in SPF mice. These data reveal a link between the gut flora composition and the development of antibody-mediated TRALI in mice. Assessment of gut microbial composition may help in TRALI risk assessment before transfusion. PMID- 29991497 TI - Respiratory symptoms among search and rescue workers who responded to the 2016 Taiwan earthquake. AB - OBJECTIVES: High respiratory hazards among search and rescue workers (SRWs) emerged after the World Trade Center attacks on 11 September 2001. There have been limited studies on respiratory symptoms among earthquake SRWs. We investigated the respiratory symptoms and the use of respiratory protective equipment among the SRWs who responded to the 2016 Taiwan earthquake. METHODS: On 6 February 2016, a 6.4-magnitude earthquake struck southern Taiwan and caused 513 injuries and 117 deaths. During the 9-day field operation, 519 firefighters affiliated with the Tainan City Government Fire Bureau participated in the search and rescue response. A standardised, self-completed questionnaire was used to collect data on demographics, dust exposures, personal protective measures and health outcomes 3 weeks after the earthquake. Descriptive and multivariate analyses adjusting for demographics and exposure variables were performed for new or worsened outcomes. RESULTS: Of the 519 SRWs, 414 (80%) responded to the questionnaire. Of these SRWs, 153 (37%) reported new or worsened respiratory symptoms, with cough (23%) as the leading symptom, followed by rhinorrhoea or nasal congestion (22%) and chest tightness (6%). More than 90% of the symptoms persisted to the third week after the earthquake. The prevalence of new or worsened respiratory symptoms was significantly higher among SRWs with a higher level of exposure to dust. Prior training in response to respiratory pollutants was only 5%. CONCLUSIONS: There were significant respiratory hazards among earthquake SRWs. The persistent symptoms and low coverage of training warrant further regular examination and occupational health programmes. PMID- 29991498 TI - Application of the Delphi method to reduce disability and mortality from coal mine dust lung disease in China; a new approach to an old problem. PMID- 29991499 TI - Safety and Efficacy of Re-treating with Immunotherapy after Immune-Related Adverse Events in Patients with NSCLC. AB - Considering retreatment following recovery from an immune-related adverse event (irAE) is a common clinical scenario, but the safety and benefit of retreatment is unknown. We identified patients with advanced non-small cell lung cancer (NSCLC) treated with anti-PD-(L)1 who had treatment held due to irAEs and divided them into two groups: those retreated with anti-PD-(L)1 (retreatment cohort) or those who had treatment stopped (discontinuation cohort). Out of 482 NSCLC patients treated with anti-PD-(L)1, 68 (14%) developed a serious irAE requiring treatment interruption. Of these, 38 (56%) were retreated and 30 (44%) had treatment discontinued. In the retreatment cohort, 18 (48%) patients had no subsequent irAEs, 10 (26%) had recurrence of the initial irAE, and 10 (26%) had a new irAE. Most recurrent/new irAEs were mild (58% grade 1-2) and manageable (84% resolved or improved to grade 1). Two treatment-related deaths occurred. Recurrent/new irAEs were more likely if the initial irAE required hospitalization, but the initial grade and time to retreatment did not influence risk. Among those with no observed partial responses prior to the irAE, progression-free survival (PFS) and overall survival (OS) were longer in the retreatment cohort. Conversely, for those with objective responses prior to the irAE, PFS and OS were similar in the retreatment and discontinuation cohorts. Among patients with early objective responses prior to a serious irAE, outcomes were similar, whether or not they were retreated. Together, data suggest that benefit may occur with retreatment in patients with irAEs who had no treatment response prior to irAE onset. Cancer Immunol Res; 6(9); 1093-9. (c)2018 AACR. PMID- 29991500 TI - RORgammat-Expressing Tregs Drive the Growth of Colitis-Associated Colorectal Cancer by Controlling IL6 in Dendritic Cells. AB - Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORgammat accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of development toward a Th17 proinflammatory phenotype. However, the role of these cells in CAC is unknown. RORgammat+FoxP3+ cells were investigated in human samples of CAC, and their phenotypic stability and function were investigated in an azoxymethane/dextran sulfate sodium model of CAC using Treg fate-mapping reporter and Treg-specific RORgammat conditional knockout mice. Tumor development and the intratumoral inflammatory milieu were characterized in these mice. The functional role of CTLA-4 expressed by Tregs and FoxO3 in dendritic cells (DC) was studied in vitro and in vivo by siRNA-silencing experiments. RORgammat expression identified a phenotypically stable population of tumor-infiltrating Tregs in humans and mice. Conditional RORgammat knockout mice showed reduced tumor incidence, and dysplastic cells exhibited low Ki67 expression and STAT3 activation. Tumor-infiltrating DCs produced less IL6, a cytokine that triggers STAT3-dependent proliferative signals in neoplastic cells. RORgammat-deficient Tregs isolated from tumors overexpressed CTLA-4 and induced DCs to have elevated expression of the transcription factor FoxO3, thus reducing IL6 expression. Finally, in vivo silencing of FoxO3 obtained by siRNA microinjection in the tumors of RORgammat-deficient mice restored IL6 expression and tumor growth. These data demonstrate that RORgammat expressed by tumor-infiltrating Tregs sustains tumor growth by leaving IL6 expression in DCs unchecked. Cancer Immunol Res; 6(9); 1082-92. (c)2018 AACR. PMID- 29991501 TI - David Oliver: Making less popular medical jobs more attractive. PMID- 29991502 TI - Remission of Spontaneous Canine Tumors after Systemic Cellular Viroimmunotherapy. AB - Dogs with spontaneous tumors treated in veterinary hospitals offer an excellent opportunity for studying immunotherapies, including oncolytic viruses. Oncolytic viruses have advanced into the clinic as an intratumorally administered therapeutic; however, intravenous delivery has been hindered by neutralization in the blood. To circumvent this hurdle, mesenchymal stem cells have been used as a "Trojan horse." Here, we present the treatment of 27 canine patients with cancer with canine mesenchymal stem cells infected with ICOCAV17, a canine oncolytic adenovirus. No significant adverse effects were found. The response rate was 74%, with 14.8% showing complete responses, including total remissions of lung metastasis. We detected virus infection, stromal degeneration, and immune cell infiltration in tumor biopsies after 4 weeks of treatment. The increased presence of antiadenoviral antibodies in the peripheral blood of treated dogs did not appear to prevent the clinical benefit of this therapy. These data indicate that oncolytic viruses loaded in mesenchymal stem cells represent an effective cancer immunotherapy.Significance: The classical clinical limitations of antitumoral viroimmunotherapy can be overcome by use of mesenchymal stem cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4891/F1.large.jpg Cancer Res; 78(17); 4891-901. (c)2018 AACR. PMID- 29991503 TI - Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes. AB - Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer. Overall, these agents have shown objective response rates of around 20% to 23%, which indicates that a significant proportion of patients do not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement in the median duration of response compared with chemotherapy, still only half of the patients develop long-term maintained remissions. Active research is ongoing in several fields, aiming to increase the number of patients that benefit from ICI, and this research is largely based on the development of biomarkers for personalized immunotherapy and novel combinations of ICI with other agents. This article will review ongoing efforts to develop combinations of ICI with other therapeutic strategies in patients with urothelial cancer, including chemotherapy, targeted agents, other immunotherapy strategies, and radiotherapy. Clin Cancer Res; 1-10. (c)2018 AACR. PMID- 29991504 TI - Prevalence and treatment of atrial fibrillation in UK general practice from 2000 to 2016. AB - OBJECTIVE: Atrial fibrillation (AF) is the most common cardiac arrhythmia and an important risk factor for stroke. Treatment with anticoagulants substantially reduces risk of stroke. Current prevalence and treatment rates of AF in the UK as well as changes in recent years are not known. The aim of this analysis was to determine trends in age-sex specific prevalence and treatment of AF in the UK from 2000 to 2016. METHODS: 17 sequential cross-sectional analyses were carried out between 2000 and 2016 using a large database of electronic primary care records of patients registered with UK general practitioners. These determined the prevalence of patients diagnosed with AF, the stroke risk of those with AF and the proportion of AF patients currently receiving anticoagulants. Stroke risk was assessed using CHA2DS2-VASc score. RESULTS: Age-sex standardised AF prevalence increased from 2.14% (95% CI 2.11% to 2.17%) in 2000 to 3.29% (95% CI 3.27% to 3.32%) in 2016. Between 2000 and 2016, the proportion of patients with AF prescribed anticoagulants increased from 35.4% (95% CI 34.7% to 36.1%) to 75.5% (95% CI 75.1% to 75.8%) in those with high stroke risk (p for change over time <0.001) and from 32.8% (95% CI 30.5% to 35.2%) to 47.1% (95% CI 45.4% to 48.7%) in those with moderate stroke risk (p<0.001). In patients with low risk of stroke, the proportion decreased from 19.9% (95% CI 17.8% to 22.2%) to 9.7% (95% CI 8.4% to 11.1%) (p<0.001).Anticoagulant prescribing performance varied between practices; in 2016, the proportion of eligible patients treated was 82.9% (95% CI 82.2% to 83.7%) and 62.0% (95% CI 61.0% to 63.0%) in the highest-performing and lowest-performing practice quintiles, respectively. There was poor agreement in individual practice performance over time from 2006 to 2016: linear-weighted kappa=0.10 (95% CI 0.02 to 0.19). CONCLUSIONS: From 2000 to 2016, the prevalence of recorded AF has increased in all age groups and both sexes. Anticoagulant treatment of eligible patients with AF has more than doubled, with marked improvements since 2011, alongside a reduction in the use of anticoagulants in ineligible patients with AF. PMID- 29991505 TI - Is incentivising stroke prevention therapy in atrial fibrillation the key? PMID- 29991506 TI - A Versatile Lentiviral Delivery Toolkit for Proximity-dependent Biotinylation in Diverse Cell Types. AB - Proximity-dependent biotinylation strategies have emerged as powerful tools to characterize the subcellular context of proteins in living cells. The popular BioID approach employs an abortive E. coli biotin ligase mutant (R118G; denoted as BirA*), which when fused to a bait protein enables the covalent biotinylation of endogenous proximal polypeptides. This approach has been mainly applied to the study of protein proximity in immortalized mammalian cell lines. To expand the application space of BioID, here we describe a set of lentiviral vectors that enable the inducible expression of BirA*-tagged bait fusion proteins for performing proximity-dependent biotinylation in diverse experimental systems. We benchmark this highly adaptable toolkit across immortalized and primary cell systems, demonstrating the ease, versatility and robustness of the system. We also provide guidelines to perform BioID using these reagents. PMID- 29991507 TI - Comparison of Nuclear Matrix and Mitotic Chromosome Scaffold Proteins in Drosophila S2 Cells-Transmission of Hallmarks of Nuclear Organization Through Mitosis. AB - Chromatin condenses several folds to form mitotic chromosomes during cell division and decondenses post-mitotically to reoccupy their nuclear territory and regain their specific transcriptional profile in a precisely lineage specific manner. This necessitates that the features of nuclear architecture and DNA topology persist through mitosis. We compared the proteome of nuclease and high salt resistant fraction of interphase nucleus known as nuclear matrix (NuMat) and an equivalent biochemical fraction in the mitotic chromosome known as mitotic chromosome scaffold (MiCS). Our study elucidates that as much as 67% of the NuMat proteins are retained in the MiCS indicating that the features of nuclear architecture in interphase nucleus are retained on the mitotic chromosomes. Proteins of the NuMat/MiCS have large dynamic range of MS signal and were detected in sub-femtomolar amounts. Chromatin/RNA binding proteins with hydrolase and helicase activity are highly enriched in NuMat as well as MiCS. Although several transcription factors involved in functioning of interphase nucleus are present exclusively in NuMat, protein components responsible for assembly of membrane-less nuclear bodies are uniquely retained in MiCS. Our study clearly indicates that the features of nuclear architecture, in the structural context of NuMat, are retained in MiCS and possibly play an important role in maintenance of cell lineage specific transcriptional status during cell division and thereby, serve as components of cellular memory. PMID- 29991508 TI - The Sleep Inbred Panel, a Collection of Inbred Drosophila melanogaster with Extreme Long and Short Sleep Duration. AB - Understanding how genomic variation causes differences in observable phenotypes remains a major challenge in biology. It is difficult to trace the sequence of events originating from genomic variants to changes in transcriptional responses or protein modifications. Ideally, one would conduct experiments with individuals that are at either extreme of the trait of interest, but such resources are often not available. Further, advances in genome editing will enable testing of candidate polymorphisms individually and in combination. Here we have created a resource for the study of sleep with 39 inbred lines of Drosophila-the Sleep Inbred Panel (SIP). SIP lines have stable long- and short-sleeping phenotypes developed from naturally occurring polymorphisms. These lines are fully sequenced, enabling more accurate targeting for genome editing and transgenic constructs. This panel facilitates the study of intermediate transcriptional and proteomic correlates of sleep, and supports genome editing studies to verify polymorphisms associated with sleep duration. PMID- 29991510 TI - NOTCH3 contributes to rhinovirus-induced goblet cell hyperplasia in COPD airway epithelial cells. AB - RATIONALE: Goblet cell hyperplasia (GCH) is one of the cardinal features of chronic obstructive pulmonary disease (COPD) and contributes to airways obstruction. Rhinovirus (RV), which causes acute exacerbations in patients with COPD, also causes prolonged airways obstruction. Previously, we showed that RV enhances mucin gene expression and increases goblet cell number in a COPD mouse model. This study examines whether RV causes sustained GCH in relevant models of COPD. METHODS: Mucociliary-differentiated COPD and normal airway epithelial cell cultures and mice with normal or COPD phenotype were infected with RV or sham and examined for GCH by immunofluorescence and/or mucin gene expression. In some experiments, RV-infected COPD cells and mice with COPD phenotype were treated with gamma-secretase inhibitor or interleukin-13 neutralising antibody and assessed for GCH. To determine the contribution of NOTCH1/3 in RV-induced GCH, COPD cells transduced with NOTCH1/3 shRNA were used. RESULTS: RV-infected COPD, but not normal cell cultures, showed sustained GCH and increased mucin genes expression. Microarray analysis indicated increased expression of NOTCH1, NOTCH3 and HEY1 only in RV-infected COPD cells. Blocking NOTCH3, but not NOTCH1, attenuated RV-induced GCH in vitro. Inhibition of NOTCH signalling by gamma secretase inhibitor, but not neutralising antibody to IL-13, abrogated RV-induced GCH and mucin gene expression. CONCLUSIONS: RV induces sustained GCH via NOTCH3 particularly in COPD cells or mice with COPD phenotype. This may be one of the mechanisms that may contribute to RV-induced prolonged airways obstruction in COPD. PMID- 29991511 TI - GRWD1 regulates ribosomal protein L23 levels via the ubiquitin-proteasome system. AB - Glutamate-rich WD40 repeat-containing 1 (GRWD1) is a Cdt1-binding protein that promotes mini-chromosome maintenance (MCM) loading through its histone chaperone activity. GRWD1 acts as a tumor-promoting factor by downregulating p53 (also known as TP53) via the RPL11-MDM2-p53 axis. Here, we identified GRWD1-interacting proteins using a proteomics approach and showed that GRWD1 interacts with various proteins involved in transcription, translation, DNA replication and repair, chromatin organization, and ubiquitin-mediated proteolysis. We focused on the ribosomal protein ribosomal protein L23 (RPL23), which positively regulates nucleolar stress responses through MDM2 binding and inhibition, thereby functioning as a tumor suppressor. Overexpression of GRWD1 decreased RPL23 protein levels and stability; this effect was restored upon treatment with the proteasome inhibitor MG132. EDD (also known as UBR5), an E3 ubiquitin ligase that interacts with GRWD1, also downregulated RPL23, and the decrease was further enhanced by co-expression of GRWD1. Conversely, siRNA-mediated GRWD1 knockdown upregulated RPL23. Co-expression of GRWD1 and EDD promoted RPL23 ubiquitylation. These data suggest that GRWD1 acts together with EDD to negatively regulate RPL23 via the ubiquitin-proteasome system. GRWD1 expression reversed the RPL23-mediated inhibition of anchorage-independent growth in cancer cells. Our data suggest that GRWD1-induced RPL23 proteolysis plays a role in downregulation of p53 and tumorigenesis. PMID- 29991509 TI - Disruption of INOS, a Gene Encoding myo-Inositol Phosphate Synthase, Causes Male Sterility in Drosophila melanogaster. AB - Inositol is a precursor for the phospholipid membrane component phosphatidylinositol (PI), involved in signal transduction pathways, endoplasmic reticulum stress, and osmoregulation. Alterations of inositol metabolism have been implicated in human reproductive issues, the therapeutic effects of drugs used to treat epilepsy and bipolar disorder, spinal cord defects, and diseases including diabetes and Alzheimer's. The sole known inositol synthetic enzyme is myo-inositol synthase (MIPS), and the homolog in Drosophilia melanogaster is encoded by the Inos gene. Three identical deletion strains (inosDeltaDF /CyO) were constructed, confirmed by PCR and sequencing, and homozygotes (inosDeltaDF /inosDeltaDF ) were shown to lack the transcript encoding the MIPS enzyme. Without inositol, homozygous inosDeltaDF deletion fertilized eggs develop only to the first-instar larval stage. When transferred as pupae to food without inositol, however, inosDeltaDF homozygotes die significantly sooner than wild type flies. Even with dietary inositol the homozygous inosDeltaDF males are sterile. An inos allele, with a P-element inserted into the first intron, fails to complement this male sterile phenotype. An additional copy of the Inos gene inserted into another chromosome rescues all the phenotypes. These genetic and phenotypic analyses establish D. melanogaster as an excellent model organism in which to examine the role of inositol synthesis in development and reproduction. PMID- 29991512 TI - PTPalpha is required for laminin-2-induced Fyn-Akt signaling to drive oligodendrocyte differentiation. AB - Extrinsic signals that regulate oligodendrocyte maturation and subsequent myelination are essential for central nervous system development and regeneration. Deficiency in the extracellular factor laminin-2 (Lm2, comprising the alpha2beta1gamma1 chains), as occurs in congenital muscular dystrophy, can lead to impaired oligodendroglial development and aberrant myelination, but many aspects of Lm2-regulated oligodendroglial signaling and differentiation remain undefined. We show that receptor-like protein tyrosine phosphatase alpha (PTPalpha, also known as PTPRA) is essential for myelin basic protein expression and cell spreading during Lm2-induced oligodendrocyte differentiation. PTPalpha complexes with the Lm2 receptors alpha6beta1 integrin and dystroglycan to transduce Fyn activation upon Lm2 engagement. In this way, PTPalpha mediates a subset of Lm2-induced signals required for differentiation, includeing mTOR dependent Akt activation but not Erk1/2 activation. We identify N-myc downstream regulated gene-1 (NDRG1) as a PTPalpha-regulated molecule during oligodendrocyte differentiation, and distinguish Lm2 receptor-specific modes of Fyn-Akt-dependent and -independent NDRG1 phosphorylation. Altogether, this reveals an Lm2-regulated PTPalpha-Fyn-Akt signaling axis that is critical for key aspects of the gene expression and morphological changes that mark oligodendrocyte maturation. PMID- 29991513 TI - Persistent actin depolarization caused by ethanol induces the formation of multiple small cortical septin rings in yeast. AB - Short-term exposure to severe ethanol stress has adverse effects on yeast cells. However, limited information is available on the effects of long-term exposure to severe ethanol stress. In this study, we examined the effects of a long-term treatment with a high ethanol concentration [10% (v/v)] on yeast morphology. We found that long-term severe ethanol stress induced the continuous depolarization of the actin cytoskeleton and hypertrophy in yeast cells, accompanied by the aberrant localization of septins, which formed multiple small cortical rings (MSCRs). The formation of MSCRs was also induced by the continuous depolarization of the actin cytoskeleton caused by a treatment with latrunculin-A, an effective inhibitor of actin polymerization. Unlike the formation of conventional septin rings, the formation of MSCRs did not require Cdc42 and its effectors, Gic1, Gic2 and Cla4. These results provide novel insights into the effects of persistent actin depolarization caused by long-term exposure to severe ethanol stress on yeast cytomorphology. PMID- 29991515 TI - Surgical mesh for stress urinary incontinence to be halted immediately in England. PMID- 29991516 TI - Analysing data in palliative care trials. PMID- 29991514 TI - Adaptive adhesion systems mediate glioma cell invasion in complex environments. AB - Diffuse brain invasion by glioma cells prevents effective surgical or molecular targeted therapy and underlies a detrimental outcome. Migrating glioma cells are guided by complex anatomical brain structures but the exact mechanisms remain poorly defined. To identify adhesion receptor systems and matrix structures supporting glioma cell invasion into brain-like environments we used 2D and 3D organotypic invasion assays in combination with antibody-, peptide- and RNA-based interference. Combined interference with beta1 and alphaV integrins abolished the migration of U-251 and E-98 glioma cells on reconstituted basement membrane; however, invasion into primary brain slices or 3D astrocyte-based scaffolds and migration on astrocyte-deposited matrix was only partly inhibited. Any residual invasion was supported by vascular structures, as well as laminin 511, a central constituent of basement membrane of brain blood vessels. Multi-targeted interference against beta1, alphaV and alpha6 integrins expressed by U-251 and E 98 cells proved insufficient to achieve complete migration arrest. These data suggest that mechanocoupling by integrins is relatively resistant to antibody- or peptide-based targeting, and cooperates with additional, as yet unidentified adhesion systems in mediating glioma cell invasion in complex brain stroma. PMID- 29991518 TI - Physical Activity, Global DNA Methylation, and Breast Cancer Risk: A Systematic Literature Review and Meta-analysis. AB - The extent to which physical activity reduces breast cancer risk through changes in global DNA methylation is unknown. We systematically identified studies that investigated the association between: (i) physical activity and global DNA methylation; or (ii) global DNA methylation and breast cancer risk. Associations were quantified using random-effects models. Heterogeneity was investigated through subgroup analyses and the Q-test and I 2 statistics. Twenty-four studies were reviewed. We observed a trend between higher levels of physical activity and higher levels of global DNA methylation [pooled standardized mean difference = 0.19; 95% confidence interval (CI), -0.03-0.40; P = 0.09] which, in turn, had a suggestive association with a reduced breast cancer risk (pooled relative risk = 0.70; 95% CI, 0.49-1.02; P = 0.06). In subgroup analyses, a positive association between physical activity and global DNA methylation was observed among studies assessing physical activity over long periods of time (P = 0.02). Similarly, the association between global DNA methylation and breast cancer was statistically significant for prospective cohort studies (P = 0.007). Despite the heterogeneous evidence base, the literature suggests that physical activity reduces the risk of breast cancer through increased global DNA methylation. This study is the first to systematically overview the complete biologic pathway between physical activity, global DNA methylation, and breast cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1320-31. (c)2018 AACR. PMID- 29991517 TI - Is Chronic Exposure to Low-Dose Organochlorine Pesticides a New Risk Factor of T cell Immunosenescence? AB - Background: T-cell immunosenescence, a hallmark of an aging immune system, is potentially linked to the risk of developing cancer and other aging-related diseases. Chronic infection by cytomegalovirus (CMV) has been widely studied as a risk factor for T-cell immunosenescence, but the role of persistent chemicals has never been examined. As a typical example of persistent chemicals, we evaluated whether organochlorine pesticides (OCPs) are related to T-cell immunosenescence in the general population.Methods: Serum concentrations of beta hexachlorocyclohexane, p,p'-DDT, p,p'-DDE, and trans-nonachlor were measured in 95 Korean adults ages 30 to 64 years. T-cell immunosenescence was assessed by the frequencies of CD8+CD57+, CD8+CD28-, CD4+CD57+, and CD4+CD28- T lymphocytes in 20 mL of fresh peripheral blood.Results: The senescence of CD8+ T lymphocytes was the most consistently associated with OCPs. For quartiles of measurements of OCPs, adjusted mean percentages of CD8+CD57+ and CD8+CD28- T lymphocytes in the CD8+ T lymphocyte population were 23.9, 27.6, 31.0, and 38.7 (P trend < 0.01) and 25.6, 27.3, 28.0, and 35.5 (P trend = 0.02), respectively. When we compared the strength of the associations among OCPs, CMV IgG titer, and age, OCPs showed the strongest association with markers of immunosenescence. Importantly, the association between OCPs and immunosenescence markers was more prominent among participants without known risk factors, such as a young age or low CMV immunoglobulin G titer.Conclusions: Chronic exposure to low-dose OCPs may be a new risk factor for T-cell immunosenescence.Impact: T-cell immunosenescence may be one possible mechanism linking low-dose OCPs and many chronic diseases. Cancer Epidemiol Biomarkers Prev; 27(10); 1159-67. (c)2018 AACR. PMID- 29991519 TI - MANAGEMENT OF ENDOCRINE DISEASE: Critical review of the evidence underlying management of glucocorticoid-induced hyperglycaemia. AB - Glucocorticoids are frequently prescribed to patients with a wide range of inflammatory and autoimmune diseases. The semi-synthetic glucocorticoid prednisolone is most commonly prescribed and in two main patterns. Prednisolone is prescribed short-term at medium-high doses to treat an acute inflammatory illness or long-term at lower doses to attenuate chronic inflammatory disease progression. In hospitalized patients with acute prednisolone-induced hyperglycaemia there is a distinct circadian pattern of glucose elevation, which occurs predominantly in the afternoon and evening. As a morning dose of isophane insulin has a pharmacokinetic pattern that matches this pattern of glucose elevation, treatment comprising a basal dose of morning isophane insulin in combination with short-acting insulin boluses is generally recommended. However, evidence is lacking that isophane-based basal bolus insulin is more efficacious than other insulin regimens. In outpatients, low dose prednisolone causes a small increase in post glucose-load glucose concentration but no change in overall glycaemic control as measured by glycosylated haemoglobin. If treatment is indicated, metformin has been shown to be effective and may attenuate other adverse effects of long-term prednisolone therapy. Further studies are necessary in order to identify factors underlying the variability in response to insulin therapy and clinical benefits of treatment in hospitalized patients with prednisolone-induced hyperglycaemia. In outpatients prescribed low dose prednisolone, the cardiovascular risk associated with postprandial hyperglycaemia and efficacy of hypoglycaemic therapies should be evaluated in future randomized clinical trials. PMID- 29991520 TI - Jerry Edward Chipuk: A powerhouse for mitochondrial biology. AB - Chipuk studies the interaction between mitochondrial dynamics and cell death in cancer. PMID- 29991522 TI - Jeremy Hunt: Farewell to the great survivor. PMID- 29991521 TI - ASM Vibrio2017 Conference Special Issue. PMID- 29991523 TI - Angiotensin receptor neprilysin inhibitors in older patients with heart failure. PMID- 29991524 TI - Who is Matt Hancock, England's new health secretary? PMID- 29991525 TI - Child carriers of antibiotic warning. PMID- 29991526 TI - Human and Bovine Colostrum for Prevention of Necrotizing Enterocolitis: A Meta analysis. AB - CONTEXT: Human and bovine colostrum (HBC) administration has been linked to beneficial effects on morbidity and mortality associated with necrotizing enterocolitis (NEC). OBJECTIVES: To determine the effectiveness and safety of HBC for reducing NEC, mortality, sepsis, time to full-feed and feeding intolerance in preterm infants. DATA SOURCES: We conducted searches through Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, and gray literature. STUDY SELECTION: Randomized controlled trials comparing human or bovine colostrum to placebo. DATA EXTRACTION: Two reviewers independently did screening, review, and extraction. RESULTS: Eight studies (385 infants) proved eligible. In comparison with placebo, HBC revealed no effect on the incidence of severe NEC (relative risk [RR]: 0.99; 95% confidence interval [CI] 0.48 to 2.02, I2 = 2.2%; moderate certainty of evidence), all-cause mortality (RR: 0.88; 95% CI 0.39 to 1.82, I2 = 0%; moderate certainty), culture-proven sepsis (RR: 0.78; 95% CI 0.53 to 1.14, I2 = 0%; moderate certainty), and feed intolerance (RR: 0.97; 95% CI 0.37 to 2.56, I2 = 55%; low certainty). HBC revealed a significant effect on reducing the mean days to reach full enteral feed (mean difference: -3.55; 95% CI 0.33 to 6.77, I2 = 41.1%; moderate certainty). The indirect comparison of bovine versus human colostrum revealed no difference in any outcome. LIMITATIONS: The number of patients was modest, whereas the number of NEC-related events was low. CONCLUSIONS: Bovine or human colostrum has no effect on severe NEC, mortality, culture-proven sepsis, feed intolerance, or length of stay. Additional research focused on the impact on enteral feeding may be needed to confirm the findings on this outcome. PMID- 29991527 TI - LINC00152 Promotes Invasion through a 3'-Hairpin Structure and Associates with Prognosis in Glioblastoma. AB - Long noncoding RNAs (lncRNA) are increasingly implicated in oncogenesis. Here, it is determined that LINC00152/CYTOR is upregulated in glioblastoma multiforme (GBM) and aggressive wild-type IDH1/2 grade 2/3 gliomas and upregulation associates with poor patient outcomes. LINC00152 is similarly upregulated in over 10 other cancer types and associates with a poor prognosis in 7 other cancer types. Inhibition of the mostly cytoplasmic LINC00152 decreases, and overexpression increases cellular invasion. LINC00152 knockdown alters the transcription of genes important to epithelial-to-mesenchymal transition (EMT). PARIS and Ribo-seq data, together with secondary structure prediction, identified a protein-bound 121-bp stem-loop structure at the 3' end of LINC00152 whose overexpression is sufficient to increase invasion of GBM cells. Point mutations in the stem-loop suggest that stem formation in the hairpin is essential for LINC00152 function. LINC00152 has a nearly identical homolog, MIR4435-2HG, which encodes a near identical hairpin, is equally expressed in low-grade glioma (LGG) and GBM, predicts poor patient survival in these tumors, and is also reduced by LINC00152 knockdown. Together, these data reveal that LINC00152 and its homolog MIR4435-2HG associate with aggressive tumors and promote cellular invasion through a mechanism that requires the structural integrity of a hairpin structure.Implications: Frequent upregulation of the lncRNA, LINC00152, in glioblastoma and other tumor types combined with its prognostic potential and ability to promote invasion suggests LINC00152 as a potential biomarker and therapeutic target. Mol Cancer Res; 16(10); 1470-82. (c)2018 AACR. PMID- 29991528 TI - PERK Regulates Glioblastoma Sensitivity to ER Stress Although Promoting Radiation Resistance. AB - The aggressive nature and inherent therapeutic resistance of glioblastoma multiforme (GBM) has rendered the median survival of afflicted patients to 14 months. Therefore, it is imperative to understand the molecular biology of GBM to provide new treatment options to overcome this disease. It has been demonstrated that the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is an important regulator of the endoplasmic reticulum (ER) stress response. PERK signaling has been observed in other model systems after radiation; however, less is known in the context of GBM, which is frequently treated with radiation-based therapies. To investigate the significance of PERK, we studied activation of the PERK-eIF2alpha-ATF4 pathway in GBM after ionizing radiation (IR). By inhibiting PERK, it was determined that ionizing radiation (IR)-induced PERK activity led to eIF2alpha phosphorylation. IR enhanced the prodeath component of PERK signaling in cells treated with Sal003, an inhibitor of phospho-eIF2alpha phosphatase. Mechanistically, ATF4 mediated the prosurvival activity during the radiation response. The data support the notion that induction of ER stress signaling by radiation contributes to adaptive survival mechanisms during radiotherapy. The data also support a potential role for the PERK/eIF2alpha/ATF4 axis in modulating cell viability in irradiated GBM.Implications: The dual function of PERK as a mediator of survival and death may be exploited to enhance the efficacy of radiation therapy.Visual Overview: http://mcr.aacrjournals.org/content/16/10/1447/F1.large.jpg Mol Cancer Res; 16(10); 1447-53. (c)2018 AACR. PMID- 29991529 TI - Taxol Induces Brk-dependent Prosurvival Phenotypes in TNBC Cells through an AhR/GR/HIF-driven Signaling Axis. AB - The metastatic cascade is a complex process that requires cancer cells to survive despite conditions of high physiologic stress. Previously, cooperation between the glucocorticoid receptor (GR) and hypoxia-inducible factors (HIF) was reported as a point of convergence for host and cellular stress signaling. These studies indicated p38 MAPK-dependent phosphorylation of GR on Ser134 and subsequent p GR/HIF-dependent induction of breast tumor kinase (PTK6/Brk), as a mediator of aggressive cancer phenotypes. Herein, p-Ser134 GR was quantified in human primary breast tumors (n = 281) and the levels of p-GR were increased in triple-negative breast cancer (TNBC) relative to luminal breast cancer. Brk was robustly induced following exposure of TNBC model systems to chemotherapeutic agents (Taxol or 5 fluorouracil) and growth in suspension [ultra-low attachment (ULA)]. Notably, both Taxol and ULA resulted in upregulation of the Aryl hydrocarbon receptor (AhR), a known mediator of cancer prosurvival phenotypes. Mechanistically, AhR and GR copurified and following chemotherapy and ULA, these factors assembled at the Brk promoter and induced Brk expression in an HIF-dependent manner. Furthermore, Brk expression was upregulated in Taxol-resistant breast cancer (MCF 7) models. Ultimately, Brk was critical for TNBC cell proliferation and survival during Taxol treatment and in the context of ULA as well as for basal cancer cell migration, acquired biological phenotypes that enable cancer cells to successfully complete the metastatic cascade. These studies nominate AhR as a p GR binding partner and reveal ways to target epigenetic events such as adaptive and stress-induced acquisition of cancer skill sets required for metastatic cancer spread.Implication: Breast cancer cells enlist intracellular stress response pathways that evade chemotherapy by increasing cancer cell survival and promoting migratory phenotypes. Mol Cancer Res; 16(11); 1761-72. (c)2018 AACR. PMID- 29991531 TI - Novel Distal Left Radial Artery Access in Anatomical Snuffbox for Recanalization of Proximal Radial Artery Total Occlusion and Percutaneous Coronary Intervention Through Left Internal Mammary Artery. PMID- 29991532 TI - Meditation-based therapies for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and meta-analysis. AB - BACKGROUND: The efficacy of meditation-based therapies for attention deficit/hyperactivity disorder (ADHD) across the lifespan remains uncertain. OBJECTIVE: To conduct a systematic review and meta-analysis of randomised controlled trials (RCTs) assessing the efficacy of meditation-based therapies for ADHD core symptoms and associated neuropsychological dysfunctions in children/adolescents or adults with ADHD. METHODS: We searched Pubmed, PsycInfo, Embase+Embase Classic, Ovid Medline and Web of Knowledge with no language, date or type of document restriction, up to 5 May 2018. Random-effects model was used. Heterogeneity was assessed with Cochran's Q and I2 statistics. Publication (small studies) bias was assessed with funnel plots and the Egger's test. Studies were evaluated with the Cochrane risk of bias (RoB) tool. Analyses were conducted using Comprehensive Meta-Analysis. FINDINGS: 13 RCTs (seven in children/adolescents, n=270 and six in adults, n=339) were retained. Only one RCT was double-blind.Meditation-based therapies were significantly more efficacious than the control conditions in decreasing the severity of ADHD core symptoms (inattention+hyperactivity/impulsivity: children/adolescents: Hedge's g=-0.44, 95% CI -0.69 to -0.19, I20%; adults: Hedge's g=-0.66, 95% CI -1.21 to -0.11, I281.81%). No significant effects were found on neuropsychological measures of inattention and inhibition in children/adolescents. In adults, significant effects were detected on working memory and inhibition, although these results were based on a small number of studies (n=3). 57% and 43% of the studies in children/adolescents were rated at overall unclear and high risk of bias, respectively. In adults, 33% and 67% of the studies were deemed at overall unclear and high risk of bias, respectively. No evidence of publication bias was found. CONCLUSIONS: Despite statistically significant effects on ADHD combined core symptoms, due to paucity of RCTs, heterogeneity across studies and lack of studies at low risk of bias, there is insufficient methodologically sound evidence to support meditation-based therapies for ADHD. TRIAL REGISTRATION NUMBER: PROSPERO 2018 [CRD42018096156]. PMID- 29991530 TI - The metabolic axis of macrophage and immune cell polarization. AB - The extracellular space of solid tumors ranges from being well-nurtured to being completely ischemic and can serve as a source of intratumoral heterogeneity, determining the behavior and molecular profiles of malignant and stromal cells. Here, we discuss how the metabolic tumor microenvironment modulates the phenotypes of the immune cells that infiltrate tumors, with an emphasis on tumor associated macrophages. These cells constitute a diverse population that has pro tumoral and anti-inflammatory properties, and are likened to anti-inflammatory 'M2' macrophages. Recent findings show how different metabolic microenvironments specify an array of phenotypic changes in macrophages. In tumors, extracellular metabolite levels vary predictably according to proximity to the vasculature, and phenotypic changes in tumor-associated macrophages and in other immune cells are also predictable. We speculate that this 'metabolic axis' of macrophage polarization modulates - and is modulated by - the response to inflammatory cues, creating a wide variety of possible phenotypic states. Understanding how extracellular metabolites influence cell phenotypes allows us to predict how tumor-associated macrophages and other tumor cells might change, with the aim of harnessing this predictability for therapy. Overall, we describe an emerging picture in which chemokines, growth factors and the metabolic tumor microenvironment act together to determine the phenotypes of tumor-infiltrating immune cells. PMID- 29991535 TI - The Protein Phosphatases ATUNIS1 and ATUNIS2 Regulate Cell Wall Integrity in Tip Growing Cells. AB - Fast tip-growing plant cells such as pollen tubes (PTs) and root hairs (RHs) require a robust coordination between their internal growth machinery and modifications of their extracellular rigid, yet extensible, cell wall (CW). Part of this essential coordination is governed by members of the Catharanthus roseus receptor-like kinase1-like (CrRLK1L) subfamily of RLKs with FERONIA (FER) and its closest homologs, ANXUR1 (ANX1) and ANX2, controlling CW integrity during RH and PT growth, respectively. Recently, Leucine-Rich Repeat Extensin 8 (LRX8) to LRX11 were also shown to be important for CW integrity in PTs. We previously reported an anx1 anx2 suppressor screen in Arabidopsis thaliana that revealed MARIS (MRI) as a positive regulator of both FER- and ANX1/2-dependent CW integrity pathways. Here, we characterize a suppressor that exhibits a weak rescue of the anx1 anx2 PT bursting phenotype and a short RH phenotype. The corresponding suppressor mutation causes a D94N substitution in a Type One Protein Phosphatase we named ATUNIS1 (AUN1). We show that AUN1 and its closest homolog, AUN2, are nucleocytoplasmic negative regulators of tip growth. Moreover, we demonstrate that AUN1D94N and AUN1H127A harboring mutations in key amino acids of the conserved catalytic site of phosphoprotein phosphatases function as dominant amorphic variants that repress PT growth. Finally, genetic interaction studies using the hypermorph MRIR240C and amorph AUN1D94N dominant variants indicate that LRX8-11 and ANX1/2 function in distinct but converging pathways to fine-tune CW integrity during tip growth. PMID- 29991537 TI - Trying to heal the scars left by the war in Bosnia. PMID- 29991538 TI - Ethical rejections of xenotransplantation? The potential and challenges of using human-pig chimeras to create organs for transplantation. PMID- 29991539 TI - Pay GPs the same as hospitals to train medical students, says royal college. PMID- 29991540 TI - Postoperative diffuse alveolar haemorrhage: insidious negative pressure or sevoflurane induced? AB - Negative pressure pulmonary oedema is well described in the literature as an uncommon but recognised complication of general anaesthe sia; negative pressure diffuse alveolar haemorrhage is a rarer consequence. We report a case of massive haemoptysis following elective general anaesthesia using a laryngeal mask airway device and sevoflurane anaesthetic maintenance. The patient had no obvious signs of laryngospasm or other cause of upper airway obstruction perioperatively. We explore the possibility that the haemoptysis was caused by clinically unapparent negative pressure generation, but also ask whether the anaesthetic agent should be considered as a culprit. PMID- 29991536 TI - Molecular Topology of the Transit Peptide during Chloroplast Protein Import. AB - Chloroplast protein import is directed by the interaction of the targeting signal (transit peptide) of nucleus-encoded preproteins with translocons at the outer (TOC) and inner (TIC) chloroplast envelope membranes. Studies of the energetics and determinants of transit peptide binding have led to the hypothesis that import occurs through sequential recognition of transit peptides by components of TOC and TIC during protein import. To test this hypothesis, we employed a site specific cross-linking approach to map transit peptide topology in relation to TOC-TIC components at specific stages of import in Arabidopsis thaliana and pea (Pisum sativum). We demonstrate that the transit peptide is in contact with Tic20 at the inner envelope in addition to TOC complex components at the earliest stages of chloroplast binding. Low levels of ATP hydrolysis catalyze the commitment of the preprotein to import by promoting further penetration across the envelope membranes and stabilizing the association of the preprotein with TOC TIC. GTP hydrolysis at the TOC receptors serves as a checkpoint to regulate the ATP-dependent commitment of the preprotein to import and is not essential to drive preprotein import. Our results demonstrate the close cooperativity of the TOC and TIC machinery at each stage of transit peptide recognition and membrane translocation during protein import. PMID- 29991541 TI - Cold agglutinin-mediated autoimmune haemolytic anaemia associated with diffuse large B cell lymphoma. AB - Cold agglutinin-mediated autoimmune haemolytic anaemia is associated with the development of autoantibodies that can agglutinate red blood cells at cold temperatures. While primary cold agglutinin disease is an idiopathic lymphoproliferative disorder, secondary cold agglutinin syndrome (CAS) complicates other diseases such as infections, autoimmune diseases and cancers, mostly low-grade lymphomas. Early recognition, treatment of CAS and treatment of its associated underlying diseases are crucial to a successful outcome. We report a case of CAS in a setting of diffuse large B cell lymphoma, in which the treatment course was complicated by worsened anaemia due to chemotherapy-induced myelosuppression. We reviewed previously reported cases and discussed diagnosis and treatment strategies, including novel complement inhibitors, as potential future therapy. PMID- 29991542 TI - Mixed extragonadal germ cell tumour of the prostate. AB - Extragonadal germ cell tumours (EGGCTs) originated in prostate are extremely rare, with <20 cases described in the literature. We report a case of a patient with a primary prostatic mixed EGGCT. A 47-year-old man presenting severe low urinary tract symptoms and signs of prostatic enlargement, with no malignancy suspicion, underwent transurethral resection of the prostate. The histopathological evaluation suggested the diagnosis of a retroperitoneal sarcoma. The patient underwent neoadjuvant chemotherapy and then was submitted to radical cystoprostatectomy. Histology revealed a mixed EGGCT of the prostate with yolk sac tumour and seminoma components. No testicular abnormalities were identified on the postoperative scrotal ultrasound. The patient went through four cycles of chemotherapy with bleomycin, etoposide and cisplatin. After 12 months of follow-up, the patient is alive and free of recurrence. PMID- 29991543 TI - Empirical treatment of tuberculosis: TB or not TB? AB - Of the 8.6 million new cases of tuberculosis (TB) that occur globally each year, a quarter occur in India. We describe the case of a 38-year-old Indian woman who presented with symptoms of hepatitis after being treated empirically with anti-TB therapy for five months. The patient was suspected to have TB after having recurrent episodes of coughing which would improve briefly before her respiratory symptoms returned, which led to her being treated at various healthcare clinics and hospitals. We highlight the challenges the patient faced due to the lack of centralised medical records which would have prevented unnecessary investigations and treatment. PMID- 29991544 TI - Recurrent minor strokes/TIA with a right to left shunt. AB - A patient came to our institution for evaluation and closure of suspected patent foramen ovale actively manifesting as cerebrovascular accident. Through further studies, we found the presence of a pulmonary arteriovenous fistula, which was subsequently and successfully closed through non-invasive percutaneous selective segmental pulmonary artery embolisation. PMID- 29991545 TI - When a patient with depression is feeling sleepy, be aware of sleep apnoea. AB - A 67-year-old man was referred to an outpatient clinic of geriatric psychiatry because of persistent symptoms of depression and anxiety, accompanied by sleepiness. The latter had been evaluated multiple times in the general practice over several years; each time it was considered to be a symptom of depression. After referral, the patient was diagnosed with severe obstructive sleep apnoea (OSA), comorbid to a depressive and anxiety disorder. Retrospectively, we conclude that affective symptoms accompanying OSA and sleepiness were wrongfully interpreted as depression, but after having led to problems at work, they have triggered psychiatric comorbidity. Treatment of OSA in addition to the psychiatric disorders resulted in a full recovery over time. The delayed diagnosis of OSA has certainly diminished the patient's quality of life and might have precipitated the depressive disorder. Moreover, OSA poses patients at an increased risk of cardiovascular disease, hypertension, stroke and traffic accidents. PMID- 29991546 TI - A novel mutation in Wiskott-Aldrich gene manifesting as macrothrombocytopenia and neutropenia. AB - Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder, described as a clinical triad of microthrombocytopenia, eczema and recurrent infections. Different mutations in WAS gene have been identified, resulting in various phenotypes and a broad range of disease severity, ranging from classic WAS to X linked thrombocytopenia and X-linked neutropenia. WAS in some cases can be fatal without haematopoietic stem cell transplantation early in life. In this particular case, we present a novel mutation with a unique presentation. An 18 year-old man incidentally found to have macrothrombocytopenia and neutropenia at 16 years of age later found to be hemizygous for c. 869T>C (p.Ile290Thr) mutation in WAS gene. The late presentation, absence of other manifestations of WAS and presence of macrothrombocytopenia, rather than microthrombocytopenia, which is usually a characteristic finding in WAS, misled the initial diagnosis. On review of literature, this mutation has not been reported as causing WAS. PMID- 29991547 TI - A case of posterior reversible encephalopathy syndrome associated with sepsis. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterised by parieto-occipital vasogenic oedema seen on MRI. Infection and sepsis has been reported as a possible cause for this disorder.We present a 19 year-old immunocompetent Caucasian man with known type 1 diabetes mellitus who presented to the emergency department with acute onset of bilateral visual loss, headaches and hypertension; he had been discharged 2 weeks ago for severe diabetic ketoacidosis and Staphylococcus aureus bacteraemia. Initial CT scan of the head was negative, but MRI showed findings suggestive of PRES. He was treated with nicardipine drip for strict blood pressure management and symptoms resolved within 4 days. PRES is a rare disease that has been increasingly reported as MRI becomes more commonplace. Usually associated with immunological disease, pre eclampsia and cytotoxic therapies but an association with sepsis due to gram positive bacteria. PMID- 29991548 TI - Gluten-free diet: a possible treatment for chronic diarrhoea in common variable immunodeficiency. AB - Gastrointestinal disorders are frequent in common variable immunodeficiency (CVID). Clinical symptoms and histological alterations in CIVD can resemble celiac disease. Usually, patients with chronic diarrhoea associated with CVID do not improve with a gluten-free diet. The authors present a case of a male patient who was diagnosed with CVID at age 33 and had chronic diarrhoea which resolved after initiating a gluten-free diet. Clinical relapse occurred after gluten reintroduction. The main objective of this case report is to alert clinicians to implement a gluten-free diet in patients with CVID with chronic diarrhoea. PMID- 29991549 TI - Multisystem amyloidosis as the unifying diagnosis for constipation, collapse and cardiomyopathy. AB - Amyloidosis a rare disorder characterised by the deposition of amyloid protein aggregates in different organ systems throughout the body with resulting functional impairment of affected organs. It can present with localised or multisystemic deposits. Diagnosis is often delayed due to the non-specific nature of the symptoms. We present the case of a 59-year-old man with a 12-month history of non-specific symptoms. Investigations revealed Helicobacter pylori positive gastritis. Blood tests showed only a normocytic anaemia and thrombocytopaenia. CT scan showed proximal sigmoid thickening. Biopsies were unremarkable. Echocardiogram and cardiac MRI scan showed restrictive cardiomyopathy. Congo red staining of gastric biopsies showed amyloid deposition. The patient had elevated serum kappa light chains and a bone marrow biopsy confirmed multiple myeloma and he was subsequently diagnosed with systemic light chain (AL) amyloidosis secondary to this. He was started on chemotherapy and parenteral nutrition; however, he deteriorated rapidly and so was started on palliative treatment and discharged home. PMID- 29991550 TI - Bilateral serpentine radio-opaque shadows near the urinary bladder: nothing but calcified vas deferens! PMID- 29991551 TI - Giant abdominal metastasis from cardiac liposarcoma. PMID- 29991552 TI - A novel cause of postmenopausal bleeding in an immunosuppressed patient. AB - Malakoplakia is a rare histiocytic disease first described in 1902 by Michaelis and Gutmann. It is associated with host immunocompromise including chronic inflammatory conditions, infectious conditions or malnutrition. Here, we report the case of uterine malakoplakia as a rare cause of postmenopausal bleeding in an immunocompromised patient. PMID- 29991553 TI - Rectus sheath haematoma causing ureteric obstruction. AB - Rectus sheath haematoma is an uncommon condition. However, its incidence is increasing, attributed to greater use of anticoagulant therapy. We present the case of an 83-year-old woman on therapeutic enoxaparin for a prior pulmonary embolus who underwent elective right hemicolectomy and developed a rectus sheath haematoma 13 days postoperatively. Her extensive haematoma compressed retroperitoneal structures including the right ureter. She was successfully managed conservatively. PMID- 29991554 TI - Unusual surgical emergency in a patient of dengue haemorrhagic fever: spontaneous rectus sheath haematoma leading to abdominal compartment syndrome. AB - Abdominal compartment syndrome (ACS) is an uncommon complication of dengue haemorrhagic fever (DHF), described so far only in association with fluid refractory shock and high-volume resuscitation. We describe an unusual case of ACS in a patient of DHF where raised intra-abdominal pressure was due to spontaneous rectus sheath haematoma causing external compression. Early recognition of the haematoma, constant vigilance and timely decision for surgical intervention could salvage the patient with complete recovery of organ function. PMID- 29991555 TI - Rare but life-threatening complication of fecalith. PMID- 29991556 TI - Single-cell approaches identify the molecular network driving malignant hematopoietic stem cell self-renewal. AB - Recent advances in single-cell technologies have permitted the investigation of heterogeneous cell populations at previously unattainable resolution. Here we apply such approaches to resolve the molecular mechanisms driving disease in mouse hematopoietic stem cells (HSCs), using JAK2V617F mutant myeloproliferative neoplasms (MPNs) as a model. Single-cell gene expression and functional assays identified a subset of JAK2V617F mutant HSCs that display defective self-renewal. This defect is rescued at the single HSC level by crossing JAK2V617F mice with mice lacking TET2, the most commonly comutated gene in patients with MPN. Single cell gene expression profiling of JAK2V617F-mutant HSCs revealed a loss of specific regulator genes, some of which were restored to normal levels in single TET2/JAK2 mutant HSCs. Of these, Bmi1 and, to a lesser extent, Pbx1 and Meis1 overexpression in JAK2-mutant HSCs could drive a disease phenotype and retain durable stem cell self-renewal in functional assays. Together, these single-cell approaches refine the molecules involved in clonal expansion of MPNs and have broad implications for deconstructing the molecular network of normal and malignant stem cells. PMID- 29991557 TI - Glutamine via alpha-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. AB - During erythroid differentiation, the erythron must remodel its protein constituents so that the mature red cell contains hemoglobin as the chief cytoplasmic protein component. For this, ~109 molecules of heme must be synthesized, consuming 1010 molecules of succinyl-CoA. It has long been assumed that the source of succinyl-coenzyme A (CoA) for heme synthesis in all cell types is the tricarboxylic acid (TCA) cycle. Based upon the observation that 1 subunit of succinyl-CoA synthetase (SCS) physically interacts with the first enzyme of heme synthesis (5-aminolevulinate synthase 2, ALAS2) in erythroid cells, it has been posited that succinyl-CoA for ALA synthesis is provided by the adenosine triphosphate-dependent reverse SCS reaction. We have now demonstrated that this is not the manner by which developing erythroid cells provide succinyl-CoA for ALA synthesis. Instead, during late stages of erythropoiesis, cellular metabolism is remodeled so that glutamine is the precursor for ALA following deamination to alpha-ketoglutarate and conversion to succinyl-CoA by alpha-ketoglutarate dehydrogenase (KDH) without equilibration or passage through the TCA cycle. This may be facilitated by a direct interaction between ALAS2 and KDH. Succinate is not an effective precursor for heme, indicating that the SCS reverse reaction does not play a role in providing succinyl-CoA for heme synthesis. Inhibition of succinate dehydrogenase by itaconate, which has been shown in macrophages to dramatically increase the concentration of intracellular succinate, does not stimulate heme synthesis as might be anticipated, but actually inhibits hemoglobinization during late erythropoiesis. PMID- 29991558 TI - Familial risks of acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms. PMID- 29991559 TI - Peritoneal Dialysis: Turning Choice Into Reality. AB - BACKGROUND: Peritoneal dialysis (PD) utilization rates vary widely between UK renal centers. Currently there are only limited data available on how many patients choose PD but subsequently fail to start their chosen modality. In the current analysis we sought to explore the outcomes of patients who chose PD in our center where all PD catheters are inserted via a mini-laparotomy with no acute-start PD service. METHODS: We retrospectively analyzed the outcomes of 658 patients over a 12-year period who, following predialysis education had chosen PD as their preferred renal replacement therapy (RRT) modality. Data were collected on patient demographics, start modality, transplantation, patient survival, and the reasons patients failed to start PD. RESULTS: Predialysis education was given to 2,749 patients, and 658 (24%) chose PD. Of the 566 (86%) who either started RRT or died, less than half started PD (n = 273, 48%). The commonest reason to start hemodialysis (HD) was an acute decline in kidney function leading to an effective 'unplanned' start on RRT. As a result, despite adjusting for older age and higher comorbidity, the transplant-censored survival at 3 years from the time of start of RRT was predictably worse in patients starting HD. Less than half the patients who started HD went on to commence PD later. CONCLUSION: Unanticipated decline in kidney function leading to unplanned start on HD contributes to the worse outcomes associated with failing to start PD. How and when we insert PD catheters appears to be key, and we have identified ways to improve our service. PMID- 29991560 TI - A LONGITUDINAL STUDY ON THE PREVALENCE AND RISK FACTORS FOR DEPRESSION AND ANXIETY, QUALITY OF LIFE, AND CLINICAL OUTCOMES IN INCIDENT PERITONEAL DIALYSIS PATIENTS. AB - BACKGROUND: Starting dialysis is an important life event. The prevalence and evolution of psychological symptoms at commencement of long-term dialysis is unclear. We examined the prevalence of and risk factors for depression and anxiety, and the quality of life (QOL) of incident peritoneal dialysis (PD) patients, and also the change of these parameters in the first year of PD in relation to clinical outcomes under the PD-first policy. METHODS: All patients commencing long-term PD from March 2011 to April 2015 were asked to complete the Hospital Anxiety and Depression Scale (HADS), World Health Organization Quality of Life-BREF and the Kidney Disease Quality of Life Instrument Short Form questionnaire. Patient demographics and the incidence of hospitalization, peritonitis, exit-site infection, and all-cause mortality were studied. The HADS was repeated after 9 - 12 months. RESULTS: A high depression score was present in 39.6% of 191 patients at commencement of PD and was more common in diabetes patients (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.09 - 3.81). A high anxiety score was present in 23.6%, and the risk factors included younger age (OR 0.96 per year, 95% CI 0.94 - 0.99) and diabetes (OR 2.59, 95% CI 1.20 - 5.57). Both high depression and anxiety scores were associated with an inferior QOL, overall and across most QOL domains. Depression and anxiety symptoms did not change in the first year of PD and were not associated with short-term clinical outcomes. CONCLUSIONS: High depression and anxiety scores were prevalent in incident PD patients where PD-first policy is adopted and were associated with inferior QOL. There was no improvement after 1 year of PD. The impact of strategic interventions targeting patient groups at risk such as those with diabetes or of younger age warrants further investigation. PMID- 29991561 TI - SURGICAL TREATMENT FOR ENCAPSULATING PERITONEAL SCLEROSIS: 24 YEARS' EXPERIENCE. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a serious complication of long-term peritoneal dialysis. The mortality rate for EPS is high, primarily due to complications related to bowel obstruction. Surgery was previously contraindicated; however, surgical enterolysis is performed for patients in whom bowel obstruction fails to improve. METHODS: This was a retrospective observational study of patients with EPS who received surgical intervention at a single center between November 1993 and October 2017. The severity of intestine damage was characterized by grade-3 peritoneal calcification on abdominal computed tomography (CT) scan and degeneration of the small intestinal wall in surgery. RESULTS: Two-hundred and forty-three patients with EPS opted for surgery. Among them, 58 had recurrence and required re-surgery; a total of 318 EPS surgeries were performed. Death was related to EPS in 61 patients (25.1%), of whom 15 died postoperatively. Sixty-seven patients (27.6%) died from other causes. The actuarial survival rates at 1, 2, 3, 5, and 8 years after EPS diagnosis were 91%, 83%, 77%, 66%, and 53% respectively. The 50% actuarial survival points after EPS diagnosis and surgery were 104 months and 85 months, respectively. Peritoneal calcification and small intestinal wall degeneration grading showed significant association with the mortality curve for EPS-related death. CONCLUSION: Excellent outcomes for EPS are achieved with surgery. The degree of peritoneal deterioration affected the clinical outcomes. Currently, EPS is no longer recognized as a fatal complication. PMID- 29991562 TI - Stability of Meropenem and Piperacillin/Tazobactam with Heparin in Various Peritoneal Dialysis Solutions. AB - BACKGROUND: Infections caused by ceftazidime-resistant Pseudomonas and extended spectrum beta-lactamase (ESBL)-producing gram-negative bacteria are increasing worldwide. Meropenem and piperacillin/tazobactam (PIP/TZB) are recommended for the treatment of peritoneal dialysis-associated peritonitis (PDAP) caused by ceftazidime-resistant Pseudomonas and other resistant gram-negative bacteria. Patients may also receive intraperitoneal heparin to prevent occlusion of their catheters. However, the stability of meropenem or PIP/TZB, in combination with heparin, in different types of peritoneal dialysis (PD) solutions used in clinical practice is currently unknown. Therefore, we investigated the stability of meropenem and PIP/TZB, each in combination with heparin, in different PD solutions. METHODS: A total of 15 PD bags (3 bags for each type of PD solution) containing meropenem and heparin and 24 PD bags (3 bags for each type of PD solution) containing PIP/TZB and heparin were prepared and stored at 4 degrees C for 168 hours. The same bags were stored at 25 degrees C for 3 hours followed by 10 hours at 37 degrees C. An aliquot withdrawn before storage and at defined time points was analyzed for the concentration of meropenem, PIP, TZB, and heparin using high-performance liquid chromatography. Samples were also analysed for particle content, pH and color change, and the anticoagulant activity of heparin. RESULTS: Meropenem and heparin retained more than 90% of their initial concentration in 4 out of 5 types of PD solutions when stored at 4 degrees C for 168 hours, followed by storage at 25 degrees C for 3 hours and then at 37 degrees C for 10 hours. Piperacillin/tazobactam and heparin were found to be stable in all 8 types of PD solutions when stored under the same conditions. Heparin retained more than 98% of its initial anticoagulant activity throughout the study period. No evidence of particle formation, color change, or pH change was observed at any time under the storage conditions employed in the study. CONCLUSIONS: This study provides clinically important information on the stability of meropenem and PIP/TZB, each in combination with heparin, in different PD solutions. The use of meropenem-heparin admixed in pH-neutral PD solutions for the treatment of PDAP should be avoided, given the observed suboptimal stability of meropenem. PMID- 29991563 TI - Correction: Femoral bone perfusion through the nutrient foramen during growth and locomotor development of western grey kangaroos (Macropus fuliginosus) (doi: 10.1242/jeb.168625). PMID- 29991565 TI - How to use FDA drug approval documents for evidence syntheses. PMID- 29991564 TI - A temporally dynamic Foxp3 autoregulatory transcriptional circuit controls the effector Treg programme. AB - Regulatory T cells (Treg) are negative regulators of the immune response; however, it is poorly understood whether and how Foxp3 transcription is induced and regulated in the periphery during T-cell responses. Using Foxp3-Timer of cell kinetics and activity (Tocky) mice, which report real-time Foxp3 expression, we show that the flux of new Foxp3 expressors and the rate of Foxp3 transcription are increased during inflammation. These persistent dynamics of Foxp3 transcription determine the effector Treg programme and are dependent on a Foxp3 autoregulatory transcriptional circuit. Persistent Foxp3 transcriptional activity controls the expression of coinhibitory molecules, including CTLA-4 and effector Treg signature genes. Using RNA-seq, we identify two groups of surface proteins based on their relationship to the temporal dynamics of Foxp3 transcription, and we show proof of principle for the manipulation of Foxp3 dynamics by immunotherapy: new Foxp3 flux is promoted by anti-TNFRII antibody, and high frequency Foxp3 expressors are targeted by anti-OX40 antibody. Collectively, our study dissects time-dependent mechanisms behind Foxp3-driven T-cell regulation and establishes the Foxp3-Tocky system as a tool to investigate the mechanisms behind T-cell immunotherapies. PMID- 29991566 TI - Maternal low protein diet programmes low ovarian reserve in offspring. AB - The ovarian reserve of primordial follicle oocytes is formed during in utero development and represents the entire supply of oocytes available to sustain female fertility. Maternal undernutrition during pregnancy and lactation diminishes offspring ovarian reserve in rats. In mice, maternal oocyte maturation is also susceptible to undernutrition, causing impaired offspring cardiovascular function. We aimed to determine whether programming of the ovarian reserve is impacted in offspring when maternal undernutrition extends from preconception oocyte development through to weaning. C57BL6/J female mice were fed normal protein (20%) or low protein (8%) diet during preconception, pregnancy and lactation periods. Maternal ovaries were harvested at weaning and offspring ovaries collected at postnatal day (PN)21 and 24 weeks of age. Total follicle estimates were obtained by histologically sampling one ovary per animal (n=5/group). There was no impact of diet on maternal follicle numbers. However, in offspring, maternal protein restriction significantly depleted primordial follicles by 37% at PN21 and 51% at 24 weeks (p<0.05). There were no effects of diet on other follicle classes. Histological analysis showed no differences in the proportion of proliferative follicles (pH3-positive), but increased atresia (cleaved caspase-3-positive, or TUNEL-positive) was detected in ovaries of protein-restricted offspring at both ages (p<0.05). Our data show that maternal diet during the preconception period, in utero development and early life has significant impacts on follicle endowment and markers of follicle health later in life. This highlights the need for further investigation into the importance of maternal preconception diet for offspring reproductive development and health. PMID- 29991567 TI - Dynamic changes in gene expression and signalling during trophoblast development in the horse. AB - Equine chorionic girdle trophoblast cells play important endocrine and immune functions critical in supporting pregnancy. Very little is known about the genes and pathways that regulate chorionic girdle trophoblast development. Our aim was to identify genes and signalling pathways active in vivo in equine chorionic girdle trophoblast within a critical 7 days window. We exploited the late implantation of the equine conceptus to obtain trophoblast tissue. An Agilent equine 44K microarray was performed using RNA extracted from Chorionic Girdle and Chorion (control) from equine pregnancy days 27, 30, 31 and 34 (n=5), corresponding to the initiation of chorionic girdle trophoblast proliferation, differentiation and migration. Data was analysed using R packages limma and maSigPro, Ingenuity Pathway Analysis and DAVID and verified using qRT-PCR, promoter analysis, western blotting and migration assays. Microarray analysis showed gene expression (absolute log FC > 2, FDR-adjusted P<0.05) was rapidly and specifically induced in the chorionic girdle between days 27 and 34 (compared to day 27, day 30=116, day 31=317, day 34=781 genes). Pathway analysis identified 35 pathways modulated during chorionic girdle development (e.g. FGF, Integrin, Rho GTPases, MAPK) including pathways that have limited description in mammalian trophoblast (e.g. IL-9, CD40 and CD28 signalling). Rho A and ERK/MAPK activity was confirmed as was a role for transcription factor ELF5 in regulation of the CGB promoter. The purity and accessibility of chorionic girdle trophoblast proved to be a powerful resource to identify candidate genes and pathways involved in early equine placental development. PMID- 29991568 TI - THE ROLE OF INTRAGESTATIONAL GHRELIN ON POSTNATAL DEVELOPMENT AND REPRODUCTIVE PROGRAMMING IN MICE. AB - The purpose of this study was to evaluate the intragestational role of ghrelin in offspring development and reproductive programming in a mouse model of ghrelin imbalance during pregnancy. Female mice were injected with ghrelin (supraphysiological levels: 4 nmol/animal/day), antagonist (endogenous ghrelin inhibition with (D-Lys3)GHRP-6, 6 nmol/animal/day) or vehicle (control=normal ghrelin levels) throughout the pregnancy. Parameters evaluated in litters were growth, physical, neurobiological, and sexual development and, at adulthood, reproductive function. Litter size and initial weight did not vary between treatments. Male pups from dams treated with ghrelin showed higher body weight increase until adulthood (31.7+/-0.8 vs control=29.7+/-0.7, n=11-14 litters/treatment; p<0.05). Postnatal physical and neurobiological development were not modified by treatments. The antagonist accelerated male puberty onset, evidenced as earlier testis descent and increased relative testicular weight (antagonist=0.5+/-0.0% vs ghrelin=0.4+/-0.0% and control=0.4+/-0.0%, n=5-10 litters/treatment; p<0.05). At adulthood, these males exhibited lower relative testicular weight and reduced sperm motility (63.9+/-3.6% vs control=70.9+/-3.3 and ghrelin=75.6+/-3.0, n=13-15 animals; p<0.05), without changes in plasma testosterone or fertility. Female pups intragestationally exposed to the antagonist showed earlier vaginal opening (statistically significant only at day 25) and higher ovarian volume (antagonist=1085.7+/-64.0mm3 vs ghrelin=663.3+/ 102.8mm3 and control=512.3+/-116.4mm3; n=4-6 animals/treatment; p<0.05), indicating earlier sexual maturation. At adulthood, these females and those exposed to ghrelin showed a tendency to higher percentages of embryo loss and/or foetal atrophy. In conclusion, ghrelin participates in reproductive foetal programming: alterations in ghrelin activity during pregnancy modified body weight increase and anticipated puberty onset, exerting (or tending to) negative effects on adult reproductive function. PMID- 29991570 TI - Do the associations of sedentary behaviour with cardiovascular disease mortality and cancer mortality differ by physical activity level? A systematic review and harmonised meta-analysis of data from 850 060 participants. AB - OBJECTIVE: To examine whether the associations between sedentary behaviours (ie, daily sitting/TV-viewing time) and mortality from cardiovascular disease (CVD) and cancer differ by different levels of physical activity (PA). DESIGN: Harmonised meta-analysis of prospective cohort studies. Data on exposure variables were harmonised according to a predefined protocol and categorised into four groups for sedentary behaviours and into quartiles of PA (MET-hour/week). DATA SOURCES: PubMed, PsycINFO, Embase, Web of Science, Sport Discus and Scopus. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Individual level data on both sedentary behaviours and PA and reported effect estimates for CVD or cancer mortality. RESULTS: Nine studies (n=850 060; deaths=25 730) and eight studies (n=777 696; deaths=30 851) provided data on sitting time and CVD and cancer mortality, respectively. Five studies had data on TV-viewing time and CVD (n=458 127; deaths=13 230) and cancer (n=458 091; deaths=16 430) mortality. A dose response association between sitting time (9%-32% higher risk; p for trend <0.001) and TV time (3%-59% higher risk; p for trend <0.001) with CVD mortality was observed in the 'inactive', lowest quartile of PA. Associations were less consistent in the second and third quartiles of PA, and there was no increased risk for CVD mortality with increasing sedentary behaviours in the most active quartile. Associations between sedentary behaviours and cancer mortality were generally weaker; 6%-21% higher risk with longer sitting time observed only in the lowest quartile of PA. CONCLUSION: PA modifies the associations between sedentary behaviours and CVD and cancer mortality. These findings emphasise the importance of higher volumes of moderate and vigorous activity to reduce, or even eliminate these risks, especially for those who sit a lot in their daily lives. PMID- 29991571 TI - Importance of both increasing physical activity and reducing sitting time. PMID- 29991572 TI - Sitting behaviour and physical activity: two sides of the same cardiovascular health coin? PMID- 29991569 TI - Metabolic traits of cancer stem cells. AB - Cancer stem cells are a subpopulation of cells within a tumour believed to confer resistance to standard cancer therapies. Although many studies have addressed the specific mechanisms of tumour recurrence driven by cancer stem cells, cellular metabolism is an often-neglected attribute. The metabolic features of cancer stem cells are still poorly understood, and they thus constitute a promising field in cancer research. The findings published so far point to a distinct metabolic phenotype in cancer stem cells, which might depend on the cancer type, the model system used or even the experimental design, and several controversies still need to be tackled. This Review describes the metabolic phenotype of cancer stem cells by addressing the main metabolic traits in different tumours, including glycolysis and oxidative, glutamine, fatty acid and amino acid metabolism. In the context of these pathways, we also mention the specific alterations in metabolic enzymes and metabolite levels that have a role in the regulation of cancer stemness. Determining the role of metabolism in supporting resistance to therapy driven by cancer stem cells can raise the opportunity for novel therapeutic targets, which might not only eliminate this resistant population, but, more importantly, eradicate the whole tumour in a relapse-free scenario. PMID- 29991573 TI - Opinion: Offshore aquaculture in the United States: Untapped potential in need of smart policy. PMID- 29991575 TI - Comparison of Antifungal Azole Interactions with Adult Cytochrome P450 3A4 versus Neonatal Cytochrome P450 3A7. AB - Adult drug metabolism is dominated by cytochrome P450 3A4 (CYP3A4), which is often inhibited by antifungal azole drugs, resulting in potential alterations in drug metabolism and adverse drug/drug interactions. In the fetal and neonatal stages of life, the 87% identical cytochrome P450 3A7 (CYP3A7) is expressed but not CYP3A4. Azole antifungals developed for adults are also used in neonates, assuming they interact similarly with both enzymes, but systematic information is lacking. Herein a method was developed for generating recombinant purified CYP3A7. Thirteen different azoles were then evaluated for binding and inhibition of purified human CYP3A4 versus CYP3A7. All imidazole-containing azoles bound both enzymes via coordination to the heme iron and inhibited both with IC50 values ranging from 180 nM for clotrimazole to the millimolar range for imidazole itself. Across this wide range of potencies, CYP3A4 was consistently inhibited more strongly than CYP3A7, with clotrimazole being the least selective (1.5-fold) inhibitor and econazole the most selective (12-fold). Observations for 1,2,4 triazole-containing azoles were more varied. Most bound to CYP3A4 via coordination to the heme iron, but several also demonstrated evidence of a distinct binding mode at low concentrations. However, only posaconazole inhibited CYP3A4. Of the triazoles, only posaconazole inhibited CYP3A7, again less potently than CYP3A4. Spectral evidence for binding was weak or nonexistent for all triazoles. Overall, although the details of binding interactions do vary, the same azole compounds inhibit both enzymes, albeit with weaker interactions with CYP3A7 compared with CYP3A4. PMID- 29991576 TI - Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis. AB - Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-alpha inhibitors. CYP3A4 phenotype was measured as serum concentration of 4beta hydroxycholesterol (4betaOHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF-alpha inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon gamma, interleukin (IL)-1beta, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF-alpha Correlations between levels of cytokines and 4betaOHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF-alpha inhibitors: i.e., IL-1ra (r = 0.408, P = 0.023), IL-6 (r = -0.410, P = 0.022) and CXCL8 (r = -0.403, P = 0.025) (P >= 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF-alpha inhibitor treatment (P > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations. PMID- 29991577 TI - Eighteen-year-old man with autism, obsessive compulsive disorder and a SHANK2 variant presents with severe anorexia that responds to high-dose fluoxetine. AB - The SHANK2 gene codes for a protein involved in organising the postsynaptic density and disruptions have been associated with autism spectrum disorders (ASDs). ASDs are frequently comorbid with intellectual disability and anxiety disorders and emerging evidence suggests potentially common aetiologies. Here, we report the case of an 18-year-old man with ASD who presented with severe anorexia due to fear of food contamination, food avoidance and stereotypies attributable to underlying obsessive compulsive disorder (OCD). The patient was found to be heterozygous for c.2518C>T (p.Pro840Ser), a likely damaging coding variant in the proline rich region of SHANK2 Interestingly, the patient's disordered eating behaviour began to improve only after high-dose fluoxetine was initiated to target OCD symptoms. Overall, this case highlights the utility of molecular genetic testing in clinical psychiatry and provides an example of how genetic information can inform clinicians in the treatment of complex neuropsychiatric syndromes. PMID- 29991578 TI - Sex-Specific Association between Family History of Diabetes and Risk of Colorectal Cancer: Two Prospective Cohort Studies. AB - Type 2 diabetes (T2D) is associated with increased risk of colorectal cancer. It remains unclear whether family history of diabetes influences colorectal cancer risk and relevant biomarkers. We followed 101,323 women from the Nurses' Health Study (1982-2012) and 48,542 men from the Health Professionals Follow-up Study (1988-2012), free of cancer and inflammatory bowel disease at baseline. Participants reported whether any of their first-degree family members ever had diabetes in multiple questionnaires administered biennially. Plasma levels of colorectal cancer-related biomarkers were measured in subsets of participants from previous nested case-control studies. We documented 1,950 colorectal cancer cases in women and 1,173 colorectal cancer cases in men. After adjustment for potential confounders including obesity and diabetes, the hazard ratio (HR) for colorectal cancer among men who had family history of diabetes was 1.19 [95% confidence interval (CI), 1.04-1.36) as compared with those who did not. The corresponding HR was 1.06 among women (95% CI, 0.96-1.17). Interestingly, for individuals younger than 60 years, these associations appeared stronger among men (HR, 1.65; 95% CI, 1.15-2.38) and possibly among women (HR, 1.23; 95% CI, 0.99 1.54). Moreover, family history of diabetes was related to reduced levels of estradiol, sex hormone binding globulin (SHBG), and adiponectin in men, with a greater reduction of SHBG for those younger than 60 years (P for interaction = 0.03). In conclusion, family history of diabetes was associated with increased colorectal cancer risk in men, which may be partly mediated by altered sex hormones and adiponectin. The possible positive association in younger women needs further confirmation. Cancer Prev Res; 11(9); 535-44. (c)2018 AACR. PMID- 29991579 TI - Detection and Genotyping of HPV DNA in a Group of Unvaccinated Young Women from Colombia: Baseline Measures Prior to Future Monitoring Program. AB - In 2012, Colombia launched human papillomavirus (HPV) vaccination program for girls ages 9 to 12, and in 2013, the target age was expanded to 9 to 17 years. Monitoring the changes of HPV infection prevalence among young women has been proposed as an endpoint for early assessment of HPV vaccination programs. However, the data on HPV prevalence in young ages are very limited. The purpose of this study was to determine the prevalence of HPV infection and the distribution of genotypes in a group of nonvaccinated women ages 18 to 25 years old in three Colombian cities as baseline for the monitoring of the HPV national vaccination program. A total of 1,782 sexually active women were included. Cervical smear samples were collected to perform the Pap smear and HPV DNA detection using a Linear Array HPV assay. Of the 1,782 specimens analyzed, 60.3% were positive for any HPV type; 42.2% were positive for high-risk HPV (HR-HVP) types, and 44.4% for low-risk HPV (LR-HPV) types. Multiple and single infections were identified in 37.1% and 23.2% of samples, respectively. HR-HPV types -16, 52, and -51 were the most predominant with proportions of 11.3%, 7.92%, and 7.9%, correspondingly. The prevalence for HR-HPV 16/18 was 14.4%. HR-HPV prevalence in women with abnormal cytology (75.16%) was higher than in women with normal cytology (38.6%). In conclusion, a high prevalence of HR-HPV was observed among younger women. This HPV type-specific prevalence baseline may be used to monitor postvaccination longitudinal changes and to determine its impact on HPV-related disease incidence in Colombia population. Cancer Prev Res; 11(9); 581-92. (c)2018 AACR. PMID- 29991580 TI - High Growth Rate of Pancreatic Ductal Adenocarcinoma in CDKN2A-p16-Leiden Mutation Carriers. AB - CDKN2A-p16-Leiden mutation carriers have a 20% to 25% risk of developing pancreatic ductal adenocarcinoma (PDAC). Better understanding of the natural course of PDAC might allow the surveillance protocol to be improved. The aims of the study were to evaluate the role of cystic precursor lesions in the development of PDAC and to assess the growth rate. In 2000, a surveillance program was initiated, consisting of annual MRI in carriers of a CDKN2A-p16 Leiden mutation. The study cohort included 204 (42% male) patients. Cystic precursor lesions were found in 52 (25%) of 204 mutation carriers. Five (9.7%) of 52 mutation carriers with cystic lesions and 8 (7.0%) of 114 mutation carriers without cystic lesions developed PDAC (P = 0.56). Three of 6 patients with a cystic lesion of >=10 mm developed PDAC. The median size of all incident PDAC detected between 9 and 12 months since the previous normal MRI was 15 mm, suggesting an annual growth rate of about 15 mm/year. In conclusion, our findings show that patients with and without a cystic lesions have a similar risk of PDAC. However, cystic precursor lesions between 10 and 20 mm increase the risk of PDAC substantially. In view of the large size of the screen-detected tumors, a shorter interval of screening might be recommended for all patients. Cancer Prev Res; 11(9); 551-6. (c)2018 AACR. PMID- 29991581 TI - Correction to "Systems Pharmacological Analysis of Paclitaxel-Mediated Tumor Priming that Enhances Nanocarrier Deposition and Efficacy". PMID- 29991582 TI - Ligand-Mediated Biofilm Formation via Enhanced Physical Interaction between a Diguanylate Cyclase and Its Receptor. AB - The bacterial intracellular second messenger, cyclic dimeric GMP (c-di-GMP), regulates biofilm formation for many bacteria. The binding of c-di-GMP by the inner membrane protein LapD controls biofilm formation, and the LapD receptor is central to a complex network of c-di-GMP-mediated biofilm formation. In this study, we examine how c-di-GMP signaling specificity by a diguanylate cyclase (DGC), GcbC, is achieved via interactions with the LapD receptor and by small ligand sensing via GcbC's calcium channel chemotaxis (CACHE) domain. We provide evidence that biofilm formation is stimulated by the environmentally relevant organic acid citrate (and a related compound, isocitrate) in a GcbC-dependent manner through enhanced GcbC-LapD interaction, which results in increased LapA localization to the cell surface. Furthermore, GcbC shows little ability to synthesize c-di-GMP in isolation. However, when LapD is present, GcbC activity is significantly enhanced (~8-fold), indicating that engaging the LapD receptor stimulates the activity of this DGC; citrate-enhanced GcbC-LapD interaction further stimulates c-di-GMP synthesis. We propose that the I-site of GcbC serves two roles beyond allosteric control of this enzyme: promoting GcbC-LapD interaction and stabilizing the active conformation of GcbC in the GcbC-LapD complex. Finally, given that LapD can interact with a dozen different DGCs of Pseudomonas fluorescens, many of which have ligand-binding domains, the ligand mediated enhanced signaling via LapD-GcbC interaction described here is likely a conserved mechanism of signaling in this network. Consistent with this idea, we identify a second example of ligand-mediated enhancement of DGC-LapD interaction that promotes biofilm formation.IMPORTANCE In many bacteria, dozens of enzymes produce the dinucleotide signal c-di-GMP; however, it is unclear how undesired cross talk is mitigated in the context of this soluble signal and how c-di-GMP signaling is regulated by environmental inputs. We demonstrate that GcbC, a DGC, shows little ability to synthesize c-di-GMP in the absence of its cognate receptor LapD; GcbC-LapD interaction enhances c-di-GMP synthesis by GcbC, likely mediated by the I-site of GcbC. We further show evidence for a ligand-mediated mechanism of signaling specificity via increased physical interaction of a DGC with its cognate receptor. We envision a scenario wherein a "cloud" of weakly active DGCs can increase their activity by specific interaction with their receptor in response to appropriate environmental signals, concomitantly boosting c-di-GMP production, ligand-specific signaling, and biofilm formation. PMID- 29991583 TI - Geobacter Strains Expressing Poorly Conductive Pili Reveal Constraints on Direct Interspecies Electron Transfer Mechanisms. AB - Cytochrome-to-cytochrome electron transfer and electron transfer along conduits of multiple extracellular magnetite grains are often proposed as strategies for direct interspecies electron transfer (DIET) that do not require electrically conductive pili (e-pili). However, physical evidence for these proposed DIET mechanisms has been lacking. To investigate these possibilities further, we constructed Geobacter metallireducens strain Aro-5, in which the wild-type pilin gene was replaced with the aro-5 pilin gene that was previously shown to yield poorly conductive pili in Geobacter sulfurreducens strain Aro-5. G. metallireducens strain Aro-5 did not reduce Fe(III) oxide and produced only low current densities, phenotypes consistent with expression of poorly conductive pili. Like G. sulfurreducens strain Aro-5, G. metallireducens strain Aro-5 displayed abundant outer surface cytochromes. Cocultures initiated with wild-type G. metallireducens as the electron-donating strain and G. sulfurreducens strain Aro-5 as the electron-accepting strain grew via DIET. However, G. metallireducens Aro-5/G. sulfurreducens wild-type cocultures did not. Cocultures initiated with the Aro-5 strains of both species grew only when amended with granular activated carbon (GAC), a conductive material known to be a conduit for DIET. Magnetite could not substitute for GAC. The inability of the two Aro-5 strains to adapt for DIET in the absence of GAC suggests that there are physical constraints on establishing DIET solely through cytochrome-to-cytochrome electron transfer or along chains of magnetite. The finding that DIET is possible with electron accepting partners that lack highly conductive pili greatly expands the range of potential electron-accepting partners that might participate in DIET.IMPORTANCE DIET is thought to be an important mechanism for interspecies electron exchange in natural anaerobic soils and sediments in which methane is either produced or consumed, as well as in some photosynthetic mats and anaerobic digesters converting organic wastes to methane. Understanding the potential mechanisms for DIET will not only aid in modeling carbon and electron flow in these geochemically significant environments but will also be helpful for interpreting meta-omic data from as-yet-uncultured microbes in DIET-based communities and for designing strategies to promote DIET in anaerobic digesters. The results demonstrate the need to develop a better understanding of the diversity of types of e-pili in the microbial world to identify potential electron-donating partners for DIET. Novel methods for recovering as-yet-uncultivated microorganisms capable of DIET in culture will be needed to further evaluate whether DIET is possible without e-pili in the absence of conductive materials such as GAC. PMID- 29991584 TI - Acinetobacter baumannii Gastrointestinal Colonization Is Facilitated by Secretory IgA Which Is Reductively Dissociated by Bacterial Thioredoxin A. AB - Multidrug-resistant Acinetobacter baumannii is among the most common causes of infectious complications associated with combat-related trauma in military personnel serving overseas. However, little is currently known about its pathogenesis. While the gastrointestinal (GI) tract has been found to be a major reservoir for A. baumannii, as well as to potentially contribute to development of multidrug resistance, no studies have addressed the mechanisms involved in gut colonization. In this study, we address this critical gap in knowledge by first assessing the interaction between secretory IgA (SIgA), the principal humoral immune defense on mucosal surfaces, and the A. baumannii clinical isolate Ci79. Surprisingly, SIgA appeared to enhance A. baumannii GI tract colonization, in a process mediated by bacterial thioredoxin A (TrxA), as evidenced by reduction of bacterial attachment in the presence of TrxA inhibitors. Additionally, a trxA targeted deletion mutant (DeltatrxA) showed reduced bacterial burdens within the GI tract 24 h after oral challenge by in vivo live imaging, along with loss of thiol-reductase activity. Surprisingly, not only was GI tract colonization greatly reduced but the associated 50% lethal dose (LD50) of the DeltatrxA mutant was increased nearly 100-fold in an intraperitoneal sepsis model. These data suggest that TrxA not only mediates A. baumannii GI tract colonization but also may contribute to pathogenesis in A. baumannii sepsis following escape from the GI tract under conditions when the intestinal barrier is compromised, as occurs with cases of severe shock and trauma.IMPORTANCEAcinetobacter baumannii is an emerging bacterial pathogen recently classified as a serious threat to U.S. and global health by both the Centers for Disease Control and Prevention and the World Health Organization. It also is one of the leading causes of combat-related infections associated with injured military personnel serving overseas. Little is known regarding mechanisms of gastrointestinal tract colonization despite this site being shown to serve as a reservoir for multidrug-resistant (MDR) A. baumannii isolates. Here, we establish that secretory IgA, the major immunoglobulin of mucosal surfaces, promotes A. baumannii GI tract colonization via bacterial thioredoxin A as evidenced through significant reduction in colonization in IgA-deficient animals. Additionally, bacterial colonization and mortality were significantly reduced in animals challenged with a thioredoxin A deficient A. baumannii mutant. Combined, these data suggest that thioredoxin A is a novel virulence factor, for which antithioredoxin therapies could be developed, for this important multidrug-resistant pathogen. PMID- 29991585 TI - The Plasmodesmal Localization Signal of TMV MP Is Recognized by Plant Synaptotagmin SYTA. AB - Plant viruses cross the barrier of the plant cell wall by moving through intercellular channels, termed plasmodesmata, to invade their hosts. They accomplish this by encoding movement proteins (MPs), which act to alter plasmodesmal gating. How MPs target to plasmodesmata is not well understood. Our recent characterization of the first plasmodesmal localization signal (PLS) identified in a viral MP, namely, the MP encoded by the Tobamovirus Tobacco mosaic virus (TMV), now provides the opportunity to identify host proteins that recognize this PLS and may be important for its plasmodesmal targeting. One such candidate protein is Arabidopsis synaptotagmin A (SYTA), which is required to form endoplasmic reticulum (ER)-plasma membrane contact sites and regulates the MP-mediated trafficking of begomoviruses, tobamoviruses, and potyviruses. In particular, SYTA interacts with, and regulates the cell-to-cell transport of, both TMV MP and the MP encoded by the Tobamovirus Turnip vein clearing virus (TVCV). Using in planta bimolecular fluorescence complementation (BiFC) and yeast two-hybrid assays, we show here that the TMV PLS interacted with SYTA. This PLS sequence was both necessary and sufficient for interaction with SYTA, and the plasmodesmal targeting activity of the TMV PLS was substantially reduced in an Arabidopsis syta knockdown line. Our findings show that SYTA is one host factor that can recognize the TMV PLS and suggest that this interaction may stabilize the association of TMV MP with plasmodesmata.IMPORTANCE Plant viruses use their movement proteins (MPs) to move through host intercellular connections, plasmodesmata. Perhaps one of the most intriguing, yet least studied, aspects of this transport is the MP signal sequences and their host recognition factors. Recently, we have described the plasmodesmal localization signal (PLS) of the Tobacco mosaic virus (TMV) MP. Here, we identified the Arabidopsis synaptotagmin A (SYTA) as a host factor that recognizes TMV MP PLS and promotes its association with the plasmodesmal membrane. The significance of these findings is two-fold: (i) we identified the TMV MP association with the cell membrane at plasmodesmata as an important PLS-dependent step in plasmodesmal targeting, and (ii) we identified the plant SYTA protein that specifically recognizes PLS as a host factor involved in this step. PMID- 29991586 TI - Stress-Induced Proliferation and Cell Cycle Plasticity of Intracellular Trypanosoma cruzi Amastigotes. AB - The mammalian stages of the parasite Trypanosoma cruzi, the causative agent of Chagas disease, exhibit a wide host species range and extensive within-host tissue distribution. These features, coupled with the ability of the parasites to persist for the lifetime of the host, suggest an inherent capacity to tolerate changing environments. To examine this potential, we studied proliferation and cell cycle dynamics of intracellular T. cruzi amastigotes experiencing transient metabolic perturbation or drug pressure in the context of an infected mammalian host cell. Parasite growth plasticity was evident and characterized by rapid and reversible suppression of amastigote proliferation in response to exogenous nutrient restriction or exposure to metabolic inhibitors that target glucose metabolism or mitochondrial respiration. In most instances, reduced parasite proliferation was accompanied by the accumulation of amastigote populations in the G1 phase of the cell cycle, in a manner that was rapidly and fully reversible upon release from the metabolic block. Acute amastigote cell cycle changes at the G1 stage were similarly observed following exposure to sublethal concentrations of the first-line therapy drug, benznidazole, and yet, unlike the results seen with inhibitors of metabolism, recovery from exposure occurred at rates inversely proportional to the concentration of benznidazole. Our results show that T. cruzi amastigote growth plasticity is an important aspect of parasite adaptation to stress, including drug pressure, and is an important consideration for growth based drug screening.IMPORTANCE Infection with the intracellular parasite Trypanosoma cruzi can cause debilitating and potentially life-threatening Chagas disease, where long-term parasite persistence is a critical determinant of clinical disease progression. Such tissue-resident T. cruzi amastigotes are refractory to immune-mediated clearance and to drug treatment, suggesting that in addition to exploiting immune avoidance mechanisms, amastigotes can facilitate their survival by adapting flexibly to diverse environmental stressors. We discovered that T. cruzi intracellular amastigotes exhibit growth plasticity as a strategy to adapt to and rebound from environmental stressors, including metabolic blockades, nutrient starvation, and sublethal exposure to the first line therapy drug benznidazole. These findings have important implications for understanding parasite persistence, informing drug development, and interpreting drug efficacy. PMID- 29991587 TI - cAMP Receptor Protein Controls Vibrio cholerae Gene Expression in Response to Host Colonization. AB - The bacterium Vibrio cholerae is native to aquatic environments and can switch lifestyles to cause disease in humans. Lifestyle switching requires modulation of genetic systems for quorum sensing, intestinal colonization, and toxin production. Much of this regulation occurs at the level of gene expression and is controlled by transcription factors. In this work, we have mapped the binding of cAMP receptor protein (CRP) and RNA polymerase across the V. cholerae genome. We show that CRP is an integral component of the regulatory network that controls lifestyle switching. Focusing on a locus necessary for toxin transport, we demonstrate CRP-dependent regulation of gene expression in response to host colonization. Examination of further CRP-targeted genes reveals that this behavior is commonplace. Hence, CRP is a key regulator of many V. cholerae genes in response to lifestyle changes.IMPORTANCE Cholera is an infectious disease that is caused by the bacterium Vibrio cholerae Best known for causing disease in humans, the bacterium is most commonly found in aquatic ecosystems. Hence, humans acquire cholera following ingestion of food or water contaminated with V. cholerae Transition between an aquatic environment and a human host triggers a lifestyle switch that involves reprogramming of V. cholerae gene expression patterns. This process is controlled by a network of transcription factors. In this paper, we show that the cAMP receptor protein (CRP) is a key regulator of V. cholerae gene expression in response to lifestyle changes. PMID- 29991588 TI - HtrA of Borrelia burgdorferi Leads to Decreased Swarm Motility and Decreased Production of Pyruvate. AB - Borrelia burgdorferi HtrA (HtrABb) is a serine protease that targets damaged or improperly folded proteins. In our previous studies, HtrABb specifically degraded basic membrane protein BmpD, chemotaxis phosphatase CheX, and outer membrane protein P66. In addition, HtrABb degrades virulence factor BB0323 and components of the extracellular matrix fibronectin and aggrecan. A proteomics-based analysis (two-dimensional difference gel electrophoresis [2-D DIGE], liquid chromatography mass spectrometry [LC-MS]) of an HtrABb-overexpressing strain of B. burgdorferi (A3HtrAOE) revealed that protein levels of P66 were reduced in comparison to wild type B. burgdorferi, confirming its status as an HtrABb substrate. Hbb, a P66-DNA binding transcription factor, was specifically degraded by HtrABb, providing supportive evidence for a role for both in the regulation of P66. A3HtrAOE exhibited reduced motility in swarm assays, a possible link between overabundance of HtrABb and its enzymatic specificity for P66. However, the DeltaP66 strain did not have reduced motility in the swarm assays, negating a role for this protein. The proteomics analyses also identified three enzymes of the glycolytic pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glycerol-3-phosphate dehydrogenase (GPDH), and glycerol kinase (GK), and one enzyme involved in carbohydrate metabolism, diphosphate-fructose-6-phosphate 1-phosphotransferase, which were reduced in A3HtrAOE. Consistent with its reduced protein levels of these glycolytic enzymes, A3HtrAOE was also deficient in production of pyruvate. We propose a model for a role for HtrABb in contributing to a decrease in metabolic activity of B. burgdorferiIMPORTANCE Being a vector-borne bacterium, B. burgdorferi must remodel its protein content as it transfers from tick to mammal. Proteolysis is a mechanism whereby remodeling can be accomplished. HtrABb degrades a number of proteins whose disappearance may help in preparing this organism for a stage of low metabolic activity. PMID- 29991590 TI - Calcium binding to a remote site can replace magnesium as cofactor for mitochondrial Hsp90 (TRAP1) ATPase activity. AB - The Hsp90 molecular chaperones are ATP-dependent enzymes that maintain protein homeostasis and regulate many essential cellular processes. Higher eukaryotes have organelle-specific Hsp90 paralogs that are adapted to each subcellular environment. The mitochondrial Hsp90, TNF receptor-associated protein 1 (TRAP1), supports the folding and activity of electron transport components and is increasingly appreciated as a critical player in mitochondrial signaling. Calcium plays a well-known and important regulatory role in mitochondria where it can accumulate to much higher concentrations than in the cytoplasm. Surprisingly, we found here that calcium can replace magnesium, the essential enzymatic cofactor, to support TRAP1 ATPase activity. Anomalous X-ray diffraction experiments revealed a calcium-binding site within the TRAP1 nucleotide-binding pocket located near the ATP alpha-phosphate and completely distinct from the magnesium binding site adjacent to the beta- and gamma-phosphates. In the presence of magnesium, ATP hydrolysis by TRAP1, as with other Hsp90s, was noncooperative, whereas calcium binding resulted in cooperative hydrolysis by the two protomers within the Hsp90 dimer. The structural data suggested a mechanism for this cooperative behavior. Because of the cooperativity, at high ATP concentrations, ATPase activity was higher with calcium, whereas the converse was observed at low ATP concentrations. Integrating these observations, we propose a model in which the divalent cation choice can control switching between noncooperative and cooperative TRAP1 ATPase mechanisms in response to varying ATP concentrations. This switching may facilitate coordination between cellular energetics, mitochondrial signaling, and protein homeostasis via alterations in the TRAP1 ATP driven cycle and its consequent effects on different mitochondrial clients. PMID- 29991589 TI - Characterization of the First "Candidatus Nitrotoga" Isolate Reveals Metabolic Versatility and Separate Evolution of Widespread Nitrite-Oxidizing Bacteria. AB - Nitrification is a key process of the biogeochemical nitrogen cycle and of biological wastewater treatment. The second step, nitrite oxidation to nitrate, is catalyzed by phylogenetically diverse, chemolithoautotrophic nitrite-oxidizing bacteria (NOB). Uncultured NOB from the genus "Candidatus Nitrotoga" are widespread in natural and engineered ecosystems. Knowledge about their biology is sparse, because no genomic information and no pure "Ca Nitrotoga" culture was available. Here we obtained the first "Ca Nitrotoga" isolate from activated sludge. This organism, "Candidatus Nitrotoga fabula," prefers higher temperatures (>20 degrees C; optimum, 24 to 28 degrees C) than previous "Ca Nitrotoga" enrichments, which were described as cold-adapted NOB. "Ca Nitrotoga fabula" also showed an unusually high tolerance to nitrite (activity at 30 mM NO2-) and nitrate (up to 25 mM NO3-). Nitrite oxidation followed Michaelis-Menten kinetics, with an apparent Km (Km(app)) of ~89 uM nitrite and a Vmax of ~28 umol of nitrite per mg of protein per h. Key metabolic pathways of "Ca Nitrotoga fabula" were reconstructed from the closed genome. "Ca Nitrotoga fabula" possesses a new type of periplasmic nitrite oxidoreductase belonging to a lineage of mostly uncharacterized proteins. This novel enzyme indicates (i) separate evolution of nitrite oxidation in "Ca Nitrotoga" and other NOB, (ii) the possible existence of phylogenetically diverse, unrecognized NOB, and (iii) together with new metagenomic data, the potential existence of nitrite-oxidizing archaea. For carbon fixation, "Ca Nitrotoga fabula" uses the Calvin-Benson-Bassham cycle. It also carries genes encoding complete pathways for hydrogen and sulfite oxidation, suggesting that alternative energy metabolisms enable "Ca Nitrotoga fabula" to survive nitrite depletion and colonize new niches.IMPORTANCE Nitrite-oxidizing bacteria (NOB) are major players in the biogeochemical nitrogen cycle and critical for wastewater treatment. However, most NOB remain uncultured, and their biology is poorly understood. Here, we obtained the first isolate from the environmentally widespread NOB genus "Candidatus Nitrotoga" and performed a detailed physiological and genomic characterization of this organism ("Candidatus Nitrotoga fabula"). Differences between key phenotypic properties of "Ca Nitrotoga fabula" and those of previously enriched "Ca Nitrotoga" members reveal an unexpectedly broad range of physiological adaptations in this genus. Moreover, genes encoding components of energy metabolisms outside nitrification suggest that "Ca Nitrotoga" are ecologically more flexible than previously anticipated. The identification of a novel nitrite-oxidizing enzyme in "Ca Nitrotoga fabula" expands our picture of the evolutionary history of nitrification and might lead to discoveries of novel nitrite oxidizers. Altogether, this study provides urgently needed insights into the biology of understudied but environmentally and biotechnologically important microorganisms. PMID- 29991591 TI - Template-primer binding affinity and RNase H cleavage specificity contribute to the strand transfer efficiency of HIV-1 reverse transcriptase. AB - During reverse transcription of the HIV-1 genome, two strand-transfer events occur. Both events rely on the RNase H cleavage activity of reverse transcriptases (RTs) and template homology. Using a panel of mutants of HIV-1BH10 (group M/subtype B) and HIV-1ESP49 (group O) RTs and in vitro assays, we demonstrate that there is a strong correlation between RT minus-strand transfer efficiency and template-primer binding affinity. The highest strand transfer efficiencies were obtained with HIV-1ESP49 RT mutants containing the substitutions K358R/A359G/S360A, alone or in combination with V148I or T355A/Q357M. These HIV-1ESP49 RT mutants had been previously engineered to increase their DNA polymerase activity at high temperatures. Now, we found that RTs containing RNase H-inactivating mutations (D443N or E478Q) were devoid of strand transfer activity, whereas enzymes containing F61A or L92P had very low strand transfer activity. The strand transfer defect produced by L92P was attributed to a loss of template-primer binding affinity and, more specifically, to the higher dissociation rate constants (koff) shown by RTs bearing this substitution. Although L92P also deleteriously affected the RT's nontemplated nucleotide addition activity, neither nontemplated nucleotide addition activity nor the RT's clamp activities contributed to increased template switching when all tested mutant and WT RTs were considered. Interestingly, our results also revealed an association between efficient strand transfer and the generation of secondary cleavages in the donor RNA, consistent with the creation of invasion sites. Exposure of the elongated DNA at these sites facilitate acceptor (RNA or DNA) binding and promote template switching. PMID- 29991592 TI - A collagen domain-derived short adiponectin peptide activates APPL1 and AMPK signaling pathways and improves glucose and fatty acid metabolisms. AB - Adiponectin is a fat tissue-derived adipokine with beneficial effects against diabetes, cardiovascular diseases, and cancer. Accordingly, adiponectin-mimetic molecules possess significant pharmacological potential. Oligomeric states of adiponectin appear to determine its biological activity. We identified a highly conserved, 13-residue segment (ADP-1) from adiponectin's collagen domain, which comprises GXXG motifs and has one asparagine and two histidine residues that assist in oligomeric protein assembly. We therefore hypothesized that ADP-1 promotes oligomeric assembly and thereby mediates potential metabolic effects. We observed here that ADP-1 is stable in human serum and oligomerizes in aqueous environments. We also found that ADP-1 activates AMP-activated protein kinase (AMPK) in an adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1)-dependent pathway and stimulates glucose uptake in rat skeletal muscle cells (L6 myotubes). ADP-1-induced glucose transport coincided with ADP-1-induced biosynthesis of glucose transporter 4 and its translocation to the plasma membrane. ADP-1 induced an interaction between APPL1 and the small GTPase Rab5, resulting in AMPK phosphorylation, in turn leading to phosphorylation of p38 mitogen-activated protein kinase (MAPK), acetyl-CoA carboxylase, and peroxisome proliferator-activated receptor alpha. Similar to adiponectin, ADP-1 increased the expression of the adiponectin receptor 1 (AdipoR1) gene. Of note, ADP-1 decreased blood glucose levels and enhanced insulin production in pancreatic beta cells in db/db mice. Further, ADP-1 beneficially affected lipid metabolism by enhancing lipid globule formation in mouse 3T3-L1 adipocytes. To our knowledge, this is the first report on identification of a short peptide from adiponectin with positive effects on glucose or fatty acid metabolism. PMID- 29991593 TI - Minimalism and functionality: Structural lessons from the heterodimeric N4 bacteriophage RNA polymerase II. AB - Genomes of phages, mitochondria, and chloroplasts are transcribed by a diverse group of transcriptional machineries with structurally related single-subunit RNA polymerases (RNAPs). Our understanding of transcription mechanisms of these enzymes is predominantly based on biochemical and structural studies of three most-studied members, transcription factor-independent phage T7 RNAP, transcription factor-dependent phage N4 virion-encapsidated RNAP, and transcription factor-dependent mitochondrial RNAPs (mtRNAP). Although these RNAPs employ completely different mechanisms for promoter recognition and transcription termination, these enzymes are relatively large and formed by single polypeptides. Historically being a model enzyme for studying the mechanisms of transcription by T7-like RNAPs, however, T7 RNAP represents only a small group of RNAPs in this family. The vast majority of T7-like RNAPs are transcription factor dependent, and several of them are heterodimeric enzymes. Here, we report X-ray crystal structures of transcription complexes of the smallest and heterodimeric form of T7-like RNAP, bacteriophage N4 RNAPII, providing insights into the structural organization of a minimum RNAP in this family. We analyze structural and functional aspects of heterodimeric architecture of N4 RNAPII concerning the mechanisms of transcription initiation and transition to processive RNA elongation. Interestingly, N4 RNAPII maintains the same conformation in promoter bound and elongation transcription complexes, revealing a novel transcription mechanism for single-subunit RNAPs. This work establishes a structural basis for studying mechanistic aspects of transcription by factor-dependent minimum RNAP. PMID- 29991594 TI - Kinesin-2 heterodimerization alters entry into a processive run along the microtubule but not stepping within the run. AB - Heterodimeric KIF3AC and KIF3AB, two members of the mammalian kinesin-2 family, generate force for microtubule plus end-directed cargo transport. However, the advantage of heterodimeric kinesins over homodimeric ones is not well-understood. We showed previously that microtubule association for entry into a processive run was similar in rate for KIF3AC and KIF3AB at ~7.0 MUm-1 s-1 Yet, for engineered homodimers of KIF3AA and KIF3BB, this constant is significantly faster at 11 MUm 1 s-1 and much slower for KIF3CC at 2.1 MUm-1 s-1 These results led us to hypothesize that heterodimerization of KIF3A with KIF3C and KIF3A with KIF3B altered the intrinsic catalytic properties of each motor domain. Here, we tested this hypothesis by using presteady-state stopped-flow kinetics and mathematical modeling. Surprisingly, the modeling revealed that the catalytic properties of KIF3A and KIF3B/C were altered upon microtubule binding, yet each motor domain retained its relative intrinsic kinetics for ADP release and subsequent ATP binding and the nucleotide-promoted transitions thereafter. These results are consistent with the interpretation that for KIF3AB, each motor head is catalytically similar and therefore each step is approximately equivalent. In contrast, for KIF3AC the results predict that the processive steps will alternate between a fast step for KIF3A followed by a slow step for KIF3C resulting in asymmetric stepping during a processive run. This study reveals the impact of heterodimerization of the motor polypeptides for microtubule association to start the processive run and the fundamental differences in the motile properties of KIF3C compared with KIF3A and KIF3B. PMID- 29991595 TI - Three SpoA-domain proteins interact in the creation of the flagellar type III secretion system in Helicobacter pylori. AB - Bacterial flagella are rotary nanomachines that contribute to bacterial fitness in many settings, including host colonization. The flagellar motor relies on the multiprotein flagellar motor-switch complex to govern flagellum formation and rotational direction. Different bacteria exhibit great diversity in their flagellar motors. One such variation is exemplified by the motor-switch apparatus of the gastric pathogen Helicobacter pylori, which carries an extra switch protein, FliY, along with the more typical FliG, FliM, and FliN proteins. All switch proteins are needed for normal flagellation and motility in H. pylori, but the molecular mechanism of their assembly is unknown. To fill this gap, we examined the interactions among these proteins. We found that the C-terminal SpoA domain of FliY (FliYC) is critical to flagellation and forms heterodimeric complexes with the FliN and FliM SpoA domains, which are beta-sheet domains of type III secretion system proteins. Surprisingly, unlike in other flagellar switch systems, neither FliY nor FliN self-associated. The crystal structure of the FliYC-FliNC complex revealed a saddle-shaped structure homologous to the FliN FliN dimer of Thermotoga maritima, consistent with a FliY-FliN heterodimer forming the functional unit. Analysis of the FliYC-FliNC interface indicated that oppositely charged residues specific to each protein drive heterodimer formation. Moreover, both FliYC-FliMC and FliYC-FliNC associated with the flagellar regulatory protein FliH, explaining their important roles in flagellation. We conclude that H. pylori uses a FliY-FliN heterodimer instead of a homodimer and creates a switch complex with SpoA domains derived from three distinct proteins. PMID- 29991596 TI - alpha-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies. AB - alpha-Synuclein (alpha-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. alpha-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of alpha-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric alpha-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson's disease patient carrying an alpha-Syn gene duplication. We further show that increased levels of alpha-Syn oligomers disrupt axonal integrity in human neurons. We apply an alpha-Syn oligomerization model by expressing alpha-Syn oligomer-forming mutants (E46K and E57K) and wild-type alpha Syn in human iPSC-derived neurons. Pronounced alpha-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of alpha-Syn oligomer formation. Furthermore, alpha-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of alpha-Syn oligomers. Together, increased dosage of alpha-Syn resulting in alpha Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies alpha-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies. PMID- 29991597 TI - Gradual progression from sensory to task-related processing in cerebral cortex. AB - Somewhere along the cortical hierarchy, behaviorally relevant information is distilled from raw sensory inputs. We examined how this transformation progresses along multiple levels of the hierarchy by comparing neural representations in visual, temporal, parietal, and frontal cortices in monkeys categorizing across three visual domains (shape, motion direction, and color). Representations in visual areas middle temporal (MT) and V4 were tightly linked to external sensory inputs. In contrast, lateral prefrontal cortex (PFC) largely represented the abstracted behavioral relevance of stimuli (task rule, motion category, and color category). Intermediate-level areas, including posterior inferotemporal (PIT), lateral intraparietal (LIP), and frontal eye fields (FEF), exhibited mixed representations. While the distribution of sensory information across areas aligned well with classical functional divisions (MT carried stronger motion information, and V4 and PIT carried stronger color and shape information), categorical abstraction did not, suggesting these areas may participate in different networks for stimulus-driven and cognitive functions. Paralleling these representational differences, the dimensionality of neural population activity decreased progressively from sensory to intermediate to frontal cortex. This shows how raw sensory representations are transformed into behaviorally relevant abstractions and suggests that the dimensionality of neural activity in higher cortical regions may be specific to their current task. PMID- 29991598 TI - Role of sodium channel subtype in action potential generation by neocortical pyramidal neurons. AB - Neocortical pyramidal neurons express several distinct subtypes of voltage-gated Na+ channels. In mature cells, Nav1.6 is the dominant channel subtype in the axon initial segment (AIS) as well as in the nodes of Ranvier. Action potentials (APs) are initiated in the AIS, and it has been proposed that the high excitability of this region is related to the unique characteristics of the Nav1.6 channel. Knockout or loss-of-function mutation of the Scn8a gene is generally lethal early in life because of the importance of this subtype in noncortical regions of the nervous system. Using the Cre/loxP system, we selectively deleted Nav1.6 in excitatory neurons of the forebrain and characterized the excitability of Nav1.6 deficient layer 5 pyramidal neurons by patch-clamp and Na+ and Ca2+ imaging recordings. We now report that, in the absence of Nav1.6 expression, the AIS is occupied by Nav1.2 channels. However, APs are generated in the AIS, and differences in AP propagation to soma and dendrites are minimal. Moreover, the channels that are expressed in the AIS still show a clear hyperpolarizing shift in voltage dependence of activation, compared with somatic channels. The only major difference between Nav1.6-null and wild-type neurons was a strong reduction in persistent sodium current. We propose that the molecular environment of the AIS confers properties on whatever Na channel subtype is present and that some other benefit must be conferred by the selective axonal presence of the Nav1.6 channel. PMID- 29991599 TI - Oscillatory inertial focusing in infinite microchannels. AB - Inertial microfluidics (i.e., migration and focusing of particles in finite Reynolds number microchannel flows) is a passive, precise, and high-throughput method for microparticle manipulation and sorting. Therefore, it has been utilized in numerous biomedical applications including phenotypic cell screening, blood fractionation, and rare-cell isolation. Nonetheless, the applications of this technology have been limited to larger bioparticles such as blood cells, circulating tumor cells, and stem cells, because smaller particles require drastically longer channels for inertial focusing, which increases the pressure requirement and the footprint of the device to the extent that the system becomes unfeasible. Inertial manipulation of smaller bioparticles such as fungi, bacteria, viruses, and other pathogens or blood components such as platelets and exosomes is of significant interest. Here, we show that using oscillatory microfluidics, inertial focusing in practically "infinite channels" can be achieved, allowing for focusing of micron-scale (i.e. hundreds of nanometers) particles. This method enables manipulation of particles at extremely low particle Reynolds number (Rep < 0.005) flows that are otherwise unattainable by steady-flow inertial microfluidics (which has been limited to Rep > ~10-1). Using this technique, we demonstrated that synthetic particles as small as 500 nm and a submicron bacterium, Staphylococcus aureus, can be inertially focused. Furthermore, we characterized the physics of inertial microfluidics in this newly enabled particle size and Rep range using a Peclet-like dimensionless number (alpha). We experimentally observed that alpha >> 1 is required to overcome diffusion and be able to inertially manipulate particles. PMID- 29991600 TI - Separation of circadian- and behavior-driven metabolite rhythms in humans provides a window on peripheral oscillators and metabolism. AB - Misalignment between internal circadian rhythmicity and externally imposed behavioral schedules, such as occurs in shift workers, has been implicated in elevated risk of metabolic disorders. To determine underlying mechanisms, it is essential to assess whether and how peripheral clocks are disturbed during shift work and to what extent this is linked to the central suprachiasmatic nuclei (SCN) pacemaker and/or misaligned behavioral time cues. Investigating rhythms in circulating metabolites as biomarkers of peripheral clock disturbances may offer new insights. We evaluated the impact of misaligned sleep/wake and feeding/fasting cycles on circulating metabolites using a targeted metabolomics approach. Sequential plasma samples obtained during a 24-h constant routine that followed a 3-d simulated night-shift schedule, compared with a simulated day shift schedule, were analyzed for 132 circulating metabolites. Nearly half of these metabolites showed a 24-h rhythmicity under constant routine following either or both simulated shift schedules. However, while traditional markers of the circadian clock in the SCN-melatonin, cortisol, and PER3 expression maintained a stable phase alignment after both schedules, only a few metabolites did the same. Many showed reversed rhythms, lost their rhythms, or showed rhythmicity only under constant routine following the night-shift schedule. Here, 95% of the metabolites with a 24-h rhythmicity showed rhythms that were driven by behavioral time cues externally imposed during the preceding simulated shift schedule rather than being driven by the central SCN circadian clock. Characterization of these metabolite rhythms will provide insight into the underlying mechanisms linking shift work and metabolic disorders. PMID- 29991601 TI - Genome-wide fitness assessment during diurnal growth reveals an expanded role of the cyanobacterial circadian clock protein KaiA. AB - The recurrent pattern of light and darkness generated by Earth's axial rotation has profoundly influenced the evolution of organisms, selecting for both biological mechanisms that respond acutely to environmental changes and circadian clocks that program physiology in anticipation of daily variations. The necessity to integrate environmental responsiveness and circadian programming is exemplified in photosynthetic organisms such as cyanobacteria, which depend on light-driven photochemical processes. The cyanobacterium Synechococcus elongatus PCC 7942 is an excellent model system for dissecting these entwined mechanisms. Its core circadian oscillator, consisting of three proteins, KaiA, KaiB, and KaiC, transmits time-of-day signals to clock-output proteins, which reciprocally regulate global transcription. Research performed under constant light facilitates analysis of intrinsic cycles separately from direct environmental responses but does not provide insight into how these regulatory systems are integrated during light-dark cycles. Thus, we sought to identify genes that are specifically necessary in a day-night environment. We screened a dense bar-coded transposon library in both continuous light and daily cycling conditions and compared the fitness consequences of loss of each nonessential gene in the genome. Although the clock itself is not essential for viability in light-dark cycles, the most detrimental mutations revealed by the screen were those that disrupt KaiA. The screen broadened our understanding of light-dark survival in photosynthetic organisms, identified unforeseen clock-protein interaction dynamics, and reinforced the role of the clock as a negative regulator of a nighttime metabolic program that is essential for S. elongatus to survive in the dark. PMID- 29991602 TI - Solute movement in the t-tubule system of rabbit and mouse cardiomyocytes. AB - Cardiac transverse (t-) tubules carry both electrical excitation and solutes toward the cell center but their ability to transport small molecules is unclear. While fluorescence recovery after photobleaching (FRAP) can provide an approach to measure local solute movement, extraction of diffusion coefficients is confounded by cell and illumination beam geometries. In this study, we use measured cellular geometry and detailed computer modeling to derive the apparent diffusion coefficient of a 1-kDa solute inside the t-tubular system of rabbit and mouse ventricular cardiomyocytes. This approach shows that diffusion within individual t-tubules is more rapid than previously reported. T-tubule tortuosity, varicosities, and the presence of longitudinal elements combine to substantially reduce the apparent rate of solute movement. In steady state, large (>4 kDa) solutes did not freely fill the t-tubule lumen of both species and <50% of the t tubule volume was available to solutes >70 kDa. Detailed model fitting of FRAP data suggests that solute diffusion is additionally restricted at the t-tubular entrance and this effect was larger in mouse than in rabbit. The possible structural basis of this effect was investigated using electron microscopy and tomography. Near the cell surface, mouse t-tubules are more tortuous and filled with an electron-dense ground substance, previously identified as glycocalyx and a polyanionic mesh. Solute movement in the t-tubule network of rabbit and mouse appears to be explained by their different geometric properties, which impacts the use of these species for understanding t-tubule function and the consequences of changes associated with t-tubule disease. PMID- 29991603 TI - Reply to Barnett et al.: Regarding interpretation of Granger causality analyses. PMID- 29991604 TI - Misunderstandings regarding the application of Granger causality in neuroscience. PMID- 29991606 TI - Variations in death notification of nursing home residents to Australian Coroners. AB - OBJECTIVES: To examine the impact of changes to the reporting requirements in coronial legislation on the nature and frequency of nursing home resident deaths reported to Coroners. DESIGN: National retrospective study of a population cohort of nursing home resident deaths. SETTING: Accredited Australian nursing homes between July 2000 and June 2013. PARTICIPANTS: Residents who died in nursing homes accredited by the Aged Care Standards and Accreditation Agency reported to Coroners. MAIN OUTCOME MEASURES: We explored three death-reporting models in the nursing home setting: comprehensive model, selective 'mechanism of death' model and selective 'age of death' model. These models were examined by manner of death subgroups: natural, falls-related and other external causes using the outcome measure of deaths notified to the Coroner per 1000 residents. We used an interrupted time series analysis using generalised linear regression with a negative binomial probability distribution and a log link function. RESULTS: The comprehensive model showed the proportion of reportable deaths due to natural causes far exceeded those from falls and other external cause. In contrast, the selective notification models reduced the total number of reportable deaths. Similarly, the selective 'age of death' model showed a decline in the reportable external cause deaths. CONCLUSIONS: Variation in the causes, locations and ages of persons whose deaths are legally required to be notified to Coroners impacts the frequency and nature of deaths of nursing home residents investigated by Coroners. This demonstrates that legislation needs to be carefully framed and applied to ensure that the prevention mandate of Coroners in Australia is to be achieved. PMID- 29991607 TI - The Impact of a 72-hour Waiting Period on Women's Access to Abortion Care at a Hospital-Based Clinic in North Carolina. AB - BACKGROUND In 2015, North Carolina became the 5th state to pass legislation requiring women to undergo state-mandated counseling 72 hours prior to abortion. Whether this legislation has changed the timing of abortion decision-making or receipt of care is not known.METHODS This is a cross-sectional study using anonymous survey data from women presenting for abortion at a hospital-based abortion clinic in North Carolina. Data were collected for 8 weeks immediately before and after implementation of the new waiting period.RESULTS 26/48 (54%) of eligible patients participated. More than half (56%) of women made their abortion decision relatively quickly (less than or equal to 3 days), but had a median time to-care of almost a week.LIMITATIONS This small study is the 1st recent evaluation of abortion decision-making and receipt of care immediately before and after implementation of a 72-hour waiting period in a Southern state. Only women presenting for care at a single hospital-based clinic were surveyed. Data were self-reported.CONCLUSION In our clinical setting, most women decided to have an abortion quickly but still waited 10-15 days before receiving care. Extended waiting periods provide no medical benefits and the potential for harm and delay of care remains. PMID- 29991605 TI - Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERalphaWT and ERalphaMUT Breast Cancer. AB - Mutations in estrogen receptor alpha (ERalpha) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy resistant breast cancer metastases continue to be dependent on ERalpha signaling, there remains a critical need to develop the next generation of ERalpha antagonists that can overcome aberrant ERalpha activity. Through our drug discovery efforts, we identified H3B-5942, which covalently inactivates both wild type and mutant ERalpha by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERalpha antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERalphaWT and ERalphaMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERalphaWT and ERalphaY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERalphaWT and ERalphaMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERalpha covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERalpha. SERCA H3B-5942 engages C530 of both ERalphaWT and ERalphaMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 1047. PMID- 29991608 TI - Implementation of the North Carolina HIV Bridge Counseling Program to Facilitate Linkage and Reengagement in Care for Individuals Infected with HIV/AIDS. AB - BACKGROUND Statewide interventions are critical to meeting the goals of the National HIV/AIDS Strategy in this country. In 2012, the North Carolina Division of Public Health developed the North Carolina State Bridge Counselor program to improve linkage to and reengagement in care for newly diagnosed persons and persons living with HIV who were out-of-care.METHODS We reviewed the planning process for the North Carolina State Bridge Counselor program, which involved a review of existing strengths-based counseling models for persons living with HIV, implementation of these models, and communication strategies with other providers. State bridge counselor responsibilities were delineated from the role of disease intervention specialists while retaining the fieldwork capability of disease intervention specialists to conduct outreach and provide services for persons living with HIV throughout the state.RESULTS Program implementation required extensive planning with stakeholders, incorporation of strengths-based counseling models, development of performance standards, and utilization of CAREWare, an HIV care software program to document referrals and data-sharing between state bridge counselors and clinics. By the end of 2014, state bridge counselor services were provided to approximately 60 of the 400 persons living with HIV (15%) who are diagnosed each quarter in North Carolina, with increasing utilization of the program.LIMITATIONS We assessed the development of this intervention specific to the North Carolina Division of Public Health, which may limit its generalizability. However, the State Bridge Counselor program was implemented in both urban and rural areas throughout the state, which increases its applicability to different public health programs throughout the country.CONCLUSION We demonstrated that a statewide State Bridge Counselor program for linkage and reengagement activities can be implemented by leveraging existing infrastructures, electronic medical records, HIV care networks, and fieldwork activities. PMID- 29991609 TI - When is a Team a Team? PMID- 29991610 TI - Exploring New Paradigms for Team-Based Care. AB - In this issue of the North Carolina Medical Journal we have focused on team-based care and recognized some of the innovative models of true collaboration aiming to improve patient and population health outcomes. This issue offers examples for integrating care in behavioral health, hospice, and primary care as well as strategies for creating unique partnerships with churches, legal services, and public health workers. We will also explore the role technology plays as a team member and the financial implications of team-based care. PMID- 29991611 TI - Let's Work Together: Interprofessional Training of Health Professionals in North Carolina. AB - Implementation of interprofessional education efforts at Duke University Health System and the University of North Carolina have enhanced teamwork, education, and mentoring for health professional learners and faculty. The IPE initiatives address the critical need for enhanced collaboration among all team members in the evolving health care arena. PMID- 29991612 TI - Is North Carolina's Workforce Prepared for Team-Based Care? AB - Evaluating the capacity of the health workforce to adopt team-based health care delivery models, nationally or in North Carolina, requires a nuanced approach that explores educational and clinical environments, payment, health systems, and regulatory levers. This paper discusses workforce challenges to team-based care and how best to train, prepare, and retool an equipped health workforce to meet the needs of team-based care. PMID- 29991613 TI - Implementing an Integrated Team-Based Model of Care. AB - Team-based methods of delivering primary care were launched nationally within the US Department of Veterans Affairs (VA) through the Patient Aligned Care Teams (PACT) initiative in 2010. The most essential component of PACT is the establishment of partnerships between veterans and their health care teams. The purpose of PACT is to improve and transform the way in which veterans receive health care. This partnership is aimed at promoting efficiency and improving the quality of care and clinical outcomes by providing holistic care that embodies the whole person. PMID- 29991614 TI - Alternative Payment Models and Team-Based Care. AB - Team-based care delivery models offer opportunities to improve quality of care and outcomes for patients, providers, and communities. Because of various barriers, including disincentives in the payment system, team-based care has not reached its potential. This commentary discusses team-based care in the context of emerging value-based payment models and the potential costs of, and opportunities afforded by, these models. PMID- 29991615 TI - Redefining the Team in Team-Based Care: Role of Public Health. AB - In North Carolina, our public health infrastructure consists of a state health department and 85 local health departments representing all 100 counties. The state health department, local health departments, health systems, and clinical providers work literally and figuratively as a team to improve the health of our citizens. In this article, we provide examples of the critical role of public health practitioners as part of the broader team addressing health, specifically in the areas of chronic disease, communicable disease, oral health, environmental health, and maternal and child health. PMID- 29991616 TI - Faith-Based Assets and Multi-Sector Community Teams: Tapping into Deeply Woven Roots. PMID- 29991617 TI - A Model of Enhanced Primary Care for Patients with Severe Mental Illness. AB - Life expectancy and other outcomes for patients with serious mental illness (SMI) are unacceptably poor, largely due to a high prevalence of poorly controlled chronic diseases, high rates of tobacco use, and low rates of preventive care services. Since many of these illnesses are effectively treated in primary care settings, integrating primary care with behavioral health care is necessary to narrow health disparities for patients with SMI. PMID- 29991618 TI - Strategies for Integrating Technology as a Team Member. AB - Interdisciplinary health care teams have numerous opportunities to investigate more efficient health care delivery mechanisms using technology that bridges information science and human-centered care. At the onset of team formation, technology can be strategically integrated to enhance health care delivery for patients and providers using multiple strategies. PMID- 29991619 TI - Primary Care Behavioral Health Integration: Promoting the Quadruple Aim. AB - Chronic medical and common behavioral health conditions have been shown to benefit from team-based care approaches that include integrated behavioral health providers. Team-based integrated care can promote the Quadruple Aim, encompassing health care outcomes, patient satisfaction, provider work/life experience, and the cost of care. PMID- 29991620 TI - The Patient and Family as Part of the Health Care Team. PMID- 29991621 TI - A Team-Based Approach to Delivering Person-Centered Care at the End of Life. AB - The use of team-based models of care is widely regarded as a mechanism for enhancing the delivery of high-quality care, especially at the end of life. Active collaboration to promote effective coordination and delivery of person centered care is an integral part of the team-based model that is the focus of this article. PMID- 29991622 TI - Medical-Legal Partnership in Western North Carolina: Addressing Social Determinants of Health Through Team-Based Care. AB - Having an attorney on a health care team helps address patients' social determinants of health. Through a medical-legal partnership, Pisgah Legal Services provides an attorney embedded within the Mountain Area Health Education Center clinical practices. The attorney impacts the Triple Aim of reducing costs by improving health and the patient experience. PMID- 29991623 TI - Philanthropy Profile: The Cone Health Foundation: Expanding Integrated Care for the Uninsured. PMID- 29991624 TI - Spotlight on the Safety Net: The Mobile Area Health Clinic: Addressing Community Needs Through a Wellness Model. PMID- 29991625 TI - UDAY: A comprehensive diabetes and hypertension prevention and management program in India. AB - INTRODUCTION: Diabetes and hypertension are two leading non-communicable conditions, which are suboptimally managed in India. Thus, innovative comprehensive approaches that can concomitantly improve their detection, prevention and control are warranted. METHODS AND ANALYSIS: UDAY, a 5-year initiative, aims to reduce the risk of diabetes and hypertension and improve management by implementing a comprehensive intervention programme in the two selected study sites, Sonipat and Visakhapatnam (Vizag). It has a pre-post evaluation design with representative cross-sectional surveys before and after intervention. Within these two sites, urban and rural subsites each with a total population of approximately 100 000 people each were selected and a baseline and postintervention assessment was conducted deploying five surveys [among general population (including body measurements or biosamples), patients, healthcare providers including physicians and pharmacists, health facilities], which will determine the knowledge levels about diabetes and hypertension, the proportion treated and controlled; the patient knowledge and self-management skills; healthcare providers' management practices; the level of access and barriers to obtaining care.The interventions will include: tailored health promotion for improving public knowledge; screening of adults aged >= 30 years for identifying those at high risk of diabetes and/or hypertension for linkage to the healthcare system; patient education using technology enabled community health workers, geographic information system (GIS) based mapping of the communities, healthcare provider training on management guidelines, community based diabetes registry and; advocacy to improve access to healthcare. The baseline surveys have been completed, the study areas mapped using GIS and the interventions are being implemented. UDAY is expected to increase over baseline the levels of: public knowledge about diabetes and hypertension; those treated and controlled; patient self-management skills; the use of guideline based management by providers and; access to healthcare, leading to improved health outcomes and inform development of a India relevant chronic care model. ETHICS AND DISSEMINATION: Ethical clearance for conduct of the study was obtained from the Institutional Ethics Committee (IEC) of the Public Health Foundation of India. The findings will be targeted primarily at public health policymakers and advocates, but will be disseminated widely through other mechanisms including conference presentations and peer-reviewed publications, as well as to the participating communities. PMID- 29991626 TI - Emergency volunteering willingness and participation: a cross-sectional survey of residents in northern China. AB - OBJECTIVES: This study aimed to identify factors that influence people's willingness to volunteer and participation in emergency volunteering in northern China. DESIGN/SETTING: This study was conducted in Heilongjiang province in September and October 2014 using a mixed methods approach, which included a cross sectional questionnaire survey on community residents and in-depth interviews with community residents and relevant organisational managers and officials in relation to emergency responses. A stratified cluster sampling strategy was employed to select questionnaire respondents. PARTICIPANTS: 2686 respondents completed the questionnaire survey; 19 key informants were interviewed. PRIMARY AND SECONDARY OUTCOME MEASURES: Willingness to volunteer was the major concern of this study. Self-reported past experience of the participants in emergency volunteering served as a secondary outcome. RESULTS: 65.7% of respondents were willing to volunteer in emergencies. 24.3% of respondents had participated in emergency actions. Higher levels of willingness to volunteer and participation in volunteering were found in those who resided in rural areas (OR=1.308 (1.064 to 1.608) for willingness; OR=1.518 (1.208 to 1.908) for participation), had stronger community attachment (OR=1.720 (1.429 to 2.069) for willingness; OR=1.547 (1.266 to 1.890) for participation), had higher recognition of responsibility (OR=1.981 (1.498 to 2.619) for willingness; OR=1.517 (1.177 to 1.955) for participation), demonstrated preparedness behaviour (OR=1.714 (1.424 to 2.064) for willingness; OR=1.391 (1.151 to 1.681) for participation) and were covered by injury insurance (OR=1.335 (1.102 to 1.619) for willingness; OR=1.822 (1.500 to 2.214) for participation). The in-depth interviews revealed that an inappropriate policy environment and poor volunteer organisational management were major barriers for converting willingness into actions. CONCLUSION: A relatively high level of willingness to volunteer in emergencies in northern China is associated with a range of individual, community and institutional factors. Efforts should be made to translate willingness into effective contributions to the emergency response system. This can be done through improving policies, regulations, coordination mechanisms and volunteer training and support. PMID- 29991627 TI - Detecting concurrent mood in daily contact networks: an online participatory cohort study with a diary approach. AB - OBJECTIVES: This paper examines how people express personal mood concurrently with those connected with them by one or two degrees of separation. DESIGN: Participatory cohort study. SETTING: Online contact diary. PARTICIPANTS: 133 participants kept online diaries for 7 months in 2014, which included 127 455 contacts with 12 070 persons. MAIN OUTCOME MEASURES: Diary keepers rated a contacted person's mood during each specific contact, as well as the strength of ties between any pairs of such contacted persons. Such rich information about ties and contacts enable us to construct a complete contact network for each diary keeper, along with the network members' mood and tie strength. We calculate one's overall mood by that person's average mood score during the study period and take the shortest path between any given pair of contacted persons as the degree of separation. We further assume that two connecting persons in a contact network have made contact with each other during the study period, which allows us to examine whether and how personal moods occur concurrently within these contact networks. RESULTS: Using mixed-effects models while controlling for covariates at individual, tie and contact levels, we show that personal mood score positively and significantly correlates with the average mood among those directly tied to the person. The same effect remains positive and significant for those connected to the person by two degrees, although the effect size is reduced by about one-half. The mood of anyone separated by more than two degrees is statistically irrelevant. CONCLUSIONS: Applying network perspectives and rich data at both tie and contact levels to inquiries about subjective well-being, the current study sheds new light on how an improved diary approach can help explain the sophisticated ways in which individuals express their personal moods concurrently during social interactions in everyday life, contact by contact. PMID- 29991628 TI - Cohort profile: prescriptions dispensed in the community linked to the national cancer registry in England. AB - PURPOSE: The linked prescriptions cancer registry data resource was set up to extend our understanding of the pathway for patients with cancer past secondary care into the community, to ultimately improve patient outcomes. PARTICIPANTS: The linked prescriptions cancer registry data resource is currently available for April to July 2015, for all patients diagnosed with cancer in England with a dispensed prescription in that time frame.The dispensed prescriptions data are collected by National Health Service (NHS) Prescription Services, and the cancer registry data are processed by Public Health England. All data are routine healthcare data, used for secondary purposes, linked using a pseudonymised version of the patient's NHS number and date of birth.Detailed demographic and clinical information on the type of cancer diagnosed and treatment is collected by the cancer registry. The dispensed prescriptions data contain basic demographic information, geography measures of the dispensed prescription, drug information (quantity, strength and presentation), cost of the drug and the date that the dispensed prescription was submitted to NHS Business Services Authority. FINDINGS TO DATE: Findings include a study of end of life prescribing in the community among patients with cancer, an investigation of repeat prescriptions to derive measures of prior morbidity status in patients with cancer and studies of prescription activity surrounding the date of cancer diagnosis. FUTURE PLANS: This English linked resource could be used for cancer epidemiological studies of diagnostic pathways, health outcomes and inequalities; to establish primary care comorbidity indices and for guideline concordance studies of treatment, particularly hormonal therapy, as a major treatment modality for breast and prostate cancer which has been largely delivered in the community setting for a number of years. PMID- 29991629 TI - B Part of It protocol: a cluster randomised controlled trial to assess the impact of 4CMenB vaccine on pharyngeal carriage of Neisseria meningitidis in adolescents. AB - INTRODUCTION: South Australia (SA) has the highest notification rate of invasive meningococcal disease in Australia with the majority of cases due to serogroup B. Neisseria meningitidis is carried in the pharynx, with adolescents having the highest rates of carriage. A vaccine designed to offer protection against serogroup B (4CMenB) is licensed in Australia. The SA MenB vaccine carriage study aims to assess the impact of 4CMenB on carriage of N. meningitidis in adolescents. METHODS AND ANALYSIS: This is a parallel cluster randomised controlled trial enrolling year 10, 11 and 12 school students (approximately 16 18 years of age) throughout SA, in metropolitan and rural/remote areas. Schools are randomised to intervention (4CMenB vaccination at baseline) or control (4CMenB vaccination at study completion) with randomisation stratified by school size and socioeconomic status, as measured by the Index of Community Socio Educational Advantage (Australian Curriculum). Oropharyngeal swabs will be taken from all students at visit 1, and 12 months later from year 11 and 12 students. Students unvaccinated in 2017 will receive vaccine at the 12-month follow-up. Carriage prevalence of N. meningitidis will be determined by PCR at baseline and 12 months following 4CMenB vaccination and compared with carriage prevalence at 12 months in unvaccinated students. A questionnaire will be completed at baseline and 12 months to assess risk factors associated with carriage. The primary outcome of carriage prevalence of disease causing N. meningitidis at 12 months will be compared between groups using logistic regression, with generalised estimating equations used to account for clustering at the school level. The difference in carriage prevalence between groups will be expressed as an OR with 95% CI. ETHICS AND DISSEMINATION: The study was approved by the Women's and Children's Health Network Human Research Ethics Committee (WCHN HREC). The protocol, informed consent forms, recruitment materials, social media and all participant materials have been reviewed and approved by the WCHN HREC and updated on ClinicalTrials.gov. Results will be published in international peer reviewed journals and presented at national and international conferences. The study findings will be provided in public forums and to study participants and participating schools. TRIAL REGISTRATION NUMBER: ACTRN12617000079347. NCT03089086; Pre-results. PMID- 29991630 TI - A retrospective study of the clinical features of new syphilis infections in an HIV-positive cohort in Alberta, Canada. AB - OBJECTIVES: Syphilis is a global health concern with an estimated 12 million infections occurring annually. Due to the increasing rates of new syphilis infections being reported in patients infected with HIV, and their higher risk for atypical and severe presentations, periodic screening has been recommended as a routine component of HIV care. We aimed to characterise incident syphilis presentation, serological features and treatment response in a well-defined, HIV infected population over 11 years. METHODS: Since 2006, as routine practice of both the Southern Alberta Clinic and Calgary STI programmes, syphilis screening has accompanied HIV viral load measures every 4 months. All records of patients who, while in HIV care, either converted from being syphilis seronegative to a confirmed seropositive or were reinfected as evidenced by a fourfold increase in rapid plasma reagin (RPR) after past successful treatment, were reviewed. RESULTS: We identified 249 incident syphilis infections in 194 different individuals infected with HIV; 72% were initial infections whereas 28% were reinfections. Half (50.8%) of the infections were asymptomatic and identified only by routine screening. Symptomatic syphilis was more common when RPR titres were higher (p=0.03). In patients with recurrent syphilis infection, a trend was noted favouring symptomatic presentation (62%, p=0.07). All 10 patients with central nervous system (CNS) syphilis involvement presented with an RPR titre >=1:32. Following syphilis infection, a decline of 42 cells/mm3 in CD4 (p=0.004) was found, but no significant changes in viral load occurred. No association was found with the stage of syphilis or symptoms at presentation and antiretroviral therapy use, CD4 count or virological suppression. CONCLUSION: Routine screening of our HIV-infected population identified many asymptomatic syphilis infections. The interaction of HIV and syphilis infection appears to be bidirectional with effects noted on both HIV and syphilis clinical and serological markers. PMID- 29991631 TI - Clinical and ultrasonographic predictors for achieving minimal disease activity in patients with psoriatic arthritis: the UPSTREAM (Ultrasound in PSoriatic arthritis TREAtMent) prospective observational study protocol. AB - INTRODUCTION: Psoriatic arthritis (PsA) occurs in 10%-15% of people with psoriasis and accounts for 10%-20% of early arthritis clinics referral. Only a few prognostic factors of therapeutic response in patients with PsA have been identified. In the last years, the role of imaging has grown up and the European League Against Rheumatism recognised that ultrasound (US) has higher sensitivity than clinical examination to detect inflammatory disease activity. The aims of the Ultrasound in PSoriatic arthritis TREAtMent (UPSTREAM) study are to integrate clinic and US in order to inform whether US has provide an added prognostic value in PsA. METHODS AND ANALYSIS: UPSTREAM is an observational prospective cohort study enrolling patients with PsA having clinically active joint disease and starting a new course of therapy. The primary objective is to evaluate the additional value of US over clinical examination in detecting patients achieving minimal disease activity after 6 months. Data will be obtained at baseline and at standard clinical follow-up visits. Patient's clinical assessment will be performed according to the core set proposed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis-Outcome Measures in Rheumatology. Sonographic evaluations will be performed by expert sonographers in 42 joints, 36 tendons, 12 entheses and 2 bursae, according to a score that will be purposely developed for PsA by the US Study Group of the Italian Society for Rheumatology. The UPSTREAM study will identify clinical and US predictors of response to treatment in patients with PsA and active peripheral arthritis starting a new course of therapy. ETHICS AND DISSEMINATION: Ethic approval for this study has been obtained from the institutional review board (IRB)/independent ethics committee (IEC) Comitato Etico Lazio 1 (Prot. N 198 02-02-2017) and then locally from the IRB/IEC of each participating centre. Results will be published in relevant scientific journals and be disseminated in international conferences. Fully anonymised data will be accessible from authors upon request. TRIAL REGISTRATION NUMBER: NCT03330769; Pre-results. PMID- 29991632 TI - Association between proprotein convertase subtilisin/kexin type 9 and late saphenous vein graft disease after coronary artery bypass grafting: a cross sectional study. AB - OBJECTIVE: The study aims to explore the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) level and saphenous vein grafts disease (SVGD) after coronary artery bypass grafting (CABG). DESIGN: A cross sectional study. SETTING: A secondary hospital in Tianjin City, China. PARTICIPANTS: A total of 231 participants were included in the study. Inclusion criteria were as follows: age >=18 years, previous CABG surgery at least 12 months ago, at least one SVG for bypass during CABG, abnormal non-invasive test results or recurrent stable angina pectoris by coronary angiography indications, and willing to participate and sign informed consent. Participants with any of the following were excluded from the study: congenital valvular disease, decompensated heart failure, anaemia defined as a haemoglobin level of <12 g/dL in women or <13 g/dL in men, malignant neoplasms, renal failure, severe hepatic disease, thyroid disease, acute or chronic inflammatory disease and chronic obstructive lung disease. PRIMARY OUTCOME MEASURE: SVGD was defined as at least one SVG with significant stenosis (>=50%). Circulating PCSK9 levels were measured using commercial ELISA kits according to the manufacturer's instructions. RESULTS: The mean PCSK9 level in the SVGD group was significantly higher than that in the patent group (275.2+/-38.6 vs 249.3+/-37.7, p<0.01). The multivariate logistic regression model revealed a significant association between serum PCSK9 and SVGD (OR 2.08, 95% CI 1.46-2.95) per 1 SD increase in serum PCSK9. CONCLUSIONS: The present study is the first to identify an independent association between PCSK9 and late SVGD after adjustment for established cardiovascular risk factors. A multicentre prospective cohort study with large sample size should be conducted in the future to further research this relationship. PMID- 29991633 TI - Use of age-specific hospital catchment populations to investigate geographical variation in inpatient admissions for children and young people in England: retrospective, cross-sectional study. AB - OBJECTIVES: To develop a method for calculating age-specific hospital catchment populations (HCPs) for children and young people (CYP) in England. To show how these methods allow geographical variation in hospital activity to be investigated and addressed more effectively. DESIGN: Retrospective, secondary analysis of existing national datasets. SETTING: Inpatient care of CYP (0-18 years) in England. PARTICIPANTS: Hospital Episode Statistics (HES) data were accessed for all inpatient admissions (elective and emergency) for CYP from birth to 18 years, 364 days, for 2011/2012-2014/2015. In 2014/2015, 857 112 admissions were analysed, from an eligible population of approximately 11.9 million CYP. OUTCOME MEASURES: For each hospital Trust, the catchment population of CYP was calculated; Trust-level admission rates per thousand per year were then calculated for admissions due to (1) any diagnostic code, (2) primary diagnosis of epilepsy and (3) epilepsy listed as primary diagnosis or comorbidity. RESULTS: Estimated 2014/2015 HCPs for CYP ranged from 268 558 for Barts Health NHS Trust to around 30 000 for the smallest acute general paediatric services and below 10 000 for many Trusts providing specialist services. As expected, the composition of HCPs was fairly consistent for age breakdown but levels of deprivation varied widely. After standardising for population characteristics, admission rates with a primary diagnosis of epilepsy ranged from 14.3 to 157.7 per 100 000 per year (11.0-fold variation) for Trusts providing acute general paediatric services. All cause admission rates showed less variation, ranging from 4033 to 11 681 per 100 000 per year (2.9-fold variation). CONCLUSIONS: Use of age-specific catchment populations allows variation in hospital activity to be linked to specific teams and care pathways. This provides an evidence base for initiatives to tackle unwarranted variation in healthcare activity and health outcomes. PMID- 29991634 TI - Endovascular treatment for symptomatic intracranial artery stenosis: protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: Atherosclerotic intracranial artery stenosis (ICAS) is one of most common causes of stroke, which is the second-leading cause of death worldwide. Medical, surgical and endovascular therapy are three major treatments for ICAS. Currently, medical therapy is considered as the standard of care for most patients with ICAS, while extracranial to intracranial bypass is only used in rare situations. Balloon angioplasty alone, balloon-mounted stent and self expanding stent, collectively called endovascular treatment, have shown promising potentials in treating specific subgroups of patients with symptomatic ICAS; however, their comparative safety and efficacy is still unclear. Therefore, a systematic review with network meta-analysis is needed to establish a hierarchy of these endovascular treatments. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols was followed to establish this protocol. The search will be limited to studies published from 1 January 2000 to the formal search date. Major databases including Cochrane Library, MEDLINE, EMBASE, Chinese Biomedical Literature Database, conference proceedings and grey literature database will be searched for clinical studies comparing at least two interventions for patients with symptomatic ICAS. Primary outcomes include short-term and long-term mortality or stroke rate. Random effects pairwise and network meta-analyses of included studies will be performed on STATA (V.14, StataCorp, 2015). The surface under the cumulative ranking curve and mean rank will be calculated in order to establish a hierarchy of the endovascular treatments. Evaluation of the risk of bias, heterogeneity, consistency, transitivity and quality of evidence will follow the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions. ETHICS AND DISSEMINATION: Ethics approval is not needed as systematic review is based on published studies. Study findings will be presented at international conferences and published on a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018084055; Pre-results. PMID- 29991635 TI - Role of personality traits in reporting the development of adverse drug reactions: a prospective cohort study of the Estonian general population. AB - OBJECTIVE: To examine the role of the Five Factor Model (FFM) personality traits in reporting the development of adverse drug reactions (ADRs) when controlling for sociodemographic variables and health status. DESIGN: Prospective cohort study. SETTING: The Estonian Biobank of the Estonian Genome Centre, University of Tartu. PARTICIPANTS: 814 women and 543 men (mean age=47.9 years; SD=15.2) who after the initial enrolment in the Estonian Biobank were re-contacted for follow up purposes about 5.3 years after the enrolment and for whom both self- and informant-reported personality data were available. MAIN OUTCOME MEASURE: Participants who did not report having any ADRs at baseline but who reported ADRs at the follow-up about 5.3 years later versus participants who did not report any ADRs at either time point. The reports of developing ADRs were predicted from the FFM personality traits after statistically controlling for sociodemographic variables (age, gender and education), baseline indicators of health status (number of diagnoses and medicines taken, body mass index and blood pressure), and the change in health status between the two measurements. RESULTS: The results of a hierarchical binary logistic regression analysis showed that participants who reported the development of ADRs between the two measurements had higher levels of conscientiousness, were more likely to be women, were taking more medicines at baseline and had a higher increase in the number of medicines taken during the study period than participants who did not report any ADRs at either time point (all p values <0.05). Higher neuroticism (p=0.067) and a higher number of diagnosed diseases at baseline (p=0.053) also made marginal contributions to predicting the development of ADRs. CONCLUSIONS: This study shows for the first time that higher levels of conscientiousness and neuroticism are associated with reporting the development of ADRs. PMID- 29991636 TI - UK nationals who received their medical degrees abroad: selection into, and subsequent performance in postgraduate training: a national data linkage study. AB - OBJECTIVES: To compare the likelihood of success at selection into specialty training for doctors who were UK nationals but obtained their primary medical qualification (PMQ) from outside the UK ('UK overseas graduates') with other graduate groups based on their nationality and where they gained their PMQ. We also compared subsequent educational performance during postgraduate training between the graduate groups. DESIGN: Observational study linking UK medical specialty recruitment data with postgraduate educational performance (Annual Review of Competence Progression (ARCP) ratings). SETTING: Doctors recruited into national programmes of postgraduate specialist training in the UK from 2012 to 2016. PARTICIPANTS: 34 755 UK-based trainee doctors recruited into national specialty training programmes with at least one subsequent ARCP outcome reported during the study period, including 1108 UK overseas graduates. MAIN OUTCOME MEASURES: Odds of being deemed appointable at specialty selection and subsequent odds of obtaining a less versus more satisfactory category of ARCP outcome. RESULTS: UK overseas graduates were more likely to be deemed appointable compared with non-EU medical graduates who were not UK citizens (OR 1.29, 95% CI 1.16 to 1.42), although less so than UK (OR 0.25, 95% CI 0.23 to 0.27) or European graduates (OR 0.66, 95% CI 0.58 to 0.75). However, UK overseas graduates were subsequently more likely to receive a less satisfactory outcome at ARCP than other graduate groups. Adjusting for age, sex, experience and the economic disparity between country of nationality and place of qualification reduced intergroup differences. CONCLUSIONS: The failure of recruitment patterns to mirror the ARCP data raises issues regarding consistency in selection and the deaneries' subsequent annual reviews. Excessive weight is possibly given to interview performance at specialty recruitment. Regulators and selectors should continue to develop robust processes for selection and assessment of doctors in training. Further support could be considered for UK overseas graduates returning to practice in the UK. PMID- 29991637 TI - Characterization of fibroblast growth factor 1 in obese children and adolescents. AB - BACKGROUND: Fibroblast growth factor 1 (FGF1) can regulate glucose and lipid metabolism in obese mice. Serum FGF1 have increased in type 2 diabetes mellitus adults and correlated with BMI. This study aimed to indicate conventional weight loss effects on FGF1 in obese children and adolescents. MATERIALS AND METHODS: Clinical and metabolic parameters of 88 lean and obese individuals (ages 5-15 years) and 39 obese individuals followed with 6 months of lifestyle intervention were collected. Serum FGF1 levels were detected through enzyme-linked immunosorbent assays. RESULTS: FGF1 levels were increased in obese individuals. Serum FGF1 levels were significantly correlated with BMI and waist circumferences (r = 0.377, P = 0.012; r = 0.301, P = 0.047, respectively). Multivariate stepwise linear regress analyses showed that FGF1 levels were significantly correlated with HbA1c and HOMA-IR (beta = 0.371, P = 0.008; beta = 0.323, P = 0.021, respectively). Weight loss (2.3 +/- 0.1 kg) was accompanied by a significant reduction of circulating FGF1 levels (7.2 +/- 0.4 pg/ml). Changes in FGF1 were significantly correlated with changes in fasting glucose, HOMA-IR and low-density lipoprotein-cholesterol (beta = 0.277, P = 0.020; beta = 0.474, P < 0.001; beta = 0.320, P = 0.008, respectively). CONCLUSION: FGF1 was related to increased risk of insulin resistance in obese children and adolescents. Serum FGF1 reduced after weight loss in obese individuals and was associated with the improvement of insulin resistance. Changes in serum FGF1 was more correlated with insulin resistance than changes in obesity per se. PMID- 29991638 TI - Biological and clinical impact of imbalanced progesterone receptor isoform ratios in breast cancer. AB - There is a consensus that progestins and thus their cognate receptor molecules, the progesterone receptors (PR), are essential in the development of the adult mammary gland and regulators of proliferation and lactation. However, a role for natural progestins in breast carcinogenesis remains poorly understood. A hint to that possible role came from studies in which the synthetic progestin medroxyprogesterone acetate was associated with an increased breast cancer risk in women under hormone replacement therapy. However, progestins have been also used for breast cancer treatment and to inhibit the growth of several experimental breast cancer models. More recently, PR have been shown to be regulators of estrogen receptor signaling. With all this information, the question is how can we target PR, and if so, which patients may benefit from such an approach? PR are not single unique molecules. Two main PR isoforms have been characterized, PRA and PRB, that exert different functions and the relative abundance of one isoform respect to the other determines the response of PR agonists and antagonists. Immunohistochemistry with standard antibodies against PR do not discriminate between isoforms. In this review, we summarize the current knowledge on the expression of both PR isoforms in mammary glands, in experimental models of breast cancer and in breast cancer patients, to better understand how the PRA/PRB ratio can be exploited therapeutically to design personalized therapeutic strategies. PMID- 29991639 TI - Regulating the local availability of tobacco retailing in Madrid, Spain: a GIS study to evaluate compliance. AB - BACKGROUND: In Spain, tobacco sales are limited to tobacco-exclusive stores and associated vending machines. A minimum of 150 m between stores is required, unless they exceed a legal sales threshold. Minimum distances to schools are recommended but not defined. We evaluated compliance with these regulations in Madrid, Spain. METHODS: Information about tobacco-exclusive stores and their sales volume was obtained in 2014. We used geographic information system to identify stores closer than 150 m between them and examine whether they exceeded the sales threshold. We estimated distances between stores and schools, considering different distance intervals (<150 m, 150-300 m and >300 m) and calculations (crow flies and street network). We assessed the association of area level demographic and socioeconomic characteristics with the distribution of tobacco stores. RESULTS: 5.3% (34/638) of tobacco stores were within 150 m of each other. Among those, 76% (26/34) did not meet the regulation sales threshold. These stores were in areas with lower proportion of young population (<15 years) and higher proportion of people with university-level education. 75% (476/638) of stores were situated closer than 300 m to schools. No differences were identified in sociodemographic and economic characteristics by the store distance to schools. CONCLUSION: Most tobacco stores are compliant with the regulations in Spain. However, these regulations are insufficient to reduce tobacco availability. More restrictive regulations are needed to limit the geographic distribution of tobacco retailers, and health criteria should also be considered in the current legislation. The evaluation of the Spanish regulatory model may provide useful insights for other jurisdictions looking to decrease the tobacco retail availability. PMID- 29991640 TI - Acute perceptions of preferred cigarettes when blinded to brand. AB - BACKGROUND: Marketing claims often have promoted specific perceptions that users should expect from acutely smoking that cigarette brand. Yet, little controlled study has determined the degree to which actual perceptions are based on the cigarette's tobacco constituents in the absence of knowledge about the brand's identity. METHODS: 194 adult dependent smokers rated their perceptions on 'liking', 'satisfying', 'strong' and perceived amount of 'nicotine' after smoking ad lib one of their preferred brands of cigarettes. All did so either when blinded (n=118) or unblinded (n=76) to the brand they were given, with the blinding conditions from separate studies. These between-groups secondary analyses determined differences in perceptions based on blinding to brand, controlling for age and cigarettes/day. RESULTS: All perceptions were lower for those smoking own brand under blinded versus unblinded conditions, as hypothesised. Consistent with lowered perceptions for smoking one's own brand obtained from the 118 blinded to brand, their 'somewhat' ratings for a 'how similar to own brand' item indicated uncertainty, just mid-way between 'not at all' and 'very much' on the 0-100 visual analogue scale. (The 76 unblinded were already informed it was their own brand.) CONCLUSIONS: Acute perceptions of one's own cigarette are substantially lower when smokers are simply unaware of brand, relative to those aware it is their preferred brand. Results support the notion that perceptions of smoking own brand are enhanced by marketing efforts to associate brands with expectations of pleasurable subjective effects, beyond the impact due solely to the cigarette's manufactured product constituents. PMID- 29991642 TI - Severe obesity and gut microbiota: does bariatric surgery really reset the system? PMID- 29991641 TI - Evolutionary history of human colitis-associated colorectal cancer. AB - OBJECTIVE: IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. DESIGN: Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. RESULTS: 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase. CONCLUSIONS: Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection. PMID- 29991643 TI - Influence of Clinical Factors and Exclusion Criteria on Mortality in ARDS Observational Studies and Randomized Controlled Trials. AB - ARDS has a high mortality in the acute setting, with long-term disability among disease survivors. In 1967, David Ashbaugh and colleagues first described the clinical features of ARDS, which were notably similar to the infantile respiratory distress syndrome. Half a century later, ARDS remains underrecognized and is associated with high mortality rates. Valuable insights from observational studies fail to demonstrate a mortality benefit in randomized controlled trials (RCTs). In the absence of a pharmacologic cure, supportive ventilator strategies limit rather than treat the ongoing lung injury. Interestingly, ARDS has higher mortality rates in observational studies compared to RCTs. Comparing mortality rates between ARDS studies and trials is problematic, partly due to varying time points at which mortality is reported. Discerning the true mortality attributable to ARDS is also difficult. The diagnostic criteria for ARDS are mainly clinical and lack the objectivity of a laboratory test or biomarker. Nonetheless, these factors are common to both studies and trials, and fail to explain the higher mortality rate of ARDS observational studies. Disease heterogeneity and complex patient characteristics can also confound mortality estimation in ARDS. We therefore examined patient and trial factors that could influence mortality outcomes in ARDS observational studies and RCTs. Unlike RCTs, observational studies include ARDS subjects with severe comorbidities and those requesting limited care. Less stringent selection criteria could thereby contribute to high mortality rates in ARDS observational studies. In contrast, exclusion criteria in RCTs meticulously scrutinize patient characteristics, confining the type and number of eligible subjects. As a result, the task of identifying, consenting, and randomizing eligible patients within the enrollment window is challenging, further decreasing the number of subjects enrolled. Moreover, ARDS RCTs strictly adhere to lung-protective strategies, while ARDS observational studies continually demonstrate variable compliance. This review highlights the impact of patient- and trial-related factors on influencing mortality rates in ARDS observational studies and RCTs. PMID- 29991644 TI - Association of Multivitamin and Mineral Supplementation and Risk of Cardiovascular Disease: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Multiple studies have attempted to identify the association between multivitamin/mineral (MVM) supplementation and cardiovascular disease (CVD) outcomes, but the benefits remain controversial. We performed a systematic review and meta-analysis of the associations between MVM supplementation and various CVD outcomes, including coronary heart disease (CHD) and stroke. METHODS AND RESULTS: We conducted a comprehensive search of Medline, Embase, and the Cochrane Library for studies published between January 1970 and August 2016. We included clinical trials and prospective cohort studies in the general population evaluating associations between MVM supplementation and CVD outcomes. Data extraction and quality assessment were independently conducted by 2 authors, and a third author resolved discrepancies. Eighteen studies with 2 019 862 participants and 18 363 326 person-years of follow-up were included in the analysis. Five studies specified the dose/type of MVM supplement and the rest did not. Overall, there was no association between MVM supplementation and CVD mortality (relative risk [RR], 1.00; 95% confidence interval [CI], 0.97-1.04), CHD mortality (RR, 1.02; 95% CI, 0.92-1.13), stroke mortality (RR, 0.95; 95% CI, 0.82-1.09), or stroke incidence (RR, 0.98; 95% CI, 0.91-1.05). There was no association between MVM supplements and CVD or CHD mortality in prespecified subgroups categorized by mean follow-up period, mean age, period of MVM use, sex, type of population, exclusion of patients with history of CHD, and adjustment for diet, adjustment for smoking, adjustment for physical activity, and study site. In contrast, MVM use did seem to be associated with a lower risk of CHD incidence (RR, 0.88; 95% CI, 0.79-0.97). However, this association did not remain significant in the pooled subgroup analysis of randomized controlled trials (RR, 0.97; 95% CI, 0.80 1.19). CONCLUSIONS: Our meta-analysis of clinical trials and prospective cohort studies demonstrates that MVM supplementation does not improve cardiovascular outcomes in the general population. PMID- 29991646 TI - Defining Exposure in Observational Studies Comparing Outcomes of Treatment Discontinuation. AB - BACKGROUND: Continuation of antiplatelet therapy beyond 12 months after a drug eluting stent procedure reduced the risk of a major adverse cardiovascular and cerebrovascular event (MACCE) in the DAPT trial (Dual Antiplatelet Therapy). Observational studies have evaluated outcomes related to different durations of therapy but are susceptible to bias. METHODS AND RESULTS: Using deidentified claims from commercially insured and Medicare populations in the United States, we compared how increasingly stringent definitions of exposure affect associations between antiplatelet continuation versus discontinuation and MACCE, myocardial infarction, and intracerebral hemorrhage or gastrointestinal bleeding in patients meeting DAPT trial inclusion criteria between 2004 and 2013. Therapy continuation at 12 months was defined as (1) having antiplatelet supply on hand versus not (landmark time); (2) refilling within 30 days versus not among individuals with antiplatelet supply; (3) criteria 2 plus continuous prior antiplatelet use; and (4) criteria 2 and 3 plus a cardiologist visit in months 10 to 12. Propensity score-adjusted hazard ratios were compared. Cohort sizes were 53 679, 27 524, 16 971, and 7948, respectively, of which 20% were discontinuers on average. Increasing restriction led to progressively larger associations with continued treatment: cohort 1 MACCE hazard ratio, 0.79 (0.73, 0.87); myocardial infarction, 0.74 (0.65, 0.83); bleed, 1.03 (0.96, 1.11) versus cohort 4 MACCE hazard ratio, 0.66 (0.48, 0.91); myocardial infarction, 0.56 (0.37, 0.86); bleed, 1.24 (0.95, 1.61). Estimates trended toward DAPT trial estimates and were associated with reduced levels of exposure misclassification. CONCLUSIONS: In an example of long-term antiplatelet use, increasing restrictions on the definition of therapy continuation yielded results consistent with trial estimates by reducing exposure misclassification. PMID- 29991645 TI - Post-Traumatic Stress Disorder and Cardiovascular Diseases: A Cohort Study of Men and Women Involved in Cleaning the Debris of the World Trade Center Complex. AB - BACKGROUND: We sought to determine whether post-traumatic stress disorder (PTSD) is a risk factor for myocardial infarction (MI) and stroke, beyond the expected effects from recognized cardiovascular risk factors and depression. METHODS AND RESULTS: World Trade Center-Heart is an observational prospective cohort study of 6481 blue-collar first responders nested within the World Trade Center Health Program in New York City. Baseline measures in 2012 and 2013 included blood pressure, weight and height, and blood lipids. PTSD, depression, smoking, and dust exposure during the 2001 cleanup were self-reported. During the 4-year follow-up, outcomes were assessed through (1) interview-based incident, nonfatal MI, and stroke, validated in medical charts (n=118); and (2) hospitalizations for MI and stroke for New York city and state residents (n=180). Prevalence of PTSD was 19.9% in men and 25.9% in women, that is, at least twice that of the general population. Cumulative incidence of MI or stroke was consistently larger for men or women with PTSD across follow-up. Adjusted hazard ratios (HRs) were 2.22 (95% confidence interval [CI], 1.30-3.82) for MI and 2.51 (95% CI, 1.39-4.57) for stroke. For pooled MI and stroke, adjusted HRs were 2.35 (95% CI, 1.57-3.52) in all and 1.88 (95% CI, 1.01-3.49) in men free of depression. Using hospitalization registry data, adjusted HRs were 2.17 (95% CI, 1.41-3.32) for MI; 3.01 (95% CI, 1.84-4.93) for stroke; and for pooled MI and stroke, the adjusted HR was 2.40 (95% CI, 1.73-3.34) in all, HR was 2.44 (95% CI, 1.05-5.55) in women, and adjusted HR was 2.27 (95% CI, 1.41-3.67) in men free of depression. World Trade Center dust exposure had no effect. CONCLUSIONS: This cohort study confirms that PTSD is a risk factor for MI and stroke of similar magnitude in men and women, independent of depression. PMID- 29991647 TI - Multivitamins Do Not Reduce Cardiovascular Disease and Mortality and Should Not Be Taken for This Purpose: How Do We Know That? PMID- 29991648 TI - Exposure Misclassification in Observational Studies: Setting New Standards. PMID- 29991651 TI - IKK promotes cytokine-induced and cancer-associated AMPK activity and attenuates phenformin-induced cell death in LKB1-deficient cells. AB - The 5' AMP-activated protein kinase (AMPK) is an energy sensor that is activated upon phosphorylation of Thr172 in its activation loop by the kinase LKB1, CAMKK2, or TAK1. TAK1-dependent AMPK phosphorylation of Thr172 is less well characterized than phosphorylation of this site by LKB1 or CAMKK2. An important target of TAK1 is IkappaB kinase (IKK), which controls the activation of the transcription factor NF-kappaB. We tested the hypothesis that IKK acted downstream of TAK1 to activate AMPK by phosphorylating Thr172 IKK was required for the phosphorylation of Thr172 in AMPK in response to treatment with the inflammatory cytokine IL 1beta or TNF-alpha or upon TAK1 overexpression. In addition, IKK regulated basal AMPK Thr172 phosphorylation in several cancer cell types independently of TAK1, indicating that other modes of IKK activation could stimulate AMPK. We found that IKK directly phosphorylated AMPK at Thr172 independently of the tumor suppressor LKB1 or energy stress. Accordingly, in LKB1-deficient cells, IKK inhibition reduced AMPK Thr172 phosphorylation in response to the mitochondrial inhibitor phenformin. This response led to enhanced apoptosis and suggests that IKK inhibition in combination with phenformin could be used clinically to treat patients with LKB1-deficient cancers. PMID- 29991650 TI - The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells. AB - The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4+ T cells. Moreover, co-engagement of the TCR and a risk variant of CD226 that is associated with autoimmunity (rs763361) further enhanced VAV1 activation and IL-17 production. Thus, our study reveals that a VAV1-based, synergistic cross-talk exists between the TCR and CD226 during both physiological and pathological T cell responses and provides a rational basis for targeting CD226 for the management of autoimmune diseases. PMID- 29991649 TI - Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity. AB - Mitochondria are integral to cellular energy metabolism and ATP production and are involved in regulating many cellular processes. Mitochondria produce reactive oxygen species (ROS), which not only can damage cellular components but also participate in signal transduction. The kinase ATM, which is mutated in the neurodegenerative, autosomal recessive disease ataxia-telangiectasia (A-T), is a key player in the nuclear DNA damage response. However, ATM also performs a redox sensing function mediated through formation of ROS-dependent disulfide-linked dimers. We found that mitochondria-derived hydrogen peroxide promoted ATM dimerization. In HeLa cells, ATM dimers were localized to the nucleus and inhibited by the redox regulatory protein thioredoxin 1 (TRX1), suggesting the existence of a ROS-mediated, stress-signaling relay from mitochondria to the nucleus. ATM dimer formation did not affect its association with chromatin in the absence or presence of nuclear DNA damage, consistent with the separation of its redox and DNA damage signaling functions. Comparative analysis of U2OS cells expressing either wild-type ATM or the redox sensing-deficient C2991L mutant revealed that one function of ATM redox sensing is to promote glucose flux through the pentose phosphate pathway (PPP) by increasing the abundance and activity of glucose-6-phosphate dehydrogenase (G6PD), thereby increasing cellular antioxidant capacity. The PPP produces the coenzyme NADPH needed for a robust antioxidant response, including the regeneration of TRX1, indicating the existence of a regulatory feedback loop involving ATM and TRX1. We propose that loss of the mitochondrial ROS-sensing function of ATM may cause cellular ROS accumulation and oxidative stress in A-T. PMID- 29991653 TI - Regional Intervention of Stroke Care to Increase Thrombolytic Therapy for Acute Ischemic Stroke. AB - Background and Purpose- The aims of this study were to investigate the effect of an intervention to unblind data on r-tPA (recombinant tissue-type plasminogen activator) administration and sharing data with chief executive officers of participating hospitals, on r-tPA administration rates postintervention and on potential healthcare cost savings implemented at 26 Southeast Texas Regional Advisory Council hospitals. Methods- Retrospective analysis of prospective data on thrombolytic therapy from 26 Southeast Texas Regional Advisory Council hospitals, collected between April 2014 and June 2016. The control (blinded) period (Q2-2014 to Q2-2015) was followed by unblinding (Q3-2015). Results- Intervention was associated with 21.1% increase in r-tPA administration rates, with 38.5% increase in r-tPA administration with door-to-needle time <=60 minutes. An absolute increase in r-tPA administration of 2.1% was seen with an average lifetime cost savings of $3.6 million. Conclusions- Transparent regional data sharing was associated with improved r-tPA administration and healthcare cost savings. PMID- 29991652 TI - Circulating HDL levels control hypothalamic astrogliosis via apoA-I. AB - Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I-/-) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I-/- compared with apoA-I+/+ mice and was associated with compromised mitochondrial function. apoA-I-/- mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I+/+ controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I-/- mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease. PMID- 29991654 TI - Intracranial Hemorrhage in Deep Vein Thrombosis/Pulmonary Embolus Patients Without Atrial Fibrillation. AB - Background and Purpose- Deep vein thrombosis (DVTs) is a common disease with high morbidity if it progresses to pulmonary embolus (PE). Anticoagulation is the treatment of choice; warfarin has long been the standard of care. Early experience with direct oral anticoagulants (DOACs) suggests that these agents may be may be a safer and equally effective alternative in the treatment of DVT/PE. Nontraumatic intracranial hemorrhage (ICH) is one of the most devastating potential complications of anticoagulation therapy. We sought to compare the rates of ICH in patients treated with DOACs versus those treated with warfarin for DVT/PE. Methods- The MarketScan Commercial Claims and Medicare Supplemental databases were used. Adult DVT/PE patients without known atrial fibrillation and with prescriptions for either a DOAC or warfarin were followed for the occurrence of inpatient admission for ICH. Coarsened exact matching was used to balance the treatment cohorts. Cox proportional-hazards regressions and Kaplan-Meier survival curves were used to estimate the association between DOACs and the risk of ICH compared with warfarin. Results- The combined cohort of 218 620 patients had a median follow-up of 3.0 months, mean age of 55.4 years, and was 52.1% women. The DOAC cohort had 26 980 patients and 8 ICH events (1.0 cases per 1000 person years), and the warfarin cohort had 191 640 patients and 324 ICH events (3.3 cases per 1000 person-years; P<0.0001). The DOAC cohort had a lower hazard ratio for ICH compared with warfarin in both the unmatched (hazard ratio=0.26; P=0.0002) and matched (hazard ratio=0.20; P=0.0001) Cox proportional-hazards regressions. Conclusions- DOACs show superior safety to warfarin in terms of risk of ICH in patients with DVT/PE. PMID- 29991655 TI - Prior Intravenous Stroke Thrombolysis Does Not Increase Complications of Carotid Endarterectomy. AB - Background and Purpose- Carotid endarterectomy (CEA) is recommended within 14 days after carotid artery stroke to prevent recurrence. However, the optimal timing of CEA after intravenous thrombolysis (IVT) remains unclear. We studied the safety of CEA after IVT while taking into account both stroke recurrence and CEA-related complications. Methods- Patients who underwent IVT followed by CEA in Helsinki University Hospital 2005 to 2016 were withdrawn from prospectively collected registers. The incidence of stroke recurrence during the time between IVT and CEA, peri/postoperative stroke, hyperperfusion syndrome or drug-resistant high blood pressure, and 3-month outcome measured by modified Rankin Scale was recorded. Stroke patients treated with CEA without preceding IVT were used as controls. Results- Altogether 128 CEAs with preceding IVT and 777 CEAs for stroke without IVT were identified. The median time from IVT to CEA was 9 days (range, 0 349 days; interquartile range, 16). Seven patients (5.5%) underwent CEA within 24 hours, 20 (15.6%) within 48 hours and 87 (68.0%) within 2 weeks from IVT. Stroke recurrence in IVT-CEA patients was 5.5% at median 4 days after IVT (range, 0-8 days). Outcome from CEAs performed within 48 hours from IVT did not differ from CEAs performed later with respect to peri/postoperative ischemic strokes (5.0% and 3.7%), hemorrhagic strokes (5.0% and 1.9%), neck hematomas (5.0% and 8.3%), myocardial infarctions (0.0% and 0.9%), or 3-month modified Rankin Scale. There was a tendency toward higher incidence of hyperperfusion syndrome in the patients operated within 48 hours from IVT (20.0% versus 6.5%; P=0.070). The CEA-related stroke rate was similar to that of the operation without thrombolysis. Only smoking was significantly associated with peri/postoperative stroke (odds ratio, 21.82; 95% confidence interval, 1.08-439.58). Conclusions- Time between IVT and CEA was not associated with CEA-related complications. The high rate of stroke recurrence during the waiting time for CEA underscores the importance of shortening surgery delays. PMID- 29991656 TI - Statin Pretreatment and Microembolic Signals in Large Artery Atherosclerosis. AB - Background and Purpose- Scarce data indicate that statin pretreatment (SP) in patients with acute cerebral ischemia because of large artery atherosclerosis may be related to lower risk of recurrent stroke because of a decreased incidence of microembolic signals (MES) during transcranial Doppler monitoring. Methods- We performed a systematic review and meta-analysis of available observational studies reporting MES presence/absence or MES burden, categorized according to SP status, in patients with acute cerebral ischemia because of symptomatic (>=50%) large artery atherosclerosis. In studies with partially-published data, authors were contacted for previously unpublished information. We also performed a sensitivity analysis of studies with data on MES burden categorized according to SP status, and an additional subgroup analysis in patients receiving higher-dose SP (atorvastatin 80 mg or rosuvastatin 40 mg daily). Results- Seven eligible study protocols were identified (610 patients, 54% with SP). SP was associated with a reduced risk of MES detection during transcranial Doppler monitoring (risk ratio=0.67; 95% CI, 0.45-0.98), with substantial heterogeneity between studies ( I2=52%). In studies reporting MES burden (n=4), a significantly lower number of MES were identified in patients with compared with those without SP (mean difference=-0.92; 95% CI, -1.64 to -0.19), with no evidence of heterogeneity between studies ( I2=49%). Subgroup analysis revealed that higher-dose SP reduced the risk of detecting MES (risk ratio=0.23; 95% CI, 0.06-0.88), with no evidence of heterogeneity between studies ( I2=0%). Conclusions- SP seems to be associated with a lower incidence and burden of MES in patients with acute cerebral ischemia because of large artery atherosclerosis. PMID- 29991657 TI - Inhibition of PAI (Plasminogen Activator Inhibitor)-1 Improves Brain Collateral Perfusion and Injury After Acute Ischemic Stroke in Aged Hypertensive Rats. AB - Background and Purpose- Aging and hypertension, comorbidities prevalent in the stroke population, are associated with poor collateral status and worsened stroke outcome. However, underlying mechanisms by which these conditions affect stroke outcome are not clear. We studied the role of PAI (plasminogen activator inhibitor)-1 that is increased in aging and hypertension on brain and vascular expression of inflammatory factors and perfusion that may contribute to worse stroke outcomes. Methods- Aged (~50 weeks) and young (~18 weeks) spontaneously hypertensive rats (SHR) were subjected to ischemia by middle cerebral artery occlusion (2 hours) and reperfusion (2 hours) with or without treatment with the PAI-1 inhibitor TM5441. Changes in middle cerebral artery and collateral perfusion territories were measured by multisite laser Doppler. Reactivity to TM5441 was studied using isolated and pressurized leptomeningeal anastomotic arterioles. Brain injury was determined by 2,3,5-triphenyltetrazolium staining and quantitative immunohistochemistry of amyloid-beta-42, PAI-1, and hemoglobin. Circulating inflammatory factors were measured by ELISA. Results- Changes in cerebral blood flow during middle cerebral artery occlusion were similar between groups, with both having poor collateral perfusion and incomplete reperfusion. However, aged SHR had greater brain injury versus young (41+/-2 versus 23+/-2%, P<0.05) as well as increased brain deposition of amyloid-beta-42 and circulating oxLDL (oxidized low-density lipoprotein). Erythrocyte aggregation and hemorrhage within the injured brain was observed in 50% of aged but no young SHR, with increased circulating PAI-1 in this subgroup of aged SHR (16+/-3 versus 6+/-2 ng/mL, P<0.05). PAI-1 inhibition with TM5441 improved brain injury but did not affect hemorrhage. TM5441 increased collateral perfusion by 38+/-7% and dilated leptomeningeal anastomotic arterioles by 44+/-10%, which was abolished by nitric oxide synthase inhibition. Conclusions- Increased injury in aged SHR seemed to be related to poor collateral perfusion, hemorrhagic transformation, increased amyloid-beta-42, and oxidative stress. PAI-1 inhibition reduced infarction in both groups of SHR that possibly due, in part, to increased collateral perfusion. PMID- 29991658 TI - Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects. AB - Background and Purpose- A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms. Methods- Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells. Results- Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin. Conclusions- HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms. PMID- 29991659 TI - [Obesity and radical prostatectomy: The enigma continues.] AB - OBJECTIVE: To determine the association between surgical and postoperative outcomes as well as cancer follow-up of patients who underwent radical prostatectomy according to body mass index (BMI). METHODS: An analytical observational study with retrospective data collection was conducted. We reviewed the medical records of all the patients who underwent radical prostatectomy between the years 2012-2014. The analysis of the data included a bivariate model to study the associations between BMI and the surgical procedure, its complications, oncologic outcomes and cancer follow-up. Then, we used multivariate logistic regression analysis to determine if there was an independent association between oncologic outcomes and BMI; the model was adjusted by age, hypertension and diabetes mellitus. RESULTS: 272 patients underwent radical prostatectomy: 98 (36.0%) had normal BMI, 142 (52.2%) were overweight and 32 (11.8%) were obese. The median age was 61 interquartile range (IQR=56-66) years old. There were no statistically significant differences in the preoperative and postoperative outcomes according to BMI. The obese patients had longer operative time (176 minutes, IQR=165.0-195.5) nonetheless, the difference was not statistically significant (p=0.18). There were no complications during the procedure (rectal, vascular or obturator nerve injury). The multivariate analysis showed that age, hypertension and diabetes mellitus were not effect modifiers. CONCLUSIONS: Our study suggests that there are no differences between surgical and postoperative outcomes according to BMI. This study represents a starting point for future research in our population to determine the impact of the BMI on prostate cancer and its management. PMID- 29991660 TI - [Correlation between symptoms and urodynamic results in patients with urinary incontinence after radical prostatectomy.] AB - OBJECTIVES: Urinary incontinence (UI) is a significant complication after radical prostatectomy (RP). Although sphincter incompetence is considered the main cause; bladder dysfunction can contribute substantially. Our objective was to evaluate the results of the urodynamic study (UDS) in men with UI after radical prostatectomy and analyze the correlation between symptoms and urodynamic parameters. METHODS: We carried out a retrospective study reviewing the symptoms and urodynamics in patients with urinary incontinence after RP. We describe the symptoms, urodynamic findings and we analyze the correlation between both. RESULTS: Our study included 74 patients. The median number of pads used per day was 3. 61% reported urgency, 63% stress urinary incontinence, 11% urgency urinary incontinence and 26% mixed urinary incontinence. The UDS showed stress urinary incontinence in 53% of patients, detrusor overactivity in 53% and, reduced bladder compliance in 43%. Urgency urinary incontinence was reported in 56% of patients with reduced bladder compliance. Urodynamics showed no incontinence in 16% of patients, of whom 80% showed urgency urinary incontinence. Urodynamics data showing obstruction of the urinary tract was reported in 17% and detrusor hypo or acontractility in 36%. Among patients with obstruction, 46% showed incontinence due to detrusor overactivity. The correlation of symptoms and urodynamics showed that only 31% of patients with stress urinary incontinence had incontinence due to detrusor overactivity in urodynamics. Among those with mixed urinary incontinence, urodynamic stress urinary incontinence only was found in 42% and 33% incontinence due to detrusor overactivity only. Finally, among those with symptoms of urgency urinary incontinence, the urodynamics showed detrusor overactivity in 27%. CONCLUSIONS: In patients with urinary incontinence after radical prostatectomy, there is a high percentage of patients with urinary tract obstruction, detrusor overactivity and decreased compliance. Moreover, the correlation between symptoms and urodynamics is low. PMID- 29991661 TI - [Comparison of the symptoms of overactive bladder in women with mixed urinary incontinence and idiopathic urge urinary incontinence.] AB - INTRODUCTION: Various authors argued that the voiding urgency component in mixed urinary incontinence (MUI) is different than urge urinary incontinence (UUI). In this last case they suggest that incontinence in MUI could be overdiagnosed in patients with SUI, misunderstanding the leak as UUI. OBJETIVES: To evaluate clinical and urodynamic characteristics of patients with MUI and pure UUI. METHODS: A retrospective study of our urodynamics database was performed evaluating 450 women with MUI and UUI. Patients with neurogenic bladder, fistulae, urethral diverticula, previous urogynecologic surgery, known infravesical obstruction, previous pelvic radiotherapy, urinary tract infection or psychiatric drugs intake. A full clinical history, physical exam, uroflowmetry, filling cystometry and pressure flow study were performed. RESULTS: There is no difference relative to age, menopause and number of births. The presence of nocturia was bigger in the UUI group (66.4% vs. 46.1%, p 0.0004) the same as increased voiding frequency (53.6% vs. 34.6%, p 0.0006). The presence of urethral hypermobility and SUI in the physical exam was greater than MUI, meanwhile the presence of reduced vaginal trophism was bigger in the UUI group. Differences in sensibility or specificity were not found. The presence of overactive detrusor was 56.4% in pure UUI vs. 33.2% in MUI (p<0.0001). No differences in pressure flow study were found. CONCLUSIONS: There is a significant difference in the clinical and urodynamic parameters between patients with MUI and pure UUI. The urgency in patients with pure UUI could be related to overactive detrusor. It is probable that many patients with MUI just have pure SUI which could lead to positive effects in the outcomes of anti-incontinence surgery. PMID- 29991662 TI - [Impact of the use of simulators on the mental workload and confidence in a digital rectal examination and bladder catheterization workshop.] AB - OBJECTIVES: Primary: to assess the use of simulators in prostate digital rectal examination and bladder catheterization on mental workload and the level of confidence in medical students. Secondary: to analyze student satisfaction and skills acquired by students with simulators. METHODS: We conducted a prospective, randomized study on medical students. Participants were divided into two groups: Group 1 (G1) (only the explanation) and group 2 (G2) (explanation + simulator workshop). For workload assessment, the validated NASA-TLX questionnaire was completed. The acceptability of the activity, the degree of confidence and the skills acquired were also evaluated. RESULTS: A total of 28 students participated in the practice of prostate examination. All participants reported a higher level of confidence after the theoretical explanation. 34 students participated in the bladder catheterization workshop and all of them increased their confidence after the activity. The G2 showed better scores on the acquired skills exam than the G1. Most students considered positive the incorporation of these models in their learning. According to the NASA-TLX results, less frustration is experienced with the use of simulators in both activities. CONCLUSIONS: The implementation of simulators in the training of students may improve their level of confidence, reducing frustration when performing these explorations in the future and improving care quality. PMID- 29991664 TI - [Spermatic cord liposarcoma. Report of two cases and bibliographic review.] AB - OBJECTIVE: We report two cases of patients diagnosed of paratesticular liposarcoma and perform a literature review of this rare entity. Our aim is to clarify its clinical and therapeutic characteristics. METHODS: Retrospective review of the medical records of two patients diagnosed of liposarcoma of the spermatic cord. RESULTS: Case 1: 65 year old male, presented a left large scrotal mass of 20 * 14 * 11 cm. He underwent radical orchiectomy. Pathology reported a well differentiated spermatic cord liposarcoma. After one year of follow-up the patient was asymptomatic and there was no evidence of local recurrence. Case 2: A 90 year old man, with past medical history of right orchiectomy for well differentiated cord liposarcoma 11 years before, and excision of recurrence 7 years ago. On follow up he presented a new 20 * 14 * 11 cm inguinal tumor recurrence. We performed excision of the mass, which was reported by pathology as well differentiated spermatic cord liposarcoma. Ten months after surgery the patient was asymptomatic without recurrence. CONCLUSIONS: Liposarcoma is a very rare entity and its diagnosis is based on the pathological findings. It is therefore difficult to establish the guidelines for treatment, prognosis and differential diagnosis. As in liposarcomas in other sites, the histological type and grade of the lesion are useful for the prognosis. Radical inguinal orchiectomy and resection of the tumor with a negative microscopic margin is the recommended treatment for liposarcoma of the spermatic cord. It has not been demonstrated the efficacy of adjuvant treatments such as chemotherapy or radiotherapy, except in specific situations. The natural history of disease is slow and it has low mortality, but high recurrence rate, so a long-term monitoring is necessary. PMID- 29991663 TI - Varicocele treatment in patients up to 35 years old: A multicentric retrospective studycomparing 3 different techniques. AB - OBJECTIVE: To report and compare the clinical outcomes after varicocele treatment managed by open surgery, laparoscopic approach and embolization, with an emphasis in terms of recurrence, complication rate and length of surgery. METHODS: 2 different Portuguese Centers collected pre and postoperative data of patients submitted to varicocele treatment. Over a period of 8 years, 251 cases were evaluated retrospectively and 161 were included and further divided in procedure related groups. Patients older than 35 years-old were excluded. Laparoscopic Palomo (without artery-sparing technique), artery-sparing Open Palomo surgery and retrograde percutaneous embolization were performed. As outcome measures recurrence/persistence, postoperative hydrocele and other complications were analyzed. Patients were followed a mean of 11.84 months. RESULTS: In the 72 cases in the laparoscopy group, varicocele persisted in 7% and hydrocele developed in 18% . In the 41 patients who underwent retrograde percutaneous embolization recurrent varicoceles were identified in 17% and 10% presented postoperative hydroceles. Of the 48 patients who underwent suprainguinal retroperitoneal open surgery with artery preservation, varicocele recurred in 17% , while hydroceles developed in 6%. The overall success rate, defined as absence of recurrence or persistence of the varicocele during follow-up, was 87.6%. Comparison of reactive hydrocele and recurrence rates with the variables of age, degree of varicocele and length of follow-up showed that both parameters were statistically dependent on the duration of postoperative surveillance (p<0.05). CONCLUSIONS: Comparison of all 3 groups did not revealed significant differences in varicocele recurrence and hydrocele formation (p>0.05). Pairwise group comparison showed that open surgery with artery preservation and retrograde embolization might carry a higher risk of recurrence/persistence compared to laparoscopic mass ligation of the spermatic vessels. On the other hand, the laparoscopic approach with en bloc ligation of the spermatic vessels may be associated with a higher risk of secondary hydrocele. According to our data varicocele embolization appears to be slightly less successful than laparoscopy, with similar overall complication rate. Most varicocele recurrences and postoperative hydrocele formation are seen in patients with more than 12 months of follow-up so appropriate length of postoperative surveillance is deemed necessary in these patients. PMID- 29991665 TI - Clinical and pathological characteristics of a series of patients with newly diagnosed primary renal liposarcoma: natural history and effect on survival. AB - OBJECTIVES: Primary renal liposarcoma is an unusual malignant mesenchymal tumor. In this context, all the previous reports were based on cases with insufficient data regarding the natural history of the disease. We decided to fill this gap, reporting the largest single institution series of patients with primary RL and a review of the already available literature. METHODS: We describe 3 cases with radiologically and histologically-confirmed RL out of 3,224 surgeries performed for primary kidney cancers over 28 years (1987-2015, 0.09%) at a single tertiary care center. RESULTS: Patients underwent open radical nephrectomy with an anterior transperitoneal access with complete resection of the retroperitoneal mass and retroperitoneal lymph node dissection; all patients died from tumor progression after a mean time of 45 months. CONCLUSIONS: In conclusion, RL is a very rare mesenchymal renal tumor, with sporadic cases reported. We reported the largest case series of primary RL. The most appropriate approach for RL is nephrectomy with complete resection of all the neoplastic tissue. Stringent follow-up scheme is required due to a high rate of disease recurrence and progression. The role of adjuvant and salvage therapy remains to be investigated. PMID- 29991666 TI - External erosion. Artificial urinary sphincter complication. PMID- 29991667 TI - Posterior Walnut Cracker Syndrome as a cause of gross hematuria. PMID- 29991668 TI - Using Work Ability Index and work-related stress to evaluate the physical and mental fitness of Iranian telecom tower climbers. AB - BACKGROUND: Working at height has always been considered as one of the most dangerous industrial activities. Workers' fitness including their physical and psychological ability plays a key role in prevention of occupational accidents. This research was conducted to investigate the physical and mental fitness of telecommunication tower climbers as well as their job stress. METHODS: This cross sectional study was conducted among employees of a contracting company which worked in the field of telecommunication tower installation in Iran during 2016. Sixty out of 93 workers voluntarily participated in this study. Data collection tools were the Persian version of the Work Ability Index (WAI), the Persian version of the Health and Safety Executive (HSE) Stress Indicator Tool and an author-developed measure to assess socio-demographic characteristics. Data was analyzed through statistical tests such as independent t-test, univariate analyses of variance (ANOVAs), Pearson's correlation coefficient, and multivariate linear regression; using SPSS 19 software. RESULTS: Workers' mean +/ SD WAI score was 29.17 +/- 10.33 and for work-related stress was 3.08 +/- 1.80. There was a significant relation between WAI and educational level, job tenure, hours of sleep per day, regular exercise, and second job. The repression modeling explained 67.4% of the total variance (adjusted R2) of the WAI score. Among the dimensions of work related stress, control (beta= 0.21) and changes (beta= -0. 40) were significant predictors of the WAI score. CONCLUSIONS: To improve the worker's work ability, intervention programs should focus on promoting level of job control, sleep quality and exercise. Additionally, implementing a comprehensive macroergonomics and participatory program for increase involvement the workers in organization changes should be considered. PMID- 29991669 TI - Necroptosis Is a Mechanism of Death in Mouse Induced Hepatocyte-Like Cells Reprogrammed from Mouse Embryonic Fibroblasts. AB - Liver transplantation is recommended for patients with liver failure, but liver donors are limited. This necessitates the development of artificial livers, and hepatocytes are necessary to develop such artificial livers. Although induced hepatocyte-like cells are used in artificial livers, the characteristics of mouse induced hepatocyte-like cells (miHeps) reprogrammed with embryonic fibroblasts have not yet been clarified. Therefore, this study investigated the mechanisms underlying the survival, function, and death of miHeps. miHeps showed decreased cell viability, increased cytotoxicity, decreased hepatic function, and albumin and urea secretion at passage 14. Addition of necrostatin-1 (NEC-1) to miHeps inhibited necrosome formation and reactive oxygen species generation and increased cell survival. However, NEC-1 did not affect the hepatic function of miHeps. These results provide a basis for development of artificial livers using hepatocytes. PMID- 29991670 TI - Evidence for Volatile Memory in Plants: Boosting Defence Priming through the Recurrent Application of Plant Volatiles. AB - Plant defence responses to various biotic stresses via systemic acquired resistance (SAR) are induced by avirulent pathogens and chemical compounds, including certain plant hormones in volatile form, such as methyl salicylate and methyl jasmonate. SAR refers to the observation that, when a local part of a plant is exposed to elicitors, the entire plant exhibits a resistance response. In the natural environment, plants are continuously exposed to avirulent pathogens that induce SAR and volatile emissions affecting neighbouring plants as well as the plant itself. However, the underlying mechanism has not been intensively studied. In this study, we evaluated whether plants "memorise" the previous activation of plant immunity when exposed repeatedly to plant defensive volatiles such as methyl salicylate and methyl jasmonate. We hypothesised that stronger SAR responses would occur in plants treated with repeated applications of the volatile plant defence compound MeSA than in those exposed to a single or no treatment. Nicotiana benthamiana seedlings subjected to repeated applications of MeSA exhibited greater protection against Pseudomonas syringae pv. tabaci and Pectobacterium carotovorum subsp. carotovorum than the control. The increase in SAR capacity in response to repeated MeSA treatment was confirmed by analysing the defence priming of the expression of N. benthamiana Pathogenesis-Related 1a (NbPR1a) and NbPR2 by quantitative reverse-transcription PCR compared with the control. We propose the concept of plant memory of plant defence volatiles and suggest that SAR is strengthened by the repeated perception of volatile compounds in plants. PMID- 29991672 TI - Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress. AB - Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is U2AF1 S34F missense mutation. Functional analyses of this mutation have been largely limited to hematological malignancies although the mutation is also frequently seen in other cancer types including lung adenocarcinoma (LUAD). We examined the impact of knockdown (KD) of wild type (wt) U2AF1 and ectopic expression of two splice variant S34F mutant proteins in terms of alternative splicing (AS) pattern and cell cycle progression in A549 lung cancer cells. We demonstrate that induction of distinct AS events and disruption of mitosis at distinct sub-stages result from KD and ectopic expression of the mutant proteins. Importantly, when compared with the splicing pattern seen in LUAD patients with U2AF1 S34F mutation, ectopic expression of S34F mutants but not KD was shown to result in common AS events in several genes involved in cell cycle progression. Our study thus points to an active role of U2AF1 S34F mutant protein in inducing cell cycle dysregulation and mitotic stress. In addition, alternatively spliced genes which we describe here may represent novel potential markers of lung cancer development. PMID- 29991671 TI - Histone Deacetylase 701 (HDT701) Induces Flowering in Rice by Modulating Expression of OsIDS1. AB - Rice is a facultative short-day (SD) plant in which flowering is induced under SD conditions or by other environmental factors and internal genetic programs. Overexpression of Histone Deacetylase 701 (HDT701) accelerates flowering in hybrid rice. In this study, mutants defective in HDT701 flowered late under both SD and long-day conditions. Expression levels of florigens Heading date 3a (Hd3a) and Rice Flowering Locus T1 (RFT1), and their immediate upstream floral activator Early heading date 1 (Ehd1), were significantly decreased in the hdt701 mutants, indicating that HDT701 functions upstream of Ehd1 in controlling flowering time. Transcript levels of OsINDETERMINATE SPIKELET 1 (OsIDS1), an upstream repressor of Ehd1, were significantly increased in the mutants while those of OsGI and Hd1 were reduced. Chromatin-immunoprecipitation assays revealed that HDT701 directly binds to the promoter region of OsIDS1. These results suggest that HDT701 induces flowering by suppressing OsIDS1. PMID- 29991674 TI - Keratin 17 Promotes Lung Adenocarcinoma Progression by Enhancing Cell Proliferation and Invasion. AB - BACKGROUND Lung adenocarcinoma (LAC) accounts for the majority of lung cancer, which is the leading cause of cancer-related mortality worldwide. Keratin 17 (KRT17) was reported to promote the tumor development of skin tumor and oral cancer. The aim of this study was to investigate the expression and function of KRT17 in LAC. MATERIAL AND METHODS Immunohistochemical staining and quantitative PCR were performed to explore the expression of KRT17 in both LAC tissues and adjacent normal liver tissues. Chi-square test, univariate analysis, and multivariate analysis were conducted to statistically evaluate the clinical significance of KRT17 in LAC. Proliferation, migration, and invasion capacities of LAC cells were assessed after overexpression or silencing KRT17. RESULTS Both the RNA and protein levels of KRT17 were up-regulated in LAC tissues compared to normal lung tissues. High expression of KRT17 was correlated with advanced TNM stage and poor overall survival. Moreover, KRT17 was identified as a novel independent prognostic factor for LAC patients. Cellular studies showed that KRT17 can enhance the proliferation, migration, and invasion capacities of LAC cells, thereby promoting tumor progression. CONCLUSIONS High expression of KRT17 is frequent in LAC tissues, which promotes tumor proliferation and invasion, and is correlated with a poor overall survival. Targeting KRT17 may be a novel direction for LAC drug development. PMID- 29991673 TI - Self-Reprogramming of Spermatogonial Stem Cells into Pluripotent Stem Cells without Microenvironment of Feeder Cells. AB - Spermatogonial stem cells (SSCs) derived from mouse testis are unipotent in regard of spermatogenesis. Our previous study demonstrated that SSCs can be fully reprogrammed into pluripotent stem cells, so called germline-derived pluripotent stem cells (gPS cells), on feeder cells (mouse embryonic fibroblasts), which supports SSC proliferation and induction of pluripotency. Because of an uncontrollable microenvironment caused by interactions with feeder cells, feeder based SSC reprogramming is not suitable for elucidation of the self-reprogramming mechanism by which SSCs are converted into pluripotent stem cells. Recently, we have established a Matrigel-based SSC expansion culture system that allows long term SSC proliferation without mouse embryonic fibroblast support. In this study, we developed a new feeder-free SSC self-reprogramming protocol based on the Matrigel-based culture system. The gPS cells generated using a feeder-free reprogramming system showed pluripotency at the molecular and cellular levels. The differentiation potential of gPS cells was confirmed in vitro and in vivo. Our study shows for the first time that the induction of SSC pluripotency can be achieved without feeder cells. The newly developed feeder-free self-reprogramming system could be a useful tool to reveal the mechanism by which unipotent cells are self-reprogrammed into pluripotent stem cells. PMID- 29991676 TI - Detection and removal of barcode swapping in single-cell RNA-seq data. AB - Barcode swapping results in the mislabelling of sequencing reads between multiplexed samples on patterned flow-cell Illumina sequencing machines. This may compromise the validity of numerous genomic assays; however, the severity and consequences of barcode swapping remain poorly understood. We have used two statistical approaches to robustly quantify the fraction of swapped reads in two plate-based single-cell RNA-sequencing datasets. We found that approximately 2.5% of reads were mislabelled between samples on the HiSeq 4000, which is lower than previous reports. We observed no correlation between the swapped fraction of reads and the concentration of free barcode across plates. Furthermore, we have demonstrated that barcode swapping may generate complex but artefactual cell libraries in droplet-based single-cell RNA-sequencing studies. To eliminate these artefacts, we have developed an algorithm to exclude individual molecules that have swapped between samples in 10x Genomics experiments, allowing the continued use of cutting-edge sequencing machines for these assays. PMID- 29991675 TI - Practical Suggestions for Prevention of Complications Arising from Oxidized Cellulose Retention: A Case Report and Review of the Literature. AB - BACKGROUND Bleeding is a major intraoperative complication during surgical procedures. When conventional methods such as ligature and diathermocoagulation are ineffective for bleeding management, hemostatic agents should be used. Oxidized cellulose is one of the major hemostatic agents used worldwide. Oxidized cellulose is often left in situ after hemostasis because of its high level of reabsorption that lasts up to 8 weeks. However, 38 cases of retaining-associated complications are reported in the literature. CASE REPORT A 51-year-old male patient presented in our emergency department with acute abdominal pain, nausea, and vomiting. The patient had been admitted in our department for laparoscopic cholecystectomy for acute cholecystitis 25 months previously. Abdominal ultrasound and CT scan showed the presence of a cystic circular mass, with homogeneous fluid content, close to the surgical clips of the previous surgery, resembling a "neogallbladder". Laparoscopic abdominal exploration and drainage were performed. Histological examination reported protein-based amorphous material with rare lymphocytes and macrophages. Culturing was negative for bacterial growth. The patient was discharged uneventfully on the 4 th postoperative day. The primary surgical report was evaluated with evidence of application of Gelita-Cel (r) Standard for hemostatic purposes. Results of 12 month follow-up were normal. CONCLUSIONS Herein, we report the first case of a complication associated with the use of Gelita-Cel (r) Standard. We reviewed the literature to better define the purpose and limits of oxidized cellulose use as a hemostatic agent. Despite the fundamental role of oxidized cellulose as a hemostatic agent, we provide some practical suggestions to prevent the reported severe complications and surgical overtreatments. PMID- 29991677 TI - Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy. AB - Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1, COL3A1, FN1, TGFB1, and PDGFA. We treated seven mdx mice with 60 mg/kg/day nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1, Col3a1, Tgfb1, and Pdgfa. Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients. PMID- 29991679 TI - Positive and negative regulation of carbon nanotube catalysts through encapsulation within macrocycles. AB - One of the most attractive applications of carbon nanomaterials is as catalysts, due to their extreme surface-to-volume ratio. The substitution of C with heteroatoms (typically B and N as p- and n-dopants) has been explored to enhance their catalytic activity. Here we show that encapsulation within weakly doping macrocycles can be used to modify the catalytic properties of the nanotubes towards the reduction of nitroarenes, either enhancing it (n-doping) or slowing it down (p-doping). This artificial regulation strategy presents a unique combination of features found in the natural regulation of enzymes: binding of the effectors (the macrocycles) is noncovalent, yet stable thanks to the mechanical link, and their effect is remote, but not allosteric, since it does not affect the structure of the active site. By careful design of the macrocycles' structure, we expect that this strategy will contribute to overcome the major hurdles in SWNT-based catalysts: activity, aggregation, and specificity. PMID- 29991678 TI - CUEDC2, a novel interacting partner of the SOCS1 protein, plays important roles in the leukaemogenesis of acute myeloid leukaemia. AB - Downregulation of suppressor of cytokine signalling-1 (SOCS1) is one of the vital reasons for JAK1-STAT3 pathway activation in acute myeloid leukaemia (AML). CUE domain-containing 2 (CUEDC2) was a novel interacting partner of SOCS1 and a positive correlation between the expression of CUEDC2 and SOCS1 was confirmed in primary AML cells and AML cell lines without SOCS1 promoter methylation. We aimed to explore roles of CUEDC2 in regulating ubiquitin-mediated degradation of SOCS1 in the leukaemogenesis of AML.According to in vitro experiments, CUEDC2 overexpression increased the level of SOCS1 protein, suppressed JAK1-STAT3 pathway activation. The suppression of this pathway inhibited AML cells' proliferation by causing G1 arrest and enhanced AML cells' sensitivity to cytarabine and idarubicin. Similarity, downregulation of CUEDC2 produced opposite results. Knockout or low expression of CUEDC2 in mouse or AML patients displayed lower overall survival and event-free survival rates, compared with these mouse and AML patients had high-CUEDC2 expression. Mechanistic studies revealed that CUEDC2 overexpression attenuated SOCS1 ubiquitination, facilitated its stabilisation by enhancing SOCS1, Elongin C and Cullin-2 (CUL2) interactions, thus inhibited JAK1-STAT3 pathway and leukaemogenesis of AML. Therefore, our novel findings indicated that CUEDC2 interacted with SOCS1 to suppress SOCS1's ubiquitin-mediated degradation, JAK1-STAT3 pathway activation and leukaemogenesis of AML. PMID- 29991680 TI - Patterns of genomic evolution in advanced melanoma. AB - Genomic alterations occurring during melanoma progression and the resulting genomic heterogeneity between metastatic deposits remain incompletely understood. Analyzing 86 metastatic melanoma deposits from 53 patients with whole-exome sequencing (WES), we show a low branch to trunk mutation ratio and little intermetastatic heterogeneity, with driver mutations almost completely shared between lesions. Branch mutations consistent with UV damage indicate that metastases may arise from different subclones in the primary tumor. Selective gain of mutated BRAF alleles occurs as an early event, contrasting whole-genome duplication (WGD) occurring as a late truncal event in about 40% of cases. One patient revealed elevated mutational diversity, probably related to previous chemotherapy and DNA repair defects. In another patient having received radiotherapy toward a lymph node metastasis, we detected a radiotherapy-related mutational signature in two subsequent distant relapses, consistent with secondary metastatic seeding. Our findings add to the understanding of genomic evolution in metastatic melanomas. PMID- 29991681 TI - Adolescent alcohol exposure epigenetically regulates CREB signaling in the adult amygdala. AB - Binge alcohol drinking in adolescence leads to increased risk for alcohol use and other psychiatric disorders in adulthood. The transcription factor cAMP-response element binding (CREB) protein is involved in the neuronal response to adult ethanol exposure, but its role in the enduring effects of adolescent alcohol exposure in adulthood is unknown. We exposed male rats to adolescent intermittent ethanol (AIE) or saline (AIS) during post-natal days 28-41 and evaluated the epigenetic regulation of CREB dynamics in the adult amygdala. A subset of these adult rats was exposed to an acute ethanol challenge. AIE decreased CREB, phosphorylated CREB, CREB-binding protein (CBP) and p300 protein levels in adult amygdaloid brain structures. AIE exposure also causes deficits in Creb1, Cbp, and p300 mRNA expression in the amygdala of AIE adult rats which are normalized after acute ethanol exposure. Interestingly, occupancy of acetylated histone H3K9/14 proteins at specific locations in the Creb1, Cbp, and p300 gene promoter regions was decreased in the amygdala of AIE adult rats and was normalized by acute ethanol exposure. These results suggest that AIE exposure epigenetically reduces CREB and other related transcriptional activators in the amygdala in adulthood that may be associated with the behavioral effects of adolescent alcohol exposure. PMID- 29991682 TI - Stochastic sequestration dynamics: a minimal model with extrinsic noise for bimodal distributions and competitors correlation. AB - Many biological processes are known to be based on molecular sequestration. This kind of dynamics involves two types of molecular species, namely targets and sequestrants, that bind to form a complex. In the simple framework of mass-action law, key features of these systems appear to be threshold-like profiles of the amounts of free molecules as a function of the parameters determining their possible maximum abundance. However, biochemical processes are probabilistic and take place in stochastically fluctuating environments. How these different sources of noise affect the final outcome of the network is not completely characterised yet. In this paper we specifically investigate the effects induced by a source of extrinsic noise onto a minimal stochastic model of molecular sequestration. We analytically show how bimodal distributions of the targets can appear and characterise them as a result of noise filtering mediated by the threshold response. We then address the correlations between target species induced by the sequestrant and discuss how extrinsic noise can turn the negative correlation caused by competition into a positive one. Finally, we consider the more complex scenario of competitive inhibition for enzymatic kinetics and discuss the relevance of our findings with respect to applications. PMID- 29991683 TI - Quantitative fibre analysis of single-molecule localization microscopy data. AB - Single molecule localization microscopy (SMLM) methods produce data in the form of a spatial point pattern (SPP) of all localized emitters. Whilst numerous tools exist to quantify molecular clustering in SPP data, the analysis of fibrous structures has remained understudied. Taking the SMLM localization coordinates as input, we present an algorithm capable of tracing fibrous structures in data generated by SMLM. Based upon a density parameter tracing routine, the algorithm outputs several fibre descriptors, such as number of fibres, length of fibres, area of enclosed regions and locations and angles of fibre branch points. The method is validated in a variety of simulated conditions and experimental data acquired using the image reconstruction by integrating exchangeable single molecule localization (IRIS) technique. For this, the nanoscale architecture of F actin at the T cell immunological synapse in both untreated and pharmacologically treated cells, designed to perturb actin structure, was analysed. PMID- 29991684 TI - Comprehensive analysis of lung cancer pathology images to discover tumor shape and boundary features that predict survival outcome. AB - Pathology images capture tumor histomorphological details in high resolution. However, manual detection and characterization of tumor regions in pathology images is labor intensive and subjective. Using a deep convolutional neural network (CNN), we developed an automated tumor region recognition system for lung cancer pathology images. From the identified tumor regions, we extracted 22 well defined shape and boundary features and found that 15 of them were significantly associated with patient survival outcome in lung adenocarcinoma patients from the National Lung Screening Trial. A tumor region shape-based prognostic model was developed and validated in an independent patient cohort (n = 389). The predicted high-risk group had significantly worse survival than the low-risk group (p value = 0.0029). Predicted risk group serves as an independent prognostic factor (high risk vs. low-risk, hazard ratio = 2.25, 95% CI 1.34-3.77, p value = 0.0022) after adjusting for age, gender, smoking status, and stage. This study provides new insights into the relationship between tumor shape and patient prognosis. PMID- 29991685 TI - Diagnosis of major depressive disorder based on changes in multiple plasma neurotransmitters: a targeted metabolomics study. AB - Major depressive disorder (MDD) is a debilitating psychiatric illness. However, there is currently no objective laboratory-based diagnostic tests for this disorder. Although, perturbations in multiple neurotransmitter systems have been implicated in MDD, the biochemical changes underlying the disorder remain unclear, and a comprehensive global evaluation of neurotransmitters in MDD has not yet been performed. Here, using a GC-MS coupled with LC-MS/MS-based targeted metabolomics approach, we simultaneously quantified the levels of 19 plasma metabolites involved in GABAergic, catecholaminergic, and serotonergic neurotransmitter systems in 50 first-episode, antidepressant drug-naive MDD subjects and 50 healthy controls to identify potential metabolite biomarkers for MDD (training set). Moreover, an independent sample cohort comprising 49 MDD patients, 30 bipolar disorder (BD) patients and 40 healthy controls (testing set) was further used to validate diagnostic generalizability and specificity of these candidate biomarkers. Among the 19 plasma neurotransmitter metabolites examined, nine were significantly changed in MDD subjects. These metabolites were mainly involved in GABAergic, catecholaminergic and serotonergic systems. The GABAergic and catecholaminergic had better diagnostic value than serotonergic pathway. A panel of four candidate plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) could distinguish MDD subjects from health controls with an AUC of 0.968 and 0.953 in the training and testing set, respectively. Furthermore, this panel distinguished MDD subjects from BD subjects with high accuracy. This study is the first to globally evaluate multiple neurotransmitters in MDD plasma. The altered plasma neurotransmitter metabolite profile has potential differential diagnostic value for MDD. PMID- 29991686 TI - Oxidative degradation of polyamines by serum supplement causes cytotoxicity on cultured cells. AB - Serum is a common supplement for cell culture due to it containing the essential active components for the growth and maintenance of cells. However, the knowledges of the active components in serum are incomplete. Apart from the direct influence of serum components on cultured cells, the reaction of serum components with tested drugs cannot be ignored, which usually results in the false conclusion on the activity of the tested drugs. Here we report the toxicity effect of polyamines (spermidine and spermine) on cultured cells, especially on drug-resistant cancer cell lines, which resulted from the oxidative degradation of polyamines by amine oxidases in serum supplement. Upon adding spermidine or spermine, high concentration of H2O2, an enzyme oxidation product of polyamines, was generated in culture media containing ruminant serum, such as fetal bovine serum (FBS), calf serum, bovine serum, goat serum or horse serum, but not in the media containing human serum. Drug-resistant cancer cell lines showed much higher sensitivity to the oxidation products of polyamines (H2O2 and acrolein) than their wild cell lines, which was due to their low antioxidative capacity. PMID- 29991687 TI - Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes. AB - Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia characterized by leukemic blasts presenting myeloid and lymphoid markers. Here we report data from integrated genomic analysis on 31 MPAL samples and compare molecular profiling with that from acute myeloid leukemia (AML), B cell acute lymphoblastic leukemia (B-ALL), and T cell acute lymphoblastic leukemia (T-ALL). Consistent with the mixed immunophenotype, both AML-type and ALL-type mutations are detected in MPAL. Myeloid-B and myeloid-T MPAL show distinct mutation and methylation signatures that are associated with differences in lineage-commitment gene expressions. Genome-wide methylation comparison among MPAL, AML, B-ALL, and T-ALL sub-classifies MPAL into AML-type and ALL-type MPAL, which is associated with better clinical response when lineage-matched therapy is given. These results elucidate the genetic and epigenetic heterogeneity of MPAL and its genetic distinction from AML, B-ALL, and T-ALL and further provide proof of concept for a molecularly guided precision therapy approach in MPAL. PMID- 29991688 TI - Acoustic Analogues of High-Index Optical Waveguide Devices. AB - High index optical waveguide devices such as slab waveguides, strip waveguides and fibers play extremely important roles in a wide range of modern applications including telecommunications, sensing, lasing, interferometry, and resonant amplification. Yet, transposing these advantageous applications from optics to acoustics remains a fundamental practical challenge, since most materials exhibit refractive indices lower than that of air for sound waves. Here, we demonstrate the relevance of acoustic metamaterials for tackling this pivotal problem. More specifically, we consider a metamaterial built from subwavelength air-filled acoustic pipes engineered to effectively exhibit a higher refractive index than homogenous air. We show that such medium can be employed to realize acoustic equivalents of dielectric slab or strip waveguides, and optical fibers. Unlike conventional acoustic pipes, our guiding approach allows the waveguide to remain open to the external medium, which opens an abundance of new opportunities in noise management, medical imaging, underwater communication systems, and sensing. PMID- 29991689 TI - Catalyst-TiO(OH)2 could drastically reduce the energy consumption of CO2 capture. AB - Implementing Paris Climate Accord is inhibited by the high energy consumption of the state-of-the-art CO2 capture technologies due to the notoriously slow kinetics in CO2 desorption step of CO2 capture. To address the challenge, here we report that nanostructured TiO(OH)2 as a catalyst is capable of drastically increasing the rates of CO2 desorption from spent monoethanolamine (MEA) by over 4500%. This discovery makes CO2 capture successful at much lower temperatures, which not only dramatically reduces energy consumption but also amine losses and prevents emission of carcinogenic amine-decomposition byproducts. The catalytic effect of TiO(OH)2 is observed with Raman characterization. The stabilities of the catalyst and MEA are confirmed with 50 cyclic CO2 sorption and sorption. A possible mechanism is proposed for the TiO(OH)2-catalyzed CO2 capture. TiO(OH)2 could be a key to the future success of Paris Climat e Accord. PMID- 29991690 TI - Benzo(a)pyrene in Cigarette Smoke Enhances HIV-1 Replication through NF-kappaB Activation via CYP-Mediated Oxidative Stress Pathway. AB - Smoking aggravates HIV-1 pathogenesis and leads to decreased responses to antiretroviral therapy. In this study, we aim to find a molecular mechanism that would explain smoking-induced HIV-1 replication. Benzo(a)pyrene (BaP), a major carcinogen in cigarette, requires metabolic activation through cytochrome P450s (CYPs) to exert its toxic effects. We hypothesized that CYP-mediated BaP metabolism generates reactive oxygen species (ROS), and the resultant oxidative stress aggravates HIV-1 replication. As expected, we observed ~3 to 4-fold increase in HIV-1 replication in U1 cells and human primary macrophages after chronic BaP exposure. We also observed ~30-fold increase in the expression of CYP1A1 at mRNA level, ~2.5-fold increase in its enzymatic activity as well as elevated ROS and cytotoxicity in U1 cells. The knock-down of the CYP1A1 gene using siRNA and treatment with selective CYP inhibitors and antioxidants significantly reduced HIV-1 replication. Further, we observed a nuclear translocation of NF-kappaB subunits (p50 and p65) after chronic BaP exposure, which was reduced by treatment with siRNA and antioxidants/CYP inhibitors. Suppression of NF-kappaB pathway using specific NF-kappaB inhibitors also significantly reduced HIV-1 replication. Altogether, our results suggest that BaP enhances HIV-1 replication in macrophages by a CYP-mediated oxidative stress pathway followed by the NF-kappaB pathway. PMID- 29991691 TI - Identifying a panel of genes/proteins/miRNAs modulated by arsenicals in bladder, prostate, kidney cancers. AB - Arsenic and arsenic-derivative compounds, named as arsenicals, represent a worldwide problem for their effect on the human health and, in particular, for their capability to increase the risk of developing cancer such as kidney, bladder and prostate cancer. The main source of arsenical exposure is drinking water. Nowadays, it is well known that the chronic exposure to arsenicals leads to a series of epigenetic alterations that have a role in arsenic-induced effects on human health including cancer. Based on these observations, the aim of our study was to select by network analysis the genes/proteins/miRNAs implicated in kidney, bladder and prostate cancer development upon arsenical exposure. From this analysis we identified: (i) the nodes linking the three molecular networks specific for kidney, bladder and prostate cancer; (ii) the relative HUB nodes (RXRA, MAP3K7, NR3C1, PABPC1, NDRG1, RELA and CTNNB1) that link the three cancer networks; (iii) the miRNAs able to target these HUB nodes. In conclusion, we highlighted a panel of potential molecules related to the molecular mechanisms of arsenical-induced cancerogenesis and suggest their utility as biomarkers or therapeutic targets. PMID- 29991692 TI - Prognostic role of c-Met in head and neck squamous cell cancer tissues: a meta analysis. AB - This meta-analysis aims to evaluate the effects of high c-Met levels in head and neck squamous cell carcinomas (HNSCC) on survival and clinicopathological features. Publications concerned with the clinical significance of c-Met protein expression in HNSCC were identified from the Scopus and Web of Science database searches. To elucidate the relationship between c-Met expression and clinical outcomes, a meta-analysis of the selected articles was conducted. Seventeen publications involving a total of 1724 patients met the inclusion criteria. c-Met overexpression was significantly correlated with poor overall survival (hazard ratio (HR) = 2.19, 95% confidence interval (CI) = 1.55-3.10). c-Met immunohistochemical staining positivity was also associated with worse relapse free survival (HR = 1.64, 95% CI = 1.24-2.17) and presence of regional lymph node metastases (odds ratio (OR) = 1.76, 95% CI = 1.26-2.45). High levels of c-Met expression in HNSCC predict unfavorable prognosis associated with common clinicopathological features. PMID- 29991694 TI - Treasure hunt. PMID- 29991695 TI - Converging inputs. PMID- 29991693 TI - Non-dissociative structural transitions of the Watson-Crick and reverse Watson Crick A.T DNA base pairs into the Hoogsteen and reverse Hoogsteen forms. AB - In this study it was theoretically shown that discovered by us recently (Brovarets' et al., Frontiers in Chemistry, 2018, 6:8; doi: 10.3389/fchem.2018.00008) high-energetical, significantly non-planar (symmetry C1), short-lived wobbled conformers of the classical Watson-Crick A.T(WC), reverse Watson-Crick A.T(rWC), Hoogsteen A.T(N) and reverse Hoogsteen A.T(rN) DNA base pairs are the intermediates of their pairwise A?T(WC)/A?T(rWC) <-> A?T(H)/A?T(rH) conformational transformations. These transitions do not require for their realization the energy-consumable anisotropic rotation of the amino group of A around the exocyclic C6-N6 bond. They are controlled by the non-planar transition states with quasi-orthogonal geometry (symmetry C1) joined by the single intermolecular (T)N3H...N6(A) H-bond (~4 kcal?mol-1). The Gibbs free energies of activation for these non-dissociative, dipole-active conformational transitions consist 7.33 and 7.81 kcal?mol-1, accordingly. Quantum-mechanical (QM) calculations in combination with Bader's quantum theory of "Atoms in Molecules" (QTAIM) have been performed at the MP2/aug-cc-pVDZ//B3LYP/6 311++G(d,p) level of QM theory in the continuum with epsilon = 4 under normal conditions. PMID- 29991696 TI - Toxicological evaluation of convulsant and anticonvulsant drugs in human induced pluripotent stem cell-derived cortical neuronal networks using an MEA system. AB - Functional evaluation assays using human induced pluripotent stem cell (hiPSC) derived neurons can predict the convulsion toxicity of new drugs and the neurological effects of antiepileptic drugs. However, differences in responsiveness depending on convulsant type and antiepileptic drugs, and an evaluation index capable of comparing in vitro responses with in vivo responses are not well known. We observed the difference in synchronized burst patterns in the epileptiform activities induced by pentylentetrazole (PTZ) and 4 aminopryridine (4-AP) with different action mechanisms using multi-electrode arrays (MEAs); we also observed that 100 uM of the antiepileptic drug phenytoin suppressed epileptiform activities induced by PTZ, but increased those induced by 4-AP. To compare in vitro results with in vivo convulsive responses, frequency analysis of below 250 Hz, excluding the spike component, was performed. The in vivo convulsive firing enhancement of the high gamma wave and beta wave component were observed remarkably in in vitro hiPSC-derived neurons with astrocytes in co culture. MEA measurement of hiPSC-derived neurons in co-culture with astrocytes and our analysis methods, including frequency analysis, appear effective for predicting convulsion toxicity, side effects, and their mechanism of action as well as the comparison of convulsions induced in vivo. PMID- 29991697 TI - Harnessing citizen science through mobile phone technology to screen for immunohistochemical biomarkers in bladder cancer. AB - BACKGROUND: Immunohistochemistry (IHC) is often used in personalisation of cancer treatments. Analysis of large data sets to uncover predictive biomarkers by specialists can be enormously time-consuming. Here we investigated crowdsourcing as a means of reliably analysing immunostained cancer samples to discover biomarkers predictive of cancer survival. METHODS: We crowdsourced the analysis of bladder cancer TMA core samples through the smartphone app 'Reverse the Odds'. Scores from members of the public were pooled and compared to a gold standard set scored by appropriate specialists. We also used crowdsourced scores to assess associations with disease-specific survival. RESULTS: Data were collected over 721 days, with 4,744,339 classifications performed. The average time per classification was approximately 15 s, with approximately 20,000 h total non gaming time contributed. The correlation between crowdsourced and expert H-scores (staining intensity * proportion) varied from 0.65 to 0.92 across the markers tested, with six of 10 correlation coefficients at least 0.80. At least two markers (MRE11 and CK20) were significantly associated with survival in patients with bladder cancer, and a further three markers showed results warranting expert follow-up. CONCLUSIONS: Crowdsourcing through a smartphone app has the potential to accurately screen IHC data and greatly increase the speed of biomarker discovery. PMID- 29991698 TI - Determinants of willingness to receive healthy lifestyle advice in the context of cancer screening. AB - BACKGROUND: Providing lifestyle advice at cancer screening may help reduce the cancer burden attributable to health-related behaviour. We examined determinants of willingness to receive advice about several behavioural cancer risk factors. METHODS: A population-based sample of English adults eligible for cancer screening (n = 1221) completed items on willingness to receive lifestyle advice. Sociodemographic, psychological (risk perceptions, cancer risk factor awareness) and behavioural factors were used to predict interest in advice about diet, weight, physical activity, smoking and alcohol consumption. RESULTS: Two thirds (62-67%) reported interest in advice about diet, weight, and physical activity; 17% were willing to receive advice about smoking, and 32% about alcohol consumption. Willingness to receive advice was higher in those not adhering to guidelines for weight, physical activity, smoking and alcohol consumption (all p < 0.01). Non-White ethnicity was associated with interest in advice about diet, physical activity and smoking (all p < 0.01). Willingness to receive advice about diet, weight, physical activity and alcohol consumption increased with greater recognition of cancer risk factors (all p < 0.01). CONCLUSIONS: Willingness to receive lifestyle advice at cancer screening was high, suggesting this context may provide an opportunity to support behaviour change. Increasing awareness of cancer risk factors may facilitate interest in lifestyle advice. PMID- 29991699 TI - Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease. AB - BACKGROUND: Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit. METHODS: In order to address this, we assessed the impact of abiraterone on cell viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations. RESULTS: Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome. CONCLUSIONS: Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer. PMID- 29991700 TI - Long-term outcomes of the GPOH NB97 trial for children with high-risk neuroblastoma comparing high-dose chemotherapy with autologous stem cell transplantation and oral chemotherapy as consolidation. AB - BACKGROUND: This study was done to investigate the long-term event free and overall survival of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), compared to maintenance chemotherapy (MT). Patterns of recurrences and late sequelae of both arms were analysed. METHODS: A randomised open label trial was conducted nationwide during 1997-2004 in Germany and Switzerland. 295 patients with high-risk neuroblastoma were randomly assigned to high-dose chemotherapy with autologous stem cell transplantation (ASCT) or maintenance chemotherapy (MT) for consolidation. Analyses were done by intention to-treat (ITT: ASCT/MT N = 149/146), as treated (AT: N = 110/102), and treated as randomised (TAR: N = 75/70). RESULTS: The event free survival was superior for the patients receiving ASCT compared to patients treated with MT in all three cohorts (hazard ratio [HR] for ITT 1.39, 95% confidence interval (CI) 1.05-1.85, P = 0.022, HR for AT 1.75, CI 1.24-2.47, P = 0.001; HR for TAR 2.07, CI 1.36 3.16, P = 0.001). Overall survival was also in favour of the ASCT groups (ITT: P = 0.075; AT: P = 0.017; TAR: P = 0.005). The frequencies of late sequelae were not different except for focal nodular hyperplasia of the liver observed more frequently in the ASCT arm. CONCLUSIONS: High-dose chemotherapy with autologous stem cell transplantation had a better long-term outcome compared to maintenance chemotherapy. PMID- 29991701 TI - Femtosecond-laser-written Microstructured Waveguides in BK7 Glass. AB - There is a deficiency of low-loss microstructured waveguides that can be fabricated with a single laser-pass to minimize stress build-up, which can enable enhanced functionality and higher compactness for integrated optical devices. We demonstrate, for the first time, a series of multi-ring claddings each with a pair of cores in BK7 glass. Each waveguide was fabricated using only a single laser-pass at 1 MHz pulse repetition rate, 5 mm/s translation speed, 250 fs pulse width, over a set of pulse energies. We obtained the lowest-reported propagation loss of 0.062 dB/cm, measured at 1155 nm wavelength from the waveguide written with 340 nJ pulse energy. The maximum observed numerical aperture is 0.020, measured at 1155 nm wavelength from the waveguide written with 620 nJ pulse energy. Such waveguides could be incorporated in integrated Raman laser platforms for biomedical applications. PMID- 29991702 TI - Expression of urotensin II is associated with placental autophagy in patients with severe preeclampsia. AB - The aims of this study are to explore the correlation between the expressions of urotensin II (UII) and autophagic markers (LC3 and P62) in patients with severe preeclampsia (SPE). A total of 64 pregnant subjects were recruited, including 29 healthy pregnancies and 35 preeclamptic patients (7 mild preeclamptic (MPE) patients and 28 SPE patients). UII and autophagic markers expression in placenta specimens was investigated by immunohistochemistry (IHC), RT-qPCR, and western blot. IHC analysis manifested that the expressions of UII and autophagic markers were mainly located in the placental cytotrophoblast and syncytiotrophoblast. Western blot and IHC analysis both indicated that the expression of UII was significantly correlated with autophagic marker LC3II (by western blot) or LC3 (by IHC) (r = 0.495, P = 0.010; r = 0.816, P = 0.007). Moreover, SPE group had higher expression of UII and LC3II, lower expression of P62 than that of normal controls. The expression of LC3II was positively related with systolic blood pressure (SBP) and urinary protein level (SBP (r = 0.501, P = 0.003) and urine protein quantitation (r = 0.509, P = 0.022)), whereas P62 had negative correlation with SBP. We first verify that UII has positive correlation with autophagic marker LC3 in placentas of preeclampsia patients; besides, autophagic levels are positively correlated with SBP and urine protein in patients with SPE. PMID- 29991703 TI - A comparison of blood pressure indices as predictors of all-cause mortality among middle-aged men and women during 701,707 person-years of follow-up. AB - High systolic blood pressure (SBP) is often used as a measure of hypertension in epidemiological studies. Alternative blood pressure (BP) indices include diastolic blood pressure (DBP), pulse pressure (PP), mid-blood pressure (MBP) and mean arterial pressure (MAP). The present study compares the predictive ability for all-cause mortality (ACM) of these indices and the novel BP index mean proportional arterial pressure (MPAP), defined as the weighted mean of SBP and DBP where the weights are proportional to SBP's and DBP's contributions to the sum of SBP and DBP. Using a Swedish cohort of 32,238 middle-aged men and women, not being on antihypertensive treatment, examined in 1989-2000 and followed-up until March 9, 2017, the predictive abilities for ACM of SBP, DBP, PP, MBP, MAP and MPAP were compared using a likelihood-based R2-type measure for adjusted and unadjusted Cox regression models. Of the included participants (mean age 45.4 years, 48.2% men), 2936 (9.1%) died during a mean follow-up time of 21.8 years, equalling 701,707 person-years at risk. Higher BP were for all indices significantly associated with increased ACM. For all models, those including MPAP had the highest predictive ability, followed in turn by models including MBP, SBP, MAP, DBP and PP, respectively. The difference was significant for SBP, DBP and PP in unadjusted models and for PP in fully adjusted models. In conclusion, MPAP and MBP are the best predictors of ACM. Until the clinical usefulness of these indices has been evaluated, they may primarily be useful for epidemiological studies. PMID- 29991705 TI - Central insulin action induces activation of paraventricular oxytocin neurons to release oxytocin into circulation. AB - Oxytocin neurons in the paraventricular nucleus (PVN) of hypothalamus regulate energy metabolism and reproduction. Plasma oxytocin concentration is reduced in obese subjects with insulin resistance. These findings prompted us to hypothesize that insulin serves to promote oxytocin release. This study examined whether insulin activates oxytocin neurons in the PVN, and explored the underlying signaling. We generated the mice deficient of 3-phosphoinositide-dependent protein kinase-1 (PDK1), a major signaling molecule particularly for insulin, specifically in oxytocin neurons (Oxy Pdk1 KO). Insulin increased cytosolic calcium concentration ([Ca2+]i) in oxytocin neurons with larger (?25 MUm) and smaller (<25 MUm) diameters isolated from PVN in C57BL/6 mice. In PDK1 Oxy Pdk1 KO mice, in contrast, this effect of insulin to increase [Ca2+]i was markedly diminished in the larger-sized oxytocin neurons, while it was intact in the smaller-sized oxytocin neurons. Furthermore, intracerebroventricular insulin administration induced oxytocin release into plasma in Oxy Cre but not Oxy Pdk1 KO mice. These results demonstrate that insulin PDK1-dependently preferentially activates PVN magnocellular oxytocin neurons to release oxytocin into circulation, possibly serving as a mechanism for the interaction between metabolism and perinatal functions. PMID- 29991704 TI - Impact of SPRINT results on hypertension guidelines: implications for "frail" elderly patients. AB - In the last years, guidelines for the treatment of hypertension recommended individualized blood pressure goals for geriatric population because of elderly susceptibility to adverse outcomes and higher mortality rate deriving from the excessive blood pressure lowering, especially in "frail" elderly. Recent findings from the SPRINT study, which demonstrated that intensive blood pressure lowering was associated with lower rates of cardiovascular events and mortality in both hypertensive fit and frail elderly subjects compared to standard treatment, heavily influenced the recent US guidelines. In SPRINT sub-study analysis of adults aged >=75 years, the most controversial issue appears the method of blood pressure measurement, the selection of patients and related-frailty degree that appears to be very light. Accordingly, it has been described that light frailty is related to good outcomes in older adults. SPRINT findings in "frail elderly patients" cannot be applied to the clinical practice because this condition has been clearly under-estimated. Thus, frailty status should be routinely and correctly quantified in order to identify the frailty degree and to find the best harms-benefits balance of antihypertensive drug treatment in frail older adults. PMID- 29991706 TI - A profiling analysis of contributions of cigarette smoking, dietary calcium intakes, and physical activity to fragility fracture in the elderly. AB - Fragility fracture and bone mineral density (BMD) are influenced by common and modifiable lifestyle factors. In this study, we sought to define the contribution of lifestyle factors to fracture risk by using a profiling approach. The study involved 1683 women and 1010 men (50+ years old, followed up for up to 20 years). The incidence of new fractures was ascertained by X-ray reports. A "lifestyle risk score" (LRS) was derived as the weighted sum of effects of dietary calcium intake, physical activity index, and cigarette smoking. Each individual had a unique LRS, with higher scores being associated with a healthier lifestyle. Baseline values of lifestyle factors were assessed. In either men or women, individuals with a fracture had a significantly lower age-adjusted LRS than those without a fracture. In men, each unit lower in LRS was associated with a 66% increase in the risk of total fracture (non-adjusted hazard ratio [HR] 1.66; 95% CI, 1.26 to 2.20) and still significant after adjusting for age, weight or BMD. However, in women, the association was uncertain (HR 1.30; 95% CI, 1.11 to 1.53). These data suggest that unhealthy lifestyle habits are associated with an increased risk of fracture in men, but not in women, and that the association is mediated by BMD. PMID- 29991707 TI - Expression of the oxygen-sensitive transcription factor subunit HIF-1alpha in patients suffering from secondary Raynaud syndrome. AB - Anti-ischemic therapy remains a challenge due to the complexity of hypoxia response pathways. Hypoxia-inducible factor (HIF)-1 is a heterodimer transcription factor consisting of 2 subunits, HIF-1alpha and HIF-1beta. Hypoxia dependent activation of HIF-1alpha regulates cellular O2 homeostasis. Raynaud syndrome (RS), as a comorbidity of the autoimmune disease systemic sclerosis (SS), is characterized by vasospasms that limit blood flow to the limbs, resulting in hypoxia. A single-center randomized study was conducted to compare prostaglandin E1 (PgE1) therapy with a treatment combining PgE1 and an endothelin 1 blocker, bosentan. A total of 30 patients suffering from SS with RS were enrolled. We examined the regulation of HIF-1alpha, its target heme oxygenase-1 (HMOX-1), and the serum levels of the HIF-1alpha protein in a subset of patients as well as in ten healthy individuals. The expression of HIF-1alpha and HMOX-1 in monocytes was measured using absolute plasmid-based quantitative real-time PCR, whereas serum HIF-1alpha levels were measured with ELISA. Samples were taken at the time of randomization and after 24 weeks. We found that HIF-1alpha and HMOX-1 mRNA expression in monocytes and serum HIF-1alpha protein levels were significantly higher in the SS/RS patients compared to the healthy control group. Single-drug therapy significantly increased HIF-1alpha and HMOX-1 mRNA expression in monocytes and serum HIF-1alpha protein levels in the SS/RS patients compared to those at the time of randomization, whereas combining PgE1 with an endothelin 1 blocker prevented the further increases in HIF-1alpha and HMOX-1 expression. We propose HIF-1alpha and HMOX-1 as novel markers for anti-ischemic therapy in RS. PMID- 29991708 TI - Developmental and behavioral effects in neonatal and adult mice following prenatal activation of endocannabinoid receptors by capsaicin. AB - Despite the apparent abundance of ligand-gated transient receptor potential vanilloid type 1 (TRPV1) and possible cross talk between the endocannabinoid and endovanilloid systems in the central nervous system (CNS), it is unclear what role TRPV1 receptor activation in CNS plays in neurobehavioral development. We previously reported that capsaicin or WIN55212-2 induces risk aversion in the plus-maze test, which was dependent on the gender and mouse strain used. In this study, pregnant BALBc mice were administered capsaicin (1.0 or 4.0 mg/kg, i.p.) during the second week of gestation. Developmental effects of prenatal exposure to capsaicin were assessed in neonates, and behavioral effects were assessed in adult offspring. Gender- and dose-specific variations in ultrasonic vocalizations, weight gain, righting reflex, and general activity of the pups were observed. Prenatal exposure to capsaicin altered plus-maze performance, especially with further exogenous capsaicin challenge. Furthermore, dose- and gender-specific effects were evident in the conditioned place preference/aversion paradigm following conditioning with capsaicin in adult animals. The capsaicin induced aversion in the plus-maze test was enhanced by WIN55212-2 and blocked by pretreatment with vanilloid antagonist capsazepine or the CB1 receptor antagonist rimonabant, demonstrating an interaction between the endocannabinoid and endovanilloid systems in CNS. Taken together, the interaction between the endocannabinoid and endovanilloid signaling systems can be exploited for therapeutic applications in health and disease. PMID- 29991709 TI - Cancer immune checkpoint blockade therapy and its associated autoimmune cardiotoxicity. AB - The immune checkpoint molecules are emerged in the evolution to protect the host from self-attacks by activated T cells. However, cancer cells, as a strategy to survive and expand, can hijack these molecules and mechanisms to suppress T cell mediated immune responses. Therefore, an idea of blocking the checkpoint molecules to enhance the anti-tumor activities of the host immune system has been developed and applied to the cancer therapy after discovery of the inhibitory T cell co-receptor, cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and further enhanced on the identification of PD-1 and its ligands. Since 2010, several checkpoint inhibitors have been approved by FDA and many more are in clinical trials. In the treatment of advanced cancers, these inhibitors significantly increased response rates and survival benefits. However, accompanied with the striking results, immune-related adverse events (irAEs) that broadly occurred in many organs were observed and reported, some of which were fatal. Herein, we first review the recent progressions in the research of the immune checkpoint molecules and the application of their blocking antibodies in cancer treatment, and then discuss the cardiac toxicity induced by the therapy and the strategy to monitor, manage this adverse event when it occurs. PMID- 29991710 TI - Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels. AB - Lappaconitine (LA) has been widely used for postoperative and cancer pain control. LA exhibits excellent analgesic activity with a longer effective time than common local anesthetics such as tetracaine and bupivacaine. However, the mechanisms underlying the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Nav1.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Nav1.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27.67 (15.68-39.66) umol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Nav1.7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more than 10 min to achieve steady-state inhibition when LA (300 umol/L) was administered. Unlike tetracaine and bupivacaine, LA affected neither the voltage-dependent activation nor the inactivation of the channels. Five residues in domain III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influence on channel activation and inactivation accompanied with the different molecular determinants suggest that LA may inhibit Nav1.7 channels in a manner different from local anesthetics. These results may help to understand the featured analgesic activity of LA, thus benefiting its application in the clinic and future drug development. PMID- 29991711 TI - mTORC2 facilitates endothelial cell senescence by suppressing Nrf2 expression via the Akt/GSK-3beta/C/EBPalpha signaling pathway. AB - Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases. Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes. However, its impact on endothelial senescence remains controversial. In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence. A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs). In these senescence models, the formation and activation of mTORC2 were significantly increased, evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR, phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473. Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated beta galactosidase (beta-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells, suggesting that mTORC2/Akt facilitates endothelial senescence. The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level, since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence. Furthermore, mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3beta/C/EBPalpha signaling pathway. These results suggest that the mTORC2/Akt/GSK-3beta/C/EBPalpha/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence. The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases. PMID- 29991712 TI - Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis. AB - Neuroprotection targeting mitochondrial dysfunction has been proposed as an important therapeutic strategy for Parkinson's disease. Ganoderma lucidum (GL) has emerged as a novel agent that protects neurons from oxidative stress. However, the detailed mechanisms underlying GL-induced neuroprotection have not been documented. In this study, we investigated the neuroprotective effects of GL extract (GLE) and the underlying mechanisms in the classic MPTP(1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine)-induced mouse model of PD. Mice were injected with MPTP to induce parkinsonism. Then the mice were administered GLE (400 mg kg-1 d 1, ig) for 4 weeks. We observed that GLE administration significantly improved locomotor performance and increased tyrosine hydroxylase expression in the substantia nigra pars compact (SNpc) of MPTP-treated mice. In in vitro study, treatment of neuroblastoma neuro-2a cells with 1-methyl-4-phenylpyridinium (MPP+, 1 mmol/L) caused mitochondrial membrane potential collapse, radical oxygen species accumulation, and ATP depletion. Application of GLE (800 MUg/mL) protected neuroblastoma neuro-2a cells against MPP+ insult. Application of GLE also improved mitochondrial movement dysfunction in cultured primary mesencephalic neurons. In addition, GLE counteracted the decline in NIX (also called BNIP3L) expression and increase in the LC3-II/LC3-I ratio evoked by MPP+. Moreover, GLE reactivated MPP+-inhibited AMPK, mTOR, and ULK1. Similarly, GLE was sufficient to counteract MPP+-induced inhibition of PINK1 and Parkin expression. GLE suppressed MPP+-induced cytochrome C release and activation of caspase-3 and caspase-9. In summary, our results provide evidence that GLE ameliorates parkinsonism pathology via regulating mitochondrial function, autophagy, and apoptosis, which may involve the activation of both the AMPK/mTOR and PINK1/Parkin signaling pathway. PMID- 29991713 TI - High-throughput screening campaigns against a PI3Kalpha isoform bearing the H1047R mutation identified potential inhibitors with novel scaffolds. AB - The phosphatidylinositol 3-kinase (PI3K) pathway is involved in many cellular functions including cell growth, metabolism, and transformation. Hyperactivation of this pathway contributes to tumorigenesis, therefore, PI3K is a major target for anticancer drug discovery. Since the PI3Kalpha isoform is implicated mostly in cancer, we conducted a high-throughput screening (HTS) campaign using a 3-step PI3K homogenous time-resolved fluorescence assay against this isoform bearing the H1047R mutation. A total of 288,000 synthetic and natural product-derived compounds were screened and of which, we identified 124 initial hits that were further selected by considering the predicted binding mode, relationship to known pan-assay interference compounds and previous descriptions as a lipid kinase inhibitor. A total of 24 compounds were then tested for concentration-dependent responses. These hit compounds provide novel scaffolds that can potentially be optimized to create novel PI3K inhibitors. PMID- 29991714 TI - Low serum osteocalcin levels are correlated with left ventricular systolic dysfunction and cardiac death in Chinese men. AB - Osteocalcin is a newly identified type of cytokine secreted by osteoblasts, which has an endocrine function, mediates energy and glycol-lipid metabolism, and is closely related to cardiovascular diseases. In this study, we investigated the value of serum osteocalcin levels in predicting left ventricular systolic dysfunction and cardiac death. A total of 258 patients in the Department of Cardiology were included. Two-dimensional echocardiography was performed in all the subjects. The cardiac death of subjects occurring with a median follow-up of 4.6 years was informed via phone calls or the electronic medical records. The serum osteocalcin levels were measured using electrochemiluminescent immunoassay. We found that the median left ventricular ejection fractions (LVEFs) were 62% in men and 63% in women. In the men with a LVEF > 62%, the serum osteocalcin levels were significantly higher than in those with LVEF <= 62% (P = 0.042), whereas this difference was absent in the women. Both the serum osteocalcin (beta = 0.095, P = 0.028) and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP; beta = -0.003, P < 0.01) levels remained independently significantly correlated with LVEF in the men but not in the women. Receiver operating characteristic (ROC) analyses of the men revealed that the serum osteocalcin (P = 0.007), serum NT-pro-BNP (P = 0.018) and serum osteocalcin + NT-pro-BNP (P < 0.01) levels were all significant in identifying left ventricular systolic dysfunction at baseline, but the pairwise comparisons of the three areas under the curves (AUCs) were all non-significant. The men in the lower osteocalcin level group at baseline suffered a greater risk of future cardiac death than those in the higher osteocalcin level group, whereas the result for NT-pro-BNP exhibited the opposite pattern. In conclusion, lower serum osteocalcin levels in the men could identify left ventricular systolic dysfunction and cardiac death in a manner that was not inferior to high serum NT-pro-BNP levels. PMID- 29991715 TI - A multifunctional human monoclonal neutralizing antibody that targets a unique conserved epitope on influenza HA. AB - The high rate of antigenic drift in seasonal influenza viruses necessitates frequent changes in vaccine composition. Recent seasonal H3 vaccines do not protect against swine-origin H3N2 variant (H3N2v) strains that recently have caused severe human infections. Here, we report a human VH1-69 gene-encoded monoclonal antibody (mAb) designated H3v-47 that exhibits potent cross-reactive neutralization activity against human and swine H3N2 viruses that circulated since 1989. The crystal structure and electron microscopy reconstruction of H3v 47 Fab with the H3N2v hemagglutinin (HA) identify a unique epitope spanning the vestigial esterase and receptor-binding subdomains that is distinct from that of any known neutralizing antibody for influenza A H3 viruses. MAb H3v-47 functions largely by blocking viral egress from infected cells. Interestingly, H3v-47 also engages Fcgamma receptor and mediates antibody dependent cellular cytotoxicity (ADCC). This newly identified conserved epitope can be used in design of novel immunogens for development of broadly protective H3 vaccines. PMID- 29991716 TI - A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1mut) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1mut from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment. PMID- 29991717 TI - miR-34a exerts as a key regulator in the dedifferentiation of osteosarcoma via PAI-1-Sox2 axis. AB - Osteosarcoma (OS) is a malignant bone cancer with severe chromosomal abnormalities and genetic aberrations. Our previous work reported the dedifferentiation of OS, which is related to poor prognosis. However, the molecular mechanism that regulates OS dedifferentiation is still a subject of exploration. Emerging evidence has suggested that microRNAs (miRNAs) are associated with the pathogenesis of OS and could potentially be developed for use as diagnostic biomarkers and therapeutic strategies. In the present study, we intended to illustrate the role of miR-34a in the dedifferentiation of OS. Upregulation of miR-34a was observed while OS cells were induced into stem-like phenotype. Notably, inhibition of miR-34a could promote the reprogramming transition of OS. Further exploration on the downstream network of miR-34a identified that blocking plasminogen activator inhibitor-1 (PAI-1) expression could restrain OS dedifferentiation into cancer stem-like cells by downregulating SRY-related-HMG box (Sox) 2. We also showed that Sox2 overexpression rescued the suppression phenotype driven by PAI-1 inhibition. Conversely, PAI-1 inhibitor (PAI-039) could suppress the upregulation of Sox2 expression caused by miR-34a inhibition. Be applying bone extracellular matrix (BEM)-OS models, we demonstrated the phenotypic heterogeneity of OS cells, consistent with a strong concordance between PAI-1 and Sox2 expression levels. Taken together, our findings proved miR-34a to be a bona fide suppressor involved in the regulation of OS dedifferentiation. Targeting miR-34a or its direct target PAI-1 could offer new strategies for OS treatment. PMID- 29991718 TI - Oncogenic addiction to high 26S proteasome level. AB - Proteasomes are large intracellular complexes responsible for the degradation of cellular proteins. The altered protein homeostasis of cancer cells results in increased dependency on proteasome function. The cellular proteasome composition comprises the 20S catalytic complex that is frequently capped with the 19S regulatory particle in forming the 26S proteasome. Proteasome inhibitors target the catalytic barrel (20S) and thus this inhibition does not allow the deconvolution of the distinct roles of 20S versus 26S proteasomes in cancer progression. We examined the degree of dependency of cancer cells specifically to the level of the 26S proteasome complex. Oncogenic transformation of human and mouse immortalized cells with mutant Ras induced a strong posttranscriptional increase of the 26S proteasome subunits, giving rise to high 26S complex levels. Depletion of a single subunit of the 19S RP was sufficient to reduce the 26S proteasome level and lower the cellular 26S/20S ratio. Under this condition the viability of the Ras-transformed MCF10A cells was severely compromised. This observation led us to hypothesize that cancer cell survival is dependent on maximal utilization of its 26S proteasomes. We validated this possibility in a large number of cancer cell lines and found that partial reduction of the 26S proteasome level impairs viability in all cancer cells examined and was not correlated with cell doubling time or reduction efficiency. Interstingly, normal human fibroblasts are refractory to the same type of 26S proteasome reduction. The suppression of 26S proteasomes in cancer cells activated the UPR and caspase 3 and cells stained positive with Annexin V. In addition, suppression of the 26S proteasome resulted in cellular proteasome redistribution, cytoplasm shrinkage, and nuclear deformation, the hallmarks of apoptosis. The observed tumor cell specific addiction to the 26S proteasome levels sets the stage for future strategies in exploiting this dependency in cancer therapy. PMID- 29991719 TI - The anti-asthmatic drug, montelukast, modifies the neurogenic potential in the young healthy and irradiated brain. AB - Brain tumors are the most common form of solid tumors in children. Due to the increasing number of survivors, it is of importance to prevent long-term treatment-induced side effects. Montelukast, a leukotriene receptor antagonist, may have the desired neuroprotective properties. The aim of the study was to determine whether montelukast could reduce adverse effects of cranial irradiation (CIR) to the young brain. Daily injections of montelukast or vehicle was given to young mice for 4 or 14 days in combination with CIR or under normal conditions. Montelukast treatment for 4 days protected against cell death with 90% more cell death in the vehicle group compared to the montelukast group 24 h after CIR. It also resulted in less microglia activation 6 h after CIR, where montelukast lowered the levels of CD68 compared to the vehicle groups. Interestingly, the animals that received montelukast for 14 days had 50% less proliferating cells in the hippocampus irrespective of receiving CIR or not. Further, the total number of neurons in the granule cell layer was altered during the sub-acute phase. The number of neurons was decreased by montelukast treatment in control animals (15%), but the opposite was seen after CIR, where montelukast treatment increased the number of neurons (15%). The results show beneficial effects by montelukast treatment after CIR in some investigated parameters during both the acute phase and with longer drug treatment. However, it also resulted in lower proliferation in the hippocampus under normal conditions, indicating that the effects of montelukast can be either beneficial or unfavorable, depending on the circumstances. PMID- 29991720 TI - The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification. AB - Haematopoietic cells arise from endothelial cells within the dorsal aorta of the embryo via a process called the endothelial-haematopoietic transition (EHT). This process crucially depends on the transcription factor RUNX1 which rapidly activates the expression of genes essential for haematopoietic development. Using an inducible version of RUNX1 in a mouse embryonic stem cell differentiation model we showed that prior to the EHT, haematopoietic genes are primed by the binding of the transcription factor FLI1. Once expressed, RUNX1 relocates FLI1 towards its binding sites. However, the nature of the transcription factor assemblies recruited by RUNX1 to reshape the chromatin landscape and initiate mRNA synthesis are unclear. Here, we performed genome-wide analyses of RUNX1 dependent binding of factors associated with transcription elongation to address this question. We demonstrate that RUNX1 induction moves FLI1 from distal ETS/GATA sites to RUNX1/ETS sites and recruits the basal transcription factors CDK9, BRD4, the Mediator complex and the looping factor LDB1. Our study explains how the expression of a single transcription factor can drive rapid and replication independent transitions in cellular shape which are widely observed in development and disease. PMID- 29991721 TI - Site-specific ion occupation in the selectivity filter causes voltage-dependent gating in a viral K+ channel. AB - Many potassium channels show voltage-dependent gating without a dedicated voltage sensor domain. This is not fully understood yet, but often explained by voltage induced changes of ion occupation in the five distinct K+ binding sites in the selectivity filter. To better understand this mechanism of filter gating we measured the single-channel current and the rate constant of sub-millisecond channel closure of the viral K+ channel KcvNTS for a wide range of voltages and symmetric and asymmetric K+ concentrations in planar lipid membranes. A model based analysis employed a global fit of all experimental data, i.e., using a common set of parameters for current and channel closure under all conditions. Three different established models of ion permeation and various relationships between ion occupation and gating were tested. Only one of the models described the data adequately. It revealed that the most extracellular binding site (S0) in the selectivity filter functions as the voltage sensor for the rate constant of channel closure. The ion occupation outside of S0 modulates its dependence on K+ concentration. The analysis uncovers an important role of changes in protein flexibility in mediating the effect from the sensor to the gate. PMID- 29991722 TI - Ultrathin and multicolour optical cavities with embedded metasurfaces. AB - Over the past years, photonic metasurfaces have demonstrated their remarkable and diverse capabilities in advanced control over light propagation. Here, we demonstrate that these artificial films of deeply subwavelength thickness also offer new unparalleled capabilities in decreasing the overall dimensions of integrated optical systems. We propose an original approach of embedding a metasurface inside an optical cavity-one of the most fundamental optical elements to drastically scale-down its thickness. By modifying the Fabry-Perot interferometric principle, this methodology is shown to reduce the metasurface based nanocavity thickness below the conventional lambda/(2n) minimum. In addition, the nanocavities with embedded metasurfaces can support independently tunable resonances at multiple bands. As a proof-of-concept, using nanostructured metasurfaces within 100-nm nanocavities, we experimentally demonstrate high spatial resolution colour filtering and spectral imaging. The proposed approach can be extrapolated to compact integrated optical systems on-a-chip such as VCSEL's, high-resolution spatial light modulators, imaging spectroscopy systems, and bio-sensors. PMID- 29991723 TI - Enhanced physicochemical stability and efficacy of angiotensin I-converting enzyme (ACE) - inhibitory biopeptides by chitosan nanoparticles optimized using Box-Behnken design. AB - Bromelain-generated biopeptides from stone fish protein exhibit strong inhibitory effect against ACE and can potentially serve as designer food (DF) with blood pressure lowering effect. Contextually, the DF refer to the biopeptides specifically produced to act as ACE-inhibitors other than their primary role in nutrition and can be used in the management of hypertension. However, the biopeptides are unstable under gastrointestinal tract (GIT) digestion and need to be stabilized for effective oral administration. In the present study, the stone fish biopeptides (SBs) were stabilized by their encapsulation in sodium tripolyphosphate (TPP) cross-linked chitosan nanoparticles produced by ionotropic gelation method. The nanoparticles formulation was then optimized via Box-Behnken experimental design to achieve smaller particle size (162.70 nm) and high encapsulation efficiency (75.36%) under the optimum condition of SBs:Chitosan mass ratio (0.35), homogenization speed (8000 rpm) and homogenization time (30 min). The SBs-loaded nanoparticles were characterized for morphology by transmission electron microscopy (TEM), physicochemical stability and efficacy. The nanoparticles were then lyophilized and analyzed using Fourier transform infra-red spectroscopy (FTIR) and X-ray diffraction (XRD). The results obtained indicated a sustained in vitro release and enhanced physicochemical stability of the SBs-loaded nanoparticles with smaller particle size and high encapsulation efficiency following long period of storage. Moreover, the efficacy study revealed improved inhibitory effect of the encapsulated SBs against ACE following simulated GIT digestion. PMID- 29991724 TI - Myeloid-derived IL-23 drives CRPC. PMID- 29991725 TI - Mechanisms of BCG immunotherapy and its outlook for bladder cancer. AB - BCG immunotherapy is the gold-standard treatment for non-muscle-invasive bladder cancer at high risk of recurrence or progression. Preclinical and clinical studies have revealed that a robust inflammatory response to BCG involves several steps: attachment of BCG; internalization of BCG into resident immune cells, normal cells, and tumour urothelial cells; BCG-mediated induction of innate immunity, which is orchestrated by a cellular and cytokine milieu; and BCG mediated initiation of tumour-specific immunity. As an added layer of complexity, variation between clinical BCG strains might influence development of tumour immunity. However, more than 40 years after the first use of BCG for bladder cancer, many questions regarding its mechanism of action remain unanswered. Clearly, a better understanding of the mechanisms underlying BCG-mediated tumour immunity could lead to improved efficacy, increased tolerance of treatment, and identification of novel immune-based therapies. Indeed, enthusiasm for bladder cancer immunotherapy, and the possibility of combining BCG with other therapies, is increasing owing to the availability of targeted immunotherapies, including checkpoint inhibitors. Understanding of the mechanism of action of BCG immunotherapy has advanced greatly, but many questions remain, and further basic and clinical research efforts are needed to develop new treatment strategies for patients with bladder cancer. PMID- 29991726 TI - The autophagic degradation of Cav-1 contributes to PA-induced apoptosis and inflammation of astrocytes. AB - The accumulation of palmitic acid (PA), implicated in obesity, can induce apoptotic cell death and inflammation of astrocytes. Caveolin-1 (Cav-1), an essential protein for astrocytes survival, can be degraded by autophagy, which is a double-edge sword that can either promote cell survival or cell death. The aim of this study was to delineate whether the autophagic degradation of Cav-1 is involved in PA-induced apoptosis and inflammation in hippocampal astrocytes. In this study we found that: (1) PA caused apoptotic death and inflammation by autophagic induction; (2) Cav-1 was degraded by PA-induced autophagy and PA induced autophagy in a Cav-1-independent manner; (3) the degradation of Cav-1 was responsible for PA-induced autophagy-dependent apoptotic cell death and inflammation; (4) chronic high-fat diet (HFD) induced Cav-1 degradation, apoptosis, autophagy, and inflammation in the hippocampal astrocytes of rats. Our results suggest that the autophagic degradation of Cav-1 contributes to PA induced apoptosis and inflammation of astrocytes. Therefore, Cav-1 may be a potential therapeutic target for central nervous system injuries caused by PA accumulation. PMID- 29991727 TI - NaV1.4 DI-S4 periodic paralysis mutation R222W enhances inactivation and promotes leak current to attenuate action potentials and depolarize muscle fibers. AB - Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNaV1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization. PMID- 29991728 TI - Efficient solar hydrogen generation in microgravity environment. AB - Long-term space missions require extra-terrestrial production of storable, renewable energy. Hydrogen is ascribed a crucial role for transportation, electrical power and oxygen generation. We demonstrate in a series of drop tower experiments that efficient direct hydrogen production can be realized photoelectrochemically in microgravity environment, providing an alternative route to existing life support technologies for space travel. The photoelectrochemical cell consists of an integrated catalyst-functionalized semiconductor system that generates hydrogen with current densities >15 mA/cm2 in the absence of buoyancy. Conditions are described adverting the resulting formation of ion transport blocking froth layers on the photoelectrodes. The current limiting factors were overcome by controlling the micro- and nanotopography of the Rh electrocatalyst using shadow nanosphere lithography. The behaviour of the applied system in terrestrial and microgravity environment is simulated using a kinetic transport model. Differences observed for varied catalyst topography are elucidated, enabling future photoelectrode designs for use in reduced gravity environments. PMID- 29991729 TI - Non-Hermitian photonics promises exceptional topology of light. AB - The band degeneracy, either the exceptional point of a non-Hermitian system or the Dirac point associated with a topological system, can feature distinct symmetry and topology. Their synergy will further produce more exotic topological effects in synthetic matter. PMID- 29991730 TI - Tumor size classification of the 8th edition of TNM staging system is superior to that of the 7th edition in predicting the survival outcome of pancreatic cancer patients after radical resection and adjuvant chemotherapy. AB - The 8th edition of TNM staging system has been released and it incorporates many changes to the T and N classifications for pancreatic cancer. Comparative study between the 7th and 8th edition of TNM staging system from Asian population has not been reported yet. This study aimed to compare the 7th and 8th edition of staging system for pancreatic cancer by using a cohort of pancreatic cancer patients from China after R0 pancreaticoduodenectomy and adjuvant chemotherapy. The results showed according to the pT classification of 7th edition, pT3 was predominant (87.25%), however, the new edition led to a more equal distribution of pT classification. pT1, pT2 and pT3 was 27.45%, 56.86% and 15.69%, respectively. According to the new pN classification, 18.63% of the patients were pN2. The pT classification in the 8th edition was significantly superior to that in the 7th edition at stratifying patients by overall survival. The pN classification in the 8th edition failed to show an advantage over the 7th edition in stratifying patients by overall survival. Therefore, the new pT classification, but not the new pN classification, showed a significant advantage over the previous edition at predicting the overall survival of pancreatic cancer patients. PMID- 29991731 TI - Rapid Screening of Ellagitannins in Natural Sources via Targeted Reporter Ion Triggered Tandem Mass Spectrometry. AB - Complex biomolecules present in their natural sources have been difficult to analyze using traditional analytical approaches. Ultrahigh-performance liquid chromatography (UHPLC-MS/MS) methods have the potential to enhance the discovery of a less well characterized and challenging class of biomolecules in plants, the ellagitannins. We present an approach that allows for the screening of ellagitannins by employing higher energy collision dissociation (HCD) to generate reporter ions for classification and collision-induced dissociation (CID) to generate unique fragmentation spectra for isomeric variants of previously unreported species. Ellagitannin anions efficiently form three characteristic reporter ions after HCD fragmentation that allows for the classification of unknown precursors that we call targeted reporter ion triggering (TRT). We demonstrate how a tandem HCD-CID experiment might be used to screen natural sources using UHPLC-MS/MS by application of 22 method conditions from which an optimized data-dependent acquisition (DDA) emerged. The method was verified not to yield false-positive results in complex plant matrices. We were able to identify 154 non-isomeric ellagitannins from strawberry leaves, which is 17 times higher than previously reported in the same matrix. The systematic inclusion of CID spectra for isomers of each species classified as an ellagitannin has never been possible before the development of this approach. PMID- 29991732 TI - Social Event Memory Test (SEMT): A Video-based Memory Test for Predicting Amyloid Positivity for Alzheimer's Disease. AB - Recent improvements in neuroimaging and molecular markers of Alzheimer's disease (AD) have aided diagnosis in the early stage of the disease, which greatly increases the chance for successful prevention and treatment. However, the expanding resources for AD diagnosis are unlikely to benefit all elderly due to economic burden. Here, we aimed to develop an inexpensive and sensitive method to detect early-stage AD. A scenario for real-world social event memory test (SEMT) was created and filmed in 360 degrees video. Participants watched the 7-min video through head-mounted display (HMD) and then answered questionnaire about the video. We categorized the SEMT score into recall, recognition, and place matching scores and compared them to scores on the Mini-Mental State Examination and Seoul Verbal Learning Test. Using the SEMT scores, we built a logistic regression model that discriminated between amyloid positivity and negativity of the participants, with a cross-validation AUC. Furthermore, a classifier was created using support vector machine, which produced 93.8-95.1% sensitivity in classifying individuals into four groups of normal, mild cognitive impairment with or without amyloid, and AD elderly. The high correlation between the SEMT score and amyloid positivity in individuals who experienced virtual social gathering through an HMD opens a new possibility for early diagnosis of AD. PMID- 29991733 TI - Insects with similar social complexity show convergent patterns of adaptive molecular evolution. AB - Eusociality has independently evolved multiple times in the hymenoptera, but the patterns of adaptive molecular evolution underlying the evolution and elaboration of eusociality remain uncertain. Here, we performed a population genomics study of primitively eusocial Polistes (paper wasps), and compared their patterns of molecular evolution to two social bees; Bombus (bumblebees), and Apis (honey bees). This species triad allowed us to study molecular evolution across a gradient of social complexity (Polistes < Bombus < Apis) and compare species pairs that have similar (i.e. Polistes and Bombus) or different (i.e. Polistes and Apis) life histories, while controlling for phylogenetic distance. We found that regulatory genes have high levels of positive selection in Polistes; consistent with the prediction that adaptive changes in gene regulation are important during early stages of social evolution. Polistes and Bombus exhibit greater similarity in patterns of adaptive evolution including greater overlap of genes experiencing positive selection, and greater positive selection on queen biased genes. Our findings suggest that either adaptive evolution of a few key genes underlie the evolution of simpler forms of eusociality, or that the initial stages of social evolution lead to selection on a few key traits orchestrated by orthologous genes and networks. PMID- 29991734 TI - Power-law relationship in the long-tailed sections of proton dose distributions. AB - The halo portion of a proton therapy dose creates a long tail in proton dose distributions, but so far study of this phenomenon has been limited. We used statistical methods and mathematical models to confirm that the long-tailed portion of proton dose distributions exhibits a power-law relationship. By analyzing 299 measured dose profiles, we found that all proton lateral dose distributions had a significant power-law scaling correlation with a high correlation coefficient in the tail. We set up a dual-mechanism model, containing both direct and indirect impact mechanisms. In the direct impact mechanism, the proximal dose deposition is mainly due to the direct impact of a proton on a particle. In the indirect mechanism, the impact of a proton on a given particle is considered in terms of the proton's impact on a neighboring particle that then impacts the given particle. We found that the indirect impact mechanism led to a tail in the distribution exhibiting a power-law relationship because the probability of the indirect impacts was proportional to the distance; i.e., the longer the distance, the larger the indirect impact probability. Upon analyzing the experimental data, we observed that the power-law exponent increased with proton energy. PMID- 29991735 TI - Selective laser sintering of inkjet-printed silver nanoparticle inks on paper substrates to achieve highly conductive patterns. AB - Development of cost-effective and environmentally friendly manufacturing methods will enable important advances for the production of large-scale flexible electronics. Laser processing has shown to be a promising candidate that offers a fast and non-destructive way to produce highly conductive patterns on flexible substrates such as plastics. However, an emerging option with a lower environmental impact is instead the use of cellulose-based flexible substrates, such as paper. In this work we investigate the use of laser sintering of silver nanoparticle inks, which were inkjet-printed on three different types of paper. Patterns with a high conductivity could be manufactured where a special care was taken to prevent the substrates from damage by the intense laser light. We found that the best results was obtained for a photopaper, with a conductivity of 1.63 * 107 S/m corresponding to nearly 26% of the bulk silver conductivity. In addition, we demonstrate laser sintering to fabricate a fully functional near field communication tag printed on a photopaper. Our results can have an important bearing for the development of cost-effective and environmentally friendly production methods for flexible electronics on a large scale. PMID- 29991736 TI - Oligomerization of a G protein-coupled receptor in neurons controlled by its structural dynamics. AB - G protein coupled receptors (GPCRs) play essential roles in intercellular communication. Although reported two decades ago, the assembly of GPCRs into dimer and larger oligomers in their native environment is still a matter of intense debate. Here, using number and brightness analysis of fluorescently labeled receptors in cultured hippocampal neurons, we confirm that the metabotropic glutamate receptor type 2 (mGlu2) is a homodimer at expression levels in the physiological range, while heterodimeric GABAB receptors form larger complexes. Surprisingly, we observed the formation of larger mGlu2 oligomers upon both activation and inhibition of the receptor. Stabilizing the receptor in its inactive conformation using biochemical constraints also led to the observation of oligomers. Following our recent observation that mGlu receptors are in constant and rapid equilibrium between several states under basal conditions, we propose that this structural heterogeneity limits receptor oligomerization. Such assemblies are expected to stabilize either the active or the inactive state of the receptor. PMID- 29991737 TI - Intrinsic and synaptic properties of hippocampal CA1 pyramidal neurons of the Wistar Audiogenic Rat (WAR) strain, a genetic model of epilepsy. AB - Despite the many studies focusing on epilepsy, a lot of the basic mechanisms underlying seizure susceptibility are mainly unclear. Here, we studied cellular electrical excitability, as well as excitatory and inhibitory synaptic neurotransmission of CA1 pyramidal neurons from the dorsal hippocampus of a genetic model of epilepsy, the Wistar Audiogenic Rat (WARs) in which limbic seizures appear after repeated audiogenic stimulation. We examined intrinsic properties of neurons, as well as EPSCs evoked by Schaffer-collateral stimulation in slices from WARs and Wistar parental strain. We also analyzed spontaneous IPSCs and quantal miniature inhibitory events. Our data show that even in the absence of previous seizures, GABAergic neurotransmission is reduced in the dorsal hippocampus of WARs. We observed a decrease in the frequency of IPSCs and mIPSCs. Moreover, mIPSCs of WARs had faster rise times, indicating that they probably arise from more proximal synapses. Finally, intrinsic membrane properties, firing and excitatory neurotransmission mediated by both NMDA and non NMDA receptors are similar to the parental strain. Since GABAergic inhibition towards CA1 pyramidal neurons is reduced in WARs, the inhibitory network could be ineffective to prevent the seizure-dependent spread of hyperexcitation. These functional changes could make these animals more susceptible to the limbic seizures observed during the audiogenic kindling. PMID- 29991738 TI - Inconclusive evidence for rapid adaptive evolution. PMID- 29991741 TI - P2RX7 keeps memory T cells fit. PMID- 29991739 TI - Paternal origin of Paleo-Indians in Siberia: insights from Y-chromosome sequences. AB - The expansion of modern humans to the American continent after the Last Glacial Maximum led the way to the present-day distribution of American aborigines. Recent advances in autosomal DNA research and expanded testing of mtDNA lineages has provided a clearer picture of the number and timing of founding lineages. However, both autosomal DNA and mtDNA research have provided unresolved competing theories between the short-term and the long-term models of the Beringian standstill hypothesis. Further, the source of founding paternal lineages of American aborigines and their relationship with ancient Siberia populations remains ambiguous. In this study, we reanalyzed a 7.0 Mbp region of 132 paternal Y-chromosome sequences, including 39 newly reported ones, of male samples from American aborigines and Eurasian populations. Among Eurasian samples, we identified Y-chromosome branches that are most closely related to known American aborigine founding lineages, that is, Q1-L804 links to Q1-M3, Q1-L330 links to Q1 Z780, Q1-M120 links to Q1-B143, and C2-F1756 links to C2-P39. The revised phylogenetic tree and age estimates indicate a narrow timeframe (~15.3-14.3 kya) for the upper time limit of human entry to the American continent. Our analysis suggests that the in situ differentiation of Q-M242 in Central Eurasia and South Siberia region gave rise to numerous sub-lineages older than 15.3 kya, and the founding of Paleo-Indian paternal lineages is part of the great Q1-L53 diffusion throughout the Eurasia after the Last Glacial Maximum. The results of our study will assist in future studies of the history of modern populations in Eurasia and the Americas. PMID- 29991742 TI - A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma. AB - Sirtuin-1 (SIRT1), the mammalian ortholog of yeast Sir2p, is well known to be a highly conserved NAD+-dependent protein deacetylase that has been emerging as a key cancer target. Autophagy, an evolutionarily conserved, multi-step lysosomal degradation process, has been implicated in cancer. Accumulating evidence has recently revealed that SIRT1 may act as a tumor suppressor in several types of cancer, and thus activating SIRT1 would represent a possible therapeutic strategy. Thus, in our study, we identified that SIRT1 was a key prognostic factor in brain cancer based upon The Cancer Genome Atlas and tissue microarray analyses. Subsequently, we screened a series of potential small-molecule activators of SIRT1 from Drugbank, and found the best candidate compound F0911 7667 (hereafter, named Comp 5), which showed a good deacetylase activity for SIRT1 rather than other Sirtuins. In addition, we demonstrated that Comp 5 induced autophagic cell death via the AMPK-mTOR-ULK complex in U87MG and T98G cells. Interestingly, Comp 5-induced mitophagy by the SIRT1-PINK1-Parkin pathway. Further iTRAQ-based proteomics analyses revealed that Comp 5 could induce autophagy/mitophagy by downregulating 14-3-3gamma, catalase, profilin-1, and HSP90alpha. Moreover, we showed that Comp 5 had a therapeutic potential on glioblastoma (GBM) and induced autophagy/mitophagy by activating SIRT1 in vivo. Together, these results demonstrate a novel small-molecule activator of SIRT1 that induces autophagic cell death/mitophagy in GBM cells, which would be utilized to exploit this compound as a leading drug for future cancer therapy. PMID- 29991740 TI - The past, present and future management of sickle cell retinopathy within an African context. AB - Sickle cell retinopathy is a potentially blinding condition that affects young people in the working age group. This review looks at the past, present and future management of sickle cell retinopathy within an African context. After Sickle cell disease was first reported in 1910, some reports from Africa were pivotal in describing the retinal changes associated with the disease. It soon became obvious that there was a varied clinical picture and clinical course. Several landmark studies were carried out in Jamaica to help elucidate the complexities of the disease and outline appropriate clinical management. In most of the developed world, the clinical management of sickle cell disease has improved with concurrent improvement in outcomes. Currently resource constraints in most Sub-Saharan African countries where there is a high burden of disease means that the management of sickle cell retinopathy is fraught with numerous challenges. Future large scale trials in Africa shall hopefully help to better elucidate the mechanisms behind proliferative sickle retinopathy and help in the development of new and improved therapeutic pathways. The use of technology can help immensely in the screening of patients with sickle cell to detect early proliferative changes and if necessary treat accordingly. PMID- 29991743 TI - Author Correction: Detection of cervical lymph node metastasis from oral cavity cancer using a non-radiating, noninvasive digital infrared thermal imaging system. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29991745 TI - Correction to: EVI2B is a C/EBPalpha target gene required for granulocytic differentiation and functionality of hematopoietic progenitors. AB - Since publication of this article, the authors identified an error in the acknowledgments section. The original sentence in acknowledgments reads as follows. PMID- 29991746 TI - Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress. AB - Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in response to endoplasmic reticulum (ER) stress; however, a recent paper challenges this conclusion. Here we validate the importance of DR5 and caspase-8 as critical signal conduits for apoptosis activation upon ER stress. PMID- 29991744 TI - CCL5-deficiency enhances intratumoral infiltration of CD8+ T cells in colorectal cancer. AB - Colorectal cancer (CRC) is the third most common solid tumor in the world and shows resistance to several immunotherapies, particularly immune checkpoint blockade which has therapeutic effects on many other types of cancer. Cytotoxic CD8+ T cell has been considered as one of the main populations of effector immune cells in antitumor immunity; however, the absence of CD8+ T cells in the central tumor area has become a major obstacle for solid tumor immunotherapy, particularly for CRC. Thus, novel therapeutic strategies that could promote CD8+ T cells to accumulate in the central tumor area are urgently needed. Here, we demonstrated that CCL5-deficiency delayed tumor growth and metastasis via facilitating CD8+ T cells to accumulate into tumor site in CRC mouse models. Furthermore, CCL5-deficiency could upregulate PD-1 and PD-L1 expression and reduce the resistance to anti-PD-1 antibody therapy in CRC mouse model. Mechanically, the results of RNA-sequencing, in vitro coculture system and hypoxia measurements demonstrated that knockdown of CCL5 could result in the metabolic disorders in CD11bhiF4/80low TAMs and suppress the expression of S100a9 to promote the migration of CD8+ T cells in the tumor microenvironment. These findings were verified by the data of clinical samples from CRC patients, suggesting that CCL5 may provide a potential therapeutic target for the combined PD-1-immunotherapy of CRC. PMID- 29991747 TI - Chimpanzees overcome the tragedy of the commons with dominance. AB - Competition over common-pool resources (CPR) is a ubiquitous challenge for social animals. Many species face similar dilemmas, yet our understanding of the evolutionary trajectory of CPR social strategies remains unexplored. Here, we provide a first look at the social strategies of our closest living relatives, chimpanzees (Pan troglodytes), in two novel resource dilemma experiments. Dyads of chimpanzees were presented with renewable resource systems, collapsible at a quantity-dependent threshold. Dyads had to continuously resist overconsumption to maximize collective gains. In study 1, dyads of chimpanzees sustained a renewing juice source. Inequality of juice acquisition between partners predicted sustaining success, indicating that one individual dominated the task while the partner inhibited. Dyads in study 2 fed together on accumulating carrot pieces but could end the accumulation any time by grabbing an immediate selfish source of carrots. Dyads with low tolerance were more successful at collectively sustaining the resource than highly tolerant dyads. Further, the dominant individual was more likely to cause collapse in dyads with low tolerance than dyads with high tolerance. These results indicate that chimpanzees use a dominance-based monopolisation strategy moderated by social tolerance to overcome the tragedy of the commons. PMID- 29991748 TI - Diffusion weighted MRI as an early predictor of tumor response to hypofractionated stereotactic boost for prostate cancer. AB - We evaluated the feasibility of using the kinetic of diffusion-weighted MRI (DWI) and the normalized apparent coefficient diffusion (ADC) map value as an early biomarker in patients treated by external beam radiotherapy (EBRT). Twelve patients were included within the frame of a multicenter phase II trial and treated for intermediate risk prostate cancer (PCa). Multiparametric MRI was performed before treatment (M0) and every 6 months until M24. Association between nADC and PSA or PSA kinetic was evaluated using the test of nullity of the Spearman correlation coefficient. The median rates of PSA at the time of diagnosis, two years and four years after EBRT were 9.29 ng/ml (range from 5.26 to 17.67), 0.68 ng/ml (0.07-2.7), 0.47 ng/ml (0.09-1.39), respectively. Median nADC increased from 1.14 * 10-3 mm2/s to 1.59 * 10-3 mm2/s between M0 and M24. Only one patient presented a decrease of nADC (1.35 * 10-3 mm2/s and 1.11 * 10-3 mm2/s at M0 and M12 respectively). The increase in nADC at M6 was correlated with PSA decrease at M18, M24 and M30 (p < 0.05). The increase in nADc at M12 was correlated with PSA decrease at M36 (p = 0.019). Early nADC variation were correlated with late PSA decrease for patients with PCa treated by EBRT. PMID- 29991749 TI - Reply to 'Inconclusive evidence for rapid adaptive evolution'. PMID- 29991750 TI - AU040320 deficiency leads to disruption of acrosome biogenesis and infertility in homozygous mutant mice. AB - Study of knockout (KO) mice has helped understand the link between many genes/proteins and human diseases. Identification of infertile KO mice provides valuable tools to characterize the molecular mechanisms underlying gamete formation. The KIAA0319L gene has been described to have a putative association with dyslexia; surprisingly, we observed that homozygous KO males for AU040320, KIAA0319L ortholog, are infertile and present a globozoospermia-like phenotype. Mutant spermatozoa are mostly immotile and display a malformed roundish head with no acrosome. In round spermatids, proacrosomal vesicles accumulate close to the acroplaxome but fail to coalesce into a single acrosomal vesicle. In wild-type mice AU040320 localises to the trans-Golgi-Network of germ cells but cannot be detected in mature acrosomes. Our results suggest AU040320 may be necessary for the normal formation of proacrosomal vesicles or the recruitment of cargo proteins required for downstream events leading to acrosomal fusion. Mutations in KIAA0319L could lead to human infertility; we screened for KIAA0319L mutations in a selected cohort of globozoospermia patients in which no genetic abnormalities have been previously identified, but detected no pathogenic changes in this particular cohort. PMID- 29991751 TI - Volumetric, Nanoscale Optical Imaging of Mouse and Human Kidney via Expansion Microscopy. AB - Although light microscopy is a powerful tool for the assessment of kidney physiology and pathology, it has traditionally been unable to resolve structures separated by less than the ~250 nm diffraction limit of visible light. Here, we report on the optimization, validation, and application of a recently developed super-resolution fluorescence microscopy method, called expansion microscopy (ExM), for volumetric interrogation of mouse and human kidney tissue with 70-75 nm lateral and ~250 nm axial spatial resolution. Using ExM with a standard confocal microscope, we resolve fine details of structures that have traditionally required visualization by electron microscopy, including podocyte foot processes, the glomerular basement membrane, and the cytoskeleton. This inexpensive and accessible approach to volumetric, nanoscale imaging enables visualization of fine structural details of kidney tissues that were previously difficult or impossible to measure by conventional methodologies. PMID- 29991753 TI - Publisher Correction: Mechanisms and impact of altered tumour mechanics. AB - In the version of this Review originally published, owing to a technical error the text 'However, given the multitude' was incorrectly introduced after the sentence beginning 'The transition to a mesenchymal state is characterized...'. This has now been amended in all online versions of the Review. PMID- 29991752 TI - Hydrothermal chimneys host habitat-specific microbial communities: analogues for studying the possible impact of mining seafloor massive sulfide deposits. AB - To assess the risk that mining of seafloor massive sulfides (SMS) from extinct hydrothermal vent environments has for changing the ecosystem irreversibly, we sampled SMS analogous habitats from the Kairei and the Pelagia vent fields along the Indian Ridge. In total 19.8 million 16S rRNA tags from 14 different sites were analyzed and the microbial communities were compared with each other and with publicly available data sets from other marine environments. The chimneys appear to provide habitats for microorganisms that are not found or only detectable in very low numbers in other marine habitats. The chimneys also host rare organisms and may function as a vital part of the ocean's seed bank. Many of the reads from active and inactive chimney samples were clustered into OTUs, with low or no resemblance to known species. Since we are unaware of the chemical reactions catalyzed by these unknown organisms, the impact of this diversity loss and bio-geo-coupling is hard to predict. Given that chimney structures can be considered SMS analogues, removal of sulfide deposits from the seafloor in the Kairei and Pelagia fields will most likely alter microbial compositions and affect element cycling in the benthic regions and probably beyond. PMID- 29991754 TI - Time-related association between fluid balance and mortality in sepsis patients: interaction between fluid balance and haemodynamics. AB - This study aimed to investigate the time-related association between cumulative fluid balance (FB) and mortality. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC) III. FB data on 8584 patients at the first (FB-fir24hr) and second (FB-sec24hr) 24 hours after intensive care unit admission were analysed. Compared to the combination of FB-fir24hr <= 0 and FB sec24 hr <= 0, the combination of FB-fir24hr > 0 and FB-sec24hr <= 0 had significantly higher FB, with an insignificant odds ratio (OR) for mortality. However, the mortality ORs of two other combinations (FB-fir24hr <= 0 and FB sec24hr > 0; FB-fir24hr > 0 and FB-sec24hr > 0) were significantly high. Furthermore, multivariable logistic analysis showed a significant stepwise increase ORs for mortality with increasing FB-sec24hr quartiles, with no significant increase in FB-fir24hr quartiles aside from quartile 4. In patients with negative FB, a stepwise decrease in mortality ORs with increasing FB-sec24hr quartiles was found with no significant difference in FB-fir24hr quartiles. In conclusion, the positive FB during the second but not the first 24 hours was associated with increased mortality in sepsis. Achieving more negative FB was associated with decreased mortality only in the second 24 hours. PMID- 29991755 TI - Deep RNA sequencing reveals the dynamic regulation of miRNA, lncRNAs, and mRNAs in osteosarcoma tumorigenesis and pulmonary metastasis. AB - Osteosarcoma (OS) is the most common pediatric malignant bone tumor, and occurrence of pulmonary metastasis generally causes a rapid and fatal outcome. Here we aimed to provide clues for exploring the mechanism of tumorigenesis and pulmonary metastasis for OS by comprehensive analysis of microRNA (miRNA), long non-coding RNA (lncRNA), and mRNA expression in primary OS and OS pulmonary metastasis. In this study, deep sequencing with samples from primary OS (n = 3), pulmonary metastatic OS (n = 3), and normal controls (n = 3) was conducted and differentially expressed miRNAs (DEmiRNAs), lncRNAs (DElncRNAs), and mRNAs (DEmRNAs) between primary OS and normal controls as well as pulmonary metastatic and primary OS were identified. A total of 65 DEmiRNAs, 233 DElncRNAs, and 1405 DEmRNAs were obtained between primary OS and normal controls; 48 DEmiRNAs, 50 DElncRNAs, and 307 DEmRNAs were obtained between pulmonary metastatic and primary OS. Then, the target DEmRNAs and DElncRNAs regulated by the same DEmiRNAs were searched and the OS tumorigenesis-related and OS pulmonary metastasis-related competing endogenous RNA (ceRNA) networks were constructed, respectively. Based on these ceRNA networks and Venn diagram analysis, we obtained 3 DEmiRNAs, 15 DElncRNAs, and 100 DEmRNAs, and eight target pairs including miR-223-5p/(CLSTN2, AC009951.1, LINC01705, AC090673.1), miR-378b/(ALX4, IGSF3, SULF1), and miR-323b 3p/TGFBR3 were involved in both tumorigenesis and pulmonary metastasis of OS. The TGF-beta superfamily co-receptor TGFBR3, which is regulated by miR-323b-3p, acts as a tumor suppressor in OS tumorigenesis and acts as a tumor promoter in pulmonary metastatic OS via activation of the epithelial-mesenchymal transition (EMT) program.In conclusion, the OS transcriptome (miRNA, lncRNA, and mRNA) is dynamically regulated. These analyses might provide new clues to uncover the molecular mechanisms and signaling networks that contribute to OS progression, toward patient-tailored and novel-targeted treatments. PMID- 29991756 TI - Water Pharmacophore: Designing Ligands using Molecular Dynamics Simulations with Water. AB - In this study, we demonstrate a method to construct a water-based pharmacophore model which can be utilized in the absence of known ligands. This method utilizes waters found in the binding pocket, sampled through molecular dynamics. Screening of compound databases against this water-based pharmacophore model reveals that this approach can successfully identify known binders to a target protein. The method was tested by enrichment studies of 7 therapeutically important targets and compared favourably to screening-by-docking with Glide. Our results suggest that even without experimentally known binders, pharmacophore models can be generated using molecular dynamics with waters and used for virtual screening. PMID- 29991757 TI - Cellomics approach for high-throughput functional annotation of Caenorhabditis elegans neural network. AB - In Caenorhabditis elegans, which has only 302 neurons, relationships between behaviors and neural networks are not easily elucidated. In this study, we proposed a novel cellomics approach enabling high-throughput and comprehensive exploration of the functions of a single neuron or a subset of neurons in a complex neural network on a particular behavior. To realize this, we combined optogenetics and Brainbow technologies. Using these technologies, we established a C. elegans library where opsin is labeled in a randomized pattern. Behavioral analysis on this library under light illumination enabled high-throughput annotation of neurons affecting target behaviors. We applied this approach to the egg-laying behavior of C. elegans and succeeded in high-throughput confirmation that hermaphrodite-specific neurons play an important role in the egg-laying behavior. This cellomics approach will lead to the accumulation of neurophysiological and behavioral data of the C. elegans neural network, which is necessary for constructing neuroanatomically grounded models of behavior. PMID- 29991758 TI - Liver-specific deletion of Eva1a/Tmem166 aggravates acute liver injury by impairing autophagy. AB - Acute liver failure (ALF) is an inflammation-mediated hepatocellular injury process associated with cellular autophagy. However, the mechanism by which autophagy regulates ALF remains undefined. Herein, we demonstrated that Eva1a (eva-1 homolog A)/Tmem166 (transmembrane protein 166), an autophagy-related gene, can protect mice from ALF induced by D-galactosamine (D-GalN)/lipopolysaccharide (LPS) via autophagy. Our findings indicate that a hepatocyte-specific deletion of Eva1a aggravated hepatic injury in ALF mice, as evidenced by increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), myeloperoxidase (MPO), and inflammatory cytokines (e.g., TNFalpha and IL-6), which was associated with disordered liver architecture exhibited by Eva1a-/- mouse livers with ALF. Moreover, we found that the decreased autophagy in Eva1a-/ mouse liver resulted in the substantial accumulation of swollen mitochondria in ALF, resulting in a lack of ATP generation, and consequently hepatocyte apoptosis or death. The administration of Adeno-Associated Virus Eva1a (AAV-Eva1a) or antophagy-inducer rapamycin increased autophagy and provided protection against liver injury in Eva1a-/- mice with ALF, suggesting that defective autophagy is a significant mechanism of ALF in mice. Collectively, for the first time, we have demonstrated that Eva1a-mediated autophagy ameliorated liver injury in mice with ALF by attenuating inflammatory responses and apoptosis, indicating a potential therapeutic application for ALF. PMID- 29991759 TI - Environmental DNA reveals quantitative patterns of fish biodiversity in large rivers despite its downstream transportation. AB - Despite the ecological and societal importance of large rivers, fish sampling remains costly and limited to specific habitats (e.g., river banks). Using an eDNA metabarcoding approach, we regularly sampled 500 km of a large river (Rhone River). Comparisons with long-term electrofishing surveys demonstrated the ability of eDNA metabarcoding to qualitatively and quantitatively reveal fish assemblage structures (relative species abundance) but eDNA integrated a larger space than the classical sampling location. Combination of a literature review and field data showed that eDNA behaves in the water column like fine particulate organic matter. Its detection distance varied from a few km in a small stream to more than 100 km in a large river. To our knowledge, our results are the first demonstration of the capacity of eDNA metabarcoding to describe longitudinal fish assemblage patterns in a large river, and metabarcoding appears to be a reliable, cost-effective method for future monitoring. PMID- 29991760 TI - Genomes of two archaeal endosymbionts show convergent adaptations to an intracellular lifestyle. AB - Endosymbiosis is a widespread phenomenon in the microbial world and can be based on diverse interactions between endosymbiont and host cell. The vast majority of the known endosymbiotic interactions involve bacteria that have invaded eukaryotic host cells. However, methanogenic archaea have been found to thrive in anaerobic, hydrogenosome-containing protists and it was suggested that this symbiosis is based on the transfer of hydrogen. Here, we used culture-independent genomics approaches to sequence the genomes of two distantly related methanogenic endosymbionts that have been acquired in two independent events by closely related anaerobic ciliate hosts Nyctotherus ovalis and Metopus contortus, respectively. The sequences obtained were then validated as originating from the ciliate endosymbionts by in situ probing experiments. Comparative analyses of these genomes and their closest free-living counterparts reveal that the genomes of both endosymbionts are in an early stage of adaptation towards endosymbiosis as evidenced by the large number of genes undergoing pseudogenization. For instance, the observed loss of genes involved in amino acid biosynthesis in both endosymbiont genomes indicates that the endosymbionts rely on their hosts for obtaining several essential nutrients. Furthermore, the endosymbionts appear to have gained significant amounts of genes of potentially secreted proteins, providing targets for future studies aiming to elucidate possible mechanisms underpinning host-interactions. Altogether, our results provide the first genomic insights into prokaryotic endosymbioses from the archaeal domain of life. PMID- 29991761 TI - Cross-feeding modulates antibiotic tolerance in bacterial communities. AB - Microbes frequently rely on metabolites excreted by other bacterial species, but little is known about how this cross-feeding influences the effect of antibiotics. We hypothesized that when species rely on each other for essential metabolites, the minimum inhibitory concentration (MIC) for all species will drop to that of the "weakest link"-the species least resistant in monoculture. We tested this hypothesis in an obligate cross-feeding system that was engineered between Escherichia coli, Salmonella enterica, and Methylobacterium extorquens. The effect of tetracycline and ampicillin were tested on both liquid and solid media. In all cases, resistant species were inhibited at significantly lower antibiotic concentrations in the cross-feeding community than in monoculture or a competitive community. However, deviation from the "weakest link" hypothesis was also observed in cross-feeding communities apparently as result of changes in the timing of growth and cross-protection. Comparable results were also observed in a clinically relevant system involving facultative cross-feeding between Pseudomonas aeruginosa and an anaerobic consortium found in the lungs of cystic fibrosis patients. P. aeruginosa was inhibited by lower concentrations of ampicillin when cross-feeding than when grown in isolation. These results suggest that cross-feeding significantly alters tolerance to antibiotics in a variety of systems. PMID- 29991762 TI - Convergent evolution of unusual complex I homologs with increased proton pumping capacity: energetic and ecological implications. AB - Respiratory complex I is part of a large family of homologous enzymes that carry out the transfer of electrons between soluble cytoplasmic electron carriers and membrane-bound electron carriers. These complexes are vital bioenergetic enzymes that serve as the entry points into electron transport chains for a wide variety of microbial metabolisms, and electron transfer is coupled to proton translocation. The core complex of this enzyme is made up of 11 protein subunits, with three major proton pumping subunits. Here, we document a large number of modified complex I gene cassettes found in genome sequences from diverse cultured bacteria, shotgun metagenomics, and environmentally derived archaeal fosmids all of which encode a fourth proton pumping subunit. The incorporation of this extra subunit into a functional protein complex is supported by large amino acid insertions in the amphipathic helix that runs the length of the protein complex. Phylogenetic analyses reveal that these modified complexes appear to have arisen independently multiple times in a remarkable case of convergent molecular evolution. From an energetic perspective, we hypothesize that this modification on the canonical complex I architecture allows for the translocation of a fifth proton per reaction cycle-the physiological utility of this modified complex is discussed. PMID- 29991763 TI - Bacterial community composition responds to changes in copepod abundance and alters ecosystem function in an Arctic mesocosm study. AB - Combining a minimum food web model with Arctic microbial community dynamics, we have suggested that top-down control by copepods can affect the food web down to bacterial consumption of organic carbon. Pursuing this hypothesis further, we used the minimum model to design and analyse a mesocosm experiment, studying the effect of high (+Z) and low (-Z) copepod density on resource allocation, along an organic-C addition gradient. In the Arctic, both effects are plausible due to changes in advection patterns (affecting copepods) and meltwater inputs (affecting carbon). The model predicts a trophic cascade from copepods via ciliates to flagellates, which was confirmed experimentally. Auto- and heterotrophic flagellates affect bacterial growth rate and abundance via competition for mineral nutrients and predation, respectively. In +Z, the model predicts low bacterial abundance and activity, and little response to glucose; as opposed to clear glucose consumption effects in -Z. We observed a more resilient bacterial response to high copepods and demonstrate this was due to changes in bacterial community equitability. Species able to use glucose to improve their competitive and/or defensive properties, became predominant. The observed shift from a SAR11-to a Psychromonodaceae - dominated community suggests the latter was pivotal in this modification of ecosystem function. We argue that this group used glucose to improve its defensive or its competitive abilities (or both). Adding such flexibility in bacterial traits to the model, we show how it creates the observed resilience to top-down manipulations observed in our experiment. PMID- 29991764 TI - Single cell genomic and transcriptomic evidence for the use of alternative nitrogen substrates by anammox bacteria. AB - Anaerobic ammonium oxidation (anammox) contributes substantially to ocean nitrogen loss, particularly in anoxic marine zones (AMZs). Ammonium is scarce in AMZs, raising the hypothesis that organic nitrogen compounds may be ammonium sources for anammox. Biochemical measurements suggest that the organic compounds urea and cyanate can support anammox in AMZs. However, it is unclear if anammox bacteria degrade these compounds to ammonium themselves, or rely on other organisms for this process. Genes for urea degradation have not been found in anammox bacteria, and genomic evidence for cyanate use for anammox is limited to a cyanase gene recovered from the sediment bacterium Candidatus Scalindua profunda. Here, analysis of Ca. Scalindua single amplified genomes from the Eastern Tropical North Pacific AMZ revealed genes for urea degradation and transport, as well as for cyanate degradation. Urease and cyanase genes were transcribed, along with anammox genes, in the AMZ core where anammox rates peaked. Homologs of these genes were also detected in meta-omic datasets from major AMZs in the Eastern Tropical South Pacific and Arabian Sea. These results suggest that anammox bacteria from different ocean regions can directly access organic nitrogen substrates. Future studies should assess if and under what environmental conditions these substrates contribute to the ammonium budget for anammox. PMID- 29991765 TI - Methanol consumption drives the bacterial chloromethane sink in a forest soil. AB - Halogenated volatile organic compounds (VOCs) emitted by terrestrial ecosystems, such as chloromethane (CH3Cl), have pronounced effects on troposphere and stratosphere chemistry and climate. The magnitude of the global CH3Cl sink is uncertain since it involves a largely uncharacterized microbial sink. CH3Cl represents a growth substrate for some specialized methylotrophs, while methanol (CH3OH), formed in much larger amounts in terrestrial environments, may be more widely used by such microorganisms. Direct measurements of CH3Cl degradation rates in two field campaigns and in microcosms allowed the identification of top soil horizons (i.e., organic plus mineral A horizon) as the major biotic sink in a deciduous forest. Metabolically active members of Alphaproteobacteria and Actinobacteria were identified by taxonomic and functional gene biomarkers following stable isotope labeling (SIP) of microcosms with CH3Cl and CH3OH, added alone or together as the [13C]-isotopologue. Well-studied reference CH3Cl degraders, such as Methylobacterium extorquens CM4, were not involved in the sink activity of the studied soil. Nonetheless, only sequences of the cmuA chloromethane dehalogenase gene highly similar to those of known strains were detected, suggesting the relevance of horizontal gene transfer for CH3Cl degradation in forest soil. Further, CH3Cl consumption rate increased in the presence of CH3OH. Members of Alphaproteobacteria and Actinobacteria were also 13C-labeled upon [13C]-CH3OH amendment. These findings suggest that key bacterial CH3Cl degraders in forest soil benefit from CH3OH as an alternative substrate. For soil CH3Cl-utilizing methylotrophs, utilization of several one-carbon compounds may represent a competitive advantage over heterotrophs that cannot utilize one-carbon compounds. PMID- 29991766 TI - Author Correction: Increased food supply mitigates ocean acidification effects on calcification but exacerbates effects on growth. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29991767 TI - Extracellular DNA release from the genome-reduced pathogen Mycoplasma hyopneumoniae is essential for biofilm formation on abiotic surfaces. AB - Mycoplasma hyopneumoniae is an economically devastating, globally disseminated pathogen that can maintain a chronic infectious state within its host, swine. Here, we depict the events underpinning M. hyopneumoniae biofilm formation on an abiotic surface and demonstrate for the first time, biofilms forming on porcine epithelial cell monolayers and in the lungs of pigs, experimentally infected with M. hyopneumoniae. Nuclease treatment prevents biofilms forming on glass but not on porcine epithelial cells indicating that extracellular DNA (eDNA), which localises at the base of biofilms, is critical in the formation of these structures on abiotic surfaces. Subpopulations of M. hyopneumoniae cells, denoted by their ability to take up the dye TOTO-1 and release eDNA, were identified. A visually distinct sub-population of pleomorphic cells, that we refer to here as large cell variants (LCVs), rapidly transition from phase dark to translucent "ghost" cells. The translucent cells accumulate the membrane-impermeable dye TOTO 1, forming readily discernible membrane breaches immediately prior to lysis and the possible release of eDNA and other intracellular content (public goods) into the extracellular environment. Our novel observations expand knowledge of the lifestyles adopted by this wall-less, genome-reduced pathogen and provide further insights to its survival within farm environments and swine. PMID- 29991768 TI - HIF-1alpha regulates COXIV subunits, a potential mechanism of self-protective response to microwave induced mitochondrial damages in neurons. AB - Anxiety and speculation about potential health hazards of microwaves exposure are spreading in the past decades. Hypoxia-inducible factor-1alpha (HIF-1alpha), which can be activated by reactive oxygen species (ROS), played pivotal roles in protective responses against microwave in neuron-like cells. In this study, we established 30 mW/cm2 microwave exposed animal model, which could result in revisable injuries of neuronal mitochondria, including ultrastructure and functions, such as ROS generation and cytochrome c oxidase (COX) activity. We found that the ratio of COXIV-1/COXIV-2, two isoforms of COXIV, decreased at 1 d and increased from 3 d to 14 d. Similar expression changes of HIF-1alpha suggested that COXIV-1 and COXIV-2 might be regulated by HIF-1alpha. In neuron like cells, 30 mW/cm2 microwave down-regulated COX activity from 30 min to 6 h, and then started to recover. And, both HIF-1alpha transcriptional activity and COXIV-1/COXIV-2 ratio were up-regulated at 6 h and 9 h after exposure. Moreover, HIF-1alpha inhibition down-regulated COXIV-1 expression, promoted ROS generation, impaired mitochondrial membrane potentials (MMP), as well as abolished microwave induced ATP production. In conclusion, microwave induced mitochondrial ROS production activated HIF-1alpha and regulated COXIV-1 expression to restore mitochondria functions. Therefore, HIF-1alpha might be a potential target to impair microwave induced injuries. PMID- 29991769 TI - Interaction of LEF1 with TAZ is necessary for the osteoblastogenic activity of Wnt3a. AB - Canonical Wnt signalling plays an important role in osteoblast differentiation and bone formation. However, the molecular mechanisms by which canonical Wnt signalling exerts its osteoblastogenic effect remain elusive. Here, we investigated the relationship between lymphoid enhancer-binding factor 1 (LEF1) and transcriptional co-activator with PDZ-binding motif (TAZ), both of which are transcriptional regulators that mediate canonical Wnt signalling during osteoblast differentiation. Reporter assay and co-immunoprecipitation experiments revealed functional and physical interaction between LEF1 and TAZ. Overexpression of dominant-negative forms of either LEF1 or TAZ markedly inhibited Wnt3a dependent osteoblast differentiation. Moreover, we found that LEF1 and TAZ formed a transcriptional complex with runt-related transcription factor 2 (Runx2) and that inhibition of LEF1 or TAZ by their dominant-negative forms dramatically suppressed the osteoblastogenic activity of Ruxn2. Additionally, Wnt3a enhanced osteoblast differentiation induced by bone morphogenetic protein 2 (BMP2), which stimulates osteoblast differentiation by regulating Runx2. Collectively, these findings suggest that interaction between LEF1 and TAZ is crucial for the osteoblastogenic activity of Wnt3a and that LEF1 and TAZ contribute to the cooperative effect of Wnt3a and BMP2 on osteoblast differentiation through association with Runx2. PMID- 29991770 TI - Radiobrominated benzimidazole-quinoline derivatives as Platelet-derived growth factor receptor beta (PDGFRbeta) imaging probes. AB - Platelet-derived growth factor receptor beta (PDGFRbeta) affects in numerous human cancers and has been recognized as a promising molecular target for cancer therapies. The overexpression of PDGFRbeta could be a biomarker for cancer diagnosis. Radiolabeled ligands having high affinity for the molecular target could be useful tools for the imaging of overexpressed receptors in tumors. In this study, we aimed to develop radiobrominated PDGFRbeta ligands and evaluate their effectiveness as PDGFRbeta imaging probes. The radiolabeled ligands were designed by modification of 1-{2-[5-(2-methoxyethoxy)-1H- benzo[d]imidazol-1 yl]quinolin-8-yl}piperidin-4-amine (1), which shows selective inhibition profile toward PDGFRbeta. The bromine atom was introduced directly into C-5 of the quinoline group of 1, or indirectly by the conjugation of 1 with the 3-bromo benzoyl group. [77Br]1-{5-Bromo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1 yl]quinoline-8-yl}piperidin-4-amine ([77Br]2) and [77Br]-N-3-bromobenzoyl-1-{2-[5 (2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}-piperidin-4-amine ([77Br]3) were prepared using a bromodestannylation reaction. In a cellular uptake study, [77Br]2 and [77Br]3 more highly accumulatd in BxPC3-luc cells (PDGFRbeta-positive) than in MCF7 cells (PDGFRbeta-negative), and their accumulation was significantly reduced by pretreatment with inhibitors. In biodistribution experiments, [77Br]2 accumulation was higher than [77Br]3 accumulation at 1 h postinjection. These findings suggest that [76Br]2 is more promising for positron emission tomography (PET) imaging of PDGFRbeta than [76Br]3. PMID- 29991771 TI - Structural insights into ubiquitin phosphorylation by PINK1. AB - Mutations of PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin (Ub) ligase parkin can cause familial parkinsonism. These two proteins are essential for ubiquitylation of damaged mitochondria and subsequent degradation. PINK1 phosphorylates Ser65 of Ub and the Ub-like (UBL) domain of parkin to allosterically relieve the autoinhibition of parkin. To understand the structural mechanism of the Ub/UBL-specific phosphorylation by PINK1, we determined the crystal structure of Tribolium castaneum PINK1 kinase domain (TcPINK1) in complex with a nonhydrolyzable ATP analogue at 2.5 A resolution. TcPINK1 consists of the N- and C-terminal lobes with the PINK1-specific extension. The ATP analogue is bound in the cleft between the N- and C-terminal lobes. The adenine ring of the ATP analogue is bound to a hydrophobic pocket, whereas the triphosphate group of the ATP analogue and two coordinated Mg ions interact with the catalytic hydrophilic residues. Comparison with protein kinases A and C (PKA and PKC, respectively) unveils a putative Ub/UBL-binding groove, which is wider than the peptide-binding groove of PKA or PKC to accommodate the globular head of Ub or UBL. Further crosslinking analyses suggested a PINK1-interacting surface of Ub. Structure-guided mutational analyses support the findings from the present structural analysis of PINK1. PMID- 29991772 TI - Whole-genome sequencing reveals selection signatures associated with important traits in six goat breeds. AB - Comparative population genomics analysis is an effective approach to identify selection signatures in farm animals. In this study, we systematically investigated the selection signatures in six phenotypically diverse goat breeds using SNPs obtained from pooled whole-genome resequencing data. More than 95.5% of 446-642 million clean reads were mapped to the latest reference goat genome, which generated a sequencing depth ranging from 22.30 to 31.75-fold for each breed. A total of 5,802,307, 6,794,020, 7,562,312, 5,325,119, 8,764,136, and 9,488,057 putative SNPs were detected in Boer, Meigu, Jintang Black, Nanjiang Yellow, Tibetan, and Tibetan cashmere goats, respectively. Based on the genome wide FST and expected heterozygosity scores along 100-kb sliding windows, 68, 89, 44, 44, 19, and 35 outlier windows were deemed as the selection signatures in the six goat breeds. After genome annotation, several genes within the selection signals were found to be possibly associated with important traits in goats, such as coat color (IRF4, EXOC2, RALY, EIF2S2, and KITLG), high-altitude adaptation (EPAS1), growth (LDB2), and reproduction traits (KHDRBS2). In summary, we provide an improved understanding of the genetic diversity and the genomic footprints under positive selection or the adaptations to the local environments in the domestic goat genome. PMID- 29991773 TI - Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability. AB - Screening 92,445 subjects in the Geisinger-Regeneron DiscovEHR cohort, we identified 5 patients heterozygous for nonsense mutations causing early terminations at Glu307 or Leu328 on the C-terminus of melanocortin 4 receptor (MC4R). Two Q307Ter carriers are severely obese (BMI > 40), while one is overweight (BMI > 25). One L328Ter carrier is overweight and the other is lean. Pedigree analysis for two Q307Ter carriers shows segregation of the variant with higher BMI. Functionally, MC4R(Q307Ter) eliminated receptor surface expression and signaling, while MC4R(L328Ter) functioned like the wild-type receptor. MC4R(Q307Ter) is therefore a loss of function (LOF) variant and the region between the two truncation sites identified in our patients is critical to MC4R function. Truncating MC4R at various C-terminal positions between these two variant sites, we find that cysteine318 sits at a critical junction for receptor trafficking and function. We show that MC4R is lipid modified at cysteine318 and cysteine319. Therefore, truncation early in the MC4R C-terminus results in haploinsufficiency in humans while truncation after the first lipid-modification site is well tolerated. MC4R haploinsufficiency clearly segregates with higher BMI; however, severe obesity is not fully penetrant even in MC4R LOF carriers, suggesting critical roles for environmental and lifestyle factors in MC4R monogenic obesity. PMID- 29991774 TI - C-reactive protein expression in adipose tissue of children with acute appendicitis. AB - OBJECTIVE: The aim of this study is to gain insights into the role of visceral adipose tissue as a source of C-reactive protein (CRP) in acute inflammation and to explore the potential relationship of CRP expression with the severity of appendicitis. METHODS: A total of 20 pediatric patients undergoing appendectomy were included in the study. Patients were divided into two groups according to appendicitis severity (uncomplicated and complicated). CRP levels were measured in visceral fat samples by western blotting, as well as in serum by biochemical testing. RESULTS: CRP was found to be expressed in visceral adipose tissue. The adipose tissue of patients with complicated appendicitis showed significantly higher CRP levels (p = 0.002) compared to patients with uncomplicated appendicitis. These results mirrored the CRP values obtained in serum (p = 0.018). CONCLUSION: In childhood, visceral adipose tissue is a source of CRP in acute inflammation, and its expression is potentially associated with the severity of local inflammation. PMID- 29991775 TI - MicroRNA-21 prevents excessive inflammation and cardiac dysfunction after myocardial infarction through targeting KBTBD7. AB - The excessive inflammation triggered by damage-associated molecular patterns (DAMPs) after myocardial infarction (MI) is responsible for the development of cardiac dysfunction and adverse remodeling, while the mechanisms by which inflammation is fine tuned remain to be fully elucidated. MicroRNA-21 (miR-21) has been shown to function in cardiovascular diseases, while its role in inflammatory responses and cardiac function post MI in mice remains unknown. Here, we found that miR-21 expression was markedly increased in border and infarct areas of cardiac tissues during the early inflammatory phase of MI model established by ligating the left-anterior descending coronary artery. MiR-21 knockout mice had decreased survival rates, worse cardiac dysfunction, and increased infarct and scar areas after MI compared with WT mice. MiR-21 knockout mice showed significantly higher levels of inflammatory cytokines including IL 1beta, IL-6, and TNF-alpha in cardiac tissues, as well as infiltration of CD11b+ monocytes/macrophages with higher expression level of inflammatory cytokines. MI induced the great release of high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60) in cardiac tissue. MiR-21 deficiency significantly promoted the inflammatory cytokine production triggered by DAMPs in macrophages, whereas, miR-21 overexpression markedly inhibited the inflammatory cytokine production. Mechanistically, miR-21 deficiency enhanced p38 and NF-kappaB signaling activation in cardiac tissue post MI and macrophages treated with DAMPs. MiR-21 was found to directly target kelch repeat and BTB (POZ) domain containing 7 (KBTBD7), which promoted DAMP-triggered inflammatory responses in macrophages. Furthermore, KBTBD7 interacted with MKK3/6 and promoted their activation, which in turn enhanced the activation of downstream p38 and NF-kappaB signaling induced by DAMPs. Therefore, our findings demonstrate that miR-21 attenuates inflammation, cardiac dysfunction, and maladaptive remodeling post MI through targeting KBTBD7 and inhibiting p38 and NF-kappaB signaling activation, suggesting that miR-21 may function as a novel potential therapeutic target for MI. PMID- 29991777 TI - Mastering molecules in virtual reality. PMID- 29991776 TI - Mystery of buried children at German 'Stonehenge'. PMID- 29991778 TI - How to tell when there's a baby whale on the way. PMID- 29991779 TI - Koala genome reveals secrets to surviving a deadly diet. PMID- 29991781 TI - First portrait of a soot molecule. PMID- 29991780 TI - Lighting the way to versatile 3D printing. PMID- 29991782 TI - Smart molecule aids natural cancer defences. PMID- 29991783 TI - Max Planck astrophysicist at centre of bullying allegations speaks up. PMID- 29991784 TI - The story of African rice, as told by genomics. PMID- 29991785 TI - Oestrogen holds promise for diabetes cure. PMID- 29991786 TI - Controversial CRISPR 'gene drives' tested in mammals for the first time. PMID- 29991787 TI - The heat is on for Majorana fermions. PMID- 29991788 TI - A fresh take on ancient climate change in the North Pacific. PMID- 29991790 TI - EPA is open to scrutiny. PMID- 29991789 TI - Local diagnostics kits for Africa being developed in Ghana. PMID- 29991791 TI - Justification for the EPA's transparency rule. PMID- 29991792 TI - Now India is electrified, bring on the renewables. PMID- 29991793 TI - Two centuries since discovery of dawn-of-life molecule. PMID- 29991794 TI - No place for bullies in science. PMID- 29991795 TI - Foreign-researcher figures stress need for immigration reform before Brexit. PMID- 29991796 TI - Coming soon to a lab near you? Genetically modified cannabis. PMID- 29991798 TI - Publisher Correction: Self-assembly of highly symmetrical, ultrasmall inorganic cages directed by surfactant micelles. AB - Change history: In Fig. 3b of this Letter, the labels for the outer (11.8 nm) and inner (7.4 nm) diameters of the structure were inadvertently omitted. Fig. 3 has been corrected online. PMID- 29991797 TI - Efficient targeted integration into the bovine Rosa26 locus using TALENs. AB - The genetic modification of cattle has many agricultural and biomedical applications. However, random integration often results in the unstable expression of transgenes and unpredictable phenotypes. Targeting genes to the "safe locus" and stably expressing foreign genes at a high level are desirable methods for overcoming these hurdles. The Rosa26 locus has been widely used to produce genetically modified animals in some species expressing transgenes at high and consistent levels. For the first time, we identified a bovine orthologue of the mouse Rosa26 locus through a genomic sequence homology analysis. According to 5' rapid-amplification of cDNA ends (5'RACE), 3' rapid-amplification of cDNA ends (3'RACE), reverse transcription PCR (RT-PCR) and quantitative PCR (Q-PCR) experiments, this locus encodes a long noncoding RNA (lncRNA) comprising two exons that is expressed ubiquitously and stably in different tissues. The bovine Rosa26 (bRosa26) locus appears to be highly amenable to transcription activator like effector nucleases (TALENs)-mediated knock-in, and ubiquitous expression of enhanced green fluorescent protein (EGFP) inserted in the bRosa26 locus was observed in various stages, including cells, embryos, fetus and cattle. Finally, we created a valuable master bRosa26-EGFP fetal fibroblast cell line in which any gene of interest can be efficiently introduced and stably expressed using recombinase-mediated cassette exchange (RMCE). The new tools described here will be useful for a variety of studies using cattle. PMID- 29991799 TI - FGFR3-TACC3 is an oncogenic fusion protein in respiratory epithelium. AB - Structural rearrangements of the genome can drive lung tumorigenesis through the generation of fusion genes with oncogenic properties. Advanced genomic approaches have identified the presence of a genetic fusion between fibroblast growth factor receptor 3 (FGFR3) and transforming acidic coiled-coil 3 (TACC3) in non-small cell lung cancer (NSCLC), providing a novel target for FGFR inhibition. To interrogate the functional consequences of the FGFR3-TACC3 fusion in the transformation of lung epithelial cells, we generated a novel transgenic mouse model that expresses FGFR3-TACC3 concomitant with loss of the p53 tumor suppressor gene. Intranasal delivery of an Ad5-CMV-Cre virus promoted seromucinous glandular transformation of olfactory cells lining the nasal cavities of FGFR3-TACC3 (LSL-F3T3) mice, which was further accelerated upon loss of p53 (LSL-F3T3/p53). Surprisingly, lung tumors failed to develop in intranasally infected LSL-F3T3 and LSL-F3T3/p53 mice. In line with these observations, we demonstrated that intranasal delivery of Ad5-CMV-Cre induces widespread Cre-mediated recombination in the olfactory epithelium. Intra-tracheal delivery of Ad5-CMV-Cre into the lungs of LSL-F3T3 and LSL-F3T3/p53 mice, however, resulted in the development of lung adenocarcinomas. Taken together, these findings provide in vivo evidence for an oncogenic function of FGFR3-TACC3 in respiratory epithelium. PMID- 29991800 TI - Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX. AB - Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells. PMID- 29991801 TI - Primary tumor-derived exosomes facilitate metastasis by regulating adhesion of circulating tumor cells via SMAD3 in liver cancer. AB - Hepatocellular carcinoma (HCC) is a fatal disease and patients with HCC frequently die from metastasis. The mechanisms of HCC metastasis are not completely understood. In the present study, in vitro and in vivo data showed that HCC cells promoted cancer cell proliferation and lung metastases formation in a paracrinal/endocrinal way. We found that HCC-derived exosomes mediated this phenomenon and observed enhanced cell adhesion in the presence of these malignant exosomes. We further identified that reactive oxygen species (ROS) regulated the adhesive molecules. Intriguingly, attached HCC cells released exosomes containing both SMAD Family Member 3 (SMAD3) protein and mRNA, which were delivered to detached HCC cells and facilitated their adhesion. These exosomes induced enhanced SMAD3 signaling in the recipient HCC cells and increased their adhesive ability. In addition, we showed that SMAD3-abundant exosomes existed in the peripheral blood of patients with HCC, and their levels correlated with disease stage and the SMAD3 expression of primary tumors. Our study suggested a possible mechanism by which primary HCC supported metastases formation and revealed the role of SMAD3 in the exosomes-mediated crosstalk between primary and circulating HCC cells. PMID- 29991803 TI - Biogenic silica-based microparticles obtained as a sub-product of the nanocellulose extraction process from pineapple peels. AB - Silica in plant tissues has been suggested as a component for enhancing mechanical properties, and as a physical barrier. Pineapples present in their shell and bracts rosette-like microparticles that could be associated to biogenic silica. In this study, we show for the first time that silica-based microparticles are co-purified during the extraction process of nanocellulose from pineapple (Ananas comosus). This shows that vegetable biomass could be an underappreciated source, not only for nanocellulose, but also for a highly valuable sub-product, like 10 um biogenic rosette-like silica-based microparticles. The recovery yield obtained was 7.2 wt.%; based on the dried initial solid. Due to their size and morphology, the microparticles have potential applications as reinforcement in adhesives, polymer composites, in the biomedical field, and even as a source of silica for fertilizers. PMID- 29991802 TI - Exposure of Barrett's and esophageal adenocarcinoma cells to bile acids activates EGFR-STAT3 signaling axis via induction of APE1. AB - The development of Barrett's esophagus (BE) and its progression to esophageal adenocarcinoma (EAC) is highly linked to exposure to acidic bile salts due to chronic gastroesophageal reflux disease (GERD). In this study, we investigated the role of Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) in STAT3 activation in response to acidic bile salts. Our results indicate that APE1 is constitutively overexpressed in EAC, whereas its expression is transiently induced in response to acidic bile salts in non-neoplastic BE. Using overexpression or shRNA knockdown of APE1, we found that APE1 is required for phosphorylation, nuclear localization, and transcriptional activation of STAT3. By using an APE1 redox-specific mutant (C65A) and APE1 redox inhibitor (E3330), we demonstrate that APE1 activates STAT3 in a redox-dependent manner. By using pharmacologic inhibitors and genetic knockdown systems, we found that EGFR is a required link between APE1 and STAT3. EGFR phosphorylation (Y1068) was directly associated with APE1 levels and redox function. Co-immunoprecipitation and proximity ligation assays indicated that APE1 coexists and interacts with the EGFR-STAT3 protein complex. Consistent with these findings, we demonstrated a significant induction in mRNA expression levels of STAT3 target genes (IL-6, IL 17A, BCL-xL, Survivin, and c-MYC) in BE and EAC cells, following acidic bile salts treatment. ChIP assays indicated that acidic bile salts treatment enhances binding of STAT3 to the promoter of its target genes, Survivin and BCL-xL. Inhibition of APE1/REF-1 redox activity using E3330 abrogated STAT3 DNA binding and transcriptional activity. The induction of APE1-STAT3 axis in acidic bile salts conditions provided a survival advantage and promoted cellular proliferation. In summary, our study provides multiple pieces of evidence supporting a critical role for APE1 induction in activating the EGFR-STAT3 signaling axis in response to acidic bile salts, the main risk factor for Barrett's carcinogenesis. PMID- 29991804 TI - 16S rRNA sequencing reveals likely beneficial core microbes within faecal samples of the EU protected slug Geomalacus maculosus. AB - The EU-protected slug Geomalacus maculosus Allman occurs only in the West of Ireland and in northern Spain and Portugal. We explored the microbial community found within the faeces of Irish specimens with a view to determining whether a core microbiome existed among geographically isolated slugs which could give insight into the adaptations of G. maculosus to the available food resources within its habitat. Faecal samples of 30 wild specimens were collected throughout its Irish range and the V3 region of the bacterial 16S rRNA gene was sequenced using Illumina MiSeq. To investigate the influence of diet on the microbial composition, faecal samples were taken and sequenced from six laboratory reared slugs which were raised on two different foods. We found a widely diverse microbiome dominated by Enterobacteriales with three core OTUs shared between all specimens. While the reared specimens appeared clearly separated by diet in NMDS plots, no significant difference between the slugs fed on the two different diets was found. Our results indicate that while the majority of the faecal microbiome of G. maculosus is probably dependent on the microhabitat of the individual slugs, parts of it are likely selected for by the host. PMID- 29991806 TI - DBM is common during adolescence. PMID- 29991807 TI - BCG vaccination for type 1 diabetes mellitus. PMID- 29991805 TI - The nature of spin excitations in the one-third magnetization plateau phase of Ba3CoSb2O9. AB - Magnetization plateaus in quantum magnets-where bosonic quasiparticles crystallize into emergent spin superlattices-are spectacular yet simple examples of collective quantum phenomena escaping classical description. While magnetization plateaus have been observed in a number of spin-1/2 antiferromagnets, the description of their magnetic excitations remains an open theoretical and experimental challenge. Here, we investigate the dynamical properties of the triangular-lattice spin-1/2 antiferromagnet Ba3CoSb2O9 in its one-third magnetization plateau phase using a combination of nonlinear spin-wave theory and neutron scattering measurements. The agreement between our theoretical treatment and the experimental data demonstrates that magnons behave semiclassically in the plateau in spite of the purely quantum origin of the underlying magnetic structure. This allows for a quantitative determination of Ba3CoSb2O9 exchange parameters. We discuss the implication of our results to the deviations from semiclassical behavior observed in zero-field spin dynamics of the same material and conclude they must have an intrinsic origin. PMID- 29991808 TI - Author Correction: Foldamers wave to the ribosome. AB - In the News & Views 'Foldamers wave to the ribosome', multiple changes to the main text were required. In paragraph 2 "whose monomer sequence is truly defined" should have read "whose monomer sequence is both diverse and truly defined" and "Truly sequence-defined..." should have read "Diverse and truly sequence defined...". In the penultimate paragraph, 'appendages 5-9' should have been "appendages 5 and 7-9"; in the sentence starting "Based on these criteria...", QPQ should have been QQQ and vice versa; and the whole sentence starting "What is interesting..." needed revising to "What is interesting is that an alternating sequence with a terminal P monomer appears essential: PQPQ is unfolded and an initiator tRNA carrying PQPQ-Gly-Phe initiates translation, whereas QPQPQ is folded and does not." Furthermore, the structures in Fig. 1a have been replaced to correct several errors in the chemical structures arising from missing -CH2- groups. The table in Fig. 1b also required changes: in the last two columns of row two, 'Fast' and 'No' should have read 'Slow and 'Yes', respectively; in the first column of row three, 'ND' should have been a tick; and in the last two columns of row four, 'Slow' and 'Yes' should have read 'Fast' and 'No', respectively. Finally, a new reference 'Milon, P. et al. EMBO Rep. 11, 312-316 (2010).' has been added to the reference list at number 13 and cited in the fifth paragraph, the references list has been renumbered accordingly. PMID- 29991809 TI - Publisher Correction: Structure-performance descriptors and the role of Lewis acidity in the methanol-to-propylene process. AB - In the version of this Article originally published, on the right side of Fig. 4b, the 'Aromatic cycle' label was erroneously shifted outside of the central circular arrow into a position on part of the reaction cycle. This has been corrected in the online versions of the Article. PMID- 29991810 TI - Regulation and biological role of the peptide/histidine transporter SLC15A3 in Toll-like receptor-mediated inflammatory responses in macrophage. AB - The peptide/histidine transporter SLC15A3 is responsible for transporting histidine, certain dipeptide and peptidomimetics from inside the lysosome to cytosol. Previous studies have indicated that SLC15A3 transcripts are mainly expressed in the lymphatic system, however, its regulation and biological role in innate immune responses and inflammatory diseases are as yet unknown. In this study, mouse peritoneal macrophages (PMs), mouse bone marrow-derived macrophages (BMDMs), the human acute monocytic leukemia cell line THP-1 and the human lung epithelial carcinoma cell line A549 were used to investigate the regulation and biological role of SLC15A3 in TLR-mediated inflammatory responses. Our results showed that SLC15A3 was upregulated by TLR2, TLR4, TLR7 and TLR9 ligands in macrophages at both the mRNA and protein levels via activation of NF-kappaB (nuclear factor-kappa-B), MAPK (mitogen-activated protein kinase) and IRF3 (interferon regulatory factor 3). Furthermore, knockdown or overexpression of SLC15A3 influenced the TLR4-triggered expression of proinflammatory cytokines. A reporter gene assay showed that the SLC15A3 promotor contained potential NF kappaB binding sites, which were reasonable for regulating SLC15A3 by TLR activation through NF-kappaB signaling. Additionally, SLC15A3 expression was increased and positively related to inflammation in mice with bacterial peritonitis. The collective findings suggest that SLC15A3 is regulated by various TLRs, and that it plays an important role in regulating TLR4-mediated inflammatory responses. PMID- 29991811 TI - Circadian challenge of astronauts' unconscious mind adapting to microgravity in space, estimated by heart rate variability. AB - It is critical that the regulatory system functions well in space's microgravity. However, the "intrinsic" cardiovascular regulatory system (beta), estimated by the fractal scaling of heart rate variability (HRV) (0.0001-0.01 Hz), does not adapt to the space environment during long-duration (6-month) space flights. Neuroimaging studies suggest that the default mode network (DMN) serves a broad adaptive purpose, its topology changing over time in association with different brain states of adaptive behavior. Hypothesizing that HRV varies in concert with changes in brain's functional connectivity, we analyzed 24-hour HRV records from 8 healthy astronauts (51.8 +/- 3.7 years; 6 men) on long (174.5 +/- 13.8 days) space missions, obtained before launch, after about 21 (ISS01), 73 (ISS02), and 156 (ISS03) days in space, and after return to Earth. Spectral power in 8 frequency regions reflecting activity in different brain regions was computed by maximal entropy. Improved beta (p < 0.05) found in 4 astronauts with a positive activation in the "HRV slow-frequency oscillation" (0.10-0.20 Hz) occurred even in the absence of consciousness. The adaptive response was stronger in the evening and early sleep compared to morning (p = 0.039). Brain functional networks, the DMN in particular, can help adapt to microgravity in space with help from the circadian clock. PMID- 29991813 TI - Personalized medicine - a new reality in psoriatic arthritis? PMID- 29991812 TI - Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin. AB - The establishment of relative size of organs and structures is paramount for attaining final form and function of an organism. Importantly, variation in the proportions of structures frequently underlies adaptive change in morphology in evolution and maybe a common mechanism underlying selection. However, the mechanism by which growth is integrated within tissues during development to achieve proper proportionality is poorly understood. We have shown that signaling by potassium channels mediates coordinated size regulation in zebrafish fins. Recently, calcineurin inhibitors were shown to elicit changes in zebrafish fin allometry as well. Here, we identify the potassium channel kcnk5b as a key player in integrating calcineurin's growth effects, in part through regulation of the cytoplasmic C-terminus of the channel. We propose that the interaction between Kcnk5b and calcineurin acts as a signaling node to regulate allometric growth. Importantly, we find that this regulation is epistatic to inherent mechanisms instructing overall size as inhibition of calcineurin is able to bypass genetic instruction of size as seen in sof and wild-type fins, however, it is not sufficient to re-specify positional memory of size of the fin. These findings integrate classic signaling mediators such as calcineurin with ion channel function in the regulation of size and proportion during growth. PMID- 29991815 TI - Competing contagion processes: Complex contagion triggered by simple contagion. AB - Empirical evidence reveals that contagion processes often occur with competition of simple and complex contagion, meaning that while some agents follow simple contagion, others follow complex contagion. Simple contagion refers to spreading processes induced by a single exposure to a contagious entity while complex contagion demands multiple exposures for transmission. Inspired by this observation, we propose a model of contagion dynamics with a transmission probability that initiates a process of complex contagion. With this probability nodes subject to simple contagion get adopted and trigger a process of complex contagion. We obtain a phase diagram in the parameter space of the transmission probability and the fraction of nodes subject to complex contagion. Our contagion model exhibits a rich variety of phase transitions such as continuous, discontinuous, and hybrid phase transitions, criticality, tricriticality, and double transitions. In particular, we find a double phase transition showing a continuous transition and a following discontinuous transition in the density of adopted nodes with respect to the transmission probability. We show that the double transition occurs with an intermediate phase in which nodes following simple contagion become adopted but nodes with complex contagion remain susceptible. PMID- 29991814 TI - Differential Effects of E-Cigarette on Microvascular Endothelial Function, Arterial Stiffness and Oxidative Stress: A Randomized Crossover Trial. AB - Propylene glycol and glycerol are electronic cigarettes vehicles allowing liquid vaporization and nicotine transport. The respective effects of these different constituents on the cardiovascular system are unknown. We assessed the differential effects of vehicles (propylene glycol and glycerol) and nicotine on microcirculatory function, arterial stiffness, hemodynamic parameters and oxidative stress. Twenty-five tobacco smokers were exposed to vaping with and without nicotine, and sham vaping, in a randomized, single blind, 3-period crossover design study. Neither sham-vaping nor vaping in the absence of nicotine resulted in modifications of cardiovascular parameters or oxidative stress. In contrast, vaping with nicotine: 1) impaired acetylcholine mediated vasodilation (mean +/- standard error mean) (area under curve, perfusion unit (PU), 3385 +/- 27PU to 2271 +/- 27PU, p < 0.0001); 2) increased indices of arterial stiffness, namely augmentation index corrected for heart rhythm (-3.5 +/- 1.5% to 1.9 +/- 2.3%; p = 0.013) and pulse wave velocity (4.9 +/- 0.1 m.s-1 to 5.3 +/- 0.1 m.s-1; p < 0.0001); 3) increased systolic and diastolic blood pressures as well as heart rate (all p < 0.0001) and finally; 4) raised plasma myeloperoxidase (median [interquartile range]) (13.6 ng.ml-1 [10-17.7] to 18.9 ng.ml-1 [12.2-54.4], p = 0.005). Our findings demonstrated that high temperature e-cigarette vehicle vaporization does not alter micro- and macro-vascular function, and oxidative stress, and that these effects are solely attributable to nicotine. PMID- 29991816 TI - Gut microbiota: a new way to take your vitamins. PMID- 29991817 TI - An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes. AB - The Endoplasmatic Reticulum Aminopeptidases ERAP1 and ERAP2 are implicated in a variety of immune and non-immune functions. Most studies however have focused on their role in shaping the HLA class I peptidome by trimming peptides to the optimal size. Genome Wide Association Studies highlighted non-synonymous polymorphisms in their coding regions as associated with several immune mediated diseases. The two genes lie contiguous and oppositely oriented on the 5q15 chromosomal region. Very little is known about the transcriptional regulation and the quantitative variations of these enzymes. Here, we correlated the level of transcripts and proteins of the two aminopeptidases in B-lymphoblastoid cell lines from 44 donors harbouring allelic variants in the intergenic region between ERAP1 and ERAP2. We found that the presence of a G instead of an A at SNP rs75862629 in the ERAP2 gene promoter strongly influences the expression of the two ERAPs with a down-modulation of ERAP2 coupled with a significant higher expression of ERAP1. We therefore show here for the first time a coordinated quantitative regulation of the two ERAP genes, which can be relevant for the setting of specific therapeutic approaches. PMID- 29991819 TI - Surface analysis and depth profiling using time-of-flight elastic recoil detection analysis with argon sputtering. AB - The recent development of new advanced materials demands extensive effort in developing new analytical techniques that can provide insight into material composition at the nanoscale, particularly at surfaces and interfaces, which is important for both fabrication and material performance. Here, we present a proof of principle for a new setup used for thin-film characterisation and depth profiling based on a combination of time-of-flight elastic recoil detection analysis (TOF-ERDA) and Ar sputtering. A quantitative depth profiling with a best achievable surface depth resolution of ~2 nm can be realised for the entire layer, which is important for the precise determination of thickness and composition of samples that are several tenths of a nanometre thick. The performance of TOF-ERDA with Ar sputtering was demonstrated using 15 nm Cu evaporated onto a Si substrate. The advantages and limits of the method are discussed in detail. PMID- 29991821 TI - New clues to the genetic links between AD and Down syndrome. PMID- 29991820 TI - Risk of dementia after TBI - a cause of growing concern. PMID- 29991818 TI - Independent losses of a xenobiotic receptor across teleost evolution. AB - Sensitivity to environmental stressors largely depend on the genetic complement of the organism. Recent sequencing and assembly of teleost fish genomes enable us to trace the evolution of defense genes in the largest and most diverse group of vertebrates. Through genomic searches and in-depth analysis of gene loci in 76 teleost genomes, we show here that the xenosensor pregnane X receptor (Pxr, Nr1i2) is absent in more than half of these species. Notably, out of the 27 genome assemblies that belong to the Gadiformes order, the pxr gene was only retained in the Merluccidae family (hakes) and Pelagic cod (Melanonus zugmayeri). As an important receptor for a wide range of drugs and environmental pollutants, vertebrate PXR regulate the transcription of a number of genes involved in the biotransformation of xenobiotics, including cytochrome P450 enzymes (CYP). In the absence of Pxr, we suggest that the aryl hydrocarbon receptor (Ahr) have evolved an extended regulatory role by governing the expression of certain Pxr target genes, such as cyp3a, in Atlantic cod (Gadus morhua). However, as several independent losses of pxr have occurred during teleost evolution, other lineages and species may have adapted alternative compensating mechanisms for controlling crucial cellular defense mechanisms. PMID- 29991823 TI - [Invitation to an integrated reading of AIR 2/2018]. PMID- 29991822 TI - Microglia show sex-specific gene expression profiles. PMID- 29991824 TI - [Razam Ashraf Al-Najjar, nurse, killed by Israeli fire while rescuing a wounded person]. PMID- 29991825 TI - [The use of physical restraints in older adults receiving home care: a cross sectional study in an italian district of northen Italy]. AB - : . The use of physical restraints in older adults receiving home care: a cross sectional study in a district of northen Italy. INTRODUCTION: Research on restraint use in home care residents cared by non professional caregivers is scarce. AIM: To evaluate the prevalence of physical restraints among the elderly assisted by the home care services in the District 1 of Bassano del Grappa ULSS7 Pedemontana (Veneto Region, Italy). METHOD: This observational cross-sectional survey was conducted by the 28 home care nurses on all subjects receiving at least one home care service by a nurse during the survey period (13 March-15 April 2017). Data were collected on functional and cognitive conditions, restraints, reasons and duration of restraints use, presence of prescription. RESULTS: Of the 510 included elderly (93.6% of the 545 service users), 175 (34.3%) were restrained; mean age 84.6(+/-11.3) years; 62.3% were women. The 15.4% (27) of restrained were bed-bound, 24% (42) had a limited mobility, 33.1% (58) were able to walk with or without help, and 27.4% (48) were confused but able to walk. The most used restraint were bed-rails (159 patients, 90.8%): for 120 (68.8%) the only restraint and for 80 (45.7%) only during the night. The main reason for restraints use was the prevention of falls from the bed or the wheelchair (85.7%). CONCLUSIONS: The prevention of falls from the bed or wheelchair was the most common reason for the use a physical restraint; in 1/3 of cases it was decided by family members. The use of restraints was higher in patients with physical or cognitive disability or confused or agitated. PMID- 29991826 TI - [The Emergency Department visits of Nursing Home residents: descriptive study in a Nursing Home]. AB - : . The Emergency Department visits of Nursing Home residents: descriptive study in a Nursing Home. INTRODUCTION: Many Emergency Departments (ED) transfers of Nursing Home (NH) residents are potentially avoidable or even inappropriate since problems could be prevented or managed in the NH. AIM: To describe characteristics and outcomes of NH residents transferred to ED for respiratory, cardiovascular and neurological problems and symptoms of infection. METHODS: A retrospective descriptive study using clinical records data from 2013-2016 of a NH was conducted. RESULTS: In 4 years (2013-2016), 143 ED accesses occurred, 55 (38.6%) for medical problems in 48 residents. The residents were mainly women, with advanced age. Forty-two/55 accesses (76.4%) resulted in an hospital admission and 16 residents (38.1%) died in hospital; of the 13 discharged, 3 died the NH after a few days. The most frequent reason for hospitalization was an infection (22): respiratory (18), urinary (2) or both (2). The week before ED admission 1/3 of residents was asymptomatic, 1/3 had only one typical symptom accompained by drowsiness or agitation (7), gastrointestinal problems (5), or other non-specific symptoms. On ED admission prevalent signs and symptoms were desaturation (13), dyspnea (10) and fever (9). Six/22 residents had started an antibiotic treatment in the NH. CONCLUSIONS: Proactive management policies need to be promoted for residents with infections, based on explicit criteria to promptly monitor changes in clinical conditions and on the education educate professionals to suspect an infection even with non-specific symptoms. PMID- 29991827 TI - [How to plan and conduct study on restraints use: notes on methods]. PMID- 29991828 TI - [For an epidemiology of everyday chronicle]. PMID- 29991829 TI - [Where is and where is the psychopharmacology going:
remembering the 40th anniversary of the 180 law]. PMID- 29991830 TI - [Genetic diet: should we eat what we are?] PMID- 29991831 TI - [How to perform a subcutaneous injection]. PMID- 29991832 TI - [Reasoning on and around the book by Marco Geddes da Filicaia]. PMID- 29991833 TI - Computed tomography-guided percutaneous biopsy of abdominal lesions: indications, techniques, results, and complications. AB - Objective: To evaluate the performance of computed tomography (CT)-guided percutaneous biopsy of abdominal lesions. Materials and Methods: This retrospective, single-center study evaluated patients submitted to CT-guided percutaneous biopsy of abdominal lesions at a cancer center, between January 2014 and June 2015. The images and patient medical records were reviewed using a standardized data collection form. Results: We included 225 procedures performed in 212 patients, of whom 143 (63.5%) had a prior diagnosis of cancer. Of the 225 lesions biopsied, 88 (39.1%) had a suspected primary origin and 137 (60.9%) were suspected metastatic lesions. Complications occurred in only 14 (6.2%), the most common being self-limited bleeding, which occurred in 12 (85.7%) of the 14. The occurrence of complications was not found to be significantly associated with the lesion location, age of the patient, presence of comorbidities, use of a supplementary technique, vascularization pattern, or proximity of the lesion to large vessels. The pathology findings were sufficient for making the diagnosis in 202 cases (89.8%), and the diagnosis was consistent with the clinical suspicion in 132 (58.6%). Conclusion: The procedure demonstrated a high (approximately 90%) rate of providing a sufficient sample for the diagnosis and a low complication rate, the most common complication being self-limiting bleeding. PMID- 29991834 TI - Computed tomography-guided preoperative localization of musculoskeletal lesions using the ROLL technique. AB - Objective: To describe the preoperative localization of musculoskeletal lesions with the radioguided occult lesion localization (ROLL) technique. Materials and Methods: In all cases, computed tomography-guided injection of technetium-99m sulfur colloid was performed, directly into or near the suspicious lesion, up to 36 hours before the surgical procedure. Lesions were detected intraoperatively with a gamma probe. Results: We report the cases of six patients submitted to radioguided surgery, including three patients with bone lesions suspicious for metastasis, two patients suspected of recurrent sarcoma, and one patient with no previous diagnosis who had a nodular lesion on the left leg. Patients tolerated the procedure well, and no complications were associated with the puncture. All marked lesions were easily identified intraoperatively and were excised with clear margins. Conclusion: The ROLL technique was effective in the intraoperative localization of occult musculoskeletal lesions, demonstrating that it is a feasible and promising technique for the surgical exploration of selected cases. PMID- 29991835 TI - One-year experience with 68Ga-PSMA PET/CT: applications and results in biochemical recurrence of prostate cancer. AB - Objective: To show the initial (first-year) experience with 68Ga-PSMA PET/CT at a clinic in Brazil. Materials and Methods: Over a one-year period, 96 examinations with 68Ga-PSMA PET/CT (85 related to prostate cancer and 11 related to kidney cancer) were performed in 90 patients. Results: In the prostate and kidney cancer patients alike, the main clinical indication for 68Ga-PSMA PET/CT was suspicion of recurrence during follow-up (in 65.8% and 63.0% of the cases, respectively). Among the prostate cancer patients, 38.5% of those with a prostate specific antigen (PSA) < 0.5 ng/mL tested positive for recurrence on 68Ga-PSMA PET/CT, compared with 71.0% of those with a PSA of 0.5-0.99, 85.7% of those with a PSA of 1.0-1.99, and 92.6% of those with a PSA > 1.99. Conclusion: Although 68Ga-PSMA PET/CT is a technique that has only recently been applied in clinical settings, despite its high cost, 68Ga-PSMA PET/CT shows great promise as a tool in the clinical management of patients with kidney and prostate cancer, especially in those with prostate cancer whose PSA levels are elevated even after treatment. PMID- 29991836 TI - The usefulness of chemical-shift magnetic resonance imaging for the evaluation of osteoid osteoma. AB - Objective: The purpose of this study was to determine whether chemical-shift magnetic resonance imaging (MRI) could be useful in the diagnosis of osteoid osteoma when clinical and radiological tumor features are inconclusive. Materials and Methods: This retrospective study included 17 patients who underwent chemical shift MRI for the evaluation of osteoid osteoma. For all patients, two musculoskeletal radiologists independently recorded signal intensities on in phase and out-of-phase images in the nidus of the tumor, in abnormal-intensity bone marrow surrounding the lesion, and in normal-appearing bone marrow. For each region, relative signal intensity ratios were calculated by dividing out-of-phase by in-phase values. Relative ratios > 1 were considered indicative of neoplastic lesions. Statistical analysis was carried out to analyze the sample. Inter observer and intra-observer agreement for each imaging method were assessed using intraclass correlation coefficients according to the Fleiss method and a value > 0.65 was considered to indicate substantial agreement. Results: The mean relative signal intensity ratios were 1.2 (range, 0.9-1.4) for the nidus and 0.35 (range, 0.11-0.66) for the surrounding tissue; these values differed significantly from the relative signal-intensity ratios for normal-appearing bone marrow (p < 0.05). Conclusion: Chemical-shift MRI is useful for the diagnosis and evaluation of osteoid osteoma. PMID- 29991837 TI - Integrating bilingual musculoskeletal imaging education into radiology and diagnostic imaging residency programs. AB - Objective: To analyze the perception of the relevance of introducing bilingual (Portuguese-English) musculoskeletal imaging education into radiology and diagnostic imaging residency programs, describing the method used. Materials and Methods: To evaluate the relevance of incorporating the bilingual study of musculoskeletal imaging into medical residency programs, we administered a questionnaire, consisting of several multiple-choice questions and one subjective question, to 21 radiology residents at a private tertiary hospital. The residents completed the questionnaire voluntarily and anonymously. Results: Integrating English teaching into radiology training was considered important by 95.2% of the residents. Approximately 90% of residents believe that the method applied at their institution is suitable for learning. Conclusion: The introduction of the English language into the teaching of musculoskeletal imaging in the radiology residency program was perceived positively by the residents, and the preceptors effectively supported those activities. PMID- 29991838 TI - Radiological findings associated with the death of newborns with necrotizing enterocolitis. AB - Objective: The aim of this study was to identify radiological and clinical risk factors for death in newborns with necrotizing enterocolitis. Materials and Methods: This was a retrospective cohort study, based on radiological examinations and medical charts of 66 infants with necrotizing enterocolitis, as confirmed by a finding of intestinal pneumatosis (stage IIA, according to modified Bell's staging criteria). Radiological and clinical variables were evaluated. Results: Of the 66 infants evaluated, 14 (21.2%) presented pneumatosis in the large and small bowel; 7 (10.6%) presented air in the portal system; and 12 (18.2%) died. Bivariate analysis revealed that the following variables were associated with death: bowel perforation; pneumatosis in the large and small bowel; air in the portal system; earlier gestational age; longer time on mechanical ventilation before the identification of pneumatosis; and longer time on mechanical ventilation before discharge or death. In the multivariate regression, the following variables remained as predictors of death: pneumatosis in the large and small intestines (odds ratio [OR] = 12.4; 95% confidence interval [95% CI] = 1.2-127.4; p = 0.035), perforation (OR = 23.2; 95% CI = 2.2 246.7; p = 0.009), and air in the portal system (OR = 69.7; 95% CI = 4.3-[not calculated]; p = 0.003). Conclusion: The set of factors most strongly associated with death in infants with necrotizing enterocolitis comprised extensive pneumatosis, pneumoperitoneum, and air in the portal system. Our findings confirm the importance of radiological imaging in the diagnosis and monitoring of necrotizing enterocolitis. PMID- 29991839 TI - Reproducibility of a quantitative system for assessing the quality of diagnostic ultrasound. AB - Objective: To present a quantitative system for assessing the quality of ultrasound examinations-SQUALUS-and to determine its reproducibility, taking into consideration the images on file, as well as the consistency between the images obtained and the final report. Materials and Methods: The system includes questions related to the number of images; the appropriateness of images in relation to the protocol established; focus adjustment; depth; gain; and appropriateness of the measurements for B-mode examinations. For Doppler examinations, the system includes questions related to the appropriateness of color images, the spectral analysis, and correction of the insonation angle. To assess the quality of the report, the system includes questions related to the consistency between the images obtained and the contents of the report. An overall numerical score was assigned by averaging the scores for image quality and for the contents of the report. Two independent examiners, each blinded to the evaluation of the other, assessed 30 different types of ultrasound examinations. Results: There was statistically significant agreement between the two examiners for 8 of the 10 questions related to image quality. For the questions related to the quality of the reports, the interexaminer agreement was almost perfect. Conclusion: The proposed quantitative system for assessing the quality of ultrasound examinations is a reproducible tool that can be used in audits and accreditation programs. PMID- 29991840 TI - Pulmonary thromboembolism: new diagnostic imaging techniques. AB - The accurate diagnosis of pulmonary thromboembolism is essential to reducing the morbidity and mortality associated with the disease. The diagnosis of pulmonary thromboembolism is challenging because of the nonspecific nature of the clinical profile and the risk factors. Imaging methods provide the definitive diagnosis. Currently, the imaging method most commonly used in the evaluation of pulmonary thromboembolism is computed tomography. The recent development of dual-energy computed tomography has provided a promising tool for the evaluation of pulmonary perfusion through iodine mapping. In this article, we will review the importance of diagnosing pulmonary thromboembolism, as well as the imaging methods employed, primarily dual-energy computed tomography. PMID- 29991841 TI - Evaluation of the fetal abdomen by magnetic resonance imaging. Part 2: abdominal wall defects and tumors. AB - Although ultrasound is still the gold standard for the assessment of fetal malformations, magnetic resonance imaging (MRI) has gained great prominence in recent years. In situations in which ultrasound has low sensitivity, such as maternal obesity, abdominal scarring, and oligohydramnios, MRI has proven to be a safe and accurate method. Regarding fetal abdominal wall defects, MRI appears to be widely used in the prognostic assessment of gastroschisis with intestinal atresia or of complications of omphalocele, allowing better perinatal management and parental counseling. In addition, MRI allows the assessment of local invasion of fetal abdominal tumors, with significant prognostic value for the postnatal period. In this article, we review the main MRI findings in the evaluation of fetal abdominal wall defects and tumors. PMID- 29991842 TI - Ultrasound evaluation of inguinoscrotal pain: an imaging-based review for the ultrasonographer. AB - Emergencies involving the inguinal region and scrotum are common and can be caused by a plethora of different causes. In most cases, such conditions have nonspecific symptoms and are quite painful. Some inguinoscrotal conditions have high complication rates. Early and accurate diagnosis is therefore imperative. Ultrasound is the method of choice for the initial evaluation of this vast range of conditions, because it is a rapid, ionizing radiation-free, low-cost method. Despite the practicality and accuracy of the method, which make it ideal for use in emergency care, the examiner should be experienced and should be familiarized with the ultrasound findings of the most common inguinoscrotal diseases. On the basis of that knowledge, the examiner should also be able to make an accurate, direct, precise report, helping the emergency room physician make decisions regarding the proper (clinical or surgical) management of each case. Here, we review most of the inguinoscrotal conditions, focusing on the imaging findings and discussing the critical points for the appropriate characterization of each condition. PMID- 29991843 TI - Leiomyoma of the seminal vesicle. PMID- 29991844 TI - Pericardial synovial sarcoma: radiological findings. PMID- 29991845 TI - Papillary tumor of the pineal region accompanied by Parinaud's syndrome: magnetic resonance imaging findings. PMID- 29991846 TI - Inguinal and scrotal extramammary Paget's disease: 18F-FDG PET/CT imaging. PMID- 29991847 TI - Congenital lobar emphysema. PMID- 29991848 TI - Erdheim-Chester disease with isolated neurological involvement. PMID- 29991849 TI - Pseudocyst in ectopic pancreas: diagnosis and percutaneous treatment guided by MDCT. PMID- 29991850 TI - Contribution of dynamic contrast enhancement and diffusion-weighted magnetic resonance imaging to the diagnosis of malignant cervical lymph nodes. PMID- 29991851 TI - Percutaneous biopsy of abdominal lesions: what is currently the best diagnostic strategy? PMID- 29991852 TI - Ultrasound in the differential diagnosis of inguinoscrotal pain. PMID- 29991853 TI - Socialist Utopia in Practice: Everyday Life and Medical Authority in a Hungarian Polio Hospital. AB - Based on oral history interviews, medical literature, hospital newsletters, memoirs and news media, this article explores the ways in which ideals of socialism interacted with medical practice in polio care in 1950s Hungary. Through the everyday life of polio hospitals, it argues that the specific care that polio demanded from hospital staff, parents and children, resonated with state socialist political discourses of gender equality and the breakdown of class barriers and conventional hierarchies in medicine. Providing opportunities, as much as failing to fulfil expectations of patients, parents and medical staff, polio care simultaneously created socialist utopias and demonstrated the limits of political ideals. PMID- 29991854 TI - Impact of Diabetes Mellitus Type 1 on Lebanese Families' Quality of Life. AB - Introduction: Diabetes mellitus type 1 (DM1) markedly alters the lives of individuals and their families. Family members can be affected by diabetes and its treatment, causing burden, distress, and reduced quality of life (QOL). Objective: The aim of this research is to study the relationship between the diabetic child and the family members, to evaluate the stress and emotional issues between siblings, and to weigh in on the psychological, affective, and financial burden that parents have to deal with in their daily life. Materials and methods: A total of 37 diabetic Lebanese families recruited from the Chronic Care Center (CCC) answered two questionnaires, one about general information and the other related to psychological and financial impact of DM1 and its oral complications on the families. Results: About 56.8% have monthly income below $1,000; 16.2% of parents have an educational upper limit of college degree; 83.8% of the mothers are housewives; 75.7% of parents feel guilty about their child's condition; 89.2% feel that their diabetic child is frustrated with their diet. For 78.4%, the siblings are jealous of the diabetic child; 13.5% of parents are well aware of the oral complications of diabetes and 86.5% think that treating the diabetic child's teeth is more important than the siblings' ones; 91.9% assist their diabetic child's toothbrushing, but 81.1% of family members do not visit the dentist regularly. A total of 100% allocate special budget for the diabetic child's diet and 59.4% have an additional budget dedicated to the diabetic child's treatment; 81.1% declared that their career is affected by their child's illness. Conclusion: The diabetic child expressed frustration with their diet. The child's siblings are jealous as they feel left behind. The parents experienced guilt feeling and psychological stress. They have social restriction and financial problems. The QOL of families living with a diabetic child is altered negatively.How to cite this article: Noueiri B, Nassif N. Impact of Diabetes Mellitus Type 1 on Lebanese Families' Quality of Life. Int J Clin Pediatr Dent 2018;11(2):61-65. PMID- 29991855 TI - Comparison of the Effectiveness of Probiotic, Chlorhexidine-based Mouthwashes, and Oil Pulling Therapy on Plaque Accumulation and Gingival Inflammation in 10- to 12-year-old Schoolchildren: A Randomized Controlled Trial. AB - Introduction: The use of a mouthwash augments mechanical removal of plaque by brushing and flossing and helps maintain oral health through its antiplaque and antibacterial chemical properties. Aim: To evaluate the effectiveness of a probiotic mouthwash, sesame oil pulling therapy, and chlorhexidine-based mouth wash on plaque accumulation and gingival inflammation in schoolchildren aged 10 to 12 years. Materials and methods: The randomized controlled trial included 45 healthy schoolchildren aged 10 to 12 years and studying in Government High School, Tiruchengode, Tamil Nadu, India. The participants were randomly divided into three groups, I, II, and III, with 15 children in each group as follows: group I: probiotic mouthwash; group II: chlorhexidine mouthwash; and group III: sesame oil. Baseline scores of plaque index (PI) and modified gingival index (GI) were recorded followed by a full mouth oral prophylaxis. The designated mouth rinses were distributed to the respective groups and they were instructed to rinse once daily. Their parents supervised the children during the use of mouthwash. On the 15th and 30th day, the children were subjected to the same clinical measurements. Children's acceptance of their plaque control method was assessed using a modified facial image scale. Results: Intragroup comparisons for both the GI and PI scores were statistically significant (p <= 0.001) in all the three groups. Difference in the GI scores between the 15th and 30th day was statistically significant for chlorhexidine group alone (p = 0.024). Intergroup comparisons between the three groups were not statistically significant. Conclusion: Probiotic mouthwash, chlorhexidine mouthwash, and sesame oil were equally effective in reducing plaque and in improving the gingival status of children. The difference between the gingival scores on the 15th and 30th day was statistically significant in the chlorhexidine group.How to cite this article: Kandaswamy SK, Sharath A, Priya PRG. Comparison of the Effectiveness of Probiotic, Chlorhexidine-based Mouthwashes, and Oil Pulling Therapy on Plaque Accumulation and Gingival Inflammation in 10- to 12-year-old Schoolchildren: A Randomized Controlled Trial. Int J Clin Pediatr Dent 2018;11(2):66-70. PMID- 29991856 TI - Estimation of Salivary Glucose, Calcium, Phosphorus, Alkaline Phosphatase, and Immunoglobulin A among Diabetic and Nondiabetic Children: A Case-Control Study. AB - Introduction: Saliva is vital for oral health and helps to maintain oral homeostasis. It may show qualitative and quantitative variations owing to any changes in the systemic health. Diabetes mellitus (DM) is a metabolic disease and the individuals may be at higher risk for oral health problems. Objective: The study was aimed to estimate the levels of various salivary components among diabetic and nondiabetic children with similar caries status and also to analyze possible association between caries status and possible caries determinants in the saliva of diabetic children. Materials and methods: A total of 70 children in the age group of 6 to 13 years with minimal dental caries (Decayed, Missing and Filled Teeth index (DMFT/dmft >1 and <5)) were selected. Group I comprised of type I diabetic children and on medication for diabetes and group II included healthy nondiabetic children. Salivary samples were collected from the participants by passive drool method and estimation of all salivary parameters was done using autoanalyzer. Results: Statistical analyses were done using Student's t-test and results are presented as mean +/- standard deviation (SD). There was a highly significant difference in mean glucose value between diabetic and nondiabetic children. Levels of salivary calcium, phosphorus, and salivary immunoglobulin A (s-IgA) did not show any significant difference between the two groups. There was also a statistically significant difference in the alkaline phosphatase (AP) levels, which was found to be higher in diabetics. Conclusion: An elevation in the levels of salivary glucose and AP was evident in diabetic children, which can be a risk marker for dental caries. There was no correlation in the levels of salivary calcium, phosphorus, and s-IgA levels among diabetic and healthy children. Clinical significance: The salivary factors evaluated in the study may prove to be useful measures of caries experience in diabetic children.How to cite this article: Uppu K, Sahana S, Madu GP, Vasa AAK, Nalluri S, Raghavendra KJ. Estimation of Salivary Glucose, Calcium, Phosphorus, Alkaline Phosphatase, and Immunoglobulin A among Diabetic and Nondiabetic Children: A Case Control Study. Int J Clin Pediatr Dent 2018;11(2):71-78. PMID- 29991857 TI - Evaluation of Antimicrobial Activity of Two Endodontic Sealers: Zinc Oxide with Thyme Oil and Zinc Oxide Eugenol against Root Canal Microorganisms- An in vitro Study. AB - Aim: The present study was aimed to find out and compare the antimicrobial effect of the paste containing zinc oxide cement mixed with thyme oil (ZO + Th oil) with that of the paste containing zinc oxide and eugenol (ZO + E) against Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Pseudomonas aeruginosa, common root canal pathogens of deciduous teeth. Materials and methods: An in vitro antimicrobial effect was carried out by the agar diffusion method. The ZO + Th oil paste was filled in the punched holes of Mueller Hinton agar at two equidistant points. The same was followed for ZO + E paste. For 24 hours, all the plates were incubated at a temperature of 37 degrees C. The inhibition zones in millimeters around the wells were calculated. There were 6 times repetitions of the test for each microorganism. Data were tabulated and analyzed statistically using one-way analysis of variance (ANOVA) and Tukey's post hoc comparison test. Level of significance for the tests was 5%. Results: Zones of bacterial inhibition were highest for ZO + Th oil paste against the pathogenic microorganisms S.aureus, followed by E. coli, E. faecalis, P. aeruginosa while for ZO + E paste, the decreasing order against pathogenic microorganisms was E. coli, S. aureus, E. faecalis, and P. aeruginosa. Statistically significant difference was found in both the pastes, ZO + Th oil paste and ZO + E paste. Conclusion: ZO + Th oil paste showed higher levels of antimicrobial effect against the root canal pathogens.How to cite this article: Thosar NR, Chandak M, Bhat M, Basak S. Evaluation of Antimicrobial Activity of Two Endodontic Sealers: Zinc Oxide with Thyme Oil and Zinc Oxide Eugenol against Root Canal Microorganisms-An in vitro Study. Int J Clin Pediatr Dent 2018;11(2):79-82. PMID- 29991858 TI - Influence of Storage Media and Duration of Fragment in the Media on the Bond Strength of the Reattached Tooth Fragment. AB - Introduction: Fracture of anterior teeth is the most frequent type of injury in the permanent dentition. Composite materials have made possible the use of adhesive materials and techniques, but storage of fragment in the media can enhance the bond strength. The purpose was to evaluate the influence of storage media and duration of the fragment in the media on the bond strength of the reattached fragment of teeth. Materials and methods: A total of 104 permanent maxillary central incisors were included. Samples were divided into four groups of 26 teeth each, further divided into eight groups of 13 teeth each and sectioned 3 mm apical to the incisal edge and stored in four storage media-tap water, artificial saliva, sodium fluoride, and Tooth Mousse at 12 and 24 hours. The bond strength was measured by universal strength testing machine. Results: Tooth Mousse showed statistically significant difference (p-value 0.001) compared with sodium fluoride, artificial saliva, and tap water when stored in both 12 and 24 hours' duration. Conclusion: Tooth Mousse was a better storage media when compared with sodium fluoride, artificial saliva, and tap water. Clinical significance: Tooth Mousse can be considered as a best storage media for fragment reattachment.How to cite this article: Jalannavar P, Tavargeri A. Influence of Storage Media and Duration of Fragment in the Media on the Bond Strength of the Reattached Tooth Fragment. Int J Clin Pediatr Dent 2018;11(2):83-88. PMID- 29991859 TI - Clinical Evaluation of Preventive Effect of Fissure Sealants on Initial Carious Lesion of Permanent Mandibular Molars Pretreated with and without Fluoride Varnish by Fluorescence Camera. AB - The important armamentarium in the present day scenario against caries prevention is considered to be a combination of preventive methods. The present study was conducted to evaluate the preventive effect of pit and fissure sealant pretreated with fluoride varnish on initial carious lesion by fluorescence camera (FC). How to cite this article: Lakshmi MS, Srilatha KT, Nandlal B, Deshmukh S. Clinical Evaluation of Preventive Effect of Fissure Sealants on Initial Carious Lesion of Permanent Mandibular Molars Pretreated with and without Fluoride Varnish by Fluorescence Camera. Int J Clin Pediatr Dent 2018;11(2):89-93. PMID- 29991860 TI - A Comparative Evaluation of Efficacy of Streptococcus mutans Counts in Saliva: An in vivo Study. AB - Dental caries is a disease of multifactorial origin and Streptococcus mutans is considered as the chief pathogen responsible for its development. However, reduction in the number of pathogenic bacteria, particularly S. mutans, with the use of various preventive measures, can reduce dental caries to a significant level. Therefore, the present clinical study was undertaken to evaluate and compare the efficacy of toothbrushing, fluoride varnish, chlorhexidine mouthwash, and a probiotic (Yakult) in reducing the S. mutans counts in the saliva using Dentocult SM Strip Mutans kit in children. A total of 40 school students between the age group of 4 and 8 years were selected for the study and S. mutans count was taken on the first dental visit using Dentocult SM Strip Mutans test kit. After the initial scores of S. mutans were obtained, the children were divided into four groups and provided with different caries preventive regimen for 2 weeks. After 2 weeks, the scores of S. mutans were reevaluated for reduction in their counts, if any. The data thus collected were tabulated and statistically analyzed. All the groups showed a significant reduction in S. mutans counts with the highest reduction from the Fluor Protector varnish followed by chlorhexidine mouthwash, probiotic (Yakult), and toothbrushing. How to cite this article: Sharma M, Pandit IK, Srivastava N, Gugnani N, Gupta M. A Comparative Evaluation of Efficacy of Streptococcus mutans Counts in Saliva: An in vivo Study. Int J Clin Pediatr Dent 2018;11(2):94-99. PMID- 29991861 TI - Determination of ABO Blood Groups and Rh Typing from Dry Salivary Samples. AB - Introduction: A unique blood group is a characteristic every individual possesses. Blood group antigens like A, B, D, H, etc., are found to be present on the cell surfaces of red blood cells (RBCs). Besides blood, these are also secreted in various body secretions like semen, sweat, amniotic fluid, and saliva. Blood grouping has several applications in forensic sciences and is also a major part of routine medical investigations. Presence of these antigens in saliva is dependent on the secretor status of an individual. Saliva samples at the crime scene are very crucial, as they help in deoxyribonucleic acid typing, sex determination, bite mark analysis, and blood grouping. Dried salivary samples are often obtained in more number of cases as compared with the wet form, due to the variable time lapse between the occurrence of the crime and the start of the investigation. Blood grouping from these samples proves to be very efficient. Thus, the present study aims at evaluating the accuracy of ABO blood group determination and Rh typing from dried salivary samples. Also, the study would establish the use of saliva as a noninvasive technique in routine blood examinations, especially in children who have needle phobia. Materials and methods: Blood grouping and Rh typing were performed on the dry salivary samples obtained from the 47 subjects using the absorption-inhibition technique. This was then compared with the results obtained using extraction socket blood and evaluated. Results: The present study showed a 100% positive correlation for ABO blood grouping, but a mere 14.81% positive correlation for Rh typing between the dried salivary samples and the extraction socket blood. Conclusion: Dried salivary samples can thus be put to immense use in several areas of forensic investigations. It could also help in developing alternate methods for routine blood investigations in children and adults.How to cite this article: Velani PR, Shah P, Lakade L. Determination of ABO Blood Groups and Rh Typing from Dry Salivary Samples. Int J Clin Pediatr Dent 2018;11(2):100-104. PMID- 29991862 TI - Manuka Honey: A Potent Cariostatic Agent- An in vitro Study. AB - Aim: The aim of the study was to test the antibacterial activity of manuka honey and compare its efficacy with another commercially available honey (Dabur honey) on the cariogenic bacteria on Streptococcus mutans and Lactobacillus. Materials and methods: An in vitro study was carried out on 40 agar specimens; the samples were divided into two groups of 20 samples consisting of S. mutans and Lactobacil lus respectively. The 20 samples in each group were further subdivided into four groups of five each, which were tested with 25% manuka honey, 100% manuka honey, 25% Dabur honey, and 100% Dabur honey for both Lactobacillus and S. mutans groups. The antibacterial activity was tested using the agar well diffusion method against S. mutans and Lacto-bacillus. Antibacterial activity was assessed by measuring the diameter of inhibition of zones surrounding the wells. The results obtained were statistically analyzed (one-way analysis of variance test, p-value). Results: The results showed that 25% of manuka honey has statistically significant (p <= 0.001) antibacterial effect than 25% of Dabur honey on both Streptococcus and Lactobacillus species, and manuka honey with 100% concentration showed a statistically significant (p <= 0.001) antibacterial effect than 100% Dabur honey on the same species of bacteria. 100% of both the honeys showed statistically significant (p <= 0.001) antibacterial effect than 25% concentrations of the same on S. mutans and Lactobacillus. Conclusion: Manuka honey had more antibacterial activity than Dabur honey on S. mutans and Lactobacillus bacteria in the in vitro study. This effect was dependent on the concentration of honey used.How to cite this article: Beena JP, Sahoo P, Konde S, Raj SN, Kumar NC, Agarwal M. Manuka Honey: A Potent Cariostatic Agent-An in vitro Study. Int J Clin Pediatr Dent 2018;11(2):105-109. PMID- 29991863 TI - Validating the Usage of Cariogram in 5- and 12-year-old School-going Children in Paonta Sahib, Himachal Pradesh, India: A 12-month Prospective Study. AB - Aim: To validate the caries risk profiles in 5- and 12-year-old school-going children and to single out main contributing factor, if any, using cariogram over a period of 1 year. Materials and methods: A cariogram model was used to create caries risk profiles on 499 children aged 5 and 12 years +/-6 months. They were divided into 2 groups. The group I and group II consisted of 250 and 249 children respectively. Re-examination was done after 1 year and caries increment was recorded. The caries risk profiles generated by the cariogram software were compared with caries increment. Results: Percentage of subject having caries increment in groups I and II in high-, medium-, and low-risk group after 1 year was 66.2, 39.5, and 13%, and 48.5, 27.3, and 13.9% respectively. The mean caries increment after 1 year in groups I and II in high-, medium-, and low-risk patients was 0.96, 0.49, and 0.13, and 0.7, 0.36, and 0.11 respectively. Linear regression analysis showed dental caries, diet content, diet frequency, plaque index, Streptococcus mutans count, fluoride, salivary flow rate, and buffer capacity are significantly associated with actual chance to avoid caries. Conclusion: The risk of developing new carious lesions consistently reduced from high-risk category to low-risk category, reflecting the cariogram ability in accurately estimating future caries. Hence, cariogram can be said to be a useful tool for caries prediction. Initial dental caries came out to be the strongest predictor of future caries.How to cite this article: Garg A, Madan M, Dua P, Saini S, Mangla R, Singhal P, Dupper A. Validating the Usage of Car-iogram in 5- and 12-year-old School-going Children in Paonta Sahib, Himachal Pradesh, India: A 12-month Prospective Study. Int J Clin Pediatr Dent 2018;11(2):110-115. PMID- 29991864 TI - Perception of Indian Dental Surgeons regarding Molar Incisor Hypomineralization. AB - Aim: To determine the perception of Indian dental professionals about prevalence, severity, and etiological factors of molar incisor hypomineralization (MIH). Materials and methods: An online survey was mailed to dental professionals encompassing various questions regarding etiology, diagnosis, prevalence, and management of MIH. Results: More than 90% of the respondents encounter teeth with hypomineralization in their practice, with less than half of them encountering such teeth on a monthly basis. Among these more than one-third find it difficult to manage one or the other aspect of MIH. The etiology was found to be varying as per the respondents. Conclusion: Molar incisor hypomineralization is a common condition encountered by dental professionals with no apparent consensus regarding the anticipated prevalence, severity, and etiology of this condition. Knowledge of clinicians' level of perception could be an incentive for pediatric dentists to become more acquainted with MIH by conducting research into its different aspects.How to cite this article: Upadhyay S, Kumar G, Dhillon JK, Gill NC. Perception of Indian Dental Surgeons regarding Molar Incisor Hypomineralization. Int J Clin Pediatr Dent 2018;11(2):116-121. PMID- 29991865 TI - A Survey on the Use of Antibiotics among the Dentists of Kolkata, West Bengal, India. AB - Introduction: Dental infections are multimicrobial in origin with their etiological factors involving a combination of Gram-positive, Gram-negative, facultative anaerobes, and obligate anaerobic bacteria. Thus, antibiotics and analgesics account for a great majority of medicines prescribed by the dental surgeons. Inappropriate prescription of antibiotics by health care professionals has become a worldwide issue nowadays. Aim: The purpose of the present study was to:* Determine the pattern of antibiotic prescription among dentists of Kolkata.* Assess the attitude of dentists toward antibiotic resistance. Materials and methods: An electronic version of the questionnaire of cross-sectional survey regarding antibiotic use and attitude toward growing antibiotic resistance was constructed using Qualtrics (Qualtrics Pvt. Limited Provo, Utah), an internet online survey tool that was e-mailed to dental surgeons of Kolkata registered with Indian Dental Association (IDA), West Bengal. A reminder e-mail was given after 1 month to recollect the responses from them. Results: The survey was e mailed to 300 dental surgeons, out of which 115 dental surgeons completed the survey, thereby achieving a response rate of 38.33%. Majority of the respondents (60%) chose amoxicillin in nonallergic patients. Average minimum duration of antibiotic therapy was 5 days. The drug of first choice for patients with an allergy to penicillin was erythromycin. The prime determinant of antibiotic use was facial swelling (68%). The prime determinant to select a particular brand of antibiotics was affordability of that brand (61%). Almost all (99%) dental surgeons were aware of antibiotic resistance being a growing concern. As per their views, there was overprescription of antibiotics.How to cite this article: Kaul R, Angrish P, Jain P, Saha S, Sengupta AV, Mukherjee S. A Survey on the Use of Antibiotics among the Dentists of Kolkata, West Bengal, India. Int J Clin Pediatr Dent 2018;11(2):122-127. PMID- 29991866 TI - Mandibular Regional Odontodysplasia in an 8-year-old Boy showing Teeth Disorders, Gubernaculum Tracts, and Altered Bone Fractal Pattern. AB - : Regional odontodysplasia (RO) is a rare nonhereditary developmental condition usually affecting maxilla and female patients. A few number of articles have used the cone beam computed tomography (CBCT) to describe imaging findings in RO. Thus, this article aims to report unusual imaging findings in a Brazilian child who presented with mandibular RO. A healthy 8-year-old boy was referred for evaluation of an anterior mandibular gingival enlargement. Radiographically, all right mandibular teeth showed wide pulp chambers and shortened roots with thin dentinal walls and open apices, featuring a "ghost teeth" appearance, which indicated a diagnosis of RO. Missing teeth and altered radiopacity were observed. Cone beam computed tomography provided great insight into RO, allowing to identify gubernaculum tracts (GTs) associated with RO teeth. Fractal analysis of the bone surrounding RO teeth revealed an altered trabecular pattern. Clinical significance: This case describes a rare developmental teeth-related pathology in a boy who showed unusual features on imaging exams. The CBCT provided the observation of RO tooth-related GTs, probably a new finding added to the international literature regarding RO, as well as the pulp chamber volume characterization of an affected tooth not published yet. In addition, it was observed an altered fractal pattern of the mandibular bone adjacent to RO teeth, which has not been described to date.How to cite this article: de Sa Cavalcante D, Fonteles CSR, Ribeiro TR, Kurita LM, Pimenta AVM, Carvalho FSR, Costa FWG. Mandibular Regional Odontodysplasia in an 8-year-old Boy showing Teeth Disorders, Gubernaculum Tracts, and Altered Bone Fractal Pattern. Int J Clin Pediatr Dent 2018;11(2):128-134. PMID- 29991867 TI - A Case of Painless Excision. AB - Soft tissue lesions of the oral cavity are seen in children at the dental office. This case report aims to showcase the ability of laser to treat recurrent soft tissue lesions in the oral cavity in a painless manner. This painless procedure provides relief to the child and parent who suffer from anxiety toward dental treatment. How to cite this article: Suyash IA, Bhatia R. A Case of Painless Excision. Int J Clin Pediatr Dent 2018;11(2):135-140. PMID- 29991868 TI - Customized Hybrid Bluegrass Appliance: An Innovative Technique. AB - Oral habits in the form of thumb sucking and tongue thrusting are commonly learned patterns of behavior seen in preschool children and they are associated with anxiety, fear, hunger, oral pressure, and sleep. Chronic practice can cause dentoalveolar, perioral problems, and atypical root resorption (ARR) of anterior primary teeth. The ARR is provoked by the thumb sucking habit, and leads to early loss of anterior primary teeth. The early loss of anterior tooth may result in speech and masticatory problems, and psychological disturbance to the child. Hence, pediatric dentists play a crucial role in giving necessary information to parents and guardians. Starting from counseling to appliance therapy, various treatment modalities have been reported in the literature. One of them is bluegrass appliance; it is a nonpunitive habit reminder therapy. The present case report describes a customized hybrid bluegrass appliance designed to eliminate thumb sucking and tongue thrusting habit, and to perform as an esthetic functional space maintainer. How to cite this article: Mohammad Z, Bagalkotkar A, Mishra A, Veerala G. Customized Hybrid Bluegrass Appliance: An Innovative Technique. Int J Clin Pediatr Dent 2018;11(2):141-145. PMID- 29991869 TI - Accelerating Treatment of Skeletal Class II Malocclusion using Fixed Twin Block Appliances. AB - Background: Patients with class II malocclusion generally seek orthodontic treatment for esthetic concern. Various myo-functionl appliances can be used for the treatment of skeletal as well as the dental malocclusion in a growing patient. Among various functional appliances, twin block appliance is most commonly used due to better patient compliances. It redirects the mandibular growth to correct the maxillomandibular relationship, enhancing facial esthet ics. This article presents a modified design of the twin block appliance which is less bulky, more esthetic, can be used concurrently with fixed orthodontic appliance, and is easily accepted by uncooperative patients. Case summary: An 11 year-old-boy, who presented himself with a skeletal class II malocclusion, was treated with simultaneous use of fixed twin block along with fixed orthodontic appliance to correct both the skeletal and dental malocclusion. The twin block design was modified to have a better compatibility with the fixed orthodontic appliance.How to cite this article: Pattanaik S, Puvvula N, Mohammad N. Accelerating Treatment of Skeletal Class II Malocclusion using Fixed Twin Block Appliances. Int J Clin Pediatr Dent 2018;11(2):146-150. PMID- 29991870 TI - Pre-emptive Intracoronal Radiolucency in First Permanent Molar. AB - Pre-eruptive intracoronal radiolucency (PECR) is characterized by the existence of a radiographic radiolucent area inside the coronal dentin prior to dental eruption. It is a rare clinical entity of unknown etiology, usually asymptomatic and diagnosed through routine radiographs. The aim of this article is to report the treatment of a PECR in an 8-year-old girl. Surgical procedure to expose the crown was conducted; upon tooth eruption, the radiolucent lesion was accessed and the tooth was restored. The case has an 18-month follow-up and emphasis on aspects linked to diagnosis and clinical approach was discussed. How to cite this article: Ilha MC, Kramer PF, Ferreira SH, Ruschel HC. Pre-eruptive Intracoronal Radiolucency in First Permanent Molar. Int J Clin Pediatr Dent 2018;11(2):151 154. PMID- 29991871 TI - Role of microRNAs in the main molecular pathways of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary liver malignant neoplasia. HCC is characterized by a poor prognosis. The need to find new molecular markers for its diagnosis and prognosis has led to a progressive increase in the number of scientific studies on this topic. MicroRNAs (miRNAs) are small non-coding RNA that play a role in almost all main cellular pathways. miRNAs are involved in the regulation of expression of the major tumor-related genes in carcinogenesis, acting as oncogenes or tumor suppressor genes. The aim of this review was to identify papers published in 2017 investigating the role of miRNAs in HCC tumorigenesis. miRNAs were classified according to their role in the main molecular pathways involved in HCC tumorigenesis: (1) mTOR; (2) Wnt; (3) JAK/STAT; (4) apoptosis; and (5) MAPK. The role of miRNAs in prognosis/response prediction was taken into consideration. Bearing in mind that the analysis of miRNAs in serum and other body fluids would be crucial for clinical management, the role of circulating miRNAs in HCC patients was also investigated. The most represented miRNA-regulated pathway in HCC is mTOR, but apoptosis, Wnt, JAK/STAT or MAPK pathways are also influenced by miRNA expression levels. These miRNAs could thus be used in clinical practice as diagnostic, prognostic or therapeutic targets for HCC treatment. PMID- 29991872 TI - Apoptosis and non-alcoholic fatty liver diseases. AB - The number of patients with nonalcoholic fatty liver diseases (NAFLD) including nonalcoholic steatohepatitis (NASH), has been increasing. NASH causes cirrhosis and hepatocellular carcinoma (HCC) and is one of the most serious health problems in the world. The mechanism through which NASH progresses is still largely unknown. Activation of caspases, Bcl-2 family proteins, and c-Jun N-terminal kinase-induced hepatocyte apoptosis plays a role in the activation of NAFLD/NASH. Apoptotic hepatocytes stimulate immune cells and hepatic stellate cells toward the progression of fibrosis in the liver through the production of inflammasomes and cytokines. Abnormalities in glucose and lipid metabolism as well as microbiota accelerate these processes. The production of reactive oxygen species, oxidative stress, and endoplasmic reticulum stress is also involved. Cell death, including apoptosis, seems very important in the progression of NAFLD and NASH. Recently, inhibitors of apoptosis have been developed as drugs for the treatment of NASH and may prevent cirrhosis and HCC. Increased hepatocyte apoptosis may distinguish NASH from NAFLD, and the improvement of apoptosis could play a role in controlling the development of NASH. In this review, the association between apoptosis and NAFLD/NASH are discussed. This review could provide their knowledge, which plays a role in seeing the patients with NAFLD/NASH in daily clinical practice. PMID- 29991873 TI - Diets, functional foods, and nutraceuticals as alternative therapies for inflammatory bowel disease: Present status and future trends. AB - Inflammatory bowel disease (IBD) is a serious health concern among western societies. The disease is also on the rise in some East Asian countries and in Australia. Health professionals and dietitians around the world are facing an unprecedented challenge to prevent and control the increasing prevalence of IBD. The current therapeutic strategy that includes drugs and biological treatments is inefficient and are associated with adverse health consequences. In this context, the use of natural products is gaining worldwide attention. In vivo studies and clinical evidence suggest that well-planned dietary regimens with specific nutrients can alleviate gastrointestinal inflammation by modulating inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-1), IL-6, IL-1beta, and IL-10. Alternatively, the avoidance of high-fat and high carbohydrate diets is regarded as an effective tool to eliminate the causes of IBD. Many functional foods and bioactive components have received attention for showing strong therapeutic effects against IBD. Both animal and human studies suggest that bioactive functional foods can ameliorate IBD by downregulating the pro-inflammatory signaling pathways, such as nuclear factor kappaB, STAT1, STAT6, and pro-inflammatory cytokines, including IL-1beta, IL-4, IL-6, COX-2, TNF-alpha, and interferon gamma. Therefore, functional foods and diets have the potential to alleviate IBD by modulating the underlying pathogenic mechanisms. Future comprehensive studies are needed to corroborate the potential roles of functional foods and diets in the prevention and control of IBD. PMID- 29991874 TI - Advances in immuno-oncology biomarkers for gastroesophageal cancer: Programmed death ligand 1, microsatellite instability, and beyond. AB - Blockade of the programmed death ligand 1 (PD-L1) and programmed cell death 1 (PD 1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction (GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability (MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatment-refractory solid tumors with MSI status and the third-line or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer. PMID- 29991875 TI - Minimally invasive donor hepatectomy, are we ready for prime time? AB - Minimally invasive surgery potentially reduces operative morbidities. However, pure laparoscopic approaches to donor hepatectomy have been limited by technical complexity and concerns over donor safety. Reduced-wound donor hepatectomy, either in the form of a laparoscopic-assisted technique or by utilizing a mini laparotomy wound, i.e., hybrid approach, has been developed to bridge the transition to pure laparoscopic donor hepatectomy, offering some advantages of minimally invasive surgery. To date, pure laparoscopic donor left lateral sectionectomy has been validated for its safety and advantages and has become the standard in experienced centres. Pure laparoscopic approaches to major left and right liver donation have been reported for their technical feasibility in expert hands. Robotic-assisted donor hepatectomy also appears to be a valuable alternative to pure laparoscopic donor hepatectomy, providing additional ergonomic advantages to the surgeon. Existing reports derive from centres with tremendous experience in both laparoscopic hepatectomy and donor hepatectomy. The complexity of these procedures means an arduous transition from technical feasibility to reproducibility. Donor safety is paramount in living donor liver transplantation. Careful donor selection and adopting standardized techniques allow experienced transplant surgeons to safely accumulate experience and acquire proficiency. An international prospective registry will advance the understanding for the role and safety of pure laparoscopic donor hepatectomy. PMID- 29991876 TI - Intra-individual comparison of therapeutic responses to vascular disrupting agent CA4P between rodent primary and secondary liver cancers. AB - AIM: To compare therapeutic responses of a vascular-disrupting-agent, combretastatin-A4-phosphate (CA4P), among hepatocellular carcinomas (HCCs) and implanted rhabdomyosarcoma (R1) in the same rats by magnetic-resonance-imaging (MRI), microangiography and histopathology. METHODS: Thirty-six HCCs were created by diethylnitrosamine gavage in 14 rats that were also intrahepatically implanted with one R1 per rat as monitored by T2-/T1-weighted images (T2WI/T1WI) on a 3.0T clinical MRI-scanner. Vascular response and tumoral necrosis were detected by dynamic contrast-enhanced (DCE-) and CE-MRI before, 1 h after and 12 h after CA4P iv at 10 mg/kg (treatment group n = 7) or phosphate-buffered saline at 1.0 mL/kg (control group n = 7). Tumor blood supply was calculated by a semiquantitative DCE parameter of area under the time signal intensity curve (AUC30). In vivo MRI findings were verified by postmortem techniques. RESULTS: On CE-T1WIs, unlike the negative response in all tumors of control animals, in treatment group CA4P caused rapid extensive vascular shutdown in all R1-tumors, but mildly or spottily in HCCs at 1 h. Consequently, tumor necrosis occurred massively in R1-tumors but patchily in HCCs at 12 h. AUC30 revealed vascular closure (66%) in R1-tumors at 1 h (P < 0.05), followed by further perfusion decrease at 12 h (P < 0.01), while less significant vascular clogging occurred in HCCs. Histomorphologically, CA4P induced more extensive necrosis in R1-tumors (92.6%) than in HCCs (50.2%) (P < 0.01); tumor vascularity heterogeneously scored +~+++ in HCCs but homogeneously scored ++ in R1-tumors. CONCLUSION: This study suggests superior performance of CA4P in metastatic over primary liver cancers, which could guide future clinical applications of vascular-disrupting-agents.. PMID- 29991877 TI - Gastric cancer in Alaska Native people: A cancer health disparity. AB - AIM: To evaluate recent trends in gastric cancer incidence, response to treatment, and overall survival among Alaska Native (AN) people. METHODS: A retrospective analysis of the Alaska Native Medical Center patient database was performed. Patient history, clinical, pathological, response to treatment and patient outcomes were collected from one-hundred and thirty-two AN gastric cancer patients. The Surveillance, Epidemiology and End Result database 18 was used to collect comparison United States non-Hispanic White (NHW) and AN gastric cancer patient data between 2006-2014. RESULTS: AN gastric cancer patients have a higher incidence rate, a poorer overall survival, and are diagnosed at a significantly younger age compared to NHW patients. AN patients differ from NHW patients in greater prevalence of non-cardia, diffuse subtype, and signet ring cell carcinomas. AN females were more likely to be diagnosed with later stage cancer, stage IV, compared to AN males. Diminished overall survival was observed among AN patients with increasing stage, O+ blood type, < 15 lymph nodes examined at resection, and no treatment. This study is the first report detailing the clinicopathologic features of gastric cancer in AN people with outcome data. CONCLUSION: Our findings confirm the importance of early detection, treatment, and surgical resection for optimizing AN patient outcomes. Further research on early detection markers are warranted. PMID- 29991878 TI - Transforming growth factor-beta and peripheral regulatory cells are negatively correlated with the overall survival of hepatocellular carcinoma. AB - AIM: To understand the cellular and molecular changes in peripheral blood that can lead to the development of hepatocellular carcinoma (HCC) and provide new methods for its diagnosis and treatment. METHODS: Peripheral blood mononuclear cells were isolated from the peripheral blood of HCC patients and normal controls and then analyzed by flow cytometry. The percentage of transforming growth factor beta (TGF-beta)+ regulatory cells (Tregs) in the peripheral blood was measured, and the expression of TGF-beta was also determined. Then, the relationship between the changes and the 5-year survival of patients was analyzed. In addition, recombinant human TGF-beta (rhTGF-beta) and recombinant human interleukin-6 were added to stimulate the cultured cells, and their effects on HCC were evaluated. RESULTS: The expression of TGF-beta and the percentage of TGF beta+ Tregs in the peripheral blood of HCC patients increased significantly compared with normal controls. Compared with the low TGF-beta expression group, the high TGF-beta expression group had a significantly lower 5-year survival rate, and the same result was found in the two TGF-beta+ Treg groups, suggesting that TGF-beta and TGF-beta+ Tregs were negatively correlated with the overall survival of the patients. In addition, rhTGF-beta promoted the growth of tumor cells and induced high expression levels of IL-6, which further promoted tumor proliferation. CONCLUSION: The results showed that TGF-beta may promote tumor growth and proliferation by inducing the production of IL-6, and TGF-beta and TGF beta+ Tregs may serve as new markers for predicting a poor prognosis in HCC. PMID- 29991880 TI - Systematic review and meta-analysis on the association of tuberculosis in Crohn's disease patients treated with tumor necrosis factor-alpha inhibitors (Anti TNFalpha). AB - AIM: To perform a meta-analysis on the risk of developing Mycobacterium tuberculosis (TB) infection in Crohn's disease (CD) patients treated with tumor necrosis factor-alpha (TNFalpha) inhibitors. METHODS: A meta-analysis of randomized, double-blind, placebo-controlled trials of TNFalpha inhibitors for treatment of CD in adults was conducted. Arcsine transformation of TB incidence was performed to estimate risk difference. A novel epidemiologically-based correction (EBC) enabling inclusions of studies reporting no TB infection cases in placebo and treatment groups was developed to estimate relative odds. RESULTS: Twenty-three clinical trial studies were identified, including 5669 patients. Six TB infection cases were reported across 5 studies, all from patients receiving TNFalpha inhibitors. Eighteen studies reported no TB infection cases in placebo and TNFalpha inhibitor treatment arms. TB infection risk was significantly increased among patients receiving TNFalpha inhibitors, with a risk difference of 0.028 (95%CI: 0.0011-0.055). The odds ratio was 4.85 (95%CI: 1.02-22.99) with EBC and 5.85 (95%CI: 1.13-30.38) without EBC. CONCLUSION: The risk of TB infection is higher among CD patients receiving TNFalpha inhibitors. Understanding the immunopathogenesis of CD is crucial, since using TNFalpha inhibitors in these patients could favor mycobacterial infections, particularly Mycobacterium avium subspecies paratuberculosis, which ultimately could worsen their clinical condition. PMID- 29991882 TI - Capacity, Vulnerability, and Informed Consent for Research. PMID- 29991879 TI - Current global trends in the incidence of pediatric-onset inflammatory bowel disease. AB - AIM: To perform a comprehensive review and provide an up-to-date synopsis of the incidence and trends of inflammatory bowel disease (IBD). METHODS: We systematically searched the MEDLINE (source PubMed), EMBASE and Cochrane Library databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (period: 1985-2018) to identify studies reporting population-based data on the incidence of pediatric-onset (< 19 years at diagnosis) IBD in full manuscripts. Two authors carried out screening and data extraction. Choropleth interactive maps and temporal trends were used to illustrate the international differences and incidences of and changes in IBD and subtypes. RESULTS: In total, one hundred forty studies reporting data from 38 countries were considered in this review. The highest annual pediatric incidences of IBD were 23/100000 person-years in Europe, 15.2/100000 in North America, and 11.4/100000 in Asia/the Middle East and Oceania. The highest annual incidences of Crohn's disease (CD) were 13.9/100000 in North America and 12.3/100000 in Europe. The highest annual incidences of ulcerative colitis (UC) were 15.0/100000 in Europe and 10.6/100000 in North America. The highest annual incidences of IBD unclassified (IBD-U) were 3.6/100000 in Europe and 2.1/100000 in North America. In the time-trend analyses, 67% of CD, 46% of UC and 11% of IBD-U studies reported an increasing incidence (P < 0.05). The risk of IBD is increasing among first-generation of migrant populations. CONCLUSION: Globally, the incidence of IBD varies greatly by geographical areas. The steadily increasing incidence of pediatric IBD over time indicates its emergence as a global disease, suggesting that studies should investigate the environmental risk factors among pediatric cohorts. PMID- 29991881 TI - Liposarcoma of the stomach: Report of two cases and review of the literature. AB - Liposarcoma of the stomach is extremely rare, and only 37 cases have been reported worldwide. We herein report two cases of liposarcoma of the stomach. The first patient was referred to our hospital with upper abdominal discomfort. The endoscopic examination revealed a tumor mass about 3 cm in diameter. The patient underwent a partial gastrectomy and had an uneventful recovery. The histopathological examination revealed a well-differentiated liposarcoma. The second patient had symptoms of upper abdominal discomfort combined with nausea and anorexia. Several palpable masses were found with endoscopy. Endoscopic submucosal dissection was the treatment used, and the postoperative course was uneventful. The histopathological diagnosis was a well-differentiated liposarcoma. The two patients did not undergo any adjuvant therapy. They are both currently in good condition without recurrence. Therefore, we believe that the outcome of liposarcoma of the stomach is positive, and surgical resection may be the first choice for treatment at present. PMID- 29991883 TI - Gastrointestinal diseases during pregnancy: what does the gastroenterologist need to know? AB - Pregnancy is characterized by numerous physiological changes that may lead to a diversity of symptoms and frequently to gastrointestinal complaints, such as heartburn, nausea and vomiting, or constipation. Chronic gastrointestinal diseases require treatment maintenance during this period, raising the challenging question whether outcomes beneficial to the mother may be harmful for the fetus. In addition, certain diseases, such as acute fatty liver of pregnancy, only develop during pregnancy and may require urgent procedures, such as fetus delivery. Even though they are not present in our day-to-day practice, knowledge of pregnancy-related diseases is fundamental and collaboration between gastroenterologists and obstetricians is often necessary. Herein, we review pregnancy-related diseases and systematize the most appropriate treatment choices according to the recent literature and guidelines, so that the article can serve as a guide to the gastroenterologist regarding the medical approach to pregnancy related gastrointestinal and liver diseases and their therapeutic management. PMID- 29991884 TI - Small bowel imaging in Crohn's disease patients. AB - Crohn's disease (CD) is a lifelong, chronic inflammatory bowel disorder. The small bowel (SB) is involved to varying extents, and the clinical course may vary from an inflammatory type to a more complicated one with stricture, fistula, and abscess formation. Esophagogastroduodenoscopy and ileocolonoscopy with biopsies are the conventional endoscopic techniques that usually establish the diagnosis. On the other hand, CD may affect SB segments that cannot be reached through these procedures. Video capsule endoscopy and enteroscopy are additional endoscopic techniques that may allow further SB evaluation in such circumstances. Computed tomographic enterography, magnetic resonance enterography, and ultrasonography are radiologic techniques that serve as a crucial adjunct to endoscopic assessment. They enable the assessment of parts of the bowel that may be difficult to reach with conventional endoscopy; this allows for the detection of active inflammation, penetrating or stricturing disease, and the appreciation of extraintestinal complications. Both endoscopic and radiologic modalities play a role in establishing the diagnosis of CD, as well as determining the disease extent, activity and response to therapy. This review is intended to evaluate these modalities in terms of specificity, sensitivity, potential side-effects, and limiting factors. This should serve as a guide to the clinician for establishing the most appropriate and reliable test within a particular clinical context. PMID- 29991886 TI - Is top-down therapy a more effective alternative to conventional step-up therapy for Crohn's disease? AB - The management of Crohn's disease involves immunosuppressive protocols in a step up approach that progresses through a therapeutic pyramid with several tiers of medication. Medications at the top are considered more potent but present greater risk. A new top-down approach to therapy inverts this procedure, using top-tier drugs for initial treatment. A critical appraisal of the current literature relating to top-down therapy was performed to evaluate its merit. A literature search was conducted on PubMed, Ovid, and PubMed Central to identify studies of the efficacy of top-down therapy. Papers were appraised critically using the Scottish Intercollegiate Guidelines Network score to evaluate current evidence for the use of top-down therapy. Nineteen studies were identified, including six randomized controlled trials, thirteen cohort studies, and two cost-benefit studies. Early combined therapy involving both biologics and immunomodulators was found to be effective at improving patient outcomes; however, early biologics alone were not shown to have a clear benefit over step-up therapy. Likewise, the early use of immunomodulators alone showed inconsistent results with respect to efficacy in terms of both remission and surgical outcomes. Evidence for application in pediatric populations was also inconclusive. The cost-benefit analyses found that top-down therapy merits investigation, as it proved to be economical given current data. Top-down therapy has the potential of being a viable alternative to step-up therapy, but further studies are needed to determine the most appropriate patients to receive this treatment. PMID- 29991885 TI - Human taeniasis/cysticercosis: a potentially emerging parasitic disease in Europe. AB - Taenia saginata (T. saginata)/Taenia solium (T. solium) taeniasis/cysticercosis disease complexes remain a significant challenge for food safety and public health. Human taeniasis is an infectious disease caused by the ingestion of the metacestode larval stage, the cysticerci of T. saginata in beef or T. solium in pork. Humans can also become infected via the ingestion of T. solium eggs. In this case, the cysticerci can establish in the central nervous system, causing the infection called neurocysticercosis. T. solium is of higher importance than T. saginata because the former species can cause neurocysticercosis in humans, a major cause of neurological morbidity in the world. The taeniasis/cysticercosis complex is included in the list of neglected zoonotic diseases by the World Health Organization and Food and Agriculture Organization, with T. solium being the number one foodborne parasite; it occurs mostly in developing countries, such as regions of Asia, Africa and Latin America, where the disease remains endemic. Long absent in Western Europe and other developed countries, cysticercosis has been recently re-emerged as a result of immigration, travel and commerce. In this review, cysticercosis is presented with special emphasis on some aspects of this neglected disease: the main clinical manifestations, risk factors and epidemiology. In addition, any recent advances in diagnostic approaches and treatment are discussed. Finally, the complexities involved in the control of the disease and the need to revise current management strategies are highlighted. PMID- 29991887 TI - Efficacy and safety of lumen-apposing metal stent for benign gastrointestinal stricture. AB - Management of benign gastrointestinal (GI) strictures refractory to primary (balloon and savary dilation) and secondary (steroid injection, fully covered self-expanding metal stent, incision therapy) treatment modalities remains a challenge. Lumen-apposing metal stents (LAMSs), originally designed for the management of pancreatic fluid collections, are an attractive option for GI stricture because of their anti-migratory property, attributable to their saddle shaped design. In this article, we reviewed 70 patients from 12 original studies who received LAMS for refractory (68/70) or treatment-naive (2/70) benign GI stricture. The technical and clinical success rates were 98.6% (69/70) and 79.7% (55/69), respectively. Endoscopic placement, with or without fluoroscopic guidance, was generally successful, with only a minority requiring endoscopic ultrasound (EUS) guidance where the lumen was completely obscured. The majority of the strictures were short (<=1 cm), but comparable technical and clinical success was noted in isolated cases with long strictures, where 2 overlapping LAMSs were placed. For the overall population, a failure rate of 21.5% (14/69) was noted and was attributed to either lack of follow up, or to persistent or de novo symptoms requiring stent removal/exchange or surgical referral. One perforation (1.4%), five stent migration events (7.1%), two bleeding events (2.9%) and two de novo strictures proximal to the LAMS (2.9%) were reported for the entire study cohort. No mortality was attributable to LAMS placement. Although experience is still evolving, LAMS placement guided by esophagogastroduodenoscopy or EUS is a technically feasible and safe procedure with good clinical outcomes for benign refractory GI strictures. PMID- 29991888 TI - Gastrointestinal and biliary granular cell tumor: diagnosis and management. AB - Granular cell tumors (GCTs) are generally thought to be of Schwann cell origin and are typically S-100 positive. Up to 11% of these tumors affect the gastrointestinal tract, most commonly the esophagus, colon, and stomach. While GCTs are mostly benign, malignant and metastatic GCTs have been reported. GCTs are usually found incidentally during esophagogastroduodenoscopy, colonoscopy, imaging studies or during the evaluation of non-specific symptoms. Endoscopically, they are typically yellow in appearance with intact mucosa. On endoscopic ultrasound, they usually are hypoechoic, homogenous, smooth-edged lesions that appear to originate from the submucosal layer, although other endoscopic and ultrasound appearances have been described. There is no consensus on how to treat GCT. Surgical and conservative approaches have been described in the literature. GCTs can also affect the biliary tract, where patients may be misdiagnosed with cholangiocarcinoma. We explore the epidemiology, histology, clinical presentation, diagnosis and treatment of these tumors in the gastrointestinal tract, including the pharynx, esophagus, stomach, small intestine, large intestine and the perianal region. In addition, GCTs in the biliary tract are reviewed. PMID- 29991889 TI - Occupation-associated health hazards for the gastroenterologist/endoscopist. AB - Advances in the field of endoscopy have allowed gastroenterologists to obtain detailed imaging of anatomical structures and to treat gastrointestinal diseases with endoscopic therapies. However, these technological developments have exposed endoscopists and staff to hazards such as musculoskeletal injuries, exposure to infectious agents, and ionizing radiation. We aimed to review the occupational hazards for the gastroenterologist and endoscopist. Using PubMed, Medline, Medscape, and Google Scholar, we identified peer-reviewed articles with the keywords "occupational hazards," "health hazards," "occupational health hazards," "endoscopy," "gastroenterologist," "infectious agents," "musculoskeletal injuries," and "radiation." Strategies for reducing exposure to infectious agents, radiation, and the risk of musculoskeletal injuries related to gastroenterology include compliance with established standard measures, the use of thyroid shields and radioprotective eyewear, and ergonomic practices. We conclude that educating endoscopic personnel and trainees in these practices, in addition to further research in these areas, will likely lead to the development of more efficient and user-friendly workspaces that are safer for patients and personnel. PMID- 29991890 TI - Can the upper esophageal sphincter contractile integral help classify achalasia? AB - Background: The use of high-resolution manometry (HRM) in achalasia patients has revealed abnormal findings concerning upper esophageal sphincter (UES) function. The introduction of the UES contractile integral (UES-CI), as with the distal contractile integral (DCI), may complement the interpretation of the manometric study of achalasia subtypes, defined by the Chicago Classification v3.0. Methods: Patients were classified into achalasia subtypes based on HRM. UES length (cm), UES resting pressure (mmHg), and UES residual pressure (mmHg) were recorded. UES CI (mmHg.sec.cm) was calculated in a manner similar to that used for the DCI measurement at rest (landmark CI), corrected for respiration, and its relation to achalasia subtypes was evaluated. Results: Twenty-four achalasia patients with mean age 55.29 years were included. Of these, 16.6% (n=4) were diagnosed with achalasia type I, 58.3% (n=14) with type II, and 25% (n=6) with type III. The landmark UES-CI, mean UES-CI, UES-CI corrected for respiration, and UES resting pressure were found to be significantly higher among patients with achalasia type II compared to the other types (1768.9 vs. 677.1, P=0.03; 1827.1 vs. 3555.1, P=0.036; 174.2 vs. 72.8, P=0.027; and 108.1 vs. 55.8, P=0.009, respectively). Conclusions: We introduce the CI index as a tool for the manometric evaluation of the UES in achalasia. UES resting pressure, landmark UES-CI and mean UES-CI were significantly higher in achalasia patients with panesophageal pressurization compared to types I and III. This finding may reflect a protective reaction against the risk of aspiration in this group, but further studying and clinical correlation is required. PMID- 29991891 TI - Artificial intelligence diagnosis of Helicobacter pylori infection using blue laser imaging-bright and linked color imaging: a single-center prospective study. AB - Background: Deep learning is a type of artificial intelligence (AI) that imitates the neural network in the brain. We generated an AI to diagnose Helicobacter pylori (H. pylori) infection using blue laser imaging (BLI)-bright and linked color imaging (LCI). The aim of this pilot study was to establish an AI diagnosing system that predicts H. pylori infection status using endoscopic images to improve the accuracy and productivity of endoscopic examination. Methods: A total of 222 enrolled subjects (105 H. pylori-positive) underwent esophagogastroduodenoscopy and a serum test for H. pylori IgG antibodies. During esophagogastroduodenoscopy, an endoscopist sequentially took 3 still images of the lesser curvature of the stomach using white light imaging (WLI), BLI-bright, and LCI. EG-L580NW endoscopic equipment (FUJIFILM Co., Japan) was used for the study. The specifications of the AI were as follows: operating system, Linux; neural network, GoogLeNet; framework, Caffe; graphic processor unit, Geforce GTX TITAN X (NVIDIA Co., USA). Results: The area under the curve (AUC) on receiver operating characteristics analysis was 0.66 for WLI. In contrast, the AUCs of BLI bright and LCI were 0.96 and 0.95, respectively. The AUCs obtained for BLI-bright and LCI were significantly larger than those for WLI (P<0.01). Conclusions: The results demonstrate that the developed AI has an excellent ability to diagnose H. pylori infection using BLI-bright and LCI. AI technology with image-enhanced endoscopy is likely to become a useful image diagnostic tool. PMID- 29991892 TI - Differences in dietary habits between patients with inflammatory bowel disease in clinical remission and a healthy population. AB - Background: Although patients with active inflammatory bowel disease (IBD) change their dietary habits according to suggestions from their healthcare team, no restriction is required in the remission phase. Accordingly, we compared eating patterns in IBD patients with drug-induced clinical remission with those in healthy subjects. Methods: A total of 150 IBD patients, 84 with Crohn's disease (CD) and 66 with ulcerative colitis (UC), in clinical remission, receiving immunomodulator/biologic therapy, and 100 healthy volunteers (controls) were enrolled. The IBD diagnosis had previously been established by a combined assessment of symptoms, endoscopy, histology and abdominal imaging. Clinical remission was defined as a Harvey Bradshaw index <5 for CD and a partial Mayo score <2 for UC. An experienced nutritionist guided the compilation of a food diary for 7 days according to current guidelines. Macronutrient and fiber intake was evaluated using dedicated software. Comparison between continuous variables was performed using Student's t-test or analysis of variance plus Bonferroni post hoc analysis. Categorical variables were tested with the chi2 test. Results: No difference in protein and carbohydrate intake was observed. IBD patients ate more calories (1970.7+/-348.4 vs. 1882.1+/-280.2 kcal/day, P=0.03), more lipids (68.9+/-15.2 vs. 59.4+/-19.0 g/day, P<0.001) and less fibers (11.9+/-4.7 vs. 15.5+/-8.3 g/day, P<0.001) than controls. No significant difference in total calories, proteins, lipids, carbohydrates or fibers was seen between CD and UC patients. Conclusion: IBD patients have a different macronutrient and fiber intake compared to healthy subjects, even when clinical remission and no symptoms do not dictate dietary restrictions. Therefore, psychological issues may be involved. PMID- 29991893 TI - Eosinophilic gastrointestinal disorder: is it what it seems to be? AB - Background: Eosinophilic gastroenteropathy is an uncommon condition whose causes can be numerous and non-specific. The aim of the study was to characterize the presence of gastrointestinal disorders in the adult Maltese population and assess the degree of association with atopic diseases. Methods: Adult patients with gastrointestinal eosinophilia in the gastrointestinal tract on histology were identified and their clinical case notes were reviewed. Patients were interviewed and asked questions regarding asthma, allergic rhinitis, and eczema. Results: Sixty-six patients (39 female) were recruited. The most common clinical symptoms were diarrhea (42.4%) and abdominal pain (33.3%). The sites involved were stomach (10.6%), colon (56.1%), small bowel (10.6%), small bowel and colon (18.2%), esophagus (1.5%), and esophagus and colon (1.5%). Forty percent had persistent lower gastrointestinal symptoms and a repeat ileocolonoscopy was performed within 12 months. These patients were diagnosed with ulcerative colitis (n=10; 47.6%), Crohn's disease (n=6; 28.6%), indeterminate colitis (n=1; 4.8%) or microscopic colitis (n=4; 19%). Allergic rhinitis was present in 39.4% of the study group, eczema in 26.1%, and asthma in 19.7%. These findings were compared with local data for atopic conditions and the study group was found to have a significantly higher prevalence of allergic rhinitis (P=0.002), but not of asthma (P=0.62) or eczema (P=0.19). Conclusions: A high proportion of patients with eosinophilic gastrointestinal infiltration were subsequently diagnosed with inflammatory bowel disease. Patients persistently symptomatic or who do not respond to treatment should be reassessed to exclude inflammatory bowel disease, given its high prevalence in this group of patients. PMID- 29991894 TI - Hepatitis B virus reactivation in HBsAg-negative, anti-HBc-positive patients receiving immunosuppressive therapy: a systematic review. AB - Background: The optimal management of HBsAg-negative, anti-HBc-positive patients who receive immunosuppression remains unclarified. We systematically reviewed the available data on potential predictors of the risk of hepatitis B virus (HBV) reactivation in such patients. Methods: A literature search identified 55 studies with 3640 HBsAg-negative, anti-HBc-positive patients who received immunosuppressive regimens. Results: HBV reactivation was reported in 236 (6.5%) patients. The pooled HBV reactivation rates did not differ between patients with detectable or undetectable HBV DNA in studies with hematological diseases or regimens containing rituximab, but it was higher in patients with detectable than in those with undetectable HBV DNA who were taking rituximab-free regimens (14% vs. 2.6%; risk ratio [RR] 12.67, 95% CI: 95%CI 2.39-67.04, P=0.003) or had non hematological diseases, although the latter was not confirmed by sensitivity analysis (RR 8.80, 95%CI 0.71-109.00, P=0.09). The pooled HBV reactivation rates were lower in patients with positive than in those with negative anti-HBs in studies with hematological (7.1% vs. 21.8%; RR 0.29, 95%CI 0.19-0.46, P<0.001) or non-hematological (2.5% vs. 10.7%; RR 0.28, 95%CI 0.11-0.76, P=0.012) diseases, and rituximab-containing (6.6% vs. 19.8%; RR 0.32, 95%CI 0.15-0.69, P=0.003) or rituximab-free (3.3% vs. 9.2%; RR 0.36, 95%CI 0.14-0.96, P=0.042) regimens. Conclusions: The risk of HBV reactivation is high; therefore, anti-HBV prophylaxis should be recommended in HBsAg-negative, anti-HBc-positive patients with hematological diseases and/or rituximab-containing regimens, regardless of HBV DNA and anti-HBs status. In contrast, patients with non-hematological diseases or rituximab-free regimens have a low risk of HBV reactivation and may not require anti-HBV prophylaxis if they have undetectable HBV DNA and positive anti-HBs. PMID- 29991895 TI - Muscle fat infiltration assessed by total psoas density on computed tomography predicts mortality in cirrhosis. AB - Background: Ongoing evidence suggests that sarcopenia adversely affects outcomes in cirrhosis. The aim of this study was to evaluate muscle fat infiltration as a component of sarcopenia and its prognostic value in this setting. Methods: In 98 consecutive patients with cirrhosis, muscle density was measured during a computed tomography scan at the level of the fourth to fifth lumbar (L4) vertebrae. Univariate and multivariate Cox regression analysis was used to determine predictors of survival. Results: Body mass index: median 26 (range 17 45.2); model for end-stage liver disease (MELD) score: median 11 (6-29); Child Pugh (CP) score: median 7 (5-13), CP class: A=49 (50.5%), B=39 (40%), C=10 (9.5%); hepatocellular carcinoma: 14 (14.3%); follow up: median 45 (1-140) months. Median L4 total psoas area (TPA): 2022 (777-3806) mm2; L4 average total psoas density (ATPD): 42.52 (21.26-59.8) HU. ATPD was significantly correlated with age (r=-0.222, P=0.034), creatinine (r=-0.41, P<0.001), albumin (r=0.224, P=0.035), MELD score (r=-0.218, P=0.034), and TPA (r=0.415, P<0.001). Fifty-four patients (55.1%) died during follow up. In the multivariate analysis, higher CP score (hazard ratio [HR] 1.2, 95% confidence interval [CI] 1.04-1.41), advanced age (HR 1.038, 95%CI 1.006-1.07) and lower ATPD (HR 0.967, 95%CI 0.937-0.997) were predictors of mortality. Conclusion: Muscle fat infiltration, as a result of sarcopenia, is a negative predictive factor of survival in cirrhosis, emphasizing the need for early identification of this subgroup of patients. PMID- 29991896 TI - A longitudinal analysis of the epidemiology and economic impact of inpatient admissions for chronic pancreatitis in the United States. AB - Background: Chronic pancreatitis (CP) is a chronic, debilitating disorder associated with multiple complications, frequently necessitating hospitalization. The aim of this study was to investigate the longitudinal trends for hospitalization, mean length of stay (LOS), and cost associated with inpatient admissions for CP across the United States. Methods: Using the Nationwide Inpatient Sample, all hospitalizations between 1997 and 2014 were analyzed. We examined annual data for rate of hospitalization, average LOS and cost for CP inpatient admissions. Trends were described over the surveillance period. Results: Between 1997 and 2014, the number of hospitalizations for patients with a primary discharge diagnosis of CP decreased by 41.5% (P<0.001). While the average LOS decreased by 21.2% from 6.2 days in 1997 to 4.9 days in 2014 (P<0.001), the mean charges for CP-related hospital admissions increased by 308.5% from $12,725 in 1997 to $39,260 (adjusted for inflation) in 2014 (P<0.001). The risk of a discharge for CP significantly increased from 1997-2014 for the 1-17 year age group (relative risk 1.518, 95% confidence interval 1.516 1.520; P<0.0001), while it significantly decreased over time for all the other age groups. Conclusions: Although it is reassuring that the average LOS has reduced, the cost associated with these hospitalizations has almost tripled. We postulate that the increase in cost is likely attributable to a greater number of studies and/or interventions. In order to deliver more cost-conscious care, further investigation is required into the effect that these additional investigations and interventions have on specific endpoints, including disease specific and all-cause morbidity and mortality. PMID- 29991897 TI - Clinical profile and treatment outcomes in autoimmune pancreatitis: a report from North India. AB - Background: Autoimmune pancreatitis (AIP) is a rare disease, and data from countries like India concerning its clinical presentation and long-term outcomes are scarce. We retrospectively evaluated the clinical presentation, imaging features and treatment outcomes of patients with AIP. Methods: We carried out a retrospective analysis of our database to identify patients diagnosed with and treated for AIP at our unit in a tertiary care hospital in North India. Results: Eighteen patients with AIP (mean age: 54.9+/-11.1 years; 13 male) were evaluated. Of these, 9 (50%) patients had probable type 1 AIP, 2 (11%) patients probable type 2 AIP, and 4 (22%) definite type 1 AIP. Patients with type 2 AIP were significantly younger than patients with type 1 (40.0+/-2.8 vs. 58.4+/-9.6 years). In type 1 AIP, other organ involvement was observed in 3/18 (17%) patients, whereas both patients with type 2 AIP had coexisting ulcerative colitis. The diagnosis of AIP was made after resective surgery in 6/18 (33.0%) patients. An accurate diagnosis of AIP could be made in all patients who underwent resection or core biopsy, but cytological examination after endoscopic ultrasound-guided fine-needle aspiration could not provide a definitive diagnosis in any patient. Initial treatment with steroids was given to 12 (67%) patients, with a 100% response, but the disease relapsed in 5/13 (38%) patients over a mean follow-up period of 34.2+/-21.6 weeks. Conclusion: AIP is not rare in India and the majority of clinical manifestations, imaging features, treatment response and long-term outcomes are similar to those reported in the literature. PMID- 29991898 TI - Diagnostic accuracy of fine-needle aspiration of solid pancreatic lesions guided by endoscopic ultrasound elastography. AB - Background: Real-time elastography (RTE) may increase the diagnostic accuracy of fine-needle aspiration guided by endoscopic ultrasound. The aim of this study was to establish the diagnostic accuracy, sensitivity, and specificity of this combined methodological approach in a cohort of patients with solid pancreatic masses. Methods: We reviewed data from 54 patients with solid pancreatic lesions referred to our institution between January 2014 and June 2015. RTE, assessed in terms of strain ratio, was performed both qualitatively and semi-quantitatively, and a 25G needle was inserted into the most suspicious part of the lesion. Sensitivity, specificity, diagnostic accuracy, positive and negative predictive values were calculated. Results: The median lesion size was 35 mm (interquartile range: 25-43 mm). A diagnosis of adenocarcinoma was confirmed in 85.1% of cases. RTE, with a strain ratio cutoff of 4.21, showed a sensitivity of 86.9%, a specificity of 75%, and diagnostic accuracy of 85.1%. The diagnostic accuracy, sensitivity, and specificity of the combined methodology were 94.4%, 93.4%, and 100%, respectively. The positive predictive value was 100%, the negative predictive value 72.7% and the negative likelihood ratio 6.5. No severe adverse events were registered. Conclusion: The combination of RTE with endoscopic ultrasound-guided fine-needle aspiration appears to be an efficient and safe technique for the characterization of solid pancreatic masses. PMID- 29991899 TI - Varioliform gastritis: an unusual endoscopic finding. PMID- 29991900 TI - Diagnostic endoscopic mucosal resection is useful for diagnosing rectal tonsil. PMID- 29991901 TI - Salvage endoscopic submucosal dissection for esophageal adenocarcinoma arising during radiofrequency ablation. AB - Radiofrequency ablation is a recommended treatment option for residual Barrett's esophagus after endoscopic resection of a visible lesion. We herein report 3 cases of esophageal adenocarcinoma arising during the course of radiofrequency ablation, all of which were successfully resected by endoscopic submucosal dissection. Partial or suboptimal response to radiofrequency ablation or early recurrence of Barrett's mucosa after radiofrequency ablation should raise suspicion for adenocarcinoma and lead to consideration of en bloc resection by endoscopic submucosal dissection. PMID- 29991902 TI - Underwater endoscopic mucosal resection for anal canal neoplasia in a patient with human immunodeficiency virus infection. PMID- 29991903 TI - Semi-automatic Extraction of Plants Morphological Characters from Taxonomic Descriptions Written in Spanish. AB - Taxonomic literature keeps records of the planet's biodiversity and gives access to the knowledge needed for its sustainable management. Unfortunately, most of the taxonomic information is available in scientific publications in text format. The amount of publications generated is very large; therefore, to process it in order to obtain high structured texts would be complex and very expensive. Approaches like citizen science may help the process by selecting whole fragments of texts dealing with morphological descriptions; but a deeper analysis, compatible with accepted ontologies, will require specialised tools. The Biodiversity Heritage Library (BHL) estimates that there are more than 120 million pages published in over 5.4 million books since 1469, plus about 800,000 monographs and 40,000 journal titles (12,500 of these are current titles). It is necessary to develop standards and software tools to extract, integrate and publish this information into existing free and open access repositories of biodiversity knowledge to support science, education and biodiversity conservation. This document presents an algorithm based on computational linguistics techniques to extract structured information from morphological descriptions of plants written in Spanish. The developed algorithm is based on the work of Dr. Hong Cui from the University of Arizona; it uses semantic analysis, ontologies and a repository of knowledge acquired from the same descriptions. The algorithm was applied to the books Trees of Costa Rica Volume III (TCRv3), Trees of Costa Rica Volume IV (TCRv4) and to a subset of descriptions of the Manual of Plants of Costa Rica (MPCR) with very competitive results (more than 92.5% of average performance). The system receives the morphological descriptions in tabular format and generates XML documents. The XML schema allows documenting structures, characters and relations between characters and structures. Each extracted object is associated with attributes like name, value, modifiers, restrictions, ontology term id, amongst other attributes. The implemented tool is free software. It was developed using Java and integrates existing technology as FreeLing, the Plant Ontology (PO), the Plant Glossary, the Ontology Term Organizer (OTO) and the Flora Mesoamericana English-Spanish Glossary. PMID- 29991904 TI - Cell free preparations of probiotics exerted antibacterial and antibiofilm activities against multidrug resistant E. coli. AB - The sharp increase in antibiotic resistance imposes a global threat to human health and the discovery of effective antimicrobial alternatives is needed. The use of probiotics to combat bacterial pathogens has gained a rising interest. Pathogenic Escherichia coli is causative of multiple clinical syndromes such as diarrheal diseases, meningitis and urinary tract infections. In this work, we evaluated the efficacy of probiotics to control multidrug-resistant E. coli and reduce their ability to form biofilms. Six E. coli resistant to at least five antibiotics (Ceftazidime, Ampicillin, Clarithromycin, Amoxicillin + Clavulanic Acid and Ceftriaxone) were isolated in this work. Preparations of cell-free spent media (CFSM) of six probiotics belonging to the genus Bifidobacterium and Lactobacillus which were grown in Man-Rogosa-Sharpe (MRS) broth exhibited strong antibacterial activity (inhibition zones of 11.77-23.10 mm) against all E. coli isolates. Two E. coli isolates, namely E. coli WW1 and IC2, which were most resistant to all antibiotics were subjected to antibiofilm experiments. Interestingly, the CFSM of MRS fermented by all probiotics resulted in inhibition of biofilm formation while B. longum caused highest inhibition (57.94%) in case of E. coli IC2 biofilms and L. plantarum was responsible for 64.57% reduction of E. coli WW1 biofilms. On the other hand, CFSM of skim milk fermented by L. helveticus and L. rhamnosus exhibited a slight inhibitory activity against IC2 isolate (inhibition percentage of 31.52 and 17. 68, respectively) while WW1 isolate biofilms was reduced by CFSM of milk fermented by B. longum and L. helveticus (70.81 and 69.49 reduction percentage, respectively). These results support the effective use of probiotics as antimicrobial alternatives and to eradicate biofilms formed by multidrug-resistant E. coli. PMID- 29991905 TI - Effect of educational intervention on healthcare providers knowledge and perception towards pharmacovigilance: A tertiary teaching hospital experience. AB - Objective: Based on the theory on planned behavior, perception or attitude is found to be a well-established predictor of healthcare providers' intentions to perform different behaviors. Also, improving knowledge was proposed to affect their practice as well. In Jordan, many studies have been conducted to evaluate healthcare providers' knowledge and perception towards pharmacovigilance but no intervention or training was provided. Thus, the aim of this study was to evaluate the impact of an educational workshop on the knowledge and perception of healthcare providers towards pharmacovigilance in a Jordanian tertiary teaching hospital. Methods: An interventional study conducted in Jordan University Hospital on various healthcare providers to assess their pre- and post-knowledge and perception towards pharmacovigilance and adverse drug reactions (ADRs) reporting via questionnaire before and after an educational workshop. Results: Among the 200 invited healthcare providers, 150 attended the educational workshop (response rate 75.0%). Pre-workshop, healthcare providers showed an overall low knowledge score (7.8/19), where only 8.7% could define pharmacovigilance correctly. On the other hand, they showed a favorable perception score (33.6/39).Following educational workshop, knowledge scores significantly improved by 67.9% (P-value <0.05). A similar finding was obtained for perception scores, where perception scores significantly improved by 10.1% following workshop (P value <0.05). Conclusion: Continuous efforts are needed to implement different strategies including education modules and the provision of appropriate training programs to increase awareness and improve perception towards pharmacovigilance among healthcare providers. Future study is needed to evaluate the impact of improving knowledge and perception on ADRs reporting practice. PMID- 29991906 TI - Pharmacy students' perceptions towards online learning in a Saudi Pharmacy School. AB - Objectives: The aim of the study was to evaluate previous exposure to online learning and preference for learning through pre-recorded online lectures with or without live active learning among pharmacy students in their fifth year. Methods: An anonymous online survey was self-administered to fifth-year students enrolled on the Graduation Research Project Course. Results: The response rate was 100%. Ninety-seven percent of students had previous experience with at least one online course during their pharmacy undergraduate curriculum; 76% of the courses were science courses. The majority of respondents preferred face-to-face, in-class lectures to online lectures, but 17% expressed no preference. Conclusion: Pharmacy students expressed some interest in online learning methods within the pharmacy curriculum. PMID- 29991908 TI - Antimicrobial activity of the biogenically synthesized core-shell Cu@Pt nanoparticles. AB - The interest in the biological synthesis of mono metal nanoparticles has been visible for years. As more attention is also given to the biological methods of synthesizing bimetallic nanoparticles, this work used the Agrimoniae herba extract in order to obtain bimetallic core-shell Cu@Pt nanoparticles. The formed core-shell Cu@Pt nanoparticles were characterized by Ultraviolet-Visible (UV vis), Fourier Transform-Infrared (FT-IR), Scanning electron microscopy (SEM), Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM) measurements. The obtained core-shell Cu@Pt nanoparticles were analysed in terms of their antibacterial activity. It was discovered that the synthesized nanoparticles exhibited maximum activity against gram-negative bacteria E. coli ATCC 25922, S. aureus ATCC 25923, and P. aeruginosa NCTC 6749. The core-shell Cu@Pt nanoparticles also exhibited activity against the yeast C. albicans ATCC 10231 and dermatophytes T. mentagrophytes ATCC 9533. PMID- 29991907 TI - Efficacy of metformin in the management of periodontitis: A systematic review and meta-analysis. AB - Periodontitis is characterized by inflammation of the periodontium and leads to loss of teeth if untreated. Although a number of surgical and pharmacological options are available for the management of periodontitis, it still affects a large proportion of population. Recently, metformin (MF), an oral hypoglycemic, has been used to treat periodontitis. The aim of this review is to systematically evaluate the efficacy of MF in the treatment of periodontitis. An electronic search was carried out using the keywords 'metformin', 'periodontal' and 'periodontitis' via the PubMed/Medline, ISI Web of Science and Google Scholar databases for relevant articles published from 1949 to 2016. The addressed focused question was: 'Is metformin effective in reducing bone loss in periodontitis? Critical review and meta-analysis were conducted of the results obtained in the selected studies. Following the removal of the duplicate results, the primary search resulted in 17 articles and seven articles were excluded based on title and abstract. Hence, 10 articles were read completely for eligibility. After exclusion of four irrelevant studies, six articles were included. The topical application of MF resulted in improved histological, clinical and radiographic outcomes. Additionally, results from the meta-analysis indicated that application of metformin improved the clinical and radiographic outcomes of scaling and root-planing, but at the same time heterogeneity was evident among the results. However, because of a lack of histological and bacterial studies, in addition to short follow-up periods and risk of bias, the long-term efficacy of MF in the treatment of bony defects is not yet ascertained. Further studies are needed to envisage the long-term efficacy of MF in the management of periodontitis. PMID- 29991909 TI - Distribution of CYP2B6 516G/T pharmacogenetically important polymorphism in the Ukrainian population. AB - The CYP2B6 is one of the members of the cytochrome P450 superfamily. This enzyme metabolizes a number of currently prescribed drugs and different compounds. In light of clinical significance of the CYP2B6*6 variant of the CYP2B6 gene, the aim of this study was to investigate the distribution of one of the gene polymorphisms, namely, the 516G/T in the Ukrainian population. The study cohort consisted of 102 healthy Ukrainian adults (48 males, 54 females). Genotyping of the CYP2B6 (rs3745274) polymorphism in the study subjects was carried out using a polymerase chain reaction. The following distribution of 516G/T CYP2B6 genotypes in the Ukrainian cohort was identified: GG - in 56%, GT - in 37% and TT - in 7%. The 516G/T allele frequency of the CYP2B6 gene in population was pG = 0.75 and qT = 0.25, respectively. The population-based sequences were analyzed by the Hardy Weinberg method. The genetic polymorphism revealed in the Ukrainian population suggests the 516G/T polymorphism of the CYP2B6 genetic testing when prescribing the drugs that are substrates of this gene. PMID- 29991910 TI - Evaluation of a novel oxiconazole nitrate formulation: The thermosensitive gel. AB - Superficial fungal infections caused by Candida species are common skin diseases. Therefore, this study aimed to develop a new formulation containing oxiconazole nitrate, which is an azole group derivative for antifungal treatment, as a thermosensitive gel since there has been no literature study until now. MIC value of the novel thermosensitive formulation against three Candida species was calculated and time-dependent antifungal activity analysis was performed. Viscosity, transition temperature Tsol-gel ( degrees C) and gelation time of the thermosensitive gel formulation were also determined in the viscometer. The measurements performed on the tensilometer device were analyzed for adhesion hardness and elongation percentages of the formulation. In the FT-IR spectrometer, the spectrum of solution and gel state was compared between 650 and 4000 cm-1 and it was found that there is no difference between them. It was found that the temperature is reversible on the formulation and did not cause any disruption of its components. Characterization parameters of the thermosensitive gel formulation containing oxiconazole nitrate and time-dependent activity against Candida species was observed to be the same as those of the solution containing only oxiconazole nitrate. MIC, MFC and time-dependent antifungal analysis did not show any particular difference between formulation and oxiconazole nitrate itself. Thermosensitive gel formulation containing oxiconazole nitrate was found to be effective on superficial fungal infections. We believe it is also appropriate for in vivo usage, but it is necessary to perform animal and human research. It is also needed to evaluate the formulation against other etiologic agents of superficial fungal infections. PMID- 29991911 TI - Risk factors for aquiring multidrug-resistant organisms in urinary tract infections: A systematic literature review. AB - Background: This is the first review to analyze literature identifying risk factors for a multidrug-resistant urinary tract infection (MDR UTI). Risk factors for other infections involving multidrug-resistant organisms have been evaluated in other reviews, but they do not assess urinary tract infections. The purpose of this study is to collect currently published data to determine the most commonly and consistently identified risk factors for UTIs. Material and methods: For this study, 3 independent researchers searched PubMed, Embase, and Cochrane database from 1966 to February 2016 for articles identifying risk factors for MDR UTI. Results: A total of 25 studies including 31,284 patients with positive cultures provide evidence for 12 possible risk factors for MDR UTI . The most commonly identified risk factor was previous antibiotic usage as evidenced in 16 of the 20 studies that evaluated this possible risk factor. The time range utilized to define previous antibiotic usage ranged from 2 days to 365 days. Other risk factors with the strongest supporting data were urinary catheterization, previous hospitalization, and nursing home residence. Conclusion: We identified 12 different possible risk factors for a MDR UTI, however several risk factors have minimal or conflicting evidence. The definitions of the risk factors varied widely among the studies, and should be standardized for future studies. PMID- 29991912 TI - Analysis of antioxidative and antiviral biomarkers beta-amyrin, beta-sitosterol, lupeol, ursolic acid in Guiera senegalensis leaves extract by validated HPTLC methods. AB - Guiera senegalensis J.F. Gmel is a broad-spectrum African folk- medicinal plant, having activities against fowlpox and herpes viruses. Very recently, we have shown the anti-hepatitis B vius (HBV) potential of G. senegalensis leaves extract (GSLE). Here, we report the antioxidative and hepatoprotective efficacy of GSLE, including HPTLC quantification of four biomarkers of known antioxidative and antiviral activities. In cultured liver cells (HuH7) GSLE attenuated DCFH-induced oxidative stress and cytotoxicity. This was supported by in vitro DPPH radical scavenging and beta-carotene-linoleic acid bleaching assays that showed strong antioxidant activity of GSLE. Further, two simple and sensitive HPTLC methods (I and II) were developed and validated to quantify beta-amyrin, beta- sitosterol, lupeol, ursolic acid in GSLE. While HPTLC-I (hexane: ethylacetate; 75:25; v/v) enabled quantification of beta-amyrin (Rf = 0.39; 20.64 MUg/mg) and beta sitosterol (Rf = 0.25; 18.56 MUg/mg), HPTLC-II (chloroform: methanol; 97:3; v/v) allowed estimation of lupeol (Rf = 0.47; 6.72 MUg/mg) and ursolic acid (Rf = 0.23; 5.81 MUg/mg) in GSLE. Taken together, the identified biomarkers strongly supported the antioxidant and anti-HBV potential of GSLE, suggesting its activity via abating the oxidative stress. To our knowledge, this is the first report on HPTLC analysis of these biomarkers in G. senegalensis that could be adopted for standardization and quality-control of herbal-formulations. PMID- 29991913 TI - 8-Cyclopentyl-1,3-dimethylxanthine enhances effectiveness of antidepressant in behavioral tests and modulates redox balance in the cerebral cortex of mice. AB - The objective of our study was to investigate whether 8-cyclopentyl-1,3 dimethylxanthine (CPT), associated with the adenosine system, enhances the antidepressant efficacy of antidepressant. All experiments were carried out on Albino Swiss mice. Following drugs: CPT (3 mg/kg) and imipramine (15 mg/kg) were administered intraperitoneally (ip), 60 min before tests. Two behavioral tests on antidepressant capability - a forced swim test (FST) and a tail suspension test (TST) - were performed. To examine whether co-administration of CPT with antidepressants affects the redox balance, the lipid peroxidation products (LPO), glutathione (GSH), glutathione disulfide (GSSG), nicotinamide adenine dinucleotide phosphate (NADP+), and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were determined in the cerebral cortex. The results have demonstrated a CPT-induced enhancement of the antidepressant-like effect of imipramine both in the FST and TST, which may indicate that the adenosine system may be involved in the increasing the effect of antidepressant. Co-administration of CPT with imipramine, such as imipramine alone, decreased the NADP+ and LPO concentrations and increased the GSH/GSSG ratio in comparison to the control, which may confirm beneficial - but comparable to imipramine - effect on redox balance under environmental stress conditions. An increase in the concentration of GSSG in the cortex of animals treated with imipramine in ineffective dose compared to control and no such changes after combined administration of both drugs may suggest a favorable oxidation-reduction potential resulting from their synergistic antidepressant effect. PMID- 29991914 TI - Validation of a score to identify inpatients at risk of a drug-related problem during a 4-year period. AB - Objective: Drug-related problems (DRP) produce high morbidity and mortality. It is therefore essential to identify patients at higher risk of these events. This study aimed to validate a DRP risk score in a large number of inpatients. Material and methods: Validation of a previously designed score to identify inpatients at risk of experiencing at least one DRP in a tertiary university hospital from 2010 to 2013. DRP were detected by a pharmacy warning system integrated in the electronic medical record. The score included the following variables associated with a higher risk of DRP: prescription of a higher number of drugs, greater comorbidity, advanced age, specific ATC groups and certain major diagnostic categories. Results: The study included a total of 52,987 admissions; of these, at least one DRP occurred in 14.9%. After validation of the score (period range, 2010-2013: 0.746-0.764), the area under the curve (AUC) was 0.751 (95% CI: 0.745-0.756). Conclusions: This value is higher than those reported in other studies describing validation of risk scores. The score showed good capacity to identify those patients at higher risk of DRP in a much larger sample of inpatients than previously described in the literature. This tool allows optimization of drug therapy monitoring in admitted patients. PMID- 29991915 TI - Release studies of undecylenoyl phenylalanine from topical formulations. AB - The aim of this study was to characterize the stability of new vehicles for the undecylenoyl phenylalanine that is used as skin-lightening agent in the melasma treatment. The purpose of this research was also to analyse the release kinetics of phenylalanine derivative from topical preparations through different synthetic membranes. Topical formulations such as two different macroemulsions, hydrogels (based on carbomer and hydroxyethylcellulose) and microemulsions were characterized in terms of stability by laser diffraction method. Additionally, multiple light scattering assessed the stability of macroemulsions. The release rates of active substance through different membranes (such as Cuprophan, nitrocellulose, cellulose acetate and Strat-M) were determined using enhancer cell. In order to explain the mechanism of release process the results were fitted with different kinetic models. New stable vehicles for Ude-Phe were successfully obtained. The results proved that the membrane structure had the influence on the release rate of undecylenoyl phenylalanine. The slowest release rate of Ude-Phe was observed when Strat-M membrane was applied. The highest amount of active substance was released from the hydrogel based on carbomer. The release of undecylenoyl phenylalanine from both macroemulsions and hydrogel based on hydroxyethylcellulose followed the Higuchi model. Whereas the release results of Ude-Phe from both microemulsion-based hydrogels and carbomer hydrogel can be described by using Korsmeyer-Peppas model. Hydrogels and microemulsion-based hydrogels could be recommended as proper vehicles for the derivative of phenylalanine. PMID- 29991916 TI - Self-medication with antibiotics in Saudi Arabia. AB - Introduction: Despite of the global dilemma of antibiotics resistance, this issue is more worsen in developing countries or places where the antibiotics can be dispensed or purchased without prescription such as in Saudi Arabia. Most health awareness campaigns and published studies regarding the self-medication with antibiotics in Saudi Arabia are conducted within hospitals. The prevalence and reasons of self-medication with antibiotics were not well studied from community perspective in Saudi Arabia. This study was conducted to investigate the prevalence of self-medication with antibiotics in Saudi Arabia. Methodology: A cross-sectional study using online survey and snowball technique was conducted during the period from January 2017 to May 2017 targeting people who are living in Saudi Arabia. Results: A total of 1264 respondent completed the questionnaire and included in the study. About 34% of respondents have used antibiotic without a prescription, and 81.3% of them knew that it might be harmful to health. The most antibiotic used for self-medication was Amoxicillin/clavulanic acid (45.1%) followed by amoxicillin (39.9%). The most common illness and reasons for seeking antibiotic without prescription were tonsillitis (76.7%) and the previous experience of using a particular antibiotic (52.1%) respectively. The major source of self-medication with antibiotic was previous doctor's prescription (36.6%). Conclusion: The relative high prevalence of self-medication with antibiotics necessitates taking serious steps by health authorities to implement the law of forbidding the sale of antibiotics without prescription. PMID- 29991917 TI - Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine. AB - In this study solid dispersions of carbamazepine in the hydrophilic Kollidon(r) VA64 polymer, adsorbed onto Neusilin(r) UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon(r) VA64 and Neusilin(r) UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin(r) UFL2. Proportion of Kollidon(r) VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon(r) VA64 concentrations up to the middle values in the studied range of Kollidon(r) VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon(r) VA64 hydrophilic polymer and Neusilin(r) UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability. PMID- 29991918 TI - Evaluation of wound healing activity of henna, pomegranate and myrrh herbal ointment blend. AB - This study assessed the wound healing potential and antimicrobial activity of henna, pomegranate and myrrh extract formulations and their blend in excision, and dead space wound models in rats in comparison to a marketed ointment (gentamycin). The natural extracts were used in ointment formulations alone or in a combination of three extracts at a total concentration of 15% w/w in medications. The percent of wound contraction in case of henna, myrrh, pomegranate, the blend and gentamycin (10 mg/kg) were 85.90-98.5%, 88.35-99.52%, 93.55-100%, 97.30-100%, and 90.25-100% from days 16 to 20, respectively. The blended formulation showed the highest increase in the percent of wound contraction and decrease in the epithelisation period compared to other formulations and showed comparable results to the standard ointment. The histological studies of excision biopsy at day 24 showed healed skin structures with normal epithelisation, the restoration of adnexa and fibrosis within the dermis in all of the formulation- and gentamycin-treated groups while the control group lagged behind in the formation of the amount of ground substance in the granulation tissue. The formulations showed antimicrobial activity against Candida, Staphylococcus aureus, mucous membrane infections and E. coli topical infections. The study proved the wound healing potential and antimicrobial activity of the herbal extract. PMID- 29991920 TI - Expression of activin receptors in the equine uteroplacental tissue: an immunohistochemical analysis. AB - Activin is secreted from equine uterine glands and plays important roles in establishment and maintenance of pregnancy in mares. This study aimed to localize activin receptors (ActRs) IA/B and IIA/B using immunohistochemistry in the uteroplacental tissues of seven pregnant Thoroughbred mares. At the time of tissue collection, the mares were at the following days of pregnancy: 88, 120, 161, 269, 290, 313, and 335 days. We fixed the uteroplacental tissues in 4% paraformaldehyde and obtained serial sections that were subsequently stained for analysis. All four isoforms of ActR were expressed in the uteroplacental tissues, including the endometrial epithelium, uterine glands, trophoblasts, and myometrium, throughout pregnancy. Our results suggested the potential role of activin in the uteroplacental tissues. PMID- 29991921 TI - Distribution of Y chromosomal haplotypes in Japanese native horse populations. AB - The distribution of Y chromosomal haplotypes in Japanese native horse populations was investigated to obtain genetic information on these populations. Here, 159 male/gelded horses from eight local populations were investigated, and three Y haplotypes (JHT-1, JHT-2, and JHT-3) were identified by analyzing five Y-linked loci. Five populations had only JHT-1, whereas two populations had only JHT-2. One population had JHT-1 and JHT-3. Based on the geographical distribution of these haplotypes and previously reported haplotypes for other Asian horses, JHT-1 is considered to be a major haplotype in ancestral native horses. The fixation of each haplotype suggests the influence of independent breeding and genetic drift in each population. These findings complement the results from previous genetic studies of Japanese native horses. PMID- 29991922 TI - Marsupialization and sclerotherapy with povidone iodine and ethanol of a branchial remnant cyst in an Arabian filly. AB - Branchial remnant cysts are an uncommon cause of masses of the throatlatch area in horses. Two methods of treatment have been proposed in literature, both with complications. This manuscript proposes a method (marsupialization and sclerotherapy) for the treatment of a cyst in a 1.5-year-old Arabian filly. Diagnosis was made by ultrasonographic, radiographic and endoscopic examinations, revealing an anechoic fluid-filled structure and a well-defined capsule not in communication with other structures. After emptying the cyst, the skin was sutured circumferentially to the cyst wall; it was then flushed first with a solution of ethanol and povidone-iodine, then with sterile saline. Eight months after surgery, the filly had no recurrence of the cyst and the stoma was healed. PMID- 29991923 TI - The effect of administration of fenbendazole on the microbial hindgut population of the horse. AB - Anthelmintics are used as anti-worming agents. Although known to affect their target organisms, nothing has been published regarding their effect on other digestive tract organisms or on metabolites produced by them. The current work investigated effects of fenbendazole, a benzimidazole anthelmintic, on bacteria and ciliates in the equine digestive tract and on and their major metabolites. Animals receiving anthelmintic treatment had high faecal egg counts relative to controls. Analysis was performed over two weeks, with temporal differences detected in bacterial populations but with no other significant differences detected. This suggests fenbendazole has no detectable effect on organisms other than its targets. Moreover it does not appear to make a contribution to changing the resulting metabolome. PMID- 29991919 TI - Natural products chemistry: The emerging trends and prospective goals. AB - The role and contributions of natural products chemistry in advancements of the physical and biological sciences, its interdisciplinary domains, and emerging of new avenues by providing novel applications, constructive inputs, thrust, comprehensive understanding, broad perspective, and a new vision for future is outlined. The developmental prospects in bio-medical, health, nutrition, and other interrelated sciences along with some of the emerging trends in the subject area are also discussed as part of the current review of the basic and core developments, innovation in techniques, advances in methodology, and possible applications with their effects on the sciences in general and natural products chemistry in particular. The overview of the progress and ongoing developments in broader areas of the natural products chemistry discipline, its role and concurrent economic and scientific implications, contemporary objectives, future prospects as well as impending goals are also outlined. A look at the natural products chemistry in providing scientific progress in various disciplines is deliberated upon. PMID- 29991924 TI - Spatial, temporal, and spatiotemporal analysis of under-five diarrhea in Southern Ethiopia. AB - Background: Despite improvements in prevention efforts, childhood diarrhea remains a public health concern. However, there may be substantial variation influenced by place, time, and season. Description of diarrheal clusters in time and space and understanding seasonal patterns can improve surveillance and management. The present study investigated the spatial and seasonal distribution and purely spatial, purely temporal, and space-time clusters of childhood diarrhea in Southern Ethiopia. Methods: The study was a retrospective analysis of data from the Health Management Information System (HMIS) under-five diarrheal morbidity reports from July 2011 to June 2017 in Sidama Zone. Annual diarrhea incidence at district level was calculated. Incidence rate calculation and seasonal trend analysis were performed. The Kulldorff SaTScan software with a discrete Poisson model was used to identify statistically significant special, temporal, and space-time diarrhea clusters. ArcGIS 10.1 was used to plot the maps. Results: A total of 202,406 under-five diarrheal cases with an annual case of 5822 per 100,000 under-five population were reported. An increasing trend of diarrhea incidence was observed over the 6 years with seasonal variation picking between February and May. The highest incidence rate (135.8/1000) was observed in the year 2016/17 in Boricha district. One statistically significant most likely spatial cluster (Boricha district) and six secondary clusters (Malga, Hulla, Aleta Wondo, Shebedino, Loka Abaya, Dale, and Wondogenet) were identified. One statistically significant temporal cluster (LLR = 2109.93, p < 0.001) during December 2013 to May 2015 was observed in all districts. Statistically significant spatiotemporal primary hotspot was observed in December 2012 to January 2015 in Malga district with a likelihood ratio of 1214.67 and a relative risk of 2.03. First, second, third, and fourth secondary hotspots occurred from January 2012 to May 2012 in Loka Abaya, December 2011 in Bursa, from March to April 2014 in Gorchie, and March 2012 in Wonsho districts. Conclusion: Childhood diarrhea was not distributed randomly over space and time and showed an overall increasing trend of seasonal variation peaking between February and May. The health department and other stakeholders at various levels need to plan targeted interventional activities at hotspot seasons and areas to reduce morbidity and mortality. PMID- 29991925 TI - Mosquito arbovirus survey in selected areas of Kenya: detection of insect specific virus. AB - Background: Many arboviral outbreaks have occurred in various locations in Kenya. Entomological surveys are suitable methods for revealing information about circulating arboviruses before human outbreaks are recognized. Therefore, mosquitoes were collected in Kenya to determine the distribution of arboviruses. Methods: Various species of mosquitoes were sampled from January to July 2012 using several collection methods. Mosquito homogenates were directly tested by reverse transcription-polymerase chain reaction (RT-PCR) using various arbovirus targeted primer pairs. Results: We collected 12,569 mosquitoes. Although no human related arboviruses were detected, Culex flavivirus (CxFV), an insect-specific arbovirus, was detected in 54 pools of 324 Culex quinquefasciatus individuals collected during the rainy season. Of these 54 positive pools, 96.3% (52/54) of the mosquitoes were collected in Busia, on the border of western Kenya and Uganda. The remaining two CxFV-positive pools were collected in Mombasa and Kakamega, far from Busia. Phylogenetic analysis revealed minimal genetic diversity among the CxFVs collected in Mombasa, Kakamega, and Busia, even though these cities are in geographically different regions. Additionally, CxFV was detected in one mosquito pool collected in Mombasa during the dry season. In addition to Culex mosquitoes, Aedes (Stegomyia) and Anopheles mosquitoes were also positive for the Flavivirus genus. Cell fusing agent virus was detected in one pool of Aedes aegypti. Mosquito flavivirus was detected in three pools of Anopheles gambiae s.l. collected in the dry and rainy seasons. Conclusions: Although no mosquitoes were positive for human-related arbovirus, insect-specific viruses were detected in various species of mosquitoes. The heterogeneity observed in the number of CxFVs in Culex mosquitoes in different locations in Kenya suggests that the abundance of human-related viruses might differ depending on the abundance of insect-specific viruses. We may have underestimated the circulation of any human-related arbovirus in Kenya, and the collection of larger samples may allow for determination of the presence of human-related arboviruses. PMID- 29991927 TI - Immobilization versus no immobilization for pelvic external beam radiotherapy. AB - Aim: To identify the most reproducible technique of patient positioning and immobilization during pelvic radiotherapy. Background: Radiotherapy plays an important role in the treatment of pelvic malignancies. Errors in positioning of patient are an integral component of treatment. The present study compares two methods of immobilization with no immobilization with an aim of identifying the most reproducible method. Materials and methods: 65 consecutive patients receiving pelvic external beam radiotherapy were retrospectively analyzed. 30, 21 and 14 patients were treated with no-immobilization with a leg separator, whole body vacuum bag cushion (VBC) and six point aquaplast immobilization system, respectively. The systematic error, random error and the planning target volume (PTV) margins were calculated for all the three techniques and statistically analyzed. Results: The systematic errors were the highest in the VBC and random errors were the highest in the aquaplast group. Both systematic and random errors were the lowest in patients treated with no-immobilization. 3D Systematic error (mm, mean +/- 1SD) was 4.31 +/- 3.84, 3.39 +/- 1.71 and 2.42 +/- 0.97 for VBC, aquaplast and no-immobilization, respectively. 3D random error (mm, 1SD) was 2.96, 3.59 and 1.39 for VBC, aquaplast and no-immobilization, respectively. The differences were statistically significant between all the three groups. The calculated PTV margins were the smallest for the no-immobilization technique with 4.56, 4.69 and 4.59 mm, respectively, in x, y and z axes, respectively. Conclusions: Among the three techniques, no-immobilization technique with leg separator was the most reproducible technique with the smallest PTV margins. For obvious reasons, this technique is the least time consuming and most economically viable in developing countries. PMID- 29991926 TI - Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis. AB - Background: Small studies have implicated plasminogen activator inhibitor-1 (PAI 1) as a predictor of cardiovascular events; however, these findings have been inconsistent.We sought out to examine the potential role of PAI-1 as a marker for major adverse cardiovascular events (MACE). Methods: We systematically reviewed all indexed studies examining the association between PAI-1 and MACE (defined as death, myocardial infarction, or cerebrovascular accident) or restenosis. EMBASE, Web of Science, Medline, and the Cochrane Library were searched through October 2016 to identify relevant studies, supplemented by letters to authors and review of citations. Studies reporting the results of PAI-1 antigen and/or activity levels in association with MACE in human subjects were included. Results: Of 5961 articles screened, we identified 38 articles published between 1991 to 2016 that reported PAI-1 levels in 11,557 patients. In studies that examined PAI-1 antigen and activity levels, 15.1% and 29.6% of patients experienced MACE, respectively. Patients with MACE had higher PAI-1 antigen levels with a mean difference of 6.11 ng/mL (95% CI, 3.27-8.96). This finding was similar among patients with and without known coronary artery disease. Comparatively, studies that stratified by PAI-1 activity levels were not associated with MACE. In contrast, studies of coronary restenosis suggest PAI-1 antigen and activity levels are negatively associated with MACE. Conclusions: Elevated plasma PAI-1 antigen levels are associated with MACE. Definitive studies are needed to ascertain if PAI-1 acts simply as a marker of risk or if it is indeed a bona fide therapeutic target. PMID- 29991928 TI - Absolute dose verification of static intensity modulated radiation therapy (IMRT) with ion chambers of various volumes and TLD detectors. AB - Aim: This study aims at examining absolute dose verification of step-and-shoot intensity modulated radiation treatment (IMRT) of prostate and brain patients by use of ion chambers of two different volumes and thermoluminescent detectors (TLD). Background: The volume of the ion chamber (IC) is very important for absolute dose verification of IMRT plans since the IC has a volume average effect. With TLD detectors absolute dose verification can be done measuring the dose of multiple points simultaneously. Materials and methods: Ion chambers FC65 P of volume 0.65 cc and semiflex of volume 0.125 cc as well as TLDs were used to measure the central axis absolute dose of IMRT quality assurance (QA) plans. The results were compared with doses calculated by a treatment planning system (TPS). The absolute doses of off axis points located 2 cm and 4 cm away from the isocenter were measured with TLDs. Results: The measurements of the 0.125 cc ion chamber were found to be closer to TPS calculations compared to the 0.65 cc ion chamber, for both patient groups. For both groups the root mean square (RMS) differences between doses of the TPS and the TLD detectors are within 3.0% for the central axis and points 2 cm away from the isocenter of each axis. Larger deviations were found at the field edges, which have steep dose gradient. Conclusions: The 0.125 cc ion chamber measures the absolute dose of the isocenter more accurately compared to the 0.65 cc chamber. TLDs have good accuracy (within 3.0%) for absolute dose measurements of in-field points. PMID- 29991929 TI - Intensity-modulated radiation therapy and volumetric modulated arc therapy versus conventional conformal techniques at high energy: Dose assessment and impact on second primary cancer in the out-of-field region. AB - The aim of this work was to estimate peripheral neutron and photon doses associated with the conventional 3D conformal radiotherapy techniques in comparison to modern ones such as Intensity modulated radiation therapy and volumetric modulated arc therapy. Assessment in terms of second cancer incidence ought to peripheral doses was also considered. For that, a dosimetric methodology proposed by the authors has been applied beyond the region where there is no CT information and, thus, treatment planning systems do not calculate and where, nonetheless, about one third of second primary cancers occurs. PMID- 29991930 TI - Patterns of treatment failure in salivary gland cancers. AB - Aim: The purpose of the study was to publish our experience of salivary gland cancer treatment with large number of patients treated at a single institution. Background: Salivary gland cancers are rare tumors of the head and neck representing about 5% of cancers in that region and about 0.5% of all malignancies. Due to the rarity of the disease, most of the studies regarding treatment outcome consist of low number of patients, thus making it difficult to draw conclusions. Material and methods: 115 patients with primary salivary gland cancer were included in a retrospective study. The subsites of tumor were the parotid gland (58% patients), submandibular gland (19%) and minor salivary glands (23%). All patients underwent primary surgical resection. The following were collected: age, stage of the disease, T status, N status, grade of tumor, perineurial invasion, lymphovascular invasion, extracapsular spread, final histological margin status and postoperative treatment. Details of local, regional or distant recurrence, disease free survival and overall survival were included. Results: The majority (65%) of patients presented in early stage, T1 and T2 tumors. 81% of patients were N0. Free surgical margins were achieved in 18% of patients, close in 28% patients and positive surgical margins in 54% (62) patients. Factors that significantly increased the risk of recurrence: T stage (p = 0.0006); N-positive status (p < 0.0001); advanced stage of the disease (p < 0.0001); high grade of tumor (p = 0.0007); PNI (p = 0.0061); LVI (p = 0.0022); ECS (p = 0.0136); positive surgical margins (p = 0.0022). On multivariate analysis, high grade of tumor and positive surgical margins remained significant independent adverse factors for recurrence formation. Conclusions: This report shows a single institution results of oncological treatment in patients with malignant salivary gland tumors, where positive surgical margins strongly correlate with patients' worse outcome. Whether to extend the procedure, which very often requires sacrificing the nerve is still a question of debate. PMID- 29991931 TI - Cross-Nucleation between Polymorphs: Quantitative Modeling of Kinetics and Morphology. AB - Cross-nucleation is defined as the nucleation of one polymorph on the surface of another polymorph of the same substance. Although the description of this particular form of heterogeneous nucleation is mainly phenomenological, recently dedicated quantitative studies are performed on several systems. In this work we propose a model framework that captures the phenomenon of cross-nucleation for a spherulitic seed-surface geometry, as well as the kinetic competition between the seed growth and the cross-nucleus formation, by the introduction of a tangential growth rate of the daughter polymorph. Regardless of the growth rate of the parent spherulite, this model describes the experimental data up to and including the final amount of cross-nuclei on its periphery, solely based on one parameter, the cross-nucleation rate. Furthermore, a strong temperature dependency of the kinetic competition between concomitantly growing alpha- and beta-phase isotactic polypropylene is observed and related to the previously reported anomalous behavior of this cross-nucleating system. PMID- 29991934 TI - Chronic Kidney Disease and Hepatitis C Virus Treatment. PMID- 29991933 TI - A Noninvasive Method to Assess Mucosal Healing in Patients* With Crohn's Disease. AB - Ongoing inflammation in the gastrointestinal tract and loss of the mucosal barrier are key components of Crohn's disease. Current treatment paradigms, including treat-to-target, are based on improvement of both clinical and endoscopic symptoms. Endoscopy is an essential tool for the evaluation of mucosal healing, but patients may be reluctant to undergo repeated procedures. Surrogate markers of inflammation, such as C-reactive protein and fecal calprotectin, are being used, yet they have several limitations in the assessment of mucosal healing. A new strategy, known as the Monitr test, assesses mucosal healing status by evaluating serum levels of 13 biomarkers in patients with Crohn's disease. The 13 biomarkers are associated with cell adhesion, inflammation, angiogenesis, extracellular matrix remodeling, cell proliferation and repair, and immune cell recruitment. Monitr testing yields a mucosal healing index score that reflects disease severity. Validation of the test showed an overall accuracy of 90%, with a negative predictive value of 92% and a positive predictive value of 87% for identifying patients with endoscopic evidence of Crohn's disease. Use of this noninvasive test may aid in the monitoring and management of patients with Crohn's disease, while potentially reducing the need for repeated endoscopy. PMID- 29991932 TI - Improving IBD Care: A Personalized Approach to Management. PMID- 29991935 TI - Hepatitis C Virus Treatment in Patients With Chronic Kidney Disease and in Kidney Transplant Recipients. AB - An important interplay exists between hepatitis C virus (HCV) infection and chronic kidney disease (CKD). HCV infection is associated with an increased risk of morbidity and mortality in patients coinfected with CKD, and patients with CKD have an increased risk of HCV infection. Direct-acting antiviral (DAA) agents have changed the landscape of treatment with excellent sustained virologic response rates and fewer side effects than previously seen. An increasing number of studies demonstrate that DAA agents are efficacious and safe both in patients on dialysis and in patients who have undergone kidney transplantation. This article reviews the current literature on approved DAA agents for the treatment of HCV infection in patients on dialysis and in kidney transplant recipients. PMID- 29991936 TI - A Review of Prevention of Post-ERCP Pancreatitis. AB - Endoscopic retrograde cholangiopancreatography (ERCP) is a diagnostic and therapeutic procedure employed in the management of disorders of the biliary system. Post-ERCP pancreatitis (PEP) is the most common complication of ERCP and can lead to significant morbidity as well as occasional mortality. In addition to adequate procedural training, therapeutic endoscopists who perform ERCPs should possess a thorough understanding of patient- and procedure-related risk factors for PEP. This knowledge can inform patient selection for ERCP and allow for appropriate management efforts to be performed in high-risk cases. Procedural techniques promoting minimally traumatic biliary cannulation should be employed when initial standard techniques are unsuccessful. In high-risk patients, several measures can be undertaken to limit the risk of PEP, including administration of rectal nonsteroidal anti-inflammatory drugs, prophylactic placement of pancreatic duct stents, and liberal administration of lactated Ringer solution. When PEP does occur, appropriate management with aggressive intravenous hydration, pain control, and early enteral nutrition should be administered. Additional research is needed to further define risk factors for PEP, optimal procedural techniques used during ERCP, and ideal prevention and treatment strategies to limit the incidence and severity of PEP in patients. PMID- 29991938 TI - Management of Patients Who Have Achieved Sustained Virologic Response for Hepatitis C Virus Infection. PMID- 29991939 TI - Diet and Irritable Bowel Syndrome. PMID- 29991937 TI - Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment. AB - Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy that can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The course of PSC is often complicated by portal hypertension, symptoms of cholestasis, and recurrent bacterial cholangitis, among other conditions, with a consequent decrease in survival (median, approximately 20 years) and quality of life. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Despite its rarity, PSC is the fifth leading indication for liver transplantation (LT) in the United States. Although the only intervention known to extend survival of patients with PSC, LT is costly and invasive, and recurrent PSC affects approximately 30% of LT recipients. Over the past several years, owing in part to progress in the understanding of PSC, novel pharmacotherapeutics have been developed, some of which are currently in the PSC clinical trial pipeline. Here, in the first of a 2-part series, we provide a review and update of the epidemiology, etiopathogenesis, clinical features, and treatment of PSC. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC. PMID- 29991940 TI - The Appropriate Use and Techniques of Tattooing in the Colon. PMID- 29991941 TI - Update on Fecal Microbiota Transplantation in Patients With Inflammatory Bowel Disease. PMID- 29991942 TI - Using Black Hole Algorithm to Improve EEG-Based Emotion Recognition. AB - Emotions are a critical aspect of human behavior. One widely used technique for research in emotion measurement is based on the use of EEG signals. In general terms, the first step of signal processing is the elimination of noise, which can be done in manual or automatic terms. The next step is determining the feature vector using, for example, entropy calculation and its variations to generate a classification model. It is possible to use this approach to classify theoretical models such as the Circumplex model. This model proposes that emotions are distributed in a two-dimensional circular space. However, methods to determine the feature vector are highly susceptible to noise that may exist in the signal. In this article, a new method to adjust the classifier is proposed using metaheuristics based on the black hole algorithm. The method is aimed at obtaining results similar to those obtained with manual noise elimination methods. In order to evaluate the proposed method, the MAHNOB HCI Tagging Database was used. Results show that using the black hole algorithm to optimize the feature vector of the Support Vector Machine we obtained an accuracy of 92.56% over 30 executions. PMID- 29991944 TI - A Retrospective Study Analyzing the Appropriateness of Initial Treatment of Clostridium difficile in Patients with Active Malignancy. AB - Background: Clostridium difficile infection (CDI) is the leading cause of hospital-associated gastrointestinal illness. Previous studies reported that patients with active malignancy are at high risk for CDIs, and yet they are still classified as nonsevere CDI and initially treated with metronidazole. Our aim is to investigate the need for the escalation of antibiotic therapy in patients with CDI and active cancer treated with oral metronidazole versus oral vancomycin. Methods: This is a retrospective study of adult patients admitted with CDI and any underlying active malignancy at Beaumont Hospital, Royal Oak, Michigan, from January 2008 to December 2014. Inclusion criteria included age > 18 years old, polymerase chain reaction- (PCR-) proven CDI, and active malignancy. Results: 197 patients were included in the final analysis. 44.8% of the metronidazole group required escalation of therapy compared to 15.2% in the vancomycin group (p value = 0.001). 29.8% of the combination group (metronidazole and vancomycin) underwent deescalation of antibiotics, which was significantly higher compared to 2.2% of patients in the vancomycin group (p value < 0.001). Discussion: Our results support the initial use of vancomycin or a combination (metronidazole and vancomycin) versus metronidazole in patients with CDI and active malignancy. PMID- 29991943 TI - Effects of Antipsychotic Drugs on the Epigenetic Modification of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampi of Chronic Restraint Stress Rats. AB - Recent studies have shown that antipsychotic drugs have epigenetic effects. However, the effects of antipsychotic drugs on histone modification remain unclear. Therefore, we investigated the effects of antipsychotic drugs on the epigenetic modification of the BDNF gene in the rat hippocampus. Rats were subjected to chronic restraint stress (6 h/d for 21 d) and then were administered with either olanzapine (2 mg/kg) or haloperidol (1 mg/kg). The levels of histone H3 acetylation and MeCP2 binding at BDNF promoter IV were assessed with chromatin immunoprecipitation assays. The mRNA levels of total BDNF with exon IV, HDAC5, DNMT1, and DNMT3a were assessed with a quantitative RT-PCR procedure. Chronic restraint stress resulted in the downregulation of total and exon IV BDNF mRNA levels and a decrease in histone H3 acetylation and an increase in MeCP2 binding at BDNF promoter IV. Furthermore, there were robust increases in the expression of HDAC5 and DNMTs. Olanzapine administration largely prevented these changes. The administration of haloperidol had no effect. These findings suggest that the antipsychotic drug olanzapine induced histone modification of BDNF gene expression in the hippocampus and that these epigenetic alterations may represent one of the mechanisms underlying the actions of antipsychotic drugs. PMID- 29991945 TI - Gastroesophageal Reflux Characteristics and Patterns in Patients with Idiopathic Subglottic Stenosis. AB - Introduction: Idiopathic subglottic stenosis represents a spectrum of subglottic disease without a clear underlying cause. Prior studies have implicated a pathogenic role of gastroesophageal reflux disease in idiopathic subglottic stenosis. The aim of this study was to examine the presence and pattern of gastroesophageal reflux in a large cohort of patients with idiopathic subglottic stenosis at a tertiary referral center. Methods: We performed a retrospective review of patients with idiopathic subglottic stenosis from January 2010 to December 2016 who had undergone combined pH impedance testing. Patients with prior gastric or esophageal surgery were excluded. Data obtained included esophageal acid exposure times, number of reflux events, patient position during reflux events (defined as upright, supine, or mixed), body mass index, and the presence of proton pump inhibitor therapy. Results: 159 patients with the idiopathic subglottic stenosis were identified, of whom 41 had undergone esophageal pH impedance testing. 40 (97.6%) were women, with a mean age of 54.8 (range 31-79) years and BMI of 31.0 (range 17-55). Overall, 19 (46.3%) patients were found to reflux as confirmed by abnormal esophageal acid exposure or abnormal number of reflux events. 15 of the 19 patients with reflux had predominantly upright gastroesophageal reflux disease, whereas 2 had supine and 2 mixed reflux. Discussion: In patients with idiopathic subglottic stenosis who underwent evaluation by combined pH impedance, close to half were found to have gastroesophageal reflux disease. The majority of gastroesophageal reflux occurred while the patients were in the upright position. PMID- 29991947 TI - A Rare Presentation of Clozapine-Induced DRESS Syndrome. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is an uncommon side effect of certain medications. It causes a skin reaction, with eosinophilia and other organ involvement. This case describes a presentation of a 32-year-old female with a past medical history significant for schizophrenia and bipolar disorder who presented for a rash. She had been started on clozapine 10 days prior to admission. After extensive workup she was found to have DRESS syndrome secondary to clozapine use. This is the second reported case in the literature of clozapine-induced DRESS syndrome. This case is unique because it is the first case to present with the common manifestations of DRESS syndrome including eosinophilia, rash, lymphadenopathy, and organ involvement after clozapine use. PMID- 29991946 TI - Long-Term Dietary Changes after Diagnosis of Rheumatoid Arthritis in Swedish Women: Data from a Population-Based Cohort. AB - Objective: To investigate long-term dietary changes after rheumatoid arthritis (RA) diagnosis in Swedish women, compared to women without RA. Methods: This study included 21,602 women from the Swedish Mammography Cohort (SMC), who completed dietary questionnaires in 1997 and 2009. Between 1997 and 2009, 191 women were diagnosed with RA. Dietary changes after RA diagnosis were analyzed based on intake of 82 food items. Statistical analysis included linear mixed models. Results: Women with RA, compared to women without RA, had significantly lower intake (mean servings per week) of animal products such as black pudding, egg, kidney, and liver paste (2.94+/-2.73 versus 2.45+/-1.82, p=0.010) and dairy products (35.14+/-20.02 versus 28.42+/-16.10, p=0.040) in 1997 and of cereals and grains (31.01+/-15.54 versus 28.00+/-14.98, p=0.009) in 2009. However, multivariable adjusted changes in dietary intake from 1997 to 2009 did not show any significant difference in intake. Nevertheless, women without RA increased their intake of whole wheat bread, wheat/oat bran, and rice more than women with RA. Conclusion: Women who had been diagnosed with RA had similar dietary patterns over time as the general population; these women did not remarkably change their diet over time due to their disease. Dietary recommendations for RA patients are needed. PMID- 29991948 TI - Odontogenic Cutaneous Fistula: A Cause of Persistent Cervical Discharge. AB - Odontogenic cutaneous fistulas often lead to intense levels of patient discomfort and suffering. Due to its rarity and the absence of dental symptoms, a considerable number of patients are usually misdiagnosed which results in inappropriate management. This case report presents a 16-year-old patient with a 2-year history of a nonhealing, persistently discharging lesion in the left submandibular region of the neck. The patient underwent exploration of the left submandibular region, and a fistulous tract directed superomedially to the ipsilateral lower molar teeth was excised. A subsequent panoramic orthopantomogram performed one week postoperatively demonstrated radiolucency is the distal root of tooth 37. A final diagnosis of odontogenic cutaneous fistula was made, and the patient was referred to the Maxillofacial Department for treatment of the offending tooth. PMID- 29991949 TI - Gastrointestinal CMV Disease and Tuberculosis in an AIDS Patient: Synergistic Interaction between Opportunistic Coinfections. AB - The AIDS pandemic has made diseases such as tuberculosis, CMV disease, and other opportunistic infections more prevalent; these diseases may even be found to be associated among themselves, and the natural history of each disease may present in an unusual manner. We report the case of a 41-year-old man with HIV (CD4 of 144 cells/dL) and HCV with hematochezia due to tuberculosis in the ileocecal valve and descending colon and CMV tissue invasive disease in the esophagus and descending colon. Coinfection among tuberculosis and cytomegalovirus in the gastrointestinal tract was described only once in a patient with a recent diagnosis of HIV that affected the distal ileum and ascending colon. We will discuss the peculiarities of the case and the behavior of the immune system in the face of simultaneous opportunistic infections. This is a challenging scenario that has scarce publications and is of great clinical importance. PMID- 29991950 TI - Effect of artemisinin and neurectomy of pterygoid canal in ovalbumin-induced allergic rhinitis mouse model. AB - Background: Allergic rhinitis (AR), characterized by sneezing, nasal itching and rhinorrhea, affects a large number of population. This study aimed to explore the effects of artemisinin alone or combined with neurectomy of pterygoid canal in ovalbumin-induced AR mouse model and illustrate the underlying mechanisms. Methods: Allergic symptoms were evaluated to verify inhibitory effect of artemisinin alone or combined with neurectomy of pterygoid canal on AR. Serum levels of histamine, immunoglobulin E (IgE) and inflammatory factors TNF, INF gamma, IL-1beta IL-10, IL-4 and IL-5 were measured by ELISA. The mRNA levels of TNF, INF-gamma, IL-1beta and IL-10 in local lymph nodes were measured by RT-qPCR. The total and phosphorylated levels of ERK and JNK were assessed by Western blot. CD4+CD25+Foxp3+ T (Treg) cells were analyzed by flow cytometry. Results: Artemisinin significantly relieved the behavior symptoms of AR mice. The administration of artemisinin strikingly suppressed the expression of histamine, IgE and inflammatory factors. An increased Treg cell proportion and inhibited ERK phosphorylation were observed in artemisinin-treated groups as compared to those in the AR group. Moreover, artemisinin plus neurectomy of pterygoid almost abolished the behavioral score increase in AR mice. Conclusions: These results indicated that artemisinin exhibited anti-allergic effect by inhibiting ERK activation and increasing Treg cell proportion, which subsequently decreased the expressions of allergic mediators. In addition, artemisinin combined with neurectomy of pterygoid showed better efficacy than artemisinin alone. PMID- 29991951 TI - Evaluation of the Wound Healing Activity of the Crude Extract of Leaves of Acanthus polystachyus Delile (Acanthaceae). AB - Background: Medicinal plants play indispensable roles to treat various ailments. Acanthus polystachyus is one of the medicinal plants used traditionally for treatment of wounds. However, there were no scientific reports documented so far on the wound healing activities of this plant. Thus, the present study provides a scientific evaluation for the wound healing potential of the crude extract of A. polystachyus leaves. Methods: The crude extraction was carried out using 80% methanol. The crude extract was prepared in 5% (w/w) and 10% (w/w) ointment and evaluated for wound healing activity using excision, infected, and incision wound models in Swiss albino mice. Results: Both 5% and 10% (w/w) ointments significantly reduced period of epithelialization and increased wound contraction rate and tensile strength compared to the negative control group (P < 0.05). The wound healing activity of 10% (w/w) ointment treated group was greater than 5% (w/w) and nitrofurazone ointment treated groups in S. aureus infected wound model. Conclusion: These results demonstrate that the crude extract of A. polystachyus leaves possesses wound healing activities. This justifies the traditional claimed use of the plant for treating uninfected and infected wounds caused by S. aureus. PMID- 29991952 TI - Effect of Liuzijue Exercise Combined with Elastic Band Resistance Exercise on Patients with COPD: A Randomized Controlled Trial. AB - Objectives: This study aimed to investigate the effect of Liuzijue exercise combined with elastic band resistance exercise on patients with chronic obstructive pulmonary disease (COPD) to provide a convenient, safe, and cost effective exercise. Methods: Subjects were randomly divided into the control group (CG), the Liuzijue exercise group (LG), and the Liuzijue exercise combined with elastic band resistance exercise group (LEG), with 20 patients in each group. The LG performed Liuzijue exercise six times a week (two exercise sessions in the hospital and four exercise sessions at home). The LEG includes Liuzijue exercise similar to the LG and elastic band resistance exercise three times a week, with elastic band exercise implemented after Liuzijue exercise. Spirometry, 6-minute walking test (6MWT), 30-second sit-to-stand test (30 s SST), handgrip strength test, and St. George's Respiratory Questionnaire (SGRQ) were performed at baseline and at the end of intervention. Results: After six-month intervention, the forced expiratory volume in 1 second (% predicted), 6-minute walking distance (6MWD), 6MWD%pred, 30 s SST, and SGRQ were significantly improved in the intervention groups (p < 0.01) and handgrip strength was increased significantly in the LG and LEG (p = 0.03 and p = 0.001, respectively). Furthermore, improvements in 6MWD and SGRQ were distinguished in the intervention groups compared with the CG (p < 0.01). No difference was significant in all of the outcomes between the LG and the LEG. Conclusions: The intervention program of Liuzijue exercise combined with elastic band resistance exercise and Liuzijue exercise only has beneficial effects on COPD patients especially in the aspect of exercise capacity and quality of life. PMID- 29991953 TI - Antiasthmatic Effects of Sanglong Pingchuan Decoction through Inducing a Balanced Th1/Th2 Immune Response. AB - Objective: To investigate the antiasthmatic effects of Sanglong pingchuan decoction (SLPCD) and to explore its mechanisms of action. Methods: The serum, bronchoalveolar lavage fluid (BALF), and lung tissues from OVA-induced allergic asthma mice were collected 24 h after the last administration. Lung pathological changes were observed by H&E staining. The inflammatory cells in BALF were counted by flow cytometry. The levels of total IgE in serum and cytokines in BALF were determined by ELISA. The expression levels of cytokine mRNA in lung were assayed by qRT-PCR. Results: SLPCD significantly inhibited airway inflammation, reduced inflammatory cells in BALF, reduced the levels of total IgE in serum and Th2 cytokines (IL-10 and IL-13) in BALF, and downregulated the mRNA expression levels of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) in lung of asthmatic mice. However, SLPCD remarkably elevated the level of Th1 cytokine IFN-gamma in BALF and upregulated the mRNA expression levels of Th1 cytokines (IL-2 and IFN-gamma) in lung of asthmatic mice. Conclusion: SLPCD could attenuate airway inflammation and alleviate the pathogenesis in asthma mice through inducing a balanced Th1/Th2 response and could act as an effective drug for treatment of asthma. PMID- 29991954 TI - Biomechanical Effects of Lateral Bending Position on Performing Cervical Spinal Manipulation for Cervical Disc Herniation: A Three-Dimensional Finite Element Analysis. AB - Background: Most studies report that the common position of cervical spinal manipulation (CSM) for treating symptomatic cervical disc herniation (CDH) is lateral bending to the herniated side. However, the rationality of lateral bending position on performing CSM for CDH is still unclear. Objective: The purpose of this study is to investigate the biomechanical effects of lateral bending position on performing CSM for CDH. Methods: A finite element (FE) model of CDH (herniated on the left side) was generated in C5-6 segment based on the normal FE model. The FE model performed CSM in left lateral bending position, neutral position, and right lateral bending position, respectively. Cervical disc displacement, annulus fiber stress, and facet joint stress were observed during the simulation of CSM. Results: The cervical disc displacement on herniated side moved forward during CSM, and the maximum forward displacements were 0.23, 0.36, and 0.45 mm in left lateral bending position, neutral position, and right lateral bending position, respectively. As the same trend of cervical disc displacement, the annulus fiber stresses on herniated side from small to large were 7.40, 16.39, and 22.75 MPa in left lateral bending position, neutral position, and right lateral bending position, respectively. However, the maximum facet stresses at left superior cartilage of C6 in left lateral bending position, neutral position, and right lateral bending position were 6.88, 3.60, and 0.12 MPa, respectively. Conclusion: Compared with neutral position and right lateral bending position, though the forward displacement of cervical disc on herniated side was smaller in left lateral bending position, the annulus fiber stress on herniated side was declined by sharing load on the left facet joint. The results suggested that lateral bending to the herniated side on performing CSM tends to protect the cervical disc on herniated side. Future clinical studies are needed to verify that. PMID- 29991955 TI - Adjuvant Therapy of Oral Chinese Herbal Medicine for Menopausal Depression: A Systematic Review and Meta-Analysis. AB - Objective. The aim of this meta-analysis was to evaluate the effectiveness of oral Chinese herbal medicine (OCHM) combined with pharmacotherapy for menopausal depression. Methods. The electronic databases were searched from their inception to December 25, 2016, comprising PubMed, Embase, Cochrane Central Register of Controlled Trials, Chinese National Knowledge Infrastructure (CNKI), Wanfang database, and Chinese Biomedical (CBM) database. Randomized controlled trials investigating the effectiveness of OCHM combined with pharmacotherapy for the people with menopausal depression were eligible. Risk of bias was evaluated according to the Cochrane handbook. Meta-analyses were performed to pool the effect size. Heterogeneity and publication bias were also examined. Results. Twenty-two RCTs with 1770 participants were included in the review. None of the studies used placebo as the control and the risk of bias was high in blinding the participants and personnel. Overall, the meta-analysis demonstrated that adjuvant therapy of OCHM was effective in reducing the Hamilton Rating Scale for Depression (HAMD) scores compared to pharmacotherapy (MD = -3.75; 95% CI = -5.22, -2.29; P < 0.00001). The meta-analysis also suggested that OCHM adjuvant therapy for menopausal depression was superior to pharmacotherapy in terms of response rate of reducing HAMD scores (RR = 1.17; 95% CI = 1.10, 1.25; I2 = 55%). Conclusions. OCHM may provide additional effectiveness to pharmacotherapy for the people with menopausal depression. RCTs including the placebo control were required to further determine the additional efficacy of OCHM for menopausal depression. PMID- 29991956 TI - Clinical Efficacy and Safety of Aidi Injection Plus Docetaxel-Based Chemotherapy in Advanced Nonsmall Cell Lung Cancer: A Meta-Analysis of 36 Randomized Controlled Trials. AB - Background. Aidi injection is an important adjuvant anticancer drug commonly used in China. Can Aidi injection plus docetaxel-based chemotherapy improve clinical efficacy with good safety in NSCLC? To further reveal its clinical effectiveness, we systematically evaluated all the related studies. Method. We collected all the studies about Aidi injection plus docetaxel-based chemotherapy for NSCLC on Medline, Embase, Web of Science, CNKI, VIP, Wanfang, CBM, CENTRAL, Chi-CTR, and US-clinical trials. We evaluated their methodological bias risk according to the Cochrane evaluation handbook (5.1.0), extracted data following the predesigned data extraction form according to the PICO principle, and synthesized the data using meta-analysis. Results. We included 36 RCTs with 2837 patients, and most studies had unclear bias risk. The merged RR values and their 95% CI of meta analysis for ORR, DCR, and QOL were as follows: 1.30 (1.19, 1.42), 1.17, (1.12, 1.22), and 1.73 (1.54, 1.95). The merged RR values for neutropenia, thrombocytopenia, anemia, gastrointestinal toxicity, hepatorenal dysfunctions, and alopecia were as follows: 0.70 (0.61, 0.79), 0.63 (0.53, 0.75), 0.60 (0.48, 0.75), 0.76 (0.65, 0.89), 0.56 (0.36, 0.88), and 0.58 (0.36, 0.93). Compared with chemotherapy alone, all differences were statistically significant. Subgroup analysis showed that, with 100 ml, 80-100 ml, and 50 ml, Aidi injection could increase the tumor response and Aidi injection plus DP, DC, and DO could increase the tumor response. Meta-analysis results had good stability. Conclusions. Aidi injection plus docetaxel-based chemotherapy, especially plus DP, DC, and DO, may significantly improve the clinical efficacy and QOL in NSCLC. It may also have low risk of hematotoxicity, gastrointestinal toxicity, and low risk of inducing hepatorenal dysfunctions. Aidi injection may have attenuation and synergistic efficacy to docetaxel chemotherapy. All these need to have new evidence to be proved. PMID- 29991957 TI - Medium-chain fatty acids decrease serum cholesterol via reduction of intestinal bile acid reabsorption in C57BL/6J mice. AB - Background: Bile acids play a pivotal role in cholesterol metabolism via the enterohepatic circulation. This study investigated the effects of medium-chain triglycerides (MCTs)/medium-chain fatty acids (MCFAs) on the reduction of bile acid absorption in the small intestine and the mechanisms of action in vivo and partially verified in vitro. Methods: Thirty-six C57BL/6 J mice with hypercholesterolaemia were randomly divided into 3 groups: fed a cholesterol-rich diet (CR group), fed a cholesterol-rich and medium-chain triglyceride diet (CR MCT group) and fed a cholesterol-rich and long-chain triglyceride diet (CR-LCT group). Body weights and blood lipid profiles were measured in all groups after 16 weeks of treatment. The concentrations of bile acids in bile and faeces were analysed using HPLC-MS (high-performance liquid chromatography-mass spectrometry). Gene transcription and the expression levels associated with bile acid absorption in the small intestines were determined using real-time PCR and Western blot. Ileal bile acid binding protein (I-BABP) was analysed using immunofluorescence. The effects of MCFAs on the permeability of bile acid (cholic acid, CA) in Caco-2 cell monolayers and I-BABP expression levels in Caco-2 cells treated with caprylic acid (C8:0), capric acid (C10:0), stearic acid (C18:0) and oleic acid (C18:1) were determined. Results: Mice in the CR-MCT group exhibited lower body weights and serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels and a higher HDL-C/LDL-C ratio than the CR-LCT group (P < 0.05). The concentrations of primary bile acids (primarily CA) and secondary bile acids in faeces and secondary bile acids in bile in the CR-MCT group were significantly higher than in the CR-LCT group (P < 0.05). C8:0 and C10:0 decreased the permeability of CA in Caco-2 cell monolayers. MCT/MCFAs (C8:0 and C10:0) inhibited I-BABP gene expression in the small intestines and Caco-2 cells (P < 0.05). Conclusions: MCT slowed the body weight increase and promoted the excretion of bile acids. MCT lowered serum cholesterol levels at least partially via reduction of bile acid absorption in the small intestine by inhibition of I BABP expression. Our results provide the basis for clinical trials of MCT as a dietary supplement for lowering plasma cholesterol and reducing risk of CHD. PMID- 29991959 TI - Bayesian functional regression as an alternative statistical analysis of high throughput phenotyping data of modern agriculture. AB - Background: Modern agriculture uses hyperspectral cameras with hundreds of reflectance data at discrete narrow bands measured in several environments. Recently, Montesinos-Lopez et al. (Plant Methods 13(4):1-23, 2017a. 10.1186/s13007-016-0154-2; Plant Methods 13(62):1-29, 2017b. 10.1186/s13007-017 0212-4) proposed using functional regression analysis (as functional data analyses) to help reduce the dimensionality of the bands and thus decrease the computational cost. The purpose of this paper is to discuss the advantages and disadvantages that functional regression analysis offers when analyzing hyperspectral image data. We provide a brief review of functional regression analysis and examples that illustrate the methodology. We highlight critical elements of model specification: (i) type and number of basis functions, (ii) the degree of the polynomial, and (iii) the methods used to estimate regression coefficients. We also show how functional data analyses can be integrated into Bayesian models. Finally, we include an in-depth discussion of the challenges and opportunities presented by functional regression analysis. Results: We used seven model-methods, one with the conventional model (M1), three methods using the B splines model (M2, M4, and M6) and three methods using the Fourier basis model (M3, M5, and M7). The data set we used comprises 976 wheat lines under irrigated environments with 250 wavelengths. Under a Bayesian Ridge Regression (BRR), we compared the prediction accuracy of the model-methods proposed under different numbers of basis functions, and compared the implementation time (in seconds) of the seven proposed model-methods for different numbers of basis. Our results as well as previously analyzed data (Montesinos-Lopez et al. 2017a, 2017b) support that around 23 basis functions are enough. Concerning the degree of the polynomial in the context of B-splines, degree 3 approximates most of the curves very well. Two satisfactory types of basis are the Fourier basis for period curves and the B-splines model for non-periodic curves. Under nine different basis, the seven method-models showed similar prediction accuracy. Regarding implementation time, results show that the lower the number of basis, the lower the implementation time required. Methods M2, M3, M6 and M7 were around 3.4 times faster than methods M1, M4 and M5. Conclusions: In this study, we promote the use of functional regression modeling for analyzing high-throughput phenotypic data and indicate the advantages and disadvantages of its implementation. In addition, many key elements that are needed to understand and implement this statistical technique appropriately are provided using a real data set. We provide details for implementing Bayesian functional regression using the developed genomic functional regression (GFR) package. In summary, we believe this paper is a good guide for breeders and scientists interested in using functional regression models for implementing prediction models when their data are curves. PMID- 29991960 TI - Medical Image Fusion Based on Sparse Representation and PCNN in NSCT Domain. AB - The clinical assistant diagnosis has a high requirement for the visual effect of medical images. However, the low frequency subband coefficients obtained by the NSCT decomposition are not sparse, which is not conducive to maintaining the details of the source image. To solve these problems, a medical image fusion algorithm combined with sparse representation and pulse coupling neural network is proposed. First, the source image is decomposed into low and high frequency subband coefficients by NSCT transform. Secondly, the K singular value decomposition (K-SVD) method is used to train the low frequency subband coefficients to get the overcomplete dictionary D, and the orthogonal matching pursuit (OMP) algorithm is used to sparse the low frequency subband coefficients to complete the fusion of the low frequency subband sparse coefficients. Then, the pulse coupling neural network (PCNN) is excited by the spatial frequency of the high frequency subband coefficients, and the fusion coefficients of the high frequency subband coefficients are selected according to the number of ignition times. Finally, the fusion medical image is reconstructed by NSCT inverter. The experimental results and analysis show that the algorithm of gray and color image fusion is about 34% and 10% higher than the contrast algorithm in the edge information transfer factor QAB/F index, and the performance of the fusion result is better than the existing algorithm. PMID- 29991958 TI - Maternal overnutrition by hypercaloric diets programs hypothalamic mitochondrial fusion and metabolic dysfunction in rat male offspring. AB - Background: Maternal overnutrition including pre-pregnancy, pregnancy and lactation promotes a lipotoxic insult leading to metabolic dysfunction in offspring. Diet-induced obesity models (DIO) show that changes in hypothalamic mitochondria fusion and fission dynamics modulate metabolic dysfunction. Using three selective diet formula including a High fat diet (HFD), Cafeteria (CAF) and High Sugar Diet (HSD), we hypothesized that maternal diets exposure program leads to selective changes in hypothalamic mitochondria fusion and fission dynamics in male offspring leading to metabolic dysfunction which is exacerbated by a second exposure after weaning. Methods: We exposed female Wistar rats to nutritional programming including Chow, HFD, CAF, or HSD for 9 weeks (pre-mating, mating, pregnancy and lactation) or to the same diets to offspring after weaning. We determined body weight, food intake and metabolic parameters in the offspring from 21 to 60 days old. Hypothalamus was dissected at 60 days old to determine mitochondria-ER interaction markers by mRNA expression and western blot and morphology by transmission electron microscopy (TEM). Mitochondrial-ER function was analyzed by confocal microscopy using hypothalamic cell line mHypoA-CLU192. Results: Maternal programming by HFD and CAF leads to failure in glucose, leptin and insulin sensitivity and fat accumulation. Additionally, HFD and CAF programming promote mitochondrial fusion by increasing the expression of MFN2 and decreasing DRP1, respectively. Further, TEM analysis confirms that CAF exposure after programing leads to an increase in mitochondria fusion and enhanced mitochondrial-ER interaction, which partially correlates with metabolic dysfunction and fat accumulation in the HFD and CAF groups. Finally, we identified that lipotoxic palmitic acid stimulus in hypothalamic cells increases Ca2+ overload into mitochondria matrix leading to mitochondrial dysfunction. Conclusions: We concluded that maternal programming by HFD induces hypothalamic mitochondria fusion, metabolic dysfunction and fat accumulation in male offspring, which is exacerbated by HFD or CAF exposure after weaning, potentially due to mitochondria calcium overflux. PMID- 29991961 TI - Fate of p-hydroxycinnamates and structural characteristics of residual hemicelluloses and lignin during alkaline-sulfite chemithermomechanical pretreatment of sugarcane bagasse. AB - Background: Preparing multiple products from lignocellulosic biomass feedstock enhances the profit and sustainability of future biorefineries. Grasses are suitable feedstocks for biorefineries as they permit a variety of possible by products due to their particular chemical characteristics and morphology. Elucidating the fate of p-hydroxycinnamates (ferulates-FAs and p-coumarates-pCAs) and major structural components during bioprocessing helps to discriminate the sources of recalcitrance in grasses and paves the way for the recovery of p hydroxycinnamates, which have multiple applications. To address these subjects, we assessed sugarcane bagasse biorefining under alkaline-sulfite chemithermomechanical (AS-CTM) pretreatment and enzymatic saccharification. Results: The mass balances of the major bagasse components were combined with 2D NMR structural evaluation of process solids to advance our understanding of sugarcane bagasse changes during biorefining. AS-CTM pretreatment provided a high yield and thoroughly digestible substrates. The pretreated material was depleted in acetyl groups, but retained 62 and 79% of the original lignin and xylan, respectively. Forty percent of the total FAs and pCAs were also retained in pretreated material. After pretreatment and enzymatic hydrolysis, the residual solids contained mostly lignin and ester-linked pCAs, with minor amounts of FAs and non-digested polysaccharides. Saponification of the residual solids, at a higher alkali load, cleaved all the ester linkages in the pCAs; nevertheless, a significant fraction of the pCAs remained attached to the saponified solids, probably to lignin, through 4-O ether-linkages. Conclusion: AS-CTM pretreatment provided soundly digestible substrates, which retain substantial amounts of xylans and lignin. Acetyl groups were depleted, but 40% of the total FAs and pCAs remained in pretreated material. Ester-linked pCAs detected in pretreated material also resisted to the enzymatic hydrolysis step. Only a more severe saponification reaction cleaved ester linkages of pCAs from residual solids; nevertheless, pCAs remained attached to the core lignin through 4-O ether linkages, suggesting the occurrence of an alkali-stable fraction of pCAs in sugarcane bagasse. PMID- 29991962 TI - Genomic and proteomic analysis of lignin degrading and polyhydroxyalkanoate accumulating beta-proteobacterium Pandoraea sp. ISTKB. AB - Background: Lignin is a major component of plant biomass and is recalcitrant to degradation due to its complex and heterogeneous aromatic structure. The biomass based research mainly focuses on polysaccharides component of biomass and lignin is discarded as waste with very limited usage. The sustainability and success of plant polysaccharide-based biorefinery can be possible if lignin is utilized in improved ways and with minimal waste generation. Discovering new microbial strains and understanding their enzyme system for lignin degradation are necessary for its conversion into fuel and chemicals. The Pandoraea sp. ISTKB was previously characterized for lignin degradation and successfully applied for pretreatment of sugarcane bagasse and polyhydroxyalkanoate (PHA) production. In this study, genomic analysis and proteomics on aromatic polymer kraft lignin and vanillic acid are performed to find the important enzymes for polymer utilization. Results: Genomic analysis of Pandoraea sp. ISTKB revealed the presence of strong lignin degradation machinery and identified various candidate genes responsible for lignin degradation and PHA production. We also applied label-free quantitative proteomic approach to identify the expression profile on monoaromatic compound vanillic acid (VA) and polyaromatic kraft lignin (KL). Genomic and proteomic analysis simultaneously discovered Dyp-type peroxidase, peroxidases, glycolate oxidase, aldehyde oxidase, GMC oxidoreductase, laccases, quinone oxidoreductase, dioxygenases, monooxygenases, glutathione-dependent etherases, dehydrogenases, reductases, and methyltransferases and various other recently reported enzyme systems such as superoxide dismutases or catalase peroxidase for lignin degradation. A strong stress response and detoxification mechanism was discovered. The two important gene clusters for lignin degradation and three PHA polymerase spanning gene clusters were identified and all the clusters were functionally active on KL-VA. Conclusions: The unusual aerobic ' CoA'-mediated degradation pathway of phenylacetate and benzoate (reported only in 16 and 4-5% of total sequenced bacterial genomes), peroxidase-accessory enzyme system, and fenton chemistry based are the major pathways observed for lignin degradation. Both ortho and meta ring cleavage pathways for aromatic compound degradation were observed in expression profile. Genomic and proteomic approaches provided validation to this strain's robust machinery for the metabolism of recalcitrant compounds and PHA production and provide an opportunity to target important enzymes for lignin valorization in future. PMID- 29991963 TI - Regioselectivity of oxidation by a polysaccharide monooxygenase from Chaetomium thermophilum. AB - Background: Polysaccharide monooxygenases (PMOs) of the auxiliary activity 9 (AA9) family have been reported to oxidize C1, C4, and C6 positions in cellulose. However, currently no direct evidence exists that PMOs oxidize C6 positions in cellulose, and molecular mechanism of C1, C4 and C6 oxidation is unclear. Results: In this study, a PMO gene (Ctpmo1) belonging to AA9 was isolated from Chaetomium thermophilum and successfully expressed and correctly processed in Pichia pastoris. A simple and effective chemical method of using Br2 to oxidize CtPMO1 reaction products was developed to directly identify C4- and C6-oxidized products by matrix-assisted laser desorption/ionization-time-of-flight tandem mass spectrometry (MALDI-TOF-MS). The PMO (CtPMO1) cleaves phosphoric acid swollen cellulose (PASC) and celloheptaose, resulting in the formation of oxidized and nonoxidized oligosaccharides. Product identification shows that the enzyme can oxidize C1, C4, and C6 in PASC and cello-oligosaccharides. Mutagenesis of the aromatic residues Tyr27, His64, His157 and residue Tyr206 on the flat surface of CtPMO1 was carried out using site-directed mutagenesis to form the mutated enzymes Y27A, H64A, H157A, and Y206A. It was demonstrated that Y27A retained complete activity of C1, C4, and C6 oxidation on cellulose; Y206A retained partial activity of C1 and C4 oxidation but completely lost activity of C6 oxidation on cellulose; H64A almost completely lost activity of C1, C4, and C6 oxidation on cellulose; and H157A completely lost activity of C1, C4, and C6 oxidation on cellulose. Conclusions: This finding provides direct and molecular evidence for C1, C4, especially C6 oxidation by lytic polysaccharide monooxygenase. CtPMO1 oxidizes not only C1 and C4 but also C6 positions in cellulose. The aromatic acid residues His64, His157 and residue Tyr206 on CtPMO1 flat surface are involved in activity of C1, C4, C6 oxidation. PMID- 29991964 TI - Release of cell wall phenolic esters during hydrothermal pretreatment of rice husk and rice straw. AB - Background: Rice husk and rice straw represent promising sources of biomass for production of renewable fuels and chemicals. For efficient utilisation, lignocellulosic components must first be pretreated to enable efficient enzymatic saccharification and subsequent fermentation. Existing pretreatments create breakdown products such as sugar-derived furans, and lignin-derived phenolics that inhibit enzymes and fermenting organisms. Alkali pretreatments have also been shown to release significant levels of simple, free phenolics such as ferulic acid that are normally esterified to cell wall polysaccharides in the intact plant. These phenolics have recently been found to have considerable inhibitory properties. The aim of this research has been to establish the extent to which such free phenolic acids are also released during hydrothermal pretreatment of rice straw (RS) and rice husk (RH). Results: RS and RH were subjected to hydrothermal pretreatments over a wide range of severities (1.57 5.45). FTIR analysis showed that the pretreatments hydrolysed and solubilised hemicellulosic moieties, leading to an enrichment of lignin and crystalline cellulose in the insoluble residue. The residues also lost the capacity for UV autofluorescence at pH 7 or pH 10, indicating the breakdown or release of cell wall phenolics. Saponification of raw RS and RH enabled identification and quantification of substantial levels of simple phenolics including ferulic acid (tFA), coumaric acid (pCA) and several diferulic acids (DiFAs) including 8-O-4' DiFA, 8,5'-DiFA and 5,5'-DiFA. RH had higher levels of pCA and lower levels of tFA and DiFAs compared with RS. Assessment of the pretreatment liquors revealed that pretreatment-liberated phenolics present were not free but remained as phenolic esters (at mM concentrations) that could be readily freed by saponification. Many were lost, presumably through degradation, at the higher severities. Conclusion: Differences in lignin, tFA, DiFAs and pCA between RS and RH reflect differences in cell wall physiology, and probably contribute to the higher recalcitrance of RH compared with RS. Hydrothermal pretreatments, unlike alkali pretreatments, release cinnamic acid components as esters. The potential for pretreatment-liberated phenolic esters to be inhibitory to fermenting microorganisms is not known. However, the present study shows that they are found at concentrations that could be significantly inhibitory if released as free forms by enzyme activity. PMID- 29991965 TI - Application of chromosomal microarray to investigate genetic causes of isolated fetal growth restriction. AB - Background: Application of chromosomal microarray analysis (CMA) to investigate the genetic characteristics of fetal growth restriction (FGR) without ultrasonic structural anomalies at 18-32 weeks. Methods: This study includes singleton fetuses with the estimated fetal weight (EFW) using the formula of Hadlock C below the 10th percentile for gestational age. FGRs without structural anomalies were selected, and the ones at high risk of noninvasive prenatal testing for trisomy 13, 18 and 21 would be excluded. The cases were divided into two groups: early-onset group (< 24+ 0 weeks) and late-onset group (24-33 weeks). All patients were offered invasive prenatal testing with CMA and karyotype analysis. Results: CMA detected 10 pathogenic copy number variants and 2 variant of uncertain significance case. CMA has a 5.5% (7/127) incremental yield of pathogenic chromosomal abnormalities over karyotyping. The positive detected rate was 9.6% (5/52) in early-onset group and 9.3% (7/75) in late-onset group respectively. Conclusions: When FGR without structural anomaly is diagnosed before 33 weeks, an invasive prenatal procedure is strongly recommended. CMA can identify a 5.5% (7/127) incremental detection rate of pathogenic chromosomal abnormalities, which would impact clinical management for FGR. PMID- 29991966 TI - The PodPAD project: a podiatry-led integrated pathway for people with peripheral arterial disease in the UK - a pilot study. AB - Background: Peripheral arterial disease affects the lower limb and is associated with diabetes, high cholesterol, smoking and obesity. It increases the risk of cardiovascular morbidity and mortality. It can be symptomatic causing intermittent claudication, but often there are few clinical signs. Podiatrists are able to detect the presence of peripheral arterial disease as part of their lower limb assessment and are well placed to give advice on lifestyle changes to help reduce disease progression. This is important to improve health outcomes and is offered as a prevention/public health intervention. Method: We describe the clinical and patient-centred outcomes of patients attending a podiatry-led integrated care pathway in a multi-use clinic situated in a venue supported by the National Centre for Sports and Exercise Medicine in the UK. At the baseline appointment, patients were given a full assessment where symptoms of intermittent claudication using the Edinburgh Intermittent Claudication Questionnaire, foot pulses, Doppler sounds, Ankle Brachial Pressure Indices, glycated haemoglobin (HbA1c) and cholesterol levels, and smoking status were recorded. A tailored treatment plan was devised, including referral to an exercise referral service, smoking cessation programmes (if applicable) and each participant was also seen by a dietician for nutritional advice. Participants were followed up at 3 and 6 months to assess any improvement in vascular status and with each completing the EQ-5D quality of life questionnaire and a simple satisfaction questionnaire at the end of the study. As this was a complex intervention a pilot study design was adopted to evaluate if the method and outcomes were suitable and acceptable to participants the results of which will then inform the design of a larger study. Results: Data was collected on 21 individuals; 15 men (71.4%) and 6 women (28.6%) across the 6-month study period. Eleven participants were referred onto the exercise referral service; 16 participants saw the dietician for nutritional advice at baseline and had one-to-one or telephone follow-up at 3 months. Five out of 14 participants had reduced scores from baseline of intermittent claudication during the study period. No evidence for substantive changes in Doppler sounds or ABPI measurements was revealed. Quality of life scores with the EQ-5D improved in 15 participants; this was statistically significant (p = 0.007) with 14 participants who completed the simple satisfaction questionnaire expressing a positive view of the programme. Of the four people who were smokers, two stopped smoking cigarettes and moved to e-cigarettes as part of smoking cessation advice. Conclusion: As this was a pilot study the sample size was low, but some statistically significant improvements with some measures were observed over the 6-month study. Podiatrists are able to provide a comprehensive vascular assessment of the lower limb and accompanying tailored advice on lifestyle changes including smoking cessation and exercise. Locating clinics in National Centres for Sports and Exercise Medicine enables easy access to exercise facilities to encourage the adoption of increased activity levels, though the long term sustainability of exercise programmes still requires evaluation.This study was reviewed and approved by London Brent Ethics Committee IRAS ID 204611 and received research governance approval from the sponsor, Sheffield Teaching Hospitals NHS Foundation Trust Research and Innovation Office STH19410. PMID- 29991967 TI - T allele at ADIPOQ rs1501299 G/T polymorphism is more susceptible to the influence of circulating adiponectin on arterial stiffness in nondiabetic men. AB - Background: Low adiponectin levels are associated with increased insulin resistance (IR) and arterial stiffness in hypertensive patients, but higher adiponectin levels are also found in heart failure patients. This discrepancy has not been fully resolved, but it may be related to the adiponectin gene (ADIPOQ) which regulates adiponectin production. We aimed to investigate whether the relationship between adiponectin and arterial stiffness is associated with ADIPOQ rs1501299 G/T polymorphism in nondiabetic Korean men. Methods: In nondiabetic men without disease (n = 301), anthropometric parameters, lipid profiles, IR, circulating adiponectin, and brachial-ankle pulse wave velocity (baPWV) were measured. rs1501299 G/T polymorphism was also analyzed. Results: Circulating adiponectin levels were negatively correlated with baPWV and homeostatic model assessment-IR in the T allele carriers (n = 167), but this correlation was not observed in the GG subjects (n = 134). However, a positive correlation between baPWV and IR was observed in the GG subjects, but not in the T carriers. These patterns were maintained after the adjustment for confounding factors. A stepwise linear regression analysis revealed that circulating adiponectin and systolic blood pressure (BP) were the main influencing factors on baPWV levels in T carriers, but systolic BP, IR and age were the main contributors to increased baPWV levels in the GG subjects. Conclusions: This study demonstrates that the relationship between circulating adiponectin and arterial stiffness is different according to ADIPOQ rs1501299 G/T polymorphism, and suggests that T allele is more susceptible to the influence of adiponectin on arterial stiffness than GG homozygotes. This information may prove to be useful for personal-based early prevention and management of atherosclerotic risk. PMID- 29991968 TI - Correction to: Fetal growth is associated with CpG methylation in the P2 promoter of the IGF1 gene. AB - [This corrects the article DOI: 10.1186/s13148-018-0489-9.]. PMID- 29991969 TI - Promoter methylation of the MGAT3 and BACH2 genes correlates with the composition of the immunoglobulin G glycome in inflammatory bowel disease. AB - Background: Many genome- and epigenome-wide association studies (GWAS and EWAS) and studies of promoter methylation of candidate genes for inflammatory bowel disease (IBD) have demonstrated significant associations between genetic and epigenetic changes and IBD. Independent GWA studies have identified genetic variants in the BACH2, IL6ST, LAMB1, IKZF1, and MGAT3 loci to be associated with both IBD and immunoglobulin G (IgG) glycosylation. Methods: Using bisulfite pyrosequencing, we analyzed CpG methylation in promoter regions of these five genes from peripheral blood of several hundred IBD patients and healthy controls (HCs) from two independent cohorts, respectively. Results: We found significant differences in the methylation levels in the MGAT3 and BACH2 genes between both Crohn's disease and ulcerative colitis when compared to HC. The same pattern of methylation changes was identified for both genes in CD19+ B cells isolated from the whole blood of a subset of the IBD patients. A correlation analysis was performed between the MGAT3 and BACH2 promoter methylation and individual IgG glycans, measured in the same individuals of the two large cohorts. MGAT3 promoter methylation correlated significantly with galactosylation, sialylation, and bisecting GlcNAc on IgG of the same patients, suggesting that activity of the GnT-III enzyme, encoded by this gene, might be altered in IBD. The correlations between the BACH2 promoter methylation and IgG glycans were less obvious, since BACH2 is not a glycosyltransferase and therefore may affect IgG glycosylation only indirectly. Conclusions: Our results suggest that epigenetic deregulation of key glycosylation genes might lead to an increase in pro-inflammatory properties of IgG in IBD through a decrease in galactosylation and sialylation and an increase of bisecting GlcNAc on digalactosylated glycan structures. Finally, we showed that CpG methylation in the promoter of the MGAT3 gene is altered in CD3+ T cells isolated from inflamed mucosa of patients with ulcerative colitis from a third smaller cohort, for which biopsies were available, suggesting a functional role of this glyco-gene in IBD pathogenesis. PMID- 29991970 TI - Diagnostic Markers for Nonspecific Inflammatory Bowel Diseases. AB - The nonspecific inflammatory bowel diseases (IBD) represent a heterogeneous group of chronic inflammatory disorders of the gastrointestinal tract, and Lesniowski Crohn's disease (CD) and ulcerative colitis (UC) are among the two major clinical forms. Despite the great progress in understanding the pathogenesis of these diseases, their etiology remains unclear. Genetic, immune, and environmental factors are thought to play a key role. The correct diagnosis of nonspecific inflammatory bowel diseases as well as the determination of disease activity, risk stratification, and prediction of response to therapy still relies on a multidisciplinary approach based on clinical, laboratory, endoscopic, and histologic examination. However, considerable effort has been devoted to the development of an accurate panel of noninvasive biomarkers that have increased diagnostic sensitivity and specificity. Laboratory biomarkers useful in differentiating IBD with functional disorders and in evaluating disease activity, prognosis, and treatment selection for IBD are presented in this study. PMID- 29991971 TI - Functional similarities of microRNAs across different types of tissue stem cells in aging. AB - Restoration of tissue homeostasis by controlling stem cell aging is a promising therapeutic approach for geriatric disorders. The molecular mechanisms underlying age-related dysfunctions of specific types of adult tissue stem cells (TSCs) have been studied, and various microRNAs were recently reported to be involved. However, the central roles of microRNAs in stem cell aging remain unclear. Interest in this area was sparked by murine heterochronic parabiosis experiments, which demonstrated that systemic factors can restore the functions of TSCs. Age related changes in secretion profiles, termed the senescence-associated secretory phenotype, have attracted attention, and several pro- and anti-aging factors have been identified. On the other hand, many microRNAs are linked with the age dependent dysregulations of various physiological processes, including "stem cell aging." This review summarizes microRNAs that appear to play common roles in stem cell aging. PMID- 29991972 TI - Cadaveric Evaluation of Different Approaches for Quadratus Lumborum Blocks. AB - Background: A quadratus lumborum (QL) block is an abdominal truncal block technique that primarily provides analgesia and anaesthesia to the abdominal wall. This cadaveric study was undertaken to compare the dye spread between different needle approaches for ultrasound-guided QL blocks in soft-embalmed cadavers. Methods: After randomization, an experienced anesthesiologist performed two lateral, three posterior, and five alternative QL blocks on the left or right sides of five cadavers. The target injection point for the alternative approach was the lumbar interfascial triangle, same as that of conventional posterior QL block, with a different needle trajectory. For each block, 20 ml of dye solution was injected. The lumbar region and abdominal flank were dissected. Results: Ten blocks were successfully performed. Regardless of the approach used, the middle thoracolumbar fascia was deeply stained in all blocks, but the anterior layer was less stained. The alternative approach was more associated with spread of injectate to the transversus abdominis and transversalis fascia plane. Despite accurate needle placement, all lateral QL blocks were associated with a certain amount of intramuscular or subcutaneous infiltration. Two posterior QL blocks showed a deeply stained posterior thoracolumbar fascia, and one of them was associated with obvious subcutaneous staining. The subcostal, iliohypogastric, and ilioinguinal nerves were mostly involved, but the thoracic paravertebral space and lumbar plexus were not affected in all blocks. Conclusions: The alternative approach for QL blocks was able to achieve a comparable extent when compared to the conventional approach. PMID- 29991973 TI - Pseudoprogression of CNS metastatic disease of alveolar soft part sarcoma during anti-PDL1 treatment. AB - Immune checkpoint inhibitors are increasingly used in treatment of metastatic renal cell carcinoma, melanoma, and nonsmall cell lung cancer, as well as in clinical trials for novel targets. We present a pediatric patient with metastatic alveolar soft part sarcoma who was treated with MPDL3280 (Atezolizumab), a monoclonal anti-programmed death ligand-1 antibody. Imaging results for the patient suggested disease progression of multiple brain metastases with stable systemic disease. The patient met response evaluation criteria in solid tumors (RECIST) criteria of progression of disease and was removed from treatment with MPDL3280. Subsequent surgical resection of the brain lesions revealed nonviable tumor with extensive lymphocytic infiltrates consistent with pseudoprogression. This case report adds to a growing number of reports that question reliance on RECIST criteria and suggest need for further refinement of RECIST or irRECIST during immune checkpoint inhibitor treatment for central nervous system metastatic lesions. PMID- 29991974 TI - Protective Effect of Ginkgo biloba and Magnetized Water on Nephropathy in Induced Type 2 Diabetes in Rat. AB - We aimed in our current study to explore the protective effect of Ginkgo biloba (GB) and magnetized water (MW) against nephrotoxicity associating induced type 2 diabetes mellitus in rat. Here, we induced diabetes by feeding our lab rats on a high fat-containing diet (4 weeks) and after that injecting them with streptozotocin (STZ). We randomly divided forty rats into four different groups: nontreated control (Ctrl), nontreated diabetic (Diabetic), Diabetic+GB (4-week treatment), and Diabetic+MW (4-week treatment). After the experiment was finished, serum and kidney tissue samples were gathered. Blood levels of glucose, triglycerides, cholesterol, creatinine, and urea were markedly elevated in the diabetic group than in the control group. In all animals treated with GB and MW, the levels of urea, creatinine, and glucose were significantly reduced (all P < 0.01). GB and MW attenuated glomerular and tubular injury as well as the histological score. Furthermore, they normalized the contents of glutathione reductase and SOD2. In summary, our data showed that GB and MW treatment protected type 2 diabetic rat kidneys from nephrotoxic damages by reducing the hyperlipidemia, uremia, oxidative stress, and renal dysfunction. PMID- 29991975 TI - Acute Toxicity, Antioxidant, and Antifatigue Activities of Protein-Rich Extract from Oviductus ranae. AB - The paper investigated the preparation, amino acid composition, acute toxicity, and in vitro and in vivo antioxidant, coupled with in vivo antifatigue activities of protein-rich extract of Oviductus ranae (PEOR). The results indicated that PEOR possesses high-safety property with maximum tolerated dose (MTD) higher than 20 g/kg in mice, shows weak scavenging capacities against hydroxyl, superoxide anion, and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, as well as ferric reducing antioxidant power in vitro, but exerts strong antioxidant effect in ethanol-induced oxidative stress mice model; it can decrease malonaldehyde (MDA) and protein carbonyl (PCO) formation and increase total superoxide dismutase (T SOD) activity and glutathione (GSH) synthesis. Besides the strong in vivo antioxidant activity, PEOR in a dose of 400 mg/kg also has antifatigue effect in mice, and it can prolong the exhaustive swimming time, reduce the elevated blood urea nitrogen (BUN) and blood lactic acid (BLA) caused by intense exercise. The in vivo activity of PEOR may be contributed by its absorbed amino acids, due to the fact that eight antioxidant amino acids and twelve glucogenic ones were found in it. This study will provide an evidence for the clinical use of PEOR as a dietary supplement for antioxidant and antifatigue in the same oral dose (400 mg/kg). PMID- 29991977 TI - Corrigendum to "Searching for drug synergy in complex dose-response landscapes using an interaction potency model" [Comput. Struct. Biotechnol. J. 13 (2015) 504 513]. AB - [This corrects the article DOI: 10.1016/j.csbj.2015.09.001.]. PMID- 29991978 TI - A case of lipomembranous panniculitis with a dramatic response to the treatment of venous insufficiency. AB - Lipomembranous panniculitis (LP) is a peculiar type of fat necrosis and is reported with various clinical conditions, mostly with peripheral vascular diseases. Here, a case of a 57-year-old woman with a painful erythematous swelling of the right leg in association with venous insufficiency has been reported. Although LP is frequently associated with venous insufficiency, to the best of our knowledge, this is the first report on the beneficial effect of venous insufficiency treatment in LP. PMID- 29991976 TI - Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease. AB - Liver steatosis without alcohol consumption, namely, nonalcoholic fatty liver disease (NAFLD), is a common hepatic condition that encompasses a wide spectrum of presentations, ranging from simple accumulation of triglycerides in the hepatocytes without any liver damage to inflammation, necrosis, ballooning, and fibrosis (namely, nonalcoholic steatohepatitis) up to severe liver disease and eventually cirrhosis and/or hepatocellular carcinoma. The pathophysiology of fatty liver and its progression is influenced by multiple factors (environmental and genetics), in a "multiple parallel-hit model," in which oxidative stress plays a very likely primary role as the starting point of the hepatic and extrahepatic damage. The aim of this review is to give a comprehensive insight on the present researches and findings on the role of oxidative stress mechanisms in the pathogenesis and pathophysiology of NAFLD. With this aim, we evaluated the available data in basic science and clinical studies in this field, reviewing the most recent works published on this topic. PMID- 29991980 TI - Foscarnet-induced genital lesions: An overview with a case report. AB - Foscarnet is an important antiviral medication used mainly in the treatment of complicated Herpes-simplex virus and cytomegalovirus (CMV) infections. Reported first in the 1990's, genital ulcers are a potential side effect in about 10% of cases. We report the case of a 29 year old man with acute myelogenous leukemia who was on ganciclovir for CMV prophylaxis. Three weeks after being switched to foscarnet because of neutropenia, he developed two, painful symmetric ulcers on the inferior aspect of glans penis. Viral and bacterial cultures were negative. Two weeks after stopping the infusion of foscarnet, the ulcers subsided without any additional treatment. It is important that physicians be aware of this potentially disfiguring side effect of foscarnet so that methods of prevention can be implemented early in the treatment of these patients. PMID- 29991979 TI - Hidradenitis suppurativa in a patient with hyperandrogenism, insulin-resistance and acanthosis nigricans (HAIR-AN syndrome). AB - The author reports a rare presentation of hidradenitis supprutiva (HS) in combination with hyperandrogenism, insulin-resistance and acanthosis nigricans (HAIR-AN syndrome) in a female patient. Recently many clues have improved the understanding of HS as a systemic disease rather as a disease only with dermatological manifestation. This report might give another hint emphasizing the endocrinological and hormonal role in HS. PMID- 29991981 TI - Addition of Neostigmine and Tramadol to 1.5 % Lidocaine for paracervical block to reduce post-operative pain in colporrhaphy. AB - Pain is a complex and multi-faceted human perception and several factors could dampen the pain. Therefore, we aimed to comparison of addition of neostigmine and tramadol to 1.5 % lidocaine with paracervical block in reduce of post-operative pain in colporrhaphy. This study was a randomized and double-blind clinical trial for 108 patients' as candidate for colporrhaphy. Patients were randomly divided in three groups (Neostigmine, tramadol and control).We recorded pain in 2 and 6 and 12 hours after surgery, duration of analgesia and mean of use narcotic drug in 24 hours after surgery for all patients. Mean of narcotic drug used in 24 hours after surgery in neostigmine group was more than tramadol group(p=0/01).Pain in 2 and 6 and 12 hours after surgery in neostigmine group was more than tramadol group (p=0/01). Duration of analgesia in tramadol group was over neostigmine group and also, it was in neostigmine group was more than placebo (p=0/01).Taken together, tramadol could reduce pain in 2 and 6 and 12 hours after surgery and mean of narcotic drug used in 24 hours after surgery and increase duration of analgesia. PMID- 29991982 TI - Comparison of calcaneus joint internal and external fractures in open surgery and minimal invasive methods in patients. AB - Surgical management of calcaneal fractures has various complications. In recent years, minimally invasive surgeries have been utilized for a wide range of surgical procedures on different body parts significantly declining complications. This paper compares surgical outcomes of calcaneal fracture management between the open reduction and internal fixation technique (ORIF) and the MIS technique. In this randomized clinical trial forty patients with calcaneus fractures were randomly assigned to two equal groups; ORIF group and MIS group. Patients were followed for 1 year post-operatively. Gissane and Bohler's angles, AOFAS questionnaire, pain intensity, ability to conduct previous activities and various complications like wound healing complications and irritation with shoe wear were assessed in the final post-operative visit. Eventually data obtained from the two groups were compared. All patients obtained fracture union. Bohler's and Gissane angles significantly increased and decreased, respectively, after the operation in both groups (p?0.05), however, no significant difference was found between the two research groups. AOFAS scores and pain intensity was similar in both groups, however, surgical duration in the MIS group was significantly less than the ORIF group (P=0.021). Only one patient from the ORIF group was not able to resume his previous occupation. 12 patients from the ORIF group and five patients from the MIS group experienced irritation from shoe wear (p=0.025). In the ORIF group, 4 patients suffered from wound healing complications, however, none of the patients of the MIS group had wound complications (p=0.035). In conclusion, based on the results, it can be concluded that the MIS technique demonstrated better functional and radiographic outcomes as well as a more favorable complication profile, thus, it is recommended for the management of calcaneus fractures. PMID- 29991983 TI - Enteral diclofenac controls pain and reduces intravenous injection during extracorporeal shock wave lithotripsy. AB - Urinary system stones are the third most common disease of urinary system following urinary infection and prostate pathology. Extracorporeal shockwave lithotripsy (ESWL) is one of the methods used to treat Urolithiasis where shockwaves are transmitted through skin and body organs and crush the stones into small pieces. This is a painful procedure which usually requires analgesics. Each analgesic drug has its own advantages and disadvantages. The present research seeks to study the effectiveness of using diclofenac suppository in order to control pain and reduce need for venous drugs during ESWL procedure. This is a double blind clinical trial. 158 patients resorting to Shahid Hasheminezhad Specialized Center for ESWL were randomly selected to take part in this projects with due consideration of inclusion criteria. The patients were equally divided into the S (diclofenac suppository) and A (placebo) groups. 2 diclofenac suppositories were used in the S group 20 minutes prior to beginning ESWL. Then, ESWL was carried out in supine position using fluoroscopic conduction with standard method. The present research has studied pain scale of patients, operator's and patient's satisfaction during the operation and patient's hemodynamic parameters in three phases prior to, during, and after ESWL. SPSS v.17 was used to study the data and Chi-Square Tests and Repeated Measure ANOVA were used to analyze the results. The level of significance in the present research was set to P-value < 0.05.A review of pain scales across both groups showed that using diclofenac suppository has a significant influence in reducing the pain scale and, hence, need for venous drugs (P-value < 0.05). No significant difference was observed between the two groups in terms of heart beat and blood pressure changes in various times (P-value > 0.05). The results also report different satisfaction levels for patients and operators across the two groups (diclofenac suppository and placebo) (P-value < 0.05). Higher satisfaction levels were observed among both patients and operators in the group receiving diclofenac suppository. A general look at the data yields the conclusion that receiving pain killers (diclofenac suppository) before starting ESWL plays a more efficient role in reducing pain scales of patients and enhancing operators' satisfaction.. PMID- 29991984 TI - Analysis of correlation between estradiol and fracture of femur neck. AB - Osteoporosis is a major public health challenge all over the world. Estrogen hormone was cited amongst other hormones to be an efficient hormone for the production and maintenance of bone density. This study was designed with the purpose of evaluating and analyzing the estradiol effect on fractures of femur neck in the Iranian society. This study evaluated men over 50 years of age suffering with mild trauma (falling off the same level height or lower) and with a fracture on their femur neck. Also, their serum level of estradiol was measured with an ELISA method. Using this procedure, the patients were assigned into groups with either normal estradiol serum level (10pg/ml and higher) or with lower than normal level (lower than 10 pg/ml). A control group including 50-year old and older men without hip fracture, or its history, was chosen to access their estradiol serum level. Data collected from these two groups were statistically compared. A total of 120 patients were evaluated (60 in the control and 60 in the test group). The mean age of patients in the control and test groups were 67.9+/-10.22 and 69.5+/-8.84 years, respectively (p=0.376). Smoker patients' percentages in the control and test groups were 35% and 31.7%, respectively (p=0.699). On the basis of the serum estradiol level, patients' percentages with low estradiol level in control and test groups were 10% and 16.7%, respectively (p=0.283). The only significant factor in predicting serum estradiol level was smoking. In conclusion, in this study it was observed that fractures of the femoral neck following a mild trauma were not correlated to low level of serum estradiol. PMID- 29991985 TI - Mindfulness for female outpatients with chronic primary headaches: an internet based bibliotherapy. AB - Our aim was to investigate effectiveness of mindfulness by bibliotherapy on disability, distress, perceived pain and mindfulness in women with tension headaches and migraines. Primary headaches have been of great interest to mental health researchers because of the high prevalence, as well as significant disability and distress in the affected people. Despite the promising results of in-person treatment and some limitations that such interventions may cause, patients may be encountered with problems when using health care services. The present study is a quasi-experimental randomized design with pre-test, post-test, and control group. The study population consisted of 1396 women with migraine headache referring to headache clinic of Baqiyatallah Hospital in Tehran. Of these, 30 patients (including tboh experimental and control group) were selected by objective sampling method and were randomly assigned to the two groups. The experimental group, in addition to medical treatment as usual, was treated for a period of 8 sessions by Mindfulness-based Stress Reduction Internet-based Bibliotherapy, but the control group used only the medical treatment. The sample had no attritions. Data were collected by the four scales of (DASS-21), Migraine Disability Assessment Test (MIDAS), McGill's Short Form Questionnaire (MPQ-SF), and Mindfulness Inventory (MAAS). We used covariance analysis to analyze the findings in the measured scales. MBSR-IBB treatment had no significant effect on pain sensory dimension (P <0.44), despite improvement of mindfulness (P <0.0001). In contrast, the greatest effect was on the level of disability (P <0.0001). We observed also a significant improvement in distress (P <0.0001). In conclusion, in spite of the presence of headaches, the mindfulness improved the quality of life and reduced the level of mental distress. In addition, using the Internet based bibliotherapy method, these services can be used with easier access, lower cost, and more flexibility. PMID- 29991986 TI - Ultrasound as a diagnostic tool in the investigation of patients with carpal tunnel syndrome. AB - Carpal tunnel syndrome (CTS) is reveled to be the most common peripheral nerve entrapment syndrome, estimating for 90% of all compressive. The diagnosis of CTS is based on the use of clinical criteria and imaging technique tests such as ultrasonography (US) and magnetic resonance imaging (MRI). US is a time-saving method in the diagnosis of CTS, which induces less discomfort to the patient and may be a more cost-effective approach to confirm clinical suspicion of this syndrome .The current study was aimed to evaluate the value of US and physical examinations in the diagnosis of CTS. This cross-sectional and cross-sectional prospective case study was conducted to evaluate the usefulness of wrist ultrasonography in diagnosing CTS. Twenty one patients (21 wrists) were invited to participate in the study along with an age- and sex-matched group of participant controls. Physical examination included Phalen, Tinel, Durkan, Tourniquet test. Anteroposterior and mediolateral dimension of carpal tunnel, and the median nerve area at the tunnel were also measured. All the patients underwent the open surgical release of the flexor retinaculum. There was a significant statistical relationship (p=0.05) between anteroposterior diameter of the carpal tunnel and clinical and electro physiologic nerve involvement. Furthermore, some qualitative findings was achieved such as median nerve splitting, hypo echogenicity of the involved nerve, thickening of flexor retinaculum and disappearance of median nerve areas (especially mediolateral direction). In conclusion, ultrasonographic examination of the wrists in the patients with suspected clinical symptoms can improve the diagnostic ability of CTS, especially by improving technology and experience. US can be applied for the median nerve area (MNA) measurement as a first line technique in patients with CTS. PMID- 29991987 TI - Prevalence of muscular dystrophy in patients with muscular disorders in Tehran, Iran. AB - Muscular dystrophy is a group of diseases that is characterized by progressive muscle wasting and the weakness of variable distribution and severity. On the basis of the distribution of predominant muscle weakness, there are many different kinds of muscular dystrophy. Some dystrophies are especially frequent in certain populations. There are no studies on the prevalence of muscular dystrophy in Iran. This study was aimed to survey the prevalence of muscular dystrophy among Iranian patients with muscular disorders. This analytical cross sectional study was conducted on 1000 patients with musculoskeletal disorders who visited the dystrophy association of Bou-Ali Hospital (Tehran) from June 2014 to June 2016. Patients' data were extracted using a checklist that included age, gender, age of onset, family history, findings from clinical diagnostic tests and types of muscular dystrophy. The clinical findings were the results of genetic tests; EMG-NCV; para-clinical findings, including LDH and CPK; and pathological findings. All data were analyzed by SPSS V.22 (IBM Inc., NY) with Chi Square and One way ANOVA tests. All analyses were performed with P = 0.05 considered as the threshold of statistical significant. Out of the 337 patients studied, 262 (77.7%) were male and 75 (22.3%) were female. Subjects had a mean (+/- SD) age of 26.08 (+/- 11.86) years with an age range of 3 to 59 years. The most common types of muscular dystrophy were found to be Duchenne dystrophy (131 cases, 38.9%), limb-girdle dystrophy (91 cases, 27%), Becker dystrophy (58 cases, 17.2%), FSHD dystrophy (31 cases, 9.2%), and SMA (26 cases, 7.7%), respectively. The results showed that a statistically significant relationship between dystrophy types and gender, age, family history, age of diagnosis, CPK and LDH levels (P < 0.001). There were no statistical relationship between dystrophy types and pathological findings (P = 0.57), EMG-NCV test results (P = 0.062), and genetic findings (P = 0.06). Since muscular dystrophies often appear during the first decade of life, any information in regard to their prevalence can contribute to better planning and provisioning of required services, as well as better treatment or control of the condition. The results also showed that genetic tests, para-clinical tests, pathology analysis, and EMG-NCV tests can serve as good diagnostic tools for different varieties of dystrophy. Thus, facilitation of these diagnostic tests, particularly the genetic tests, can lead to a faster and more accurate diagnosis of dystrophy, especially in people with a family history of the disease. PMID- 29991988 TI - Frequency of symptoms associated with gallstone disease: a hospital-based cross sectional study. AB - This study investigated the likely outcomes of gallstone disease and frequency of symptoms associated with this. This cross sectional study was performed at the Aliebn Abitaleb hospital in Rafsanjan over a period of twelve months from 2000 to 2001. A total sample of 70 individuals were included in the study, interviewing them using of a questionnaire covering data in terms of demographic features and medical history.The majority of patients belonged to the age group of 41 to 60 years (44.3% of all patients), while the lowest frequency was in the age group of 20 years or less. Frequency of females was higher than males. The frequency of female patients increased with the number of child birth, the highest being in women who had more than 5 child births. The most common complaint of pain was revealed as upper right abdominal quadrant (RUQ), which accounted for 95.7% of cases. Vomiting was observed in 52.9% of patients. In addition, the frequency of patients with chronic pain initiation was more than those with acute pain initiation. Among women, 17.5% had oral contraceptive pill constipation. It is worth noting that ultrasonography was the best diagnostic tool for evaluating patients. It is noteworthy that the most common symptom was right upper quadrant tenderness. Our data indicate that diabetes was the most common illness associated with gallstone disease and that 8.6% of patients had a family history of gallstone disease. PMID- 29991989 TI - Studying the expression rate and methylation of Reprimo gene in the blood of patients suffering from gastric cancer. AB - As gastric cancer has no exclusive signals in its initial phases, it is usually diagnosed in advanced phases. Although many researches have been conducted on methylation and diagnosis of cancer's markers, the methylation and expression of Reprimo gene and its correlation with gastric cancer has not been thoroughly studied. Methylation of Reprimo promoter is a repetitive procedure exclusive to cancer which nullifies its expression and performance. The present research seeks to study the expression and methylation of Reprimo among people suffering with gastric cancer so that it may be used as a biomarker for early diagnosis. Fifty blood samples taken from healthy people (normal samples) and 50 blood samples obtained from gastric cancer patients were analyzed using Real-Time PCR. The methylation status of the promoter of Reprimo was studied using Methylation Specific PCR technique in normal samples and in gastric cancer Iranian patients. We observed reduction in expression rate of Reprimo in the blood samples of patients suffering with gastric cancer in comparison to normal blood samples. A significant correlation was also observed between the expression rate of this gene, age and methylation of its promoter among patients suffering with gastric cancer and various analysis points to a correlation between reduced expressions of Reprimo gene in gastric cancer patients. In conclusion, reduced expression of Reprimo gene and greater levels of methylation of its promoter seems to be promising biomarkers for early diagnosis of gastric cancer. PMID- 29991990 TI - Culture conditions influence satellite cell activation and survival of single myofibers. AB - Single myofiber isolation protocols allow to obtain an in vitro system in which the physical association between the myofiber and its stem cells, the satellite cells, is adequately preserved. This technique is an indispensable tool by which the muscle regeneration process can be recapitulated and studied in each specific phase, from satellite cell activation to proliferation, from differentiation to fusion. This study aims to clarify the effect of different culture conditions on single myofibers, their associated satellite cells, and the physiological behavior of the satellite cells upon long term culture. By direct observations of the cultures, we compared different experimental conditions and their effect on both satellite cell behavior and myofiber viability. PMID- 29991991 TI - Chemotherapy-induced muscle wasting: an update. AB - The majority of cancers are associated to cachexia, a severe form of weight loss mostly accounted for by skeletal muscle wasting. Cancer patients are often treated with chemotherapy, whose side effects are at times neglected or underestimated. Paradoxically, chemotherapy itself can induce muscle wasting with severe, cancer-independent effects on muscle homeostasis. Since muscle wasting is a primary marker of poor prognosis for cancer patients and negatively affects their quality of life, the systemic consequences of chemotherapy in this context must be fully characterized and taken into account. Ten years ago a precursor study in an animal cancer model was published in the European Journal of Translation Myology (back then, Basic and Applied Myology), highlighting that the side effects of chemotherapy include muscle wasting, possibly mediated by NF kappaB activation. This paper, entitled "Chemotherapy-induced muscle wasting: association with NF-kappaB and cancer cachexia", is now being reprinted for the inaugural issue of the "Ejtm Seminal Paper Series". In this short review we discuss those results in the light of the most recent advances in the study of chemotherapy-induced muscle wasting. PMID- 29991993 TI - Implementing EjtM3 (European Journal of Translational Myology, Mobility, Medicine) along the silk-road. AB - Two main novelties will appear in the second 2018 Issue of the European Journal of Translational Myology demonstrating that the journal is vital and in expansion, one novelty is that the journal is implementing its authorship and readership to broader clinical fields from muscle myology and mobility to clinical medicine and surgery. Consequently, the Editorial Board is also expanding to allow a broader expert evaluation of Authors submitted typescripts. The expanded Editorial Board recently evaluated the option to change the name of the journal from Ejtm to EjtM3 (Myology, Mobility, Medicine), in order to expand the original journal title meaning. Another important novelty is the first BAM Seminal Paper by Damraurer et al. 18(5): 139-148, 2008. It is now reprinted (with Basic and Applied Myology permission) in this Ejtm 28(2), 2018. The topic (chemotherapy-induced muscle wasting) was up-dated by one of our Editors stressing the relevance of the BAM 2008 paper to focus attention not only of myologists, but also of oncologists. From 2008, BAM (renamed from 2010 European Journal of Translational Myology) went far beyond the limits of pure Myology. Al last, but hopefully not at least, a series of Rapid Reports from Iranian Authors are paving the pathway Venetia-extreme Orient, along the ancient silk-road. Ejtm will enthusiastically publish clinical activities from surrounding and extreme Orient. The Marco Polo tradition and his bravery seem successfully continuing. PMID- 29991992 TI - Chemotherapy-induced muscle wasting: association with NF-kappaB and cancer cachexia. AB - A compounding feature of greater than 50% of all cancers is the high incidence of the cachexia syndrome, a complex metabolic disorder characterized by extreme weight loss due mainly to the gross depletion of skeletal muscle tissue. Although studies into the cause of cancer cachexia has spanned over multiple decades, little is known about the effects of various cancer treatments themselves on cachexia. For example, chemotherapy agents induce side effects such as nausea and anorexia, but these symptoms do not fully account for the changes seen with cancer cachexia. In this study we examine the effects of chemotherapeutic compounds, specifically, cisplatin in the colon-26 adenocarcinoma model of cancer cachexia. We find that although cisplatin is able to reduce tumor burden as expected, muscle wasting in mice nevertheless persists. Strikingly, cisplatin alone was seen to regulate muscle atrophy, which was independent of the commonly implicated ubiquitin proteasome system. Finally, we show that cisplatin is able to induce NF-kappaB activity in both mouse muscles and myotube cultures, suggesting that an additional side effect of cancer treatment is the regulation of muscle wasting that may be mediated through activation of the NF-kappaB signaling pathway. PMID- 29991994 TI - Asymmetric hearing loss and chronic dizziness in a patient with idiopathic normal pressure hydrocephalus. AB - We report a case of a 54-year old female patient, complaining for chronic dizziness, hearing loss, tension headaches without aura, postural instability and gait dysfunction. The patient referred having these symptoms from 1992, but the last few months she experienced a noticeable aggravation of the symptoms. A magnetic resonance imaging test revealed a triventricular hydrocephalus, not associated with signs of intracranial hypertension decompensation. The ENT Audiology evaluation revealed a bilateral sensorineural hearing loss with a conductive component, video-nystagmography resulted in an areflexia of the right ear and a reduced vestibular activity for the left ear. Auditory brainstem response test was also carried out and showed pathologic findings for the latencies of the waves I-III, III-V and I-V bilaterally but more significant in the right ear. On January 2016 the patient had endoscopic third ventriculostomy. On the follow up the patient referred an important subjective improvement regarding instability and gait dysfunction. In this paper we study the correlation between hydrocephalus, hearing loss and vestibular dysfunction. PMID- 29991995 TI - Evaluating the Effects of Kinesthetic Biofeedback Delivered Using Reaction Wheels on Standing Balance. AB - Aging, injury, or ailments can contribute to impaired balance control and increase the risk of falling. Provision of light touch augments the sense of balance and can thus reduce the amount of body sway. In this study, a wearable reaction wheel-based system is used to deliver light touch-based balance biofeedback on the subject's back. The system can sense torso tilt and, using reaction wheels, generates light touch. A group of 7 healthy young individuals performed balance tasks under 12 trial combinations based on two conditions each of standing stance and surface types and three of biofeedback device status. Torso tilt data, collected from a waist-mounted smartphone during all the trials, were analyzed to determine the efficacy of the system. Provision of biofeedback by the device significantly reduced RMS of mediolateral (ML) trunk tilt (p < 0.05) and ML trunk acceleration (p < 0.05). Repeated measures ANOVA revealed significant interaction between stance and surface on reduction in RMS of ML trunk tilt, AP trunk tilt, ML trunk acceleration, and AP trunk acceleration. The device shows promise for further applications such as virtual reality interaction and gait rehabilitation. PMID- 29991996 TI - Comparison between High- and Low-Cost Transmission of Tele-Anesthesia in Japan. AB - Background: We previously reported a tele-anesthesia system that connected Sado General Hospital (SGH) to Yokohama City University Hospital (YCUH) using a dedicated virtual private network (VPN) that guaranteed the quality of service. The study indicated certain unresolved problems, such as the high cost of constantly using a dedicated VPN for tele-anesthesia. In this study, we assessed whether use of a best-effort system affects the safety and cost of tele anesthesia in a clinical setting. Methods: One hundred patients were enrolled in this study. We provided tele-anesthesia for 65 patients using a guaranteed transmission system (20 Mbit/s; guaranteed, 372,000 JPY per month: 1 JPY = US$0.01) and for 35 patients using a best-effort system (100 Mbit/s; not guaranteed, 25,000 JPY per month). We measured transmission speed and number of commands completed from YCUH to SGH during tele-anesthesia with both transmission systems. Results: In the guaranteed system, anesthesia duration was 5780 min (88.9 min/case) and surgical duration was 3513 min (54.0 min/case). In the best effort system, anesthesia duration was 3725 min (106.4 min/case) and surgical duration was 2105 min (60.1 min/case). The average transmission speed in the best effort system was 17.3 +/- 3.8 Mbit/s. The system provided an acceptable delay time and frame rate in clinical use. All commands were completed, and no adverse events occurred with both systems. Discussion: In the field of tele-anesthesia, using a best-effort internet VPN system provided equivalent safety and efficacy at a better price as compared to using a guaranteed internet VPN system. PMID- 29991998 TI - Surgical treatment of mucocele of the appendix: a systematic review and case report. AB - Introduction: Appendicular mucocele is a rare well-described clinico-pathological occurrence. It denotes an obstructive dilatation of the appendicular lumen by mucinous secretions. Case report: A 60-year-old patient presented with right lower abdominal pain and nausea for 2 years. Abdominal CT scan suggested a diagnosis of a appendicular mucocele. Following informed consent, surgical exploration revealed a cystic mass arising from the body of the appendix with inflamed walls with no evidence of perforation. Simple appendectomy was performed as the caecum and the mesenteric nodes were free of pathological involvement. The final diagnosis of mucinous cystadenoma was confirmed by histopathology. Postoperative course was uneventful. The patient was in good health during a four years regular follow-up. Discussion: Appendicular mucocele is a rare disease with vague symptoms. Abdominal imaging is an important diagnostic tool, but histopathology is the standard for definitive diagnosis. Surgery for benign appendicular mucoceles has an excellent long-term prognosis. PMID- 29991997 TI - Functional traits partially mediate the effects of chronic anthropogenic disturbance on the growth of a tropical tree. AB - Understanding how trees mediate the effects of chronic anthropogenic disturbance is fundamental to developing forest sustainable management strategies. The role that intraspecific functional diversity plays in such process is poorly understood. Several tree species are repeatedly defoliated at large scale by cattle breeders in Africa to feed livestock. In addition, these tree species are also debarked for medicinal purposes. These human-induced disturbances lead to biomass loss and subsequent decline in the tree growth. The main objective of this work is to investigate how functional traits mediate tree response to chronic anthropogenic disturbance. We used a unique data set of functional traits and growth rate of 503 individual tree of Afzelia africana. We collected data on leaf mass per area (LMA), wood density (WD) and growth rate, and recorded history of human disturbances (debarking, pruning) on individual tree from 12 populations of A. africana distributed in two ecological zones in Benin (West Africa). We tested the effect of disturbances on absolute growth rate across ontogenetic stages, assessed the role of intraspecific trait variability on growth and tested the role of tree functional strategy on the tree growth response to debarking and pruning. We found that debarking did not affect stem growth, suggesting a fast compensatory regrowth of bark wounded. Moreover, tree response to debarking was independent of the functional strategy. By contrast, we found that pruning reduced tree absolute growth; however, trees with low WD were more strongly affected by pruning than trees with high WD. Our results emphasize the importance for plant functioning of the interplay between the availability of leaves for resource acquisition and a resilience strategy by mobilizing stored resources in stem wood to be reinvested for growth under severe disturbances. PMID- 29991999 TI - Sodium polystyrene sulfonate crystals in the gastric wall of a patient with upper gastrointestinal bleeding and gastric perforation: an incidental finding or a pathogenic factor? AB - Sodium polystyrene sulfonate, or Kayexalate, is an ion-exchange resin used to treat hyperkalemia. It is sometimes used with sorbitol, an osmotic laxative that prevents constipation. Small and large bowel necrosis and perforation due to Kayexalate were previously reported. However, no previous cases of gastric perforation were described. We present a case of gastric perforation in a 48-year old patient, with chronic kidney disease (CKD), lung transplant under chronic corticosteroids, and two previous Nissen fundoplications. He presented with sudden epigastralgia, hematemesis and hemodynamic instability. Esophagogastroduodenoscopy was not able to localize the site of bleeding. Surgical exploration revealed perforation of the lesser curvature of the stomach. Antrectomy with a Billroth II reconstruction was performed. Pathological examination revealed no abnormalities except fibrinoleukocytic debris with Kayexalate crystals in the gastric wall. Kayexalate is believed to be a trigger for the gastric injury in a patient with tissues impaired by corticosteroids, CKD and immunosuppressors. PMID- 29992000 TI - Hydroxyapatite implantation for the repair of a congenital nasal anomaly: 10 years follow-up. AB - Frontonasal dysplasia is a rare congenital anomaly characterized by ocular hypertelorism, a broad nasal root, and vertical median cleft of the nose and/or upper lip and palate. We report a case of frontonasal dysplasia in which hydroxyapatite was used to treat a nasal deformity in early childhood. In the 10 years of follow-up of our case, there were no complications such as infection, malpositioning, or exposure, and computed tomography revealed no resorption or malpositioning of the implant. Hydroxyapatite implants may be a viable alternative to autologous bone/cartilage grafts for the repair of congenital nasal anomalies until nasal development is completed. PMID- 29992001 TI - Prolapsed fundic gastric polyp causing gastroduodenal intussusception and acute pancreatitis. AB - An 86-year-old female presented with a 6-month history of recurrent intermittent epigastric abdominal pain, postprandial fullness with nausea, vomiting, anemia and a 15-pound weight loss. A large fundic gastric polyp was intussuscepting into the duodenum causing intermittent compression and obstruction of the ampulla of Vater leading to acute pancreatitis. An overview of the clinical presentation, diagnosis and management of this entity, in addition to a review of the literature is provided. PMID- 29992002 TI - Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the external auditory canal, an unusual presentation in an adult female: a case report. AB - INTRODUCTION: Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare entity that usually occurs as 0.5-3 cm, pink-to-brown nodules on the skin surface and subcutaneous tissues of the head and neck (Al-Muharraqi MA, Faqi MK, Uddin F, Ladak K, Darwish A. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the face: an unusual presentation. Int J Surg Case Rep 2011;2:258 60.; Suzuki H, Hatamochi A, Horie M, Suzuki T, Yamazaki S. A case of angiolymphoid hyperplasia with eosinophilia (ALHE) of the upper lip. J Dermatol 2005; 32:991-5.). CASE PRESENTATION: A 29-year-old woman presented to our ENT (ear-nose-throat) clinic with multiple, small reddish to pinkish nodules of approximately 1 * 2 cm2 in dimension. A biopsy from the surface of the left external auditory canal skin, where she had severe itching, showed features consistent with Angiolymphoid hyperplasia with eosinophilia ALHE. DISCUSSION: Whether angiolymphoid hyperplasia with an eosinophilia etiology is a neoplastic or atopic hypersensitivity reaction (unusual reactive process) is controversial. The definitive treatment is surgical excision and follow-up (Al-Muharraqi MA, Faqi MK, Uddin F, Ladak K, Darwish A Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) of the face: An unusual presentation. Int J Surg Case Rep 2011;2:258-60.; Barnes L, editor. Surgical Pathology of the Head and Neck. 3rd edn. New York: Marcel Decker; 2001.). CONCLUSION: Although ALHE of <3 cm has been rarely reported in the literature, it should be considered in the differential diagnosis of large subcutaneous tumors of the head and neck. PMID- 29992003 TI - Multidisciplinary management of complicated bilateral renal artery aneurysm in a woman of childbearing age. AB - Ruptured renal artery aneurysm (RAA) during pregnancy is a rare condition associated with high mortality rates to both the mother and the foetus. We report on a 41-year-old woman at her second trimester who presented with shock to the emergency department as a result of a ruptured left RAA. While the bleeding was successfully treated with angiographic embolization, a contralateral RAA, also at risk of rupture, was discovered. Due to its position on the artery bifurcation, this lesion was considered not suitable for interventional radiology and was therefore managed by hand-assisted retroperitoneoscopic nephrectomy, ex-vivo repair and autotransplantation. This was done in order to preserve renal mass and give our patient a chance of having future pregnancies without risk of rupture. Three years later, her renal function is normal, there is no evidence of recurrence, and more importantly she had two successful and uncomplicated pregnancies. PMID- 29992004 TI - Appendicular schwannoma presenting as vague abdominal pain. AB - Appendicular schwannomas are very rare condition with nonspecific clinical symptoms and frequently recognized during pathological examination. They arise less frequently in the gastrointestinal tract and comprise ~1% of all malignant gastrointestinal tumours. We presented a rare case of an appendicular schwannoma that was discovered incidentally in a 25-year-old student diagnosed with appendicular mucocoele with a suspected obstructing tumoural lesion based on computed tomography findings. A colonoscopy examination showed a bulging, nodular, erythematous lesion at the base of the caecum (appendiceal orifice). Biopsies showed mixed inflammatory infiltration in the lamina propria, with lymphoid-filled formations. No evidence of dysplasia or neoplasia. Tumour markers were negative. Appendicular neoplasms, such as schwannomas of the appendix, are rarely associated with nonspecific clinical symptoms and are frequently recognized during pathological examination of the resected appendix. Laparoscopic surgery with a clear resection margin is the cornerstone of treatment for appendicular schwannoma, and it is associated with a favourable prognosis. PMID- 29992005 TI - Intussusception secondary to descending colon lipoma presenting with simultaneous acute appendicitis. AB - We report a patient with a descending colon lipoma presenting with hematochezia who developed intussusception, which was simultaneously accompanied by acute appendicitis. A 43-year-old man presented with hematochezia. Colonoscopy revealed a submucosal tumor with a reddish surface in the descending colon. A solid mass with fat density value measuring 5 cm in diameter was observed in the descending colon on CT. While awaiting elective resection, the patient developed lower abdominal pain. CT demonstrated antegrade colo-colonic intussusception in the descending colon. Simultaneously, the appendix was inflamed with a high density intraluminal lesion suspected to be a fecalith. The diagnosis of simultaneous intussusception and acute appendicitis was made. Appendectomy and partial resection of the descending colon was performed. Histopathological examination was consistent with descending colon lipoma and acute appendicitis. The mechanism for developing hematochezia and the risk for development of colo-colonic intussusception due to large colon lipoma and acute appendicitis were highlighted. PMID- 29992006 TI - Gallstone ileus 1 year after cholecystectomy. AB - Post-cholecystectomy gallstone ileus (GSI) is very rare with only 16 cases reported in the literature. This condition poses diagnostic challenges both because of its rarity and since the gallbladder had been previously removed. A high index of suspicion is needed for diagnosis. We report a case of a 37-year old female who presented with GSI 12 months post-cholecystectomy. PMID- 29992007 TI - Thalamic germinoma: a challenging diagnosis, case report and literature review. AB - The thalamus and basal ganglia are unusual locations for an intracranial germ cell tumors. We are reporting a rare case of thalamic germinoma in an 18-year-old male. Challenging presentation, radiological appearance and pathological finding after surgical intervention delayed the diagnosis and treatment. Also, we are providing an extensive literature review. Diagnosis of thalamic germinoma is challenging because of non-specific symptoms, rare location and inconclusive radiological findings. An early tissue diagnosis associated with good outcome. PMID- 29992008 TI - Complete small bowel obstruction without intussusception due to a submucosal lipoma. AB - Submucosal lipomas of the small bowel are rare, often asymptomatic, benign tumors. Large lesions may present with acute symptoms such as a bowel obstruction from an intussusception or acute hemorrhage. Acute findings such as these require operative intervention. In this case, we present a 53-year-old female with a complete small bowel obstruction secondary to a submucosal lipoma without signs of an intussusception. PMID- 29992009 TI - Small bowel gastrointestinal stromal tumor disguised as an adnexal mass: a source for midgut volvulus. AB - BACKGROUND: The abdominal cavity has an infinite number of potential pathologies and gynecologic pathology is often intertwined with intestinal disease. CASE PRESENTATION: A 74-year-old female believed to have an adnexal mass on prior imaging presented with small bowel obstruction, which failed to resolve with non operative management. Given her suspected adnexal mass, multidisciplinary operative intervention was arranged. She was found to have a large, extraluminal mass on her small intestines; serving as the lead point for her midgut volvulus and resultant small bowel obstruction. CONCLUSION: Physical exam and radiographic discordance should prompt consideration of alternative diagnoses. Making the appropriate initial diagnosis is key in correct patient management; however, this is not always possible and appropriate pre-operative planning should be arranged for best patient outcomes. PMID- 29992010 TI - Gallbladder duplication and cholecystitis. AB - Cholecystitis is a common gallbladder pathology characterized by abdominal pain, positive Murphy sign and elevated white blood count. Abdominal ultrasound usually gives a definite diagnosis. Duplication of the gallbladder is a rare congenital anomaly that can either be asymptomatic or and can present with symptoms associated with cholelithiasis, cholecystitis, cholangitis or pancreatitis. Clinically indistinguishable from regular gallbladder pathologies. The management of duplicated gallbladder is similar to that of other gallbladder diseases, if one or both gallbladders cause symptoms, cholecystectomy should be done for both gallbladders. We present a case of a 50-year-old female patient, she presented to the emergency room with abdominal pain and tenderness. Ultrasound detected a gallbladder duplication with cholecystitis in one of them and magnetic resonance cholangiopancreatography confirmed this diagnosis. Surgery was decided and the patient underwent full recovery. Y-shaped gallbladder duplication with cholecystitis due to cholelithiasis in one of them was the final diagnosis. PMID- 29992011 TI - Small bowel obstruction as a result of an obturator hernia: a rare cause and a challenging diagnosis. AB - Obturator hernias are exceedingly rare in surgical routine, constituting 0.073% of all intra-abdominal hernias in the West and 1% in the far East. Commonly known as 'little old lady's hernia', obturator hernias are usually seen in frail, octogenarian multiparous women. This case report discusses an 85-year-old female who had symptoms of acute bowel obstruction; thanks to high degree of clinical suspicion and aided by a computed tomography (CT) of abdomen and pelvis, an incarcerated right obturator hernia was diagnosed preoperatively and treated successfully. Obturator hernia is a rare condition associated with a high rate of morbidity and mortality. CT scan is the most accurate imaging method for pre operative diagnosis. Early diagnosis and surgical intervention are fundamentals to lead to better outcomes for the patients. PMID- 29992012 TI - Parasitic leiomyoma of the greater omentum presenting as small bowel obstruction. AB - Parasitic leiomyomas (PL) are rare intra-abdominal tumors usually found in young women and are considered a type of uterine leiomyomas. They are usually reported in women who underwent laparoscopic morcellation of fibroids and frequently present with symptoms such as abdominal pain and distention. Treatment usually involves en bloc removal of the mass after dividing its blood supply from the host organ. In this case report, we describe the case of a middle-aged female who developed high-grade small bowel obstruction due to compression from a large PL with blood supply from the greater omentum. The patient underwent operative resection of the PL and subsequently fared very well. Meticulous attention to blood supply and attachments of PL to host organs is necessary for safe resection. PMID- 29992013 TI - Reversible rituximab-induced rectal Kaposi's sarcoma misdiagnosed as ulcerative colitis in a patient with HIV-negative follicular lymphoma. AB - Background: Kaposi's sarcoma is a low-grade mesenchymal angioproliferative tumor, most commonly observed in immunocompromised individuals, such as HIV-infected patients. Iatrogenic Kaposi's sarcoma occurs in patients undergoing immunosuppressive therapies. Rituximab is a chimeric monoclonal antibody targeted against the pan B cell marker CD20. Because of its immunosuppressive effects through reduction of mature B-cells, it may exacerbate Kaposi's sarcoma in HIV positive patients. Rituximab-related Kaposi's sarcomas have been previously reported in only two HIV-negative patients and were treated surgically. Case presentation: Here, we report on a Kaposi's sarcoma that developed under rituximab treatment in a HIV-negative 55-year-old patient treated for follicular lymphoma. The lesion developed during the maintenance rituximab therapy at the rectal level with an aspect of apparent ulcerative colitis, without any cutaneous lesion. The premature stop of rituximab led to the complete regression of Kaposi's sarcoma, without any additional specific treatment. Conclusions: To our knowledge, this is the third case of Kaposi's sarcoma diagnosed under rituximab in a HIV-negative patient, the first one at the rectal level and the first one that completely regresses after stop of rituximab. This case raises awareness of iatrogenic Kaposi's sarcoma in HIV-negative patients treated with rituximab, and further highlights the importance of immunosuppression in the pathophysiology of disease. PMID- 29983910 TI - Hepatic deletion of p110alpha and p85alpha results in insulin resistance despite sustained IRS1-associated phosphatidylinositol kinase activity. AB - Background: Class IA phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) is an integral mediator of insulin signaling. The p110 catalytic and p85 regulatory subunits of PI3K are the products of separate genes, and while they come together to make the active heterodimer, they have opposing roles in insulin signaling and action. Deletion of hepatic p110alpha results in an impaired insulin signal and severe insulin resistance, whereas deletion of hepatic p85alpha results in improved insulin sensitivity due to sustained levels of phosphatidylinositol (3,4,5)-trisphosphate. Here, we created mice with combined hepatic deletion of p110alpha and p85alpha (L-DKO) to study the impact on insulin signaling and whole body glucose homeostasis. Methods: Six-week old male flox control and L-DKO mice were studied over a period of 18 weeks, during which weight and glucose levels were monitored, and glucose tolerance tests, insulin tolerance test and pyruvate tolerance test were performed. Fasting insulin, insulin signaling mediators, PI3K activity and insulin receptor substrate (IRS)1-associated phosphatidylinositol kinase activity were examined at 10 weeks. Liver, muscle and white adipose tissue weight was recorded at 10 weeks and 25 weeks. Results: The L-DKO mice showed a blunted insulin signal downstream of PI3K, developed markedly impaired glucose tolerance, hyperinsulinemia and had decreased liver and adipose tissue weights. Surprisingly, however, these mice displayed normal hepatic glucose production, normal insulin tolerance, and intact IRS1-associated phosphatidylinositol kinase activity without compensatory upregulated signaling of other classes of PI3K. Conclusions: The data demonstrate an unexpectedly overall mild metabolic phenotype of the L-DKO mice, suggesting that lipid kinases other than PI3Ks might partially compensate for the loss of p110alpha/p85alpha by signaling through other nodes than Akt/Protein Kinase B. PMID- 29983921 TI - Role of extracellular matrix in breast cancer development: a brief update. AB - Evidence is increasing on the crucial role of the extracellular matrix (ECM) in breast cancer progression, invasion and metastasis with almost all mortality cases owing to metastasis. The epithelial-mesenchymal transition is the first signal of metastasis involving different transcription factors such as Snail, TWIST, and ZEB1. ECM remodeling is a major event promoting cancer invasion and metastasis; where matrix metalloproteinases (MMPs) such as MMP-2, -9, -11, and 14 play vital roles degrading the matrix proteins for cancer spread. The beta-D mannuronic acid (MMP inhibitor) has anti-metastatic properties through inhibition of MMP-2, and -9 and could be a potential therapeutic agent. Besides the MMPs, the enzymes such as LOXL2, LOXL4, procollagen lysyl hydroxylase-2, and heparanase also regulate breast cancer progression. The important ECM proteins like integrins (b1-, b5-, and b6- integrins), ECM1 protein, and Hic-5 protein are also actively involved in breast cancer development. The stromal cells such as tumor associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and adipocytes also contribute in tumor development through different processes. The TAMs become proangiogenic through secretion of VEGF-A and building vessel network for nourishment and invasion of the tumor mass. The latest developments of ECM involvement in breast cancer progression has been discussed in this review and this study will help researchers in designing future work on breast cancer pathogenesis and developing therapy targeted to the ECM components. PMID- 29992016 TI - Carbapenem non-susceptibility of Klebsiella pneumoniae isolates in hospitals from 2011 to 2016, data from the German Antimicrobial Resistance Surveillance (ARS). AB - Background: Carbapenem resistance in Klebsiella pneumoniae is of significant public health concern and recently spread across several countries. We investigated the extent of carbapenem non-susceptibility in K. pneumoniae isolates in Germany. Methods: We analysed 2011-2016 data from the German Antimicrobial Resistance Surveillance (ARS) System, which contains routine data of antimicrobial susceptibility testing from voluntarily participating German laboratories. Klebsiella pneumoniae isolates tested resistant or intermediate against an antibiotic were classified as non-susceptible. Results: We included 154,734 isolates from 655 hospitals in the analysis. Carbapenem non susceptibility in K. pneumoniae isolates was low in Germany 0.63% (95% CI 0.51 0.76%). However, in continuously participating hospitals the number of K. pneumoniae isolates almost doubled and we found evidence for a slowly increasing trend for non-susceptibility (OR = 1.20 per year, 95% CI 1.09-1.33, p < 0.001). Carbapenem non-susceptibility was highest among isolates from patients aged 20-39 in men but not in women. Moreover, carbapenem non-susceptibility was more frequently reported for isolates from tertiary care, specialist care, and prevention and rehabilitation care hospitals as well as from intensive care units. Co-resistance of carbapenem non-susceptible isolates against antibiotics such as tigecycline, gentamicin, and co-trimoxazole was common. Co-resistance against colistin was 13.3% (95% CI 9.8-17.9%) in carbapenem non-susceptible isolates. Conclusion: Carbapenem non-susceptibility in K. pneumoniae isolates in Germany is still low. However, it is slowly increasing and in the light of the strong increase of K. pneumoniae isolates over the last year this poses a significant challenge to public health. Continued surveillance to closely monitor trends as well as infection control and antibiotic stewardship activities are necessary to preserve treatment options. PMID- 29992017 TI - Let food be thy medicine and medicine be thy food? AB - Ensuring adequate nutrition in children with chronic kidney disease whilst avoiding hyperkalaemia can be a difficult balance to achieve. Pre-treatment of feeds, whether milk, formula or enteral nutrition, with sodium polystyrene sulfonate (SPS) is practiced in some paediatric centres internationally. Such treatments are purported to avoid the potentially serious complications of direct administration of SPS, such as intestinal necrosis, aspiration pneumonitis and metabolic alkalosis to name but a few. Although described some 45 years ago, this study by Palma et al. is only the second retrospective study to describe the clinical consequence of pre-treating feeds with SPS with the majority of earlier studies describing only the in vitro effects of this method. Whilst effective in reducing serum potassium, the authors justifiably highlight the high incidence of complications, such as hypokalaemia (31.6%) and hypernatraemia (26.3%). We have further highlighted this with a summary of the available literature on this subject demonstrating the gross alterations of the electrolyte composition of feeds following SPS pre-treatment and clinical complications in its application. We heartily agree and support the conclusion by Palma et al. that where this therapy is practiced, close monitoring of electrolytes is essential and much more work is needed to identify those patient cohorts for which this can indeed be considered a safe and effective intervention. PMID- 29992018 TI - Extracorporeal shock wave lithotripsy versus flexible ureterorenoscopy in the treatment of untreated renal calculi. AB - Background: The reported success rates for treatments of kidney stones with either extracorporeal shock wave lithotripsy (ESWL) or flexible ureterorenoscopy (URS) are conflicting. We aimed to compare the efficacy and safety of ESWL and URS for previously untreated renal calculi. Methods: All patients treated with ESWL or URS at our tertiary care centre between 2003 and 2015 were retrospectively identified. Patients with previously untreated kidney stones and a stone diameter of 5-20 mm were included. Stone-free, freedom from reintervention and complication rates were recorded. Independent predictors of stone-free and freedom from reintervention rates were identified by multivariable logistic regression and a propensity score-matched analysis was performed. Results: A total of 1282 patients met the inclusion criteria, of whom 999 (78%) underwent ESWL and 283 (22%) had URS. During post-operative follow-up, only treatment modality and stone size could independently predict stone-free and freedom from reintervention rates. After propensity score matching, ESWL showed significantly lower stone-free rates [ESWL (71%) versus URS (84%)] and fewer patients with freedom from reintervention [ESWL (55%) versus URS (79%)] than URS. Complications were scarce for both treatments and included Clavien Grade 3a in 0.8% versus 0% and Grade 3b in 0.5% versus 0.4% of ESWL and URS treated patients, respectively. Conclusions: Treatment success was mainly dependent on stone size and treatment modality. URS might be the better treatment option for previously untreated kidney stones 5-20 mm, with similar morbidity but higher stone-free rates and fewer reinterventions than ESWL. PMID- 29992019 TI - Chronic kidney disease stage affects small, dense low-density lipoprotein but not glycated low-density lipoprotein in younger chronic kidney disease patients: a cross-sectional study. AB - Background: Small, dense low-density lipoprotein (sd-LDL) and glycated LDL (g LDL) have been associated with cardiovascular disease (CVD) in chronic kidney disease (CKD) in patients >60 years of age. Since young adult and paediatric patients have shorter exposure to Framingham-type risk factors, our study aims to determine whether younger CKD patients exhibit the same sd-LDL and g-LDL pattern. Methods: After ethics board approval, this cross-sectional study was conducted at two universities with 44 patients (mean +/- standard deviation age 12.6 +/- 4.9, range 2-24 years) with CKD stage of 1-5. Laboratory parameters studied were Cystatin C (CysC), CysC estimated glomerular filtration rate (eGFR) (calculated from the Filler formula), sd-LDL, g-LDL and albumin. Lipid samples were measured for sd-LDL and g-LDL using ELISA. Non-linear correlation analysis was performed to determine the relationship between g-LDL, sd-LDL and eGFR. Clinical Trials Registration is at clinicaltrials.gov, NCT02126293, https://clinicaltrials.gov/ct2/show/NCT02126293. Results: Triglycerides, but not total cholesterol and calculated LDL, were associated with CKD stages (ANOVA P = 0.0091). As in adults, sd-LDL was significantly associated with CKD stages (ANOVA P = 0.0133), CysC eGFR (r = -0.6495, P < 0.00001), and body mass index (r = 0.3895, P = 0.0189), but not with age. By contrast, there was no significant correlation between g-LDL and CKD stages or CysC eGFR (P = 0.9678). Conclusions: Our study demonstrates that only triglycerides and sd-LDL were associated with CKD stages in this young cohort without confounding Framingham-type CVD risk factors. While larger studies are needed, this study suggests that lowering sd LDL levels may be a potential target to ameliorate the long-term CVD risks in paediatric CKD patients. PMID- 29992020 TI - Controversies in the management of the haemodialysis-related arteriovenous fistula following kidney transplantation. AB - Arteriovenous fistula (AVF) is regarded as the best vascular access for chronic haemodialysis (HD). Still, AVF inherently causes significant haemodynamic changes. Although the necessity for vascular access despite its putative cardiovascular complications favours AVF creation in patients under chronic HD, one may question whether sustaining a functional AVF after successful kidney transplantation extends the haemodynamic threat. Small prospective series suggest that AVF ligation causes rapid and sustained reduction in left ventricular hypertrophy. Still, the benefits of such a cardiac remodelling in long-terms of cardiovascular morbi-mortality still need to be proven. Furthermore, the elevation of diastolic blood pressure and arterial stiffness caused by AVF ligation may blunt the expected cardio-protection. Finally, the closure of a functioning AVF may accelerate the decline of kidney graft function. As a whole, the current management of a functioning AVF in kidney transplant recipients remains controversial and does not rely on strong evidence-based data. The individual risk of graft dysfunction and a return to chronic HD also needs to be balanced. Careful pre-operative functional assessments, including cardio pulmonary testing and estimated glomerular filtration rate slope estimation, may help better selection of who might benefit the most from AVF closure. Large-scale prospective, ideally multi-centric, trials are essentially needed. PMID- 29992021 TI - Molecular characterization and expression patterns of Nanog gene validating its involvement in the embryonic development and maintenance of spermatogonial stem cells of farmed carp, Labeo rohita. AB - Background: The homeobox containing transcription factor Nanog plays crucial roles in embryonic development/proliferation and/or maintenance of spermatogonial stem cells (SSCs) via interacting with transcription factors such as Oct4 and Sox2 in mammals. However, knowledge of its exact mechanistic pathways remains unexploited. Very little is known about teleost Nanog. Information on the Nanog gene of farmed rohu carp (Labeo rohita) is lacking. We cloned and characterized the Nanog gene of rohu carp to understand the expression pattern in early developmental stages and also deduced the genomic organization including promoter elements. Results: Rohu Nanog (LrNanog) cDNA comprised an open reading frame of 1,161 nucleotides bearing a structural homeodomain; whereas, the genomic structure contained four exons and three introns suggesting that it is homologous to mammalian counterparts. Phylogenetically, it was closely related to freshwater counterparts. Protein sequence (386 AA of 42.65 kDa) comparison revealed its low similarity with other vertebrate counterparts except that of the conserved homeodomain. Tissue distribution analysis revealed the existence of LrNanog transcripts only in adult gonads. The heightened abundances in the ovary and proliferating spermatogonia suggested its participations in maternal inheritance and male germ cell development. The potentiating abundances from fertilized egg onwards peaking at blastula stage vis- a-vis decreasing levels from gastrula stage onwards demonstrated its role in embryonic stem cell development. We also provided evidence of its presence in SSCs by western blotting analysis. Further, the promoter region was characterized, predicting a basal core promoter and other consensus elements. Conclusion: The molecular characterization of LrNanog and its documented expression profiling at transcript and protein levels are indicative of its functional linkage with embryonic/spermatogonial stem cell maintenance. This is the first report of LrNanog genomic organization including its promoter sequence information with predicted regulatory elements of a large-bodied carp species. This will be useful for elucidating its mechanism expression in future. Nanog could be used as a potential biomarker for proliferating carp SSCs. PMID- 29992022 TI - Enhanced access to anthropogenic food waste is related to hyperglycemia in raccoons (Procyon lotor). AB - Urban landscapes have well-known effects on wildlife populations. Many species of urban wildlife feed on anthropogenic food wastes, and little is known regarding the sub-lethal physiological consequences of this novel diet. We use samples from three populations of raccoons to test the hypothesis that access to anthropogenic food waste will lead to elevated body mass, blood glucose and serum leptin. Each population varied in their presumed access to food waste. We found that raccoons from the site with the highest presumed access to food waste were significantly heavier and had significantly higher levels of glycated serum protein (GSP, a marker of elevated blood glucose). In addition, GSP concentration was positively related to body mass. No significant differences in serum leptin were detected, nor was serum leptin related to body mass. Urban diets may have significant physiological consequences for urban wildlife related to glucose metabolism. Further research will be needed to determine the evolutionary consequences of the novel urban diet, and whether adaptation is occurring. PMID- 29992023 TI - Exploring the link between ultraviolet B radiation and immune function in amphibians: implications for emerging infectious diseases. AB - Amphibian populations the world over are under threat of extinction, with as many as 40% of assessed species listed as threatened under IUCN Red List criteria (a significantly higher proportion than other vertebrate group). Amongst the key threats to amphibian species is the emergence of novel infectious diseases, which have been implicated in the catastrophic amphibian population declines and extinctions seen in many parts of the world. The recent emergence of these diseases coincides with increased ambient levels of ultraviolet B radiation (UVBR) due to anthropogenic thinning of the Earth's protective ozone layer, raising questions about potential interactions between UVBR exposure and disease in amphibians. While reasonably well documented in other vertebrate groups (particularly mammals), the immunosuppressive capacity of UVBR and the potential for it to influence disease outcomes has been largely overlooked in amphibians. Herein, we review the evidence for UVBR-associated immune system disruption in amphibians and identify a number of direct and indirect pathways through which UVBR may influence immune function and disease susceptibility in amphibians. By exploring the physiological mechanisms through which UVBR may affect host immune function, we demonstrate how ambient UVBR could increase amphibian susceptibility to disease. We conclude by discussing the potential implications of elevated UVBR for inter and intraspecific differences in disease dynamics and discuss how future research in this field may be directed to improve our understanding of the role that UVBR plays in amphibian immune function. PMID- 29992024 TI - Feasibility of sun and magnetic compass mechanisms in avian long-distance migration. AB - Birds use different compass mechanisms based on celestial (stars, sun, skylight polarization pattern) and geomagnetic cues for orientation. Yet, much remains to be understood how birds actually use these compass mechanisms on their long distance migratory journeys. Here, we assess in more detail the consequences of using different sun and magnetic compass mechanisms for the resulting bird migration routes during both autumn and spring migration. First, we calculated predicted flight routes to determine which of the compasses mechanisms lead to realistic and feasible migration routes starting at different latitudes during autumn and spring migration. We then compared the adaptive values of the different compass mechanisms by calculating distance ratios in relation to the shortest possible trajectory for three populations of nocturnal passerine migrants: northern wheatear Oenanthe oenanthe, pied flycatcher Ficedula hypoleuca, and willow warbler Phylloscopus trochilus. Finally, we compared the predicted trajectories for different compass strategies with observed routes based on recent light-level geolocation tracking results for five individuals of northern wheatears migrating between Alaska and tropical Africa. We conclude that the feasibility of different compass routes varies greatly with latitude, migratory direction, migration season, and geographic location. Routes following a single compass course throughout the migratory journey are feasible for many bird populations, but the underlying compass mechanisms likely differ between populations. In many cases, however, the birds likely have to reorient once to a few times along the migration route and/or use map information to successfully reach their migratory destination. PMID- 29992026 TI - Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype. AB - Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (-)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6,CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(-)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(-)-enantiomer ratio of O desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake. PMID- 29992025 TI - Emotion dysregulation as a transdiagnostic mechanism of opioid misuse and suicidality among chronic pain patients. AB - Background: Chronic pain is a prevalent condition that causes functional impairment and emotional suffering. To allay pain-induced suffering, opioids are often prescribed for chronic pain management. Yet, chronic pain patients on opioid therapy are at heightened risk for opioid misuse-behaviors that can lead to addiction and overdose. Relatedly, chronic pain patients are at elevated risk for suicidal ideation and suicidal behaviors. Main body: Opioid misuse and suicidality are maladaptive processes aimed at alleviating the negative emotional hyperreactivity, hedonic hyporeactivity, and emotion dysregulation experienced by chronic pain patients on opioid therapy. In this review, we explore the role of emotion dysregulation in chronic pain. We then describe why emotionally dysregulated chronic pain patients are vulnerable to opioid misuse and suicidality in response to these negative affective states. Conclusion: Emotion dysregulation is an important and malleable treatment target with the potential to reduce or prevent opioid misuse and suicidality among opioid-treated chronic pain patients. PMID- 29992028 TI - Relationship between occupational injuries and the provision of safety and health information: data from the 4th Korean working conditions survey. AB - Background: The aim of this study was to examine the relationship between the provision of safety and health information (PSHI) and occupational injuries. Methods: This study was based on data from the 4th Korean Working Conditions Survey (KWCS) (2014). The sample consisted of data from 24,527 wage workers and was divided into high-risk and low-risk groups, depending on the probability of occupational injury. The high-risk group included subjects who could cause harm to themselves or others due to errors during work. We applied chi-squared tests and logistic regression analyses to examine the relationship between PSHI and occupational injuries. Results: In the high-risk group, workers with no PSHI showed an adjusted odds ratio of 1.81 for occupational injury (95% CI 1.33-2.47). In contrast, there was no statistically significant relationship between PSHI and the incidence of occupational injury in the low-risk group. Conclusions: To prevent occupational injuries, multi-faceted approaches that take different levels of injury risk into account are needed. Among workers with a high risk of occupational injury, more a stringent safety education program is required. PMID- 29992027 TI - Noncontiguous finished genome sequences and descriptions of Actinomyces ihuae, Actinomyces bouchesdurhonensis, Actinomyces urinae, Actinomyces marseillensis, Actinomyces mediterranea and Actinomyces oralis sp. nov. identified by culturomics. AB - The taxonogenomic approach, including the culturomics techniques, is now currently used to isolate and characterize new bacteria. These approaches notably allowed us to discover six new species of the Actinomyces genus: Actinomyces ihuae strain SD1, Actinomyces bouchesdurhonensis strain Marseille-P2825, Actinomyces urinae strain Marseille-P2225, Actinomyces marseillensis strain Marseille-P2818, Actinomyces mediterranea strain Marseille-P3257 and Actinomyces oralis strain Marseille-P3109. Each is the type strain of the corresponding bacterial species. 16S ribosomal RNA gene sequence comparison was used to classify these strains among the Actinomyces genus. These strains are all Gram positive, rod shaped and facultative aerobic. We describe the main characteristics of each bacterium and present their complete genome sequence and annotation. PMID- 29992029 TI - Pneumoconiosis in a polytetrafluoroethylene (PTFE) spray worker: a case report with an occupational hygiene study. AB - Background: Using analysis of air samples from the workplace, we report on one case of pneumoconiosis in an individual who has been working in a polytetrafluoroethylene (PTFE) spraying process for 28 years. Case presentation: The patient was diagnosed with granulomatous lung disease caused by PTFE using computed tomography (CT), lung biopsy and electron microscopy. To assess the qualitative and quantitative exposure to PTFE in workplace, Fourier transform infrared spectroscopy (FT-IR), energy-dispersive X-ray spectroscopy (EDX) and thermogravimetric analysis (TGA) were performed on air samples from the workplace. The presence of PTFE particles was confirmed, and the airborne concentration of PTFE was estimated to be 0.75 mg/m3. Conclusions: This case demonstrates that long-term exposure to PTFE spraying can cause granulomatous lung lesions such as pneumoconiosis; such lesions appear to be caused not by the degradation products of PTFE from high temperatures but by spraying the particles of PTFE. Along with air-sampling analysis, we suggest monitoring the concentration of airborne PTFE particles related to chronic lung disease. PMID- 29992031 TI - Management of small bowel perforation following foreign object ingestion. PMID- 29992030 TI - Measurement equivalence of child feeding and eating measures across gender, ethnicity, and household food security. AB - Background: Although there have been extensive studies that make group comparisons on child eating and feeding practices, few studies have examined measurement equivalence to ensure that measures used to make such group comparisons are equivalent across important group characteristics related to childhood obesity. Methods: Using a sample of 243 caregivers with children between the ages of 4 to 6 years, we conducted a measurement equivalence analysis across gender, ethnicity (Latino versus non-Latino White), and household food security. The subscales of the Child Feeding Questionnaire (CFQ) and the Child Eating Behaviour Questionnaire (CEBQ) were examined separately using a one factor multi-group confirmatory factor analysis. Results: For the CFQ, Concern about Child Weight and Parental Responsibility subscales were consistent across all groups examined. In contrast, Pressure to Eat, Restriction, and Perceived Parent Weight subscales varied or fit poorly across the groups. For the CEBQ, Emotional Overeating, Enjoyment of Food, and Satiety Responsiveness performed consistently across the groups. On the other hand, Food Fussiness, Desire to Drink, Slowness in Eating, and Emotional Undereating subscales varied or fit poorly across the groups. Conclusions: Findings from this study suggest both of these measures need continued psychometric work, and group comparisons using some subscales should be interpreted cautiously. Some subscales such as Food Responsiveness and Parental Restriction may be assessing behaviors that occur in food secure households and are less applicable to food insecure environments. PMID- 29992032 TI - Successful management of giant hydrocolpos in a limited-resource setting. AB - Abdominal distention and urinary retention are rare manifestations in newborns. The differential diagnosis of a female neonate presenting these signs, especially when combined, should include hydrocolpos due to imperforate hymen. The prognosis of imperforate hymen is generally good, although it can be associated with serious nephro-urologic and infectious complications. Early diagnosis and drainage of hydrocolpos allow prevention and/or improvement of these possible complications. In limited-resource settings, diagnostic imaging is more difficult to obtain, and, therefore, increased caution and an accurate physical exam with perineal inspection are essential. We report the case of a 8-day-old female neonate showing abdominal distention and urinary retention. She had a final diagnosis of imperforate hymen with giant hydrocolpos, complicated by obstructive uropathy and following urosepsis and bladder perforation. PMID- 29992033 TI - Successful eradication of leptomeningeal plasma cell disease. AB - Plasma cell leukaemia (PCL) is a rare and aggressive form of malignant monoclonal gammopathy characterized by the presence of high levels of plasma cells in peripheral blood. Central nervous system involvement of PCL has no established treatment and an extremely poor prognosis. We here present a 59-year-old male patient diagnosed with PCL, initially treated with induction chemotherapy followed by autologous peripheral blood hematopoietic stem cell transplantation. After achieving a partial response, he relapsed and presented with leptomeningeal disease. He was then successfully treated with dexamethasone, pomalidomide, and an intrathecal combination of methotrexate, methylprednisolone and cytarabine. This cleared his cerebrospinal fluid from plasma cells achieving a durable partial response. PMID- 29992034 TI - Whole-genome sequencing reveals highly specific gene targeting by in vitro assembled Cas9-ribonucleoprotein complexes in Aspergillus fumigatus. AB - Background: CRISPR/Cas9-based genome editing is quickly becoming a powerful tool within the field of fungal genetics. Adaptation of CRISPR/Cas9 systems are allowing for rapid and highly efficient gene targeting within fungi. We recently reported the adaptation of a simple CRISPR/Cas9 system for gene deletion that is effective across multiple genetic backgrounds of Aspergillus fumigatus. This system employs in vitro assembly of Cas9 ribonucleoproteins (RNPs) coupled with micro-homology repair templates for gene deletion. Although highly efficient at gene targeting in wild type genetic backgrounds of A. fumigatus, the potential for our system to produce unwanted off-target mutations has not been addressed. Results: Next-generation Illumina sequencing was used to identify genome mutations among transformants isolated from standard (no Cas9) and Cas9-mediated integration of a hygromycin deletion cassette. Two different concentrations of Cas9 were utilized to examine the association of Cas9 concentration with total numbers and types of genomic mutations. For each of the three test groups (zero, low, and high Cas9), three transformants were sequenced and compared to the parent strain. Bioinformatics analyses revealed the average number of total mutations to be similar among all three test groups. A. fumigatus transformation using standard, non-Cas9-mediated methods resulted in an average of 373 +/- 28 mutations. In comparison, transformation with in vitro assembled Cas9-RNPs using either high (1 ug/ul) or low (0.5 ug/ul) levels of Cas9 resulted in an average of 326 +/- 19 and 395 +/- 69 mutations, respectively. In all cases, the vast majority of mutations identified were intergenic. No correlation between the amount of Cas9 utilized for transformation and the overall number of mutations was found. Finally, the specific type of mutation introduced during the transformation process was not Cas9-dependent, as both single-nucleotide polymorphisms and insertion/deletion events were not significantly different between the experimental groups. Conclusions: CRISPR/Cas9-based genome editing in A. fumigatus using in vitro assembled RNPs coupled with microhomology templates is a reliable method of gene targeting. This system is highly efficient and is not associated with increased off-target mutations caused by introduction of the Cas9 nuclease. PMID- 29992035 TI - Facilitators and barriers to birth preparedness and complication readiness in rural Rwanda among community health workers and community members: a qualitative study. AB - Background: Birth preparedness and complication readiness (BP/CR) comprise a strategy to make women plan for birth and encourage them to seek professional care in order to reduce poor pregnancy outcome. We aimed to understand the facilitators and barriers to BP/CR among community health workers (CHWs) and community members in rural Rwanda. Methods: Eight focus group discussions were conducted with 88 participants comprising of CHWs, elderly women aged 45-68 and men aged 18-59, as well as two key informant interviews in Musanze district, Rwanda, between November and December 2015. Qualitative data were digitally recorded, transcribed verbatim and analysed using content analysis. Results: Participants perceived the importance of family assistance, medical insurance and attending antenatal care (ANC) to facilitate BP/CR and enhance professional care at birth. CHWs reinforced BP/CR messages by SMS alerts and during community gatherings. 'Ubudehe (collective action to combat poverty)' was known as a tool to identify the poorest families in need of government aid to pay for medical care. Disrespect and abuse of women during labor by health workers were perceived as important barriers to access professional care, as well as conflicting health policies such as user fees for ANC and family planning services, and imposing fines on women giving birth outside health facilities. Conclusion: CHWs, ANC and medical insurance are perceived to be important facilitators of BP/CR. Respectful care is paramount for improved maternal health. There is a need for addressing inconsistent health policies hindering the intention to access professional care. PMID- 29992036 TI - Analysis of protein-protein interaction network based on transcriptome profiling of ovine granulosa cells identifies candidate genes in cyclic recruitment of ovarian follicles. AB - After pubertal, cohort of small antral follicles enters to gonadotrophin sensitive development, called recruited follicles. This study was aimed to identify candidate genes in follicular cyclic recruitment via analysis of protein protein interaction (PPI) network. Differentially expressed genes (DEGs) in ovine granulosa cells of small antral follicles between follicular and luteal phases were accumulated among gene/protein symbols of the Ensembl annotation. Following directed graphs, PTPN6 and FYN have the highest indegree and outdegree, respectively. Since, these hubs being up-regulated in ovine granulosa cells of small antral follicles during the follicular phase, it represents an accumulation of blood immune cells in follicular phase in comparison with luteal phase. By contrast, the up-regulated hubs in the luteal phase including CDK1, INSRR and TOP2A which stimulated DNA replication and proliferation of granulosa cells, they known as candidate genes of the cyclic recruitment. PMID- 29992037 TI - ACTIVE - a randomised feasibility trial study protocol of a behavioural intervention to reduce fatigue in women undergoing radiotherapy for early breast cancer: study protocol. AB - Background: Fatigue is rated as the most distressing side effect of radiotherapy treatment for curable breast cancer. About four in ten women treated experience fatigue, which can last for years after treatment. The impact of this debilitating tiredness is loss of independence and impaired physical and mental function. Our study will take a behavioural intervention with demonstrated effect in treating fatigue in a mixed group of chemotherapy patients and adapt it for women undergoing radiotherapy for early breast cancer. The purpose of this trial is to evaluate the feasibility of delivering the intervention in the radiotherapy pathway for patients at a high risk of fatigue and to explore participants' experiences of the trial and intervention. Methods: A pragmatic single-site non blinded feasibility trial of a behavioural intervention. Main inclusion criteria are prescription of the UK standard 40 Gy in 15 fractions over 3 weeks of radiotherapy (+/- tumour bed boost) for early (stage 0-IIIa) breast cancer. The total projected sample size after attrition is 70. A previously developed fatigue risk score tool will be used to predict individual's likelihood of experiencing fatigue. Thirty women predicted to be at a high risk of experiencing significant fatigue will be allocated in the ratio 2:1 to the behavioural intervention or education trial arms, respectively. These feasibility trial participants will be assessed at baseline, after 10 and 15 fractions of radiotherapy and 10 days, 3 weeks and 6 months after radiotherapy. A further 40 women predicted to be at a lower risk of fatigue will join a risk score validation group.Measures to assess feasibility include recruitment, retention and completion rates and variation in implementation of the intervention. Process evaluation with intervention providers and users includes fidelity and adherence checks and qualitative interviews to understand how changes in behaviour are initiated and sustained. Discussion: This feasibility study collates data to both inform the progression to and design of a future definitive trial and to refine the intervention. Trial registration: ISRCTN 10303368. Registered August 2017 (retrospectively registered); Health and Care Research Wales Clinical Research Portfolio (CRP) registration 31419. PMID- 29992038 TI - Design and development of a complex narrative intervention delivered by text messages to reduce binge drinking among socially disadvantaged men. AB - Background: Socially disadvantaged men are at high risk of suffering from alcohol related harm. Disadvantaged groups are less likely to engage with health promotion. There is a need for interventions that reach large numbers at low cost and which promote high levels of engagement with the behaviour change process. The aim of this study was to design a theoretically and empirically based text message intervention to reduce binge drinking by socially disadvantaged men. Results: Following MRC guidance, the intervention was developed in four stages. Stage 1 developed a detailed behaviour change strategy based on existing literature and theory from several areas. These included the psychological theory that would underpin the intervention, alcohol brief interventions, text message interventions, effective behaviour change techniques, narratives in behaviour change interventions and communication theory. In addition, formative research was carried out. A logic model was developed to depict the pathways between intervention inputs, processes and outcomes for behaviour change. Stage 2 created a narrative which illustrated and modelled key steps in the strategy. Stage 3 rendered the intervention into a series of text messages and ensured that appropriate behavioural change techniques were incorporated. Stage 4 revised the messages to ensure comprehensive coverage of the behaviour change strategy and coherence of the narrative. It also piloted the intervention and made final revisions to it. Conclusions: The structured, systematic approach to design created a narrative intervention which had a strong theoretical and empirical basis. The use of a narrative helped make the intervention realistic and allowed key behaviour change techniques to be modelled by characters. The narrative was intended to promote engagement with the intervention. The intervention was rendered into a series of short text messages, and subsequent piloting showed they were acceptable in the target group. Delivery of an intervention by text message offers a low-cost, low-demand method that can reach large numbers of people. This approach provides a framework for the design of behaviour change interventions which could be used for interventions to tackle other health behaviours. PMID- 29992039 TI - A randomized, controlled, crossover pilot study of losartan for pediatric nonalcoholic fatty liver disease. AB - Background: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children, and currently, there are no FDA-approved therapies. Plasminogen activator inhibitor-1 (PAI-1) is elevated in children with NAFLD and associated with increased disease severity. Losartan potassium (losartan) is an angiotensin II receptor blocker (ARB) that reduces PAI-1 production and improves insulin sensitivity that has been proposed as a treatment for pediatric NAFLD but has not previously been tested. Methods: This was an 8-week randomized, double blind, placebo-controlled, phase 2a, crossover study (with a 6-week washout between conditions) for safety and preliminary efficacy of losartan 50 mg a day taken orally in 12 normotensive children with biopsy proven nonalcoholic steatohepatitis (NASH). Results: Twelve children enrolled in the study, and nine completed all visits. No changes in blood pressure or serious adverse events occurred during the study. Trends in improvement in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and homeostatic model assessment insulin resistance (HOMA-IR) were seen with losartan treatment compared to the placebo time-period. More participants decreased ALT on losartan as compared to placebo (89% [8 out 9] vs. 56% [5 out of 9], respectively). Conclusions: This data provides preliminary evidence that losartan treatment is safe over 8 weeks in children with NAFLD and supports consideration of larger studies to test its efficacy. Trial registration: URL and trial identification number: https://clinicaltrials.gov/show/NCT01913470, NCT01913470.Date registered: August 1, 2013. PMID- 29992041 TI - Trial of Remote Continuous versus Intermittent NEWS monitoring after major surgery (TRaCINg): protocol for a feasibility randomised controlled trial. AB - Background: Despite medical advances, major surgery remains high risk. Up to 44% of patients experience postoperative complications, which can have huge impacts for patients and the healthcare system. Early recognition of postoperative complications is crucial in reducing morbidity and preventing long-term disability. The current standard of care is intermittent manual vital signs monitoring, but new wearable remote monitors offer the benefits of continuous vital signs monitoring without limiting the patient's mobility. The aim of this study is to evaluate the feasibility, acceptability and clinical impacts of continuous remote monitoring after major surgery. Methods: The study is a randomised, controlled, unblinded, parallel group, feasibility trial. Adult patients undergoing elective major surgery will be invited to participate if they have the capacity to provided informed, written consent and do not have a cardiac pacemaker or an allergy to adhesives. Participants will be randomly assigned to receive continuous remote monitoring and normal National Early Warning Score (NEWS) monitoring (intervention group) or normal NEWS monitoring alone (control group). Continuous remote monitoring will be achieved using the SensiumVitals(r) wireless patch which is worn on the patient's chest and monitors heart rate, respiratory rate and temperature continuously and alerts the nurse when there is deviation from pre-set physiological norms. Participants will be followed up throughout their hospital admission and for 30 days after discharge. Feasibility will be assessed by evaluating recruitment rate, adherence to protocol and randomisation, and the amount of missing data. The acceptability of the patch to nursing staff and patients will be assessed using questionnaires and interviews. Clinical outcomes will include time to antibiotics in cases of sepsis, length of hospital stay, number of critical care admissions and rate of readmission within 30 days of discharge. Discussion: Early detection and treatment of complications minimises the need for critical care, improves patient outcomes, and produces significant cost savings for the healthcare system. Remote continuous monitoring systems have the potential to allow earlier detection of complications, but evidence from the literature is mixed. Demonstrating significant benefit over intermittent monitoring to offset the practical and economic implications of continuous monitoring requires well-controlled studies in high-risk populations to demonstrate significant differences in clinical outcomes; this feasibility trial seeks to provide evidence of how best to conduct such a confirmatory trial. Trial registration: This study is listed on the ISRCTN registry with study ID ISRCTN16601772. PMID- 29992040 TI - eRAPID electronic patient self-Reporting of Adverse-events: Patient Information and aDvice: a pilot study protocol in pelvic radiotherapy. AB - Background: An estimated 17,000 patients are treated annually in the UK with radical radiotherapy (RT) for pelvic cancer. New treatment approaches in RT have increased survivorship and changed the subjective toxicity profile for patients who experience acute and long-term pelvic-related adverse events (AE). Multi disciplinary follow-up creates difficulty for monitoring and responding to these events during treatment and beyond. Originally developed for use in systemic oncology therapy eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and aDvice) is an online system for patients to report AEs from home. eRAPID enables patient data to be integrated into the electronic patient records for use in clinical practice, provides patient management advice for mild and moderate AE and advice to contact the hospital for severe AE. The system has now been developed for pelvic RT patients, and we aim to test the intervention in a pilot study with staff and patients to inform a future randomised controlled trial (RCT). Methods: Eligible patients are those attending St James's University hospital cancer centre and The Christie Hospital Manchester undergoing pelvic radiotherapy+/-chemotherapy/hormonotherapy for prostate, lower gastrointestinal and gynaecological cancers. A prospective 1:1 randomised (intervention or usual care) parallel group design with repeated measures and mixed methods will be employed. We aim to recruit 168 patients following recommendations for sample size estimates for pilot studies. Participants using eRAPID will report AE (at least weekly) from home weekly for 6 weeks and 6 weeks post-treatment (12-week total) then at 18 and 24 weeks. Hospital staff will review eRAPID reports and use information during consultations. Notifications will be sent to the relevant clinical team when severe symptoms are reported. We will measure patient-reported outcomes using validated questionnaires (Functional Assessment in Cancer Therapy Scale-General (FACT-G), European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC-QLQ C30), process of care impact (hospital records of patient contacts and admissions) and economic variables (EQ5D-5L, patient use of resources)). Staff and patient experiences will be explored via semi-structured interviews. Discussion: The objectives are to establish feasibility, recruitment, integrity of the system and attrition rates, determine effect sizes and aid selection of the primary outcome measure for a future RCT. We will also refine the intervention by exploring staff and patient views. The overall goal of this complex intervention is to improve the safe delivery of cancer treatments, enhance patient care and standardise documentation of AE within the clinical datasets. Trial registration: ClinicalTrials.gov NCT02747264. PMID- 29992043 TI - Sex-changing patterns of Akoya pearl oyster (Pinctada fucata). AB - Background: Pearl production by transplantation in Akoya pearl oyster (Pinctada fucata) is a biotechnology developed in Japan that skillfully utilizes the pearl forming ability of oysters. In this method, cultured pearls are formed from a pearl nucleus and a small piece of mantle transplanted into the gonads of recipient pearl oysters. In this study, we hypothesized that the sex of the recipient pearl oyster might affect the quality of pearl produced. While some previous studies have examined the sex of Akoya pearl oyster, detailed information is lacking. Results: To investigate sex in Akoya pearl oyster, we collected small gonadal fragments from 1-year-old pearl oysters by biopsy. Using the collected gonad fragment, the sex of the oysters was determined by microscopic observation, and the remaining samples were stored for gene expression analyses. All oysters were labeled to distinguish each individual for serial samplings every four months over the 2-year study period. At the start of experiment, nearly all of the pearl oysters were male, but the male:female ratio ofmale decreased over the course of the experiment. Interestingly, the number of males increased after spring, during the breeding season. This suggests that, in pearl oyster, sex is affected by season. Expression analysis of sex-related genes (Dmrt2, Vtg, Zp) indicated that all genes were expressed in all individuals and all periods. Conclusions: These results suggest that Akoya pearl oysters are hermaphroditic, and that females appear as necessary, such as during the breeding season. These findings could contribute to higher efficiency and quality of pearl cultivation. PMID- 29992042 TI - Use and discontinuation of intrauterine contraceptive device in the Greater Accra Region of Ghana. AB - Background: The intrauterine contraceptive device is one of the modern long acting and reversible contraception that is very safe and effective. Yet, less than 2 % of women are using intrauterine devices in Ghana. This study therefore explored the experiences and barriers to intrauterine contraceptive device use and discontinuation in Greater Accra Region, Ghana. Methods: Intrauterine contraceptive device users and providers were purposively selected from eight private family planning clinics in the Greater Accra Region. Semi-structured interview guides were used for in-depth interviews during data collection. The interviews were audio-taped to ascertain accurate accounts of the interviews and recordings replayed for analytical responses. Field assistants transcribed the interviews conducted themselves and read through the transcripts produced twice to increase familiarity with the dataset. A list of code labels was created and a series of categories for the main themes that emerged from the transcripts were developed. The transcribed data was organized, coded and manually thematically analysed in word. Study results were presented in tables and quotes from respondents. Results: Results showed that key motivations for intrauterine contraceptive device use include effectiveness, benefits, and efficacy of the device, fertility regulation, peace of mind, contraceptive method switching, health provider effects, desire for long-acting contraceptive method, and partner characteristics. Intrauterine contraceptive device discontinuation was due to bleeding irregularities, vaginal infections, desire to increase fertility, physical features of the intrauterine device, and partner disapproval of use. Other reasons in both cases pertained to non-hormonal aspects of the intrauterine device, partner characteristics, and provider encouragement and influence. Conclusions: Several factors influence the use and discontinuation of intrauterine device in Ghana. Comprehensive contraceptive counselling on the intrauterine device is essential in promoting uptake and knowledge of the intrauterine device at the health facility level. Various targeted messages are also needed to dispel misconceptions at the community level. PMID- 29992044 TI - Using patient and public involvement to improve the research design and funding application for a project aimed at fostering a more collaborative approach to the NHS health check: the CaVIAR project (better Care Via Improved Access to Records). AB - Background: Following an initial NHS Health Check appointment, the National Institute for Health and Care Excellence (NICE) suggest patients with QRISK2 scores of >=10% should be offered advice on lifestyle and the risks and benefits of starting a statin. NICE recommend GPs should ascertain patients' pre-existing knowledge of cardiovascular disease risk, explore health beliefs, assess readiness to change, offer support, and engage family members. Condensing this complex discussion into a short consultation may result in inadequate patient understanding of the benefits of preventive measures. An alternative approach is needed. We propose a digital adjunct giving patients the opportunity to interact with their health check results from home before returning to see their GP. Before embarking on funding applications we sought the views of patients and members of the public. Methods: We consulted the Primary Care Research in Manchester Engagement Resource (PRIMER), an established departmental Patient and Public Involvement (PPI) group (N = 9) and then ran a workshop with 19 members of the public, co-facilitated by 4 members of PRIMER. Following a brief presentation on the background to the project, attendees were split into four groups and introduced to Ketso, a toolkit for creative engagement. Ketso was used to encourage group discussions regarding the project idea. Results: This PPI work improved the study design and proposed intervention. Discussions focussed on three themes: 1) positive feedback, 2) challenges and solutions, and 3) improvements/alternatives. Positive feedback included benefits to the NHS and patients. Challenges identified related to: 1) access, 2) data security, 3) engagement, and 4) negative consequences. Workshop members generated various solutions to these challenges and made additional suggestions for improvement relating to: 1) population (e.g. also including those with QRISK2 scores <=10%), 2) duration (e.g. ongoing access to provide continued feedback), and 3) platform content (e.g. signposting to relevant services). Conclusions: This PPI work helped identify potential challenges and solutions not previously considered by the research team. Findings have informed the subsequent intervention design and strengthened the bid for funding. We aim to ensure ongoing patient and public involvement in all future stages. PMID- 29992045 TI - The utility of ultra-widefield fluorescein angiography in pediatric retinal diseases. AB - Background: Ultra-widefield angiography is the latest technology in the evolution of fundus fluorescein angiography. With the ability to capture up to 200 degrees of the fundus in a single image, far peripheral retinal pathology can be imaged. Generally, obtaining high-quality fundus fluorescein angiography in a child without sedation in the outpatient setting is exceedingly challenging. Therefore, there are advantages to imaging platforms that can capture the peripheral retina in young children without anesthesia. Often pediatric retinal diseases have pathology localized to the far periphery, which further validates the utility of ultra-widefield angiography. Ultra-widefield angiography has been successfully used without sedation for evaluation of children with various pediatric retinal diseases such as Coats disease, familial exudative vitreoretinopathy, and retinopathy of prematurity. Conclusion: This non-contact, non-mydriatic modality has been utilized in the evaluation of pediatric retinal diseases and demonstrated to have benefits over conventional fluorescein angiography techniques. PMID- 29992046 TI - Correction to: The diagnosis and treatment of primary vitreoretinal lymphoma: a review. AB - [This corrects the article DOI: 10.1186/s40942-018-0120-4.]. PMID- 29992047 TI - Ethics reporting practices in randomized controlled trials of physical therapy interventions after stroke. AB - Background: Adequate reporting of ethics-related research methods promotes convergence on best ethics practices. In physical therapy, studies on ethics reporting are limited to few aspects, and none focuses on stroke research. Our objectives were to investigate the reporting of multiple ethics-related features and its variation over time, and the characteristics of the studies associated with ethics reporting in Randomized Controlled Trials (RCTs) of physical therapy interventions after stroke. Methods: A random sample of RCTs published in the years 2004, 2009 and 2014, was extracted from the PubMed database, regardless of the publishing journal. For each trial we investigated year of publication, trial registration, sample size, stroke subtype, phase of the disease, setting, interventions and dosing, outcome measures, outcome of the study, PEDro score and 5-year impact factor of the publishing journal. Reporting of ethics-related issues was analyzed. Differences between groups were examined. Multiple regression was used to evaluate the relationship between ethics-related issues reporting and some studies' characteristics. Results: Eighty studies were reviewed. Groups differed in the proportion of registered trials (p = .009), 5 year impact factor (p = .011), assessment of cognitive capacity (p = .049), declaration about conflict of interest (p < .001), and number of ethics-related issues reported (p = .009). The proportion of issues reported ranged from 92.5% (consent obtaining) to 0% (eventual follow up care). Post-hoc comparisons showed significantly greater reporting of ethics issues in trials published in the year 2014 compared to 2004 (p = .014, 95%CI = 0.40/4.26). Year of publication and PEDro score were significant predictors of adequate reporting. Conclusions: Authors, editors, and reviewers should be more rigorous and demanding about the reporting of ethic-related methods in randomized controlled trials of physical therapy interventions after stroke. PMID- 29992048 TI - An ultrasonographic analysis of the activation patterns of abdominal muscles in children with spastic type cerebral palsy and in typically developing individuals: a comparative study. AB - Background: Abdominal muscles have stiffer appearance in individuals with spastic type cerebral palsy (STCP) than in their typically developing (TD) peers. This apparent stiffness has been implicated in pelvic instability, mal-rotation, poor gait and locomotion. This study was aimed at investigating whether abdominal muscles activation patterns from rest to activity differ in the two groups. Method: From ultrasound images, abdominal muscles thickness during the resting and active stages was measured in 63 STCP and 82 TD children. The thickness at each stage and the change in thickness from rest to activity were compared between the two groups. Results: Rectus abdominis (RA) muscle was the thickest muscle at rest as well as in active stage in both groups. At rest, all muscles were significantly thicker in the STCP children (p < 0.001). From rest to active stages muscle thickness significantly increased (p < 0.001) in the TD group and significantly decreased (p < 0.001) in the STCP children, except for RA, which became thicker during activity in both groups. In active stages, no significant differences in the thickness in the four abdominal muscles were found between the STCP and the TD children. Conclusion: Apart from the RA muscle, the activation pattern of abdominal muscles in individuals with STCP differs from that of TD individuals. Further studies required for understanding the activation patterns of abdominal muscles prior to any physical fitness programmes aimed at improving the quality of life in individuals with STCP. Trial registration: HREC REF: 490/2011. Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town, South Africa. November 17, 2011. PMID- 29992049 TI - Diet changes alter paternally inherited epigenetic pattern in male Wild guinea pigs. AB - Epigenetic modifications, of which DNA methylation is the most stable, are a mechanism conveying environmental information to subsequent generations via parental germ lines. The paternal contribution to adaptive processes in the offspring might be crucial, but has been widely neglected in comparison to the maternal one. To address the paternal impact on the offspring's adaptability to changes in diet composition, we investigated if low protein diet (LPD) in F0 males caused epigenetic alterations in their subsequently sired sons. We therefore fed F0 male Wild guinea pigs with a diet lowered in protein content (LPD) and investigated DNA methylation in sons sired before and after their father's LPD treatment in both, liver and testis tissues. Our results point to a 'heritable epigenetic response' of the sons to the fathers' dietary change. Because we detected methylation changes also in the testis tissue, they are likely to be transmitted to the F2 generation. Gene-network analyses of differentially methylated genes in liver identified main metabolic pathways indicating a metabolic reprogramming ('metabolic shift'). Epigenetic mechanisms, allowing an immediate and inherited adaptation may thus be important for the survival of species in the context of a persistently changing environment, such as climate change. PMID- 29992050 TI - Neuroprotective Effect of ZnT3 Knockout on Subarachnoid Hemorrhage. AB - Background: The pathophysiology of early brain injury (EBI) after subarachnoid hemorrhage (SAH) is poorly understood. The present study evaluates the influence of zinc transporter 3 (ZnT3) knockout and the depletion of vesicular zinc on EBI. Methodology: SAH was induced in ZnT3 KO mice by internal carotid artery perforation. The changes in behavior were recorded at 24 hours after SAH. Hematoxylin-eosin, Nissl and TUNEL staining were performed to evaluate neuronal apoptosis. Data from mice with a score of 8-12 in intracerebral bleeding (i.e. moderate SAH), were analyzed. Results: The degree of SAH-induced neuronal injury was directly correlated to the amount of blood lost, which in turn was negatively reflected in their behavior. The Wild Type (WT)-SAH group behaved poorly when compared to the knockout (KO)-SAH mice and their poor neurological score was accompanied by an increase in the number of apoptotic neurons. Conversely, the improvement of behavior in the KO-SAH group was associated with a marked reduction in apoptotic neurons. Conclusions: These results suggest that ZnT3 knockout may have played a vital role in the attenuation of neuronal injury after SAH and that ZnT3 may prove to be a potential therapeutic target for neuroprotection in EBI. PMID- 29992051 TI - Beneficial Effect of beta-Elemene Alone and in Combination with Hyperbaric Oxygen in Traumatic Brain Injury by Inflammatory Pathway. AB - Background: Present study evaluates the neuroprotective effect of beta-elemene alone and in combination with hyperbaric oxygen (HO) in traumatic brain injury (TBI). Methodology: TBI was induced by dropping a weight from a specific height. All the animals were separated in to five groups (n=20) like control group; TBI group; beta-elemene treated group which receives beta-elemene (100 mg/kg, i.p.) half an hour after the injury; HO group which receives hyperbaric oxygen therapy and beta-elemene + HO group which receives beta-elemene (100 mg/kg, i.p.) half an hour after the injury and hyperbaric oxygen therapy. Neurological function was assessed to evaluate the effect of beta-elemene in TBI rats. Thereafter level of inflammatory cytokines and expression of protein of inflammatory pathway was assessed in the brain tissues of TBI rats. In addition TUNEL assay was also done for the determination apoptosis in neuronal cells. Result: Data of the report reveals that beta-elemene alone and in combination with hyperbaric oxygen (HO) significantly decreases the neurological score Compared to TBI group. Moreover level of inflammatory cytokines and expression of LTR4 and casepase 3 significantly decrease and increase in the expression of IkB in beta-elemene alone and in combination with hyperbaric oxygen (HO) treated group compared to TBI group. Data of TUNEL assay also reveals that beta-elemene treated group shows significant decrease in the TUNEL positive cells and apoptosis index compared to TBI group. Conclusion: Thus present study concludes the neuroprotective effect of beta-elemene against TBI and it shows synergistic effect on TBI when treated with HO. PMID- 29992052 TI - Carotid Intima Media Thickness Reference Intervals for a Healthy Argentinean Population Aged 11-81 Years. AB - Reference intervals (RIs) of carotid intima media thickness (CIMT) from large healthy population are still lacking in Latin America. The aim of this study was to determine CIMT RIs in a cohort of 1012 healthy subjects from Argentina. We evaluated if RIs for males and females and for left and right carotids were necessary. Second, mean and standard deviation (SD) age-related equations were obtained for left, right, and average (left + right)/2) CIMT using parametric regression methods based on fractional polynomials, in order to obtain age specific percentiles curves. Age-specific percentile curves were obtained. Males showed higher A-CIMT (0.577 +/- 0.003 mm versus 0.566 +/- 0.004 mm, P = 0.039) in comparison with females. For males, the equations were as follows: A-CIMT mean = 0.42 + 8.14 * 10-5*Age2; A-CIMT SD = 5.9 * 10-2 + 1.09 * 10-5*Age2. For females, they were as follows: A-CIMT mean = 0.40 + 8.20 * 10-5*Age2; A-CIMT SD = 4.67 * 10-2 + 1.63 * 10-5*Age2. Our study provides the largest database concerning RIs of CIMT in healthy people in Argentina. Specific RIs and percentiles of CIMT for children, adolescents, and adults are now available according to age and gender, for right and left common carotid arteries. PMID- 29992053 TI - Beneficial Role of Mg2+ in Prevention and Treatment of Hypertension. AB - Hypertension constitutes one of the most widespread pathological conditions in developed and developing countries. Currently, more than 1 billion people worldwide are affected by the condition, either as frank hypertension or as prehypertension, raising the risk for major long-term complications and life threatening pathologies. The costs in terms of health care services, medications for the treatment of hypertension and its complications, and associated loss in productivity represent a major economic burden for the various countries. The necessity of developing treatments that are economically more sustainable and with better compliance has been increasing alongside the incidence of the pathology. Along these lines, attention has been paid to the implementation of affordable but nutritious diets that deliver appropriate levels of macro- and micronutrients as integral part of the diets themselves or as supplements. In particular, experimental and clinical evidence suggests that an appropriate intake of dietary magnesium can be beneficial in controlling blood pressure. Additional advantages of a more diffuse therapeutic and/or preventive utilization of magnesium supplements are the virtual absence of side-effects and their affordable costs. The present review will attempt to frame our knowledge of how magnesium exerts its beneficial effects on blood pressure maintenance, which may lead to the development of more effective treatments of hypertension and its main complications. PMID- 29992054 TI - Trauma and Growth: Impact of AIDS Activism. AB - Introduction: Our goal was to assess the long-term impact of AIDS activism of ACT UP/New York on the current adjustment of those who were members during its peak years (1987-1992), including assessment of trauma sequelae as well as posttraumatic growth. Methods: A 90-minute semistructured interview and 6 validated self-report scales were administered. We relied on purposive and snowball sampling to recruit potential participants. Areas covered include demographics, ACT UP participation, and psychiatric problems. Self-report scales provided approximate diagnoses of PTSD and depression, as well as coping, optimism, and related concepts. Results: Participants included 102 men (40% HIV positive) and 23 women. Seventeen percent reported current symptoms suggesting PTSD, slightly above the range in general population studies. Symptoms consistent with depression were reported by 8% overall, with higher rates for HIV+ men. Enhanced sense of self, belief in change, and empowerment were reported by 93% of respondents, independent of concurrent PTSD or depression. Conclusions: Twenty eight years later, ACT UP study participants recall their activist days during the AIDS epidemic as the peak experience of their lives. While some continue to have symptoms of stress and depression, most found that their activism has enriched their subsequent lives. PMID- 29992055 TI - Correlates of Falls among Community-Dwelling Elderly in Thailand. AB - Nearly every nation is experiencing rapid population aging. One area of major concern is health; a major health risk for older adults is falling, and there are multiple negative consequences of falling. This is a global concern yet is underresearched in many nations. This study examines demographic, health, and environmental correlates of falling among community-dwelling Thai elderly. Data were collected from a sample of 406 adults aged 60-69. Significant (p < 0.05) fall correlates were urban residence, older age, greater BMI, impaired and uncorrected vision, chronic health conditions, medication use and medication side effects, poor muscle tone, and hazardous indoor and outdoor home environments. Results lead to recommendations for interventions to reduce fall risk that are both evidence-based and culturally acceptable. PMID- 29992056 TI - Postrecruitment Function of Yeast Med6 Protein during the Transcriptional Activation by Mediator Complex. AB - Med6 protein (Med6p) is a hallmark component of evolutionarily conserved Mediator complexes, and the genuine role of Med6p in Mediator functions remains elusive. For the functional analysis of Saccharomyces cerevisiae Med6p (scMed6p), we generated a series of scMed6p mutants harboring a small internal deletion. Genetic analysis of these mutants revealed that three regions (amino acids 33-42 (Delta2), 125-134 (Delta5), and 157-166 (Delta6)) of scMed6p are required for cell viability and are located at highly conserved regions of Med6 homologs. Notably, the Med6p-Delta2 mutant was barely detectable in whole-cell extracts and purified Mediator, suggesting a loss of Mediator association and concurrent rapid degradation. Consistent with this, the recombinant forms of Med6p having these mutations partially (Delta2) restore or fail (Delta5 and Delta6) to restore in vitro transcriptional defects caused by temperature-sensitive med6 mutation. In an artificial recruitment assay, Mediator containing a LexA-fused wild-type Med6p or Med6p-Delta5 was recruited to the lexA operator region with TBP and activated reporter gene expression. However, the recruitment of Mediator containing LexA Med6p-Delta6 to lexA operator region resulted in neither TBP recruitment nor reporter gene expression. This result demonstrates a pivotal role of Med6p in the postrecruitment function of Mediator, which is essential for transcriptional activation by Mediator. PMID- 29992058 TI - Comment on "DKA-Induced Takotsubo Cardiomyopathy in Patient with Known HOCM". PMID- 29992057 TI - Incidental Finding of the Anomalous Origin of Left Main Coronary Artery from Pulmonary Artery in an Adult Presenting with Arrhythmia-Induced Myocardial Ischemia. AB - Anomalous origin of the left main coronary artery from the pulmonary artery (ALCAPA) is a rare congenital coronary anomaly with high mortality. It is associated with cardiovascular complications and is usually diagnosed soon after birth. Those who survive into adulthood can present with signs of myocardial infarction, heart failure, mitral regurgitation, severe pulmonary hypertension, or sudden cardiac death. We present a 53-year-old female presenting with atrial fibrillation and found to have an incidental diagnosis of ALCAPA who refused surgical correction. We also review the epidemiology, diagnosis, age-based clinical presentations, and treatment options for ALCAPA. PMID- 29992060 TI - Corrigendum to "Fibrous Dysplasia versus Juvenile Ossifying Fibroma: A Dilemma". AB - [This corrects the article DOI: 10.1155/2016/6439026.]. PMID- 29992059 TI - Ceramic Laminate Veneers for Reestablishment of Esthetics in Case of Lateral Incisor Agenesis. AB - The increasing demand of patients looking for esthetics has resulted in the development of several techniques to restore anterior teeth. Conservative treatments should always be the first therapeutic option for the solution of aesthetic problems involving morphological changes and usually provide the result that the patient expects. In this context, ceramic laminate veneers, also known as "contact lenses," are capable to provide an extremely faithful reproduction of natural teeth with great color stability and periodontal biocompatibility. Minimal or no preparation veneers are heavily advertised as the answer to patients' cosmetic needs, when properly indicated by the dentist. This paper reports a clinical case where lateral incisor agenesis was aesthetically corrected using ceramic laminates. PMID- 29992061 TI - Two Cases of Pachydermodactyly Presenting as Polyarthritis. AB - Pachydermodactyly is characterized by asymptomatic, progressive swelling of the lateral aspects of the 2nd to 4th finger along the proximal interphalangeal (PIP) joint without involving the joint itself. We present 2 interesting cases of patients with periarticular swelling who were initially diagnosed and treated as juvenile idiopathic arthritis (JIA) with subsequent clinical and pathology confirmation of pachydermodactyly. These cases emphasize the importance of considering pachydermodactyly in young patients with development of periarticular swelling and no joint involvement. PMID- 29992062 TI - Thyroid Storm and Complete Heart Block after Treatment with Radioactive Iodine. AB - Thyroid storm is a rare endocrine emergency characterized by dysfunction of multiple organ systems. Thyroid storm is more common in Graves' disease and can be precipitated by surgery, trauma, infection, metabolic abnormalities, iodine load, and parturition. We present a diagnostically challenging case of thyroid storm precipitated by radioiodine therapy and accompanied by bradycardia, a rare but life-threatening complication related to treatment for hyperthyroidism. PMID- 29992063 TI - A Rare Case of ALK-Positive Large B-Cell Lymphoma with CD33 Expression. AB - Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a very rare and aggressive subtype of diffuse large B-cell lymphoma characterized by ALK rearrangement. Immunophenotypically, the tumor cells are typically negative for common B-cell markers, T-cell markers, and CD30; however, they express markers of terminally differentiated B cells/plasma cells such as CD38, CD138, and MUM 1/IRF4. The diagnosis of ALK+ LBCL can be challenging, and often a large panel of immunostains is required to exclude other hematopoietic and nonhematopoietic neoplasms. To date, approximately 130-140 cases have been reported, but here we report the first known case of ALK+ LBCL with unusual CD33 expression. PMID- 29992064 TI - A 36-Year-Old Renal Transplant Recipient Female with Leg Ulcer: A Case Report and Brief Review. AB - Background: Opportunistic infections are common in organ transplant recipients. After 6 months of transplantation, patients have the highest risk of opportunistic infections such as cryptococcosis. Case Presentation: The report presents the case of a 36-year-old female renal transplant recipient, with complaints of few subcutaneous painful and warm nodules and large, warm, erythematous, nontender plaques on the mildly edematous right leg and ankle. Incisional biopsy of the subcutaneous nodule over the leg showed panniculitis with small- to medium-sized vasculitis associated with round yeast forms, and culture of the fragments revealed C. neoformans var. grubii. Conclusions: This article also reviews in brief the treatment of this rare complication. Reviewing the literature showed that since the cryptococcal cutaneous lesions are often nonspecific, the clinical picture solely is not enough to construct a definite diagnosis and there must be a high clinical suspicion. PMID- 29992065 TI - Pancreas as an Occult Source of Recurrent Salmonella enteritidis Bacteremia in an Immunocompromised Patient. AB - Salmonella infection usually presents as gastroenteritis and enteric fever. Some cases of bacteremia can lead to invasion of different organ systems and become occult sources for recurrence. Almost all organs of the body can be affected and have been reported in the literature. We report a rare case of repeated Salmonella enteritidis infection in a patient with systemic lupus erythematosus. She was treated with intravenous and oral antibiotics but still had recurrence of fevers and bacteremia. After a thorough workup, pancreatic abscesses were identified and drained with abscess culture revealing Salmonella enteritidis. She was then treated with a prolonged course of antibiotics and finally cleared the infection. This case demonstrates that nontyphoid Salmonella can be invasive and cause persistent infection. This is particularly pertinent in immunocompromised patients who are at an increased risk of infection. An aggressive workup and prolonged antibiotic course might be beneficial for this subset of patients. PMID- 29992066 TI - Bacterial Spinal Epidural and Psoas Abscess in Pregnancy Associated with Intravenous Drug Use. AB - Spontaneous spinal epidural abscess (SEA) is a rare infection of the central nervous system. We report a case of a 25-year-old G3 P0020 at 36 weeks of gestational age with history of intravenous drug abuse presenting with acute onset and severe back pain. Despite antibiotic therapy, pain worsened and she developed lower extremity weakness. Magnetic resonance imaging (MRI) revealed an SEA, and cesarean delivery was performed secondary to increasing weakness, followed by laminectomy (T9-12) and decompression of epidural abscess. Postoperative course was complicated by a psoas muscle abscess and persistent SEA refractory to antibiotic therapy, requiring surgical reexploration and extended treatment with antibiotics. She was discharged home in stable condition and neonate did well with no resulting sequelae. Spinal epidural and psoas abscesses are rare and diagnosis is often delayed. Prompt recognition and treatment are necessary to prevent catastrophic neurologic consequences, and the diagnosis should be considered in pregnant patients presenting with back pain, especially in those with risk factors. PMID- 29992067 TI - Severe Postpartum Hemorrhage Complicated with Liver Infarction Resulting in Hepatic Failure Necessitating Liver Transplantation. AB - Postpartum hemorrhage remains a major threat to maternal health. Intervention after critical blood loss or development of disseminated intravascular coagulation may lead to disastrous organ failure and poor outcomes. A 30-year-old woman was transferred to our emergency department due to massive postpartum hemorrhage. Shock and disseminated intravascular coagulation ensued, and the patient's condition quickly deteriorated. We performed an emergency hysterectomy, but blood loss had been massive. Moreover, there was another episode of internal bleeding that led to further blood loss. Ischemic injury to the liver was tremendous, with resulting progressive jaundice and hepatic encephalopathy. The patient required liver transplantation. Imaging studies and operative findings showed a large area of hepatic infarction. Unfortunately, the patient died of intractable sepsis shortly after liver transplantation. Disseminated intravascular coagulation and resultant hepatic infarction combined with ischemic hepatitis were the direct cause of death in our case. PMID- 29992068 TI - Pregnancy Complications in a-Thalassemia (Hemoglobinopathy H): A Case Study. AB - Thalassemia intermedia (TI) is a clinical definition which represents a wide spectrum of thalassemia genotypes but mainly includes patients who do not require or only occasionally require transfusion. An uncommon case of a 32-year-old Greek woman, para 1, at the 22nd week + day 3 of gestation with thalassemia intermedia (she was splenectomized), where her pregnancy was complicated with portal vein thrombosis, splenic thrombosis, and partial HELLP, is described. This is a generally uncommon event in thalassemia intermedia. She had no transfusion as her hematologist consulted and she took anticoagulation therapy. Thus, we present for the first time in the literature a case of HbH a-thalassemia pregnant woman whose pregnancy was complicated with portal vein thrombosis, splenic vein thrombosis, and partial HELLP; she was treated with anticoagulation therapy and she had a successful outcome. PMID- 29992069 TI - Case Reports in Oncological Medicine Myoepithelioma: A New Rearrangement Involving the LPP Locus in a Case of Multiple Bone and Soft Tissue Lesions. AB - We report a case of multiple myoepithelioma with synchronous bone and soft tissue tumors, associated with a new genomic alteration of the LPP locus. The lesions occurred in the foot by presenting one lump in the plantar soft tissue, and three lesions were detected in the calcaneus and in the navicular bone. All tumors showed the double immunophenotype of epithelial markers and S100 protein expression. No rearrangement of the EWSR1 and FUS loci was detected as reported in myoepitheliomas. However, molecular karyotyping detected an unbalanced rearrangement of the LPP locus, not involving the HMGA2 locus, which is the most frequent translocation partner observed in benign mesenchymal tumors such as lipomas (of soft tissue as well as parosteal) and pulmonary chondroid hamartoma. PMID- 29992070 TI - Reconstruction of Photoreceptor Outer Layers after Steroid Therapy in Solar Retinopathy. AB - Purpose: To report the clinical course of solar retinopathy after steroid therapy. Case Presentation: A 45-year-old male gazed at the sun and noticed bilateral central scotoma and decreased vision after the episode. After 7 weeks from onset, ophthalmic examinations were firstly performed. Decimal best corrected visual acuity (BCVA) was decreased to 0.8 and 0.7 in the right and left eyes. Funduscopy showed a tiny, yellowish spot in the fovea bilaterally. Corresponding to the lesion, optical coherence tomography (OCT) images showed an elevated and blurred ellipsoid zone and loss of the interdigitation zone. A posterior sub-Tenon triamcinolone injection in the right eye and oral prednisolone therapy were performed as a medication. BCVA was improved to 1.2 and 1.0 in the right and left eyes at 9 weeks after medication. OCT images showed ellipsoid zone was gradually improved bilaterally, which became nearly normal at 4 weeks in the right eye and at 21 weeks in the left eye. The loss of the interdigitation zone remained at 12 weeks in the right eye and at 21 weeks at the left eye. Conclusions: We described a case with solar retinopathy who exhibited anatomical recovery of the photoreceptor outer layers by steroid therapy, started after 7 weeks from onset. PMID- 29992071 TI - The Benefits of an In-Office Arthroscopy in the Diagnosis of Unresolved Knee Pain. AB - We report a patient who developed persistent knee pain with mechanical symptoms after an uncomplicated patellofemoral arthroplasty. The etiology of his knee pain remained inconclusive following magnetic resonance imaging due to metallic artifact image distortion. With the use of an in-office needle arthroscopy, an immediate and definitive diagnosis was obtained, preventing an unnecessary surgery for a diagnostic arthroscopy. We discovered a lateral meniscus tear, an anterior cruciate ligament tear, and a medial femoral condyle chondral defect for which the patient underwent arthroscopic partial meniscectomy, ligament reconstruction, and osteochondral allograft transplantation, with resolution of his knee pain. PMID- 29992072 TI - A Case Report of an Isolated Dislocation of the Scaphoid in a Lesser Arc Injury and a Review of the Literature. AB - Isolated dislocations of the scaphoid are extremely uncommon injuries and are often associated with significant ligamentous failures. Since scaphoid dislocations typically present with associated carpal fractures, few cases of isolated dislocations of the scaphoid exist in the literature. The proposed treatment options in the literature range from closed reduction and casting to open reduction and internal fixation. We present the case of a 41-year-old male with an isolated scaphoid dislocation in whom open reduction and internal fixation was performed with K-wires. At five months follow-up, the patient had returned to work and all desired activities. PMID- 29992073 TI - Uterine Carcinosarcoma with Alpha-Fetoprotein-Producing Hepatoid Component: A Case Report and Literature Review. AB - A 67-year-old woman presented with postmenopausal vaginal bleeding. Full body imaging demonstrated an intrauterine mass with deep myometrial invasion but no nodal or other metastatic disease. Uterine curettage was performed. Histologically, the tumor was an endometrioid adenocarcinoma with sarcomatous element and a hepatoid component, the latter was immunohistochemically positive for alpha-fetoprotein, HepPar-1, and arginase-1. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy. Serum alpha fetoprotein level decreased from 31896 ug/l preoperatively to 2063 ug/l postoperatively. Eight weeks later, a rise in serum alpha-fetoprotein was detected, and a biopsy-proven vaginal recurrence was diagnosed. Palliative chemotherapy led to tumor shrinkage and a concurrent decrease in the serum alpha fetoprotein level. A rise in serum alpha-fetoprotein, refractory to second-line chemotherapy, was accompanied by subsequent development of ureteric obstruction, ascites, and radiological evidence of peritoneal metastases. This is an unusual case of uterine carcinosarcoma with an alpha-fetoprotein-producing hepatoid adenocarcinoma component. Serum alpha-fetoprotein level corresponds to disease recurrence and progression. PMID- 29992074 TI - Diagnostic, Treatment, and System Challenges in the Management of Recurrent Neuroleptic Malignant Syndrome on a General Medical Service. AB - Neuroleptic malignant syndrome (NMS), an iatrogenic form of malignant catatonia, carries high morbidity and mortality rates especially in the context of delayed recognition and standard intervention protocol of lorazepam trial. However, there is limited guidance available through literature for further management if benzodiazepine treatment is ineffective and electroconvulsive therapy (ECT) is not readily accessible. This case report describes a multimodal approach to address the diagnostic, treatment, and logistical system challenges in an acute medical hospital through the case of a 69-year-old man with schizophrenia who represented from a psychiatric ward with neuroleptic malignant syndrome. We educated our inpatient colleagues for timely recognition of hyperexcited subtype of catatonia to avoid iatrogenic progression to neuroleptic malignant syndrome and our medical colleagues on the clinical course of catatonic symptoms to avoid any further disagreements and delays in treatment. We advocated for timely electroconvulsive therapy in the setting of limited access and utilized creative pharmacologic strategies such as N-methyl-D-aspartate (NMDA) receptor antagonists and longer acting benzodiazepines while managing medical complications. PMID- 29992075 TI - Endovascular Embolization of Spontaneous Iliopsoas Hematoma: First Experience with Squidperi. AB - A 79-year-old man, suffering from atrial fibrillation and on anticoagulation therapy, was admitted at the emergency department of our institution because of a worsening respiratory insufficiency. After a diagnostic work-up, he was found to suffer from pneumonia, and antibiotic therapy was settled. He was kept under observation for his pulmonary conditions but, within a week, he developed a spontaneous iliopsoas hematoma, due to a sudden dysregulation of anticoagulation therapy subsequent to new in-hospital treatments. An endovascular approach was attempted and the bleeding vessels were embolized with a new liquid agent, named Squidperi (Emboflu, Switzerland). Complete exclusion of the diseased vessels was obtained and no complications occurred after the procedure. We conclude that Squidperi can be considered as an option for treatment of spontaneous iliopsoas hematomas. PMID- 29992076 TI - Glioblastoma with Both Oligodendroglioma and Primitive Neuroectodermal Tumor-Like Components in a Case with 9-Year Survival. AB - Introduction: Glioblastoma multiforme (GBM), the most common primary malignant brain tumor in adults, is characterized by extensive heterogeneity in its clinicopathological presentation. A primary brain tumor with both astrocytic differentiation and neuronal immunophenotype features is rare. Here, we report a long-term survival patient who presented this rare form of GBM in the disease course. Presentation of Case: A 23-year-old woman, presenting with rapidly progressive headache and right-side weakness, was diagnosed with brain tumor over the left basal ganglion. She underwent the first craniectomy for tumor removal, and histopathology revealed classic GBM. Tumor recurrence occurred 8 years later. Another gross total resection was performed and pathology revealed GBM with the oligodendroglioma component (GBM-O). Due to disease progression, she received debulking surgery the following year. The third pathology revealed glioblastoma with primitive neuroectodermal tumor-like component (GBM-PNET). Discussion: GBM PNETs are collision tumors with both neuronal and glial components. They are rare, and a few case reports have suggested that these tumors are associated with favorable outcomes but a higher risk of cerebrospinal fluid dissemination. Conclusion: We report a patient who developed the distinct pathologic variants of classic GBM, GBM-O, and GBM-PNET, throughout the disease course. Young age, aggressive surgical resection, and pathologic and genetic features may have contributed to the long-term survival of the patient. PMID- 29992077 TI - Coexistence of Primary GEJ Adenocarcinoma and Pedunculated Gastric Gastrointestinal Stromal Tumor. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive system, although they account for only 0.1-3% of all gastrointestinal (GI) malignancies. They can arise anywhere along the GI tract with gastric predominance. Concurrent occurrence of GIST and gastroesophageal junction (GEJ) neoplasm is rare. We report a 55-year-old gentleman presenting with a polyp at the GEJ and a synchronous, large, and pedunculated gastric mass at the greater curvature. Those were treated with a wedge resection of the gastric pedunculated mass with negative margins along with transgastric submucosal resection of the GEJ polyp. Pathological examination confirmed synchronous invasive GEJ adenocarcinoma and a high-grade gastric GIST. PMID- 29992078 TI - Giant Adrenal Myelolipoma in a Patient without Endocrine Disorder: A Case Report and a Review of the Literature. AB - We herein present a surgically treated case of huge adrenal myelolipoma. A 62 year-old woman presented to our surgical outpatient clinic with a retroperitoneal tumor. A clinical examination revealed an elastic soft, smooth-surfaced, painless, child-head-sized tumor with poor mobility, which was located in the left upper abdomen. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed an uneven tumor surrounding the stomach, spleen, pancreas, and left kidney, which was 20 * 18 * 10 cm in size. The retroperitoneal tumor was resected. The tumor was attached to the surrounding organs, including the pancreas, spleen, and left kidney, but had not directly invaded these organs. The tumor was yellow and elastic soft and covered with a thin film. The origin of the tumor was suggested to be the left adrenal gland. The weight of the excised tumor was 1500 g. The histopathological diagnosis was adrenal myelolipoma. The patient had an uneventful recovery and was discharged from the hospital on the thirteenth day after the operation. She has been followed up in our outpatient clinic. PMID- 29992079 TI - Development of Global Chemical Profiling for Quality Assessment of Ganoderma Species by ChemPattern Software. AB - Triterpenoids are the major secondary metabolites and active substances in Ganoderma, considered as the "marker compounds" for the chemical evaluation or standardization of Ganoderma. A response surface methodology was used to optimize the ultrasonic-assisted extraction of triterpenoids. The extraction rate was 7.338 +/- 0.150 mg/g under the optimum conditions: 87% ethanol, ratio of solid to liquid (w : v) 1 : 28, and ultrasound extraction time 36 min. Based on the high sensitivity and selectivity of HPLC-LTQ-Orbitrap-MS n , 24 components of triterpenoids were tentatively identified in the negative mode. Then, the global chemical profiling consisting of HPLC and TLC fingerprints generated by ChemPatternTM software was developed for evaluation of Ganoderma species. For fingerprint analysis, 11 peaks of triterpenoids were selected as the characteristic peaks to evaluate the similarities of different samples. The correlation coefficients of similarity were greater than 0.830. The cluster analysis showed a clear separation of three groups, and 11 peaks played key roles in differentiating these samples. The developed global chemical profiling method could be applied for rapid evaluation, quality control, and authenticity identification of Ganoderma and other herbal medicines. PMID- 29992081 TI - Metabolic health and academic achievement in youth at risk for high school dropout in rural Mississippi: The role of classroom management. AB - Disparities in health and academic achievement affect large cross-sections of the same population subgroups. This study examined the relationship metabolic health and academic achievement in youth "at risk" for school dropout in rural Mississippi. Fifteen adolescents participated in a studio based learning educational summer camp and subsequent follow-up sessions during the regular school year that were aimed at developing knowledge of core curriculum subjects by developing design projects based on the camp STEM-related theme. These projects are characteristic of a pedagogical technique known as Studio Based Learning (SBL) and involve more movement than a traditional classroom setting. Participants' metabolic health was assessed via measurements of blood lipids and glucose, blood pressure, BMI and waist circumference, and examined individually and as a combined risk score. Academic achievement measurements were obtained from district standardized testing. Mean BMI for this sample was classified as overweight; however, other metabolic parameters (blood lipids and glucose, and resting blood pressure) were in normal ranges for this age group. Little association was found between metabolic health and academic achievement and in this sample for math of language (r = -0.56 and 0.20, respectively). Participants took part in notable amounts of moderate-to-vigorous physical activity during the SBL camp and very little in the traditional classroom setting (approximately 30 vs. 7 min/day, respectively). Actively engaging teaching strategies, such as SBL, may impart a meaningful impact on physical activity levels of school-aged children, which may have long term, positive health outcomes. PMID- 29992080 TI - Anti-protein immunoglobulin M responses to pneumococcus are not associated with aging. AB - Background: The incidence of community-acquired pneumonia and lower respiratory tract infection rises considerably in later life. Immunoglobulin M (IgM) antibody levels to pneumococcal capsular polysaccharide are known to decrease with age; however, whether levels of IgM antibody to pneumococcal proteins are subject to the same decline has not yet been investigated. Methods: This study measured serum levels and binding capacity of IgM antibody specific to the pneumococcal surface protein A (PspA) and an unencapsulated pneumococcal strain in serum isolated from hospital patients aged < 60 and >= 60, with and without lower respiratory tract infection. A group of young healthy volunteers was used as a comparator to represent adults at very low risk of pneumococcal pneumonia. IgM serum antibody levels were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry was performed to assess IgM binding capacity. Linear regression and one-way analysis of variance (ANOVA) tests were used to analyse the results. Results: Levels and binding capacity of IgM antibody to PspA and the unencapsulated pneumococcal strain were unchanged with age. Conclusions: These findings suggest that protein-based pneumococcal vaccines may provide protective immunity in the elderly. Trial registration: The LRTI trial (LRTI and control groups) was approved by the National Health Service Research Ethics Committee in October 2013 (12/NW/0713). Recruitment opened in January 2013 and was completed in July 2013. Healthy volunteer samples were taken from the EHPC dose-ranging and reproducibility trial, approved by the same Research Ethics Committee in October 2011 (11/NW/0592). Recruitment for this study ran from October 2011 until December 2012. LRTI trial: (NCT01861184), EHPC dose-ranging and reproducibility trial: (ISRCTN85403723). PMID- 29992082 TI - Human papillomavirus (HPV) types prevalence in cervical samples of female sex workers on Curacao. AB - : Sex-workers have an increased risk for high-risk HPV(hrHPV) cervical cancer. On Curacao, legal and illegal prostitution practice is high and the promiscuous lifestyle is common. We aimed to gain insight in HPV-genotype prevalence in cervical scrapes of female sex workers (FSW) and related risk factors in comparison with women not working in the sex industry. Cervical samples were taken from 76 FSW and 228 non-FSW (NFSW) age matched controls in the period between 2013 and 2015. HPV was detected by GP5+/6+ PCR-EIA followed by genotyping via reverse line-blot. HPV prevalence in FSWs was 25.0% and in NFSWs 29.4% (p = 0.14). NFSW had more often untypable HPV-genotypes (HPV-X:5.3% vs 0.0%; p = 0.042). A trend for statistical difference was observed in HPV prevalence between FSWs from Dominican Republic (42.1%) and FSWs from Colombia (19.2%; p = 0.067). Young age was the only risk factor related to HPV prevalence in FSWs. (Mean age FSW 29.2 y +/-7.8 and NFSW 33 y +/-6.2) Smoking and drugs consumption were significantly higher among FSW. A significant higher number of women with history of any STD was reported by NFSWs. In addition, >90% of FSW had their previous Pap smear <3 years ago, while >35% NFSW never had a previous Pap smear (p < 0.001). IN CONCLUSION: no significant difference in HPV prevalence is observed between FSW and NFSW. HPV prevalence in FSW was associated with a lower age. During interviews, FSW seemed more aware about prevention strategies, reported less history of STD's and were more updated with cervical cancer screening, compared to NFSWs. PMID- 29992083 TI - Promoting smoking abstinence among patients with chronic obstructive pulmonary disease: Initial feasibility. AB - Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the U.S., with the majority of COPD deaths attributable to cigarette smoking. Despite this, individuals with COPD have a higher prevalence of smoking, poorer quit rates, and higher relapse rates compared to smokers without a COPD diagnosis. We examined the feasibility of an incentives-based intervention for producing an initial period of biochemically-verified smoking abstinence among daily smokers with COPD. Participants were randomly assigned to a Contingent (n = 13) or Noncontingent (n = 16) incentives condition and visited the clinic for 14 consecutive days. Contingent participants earned vouchers with monetary value contingent on breath carbon monoxide (CO) levels during Study Days 1-5 and urinary cotinine during Days 6-14. Voucher earnings began at $9.00 and increased by $1.50 with each subsequent negative sample for maximum possible of $362.50. Noncontingent participants received vouchers of comparable value independent of smoking status. Differences between conditions varied across study days for daily smoking abstinence (X2 = 45.27, p < 0.0001), CO (F(13, 280) = 1.95, p = 0.025), and cotinine (F(13, 279) = 2.20, p = 0.010), with generally higher rates of abstinence and lower CO and cotinine levels observed in the Contingent vs. Noncontingent conditions. Results from this randomized pilot study support the potential efficacy of an incentives-based intervention for reducing cigarette smoking among individuals with COPD. Further research efforts should seek to promote and evaluate longer-term abstinence and associated changes in respiratory function. PMID- 29992084 TI - Objectively measured habitual physical activity and sleep-related phenomena in 1645 people aged 1-91 years: The Nakanojo Community Study. AB - Relationships between habitual physical activity and sleep-related phenomena were examined in 623 male and 1022 female Japanese participating in the Nakanojo Community Study, using data collected in 2012-2013. Ages ranged from infancy to very old. Daily step count and daily duration of exercise at an intensity >3 metabolic equivalents (METs) were determined by pedometer/accelerometer, 24 h/day for 1 week. Duplicate axillary temperatures were also taken on rising and when retiring. Total bed time was noted, and the efficiency of sleep determined as hours of actual sleep (from a validated pedometer/accelerometer algorithm) divided by bed time. Step counts and especially duration of activity >3 METs peaked in teenagers and decreased as age advanced (p < 0.001). Both axillary temperatures subsequently showed a gradual age-related decline (p < 0.001). The duration and efficiency of sleep also showed a small age-dependent decrease (p < 0.001). Multivariate-adjusted correlation coefficients indicated a better quality of sleep in individuals who took greater habitual physical activity. In individuals aged >=40 years, these findings were modified by chronic disease conditions including hypertension, diabetes mellitus and hyperlipemia; after controlling statistically for potential confounders, both physical activity and axillary temperature were lower (p < 0.05 or 0.01), and the time spent lying was longer but the efficiency of sleep was poorer (p < 0.01) in those with chronic conditions. These results suggest that habitual physical activity bears an important relationship to sleep-related phenomena at all ages, with a modification of relationships by chronic disease in people aged >=40 years. PMID- 29992085 TI - Prevalence and correlates of intentional outdoor and indoor tanning among adolescents in the United States: Findings from the FLASHE survey. AB - A body of research has focused on adolescents' indoor tanning behaviors but relatively little is known about the prevalence of adolescents' intentional outdoor tanning (time spent outdoors to get a tan). The present study used data from the National Cancer Institute's 2014 Family Life, Activity, Sun, Health and Eating (FLASHE) cross-sectional survey to examine the prevalence and correlates of intentional outdoor and indoor tanning among adolescents in the United States. Both unadjusted (bivariate) and adjusted (multi-variate) logistic regressions were performed to test the associations between demographic variables, time spent on media (e.g., using computers), emotional status and outdoor or indoor tanning. The overall prevalence of frequent outdoor tanning among adolescents in the U.S. was 15.6% (95% CI 13.8-17.4%) and the rate of indoor tanning in the past 12 months was 3% (95% CI 2.2-3.9). The adjusted odds of intentional outdoor tanning were significantly higher among girls (AOR 2.39, 95% CI 1.75-3.27), Non-Hispanic Whites (AOR 2.85, 95% CI 1.99-4.07), and those who spent more time on cell phones (AOR 1.40, 95% CI 1.25-1.57). The adjusted odds of indoor tanning were significantly higher among those who spent more time on computers (AOR 1.38, 95% CI 1.09-1.74) and cell phones (AOR 1.49, 95% CI 1.19-1.87). This study provides evidence for the relationship between media use and tanning behaviors among adolescents. PMID- 29992086 TI - Fundamental movement skills: Where do girls fall short? A novel investigation of object-control skill execution in primary-school aged girls. AB - Fundamental movement skill (FMS) proficiency is positively associated with a range of health outcomes, and is a predictor of lifelong participation in physical activities and sport. Yet low FMS proficiency levels in children prevail, particularly among girls performing object-control skills (e.g., kicking, catching). To identify where girls require the most support and inform future teaching resources and interventions, this cross-sectional study investigated proficiency levels of object-control skills and their specific performance components (subskills) in girls; and aimed to determine whether patterns in subskill mastery were evident in girls from two different developmental stages. This study included 153 girls (aged 4-12 years; mean age = 7.7, SD = 1.8) from the Hunter Region, Australia. Six object-control skills were video-assessed using the Test of Gross Motor Development (TGMD-2, TGMD-3); overall skill proficiency levels and mastery levels of subskills were determined. In summary, <5% (of the total group, 4-8 years or 9-12 years) demonstrated mastery or advanced skill level in the strike, stationary dribble, overhand throw or kick. Mastery levels were also poor for the majority of the 24 subskills, with mastery levels below 40% for the total group for 17 of the 24 subskills. Deficiencies in specific subskills were evident in the preparation, action and recovery phases of the six object-control skills. Only 6 of the 24 subskills mastery levels were significantly higher in the older age-group. Our investigation provides new evidence that may be useful for practitioners and researchers looking to support the optimal development of FMS proficiency among girls. Australian New Zealand Clinical Trials Registry: ACTRN12615000022561. PMID- 29992087 TI - Framing marijuana: How U.S. newspapers frame marijuana legalization stories (1995 2014). AB - Marijuana legalization has been one of the most controversial issues in the public health field. Since news frames can influence the public's perceptions about public health policy including marijuana legalization, it is important to understand how the media report this issue. Thus, we explore how U.S. newspapers present marijuana legalization stories, examining two key dimensions of framing: an organizing theme and a story tone. We analyzed news articles of national and regional newspapers between 1995 and 2014 (N = 640). Findings revealed that newspapers have largely presented marijuana legalization as a law enforcement issue, rather than an economic issue or a medical issue. Marijuana legalization has been differently presented according to each presidential period. Overall, marijuana legalization stories have been described using a neutral tone. However, findings showed that newspapers that were classified as politically liberal adopted a positive tone more frequently than newspapers that were classified as conservative. Our findings can help public health providers or policy makers understand the relationships between news stories and public opinion toward marijuana legalization. Conclusively, this study can provide a comprehensive analysis of news framing of marijuana legalization, examining two key dimensions of framing: organizing theme and story tone. PMID- 29992088 TI - Corrigendum to "Office workers' objectively assessed total and prolonged sitting time: Individual-level correlates and worksite variations" [Prev. Med. Rep. 4 (2016) 184-191]. AB - [This corrects the article DOI: 10.1016/j.pmedr.2016.06.011.]. PMID- 29992089 TI - Irradiation enhanced the effects of PD-1 blockade in brain metastatic osteosarcoma. AB - Brain metastasis of osteosarcoma are rare but carry a dismal prognosis. Despite the advances in both systemic immunotherapy and localized radiation, it is still difficult to treat brain metastasis, with less than 12 months of survival from the time of diagnosis for most patients. Currently, there is interest in combining strategies to take advantage of the potential synergy. In this study, the mouse model of metastatic osteosarcoma to brain was used to explore the ability of local radiation and anti-PD-1 blockade to induce beneficial anti-tumor immune responses against distant, unirradiated brain metastatic tumors. Immune markers from the peripheral blood and tumor tissue were analyzed by flow cytometry, real-time PCR and western blot. The combination treatment produced a stronger systemic anti-tumor response than either treatment alone, shown by the reduced tumor burden and larger numbers of cytotoxic CD8+ T cells in the unirradiated tumors, indicating an abscopal effect. These data suggested that combination treatment of irradiation with anti-PD-1 immunotherapy can induce abscopal anti-tumor responses and improve both local and distant control. PMID- 29992090 TI - Diagnostic and prognostic values of blood microRNA-Let7A for osteosarcoma. AB - Objective: In view of the poor prognosis and difficulties in the diagnosis of osteosarcoma, and the functionality of microRNA-Let7A in different types of human cancers, our study aimed to explore the diagnostic and prognostic values of microRNA-Let7A for osteosarcoma. Methods: A total of 39 patients with osteosarcoma and 19 normal healthy people were included in this study. All patients received surgical resection, and tumor tissues as well as pericarcinomatous tissues were collected during surgical operation. Venous blood (2 ml) was extracted from each participant. Expression of microRNA-Let7A in tumor tissues and pericarcinomatous tissues, and expression of E2F2 and microRNA-Let7A in blood of each participant was detected by qRT-PCR. ROC analysis was performed to evaluate the diagnostic values of blood E2F2 and microRNA-Let7A for osteosarcoma, and prognostic values of microRNA-Let7A for osteosarcoma was evaluated by survival curve comparisons. Results: Expression level of microRNA Let7A was significantly lower in tumor tissues than that in pericarcinomatous tissues. MicroRNA-Let7A expression in blood was significantly downregulated in osteosarcoma patients compared with normal control. Expression of microRNA-Let7A was negatively correlated with the expression of E2F2 in blood of osteosarcoma patients. Compared with E2F2, blood microRNA-Let7A can more effectively predict osteosarcoma. Overall survival rate of osteosarcoma patient with low blood expression level of miRNA-let-7a was significantly lower than that of patients with high blood expression level of miRNA-let-7a. Conclusion: Blood microRNA Let7A is a promising diagnostic and prognostic biomarker for osteosarcoma. PMID- 29992091 TI - Response to Finsterer: CPT-II deficiency needs to be detected in army personnel. PMID- 29992093 TI - Appendicitis: A rare case caused by metastatic prostate cancer. PMID- 29992092 TI - Purple urine bag syndrome, a disturbing urine discoloration. PMID- 29992094 TI - Toxicodynamics of Lead, Cadmium, Mercury and Arsenic- induced kidney toxicity and treatment strategy: A mini review. AB - Environmental pollution has become a concerning matter to human beings. Flint water crisis in the USA pointed out that pollution by heavy metal is getting worse day by day, predominantly by Lead, Cadmium, Mercury and Arsenic. Despite of not having any biological role in flora and fauna, they exhibit detrimental effect following exposure (acute or chronic). Even at low dose, they affect brain, kidney and heart. Oxidative stress has been termed as cause and effect in heavy metal-induced kidney toxicity. In treatment strategy, different chelating agent, vitamins and minerals are included, though chelating agents has been showed different fatal drawbacks. Interestingly, plants and plants derived compounds had shown possible effectiveness against heavy metals induced kidney toxicity. This review will provide detail information on toxicodynamics of Pb, Cd, Hg and As, treatment strategy along with the possible beneficiary role of plant derived compound to protect kidney. PMID- 29992095 TI - Molecular detection of human papillomavirus (HPV) in highly fragmented DNA from cervical cancer biopsies using double-nested PCR. AB - Archived Formalin-Fixed Paraffin-Embedded (FFPE) tissue specimens can be a valuable source of human papillomavirus (HPV) nucleic acids for molecular biological analyses in retrospective studies. Although successful amplification with polymerase chain reaction (PCR) is essential for analysis of HPV DNA extracted from cervical FFPE specimens, extensive DNA damage due to cross-linking and fragmentation results in poor yield. Therefore, techniques to improve the diagnostic rate and sensitivity from FFPE tissues through PCR is highly desired and of wider interest. To overcome this, a highly sensitive double-nested PCR methodology was designed and optimized for limited-resource laboratories coupled with an organic extraction of DNA. This method allows the detection of a broad range of HPV genotypes and also allowing the sequencing of the final amplicon. Validation of the new approach developed was done with an automated DNA extraction coupled with Real Time PCR. Results showed that the proposed method achieves 96.3% of HPV detection as compared to 100% Abbott m2000rt used as 'gold standard'. Moreover, the concordance rate between the two methods was equal for detecting HPV -16 or -18 genotypes. Nevertheless, the newly introduced assay has an advantage of: *Simultaneously identifying broad range of HPV genotypes besides HPV-16 and -18 from clinical samples.*It is an easy and cost-effective method that can be beneficial in resource-limited setting and can be employed for various molecular applications.*The method is indicated for highly degraded FFPE samples. PMID- 29992096 TI - Field based pilot-scale drinking water distribution system: Simulation of long hydraulic retention times and microbiological mediated monochloramine decay. AB - Drinking water distribution systems with long hydraulic retention times (HRTs) commonly encounter rapid microbiological-mediated monochloramine decay that results in microbial regrowth and nitrification with reduction in alkalinity. In this paper, we report the design and operation of a field-based pilot-scale distribution system (PDS) operated at flows that simulate long HRTs (~10 days) to promote rapid microbiological monochloramine decay over long periods. The PDS is designed to enable the testing of chemical treatment for the control of nitrification and monochloramine decay. The PDS has two identical cylindrical polyethylene tanks (DS1 & DS2), each of 1 m diameter and 1.8 m height (~1 kL) holding 900 m of polyethylene (PE) tubing with sampling points every 300 m intervals. Microbial mediated decay (determined by the Fm test) of monochloramine occurred as treated (alum coagulated and flocculated) and chloraminated water passed through the DSs. In this manuscript we report: *An inexpensive, flexible and compact system that can be readily set-up at a full-scale water treatment plant, requiring minimal supervision for operation.*A 'draw & fill' system for achieving control on HRT's through the pipes. PMID- 29992097 TI - Evaluation of dairy processing wastewater biotreatment in an IASBR system: Aeration rate impacts on performance and microbial ecology. AB - Dairy processing generates large volumes of wastewater that require extensive nutrient remediation prior to discharge. Significant commercial opportunities exist therefore for cost-effective biotechnologies capable of achieving this requirement. In this study the authors evaluated the use of intermittently aerated sequencing batch reactors, (IASBRs), as a single-tank biotreatment system for co-removal of COD, nitrogen and phosphorus from synthetic dairy processing wastewater. Variation of the IASBR aeration rates, (0.8, 0.6 and 0.4 L/min), had significant impacts on the respective nutrient removal efficiencies and underlying microbial diversity profiles. Aeration at 0.6 L/min was most effective and resulted in >90% co-removal of orthophosphate and ammonium. 16S rRNA based pyrosequencing of biomass DNA samples revealed the family Comamonadaceae was notably enriched (>80% relative abundance) under these conditions. In silico predictive metabolic modelling also identified Comamonadaceae as the major contributor of several known genes for nitrogen and phosphorus assimilation (nirK, nosZ, norB, ppK, ppX and phbC). PMID- 29992098 TI - Functional redundancy in Echinocandin B in-cluster transcription factor ecdB of Emericella rugulosa NRRL 11440. AB - Echinocandin B is a potent antifungal against the majority of fungal pathogens and its biosynthesis occurred by ecd and hty gene clusters in Emericella rugulosa NRRL 11440. We elucidated the functional necessity of in-clustered transcription factor; ecdB in the production of echinocandin B. We deleted the ecdB gene and found that DeltaecdB mutant has no significant effect on echinocandin B production. The expression level of most of the ecd and hty cluster genes was not significantly altered except few of them up-regulated in knockout strain. The complete abrogation in ecdB gene expression was observed in DeltaecdB strain. However, the interactions of purified EcdB protein with DNA sequence of ecdA, ecdH, ecdK and ecdI promoter was confirmed in-vitro. Our results conclude that EcdB protein in-vitro binds to the ecdA, ecdH, ecdK and ecdI promoter but in vivo, it could not significantly affect the gene expression and echinocandin B production in Emericella rugulosa. PMID- 29992099 TI - Combined microbiological approach to screening of producers of proteases with hemostasis system proteins activity among micromycetes. AB - A scheme for screening of micromycetes - producers of proteases with the activity of hemostasis system proteins, based on their enzymatic indices determination and the activity towards chromogenic peptide substrates for proteins of the hemostasis system was developed. Depending on the ability of proteases producers to cleave such substrates, an enzymatic reaction in conditions containing human plasma is suggested, which makes it possible to identify the potentiality of the target plasma hemostasis proenzymes activation. PMID- 29992101 TI - Evaluation and modification of lanthanum-based flocculation for isolation of bacteria from water samples. AB - Molecular detection of pathogenic microorganisms in drinking and natural water is often challenged by low concentrations of the sought-after agents. Convenient methods to concentrate bacteria from water samples ranging from 1-10 L are highly warranted. Here we account for the evaluation of a lanthanum-based flocculation method to concentrate bacteria from water samples, applying four different bacterial species in tap water as well as river water. Our results show that the success of lanthanum-based flocculation is determined by both the bacterial species and the nature of the water sample. For tap water, satisfying flocculation efficiencies (above 60 %) were only reached for autoclaved water samples. However, the performance of the lanthanum-based flocculation method for non-autoclaved water was markedly improved by the addition of 20 mM bicarbonate to increase alkalinity. Our modified flocculation protocol may be applied as an alternative concentration method for bacteria in water samples of one liter or more. PMID- 29992100 TI - Leptospira interrogans thermolysin refolded at high pressure and alkaline pH displays proteolytic activity against complement C3. AB - Enzymes from the thermolysin family are crucial factors in the pathogenesis of several diseases caused by bacteria and are potential targets for therapeutic interventions. Thermolysin encoded by the gene LIC13322 of the causative agent of leptospirosis, Leptospira interrogans, was shown to cleave proteins from the Complement System. However, the production of this recombinant protein using traditional refolding processes with high levels of denaturing reagents for thermolysin inclusion bodies (TL-IBs) solubilization results in poor recovery and low proteolytic activity probably due to improper refolding of the protein. Based on the assumption that leptospiral proteases play a crucial role during infection, the aim of this work was to obtain a functional recombinant thermolysin for future studies on the role of these metalloproteases on leptospiral infection. The association of high hydrostatic pressure (HHP) and alkaline pH was utilized for thermolysin refolding. Incubation of a suspension of TL-IBs at HHP and a pH of 11.0 is non-denaturing but effective for thermolysin solubilization. Soluble protein does not reaggregate by dialysis to pH 8.0. A volumetric yield of 46 mg thermolysin/L of bacterial culture and a yield of near 100% in relation to the total thermolysin present in TL-IBs were obtained. SEC purified thermolysin suffers fragmentation, likely due to autoproteolysis and presents proteolytic activity against complement C3 alpha-chain, possibly by a generation of a C3b-like molecule. The proteolytic activity of thermolysin against C3 was time and dose-dependent. The experience gained in this study shall help to establish efficient HHP-based processes for refolding of bioactive proteins from IBs. PMID- 29992102 TI - Biosynthesis, characterization, and evaluation of bioactivities of leaf extract mediated biocompatible gold nanoparticles from Alternanthera bettzickiana. AB - The objective of the study was to synthesize gold nanoparticles (Au NPs) using leaf extract of Alternanthera bettzickiana (A. bettzickiana). The biosynthesized Au NPs were characterized using UV-vis spectroscopy, X-ray Diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Energy dispersive X-ray analysis (EDX), Zeta potential and Transmission electron microscopy (TEM). Morphologically, the Au NPs showed spherical shaped structures. Size distribution of Au NPs calculated using Scherrer's formula, showed an average size of 80-120 nm. Au NPs were studied for invitro anti bacterial and cytotoxic activities. Au NPs exhibited significant anti-microbial activity against Bacillu subtilis, Staphylococcus aureus, Salmonella typhi, Pseudomonas aeroginosa, Micrococcus luteus, and Enterobacter aerogenes by agar well diffusion method. The cytotoxic effect of the biogenic synthesized Au NPs against A549 human lung cancer cell lines provided a vigorous evidence of anticancer activity of Au NPs. Further, the toxicity study of the green synthesized Au NPs on Danio rerio (Zebra fish) embryo was evaluated. This study reports that colloidal Au NPs can be synthesized by simple, non-hazardous methods and that bio-synthesized Au NPs have significant therapeutic properties. PMID- 29992103 TI - Effects of lipid concentration on thermophilic anaerobic co-digestion of food waste and grease waste in a siphon-driven self-agitated anaerobic reactor. AB - To investigate the influence of lipid concentration (of total solids, w/w) on anaerobic treatment of food waste under thermophilic condition, a siphon-driven self-agitated anaerobic reactor was operated for 220 days. The average lipid concentration was changed from 12.8% to 59.3% (w/w) step by step. The gas production rate increased from 1.97 to 2.31 L/L/d with lipid concentration increased from 12.8% to 19.7% (w/w), whereas decreased sharply to 0.78 L/L/d when the concentration further increased to 59.3% (w/w). The COD recovery from output at different lipid concentration was analyzed in this study. With the concentration increased from 12.8% to 59.3% (w/w), the percentage of COD recovered as methane gas decreased from 80.9% to 35.4%, while the percentage of COD remained in the effluent was also decreased significantly from 15.5% to 2.60%. The lipid concentration under 40% (w/w) was recommended in the co digestion of food waste and grease trap waste. PMID- 29992104 TI - Characterization, antioxidant and immunomodulatory potential on exopolysaccharide produced by wild type and mutant Weissella confusa strains. AB - Characterization, antioxidant and immunomodulatory potential of exopolysaccharide (EPS) produced by wild type and mutant Weissella confusa was investigated. The EPS production ranged from 5490.2 to 5580.7 mg/L. Wild type Weissella confusa (WWCEPS) had the highest EPS production. Eight (8) sugar moieties were present in the EPS. Galactose had the highest EPS composition (34.6 mg/100 g and 33.5 mg/100 g EPS) in Wild type Weissella confusa EPS (WWCEPS) and mutant Weissella confusa EPS (MWCEPS). Wild type Weissella confusa and mutant Weissella confusa EPS had antioxidant capacity. The scavenging assay for the antioxidant increased in a dose dependent (0.5-10 mg/mL) manner. Wild type Weissella confusa EPS had the highest 1,1-Diphemy 1-2-picryl-hydrazyl (DPPH) capacity, total antioxidant activity, hydrogen peroxide and reducing power activity (71%, 1.9%, 86.7% and 1.9%). The mice injected peritorially with mutant Weissella confusa EPS had the highest IgG and IgM (68-87 mg/dL and 64-70 mg/dL). IgA of the mice treated with Wild type Weissella confusa EPS increased from 67 to 73 mg/dL. Wild type and mutant Weissella confusa EPS had immunomodulatory activity on the treated mice. PMID- 29992105 TI - Medicinal and health benefit effects of functional sea cucumbers. AB - Sea cucumbers have long been used as food and traditional medicine in Asian countries with Stichopus hermanni, Thelenota ananas, Thelenota anax, Holothuria fuccogilva, and Actinopyga mauritiana as most highly-valued species. These organisms are potential source of high value-added compounds with therapeutic properties such as triterpene glycosides, carotenoids, bioactive peptides, vitamins, minerals, fatty acids, collagens, gelatins, chondroitin sulfates, amino acids. In the recent years, health benefit effects of sea cucumbers have been validated through scientific research and have shown medicinal value such as wound healing, neuroprotective, antitumor, anticoagulant, antimicrobial, and antioxidant. These functional materials lead to potential development in various foods and biomedicine industries. In this review, we have presented a general view of major medicinal and health benefit effects of functional sea cucumbers from Asia region. The structural significance and the potential application of sea cucumber-derived functional materials as well as their nutritional value are also discussed. PMID- 29992106 TI - Herbal remedies for liver fibrosis: A review on the mode of action of fifty herbs. AB - Liver fibrosis is a dynamic pathological condition which can be slowed down in its initial phases. Without proper clinical management of fibrosis, progressive liver damage may lead to cirrhosis and ultimately to liver failure or primary liver cancer, which are irreversible conditions. Therefore, in order to cure fibrotic damage to liver, its early stages should be the centre of attention. In this context, some supplements and 'complementary and alternative medicine (CAM)' deserve specific mention, because of their already recognized natural way of healing and long lasting curative effects. Moreover, CAM display negligible side effects and hence it is gaining worldwide importance in clinical practices. In particular, herbal medicines are now replacing synthetic pharmaceuticals and looked upon as the sources of novel bioactive substances. To develop satisfactory herbal combinations for treating liver fibrosis, phytoproducts need to be systematically evaluated for their potency as anti-fibrotic, anti-hepatotoxic and antioxidant agents. More importantly, the identified herb/agent should have the remarkable tendency to stimulate hepatocytes regeneration. The present review is a systematic account of at least fifty medicinal herbs and their products which in experimental models have demonstrated antifibrotic activity and thus, most likely candidates to offer therapeutic protection to liver. Nevertheless, much additional work is still needed to explore molecular pathways to discover potential applications of these medicines so as to open up new vistas in biomedical research. PMID- 29992109 TI - Effects of preoperative administration of ginger (Zingiber officinale Roscoe) on postoperative nausea and vomiting after laparoscopic cholecystectomy. AB - One of the most common postoperative problems is nausea and vomiting. Although using some anesthetic materials has been considered as the mainstay of this phenomenon, the exact factors are not known. Because of several morbidities associated with postoperative nausea and vomiting (PONV), its prevention and treatment has been a challenge for physicians, so several drugs have been recommended for this purpose. Based on the documented antiemetic specificity of ginger, we evaluated and compared the effects of preoperative administration of ginger on PONV with ondansetron administration as the standard medication. The participants included 100 patients with cholelitiasis who were candidate for laparoscopic cholecystectomy. Patients were divided into two groups: group A comprised 50 patients who received 500 mg oral ginger 1 h before surgery, and group B included 50 patients who received 4 mg intravenous ondansetron before completion of surgery. Antiemetic efficacy was assessed by visual analogue scale scores of nausea intensity at 0, 4, 8, 16, and 24 h after surgery and frequency of vomiting during the evaluation period. Although multifactor analysis showed that nausea severity was significantly lower in the ginger group, the data indicated that except 16 h after operation, the differences between two groups in the frequency of vomiting was not significant. In conclusion, though complementary studies are needed to have a strong suggestion, based on this study, we recommend administration of oral ginger 1 h before operation to control the severity of PONV in patients undergoing laparoscopic cholecystectomy. PMID- 29992108 TI - Anti-rheumatoid activity of ethanolic extract of Sesamum indicum seed extract in Freund's complete adjuvant induced arthritis in Wistar albino rats. AB - Sesamum indicum, one of the first recorded plants used for its seeds, is reported to have analgesic, antioxidant, anticancer, anti-obesity as well as hepato and nephro protective activities. The current study evaluated the effects of two doses (400 and 800 mg/kg) of ethanolic extract of S. indicum seeds in Freund's complete adjuvant induced arthritis in rats in comparison with diclofenac and methotrexate by the changes produced in body weight, body temperature, paw volume and spontaneous activity, hemoglobin, erythrocyte sedimentation rate, total white blood cells, red blood cells, Interleukin-6 and Tumor necrosis factor-alpha as well as joint changes in X-ray and histological changes in joint tissue. Unlike the untreated group, the groups treated with S. indicum showed significant decrease in paw volume, body weight, white blood cell count, erythrocyte sedimentation rate, Interleukin-6 and Tumor necrosis factor-alpha and an increase in body weight, spontaneous activity, hemoglobin level, and red blood cell count. Histopathological examination showed gross reduction in synovial inflammation and cartilage damage. X-ray revealed significant improvement in joint space. The effect of ethanolic extract of S. indicum was found to be equivalent to methotrexate and greater than diclofenac. PMID- 29992107 TI - An update on natural compounds in the remedy of diabetes mellitus: A systematic review. AB - Herbal medicine, phytomedicine or botanical medicine are synonymous, utilizes plants intended for medicinal purposes. Medicinal use of herbal medicine in the treatment and prevention of diseases including diabetes has a long history compared to conventional medicine. Diabetes is one of the major public health concerns over the world. Diabetes or hyperglycemia is considered to be one of the common public health hazard; optimal control of which is still not possible. Persistent hyperglycemia or uncontrolled diabetes has the potential to cause serious complications such as kidney disease, vision loss, cardiovascular disease, and lower-limb amputations which contributed towards morbidity and mortality in diabetes. There are various approaches to treat and prevent diabetes as well as its secondary complications, one of it is herbal medicines. However, the selection of herbs might depends on several factors, which include the stage of progression of diabetes, types of comorbidities that the patients are having, availability, affordability as well as the safety profile of the herbs. This review focuses on the herbal and natural remedies that play the role in the treatment or prevention of this morbid disorder - diabetes, including their underlying mechanisms for the blood glucose-lowering property and the herbal products already been marketed for the remedial action of diabetes. PMID- 29992110 TI - Impact of green tea extract on serum lipid of postmenopausal women: A randomized controlled trial. AB - Background: This study aimed to evaluate the impact of green tea extract on serum lipid level in postmenopausal women. Method: In this randomized controlled trial 100 postmenopausal women with an abnormality in at least one lipid profile were recruited and randomly assigned to one of the two groups: green tea extract (n = 50) and control group (n = 50). The intervention group received two capsules (400 mg) of green tea extract two times daily; the control group received a placebo for 4 weeks. The serum level of the lipid profile (total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride, and fasting blood sugar) was measured at baseline and 4 weeks after intervention. Results: In total, 79 women completed the study. The mean total cholesterol in the green tea group was significantly decreased after 4 weeks of intervention (mean difference 18.1 vs. -5 mg/dL in the green tea and placebo groups, p < 0.04). The triglyceride and LDL also decreased significantly in the green tea group compared to the control group (p = 0.002 and p = 0.04 respectively). The level of HDL and fasting blood sugar did not change within the group and between groups. Conclusion: Green tea extract is cost-effective way to decrease lipid profile in postmenopausal women without major side effects. Using this herb is recommended in women who have slight lipid profile abnormalities. PMID- 29992112 TI - Molecular mechanism of apoptosis induction in Jurkat E6-1 cells by Tribulus terrestris alkaloids extract. AB - The present study demonstrates apoptosis-inducing potential and mechanism of action of Tribulus terristris alkaloid extract in Jurkat E6-1 cancer cell line. Liquid Chromatography-Mass Spectrometry and High Resolution-Mass Spectrometry analysis identified the presence of four N-feruloyltyramine derivatives, namely trans-N-feruloyl-3-hydroxytyramine (1), trans-N-coumaroyltyramine (2), trans-N feruloyltyramine (3) and trans-N-feruloyl-3-ethoxytyramine (4) in the alkaloid extract. Compounds 2 and 3 have not been yet reported in the alkaloid extract of T. terristris. In silico analysis revealed therapeutic potential of N feruloyltyramine derivatives and strong binding efficiency to both chains of Tumor Necrosis Factor Receptor 1. Treatment of alkaloids extract to Jurkat E6-1 clone induced dose-dependent cytotoxicity (LC50 140.4 MUg mL-1). Jurkat cells treated with alkaloids extract at sub-lethal concentration showed DNA fragmentation, enhancement in caspase-3 activity and phosphatidylserine translocation (apoptosis indicator) compared to control cells. Gene expression analysis using Human Apoptosis RT2 Profiler PCR Array analysis upon alkaloid treatment was found to significantly alter expression of critical genes such as TNFR1, FADD, AIFM, CASP8, TP53, DFFA and NFKB1. These genes are predicted to mediate apoptotic cell death via both intrinsic and extrinsic apoptosis pathway. In summary, we report the identification of new N-feruloyltyramine derivatives from alkaloid extract of T. terristris fruit with probable anti-leukemic and pharmacological potential. PMID- 29992111 TI - Kolaviron attenuated arsenic acid induced-cardiorenal dysfunction via regulation of ROS, C-reactive proteins (CRP), cardiac troponin I (CTnI) and BCL2. AB - Arsenic acid is one of the abundant environmental pollutants present in soil, water and the air. Undoubtedly, it has found its way to the food chain in which humans and animals are the final targets thereby causing arrays of disease conditions including cardiovascular and renal dysfunction. Hence, the use of phytochemicals present in medicinal plants has gained global acceptance as chemotherapeutic agents that can prevent, ameliorate, reverse or treat diseases. From our study, arsenic acid intoxication led to significant increase in heart rate (HR), QRS, together with prolonged QT and QTc interval. However, Kolaviron (KV) at the dosage of 100 and 200 mg/kg body weight reversed the aforementioned electrocardiographic (ECG) changes. KV pre-treatment also ameliorated cardiorenal dysfunction via significant reduction in cardiac and renal markers of oxidative stress such as malondialdehyde, hydrogen peroxide generation, myeloperoxidase activity and nitric oxide contents. Immunohistochemistry revealed expressions of renal C-reactive proteins (CRP) and expressions of anti-apoptotic protein BCL2 in KV treated rats. Furthermore, cardiac troponin I (CTnI) expressions were lower in KV treated rats. Taken together, KV mitigated arsenic-acid induced cardiovascular dysfunction via up-regulation of antioxidant defense system and down-regulation of inflammatory and apoptotic signaling pathways. PMID- 29992114 TI - Types of Special Infant Formulas Marketed in Korea and Their Indications. AB - Infant formula is classified into standard cow's milk-based and special formulas. This review aimed at summarizing the types of special milk formulas currently sold in Korea, and the appropriate indications for the use of these formulas; lactose free formula, soy-based formula, protein hydrolysate formula, amino acid based formula, preterm formula, medium chain triglyceride formula, low-phosphorus formula, protein-energy-enriched formula, and formulas for inborn errors of metabolism. PMID- 29992113 TI - DNA scission and LDL cholesterol oxidation inhibition and antioxidant activities of Bael (Aegle marmelos) flower extracts. AB - Phenolic compounds and other antioxidants have been implicated in protection against non-communicable diseases (NCDs) in which oxidative stress is a main contributor. The extracts of Bael (Aegle marmelos) flower were examined for their phenolic content, free radical scavenging efficacy and inhibition of low density lipoprotein (LDL) cholesterol oxidation and DNA scission activities. The extracts of Bael flowers were prepared using different solvent systems and their total phenolic content (TPC) and total flavonoid content (TFC) determined. Selected extracts which showed high TPC were subsequently used to determine their efficacy in scavenging hydroxyl, and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, using electron paramagnetic resonance (EPR) spectroscopy. The corresponding peroxyl radical scavenging activity was measured using oxygen radical absorbance capacity (ORAC) assay. The potency of the extracts in inhibiting hydroxyl and peroxyl radical-induced supercoiled DNA scission and inhibition of LDL cholesterol oxidation was also evaluated. The chemical identity of phenolic compounds present in the extracts was tentatively unraveled using HPLC-MS. Phenolic extracts of Bael flowers effectively inhibited hydroxyl, and peroxyl radicals. Phenolic extracts demonstrated notable inhibitory activity against hydroxyl and peroxyl radical-induced DNA scission and LDL oxidation. Vanillic, p-coumaric, chlorogenic, caffeic, and gentisic acids were identified as major phenolic acids, along with flavonoids, mainly catechin, and quercetin. The knowledge gained here may help better use of Bael flower extracts as functional herbal beverage ingredients in the prevention of NCDs. PMID- 29992115 TI - Gastritis Associated with Initially Pediatric Crohn's Disease and Ulcerative Colitis. AB - Purpose: The aim of this study is to determine the involvement of the upper gastrointestinal system (GIS) in patients diagnosed with Crohn's disease (CD), ulcerative colitis (UC), and non-inflammatory bowel disease (IBD) and to compare their differences. Methods: This study included patients aged between 2 and 18 years who underwent colonoscopy and esophagogastroduodenoscopy (EGD) for the first time due to the prediagnosis of IBD. In EGD, samples were taken from duodenum, antrum, corpus, and esophagus; and gastritis, duodenitis, and esophagitis were identified through histopathologic examination. The data gathered the ends of the research were compared between IBD with non-IBD groups and between CD-UC with non-IBD groups, and the presence of significant differences between groups were determined. Results: In our study, 16 patients were diagnosed with CD, 13 with UC, 3 with undeterminate colitis, and 13 with non IBD. In the histopathological examination of the groups, GIS involvement was found in 94.1% of patients diagnosed with IBD and in 38.5% of non-IBD patients. Moreover, the difference was found to be statistically significant (p=0.032). No significant difference was found between the CD and UC groups. Gastritis was mostly observed in 93.8% of CD-diagnosed patients, 76.8% of UC-diagnosed patients, 81.2% of IBD-diagnosed patients, and 38.5% of non-IBD-diagnosed patients. On the other hand, significant differences were found between CD and non-IBD groups (p=0.03), UC and non-IBD groups (p=0.047), and IBD and non-IBD groups (p=0.03). Conclusion: The results of the study show that gastritis was highly observed in UC- and CD-diagnosed patients than in non-IBD-diagnosed patients. PMID- 29992116 TI - An Electronic Questionnaire Survey Evaluating the Perceived Prevalence and Practices of Lactose Intolerance in 1 to 5 Year Old Children in South East Asia. AB - Purpose: Lactose intolerance (LI) is perceived to be frequent in Asia and has been reported to have considerable impact on dietary intake, nutritional status and the quality of life. We aimed to gather information from healthcare professionals on the perceived incidence, diagnosis and management of LI in 1 to 5 year old children in Southeast Asia. Methods: An anonymous electronic survey was sent randomly among healthcare professionals registered in the database of the pediatric societies in Thailand, Indonesia, and Singapore between June and October 2016. Results: In total, 259 health care professionals responded of which 45.5% (n=118) were from Thailand, 37.4% (n=97) from Indonesia and 16.9% (n=44) from Singapore. Of the participants who responded (n=248), primary LI prevalence among children 1 to 3 years of age was estimated to be less than 5% by 56.8%. However, about 18.9% (n=47) answered they did not know/unsure. Regarding secondary LI, 61.6% of respondents (n=153) estimated the prevalence to be less than 15%. But again, 10.8% (n=27) answered they did not know or unsure. Rotavirus gastroenteritis was ranked as the top cause for secondary LI. There was considerable heterogeneity in the diagnostic methods used. The majority of respondents (75%) recommended lactose-free milk to manage primary and secondary LI. Conclusion: More education/training of pediatricians on this topic and further epidemiological studies using a more systematic approach are required. PMID- 29992117 TI - Surveillance Study of Acute Gastroenteritis Etiologies in Hospitalized Children in South Lebanon (SAGE study). AB - Purpose: Acute gastroenteritis (AGE) is a major cause of morbidity and remains a major cause of hospitalization. Following the Syrian refugee crisis and insufficient clean water in the region, this study reviews the etiological and epidemiological data in Lebanon. Methods: We prospectively analyzed demographic, clinical and routine laboratory data of 198 children from the age of 1 month to 10 years old who were admitted with the diagnosis of AGE to a private tertiary care hospital located in the district of Nabatieh in south Lebanon. Results: Males had a higher incidence of AGE (57.1%). Pathogens were detected in 57.6% (n=114) of admitted patients, among them single pathogens were found in 51.0% (n=101) of cases that consisted of: Entamoeba histolytica 26.3% (n=52), rotavirus 18.7% (n=37), adenovirus 6.1% (n=12) and mixed co-pathogens found in 6.6% (n=13). Breast-fed children were significantly less prone to rotavirus (p=0.041). Moreover, children who had received the rotavirus vaccine were significantly less prone to rotavirus (p=0.032). Conclusion: Our findings highlight the high prevalence of E. histolytica infection as the major cause of pediatric gastroenteritis in hospitalized children, during the summer period likely reflecting the insanitary water supplies and lack of hygiene. Moreover the 42.4% of unidentified causative pathogens should prompt us to widen our diagnostic laboratory arsenal by adopting new diagnostic technologies. PMID- 29992118 TI - Significance of Perianal Lesion in Pediatric Crohn Disease. AB - Purpose: Despite the increasing incidence of pediatric Crohn disease (CD) in Korea, data on the characteristics of perianal lesions are scarce. Therefore, we aimed to investigate the characteristics of pediatric CD with accompanying perianal lesions in Korea. Methods: We retrospectively reviewed the medical records of children (age <=18 years) with confirmed CD at Gachon University Gil Medical Center between 2000 and 2014. Patients were classified into two groups based on the presence or absence of any perianal lesions including skin tags. Additional analysis was performed according to the presence or absence of perianal perforating lesions. Results: Among the 69 CD children (mean age, 15.4 years) include in the analysis, 54 (78.3%) had a perianal lesion and 29 (42.0%) had a perianal perforating lesion. The median duration of chief complaints was longer in pediatric CD with any accompanying perianal lesions (5.40 months vs. 1.89 months, p=0.02), while there was no difference between pediatric CD with and without perianal perforating lesions (5.48 months vs. 4.02 months, p=0.18). Perianal symptoms preceded gastrointestinal symptoms in 13 of 29 (44.8%) patients with perianal perforating lesions. Conclusions: CD should be suspected in children with perianal lesions, even in circumstances when gastrointestinal symptoms are absent. PMID- 29992119 TI - Amino Acid-Based Formula in Premature Infants with Feeding Intolerance: Comparison of Fecal Calprotectin Level. AB - Purpose: We investigated fecal calprotectin (FC) levels in preterm infants with and without feeding intolerance (FI), and compared the FC levels according to the type of feeding. Methods: The medical records of 67 premature infants were reviewed retrospectively. The fully enteral-fed infants were classified into two groups; the FI group (29 infants) and the control group (31 infants). Seven infants with necrotizing enterocolitis, sepsis, and perinatal asphyxia were excluded. If breast milk (BM) or preterm formula (PF) could not be tolerated by infants with FI, amino acid-based formula (AAF) was tried temporarily. Once FI improved, AAF was discontinued, and BM or PF was resumed. We investigated the FC levels according to the type of feeding. Results: Significant differences were found in gestational age, birth weight, age when full enteral feeding was achieved, and hospital stay between the FI and control group (p<0.05). The FC levels in the FI group were significantly higher than those in the control group (p<0.05). The FC levels in the AAF-fed infants with FI were significantly lower than those in the BM- or PF-fed infants (p<0.05). The growth velocities (g/d) and z scores were not significantly different between the FI and control group (p>0.05). Conclusion: The FC levels in AAF-fed infants with FI showed significantly lower than those in the BM- or PF-fed infants with FI. The mitigation of gut inflammation through the decrease of FC levels in AAF-fed infants with FI could be presumed. PMID- 29992120 TI - Clinical Characteristics of Children Needing Inpatient Treatment after Failed Outpatient Treatment for Fecal Impaction. AB - Purpose: Treatment of chronic constipation and fecal impaction is usually outpatient and requires high or frequent doses of laxatives. However, there are children who fail outpatient treatments, sometimes repeatedly, and are ultimately hospitalized. We sought to compare the characteristics of the children who failed outpatient treatment and needed inpatient treatment vs those who achieved success with outpatient treatment, in an effort to identify attributes that might be associated with a higher likelihood towards hospitalization. Methods: In this retrospective cohort study, we reviewed the medical records of all patients aged 0 to 21 years, with chronic functional constipation and fecal impaction seen in the pediatric gastroenterology clinic over a period of 2 years. Results: Total of 188 patients met inclusion criteria. While 69.2% were successfully treated outpatient (referred to as the outpatient group), 30.9% failed outpatient treatment and were hospitalized (referred to as the inpatient group). The characteristics of the inpatient group including age at onset of 3.6+/-3.6 years (p=0.02); black ethnicity (odds ratio [OR] 4.31, 95% confidence interval [95% CI] 2.04-9.09); p<0.001); prematurity (OR 2.39, 95% CI 1.09-5.26; p=0.02]; developmental delay (OR 2.20, 95% CI 1.12-4.33; p=0.02); overflow incontinence (OR 2.26, 95% CI 1.12-4.53, p=0.02); picky eating habits (OR 2.02, 95% CI 1.00 4.08; p=0.04); number of ROME III criteria met: median 4, interquartile range 3-5 (p=0.04) and 13+/-13.7 constipation related prior encounters (p=0.001), were significantly different from the outpatient group. Conclusion: Identification of these characteristics may be helpful in anticipating challenges and potential barriers to effective outpatient treatment. PMID- 29992121 TI - Management of Pediatric Patients Presenting with Acute Abdomen Accompanying Dilatation of the Common Bile Duct. AB - Purpose: The aim of this study was to describe our treatment experiences with patients who had acute abdomen (AA) with common bile duct (CBD) dilatation. Methods: The treatment outcomes in children with AA and CBD dilatation were retrospectively reviewed. According to the shape of the intrahepatic bile ducts on ultrasonography (US), the origin of the pain was estimated as choledochal cyst (CC) complication or choledocholithiasis in normal CBD. Patients with complicated CC underwent surgery, and patients with choledocholithiasis in a normal appearing CBD underwent symptomatic treatment initially. Results: Of the 34 patients, 30 (88.2%) were female. The mean age of the patients was 6.4+/-4.9 (range, 0.8-17) years. Seventeen (50.0%) patients had CBD stones and 17 (50.0%) did not. Surgical treatment was performed in 20 (58.8%) patients, 2 of whom underwent preoperative stone removal with endoscopic retrograde cholangiopancreatography and an operation. Conservative treatment was applied in 12 (35.3%) patients (8 with and 4 without stones), 1 of whom developed symptom relapse and underwent an operation. Among the 8 patients with CBD stones, 4 (4/17, 23.5%) had complete resolution of the stones and recovery of the CBD diameter after conservative treatment. US findings of patients with stone showed a fusiform or cylindrical shape of the CBD in 14 (82.4%) patients. Conclusion: The presence of stones in the distal CBD and the US features of CBD dilatation may be helpful to diagnose and treat the causes of biliary dilatation. Conservative treatment can be considered as initial therapy in patients with uncomplicated CBD dilatation with stone. PMID- 29992122 TI - Incidentally Discovered Solitary Gastrointestinal Polyp with Pathological Significance in Children: Four Case Reports. AB - Most solitary gastrointestinal (GI) polyps in children are either inflammatory or hamartomatous. Solitary hyperplastic polyp, sentinel polyp and solitary adenomatous polyp have been occasionally diagnosed in adults, but very rarely reported in Korean children. We recently came across a case with adenomatous polyp in the colon, a case with hyperplastic polyp beneath the gastroesophageal junction, a case with hyperplastic polyp in the prepyloric area, and a case with sentinel polyp in the distal esophagus, which are unusual pathologic types in children. These mucosal lesions were diagnosed incidentally during elective endoscopic examinations for GI symptoms. Most polyps do not cause significant symptoms, so the diagnosis might be delayed, especially in children, in whom GI endoscopy is not commonly performed for screening purpose as in the adults. PMID- 29992123 TI - Lemierre Syndrome in Adolescent with Active Ulcerative Colitis. AB - Inflammatory bowel disease (IBD) is a well-recognized risk factor for thrombotic events in adults but data on children are scarce. In the great majority of adult patients, thrombotic events are usually deep vein thrombosis and pulmonary embolism. Other sites such as jugular veins are extremely rare. We present a case of Lemierre syndrome in an adolescent girl with active ulcerative colitis and discuss possible risk factors. This is the first reported case of severe Lemierre syndrome with thrombus extension to cranial veins in a patient with ulcerative colitis. Early recognition of Lemierre syndrome in patients who present with rapidly worsening symptoms of neck pain, fever and signs of pharyngitis is imperative because it increases a chance of favorable prognosis. It is important for pediatricians treating IBD patients not to underestimate possible thrombotic events in children with IBD. Recognition of additional risk factors is crucial for prompt diagnosis and adequate treatment. PMID- 29992124 TI - Diagnostic Accuracy of Focused Assessment With Sonography for Trauma in the Emergency Department. AB - Background: Trauma is currently the fourth leading cause of death in developed countries. One of the main objectives in abdominal trauma patients is to develop a rapid and accurate diagnosis. There is a tendency to use emergency abdominal ultrasound with abdominal trauma, therefore, it is recommended in some centers as a diagnostic tool and as a primary choice in abdominal trauma. Objectives: The aim of this study was to determine the diagnostic accuracy of sonography for trauma by emergency medicine residents and radiology residents. Patients and Methods: This was a descriptive and analytical study performed on patients with abdominal blunt trauma who referred to the emergency ward. The diagnostic accuracy of sonography for trauma by emergency medicine residents and radiology residents was evaluated. Results: Of the 380 patients, 296 were males and 84 were females. The mean ages of male and female patients were 34.52 +/- 16.38 years and 41.19 +/- 21.38 years, respectively (P = 0.009). The sonographies performed by emergency residents were positive in 46 patients, with 22 of these confirmed by CT scans. The sensitivity and specificity of the sonography by emergency residents, as confirmed by CT scans, were 78.5% and 93.2%, respectively. The sonographies performed by radiology residents were positive in 38 patients, with 24 being confirmed by CT scans. Conclusions: The sensitivity and specificity of the sonography by radiology residents, as confirmed by CT scans, were 85.7% and 96%, respectively. Sonographies performed by emergency residents were positive in 46 patients with 34 of these being confirmed by sonographies by radiology residents. The sensitivity and specificity of the sonographies by emergency residents, as confirmed by sonographies by radiology residents, were 89.5% and 96.5%, respectively. PMID- 29992125 TI - Dangerous Toys for Teenagers: Air Weapons. AB - Introduction: Air weapons are used for sport, hunting, firearm training or just for fun, especially by teenagers, worldwide. These weapons are generally regarded as toys, and injuries from these weapons are thought to be harmless by users, parents and even officials. Improvements in weapons technology make the penetration power of these toys similar to conventional hand guns. To increase awareness about the serious injuries associated with these guns. Case Presentation: The medical records of four teenage boys shot by air weapons between January 2012 and January 2013 in Mersin, Turkey, were retrospectively reviewed in this study. Of the four boys, two needed prompt thoracic intervention due to pneumo/hemothorax, one needed urgent abdominal exploration due to pneumoperitoneum and bleeding from the spleen and one was treated conservatively. Conclusions: Air weapons can cause serious injuries among children. Increased public awareness, limitations to their usage and strict legislation are needed to protect children. PMID- 29992126 TI - Validation of an Iranian Trauma Data Collection Form. AB - Background: Knowing the direction of traumatic injury is important as the information can help avoid death after trauma. A trauma registry usually entails detailed information about the demographics, cause, intensity of the injury, and the final diagnosis and outcome of the trauma-affected patient. Researchers should be able to evaluate all aspects of trauma injury and the patient's status. Objectives: The purpose of this study was to develop a trauma data collection form. Materials and Methods: The development of the trauma registry form began in February 2013. The variables were finalized by a team consisting of general and trauma surgeons, specialists in emergency medicine, orthopedists, neurosurgeons, and public health professionals who have special interest in trauma research. The scale was sent to 10 specialists for validation. Results: After assessing the scale validity twice, it was accepted with an integrator agreement of 0.89. The test-retest reliability was assessed in a convenience sample of 20 physicians (Kendall t = 0.97; P < 0.001). Such a high reliability may reflect redundancy of some items. Conclusions: It is essential to establish a secure multicenter trauma registry in Iran for data collection, storage, and assessment of traumatic injury and these registries must be easy to install and use. PMID- 29992127 TI - Immune Condition of Colorectal Cancer Patients Featured by Serum Chemokines and Gene Expressions of CD4+ Cells in Blood. AB - Background: Colorectal cancer (CRC), the most common malignancy worldwide, causes inflammation. We explored the inflammatory pathophysiology of CRC by assessing the peripheral blood parameters. Methods: The differences in gene expression profiles of whole blood cells and cell subpopulations between CRC patients and healthy controls were analyzed using DNA microarray. Serum cytokine/chemokine concentrations in CRC patients and healthy controls were measured via multiplex detection immunoassays. In addition, we explored correlations between the expression levels of certain genes of peripheral CD4+ cells and serum chemokine concentrations. Results: The gene expression profiles of peripheral CD4+ cells of CRC patients differed from those of healthy controls, but this was not true of CD8+ cells, CD14+ cells, CD15+ cells, or CD19+ cells. Serum IL-8 and eotaxin-1 levels were significantly elevated in CRC patients, and the levels substantially correlated with the expression levels of certain genes of CD4+ cells. Interestingly, the relationships between gene expression levels in peripheral CD4+ cells and serum IL-8 and eotaxin-1 levels resembled those of monocytes/macrophages, not T cells. Conclusions: Serum IL-8 and eotaxin-1 concentrations increased and were associated with changes in the gene expression of peripheral CD4+ cells in CRC patients. PMID- 29992130 TI - Antagonism between salicylate and the cAMP signal controls yeast cell survival and growth recovery from quiescence. AB - Aspirin and its main metabolite salicylate are promising molecules in preventing cancer and metabolic diseases. S. cerevisiae cells have been used to study some of their effects: (i) salicylate induces the reversible inhibition of both glucose transport and the biosyntheses of glucose-derived sugar phosphates, (ii) Aspirin/salicylate causes apoptosis associated with superoxide radical accumulation or early cell necrosis in MnSOD-deficient cells growing in ethanol or in glucose, respectively. So, treatment with (acetyl)-salicylic acid can alter the yeast metabolism and is associated with cell death. We describe here the dramatic effects of salicylate on cellular control of the exit from a quiescence state. The growth recovery of long-term stationary phase cells was strongly inhibited in the presence of salicylate, to a degree proportional to the drug concentration. At high salicylate concentration, growth reactivation was completely repressed and associated with a dramatic loss of cell viability. Strikingly, both of these phenotypes were fully suppressed by increasing the cAMP signal without any variation of the exponential growth rate. Upon nutrient exhaustion, salicylate induced a premature lethal cell cycle arrest in the budded G2/M phase that cannot be suppressed by PKA activation. We discuss how the dramatic antagonism between cAMP and salicylate could be conserved and impinge common targets in yeast and humans. Targeting quiescence of cancer cells with stem-like properties and their growth recovery from dormancy are major challenges in cancer therapy. If mechanisms underlying cAMP-salicylate antagonism will be defined in our model, this might have significant therapeutic implications. PMID- 29992129 TI - Shepherding DNA ends: Rif1 protects telomeres and chromosome breaks. AB - Cells have evolved conserved mechanisms to protect DNA ends, such as those at the termini of linear chromosomes, or those at DNA double-strand breaks (DSBs). In eukaryotes, DNA ends at chromosomal termini are packaged into proteinaceous structures called telomeres. Telomeres protect chromosome ends from erosion, inadvertent activation of the cellular DNA damage response (DDR), and telomere fusion. In contrast, cells must respond to damage-induced DNA ends at DSBs by harnessing the DDR to restore chromosome integrity, avoiding genome instability and disease. Intriguingly, Rif1 (Rap1-interacting factor 1) has been implicated in telomere homeostasis as well as DSB repair. The protein was first identified in Saccharomyces cerevisiae as being part of the proteinaceous telosome. In mammals, RIF1 is not associated with intact telomeres, but was found at chromosome breaks, where RIF1 has emerged as a key mediator of pathway choice between the two evolutionary conserved DSB repair pathways of non-homologous end joining (NHEJ) and homologous recombination (HR). While this functional dichotomy has long been a puzzle, recent findings link yeast Rif1 not only to telomeres, but also to DSB repair, and mechanistic parallels likely exist. In this review, we will provide an overview of the actions of Rif1 at DNA ends and explore how exclusion of end-processing factors might be the underlying principle allowing Rif1 to fulfill diverse biological roles at telomeres and chromosome breaks. PMID- 29992132 TI - Prevalence and Associated Factors of Suicide Ideation and Attempt among Adolescent High School Students in Dangila Town, Northwest Ethiopia. AB - Background: Suicide is a major public health problem and is common among adolescents worldwide. The true extent of the problem in Ethiopia is difficult to ascertain as suicides and suicidal behavior are significantly underreported and understudied. Objective: We assessed the prevalence and factors associated with suicide ideation and suicide attempt among adolescent high school students in Dangila Town, Ethiopia. Methods: This school-based cross-sectional study was conducted from April to May 2015 in Dangila Town. Data were collected from adolescent high school students using pretested, self-administered Amharic language questionnaire. We conducted bivariable and multivariable logistic regression to identify the independent factors associated with suicide ideation and attempt. Results: A total of 573 of 603 sampled students participated in the study (95% response rate). The mean (+/-SD) age of the respondents was 17.52 (+/ 0.97) years. The minimum and maximum ages were 15 and 19 years, respectively. The prevalence of suicide ideation and attempt was 22.5% and 16.2%, respectively. School absenteeism [AOR 4.30, 95% CI (2.03, 9.10)] and poor social support [AOR 5.58, 95% CI (2.25, 13.84)] were positively associated with suicide ideation. Poor social support [AOR 4.55, 95% CI (1.40, 14.77)] and being physically hurt [AOR 4.25, 95% CI (1.77, 10.20)] were positively associated with suicide attempt. Unlike previous studies of adolescents in low-income countries, we find no association between gender or alcohol use and suicidal thoughts or attempts. Conclusion: This study revealed that at least one in five of the adolescents in our sample had experienced suicide ideation and one in six had attempted suicide. School absenteeism, poor social support, and experience of violence were identified as independent contributors to suicide ideation and attempt. These findings suggest a need for education policymakers to implement school-based behavioral therapy programs in collaboration with health institutions and programs to provide social support for vulnerable students. PMID- 29992131 TI - Microbial and host immune factors as drivers of COPD. AB - Compartmentalisation of the respiratory tract microbiota in patients with different chronic obstructive pulmonary disease (COPD) severity degrees needs to be systematically investigated. In addition, it is unknown if the inflammatory and emphysematous milieux in patients with COPD are associated with changes in the respiratory tract microbiota and host macrophage gene expression. We performed a cross-sectional study to compare non-COPD controls (n=10) to COPD patients (n=32) with different disease severity degrees. Samples (n=187) were obtained from different sites of the upper and lower respiratory tract. Microbiota analyses were performed by 16S ribosomal RNA gene sequencing and host gene expression analyses by quantitative real-time PCR of distinct markers of bronchoalveolar lavage cells. Overall, the microbial communities of severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 3/4) patients clustered significantly differently to controls and less severe COPD (GOLD 1/2) patients (permutational multivariate ANOVA (MANOVA), p=0.001). However, we could not detect significant associations between the different sampling sites in the lower airways. In addition, the chosen set of host gene expression markers significantly separated COPD GOLD 3/4 patients, and we found correlations between the composition of the microbiota and the host data. In conclusion, this study demonstrates associations between host gene expression and microbiota profiles that may influence the course of COPD. PMID- 29992133 TI - The High Origin of the Radial Artery (Brachioradial Artery): Its Anatomical Variations, Clinical Significance, and Contribution to the Blood Supply of the Hand. AB - Background: This study thoroughly analyzes the anatomic variations of the brachioradial artery (radial artery of high origin) based on the variability of its origin, the presence and types of anastomosis with the brachial artery in the cubital fossa ("cubital crossover" or "cubital connection"), and the pattern of radial recurrent arteries, as well as the vascular territory within the hand. Material and Methods: One hundred and twenty randomly selected, isolated upper limbs fixed in 10% formalin solution were dissected. Results: The radial artery was found to have a high origin in 9.2% of total number of the limbs: two cases from the axillary artery; nine cases from the brachial artery. Anastomosis between the brachioradial and "normal" brachial arteries in the cubital fossa was also frequently observed (54.6%). The anastomosis ("cubital crossover") was dominant in one case, balanced in three cases, minimal in two cases, and absent in five cases. Conclusions: The brachioradial artery may originate from the brachial and, less frequently, from the axillary artery. Anastomosis between the brachioradial and "normal" brachial arteries in the cubital fossa may be dominant, balanced, minimal, or absent. A complete radioulnar arch was found more often when the brachioradial artery was present as a variant. PMID- 29992128 TI - Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms. AB - Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research. To direct advancements in this field, here we present an overview of the methods currently available for determining (i) the susceptibility or resistance of fungal isolates or biofilms to antifungal or antibiofilm compounds and compound combinations; (ii) the in vivo efficacy of antifungal and antibiofilm compounds and compound combinations; and (iii) the in vitro and in vivo performance of anti-infective coatings and materials to prevent fungal biofilm-based infections. PMID- 29992134 TI - Reference Gene Selection for Quantitative Real-Time PCR of Mycelia from Lentinula edodes under High-Temperature Stress. AB - Housekeeping genes are important for measuring the transcription expression of functional genes; 10 traditional reference genes, TUB, TUA, GADPH, EF1, 18S, GTP, ACT, UBI, UBC, and H2A, were tested for their adequacy in Lentinula edodes (L. edodes). Using specific primers, mRNA levels of these candidate housekeeping genes were evaluated in mycelia of L. edodes, which were treated with high temperature stress at 37 degrees C for 0, 4, 8, 12, 18, and 24 hours. After treatment, expression stability of candidate genes was evaluated using three statistical software programs: geNorm, NormFinder, and BestKeeper. According to geNorm, TUB had the lowest M values in L. edodes strains 18 and 18N44. Using NormFinder, the best candidate reference gene in strain 18 was TUB (0.030), and the best candidate reference gene in strain 18N44 was UBI (0.047). In BestKeeper analysis, the standard deviation (SD) values of UBC, TUA, H2A, EF1, ACT, 18S, and GTP in strain 18 and those of GADPH and GTP in strain 18N44 were greater than 1; thus, these genes were disqualified as reference genes. Taken together, only UBI and TUB were found to be desirable reference genes by BestKeeper software. Based on the results of three software analyses, TUB was the most stable gene under all conditions and was verified as an appropriate reference gene for quantitative real-time polymerase chain reaction in L. edodes mycelia under high-temperature stress. PMID- 29992135 TI - Evaluation of the Effect of Different Types of Abrasive Surface Treatment before and after Zirconia Sintering on Its Structural Composition and Bond Strength with Resin Cement. AB - This study evaluated the effect of air abrasion before and after sintering with different particle type, shape, and size on the surface morphology, monoclinic phase transformation, and bond strength between resin cement and zirconia surface using primer containing silane and MDP. Airborne particle abrasion (APA) was performed on zirconia before and after sintering with different particle shape and size (50 MUm Al2O3 and 25 MUm silica powder). 120 square shaped presintered zirconia samples (Amann Girrbach) were prepared (3 mm height * 10 mm width * 10 mm length) and polished with grit papers #800, 1000, 1200, 1500, and 2000. Samples were divided into 6 groups according to surface treatment-group A: (control) no surface treatment; group B: APA 50 MUm Al2O3 before sintering (BS); group C: APA 50 MUm Al2O3 after sintering (AS); group D: APA25 MUm silica powder (BS); group E: APA25 MUm silica powder (AS) at a pressure of 3.5 bar; and group F: APA 25 MUm silica powder (AS) at a pressure of 4 bar. Samples were analyzed using XRD, AFM, and SEM. The samples were submitted to shear bond strength (SBS) test. A dual cure resin cement (RelyX Ultimate) and primer (Scotchbond Universal) were used. Data were analyzed with ANOVA and Tukey test (alpha >= 0.05). APA in group B significantly increased the surface roughness when compared to all other groups. A significant monoclinic phase transformation (t-m) value was observed in groups C and F and a reverse transformation occurred in presintered groups. The SBS value of group A was 11.58 +/- 1.43 and the highest significant shear bond strength value was for groups B (15.86 +/- 1.92) and C (17.59 +/- 2.21 MPa) with no significant difference between them. Conclusions. The use of APA 50 MUm Al2O3 before sintering and the application of primer containing MDP seem to be valuable methods for durable bonding with zirconia. The use of APA 50 MUm Al2O3 after sintering induced the highest (t-m) phase transformation. PMID- 29992136 TI - Burkholderia pseudomallei Adaptation for Survival in Stressful Conditions. AB - Burkholderia pseudomallei is a Gram-negative bacterium that causes melioidosis, which can be fatal in humans. Melioidosis is prevalent in the tropical regions of Southeast Asia and Northern Australia. Ecological data have shown that this bacterium can survive as a free-living organism in environmental niches, such as soil and water, as well as a parasite living in host organisms, such as ameba, plants, fungi, and animals. This review provides an overview of the survival and adaptation of B. pseudomallei to stressful conditions induced by hostile environmental factors, such as salinity, oxidation, and iron levels. The adaptation of B. pseudomallei in host cells is also reviewed. The adaptive survival mechanisms of this pathogen mainly involve modulation of gene and protein expression, which could cause alterations in the bacteria's cell membrane, metabolism, and virulence. Understanding the adaptations of this organism to environmental factors provides important insights into the survival and pathogenesis of B. pseudomallei, which may lead to the development of novel strategies for the control, prevention, and treatment of melioidosis in the future. PMID- 29992138 TI - Identification of Hub Genes and Key Pathways Associated with Two Subtypes of Diffuse Large B-Cell Lymphoma Based on Gene Expression Profiling via Integrated Bioinformatics. AB - There is a significant difference in prognosis between the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes of diffuse large B-cell lymphoma (DLBCL). However, the signaling pathways and driver genes involved in these disparate subtypes are ambiguous. This study integrated three cohort profile datasets, including 250 GCB samples and 250 ABC samples, to elucidate potential candidate hub genes and key pathways involved in these two subtypes. Differentially expressed genes (DEGs) were identified. After Gene Ontology functional enrichment analysis of the DEGs, protein-protein interaction (PPI) network and sub-PPI network analyses were conducted using the STRING database and Cytoscape software. Subsequently, the Oncomine database and the cBioportal online tool were employed to verify the alterations and differential expression of the 8 hub genes (MME, CD44, IRF4, STAT3, IL2RA, ETV6, CCND2, and CFLAR). Gene set enrichment analysis was also employed to identify the intersection of the key pathways (JAK-STAT, FOXO, and NF-kappaB pathways) validated in the above analyses. These hub genes and key pathways could improve our understanding of the process of tumorigenesis and the underlying molecular events and may be therapeutic targets for the precise treatment of these two subtypes with different prognoses. PMID- 29992137 TI - NAT2 Gene Polymorphisms in Turkish Patients with Psoriasis Vulgaris. AB - Psoriasis is a common, chronic, and autoimmune skin disease. Factors that play a role in etiopathogenesis of psoriasis include internal factors such as genetic susceptibility and immunological factors and external factors such as stress, infection, trauma, drug, and environmental compounds. N-acetyltransferase 2 (NAT2) is a xenobiotic enzyme that is involved in the metabolism of drugs, environmental toxins, and carcinogens. In this study, we aimed to demonstrate whether the variations in the NAT2 gene lead to a predisposition to psoriasis by affecting the enzyme's ability to metabolize drugs and environmental components or not. Three polymorphisms (rs1799929, rs1799930, and rs1799931) in NAT2 gene were genotyped and compared by real-time PCR method in 260 psoriasis vulgaris patients and 200 healthy controls. There was no difference in the genotype distributions and allele frequencies of polymorphisms between psoriasis vulgaris patients and controls. When the effects of polymorphisms on the clinical features of the disease, such as onset age and severity, are assessed, it has been found that rs1799930 and rs1799929 are, respectively, associated with early onset age and severity of the disease. In conclusion, rs1799929, rs1799930, and rs1799931 polymorphisms of the NAT-2 gene do not appear to be a risk factor for the development of psoriasis. Conversely, they may have an effect on either more severe or early onset cases of the disease. PMID- 29992139 TI - Bioinformatical Analysis of Organ-Related (Heart, Brain, Liver, and Kidney) and Serum Proteomic Data to Identify Protein Regulation Patterns and Potential Sepsis Biomarkers. AB - During the last years, proteomic studies have revealed several interesting findings in experimental sepsis models and septic patients. However, most studies investigated protein alterations only in single organs or in whole blood. To identify possible sepsis biomarkers and to evaluate the relationship between protein alteration in sepsis affected organs and blood, proteomics data from the heart, brain, liver, kidney, and serum were analysed. Using functional network analyses in combination with hierarchical cluster analysis, we found that protein regulation patterns in organ tissues as well as in serum are highly dynamic. In the tissue proteome, the main functions and pathways affected were the oxidoreductive activity, cell energy generation, or metabolism, whereas in the serum proteome, functions were associated with lipoproteins metabolism and, to a minor extent, with coagulation, inflammatory response, and organ regeneration. Proteins from network analyses of organ tissue did not correlate with statistically significantly regulated serum proteins or with predicted proteins of serum functions. In this study, the combination of proteomic network analyses with cluster analyses is introduced as an approach to deal with high-throughput proteomics data to evaluate the dynamics of protein regulation during sepsis. PMID- 29992140 TI - Fecal Microbiota Transplantation Is Effective in Relieving Visceral Hypersensitivity in a Postinfectious Model. AB - Aim: To investigate the effect of fecal microbiota transplantation on visceral hypersensitivity compared with Bifidobacterium longum. Methods: Mice visceral hypersensitivity was induced by Trichinella spiralis. After 8 weeks, they were divided into three groups (controls, Bifidobacterium longum, and fecal microbiota transplantation) and were daily treated by gavage with 0.2 ml PBS, Bifidobacterium longum HB55020, or fecal microbiota for 7 days. Visceral hypersensitivity was tested with abdominal withdrawal reflex. Permeability of colon epithelium was assessed with Ussing chamber. Results: After administration of Bifidobacterium longum, compared with mice in postinfectious group, mice had higher pain threshold (p < 0.05). After administration of fecal microbiota, compared with mice in postinfectious group, mice had higher pain threshold (p < 0.05). Fecal microbiota transplantation was as effective as Bifidobacterium in relieving visceral hypersensitivity. Administration of Bifidobacterium longum or fecal microbiota transplantation improved colon epithelium permeability. Expression of occluding-1 was increased. Conclusion: Manipulation of microbiota is effective in relieving visceral hypersensitivity. Fecal microbiota transplantation is as effective as Bifidobacterium longum administration. PMID- 29992141 TI - In Vivo Study on Analgesic, Muscle-Relaxant, Sedative Activity of Extracts of Hypochaeris radicata and In Silico Evaluation of Certain Compounds Present in This Species. AB - Background: Hypochaeris radicata (flatweed) from the family Asteraceae is a medicinal plant found in Europe, Middle East, and India. In folkloric medication, it is used to heal jaundice, dyspepsia, constipation, rheumatism, and hypoglycemia as well as renal problems. Leaves and roots of the plant have antioxidant and antibacterial properties. The plant is a rich source of pharmacologically active phytochemicals; however, it is explored scantily. The objective of the current study was to identify the chemical composition and investigate the in vivo biological potency of crude extracts of this plant. Methods: The crude extract and the fractions were screened for various phytochemical groups of constituents following standard procedures. The acute toxicity was assayed for safe range of dose determination. The analgesic potential of the extract and fractions was assessed by acetic acid-induced writhing test. The muscle-relaxant activity was examined by standard inclined plane test and traction test. Sedative potential of extract/fractions was assessed by using standard white wood procedures. Furthermore, docking analysis of two compounds present in the ethyl acetate fraction of the plant was assessed against 3D cyclooxygenase-1 and -2 (COX-1 and COX-2). Results: The extract/fractions of H. radicata showed significant analgesic effect in in vivo model of peripheral algesia. The docking analysis of previously isolated molecules from the plant also exhibited promising interaction with COX-1 and COX 2. Also, the plant has a mild sedative and muscle-relaxant potential. Thus, our study provided pharmacological rationale for the traditional uses of the plant as analgesic and anti-inflammatory remedy. Conclusion: The crude extracts and fractions exhibited excellent activity due to active phytochemicals. These active phytochemicals also exhibited promising interaction with COX-1 and COX-2. These findings directed researcher to isolate active compounds from H. radicata which may be used as a potential source of active secondary metabolites. PMID- 29992142 TI - Serum Adipocyte Fatty Acid-Binding Protein 4 Levels Are Independently Associated with Radioisotope Glomerular Filtration Rate in Type 2 Diabetic Patients with Early Diabetic Nephropathy. AB - Serum fatty acid-binding protein 4 (FABP4) has been linked to renal dysfunction. This study evaluated the association between serum FABP4 and the radioisotope glomerular filtration rate (rGFR) in type 2 diabetic patients (T2DM) with early diabetic nephropathy. Twenty healthy controls and 172 patients with T2DM were enrolled. Serum FABP4 and renal impairment biomarkers including urinary albumin to-creatinine ratio (UACR), serum retinal-binding protein 4 (RBP4), urinary cystatin C-to-creatinine ratio (CysC/Cr), and neutrophil gelatinase-associated lipocalin-to-creatinine ratio (NGAL/Cr) were measured. Diethylenetriaminepentaacetic acid (99mTc-DTPA) was used to test rGFR. Serum FABP4 levels were higher in T2DM patients compared with the controls. There was no significant correlation between serum FABP4 and UACR in patients with T2DM. Multivariate stepwise regression analysis showed that, in patients with T2DM, FABP4 was significantly associated with rGFR while CysC/Cr and RBP4 were significantly associated with UACR independently. But UACR had no independent association with rGFR. NGAL/Cr had no significant correlation with either rGFR or UACR. FABP4 might be an early biomarker for diabetic nephropathy if combined with UACR. PMID- 29992143 TI - Precision Medicine in Targeted Therapies for Severe Asthma: Is There Any Place for "Omics" Technology? AB - According to the current guidelines, severe asthma still represents a controversial topic in terms of definition and management. The introduction of novel biological therapies as a treatment option for severe asthmatic patients paved the way to a personalized approach, which aims at matching the appropriate therapy with the different asthma phenotypes. Traditional asthma phenotypes have been decomposing by an increasing number of asthma subclasses based on functional and physiopathological mechanisms. This is possible thanks to the development and application of different omics technologies. The new asthma classification patterns, particularly concerning severe asthma, include an increasing number of endotypes that have been identified using new omics technologies. The identification of endotypes provides new opportunities for the management of asthma symptoms, but this implies that biological therapies which target inflammatory mediators in the frame of specific patterns of inflammation should be developed. However, the pathway leading to a precision approach in asthma treatment is still at its beginning. The aim of this review is providing a synthetic overview of the current asthma management, with a particular focus on severe asthma, in the light of phenotype and endotype approach, and summarizing the current knowledge about "omics" science and their therapeutic relevance in the field of bronchial asthma. PMID- 29992144 TI - The PIEPEAR Workflow: A Critical Care Ultrasound Based 7-Step Approach as a Standard Procedure to Manage Patients with Acute Cardiorespiratory Compromise, with Two Example Cases Presented. AB - Critical care ultrasound (CCUS) has been widely used as a useful tool to assist clinical judgement. The utilization should be integrated into clinical scenario and interact with other tests. No publication has reported this. We present a CCUS based "7-step approach" workflow-the PIEPEAR Workflow-which we had summarized and integrated our experience in CCUS and clinical practice into, and then we present two cases which we have applied the workflow into as examples. Step one is "problems emerged?" classifying the signs of the deterioration into two aspects: acute circulatory compromise and acute respiratory compromise. Step two is "information clear?" quickly summarizing the patient's medical history by three aspects. Step three is "focused exam launched": (1) focused exam of the heart by five views: the assessment includes (1) fast and global assessment of the heart (heart glance) to identify cases that need immediate life-saving intervention and (2) assessing the inferior vena cava, right heart, diastolic and systolic function of left heart, and systematic vascular resistance to clarify the hemodynamics. (2) Lung ultrasound exam is performed to clarify the predominant pattern of the lung. Step four is "pathophysiologic changes reported." The results of the focused ultrasound exam were integrated to conclude the pathophysiologic changes. Step five is "etiology explored" diagnosing the etiology by integrating Step two and Step four and searching for the source of infection, according to the clues extracted from the focused ultrasound exam; additional ultrasound exams or other tests should be applied if needed. Step six is "action" supporting the circulation and respiration sticking to Step four. Treat the etiologies according step five. Step seven is "recheck to adjust." Repeat focused ultrasound and other tests to assess the response to treatment, adjust the treatment if needed, and confirm or correct the final diagnosis. With two cases as examples presented, we insist that applying CCUS with 7-step approach workflow is easy to follow and has theoretical advantages. The coming research on its value is expected. PMID- 29992145 TI - The Ethyl Acetate Extract of Gynura formosana Kitam. Leaves Inhibited Cervical Cancer Cell Proliferation via Induction of Autophagy. AB - Gynura formosana Kitam. belongs to the Compositae family and has been traditionally used for the prevention of cancer, diabetes, and inflammation in China. Previous studies had indicated that the ethyl acetate extract of Gynura formosana Kitam. leaves (EAEG) exhibited antioxidant and anti-inflammatory activity. In this report, we demonstrated that EAEG possessed potent anticancer activity through autophagy-mediated inhibition of cell proliferation. EAEG induced a strong cytostatic effect towards HeLa cells and, to a lesser extent, HepG2 and MCF-7 cells. This cytostatic effect of EAEG was not a consequence of increased apoptosis, as neither DNA fragmentation nor change in protein expression level for a number of apoptosis-related genes including Bid, Bax, Bcl 2, and caspase-3 was observed after EAEG treatment, and the apoptosis inhibitor Z VAD-FMK did not inhibit the EAEG-elicited cytostatic effect. On the other hand, EAEG induced autophagy in a dose-dependent fashion, as shown by increased GFP puncta formation, enhanced conversion of the microtubule-associated protein light chain LC3-I to LC3-II, and downregulation of the p62 protein. Treating the HeLa cells with EAEG together with Chloroquine (CQ) further accelerated LC3 conversion and p62 clearance, indicating that EAEG induced complete autophagy flux. Importantly, the autophagy inhibitor 3-methyladenine (3MA) significantly abrogated the cytostatic effect of EAEG, strongly suggesting that EAEG inhibited HeLa cell proliferation through the induction of autophagy rather than apoptosis. Our results provided a novel and interesting mechanistic insight into the anticancer action of EAEG, supporting the traditional use of this plant for the treatment of the cancer. PMID- 29992146 TI - The Changes of Cheek Line (Lateral) and Face Line (Frontal) after Correction of Mandibular Prognathism. AB - Objective: The purpose of the present study was to investigate the improvements of facial profile and postoperative stability by single mandibular setback surgery. Materials and Methods: The study included twenty-seven patients who underwent mandibular prognathism correction by sagittal split ramus osteotomy (SSRO). Cephalometric radiograms (lateral and frontal) were collected and analyzed at three intervals: preoperatively (T1), immediately postoperatively (T2), and final follow-up postoperatively (T3). The lateral and frontal cephalometric parameters were measured. The immediate postoperative change (T21), postoperative stability (T32), and final surgical change (T31) were calculated and analyzed. The null hypothesis is that postoperative stability (T32) was not significantly correlated to amount of mandibular setback (T21). Results: The immediate postoperative change (T21) of menton (Me) was significantly backward 8.7 mm. In the final postoperative change (T31), average chin points anterior movements were approximately 0.32 mm. Investigating frontal appearance, inter ramus posterior (InterRp) and intergonion (InterGo) widths were significantly increased with 1.8 and 2.2 mm, respectively. Bilateral ramus angles were not significantly increased, about 1 degrees . The horizontal Me (T32) had significant correlation (p = 0.028) with amount of setback (T21). Therefore, null hypothesis is rejected. Conclusion: Postoperative relapse was significantly correlated to the amount of setback. The frontal transverse changes (InterRp and InterGo) were significantly increased. PMID- 29992147 TI - Stomatitis and VEGFR-Tyrosine Kinase Inhibitors (VR-TKIs): A Review of Current Literature in 4369 Patients. AB - Background: Multitargeted tyrosine kinase inhibitors (TKIs) represent a new class of target-specific antineoplastic agents. These agents show some specific adverse events such as fatigue/asthenia, anorexia/loss of appetite, dysgeusia, diarrhea/abdominal pain, hypothyroidism, hypertension, myelosuppression, and stomatitis. Materials and Methods: A systematic search was performed on PubMed online database using a combination of MESH terms and free text words, "sunitinib" OR "sorafenib" OR "axitinib" OR "cabozantinib" OR "pazopanib" OR "regorafenib" OR "nintedanib" OR "vatalanib" combined through the use of Boolean operator AND with the key words "stomatitis" OR "mucositis," (i) on human subjects, (ii) written in the English language, and (iii) reporting about the incidence of stomatitis or oral mucositis. Results: The incidence of stomatitis of any grade was 35.2% for sunitinib, 20.52% for sorafenib, 20.63% for axitinib, and 34.21% for cabozantinib. All the agents showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was very low. Conclusions: Analysis of the reports with patients treated with sunitinib, sorafenib, axitinib, and cabozantinib showed a clear prevalence of stomatitis grade 1 or grade 2. These data differ from those of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or grade 4. PMID- 29992148 TI - Bioactive Natural Products 2018. PMID- 29992149 TI - Comparison of Kinematics in Cruciate Retaining and Posterior Stabilized for Fixed and Rotating Platform Mobile-Bearing Total Knee Arthroplasty with respect to Different Posterior Tibial Slope. AB - Reconstructed posterior tibial slope (PTS) plays a significant role in kinematics restoration after total knee arthroplasty (TKA). However, the effect of increased and decreased PTS on prosthetic type and design has not yet been investigated. We used a finite element model, validated using in vitro data, to evaluate the effect of PTS on knee kinematics in cruciate-retaining (CR) and posterior stabilized (PS) fixed TKA and rotating platform mobile-bearing TKA. Anterior posterior tibial translation and internal-external tibial rotation were investigated for PTS ranging from -3 degrees to 15 degrees , with increments of 1 degrees , for three different designs of TKA. Tibial posterior translation and external rotation increased as the PTS increased in both CR and PS TKAs. In addition, there was no remarkable difference in external rotation between CR and PS TKAs. However, for the mobile-bearing TKA, PTS had less effect on the kinematics. Based on our computational simulation, PTS is the critical factor that influences kinematics in TKA, especially in the CR TKA. Therefore, the surgeon should be careful in choosing the PTS in CR TKAs. PMID- 29992150 TI - Salivary Antioxidant Status in Patients with Oral Lichen Planus: Correlation with Clinical Signs and Evolution during Treatment with Chamaemelum nobile. AB - Oral lichen planus (OLP) is a chronic inflammatory mucocutaneous disease, which manifests as a succession of outbreaks. OLP was associated with salivary oxidative stress. Randomized, double blind, parallel-group study was performed. The sample consisted of 55 clinically and histopathologically diagnosed OLP patients. Twenty-six patients were treated with 2% Chamaemelum nobile gel and 29 with a placebo. Nonstimulated (basal) saliva was collected on the first day of the study and 4 weeks later. Salivary total antioxidant status (TAS) was evaluated by four different methods: two TAC (6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid) equivalent antioxidant capacity methods (TAC1 and TAC2), cupric reducing antioxidant capacity (CUPRAC), and ferric reducing ability of plasma (FRAP). At baseline (T1), no statistically significant differences were detected in any of the TAS analytes between the two groups of patients. After four weeks of treatment, a statistically significant increase was detected in FRAP in the placebo group (0.323 [0.090-0.467] versus 0.406 [0.197 0.848] mmol/g*10-3) (P < 0.05). Significant correlations were observed between pain and drainage and TAC1, CUPRAC, and FRAP and between xerostomia and the TAC1, TAC2, CUPRAC, and FRAP. The results of the present study showed that in patients with OLP increases of TAS in saliva are associated with increase in pain and xerostomia and decrease in drainage, suggesting a worsening condition of the patient. The use of Chamaemelum nobile gel would be recommended for disease stabilization. PMID- 29992151 TI - Inhibition of Amphiphilic N-Alkyl-O-carboxymethyl Chitosan Derivatives on Alternaria macrospora. AB - Cotton leaf spot (Alternaria macrospora) is a widespread disease that occurs in the main cotton-producing area of China. In managing this disease, a novel chitosan-based biopesticide, an amphiphilic N-alkyl-O-carboxymethyl chitosan derivative, was prepared. The product was selected from variations of chitosan with different molecular structures, which were obtained via a two-step reaction. First, carboxymethyl chitosans with varying molecular sizes were obtained by etherification with chloroacetic acid; then the carboxymethyl chitosan was alkylated with C4-C12 fatty aldehyde through a Schiff-base reaction. This procedure resulted in derivatives of amphiphilic N-alkyl-O-carboxymethyl chitosan, which showed strong antifungal activities against A. macrospora, and the efficacy was determined by its molecular structure. PMID- 29992152 TI - Clinical Outcomes after Liver Transplantation for Hepatorenal Syndrome: A Systematic Review and Meta-Analysis. AB - Aims: Hepatorenal syndrome (HRS) decreases survival of cirrhotic patients. The outcomes of HRS after liver transplantation (LT) were inconsistently reported. We conducted a systematic review and meta-analysis study to estimate the post-LT rates of death and HRS reversal. Methods: A thorough search of literatures was performed on PubMed, Scopus, and conference abstracts for reports on post-LT survival and HRS reversal. Data for the posttransplant rates of HRS reversal, death, and acute rejection were extracted. The rates were pooled using inverse variance method if there was no heterogeneity between studies. Otherwise, the random effect model was applied. Results: Twenty studies were included. Pooling HRS reversal rates indicated high heterogeneity with a pooled rate of 0.834 (95% CI: 0.709-0.933). The pooled overall death rates for HRS and non-HRS after LT were 0.25 (95% confidence interval (CI): 0.18-0.33) and 0.19 (95% CI: 0.14-0.26). The risk ratio of death between HRS and non-HRS patients was 1.29 (95% CI: 1.14 1.47, P < 0.001). The probability of death at 1, 3, and 5 years tended to be higher among HRS. Conclusions: HRS is reversible in about 83% of patients after LT. However, the posttransplant mortality rate of HRS patients is still increased. PMID- 29992153 TI - Ethical Use and Impact of Participatory Approaches to Research in Post-Disaster Environments: An Australian Bushfire Case Study. AB - This paper presents a case study of Beyond Bushfires, a large, multisite, mixed method study of the psychosocial impacts of major bushfires in Victoria, Australia. A participatory approach was employed throughout the study which was led by a team of academic investigators in partnership with service providers and government representatives and used on-site visits and multiple methods of communication with communities across the state to inform decision-making throughout the study. The ethics and impacts of conducting and adapting the approach within a post-disaster context will be discussed in reference to theories and models of participatory health research. The challenges of balancing local interests with state-wide implications will also be explored in the description of the methods of engagement and the study processes and outcomes. Beyond Bushfires demonstrates the feasibility of incorporating participatory methods in large, post-disaster research studies and achieving rigorous findings and multilevel impacts, while recognising the potential for some of the empowering aspects of the participatory experience to be reduced by the scaled-up approach. PMID- 29992154 TI - Insights into Brevibacillus borstelensis AK1 through Whole Genome Sequencing: A Thermophilic Bacterium Isolated from a Hot Spring in Saudi Arabia. AB - Brevibacillus borstelensis AK1 is a thermophile which grows between the temperatures of 45 degrees C and 70 degrees C. The present study is an extended genome report of B. borstelensis AK1 along with the morphological characterization. The strain is isolated from a hot spring in Saudi Arabia (southeast of the city Gazan). It is observed that the strain AK1 is rod-shaped, motile, and strictly aerobic bacterium. The whole genome sequence resulted in 29 contigs with a total length of 5,155,092 bp. In total, 3,946 protein-coding genes and 139 RNA genes were identified. Comparison with the previously submitted strains of B. borstelensis strains illustrates that strain AK1 has a small genome size but high GC content. The strain possesses putative genes for degradation of a wide range of substrates including polyethylene (plastic) and long-chain hydrocarbons. These genomic features may be useful for future environmental/biotechnological applications. PMID- 29992156 TI - The Use of Phage Display and Yeast Based Expression System for the Development of a Von Willebrand Factor Propeptide Assay: Development of a Von Willebrand Factor Propeptide Assay. AB - Background: The diagnosis of von Willebrand disease is complex due to the heterogeneity of the disease. About eighty percent of von Willebrand disease patients are diagnosed with a quantitative defect of von Willebrand factor (VWF) where fifty percent is due to an increased clearance of von Willebrand factor. These patients do not respond well to the treatment of choice, Desmopressin (DDAVP) due to decreased efficacy. The ratio between the VWF propeptide and the mature VWF antigen is used to diagnose these patients. Commercial VWF propeptide assays are too expensive for use in developing countries. In this study, we developed a cost-effective ELISA assay. Methods: We first displayed VWF propeptide on yeast. Antibody fragments were selected against the displayed VWF propeptide by using phage display technology. The antibodies were used to develop a cost-effective VWF propeptide assay and compared to a commercial VWF propeptide assay. Results: Two of these antibody fragments bound specific to the VWF propeptide and not to the yeast used for the expression of the propeptides. These purified antibody fragments were able to detect VWF propeptide in normal plasma. Conclusion: Our assay performed well when compared to a commercial kit. It also showed a higher binding affinity for VWF propeptide in plasma at especially lower plasma concentrations. PMID- 29992155 TI - Genome-Wide Identification, Classification, and Expression Divergence of Glutathione-Transferase Family in Brassica rapa under Multiple Hormone Treatments. AB - The GSTs is one of the most important multifunctional protein families which has been playing a crucial role in the different aspects of plant growth. This extensive study about GSTs may establish a solid foundation for the brief functional analysis of BraGSTs in future. In this study, a total of 75 genes were identified in B. rapa. Phylogenetic analysis characterized them into eight different subclasses, while Tau and Phi subclasses were the most numerous. The exon-intron structure and the motif composition of BraGSTs were exhibited accordingly to their subclasses. Notably, we also investigated 15 tandem paralogous pairs of genes, which highlighted that all the pairs were purifying in nature as their synonymous values were lower than 1.00. Duplication analysis indicated that about 45.33% of genes mainly occurred through tandem duplication in B. rapa. Predominately, the tandem cluster of genes in subclass Tau was greater than the other subclasses. Furthermore, among eight multiple hormonal treatments (ABA, GA, BR, ETH, IAA, IBA, NPA, and JA), most number of BraGSTs was activated by NPA, BR, and ABA treatments. This analysis has provided comprehensive information about GSTs family which may assist in elucidating their exact functions in B. rapa. PMID- 29992158 TI - Condylar Degradation from Decreased Occlusal Loading following Masticatory Muscle Atrophy. AB - Objective: The masticatory muscles are the most important contributor to bite force, and the temporomandibular joint (TMJ) receives direct occlusal loading. The present study aimed to investigate condylar remodeling after masseter muscle atrophy in rats. Methods: Sixty 5-week-old female Sprague-Dawley rats were divided into the following 3 groups: the control group, soft diet (SD) group, and botulinum toxin (BTX) group. The cross-sectional area (CSA) of the masseter muscles was investigated as well as atrogin-1/MuRF-1 expression. Changes in the condylar head were evaluated by H-E, toluidine blue staining, and contour measurements. The biomechanical sensitive factors PTHrP Ihh, Col2a1, and ColX of condylar cartilage were detected by immunohistochemical staining and western blotting. Furthermore, micro-CT and tartrate-resistant acid phosphatase (TRAP) staining were performed to determine the osteopenia in subchondral bone. Results: The histological and protein analysis demonstrated muscle hypofunction in the SD and BTX groups. Condylar cartilage contour was diminished due to different treatments; the immunohistochemistry and protein examination showed that the expressions of PTHrP, Ihh, Col2a1, and ColX were suppressed in condylar cartilage. A steady osteoporosis in subchondral bone was found only in the BTX group. Conclusion: The current results suggested that a steady relationship between muscular dysfunction and condylar remodeling exists. PMID- 29992159 TI - Biological Aspect of Pathophysiology for Frozen Shoulder. AB - It is fairly well understood that frozen shoulder involves several stages, which reflect the series of process from capsular inflammation and fibrosis to spontaneous resolution of this fibrosis. However, the underlying pathophysiologic process remains poorly determined. For this reason, management of frozen shoulder remains controversial. Determining the pathophysiological processes of frozen shoulder is a pivotal milestone in the development of novel treatment for patients with frozen shoulder. This article reviews what is known to date about the biological pathophysiology of frozen shoulder. Although articles for the pathophysiology of frozen shoulder provide inconsistent and inconclusive results, they have suggested both inflammation and fibrosis mediated by cytokines, growth factors, matrix metalloproteinases, and immune cells. Proinflammatory cytokines and growth factors released from immune cells control the action of fibroblast and matrix remodeling is regulated by the matrix metalloproteinases and their inhibitors. To improve our understanding of the disease continuum, better characterizing the biology of these processes at clearly defined stages will be needed. Further basic studies that use standardized protocols are required to more narrowly identify the role of cytokines, growth factors, matrix metalloproteinases, and immune cells. The results of these studies will provide needed clarity into the control mechanism of the pathogenesis of frozen shoulder and help identify new therapeutic targets for its treatment. PMID- 29992157 TI - Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects. AB - Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of ''omics" technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability. PMID- 29992160 TI - Artificial Liver and Renal Support System for Cynomolgus Monkeys with Surgery Induced Acute Renal Failure: A Preclinical Study. AB - Renal dysfunction is one of the most common complications of liver cirrhosis and is associated with increased morbidity and mortality. However, no available technology can simultaneously support liver and renal function in these patients. The aim of this study was to evaluate the safety and efficacy of an artificial liver and renal support system in cynomolgus monkeys with surgery-induced ARF. The ARF model was established by ligature of bilateral renal arteries in eight cynomolgus monkeys, which were randomly divided into a treatment group (n = 4) and control group (n = 4). Biochemical indexes were determined before and after surgery. Blood endotoxin levels, biochemical indexes, and bacterial cultures were assessed at 0, 3, and 6 h during treatment. System pressures and vital signs were recorded at 1 h intervals. Pathological examination was performed after death. ARF was successfully established, based on significant elevation of biochemical indexes and pathological examination. The treatment group had significantly reduced biochemical indexes relative to the control group. Measurement of blood endotoxins and aerobic and anaerobic bacteria cultures indicated no bacterial growth. The system pressures and vital signs were stable during treatment. The results indicate that our support system for the treatment of cynomolgus monkeys with surgery-induced acute renal failure is safe and effective. PMID- 29992161 TI - Bibliometric Analysis of Global Scientific Research on lncRNA: A Swiftly Expanding Trend. AB - To investigate trends in long-noncoding (lnc) RNA research systematically, we compared the contribution of publications among different regions, institutions, and authors. Publications on lncRNA were retrieved from Web of Science (WoS) from 1975 to 2017. A total of 3879 papers were identified, and together they were cited 62967 times. The literature on lncRNA had been continuously growing since 2006, and the expansion might continue at a rapid pace until around 2021. China contributed the greatest proportion (63.47%) of lncRNA publications, and the USA ranked second in the number of publications (944 articles), while it had the highest citation frequency (43168 times) and H-index (97). The journal Oncotarget has the greatest number of publications on lncRNA research, with 305 papers. The keywords could be stratified into two clusters: cluster 1 (application) and cluster 2 (characteristics). Correspondingly, the "TNM stage," "epithelial mesenchymal transition (EMT)," "cell apoptosis," and "overall survival" are research hotspots since 2015. Thus, research on lncRNA showed a swiftly expanding trend, with China making the largest contribution. The focus on lncRNA is gradually shifting from "characteristics" to "application." PMID- 29992162 TI - Microcrystalline Cellulose for Delivery of Recombinant Protein-Based Antigen against Erysipelas in Mice. AB - The study describes the development of a vaccine using microcrystalline cellulose (Avicel PH-101) as a delivery carrier of recombinant protein-based antigen against erysipelas. Recombinant SpaA, surface protective protein, from a gram positive pathogen Erysipelothrix rhusiopathiae was fused to a cellulose-binding domain (CBD) from Trichoderma harzianum endoglucanase II through a S3N10 peptide. The fusion protein (CBD-SpaA) was expressed in Escherichia coli and was subsequently bound to Avicel PH-101. The antigenicity of CBD-SpaA bound to the Avicel was evaluated by enzyme-linked immunosorbent (ELISA) and confocal laser scanning microscope (CLSM) assays. For the examination of its immunogenicity, groups of mice were immunized with different constructs (soluble CBD-SpaA, Avicel coated with CBD-SpaA, whole bacterin of E. rhusiopathiae (positive control), and PBS (negative control)). In two weeks after immunization, mice were challenged with 1x107 CFU of E. rhusiopathiae and Avicel coated with CBD-SpaA induced protective immunity in mice. In conclusion, this study demonstrates the feasibility of microcrystalline cellulose as the delivery system of recombinant protein subunit vaccine against E. rhusiopathiae infection in mice. PMID- 29992163 TI - Composite Scaffolds Based on Intestinal Extracellular Matrices and Oxidized Polyvinyl Alcohol: A Preliminary Study for a New Regenerative Approach in Short Bowel Syndrome. AB - Pediatric Short Bowel Syndrome is a rare malabsorption disease occurring because of massive surgical resections of the small intestine. To date, the issues related to current strategies including intestinal transplantation prompted the attention towards tissue engineering (TE). This work aimed to develop and compare two composite scaffolds for intestinal TE consisting of a novel hydrogel, that is, oxidized polyvinyl alcohol (OxPVA), cross-linked with decellularized intestinal wall as a whole (wW/OxPVA) or homogenized (hW/OxPVA). A characterization of the supports was performed by histology and Scanning Electron Microscopy and their interaction with adipose mesenchymal stem cells occurred by MTT assay. Finally, the scaffolds were implanted in the omentum of Sprague Dawley rats for 4 weeks prior to being processed by histology and immunohistochemistry (CD3; F4/80; Ki-67; desmin; alpha-SMA; MNF116). In vitro studies proved the effectiveness of the decellularization, highlighting the features of the matrices; moreover, both supports promoted cell adhesion/proliferation even if the wW/OxPVA ones were more effective (p < 0.01). Analysis of explants showed a continuous and relatively organized tissue wall around the supports with a connective appearance, such as myofibroblastic features, smooth muscle, and epithelial cells. Both scaffolds, albeit with some difference, were promising; nevertheless, further analysis will be necessary. PMID- 29992164 TI - Polymorphisms in Autophagy-Related Gene IRGM Are Associated with Susceptibility to Autoimmune Thyroid Diseases. AB - Background: To date, studies have shown that polymorphisms in an autophagy related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods: Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves' disease, 292 with Hashimoto's thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results: T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves' disease patients than controls, and the ORs were OR = 1.207 (P = 0.022), OR = 1.207 (P = 0.027), and OR = 1.200 (P = 0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P = 0.033) and 1.33 (P = 0.024), while the adjusted ORs for rs13361189 were 1.19 (P = 0.042) and 1.33 (P = 0.026), respectively. No significant difference was found between Hashimoto's thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves' disease patients (OR = 1.195, P = 0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves' disease patients (OR = 0.861, P = 0.044; OR = 0.816, P = 0.017). Conclusions: Our study reveals IRGM as a susceptibility gene of AITD and Graves' disease for the first time. PMID- 29992165 TI - Pseudomonas aeruginosa Isolates from Spanish Children: Occurrence in Faecal Samples, Antimicrobial Resistance, Virulence, and Molecular Typing. AB - Pseudomonas aeruginosa is a major opportunistic human pathogen, responsible for nosocomial infections and infections in patients with impaired immune systems. Little data exist about the faecal colonisation by P. aeruginosa isolates in healthy humans. The occurrence, antimicrobial resistance phenotype, virulence genotype, and genetic lineages of P. aeruginosa from faecal samples of children from two different Spanish regions were characterised. Seventy-two P. aeruginosa were isolated from 1,443 faecal samples. Low antimicrobial resistance levels were detected: ceftazidime (8%), cefepime (7%), aztreonam (7%), gentamicin (3%), ciprofloxacin (1%), and imipenem (1%); susceptibility to meropenem, amikacin, tobramycin, levofloxacin, and colistin. Four multidrug-resistant strains were found. Important differences were detected between both geographical regions. Forty-one sequence types were detected among the 48 tested strains. Virulence and quorum sensing genes were analysed and 13 virulotypes were detected, being 26 exoU-positive strains. Alteration in protein OprD showed eight different patterns. The unique imipenem-resistant strain showed a premature stop codon in OprD. Intestinal colonisation by P. aeruginosa, mainly by international clones (as ST244, ST253, and ST274), is an important factor for the systemic infections development and the environmental dissemination. Periodic active surveillance is useful to identify these community human reservoirs and to control the evolution of antibiotic resistance and virulence activity. PMID- 29992166 TI - Autophagy Suppresses Invasiveness of Endometrial Cells through Reduction of Fascin-1. AB - Objective: Autophagy has been reported to be involved in the development of various disorders such as neurodegenerative and metabolic diseases and tumors. Autophagy activators and inhibitors are also potential therapeutics for these diseases. However, the mechanism of autophagic involvement in different diseases is not the same, and the role of autophagy in endometriosis (EM) has not yet been elucidated. This research investigated the mechanism by which autophagy acts in EM, with the aim of establishing a theoretical basis for its prevention and treatment through the targeted interference with autophagy. Methods: We used an RNA interference fragment targeting ATG5, the autophagy activator rapamycin, and the autophagy inhibitor 3-MA or overexpression of filopodia-related protein fascin-1, in conjunction with clonogenic assays, growth curves, and scratch assay to investigate the influence of autophagy on cellular growth, proliferation, and invasiveness. We collected specimens from 20 clinical cases of EM and investigated the protein expression of the autophagic marker LC3-II, the autophagic substrate p62, and fascin-1. Results: Rapamycin was able to inhibit the proliferation and colony formation of the endometriotic cell line CRL-7566, whereas the autophagy inhibitor 3-MA as well as the interference with the autophagy-related gene ATG5 had the opposite effect. More importantly, the autophagy activator rapamycin was able to inhibit the growth of filopodia in the endometriotic cells, and the overexpression of the fascin-1 restored the rapamycin-induced decrease of invasiveness. We found that the expression of the autophagy marker LC3-II was significantly reduced among the clinical EM specimens compared to the control group, while the expressions of fascin-1 and autophagic substrate p62 were increased. Conclusion: Our results indicate that the inhibition of autophagy and exogenous expression of fascin-1 may promote the invasiveness of endometrial cells. As a corollary, autophagy represents a potential target for the treatment of EM. PMID- 29992167 TI - The Evolving Role of Ultrasound Guided Percutaneous Laser Ablation in Elderly Unresectable Breast Cancer Patients: A Feasibility Pilot Study. AB - Background and Objectives: Breast-conserving surgery represents the standard of care for the treatment of small breast cancers. However, there is a population of patients who cannot undergo the standard surgical procedures due to several reasons such as age, performance status, or comorbidity. Our aim was to investigate the feasibility and safety of percutaneous US-guided laser ablation for unresectable unifocal breast cancer (BC). Methods: Between December 2012 and March 2017, 12 consecutive patients underwent percutaneous US-guided laser ablation as radical treatment of primary inoperable unifocal BC. Results: At median follow-up of 28.5 months (range 6-51), no residual disease or progression occurred; the overall success rate for complete tumor ablation was therefore 100%. No significant operative side effects were observed, with only 2 (13.3%) experiencing slight to mild pain during the procedure, and all patients complained of a mild dull aching pain in the first week after procedure. Conclusions: Laser ablation promises to be a safe and feasible approach in those patients who are not eligible to the standard surgical approach. However, longer follow-up results and larger studies are strongly needed. PMID- 29992168 TI - Comparative Hemolymph Proteomic and Enzymatic Analyses of Two Strains of Rhipicephalus (Boophilus) microplus Ticks Resistant and Susceptible to Ixodicides. AB - The cattle tick Rhipicephalus (Boophilus) microplus is one of the most harmful ectoparasites affecting bovines worldwide. It represents a major threat to livestock industry due to the economic losses caused and diseases associated with these ticks. The most important tick control strategy has been the use of ixodicides, resulting in chemically resistant tick populations. It is necessary to understand the mechanisms that result in resistance so as to create new strategies increasing the lifespan of ixodicides or finding alternative targets to produce new acaricides. In this paper, in order to obtain an insight into the mechanisms that govern ixodicides resistance, we will compare the hemolymph proteome of two tick R. microplus strains, one susceptible (MJ) and one resistant (SA) to ixodicides, using HPLC and 2D electrophoresis. Significant differences were found in protein content between strains using HPLC. 2D electrophoresis revealed that 68 hemolymph protein spots were common between strains; however, 26 spots were unique to the susceptible strain MJ and 5 to the resistant strain SA. The most distinctive protein spots on the preparative gels were selected for further analyses. Nine protein spots were identified by mass fingerprinting, ?revealing proteins that may have a role in the ixodicides resistance or susceptibility. In this paper, we present the tick hemolymph proteome revealing a set of proteins which suggest a possible role in tick detoxification. PMID- 29992169 TI - Health Literacy Status and Understanding of the Prescription Instructions in Diabetic Patients. AB - This study aimed to assess the health literacy (HL) of patients having diabetes mellitus, their understanding of prescription instructions (PI), and the correlation between HL and understanding of PI. A cross-sectional survey was conducted in 263 adult diabetic patients who were assessed for their understanding of route of intake of the prescribed medication(s), frequency of intake, number of medication(s) to be consumed each time, indication for the medication(s), and the relation of drug intake with food. The HL of the patients was assessed by using Rapid Estimate of Adult Literacy in Medicine, a screening test comprising of 66 health-related words. The number of correctly pronounced words was used to assign a grade-equivalent reading level. There was a significant difference in the understanding of PI in patients with low and high HL levels. A significant difference was observed between the mean total score for interpreting PI in patients with 7 or fewer years of education compared with the other groups with a higher educational status (P < 0.001). To conclude, diabetic patients with low HL level will have difficulty in understanding PI. Hence, an alternative comprehensive strategy needs to be adopted in clinical practice in these patients to provide them the instructions to take medications properly. PMID- 29992171 TI - Asymptomatic HIV People Present Different Profiles of sCD14, sRAGE, DNA Damage, and Vitamins, according to the Use of cART and CD4+ T Cell Restoration. AB - We aimed to analyze markers of immune activation, inflammation, and oxidative stress in 92 asymptomatic HIV-infected patients according to the adequate (AR, >500 cells/mm3) or inadequate (IR, <500 cells/mm3) CD4+ T recovery and the presence or absence of antiretroviral treatment (cART). In relation to those newly diagnosed, they were divided into two groups, cART-naive IR (nIR) and cART naive AR (nAR). Among those diagnosed more than five years ago, the following division was made: the cART-naive long-term nonprogressors (LTNP); patient under cART and AR (tAR); and patients under cART and IR (tIR). We investigated the expression of soluble receptor for advanced glycation end products (sRAGE), high mobility group-box protein -1 (HMGB1), soluble CD14 (sCD14), IL-8, IL-10, 8 isoprostane, vitamins, and DNA damage. We observed higher levels of sRAGE in tAR as compared to nIR, nAR, LTNP, and more sCD14 than in nIR and nAR. As for IL-10 levels, we found nIR > nAR > LTNP > tAR > tIR. Higher levels of 8-isoprostane were observed in nIR. LTNP presented a higher retinol dosage than tAR and less genotoxic damage induced by oxidative stress than the other groups. We suggest that the therapy, despite being related to lesser immune activation and inflammation, alters the vitamin profile and consequently increases the oxidative stress of patients. In addition, the lowest genotoxic index for LTNP indicates that both VL and cART could be responsible for the increased DNA damage. More studies are needed to understand the influence of cART on persistent immune activation and inflammation. PMID- 29992172 TI - Implementation of a Rapid Entry Program Decreases Time to Viral Suppression Among Vulnerable Persons Living With HIV in the Southern United States. AB - Background: Rapid entry programs (REPs) improve time to antiretroviral therapy (ART) initiation (TAI) and time to viral suppression (TVS). We assessed the feasibility and effectiveness of a REP in a large HIV clinic in Atlanta, Georgia, serving a predominately un- or underinsured population. Methods: The Rapid Entry and ART in Clinic for HIV (REACH) program was implemented on May 16, 2016. We performed a retrospective cohort study with the main independent variable being period of enrollment: January 1, 2016, through May 15, 2016 (pre-REACH); May 16, 2016, through July 31, 2016 (post-REACH). Included individuals were HIV-infected and new to the clinic with detectable HIV-1 RNA. Six-month follow-up data were collected for each participant. Survival analyses were conducted for TVS. Logistic and linear regression analyses were used to evaluate secondary outcomes: attendance at first clinic visit, viral suppression, TAI, and time to first attended provider visit. Results: There were 117 pre-REACH and 90 post-REACH individuals. Median age (interquartile range [IQR]) was 35 (25-45) years, 80% were male, 91% black, 60% men who have sex with men, 57% uninsured, and 44% active substance users. TVS decreased from 77 (62-96) to 57 (41-70) days (P < .0022). Time to first attended provider visit decreased from 17 to 5 days, and TAI from 21 to 7 days (P < .0001), each remaining significant in adjusted models. Conclusions: This is the largest rapid entry cohort described in the United States and suggests that rapid entry is feasible and could have a positive impact on HIV transmission at the population level. PMID- 29992170 TI - The Regulation of Inflammation by Innate and Adaptive Lymphocytes. AB - Inflammation plays an essential role in the control of pathogens and in shaping the ensuing adaptive immune responses. Traditionally, innate immunity has been described as a rapid response triggered through generic and nonspecific means that by definition lacks the ability to remember. Recently, it has become clear that some innate immune cells are epigenetically reprogrammed or "imprinted" by past experiences. These "trained" innate immune cells display altered inflammatory responses upon subsequent pathogen encounter. Remembrance of past pathogen encounters has classically been attributed to cohorts of antigen specific memory T and B cells following the resolution of infection. During recall responses, memory T and B cells quickly respond by proliferating, producing effector cytokines, and performing various effector functions. An often overlooked effector function of memory CD4 and CD8 T cells is the promotion of an inflammatory milieu at the initial site of infection that mirrors the primary encounter. This memory-conditioned inflammatory response, in conjunction with other secondary effector T cell functions, results in better control and more rapid resolution of both infection and the associated tissue pathology. Recent advancements in our understanding of inflammatory triggers, imprinting of the innate immune responses, and the role of T cell memory in regulating inflammation are discussed. PMID- 29992173 TI - Real-world Efficacy of Direct-Acting Antiviral Therapy for HCV Infection Affecting People Who Inject Drugs Delivered in a Multidisciplinary Setting. AB - Background: Many clinicians and insurance providers are reluctant to embrace recent guidelines identifying people who inject drugs (PWID) as a priority population to receive hepatitis C virus (HCV) treatment. The aim of this study was to evaluate the efficacy of direct-acting antiviral (DAA) HCV therapy in a real-world population comprised predominantly of PWID. Methods: A retrospective analysis was performed on all HCV-infected patients who were treated at the Vancouver Infectious Diseases Centre between March 2014 and December 2017. All subjects were enrolled in a multidisciplinary model of care, addressing medical, psychological, social, and addiction-related needs. The primary outcome was achievement of sustained virologic response (undetectable HCV RNA) 12 or more weeks after completion of HCV therapy (SVR-12). Results: Overall, 291 individuals were enrolled and received interferon-free DAA HCV therapy. The mean age was 54 years, 88% were PWID, and 20% were HCV treatment experienced. At data lock, 62 individuals were still on treatment and 229 were eligible for evaluation of SVR by intent-to-treat (ITT) analysis. Overall, 207 individuals achieved SVR (90%), with 13 losses to follow-up, 7 relapses, and 2 premature treatment discontinuations. ITT SVR analysis show that active PWID and treatment-naive patients were less likely to achieve SVR (P = .0185 and .0317, respectively). Modified ITT analysis of active PWID showed no difference in achieving SVR (P = .1157) compared with non-PWID. Conclusion: Within a multidisciplinary model of care, the treatment of HCV-infected PWID with all-oral DAA regimens is safe and highly effective. These data justify targeted efforts to enhance access to HCV treatment in this vulnerable and marginalized population. PMID- 29992174 TI - Maternal Hepatitis B Infection and Pregnancy Outcomes in the United States: A Population-Based Cohort Study. AB - Background: Hepatitis B virus (HBV) infection in pregnancy has been associated with risk of adverse maternal and infant outcomes in highly endemic settings, but this association is not well characterized in the United States. Methods: We conducted a retrospective population-based cohort study in Washington State using linked birth certificate and hospital discharge records from 1992-2014. Among pregnant women with hepatitis B (n = 4391) and a hepatitis B-negative group (n = 22 410), we compared the risk of gestational diabetes, pre-eclampsia, eclampsia, placenta previa, preterm delivery, low birthweight, small for gestational age, and large for gestational age using multivariate logistic regression. Results: Hepatitis B-infected pregnant women were more likely to be Asian (61% vs 8%, P < .001), foreign-born (76% vs 23%, P < .001), and older in age (77% vs 64% >=26 years, P < .001). They were less commonly overweight or obese (33% vs 50%, P < .001). There was a lower risk of small for gestational age infants among HBV infected women (adjusted RR [aRR], 0.79; 95% confidence interval [CI], 0.67 0.93). The risk of other adverse outcomes was not significantly different between hepatitis B-infected and -negative women (gestational diabetes: aRR, 1.11; 95% CI, 0.92-1.34; pre-eclampsia: aRR, 1.06; 95% CI, 0.82-1.35; eclampsia: aRR, 2.31; 95% CI, 0.90-5.91; placenta previa: aRR, 1.16; 95% CI, 0.35-3.84; preterm delivery: aRR, 1.15; 95% CI, 0.98-1.34; low birth weight: aRR, 1.08; 95% CI, 0.90 1.29; large for gestational age: aRR, 1.01; 95% CI, 0.82-1.24). Conclusions: In a low-burden setting in the United States, hepatitis B infection was not associated with adverse pregnancy outcomes. PMID- 29992175 TI - Can the Ceftriaxone Breakpoints Be Increased Without Compromising Patient Outcomes? AB - Background: In 2010, the Clinical Laboratory and Standards Institute recommended a 3-fold lowering of ceftriaxone breakpoints to 1 mcg/mL for Enterobacteriaceae. Supportive clinical data at the time were from fewer than 50 patients. We compared the clinical outcomes of adults with Enterobacteriaceae bloodstream infections treated with ceftriaxone compared with matched patients (with exact matching on ceftriaxone minimum inhibitory concentrations [MICs]) treated with extended-spectrum agents to determine if ceftriaxone breakpoints could be increased without negatively impacting patient outcomes. Methods: A retrospective cohort study was conducted at 3 large academic medical centers and included patients with Enterobacteriaceae bacteremia with ceftriaxone MICs of 2 mcg/mL treated with ceftriaxone or extended-spectrum beta-lactams (ie, cefepime, piperacillin/tazobactam, meropenem, or imipenem/cilastatin) between 2008 and 2014; 1:2 nearest neighbor propensity score matching was performed to estimate the odds of recurrent bacteremia and mortality within 30 days. Results: Propensity score matching yielded 108 patients in the ceftriaxone group and 216 patients in the extended-spectrum beta-lactam group, with both groups well balanced on demographics, preexisting medical conditions, severity of illness, source of bacteremia, and source control interventions. No difference in recurrent bacteremia (odds ratio [OR], 1.16; 95% confidence interval [CI], 0.49 2.73) or mortality (OR, 1.27; 95% CI, 0.56-2.91) between the treatment groups was observed for patients with isolates with ceftriaxone MICs of 2 mcg/mL. Only 6 isolates (1.6%) with ceftriaxone MICs of 2 mcg/mL were extended-spectrum beta lactamase (ESBL)-producing. Conclusions: Our findings suggest that patient outcomes are similar when receiving ceftriaxone vs extended-spectrum agents for the treatment of Enterobacteriaceae bloodstream infections with ceftriaxone MICs of 2 mcg/mL. This warrants consideration of adjusting the ceftriaxone susceptibility breakpoint from 1 to 2 mcg/mL, as a relatively small increase in the antibiotic breakpoint could have the potential to limit the use of large numbers of extended-spectrum antibiotic agents. PMID- 29992176 TI - Diagnostic Approach for Classic Compared With Localized Whipple Disease. AB - Background: Whipple disease (WD), a rare systemic infection caused by Tropheryma whipplei, can be a diagnostic challenge due to its variable presentation. The role of T. whipplei polymerase chain reaction (PCR) is unclear as small bowel biopsy with Periodic acid-Schiff (PAS) staining remains the diagnostic gold standard. Individualized diagnostic approaches based on variable clinical manifestations are underutilized. We investigated the methodologies employed at our institution to diagnose WD. Methods: We retrospectively collected all cases of WD diagnosed from 1994 to 2016. Microbiology laboratory and anatomic pathology databases were queried. Case characteristics and disease clinical phenotypes (classical, localized WD arthritis, and localized central nervous system [CNS] disease) were described. The diagnostic approach and testing yield were analyzed and reported. Results: Thirty-three cases of WD were diagnosed (18 classic WD [CWD], 9 localized WD arthritis [LWD], 6 CNS WD). Misdiagnosis and delay in diagnosis were frequent. Diagnostic approach and test yield differed by classical vs localized WD involvement. Small bowel tissue biopsy PAS stain/PCR was overwhelmingly positive (86%/92%) in CWD, yet seldom positive (12%/42%) in LWD (P < .001). Affected joint synovial fluid PCR was frequently positive in both CWD (100%, 3/3) and LWD (85%, 6/7). Conclusions: These results support the role of small bowel biopsy PAS stain/PCR in the diagnosis of CW, though this approach may be of limited utility in LWD or CNS WD without gastrointestinal symptoms. Affected joint synovial fluid or cerebrospinal fluid PCR was frequently positive in both CWD and LWD, supporting its diagnostic usefulness. PMID- 29992177 TI - Markers of Tissue Repair and Cellular Aging Are Increased in the Liver Tissue of Patients With HIV Infection Regardless of Presence of HCV Coinfection. AB - Liver disease is a leading cause of HIV-related mortality. Hepatitis C virus (HCV)-related fibrogenesis is accelerated in the setting of HIV coinfection, yet the mechanisms underlying this aggressive pathogenesis are unclear. We identified formalin-fixed paraffin-embedded liver tissue for HIV-infected patients, HCV infected patients, HIV/HCV-coinfected patients, and controls at Duke University Medical Center. De-identified sections were stained for markers against the wound repair Hedgehog (Hh) pathway, resident T-lymphocytes, and immune activation and cellular aging. HIV infection was independently associated with Hh activation and markers of immune dysregulation in the liver tissue. PMID- 29992178 TI - GMP Production and Scale-Up of Adherent Neural Stem Cells with a Quantum Cell Expansion System. AB - Cell-based therapies hold great promise for a myriad of clinical applications. However, as these therapies move from phase I to phase II and III trials, there is a need to improve scale-up of adherent cells for the production of larger good manufacturing practice (GMP) cell banks. As we advanced our neural stem cell (NSC)-mediated gene therapy trials for glioma to include dose escalation and multiple treatment cycles, GMP production using cell factories (CellStacks) generated insufficient neural stem cell (NSC) yields. To increase yield, we developed an expansion method using the hollow fiber quantum cell expansion (QCE) system. Seeding of 5.2 * 107 NSCs in a single unit yielded up to 3 * 109 cells within 10 days. These QCE NSCs showed genetic and functional stability equivalent to those expanded by conventional flask-based methods. We then expanded the NSCs in 7 units simultaneously to generate a pooled GMP-grade NSC clinical lot of more than 1.5 * 1010 cells in only 9 days versus 8 * 109 over 6 weeks in CellStacks. We also adenovirally transduced our NSCs within the QCE. We found the QCE system enabled rapid cell expansion and increased yield while maintaining cell properties and reducing process time, labor, and costs with improved efficiency and reproducibility. PMID- 29992179 TI - Effect of a cathepsin K inhibitor on arthritis and bone mineral density in ovariectomized rats with collagen-induced arthritis. AB - Objectives: Cathepsin K is expressed by osteoclasts and synovial fibroblasts and degrades key components of bone and cartilage. Inhibition of cathepsin K protease activity may be beneficial for the prevention of bone erosion and cartilage degradation in rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) rat model is well established for studying the pathology and treatment of RA. We investigated the effect of ONO-KK1-300-01, a cathepsin K inhibitor (CKI), on arthritis and bone mineral density (BMD) in rats with CIA. Methods: Seven-month old female Sprague Dawley rats were divided into 5 groups: rats without CIA (CNT); CIA rats that underwent ovariectomy (OVX) and were treated with CKI; CIA rats that underwent OVX and were treated with vehicle (Veh); CIA rats that underwent sham surgery and were treated with CKI; and CIA rats that underwent sham surgery and were treated with Veh. CKI was orally administered at a dose of 15 mg/kg, thus initiating collagen sensitization, until death at 4 weeks. We evaluated hind paw thickness and the arthritis score every week until death. Radiographs of the resected left foot were obtained with a soft X-ray apparatus. Destruction of bone and cartilage was classified and scored as previously described by Engelhardt et al. BMD was measured by bone densitometry at the halfway point between the distal metaphysis and the diaphysis of the resected right femur. We also performed histomorphometry of the proximal left tibia, histological evaluation of arthritis, and a bone strength test. Results: CKI administration significantly reduced hind paw thickness and the arthritis score, and prevented a decrease in BMD. The radiographic score was significantly lower in the CKI group than in the Veh group. In the histomorphometric analysis, bone resorption parameters were significantly lower in the CKI groups than in the Veh groups. CKI significantly inhibited synovial proliferation in the CIA rats. In the bone strength test, the ultimate stress was significantly higher in the CKI groups than in the Veh groups. Conclusion: Our findings indicate that cathepsin K inhibitors may inhibit systemic and local bone loss, ameliorate arthritis, and attenuate the decrease of bone strength in an animal model of arthritis. PMID- 29992180 TI - Bisphosphonate conjugation for bone specific drug targeting. AB - Bones provide essential functions and are sites of unique biochemistry and specialized cells, but can also be sites of disease. The treatment of bone disorders and neoplasia has presented difficulties in the past, and improved delivery of drugs to bone remains an important goal for achieving effective treatments. Drug targeting strategies have improved drug localization to bone by taking advantage of the high mineral concentration unique to the bone hydroxyapatite matrix, as well as tissue-specific cell types. The bisphosphonate molecule class binds specifically to hydroxyapatite and inhibits osteoclast resorption of bone, providing direct treatment for degenerative bone disorders, and as emerging evidence suggests, cancer. These bone-binding molecules also provide the opportunity to deliver other drugs specifically to bone by bisphosphonate conjugation. Bisphosphonate bone-targeted therapies have been successful in treatment of osteoporosis, primary and metastatic neoplasms of the bone, and other bone disorders, as well as refining bone imaging. In this review, we focus upon the use of bisphosphonate conjugates with antineoplastic agents, and overview bisphosphonate based imaging agents, nanoparticles, and other drugs. We also discuss linker design potential and the current state of bisphosphonate conjugate research progress. Ongoing investigations continue to expand the possibilities for bone-targeted therapeutics and for extending their reach into clinical practice. PMID- 29992183 TI - Associations of personality traits with marijuana use in a nationally representative sample of adolescents in the United States. AB - Introduction: Identifying adolescents at risk for marijuana use who can be targeted for intervention efforts is critical. Certain personality traits are strongly associated with substance use, including marijuana use. We investigated the associations of impulsivity (and its subscales sensation seeking and lack of planning), aggression, and neuroticism with marijuana use (lifetime and frequency of past 12-month use) in a national sample of adolescents. Methods: We used data from the National Comorbidity Survey: Adolescent Supplement, a nationally representative, cross-sectional study of 8495 U.S. adolescents aged 14 to 18 years. We calculated adjusted prevalence ratios and odds ratios to assess associations of the five personality scales with lifetime use and frequency of past 12-month use and examined gender as a potential moderator of these associations. Results: Each of the personality traits was positively associated with lifetime use (all p < 0.001). Impulsivity (the total scale and both subscales) and aggression (all p < 0.05) were positively associated with frequency of past 12-month use. The neuroticism-lifetime use association was stronger among girls (p < 0.001) than boys (p < 0.05), and the associations of impulsivity and lack of planning with frequency of use were significant only among girls, with moderate female users reporting higher levels of the personality scales than infrequent users (both p < 0.01). Conclusions: Our study highlights the potential importance of identifying personality traits, specifically disinhibition-related traits such as impulsivity and aggression, to reduce and prevent adolescent marijuana use. PMID- 29992182 TI - Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa. AB - Background & Aims: Aging gastric mucosa has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully known. We examined whether impairment of angiogenesis in aging gastric mucosa is caused by deficiency of nerve growth factor (NGF) in gastric endothelial cells (ECs), and whether NGF therapy could reverse this impairment. Methods: In gastric mucosal ECs (GECs) isolated from young and aging rats we examined the following: (1) in vitro angiogenesis, (2) NGF expression, and (3) the effect of NGF treatment on angiogenesis, GEC proliferation and migration, and dependence on serum response factor. In in vivo studies in young and aging rats, we examined NGF expression in gastric mucosa and the effect of NGF treatment on angiogenesis and gastric ulcer healing. To determine human relevance, we examined NGF expression in gastric mucosal biopsy specimens of aging (>=70 y) and young (<=40 y) individuals. Results: In cultured aging GECs, NGF expression and angiogenesis were reduced significantly by 3.0-fold and 4.1-fold vs young GECs. NGF therapy reversed impairment of angiogenesis in aging GECs, and serum response factor silencing completely abolished this response. In gastric mucosa of aging rats, NGF expression in GECs was reduced significantly vs young rats. In aging rats, local NGF treatment significantly increased angiogenesis and accelerated gastric ulcer healing. In aging human subjects, NGF expression in ECs of gastric mucosal vessels was 5.5-fold reduced vs young individuals. Conclusions: NGF deficiency in ECs is a key mechanism underlying impaired angiogenesis and delayed ulcer healing in aging gastric mucosa. Local NGF therapy can reverse these impairments. PMID- 29992184 TI - Cardiovascular risk and mannose binding lectin in patients with rheumatoid arthritis from southern Brazil. AB - Background: Mannose binding lectin (MBL) appears to be involved in susceptibility to rheumatoid arthritis (RA), in the inflammatory process and in the genesis of atherosclerotic disease. Objective: To study the association of MBL serum levels and its genotypic variation with carotid arteries intimal thickness (IMT) in RA patients from Southern Brazil. Methods: MBL serum levels, MBL2 genotyping and IMT were investigated in 90 RA patients along with their demographic, clinical and laboratory profile. MBL levels and MBL2 genotyping were evaluated in 90 healthy controls. Results: A significant lower MBL serum concentration was observed in patients with RA in relation to controls (528 ng/mL vs 937.5 ng/mL, p = 0.05, respectively). The median IMT in RA patients was 0.59 mm (0.51 to 0.85 mm). There was no correlation between levels of MBL with disease activity, erythrocyte sedimentation rate, autoantibodies presence or IMT (p = NS). A weak and negative correlation was found between MBL and CRP levels (Rho = -0.24; p = 0.02;). The MBL2 variant at codon 54 (variant B) and HYPA haplotype were the most frequently observed in the RA sample (67.5% and 31.7%). MBL2 wild type (A/A) were associated with lower IMT when compared with heterozygotes (A/O; p = 0.04) and low producers (O/O; p = 0.05). In addition, high producers genotypes had lower levels of CRP when compared with medium (p = 0.04) or with low producers (p = 0.05). Conclusion: RA patients had lower MBL levels than controls. MBL were negatively associated with CRP serum levels; low MBL genotypes producers increased thickness of the IMT than high producers. PMID- 29992181 TI - Chronic stress as a risk factor for Alzheimer's disease: Roles of microglia mediated synaptic remodeling, inflammation, and oxidative stress. AB - Microglia are the predominant immune cells of the central nervous system (CNS) that exert key physiological roles required for maintaining CNS homeostasis, notably in response to chronic stress, as well as mediating synaptic plasticity, learning and memory. The repeated exposure to stress confers a higher risk of developing neurodegenerative diseases including sporadic Alzheimer's disease (AD). While microglia have been causally linked to amyloid beta (Abeta) accumulation, tau pathology, neurodegeneration, and synaptic loss in AD, they were also attributed beneficial roles, notably in the phagocytic elimination of Abeta. In this review, we discuss the interactions between chronic stress and AD pathology, overview the roles played by microglia in AD, especially focusing on chronic stress as an environmental risk factor modulating their function, and present recently-described microglial phenotypes associated with neuroprotection in AD. These microglial phenotypes observed under both chronic stress and AD pathology may provide novel opportunities for the development of better-targeted therapeutic interventions. PMID- 29992185 TI - Identification of Synergistic Interaction Between Cannabis-Derived Compounds for Cytotoxic Activity in Colorectal Cancer Cell Lines and Colon Polyps That Induces Apoptosis-Related Cell Death and Distinct Gene Expression. AB - Introduction: Colorectal cancer remains the third most common cancer diagnosis and fourth leading cause of cancer-related mortality worldwide. Purified cannabinoids have been reported to prevent proliferation, metastasis, and induce apoptosis in a variety of cancer cell types. However, the active compounds from Cannabis sativa flowers and their interactions remain elusive. Research Aim: This study was aimed to specify the cytotoxic effect of C. sativa-derived extracts on colon cancer cells and adenomatous polyps by identification of active compound(s) and characterization of their interaction. Materials and Methods: Ethanol extracts of C. sativa were analyzed by high-performance liquid chromatography and gas chromatograph/mass spectrometry and their cytotoxic activity was determined using alamarBlue-based assay (Resazurin) and tetrazolium dye-based assay (XTT) on cancer and normal colon cell lines and on dysplastic adenomatous polyp cells. Annexin V Assay and fluorescence-activated cell sorting (FACS) were used to determine apoptosis and cell cycle, and RNA sequencing was used to determine gene expression. Results: The unheated cannabis extracts (C2F), fraction 7 (F7), and fraction 3 (F3) had cytotoxic activity on colon cancer cells, but reduced activity on normal colon cell lines. Moreover, synergistic interaction was found between F7 and F3 and the latter contains mainly cannabigerolic acid. The F7 and F7+F3 cytotoxic activity involved cell apoptosis and cell cycle arrest in S or G0/G1 phases, respectively. RNA profiling identified 2283 differentially expressed genes in F7+F3 treatment, among them genes related to the Wnt signaling pathway and apoptosis-related genes. Moreover, F7, F3, and F7+F3 treatments induced cell death of polyp cells. Conclusions:C. sativa compounds interact synergistically for cytotoxic activity against colon cancer cells and induce cell cycle arrest, apoptotic cell death, and distinct gene expression. F3, F7, and F7+F3 are also active on adenomatous polyps, suggesting possible future therapeutic value. PMID- 29992187 TI - Retained Needle in the AirSeal Trocar During Robot-Assisted Laparoscopic Radical Prostatectomy: Lessons Learned. AB - Background: Unique case of retained needle in the AirSeal trocar during robot assisted laparoscopic radical prostatectomy. Case Presentation: A 68-year-old male with prostate cancer underwent robot-assisted laparoscopic radical prostatectomy. Upon laparoscopic removal of final intra-abdominal suture by bedside assistant, needle became dislodged from suture and was unable to be located after a standard systematic search. Ultimately, needle was found caught in the assistant's AirSeal trocar device. Conclusion: Intraoperative loss of a foreign body should include inspection, and possible radiographic evaluation, of the trocar mechanism as part of a complete systematic approach. PMID- 29992186 TI - Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Delta8/9 Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells. AB - Introduction: Delta9-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in Cannabis, is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. Objectives: The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC. Methods: In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC. Results: Photoaffinity probe 1, containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein hits is a first step towards a better understanding of the protein interaction profile of THC, which could ultimately lead to the development of novel therapeutics based on THC. PMID- 29992188 TI - Genetic Testing: Ethical Aspects. AB - The aim of this article is to provide an analysis of the main issues related to the application of predictive medicine by analysing the most significant ethical implications. Genetic medicine is indeed a multidisciplinary matter that covers broad contexts, sometimes transversely. Its extreme complexity, coupled with possible perceived repercussions on an individual's life, involves important issues in the ethical, deontological and legal medical field. The aspects related to the execution of genetic testing have to be addressed at different levels, starting with the correct information about the "cognitive" meaning they intend (by forcefully disassociating it from the strange "preventive aspect") to the legal medical issues that can be aroused in the field of forensic pathology, medical responsibility and insurance. There is no doubt that in recent years, from the decoding of the human genome, genetic research has exponentially expanded with an equally exponential increase in its use in clinical practice and the ethical and social evolution of it. PMID- 29992189 TI - Intervention for Physician Burnout: A Systematic Review. AB - Burnout is an important problem for physicians, with a strong impact on their quality of life and a corresponding decrease in the quality of care with an evident economical burden for the healthcare system. However, the range of interventions used to decrease this problem could be very fragmented and with the aim to shed some light on this issue, this study reviews and summarizes the currently available studies. We conducted a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify studies about intervention on physician burnout. Two authors independently searched into scientific databases to analyze and review the full papers that met the inclusion criteria. As a result, from an initial search of 11029 articles, 13 studies met full criteria and were included in this review. Of the 13 studies presented, only 4 utilized randomized controlled trials, therefore the results should be interpreted with caution. Future interventions should focus on a more holistic approach using a wider range of techniques. According to the studies selected in this review, it appears that a successful intervention for burnout should take into account the broad range of causes incorporating a variety of therapeutic tools. PMID- 29992190 TI - The Melanin-concentrating Hormone System in Human, Rodent and Avian Brain. AB - Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic hypothalamic peptide. MCH is located in the lateral and dorsal hypothalamus, as well as in the zona incerta. In mammals MCH increases food intake, contributes to regulation of energy balance, temperature, reproductive function, endocrine homeostasis and biological rhythms. Several studies have proved the significance of MCH in obesity, diabetes and depression. Although the peptide is well characterized in mouse models, much less is known about its functions in avians. In birds the MCH system especially in the lateral and basal hypothalamus has important connections to the limbic system and it coordinates the vegetative and endocrine functions, as well as the emotional behaviour. Pharmacological modulation of MCH system could contribute to the therapy of eating disorders and improve agricultural efficiency regarding avians. Reviewing the current knowledge on MCH system in human, rodents and avians may stimulate a new wave of studies in the field. PMID- 29992192 TI - The Quality Sequencing Minimum (QSM): providing comprehensive, consistent, transparent next generation sequencing data quality assurance. AB - Next generation sequencing (NGS) is routinely used in clinical genetic testing. Quality management of NGS testing is essential to ensure performance is consistently and rigorously evaluated. Three primary metrics are used in NGS quality evaluation: depth of coverage, base quality and mapping quality. To provide consistency and transparency in the utilisation of these metrics we present the Quality Sequencing Minimum (QSM). The QSM defines the minimum quality requirement a laboratory has selected for depth of coverage (C), base quality (B) and mapping quality (M) and can be applied per base, exon, gene or other genomic region, as appropriate. The QSM format is CX_BY(P Y)_MZ(P Z). X is the parameter threshold for C, Y the parameter threshold for B, P Y the percentage of reads that must reach Y, Z the parameter threshold for M, P Z the percentage of reads that must reach Z. The data underlying the QSM is in the BAM file, so a QSM can be easily and automatically calculated in any NGS pipeline. We used the QSM to optimise cancer predisposition gene testing using the TruSight Cancer Panel (TSCP). We set the QSM as C50_B10(85)_M20(95). Test regions falling below the QSM were automatically flagged for review, with 100/1471 test regions QSM-flagged in multiple individuals. Supplementing these regions with 132 additional probes improved performance in 85/100. We also used the QSM to optimise testing of genes with pseudogenes such as PTEN and PMS2. In TSCP data from 960 individuals the median number of regions that passed QSM per sample was 1429 (97%). Importantly, the QSM can be used at an individual report level to provide succinct, comprehensive quality assurance information about individual test performance. We believe many laboratories would find the QSM useful. Furthermore, widespread adoption of the QSM would facilitate consistent, transparent reporting of genetic test performance by different laboratories. PMID- 29992193 TI - A "Hole Punched Plate" method for easy generation and harvesting of microconidia in the dermatophyte Trichophyton rubrum. AB - Handling of the medically important dermatophyte Trichophyton rubrum in the laboratory typically requires the generation of spores - for storage, treatment and plating when needed. The described method allows technically simple but efficient generation and harvesting of microconidia by cutting holes in Sabouraud dextrose agar medium that is covered by a mature T. rubrum mycelium. PMID- 29992191 TI - Delivery of public health services by community health workers (CHWs) in primary health care settings in China: a systematic review (1996-2016). AB - Background: Community Health Workers (CHWs) have been widely used in response to the shortage of skilled health workers especially in resource limited areas. China has a long history of involving CHWs in public health intervention project. CHWs in China called village doctors who have both treatment and public health responsibilities. This systematic review aimed to identify the types of public health services provided by CHWs and summarized potential barriers and facilitating factors in the delivery of these services. Methods: We searched studies published in Chinese or English, on Medline, PubMed, Cochrane, Google Scholar, and CNKI for public health services delivered by CHWs in China, during 1996-2016. The role of CHWs, training for CHWs, challenges, and facilitating factors were extracted from reviewed studies. Results: Guided by National Basic Public Health Service Standards, services provided by CHW covered five major areas of noncommunicable diseases (NCDs) including diabetes and/or hypertension, cancer, mental health, cardiovascular diseases, and common NCD risk factors, as well as general services including reproductive health, tuberculosis, child health, vaccination, and other services. Not many studies investigated the barriers and facilitating factors of their programs, and none reported cost effectiveness of the intervention. Barriers challenging the sustainability of the CHWs led projects were transportation, nature of official support, quantity and quality of CHWs, training of CHWs, incentives for CHWs, and maintaining a good rapport between CHWs and target population. Facilitating factors included positive official support, integration with the existing health system, financial support, considering CHW's perspectives, and technology support. Conclusion: CHWs appear to frequently engage in implementing diverse public health intervention programs in China. Facilitators and barriers identified are comparable to those identified in high income countries. Future CHWs-led programs should consider incorporating the common barriers and facilitators identified in the current study to maximize the benefits of these programs. PMID- 29992194 TI - Doxorubicin-conjugated pH-responsive gold nanorods for combined photothermal therapy and chemotherapy of cancer. AB - Cancer chemotherapy can be hindered by drug resistance which leads to lower drug efficiency. Here, we have developed a drug delivery system that tethers doxorubicin to the surface of gold nanorods via a pH-sensitive linkage (AuNRs@DOX), for a combined photothermal and chemical therapy for cancer. First, AuNRs@DOX is ingested by HepG2 liver cancer cells. After endocytosis, the acidic pH triggers the release of doxorubicin, which leads to chemotherapeutic effects. The gold nanorods are not only carriers of DOX, but also photothermal conversion agents. In the presence of an 808 nm near-infrared laser, AuNRs@DOX significantly enhance the cytotoxicity of doxorubicin via the photothermal effect, which induces elevated apoptosis of hepG2 cancer cells, leading to better therapeutic effects in vitro and in vivo. PMID- 29992195 TI - Study of locust bean gum reinforced cyst-chitosan and oxidized dextran based semi IPN cryogel dressing for hemostatic application. AB - Severe blood loss due to traumatic injuries remains one of the leading causes of death in emergency settings. Chitosan continues to be the candidate material for hemostatic applications due to its inherent hemostatic properties. However, available chitosan-based dressings have been reported to have an acidic odor at the wound site due to the incorporation of acid based solvents for their fabrication and deformation under compression owing to low mechanical strength limiting its usability. In the present study semi-IPN cryogel was fabricated via Schiff's base cross-linking between the polyaldehyde groups of oxidized dextran and thiolated chitosan in presence of locust bean gum (LBG) known for its hydrophilicity. Polymerization at -12 degrees C yielded macroporous semi-IPN cryogels with an average pore size of 124.57 +/- 20.31 MUm and 85.46% porosity. The hydrophobicity index of LBG reinforced semi-IPN cryogel was reduced 2.42 times whereas the swelling ratio was increased by 156.08% compare to control cryogel. The increased hydrophilicity and swelling ratio inflated the compressive modulus from 28.1 kPa to 33.85 for LBG reinforced semi-IPN cryogel. The structural stability and constant degradation medium pH were also recorded over a period of 12 weeks. The cryogels demonstrated lower adsorption affinity towards BSA. The cytotoxicity assays (direct, indirect) with 3T3-L1 fibroblast cells confirmed the cytocompatibility of the cryogels. The hemolysis assay showed <5% hemolysis confirming blood compatibility of the fabricated cryogel, while whole blood clotting and platelet adhesion assays confirmed the hemostatic potential of semi-IPN cryogel. PMID- 29992196 TI - Can doctors help to heal the NHS? PMID- 29992197 TI - The Clinical Frailty Scale predicts inpatient mortality in older hospitalised patients with idiopathic Parkinson's disease. AB - : Parkinson's disease and frailty are both common conditions affecting older people. Little is known regarding the association of the Clinical Frailty Scale with hospital outcomes in idiopathic Parkinson's disease patients admitted to the acute hospital. We aimed to test whether frailty status was an independent predictor of short-term mortality and other hospital outcomes in older inpatients with idiopathic Parkinson's disease. METHOD: We conducted an observational retrospective study in a large tertiary university hospital between October 2014 and October 2016. Routinely measured patient characteristics included demographics (age and sex), Clinical Frailty Scale, acute illness severity (Emergency Department Modified Early Warning Score), the Charlson Comorbidity Index, discharge specialty, history of dementia, history of depression and the presence of a new cognitive impairment. Outcomes studied were inpatient mortality, death within 30 days of discharge, new institutionalisation, length of stay >= 7 days and readmission within 30 days to the same hospital. RESULTS: There were 393 first admission episodes of idiopathic Parkinson's disease patients aged 75 years or more; 166 (42.2%) were female. The mean age (standard deviation) was 82.8 (5.0) years. The mean Clinical Frailty Scale was 5.9 (1.4) and the mean Charlson Comorbidity Index was 1.3 (1.5). After adjustment for covariates, frailty and acute illness severity were independent predictors of inpatient mortality; odds ratio for severely/very severely frail or terminally ill = 8.1, 95% confidence interval 1.0-63.5, p = 0.045 and odds ratio for acute illness severity: 1.3, 95% confidence interval 1.1-1.6, p = 0.005). The Clinical Frailty Scale did not significantly predict other hospital outcomes. CONCLUSIONS: The Clinical Frailty Scale was a significant predictor of inpatient mortality in idiopathic Parkinson's disease patients admitted to the acute hospital and it may be useful as a marker of risk in this vulnerable population. PMID- 29992198 TI - Reliable consultant level data from an Acute Medical Unit: a powerful tool for improvement. AB - The development of a novel database interrogating the patient management system in the Acute Medical Unit at Forth Valley Royal Hospital, Scotland, has allowed, for the first time, acquisition of reliable individual consultant-level process and outcome data over a 2-year period. These data have a number of uses, including understanding the level of variation between consultant physicians in AMU across key indicators, such as direct discharge percentage (67.5-44.3%), and readmission percentage (4.0-6.8%). Looking at overnight admissions only effectively excluded case mix as a confounder to identify variation in 30-day mortality (0-2.8%). This has allowed benchmarking, and exploring of relationships between volume of work, physician experience, and patient outcomes. For example, no significant relationship was seen between direct discharge percentage and readmission percentage. Furthermore it is extremely useful for individual clinician appraisal and governance. Finally it has practical uses when designing consultant rotas in order to minimise system variation. A key consideration throughout this work has been clear provenance and local clinical ownership of these data, unlike centrally generated data that may not accurately reflect Acute Medical Unit activity. PMID- 29992199 TI - Rapid species identification of Candida directly from blood culture broths by Sepsityper-MALDI-TOF mass spectrometry: impact on antifungal therapy. AB - : Rapid identification of Candida species facilitates pathogen-directed therapy with either fluconazole or an echinocandin. METHOD: We applied Sepsityper matrix assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS) technology on positive blood culture broths for rapid species identification. RESULTS: Of the 74 patients with candidaemia, 25 had the species identified on the day of the positive blood culture directly from the broth (rapid identification group) while the remaining 49 had the species identified from culture (conventional identification group). Three (13.6%) out of 22 treated patients in the rapid identification group received echinocandin compared to 20/45 (44.4%) in the conventional identification group. The appropriateness of therapy was 90.9% in the rapid identification group and 62.2% in the conventional identification group (p = 0.01). Cost savings were more than L10,000 in the first three days of treatment. CONCLUSION: Sepsityper-MALDI-TOF-MS is a useful tool in supporting antifungal stewardship programmes. PMID- 29992200 TI - Anterior spinal artery syndrome from type A aortic dissection in a patient with Marfan syndrome due to a novel fibrillin mutation. AB - Type A aortic dissection is a rare but important cardiac surgical emergency. Few reports exist in the literature describing anterior spinal artery syndrome as a presenting feature. We report a case of anterior spinal artery syndrome due to aortic dissection in a patient with Marfan syndrome caused by a novel fibrillin mutation. A 53-year old female presented with chest pain and sudden-onset paralysis. Neurological examination revealed normal upper limb examination, reduced lower limb power and reflexes but normal sensation. CT scanning revealed type A acute aortic dissection which was treated with emergent cardiac surgical repair. At clinic follow up 3 years later, signs of Marfan syndrome were opportunistically noted and genetic testing revealed a novel mutation in the Fibrillin 1 gene. This case emphasises the importance of a good initial clinical assessment, including thorough neurological examination, as well as a low threshold of clinical suspicion for an aortic dissection in such a constellation of symptoms. The importance of family history should also be emphasised given the coincidental diagnosis of Marfan syndrome in a first-degree relative. Furthermore, this case illustrates the classical signs of anterior spinal artery syndrome. PMID- 29992201 TI - A patient with persistent consolidation and a pulmonary mass. AB - Community-acquired pneumonia is a common condition and 6-24% of patients will fail to improve as expected. We present a patient who was initially treated for community-acquired pneumonia but did not make the anticipated recovery. We explore potential differentials, and the investigation and management of the rare condition we subsequently diagnosed. PMID- 29992202 TI - Drug induced thrombotic microangiopathy caused by levofloxacin. AB - Thrombotic microangiopathy is a rare but serious manifestation of a variety of diseases. The key features are microangiopathic haemolysis, thrombocytopaenia, renal dysfunction and neurological symptoms. Here we discuss the case of a previously well male presenting with community-acquired pneumonia who developed thrombotic microangiopathy during admission. This case illustrates the difficulties in the differential diagnosis and reminds us of the importance of the peripheral blood film in identifying the cause of thrombocytopaenia. One life threatening cause of thrombotic microangiopathy is thrombotic thrombocytopaenia purpura and when that diagnosis is suspected emergency plasma exchange is essential. Many drugs can cause thrombotic microangiopathy and here we highlight the commonly-prescribed antibiotic levofloxacin as the culprit. PMID- 29992203 TI - IgG4-related pulmonary disease: the protean impersonator? AB - IgG4-related disease is an immune-mediated fibro-inflammatory disease, characterised by distinct pathological features. An increasing number of clinical phenotypes are described, from single-organ disease to a multisystem disorder, which can present to a variety of different specialities. Recognition is key; its protean manifestations can mimic other inflammatory diseases, infection and malignancy. Here, we present three cases to highlight the importance of being familiar with this condition in its various forms. PMID- 29992204 TI - What might Brexit mean for British tourists travelling to the rest of Europe? AB - Brexit will have profound implications for British tourists visiting the rest of the European Union, in particular because of the likely loss of coverage of healthcare should they be injured or fall ill. This paper compares the cost of travel insurance within the EU and in comparable countries outside it, asking how it varies by age and pre-existing conditions. Fictitious patients, differing by age, pre-existing condition, and destination (France, an EU Member State; Israel and Canada, two high income non-EU frequent destinations) were entered into an insurance price comparison website to assess the influence of these characteristics on prices quoted. Cost of travel insurance increases with age, pre-existing health conditions and by destination. In those with no pre-existing conditions, there is a marked difference between France, where the cost rises steadily with age, and Israel and Canada, where there is a sharp increase after age 75. For individuals with any one pre-existing condition, there is no similar jump in cost but rather a progressive increase with age, although the rate of increase accelerates as the individuals concerned get older. For all travellers, the cost of insurance is highest for Canada and lowest for France. At present, pre-existing health conditions in British tourists travelling in the rest of the EU are covered by the European Health Insurance Card. With the UK's probable exit from the EU and almost certain loss of this coverage, travellers in the older age groups may have to pay much more for their travel insurance, with some possibly tempted to forgo travel insurance coverage because of the cost. It is essential that health professionals understand how leaving the EU may impact on those seeking their advice. PMID- 29992205 TI - An update on cardiac implantable electronic devices for the general physician. AB - Cardiac electronic device implantation is a common and important intervention for patients with tachy-and bradyarrhythmia. An increasing number of patients are receiving more complex devices such as cardiac resynchronisation therapy or devices with a defibrillation function. Over the last 5 years, two new models of cardiac device have emerged, subcutaneous defibrillators and leadless pacemakers. With an ageing population and data demonstrating 2000 per 100,000 of the population aged over 75 years have a cardiac device, it is essential that the general physician remains updated on the common pacemaker indications and available therapies. PMID- 29992206 TI - Paper versus electronic feedback in high stakes assessment. AB - : Tablet computers have emerged as increasingly useful tools in medical education, particularly for assessment. However, it is not fully established whether tablet computers influence the quality and/or quantity of feedback provided in high stakes assessments. It is also unclear how electronically recorded feedback relates to student performance. Our primary aim was to determine whether differences existed in feedback depending on the tool used to record it. METHODS: We compared quantitative and qualitative feedback between paper-scoring sheets versus iPadsTM across two consecutive years of a final year MBChB (UK medical degree) Objective Structured Clinical Examination. Quality of comments (using a validated five-point rating scale), number of examiner comments and number of words were compared across both methods of recording assessment performance using chi-squared analysis and independent t-test. We also explored relationships between student performance (checklist and global scoring) and feedback. RESULTS: Data from 190 students (2850 paper scored interactions) in 2015 and 193 (2895 iPadTM scored interactions) in 2016 were analysed. Overall, a greater number of comments were given with iPadTM compared to written (42% versus 20%; p < 0.001) but the quality of feedback did not differ significantly. For both written and electronic feedback, students with low global scores were more likely to receive comments (p < 0.001). CONCLUSION: The use of iPadsTM in high stakes assessment increases the quantity of feedback compared to traditional paper scoring sheets. The quantity and quality of feedback for poorer performing candidates (by global score) were also better with iPadTM feedback. PMID- 29992207 TI - Finding the truth: multivariable analysis and the assassination of Abraham Lincoln. PMID- 29992208 TI - Collectors of natural knowledge: the Edinburgh Medical Society and the associational culture of Scotland and the North Atlantic world in the 18th Century. AB - This paper reappraises the role of medical clubs and societies in the production and consumption of knowledge in 18th-century Scotland and the wider North Atlantic world. It focuses on the Edinburgh Medical Society, founded in 1731 by Alexander Monro primus; and on the student Medical Society, founded in 1734 and constituted in 1737 as the Medical Society of Edinburgh, ultimately becoming the Royal Medical Society of Edinburgh in 1778. The paper examines how Monro, as editor of the transactions of the Edinburgh Medical Society, sought to adapt medical learning to a world of polite sociability; and how that world came under pressure in the student Medical Society, where prevailing orthodoxies, such as the system of Herman Boerhaave and, later, William Cullen, were challenged. In the febrile atmosphere of the 1790s, William Thomson accused the Royal Medical Society of Edinburgh of promoting visionary theories and abandoning the proper experimental method in medical science. Yet with its overarching commitment to the sceptical and empirical principles laid down by the Royal Society of London (founded in 1660), the Royal Medical Society of Edinburgh provided a model for the establishment of similar clubs and societies on both sides of the Atlantic. PMID- 29992209 TI - Mood disorder in the personal correspondence of Robert Burns: testing a novel interdisciplinary approach. AB - Robert Burns has long been recognised as someone who experienced episodes of melancholia, but no detailed, systematic and objective assessment of his mental health has been undertaken. We tested a novel methodology, combining psychiatric and literary approaches, to assess the feasibility of using Burns's extensive personal correspondence as a source of evidence for assessing the presence of symptoms of a clinically significant mood disorder. We confirmed the potential of this approach and identified putative evidence of episodes of depression and hypomania within the correspondence. While not conclusive of a formal diagnosis of bipolar disorder, this work highlights a need for further systematic examination of Burns's mental health and how this may have influenced his work. PMID- 29992210 TI - The origins of sport for disabled people. AB - The disabled sports movement is considered to have started in 1948 when, under the aegis of Ludwig Guttmann, England hosted the first wheelchair games at Stoke Mandeville Hospital. In this review, we challenge the assumption that sport for disabled people started after the Second World War and contend that it was already practised in an organised fashion in France, Germany and the UK before and after the First World War. PMID- 29992211 TI - Witnessing history: a personal view of half a century in public health. AB - Former Chief Medical Officer Sir Kenneth Calman recently celebrated 50 years in medicine. It was a period which saw the evolution of the public health agenda from communicable diseases to diseases of lifestyle, the change from a hospital orientated health service to one dominated by community-based services, and the increasing recognition of inequalities as a major determinant of health. This paper documents selected highlights from his career including the Aberdeen typhoid outbreak, AIDS, bovine spongiform encephalopathy, foot and mouth disease, radioactive fallout, the invention of computerised tomography and magnetic resonance imaging, and draws parallels between the development of the modern understanding of public health and the theoretical background to the science 100 years earlier. PMID- 29992212 TI - Correction: Hydrazone-Pd-catalyzed direct intermolecular reaction of o alkynylphenols with allylic acetates. AB - Correction for 'Hydrazone-Pd-catalyzed direct intermolecular reaction of o alkynylphenols with allylic acetates' by Kohei Watanabe et al., Org. Biomol. Chem., 2018, 16, 575-584. PMID- 29992213 TI - Theoretical study of CO2 hydrogenation into formic acid on Lewis acid zeolites. AB - Conversion of carbon dioxide (CO2) to more valuable chemicals is nowadays receiving increasing attention from an environmental and industrial point of view. Herein, we computationally investigated CO2 hydrogenation to formic acid on Lewis acid zeolites by means of density functional theory (DFT) with the M06-L functional. The reaction proceeds in two steps, hydrogenation of CO2 to form the formate intermediate and hydrogen-abstraction to form formic acid. A defect zeolite seems to be favored over a perfect one, leading to its low rate determining step barrier of 5.2 kcal mol-1. We also considered the effect of the zeolite frameworks and found that the catalytic activities are in the order Sn ZSM-5 > Sn-BEA > Sn-FAU. Finally, we performed catalytic activity screenings of tetravalent metals (Ge, Zr and Hf) substituted into the defect Sn-ZSM-5 zeolite. The order Hf > Zr > Sn > Ge was found based on the rate determining step activation energy. The difference in activation energy can be explained by the difference in charge transfer from the catalytic site to the reacting molecules. PMID- 29992214 TI - A colorimetric and fluorometric dual-modal sensor for methanol based on a functionalized pentacenequinone derivative. AB - A functionalized pentacenequinone derivative, ZR1, as a highly selective sensor for methanol has been prepared. Based on the methanol-induced keto-enol tautomerization of the pentacene-quinone moiety, ZR1 shows specific selectivity toward methanol, which leads to dual-modal detection of methanol with a very low detection limit of 0.038% in ethanol. PMID- 29992215 TI - Microphysiological flux balance platform unravels the dynamics of drug induced steatosis. AB - Drug development is currently hampered by the inability of animal experiments to accurately predict human response. While emerging organ on chip technology offers to reduce risk using microfluidic models of human tissues, the technology still mostly relies on end-point assays and biomarker measurements to assess tissue damage resulting in limited mechanistic information and difficulties to detect adverse effects occurring below the threshold of cellular damage. Here we present a sensor-integrated liver on chip array in which oxygen is monitored using two frequency phase modulation of tissue-embedded microprobes, while glucose, lactate and temperature are measured in real time using microfluidic electrochemical sensors. Our microphysiological platform permits the calculation of dynamic changes in metabolic fluxes around central carbon metabolism, producing a unique metabolic fingerprint of the liver's response to stimuli. Using our platform, we studied the dynamics of human liver response to the epilepsy drug Valproate (DepakineTM) and the antiretroviral medication Stavudine (ZeritTM). Using E6/E7LOW hepatocytes, we show TC50 of 2.5 and 0.8 mM, respectively, coupled with a significant induction of steatosis in 2D and 3D cultures. Time to onset analysis showed slow progressive damage starting only 15-20 hours post-exposure. However, flux analysis showed a rapid disruption of metabolic homeostasis occurring below the threshold of cellular damage. While Valproate exposure led to a sustained 15% increase in lipogenesis followed by mitochondrial stress, Stavudine exposure showed only a transient increase in lipogenesis suggesting disruption of beta-oxidation. Our data demonstrates the importance of tracking metabolic stress as a predictor of clinical outcome. PMID- 29992216 TI - Hierarchically stimuli-responsive nanovectors for improved tumor penetration and programed tumor therapy. AB - Poor drug delivery to solid tumors remains a great challenge for effective antitumor therapy. Herein, multistage stimuli-responsive nanovectors based on hollow mesoporous silica nanoparticles (HMSNs) were prepared to avoid delivery barriers for improved penetration and programmed tumor therapy. The versatile nanosystem was constructed through electrostatic complexation between the functional HMSNs loaded with gemcitabine (GEM) and the small-sized platinum prodrug-conjugated poly(amidoamine) dendrimer (PAMAM-Pt). The HMSNs were functionalized with dimethylmaleic anhydride tethered chitosan oligosaccharide to endow the particles of HMSN-CS(DMA) with charge-reversal properties. The as prepared nanosystem had a stable structure of size ~130 nm at pH 7.4, which is beneficial for blood circulation and tumor vessel extravasation of nanocarriers. Once it reaches the tumor site, the nanosystem can dissociate into HMSN@GEM-CS (~120 nm) and PAMAM-Pt dendrimer nanocarriers (~5 nm) in response to the acidic tumor microenvironment because of the acid-mediated charge-reversal, then the HMSN@GEM can play the antitumor role in surface tumor tissues. The dissociated PAMAM-Pt showed excellent performance in tumor penetration, cell uptake and intracellular trafficking due to the small size and positive charge, which was supported by the study of three-dimensional multicellular spheroids in vitro. Finally, the active cisplatin was released from the PAMAM-Pt dendrimer under the intracellular reducing environment to kill cells in deep tumor tissues. The significant tumor suppression of this system in vivo was validated in the A549 tumor xenografted mouse model. Such a stimuli-responsive nanosystem that integrates simple preparation, biocompatibility, biodegradability and programmed tumor therapy manifests great potential for clinical trials. PMID- 29992217 TI - Hard-template synthesis of micro-mesoporous organic frameworks with controlled hierarchicity. AB - This work reports a new synthesis strategy called hard-template synthesis to create hierarchical pores in porous organic framework materials. Two different mesoporous silicas (SBA-15 and B56-E-20) were used as the hard templates and biphenyl was employed as the single organic precursor. PAF-45 was prepared by in situ coupling biphenyl within the voids of mesoporous silica. After etching silica, controlled mesopores with sizes ranging from 3 to 10 nm were generated and microporosity was inherited as well in the mesoporous PAF-45HX materials. PMID- 29992218 TI - Unexpected ionic transport behavior in hydrophobic and uncharged conical nanopores. AB - We investigated ionic transport behavior in the case of uncharged conical nanopores. To do so, we designed conical nanopores using atomic layer deposition of Al2O3/ZnO nanolaminates and then coated these with trimethylsilane. The experimental results are supported by molecular dynamics simulations. The ionic transport reveals an unexpected behavior: (i) a current rectification and (ii) a constant conductance at low salt concentration which are usually reported for charged conical nanopore. To explain these results, we have considered different assumptions: (i) a default of functionalization, (ii) the adsorption anion and (iii) the slippage. The first one was refuted by the study of the poly-l-lysine transport through the nanopore. To verify the second assumption, we investigate the effect of pH on the current rectification and the molecular dynamics simulations. Finally our study demonstrates that the unexpected ionic transport is provided to a predominant effect of slippage due to the water organization at the solid/liquid interface. PMID- 29992219 TI - The spin-dependent Seebeck effect and the charge and spin figure of merit in a hybrid structure of single-walled carbon nanotubes and zigzag-edge graphene nanoribbons. AB - A hybrid structure of carbon nanotubes and graphene nanoribbons was predicted and synthesized (Y. Li et al., Nat. Nanotechnol., 2012, 7, 394-400; P. Lou, J. Phys. Chem. C, 2014, 118, 4475-4482). Herein, using the non-equilibrium Green's function (NEGF) combined with density functional theory (DFT), the thermal spin transport properties and the figure of merit (a material constant proportional to the efficiency of a thermoelectric couple made with the material) of a composite of single-walled carbon nanotubes and zigzag-edge graphene nanoribbons, labeled (6,6)SWCNT/n-ZGNR, are investigated for n = 1, 2, 3, and 8. The results manifest that spin-dependent currents with opposite flow directions were generated when a temperature gradient was applied between two electrodes, indicating the occurrence of the spin-dependent Seebeck effect (SDSE). Remarkably, when n = 3, the charge current is equal to zero, meaning that a perfect SDSE is observed. Moreover, a pure spin-dependent Seebeck diode (SDSD) effect can be observed. Finally, we notice that the device presents an n-type characteristic when n = 1, while the device has a p-type feature when n = 2. In particular, the spin-up thermopower is equal to the spin-down thermopower when n = 3; as a consequence, the charge thermopower is equal to zero, further demonstrating that a perfect SDSE is generated. These discoveries indicate that the (6,6)SWCNT/n-ZGNR is a promising candidate for spin caloritronics devices. PMID- 29992220 TI - Copper-catalysed cross-coupling of alkyl Grignard reagents and propargylic ammonium salts: stereospecific synthesis of allenes. AB - Herein we describe a robust and practical method to prepare enantiomerically enriched trisubstituted allenes using alkyl Grignard reagents and bench stable propargylic ammonium salts. Excellent yields as well as regio- and stereoselectivities are observed. Our conditions provide a solution to the allene racemization, which has been a long-standing problem when using Grignard reagents. PMID- 29992221 TI - Group 2 metal bis(arenecarbochalcogenoate)(crown ether) complexes: isolation and structural analysis. AB - A series of Group 2 metal bis(arenecarbochalcogenoato)(crown ether) complexes M(EE'CAr)2(L)(L')x (M = Mg, Ca, Sr, Ba; Ar = aryl; E = S, Se; E' = O, S; L = H2O or THF; L' = 15-crown-5, 18-crown-6) were synthesized and their structures were revealed by X-ray analyses. The two carbothioato ligands in Mg, Ca and Sr 15 crown-5 complexes are located on the same side of the crown ether plane, while those in Mg, Ca, Sr, and Ba 18-crown-6 compounds are on both sides of the 18 crown-6 plane (trans relative to the plane). For the Ca 15-crown-5 complex, both carbothioato ligands are connected to the central Ca ion through an oxygen atom in a monodentate manner, and the two hydrogen atoms of the coordinated water molecule are intramolecularly hydrogen-bonded with thiocarbonyl sulfur atoms. One of the two carbothioate groups in the Ca 18-crown-6 complex is connected in a bidentate manner to the central metal, while the other is connected in a monodentate manner through an oxygen atom. The two thiocarboxylato ligands in the Sr 15-crown-5 congener are connected in a bidentate fashion to the same side of the crown ether plane. The Ca and Sr compounds are the first examples of alkali earth metal carbochalcogenoate complexes in which carbochalcogenolato ligands are connected in a monodentate manner through an oxygen atom. Both chalcogenoato ligands in Ba(SOCC6H4Me-4)2(18-crown-6) and Sr(SeOCC6H4Me-4)2(18-crown-6) are coordinated in a bidentate manner to the central metal ion. PMID- 29992227 TI - Longitudinal Assessment of Aesthetic Plastic Surgery Training in the United States: The Effect of Increased ACGME Case Log Minimum Requirements. AB - Background: In 2014, the Accreditation Council for Graduate Medical Education (ACGME) increased the minimum required aesthetic surgery cases for graduation from plastic surgery residency from 50 to 150. To date, there has been no research into how this has impacted resident aesthetic surgery training focusing on the resident perception. Objective: We sought to evaluate resident perception and satisfaction with their aesthetic surgery training before and after the ACGME case log requirement increase to assess its impact on training and comfort level. Methods: A survey was administered to all graduating senior residents attending the Senior Residents Conference of the ASPS Annual Meeting in 2014 and 2017. The survey evaluated senior resident aesthetic surgery experience and their confidence and satisfaction with their training. Results: The response rate was 70% in 2014 and 45% in 2017. There was an increase in the number of programs with resident-run cosmetic clinics (14% increase) and designated aesthetic rotations (33% increase) during that time. Resident-run cosmetic clinics were consistently considered the most valuable form of aesthetic training for residents. There also was a substantial increase in the percentage of residents feeling prepared to incorporate aesthetic surgery into their practice after graduation, increasing from 36% to 59% in 2017. The majority of responding residents felt that the ACGME case log requirement increase in 2014 was beneficial for their aesthetic surgery training (68%). Conclusions: The recent ACGME case log requirement increase for aesthetic surgery training has had a positive effect on resident comfort with aesthetic procedures and their ability to incorporate them into future practice. PMID- 29992226 TI - Physical Exertion Immediately Prior to Placental Abruption: A Case-Crossover Study. AB - While there is consistent evidence that episodes of physical exertion are associated with an immediately higher risk of acute ischemic vascular events, the risk of placental abruption immediately following episodes of physical exertion has not been studied. In a multicenter case-crossover study, we interviewed 663 women with placental abruption at 7 Peruvian hospitals between January 2013 and August 2015. We asked women about physical exertion in the hour before symptom onset and compared this with their frequency of physical exertion over the prior week. Compared with times with light or no exertion, the risk of placental abruption was 7.8 (95% confidence interval (CI): 5.5, 11.0) times greater in the hour following moderate or heavy physical exertion. The instantaneous incidence rate ratio of placental abruption within an hour of moderate or heavy physical exertion was lower for women who habitually engaged in moderate or heavy physical activity more than 3 times per week in the year before pregnancy (rate ratio (RR) = 3.0, 95% CI: 1.6, 5.9) compared with more sedentary women (RR = 17.3, 95% CI: 11.3, 26.7; P for homogeneity < 0.001), and the rate ratio was higher among women with preeclampsia/eclampsia (RR = 13.6, 95% CI: 7.0, 26.2) than among women without (RR = 6.7, 95% CI: 4.4, 10.0; P for homogeneity = 0.07). PMID- 29992228 TI - Effects of systemic medication on root resorption associated with orthodontic tooth movement: a systematic review of animal studies. AB - Background: Theoretically, root resorption could be modulated by any medication taken that exhibits possible effects on the implicated molecular pathways. Objectives: To systematically investigate and appraise the quality of the available evidence from animal studies, regarding the effect of commonly prescribed systemic medication on root resorption associated with orthodontic tooth movement. Search methods: Search without restrictions in eight databases (PubMed, Central, Cochrane Database of Systematic Reviews, SCOPUS, Web of Science, Arab World Research Source, ClinicalTrials.gov, ProQuest Dissertations and Theses Global) and hand searching until April 2018 took place. One author developed detailed search strategies for each database that were based on the PubMed strategy and adapted accordingly. Selection criteria: Controlled studies investigating the effect of systemic medications on root resorption associated with orthodontic tooth movement. Data collection and analysis: Following study retrieval and selection, relevant data were extracted and the risk of bias was assessed using the SYRCLE's Risk of Bias Tool. Results: Twenty-one studies were finally identified, most of which at unclear risk of bias. Root resorption was shown to increase in Vitamin C treated animals in comparison with the control group, whereas a comparative decrease was noted after the administration of the alendronate, ibuprofen, growth hormone, low doses of meloxicam, simvastatin, lithium chloride and strontium ranelate. No difference was noted for acetaminophen, aspirin, fluoxetine, atorvastatin, misoprostol, zoledronic acid and zinc. Finally, inconsistent effects were observed after the administration of celecoxib, prednisolone and L-thyroxine. The quality of the available evidence was considered at best as low. Conclusions: The pharmaceutical substances investigated were shown to exhibit variable effects on root resorption. Although the overall quality of evidence provides the clinician with a cautious perspective on the strength of the relevant recommendations, good practice would suggest that it is important to identify patients consuming medications and consider the possible implications. Registration: PROSPERO (CRD42017078208). PMID- 29992229 TI - Mediterranean diet and health outcomes: a systematic meta-review. AB - Background: The Mediterranean diet (MeDi) is considered a healthy dietary pattern, and greater adherence to this diet may improve health status. It also may reduce the social and economic costs of diet-related illnesses. This meta review aims to summarize, synthesize and organize the effects of MeDi pattern on different health outcomes. Methods: This meta-review was performed following the PRISMA guidelines. A systematic search was conducted in the electronic databases PubMed, Web of Science and Scopus. Two researchers screened all the records to eliminate any duplicate, and they selected the articles to be fully reviewed. A third researcher was consulted to resolve discrepancies and so reach a consensus agreement. Results: Thirty-three articles were included, nine were systematic reviews and twenty-four were meta-analyses. Most of the diseases analysed are catalogued as non-communicable diseases (NCD), and the impact of these in populations may have major financial consequences for healthcare spending and national income. The results showed that the MeDi may improve health status, and it also may reduce total lifetime costs. Conclusion: MeDi has been shown to be a healthy dietary pattern that may reduce risk related to NCD. The effect is larger if the pattern is combined with physical activity, and tobacco and excessive alcohol consumption are avoided. Promoting the MeDi as a healthy dietary pattern presents challenges which need the collaboration of all levels of society. PMID- 29992230 TI - Improvement in the Retention Rate of Transplanted Fat in Muscle by Denervation. AB - Background: Improvement in the retention rate of transplanted fat is currently a topic of interest. The retention of transplanted fat relies heavily on the reestablishment of blood supply and the function of the adipose-derived stem cells (ADSCs), which may both be impeded by mechanical force. However, the effect of mechanical force on the retention of adipose implants remains unclear. Objectives: This study aimed to evaluate the effectiveness of immobilization on fat retention rate. Methods: Immobilization was carried out by denervation of the hind limb of rats to reduce the mechanical force. Sprague-Dawley (SD) rats were used, and the two hind limbs were assigned at random to the immobilization side and the control side. On average, 0.4 mL of fat was injected into the bilateral muscle and subcutaneous space of the hind limb, and 6 rats were sacrificed at each time point. The outcome measures included the retention rate, the histologic evaluation, and the density of new vessels and proliferative ADSCs. Results: For the muscle fat, the retention rate improved, and more proliferative ADSCs and new vessels were found in the immobilization group. The histologic evaluation between the two sides was of no statistical significance. For the fat in the subcutaneous space, no statistical difference was observed in all the outcome measures between the two sides. Conclusions: Regional immobilization of the recipient site by denervation can improve the retention of the fat graft in muscles owing to improved density of the new vessels and proliferative ADSCs. PMID- 29992231 TI - Optimal Discriminating Concentrations of Six Synthetic Pyrethroids for Monitoring Insecticide Susceptibility in Anopheles minimus (Diptera: Culicidae), a Primary Malaria Vector in Thailand. AB - Malaria is a serious mosquito-borne disease transmitted to humans by Anopheles mosquitoes. Seven species of Anopheles are important malaria vectors in Thailand and all remain susceptible to pyrethroid insecticides, despite decades of use in public health mosquito control programs. However, for a more refined and accurate approach to temporal monitoring of susceptibility patterns to commonly used pyrethroids to control adult Anopheles mosquitoes, it is preferred to have specific concentrations for more discriminating testing. A laboratory strain of Anopheles minimus Theobald was used to establish baseline concentrations for susceptibility to six different synthetic pyrethroids-deltamethrin, permethrin, bifenthrin, cypermethrin, alpha-cypermethrin, and lambda-cyhalothrin using the World Health Organization (WHO) adult bioassay system. Final discriminating concentrations of each active ingredient were determined based on doubling LC99 for each chemical to arrive at the following percent concentrations: deltamethrin (0.009%), permethrin (0.551%), bifenthrin (0.12%), cypermethrin (0.104%), alpha cypermethrin (0.034%), and lambda-cyhalothrin (0.019%). For permethrin, deltamethrin, alpha-cypermethrin, and lambda-cyhalothrin, all revised percentages were lower than currently recommended discriminating concentrations by WHO. Using the newly derived concentrations, insecticide susceptibility tests were followed in a field population of An. minimus s.l. from Kanchanaburi Province. Deltamethrin, bifenthrin, and lambda-cyhalothrin produced 100% kill, whereas permethrin, cypermethrin, and alpha-cypermethrin gave between 92.9 and 97.7% mortality, indicating lower sensitivity (tolerance). Routine monitoring of insecticide susceptibility in An. minimus wild populations throughout Thailand should continue to ensure that insecticides in use are effective to control this vector species. PMID- 29992233 TI - Cancer immunotherapy for metastasis: past, present and future. AB - Cancer is a complex and refractory disease, which can disseminate from primary site to a different site even at an early stage. Cancer immunotherapy harnesses host immune system to battle against cancer, but only a minority of patients benefit from it. Genetic-based technologies have significantly promoted the development of cancer immunotherapy. Here we describe genetic-based cancer immunotherapies in three aspects: recombinant cancer vaccine, immune checkpoint blockade therapy and adoptive cell transfer. In the future, multi-disciplinary collaboration will greatly increase the scope and effectiveness of cancer immunotherpy. PMID- 29992232 TI - Three classes of response elements for human PRC2 and MLL1/2-Trithorax complexes. AB - Polycomb group (PcG) and Trithorax group (TrxG) proteins are essential for maintaining epigenetic memory in both embryonic stem cells and differentiated cells. To date, how they are localized to hundreds of specific target genes within a vertebrate genome had remained elusive. Here, by focusing on short cis acting DNA elements of single functions, we discovered three classes of response elements in human genome: Polycomb response elements (PREs), Trithorax response elements (TREs) and Polycomb/Trithorax response elements (P/TREs). In particular, the four PREs (PRE14, 29, 39 and 48) are the first set of, to our knowledge, bona fide vertebrate PREs ever discovered, while many previously reported Drosophila or vertebrate PREs are likely P/TREs. We further demonstrated that YY1 and CpG islands are specifically enriched in the four TREs (PRE30, 41, 44 and 55), but not in the PREs. The three classes of response elements as unraveled in this study should guide further global investigation and open new doors for a deeper understanding of PcG and TrxG mechanisms in vertebrates. PMID- 29992234 TI - Loss of cytosolic glucose-6-phosphate dehydrogenase increases the susceptibility of Arabidopsis thaliana to root-knot nematode infection. AB - Background and Aims: Root knot nematodes (RKNs, Meloidogyne spp.) are microscopic roundworms with a wide host range causing great economic losses worldwide. Understanding how metabolic pathways function within the plant upon RKN infection will provide insight into the molecular aspects of plant-RKN interactions. Glucose-6-phosphate dehydrogenase (G6PDH), the key regulatory enzyme of the oxidative pentose phosphate pathway (OPPP), is involved in plant responses to abiotic stresses and pathogenesis. In this study, the roles of Arabidopsis cytosolic G6PDH in plant-RKN interactions were investigated. Methods: Enzyme assays and western blotting were used to characterize changes in total G6PDH activity and protein abundance in wild-type Arabidopsis in response to RKN infection. The susceptibility of wild-type plants and the double mutant g6pd5/6 to RKNs was analysed and the expression of genes associated with the basal defence response was tested after RKN infection using quantitative reverse transcription PCR. Key Results: RKN infection caused a marked increase in total G6PDH activity and protein abundance in wild-type Arabidopsis roots. However, the transcript levels of G6PDH genes except G6PD6 were not significantly induced following RKN infection, suggesting that the increase in G6PDH activity may occur at the post-transcriptional level. The double mutant g6pd5/6 with loss-of function of the two cytosolic isoforms G6PD5 and G6PD6 displayed enhanced susceptibility to RKNs. Moreover, reactive oxygen species (ROS) production and gene expression involved in the defence response including jasmonic acid and salicylic acid pathways were suppressed in the g6pd5/6 mutant at the early stage of RKN infection when compared to the wild-type plants. Conclusions: The results demonstrated that the G6PDH-mediated OPPP plays an important role in the plant RKN interaction. In addition, a new aspect of G6PDH activity involving NADPH production by the OPPP in plant basal defence against RKNs is defined, which may be involved in ROS signalling. PMID- 29992236 TI - Satisfaction of physicians working in hospitals within the European Union: state of the evidence based on systematic review. AB - Background: Despite the wide range of studies concerning physician satisfaction in different European countries, there is a lack of literature reviews synthesizing and analyzing current evidence evaluating satisfaction of physicians working in European hospitals. The goal of our research was to provide a general overview of the studies in this area and their results. Methods: We searched MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library from January 2000 to January 2017 including both MESH/Emtree terms and free text words related to the subject with no language restrictions. The eligibility criteria included: (i) target population: physicians working in European hospitals, (ii) quantitative research aimed at assessing physician satisfaction and (iii) validated tools. We performed a narrative synthesis and meta-analysis. Results: A total of 8585 abstracts and 368 full text articles were independently screened by 2 reviewers against inclusion/exclusion criteria. Finally 61 studies were eligible for qualitative analysis. Included studies enrolled a total of 50 001 physicians from 17 countries. Sample sizes varied between 54 and 7090 participants (median: 336). According to our review ~59% of physicians working in European hospitals are overall satisfied, 3.54 was the mean satisfaction among studies reporting data on a scale from 1 to 5, 4.81 for studies with a scale from 1 to 7, 6.12 among studies reporting data on a scale from 1 to 10, and 59.65 among studies with a scale from 0 to 100. Conclusions: The level of physician satisfaction in Europe is moderate. There is a large variety of tools and scales used to assess it. PMID- 29992235 TI - Behcet's disease as a causative factor of cerebral venous sinus thrombosis: subgroup analysis of data from the VENOST study. AB - Objective: This study was performed to determine the rate of cerebral venous sinus thrombosis (CVST) among cases of Behcet's disease (BD) included in a multicentre study of cerebral venous sinus thrombosis (VENOST). Methods: VENOST was a retrospective and prospective national multicentre observational study that included 1144 patients with CVST. The patients were classified according to aetiologic factors, time of CVST symptom onset, sinus involvement, treatment approach and prognosis. Results: BD was shown to be a causative factor of CVST in 108 (9.4%) of 1144 patients. The mean age of patients in the BD group was 35.27 years and 68.5% were men, whereas in the non-BD CVST group, the mean age was 40.57 years and 28.3% were men (P < 0.001). Among the aetiologic factors for patients aged 18-36 years, BD was predominant for men, and puerperium was predominant for women. The onset of symptoms in the BD group was consistent with the subacute form. The transverse sinuses were the most common sites of thrombosis, followed by the superior sagittal sinuses. The most common symptom was headache (96.2%), followed by visual field defects (38%). Conclusions: BD was found in 9.4% of patients in our VENOST series. Patients with BD were younger and showed a male predominance. The functional outcome of CVST in patients with BD was good; only 12% of patients presenting with cranial nerve involvement and altered consciousness at the beginning had a poor outcome (modified Rankin Score ?2). PMID- 29992237 TI - Ultra-high density electroanatomic mapping through transbaffle approach of re entrant tachycardia after Senning operation. PMID- 29992238 TI - Characterizing the 3D structure and dynamics of chromosomes and proteins in a common contact matrix framework. AB - Conformational ensembles of biopolymers, whether proteins or chromosomes, can be described using contact matrices. Principal component analysis (PCA) on the contact data has been used to interrogate both protein and chromosome structures and/or dynamics. However, as these fields have developed separately, variants of PCA have emerged. Previously, a variant we hereby term Implicit-PCA (I-PCA) has been applied to chromosome contact matrices and revealed the spatial segregation of active and inactive chromatin. Separately, Explicit-PCA (E-PCA) has previously been applied to proteins and characterized their correlated structure fluctuations. Here, we swapped analysis methods (I-PCA and E-PCA), applying each to a different biopolymer type (chromosome or protein) than the one for which they were initially developed. We find that applying E-PCA to chromosome distance matrices derived from microscopy data can reveal the dominant motion (concerted fluctuation) of these chromosomes. Further, by applying E-PCA to Hi-C data across the human blood cell lineage, we isolated the aspects of chromosome structure that most strongly differentiate cell types. Conversely, when we applied I-PCA to simulation snapshots of proteins, the major component reported the consensus features of the structure, making this a promising approach for future analysis of semi-structured proteins. PMID- 29992240 TI - Matrix sieving-enforced retrograde transcytosis regulates tissue accumulation of C-reactive protein. AB - Aims: Circulating proteins larger than 3 nm can be transported across continuous endothelial barrier of blood vessels via transcytosis. However, excessive accumulation of serum proteins within the vessel walls is uncommon even for those abundant in the circulation. The aim of this study was to investigate how transcytosis regulates tissue accumulation of the prototypical acute-phase reactant C-reactive protein (CRP) and other serum proteins. Methods and Results: Transcytosis of CRP as well as of transferrin and low-density lipoprotein across aortic endothelial cells is bidirectional with directional preference from the apical (blood) to basolateral (tissue) direction both in vitro and in vivo. This directional preference is, however, reversed by the basement membrane (BM) matrix underlying the basolateral surface of endothelial cells. This is due to the sieving effect of the BM that physically hinders the diffusion of transcytosed proteins from the apical compartment towards underlying tissues, resulting in immediate retrograde transcytosis that limits basolateral protein accumulation. Conversely, CRP produced within vessel wall lesions can also be transported into the circulation. Conclusions: Our findings identify matrix sieving-enforced retrograde transcytosis as a general mechanism that prevents excessive tissue accumulation of blood-borne proteins, and suggest that lesion-derived CRP might also contribute to elevated serum CRP levels associated with increased risk for cardiovascular diseases. PMID- 29992239 TI - Light-regulated PAS-containing histidine kinases delay gametophore formation in the moss Physcomitrella patens. AB - Two-component systems (TCSs) are signal transduction mechanisms for responding to various environmental stimuli. In angiosperms, TCSs involved in phytohormone signaling have been intensively studied, whereas there are only a few reports on TCSs in basal land plants. The moss Physcomitrella patens possesses several histidine kinases (HKs) that are lacking in seed plant genomes. Here, we studied two of these unique HKs, PAS-histidine kinase 1 (PHK1) and its paralog PHK2, both of which have PAS (Per-Arnt-Sim) domains, which are known to show versatile functions such as sensing light or molecular oxygen. We found homologs of PHK1 and PHK2 only in early diverged clades such as bryophytes and lycophytes, but not in seed plants. The PAS sequences of PHK1 and PHK2 are more similar to a subset of bacterial PAS sequences than to any angiosperm PAS sequences. Gene disruption lines that lack either PHK1 or PHK2 or both formed gametophores earlier than the wild-type, and consistently, more caulonema side branches were induced in response to light in the disruption lines. Therefore, PHK1 and PHK2 delay the timing of gametophore development, probably by suppressing light-induced caulonema branching. This study provides new insights into the evolution of TCSs in plants. PMID- 29992241 TI - Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. AB - Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in >=1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806. PMID- 29992243 TI - Microglia: An Intrinsic Component of the Proliferative Zones in the Fetal Rhesus Monkey (Macaca mulatta) Cerebral Cortex. AB - Microglial cells are increasingly recognized as modulators of brain development. We previously showed that microglia colonize the cortical proliferative zones in the prenatal brain and regulate the number of precursor cells through phagocytosis. To better define cellular interactions between microglia and proliferative cells, we performed lentiviral vector-mediated intraventricular gene transfer to induce enhanced green fluorescent protein expression in fetal cerebrocortical cells. Tissues were collected and counterstained with cell specific markers to label microglial cells and identify other cortical cell types. We found that microglial cells intimately interact with the radial glial scaffold and make extensive contacts with neural precursor cells throughout the proliferative zones, particularly in the rhesus monkey fetus when compared to rodents. We also identify a subtype of microglia, which we term 'periventricular microglia', that interact closely with mitotic precursor cells in the ventricular zone. Our data suggest that microglia are structural modulators that facilitate remodeling of the proliferative zones as precursor cells migrate away from the ventricle and may facilitate the delamination of precursor cells. Taken together, these results indicate that microglial cells are an integral component of cortical proliferative zones and contribute to the interactive milieu in which cortical precursor cells function. PMID- 29992242 TI - Reorganization of cortical oscillatory dynamics underlying disinhibition in frontotemporal dementia. AB - The distribution of pathology in frontotemporal dementia is anatomically selective, to distinct cortical regions and with differential neurodegeneration across the cortical layers. The cytoarchitecture and connectivity of cortical laminae preferentially supports frequency-specific oscillations and hierarchical information transfer between brain regions. We therefore predicted that in frontotemporal dementia, core functional deficits such as disinhibition would be associated with differences in the frequency spectrum and altered cross-frequency coupling between frontal cortical regions. We examined this hypothesis using a 'Go-NoGo' response inhibition paradigm with 18 patients with behavioural variant frontotemporal dementia and 20 healthy aged-matched controls during magnetoencephalography. During Go and NoGo trials, beta desynchronization was severely attenuated in patients. Beta power was associated with increased impulsivity, as measured by the Cambridge Behavioural Inventory, a carer-based questionnaire of changes in everyday behaviour. To quantify the changes in cross frequency coupling in the frontal lobe, we used dynamic causal modelling to test a family of hierarchical casual models, which included the inferior frontal gyrus, pre-supplementary motor area (preSMA) and primary motor cortex. This analysis revealed evidence for cross-frequency coupling in a fully connected network in both groups. However, in the patient group, we identified a significant loss of reciprocal connectivity of the inferior frontal gyrus, particularly for interactions in the gamma band and for theta to alpha coupling. Importantly, although prefrontal coupling was diminished, gamma connectivity between preSMA and motor cortex was enhanced in patients. We propose that the disruption of behavioural control arises from reduced frequency-specific connectivity of the prefrontal cortex, together with a hyper-synchronous reorganization of connectivity among preSMA and motor regions. These results are supported by preclinical evidence of the selectivity of frontotemporal lobar degeneration on oscillatory dynamics, and provide a clinically relevant yet precise neurophysiological signature of behavioural control as a potential pharmacological target for early phase experimental medicines studies. PMID- 29992244 TI - The Biota Project: A Case Study of a Multimedia, Grassroots Approach to Scientific Communication for Engaging Diverse Audiences. AB - SYNOPSIS: The Biota Project communicates science to populations historically ignored by the scientific community. The Biota Project is comprised of a team of young professionals from a myriad of backgrounds and locations with interests in promoting science accessibility and equity. We do this by highlighting research conducted by scientists from underrepresented groups in relatable yet underrated locations with the intention of increasing the participation of underrepresented populations in science. The Biota Project centers on the scientific definition of symbiosis as a tool for both educating and learning from its followers. We deliver stories on the environments of our own backyards by merging art and science and distributing these publicly available stories widely online through short films, media clips, drawings, paintings, blogs, and e-newsletters. This project demonstrates a fresh, transferable perspective on strengthening science communication in a way that conjoins scientific discovery with social justice through the promotion of critical thinking by its target audience. Likewise, contributors learn how to better support local communities with each new story and environment. The Biota Project thus sets a symbiotic tone for re-calibrating the balance between academics, researchers, and local communities. When science is made relevant through understanding, its quality and significance are enhanced, and public recognition of its value is increased. PMID- 29992246 TI - alpha7 Nicotinic Acetylcholine Receptor Regulates the Function and Viability of L Cells. AB - Enteroendocrine L cells secrete the incretin hormone glucagon-like peptide-1 (GLP 1), and they also express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), which may regulate GLP-1 secretion. Here, GTS-21, a selective alpha7nAChR agonist, was used to examine the effect of alpha7nAChR activation in L-cell lines, mouse intestinal primary cell cultures, and C57BL/6 mice. GTS-21 stimulated GLP-1 secretion in vitro, and this effect was attenuated by an alpha7nAChR antagonist or by alpha7nAChR-specific small interfering RNA. Under in vitro cell culture conditions of glucotoxicity, GTS-21 restored GLP-1 secretion and improved L-cell viability while also acting in vivo to raise levels of circulating GLP-1 in mice. To assess potential signaling mechanisms underlying these actions of GTS-21, we first monitored Ca2+, cAMP, and phosphatidylinositol 3-kinase (PI3K) activity. As expected for a GLP-1 secretagogue promoting Ca2+ influx through alpha7nAChR cation channels, [Ca2+]i increased in response to GTS 21, but [cAMP]i was unchanged. Surprisingly, pharmacological inhibition of growth factor signaling pathways revealed that GTS-21 also acts on the PI3K-protein kinase B-mammalian target of rapamycin pathway to promote L-cell viability. Moreover, the Ca2+ chelator BAPTA-AM counteracted GTS-21-stimulated PI3K activity, thereby indicating unexpected crosstalk of L-cell Ca2+ and growth factor signaling pathways. Collectively, these data demonstrate that alpha7nAChR activation enhances GLP-1 secretion by increasing levels of cytosolic Ca2+ while also revealing Ca2+- and PI3K-dependent processes of alpha7nAChR activation that promote L-cell survival. PMID- 29992245 TI - Fission yeast telosomes: non-canonical histone-containing chromatin structures dependent on shelterin and RNA. AB - Despite the prime importance of telomeres in chromosome stability, significant mysteries surround the architecture of telomeric chromatin. Through micrococcal nuclease mapping, we show that fission yeast chromosome ends are assembled into distinct protected structures ('telosomes') encompassing the telomeric DNA repeats and over half a kilobase of subtelomeric DNA. Telosome formation depends on the conserved telomeric proteins Taz1 and Rap1, and surprisingly, RNA. Although yeast telomeres have long been thought to be free of histones, we show that this is not the case; telomere repeats contain histones. While telomeric histone H3 bears the heterochromatic lys9-methyl mark, we show that this mark is dispensable for telosome formation. Therefore, telomeric chromatin is organized at an architectural level, in which telomere-binding proteins and RNAs impose a unique nucleosome arrangement, and a second level, in which histone modifications are superimposed upon the higher order architecture. PMID- 29992247 TI - Do employment factors reduce the effect of low education on mental health? A causal mediation analysis using a national panel study. AB - Background: Young people with low education have worse health than those with higher education. This paper examined the extent to which employment and income reduced the adverse effects of low education on mental health among people aged 20-35 years. Methods: We used causal mediation analyses to estimate the total causal effect (TCE) of low education on mental health and to decompose the effect into the natural direct effect (NDE) and the natural indirect effect (NIE) through two mediators examined sequentially: employment (labour-force participation/occupation skill level) and income. Three waves of the Household, Income and Labour Dynamics in Australia (HILDA) survey (2012-14) were used to establish a temporal sequence between low education (not completing high school), mediators and mental health [the Mental Health Inventory (MHI-5)] among participants aged 20-35 years. Among those who were employed, we conducted further analyses examining the effect of job characteristics as a mediator of the relationship between low education and mental health. Results: The TCE of low education on the MHI-5 was -3.61 [95% confidence interval (CI) -5.30 to -1.92]. The NIE through labour force status and occupational skill level was -1.09 (95% CI -2.29 to 0.10) and -1.49 (95% CI -2.79 to -0.19) through both labour-force status/occupational skill level and income, corresponding to a percentage mediated of 41%. Among the employed, education had a much smaller effect on the MHI-5. Conclusions: Improving employment opportunities could reduce nearly half of the adverse effects of low education on the mental health of young people. PMID- 29992248 TI - Association Between IBD Disability and Reduced Work Productivity (Presenteeism): A Population-Based Study in Manitoba, Canada. AB - Background: One effect of IBD disability is reduced productivity when at work (presenteeism). We explored potential predictors of work presenteeism and compared the predictive ability of the recently developed IBD Disability Index (IBDDI) with 4 other scales in predicting presenteeism. Methods: Participants (aged 18-65 years) were recruited from the University of Manitoba IBD Research Registry. We calculated a presenteeism score (range, 0-24) from the Stanford Presenteeism Scale (SPS), with higher scores representing greater degrees of presenteeism. Using receiver operating characteristic curves and linear regression, we explored associations between presenteeism and the IBDDI, the World Health Organization Disability Assessment Schedule (WHODAS 2.0), the Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Kessler-6 (K6) distress scale. Results: Out of 744 respondents working at least half-time (20+ hours/wk), 472 (63%) reported no reduced productivity in the previous 14 days. Reduced productivity was reported for 1-2 days by 131 (18%), for 3-9 days by 119 (16%), and on most days by 22 (3%). When predicting the SPS, similar model fits were found for the IBDDI, WHODAS, WSAS, IBDQ, and K6. Each increase of 10 on the IBDDI score was associated with an increase of 2.19 (95% confidence interval, 2.00-2.37) on the SPS. Each additional year of disease duration was associated with a reduction in SPS score of 0.08 (P < 0.01). Conclusions: More than one-third of persons with IBD report presenteeism. We found strong associations between presenteeism and disability, lower quality of life, and emotional distress. The IBDDI performs equally as well as the more established scales in predicting presenteeism. PMID- 29992250 TI - Corrigendum. PMID- 29992251 TI - Ultrafast electron microscopy with relativistic femtosecond electron pulses. AB - Ultrafast electron microscopy (UEM) with femtosecond temporal resolution is a 'dream machine' that has been long envisioned for the study of ultrafast structural dynamics in materials. For this purpose, we developed a prototype UEM with relativistic femtosecond electron pulses generated by a radio-frequency acceleration-based photoemission gun. TEM images of polystyrene latex particles and gold nanoparticles were observed using approximately 100-fs-long electron pulses with energies of 3.1 MeV. The effect of emittance and the number of pulses on the images were investigated. We demonstrated single-shot imaging with the femtosecond electron pulse at low magnification of approximately 500*. PMID- 29992254 TI - Antifungal stilbene impregnation: transport and distribution on the micron-level. AB - The transition from the living water-transporting sapwood to heartwood involves in many tree species impregnation with extractives. These differ in amount and composition, and enhance resistance against bacteria, insects or fungi. To understand the synthesis, transport and impregnation processes new insights into the biochemical processes are needed by in-situ methods. Here we show the extractive distribution in pine (Pinus sylvestris) microsections with a high lateral resolution sampled in a non-destructive manner using Confocal Raman Microscopy. Integrating marker bands of stilbenes and lipids enables to clearly track the rapid change from sapwood to heartwood within one tree ring. The higher impregnation of the cell corner, compound middle lamella, the S3 layer and pits reveals the optimization of decay resistance on the micron-level. Furthermore, deposits with changing chemical composition are elucidated in the rays and lumen of the tracheids. The spectral signature of these deposits shows the co-location of lipids and pinosylvins with changing ratios from the living to the dead tissue. The results demonstrate that the extractive impregnation on the micro- and nano-level is optimized by a symbiotic relationship of lipids and pinosylvins to enhance the tree's resistance and lifetime. PMID- 29992256 TI - Prevalence and Patterning of Mental Disorders Through Adolescence in 3 Cohorts of Black and White Americans. AB - The tendency for US blacks to report similar or lower rates of mental disorder than whites is well-established. However, whether these disparities are stable across cohorts of black and white Americans is not well understood. In the current study, we examined black-white differences in the lifetime prevalence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, mood, anxiety, impulse control, and substance use disorders and any mental disorders across 3 cohorts of blacks and whites aged 4-18 years. Using merged data from the National Comorbidity Survey Replication (2001-2003) and the National Comorbidity Survey Adolescent Supplement (2001-2004), we observed a change in the black-white patterning of mental disorder between 1957 and 2004. Blacks born during 1957-1969 reported lower rates of anxiety disorders than their white counterparts (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.52, 0.91); blacks born during 1970-1982 reported no difference in the rates of anxiety disorders relative to whites (OR = 0.97, 95% CI: 0.76, 1.25); and blacks born during 1983-1991 reported higher rates of anxiety disorders than whites (OR = 1.30, 95% CI: 1.18, 1.43). Similar but less distinct trends were observed for mood disorders, impulse control disorders, and any disorders. Our results suggest that the black-white patterning of mental disorder in the United States has changed across cohorts, to the disadvantage of black Americans. PMID- 29992253 TI - Integrative DNA copy number detection and genotyping from sequencing and array based platforms. AB - Motivation: Copy number variations (CNVs) are gains and losses of DNA segments and have been associated with disease. Many large-scale genetic association studies are performing CNV analysis using whole exome sequencing (WES) and whole genome sequencing (WGS). In many of these studies, previous single-nucleotide polymorphism (SNP)-array data are available. An integrated cross-platform analysis is expected to improve resolution and accuracy, yet there is no tool for effectively combining data from sequencing and array platforms. The detection of CNVs using sequencing data alone can also be further improved by the utilization of allele-specific reads. Results: We propose a statistical framework, integrated CNV (iCNV) detection algorithm, which can be applied to multiple study designs: WES only, WGS only, SNP array only, or any combination of SNP and sequencing data. iCNV applies platform-specific normalization, utilizes allele specific reads from sequencing and integrates matched NGS and SNP-array data by a hidden Markov model. We compare integrated two-platform CNV detection using iCNV to naive intersection or union of platforms and show that iCNV increases sensitivity and robustness. We also assess the accuracy of iCNV on WGS data only and show that the utilization of allele-specific reads improve CNV detection accuracy compared to existing methods. Availability and implementation: https://github.com/zhouzilu/iCNV. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29992257 TI - Neutrophils promote atherosclerotic plaque destabilization in a mouse model of endotoxinaemia. PMID- 29992252 TI - Molecular dynamics-derived rotamer libraries for d-amino acids within homochiral and heterochiral polypeptides. AB - Computational resources have contributed to the design and engineering of novel proteins by integrating genomic, structural and dynamic aspects of proteins. Non canonical amino acids, such as d-amino acids, expand the available sequence space for designing and engineering proteins; however, the rotamer libraries for d amino acids are usually constructed as the mirror images of l-amino acid rotamer libraries, an assumption that has not been tested. To this end, we have performed molecular dynamics (MD) simulations of model host-guest peptide systems containing d-amino acids. Our simulations systematically address the applicability of the mirror image convention as well as the effects of neighboring residue chirality. Rotamer libraries derived from these systems provide realistic rotamer distributions suitable for use in both rational and computational design workflows. Our simulations also address the impact of chirality on the intrinsic conformational preferences of amino acids, providing fundamental insights into the relationship between chirality and biomolecular dynamics. While d-amino acids are rare in naturally occurring proteins, they are used in designed proteins to stabilize a desired conformation, increase bioavailability or confer favorable biochemical and physical attributes. Here, we present d-amino acid rotamer libraries derived from MD simulations of alanine based host-guest pentapeptides and show how certain residues can deviate from mirror image symmetry. Our simulations directly model d-amino acids as guest residues within the chiral l-Ala and d-Ala pentapeptide series to explicitly incorporate any contributions resulting from the chiralities of neighboring residues. PMID- 29992255 TI - Precision targeting for more equitable distribution of health professionals in rural China. AB - A strong health workforce is widely recognized as a prerequisite for health care and a crucial determinant of health system performance. The number of health professionals in China increased following the 2009 health system reform, which, in part, aimed to address the shortage and unequal distribution of health professionals. We examined whether the distribution of health professionals was more equitable following the reform and whether the reform had targeted impacts in terms of the quantity of health professionals. We interacted economic (poor and non-poor counties) and geographic (eastern, central and western regions) dimensions to more precisely target vulnerable areas, focussing on the quantity and distribution of health professionals in rural China. We used a county-level longitudinal dataset from the National Health and Family Planning Commission consisting of 1978 counties in all 31 provinces in rural China, with measurements taken every other year from 2008 to 2014. The distribution of health professionals was summarized using descriptive and interaction analyses. We found a constant improvement in the number of health professionals per 1000 population co-existing with a worsening of the distribution across rural China following the health system reform. Most of the non-poor counties improved faster compared with poor counties across all geographic regions, especially in the western and eastern regions. The growth of the number of health professionals per 1000 population was greatest and fastest in western-non-poor counties and least and slowest in eastern-poor counties. As an example of the 'Central Region Downfall' phenomenon, the central counties (both poor and non-poor) performed poorly in terms of the quantity and distribution of health professionals. Based on an analysis of multiple dimensions, targeted and differential measures should be taken to reduce inequalities, and the central region should not be ignored in efforts to improve the distribution of health professionals in rural China. PMID- 29992258 TI - Now the dust has settled over immune checkpoint blockade in metastatic prostate cancer. PMID- 29992259 TI - NMDA Receptor-Mediated Motor Cortex Plasticity After 20 Hz Transcranial Alternating Current Stimulation. AB - Transcranial alternating current stimulation (tACS) has been shown to modulate neural oscillations and excitability levels in the primary motor cortex (M1). These effects can last for more than an hour and an involvement of N-methyl-d aspartate receptor (NMDAR) mediated synaptic plasticity has been suggested. However, to date the cortical mechanisms underlying tACS after-effects have not been explored. Here, we applied 20 Hz beta tACS to M1 while participants received either the NMDAR antagonist dextromethorphan or a placebo and the effects on cortical beta oscillations and excitability were explored. When a placebo medication was administered, beta tACS was found to increase cortical excitability and beta oscillations for at least 60 min, whereas when dextromethorphan was administered, these effects were completely abolished. These results provide the first direct evidence that tACS can induce NMDAR-mediated plasticity in the motor cortex, which contributes to our understanding of tACS induced influences on human motor cortex physiology. PMID- 29992260 TI - Accurate multiple alignment of distantly related genome sequences using Filtered Spaced Word Matches as anchor points. AB - Motivation: Most methods for pairwise and multiple genome alignment use fast local homology search tools to identify anchor points, i.e. high-scoring local alignments of the input sequences. Sequence segments between those anchor points are then aligned with slower, more sensitive methods. Finding suitable anchor points is therefore crucial for genome sequence comparison; speed and sensitivity of genome alignment depend on the underlying anchoring methods. Results: In this paper, we use filtered spaced word matches to generate anchor points for genome alignment. For a given binary pattern representing match and don't-care positions, we first search for spaced-word matches, i.e. ungapped local pairwise alignments with matching nucleotides at the match positions of the pattern and possible mismatches at the don't-care positions. Those spaced-word matches that have similarity scores above some threshold value are then extended using a standard X-drop algorithm; the resulting local alignments are used as anchor points. To evaluate this approach, we used the popular multiple-genome-alignment pipeline Mugsy and replaced the exact word matches that Mugsy uses as anchor points with our spaced-word-based anchor points. For closely related genome sequences, the two anchoring procedures lead to multiple alignments of similar quality. For distantly related genomes, however, alignments calculated with our filtered-spaced-word matches are superior to alignments produced with the original Mugsy program where exact word matches are used to find anchor points. Availability: http://spacedanchor.gobics.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29992261 TI - Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab. AB - Background: The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Methods: Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Results: Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Conclusions: Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal. PMID- 29992262 TI - Myocardial perfusion during atrial fibrillation in patients with non-ischaemic systolic heart failure: a cross-sectional study using Rubidium-82 positron emission tomography/computed tomography. AB - Aims: Patients with non-ischaemic systolic heart failure often have reduced myocardial blood flow without significant coronary atherosclerosis. Likewise, patients with atrial fibrillation (AF) have reduced myocardial perfusion during AF compared with sinus rhythm. The aim of this study was to explore whether there is an additive negative effect of AF during scan on the myocardial perfusion in patients with non-ischaemic systolic heart failure. Methods and results: We included 27 young healthy controls and 114 patients with non-ischaemic systolic heart failure to a Rubidium-82 positron emission tomography/computed tomography perfusion scan (23 with AF during scan). To obtain the myocardial flow reserve (MFR = stress flow/rest flow), patients were scanned at rest and during adenosine induced stress. Among patients, those with AF were older [years: 73; interquartile range (IQR) 65-78 vs. 67; IQR 60-74; P = 0.03] and more were men (87% vs. 62%; P = 0.02). Distribution of sex in controls did not differ from either patient group. Patients with AF had significantly lower MFR than patients without [MFR: 1.87; 95% confidence interval (CI) 1.58-2.22 vs. 2.50; 95% CI 2.06 2.86; percent difference: -21.5%; P = 0.01]. MFR remained significantly lower in the group with AF (estimate -24.2%; 95% CI -39.6% to -4.8%; P = 0.02) in an adjusted multivariable regression analysis. Further, patients had lower MFR compared with controls: 3.46; 95% CI 3.03-3.94; P < 0.0001. Additionally, coronary vascular resistance was highest in patients with AF and lowest in controls. Conclusion: Patients with systolic heart failure had lower flow reserve than healthy controls and even lower MFR if they had AF during scan. PMID- 29992263 TI - Proteomic profile of patients with atrial fibrillation undergoing cardiac surgery. AB - OBJECTIVES: Proteomic analysis of patients with advanced cardiovascular disease was conducted to identify possible biomarkers for atrial fibrillation (AF). METHODS: A total of 123 patients undergoing cardiac surgery (22 with AF and 101 without AF) and 20 healthy subjects were recruited. Demographic data, patient history and blood samples were collected. Growth/differentiation factor 15, resistin, intracellular adhesion molecule-1, galectin-3, trefoil factor 3, tissue inhibitor of metalloproteinases 1, matrix metallopeptidase 9, high-sensitive troponin T, interleukins 6, 1alpha, 3, 4, 8, 20 and 22, tumour necrosis factor alpha, C-X-C motif chemokines 10 and 11, S100A6 and Type III procollagen were measured in blood serum. Differential expression between any 2 groups for any of the measured proteins was identified by fitting linear models, whereas Matthews Correlation Coefficient was used to evaluate their predictive capacity. Combined markers using more than 1 protein were attained via weighted Support Vector Machines. RESULTS: Although serum levels of the markers were higher in patients with cardiovascular disease than in healthy subjects, only growth/differentiation factor 15 and resistin were significantly higher in patients with AF among the subpopulation who underwent heart surgery (P = 0.029 and P = 0.007, respectively). Specific pairs of several biomarkers had mediocre predictive capacity for AF. CONCLUSIONS: Growth/differentiation factor 15 and resistin are 2 markers that could be helpful in stratifying risk for AF in patients with cardiovascular disease. Yet, more research in terms of proteomics and investigation of possible molecular pathways implicated is required. PMID- 29992264 TI - Standardized classification and framework for reporting, interpreting, and analysing medication non-adherence in cardiovascular clinical trials: a consensus report from the Non-adherence Academic Research Consortium (NARC). AB - Non-adherence has been well recognized for years to be a common issue that significantly impacts clinical outcomes and health care costs. Medication adherence is remarkably low even in the controlled environment of clinical trials where it has potentially complex major implications. Collection of non-adherence data diverge markedly among cardiovascular randomized trials and, even where collected, is rarely incorporated in the statistical analysis to test the consistency of the primary endpoint(s). The imprecision introduced by the inconsistent assessment of non-adherence in clinical trials might confound the estimate of the calculated efficacy of the study drug. Hence, clinical trials may not accurately answer the scientific question posed by regulators, who seek an accurate estimate of the true efficacy and safety of treatment, or the question posed by payers, who want a reliable estimate of the effectiveness of treatment in the marketplace after approval. The Non-adherence Academic Research Consortium is a collaboration among leading academic research organizations, representatives from the U.S. Food and Drug Administration and physician-scientists from the USA and Europe. One in-person meeting was held in Madrid, Spain, culminating in a document describing consensus recommendations for reporting, collecting, and analysing adherence endpoints across clinical trials. The adoption of these recommendations will afford robustness and consistency in the comparative safety and effectiveness evaluation of investigational drugs from early development to post-marketing approval studies. These principles may be useful for regulatory assessment, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. PMID- 29992265 TI - Development of effective antimicrobial cocktails to prevent bacterial contamination of allograft tissues under low temperature conditions. AB - OBJECTIVES: Prevention of bacterial transmission in recipient patients via allograft decontamination with an antimicrobial cocktail consisting of cefmetazole (cefoxitin), vancomycin, lincomycin and polymyxin B is an important procedure commonly practised in tissue banks. However, some allografts are lost due to the failure of decontamination under low temperature conditions. Here, we aimed to develop new antimicrobial cocktails that exert a high bactericidal activity at 4 degrees C. METHODS: Bacterial species used in this study were selected as major causative pathogens of allograft tissue contamination. The efficacy of the combination of 2 antimicrobial agents was determined by the checkerboard titration method. The bactericidal effects of the new antimicrobial cocktails were evaluated under the same conditions as those used for the storage and preservation of allograft tissues. RESULTS: Among the selected antimicrobial agents, daptomycin exhibited the highest bactericidal activity against methicillin-resistant Staphylococcus aureus under low temperature conditions. The combination of daptomycin + gentamicin and daptomycin + levofloxacin showed a synergistic or additive effect against various bacterial species. The antimicrobial cocktail containing 200 MUg/ml of daptomycin, gentamicin and levofloxacin could eradicate <=104 colony-forming units/ml of methicillin resistant S. aureus and Enterococcus faecalis, which exhibit a low susceptibility to antimicrobial agents at 4 degrees C for 24 h. CONCLUSIONS: We have developed a new formula for an antimicrobial cocktail to effectively and sufficiently prevent bacterial contamination of allograft tissues under low temperature conditions in vitro. PMID- 29992267 TI - Erratum to "The Intersections of Chronic Noncancer Pain: Culturally Diverse Perspectives on Disease Burden". PMID- 29992266 TI - Generic Irradiation and Hot Water Phytosanitary Treatments for Mango Fruits cv. 'Ataulfo' nino Infested by Anastrepha ludens and Anastrepha obliqua (Diptera: Tephritidae). AB - The mango fruit cv. 'Ataulfo' nino is an underdeveloped fruit that has a split on the back and a pronounced peak, and among the current total supply of commercialized mangoes cv. 'Ataulfo', approximately 2% are classified as 'Ataulfo' nino, which are strongly infested by Anastrepha ludens (Loew) (Diptera: Tephritidae) and Anastrepha obliqua Mcquart. The objective of this study was to determine the tolerance to 150-Gy generic irradiation for fruit flies of the Anastrepha genus in comparison to the development of a hot water treatment (HWT) as phytosanitary treatments for mango fruits cv. 'Ataulfo' nino infested by A. ludens and A. obliqua. The results indicated that both treatments were effective; 150-Gy irradiation and HWT at 46.3-47 degrees C for 51 min did not result in significant effects on the external and internal color, total sugar content, firmness, pH, or weight. The sensorial quality described by the appearance, flavor, color, and odor did not show any significant differences between treatments. For both A. ludens and A. obliqua, the third larval instar was the most thermotolerant. The efficacy test was conducted with an immersion time of 47 min. A. ludens did not survive, but for A. obliqua, three larvae out of a total of 6,890 did survive and pupate. Consequently, the confirmatory test consisted of submerging mangoes infested with third-instar A. ludens and A. obliqua in water at 46.3-47 degrees C for 51 min. In total, 67,392 A. ludens and 22,086 A. obliqua larvae were treated, and no surviving larvae were observed. PMID- 29992268 TI - Measuring precarious employment in Europe 8 years into the global crisis. AB - Background: The objective of this study is to describe the prevalence of precarious employment in the European Union (EU) using a multidimensional approach, 8 years into the economic crisis (2014). Methods: We use data from the Flash Eurobarometer 398 among salaried workers (n = 7702). We calculated the proportion and its 95% confidence intervals (CI 95%) for each of the precarious employment dimensions (not having the ability to exercise rights, vulnerability, disempowerment and temporariness), the prevalence of precarious employment (presenting at least one dimension) and the proportion of workers presenting one, two, three or four dimensions. Results: Two out of three workers had a precarious employment. The prevalence of precariousness was higher in Eastern (72.64%; CI 95%: 61.78; 81.34) than in Nordic European countries (51.17%; CI 95%: 44.30; 58.00). The most prevalent dimension was not having the ability to exercise rights (42.39%). Conclusions: Precarious employment is an important social determinant of health. Therefore, the EU policy-makers should take into consideration the new forms of employment and legislate accordingly. PMID- 29992269 TI - APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries. AB - Background: Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis (FSGS) in populations with African ancestry. We determined the frequency of G1/G2 variants in steroid-resistant nephrotic syndrome (SRNS)/FSGS patients with African or French West Indies ancestry in France and its relationships with other SRNS genes. Methods: In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped by direct Sanger sequencing and pathogenic mutations were screened by next generation sequencing with a panel including 35 SRNS genes. Results: The two risk allele [high-risk (HR)] genotypes were found in 43.1% (66/152) of subjects compared with 18.9% (106/562) in a control population (P < 0.0001): 33 patients homozygous for APOL1 G1 alleles, 4 homozygous for G2 and 29 compound heterozygous for G1 and G2. Compared with patients in the low-risk (LR) group, patients in the HR group were more likely to originate from the French West Indies than from Africa [45/66 (68.2%) versus 30/86 (34.9%); P < 0.0001]. There were more familial cases in the HR group [27 (41.5%) versus 8 (11.4%); P < 0.0001]. However, causative mutations in monogenic SRNS genes were found in only 1 patient in the HR group compared with 16 patients (14 families) in the LR group (P = 0.0006). At diagnosis, patients in the HR group without other mutations were more often adults [35 (53.8%) versus 19 (27.1%); P = 0.003] and had a lower estimated glomerular filtration rate (78.9 versus 98.8 mL/min/1.73 m2; P = 0.02). Conclusions: The HR genotype is frequent in FSGS patients with African ancestry in our cohort, especially in those originating from the West Indies, and confer a poor renal prognosis. It is usually not associated with other causative mutations in monogenic SRNS genes. PMID- 29992270 TI - Monitoring for paroxysmal atrial fibrillation and for other modifiable risk factors for stroke. PMID- 29992271 TI - De novo designed transmembrane peptides activating the alpha5beta1 integrin. AB - Computationally designed transmembrane alpha-helical peptides (CHAMP) have been used to compete for helix-helix interactions within the membrane, enabling the ability to probe the activation of the integrins alphaIIbbeta3 and alphavbeta3. Here, this method is extended towards the design of CHAMP peptides that inhibit the association of the alpha5beta1 transmembrane (TM) domains, targeting the Ala X3-Gly motif within alpha5. Our previous design algorithm was performed alongside a new workflow implemented within the widely used Rosetta molecular modeling suite. Peptides from each computational approach activated integrin alpha5beta1 but not alphaVbeta3 in human endothelial cells. Two CHAMP peptides were shown to directly associate with an alpha5 TM domain peptide in detergent micelles to a similar degree as a beta1 TM peptide does. By solution-state nuclear magnetic resonance, one of these CHAMP peptides was shown to bind primarily the integrin beta1 TM domain, which itself has a Gly-X3-Gly motif. The second peptide associated modestly with both alpha5 and beta1 constructs, with slight preference for alpha5. Although the design goal was not fully realized, this work characterizes novel CHAMP peptides activating alpha5beta1 that can serve as useful reagents for probing integrin biology. PMID- 29992272 TI - A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. AB - Background: Animal studies suggest a positive role for nicotinamide riboside (NR) on insulin sensitivity and hepatic steatosis in models of obesity and type 2 diabetes. NR, an NAD+ precursor, is a member of the vitamin B-3 family now available as an over-the-counter supplement. Although data from preclinical trials appear consistent, potential effects and safety need to be evaluated in human clinical trials. Objective: The aim of this study was to test the safety of dietary NR supplementation over a 12-wk period and potential to improve insulin sensitivity and other metabolic parameters in obese, insulin-resistant men. Design: In an investigator-initiated randomized, placebo-controlled, double blinded, and parallel-group designed clinical trial, forty healthy, sedentary men with a body mass index (BMI) > 30 kg/m2, age-range 40-70 y were randomly assigned to 12 wk of NR (1000 mg twice daily) or placebo. We determined the effects of NR supplementation on insulin sensitivity by a hyperinsulinemic euglycemic clamp and substrate metabolism by indirect calorimetry and labeled substrates of tritiated glucose and palmitate. Body composition and fat mass distribution were determined by whole-body dual-energy X-ray absorptiometry (DXA) and MRI scans, and measurements of intrahepatic lipid content were obtained by MR spectroscopy. Results: Insulin sensitivity, endogenous glucose production, and glucose disposal and oxidation were not improved by NR supplementation. Similarly, NR supplementation had no effect on resting energy expenditure, lipolysis, oxidation of lipids, or body composition. No serious adverse events due to NR supplementation were observed and safety blood tests were normal. Conclusion: 12 wk of NR supplementation in doses of 2000 mg/d appears safe, but does not improve insulin sensitivity and whole-body glucose metabolism in obese, insulin-resistant men. This trial was registered at clinicaltrials.gov as NCT02303483. PMID- 29992273 TI - A cross-sectional study on renal involvement among HIV-infected patients attending a tertiary care hospital in Kolkata. AB - Background and objectives: The HIV-associated renal diseases represent a spectrum. Indian data on this is sparse. This study was undertaken to find out the prevalence and clinicopathological spectrum of renal involvement in HIV among antiretroviral therapy (ART) naive patients (Group 1) and among those on ART (Group 2). Methods: Systematic random sampling was undertaken to select 109 patients each from virology outpatient department (VOPD) and ART centre of a tertiary care hospital. They were screened and further investigated if renal involvement was found. Results: Renal involvement was present in 25/109 (22.94%) and 15/109 (13.76%) patients of Groups 1 and 2, respectively. Among patients of Groups 1 and 2, 9/24 (37.5%) and 2/13 (15.4%), respectively, had clinically significant proteinuria, but none in the nephrotic range. Statistically significant relationships of renal involvement were observed with CD4 count <100/MUl and with low BMI. Of the patients of Group 2, 20% of those on a tenofovir-based regimen had renal involvement with tubular changes, while only 4.6% of those on other regimens had renal involvement. This difference was statistically significant (p<0.05; OR=5.25). Conclusion: Renal involvement was less common among those on ART. Low CD4 count and body mass index (BMI) were associated with renal dysfunction. Patients on a tenofovir-based regimen had more renal involvement compared with not on a tenofovir-based regimen. PMID- 29992274 TI - A Rapid and Precise Liquid Chromatographic Method for Simultaneous Determination of Alpha Lipoic Acid and Docetaxel in Lipid-Based Nanoformulations. AB - Combinational drug delivery successfully merges the benefits of nanotechnology and combination therapy by providing diversity to improve the carrier properties and better control over tailoring them as per the need of cancer treatment. A combination of conventional chemotherapeutic agent; docetaxel (DTX) and antioxidant agent; alpha lipoic acid (ALA) which acts by preventing metastasis may fulfill idealness of control and targeted drug delivery against breast cancer. The objective of the current study is to develop a reverse-phase HPLC-UV method for simultaneous determination of DTX and ALA in lipid-based nanoformulations. DTX and ALA were separated on Intersil(r) ODS (C18) column (250 * 4.6 mm, 5 MUm) with a mobile phase consisting of acetonitrile: sodium acetate buffer (pH 3.5; 10 mM) (65:35% v/v) run in isocratic mode at a flow rate of 1 mL/min. The developed method was validated as per ICH guidelines. The method showed linearity in the concentration range of 1-15 MUg/mL for DTX and 2-30 MUg/mL for ALA. It can detect minimum 200 ng/mL of DTX and 500 ng/mL of ALA. The method was further successfully applied in lipid-based formulation characterization. In conclusion, a simple, accurate and precise reverse-phase HPLC-UV method was established for simultaneous determination of DTX and ALA in nanoformulations. PMID- 29992275 TI - Effects of Coronary Revascularisation on Global Coronary Flow Reserve in Stable Coronary Artery Disease. AB - Aims: Coronary flow reserve (CFR) is an integrated measure of the entire coronary vasculature and is a powerful prognostic marker in coronary artery disease (CAD). The extent to which coronary revascularisation can improve CFR is unclear. This study aimed to evaluate the impact of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on CFR in patients with stable CAD. Methods and Results: In a prospective, multicentre observational study, CFR was measured by 15O-water positron emission tomography as the ratio of stress to rest myocardial blood flow at baseline and 6 months after optimal medical therapy (OMT) alone, PCI, or CABG. Changes in the SYNTAX and Leaman scores were angiographically evaluated as indicators of completeness of revascularisation. Follow-up was completed by 75 (25 OMT alone, 28 PCI, and 22 CABG) out of 82 patients. The median SYNTAX and Leaman scores, and baseline CFR were 14.5 (interquartile range [IQR]: 8-24.5), 5.5 (IQR: 2.5-12.5), and 1.94 (IQR: 1.67 2.66), respectively. Baseline CFR was negatively correlated with the SYNTAX (rho = -0.40, P <0.001) and Leaman scores (rho = -0.33, P=0.004). Overall, only CABG was associated with a significant increase in CFR (1.67 [IQR: 1.14-1.96] vs. 1.98 [IQR: 1.60-2.39], P <0.001). Among patients with CFR<2.0 (n=41), CFR significantly increased in the PCI (1.70 [IQR: 1.42-1.79] vs. 2.21 [IQR: 1.78 2.49], P=0.002, P <0.001 for interaction between time and CFR) and CABG groups (1.28 [IQR: 1.13-1.80] vs. 1.86 [IQR: 1.57-2.22], P <0.001). The reduction in SYNTAX or Leaman scores after PCI or CABG was independently associated with the percent increase in CFR after adjusting for baseline characteristics (P=0.012 and P=0.011, respectively). Conclusion(s): Coronary revascularisation ameliorated reduced CFR in patients with obstructive CAD. The degree of improvement in angiographic CAD burden by revascularisation was correlated with magnitude of improvement in CFR. PMID- 29992276 TI - Demographic and clinical characteristics of refugees seeking primary healthcare services in Greece in the period 2015-2016: a descriptive study. AB - Background: In 2015-2016, more than a million refugees entered Greece. Along with other organizations, PRAKSIS, a local non-governmental organization, deployed mobile medical units on three islands and in temporary settlements in Athens. Methods: This is a descriptive cross-sectional study aimed at analysing the demographic and clinical characteristics of the population (n=6688) that received services from PRAKSIS between October 2015 and June 2016 in different locations (islands of Samos, Kos and Leros in the southeastern Aegean Sea and on the mainland at Athens-Piraeus Port Gate E) before and after the closure of European borders in March 2016. Results: The majority (88%) of the population came from Syria, Afghanistan and Iraq. Among them, 53% were women and children. Infectious diseases decreased as the population moved from the islands to the Athens-Piraeus Port, while all other disease categories increased in relative frequency, the difference being statistically significant (p<0.05). Among all consultations, dental and oral cavity health complaints also increased in the Athens-Piraeus Port, but failed to reach statistical significance (p=0.11). Referrals from the mobile health units to specialist care rose from 4.2% of all patients clinically examined on the islands to 9.9% in the Athens-Piraeus Port, and the difference was statistically significant (p<0.05). Conclusions: More research and systematic data collection are needed to inform appropriate policies for the humanitarian challenges posed by the recent refugee and migrant waves in Europe. PMID- 29992277 TI - Dominant pollinators drive non-random community assembly and shared flower colour patterns in daisy communities. AB - Background and Aims: As most plants rely on pollination for persistence in communities, pollination interactions should be important determinants of plant community assembly. Here, trait and phylogenetic null modelling approaches were combined with pollinator interaction networks to elucidate the processes structuring flower colour assembly patterns in Asteraceae communities in Namaqualand, South Africa. Methods: Plant species were assigned to flower colour pattern categories (CPCs) that incorporate the complexity of the bulls-eye colour pattern, using pollinator vision models. Null models were used to assess whether daisy communities exhibit clustering (driven by filtering, facilitation or convergence) or overdispersion (driven by competitive exclusion or character displacement) of CPCs. Next, flower visitor networks were constructed for communities with non-random CPC assembly to confirm the functional role of pollinators in determining floral trait assembly. Key Results: Plant species are unevenly distributed across CPCs, the majority of which are not phylogenetically conserved, suggesting that certain CPCs have a selective advantage. Clustering of CPCs in communities is more frequent than overdispersion, and this does not reflect non-random phylogenetic assembly. In most communities at least one CPC is overrepresented relative to null assemblages. Interaction networks show that each community has a single dominant pollinator that strongly interacts with the overrepresented CPC, suggesting a role for pollinator preferences in driving clustered assembly of CPCs within daisy communities. Conclusion: This novel approach, which demonstrates non-random assembly of complex flower colour patterns and corroborates their functional association with particular pollinators, provides strong evidence that pollinators influence plant community assembly. Results suggest that in some community contexts the benefits of pollinator sharing outweigh the costs of heterospecific pollen transfer, generating clustered assembly. They also challenge the perception of generalized pollination in daisies, suggesting instead that complex daisy colour patterns represent a pollination syndrome trait linked to specific fly pollinators. PMID- 29992278 TI - Mitral annuloplasty ring with selective flexibility for septal-lateral contraction and remodelling properties. AB - OBJECTIVES: To develop and evaluate a novel mitral annuloplasty ring with selective flexibility for septal-lateral contraction and rigidity for septal lateral dilatation in an acute porcine model. METHODS: The novel mitral annuloplasty ring was designed with slits in the luminal posterior segment and annular lateral segments. The slits were designed to allow inward motion during contraction and to block outward motion during dilation. The novel mitral annuloplasty ring was tested in vitro with a dedicated mechanical test bench, followed by in vivo characterization, using sonomicrometry and echocardiography for annular and leaflet geometry, in an acute porcine model. RESULTS: From the in vitro characterization, we verified that the ring could easily contract (0.7 mm/N) in the septal-lateral dimension, while dilatation was restrained (0.4 mm/N). In vivo characterization showed a cyclic range of 2.8 +/- 0.0 mm for septal-lateral contraction. CONCLUSIONS: A novel saddle-shaped remodelling mitral annuloplasty ring was developed with selective flexibility for septal-lateral contraction and rigidity for septal-lateral dilatation. The advantages of this specific ring is that it re-establishes the coaptation plane, ensures leaflet mobility and septal-lateral flexibility and at the same time improves tissue adaptation and thereby decreases the risk of ring dehiscence and redilatation of the mitral annulus. This concept may prove beneficial for patients with ischaemic mitral valve regurgitation or degenerative valve disease. PMID- 29992279 TI - The resistance of Eimeria spp. to toltrazuril in black grouse (Lyrurus tetrix) kept in an aviary. AB - The black grouse is a critically endangered species in Europe. Aviary breeding and re-introduction programs have contributed to the reinstatement of black grouse populations. Parasitic diseases can influence the species' behavior, choice of habitats, and survival rates. Protozoa of the genus Eimeria are the most prevalent parasites in black grouse. The aim of this study was to evaluate the effectiveness of toltrazuril (TOL) against Eimeria spp. in black grouse kept in an aviary. Eimeria spp. oocysts (mean OPG for all birds = 7,047.84; SD = 5,625.05) were detected in feces samples in a routine parasitological examination. Parasitic infections were treated with toltrazuril Baycox 2.5% (Bayer, Leverkusen, Germany) at 1 ml/1 l H2O administered per os with drinking water twice a day for 2 d, 12 h/24 h. High oocysts counts persisted upon the second parasitic examination. Therefore, the birds were divided into 3 groups in 3 existing aviaries. Toltrazuril was administered according to the same protocol, and its uptake with drinking water was monitored. A parasitological examination conducted 5 d later revealed the presence of parasites, and the TOL dose was increased to 3 ml/1 l H2O. When oocysts were detected in a successive exam, the TOL dose was further increased to 5 ml/1 l H2O. The increase in TOL dose did not eliminate parasites, therefore, the treatment was discontinued. The fecal egg count reduction test (FECRT) revealed that 1 ml of TOL reduced fecal oocysts counts (OPG) by 0.02%, the second application of the same TOL dose reduced OPG by 0%, 3 ml of TOL reduced OPG by 0%, and 5 ml of TOL reduced OPG by 65.7%. The applied doses of TOL did not induce significant differences in the fecal oocysts counts of any of the identified species of coccidia. The results indicate that the coccidia species infecting black grouse have natural resistance to TOL. PMID- 29992280 TI - Atrial tachycardia after conversion to extra-cardiac Fontan conduit: critical role of surgery-related electrical gaps. PMID- 29992281 TI - Brenda Milner on her 100th birthday: a lifetime of 'good ideas'. PMID- 29992282 TI - Minimally Invasive Microsurgical Resection of Primary, Intradural Spinal Tumors is Feasible and Safe: A Consecutive Series of 83 Patients. AB - BACKGROUND: To date, the traditional approach to intraspinal tumors has been open laminectomy or laminoplasty followed by microsurgical tumor resection. Recently, however, minimally invasive approaches have been attempted by some. OBJECTIVE: To investigate the feasibility and safety of minimally invasive surgery (MIS) for primary intradural spinal tumors. METHODS: Medical charts of 83 consecutive patients treated with MIS for intradural spinal tumors were reviewed. Patients were followed up during the study year, 2015, by either routine history/physical examination or by telephone consultation, with a focus on tumor status and surgery-related complications. RESULTS: Mean age at surgery was 53.7 yr and 52% were female. There were 49 schwannomas, 18 meningeomas, 10 ependymomas, 2 hemangioblastomas, 1 neurofibroma, 1 paraganglioma, 1 epidermoid cyst, and 1 hemangiopericytoma. The surgical mortality was 0%. In 87% of cases, gross total resection was achieved. The complication rate was 11%, including 2 cerebrospinal fluid leakages, 1 asymptomatic pseudomeningocele, 2 superficial surgical site infections, 1 sinus vein thrombosis, and 4 cases of neurological deterioration. There were no postoperative hematomas, and no cases of deep vein thrombosis or pulmonary embolism. Ninety-three percent of patients were ambulatory and able to work at the time of follow-up. CONCLUSION: This study both demonstrates that it is feasible and safe to remove select, primary intradural spinal tumors using MIS, and augments the previous literature in favor of MIS for these tumors. PMID- 29992284 TI - Exploiting SPL genes to improve maize plant architecture tailored for high density planting. AB - Maize (Zea mays ssp. mays) is an agronomically important crop and also a classical genetic model for studying the regulation of plant architecture formation, which is a critical determinant of grain yield. Since the 1930s, increasing planting density has been a major contributing factor to the >7-fold increase in maize grain yield per unit land area in the USA, which is accompanied by breeding and utilization of cultivars characterized by high-density-tolerant plant architecture, including decreased ear height, lodging resistance, more upright leaves, reduced tassel branch number, and reduced anthesis-silking interval (ASI). Recent studies demonstrated that phytochrome-mediated red/far-red light signaling pathway and the miR156/SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) regulatory module co-ordinately regulate the shade avoidance response and diverse aspects of plant architecture in responding to shading in Arabidopsis. The maize genome contains 30 ZmSPL genes, and 18 of them are predicted as direct targets of zma-miR156s. Accumulating evidence indicates that ZmSPL genes play important roles in regulating maize flowering time, plant/ear height, tilling, leaf angle, tassel and ear architecture, and grain size and shape. Finally, we discuss ways to exploit maize SPL genes and downstream targets for improving maize plant architecture tailored for high-density planting. PMID- 29992285 TI - Reply to the letter to the editor 'Age at diagnosis and prognosis among prostate cancer patients treated with radiotherapy: evidenced from three independent cohort studies' by X. Dong, G. Ma and F. Chen. PMID- 29992287 TI - Reply to the letter to the editor 'Anti-EGFR therapy in oesophagogastric cancer: precise but not enough' by M. Salati and S. Cascinu. PMID- 29992286 TI - Pharmacokinetics and investigation of optimal dose ertapenem in intermittent hemodialysis patients. AB - Background: Previous pharmacokinetic studies demonstrated an increase in serum ertapenem concentrations with decreasing kidney function, including patients receiving renal replacement therapy. This study evaluated the pharmacokinetic parameters of ertapenem in patients receiving hemodialysis. Methods: This prospective, single-center, open-label study examined the pharmacokinetics of a single intravenous (IV) dose of ertapenem 1 g in seven hospitalized noninfected patients undergoing hemodialysis. Blood samples were collected prior to ertapenem administration and at 0.5, 1, 2, 6, 12 and 48 hours (h) after administration. Ertapenem concentrations were determined by validated liquid chromatography mass spectrometry assay. Results: Following an IV bolus of 1 g ertapenem, plasma concentrations declined relatively slowly with a mean +/-standard deviation (SD) elimination half-life of 19.3 +/-6.6 h. Plasma concentrations were similar in all subjects, with maximum mean plasma concentration observed of 343+/-48 ug/mL postdose. The mean +/-SD values for systemic plasma clearance (CL) and volume of distribution at steady state (Vss) were 2+/-0.5 mL/min and 3295+/-1187 mL, respectively. The area under the curve for 0 h-infinity (AUCinf) was 7494 +/-1424 h*ug/mL. No gender effect was observed and no serious adverse events were reported. Conclusions: Ertapenem half-life was prolonged in hemodialysis patients. Considering the nonrenal clearance and the expected 70% removal with high-efficacy hemodialysis, the dose of 1 g ertapenem, three times weekly, after hemodialysis may produce pharmacodynamically sufficient exposure for potential antimicrobial efficacy. Further studies are warranted to assess the clinical efficacy and safety of this dose with prolonged duration of therapy. PMID- 29992288 TI - Crumble: reference free lossy compression of sequence quality values. AB - Motivation: The bulk of space taken up by NGS sequencing CRAM files consists of per-base quality values. Most of these are unnecessary for variant calling, offering an opportunity for space saving. Results: On the CHM1+CHM13 test set, a 17 fold reduction in the quality storage portion of a CRAM file can be achieved while maintaining variant calling accuracy. The size reduction of an entire CRAM file varied from 2.2 to 7.4 fold, depending on the non-quality content of the original file. See Supplementary Data section 6 for details. Availability: Crumble is OpenSource and can be obtained from https://github.com/jkbonfield/crumble. Supplementary information: Supplementary data are available at Bioinformatics. PMID- 29992283 TI - Epigenetic regulation in development: is the mouse a good model for the human? AB - BACKGROUND: Over the past few years, advances in molecular technologies have allowed unprecedented mapping of epigenetic modifications in gametes and during early embryonic development. This work is allowing a detailed genomic analysis, which for the first time can answer long-standing questions about epigenetic regulation and reprogramming, and highlights differences between mouse and human, the implications of which are only beginning to be explored. OBJECTIVE AND RATIONALE: In this review, we summarise new low-cell molecular methods enabling the interrogation of epigenetic information in gametes and early embryos, the mechanistic insights these have provided, and contrast the findings in mouse and human. SEARCH METHODS: Relevant studies were identified by PubMed search. OUTCOMES: We discuss the levels of epigenetic regulation, from DNA modifications to chromatin organisation, during mouse gametogenesis, fertilisation and pre- and post-implantation development. The recently characterised features of the oocyte epigenome highlight its exceptionally unique regulatory landscape. The chromatin organisation and epigenetic landscape of both gametic genomes are rapidly reprogrammed after fertilisation. This extensive epigenetic remodelling is necessary for zygotic genome activation, but the mechanistic link remains unclear. While the vast majority of epigenetic information from the gametes is erased in pre-implantation development, new insights suggest that repressive histone modifications from the oocyte may mediate a novel mechanism of imprinting. To date, the characterisation of epigenetics in human development has been almost exclusively limited to DNA methylation profiling; these data reinforce that the global dynamics are conserved between mouse and human. However, as we look closer, it is becoming apparent that the mechanisms regulating these dynamics are distinct. These early findings emphasise the importance of investigations of fundamental epigenetic mechanisms in both mouse and humans. WIDER IMPLICATIONS: Failures in epigenetic regulation have been implicated in human disease and infertility. With increasing maternal age and use of reproductive technologies in countries all over the world, it is becoming ever more important to understand the necessary processes required to establish a developmentally competent embryo. Furthermore, it is essential to evaluate the extent to which these epigenetic patterns are sensitive to such technologies and other adverse environmental exposures. PMID- 29992289 TI - Electromagnetic interference in cardiac electronic implants caused by novel electrical appliances emitting electromagnetic fields in the intermediate frequency range: a systematic review. AB - Electromagnetic fields (EMF) in the intermediate frequency (IF) range are generated by many novel electrical appliances, including electric vehicles, radiofrequency identification systems, induction hobs, or energy supply systems, such as wireless charging systems. The aim of this systematic review is to evaluate whether cardiovascular implantable electronic devices (CIEDs) are susceptible to electromagnetic interference (EMI) in the IF range (1 kHz-1 MHz). Additionally, we discuss the advantages and disadvantages of the different types of studies used to investigate EMI. Using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement, we collected and evaluated studies examining EMI in in vivo studies, in vitro studies (phantom studies, benchmark tests), and simulation studies. Our analysis revealed that cardiac implants are susceptible to malfunction induced by EMF in the IF range. Electromagnetic interference may in particular be provoked by security systems and induction hobs. The results of the studies evaluated in this systematic review further indicate that the likelihood for EMI is dependent on exposure related parameters (field strength, frequency, and modulation) and on implant- as well as on lead-related parameters (model, type of implant, implant sensitivity setting, lead configuration, and implantation site). The review shows that the factors influencing EMI are not sufficiently characterized and EMF limit values for CIED patients cannot be derived yet. Future studies should therefore, consider exposure-related parameters as well as implant- and lead-related parameters systematically. Additionally, worst-case scenarios should be considered in all study types where possible. PMID- 29992290 TI - Spreading the message of antimicrobial resistance: A detailed account of a successful public engagement event. AB - The increase in Antimicrobial resistance (AMR) microorganisms has been exacerbated by exposure to antimicrobial drugs (e.g. antibiotics). A solution to AMR may require academic researchers to not only contribute to the drug discovery pipeline through laboratory research, but also to engage and inform non specialist audiences using a variety of interventions in order to change behaviour towards our use of antibiotics. In this paper, the authors describe a hands-on public engagement event focusing on AMR. 'A Spoonful of Soil', was created by drawing on the past experiences of the delivering team (also described), with planning focusing on clear concise messages, selection of an appropriate audience and ensuring the event would be of significant interest to the audience. The event had a significant footfall of over 300 visitors. Key messages which aimed to raise awareness of AMR and educate visitors on the actions and behaviours that can help address the global issue of AMR were delivered by appropriate experts successfully, however success in reaching audience cannot be concluded from the feedback and evaluation gathered. PMID- 29992292 TI - Chronic Myeloid Leukemia Following Treatment for Primary Neoplasms or Other Medical Conditions: A Report of 21 Cases and Review of the Literature. AB - Objectives: Therapy-related chronic myeloid leukemia (CML) has been reported, but its clinical presentation and pathologic features have not yet been well characterized. Methods: Twenty-one cases of CML following treatment for primary diseases were collected and retrospectively analyzed. Results: The clinical presentation, pathologic features, and cytogenetic profile were similar to de novo CML. In particular, those with an isolated Philadelphia chromosome constituted 88.9% of our cases, and additional aberrations characteristic of therapy-related acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) were not identified in this study. The patients responded to imatinib/derivatives and survived with limited follow-up. Conclusions: Therapy-related CML has a clinical presentation, pathologic features, and cytogenetic profile akin to de novo CML. Absence of additional significant aberrations seems to suggest a pathogenesis different from therapy-related AML/MDS. Therapy-related CML exhibits a robust therapeutic response to imatinib/derivatives and favorable clinical outcomes similar to de novo CML. PMID- 29992291 TI - An early ABA-induced stomatal closure, Na+ sequestration in leaf vein and K+ retention in mesophyll confer salt tissue tolerance in Cucurbita species. AB - Tissue tolerance to salinity stress is a complex physiological trait composed of multiple 'sub-traits' such as Na+ compartmentalization, K+ retention, and osmotic tolerance. Previous studies have shown that some Cucurbita species employ tissue tolerance to combat salinity and we aimed to identify the physiological and molecular mechanisms involved. Five C. maxima (salt-tolerant) and five C. moschata (salt-sensitive) genotypes were comprehensively assessed for their salt tolerance mechanisms and the results showed that tissue-specific transport characteristics enabled the more tolerant lines to deal with the salt load. This mechanism was associated with the ability of the tolerant species to accumulate more Na+ in the leaf vein and to retain more K+ in the leaf mesophyll. In addition, C. maxima more efficiently retained K+ in the roots when exposed to transient NaCl stress and it was also able to store more Na+ in the xylem parenchyma and cortex in the leaf vein. Compared with C. moschata, C. maxima was also able to rapidly close stomata at early stages of salt stress, thus avoiding water loss; this difference was attributed to higher accumulation of ABA in the leaf. Transcriptome and qRT-PCR analyses revealed critical roles of high-affinity potassium (HKT1) and intracellular Na+/H+ (NHX4/6) transporters as components of the mechanism enabling Na+ exclusion from the leaf mesophyll and Na+ sequestration in the leaf vein. Also essential was a higher expression of NCED3s (encoding 9-cis-epoxycarotenoid dioxygenase, a key rate-limiting enzyme in ABA biosynthesis), which resulted in greater ABA accumulation in the mesophyll and earlier stomata closure in C. maxima. PMID- 29992294 TI - Music Therapy When Death Is Imminent: A Phenomenological Inquiry. AB - Music therapists have described powerful case examples and personal experiences of providing music therapy for clients who are actively dying that suggest a complex experience that merits further exploration. This phenomenological study was conducted to gain a better understanding of the lived experience of music therapists working with clients who are actively dying. Four music therapists (2 female, 2 male), with an average of 10 years' hospice care experience, participated in semi-structured interviews. Data were analyzed using a phenomenological approach (Moustakas, 1994). Ten themes were distilled from the interviews and grouped into four categories: ongoing assessment, intuitive processes, countertransference, and the role of aesthetics and transformation. Participants described a flexible, dynamic clinical and personal process informed by ongoing assessment. These findings point to the importance of further discussion surrounding the clinical implications of the music therapist's internal experience and the role of assessment, intuition, and aesthetics in hospice music therapy. PMID- 29992295 TI - A pilot study using wearable global positioning system data loggers to compare water contact levels: Schistosoma haematobium infection in pre-school-age children (PSAC) and their mothers at Barombi Kotto, Cameroon. AB - Background: Barombi Kotto, Cameroon serves as a reference location for assessing intervention strategies against Schistosoma haematobium. Methods: As part of a pilot study, the whole community was treated with praziquantel, inclusive of pre school-age children (PSAC) and their mothers. One year later, egg-patent infections were reassessed and water contact patterns of 12 pairs of PSAC and their mothers were measured with global positioning system (GPS) data loggers. Results: A substantial reduction in general infection prevalence, from 44.8% to 12.2%, was observed but certain PSAC and mothers continued to have egg-patent infections. Analysis of GPS data demonstrated similar water contact levels between the child and mother groups, although certain individuals were numerical outliers. Conclusions: This study shows the potential of GPS data loggers to clarify the at-risk status of PSAC and mothers. PMID- 29992293 TI - SRSF9 selectively represses ADAR2-mediated editing of brain-specific sites in primates. AB - Adenosine-to-inosine (A-to-I) RNA editing displays diverse spatial patterns across different tissues. However, the human genome encodes only two catalytically active editing enzymes (ADAR1 and ADAR2), suggesting that other regulatory factors help shape the editing landscape. Here, we show that the splicing factor SRSF9 selectively controls the editing of many brain-specific sites in primates. SRSF9 is more lowly expressed in the brain than in non-brain tissues. Gene perturbation experiments and minigene analysis of candidate sites demonstrated that SRSF9 could robustly repress A-to-I editing by ADAR2. We found that SRSF9 biochemically interacted with ADAR2 in the nucleus via its RRM2 domain. This interaction required the presence of the RNA substrate and disrupted the formation of ADAR2 dimers. Transcriptome-wide location analysis and RNA sequencing revealed 1328 editing sites that are controlled directly by SRSF9. This regulon is significantly enriched for brain-specific sites. We further uncovered a novel motif in the ADAR2-dependent SRSF9 binding sites and provided evidence that the splicing factor prevents loss of cell viability by inhibiting ADAR2-mediated editing of genes involved in proteostasis, energy metabolism, the cell cycle and DNA repair. Collectively, our results highlight the importance of SRSF9 as an editing regulator and suggest potential roles for other splicing factors. PMID- 29992296 TI - Age at diagnosis and prognosis among prostate cancer patients treated with radiotherapy: evidenced from three independent cohort studies. PMID- 29992297 TI - Determination of Phosphodiesterase Inhibitors Tadalafil, Roflumilast and Roflumilast N-Oxide Using LC-MS in Guinea Pig Plasma. AB - Phosphodiesterases are known as a super-family of 11 isoenzymes, which can exert various functions based on their organ distribution. In this work, a rapid and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method was developed for quantification of tadalafil (phosphodiesterase five inhibitor), roflumilast (RF) (phosphodiesterase four inhibitor) and its active metabolite, RF N-oxide in guinea pig plasma. Chromatographic separation was carried out on UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) at a flow rate 0.5 mL/min, using 0.2% formic acid in acetonitrile and 0.2% formic acid in water as mobile phases within 4 min. Detection was performed using a triple quadrupole mass spectrometer employing electrospray ionization operated in positive mode using multiple reaction monitoring mode. The method utilized deuterium labeled internal standards, and was validated according to European Medicines Agency guidelines. It showed excellent linearity in the range of 0.5-500.0 ng/mL for all analytes with coefficient of determination >0.99. The intra- and inter-day precisions (relative standard deviation %) were within 6.7%, and the recoveries were greater than 73.4%. Using this method, plasma samples from experiments of phosphodiesterase four, and five inhibitors in a model of ovalbumin-induced allergic inflammation in guinea pigs were analyzed. PMID- 29992298 TI - Scientific updates on the interaction of genes, epigenetics, and multicellularity in cardiovascular diseases: the Working Group of Myocardial Function of the ESC. PMID- 29992299 TI - How has the Zimbabwe mycobacterial culture and drug sensitivity testing system among re-treatment tuberculosis patients functioned during the scale-up of the Xpert MTB/RIF assay? AB - Background: In Zimbabwe, while the Xpert MTB/RIF assay is being used for diagnosing tuberculosis and rifampicin-resistance, re-treatment tuberculosis (TB) patients are still expected to have culture and drug sensitivity testing (CDST) performed at national reference laboratories for confirmation. The study aim was to document the Xpert MTB/RIF assay scale-up and assess how the CDST system functioned for re-treatment TB patients. Methods: We performed an ecologic study using national aggregate data. Results: Use of the Xpert MTB/RIF assay increased from 11 829 to 68 153 between 2012 and 2016. Xpert assays worked well, with successful tests in more than 90% of cases, TB detection rates at 15-17% and rifampicin resistance in <10%. During Xpert scale-up, the number of sputum specimens from re-treatment TB patients reaching national reference laboratories for CDST increased from 12% to 51%. In terms of laboratory performance, culture contamination increased from 3% to 17%, positive cultures from 13% to 17% and successful CDST from 6% to 14%: the proportion of CDST showing any resistance to rifampicin averaged 44%. From 2009 to 2016, the proportion of notified re treatment TB patients with successful CDST increased from <1% to 7%. Conclusions: While components of Zimbabwe's CDST system for re-treatment TB patients showed some changes during the scale-up of the Xpert MTB/RIF assay, overall performance was poor. The country must either invest in improving CDST performance or in advanced molecular diagnostic technology. PMID- 29992300 TI - Chahal et al. Respond to "Physical Exertion and Placental Abruption". PMID- 29992301 TI - Survey-Defined and Interview-Elicited Challenges That Faced Ethiopian Government Hospital Laboratories as They Applied ISO 15189 Accreditation Standards in Resource-Constrained Settings in 2017. AB - Objectives: The World Health Organization African Regional Office recommends ISO 15189 standards to improve performance quality in sub-Saharan African laboratories. We specify challenges Ethiopian laboratorians encountered applying ISO 15189 standards. Methods: From a structured survey at 12 Ethiopian government hospitals, 175 laboratory staff replied; all were aware of the ISO standards and 138 had been involved in the ISO 15189 inspection process. In addition, 11 laboratory heads, 10 quality officers, and three medical directors were interviewed in depth. Results: Half or more respondents identified six challenges obstructing accreditation to a "large" or "very large" degree: (1) low management support, (2) inadequate training, (3) insufficient infrastructure, (4) excessive documentation, (5) little mentorship, and (6) increased accreditation-related workload. Interviewees added (7) poor equipment, (8) unavailable/poor-quality reagents, and (9) high staff turnover. Conclusions: The survey and interviews specified nine major challenges for Ethiopian government hospital laboratories that seriously obstruct meeting ISO 15189 demands. PMID- 29992302 TI - Limited Health Literacy Is Associated With Worse Patient-Reported Outcomes in Inflammatory Bowel Disease. AB - Background: Patients with inflammatory bowel disease (IBD) face complex health tasks and decisions. Limited health literacy is a risk factor for poor health outcomes, but this has not been examined in IBD. This study aims to assess the role of health literacy for patients with IBD. Methods: We prospectively enrolled adults with IBD receiving care from the Section of Gastroenterology at the Boston Medical Center. In-person, standardized questionnaires were administered to measure health literacy with the Newest Vital Sign, self-efficacy with the Medication Use and Self-Efficacy Scale, quality of life with the 10-question Short Inflammatory Bowel Disease Questionnaire, depression with the Patient Reported Outcomes Measurement System Short Form, and clinical disease activity for patients with Crohn's disease with the Harvey-Bradshaw Index and for patients with ulcerative colitis with the Simple Clinical Colitis Activity Index (SCCAI). The relationships between health literacy and these variables were subsequently examined. Results: Of 112 patients invited to participate, 99 enrolled and completed the interview. Limited health literacy was identified in 40% (n = 40) of patients. Patients with limited health literacy reported significantly worse overall health (P = 0.03) and more depressive symptoms (P = 0.01). Of the 56 patients with Crohn's disease, those with adequate health literacy were more likely to be in clinical remission (mean Harvey-Bradshaw Index score < 5), compared with those with limited health literacy (odds ratio, 4.15; 95% confidence interval, 1.37 to 13.45; P = 0.01). There was no significant association between health literacy and clinical disease activity (SCCAI) in patients with ulcerative colitis. Conclusions: Limited health literacy is associated with lower ratings of subjective health and depression in IBD and more symptoms of active disease in patients with Crohn's disease. PMID- 29992303 TI - Helping to understand heart failure with preserved ejection fraction. PMID- 29992304 TI - Association of Neisseria gonorrhoeae genogroups and specific PBP2/MtrR/PorB mutation patterns with susceptibility to penicillin in a susceptible gonococcal population. AB - Objectives: To ascertain whether the antimicrobial susceptibility of Neisseria gonorrhoeae isolates with differing susceptibilities to penicillin is associated with genogroups (GGs) and combined mutation patterns in PBP2 (penA), the multiple transfer resistance repressor (MtrR; mtrR) and porin B (PorB; porB). Methods: The susceptibility of 146 clinical N. gonorrhoeae isolates to penicillin was determined using the agar dilution method and the interpretation criteria of CLSI. The DNA sequences of penA, mtrR and porB in isolates were compared with WT sequences and mutation patterns were determined. Isolates were typed by N. gonorrhoeae multi-antigen sequence typing (NG-MAST) and STs were grouped into specific GGs. Results: The isolates tested carried 9 mutation patterns in PBP2 and 12 mutation patterns in each of MtrR and PorB. Of the 146 isolates, 121 (82.9%) were grouped into 13 different GGs. Isolates with penicillin MICs of 0.03 0.06 mg/L were significantly associated with GG25 (P < 0.05) and PBP2/MtrR/PorB mutation pattern I/WT/WT (P < 0.01). Isolates with a penicillin MIC of 1.0 mg/L were associated (P < 0.05) with: (i) GG3655 and mutation pattern XXII/A ;G45D/G120K;A121N; (ii) GG921 and mutation pattern IX/G45D/G120D;A121N; and (iii) GG1109 and mutation pattern IX/G45D/WT. Sixty percent (9/15) of penicillin resistant isolates (MIC >=2 mg/L) were GG3654 (P < 0.0001) and carried mutation pattern IX/G45D/G120K;A121D or IX/G45D/G120D;A121D (P < 0.05). Conclusions: Specific mutation patterns in PBP2/MtrR/PorB were associated with specific GGs and penicillin susceptibility. This approach of typing strains and resistance patterns is ideal for predicting antimicrobial resistance and should be used in instances in which gonococcal culture is not available but DNA can be obtained from clinical specimens. PMID- 29992307 TI - Sibling-Controlled Study of Parental Bonding, Coping, and Urgent Health-Care Use in Families With Children With Nonepileptic Seizures. AB - Objectives: Pediatric psychogenic nonepileptic seizures (PNES) is a functional somatic symptom condition with significant health-care service burden. While both family and individual factors play an important role in the development and maintenance of PNES, little is known about what predicts urgent health-care use in families with children who have PNES. The aim of the current study was to explore whether child coping and parental bonding styles influence the decision to seek urgent medical care in these families. Methods: Data were analyzed from youth of age 8-18 years, 47 with PNES, and their 25 sibling controls. Parents provided the number of youth emergency room visits and hospitalizations in the preceding year. Youth completed a questionnaire about their coping styles and a measure about their mothers' and fathers' bonding styles. Using a mixed model with family as a random effect, we regressed urgent health-care use on participant type (youth with PNES or sibling), parental bonding style, and youth coping style, controlling for number of child prescription medications. Results: Higher urgent health-care use was associated with having PNES, coping via monitoring, and perceiving one's father to be rejecting and overprotective. Lower urgent health-care use was associated with coping via venting and with perceiving one's mother to be caring and overprotective. Conclusions: This study provides preliminary empirical support for family-based clinical efforts to reduce child urgent health-care use by enhancing effective child coping skills and improving parental response to child impairment and distress in families with youth with PNES. PMID- 29992308 TI - Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. PMID- 29992309 TI - Resolution of dynamic MDR structures among the plasmidome of Salmonella using MinION single-molecule, long-read sequencing. AB - Background: ISCR1 is an important mobile genetic element mediating the transfer of antibiotic resistance genes. Genetic diversity regarding distribution and copy numbers of ISCR1 within a bacterial population derived from an ancestral strain, which may reflect the degree of genetic plasticity conferred by such an element, has not been studied. Objectives: To investigate the plasmid heterogeneity in Salmonella conferred by ISCR1. Methods: Nanopore long-read and other sequencing technologies were used to resolve the structures harbouring different copies of ISCR1-qnrB6 from the perspective of single molecules. Results: Salmonella London Sa128 was positive for ISCR1-qnrB6 and harboured an MDR-encoding conjugative IncF plasmid, pSa128, containing a complex class 1 integron. The plasmid pSa128T from the transconjugant was larger compared with the original plasmid pSa128, presumably due to amplification of ISCR1-qnrB6. Single-molecule, long-read analysis indicated that both plasmids in the donor and transconjugant strains were in a heterogeneous state that contains variable numbers of ISCR1-qnrB6, with four and eight copies in single plasmids being the dominant types. This type of plasmid heterogeneity in populations of one strain can be regarded as an atypical plasmidome. Conclusions: This study highlights the importance of investigation of a single plasmid structure based on long-read sequencing technologies, with a focus on analysing the complex structures of the MDR region, which is expected to exhibit genetic polymorphism or plasmid heterogeneity in various MDR-encoding elements even among members of the same strain. The availability of a single molecule sequencing technique represents a paradigm shift in the capability of performing population genetic analysis of antibiotic-resistant organisms. PMID- 29992310 TI - Recent advancement toward significant association between disordered transcripts and virus-infected diseases: a survey. AB - In the current era of epigenetics research, we have observed many examples of epigenetic modifications, like histone modification and DNA methylation, in various fatal diseases. These include solid tumors, hematological malignancies and viral infections with DNA or RNA viruses. The purpose of this review is to summarize the role of epigenetic modifications during the abovementioned viral infections, viral-associated and independent malignancies. In this article, the essential biological aspects of DNA methylation are discussed. Then, the relationship between cancer and DNA methylation is explained followed by the examples of methylation because of infections with the hepatitis B virus infection, Epstein-Barr virus infection. Subsequently, histone modifications and DNA methylation are separately observed in the HIV-1 strain infections. The relation between HIV latency and epigenetic modifications is also discussed. Besides that, epigenetic changes because of the comorbid effects of drug abuse and HIV-1 infection are reported. Finally, a DNA methylation analysis of human brain tissue experiment was performed. As a result, we observed few cases such as HIV-mediated dementia, or impaired cell adhesion during cell cycle, which justify the observations discussed in the rest of the article. PMID- 29992311 TI - The effects of inulin on the mucosal morphology and immune status of specific pathogen-free chickens. AB - This study investigated the effects of inulin on mucosal morphology and immune function of specific pathogen-free (SPF) chickens. A total of 200 one-day-old White Leghorns SPF chickens were divided into 5 groups of 4 replicates of 10 chickens each. All SPF chickens were fed a basal diet supplemented with 0, 0.25, 0.5, 1.0, or 2.0% inulin. The mucosal morphology and immune indexes were analyzed on days 7, 14, and 21, respectively. Our results showed that the concentrations of acetate and propionate in the cecum and serum had increased with dietary inulin supplementation on day 21 (P < 0.05). Butyrate could not be detected in the cecal digesta, but was increased in the serum of 1 and 2% groups, as compared with the control group (P < 0.05). The villi height was increased (P < 0.05) and the crypt depth was decreased (P < 0.05) in the duodenum and ileum of SPF chickens fed inulin, as compared with the control group. Also, inulin at a low concentration (0.25 or 0.5%) significantly decreased (P < 0.05) the gene expression of nuclear factor-kappaB (NF-kappaB), lipopolysaccharide-induced tumor necrosis factor (LITAF) at 7, 14, and 21 d, and of interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) at 7 and 14 d, and increased that of mucin 2 (MUC2) and claudin-1 in the ileum of SPF chickens at 7, 14, and 21 d. High inulin supplementation (2%) significantly increased the gene expression of NF kappaB, LITAF, IL-6, iNOS, and Claudin-1 at 14 and 21 d compared to low inulin concentration (0.25 or 0.5%). The results indicated that the effects of inulin on mucosal immune function occurred in a dose-dependent manner. A low concentration (0.25 or 0.5%) of inulin may be beneficial in promoting intestinal immune function. PMID- 29992312 TI - First report on seroprevalence and risk factors of dengue virus in Jordan. AB - Background: There are no data available on dengue epidemiology in Jordan. This is the first study of the seroprevalence and risk factors of dengue virus (DENV) infection in Jordan. Methods: Sera samples from 892 apparently healthy individuals from all over Jordan were tested for DENV by enzyme-linked immunosorbent assay and a validated questionnaire was completed by all participants to identify and rank possible risk factors. Results: The seroprevalence was 24.6% (95% confidence interval 21.8 to 27.5). In univariate regression analysis, age, education, history of travel, living in rainy areas and practicing agriculture were significantly (p<0.05) associated with seropositivity. The multivariate logistic regression model showed that those who live in a rainy climate (odd ratio [OR] 1.7), are older (OR 2.3), have a history of international travel (OR 1.5) and are male with a history of international travel had a significantly greater odds of DENV seropositivity (OR 3.4). Conclusions: These data suggest that DENV circulates in Jordan and that cases may be imported or locally transmitted. Further research is needed to determine the circulating DENV serotypes and vectors in Jordan. Given the high rate of DENV seropositivity, dengue should be considered as a differential diagnosis in febrile diseases in Jordan, especially among populations living in rainy climates. PMID- 29992313 TI - Team Players or Opponents: Coadministration of Selective Glucagon and GLP-1 Receptor Agonists in Obese Diabetic Monkeys. AB - We assessed the therapeutic contribution of the individual components of glucagon like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonists alone and in combination upon energy homeostasis and glycemic control in diet-induced obese, diabetic nonhuman primates. The pharmacological active dose ranges of selective agonists were established through a dose-finding study, followed by a 6 week chronic study. Repeated subcutaneous administration of a selective GCGR agonist (30 ug/kg once daily) did not affect food intake or body weight, whereas the selective GLP-1R agonist (3 ug/kg once daily) alone decreased energy intake by 18% and body weight by 3.8% +/- 0.9%. Combination of both agonists reduced significantly cumulative food intake by 27% and body weight by 6.6% +/- 0.9%. Fasting plasma glucose (FPG) was improved by GLP-1R agonist (baseline vs end of study, 176.7 +/- 34.0 vs 115.9 +/- 16.1 mg/dL). In contrast, groups exposed to GCGR agonist experienced nonsignificant elevations of FPG. More accurate assessment of therapeutic interventions on glucose homeostasis was tested by an IV glucose tolerance test. Glucose excursion was significantly elevated by chronic GCGR agonist administration, whereas it was significantly decreased in GLP-1R agonist-treated monkeys. In the combination group, a nonsignificant increase of glucose excursion was seen, concomitantly with significantly increased insulin secretion. We conclude that chronic glucagon agonism does not affect energy homeostasis in nonhuman primates. In combination with GLP-1R agonism, glucagon agonism synergistically enhances negative energy balance with resulting larger body weight loss. However, adding GCGR to GLP-1R agonism diminishes glycemic control in diabetic monkeys. Therefore, long-term therapeutic implications of using GLP-1R/GCGR coagonists for weight management in diabetes warrants further scrutiny. PMID- 29992314 TI - Diagnostic of guinea fowl (Numida meleagris) farming in Ivory Coast. AB - In order to promote farming of guinea fowl and to diversify the sources of income of Ivorian farmers, a survey was conducted in 2016 in 15 regions (197 farmers) out of a total of 31 regions in Ivory Coast. The aims were 1) to establish a better knowledge of guinea fowl farming; 2) to assess the level of technical knowledge of farmers; and 3) to establish a global typology of farmers based on their socio-economic profile, the goal of the farming (sale or consumption), and their level of technical knowledge. The sampling was realized according to a snowball type design (chain referral sampling method) a non-probabilistic method where farmers were selected not from a sampling frame but from the friendship network of existing farmers of the sample. Guinea fowl farming was undertaken by persons from all the social levels with no distinctions due to sex, religion, ethnic group, or level of education. For farmers with more than 48 guinea fowl and farmers who were Muslims, farming was a source of income. Owners of guinea fowl under 60 yr old, Christians and atheists kept a part of their production for their own consumption and marketed the remainder of the flock. Incubation was primarily accomplished by a laying hen, with an estimated hatching rate of 72%. In our survey, 68.5% of the farmers had a good practical knowledge of guinea fowl farming. The identified weaknesses of guinea fowl farming in the regions where the survey took place were the absence of knowledge of guinea fowl farming and the poverty of farmers who could not afford incubators nor provide a good nutrition to their animals. The future development of this farming will have to take into account all these weaknesses that are also limitations to this development. PMID- 29992315 TI - Demography and Uncertainty of Population Growth of Conogethes punctiferalis (Lepidoptera: Crambidae) Reared on Five Host Plants With Discussion on Some Life History Statistics. AB - The development, survival, and fecundity data of Conogethes punctiferalis (Guenee) (Lepidoptera: Crambidae) reared on chestnut (Castanea mollissima Blume), maize (Zea mays L.), sunflower (Helianthus annuus L.), hawthorn (Crataegus pinnatifida Bunge), and apple (Malus domestica Miller) were collected at 25 +/- 1 degrees C and 70 +/- 5% RH. Raw data were analyzed and compared by using the age stage, two-sex life table. The mean fecundity (F) was the highest (282.3 eggs per female) when larvae were reared on chestnut. The lowest mean fecundity (19.2 eggs per female) occurred on apple. The net reproductive rates (R0) were 134.52, 106.77, 30.29, 27.61, and 8.63 offspring on chestnut, maize, sunflower, hawthorn, and apple, respectively. The intrinsic rates of increase (r) were 0.1359, 0.1326, 0.0807, 0.0811, and 0.0448 d-1 on chestnut, maize, sunflower, hawthorn, and apple, respectively. Computer projections based on the age-stage, two-sex life table revealed the stage structure and variability of the population growth of C. punctiferalis. Our results demonstrated that although chestnut and maize were the most suitable host plants for C. punctiferalis, the moths were also able to develop and reproduce on sunflower, hawthorn, and apple. PMID- 29992316 TI - Invited Commentary: Physical Exertion and Placental Abruption-Public Health Implications and Future Directions. AB - Chahal et al. (Am J Epidemiol. 2018;187(10):2073-2079) assessed the risk of placental abruption due to physical exertion using a case-crossover design. The authors found an increased risk of placental abruption following increased physical exertion in the hour prior to the abruption. The risk was greater among women who were primarily sedentary during pregnancy or prior to becoming pregnant compared with those who were more physically active. The authors used a case crossover design to assess the association of an intermittent exposure on an acute event. Chahal et al. address the limitations of the study, including the inability to control for time-varying confounders as well as the potential for recall bias. The public health implications of the study must be carefully evaluated given that physical activity prior to and during pregnancy can lead to healthy outcomes and is likely recommended. While the current study is unable to determine the type of physical exertion associated with placental abruption, future studies are recommended to determine the type of activity that presents increased risk. Additionally, studies among larger samples and in other countries will help determine the generalizability of the results. PMID- 29992317 TI - Assessment of sympathetic neural activity in chronic insomnia: evidence for elevated cardiovascular risk. PMID- 29992319 TI - Landscape Effects on Solenopsis invicta (Hymenoptera: Formicidae) and Geocoris spp. (Hemiptera: Geocoridae), Two Important Omnivorous Arthropod Taxa in Field Crops. AB - The economically important brown stink bug, Euschistus servus (Say) (Hemiptera: Pentatomidae), is a native pest of many crops in southeastern United States and insecticide applications are the prevailing method of population suppression. To elucidate biological control of E. servus populations, we investigated two egg predators' (red imported fire ants, Solenopsis invicta Buren (Hymenoptera: Formicidae), and Geocoris spp. (Hemiptera: Geocoridae)) responses to both local and landscape factors that may have influenced their combined ability to cause mortality in immature E. servus. We estimated the density of fire ants and Geocoris spp. on four major crop hosts-maize, peanut, cotton, and soybean-in 16 landscapes over 3 yr in the coastal plain of Georgia, USA. Both Geocoris spp. and fire ant populations were concentrated on specific crops in this study, maize and soybean for Geocoris spp. and peanut and cotton for fire ants, but the percentage area of specific crops and woodland and pasture in the landscape and year also influenced their density in focal fields. The crop specific density of both taxa, the influence of the percentage area of specific crops and woodland in the landscape, and the variability in density over years may have been related to variable alternative resources for these omnivores in the habitats. Despite the variability over years, differential habitat use of fire ants and Georcoris spp. may have contributed to their combined ability to cause E. servus immature mortality. PMID- 29992318 TI - Loss of tumor suppressor IGFBP4 drives epigenetic reprogramming in hepatic carcinogenesis. AB - Genomic sequencing of hepatocellular carcinoma (HCC) uncovers a paucity of actionable mutations, underscoring the necessity to exploit epigenetic vulnerabilities for therapeutics. In HCC, EZH2-mediated H3K27me3 represents a major oncogenic chromatin modification, but how it modulates the therapeutic vulnerability of signaling pathways remains unknown. Here, we show EZH2 acts antagonistically to AKT signaling in maintaining H3K27 methylome through epigenetic silencing of IGFBP4. ChIP-seq revealed enrichment of Ezh2/H3K27me3 at silenced loci in HBx-transgenic mouse-derived HCCs, including Igfbp4 whose down regulation significantly correlated with EZH2 overexpression and poor survivals of HCC patients. Functional characterizations demonstrated potent growth- and invasion-suppressive functions of IGFBP4, which was associated with transcriptomic alterations leading to deregulation of multiple signaling pathways. Mechanistically, IGFBP4 stimulated AKT/EZH2 phosphorylation to abrogate H3K27me3-mediated silencing, forming a reciprocal feedback loop that suppressed core transcription factor networks (FOXA1/HNF1A/HNF4A/KLF9/NR1H4) for normal liver homeostasis. Consequently, the in vivo tumorigenicity of IGFBP4-silenced HCC cells was vulnerable to pharmacological inhibition of EZH2, but not AKT. Our study unveils chromatin regulation of a novel liver tumor suppressor IGFBP4, which constitutes an AKT-EZH2 reciprocal loop in driving H3K27me3-mediated epigenetic reprogramming. Defining the aberrant chromatin landscape of HCC sheds light into the mechanistic basis of effective EZH2-targeted inhibition. PMID- 29992320 TI - Identifying frequent patterns in biochemical reaction networks: a workflow. AB - Computational models in biology encode molecular and cell biological processes. Many of these models can be represented as biochemical reaction networks. Studying such networks, one is mostly interested in systems that share similar reactions and mechanisms. Typical goals of an investigation thus include understanding of model parts, identification of reoccurring patterns and recognition of biologically relevant motifs. The large number and size of available models, however, require automated methods to support researchers in achieving their goals. Specifically for the problem of finding patterns in large networks only partial solutions exist. We propose a workflow that identifies frequent structural patterns in biochemical reaction networks encoded in the Systems Biology Markup Language. The workflow utilizes a subgraph mining algorithm to detect the network patterns. Once patterns are identified, the textual pattern description can automatically be converted into a graphical representation. Furthermore, information about the distribution of patterns among a selected set of models can be retrieved. The workflow was validated with 575 models from the curated branch of BioModels. In this paper, we highlight interesting and frequent structural patterns. Furthermore, we provide exemplary patterns that incorporate terms from the Systems Biology Ontology. Our workflow can be applied to a custom set of models or to models already existing in our graph database MaSyMoS. The occurrences of frequent patterns may give insight into the encoding of central biological processes, evaluate postulated biological motifs or serve as a similarity measure for models that share common structures.Database URL: https://github.com/FabienneL/BioNet-Mining. PMID- 29992321 TI - Atlas of Schistosoma mansoni long non-coding RNAs and their expression correlation to protein-coding genes. AB - Long non-coding RNAs (lncRNAs) have been widely discovered in several organisms with the help of high-throughput RNA sequencing. LncRNAs are over 200 nt-long transcripts that do not have protein-coding (PC) potential, having been reported in model organisms to act mainly on the overall control of PC gene expression. Little is known about the functionality of lncRNAs in evolutionarily ancient non model metazoan organisms, like Schistosoma mansoni, the parasite that causes schistosomiasis, one of the most prevalent infectious-parasitic diseases worldwide. In a recent transcriptomics effort, we identified thousands of S. mansoni lncRNAs predicted to be functional along the course of parasite development. Here, we present an online catalog of each of the S. mansoni lncRNAs whose expression is correlated to PC genes along the parasite life-cycle, which can be conveniently browsed and downloaded through a new web resource http://verjolab.usp.br. We also provide access now to navigation on the co expression networks disclosed in our previous publication, where we correlated mRNAs and lncRNAs transcriptional patterns across five life-cycle stages/forms, pinpointing biological processes where lncRNAs might act upon.Database URL: http://verjolab.usp.br. PMID- 29992322 TI - KM-express: an integrated online patient survival and gene expression analysis tool for the identification and functional characterization of prognostic markers in breast and prostate cancers. AB - The identification and functional characterization of novel biomarkers in cancer requires survival analysis and gene expression analysis of both patient samples and cell line models. To help facilitate this process, we have developed KM Express. KM-Express holds an extensive manually curated transcriptomic profile of 45 different datasets for prostate and breast cancer with phenotype and pathoclinical information, spanning from clinical samples to cell lines. KM Express also contains The Cancer Genome Atlas datasets for 30 other cancer types with matching cell line expression data for 23 of them. We present KM-Express as a hypothesis generation tool for researchers to identify potential new prognostic RNA biomarkers as well as targets for further downstream functional cell-based studies. Specifically, KM-Express allows users to compare the expression level of genes in different groups of patients based on molecular, genetic, clinical and pathological status. Moreover, KM-Express aids the design of biological experiments based on the expression profile of the genes in different cell lines. Thus, KM-Express provides a one-stop analysis from bench work to clinical prospects. We have used this tool to successfully evaluate the prognostic potential of previously published biomarkers for prostate cancer and breast cancer. We believe KM-Express will accelerate the translation of biomedical research from bench to bed.Database URL: http://ec2-52-201-246-161.compute 1.amazonaws.com/kmexpress/index.php. PMID- 29992324 TI - Reply to the letter to the editor 'What type of man against machine?' by H. Smith. PMID- 29992323 TI - CeleryDB: a genomic database for celery. AB - Celery (Apium graveolens L.) is a plant belonging to the Apiaceae family, and a popular vegetable worldwide because of its abundant nutrients and various medical functions. Although extensive genetic and molecular biological studies have been conducted on celery, its genomic data remain unclear. Given the significance of celery and the growing demand for its genomic data, the whole genome of 'Q2-JN11' celery (a highly inbred line obtained by artificial selfing of 'Jinnan Shiqin') was sequenced using HiSeq 2000 sequencing technology. For the convenience of researchers to study celery, an online database of the whole-genome sequences of celery, CeleryDB, was constructed. The sequences of the whole genome, nucleotide sequences of the predicted genes and amino acid sequences of the predicted proteins are available online on CeleryDB. Home, BLAST, Genome Browser, Transcription Factor and Download interfaces composed of the organizational structure of CeleryDB. Users can search the celery genomic data by using two user friendly query tools: basic local alignment search tool and Genome Browser. In the future, CeleryDB will be constantly updated to satisfy the needs of celery researchers worldwide.Database URL: http://apiaceae.njau.edu.cn/celerydb. PMID- 29992326 TI - Imidacloprid Pesticide Regulates Gynaikothrips uzeli (Thysanoptera: Phlaeothripidae) Host Choice Behavior and Immunity Against Lecanicillium lecanii (Hypocreales: Clavicipitaceae). AB - We attempted to develop an efficient management strategy against gall thrips (Gynaikothrips uzeli Zimmermann (Thysanoptera: Phlaeothripidae)) via the combined application of a systemic insecticide (imidacloprid) and an entomopathogenic fungus (Lecanicillium lecanii Zimmerman (Hypocreales: Clavicipitaceae)). The attraction of G. uzeli to Ficus microcarpa volatiles after imidacloprid treatment was weaker than for untreated plants, which could be due to modulation of volatile metabolite profiles by imidacloprid. The toxicity of L. lecanii against nymph and adult thrips was much higher for those that fed on plants treated with a 50% lethal concentration (LC50) of imidacloprid than for the controls. Phenoloxidase (PO) activity was significantly inhibited in treated G. uzeli, while hemocyte abundances were not different in treated and healthy individuals. Thus, imidacloprid impacted the PO-related humoral immunity of G. uzeli, but not their cellular immunity. Overall, F. microcarpa treated with imidacloprid at LC50 concentrations exhibited volatile profiles that decreased the attraction of G. uzeli and also indirectly increased the pathogenicity of L. lecanni by inhibiting the humoral immunity of gall thrips. The results reported here suggest that combined application of imidacloprid and L. lecanii could be used as a new integrated control strategy against gall thrips. PMID- 29992327 TI - The phenomenon of the monovular twinning in the endangered zatorska goose. AB - The phenomenon of multiple embryos in birds and other oviparous vertebrates is very rare and thus poorly studied. Some populations of wild birds or lines of poultry, including the zatorska goose, may be particularly predisposed to developing monovular twin embryos (MTE). The aim of the study was to investigate the frequency of single yolk twin embryos in the zatorska goose and to establish whether these embryos are generated as a result of polyembryony or other developmental anomalies.Embryopathological analysis, which included identification of the developmental stages of all MTEs at the time of death, was carried out on 1,955 unhatched eggs obtained from 20 pedigree breeding flocks of the zatorska goose. Post-mortem examinations revealed as many as 13 MTEs (0.66% compared to embryonated eggs) at varying developmental stages.The results of genotyping of the microsatellite loci of 7 pairs of twins demonstrated genetic similarity in 6 of them; this suggests that they developed from 1 blastoderm, while differences in 2 loci of 1 pair show that the MTE originates from 2 blastodiscs. Pedigree analysis of the MTEs does not provide evidence that predisposition toward twinning results from the genetic background. However, more frequent MTE occurrence could be seen in eggs stored for more than 8 d. It seems that embryos of the zatorska goose are more susceptible to duplication under special conditions, such as prolonged egg storage. PMID- 29992325 TI - Low-protein diet improves meat quality of growing and finishing pigs through changing lipid metabolism, fiber characteristics, and free amino acid profile of the muscle. AB - The objective of the study was to investigate the effect of feeding reduced CP, AA-supplemented diets on meat quality in growing and finishing pigs as well as the related mechanism. In experiment 1, 18 growing pigs (36.5 kg BW) were assigned randomly and fed 1 of 3 corn-soybean meal diets containing either 18% CP (normal protein, NP), 15% CP (low protein, LP), or 12% CP (very low protein, VLP). In experiment 2, 18 finishing pigs (62.3 kg BW) were allotted randomly into 1 of the following diets: 16% CP (NP), 13% CP (LP), or 10% CP (VLP). In both experiments, the LP and VLP diets were supplemented with crystalline AA to achieve equal content of standardized ileal digestible lysine, methionine, threonine, and tryptophan. At the end of each experiment, all pigs were slaughtered to collect longissimus dorsi muscle (LM) samples. Samples were used for determining meat quality, intramuscular fat (IMF) content, fatty acid composition, free AA profile, and expression of genes for myosin heavy chain isoforms. Results showed that growing and finishing pigs fed the LP diets increased (P < 0.05) redness value of LM, while finishing pigs fed the LP and VLP diets decreased (P < 0.05) the shear force values. Compared with the NP diet, growing and finishing pigs fed lower CP diets had higher (P < 0.05) contents of IMF and MUFA, and lower (P < 0.05) contents of PUFA. Besides, higher (P < 0.05) expression levels of type I and/or IIa muscle fibers were observed in LP diet-fed growing and finishing pigs, and greater concentrations of taurine and tasty AA in VLP diet-fed growing and finishing pigs. Taken together, our results indicate that low-protein diets could positively affect meat quality of growing and finishing pigs, and likely through regulation of IMF content and fatty acid composition, fiber characteristics, and free AA profile in the muscle. PMID- 29992328 TI - APPLE score in atrial fibrillation: a simple solution to predict a complex process? PMID- 29992329 TI - Low light intensity in Pekin duck breeder barns has a greater impact on the fertility of drakes than hens. AB - The Pekin duck is an excellent model for the study of seasonal reproduction. To more completely understand the lighting requirements for maximal fertility in duck breeder houses, we housed adult (45 week old) drakes and hens in the Hope College aviary as 5 drakes and 25 hens. Light conditions in each floor pen were normalized based upon quantal energy and divided into the following categories: (1) to simulate summer, 14.5 h 65 lux with 9.5 h 1 lux; (2) to simulate winter, 8 h 65 lux with 16 h 1 lux; (3) winter augmented, 8 h 65 lux with 16 h at 15 lux. The experiment was repeated with rotation of light treatments among 3 pens until a final N = 6 was obtained. Daily, total number of eggs laid was tallied, and a daily average of eggs laid was calculated throughout the study. Weekly, eggs were weighed and the perivitilline membrane was assayed for the number of sperm holes as an indirect measure of drake fertility. As expected, winter conditions caused a reduction in the percent of eggs laid and a reduction in the number of fertilized eggs compared to the summer light conditions. The augmented winter light conditions prevented the loss in the percent eggs laid and fertilized eggs. Surprisingly, even after 4 wk of the study, the winter conditions did not cause a complete loss of fertility in the Pekin ducks. At the end of the study, no differences in the relative expression in brain deep brain photoreceptors or gonadotropin inhibitory hormone mRNAs were observed among any light treatment. Although a minimum (1 lux) of light can support some fertility, our findings suggest commercial Pekin duck barns may benefit from increasing the augmented light to 15 lux to maintain optimal fertility during winter months. Furthermore, our data suggest that drakes may be more sensitive to environmental light conditions than hens. PMID- 29992330 TI - Maternal Exposure to DDT and Pyrethroids and Birth Outcomes Among Residents of an Area Sprayed for Malaria Control Participating in the VHEMBE Birth Cohort Study. AB - Although effective in controlling malaria, Indoor Residual Spraying results in elevated exposure to insecticides such as dichlorodiphenyltrichloroethane (DDT) and pyrethroids. These chemicals cross the placenta but no studies have examined their associations with birth outcomes in populations residing in indoor residual spraying areas. We investigated this question in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study of 751 South African children born between 2012 and 2013. We measured maternal peripartum serum DDT and urine pyrethroid metabolite concentrations and collected data on birth weight, length, head circumference and gestational duration. We analyzed data using marginal structural models with inverse probability of treatment weights, generalized propensity scores and standard conditional linear regression. p,p'-DDT, o,p'-DDT and, to a lesser extent, p,p' dichlorodiphenyldichloroethylene were related to elevated birth weight, length and head circumference among girls only, using all three analytical methods. Changes in gestational duration did not mediate this relation, suggesting exposures accelerate fetal growth, which is consistent with the known estrogenic properties of o,p'-DDT and p,p'-DDT. No associations were found with pyrethroid metabolites. Results suggest prenatal exposure to DDT is related to elevated birth size. Further studies are needed to elucidate the implications of these findings. PMID- 29992331 TI - The potential effect of low cell osmolarity on cell function through decreased concentration of enzyme substrates. AB - Some freshwater algae have lower (<130 osmol m-3) intracellular osmolarities than most others (>180 osmol m-3). Low osmolarities are related to the presence of flagella and the low energy cost of active water efflux following downhill water influx unconstrained by cell walls covering the plasmalemma, and the low resource cost of cell wall synthesis with the same mechanical degree of safety. One consequence of low intracellular osmolarity is limitation on the concentration of metabolites, that is, substrates and products of enzyme activity. Models of the flux through metabolic pathways, and hence the specific growth rate, using steady state concentrations of enzymes and metabolites have involved organisms with intracellular metabolite osmolarities >280 osmol m-3, where the metabolite concentrations are much greater than the total osmolarity of some freshwater algae. Since the protein concentration (mol m-3) in the cells and the specific growth rates of freshwater cells with low and with higher intracellular osmolarity are highly similar, the models of trade-offs between enzyme and metabolite concentrations for cells with high intracellular osmolarity need modification for cells with low intracellular osmolarity. The soluble free radical scavenger ascorbate can constitute as little as 0.2% of the low intracellular metabolite concentration (mol m-3) of low-intracellular-osmolarity cells. PMID- 29992332 TI - Outcome reporting discrepancies between trial entries and published final reports of orthodontic randomized controlled trials. AB - Background/Objectives: The aim of this study was to identify outcome-related discrepancies between registry trial entries and final published reports in orthodontic randomized controlled trials (RCTs). The percentage of registered orthodontic RCTs was also recorded. Materials/Method: Five trial registries, ClinicalTrials.gov (https://clinicaltrials.gov/), International Standard Randomised Controlled Trial Number registry (http://www.isrctn.com/), European Union Clinical Trials Register (https://www.clinicaltrialsregister.eu/), Australia New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) and Clinical Trials Registry of India (www.ctri.nic.in/) were searched up to April 2018 in order to identify completed orthodontic RCTs. The unique trial identifier, the title and authors name were used to search for publications based on entries within Google (https://www.google.com), Google Scholar (https://scholar.google.gr/) and MEDLINE via PubMed (https://www.ncbi.nlm.nih.gov/pubmed/). Outcome reporting discrepancies and a number of other entry/publication characteristics were recorded including timing of registration, type of journal/publication, significance of the primary outcome in the final report. The number of trials registered among the total number of published RCTs in orthodontics was recorded within the time span assessed. Results: One hundred and twenty-four entries were identified for completed orthodontic RCTs, whereas 53 of those were related to published final reports. Outcome reporting discrepancies were ascertained for 47 per cent of publications (n = 2 5); discrepancies were more prevalent for non-primary outcomes (n = 21, 40 per cent). Only 16 per cent of the published orthodontic RCTs had been registered. Limitations: Only a subset of trial entries were assessed as these were related to publication records. Conclusions/Implications: Registration of clinical trials in orthodontics remains far from universal. A significant level of outcome reporting discrepancy was observed within this subset of registered trials. PMID- 29992333 TI - Toxicity of Chlorine Dioxide Gas to Phosphine-Susceptible and -Resistant Adults of Five Stored-Product Insect Species: Influence of Temperature and Food During Gas Exposure. AB - Adults of phosphine-susceptible and -resistant strains of the red flour beetle, Tribolium castaneum (Herbst); lesser grain borer, Rhyzopertha dominica (F.); sawtoothed grain beetle, Oryzaephilus surinamensis (L.); maize weevil, Sitophilus zeamais Motschulsky; and rice weevil, Sitophilus oryzae (L.), were exposed for 2 12 h to a chlorine dioxide gas concentration of 1.40 g/m3 (520 ppm) in an outdoor trailer during July and October of 2015. The mean +/- SE temperatures in July and October were 32.8 +/- 0.5 degrees C and 24.8 +/- 0.6 degrees C, respectively. In July, complete mortality after 5 d was achieved for all species and strains in vials with wheat after a 4- or 8-h exposure; in October, a longer exposure time was needed for complete mortality of insects in vials with wheat. Chlorine dioxide was more toxic to all insect species and strains at warmer than cooler temperature and in vials without wheat than those with wheat. Both phosphine resistant and -susceptible strains were equally susceptible to chlorine dioxide. The presence of wheat resulted in delayed mortality of insects because of reaction of chlorine dioxide with active sites on kernels. Progeny production 8 wk after chlorine dioxide exposure showed a significant reduction (72-100%), compared with that in control vials for strains of R. dominica, S. zeamais, and S. oryzae. There was no progeny production in control and treatment vials for T. castaneum and O. surinamensis, as these species require dockage. Chlorine dioxide is a potential fumigant to control phosphine-resistant strains of the five stored product insect species. PMID- 29992334 TI - Monitoring for paroxysmal atrial fibrillation and for other modifiable risk factors for stroke - Reply. PMID- 29992335 TI - The role of neuronal nitric oxide synthase in cocaine place preference and mu opioid receptor expression in the nucleus accumbens. AB - RATIONALE: There is evidence that central mu opioid receptors (MORs) are implicated in several aspects of cocaine addiction, and that MOR expression is elevated by cocaine in vitro and in the nucleus accumbens (NAc) when administered in vivo. OBJECTIVE: To understand the cellular mechanisms involved in regulating MOR expression, this study explored whether neuronal nitric oxide synthase (nNOS) modulates the neurochemical and behavioral effects of acute and repeated cocaine administration. METHODS: Male Sprague-Dawley rats received a single cocaine injection (20 mg/kg, i.p.) in combination with the selective nNOS inhibitor 7 nitroindazole (7-NI) (0, 25, or 50 mg/kg, i.p.), and the expression of MOR and nNOS messenger RNA (mRNA) and protein levels in the NAc were measured. In a separate conditioned place preference (CPP) experiment, 7-NI (0, 25, or 50 mg/kg, i.p.) was administered prior to cocaine (0 or 20 mg/kg, i.p.) conditioning sessions, and levels of MOR and nNOS mRNA and protein in the NAc were measured following CPP test. RESULTS: Acute cocaine administration significantly enhanced nNOS and MOR mRNA and protein expression in the NAc, and this increase in MOR expression was blocked by 7-NI. Furthermore, in 7-NI pre-treated rats, cocaine induced CPP was not statistically significant and the increase in MOR mRNA expression in the NAc in these animals was attenuated. CONCLUSIONS: These findings suggest that nNOS modulates MOR expression following acute cocaine administration, and that cocaine CPP and associated upregulation of MOR expression involve both nNOS-dependent and independent mechanisms. Elucidation of these molecular events may identify useful therapeutic target for cocaine addiction. PMID- 29992336 TI - Focus on anatomical aspects of soft tissue coverage options in elbow reconstruction: an updating review. AB - INTRODUCTION: The elbow joint is particularly exposed to soft tissue injuries associated with fractures and dislocations. Different coverage options within the past decades for recovering loss of soft tissue defects around the elbow region have been proposed based on anatomical research. Our aim was to make an updated focus on the anatomical basis of different techniques of coverage of loss of tissues around the elbow. MATERIALS AND METHODS: The main procedures of flaps were defined: local random, axial fasciocutaneous, local muscle pedicle, propeller and free microvascular flaps. A systematic literature review on anatomical basis on these different flaps options was conducted searching on PubMed databases and the selection process was undergone according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guideline. Inclusion criteria were: review and original articles, including anatomical basis of the procedures, in English and French languages. RESULTS: The final analysis included 37 relevant articles out of 1499 published references. 640 flaps were referenced, for covering 302 elbows. Local random flaps provide a good quality skin for small tissue defects in posterior elbow and periolecranon area, and depend on dermal and subdermal blood supply. Axial fasciocutaneous flaps have well-defined blood supplies and are designed as peninsular, island, or microvascular free flaps, as the radial forearm, lateral arm, ulnar artery, antecubital fasciocutaneous, and posterior interosseous flaps. Muscular flaps have advantages as strength, capacity to contrast local infection and to avoid empty spaces, and can be used as pedicle or as free transfers. Propeller flaps can be rotated up to 180 degrees around an axis corresponding to the perforator vessel and do not require the sacrifice of a major artery or functional muscle. The concept of perforasome is evoked. Free microsurgical transfers can be proposed to cover any defect around the elbow. DISCUSSION AND CONCLUSION: The anatomical basis of the flap's harvesting and the possibilities of elbow coverage are discussed through the selected articles. The different indications according to the areas of soft tissues defects are considered. PMID- 29992337 TI - Transplant Tolerance: Current Insights and Strategies for Long-Term Survival of Xenografts. AB - Xenotransplantation is an attractive solution to the problem of allograft shortage. However, transplants across discordant species barriers are subject to vigorous immunologic and pathobiologic hurdles, some of which might be overcome with the induction of immunologic tolerance. Several strategies have been designed to induce tolerance to a xenograft at both the central (including induction of mixed chimerism and thymic transplantation) and peripheral (including adoptive transfer of regulatory cells and blocking T cell costimulation) levels. Currently, xenograft tolerance has been well-established in rodent models, but these protocols have not yet achieved similar success in nonhuman primates. This review will discuss the major barriers that impede the establishment of immunological tolerance across xenogeneic barriers and the potential solution to these challenges, and provide a perspective on the future of the development of novel tolerance-inducing strategies. PMID- 29992338 TI - Efficacy of Inverted "V" Release Surgery in the Correction of a Special Type of Epicanthus. AB - OBJECTIVE: To evaluate the efficacy of a new correction method (inverted "V" release surgery) for epicanthus as a cause of congenital entropion/trichiasis in the lower eyelid. METHODS: From May 2014 to May 2017, 60 eyes of 30 patients (13 male and 17 female patients, with the age of 6.85 +/- 4.52 years underwent inverted "V" release surgery to correct epicanthus. The incision in the epicanthus and entropion was continuous. Lower eyelid entropion/trichiasis was corrected by a two-layered suture. We separately assessed the width of the palpebral fissure, exposed ratio of the lacrimal caruncle, eyelash direction, and incision scar at one and 6 months after surgery. RESULTS: All patients were followed up for 6-18 months. At 6 months after surgery, the palpebral fissure width of all patients was extended by 3-4 mm. The ratio of the exposed lacrimal caruncle was enhanced from 0.24 +/- 0.22 to 0.75 +/- 0.08. All patients presented with natural inner canthal angles, and their eyelashes clearly extended outward, with a 100% total effective rate. The inner canthal incision scars in 83% of patients were invisible 6 months after surgery. CONCLUSION: Based on our experience, both functionality and aesthetics can be obtained by using inverted "V" release surgery to correct a special type of epicanthus that aggravates congenital entropion/trichiasis in the lower eyelid. Thus, this technique is suitable for clinical application. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29992339 TI - [Corrective osteotomy of the hand]. AB - Fractures of fingers and metacarpals are among the most frequent injuries. Many fractures can be successfully treated conservatively. Nevertheless, various malformations, such as malrotation, spur development, bone shortening, deviation of the axis and combinations of these individual deformities may appear in the course of time. Corrective osteotomy can correct these deformities with clinically impaired function and improve/optimize hand function. Prerequisites for corrective osteotomy are a precise analysis of the deformity, precise osteotomy, exercise stable osteosynthesis and intensive follow-up treatment of the hand. Complications, such as implant failure, postoperative tendon and joint adhesions, joint contracture and nonunion are however possible. PMID- 29992340 TI - [Orbital traumatology]. AB - BACKGROUND: In the case of trauma to the midface, an accompanying fracture of the orbit is common because to the anatomical conditions (bony buttresses of the midface). Etiology varies according to locoregional conditions. MATERIALS AND METHODS: An overview of orbital traumatology including diagnostic procedures, symptoms and therapy is provided. In addition, our own patient collective over one year including a 5-year follow-up was prospectively analyzed. RESULTS: The possible fractures of the midface with involvement of the orbit including their classifications are listed. The key clinical symptoms and the diagnostic procedure are described. As part of the therapeutic management, in addition to the-mostly required-surgical approach, the conservative therapeutic options and prerequisites for conservative therapy are discussed. In our own patients, clear differences in the accident mechanisms were evident. Violence was the most frequent mechanism for younger, male patients, while in female, elderly patients a fall was the reason for the fracture. Overall, 17% of cases received conservative therapy and 83% underwent surgical treatment. CONCLUSION: Traumatology of the orbit requires that therapeutic decisions be made on an individual patient basis. Even a conservative regime can lead to good results. The treatment of fractures of the orbit and the midface should be in the hands of experienced midface surgeons due to the technical competence with regard to the anatomy of the neighboring structures. PMID- 29992341 TI - The impact of economic recessions on depression and individual and social well being: the case of Spain (2006-2013). AB - PURPOSE: Although there is abundant evidence about the impact of economic crises on depression and other mental health problems, little is known about the protective role of variables linked to positive functioning (i.e., psychological well-being). METHODS: We analyzed data from Spain, one of the European countries most affected by the 2008-2013 economic recession, collected in Round 3 (R3, 2006) and Round 6 (R6, 2013) of the European Social Survey interviews. Both surveys included measures of psychological well-being, social well-being and depression. Both samples were nationally representative of the general population (R3: 1877 participants, 49.2% men; R6: 1889 participants, 48.9% men). RESULTS: Data from the R6 survey showed that, compared to data gathered in R3 (i.e., before the onset of the recession) Spanish citizens showed significantly less life satisfaction (95% CIs 0.37-0.63), less personal optimism (95% CIs 0.03 0.15), less social optimism (95% CIs 0.75-0.85), and higher levels of depressive symptoms (95% CIs - 0.74 to - 0.19). Structural equation modeling revealed that protective factors for depression changed in both rounds. In R3 (2006), close relationships, social optimism and social trust were significant mediators between well-being and depression. However, social optimism and social trust were no longer significant in R6 (2013), whereas close relationships remained a partial mediator of the effects of psychological well-being on depression. CONCLUSIONS: Economic crises are associated with a significant increase in depressive symptoms. Furthermore, financial crises seem to have a corrosive impact on mental health by reducing the mediating effects of positive beliefs regarding the good nature of society. PMID- 29992342 TI - Correction to: Impact of socioeconomic position and distance on mental health care utilization: a nationwide Danish follow-up study. AB - In the original publication of this article, Table 3 was published incorrectly. The corrected table is shown below. PMID- 29992343 TI - CVIR Editors' Medal 2018. PMID- 29992344 TI - Don't Call It "Hemangioma". PMID- 29992345 TI - Incidence and Endovascular Treatment of Isolated Atherosclerotic Popliteal Artery Disease: Outcomes from the IPAD Multicenter Study. AB - PURPOSE: To report the incidence and long-term outcomes following endovascular treatment of symptomatic, atherosclerotic isolated popliteal artery disease (IPAD). MATERIALS AND METHODS: This retrospective, multicenter study included all patients who underwent endovascular treatment of IPAD between January 2010 and December 2016 because of intermittent claudication or critical limb ischemia (CLI), in three tertiary University Hospitals. In total, 4717 peripheral arterial disease (PAD) procedures were analyzed. The study's primary outcome measures were: IPAD incidence, binary restenosis rate and freedom from target lesion revascularization (TLR). Secondary outcome measures included technical success, limb salvage rate and the identification of predictors of outcomes. RESULTS: The incidence of IPAD was 0.98% (46/4717 PAD procedures). In total, 46 patients (38 male; mean age 73 +/- 12 years) underwent plain balloon (69.5%) or bail-out stenting (30.5%) procedures. Most patients suffered from CLI (65.2%). Mean lesion length was 52.5 +/- 32.0 mm and 45.6% of the cases were occlusions. Severe calcifications were noted in 26.1%. Technical success was 100%. Mean time follow up was 32.6 +/- 25.6 months. According to Kaplan-Meier analysis, restenosis was 15.8, 40.9, 45.8% and TLR-free rate was 90.5, 79.0, 74.1%, at 1, 2 and 3 years, respectively. Survival and limb salvage rates were 73.6 and 88.1%, at 5 years, respectively. The major amputation rate for CLI patients was 10.0% (3/29 limbs), while no major amputations occurred in the claudication subgroup. Cox multivariable analysis detected baseline occlusion as an independent predictor of increased restenosis (HR 5.3; 95% CI 0.21-0.66, p = 0.02). CONCLUSIONS: Isolated popliteal lesions requiring treatment appear in nearly 1% of patients with PAD. Balloon angioplasty and bail-out stenting resulted in acceptable long-term clinical outcomes. Treatment of occlusions was correlated with increased restenosis rate. PMID- 29992346 TI - Presence of the Posterior Communicating Artery Contributes to the Clinical Outcome After Endovascular Treatment of Patients with MCA Occlusions. AB - PURPOSE: In patients with acute occlusions of the middle cerebral artery, the collaterals play an important role in infarct growth and potentially on clinical outcome. As the primary collateral pathway, the posterior cerebral artery with the posterior communicating artery (PComA) is important. We analyzed the influence of the presence of an ipsilateral PComA on infarct growth and clinical outcome. METHODS: We included 101 patients with M1 occlusions and subsequent endovascular treatment and differentiated patients without an ipsilateral PComA from those with an ipsilateral PComA. RESULTS: There was no difference in the rate of successful recanalizations and procedural parameters between both groups. Of the patients with an existing PComA, 51% showed an excellent clinical outcome (90d mRS < 2), but only 28% of the patients without PComA had an excellent clinical outcome (p = 0.02). The presence of an ipsilateral PComA was independently associated with the rate of excellent clinical outcome (aOR 3.9, 95% CI 1.2-9.8; p = 0.021) and lower infarct volume (38 +/- 8 cm3 vs. 78 +/- 13 cm3, p = 0.032). CONCLUSION: The presence of an ipsilateral PComA is a predictor for excellent clinical outcome independently from the technical success of mechanical recanalization. This finding provides insights into the changes of circulation in patients suffering from an acute stroke and underlines the importance of collateralization. PMID- 29992347 TI - Efficacy of Automated Supplying Artery Tracking Software Using Multidetector-Row Computed Tomography Images for Emergent Transcatheter Arterial Embolization. AB - PURPOSE: To assess the reliability of a prototype automated supplying artery tracking software (ASATS) using multidetector-row CT (MDCT) images in emergent TAE. MATERIALS AND METHODS: Consecutive 53 patients underwent 57 sessions of emergent TAE during 7 months. Twenty-one cases were excluded due to a lack of CT data (n = 12) or negative angiographic findings (n = 9). Remaining 34 sessions of TAE and MDCT images in 32 patients (mean age 62.9 years; age range 37-92 years) were enrolled. ASATS was retrospectively conducted for the identification of supplying arteries which were confirmed with angiography (automated method). Manual modification was added as needed (semi-automated method). Two observers independently reviewed the MDCT images to detect supplying arteries (manual method). Detectability of supplying artery and time to analysis were compared among the automated, semi-automated, and manual methods by both observers. RESULTS: A total of 64 bleeding sites were demonstrated on angiography. The detectability was 28 (43.8%) for automated method, 53 (82.8%) for semi-automated method, 55 (85.9%) for observer 1, and 58 (90.6%) for observer 2. Detectability of semi-automated method was significantly better than of automated method (P = 0.000) and comparable with manual method by both observers (P = 0.193 and 0.081). Average time to analysis was 185.4 s for automated method, 297.2 s for semi automated method, 186.2 s for observer 1, and 243.7 s for observer 2. CONCLUSION: ASATS has a sufficient ability to identify supplying arteries of bleeding by adding manual modification as needed and can be used for emergent TAE. LEVEL OF EVIDENCE: Level 4, Case Control Study. PMID- 29992349 TI - Treatment strategies for children with steroid-dependent nephrotic syndrome: in need of controlled studies. PMID- 29992348 TI - Retroelements and DNA Methylation Could Contribute to Diversity of 5S rDNA in Agave L. AB - Agave L. is a genus of economic importance, and many of the 166 species in the American plant genus Agave L. inhabit high-stress environments, which makes the genus promising for facing global climate change. However, sustainable use of economically important species without interfering with their ecology and evolution requires generating knowledge about the factors responsible for their genetic variation and diversity and, on this basis, their adaptation and speciation. Few genetic studies exploring the evolutionary relationships, speciation processes, genetic variability and diversity within species of Agave are currently available. Analyses of rDNA loci have been performed with the purpose of determining the genetic variability and diversity of the genus Agave, and these loci have been used as genetic markers of ploidy. However, the factors involved in the diversity of 5S rDNA regions in Agave have not yet been studied in depth. Our study explored the possible mechanisms of genetic (retroelements) and epigenetic (DNA methylation) diversity in 5S rDNA regions in Agave. We characterized the 5S rDNA gene tandem in species of the genus with different ploidy numbers and determined the levels of methylation in 13 haplotypes of 5S rDNA and in four non-transcribed spacers (NTS). Our results showed highly dynamic methylation with a high percentage in haplotypes and NTS of 5S rDNA regions in Agave. The characterization of the 5S rDNA tandem array in Agave revealed vestigial remains of the Cassandra terminal-repeat retrotransposon in miniature (TRIM). Our analysis supported previous results suggesting that in species of Agave L., regulation and diversity of 5S rDNA regions are controlled by coordinated genetic and epigenetic events, which will vary according to the species and the level of ploidy. The artificial pressure to which some agave crops are subjected may affect the mechanisms of evolution of gene 5S rDNA. PMID- 29992350 TI - Myelin oligodendrocyte glycoprotein antibody-associated disease: characterising clinical disease. PMID- 29992351 TI - The accuracy of the clinical diagnosis of Parkinson disease. The HUNT study. AB - Diagnostic accuracy is crucial not only for prognostic and therapeutic reasons, but also for epidemiologic studies. We aimed to study the accuracy of the clinical diagnosis of Parkinson disease (PD) for participants in The Nord Trondelag Health Study (HUNT), a health survey, containing data from approximately 126,000 individuals and biological material from 80,000 individuals. We included 980 participants from the HUNT study diagnosed with PD or secondary parkinsonism/related parkinsonian disorders. The participants had been diagnosed in conjunction with admission to hospitals in Trondelag or through out-patient examination. We validated the diagnosis of PD by reviewing available Electronic Health Records (EHRs) using the MDS Clinical Diagnostic Criteria as gold standard. In total 61% (601/980) of the participants had available EHRs and were selected for validation. Out of those, 92% (550/601) had been diagnosed with PD while 8% (51/601) had been diagnosed with secondary parkinsonism/related parkinsonian disorders. The main outcome measure was the accuracy of the clinical diagnosis of PD for participants in the HUNT study. We verified PD in 65% (358/550) and excluded PD in 35% (192/550) of the participants. According to our results, the overall quality of the clinical diagnosis of PD for participants in the HUNT study is not optimal. Quality assurance of ICD codes entered into health registers is crucial before biological material obtained from these populations can be used in the search of new biomarkers for PD. PMID- 29992353 TI - Is REThink therapeutic game effective in preventing emotional disorders in children and adolescents? Outcomes of a randomized clinical trial. AB - : Therapeutic games represent a promising solution for addressing emotional difficulties in youths. The aim of the present study was to investigate the effectiveness of the REThink game, in helping children and adolescents, to develop psychological resilience. Therefore, 165 children aged between 10 and 16 years were randomly assigned in one of the three groups: 54 participants in the REThink condition, 55 participants in the Rational Emotive Behavior Education condition, and 56 participants in the waitlist condition. Results indicated that the REThink intervention had a significant impact on emotional symptoms (a moderate-effect size, d = 0.46) and on depressive mood (a large-effect size, d = 0.84). Furthermore, REThink had a significant impact on children's ability to regulate their emotions, with a significant effect on emotional awareness (d = 0.64), and on the ability for emotional control (d = 0.69). In conclusion, the implications of the REThink game are discussed in relationship with resiliency building programs designed for youths. TRIAL REGISTRATION: ClinicalTrials.gov NCT03308981. PMID- 29992352 TI - Inpatient care in Serbia: trends in hospitalization and diagnostics over time. PMID- 29992355 TI - Assessing the effect of weather on human outdoor perception using Twitter. AB - Human comfort in outdoor spaces (HCOS) is linked to people's psychological responses to environmental variables. Previous studies have established comfort ranges for these variables through interviews and questionnaires, reaching only limited populations. However, larger amounts of data would not only generate more robust results in local studies, but it would also allow for the possibility of creating an approach that could be applied to a wider range of weather conditions and different climates. Therefore, this study describes a new methodology to assess people's perception of weather based on human responses to weather conditions extracted from tweets, with the purpose of establishing comfort ranges for environmental variables. Tweets containing weather-associated keywords were collected, stored, and then linked to real-time meteorological data acquired nearby the locations in which the tweets were posted. Afterwards, people's perception of weather was extracted from the tweets using a classifier trained specifically on weather data that identified irrelevant, neutral, positive, and negative tweets. The obtained tweets and their related atmospheric data were analyzed to establish comfort ranges. The tweets' responses to effective temperature were very similar to those obtained in previous studies, although the peak of comfort is shifted towards the cold stress. Similarly, the tweets' responses to the thermohygrometric index were alike to previous results, but the peak of comfort is shifted towards the heat stress. Regarding the single weather variables under study, the obtained comfort ranges are similar to the ones found in previous research; in particular, the temperature comfort range matches perfectly at 20-22 degrees C. Therefore, it was concluded that tweets can be used to assess HCOS; not only are the results of this methodology comparable to results obtained in previous studies, but the procedure itself also shows new features and unexpected future applications. PMID- 29992354 TI - An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors. AB - PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751. PMID- 29992356 TI - [An uncommon skin tumor in the emergency department]. PMID- 29992358 TI - Exopolysaccharides of Agrobacterium tumefaciens. AB - Agrobacterium exopolysaccharides play a major role in the life of the cell. Exopolysaccharides are required for bacterial growth as a biofilm and they protect the bacteria against environmental stresses. Five of the exopolysaccharides made by A. tumefaciens have been characterized extensively with respect to their structure, synthesis, regulation, and role in the life of the bacteria. These are cyclic-beta-(1, 2)-glucan, cellulose, curdlan, succinoglycan, and the unipolar polysaccharide (UPP). This chapter describes the structure, synthesis, regulation, and function of these five exopolysaccharides. PMID- 29992357 TI - [Caregiver burden among older informal caregivers of patients with dementia and its influence on quality of life : A systematic literature review]. AB - BACKGROUND: Projections revealed that the age group of 60+ years will increase to 1.4 billion people worldwide by 2030. Germany is affected by the demographic change with an increase in people suffering from dementia and a substantial proportion will be cared for by informal caregivers. Quality of life (QOL) is of utmost importance for the stability of domestic care arrangements. OBJECTIVES: This review aimed at collecting and analyzing articles on the association between burden of care and QOL in older informal caregivers of people with dementia. MATERIAL AND METHODS: A systematic literature search was conducted in the databases Web of Science and PubMed. German and English papers were considered. RESULTS: Caregiver burden, health-related characteristics of the informal caregiver, dementia-related characteristics, sociodemographics and contextual factors were significantly negatively associated with informal caregivers' QOL. Support arrangements in order to relieve caregivers were rarely utilized. CONCLUSION: Despite different methods of analysis and instruments used, consistent results regarding the association between caregiver burden and QOL in older informal caregivers were found. The existence of a care situation already negatively influenced the caregivers' QOL. Especially older informal caregivers require special support. PMID- 29992359 TI - The Mechanism of T-DNA Integration: Some Major Unresolved Questions. AB - The mechanism of T-DNA integration into plant genomes during Agrobacterium mediated genetic transformation is still not understood. As genetic transformation of plants via Agrobacterium has become a routine practice among plant biologists, understanding T-DNA integration remains important for several reasons. First, T-DNA is the final step in one of the unique cases of inter kingdom horizontal gene transfer in nature. Second, understanding T-DNA integration is important for biotechnological applications. For example, better knowledge of this process may help develop methods to transform species that are currently not susceptible to Agrobacterium-mediated transformation. In addition, regulatory agencies usually require "clean" and "precise" transgenic insertion events, whereas transgenic insertions are commonly complex unpredictable structures. Furthermore, whereas T-DNA integration under natural conditions occurs randomly, technology to direct T-DNA to specific sites in the genome is highly desired. A better understanding of T-DNA integration may help develop methods to achieve more desirable results. Finally, gene targeting methods that require a foreign DNA template for precise DNA modifications in plants often utilize Agrobacterium to deliver the DNA template. Better understanding of the fate of T-DNA in the plant nucleus may help utilize T-DNA for more efficient gene targeting. For introducing gene targeting reagents, efficient delivery of T-DNA without ectopic integration would be useful. The following review summarizes current knowledge related to T-DNA integration. Five major open questions related to T-DNA integration are being presented. Finally, different models for T-DNA integration are being discussed, and a revised model is proposed. PMID- 29992360 TI - The Agrobacterium Type VI Secretion System: A Contractile Nanomachine for Interbacterial Competition. AB - The bacterial type VI secretion system (T6SS) is a contractile nanomachine dedicated to delivering molecules out of bacterial cells. T6SS-encoding loci are in the genome sequences of many Gram-negative bacteria, and T6SS has been implicated in a plethora of roles. In the majority of cases, the T6SSs deliver effector proteins in a contact-dependent manner to antagonize other bacteria. Current models suggest that the effectors are deployed to influence social interactions in microbial communities. In this chapter, we describe the structure, function, and regulation of the T6SS and its effectors. We provide focus on the T6SS of Agrobacterium tumefaciens, the causative agent of crown gall disease, and relate the role of the T6SS to the ecology of A. tumefaciens. PMID- 29992361 TI - The Role of Uric Acid in Preeclampsia: Is Uric Acid a Causative Factor or a Sign of Preeclampsia? AB - PURPOSE OF REVIEW: Because of the significant discrepancies on this topic, this review will focus on the role of uric acid in PE, uric acid as a predictor of preeclampsia and fetal growth retardation. We considered eligible review and original articles relevant to the research question. RECENT FINDINGS: Hypertensive disorders of pregnancy such as preeclampsia (PE) are a major cause of both maternal and fetal morbidity and mortality worldwide. Uric acid has been reported as a key factor contributing to the pathogenesis of PE. Some studies have indicated that serum uric acid levels increase with the severity of PE, while several studies have shown contradictory results. Some studies suggested high uric acid levels lead to PE, while others state that PE causes an increase in uric acid levels. Despite the strong association of uric acid in the pathogenesis of preeclampsia, current data is still contradictory hence genetic and high-end laboratory investigations may clarify this enigma. PMID- 29992363 TI - A comparative study of the enzymatic hydrolysis of batch organosolv-pretreated birch and spruce biomass. AB - A shift towards a sustainable and green society is vital to reduce the negative effects of climate change associated with increased CO2 emissions. Lignocellulosic biomass is both renewable and abundant, but is recalcitrant to deconstruction. Among the methods of pretreatment available, organosolv (OS) delignifies cellulose efficiently, significantly improving its digestibility by enzymes. We have assessed the hydrolysability of the cellulose-rich solid fractions from OS-pretreated spruce and birch at 2% w/v loading (dry matter). Almost complete saccharification of birch was possible with 80 mg enzyme preparation/gsolids (12 FPU/gsolids), while the saccharification yield for spruce was only 70%, even when applying 60 FPU/gsolids. As the cellulose content is enriched by OS, the yield of glucose was higher than in their steam-exploded counterparts. The hydrolysate was a transparent liquid due to the absence of phenolics and was also free from inhibitors. OS pretreatment holds potential for use in a large-scale, closed-loop biorefinery producing fuels from the cellulose fraction and platform chemicals from the hemicellulose and lignin fractions respectively. PMID- 29992364 TI - Individual particle SEM-EDS analysis of atmospheric aerosols in rural, urban, and industrial sites of Central Italy. AB - PM10 samples were collected simultaneously at three representative areas (urban, industrial, and rural areas). Their morphology and elemental composition were determined by scanning electron microscopy coupled with energy-dispersive analysis (SEM-EDS). Twenty-four chemical parameters (C, O, Na, Mg, Al, Si, P, Cd, Cl, K, Ca, S, Sn, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, W, and Pb) were determined and three morphological parameters (area, roundness, and fractal dimension) were measured by Image Pro Analyzer 6.3. The particles were classified into ten groups based on morphology and elemental composition: Ca-rich and metal particles, soot aggregates, cenosphere, alumosilicates, sea salt, calcium sulfate, spherical particles of iron, biological carbonaceous particles, and various. Particles of natural origin were predominantly found in the coarse size fraction and particles of anthropogenic origin in the fine size fraction. The greatest contribution to particulate matter belonged to aluminum-silicates and calcium-rich particles. The cenosphere were recognized only in the coastal urban site, while all the other particles were present in each site. The coastal industrial site was characterized by the prevalence of alumosilicates and Ca-rich particles, due to construction activity in this site during the sampling period (movement of vehicles, transport of terrigenous materials, and use of construction products). The coastal urban site was characterized by a higher amount of soot and by the presence of cenosphere, due to the presence of vehicular traffic. PMID- 29992365 TI - Correction to: Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings. AB - The published online version contain mistake in the author list. Instead of "A.M.Ilyas" it should have been "M.Ilyas ". PMID- 29992366 TI - [Emergency treatment of bradycardias]. AB - Bradycardia in the acutely symptomatic patient is often associated with a poor prognosis and requires urgent diagnostic and therapeutic intervention. However, sinus bradycardia can also be purely chronic and harmless. In this situation, a structured approach to diagnosis and clinical assessment of the bradycardia is paramount. In this article, an overview of bradycardia, its pathogenesis, and the differential diagnosis is provided. PMID- 29992362 TI - Visceral Adipose Tissue Accumulation and Residual Cardiovascular Risk. AB - PURPOSE OF THE REVIEW: Low-grade systemic inflammation increases residual cardiovascular risk. The pathogenesis of low-grade systemic inflammation is not well understood. RECENT FINDINGS: Visceral adipose tissue accumulates when the subcutaneous adipose tissue can no longer store excess nutrients. Visceral adipose tissue inflammation initially facilitates storage of nutrients but with time become maladaptive and responsible for low-grade systemic inflammation. Control of low-grade systemic inflammation requires reversal of visceral adipose tissue accumulation with intense and sustained aerobic exercise or bariatric surgery. Alternatively, pharmacologic inhibition of the inflammatory signaling pathway may be considered. Reversal visceral adipose tissue accumulation lowers residual cardiovascular risk. PMID- 29992367 TI - Intra-individual study of mindfulness: ecological momentary perspective in post surgical lung cancer patients. AB - The period of recovery following a lung-cancer surgery presents unique challenges and psychological demands. The study utilized ecological momentary assessments (EMA) to repeatedly sample mindfulness states in a sample of mindfulness untrained individuals following hospital discharge. Intra- and inter- individual variability was assessed to examine cancer patients' natural capacity to exhibit mindfulness states during two weeks of recovery. Fifty nine stage I lung cancer patients (61% women, mean age = 66.1, SD = 7.9) completed EMA twice a day for two weeks. Mean level of mindfulness in the sample was low and equaled .49 (SD = .51) on the 5 point scale, with older participants being less likely to endorse mindful states. Net variability in mindfulness, defined as the person-based standard deviation in momentary scores, equaled .42 (SD = .26), ranging for 0 to 1.3 and indicating very modest variability for most participants. Results of the multi-level variance partitioning model revealed 41.4% of variance in mindfulness scores at the inter-individual, 2.4% on the temporal (i.e., .2% weekly and 2.2% daily), and 56.2% on the momentary levels. Findings indicate that, for cancer patients recovering from surgery, the innate ability to exhibit mindfulness is limited. From the methodological standpoint, consideration of intra-individual variability has implications for conceptualization and design of EMA studies. PMID- 29992369 TI - From zero to hero: the past, present and future of grain amaranth breeding. AB - KEY MESSAGE: Grain amaranth is an underutilized crop with high nutritional quality from the Americas. Emerging genomic and biotechnological tools are becoming available that allow the integration of novel breeding techniques for rapid improvement of amaranth and other underutilized crops. Out of thousands of edible plants, only three cereals-maize, wheat and rice-are the major food sources for a majority of people worldwide. While these crops provide high amounts of calories, they are low in protein and other essential nutrients. The dependence on only few crops, with often narrow genetic basis, leads to a high vulnerability of modern cropping systems to the predicted climate change and accompanying weather extremes. Broadening our food sources through the integration of so-called orphan crops can help to mitigate the effects of environmental change and improve qualitative food security. Thousands of traditional crops are known, but have received little attention in the last century and breeding efforts were limited. Amaranth is such an underutilized pseudocereal that is of particular interest because of its balanced amino acid and micronutrient profiles. Additionally, the C4 photosynthetic pathway and ability to withstand environmental stress make the crop a suitable choice for future agricultural systems. Despite the potential of amaranth, efforts of genetic improvement lag considerably behind those of major crops. The progress in novel breeding methods and molecular techniques developed in model plants and major crops allow a rapid improvement of underutilized crops. Here, we review the history of amaranth and recent advances in genomic tools and give a concrete perspective how novel breeding techniques can be implemented into breeding programs. Our perspectives are transferable to many underutilized crops. The implementation of these could improve the nutritional quality and climate resilience of future cropping systems. PMID- 29992370 TI - Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial. AB - AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI >=30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean +/- SE weight change (baseline 111 kg) was -3.1 +/- 1.2% with placebo (n = 22) vs 13.5 +/- 1.1% and -12.7 +/- 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was 6.6 +/- 2.2 mmol/mol (-0.6 +/- 0.2%) with placebo vs -21.9 +/- 2.2 mmol/mol (-2.0 +/- 0.2%) or -21.9 +/- 3.3 mmol/mol (-2.0 +/- 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc. PMID- 29992371 TI - Against the iDoctor: why artificial intelligence should not replace physician judgment. AB - Experts in medical informatics have argued for the incorporation of ever more machine-learning algorithms into medical care. As artificial intelligence (AI) research advances, such technologies raise the possibility of an "iDoctor," a machine theoretically capable of replacing the judgment of primary care physicians. In this article, I draw on Martin Heidegger's critique of technology to show how an algorithmic approach to medicine distorts the physician-patient relationship. Among other problems, AI cannot adapt guidelines according to the individual patient's needs. In response to the objection that AI could develop this capacity, I use Hubert Dreyfus's analysis of AI to argue that attention to the needs of each patient requires the physician to attune his or her perception to the patient's history and physical exam, an ability that seems uniquely human. Human physician judgment will remain better suited to the practice of primary care despite anticipated advances in AI technology. PMID- 29992372 TI - Hypersexuality, Higher Rates of Intercourse, Masturbation, Sexual Fantasy, and Early Sexual Interest Relate to Higher Sexual Excitation/Arousal. PMID- 29992368 TI - Female Chemical Signalling Underlying Reproduction in Mammals. AB - Chemical communication plays many key roles in mammalian reproduction, although attention has focused particularly on male scent signalling. Here, we review evidence that female chemical signals also play important roles in sexual attraction, in mediating reproductive competition and cooperation between females, and in maternal care, all central to female reproductive success. Female odours function not only to advertise sexual receptivity and location, they can also have important physiological priming effects on male development and sperm production. However, the extent to which female scents are used to assess the quality of females as potential mates has received little attention. Female investment in scent signalling is strongly influenced by the social structure and breeding system of the species. Although investment is typically male-biased, high competition between females can lead to a reversed pattern of female- biased investment. As among males, scent marking and counter-marking are often used to advertise territory defence and high social rank. Female odours have been implicated in the reproductive suppression of young or subordinate females across a range of social systems, with females of lower competitive ability potentially benefiting by delaying reproduction until conditions are more favourable. Further, the ability to recognise individuals, group members and kin through scent underpins group cohesion and cooperation in many social species, as well as playing an important role in mother-offspring recognition. However, despite the diversity of female scent signals, chemical communication in female mammals remains relatively understudied and poorly understood. We highlight several key areas of future research that are worthy of further investigation. PMID- 29992373 TI - Improving Rates of Early Entry Prenatal Care in an Underserved Population. AB - Introduction Early prenatal care can improve pregnancy outcomes, reduce complications, and ensure a healthier pregnancy. Unfortunately, many pregnant women do not seek early care. This research provides a framework for improving prenatal care in a low income community-based obstetrics clinic. Methods A multi disciplinary quality improvement initiative was implemented at a large federally qualified health clinic in Houston, Texas to improve the rate of early entry into prenatal care by identifying barriers through patient surveys, focus groups, stakeholder feedback, and improving processes to reduce these barriers. Results A significant increase in early prenatal care was achieved by redesigning operational and clinical processes to improve access to care, expand patient education and outreach, increase resources, extend hours of operation, and increase presumptive insurance eligibility. Three months post implementation, an increase of 44.5% (p < 0.001) occurred in patients who had a prenatal visit in the first trimester. Patients with early prenatal care had better obstetrical and neonatal outcomes; however, the results were not statistically significant likely due to the small sample size. Discussion This quality improvement project provides various strategies and resources for other community-based clinics to consider when seeking improvement in their rates of early prenatal care. PMID- 29992374 TI - Auxin-mediated regulation of vascular patterning in Arabidopsis thaliana leaves. AB - The vascular system develops in response to auxin flow as continuous strands of conducting tissues arranged in regular spatial patterns. However, a mechanism governing their regular and repetitive formation remains to be fully elucidated. A model system for studying the vascular pattern formation is the process of leaf vascularization in Arabidopsis. In this paper, we present current knowledge of important factors and their interactions in this process. Additionally, we propose the sequence of events leading to the emergence of continuous vascular strands and point to significant problems that need to be resolved in the future to gain a better understanding of the regulation of the vascular pattern development. PMID- 29992375 TI - Analysis of the affinity of influenza A virus protein epitopes for swine MHC I by a modified in vitro refolding method indicated cross-reactivity between swine and human MHC I specificities. AB - In vitro refolding assays can be used to investigate the affinity and stability of the binding of epitope peptides to major histocompatibility complex (MHC) class I molecules, which are key factors in the presentation of peptides to cytotoxic T lymphocytes (CTLs). The recognition of peptide epitopes by CTLs is crucial for protection against influenza A virus (IAV) infection. The peptide binding motif of the swine SLA-3*hs0202 molecule has been previously reported and partly overlaps with the binding motif of the most abundant human MHC allele, HLA A*0201. In this study, we screened all the protein sequences of the swine-origin epidemic IAV strain A/Beijing/01/2009 (H1N1), and a total of 73 9-mer epitope peptides were predicted to fit the consensus motif of the swine SLA-3*hs0202 or HLA-A*0201 molecule. Then, 14 peptides were selected, and their affinities to SLA 3*hs0202 were tested by a modified in vitro refolding assay. Our results show that ten epitopes could tolerate gel filtration, indicating that these epitopes formed stable or partly stable complexes with SLA-3*hs0202. Eight out of the ten epitopes have been previously reported as HLA-A2-restricted epitopes, which implied cross-reactivity between swine and human MHC I specificities. Furthermore, the modified mini-system refolding method could be applied for the screening of peptides because the refolding efficiency remained almost unchanged with the positive peptide (HA-KMN9) subjected to size-exclusion chromatography and Resource Q anion-exchange chromatography. The results presented here provide new insight into the development of epitope-based vaccines to control IAV and increase our understanding of swine molecular immunology. PMID- 29992376 TI - Force distribution of a cylindrical grip differs between dominant and nondominant hand in healthy subjects. AB - INTRODUCTION: Grip strength and load distribution of the hand are important parameters for evaluating hand function. The purpose of this study was to analyze and compare grip force and load distribution of dominant and nondominant hands in right-handed healthy subjects. METHODS: Gripping measurements were performed on 40 healthy right-handed subjects using a cylindrical gripping device. Two different cylinders with circumferences of 150 mm (small cylinder) and 200 mm (large cylinder), respectively, were used for the measurements. Subjects were assigned to either the small or the large cylinder with respect to their hand size. Maximum and mean force applied during three intervals of gripping as well as the percent contribution of each digit, thenar, and hypothenar in relation to the total load applied were acquired. Values of dominant and nondominant hands were compared. RESULTS: Percent contribution of mean grip strength differed for the thumb (p = 0.007), ring finger (p < 0.001), little finger (p = 0.047), and palm (p < 0.001). Comparing the dominant and nondominant side, the dominant hand showed a lower contribution of the thumb, ring finger, and little finger, but a higher contribution of the palm. When analyzing maximum grip, percent contribution of the small fingers was equal between dominant and nondominant side (p = 0.1). Differences between dominant and nondominant thumb, ring finger, and palm persisted (p = 0.007, p = 0.001, p = 0.005, respectively). No differences could be shown for the index finger, middle finger, thenar, and hypothenar when analyzing both mean and maximum force. DISCUSSION AND CONCLUSION: Percent contribution of the thumb and the fingers to total grip strength differed between dominant and nondominant hands with a change in distribution when assessing maximum grip force. In right-handed subjects, thumb and ring finger have important roles during gripping. PMID- 29992377 TI - Preoperative disinfection of foot and ankle: microbiological evaluation of two disinfection methods. AB - BACKGROUND: The aim of the current study was to investigate the effect of a footbath in alcohol prior to preoperative disinfection on bacterial flora of the foot and ankle. METHODS: Twenty-two volunteers underwent skin preparation mimicking pre-surgical disinfection. One foot was submerged in a bag filled with 70% ethanol containing 10% IPA for 5 min after which it was painted with regular 0.5% chlorhexidine in 70% alcohol. The other foot was only painted with 0.5% chlorhexidine in 70% alcohol. Swabs were taken at four locations: (1) under the nailfold of the first toe, (2) first webspace, (3) sinus tarsi and (4) pre tibial. A quantitative and qualitative analysis of the cultures was performed. RESULTS: No statistically significant difference between the number of positive cultures between the two methods was observed. The number of colony forming units was statistically significantly lower on two locations in the footbath group (i.e., subungual and the first webspace) (median 1 versus median 92 p =0.03 and median 0 versus median 1 p =0.03, respectively). The number of cultures with heavy growth was lower in the footbath group under the nailfold of the first toe (5 versus 13 p =0.008). Thirty-eight different microorganisms were cultured. CONCLUSION: A footbath in alcohol prior to regular preoperative skin antisepsis significantly reduces the amount of bacteria under the nailfold and in the first webspace. The number of cultures with heavy growth is lower after a footbath in alcohol. LEVEL OF EVIDENCE: IV. PMID- 29992379 TI - Barrett's esophagus in children: what is the evidence? AB - BACKGROUND: This study systematically reviewed etiology, prevalence, treatment and outcome of Barrett's esophagus (BE) in the pediatric population. METHODS: PubMed(r) was searched for terms "Barrett's esophagus" and "children". End points were age of patients, etiology, association with other syndromes, treatment, incidence of carcinoma and outcome. This review was conducted according to the PRISMA guidelines. Data were collected, entered and analyzed into a Microsoft Excel(r) spreadsheet database. RESULTS: Search revealed 278 articles published between 1984 and 2017, of which 18 met the inclusion criteria. There were 130 patients for analysis with a mean age 10.6 years (0.8-17.2 years). BE was diagnosed in 80 patients with confirmed gastroesophageal reflux (GER) only; further 20 patients were neurologically impaired and had GER, 13 after esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) repair with associated GER, 6 post-chemotherapy, 1 after post caustic burns, 1 after esophageal replacement with stomach, 1 after peptic esophageal stricture, 1 with secretory diarrhea, 1 with Fanconi anemia, 1 tetralogy of Fallot, and 5 healthy children. Regarding treatment, 26 were on medical treatment only, 16 had surgeries combined with medical treatment, 80 patients underwent surgery only, 1 was on diet management, 4 were on surveillance only and 2 were never treated for BE as death occurred because of associated conditions. Fundoplication was the most commonly performed surgery (82.2%). Adenocarcinoma was found in one 23-year old patient. Mean follow-up was 3.45 years (10 months-13 years) and long-term outcome showed recurrences in 8 and esophago-mediastinal fistula and proximal esophagus ulcer in 1. There were 7 lethal outcomes which were not directly associated with BE. CONCLUSIONS: Although BE is considered a premalignant condition; incidence of carcinoma in pediatric population is low. Long-term follow-up with endoscopies and biopsies seems to be advisable for BE evidence and malignant alterations. PMID- 29992378 TI - Bioenergetics of life, disease and death phenomena. AB - In this article, some new aspects of unified cell bioenergetics are presented. From the perspective of unified cell bioenergetics certain subsequent stages of cancer development, from initiation stage, through transformation to metastasis, are analyzed. Here we show that after transformation, cancer cells are permanently exposed to reactive oxygen species, that causes continual random DNA mutations and as a result genome and chromosomal destabilizations. The modern cancer attractor hypothesis has been extended in explaining cancer development. Discussion is conducted in light of current cancerogenesis research, including bioenergetic cancer initiation, the somatic mutation theory and the tissue organization field theory. In the article reasons complicating the discovery of patterns of cancer genome changes and cancer evolution are presented. In addition certain cancer therapeutic aspects are given attention to. PMID- 29992380 TI - Inverse stage migration patterns in North American patients undergoing local prostate cancer treatment: a contemporary population-based update in light of the 2012 USPSTF recommendations. AB - PURPOSE: Recent studies demonstrated ongoing inverse stage migration in prostate cancer (PCa) patients towards more advanced and unfavorable tumors. The USPSTF grade D recommendation may impact this trend in North American patients. We assessed contemporary stage migration and treatment trends in a large North American cohort diagnosed with PCa 2009-2014. METHODS: Time-trend analyses were performed in patients within the Surveillance, Epidemiology, and End Results database, with complete data of clinical tumor stage, biopsy Gleason score, and validated PSA values, resulting in 211,645 assessable patients. Patients were stratified according to their different treatment methods [radical prostatectomy (RP), radiotherapy (RT), and no local treatment (NLT)] and according to clinical and pathological risk stratification (D'Amico and CAPRA-S score). RESULTS: Over time, proportions of D'Amico low-risk (LR) decreased, with an increase in intermediate-to-high-risk (IR/HR) patients. These trends were more distinct in men >= 70 years. NLT proportions increased, most notably in D'Amico LR and/or older patients. Conversely, RP proportions remained stable in younger HR and increased in older HR patients. Similar patterns were demonstrated in the RP treated subgroup: D'Amico HR, pT3, and/or lymph-node invasion or CAPRA-S HR proportions increased from 23.5 to 30.8, 24.3 to 32.9, and 10.7 to 16.3% (each p <= 0.015). CONCLUSIONS: Inverse stage migration with increase of unfavorable PCa continues in most contemporary North American patients. However, a paradigm shift to treat LR patients with less invasive methods (NLT) was demonstrated. Contrary, HR patients increasingly undergo LT. Future studies with long-term follow-up might answer if inverse stage migration vs. treatment trends translate into different PCa metastases/mortality rates vs. proposed NLT benefits, particularly related to USPSTF-recommended reduced PSA screening. PMID- 29992381 TI - An increased body mass index is associated with a worse prognosis in patients administered BCG immunotherapy for T1 bladder cancer. AB - PURPOSE: The body mass index (BMI) may be associated with an increased incidence and aggressiveness of urological cancers. In this study, we aimed to evaluate the impact of the BMI on survival in patients with T1G3 non-muscle-invasive bladder cancer (NMIBC). METHODS: A total of 1155 T1G3 NMIBC patients from 13 academic institutions were retrospectively reviewed and patients administered adjuvant intravesical Bacillus Calmette-Guerin (BCG) immunotherapy with maintenance were included. Multivariable Cox regression analysis was performed to identify factors predictive of recurrence and progression. RESULTS: After re-TURBT, 288 patients (27.53%) showed residual high-grade NMIBC, while 867 (82.89%) were negative. During follow-up, 678 (64.82%) suffered recurrence, and 303 (30%) progression, 150 (14.34%) died of all causes, and 77 (7.36%) died of bladder cancer. At multivariate analysis, tumor size (hazard ratio [HR]:1.3; p = 0.001), and multifocality (HR:1.24; p = 0.004) were significantly associated with recurrence (c-index for the model:55.98). Overweight (HR: 4; p < 0.001) and obesity (HR:5.33 p < 0.001) were significantly associated with an increased risk of recurrence. Addition of the BMI to a model that included standard clinicopathological factors increased the C-index by 9.9. For progression, we found that tumor size (HR:1.63; p < 0.001), multifocality (HR:1.31; p = 0.01) and concomitant CIS (HR: 2.07; p < 0.001) were significant prognostic factors at multivariate analysis (C-index 63.8). Overweight (HR: 2.52; p < 0.001) and obesity (HR: 2.521 p < 0.001) were significantly associated with an increased risk of progression. Addition of the BMI to a model that included standard clinicopathological factors increased the C index by 1.9. CONCLUSIONS: The BMI could have a relevant role in the clinical management of T1G3 NMIBC, if associated with bladder cancer recurrence and progression. In particular, this anthropometric factor should be taken into account at initial diagnosis and in therapeutic strategy decision making. PMID- 29992382 TI - Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. AB - Patients with acute myocardial infarction receive a P2Y12 receptor antagonist prior to reperfusion, a treatment that has reduced, but not eliminated, mortality, or heart failure. We tested whether the caspase-1 inhibitor VX-765 given at reperfusion (a requirement for clinical use) can provide sustained reduction of infarction and long-term preservation of ventricular function in a pre-clinical model of ischemia/reperfusion that had been treated with a P2Y12 receptor antagonist. To address, the hypothesis open-chest rats were subjected to 60-min left coronary artery branch occlusion/120-min reperfusion. Vehicle or inhibitors were administered intravenously immediately before reperfusion. With vehicle only, 60.3 +/- 3.8% of the risk zone suffered infarction. Ticagrelor, a P2Y12 antagonist, and VX-765 decreased infarct size to 42.8 +/- 3.3 and 29.2 +/- 4.9%, respectively. Combining ticagrelor with VX-765 further decreased infarction to 17.5 +/- 2.3%. Similar to recent clinical trials, combining ticagrelor and ischemic postconditioning did not result in additional cardioprotection. VX-765 plus another P2Y12 antagonist, cangrelor, also decreased infarction and preserved ventricular function when reperfusion was increased to 3 days. In addition, VX 765 reduced infarction in blood-free, isolated rat hearts indicating at least a portion of injurious caspase-1 activation originates in cardiac tissue. While the pro-drug VX-765 only protected isolated hearts when started prior to ischemia, its active derivative VRT-043198 provided the same amount of protection when started at reperfusion, indicating that even in blood-free hearts, caspase-1 appears to exert its injury only at reperfusion. Moreover, VX-765 decreased circulating IL-1beta, prevented loss of cardiac glycolytic enzymes, preserved mitochondrial complex I activity, and decreased release of lactate dehydrogenase, a marker of pyroptosis. Our results are the first demonstration of a clinical grade drug given at reperfusion providing additional, sustained infarct size reduction when added to a P2Y12 receptor antagonist. PMID- 29992383 TI - Intracranial pressure (ICP) monitoring in diffuse brain injury: to do or not to do? PMID- 29992384 TI - Motion-corrected multiparametric renal arterial spin labelling at 3 T: reproducibility and effect of vasodilator challenge. AB - OBJECTIVES: We investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1. METHODS: In a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 +/- 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots. RESULTS: Inter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 +/- 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant. CONCLUSIONS: Free-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge. KEY POINTS: * Multiple inversion time arterial spin labelling (ASL) of the kidneys is feasible and reproducible at 3 T. * This approach allows simultaneous mapping of renal perfusion, bolus arrival time and tissue T 1 during free breathing. * This technique enables repeated measures of renal haemodynamic characteristics during pharmacological challenge. PMID- 29992385 TI - Correction to: CT metal artifacts in patients with total hip replacements: for artifact reduction monoenergetic reconstructions and post-processing algorithms are both efficient but not similar. AB - The original version of this article, published on 03 May 2018, unfortunately contained a mistake. The following correction has therefore been made in the original. PMID- 29992386 TI - Sonoelastography for differential diagnosis between malignant and benign parotid lesions: a meta-analysis. AB - OBJECTIVES: To assess the performance of sonoelastography for differential diagnosis between malignant and benign parotid lesions using a meta-analysis. METHODS: An independent literature search of English medical databases, such as PubMed, Embase and Medline ( Embase.com ), Web of Science, Cochrane Library and Ovid was performed. The diagnostic accuracy of sonoelastography was compared with that of histopathology and/or cytology, which was used as reference standard. The pooled sensitivity, specificity, diagnostic odds ratio (DOR) and area under the curve (AUC) were calculated to evaluate the accuracy of sonoelastography. A meta regression analysis evaluating imaging mechanisms, shear wave elastography techniques, assessment methods and QUADAS scores was performed. RESULTS: Ten eligible studies that included a total sample of 711 patients with 725 parotid lesions were included. Sonoelastography showed a pooled sensitivity of 0.67 (95% CI 0.59-0.74), specificity of 0.64 (95% CI 0.60-0.68), DOR of 8.00 (95% CI 2.96 21.63) and an AUC of 0.77. The results of the meta-regression analysis revealed that no heterogeneity was due to the imaging mechanism (p = 0.119), shear wave elastography technique (p = 0.473) or QUADAS score (p = 0.462). However, the assessment method was a significant factor that affected the study heterogeneity (p = 0.035). According to the subgroup analysis, quantitative and semiquantitative methods performed better than qualitative ones. CONCLUSION: Overall, sonoelastography has a limited value for differential diagnosis between malignant and benign parotid lesions. Quantitative and semiquantitative methods perform better than qualitative ones. KEY POINTS: * Overall, sonoelastography has a limited value for differential diagnosis between malignant and benign parotid lesions. * Quantitative and semiquantitative assessment methods perform better than qualitative ones. * Semiquantitative and quantitative methods are automatically calculated by an ultrasound machine and are thus less operator dependent. PMID- 29992387 TI - Lung cancer screening with MRI: Evaluation of MRI for lung cancer screening by comparison of LDCT- and MRI-derived Lung-RADS categories in the first two screening rounds. AB - PURPOSE: To evaluate MRI for lung cancer screening comparing LDCT- and MRI derived Lung-RADS categories in the first two screening rounds. MATERIALS AND METHODS: 224 participants in a lung cancer screening study were examined with MRI and low-dose CT (LDCT). Acquired MRI sequences were T2, balanced, T1 and DWI. MRI was prospectively analysed regarding nodules. Minimum nodule size was 4 mm. Nodules were assigned a Lung-RADS score based on appearance and size at baseline and after 3, 6 and 12 months. MRI findings were correlated with LDCT. RESULTS: The early recall rate dropped from 13.8% at baseline to 1.9% in the second screening round with biopsy rates of 3.6% in the first round and 0.5% in the second round. Histology revealed lung cancer in 8/9 participants undergoing biopsy/surgery. All eight cancers were accurately depicted by MRI. The following categories were assigned on MRI (results of LDCT in parentheses): 4B/4X in 10 (10) cases, 4A in 16 (15) cases, 3 in 13 (12) cases, 2 in 77 (92) cases and 1 in 140 (126) cases. Lung-RADS scoring correlated significantly between MRI and CT. The score was overestimated by MRI in one case for category 4A, in two cases for category 3 and in five cases for category 2. MRI-based Lung-RADS score was underestimated for category 1 in 20 cases. CONCLUSION: Lung-RADS might be applied for lung cancer screening with MRI, since findings correlated with LDCT. Relevant findings with a Lung-RADS score of 3 and higher were never missed or underestimated by MRI KEY POINTS: * MRI performed comparably to low-dose CT in a lung cancer-screening programme. * Lung-RADS might be applied for lung cancer screening with MRI. * Lung-RADS findings score of 3 and higher were never missed by MRI. PMID- 29992388 TI - Delayed tumour enhancement on gadoxetate-enhanced MRI is associated with overall survival in patients with colorectal liver metastases. AB - OBJECTIVES: To determine whether tumour enhancement on preoperative delayed-phase gadoxetate-enhanced MRI can predict long-term survival in patients with colorectal liver metastases (CRCLM) post-hepatectomy. MATERIALS AND METHODS: Sixty-five patients who received a preoperative gadoxetate-enhanced MRI prior to liver resection for CRCLM from January 1, 2010, to December 31, 2012, were included in this retrospective study. Target tumour enhancement (TuEn) was calculated as the mean percentage increase in SNR from precontrast to 10-min or 20-min delayed phase for up to two target lesions. Per-patient TuEn was stratified into weak and strong enhancement based on the cut-off determined by the Youden Index for 3-year survival. Kaplan-Meier and Cox regression analyses were used to determine whether tumour enhancement could predict overall survival independent of potential confounders (clinical risk score). RESULTS: The proportion surviving at 3 years was 85.1% in patients with strong TuEn at 10 min vs. 56.5% in those with weak TuEn at 10 min (p = 0.001). The proportion surviving at 3 years was 79.4% in patients with strong TuEn at 20 min vs. 58.7% in those with weak TuEn at 20 min (p = 0.011). After adjusting for potential confounders, the hazard ratio of death was 0.24 (p = 0.009) in patients who had weak TuEn at 10 min and 0.32 (p = 0.018) in patients who had weak TuEn at 20 min. CONCLUSIONS: Strong delayed tumour enhancement seen on gadoxetate-enhanced MRI is associated with overall survival in patients with CRCLM post-hepatectomy and may be useful for preoperative risk stratification. KEY POINTS: * Delayed tumour enhancement of colorectal liver metastases on gadoxetate-enhanced MRI is associated with survival post-hepatectomy * Delayed tumour enhancement of colorectal liver metastases on gadoxetate-enhanced MRI can be measured at both 10 min and 20 min post-contrast injection. PMID- 29992389 TI - Definitive chemoradiotherapy for anal canal cancer: single-center experience. AB - BACKGROUND: Chemoradiotherapy (CRT) is a standard treatment for anal canal cancer although many patients with anal canal cancer undergo surgery in Japan. The efficacy of CRT for anal canal cancer was evaluated retrospectively. METHODS: Medical charts of 13 patients with anal canal cancer treated by definitive CRT from October 2004 to May 2016 were reviewed. Twelve patients had squamous cell carcinoma and one had adeno-squamous carcinoma. PET/CT simulation was performed in nine patients. The median total dose was 59.4 Gy (range 57.6-63.4 Gy) with fractions of 1.8-2.0 Gy. Ten patients received chemotherapy with mitomycin C (10 mg/m2) and fluorouracil (5-FU) (800 mg/m2 over 4 days) in weeks 1 and 5, while two patients were treated with cisplatin (40 mg) and 5-FU (750 mg over 5 days) in weeks 1 and 5. One elderly patient received radiotherapy (RT) alone. RESULTS: All 13 patients were alive after a median follow-up period of 102 months (range 16 121 months). Local failure only occurred in the patient with adeno-squamous cell carcinoma, while there was no loco-regional recurrence or distant metastasis in the other 12 patients. The 5-year loco-regional control rate (LRC) and 5-year overall survival rate (OS) were 92% and 100%, respectively. Acute toxicities of >= grade 3 were observed in six patients (46%), mainly being dermatitis around the anal verge, and late toxicity of >= grade 3 occurred in one patient. CONCLUSION: CRT for squamous cell carcinoma of the anal canal achieved good LRC and OS with acceptable toxicities. PMID- 29992391 TI - A Developmental Perspective on Processing Semantic Context: Preliminary Evidence from Sentential Auditory Word Repetition in School-Aged Children. AB - The current investigation examined the developmental changes involved in processing semantic context in auditorily presented sentences, as well as underlying attentional and suppression mechanisms. Thirty-nine typically developing school-aged children aged 6;0-14;0 years participated in the current cross-sectional sentential auditory word repetition study. Component processes involved in auditory word recognition were examined and their respective developmental trajectories systematically delineated. Experimental manipulations included semantic congruity (congruous, incongruous), sentence constraint (high, low), cloze probability (high, low), and processing mode. High sentence constraints elicited top-down pre-potency type effects, which resulted in active suppression of anticipated cloze words and longer naming latencies of perceived cloze words when violated with conflicting bottom-up information. In addition, developmental changes in component processes reflected underlying changes in attention, with evidence that suppression mechanisms remained relatively constant with age. Findings are interpreted in line with the Trace (McClelland and Elman in Cogn Psychol 18(1):1-86, 1986) model of auditory word recognition. PMID- 29992390 TI - Genome-Wide Sequencing Reveals Small Nucleolar RNAs Downregulated in Cerebral Cavernous Malformations. AB - Cerebral cavernous malformations (CCM) are vascular malformations associated with abnormally dilated blood vessels and leaky capillaries that often result in hemorrhages. Despite recent advances, precise understanding of the cellular and molecular mechanism leading to the pathogenesis of CCM remains elusive. Emerging evidence indicates that small nucleolar RNAs (snoRNAs), belonging to the class of non-coding RNAs, may play a significant role as diagnostic markers in human diseases. However, there is no report till date that studied the role of snoRNAs in CCM biology. The objective of the current study was to identify snoRNAs associated with CCM pathogenesis. Using genome-wide small RNA sequencing, we identified a total of 271 snoRNAs reliably expressed in CCM. By applying additional statistical stringency, three snoRNAs (SNORD115-32, SNORD114-22, and SNORD113-3) were found to be significantly downregulated in CCM patient tissue samples (n = 3) as compared to healthy brains (n = 3). Deregulation of the selected snoRNAs was further validated by qRT-PCR. Further, cellular localization via in situ hybridization also confirmed robust reduction in the expression of SNORD115-32 and SNORD114-22 in CCM tissues as compared to the healthy controls. By applying high-throughput sequencing and cellular localization analyses, we report here for the first time the genome-wide expression profile of snoRNAs in CCM tissues and a robust downregulation of candidate snoRNAs in CCM conditions. Future studies should warrant the screening in large CCM patient cohorts and will be helpful in the development of potential biomarkers and improved clinical diagnosis. PMID- 29992392 TI - Evaluation of machine learning algorithms performance for the prediction of early multiple sclerosis from resting-state FMRI connectivity data. AB - Machine Learning application on clinical data in order to support diagnosis and prognostic evaluation arouses growing interest in scientific community. However, choice of right algorithm to use was fundamental to perform reliable and robust classification. Our study aimed to explore if different kinds of Machine Learning technique could be effective to support early diagnosis of Multiple Sclerosis and which of them presented best performance in distinguishing Multiple Sclerosis patients from control subjects. We selected following algorithms: Random Forest, Support Vector Machine, Naive-Bayes, K-nearest-neighbor and Artificial Neural Network. We applied the Independent Component Analysis to resting-state functional-MRI sequence to identify brain networks. We found 15 networks, from which we extracted the mean signals used into classification. We performed feature selection tasks in all algorithms to obtain the most important variables. We showed that best discriminant network between controls and early Multiple Sclerosis, was the sensori-motor I, according to early manifestation of motor/sensorial deficits in Multiple Sclerosis. Moreover, in classification performance, Random Forest and Support Vector Machine showed same 5-fold cross validation accuracies (85.7%) using only this network, resulting to be best approaches. We believe that these findings could represent encouraging step toward the translation to clinical diagnosis and prognosis. PMID- 29992393 TI - Adverse childhood experience and rheumatic diseases. AB - It has been suggested that the adaptive stress response may be disrupted by life adverse events such as childhood maltreatment. To investigate if the number of adverse childhood experiences (ACEs) increases susceptibility to systemic lupus erythematosus (SLE), spondyloarthritis (SpA), scleroderma (SSc), and rheumatoid arthritis (RA), we interviewed 315 patients with rheumatic disease (100 SLE; 40 SSc; 60 SpA; 115 RA) and 272 controls, using questions of the ACEs study questionnaire validated to ask about experiences of childhood abuse, negligence, domestic violence, and household dysfunctions. The questionnaire score ranges from zero (best result) to 8 (worst scenario). Patients and controls did not differ regarding the median number of ACEs (3 in both groups, patient IQR = 2.5-5 vs. control IQR = 2-5, p = 0.45). Among the patients, 63.8% (201/315) presented ACE score >= 3, compared with 59.9% (163/272) of the controls (p = 0.31). The proportion of patients with at least 3 ACEs did also not differ among those with different rheumatic diseases. Specifically, 64% (64/100) of those with SLE, 60% (24/40) of those with SSc, 60% (36/60) of those with SpA, and 66.9% (77/115) of those with RA reported at least 3 ACEs. There was also no difference between the distribution of ACE scores and number of individuals with ACEs >= 3 between patients with different rheumatic diseases and controls. Nevertheless, there was a trend for association between higher ACE score and susceptibility to RA (p = 0.06). In this setting, the occurrence of ACEs was not associated with susceptibility to rheumatic diseases in adulthood. PMID- 29992394 TI - Ultrasonographic findings in a patient with reactive arthritis induced by intravesical BCG therapy for bladder cancer. AB - Intravesical bacillus Calmette-Guerin (BCG) therapy is an effective and safe immunotherapy for superficial bladder cancer. However, reactive arthritis (ReA) is reported as an adverse event in about 0.5-1% of patients receiving intravesical BCG therapy. ReA is known as a kind of spondyloarthritis, the main pathological finding of which is enthesitis. Here we report a patient with ReA induced by intravesical BCG therapy for bladder cancer, in whom the diagnosis of ReA was supported by ultrasonographic findings of enthesitis and synovitis. A 69 year-old male was diagnosed with carcinoma in situ of the bladder and treated with intravesical BCG therapy. After the third intravesical BCG injection, pain and swelling appeared in both wrists. Ultrasonographic examination revealed not only intra-articular synovitis in the bilateral wrist joint, wrist flexor tenosynovitis, and wrist extensor tenosynovitis, but also enthesitis of the flexor carpi radialis tendon (FCR). The severe enthesitis of the FCR in both wrists was considered to be an important finding that supported the diagnosis in this patient. Thus, we diagnosed this case as ReA induced by intravesical BCG therapy. In clinical practice, ReA is often difficult to distinguish from seronegative rheumatoid arthritis and other rheumatic diseases. Ultrasonographic findings of enthesitis may support a definitive diagnosis for these patients. PMID- 29992395 TI - Why is chlorophyll b only used in light-harvesting systems? AB - Chlorophylls (Chl) are important pigments in plants that are used to absorb photons and release electrons. There are several types of Chls but terrestrial plants only possess two of these: Chls a and b. The two pigments form light harvesting Chl a/b-binding protein complexes (LHC), which absorb most of the light. The peak wavelengths of the absorption spectra of Chls a and b differ by c. 20 nm, and the ratio between them (the a/b ratio) is an important determinant of the light absorption efficiency of photosynthesis (i.e., the antenna size). Here, we investigated why Chl b is used in LHCs rather than other light-absorbing pigments that can be used for photosynthesis by considering the solar radiation spectrum under field conditions. We found that direct and diffuse solar radiation (PARdir and PARdiff, respectively) have different spectral distributions, showing maximum spectral photon flux densities (SPFD) at c. 680 and 460 nm, respectively, during the daytime. The spectral absorbance spectra of Chls a and b functioned complementary to each other, and the absorbance peaks of Chl b were nested within those of Chl a. The absorption peak in the short wavelength region of Chl b in the proteinaceous environment occurred at c. 460 nm, making it suitable for absorbing the PARdiff, but not suitable for avoiding the high spectral irradiance (SIR) waveband of PARdir. In contrast, Chl a effectively avoided the high SPFD and/or high SIR waveband. The absorption spectra of photosynthetic complexes were negatively correlated with SPFD spectra, but LHCs with low a/b ratios were more positively correlated with SIR spectra. These findings indicate that the spectra of the photosynthetic pigments and constructed photosystems and antenna proteins significantly align with the terrestrial solar spectra to allow the safe and efficient use of solar radiation. PMID- 29992396 TI - Effects of Postponing Treatment in the Second Year of Cladribine Administration: Clinical Trial Simulation Analysis of Absolute Lymphocyte Counts and Relapse Rate in Patients with Relapsing-Remitting Multiple Sclerosis. AB - INTRODUCTION: Cladribine Tablets (MAVENCLAD(r)) selectively reduce absolute lymphocyte counts (ALCs) in patients with multiple sclerosis. The recommended cumulative dose of Cladribine Tablets is 3.5 mg/kg over 4-5 days in months 1 and 2 of treatment years 1 and 2, followed by prolonged efficacy with no additional treatment. After the cladribine-induced reduction, ALCs recover to normal within each treatment year in most patients. Those patients with slow ALC recovery can develop Grade 3-4 lymphopenia, especially those patients with Grade >= 2 lymphopenia at the start of year 2. Guidelines allowing treatment postponements during year 2 have been proposed for patients with a low ALC, subsequent to CLARITY, the pivotal clinical trial. METHODS: A virtual population was generated using characteristics from CLARITY patients. A clinical trial simulation was performed to determine the impact of alternative treatment scenarios on ALC and relapse rate, by postponing treatment in year 2 to allow for longer ALC recovery time in patients who required it. Should a patient not recover to normal ALC (Grade 0) or Grade 1 lymphopenia within the period defined in the treatment algorithm, treatment in year 2 was suspended. RESULTS: Results were similar across considered scenarios, which implemented different postponement durations. Specifically, ~ 92% of virtual subjects did not require treatment postponement and < 1% discontinued due to Grade 2-4 lymphopenia at the end of the maximally permitted postponement. Less severe lymphopenia was observed during year 2 when a treatment algorithm was applied. The effect on relapse rate over 2 years was negligible. CONCLUSIONS: Results support treatment guidelines to decrease the risk of severe lymphopenia following treatment with Cladribine Tablets, while preserving efficacy. TRIAL REGISTRATION: CLARITY; ClinicalTrials.gov: NCT00213135. PMID- 29992397 TI - Antioxidative and antifungal response of woody species to environmental conditions in the urban area. AB - The complexity of ecological conditions in urban areas imposes the plant species need for the development of various biochemical and physiological adaptive strategies. The aim of our research was to examine the antioxidative and antifungal metabolism of species Pinus nigra, Picea omorika, Tilia cordata and Betula pendula from the area of Banja Luka City (urban area) during two vegetation seasons (spring and autumn) and compared with the same species from forest habitats. Changes in the protein concentration, activity and isoenzyme profiles of peroxidases (POD, EC 1.11.1.7), content and antioxidative activity of total phenols and antifungal activity in leaves and needles of the plants from the urban area and forest habitats were monitored. The obtained results indicate that urban areas induce changes in antioxidative metabolism in all examined species, but that the response is species specific. The most sensitive parameter that indicates different adaptation strategy of Pinus nigra, Picea omorika, Tilia cordata and Betula pendula to environment conditions in the urban area were peroxidase isoenzyme patterns. Less specific parameter was phenol content even though there are some indications for role of their antioxidative capacity in the adjustment to specific habitat. In addition, each species had different metabolic strategy to cope with the changes caused by the urban environment. PMID- 29992398 TI - Linking pesticide marketing authorisations with environmental impact assessments through realistic landscape risk assessment paradigms. AB - Each year, the European Food Safety Authority, supported by a network of experts in the EU Member States, assesses and publishes the environmental risks of 30-40 pesticides active substances. The assessments support hundreds of national risk evaluations for marketing (re-)authorisations of Plant Protection Products. These prospective regulatory evaluations are based on worst-case scenarios in order to provide the high level of protection required by the EU legislations, and establishes the conditions for a correct use of the products including risk mitigations options. However, recent publications suggest that the desired high level of protection may not be achieved with the current risk assessment paradigm. The consideration of larger spatial scales and multiple stressors, including different pesticide uses, could improve the risk assessment process. A next step is the use of these larger spatial scales for evidence-based assessments, evaluating the overall impact of pesticide use on the European environment and biodiversity. Reaching this level would provide science-based support to the National Plans on sustainable use of pesticides and to the broader EU policies defined in the EU Environmental Action Programmes. Recent technological developments, as well as policy efforts, have solved two of the key issues blocking this progress in the past. Data availability and technical capacity for handling Big Data are no longer an unaffordable obstacle. The current proposal presents an alternative environmental risk assessment paradigm, integrating use patterns and pesticides properties with landscape ecotypes and eco-regions, covering the variability of the European agro-environmental conditions. The paradigm is suggested to be implemented in a spatially explicit conceptual model, using the ecosystem services approach and vulnerable key driver species to represent the service providing units. This approach would allow mapping the likelihood and magnitude of the impact of pesticide use on ecosystems functions, environmental resources, and biodiversity at the EU scale. PMID- 29992399 TI - Determination of the expression level of stress-related genes in Cicer arietinum root cell under Cd stress and the relationship to H2O2 concentrations. AB - In this study, stress-related gene expression levels and the concentrations of malondialdehyde (MDA) and hydrogen peroxide (H2O2), which are oxidative stress markers, were investigated in the chickpea (Cicer arietinum) plant's roots that are exposed to cadmium (Cd). MDA and H2O2 concentrations showed a linear increase. It was found that metallothionein-like gene (MT2) stress genes had a high level of expression at the 12-h application, while the kinetics of expression levels of glutathione reductase (GR1) and superoxide dismutase (Cu Zn/SOD) genes increased until 24 h of application with a decrease in expression levels by 48 h of application. It has been observed that catalase (CAT) continues to be expressed at 24 and 48 h of Cd exposure. This study found that the expression of stress-related genes can be related to the oxidative status of the cell and the H2O2 concentration in the mechanism of signalization. This may up regulate the expression of the stress genes until a certain concentration degree, while a higher concentration of H2O2 may down-regulate the gene expressions. The findings of this study may contribute to further oxidative signalling studies. PMID- 29992400 TI - Autophagy plays a protective role against apoptosis induced by toxicarioside N via the Akt/mTOR pathway in human gastric cancer SGC-7901 cells. AB - Toxicarioside N (Tox N), a natural product extract from Antiaris toxicaria, has been reported to induce apoptosis in human gastric cancer cells. However, the mechanism and actual role of autophagy in Tox N-induced apoptosis of human gastric cancer cells remains poorly understood. In the current study, we demonstrated that Tox N could induce autophagy by inhibiting the Akt/mTOR signaling pathway in SGC-7901 cells. Moreover, we found that the inhibition of autophagy by 3-methyladenine, an autophagy inhibitor, enhanced Tox N-induced apoptotic cell death. However, the stimulation of autophagy by rapamycin, an autophagy activator, remarkably suppressed Tox N-induced apoptosis, suggesting that autophagy plays a protective role in Tox N-induced apoptosis. Thus, the results from this study suggested that Tox N combination with an autophagy inhibitor might be a promising strategy to enhance the anticancer activity of Tox N for the treatment of human gastric cancer. PMID- 29992401 TI - [Imaging findings of intramammary malignant lymphoproliferative disease]. AB - Intramammary manifestation of lymphoproliferative disease is rare. The radiological evaluation follows in most cases the clinical suspicion and therefore the radiologist takes an important place in diagnostics. The aim of this work is to demonstrate typical radiological patterns of this rare entity with multimodal cases and to sensitize for it. The differential diagnosis to other breast tumors, especially primary breast carcinoma, can be radiologically difficult, so the suspicious lesion must be histologically verified by biopsy. PMID- 29992402 TI - [Normal tissue: radiosensitivity, toxicity, consequences for planning]. AB - Along with chemotherapy, surgery and immunotherapy, radiotherapy is a mainstay of cancer treatment. Considering the improving survival rates for various malignancies during the past decades, the importance of radiation-induced late normal tissue response is increasing. Quality of life is becoming an important issue in modern cancer treatment and is correlated with acute and late normal tissue response after radiotherapy. A profound understanding of radiation-induced normal tissue response is necessary to sufficiently diagnose and treat radiation induced side effects and thereby increase the patients' quality of life. Here, the various normal tissue responses in consideration of the radiation biology are specified and prospective options to attenuate radiation-induced side effects are discussed. PMID- 29992403 TI - Preparation of Folic Acid-Targeted Temperature-Sensitive Magnetoliposomes and their Antitumor Effects In Vitro and In Vivo. AB - BACKGROUND: Ovarian cancer is a common gynecologic malignancy with poor prognosis, requiring innovative new therapeutic strategies. Temperature controlled drug delivery to cancer cells represents a novel, promising, targeted treatment approach. OBJECTIVE: We prepared folate receptor-targeted thermosensitive liposomes wrapped with the HSP90 inhibitor 17-AAG and superparamagnetic material (17-AAG/MTSLs-FA), and tested the efficacy of these targeted magnetoliposomes in vitro and in vivo. METHODS: Magnetic thermosensitive liposomes wrapped with 17-AAG were coprecipitated with Fe3O4 magnetic nanoparticles and prepared by a rotary evaporation method. Experiments were conducted with SKOV3 human ovarian cancer cells and MCF7 human breast carcinoma cells to evaluate the anti-tumor effects. RESULTS: 17-AAG/MTSLs-FA prepared in this study met the basic requirements for therapeutic application. The preparation method is relatively simple and the raw materials are readily available. The product exhibited strong magnetism, high encapsulation efficiencies, and satisfactory performance. The liposomes combined with hyperthermia significantly inhibited the proliferation of SKOV3 cells and induced apoptosis. Experiments using a mouse subcutaneous model as well as an ascites tumor xenograft model indicated that 17-AAG/MTSLs-FA was stable in vivo and effectively targeted tumor tissues expressing the folate receptor. CONCLUSIONS: Folic acid-conjugated 17-AAG magnetic thermosensitive liposomes in combination with an alternating magnetic field for heating can achieve a synergistic anti tumor effect of chemotherapy and heat treatment, potentially offering a new method for ovarian cancer treatment. PMID- 29992404 TI - Minimally invasive interval cytoreductive surgery in ovarian cancer: systematic review and meta-analysis. AB - The introduction of minimally invasive surgery in other gynecologic cancers has shown benefits with similar oncologic outcomes. However, the biology and complexity of surgery for ovarian cancer may preclude this approach for ovarian cancer patients. Our objective is to assess feasibility to achieve complete cytoreductive surgery after neoadjuvant chemotherapy for stage IIIC-IV ovarian cancer patients via minimally invasive surgery. Our data sources include PubMed, Embase, Scopus, Biosis, Clinicaltrials.gov, and the Cochrane Library. Meta analysis was performed using the random-effects model with DerSimonian and Laird estimator for the amount of heterogeneity to estimate the pooled outcomes. A funnel plot and Egger's regression test were used to test publication bias. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. There were 6 studies (3 prospective, 3 retrospective) that met the criteria for meta-analysis with a total of 3231 patients, 567 were in the minimally invasive group and 2664 in the laparotomy group. Both groups were similar in stage and serous histology. Complete cytoreductive surgery was achieved in 74.50% (95% CI 40.41-97.65%) and 53.10% (95% CI 4.88-97.75%) of patients in the minimally invasive and laparotomy groups, respectively. There was no statistical significant difference between these 2 pooled proportions (p = 0.52). Three studies compared minimally invasive surgery vs laparotomy. No significant difference was observed between the 2 groups in obtaining complete cytoreductive surgery [OR = 0.90 (95% CI 0.70-1.16; p = 0.43)]. A symmetrical funnel plot indicated no publication bias. The pooled proportion for grade > 2 postoperative complications was not significant among the laparoscopy group [3.11% (95% CI 0.00-10.24%; p = 0.15)]. Complete cytoreductive surgery appears feasible and safe with minimally invasive surgery in selected advanced ovarian cancer patients after neoadjuvant chemotherapy. PMID- 29992405 TI - Non-contact mapping in cardiac electrophysiology. AB - Catheter ablation of atrial and ventricular arrhythmias is now considered a standard technology for selected patients. In some patients, however, cure of the arrhythmia is hampered by the complexity of the arrhythmia or the way the arrhythmia presents in the electrophysiological laboratory: some focal atrial and ventricular arrhythmias are difficult to induce using electrical stimulation or medical provocation. Precise mapping of these arrhythmias is challenging or even impossible by contact mapping, while other arrhythmias are poorly tolerated and need early termination.In these scenarios, use of non-contact mapping technology can be an alternative to conventional mapping, since isopotential maps may require no more than one ectopic beat identical with the clinical focal arrhythmia to reconstruct its endocardial origin. This review article presents the technology of non-contact cardiac mapping, as well as various arrhythmias that have been successfully treated using this technology in the past. The possibilities and limitations of using non-contact cardiac mapping under various conditions are also presented. PMID- 29992406 TI - Hydrothermal and plasma nitrided electrospun carbon nanofibers for amperometric sensing of hydrogen peroxide. AB - Nitrogen-doped carbon nanofibers (CNFs) were prepared by an electrospinning method, this followed by a hydrothermal reaction or nitrogen plasma treatment to obtain electrode for non-enzymatic amperometric sensing of H2O2. The hydrothermally treated electrode performs better. Its electrochemical surface is 3.7 * 10-3 mA cm-2, which is larger than that of a nitrogen plasma treated electrode (8.9 * 10-4) or a non-doped CNF (2.45 * 10-4 mA cm-2). The hydrothermally treated CNF with rough surface and a complex profile with doped N has a higher sensitivity (357 MUA?mM-1?cm-2), a lower detection limit (0.62 MUM), and a wider linear range (0.01-0.71 mM) than N-CNFP at a working potential of 0.4 V (vs. Ag/AgCl). The electrode gave high recoveries when applied to the analysis of milk samples spiked with H2O2. Graphical abstract Nitrogen-doped carbon nanofibers prepared by an electrospinning method followed by a hydrothermal reaction (N-CNFht) or nitrogen plasma treatment (N-CNFP) are directly used as non-enzymatic amperometric H2O2 sensors. PMID- 29992407 TI - [Disseminated linear and irregular pigmentation of the skin]. PMID- 29992408 TI - Preprocessing pupil size data: Guidelines and code. AB - Pupillometry has been one of the most widely used response systems in psychophysiology. Changes in pupil size can reflect diverse cognitive and emotional states, ranging from arousal, interest and effort to social decisions, but they are also widely used in clinical practice to assess patients' brain functioning. As a result, research involving pupil size measurements has been reported in practically all psychology, psychiatry, and psychophysiological research journals, and now it has found its way into the primatology literature as well as into more practical applications, such as using pupil size as a measure of fatigue or a safety index during driving. The different systems used for recording pupil size are almost as variable as its applications, and all yield, as with many measurement techniques, a substantial amount of noise in addition to the real pupillometry data. Before analyzing pupil size, it is therefore of crucial importance first to detect this noise and deal with it appropriately, even prior to (if need be) resampling and baseline-correcting the data. In this article we first provide a short review of the literature on pupil size measurements, then we highlight the most important sources of noise and show how these can be detected. Finally, we provide step-by-step guidelines that will help those interested in pupil size to preprocess their data correctly. These guidelines are accompanied by an open source MATLAB script (available at https://github.com/ElioS-S/pupil-size ). Given that pupil diameter is easily measured by standard eyetracking technologies and can provide fundamental insights into cognitive and emotional processes, it is hoped that this article will further motivate scholars from different disciplines to study pupil size. PMID- 29992409 TI - Restoring Axonal Function with 4-Aminopyridine: Clinical Efficacy in Multiple Sclerosis and Beyond. AB - The oral potassium channel blocker 4-aminopyridine has been used in various neurological conditions for decades. Numerous case reports and studies have supported its clinical efficacy in ameliorating the clinical presentation of certain neurological disorders. However, its short half-life, erratic drug levels, and safety-related dose restrictions limited its use as a self-compounded drug in clinical practice. This changed with the introduction of a prolonged release formulation, which was successfully tested in patients with multiple sclerosis. It was fully approved by the US FDA in January 2010 but initially received only conditional approval from the European Medicines Agency (EMA) in July 2011. After additional clinical studies, this conditional approval was changed to unrestricted approval in August 2017. This article reviews and discusses these recent studies and places aminopyridines and their clinical utility into the context of a broader spectrum of neurological disorders, where clinical efficacy has been suggested. In 2010, prolonged-release 4-aminopyridine became the first drug specifically licensed to improve walking in patients with multiple sclerosis. About one-third of patients across disease courses benefit from this treatment. In addition, various reports indicate clinical efficacy beyond multiple sclerosis, which may broaden its use in clinical practice. PMID- 29992410 TI - Cancer initiation and progression within the cancer microenvironment. AB - Within the cancer microenvironment, the growth and proliferation of cancer cells in the primary site as well as in the metastatic site represent a global biological phenomenon. To understand the growth, proliferation and progression of cancer either by local expansion and/or metastasis, it is important to understand the cancer microenvironment and host response to cancer growth. Melanoma is an excellent model to study the interaction of cancer initiation and growth in relationship to its microenvironment. Social evolution with cooperative cellular groups within an organism is what gives rise to multicellularity in the first place. Cancer cells evolve to exploit their cellular environment. The foundations of multicellular cooperation break down in cancer because those cells that misbehave have an evolutionary advantage over their normally behaving neighbors. It is important to classify evolutionary and ecological aspects of cancer growth, thus, data for cancer growth and outcomes need to be collected to define these parameters so that accurate predictions of how cancer cells may proliferate and metastasize can be developed. PMID- 29992411 TI - Aggregate and disaggregate analysis on energy consumption and economic growth nexus in China. AB - This study examines the relationship between energy consumption and economic growth based on three models in China covering the period of 1982-2015. From the Ng-Perron (NP) and Zivot-Andrews (ZA) unit root test, each variable has no unit root in the first difference. Based on Johansen multivariable co-integration test and autoregressive distributed lag (ARDL) bounds test, the co-integrating relationship existed between selected variables. Moreover, dynamic ordinary least squares (DOLS), fully modified ordinary least squares (FMOLS), and ARDL estimates are used to estimate the coefficients of each variable, which presents that any increasing of each kinds of energy sources can increase China's economic growth in the long term. Additionally, the vector error correction model (VECM) Granger causality test based on three models is investigated. Some implications based on the empirical results are given. PMID- 29992412 TI - Responses of magnetic properties to heavy metal pollution recorded by lacustrine sediments from the Lugu Lake, Southwest China. AB - Environmental magnetism, which is rapid, sensitive, economical, and non destructive, has been used to assess heavy metal pollution in lake sediments based on the relationships between magnetic properties and heavy metal concentrations. We conducted a systematic environmental magnetic and heavy metal study of the sediments of the core LGS from Lugu Lake in Southwest China. The results show that the concentration-related magnetic parameters (chi, chiARM, and SIRM) in the core LGS showed an increasing trend from bottom to top. The results of rock magnetism indicated that the dominant magnetic particles were magnetite. Two sources of magnetic minerals can be distinguished by the correlations of chi vs. chifd% and chi vs. chiARM/chi: the surrounding catchment and anthropogenic activities. In addition, Pearson correlation analysis and principal component analysis showed that the concentration-dependent magnetic parameters have significant correlations with heavy metal (Al, Ti, Fe, Cr, Ni, Cu, Zn, and Cd) concentrations as well as the Tomlinson pollution load index (PLI), indicating that there are essential linkages of sources, deposition, and migration between magnetic particles and heavy metals. Based on previously reported 137Cs and 210Pb data, the historical trends of heavy metal pollution in Lugu Lake were successfully reconstructed, and the causes of heavy metal pollution were mainly agricultural practices and atmospheric metal depositions from anthropogenic sources. The significant correlations between magnetic parameters, heavy metals, and the PLI indicate that magnetic parameters can potentially be used as an index of heavy metal pollution in lacustrine deposits. PMID- 29992413 TI - Enhancing bacterial transport with saponins in saturated porous media for the bioaugmentation of groundwater: visual investigation and surface interactions. AB - The success of bioaugmentation processes for the remediation of groundwater contamination relies on effective transport of the injected microorganisms in a subsurface environment. Biosurfactants potentially affect bacterial attachment and transport behavior in porous media. Although saponins as biosurfactants are abundant in nature, their influence on bacterial transport in groundwater systems remains unknown. In this research, tank visual-transport experiments, breakthrough curve monitoring, and surface property measurement were performed to evaluate the effects of saponins on the transport of Pseudomonas migulae AN-1 cells, which were used as a model bacterium in saturated sand. Results show that the 0.1% saponins could effectively facilitated the AN-1 secondary transport and the addition of saponins decreased the hydrophobicity of AN-1 and sand. The role of the promotion of saponins was more dominant than that of the inhibition of ions on AN-1 transport in a saturated porous medium when ions and saponins coexisted. The interactions between AN-1 and sand grains with saponins and ions were explained in accordance with the Derjaguin-Landau-Verwey-Overbeek theory. PMID- 29992414 TI - Bio-cord plays a similar role as submerged macrophytes in harboring bacterial assemblages in an eco-ditch. AB - Artificial carriers are widely used to enhance the formation of biofilm and improve pollutants' removal efficiency in agricultural wastewater treatment ditches (eco-ditches), yet comprehensive insight into their bacterial community is scarce. In this study, bacterial diversities in four different habitats-the water column, surface sediments, submerged macrophytes (Myriophyllum verticillatum L.), and the artificial carriers (bio-cord)-were compared in a Chinese eco-ditch. Comparable richness and evenness of bacterial communities were observed on M. verticillatum and bio-cord, both being higher than for free-living bacteria in the water column but lower than for bacteria in the surface sediment. The highest similarity of bacterial community composition and structure also occurred between M. verticillatum and the bio-cord, dominated by alpha- and gamma proteobacteria, Verrucomicrobia, and Bacteroidetes. Firmicutes and Planctomycetes, respectively, were the exclusive abundant phyla in M. verticillatum and the bio-cord, probably indicating the unique interaction between M. verticillatum and their epiphytic bacteria. Some abundant genera, such as Roseomonas, Pseudomonas, and Rhodopirellula, which were exclusively observed in M. verticillatum or the bio-cord, have been reported to have the same capacity to remove nitrogen and organic matter in wastewater treatment systems. In conclusion, in the studied eco-ditch, the bio-cord was found to play a similar role as submerged macrophytes in harboring bacterial assemblages, and we therefore propose that bio-cord may be a good alternative or supplement to enhance wastewater treatment in agricultural ditches. PMID- 29992415 TI - Production, characterization, and potential of activated biochar as adsorbent for phenolic compounds from leachates in a lumber industry site. AB - There is growing interest in low-cost, efficient materials for the removal of organic contaminants in municipal and industrial effluents. In this study, the efficiency of biochar and activated biochar, as promising adsorbents for phenol removal, was investigated at high (up to 1500 mg L-1) and low concentrations (0.54 mg L-1) in synthetic and real effluents (from wood-residue deposits in Quebec), respectively. The performance of both materials was then evaluated in batch adsorption experiments, which were conducted using a low solid/liquid ratio (0.1 g:100 mL) at different phenol concentrations (C0 = 5-1500 mg L-1), and at 20 degrees C. Activated biochars presented higher phenol adsorption capacity compared to biochars due to their improved textural properties, higher micropore volume, and proportion of oxygenated carbonyl groups connected to their surface. The sorption equilibrium was reached within less than 4 h for all of materials, while the Langmuir model best described their sorption process. The maximum sorption capacity of activated biochars for phenol was found to be twofold relative to biochars (303 vs. 159 mg g-1). Results also showed that activated biochars were more effective than biochars in removing low phenol concentrations in real effluents. In addition, 95% of phenol removal was attained within 96 h (although 85% was removed after 4 h), thus reaching below the maximum authorized concentration allowed by Quebec's discharge criteria (0.05 mg L-1). These results show that activated biochars made from wood residues are promising potential adsorbent materials for the efficient treatment of phenol in synthetic and real effluents. PMID- 29992416 TI - Individual specialization in a migratory grazer reflects long-term diet selectivity on a foraging ground: implications for isotope-based tracking. AB - Stable isotope analysis (SIA) can be a useful tool for tracking the long-distance movements of migratory taxa. However, local-scale sources of isotopic variation, such as differences in habitat use or foraging patterns, may complicate these efforts. Few studies have evaluated the implications of local-scale foraging specializations for broad-scale isotope-based tracking. Here, we use > 300 h of animal-borne video footage from green turtles (Chelonia mydas) paired with SIA of multiple tissues, as well as fine-scale Fastloc-GPS satellite tracking, to show that dietary specialization at a single foraging location (Shark Bay, Western Australia) drives a high level of among-individual delta13C variability (delta13C range = 13.20/00). Green turtles in Shark Bay were highly omnivorous and fed selectively, with individuals specializing on different mixtures of seagrasses, macroalgae and invertebrates. Furthermore, green turtle skin delta13C and delta15N dispersion within this feeding area (total isotopic niche area = 41.6) was comparable to that from a well-studied rookery at Tortuguero, Costa Rica, where isotopic dispersion (total isotopic niche area = 44.9) is known to result from large-scale (> 1500 km) differences in foraging site selection. Thus, we provide an important reminder that two different behavioral dynamics, operating at very different spatial scales, can produce similar levels of isotopic variability. We urge an added degree of caution when interpreting isotope data for migratory species with complex foraging strategies. For green turtles specifically, a greater appreciation of trophic complexity is needed to better understand functional roles, resilience to natural and anthropogenic disturbances, and to improve management strategies. PMID- 29992417 TI - Antithrombotic Activity of Brewers' Spent Grain Peptides and their Effects on Blood Coagulation Pathways. AB - Antithrombotic activity of brewers' spent grain peptides before and after simulated gastrointestinal digestion and their effects on blood coagulation pathways were evaluated. Two hydrolysates were produced using sequential enzymatic systems: alkaline protease + Flavourzyme (AF) and neutral protease + Flavourzyme (PF). Simulation of gastrointestinal digestion of AF and PF hydrolysates was made using porcine pepsin and pancreatin enzymes, obtaining the corresponding digested samples: AFD and PFD, respectively. Peptides were fractionated by ultrafiltration using a 1 kDa cut-off membrane. Hydrolysates had peptides with medium and low molecular weights (2100 and 500 Da, respectively), and Glu, Asp, Leu, Ala, and Phe were the most abundant amino acids. Gastrointestinal digested hydrolysates presented high proportion of small peptides (~500 Da), and higher amount of Val, Tyr, and Phe than hydrolysates. Mass spectrum (HDMS Q-TOF) of AFD-ultrafiltered fraction <1 kDa exhibited peptides from 500 to 1000 Da, which are not present in AF. PFD showed the generation of new peptides from 430 to 1070 Da. All samples showed thrombin inhibitory activity. However, no effect was observed on prothrombin time. Peptides <1 kDa from hydrolysates and digested samples delayed thrombin and thromboplastin time respect to the control (~63%). Also the samples showed thrombin inhibitory activity at common pathway level. Thus, brewers' spent grain peptides exerted their antithrombotic activity by inhibiting the intrinsic and common pathways of blood coagulation. This is the first report to demonstrate that brewers' spent grain peptides are able to delay clotting time after simulated gastrointestinal digestion. PMID- 29992418 TI - Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival. AB - PURPOSE: The purpose of the study was to define quantitative measures of intra tumor heterogeneity in breast cancer based on histopathology data gathered from multiple samples on individual patients and determine their association with distant recurrence-free survival (DRFS). METHODS: We collected data from 971 invasive breast cancers, from 1st January 2000 to 23rd March 2014, that underwent repeat tumor sampling at our institution. We defined and calculated 31 measures of intra-tumor heterogeneity including ER, PR, and HER2 immunohistochemistry (IHC), proliferation, EGFR IHC, grade, and histology. For each heterogeneity measure, Cox proportional hazards models were used to determine whether patients with heterogeneous disease had different distant recurrence-free survival (DRFS) than those with homogeneous disease. RESULTS: The presence of heterogeneity in ER percentage staining was prognostic of reduced DRFS with a hazard ratio of 4.26 (95% CI 2.22-8.18, p < 0.00002). It remained significant after controlling for the ER status itself (p < 0.00062) and for patients that had chemotherapy (p < 0.00032). Most of the heterogeneity measures did not show any association with DRFS despite the considerable sample size. CONCLUSIONS: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk. PMID- 29992420 TI - Is It a Single Anastomosis Gastric Bypass or Is It a Single Anastomosis Biliopancreatic Diversion? PMID- 29992421 TI - Smarter through group living? AB - Wild Australian magpies living (or growing up) in larger social groups take fewer trials to solve a battery of four cognitive tests than those living (or growing up) in smaller groups. The tests all draw on a common underlying factor, but is this factor cognitive or motivational? PMID- 29992419 TI - A mouse model of the Delta133p53 isoform: roles in cancer progression and inflammation. AB - This review paper outlines studies on the Delta122p53 mouse, a model of the human Delta133p53 isoform, together with studies in other model organisms, cell culture, and where available, clinical investigations. In general, these studies imply that, in contrast to the canonical p53 tumor suppressor, Delta133p53 family members have oncogenic capability. Delta122p53 is multi-functional, conferring survival and proliferative advantages on cells, promoting invasion, metastasis and vascularization, as does Delta133p53. Cancers with high levels of Delta133p53 often have poor prognosis. Delta122p53 mediates its effects through the JAK-STAT and RhoA-ROCK signaling pathways. We propose that Delta133p53 isoforms have evolved as inflammatory signaling molecules to deal with the consequent tissue damage of p53 activation. However, if sustained expression of the isoforms occur, pathologies may result. PMID- 29992424 TI - Atypical Pressure Ulcer as Cellulitis Mimic. PMID- 29992422 TI - An Overview of Clinical Outcomes in Transvenous and Subcutaneous ICD Patients. AB - PURPOSE OF REVIEW: Clear guidelines on when to select a subcutaneous ICD (S-ICD) over a transvenous ICD (TV-ICD) are lacking. This review will provide an overview of the most recent clinical data on S-ICD and TV-ICD therapy by pooling comparison studies in order to aid clinical decision making. RECENT FINDINGS: Pooling of observational-matched studies demonstrated an incidence rate ratio (IRR) for device-related complication of 0.90 (95% CI 0.58-1.42) and IRR for lead related complications of 0.15 (95% CI 0.06-0.39) in favor of S-ICD. The IRR for device infections was 2.00 (95% CI 0.95-4.22) in favor of TV-ICD. Both appropriate shocks (IRR 0.67 (95% CI 0.42-1.06)) and inappropriate shocks (IRR 1.17 (95% CI 0.77-1.79)) did not differ significantly between both groups. With randomized data underway, the observational data demonstrate that the S-ICD is associated with reduced lead complications, but this has not yet resulted in a significant reduction in total number of complications compared to TV-ICDs. New technologies are expected to make the S-ICD a more attractive alternative. PMID- 29992423 TI - Prevalence of Behavioral Health Conditions Across Frequency of Cannabis Use Among Adult Primary Care Patients in Washington State. PMID- 29992425 TI - Increasing Resident Participation in Research: Capitalizing on Local Resources to Maximize Success. PMID- 29992426 TI - Capsule Commentary on Goto et al.'s Incidence of Acute Cardiovascular Event After Acute Exacerbation of COPD. PMID- 29992427 TI - Patient Perspectives on Clinical Scribes in Primary Care. PMID- 29992428 TI - "It's like a mirror image of my illness": Exploring Patient Perceptions About Illness Using Health Mind Mapping-a Qualitative Study. AB - BACKGROUND: A patient's self-management of chronic disease is influenced in part by their explanatory model of illness (EMI) and daily lived experiences (DLE). Unfortunately, assessing patient's EMI and using this information to engage patients in chronic illness self-management continues to be a challenge. OBJECTIVE: "Health mind mapping" (HMM) is a novel process that captures a patient's EMI and DLE through the use of a graphic representation of ideas. We aimed to explore patient's experiences using HMM. DESIGN: Qualitative study utilizing semi-structured interviews. PARTICIPANTS: Adult patients with uncontrolled type 2 diabetes from a primary care clinic. APPROACH: A facilitator guided 20 participants through the process of developing a health mind map. Subsequently, each participant completed a semi-structured interview about their experience with the process and perceptions about how their maps could be used. The process and interviews were video and audio recorded. We conducted a content analysis of the maps and a thematic analysis, using an inductive approach, of the interview data. RESULTS: Participants explored a wide range of EMs and DLEs in their HMM process. Participants reported that the HMM process (1) helped to develop insight about self and illness; (2) was a catalyst for wanting to take actions to improve illness; and (3) represented an opportunity to actively share illness experiences. They reported potential uses of the map: (1) to communicate about their illness to others in their social network; (2) to communicate about their illness to providers; (3) to help others with diabetes manage their illness; and (4) to encourage ongoing engagement in diabetes self-care. CONCLUSIONS: Participants reported that HMM helped them develop new insight about their illness and was a catalyst for encouraging them to take control of their illness. HMM has the potential to facilitate communication with providers and engage patients in collaborative goal setting to improve self-care in chronic illness. PMID- 29992429 TI - Heart Failure Home Management Challenges and Reasons for Readmission: a Qualitative Study to Understand the Patient's Perspective. AB - BACKGROUND: Heart failure patients have high 30-day hospital readmission rates. Interventions designed to prevent readmissions have had mixed success. Understanding heart failure home management through the patient's experience may reframe the readmission "problem" and, ultimately, inform alternative strategies. OBJECTIVE: To understand patient and caregiver challenges to heart failure home management and perceived reasons for readmission. DESIGN: Observational qualitative study. PARTICIPANTS: Heart failure patients were recruited from two hospitals and included those who were hospitalized for heart failure at least twice within 30 days and those who had been recently discharged after their first heart failure admission. APPROACH: Open-ended, semi-structured interviews. Conclusions vetted using focus groups. KEY RESULTS: Semi-structured interviews with 31 patients revealed a combination of physical and socio-emotional influences on patients' home heart failure management. Major themes identified were home management as a struggle between adherence and adaptation, and hospital readmission as a rational choice in response to distressing symptoms. Patients identified uncertainty regarding recommendations, caused by unclear instructions and temporal incongruence between behavior and symptom onset. This uncertainty impaired their competence in making routine management decisions, resulting in a cycle of limit testing and decreasing adherence. Patients reported experiencing hopelessness and frustration in response to perceiving a deteriorating functional status. This led some to a cycle of despair characterized by worsening adherence and negative emotions. As these cycles progressed and distressing symptoms worsened, patients viewed the hospital as the safest place for recovery and not a "negative" outcome. CONCLUSION: Cycles of limit testing and despair represent important patient-centered struggles in managing heart failure. The resulting distress and fear make readmission a rational choice for patients rather than a negative outcome. Interventions (e.g., palliative care) that focus on methods to address these patient-centered factors should be further studied rather than methods to reduce hospital readmissions. PMID- 29992430 TI - Why Do Medical Professional Regulators Dismiss Most Complaints From Members of the Public? Regulatory Illiteracy, Epistemic Injustice, and Symbolic Power. AB - Drawing on an analysis of complaint files that we conducted for the Irish Medical Council (Madden and O'Donovan 2015), this paper offers three possible explanations for the gap between the ubiquity of official commitments to taking patients' complaints seriously and medical professional regulators' dismissal-as not warranting an inquiry-of the vast majority of complaints submitted by members of the public. One explanation points to the "regulatory illiteracy" of many complainants, where the remit and threshold of seriousness of regulators is poorly understood by the general public. Another points to possible processes of "institutional epistemic injustice" (Fricker 2007; Anderson 2012) that unjustly undermine the credibility of certain complainants, such as those with low levels of formal education. A third explanation highlights the marginalization of the general public from "symbolic power" (Bourdieu 1989) to define what matters in medical professional regulation. The paper is offered in a spirit of ideas in progress and raising questions rather than definitive insights into the regulatory process. PMID- 29992431 TI - Influence of riociguat treatment on pulmonary arterial hypertension : A meta analysis of randomized controlled trials. AB - BACKGROUND: Riociguat treatment might be beneficial for pulmonary arterial hypertension. However, the results of studies to date are controversial. We conducted a systematic review and meta-analysis to explore the influence of riociguat treatment on pulmonary arterial hypertension. METHODS: The PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of riociguat treatment on pulmonary arterial hypertension were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. This meta-analysis was performed using the random effects model. RESULTS: Seven RCTs were included in the meta-analysis. Compared with a control intervention in pulmonary arterial hypertension, riociguat treatment was able to substantially improve results of the six-minute walking distance (6-MWD; standardized mean difference [SMD] = 0.53; 95% CI = 0.36-0.69; p < 0.00001), EQ 5D score (SMD = 0.35; 95% CI = 0.15-0.54; p = 0.0005), and cardiac index (SMD = 0.94; 95% CI = 0.59-1.29; p < 0.00001). The Living With Pulmonary Hypertension (LPH) score (SMD = -0.33; 95% CI = -0.50--0.17; p < 0.0001) and pulmonary vascular resistance (PVR; SMD = -0.88; 95% CI = -1.05--0.70; p < 0.00001) were significantly reduced after riociguat treatment. There was no increase in adverse events with riociguat treatment compared with the control intervention (RR = 1.04; 95% CI = 0.98-1.09; p = 0.19). CONCLUSION: Riociguat treatment for pulmonary arterial hypertension led to a significant increase in the 6-MWD, EQ-5D score, and cardiac index, as well as a decrease in LPH score and PVR. PMID- 29992432 TI - Effectiveness of Health Belief Model on Oral Cancer Prevention in Smoker Men. AB - The purpose of the present study is investigating the effect of educational intervention based on health belief model (HBM) on oral cancer prevention in smoker men. This is a quasi-experimental study carried out on 200 smoker men with the age of 40 or older (100 subjects for the experimental group and 100 subjects for control group) resident in Fasa City, Fars Province, Iran, in 2017-2018. The educational intervention for the experimental group included seven educational sessions for 50 or 55 min-based HBM. A questionnaire consisted of items about demographic information, knowledge, HBM constructs (perceived susceptibility, severity, benefits, barriers, self-efficacy, and cues to action) was used to measure the oral cancer prevention before and 6 months after the intervention. The mean age of the men was 51.35+/-8.41 years in the experimental group and 52.28+/-8.09 years in the control group. Based on the obtained results, significant enhancement is observed in average scores of knowledge, perceived susceptibility, severity, benefits, self-efficacy, cues to action, and oral cancer prevention behaviors in experimental group; however, no significant changes are observed in average scores of knowledge, perceived susceptibility, severity, benefits, self-efficacy, cues to action, and oral cancer prevention behaviors of control group. Also, results indicated that, the educational program based on HBM model have positive effect on oral cancer prevention with the improvement of subject's knowledge, perceived susceptibility, severity, benefits, and self-efficacy. PMID- 29992433 TI - Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging. AB - OBJECTIVE: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers. METHODS: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery. RESULTS: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI. CONCLUSION: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of <= 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET. IMPORTANCE OF THE STUDY: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies. PMID- 29992434 TI - Pineal region glioblastomas display features of diffuse midline and non-midline gliomas. AB - INTRODUCTION: Pineal region glioblastomas (GBM) are very rare, with approximately 46 cases described in the literature. The epidemiology, pathogenesis, and treatment of these lesions are poorly characterized. METHODS: We identified all cases of pineal region GBM treated surgically at our institution between 1990 and 2017. Demographic and clinical follow-up data were extracted from the medical records for all cases. Pathology was reviewed and classified according to 2016 World Health Organization (WHO) criteria. Specific attention was given to the frequency of histone H3 K27M mutations in these midline gliomas. RESULTS: Eight patients (seven men, one woman) with pineal region GBM, WHO grade IV, were identified. The most common presenting symptoms were headache (75%), vision changes (75%), and gait imbalance/ataxia (50%). Median age at diagnosis was 48.5 years (range 36-74 years). Radical subtotal resection, via a supracerebellar infratentorial approach, was achieved in 75% of patients. Review of the surgical pathology revealed seven primary GBMs (including one giant cell GBM) and one pineal region GBM that developed three years after resection of a pineal parenchymal tumor of intermediate differentiation. No cases demonstrated evidence of IDH-1 R132H mutation (N = 6) or 1p/19q co-deletion (N = 3). One case tested positive for the histone H3 K27M-mutation. Targeted exome sequencing of 467 cancer-related genes revealed nonsense mutations in ATRX and NF1. Adjuvant radiation and chemotherapy was employed in 87.5% and 75.0% of patients, respectively. Median overall survival (OS) was 15 months (range 2-24 months) from GBM diagnosis. CONCLUSIONS: This study expands the clinical and pathologic spectrum of pineal region GBM, and provides the first report of the genetic landscape of these tumors. PMID- 29992435 TI - Identification and characterisation of short chain rhamnolipid production in a previously uninvestigated, non-pathogenic marine pseudomonad. AB - This study aimed to identify and characterise biosurfactant compounds produced by bacteria associated with a marine eukaryotic phytoplankton bloom. One strain, designated MCTG214(3b1), was isolated by enrichment with polycyclic aromatic hydrocarbons and based on 16S rDNA, and gyrB sequencing was found to belong to the genus Pseudomonas, however not related to P. aeruginosa. Cell-free supernatant samples of strain MCTG214(3b1) at stationary phase showed significant reductions in surface tension. HPLC-MS and NMR analysis of these samples indicated the presence of five different rhamnolipid (RL) congeners. Di rhamnolipids accounted for 87% relative abundance and all congeners possessed fatty acid moieties consisting of 8-12 carbons. PCR screening of strain MCTG214(3b1) DNA revealed homologues to the P. aeruginosa RL synthesis genes rhlA and rhlB; however, no rhlC homologue was identified. Using the Galleria mellonella larvae model, strain MCTG214(3b1) was demonstrated to be far less pathogenic than P. aeruginosa. This study identifies for the first time a significantly high level of synthesis of short chain di-rhamnolipids by a non pathogenic marine Pseudomonas species. We postulate that RL synthesis in Pseudomonas sp. MCTG214(3b1) is carried out by enzymes expressed from rhlA/B homologues similar to those of P. aeruginosa; however, a lack of rhlC potentially indicates the presence of a second novel rhamnosyltransferase responsible for the di-rhamnolipid congeners identified by HPLC-MS. PMID- 29992436 TI - Degradation of plastics and plastic-degrading bacteria in cold marine habitats. AB - Synthetic plastics present in everyday materials constitute the main anthropogenic debris entering the Earth's oceans. The oceans provide important and valuable resources such as food, energy, and water. They are also the main way of international trade and the main stabilizer of the climate. Hence, changes in the marine ecosystem caused by anthropogenic influences such as plastic pollution can have a dramatic impact on a global scale. Although the problem of plastics still remains unsolved, different ways are being considered to reduce their impact on the environment. One of them is to use microorganisms capable of degradation of plastic. A particularly interesting area is the application of microorganisms isolated from cold regions in view of their unique characteristics. Nevertheless, the interactions between plastic and microorganisms are still poorly known. Here, we present a review of current knowledge on plastic degradation and plastic-microorganism interactions in cold marine habitats. Moreover, we highlight the advantages of microorganisms isolated from this environment for eliminating plastic waste from ecosystems. PMID- 29992437 TI - On learning in the clinical environment. AB - INTRODUCTION: The clinical environment has been increasingly acknowledged as an important setting for learning within healthcare professional education. In particular, researchers have highlighted the need to advance the knowledge on the social nature of learning in the workplace setting. The aim of the thesis was to explore workplace learning among undergraduate medical and nursing students. METHOD: The thesis adopted a socio-cultural perspective on learning and employed a qualitative approach embedded in an interpretative tradition of inquiry. Four consecutive studies were included in the thesis, the first one designed according to qualitative description whereas the other three had an ethnographic approach. Data were collected through individual interviews and field observations. Content analysis and thematic analysis were employed. RESULTS: For the medical students, workplace learning entailed access to a variety of activities in the role of a marginal member of the healthcare team. Medical students demonstrated an adaptive approach to workplace learning. For the nursing students, workplace learning involved being entrusted to hold responsibility for patient care and the need to negotiate their basic values with those of the workplaces. Nursing students showed a hesitant approach to workplace learning. DISCUSSION: Workplace learning was built upon varying theoretical perspectives of learning in the medical and nursing contexts respectively. The main message in the thesis argued for an upgrading of students as a powerful and active stakeholder in workplace learning, so as not to view students as passive consumers of clinical education. PMID- 29992438 TI - Applying four-component instructional design to develop a case presentation curriculum. AB - Medical students must gain proficiency with the complex skill of case presentations, yet current approaches to instruction are fragmented and often informal, resulting in suboptimal transfer of this skill into clinical practice. Whole task approaches to learning have been proposed to teach complex skill development. The authors describe a longitudinal case presentation curriculum developed using a whole task approach known as four-component instructional design (4-C/ID). 4-C/ID is based on cognitive psychology theory, and carefully attends to titrating a learner's cognitive load, aiming to always keep students in their zone of proximal development. A multi-institutional group of medical educators convened to develop expert consensus regarding case presentation instruction using the 4-C/ID model. A curriculum consisting of 1) learning tasks, 2) supportive information, 3) just-in-time information, and 4) part-task practice was developed. Domains were identified that make the task of delivering a case presentation complex. A simplifying conditions approach was applied to each domain to develop sequential task class descriptions. Examples of the four components are given to facilitate understanding of the 4-C/ID model, making it more accessible to medical educators. Applying 4-C/ID to curriculum development for the complex skill of case presentation delivery may optimize instruction. The provision of the complete curricular outline may facilitate transfer and implementation of this case presentation curriculum, as well as foster the application of 4-C/ID to other complex skill development in medical education. PMID- 29992439 TI - [Strangulation as scenic behavior. A case report of a pseudosuicide in the course of a NREM-parasomnia]. AB - It is generally accepted, that sleepwalkers show complex behaviors leading to non intended consequences. It is not unusual that these persons are thereby injured. However, sporadically a bizarre endangering of themselves or others is reported also, which ranges from homicide of the life partner to accidental (pseudo )suicide.In this article, we report on a 28year-old man who unexpectedly attempted to hang himself by a whip at night. We discuss the reasons, why this bizarre act should actually be taken as a scenic behavior in the course of a NREM parasomnia, and the difficulty to proof this claim. PMID- 29992440 TI - The efficacy of fascial granuloma excision with conjunctival autografting after pterygium surgery. AB - BACKGROUND AND OBJECTIVE: Pterygium has a high recurrence rate after simple excision, and fascial granuloma is one of the common complications of pterygium excision. This study aimed to investigate the treatment for the fascial granuloma. METHODS: In this study, the 36 eyes of 36 cases with fascial granuloma after pterygium excision were collected and divided into two groups to receive granuloma excision and conjunctival autografting or simple granuloma excision. The patients in the treatment group containing 20 cases received granuloma excision and conjunctival autografting, while the patients in the control group containing 16 cases received simple granuloma excision. RESULTS: The pathology examination results showed that all the removed granulomas were inflammatory granulation tissues that without bacterial infection. After 12 months' follow-up, there was no recurrence of fascia granuloma and pterygium in the treatment group, in which the cure rate was up to 100%. In the control group, 6 cases experienced a recurrence of the granuloma fascia 2~3 weeks after operation; after further granuloma excision and conjunctival autografting, pterygium recurred in 8 cases. CONCLUSION: The fascial granuloma excision with conjunctival autografting is effective and safe in treating fascial granuloma after pterygium surgery, which contributes to reducing the recurrence of pterygium. PMID- 29992441 TI - Osteochondritis dissecans shows a severe course and poor outcome in patients with juvenile idiopathic arthritis: a matched pair study of 22 cases. AB - Juvenile osteochondritis dissecans (JOCD) and juvenile idiopathic arthritis (JIA) are both common diseases which may affect joints and bony structures in pediatric patients. In some cases, JOCD and JIA occur at the same time. In this study, the course of JOCD in patients with JIA was therefore evaluated to provide possible recommendations for further treatment opportunities and control examinations. From 06/2012 to 03/2018 55 children with JOCD with or without JIA were examined. Inclusion criteria were: (1) age <= 16 years, (2) diagnosis of a JOCD with or without JIA and (3) two routine MRI controls. The JOCD evaluation based on the classification according to Bruns and the measurement of the largest extent via MRI. 18 of these 55 children met our criteria: 11 JOCD findings of 7 patients with JIA (group A) were matched according to age and localization of JOCD to 11 patients without JIA (group B). Mean age of disease onset of JIA was 8.2 years (oligo JIA) and of JOCD 11.6 years. The mean time follow-up was 17.7 months. At all observation time points more JOCD findings (with stage III degrees and IV degrees , respectively) along with a significant deterioration was seen in group A compared to group B. The comparison of the last MRI control between group A and group B shows a significant smaller defect size (decrease of 54.5%, p = 0.028) in group B (97.9 +/- 48.9 mm2) as in group A (185.1 +/- 102.9 mm2). In comparison of first (169.7 +/- 84.2 mm2) and last MRI (97.9 +/- 48.9 mm2) a significant decrease in lesion size of JOCD in group B was seen (decrease of 58.4%, p = 0.048). Patients with JIA show a more progressive and severe course of JOCD. Therefore, we recommend (1) the early use of MRI in patients with JIA and persistent joint pain to detect potential JOCD and (2) in presence of JIA and JOCD regular MRI follow-up controls to identify deteriorating JOCD findings and prevent early joint destruction in pediatric patients. PMID- 29992442 TI - A single-center retrospective study of onabotulinumtoxinA for treatment of 245 chronic migraine patients: survey results of a real-world experience. AB - Preventive treatment in migraine is associated with poor adherence and persistence. In this observational study, our first aim was to evaluate the perceived effectiveness of onabotulinumtoxinA based on our chronic migraine (CM) patients' treatment experience. The second purpose of this study was to determine the compliance with onabotulinumtoxinA treatment in our cohort. Third, we assessed the reasons for withdrawal from treatment in our CM patients. A total of 245 consecutive patients with CM (40.43 +/- 10.15 years; 214 females, 31 males) were treated with at least one onabotulinumtoxinA. Data were collected by a standardized interview over the telephone. One-hundred and eighty patients were willing to answer questions about: (1) perceived effectiveness of onabotulinumtoxinA based on their treatment experience; (2) the current continuity of the treatment; (3) their current migraine-related disability; and (4) their current medication usage. The mean number of onabotulinumtoxinA cycles of all patients and the participants were 2.58 and 2.90, respectively. Of the 180 participants, 149 patients (82.8%) thought that onabotulinumtoxinA was effective in controlling their headaches. The mean score for perceived effectiveness of onabotulinumtoxinA treatment given by the participants was as 6.94 +/- 2.4 (on a scale from 0 to 10). Of the 245 treated subjects, 31 (12.6%) were treated for 12 months. Compliance rates with onabotulinumtoxinA were very low in our population. However, even CM patients who did not complete five cycles of the treatment showed marked improvement of their current migraine-related disability and reduction of their medication intake as compared to baseline. PMID- 29992443 TI - Radiological Estimation of Intracranial Blood Volume and Occurrence of Hydrocephalus Determines Stress-Induced Hyperglycemia After Aneurysmal Subarachnoid Hemorrhage. AB - Acute phase after aneurysmal subarachnoid hemorrhage (aSAH) is associated with several metabolic derangements including stress-induced hyperglycemia (SIH). The present study is designed to identify objective radiological determinants for SIH to better understand its contributory role in clinical outcomes after aSAH. A computer-aided detection tool was used to segment admission computed tomography (CT) images of aSAH patients to estimate intracranial blood and cerebrospinal fluid volumes. Modified Graeb score (mGS) was used as a semi-quantitative measure to estimate degree of hydrocephalus. The relationship between glycemic gap (GG) determined SIH, mGS, and estimated intracranial blood and cerebrospinal fluid volumes were evaluated using linear regression. Ninety-four [94/187 (50.3%)] among the study cohort had SIH (defined as GG > 26.7 mg/dl). Patients with SIH had 14.3 ml/1000 ml more intracranial blood volume as compared to those without SIH [39.6 ml (95% confidence interval, CI, 33.6 to 45.5) vs. 25.3 ml (95% CI 20.6 to 29.9), p = 0.0002]. Linear regression analysis of mGS with GG showed each unit increase in mGS resulted in 1.2 mg/dl increase in GG [p = 0.002]. Patients with SIH had higher mGS [median 4.0, interquartile range, IQR 2.0-7.0] as compared to those without SIH [median 2.0, IQR 0.0-6.0], p = 0.002. Patients with third ventricular blood on admission CT scan were more likely to develop SIH [67/118 (56.8%) vs. 27/69 (39.1%), p = 0.023]. Hence, the present study, using unbiased SIH definition and objective CT scan parameters, reports "dose-dependent" radiological features resulting in SIH. Such findings allude to a brain injury stress response-neuroendocrine axis in etiopathogenesis of SIH. PMID- 29992444 TI - Implementation of the Amsterdam Pediatric Wrist Rules. AB - BACKGROUND: The Amsterdam Pediatric Wrist Rules have been developed and validated to reduce wrist radiographs following wrist trauma in pediatric patients. However, the actual impact should be evaluated in an implementation study. OBJECTIVE: To evaluate the effect of implementation of the Amsterdam Pediatric Wrist Rules at the emergency department. MATERIALS AND METHODS: A before-and after comparative prospective cohort study was conducted, including all consecutive patients aged 3 to 18 years presenting at the emergency department with acute wrist trauma. The primary outcome was the difference in the number of wrist radiographs before and after implementation. Secondary outcomes were the number of clinically relevant missed fractures of the distal forearm, the difference in length of stay at the emergency department and physician compliance with the Amsterdam Pediatric Wrist Rules. RESULTS: A total of 408 patients were included. The absolute reduction in radiographs was 19% compared to before implementation (chi-square test, P<0.001). Non-fracture patients who were discharged without a wrist radiograph had a 26-min shorter stay at the emergency department compared to patients who received a wrist radiograph (68 min vs. 94 min; Mann-Whitney U test, P=0.004). Eight fractures were missed following the recommendation of the Amsterdam Pediatric Wrist Rules. However, only four of them were clinically relevant. CONCLUSION: Implementing the Amsterdam Pediatric Wrist Rules resulted in a significant reduction in wrist radiographs and time spent at the emergency department. The Amsterdam Pediatric Wrist Rules were able to correctly identify 98% of all clinically relevant distal forearm fractures. PMID- 29992445 TI - ITIH3 and ITIH4 polymorphisms and depressive symptoms during pregnancy in Japan: the Kyushu Okinawa Maternal and Child Health Study. AB - ITIH3 and ITIH4 are involved in the stabilization of the extracellular matrix. Several genome-wide association studies and case-control studies regarding psychiatric disorders have identified ITIH3 and ITIH4 single nucleotide polymorphisms (SNPs). The present case-control study examined the relationship between ITIH3 SNPs rs2535629 and rs736408 and ITIH4 SNPs rs3821831 and rs2239547 and depressive symptoms during pregnancy in Japan. Cases comprised 273 women with depressive symptoms during pregnancy defined as a Center for Epidemiological Studies Depression Scale (CES-D) score >= 16. Control subjects comprised 1176 women without depressive symptoms during pregnancy, according to the CES-D criteria, who had not been diagnosed with depression by a doctor. Adjustment was made for age, gestation at baseline, region of residence, the presence of children, family structure, smoking, employment, and education. Compared with the TT genotype of ITIH4 SNP rs2239547, the CC genotype was significantly related to a reduced risk of depressive symptoms during pregnancy: the adjusted odds ratio (95% CI) was 0.84 (0.63-1.11) for the TC genotype and 0.57 (0.36-0.91) for the CC genotype. ITIH3 SNPs rs2535629 and rs736408 and ITIH4 SNP rs3821831 were not related to depressive symptoms during pregnancy. The GCCT haplotype of rs2535629, rs736408, rs3821831, and rs2239547 was significantly positively associated with depressive symptoms during pregnancy. A significant interaction was found between rs2239547 and the presence of children. This is the first study to show significant associations of ITIH4 SNP rs2239547 and the GCCT haplotype with depressive symptoms during pregnancy. The effect of the presence of children might depend on rs2239547. PMID- 29992446 TI - Rhodococcus bacteria as a promising source of oils from olive mill wastes. AB - The accumulation of triacylglycerols (TAG) is a common feature among actinobacteria belonging to Rhodococcus genus. Some rhodococcal species are able to produce significant amounts of those lipids from different single substrates, such as glucose, gluconate or hexadecane. In this study we analyzed the ability of different species to produce lipids from olive oil mill wastes (OMW), and the possibility to enhance lipid production by genetic engineering. OMW base medium prepared from alperujo, which exhibited high values of chemical oxygen demand (127,000 mg/l) and C/N ratio (508), supported good growth and TAG production by some rhodococci. R. opacus, R. wratislaviensis and R. jostii were more efficient at producing cell biomass (2.2-2.7 g/l) and lipids (77-83% of CDW, 1.8-2.2 g/l) from OMW than R. fascians, R. erythropolis and R. equi (1.1-1.6 g/l of cell biomass and 7.1-14.0% of CDW, 0.1-0.2 g/l of lipids). Overexpression of a gene coding for a fatty acid importer in R. jostii RHA1 promoted an increase of 2.2 fold of cellular biomass value with a concomitant increase in lipids production during cultivation of cells in OMW. This study demonstrates that the bioconversion of OMW to microbial lipids is feasible using more robust rhodococal strains. The efficiency of this bioconversion can be significantly enhanced by engineering strategies. PMID- 29992448 TI - Lumbar lordosis does not correlate with pelvic incidence in the cases with the lordosis apex located at L3 or above. AB - PURPOSE: To test the hypothesis that the relationship between PI and L1-S1 lumbar lordosis (LL) is always positive, even in cases with different lumbar sagittal profiles. METHODS: Standing whole-spine sagittal alignment was measured with EOS system in 100 healthy adults (46 men, 54 women, mean age 40.9 years). The apex of lumbar lordosis was defined as the most anterior lumbar vertebra or intervertebral disk from the gravity line determined by a force plate measurement. Subjects were stratified into three groups: the upper group with an apex between L1 and L3 (UppA, n = 19), the middle group with an apex from L3/4 to L4/5 (MidA, n = 67), and the lower group with an apex at L5 or below (LowA, n = 14). PI, PT, SS, thoracic kyphosis (TK), LL, SVA, T1 pelvic angle, and knee flexion angle were compared between the groups. The correlation between LL and PI in each group was also compared. RESULTS: PI and SS differed significantly between the three groups, and LL was significantly different between LowA and MidA and UppA. TK and KF did not differ significantly between groups. LL and PI were significantly positively correlated in the MidA and LowA groups, but not in the UppA group. CONCLUSION: Contrary to the hypothesis, the correlation coefficient between PI and LL was not significant in the cases with apex above L3, suggesting that the relationship between PI and LL is not always constant, and whole sagittal alignment should be taken into account. These slides can be retrieved under Electronic Supplementary Material. PMID- 29992447 TI - The East-West blood trade : How the German Democratic Republic obtained foreign currency with blood products (1983-1990). AB - Using the East-West blood trade of the German Democratic Republic (GDR) in the 1980s as an example, this study aims to show what kind of problems arise when trade agreements are made with authoritarian regimes, where transparency is lacking and the general public is not informed about the trading conditions. Files from the Ministry of Health and the Foreign Trade Ministry show the extent, aims, and scope of the blood exports to the West. Within the East-West trade, blood was regarded solely as a commercial good; ethical concerns played no part. The blood trade was the most important income source of unscheduled foreign currency for the GDR health sector. People were asked to donate for the wellbeing of society and without receiving remuneration. They were unaware that their blood was an object of commercial trade. Most of the revenue was put into secret accounts of the GDR Foreign Trade Ministry or went to Western intermediaries. The regulations for blood deliveries often challenged the blood donation institutes; they lacked donors, modern techniques/equipment, and personal. Buyers in the West repeatedly complained about the quality of the blood products. The Western intermediaries sold the goods to bulk-buyers, predominantly in German-speaking countries. PMID- 29992449 TI - Designing patient-specific solutions using biomodelling and 3D-printing for revision lumbar spine surgery. AB - PURPOSE: Despite the variety of "off-the-shelf" implants and instrumentation, outcomes following revision lumbosacral surgery are inconstant. Revision fusion surgery presents a unique set of patient-specific challenges that may not be adequately addressed using universal kits. This study aims to describe how patient-specific factors, surgeon requirements, and healthcare efficiencies were integrated to design and manufacture anatomically matched surgical tools and implants to complement a minimally invasive posterior approach for revision lumbar fusion surgery. METHODS: A 72-year-old woman presented with sciatica and a complex L5-S1 pseudoarthrosis 12 months after L2-S1 fixation surgery for symptomatic degenerative scoliosis. Patient computed tomography data were used to develop 1:1 scale biomodels of the bony lumbosacral spine for pre-operative planning, patient education, and intraoperative reference. The surgeon collaborated with engineers and developed a patient-specific 3D-printed titanium lumbosacral fixation implant secured by L2-L5, S2, and iliac screws. Sizes and trajectories for the S2 and iliac screws were simulated using biomodelling to develop a stereotactic 3D-printed drill guide. Self-docking 3D-printed nylon tubular retractors specific to patient tissue depth and bony anatomy at L5-S1 were developed for a minimally invasive transforaminal approach. The pre-selected screws were separately sourced, bundled with the patient-specific devices, and supplied as a kit to the hospital before surgery. RESULTS: At 6-month follow-up, the patient reported resolution of symptoms. No evidence of implant dysfunction was observed on radiography. CONCLUSION: Pre-operative planning combined with biomodelling and 3D printing is a viable process that enables surgical techniques, equipment, and implants to meet patient and surgeon-specific requirements for revision lumbar fusion surgery. PMID- 29992450 TI - Impacts of selenium and vitamin E supplementation on mRNA of heat shock proteins, selenoproteins and antioxidants in broilers exposed to high temperature. AB - The study was carried out to investigate the effect of dietary selenium (Se) and vitamin E (VE) supplementation on mRNA level of heat shock proteins, selenoproteins, and antioxidant enzyme activities in the breast meat of broilers under summer heat stress conditions. A total of 200 male broilers (Ross 308) of 1 day age were randomly separated into 4 groups in a complete randomized design and were given a basal diet (Control, 0.08 mg Se/kg diet) or basal diet supplemented with VE (250 mg/kg VE), sodium selenite (0.2 mg/kg Se), or Se + VE (0.2 mg/kg Se + 250 mg/kg VE) to investigate the expression of key antioxidant and heat shock protein (HSP) genes under high temperature stress. Dietary Se, VE and Se + VE significantly enhanced the activities and mRNA levels of catalase as well as superoxide dismutase (SOD) but decreased the mRNA levels of HSP70 and HSP90. Se alone or combined with VE increased the concentration of selenoprotein P and selenoproteins mRNA level and decreased the expression of HSP60. In addition, Se and Se + VE significantly enhanced the glutathione peroxidase (GPx) activity and the expression of GPx1 and GPx4 in breast muscle tissues. It is noteworthy that all the treatments significantly decreased malondialdehyde (MDA) level in the breast meat. Overall results showed that Se in combination with VE has maximal effects to mitigate heat stress. Based on given results it can be recommended that Se + VE are a suitable dietary supplement for broilers to ameliorate the negative effects of summer heat stress conditions. PMID- 29992451 TI - Mucinous adenocarcinoma, gastric type of the uterine cervix: clinical features and HER2 amplification. AB - Mucinous adenocarcinoma, gastric type (GAS) is difficult to diagnose and shows poor prognosis. Trastuzumab, an anti-human epidermal growth factor type 2 (HER2) monoclonal antibody, is effective in HER2-positive stomach cancer. The objectives of this study were to identify the clinicopathological characteristics of GAS and to evaluate HER2 expression in GAS. We retrospectively reviewed 322 cervical cancer cases diagnosed at the Kyoto University Hospital from 2010 to 2016. The incidence, clinical factors including age, stage, and lymph node status, tumor markers, immunoreactive expression of MUC6, HIK1083, and HER2, and HER2 amplification were evaluated. Of the 322 cases of cervical cancer, 13 cases of the adenocarcinoma cases were diagnosed as GAS. Watery discharge, lower abdominal pain, CA19-9 elevation, and lymph node metastasis were frequently observed in GAS (p = 0.0226, p = 0.0400, p = 0.0346, and p = 0.0274, respectively). Immunohistochemistry showed positive MUC6 status in all 13 cases and positive HIK1083 status in 8 cases. The HER2 expression status was equivocal in six cases by immunohistochemistry and HER2 amplification was identified in one case. GAS exhibits frequent lymph node metastasis and clinical symptoms such as watery discharge and lower abdominal pain, high levels of CA19-9. In addition, some parts of GAS exhibit HER2 amplification. PMID- 29992453 TI - S-Leaping: An Adaptive, Accelerated Stochastic Simulation Algorithm, Bridging [Formula: see text]-Leaping and R-Leaping. AB - We propose the S-leaping algorithm for the acceleration of Gillespie's stochastic simulation algorithm that combines the advantages of the two main accelerated methods; the [Formula: see text]-leaping and R-leaping algorithms. These algorithms are known to be efficient under different conditions; the [Formula: see text]-leaping is efficient for non-stiff systems or systems with partial equilibrium, while the R-leaping performs better in stiff system thanks to an efficient sampling procedure. However, even a small change in a system's set up can critically affect the nature of the simulated system and thus reduce the efficiency of an accelerated algorithm. The proposed algorithm combines the efficient time step selection from the [Formula: see text]-leaping with the effective sampling procedure from the R-leaping algorithm. The S-leaping is shown to maintain its efficiency under different conditions and in the case of large and stiff systems or systems with fast dynamics, the S-leaping outperforms both methods. We demonstrate the performance and the accuracy of the S-leaping in comparison with the [Formula: see text]-leaping and R-leaping on a number of benchmark systems involving biological reaction networks. PMID- 29992452 TI - Sediment quality, elemental bioaccumulation and antimicrobial properties of mangroves of Indian Sundarban. AB - Mangroves have wide applications in traditional medicines due to their several therapeutic properties. Potentially toxic elements (PTEs), in mangrove habitats, need serious concern because of their toxicity, bioaccumulation capacity and ecotoxicological risks. In the current study, we aimed to examine sediment quality and bioaccumulation of PTEs in a mangrove-dominated habitat of Sundarban, India, and their relation with antimicrobial property of ten mangrove species of the region. Antimicrobial activity of different solvent fractions of mangrove leaves was assessed against seven microorganisms. The highest antimicrobial activity was detected in ethyl acetate and acetone-extracted fractions of Avicennia alba. Various sediment quality indices revealed progressively deteriorating nature of surface sediment having moderate contamination, however, low ecotoxicological risk. The accumulation factors (AF) for different PTEs indicate a gradual metal bioaccumulation in leaf tissue. Antimicrobial activities indicated both positive and negative correlations with manganese (Mn), copper (Cu), iron (Fe) and zinc (Zn) concentrations of mangrove species. Concentration of Mn showed a significant correlation with almost all the fractions, whereas Cu had correlation with ethyl acetate, acetone and methanol fractions (P < 0.05). The AF of Mn and Cu exhibited correlation with antimicrobial activities of acetone and methanol fractions, whereas Fe and Zn had correlation with hexane and ethyl acetate fractions. Overall, Mn, Fe, Cu and Zn concentrations of Acanthus ilicifolius and Avicennia alba leaves and in the surface sediments demonstrated the strongest association (P < 0.05) with their antimicrobial activity as also depicted in correlation and cluster analysis studies. Thus, this study will help to establish a link between the PTEs in mangrove ecosystem with their bioactivity. PMID- 29992454 TI - Accuracy Analysis of Hybrid Stochastic Simulation Algorithm on Linear Chain Reaction Systems. AB - Noise in cellular systems is often modeled and simulated with Gillespie's stochastic simulation algorithm (SSA), but the low efficiency of the SSA limits its application to large biochemical networks. To improve the efficiency of stochastic simulations, Haseltine and Rawlings (HR) proposed a hybrid algorithm, which combines ordinary differential equations for traditional deterministic models and the SSA for stochastic models. In this paper, accuracy of the HR hybrid method is studied based on a linear chain reaction system. Mathematical analysis and numerical results both show that the HR hybrid method is accurate if either the quantity of reactant molecules in fast reactions is above a certain threshold, or the reaction rates of fast reactions are much larger than those of slow reactions. This analysis also shows that the HR hybrid method approximates the chemical master equation well for a much greater region in system parameter space than the slow-scale SSA and the stochastic quasi-steady-state assumption methods. PMID- 29992456 TI - Bioinformatics analysis to reveal the key genes related to obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea (OSA) is induced by obstruction of the upper airway, which can raise multiple health risks. This study is designed to reveal the key genes involved in OSA. METHODS: GSE38792 was extracted from Gene Expression Omnibus database, including ten visceral adipose tissues from OSA patients and eight visceral adipose tissues from normal controls. Differential expression analysis was conducted using limma package, and then the functions of the differentially expressed genes (DEGs) were analyzed using DAVID database, followed by protein-protein interaction (PPI) network, and integrated regulatory network analysis was performed using Cytoscape software. RESULTS: A total of 368 DEGs (176 upregulated and 192 downregulated) were identified in OSA samples. Epstein-Barr virus infection (involving IL10RB, MAPK9, and MAPK10) and olfactory transduction were the main pathways separately enriched for the upregulated genes and the downregulated genes. After the PPI network was built, the top ten network nodes (such as TXN) were selected according to node degrees. Two significant PPI network modules were identified. Moreover, the integrated regulatory network was constructed. CONCLUSION: IL10RB, MAPK9, MAPK10, and TXN might function in the pathogenesis of OSA. PMID- 29992457 TI - Affinity determination of biomolecules: a kinetic model for the analysis of pre equilibrium titration curves. AB - Equilibrium titration curves have been used to determine the affinity of biomolecules using a variety of platforms and technologies. Such measurements, however, are experimentally limited by the time that is needed for the system to reach the equilibrium, which may exceed the time during which the studied biomolecules are stable. We propose here a kinetic model to analyze titration curves obtained prior to full equilibration of the system. PMID- 29992455 TI - Regional cortical thinning in young adults with schizophrenia but not psychotic or non-psychotic bipolar I disorder. AB - BACKGROUND: Schizophrenia shares some genetic risk and clinical symptoms with bipolar disorder. Clinical heterogeneity across subjects is thought to contribute to variable structural imaging findings across studies. The current study investigates cortical thickness in young adults diagnosed with schizophrenia or bipolar I disorder with a history of hyperthymic mania. We hypothesize that cortical thickness will be most similar between SCZ and the psychotic bipolar 1 disorder subtype. METHODS: Patients with schizophrenia (n = 52), psychotic bipolar I disorder (PBD; n = 49) and non-psychotic bipolar I disorder (NPBD; n = 24) and healthy controls (n = 40) were scanned in a 3T Trio MRI. The thickness of 34 cortical regions was estimated with FreeSurfer, and analyzed using univariate analyses of variance. Relationships to psychotic (SAPS) and negative (SANS) symptoms were investigated using linear regression. RESULTS: Cortical thickness showed significant group effects, after covarying for sex, age, and intracranial volume (p = 0.001). SCZ subjects had thinner paracentral, inferior parietal, supramarginal and fusiform cortices compared to CON. Caudal anterior cingulate cortical thickness was increased in SCZ, PBD and NPBD. Cortical thickness in PBD and NPBD were not significantly different from controls. Significant partial correlations were observed for SAPS severity with middle temporal (r = - 0.26; p = 0.001) and fusiform (- 0.26; p = 0.001) cortical thickness. CONCLUSIONS: Individuals with SCZ displayed significantly reduced cortical thickness in several cortical regions compared to both CON and bipolar. We found that SCZ participants had significant cortical thinning relative to CON and bipolar disorder most significantly in the frontal (i.e. paracentral), parietal (i.e. inferior parietal, supramarginal), and temporal (i.e. middle temporal, fusiform) cortices. PMID- 29992459 TI - Removal of Hydrocarbons from Contaminated Soils by Using a Thermally Expanded Graphite Sorbent. AB - Lab-scale experiments on three soil matrices featured by increasing granulometry (sea sand, silica sand and gravel) were carried out in order to evaluate the adsorption capability and the removal efficiency of a new graphene-based material. Soil samples, firstly contaminated with different quantities of used lubricant oil up to final concentrations of 12.5, 25.0, 50.0 g kg-1, were treated with an opportune amount of thermally expanded graphite (TEG) (i.e. 1/10, 1/20, 1/40 as TEG/pollutant ratio). Results show that the removal efficiency of TEG is directly correlated to the contamination level of the soil. The best removal efficiency (87.04%) was obtained during the treatment of gravel samples at the maximum contamination level by using the highest dosage of TEG. A good removal efficiency (80.83%) was also achieved using lower TEG/pollutant ratio. Moreover, TEG at ratio 1/10 showed worse removal efficiencies in treating sea (81.17%) and silica sand (63.52%) than gravel. In this study, also the thermal regeneration was investigated in order to evaluate a possible reuse of TEG with subsequent technical and economic advantages. TEG-technique proves to be technologically and economically competitive with other currently used technologies, revealing the best choice for the remediation of hydrocarbon-contaminated soils. PMID- 29992458 TI - A Novel Fluorescent Nanoparticle for Sensitive Detection of Cry1Ab Protein In Vitro and In Vivo. AB - Here, we report the synthesis and characterization of CoFe2O4 doping Ag2S dendrimer-modified nanoparticles (CoFe2O4-Ag2S DMNs) in Cry1Ab protein detection and imaging. The near-infrared Ag2S quantum dots were first prepared by using the thermal decomposition method, followed by modification of the water-soluble quantum dots using the method of solvent evaporation and ligand exchange, and finally the fluorescent magnetic bifunctional nanoparticles were obtained by binding with CoFe2O4. As-prepared CoFe2O4-Ag2S DMNs were characterized by fluorescence (FL) spectroscopy and transmission electron microscopy (TEM). Results showed that Ag2S DMNs could sensitively detect Cry1Ab both in vitro and in vivo. In vitro, the enhanced FL intensity as a function of the concentration is notably consistent with the Langmuir binding isotherm equation in the range of 0-200 ng/mL of Cry1Ab proteins. The detection limit of this method was found to be 0.2 ng/mL. Meanwhile, the fluorescence wavelength was extended to the second near-infrared range (NIR-II, 1.0~1.4 MUm), which enables in vivo imaging. This study highlights the importance of NIR QDs doping magnetic materials as a new method to trace Bacillus thuringiensis (Bt) in insects and their potential applications in in vivo NIR tissue imaging. PMID- 29992460 TI - FAM98A is localized to stress granules and associates with multiple stress granule-localized proteins. AB - Stress granules are evolutionally conserved ribonucleoprotein structures that are formed in response to various stress stimuli. Recent studies have demonstrated that proteins with low complexity (LC) regions play a critical role for the formation of stress granules. In this study, we report that FAM98A, whose biological functions are unknown, is a novel component of stress granules. FAM98A is localized to stress granules, but not to P-bodies, after various stress stimuli. Analysis with deletion mutants revealed that C-terminal region that contains LC region was essential for FAM98A accumulation to stress granules. Depletion of FAM98A using two different siRNAs decreased the number of stress granules formed per cell. Finally, we show that FAM98A associates with stress granule-localized proteins, such as DDX1, ATXN2, ATXN2L, and NUFIP2. Our results show a partial role of FAM98A for the organization of stress granules. PMID- 29992461 TI - Association between circulating visfatin and gestational diabetes mellitus: a systematic review and meta-analysis. AB - AIMS: Gestational diabetes mellitus (GDM) is a medical complication of any degree of glucose intolerance with onset or first recognition during pregnancy. Although visfatin is commonly considered to be related to GDM, studies revealed inconsistent results. This study aimed to clarify the relationship between visfatin and GDM. METHODS: The protocol for this study was registered in PROSPERO (No. CRD42018086204) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed and Embase databases were used to search for relevant studies published up to September 30, 2017. The difference of visfatin levels between women with GDM and the controls was measured by standardised mean difference (SMD) and 95% confidence interval (CI). RESULTS: Twenty-six studies that were published in 24 articles met the inclusion criteria, in which 2305 participants (1033 with GDM, mean age 31.39 years and 1272 controls, and mean age 29.99 years) were included. The quantitative meta analysis revealed no significant difference in circulating visfatin levels between women with GDM and the controls (SMD = 0.249, 95% CI = - 0.079 to 0.576, P = 0.137). Subgroup analyses were performed referring to body mass index (BMI) where inconsistent results have been observed between cases and controls groups. For the ten studies, in which the level of BMI in women with GDM was higher than that in the control group, the pooled result showed that circulating visfatin was significantly higher among women with GDM than the controls (SMD = 0.367, 95% CI = 0.06 to 0.728, P = 0.046). Of other 16 studies BMI-matched, the pooled SMD illustrated no difference of visfatin. CONCLUSIONS: Our study elucidates that visfatin is not independently associated with GDM. Visfatin is linked to GDM through maternal overweight/obesity, which is one of the major factors leading to the development of GDM. PMID- 29992462 TI - Controversies in the management of stage I seminoma: adjuvant carboplatin revisited. PMID- 29992463 TI - Multiparametric MRI for prostate cancer: a national survey of patterns of practice among radiation oncologists in Spain. AB - PURPOSE: To investigate patterns of practice among Spanish radiation oncologists in the use of multiparametric magnetic resonance imaging (mpMRI) for the treatment of prostate cancer (PCa). We evaluated (1) access to mpMRI, (2) current clinical practices, and (3) physician expectations of mpMRI. METHODS: Cross sectional survey of 118 radiation oncologists at 75 Radiation Oncology (RO) departments in Spain. RESULTS: A total of 55 radiation oncologists from 52 RO departments (52/75; 69%) completed the survey. Prostate mpMRI is performed at 94.5% of the centres that provided data. The most common indications for mpMRI in routine clinical practice were: (1) detection/localization of the tumour prior to second biopsy (82.7%), (2) cancer staging (80.8%), and (3) detection of recurrence after definitive treatment (80.8%). Most respondents (72.7%) reported modifying the primary radiotherapy treatment when mpMRI findings indicate a more advanced T stage with a resultant change in the risk group. Most respondents (90.5%) treat macroscopic local recurrence after prostatectomy with high doses, ranging from 71 to 83 Gy; in 37.7% of cases, the full dose is delivered to the entire prostate bed. In pelvic nodal recurrence, more than half (59.3%) of the respondents reported performing elective pelvic radiotherapy, including the prostate bed, with a boost to the involved nodes. CONCLUSIONS: This survey shows that prostate mpMRI is routinely used by radiation oncologists in Spain in a wide range of clinical scenarios. The findings reported here underscore the need to standardize treatment protocols for definitive and salvage radiotherapy in patients evaluated with mpMRI. PMID- 29992464 TI - Avulsion fracture of the distal fibula is associated with recurrent sprain after ankle sprain in children. AB - PURPOSE: The purpose of this study was to clarify radiographic and clinical outcomes, as well as their association, of ankle sprain in children. METHODS: Patients who sustained a first-time ankle sprain were prospectively surveyed. Patients underwent radiography of the ankle in the mortise, lateral, anterior talofibular ligament (ATFL), and calcaneofibular ligament views at the first clinic visit to assess avulsion fractures of the distal fibula. Patients with avulsion fractures underwent radiography after 8 weeks to assess bone union. The treatment method was not standardized and was determined by the patient, their parents, and the treating physician. Recurrent sprain and quality of life were evaluated by using the Self-Administered Foot Evaluation Questionnaire and reviewing the medical records of patients. The association between avulsion fracture and recurrent sprain was assessed using univariate and multivariate analyses. RESULTS: A total of 143 patients with a median age of 9 (range 6-12) years were analyzed. Avulsion fractures were present in 89 (62%) patients. The sensitivity of the ATFL view for the diagnosis of avulsion fractures was 0.94, whereas that for the anteroposterior and lateral views was significantly lower at 0.46 (P < 0.001). Only 17% of fractures united at 8 weeks. Of 114 (follow-up rate, 80%) patients who were followed up for a median period of 24 months, recurrent sprain occurred in 41 (36%) patients. The incidence rate was significantly higher in patients with avulsion fractures than in patients without the fractures (44 vs. 23%, P = 0.027). In multivariate logistic regression analysis, avulsion fracture was independently associated with recurrent sprain (P = 0.027). CONCLUSION: More than one-third of patients experienced recurrent sprain. The presence of avulsion fracture was associated with an increased risk of recurrent sprain. Patients with avulsion fracture and their parents should be informed about the risk of recurrent sprain and subsequent ankle instability, and careful follow-up is needed for these patients. LEVEL OF EVIDENCE: III. PMID- 29992465 TI - Weight-bearing radiography depends on limb loading. AB - PURPOSE: The mechanical axis of the lower limb has shown to vary between different weight-bearing conditions and change after total knee arthroplasty (TKA). The purpose of this study was to investigate the correlation between mechanical axis alignment in standing long-leg radiographs and limb loading after TKA. METHODS: Mechanical axis of the lower limb and limb loading have been prospectively evaluated in 115 patients 10 days and 3 months after TKA. By the moment of standing long-leg radiography for analysis of the mechanical leg axis, two digital scales separately captured the load of each limb. RESULTS: Mechanical axis changed from an initial - 1 degrees +/- 2 degrees valgus alignment to a varus axis of + 1 degrees +/- 2 degrees (p < 0.01). This change in alignment was associated with an increase of limb loading from 89.9 +/- 10.7 to 93.0 +/- 7.0% (p < 0.01). The mechanical axis strongly correlated with relative limb loading at the first and second measurements (r = 0.804, p < 0.001, respectively, r = 0.562, p < 0.001). A significant change in the rate of outliers was registered within the observation period. These alterations and distinctions were much more pronounced in patients with postoperative incomplete extension (n = 15). CONCLUSIONS: The postoperative mechanical axis correlates with limb loading. A clinical relevant change in frontal alignment of the lower limb is associated with increased limb loading after TKA. The actual mechanical axis can only be assessed at physiological limb loading in long-leg radiographs with complete extension at full weight bearing. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 29992467 TI - Developing and validating a tool for measuring the educational environment in clinical anesthesia. AB - PURPOSE: We aimed to develop a contemporary measure for anesthesia teaching and learning in the operating theatre that was applicable to a variety of training jurisdictions, the Measure for the Anaesthesia Theatre Educational Environment (MATE). METHODS: A systematic review of the literature and modified Delphi approach was used to identify items for content validity. Reliability and exploratory factor analyses were conducted after a pilot survey of trainees to show construct validity, with removal of redundant items. Item domains were identified through a global assessment of factor structure accuracy and relation to real-world constructs. RESULTS: Literature review generated an initial 73-item list. A modified Delphi approach with 24 experts identified 44 relevant items. The pilot survey generated 390 responses. Reliability analysis, exploratory factor analysis, and global assessment refined the measure to 33 items. Four domains were identified according to factor structure: teaching preparation and practice, assessment and feedback, procedures and responsibility, and overall atmosphere. The educational environment was rated by trainees at 74.6 +/- 15.6% with excellent internal consistency (Cronbach's alpha = 0.975). CONCLUSION: The MATE survey tool generated valid and reliable scores when measuring the educational environment in the operating theatre. Further research is required to investigate possible differences between the training countries and age of junior doctors and the associated underlying factors. Other researchers are invited to administer the survey and share results within a central database. PMID- 29992466 TI - Neuromuscular and perceptual responses to moderate-intensity incline, level and decline treadmill exercise. AB - PURPOSE: To describe the neuromuscular and perceptual responses to incline, decline or level treadmill exercise. METHODS: Fifteen healthy subjects performed on separate days 45 min treadmill exercise at 75% heart rate reserve in a level (+ 1% slope), incline (+ 15%) or decline condition (- 15%). Neuromuscular function of the knee extensors (KE) was assessed before and after exercise. Perception of effort, muscle pain and pleasure were measured during the exercise. Muscle pain was also reported up to 96 h after exercise. RESULTS: At the same heart rate, the decline exercise was performed at a higher velocity. This higher velocity was associated with a higher perceived effort and muscle pain, as well as lower pleasure. Maximal isometric KE peak torque and maximal voluntary activation similarly decreased in the three conditions (~ 15 +/- 12 and ~ 4 +/- 4%). M-wave amplitude of the vastus medialis muscle decreased in the three conditions (~ - 12 +/- 13%). M-wave amplitude of the rectus femoris muscle decreased only after the decline exercise (- 12 +/- 16%). Peak twitch torque of the electrically evoked contractions was reduced after incline and decline exercises for both 10 and 100 Hz doublets (- 8 +/- 9 and - 17 +/- 18%). The Dt10/Dt100 ratio was reduced only after decline exercise (- 24 +/- 19%). CONCLUSION: At the same moderate intensity, decline exercise induced a greater level of muscle fatigue associated with a higher perceived effort and muscle pain than incline and level exercise. Exercise intensity should be carefully monitored during decline locomotion for training or rehabilitation purposes. PMID- 29992468 TI - Thermosetting Polymers from Lignin Model Compounds and Depolymerized Lignins. AB - Lignin is the most abundant source of renewable ready-made aromatic chemicals for making sustainable polymers. However, the structural heterogeneity, high polydispersity, limited chemical functionality and solubility of most technical lignins makes them challenging to use in developing new bio-based polymers. Recently, greater focus has been given to developing polymers from low molecular weight lignin-based building blocks such as lignin monomers or lignin-derived bio oils that can be obtained by chemical depolymerization of lignins. Lignin monomers or bio-oils have additional hydroxyl functionality, are more homogeneous and can lead to higher levels of lignin substitution for non-renewables in polymer formulations. These potential polymer feed stocks, however, present their own challenges in terms of production (i.e., yields and separation), pre polymerization reactions and processability. This review provides an overview of recent developments on polymeric materials produced from lignin-based model compounds and depolymerized lignin bio-oils with a focus on thermosetting materials. Particular emphasis is given to epoxy resins, polyurethanes and phenol formaldehyde resins as this is where the research shows the greatest overlap between the model compounds and bio-oils. The common goal of the research is the development of new economically viable strategies for using lignin as a replacement for petroleum-derived chemicals in aromatic-based polymers. PMID- 29992469 TI - White matter correlates of temporal discounting in older adults. AB - Temporal discounting, the tendency to select a smaller reward offered sooner over a larger reward offered at a later time, has been associated with a number of real-world decision-making outcomes important for health and wellbeing. Neurobiological mechanisms supporting temporal discounting have been explored among younger participants, and these have considered white matter integrity. However, the white matter correlates of temporal discounting in older adults are unclear. We hypothesized that greater temporal discounting would be associated with poorer white matter integrity measures, more specifically lower fractional anisotropy and higher trace, in older adults. Participants were 302 older persons without dementia (mean age = 81.38, mean years of education = 15.75, 75.5% female, mean MMSE = 28.29) from the Rush Memory and Aging Project, a community based longitudinal study of aging. Temporal discounting was assessed using standard elicitation questions. White matter integrity was assessed with diffusion tensor imaging (DTI). Regression models were adjusted for the effects of age, sex, education, and white matter lesions. Secondary models further adjusted for global cognition. Results revealed significant associations between temporal discounting and white matter integrity measures (FA and trace) in bilateral frontal, frontostriatal, and temporal-parietal lobe white matter tracts, and results remained significant after further accounting for global cognition. These results suggest that temporal discounting is inversely associated with white matter integrity in old age and that this association is independent of global cognition. PMID- 29992470 TI - Altered functional network connectivity in preterm infants: antecedents of cognitive and motor impairments? AB - Very preterm infants (<= 31 weeks gestational age) are at high risk for brain injury and delayed development. Applying functional connectivity and graph theory methods to resting state MRI data (fcMRI), we tested the hypothesis that preterm infants would demonstrate alterations in connectivity measures both globally and in specific networks related to motor, language and cognitive function, even when there is no anatomical imaging evidence of injury. Fifty-one healthy full-term controls and 24 very preterm infants without significant neonatal brain injury, were evaluated at term-equivalent age with fcMRI. Preterm subjects showed lower functional connectivity from regions associated with motor, cognitive, language and executive function, than term controls. Examining brain networks using graph theory measures of functional connectivity, very preterm infants also exhibited lower rich-club coefficient and assortativity but higher small-worldness and no significant difference in modularity when compared to term infants. The findings provide evidence that functional connectivity exhibits deficits soon after birth in very preterm infants in key brain networks responsible for motor, language and executive functions, even in the absence of anatomical lesions. These functional network measures could serve as prognostic biomarkers for later developmental disabilities and guide decisions about early interventions. PMID- 29992473 TI - Causes and Means of Healing: An Islamic Ontological Perspective. AB - Healthcare practitioners are increasingly aware that patients may utilize faith based healing practices in place of conventional medicine based on their spiritual and/or religious understandings of health and illness. Therefore, elucidating the ontological understandings of patients utilizing such religion based treatments may clarify why patients and clinicians have differing understandings of 'who' heals and 'what' are means for healing. This paper describes an Islamic ontological schema that includes the following realms: Divine existence; spirits/celestial beings; non-physical forms/similitudes; and physical bodies. Ontological schema-based means of healing include conventional medicine, religion-based means (e.g., supplication, charity, prescribed incantations/amulets), and active adoption of Islamic virtues (e.g., reliance on God [tawakkul] and patience [sabr]). An ontological schema-based description of causes and means of healing can service a more holistic model of healthcare by integrating the overlapping worlds of religion and medicine and can support clinicians seeking to further understand and assess patient responses and attitudes toward illness and healing. PMID- 29992472 TI - Prospects for Monoclonal Antibody Therapy in Pediatric Asthma. AB - PURPOSE OF REVIEW: The profile of biologic therapies for asthma is growing rapidly. We discuss how to match the proper pediatric patient with the most effective therapy. RECENT FINDINGS: Currently available biologic therapies are most effective in patients with T2 high asthma. Newer drugs are currently being studied which target TSLP and interleukin 33. These newer drugs may provide options for asthmatics who do not respond to the current anti-IgE, anti-IL5, and anti-IL4/13 therapies. Asthma is a heterogeneous disease which can be driven by different inflammatory mediators in different patients. To select the most effective biologic therapy for a pediatric patient, the asthma phenotype must first be determined. The steep cost of biologics limits their use, which makes proper pairing of patient to therapy even more crucial. Presently, several therapies exist for T2 high asthma, but it is hoped in the future that development of drugs effective for T2 low asthmatics will be available as well. PMID- 29992471 TI - The mesenchymoangioblast, mesodermal precursor for mesenchymal and endothelial cells. AB - Mesenchymoangioblast (MB) is the earliest precursor for endothelial and mesenchymal cells originating from APLNR+PDGFRalpha+KDR+ mesoderm in human pluripotent stem cell cultures. MBs are identified based on their capacity to form FGF2-dependent compact spheroid colonies in a serum-free semisolid medium. MBs colonies are composed of PDGFRbeta+CD271+EMCN+DLK1+CD73- primitive mesenchymal cells which are generated through endothelial/angioblastic intermediates (cores) formed during first 3-4 days of clonogenic cultures. MB derived primitive mesenchymal cells have potential to differentiate into mesenchymal stromal/stem cells (MSCs), pericytes, and smooth muscle cells. In this review, we summarize the specification and developmental potential of MBs, emphasize features that distinguish MBs from other mesenchymal progenitors described in the literature and discuss the value of these findings for identifying molecular pathways leading to MSC and vasculogenic cell specification, and developing cellular therapies using MB-derived progeny. PMID- 29992474 TI - Muslim Traditional Healers in Accra, Ghana: Beliefs About and Treatment of Mental Disorders. AB - Traditional and faith healing is a common practice in many low- and middle-income countries due to resource limitations and belief systems, particularly for disorders such as mental disorders. We report on the beliefs about mental illness from the perspective of one category of alternative healers in Ghana-the Muslim faith healers. We also report on their methods of diagnoses and treatment for mental disorders. Results show that the healers' beliefs about mental illness revolved around the notion of Jinn as causing most mental illness. Emerging themes are discussed with reference to their potential implications for patients' care and health-seeking behaviour. PMID- 29992475 TI - Sociodemographic Factors Associated with Types of Projects Implemented by Volunteer Lay Health Educators in Their Congregations. AB - This study focused on the association between type of community health interventions and lay health educator variables. Lay health educators are volunteers from local faith communities who complete a healthcare training program, taught by physicians in-training. Lay health educators are instructed to implement health-related initiatives in their respective communities after graduation. Of the 72 graduates since 2011, we surveyed 55 lay health educators to gain insight into their involvement with their congregation and the type of health projects they have implemented. We dichotomized the health projects into "raising awareness" and "teaching new health skills." Using adjusted logistic regression models, variables associated with implementing health projects aimed at teaching health skills included length of time as a member of their congregation, current employment, and age. These results may help future programs prepare lay health community educators for the type of health interventions they intend to implement in their respective communities. PMID- 29992476 TI - Health and Religions: A Bibliometric Analysis of Health Literature Related to Abrahamic Religions Between 1975 and 2017. AB - Bibliometrics is a high-demand and fast-growing statistical area for the analysis of scientific literature in a certain field. Although religion and health (R&H) field has been a developing study area in recent years, only a few bibliometric studies have been published on the literature in R&H. In this study, we aimed to perform bibliometric analysis of the health literature related to the most populous Abrahamic religions during the period of 1975-2017 by using Web of Science database including WoS Collection Core Collection, Korean Journal Database, Russian Science Citation Index and SciELO Citation Index. In overall evaluation, the USA ranked first in publication productivity with 1388 items and covered 37.21% of total literature. The Journal of Religion and Health published the highest number of documents (n = 351). We found a total of 1329 items in health and Christianity field, and the USA was the most productive country followed by the UK and Canada (n = 166 and 63 documents, respectively). Loma Linda University was found to publish the highest number of items. We detected 1965 publications in Islam and health area, and top three countries were the USA, the UK and Saudi Arabia (n = 387, 194 and 137 items, respectively). University of London was the most productive institution (n = 72, 3.67%). A total of 436 articles were detected in Judaism and health. Top three countries in productivity were the UK, Israel and the UK (211, 151 and 36 items, respectively). Hebrew University of Jerusalem produced 17.43% of total documents as the topmost institution. Although Abrahamic religions originated from Middle East, we noted that most productive authors in this field were not Middle Eastern and from developed countries. Researchers from developing or least developed countries should be encouraged to carry out more studies in R&H field. PMID- 29992477 TI - [Control of severe bleeding]. PMID- 29992478 TI - ? PMID- 29992479 TI - Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex. AB - Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy. PMID- 29992480 TI - Cardiovascular Risk Assessment in Patients with Hypertriglyceridemia. AB - PURPOSE OF REVIEW: Assessing the cardiovascular risk associated with hypertriglyceridemia can be challenging due to frequent confounding conditions such as hypertension, diabetes mellitus, and hyperlipidemia. We sought to quantify this risk by examining several meta-analyses as well as subgroup analyses of previously published major randomized controlled trials that focused on the treatment of hyperlipidemia. RECENT FINDINGS: Recent trials measuring the effects of PCSK9 inhibitors such as evolocumab and alirocumab on cardiovascular outcomes have demonstrated a high degree of residual cardiovascular risk even after profound reductions in low-density-lipoprotein cholesterol (LDL-C). Despite optimization of LDL-C through the use of statins, PCSK9 inhibitors and adjunctive therapies such as ezetimibe, bile acid sequestrants and niacin, residual cardiovascular risk remains significant. Several ongoing trials are assessing the efficacy of pemafibrate and omega-3 fatty acids for the treatment of hypertriglyceridemia and their effects on major cardiovascular outcomes. PMID- 29992481 TI - Optimization of combination therapy for chronic myeloid leukemia with dosing constraints. AB - In this work, we demonstrate a mathematical technique for optimizing combination regimens with constraints. We apply the technique to a mathematical model for treatment of patients with chronic myeloid leukemia. The in-host model includes leukemic cell and immune system dynamics during treatment with tyrosine kinase inhibitors and immunomodulatory compounds. The model is minimal (semi mechanistic) with just enough detail that all relevant therapeutic effects can be represented. The regimens are optimized to yield the highest possible reduction in disease burden, taking into account dosing constraints and side effect risks due to drug exposure. We compare the following three types of regimens: (1) regimens that are restricted to certain discrete dose levels, which can only change every three months; (2) optimal regimens determined using optimal control; and (3) regimens that are piecewise-constant like the first type of regimen, but are obtained as approximations to the optimal control regimens. All three types of regimens result in similar outcomes, but the last one is easy to compute in addition to being clinically feasible. PMID- 29992482 TI - Molecular phylogeny of ten intertidal hermit crabs of the genus Pagurus inferred from multiple mitochondrial genes, with special emphasis on the evolutionary relationship of Pagurus lanuginosus and Pagurus maculosus. AB - The hermit crab genus Pagurus exhibits high species diversity and a wide geological distribution. Despite the high species diversity of hermit crabs in the western Pacific coast of Japan, molecular phylogenetic studies of these species have yet to be conducted. To investigate their molecular phylogeny and genetic diversity, we obtained nearly complete mitochondrial genome sequences for ten Pagurus species found along the Pacific coast of Japan by next-generation sequencing, which were compared to other congeners deposited in the GenBank database. The genomes ranged from 13,458 to 16,401 base pairs in length, possessing 13 protein-coding genes, 2 rRNAs, and 22 tRNA genes. Based on the reconstructed phylogeny, we found that (1) Japanese Pagurus species separated into three groups, nested within the Northern Pacific species. (2) Pagurus lanuginosus and Pagurus maculosus, showed high morphological similarities, implying close kinship. Indeed, these two species were genetically closest to each other, compared to the remaining species studied. (3) An unspecified specimen sampled from the deep sea, which morphologically resembled Pagurus, might be a member of the Pagurus genus, but is genetically distant from the other Japanese Pagurus species. The novel data reported here may provide new perspectives for systematic studies of hermit crabs; these results provide important information that will facilitate population-level research and identifying intraspecific variation of these non-model, but ecologically important, decapod species. PMID- 29992483 TI - Electrophysiological measures reveal the role of anterior cingulate cortex in learning from unreliable feedback. AB - Although a growing number of studies have investigated the neural mechanisms of reinforcement learning, it remains unclear how the brain responds to feedback that is unreliable. A recent theory proposes that the reward positivity (RewP) component of the event-related brain potential (ERP) and frontal midline theta (FMT) power reflect separate feedback-related processing functions of anterior cingulate cortex (ACC). In the present study, the electroencephalogram (EEG) was recorded from participants as they engaged in a time estimation task in which feedback reliability was manipulated across conditions. After each response, they received a cue that indicated that the following feedback stimulus was 100%, 75%, or 50% reliable. The results showed that participants' time estimates adjusted linearly according to the feedback reliability. Moreover, presentation of the cue indicating 100% reliability elicited a larger RewP-like ERP component than the other cues did, and feedback presentation elicited a RewP of approximately equal amplitude for all of the three reliability conditions. By contrast, FMT power elicited by negative feedback decreased linearly from the 100% condition to 75% and 50% condition, and only FMT power predicted behavioral adjustments on the following trials. In addition, an analysis of Beta power and cross-frequency coupling (CFC) of Beta power with FMT phase suggested that Beta-FMT communication modulated motor areas for the purpose of adjusting behavior. We interpreted these findings in terms of the hierarchical reinforcement learning account of ACC, in which the RewP and FMT are proposed to reflect reward processing and control functions of ACC, respectively. PMID- 29992484 TI - Ocular signatures of proactive versus reactive cognitive control in young adults. AB - During the execution of a cognitive task, the brain maintains contextual information to guide behavior and achieve desired goals. The AX-Continuous Performance Task is used to study proactive versus reactive cognitive control. Young adults tend to behave proactively in standard testing conditions. However, it remains unclear how interindividual variability (e.g., in cognitive and motivational factors) may drive people into more reactive or proactive control under the same task demands. We investigated the use of control strategies in a large population of healthy young adults. We computed the proactive behavioral index and consequently divided participants into proactive, reactive, and intermediate groups. We found that reactive participants were generally slower, presented lower context sensitivity, and larger response variability. Pupillary changes and blink rate index cognitive effort allocation. We measured, concomitantly to the task, the pupil size and frequency of blinks associated with the cue maintenance and response intervals. During the cue period, nonfrequent, nontarget cues led to increased pupil dilation and number of blinks in all participants. During the response interval, we found more errors and increased pupil dilation to the probe when all participants had to overcome a response bias generated by the frequent cue. Only reactive participants showed larger response related pupil when they had to overcome a response bias related to the frequent probe. Contrary to expectations, groups did not differ in ocular measures in the cue period. In conclusion, interindividual differences in cognitive control between healthy adults can be mapped onto different patterns of effort allocation indexed by the pupil. PMID- 29992486 TI - Effects of a combined exercise plus diet program on cardiorespiratory fitness of breast cancer patients. AB - BACKGROUND: Decreases in cardiorespiratory fitness among breast cancer patients have often been reported in previous studies, affecting patients' health and survival. Peak oxygen uptake ([Formula: see text]) is the gold standard for assessing cardiorespiratory fitness and is inversely correlated with cardiovascular disease among women with breast cancer. Some previous studies have reported that aerobic exercise and proper diet positively influence [Formula: see text]. However, almost all studies have been conducted in the Western countries, and few studies are investigating on Asian women who have lower BMI compared with Western ones. PURPOSE: Investigating the effects of a combined exercise and diet program among Japanese cancer patients undergoing therapy on [Formula: see text]. METHODS: Thirty-two Japanese women with breast cancer undergoing endocrine therapy (age; 50 +/- 6 years, body weight; 59 +/- 10 kg) were voluntarily assigned to either intervention group (n = 21) or control group (n = 11). The intervention group completed a 12-week combined exercise plus diet program, consisting of weekly aerobic exercise and maintaining a nutritionally well balanced 1200 kcal/day diet. The control group was instructed to continue with their usual activities. Anthropometric indices and [Formula: see text] were measured at baseline and after the 12-week program. RESULTS: All 21 women completed the 12-week program. The [Formula: see text] significantly increased from 26.7 to 30.4 mL/kg/min (1.57-1.62 L/min) in the intervention group, while it remained unchanged (26.9-26.9 mL/kg/min) in the control group. Mean reduction of body mass index was - 2.1 in the intervention group (P < .001) and + 0.1 in the control group. CONCLUSIONS: Our combined exercise plus diet program may contribute to improvement in cardiorespiratory fitness and body weight compared with control group. PMID- 29992487 TI - The history of intracranial infections. AB - The 19th and 20th centuries heralded the advancement of our understanding of surgical infections, reducing the risk of morbidity and mortality to patients by overturning long-held dogmas surrounding infections and perioperative care. These advancements impacted the development and establishment of the field of neurological surgery by minimizing surgical risk through aseptic techniques and promoting surgical benefit via improved neurological localization and surgical technique. Infections were significant contributors to morbidity and mortality for all surgical patients, and historically almost half of patients lost their lives as a consequence of perioperative wound contamination. With advancing understanding of germ theory, contagion, antisepsis, and subsequently asepsis, the surgeon began embracing the knowledge and techniques which would hone their craft and allow for a renaissance in the management of neurological disorders in an unprecedented manner. PMID- 29992485 TI - Seeing minds in others: Mind perception modulates low-level social-cognitive performance and relates to ventromedial prefrontal structures. AB - In social interactions, we rely on nonverbal cues like gaze direction to understand the behavior of others. How we react to these cues is affected by whether they are believed to originate from an entity with a mind, capable of having internal states (i.e., mind perception). While prior work has established a set of neural regions linked to social-cognitive processes like mind perception, the degree to which activation within this network relates to performance in subsequent social-cognitive tasks remains unclear. In the current study, participants performed a mind perception task (i.e., judging the likelihood that faces, varying in physical human-likeness, have internal states) while event-related fMRI was collected. Afterwards, participants performed a social attention task outside the scanner, during which they were cued by the gaze of the same faces that they previously judged within the mind perception task. Parametric analyses of the fMRI data revealed that activity within ventromedial prefrontal cortex (vmPFC) was related to both mind ratings inside the scanner and gaze-cueing performance outside the scanner. In addition, other social brain regions were related to gaze-cueing performance, including frontal areas like the left insula, dorsolateral prefrontal cortex, and inferior frontal gyrus, as well as temporal areas like the left temporo-parietal junction and bilateral temporal gyri. The findings suggest that functions subserved by the vmPFC are relevant to both mind perception and social attention, implicating a role of vmPFC in the top-down modulation of low-level social-cognitive processes. PMID- 29992489 TI - Antioxidant Potential and Extracellular Auxin Production by White Rot Fungi. AB - Selective lignin degrading white rot fungi viz. Phanerochaete chrysosporium, Phlebia brevispora, and Phlebia floridensis were selected to evaluate antioxidant potential and auxin (indole acetic acid) production in complex and synthetic medium. Antioxidant potential of these fungi was tested against different free radicals including 2, 2-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide, ferrous ion, and ferric ion along with total phenolic content. All the fungal strains produce phenolics ranging from 5.2 to 16.7 mg/ml and demonstrated various free radical and metal ion scavenging activity. Growth medium significantly affected all the activities. Almost similar antioxidant activity (~ 72% DPPH scavenging activity) was demonstrated by all the fungi in yeast extract glucose medium; however, the activity was lower in Czapek dox's medium (from 60 to 45%). Indole acetic acid production was maximum in P. brevispora (31 MUg/ml), which was closely followed by P. chrysosporium and P. floridensis. The extracts did not show any mutagenic or cytotoxic effect. Thus, these white rot fungi highlight their significance as a new source for the prompt production of extracellular antioxidants and auxin. PMID- 29992488 TI - AhR activation protects intestinal epithelial barrier function through regulation of Par-6. AB - The Par complex (Par-6/Par-3/aPKC) plays a key role in the maintenance of the intestinal barrier function through the regulation of epithelial junction formation. The aryl hydrocarbon receptor (AhR) has been shown to be an important regulator for intestinal homeostasis. In this study, we investigated the role of the AhR activation on the regulation of Par complex. AhR activation by 6 formylindolo (3,2-b) carbazole (FICZ) represses the abnormal expression of the Par complex in a mouse model of dextran sulphate sodium (DSS)-induced colitis. In T84 cells, overexpression of Par-6 causes intestinal barrier dysfunction. Lipopolysaccharide (LPS)-induced intestinal epithelial barrier dysfunction and increase in Par-6 expression was prevented by AhR activation. However, FICZ did not alter the expression of Par-3 or aPKC. Furthermore, AhR activation alleviated LPS-induced increase of Par-6 through repressing the expression of activating protein-2gamma (Ap-2gamma). These results reveal the protective effects of AhR activation on LPS induced disruption of intestinal epithelial barrier function through suppressing the expression of Par-6 expression. Our findings provide novel insights into the protective role of AhR in intestinal barrier function. PMID- 29992490 TI - Evaluation of Cardiovascular Disease Risk in HIV-1-Infected Patients Treated with Darunavir. AB - INTRODUCTION: We evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post marketing pharmacovigilance databases, and administrative claims databases. METHODS: First, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2-4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)-infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases. RESULTS: Among 19 Janssen-sponsored clinical trials (treatment durations <= 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91-11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16 3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94 16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1-infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases. CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir. PMID- 29992491 TI - PBMT and topical diclofenac as single and combined treatment on skeletal muscle injury in diabetic rats: effects on biochemical and functional aspects. AB - Physical exercise generates several benefits in a short time in patients with diabetes mellitus. However, it can increase the chances of muscle damage, a serious problem for diabetic patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat these injuries, despite the serious adverse effects. In this way, photobiomodulation therapy (PBMT) with low-level laser therapy (LLLT) and/or light emitting diode therapy (LEDT) can be used as an alternative in this case. However, its efficacy in tissue repair of trauma injuries in diabetes mellitus until now is unknown, as well as the combination between PBMT and NSAIDs. The objective of the present study was to evaluate the effects of NSAIDs and PBMT applied alone or combined on functional and biochemical aspects, in an experimental model of muscle injury through controlled trauma in diabetic rats. Muscle injury was induced by means of a single trauma to the animals' anterior tibialis muscle. After 1 h, the rats were treated with PBMT (830 nm; continuous mode, with a power output of 100 mW; 3.57 W/cm2; 3 J; 107.1 J/cm2, 30 s), diclofenac sodium for topical use (1 g), or combination of them. Our results demonstrated that PBMT + diclofenac, and PBMT alone reduced the gene expression of cyclooxygenase-2 (COX-2) at all assessed times as compared to the injury and diclofenac groups (p < 0.05 and p < 0.01 respectively). The diclofenac alone showed reduced levels of COX-2 only in relation to the injury group (p < 0.05). Prostaglandin E2 levels in blood plasma demonstrated similar results to COX2. In addition, we observed that PBMT + diclofenac and PBMT alone showed significant improvement compared with injury and diclofenac groups in functional analysis at all time points. The results indicate that PBMT alone or in combination with diclofenac reduces levels of inflammatory markers and improves gait of diabetic rats in the acute phase of muscle injury. PMID- 29992492 TI - Relationship between post-surgery detection of methylated circulating tumor DNA with risk of residual disease and recurrence-free survival. AB - PURPOSE: Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence. METHODS: ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival. RESULTS: Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3-29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5-18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5-9.5, p = 0.004). CONCLUSIONS: CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit. PMID- 29992493 TI - Long-Term IL-2 Incubation-Induced L-type Calcium Channels Activation in Rat Ventricle Cardiomyocytes. AB - The following study examined the impact of IL-2 on Ca2+ channel activity in the event of several hours' incubation in IL-2. The right ventricle free wall for action potential measurements was isolated and perfused with Tyrode solution. The whole-cell voltage clamp experiments were performed on enzymatically isolated single cardiomyocytes. The whole-cell voltage clamp recording of Ca2+ currents was performed using the Cs+-based pipette and bath solutions. The protocol with depolarizing prepulse (- 40 mV) was used to inactivate both Na+ current and Ca2+ T-type current. The L-type Ca2+ current was elicited by a series of 250 ms depolarizing square pulses with 10 mV increments. At the 15th minute of continuous recording, the peak density at 0 mV was - 3.036 +/- 0.3015 pA/pF under IL-2 and - 3.008 +/- 0.3452 pA/pF in control conditions. The IL-2 in moderate concentration (1 ng/mL) has no acute effects on ICa.L in rat ventricular cells. In contrast, to the lack of acute effects, the long-term incubation with IL-2 (2 h or more) produced a prominent enhancement of Ca2+ L-type current. In rat, ventricular myocardium IL-2 (1 ng/mL) produced a very gradual prolongation of subendocardial APs which reached a maximal extent after 3-4 h of treatment. The patch clamp study shows an IL-2-induced ICa.L current activation, while the action potential studies on multicellular ventricular preparations suggest an IL 2-induced L-type Ca2+ channel participation in the development of AP. PMID- 29992494 TI - Predictive Role of the Cervical Sympathetic Trunk Ischemia on Lower Heart Rates in an Experimentally Induced Stenoocclusive Carotid Artery Model by Bilateral Common Carotid Artery Ligation. AB - Bilateral common carotid artery ligation (BCCAL) leads to acute craniocervicocerebral ischemia, retrograde blood flow, increased blood pressure, and significant hemodynamic and histomorphological changes at the posterior cerebral vasculature. We examined the potential relationship between denervation injury following BCCAL-induced cervical sympathetic trunk (CST) ischemia and heart rate after permanent BCCAL. Rabbits (n = 25) were randomly divided into three groups: an unoperated control group (GI, n = 6); a sham-operated control group (GII, n = 6), and an experimental group subjected to BCCAL (GIII, n = 13); and then followed for one month. All animals were then sacrificed and the stellate ganglia (STGs) were examined histologically using stereological methods. The densities of degenerated neurons in the STGs were compared with heart rates and the results were analyzed with the Mann-Whitney U test. The mean normal neuron density in STGs was 10.340 +/- 954/mm3 and the degenerated neuron density was 12 +/- 3/mm3 in the GI group (p > 0.5). The mean heart rates and degenerated neuron densities of STGs were recorded as 267 +/- 19/min and 237 +/- 45/mm3 in GII (p < 0.005 for GII vs. GI); and 190 +/- 11/min 1421 +/- 230/mm3 in GIII (p < 0.0001 for GIII vs. GI and p < 0.005 for GIII vs. GII). An inverse and meaningful association was observed between the heart rate and degenerated neuronal density in the STGs. BCCAL may lead to hazardous histomorphological changes in the CST. A high density of degenerated neurons in the STG may provoke excessive sympathetic hypoactivity-related cardiac damage and bradyarrhythmias after stenoocclusive carotid artery diseases. PMID- 29992495 TI - Fat-free mass and glucose homeostasis: is greater fat-free mass an independent predictor of insulin resistance? AB - BACKGROUND: A greater fat-free mass (FFM) is purported to be associated with protective effects on insulin resistance (IR). However, recent studies suggested negative associations between FFM and IR. OBJECTIVES: (1) To explore the direction of the association between FFM and IR in a large heterogeneous sample after controlling for confounding factors. (2) To determine cut off values of FFM associated with an increased risk of IR. METHODS: Outcome variables were measured in 7044 individuals (48.6% women, 20-79 years; NHANES, 1999-2006): body composition [fat mass (FM), FFM and appendicular FFM (aFFM); DXA], FFM index [FFMI: FFM/height (kg/m2)], appendicular FFMI [aFFM/height (kg/m2)] and insulin resistance (HOMA-IR). Multivariate regression analyses were performed to determine the independent predictors of HOMA-IR in younger (20-49 years) and older (50-79 years) men and women. ROC analyses were used to determine FFM cut offs to identify a higher risk of insulin resistance (HOMA-IR > 75th percentile). RESULTS: aFFMI was an independent predictor of IR in younger (men: beta = 0.21; women: beta = 0.31; all p <= 0.001) and older (men: beta = 0.11; women: beta = 0.37; all p <= 0.001) individuals. Thresholds for aFFMI at which the risk of IR was significantly increased were 8.96 and 8.39 kg/m2 in younger and older men, and 7.22 and 6.64 kg/m2 in younger and older women, respectively. CONCLUSION: Independently of age, a greater aFFMI was an independent predictor of IR. These results suggest revisiting how we envision the link between FFM and IR and explore potential mechanisms. PMID- 29992496 TI - Satisfaction and Sustainability in a Surgical Career. PMID- 29992497 TI - MeCP2 Differentially Regulate the Myelin MBP and PLP Protein Expression in Oligodendrocytes and C6 Glioma. AB - MeCP2 (methyl-CpG binding protein 2), an epigenetic regulator, has been shown to regulate the function of neurons and glial cells. Our previous study has demonstrated that MeCP2 repress the myelin gene expression in rat oligodendrocytes but whether MeCP2 bind to myelin gene MBP and PLP is not yet known. Besides oligodendrocytes, C6 glioma also expresses myelin genes and could be used as a model system to study myelin gene expression. In the present study, we determined that MeCP2 directly bind to MBP, PLP, and BDNF promoter in oligodendrocytes. Further, it was found that MeCP2 differentially regulates the myelin gene expression in oligodendrocytes and C6 glioma. In contrast to oligodendrocytes, MeCP2 does not bind to promoter region of MBP and PLP in C6 glioma suggest that MeCP2 differentially regulates the gene expression in different cell types. PMID- 29992498 TI - Pre-Injection of Small Interfering RNA (siRNA) Promotes c-Jun Gene Silencing and Decreases the Survival Rate of Axotomy-Injured Spinal Motoneurons in Adult Mice. AB - Brachial plexus injury is a common clinical peripheral nerve trauma. A series of genes in motoneurons were activated in the corresponding segments of the spinal cord after brachial plexus roots axotomy. The spatial and temporal expression of these genes directly affects the speed of motoneuron axon regeneration and precise target organ reinnervation. In a previous study, we observed the overexpression of c-Jun in motoneurons of the spinal cord ventral horn after brachial plexus injury in rats. However, the relevance of c-Jun expression with respect to the fate of axotomy-induced branchial plexus injury in adult mice remains unknown. In the present study, we explored the function of c-Jun in motoneuron recovery after axotomy. We pre-injected small interfering RNA (siRNA) to knockdown c-Jun expression in mice and examined the effects of the overexpression of c-Jun in motoneurons after the axotomy of the brachial plexus in vivo. Axotomy induced c-Jun overexpression in the ventral horn motoneurons of adult mice from 3 to 14 days after injury. In addition, the pre-injection of siRNA transiently inhibited c-Jun expression and decreased the survival rate of axotomy-injured motoneurons. These findings indicate that the axotomy-induced overexpression of c-Jun plays an important role in the survival of ventral horn motoneurons in adult mice. In addition, the pre-injection of c-Jun siRNA through the brachial plexus stem effectively adjusts c-Jun gene expression at the ipsilateral side. PMID- 29992500 TI - [Persistent postsurgical pain in children and young people : Prediction, prevention, and management]. PMID- 29992499 TI - Expression Analysis of CYFIP1 and CAMKK2 Genes in the Blood of Epileptic and Schizophrenic Patients. AB - Schizophrenia and epilepsy are two prevalent neurological disorders with high global burden to the society. Genome-wide studies have identified potential underlying causes for these neurological diseases. In the present case-control study, we have assessed expression of CYFIP1 and CAMKK2 genes in the blood samples of epileptic and schizophrenic patients compared with healthy subjects. A total of 180 subjects including 40 epileptic patients, 50 schizophrenic patients, and 90 healthy individuals participated in the study. Expression of the mentioned genes was measured using TaqMan real-time PCR. The results demonstrated a significant upregulation of CYFIP1 gene expression in epileptic patients (P = 0.029). CAMKK2 was downregulated in female schizophrenic patients compared with female healthy individuals (P = 0.048). These results may provide new insight into the pathogenesis of epilepsy and schizophrenia and suggest these genes as potential therapeutic targets for these neurological disorders. Future studies should evaluate these results in larger cohorts of patients. PMID- 29992501 TI - Is there an association between early weight status and utility-based health related quality of life in young children? AB - PURPOSE: Few studies focus on the health-related quality of life (HRQoL) of preschool children with overweight or obesity. This is relevant for evaluation of obesity prevention trials using a quality-adjusted life year (QALY) framework. This study examined the association between weight status in the preschool years and HRQoL at age 5 years, using a preference-based instrument. METHODS: HRQoL [based on parent proxy version of the Health Utilities Index Mark 3 (HUI3)] and weight status were measured in children born in Australia between 2007 and 2009. Children's health status was scored across eight attributes of the HUI3-vision, hearing, speech, ambulation, dexterity, emotion, cognition and pain, and these were used to calculate a multi-attribute utility score. Ordinary least squares (OLS), Tobit and two-part regressions were used to model the association between weight status and multi-attribute utility. RESULTS: Of the 368 children for whom weight status and HUI3 data were available, around 40% had overweight/obesity. After adjusting for child's sex, maternal education, marital status and household income, no significant association between weight status in the preschool years and multi-attribute utility scores at 5 years was found. CONCLUSIONS: Alternative approaches for capturing the effects of weight status in the preschool years on preference-based HRQoL outcomes should be tested. The application of the QALY framework to economic evaluations of obesity-related interventions in young children should also consider longitudinal effects over the life-course. Clinical Trial Registration The Healthy Beginnings Trial was registered with the Australian Clinical Trial Registry (ACTRNO12607000168459). PMID- 29992502 TI - DNA methylation alterations as therapeutic prospects in thyroid cancer. AB - BACKGROUND: Thyroid cancer is one of the most common endocrine malignancies. Although the 10-year survival rate of differentiated thyroid cancer (DTC) is about 90% after conventional treatments, a small proportion of patients still suffer from tumor recurrence or drug resistance. OBJECTIVE: This review article summarizes recent researches and clinical trials related to target drugs that reduce mortality in thyroid cancer. METHODS: This is a review of the recent literature and clinical trials on the three main aspects including methylation genes in thyroid cancers, the relationship between BRAF mutation and gene methylation, target and dehypermethylation drugs in clinical trials. RESULTS: We propose new approaches to treating malignant thyroid cancer, based on advances in understanding the relationship between genetic and epigenetic changes in thyroid cancer. Although the effect of traditional treatment for thyroid cancer is relatively good, a small proportion of patients still suffer from tumor recurrence or drug resistance. Molecular targeted drugs and dehypermethylation drugs have more promising outcomes in aggressive thyroid cancer compared with conventional treatments. CONCLUSION: Based on what was discussed in this review, we suggest that integration of epigenetic and targeted therapies into conventional treatments will reduce the occurrence of refractory radioiodine differentiated thyroid cancer and improve the outcomes in aggressive thyroid cancer patients. PMID- 29992503 TI - Complications of Cardiac Transplantation. AB - PURPOSE OF REVIEW: Despite the improvement in medical therapy for heart failure and the advancements in mechanical circulatory support, heart transplantation (HT) still remains the best therapeutic option to improve survival and quality of life in patients with advanced heart failure. Nevertheless, HT recipients are exposed to the risk of several potential complications that may impair their outcomes. In this article, we aim to provide a practical and scholarly framework for clinicians approaching heart transplant medicine, as well as a concise update for the experienced readers on the most relevant post-HT complications. RECENT FINDINGS: While recognizing that most of the treatments herein discussed are based more on experience than on solid scientific evidence, significant step forward has been made in particular in the recognition and management of primary graft dysfunction, antibody-mediated rejection, and renal dysfunction. Complications after HT may vary according to the time from surgery and can be related to graft function and pathology or to diseases and dysfunctions occurring in other organs or systems, mainly as side effects of immunosuppressive drugs and progression of pre-existing conditions. Future research needs to focus on improving precision diagnostics of causes of graft dysfunction and on reaching an optimal and customized balance between efficacy and toxicities of immunosuppressive strategies. PMID- 29992505 TI - Estimating land market values from real estate offers: A replicable method in support of biodiversity conservation strategies. AB - While cost estimation is a very positive tool for spatial conservation prioritisation, there are few examples where costs (in monetary terms) are applied. We present a repeatable method to estimate and map field values in monetary terms using common correlative models. We modelled, with a resolution of 1 km2, the information obtained by several real estate's agencies with a set of eleven environmental, climatic, and anthropogenic variables. Land cover was the main influencing factor, but further variables were affecting bids on field sales according to the socio-economic specificity of each administrative province. The estimated values were related to endemic plant species richness, their conservation status and altitudinal ranges. Richest areas in endemics have lower values given current market conditions and, within these endemic rich areas, values near the coast were generally higher than the rest of endemic-rich territories. Despite their limits, our method offers an alternative perspective on the challenges of simplifying the extrapolation of useful information for planning and disseminating the conservation of many ecosystem services providers. PMID- 29992504 TI - Orexins, Sleep, and Blood Pressure. AB - PURPOSE OF REVIEW: The aim of this review was to summarize collected data on the role of orexin and orexin neurons in the control of sleep and blood pressure. RECENT FINDINGS: Although orexins (hypocretins) have been known for only 20 years, an impressive amount of data is now available regarding their physiological role. Hypothalamic orexin neurons are responsible for the control of food intake and energy expenditure, motivation, circadian rhythm of sleep and wake, memory, cognitive functions, and the cardiovascular system. Multiple studies show that orexinergic stimulation results in increased blood pressure and heart rate and that this effect may be efficiently attenuated by orexinergic antagonism. Increased activity of orexinergic neurons is also observed in animal models of hypertension. Pharmacological intervention in the orexinergic system is now one of the therapeutic possibilities in insomnia. Although the role of orexin in the control of blood pressure is well described, we are still lacking clinical evidence that this is a possibility for a new approach in the treatment of cardiovascular diseases. PMID- 29992506 TI - Progranulin Is Positively Associated with Intervertebral Disc Degeneration by Interaction with IL-10 and IL-17 Through TNF Pathways. AB - Progranulin (PGRN) is a widely expressed growth factor that effectively inhibits tumor necrosis factor alpha (TNFalpha)-mediated inflammatory response. TNFalpha is involved in intervertebral disc degeneration (IDD) and plays a key role. This study aims to determine the role of PGRN in the intervertebral disc degeneration process. We collected intervertebral discs (IVDs) from humans and mice with different genetic backgrounds. We examined the expression of PGRN in IVD tissues by immunohistochemistry staining and Western blotting assay. We examined the peripheral serum level of PGRN by ELISA assay. Murine IVD tissue samples were taken to undergo safranin O, HE, and immunohistochemistry staining. Primary human nucleus pulposus cells were used for ELISA and RT-PCR assays. PGRN as well as interlukin-10 (IL-10) and interlukin-17 (IL-17) expressions were elevated in degenerative discs and peripheral blood sera. Loss of PGRN led to accelerated disc degeneration in the animal model, along with decreased expression of IL-10 and increased expression of IL-17. Additionally, the PGRN level was positively related to levels of IL-10 and IL-17. In vitro study suggested that PGRN protected against disc degeneration by inducing IL-10 and reducing IL-17. PGRN is associated with intervertebral disc degeneration through interfering with IL-10 and IL-17; thus, PGRN could be an interesting biomarker for diagnosis and a potential treatment target. PMID- 29992507 TI - Can variable practice habits and injection port dead-volume put patients at risk? AB - Injection ports used to administer medications and draw blood samples have inherent dead-volume. This volume can potentially lead to inadvertent drug administration, contribute to erroneous laboratory values by dilution of blood samples, and increase the risk of vascular air embolism. We sought to characterize provider practice in management of intravenous (IV) and arterial lines and measure dead-volumes of various injection ports. A survey was circulated to anesthesiology physicians and nurses to determine practice habits when administering medications and drawing blood samples. Dead-volume of one and four-way injection ports was determined by injecting methylene blue to simulate medication administration or blood sample aspiration and using absorption spectroscopy to measure sample concentration. Among the 65 survey respondents, most (64.52%) increase mainstream flow rate to flush medication given by a 1-way injection port. When using 4-way stopcocks, 56.45% flush through the same injection site. To obtain a sample from an arterial line, 67.74% draw back blood and collect the sample from the same 4-way stopcock; 32.26% use a different stopcock. Mean (SD) dead-volume in microliters ranged from 0.1 (0.0) to 5.6 (1.0) in 1-way injection ports and from 54.1 (2.8) to 126.5 (8.3) in 4-way injection ports. The practices of our providers when giving medications and drawing blood samples are variable. The dead-volume associated with injection ports used at our institution may be clinically significant, increasing errors in medication delivery and laboratory analysis. PMID- 29992508 TI - Aldo-keto reductase 1C3 (AKR1C3): a missing piece of the puzzle in the dinaciclib interaction profile. AB - Dinaciclib is a multi-specific cyclin-dependent kinase (CDK) inhibitor with significant preclinical and clinical activity. It inhibits CDK1, CDK2, CDK5, CDK9 and CDK12 in the nanomolar range and exhibits potent antiproliferative effects on various cancers in vitro and in vivo. Aldo-keto reductases (AKR) and carbonyl reductases (CBR) are enzymes involved at the biosynthesis, intermediary metabolism and detoxification processes, but can also play a significant role in cancer resistance. Here, we report that dinaciclib is a strong inhibitor of aldo keto reductase 1C3 (AKR1C3), an enzyme that is known to be an important regulator of cell proliferation and differentiation. AKR1C3 is overexpressed in a range of cancer types and is also involved in tumour cell resistance to anthracyclines. In our study, dinaciclib displayed tight-binding inhibition of human recombinant AKR1C3 (Kiapp = 0.07 uM) and was also active at the cellular level (IC50 = 0.23 uM). Dinaciclib acts as a noncompetitive inhibitor with respect to daunorubicin and as an uncompetitive inhibitor with respect to the NADPH. In subsequent experiments, pretreatment with dinaciclib (0.1 uM) significantly sensitized AKR1C3-overexpressing anthracycline-resistant cancer cells to daunorubicin. In conclusion, our results indicate that dinaciclib may potentially increase the therapeutic efficacy and safety of anthracyclines by preventing anthracycline resistance and minimizing their adverse effects. PMID- 29992509 TI - Understanding osteoporotic pain and its pharmacological treatment: supplementary presentation. AB - Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic nociceptive and neuropathic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and non-pharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post-fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients. PMID- 29992510 TI - Incident fracture is associated with a period of accelerated loss of hip BMD: the Study of Osteoporotic Fractures. AB - : Bone loss following a fracture could increase the risk of future fractures. In this study, we found that elderly women who had an upper body fracture or multiple fractures lost more bone at the hip than those who did not fracture. This suggests a possible systemic bone loss response initiated by fracture. INTRODUCTION: A prior fracture is one of the strongest predictors of subsequent fracture risk, but the etiology of this phenomenon remains unclear. Systemic bone loss post-fracture could contribute to increased risk of subsequent fractures. Therefore, in this study, we investigated whether incident fractures, including those distant to the hip, are associated with accelerated loss of hip bone mineral density (BMD) in elderly women. METHODS: We analyzed data from 3956 Caucasian women aged >= 65 years who were enrolled in the Study of Osteoporotic Fractures and completed hip BMD measurements at study visit 4 (year 6) and visit 6 (year 10). Clinical fractures between visits 4 and 6 were ascertained from triannual questionnaires and centrally adjudicated by review of community radiographic reports. Subjects provided questionnaire information and clinical variables at examinations for known and potential covariates. Generalized linear models were used to calculate average annual percent change in total hip BMD between visits 4 and 6 for each incident fracture type and for upper body and lower body fractures combined. A subset of women (n = 3783) was analyzed for annual total hip BMD change between study visits 4 and 5 and between study visits 5 and 6 to evaluate change in total hip BMD during these 2-year intervals. RESULTS: Women with incident upper body fracture or incident lower body fracture exhibited reductions in total hip BMD of 0.89 and 0.77% per year, respectively, while women who did not fracture exhibited reductions in total hip BMD of 0.66% per year during the 4-year period. Accelerated loss of hip BMD was isolated to the 2-year time interval that included the fracture. Loss of total hip BMD was not affected by the number of days from fracture to follow up DXA. CONCLUSIONS: Systemic bone loss following fracture may increase the risk of future fractures at all skeletal sites. There is a need for improved understanding of mechanisms leading to apparent accelerated bone loss following a fracture in order to reduce subsequent fracture risk. PMID- 29992511 TI - Potential Role of Brain-Derived Neurotrophic Factor and Dopamine Receptor D2 Gene Variants as Modifiers for the Susceptibility and Clinical Course of Wilson's Disease. AB - Wilson's disease (WD), an inborn error of copper metabolism caused by mutations in the ATPase copper transporting beta (ATP7B) gene, manifests variable age of onset and different degrees of hepatic and neurological disturbances. This complex phenotypical outcome of a classical monogenic disease can possibly be explained by modifier loci regulating the clinical course of the disease. The brain-derived neurotropic factor (BDNF), critical for the survival, morphogenesis, and plasticity of the neurons, and the dopamine receptor D2 (DRD2), one of the most abundant dopamine receptors in the brain, have been highlighted in the pathophysiology of various neuropsychiatric diseases. This study aims to identify the potential association between BDNF and DRD2 gene polymorphisms and WD and its clinical characteristics. A total of 164 WD patients and 270 controls from India were included in this study. Two BDNF polymorphisms [p.Val66Met (c.G196A) and c.C270T] and the DRD2 Taq1A (A2/A1 or C/T) polymorphism were examined for their association with WD and some of its clinical attributes, using polymerase chain reaction, restriction fragment length digestion, and bidirectional sequencing. The C allele and CC genotype of BDNF C270T were significantly overrepresented among controls compared to WD patients. In addition, a significantly higher proportion of the allele coding for Val and the corresponding homozygous genotype of BDNF Val66Met polymorphism was found among WD patients with age of onset later than 10 years. Furthermore, the A1A1 genotype of DRD2 Taq1A polymorphism was significantly more common among WD patients with rigidity. Our data suggest that both BDNF and DRD2 may act as potential modifiers of WD phenotype in the Indian context. PMID- 29992512 TI - Hepatitis C virus genotype 4-infection and interferon-free treatment in Egypt. PMID- 29992514 TI - Human Hair Follicle Associated-Pluripotent (hHAP) Stem Cells Differentiate to Cardiac Muscle Cells. AB - Human hair follicle-associated pluripotent (hHAP) stem cells were isolated from the upper parts of human hair follicles. hHAP stem cells were suspended in DMEM containing 10% fetal bovine serum (FBS) where they differentiated to cardiac muscle cells as well as neurons, glial cells, keratinocytes, and smooth muscle cells. The methods of this chapter are appropriate for use of human hair follicles to produce hHAP stem cells in sufficient quantities for future heart, nerve, and spinal cord regeneration in the clinic. PMID- 29992513 TI - Extreme clustering of type-1 NF1 deletion breakpoints co-locating with G quadruplex forming sequences. AB - The breakpoints of type-1 NF1 deletions encompassing 1.4-Mb are located within NF1-REPa and NF1-REPc, which exhibit a complex structure comprising different segmental duplications in direct and inverted orientation. Here, we systematically assessed the proportion of type-1 NF1 deletions caused by nonallelic homologous recombination (NAHR) and those mediated by other mutational mechanisms. To this end, we analyzed 236 unselected type-1 deletions and observed that 179 of them (75.8%) had breakpoints located within the NAHR hotspot PRS2, whereas 39 deletions (16.5%) had breakpoints located within PRS1. Sixteen deletions exhibited breakpoints located outside of these NAHR hotspots but were also mediated by NAHR. Taken together, the breakpoints of 234 (99.2%) of the 236 type-1 NF1 deletions were mediated by NAHR. Thus, NF1-REPa and NF1-REPc are strongly predisposed to recurrent NAHR, the main mechanism underlying type-1 NF1 deletions. We also observed a non-random overlap between type-1 NF1-deletion breakpoints and G-quadruplex forming sequences (GQs) as well as regions flanking PRDM9A binding-sites. These findings imply that GQs and PRDM9A binding-sites contribute to the clustering of type-1 deletion breakpoints. The co-location of both types of sequence was at its highest within PRS2, indicative of their synergistic contribution to the greatly increased NAHR activity within this hotspot. PMID- 29992516 TI - Controlled drainage of subretinal fluid during scleral buckling surgery for rhegmatogenous retinal detachment: the pigment stream sign. AB - PURPOSE: To describe the macroscopic characteristics of the subretinal fluid (SRF) and its spilling modality during evacuative puncture in scleral buckling (SB) surgery for rhegmatogenous retinal detachment. METHODS: We retrospective reviewed all the SB surgeries performed over a period of 26 months at the University Eye Clinic of Trieste, Italy. We selected a cohort of 102 patients in which SRF drainage by means of evacuative puncture was performed. A high definition video was recorded during the whole duration of the procedures, and the macroscopic characteristics of the SRF leakage were assessed. RESULTS: Pigmented dark-brownish deposits spilling in the fluid outcoming from the evacuative puncture was observed during the surgeries. In all cases, this macroscopic feature was detected during the late phases of the drainage. Moreover, indirect ophthalmoscopic evaluation showed the almost complete SRF drainage and a flattened retina at that moment. CONCLUSIONS: The pigment stream sign, easily detectable by the surgeon, allows to understand, during the evacuative puncture, when the SRF has been drained almost completely and that the drainage procedure is therefore close to the end. PMID- 29992515 TI - Preventing Major Amputations in Patients with Critical Limb Ischemia. AB - PURPOSE OF REVIEW: This review summarizes the risks of lower extremity amputation associated with critical limb ischemia (CLI) and discusses current therapies that can prevent amputation in CLI. RECENT FINDINGS: CLI remains an under-recognized condition associated with high rates of major amputation and disparities in care. Optimal medical therapy can reduce the risk of major adverse cardiovascular and limb events, but revascularization combined with close wound care remains the cornerstone of amputation prevention. Endovascular revascularization has become more common over time and has been associated with a reduction in amputation rates. Ongoing clinical trials will help inform best practices for revascularization strategies and techniques. Vascular care is inconsistent across the USA, with significant variation in access to care revascularization rates and rates of major amputation. Major amputation can be prevented in patients with CLI when optimal medical therapy, lifestyle modification, and revascularization are provided in a multidisciplinary setting. PMID- 29992517 TI - Viruses do not have polythetic properties; species are polythetic classes and do not have any properties. PMID- 29992518 TI - Characterization of two Pantoea strains isolated from extra-virgin olive oil. AB - The olive oil is an unfavorable substrate for microbial survival and growth. Only few microorganisms use olive oil fatty acids as carbon and energy sources, and survive in the presence of olive oil anti-microbial components. In this study, we have evaluated the occurrence of microorganisms in 1-year-stored extra-virgin olive oil samples. We detected the presence of bacterial and yeast species with a recurrence of the bacterium Stenotrophomonas rhizophila and yeast Sporobolomyces roseus. We then assayed the ability of all isolates to grow in a mineral medium supplemented with a commercial extra-virgin olive oil as a sole carbon and energy source, and analyzed the utilization of olive oil fatty acids during their growth. We finally focused on two bacterial isolates belonging to the species Pantoea septica. Both these isolates produce carotenoids, and one of them synthesizes bioemulsifiers enabling the bacteria to better survive/growth in this unfavorable substrate. Analyses point to a mixture of glycolipids with glucose, galactose and xylose as carbohydrate moieties whereas the lipid domain was constituted by C6-C10 beta-hydroxy carboxylic acids. PMID- 29992519 TI - Postoperative Infectious Complications Impact Long-Term Survival in Patients Who Underwent Hepatectomies for Colorectal Liver Metastases: a Propensity Score Matching Analysis. AB - OBJECTIVE: Postoperative complications strongly impact the postoperative course and long-term outcome of patients who underwent liver resection for colorectal liver metastases (CRLM). Among them, infectious complications play a relevant role. The aim of this study was to evaluate if infectious complications still impact overall and disease-free survival after liver resection for CRLM once patients were matched with a propensity score matching analysis based on Fong's criteria. METHODS: A total of 2281 hepatectomies were analyzed from a multicentric retrospective cohort of hepatectomies. Patients were matched with a 1:3 propensity score analysis in order to compare patients with (INF+) and without (INF-) postoperative infectious complications. RESULTS: Major resection (OR = 1.69 (1.01-2.89), p = 0.05) and operative time (OR = 1.1 (1.1-1.3), p = 0.05) were identified as risk factors of infectious complications. After propensity score matching, infectious complications are associated with overall survival (OS), with 1-, 3-, 5-year OS at 94, 81, and 66% in INF- and 92, 66, and 57% in INF+ respectively (p = 0.01). Disease-free survival (DFS) was also different with regard to 1-, 3-, 5-year survival at 65, 41, and 22% in R0 vs. 50, 28, and 17% in INF+ (p = 0.007). CONCLUSION: Infectious complications are associated with decreased overall and disease-free survival rates. PMID- 29992520 TI - Indocyanine Green Tissue Angiography Can Reduce Extended Bowel Resections in Acute Mesenteric Ischemia. AB - PURPOSE: Surgical exploration and bowel resection are frequently required for treating non-occlusive mesenteric ischemia. Intraoperative evaluation of intestinal perfusion is subjective and challenging. In this feasibility study, ICG fluorescence angiography was performed in order to evaluate intestinal perfusion in patients with acute mesenteric ischemia. METHODS: This is a retrospective analysis of 52 patients who were operated for acute mesenteric ischemia using ICG fluorescence angiography. Patients with occlusive disease requiring recanalization were excluded. The SPY and PinPoint imaging systems were used for open and laparoscopic surgery, respectively. Intraoperative macroscopic assessment of perfusion was compared with the ICG angiography results. RESULTS: Surgical exploration was performed for ischemia of the colon (n = 12), the small bowel (n = 23), or both (n = 16). One patient had ischemia of the esophagus and stomach. All patients had a preoperative CT angiography to rule out stenosis or occlusion of the mesenteric vessels. In 18 cases (34.6%), ICG fluorescence angiography provided information that was supplemental to macroscopic evaluation, but most patients did not survive the postoperative course. However, in six of those cases (11.5%), ICG angiography led to a major change in operative strategy resulting in a significant clinical benefit for those patients. For two cases, ICG fluorescence produced false negative results. DISCUSSION: ICG tissue angiography is feasible and technically reliable for evaluating intestinal perfusion in acute mesenteric ischemia and led to a significant clinical benefit in 11% of our patients. A relevant discrepancy between surgical visual assessment and fluorescence angiography was found in 35% of the cases, which may help to define resection margins more accurately and thus support surgical decision making. PMID- 29992521 TI - Individual and Sibling Characteristics: Parental Differential Treatment and Adolescent Externalizing Behaviors. AB - Adolescents' reports of parental differential treatment have been linked to increased externalizing behaviors. The current study investigated whether adolescent self-esteem and sibling relationship characteristics (age-spacing and sibling relationship quality) moderated associations between parental differential treatment and later externalizing behavior. Data was gathered at two assessments from 708 sibling pairs (94% White; 51% male; same-gender pairs <4 years apart in age). Older/younger siblings were aged MAssessment1 = 13.5/12.1 and MAssessment2 = 16.2/14.7 years. We found that higher levels of maternal differential treatment predicted greater residualized gains in externalizing behavior among older siblings who were (a) the same age as their sibling or near to and had low self-esteem or (b) three years older than their sibling and had higher self-esteem. Higher levels of paternal differential treatment predicted greater residual gains in externalizing for older siblings with wider age ranges (regardless of self-esteem), and among older siblings with high levels of self esteem (regardless of age difference). Surprisingly, maternal differential treatment was protective in one case: for adolescents with low self-esteem who were at least three years older than their siblings, maternal differential treatment predicted reduced externalizing behaviors. Paternal differential treatment was protective for more youth than maternal differential treatment: older siblings with low self-esteem who experienced paternal differential treatment exhibited decreased externalizing behaviors across adolescence, regardless of age difference. The findings highlight the importance of self esteem and sibling age-spacing as particularly salient contextual influences in older siblings' perceptions of maternal and paternal differential treatment, and that maternal and especially paternal differential treatment does not always serve as a risk factor for externalizing problems. PMID- 29992522 TI - Correction to: A challenging case of carbapenemase-producing Klebsiella pneumoniae septic thrombophlebitis and right mural endocarditis successfully treated with ceftazidime/avibactam. AB - The given names and family names of all authors were transposed in the original publication. The original article has been corrected. PMID- 29992523 TI - Charite Hospital and infectious diseases. AB - Films are useful for medical education and introduce Science fiction movies or historic documentaries and pioneering scientists who developed the field of infectious disease research. Between the late nineteenth and early twentieth centuries, expert talents such as von Behring, Koch, and Ehrlich were present at the Charite Hospital. These individuals contributed significantly to the scientific study of infections, their prevention, treatment, and social impact. Here, we compare the relative impact of infectious disease research centers during the study period (late nineteenth and early twentieth centuries) by assuming that the number of publications listed on Wikipedia about the individual scientists working in London, Paris, and Berlin is Poisson distributed. We show that using reference counts that appear after individuals' names on Wikipedia is a useful tool to assess the impact of centers of excellence in the study of infectious diseases. However, the accumulation of talent in Berlin during a relatively short period, even though historically the protagonists did not interact or support each other, lead to greater advances in the treatment and prevention of infections in humans than the work of individuals such as Pasteur in Paris or Lister in London. PMID- 29992524 TI - Prognostic effect and modulation of cardiac sympathetic function in heart failure patients treated with cardiac resynchronization therapy. AB - BACKGROUND: Cardiac autonomic dysfunction as assessed by 123I metaiodobenzylguanidine (123I-mIBG) scintigraphy is associated with poor prognosis in heart failure (HF) patients. Although cardiac resynchronization therapy (CRT) has emerged as an effective therapy in improving outcomes on HF patients, its effect on cardiac sympathetic nervous function is still not fully understood. We aimed to study the value of pre-implantation 123I-mIBG late heart to-mediastinum ratio (HMR) as a predictor of response and outcomes after CRT and to correlate modification in this parameter with CRT response and functional improvement. METHODS AND RESULTS: BETTER-HF (Benefit of exercise training therapy and cardiac resynchronization in HF patients) is a prospective randomized clinical trial including HF patients submitted CRT (mean LVEF 24 +/- 8%, 74% NYHA class >= III) who underwent a clinical, echocardiographic, and scintigraphic assessment before and 6 months after CRT. One-hundred and twenty-one patients were included. Echocardiographic response was observed in 54% and composite outcome of cardiac mortality, cardiac transplant or heart failure hospitalization in 24% of patients. Baseline late HMR was an independent predictor of CRT response (regression coefficient 2.906, 95% CI 0.293-3.903, P .029) and outcomes (HR 0.066 95% CI 0.005-0.880, P .040). At follow-up, 123I-mIBG imaging showed positive changes in cardiac sympathetic nerve activity only in responders to CRT (1.36 +/- 0.14 prior vs. 1.42 +/- 0.16 after CRT, P .039). There was a significant correlation between improvement in late HMR and improvement in peak oxygen consumption (r 0.547, P < .001). CONCLUSION: In our study, baseline cardiac denervation predicted response and clinical outcomes after CRT implantation. Cardiac sympathetic function was improved only in patients who responded to CRT and these positive changes were correlated with improvement in functional capacity. PMID- 29992525 TI - In search of the vulnerable patient or the vulnerable plaque: 18F-sodium fluoride positron emission tomography for cardiovascular risk stratification. AB - Cardiovascular disease (CVD) remains a leading cause of death. Preventative therapies that reduce CVD are most effective when targeted to individuals at high risk. Current risk stratification tools have only modest prognostic capabilities, resulting in over-treatment of low-risk individuals and under-treatment of high risk individuals. Improved methods of CVD risk stratification are required. Molecular imaging offers a novel approach to CVD risk stratification. In particular, 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) has shown promise in the detection of both high-risk atherosclerotic plaque features and vascular calcification activity, which predicts future development of new vascular calcium deposits. The rate of change of coronary calcium scores, measured by serial computed tomography scans over a 2-year period, is a strong predictor of CVD risk. Vascular calcification activity, as measured with 18F-NaF PET, has the potential to provide prognostic information similar to consecutive coronary calcium scoring, with a single-time-point convenience. However, owing to the rapid motion and small size of the coronary arteries, new solutions are required to address the traditional limitations of PET imaging. Two different methods of coronary PET analysis have been independently proposed and here we compare their respective strengths, weaknesses, and the potential for clinical translation. PMID- 29992527 TI - Erratum to: RNA-Seq and Expression Arrays: Selection Guidelines for Genome-Wide Expression Profiling. AB - The original version of the book was inadvertently published with incorrect spelling of the author name "Qiuchen Guo" corrections. The author name has now been corrected and approved by the author. PMID- 29992528 TI - Convolutional neural network scoring and minimization in the D3R 2017 community challenge. AB - We assess the ability of our convolutional neural network (CNN)-based scoring functions to perform several common tasks in the domain of drug discovery. These include correctly identifying ligand poses near and far from the true binding mode when given a set of reference receptors and classifying ligands as active or inactive using structural information. We use the CNN to re-score or refine poses generated using a conventional scoring function, Autodock Vina, and compare the performance of each of these methods to using the conventional scoring function alone. Furthermore, we assess several ways of choosing appropriate reference receptors in the context of the D3R 2017 community benchmarking challenge. We find that our CNN scoring function outperforms Vina on most tasks without requiring manual inspection by a knowledgeable operator, but that the pose prediction target chosen for the challenge, Cathepsin S, was particularly challenging for de novo docking. However, the CNN provided best-in-class performance on several virtual screening tasks, underscoring the relevance of deep learning to the field of drug discovery. PMID- 29992526 TI - An Overview of Metabolic Phenotyping in Blood Pressure Research. AB - PURPOSE OF THE REVIEW: This review presents the analytical techniques, processing and analytical steps used in metabolomics phenotyping studies, as well as the main results from epidemiological studies on the associations between metabolites and high blood pressure. RECENT FINDINGS: A variety of metabolomic approaches have been applied to a range of epidemiological studies to uncover the pathophysiology of high blood pressure. Several pathways have been suggested in relation to blood pressure including the possible role of the gut microflora, inflammatory, oxidative stress, and lipid pathways. Metabolic changes have also been identified associated with blood pressure lowering effects of diets high in fruits and vegetables and low in meat intake. However, the current body of literature on metabolic profiling and blood pressure is still in its infancy, not fully consistent and requires careful interpretation. Metabolic phenotyping is a promising approach to uncover metabolic pathways associated with high blood pressure and throw light into the complex pathophysiology of hypertension. PMID- 29992529 TI - MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson's Disease Patients. AB - Dyskinesia induced by L-DOPA administration (LID) is one of the most invalidating adverse effects of the gold standard treatment restoring dopamine transmission in Parkinson's disease (PD). However, LID manifestation in parkinsonian patients is variable and heterogeneous. Here, we performed a candidate genetic pathway analysis of the mTOR signaling cascade to elucidate a potential genetic contribution to LID susceptibility, since mTOR inhibition ameliorates LID in PD animal models. We screened 64 single nucleotide polymorphisms (SNPs) mapping to 57 genes of the mTOR pathway in a retrospective cohort of 401 PD cases treated with L-DOPA (70 PD with moderate/severe LID and 331 with no/mild LID). We performed classic allelic, genotypic, and epistatic analyses to evaluate the association of individual or combinations of SNPs with LID onset and with LID severity after initiation of L-DOPA treatment. As for the time to LID onset, we found significant associations with SNP rs1043098 in the EIF4EBP2 gene and also with an epistatic interaction involving EIF4EBP2 rs1043098, RICTOR rs2043112, and PRKCA rs4790904. For LID severity, we found significant association with HRAS rs12628 and PRKN rs1801582 and also with a four-loci epistatic combination involving RPS6KB1 rs1292034, HRAS rs12628, RPS6KA2 rs6456121, and FCHSD1 rs456998. These findings indicate that the mTOR pathway contributes genetically to LID susceptibility. Our study could help to identify the most susceptible PD patients to L-DOPA in order to prevent the appearance of early and/or severe LID in a future. This information could also be used to stratify PD patients in clinical trials in a more accurate way. PMID- 29992530 TI - Neuroglobin Expression in the Brain: a Story of Tissue Homeostasis Preservation. AB - After its discovery in 2000, the notion grew that neuroglobin, a neuronal specific heme protein, is involved in cytoprotection. To date, neuroglobin levels have been positively correlated with a beneficial outcome in a plethora of neurotoxic insults, e.g., ischemic and traumatic brain injuries and Alzheimer's disease. The first part of this review goes further into these changes of neuroglobin expression upon different neuronal insults as well as the underlying regulation. In the second part, we shed light on the mechanisms by which neuroglobin contributes to neuroprotection, being (i) the scavenging and detoxification of reactive oxygen/nitrogen species, (ii) the augmentation of the threshold for apoptosis initiation, (iii) its contribution to an anti inflammatory milieu, and (iv) tissue regeneration. We also consider different neuroglobin models to address as yet unanswered questions. Based on the recent findings and progress in the field, we invigorate the avenues of neuroglobin in neurological ailments to increase in the coming years. PMID- 29992531 TI - Ischemic Injury-Induced CaMKIIdelta and CaMKIIgamma Confer Neuroprotection Through the NF-kappaB Signaling Pathway. AB - Ca2+/calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the CaMKII family in neuronal survival during I/R. Our data indicated that CAMK2D/CaMKIIdelta and CAMK2G/CaMKIIgamma were selectively upregulated in a time dependent manner at both transcriptional and protein levels after acute ischemia. Overexpression of CaMKIIdelta promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar to CaMKIIdelta, knockdown of CAMKIIgamma resulted in significant neuronal death after I/R. We further identified CaMKIIdelta2 as the subtype that is selectively induced by I/R in primary neurons. The induction of CaMKIIdelta was controlled in part by a pair of long non-coding RNAs (lncRNAs), C2dat1 and C2dat2. C2dat2, similar to C2dat1, was upregulated by I/R and cooperated with C2dat1 to modulate CaMKIIdelta expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKIIdelta expression and decreased neuronal survival but did not affect the levels of CaMKIIgamma, indicating specific targeting of CAMK2D by C2dat1/2. Mechanistically, I/R-induced CaMKIIdelta and CaMKIIgamma caused the upregulation of IKKalpha/beta and further activation of the NF-kappaB signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-kappaB in mice increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/IkappaBalpha/NF kappaB signaling axis. In summary, CaMKIIdelta and CaMKIIgamma are novel I/R induced genes that promote neuronal survival during ischemic injury. The upregulation of these CaMKII kinases led to activation of the NF-kappaB signaling pathway, which protects neurons from ischemic damage. PMID- 29992532 TI - Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis. AB - OBJECTIVE: To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder. METHOD: A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018. RESULTS: There were 706 cases of anti NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period. CONCLUSION: The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification. PMID- 29992533 TI - Estimating the causal effect of treatment regimes for organ transplantation. AB - Patients awaiting cadaveric organ transplantation face a difficult decision if offered a low-quality organ: accept the organ or remain on the waiting list and hope a better organ is offered in the future. A dynamic treatment regime (DTR) for transplantation is a rule that determines whether a patient should decline an offered organ. Existing methods can estimate the effect of DTRs on survival outcomes, but these were developed for applications where treatment is abundantly available. For transplantation, organ availability is limited, and existing methods can only estimate the effect of a DTR assuming a single patient follows the DTR. We show for transplantation that the effect of a DTR depends on whether other patients follow the DTR. To estimate the anticipated survival if the entire population awaiting transplantation were to adopt a DTR, we develop a novel inverse probability weighted estimator (IPCW) which re-weights patients based on the probability of following their transplant history in the counterfactual world in which all patients follow the DTR of interest. We estimate this counterfactual probability using hot deck imputation to fill in data that is not observed for patients who are artificially censored by IPCW once they no longer follow the DTR of interest. We show via simulation that our proposed method has good finite sample properties, and we apply our method to a lung transplantation observational registry. PMID- 29992534 TI - An Entity Theory of Intelligence Predicts Higher Cortisol Levels When High School Grades Are Declining. AB - Grades often decline during the high school transition, creating stress. The present research integrates the biopsychosocial model of challenge and threat with the implicit theories model to understand who shows maladaptive stress responses. A diary study measured declines in grades in the first few months of high school: salivary cortisol (N = 360 students, N = 3,045 observations) and daily stress appraisals (N = 499 students, N = 3,854 observations). Students who reported an entity theory of intelligence (i.e., the belief that intelligence is fixed) showed higher cortisol when grades were declining. Moreover, daily academic stressors showed a different lingering effect on the next day's cortisol for those with different implicit theories. Findings support a process model through which beliefs affect biological stress responses during difficult adolescent transitions. PMID- 29992535 TI - Psoriasis and cancer. An Australian/New Zealand narrative. AB - Patients with psoriasis have an increased risk of cancer, which may be due to impaired immune surveillance, immune modulatory treatments, chronic inflammation and/or co-risk factors such as obesity. The increase in treatment-independent solid cancers, including urinary/bladder cancers, oropharynx/larynx, liver/gallbladder and colon/rectal cancers, seem to be linked to alcohol and smoking. Lung cancer and nonmelanoma skin cancer are also increased in patients with psoriasis. The risk of nonmelanoma skin cancer increases with age and severity of psoriasis. It is also higher in men, particularly for squamous cell carcinoma, which may reflect previous exposure to PUVA and/or ciclosporin. The risk of cutaneous T-cell lymphoma is substantially higher in patients with moderate-to-severe psoriasis. Biologic therapies are independently associated with a slight increase risk of cancer, but this is less than ciclosporin, with the risk confounded by disease severity and other co-risk factors. The risk of cancer from low-dose methotrexate is likely minimal. In contrast, acitretin is likely protective against a variety of solid and haematological malignancies. The data on small molecule therapies such as apremilast are too immature for comment, although no signal has yet been identified. The decision whether to stop psoriasis immune modulatory treatments following a diagnosis of cancer, and when to resume, needs to be considered in the context of the patients' specific cancer. However, there is no absolute need to stop any treatment other than possibly ciclosporin, unless there is a concern over an increased risk of serious infection or drug-drug interaction with cancer-directed therapies, including radiotherapy. PMID- 29992536 TI - Robust and local positional information within a fin ray directs fin length during zebrafish regeneration. AB - It has been proposed that cells are regulated to form specific morphologies and sizes according to positional information. However, the entity and nature of positional information have not been fully understood yet. The zebrafish caudal fin has a characteristic V-shape; dorsal and ventral fin rays are longer than the central ones. This fin shape regenerates irrespective of the sites or shape of fin amputation. It is thought that reformation of tissue occurs according to positional information. In this study, we developed a novel transplantation procedure for grafting a whole fin ray to an ectopic position and examined whether the information that specifies fin length exists within each fin ray. Intriguingly, when long and short fin rays were swapped, they regenerated to form longer or shorter fin rays than the adjacent host fin rays, respectively. Further, the abnormal fin ray lengths were maintained for a long time, more than 5 months, and after further re-amputation. In contrast to intra-fin grafting, when fin ray grafting was performed between fish, cells in the grafts disappeared due to immune rejection, and the grafted fin rays adapted to the host position to form a normal fin. Together, our data suggest that the information that directs fin length does exist in cells within a single fin ray and that it has a robust property-it is stable for a long time and is hard to rewrite. Our study highlighted a novel positional information mechanism for directing regenerating fin length. PMID- 29992537 TI - CBL1-CIPK26-mediated phosphorylation enhances activity of the NADPH oxidase RBOHC, but is dispensable for root hair growth. AB - Root hairs (RH) are tip growing polarized cells aiding the uptake of nutrients and water into plants. RH differentiation involves the interplay of various hormones and second messengers. Tightly regulated production of reactive oxygen species by the NADPH oxidase RBOHC crucially functions in RH differentiation and Ca2+ -dependent phosphorylation has been implemented in these processes. However, the kinases regulating RBOHC remained enigmatic. Here we identify CBL1-CIPK26 Ca2+ sensor-kinase complexes as modulators of RBOHC activity. Combined genetic, cell biological and biochemical analyses reveal synergistic function of CIPK26 mediated phosphorylation and Ca2+ binding for RBOHC activation. Complementation of rbohC mutant RH phenotypes by a S318/322 phosphorylation deficient RBOHC version suggests flexible and alternating phosphorylation patterns as mechanism fine-tuning ROS production in RH development. PMID- 29992538 TI - Use of Lipid-Lowering Drugs and the Risk of Cataract: A Population-Based Nested Case-Control Study. AB - Eye lens membrane cells require high cholesterol concentrations that might be counteracted by lipid-lowering drugs. Using a nationwide database, we conducted a nested case-control study to evaluate the risk of cataract development associated with the use of lipid-lowering drugs. Patients aged 45 years and over with first cataract surgery in 2014 (cases) and up to four controls matched on age, gender, diabetes, hypothyroidism, glucocorticoid use, cardiovascular risk, and area of residence were included in the study. Among the 2,811 cases and 11,106 matched controls included, analyses showed a significantly increased risk of cataract surgery for a cumulative exposure to fibrates exceeding 5 years (adjusted odds ratio (aOR) 1.58; 95% confidence interval (CI): 1.17-2.15), unlike cumulative exposure to statins, whatever the dose or duration of treatment (aORs from 1.00 1.08, none being significant). This study highlighted an increased risk of cataract surgery with prolonged use of fibrates but not of statins. PMID- 29992539 TI - Prognostic role of soluble ST2 in acute coronary syndrome with diabetes. AB - BACKGROUND: Acute coronary syndrome (ACS) patients are at an increased risk of major adverse cardiovascular events (MACE). The objective of our study was to assess whether cardiac biomarker like soluble ST2 (sST2) can predict MACE among ACS patients with diabetes. MATERIALS AND METHODS: A total of 122 patients with ACS were included in the study. sST2 level in blood plasma samples was quantified using enzyme-linked immunosorbent assay (ELISA). Prognostic utility of sST2 for the primary outcome of MACE which included mortality, rehospitalization due to chest pain, unstable angina, recurrent myocardial infarction (MI) and stroke, was assessed during follow-up. RESULTS: The median follow-up period was of 180 days. ROC (receiver operating characteristic) curve demonstrated that elevated levels of sST2 were able to predict mortality, and MACE in ACS patients, along with increased risk of occurrence of MACE and mortality in ACS patients having diabetes. Kaplan-Meier plots revealed a significant increase in the occurrence of MACE in diabetic ACS patients (P = 0.006; by log-rank test). Cox regression analysis revealed that sST2 is not an independent predictor of mortality and MACE in ACS patients having diabetes; however, high sST2 level was found to be a predictor of MACE in all ACS subjects in the fully adjusted model with a hazard ratio (HR) of 5.8 (P = 0.032). CONCLUSION: The current study indicates that elevated levels of sST2 might be a suitable biomarker to evaluate the risk of future adverse cardiovascular events in ACS patients with diabetes. PMID- 29992540 TI - Serum cardiovascular risk biomarkers in pre-pubertal obese children. AB - BACKGROUND: Childhood obesity is associated with premature cardiovascular complications. However, little is known about the effect of a family-based behavioural intervention on the relationship between arterial function, blood pressure and biomarkers in pre-pubertal children with obesity. DESIGN: This was a single centre randomized controlled trial (RCT) including 74 children randomized to a 6-month behavioural intervention to treat obesity. In 48 children (13 controls and 35 interventions), we assessed: serum level of cytokine (CCL2), adiponectin, and neutrophil product (MMP-8), as well as carotid intima-media thickness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation; arterial stiffness (incremental elastic modulus, Einc), pulse wave velocity (PWV), resting and 24-hour blood pressure (BP). RESULTS: At baseline, resting systolic BP was positively associated with MMP-8 levels which was significantly higher in children with hypertension (P = 0.033). Biochemical markers were not related to endothelial function at baseline, but they globally increased after 6 months in the intervention group. The significant increase of CCL2 levels in the intervention group was associated with a decrease in diastolic BP. Furthermore, adiponectin change was positively related to a change in FMD and negatively to change in Einc and PWV. CONCLUSIONS: The usefulness of serum biomarkers for the detection of cardiovascular diseases is not well established in children. In our population, MMP-8 concentration was higher in hypertensive children. Furthermore, behavioural interventions resulted in a paradoxical increase in some biomarkers in children, with potentially beneficial effects detected with CCL2 changes. Caution should be taken when using nonspecific serum biomarkers for the clinical monitoring of children with obesity. PMID- 29992541 TI - Assessing the accuracy of the Modified Checklist for Autism in Toddlers: a systematic review and meta-analysis. AB - AIM: The Modified Checklist for Autism in Toddlers (M-CHAT) could be appropriate for universal screening for autism spectrum disorder (ASD) at 18 months and 24 months. Validation studies, however, reported differences in psychometric properties across sample populations. This meta-analysis summarized its accuracy measures and quantified their change in relation to patient and study characteristics. METHOD: Four electronic databases (MEDLINE, PsycINFO, CINAHL, and Embase) were searched to identify articles published between January 2001 and May 2016. Bayesian regression models pooled study-specific measures. Meta regressions covariates were age at screening, study design, and proportion of males. RESULTS: On the basis of the 13 studies included, the pooled sensitivity was 0.83 (95% credible interval [CI] 0.75-0.90), specificity was 0.51 (95% CI 0.41-0.61), and positive predictive value was 0.53 (95% CI 0.43-0.63) in high risk children and 0.06 (95% CI <0.01-0.14) in low-risk children. Sensitivity was higher for screening at 30 months compared with 24 months. INTERPRETATION: Findings indicate that the M-CHAT performs with low to moderate accuracy in identifying ASD among children with developmental concerns, but there was a lack of evidence on its performance in low-risk children or at age 18 months. Clinicians should account for a child's age and presence of developmental concern when interpreting their M-CHAT score. WHAT THIS PAPER ADDS: The Modified Checklist for Autism in Toddlers (M-CHAT) performs with low-to-moderate accuracy in children with developmental concerns. There is limited evidence supporting its use at 18 months or in low-risk children. PMID- 29992542 TI - Reproductive isolation in alpine gingers: How do coexisting Roscoea (R. purpurea and R. tumjensis) conserve species integrity? AB - Multiple barriers may contribute to reproductive isolation between closely related species. Understanding the relative strength of these barriers can illuminate the ecological factors that currently maintain species integrity and how these factors originally promoted speciation. Two Himalayan alpine gingers, Roscoea purpurea and R. tumjensis, occur sympatrically in central Nepal and have such similar morphology that it is not clear whether or how they maintain a distinct identity. Our quantitative measurements of the components of reproductive isolation show that they are, in fact, completely isolated by a combination of phenological displacement of flowering, earlier for R. tumjensis and later for R. purpurea, and complete fidelity of visitation by different pollinator species, bumblebees for R. tumjensis and a long-tongued fly for R. purpurea. Furthermore, the nectar of R. tumjensis flowers is available to the shorter tongued bumblebees while R. purpurea nectar is less accessible, requiring deep probing from long-tongued flies. Although flowering phenology is a strong current barrier that seemingly obviates any need for pollinator discrimination, this current pattern need not reflect selective forces occurring at the initial divergence of R. tumjensis. There has been considerable pollinator switching during the radiation of the Himalayan Roscoea, and the association of flowering time with type of pollinator in these sympatric species may have originated among the earliest or latest flowering individuals or populations of an ancestor to exploit either bumblebee activity early in the breeding season or long-tongued fly abundance later in the season. These two sympatric Roscoea species add to accumulating evidence of the primacy of prezygotic pollination traits in speciation among angiosperms even in the absence of postzygotic incompatibility. PMID- 29992543 TI - A robust approach to sample size calculation in cancer immunotherapy trials with delayed treatment effect. AB - Immunotherapies are taking the center stage for cancer drug development and research. Many of these therapies, for example, immune checkpoint inhibitors, are known to have possible lag periods to achieve their full effects. Therefore, the proportional hazard assumption is violated when comparing survival curves in randomized clinical trials evaluating such therapies. Limited work exists in determining sample size to account for the lag period which is usually unknown. Assuming that the lag period is within some reasonable range, this article presents an approach to calculate sample size based on a maximin efficiency robust test. Both theoretical derivations and simulation results show the proposed approach can guarantee the desired power in worst case scenarios and often much more efficient than existing approaches. Application to a real trial design is also illustrated. PMID- 29992544 TI - Biological Sensitivity to the Effects of Maternal Postpartum Depressive Symptoms on Children's Behavior Problems. AB - Resting respiratory sinus arrhythmia (RSA) may confer infant susceptibility to the postpartum environment. Among infants with higher RSA, there may be a positive relation between depressive symptoms across the first 6 months postpartum (PPD) and later behavior problems, and toddlers' dysregulation during mother-child interactions may partially explain the effects. Among a sample of low-income Mexican-American families, infant RSA (N = 322; 46% male) was assessed at 6 weeks of age; mothers (Mage = 27.8, SD = 6.5) reported PPD symptoms every 3 weeks from 6 to 24 weeks and infant behavior problems at 36 months. Dysregulation was observed at 24 months. PPD was positively associated with behavior problems only among infants with lower RSA; however, this relation was not mediated by dysregulation. PMID- 29992545 TI - Analysis of multiple survival events in generalized case-cohort designs. AB - Generalized case-cohort design has been proposed to assess the effects of exposures on survival outcomes when measuring exposures is expensive and events are not rare in the cohort. In such design, expensive exposure information is collected from both a (stratified) randomly selected subcohort and a subset of individuals with events. In this article, we consider extension of such design to study multiple types of survival events by selecting a proportion of cases for each type of event. We propose a general weighting scheme to analyze data. Furthermore, we examine the optimal choice of weights and show that this optimal weighting yields much improved efficiency gain both asymptotically and in simulation studies. Finally, we apply our proposed methods to data from the Atherosclerosis Risk in Communities study. PMID- 29992546 TI - Epilepsy genetics: Current knowledge, applications, and future directions. AB - The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease. PMID- 29992547 TI - Model assisted sensitivity analyses for hidden bias with binary outcomes. AB - In medical and health sciences, observational studies are a major data source for inferring causal relationships. Unlike randomized experiments, observational studies are vulnerable to the hidden bias introduced by unmeasured confounders. The impact of unmeasured covariates on the causal effect can be assessed by conducting a sensitivity analysis. A comprehensive framework of sensitivity analyses has been developed for matching designs. Sensitivity parameters are introduced to capture the association between the missing covariates and the exposure or the outcome. Fixing sensitivity parameter values, it is possible to compute the bounds of the p-value of a randomization test on causal effects. We propose a model assisted sensitivity analysis with binary outcomes for the general 1:k matching design, which provides results equivalent to the conventional nonparametric approach in large sample. By introducing a conditional logistic outcome model, we substantially simplify the implementation and interpretation of the sensitivity analysis. More importantly, we are able to provide a closed form representation for the set of sensitivity parameters for which the maximum p-values are non-significant. This methodology can be easily extended to matching designs with multilevel treatments. We illustrate our method using a U.S. trauma care database to examine mortality difference between trauma care levels. PMID- 29992548 TI - Groundwater Quality and Hydraulic Fracturing: Current Understanding and Science Needs. AB - Hydraulic fracturing (fracking) is a process used for the stimulation and production of ultra-low permeability shale gas and tight oil resources. Fracking poses two main risks to groundwater quality: (1) stray gas migration and (2) potential contamination from chemical and fluid spills. Risk assessment is complicated by the lack of predrilling baseline measurements, limited access to well sites and industry data, the constant introduction of new chemical additives to frack fluids, and difficulties comparing data sets obtained by different sampling and analytical methods. Specific recommendations to reduce uncertainties and meet science needs for better assessment of groundwater risks include improving data-sharing among researchers, adopting standardized methodologies, collecting predrilling baseline data, installing dedicated monitoring wells, developing shale-specific environmental indicators, and providing greater access to field sites, samples, and industry data to the research community. PMID- 29992549 TI - Regulatory T cells control epitope spreading in autoimmune arthritis independent of cytotoxic T-lymphocyte antigen-4. AB - CD4+ Foxp3+ regulatory T (Treg) cells can control both cellular and humoral immune responses; however, when and how Treg cells play a predominant role in regulating autoimmune disease remains elusive. To deplete Treg cells in vivo at given time-points, we used a mouse strain, susceptible to glucose-6-phosphate isomerase peptide-induced arthritis (GIA), in which the deletion of Treg cells can be controlled by diphtheria toxin treatment. By depleting Treg cells in the GIA mouse model, we found that a temporary lack of Treg cells at both priming and onset exaggerated disease development. Ablation of Treg cells led to the expansion of antigen-specific CD4+ T cells including granulocyte-macrophage colony-stimulating factor, interferon-gamma and interleukin-17-producing T cells, and promoted both T-cell and B-cell epitope spreading, which perpetuated arthritis. Interestingly, specific depletion of cytotoxic T-lymphocyte antigen-4 (CTLA-4) on Treg cells only, was sufficient to protect mice from GIA, due to the expansion of CTLA-4- Treg cells expressing alternative suppressive molecules. Collectively, our findings suggest that Treg cells, independently of CTLA-4, act as the key driving force in controlling autoimmune arthritis development. PMID- 29992550 TI - Risk factors of acute kidney injury in children after cardiac surgery. AB - BACKGROUND: The objective of this retrospective study was to determine the risk factors for acute kidney injury (AKI), including albumin, in children who underwent cardiac surgery. In addition, we evaluated the association between preoperative serum albumin level and postoperative AKI in these patients. METHODS: This retrospective study included 505 pediatric patients who underwent congenital cardiac surgery. Preoperative and perioperative risk factors for AKI, including serum albumin level, were assessed. AKI incidence within 7 postoperative days was determined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Multivariable logistic regression analysis was performed to evaluate the association between possible risk factors and postoperative AKI. RESULTS: Of 505 pediatric patients, 185 (36.6%) developed postoperative AKI. The preoperative serum albumin level was associated with postoperative AKI (odds ratio [OR] 0.506, 95% confidence interval [CI] 0.325 0.788; P = 0.003). Other independent factors associated with AKI were age <12 months (OR 1.911, 95% CI 1.166-3.132; P = 0.007), preoperative pulmonary hypertension (OR 1.853, 95% CI 1.182-2.907; P = 0.01), and cardiopulmonary bypass (CPB) duration (OR 1.006, 95% CI 1.003-1.009; P = 0.002). Patients with AKI had higher incidence of postoperative complications, longer mechanical ventilation times, and more prolonged intensive care unit and hospital stays than patients without AKI. CONCLUSIONS: Preoperative serum albumin level, age <12 months, preoperative pulmonary hypertension, and CPB duration were associated with risk for postoperative AKI in children who underwent congenital cardiac surgery. PMID- 29992551 TI - Patient-dentist relationship and dental anxiety among young Sudanese adult patients. AB - OBJECTIVE: To evaluate the effects of the patient-dentist relationship on dental anxiety among young adult Sudanese patients. MATERIALS AND METHODS: In this cross sectional study, 864 patients attending outpatient dental clinics of the governmental dental hospitals in Khartoum, Sudan were recruited; 51.2% were males and 48.8% were females, with an age range of 18-24 years. The questionnaire used evaluated the socio-demographics, education levels, economic status, patient experience, and also included the Dental Anxiety Scale, Corah (J Dent Res 1969 48: 596). RESULTS: High dental anxiety was reported by 22.2%, 29.5% reported moderate dental anxiety, and 48.3% reported low or no dental anxiety. There were statistically significant associations between dental anxiety and gender, time lapse since the previous dental visit (P < 0.004) and the reason for the previous visit (P < 0.001). In addition, the dental clinic environment (P < 0.002), the time waiting before seeing the dentist (P < 0.001) and the overhearing of pain expressed by other patients (P < 0.001) were also statistically significant. Negative comments by the treating dentist also had a statistically significant impact (P < 0.032). In contrast, a clear explanation of related dental care (P < 0.008), as well as the allowance of adequate time to discuss oral health (P < 0.006), had significantly positive effects. CONCLUSION: The study showed that the patient-dentist relationship had a significant association with dental anxiety, and may be an important target for improving the delivery and standards of oral health in dentally anxious patients in this region. PMID- 29992552 TI - Exome sequencing identifies novel compound heterozygous mutations in GJB3 gene that cause erythrokeratodermia variabilis et progressiva. PMID- 29992553 TI - Breast cancer in women living with HIV: A first global estimate. AB - There is a growing population of older women living with HIV/AIDS (WLWHA). Breast cancer is a common cancer in women worldwide, but the global number of breast cancers in WLWHA is not known. We estimated, for each UN sub-region, the number and age distribution of WLWHA who were diagnosed with breast cancer in 2012, by combining IARC-GLOBOCAN estimates of age-country specific breast cancer incidence with corresponding UNAIDS HIV prevalence. Primary analyses assumed no HIV-breast cancer association, and a breast cancer risk reduction scenario was also considered. Among 16.0 million WLWHA aged 15+ years, an estimated 6,325 WLWHA were diagnosed with breast cancer in 2012, 74% of whom were in sub-Saharan Africa, equally distributed between Eastern, Southern and Western Africa. In most areas, 70% of HIV-positive breast cancers were diagnosed under age 50. Among all breast cancers (regardless of HIV status), HIV-positive women constituted less than 1% of the clinical burden, except in Eastern, Western and Middle Africa where they comprised 4-6% of under age 50 year old breast cancer patients, and in Southern Africa where this patient subgroup constituted 26 and 8% of breast cancers diagnosed under and over age 50 respectively. If a deficit of breast cancer occurs in WLWHA, the global estimate would reduce to 3,600. In conclusion, worldwide, the number of HIV-positive women diagnosed with breast cancer was already substantial in 2012 and with an expected increase within the next decade, early detection and treatment research targeted to this population are needed. PMID- 29992554 TI - Anthropogenic versus fish-derived nutrient effects on seagrass community structure and function. AB - Humans are altering nutrient dynamics through myriad pathways globally. Concurrent with the addition of nutrients via municipal, industrial, and agricultural sources, widespread consumer exploitation is changing consumer mediated nutrient dynamics drastically. Thus, altered nutrient dynamics can occur through changes in the supply of multiple nutrients, as well as through changes in the sources of these nutrients. Seagrass ecosystems are heavily impacted by human activities, with highly altered nutrient dynamics from multiple causes. We simulate scenarios of altered nutrient supply and ratios, nitrogen:phosphorus (N:P), from two nutrient sources in seagrass ecosystems: anthropogenic fertilizer and fish excretion. In doing so we tested expectations rooted in ecological theory that suggest the importance of resource dynamics for predicting primary producer dynamics. Ecosystem functions were strongly altered by artificial fertilizer (e.g., seagrass growth increased by as much as 140%), whereas plant/algae community structure was most affected by fish-mediated nutrients or the interaction of both treatments (e.g., evenness increased by ~140% under conditions of low fish nutrients and high anthropogenic nutrients). Interactions between the nutrient sources were found for only two of six response variables, and the ratio of nutrient supply was the best predictor for only one response. These findings show that seagrass structure and function are well predicted by supply of a single nutrient (either N or P). Importantly, no single nutrient best explained the majority of responses-measures of community structure were best explained by the primary limiting nutrient to this system (P), whereas measures of growth and density of the dominant producer in the system were best explained by N. Thus, while our findings support aspects of theoretical expectations, the complexity of producer community responses belies broad generalities, underscoring the need to manage for multiple simultaneous nutrients in these imperiled coastal ecosystems. PMID- 29992555 TI - Pharmacy access to medical abortion from trained providers and post-abortion contraception in Nepal. AB - OBJECTIVE: To examine whether auxiliary nurse-midwife provision of medical abortion in pharmacies was associated with reduced post-abortion contraceptive use in Nepal. METHODS: The present prospective observational study compared contraceptive use among women aged 16-45 years and up to 63 days of pregnancy, who presented at one of six privately-owned pharmacies or six public health facilities in the Chitwan and Jhapa districts of Nepal for medical abortion between October 16, 2014, and September 1, 2015. Participants obtained medical abortions per Nepali protocol and completed a follow-up visit and interview at 14 21 days. Effective contraceptive use was compared between abortion care settings using multivariable mixed effects logistic regression. RESULTS: Of 605 participants, 600 completed follow-up at 14-21 days; 474 (79.0%) were using a contraceptive method, most commonly pills (180 [30.0%]) and injectables (175 [29.2%]), followed by condoms (82 [13.7%]), long-acting reversible methods (33 [5.5%]), and sterilization (4 [0.7%]). Receipt of care from a private pharmacy was not associated with a difference in the use of hormonal or long-acting methods (adjusted odd ratio 0.89, 95% confidence interval 0.60-1.33). CONCLUSION: Medical abortion provision from pharmacies by qualified providers can provide women with necessary induced-abortion care while not compromising longer-term pregnancy prevention. PMID- 29992556 TI - The metastatic microenvironment: Melanoma-microglia cross-talk promotes the malignant phenotype of melanoma cells. AB - Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation. PMID- 29992557 TI - Efficacy and safety of everolimus plus exemestane in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: Results of the single-arm, phase IIIB 4EVER trial. AB - In BOLERO-2, adding everolimus to exemestane resulted in a twofold increase in median progression-free survival (PFS) vs exemestane in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (aBC) after progression on a non steroidal aromatase inhibitor (NSAI). Here, we report on the open-label, single arm, phase IIIB 4EVER trial (NCT01626222). This trial evaluated the clinical effectiveness of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC who had progressed on or after an NSAI, but with no restrictions on the time of progression after NSAI, prior chemotherapy for advanced disease or previous exemestane. The primary endpoint was overall response rate (ORR; i.e. the percentage of patients with a best overall response of complete or partial response per RECIST 1.1) within the first 24 weeks of treatment. Secondary endpoints included PFS, overall survival, safety and health-related quality of life. Between June 2012 and November 2013, 299 patients were enrolled at 82 German centers: 281 patients were evaluable for efficacy and 299 for safety. The ORR was 8.9% (95% confidence interval [CI]: 5.8-12.9%). Median PFS was 5.6 months (95% CI: 5.4-6.0 months). The most frequent grade 3/4 adverse events were stomatitis (8.4%), general physical health deterioration (6.7%), dyspnea (4.7%) and anemia (4.3%). The ORR in 4EVER was lower than in BOLERO-2, likely due to inclusion of patients with more advanced disease and extensive pretreatment. These data confirm the clinical benefits and known safety profile of everolimus plus exemestane in postmenopausal women with HR+, HER2- aBC. PMID- 29992558 TI - Somatic mutations in specific and connected subpathways are associated with short neuroblastoma patients' survival and indicate proteins targetable at onset of disease. AB - Neuroblastoma (NB) is an embryonic malignancy of the sympathetic nervous system with heterogeneous biological, morphological, genetic and clinical characteristics. Although genomic studies revealed the specific biological features of NB pathogenesis useful for new therapeutic approaches, the improvement of high-risk (HR)-NB patients overall survival remains unsatisfactory. To further clarify the biological basis of disease aggressiveness, we used whole-exome sequencing to examine the genomic landscape of HR-NB patients at stage M with short survival (SS) and long survival (LS). Only a few genes, including SMARCA4, SMO, ZNF44 and CHD2, were recurrently and specifically mutated in the SS group, confirming the low recurrence of common mutations in this tumor. A systems biology approach revealed that in the two patient groups, mutations occurred in different pathways. Mutated genes (ARHGEF11, CACNA1G, FGF4, PTPRA, PTK2, ANK3, SMO, NTNG2, VCL and NID2) regulate the MAPK pathway associated with the organization of the extracellular matrix, cell motility through PTK2 signaling and matrix metalloproteinase activity. Moreover, we detected mutations in LAMA2, PTK2, LAMA4, and MMP14 genes, impairing MET signaling, in SFI1 and CHD2 involved in centrosome maturation and chromosome remodeling, in AK7 and SPTLC2, which regulate the metabolism of nucleotides and lipoproteins, and in NALCN, SLC12A1, SLC9A9, which are involved in the transport of small molecules. Notably, connected networks of somatically mutated genes specific for SS patients were identified. The detection of mutated genes present at the onset of disease may help to address an early treatment of HR-NB patients using FDA-approved compounds targeting the deregulated pathways. PMID- 29992559 TI - Quickly responding C-fibre nociceptors contribute to heat hypersensitivity in the area of secondary hyperalgesia. AB - KEY POINTS: A recent animal study showed that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long-term potentiation at the spinal cord that is hypothesized to mediate secondary hyperalgesia in humans. Here this hypothesis was tested by predominantly activating C-fibre nociceptors in the area of secondary mechanical hyperalgesia induced by HFS in humans. It is shown that heat perception elicited by stimuli predominantly activating C-fibre nociceptors is greater, as compared to the control site, after HFS in the area of secondary mechanical hyperalgesia. This is the first study that confirms in humans the involvement of C-fibre nociceptors in the changes in heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. ABSTRACT: It has recently been shown that high frequency electrical stimulation (HFS) of C-fibres induces a gliogenic heterosynaptic long term potentiation (LTP) at the spinal cord in animals, which has been hypothesized to be the underlying mechanism of secondary hyperalgesia in humans. Here we tested this hypothesis using a method to predominantly activate quickly responding C-fibre nociceptors in the area of secondary hyperalgesia induced by HFS in humans. HFS was delivered to one of the two volar forearms in 18 healthy volunteers. Before, 20 min and 45 min after HFS, short-lasting (10 ms) high intensity CO2 laser heat stimuli delivered to a very small area of the skin (0.15 mm2 ) were applied to the area of increased mechanical pinprick sensitivity at the HFS-treated arm and the homologous area of the contralateral control arm. During heat stimulation the electroencephalogram, reaction times and intensity of perception (numerical rating scale 0-100) were measured. After HFS, we observed a greater heat sensitivity, an enhancement in the number of detected trials, faster reaction times and an enhancement of the N2 wave of C-fibre laser-evoked potentials at the HFS-treated arm compared to the control arm. This is the first study that confirms in humans the involvement of C-fibre nociceptors in enhanced heat sensitivity in the area of secondary mechanical hyperalgesia induced by HFS. PMID- 29992560 TI - Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma: A 16-year prospective analysis from the NIH-AARP diet and health cohort. AB - The role of alcoholic beverages in the etiology of gastric cancer is unclear. Recent summaries showed a positive association between higher alcohol intake and gastric cancer risk, but the magnitude of association is small, there is moderate heterogeneity among studies, and most cases were from Asian populations. We prospectively investigated the associations of alcohol consumption with gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA) in 490,605 adults, aged 50-71 years at baseline who participated in the NIH-AARP diet and health study. Alcohol consumption in the past year was assessed at baseline by questionnaire and defined as total grams of ethanol intake per day or as a categorical variable: nondrinker, up to or including one drink per day, one to three drinks per day and greater than three drinks per day. We used multivariable-adjusted Cox proportional hazards regression to calculate the hazard ratios (HR) and 95% confidence intervals (CI) for associations between alcohol intake and risk of gastric adenocarcinomas. Through 2011, 662 incident cases of GCA and 713 of GNCA occurred. We found no association between higher alcohol consumption and GCA or GNCA, when examined as total alcoholic beverage intake or individual beverage types of beer, wine and liquor. Furthermore, we observed no association by stratum of sex, ethnic group, educational level or smoking status. We did, however, observe lower risk of GNCA among participants who drank up to one drink per day (HR = 0.81, 95% CI: 0.67-0.97) compared to nondrinkers. In conclusion, alcohol consumption was not associated with increased risk of GCA or GNCA in this large U.S. cohort. PMID- 29992561 TI - Introgressive hybridization between wild and domestic individuals and its relationship with parasitism in brook charr Salvelinus fontinalis. AB - The effects of introgression on parasitism in brook charr Salvelinus fontinalis were investigated in 28 lakes with various levels of stocking in Quebec, Canada. No effect of genetic background on parasitism was found at the individual level. Body length seemed to explain most of the variation observed at this level, with largest fish being more infected. However, lakes with the greater average domestic genetic background were found to display significantly lower parasite prevalence and diversity. Since our results indicate no effect of domestic genes at the individual level, the negative association with introgression found at the population level may be mainly attributed to differences in intrinsic environmental quality of lakes (e.g. fishing pressure, availability of food resources, abiotic characteristics). PMID- 29992563 TI - Weight change since age 20 and incident risk of obesity-related cancer in Japan: a pooled analysis of the Miyagi Cohort Study and the Ohsaki Cohort Study. AB - It is unclear whether weight change during adulthood affects the risk of obesity related cancers such as those of the esophagus, colorectum, pancreas, breast, endometrium, and kidney among Japanese, where obesity is less frequent and less severe. We examined the association between weight change during adulthood and the risk of obesity-related cancer among Japanese by conducting a pooled analysis of two prospective studies of residents in Miyagi Prefecture, Japan. A total of 78,743 persons (40,422 women and 38,321 men) aged 40-79 years participated in the Miyagi Cohort Study in 1990 and in the Ohsaki Cohort Study in 1994. Weight change since age 20 was divided into four categories (weight loss; stable weight; moderate weight gain; high weight gain). Cox proportional hazards regression analysis was used to estimate the multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for obesity-related cancer incidence. During 1,057,899 person-years of follow up, 4,467 cases of obesity-related cancer (women; 1,916 cases, men; 2,551cases) were identified. In women, compared to the stable weight, weight gain was associated with an increased risk of obesity-related cancer (moderate weight gain; HRs = 1.10, 95%CIs: 0.97-1.26, high weight gain; HRs = 1.29, 95%CIs: 1.14-1.47). The results indicate that weight gain since age 20 was associated with a significantly increased risk of obesity-related cancer among Japanese women. By contrast, in men, our study found that weight change is not associated with the incidence of obesity-related cancer. PMID- 29992562 TI - Desensitizing mouse cardiac troponin C to calcium converts slow muscle towards a fast muscle phenotype. AB - KEY POINTS: The Ca2+ -desensitizing D73N mutation in slow skeletal/cardiac troponin C caused dilatated cardiomyopathy in mice, but the consequences of this mutation in skeletal muscle were not known. The D73N mutation led to a rightward shift in the force versus pCa (-log [Ca]) relationship in slow-twitch mouse fibres. The D73N mutation led to a rightward shift in the force-stimulation frequency relationship and reduced fatigue resistance of mouse soleus muscle. The D73N mutation led to reduced cross-sectional area of slow-twitch fibres in mouse soleus muscle without affecting fibre type composition of the muscle. The D73N mutation resulted in significantly shorter times to peak force and to relaxation during isometric twitches and tetani in mouse soleus muscle. The D73N mutation led to major changes in physiological properties of mouse soleus muscle, converting slow muscle toward a fast muscle phenotype. ABSTRACT: The missense mutation, D73N, in mouse cardiac troponin C has a profound impact on cardiac function, mediated by a decreased myofilament Ca2+ sensitivity. Mammalian cardiac muscle and slow skeletal muscle normally share expression of the same troponin C isoform. Therefore, the objective of this study was to determine the consequences of the D73N mutation in skeletal muscle, as a potential mechanism that contributes to the morbidity associated with heart failure or other conditions in which Ca2+ sensitivity might be altered. Effects of the D73N mutation on physiological properties of mouse soleus muscle, in which slow-twitch fibres are prevalent, were examined. The mutation resulted in a rightward shift of the force stimulation frequency relationship, and significantly faster kinetics of isometric twitches and tetani in isolated soleus muscle. Furthermore, soleus muscles from D73N mice underwent a significantly greater reduction in force during a fatigue test. The mutation significantly reduced slow fibre mean cross sectional area without affecting soleus fibre type composition. The effects of the mutation on Ca2+ sensitivity of force development in soleus skinned slow and fast fibres were also examined. As expected, the D73N mutation did not affect the Ca2+ sensitivity of force development in fast fibres but resulted in substantially decreased Ca2+ sensitivity in slow fibres. The results demonstrate that a point mutation in a single constituent of myofilaments (slow/cardiac troponin C) led to major changes in physiological properties of skeletal muscle and converted slow muscle toward a fast muscle phenotype with reduced fatigue resistance and Ca2+ sensitivity of force generation. PMID- 29992564 TI - HPV knowledge, vaccine knowledge, and vaccine acceptance in women with cervical cytology anomalies attending colposcopy clinics in Puerto Rico. AB - OBJECTIVE: To assess HPV knowledge as well as knowledge and acceptance of HPV vaccines. METHODS: The present cross-sectional study surveyed women with cervical cytology anomalies referred to colposcopy clinics at the University of Puerto Rico and San Juan City Hospital between November 1, 2013, and November 30, 2015. The data were analyzed using descriptive statistics and multivariate logistic regression models. RESULTS: Of 418 participants, 333 had heard of HPV. Of these, 273 of 331 (82.5%) knew it causes cervical cancer and 284 of 332 (85.8%) knew it is sexually transmitted; 313 were aware of the vaccine(s). Of 278 participants, 270 (97.1%) were willing to vaccinate their children and 125 of 285 (43.9%) desired vaccination. Only 13 (10.9%) of 119 age-eligible women had been vaccinated. Women who had completed high school had increased odds of having heard of HPV (adjusted OR 2.3, 95% CI 1.2-4.4; P=0.014), with a similar increase in the odds of having heard of the vaccine(s). Women who knew about HPV had greatly increased odds of knowing about the vaccine(s) (adjusted OR 19.7, 95% CI 9.8-41.6). CONCLUSION: Knowledge of HPV and HPV vaccine(s) was high, but vaccine uptake was low in the study population. Physicians' active roles in HPV education and vaccination are crucial. PMID- 29992565 TI - Changes in the appendicular skeleton during metamorphosis in the axolotl salamander (Ambystoma mexicanum). AB - Axolotl salamanders (Ambystoma mexicanum) remain aquatic in their natural state, during which biomechanical forces on their diarthrodial limb joints are likely reduced relative to salamanders living on land. However, even as sexually mature adults, these amphibians can be induced to metamorphose into a weight-bearing terrestrial stage by environmental stress or the exogenous administration of thyroxine hormone. In some respects, this aquatic to terrestrial transition of axolotl salamanders through metamorphosis may model developmental and changing biomechanical skeletal forces in mammals during the prenatal to postnatal transition at birth and in the early postnatal period. To assess differences in the appendicular skeleton as a function of metamorphosis, anatomical and gene expression parameters were compared in skeletal tissues between aquatic and terrestrial axolotls that were the same age and genetically full siblings. The length of long bones and area of cuboidal bones in the appendicular skeleton, as well as the cellularity of cartilaginous and interzone tissues of femorotibial joints were generally higher in aquatic axolotls compared with their metamorphosed terrestrial siblings. A comparison of steady-state mRNA transcripts encoding aggrecan core protein (ACAN), type II collagen (COL2A1), and growth and differentiation factor 5 (GDF5) in femorotibial cartilaginous and interzone tissues did not reveal any significant differences between aquatic and terrestrial axolotls. PMID- 29992566 TI - Salmo macrostigma (Teleostei, Salmonidae): Nothing more than a brown trout (S. trutta) lineage? AB - We examined specimens of the macrostigma trout Salmo macrostigma, which refers to big black spots on the flanks, to assess whether it is an example of taxonomic inflation within the brown trout Salmo trutta complex. Using new specimens, publicly available data and a mitogenomic protocol to amplify the control and cytochrome b regions of the mitochondrial genome from degraded museum samples, including one syntype specimen, the present study shows that the macrostigma trout is not a valid species. Our results suggest the occurrence of a distinct evolutionary lineage of S. trutta in North Africa and Sicily. The name of the North African lineage is proposed for this lineage, which was found to be sister to the Atlantic lineage of brown trout, S. trutta. PMID- 29992567 TI - Studying the effects of synaptic clustering in silico: when the neighbourhood party gets too loud. PMID- 29992568 TI - Detection of endogenously circulating mesenchymal stem cells in human cancer patients. AB - Mesenchymal stem cells (MSCs) can play a vital role in tumor progression and anticancer therapy response, as demonstrated by various in vitro and in vivo model systems. Their ability to home to developing tumors and modulate the tumor microenvironment, by suppressing T-cell responses and contributing to the tumor stroma, is suggested to have a significant impact on disease progression, metastasis formation, and therapy response. Most evidence, however, is derived from artificial models using exogenously administered MSCs. The contribution of endogenous MSCs to tumor progression is currently unclear. Furthermore, few studies have been conducted in humans. A prospective biomarker study was therefore undertaken in 40 human cancer patients and 10 healthy controls of similar age, aimed at (i) exploring and quantifying circulating MSC levels in healthy volunteers and patients with advanced malignancies, (ii) determining the variability of MSC levels between healthy volunteers and cancer patients with different histologic tumor types, and (iii) exploring biomarkers associated with MSC levels. Significantly increased levels of circulating MSC-like cells were observed in cancer patients when compared to healthy individuals (1.72 fold difference, 95% CI 1.03-2.81%, p = 0.03). In addition, prior systemic therapy was associated with a significant increase in MSC-like cells (1.73 fold difference, 95% CI 1.02-2.95, p = 0.04). These results indicate that the amount of endogenously circulating MSCs in humans is increased in response to cancer, and that systemic anticancer treatment can influence MSC levels. Further research is needed to determine whether MSCs have a predictive value. PMID- 29992569 TI - Myeloid-derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy. AB - Cancer progression is closely related to the tumor microenvironment in which the tumor exists, including surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, signaling molecules and the extracellular matrix. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can impact the growth and evolution of cancerous cells. One of major cell components in the tumor microenvironment is myeloid-derived suppressor cells (MDSCs), which promote tumor growth and metastasis directly or indirectly by recognizing other immune cells, producing cytokines and exerting their immunosuppression functions. MDSCs have emerged as major regulators of immune responses in cancer and key targets for treating cancer. There are many limitations and side-effect in approaches of conventional cancer therapy, including radiotherapy. It has grown up to be a burgeoning field that a combination of radiotherapy and immunotherapy applied to cancer therapy. Therefore, it is fundamental to explore the immune mechanism in the process of cancer treatment. Here, we reviewed the recent progress of MDSCs in roles of the tumor microenvironment and tumor radiotherapy. PMID- 29992570 TI - A novel tumor-based epithelial-to-mesenchymal transition score that associates with prognosis and metastasis in patients with Stage II/III colorectal cancer. AB - It is increasingly appreciated that host factors within the tumor center and microenvironment play a key role in dictating colorectal cancer (CRC) outcomes. As a result, the metastatic process has now been defined as a result of epithelial-mesenchymal transition (EMT). Establishment of the role of EMT within the tumor center and its effect on the tumor microenvironment would be beneficial for prognosis and therapeutic intervention in CRC. The present study assessed five immunohistochemical EMT markers within the tumor center on a 185 Stage II/III CRC patient tissue microarray. In 185 patients with CRC, cytoplasmic snail (HR 1.94 95% confidence interval [CI] 1.15-3.29, p = 0.012) and a novel combined EMT score (HR 3.86 95% CI 2.17-6.86, p < 0.001) were associated with decreased cancer-specific survival. The combined EMT score was also associated with increased tumor budding (p = 0.046), and systemic inflammation (p = 0.007), as well as decreased memory T-cells within the stroma (p = 0.030) and at the invasive margin (p = 0.035). Furthermore, the combined EMT score was associated with cancer-specific survival independent of TNM-stage (HR 4.12 95% CI 2.30-7.39, p < 0.001). In conclusion, a novel combined EMT score stratifies patient's survival in Stage II/III CRC and associates with key factors of tumor metastasis. Therefore, the combined EMT score could be used to identify patients at risk of micrometastases and who may benefit from standard adjuvant therapy, potentially in combination with EMT blockade. PMID- 29992571 TI - Interspecific difference in downstream migratory season between two tropical eels, Anguilla celebesensis and Anguilla marmorata. AB - Downstream-migrating Anguilla celebesensis eels were predominant relative to Anguilla marmorata in October, November, December, January and February (75.9 92%), while no A. celebesensis occurred and A. marmorata were predominant in May and July (96-100%), at the outlet of Poso Lake, Sulawesi Island, Indonesia. Merging these results with those from published data suggests that most A. celebesensis start downstream migration during the early to middle rainy season, and A. marmorata migrate almost year-round with a peak from the late rainy to middle dry season. PMID- 29992572 TI - Antiageing properties of Damaurone D in Caenorhabditis elegans. AB - OBJECTIVES: This study was conducted to evaluate the longevity potential of damaurone D (DaD), a component of the damask rose, in the animal model Caenorhabditis elegans. METHODS: To investigate the effect of DaD on the longevity, lifespan assay was carried out. Fluorescence intensity of transgenic mutants was quantified to test the expression levels of stress proteins. A genetic study using single gene knockout mutants was designed to determine the target genes of DaD. KEY FINDINGS: DaD prolonged the mean lifespan of wild-type nematodes by 16.7% under normal conditions and also improved their stress endurance under thermal, osmotic, and oxidative stress conditions. This longevity promoting effect could be attributed to in vivo antioxidant capacity and its up regulating effects on the expressions of stress-response proteins such as SOD-3 and HSP-16.2. In addition, DaD treatment attenuated food intake, body length, lipofuscin accumulation and age-dependent decline of motor ability. Gene-specific mutant studies showed the involvement of genes such as daf-2, age-1, and daf-16. CONCLUSIONS: These results suggest that DaD has beneficial effects on the longevity, and thus it can be a valuable plant origin lead compound for the development of nutraceutical preparations targeting ageing and ageing-related diseases. PMID- 29992573 TI - Comment on ischemic stroke after herpes zoster. PMID- 29992574 TI - Part 2: Dynamic mixed beam radiotherapy (DYMBER): Photon dynamic trajectories combined with modulated electron beams. AB - PURPOSE: The purpose of this study was to develop a treatment technique for dynamic mixed beam radiotherapy (DYMBER) utilizing increased degrees of freedom (DoF) of a conventional treatment unit including different particle types (photons and electrons), intensity and energy modulation and dynamic gantry, table, and collimator rotations. METHODS: A treatment planning process has been developed to create DYMBER plans combining photon dynamic trajectories (DTs) and step and shoot electron apertures collimated with the photon multileaf collimator (pMLC). A gantry-table path is determined for the photon DTs with minimized overlap of the organs at risk (OARs) with the target. In addition, an associated dynamic collimator rotation is established with minimized area between the pMLC leaves and the target contour. pMLC sequences of photon DTs and electron pMLC apertures are then simultaneously optimized using direct aperture optimization (DAO). Subsequently, the final dose distribution of the electron pMLC apertures is calculated using the Swiss Monte Carlo Plan (SMCP). The pMLC sequences of the photon DTs are then re-optimized with a finer control point resolution and with the final electron dose distribution taken into account. Afterwards, the final photon dose distribution is calculated also using the SMCP and summed together with the one of the electrons. This process is applied for a brain and two head and neck cases. The resulting DYMBER dose distributions are compared to those of dynamic trajectory radiotherapy (DTRT) plans consisting only of photon DTs and clinically applied VMAT plans. Furthermore, the deliverability of the DYMBER plans is verified in terms of dosimetric accuracy, delivery time and collision avoidance. For this purpose, The DYMBER plans are delivered to Gafchromic EBT3 films placed in an anthropomorphic head phantom on a Varian TrueBeam linear accelerator. RESULTS: For each case, the dose homogeneity in the target is similar or better for DYMBER compared to DTRT and VMAT. Averaged over all three cases, the mean dose to the parallel OARs is 16% and 28% lower, D2% to the serial OARs is 17% and 37% lower and V10% to normal tissue is 12% and 4% lower for the DYMBER plans compared to the DTRT and VMAT plans, respectively. The DYMBER plans are delivered without collision and with a 4-5 min longer delivery time than the VMAT plans. The absolute dose measurements are compared to calculation by gamma analysis using 2% (global)/2 mm criteria with passing rates of at least 99%. CONCLUSIONS: A treatment technique for DYMBER has been successfully developed and verified for its deliverability. The dosimetric superiority of DYMBER over DTRT and VMAT indicates utilizing increased DoF to be the key to improve brain and head and neck radiation treatments in future. PMID- 29992575 TI - The genus Closterium, a new model organism to study sexual reproduction in streptophytes. AB - Contents Summary 99 I. Introduction 99 II. Life cycle of Closterium 100 III. Sexual reproductive processes in the heterothallic Closterium peracerosum strigosum-littorale complex 101 IV. Homothallism in the C. psl. complex 102 V. Sexual reproduction and inheritance of mating types in Closterium ehrenbergii 102 VI. mt-determining gene of the C. psl. complex 103 VII. Future perspectives 103 Acknowledgements 103 References 103 SUMMARY: Closterium occupies a key phylogenetic position as an ancestor of land plants and is the best-characterized Charophycean alga in terms of the process of sexual reproduction. Zygospores form as a result of sexual reproduction between genetically determined mating type plus (mt+ ) and mating type minus (mt- ) cells in heterothallic strains, or between clonal cells in homothallic strains. Here we review knowledge on the intercellular communication and mating type determination for successful sexual reproduction in Closterium. Using genomic information and transgenic techniques, the genus could be a model organism to study the mechanisms and evolution of sexual reproduction in streptophytes. PMID- 29992576 TI - Physicochemical Compatibility of Amiodarone with Parenteral Nutrition. AB - BACKGROUND: Y-site administration of total parenteral nutrition (TPN) and drugs is frequently required in the intensive care setting. Amiodarone is commonly administered by continuous intravenous infusion and subject to be co-administered via a Y-site with TPN. The aim of this study is to determine the physicochemical stability of amiodarone Y-site administered with TPN. METHODS: Two standard TPN and 2 amiodarone solutions were designed. The 2 TPN differed in the lipid source (Lipofundin MCT/LCT(r) 20% or SMOFlipid(r) 20%). The 2 amiodarone solutions were prepared at different concentrations (900 mg and 1200 mg in 250 mL of dextrose 5% in water). Each TPN and amiodarone solutions ran at a rate that simulated a 24 hour Y-site infusion to obtain different admixture samples. Each sample was then visually examined and further tested to determine the mean lipid droplet size distribution by dynamic light scattering and amiodarone concentrations by HPLC. RESULTS: No alterations were detected by visual inspection. Average droplet size remained below 500 nm (252.5 +/- 5.9 nm for Lipofundin MCT/LCT(r) TPN and 327.7 +/- 14.4 nm for SMOFlipid(r) TPN). For the samples obtained after running 900 mg and 1200 mg amiodarone solutions with TPN, the concentrations observed at 24 hours were 0.4491 +/- 0.0111 mg/mL and 0.5773 +/- 0.0214 mg/mL, respectively. These results represent approximately 100% of the zero-time concentrations and are within +/-15% of the predicted values. No degradation products were observed in the chromatograms. CONCLUSION: Amiodarone is physicochemically compatible with standard TPN via a Y-site administration at the tested amiodarone concentrations. PMID- 29992577 TI - Ovine vital neutrophil extracellular traps bind and impair Haemonchus contortus L3 in a breed-dependent manner. AB - This study aimed to characterize neutrophil response to Haemonchus contortus (Hc) in vitro using cells from parasite-resistant St. Croix (STC) and parasite susceptible Suffolk (SUF) sheep. Neutrophils from Hc-primed and naive STC and SUF sheep were incubated with Hc larval antigen (HcLA), Hc worm antigen (HcWA) or complete media (CM). After HcLA exposure, neutrophils from STC and SUF formed extracellular traps composed of DNA. Stimulation with HcLA induced a 35-fold increase in extracellular DNA compared to CM controls. However, extracellular DNA was not found when neutrophils were cultured with HcWA. The formation of neutrophil extracellular traps (NET) in response to HcLA yields a low percentage of necrotic cells indicating a form of vital NETosis. Neutrophils from primed and naive STC bound Hc L3 greater (93% and 68%) than SUF (78% and 45%; P < 0.001). Furthermore, STC neutrophils significantly reduced larval ATP levels compared to SUF neutrophils (0.05 MUmol/L vs 0.1 MUmol/L ATP, P < 0.001). These data indicate that ovine neutrophils bind, form vital NET and reduce ATP to Hc L3 in a breed and infection status-dependent manner. PMID- 29992578 TI - GPRC5A deficiency leads to dysregulated MDM2 via activated EGFR signaling for lung tumor development. AB - GPRC5A, a retinoic acid induced gene, is preferentially expressed in lung tissue. Gprc5a gene deletion leads to spontaneous lung tumor development. However, the mechanism of Gprc5a-mediated lung tumor suppression is not fully understood. Here we showed that MDM2, a p53-negative regulator, was dysregulated in Gprc5a knockout (ko) mouse tracheal epithelial cells (KO-MTEC) compared to wild type ones. Targeting MDM2 in 1601-a Gprc5a-ko mouse derived lung tumor cell line-and A549-human lung cancer cells, by MDM2 inhibitor Nutlin-3a or small hairpin RNA (sh-RNA)-restored p53 signaling pathway, reduced cancer stem cell markers, and inhibited tumorigenicity. This suggests that dysregulated MDM2 pathway is essential for the oncogenic activities of these cells. MDM2 was found to be stabilized mainly by activated EGFR signaling as targeting EGFR by Erlotinib or sh-RNA repressed MDM2 in a transcription-independent manner. Importantly, overexpression of MDM2 and reduced GPRC5A expression at both protein and mRNA levels were frequently found in clinical human lung cancer tissues. Taken together, GPRC5A deficiency contributes to dysregulated MDM2 via activated EGFR signaling, which promotes lung tumor development. PMID- 29992579 TI - Combined detection of AC-electrokinetic effects: Experiments with three-axial chicken red blood cells. AB - Dielectrophoresis (DEP), electrorotation (ROT), and electro-orientation were used for the dielectric spectroscopy of nucleated three-axial chicken red blood cells (CRBCs). Because the different AC-electrokinetic effects are not mutually independent, their DEP and ROT spectra were combined in ranges separated by the reorientation of the CRBCs in the inhomogeneous linear DEP and circular ROT fields. This behavior can be qualitatively described by a single-shell ellipsoidal model. Whereas in linear fields, the maximum of the Clausius-Mossotti factor along the three axes determines the orientated axis, in circular fields, the minimum of the factor determines the axis perpendicularly orientated to the field plane. Quantitatively, it has not been possible to find a consistent parameter set for fitting the DEP and ROT spectra, as well as the reorientation frequencies. Our ellipsoidal CRBC standard model had semiaxes of a = 7.7 MUm, b = 4.0 MUm, and c = 1.85 MUm, a relative permittivity of 35 to 45 and conductivity of 0.36 to 0.04 S/m for the cytoplasm, combined with a specific capacitance of 10 to 14 mF/m2 and a conductivity of 3500 S/m2 for the cell membrane. The fits in different external conductivity ranges between external conductivities of 0.015 and 1.0 S/m were improved when the membrane capacitance was changed between 4 to 25 mF/m2 depending on the method used. A similar transition was reflected in the effective properties of a three-shell spherical model containing an internal membranous sphere with the geometry of the CRBC nucleus. Our findings suggest that the simultaneous interpretation of various AC-electrokinetic spectra is a step toward the dielectric fingerprinting of biological cells. PMID- 29992580 TI - Clinical cut-off point for the Distrust dimension of the Dimensional Clinical Personality Inventory 2 (IDCP-2). AB - The Clinical Dimensional Personality Inventory 2 (IDCP-2) is a 206-item self report tool developed for the assessment of 12 dimensions (divided into 47 factors) of personality pathology. One of the scales comprising the instrument, the Distrust scale, is intended to provide psychometric information on traits closely related to the Paranoid Personality Disorder (PPD). In the present research, we used the Item Response Theory and the Receiver Operating Characteristic curve analysis to establish a clinical meaningful cutoff for the Distrust scale. Participants were 1,679 adults, among outpatients diagnosed with PPD, outpatients diagnosed with other PDs, and adults from the community. The Wright map revealed that outpatients were located at the very high levels on the latent continuum of the Distrust scale, with a very large effect size for the mean difference between patients and non-patients. The ROC curve supported a cutoff at -1.00 score in theta standardization which yielded 0.87 of sensitivity and 0.54 of specificity. Findings from the present investigation suggest the IDCP 2 Distrust scale is useful as a screening tool of the core features of the PPD. We address potential clinical applications for the instrument and discuss limitations from the present study. PMID- 29992581 TI - Low prevalence of diabetes with chronic complications in patients with Takotsubo syndrome. PMID- 29992583 TI - Young children's television viewing and the quality of their interactions with parents: A prospective community study. AB - Television is one of the most commonly viewed forms of media by children throughout the world. Excessive television viewing can influence the quality of children's relationships and interactions with their parents. We examined the emotional availability (EA) of children toward their parents by assessing child responsiveness and child involvement, using a cross-sectional and longitudinal design. We employed a large and representative community sample of Norwegian 4 year-olds (n = 995) who were followed up at 6 years old (n = 795). The results illustrate that, when viewing excessive amounts of television, children are less likely to be involved with their parents in ordinary toy-play. We argue in favor of the displacement hypothesis, stating that time-demanding technologies are negatively related to the quality of parent-child relationships because spending more time watching television will leave less time for developing nurturing social relationships. PMID- 29992582 TI - Rising rates of bilateral mastectomy with reconstruction following neoadjuvant chemotherapy. AB - Neoadjuvant chemotherapy (NAC) is used to allow more limited breast surgery without compromising local control. We sought to evaluate nationwide surgical trends in patients with operable breast cancer treated with NAC and factors associated with surgical type. We used the National Cancer Database to identify 235,339 women with unilateral T1-3 N0-3 M0 breast cancer diagnosed between 2010 and 2014 and treated with surgery and chemotherapy. Of these, 59,568 patients (25.3%) were treated with NAC. Rates of pathological complete response (pCR) to NAC increased from 33.3% at the start of the study period in 2010 to 46.3% at the end of the period in 2014 (p = 0.02). Rates of breast-conserving surgery (BSC) changed little, from 37.0 to 40.8% (p = 0.22). Although rates of unilateral mastectomy decreased from 43.3 to 34.7% (p = 0.02) and rates of bilateral mastectomy without immediate reconstruction remained similar (11.7-11.5%; p = 0.82), rates of bilateral mastectomy with immediate reconstruction rose from 8.0 to 13.1% (p = 0.02). Patients who were younger, with private/managed care insurance, and diagnosed in more recent years were more likely to achieve pCR; however, these same characteristics were associated with receipt of bilateral mastectomy (vs. BCS). In addition, non-Hispanic white ethnic and higher area education attainment were both associated with bilateral mastectomy. These findings did not differ by age or molecular subtype. Further study of nonclinical factors that influence selection of more extensive surgery despite excellent response to NAC is warranted. PMID- 29992584 TI - Association of IFNlambda4 rs12979860 polymorphism with the acquisition of HCV and HIV infections among people who inject drugs. AB - We investigated the presence of a single-nucleotide polymorphism designated rs12979860 in the interferon lambda4 (IFNlambda4) gene among 345 people who inject drugs (PWID) and 495 blood donors to evaluate associations between the rs12979860 genotypes and human immunodeficiency virus/hepatitis C virus (HIV/HCV). The rs12979860 TT genotype was over-represented among HIV+ PWID than HIV- PWID and blood donors (16% vs 8% and 10%, P = 0.03, respectively). PWID with TT genotype had approximately twice the probability of being HIV+ (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.11 to 4.33) than PWID without TT. Every additional year of intravenous drug use (IVDU) decreased the OR 1.16 times (OR, 0.86; 95% CI, 0.75 to 0.98). This suggests that rs12979860 TT increases susceptibility to HIV and this impact decreases with increasing duration of IVDU. PMID- 29992585 TI - Extracellular maltotriose hydrolysis by Saccharomyces cerevisiae cells lacking the AGT1 permease. AB - : In brewing, maltotriose is the least preferred sugar for uptake by Saccharomyces cerevisiae cells. Although the AGT1 permease is required for efficient maltotriose fermentation, we have described a new phenotype in some agt1Delta strains of which the cells do not grow on maltotriose during the first 3-4 days of incubation, but after that, they start to grow on the sugar aerobically. Aiming to characterize this new phenotype, we performed microarray gene expression analysis which indicated upregulation of high-affinity glucose transporters (HXT4, HXT6 and HXT7) and alpha-glucosidases (MAL12 and IMA5) during this delayed cellular growth. Since these results suggested that this phenotype might be due to extracellular hydrolysis of maltotriose, we attempted to detect glucose in the media during growth. When an hxt-null agt1Delta strain was grown on maltotriose, it also showed the delayed growth on this carbon source, and glucose accumulated in the medium during maltotriose consumption. Considering that the poorly characterized alpha-glucosidase encoded by IMA5 was among the overexpressed genes, we deleted this gene from an agt1Delta strain that showed delayed growth on maltotriose. The ima5Delta agt1Delta strain showed no maltotriose utilization even after 200 h of incubation, suggesting that IMA5 is likely responsible for the extracellular maltotriose hydrolysis. SIGNIFICANCE AND IMPACT OF THE STUDY: Maltotriose is the second most abundant sugar present in brewing. However, many yeast strains have difficulties to consume maltotriose, mainly because of its low uptake rate by the yeast cells when compared to glucose and maltose uptake. The AGT1 permease is required for efficient maltotriose fermentation, but some strains deleted in this gene are still able to grow on maltotriose after an extensive lag phase. This manuscript shows that such delayed growth on maltotriose is a consequence of extracellular hydrolysis of the sugar. Our results also indicate that the IMA5-encoded alpha-glucosidase is likely the enzyme responsible for this phenotype. PMID- 29992586 TI - The Effect of Additives for Reflux or Dysphagia Management on Osmolality in Ready to-Feed Preterm Formula: Practice Implications. AB - BACKGROUND: A common osmolality threshold for feedings is to stay <450 mOsm/kg for normal infants. Preterm formulas are frequently modified to improve growth, modify nutrition, and manage gastroesophageal reflux (GER) or dysphagia. Relationships between osmolality and additives to ready-to-feed preterm formulas are unclear. Our aims were to evaluate and compare the effects of caloric density, thickening agent recipes, and supplements to ready-to-feed preterm formula on osmolality. METHODS: A freezing point osmometer was used to measure the osmolality of 47 preterm infant formula combinations with varying caloric densities (ready-to-feed 22 and 30 cal/oz), thickening agents (rice vs oatmeal cereal), thickener amounts (0.0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 tsp/oz), and combinations of supplements (saline, iron, vitamin D, or multivitamin). Ten samples per combination were tested using a 10-MUL pipette. Comparisons were made using analysis of variance and t-tests for group and pair-wise comparisons, respectively. RESULTS: A total of 470 osmolality samples were analyzed: (1) raters had high agreement (r = 0.98; P < .001); (2) for every 0.5 tsp/oz of thickener, the osmolality increases by 30 mOsm/kg (P < .001); (3) osmolality was higher with the oatmeal (vs rice) thickening agent (P < .001); and (4) vitamin and electrolyte supplement combinations increase osmolality. CONCLUSIONS: Alteration of ready-to-feed preterm formulas may significantly increase osmolality and have unintended consequences. Caution and monitoring should be exercised with modifying ready-to-feed preterm formulas for regurgitation, rumination, GER, dysphagia, feeding intolerance, or emesis. This study supports the concept of achieving volume tolerance before further manipulation of additives. PMID- 29992587 TI - Part 1: Optimization and evaluation of dynamic trajectory radiotherapy. AB - PURPOSE: Although volumetric modulated arc therapy (VMAT) is a well-accepted treatment technique in radiotherapy using a coplanar delivery approach, VMAT might be further improved by including dynamic table and collimator rotations leading to dynamic trajectory radiotherapy (DTRT). In this work, an optimization procedure for DTRT was developed and the potential benefit of DTRT was investigated for different treatment sites. METHODS: For this purpose, a dedicated optimization framework for DTRT was developed using the Eclipse Scripting Research Application Programming Interface (ESRAPI). The contours of the target and organs at risk (OARs) structures were exported by applying the ESRAPI and were used to determine the fractional volume-overlap of the OARs with the target from several potential beam directions. Thereby, an additional weighting was applied taking into account the relative position of the OAR with respect to the target and radiation beam, that is, penalizing directions where the OAR is proximal to the target. The resulting two-dimensional gantry-table map was used as input for an A* path finding algorithm returning an optimized gantry table path. Thereby, the process is also taking into account CT scan length and collision restrictions. The A* algorithm was used again to determine the dynamic collimator angle path by optimizing the area between the MLC leaves and the target contour for each gantry-table path leading to gantry-collimator paths. The resulting gantry-table and gantry-collimator paths are combined and serve as input for the intensity modulation optimization using a research VMAT optimizer and the ESRAPI resulting in dynamic trajectories. This procedure was evaluated for five clinically motivated cases: two head and neck, one lung, one esophagus, and one prostate. Final dose calculations were performed using the Swiss Monte Carlo Plan (SMCP). Resulting dose distributions for the DTRT treatment plans and for the standard VMAT plans were compared based on dose distributions and dose volume histogram (DVH) parameters. For this comparison, the dose distribution for the VMAT plans were recalculated using the SMCP. In addition, the suitability of the delivery of a DTRT treatment plan was demonstrated by means of gafchromic film measurements on a TrueBeam linear accelerator. RESULTS: DVHs for the target volumes showed similar or improved coverage and dose homogeneity for DTRT compared with VMAT using equal or less number of dynamic trajectories for DTRT than arcs for VMAT for all cases studied. Depending on the case, improvements in mean and maximum dose for the DTRT plans were achieved for almost all OARs compared with the VMAT plans. Improvements in DTRT treatment plans for mean and maximum dose compared to VMAT plans were up to 16% and 38% relative to the prescribed dose, respectively. The measured and calculated dose values resulted in a passing rate of more than 99.5% for the two-dimensional gamma analysis using 2% and 2 mm criteria and a threshold of 10%. CONCLUSIONS: DTRT plans for different treatment sites were generated and compared with VMAT plans. The delivery is suitable and dose comparisons demonstrate a high potential of DTRT to reduce dose to OARs using less dynamic trajectories than arcs, while target coverage is preserved. PMID- 29992588 TI - Correlated evolution of self and interspecific incompatibility across the range of a Texas wildflower. AB - Selection to prevent interspecific mating can cause an increase or a decrease in self-pollination in sympatric populations. Characterizing the geographical variation in self and interspecific incompatibilities within a species can reveal if and how the evolution of self and interspecific mate choice are linked. We used controlled pollinations to characterize the variation in self and interspecific incompatibility across 29 populations of Phlox drummondii. We evaluated seed set from these pollinations and described the developmental timing of variation in pollen-pistil compatibility. There is extensive quantitative variation in self-incompatibility and interspecific-incompatibility with its close congener P. cuspidata. Phlox drummondii populations that co-occur and hybridize with P. cuspidata have significantly higher interspecific incompatibility and self-incompatibility than geographically isolated P. drummondii populations. The strength of self and interspecific incompatibility is significantly correlated among individuals and the strength of both incompatibilities is explained by the success of pollen adhesion to the stigma. The correlated strength of self and interspecific incompatibility across the range of P. drummondii and the concurrent developmental timing of the pollen pistil interaction, suggests these incompatibilities have an overlapping molecular mechanism. The geographical distribution of variation in incompatibilities indicates that this mechanistic link between incompatibilities may affect the evolution of mate choice in plants. PMID- 29992589 TI - Continuous versus discontinuous tumor involvement: A dilemma in prostate biopsy quantitation. AB - BACKGROUND: No consensus has been reached for an optimal method of quantifying discontinuous tumor foci separated by intervening benign tissue on prostate biopsy (PBx). We examined sets of PBx, where cancer involved only one core, and corresponding radical prostatectomy (RP) specimens. METHODS AND RESULTS: Cases were divided into 3 groups-Group 1 (n = 80): <3 mm in end-to-end tumor measurement (continuous/discontinuous); Group 2 (n = 22): >=3 mm in tumor length (continuous); and Group 3 (n = 15): >=3 mm in end-to-end tumor measurement (discontinuous). The rate of Gleason score >=7 was considerably lower in Group 1 (9%/30% on PBx/RP) than in Group 2 (50% [P < 0.001]/59% [P = 0.015] on PBx/RP) or Group 3 (40% [P = 0.005]/46% [P = 0.237] on PBx/RP). pT2 disease was significantly more often found in Group 1 (88%) than in Group 2 (68%, P = 0.049) or Group 3 (60%, P = 0.018). Surgical margin was significantly more often positive in Group 3 (27%) than in Group 1 (5%, P = 0.020), but not Group 2 (9%, P = 0.198). Moreover, estimated cancer volume (cc, mean +/- SD) was significantly smaller in Group 1 (1.89 +/- 1.98) than in Group 2 (3.56 +/- 2.92, P = 0.026) or Group 3 (3.44 +/- 2.02, P = 0.013). Kaplan-Meier analysis revealed higher risks of biochemical recurrence after RP in Group 2, compared with Group 1 (P = 0.001) or Group 3 (P = 0.096). In 93 patients with biopsy Gleason score 6 cancer, higher rates of pT2+/3 disease (P = 0.023) and positive margin (P = 0.026), as well as larger cancer volume (P = 0.063), on RP were still seen in Group 3, compared with Group 1, but their differences were not statistically significant between Group 2 and Group 3. CONCLUSIONS: Linear quantitation including intervening benign tissue on PBx may more precisely predict the actual tumor extent. PMID- 29992590 TI - One-year follow-up of the prospective registry of patients using the wearable defibrillator (WEARIT-II Registry). AB - BACKGROUND: The WEARIT-II Registry demonstrated efficacy and safety of the wearable cardioverter defibrillator (WCD) for at-risk cardiac patients. However, 1-year outcomes in this population have not been reported. METHODS: The WEARIT-II Registry enrolled 2,000 U.S. patients prescribed the WCD. One-year mortality data from start of WCD use were prospectively collected for 1,846 patients (93%). Outcome data were analyzed by disease etiology and implantable cardioverter defibrillator (ICD) implantation following WCD use. RESULTS: During 12 months of follow-up, 73 patients died (4%). Kaplan-Meier survival analysis showed differences in all-cause mortality from WCD prescription between patients with ischemic versus nonischemic cardiomyopathy versus congenital/inherited heart disease (4% vs 3% vs 7%, P = 0.013). Patients with ventricular arrhythmia events during WCD use had a higher 1-year mortality (10% vs 3%, P = 0.042). Renal disease, increasing age, prior syncope, and nonbeta-blocker use predicted mortality. One-year mortality was similar in patients who did versus did not receive an ICD following WCD use in ischemic (3% vs 4%, P = 0.470) and nonischemic cardiomyopathy (3% vs 3%, P = 0.892). Patients with congenital/inherited heart disease with no implanted ICD had a trend toward a higher rate of mortality than those who received an ICD (8% vs 3%, P = 0.082). Multivariate models confirmed these findings. CONCLUSION: One-year follow-up from the WEARIT-II Registry shows an overall good survival in patients prescribed the WCD. Short-term use of WCD allows appropriate risk stratification for decision on an ICD implantation in at-risk ischemic and nonischemic cardiomyopathy patients. Congenital/inherited heart disease patients had a higher risk of 1-year mortality even without an implanted ICD post-WCD. PMID- 29992591 TI - Semiparametric varying-coefficient regression analysis of recurrent events with applications to treatment switching. AB - This paper investigates the semiparametric statistical methods for recurrent events. The mean number of the recurrent events are modeled with the generalized semiparametric varying-coefficient model that can flexibly model three types of covariate effects: time-constant effects, time-varying effects, and covariate varying effects. We assume that the time-varying effects are unspecified functions of time and the covariate-varying effects are parametric functions of an exposure variable specified up to a finite number of unknown parameters. Different link functions can be selected to provide a rich family of models for recurrent events data. The profile estimation methods are developed for the parametric and nonparametric components. The asymptotic properties are established. We also develop some hypothesis testing procedures to test validity of the parametric forms of covariate-varying effects. The simulation study shows that both estimation and hypothesis testing procedures perform well. The proposed method is applied to analyze a data set from an acyclovir study and investigate whether acyclovir treatment reduces the mean relapse recurrences. PMID- 29992592 TI - Blockade of the cholinergic system during sensitization enhances lung responsiveness to allergen in rats. AB - Although acute prophylactic administration of atropine modulates airway responsiveness, the role of the parasympathetic nervous system in the pathogenesis of sensitization and in antigen-induced bronchoconstriction remains unclear. The aim of the present study is to determine whether blocking muscarinic receptors during chronic allergen exposure modulates lung responsiveness to the specific allergen. Forty rats were randomly assigned to one of the following five treatment groups: sensitization with saline vehicle, intraperitoneal injection of ovalbumin (1 mg) with or without atropine treatment (10 mg/kg per day) and repeated ovalbumin aerosol (1.25 mg/mL for 20 minutes) either alone or combined with atropine. Lung responsiveness to methacholine (4-16 MUg/kg per minute) and intravenous ovalbumin (2 mg) was established before and 21 days after treatment with forced oscillations following bilateral vagotomy. Lung cellularity was determined by analysis of bronchoalveolar lavage fluid (BALF). A lung inflammatory response in all sensitized animals was defined as an increase in the number of inflammatory cells in the BALF. Baseline respiratory mechanics and methacholine responsiveness on Days 0 and 21 were comparable in all groups. However, increases in airway resistance following intravenous allergen challenge were significantly exacerbated in rats that received atropine. Inhibition of the cholinergic nervous system during allergic sensitization potentiates bronchoconstriction following exposure to the specific allergen. These findings highlight the role of the cholinergic neuronal pathway in airway sensitization to a specific allergen. PMID- 29992593 TI - Liver biochemical abnormalities in Turner syndrome: A comprehensive characterization of an adult population. AB - OBJECTIVE: Abnormal liver function tests (LFTs) are frequent in Turner syndrome (TS). The causes and clinical significance are unclear. AIMS: To investigate the prevalence of elevated LFTs in adult TS; secondly, to analyse the associations between elevated LFTs, TS-karyotypes and TS-related conditions; and thirdly, to evaluate liver stiffness and histological assessment. METHODS: A total of 125 TS women were retrospectively studied. Karyotypes, clinical and biochemical details and aortic measurements were recorded. Fibroscan and liver biopsy results were noted. RESULTS: Elevated LFTs were found in 49.6%: gamma-glutamyltransferase (GGT) in 88.7%, ALK in 45.2%, ALT in 40.3% and AST in 29%. A FIB-4 index >1.3 was found in 11.8%. Women with isochromosome of the X long arm, iso[X](q), had a higher prevalence of elevated LFTs. A lower prevalence of abnormal GGT was found in patients with 45,X/46,XX, 45,X/47,XXX or 45,X/46,XX/47,XXX. Subjects with raised GGT were older, shorter and more likely to have higher triglyceride levels. There was no association with HRT duration after adjusting for age. Among patients with elevated aminotransferases, no differences were noted, except for higher HDL-cholesterol levels. The sinuses and ascending aorta diameter were greater in the elevated LFTs group. Fibroscan was suggestive of significant liver fibrosis in 38.1%. Among 11 biopsies, liver architectural changes were reported in 45.4%, including two with cirrhosis. CONCLUSIONS: Elevated LFTs in TS are common and important to detect given the possible progression towards severe liver disease. An association between raised LFTs and karyotype iso[X]q was demonstrated. We have also shown a new association between abnormal LFTs and aortic dilatation. PMID- 29992595 TI - Aggregation characteristics of protein during wheat flour maturation. AB - BACKGROUND: The protein aggregation characteristics of three types of freshly milled wheat flour with high, medium or low gluten were investigated during 90 days of maturation. Changes in the content and particle size of the glutenin macropolymer (GMP), contents of sulfhydryl groups and disulfide bonds (SS), and secondary structure and molecular weight distribution of the protein were determined. RESULTS: For high, medium and low gluten flour, GMP content increased to 22.25, 13.72 and 10.32 g kg-1 ; free sulfhydryl group content decreased by 5.5%, 4.1% and 4.4%; and SS content increased by 1.6%, 1.8% and 2%, respectively. The proportion of beta-sheet and random coil increased, and the proportion of alpha-helix and beta-turns decreased. The polymeric protein content increased, whereas that of gliadin decreased. CONCLUSION: Protein aggregation mediated by SS cross-linking helped develop a stronger gluten network. The findings provide theoretical support for the changes in protein structure during flour maturation and also help to predict the quality of wheat flour and its products. (c) 2018 Society of Chemical Industry. PMID- 29992594 TI - Morbidity following transcrestal and lateral sinus floor elevation: A randomized trial. AB - AIM: To comparatively evaluate the morbidity following maxillary sinus floor elevation according to either transcrestal (tSFE) or lateral (lSFE) approach with concomitant implant placement. MATERIALS & METHODS: Patients with >=1 edentulous maxillary posterior site with residual bone height (RBH) of 3-6 mm were enrolled. tSFE was performed in association with a xenograft and a collagen matrix. For lSFE, the sinus was grafted with the xenograft, and the antrostomy was covered with a membrane. Implants were inserted concomitantly. The postoperative course was assessed through questionnaires. Pain level (VASpain ) was recorded using a 100-mm visual analogue scale. RESULTS: Twenty-nine and 28 patients were included in tSFE and lSFE group, respectively. On the day of surgery, VASpain was significantly higher for tSFE compared to lSFE, and similar from day 1 to 14. tSFE was characterized by significantly lower incidence of swelling, bruising and nasal discharge/bleeding. Significantly less severe limitation in swallowing, continuing daily activities, eating, speaking, opening the mouth and going to school/work was found for tSFE only at specific postsurgery intervals. CONCLUSIONS: lSFE was associated with lower pain on the day of surgery, and tSFE revealed lower postoperative morbidity as well as more tolerable postoperative course. PMID- 29992596 TI - Connections between academic burnout, resilience, and psychological well-being in nursing students: A longitudinal study. AB - AIMS: The aim of this study was to explore the longitudinal associations between academic burnout and resilience and psychological well-being, and the stability of these variables in a sample of university nursing students. BACKGROUND: Nursing students frequently suffer academic burnout, which is brought on by different situations experienced during the training process and that can concern his psychological well-being. Resilience is a personal resource that allows adverse situations to be handled in a successful way. DESIGN: Longitudinal design. METHODS: Data were collected at two moments separated by 18 months (2014 2016), with 218 students at T1 and 113 at T2. At each time a questionnaire was given to them, with questions about socioeconomic demographics and three validated scales to measure academic burnout, resilience, and psychological well being. RESULTS: The three dimensions that make up academic burnout remained steady over time, while resilience increased and psychological well-being improved. Hierarchical regression analyses revealed the longitudinal effect of emotional exhaustion at T1 and at T2 they showed the longitudinal effect of resilience on psychological well-being at T2. The inverse hierarchical regression analyses did not reveal significant relationships for any of the variables measured at T2 in connection with psychological well-being measured at T1. CONCLUSIONS: Emotional exhaustion was the most relevant dimension of academic burnout when predicting psychological well-being in the analysed sample. Moreover, resilience has an important positive effect on psychological well-being in the analysed sample. The practical implications of the results are discussed from the perspective of academic training and some recommendations are given for future research in this field. PMID- 29992597 TI - Editorial: Sweet nothings - the value of negative findings for scientific progress. AB - It is well-known that selective outcome reporting and publication distort the information that is made publicly available, and so undermine the reliability of what we consider evidence-based knowledge. Perhaps less known is that the risk of bias extends beyond the process of reporting and publishing results. Two further sources of bias are spin and selective citing. Spin relates to selective interpretation, meant to transform a basically negative conclusion into a more positively toned one; citation bias is the phenomenon that positive findings tend to be cited more than negative ones. The effects of these sources of imbalance accumulate, and the consequences can be huge. This issue of JCPP contains several articles with wholly or partly negative findings, which hopefully will be cited frequently. Publications regarding negative findings comprise an underrepresented and often undervalued minority, and therefore deserve all the support they can get. PMID- 29992598 TI - Redefining and reinvigorating the role of physics in clinical medicine: A Report from the AAPM Medical Physics 3.0 Ad Hoc Committee. AB - Derived from 2 yr of deliberations and community engagement, Medical Physics 3.0 (MP3.0) is an effort commissioned by the American Association of Physicists in Medicine (AAPM) to devise a framework of strategies by which medical physicists can maintain and improve their integral roles in, and contributions to, health care and its innovation under conditions of rapid change and uncertainty. Toward that goal, MP3.0 advocates a broadened and refreshed model of sustainable excellence by which medical physicists can and should contribute to health care. The overarching conviction of MP3.0 is that every healthcare facility can benefit from medical physics and every patient's care can be improved by a medical physicist. This large and expansive challenge necessitates a range of strategies specific to each area of medical physics: clinical practice, research, product development, and education. The present paper offers a summary of the Phase 1 deliberations of the MP3.0 initiative pertaining to strategic directions of the discipline primarily but not exclusively oriented toward the clinical practice of medical physics in the United States. PMID- 29992599 TI - IMPACT of nurses' solution-focused communication on the fluid adherence of adult patients on haemodialysis. AB - AIM: To test the hypothesis that fluid adherence in patients on haemodialysis can be improved through nurses' solution-focused communication with patients on issues of adherence. BACKGROUND: Adherence to fluid-intake restrictions is low in patients on haemodialysis, creating serious health risks. Psychosocial interventions to increase adherence have typically focused on patients and ignored patient/staff interactions. DESIGN: This is a single-group, pre-post pilot study registered in ClinicalTrials.gov (identifier: NCT03432988). METHOD: A 1-month baseline of interdialytic weight gain was taken in April 2016 for a group of 36 adult patients in a hospital haemodialysis unit. Then, the nurses of the unit received a 4 hr training in solution-focused communication on issues of fluid adherence and applied it with the patients of the sample. Interdialytic weight gains were measured during another month. One month after the training, in October 2016, interdialytic weight gains were measured for another month. RESULTS: After introducing solution-focused communication on fluid adherence, patients' average interdialytic weight gains decreased significantly, below the level considered indicative of problematic adherence. These results were maintained at follow-up. CONCLUSIONS: Our results suggest that a novel approach to adherence, nurses' solution-focused communication with patients on haemodialysis, may improve patients' adherence to fluid restriction. More rigorous, controlled studies are required to confirm long-term benefits and to understand the causal mechanisms that may underlie the effectiveness of this intervention. PMID- 29992600 TI - The effect of a self-help psychoeducation programme for people with coronary heart disease: A randomized controlled trial. AB - AIM: To examine the effect of a self-help psychoeducation program for people with coronary heart disease in Singapore. BACKGROUND: Cardiac rehabilitation has shown benefits for mitigating many cardiac risk factors and can lead to improvement in health-related quality of life and psychological well-being in people with heart disease. However, traditional hospital-based cardiac rehabilitation faces substantial challenges. A self-management cardiac rehabilitation program offers an avenue to increase uptake and empowers patients to manage their condition at home. DESIGN: A two-arm, randomized controlled trial. METHODS: A total of 129 patients with coronary heart disease were recruited from an outpatient clinic in a public hospital in Singapore from April 2015-January 2016. They were randomly assigned to the intervention group or the control group. Participants in the intervention group received the 4-week home-based self-help psychoeducation program. Outcomes were measured at baseline and at 4 weeks and 16 weeks from the baseline. RESULTS: There were no significant differences in health-related quality of life, psychological status (i.e., perceived stress level, anxiety, and depression levels), or cardiac physiological risk parameters between the intervention and the control groups immediately after the program or at different time points. There was also no significant difference in unplanned health service use at the 16 week posttest point between the two groups. CONCLUSIONS: This study did not find any significant effect of our program on outpatients with coronary heart disease. Nonetheless, findings on participant characteristics may offer healthcare professionals valuable insights to help facilitate future development of an effective cardiac rehabilitation program catered to outpatients with coronary heart disease. TRIAL REGISTRATION: The study has been registered with ISRCTN registry. The trial registration number is ISRCTN15839687. PMID- 29992601 TI - Development and Validity Testing of the School Health Score Card. AB - BACKGROUND: The objective of this study was to develop the School Health Score Card (SHSC) and validate its psychometric properties. METHODS: The development of the SHSC questionnaire included 3 phases: item generation, construction of domains and items, and field testing with validation. To assess the instrument's reliability and validity, we recruited 15 middle schools and 15 high schools in the Republic of Korea. RESULTS: We developed the SHSC questionnaire of 158 items categorized into 5 domains: (1) Governance and Infrastructure, (2) Need Assessment, (3) Planning, (4) Health Prevention and Promotion Program, and (5) Monitoring and Feedback. All SHSC domains and subdomains demonstrated acceptable reliability with good internal consistency. Each domain and subdomain except for "Planning" was associated significantly with students' health status. Most subdomains, including school health philosophy, school policy, communication, the evaluation system, and monitoring, were significantly and negatively associated with student absence. CONCLUSIONS: The SHSC shows significant association with the overall student health and can be useful in assessing comprehensive school health programs. PMID- 29992602 TI - Evaluation of a Free Milk in Schools Program in New Zealand: Effects on Children's Milk Consumption and Anthropometrics. AB - BACKGROUND: While dietary sources of calcium are important for bone health, the intake of milk and milk products decreases as children get older. A free milk in schools program may mitigate this decrease in milk consumption. We evaluated the Fonterra Milk for schools program (a free milk initiative) by determining changes in children's milk consumption and anthropometric measures over a 2-year period. METHODS: The evaluation was conducted in children aged 7-9 years in a representative sample of primary schools participating in the free milk program, in Auckland, New Zealand. The primary outcome was the proportion of children meeting the New Zealand guidelines for dairy and milk product consumption over 7 days (>=2 servings per day). Changes in anthropometric measures were also assessed as secondary outcomes. RESULTS: Nine schools (N = 511 children) participated in the evaluation. The proportion of children meeting the New Zealand guidelines for milk and milk product consumption over 7 days increased significantly from baseline to 2 years' follow-up (72% vs 94%; p < .001). Body mass index z scores did not change significantly between baseline and 2 years' follow-up. CONCLUSIONS: The Fonterra Milk for Schools initiative appears to be an effective way of increasing milk/milk product consumption behaviors in school aged children. PMID- 29992603 TI - Body Dissatisfaction, Perceptions of Competence, and Lesson Content in Physical Education. AB - BACKGROUND: Significant proportions of young people experience body dissatisfaction, which has implications for psychological and physical well being. Lesson content and perceived competence may be important variables for the experience of body dissatisfaction, yet these have been underexplored in physical education. The aim of this cross-sectional study is to identify the relationships between body dissatisfaction and perceptions of competence, and to explore whether body dissatisfaction depends on lesson content. METHODS: A paper-and pencil questionnaire was completed by 446 (210 boys, 236 girls) 13- to 14-year old pupils from 37 physical education classes. The questionnaire assessed body dissatisfaction and perceived competence in physical education. Lesson content was also recorded. Twenty-nine of the classes were engaged in team activities, eg, ball games. Eight classes were engaged in individual activities, eg, fitness. RESULTS: Multilevel analysis identified a significant negative association between body dissatisfaction and perceptions of competence in physical education. Lesson content did not significantly predict variations in body dissatisfaction scores. CONCLUSIONS: Teachers should focus on enhancing pupils' perceptions of competence in physical education to support the development of body satisfaction. PMID- 29992604 TI - Examining Time to Treatment and the Role of School-Based Health Centers in a School-Based Sexually Transmitted Infection Program. AB - BACKGROUND: Barriers to health care service utilization contribute to the spread of sexually transmitted infections (STIs) among teens. School-based STI screening programs reach adolescents outside of the clinic-based health care model and schools with school-based health centers (SBHCs) may expedite treatment because of their proximity to the population. This study examined whether students who tested positive for STIs in a school-based screening program had differing times to treatment based on treatment location. METHODS: All positive cases of chlamydia and gonorrhea from the 2012-2013 school year in a Chicago Department of Public Health (CDPH) and Chicago Public Schools school-based STI screening program were reviewed. Median time to treatment was compared for those treated at an SBHC versus those treated elsewhere (CDPH STI clinic, community health center, private physician). RESULTS: Overall, 540 students had positive results. The median age was 17 years, 427 had chlamydia (79.1%), 59 had gonorrhea (10.9%), and 54 had dual infections (10.0%); 144 were tested in a school with a SBHC on site (26.7%). Of the 483 students who received treatment (89.4%), those treated at a SBHC had a faster time to treatment compared to CDPH STI clinics (median 17 days versus 28 days, respectively, p < .001). CONCLUSIONS: For students testing positive in the Chicago school-based STI program, time to treatment is accelerated in locations with SBHCs. PMID- 29992605 TI - Trend Disparities in Emotional Distress and Suicidality Among Sexual Minority and Heterosexual Minnesota Adolescents From 1998 to 2010. AB - BACKGROUND: Sexual minority young people have demonstrated higher rates of emotional distress and suicidality in comparison to heterosexual peers. Research to date has not examined trends in these disparities, specifically, whether there have been disparity reductions or increases and how outcomes have differed over time by sex and sexual orientation group. METHODS: Minnesota Student Survey data, collected from 9th and 12th graders in 3 cohorts (1998, 2004, 2010) were used to examine emotional distress and suicidality rates. Logistic regression analyses were completed to examine outcome changes over time within and across sexual orientation/sex groups. RESULTS: With few exceptions, sexual minority youth are at increased risk of endorsing emotional distress and suicidality indicators in each surveyed year between 1998 and 2010. Young people with both-sex partners reported more emotional distress across all health indicators compared to their opposite-sex partnered peers. With a few exceptions, gaps in disparities between heterosexual and sexual minority have not changed from 2004 to 2010. CONCLUSIONS: Disparities in emotional health persist among youth. Research is needed to advance understanding of mental health disparities, with consideration of sexual orientation differences and contextualized to sociocultural status and changes over time. Personalized prevention strategies are needed to promote adolescent mental health. PMID- 29992606 TI - Relationship Between Cardiorespiratory Fitness, Weight Status, and Academic Performance: Longitudinal Evidence From 1 School District. AB - OBJECTIVES: We examined the longitudinal relationship between cardiovascular fitness (CRF) and academic performance (AP) among students in a diverse public school district. Furthermore, we determined whether the relationship between CRF and AP varied by student sociodemographic characteristics. METHODS: This study used data from 2005-2006 to 2008-2009. AP was assessed by Massachusetts Comprehensive Assessment System (MCAS) math (N = 1224) and English Language Arts (ELA) (N = 1248) z-scores. CRF was assessed by an age- and sex-adjusted 20-yard shuttle run (pass/fail). Multilevel growth models were used to estimate the relationship between MCAS z-scores and changes in grade, CRF, and weight status, controlling for student sociodemographic characteristics. RESULTS: Students who passed the fitness test performed better on MCAS tests (ELA: .159, p < .001; Math: 0.346, p < .001) at each study wave relative to those who did not pass. The relationship between AP and fitness was attenuated for low socioeconomic status(ELA: -.111, p < .05) and minority (Math: black -0.249, p < .01; Latino 0.216, p < .01) students. CONCLUSIONS: These results add to the literature highlighting the role of CRF as an important predictor of performance on standardized tests. More research is needed to understand the disparities experienced by low-income and minority students. PMID- 29992607 TI - School-Level Socioeconomic Status Influences Adolescents' Health-Related Lifestyle Behaviors and Intentions. AB - BACKGROUND: School-level socioeconomic status (SES) influences on adolescents' lifestyle behaviors is understudied. We examined how school-level SES and sex influence adolescents' health-related lifestyle behaviors and intentions. METHODS: Grade 8 students aged 13-14 years completed an online questionnaire regarding their sociodemographic characteristics, dietary behaviors, physical activity participation and recreational screen-time, and intentions regarding these behaviors. School-level SES, based on an Index of Community Socio Educational Advantage (ICSEA), was categorized as low or high. Generalized estimating equations estimated individual-level summary statistics, adjusted for clustering. RESULTS: Students (N = 2538; response rate = 79%) from 23 high schools (low ICSEA = 16) participated. Compared with low ICSEA students, high ICSEA students were more likely to report eating breakfast daily (OR 1.9 [95% CI 1.5, 2.4]), not drinking sugar-sweetened beverages (SSBs) daily (2.9 [1.9, 4.3]), and were more likely to have intentions to eat breakfast (1.8 [1.3, 2.3]) and >= 5 vegetable serves (1.2 [1.0, 1.5]) daily. Boys were more likely than girls to meet recommendations for breakfast eating, vegetable intake, moderate-to-vigorous physical activity and screen-time, but boys were less likely to meet recommendations regarding SSB intake. CONCLUSIONS: Students from low ICSEA schools would benefit from additional support to improve dietary-related behaviors and intentions. More research is required to identify what targeted approaches will address sex differences in adolescents' lifestyle behaviors. PMID- 29992608 TI - Impacts of a School-Wide, Peer-Led Approach to Sexuality Education: A Matched Comparison Group Design. AB - BACKGROUND: Teen Prevention Education Program (PEP) is a school-wide, peer-led comprehensive sexuality education program currently implemented in more than 50 schools across 2 states. Many teen pregnancy prevention researchers and practitioners view peer-led programs as a promising approach for reducing teen pregnancy and associated sexual risk behaviors. However, prior research on the effectiveness of these programs indicates mixed results. METHODS: We randomly assigned schools to implement Teen PEP immediately (intervention group) or on a delayed schedule (comparison group) and used propensity score matching to improve the comparability of the study groups. We surveyed students at baseline and about 6 months after the program ended. RESULTS: Teen PEP did not significantly impact rates of sexual activity or unprotected sex; however, the program led to improvements in exposure to information about sexual health topics and knowledge of preventing pregnancy and transmission of sexually transmitted infections. CONCLUSIONS: Teen PEP succeeded in accomplishing some of its most proximal goals, increasing students' access to information and knowledge. However, we found little evidence that the program affects sexual risk-taking within 6 months of its conclusion. Future research will examine the program's longer-term impacts on sexual risk behaviors. PMID- 29992609 TI - School Professionals' Knowledge and Beliefs About Youth With Chronic Illness. AB - BACKGROUND: Existing research demonstrates that youth with chronic illness often experience challenges including poor academic performance, attendance, and social success. However, past research demonstrates a lack of support for teachers to best educate students with chronic illness. In this study, we aim to describe the needs of local educators when working with students with chronic illness. METHODS: A questionnaire was completed by 383 middle or high school professionals. Responses were analyzed using descriptive statistics. ANOVA was used to examine differences between school professional groups and chronic illness types. RESULTS: Participants tended to disagree that students with chronic illness faced challenges in school and agreed that they had enough support to meet students' needs. They tended to agree that more collaboration between the health care team, schools, and families was needed. Participants reported feeling least prepared in working with students who had cystic fibrosis, epilepsy, or sickle cell disease. School nurses were more likely to recognize the challenges, supports, and collaboration needed. CONCLUSIONS: More training and support is needed for school professionals in their work with students with chronic illness. Assessments may be useful at a local level to help schools develop better policies and plans for educating youth with chronic illness. PMID- 29992610 TI - An atypical persistent eruption of adult-onset Still's disease with neutrophilic urticarial dermatosis-like dermal features: A case report and review of the literature. PMID- 29992611 TI - Increased salt sensitivity in offspring of pregnancies complicated by experimental preeclampsia. AB - Preeclampsia is a hypertensive disorder of pregnancy known to increase the risk of cardiovascular disease in mothers and offspring. Offspring exposed to a suboptimal intrauterine environment may experience altered fetal programming and subsequent long-term cardiovascular changes. This study investigated changes in the vascular response in offspring from experimental preeclampsia (EPE) induced by uterine artery ligation, in the absence of fetal growth restriction, compared to normal baboon pregnancies (controls), following a high salt diet challenge. After 1 week of standard diet (containing <1% salt), animals were fed a high salt diet (6%) for 2 weeks. Systolic and diastolic blood pressure (SBP, DBP), aldosterone, renin and creatinine clearance were evaluated in EPE (n = 6, 50% male) and control (n = 6, 50% male) offspring. A repeated measures analysis was performed, and P < 0.05 was considered significant. At baseline, there were no differences between the groups in any parameter (EPE, mean age and weight 3.2 +/- 1.2 years, 6.8 +/- 1.0 kg, respectively; Control, 2.9 +/- 0.8 years, 7.1 +/- 1.5 kg). After salt loading the EPE group had significantly higher SBP (92 +/- 5 mm Hg) compared to the control group (83 +/- 4 mm Hg, P = 0.03). Aldosterone concentration was higher in the EPE group despite the same salt excretion and no difference in renal function. Salt sensitivity may differ in offspring from hypertensive pregnancies due to fetal programming. This could have long-term consequences for cardiovascular health of EPE offspring and further research is required to determine the exact pathological mechanisms. PMID- 29992612 TI - Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS. AB - OBJECTIVE: Insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic low-grade inflammation may act together in a vicious cycle in the pathophysiology of PCOS. However, the inter-relationships of these components are not fully understood. We aimed to study these mechanisms in the pathophysiology of PCOS. PARTICIPANTS AND METHODS: Premenopausal women with PCOS (Rotterdam diagnostic criteria) and without PCOS were recruited from a community setting into a cross-sectional substudy within a randomized control trial. Insulin resistance (fasting insulin and glucose), hyperandrogenism (testosterone, sex hormone-binding globulin [SHBG] and Free Androgen Index [FAI]), muscle sympathetic nerve activity (MSNA) and markers of chronic low-grade inflammation (high sensitivity C-reactive protein [hs-CRP] and high molecular weight adiponectin [HMW-adiponectin]) were measured. RESULTS: Forty-nine women with PCOS (mean age 30 +/- 6 mean BMI 29 +/- 5) and 23 controls (mean age 29 +/- 8 mean BMI 33 +/- 7) with included in this analysis. MSNA and testosterone level were most significantly associated with PCOS status, after adjustment for age and BMI. In women with PCOS, markers of sympathetic activity correlated inversely with HMW adiponectin and HMW-adiponectin correlated inversely with FAI. Testosterone and FAI both correlated positively with insulin resistance in women PCOS. CONCLUSION: Sympathetic dysfunction and hyperandrogenism are significantly associated with PCOS. Chronic low-grade inflammation potentially mediates the effect of sympathetic dysfunction on hyperandrogenism and insulin resistance. PMID- 29992613 TI - The effects of zoo visitors on Quokka (Setonix brachyurus) avoidance behavior in a walk-through exhibit. AB - The behavior of zoo animals may be influenced by visitors, with possible implications on animal welfare. We examined the effects of the presence of visitors on the presence and visibility of free-ranging quokkas (Setonix brachyurus) in preferred areas of a walk-through enclosure at Melbourne Zoo, Australia. In a controlled experiment, two visitor treatments were randomly imposed: (1) enclosure open to visitors as normal ("Open") and (2) enclosure closed to visitors ("Closed"). Treatments were imposed for 2-day periods, with five replicates of each treatment (10 2-day periods in total). Instantaneous point sampling of camera footage at 1-min intervals from 09:00 to 16:00 hr each day recorded the location and visibility of quokkas. Data were analyzed using a two-factor ANOVA (visitor treatment and study area), with 2-day summary values as the unit of analysis. While the presence of quokkas in the study areas was not affected by treatment, fewer (p < 0.05) quokkas were visible from the visitor paths and more (p < 0.05) quokkas were obscured from the visitor paths in the "Open" treatment than the "Closed" treatment. Number of quokkas differed between study areas across treatments (p < 0.01), but there was no interaction (p > 0.05) between visitor treatment and study area. The reduction in quokka visibility when visitors were present indicates that visitors were at least moderately fear provoking for the quokkas in this experiment, but further research is required to examine the effects of visitor presence and behaviors on the behavior and stress physiology of quokkas in walk-through enclosures, as there may be possible welfare implications. PMID- 29992614 TI - An 17 O NMR study of diamagnetic and paramagnetic lanthanide-tris(oxydiacetate) complexes in aqueous solution. AB - 17 O-enriched complexes between oxydiacetate ligand and several diamagnetic and paramagnetic lanthanide(III) metal ions (Ln) were investigated by solution-state 17 O NMR spectroscopy. The bound-state signals of chelating (Oin ) and nonchelating (Oout ) oxygen atoms of the carboxylate groups were observed for all the samples investigated. The data indicate that the 17 O line width is dominated by contributions from both quadrupole relaxation and chemical exchange in the case of Pr and Nd complexes. Dissection of the chemical shift induced by metal ions on Oin into Fermi contact and pseudocontact contributions was performed , and the hyperfine coupling constant (A/h) was estimated. No evidence of structural changes within the series was detected. PMID- 29992615 TI - Immunology & Cell Biology Publication of the Year Awards 2017. PMID- 29992616 TI - The time has come to stop placebo-controlled trials of milk oral immunotherapy and focus on real-life studies. PMID- 29992617 TI - Narrow QRS tachycardia with apparent concentric atrial activation pattern: What is the mechanism? PMID- 29992618 TI - Retrospective analysis of local injection site adverse reactions associated with 230 allogenic administrations of bone marrow-derived mesenchymal stem cells in 164 horses. AB - BACKGROUND: Bone marrow-derived mesenchymal stem cells (BM-MSCs) are frequently used in the treatment of musculoskeletal injuries. Fully characterised cells that are readily available for use is optimum. Allogenic BM-MSCs can satisfy the need for rapid treatment, however, their safety has been questioned. OBJECTIVES: Objectives were to characterise BM-MSCs from an adult donor horse, in vitro, and to identify and describe adverse reactions that occurred following their injection into other horses. We hypothesised that BM-MSCs capable of proliferation, differentiation and lacking MHC II from one donor could be implanted into another individual without significant adverse reactions and the frequency of adverse reactions in clinical cases would be similar to that previously reported for autologous BM-MSCs. STUDY DESIGN: Retrospective clinical study. METHODS: BM-MSCs were proliferated and characterised from one donor and cryopreserved for clinical use. Medical records for horses injected with allogenic BM-MSCs from this donor at a single hospital were used. After routine lameness exam, lesions were identified using diagnostic ultrasound or MRI. Post injection reaction was defined as increased pain, swelling, or heat at or near injection site, or increased lameness. Treatments required for each reaction were noted. RESULTS: BM-MSCs proliferated and underwent differentiation. Cells were found to be negative for MHC-II (<2%) and were viable after cryopreservation and shipping. Ten of 230 (4.35%) injections were noted to be associated with an adverse reaction. Adverse reactions occurred in synovial structures (n = 3) and in soft tissues (n = 7). MAIN LIMITATIONS: This investigation could underestimate the number and severity of reactions. Mild reactions, such as synovitis, may have been missed. Also, anti-inflammatory drugs could overshadow mild reactions, making them less likely to be detected. CONCLUSIONS: Fully characterised allogenic BM-MSCs originating from a single donor horse can be administered to horses with soft tissue injuries with a low rate of adverse reaction. The Summary is available in Portuguese - see Supporting Information. PMID- 29992619 TI - Adipose tumors of the heart. AB - BACKGROUND: Primary cardiac adipose tumors are rare. There are two distinct pathologically defined entities that represent this tumor type: lipoma and lipomatous hypertrophy of the interatrial septum (LHIS). We present a single center experience with these tumors and demonstrate that the location may not correspond to the pathologic diagnosis. METHODS: A retrospective review of a prospectively collected cardiac surgery database from January 1990 to July 2016 identified 254 cases of surgically treated primary cardiac tumors at our Institution. Of these, 06/254 (2%) were primary adipose tumors. RESULTS: In 3/6 (50%) cases, patients were asymptomatic or had symptoms referable to other known intracardiac lesions. Five patients (83%) had preserved ventricular function. In 4/6 cases (67%), the tumor was identified preoperatively. All patients presented in New York Heart Association functional class <=2. Pathologic diagnosis of LHIS was made in 5/6 cases (83%), with 2/5 LHIS (40%) located in the interatrial septum. A bovine pericardial patch was utilized for reconstruction following tumor resection in 3/6 cases (50%). Mean cardiopulmonary bypass time was 88 +/- 43 min. All the patients tolerated the procedure well without any postoperative complications. CONCLUSIONS: Primary cardiac adipose tumors are responsible for a small portion of all primary heart tumors. Surgical resection provided excellent outcomes, and did not affect cardiac performance, in spite of the need for extensive resections. LHIS was identified in locations other than the interatrial septum and was usually symptomatic. PMID- 29992620 TI - Hiding in a plain sight: A high prevalence of androgen deficiency due to primary hypogonadism among acute medical inpatients with anaemia. PMID- 29992621 TI - Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications. AB - BACKGROUND AND AIMS: Clinical syndromes associated with biallelic mutations of bile acid (BA) transporters usually present in childhood. Subtle mutations may underlie intrahepatic cholestasis of pregnancy (ICP) and oral contraceptive steroid (OCS) induced cholestasis. In five women with identified genetic mutations of such transporters, with eight observed pregnancies complicated by ICP, we examined relationships between transporter mutations, clinical phenotypes, and treatment outcomes. METHODS: Gene mutation analysis for BA transporter deficiencies was performed using Next Generation/Sanger sequencing, with analysis for gene deletions/duplications. RESULTS: Intrahepatic cholestasis of pregnancy was early-onset (9-32 weeks gestation) and severe (peak BA 74-370 MUmol/L), with premature delivery (28+1 -370 weeks gestation) in 7/8 pregnancies, in utero passage of meconium in 4/8, but overall good perinatal outcomes, with no stillbirths. There was generally no response to ursodeoxycholic acid and variable responses to rifampicin and chelation therapies; naso-biliary drainage appeared effective in 2/2 episodes persisting post-partum in each of the two sisters. Episodic jaundice occurring spontaneously or provoked by non-specific infections, and OCS-induced cholestasis, had previously occurred in 3/5 women. Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4 mutation and a fourth case was heterozygous for another ABCB4 mutation. CONCLUSIONS: Early-onset or recurrent ICP, especially with previous spontaneous or OCS-induced episodes of cholestasis and/or familial cholestasis, may be attributable to transporter mutations, including biallelic mutations of one or more transporters. Response to standard therapies for ICP is often incomplete; BA sequestering therapy or naso-biliary drainage may be effective. Optimized management can produce good outcomes despite premature birth and evidence of fetal compromise. PMID- 29992622 TI - Development of an orthotopic canine prostate cancer model expressing human GRPr. AB - BACKGROUND: Ace-1 canine prostate cancer cells grow orthotopically in cyclosporine immunosuppressed laboratory beagles. We previously transfected (human Gastrin-Releasing Peptide Receptor, huGRPr) into Ace-1 cells and demonstrated receptor-targeted NIRF imaging with IR800-G-Abz4-t-BBN, an agonist to huGRPr. Herein, we used the new cell line to develop the first canine prostate cancer model expressing a human growth factor receptor. METHODS: Dogs were immunosuppressed with cyclosporine, azathioprine, prednisolone, and methylprednisolone. Their prostate glands were implanted with Ace-1huGRPr cells. The implantation wounds were sealed with a cyanoacrylic adhesive to prevent extraprostatic tumor growth. Intraprostatic tumors grew in 4-5 week. A lobar prostatic artery was then catheterized via the carotid artery and 25-100 nmol IR800-Abz4-t-BBN was infused in 2 mL followed by euthanasia in dogs 1-2, and recovery for 24 h before euthanasia in dogs 3-6. Excised tissues were imaged optically imaged, and histopathology performed. RESULTS: Dog1 grew no tumors with cyclosporine alone. Using the four drug protocol, Dogs 2-6 grew abundant 1-2 mm intracapsular and 1-2 cm intraglandular tumors. Tumors grew >5 cm when the prostate cancer cells became extracapsular. Dogs 4-6 with sealed prostatic capsule implantation sites had growth of intracapsular and intraglandular tumors and LN metastases at 5 weeks. High tumor to background BPH signal in the NIRF images of sectioned prostate glands resulted from the 100 nmol dose (~8 nmol/kg) in dogs 2-4 and 50 nmol dose in dog 5, but not from the 25 nmol dose in Dog 6. Imaging of mouse Ace-1huGRPr tumors required an intravenous dose of 500 nmol/kg body wt. A lymph node that drained the prostate gland was detectable in Dog 4. Histologic findings confirmed the imaging data. CONCLUSION: Ace-1huGRPr cells created viable, huGRPr-expressing tumors when implanted orthotopically into immune-suppressed dogs. Local delivery of an imaging agent through the prostatic artery allowed a very low imaging dose, suggesting that therapeutic agents could be used safely for treatment of early localized intraglandular prostate cancer as adjuvant therapy for active surveillance or focal ablation therapies, or for treating multifocal intraglandular disease where focal ablation therapies are not indicated or ineffective. PMID- 29992623 TI - Who wants to pay more taxes to improve public health care? AB - We study the factors that influence willingness to pay to improve public health care in 29 post-communist countries, Eastern and Southern Europe, and Eurasia using 2 up-to-date cross-sectional surveys conducted in 2010 and 2016 (N = 34 768). Three hypotheses received full degree of support through empirical analysis: increase in satisfaction with health care, university education, and higher level of wealth positively associated with willingness to pay in all regions. In comparison, having a higher level social trust and adhering to left leaning ideological position strengthens support for public health care in Southern Europe and Eurasia only, while having a higher level of institutional trust strengthens support for public health care in Eastern Europe and Eurasia only. PMID- 29992624 TI - Roux-en-Y gastric bypass surgery normalizes dopamine D1, D2, and DAT levels. AB - Roux-en-Y gastric bypass surgery (RYGB) is one of the most effective treatments for morbid obesity. However, increased substance abuse following RYGB has been observed clinically. This study examined the effects of RYGB on the dopamine system to elucidate these observed changes in reward-related behavior. Rats were assigned to four groups: normal diet with sham surgery, ad libitum high fat (HF) diet with sham surgery, restricted HF diet with sham surgery, and HF diet with RYGB surgery. Following surgeries, rats were kept on their respective diets for 9 weeks before they were sacrificed. [3 H]SCH 23390, [3 H]Spiperone, and [3 H]WIN35 428 autoradiography was performed to quantify the effects of diet and RYGB surgery on dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter (DAT) binding. Rats on a chronic HF diet became obese with reduced D1R-like binding within the ventrolateral striatum and the nucleus accumbens core, reduced D2R-like binding in all areas of the striatum and nucleus accumbens core and shell, and reduced DAT binding in the dorsomedial striatum. Restricted HF diet rats showed similar reductions in D1R like and D2-R-like binding as the obese rats, and reduced DAT binding within all areas of the striatum. Both RYGB and restricted HF diet rats showed similar weight reductions, with RYGB rats showing no difference in binding compared to controls. The observed changes in binding between non-treated obese rats and RYGB rats demonstrates that HF dietary effects on the dopamine system were reversed by RYGB. PMID- 29992625 TI - Hematopoietic cell-derived RELMalpha regulates hookworm immunity through effects on macrophages. AB - Resistin-like molecule alpha (RELMalpha) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELMalpha dampens Th2 inflammatory responses. RELMalpha is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELMalpha is unknown. We generated bone marrow (BM) chimeras that were RELMalpha deficient (RELMalpha-/ - ) in BM or non BM cells and infected them with Nb. Non BM RELMalpha-/- chimeras had comparable inflammatory responses and parasite burdens to RELMalpha+/+ mice. In contrast, both RELMalpha-/- and BM RELMalpha-/- mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c+ lung macrophages were the dominant BM-derived source of RELMalpha and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELMalpha regulates macrophage-mediated Nb killing. Compared to RELMalpha+ /+ macrophages, RELMalpha /- macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELMalpha partially reversed this phenotype. Gene expression analysis revealed that RELMalpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage mediated helminth killing. Collectively, these studies demonstrate that BM derived RELMalpha is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELMalpha is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELMalpha acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion. PMID- 29992626 TI - Synthesis of carbon-14 labeled ketamine and norketamine. AB - Ketamine is a well-known general anesthetic that inhibits cerebral NMDA receptors. Norketamine is a major circulating metabolite of this drug. A nasal spray formulation of esketamine, the S enantiomer of ketamine, is under development for the management of treatment-resistant depression. To assess the pharmacokinetic properties, C-14 labeled ketamine and norketamine were prepared separately from commercially available [14 C]CuCN through a five-step sequence with the C-14 label at the quaternary carbon of the cyclohexyl ring. Chiral resolution of [14 C]ketamine and chiral column separation of [14 C]norketamine resolved/separated the (S)-enantiomers from (R)-enantiomers. PMID- 29992627 TI - Thermoresponsive aerification and tissue vacuolization for facilitating endoscopic submucosal resection. AB - BACKGROUND AND AIMS: Mucosal lifting and its persistence are critical for maintaining the operational space and preventing perforation in endoscopic operation. Although numerous agents have been investigated, optimization is still required for improving their clinical performance. In the present study, we proposed a novel concept of thermoresponsive aerification and tissue vacuolization for submucosal injection. METHODS: Lifting performance and operational condition were first evaluated in porcine stomachs in vitro and rabbits in vivo. Dodecafluoropentane (DDFP) injection dosage, lifting persistency and operational assistance were quantitatively recorded. Gross and histological pathology were also analyzed to identify DDFP acute toxicity and long-term safety. The endoscopic submucosal dissection (ESD) procedure with DDFP was carried out on pigs in vivo to confirm its operational feasibility, efficacy, and safety. RESULTS: Dodecafluoropentane aerification could achieve better mucosal lift with lower dosage (1% of normal saline dosage). Thermoresponsive DDFP aerification could provide continuous replenishment and longer persistence. Meanwhile, its tissue vacuolization effect significantly facilitated submucosal tissue dissection in in vitro study. Similar performance was verified in vivo. The particular vacuole-like submucosal structure was seen after DDFP onset, which also promoted reepithelization and wound healing. No tissue damage, gas embolism, biotoxicity, and physicochemical risk were observed. CONCLUSION: Bioinert DDFP was feasible, efficient, and safe as the novel submucosal lifting candidate. PMID- 29992628 TI - Linkages between measures of biodiversity and community resilience in Pacific Island agroforests. AB - Designing agroecosystems that are compatible with the conservation of biodiversity is a top conservation priority. However, the social variables that drive native biodiversity conservation in these systems are poorly understood. We devised a new approach to identify social-ecological linkages that affect conservation outcomes in agroecosystems and in social-ecological systems more broadly. We focused on coastal agroforests in Fiji, which, like agroforests across other small Pacific Islands, are critical to food security, contain much of the country's remaining lowland forests, and have rapidly declining levels of native biodiversity. We tested the relationships among social variables and native tree species richness in agroforests with structural equation models. The models were built with data from ecological and social surveys in 100 agroforests and associated households. The agroforests hosted 95 native tree species of which almost one-third were endemic. Fifty-eight percent of farms had at least one species considered threatened at the national or international level. The best fit structural equation model (R2 = 47.8%) showed that social variables important for community resilience-local ecological knowledge, social network connectivity, and livelihood diversity-had direct and indirect positive effects on native tree species richness. Cash-crop intensification, a driver of biodiversity loss elsewhere, did not negatively affect native tree richness within parcels. Joining efforts to build community resilience, specifically by increasing livelihood diversity, local ecological knowledge, and social network connectivity, may help conservation agencies conserve the rapidly declining biodiversity in the region. PMID- 29992630 TI - Human Milk Fortification with Bovine Colostrum Is Superior to Formula-Based Fortifiers to Prevent Gut Dysfunction, Necrotizing Enterocolitis, and Systemic Infection in Preterm Pigs. AB - BACKGROUND: Fortification of donor human milk (DHM) is required for optimal growth of very preterm infants, but there are concerns of more gut dysfunction and necrotizing enterocolitis (NEC) when using formula-based fortifiers (FFs), especially soon after birth. Intact bovine colostrum (BC) is rich in nutrients and bioactive factors, and protects against NEC in preterm pigs. We hypothesized that fortification of DHM with BC is superior to FFs to prevent gut dysfunction and infections when provided shortly after preterm birth. METHODS: Two FF products, Enfamil (ENF; intact protein, vegetable oil) and PreNAN+Nutrilon (NAN; extensively hydrolyzed protein, maltodextrin), were compared with BC as fortifier to DHM fed to preterm pigs for 5 days. RESULTS: Relative to the DHM+BC group, DHM+FF groups had higher diarrhea score and lower hexose uptake and lactase activity, and specifically the DHM+NAN group showed higher gut permeability, NEC score, more mucosa-adherent bacteria with altered gut microbiota structure (ie, lower diversity, increased Enterococcus, decreased Staphylococcus abundance). Both DHM+FF groups showed higher expression of intestinal cytokine and inflammation-related genes, more gut-derived bacteria in the bone marrow, lower density of mucin-containing goblet cells, and slightly higher colon lactate, stomach pH and acetate, and blood neutrophil-to-lymphocyte levels than the DHM+BC group. CONCLUSIONS: Used as a fortifier to DHM, BC is superior to FFs to support gut function, nutrient absorption, and bacterial defense mechanisms in preterm pigs. It is important to optimize the composition of nutrient fortifiers for preterm infants fed human milk. PMID- 29992629 TI - Genetic diversity of Pneumocystis jirovecii from a cluster of cases of pneumonia in renal transplant patients: Cross-sectional study. AB - Pneumocystis jirovecii can cause severe potentially life-threatening pneumonia (PCP) in kidney transplant patients. Prophylaxis of patients against PCP in this setting is usually performed during 6 months after transplantation. The aim of this study is to describe the molecular epidemiology of a cluster of PCP in renal transplant recipients in Brazil. Renal transplant patients who developed PCP between May and December 2011 had their formalin-fixed paraffin-embedded (FFPE) lung biopsy samples analysed. Pneumocystis jirovecii 23S mitochondrial large subunit of ribosomal RNA (23S mtLSU-rRNA), 26S rRNA, and dihydropteroate synthase (DHPS) genes were amplified by polymerase chain reaction (PCR), sequenced, and analysed for genetic variation. During the study period, 17 patients developed PCP (only four infections were documented within the first year after transplantation) and six (35.3%) died. Thirty FFPE samples from 11 patients, including one external control HIV-infected patient, had fungal DNA successfully extracted for further amplification and sequencing for all three genes. A total of five genotypes were identified among the 10 infected patients. Of note, four patients were infected by more than one genotype and seven patients were infected by the same genotype. DNA extracted from FFPE samples can be used for genotyping; this approach allowed us to demonstrate that multiple P. jirovecii strains were responsible for this cluster, and one genotype was found infecting seven patients. The knowledge of the causative agents of PCP may help to develop new initiatives for control and prevention of PCP among patients undergoing renal transplant and improve routine PCP prophylaxis. PMID- 29992631 TI - Position statement for the management of comorbidities in psoriasis. AB - BACKGROUND: The association between psoriasis and some diseases has become relevant in recent years. Providing appropriate management of psoriasis from an early stage requires prompt diagnosis and treatment of concomitant diseases and to prevent any potential comorbidity. This approach should consider the adverse events of the drugs used to treat psoriasis potentially related to the onset of comorbidities. OBJECTIVE: To provide the dermatologist with an accurate and friendly tool for systematizing the diagnosis of psoriasis-associated comorbidities, which generally escapes the scope of the dermatology setting, and to facilitate decision-making about the referral and treatment of patients with comorbidities. METHODS: These position statement recommendations were developed by a working group composed of ten experts (four dermatologists, one cardiologist, one rheumatologist, one gastroenterologist, one nephrologist, one endocrinologist and one psychiatrist) and two health services researchers. The expert group selected the psoriasis comorbidities considered according to their relevance in the dermatology setting. The recommendations on diagnostic criteria are based on the current clinical practice guidelines for each of the comorbidities. The information regarding the repercussion of psoriasis medical treatments on associated comorbid diseases was obtained from the summary of product characteristics of each drug. RESULTS: Recommendations were developed to detect and refer the following psoriasis comorbidities: psoriatic arthritis, cardiovascular risk factors (diabetes, dyslipidaemia, obesity, hypertension and metabolic syndrome), non-alcoholic fatty liver disease, inflammatory bowel disease, kidney disease and psychological disorders (anxiety and depression). In addition, alcohol consumption and tobacco consumption were included. The tables and figures are precise, easy-to-use tools to systematize the diagnosis of comorbidities in patients with psoriasis and facilitate the decision-making process regarding referral and treatment of patients with an associated disease. CONCLUSION: The application of these position statement recommendations will facilitate the dermatologist practice, and benefit psoriasis patients' health and quality of life. PMID- 29992632 TI - Rare clinical manifestations of leukemia cutis. PMID- 29992633 TI - Fungal keratitis: An overview of clinical and laboratory aspects. AB - Mycotic keratitis or keratomycosis is a fungal infection with global distribution. The dominant aetiology of this disease varies based on geographical origin, socioeconomic status, and climatic condition. Generally, Aspergillus spp. and Fusarium spp. are common in tropical and subtropical regions and Candida spp. are dominant in temperate areas. Demonstration of fungal elements in microscopic examination besides the isolation of fungi in culture is the gold standard of laboratory diagnosis. As the culture is a time-consuming procedure, other approaches such as in vivo confocal microscopy which produces real-time imaging of corneal tissue and molecular techniques have been developed to facilitate rapid diagnosis of fungal keratitis. The first choice of treatment is topical natamycin, although topical amphotericin B is the best choice for Aspergillus and Candida keratitis. Regarding the diversity of fungal aetiology and the emergence of drug resistance in some genera and species, proper identification using molecular methods and antifungal susceptibility testing could provide useful data. Furthermore, as the better efficacy of combination therapy in comparison to monotherapy is reported, in vitro determination of interactions between various drugs seem informative. This review aims to provide a general and updated view on the aetiology, risk factors, epidemiology, clinical and laboratory diagnosis, and management of fungal keratitis. PMID- 29992634 TI - Mechanical complications of central venous catheter insertions: A retrospective multicenter study of incidence and risks. AB - BACKGROUND: Incidence and risk factors for complications after insertion of central venous catheters have previously been reported for smaller cohorts. The aim of this observational multicenter study was to study risk factors for mechanical complications in a large, recently collected cohort of patients. METHODS: Records of central venous catheter insertions from 8 hospitals in southern Sweden from 2013 to 2016 were collected from the regional chart system. Data on blood coagulation tests, use of ultrasonography, central venous catheter location, bore size, number of needle passes, arterial puncture, the chronological order of the central venous catheter insertion, and mechanical complications were extracted. Only one insertion/patient was included using worst case selection criteria. Predefined primary outcome was mechanical complications defined as bleeding, pneumothorax, nerve injury, or malignant arrhythmia. Severe mechanical complications were defined as bleeding requiring intervention or transfusion, pneumothorax, persistent nerve injury, or non-self-limiting arrhythmias. RESULTS: We included 10 949 insertions and identified 118 (1.1%) incidents of mechanical complication, of which 85 (0.8%) were bleedings, 21 (0.2%) were pneumothoraces, 7 (0.06%) were transient nerve injuries, and 5 (0.05%) were self-limiting arrhythmias. Severe mechanical complications occurred in 23 (0.2%) cases. CONCLUSIONS: In this retrospective, multicenter observational study on 10 949 central venous catheter insertions, mechanical complications were rare. Preprocedural coagulopathy, number of needle passes, and arterial puncture were associated with grade 2-4 bleeding. Subclavian vein insertions, arterial puncture, and chronological order of the central venous catheter insertion were associated with pneumothorax. PMID- 29992635 TI - Impact of pretransplant recipient body mass index on post heart transplant mortality: A systematic review and meta-analysis. AB - The ISHLT's 2016 Guidelines on the selection of heart transplant (HT) candidates recommends weight loss prior to listing for persons with body mass (BMI) index greater than 35 kg/m2 . We conducted a systematic review to assess the impact of BMI on all-cause mortality. We searched to identify eligible observational studies that followed HT recipients. We used the GRADE system to quantify absolute effects and quality of evidence, and meta-analyzed survival curves to assess post-transplant mortality across BMI categories. We found a significantly increased risk of mortality in patients with BMI > 30 kg/m2 across all age categories, independently of transplant era and study source (BMI 30-34.9: HR 1.10, 95% CI 1.04-1.17; BMI >= 35: HR 1.24, 95% CI 1.12-1.38). We also found an increased risk of death in underweight (BMI < 18.5 kg/m2 ) candidates over 39 years of age (Age 40-65: HR 1.24, 95% CI 1.02-1.53; Age > 65: HR 1.70, 95% 1.13 2.57). We found obesity and underweight BMI to be associated with mortality post HT. The similar and overlapping increased risk of mortality in patients with BMI 30-34.9 and BMI >= 35 does not support the recently updated ISHLT guidelines. Future evidence in the form of randomized controlled trials is required to assess effectiveness of interventions targeting obesity-related comorbidities and weight management. PMID- 29992636 TI - Association of CD28 and CTLA4 haplotypes with susceptibility to primary Sjogren's syndrome in Mexican population. AB - BACKGROUND: Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by destruction of exocrine glands as a result of T and B cells infiltrated in glandular tissue. CD28 and CTLA-4 play a crucial role in T cell activation and inhibition. The aim of this study was to associate CD28 and CTLA4 haplotypes with susceptibility to pSS in patients from western Mexico. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were performed to identify CD28 and CTLA4 genotypes in 111 patients with pSS and 138 control subjects (CS). Haplotype analysis was carried out by SHEsis program. Soluble serum levels of CD28 (sCD28) and CTLA-4 (sCTLA-4) were quantified by ELISA kit. RESULTS: The CD28 GC haplotype was associated with low risk to pSS (2.5-folds, P < 0.001). CTLA4 CAG and CGA were identified as genetic risk factor (P < 0.001;OR = 3.82[CI95%:2.022-7.296] and P < 0.001; OR = 11.38[CI95%:3.282 37.69] respectively). No difference in sCD28 and sCTLA-4 were found between patients and CS. However, pSS patients carriers of CD28 IVS3 + 17TC genotype showed high sCD28 (P = 0.039 vs TT carriers in CS). In regard to sCTLA-4, patient who carry CTLA4-319C>T, +49 A>G, and +6230 G>A, or their haplotypes did not show any difference. CONCLUSION: Our findings suggest that CD28 GC, CTLA4 CAG, and CGA haplotypes are associated with susceptibility to pSS in patients from western Mexico. It seems that genetic control of CD28 and CTLA4 as well as local immune response in glandular tissue may regulate the impact of the gene expression in pSS. It is necessary to confirm this hypothesis in an integrative study. PMID- 29992637 TI - Correlating Charge-Carrier Dynamics with Efficiency in Quantum-Dot Solar Cells: Can Excitonics Lead to Highly Efficient Devices? AB - The photovoltaic performance of quantum-dot solar cells strongly depends on the charge-carrier relaxation and recombination processes, which need to be modulated in a favorable way to obtain maximum efficiency. Recently, significant efforts have been devoted to investigate the carrier dynamics of nanocrystal sensitizers, both in solution and deposited on TiO2 photoanodes, with the aim to correlate the excitonics with solar-energy conversion efficiency. This Minireview summarizes some proof of the concepts that efficiency can be directly correlated to the exciton dynamics of quantum-dot solar cells. The presented findings are based on CdSeS alloy, CdSe/CdS core/shell, Au/CdSe nanohybrids, and Mn-doped CdZnSSe nanocrystals, where the favourable excitonic processes are optimized to enhance the efficiency. Future prospects and limitations are addressed as well. PMID- 29992639 TI - Acute generalized exanthematous pustulosis: a case series of 13 patients in Brazil. PMID- 29992638 TI - Factors influencing sessions' and speakers' evaluation: an analysis of seven consecutive European Academy of Dermatology and Venereology congress editions. AB - BACKGROUND: The variables affecting participants' satisfaction with a scientific conference in dermatology have not been systematically assessed. The European Academy of Dermatology and Venereology (EADV) has collected a huge number of questionnaires related to sessions' and speakers' evaluation over the years. The critical analysis of satisfaction's score is important and helpful for continuous improvement of the scientific programming. OBJECTIVE: To identify factors that positively or negatively affect sessions' and speakers' scoring in the largest European congress of dermatology. METHODS: This was a retrospective analysis of all sessions' evaluation forms collected between 2009 and 2015 during seven consecutive EADV congresses. A predictive model for sessions' and another for speakers' score evaluation were built based on multivariate linear regression. RESULTS: Overall, 4964 speakers and 1022 sessions were evaluated. Topics more positively associated with total sessions' scoring were as follows: dermoscopy, neutrophilic diseases and hidradenitis suppurativa. Conversely, types of sessions which considerably negatively associated with total sessions' scoring included short thematic presentations and free communications. Furthermore, types of sessions which were more positively associated with high total speakers' scoring consisted of focus sessions and plenary lectures, whereas the most appreciated topics encompassed dermoscopy, screening programs, melanocytic naevi, panniculitis, organ transplanted and immunosuppressed patients, neutrophilic diseases, dermatopathology and history of dermatology. Finally, short thematic presentations, free communications and guidelines session showed overall poor scores. CONCLUSION: Focused and specialized topics are more prone to capture attention of participants when compared to sessions of heterogeneous content. Quite surprisingly, a practice-oriented topics such as guidelines, did not achieve a high score. Our findings provide new knowledge about components, which increase the level of satisfaction of participants and should facilitate the programming of attractive scientific congresses associated with increased training satisfaction. PMID- 29992640 TI - Catalytic Asymmetric [8+3] Annulation Reactions of Tropones or Azaheptafulvenes with meso-Aziridines. AB - Highly enantioselective [8+3] high-order cycloaddition reactions of tropones or azaheptafulvenes with meso-aziridines were achieved by a desymmetrization/annulation process in the presence of chiral N,N' dioxide/Mg(OTf)2 complex. The corresponding tetrahydrocyclohepta[b][1,4]oxazines and tetrahydro-1H-cyclohepta- [b]-pyrazines were obtained in good yields (66-98 %) with excellent diastereo- and enantioselectivities (>19:1 d.r., 90-96 % ee). A possible transition state model was proposed to elucidate the origin of chiral induction based on the control experiments and X-ray crystal structure of the catalyst. PMID- 29992641 TI - Slow Magnetic Relaxation in Lanthanoid Crown Ether Complexes: Interplay of Raman and Anomalous Phonon Bottleneck Processes. AB - The combination of lanthanoid nitrates with 18-crown-6 (18-c-6) and tetrahalocatecholate (X4 Cat2- , X=Cl, Br) ligands has afforded two compound series [Ln(18-c-6)(X4 Cat)(NO3 )]?MeCN (X=Cl, 1-Ln; X=Br, 2-Ln; Ln=La, Ce, Nd, Gd, Tb, Dy). The 18-c-6 ligands occupy equatorial positions of a distorted sphenocorona geometry, whereas the charged ligands occupy the axial positions. The analogues of both series with Ln=Ce, Nd, Tb and Dy exhibit out-of-phase ac magnetic susceptibility signals in the presence of an applied magnetic field, indicative of slow magnetization relaxation. When diluted into a diamagnetic La host to reduce dipolar interactions, the Dy analogue exhibits slow relaxation up to 20 K in the absence of an applied dc field. Concerted magnetic measurements, EPR spectroscopy, and ab initio calculations have allowed elucidation of the mechanisms responsible for slow magnetic relaxation. A consistent approach has been applied to quantitatively model the relaxation data for different lanthanoid analogues, suggesting that the spin dynamics are governed by Raman processes at higher temperatures, transitioning to a dominant phonon bottleneck process as the temperature is decreased, with an observed T-6 rather than the usual T-2 dependence (T is temperature). This anomalous thermal dependence of the phonon bottleneck relaxation is consistent with anharmonic effects in the lattice dynamics, which was predicted by Van Vleck more than 70 years ago. PMID- 29992643 TI - Predictive factors of overall functioning improvement in patients with chronic schizophrenia and schizoaffective disorder treated with paliperidone palmitate and aripiprazole monohydrate. PMID- 29992642 TI - Basic mechanisms of the regulation of L-carnitine status in monogastrics and efficacy of L-carnitine as a feed additive in pigs and poultry. AB - A great number of studies have investigated the potential of L-carnitine as feed additive to improve performance of different monogastric and ruminant livestock species, with, however, discrepant outcomes. In order to understand the reasons for these discrepant outcomes, it is important to consider the determinants of L carnitine status and how L-carnitine status is regulated in the animal's body. While it is a long-known fact that L-carnitine is endogenously biosynthesized in certain tissues, it was only recently recognized that critical determinants of L carnitine status, such as intestinal L-carnitine absorption, tissue L-carnitine uptake, endogenous L-carnitine synthesis and renal L-carnitine reabsorption, are regulated by specific nutrient sensing nuclear receptors. This review aims to give a more in-depth understanding of the basic mechanisms of the regulation of L carnitine status in monogastrics taking into account the most recent evidence on nutrient sensing nuclear receptors and evaluates the efficacy of L-carnitine as feed additive in monogastric livestock by providing an up-to-date overview about studies with L-carnitine supplementation in pigs and poultry. PMID- 29992644 TI - Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta. AB - AIM: To evaluate the relationship between corticotropin-releasing hormone (CRH) expression in the placenta and the risk of school-related dysfunctions at the age of 10 years among children born extremely preterm (EP). METHODS: Corticotropin releasing hormone expression was measured in the placenta of 761 EP children, who had the following assessments at the age of 10 years: Differential Ability Scales, Oral and Written Language Scales, the Wechsler Individual Achievement Test-III, NEPSY-II and the Child Symptom Inventory-4. We evaluated whether lowest and highest quartiles of CRH mRNA were associated with undesirable scores on these assessments. With 272 evaluations, we would expect 14 to be significant at p < 0.05. RESULTS: Only 16 associations were statistically significant. On the other hand, seven of these were social limitations among girls whose placenta CRH mRNA was in the top quartile. Adjusting for delivery indication or restricting the sample to one delivery indication group resulted in few differences. CONCLUSION: Overall, placenta CRH mRNA concentrations in the top or bottom quartiles were not associated with increased risks of dysfunctions 10 years later. Girls whose placenta CRH expression was in the top quartile, however, were at increased risk of seven indicators/correlates of social limitations. PMID- 29992645 TI - Gly m 5/Gly m 8 fusion component as a potential novel candidate molecule for diagnosing soya bean allergy in Japanese children. AB - BACKGROUND: Soya bean is a major food allergen in children. Component-resolved diagnostics has improved the accuracy of diagnosing immunoglobulin E (IgE) mediated food allergies. OBJECTIVE: We aimed to develop a novel component for the diagnosis of soya bean allergy using recombinant technology. METHODS: Japanese paediatric patients with suspected soya bean allergy (n = 91) were included, and symptomatic (n = 40) and asymptomatic (n = 51) cases were divided through oral food challenge testing. Specific IgE (sIgE) antibodies to each recombinant allergen component were analysed by enzyme-linked immunosorbent assay, and the diagnostic performances of the components were assessed by area under the receiver operating characteristic curves (AUC). RESULTS: Among the recombinant components, sIgE antibody levels to Gly m 8 showed the highest AUC (0.706). A combination of Gly m 8 and alpha' subunit of Gly m 5, improved the diagnostic performance of the single components. Moreover, the N-terminal extension region of alpha' subunit of Gly m 5, which has low cross-reactivity among the vicilins, showed higher diagnostic performance (AUC 0.695) than the full-length alpha' subunit of Gly m 5 (AUC 0.613). Based on these findings, we developed a fusion protein of Gly m 8 plus the extension region of alpha' subunit of Gly m 5; this fusion protein was very efficient for diagnosing soya bean allergy (AUC 0.801). CONCLUSION: A fusion protein of Gly m 8 and the extension region of alpha' subunit of Gly m 5 could potentially diagnose soya bean allergy in paediatric patients. Fusion proteins may be useful for producing novel allergen components with improved diagnostic value. PMID- 29992646 TI - Impaired ankle-brachial index in antiphospholipid syndrome: Beyond the traditional risk factors. AB - INTRODUCTION: The patients with antiphospholipid syndrome (APS) associate an increased risk of atherosclerosis. OBJECTIVE: To determine the predictors of an abnormal ankle-brachial index (ABI), surrogate measure of atherosclerosis, in patients with APS. METHODS: The ABI was measured according to standard recommendations in 106 patients. Traditional cardiovascular risk factors were assessed in all cases. A large spectrum of APS antibodies was determined in 73 patients. RESULTS: A total of 106 patients diagnosed with APS were included. 28.3% patients included were found to have low ABI. Anti-beta 2-glycoprotein I (abeta2GPI) IgG antibodies [4.00 (1.00-79.00) vs 3.00 (0.00-29.00) U/mL, P = 0.02] and antiprothrombin (aPT) IgM antibodies [4.50 (0.00-82.00) vs 3.00 (0.00 14.00) U/mL, P = 0.05] titers were found to be higher in patients with abnormal ABI. However, after multivariate regression analysis, only the abeta2GPI IgG titer remained predictor of low ABI (P = 0.04). CONCLUSIONS: abeta2GPI IgG associated with impaired ABI in patients with APS. This relation might reflect their involvement in the atherosclerosis occurrence. PMID- 29992647 TI - Cyanobacterial extract with serotonin receptor subtype 7 (5-HT7 R) affinity modulates depression and anxiety-like behavior in mice. AB - Marine cyanobacteria represent a unique source in the field of drug discovery due to the secondary metabolites they produce and the structural similarity these compounds have to endogenous mammalian receptor ligands. A series of cyanobacteria were subjected to extraction, fractionation by column chromatography and screened for affinity against CNS targets with a focus on serotonin receptors (5-HTRs). Out of 276 fractions screened, 21% had activity at 5-HTRs and/or the 5-HT transporter (SERT). One sample, a cyanobacterium identified by 16S rRNA sequencing as Leptolyngbya from Las Perlas archipelago in Panama, contained a fraction with noted affinity for the 5-HT7 receptor (5-HT7 R). This fraction (DUQ0002I) was screened via intracerebroventricular (ICV) injections in mice using depression and anxiety assays including the forced swim, tail suspension, elevated zero maze, and light-dark preference tests. DUQ0002I decreased depression and anxiety-like behaviors in males and did not have effects in 5-HT7 R knockout or female mice. Administration of DUQ0002I to the CA1 of the hippocampus induced antidepression-like, but not anxiolytic-like behaviors. Testing of further purified materials showed no behavioral effects, leading us to hypothesize that the behavioral effects are likely caused by a synergistic effect between multiple compounds in the fraction. Finally, DUQ0002I was used in a model of neuropathic pain with comorbid depression (spared nerve injury-SNI). DUQ0002I had a similar antidepressant effect in animals with SNI, suggesting a role for the 5-HT7 R in the development of comorbid pain and depression. These results demonstrate the potential that cyanobacterial metabolites have in the field of neuropharmacognosy. PMID- 29992648 TI - Authors' reply to: Anti-Mullerian hormone and breast cancer risk: is the correlation possibly associated with PCOS. PMID- 29992650 TI - Gastrointestinal: Afatinib-induced acute esophageal necrosis. PMID- 29992651 TI - Impact of preoperative biliary drainage on postoperative outcome after pancreaticoduodenectomy. PMID- 29992652 TI - Shifting through the forest: home range, movement patterns, and diet of the eastern chimpanzee (Pan troglodytes schweinfurthii) in Nyungwe National Park, Rwanda. AB - Populations of the endangered eastern chimpanzee (Pan troglodytes schweinfurthii) are declining throughout their range. Although Nyungwe National Park (NNP) harbors the largest remaining eastern chimpanzee population in Rwanda, we know little about their space use and dietary patterns. We studied home range, movement, and diet of two communities of chimpanzees in NNP using daily tracking data (6:00 am to 6:00 pm) collected from 2000 to 2015. One community, Mayebe, resided in the forest center, and the other community, Cyamudongo, inhabited a forest fragment located about 10 km from the main forest. Home range estimated with the 95% kernel density estimation (KDE) method was 21 km2 for the Mayebe community and 4 km2 for the Cyamudongo community. Chimpanzee home range sizes were smaller during the dry versus wet season and varied monthly throughout the year. The Mayebe community had an average hourly step length of 75 +/- SE 5 m with a daily movement range of 987 +/- SE 71 m, while the Cyamudongo community had a shorter hourly step length of 52 +/- SE 3 m with a daily movement range of 651 +/- SE 71 m. Both chimpanzee communities fed primarily on Ficus spp. Other important dietary items included fruits of Symphonia globulifera, Syzygium guineense, and Chrysophyllum gorungosanum for the Mayebe community and Trilepisium madagascariense for the Cyamudongo community. Food choice varied monthly and seasonally for each chimpanzee community. Our study provides the first estimates of home range size and movement parameters for chimpanzees in Rwanda and documents their food habits and seasonal variations therein. We also identified the 50% core home range for each chimpanzee community and suggest this area as the focus of management actions. These results could help park management reduce threats to chimpanzees and other sympatric species by improving the efficiency of ranger patrols. PMID- 29992653 TI - Access to assistive technology for people with intellectual disabilities: a systematic review to identify barriers and facilitators. AB - BACKGROUND: The World Health Organisation has launched a programme to promote Global Cooperation on Assistive Technology. Its aim is to increase access to high quality affordable assistive products (AP) for everybody in need. People with intellectual disabilities (ID) are a specific group that could benefit from AP, but use less AP compared to their non-intellectual disabled peers. METHOD: A systematic literature search was carried out to identify barriers and potential facilitators for access to AP for people with ID globally. The search strategy terms were 'Intellectual Disability' and 'Assistive Technology' with the following electronic literature databases PubMed, Embase, ASSIA, Web of Science, Medline, CINAHL complete, PsycInfo, Scopus and ERIC. The quality and relevance of the studies were assessed. Factors associated with access were identified thematically, categorised into barriers and facilitators and mapped into themes. RESULTS: In all, 22 key studies were retrieved, describing 77 barriers and 56 facilitators. The most frequently reported barriers were related to lack of funding and cost of AP, lack of awareness about AP and inadequate assessment. An increase of knowledge and awareness about AP and the need of AP for people with ID were most often extracted as factors that could potentially facilitate access. CONCLUSIONS: This review proposes actions linked to the barriers and facilitators that have a particular importance for people with ID to access AP. Yet, only limited research is available describing factors that influence access to AP for people with ID in low and middle income countries and rural areas. PMID- 29992654 TI - On the Viability of Catalytic Turnover via Al-O/B-H Metathesis: The Reactivity of beta-Diketiminate Aluminium Hydrides towards CO2 and Boranes. AB - A series of beta-diketiminate stabilized aluminium hydrides of the type (Nacnac)Al(R)H has been synthesized offering variation in the auxiliary R substituent and in the Nacnac backbone. These show significant variation in the nature of the Al-H bond: electron-donating R groups give rise to weaker (and presumably more hydridic) Al-H bonds, leading to enhanced rates of reactivity towards CO2 . The resulting kappa1 -formate complexes (Nacnac)Al(R){OC(O)H} have been isolated and their reactivity towards B-H-containing reductants probed. In the case of HBpin no reaction is observed (even under forcing conditions), while the more reactive boranes HBcat and {H(9-BBN)}2 ultimately yield boryloxy complexes of the type (Nacnac)Al(R)(OBX2 ) (X2 =cat, 9-BBN). However, no hint of Al-O/B-H metathesis is observed even under forcing conditions. With BH3 ?SMe2 the major product is a related boryloxy system, although (uniquely) in this case a minor product is observed which contains an Al-H bond. We hypothesize that (Nacnac)Al(R)(kappa2 -BH4 ) is formed (despite the unfavourable thermodynamics of Al-O/B-H metathesis) due to the additional driving force provided by coordination of the strongly Lewis acidic BH3 unit to the Al-H bond. That said, we find that (unlike the analogous gallium systems) no catalytic turnover can be achieved in the reduction of CO2 by boranes mediated by these aluminium hydrides. PMID- 29992655 TI - Surgical management of outflow tract obstruction after transapical mitral valve implantation. AB - Left ventricular outflow tract (LVOT) obstruction due to systolic anterior motion of the anterior mitral valve leaflet (AML) is a known complication after mitral valve repair or transfemoral/transapical mitral valve implantation (TMVI). We present a patient with a previous mitral valve repair who developed LVOT obstruction after TMVI in whom the AML was surgically resected using a transaortic approach. PMID- 29992656 TI - Understanding medicines with a propensity to increase the risk of heart failure: Combining existing knowledge with targeted population assessment. AB - PURPOSE: Existing knowledge of medicines that increase the risk of an adverse event may be corroborated and augmented by population studies specifically assessing the risk associated with the concurrent use of these medicines and use by patients with existing comorbidity. An American Heart Association review recently identified a variety of medicines that may cause or exacerbate heart failure (HF), many with evidence from limited evaluation of population data. We assessed the risk of first-time HF associated with the use of 50 of these medicines by New Zealand's primary care population. METHODS: Case-control study utilising national pharmaceutical use and hospital admissions data 2007-2015; 22,989 patients with first-time HF 2008-2015 were matched with 114 498 control patients. The primary outcome was first-time HF and its association with medicine exposure in the prior 90 days, estimated using conditional logistic regression. We also assessed the risk associated with new use of medicines in the prior month, concurrent use, and in patients with existing comorbidity. RESULTS: Eleven medicines were significantly associated with HF with several other infrequently used medicines providing signals of increased risk. A high risk was associated with the use of salbutamol (adjusted odds ratio 2.63; 95% CI, 2.48-2.78), clozapine (2.70; 2.46-4.98), diltiazem (1.52; 1.44-1.60), indomethacin (2.51; 1.54-4.10), pioglitazone (1.50; 1.16-1.95), and antifungal medicines. New use of medicines and use of medicine combinations increased this risk in many cases. CONCLUSIONS: Our study provides further evidence to inform cautious use of these medicines in patients with HF or at risk of developing HF. PMID- 29992657 TI - Ultrasound measurements of subcutaneous adipose tissue thickness show sexual dimorphism in children of three to five years of age. AB - AIM: A standard approach to measure subcutaneous adipose tissue (SAT) using ultrasound has proved successful in adults, but has not been studied in children. This study addressed that gap in children aged three to five years. METHODS: In autumn 2016, 24 preschools in Southwest Germany, recruited via mail, agreed to take part in this study and 274 children (51.4% boys) with a mean age of 4.6 +/- 0.7 years participated in measurements of SAT and anthropometry. Differences in measurements were explored between the sexes and anthropometric predictors of mean SAT thickness were identified. Intra-observer reliability for ultrasound measurements of SAT was also assessed. RESULTS: The mean SAT thickness showed significant differences between the boys and girls (5.3 +/- 2.0 and 6.3 +/- 2.0 mm, respectively, p < 0.01). The children's body mass, height and sex explained 66% of the variance in the mean SAT thickness, as SAT was larger with a higher body mass, a smaller stature and in girls. Intra-observer reliability resulted in an intra-class correlation coefficient of 0.994 (p < 0.01) with a 95% confidence interval of 0.983-0.998. CONCLUSION: Subcutaneous adipose tissue thickness differed between boys and girls with a mean age of 4.6 years. Intra-observer reliability was excellent. This standardised approach enabled high-precision measurements of SAT in a paediatric population. PMID- 29992658 TI - Highly Efficient Encapsulation and Phase Separation of Apolar Molecules by Magnetic Shell-by-Shell-Coated Nanocarriers in Water. AB - We report on the development of a supramolecular nanocarrier concept that allows for the encapsulation and separation of small apolar molecules from water. The nanocarriers consist of shell-by-shell-coated nanoparticles such as TiO2 and ferromagnetic Fe3 O4 . The first ligand shell is provided by covalently bound hexadecyl phosphonic acid (PAC16 ) and the second shell by noncovalently assembled amphiphiles rendering the hybrid architecture soluble in water. Agitation of these constructs with water containing the hydrocarbons G1-G4, the fluorescent marker G5, the polychlorinated biphenyl PCB 77, or crude oil leads to a very efficient uptake (up to 411 %) of the apolar contaminant. In case of the hybrids containing a Fe3 O4 core, straightforward phase separation by the action of an external magnet is provided. The load can easily be released by a final treatment with an organic solvent. PMID- 29992659 TI - Common genetic causes of holoprosencephaly are limited to a small set of evolutionarily conserved driver genes of midline development coordinated by TGF beta, hedgehog, and FGF signaling. AB - Here, we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). We now show that comparisons of variant transmission versus nontransmission among 136 HPE Trios indicates some reported genes now lack confirmation, while novel genes are implicated. Furthermore, we demonstrate that variation of modest intrinsic effect can synergize with these driver mutations as gene modifiers. PMID- 29992660 TI - Identification of seminal markers of male accessory gland inflammation: From molecules to proteome. AB - Male accessory gland infection/inflammation (MAGI) is a frequent disease, mostly with a chronic course, involving 1 or more sexual accessory glands. Majority of the MAGIs remain asymptomatic, thereby leading to a dilemma whether to treat these patients or not. It is moreover noteworthy that the diagnosis of MAGI is difficult, since patients are frequently asymptomatic and semen samples or prostatic secretions are often free from bacteria. As a consequence the identification of novel and reliable markers of inflammation in seminal plasma is an open challenge. If leukocytospermia and polymorphonuclear elastase and the analysis of the secretory products of male accessory glands have been widely used in the past, their diagnostic significance is discussed. Some cytokines (IL-6 and IL-8) and protein markers (suPAR) have been reported in the last years as the most promising markers for the diagnosis and the follow-up of MAGI. Recent advances in proteomic techniques undoubtedly represent a real promise in the future for the identification of novel markers of MAGI. This article provides an overview of key seminal biomarkers of MAGI, including the novel perspectives of the putative markers deriving by the most recent proteomic approaches. PMID- 29992661 TI - Texture-modified foods and thickened fluids used in dysphagia: Israeli standardised terminology and definitions. AB - BACKGROUND: Texture-modified foods and thickened fluids are used as a strategy that aims to compensate for dysphagia and improve the safety and efficiency of swallowing. Currently, in Israel, there are no standardised terminologies and definitions for texture-modified diets. The inconsistent terminology adversely affects patient safety and the efficiency of communication between staff members both within and between health institutions. This present study describes a project of the Israeli Ministry of Health in which the labels and definitions of prevalent foods and fluids used in health institutions are mapped to develop a consensus on national standards. METHODS: A multidisciplinary committee of speech language pathologists (SLPs) and registered dietitians (RDs) was appointed. A questionnaire was developed to identify the labels of texture-modified foods and fluids used in the Israeli healthcare system. The questionnaire included questions on knowledge, attitudes and barriers related to the need for a consistent national terminology for texture-modified diets. Questionnaires were sent to 120 institutions. The project was conducted between September 2016 and December 2017. RESULTS: Twenty-six SLPs and 42 RDs responded. The answers revealed that there were 50 labels in use for texture-modified foods. When asked to describe the texture of a particular food item, up to 17 different labels were used. There was broad support for a standardised terminology. CONCLUSIONS: The results of the present study confirm the lack of national standards in clinical practice and the need for a consistent terminology. A consensus was achieved between the committee members and the committee adopted the International Dysphagia Diet Standardization Initiative (IDDSI) recommendations and adapted the terminology to Hebrew. PMID- 29992662 TI - Factors associated with emergency cesarean delivery during induction of labor in nulliparous women aged 35 years or older at term. AB - AIM: To examine the intrapartum cesarean delivery rate following failure of induction of labor (IOL) as well as risk factors associated with failed IOL among nulliparous women of advanced maternal age (AMA). METHODS: This was a retrospective cohort study conducted at a single perinatal care center. We retrospectively reviewed the medical records of nulliparous AMA women (aged 35 years or older) with singleton vertex pregnancy who underwent IOL at term. Data regarding maternal baseline characteristics and pregnancy course, including complications during pregnancy and maternal status at time of IOL, were collected. Rate of emergency cesarean section (eCS) as well as risk factors associated with failed IOL were investigated by means of logistic regression analysis. RESULTS: Among 234 women included in this study, 103 (44%) had failed IOL and delivered by eCS. Hypertensive disorder during pregnancy (adjusted odds ratio [aOR], 2.01; 95% confidence interval [CI], 1.0-4.12; P = 0.025) and unfavorable cervical status (aOR, 1.92; 95% CI, 1.08-3.41; P = 0.038) were identified as independent risk factors for failed IOL. CONCLUSION: IOL failed in 44% of nulliparous AMA women. Hypertensive disorder and immature cervical status should be considered as independent risk factors for eCS among such women. PMID- 29992663 TI - Boosting Lithium Storage Properties of MOF Derivatives through a Wet-Spinning Assembled Fiber Strategy. AB - Graphene composite fibers are of great importance in constructing electrode materials with high flexibility and conductivity for energy storage and electronic devices. Integration of multifunctional metal-organic frameworks (MOFs) into graphene fiber scaffolds enables novel functions and enhanced physical/chemical properties. The close-packed and aligned graphene sheets along with the porous MOF-derived structures can achieve excellent lithium storage performance through synergetic effects. In this work, a facile and general strategy is demonstrated for the preparation of MOF/graphene oxide (GO) fibers, which serve as precursors for the subsequent preparation of porous metal oxide/reduced graphene oxide (rGO) composite fibers. The obtained composites, for example, porous Fe2 O3 /rGO and Co3 O4 /rGO fibers, possess unique features of MOF-derived porous structures and excellent electrical conductivity. When tested as anode materials for lithium-ion batteries in coin cells, the MOF/GO fiber derived porous metal oxide/rGO composite fibers exhibited high specific capacity, excellent rate capability and cycling performance. Moreover, a flexible fiber battery was fabricated based on the Fe2 O3 /rGO composite fiber, which demonstrates its potential application for flexible electronic devices. PMID- 29992664 TI - Novel amides of 1,1-bis-(carboxymethylthio)-1-arylethanes: Synthesis, characterization, acetylcholinesterase, butyrylcholinesterase, and carbonic anhydrase inhibitory properties. AB - The thiolation reaction was carried out in a benzene solution at 80 degrees C and p-substituted ketones and mercaptoacetic acid in a molar ratio (1:4) of in the presence of a catalytic amount of toluene sulfonic acids. The enzyme inhibition activities of the novel amides of 1,1-bis-(carboxymethylthio)-1-arylethanes derivatives were investigated. These novel amides of 1,1-bis-(carboxymethylthio) 1-arylethanes derivatives showed good inhibitory action against acetylcholinesterase (AChE) butyrylcholinesterase (BChE), and human carbonic anhydrase I and II isoforms (hCA I and II). AChE inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. Many clinically established drugs are carbonic anhydrase inhibitors, and it is highly anticipated that many more will eventually find their way into the market. The novel synthesized compounds inhibited AChE and BChE with Ki values in the range of 0.64-1.47 nM and 9.11-48.12 nM, respectively. On the other hand, hCA I and II were effectively inhibited by these compounds, with Ki values between 63.27 132.34 and of 29.63-127.31 nM, respectively. PMID- 29992665 TI - Tropomyosins in mosquito and house dust mite cross-react at the humoral and cellular level. AB - BACKGROUND: Aedes aegypti and Dermatophagoides pteronyssinus contain important allergens including cross-reactive tropomyosins. However, the functional and clinical relevance of their cross-reactivity is still debated. OBJECTIVE: To analyse the humoral and cellular cross-reactivity of recombinant Aed a 10.01, Aed a 10.02 and Der p 10. METHODS: Sera from 15 Austrian house dust mite-allergic, Der p 10-sensitized individuals were tested for IgE reactivity to recombinant tropomyosins in ELISA, inhibition ELISA and basophil activation tests. BALB/c mice were immunized with Aed a 10.01 or Aed a 10.02, and their sera were assessed for reactivity to all tropomyosins. Splenocytes were stimulated with all tropomyosins and synthetic peptides representing the amino acid sequence of Aed a 10.01. RESULTS: IgE antibodies of Der p 10-sensitized patients cross-reacted with both tropomyosins from A. aegypti. Aed a 10.01 was a more potent inhibitor of IgE binding to Der p 10 and a stronger activator of basophils sensitized with Der p 10-specific IgE than Aed a 10.02. Murine antibodies raised against Aed a 10.01 and Aed a 10.02 cross-reacted with Der p 10. Aed a 10.01-specific antibody showed stronger cross-reactivity with Der p 10 than Aed a 10.02-specific antibody. Splenocytes from both groups of mice proliferated similarly to all tropomyosins. Five cross-reactive T cell-activating regions were identified. CONCLUSION AND CLINICAL RELEVANCE: Tropomyosins from D. pteronyssinus and A. aegypti show humoral and cellular cross-reactivity, involving 5 potential T cell-activating regions. The more pronounced cross-reactivity of Aed a 10.01 and Der p 10 matched the higher sequence similarity of both proteins. PMID- 29992667 TI - Effects of sperm direction in Piezo-ICSI on oocyte survival, fertilization, embryo development and implantation ability in humans: A preliminary study. AB - AIMS: The objective of this study was to investigate the effect of the head-first or tail-first injection of sperm into the cytoplasm by Piezo-ICSI (PICSI) on oocyte survival, fertilization, embryo development and implantation ability in humans. METHODS: We retrospectively investigated 632 mature oocytes retrieved from 152 infertile patients who attended our PICSI-ET program at the Niji Clinic between October 2010 and January 2014. Of these, 342 mature oocytes retrieved from 75 patients were injected with sperm head first, and 290 mature oocytes retrieved from 77 patients were injected with sperm tail first into the cytoplasm. The rates of oocyte survival, fertilization, good-quality day-3 embryos, pregnancy, implantation and live birth were evaluated in both groups. RESULTS: There were no differences among the two groups with respect to survival, fertilization, good-quality day-3 embryos, pregnancy, implantation and live birth rates. CONCLUSION: Sperm direction (i.e., head first or tail first) does not influence the outcome of PICSI in human oocytes, including oocyte survival, fertilization, embryo development and implantation ability. These findings contribute to an understanding of factors that influence the success of human intracytoplasmic sperm injection (ICSI) techniques. PMID- 29992666 TI - Selective Synthesis of Tetrasubstituted Olefins by Copper-Mediated Acetoxythiolation of Internal Alkynes: Scope and Mechanistic Studies. AB - The Cu-mediated synthesis of tetrasubstituted olefins by the addition of an acetate group and a thiolate to an unactivated internal alkyne is described. The reaction is fully stereoselective, because only the E alkene is obtained. If the alkyne is asymmetric, the reaction also shows a very high degree of regioselectivity. The mechanism of the reaction is elucidated by DFT methods, which show that it takes place through Cu-stabilized radical species. Calculations highlight the crucial role of the dimeric copper(II) diacetate in the process, as it generates the active species in which the sulfur center has an incipient thiyl radical character and accepting, through a series of changes in the oxidation states of the two copper centers, the two electrons released in the addition of two nucleophiles to the alkyne. PMID- 29992669 TI - Folding Large Graphene-on-Polymer Films Yields Laminated Composites with Enhanced Mechanical Performance. AB - A folding technique is reported to incorporate large-area monolayer graphene films in polymer composites for mechanical reinforcement. Compared with the classic stacking method, the folding strategy results in further stiffening, strengthening, and toughening of the composite. By using a water-air-interface facilitated procedure, an A5-size 400 nm thin polycarbonate (PC) film is folded in half 10 times to a ~0.4 mm thick material (1024 layers). A large PC/graphene film is also folded by the same process, resulting in a composite with graphene distributed uniformly. A three-point bending test is performed to study the mechanical performance of the composites. With a low volume fraction of graphene (0.085%), the Young's modulus, strength, and toughness modulus are enhanced in the folded composite by an average of 73.5%, 73.2%, and 59.1%, respectively, versus the pristine stacked polymer films, or 40.2%, 38.5%, and 37.3% versus the folded polymer film, proving a remarkable mechanical reinforcement from the combined folding and reinforcement of graphene. These results are rationalized with combined theoretical and computational analyses, which also allow the synergistic behavior between the reinforcement and folding to be quantified. The folding approach could be extended/applied to other 2D nanomaterials to design and make macroscale laminated composites with enhanced mechanical properties. PMID- 29992668 TI - In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin. AB - Acute renal failure is one of the most frequent effects observed after taking medicine. Such situations have been tardily discovered, given that existing methods for assessing toxicity are not predictive. In this light, the present work evaluated the effects of gentamicin, a form of nephrotoxic drug, on HK-2 and HEK-293 cells. By using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and flow cytometry, both cells demonstrated that cytotoxicity occurs in a dose-dependent manner through the processes of apoptosis and cell necrosis. Gene expression analysis showed a relative increase of expression for genes related to cell processes and classic biomarkers, such as TP53, CASP3, CASP8, CASP9, ICAM-1, EXOC3, KIM-1, and CST3. A decrease in expression for genes BCL2L1 and EGF was observed. This study, therefore, indicates that, when the methods are used together, gene expression analysis is able to evaluate the nephrotoxic potential of a substance. PMID- 29992670 TI - Genome-wide association studies and expression-based quantitative trait loci analyses reveal roles of HCT2 in caffeoylquinic acid biosynthesis and its regulation by defense-responsive transcription factors in Populus. AB - 3-O-caffeoylquinic acid, also known as chlorogenic acid (CGA), functions as an intermediate in lignin biosynthesis in the phenylpropanoid pathway. It is widely distributed among numerous plant species and acts as an antioxidant in both plants and animals. Using GC-MS, we discovered consistent and extreme variation in CGA content across a population of 739 4-yr-old Populus trichocarpa accessions. We performed genome-wide association studies (GWAS) from 917 P. trichocarpa accessions and expression-based quantitative trait loci (eQTL) analyses to identify key regulators. The GWAS and eQTL analyses resolved an overlapped interval encompassing a hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyl transferase 2 (PtHCT2) that was significantly associated with CGA and partially characterized metabolite abundances. PtHCT2 leaf expression was significantly correlated with CGA abundance and it was regulated by cis-eQTLs containing W-box for WRKY binding. Among all nine PtHCT homologs, PtHCT2 is the only one that responds to infection by the fungal pathogen Sphaerulina musiva (a Populus pathogen). Validation using protoplast-based transient expression system suggests that PtHCT2 is regulated by the defense-responsive WRKY. These results are consistent with reports of CGA functioning as an antioxidant in response to biotic stress. This study provides insights into data-driven and omics-based inference of gene function in woody species. PMID- 29992671 TI - Eu3+ -Activated Gd8 V2 O17 : Energy Transfer, Luminescence, and Temperature Dependence Characteristics. AB - A new phosphor of the type Gd8(1-x) Eu8 x V2 O17 (x=0-1.0) was synthesized through the solid-state reaction ceramics method. A pure phase formation was verified by using X-ray powder diffraction measurements. The luminescence of Gd8 V2 O17 :Eu3+ was investigated through optical and laser excitation spectroscopy. The luminescence curves were investigated in the temperature region 10 to 300 K. Gd8 V2 O17 shows a self-activated luminescence under excitation with UV- and near UV light. The spectra, the decay lifetimes, and the thermal stability of Gd8(1-x) Eu8 x V2 O17 (x=0.005-1.0) strongly depend on both the Eu3+ concentration and the temperature. The tunable luminescence is realized by controlling the Eu3+ -doping level to adjust the host energy-transfer efficiency from the VO43- groups to the Eu3+ activators. At low Eu3+ concentrations (<30 mol %), the intensity and lifetime show an unusual change with an increase of the temperature from 10-300 K, that is, the luminescence experiences a straightforward enhancement. The energy transfer from the VO43- group to the Eu3+ ions could be accelerated with an increase of the temperature resulting in an unusual enhancement of the Eu3+ luminescence and lifetime. However, the emission of the Eu3+ ions decreased for highly Eu-doped samples (>30 mol %) with an increase of the temperature. The luminescence mechanism was discussed on the basis of the charge-transfer band of the Eu3+ ions, the doping concentration, and the proposed microstructures in the lattices. PMID- 29992672 TI - Dienogest therapy during the early stages of recurrence of endometrioma might be an alternative therapeutic option to avoid repeat surgeries. AB - AIM: We aimed to evaluate whether hormonal therapy immediately after postsurgical recurrence of ovarian endometrioma controls disease progression and can be an alternative therapeutic option to avoid multiple repeat surgeries. METHODS: We enrolled 146 patients treated for endometrioma at the University Hospital of Kyoto Prefectural University of Medicine between 2009 and 2015. After laparoscopic cystectomy using the stripping technique, opening of cul-de-sac obliterations and complete resection of the deep infiltrating endometriosis lesions, the patients either received no treatment (n = 83), oral contraceptives (OC; n = 32) or dienogest (DNG; n = 27), depending on their medical history. Four patients were excluded because they changed their regimens during the follow-up period. All patients were followed up every 3 months. Patients who developed recurrence of endometrioma immediately received DNG, OC or gonadotropin-releasing hormone agonist. RESULTS: Overall, 16 patients developed a recurrence of the endometrioma (12 in the nontreatment group, three in the OC group and one in the DNG group). The 11 patients with recurrence were treated with DNG immediately after the diagnosis of recurrent endometrioma. Among them, seven patients continued treatment with DNG (2 mg) for 24 months. After 24 months of treatment with DNG, complete resolution of recurrent endometrioma was achieved in four (57.1%) of seven patients. There was no improvement in the three patients who received OC and one patient who underwent secondary surgery. CONCLUSION: DNG therapy early after recurrence of postsurgical endometrioma appears to be viable for reducing the risk of repeated surgery. PMID- 29992673 TI - Direct Enantio- and Diastereoselective Oxidative Homocoupling of Aldehydes. AB - A novel strategy for the direct enantioselective oxidative homocoupling of alpha branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon-carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines. Experimental mechanistic investigations based on competition experiments combined with computational studies indicate that the reaction proceeds through a radical cation intermediate and that reactivity and stereoselectivity follow different trends. PMID- 29992674 TI - The effects of state-level pharmacist regulations on generic substitution of prescription drugs. AB - Substituting generic for brand name drugs whenever possible has been proposed to control prescription drug expenditure growth in the United States. This work investigates two types of state laws that regulate the procedures under which pharmacists substitute bioequivalent generic versions of brand name drugs. Mandatory substitution laws require pharmacists to use the generic as a default, and presumed consent laws allow them to assume that the patient agrees to the substitution. Both situations can be overruled by the patient. Using plausibly exogenous changes in states' laws, we use difference-in-differences and a discrete choice model to show that although the mandatory switching laws have little effect, the presumed consent laws reduce consumers' probability of purchasing brand name drugs by 3.2% points. The differential effectiveness of the laws is likely caused by pharmacists' profit motives. These results offer important implications for policies that seek to reduce drug expenditures by incentivizing the use of generic drugs. PMID- 29992675 TI - A 3-year longitudinal study of skeletal effects and growth in children after kidney transplantation. AB - This prospective study investigated growth and skeletal development for 3 years after kidney transplantation in pediatric patients, 3.4-15.0 years of age. Growth, BMD, bone resorption markers (CTX and TRACP5b), bone formation markers (PINP, ALP, and osteocalcin), PTH, and vitamin D were assessed at start, 3, 12, and 36 months after transplantation. Median GFR was 63 (range 37-96) mL/min/1.73 m2 after 3 years. The median height SDS increased from -1.7 to -1.1, and median BMI SDS increased from -0.1 to 0.6 over 3 years, which shows that transplantation had a favorable outcome on growth. Fat mass increased after transplantation at all time points, whereas lean mass increased after 1 year and 3 years. Total BMC increased at all time points. No changes were observed for total BMD. Bone resorption markers decreased initially after 3 months and remained stable throughout the study, whereas the bone formation markers decreased initially, but successively increased over the study period. In conclusion, this study demonstrates that height SDS and BMI SDS increased, along with the increased formation markers that reveal a positive bone acquisition after kidney transplantation, which was reflected by the significant increase in total body BMC. PMID- 29992676 TI - Real-Time Cerebral Hemodynamic Response to Tactile Somatosensory Stimulation. AB - BACKGROUND AND PURPOSE: Recent studies in rodents suggest that somatosensory stimulation could provide neuroprotection during ischemic stroke by inducing plasticity in the cortex-vasculature relationship. While functional magnetic resonance imaging (fMRI) has shown that somatosensory stimulation increases cerebral blood flow (CBF) over several seconds, subsecond changes in CBF in the basal cerebral arteries have rarely been studied due to temporal resolution limitations. This study characterized hemodynamic changes in the middle cerebral arteries (MCAs) during somatosensory stimulation with high temporal resolution (100 samples/s) using functional transcranial Doppler ultrasound (fTCD). METHODS: Pneumotactile somatosensory stimulation, consisting of punctate pressure pulses traversing the glabrous skin of the hand at 25 cm/s, was used to induce CBF velocity (CBFV) response curves. Changes in CBFV were measured in the bilateral MCAs using fTCD. All 12 subjects underwent three consecutive trials consisting of 20 seconds of stimulation followed by 5 minutes of rest. RESULTS: Sharp, bilateral increases in CBFV of about 20% (left MCA = 20.5%, right MCA = 18.8%) and sharp decreases in pulsatility index of about 8% were observed during stimulation. Left lateralization of up to 3.9% was also observed. The magnitude of the initial increase in CBFV showed significant adaptation between subsequent trials. CONCLUSIONS: Pneumotactile somatosensory stimulation is a potent stimulus that can evoke large, rapid hemodynamic changes, with adaptation between successive stimulus applications. Due to its high temporal resolution, fTCD is useful for identifying quickly evolving hemodynamic responses, and for correlating changes in hemodynamic parameters such as pulsatility index (PI) and CBFV. PMID- 29992677 TI - Resisting annihilation: relationships between functional trait dissimilarity, assemblage competitive power and allelopathy. AB - Allelopathic species can alter biodiversity. Using simulated assemblages that are characterised by neutrality, lumpy coexistence and intransitivity, we explore relationships between within-assemblage competitive dissimilarities and resistance to allelopathic species. An emergent behaviour from our models is that assemblages are more resistant to allelopathy when members strongly compete exploitatively (high competitive power). We found that neutral assemblages were the most vulnerable to allelopathic species, followed by lumpy and then by intransitive assemblages. We find support for our modeling in real-world time series data from eight lakes of varied morphometry and trophic state. Our analysis of this data shows that a lake's history of allelopathic phytoplankton species biovolume density and dominance is related to the number of species clusters occurring in the plankton assemblages of those lakes, an emergent trend similar to that of our modeling. We suggest that an assemblage's competitive power determines its allelopathy resistance. PMID- 29992678 TI - Reducing pediatric psychiatric hospital readmissions and improving quality care through an innovative Readmission Risk Predictor Tool. AB - PROBLEM: Less than 30-day readmission has become a national problem. This pediatric medical center discovered that the primary diagnosis of Mood Disorder, not otherwise specified, was the third most common readmission diagnosis hospital wide. Administration actively sought a resolution to less-than-30-day readmissions because All-Patient-Refined-Diagnostic-Related Groups would soon include pediatric hospitals with reimbursement impact. METHODS: The Iowa Model for evidence-based practice framed the work of case management to identify readmission risk, reduce readmissions, and improve patient quality. In July 2014, the Readmit Predictor Tool (RPT) and Protocol were developed from literature review of contributing factors of pediatric psychiatric readmissions and assessed levels of readmission risk. The nurse case manager provided follow-up telephone calls to caregivers with children identified as moderate-to-high risk for readmissions. FINDINGS: Effects of RPT use resulted in decreased readmissions by 29.5% in the first year, followed by 7.8% and 5.1% reductions in the second and third years, respectively, despite substantial increases in patient acuity during the period. CONCLUSION: Using the RPT and initiating the psychiatry nurse case manager position, less-than-30-day readmissions decreased over a 3-year period. PMID- 29992679 TI - Benefits of combining change-point analysis with disproportionality analysis in pharmacovigilance signal detection. AB - BACKGROUND: Change-point analysis (CPA) is a powerful method to analyse pharmacovigilance data but it has never been used on the disproportionality metric. OBJECTIVES: To optimize signal detection investigating the interest of time-series analysis in pharmacovigilance and the benefits of combining CPA with the proportional reporting ratio (PRR). METHODS: We investigated the couple benfluorex and aortic valve incompetence (AVI) using the French National Pharmacovigilance and EudraVigilance databases: CPA was applied on monthly counts of reports and the lower bound of monthly computed PRR (PRR-). We stated a CPA hypothesis that the substance-event combination is more likely to be a signal when the 2 following criteria are fulfilled: PRR- is greater than 1 with at least 5 cases, and CPA method detects at least 2 successive change points of PRR- which made consecutively increasing segments. We tested this hypothesis by 95 test cases identified from a drug safety reference set and 2 validated signals from EudraVigilance database: CPA was applied on PRR-. RESULTS: For benfluorex and AVI, change points detected by CPA on PRR- were more meaningful compared with monthly counts of reports: More change points detected and detected earlier. In the reference set, 14 positive controls satisfied CPA hypothesis, 6 positive controls only met first requirements, 3 negative controls only met first requirement, and 2 validated signals satisfied CPA hypothesis. CONCLUSIONS: The combination of CPA and PRR represents a significant advantage in detecting earlier signals and reducing false-positive signals. This approach should be confirmed in further studies. PMID- 29992680 TI - Ultrasound Promoted Step-Growth Polymerization and Polymer Crosslinking Via Copper Catalyzed Azide-Alkyne "Click" Reaction. AB - Mechano-activated chemistry is a powerful tool for remodeling of synthetic polymeric materials, however, few reactions are currently available. Here we show that using piezochemical reduction of a CuII -based pre-catalyst, a step-growth polymerization occurs via the copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction to form a linear polytriazole. Furthermore, we show that a linear polymer can be crosslinked mechanochemically using the same chemistry to form a solid organogel. We envision that this chemistry can be used to harness mechanical energy for constructive purposes in polymeric materials. PMID- 29992681 TI - Cross-sex hormone therapy in Australia: the prescription patterns of clinicians experienced in adult transgender healthcare. AB - BACKGROUND: Despite increasing demand for transgender healthcare, guidelines for cross-sex hormone therapy are based on low-level evidence only. As most data are based on international expert opinions, interpretations and practices vary significantly. AIMS: To aid the development of Australian clinical guidelines, we aimed to identify cross-sex hormone therapy prescribing patterns amongst medical practitioners experienced in adult transgender healthcare. METHODS: We conducted an anonymous online survey of experienced hormone prescribers who were members of the Australian and New Zealand Professional Association for Transgender Health. RESULTS: We received 35 responses from 43 individuals listed with ANZPATH. Mental health assessments prior to commencement of hormonal therapy were recommended by 80% of prescribers. The preferred first-line masculinising hormone therapy was intramuscular testosterone undecanoate (46% of respondents). The most commonly prescribed feminising agents were oral estradiol valerate (first-line in 71.4%) with either spironolactone or cyproterone acetate. Most respondents (>90%) targeted sex steroid reference ranges of the affirmed gender and 71.4% reviewed individuals every 2-3 months in the first year. Better training for doctors was seen as the most pressing priority for government funding, and 79.3% supported the development of local Australian-based guidelines. CONCLUSIONS: Experienced hormone prescribers in Australia largely use medication regimens and monitor sex steroid levels and potential adverse effects of sex hormone therapy in accordance with broad, subjective recommendations listed in international guidelines. Additional practitioner training is necessary, and local Australian-based guidelines would offer specific, relevant guidance to clinicians in the initiation and monitoring of cross-sex hormone therapy for adult transgender individuals. This article is protected by copyright. All rights reserved. PMID- 29992682 TI - A Fully Automated Continuous-Flow Platform for Fluorescence Quenching Studies and Stern-Volmer Analysis. AB - Herein, we report the first fully automated continuous-flow platform for fluorescence quenching studies and Stern-Volmer analysis. All the components of the platform were automated and controlled by a self-written Python script. A user-friendly software allows even inexperienced operators to perform automated screening of novel quenchers or Stern-Volmer analysis, thus accelerating and facilitating both reaction discovery and mechanistic studies. The operational simplicity of our system affords a time and labor reduction over batch methods while increasing the accuracy and reproducibility of the data produced. Finally, the applicability of our platform is elucidated through relevant case studies. PMID- 29992684 TI - A systematic review: Candidate gene and environment interaction on alcohol use and misuse among adolescents and young adults. AB - BACKGROUND AND OBJECTIVES: Youth drinking is a pervasive public health concern with serious negative developmental implications. Candidate gene and environment interaction studies (cGxE) show that environmental effects on drinking behaviors may differ by individuals' genotypes. Yet little is known about whether genetic and environmental effects on drinking behaviors are developmentally specific. METHODS: This systematic review evaluated 42 cGxE studies of drinking in adolescence and young adulthood. RESULTS: Although there are mixed findings, studies of cGxE effects involving DRD4, 5-HTTLPR, DRD2, and OPRM1 genotypes showed relatively consistent patterns. The effects of under-controlled environments (eg, low levels of parental monitoring) on early and middle adolescent drinking appeared to differ across DRD2 or OPRM1 genotypes. Effects of alcohol-facilitating environments (eg, heavy drinking peers) on late adolescent and young adult drinking appeared to differ across DRD4 or OPRM1 genotypes. Interactions between 5-HTTLPR genotype with stressful environments (eg, negative life events) were found throughout adolescence and young adulthood, although there were some inconsistencies regarding the risk-conferring allele. There was limited evidence for other cGxE effects due to the small number of studies. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This review suggests that GxE findings may advance our knowledge regarding which developmentally specific conditions result in the expression of candidate genes that influence youth alcohol use and misuse. However, since a significant number of studies had small sample sizes and most studies had small effect sizes, findings need replication across independent studies with large samples. (Am J Addict 2018;XX:1-19). PMID- 29992683 TI - Juglone-ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities. AB - Anaplastic thyroid carcinoma (ATC) requires more innovative approaches as the current regimes for therapy are inadequate, also most anticancer drugs cause general suppression of physiological functions. However, therapy with limited nontarget tissue damage is desirable. In the present study, we show prooxidant ability of ascorbic acid, which enhances cytotoxicity induced by juglone. We decipher that juglone-ascorbate combination induces reactive oxygen species mediated apoptosis leading to cell death in ARO cell line originated from ATC. This combination also affects enzyme activity of catalase, glutathione reductase, and superoxide dismutase destabilizing redox balance in cell and thereby making juglone effective at a lower dose. We also show that juglone-ascorbate combination suppresses cell migration, invasion, and expression of tumor promoting, and angiogenic genes in ARO cell line, thereby disrupting epithelial mesenchymal transition ability of the cells. Overall, we show that ascorbic acid increases cytotoxic potency of juglone through redox cycling when used in synergy. PMID- 29992685 TI - Silence is golden. PMID- 29992686 TI - Student support from peers to optimise clinical exposure. PMID- 29992688 TI - A health professions education editors' open letter to our community. PMID- 29992689 TI - Attending to relationships: a necessary evolution in the clerkship. PMID- 29992690 TI - Context, culture and beyond: medical oaths in a globalising world. PMID- 29992691 TI - In response to Vanneman et al. on 'Studies on the effectiveness of flipped classrooms'. PMID- 29992692 TI - Setting and length: why rural exposure matters. PMID- 29992693 TI - Being a surgeon or doing surgery? A qualitative study of learning in the operating room. AB - CONTEXT: A key concern for surgical educators is to prepare students to perform in the operating room while ensuring patient safety. Recent years have seen a renewed discussion of medical education through practice theoretical and sociomaterial lenses. These lenses are introduced to understand and prepare the learner to perform in the given context. This paper takes its point of departure from practice theory by introducing a lens through which to understand learning environments in surgery. METHODS: Using a multi-site ethnographic and practice based design, this study investigates how aspiring surgical students are stirred into surgical practices and learn to engage as surgeons. During 70 hours of observations of medical students' participation in the operating room, we analysed how the phenomenon of surgical learning can be perceived as instances of transformation in and among social practices. RESULTS: By applying an analytical perspective, this article highlights the use of practice theory in surgical education, which can help to establish a firmer understanding of the learning environment and thereby help educators to improve curricula and prepare students more effectively to enter surgical training. CONCLUSIONS: The use of a practice theory adds the perspective that the education of surgeons needs to take the sayings, doings and relatings that constitute a surgical practice into account when preparing students to perform in their future workplace. In this way, surgical training can be perceived as a process of being stirred into practice. This means that one learns by participating in the practice of providing high quality care, where the aim is to teach students to be surgeons instead of teaching them to perform surgery. PMID- 29992694 TI - The relationship between pulse pressure and inflammation with left ventricular diastolic dysfunction in chronic kidney disease patients. AB - INTRODUCTION: Diastolic dysfunction (DD) is an important cause of cardiovascular disease (CVD) mortality in chronic kidney disease (CKD) patients. Non-traditional risk factors such as arterial stiffness and inflammation are implicated in the pathogenesis of DD in CKD patients. AIM: To determine the association between inflammatory markers [interleukin(IL)-12, IL-18, highly sensitive C-reactive protein (hsCRP)] and non-invasive markers of arterial stiffness [24-hour pulse pressure (PP)] with DD in stage 3-4 CKD patients. METHODS: We performed a sub analysis of 78 non-diabetic stage 3-4 CKD subjects to determine the relationship between 24-hour PP, IL-12, IL-18 and hsCRP with DD. RESULTS: DD was present in 38 subjects (49%). Subjects with DD were significantly older (61.0+/-1.9 vs 50.2+/ 2.0years; p<0.001) and had higher 24-hour PP [48(95%CI 45, 52) vs 43(95%CI 41, 45)mmHg; p<0.005]. 24-hour PP was associated with DD (p=0.02) but this was no longer significant after adjustment for age (p=0.31). Serum IL-12, IL-18 and hsCRP levels were not significantly different between subjects with or without DD. CONCLUSION: Asymptomatic subclinical DD was present in 50% of a cohort of stage 3-4 CKD patients but was not associated with IL-12, IL-18 or hsCRP. The association between 24-hour PP and DD was no longer apparent following adjustment for age but given the small sample size our findings will need to be explored in larger sized cohorts of individuals with moderate stage CKD. This article is protected by copyright. All rights reserved. PMID- 29992696 TI - Diagnostic ability of a smart phone app (injured tooth) in diagnosing traumatic injuries to the teeth - a multicentre analysis. AB - BACKGROUND: Dental trauma is not uncommon. The initial management provided at the time of injury is critical in predicting prognosis. However, initial management depends on correct diagnosis. Recently an App named 'Injured Tooth' was made available to diagnose traumatic injuries to the teeth and supporting structures. AIM: To test the diagnostic ability of the Injured Tooth App compared with the conventional method of diagnosing traumatic injuries to the teeth. DESIGN: A cross-sectional study was conducted at three different centres with 176 patients aged 0-15 years, having 201 injured teeth. Diagnosis of the injured teeth in these children at every centre was done independently by one experienced faculty using the traditional method and by a student using the Injured Tooth App. RESULTS: Injured Tooth App gave a correct diagnosis for 197 teeth included in the study. Statistical analysis showed that there was good agreement (Kappa = 0.973) between the diagnosis given by the App and the experienced faculty. CONCLUSIONS: The study found that the diagnosis given by the Injured Tooth App was in good agreement with the diagnosis given by an experienced faculty. Hence, the App can be successfully used by dental students to arrive at diagnosis. PMID- 29992695 TI - Differences in patterns of cannabis use among youth: Prevalence, perceptions of harm and driving under the influence in the USA where non-medical cannabis markets have been established, proposed and prohibited. AB - INTRODUCTION AND AIMS: Cannabis use is the most widely used illicit substance in the USA. Currently, over half of US jurisdictions have legalised medical cannabis and nine US jurisdictions (and Washington DC) have legalised non-medical cannabis. Comparisons across jurisdictions can help to evaluate the impact of these policies. The current study examined patterns of cannabis use among youth in three categories: (i) states that have legalised non-medical cannabis with established markets; (ii) jurisdictions that recently legalised non-medical cannabis without established markets; and (iii) all other jurisdictions where non medical cannabis is prohibited. DESIGN AND METHODS: Data come from an online survey conducted among 4097 US youth aged 16-19 recruited through a commercial panel in July/August 2017. Regression models were fitted to examine differences between regulatory categories for cannabis consumption, perceived access to cannabis, modes of use, perceptions of harm and cannabis-impaired driving. All estimates represent weighted data. RESULTS: States that had legalised non-medical cannabis had higher prevalence, easier access and lower driving rates than non legal states. There were few differences between states with established non medical cannabis markets and those that had recently legalised. DISCUSSION AND CONCLUSIONS: Cannabis use among youth was higher in states that have legalised non-medical cannabis, regardless of how long the policy had been implemented or whether markets had been established. This suggests that differences between states with and without legal non-medical cannabis may partly be due to longer term patterns established prior and highlights the importance of longitudinal evidence to evaluate the impact of cannabis policies. PMID- 29992697 TI - Combining aggregated and dispersed tree retention harvesting for conservation of vascular plant communities. AB - Retention harvesting (also called tree retention or structural retention), in which live mature trees are selectively retained within harvested stands at different retention levels and in different patterns (aggregated to dispersed), is increasingly being used to mitigate the negative impacts of forest harvesting on biodiversity. However, the effectiveness of combining different patterns of retention harvesting for conservation and recovery of understory vascular plants in the long term is largely unknown. To address this gap, we compared understory vascular plant diversity, abundance, and composition between aggregated retention and five levels of surrounding dispersed retention (0% [clearcut], 10%, 20%, 50%, 75%) 15 yr postharvest. We also investigated the influence of dispersed retention on the ability of embedded retention patches to support plant communities characteristic of unharvested forests, and whether it varies by patch size of aggregated retention (0.20 ha or 0.46 ha) and position within patches (edge or interior). Species richness, diversity, and cover were higher in the dispersed retention than in the patch retention as the harvested areas favored early-seral plant species. Graminoid cover was greater at the edges than in the interior of large patches. Retention patches as small as 0.2 ha more effectively supported shade-tolerant (forest interior) plant communities when they were surrounded by higher levels of dispersed retention (as compared to patches retained within clearcuts). Overall, the combined use of both aggregated and dispersed retention within a given cutblock benefits both late- and early-seral plant species and thus could effectively conserve understory plant assemblages in harvested landscapes. Sustainable forest management should therefore consider using a range of retention patch sizes combined with varying levels of surrounding dispersed retention in harvest designs to achieve objectives for plant conservation. PMID- 29992698 TI - Reestablishing a host-affiliate relationship: migratory fish reintroduction increases native mussel recruitment. AB - Co-extirpation among host-affiliate species is thought to be a leading cause of biodiversity loss worldwide. Freshwater mussels (Unionida) are at risk globally and face many threats to survival, including limited access to viable host fish required to complete their life history. We examine the relationship between the common eastern elliptio mussel (Elliptio complanata) and its migratory host fish the American eel (Anguilla rostrata), whose distribution in the Chesapeake Bay watershed is limited, in part, by dams. We examined population demographics of E. complanata across locations in the Chesapeake Bay watershed, primarily in the Susquehanna River in the absence of American eels, and conducted experimental restocking of eels to assess potential impacts on mussel recruitment. Compared to surveys completed ~20 yr prior, E. complanata could be experiencing declines at several historically abundant sites. These sites also had extremely limited evidence of recruitment. Restoration of host fish improved recruitment, but results were not equivalent between stocking sites, indicating that host reintroduction alone may not be fully effective in reestablishing mussel populations. One site where eels were introduced (Pine Creek, Tioga County, Pennsylvania, USA) experienced an increase from 0 juveniles found during quantitative surveys prior to eel stocking to 151 (21% of individuals collected during quantitative surveys) E. complanata juveniles found four years after stocking. A second site (Buffalo Creek, Union County, Pennsylvania) experienced a more moderate increase from 2 to 7 juveniles found during 2010 and 2014 quantitative surveys, respectively. Continued examination of other potential interacting factors affecting recruitment, including water quality or habitat conditions, is necessary to target favorable sites for successful restoration. PMID- 29992699 TI - Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: A systematic review. AB - BACKGROUND: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. METHODS: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. RESULTS: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1 , PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n = 1629), and 3 ADRB2 rs1800888 (n = 1892). The association of ADRB2 rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. CONCLUSIONS: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed. PMID- 29992700 TI - Targeted and Sustained Corelease of Chemotherapeutics and Gene by Injectable Supramolecular Hydrogel for Drug-Resistant Cancer Therapy. AB - Coadministration of chemotherapeutics as well as therapeutic gene could play a synergistic effect on cancer treatment. It is noteworthy that targeted and sustained codelivery of chemotherapeutic and therapeutic gene was rarely achieved in previous reports, while it might serve as an important platform for treating solid tumor with possible surrounding lesions. Herein, an injectable supramolecular hydrogel formed by alpha-cyclodextrin (alpha-CD) and cationic amphiphilic copolymer made of methoxy-poly(ethylene glycol)-b-poly(epsilon caprolactone)-b-poly(ethylene imine) with folic acid targeted group (MPEG-PCL-PEI FA), is rationally designed to achieve sustained codelivery of chemotherapeutic paclitaxel (PTX) and B-cell lymphoma-2 (Bcl-2) conversion gene Nur77 in the form of nanocomplex up to 7 days, to effectively inhibit the growth of folate receptor overexpressing H460/Bcl-2 therapeutic-resistant tumors (induced by overexpression of anti-apoptotic Bcl-2 protein), with peritumoral injection rather than direct intratumoral injection of hydrogel. To the best of our knowledge, this is a pioneer report on injectable MPEG-PCL-PEI-FA/alpha-CD supramolecular hydrogel with the ability to codeliver and sustainedly release PTX and Nur77 gene to combat Bcl-2 overexpressed therapeutic-resistant tumors in a targeted manner, which might be beneficial for further design in personalized medicine. PMID- 29992701 TI - Outcomes of cinacalcet withdrawal in Australian dialysis patients. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) in chronic kidney disease is associated with cardiovascular and bone pathology. Measures to achieve parathyroid hormone (PTH) target values and control biochemical abnormalities associated with SHPT require complex therapies, and severe SHPT often requires parathyroidectomy or the calcimimetic cinacalcet. In Australia, cinacalcet was publicly funded for dialysis patients from 2009 to 2015 when funding was withdrawn following publication of the EVOLVE study, which resulted in most patients on cinacalcet ceasing therapy. We examined the clinical and biochemical outcomes associated with this change at Australian renal centres. METHODS: We conducted a retrospective study of dialysis patients who ceased cinacalcet after August 2015 in 11 Australian units. Clinical outcomes and changes in biochemical parameters were assessed over a 24- and 12-month period respectively from cessation of cinacalcet. RESULTS: 228 patients were included (17.7% of all dialysis patients from the units). Patients were aged 63+/-15 years with 182 patients on haemodialysis and 46 on peritoneal dialysis. Over 24 months following cessation of cinacalcet, we observed 26 parathyroidectomies, 3 episodes of calciphylaxis, 8 fractures and 50 deaths. Seven patients recommenced cinacalcet, meeting criteria under a special access scheme. Biochemical changes from baseline to 12 months after cessation included increased levels of serum PTH from 54 (IQR 27-90) pmol/L to 85 (IQR 41-139) pmol/L (p<0.0001), serum calcium from 2.3+/ 0.2mmol/L to 2.5+/-0.1mmol/L (p<0.0001) and alkaline phosphatase (ALP) from 123 (92-176) IU/L to 143 (102-197) IU/L (p<0.0001). CONCLUSION: Significant increases in serum PTH, calcium and ALP occurred over a 12-month period following withdrawal of cinacalcet. Longer term follow-up will determine if these biochemical and therapeutic changes are associated with altered rates of parathyroidectomies and cardiovascular mortality and morbidity. This article is protected by copyright. All rights reserved. PMID- 29992702 TI - The red bayberry genome and genetic basis of sex determination. AB - Morella rubra, red bayberry, is an economically important fruit tree in south China. Here, we assembled the first high-quality genome for both a female and a male individual of red bayberry. The genome size was 313-Mb, and 90% sequences were assembled into eight pseudo chromosome molecules, with 32 493 predicted genes. By whole-genome comparison between the female and male and association analysis with sequences of bulked and individual DNA samples from female and male, a 59-Kb region determining female was identified and located on distal end of pseudochromosome 8, which contains abundant transposable element and seven putative genes, four of them are related to sex floral development. This 59-Kb female-specific region was likely to be derived from duplication and rearrangement of paralogous genes and retained non-recombinant in the female specific region. Sex-specific molecular markers developed from candidate genes co segregated with sex in a genetically diverse female and male germplasm. We propose sex determination follow the ZW model of female heterogamety. The genome sequence of red bayberry provides a valuable resource for plant sex chromosome evolution and also provides important insights for molecular biology, genetics and modern breeding in Myricaceae family. PMID- 29992703 TI - Transcatheter stenting of superior vena cava obstruction after pediatric heart transplantation: A single-center experience assessing risk factors and outcomes. AB - Transcatheter stent implantation for SVC obstruction following OHT has been well described, particularly in pediatric patients. This study describes a large single-center pediatric heart transplant experience that investigates the risk factors for SVC stenosis requiring stent implantation and its associated outcomes. All pediatric OHTs between January 1, 2000, and December 12, 2016, were examined for risk factors. Twelve of 349 (3.4%) OHTs required SVC stent implantation. Patients who required stents were younger (2.5 years vs 10.0 years, P = 0.0097), weighed less (8.6 kg vs 26.0 kg, P = 0.0024), and were more likely to have had CHD (83% vs 32%, P = 0.001) or previous SCPA (58% vs 18%, P = 0.002). Bicaval anastomosis was not associated with subsequent SVC stent implantation. Symptoms included SVC syndrome and chylous effusions. All 12 patients had evidence of significant SVC obstruction by both echocardiographic Doppler interrogation and transcatheter angiography. There were no acute procedural complications; however, reinterventions were common (four of 12 patients) and occurred at a mean of 5.7 +/- 3.6 months poststent implantation. In conclusion, transcatheter SVC stent implantation is safe and effective after OHT. There were significant associations between SVC stent implantation and younger age, smaller weight, CHD, and history of SCPA, but not with bicaval anastomosis or donor recipient weight ratio. PMID- 29992705 TI - Regiodivergent Copper Catalyzed Borocyanation of 1,3-Dienes. AB - Copper catalyzed multi-functionalization of unsaturated carbon-carbon bonds is a powerful tool for the generation of complex molecules. We report a regiodivergent process that allows a switch between 1,4-borocupration and 4,1-borocupration of 1,3-dienes upon a simple change in ligand. The subsequently generated allyl coppers are trapped in an electrophilic cyanation to selectively generate densely functionalized and synthetically versatile 1,2- or 4,3-borocyanation products. PMID- 29992704 TI - Plasma proteomic signature of age in healthy humans. AB - To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22-93 years old, who were disease- and treatment-free and had no physical and cognitive impairment. Using a p <= 3.83 * 10-5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 +/- 0.001, p = 7.49 * 10-56 ). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age-associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort. PMID- 29992707 TI - Metagenomic evaluation of the effects of storage conditions on the bacterial microbiota of oysters Crassostrea gasar (Adanson, 1757). AB - AIMS: To evaluate the influence of storage conditions on the composition of the bacterial microbiota of living oysters Crassostrea gasar. METHODS AND RESULTS: The oysters used in this study came from marine farms (Guaratuba Bay, Brazil) and were exposed to two conditions that simulated different storage situations: immersion in water (group I) and exposure to air (group II). The animals were subjected to five different temperatures (5-25 degrees C), for 10 days. The 16S rRNA gene from oysters was amplified and sequenced to determine the taxonomic units and bacterial strains present in the samples. Group I showed higher diversity of bacteria (163 genera) rather than group II (104 genera). In all, 59 bacterial genera potentially pathogenic to humans were identified (n = 56 in group I and n = 45 in group II). CONCLUSIONS: The storage conditions having a direct influence on the oyster microbiota. Live C. gasar should be stored exposed to air at 5-25 degrees C, because it favours a lower prevalence of bacteria potentially pathogenic to humans. SIGNIFICANCE AND IMPACT OF THE STUDY: During the oyster commercialization process, some conditions of storage, time and temperature must be followed in order to reduce the prevalence of bacteria potentially pathogenic to humans. PMID- 29992709 TI - Birth Control Implant. PMID- 29992708 TI - The impact of donor/recipient age difference and HLA mismatch on graft outcome in pediatric kidney transplantation. AB - BACKGROUND: Understanding the relationship between the factors that influence long-term kidney transplant survival remains a key priority for pediatric nephrologists. We assessed the relative impact of donor/recipient age difference and HLA matching on long-term graft outcomes. METHODS: We conducted a retrospective cohort study of pediatric and adolescent recipients who received a primary kidney transplant in Australia and New Zealand between January 1, 1990, and December 31, 2015. The primary outcome was graft survival analyzed by Kaplan Meier method. RESULTS: During the 26-year period, 1134 primary (395 DD and 739 LD) kidney transplants were performed in recipients less than 20 years of age. The median follow-up time was 10.2 years. Overall, 405 patients (35.7%) lost their transplant with graft survival 93.8% at 1 year, 82.5% at 5 years, 65.8% at 10 years, and 49.9% at 15 years post-transplant. There was consistently higher graft loss of DD kidneys as compared to LD kidneys at each time point. Both increasing donor/recipient age difference (aHR 1.11 per 10 years; 95% CI, 1.02 1.20; P = 0.009) and increasing HLA mismatch (aHR 1.20 per mismatch; 95% CI, 1.10 1.30; P < 0.001) were associated with decreased graft survival. CONCLUSIONS: Donor/recipient age difference and HLA matching are important factors influencing long-term graft outcomes in pediatric kidney transplantation. HLA mismatch remains a strong predictor of graft loss. For patients without the option of a LD, we suggest that the degree of HLA mismatch should not be discounted as part of the decision-making process of organ allocation. PMID- 29992706 TI - The Chaotropic Effect as an Assembly Motif in Chemistry. AB - Following up on scattered reports on interactions of conventional chaotropic ions (for example, I- , SCN- , ClO4 - ) with macrocyclic host molecules, biomolecules, and hydrophobic neutral surfaces in aqueous solution, the chaotropic effect has recently emerged as a generic driving force for supramolecular assembly, orthogonal to the hydrophobic effect. The chaotropic effect becomes most effective for very large ions that extend beyond the classical Hofmeister scale and that can be referred to as superchaotropic ions (for example, borate clusters and polyoxometalates). In this Minireview, we present a continuous scale of water solute interactions that includes the solvation of kosmotropic, chaotropic, and hydrophobic solutes, as well as the creation of void space (cavitation). Recent examples for the association of chaotropic anions to hydrophobic synthetic and biological binding sites, lipid bilayers, and surfaces are discussed. PMID- 29992711 TI - Bacterascites: A study of clinical features, microbiological findings, and clinical significance. AB - BACKGROUND: Knowledge about bacterascites is limited and management guidelines are based on small patient series. The purpose of this study was to add further insight into the clinical characteristics, microbiological findings, and prognosis of patients diagnosed with bacterascites. METHODS: Retrospective analysis of patients with advanced chronic liver disease diagnosed with bacterascites and SBP between January 2003 and August 2016. RESULTS: In this study, 123 patients were included with 142 episodes of bacterascites. The median MELD score was 20 and clinical symptoms of infection were present in 78%. Empiric antibiotic treatment was initiated in 68%. In 26 untreated patients undergoing repeated paracentesis, 42% were diagnosed with either ongoing bacterascites or SBP. The presence of signs or symptoms of infection was not an independent predictor for mortality or spontaneous resolution of infection. The 1-month and 1 year mortality rates of the 123 patients studied, were 32% and 60%, respectively; these results were in line with data pertaining to the prognosis of SBP. CONCLUSIONS: Patients with bacterascites and SBP are highly comparable with respect to severity of liver disease and overall prognosis. If left untreated, bacterascites is likely to persist or to evolve to SBP in a significant proportion of patients. The results of this study support current guidelines regarding the treatment of ascitic fluid infection, but could not confirm the prognostic relevance of symptomatic disease at the time of diagnosis. We suggest that the threshold to initiate antibiotic treatment, in particular in cases with severely advanced liver disease, should be low. PMID- 29992710 TI - Mechanism of BRAF Activation through Biochemical Characterization of the Recombinant Full-Length Protein. AB - BRAF kinase plays an important role in mitogen-activated protein kinase (MAPK) signaling and harbors activating mutations in about half of melanomas and in a smaller percentage in many other cancers. Despite its importance, few in vitro studies have been performed to characterize the biochemical properties of full length BRAF. Herein, a strategy to generate an active, intact form of BRAF protein suitable for in vitro enzyme kinetics is described. It is shown that purified, intact BRAF protein autophosphorylates the kinase activation loop and this can be enhanced by binding the MEK protein substrate through an allosteric mechanism. These studies provide in vitro evidence that BRAF selectively binds to active RAS and that the BRAF/CRAF heterodimer is the most active form, relative to their respective homodimers. Full-length BRAF analysis with small-molecule BRAF inhibitors shows that two drugs, dabrafenib and vemurafenib, can modestly enhance kinase activity of BRAF at low concentration. Taken together, this characterization of intact BRAF contributes to a framework for understanding its role in cell signaling. PMID- 29992712 TI - Screening for child abuse using a checklist and physical examinations in the emergency department led to the detection of more cases. AB - AIM: We studied the accuracy of a screening checklist (SPUTOVAMO), complete physical examination (top-to-toe inspection, TTI) and their combination in detecting child abuse in the emergency department (ED). METHODS: Consecutive patients admitted to the ED of the Academic Medical Center in Amsterdam between January 2011 and 1 July 2013 were included. An Expert Panel assigned a consensus diagnosis to positive cases. For all other and missed cases, the Child Abuse Counselling and Reporting Centre diagnosis was used. RESULTS: We included 17 229 admissions of 12 198 patients. In 46%, SPUTOVAMO was performed, in 33% TTI; 421 children (4.3%) tested positive on either or both, with 68 positive consensus diagnoses. In eight children not reported to the Expert Panel, the Child Abuse Counselling and Reporting Center diagnosis was positive. Ten of 3519 (0.3%) children testing negative on both were child abuse cases; 0.88% of the study group had a final child abuse diagnosis. The estimated PPV was 0.46 for SPUTOVAMO, 0.44 for TTI and 0.43 for the combination. CONCLUSION: Combining screening tests significantly increased the number of test positives and led to more child abuse cases detected. Combined screening for child abuse in all children less than 18 years old presenting to an ED is recommended. PMID- 29992713 TI - Continuous positive airway pressure for obstructive sleep apnoea does not improve asthma control. AB - BACKGROUND AND OBJECTIVE: Unrecognized obstructive sleep apnoea syndrome (OSAS) may lead to poor asthma control despite optimal therapy. We assessed asthma control, airway responsiveness, daytime sleepiness and health status at baseline and 3 months after continuous positive airway pressure (CPAP) treatment among asthma patients with nocturnal symptoms and OSAS. METHODS: Patients with nocturnal asthma symptoms despite receiving at least moderate-dose inhaled corticosteroid and long-acting bronchodilators underwent a home sleep study using 'Embletta' portable diagnostic system. Patients with significant OSAS (apnoea hypopnoea index (AHI) >=10/h) were randomized to receive either CPAP or conservative treatment for 3 months. RESULTS: Among 145 patients recruited, 122 underwent sleep study with 41 (33.6%) having AHI >=10/h. Patients with significant OSAS had higher BMI (27.4 (5.1) vs 25.1 (4.5) kg/m2 , P = 0.016), bigger neck circumference (36.6 (3.1) vs 34.8 (3.6) cm, P = 0.006) and lower minimum SaO2 (80.7 (6.6) vs 87.2 (3.9) %, P < 0.001). Using intention-to-treat analysis among 37 patients with AHI >=10/h (CPAP group (n = 17) vs control group (n = 20)), there was no significant difference in Asthma Control Test score (CPAP 3.2 (2.7) vs control 2.4 (5.7), P = 0.568) but the CPAP group had a greater improvement in Epworth Sleepiness Scale (-3.0 (4.5) vs 0.5(3.8), P = 0.014), Asthma Quality of Life Questionnaire (0.6 (0.8) vs 0.02 (0.7), P = 0.022) and vitality domain in the SF-36 questionnaire (14.7 (16.8) vs 0.3 (16.2), P = 0.012) after 3 months. Data are presented as mean (SD) unless otherwise stated. CONCLUSION: A high prevalence of OSAS was found among patients with asthma and snoring. CPAP therapy for 3 months did not enhance asthma control but improved daytime sleepiness, quality of life and vitality. PMID- 29992714 TI - Outcome of treosulfan-based reduced-toxicity conditioning regimens for HSCT in high-risk patients with primary immune deficiencies. AB - INTRODUCTION: HSCT is the curative therapeutic option in PIDs. Due to the increase in survival rates, reduced-toxicity conditioning regimens with treosulfan have become another alternative. The purpose of this retrospective study was to analyze the outcome of treosulfan-based conditioning before HSCT for patients with PID. METHOD: A total of 15 patients that received a treosulfan based conditioning regimen for HSCT were recruited. Type of diagnosis, donor and stem cell source, pretransplant organ damage, infections, engraftment, chimerism, and transplant-related toxicities were analyzed. RESULTS: At a median follow-up time of 32 months, the overall survival was 86.7%. Following HSCT, 14 of 15 patients had engraftment, with 86.7% of the cohort having full-donor chimerism. The most common toxicity was seen on the skin (53.3%). Acute GVHD and chronic GVHD were documented in 53% and 20% of the study population, respectively. Although the cohort consisted of patients with pretransplant liver damage, SOS manifestations were documented in 20%. CONCLUSION: Treosulfan-based conditioning regimens before HSCT are associated with lower toxicity compared to myeloablative regimens, are safe, and have high engraftment rates with full-donor chimerism in patients having PID, regardless of the specified genetic diagnosis and donor type. PMID- 29992715 TI - Adverse effects on macrophage lipid transport and survival by high density lipoprotein from patients with coronary heart disease. AB - High density lipoprotein (HDL)-macrophage interactions have the potential to modulate macrophage function in a beneficial way to prevent the development of lipid-loaded foam cell formation in atherosclerosis. Although HDL is atheroprotective, it can become dysfunctional in chronic inflammatory conditions and increase cardiovascular risk. Here, we examined the effect of dysfunctional HDL from patients with coronary artery disease, on macrophage function in comparison to functional-HDL from controls. Exposure of macrophages to dysfunctional-HDL for 24 h resulted significant increase in cellular oxidative stress, cholesterol, and cytotoxicity. It also stimulated mitochondrial membrane depolarization, DNA damage, apoptosis, and cleavage of poly (ADP-ribose) polymerase, which are characteristics of proapoptotic pathways. In contrast, functional-HDL treatment maintained cholesterol homeostasis, essential membrane potential, DNA integrity, and cell survival. These results demonstrate that HDL from coronary artery disease (CAD) patient promotes proatherogenic effects that in turn trigger macrophage apoptosis, an important feature in atherogenesis and thereby providing new insight in our understanding of the atherogenic mechanisms. PMID- 29992716 TI - Thorium Oxo-Clusters as Building Blocks for Open Frameworks. AB - Fundamental understanding of tetravalent actinide chemistry is essential to optimize many steps of the nuclear fuel cycle, as well as to predict actinide speciation in the environment. Herein, we report synthesis and structure of three open inorganic frameworks composed of Th4+ -oligomers and sulfate anions. The compounds [Th10 O4 (OH)8 (SO4 )12 (H2 O)18 ]?28 H2 O (1), [Th9 O4 (OH)5 (SO4 )12 (H2 O)18 ]? 1 TMA?18 H2 O (2), and [Th8.5 O4 (OH)4 (SO4 )12 (H2 O)18 ]?2 TMA?n H2 O (3) were obtained by slow evaporation of aqueous Th4+ -SO42- solutions, with variable SO42- :Th4+ ratios (SO42- :Th4+ =1:1, 1.5:1 and 2:1 for 1, 2, and 3; TMA=tetramethylammonium). The structure of 1 features a neutral open framework architecture with two interpenetrating networks, built from Th6 O4 (OH)412+ hexamers and Th2 (OH)26+ dimers, linked by sulfate anions. The complex anionic framework of 2 is built from hexamers, dimers, and monomers, with charge balancing TMA cations. Compound 3 is very similar to 2, but it is constructed only from hexamers and monomers. Small angle X-ray scattering (SAXS) of the reaction solutions reveals pre-assembled hexamer building units in the presence of sulfate, and underlines the key role of the sulfate-oxoanion ligand on thorium polymerization processes. PMID- 29992717 TI - Narrow-band imaging pattern classification in oral cavity. AB - OBJECTIVE: Narrow-band imaging is widely used in the diagnostic work-up of oral lesions. Different oral subsites present three epithelial types (1, 2a and 2b), each with a different structure and function. The aim of this study was to analyse and describe the different vascular patterns seen on narrow-band imaging according to oral epithelial type and histology. MATERIALS AND METHODS: The narrow-band imaging photographs of healthy, dysplastic and neoplastic oral mucosa were retrospectively reviewed and divided according to epithelial type and histology. The different narrow-band imaging patterns were analysed, related to the clinical appearance of the specific area, accurately described and drawn by a professional designer. RESULTS: The photographs of 302 patients were considered. Six patterns were identified: Normal mucosa exhibited different appearance in each type of epithelium; dysplastic mucosa presented the same pattern in type 1 and 2a epithelia, which differed from that of type 2b epithelium; in cancer, mucosal appearance was identical irrespective of epithelial type, due to complete vascular destruction. CONCLUSIONS: The proposed classification could serve as a guide for clinicians approaching narrowband imaging, especially at early stages of the learning curve, to differentiate normal mucosa from malignant lesions and possibly reduce the number of unnecessary biopsies. PMID- 29992718 TI - "Put bluntly, they are targeted by the worst creeps society has to offer": Police and professionals' views and actions relating to domestic violence and women with intellectual disabilities. AB - BACKGROUND: Little is known about the attitudes and practices of key personnel towards the domestic violence experienced by women with intellectual disabilities. METHOD: An online survey was conducted of Police officers and health and social care professionals. A total of 717 Police and other professionals across a wide variety of UK sites responded. Research questions were focussed on direct experience, attitudes and responses. RESULTS: Approximately half of all respondents had direct experience of working with a woman with intellectual disabilities who had been through domestic violence. Professionals were more likely than the Police to see women with intellectual disabilities as being especially vulnerable. The majority of both professionals and Police believed women with intellectual disabilities were deliberately targeted by violent and abusive men. CONCLUSIONS: More training is needed for both the Police and health and social care professionals specifically in domestic violence as it affects women with intellectual disabilities. PMID- 29992719 TI - In vitro and in vivo trypanocidal activities of 8-methoxy-3-(4-nitrobenzoyl)-6 propyl-2H-cromen-2-one, a new synthetic coumarin of low cytotoxicity against mammalian cells. AB - Natural and synthetic coumarins have been described as prototypes of new drug candidates against Chagas' disease. During a typical screening with new compounds, we observed the potential of a new synthetic nitrobenzoylcoumarin (1) as trypanocidal against Trypanosoma cruzi epimastigotas. Then, we decided to prepare and evaluate a set of analogues from 1 to check the major structural requirements for trypanocidal activity. The structural variations were conducted in six different sites on the original compound and the best derivative (3) presented activity (IC50 28 +/- 3 MUM) similar to that of benznidazole (IC50 25 +/- 10 MUM). The enhancement of trypanocidal activity was conditioned to a change in the side chain at C6 (allyl to n-propyl group) and the preservation of coumarin nucleus and the nitrobenzoyl group at C3. Exposure of 3 to H9C2 cells showed low toxicity (CC50 > 200 MUM) and its activity on T. cruzi amastigotes (IC50 13 +/- 0.3 MUM) encouraged us to perform an evaluation of its potential when given orally to mice infected with trypomastigote forms. Derivative 3 was able to reduce parasitemia when compared to the group of untreated animals. Taken together, these results show the potential therapeutic application of the synthetic coumarins. PMID- 29992720 TI - Response to letter to the editor: Is revaccination required in children who received a full primary vaccination against hepatitis B in infancy?! A response letter from the authors of Changes and analysis of anti-HBs titres after primary immunization in 1-to 16-year-old Chinese children: A hospital-based study. PMID- 29992721 TI - Nonsurgical treatment of earlobe aging in Mowlavi stages I and II earlobe ptosis with Hyaluronic acid fillers. AB - BACKGROUND: Earlobe deflation caused by fat atrophy is normally treated with lipofilling, mostly in the context of facelift surgery. In this report, we aim at reporting on Hyaluronic Acid injections to treat earlobe deflation. MATERIALS AND METHODS: 16 Mowlavi Grade I and II patients were treated with HA injections, followed by molding to shape the lobule. RESULTS: Effective correction, lasting 14 months on average, is achieved. Five patients needed a touch-up procedure after 4-6 months to improve the result. CONCLUSIONS: Earlobe augmentation with HA is an ideal option for correction of earlobe atrophy in cases of Mowlavi Grades I and II ptosis. Long-lasting (about 14 months) correction is achieved with no downtime. PMID- 29992722 TI - Clinical Studies for the Sake of Negative Data: The Proof Is in the Pudding. PMID- 29992723 TI - Hydrogen peroxide modulates redox status, energy metabolism, and gene expression in a dose- and time-dependent manner in rat liver. AB - AIM: The aim of this study was to investigate the effect of three different hydrogen peroxide (H2 O2 ) levels on blood and liver oxidative status, energy metabolites, and gene expression in male albino rats at two time intervals (2 and 4 weeks). METHODS: A total of 32 rats were divided into four groups. The first group received tap water and served as control. The second group received low dose of hydrogen peroxide (H2 O2 ; 0.25%), The third group received medium dose of H2 O2 (0.5%) and the fourth group received high dose of H2 O2 (1%) in drinking water. RESULTS: Present data showed that medium and high dose increased oxidative stress markers, decreased cell energy, and decreased antioxidant enzyme gene expression (GPx and Nrf2) and its downstream in contrast low dose did not show significant effects. CONCLUSION: This study might indicate that hydrogen peroxide medium level is the best dose for redox model status. PMID- 29992724 TI - Surface Immobilization of Redox-Labile Fluorescent Probes: Enabling Single-Cell Co-Profiling of Aerobic Glycolysis and Oncogenic Protein Signaling Activities. AB - An analytical method is described for profiling lactate production in single cells via the use of coupled enzyme reactions on surface-grafted resazurin molecules. The immobilization of the redox-labile probes was achieved through chemical modifications on resazurin, followed by bio-orthogonal click reactions. The lactate detection was demonstrated to be sensitive and specific. The method was incorporated into a single-cell barcode chip for simultaneous quantification of aerobic glycolysis activities and oncogenic signaling phosphoproteins in cancer. The interplay between glycolysis and oncogenic signaling activities was interrogated on a glioblastoma cell line. Results revealed a drug-induced oncogenic signaling reliance accompanying shifted metabolic paradigms. A drug combination that exploits this induced reliance exhibited synergistic effects in growth inhibition. PMID- 29992726 TI - Handheld multi-modal imaging for point-of-care skin diagnosis based on akinetic integrated optics optical coherence tomography. AB - A handheld skin imaging system with joint optical coherence tomography (OCT) at 1300 nm and digital epiluminescence microscopy (EM) is presented. The 2 modalities are physically co-registered in a common-path configuration. The instrument is enabled by a dedicated planar lightwave circuit with a footprint of only 1.1 * 19.5 mm2 that provides akinetic axial OCT scanning at speeds up to 24 kHz. Lateral scanning is implemented through a low-voltage Micro Electro Mechanical System (MEMS) mirror packaged with the axial scanner in a hermetic butterfly module. The OCT system, with a volume of only 80 * 27 * 14 mm3 , achieves an isotropic resolution of ~11 MUm in tissue, -93 dB sensitivity, 12 mm lateral field of view, and an axial scanning range of 2.8 mm in air. The complete battery-powered device has a weight of 3 kg in a tablet format, enabling point-of care use cases. This work shows that integration of complementary imaging modalities through miniaturization technology results in clinically valuable instruments supporting a patient-centered diagnostic imaging workflow. PMID- 29992727 TI - The American College of Cardiology/American Heart Association 2017 hypertension guideline: Implications for incorporation in Latin America, the Caribbean, and other resource-limited settings. PMID- 29992725 TI - The emerging roles of protein homeostasis-governing pathways in Alzheimer's disease. AB - Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin-proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid-beta (Abeta) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD-like phenotypes. While both Abeta plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease. PMID- 29992728 TI - First report of foregut microbial community in proboscis monkeys: are diverse forests a reservoir for diverse microbiomes? AB - Foregut fermentation is well known to occur in a wide range of mammalian species and in a single bird species. Yet, the foregut microbial community of free ranging, foregut-fermenting monkeys, that is, colobines, has not been investigated so far. We analysed the foregut microbiomes in four free-ranging proboscis monkeys (Nasalis larvatus) from two different tropical habitats with varying plant diversity (mangrove and riverine forests), in an individual from a semi-free-ranging setting with supplemental feeding, and in an individual from captivity, using high-throughput sequencing based on 16S ribosomal RNA genes. We found a decrease in foregut microbial diversity from a diverse natural habitat (riverine forest) to a low diverse natural habitat (mangrove forest), to human related environments. Of a total of 2700 bacterial operational taxonomic units (OTUs) detected in all environments, only 153 OTUs were shared across all individuals, suggesting that they were not influenced by diet or habitat. These OTUs were dominated by Firmicutes and Proteobacteria. The relative abundance of the habitat-specific microbial communities showed a wide range of differences among living environments, although such bacterial communities appeared to be dominated by Firmicutes and Bacteroidetes, suggesting that those phyla are key to understanding the adaptive strategy in proboscis monkeys living in different habitats. PMID- 29992729 TI - A systematic review of local excision followed by adjuvant therapy in early rectal cancer: are pT1 tumours the limit? AB - AIM: Total mesorectal excision remains the cornerstone of treatment for rectal cancer. Significant morbidity means local excision may be more appropriate in selected patients. Adjuvant therapy reduces local recurrence and improves survival; however, there is a paucity of data on its impact following local excision, which this systematic review aims to address. METHODS: A systematic search of the MEDLINE, Embase and Cochrane databases using validated terms for rectal cancer, adjuvant therapy and local excision was performed. Included studies focused on local excision with adjuvant therapy for adenocarcinoma of the rectum. Primary outcome measures were local recurrence, survival and morbidity. Studies providing neoadjuvant therapy or local excision alone were excluded. RESULTS: Twenty-two studies described 804 patients. Indications for local excision included favourable histology, patient choice and comorbidities. T1, T2 and T3 tumours accounted for 35.1%, 58.0% and 6.9% of cases, respectively. The most frequent local excision technique was transanal excision (77.7%). Adjuvant therapy included long-course chemoradiation or radiotherapy. Median follow-up was 51 months (range 1-165). The pooled local recurrence was 5.8% (95% CI 3.0-9.5) for pT1, 13.8% (95% CI 10.1-17.9) for pT2 and 33.7% (95% CI 19.2-50.1) for pT3 tumours. The overall median disease-free survival was 88% (range 50%-100%) with a pooled overall morbidity of 15.1% (95% CI 11.0-18.7). CONCLUSIONS: This area remains highly relevant to modern clinical practice. The data suggest that local excision followed by adjuvant therapy can achieve acceptable long-term outcomes in high-risk pT1 tumours, but not in T2 tumours and above in whom radical surgery should be offered. PMID- 29992730 TI - Unveiling the Photophysical Properties of Boron Heptaaryldipyrromethene Derivatives. AB - Increased interest has been devoted to the discovery of multifunctional materials with desirable properties, as continuous performance enhancement of various devices mainly depends on high-performance materials. Now, density functional theory has become a powerful tool to design new materials and rationalize experimental observations. In this work, we explored the photophysical properties origin of chiral boron heptaaryldipyrromethene (heptaaryl-BODIPY), which has charming optoelectronic properties. At the same time, we designed the other five compounds on the basis of heptaaryl-BODIPY. The simulated electronic absorption and emission spectra of heptaaryl-BODIPY are in agreement with experimental ones, allowing us to reliably assign its electronic transition property. The designed compound 6 shows remarkably large first hyperpolarizability value up to 82.78*10 30 esu. For this kind of compounds, their NLO response values associate with not only position but also electronic nature of substituent groups. Moreover, electron reorganization energies of compounds 1-4 are comparable to tris(8 hydroxyquinolinato)aluminium(III) which is a typical electron transport material. Intriguingly, the studied compounds are the excellent fluorescent probe materials from the standpoint of large Stokes shift and high emission efficiency. Our work enables an opportunity for understanding the relationship between microelectronic structure and macroscopic performance of BODIPY derivatives. PMID- 29992731 TI - Vaginal prevalence of human papillomavirus infections in women with uterovaginal aplasia before and after laparoscopically assisted creation of a neovagina: a prospective epidemiological observational study. AB - OBJECTIVE: To study vaginal as opposed to cervical human papillomavirus (HPV) acquisition with regard to true prevalence, HPV types, and the role of co-factors in virgins and after their sexual debut. DESIGN: Prospective epidemiological observational study. SETTING: University hospital specialised in genital malformations. POPULATION: Women diagnosed with Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) and undergoing neovaginoplasty between November 2011 and July 2017. METHODS: This is a prospective study including 186 women with MRKHS before and after sexual debut. MAIN OUTCOME MEASURES: Conventional vaginal cytology and different HPV tests were performed at surgery and during routine gynaecological follow-up 1, 3, 6 and >= 11 months after surgery and risk factors were documented. RESULTS: The mean age of all women at surgery was 20.1 years (SD 5.4), mean body mass index (BMI) was 22.1 kg/m2 (SD 4.6). In 83 vaginal samples from 41 different women at least one of the HPV tests was positive. Thirty-three different HPV types were detected. The prevalence of 41/186 = 22.0% as well as type distribution are comparable with those found in a young German female population. The overall rate of acquisition was clearly associated with sexual activity and smoking habits. Out of 367 Papanicolaou smears only six were abnormal with Pap IIID (MN II) and no obvious vaginal lesion was detected. CONCLUSIONS: Vaginal HPV prevalence and HPV types in previously virgin women after creation of a neovagina are not different from the acquisition of cervical infections in the general population and is clearly associated with sexual activity and with smoking habits. However, abnormal Papanicolaou smears are rarely seen. TWEETABLE ABSTRACT: Vaginal HPV prevalence after creation of a neovagina is similar to that on the cervix in the general population. PMID- 29992733 TI - Monitoring chemotherapy-induced alopecia with trichoscopy. AB - BACKGROUND: Chemotherapy-induced alopecia (CIA) ranks among the psychologically most devastating effects of cancer treatment for oncological patients, with an overall incidence of 65%. Nowadays trichoscopy is largely employed in the diagnosis of alopecia, but no description of CIA trichoscopic pattern is present in literature. AIMS: We want to create an organic description of CIA trichoscopic aspects. METHODS: Oncological patients candidate to chemotherapy drugs, afferent to our trichological outpatient were studied. Anamnesis, clinical exam, clinical global photography, pull test, trichogram, and trichoscopy were conducted at the different moments of therapeutic treatment. RESULTS: A definite trichoscopic pattern in the different phases of treatment was observed. After the first 3 weeks of chemotherapy rare and scattered black dots, broken hairs, flame hairs and pohl pinkus appeared. At the end of chemotherapy besides the features described above, numerous thin hair in regrowth were detected, together to rare terminal hair, scattered black dots and circle hair. Three months after chemotherapy a progressive increase of follicular units and elongation of the existing hair were visible. CONCLUSIONS: We propose an description of CIA trichoscopic pattern and its evolution during the different phases of chemotherapy. PMID- 29992732 TI - Exploratory analysis using machine learning to predict for chest wall pain in patients with stage I non-small-cell lung cancer treated with stereotactic body radiation therapy. AB - BACKGROUND AND PURPOSE: Chest wall toxicity is observed after stereotactic body radiation therapy (SBRT) for peripherally located lung tumors. We utilize machine learning algorithms to identify toxicity predictors to develop dose-volume constraints. MATERIALS AND METHODS: Twenty-five patient, tumor, and dosimetric features were recorded for 197 consecutive patients with Stage I NSCLC treated with SBRT, 11 of whom (5.6%) developed CTCAEv4 grade >=2 chest wall pain. Decision tree modeling was used to determine chest wall syndrome (CWS) thresholds for individual features. Significant features were determined using independent multivariate methods. These methods incorporate out-of-bag estimation using Random forests (RF) and bootstrapping (100 iterations) using decision trees. RESULTS: Univariate analysis identified rib dose to 1 cc < 4000 cGy (P = 0.01), chest wall dose to 30 cc < 1900 cGy (P = 0.035), rib Dmax < 5100 cGy (P = 0.05) and lung dose to 1000 cc < 70 cGy (P = 0.039) to be statistically significant thresholds for avoiding CWS. Subsequent multivariate analysis confirmed the importance of rib dose to 1 cc, chest wall dose to 30 cc, and rib Dmax. Using learning-curve experiments, the dataset proved to be self-consistent and provides a realistic model for CWS analysis. CONCLUSIONS: Using machine learning algorithms in this first of its kind study, we identify robust features and cutoffs predictive for the rare clinical event of CWS. Additional data in planned subsequent multicenter studies will help increase the accuracy of multivariate analysis. PMID- 29992734 TI - Tunable Low Loss 1D Surface Plasmons in InAs Nanowires. AB - Due to the ability to manipulate photons at nanoscale, plasmonics has become one of the most important branches in nanophotonics. The prerequisites for the technological application of plasmons include high confining ability (lambda0 /lambdap ), low damping, and easy tunability. However, plasmons in typical plasmonic materials, i.e., noble metals, cannot satisfy these three requirements simultaneously and cause a disconnection to modern electronics. Here, the indium arsenide (InAs) nanowire is identified as a material that satisfies all the three prerequisites, providing a natural analogy with modern electronics. The dispersion relation of InAs plasmons is determined using the nanoinfrared imaging technique, and show that their associated wavelengths and damping ratio can be tuned by altering the nanowire diameter and dielectric environment. The InAs plasmons possess advantages such as high confining ability, low loss, and ease of fabrication. The observation of InAs plasmons could enable novel plasmonic circuits for future subwavelength applications. PMID- 29992735 TI - International normalised ratio monitoring in the community populations of the Auckland and Northland regions of New Zealand: time in therapeutic range and frequency of testing. AB - BACKGROUND: Warfarin remains a commonly used anticoagulant for the treatment and prevention of thrombosis. To balance the risks and benefits of therapy, monitoring of the international normalised ratio (INR) is necessary. Patients derive most benefit from warfarin when they spend >=65% of time in the therapeutic range (INR 2-3). We performed an analysis of INR monitoring for the Auckland and Northland regions of New Zealand in order to estimate anticoagulation control and appropriateness of testing at the population level. METHODS: INR test results and patient demographics (age and sex) were extracted from the laboratory information system of Labtests and Northland Pathology Laboratories for the period of 1 January 2016 to 27 July 2016. RESULTS: We included 126 184 INR results from 10 922 patients. The median age of patients represented was 74 years and 57% were male. The overall mean time in therapeutic range was 63%, with a mean interval between INR tests of 14 days. CONCLUSION: Our results indicate that anticoagulant control in our communities could be improved, and that inappropriately frequent INR testing should be redressed. Appropriate interventions could lead to net clinical benefits and reduce resource misallocation. PMID- 29992736 TI - Mechanical Cooperativity in DNA Cruciform Structures. AB - Unlike short-range chemical bonds that maintain chemical properties of a biological molecule, long-range mechanical interactions determine mechanochemical properties of molecules. Limited by experimental approaches, however, direct quantification of such mechanical interactions is challenging. Using magneto optical tweezers, herein we found torque can change the topology and mechanochemical property of DNA cruciform, a naturally occurring structure consisting of two opposing hairpin arms. Both mechanical and thermodynamic stabilities of DNA cruciforms increase with positive torque, which have been attributed to the topological coupling between DNA template and the cruciform. The coupling exists simultaneously in both arms of a cruciform, which coordinates the folding and unfolding of the cruciform, leading to a mechanical cooperativity not observed previously. As DNA torque readily varies during transcriptions, our finding suggests that DNA cruciforms can modulate transcriptions by adjusting their properties according to the torque. PMID- 29992737 TI - Transanal endoscopic microsurgery as day surgery - a single-centre experience with 500 patients. AB - AIM: Transanal endoscopic microsurgery (TEM) is the current treatment of choice for rectal adenomas and early rectal cancer. Postoperative admission to hospital is common but possibly unnecessary. Our objective was to analyse predictors and outcomes of TEM patients having same day discharge (TEM-D) compared with those who were admitted to hospital (TEM-A). METHOD: At St Paul's Hospital (SPH), demographic, surgical, pathological and follow-up data have been collected prospectively since TEM was started in 2007. Trends in admission and readmission rates were analysed using the Cochran-Armitage trend test, and predictors of admission were analysed using univariate and multivariate logistic regressions. RESULTS: Between 2007 and 2016, 500 patients were treated by TEM at SPH. The overall admission rate was 29% (145/500), but this decreased to 19% in the last 3 years of the study (P < 0.001). The readmission rate was 5.2% (n = 26/500) and did not change significantly over the study period (P = 0.30). Reasons for admission included the following: surgeon discretion/monitoring (35%), urinary retention (26%), haemorrhage (10%), breach of peritoneal cavity (7%), infection (7%) and other (15%). The most common reasons for readmission were haemorrhage (54%, n = 14), pain (19%, n = 5) and infection (12%, n = 3). Factors associated with admission were as follows: tumour height (OR 1.09, 1.02-1.17), prolonged operative time (OR 1.25, 1.14-1.37), unsutured surgical defect (OR 1.99, 1.22 3.25) and surgeon experience (OR 4.62, 2.75-7.77). CONCLUSION: Outpatient TEM is safe and carries a low risk of readmission. In centres with an outpatient TEM strategy, predictors of hospital admission include proximal tumours, prolonged surgical time and open management of the surgical defect. PMID- 29992738 TI - Economic cost of lumpy skin disease outbreaks in three Balkan countries: Albania, Bulgaria and the Former Yugoslav Republic of Macedonia (2016-2017). AB - Lumpy skin disease (LSD) is an emerging viral disease that was detected for the first time in the Balkan Peninsula in Greece in 2015. In April 2016, there was a reoccurrence in Greece and the spread of the disease for the first time into Bulgaria, the Former Yugoslav Republic of Macedonia, Serbia, Kosovo, Albania and Montenegro. The veterinary services of the countries responded with different strategies to control the disease, mostly based on mass vaccination campaigns and diverse stamping out approaches. During 2017, the epidemic was mostly controlled except for outbreaks reported in Albania, Greece and the Former Yugoslav Republic of Macedonia. The study aims to quantify the cost of disease and control measures in three selected Balkan countries, that is, Albania, Bulgaria and the Former Yugoslav Republic of Macedonia, which were differently affected by the disease, had different animal production structures and implemented different control strategies. The total cost for the three countries was 20.9 million Euro (EUR 20.9 m), mostly incurred in 2016 (EUR 16.6 m), when the disease was spreading throughout the Balkan region. In 2017 (data until October), the cost was EUR 4.0 m, mainly due to vaccination costs. Bulgaria was the country with the highest total cost at EUR 8.6 m, followed by the Former Yugoslav Republic of Macedonia (EUR 6.7 m) and Albania (EUR 5.3 m). According to our data, the average cost per affected herd in 2016 was EUR 869, EUR 6,994 and EUR 3,071 in Albania, Bulgaria and the Former Yugoslav Republic of Macedonia, respectively. The cost per animal in the affected herds was EUR 539, 147 and 258, respectively. The results from this study are useful to understand the cost of LSD outbreaks in the region, which might contribute to improve the surveillance and control of the disease. PMID- 29992739 TI - Circulating monocytes accelerate acute liver failure by IL-6 secretion in monkey. AB - Acute liver failure (ALF) is associated with high mortality, and a poor understanding of the underlying pathophysiology has resulted in a lack of effective treatments so far. Here, using an amatoxin-induced rhesus monkey model of ALF, we panoramically revealed the cellular and molecular events that lead to the development of ALF. The challenged monkeys with toxins underwent a typical course of ALF including severe hepatic injury, systemic inflammation and eventual death. Adaptive immune was not noticeably disturbed throughout the progress of ALF. A systematic examination of serum factors and cytokines revealed that IL-6 increase was the most rapid and drastic. Interestingly, we found that IL-6 was mainly produced by circulating monocytes. Furthermore, ablation of monocyte derived IL-6 in mice decreased liver injury and systemic inflammation following chemical injection. Our findings reveal a critical role of circulating monocytes in initiating and accelerating ALF, indicating a potential therapeutic target in clinical treatment for ALF. PMID- 29992740 TI - A mutation of SCN1B associated with GEFS+ causes functional and maturation defects of the voltage-dependent sodium channel. AB - Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore-forming alpha-subunit, and one or more auxiliary beta subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the beta1 subunit, coded by the gene SCN1B, has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In human embryonic kidney 293 (HEK) cells, the heterologous coexpression of D25N-beta1 subunit with Nav1.2, Nav1.4, and Nav1.5 alpha subunits, representative of brain, skeletal muscle, and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves. The D25N mutation of the beta1 subunit causes a maturation (glycosylation) defect of the protein, leading to a reduced targeting to the plasma membrane. Also the beta1-dependent gating properties of the sodium channels are abolished by the mutation, suggesting that D25N is no more able to interact with the alpha subunit. Our work underscores the role played by the beta1 subunit, highlighting how a defective interaction between the sodium channel constituents could lead to a disabling pathological condition, and opens the possibility to design a mutation-specific GEFS+ treatment based on protein maturation. PMID- 29992741 TI - Reply to 'Comments on a new classification, treatment algorithm and prognosis estimating system for sigmoid volvulus: factors affecting recurrence'. PMID- 29992742 TI - Emergence of a novel highly pathogenic recombinant virus from three lineages of porcine reproductive and respiratory syndrome virus 2 in China 2017. AB - A novel porcine reproductive and respiratory syndrome virus 2 (PRRSV2) was isolated from diseased piglets in Shandong, China in 2017 and denominated as SD17 38. ORF5 sequencing showed that SD17-38 contains a unique serine/asparagine deletion at position 33 and an asparagine insertion at position 60 of GP5, which has never been described. The SD17-38 complete genome was then determined, and genome-based phylogenetic analysis showed that SD17-38 is clustered with NADC30 like isolates. Sequence alignment and recombination analyses by RDP4 and SimPlot all indicated that SD17-38 is a recombinant virus from NADC30 (lineage 1), BJ-4 (lineage 5) and TJ (lineage 8) isolates. Animal challenge study in 4-week piglets showed that SD17-38 causes high fever (>=41 degrees C), 100% morbidity and 40% mortality. In addition, significantly lower weight gain and severe histopathological lung lesions could be observed in SD17-38-infected pigs. In particular, the unique deletion and insertion in GP5 were stable during the challenge study. This study provides direct evidence for the natural occurrence of recombination events among three lineages of PRRSV2 in Chinese swine herds, resulting in the emergence of novel PRRSV variant with unique genetic property and high pathogenicity. PMID- 29992743 TI - VCAM-1 upregulation accompanies muscle remodeling following resistance-type exercise in Snell dwarf (Pit1dw/dw ) mice. AB - Snell dwarf mice (Pit1dw/dw ) exhibit deficiencies in growth hormone, prolactin, and thyroid stimulating hormone. Besides being an experimental model of hypopituitarism, these mice are long-lived (>40% lifespan extension) and utilized as a model of slowed/delayed aging. Whether this longevity is accompanied by a compromised quality of life in terms of muscular performance has not yet been characterized. In this study, we investigated nontrained and trained muscles 1 month following a general validated resistance-type exercise protocol in 3-month old Snell dwarf mice and control littermates. Nontrained Snell dwarf gastrocnemius muscles exhibited a 1.3-fold greater muscle mass to body weight ratio than control values although muscle quality, maximum isometric torque normalized to muscle mass, and fatigue recovery were compromised. For control mice, training increased isometric torque (17%) without altering muscle mass. For Snell dwarf mice, isometric torque was unaltered by training despite decreased muscle mass that rendered muscle mass to body weight ratio comparable to control values. Muscle quality and fatigue recovery improved twofold and threefold, respectively, for Snell dwarf mice. This accompanied a fourfold increase in levels of vascular cell adhesion molecule-1 (VCAM-1), a mediator of progenitor cell recruitment, and muscle remodeling in the form of increased number of central nuclei, additional muscle fibers per unit area, and altered fiber type distribution. These results reveal a trade-off between muscle quality and longevity in the context of anterior pituitary hormone deficiency and that resistance-type training can diminish this trade-off by improving muscle quality concomitant with VCAM-1 upregulation and muscle remodeling. PMID- 29992744 TI - Sleep disordered breathing and ventilatory support in children with Down syndrome. AB - STUDY OBJECTIVES: Obstructive sleep apnoea (OSAS) in children with Down syndrome (DS) is now well recognized, but other forms of sleep disordered breathing (SDB) in this population are less well described. Anecdotally, respiratory support for SDB treatment in this population is not easily tolerated. We aimed to characterize the types of SDB in children with DS referred to a tertiary respiratory center and to assess the effectiveness and adherence to respiratory support. METHODS: Retrospective study of DS patients <18 years old under follow up at a tertiary respiratory center. Anthropometrics, comorbidities, sleep study results, and details of respiratory support were collected. Satisfactory adherence to oxygen (O2 ), Continuous Positive Airway Pressure (CPAP), or bilevel noninvasive ventilation (NIV) was defined as use >4 h/night for >50% nights. RESULTS: Sixty patients were included, median age 1.5 (0.7-5.3) years; 49 (82%) had congenital heart disease, 16 (27%) pulmonary hypertension, 28 (47%) gastroesophageal reflux, 38 (63%) swallowing impairment; 16/17 who underwent CT scanning had evidence of aspiration. Forty-two had SDB: 27 (61%) OSAS (10 mild, 5 moderate, 12 severe), 11 (25%) central apnoeas, 19 (32%) nocturnal hypoventilation. Twenty-six had baseline saturations <95%. Lower SpO2 correlated with pulmonary hypertension (r2 = 0.1, P = 0.04). Thirty-nine (65%) patients started respiratory support (14 O2 , 18 CPAP, 7 NIV) and 22 (56%) have regularly used it. After a 1.9 years follow up 11/24 had satisfactory adherence to CPAP/NIV (average use 8 h/night). CONCLUSIONS: Our results confirm the high prevalence of OSAS in children with DS. A significant number also have low baseline saturations, central apnoeas, and nocturnal hypoventilation. Contrary to popular belief, more than half of children with DS had satisfactory adherence to respiratory support. PMID- 29992745 TI - Donor sclera versus bovine pericardium as patch graft material in glaucoma implant surgery and the impact of a drainage suture. AB - PURPOSE: To compare the use of human donor sclera with bovine pericardium as patch graft material for a glaucoma drainage device (GDD), with respect to the incidence of tube exposure, and to study the role of a drainage suture. METHODS: All GDD surgeries between 2010 and 2014 performed at the VU Medical Center were examined in this comparative, retrospective cohort study. A total of 244 cases were included; 163 in the human donor sclera cohort and 81 in the bovine pericardium cohort with a median follow-up of 31 and 36 months, respectively. The primary outcome measure was occurrence of tube exposure. Survival analysis for tube exposure was carried out and Kaplan-Meier curves compared. Secondary outcomes were postoperative intraocular pressure (IOP), number of glaucoma medications and the effect of a drainage suture. RESULTS: In the bovine pericardium cohort, eleven (13.6%) eyes developed tube exposure compared to none in the human donor sclera cohort. Their Kaplan-Meier survival curves differed significantly from each other (chi2 = 21.1, p < 0.001, log-rank test). Mean IOP and number of glaucoma medications did not differ significantly between patch graft materials at three months of follow-up. The use of a drainage suture directly lowered IOP after surgery in both cohorts. Within the bovine pericardium cohort, eyes with a drainage suture experienced more tube exposure, although this difference was not statistically significant (p = 0.09). CONCLUSION: Human donor sclera leads to less tube exposure than bovine pericardium. A drainage suture directly lowers IOP after surgery. With bovine pericardium, but not with donor sclera, exposure tends to be enhanced by a drainage suture. PMID- 29992746 TI - Association between serum levels of insulin-like growth factor-1, bioavailable testosterone, and pathologic Gleason score. AB - BACKGROUND: We evaluated the association between serum levels of insulin-like growth factor-1 (IGF-1), bioavailable testosterone, and surgical Gleason score (GS). METHODS: We analyzed 793 patients who underwent radical prostatectomy and 272 men with negative prostate biopsy. Serum levels of IGF-1 and testosterone were measured before surgery or biopsy. RESULTS: The mean IGF-1 levels of prostate cancer patients and men with a negative biopsy were 143.8 and 118.9 ng/mL, respectively (P < 0.001). Men with high serum IGF-1 were more likely to have prostate cancer (highest vs lowest quartile, odds ratio [OR] = 3.35; Ptrend < 0.001). However, among men with prostate cancer, the mean IGF-1 levels of those with low (GS <= 6), intermediate (GS = 7), and high surgical GS (GS >=8) were 151.7, 144.1, and 132.9 ng/mL, respectively (P < 0.001). Using quartile analysis, high serum IGF-1 levels were shown to be associated with a low risk of high surgical GS (OR = 0.464; Ptrend = 0.006). Serum bioavailable testosterone concentration was positively correlated with serum IGF-1 level (r = 0.157, P < 0.001). High bioavailable testosterone level was also associated with a low risk of high surgical GS in patients without diabetes mellitus (OR = 0.569; Ptrend = 0.040). Among men with biopsy GS <= 3 + 4 (n = 460), upgrading to high surgical GS was more frequent in patients with low IGF-1 level (<=116.0 ng/mL; 9.9%) or low bioavailable testosterone level (<=0.85 ng/mL; 9.3%) than in patients with normal IGF-1 and bioavailable testosterone levels (2.6%; P = 0.004). CONCLUSIONS: Serum levels of IGF-1 and bioavailable testosterone show inverse associations with high surgical GS. This suggests that high-grade prostate cancer develops independently of these two substances. PMID- 29992747 TI - Clarifying the Associations between Mindfulness Meditation and Emotion: Daily High- and Low-arousal Emotions and Emotional Variability. AB - BACKGROUND: Research examining the effects of mindfulness meditation (MM) on emotion seldom considers differences by arousal level or emotion variability. METHODS: In the present study, 115 participants (64% Female, 72% White, Mage = 19.03) were randomly assigned to a brief MM intervention condition (n = 60) or a wait-list control condition (n = 51). Participants in the MM condition were trained in MM and instructed to practice MM daily for one week. All participants provided daily diary reports of both higher- and lower-arousal positive (PE) and negative (NE) emotions. Emotions were weighted by valence and arousal. Multilevel modeling was used to examine valence, arousal, and their interaction; multivariate regression was used to examine emotional variability. RESULTS: More time spent meditating (but not the MM condition itself) was associated with increased lower arousal emotions, and exhibited a significant effect on the interaction between valence and arousal. Examination of individual emotion items suggested that more time meditating significantly predicted increased feelings of quiet and calm and marginally increased relaxation and sleepiness among participants, but did not predict any other emotions assessed in daily life. MM was not associated with emotional variability. CONCLUSION: These results may suggest that PE should be separated by arousal when examining the effects of MM interventions. PMID- 29992749 TI - Extent of intraluminal exfoliated malignant cells during surgery for colon cancer: Differences in cell abundance ratio between laparoscopic and open surgery. AB - INTRODUCTION: Laparoscopic colectomy with intracorporeal anastomosis is a minimally invasive surgical procedure for patients with colon cancer. However, there are often concerns about the presence of intraluminal exfoliated malignant cells in the intracorporeal anastomosis. This study investigated the relationship between colon cancer surgery and the incidence of intraluminal exfoliated malignant cells and several factors. METHODS: Eighty-nine consecutive patients who underwent either laparoscopic or open colectomy were prospectively studied in our department between 2007 and 2011. Before anastomosis, the proximal and distal lumens were irrigated with normal saline and subjected to cytological examination. RESULTS: In 27 patients (30.3%), exfoliated cancer cells were detected. On the distal side, the frequency of positive cytology findings of exfoliated malignant cells was significantly lower in the laparoscopic colectomy group than in the open colectomy group (P = 0.01). In the laparoscopic colectomy group, there were no cases of positive cytology findings for exfoliated malignant cells more than 100 mm from the primary tumor. The incidence of positive cytology more than 100 mm from the primary tumor was significantly lower than the incidence of positive cytology less than 100 mm from the primary tumor (P = 0.04). CONCLUSIONS: Exfoliated malignant cells were detected at anastomosis sites in patients with colon cancer. On the distal side, laparoscopic colectomy may prevent the development of exfoliated malignant cells. PMID- 29992750 TI - The radial forearm free flap for scalp and forehead reconstruction: A 20-year experience. PMID- 29992748 TI - Convective Dialysis Reduces Mortality Risk: Results From a Large Observational, Population-Based Analysis. AB - According to many studies, extracorporeal dialysis with convective methods is associated with better clinical outcomes and a survival benefit compared to diffusive techniques. However, there is no full agreement on the actual superiority of this kind of renal replacement therapy on hard end-points such as mortality. We performed a retrospective epidemiological cohort study to provide "real-world" evidence on the impact of convective and non-convective dialysis techniques on all-cause and cardiac mortality and biochemical outcomes among dialysis patients in Sicily, the southernmost region of Italy. Data of all incident adult patients (N = 6529) who have started chronic extracorporeal dialysis over the period 2009-2015 were retrieved from the Sicilian Registry of Nephrology, Dialysis and Transplantation. There were 1558 patients receiving convective techniques (23.86%). Overall mortality rate was 45.21% with a significant difference between convective (31.39%) and non-convective (49.55%) groups (P < 0.0001). After adjustment for potential confounders in multiple Cox regression models of increasing complexity, the mortality risk remained significantly lower for patients treated with convective methods (HR, 0.581; 95%CI, 0.525 to 0.643; P < 0.0001). Moreover, the convective group had a better blood chemistry profile, improved dialysis efficacy, and reduced mortality rate from cardiac diseases compared to the non-convective group. As a sensitivity analysis, patients were categorized according to propensity score quartiles and the hazard ratio for both all-cause and cardiac mortality was significantly lower for the convective group in each quartile. In conclusion, despite the observational and retrospective design, the results of the present study further support the use of convective therapies for the treatment of end-stage renal disease. PMID- 29992752 TI - Different rhinologic diseases cause a similar multidimensional decrease in generic health-related quality of life. AB - BACKGROUND: Previous studies illustrated that chronic rhinosinusitis and allergic rhinitis represent individual and socioeconomic burdens to a patient. However, few studies exist on the health-related quality of life (HRQoL) amongst other rhinologic patients. Our study investigated the generic HRQoL in different rhinologic diseases. METHODOLOGY: Unselected adult rhinologic patients requiring special care at the Helsinki University Hospital were enrolled in this cross sectional, questionnaire-based prospective study in February, May, August and November 2014. Patients were mailed a medical history questionnaire and a generic 15-dimension (15D) HRQoL questionnaire. Diagnostic data were collected from electronic patient records following outpatient visits. Patient HRQoL scores were compared to an age- and sex-standardised general population sample obtained from a large national health examination survey. RESULTS: This study consisted of 337 rhinologic patients (mean age 50.2 years, 50.4% men). The mean 15D score amongst rhinologic patients (0.865) was both statistically significant and clinically poorer than that amongst the general population (0.929). Rhinologic patients fared poorly on most dimensions of the 15D instrument, particularly on sleep, discomfort and symptoms, breathing and vitality. Patients with obstructive sleep apnoea (OSA) were particularly affected. Yet, comparing the five most common rhinologic diagnostic groups revealed no significant differences in the mean 15D scores. CONCLUSIONS: Rhinologic diseases, independent of the underlying cause, substantially and negatively affect patients' HRQoL. OSA decreases HRQoL in these patients, although patients without an OSA diagnosis still suffer from a clinically important impairment of HRQoL and poor quality sleep. PMID- 29992751 TI - Emerging findings into molecular mechanism of brain metastasis. AB - Brain metastasis is an important cause of morbidity and mortality in cancer patients. Hence, the need to develop improved therapies to prevent and treat metastasis to the brain is becoming urgent. Recent studies in this area are bringing about some advanced progress on brain metastasis. It was concluded that the occurrence and poor prognosis of brain metastasis have been mostly attributed to the exclusion of anticancer drugs from the brain by the blood-brain barrier. And several highly potent new generation targeted drugs with enhanced CNS distribution have been developed constantly. However, the noted "seed and soil" hypothesis also suggests that the outcome of metastasis depends on the relationship between unique tumor cells and the specific organ microenvironment. Moreover, increasing studies in multiple tumor types demonstrated that brain metastasis has great molecular differences between primary tumors and extracranial metastasis to a large extent. Here, the authors summarized the most common malignancies that could lead to brain metastasis-lung cancer, breast cancer and melanoma and their related mutated factors. Only by comprehending a deeper understanding of the molecular mechanisms, more effective brain-specific therapies will be developed for brain metastasis. PMID- 29992754 TI - The autonomic control of upright posture tachycardia in the arboreal lizard Iguana iguana. AB - In terrestrial environments, upright spatial orientation can dramatically influence animals' hemodynamics. Generally, large and elongated species are particularly sensitive to such influence due to the greater extent of their vascular beds being verticalized, favoring the establishment of blood columns in their bodies along with caudal blood pooling, and thus jeopardizing blood circulation through a cascade effect of reductions in venous return, cardiac filling, stroke volume, cardiac output, and arterial blood pressure. This hypotension triggers an orthostatic-(baroreflex)-tachycardia to normalize arterial pressure, and despite the extensive observation of this heart rate (fH ) adjustment in experiments on orthostasis, little is known about its mediation and importance in ectothermic vertebrates. In addition, most of the knowledge on this subject comes from studies on snakes. Thus, our objective was to expand the knowledge on this issue by investigating it in an arboreal lizard (Iguana iguana). To do so, we analyzed fH , cardiac autonomic tones, and fH variability in horizontalized and tilted iguanas (0 degrees , 30 degrees . and 60 degrees ) before and after muscarinic blockade with atropine and double autonomic blockade with atropine and propranolol. The results revealed that I. Iguana exhibits significant orthostatic-tachycardia only at 60o inclinations-a condition that is primarily elicited by a withdrawal of vagal drive. Also, as in humans, increases in low-frequency fH oscillations and decreases in high-frequency fH oscillations were observed along with orthostatic-tachycardia, suggesting that the mediation of this fH adjustment may be evolutionarily conserved in vertebrates. PMID- 29992753 TI - The involvement of Toll-like receptor 9 in the pathogenesis of erosive autoimmune arthritis. AB - Endogenous nucleic acids and their receptors may be involved in the initiation of systemic autoimmune diseases including rheumatoid arthritis (RA). As the role of the DNA sensing Toll-like receptor (TLR) 9 in RA is unclear, we aimed to investigate its involvement in the pathogenesis of autoimmune arthritis using three different experimental models of RA. The data obtained revealed involvement of TLR9 in the T cell-dependent phase of inflammatory arthritis. In rats with pristane-induced arthritis (PIA), TLR9 inhibition before disease onset reduced arthritis significantly and almost completely abolished bone erosion. Accordingly, serum levels of IL-6, alpha-1-acid-glycoprotein and rheumatoid factor were reduced. Moreover, in TLR9-/- mice, streptococcal cell wall (SCW) induced arthritis was reduced in the T cell-dependent phase, whereas T cell independent serum-transfer arthritis was not affected. Remarkably, while TLR7 expression did not change during in vitro osteoclastogenesis, TLR9 expression was higher in precursor cells than in mature osteoclasts and partial inhibition of osteoclastogenesis was achieved only by the TLR9 antagonist. These results demonstrate a pivotal role for TLR9 in the T cell-dependent phases of inflammatory arthritis and additionally suggest some role during osteoclastogenesis. Hence, endogenous DNA seems to be crucially involved in the pathophysiology of inflammatory autoimmune arthritis. PMID- 29992755 TI - Heat-shock transcription factor 1 is critically involved in the ischaemia-induced cardiac hypertrophy via JAK2/STAT3 pathway. AB - Cardiac hypertrophy after myocardial infarction (MI) is an independent risk factor for heart failure. Regression of cardiac hypertrophy has emerged as a promising strategy in the treatment of MI patients. Here, we have been suggested that heat-shock transcription factor 1 (HSF1) is a novel repressor of ischaemia induced cardiac hypertrophy. Ligation of left anterior descending coronary was used to produce MI in HSF1-deficient heterozygote (KO), HSF1 transgenic (TG) mice and their wild-type (WT) littermates, respectively. Neonatal rat cardiomyocytes (NRCMs) were treated by hypoxia to mimic MI in vitro. The HSF1 phosphorylation was significantly reduced in the infarct border zone of mouse left ventricles (LVs) 1 week after MI and in the hypoxia-treated NRCMs. HSF1 KO mice showed more significant maladaptive cardiac hypertrophy and deteriorated cardiac dysfunction 1 week after MI compared to WT MI mice. Deficiency of HSF1 by siRNA transfection notably increased the hypoxia-induced myocardial hypertrophy in NRCMs. Mechanistically, Janus kinase 2 (JAK2) and its effector, signal transducer and activator of transcription 3 (STAT3) were found to be significantly increased in the LV infarct border zone of WT mice after MI as well as the NRCMs treated by hypoxia. These alterations were more significant in HSF1 KO mice and NRCMs transfected with HSF1 SiRNA. Inversely, HSF1 TG mice showed significantly ameliorated cardiac hypertrophy and heart failure 1 week after LAD ligation compared to their WT littermates. Our data collectively demonstrated that HSF1 is critically involved in the pathological cardiac hypertrophy after MI via modulating JAK2/STAT3 signalling and may constitute a potential therapeutic target for MI patients. PMID- 29992756 TI - Fragmentation of the main triterpene acids of apple by LC-APCI-MSn. AB - In this paper, we investigated the fragmentation of the main triterpene acids of apple using an liquid chromatography atmospheric pressure chemical ionization mass spectrometry (LC-APCI-MSn ) approach and high-resolution mass spectrometry (HR-MS) (Q-TOF). Triterpenes were isolated using semipreparative high-performance liquid chromatography, and chemical structures were elucidated by HR-MS and nuclear magnetic resonance spectroscopy. Finally, compounds were used to study MSn behavior in ion trap. Isolated triterpenes present similar structures, bearing carboxyl group linked to C-17 and different substitutions. We observed significant changes in MS2 spectra, which were useful for further compound identification. The observed fragments allowed the discrimination of different derivatives, namely, pomaceic, annurcoic, euscaphic, pomolic, corosolic, maslinic, betulinic, oleanolic, and ursolic acids. The proposed method allows a rapid identification of triterpene acids, and it could be useful for the analysis of these compounds in apple fruits and in other natural sources. PMID- 29992757 TI - Club cell secretory protein (CC16) in gastric fluid at birth and subsequent lung disease in preterm infants. AB - BACKGROUND: Club cell secretory protein (CC16) probably has a role in protecting the lung from inflammation. AIM: To evaluate if low levels of CC16 in gastric fluid at birth, reflecting low levels of CC16 in the lung, would be associated with lung inflammation and respiratory morbidity. METHODS: A study of 64 infants with mean gestational age 26.1 weeks. CC16 was analyzed in gastric fluid at birth. CC16, pro-inflammatory cytokines, and MMP-9 were analyzed in tracheal aspirate within 24 h from birth. RESULTS: CC16 in gastric fluid increased with gestational age (P = 0.033). Lower concentrations of CC16 in gastric fluid at birth were associated with higher concentrations of IL-1beta (P = 0.028), TNF alpha (P = 0.034), and MMP-9 (P = 0.015) in tracheal aspirate. Infants who needed mechanical ventilation at 24 and 72 h of age had lower CC16 in gastric fluid than those not ventilated at these ages (P = 0.011 and P = 0.024, respectively). Lower CC16 in gastric fluid was associated with higher FiO2 at 6 h (P = 0.009), higher PaCO2 at 24 h (P = 0.03), more ventilator days (P = 0.012) and more days with supplemental oxygen (P = 0.03). Infants who had either died or were still treated with supplemental oxygen at 36 weeks postmenstrual age had lower CC16 in gastric fluid than infants with none of these outcomes (P = 0.049). CONCLUSION: A low CC16 concentration in gastric fluid at birth was associated with increased inflammation in the trachea within the first 24 h of life and with more need for respiratory support in the neonatal period. PMID- 29992758 TI - The expression of MMP-1 and MMP-9 is up-regulated by smooth muscle cells after their cross-talk with macrophages in high glucose conditions. AB - Patients with diabetes mellitus have an increased risk of myocardial infarction and coronary artery disease-related death, exhibiting highly vulnerable plaques. Many studies have highlighted the major role of macrophages (MAC) and smooth muscle cells (SMC) and the essential part of metalloproteases (MMPs) in atherosclerotic plaque vulnerability. We hypothesize that in diabetes, the interplay between MAC and SMC in high glucose conditions may modify the expression of MMPs involved in plaque vulnerability. The SMC-MAC cross-talk was achieved using trans-well chambers, where human SMC were grown at the bottom and human MAC in the upper chamber in normal (NG) or high (HG) glucose concentration. After cross-talk, the conditioned media and cells were isolated and investigated for the expression of MMPs, MCP-1 and signalling molecules. We found that upon cross-talk with MAC in HG, SMC exhibit: (i) augmented expression of MMP-1 and MMP 9; (ii) significant increase in the enzymatic activity of MMP-9; (iii) higher levels of soluble MCP-1 chemokine which is functionally active and involved in MMPs up-regulation; (iv) activated PKCalpha signalling pathway which, together with NF-kB are responsible for MMP-1 and MMP-9 up-regulation, and (v) impaired function of collagen assembly. Taken together, our data indicate that MCP-1 released by cell cross-talk in diabetic conditions binds to CCR2 and triggers MMP 1 and MMP-9 over-expression and activity, features that could explain the high vulnerability of atherosclerotic plaque found at diabetic patients. PMID- 29992759 TI - Kallistatin attenuates endothelial senescence by modulating Let-7g-mediated miR 34a-SIRT1-eNOS pathway. AB - Kallistatin, a plasma protein, protects against vascular and organ injury. This study is aimed to investigate the role and mechanism of kallistatin in endothelial senescence. Kallistatin inhibited H2 O2 -induced senescence in human endothelial cells, as indicated by reduced senescence-associated-beta galactosidase activity, p16INK4a and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked H2 O2 -induced superoxide formation, NADPH oxidase levels and VCAM-1, ICAM-1, IL-6 and miR-34a synthesis. Kallistatin reversed H2 O2 -mediated inhibition of endothelial nitric oxide synthase (eNOS), SIRT1, catalase and superoxide dismutase (SOD)-2 expression, and kallistatin alone stimulated the synthesis of these antioxidant enzymes. Moreover, kallistatin's anti-senescence and anti-oxidant effects were attributed to SIRT1-mediated eNOS pathway. Kallistatin, via interaction with tyrosine kinase, up-regulated Let-7g, whereas Let-7g inhibitor abolished kallistatin's effects on miR-34a and SIRT1/eNOS synthesis, leading to inhibition of senescence, oxidative stress and inflammation. Furthermore, lung endothelial cells isolated from endothelium-specific kallistatin knockout mice displayed marked reduction in mouse kallistatin levels. Kallistatin deficiency in mouse endothelial cells exacerbated senescence, oxidative stress and inflammation compared to wild-type mouse endothelial cells, and H2 O2 treatment further magnified these effects. Kallistatin deficiency caused marked reduction in Let 7g, SIRT1, eNOS, catalase and SOD-1 mRNA levels, and elevated miR-34a synthesis in mouse endothelial cells. These findings indicate that endogenous kallistatin through novel mechanisms protects against endothelial senescence by modulating Let-7g-mediated miR-34a-SIRT1-eNOS pathway. PMID- 29992760 TI - A Danish population-based cohort study of desmopressin use in adults with nocturia or nocturnal enuresis. AB - OBJECTIVE: This study investigated how desmopressin is prescribed to adults in Denmark. METHODS: All adult users of desmopressin over an 8-year period were identified from the Danish National Prescription Registry. Adult patients with nocturia or nocturnal enuresis (NE) were identified by indication codes for "frequent nocturnal voiding" or "involuntary nocturnal voiding", respectively. Patient demographics, desmopressin formulation and dose, and concomitant medication were investigated. RESULTS: In all, 13 871 adults with nocturia and 2872 adults with chronic (i.e. >10 prescriptions) NE were given 102 547 and 43 712 desmopressin prescriptions, respectively. Across the entire patient cohort, 57% were women and mean patient age was 62 years. Over 40% of prescriptions were to elderly patients (>=65 years), and desmopressin use for adult enuresis increased with age. Orally disintegrating tablets were the most frequently used formulation (57%-65% of prescriptions), and a greater proportion of women than men used low-dose desmopressin (60 MUg). Concomitant use of painkillers (opioids: 18%-26.7% of prescriptions; non-steroidal anti-inflammatory drugs: 14.2%-16.4% of prescriptions) and antidepressants (14.4%-18.1% of prescriptions) was common in both conditions, and 5.4%-9.2% of concomitant prescriptions were for overactive bladder medications. CONCLUSIONS: This study provides insights into desmopressin use among Danish adults. Nearly half the prescriptions were to patients aged >=65 years, despite historical manufacturer recommendations that desmopressin be restricted to patients <65 years of age. NE is considered a childhood condition, but desmopressin use for adult NE increased with age. A greater proportion of desmopressin prescriptions to women than men were for the lowest dose, consistent with greater sensitivity to desmopressin in women. PMID- 29992761 TI - Trends in inferior turbinate surgery: analysis of patients using the Medicare database. AB - BACKGROUND: The aim of this study was to characterize trends in turbinate reduction procedures from 2000 to 2015. METHODS: Annual procedure data were obtained for the period 2000-2015 and detailed Medicare provider and payment data were obtained for 2012-2015. Turbinate procedures analyzed included turbinate soft tissue mucosal ablation (TMA), turbinate soft tissue submucosal ablation (TSMA), turbinate excision (TE), and turbinate submucous resection (TSR). TMA and TSMA were grouped as turbinate soft tissue ablation (TA) for analysis. From 2012 to 2015, the type and location-facility (F) or nonfacility (NF)-of the providers performing the procedures were assessed. RESULTS: From 2000 to 2015, the total number of turbinate reduction procedures increased by an average of 3.8% annually. TSR had the highest annual increase at 5.4%. TE is the only procedure to show a decrease, by an average of -2.3% annually. From 2012 to 2015, the number of turbinate reduction procedures changed by -1.6% and 107.7% at F and NF locations, respectively. NF TSMA and TSR had the largest increases at 121.6% and 260.1%, respectively. Of the NF TA procedures, there was an average annual increase of 50% by non-otolaryngologists. For TA, the average F charge was 78.0% more than the NF charge, and the average NF otolaryngologist charge 11.5% more than the non-otolaryngologist charge. CONCLUSION: The number of turbinate reduction procedures increased steadily between 2000 and 2015, with the majority being TSRs. This is consistent with previous studies demonstrating that TSR leads to better outcomes. There has been a significant increase in turbinate reduction procedures performed in outpatient/ambulatory settings by otolaryngologists, non otolaryngologists, and midlevel providers. PMID- 29992762 TI - Increased survival of patients aged 0-29 years with osteosarcoma: A period analysis, 1984-2013. AB - PURPOSE: Osteosarcoma is the most common primary malignancy of bone, and typically occurs among children and adolescence. This study aims to evaluate treatment outcomes among children, adolescents and young adults with osteosarcoma over the three decades by the changes in the long-term relative survival. METHODS: Osteosarcoma incidence and relative survival data from Surveillance, Epidemiology, and End Results (SEER) registries during 1984-2013 were analyzed. The survival differences over three decades, age, sex, race, and socioeconomic status (SES) were assessed by comparing Kaplan-Meier curves. RESULTS: The overall incidence of osteosarcoma kept relatively stable with 0.4 per 100 000 in the three decades with the peak incidence occurring in the aged 10-19 group. The 10 year relative survival rate (RSR) increased from 57.7% to 61.0% in the three decades, with the greatest increase in the aged 0-9 group from 48.2% to 65.7%. The 10-year RSR improved from 54.1% to 61.5% in males, and from 62.4% to 63.0% in females, respectively, in the three decades. Furthermore, survival dramatically improved from 30% to 60% in the high-poverty group over the three decades. CONCLUSION: This study demonstrated that the overall incidence of osteosarcoma remained stable, with an improvement in survival in the three decades. The improved survival was greater in males than in females in the three decades. Furthermore, the survival significantly increased in high-poverty group, which was attributed to increasing improved health care system and patients with low finance can also have access to receiving effective and consistent treatment without distinction. PMID- 29992763 TI - Silk structure rather than tensile mechanics explains web performance in the moth specialized spider, Cyrtarachne. AB - Orb webs intercept and retain prey so spiders may subdue them. Orb webs are composed of sticky, compliant spirals of capture silk spun across strong, stiff major ampullate silk threads. Interplay between differences in the mechanical properties of these silks is crucial for prey capture. Most orb webs depend upon insects contacting several radial and capture threads for successful retention. Moths, however, escape quickly from most orb webs due to the sacrificial scales covering their bodies. Cyrtarachne orb webs are unusual as they contain a reduced number of capture threads and moths stick unusually well to single threads. We aimed to determine how the tensile properties of the capture spiral and radial threads spun by Cyrtarachne operate in retention of moth prey. A NanoBionix UTM was used to quantify the material properties of flagelliform and major ampullate threads to test if Cyrtarachne's reduced web architecture is accompanied by improvements in tensile performance of its silk. Silk threads showed tensile properties typical of less-specialized orb-weavers, with the exception of high extensibility in radial threads. Radial thread diameters were 62.5% smaller than flagelliform threads, where commonly the two are roughly similar. We utilized our tensile data to create a finite element model of Cyrtarachne's web to investigate energy dissipation during prey impact. Large cross-sectional area of the flagelliform threads played a key role in enabling single capture threads to withstand prey impact. Rather than extraordinary silk, Cyrtarachne utilizes structural changes in the size and attachment of silk threads to facilitate web function. PMID- 29992764 TI - Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin specific peptidase 9, X-linked in oral squamous cell carcinoma. AB - BACKGROUND: The immune checkpoint protein programmed cell death ligand 1 (PD-L1) binds to PD1 to promote tumor cell escape from the killing effect of the immune system. However, there are few studies on the regulatory mechanisms of PD-L1 in tumors. Although PD-L1 has been reported to undergo ubiquitination in some cancers, its regulatory mechanisms in oral squamous cell carcinoma (OSCC) are unclear. Therefore, we aimed to investigate this phenomenon. METHODS: We examined the expression and function of USP9X and PD-L1 in human oral keratinocytes (HOK) and OSCC cell lines (HN4 and HN30) as the control and relevant cancer cells using western blotting, immunoprecipitation, immunohistochemistry (IHC), T-cell mediated tumor cell killing assay, and liquid chromatography-mass spectrometry. RESULTS: Programmed cell death ligand 1 was highly expressed in OSCC by the regulation of the ubiquitin-proteasome pathway. Furthermore, we discovered that ubiquitin-specific peptidase 9, X-linked (USP9X) could be combined with PD-L1 to induce its deubiquitination and stabilize its protein expression in OSCC. CONCLUSION: Our data indicate that USP9X deubiquitinates and stabilizes PD-L1. Suppressing the expression of USP9X blocks tumor cell growth. The results provide a theoretical basis for USP9X as a therapeutic target. PMID- 29992765 TI - Community characteristics modify the relationship between obesity prevention efforts and dietary intake in children: the Healthy Communities Study. AB - BACKGROUND: The influence of community characteristics on the effectiveness of childhood obesity prevention efforts is not well understood. OBJECTIVE: Examine the interaction of community characteristics with the relationship between community programmes and policies (CPPs) and dietary intake. METHODS: An observational study of 5138 children in grades K-8 in 130 US communities was conducted in 2013-2015. Key informant interviews identified and characterized CPPs. CPP scores were generated for the number of target behaviours (CPP-Behav) and the number of behaviour change strategies (CPP-Strat) addressed by all CPPs and CPPs with nutrition goals over the prior 6 years in each community. Dietary intake was assessed by dietary screener and included intake of sugar from sugar sweetened beverages; energy-dense foods; fruits and vegetables; whole grains; and fibre. Multivariate statistical models assessed the interactions between US region, urbanicity, community-level income, and community-level race/ethnicity and CPP scores in relation to dietary intake. RESULTS: CPP-Strat was positively associated with healthier dietary intakes in the Northeast and West, and in high Hispanic communities; the reverse was true in the South, and in high African American and low-income communities. The CPP-Behav was positively associated with healthier dietary intakes in the South and rural areas, and the reverse was true in the West. CONCLUSION: The relationships between CPP index scores and dietary intake were most strongly influenced by region and urbanicity and to a lesser extent by community-level race/ethnicity and income. Findings suggest that different considerations may be needed for childhood obesity prevention efforts in communities with different characteristics. PMID- 29992766 TI - Segmentation of Drosophila heart in optical coherence microscopy images using convolutional neural networks. AB - Convolutional neural networks (CNNs) are powerful tools for image segmentation and classification. Here, we use this method to identify and mark the heart region of Drosophila at different developmental stages in the cross-sectional images acquired by a custom optical coherence microscopy (OCM) system. With our well-trained CNN model, the heart regions through multiple heartbeat cycles can be marked with an intersection over union of ~86%. Various morphological and dynamical cardiac parameters can be quantified accurately with automatically segmented heart regions. This study demonstrates an efficient heart segmentation method to analyze OCM images of the beating heart in Drosophila. PMID- 29992768 TI - A Direct Ammonia Microfluidic Fuel Cell using NiCu Nanoparticles Supported on Carbon Nanotubes as an Electrocatalyst. AB - This work demonstrates the use of a NiCu electrocatalyst prepared by hydrothermal method with different Ni/Cu mass ratios (70:30, 50:50 and 30:70) supported on carbon nanotubes (CNTs), which was studied with regards to its electrochemical behavior in the ammonia oxidation reaction and direct ammonia microfluidic fuel cell (DAMFC) performance. XRD and SEM-EDX showed the formation of NiCu alloy while TEM showed the particles size to be 15-20 nm. Cyclic voltammetry and chronoamperometry showed that NiCu had higher catalytic activity than pure Ni and pure Cu, and that the active species was a NiCu oxyhydroxide. In DAMFC tests, 50 wt % Ni50 Cu50 /CNTs was found to be the most suitable one since it showed a 43 % higher peak power density and 65 % higher maximum current density than Ni electrode. The improved performance was attributed to the NiCu oxyhydroxides formation, which improved the anodic catalytic activity by increasing amounts of active sites and the combined electronic effect of the Ni-Cu bimetallic catalysts. PMID- 29992767 TI - No difference in human mast cells derived from peanut allergic versus non allergic subjects. AB - INTRODUCTION: Mast cells are the primary effector cells of allergy. This study aimed at characterizing human peripheral blood-derived mast cells (PBdMC) from peanut allergic and non-allergic subjects by investigating whether the molecular and stimulus-response profile of PBdMC discriminate between peanut allergic and healthy individuals. METHODS: PBdMC were generated from eight peanut allergic and 10 non-allergic subjects. The molecular profile (cell surface receptor expression) was assessed using flow cytometry. The stimulus-response profile (histamine release induced by secretagogues, secretion of cytokines/chemokines and changes in miRNA expression following anti-IgE activation) was carried out with histamine release test, luminex multiplex assay and miRNA arrays. RESULTS: Expression of activating receptors (FcepsilonRI, CD48, CD88, CD117, and C3aR) on PBdMC was not different among peanut allergic and non-allergic subjects. Likewise, inhibitory receptors (CD32, CD200R, CD300a, and siglec-8) displayed comparable levels of expression. Both groups of PBdMC were unresponsive to substance P, compound 48/80 and C5a but released comparable levels of histamine when stimulated with anti-IgE and C3a. Interestingly, among the secreted cytokines/chemokines (IL-8, IL-10, IL-13, IL-23, IL-31, IL-37, MCP-1, VEGF, GM CSF) PBdMC from peanut allergic subjects showed a different secretion pattern of IL-31 compared to non-allergic subjects. Investigating miRNA expression from resting or activated PBdMC revealed no significantly difference between peanut allergic and non-allergic subjects. CONCLUSION: The molecular and stimulus response profile revealed that PBdMC from peanut allergic subjects differently express IL-31 compared to non-allergic subjects. However, since only one altered parameter was found among 893 investigated, it is still questionable if the pathophysiological mechanisms of peanut allergy are revealed in PBdMC. PMID- 29992769 TI - Submicron Inverse Pickering Emulsions for Highly Efficient and Recyclable Enzymatic Catalysis. AB - Herein, we report the utilization of a submicron Pickering emulsion (SPE) for the encapsulation of enzymes (e.g., lipase from Candida sp.) in water droplets that were solely stabilized by hydrophobic solid or mesoporous silica nanoparticles in toluene for use in biphasic reactions. The catalytic performance of encapsulated lipase was evaluated in the esterification of 1-hexanol and hexanoic acid under stirring-free conditions, which was favorable for maintaining enzymatic activity. Remarkably, the SPE significantly increased the specific activity of encapsulated lipase, owing to the exceptionally high water/oil interfacial area and short diffusion distance of the reagents in the SPE. With mesoporous silica nanoparticles, the activity of lipase was approximately 25.5- and 2.8-times higher than that of free lipase and encapsulated lipase in the micron Pickering emulsion, respectively. The higher water/toluene interfacial area was attributed to the smaller submicron-scale water droplets and the increase in the mass transfer of enzymes or substrates was further improved by using mesoporous Pickering stabilizers. In addition, the encapsulated lipase in SPE also demonstrated excellent stability and could be recycled up to 15 times without significant loss of activity. PMID- 29992770 TI - Tongue Cancer Patients Can be Distinguished from Healthy Controls by Specific N Glycopeptides Found in Serum. AB - PURPOSE: There are no blood biomarkers to detect early-stage oral cavity squamous cell carcinoma (OSCC) prior to clinical signs. Most OSCC incidence is associated with significant morbidity and poor survival. The authors aimed to use mass spectrometry (MS) technology to find specific N-glycopeptides potentially serving as serum biomarkers for preclinical OSCC screening. EXPERIMENTAL DESIGN: Serum samples from 14 patients treated for OSCC (stage I or stage IV) with 12 age- and sex-matched controls are collected. Quantitative label-free N-glycoproteomics is performed, with MS/MS analysis of the statistically significantly different N glycopeptides. RESULTS: Combined with a database search using web-based software (GlycopeptideID), MS/MS provided detailed N-glycopeptide information, including glycosylation site, glycan composition, and proposed structures. Thirty-eight tryptic N-glycopeptides are identified, having 19 unique N-glycosylation sites representing 14 glycoproteins. OSCC patients, including stage I tumors, can be differentiated from healthy controls based on the expression levels of these glycoforms. N-glycopeptides of IgG1, IgG4, haptoglobin, and transferrin have statistically significant different abundances between cases and controls. CONCLUSIONS AND CLINICAL RELEVANCE: The authors are the first to suggest specific N-glycopeptides to serve as potential serum biomarkers to detect preclinical OSCC in patients. These N-glycopeptides are the lead candidates for validation as future diagnostic modalities of OSCC as early as stage I. PMID- 29992771 TI - Identification of the novel HLA-A*32:01:01:08 allele in a Saudi individual. AB - HLA-A*32:01:01:08 differs from HLA-A*32:01:01:01 by a single nucleotide substitution (G -> A) at position 2200. PMID- 29992772 TI - Current Status of Proteomics in Ewing's Sarcoma. AB - Ewing's sarcoma is an extremely rare mesenchymal malignancy of the bone, which predominantly occurs in children and young adolescents. Ewing's sarcoma is characterized by chromosomal translocations resulting in the formation of chimeric fusions between the EWS gene and transcription factors of the ETS family, such as EWS-FLI-1. The clinical outcome of Ewing's sarcoma remains poor, and novel therapeutic approaches are required. Proteomic analyses have been applied to identify the functions of the fusion gene product, and a novel mechanism of EWS-FLI-1 turnover has been proposed. Furthermore, proteomics has revealed the regulation of IL-6 secretion by EWS-FLI-1, which may promote malignant behavior in tumor cells. In addition, proteomic approaches have been used to assess the effects of unique genes and drugs on Ewing's sarcoma and to determine specific biomarker candidates for the prediction of drug resistance and recurrence. By identifying the proteins relevant to the molecular backgrounds of clinical characters of Ewing's sarcoma, we can understand the biology of Ewing's sarcoma and develop clinical applications. Fundamental research systems such as tumor cell and tissue biobanks and databases are required to make effective use of the limited clinical materials and promote research into Ewing's sarcoma. PMID- 29992773 TI - Circumferential resection margin as a prognostic factor after rectal cancer surgery: A large population-based retrospective study. AB - AIM: This study aimed to investigate circumferential resection margin (CRM) as a prognostic factor for long-term oncologic survival after rectal cancer surgery. METHODS: Patients diagnosed with malignant rectal cancer between 1 January 2010 and 31 December 2014, from the Surveillance, Epidemiology, and End Results (SEER) program were identified for this study. The patients were divided into five CRM groups to compare the baseline characteristics and assess cancer-specific survival (CSS): 0-1 mm, 1.1-2.0 mm, 2.1-5.0 mm, 5.1-10.0 mm, and >10 mm. The main endpoint was CSS. RESULTS: Circumferential resection margin <=1 mm was independently associated with 99% increased risk of cancer-specific mortality in rectal cancer [hazard ratio (HR) = 1.990, 95% confidence interval (CI) = 1.613 2.454, P < 0.001, using CRM (1.1-2.0 mm) as a reference]. CRM (5.1-10.0 mm) was independently associated with 29.2% decreased risk of cancer-specific mortality [HR = 0.708, 95% CI = 0.525-0.954, P = 0.152, using group (2.1-5.0 mm) as reference]. CRM <=2 mm or <=0.4 mm was not obviously associated with CSS. CONCLUSIONS: circumferential resection margin is an independent prognostic factor in rectal cancer. Surgeons should try to maximize the CRM. Rectal cancer patients with CRM <=1 mm should receive more postoperative attention depending on individual situation. Also, CRM should be accurately measured in millimeters in a preoperative magnetic resonance imaging or pathological report, rather than simply described as "involved" or "clear." PMID- 29992774 TI - Identification and functional annotation of metabolism-associated lncRNAs and their related protein-coding genes in gastric cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) play important roles in carcinogenesis. However, the roles of metabolism-associated lncRNAs in cancers are still unclear. METHODS: A microarray of metabolism-associated lncRNAs was used to detect their expression patterns between gastric cancer and paired nontumorous tissues. Its results and gastric cancer differential gene expression data from public databases were used to screen the metabolic pathway-associated lncRNAs. A metabolic network with microRNAs (miRNAs), lncRNAs, and protein-coding genes was further constructed. Finally, the expression of TOPORS antisense RNA 1 (TOPORS AS1), a screened highly expressed lncRNA and its associated protein-coding gene, NADH: ubiquinone oxidoreductase subunit B6 (NDUFB6), were verified by reverse transcription polymerase chain reaction. RESULTS: A total of eight upregulated and one downregulated lncRNAs and 25 upregulated and 20 downregulated protein coding genes were found to be involved in metabolism in gastric cancer. Within the lncRNAs-miRNAs-mRNAs metabolic network, 78 miRNA-target links, 546 positive coexpression relationships, and 191 protein-protein interactions were found. The expression of TOPORS-AS1 and its associated gene, NDUFB6 in gastric cancer tissues was significantly lower than that in adjacent nontumor tissues. Moreover, NDUFB6 expression was associated with the invasion and distal metastasis of gastric cancer. CONCLUSIONS: The metabolism-associated lncRNAs play important roles in the occurrence of gastric cancer. PMID- 29992775 TI - The myriad challenges of respiratory fungal infection in cystic fibrosis. AB - Fungal infection in cystic fibrosis (CF) is a recognized challenge, with many areas requiring further investigation. Consensus definitions exist for allergic bronchopulmonary aspergillus in CF, but the full scope of clinically relevant non allergic fungal disease in CF-asymptomatic colonization, transient or chronic infection localized to endobronchial mucus plugs or airway tissue, and invasive disease-is yet to be clearly defined. Recent advances in mycological culture and non-culture identification have expanded the list of both potential pathogens and community commensals in the lower respiratory tract. Here we aim to outline the current understanding of fungal presence in the CF respiratory tract, risk factors for acquiring fungi, host-pathogen interactions that influence the role of fungi from bystander to pathogen, advances in the diagnostic approaches to isolating and identifying fungi in CF respiratory samples, challenges of classifying clinical phenotypes of CF patients with fungi, and current treatment approaches. Development and validation of biomarkers characteristic of different fungal clinical phenotypes, and controlled trials of antifungal agents in well characterized target populations, remain central challenges to surmount and goals to be achieved. PMID- 29992776 TI - Nearly complete genome sequence of one GII.17 Norovirus identified by direct sequencing from HuZhou, China. AB - BACKGROUND: Human norovirus is the leading cause of acute gastroenteritis worldwide. However, in vitro culture system is complicated for human norovirus. Sequence analysis became more useful for norovirus research, particularly when using complete genomic sequences. METHODS: Real-time RT-PCR (qPCR) was performed for norovirus detection. Three modified paris of PCR primes were designed based on the alignment of the novel GII.17 norovirus complete sequence available in Genbank., which could amplify three overlapping fragments cover the whole genome. The PCR fragments were sequencing by Sanger sequence with Primer walking methods. Genogroup and genotype were assigned using the Norovirus Noronet typing tool and the strains were named according to the time of isolation. The phylogenetic analysis was conducted using MEGA software (ver. 6.06). RESULTS: One nearly complete genome sequence were obtained from sample collected from Huzhou, China. The partial genome sequence of the HuzhouNS2014603 strain is composed of 7556 nucleotides (nt).The strain was classified as GII.17 genotype both in ORF1 and ORF2, and was most closely related to the LC037415.1/Hu/GII.17/Kawasaki308 strain. Within the GII.17 cluster, the 2013/14 season strains were grouped separately from the GII.17 strains detected in 2014/15. HuzhouNS2014603 was clustered with the 2014/15 season strains. Compared with other strains selected, there are 98 variable residues across the VP1 domain. Among the 98 variable amino acids, 13 (13.3%) were observed in the shell domain and 22 (22.4%) in the P1domain; most of the substitutions and insertions were located in the P2 domain, account for 63 (64.3%). CONCLUSIONS: This is the first report of the nearly complete genome of the novel GII.17 by direct sequencing method in the Huzhou area. The results of this study could be helpful for the study of the genetic evolution of the virus, the development of rapid diagnostic reagents and the design of vaccine. PMID- 29992777 TI - Sex-dependent effects of maternal stress: Stressed moms invest less in sons than daughters. AB - Multigenerational effects can have important and sex-dependent effects on offspring. Sex allocation theory predicts that females should differentially invest in sons and daughters depending on sex-specific fitness returns and costs of investment. Maternal stress-relevant (glucocorticoid) hormones may be one mechanism driving this effect. We investigated how maternal stress hormones differentially affected sons and daughters by manipulating levels of the glucocorticoid, corticosterone (CORT), in gravid female eastern fence lizards (Sceloporus undulatus) and quantifying reproductive investment and sex ratio of resulting clutches, and the mass, snout-vent length, and body condition of sons versus daughters at hatching. We found no effect of maternal CORT-treatment on the number or size of eggs laid or on the sex ratio of resulting offspring, but sons of CORT-treated mothers were shorter, lighter, and of poorer body condition at hatching than were sons of control mothers. We found no difference in size or condition of daughters with maternal treatment. Our results suggest that maternal stress, mediated by elevations in maternal CORT concentrations, can have sex specific effects on offspring manifesting as lower investment in sons. PMID- 29992778 TI - Droplet-Based Microfluidic Templating of Polyglycerol-Based Microgels for the Encapsulation of Cells: A Comparative Study. AB - Cell microencapsulation holds great promise as a therapeutic strategy for the controlled and sustained delivery of biologically relevant agents. The authors developed cell-laden microgel scaffolds with excellent long-term viabilities by combining bioorthogonal strain promoted azide-alkyne cycloaddition (SPAAC) and droplet-based microfluidic templating. Star-shaped polyglycerol hexaazide, alpha,omega-bis azido-linear polyglycerol or polyethylene glycol as well as dendritic polyglycerol-(polycyclooctyne) served as bioinert hydrogel precursors. The authors demonstrate for the first time the generation of entirely polyglycerol-based microcapsules with excellent stability and full retention of viability of the packed cells for longer than 3 weeks. As a result, our microgel particles could be used for long-term immunoisolation of cells enabling their study during encapsulation. PMID- 29992779 TI - Remembrance of stresses past: heat shock factors and histone hypermethylation are key. PMID- 29992781 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 29/2018. PMID- 29992780 TI - Effect of European Medicines Agency's restrictions on trimetazidine utilization in Portugal. AB - PURPOSE: Following safety concerns regarding trimetazidine, the European Medicines Agency (EMA) recommended restrictions on its use. Our objective was to determine the impact of regulatory actions on trimetazidine utilization in Portugal. METHODS: Retrospective interrupted time-series analysis of monthly ambulatory pharmacy reimbursement records for the Portuguese National Health Service between January 2006 and December 2015. Regulatory actions were identified by searching the EMA, Portuguese Medicines Authority, and European Commission's websites. Concurrent factors in the same period were also identified. The main outcome was the dispensing of trimetazidine-containing products per month in Portugal. RESULTS: Two interruption periods were defined in the series: May 2011, when EMA announced it would review trimetazidine safety, and June 2012 to January 2013, when EMA announced it had reached a final opinion recommending restrictions; the European Commission approved EMA's recommendation; the Portuguese Medicines Authority issued safety alerts, changed the summary of product characteristics, and approved a direct health-care professional letter; and a regional bulletin was issued. Interruption 1 had no effect on trimetazidine use, but interruption 2 resulted in decreases in level and trend-from 8.3 million defined daily doses in 2010 to 2.8 million in 2015. After interruption 2, trimetazidine use tended towards a lower steady state. CONCLUSIONS: There was a significant decrease in trimetazidine use in Portugal following a complex intervention that included safety alerts, changes to the summary of product characteristics, a direct health-care professional letter, and a regional drug bulletin. No effect was seen when EMA announced its review of trimetazidine safety. PMID- 29992782 TI - Corrigendum: Degradable Vanadium Disulfide Nanostructures with Unique Optical and Magnetic Functions for Cancer Theranostics. PMID- 29992783 TI - Isolation and genomic characterization of lymphocytic choriomeningitis virus in ticks from northeastern China. AB - Lymphocytic choriomeningitis virus (LCMV) is a rodent-borne arenavirus that is considered a neglected cause of neurologic diseases in humans. In this study, we described genomic characterization of newly isolated LCMVs in Haemaphysalis longicornis, Dermacentor nuttalli, Dermacentor silvarum and Ixodes persulcatus in Jilin Province, northeastern China. The complete sequences of the small (S) and large (L) segments of LCMVs in ticks contained 3,375 and 7,235-7,241 nucleotides, respectively. Sequence comparison showed 82.1%-86.0% identity of S segment with other lineage I strains at the nucleotide level and 91.2%-97.5% at the deduced amino acid level, while a lower identity was observed in the L segment at both nucleotide (75.4%-82.2%) and amino acid (82.4%-93.4%) levels. Phylogenetic analysis grouped the tick LCMVs together with the lineage I strains, but in an isolated cluster with a high bootstrap value. Bayesian analysis indicated that the molecular evolutionary rate was estimated to be 3.3 * 10-4 substitutions/site/year for the S segment and 6.3 * 10-4 substitutions/site/year for the L segment, and the time to most recent common ancestor was 1980 and 1970 years ago, respectively, showing that tick LCMVs were predicted to originate between 1970s and 1980s. A long evolutionary history and high prevalence of LCMV in H. longicornis were found compared to other tick species. This study represented the first report on isolation of LCMV in China, showing that LCMV is circulating among ticks in Jilin Province, but the role of ticks in the epidemiology of LCMV remains to be explored. PMID- 29992784 TI - The synthesis of N-benzoylindoles as inhibitors of rat erythrocyte glucose-6 phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. AB - Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD) play an important function in various biochemical processes as they generate reducing power of the cell. Thus, metabolic reprogramming of reduced nicotinamide adenine dinucleotide phosphate (NADPH) homeostasis is reported to be a vital step in cancer progression as well as in combinational therapeutic approaches. In this study, N-benzoylindoles 9a--9d, which form the main framework of many natural indole derivatives such as indomethacin and N benzoylindoylbarbituric acid, were synthesized through three easy and effective steps as an in vitro inhibitor effect of G6PD and 6PGD. The N-benzoylindoles inhibited the enzymatic activity with IC50 in the range of 3.391505 MUM for G6PD and 2.19-990 MUM for 6PGD. PMID- 29992785 TI - The evaluation of psychiatric comorbidity, self-injurious behavior, suicide probability, and other associated psychiatric factors (lonileness, self-esteem, life satisfaction) in adolescents with acne: A clinical pilot study. AB - BACKGROUND: Since adolescents are psychologically more unstable, the emergence of acne vulgaris during adolescence makes this disease a focal point of concern for many individuals. AIM: In this study, psychiatric comorbidity and levels of self injurious behavior, suicide probability, life satisfaction, self-esteem and loneliness in adolescents with acne was assessed and compared with a control group. METHODS: The study was conducted with 104 adolescents with acne and 102 age- and sex-matched healthy controls. The Rosenberg Self-Esteem Scale, Suicide Probability Scale (SPS), Life Satisfaction Inventory, Short form of the UCLA Loneliness Scale and Inventory of Statements About Self-Injury (ISAS) were administered to the case and control groups. Both groups were assessed according to the Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime Version-Turkish Version. RESULTS: Adolescents with acne were found to have lower levels of self-esteem and life satisfaction and higher levels of loneliness compared to controls. The mean scores of SPS and its negative self evaluation/hostility subscales were found to be significantly higher in adolescents with acne. The presence of self-injurious behavior and psychiatric comorbidity were shown to be significantly higher in adolescents with acne. CONCLUSIONS: The presence of high levels of psychiatric comorbidity, suicide probability, and self-injurious behavior in adolescents with acne in our study suggests that psychiatric evaluation should be included in acne treatment plans. Psychological assessment of adolescents with acne vulgaris is important for contributing to the detection of any potential covert sexual abuse. Our study demonstrates the importance of a multidisciplinary approach for acne treatment. PMID- 29992787 TI - Abstracts of the UROFAIR 2018, Integrating Scientific Knowledge, Technology and Clinical Urology, 12-14 July 2018, Singapore. PMID- 29992786 TI - Neurocognitive disorders and sleep in children with primary ciliary dyskinesia. AB - BACKGROUND: Primary ciliary dyskinesia (PCD) patients have higher incidence of sleep disordered breathing which lead neurocognitive impairments such as attention-deficit/hyperactivity disorder (ADHD). It may effect academic performance of children and may cause impairment in emotional relationships. This study aim to evaluate hyperactivity and attention deficiency in PCD patients and investigate the relationship between sleep and hyperactivity and attention deficiency in PCD patients. METHOD: Fifteen PCD patients aged 8-18 years and 31 age-matched healthy controls were compared. Ear, nose, and throat examination and home sleep testing were performed in PCD patients. Pediatric sleep questionnaire, Conners' Parents and Teacher scale and Stroop test were applied in both groups in order to investigate the relation between sleep disordered breathing and ADHD in PCD children. RESULTS: PCD patients had chronic rhinosinusitis (100%), tonsillar hypertrophy (80%) and adenoidal hypertrophy (60%). FEF25-75 was low in pulmonary function test. Sixty percent of the PCD patients had mild obstructive sleep apnea syndrome in home sleep testing. Mean AHI was 1.54 +/- 0.27. Compared with the controls PCD patients had higher PSQ scores. Hyperactivity scores on Conners' Parents scale and inattention findings in Stroop test were higher in PCD patients than the healthy controls (P < 0.05). CONCLUSION: Most of PCD children had mild obstructive sleep apnea syndrome. Hyperactivity and inattention findings were higher in PCD patients. Sleep disordered breathing assessment should be a routine part of PCD patients management and these patients should be carefully monitored in terms of hyperactivity and inattention. PMID- 29992788 TI - Expression of 15-lipoxygenase-1 in Merkel cell carcinoma is linked to advanced disease. AB - BACKGROUND: The purpose of this study was to determine whether the expression of 15-lipoxygenase-1 (ALOX15) in primary tumour specimens predicts lymph node metastasis and subsequently clinical outcome in Merkel cell carcinoma (MCC) patients. METHODS: A retrospective medical chart review of 33 patients was performed between 1994 and 2014. Eleven out of 33 (33%) Patients with primary MCC stages I and II were categorised as group I. Twenty two out of 33 (67%) Patients with regional lymph node metastases and/or distant metastases were defined as group II. All available tumour samples were immunostained for ALOX15, Podoplanin and MCPyV large T-protein antibody. RESULTS: ALOX15 expression was observed in 19/23 (83%) primary tumour samples and in all lymph node metastasis. Primary tumours in patients with stage III and IV disease showed a higher expression rate of ALOX15 compared to patients with early stage disease (11/12 (92%) and 8/11 (73%), respectively). In group I, five patients (45%) were MCPyV positive, whereas in group II, 15 patients (68%) were MCPyV positive. The median lymphatic vessel density in ALOX15 negative group I primary tumour samples was lower compared to the median lymphatic vessel density in ALOX15 positive group I primary tumour probes (2.7 range, 1-4.3 vs 4.7 range, 4.0-7.3). Furthermore, all 17 samples of MCC metastases showed ALOX15 expression with a median lymphatic vessel density (not lymph node metastases) of 5.3 (range 2.0-7.3). CONCLUSION: In the current study, we were able to show ALOX15 expression in the primary MCC sample and the metastasis sample. Based on the findings of the current study, expression rate of ALOX15 in primary MCC and metastases is possibly linked to an increased lymphatic vessel density. PMID- 29992789 TI - Aldolase A as a prognostic factor and mediator of progression via inducing epithelial-mesenchymal transition in gastric cancer. AB - Glycolysis is regarded as the hallmark of cancer development and progression, which involves a multistep enzymatic reaction. This study aimed to explore the clinicopathological significance and potential role of glycolytic enzyme aldolase A (ALDOA) in the carcinogenesis and progression of gastric cancer (GC). ALDOA was screened from three paired liver metastasis tissues and primary GC tissues and further explored with clinical samples and in vitro studies. The ALDOA protein level significantly correlated with a larger tumor diameter (P = .004), advanced T stage (P < .001), N stage (P < .001) and lymphovascular invasion (P = .001). Moreover, the expression of ALDOA was an independent prognostic factor for the 5 year overall survival and disease-free survival of patients with GC in both univariate and multivariate survival analyses (P < .05). Silencing the expression of ALDOA in GC cell lines significantly impaired cell growth, proliferation and invasion ability (P < .05). Knockdown of the expression of ALDOA reversed the epithelial-mesenchymal transition process. Mechanically, ALDOA could affect the hypoxia-inducible factor (HIF)-1alpha activity as demonstrated by the HIF-1alpha response element-luciferase activity in GC cells. Collectively, this study revealed that ALDOA was a potential biomarker of GC prognosis and was important in the carcinogenesis and progression of human GC. PMID- 29992791 TI - Analyzing histological material to determine ajmaline and other drugs using high performance liquid chromatography/tandem mass spectrometry. PMID- 29992790 TI - HOXA11 antisense long noncoding RNA (HOXA11-AS): A promising lncRNA in human cancers. AB - The cancers are the leading cause of disease-related deaths worldwide with a high risk of morbidity and mortality. Long noncoding RNAs (lncRNAs) play a critical role in a wide range of biological processes, including tumorigenesis. HOXA11-AS (NCRNA00076), the antisense strands of HOXA11 gene, was initially revealed in a mouse embryonic cDNA library in 2009 and it was a fairly novel lncRNA. This review summarized the advanced research progression concerning the expression and role of HOXA11-AS in different human malignancies. The expression of HOXA11-AS is aberrantly altered in many cancers, either as a tumor suppressor or as a tumor accelerator. The different underlying mechanism of HOXA11-AS in different cancers (including, nonsmall cell lung cancers, osteosarcoma, uveal melanoma, glioma, hepatocellular carcinoma, gastric cancer, breast cancer, cervical cancer, ovarian cancer, colorectal cancer, ovarian cancer, and glioblastoma) was also detailed. These findings lead us to conclude that HOXA11-AS participate in the complex network of cancers and plays an important role in the tumorigenesis and progression. Functional HOXA11-AS could be a promising biomarker for early detection as well as prognosis evaluation in cancer patients. Future HOXA11-AS targeted intervention may become a valuable novel therapeutic tool, improving the clinical management of cancers. PMID- 29992792 TI - Plasma Proteome Profiles of Stable CAD Patients Stratified According to Total Apo C-III Levels. AB - PURPOSE: The present research reports the study the of plasma proteome profile of stable coronary artery disease (CAD) patients characterized by different levels of total Apolipoprotein-CIII (Apo C-III), a prognostic marker for cardiovascular risk. EXPERIMENTAL DESIGN: Two subgroups of CAD patients (n = 52) with divergent concentrations of total circulating Apo C-III (<= and >=10 mg dL-1 ) are examined using a shotgun proteomic approach. Validation experiments are also performed with immunochemistry methods including both the patients affected by CAD (n = 119) and the subjects without CAD (CAD-free; n = 58). Results are analyzed by bioinformatics tools and multivariate statistics. RESULTS: A total of 188 proteins are quantified among the patients. The fold change analysis and the partial least square discriminant analysis show a clear separation of the two groups. Lipoproteins (Apo C-II and Apo E), retinol-binding protein 4, and vitronectin are upregulated in patients with high Apo C-III, while alpha-1 antitrypsin is downregulated. CONCLUSIONS AND CLINICAL RELEVANCE: In this pilot study, the differential expression of plasma proteins related to different concentrations of Apo C-III is defined, suggesting possible new players involved in the Apo C-III-associated process of arterial damage. Data are available via ProteomeXchange with identifier PXD005973. PMID- 29992793 TI - Motivations and Experiences of People Seeking Medication Abortion Online in the United States. AB - CONTEXT: State legislation restricting access to abortion in the clinic setting raises the possibility that an increasing number of individuals in the United States will self-manage their abortion at home. Medications sourced online represent a potential pathway to abortion self-management. Yet, very little is known about the reasons U.S. residents may seek abortion online or their experiences finding medications and information. METHODS: In January-June 2017, anonymous in-depth interviews were conducted with 32 people from 20 states who sought abortion medications online (30 women and two men seeking medications for their partners). Participants were asked about their (or their partners') motivations for considering self-managed abortion, the sources of medications they identified and any other methods they considered. Transcripts were coded and analyzed according to the principles of grounded theory. RESULTS: The analysis revealed four key themes: Seeking abortion medications online can be a response to clinic access barriers both in states with and in ones without restrictive abortion laws; self-managed abortion can be a preference over clinical care; online options offer either information or medications, but not both; and the lack of trusted online options can delay care and lead to consideration of ineffective or unsafe alternatives. CONCLUSION: Current online options for abortion medications leave many important needs unmet, particularly for women who encounter barriers to obtaining clinic-based abortion services. There is a public health justification to reduce clinic access barriers and to make medication abortion that is sourced online and managed at home as safe and supported as possible. PMID- 29992794 TI - Absorbable barbed suture device for laparoscopic peritoneal closure after hernia repair via the transabdominal preperitoneal approach: A single-center experience with 257 cases. AB - INTRODUCTION: The laparoscopic transabdominal preperitoneal approach requires peritoneal closure and technically skilled knotting. We have started to use a barbed running suturing device (V-Loc 180) without knotting for transabdominal preperitoneal repair of hernias. This study aimed to determine whether using V Loc 180 was safe and shortened the time for laparoscopic peritoneal closure. METHODS: Between December 2010 and February 2017, 3-0 V-Loc 180 and a multifilament absorbable running suture (3-0 Vicryl) were used for three-port transabdominal preperitoneal repair of inguinal hernia in 363 cases. Data including peritoneal closure time and the complications were retrospectively recorded. RESULTS: Factors identified as significantly prolonging the peritoneal closure time were the hernia side (P = 0.0269), the type of hernia (P = 0.001), the suture device used (P < 0.0001), and the surgeon's experience (P < 0.0001). Use of the barbed suture was associated with a significantly shorter peritoneal closure time than the multifilament suture (mean closure time: 10.2 and 12.7 min, respectively). While there were no postoperative complications in the barbed suture group, there were two cases (1.9%) of postoperative complications in the multifilament suture group (P = 0.0272). CONCLUSION: We demonstrated that the use of the barbed suturing device for laparoscopic peritoneal closure was safe and feasible. PMID- 29992796 TI - Estimating relative chromophore concentrations from multiwavelength photoacoustic images using independent component analysis. AB - Independent component analysis (ICA) is an unmixing method based on a linear model. It has previously been applied in in vivo multiwavelength photoacoustic imaging studies to unmix the components representing individual chromophores by assuming that they are statistically independent. Numerically simulated and experimentally acquired two-dimensional images of tissue-mimicking phantoms are used to investigate the conditions required for ICA to give accurate estimates of the relative chromophore concentrations. A simple approximate fluence correction was applied to reduce but not completely remove the nonlinear fluence distortion, as might be possible in practice. The results show that ICA is robust against the residual effect of the partially corrected fluence distortion. ICA is shown to provide accurate unmixing of the chromophores when the absorption coefficient is within a certain range of values, where the upper absorption threshold is comparable to the absorption of blood. When the absorption is increased beyond these thresholds, ICA abruptly fails to unmix the chromophores accurately. The ICA approach was compared to a linear spectroscopic inversion (SI) with known absorption spectra. In cases where the mixing matrix with the specific absorption spectra is ill-conditioned, ICA is able to provide accurate unmixing when SI results in large errors. PMID- 29992795 TI - Associations of community programs and policies with children's dietary intakes: the Healthy Communities Study. AB - BACKGROUND: The impact of community-based obesity prevention efforts on child nutrition has not been adequately studied. OBJECTIVE: Examine relationships between number, type and intensity of community programs and policies (CPPs) and child nutrition. METHODS: An observational study of 5138 children (grades K-8) in 130 U.S. communities was conducted in 2013-2015. CPPs were identified by 10-14 key informant interviews per community. CPPs were characterized based on: count, intensity, number of different strategies used and number of different behaviours targeted. Scores for the prior 6 years were calculated separately for CPPs that addressed primarily nutrition, primarily physical activity (PA) or total combined. Child intakes were calculated from a dietary screener and dietary behaviours were based on survey responses. Multi-level statistical models assessed associations between CPP indices and nutrition measures, adjusting for child and community-level covariates. RESULTS: Implementing more types of strategies across all CPPs was related to lower intakes of total added sugar (when CPPs addressed primarily PA), sugar-sweetened beverages (for nutrition and PA CPPs) and energy-dense foods of minimal nutritional value (for total CPPs). Addressing more behaviours was related to higher intakes of fruit and vegetables (for nutrition and total CPPs) and fibre (total CPPs). Higher count and intensity (PA and total CPPs) were related to more consumption of lower fat compared with higher fat milk. A higher count (PA CPPs) was related to fewer energy-dense foods and whole grains. No other relationships were significant at P < 0.05. CONCLUSION: Multiple characteristics of CPPs to prevent obesity appear important to improve children's diets. PMID- 29992798 TI - Application of cmOCT and continuous wavelet transform analysis to the assessment of skin microcirculation dynamics. AB - Correlation mapping optical coherence tomography (cmOCT) is a powerful technique for the imaging of skin microvessels structure, based on the discrimination of the static and dynamic regions of the tissue. Although the suitability of cmOCT to visualize the microcirculation has been proved in humans and animal models, less evidence has been provided about its application to examine functional dynamics. Therefore, the goal of this research was validating the cmOCT method for the investigation into microvascular function and vasomotion. A spectral domain optical coherence tomography (SD-OCT) device was employed to image 90 sequential three-dimensional (3-D) OCT volumes from the forearm of 12 volunteers during a 25-min postocclusive reactive hyperemia (PORH) test. The volumes were processed using cmOCT to generate blood flow maps at selected cutaneous depths. The maps clearly trace flow variations during the PORH response for both capillaries and arterioles/venules microvascular layers. Continuous blood flow signals were reconstructed from cmOCT maps to study vasomotion by applying wavelet transform spectral analysis, which revealed fluctuations of flow during PORH, reflecting the regulation of microvascular tone mediated by endothelial cells and sympathetic nerves. The results clearly demonstrate that cmOCT allows the generation of functional information that may be used for diagnostic applications. PMID- 29992797 TI - Evaluating integrin activation with time-resolved flow cytometry. AB - Forster resonance energy transfer (FRET) continues to be a useful tool to study movement and interaction between proteins within living cells. When FRET as an optical technique is measured with flow cytometry, conformational changes of proteins can be rapidly measured cell-by-cell for the benefit of screening and profiling. We exploit FRET to study the extent of activation of alpha4beta1 integrin dimers expressed on the surface of leukocytes. The stalk-like transmembrane heterodimers when not active lay bent and upon activation extend outward. Integrin extension is determined by changes in the distance of closest approach between an FRET donor and acceptor, bound at the integrin head and cell membrane, respectively. Time-resolved flow cytometry analysis revealed donor emission increases up to 17%, fluorescence lifetime shifts over 1.0 ns during activation, and FRET efficiencies of 37% and 26% corresponding to the inactive and active integrin state, respectively. Last, a graphical phasor analysis, including population clustering, gating, and formation of an FRET trajectory, added precision to a comparative analysis of populations undergoing FRET, partial donor recovery, and complete donor recovery. This work establishes a quantitative cytometric approach for profiling fluorescence donor decay kinetics during integrin conformational changes on a single-cell level. PMID- 29992799 TI - Low-cost high sensitivity pulsed endomicroscopy to visualize tricolor optical signatures. AB - A highly sensitive, modular three-color fluorescence endomicroscopy imaging platform spanning the visible to near-infrared (NIR) range is demonstrated. Light emitting diodes (LEDs) were sequentially pulsed along with the camera acquisition to provide up to 20 frames per second (fps) three-color imaging performance or 60 fps single color imaging. The system was characterized for bacterial and cellular molecular imaging in ex vivo human lung tissue and for bacterial and indocyanine green imaging in ex vivo perfused sheep lungs. A practical method to reduce background tissue autofluorescence is also proposed. The platform was clinically translated into six patients with pulmonary disease to delineate healthy, cancerous, and fibrotic tissue autofluorescent structures. The instrument is the most broadband clinical endomicroscopy system developed to date (covering visible to the NIR, 500 to 900 nm) and demonstrates significant potential for future clinical utility due to its low cost and modular capability to suit a wide variety of molecular imaging applications. PMID- 29992800 TI - Refractive index correction in optical coherence tomography images of multilayer tissues. AB - We propose an algorithm to compensate for the refractive index error in the optical coherence tomography (OCT) images of multilayer tissues, such as skin. The performance of the proposed method has been evaluated on one- and two-layer solid phantoms, as well as the skin of rat paw. PMID- 29992801 TI - How the Affordable Care Act Has Affected Health Coverage for Young Men with Higher Incomes. AB - Issue: The Affordable Care Act (ACA) regulates the price of health plans sold in the nongroup market. Premiums cannot be based on gender or health status, and price increases related to age are limited. These changes have lowered premiums for older, sicker people but raised them for younger, healthier ones--especially young men ineligible for premium subsidies. This has raised concerns that the latter have failed to gain coverage. Goal: Compare the impact of the ACA's rating rules on the number of insured young men, older adults, and others. Methods: We compared overall and nongroup coverage trends pre- and post-ACA among demographic groups, comparing residents of states where the rule changes had little effect on premiums to states where the rules had greater effect. Findings: People whose premiums fell because of the ACA's rating rules were slightly more likely to get nongroup coverage than those whose premiums rose. All groups, including higher income young men, gained coverage because of the combined effects of ACA changes. Conclusion: Coverage rose after the ACA took effect among all demographic groups. Taken together, the ACA's individual mandate, marketing efforts, and effects on how people perceive the value of having insurance outweighed the impacts of changes in rating and benefit rules. PMID- 29992802 TI - What Commissioner Gottlieb's FDA Is Doing to Lower Prescription Drug Prices and Steps Congress Can Take to Help. AB - Issue: Prescription drug prices have been climbing, creating significant barriers for patients. Since becoming U.S. Food and Drug Administration (FDA) Commissioner, Scott Gottlieb announced an action plan and several policy changes to increase generic drug competition and transparency to address high prescription drug prices. Goal: This issue brief aims to explain the FDA's plan of action and assess its implementation to date. It also aims to assess whether FDA actions, if implemented, address the known problems leading to high drug pricing. Methods: We analyzed the FDA's announced plans and actions as of March 31, 2018, and compared them to a comprehensive list of potential actions that could improve price competition among drug manufacturers included in our report, Getting to the Root of High Prescription Drug Prices: Drivers and Potential Solutions. Findings: The FDA's plan includes actions that could indirectly lower prescription drug prices through increased competition. The agency has made progress in implementing its proposed changes, but has not fully executed them. The FDA could use its broad authority over the approval of drug products to take additional actions that improve market competition. Congress also could take action to support the FDA's efforts in increasing competition and addressing anticompetitive behaviors. Conclusion: Implementation of the FDA's vision could create a more competitive drug market leading to more affordable drugs for patients. The FDA should consider additional steps under its current authority to address factors that impact competition and prices, while Congress should do more to support the FDA's work to lower prescription drug prices by working with the FDA and other federal agencies. PMID- 29992803 TI - Assessing the Promise and Risks of Income-Based Third-Party Payment Programs. AB - Issue: Consumers' concerns about affordability limit participation in ACA marketplaces. Funded by local hospital systems and run by independent nonprofits, third-party payment (TPP) programs improve affordability for low-income consumers by paying premium costs not covered by tax credits. Goal: To assess the potential of TPP to make marketplace coverage more affordable, without harming insurance risk pools. Methods: Interviews in May and June 2016 with program administrators, hospital systems, carriers, and consumer groups in five localities and the Washington State marketplace. Key Findings: The most effective local program reached 1,148 people, or 25 percent of all eligible marketplace enrollees. Other local programs served between 202 and 934 consumers; the Washington State program reached 1,133. Findings suggest that without TPP, numerous beneficiaries would have remained uninsured. Hospitals funding these programs reported net financial benefits, with declines in uncompensated care exceeding program costs. Carriers reported no adverse selection in these carefully designed programs. Conclusions: Widespread adoption of TPP could help additional low-income consumers obtain marketplace coverage. Hospitals' financial gains from TPP programs make replication more feasible. However, broader policies, such as increased premium tax credits and cost-sharing reductions, are likely needed for major nationwide improvements to affordability. PMID- 29992804 TI - Biomimetic, Flexible, and Self-Healable Printed Silver Electrode by Spontaneous Self-Layering Phenomenon of a Gelatin Scaffold. AB - Organic-inorganic hybrid layer-by-layer (LBL) composite structures can not only increase the strength and ductility of materials but also well disperse nanomaterials for better-conducting pathways. Here, we discovered the self assembly process of an organic and silver (Ag) LBL hybrid structure having excellent sustainability during the long-term bending cycle. During the assembly process, the organic and Ag hybrid structure can be self-assembled into a layered structure. Unlike other conventional LBL fabrication processes, we applied the hydrogel scaffold of a biological polymer, which can spontaneously phase separate into an LBL structure in a water/alcohol solvent system. This new hydrogel-based Ag LBL patterns can successfully be printed on a flexible polyimide film without nozzle-clogging problem. Although these Ag LBL patterns cracked during the bending cycle, carbonized organic compounds between the Ag layers help to self heal within few minutes at a low temperature (<80 degrees C). On the basis of our new hydrogel-based Ag ink, we could fabricate a fully printed reliable microscale flexible heater. We expect that our self-layering phenomenon can expand to the broad research field of flexible electronics in the near future. PMID- 29992805 TI - Interference-Enhanced Raman Spectroscopy as a Promising Tool for the Detection of Biomolecules on Raman-Compatible Surfaces. AB - Raman spectroscopy in combination with appropriate sample preparation strategies, for example, enrichment of bacteria on metal surfaces, has been proven to be a promising approach for rapidly diagnosing infectious diseases. Unfortunately, the fabrication of the required chip substrates is usually very challenging due to the lack of feasible instruments that can be used for quality control in the surface modification process. The intrinsically weak Raman signal of the biomolecules, employed for the enrichment of the micro-organisms on the chip surface, does not allow for monitoring of the successful immobilization by means of a Raman spectroscopic approach. Within this contribution, we demonstrate how a simple modification of a plain aluminum surface enables enhancement (or a decrease, if desired) of the Raman signal of molecules deposited on that surface. The manipulation of the Raman signal strength is achieved via exploiting interference effects that occur, if the highly reflective aluminum surface is modified with thin layers of transparent dielectrics like aluminum oxide. The thicknesses of these layers were determined by theoretical considerations and calculations. For the first time, it is shown that the interference effects can be used for the detection of biomolecules as well by investigating the siderophore ferrioxamine B. The observed degree of enhancement was approximately 1 order of magnitude. Moreover, the employed aluminum/aluminum oxide layers have been thoroughly characterized using atomic force and scanning electron microscopy as well as X-ray reflectometry and UV-Vis measurements. PMID- 29992806 TI - Emission Tuning of Heteroleptic Arylborane-Ruthenium(II) Complexes by Ancillary Ligands: Observation of Strickler-Berg-Type Relation. AB - Novel heteroleptic arylborane-ruthenium(II) complexes having a series of ancillary ligands L' ([Ru(B2bpy)L'2]2+) in CH3CN showed low-energy/intense metal to-ligand charge transfer (MLCT)-type absorption and intense/long-lived emission compared to the reference complexes. The spectroscopic and photophysical properties of [Ru(B2bpy)L'2]2+ were shown to be manipulated synthetically by the electron-donating ability of the ancillary ligand(s). The intense and long-lived emission observed for [Ru(B2bpy)L'2]2+ in CH3CN at 298 K is responsible for the accelerated radiative and decelerated nonradiative decay processes, which are controllable through the electronic structures of the ancillary ligand(s). On the basis of the present systematic study, furthermore, we succeeded in demonstrating the Strickler-Berg-type relation between the molar absorption coefficients of the MLCT bands and the radiative rate constants of the complexes. PMID- 29992807 TI - Multifunctional Nanocracks in Silicon Nanomembranes by Notch-Assisted Transfer Printing. AB - Manipulating nanocracks to produce various nanodevices has attracted increasing interest. Here, based on the mature transfer printing technique, a novel notch assisted transfer printing technique was engaged to produce nanocracks by simply introducing notch structures into the transferred nanomembranes. Both experiments and finite element simulations were used to elucidate the probability of nanocrack formation during the transfer process, and the results demonstrated that the geometry of nanomembranes played a key role in concentrating stress and producing nanocracks. We further demonstrated that the obtained nanocrack can be used as a surface-enhanced Raman scattering substrate because of the significant enhancement of electric fields. In addition, the capillary condensation of water molecules in the nanocrack led to an obvious change of resistance, thus providing an opportunity for the crack-based structure to be used as an ultrasensitive humidity sensor. The current approach can be applied to producing nanocracks from multiple materials and will have important applications in the field of nanodevices. PMID- 29992808 TI - Co3O4-Au Polyhedra: A Multifunctional Signal Amplifier for Sensitive Photoelectrochemical Assay. AB - Taking the zeolitic imidazolate framework (ZIF-67) as the precursor, p-type semiconducting Co3O4-Au polyhedra were synthesized and used as the signal amplifier to construct a sensitive photoelectrochemical (PEC) sensor for caspase 3 activity assay. Here, the n-type semiconductor Bi2S3-modified indium-tin oxide (ITO) slice was used as the photoelectrode. After immobilization of the biotin DEVD-peptide (biotin-Gly-Asp-Gly-Asp-Glu-Val-Asp-Cys) onto the Bi2S3 surface, the streptavidin-labeled Co3O4-Au polyhedra were introduced to the sensing platform via the specific interaction between biotin and streptavidin. The Co3O4-Au polyhedra can not only quench the photocurrent of the Bi2S3 because of the competitive consumption of electron donors and exciting light energy (p-n-type semiconductor quenching effect), but also act as peroxidase mimetics to produce catalytic precipitate. Additionally, the steric hindrance effect from the Co3O4 Au polyhedra will decrease the PEC response of the Bi2S3. Ingeniously, the precipitates can not only deposit on the ITO electrode to decrease the photocurrent of PEC sensor, but also act as electron acceptors to scavenge the photogenerated electrons of Co3O4-Au polyhedra, leading to enhanced quenching ability of the Co3O4-Au polyhedra. When caspase-3 exists, caspase-3 can specifically recognize and cleave the biotin-DEVD-peptide, resulting in the increase of PEC response. Based on the multifunctional Co3O4-Au polyhedra, caspase-3 is detected sensitively with a linear range from 0.5 to 50 ng mL-1 and limit of detection down to 0.10 ng mL-1. The Co3O4-Au polyhedra provide a novel signal amplifier to construct PEC sensing platform and may have potential applications in bioanalysis, disease diagnostics, and clinical biomedicine. PMID- 29992809 TI - High-Performance Ternary Nonfullerene Polymer Solar Cells with Both Improved Photon Harvesting and Device Stability. AB - Efficiency and stability of polymer solar cells (PSCs) are the two most significant decisive factors for the purpose of actual applications. Here, highly efficient and stable ternary PSCs were fabricated by incorporating two well compatible polymer donors (poly[4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2- b;4,5- b0]dithiophene-2,6-diyl- alt-(4-(2-ethylhexyl)-3-fluorothieno[3,4- b]thiophene-)-2-carboxylate-2-6-diyl] and poly[[9-(1-octylnonyl)-9 H-carbazole 2,7-diyl]-2,5-thiophenediyl-2,1,3-benzothiadiazole-4,7-diyl-2,5-thiophenediyl]) with one narrow band gap nonfullerene acceptor (3,9-bis(2-methylene-(3-(1,1 dicyanomethylene)-indanone)-5,5,11,11-tetrakis(4-hexylphenyl)-dithieno[2,3- d:2',3'- d']- s-indaceno[1,2- b:5,6- b']dithiophene)). It is found that Forster resonance energy transfer acts as an efficient pathway to further strengthen photon harvesting in this ternary system, which results in a significant improvement in current density ( JSC) without sacrificing the strong absorption of binary blends in the near-infrared region. Meanwhile, both of the inverted and conventional ternary PSCs exhibit better stability compared with the related binary PSCs in air condition because of the interlocked morphology in ternary films. The optimized ternary PSCs exhibit an outstanding power conversion efficiency (PCE) of 9.53% resulting from the synchronous improvements in JSC and fill factor. Moreover, this ternary strategy can be further confirmed by the use of an ultranarrow-band gap nonfullerene acceptor IEICO-4F, and the champion PCE of ternary PSCs reaches to 12.15%. PMID- 29992810 TI - Graphene/Boron Nitride-Polyurethane Microlaminates for Exceptional Dielectric Properties and High Energy Densities. AB - Hexagonal boron nitride (h-BN) has tremendous potential for dielectric energy storage by rationally assembling with graphene. We report the fabrication of microlaminate composites consisting of alternating reduced graphene oxide (rGO) and h-BN nanosheets embedded in a polyurethane (PU) matrix using a novel, two step bidirectional freeze casting process. Porous, highly-aligned rGO-PU aerogels having ultrahigh dielectric constants with relatively high dielectric losses and low dielectric strengths are fabricated by initial freeze casting. The losses are suppressed, whereas the dielectric strengths are restored by assembling the porous rGO-PU skeleton with electrically insulating BN-PU tunneling barrier layers in the second freeze casting routine. The ligaments bridging the conductive rGO-PU layers are effectively removed by the BN-PU barrier layers, eliminating the current leakage in the transverse direction. The resultant rGO PU/BN-PU microlaminate composites deliver a remarkable dielectric constant of 1084 with a low dielectric loss of 0.091 at 1 kHz. By virtue of synergy arising from both the rGO-PU layers with a high dielectric constant and the BN-PU barrier layers with a high dielectric strength, the microlaminate composites present a maximum energy density of 22.7 J/cm3, 44 folds of the neat rGO-PU composite acting alone. The promising overall dielectric performance based on a microlaminate structure offers a new insight into the development of next generation dielectric materials. PMID- 29992812 TI - The Herbicide Glyphosate Negatively Affects Midgut Bacterial Communities and Survival of Honey Bee during Larvae Reared in Vitro. AB - Effects of glyphosate on survival, developmental rate, larval weight, and midgut bacterial diversity of Apis mellifera were tested in the laboratory. Larvae were reared in vitro and fed diet containing glyphosate 0.8, 4, and 20 mg/L. The dependent variables were compared with negative control and positive control (dimethoate 45 mg/L). Brood survival decreased in 4 or 20 mg/L glyphosate treatments but not in 0.8 mg/L, and larval weight decreased in 0.8 or 4 mg/L glyphosate treatments. Exposure to three concentrations did not affect the developmental rate. Furthermore, the intestinal bacterial communities were determined using high-throughput sequencing targeting the V3-V4 regions of the 16S rDNA. All core honey bee intestinal bacterial phyla such as Proteobacteria (30.86%), Firmicutes (13.82%), and Actinobacteria (11.88%) were detected, and significant changes were found in the species diversity and richness in 20 mg/L glyphosate group. Our results suggest that high concentrations of glyphosate are deleterious to immature bees. PMID- 29992811 TI - Enantioselective Ruthenium-Catalyzed Benzocyclobutenone-Ketol Cycloaddition: Merging C-C Bond Activation and Transfer Hydrogenative Coupling for Type II Polyketide Construction. AB - The first enantioselective intermolecular metal-catalyzed cycloadditions of benzocyclobutenones via C-C bond oxidative addition are described. In the presence of a ruthenium(0) complex modified by ( R)-DM-SEGPHOS, tetralone-derived ketols and benzocyclobutenones combine to form cycloadducts with complete regio- and diastereoselectivity and high enantioselectivity. Using this method, the "bay region" substructure of the angucycline natural product arenimycin was prepared. PMID- 29992814 TI - Type-II Multiferroic Hf2VC2F2 MXene Monolayer with High Transition Temperature. AB - Achieving multiferroic two-dimensional (2D) materials should enable numerous functionalities in nanoscale devices. Until now, however, predicted 2D multiferroics are very few and with coexisting yet only loosely coupled (type-I) ferroelectricity and magnetism. Here, a type-II multiferroic MXene Hf2VC2F2 monolayer is identified, where ferroelectricity originates directly from its magnetism. The noncollinear 120 degrees Y-type spin order generates a polarization perpendicular to the spin helical plane. Remarkably, the multiferroic transition is estimated to occur above room temperature. Our investigation should open the door to a new branch of 2D materials in the pursuit of intrinsically strong magnetoelectricity. PMID- 29992813 TI - Degradation of 4,4'-Dinitrocarbanilide in Chicken Breast by Thermal Processing. AB - Nicarbazin is one of the major anticoccidials used in broiler feeds. The compound 4,4'-dinitrocarbanilide (DNC) is the marker residue of concern left from nicarbazin in chicken meat. The effect of thermal processing on DNC content accumulated in chicken breast was assessed, and samples were analyzed by liquid chromatography-tandem mass spectrometry. Five conventional cooking methods were evaluated: boiling, grilling, microwaving, frying, and roasting. To ensure DNC in meat, broilers were fed nicarbazin without withdrawal period. All heating methods surpassed the 70 degrees C end point core temperature in chicken breast. Maximum DNC degradation was reached at 10 min for boiling, at 30 min for grilling, and at 2 min for microwaving, and no further reduction was observed for longer thermal processing time. Boiling was more efficient in reducing DNC (69%). Grilling, microwaving, and frying achieved on average 55% of degradation. The outcomes reported herein may be considered in decision-making regarding further review of maximum residue limits. PMID- 29992815 TI - A Nitrido-bridged Heterometallic Ruthenium(IV)/Iron(IV) Phthalocyanine Complex Supported by A Tripodal Oxygen Ligand, [Co(eta5-C5H5){P(O)(OEt)2}3]-: Synthesis, Structure, and Its Oxidation to Give Phthalocyanine Cation Radical and Hydroxyphthalocyanine Complexes. AB - Dinuclear iron nitrido phthalocyanine complexes are of interest owing to their applications in catalytic oxidation of hydrocarbons. While nitrido-bridged diiron phthalocyanine complexes are well documented, the oxidation chemistry of heterodinuclear iron(IV) phthalocyanine nitrides has not been well explored. In this paper we report on the synthesis of a heterometallic FeIV/RuIV phthalocyanine nitride and its oxidation to yield phthalocyanine cation radical and hydroxyphthalocyanine complexes. Treatment of [FeII(Pc)] (Pc2- = phthalocyanine dianion) with [RuVI(LOEt)(N)Cl2] (LOEt- = [Co(eta5 C5H5){P(O)(OEt)2}3]-) (1) afforded the heterometallic MU-nitrido complex [Cl2(LOEt)RuIV(MU-N)FeIV(Pc)(H2O)] (2) that contains an RuIV=N = FeIV linkage with the Ru-N and Fe-N distances of 1.689(6) and 1.677(6) A, respectively, and Ru N-Fe angle of 176.0(4) degrees . Substitution of 2 with 4- tert-butylpyridine (Bupy) gave [Cl2(LOEt)RuIV(MU-N)FeIV(Pc)(Bupy)]. The cyclic voltammogram of 2 displayed a reversible Pc-centered oxidation couple at +0.18 V versus Fc+/0 (Fc = ferrocene). The oxidation of 2 with [N(4-BrC6H4)3]SbCl6 led to isolation of the cationic complex [Cl2(LOEt)RuIV(MU-N)FeIV(Pc.+)(H2O)][SbCl6]0.85[SbCl5(OH)]0.15 (2[SbCl6]0.85[SbCl5(OH)]0.15), whereas that with PhICl2 yielded the chloride complex [Cl2(LOEt)RuIV(MU-N)FeIV(Pc.+)Cl] (3). Complexes 2[SbCl6]0.85[SbCl5(OH)]0.15 and 3 have been characterized by X-ray crystallography. The UV/visible spectra of 2+ (lambdamax = 515 and 747 nm) and 3 (lambdamax = 506 and 748 nm) displayed absorption bands that are characteristic of Pc cation radical. The EPR spectrum of 3 showed a signal with the g value of 2.0012 (width = 5 G) that is consistent with an organic radical. The spectroscopic data support the formulation of 2+ and 3 as RuIV-FeIV Pc cation radical complexes. The reaction of 2 with PhI(CF3CO2)2 in dried CH2Cl2 afforded a mixture of [Cl2(LOEt)RuIV(MU-N)FeIV(Pc.+)(CF3CO2)] (4) and a hydroxyphthalocyanine complex, [Cl2(LOEt)RuIV(MU-N)FeIV(Pc-OH)(H2O)](CF3CO2) (5), whereas that in wet CH2Cl2 (containing ca. 0.5% water) led to isolation of 5 as the sole product. Complex 4 was independently prepared by salt metathesis of 3 with AgCF3CO2. PMID- 29992816 TI - A High Voltage Cathode Material for Sodium Batteries: Na3V(PO4)2. AB - A novel layered Na3V(PO4)2 compound was synthesized and studied as a positive electrode material for Na-ion batteries for the first time. The as-prepared material exhibits two relatively high voltage plateaus at around 3.6 and 4.0 V vs Na+/Na. Operando X-ray diffraction investigation provides insight into the mechanisms of structural transformations upon cycling. PMID- 29992817 TI - Visible Photosensitization of trans-Styrylpyridine Coordinated to fac [Re(CO)3(dcbH2)]+: New Insights. AB - A strategic methodology has been developed to effectively synthesize the fac [Re(CO)3(dcbH2)( trans-stpy)]+ complex, where dcbH2 = 2,2'-bipyridine-4,4' dicarboxylic acid and trans-stpy = trans-4-styrylpyridine, which has been designed to efficiently absorb visible light. The complex exhibits outstanding trans-to- cis photoisomerization with 436 nm irradiation (Phi trans-> cis = 0.50 +/- 0.03), in contrast to the photochemical behavior previously reported in the literature (Faustino, L. A.; et al. Inorg. Chem. 2018, 57, 2933-2941). The main emphasis here is to address the synthetic strategy for obtaining the actual complex, its characterization, and an accurate description of its photochemical and photophysical behavior, which reveal new insights into this complex. PMID- 29992818 TI - Control of Crystallinity in PbPc:C60 Blend Film and Application for Inverted Near Infrared Organic Photodetector. AB - Inverted near-infrared (NIR) organic photodetectors (OPDs) are required to combine the OPDs with an n-channel silicon-based integrated circuit. NIR absorption in the 930-960 nm range is important because the intensity of solar irradiation is low in this wavelength regime. Here, we controlled the crystallinity of lead(II) phthalocyanine (PbPc) in a PbPc:C60 blend film to obtain NIR absorption. To form a triclinic phase responsible for NIR light absorption, a substrate was heated during fabrication and C60 was used as a templating layer, as well as an electron extraction layer, for an inverted structure. NIR absorption near 950 nm was enhanced, and the structural properties of the film changed dramatically. The OPD with enhanced NIR absorption exhibited a responsivity of 244 mA/W and an external quantum efficiency of 31.1% at a reverse bias of -3 V and 970 nm. The OPD detectivity also increased to 9.01 * 1012 and 1.36 * 1011 cm Hz1/2/W under a zero bias and a reverse bias of -3 V, respectively. PMID- 29992819 TI - Discrete pi-Stacks of Perylene Bisimide Dyes within Folda-Dimers: Insight into Long- and Short-Range Exciton Coupling. AB - Four well-defined pi-stacks of perylene bisimide (PBI) dyes were obtained in solution by covalent linkage of two chromophores with spacer units of different length and sterical demand. Structural elucidation of the folda-dimers by in depth nuclear magnetic resonance studies and geometry optimization at the level of density functional theory suggest different, but highly defined molecular arrangements of the two chromophores in the folded state enforced by the various spacer moieties. Remarkably, the dye stacks exhibit considerably different optical properties as investigated by UV/vis absorption and fluorescence spectroscopy, despite only slightly different chromophore arrangements. The distinct absorption properties can be rationalized by an interplay of long- and short-range exciton coupling resulting in optical signatures ranging from conventional H-type to monomer like absorption features with low and appreciably high fluorescence quantum yields, respectively. To the best of our knowledge, we present the first experimental proof of a PBI-based "null-aggregate", in which long- and short-range exciton coupling fully compensate each other, giving rise to monomer-like absorption features for a stack of two PBI chromophores. Hence, our insights pinpoint the importance of charge-transfer mediated short-range coupling that can significantly influence the optical properties of PBI pi stacks. PMID- 29992820 TI - Functionalizing a Metal-Organic Framework by a Photoassisted Multicomponent Postsynthetic Modification Approach Showing Highly Effective Hg(II) Removal. AB - We present here the first use of a photoassisted multicomponent postsynthetic modification method to anchor a ZIF-90 scaffold with a pyrimidinethione fragment. The resultant materials, namely, ZIF-90-THP and ZIF-90-THF, show ultrahigh Hg(II) adsorption capacity values of up to 596 and 403 mg/g, respectively, relative to the pristine ZIF-90, which just affords a corresponding value of 47 mg/g, suggesting a 12.7- and 8.6-fold enhancement in the Hg(II) adsorption capacity. PMID- 29992821 TI - Direct Catalytic Asymmetric Cyclopropylphosphonation Reactions of N,N-Dialkyl Groups of Aniline Derivatives by Ru(II)-Pheox Complex. AB - Novel catalysis involving phosphonomethylation of N-methylaniline and asymmetric cyclopropylphosphonation reactions of N,N-diethylaniline derivatives with diazomethylphosphonates are reported. Optically active cyclopropylphosphonate derivatives were directly synthesized from diazomethylphosphonates and N,N diethylaniline derivatives catalyzed by a Ru(II)-Pheox complex in one step in good yields and high diastereoselectivities (up to trans/ cis = > 99:1<) and enantioselectivities (up to 99% ee). D-labeling mechanistic studies of phosphonomethylation and cyclopropylphosphonation suggested that an enamine or iminium intermediate was generated in the reaction process. PMID- 29992822 TI - In silico approaches for investigating the binding propensity of apigenin and luteolin against class I HDAC isoforms. AB - AIM: Aberrant activity of class I histone deacetylases (HDACs) has strong implications for various cancers. Targeting these HDACs with synthetic HDAC inhibitors has shown significant side effects such as atrial fibrillation and QT prolongation emphasizing the need of natural inhibitors as substitutes to synthetic ones. RESULTS: The binding propensity of the two plant-derived inhibitors apigenin and luteolin towards class I HDAC isoforms was checked using extra-precision molecular docking and implicit solvation MMGBSA. Apigenin showed a superior binding affinity against these isoforms as compared to luteolin. Both inhibitors docked stable to the binding pocket of these HDACs as determined by molecular dynamics simulation study. CONCLUSION: Apigenin and luteolin may serve as substitutes to synthetic inhibitors for effective HDAC based anticancer therapy. PMID- 29992823 TI - Erratum. AB - S Wang, J Liu, F Yuan et al. The ability of ADC measurements in the assessment of patients with stage I endometrial carcinoma based on three risk categories. Acta Radiol. Epub ahead of print 18 April 2018. DOI: 10.1177/0284185118768105. In this article, the authorship was incorrectly listed as "Shijia Wang, Jia Liu, Feng Yuan, Xiaojun Chen, Fenghua Ma, Guofu Zhang and Xiaomei Tian" in the initial OnlineFirst version. The online and print versions have been updated to reflect the correct authorship, "Jia Liu, Feng Yuan, Shijia Wang, Xiaojun Chen, Fenghua Ma, Guofu Zhang and Xiaomei Tian." PMID- 29992824 TI - Effects of Information Technology-Based Two-Way Referral on Diagnosis and Management of Cervical Lesions: A Cluster-Controlled Trial in China. AB - This study investigates the effectiveness of information technology-based 2-way referral in the diagnosis and management of cervical lesions in Minhang District, Shanghai, China. Women who underwent screening for cervical lesions in 4 community health centers constituted the intervention group, whereas women from the other 9 community health centers were included as controls. The diagnosis rate of cervical lesions was higher in the intervention group (7.61%) than in the control group (0.36%; P = .000). The diagnosis rate of early cervical lesion was 97.11% in the intervention group and 85.71% in the control group, showing no statistically significant differences ( P = .080). However, early diagnosis rate of precancerous lesion was much higher in the intervention group (95.45%) compared with the control group (64.29%; P = .001). In conclusion, higher effectiveness of early diagnosis and management of cervical lesions was observed in the intervention group compared with the control group. PMID- 29992825 TI - Ask the experts: computational chemistry. PMID- 29992826 TI - Prevalence and correlates of psychotic experiences in a nationally representative sample of Australian adolescents. AB - OBJECTIVE: Despite growing literature on psychotic experiences, no nationally representative study has reported on the prevalence of both hallucinatory experiences and delusional experiences in Australian adolescents. Also, while many studies have examined the association between psychotic experiences and certain demographic and clinical correlates, there are more variables of interest to be investigated, including disordered eating behaviour and hours of sleep. The aims of this study were to examine (1) the prevalence of hallucinatory experiences and delusional experiences in Australian adolescents, and (2) the associations between different types of psychotic experiences with a broad range of demographic, clinical, and psychosocial variables. METHODS: A random sample of Australian adolescents aged 14- to 17-year-olds were recruited in 2013-2014 as part of the Young Minds Matter Survey. Participants completed self-report questions regarding five different psychotic experience types (auditory and visual hallucinatory experiences, and thoughts read, special messages, spied upon) experienced in the past 12 months. Using logistic regression analyses, we investigated associations between psychotic experiences and demographic, clinical, and psychosocial factors. RESULTS: The 12-month prevalence ranged from 3.3% (95% confidence interval = [2.6, 4.3]) for special messages to 14.0% (95% confidence interval = [12.3, 15.8]) for auditory hallucinatory experiences. At the bivariate level, each psychotic experience subtype was associated with increased likelihood of major depression, being bullied, psychological distress, low self-esteem, mental health service use and insufficient sleep (<8 hours per night). Multivariate analyses revealed both auditory and visual hallucinatory experiences were associated with an increased likelihood of four of these variables (depression, being bullied, service use, insufficient sleep), whereas associations with delusional experiences were inconsistent. CONCLUSION: Hallucinatory and delusional experiences are common in Australian adolescents. Hallucinatory experiences, rather than delusional experiences, may be more clinically relevant in this demographic. When psychotic experiences are endorsed by adolescents, further assessment is indicated so as to ascertain more detail on the phenomenology of the experiences to better understand their clinical relevance. PMID- 29992827 TI - Quantum crystallography in medicinal chemistry. PMID- 29992828 TI - Emotion regulation contributes to the well-being of patients with autoimmune diseases through illness-related emotions: A prospective study. AB - This prospective study aimed to examine whether illness-related negative emotions mediate the relationship of cognitive reappraisal and expressive suppression to the well-being of 99 patients with rheumatoid arthritis or multiple sclerosis. After adjusting for disease and patient-related parameters, only cognitive reappraisal was associated with physical and psychological well-being through emotions. Expressive suppression was associated with psychological well-being only for patients reporting less use of cognitive reappraisal. These results underscore the need for prospective studies that will investigate the long-term impact of emotion regulation on adaptation to chronic illness and the conditions under which this impact takes place. PMID- 29992829 TI - Anticarcinogenic effect of indole-3-carbinol (I3C) on human hepatocellular carcinoma SNU449 cells. AB - Many cruciferous vegetables, including cabbage, contain indole-3-carbinol (I3C), which is a known anticarcinogen. However, the anticarcinogenic effects of I3C on liver cancer have not been investigated. Therefore, this study was conducted to evaluate the anticarcinogenic effects of I3C in human hepatocellular carcinoma (HCC) SNU449 cells. The results of MTT and WST-1 assays indicated that treatment of SNU449 cells with I3C decreased viability in dose- and time-dependent manners, while colony formation assays indicated that I3C also inhibited proliferation of SNU449 cells. Moreover, fluorescence-activated cell sorter analysis showed that I3C induced apoptosis in SNU449 cells in dose- and time-dependent manners. Furthermore, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling revealed that I3C induced DNA fragmentation in SNU449 cells in a time-dependent manner, while Western blotting showed that apoptotic proteins such as p53, cleaved PARP, caspase-3, and caspase-7 were activated in SNU449 cells following treatment with I3C. Finally, reactive oxygen species-related protein peroxiredoxin-1 and thioredoxin-1 expression decreased in I3C-treated SNU449 cells. The aim of our study is to investigate the unknown mechanisms responsible for the apoptotic effects of I3C on human HCC SNU449 cells, and the results suggest that I3C may be useful for the prevention and treatment of liver cancer. PMID- 29992831 TI - Clinical efficacy of once-daily micronized purified flavonoid fraction 1000 mg tablet in patients with symptomatic chronic venous disease. AB - AIM: To investigate the clinical efficacy of micronized purified flavonoid fraction (MPFF) 1000 mg given as a single 1000 mg tablet once daily in patients suffering from chronic venous disease (CVD) vs MPFF 500 mg twice daily. METHODS: In an international, randomized, double-blind, parallel-group study, patients classified C0s to C4 according to Clinical Etiological Anatomic Pathophysiologic [CEAP] classification and with leg pain graded as superior to 4 cm on a 10-cm visual analog scale (VAS), were treated for 8 weeks with either MPFF 1000 mg once daily or MPFF 500 mg twice daily. The present post-hoc analysis focuses on the effect of treatment over time in patients randomized to the MPFF 1000 mg group. Leg pain was assessed at each follow-up visit by VAS. VAS scores over time were compared between each visit using paired Student t-tests. RESULTS: In total, 87 patients out of 174 were randomized to the MPFF 1000 mg group. Mean age +/- SD was 49.1 +/- 12.2 years, most of the patients were female (81.6%), the main CEAP classes of the most affected leg were C1 (20.7%), C2 (39.1%), C3 (33.33%), and the mean duration of CVD was 14.6 +/- 10.9 years. Patients with previous CVD treatment represent 27.6% of the patients. A MPFF 1000 mg tablet once daily was associated with a significant and continuous reduction in leg pain throughout the treatment period: -1.54 cm (+/-1.45) from baseline to week 2 (p < .01), -1.11 cm (+/-1.06) from week 2 to week 4 (p < .01), -1.57 cm (+/-1.05) from week 4 to week 8 (p < .01). CONCLUSIONS: The new MPFF 1000 mg dose regimen in once daily tablets was associated with a rapid and continuous reduction in leg pain throughout the 8 week treatment period. PMID- 29992830 TI - Elevated levels of insulin-like growth factor-binding protein 1 predict outcome after acute myocardial infarction: A long-term follow-up of the glucose tolerance in patients with acute myocardial infarction (GAMI) cohort. AB - OBJECTIVE: To investigate the long-term prognostic value of insulin-like growth factor-binding protein 1 in patients with acute myocardial infarction. METHODS: Patients ( n = 180) with admission glucose < 11 mmol/L without previously known diabetes admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/severe heart failure) until the end of 2011 (median 11.6 years). Fasting levels of insulin-like growth factor-binding protein 1 at day 2 were related to outcome in Cox proportional hazard regression analyses. RESULTS: Median age was 64 years, 69% were male and median insulin-like growth factor-binding protein 1 was 20 ug/L. Total mortality was 34% ( n = 61) and 44% ( n = 80) experienced a cardiovascular event during a median follow-up time of 11.6 years. After age adjustment, insulin-like growth factor-binding protein 1 was associated with all-cause (1.40; 1.02-1.93, p = 0.039) and cancer mortality (2.09; 1.15-3.79, p = 0.015) but not with cardiovascular death ( p = 0.29) or cardiovascular events ( p = 0.57). After adjustments also for previous myocardial infarction, previous heart failure and body mass index, insulin-like growth factor-binding protein 1 was still associated with all-cause mortality (1.38; 1.01-1.89, p = 0.046). CONCLUSION: In patients with acute myocardial infarction without previously known diabetes, high insulin-like growth factor-binding protein 1 was associated with long-term all-cause and cancer mortality but not with cardiovascular events. PMID- 29992833 TI - Need and acceptability of story books intended to help with the process of informing children about their HIV status in Malawi: a mixed methods study. AB - The rate of disclosure of HIV status to children living with HIV in sub-Saharan Africa remains low despite the World Health Organisation's recommendation that children should be told about their HIV status by the age of 12 years. Authors of previous studies have identified lack of disclosure materials as the main barrier to disclosure of HIV status. This study aimed to assess the need and acceptability of a series of age-appropriate children story books intended to help with informing children about their HIV status. Questionnaires, interviews, and focus group discussions were used to collect data from caregivers, healthcare workers, and school teachers, adolescents living with HIV, and community leaders across the three administrative regions of Malawi. Information about the need and acceptability of the story books and the sociodemographic characteristics of the participants was collected using reliable instruments. Quantitative data were tabulated while thematic analysis was used to analyse qualitative data. Almost 600 participants responded to the survey questionnaire, and 19 interviews and 12 focus groups were conducted with 106 participants. Ninety-eight per cent of participants supported the idea of developing the proposed series of story books and reported that they would use the books once they are developed. Most of the participants expressed that the books will help to improve their knowledge and understanding of HIV disclosure, increase their confidence on how to disclose and help to provide consistent information about HIV disclosure to children.The results of this study show a high acceptability rate of the story books. The process of HIV disclosure to children is a very complex issue that will require the development of guidelines and materials that are rigorously evaluated prior to dissemination. PMID- 29992832 TI - Identification of the first homozygous POLG mutation causing non-syndromic ovarian dysfunction. AB - OBJECTIVE: To investigate the genetic cause of non-syndromic ovarian dysfunction in a patient from a consanguineous family. METHODS: This study examined a patient with irregular menstrual cycles and abnormal oocytes. The patient had undergone irregular hormone replacement therapy over 3 years to adjust the menstrual cycle and improve ovarian function. Prior to ovarian stimulation in our hospital, 3 months of androgen and regular hormone therapy were used as an intervention method. No follicular development was detected in the subsequent three cycles using letrozole treatment. The patient then received a constantly adjusted dose of menotropins, but produced only one oocyte. RESULTS: Whole-exome sequencing analysis identified the first homozygous POLG mutation (c.2890C > T; p.R964C) associated with ovarian dysfunction. Sanger sequencing was used to validate. In silico analysis suggested that the p.R964C mutation was pathogenic. Conservation analysis demonstrated that R964 was an important site for the DNA polymerase function of POLG. CONCLUSIONS: Biallelic mutations in POLG may be associated with ovarian dysfunction. This study has improved our understanding of POLG-related genetic mutations in ovarian dysfunction, and the mode of inheritance of certain sequence variants. This information will assist genetic counseling and precision medicine in the future. PMID- 29992834 TI - Words with weight: The construction of obesity in eating disorders research. AB - In current public health discourse, obesity is conceptualized as a disease epidemic, with treatment being weight loss. The pursuit of weight loss as a treatment for the "disease" of obesity is in direct contradiction to the history of research in eating disorders, which has demonstrated the risks for the development of eating disorders. In this study, we critically examined the eating disorder literature to explore this contradiction. We analyzed 30 of the top cited articles in the eating disorder literature between 1994 and 2011, asking: how is the concept of obesity examined in eating disorder research? We identified tensions related to body mass index and the perceived associated risks of lower or higher body mass index, assumptions of the "causes" of fatness (i.e. overeating and inactivity), and the anti-diet voice challenging the prescription of dieting for those in fat bodies. In our analysis, we highlight the problematics of, for instance, prescribing a body mass index range of 20-24 in eating disorder recovery, how many studies in eating disorders do not problematize the presumption that a higher body mass index is necessarily associated with ill health, and a lack of cultural sensitivity and acknowledgment of intersectional spaces of belonging. We discuss these themes in the context of biomedical discourses of obesity contributing to the cultural thin ideal. We argue that biomedical discourses on obesity contribute to the thin ideal nuanced against discourses of healthism that permeate our society. Rather than an ideal of emaciation, it is an ideal of a healthy, productive person, often constructed as morally superior. The moral panic around obesity is evident throughout the eating disorder literature, which is a concern given that we would hope that the aim of eating disorder treatment would be to promote wellness for all-not only those who are thin. PMID- 29992835 TI - Radiation Exposure in Pediatric Intensive Care Unit Patients: How Much Is Too Much? AB - We aimed to determine median cumulative radiation exposure in pediatric intensive care unit (PICU) patients, proportion of patients with high radiation exposure (above annual average radiation per person of 6.2 mSv), and determine risk factors for high exposure. This was a retrospective chart review of PICU patients up to 18 years of age admitted to a large community hospital over 2 years. Radiologic studies and radiation exposure were determined for each patient, and total hospital radiation exposure was classified as high (>6.2 mSv) or not (<=6.2 mSv). Median radiation exposure per patient was 0.2 mSv (interquartile range = 2.1) and 11.7% of patients received >6.2 mSv radiation during their hospitalization. Factors associated with high radiation exposure included admission for trauma or surgery, number of computed tomography scans, age, and PICU length of stay (all P < .0001). We concluded that subsets of PICU patients are at risk of high radiation exposure. Policies and protocols may help minimize radiation exposure among PICU patients. PMID- 29992836 TI - Synthesis and evaluation of nitrofuranyl methyl N-heterocycles derivatives as novel antitubercular agents. AB - AIM: Tuberculosis (TB) is one of the world's deadliest chronic infectious diseases caused mainly by Mycobacterium tuberculosis (MTB). Many nitrofuran derivatives were found to possess promising anti-TB potential and have been widely studied. In our previous study, we discovered diazaspiro-nitrofuran IMB1701-1702 as potent anti-TB agents. METHODOLOGY: We report herein a series of nitrofuranyl methyl N-heterocycles based on IMB1701-1702. Results reveal that most of them show potent activity (minimum inhibitory concentration: <0.016-0.062 MUg/ml) against MTB H37Rv strain. Especially, compound 7h without cytotoxicity, has the same minimum inhibitory concentration value of <=0.016 MUg/ml as PBTZ169 against both MTB H37Rv strain and two clinically isolated multidrug-resistant MTB strains. CONCLUSION: The newly designed compound 7h might be a promising anti-TB candidate. PMID- 29992838 TI - A systematic review of parent-infant interaction in infants at risk of autism. AB - Social communicative precursors to autism spectrum disorder may influence how infants who are later diagnosed with autism spectrum disorder interact with their social partners and the responses they receive, thus bidirectionally influencing early social experience. This systematic review aimed to identify a developmental timeline for parent-infant interaction in the first 2 years of life in at-risk infants and in emergent autism spectrum disorder, and to examine any parent infant interaction associations with later social-communicative outcomes. In total, 15 studies were identified investigating parent-infant interaction in infants at familial autism risk (i.e. with an older sibling with autism spectrum disorder). Starting from the latter part of the first year, infants at risk of autism spectrum disorder (and particularly infants with eventual autism spectrum disorder) showed parent-infant interaction differences from those with no eventual autism spectrum disorder, most notably in infant gesture use and dyadic qualities. While parental interactions did not differ by subsequent child autism spectrum disorder outcome, at-risk infants may receive different 'compensatory' socio-communicative inputs, and further work is needed to clarify their effects. Preliminary evidence links aspects of parent-infant interaction with later language outcomes. We discuss the potential role of parent-infant interaction in early parent-mediated intervention. PMID- 29992837 TI - Suicidal ideation in non-depressed individuals: The effects of a chronic, misunderstood illness. AB - Chronic illness is a risk factor for suicide but is often explained with depression. Research has shown an increased suicide rate in patients with myalgic encephalomyelitis and chronic fatigue syndrome, but specific risk factors have been unexplored. We qualitatively analyzed responses from 29 patients who endorsed suicidal ideation but did not meet depression criteria. Two themes were developed: (1) feeling trapped and (2) loss of self, loss of others, stigma and conflict. Myalgic encephalomyelitis and chronic fatigue syndrome caused patients severe disability, restructured their lives, and inflicted serious pain. Participants emphasized that they were not depressed, but felt trapped by the lack of treatments available. PMID- 29992839 TI - The endoplasmic reticulum co-chaperone ERdj3/DNAJB11 promotes hepatocellular carcinoma progression through suppressing AATZ degradation. AB - AIM: The co-chaperone ERdj3/DNAJB11 is involved in the endoplasmic reticulum stress response observed in cancer cells. We hypothesized that ERdj3 functions as a hepatocellular carcinoma (HCC) oncogene by inhibiting AATZ degradation. MATERIALS & METHODS: ERdj3 and AATZ expressions were analyzed in 84 HCC patients. Cell proliferation, epithelial-mesenchymal transition marker expression, migration and invasiveness were assessed in HepG2 and Huh-7 cells. A murine xenograft tumor model was constructed. RESULTS: ERdj3 is upregulated in HCC tumors and cell lines. Tumor ERdj3 levels are positively associated with cirrhosis, enhanced HCC status, inferior survival outcomes and AATZ levels. ERdj3 suppresses AATZ degradation. ERdj3 overexpression enhances proliferation, epithelial-mesenchymal transition marker expression, migration, invasiveness and xenograft tumor growth in an AATZ-dependent manner. CONCLUSION: ERdj3 enhances HCC progression through suppressing AATZ degradation. PMID- 29992840 TI - Roles of large aggregating proteoglycans in human intervertebral disc degeneration. AB - Degeneration of the intervertebral discs, a natural progression of the aging process, is strongly implicated as a cause of low back pain. Aggrecan is the major structural proteoglycan in the extracellular matrix of the intervertebral disc. It is large, possessing numerous glycosaminoglycan chains and the ability to form aggregates in association with hyaluronan. The negatively charged glycosaminoglycan side chains in aggrecan in the nucleus pulposus of the intervertebral discs can bind electrostatically to polar water molecules, which are crucial for maintaining the well-hydrated state that enables the discs to undergo reversible deformation under compressive loading. A more in-depth understanding of the molecular basis of disc degeneration is essential to the design of therapeutic solutions to treat degenerative discs. Within this scope, we discuss the current knowledge concerning the structure and function of aggrecan in intervertebral disc degeneration. These data suggest that aggrecan plays a central role in the function and degeneration of the intervertebral disc, which may suggest potential aggrecan-based therapies for disc regeneration. PMID- 29992841 TI - Artificial intelligence: a new clinical support tool for stress echocardiography. PMID- 29992842 TI - Stratified medicine and child psychology and psychiatry: An old or new paradigm? PMID- 29992843 TI - The impact of risk minimization measures on compliance and prescribing practices of flupirtine in Germany. AB - OBJECTIVE: In response to safety concerns, risk minimization measures (RMM) for flupirtine were implemented in Europe in 2013 to reduce hepatotoxicity risk. This study aims to characterize compliance and prescribing practices of flupirtine before and after RMM implementation. RESEARCH DESIGN AND METHODS: A retrospective pre-post design cohort study was conducted in the outpatient setting using a longitudinal electronic medical record database in Germany. The study population included patients who initiated flupirtine. One-year pre- and post-implementation periods were assessed. MAIN OUTCOME MEASURES: Six RMM elements were evaluated, including indication of acute pain, use for maximum of 2 weeks, use when other analgesics are contraindicated, no pre-existing liver disease or alcohol abuse, no concomitant drug induced liver injury, and weekly liver function tests. RESULTS: The number of flupirtine users decreased by 34.4% from 18,291 in the pre implementation period (2012) to 12,000 in the post-implementation period (April 2015 to March 2016). Elements of RMM with substantial improvement included flupirtine prescription duration, where the proportion of patients with duration <=14 days increased significantly by 16.5% from 74.8% to 91.3% in the pre- and post-implementation periods, respectively. RMM with a moderate-to-high degree of compliance during the post-implementation period, although with a very small or no change from the pre- implementation period, included restriction of flupirtine prescribing to patients with acute pain when other analgesics are contraindicated, and avoiding use in patients with either pre-existing liver disease or concomitant drugs known to have a potential hepatotoxic effect. Weekly liver function tests had a low degree of compliance. CONCLUSIONS: These findings demonstrate that, while physicians restricted flupirtine prescriptions to short term use in the target population of acute pain, not all drug labeling elements were followed to the same extent in routine practice. PMID- 29992844 TI - A Vasculitis-Associated Neuromuscular and Vascular Hamartoma Presenting as a Fatal Form of Abdominal Cocoon. AB - Neuromuscular and vascular hamartoma (NMVH), also known as neuromesenchymal hamartoma, is a rare hamartomatous condition of the intestine. It usually presents with submucosal humps protruding in the intestinal lumen causing obstructive features. The other clinical manifestations are hematochezia or melena and protein-losing enteropathy. The etiopathogenesis of these lesions is not well known, although an association with small bowel Crohn's disease and diaphragm disease had been postulated, the latter related to chronic nonsteroidal anti-inflammatory drug intake. Only 24 cases of NMVH are reported in the English literature and all of them could be adequately cured by resection of the affected part of the bowel. Moreover, none of these cases presented with abdominal cocoon or showed any evidence of vasculitis. We describe a peculiar case of NMVH in a 45 year-old male who presented with abdominal cocoon with symptomatic recurrence and fatal outcome within a month of surgery. Histopathology revealed classical histomorphology of NMVH with evidence of vasculitis. This appears to be the first case of a fatal form of NMVH, presenting with abdominal cocoon and associated with vasculitis. PMID- 29992845 TI - Systemic lupus erythematosus and associated healthcare resource consumption in selected cities from the Russian Federation, Republic of Kazakhstan and Ukraine: the ESSENCE study. AB - OBJECTIVES: To evaluate healthcare resource (HR) consumption associated with Systemic Lupus Erythematosus (SLE) management in adult patients with active autoantibody positive disease in the Russian Federation, Republic of Kazakhstan, and Ukraine. METHODS: The ESSENCE was a retrospective, observational study, and included data on patients' clinical characteristics and SLE-related HR use (laboratory, biopsy, imaging tests, medications, visits to specialists, outpatient visits, hospitalizations) during 2010 from the 12 specialized rheumatologic centers. RESULTS: A total of 436 SLE patients were included in the analyses, with 232 patients being enrolled in Russia, 110 in Kazakhstan, and 94 in Ukraine. The mean age was 36-42 years and median SLE duration was 3-6.8 years across the countries. Extrapolation to total country population showed that, in 2010, visits to specialists (who assign treatment for organs involved/damaged by SLE) were the most frequently used HR (from 13,439 visits in Kazakhstan to 23,510 in Russia), followed by hospitalizations (from 2,950 in Kazakhstan to 6,267 in Russia) and outpatient visits (from 1,654 visits in Russia to 8,064 in Kazakhstan). Compared to chronic active patients (SLE persistent during last year), patients with relapsing-remitting SLE (at least one flare alternated by one remission per year) had a higher rate of visits to specialists (100% vs 60.8%, p < .001) and hospitalizations (98.9% vs 60.8%, p < .001). Compared to patients without flares, patients experiencing flares had a higher rate of unplanned visits to specialists (86.2% vs 6.3%, p < .001), were more often hospitalized (both ICU and non-ICU) (100.0% vs 50.0%, p < .001), and had a longer duration of ICU hospitalization (25.9 days vs 17.5 days, p < .001). CONCLUSIONS: Specialist visits are the most frequently consumed SLE-related healthcare recourse in the Commonwealth of Independent States (CIS) countries. A relapsing remitting SLE profile and the occurrence of flares significantly raise healthcare resource consumption. PMID- 29992846 TI - The impact of affective symptoms on personal recovery of patients with severe mental illness. AB - BACKGROUND: Clinical recovery is often defined as remission of symptoms. Personal recovery is described as growing beyond the catastrophic effects of mental illness, sometimes despite ongoing symptoms. AIMS: To examine the relationship between the severity of clinical symptom domains and personal recovery in patients with severe mental illness (SMI). METHODS: Symptom severity and personal recovery of 105 outpatients with SMI at Mentrum, part of Arkin Institute for Mental Health in Amsterdam, the Netherlands, were assessed using the Brief Psychiatric Rating Scale-Expanded Version (BPRS-E) and the Mental Health Recovery Measure (MHRM). Correlation and regression analyses were used to investigate the associations. RESULTS: The multiple regression analysis showed that only affective symptoms significantly predicted personal recovery, whereas neither positive nor negative symptom severity added to the explained variance in the model. CONCLUSION: The association between affective symptoms and personal recovery in patients with SMI implies that treatment of affective symptoms may advance personal recovery, and/or support of personal recovery may improve mood, whereas focussing on treatment of psychotic symptoms might not be the key to personal recovery. More research is needed to elucidate causal interrelations. PMID- 29992847 TI - Histopathological Predictors of Recurrence in Stage III Colon Cancer: Reappraisal of Tumor Deposits and Tumor Budding Using AJCC8 Criteria. AB - Patients with stage III colonic adenocarcinoma have a spectrum of risk for recurrent disease, and histopathological variables that predict recurrence can help stratify patients into prognostic groups. To identify histopathological predictors of recurrence, we investigated the effect of implementation of the eighth edition of the American Joint Committee on Cancer (AJCC8) staging system definition of tumor deposits and International Tumor Budding Consensus Conference (ITBCC) criteria for tumor budding compared with other known prognostic variables in 256 resected colonic adenocarcinomas, including 150 stage III and 106 stage II tumors. In stage III colon cancer, tumor deposits and high tumor budding were the only independent histological variables that predicted disease recurrence. In a multivariable analysis in stage III colon cancer, tumor deposits and high tumor budding were associated with a 2.2- and 1.5-fold increased risk of developing disease recurrence, respectively (95% CI = 1.1-4,2, P = .02, and 95% CI = 1.1 2.1, P = .01, respectively). The negative prognostic effect of tumor deposits was most pronounced in patients with stage IIIB disease in which tumor deposits were associated with a 3.2-fold increased risk of disease recurrence (95% CI = 1.4 7.1; P = .005). Within the N1 cohort, patients with tumor deposits without concurrent positive lymph nodes (N1c) had a significantly decreased disease-free survival compared with patients with N0 tumors ( P < .001) and patients with N1a/b tumors ( P = .02). As independent risk factors for recurrence, tumor deposits and high tumor budding are important histopathological variables and should be included as a part of a routine comprehensive pathological risk assessment in stage III colon cancer. PMID- 29992848 TI - The quest for the in medio stat virtus price in the oncology sector. PMID- 29992849 TI - Associations of exercise ankle-brachial index, pain-free walking distance and maximum walking distance with the Peripheral Artery Questionnaire: Finding from the PORTRAIT PAD Registry. AB - An exercise ankle-brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients' symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD. We fit a hierarchical logistic regression model, adjusting for patient factors, country and site, to examine predictors of and variation in ordering exercise ABI testing. We also examined the associations between test components and health status as quantified by the Peripheral Artery Questionnaire (PAQ) using semi-parametric regression methods. Testing was ordered in 22% in the United States versus 80% in the Netherlands and 90% in Australia. Testing was likely to be performed if the patient was male, younger, had typical symptoms and a higher resting ABI, with substantial variability across sites (median odds ratio=5.9, 95% CI: 3.2-19.5). Adjusting for country and site, the resting ABI and all exercise ABI metrics were associated with the PAQ Physical Limitation score. In addition, important components of the test, namely time to onset of claudication, pain-free walking distance (PFWD), and maximum walking distance (MWD), were also associated with PAQ Symptoms and Summary scores. More importantly, even after adjusting for resting ABI, a patient with a post-exercise ABI of 0.29 (25th percentile), compared to 0.61 (75th percentile), achieved 4.4 (95% CI: 0.4-8.4, p=0.031) points less on the PAQ Physical Limitation score. Exercise ABI test use is remarkably variable, and less used in the United States. Its data, specifically PFWD and MWD, might help in objectively assessing the impact of PAD on patients' functioning and quality of life. PMID- 29992850 TI - Pharmacogenetics and the treatment of HIV-/HCV-coinfected patients. AB - This review will summarize the role of pharmacogenetics in the natural history of hepatitis C, particularly in patients with HIV/HCV and will take the perspective of pharmacogenetics and its influence on the response to antiviral therapy and the susceptibility to develop adverse effects. This review will also devote a section to host genetics in other clinical situations, such as disease progression and acute HCV infection, which may determine whether treatment of HIV /HCV-coinfected patients is implemented or deferred. PMID- 29992852 TI - Mulberry-Like Bodies: An Artifact of Autolysis. PMID- 29992851 TI - Socio-demographic and behavioural determinants of body mass index among an adult population in rural Northern Ghana: the AWI-Gen study. AB - BACKGROUND: Obesity and associated cardiometabolic diseases are increasing in urban sub-Saharan Africa due to a complex epidemiological and nutritional transition. Related data on rural communities is scarce. OBJECTIVES: The study characterized the socio-demographic and behavioural factors influencing body mass index (BMI) among adults in rural Northern Ghana Methods: A population-based cross-sectional study involving adults aged 40-60 years residing in the Kassena Nankana districts was undertaken. Demographic, socio-economic and behavioural data were collected along with measures of anthropometry. We determined factors associated with BMI among women and men. RESULTS: A total of 2014 adults were studied. The median age was 51 (IQR 45-57) years and 54% were women. The prevalence of overweight/obesity was higher among women than men (18.4% vs. 7.2%; p < 0.001), whilst underweight was more prevalent in men (18.3% vs. 13.1%; p = 0.001). Participants with the highest level of education and a high household socio-economic status had higher BMIs than those in the lowest strata in both men (beta = 0.074, p = 0.028 and beta = 0.072, p < 0.001, respectively) and women (beta = 0.174, p = 0.001 and beta = 0.109, p < 0.001, respectively). Men (beta = 0.050; p < 0.001) and women (beta = -0.073; p < 0.001) of the Nankana ethnic group had a lower BMI than the Kassena ethnic group. Among men, alcohol consumption (beta = -0.021; p = 0.001) and smoking (beta = -0.216; p < 0.001) were associated with lower BMI. Smokeless tobacco was associated with lower BMI among women. Pesticide exposure was associated with higher BMI (beta = 0.022; p = 0.022) among men. CONCLUSION: Age, sex, ethno-linguistic group and prevailing socio-demographic and behavioural factors within this rural community in Northern Ghana influence BMI. The observed positive association between pesticide use and BMI warrants further investigation. PMID- 29992853 TI - Corrigendum. AB - Abstracts: 23rd Annual RIMS Conference 2018. Mult Scler 2018; 24: 832-837. DOI: 10.1177/1352458518771862 . In the above conference abstracts, published in the May 2018 issue of Multiple Sclerosis Journal, the co-authors were missed from submission ID 103. The correct list of authors appears below. PMID- 29992854 TI - Comparison of different exercise ankle pressure indices in the diagnosis of peripheral artery disease. AB - Although the resting ankle-brachial index (ABI) is commonly used as a tool to diagnose peripheral artery disease (PAD), several additional indices measured after exercise may have increased sensitivity for identifying PAD. The aim of this study was to determine the utility of resting ABI and three post-exercise physiological parameters for diagnosing PAD confirmed by arterial imaging studies. For each qualifying study, we assessed the performance measures for identifying PAD for resting ABI < 0.90, exercise ABI < 0.90, a decrease in ABI > 20% with exercise, and a decrease in ankle pressure > 30 mmHg with exercise. Of the 199 exams that met our inclusion criteria, imaging showed a > 75% stenotic lesion in at least one limb in 138 (69%) of patients. For stenoses > 75%, resting ABI < 0.90 had a sensitivity of 64% (95% CI: 56-72%) and exercise ABI < 0.90 had a sensitivity of 88% (95% CI: 82-93%). The sensitivity for a post-exercise ABI decrease > 20% was 67% (95% CI: 59-75%) and the sensitivity for a decrease in ankle pressure > 30 mmHg was 4% (95% CI: 2-9%). For individuals with a normal resting ABI but stenotic lesions > 75% confirmed by imaging ( n=49), the addition of exercise ABI testing correctly identified an additional 25% of this population. Overall, exercise ABI < 0.90 exhibits a greater sensitivity for detecting PAD compared to resting ABI. Furthermore, exercise ABI < 0.90 had added clinical utility in patients with normal resting ABIs and was superior to other commonly used exercise indices. PMID- 29992855 TI - Filicide-suicide: An unusual variant of dyadic death. AB - Dyadic suicides may be committed simultaneously or one after another by two or more people who may or may not have made a prior pact. The perpetrator is usually male and their victims female, and generally their intimate partners, with children less commonly involved. Another distinct type of homicide-suicide is the killing of children by a parent (filicide-suicide). The terms 'maternal filicide' or 'paternal filicide' are used respectively when the perpetrator is the mother or the father of the victim. We report a rare case of maternal filicide, where the mother drowned her three children and then herself in the same water tank. The case highlights the extreme stress put on a mother of girls in a patriarchal society where there is an overriding expectation and wish for sons. The resulting pressure on this mother for her 'failure' caused her to take her own and her children's lives. PMID- 29992856 TI - Histopathological correlation of diffusion basis spectrum imaging metrics of a biopsy-proven inflammatory demyelinating brain lesion: A brief report. AB - Diffusion basis spectrum imaging (DBSI) models diffusion-weighted magnetic resonance imaging (MRI) signals as a combination of discrete anisotropic diffusion tensors and a spectrum of isotropic diffusion tensors. Here, we report the histopathological correlates of DBSI in the biopsied brain tissue of a patient with an inflammatory demyelinating lesion typical of multiple sclerosis (MS). Increased radial diffusivity (marker of demyelination), decreased fiber fraction (apparent axonal density), elevated nonrestricted isotropic fraction (marker of vasogenic edema), but unchanged axial diffusivity (marker of integrity of residual axons) seen in the lesion appeared consistent with histopathological findings of inflammatory demyelination with relative axonal sparing. Our report supports the application of DBSI as a biomarker in human studies of MS. PMID- 29992857 TI - Ticagrelor versus clopidogrel in patients with symptomatic peripheral artery disease and prior coronary artery disease: Insights from the EUCLID trial. AB - Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular morbidity and mortality. We sought to evaluate the risk of concomitant coronary artery disease (CAD) in patients with symptomatic PAD versus PAD without diagnosed CAD, and whether ticagrelor was superior to clopidogrel in reducing that risk. The EUCLID trial randomized 13,885 patients with PAD to antithrombotic monotherapy with ticagrelor or clopidogrel. CAD was defined as prior myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery. Median follow-up was 30 months. Among 4032 (29%) patients with PAD and CAD, 63% had prior MI, 54% prior PCI, and 38% prior CABG. After adjustment for baseline characteristics, patients with PAD and CAD had significantly higher rates of the primary endpoint (cardiovascular death/MI/stroke, 15.3% vs 8.9%, hazard ratio (HR) 1.50, 95% CI: 1.13-1.99; p=0.005), but no statistically significant increase in acute limb ischemia (HR 1.28, 95% CI: 0.57-2.85; p=0.55) or major bleeding (HR 1.10, 95% CI: 0.49-2.48; p=0.81) versus PAD without CAD. Among patients with PAD and CAD, there was no differential treatment effect between ticagrelor versus clopidogrel for the primary efficacy endpoint (HR 1.02, 95% CI: 0.87-1.19; p=0.84), acute limb ischemia (HR 1.03, 95% CI: 0.63-1.69; p=0.89), or major bleeding (HR 1.06, 95% CI: 0.66-1.69; p=0.81). There was a statistically significant interaction between prior coronary stent placement and study treatment ( p=0.03) with a numerical reduction in the primary efficacy endpoint with ticagrelor versus clopidogrel (13.8% vs 16.8%, HR 0.82, 95% CI: 0.65-1.03; p=0.09). Patients with PAD and prior CAD had higher composite rates of cardiovascular death, MI, and ischemic stroke versus PAD without diagnosed CAD. There were no significant differences between ticagrelor and clopidogrel in cardiovascular events or major bleeding. ClinicalTrials.gov Identifier: NCT01732822. PMID- 29992858 TI - Cryptic ETV6-PDGFRB fusion in a highly complex rearrangement of chromosomes 1, 5, and 12 due to a chromothripsis-like event in a myelodysplastic syndrome/myeloproliferative neoplasm. PMID- 29992859 TI - Risk Factors and Outcomes Associated With Sepsis After Coronary Artery Bypass and Open Heart Valve Surgeries. AB - PURPOSE: Sepsis causes significant morbidity and mortality after cardiac surgery and carries a significant burden on health care costs. There is a general association of increased risk of post-cardiac surgery sepsis in patients with postoperative complications. We sought to investigate significant patient and procedural risk factors and outcomes associated with sepsis after cardiac surgery. MATERIALS AND METHODS: In this retrospective study, we analyzed 531 coronary artery bypass grafting and open heart valve surgery cases that developed postoperative sepsis in the National Surgical Quality Improvement Program database between 2007 and 2014. Patient-based and surgery-based parameters were analyzed for risk factors and outcomes reported in the 30 days postoperatively. The association between sepsis and patient outcomes was assessed in a propensity matched cohort using univariable logistic regression. RESULTS: Modifiable and nonmodifiable patient characteristics, including age >80, poor preoperative functional status, chronic diseases such as diabetes mellitus, congestive heart failure, chronic kidney disease with serum creatinine ?1.5, as well as serum albumin <3.5 and emergent nature of the case were associated with post-cardiac surgery sepsis. Surgical outcomes associated with sepsis included mortality (15.4% vs 4.5%), unplanned intubation (29.8% vs 8.2%), transfusion (53.4% vs 48.4%), acute kidney injury (7.1% vs 1.4%), postoperative dialysis (18.8% vs 3.5%), and return to the operating room (29.8% vs 8.2%). CONCLUSIONS: We identified multiple patient and surgical characteristics as well as postoperative outcomes associated with postoperative sepsis development in the high-risk population of patients undergoing cardiac surgery. Early identification of patients who are at high risk for postoperative sepsis can facilitate early treatment interventions. PMID- 29992860 TI - Boerhaave's Mineral Chemistry and Its Influence on Eighteenth-Century Pharmacy in the Netherlands and England. AB - In the eighteenth century, the use of mineral or fossil substances was relatively common in European medicine and pharmacy. However, this period also saw profound changes in ideas about the nomenclature, chemistry, and curative properties of minerals. Jonathan Simon has recently argued that an increasing orientation towards the mineral kingdom and the chemical transformation of minerals, and a rise in the number of mineral preparations demanded of the pharmacist, were characteristic for eighteenth-century chemistry within pharmacy. Yet in the Netherlands, and to a certain extent in England, another pattern is visible: although there certainly was an interest in the mineral kingdom and the chemical transformation of nonorganic materials, nothing suggests that this resulted in a strong increase in the demand for mineral-based pharmaceutical preparations - rather the contrary. Unlike English and French eighteenth-century pharmacy, Dutch pharmacy and its relation to academic medicine and chemistry have hardly received attention from historians of science thus far. This paper aims to fill that gap and argues that Herman Boerhaave's (1668-1738) view on mineral medicine was crucial in the development of a certain wariness of "mineral medicine" in the eighteenth-century Netherlands and England, especially among apothecaries. PMID- 29992861 TI - CYP2D6 genotype analysis of a Thai population: platform comparison. AB - The highly polymorphic CYP2D6 gene locus leads to a wide range of enzyme activity. Since there are limited data for Thai, the major aim was to investigate CYP2D6 genetic variation in a large Thai population (n = 920). CYP2D6 genotyping was performed using four different platforms. Genotype call rates of the Luminex xTAG(r) and AmpliChip CYP450 test were 96.5% and 87.4%, respectively. Based on Luminex xTAG(r) data, the most common alleles and genotypes were *1 0 (49.6%), *1 (24.6%), *2 (10.8%), *5 (6.7%), *41 (6.5%) and *1/*10 (23.9%), *10/*10 (21.5%), *2/*10 (9.4%), *5/*10 (6.9%), *10/*41 (5.7%), respectively. Challenges and limitations of the platforms evaluated are discussed. These data add to our knowledge regarding interethnic variability in CYP2D6 activity and contribute to improving drug therapy in the Thai. PMID- 29992862 TI - Malignant Solitary Fibrous Tumor of the Renal Vein Presenting as a Giant Renal Artery Aneurysm: A Case Report and Review of Literature. AB - OBJECTIVES: To discuss an unusual presentation of solitary fibrous tumor (SFT) as well as the first description of SFT originating from the renal vein. CASE REPORT: In this article, we report the case of a 56-year-old man who presented with nonspecific epigastric pain and was found on computed tomography to have a large 10-cm renal artery aneurysm with evidence of contained rupture, segmental ischemia of the kidney, and suggestion of renal vein thrombosis. This was treated by a multidisciplinary team of urologists, vascular surgeons, and interventional radiologists with both renal artery coil embolization and radical nephrectomy. The thrombosis was found on pathologic review to be a malignant SFT originating from the renal vein with likely erosion into the renal artery. CONCLUSION: This report describes the first case of SFT originating from the renal vein and demonstrates the potential for mimicry as a giant renal artery aneurysm. PMID- 29992863 TI - [Editorial]. PMID- 29992864 TI - [Psychosocial Risk Factors and Negative Emotionality in Early Childhood: Mothers' Perspective]. AB - Psychosocial Risk Factors and Negative Emotionality in Early Childhood: Mothers' Perspective Based on a nationally representative study of parents, this study examines risk factors for mothers' perceptions of young children's negative emotionality, focusing the role of mothers' educational resources and related psychosocial risk factors. Participants were 7,311 mothers with children below age 48 month. Mothers' perception of child emotionality was assessed through two factors, irritability and defiance. Findings from regression analyses showed a stable negative relationship between maternal education and perceived defiance of the child. Although this effect was partly mediated by further psychosocial risk factors, lower education was consistently related with higher perceived defiance. Perceived irritability, in contrast, was not affected by mother's education. Further analyses showed age-specific effects (stronger effects for younger children) as well as a predictive value of mothers' perceptions regarding the occurrence of child abuse or neglect. The results are discussed in the context of early prevention programs in Germany, emphasizing the relevance of identifying risk-groups and offering early and multidimensional prevention. PMID- 29992865 TI - [Parental Reflective Functioning and its Relation to Parenting Stress in a Sample with Early Regulatory Disorders]. AB - Parental Reflective Functioning and its Relation to Parenting Stress in a Sample with Early Regulatory Disorders Parents' capacity to reflect on their child as a mental agent, is defined as an important competence for the early parent-infant relationship. One way to operationalize this is parental reflective functioning (PRF) that distinguishes between mentalizing and non-mentalizing modes of reflection. Until today PRF has not been investigated in samples of infants/toddlers with early regulatory disorders. Goal of the present study is to investigate PRF by comparing a clinical group with parents of infants/toddlers with early regulatory disorders (N = 98) with a healthy control group (N = 27) and testing if PRF is related to parenting stress, past mental illness of the mother, and stress factors related to pregnancy and birth. A semi-structured clinical interview, the Parenting Stress Index, the Symptom-Check-List-90R-S, the Parental Reflective Functioning Questionnaire, and an anamnestic questionnaire were used. Compared to the control group, mothers of infants/toddlers with early regulatory disorders reported significant more prementalizing. Prementalizing in the total sample was significantly predicted by parenting stress, accounting for 16.3 % of the variance. None of the other independent variables significantly predicted prementalizing. Results are discussed in relation to early regulatory disorders and implications for clinical practice. PMID- 29992868 TI - [One Size Fits All? Using Psychosocial Risk Assessments to Predict Service Use in Early Intervention and Prevention]. AB - One Size Fits All? Using Psychosocial Risk Assessments to Predict Service Use in Early Intervention and Prevention Early intervention and prevention services offer a variety of programs. At the same time, program participants differ widely in their service use. This study aims at investigating the prognostic validity of psychosocial risk assessments in predicting the participants' service use. The psychosocial risk assessment "Heidelberg Stress Scale" is used to predict aspects of service use (dosage, attrition, intervention content, working relationship). Service use data of N = 1.514 participants of a home-visiting program will be analyzed via Machine-Learning-Algorithms. Dosage and intervention content can be predicted with psychosocial risk assessments. The classification strength is small. Global and continuous risk scales have a prognostic advantage over single categorical risk items. Financial burden has a significant influence on every aspect of service use. Psychosocial risk assessments provide additional information that can support intervention planning. Yet, these instruments should be supplemented by additional diagnostic information. PMID- 29992869 TI - [Factors Influencing Theory of Mind Development in Preschoolers within the Context of Early Interventions]. AB - Factors Influencing Theory of Mind Development in Preschoolers within the Context of Early Interventions The Theory of Mind (ToM) competency is closely related to the child's cognitive, language, and socio-emotional development. In early interventions, skills and developmental processes associated with ToM development are often primary intervention targets, but empirical support for direct or indirect influences of early interventions on ToM development is missing so far. Within the home visiting program "Pro Kind" N = 755 families were accompanied by professionals from the last trimester of pregnancy until the child's second birthday. In the present follow-up study we investigated influences of treatment, pre- and postnatal family environment, parental competencies and child competencies on the ToM ability in a sample of n = 39 five-year-old children using Ctree analyses. Prenatal and current parental stress as well as an enriched family learning environment, and children's language competencies in interaction with temperament significantly predicted ToM competency. The treatment had no direct influence on ToM development. Thus, the results argue for the urgent need to address maternal stress regulation and mentalizing competencies in early interventions during pregnancy, as well as to focus on promoting positive stimulating learning environments and language development after the child's birth. PMID- 29992872 TI - Top-rated AMEE MedEdPublish Papers - February 2018. PMID- 29992871 TI - [The Multiperspective Parent-Child Relationship Questionnaire (M-PCR)]. AB - The Multiperspective Parent-Child Relationship Questionnaire (M-PCR) Parent-child relationship quality may considerably impact child mental health. Yet many instruments apply effortful behavioral observation methods. In this paper we aim to develop a multiperspective questionnaire of parent-child relationships. Several experts in the field of parent-child interaction treatment generated 18 items to assess aspects of the parent-child relationship. Mothers, therapists and assistant therapists rated 129 mother-child dyads that were treated at the Child Psychiatric Family Day Hospital for preschool children in Munster, Germany at the beginning and again at the end of treatment. For validity purposes, a global measure of relationship quality (PIRGAS) and measures of maternal psychopathology (SCL-90-R) and child behavior problems (CBCL/1.5-5; C-TRF/1.5-5) completed the assessment.Six principal component analyses and subsequent oblique rotation revealed a stable patternof two interpretable factors labeled as "Affective Bond" and "Functional-Conflict" with highinternal consistency and retest-reliability. Validity of the MEK scales was supported by significant correlations with the global rating of relationship quality PIRGAS by experts (therapistsand assistant therapists) and measures of maternal and child psychopathology, particularlyexternalizing problems, and therapy outcome. The MEK appears as a valid, reliable and user-friendly instrument for assessing the quality of parent child relationship in clinical contextsfrom different perspectives. PMID- 29992873 TI - Medical Teacher In Ten Minutes. PMID- 29992874 TI - Editorial: Advances in Therapies of Cerebellar Disorders. PMID- 29992875 TI - Conference Report: 184th American Association for the Advancement of Science Annual Meeting, Austin TX, USA Feb. 15-19, 2018. PMID- 29992876 TI - Targeting Cancer Metabolism as a Novel Anticancer Strategy. PMID- 29992877 TI - Cell stress signaling cascades regulating cell fate. AB - Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics. PMID- 29992878 TI - Coronary Microcirculation in Heart Failure with Preserved Systolic Function. AB - BACKGROUND: The Heart Failure with Preserved Ejection Fraction (HFpEF) is defined as the preserved left ventricular ejection fraction (LVEF) with the signs of heart failure, elevated natriuretic peptides, and either the evidence of the structural heart disease or diastolic dysfunction. The importance of this form of heart failure was increased after studies where the mortality rates and readmission to the hospital were founded similar as in patients with HF and reduced EF (HFrEF). Coronary microvascular ischemia, cardiomyocyte injury and stiffness could be important factors in the pathophysiology of HFpEF. METHODS: The goal of this work is to analyse the relationship of HFpEF and coronary microcirculation in previous studies. RESULTS: The useful diagnostic marker of coronary microcirculation in HFpEF may be the parameters measured by transthoracic echocardiography (TTE), the coronary flow reserve (CFR), as well as fractional flow reserve (FFR) and quantitative myocardial contrast echocardiography (MCE). Cardiac magnetic resonance (CMR) imaging represents the diagnostic gold standard in HFpEF. Coronary microvascular dysfunction in the absence of obstructive coronary artery disease (CAD) is poorly understood and may be more prevalent amongst women than men. Troponin level may be important in risk stratification of HEpEF patients. CONCLUSION: There are no precise answers with respect to the pathophysiological mechanism, nor are there any precise practical clinical assessment of and diagnostic method for coronary microvascular dysfunction and diastolic dysfunction. In accordance with that, there is no well established treatment for HFpEF. PMID- 29992879 TI - Beneficial Effect of Minimal Interference on Item Memory But Not on Source Memory in Alzheimer's Disease. AB - OBJECTIVES: Research suggests beneficial effects of minimal interference on item memory in mild Alzheimer's disease (AD). We conducted a study to test whether these beneficial effects extend to source memory, i.e., the ability to remember the episodic context in which an information was previously acquired. METHOD: Twenty-six mild AD participants and 28 controls manipulated six objects or watched the experimenter manipulating six other objects. After immediate item recall ("what were the items?") and source recall ("by whom the items were previously manipulated?"), an interference or a minimal interference condition was administrated. In the interference condition, participants were assessed with neuropsychological tests for 10 min. In the minimal interference condition, they rested alone in a dark and quiet room for 10 minutes. Both interference and minimal interference conditions were followed by the delayed recall, on which participants were asked to remember the previously-presented objects and their source. RESULTS: Higher item memory was observed following minimal interference than following interference in AD participants (p < .01) and controls (p < .01). Also, AD participants demonstrated higher item memory on immediate recall than following interference (p < .001) or minimal interference (p < .001); controls also demonstrated higher item memory on immediate recall than following interference (p < .001) or minimal interference (p < .001). Considering source memory, similar source memory was observed following interference and minimal interference in AD participants (p > .1) and controls (p > .1). Also, AD participants demonstrated higher source memory on immediate recall than following interference (p < .001) or minimal interference (p < .001); controls also demonstrated higher source memory on immediate recall than following interference (p < .001) or minimal interference (p < .001). CONCLUSION: Failures of hippocampus-dependent associative or consolidation processes in AD may preclude benefits of minimal interference for source memory. Nevertheless, AD patients may show some capacity to retain simple material, should the material presentation be followed by short delays that are free of further stimuli. PMID- 29992880 TI - Tacrine-coumarin and Tacrine-7-chloroquinoline Hybrids with Thiourea Linkers: Cholinesterase Inhibition Properties, Kinetic Study, Molecular Docking and Permeability Assay for Blood-brain Barrier. AB - BACKGROUND: The design of new heterodimeric dual binding site acetylcholinesterase inhibitors constitutes the main goal-directed to the development of new anticholinesterase agents with the expanded pharmacological profile. Multi-target compounds are usually designed by combining in a hybrid molecule with two or more pharmacophoric moieties that are known to enable interaction with the selected molecular targets. METHODS: All compounds were tested for their inhibitory activity on human AChE/BChE. The Ellman's method was used to determine inhibition kinetics and IC50 values. In order to predict passive bloodbrain penetration of novel compounds, modification of the parallel artificial membrane permeation assay has been used. Docking studies were performed in order to predict the binding modes of new hybrids with hAChE/ hBChE respectively. RESULTS: In this study, we described the design, synthesis, and evaluation of series tacrine-coumarin and tacrine-quinoline compounds which were found to show potential inhibition of ChEs and penetration of the blood-brain barrier. CONCLUSION: Tacrine-quinoline hybrids 7a exhibited the highest activity towards hBChE (IC50 = 0.97 umol) and 7d towards hAChE (IC50 = 0.32 umol). Kinetic and molecular modelling studies revealed that 7d was a mixed-type AChE inhibitor (Ki = 1.69 umol) and 7a was a mixed-type BChE inhibitor (Ki = 1.09 umol). Moreover, hybrid 5d and 7c could penetrate the CNS. PMID- 29992881 TI - Linc01638 promotes tumorigenesis in HER2+ breast cancer. AB - Long non-coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non-coding RNA01638 (linc01638) in breast cancer, especially in HER2-positive breast cancer,remains largely unknown. In this study, linc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and invasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b,and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models, indicating that linc01638 promoted tumorigenesis, partly by stimulating DNMTs signaling pathway and inhibiting expression of BRCA1/PTEN in HER2-positive breast cancer. These findings collectively suggest that linc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer. PMID- 29992882 TI - Inhibition of Biofilm and Virulence Factors of Candida albicans by Partially Purified Secondary Metabolites of Streptomyces chrestomyceticus Strain ADP4. AB - BACKGROUND: Despite several advancements in antifungal drug discovery, fungal diseases like Invasive Candidiasis (IC) still remain associated with high rates of morbidity and mortality worldwide. Thus there is an enormous need for anti Candida drugs. OBJECTIVE: The main objectives of the work included: 1. To investigate therapeutically significant classes of secondary metabolites produced by S. chrestomyceticus strain ADP4. 2. To investigate and analyze inhibition of significant virulence attributes of C. albicans, such as, biofilm and secretory hydrolytic enzymes by ADP4 secondary metabolites. 3. Mechanistic analysis of probable compounds for their site of action on Secretary Aspartyl Proteinase 3 (Sap3). METHODS: Metabolite extract-SDB (MESDB) of S. chrestomyceticus strain ADP4 was fractionated on silica gel column chromatography. Fractions were analyzed for anti-Candida activity by disc diffusion assay. Active fractions were further purified by differential solvent treatment. MIC90 values were determined by broth dilution method. MFC was based on counting viable cells. Inhibition of yeast to hyphae transition and that of production of hydrolytic enzymes were estimated by plate assays. GC-MS of MESDB and Partially Purified Metabolite preparations (PPMs) was done. GRIP docking studies with Sap 3 of C. albicans was done using VLife MDS 4.6 software. RESULTS: Chemical profiling showed that ADP4 secondary metabolites contained alkaloids, flavonoids, polyphenols, terpenoids and triterpenes. The MESDB and the PPMs showed low or no cytotoxicity but were able to effectively contain virulence attributes of Candida pathogen. Docking studies revealed that some of the probable compounds have affinity for aspartic acid residue in Sap3 enzyme of C. albicans. CONCLUSION: Secondary metabolite of strain ADP4 included important classes of therapeutically important compounds. Their anti-Candida activity was mediated by inhibition of critical virulence factors of the pathogen. PMID- 29992883 TI - Intervention and Observational Trials are Complementary in Metabolomics: Diabetes and the Oral Glucose Tolerance Test. AB - Observational experimental designs are usually employed in metabolomics to elucidate pathological mechanisms underlying disease development and to discover candidate biomarkers for diagnosis. However, intervention trials can also be a suitable starting point before performing a validation study in lager epidemiological cohorts, with a great potential in personalized medicine to investigate how different patients respond to similar stimuli. In the present work, we provide a review of the literature on the application of metabolomics to investigate metabolic alterations associated with diabetes, the diabetes predisposing state of insulin resistance and the oral glucose tolerance test as a case study to demonstrate the complementarity of observational and interventional study designs. PMID- 29992884 TI - Role of Morin in Neurodegenerative Diseases: A Review. AB - Neurodegenerative diseases are likely to emerge as the second cause of mortality in the world in coming years. NDDs cause tremendous financial burden on the healthcare system along with profound effect on families and patient. Disease modifying treatment strategies with proven efficacy for these disorders are still lacking. Documentation proved that oxidative stress plays a leading role in the pathophysiology of many neurodegenerative disorders. Molecules with good antioxidant profile could be explored for the doctoring of these conditions. Neuroprotective effects of bioflavonoid morin have been well recognized in the literature. Morin being super antioxidant compound helped in preventing and curing these disorders by suppression of ROS and by inhibition of multiple targets. In this review, we tried to explain various neuropathological conditions with their target sites and neurobiological mechanisms of morin. PMID- 29992885 TI - Toward Reproducible Results from Targeted Metabolomic Studies: Perspectives for Data Pre-processing and a Basis for Analytic Pipeline Development. AB - Contemporary metabolomics experiments generate a rich array of complex high dimensional data. Consequently, there have been concurrent efforts to develop methodological standards and analytical workflows to streamline the generation of meaningful biochemical and clinical inferences from raw data generated using an analytical platform like mass spectrometry. While such considerations have been frequently addressed in untargeted metabolomics (i.e., the broad survey of all distinguishable metabolites within a sample of interest), this methodological scrutiny has seldom been applied to data generated using commercial, targeted metabolomics kits. We suggest that this may, in part, account for past and more recent incomplete replications of previously specified biomarker panels. Herein, we identify common impediments challenging the analysis of raw, targeted metabolomic abundance data from a commercial kit and review methods to remedy these issues. In doing so, we propose an analytical pipeline suitable for the pre processing of data for downstream biomarker discovery. Operational and statistical considerations for integrating targeted data sets across experimental sites and analytical batches are discussed, as are best practices for developing predictive models relating pre-processed metabolomic data to associated phenotypic information. PMID- 29992886 TI - Menopause and Non-Alcoholic Fatty Liver Disease: A Review Focusing on Therapeutic Perspectives. AB - There is increasing evidence that menopause is associated with the progression and severity of non-alcoholic fatty liver disease (NAFLD). Estrogen deficiency worsens non-alcoholic steatohepatitis (NASH) in mice models with fatty liver. The prevalence of NAFLD seems to be higher in postmenopausal compared with premenopausal women. Although more data are needed, lower serum estradiol levels are associated with NASH in postmenopausal women. Apart from estrogen deficiency, relative androgen excess and decrease in sex hormone-binding protein are observed in postmenopausal women. These hormonal changes seem to interplay with an increase in abdominal adipose mass, also observed in postmenopausal women, and aging, which are both closely related to the severity and progressive forms of NAFLD. NAFLD adds extra morbidity to postmenopausal women, possibly increasing the risk of type 2 diabetes mellitus and cardiovascular disease. Improving parameters of the metabolic syndrome via modifications in diet and physical exercise may reduce the risk of NAFLD and its related morbidity. Limited studies have shown a beneficial effect of hormone replacement therapy (HRT) on NAFLD, although adverse hepatic effects have been attributed to progesterone in one study. Phytoestrogens may be alternatives to HRT, but their long-term efficacy and safety remain to be shown. The aim of this review was to summarize evidence linking menopause with NAFLD with a special focus on potential therapeutic perspectives. PMID- 29992888 TI - Therapeutic Outcomes in AIDS-Associated Kaposi's Sarcoma Patients on Antiretroviral Therapy Treated with Chemotherapy at Two Tertiary Hospitals in Lusaka, Zambia. AB - : The incidence of HIV-associated Kaposi's sarcoma (KS) remains high in Zambia in the antiretroviral therapy era. The most efficacious treatment regimen for KS has yet to be established. In both developed and developing countries, treatment regimens have had limited efficacy. Late presentation in Africa affects therapeutic outcomes. OBJECTIVE: The aim of this study was to determine therapeutic outcomes of epidemic KS patients on combination antiretroviral therapy (cART) after completion of six cycles of Adriamycin, Bleomycin, and Vincristine (ABV) chemotherapy. METHODS: This was a descriptive cross-sectional study. Study participants were drawn from a study database of confirmed incident KS patients seen at the Skin Clinic of the University Teaching Hospitals (UTH) during the period between August, 2015 and September, 2016. RESULTS: Of the 38 successfully recruited study participants, a complete response was documented in 18 (47%) after 6 cycles of ABV whereas 20 (53%) experienced a partial response. KS recurrence was observed in 8 (44%) of the individuals that experienced an initial complete response. At the time of the study, clinical assessment revealed that KS lesions had completely regressed in 21 (55%) of all the patients. CONCLUSION: ABV chemotherapy appears ineffective in long-term resolution of epidemic KS patients on ART. Recurrence rates are high after chemotherapy in patients that experience initially favorable responses to treatment. There is a need to diagnose KS earlier, and to develop more efficacious treatment options in order to reduce recurrence rates for epidemic KS. PMID- 29992889 TI - Bone mineral density in type 2 diabetes patients with Charcot arthropathy. AB - INTRODUCTION: Charcot arthropathy is one of the disabling diabetes complications. There are enigmatic areas concerning its underlying pathophysiology and risk predictors. Osteoporosis and local osteopenia has been postulated to have a role in Charcot arthropathy development, but it is still controversial AIM: To Compare bone mineral density among type 2 diabetics with and without Charcot arthropathy. METHODOLOGY: Two groups with type 2 diabetes participated in this study. Group I [30] patients with charcot arhropathy while Group II [30] patients without charcot arthropathy. All patients underwent full history taking and full clinical examination with special emphasis on the feet. Laboratory investigations were done that included fasting blood sugar, post prandial blood sugar, glycosylated hemoglobin, serum calcium, serum phosphorus, and alkaline phosphatase. All patients underwent MRI for both feet and and dual energy X-ray absorptiometry scan of the lumbar spine and femur. The demographic data, clinical data, the presence or absence of comorbidities and bone mineral density were compared for both groups RESULT: Bone mineral density was significantly lower in Group I than Group II with median lumber T score (-0.15, 1.99 p <0.001), median Femur T score (0.050, 2.400, p <0.001). Group I showed higher propensity for hypertension, neuropathy, micro-albuminuria with peripheral arterial disease (23.33 %) compared to Group II (p <0.001). Multiple logistic regression analysis revealed that female gender and low femur bone mineral density can be risk predictors of the condition. CONCLUSION: Bone mineral density is lower in patients with Charcot arthropathy with female gender and Femur T score as risk predictors. Peripheral arterial disease shows greater incidence in Charcot patients than was previously reported. PMID- 29992887 TI - Sexual Roles, Risk Sexual Behaviours, and HIV Prevalence among Men who Have Sex with Men Seeking HIV Testing in Changsha, China. AB - BACKGROUND: HIV infection is prevalent among men who have sex with men (MSM), and sexual roles may be important factors related to it. This study aims to describe the sexual roles, risky sexual behaviors and HIV prevalence among MSM, and to determine associated factors for HIV prevalence. METHODS: A convenient sampling method was used to recruit participants in a non-government organization in Changsha, China. The participants were asked to complete a 38-item self administered questionnaire regarding demographic characteristics and risky sexual behaviours before collecting blood samples for HIV testing. Chi-square tests and logistic regression analysis were conducted with the Statistical Package for the Social Sciences Version 18.0 and other indexes were statistically described. RESULTS: A total of 601 MSMs who came to a local non-government organization for voluntary counseling and testing completed a pencil-and-paper survey and were tested for HIV. The overall HIV prevalence of this sample was 13.3%, and that of the bottoms (16.3%) was similar to the versatiles (15.9%) but higher than the tops (6.1%). Bivariate analyses showed that there were significant differences in age, marital status, monthly income, sexual orientation, age at first sex, sex of the first sex partner, sex with a woman in the last 6 months, oral sex with a man in the last 6 months and role of oral sex among 3 subgroups of MSM (p < 0.05). Multivariate analyses indicated that MSMs who played the role of either the bottoms or the versatiles were more likely to be HIV positive than the tops. While MSMs who used condoms in anal sex in the last 6 months, had sex with a woman in the last 6 months or had oral sex with a man in the last 6 months were less likely to be HIV positive. CONCLUSION: Different sexual roles are associated with high-risk sexual behaviors among MSMs and their HIV infection status. Further research should target preventive interventions, and improve the effectiveness of the intervention according to the characteristics of the subgroups to reduce the HIV transmission among Chinese MSM. PMID- 29992890 TI - Diabetes Discharge Planning and Transitions of Care: A Focused Review. AB - BACKGROUND: Diabetes is a growing problem in the United States. Increasing hospital admissions for diabetes patients demonstrate the need for evidence based care of diabetes patients by inpatient providers, as well as the importance of continuity of care when transitioning patients from inpatient to outpatient providers. METHOD: A focused literature review of discharge planning and transitions of care in diabetes, conducted in PubMed is presented. Studies were selected for inclusion based on content focusing on transitions of care in diabetes, risk factors for readmission, impact of inpatient diabetes education on patient outcomes, and optimal medication management of diabetes during care transitions. American Diabetes Association (ADA) guidelines for care of patients during the discharge process are presented, as well considerations for designing treatment regimens for a hospitalized patient transitioning to various care settings. RESULTS: Multiple factors may make transitions of care difficult, including poor communication, poor patient education, inappropriate follow-up, and clinically complex patients. ADA recommendations provide guidance, but an individualized approach for medication management is needed. Use of scoring systems may help identify patients at higher risk for readmission. Good communication with patients and outpatient providers is needed to prevent patient harm. A team based approach is needed, utilizing the skills of inpatient and outpatient providers, diabetes educators, nurses, and pharmacists. CONCLUSION: Structured discharge planning per guideline recommendations can help improve transitions in care for patients with diabetes. A team based, patient-centered approach can help improve patient outcomes by reducing medication errors, delay of care, and hospital readmissions. PMID- 29992891 TI - Type 2 Diabetes And Asthma: Systematic Review. AB - Background and objective Obesity is an important contributor to the risk of both asthma and type 2 diabetes (T2DM). However, it has been suggested that T2DM and asthma are also independently associated. The aim of this systematic review was to synthesise the evidence for an independent relationship between T2DM and asthma. Methods MEDLINE and EMBASE were searched for studies reporting the relationship between asthma and T2DM in adults. Given a potential bidirectional relationship, articles relating to T2DM as a risk factor for asthma, and asthma as a risk factor for T2DM were examined separately. Results Eight studies were identified for inclusion in the review (n=2,934,399 participants). Four studies examined incident diabetes in those with asthma. The pooled (random effects model) adjusted hazard ratio for incident T2DM in asthma was 1.37 (95%CI 1.12 1.69; p <0.001) after controlling for BMI. Four studies reported prevalence or incidence rates of asthma in people with T2DM; higher rates of asthma in those with T2DM were reported in all four studies. Meta-analysis of results was not possible due to methodological heterogeneity. The quality of included studies was good, but due to small numbers, publication bias cannot be excluded. Conclusions The published literature suggests a bidirectional independent relationship between T2DM and asthma, although we cannot exclude publication bias. PMID- 29992892 TI - Chronic Kidney Disease and Cardiovascular Disease: is there any relationship? AB - Chronic Kidney Disease is a growing health burden world widely. Traditional and mutual risk factors between CVD and CKD are age, hypertension, diabetes mellitus, dyslipidemia, tobacco use, family history and male gender. In this review, we will focus on whether or not early CKD is an important risk factor for the presence, severity and progression of CVD. Specifically, we will examine both traditional and novel risk factors of both CKD and CVD and how they relate to each other. We will also assess if early treatment of CKD, intensive compared to standard, has an important effect on the halt of the development of CKD as well as CVD. Insights into the pathogenesis and early recognition of CKD as well as the importance of novel kidney biomarkers will be pointed out. Also, common pathogenetic mechanisms between CKD and CVD will be discussed. PMID- 29992893 TI - Synthesis & Anticancer Evaluation of New Substituted 2-(3,4 Dimethoxyphenyl)benzazoles. AB - A series of new 2-(3,4-dimethoxyphenyl)-1H-benz(or pyrido)imidazoles 2, 4-25 were synthesized and evaluated for their anticancer and antimicrobial activities. The NMR assignments of the dimethoxy groups were established by the NOESY spectra. Compound 12 bearing two chlorine atoms at the 5(4) and 7(6) positions of the benzene moiety of benzimidazole was found the most potent analogue, against A549 cells with the GI50 value of 1.5 ug/mL. Moreover, compound 24 showed remarkable cell growth inhibition against MCF-7 and HeLa cells with the GI50 values of 7 and 5.5 ug/mL, respectively. The synthesized compounds have no important antibacterial and antifungal activities. PMID- 29992894 TI - Second-line Treatment of Advanced Non-small Cell Lung Cancer Non-oncogene Addicted: New Treatment Algorithm in the Era of Novel Immunotherapy. AB - BACKGROUND: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options. METHODS: The Italian Association of Thoracic Oncology (AIOT) organized five meetings in different Italian regions representing North, Middle and South of the country in order to discuss the issue. RESULTS: In light of these new approvals, it is valuable to understand the uptake of these new therapies in routine clinical practice and their impact on patient care. With these treatment options to define an appropriate algorythm is object of debate. CONCLUSION: The present paper discusses the old and new treatment opportunities, proposing a shared algorithm for second-line setting in advanced NSCLC. PMID- 29992895 TI - Nanovehicle-based small interfering RNA (siRNA) delivery for therapeutic purposes: a new molecular approach in the pharmacogenomics. AB - RNA interference (RNAi) is a process for regulating the gene expression in which small interfering RNAs (siRNAs) silence target genes. siRNA-based therapy as a new molecular treatment approach, offers therapeutic prospects for many common diseases such as cancer and cardiovascular disorders. Nevertheless, the efficacy of siRNA delivery has, so far, remained a challenging issue. This is due to their easy degradation through the circulation system and the difficulties in the intracellular delivery to specific tissues where they silence the target genes. There have been many efforts to develop suitable, safe and effective siRNA delivery systems in the past decades. These efforts specifically aimed to protect siRNA from serum nucleases and deliver it to an intracellular region in the desired target cells. In this context, one of the new and popular approaches is nanovehicle-mediated siRNA delivery systems. The systems potentially may be used in future medicine, particularly for untreatable or poorly treated diseases. As we learn more about these delivery systems, we can better use the tremendous opportunities provided by siRNA-based therapeutics. The results of ongoing clinical trials will play an important role in determining whether siRNA-based drugs can be considered as a new class of drugs. Here, the authors reviewed and highlighted the recent advances in this exciting and fast growing field to help in the development of effective therapeutic tools in controlling human diseases. PMID- 29992896 TI - Notoginsenoside R1 Promotes the Growth of Neonatal Rat Cortical Neurons via the Wnt/beta-catenin Signaling Pathway. AB - BACKGROUND & OBJECTIVE: Notoginsenoside R1 (NGR1) is one of the main effective components of Panax notoginseng. METHOD: Primary cortical neurons were harvested from neonatal rats and cultured to analyze the role of NGR1 in neuronal growth and the effects of NGR1 on the Wnt/beta-catenin signaling pathway. Following treatment with NGR1, immunocytochemistry was used to detect expression of Tuj1 and MAP2, and RT-qPCR was used to measure mRNA levels of key factors in the Wnt signaling pathway. RESULTS: Results showed that NGR1 promotes growth of cultured neurons and significantly upregulates mRNA levels of beta-catenin, Dishevelled, and Frizzled. To further confirm whether NGR1 promoted cortical neuron growth via the Wnt/beta-catenin signaling pathway, we knocked down beta- catenin mRNA by siRNA interference; following NGR1 treatment of beta-catenin-knockdown neurons, beta-catenin mRNA levels increased significantly. CONCLUSION: In conclusion, these results demonstrate that NGR1 promotes growth of cultured cortical neurons from the neonatal rat, possibly via the Wnt/beta-catenin signaling pathway. PMID- 29992897 TI - Small Regulatory RNAs in the Enterobacterial Response to Envelope Damage and Oxidative Stress. AB - The ability of bacteria to thrive in diverse habitats and to adapt to ever changing environmental conditions relies on the rapid and stringent modulation of gene expression. It has become evident in the past decade that small regulatory RNAs (sRNAs) are central components of networks controlling the bacterial responses to stress. Functioning at the posttranscriptional level, sRNAs base pair with cognate mRNAs to alter translation, stability, or both to either repress or activate the targeted transcripts; the RNA chaperone Hfq participates in stabilizing sRNAs and in promoting pairing between target and sRNA. In particular, sRNAs act at the heart of crucial stress responses, including those dedicated to overcoming membrane damage and oxidative stress, discussed here. The bacterial cell envelope is the outermost protective barrier against the environment and thus is constantly monitored and remodeled. Here, we review the integration of sRNAs into the complex networks of several major envelope stress responses of Gram-negative bacteria, including the RpoE (sigmaE), Cpx, and Rcs regulons. Oxidative stress, caused by bacterial respiratory activity or induced by toxic molecules, can lead to significant damage of cellular components. In Escherichia coli and related bacteria, sRNAs also contribute significantly to the function of the RpoS (sigmaS)-dependent general stress response as well as the specific OxyR- and SoxR/S-mediated responses to oxidative damage. Their activities in gene regulation and crosstalk to other stress-induced regulons are highlighted. PMID- 29992898 TI - Antimicrobial Resistance among Staphylococci of Animal Origin. AB - Antimicrobial resistance among staphylococci of animal origin is based on a wide variety of resistance genes. These genes mediate resistance to many classes of antimicrobial agents approved for use in animals, such as penicillins, cephalosporins, tetracyclines, macrolides, lincosamides, phenicols, aminoglycosides, aminocyclitols, pleuromutilins, and diaminopyrimidines. In addition, numerous mutations have been identified that confer resistance to specific antimicrobial agents, such as ansamycins and fluoroquinolones. The gene products of some of these resistance genes confer resistance to only specific members of a class of antimicrobial agents, whereas others confer resistance to the entire class or even to members of different classes of antimicrobial agents, including agents approved solely for human use. The resistance genes code for all three major resistance mechanisms: enzymatic inactivation, active efflux, and protection/modification/replacement of the cellular target sites of the antimicrobial agents. Mobile genetic elements, in particular plasmids and transposons, play a major role as carriers of antimicrobial resistance genes in animal staphylococci. They facilitate not only the exchange of resistance genes among members of the same and/or different staphylococcal species, but also between staphylococci and other Gram-positive bacteria. The observation that plasmids of staphylococci often harbor more than one resistance gene points toward coselection and persistence of resistance genes even without direct selective pressure by a specific antimicrobial agent. This chapter provides an overview of the resistance genes and resistance-mediating mutations known to occur in staphylococci of animal origin. PMID- 29992899 TI - Large Noncoding RNAs in Bacteria. AB - Bacterial noncoding RNA (ncRNA) classes longer than 200 nucleotides are rare but are responsible for performing some of the most fundamental tasks in living cells. RNAs such as 16S and 23S rRNA, group I and group II introns, RNase P ribozymes, transfer-messenger RNAs, and coenzyme B12 riboswitches are diverse in structure and accomplish biochemical functions that rival the activities of proteins. Over the last decade, a number of new classes of large ncRNAs have been uncovered in bacteria. A total of 21 classes with no established functions have been identified through the use of bioinformatics search strategies. Based on precedents for bacterial large ncRNAs performing sophisticated functions, it seems likely that some of these structured ncRNAs also will prove to carry out complex functions. Thus, determining their roles will provide a better understanding of fundamental biological processes. A few studies have produced data that provide clues to the purposes of some of these recently found classes, but the true functions of most classes remain mysterious. PMID- 29992901 TI - The voice of evidence. AB - In an era in which evidence is being disregarded, scientists need to speak up in support of the pursuit for truth. PMID- 29992902 TI - Coronary artery treatment with an urea-based paclitaxel-coated balloon: The European wide Falcon all comers DCB Registry (FALCON-Registry). AB - AIMS: To investigate the use of drug-coated balloon (DCB) in daily clinical practice and provide further evidence for safety and efficacy of paclitaxel coated balloon treatment using urea as inert excipient. METHODS AND RESULTS: Between December 2013 and December 2015, 757 patients treated for coronary lesions with the IN.PACT Falcon balloon were enrolled in this prospective real world all comers registry. Primary outcome was clinically driven target lesion revascularization (TLR) rate at 12 months. Secondary outcome was major adverse cardiac events (MACE) defined as cardiac death, myocardial infarction, TLR and target vessel revascularization (TVR). 43.1% out of 805 lesions were de novo, 53.2% drug-eluting stent (DES) or bare-metal stent (BMS) in-stent restenosis (ISR). TLR at 12 months was 6.2% and TVR 8.3%. MACE occurred in 9.7% of patients with a composite of cardiac death in 0.8% and myocardial infarction in 2.7% plus TLR/TVR. Subgroup analysis confirmed a TLR rate of 7.5% for ISR (2.1 % BMS and 9.5% DES) and 4.9% for de novo lesions. CONCLUSIONS: The IN.PACT Falcon urea based paclitaxel-coated balloon is safe and efficient in de novo and ISR lesions with low TLR/TVR. The high proportion of treatment of de novo lesions, indicates that DCB only strategy is nowadays common. PMID- 29992903 TI - Acute Myocardial Infarction and Coronary Intramural Hematoma: a Clue to Aortic Dissection. PMID- 29992900 TI - Embryonic hematopoiesis modulates the inflammatory response and larval hematopoiesis in Drosophila. AB - Recent lineage tracing analyses have significantly improved our understanding of immune system development and highlighted the importance of the different hematopoietic waves. The current challenge is to understand whether these waves interact and whether this affects the function of the immune system. Here we report a molecular pathway regulating the immune response and involving the communication between embryonic and larval hematopoietic waves in Drosophila. Down-regulating the transcription factor Gcm specific to embryonic hematopoiesis enhances the larval phenotypes induced by over-expressing the pro-inflammatory Jak/Stat pathway or by wasp infestation. Gcm works by modulating the transduction of the Upd cytokines to the site of larval hematopoiesis and hence the response to chronic (Jak/Stat over-expression) and acute (wasp infestation) immune challenges. Thus, homeostatic interactions control the function of the immune system in physiology and pathology. Our data also indicate that a transiently expressed developmental pathway has a long-lasting effect on the immune response. PMID- 29992904 TI - One-year outcomes of patients with severe aortic stenosis and an STS PROM of less than three percent in the SURTAVI trial. AB - AIMS: The indication for transcatheter aortic valve implantation (TAVI) has evolved from inoperable patients to patients at increased surgical risk. In low risk patients, surgical aortic valve replacement (SAVR) remains the standard of care. The aim of this study was to explore the outcomes of TAVI and SAVR in patients with a Society of Thoracic Surgeons (STS) predicted risk of mortality (PROM) score below 3% in the SURTAVI trial. METHODS AND RESULTS: In SURTAVI, patients at intermediate surgical risk based on Heart Team consensus were randomised to TAVI or SAVR. We stratified the overall patient population into quintiles based on the STS PROM score; the one-year mortality was correlated with the mean STS PROM score in each quintile. The quintiles were regrouped into three clinically relevant categories of STS score: less than 3%, 3 to <5%, and >5%. All cause mortality or disabling stroke in each risk stratum was compared between TAVI and SAVR. Linear regressions between mean values of STS PROM in each quintile and observed all-cause mortality at one year showed great association for the global population (r2=0.92), TAVI (r2=0.89) and SAVR cohorts (r2=0.73). All-cause mortality or disabling stroke of TAVI vs. SAVR was 1.5% vs. 6.5% (p=0.04), 6.5% vs. 7.6% (p=0.52) and 13.5% vs. 11.0% (p=0.40) in the <3%, 3-5%, and >=5% STS score strata, respectively. CONCLUSIONS: Among patients at intermediate surgical risk but with an STS PROM <3%, TAVI may achieve superior clinical outcomes compared to SAVR. These findings support the need for an adequately powered randomised trial to compare TAVI with SAVR in patients at low operative risk. PMID- 29992905 TI - Use of covered stents in the field of congenital heart diseases: the role of new players. PMID- 29992907 TI - Multi-band effects in in-plane resistivity anisotropy of strain-detwinned disordered Ba(Fe1-xRux)2As2. AB - In-plane resistivity anisotropy was measured in strain-detwinned as-grown and partially annealed samples of isovalently-substituted [Formula: see text] ([Formula: see text]) and the results were contrasted with previous reports on anneal samples with low residual resistivity. In samples with high residual resistivity, detwinned with application of strain, the difference of the two components of in-plane resistivity in the orthorhombic phase, [Formula: see text], was found to obey Matthiessen rule irrespective of sample composition, which is in stark contrast with observations on annealed samples. Our findings are consistent with two-band transport model in which contribution from high mobility carriers of small pockets of the Fermi surface has negligible anisotropy of residual resistivity and is eliminated by disorder. Our finding suggests that magnetic/nematic order has dramatically different effect on different parts of the Fermi surface. It predominantly affects inelastic scattering for small pocket high mobility carriers and elastic impurity scattering for larger sheets of the Fermi surface. PMID- 29992906 TI - Estimating the NEMA characteristics of the J-PET tomograph using the GATE package. AB - A novel whole-body positron emission tomography (PET) system based on plastic scintillators is developed by the J-PET Collaboration. It consists of plastic scintillator strips arranged axially in the form of a cylinder, allowing the cost effective construction of the total-body PET system. In order to determine the properties of the scanner prototype and optimize its geometry, advanced computer simulations were performed using the GATE (Geant4 application for tomographic emission) software. The spatial resolution, sensitivity, scatter fraction and noise equivalent count rate were estimated according to the National Electrical Manufacturers Association norm, as a function of the length of the tomograph, the number of detection layers, the diameter of the tomographic chamber and for various types of applied readout. For the single-layer geometry with a diameter of 85 cm, a strip length of 100 cm, a cross-section of 4 mm * 20 mm and silicon photomultipliers with an additional layer of wavelength shifter as the readout, the spatial resolution (full width at half maximum) in the centre of the scanner is equal to 3 mm (radial, tangential) and 6 mm (axial). For the analogous double layer geometry with the same readout, diameter and scintillator length, with a strip cross-section of 7 mm * 20 mm, a noise equivalent count rate peak of 300 kcps was reached at 40 kBq cc-1 activity concentration, the scatter fraction is estimated to be about 35% and the sensitivity at the centre amounts to 14.9 cps kBq-1. Sensitivity profiles were also determined. PMID- 29992908 TI - Colloidal branched CdSe/CdS 'nanospiders' with 2D/1D heterostructure. AB - In this paper we report the synthesis of colloidal CdSe/CdS core-shell heteronanoplatelets with epitaxially grown wurtzite (WZ) 1D CdS branches or legs by using cadmium diethyldithiocarbamate as a single-source precursor. The growth of WZ branches was achieved by exploiting zinc blende-wurtzite polytypism of cadmium chalcogenides induced by oleylamine. Synthesized 'nanospiders' exhibit enhanced absorption in the UV-blue region and narrow and relatively intense red photoluminescence depending on the amount of CdS in the heteronanostructure. PMID- 29992909 TI - Transesophageal 2D ultrasound to 3D computed tomography registration for the guidance of a cardiac arrhythmia therapy. AB - The work aims to develop a new image-processing method to improve the guidance of transesophageal high intensity focused ultrasound (HIFU) atrial fibrillation therapy. Our proposal is a novel registration approach that aligns intraoperative 2D ultrasound with preoperative 3D-CT information. This approach takes advantage of the anatomical constraints imposed at the transesophageal HIFU probe to simplify the registration process. Our proposed method has been evaluated on a physical phantom and on real clinical data. PMID- 29992910 TI - Taking the road less traveled: Economic analyses for advancing universal health coverage. PMID- 29992911 TI - Burnout in medical residents: A growing concern. PMID- 29992912 TI - Hypothyroidism-induced reversible dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is an idiopathic condition that results from impaired ventricular systolic function. Thyroid diseases have been known to cause myriad changes in the structure and function of the heart. Diastolic dysfunction is a common abnormality reported in hypothyroidism. However, hypothyroidism induced DCM and systolic dysfunction is an uncommon phenomenon, especially as the initial presenting manifestation of hypothyroidism. The current article describes the case of a young female who presented with symptoms of heart failure and was diagnosed as having DCM as echocardiography revealed left ventricular global hypokinesia and severely depressed systolic function. Thyroid profile revealed a grossly elevated thyroid-stimulating hormone (TSH) value of 313 MUIU/ml; free thyroxine (fT4) was 0.220 ng/dl. The present case presented with DCM as the initial presentation of hypothyroidism and improved significantly after five months of levothyroxine replacement therapy. PMID- 29992913 TI - Novel fructose bisphosphatase 1 gene mutation presenting as recurrent episodes of vomiting in an Indian child. AB - Fructose-1, 6-bisphosphatase 1 (FBP1) deficiency is an autosomal recessive disorder of gluconeogenesis resulting in severe and recurrent life-threatening episodes of hypoglycemia and lactic acidosis in infancy. We report a 16 month-old girl who presented with recurrent episodes of vomiting, rapid breathing, lactic acidosis, hyperuricemia, and hypertriglyceridemia. Genetic analysis revealed a novel compound heterozygous mutation in FBP1 gene confirming the diagnosis of FBP1 deficiency. The patient was managed with treatment of acute episodes and preventive long-term dietary modifications. Long-term prognosis of FBP1 deficiency is excellent underlining the importance of early recognition of clinical signs, prompt diagnosis, and avoidance of fasting in this disease. FBP1 gene mutations have been described from various ethnic backgrounds, but there is limited data available from Indian population, hence the importance of this case. PMID- 29992914 TI - Pneumohernios due to perforated cecum in left Amyand's hernia. AB - We report a case of incarcerated left indirect inguinal hernia in a male child which on exploration revealed the presence of free air and fecal matter containing fluid in the hernial sac. This is the second reported case of the presence of cecal perforation in left Amyand's hernia in pediatric age group and unique in the sense of the form of abnormal anatomy encountered per-operatively. PMID- 29992915 TI - Atypical Kawasaki disease: Diagnosis underneath diapers. PMID- 29992916 TI - Scrotal extratesticular schwannoma: A common tumor at an uncommon location. PMID- 29992917 TI - Comparison of Esophageal Function Tests to Investigate the Effect of Helicobacter Pylori Infection on Gastroesophageal Reflux Disease (GERD). AB - BACKGROUND The effects of Helicobacter pylori (H. pylori) infection on gastroesophageal reflux disease (GERD) remain unclear. The aim of this study was to compare the results of clinical esophageal function tests and the effect of H. pylori infection on GERD. MATERIAL AND METHODS A prospective clinical study included 124 patients diagnosed with GERD (four grades). H. pylori infection was determined by gastroscopy and a rapid urease test (RUT) to divide patients into an HP-positive and an HP-negative group. Esophageal function tests included high resolution manometry (HRM), peristalsis break (PB), and 24-hour pH monitoring (composite pH DeMeester score). Different grades of GERD, with and without H. pylori infection, esophageal function test results were analyzed. RESULTS The HP positive group, compared with the HP-negative group with GERD, showed a significantly reduced median PB value (3.41+/-3.65 vs. 6.18+/-5.27), reduced PBs >5 cm per ten swallows (2.23+/-3.05 vs. 4.04+/-3.70) indicating that that H. pylori infection improved esophageal peristalsis. During 24-hour esophageal pH monitoring, the HP-positive group showed a significantly reduced percentage of time for esophageal pH <4.0, number of reflux events >5 min, and number of reflux episodes in 24 hours, compared with the HP-negative group. The DeMeester score was significantly increased in the HP-negative group, indicating a higher esophageal acid exposure (9.11+/-8.15 vs. 24.30+/-30.27). CONCLUSIONS H. pylori infection improved esophageal peristalsis, enhanced lower esophageal sphincter (LES) pressure, and reduced esophageal acid exposure, which might be protective factors for GERD. PMID- 29992918 TI - [B.V. Petrovsky and development of home coronary surgery]. AB - Academician B.V. Petrovsky had considerable impact on coronary surgery development in our country. Current Russian coronary surgery comparable with world standards is based on scientific and practical initiatives initiated and developed by B.V. Petrovsky and his students. PMID- 29992919 TI - [Surgical treatment of DeBakey type 1 aortic dissection]. AB - The article is devoted to the founder of Russian Research Center for Surgery, academician B.V. Petrovsky, who created a multi-field surgical institution of the highest world standards. Treatment of thoracoabdominal aortic aneurysms and dissections being the most difficult and laborious has been solved at the Russian Research Center for Surgery from initial procedures to the most difficult hybrid interventions and total aortic repair. PMID- 29992920 TI - [The results of coronary artery bypass grafting by using of surgical microscope]. AB - AIM: To present an experience of coronary artery bypass grafting (CABG) by using of surgical microscope in patients with coronary artery disease at Cardiac Surgery Department #2 (surgical treatment of myocardial dysfunction and heart failure) of Petrovsky Russian Research Center for Surgery. MATERIAL AND METHODS: There were 41 CABG procedures with surgical microscope. Indications for myocardial revascularization, surgical technique, intraoperative and postoperative complications are comprehensively described. RESULTS: CABG by using of surgical microscope is a successfully reproducible technique followed by good immediate outcomes. PMID- 29992921 TI - [Evolution of mitral valve replacement]. AB - Historical development of mitral valve surgery at Petrovsky Russian Research Center for Surgery is described in the article. Evolution of artificial heart valves design and development of surgical techniques are presented. PMID- 29992922 TI - [Cardiopulmonary bypass and circulatory support in Petrovsky Russian Research Center for Surgery]. AB - Since initial application of cardiopulmonary bypass (1960) and circulatory support (1977) unique methods of extracorporeal circulation have been developed at Petrovsky Russian Research Center for Surgery. Some of them were introduced for the first time in the country (USSR and then in the Russian Federation). It was possible due to creative team of Boris Vasilyevich Petrovsky, whose potential was aimed at expanding the indications for surgical treatment of cardiac, aortic, liver, lung and kidney diseases under artificial circulation and then circulatory support. PMID- 29992923 TI - [Thoracoscopic subtotal esophageal resection for benign esophageal diseases]. AB - AIM: To investigate the role of video-assisted subtotal esophageal resection in treatment of patients with benign esophageal diseases. MATERIAL AND METHODS: Fifty-one patients with benign esophageal diseases have undergone subtotal esophageal resection in our department for the period 2010-2017. Thoracoscopic technique was applied in 25 cases, open approach - in 26 patients. Total surgery time, thoracoscopic stage duration, length of hospital-stay (LOS), ICU-stay, Clavien-Dindo morbidity rates with separate registration of respiratory complications, mortality have been considered. RESULTS: Groups were similar in terms of age, gender, ASA status. Thoracoscopic stage duration gradually decreased from 175 to 65 min with average time of 102 (75; 123) min. Total surgery time was 390 (270; 495) min in group 1 and 465 (341; 561) min in the control group (r=0.035). Mean ICU-stay decreased up to 2 (1.25; 3.75) days compared with the control group (5 (3.92; 5.85) days, r<0.0001). Conversion rate was 8%. In the main group complications Clavien-Dindo grade 2 were detected in 10 (40%) patients compared with 20 (69%) cases in the control group (r=0.009). Respiratory complications occurred in 5 patients in group 1 and in 13 cases of the control group (r=0.039). Mortality was absent. CONCLUSION: Thoracoscopic subtotal esophageal resection may be advisable alternative to open surgery for patients with benign esophageal diseases due to lower postoperative morbidity and earlier rehabilitation followed by improved outcomes. PMID- 29992924 TI - [Surgical treatment of spine injuries]. AB - The history of spinal fixation started in the 19th century and had an intensive development in subsequent years. Special progress in surgery for spinal traumatic injuries was noted in the Second World War. Last decades minimally invasive spinal surgical techniques are developed and introduced in everyday practice. PMID- 29992925 TI - [Selective approach for splenic flexure mobilization in total mesorectal excision followed by low colorectal anastomoses]. AB - AIM: To evaluate the results of selective approach for splenic flexure mobilization (SFM) after total mesorectal excision with low colorectal anastomoses. MATERIAL AND METHODS: Clinical data were obtained from the multicenter RCT database comparing ileostomy and colostomy in patients with rectal cancer who underwent total mesorectal excision from 2012 to 2017. Our clinic policy is performing paraaortic lymph node dissection with 'low' inferior mesenteric artery ligation, left colic artery preservation and use of sigmoid colon for colorectal anastomosis. SFM was used only in cases of inability to apply above-mentioned procedure (selective approach for SFM). RESULTS: SFM was performed in 15 (13%) out of 115 patients. The most frequent reasons for SFM were sigmoid colon diverticulosis, impaired blood supply or inadequate length of sigmoid colon. There were no differences in intraoperative and postoperative complications between TME without SFM and TME with SFM. CONCLUSION: Selective SFM in TME followed by advanced paraaortic lymph node dissection and left colic artery preservation is safe and may be considered as a viable option to routine SFM in rectal cancer surgery. PMID- 29992926 TI - [Modern possibilities of multi-field surgical clinic in diagnosis and treatment of myocardial infarction with nonobstructive coronary arteries (MINOCA)]. PMID- 29992928 TI - [Academician B.V. Petrovsky's contribution to esophageal surgery (by the 110th anniversary)]. PMID- 29992927 TI - [Inflammatory myofibroblastic tumor of common bile duct]. PMID- 29992929 TI - [Diaphragm relaxation surgery: since B.V. Petrovsky to the present day]. PMID- 29992930 TI - [Modern approaches to components of therapy of patients with diabetes mellitus operated on for malignant neoplasms of small pelvic organs]. AB - The purpose of this study was assessment of the effect of cytoflavin preparation inclusion in surgical treatment of patients with malignant neoplasms of small pelvic organs and diabetes mellitus. A prospective examination of 51 patients aged 56 to 76 years suffering from diabetes mellitus and malignant neoplasms of the pelvic organs was performed. Patients were divided into two groups: the first group consisted of 27 patients whose adaptive potential was characterized by tension of adaptation mechanisms, the second one - 24 patients with poor adaptation. In turn, in each group, patients were divided into subgroups depending on the treatment regimen: in the main subgroup of the first group (14 people) the treatment program was supplemented with cytoflavin (10 ml 2 times a day), in the main subgroup of the second group were 13 patients with cytoflavin supplement (20 ml 2 times a day). Patients of control groups underwent standard therapy. State of energy deficiency was assessed by methemoglobin, carbohemoglobin, P50, oxygen delivery, consumption and extraction. Concentration of glucose, lactate, lactate dehydrogenase was assessed. The results of the study showed clear relationship between the nature of changes in transport and oxygen consumption, adaptation adaptive reactions, allowing to identify mechanisms that characterize formation of various types of energy deficiency in perioperative period in patients with malignant diseases of the pelvic organs and diabetes. Use of cytoflavin contributed to a qualitative and effective correction of energy deficiency as well as reduction in the patients stay in the hospital. PMID- 29992931 TI - [The role of Sonic Hedgehog signaling pathway in the development of oral squamous cell carcinoma]. AB - The research of the Sonic Hedgehog signaling pathway activity was carried out on biopsy specimens of 43 patients with oral hyperplasia, squamous intraepithelial neoplasia and oral squamous cell carcinoma. Tissue antigens were determined using a mouse monoclonal antibody to Ki-67 protein and rabbit monoclonal antibody to Gli-1 protein. In squamous intraepithelial neoplasia and oral squamous cell carcinoma specimens Gli-1 was detected in the cytoplasm of cells only. The correlation was found between the proliferative activity of epithelial cells and Gli-1 distribution. Protein Gli-1 can be used for early diagnosis of malignant transformation of oral stratified squamous epithelium. PMID- 29992932 TI - [Differences in the cytocompatibility of bone-plastic materials from xenogeneic hydroxyapatite with stem cells from human exfoliated deciduous teeth and adipose tissue-derived mesenchymal stem cells]. AB - AIM: To compare the cytocompatibility of osteoplastic materials used in dentistry with stem cells from human exfoliated deciduous teeth (SHED) and adipose tissue derived mesenchymal stem cells (AD-MSC). MATERIAL AND METHODS: Materials of the brands 'Bio-Oss', 'Indost', 'Bioplast', 'Viscoll' and 'Trikafor' were selected for study purposes. Cultures of SHED and AD-MSC were used for testing. The cytotoxic effect of the materials was determined using MTT test and vital staining with trypan blue. Cell adhesion was assessed by the vital staining of PKH-26. RESULTS: Water extracts of bone-plastic materials from xenogeneic hydroxyapatite of the brands 'Bio-Oss', 'Indost' and 'Bioplast' exert a cytotoxic effect on SHED and do not cause the death of AD-MSC. Materials based on collagen and beta-tricalcium phosphate possess high cytocompatibility with all cell cultures under study. CONCLUSION: From the point of cytocompatibility all the examined bone-plastic materials may be considered safe for the restoration of bone defects. It should be noted that SHED transplantation on the surface of materials containing xenogeneic hydroxypatite is unacceptable. PMID- 29992933 TI - [Before arrival of emergency ambulance...]. AB - Safety is one of fundamental requirements of modern dentistry. The emergency situation when immediate treatment is required for stabilization of the general condition of the patient, can occur to the dentist of any specialty. For rendering the urgent, emergency or resuscitation help it is necessary to know modern treatment protocols, to be able to demonstrate a workplace steady skills of saving actions in the conditions of effective team interaction, and also to have for this purpose all necessary equipment and medicines. PMID- 29992934 TI - [Oral fluid indicators dynamics in pregnant women by topical calcium-phosphate fluoride gel application]. AB - In this article the most significant oral fluid indicators in pregnant women have been studied before and after the caries prevention course with using the ternary calcium phosphate-fluoride-containing gel. The topical application of the gel has been established to result in improving the majority of studied oral fluid parameters values. In addition the probability risk of the oral fluid indicators impact on the dental caries growth rate was assessed in the paper. Herewith the influence of the same oral fluid parameters on the dental caries growth intensity has been proved to be probably different before and after carrying out the local prophylactic caries impacts. PMID- 29992935 TI - [Subjective, functional and microbiological parameters of the oral cavity in gastroesophageal reflux patients with acidic and subacidic refluctant]. AB - The aim of the study was to compare dental and periodontal status, oral hygiene, salivation rate, functional parameters of saliva and oral microbiota composition in patients with gastroesophageal reflux disease (GERD) with acidic and subacidic refluctant. The study comprised 69 participants divided in 3 groups: 22 healthy volunteers (controls) and 2 main groups: 25 GERD patients with acidic (group 2) and 22 patients with subacidic refluctant (group 3). Poor dental and periodontal condition was revealed in group 3 patients probably because of aggressive intestinal content reflux in the oral cavity resulting in higher PMA an saliva pH values, Escherichia coli species in oral microbiota and low buffer capacity of saliva. The results show that GERD may be suspected due to oral manifestations thus promoting it's prompt treatment. PMID- 29992937 TI - [Evolution of the mandibular defects reconstruction with free fibula flapx]. AB - One of the most important steps in achieving aesthetical and functional result in mandible reconstruction with fibula free flap is positioning of the bony part relative to the basis of the native mandible. Positioning fibular bony part continuing inferior mandible border may produce a high discrepancy between the residual mandible and fibula bone that results in difficulty in denture rehabilitation. Positioning fibular bony part continuing alveolar mandible border creates asymmetric jowls and changed shape of jawline in border-line zone. The double-barrel technique solves this problem, but needs a meticulous preoperative planning and precision free fibula flap modelling. PMID- 29992936 TI - [Treatment of traumatic prosthetic stomatitis in elderly and senium people with 'dry mouth' syndrome]. AB - There was clinical observation of the treatment of traumatic prosthetic stomatitis in 44 people (9 men and 35 women) aged 61 and 82 years suffering from 'dry mouth' syndrome due to radiation and (or) drug sialoadenopathies developed after combined treatment of malignant neoplasms of the organs of the oropharyngeal zone. Using semi-quantitative method, a comparative evaluation of the effectiveness of a new drug based on chelate organic germanium guanine complex, sodium alginate and xylitol (main study group) and previously used drug (control group) for local therapy of traumatic lesions of the oral mucosa was made. It was found that on day 9 in the main study group the effectiveness of treatment was significantly higher (95.0%) than in the control group (80.8%). PMID- 29992938 TI - [Cephalometric evaluation of the effect of dynamax and monoblock appliances on vertical facial height in patients with distal malocclusion]. AB - The most common abnormality in orthodontics is distal malocclusion. The patient will benefit more if is treated during active growth phase. Various types of functional appliances are used in order to control maxillary and mandibular growth. In this article we compared vertical changes in mandibular position as a result of 3 different distal malocclusion treatment methods. To this end, groups consisting of, 17 patients treated with dynamax appliance, 17 patients treated with Monoblock appliance, 16 patients treated with a Monoblock-Headgear combination were created. Research has shown that, treatment with removable functional appliances results in parallel downward positioning of mandible; treatment with semiremovable appliances results in backward and downward rotation of mandible and that the extraoral appliances are useless to control the lower facial height. PMID- 29992940 TI - [The 'axial' method of teeth preparation for fixed partial and telescopic dentures]. AB - The article describes the method preparation of teeth which would be united by single construction of prosthesis. The proposed method has 2 features from the currently known methods. Firstly, axial preparation lines are applied on each abutment teeth by using needle narrow diamond bur. Lines could be performed on 3 walls of abutment teeth (vestibular, occlusal, lingval) and should be parallel each other. Secondly, the mirror for intraoral dental photography is used during the preparation by this method. The large surface of this mirror allows to see several teeth at the same time. The mirror is placed in the mouth at different angles which helps to accurately visualize the convergence all walls of abutment teeth. The advantage of this method is ability to use a microscope or binoculars for magnification during preparation. PMID- 29992939 TI - [Complex rehabilitation of children with congenital cleft lip and palate at stomatological treatment stages]. AB - Congenital malformations of the maxillofacial area - congenital cleft lip and palate (CCLP) due to their frequency, the severity of anatomical and functional disorders, the difficulty of social adaptation of patients, economic aspects are one of the most important problems of medicine. It is established that for timely stage surgical treatment of children with IAPC the emphasis is on the somatic status of the child, anti-infective resistance, the ability to safely tolerate surgery, which is important for the restoration of anatomical defects, communication functions and psychosomatic health. Children with CCLP are at risk for increased occurrence of postoperative complications, since upper respiratory tract infection and exacerbation of chronic respiratory tract diseases and ENT organs is a contraindication to surgical intervention. The study of immune status revealed deep violations of antiviral and antibacterial immunity in children with CCPC aged from 6 to 12 years. A program of combine interferon- and immunotherapy has been created. Positive clinical and immunological efficacy of combine interferon-(gel Viferon - recombinant IFNalpha2b in combination with antioxidant) and immunotherapy in the rehabilitation of children with CCPC aged 6 to 12 years was demonstrated. PMID- 29992941 TI - [Needle fractures during mandibular block: prevention and emergency care algorithm]. AB - Cases of dental needle fracture during mandibular block were studied in the last 10 years. Despite dental anesthesia development, the cases of needle fracture occur regularly in the world practice. Some of these complications has iatrogenic nature while others may be attributed to independent reasons like patients' sharp movement and needle manufacturing defect. In most of the cases the needle migrates to surrounding anatomical spaces making operative removing a challenging task. Subsequent surgical removing of a foreign body has severe consequences to patient in the form of a large operating injury, long-term disability and functional limitations. The article presents an algorithm for prevention and emergency care for a patient with dental needle fracture during mandibular block. PMID- 29992942 TI - [Pitfalls in diagnostic and treatment of salivary glands disorders]. AB - The paper presents a clinical case demonstrating difficulties in differential diagnosis of salivary glands disorders. The patient underwent several surgical procedures none of which was indicated. The article summarizes the reasons for diagnostic pitfalls of the case. PMID- 29992943 TI - [Clinical manifestations of syphilis in maxillofacial area. Part II]. AB - The article presents a review of the literature with a description of typical manifestations in the maxillofacial area in secondary, tertiary period of syphilis and the description of photo-images of the authors' clinical observations. In the secondary period of syphilis rashes can be found both on the skin and mucous membranes. In secondary reccurent syphilis the oral cavity is affected in 56% of the cases. Typical manifestations of this period are: roseola, papular and pustular syphilides. In the mouth the most frequently observed manifestation is popular syphilide or erythematous sore throat. The syphilitic papule of the mucous membrane of the mouth is flat, sharply demarcated, gets frequently eroded due to maceration or trauma. This papule is highly contagious element. Pustular syphilides are found mostly on the face and are a manifestation of a malignant course of the disease. Tertiary syphilis is a rare form of infection, which is observed as destructive injuries of organs and systems. The most frequent localization of gummy syphilide is the head. This article is highly revalent due to the high frequency of infection manifestation in maxillo-facial area, oral mucosa, and the high contagiousness symptoms, also affecting children. PMID- 29992945 TI - [Scientific advances in dentistry and maxillofacial surgery (materials of IX Young Scientists Conference)]. PMID- 29992944 TI - [Barrier drugs with prolonged release in dental practice]. AB - Pathological lesions associated with multiple causes (infections, physical, chemical and thermal agents) of oral mucosa are equally widespread in all spheres of dental practice. The actual importance of pharmaceutical therapy of lesions of oral mucosa is associated with the lack of reliable traditional topical drugs - ointments, gels, pastes, lacquers, discs - caused by their little efficiency associated with poor maintaining of permanent concentration, short contact period, discomfort and long-term treatment. All the mentioned facts caused the development of various pharmaceutical forms with prolonged activity with improved adhesion to oral mucosa, prolonged saving of useful properties and protecting the lesion from oral infection and external influences and reducing the intensity of painful sensations during mastication and mimics. These drugs form the group of barrier drugs and drugs with prolonged release of medicine of the wide specter. During all the time of existence this group of drugs has undergone and is still undergoing several changes targeted on improvement of adhesion and maintaining of constant concentration of medicine in the lesion and extension of indications for use. The development of new pharmaceutical forms is still continuing. PMID- 29992946 TI - Discovery of a drug candidate for GLIS3-associated diabetes. AB - GLIS3 mutations are associated with type 1, type 2, and neonatal diabetes, reflecting a key function for this gene in pancreatic beta-cell biology. Previous attempts to recapitulate disease-relevant phenotypes in GLIS3-/- beta-like cells have been unsuccessful. Here, we develop a "minimal component" protocol to generate late-stage pancreatic progenitors (PP2) that differentiate to mono hormonal glucose-responding beta-like (PP2-beta) cells. Using this differentiation platform, we discover that GLIS3-/- hESCs show impaired differentiation, with significant death of PP2 and PP2-beta cells, without impacting the total endocrine pool. Furthermore, we perform a high-content chemical screen and identify a drug candidate that rescues mutant GLIS3 associated beta-cell death both in vitro and in vivo. Finally, we discovered that loss of GLIS3 causes beta-cell death, by activating the TGFbeta pathway. This study establishes an optimized directed differentiation protocol for modeling human beta-cell disease and identifies a drug candidate for treating a broad range of GLIS3-associated diabetic patients. PMID- 29992947 TI - Systemic control of immune cell development by integrated carbon dioxide and hypoxia chemosensation in Drosophila. AB - Drosophila hemocytes are akin to mammalian myeloid blood cells that function in stress and innate immune-related responses. A multi-potent progenitor population responds to local signals and to systemic stress by expanding the number of functional blood cells. Here we show mechanisms that demonstrate an integration of environmental carbon dioxide (CO2) and oxygen (O2) inputs that initiate a cascade of signaling events, involving multiple organs, as a stress response when the levels of these two important respiratory gases fall below a threshold. The CO2 and hypoxia-sensing neurons interact at the synaptic level in the brain sending a systemic signal via the fat body to modulate differentiation of a specific class of immune cells. Our findings establish a link between environmental gas sensation and myeloid cell development in Drosophila. A similar relationship exists in humans, but the underlying mechanisms remain to be established. PMID- 29992948 TI - Large-scale gene losses underlie the genome evolution of parasitic plant Cuscuta australis. AB - Dodders (Cuscuta spp., Convolvulaceae) are root- and leafless parasitic plants. The physiology, ecology, and evolution of these obligate parasites are poorly understood. A high-quality reference genome of Cuscuta australis was assembled. Our analyses reveal that Cuscuta experienced accelerated molecular evolution, and Cuscuta and the convolvulaceous morning glory (Ipomoea) shared a common whole genome triplication event before their divergence. C. australis genome harbors 19,671 protein-coding genes, and importantly, 11.7% of the conserved orthologs in autotrophic plants are lost in C. australis. Many of these gene loss events likely result from its parasitic lifestyle and the massive changes of its body plan. Moreover, comparison of the gene expression patterns in Cuscuta prehaustoria/haustoria and various tissues of closely related autotrophic plants suggests that Cuscuta haustorium formation requires mostly genes normally involved in root development. The C. australis genome provides important resources for studying the evolution of parasitism, regressive evolution, and evo devo in plant parasites. PMID- 29992949 TI - A TFEB nuclear export signal integrates amino acid supply and glucose availability. AB - How cells coordinate the response to fluctuating carbon and nitrogen availability required to maintain effective homeostasis is a key issue. Amino acid limitation that inactivates mTORC1 promotes de-phosphorylation and nuclear translocation of Transcription Factor EB (TFEB), a key transcriptional regulator of lysosome biogenesis and autophagy that is deregulated in cancer and neurodegeneration. Beyond its cytoplasmic sequestration, how TFEB phosphorylation regulates its nuclear-cytoplasmic shuttling, and whether TFEB can coordinate amino acid supply with glucose availability is poorly understood. Here we show that TFEB phosphorylation on S142 primes for GSK3beta phosphorylation on S138, and that phosphorylation of both sites but not either alone activates a previously unrecognized nuclear export signal (NES). Importantly, GSK3beta is inactivated by AKT in response to mTORC2 signaling triggered by glucose limitation. Remarkably therefore, the TFEB NES integrates carbon (glucose) and nitrogen (amino acid) availability by controlling TFEB flux through a nuclear import-export cycle. PMID- 29992950 TI - Colletotrichum Species Causing Anthracnose of Rubber Trees in China. AB - Anthracnose caused by Colletotrichum is one of the most severe diseases of Hevea brasiliensis. However, research on the diversity and geographical distribution of Colletotrichum remains limited in China. In this study, we investigated the phylogenetic diversity of Colletotrichum isolates associated with symptomatic tissues of H.brasiliensis from four provinces of China (Hainan, Guangdong, Guangxi, and Yunnan). Based on multi-locus phylogenetic analyses and phenotypic characteristics, five species were distinguished, including two known species (C. fructicola, C. siamense), one novel species of C. gloeosporioides species complex (C. ledongense), and two novel species of C. acutatum species complex (C. bannanense and C. australisinense). Of these, C. siamense and C. australisinense have been recognized as major causative agents of anthracnose of H. brasiliensis. PMID- 29992951 TI - A full utilization of rice husk to evaluate phytochemical bioactivities and prepare cellulose nanocrystals. AB - Rice husks (RHs) as an agro-waste generated from rice production, while its application is limited. This study was designed to introduce a full utilization of rice husks, which extracted the phytochemical at first and then produced cellulose nanocrystals (CNCs) as the use of the residue. Furthermore, the phytochemicals extracted from rice husk was identified and its biological activity, including antioxidant activity, cellular antioxidant activity (CAA) and antiproliferative activity, had been detected as well. Results showed the bound fraction of rice husk had higher antioxidant than common fruit and grain. Free fraction of rice husk deserved to have further analysis in antiproliferative activity due to its low cytotoxicity. The CNCs produced by residue was using delignification process and acid hydrolysis treatments. The chemical composition of the residue obtained after phytochemical extraction was determined. CNCs morphological investigation was performed using an optical microscope and atomic force microscopy (AFM). Our strategy is to achieve a comprehensive utilization of rice husks with both economy and environment benefits. PMID- 29992952 TI - High Levels of Glyphosate Resistance in Conyza canadensis from Agricultural and Non-Agricultural Sites in Ohio and Iowa. AB - Glyphosate is an important herbicide worldwide, but its efficacy has been compromised where weed species have evolved glyphosate resistance. To better understand evolutionary outcomes of continued and strong selection from glyphosate exposure, we characterized variation in resistance in self-pollinating Conyza canadensis (horseweed) in Ohio and Iowa, where glyphosate resistance was first reported in 2002 and 2011, respectively. In 2015, we collected seeds from a total of 74 maternal plants (biotypes) from no-till soybean fields vs. non agricultural sites in each state, using one representative plant per site. Young plants from each biotype were sprayed with glyphosate rates of 0x, 1x (840 g ae ha-1), 8x, 20x, or 40x. Resistant biotypes with at least 80% survival at each dosage were designated as R1 (1x), R2 (8x), R3 (20x), or R4 (40x). Nearly all Ohio agricultural biotypes were R4, as were 62% of biotypes from the non agricultural sites. In Iowa, R4 biotypes were clustered in the southeastern soybean fields, where no-till agriculture is more common, and 45% of non agricultural biotypes were R1-R4. Our results show that resistance levels to glyphosate can be very high (at least 40x) in both states, and that non agricultural sites likely serve as a refuge for glyphosate-resistant biotypes. PMID- 29992953 TI - Publisher Correction: Spatio-temporal variability of processes across Antarctic ice-bed-ocean interfaces. AB - The original version of this Article contained an error in the spelling of the author Florence Colleoni, which was incorrectly given as Florence Colloni. This has been corrected in both the PDF and HTML versions of the Article. PMID- 29992954 TI - Targeting CD44v6 for fluorescence-guided surgery in head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) is an often highly invasive tumor, infiltrating functionally important tissue areas. Achieving complete tumor resection and preserving functionally relevant tissue structures depends on precise identification of tumor-free resection margins during surgery. Fluorescence-guided surgery (FGS), by intraoperative detection of tumor cells using a fluorescent tracer, may guide surgical excision and identify tumor positive resection margins. Using a literature survey on potential surface molecules followed by immunohistochemical validation, we identified CD44 variant 6 (CD44v6) as a constitutively expressed antigen in the invasion zone of HNSCC lesions. The monoclonal anti-CD44v6 antibody BIWA was labeled with both a near infrared fluorescent dye (IRDye800CW) and a radioactive label (Indium-111) and dual-modality imaging was applied in a locally invasive tumor mouse model. BIWA accurately detected human HNSCC xenografts in mice with a tumor uptake of 54 +/- 11% ID/g and invasion regions with an accuracy of 94%. When dissected under clinical-like conditions, tumor remnants approximately 0.7 mm in diameter consisting of a few thousand cells were identified by fluorescence imaging, resulting in reliable dissection of invasive microregions. These data indicate that CD44v6 is a suitable target for reliable near-infrared detection and FGS of invasive HNSCC lesions in vivo. PMID- 29992955 TI - Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57. AB - Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity. Herein we identify the antiprotozoal/antimicrobial nitazoxanide as a potential anti-paramyxovirus drug targeting the F-protein. We show that nitazoxanide and its circulating-metabolite tizoxanide act at post-entry level by provoking Sendai virus and RSV F-protein aggregate formation, halting F-trafficking to the host plasma membrane. F-protein folding depends on ER-resident glycoprotein-specific thiol-oxidoreductase ERp57 for correct disulfide-bond architecture. We found that tizoxanide behaves as an ERp57 non-competitive inhibitor; the putative drug binding-site was located at the ERp57-b/b' non-catalytic domains interface. ERp57-silencing mimicked thiazolide-induced F-protein alterations, suggesting an important role of this foldase in thiazolides anti-paramyxovirus activity. Nitazoxanide is used in the clinic as a safe and effective antiprotozoal/antimicrobial drug; its antiviral activity was shown in patients infected with hepatitis-C virus, rotavirus and influenza viruses. Our results now suggest that nitazoxanide may be effective also against paramyxovirus infection. PMID- 29992956 TI - Tools for engineering coordinated system behaviour in synthetic microbial consortia. AB - Advancing synthetic biology to the multicellular level requires the development of multiple cell-to-cell communication channels that propagate information with minimal signal interference. The development of quorum-sensing devices, the cornerstone technology for building microbial communities with coordinated system behaviour, has largely focused on cognate acyl-homoserine lactone (AHL)/transcription factor pairs, while the use of non-cognate pairs as a design feature has received limited attention. Here, we demonstrate a large library of AHL-receiver devices, with all cognate and non-cognate chemical signal interactions quantified, and we develop a software tool that automatically selects orthogonal communication channels. We use this approach to identify up to four orthogonal channels in silico, and experimentally demonstrate the simultaneous use of three channels in co-culture. The development of multiple non interfering cell-to-cell communication channels is an enabling step that facilitates the design of synthetic consortia for applications including distributed bio-computation, increased bioprocess efficiency, cell specialisation and spatial organisation. PMID- 29992958 TI - A quantitative criterion for determining the order of magnetic phase transitions using the magnetocaloric effect. AB - The ideal magnetocaloric material would lay at the borderline of a first-order and a second-order phase transition. Hence, it is crucial to unambiguously determine the order of phase transitions for both applied magnetocaloric research as well as the characterization of other phase change materials. Although Ehrenfest provided a conceptually simple definition of the order of a phase transition, the known techniques for its determination based on magnetic measurements either provide erroneous results for specific cases or require extensive data analysis that depends on subjective appreciations of qualitative features of the data. Here we report a quantitative fingerprint of first-order thermomagnetic phase transitions: the exponent n from field dependence of magnetic entropy change presents a maximum of n > 2 only for first-order thermomagnetic phase transitions. This model-independent parameter allows evaluating the order of phase transition without any subjective interpretations, as we show for different types of materials and for the Bean-Rodbell model. PMID- 29992957 TI - Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance. AB - Exploiting the full potential of anti-cancer drugs necessitates a detailed understanding of their cytotoxic effects. While standard omics approaches are limited to cell population averages, emerging single cell techniques currently lack throughput and are not applicable for compound screens. Here, we employed a versatile and sensitive high-content microscopy-based approach to overcome these limitations and quantify multiple parameters of cytotoxicity at the single cell level and in a cell cycle resolved manner. Applied to PARP inhibitors (PARPi) this approach revealed an S-phase-specific DNA damage response after only 15 min, quantitatively differentiated responses to several clinically important PARPi, allowed for cell cycle resolved analyses of PARP trapping, and predicted conditions of PARPi hypersensitivity and resistance. The approach illuminates cellular mechanisms of drug synergism and, through a targeted multivariate screen, could identify a functional interaction between PARPi olaparib and NEDD8/SCF inhibition, which we show is dependent on PARP1 and linked to PARP1 trapping. PMID- 29992959 TI - First cases and risk factors of super yeast Candida auris infection or colonization from Shenyang, China. AB - For the first time, we identified 15 cases of Candida auris in Shenyang, China, and then performed a risk factor assessment for these patients compared with 30 control subjects who were hospitalized in the same ward during the same period of time as the infected patients. We found that diarrhea, gastrointestinal decompression, infection, or colonization with other Candida isolates (especially Candida albicans) and tetracycline antibiotics were all risk factors for C. auris infection or colonization. Diarrhea and tetracycline antibiotics were independent risk factors. We suggest clinicians pay special attention to the emergence of multidrug-resistant C. auris infections or colonization. PMID- 29992961 TI - k-space imaging of anisotropic 2D electron gas in GaN/GaAlN high-electron mobility transistor heterostructures. AB - Nanostructures based on buried interfaces and heterostructures are at the heart of modern semiconductor electronics as well as future devices utilizing spintronics, multiferroics, topological effects, and other novel operational principles. Knowledge of electronic structure of these systems resolved in electron momentum k delivers unprecedented insights into their physics. Here we explore 2D electron gas formed in GaN/AlGaN high-electron-mobility transistor heterostructures with an ultrathin barrier layer, key elements in current high frequency and high-power electronics. Its electronic structure is accessed with angle-resolved photoelectron spectroscopy whose probing depth is pushed to a few nanometers using soft-X-ray synchrotron radiation. The experiment yields direct k space images of the electronic structure fundamentals of this system-the Fermi surface, band dispersions and occupancy, and the Fourier composition of wavefunctions encoded in the k-dependent photoemission intensity. We discover significant planar anisotropy of the electron Fermi surface and effective mass connected with relaxation of the interfacial atomic positions, which translates into nonlinear (high-field) transport properties of the GaN/AlGaN heterostructures as an anisotropy of the saturation drift velocity of the 2D electrons. PMID- 29992962 TI - Author Correction: Cryo-EM reveals the structural basis of microtubule depolymerization by kinesin-13s. AB - The previously published version of this Article contained an error in Fig. 5. In panels f and g, the alpha and beta symbols were swapped. The error has been corrected in both the PDF and HTML versions of the Article. PMID- 29992960 TI - An in vitro paradigm to assess potential anti-Abeta antibodies for Alzheimer's disease. AB - Although the amyloid beta-protein (Abeta) is believed to play an initiating role in Alzheimer's disease (AD), the molecular characteristics of the key pathogenic Abeta forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Abeta. Here, we combined the use of Abeta-rich aqueous extracts of brain samples from AD patients as a source of human Abeta and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Abeta antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Abeta antibody, which better protects against forms of Abeta oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Abeta therapeutics. PMID- 29992963 TI - Arf6-driven cell invasion is intrinsically linked to TRAK1-mediated mitochondrial anterograde trafficking to avoid oxidative catastrophe. AB - Mitochondria dynamically alter their subcellular localization during cell movement, although the underlying mechanisms remain largely elusive. The small GTPase Arf6 and its signaling pathway involving AMAP1 promote cell invasion via integrin recycling. Here we show that the Arf6-AMAP1 pathway promote the anterograde trafficking of mitochondria. Blocking the Arf6-based pathway causes mitochondrial aggregation near the microtubule-organizing center, and subsequently induces detrimental reactive oxygen species (ROS) production, likely via a mitochondrial ROS-induced ROS release-like mechanism. The Arf6-based pathway promotes the localization of ILK to focal adhesions to block RhoT1-TRAK2 association, which controls mitochondrial retrograde trafficking. Blockade of the RhoT1-TRAK1 machinery, rather than RhoT1-TRAK2, impairs cell invasion, but not two-dimensional random cell migration. Weakly or non-invasive cells do not notably express TRAK proteins, whereas they clearly express their mRNAs. Our results identified a novel association between cell movement and mitochondrial dynamics, which is specific to invasion and is necessary for avoiding detrimental ROS production. PMID- 29992964 TI - A subduction and mantle plume origin for Samoan volcanism. AB - The origin of Samoan volcanism in the southwest Pacific remains enigmatic. Whether mantle melting is solely caused by a mantle plume is questionable because some volcanism, here referred to as non-hotspot volcanism, defies the plume model and its linear age-progression trend. Indeed, non-hotspot volcanism occurred as far as 740 km west of the predicted Samoan hotspot after 5 Ma. Here we use fully dynamic laboratory subduction models and a tectonic reconstruction to show that the nearby Tonga-Kermadec-Hikurangi (TKH) subduction zone induces a broad mantle upwelling around the northern slab edge that coincides with the non-hotspot volcanic activity after 5 Ma. Using published potential mantle temperatures for the ambient mantle and Samoan mantle plume, we find that two geodynamic processes can explain mantle melting responsible for intraplate volcanism in the Samoan region. We propose that before 5 Ma, the volcanism is consistent with the plume model, whereas afterwards non-hotspot volcanism resulted from interaction between the Subduction-Induced Mantle Upwelling (SIMU) and Samoan mantle plume material that propagated west from the hotspot due to the toroidal component of slab rollback-induced mantle flow. In this geodynamic scenario, the SIMU drives decompression melting in the westward-swept plume material, thus producing the non-hotpot volcanism. PMID- 29992965 TI - Direct electric field control of the skyrmion phase in a magnetoelectric insulator. AB - Magnetic skyrmions are topologically protected spin-whirls currently considered as promising for use in ultra-dense memory devices. Towards achieving this goal, exploration of the skyrmion phase response and under external stimuli is urgently required. Here we show experimentally, and explain theoretically, that in the magnetoelectric insulator Cu2OSeO3 the skyrmion phase can expand and shrink significantly depending on the polarity of a moderate applied electric field (few V/MUm). The theory we develop incorporates fluctuations around the mean-field that clarifies precisely how the electric field provides direct control over the free energy difference between the skyrmion and the surrounding conical phase. The quantitative agreement between theory and experiment provides a solid foundation for the development of skyrmionic applications based on magnetoelectric coupling. PMID- 29992966 TI - Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude. AB - Drug delivery by nanocarriers (NCs) has long been stymied by dominant liver uptake and limited target organ deposition, even when NCs are targeted using affinity moieties. Here we report a universal solution: red blood cell (RBC) hitchhiking (RH), in which NCs adsorbed onto the RBCs transfer from RBCs to the first organ downstream of the intravascular injection. RH improves delivery for a wide range of NCs and even viral vectors. For example, RH injected intravenously increases liposome uptake in the first downstream organ, lungs, by ~40-fold compared with free NCs. Intra-carotid artery injection of RH NCs delivers >10% of the injected NC dose to the brain, ~10* higher than that achieved with affinity moieties. Further, RH works in mice, pigs, and ex vivo human lungs without causing RBC or end-organ toxicities. Thus, RH is a clinically translatable platform technology poised to augment drug delivery in acute lung disease, stroke, and several other diseases. PMID- 29992967 TI - Graphene's nonlinear-optical physics revealed through exponentially growing self phase modulation. AB - Graphene is considered a record-performance nonlinear-optical material on the basis of numerous experiments. The observed strong nonlinear response ascribed to the refractive part of graphene's electronic third-order susceptibility chi(3) cannot, however, be explained using the relatively modest chi(3) value theoretically predicted for the 2D material. Here we solve this long-standing paradox and demonstrate that, rather than chi(3)-based refraction, a complex phenomenon which we call saturable photoexcited-carrier refraction is at the heart of nonlinear-optical interactions in graphene such as self-phase modulation. Saturable photoexcited-carrier refraction is found to enable self phase modulation of picosecond optical pulses with exponential-like bandwidth growth along graphene-covered waveguides. Our theory allows explanation of these extraordinary experimental results both qualitatively and quantitatively. It also supports the graphene nonlinearities measured in previous self-phase modulation and self-(de)focusing (Z-scan) experiments. This work signifies a paradigm shift in the understanding of 2D-material nonlinearities and finally enables their full exploitation in next-generation nonlinear-optical devices. PMID- 29992968 TI - Ultrahigh-temperature tensile creep of TiC-reinforced Mo-Si-B-based alloy. AB - In this study, the ultrahigh-temperature tensile creep behaviour of a TiC reinforced Mo-Si-B-based alloy was investigated in the temperature range of 1400 1600 degrees C at constant true stress. The tests were performed in a stress range of 100-300 MPa for 400 h under vacuum, and creep rupture data were rationalized with Larson-Miller and Monkman-Grant plots. Interestingly, the MoSiBTiC alloy displayed excellent creep strength with relatively reasonable creep parameters in the ultrahigh-temperature range: a rupture time of ~400 h at 1400 degrees C under 137 MPa with a stress exponent (n) of 3 and an apparent activation energy of creep (Qapp) of 550 kJ/mol. The increasing rupture strains with decreasing stresses (up to 70%) and moderate strain-rate oscillations in the creep curves suggest that two mechanisms contribute to the creep: phase boundary sliding between the hard T2 and (Ti,Mo)C phases and the Moss phase, and dynamic recovery and recrystallization in Moss, observed with orientation imaging scanning electron microscopy. The results presented here represent the first full analysis of creep for the MoSiBTiC alloy in an ultrahigh-temperature range. They indicate that the high-temperature mechanical properties of this material under vacuum are promising. PMID- 29992969 TI - Deep-UV photoinduced chemical patterning at the micro- and nanoscale for directed self-assembly. AB - Deep-UV (DUV) laser patterning has been widely used in recent years for micro- and nanopatterning, taking advantage of the specific properties of irradiation with high-energy photons. In this paper, we show the usefulness of DUV laser patterning for preparing surfaces with controlled chemical properties at the micro- and nanoscale. Our motivation was to develop a simple and versatile method for chemical patterning at multiscales (from mm to nm) over relatively wide areas (mm2 to cm2). The chemical properties were provided by self-assembled monolayers (SAMs), prepared on glass or silicon wafers. We first investigated their modification under our irradiation conditions (ArF laser) using AFM, XPS and contact angle measurements. Photopatterning was then demonstrated with minimum feature sizes as small as 75 nm, and we showed the possibility to regraft a second SAM on the irradiated regions. Finally, we used these chemically patterned surfaces for directed self-assembly of several types of objects, such as block copolymers, sol-gel materials and liquids by vapor condensation. PMID- 29992970 TI - Author Correction: Three-dimensional quantitative fracture analysis of tight gas sandstones using industrial computed tomography. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29992971 TI - MiR-494-3p promotes PI3K/AKT pathway hyperactivation and human hepatocellular carcinoma progression by targeting PTEN. AB - Recent studies have shown that miR-494-3p is oncogene and has a central role in many solid tumors; however, the role of miR-494-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. In this study, it was found that miR-494-3p was up-regulated in HCC tissues. The high level of miR 494-3p in HCC tumors was correlated with aggressive clinicopathological characteristics and predicted poor prognosis in HCC patients. Functional study demonstrated that miR-494-3p significantly promoted HCC cell metastasis in vitro and vivo. Since phosphoinositide 3-kinase/protein kinase-B (PI3K/AKT) signaling is a basic oncogenic driver in HCC, a potential role of miR-494-3p was explored as well as its target genes in PI3K/AKT activation. Of all the predicted target genes of miR-494-3p, the tumor-suppressor phosphatase and tensin homolog (PTEN) were identified. In conclusion, the data we collected could define an original mechanism of PI3K/AKT hyperactivation and sketch the regulatory role of miR-494 3p in suppressing the expression of PTEN. Therefore, targeting miR-494-3p could provide an effective therapeutic method for the treatment of the disease. PMID- 29992972 TI - Nucleation Mechanisms of CO2 Hydrate Reflected by Gas Solubility. AB - The concentration of gas has been confirmed as a key factor dominating hydrate nucleation. In this study, CO2 hydrates were formed in pure water and a sodium dodecyl sulphate (SDS) solution using a temperature reduction method under constant pressure at different temperatures. The dissolving properties of CO2 throughout the whole induction period were investigated in detail. The experimental results showed that the 'memory effect' of hydrate might not be attributed to residual water structures after hydrate dissociation. Instead, residual gas molecules in the aqueous phase should receive more attention. Hydrate nucleation was confirmed to be a type of chain reaction. Low temperature was a significant factor that promoted hydrate nucleation. As a result, these two factors enhanced the stochastic features of the CO2 hydrate nucleation reaction. Even under the same conditions, critical gas concentrations beyond the threshold that hydrates can spontaneously nucleate were not fixed, but they still exhibited linear relations regarding a set temperature. Taking the significant influences of temperature into account, a new nucleation mechanism for CO2 hydrates was established based on the potential of the reaction system. Therefore, this study sheds new light when explaining the reason for the formation of gas hydrates in natural reservoirs. PMID- 29992974 TI - Squeezing dynamics of a nanowire system with spin-orbit interaction. AB - We analyze the dynamics of squeezing in a ballistic quantum wire with Rashba spin orbit interaction in the presence of both strong and weak magnetic fields and for different initial states of the system. Compared to the more standard measure of squeezing based on variances, we show that entropy squeezing is a more sensitive measure. Our results show that there is a strong relationship between the spin orbit interaction and the strength of entropy squeezing. Furthermore, there is a relationship between the initial state and the number of squeezed components. This allows new knobs to control the strength and the component of entropy squeezing in a nanowire system. PMID- 29992973 TI - A Requirement for Zic2 in the Regulation of Nodal Expression Underlies the Establishment of Left-Sided Identity. AB - ZIC2 mutation is known to cause holoprosencephaly (HPE). A subset of ZIC2 HPE probands harbour cardiovascular and visceral anomalies suggestive of laterality defects. 3D-imaging of novel mouse Zic2 mutants uncovers, in addition to HPE, laterality defects in lungs, heart, vasculature and viscera. A strong bias towards right isomerism indicates a failure to establish left identity in the lateral plate mesoderm (LPM), a phenotype that cannot be explained simply by the defective ciliogenesis previously noted in Zic2 mutants. Gene expression analysis showed that the left-determining NODAL-dependent signalling cascade fails to be activated in the LPM, and that the expression of Nodal at the node, which normally triggers this event, is itself defective in these embryos. Analysis of ChiP-seq data, in vitro transcriptional assays and mutagenesis reveals a requirement for a low-affinity ZIC2 binding site for the activation of the Nodal enhancer HBE, which is normally active in node precursor cells. These data show that ZIC2 is required for correct Nodal expression at the node and suggest a model in which ZIC2 acts at different levels to establish LR asymmetry, promoting both the production of the signal that induces left side identity and the morphogenesis of the cilia that bias its distribution. PMID- 29992975 TI - A Data Mining-based Prognostic Algorithm for NAFLD-related Hepatoma Patients: A Nationwide Study by the Japan Study Group of NAFLD. AB - The prognosis of patients with nonalcoholic fatty liver disease-related hepatocellular carcinoma (NAFLD-HCC) is intricately associated with various factors. We aimed to investigate the prognostic algorithm of NAFLD-HCC patients using a data-mining analysis. A total of 247 NAFLD-HCC patients diagnosed from 2000 to 2014 were registered from 17 medical institutions in Japan. Of these, 136 patients remained alive (Alive group) and 111 patients had died at the censor time point (Deceased group). The random forest analysis demonstrated that treatment for HCC and the serum albumin level were the first and second distinguishing factors between the Alive and Deceased groups. A decision-tree algorithm revealed that the best profile comprised treatment with hepatectomy or radiofrequency ablation and a serum albumin level >=3.7 g/dL (Group 1). The second-best profile comprised treatment with hepatectomy or radiofrequency ablation and serum albumin levels <3.7 g/dL (Group 2). The 5-year overall survival rate was significantly higher in the Group 1 than in the Group 2. Thus, we demonstrated that curative treatment for HCC and serum albumin level >3.7 g/dL was the best prognostic profile for NAFLD-HCC patients. This novel prognostic algorithm for patients with NAFLD-HCC could be used for clinical management. PMID- 29992976 TI - Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. AB - Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs. PMID- 29992977 TI - An Optimized Structure-Function Design Principle Underlies Efficient Signaling Dynamics in Neurons. AB - Dynamic signaling on branching axons is critical for rapid and efficient communication between neurons in the brain. Efficient signaling in axon arbors depends on a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron's morphology (material cost). However, where the balance between structural and dynamical considerations for achieving signaling efficiency is, and the design principle that neurons optimize to preserve this balance, is still elusive. In this work, we introduce a novel analysis that compares morphology and signaling dynamics in axonal networks to address this open problem. We show that in Basket cell neurons the design principle being optimized is the ratio between the refractory period of the membrane, and action potential latencies between the initial segment and the synaptic terminals. Our results suggest that the convoluted paths taken by axons reflect a design compensation by the neuron to slow down signaling latencies in order to optimize this ratio. Deviations in this ratio may result in a breakdown of signaling efficiency in the cell. These results pave the way to new approaches for investigating more complex neurophysiological phenomena that involve considerations of neuronal structure-function relationships. PMID- 29992979 TI - Inhibition of the precursor and mature forms of HIV-1 protease as a tool for drug evaluation. AB - HIV-1 protease (PR) is a homodimeric enzyme that is autocatalytically cleaved from the Gag-Pol precursor. Known PR inhibitors bind the mature enzyme several orders of magnitude more strongly than the PR precursor. Inhibition of PR at the precursor level, however, may stop the process at its rate-limiting step before the proteolytic cascade is initiated. Due to its structural heterogeneity, limited solubility and autoprocessing, the PR precursor is difficult to access by classical methods, and limited knowledge regarding precursor inhibition is available. Here, we describe a cell-based assay addressing precursor inhibition. We used a reporter molecule containing the transframe (TFP) and p6* peptides, PR, and N-terminal fragment of reverse transcriptase flanked by the fluorescent proteins mCherry and EGFP on its N- and C- termini, respectively. The level of FRET between EGFP and mCherry indicates the amount of unprocessed reporter, allowing specific monitoring of precursor inhibition. The inhibition can be quantified by flow cytometry. Additionally, two microscopy techniques confirmed that the reporter remains unprocessed within individual cells upon inhibition. We tested darunavir, atazanavir and nelfinavir and their combinations against wild type PR. Shedding light on an inhibitor's ability to act on non-mature forms of PR may aid novel strategies for next-generation drug design. PMID- 29992978 TI - Estimation of Cardiovascular Risk Predictors from Non-Invasively Measured Diametric Pulse Volume Waveforms via Multiple Measurement Information Fusion. AB - This paper presents a novel multiple measurement information fusion approach to the estimation of cardiovascular risk predictors from non-invasive pulse volume waveforms measured at the body's diametric (arm and ankle) locations. Leveraging the fact that diametric pulse volume waveforms originate from the common central pulse waveform, the approach estimates cardiovascular risk predictors in three steps by: (1) deriving lumped-parameter models of the central-diametric arterial lines from diametric pulse volume waveforms, (2) estimating central blood pressure waveform by analyzing the diametric pulse volume waveforms using the derived arterial line models, and (3) estimating cardiovascular risk predictors (including central systolic and pulse pressures, pulse pressure amplification, and pulse transit time) from the arterial line models and central blood pressure waveform in conjunction with the diametric pulse volume waveforms. Experimental results obtained from 164 human subjects with a wide blood pressure range (systolic 144 mmHg and diastolic 103 mmHg) showed that the approach could estimate cardiovascular risk predictors accurately (r >= 0.78). Further analysis showed that the approach outperformed a generalized transfer function regardless of the degree of pulse pressure amplification. The approach may be integrated with already available medical devices to enable convenient out-of-clinic cardiovascular risk prediction. PMID- 29992980 TI - Thermostatic properties of nitrate molten salts and their solar and eutectic mixtures. AB - Nitrate molten salts are extensively used for sensible heat storage in Concentrated Solar Power (CSP) plants and thermal energy storage (TES) systems. They are the most promising materials for latent heat storage applications. By combining classical molecular dynamics and differential scanning calorimetry experiments, we present a systematic study of all thermostatic, high temperature properties of pure KNO3 and NaNO3 salts and their eutectic and "solar salt" mixtures, technologically relevant. We first study, in solid and liquid regimes, their mass densities, enthalpies, thermal expansion coefficients and isothermal compressibilities. We then analyze the cP and cV specific heats of the pure salts and of the liquid phase of the mixtures. Our theoretical results allow to resolve a long-standing experimental uncertainty about the cP(T) thermal behaviour of these systems. In particular, they revisit empirical laws on the cP(T) behaviour, extensively used at industrial level in the design of TES components employing the "solar salt" as main storage material. Our findings, numerically precise and internally consistent, can be used as a reference for the development of innovative nanomaterials based on nitrate molten salts, crucial in technologies as CSP, waste heat recovery, and advanced adiabatic compressed air energy storage. PMID- 29992981 TI - Engineering biofunctional in vitro vessel models using a multilayer bioprinting technique. AB - Recent advances in the field of bioprinting have led to the development of perfusable complex structures. However, most of the existing printed vascular channels lack the composition or key structural and physiological features of natural blood vessels or they make use of more easily printable but less biocompatible hydrogels. Here, we use a drop-on-demand bioprinting technique to generate in vitro blood vessel models, consisting of a continuous endothelium imitating the tunica intima, an elastic smooth muscle cell layer mimicking the tunica media, and a surrounding fibrous and collagenous matrix of fibroblasts mimicking the tunica adventitia. These vessel models with a wall thickness of up to 425 um and a diameter of about 1 mm were dynamically cultivated in fluidic bioreactors for up to three weeks under physiological flow conditions. High cell viability (>83%) after printing and the expression of VE-Cadherin, smooth muscle actin, and collagen IV were observed throughout the cultivation period. It can be concluded that the proposed novel technique is suitable to achieve perfusable vessel models with a biofunctional multilayer wall composition. Such structures hold potential for the creation of more physiologically relevant in vitro disease models suitable especially as platforms for the pre-screening of drugs. PMID- 29992982 TI - Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFbeta dependent manner and limits osteoarthritis in mice. AB - Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor alpha1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), alpha1-PDX (14 ug/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 +/- 0.75 vs 9.16 +/- 0.6, p < 0.01), and the number of MMP-13(+) chondrocytes was lower (4.96 +/- 0.60% vs 20.96 +/- 8.49%, p < 0.05). Moreover, furin prevented the increase in ALK1/ALK5 ratio in cartilage induced by OA. Conversely, alpha1-PDX had no effect on OA cartilage structure. These results support a protective role for furin in OA by maintaining ALK5 receptor levels and reducing MMP-13 expression. Therefore, furin might be a potential target mediating the development of OA. PMID- 29992984 TI - Effect of Nitrogen Doping and Temperature on Mechanical Durability of Silicon Carbide Thin Films. AB - Amorphous silicon carbide (a-SiC) films are promising solution for functional coatings intended for harsh environment due to their superior combination of physical and chemical properties and high temperature stability. However, the structural applications are limited by its brittleness. The possible solution may be an introduction of nitrogen atoms into the SiC structure. The effect of structure and composition on tribo-mechanical properties of magnetron-sputtered a SiCxNy thin films with various nitrogen content (0-40 at.%) and C/Si close to one deposited on silicon substrates were evaluated before and after exposure to high temperatures up to 1100 degrees C in air and vacuum. IR transmission spectroscopy revealed formation of multiple C-N bonds for the films with N content higher than 30 at.%. Improvement of the organization in the carbon phase with the increase of nitrogen content in the a-SiCN films was detected by Raman spectroscopy. Nanoindentation and scratch test point out on the beneficial effect of the nitrogen doping on the tribo-mechanical performance of a-SiCxNy coatings, especially for the annealed coatings. The improved fracture resistance of the SiCN films stems from the formation of triple C=N bonds for the as deposited films and also by suppression of SiC clusters crystallization by incorporation of nitrogen atoms for annealed films. This together with higher susceptibility to oxidation of a-SiCN films impart them higher scratch and wear resistance in comparison to SiC films before as well as after the thermal exposure. The best tribo-mechanical performance in term of high hardness and sufficient level of ductility were observed for the a-Si0.32C0.32N0.36 film. The enhanced performance is preserved after the thermal exposure in air (up to 1100 degrees C) and vacuum (up to 900 degrees C) atmosphere. Annealing in oxidizing atmosphere has a beneficial effect in terms of tribological properties. Harder films with lower nitrogen content suffer from higher brittleness. FIB-SEM identified film-confined cracking as the initial failure event in SiC, while it was through-interface cracking for SiCN at higher loads. This points out on the higher fracture resistance of the SiCN films where higher strains are necessary for crack formation. PMID- 29992983 TI - Effects of collagen-derived bioactive peptides and natural antioxidant compounds on proliferation and matrix protein synthesis by cultured normal human dermal fibroblasts. AB - Nutraceuticals containing collagen peptides, vitamins, minerals and antioxidants are innovative functional food supplements that have been clinically shown to have positive effects on skin hydration and elasticity in vivo. In this study, we investigated the interactions between collagen peptides (0.3-8 kDa) and other constituents present in liquid collagen-based nutraceuticals on normal primary dermal fibroblast function in a novel, physiologically relevant, cell culture model crowded with macromolecular dextran sulphate. Collagen peptides significantly increased fibroblast elastin synthesis, while significantly inhibiting release of MMP-1 and MMP-3 and elastin degradation. The positive effects of the collagen peptides on these responses and on fibroblast proliferation were enhanced in the presence of the antioxidant constituents of the products. These data provide a scientific, cell-based, rationale for the positive effects of these collagen-based nutraceutical supplements on skin properties, suggesting that enhanced formation of stable dermal fibroblast derived extracellular matrices may follow their oral consumption. PMID- 29992985 TI - Preparation from a revisited wet chemical route of phase-pure, monocrystalline and SHG-efficient BiFeO3 nanoparticles for harmonic bio-imaging. AB - We present two new synthetic routes for bismuth ferrite harmonic nanoparticles (BiFeO3 HNPs). Both phase-pure and mixed phase BiFeO3 materials were produced after improvement of the solvent evaporation and sol-gel combustion routes. Metal nitrates with a series of dicarboxylic acids (tartronic, tartaric and mucic) were used to promote crystallization. We found that the longer the carbon backbone with a hydroxyl group attached to each carbon, the lower the annealing temperature. We also demonstrate that nanocrystals more readily formed at a given temperature by adding glycerol but to the detriment of phase purity, whereas addition of NaCl in excess with mucic acid promotes the formation of phase-pure, monocrystalline nanoparticles. This effect was possibly associated with a better dispersion of the primary amorphous precursors and formation of intermediate complexes. The nanoparticles have been characterized by XRD, TEM, zeta-potential, photon correlation spectroscopy, two-photon microscopy and Hyper-Rayleigh Scattering measurements. The improved crystallization leads to BiFeO3 HNPs without defect-induced luminescence and with a very high averaged second harmonic efficiency (220 pm/V), almost triple the efficiency previously reported. This development of simple, scalable synthesis routes which yield phase-pure and, crucially, monocrystalline BiFeO3 HNPs demonstrates a significant advance in engineering the properties of nanocrystals for bio-imaging and diagnostics applications. PMID- 29992987 TI - Demographic and socioeconomic factors influencing the incidence of ankle fractures, a national population-based survey of 512187 individuals. AB - This study aimed to investigate the population-based incidence rate of ankle fracture and associated risk factors in China. All the data on ankle fractures were available from the China National Fracture Survey (CNFS) conducted between January and May in 2015. All eligible household members were sampled from 8 provinces, 24 urban cities and 24 rural counties in China, using stratified random sampling and the probability proportional to size method. Questionnaires were sent to every participant for data collection and quality control was accomplished by our quality control team members. A total of 512187 valid questionnaires were collected and relevant data were abstracted and analyzed. One hundred and ninety patients sustained 193 ankle fractures in 2014, indicating the incidence rate was 37.1 (95% CI, 31.8-42.4)/100,000 person-year. Alcohol consumption, living alone and average sleep time <7 h/d were identified as independent risk factors for ankle fracture in both males and females. Previous history of fracture was identified as significant risk factor of ankle fracture in females but not in males. Therefore, specific public health policies focusing on decreasing alcohol consumption and encouraging individuals to obtain sufficient sleep should be implemented. Individuals living alone should focus more on healthcare, especially in those with previous fracture. PMID- 29992986 TI - The influenza virus hemagglutinin head evolves faster than the stalk domain. AB - The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing. Here, we performed an evolutionary analysis of the stalk domains of the hemagglutinin of pre-pandemic seasonal H1N1, pandemic H1N1, seasonal H3N2, and influenza B viruses and show quantitatively for the first time that the stalk domain is evolving at a rate that is significantly slower than that of the head domain. Additionally, we found that the cross-reactive epitopes in the stalk domain targeted by broadly neutralizing monoclonal antibodies are evolving at an even slower rate compared to the full head and stalk regions of the protein. Finally, a fixed-effects likelihood selection analysis was performed for these virus groups in both the head and stalk domains. While several positive selection sites were found in the head domain, only a single site in the stalk domain of pre-pandemic seasonal H1 hemagglutinin was identified at amino acid position 468 (H1 numbering from methionine). This site is not located in or close to the epitopes of cross-reactive anti-stalk monoclonal antibodies. Furthermore, we found that changes in this site do not significantly impact virus binding or neutralization by human anti-stalk antibodies, suggesting that some positive selection in the stalk domain is independent of immune pressures. We conclude that, while the stalk domain does evolve over time, this evolution is slow and, historically, is not directed to aid in evading neutralizing antibody responses. PMID- 29992988 TI - Cellular Uptake and Bioavailability of Tocotrienol-Rich Fraction in SIRT1 Inhibited Human Diploid Fibroblasts. AB - Tocotrienol-rich fraction (TRF) is palm vitamin E that consists of tocopherol and tocotrienol. TRF is involved in important cellular regulation including delaying cellular senescence. A key regulator of cellular senescence, Sirtuin 1 (SIRT1) is involved in lipid metabolism. Thus, SIRT1 may regulate vitamin E transportation and bioavailability at cellular level. This study aimed to determine the role of SIRT1 on cellular uptake and bioavailability of TRF in human diploid fibroblasts (HDFs). SIRT1 gene in young HDFs was silenced by small interference RNA (siRNA) while SIRT1 activity was inhibited by sirtinol. TRF treatment was given for 24 h before or after SIRT1 inhibition. Cellular concentration of TRF isomers was determined according to the time points of before and after TRF treatment at 0, 24, 48, 72 and 96 h. Our results showed that all tocotrienol isomers were significantly taken up by HDFs after 24 h of TRF treatment and decreased 24 h after TRF treatment was terminated but remained in the cell up to 72 h. The uptake of alpha-tocopherol, alpha-tocotrienol and beta-tocotrienol was significantly higher in senescent cells as compared to young HDFs indicating higher requirement for vitamin E in senescent cells. Inhibition of SIRT1 gene increased the uptake of all tocotrienol isomers but not alpha-tocopherol. However, SIRT1 inhibition at protein level decreased tocotrienol concentration. In conclusion, SIRT1 may regulate the cellular uptake and bioavailability of tocotrienol isomers in human diploid fibroblast cells while a similar regulation was not shown for alpha-tocopherol. PMID- 29992989 TI - Gas Phase Chemical Evolution of Uranium, Aluminum, and Iron Oxides. AB - We use a recently developed plasma-flow reactor to experimentally investigate the formation of oxide nanoparticles from gas phase metal atoms during oxidation, homogeneous nucleation, condensation, and agglomeration processes. Gas phase uranium, aluminum, and iron atoms were cooled from 5000 K to 1000 K over short time scales (?t < 30 ms) at atmospheric pressures in the presence of excess oxygen. In-situ emission spectroscopy is used to measure the variation in monoxide/atomic emission intensity ratios as a function of temperature and oxygen fugacity. Condensed oxide nanoparticles are collected inside the reactor for ex situ analyses using scanning and transmission electron microscopy (SEM, TEM) to determine their structural compositions and sizes. A chemical kinetics model is also developed to describe the gas phase reactions of iron and aluminum metals. The resulting sizes and forms of the crystalline nanoparticles (FeO-wustite, eta Al2O3, UO2, and alpha-UO3) depend on the thermodynamic properties, kinetically limited gas phase chemical reactions, and local redox conditions. This work shows the nucleation and growth of metal oxide particles in rapidly-cooling gas is closely coupled to the kinetically-controlled chemical pathways for vapor-phase oxide formation. PMID- 29992990 TI - Thiamine tetrahydrofurfuryl disulfide promotes voluntary activity through dopaminergic activation in the medial prefrontal cortex. AB - A physically active lifestyle is associated with better health in body and mind, and it is urgent that supporting agents for such lifestyles be developed. In rodents, voluntary locomotor activity as an active physical behavior may be mediated by dopaminergic neurons (DNs). Thiamine phosphate esters can stimulate DNs, and we thus hypothesized that thiamine tetrahydrofurfuryl disulfide (TTFD), a thiamine derivative, promotes locomotor activity via DNs in rats. Acute i.p. administration of TTFD enhanced rat locomotor activity in a normal cage. In vivo microdialysis revealed that TTFD-enhanced locomotor activity was synchronized with dopamine release in the medial prefrontal cortex (mPFC). Antagonism of the dopamine D1 receptor, but not D2 receptor, in the mPFC fully suppressed TTFD enhanced locomotor activity. Finally, we found a TTFD dose-dependent increase in voluntary wheel running. Our findings demonstrate that DNs in the mPFC mediates TTFD-enhanced locomotor activity, suggesting the potential of TTFD to induce active physical behavior. PMID- 29992991 TI - Mapping the Dynamic Functions and Structural Features of AcrB Efflux Pump Transporter Using Accelerated Molecular Dynamics Simulations. AB - Multidrug efflux pumps confer resistance to their bacterial hosts by pumping out a diverse range of compounds, including most antibiotics. Being more familiar with the details of functional dynamics and conformations of these types of pumps could help in discovering approaches to stop them functioning properly. Computational approaches, particularly conventional molecular dynamics simulations followed by diverse post simulation analysis, are powerful methods that help researchers by opening a new window to study phenomena that are not detectable in as much detail in vitro or in vivo as they are in silico. In this study, accelerated molecular dynamics simulations were applied to study the dynamics of AcrB efflux pump transporters in interaction with PAbetaN and tetracycline as an inhibitor and a substrate, respectively, to compare the differences in the dynamics and consequently the mechanism of action of the pump. The different dynamics for PAbetaN -bound form of AcrB compared to the TET-bound form is likely to affect the rotating mechanism typically observed for AcrB transporter. This shows the dynamics of the active AcrB transporter is different in a substrate-bound state compared to an inhibitor-bound state. This advances our knowledge and helps to unravel the mechanism of tripartite efflux pumps. PMID- 29992992 TI - Structural analyses of FERM domain-mediated membrane localization of FARP1. AB - FARP1 is a multi-domain protein that is involved in regulating neuronal development through interacting with cell surface proteins such as class A Plexins and SynCAM 1. The N-terminal FERM domain in FARP1 is known to both promote membrane localization and mediate these protein interactions, for which the underlying molecular mechanisms remain unclear. Here we determined the crystal structures of the FERM domain of FARP1 from zebrafish, and those of FARP2 (a close homolog of FARP1) from mouse and zebrafish. These FERM domains adopt the three-leaved clover fold that is typical of all FERM domains. Our structures reveal a positively charged surface patch that is highly conserved in the FERM domain of FARP1 and FARP2. In vitro lipid-binding experiments showed that the FARP1 FERM domain binds specifically to several types of phospholipid, which is dependent on the positively charged surface patch. We further determined through cell-based analyses that this surface patch on the FERM domain underlies the localization of FARP1 to the plasma membrane, and that FERM domain interactions recruit it to postsynaptic sites in neurons. PMID- 29992993 TI - Occupational radiation exposure and glaucoma and macular degeneration in the US radiologic technologists. AB - There are well-documented associations of glaucoma with high-dose radiation exposure, but only a single study suggesting risk of glaucoma, and less conclusively macular degeneration, associated with moderate-dose exposure. We assessed risk of glaucoma and macular degeneration associated with occupational eye-lens radiation dose, using participants from the US Radiologic Technologists Study, followed from the date of surveys in 1994-1998, 2003-2005 to the earliest of diagnosis of glaucoma or macular degeneration, cancer other than non-melanoma skin cancer, or date of last survey (2012-2014). We excluded those with baseline disease or previous radiotherapy history. Cox proportional hazards models with age as timescale were used. There were 1631 cases of newly self-reported doctor diagnosed cases of glaucoma and 1331 of macular degeneration among 69,568 and 69,969 eligible subjects, respectively. Estimated mean cumulative eye-lens absorbed dose from occupational radiation exposures was 0.058 Gy. The excess relative risk/Gy for glaucoma was -0.57 (95% CI -1.46, 0.60, p = 0.304) and for macular degeneration was 0.32 (95% CI -0.32, 1.27, p = 0.381), suggesting that there is no appreciable risk for either endpoint associated with low-dose and low dose-rate radiation exposure. Since this is the first examination of glaucoma and macular degeneration associated with low-dose radiation exposure, this result needs to be replicated in other low-dose studies. PMID- 29992995 TI - Angiotropism and extravascular migratory metastasis in cutaneous and uveal melanoma progression in a zebrafish model. AB - Cutaneous melanoma is a highly aggressive cancer with a propensity for distant metastasis to various organs. In contrast, melanoma arising in pigmented uveal layers of the eye metastasizes mostly in the liver. The mechanisms of these metastases, which are ultimately resistant to therapy, are still unclear. Metastasis via intravascular dissemination of tumour cells is widely accepted as a central paradigm. However, we have previously described an alternative mode of tumour dissemination, extravascular migratory metastasis, based on clinical and experimental data. This mechanism is characterised by the interaction of cancer cells with the abluminal vascular surface, which defines angiotropism. Here, we employed our 3D co-culture approach to monitor cutaneous and uveal human melanoma cells dynamics in presence of vascular tubules. Using time-lapse microscopy, we evaluated angiotropism, the migration of tumour cells along vascular tubules and the morphological changes occurring during these processes. Cutaneous and uveal melanoma cells were injected in zebrafish embryos in order to develop xenografts. Employing in vivo imaging coupled with 3D reconstruction, we monitored the interactions between cancer cells and the external surface of zebrafish vessels. Overall, our results indicate that cutaneous and uveal melanoma cells spread similarly along the abluminal vascular surfaces, in vitro and in vivo. PMID- 29992994 TI - The short-term impact of probiotic consumption on the oral cavity microbiome. AB - The dysbiosis of the oral microbiome is associated with both localized and systemic diseases. Modulating the resident microbial communities by the dietary consumption of probiotics has become an appealing means to promote host health by either restoring host-microbe balance or preventing dysbiosis. Most probiotics strategies target the intestinal microbiome, but little is known about their impact on the oral microbiome. We analyzed here the saliva microbiome from 21 volunteers, longitudinally collected before, during, and after consumption of a commercial probiotic and a standard yoghurt using 16S amplicon sequencing. The alpha diversity of the saliva microbiome had a statistically significant increase (P-value = 0.0011) in one of the groups that consumed the probiotic. The overall structure of the microbiome was however not significantly impacted by the probiotic, although oligotyping analysis revealed that both Streptococci and Lactobacilli present in the probiotic product persisted in the saliva microbiome. In contrast, non-probiotic yoghurt consumption had a lesser impact on the overall diversity and Lactobacillus and Streptococcus persistence. Our results suggest that consumption of commercial probiotics in healthy subjects increase the overall diversity of the oral cavity microbiome in the short term, but such dietary interventions are not able to substantially modify the structure of the microbiome. PMID- 29992996 TI - Loss-of-function mutations of SCN10A encoding NaV1.8 alpha subunit of voltage gated sodium channel in patients with human kidney stone disease. AB - Human kidney stone disease (KSD) causes significant morbidity and public health burden worldwide. The etiology of KSD is heterogeneous, ranging from monogenic defects to complex interaction between genetic and environmental factors. However, the genetic defects causing KSD in the majority of affected families are still unknown. Here, we report the discovery of mutations of SCN10A, encoding NaV1.8 alpha subunit of voltage-gated sodium channel, in families with KSD. The region on chromosome 3 where SCN10A locates was initially identified in a large family with KSD by genome-wide linkage analysis and exome sequencing. Two mutations (p.N909K and p.K1809R) in the same allele of SCN10A co-segregated with KSD in the affected family. Additional mutation (p.V1149M) of SCN10A was identified in another affected family, strongly supporting the causal role of SCN10A for KSD. The amino acids at these three positions, N909, K1809, and V1149, are highly conserved in vertebrate evolution, indicating their structural and functional significances. NaV1.8 alpha subunit mRNA and protein were found to express in human kidney tissues. The mutant proteins expressed in cultured cells were unstable and causing reduced current density as analyzed by whole-cell patch clamp technique. Thus, loss-of-function mutations of SCN10A were associated with KSD in the families studied. PMID- 29992998 TI - Leptomeningeal metastasis from solid tumors: clinical features and its diagnostic implication. AB - In this study, we examined the characteristics and aimed to increase the knowledge of clinical features of leptomeningeal metastasis (LM). The clinical data, including initial diagnosis and treatment of primary tumor, clinical manifestations, neuroimaging findings, cerebrospinal fluid (CSF) examination, were analyzed. For the patients with adenocarcinoma/breast cancer, the incidence of cranial lesions and cranial nerve paralysis was obviously higher than patients with small cell lung cancer. Whereas, the incidence of involvement of intravertebral canal was obviously lower than that of small cell lung cancer. Patients with adenocarcinoma/breast cancer showed more incidence of leptomeningeal enhancement compared to those with small cell lung cancer. Persistent severe headache was noticed in those with squamous carcinoma, and usually showed absence of abnormally LM-related neuroimaging and CSF cytological findings, which resulted in a challenge in the diagnosis of LM from squamous carcinoma. Patients with different primary tumors showed differential clinical features. Significant differences were observed in clinical features between patients with adenocarcinoma/breast cancer and small cell lung cancer. Our study contributes to the understanding of clinical characteristics of LM, and contributes to improvement of LM diagnosis in clinical practice. PMID- 29992997 TI - Honey bees overwintering in a southern climate: longitudinal effects of nutrition and queen age on colony-level molecular physiology and performance. AB - Honey bee colony nutritional ecology relies on the acquisition and assimilation of floral resources across a landscape with changing forage conditions. Here, we examined the impact of nutrition and queen age on colony health across extended periods of reduced forage in a southern climate. We measured conventional hive metrics as well as colony-level gene expression of eight immune-related genes and three recently identified homologs of vitellogenin (vg), a storage glycolipoprotein central to colony nutritional state, immunity, oxidative stress resistance and life span regulation. Across three apiary sites, concurrent longitudinal changes in colony-level gene expression and nutritional state reflected the production of diutinus (winter) bees physiologically altered for long-term nutrient storage. Brood production by young queens was significantly greater than that of old queens, and was augmented by feeding colonies supplemental pollen. Expression analyses of recently identified vg homologs (vg like-A, -B, and -C) revealed distinct patterns that correlated with colony performance, phenology, and immune-related gene transcript levels. Our findings provide new insights into dynamics underlying managed colony performance on a large scale. Colony-level, molecular physiological profiling is a promising approach to effectively identify factors influencing honey bee health in future landscape and nutrition studies. PMID- 29992999 TI - Differentiation of Normal and Radioresistant Prostate Cancer Xenografts Using Magnetization Transfer-Prepared MRI. AB - The ability of MRI to differentiate between normal and radioresistant cancer was investigated in prostate tumour xenografts in mice. Specifically, the process of magnetization exchange between water and other molecules was studied. It was found that magnetization transfer from semisolid macromolecules (MT) and chemical exchange saturation transfer (CEST) combined were significantly different between groups (p < 0.01). Further, the T2 relaxation of the semisolid macromolecular pool (T2,B), a parameter specific to MT, was found to be significantly different (p < 0.01). Also significantly different were the rNOE contributions associated with methine groups at -0.9 ppm with a saturation B1 of 0.5 uT (p < 0.01) and with other aliphatic groups at -3.3 ppm with 0.5 and 2 uT (both p < 0.05). Independently, using a live-cell metabolic assay, normal cells were found to have a greater metabolic rate than radioresistant ones. Thus, MRI provides a novel, in vivo method to quantify the metabolic rate of tumours and predict their radiosensitivity. PMID- 29993000 TI - Myosin X is required for efficient melanoblast migration and melanoma initiation and metastasis. AB - Myosin X (Myo10), an actin-associated molecular motor, has a clear role in filopodia induction and cell migration in vitro, but its role in vivo in mammals is not well understood. Here, we investigate the role of Myo10 in melanocyte lineage and melanoma induction. We found that Myo10 knockout (Myo10KO) mice exhibit a white spot on their belly caused by reduced melanoblast migration. Myo10KO mice crossed with available mice that conditionally express in melanocytes the BRAFV600E mutation combined with Pten silencing exhibited reduced melanoma development and metastasis, which extended medial survival time. Knockdown of Myo10 (Myo10kd) in B16F1 mouse melanoma cell lines decreased lung colonization after tail-vein injection. Myo10kd also inhibited long protrusion (LP) formation by reducing the transportation of its cargo molecule vasodilator stimulated phosphoprotein (VASP) to the leading edge of migrating cells. These findings provide the first genetic evidence for the involvement of Myo10 not only in melanoblast migration, but also in melanoma development and metastasis. PMID- 29993001 TI - Circular-polarized-light-induced spin polarization characterized for the Dirac cone surface state at W(110) with C2v symmetry. AB - The C2v surface symmetry of W(110) strongly influences a spin-orbit-induced Dirac cone-like surface state and its characterization by spin- and angle-resolved photoelectron spectroscopy. In particular, using circular polarized light, a distinctive k-dependent spin texture is observed along the [Formula: see text] direction of the surface Brillouin zone. For all spin components Px, Py, and Pz, non-zero values are detected, while the initial-state spin polarization has only a Py component due to mirror symmetry. The observed complex spin texture of the surface state is controlled by transition matrix element effects, which include orbital symmetries of the involved electron states as well as the geometry of the experimental set-up. PMID- 29993002 TI - Tool Use and Generalized Motor Programs: We All Are Natural Born Poly-Dexters. AB - For most people, human tool use is inextricably entwined with manual dexterity. This folk belief is widespread among scientists too. In this line, human tool use is based on motor programs about how the hand interacts with tools, implying that the use of end-effectors other than the hand should generate motor control difficulties (e.g., inability to reproduce a specific tool-use action over time), because these so-called programs characterize the spatiotemporal parameters of hand movements, but not of other end-effectors. To test this, we asked participants to perform three tool-use actions (e.g., pounding a nail) with four end-effectors (i.e., right foot, right elbow, left hand, right hand). We show that participants not only spontaneously performed the tool-use actions effectively, but also crucially kept tools' spatiotemporal parameters constant among the end-effectors. This phenomenon, which we call poly-dexterity, is at odds with the view that the human brain stores hand-centered motor programs for tool use. Poly-dexterity is instead consistent with the idea that, once the tool use action is formed mentally, general motor programs can be applied to a variety of end-effectors. Reversing the usual evolutionary perspective, our findings support that, in the course of evolution, manual dexterity has come after tool use skills. PMID- 29993003 TI - Solid-phase synthesis of peptides containing aminoadipic semialdehyde moiety and their cyclisations. AB - Pathological levels of oxidative stress (OS) have been implicated in many diseases including diabetes mellitus, neurodegenerative diseases, inflammatory diseases, atherosclerosis, and cancer. Studies of oxidative stress are however complicated by the low concentration of oxidation products. To resolve this problem, we tested a new derivative of aminoadipic semialdehyde (Fmoc-Aea-OH) in the solid-phase synthesis of carbonylated peptides. We prepared a series of peptides with free and acetylated N-terminal amino groups using the Fmoc-Aea-OH reagent. LC-MS, ESI-MS, and MS/MS spectra confirmed the sequences of the modified peptides, although the LC-MS and ESI-MS spectra were dominated by signals corresponding to dehydration products. NMR studies of acetylated products revealed that the dominant product formed in this reaction contains a 1,2,3,4 tetrahydropyridine-2-carboxylic acid residue. Another side reaction in this system was the cleavage of the amide bond between the Aea residue and the amino acid moiety preceding it resulting in the formation of a side product with a six membered ring at the N-terminus (2,3,4,5-tetrahydropyridine-2-carboxylic acid residue). We found that, depending on the peptide sequence, one of those side products is predominant. Our work suggests new methods for the solid-state synthesis of peptides containing unnatural amino acids. PMID- 29993004 TI - Silver oxide decomposition mediated direct bonding of silicon-based materials. AB - Silicon-based materials are widely promising electronic components by the combination with metals in power electronics field. However, bonding metal and silicon-based materials generally requires specific surface modification due to their different chemical bonds. Here, we demonstrate a process for directly bonding metals to silicon-based materials that does not require surface treatment, based on the in situ decomposition of Ag2O paste, forming Ag nanoparticles (AgNPs). We demonstrate sound joints of Ag/silicon-based materials at 300-500 degrees C with the formation of a silicon oxide interlayer containing AgNPs. We propose that Ag in the interlayer attracted other Ag particles to the interface, playing a unique role in this direct bonding process. This process is suitable for various bonding applications in electronics, as well the fabrication of conducting paths for photovoltaic and other applications. PMID- 29993005 TI - Author Correction: Tailoring the structural, morphological, optical and dielectric properties of lead iodide through Nd3+ doping. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29993006 TI - Publisher Correction: Interactions of the Calcite {10.4} Surface with Organic Compounds: Structure and Behaviour at Mineral - Organic Interfaces. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29993007 TI - The leaf transcriptome of fennel (Foeniculum vulgare Mill.) enables characterization of the t-anethole pathway and the discovery of microsatellites and single-nucleotide variants. AB - Fennel is a plant species of both agronomic and pharmaceutical interest that is characterized by a shortage of genetic and molecular data. Taking advantage of NGS technology, we sequenced and annotated the first fennel leaf transcriptome using material from four different lines and two different bioinformatic approaches: de novo and genome-guided transcriptome assembly. A reference transcriptome for assembly was produced by combining these two approaches. Among the 79,263 transcripts obtained, 47,775 were annotated using BLASTX analysis performed against the NR protein database subset with 11,853 transcripts representing putative full-length CDS. Bioinformatic analyses revealed 1,011 transcripts encoding transcription factors, mainly from the BHLH, MYB-related, C2H2, MYB, and ERF families, and 6,411 EST-SSR regions. Single-nucleotide variants of SNPs and indels were identified among the 8 samples at a frequency of 0.5 and 0.04 variants per Kb, respectively. Finally, the assembled transcripts were screened to identify genes related to the biosynthesis of t-anethole, a compound well-known for its nutraceutical and medical properties. For each of the 11 genes encoding structural enzymes in the t-anethole biosynthetic pathway, we identified at least one transcript showing a significant match. Overall, our work represents a treasure trove of information exploitable both for marker-assisted breeding and for in-depth studies on thousands of genes, including those involved in t-anethole biosynthesis. PMID- 29993008 TI - The morphospace of language networks. AB - What is the nature of language? How has it evolved in different species? Are there qualitative, well-defined classes of languages? Most studies of language evolution deal in a way or another with such theoretical contraption and explore the outcome of diverse forms of selection on the communication matrix that somewhat optimizes communication. This framework naturally introduces networks mediating the communicating agents, but no systematic analysis of the underlying landscape of possible language graphs has been developed. Here we present a detailed analysis of network properties on a generic model of a communication code, which reveals a rather complex and heterogeneous morphospace of language graphs. Additionally, we use curated data of English words to locate and evaluate real languages within this morphospace. Our findings indicate a surprisingly simple structure in human language unless particles with the ability of naming any other concept are introduced in the vocabulary. These results refine and for the first time complement with empirical data a lasting theoretical tradition around the framework of least effort language. PMID- 29993009 TI - Publisher Correction: Effects of water level regulation on the seed germination and production of annual plant Xanthium sibiricum in the water-level-fluctuating zone of Three Gorges Reservoir. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29993010 TI - Repeated social defeat stress impairs attentional set shifting irrespective of social avoidance and increases female preference associated with heightened anxiety. AB - Repeated social defeat stress (R-SDS) induces multiple behavioral changes in mice. However, the relationships between these behavioral changes were not fully understood. In the first experiment, to examine how the social avoidance is related to R-SDS-impaired behavioral flexibility, 10-week-old male C57BL/6N mice received R-SDS followed by the social interaction test and the attentional set shifting task. R-SDS impaired attentional set shifting irrespective of the development of social avoidance. In the second experiment, to examine whether R SDS affects sexual preference and how this behavioral change is related to the social avoidance and R-SDS-heightened anxiety, another group of 10-week-old male C57BL/6N mice were subjected to R-SDS followed by the social interaction test, the female encounter test and the elevated plus maze test. The anxiety was heightened in the defeated mice without social avoidance, but not in those which showed social avoidance. Furthermore, female preference was increased specifically in the defeated mice which showed heightened anxiety, but was not related to the level of social avoidance. Together, these results showed that attentional set shifting is more sensitive to R-SDS than social interaction, and that female preference is affected by R-SDS in association with heightened anxiety rather than the social avoidance. PMID- 29993011 TI - Author Correction: Plasmonic Chromatic Electrode with Low Resistivity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29993012 TI - Expression patterns and genetic variation of the ovine skeletal muscle transcriptome of sheep from five Spanish meat breeds. AB - The goal of the current study is to analyse the gene expression profile of the ovine skeletal muscle as well as to characterize the genetic variation of transcripts expressed in such tissue. This aim has been achieved by sequencing the longissimus dorsi transcriptomes of 50 sheep distributed in five pools representing the Canaria de Pelo, Roja Mallorquina, Gallega, Xisqueta and Ripollesa Spanish autochthonous breeds. Approximately, 363 million reads per pool have been produced and 71.9-82.9% have been successfully mapped to the ovine genome in a paired-end mode (2 * 75 bp). The 200 most expressed muscle transcripts (~1% of the total transcript count) account for 51% (Canaria de Pelo) to 67% (Gallega) of the total ovine skeletal muscle mRNA expression. These highly expressed genes play key roles in pathways related with striated muscle contraction, gluconeogenesis, glycolysis, citric acid cycle and respiratory electron transport. RNA-Sequencing of muscle transcripts has also revealed that ~72% of the SNPs detected with this approach are shared by at least two pools, and 10% of them segregate in the five pools under analysis. Most of the substitutions detected by RNA-Seq are synonymous or missense and only a minority are predicted to have consequences on protein function. PMID- 29993013 TI - Extracellular matrix scaffold and hydrogel derived from decellularized and delipidized human pancreas. AB - Extracellular matrix (ECM) plays an important developmental role by regulating cell behaviour through structural and biochemical stimulation. Tissue-specific ECM, attained through decellularization, has been proposed in several strategies for tissue and organ replacement. Decellularization of animal pancreata has been reported, but the same methods applied to human pancreas are less effective due to higher lipid content. Moreover, ECM-derived hydrogels can be obtained from many decellularized tissues, but methods have not been reported to obtain human pancreas-derived hydrogel. Using novel decellularization methods with human pancreas we produced an acellular, 3D biological scaffold (hP-ECM) and hydrogel (hP-HG) amenable to tissue culture, transplantation and proteomic applications. The inclusion of a homogenization step in the decellularization protocol significantly improved lipid removal and gelation capability of the resulting ECM, which was capable of gelation at 37 degrees C in vitro and in vivo, and is cytocompatible with a variety of cell types and islet-like tissues in vitro. Overall, this study demonstrates the characterisation of a novel protocol for the decellularization and delipidization of human pancreatic tissue for the production of acellular ECM and ECM hydrogel suitable for cell culture and transplantation applications. We also report a list of 120 proteins present within the human pancreatic matrisome. PMID- 29993014 TI - Inhibition of angiogenesis in endothelial cells by Human Lysyl oxidase propeptide. AB - Angiogenesis is a critical process involved in normal physiology. Pathological angiogenesis is observed in vascular diseases and neoplasia. The propeptide domain of LOX (LOX-PP) has been shown to inhibit tumorigenesis in various cancers. In this study, we explored the role of both overexpressed and recombinant LOX-PP in naive human umbilical vein endothelial cell with the addition of vascular endothelial growth factor (VEGF). Primarily, we observed a significant reduction in the angiogenesis signaling pathways upon LOX-PP overexpression by proteomic analysis. Further functional analysis showed that the VEGF induced cell proliferation, migration, adhesion and tube formation was inhibited by LOX-PP. Moreover, LOX-PP arrested cells at S-phase, reduced F-actin levels and decreased phosphorylation of focal adhesion kinase (FAK) and extracellular signal regulated kinase (ERK). The anti-angiogenic effect of LOX-PP was further confirmed by the reduction in the vascular network formation in chick chorioallantoic membrane (CAM). These results indicate that inhibition of angiogenesis events is not only achieved by overexpressing LOX-PP but also by addition of rLOX-PP. Taken together our findings discovered the anti-angiogenic role of LOX-PP in endothelial cells which suggests that harnessing this potential can be a promising strategy to inhibit angiogenesis. PMID- 29993015 TI - Multilayered Plasmonic Heterostructure of Gold and Titania Nanoparticles for Solar Fuel Production. AB - Solar fuel production via photoelectrochemical (PEC) water splitting has attracted great attention as an approach to storing solar energy. However, a wide range of light-harvesting materials is unstable when exposed to light and oxidative conditions. Here we report a robust, multilayered plasmonic heterostructure for water oxidation using gold nanoparticles (AuNPs) as light harvesting materials via localized surface plasmon resonance (LSPR). The multilayered heterostructure is fabricated using layer-by-layer self-assembly of AuNPs and TiO2 nanoparticles (TNPs). Plasmon-induced hot electrons are transferred from AuNPs to TNPs over the Au/TiO2 Schottky barrier, resulting in charge separation of hot carriers. Plasmonic photoanodes for water oxidation are completed by incorporating a Co-based oxygen-evolving catalyst on the multilayered heterostructure to scavenge hot holes. Light absorption capability and PEC properties of the photoanodes are investigated as a function of the number of AuNP/TNP bilayers. The PEC properties exhibits dependence on the number of the bilayers, which is affected by charge transport within the multilayered heterostructures. Photocurrent density and decrease in impedance by irradiation indicates significant photoactivity by LSPR excitation. PMID- 29993016 TI - Efficient Blue-emitting Phosphor SrLu2O4:Ce3+ with High Thermal Stability for Near Ultraviolet (~400 nm) LED-Chip based White LEDs. AB - Blue-emitting phosphors for near ultraviolet (NUV) based tri-color RGB phosphor blend converted white light emitting diodes (LEDs) have been extensively investigated in the past few years. LED chip peaked near 400 nm is the most efficient among the NUV chips currently. However, most of blue phosphors show inefficient excitation around 400 nm. Herein, a novel blue phosphor SrLu2O4:Ce3+ matching well with near 400 nm chip and showing high thermal stability has been developed. The photoluminescence spectrum presents a broad emission band peaking at 460 nm with a bandwidth of nearly 90 nm. By optimizing the Ce3+ concentration, an internal quantum efficiency (IQE) as high as 76% was achieved. Furthermore, 86% of the room-temperature emission intensity is still maintained at 150 degrees C, indicating a good thermal stability and practicality. A series of white LEDs were fabricated based on 405 nm chips coated with a blend of the new blue phosphor with the commercial yellow and red phosphors. High color rendering indexes (>=90) were achieved while the correlated color temperature was tuneable in the range of 3094 to 8990 K. These results suggest that SrLu2O4:Ce3+ can be utilized as a blue-emitting phosphor in NUV based white LEDs. PMID- 29993017 TI - Isolation of Cottonseed Extracts That Affect Human Cancer Cell Growth. AB - Cottonseeds are classified as glanded or glandless seeds depending on the presence or absence of gossypol glands. Glanded cottonseed has anticancer property and glandless cottonseed was reported to cause cancer in one animal study. It is important to investigate the effect of bioactive components from cottonseeds. Our objectives were to isolate ethanol extracts from cottonseeds and investigate their effects on human cancer cells. A protocol was developed for isolating bioactive extracts from seed coat and kernel of glanded and glandless cottonseeds. HPLC-MS analyzed the four ethanol extracts but only quercetin was identified in the glandless seed coat extract. Residual gossypol was detected in the glanded and glandless seed kernel extracts and but only in the glanded seed coat extract. Ethanol extracts were used to treat human cancer cells derived from breast and pancreas followed by MTT assay for cell viability. Ethanol extracts from glanded and glandless cottonseed kernels and gossypol significantly decreased breast cancer cell mitochondrial activity. Ethanol extract from glanded cottonseed kernel and gossypol also significantly decreased pancreas cancer cell mitochondrial activity. These results suggest that ethanol extracts from cottonseeds, like gossypol, contain anticancer activities. PMID- 29993018 TI - Photosynthesis of subtropical forest species from different successional status in relation to foliar nutrients and phosphorus fractions. AB - The ecophysiological linkages of leaf nutrients to photosynthesis in subtropical forests along succession remain elusive. We measured photosynthetic parameters (Amax, Vcmax, Jmax, PPUE), leaf phosphorus (P) and nitrogen (N), foliar P fractions and LMA from 24 species (pioneer, generalist, and climax). Amax was significantly related to N and P for the pooled data, while significant relationship between Amax and P was only found in climax species. The mixed effect model including variables (N, P, and SLA or LMA) for predicting Vcmax and Jmax best fitted but varied remarkably across succession. Climax species had higher N: P ratios, indicating an increasing P limitation at later succession stage; photosynthesis, however, did not show stronger P than N limitations across all species. Nevertheless, climax species appeared to increase nucleic acid P allocation and residual P utilization for growth, thereby reducing the overall demand for P. Our results indicate that the scaling of photosynthesis with other functional traits could not be uniform across succession, growth variables (e.g. photosynthesis) and species trait identity (e.g. successional strategy) should be considered in combination with N: P ratio when we investigate P limitation in subtropical forests, and variations in P allocation state further influencing photosynthetic rates and P-use efficiency. PMID- 29993019 TI - Marine forests of the Mediterranean-Atlantic Cystoseira tamariscifolia complex show a southern Iberian genetic hotspot and no reproductive isolation in parapatry. AB - Climate-driven range-shifts create evolutionary opportunities for allopatric divergence and subsequent contact, leading to genetic structuration and hybrid zones. We investigate how these processes influenced the evolution of a complex of three closely related Cystoseira spp., which are a key component of the Mediterranean-Atlantic seaweed forests that are undergoing population declines. The C. tamariscifolia complex, composed of C. tamariscifolia s.s., C. amentacea and C. mediterranea, have indistinct boundaries and natural hybridization is suspected. Our aims are to (1) infer the genetic structure and diversity of these species throughout their distribution ranges using microsatellite markers to identify ancient versus recent geographical populations, contact zones and reproductive barriers, and (2) hindcast past distributions using niche models to investigate the influence of past range shifts on genetic divergence at multiple spatial scales. Results supported a single, morphologically plastic species the genetic structure of which was incongruent with a priori species assignments. The low diversity and low singularity in northern European populations suggest recent colonization after the LGM. The southern Iberian genetic hotspot most likely results from the role of this area as a climatic refugium or a secondary contact zone between differentiated populations or both. We hypothesize that life-history traits (selfing, low dispersal) and prior colonization effects, rather than reproductive barriers, might explain the observed genetic discontinuities. PMID- 29993020 TI - Hyperspectral near infrared imaging quantifies the heterogeneity of carbon materials. AB - For many applications heterogeneity is a direct indicator of material quality. Reliable determination of chemical heterogeneity is however not a trivial task. Spectral imaging can be used for determining the spatial distribution of an analyte in a sample, thus transforming each pixel of an image into a sampling cell. With a large amount of image pixels, the results can be evaluated using large population statistics. This enables robust determination of heterogeneity in biological samples. We show that hyperspectral imaging in the near infrared (NIR) region can be used to reliably determine the heterogeneity of renewable carbon materials, which are promising replacements for current fossil alternatives in energy and environmental applications. This method allows quantifying the variation in renewable carbon and other biological materials that absorb in the NIR region. Reliable determination of heterogeneity is also a valuable tool for a wide range of other chemical imaging applications. PMID- 29993021 TI - Exploring pancreatic pathology in Plasmodium falciparum malaria patients. AB - Hypoglycaemia is an important complication of Plasmodium falciparum malaria infection, which can be lethal if not treated. A decrease in blood sugar (BS) level has been correlated with disease severity, parasitaemia and the use of certain antimalarial drugs. This study explored the relationship between pancreatic pathology, including the expressions of insulin and glucagon in the islets of Langerhans, and the BS levels in P. falciparum malaria patients. Pancreatic tissues from malaria patients were divided into three groups, namely those with BS < 40 mg/dl, BS = 40-120 mg/dl, and BS > 120 mg/dl. In P. falciparum malaria, pancreatic tissues showed numerous parasitised red blood cells (PRBCs) in the capillaries, oedema, acinar necrosis and the presence of inflammatory cells. The islet size and the expression of insulin were significantly increased in P. falciparum malaria patients with hypoglycaemia. In addition, insulin expression was positively correlated with islet size and negatively correlated with BS levels. This pioneer study documents an increase in insulin expression and an increase in islet size in hypoglycaemic patients with P. falciparum malaria. This could contribute to the pathogenesis of hypoglycaemia and provides evidence for the potential need to effectively manage the hypoglycaemia seen in malaria infection. PMID- 29993022 TI - Prediction Models of Cognitive Trajectories in Patients with Nonamnestic Mild Cognitive Impairment. AB - To evaluate prediction models of cognitive trajectories in patients with nonamnestic mild cognitive impairment (naMCI) using group-based trajectory analysis, we evaluated 121 patients with naMCI who underwent at least their first three yearly assessments. Group-based trajectory models were used to classify cognitive trajectories based on Clinical Dementia Rating Sum of Boxes scores over four years in patients with naMCI. A total of 22 patients (18.2%) were classified into the "fast-decliners" group, while 99 patients (81.8%) were classified into the "slow-decliners" group. The mean age was higher in the fast-decliners than in the slow-decliners (p = 0.037). Compared to the slow-decliners, the fast decliners were more frequently impaired in the domains of language (p = 0.038) and frontal/executive functions (p = 0.042), and had more frequent multiple domain cognitive impairment (p = 0.006) on baseline neuropsychological tests. The rate of conversion to dementia was significantly higher in the fast-decliners than in the slow-decliners (86.4% vs. 10.1%, p < 0.001). Our findings showed that there are indeed distinct patterns of cognitive trajectories in patients with naMCI. Close observation of naMCI patients' baseline demographic and clinical profiles in clinical settings may help identify individuals at greatest risk for dementia. PMID- 29993023 TI - Providing reducing power by microalgal photosynthesis: a novel perspective towards sustainable biocatalytic production of bulk chemicals exemplified for aliphatic amines. AB - A biotechnological process is reported, which enables an enzymatic reduction without the need for addition of an organic co-substrate for in situ-cofactor recycling. The process is based on merging the fields of enzymatic reductive amination with formate dehydrogenase-based in situ-cofactor recycling and algae biotechnology by means of the photoautotrophic microorganism Chlamydomonas reinhardtii, providing the needed formate in situ by formation from carbon dioxide, water and light. This biotransformation has been exemplified for the synthesis of various aliphatic amines known as bulk chemicals. PMID- 29993024 TI - The composition of the perinatal intestinal microbiota in cattle. AB - Recent research suggests that the microbial colonization of the mammalian intestine may begin before birth, but the observations are controversial due to challenges in the reliable sampling and analysis of low-abundance microbiota. We studied the perinatal microbiota of calves by sampling them immediately at birth and during the first postnatal week. The large size of the bovine newborns allows sampling directly from rectum using contamination-shielded swabs. Our 16S rDNA data, purged of potential contaminant sequences shared with negative controls, indicates the existence of a diverse low-abundance microbiota in the newborn rectal meconium and mucosa. The newborn rectal microbiota was composed of Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes. The microbial profile resembled dam oral rather than fecal or vaginal vestibular microbiota, but included typical intestinal taxa. During the first postnatal day, the rectum was invaded by Escherichia/Shigella and Clostridia, and the diversity collapsed. By 7 days, diversity was again increasing. In terms of relative abundance, Proteobacteria were replaced by Firmicutes, Bacteroidetes and Actinobacteria, including Faecalibacterium, Bacteroides, Lactobacillus, Butyricicoccus and Bifidobacterium. Our observations suggest that mammals are seeded before birth with a diverse microbiota, but the microbiota changes rapidly in the early postnatal life. PMID- 29993025 TI - Dietary non-fermentable fiber prevents autoimmune neurological disease by changing gut metabolic and immune status. AB - The autoimmune neurological disease, Multiple Sclerosis (MS), have increased at alarming rates in the Western society over the last few decades. While there are numerous efforts to develop novel treatment approaches, there is an unmet need to identify preventive strategies. We explored whether central nervous system (CNS) autoimmunity can be prevented through dietary manipulation using a spontaneous autoimmune encephalomyelitis mouse model. We report that the nutritional supplementation of non-fermentable fiber, common components of a vegetarian diet, in early adult life, prevents autoimmune disease. Dietary non-fermentable fiber alters the composition of the gut microbiota and metabolic profile with an increase in the abundance of long-chain fatty acids. Immune assays revealed that cecal extracts and a long chain fatty acid but not cecal lysates promoted autoimmune suppressive TH2 immune responses, demonstrating that non-fermentable fiber-induced metabolic changes account for the beneficial effects. Overall, these findings identify a non-invasive dietary strategy to prevent CNS autoimmunity and warrants a focus on nutritional approaches in human MS. PMID- 29993026 TI - Bridging the scales in high-throughput dielectrophoretic (bio-)particle separation in porous media. AB - Dielectrophoresis (DEP) is a versatile technique for the solution of difficult (bio-)particle separation tasks based on size and material. Particle motion by DEP requires a highly inhomogeneous electric field. Thus, the throughput of classical DEP devices is limited by restrictions on the channel size to achieve large enough gradients. Here, we investigate dielectrophoretic filtration, in which channel size and separation performance are decoupled because particles are trapped at induced field maxima in a porous separation matrix. By simulating microfluidic model porous media, we derive design rules for DEP filters and verify them using model particles (polystyrene) and biological cells (S. cerevisiae, yeast). Further, we bridge the throughput gap by separating yeast in an alumina sponge and show that the design rules are equally applicable in real porous media at high throughput. While maintaining almost 100% efficiency, we process up to 9 mL min-1, several orders of magnitude more than most state-of-the art DEP applications. Our microfluidic approach provides new insight into trapping dynamics in porous media, which even can be applied in real sponges. These results pave the way toward high-throughput retention, which is capable of solving existing problems such as cell separation in liquid biopsy or precious metal recovery. PMID- 29993028 TI - Author Correction: Exploring the Relationship between Blood Flux Signals and HRV following Different Thermal Stimulations using Complexity Analysis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29993030 TI - Gene dimmer switch. PMID- 29993029 TI - Inhibition and Eradication of Pseudomonas aeruginosa Biofilms by Host Defence Peptides. AB - P. aeruginosa is a notorious biofilm producer that causes a wide variety of acute and chronic infections. In this study the in vitro anti-biofilm activity of 13 Host Defence Peptides from different species was tested against P. aeruginosa biofilms. Most HDPs were able to prevent biofilm attachment, due to their antimicrobial effect on planktonic bacteria in the starting inoculum. Activity of HDPs against pre-formed biofilms was also observed, although mainly at short incubation times. Several HDPs were able to kill bacteria in the biofilm (colony counting of biofilm associated bacteria) but only CRAMP eradicated the whole biofilm (crystal violet staining). These results were quantitatively confirmed by confocal microscopy studies using a live/dead stain of the biofilms. Furthermore, for chicken CATH-2 (one of the more potent HDPs) it was shown that the peptide could indeed penetrate the biofilm structures and kill bacteria within the biofilm. These studies highlight the potency but also the limitations of HDPs as new potential anti-biofilm agents. PMID- 29993027 TI - Improving the structure-function relationship in glaucomatous and normative eyes by incorporating photoreceptor layer thickness. AB - The purpose of the study was to investigate whether the structure-function relationship in glaucomatous and normative eyes is improved by considering photoreceptor layer thickness. Humphrey 10-2 visual fields (VF) and optical coherence tomography were carried out in 615 eyes of 391 subjects, including 100 eyes of 53 healthy controls and 515 eyes of 338 glaucoma patients. The relationship between mean VF sensitivity and the thickness of the retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer (GCL + IPL) was analyzed using linear mixed models, by glaucoma status and degree of myopia. The structure-function relationship was also analyzed by supplementing the RNFL and GCL + IPL thickness with the thicknesses of: (i) the inner nuclear layer and outer plexiform layer (INL + OPL); (ii) the outer nuclear layer and inner segment of photoreceptor layer (ONL + ISL); (iii) the outer segment layer of photoreceptor and retinal pigment epithelium (OSL + RPE). The model included total thickness of RNFL, GCL + IPL and OSL + RPE was highly more optimal than the model that only included the total thickness of RNFL and GCL + IPL, in all subsets of eyes by glaucoma status and degree of myopia. PMID- 29993031 TI - Concentrating on intrinsic disorder. PMID- 29993032 TI - Reversibility of a Point Mutation Induced Domain Shift: Expanding the Conformational Space of a Sucrose Phosphorylase. AB - Despite their popularity as enzyme engineering targets structural information about Sucrose Phosphorylases remains scarce. We recently clarified that the Q345F variant of Bifidobacterium adolescentis Sucrose Phosphorylase is able to accept large polyphenolic substrates like resveratrol via a domain shift. Here we present a crystal structure of this variant in a conformation suitable for the accommodation of the donor substrate sucrose in excellent agreement with the wild type structure. Remarkably, this conformation does not feature the previously observed domain shift which is therefore reversible and part of a dynamic process rather than a static phenomenon. This crystallographic snapshot completes our understanding of the catalytic cycle of this useful variant and will allow for a more rational design of further generations of Sucrose Phosphorylase variants. PMID- 29993033 TI - The genetics of loneliness. PMID- 29993034 TI - Frontline immunotherapy for NSCLC: alone or not alone? PMID- 29993035 TI - High-resolution imaging of photoreceptors in healthy human eyes using an adaptive optics retinal camera. AB - PURPOSE: To determine the effects of age on perifoveal cone density in healthy subjects using adaptive optics. METHODS: Healthy subjects of various ages were imaged using an adaptive optics retinal camera (RTX-1(r) Imagine Eyes, Orsay, France). All patients underwent a comprehensive ophthalmologic examination and retinal imaging using spectral-domain optical coherence tomography (Spectralis(r), Heidelberg Engineering, Heidelberg, Germany). Cone density together with cone spacing and cone mosaic packing were measured in the nasal and temporal area 450 um from the fovea. A multivariate analysis was performed to determine which of the following parameters were related to a decrease in cone density: age, axial length, central macular thickness, and retrofoveal choroidal thickness. RESULTS: One hundred and sixty-seven eyes of 101 subjects aged 6-78 years were studied. Perifoveal cone density significantly decreased with age (R2 = 0.17, p<0.01). Inversely, cone spacing increased with age (R2=0.18, p<0.01). There was no change in the cone packing mosaic (p>0.05). The mean coefficient of variation between fellow eyes was 3.9%. Age and axial length were related to a cone density decrease, while choroidal and retinal thicknesses did not affect cone metrics in healthy subjects. CONCLUSIONS: A moderate perifoveal cone loss occurs with age. The precise consequences of these findings on visual function should be investigated. In addition to a better understanding of normal retinal anatomy, these results could act as a comparative database for further studies on normal and diseased retinas. PMID- 29993037 TI - Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. AB - Mucins are heavily glycosylated proteins that play critical roles in the pathogenesis of tumour malignancies. Pancreatic ductal adenocarcinoma (PDAC) is characterised by the aberrant expression of mucins. However, the role of mucin (MUC) 20 in PDAC remains unclear. PDAC is usually surrounded by a dense fibrotic stroma consisting of an extracellular matrix and pancreatic stellate cells (PSCs). The stroma creates a nutrient-deprived, hypoxic, and acidic microenvironment, and promotes the malignant behaviours of PDAC cells. In this study, immunohistochemical staining demonstrated that high MUC20 expression correlated with poor progression-free survival and high local recurrence rate of PDAC patients (n = 61). The expression of MUC20 was induced by serum deprivation, hypoxia, and acidic pH in PDAC cells. MUC20 knockdown with siRNA decreased cell viability, as well as migration and invasion induced by PSCs in HPAC and HPAF-II cells. In intraperitoneal, subcutaneous, and orthotopic injection models, MUC20 knockdown decreased tumour growth in immunodeficient mice. Phospho-RTK array and western blot analysis indicated that MUC20 knockdown decreased HGF-mediated phosphorylation of MET in PDAC cells. Moreover, HGF-induced malignant phenotypes could be suppressed by MUC20 knockdown. Co-immunoprecipitation revealed the physical association of MUC20 and MET. These findings suggest that MUC20 knockdown suppresses the malignant phenotypes of PDAC cells at least partially through the inhibition of the HGF/MET pathway and that MUC20 could act as a potential therapeutic target. PMID- 29993036 TI - PSTPIP2 connects DNA methylation to macrophage polarization in CCL4-induced mouse model of hepatic fibrosis. AB - Macrophages play a crucial role in the progression of hepatic fibrosis (HF). In macrophages, epigenetic mechanisms are increasingly being recognized as crucial controllers of their phenotype. However, the functions of macrophage DNA methylation in experimental models of hepatic fibrosis have not been fully addressed. Here, we analyzed isolated hepatic macrophages DNA methylation from CCL4-induced (4 weeks) mice using reduced representation bisulfite sequencing (RRBS). We identified and validated the methylation status of 26 gene promoter regions associated with CpG islands. We further investigated the function of PSTPIP2 in HF by hepatic-adeno-associated virus (AAV9)-PSTPIP2 overexpression. The molecular mechanisms underlying PSTPIPS2-regulated HF were further explored in mice and RAW264.7 cell line. RRBS results show hypermethylation of PSTPIP2 (chr18: 77,843,840-77,843,968) in the 5'-UTR region. PSTPIP2 expression was significantly decreased in isolated hepatic macrophages from CCL4-induced mice. PSTPIP2 hypermethylation is mediated by the methyltransferases DNMT3a and DNMT3b in LPS-induced RAW264.7 cell line. Further investigation indicated that specific overexpression of PSTPIP2 in C57BL/6 mice reduced the inflammatory response and ameliorated liver fibrosis. These data indicated that hypermethylation of PSTPIP2 caused a mixed induction of hepatic classical macrophage (M1) and alternative macrophage (M2) biomarkers in CCL4-induced HF mice. Furthermore, overexpression of PSTPIP2 inhibited the expression of M1 markers by suppressing STAT1 activity, and enhanced the expression of M2 markers by promoting STAT6 activity. In contrast, knockdown of PSTPIP2 promoted M1 polarization and suppressed M2 polarization in vitro. Adding PSTPIP2 expression alleviates liver fibrosis and hepatic inflammation in mice by regulating macrophage polarization. PMID- 29993039 TI - Grand challenges in humanitarian aid. PMID- 29993040 TI - Governments must weigh the environmental costs of deep-sea mining. PMID- 29993038 TI - Notch signaling promotes a HIF2alpha-driven hypoxic response in multiple tumor cell types. AB - Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2alpha, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2alpha by Notch under normoxic conditions leads to elevated HIF2alpha protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma, and renal cell carcinoma cell lines. The elevated level of HIF2alpha protein was in certain tumor cell types accompanied by downregulation of HIF1alpha protein levels, indicating that high Notch signaling may drive a HIF1alpha-to-HIF2alpha switch. At the transcriptome level, the presence of HIF2alpha was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2alpha expression was knocked down by HIF2alpha siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2alpha, which may be important for future cancer therapies. PMID- 29993041 TI - Evolutionary constraints in fitness landscapes. AB - In the last years, several genotypic fitness landscapes-combinations of a small number of mutations-have been experimentally resolved. To learn about the general properties of "real" fitness landscapes, it is key to characterize these experimental landscapes via simple measures of their structure, related to evolutionary features. Some of the most relevant measures are based on the selectively acessible paths and their properties. In this paper, we present some measures of evolutionary constraints based on (i) the similarity between accessible paths and (ii) the abundance and characteristics of "chains" of obligatory mutations, that are paths going through genotypes with a single fitter neighbor. These measures have a clear evolutionary interpretation. Furthermore, we show that chains are only weakly correlated to classical measures of epistasis. In fact, some of these measures of constraint are non-monotonic in the amount of epistatic interactions, but have instead a maximum for intermediate values. Finally, we show how these measures shed light on evolutionary constraints and predictability in experimentally resolved landscapes. PMID- 29993042 TI - Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2B-mediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell. AB - Patients with neuropathic pain are usually accompanied by depression. Chemokine mediated neuroinflammation is involved in a variety of diseases, including neurodegenerative diseases, depression, and chronic pain. The nucleus accumbens (NAc) is an important area in mediating pain sensation and depression. Here we report that spinal nerve ligation (SNL) induced upregulation of chemokine CCL2 and its major receptor CCR2 in both dopamine D1 and D2 receptor (D1R and D2R) containing neurons in the NAc. Inhibition of CCR2 by shRNA lentivirus in the NAc shell attenuated SNL-induced pain hypersensitivity and depressive behaviors. Conversely, intra-NAc injection of CCL2-expressing lentivirus-induced nociceptive and depressive behaviors in naive mice. Whole-cell patch clamp recording of D1R positive or D2R-positive medium spiny neurons (MSNs) showed that SNL increased NMDA receptor (NMDAR)-mediated currents that are induced by stimulation of prefrontal cortical afferents to MSNs, which was inhibited by a CCR2 antagonist. Furthermore, Ccr2 shRNA also reduced NMDAR-mediated currents, and this reduction was mainly mediated via NR2B subunit. Consistently, NR2B, colocalized with CCR2 in the NAc, was phosphorylated after SNL and was inhibited by intra-NAc injection of Ccr2 shRNA. Furthermore, SNL or CCL2 induced ERK activation in the NAc. Inhibition of ERK by a MEK inhibitor reduced NR2B phosphorylation induced by SNL or CCL2. Finally, intra-NAc injection of NR2B antagonist or MEK inhibitor attenuated SNL-induced pain hypersensitivity and depressive behaviors. Collectively, these results suggest that CCL2/CCR2 signaling in the NAc shell is important in mediating neuropathic pain and depression via regulating NR2B mediated NMDAR function in D1R- and D2R-containing neurons following peripheral nerve injury. PMID- 29993044 TI - Changing of the Genomic Pattern of Salmonella Enteritidis Strains Isolated in Brazil Over a 48 year-period revealed by Whole Genome SNP Analyses. AB - Salmonella Enteritidis became the main serovar isolated from gastroenteritis cases in Brazil after the 90's. In this study we used whole genome sequence analysis to determine the phylogenetic relationships among a collection of strains isolated in Brazil to identify possible genomic differences between the strains isolated in the pre and post-epidemic period. Also, we compared our data from strains isolated in Brazil to strains available in the public domain from other South American countries. Illumina technology was used to sequence the genome of 256 Salmonella Enteritidis strains isolated over a 48 year-period in Brazil, comprising the pre- and post-epidemic period. Phylogenetic analyses revealed distinct lineages for strains isolated before and after 1994. Moreover, the phage region SE20 that may be related to the emergence of Salmonella Enteritidis worldwide was present only in strains of the post-epidemic cluster. In conclusion, our results showed that the genomic profile of Salmonella Enteritidis strains isolated in Brazil shifted after 1994, replaced by a global epidemic group of strains. It may be hypothesized that the presence of the prophage SE20 might have conferred to these strains a better ability to colonize chicken and consequently to infect and cause disease in humans, which might better explain the increase in the number of S. Enteritidis cases in Brazil and other South American countries. However, to verify this hypothesis further studies are needed. PMID- 29993045 TI - Recent advances in the application of Diels-Alder reactions involving o quinodimethanes, aza-o-quinone methides and o-quinone methides in natural product total synthesis. AB - In recent decades, transient and highly reactive ortho-quinodimethanes (o-QDMs), ortho-quinone methides (o-QMs) and aza-ortho-quinone methides (aza-o-QMs) have attracted much attention and have been extensively studied and applied in organic synthesis, especially natural product total synthesis. This review summarizes recent advances in Diels-Alder reactions involving in situ-generated o-QDMs, o QMs and aza-o-QMs, highlighting the power and potential of this strategy in organic synthesis and natural product total synthesis. An overview of the methods for generating these intermediates is also available. PMID- 29993043 TI - Osteogenic Differentiation of Human Mesenchymal Stem cells in a 3D Woven Scaffold. AB - Fiber-based scaffolds produced by textile manufacturing technology offer versatile materials for tissue engineering applications since a wide range of crucial scaffold parameters, including porosity, pore size and interconnectivity, can be accurately controlled using 3D weaving. In this study, we developed a weavable, bioactive biodegradable composite fiber from poly (lactic acid) (PLA) and hydroxyapatite powder by melt spinning. Subsequently, scaffolds of these fibers were fabricated by 3D weaving. The differentiation of human mesenchymal stem cells (hMSCs) in vitro was studied on the 3D scaffolds and compared with differentiation on 2D substrates having the same material composition. Our data showed that the 3D woven scaffolds have a major impact on hMSCs proliferation and activation. The 3D architecture supports the differentiation of the hMSCs into osteoblast cells and enhances the production of mineralized bone matrix. The present study further confirms that a 3D scaffold promotes hMSCs differentiation into the osteoblast-lineage and bone mineralization. PMID- 29993046 TI - Ferrocifens labelled with an infrared rhenium tricarbonyl tag: synthesis, antiproliferative activity, quantification and nano IR mapping in cancer cells. AB - Antiproliferative activities of several members of the ferrocifen family, both in vitro and in vivo, are well documented although their precise location in cancer cells has not yet been elucidated. However, two different infrared imaging techniques have been used to map the non-cytotoxic cyrhetrenyl analogue of ferrociphenol in a single cell. This observation prompted us to tag two ferrocifens with a cyrhetrenyl unit [CpRe(CO)3; Cp = eta5-cyclopentadienyl] by grafting it, via an ester bond, either to one of the phenols (4, 5) or to the hydroxypropyl chain (6). Complexes 4-6 retained a high cytotoxicity on breast cancer cells (MDA-MB-231) with IC50 values in the range 0.32-2.5 MUM. Transmission IR spectroscopy was used to quantify the amount of cyrhetrenyl tag present in cells incubated with 5 or 6. The results show that after a 1-hour incubation of cells at 37 degrees C, complexes 5 and 6 are mainly present within cells while only a limited percentage, quantified by ICP-OES, remained in the incubation medium. AFM-IR spectroscopy, a technique coupling infrared irradiation with near-field AFM detection, was used to map the cyrhetrenyl unit in a single MDA-MB-231 cell, incubated at 37 degrees C for 1 hour with 10 MUM of 6. The results show that signal distribution of the characteristic band of the Re(CO)3 entity at 1950 cm-1 matched those of amide and phosphate, thus indicating a location of the complex mainly in the cell nucleus. PMID- 29993047 TI - A ratiometric fluorescent hydrogen peroxide chemosensor manipulated by an ICT activated FRET mechanism and its bioimaging application in living cells and zebrafish. AB - A H2O2-responsive fluorescent chemosensor (CNBE) with a ratiometric emission signal was elaborately designed and synthesized. The ratio signal of the chemosensor was manipulated by an interplaying ICT-activated FRET mechanism. The ratiometric fluorescence imaging was successfully applied to detect H2O2 using CNBE in living cells and zebrafish. PMID- 29993048 TI - Redox-induced switch between luminescence and magnetism in a trinuclear cyanide bridged compound. AB - A trinuclear cyanide-bridged luminescent compound, trans RuII(DMAP)4(CN)2[(PY5Me2)Mn]2[PF6]4 (1-R), and its oxidation product, ferromagnetic trans-RuIII(DMAP)4(CN)2[(PY5Me2)Mn]2-[PF6]5 (1-O), were synthesized and fully characterized. This is the first example of a molecular material showing a redox-controlled transformation between fluorescence and ferromagnetism. PMID- 29993049 TI - Quantifying vapor transfer into evaporating ethanol drops in a humid atmosphere. AB - The effect of ambient temperature and relative humidity on the dynamics of ethanol drop evaporation is investigated. Although drop evaporation of mixtures and pure fluids has been extensively studied, very little is known about the transition from a pure fluid to a binary mixture following transfer of a second component present in the atmosphere. This is of importance for industrial, biological and medical applications where the purity of the solvent is paramount. Adsorption-absorption and/or condensation of water into ethanol drops during evaporation is presented through direct quantification of the drop composition in time. In particular, we combine drop profile measurements with Gas Injection Chromatography (GIC) to directly quantify the amount of ethanol evaporated and that of water intake over time. As expected, drops evaporate faster at higher temperatures since both the ethanol saturation concentration and the vapor diffusion coefficient are directly proportional to temperature. On the other hand, increases in the ethanol evaporation rate and in the water intake are observed at higher relative humidity. The increase in ethanol evaporation at higher relative humidity is interpreted by the greater diffusion coefficient of ethanol into humid air when compared to dry air. Moreover, as ethanol evaporates in a high humidity environment, the drop interfacial temperature falls below the dew point due to evaporative cooling and water condenses compared to lower humidity conditions. As a consequence of the heat released by adsorption absorption and/or condensation, a greater temperature is reported at the liquid vapor interface as confirmed by IR thermography, inducing a greater ethanol saturation concentration at the surface and hence a greater driving force for evaporation. By coupling the drop profile and the composition of ethanol and water within the drop, we propose a combined evaporation-adsorption/absorption and/or condensation empirical correlation. The proposed correlation accounts for: the decreases in ethanol concentration due to water adsorption-absorption and/or condensation, the diffusion coefficient dependence on relative humidity, and the amount of water intake during evaporation. The proposed empirical correlation agrees remarkably well with experimental observations. PMID- 29993050 TI - Insights into the role of nanoalloy surface compositions toward catalytic acetone hydrogenation. AB - A significant composition-dependent catalysis behavior was observed in catalytic acetone hydrogenation. Carbon supported PtRu alloy nanoparticles (NPs) with optimal surface composition achieved ultra-efficient and highly selective production of isopropyl alcohol. PMID- 29993051 TI - Asymmetric synthesis of tetrahydroisoquinoline-fused spirooxindoles as Ras-GTP inhibitors that inhibit colon adenocarcinoma cell proliferation and invasion. AB - Here we report the synthesis of a library of chiral THIQ-fused spirooxindoles, which combine two privileged scaffolds in antitumor medicinal chemistry. Some of the library members inhibit the proliferation and invasion ability of Ras-mutated colon adenocarcinoma cells. Mechanistic studies suggest that the most potent compound, 3m, inhibits Ras-GTP and thereby suppresses downstream signaling mediated by MAPK, PI3K-Akt and Wnt. Ultimately this leads to mitochondrial apoptosis. PMID- 29993052 TI - Photocatalytic production of hydrogen peroxide through selective two-electron reduction of dioxygen utilizing amine-functionalized MIL-125 deposited with nickel oxide nanoparticles. AB - Photocatalytic H2O2 production via two-electron reduction of O2 was realized by visible-light irradiation of a metal-organic framework, MIL-125-NH2, in the presence of TEOA and benzylalcohol. Deposition of NiO nanoparticles onto MIL-125 NH2 dramatically enhanced the catalytic activity. Further studies suggested that fast disproportionation of the O2- intermediate to H2O2 resulted in the enhancement. PMID- 29993053 TI - AlF3-Modified carbon nanofibers as a multifunctional 3D interlayer for stable lithium metal anodes. AB - A versatile interlayer in which AlF3 particles are embedded within carbon nanofibers (AlF3@CNFs) is reported to induce controllable Li+ deposition and achieve a dendrite free Li metal anode. Due to the AlF3 reducing Li nucleation overpotential and CNFs providing high Young's moduli up to 47 GPa, a high Coulombic efficiency (97.2%) and a long lifespan (900 h) are achieved in the carbonate-based electrolyte. A long cycling life is also realized by using interlayer-protected lithium anodes in Li-S batteries. PMID- 29993054 TI - Lactoferrin level in breast milk: a study of 248 samples from eight regions in China. AB - Lactoferrin plays an important role in infant gastrointestinal health and immunity responses. This study measured the change of the lactoferrin level in breast milk over the lactation time in Chinese women, and explored potential influencing factors in terms of various maternal factors. 248 lactating women were recruited from eight different regions across China, covering 330 days of lactation. The nutrition information of each woman as well as the gender information of infants were collected. Breast milk lactoferrin level was determined by ultra-performance liquid chromatography (UPLC). A twenty-four-hour maternal food recall was used to collect the dietary information. The lactoferrin level decreased progressively from day 1 to day 30 (p < 0.01), and remained constant from day 31 to day 330. Among the eight regions, the breast milk samples from Gansu contained the highest mean lactoferrin level (1.40 g L-1) while the breast milk samples from Zhejiang contained the least mean lactoferrin level, 0.94 g L-1 (p < 0.01). Dietary pattern and maternal BMI showed no correlation with the breast milk lactoferrin level. Maternal ethnicity and age were associated with the breast milk lactoferrin level. The breast milk samples collected from Tibetan ethnicity had 1.45 g L-1 lactoferrin while those collected from Dai ethnicity had 1.02 g L-1 lactoferrin. Women in the elder age group (30 years old and above) had 0.95 g L-1 breast milk lactoferrin, which was significantly lower than the lactoferrin level (1.3 g L-1) in the younger age group (20-25 years old) (p < 0.01). In conclusion, this study showed that lactoferrin levels in the breast milk of Chinese lactating women were influenced by lactation time. Besides, ethnicity and maternal age were two impact factors on the breast milk lactoferrin level. PMID- 29993055 TI - Mechanochemical dehydrocoupling of dimethylamine borane and hydrogenation reactions using Wilkinson's catalyst. AB - Mechanochemistry enabled the selective synthesis of the recherche orange polymorph of Wilkinson's catalyst [RhCl(PPh3)3]. The mechanochemically prepared Rh-complex catalysed the solvent-free dehydrogenation of Me2NH.BH3 in a ball mill. The in situ-generated hydrogen (H2) could be utilised for Rh-catalysed hydrogenation reactions by ball milling. PMID- 29993056 TI - Transformation of single MOF nanocrystals into single nanostructured catalysts within mesoporous supports: a platform for pioneer fluidized-nanoreactor hydrogen carriers. AB - Well-dispersed nanostructured catalysts along mesoporous materials have been systematically prepared via a novel multistep approach involving either the pyrolysis under nitrogen, the calcination under oxygen or the reduction under hydrogen of MOF nanocrystals decorated with transition metal complexes and previously confined within the mesoporous cavities via novel solid state synthesis. The resulting supported nanostructured catalysts can be composed of metals, metal oxides, heteroatom-doped carbons and combinations thereof depending on the transformation conditions. The pioneering concept of Fluidized-Nanoreactor Hydrogen Carriers has been proposed for the first time by using the resulting nanostructured catalysts within fluidized mesoporous silica. PMID- 29993057 TI - Gold-catalyzed glycosylation in the synthesis of complex carbohydrate-containing natural products. AB - The methodological developments in gold(i)- and gold(iii)-catalyzed glycosylation reactions are fully surveyed, which exploit the special alkynophilicity or the Lewis acidity of the gold cationic complexes. The application of the new methods in the total synthesis of naturally occurring glycoconjugates and glycans is comprehensively reviewed, with a focus on glycosylation of various complex aglycones. PMID- 29993058 TI - Chemoselective isocyanide insertion into the N-H bond using iodine-DMSO: metal free access to substituted ureas. AB - Insertion of isocyanides into the N-H bond gives access to many medicinally important and structurally diverse complex nitrogen-containing heterocycles. Although the transition metal catalyzed isocyanide insertion into the N-H bond is very common, polymerization of isocyanides in the presence of a transition metal and their strong coordination with metals are the common drawbacks. On the other hand, the inertness of most of the isocyanides towards amines in the absence of a metal catalyst has stymied the growth of the metal-free approach for isocyanide insertion into amines. As a result, only a handful of metal catalysed methods with limited substrate scopes have been reported for the synthesis of ureas via isocyanide insertion into amines and no metal-free version has been reported yet. Interestingly, chemoselective isocyanide insertion into amines has not been reported in the literature. We employed the I2-DMSO reagent system for the chemoselective synthesis of ureas, where isocyanides react with aliphatic amines only, while aromatic amines need a nucleophilic activator (DABCO) to facilitate the formation of ureas. This method gave direct and chemoselective access to ureas by evading the commonly used yet toxic isocyanates. PMID- 29993059 TI - What's in a name? 'Coinage-metal' non-covalent bonds and their definition. AB - Many complexes of the type BMX, (where B is a Lewis base such as H2, N2, ethyne, ethene, cyclopropane, H2O, H2S, PH3, or NH3, M is a coinage-metal atom Cu, Ag or Au, and X is a halogen atom) have now been characterised in the gas phase through their rotational spectra. It is pointed out that, for a given B, such complexes have angular geometries that are isomorphous with those of their hydrogen- and halogen-bonded counterparts BHX and BXY, respectively. Since the MX are, like the B, HX and XY referred to, closed-shell molecules, the complexes BMX also involve a non-covalent bond. Therefore, the name 'coinage-metal' bond is suggested for the non-covalent interaction in BMX, by analogy with hydrogen and halogen bonds. A generalised definition that covers all non-covalent bonds is also presented. PMID- 29993060 TI - Vibrational entropy of disorder in Cu3Au with different degrees of short-range order. AB - L12 ordered Cu3Au and fcc-disordered samples with different degrees of short range order were synthesised by annealing and/or quenching experiments. Low temperature heat capacities were determined by relaxation calorimetry. From these data the vibrational entropy of disorder was derived. The calorimetric results show that the vibrational entropy does not depend on the degree of short-range order. The calorimetric investigations were complemented by density functional calculations with different functionals simulating various atomic configurations by super cells of different size. Using super cells containing 32 atoms, the computed entropies show only small variations with the change of short-range order in good agreement with the calorimetric results. Using, however, super cells with only 8 atoms, the results depend strongly on the chosen atomic configuration at variance with the calorimetric data. This result is important for investigating substances with larger molecules (e.g., silicate solid solutions) because such investigations are typically limited on super cells containing only a few sites on which substitution takes place. PMID- 29993061 TI - Octacyanometallate qubit candidates. AB - We report the temperature dependence of the spin dynamics of the octacyanometallates [Mo(CN)8]3- and [W(CN)8]3-. At 5 K, these complexes display remarkably long spin-lattice relaxation times of 1.05 s, and 0.63 s, respectively. We probe the contributing factors to the spin relaxation and demonstrate the impact of spin-orbit coupling as a handle to tune vibrationally mediated spin-lattice relaxation. PMID- 29993062 TI - Ultrathin CsPbX3 (X = Cl, Br, I) nanoplatelets: solvothermal synthesis and optical spectroscopic properties. AB - The preparation of CsPbX3 nanoplatelets and the investigation of their optical properties have been rarely reported. Herein, the successful development of all inorganic CsPbX3 (X = Cl, Br, or I) perovskite quantum dots has been achieved and their unique optical and electrical properties are discussed. apre-dissolution assisted solvothermal reaction was developed to synthesize ultrathin (~3 nm) CsPbBr3 nanoplatelets with strong exciton absorption, with a 0.41 eV blue-shifted emission relative to that of CsPbBr3 nanocrystals and a high quantum yield of 28%. Anion exchange allowed the variation of the halogen content of the nanoplatelets and allowed them to retain their shape and size and achieve multi color emission. PMID- 29993063 TI - Programming hierarchical self-assembly of colloids: matching stability and accessibility. AB - Encoding hierarchical self-assembly in colloidal building blocks is a promising bottom-up route to high-level structural complexity often observed in biological materials. However, harnessing this promise faces the grand challenge of bridging hierarchies of multiple length- and time-scales, associated with structure and dynamics respectively along the self-assembly pathway. Here we report on a case study, which examines the kinetic accessibility of a series of hollow spherical structures with a two-level structural hierarchy self-assembled from charge stabilized colloidal magnetic particles. By means of a variety of computational methods, we find that for a staged assembly pathway, the structure, which derives the strongest energetic stability from the first stage of assembly and the weakest from the second stage, is most kinetically accessible. Such a striking correspondence between energetics and kinetics for optimal design principles should have general implications for programming hierarchical self-assembly pathways for nano- and micro-particles, while matching stability and accessibility. PMID- 29993064 TI - Dynamics of N2 sticking on W(100): the decisive role of van der Waals interactions. AB - The reactive dynamics of N2 on W(100) has been investigated by means of quasi classical trajectory calculations using an interpolated six-dimensional potential energy surface (PES) based on density functional theory energies obtained employing the vdW-DF2 functional. The dynamics are compared to those obtained using the PW91 functional and to experimental data. The results show that the new PES provides a significant improvement in the description of the reactivity in this system. We show that the long standing problem that constituted the large qualitative disagreement between the simulations performed with the PW91-PES and the experiments was due to the presence of energy barriers in the entrance channel that disappear when vdW forces are accounted for. PMID- 29993065 TI - Translational opportunities for amyloid-targeting fluorophores. AB - Advances in diagnostic medicine have led to an increased awareness and heightened concern for the high prevalence of amyloid-associated neurodegenerative diseases, especially in the elderly. These diseases have characteristic late stage symptoms that often make it possible to distinguish one disorder from another, though methods to diagnose neurodegeneration pre-symptomatically remain a critical challenge. At the molecular level, misfolded protein aggregates known as amyloids are ubiquitously found in many neurodegenerative diseases, and have been suggested to appear before clinical symptoms manifest. Amyloids have, thus, become a valuable potential diagnostic target for chemists, and recent work by many groups have shown that they can be selectively targeted by small molecule fluorescent probes. Here, we summarize some of the exciting work currently under investigation in the area of fluorescence-based amyloid detection and highlight recent efforts to expand the utility of amyloid-targeting fluorophores as clinical tools for disease diagnostics. PMID- 29993066 TI - Developing near-infrared long-lasting phosphorescence of Yb3+ through a medium: insights into energy transfer in the novel material Zn1.98Li0.02P2O7:Yb3. AB - Near-infrared (NIR) long-lasting phosphorescence (LLP) phosphors have potential applications in biological and military fields. However, the properties of these phosphors are insufficient to satisfy the demands. Herein, we report a series of novel LLP phosphors Zn1.98-xLi0.02P2O7:xYb3+ with strong NIR LLP. By investigating the O-Yb3+ charge transfer (CT) band and host thoroughly, it can be confirmed that distinct photoluminescence (PL) of the two can be realized by selecting an appropriate excitation. For NIR emission, considering that the emission of Yb3+ originates from the characteristic 4f-4f transition between 4F5/2 and 4F7/2 levels and the difference between these two levels is too small to be excited by UV light, it is practicable to use the energy transfer of the host rather than that of the O-Yb3+ CT band as its energy level does not match with that of Yb3+. LLP is different from PL of the O-Yb3+ CT band, host or Yb3+, and it is strongly dependent on the appropriate depths of the traps; therefore, the selection and regulation of the traps are crucial. Considering the practicability and the demand of NIR LLP materials, we focus on how to excite Yb3+ and obtain LLP. PMID- 29993067 TI - The crystal structure and luminescence properties of a novel green-yellow emitting Ca1.5Mg0.5Si1-xLixO4-delta:Ce3+ phosphor with high quantum efficiency and thermal stability. AB - A novel green-yellow emitting Ca1.5Mg0.5Si1-xLixO4-delta:Ce3+ phosphor with high quantum efficiency and thermal stability was discovered for applications in near ultraviolet pumped white light-emitting diodes. Its crystal structure was determined with a single-particle diagnosis approach. The Si sites in the SiO4 tetrahedra are reported for the first time to accommodate Li+ ions. This substitution, confirmed by 6Li solid-state NMR and T.O.F. neutron powder diffraction, causes a disordered occupation of Ca/Mg in the Ca3MgSi2O8 host and favors a phase transformation at ~330 degrees C, which results in the formation of the novel phosphor. The produced phosphor was efficiently excited by near UV light peaking at 365 and 410 nm and produced broad green-yellow emission with peaks at 500 and 560 nm, respectively. Its quantum efficiency reached 88.4% (internal) and 55.7% (external) under excitation at 365 nm, and 80.5% (internal) and 42.7% (external) under excitation at 410 nm, while the decrease of luminescence intensity at 200 degrees C was small (~26%). A WLED lamp with a high color rendering index of Ra = 92.8 was produced with the combination of a 365 nm emitting chip with blue emitting BaMgAl10O17:Eu2+, green-yellow emitting CMSL:0.01Ce, and red emitting Sr2Si5N8:Eu2+ phosphors. PMID- 29993068 TI - Coordination polymers from alkaline-earth nodes and pyrazine carboxylate linkers. AB - A new series of alkaline-earth-metal based coordination polymers were synthesized by using a pyrazine-2,5-dicarboxylic acid (2,5-H2pzdc) ligand under hydrothermal conditions. These compounds show a variety of structural topologies, reflecting the variable coordination geometries of the alkaline-earth ions as well as the key role of the metal precursor salts. Ca, Sr, and Ba give porous three dimensional compounds, namely [Ca(2,5-pzdc)(H2O)2].H2O (1), [Sr(2,5 pzdc)(H2O)4].H2O (3), [Ba(2,5-pzdc)(H2O)4].2H2O (4) and [Ba(2,5pzdc)(H2O)2] (5), that feature one-dimensional hydrophilic channels which are filled with water molecules. The Sr compound retains its structure when the lattice water molecules are removed, while the other compounds undergo a structural rearrangement. The hydrophilicity of the Sr compound combined with its high stability even in the absence of guest molecules are the key characteristics that determine its good water adsorption and proton conductivity properties. PMID- 29993069 TI - Reversible lithium storage in a porphyrin-based MOF (PCN-600) with exceptionally high capacity and stability. AB - An iron porphyrin-based metal organic framework (namely PCN-600) is firstly used as an anodic electrode for lithium ion batteries (LIBs) with an extraordinary combination of capacity, rate capability, and cycling stability. The PCN-600 electrode delivers a reversible specific capacity as high as ~1300 mA h g-1 at a current density of 0.4 A g-1, and the capacity is maintained at 610 mA h g-1 even when cycling at high current densities 760 times, which reaches a record value amongst the presented MOF electrode materials. At the same time, the presence of porphyrin ligands is beneficial for the transport of lithium ions and electrons, which will boost the rate performance of the PCN-600 electrode. PMID- 29993070 TI - A novel color-tunable phosphor, Na5Gd9F32:Ln3+ (Ln = Eu, Tb, Dy, Sm, Ho) sub microcrystals: structure, luminescence and energy transfer properties. AB - Ln3+-Doped fluorides are economical and highly efficient luminescent materials, which play a crucial role in LEDs, biolabeling, and sensors. Therefore, Na5Gd9F32:Ln3+ sub-microspheres with tunable multicolor emissions were successfully synthesized via a simple water bath method employing colloidal Gd(OH)CO3 spheres as precursors. Samples were characterized by XRD, SEM, TEM, EDS and PL. It was found that the hydrolysis of BF4- ions had a dynamic effect on the retention of the morphology of the product owing to the mild reaction environment caused by the low hydrolysis rate of BF4- ions. Upon excitation by ultraviolet light, the Na5Gd9F32:Ln3+ (Ln = Eu, Tb, Dy, Sm, Ho) phosphors underwent characteristic f-f transitions and gave rise to red, green, green, yellow, and pale green emissions, respectively. Moreover, various emission colors could be obtained by using different excitation wavelengths and adjusting the Eu3+/Tb3+ molar ratio owing to energy transfer between Tb3+ and Eu3+ ions in the Na5Gd9F32 host. The energy transfer mechanism was demonstrated to be a dipole-dipole interaction. The multicolor luminescent phosphors with a certain dopant concentration based on a single host and excitation wavelength may have potential applications in the field of lighting displays. PMID- 29993071 TI - Alkyltin clusters: the less symmetric Keggin isomers. AB - The Keggin structure is prevalent in nature and synthesis, self-assembled from many metals across the periodic table as both isolated clusters and building blocks of condensed framework oxides. Here we present a one-step synthesis to obtain the sodium-centered butyltin Keggin ion in high yield and high purity, important for mechanistic nanolithography studies. Extensive solution characterization (small-angle X-ray scattering, 1H, 13C and 119Sn nuclear magnetic resonance, electrospray mass spectrometry) also confirms solutions contain only the Na-centered dodecamers. We report three butyltin Keggin structures: the beta-isomer (beta-NaSn12), the gamma-isomer (gamma-NaSn12), and a gamma-isomer capped with an additional butyltin (gamma-NaSn13). All Keggin ions presented here have the general formula [NaO4BuSn12(OCH3)12(O,OH)12] (Bu = butyl), and are of neutral charge. The lack of counterions (OH-) facilitates mechanistic lithographic studies without inference from hydrolysis chemistry. The methanol reaction media enables solubility and ligates the cluster, both important to obtain high purity materials. Despite the monospecific nature of the NaSn12 solutions, NMR reveals both isomer interconversion and ligand exchange. DFT computational comparisons of our three isolated structures, the capped beta isomer (beta-NaSn13), along with hypothetical alpha-isomers (alpha-NaSn12 and alpha-NaSn13), showed that the stability ranks beta-NaSn12 > gamma-NaSn12 > alpha NaSn12, consistent with experimental observation. The uncapped isomers were computationally determined to be more stable than the respective capped analogues. These clusters provide a unique opportunity to investigate the lower symmetry Keggin isomers, and to determine structural factors that control isomer selectivity as well as isomer labilization. PMID- 29993072 TI - Involvement of autophagy in the beneficial effects of resveratrol in hepatic steatosis treatment. A comparison with energy restriction. AB - Autophagy eliminates damaged cellular components. In the liver, it has been proposed that it mediates the breakdown of lipid droplets. This study aimed to compare the involvement of autophagy and the oxidative status in the effects of resveratrol and energy restriction as therapeutic tools for managing liver steatosis. In addition, potential additive or synergic effects were studied. Rats were fed a high-fat high-sucrose diet for 6 weeks and then divided into four experimental groups and fed a standard diet: a control group (C), a resveratrol treated group (RSV, 30 mg kg-1 d-1), an energy restricted group (R, -15%), and an energy restricted group treated with resveratrol (RR). Liver triacylglycerols (TGs) were measured by Folch's method. TBARS, GSH, GSSG, GPx and SOD were assessed using commercial kits. The protein expression of beclin, atg5 and p62, as well as ratios of pSer555 ULK1/total ULK1, pSer757 ULK1/total ULK1 and LC3 II/I were determined by western blotting. Energy restriction increased the protein expression of beclin, atg5 and pSer757 ULK1/total ULK1 and LC3 II/I ratios, and reduced the protein expression of p62, thus indicating that it induced autophagy activation. The effects of resveratrol were similar but less marked than the hypocaloric diet. No differences were observed in oxidative stress determinants except for TBARS, which was decreased by energy restriction. In conclusion, resveratrol can reverse partially dietary-induced hepatic lipid accumulation, although less efficiently than energy restriction. The delipidating effect of energy restriction is mediated in part by the activation of autophagy; however, the involvement of this process in the effects of resveratrol is less clear. PMID- 29993073 TI - Development of a microparticulate system containing Brazilian propolis by-product and gelatine for ascorbic acid delivery: evaluation of intestinal cell viability and radical scavenging activity. AB - The use of propolis by-product (PBP) microparticles (MP) as delivery systems can be a promising tool to surpass drawbacks related to low stability of ascorbic acid (AA). The objective of this study was to develop and characterize MP prepared with PBP containing AA. The MP was characterized regarding morphology, particle size, polydispersity index (PDI), association efficiency (AE), drug loading (DL), infrared and Raman spectroscopy as well as antioxidant and radical scavenging activity, in vitro release, and cellular studies. MP was shown to be spherical with some agglomeration. Its particle size was 1654 +/- 0.210 nm with a PDI of 0.7. The AE and DL were, respectively, 100.30 +/- 2.66% and 13.16 +/- 0.59. Spectroscopic studies indicated a possible interaction between the PBP and AA. 2,2-Diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulphonic acid) (ABTS) and ferric reducing antioxidant power (FRAP) assays demonstrated that the MP containing AA have an excellent antioxidant capacity as well as a considerable scavenging activity against reactive oxygen and nitrogen species. The in vitro release profile showed a slow pattern of drug release of AA from MP. Viability studies with intestinal cells revealed that MP did not present toxicity in Caco-2 and HT29-MTX. Moreover, AA could permeate Caco-2 monolayers and triple co-culture substantially at the end of 8 h, opposite to the MP. Therefore, the proposed MP formulation represents a promising platform for oral delivery of AA with a local effect on intestines. PMID- 29993074 TI - Triterpenoids. AB - Covering 2014. Previous review: Nat. Prod. Rep., 2017, 34, 90-122This review covers the isolation and structure determination of triterpenoids reported during 2014 including squalene derivatives, lanostanes, holostanes, cycloartanes, cucurbitanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, quassinoids, lupanes, oleananes, friedelanes, ursanes, hopanes, serratanes, isomalabaricanes and saponins; 374 references are cited. PMID- 29993076 TI - Asymmetric organocatalytic synthesis of chiral 3,3-disubstituted oxindoles via a 1,6-conjugate addition reaction. AB - A highly efficient synthesis of chiral 3,3-disubstituted oxindoles was developed using a chiral spirocyclic phosphoric acid catalyzed 1,6-conjugate addition reaction of para-quinone methides derived from N-unprotected isatins with indoles. The reaction proceeds under mild reaction conditions to provide indole containing N-unprotected oxindoles bearing quaternary stereocenters in good yields and with moderate to excellent enantioselectivities (up to 97% ee). PMID- 29993075 TI - Targeting heme oxygenase-1 by quercetin ameliorates alcohol-induced acute liver injury via inhibiting NLRP3 inflammasome activation. AB - Alcoholic hepatitis (AH) is characterized by inflammation and necrosis of liver tissue caused by excessive alcohol consumption and it even causes organ failure sometimes, in which oxidative stress plays an important role. Quercetin is a bioactive flavonoid in the class of polyphenols with a free-radical scavenging ability and anti-inflammatory activity. Recently it has aroused great interest because of its potential benefits in the prevention and intervention of cancer, cardiovascular abnormalities, neurodegenerative diseases, metabolic disorders and liver fibrosis. However, its role in alcoholic liver injury is still unclear and needs to be elucidated. Through database analysis and serum measurements, we found that there was a decline in the level of heme oxygenase-1 (HO-1) in patients with acute alcoholic hepatitis compared to healthy controls. Quercetin could elevate the expression of nuclear factor E2-related factor 2(Nrf2)/HO-1 and ameliorate ethanol-induced acute liver injury in rats. Moreover, this protective effect of quercetin could be diminished when combined with the HO-1 inhibitor ZnppIX which demonstrated a critical role of HO-1 in quercetin's hepatoprotection. The underlying mechanism of quercetin's benefit on the liver may be explained by its anti-oxidant properties and inhibitory effect on the ROS/NF-kappaB/NLRP3 inflammasome/IL-1beta and IL-18 pathway by inducing HO-1. Meanwhile, quercetin also upregulated the anti-inflammatory factor IL-10, while it was found uncorrelated with HO-1 expression. In conclusion, quercetin can preserve the function of the liver in acute alcoholic injury by upregulating the expression of IL-10 and HO-1 and thus inhibiting NLRP3 inflammasome activation and inflammatory factor secretion. In other words, quercetin looks promising as an alternative treatment and HO-1 may be a potential target in the crosstalk of inflammation and oxidative stress in alcoholic liver damage. PMID- 29993077 TI - Metal-free, base promoted sp2 C-H functionalization in the sulfonamidation of 1,4 naphthoquinones. AB - A novel, metal-free, base promoted sp2 C-H functionalization in the sulfonamidation of 1,4-naphthoquinones via a [3 + 2] cycloaddition reaction using sulfonyl azides under mild reaction conditions is reported. In this straightforward atom- and step-economical protocol, the active alkene moiety of quinone undergoes a thermal azide-alkene [3 + 2] cycloaddition followed by proton abstraction, ring opening and elimination of a nitrogen molecule to form sulfonamidation products in good yield and all the synthesized sulfonamidation derivatives exhibit good absorption and emission characteristics. In addition, the electrochemical properties of both 1,4-naphthoquinone and menadione sulfonamidation derivatives are studied and significant redox potentials are observed. Other important features of this methodology are readily accessible and easy to handle starting materials, milder conditions, reaction with a wide range of substrates and shorter reaction times with good yields. PMID- 29993078 TI - Intramolecular electron transfer of light harvesting perylene-pyrene supramolecular conjugate. AB - Electronic interactions between the cationic N,N'-bis(2(trimethylammonium iodide) ethylene)perylene-3,4,9,10-tetracarboxyldiimide (TAIPDI) with two electron donors, namely, pyrene (Py) and 1-pyrenesulfonic acid sodium salt (PySA), have been investigated. The spectroscopic studies showed the formation of the supramolecular conjugate between TAIPDI and PySA via ionic interaction, but not with Py. Density functional theory (DFT) combined with a natural energy decomposition analysis (NEDA) technique showed an S-like structure of the supramolecular conjugate TAIPDI-PySA via an ionic interaction. The formation constant of the TAIPDI-PySA supramolecular conjugate was determined to be 3.0 * 104 M-1, suggesting a fairly stable complex formation. The excited state events were monitored by both steady state and time-resolved emission techniques. Upon excitation, the quenching pathways via the singlet-excited states of TAIPDI and PySA involved the intramolecular electron transfer from the electron donating PySA to the electron accepting TAIPDI with a rate constant of 1.10 * 1011 s-1 and a quantum yield of 0.99. The thermodynamic parameters of the supramolecular TAIPDI-PySA conjugate have been determined using the stopped-flow technique. PMID- 29993079 TI - Hierarchical self-assembled Bi2S3 hollow nanotubes coated with sulfur-doped amorphous carbon as advanced anode materials for lithium ion batteries. AB - Bismuth sulfide (Bi2S3) is considered as a promising anode material for lithium ion batteries (LIBs) owing to its high theoretical specific capacity and intriguing reaction mechanism. However, capacity fading and cycling instability due to volume variation during the lithiation/delithiation process still remain a great challenge. Herein, we proposed a simple glucose assisted hydrothermal strategy and followed a post-treatment process to prepare hierarchical sulfur doped carbon Bi2S3 (Bi2S3@SC) hollow nanotubes that self-assembled into sulfur doped amorphous carbon coated Bi2S3 nanocrystals as building blocks. Glucose plays a decisive role in the formation process of Bi2S3 nanocrystals and subsequent self-assembly, forming Bi2S3@SC hollow nanotubes. The polysaccharide shell formed on the surface of Bi2S3 nanocrystals during the hydrothermal process was transformed into the sulphur-doped amorphous carbon layer after the post treatment process. Electrochemical tests reveal that the resulting composites exhibit excellent electrochemical performance with a highly reversible cycling capacity of ~950 mA h g-1 at a current density of 100 mA g-1, as well as a good rate capability and significantly enhanced cycling stability derived from their unique structural features, thus demonstrating the potential of Bi2S3@SC hollow nanotubes as high performance anode materials for LIBs. The analysis of electrochemical kinetics confirmed that the pseudocapacitive behavior dominates the overall storage process of Bi2S3@SC hollow nanotubes. PMID- 29993080 TI - Synthesis and evaluation of analogues of the glycinocin family of calcium dependent antibiotics. AB - The glycinocins are a class of calcium-dependent, acidic cyclolipopeptide antibiotics that are structurally related to the clinically approved antibiotic daptomycin. In this article, we describe the synthesis of a small library of glycinocin analogues that differ by variation in the exocyclic fatty acyl substituent. The glycinocin analogues were screened against a panel of Gram positive bacteria (as well as Gram-negative P. aeruginosa). These analogues exhibited similar calcium-dependent activity to the parent natural products against Gram-positive bacteria but showed no activity against P. aeruginosa. The length of the fatty acid was shown to be important for optimal biological activity, while the hybridisation at the alpha,beta position and branching within the fatty acyl chain had only subtle effects on activity. PMID- 29993081 TI - Tuning photovoltaic response in Bi2FeCrO6 films by ferroelectric poling. AB - Ferroelectric materials are interesting candidates for future photovoltaic applications due to their potential to overcome the fundamental limits of conventional single bandgap semiconductor-based solar cells. Although a more efficient charge separation and above bandgap photovoltages are advantageous in these materials, tailoring their photovoltaic response using ferroelectric functionalities remains puzzling. Here we address this issue by reporting a clear hysteretic character of the photovoltaic effect as a function of electric field and its dependence on the poling history. Furthermore, we obtain insight into light induced nonequilibrium charge carrier dynamics in Bi2FeCrO6 films involving not only charge generation, but also recombination processes. At the ferroelectric remanence, light is able to electrically depolarize the films with remanent and transient effects as evidenced by electrical and piezoresponse force microscopy (PFM) measurements. The hysteretic nature of the photovoltaic response and its nonlinear character at larger light intensities can be used to optimize the photovoltaic performance of future ferroelectric-based solar cells. PMID- 29993082 TI - Tunability in the optical response of defective monolayer WSe2 by computational analysis. AB - In aiming to achieve red-shifted single-photon emitters that result from localized excitons in monolayer WSe2, we report in this work a theoretical investigation on the optical properties of nanostructures with vacancies and rotational defects. We find that for pristine monolayer WSe2, the complex excitonic manifold, namely, the energies of the bright and dark excitons and the exciton binding energy, agree well with the experimental data when using the GW (Green's function approximation with a screened Coulomb interaction W)-Bethe Salpeter Equation (GW-BSE) method, including spin-orbit coupling. The predicted second and third lowest dark excitons are close in energy and appear below the second bright exciton. Upon introduction of single or double Se vacancies, or a single W vacancy within monolayer WSe2, accurate computational results demonstrate emergence of deeper defect excitons in comparison to shallower values observed for edges, which are consistent with measured emissions upon Ar+ plasma treatment of WSe2 for longer periods of time. Furthermore, using corrected RPA (random phase approximation) calculations, we find that defect excitons red-shift significantly for large rotational defects that pattern the monolayer. Finally, interestingly, first-order Raman intensity calculations demonstrate that a comparison between pristine and defective monolayer WSe2 with a single vacancy can provide a fingerprint for defect characterization. Overall, our results will encourage experimental defect engineering to enable the development of red shifted single-photon emitters, such as by inducing extended patterning of monolayer WSe2. PMID- 29993083 TI - Strategies for the synthesis of spiropiperidines - a review of the last 10 years. AB - Spiropiperidines have gained in popularity in drug discovery programmes as medicinal chemists explore new areas of three-dimensional chemical space. This review focuses on the methodology used for the construction of 2-, 3- and 4 spiropiperidines, covering the literature from the last 10 years. It classifies the synthesis of each of the types of spiropiperidine by synthetic strategy: the formation of the spiro-ring on a preformed piperidine ring, and the formation of the piperidine ring on a preformed carbo- or heterocyclic ring. While 3- and 4 spiropiperidines are predominantly synthesised for drug discovery projects, 2 spiropiperidines are synthesised en route to natural products. The lack of 2 spiropiperidines in drug discovery is presumably due to limited general procedures for their synthesis. PMID- 29993084 TI - C-H alkylation reactions of indoles mediated by Pd(ii) and norbornene: applications and recent developments. AB - The Catellani reaction enables an ortho-C-H activation based on oxidative addition of Pd(0) and an intermediary carbopalladation of norbornene. Among its variants, the recently developed C2-selective alkylation of indoles is particular as it employs Pd(ii) as the source of palladium. This review describes the mechanistic background of this transformation. Applications in total synthesis and in the synthesis of biologically relevant molecules are illustrated and further developments of the method are discussed. PMID- 29993085 TI - Pd-Catalyzed cascade cyclization of o-alkynylanilines via C-H/C-N bond cleavage leading to dibenzo[a,c]carbazoles. AB - A new and efficient Pd-catalyzed cascade cyclization of biaryl-tethered o alkynylanilines for the formation of dibenzo[a,c]carbazole derivatives has been reported. The use of the alkyl-substituted tertiary anilines together with the combination of the PdCl2 catalyst with the MnO2 oxidant and PivOH is vital for giving rise to 5-endo cyclization, C-N bond cleavage, and C-H bond activation in a cascade manner to produce the corresponding products with structural diversity. PMID- 29993086 TI - Difference in the action spectra for UVR8 monomerisation and HY5 transcript accumulation in Arabidopsis. AB - The photoreceptor UV RESISTANCE LOCUS 8 (UVR8) activates photomorphogenic responses when plants are exposed to ultraviolet-B (UV-B) light. However, whereas the absorption spectrum of UVR8 peaks at 280 nm, action spectra for several photomorphogenic UV-B responses show maximal photon effectiveness at 290-300 nm. To investigate this apparent discrepancy we measured the effectiveness of UV wavelengths in initiating two responses in Arabidopsis: photoconversion of homodimeric UVR8 into the monomeric form, which is active in signaling, and accumulation of transcripts of the ELONGATED HYPOCOTYL 5 (HY5) transcription factor, which has a key role in UVR8-mediated responses. When purified UVR8 or Arabidopsis leaf extracts were exposed to UV light monomerisation was maximal at approximately 280 nm, which correlates with the UVR8 absorption spectrum. When intact plants were exposed to UV, monomerisation was most strongly initiated at approximately 290 nm, and this shift in maximal effectiveness could be explained by strong absorption or reflectance at 280 nm by leaf tissue. Notably, the action spectrum for accumulation of HY5 transcripts in the same leaf tissue samples used to assay UVR8 dimer/monomer status peaked at approximately 300 nm. Possible reasons for the difference in maximal photon effectiveness of UVR8 monomerisation and HY5 transcript accumulation in leaf tissue are discussed. PMID- 29993087 TI - Role of cationic groups on structural and dynamical correlations in hydrated quaternary ammonium-functionalized poly(p-phenylene oxide)-based anion exchange membranes. AB - Extensive atomistic molecular dynamics (MD) simulations employing a polarizable force field have been conducted to study hydrated anion exchange membranes comprised of a poly(p-phenylene oxide) (PPO) homopolymer functionalized with quaternary ammonium cationic side groups and hydroxide anions. Representative membranes with different cationic structures have been investigated to study correlations between polymer architecture, morphology and transport properties of hydrated membranes. Specifically, hydrated polymers with five different quaternary ammonium cationic groups (R1: -CH3, R2: -C2H5, R3: -C3H7, R4: -C6H13 and R5: -C4H8OCH3) and degree of functionalization of 50% were investigated at three hydration levels (lambda = Nwater/Ncation = 5, 10 and 17). Effects of the polymer structure on the distribution of water-rich domains and dynamic relaxations were systematically investigated to uncover the complex interplay between the degree of hydrophobicity/hydrophilicity of the cationic groups, morphology, connectivity of water domains, and the hydroxide transport mechanisms. Structural and dynamical analysis indicates that the bottlenecks, formed between the water-rich domains, create a substantial free energy barrier for hydroxide transport associated with the partial loss of anion hydration structure. The energy penalty associated with the loss of the hydration structure hinders the vehicular transport of the hydroxide anion. The optimal structure of functionalized homopolymer chains should be sufficiently hydrophobic to create nanophase segregation and form an interconnected network of water channels with a minimal amount of narrow bottlenecks that inhibit the vehicular motion of hydrated anions. We demonstrate that utilization of asymmetrically modified cationic groups is a promising route to achieve the desired water channel morphology at low hydration levels. PMID- 29993088 TI - Effect of Copper Alloying on Electro-Catalytic Activity of Nickel for Ethanol Oxidation in Alkaline Media. AB - In this research, the electro-catalytic activity of nickel-copper (Ni-Cu) alloy towards oxidation of ethanol and its possible redox process were investigated in alkaline solution. For this purpose, cyclic voltammetry, chronoamperometry and electrochemical impedance spectroscopy techniques were employed. According to the cyclic voltammetry studies, Ni- Cu alloy compared to pure nickel can demonstrate a significantly higher response for ethanol oxidation. So, the enhancement of the anodic peak current corresponding to the oxidation of nickel hydroxide was accompanied with attenuated cathodic current in the presence of ethanol. The anodic peak currents have a linearly dependence on the square root of scan rate which is the characteristic of diffusion-controlled processes. Based on the chronoamperometry measurements, the reaction exhibited a Cottrellian behavior and the diffusion coefficient of ethanol was found to be 1.26 - 10-5 cm2 s-1. The impedance spectroscopy declared electro-catalytic behavior of Ni-Cu electrode for oxidation of ethanol and showed that the charge transfer resistance decreases by increasing the ethanol concentration. PMID- 29993089 TI - Investigation of High-Activity Activated Carbon-Supported Co-Cr-B Catalyst in the Generation of Hydrogen from Hydrolysis of Sodium Borohydride. AB - In this study, activated carbon-supported Co-Cr-B catalyst was synthesized by chemical impregnation and precipitation method for use in the catalytic hydrolysis of sodium borohydride (NaBH4). The activity of Co-Cr-B / activated carbon (5-20%) obtained by using different ratios was investigated while synthesizing activated carbon-supported Co-Cr-B catalyst. The effects of some parameters such as NaOH Concentration (0-5%), NaBH4 concentration (2.5-10%), amount of catalyst (25-100 mg) and solution ambient temperature were investigated in the catalytic hydrolysis of NaBH4. The hydrogen production rate of Co-Cr-B catalyst without support in hydrolysis of NaBH4 was found as 6.5 Lg-1 min-1 catalyst while the hydrogen production rate of activated carbon supported Co-Cr-B catalyst was found as 30.2 Lg-1 min-1 catalyst. In presence of activated carbon supported Co-Cr-B catalyst, the hdyrolysis kinetic order and activation energy of NaBH4 were found as 0.126 and 16.27 kJ/mol, respectively. The results suggest that activated carbon-supported Co-Cr-B catalysts can be used for mobile applications of Proton exchange membrane fuel cell (PEMFCs) systems. PMID- 29993090 TI - A Highly Selective DNA Sensor Based on Graphene Oxide-Silk Fibroin Composite and AuNPs as a Probe Oligonucleotide Immobilization Platform3667. AB - In this study, a simple and novel electrochemical biosensor based on a glassy carbon electrode (GCE) modified with a composite of graphene oxide (GO) - silk fibroin nanofibers (SF) and gold nanoparticles (MCH/ssDNA/AuNPs/SF/GO/GCE) was developed for detection of DNA sequences. The fabrication processes of electrochemical biosensor were characterized by scanning electron microscopy (SEM), FT-IR and electrochemical methods. Some experimental conditions such as immobilization time of probe DNA and MCH incubation time, time and temperature of hybridization were optimized. The designed biosensor revealed a wide linear range of 1.0 * 10-16 - 1.0 * 10-8 mol L-1 and a low detection limit (3.3 * 10-17 mol L 1) for detection of BRCA1 5382 mutation by EIS technique. The designed biosensor revealed high selectivity for discrimination of the complementary (P1C) sequences from various non-complementary sequences of (P1nC1, P1nC2 and P1nC3). Also, the biosensor revealed a high reproducibility (RSD of 7.5% (n=4)) and high stability (92% of its initial response after 8 days). So, the fabricated biosensor has a suitable potential to be applied for detection of breast cancer sequences in the initial stages of the cancer. PMID- 29993091 TI - Determination of Titanium Dioxide Content in Bauxites Using X-ray Fluorescence Spectrometry by Fusion and by Pressing. AB - Bauxites of different deposits were analysed for their content of TiO2 (mass %), using X-ray fluorescence spectrometry and the reference spectrophotometric method JUS B.G8.514. The samples were prepared in two ways: fusion with a borax technique and pressing, after which beads were formed for the purpose of analysis. Certified reference samples of bauxite were used for producing a calibration curve. The equation for calculating the content of TiO2 (mass %) in the samples of bauxite was derived from the calibration curve. Results of the XRF method were tested statistically by means of the F-test and the t-test (the standard sample of the bauxite and the reference method). The values obtained from the afore mentioned tests for the fusion beads showed that the XRF method was precise and correct and that there were no systematic errors, whereas for the pressed beads this method showed significant systematic errors. PMID- 29993092 TI - Factors Influencing Imazapyr Herbicide Removal from Wastewater Using Photocatalytic Ozonation. AB - This study investigates the degradation of imazapyr herbicide from wastewater by photocatalytic ozonation using TiO2 as a semiconductor. Effects of operational parameters on imazapyr removal efficiency including TiO2 dosing, initial herbicide concentration and pH were also studied. Obtained results showed that more than 90% of removal efficiency representing the disappearance of imazapyr was maintained until 7 uM in the presence of 200 mgL-1of UV100-TiO2. Otherwise, the degradation of imazapyr followed the first-order kinetics with a photocatalytic rate constant of 0.247 min-1, and complete degradation was achieved within 20 min using photocatalytic ozonation for 5 uM of Imazapyr at pH 7. PMID- 29993093 TI - Computational Modelling of Liver Metabolism and its Applications in Research and the Clinics. AB - Computational models of liver metabolism are gaining an increasing importance within the research community. Moreover, their first clinical applications have been reported in recent years in the context of personalised and systems medicine. Herein, we survey selected experimental models together with the computational modelling approaches that are used to describe the metabolic processes of the liver in silico. We also review the recent developments in the large-scale hepatic computational models where we focus on object-oriented models as a part of our research. The object-oriented modelling approach is beneficial in efforts to describe the interactions between the tissues, such as how metabolism of the liver interacts with metabolism of other tissues via blood. Importantly, this modelling approach can account as well for transcriptional and post-translational regulation of metabolic reactions which is a difficult task to achieve. The current and potential clinical applications of large-scale hepatic models are also discussed. We conclude with the future perspectives within the systems and translational medicine research community. PMID- 29993094 TI - Synthesis of Cyclic and Acyclic Pyrimidine Nucleosides Analogues with Anticipated Antiviral Activity. AB - A convenient method for preparation of cyclic and acyclic nucleosides was achieved by alkylation of 6-(2,4-dichlorophenoxymethyl) pyrimidine-2,4-dione (1) with a variety of acyclic and cyclic activated sugar analogues, namely (2 acetoxyethoxy)methyl acetate (3), 2-(acetoxymethoxy)propane-1,3-diyl dibenzoate (4), benzyloxymethyl acetate (5), 2-acetoxy-5-(benzoyloxymethyl)tetrahydrofuran 3,4-diyl dibenzoate (12), 5-chloro-2-((4-chlorobenzoyloxy)methyl) tetrahydrofuran 3-yl 4-chlorobenzoate (13) and 2-(acetoxymethyl)-6-bromotetrahydro-2H-pyran-3,4,5 triyl triacetate (14), respectively. Deprotection of the synthesized nucleosides was achieved by using methanolic ammonia. The structures of the newly synthesized nucleoside analogues were fully characterized by analytical methods (mass spectrometry, 1H NMR, 13C NMR, and elemental analysis). PMID- 29993095 TI - Copper(II) Schiff Base Complexes with Catalyst Property: Experimental, Theoretical, Thermodynamic and Biological Studies. AB - Two novel copper(II) Schiff base complexes were synthesized and characterized by various physico-chemical and spectroscopic methods, revealing a distorted square planar geometry around the copper atom. The analytical data confirmed the 1:1 metal to ligand stoichiometry of the complexes. B3LYP/(LANL2DZ/6-311G**) density functional theory (DFT) were used to investigate structural and electronic properties of the synthesized compounds in gas phase. The computational results support the conclusion obtained by the experimental studies. Thermodynamic study of complex formation in solution was carried out spectrophotometrically at 25 degrees C. These compounds were also subjected to study in vitro antibacterial screening against some bacteria. Also, click reaction was investigated for its catalytic properties. The synthesized Schiff base copper complexes catalyzed 1,3 dipolar Huisgen cycloaddition of different functionalized ?-azido alcohols and alkynes in the presence of ascorbic acid in a solution of THF/H2O (2:1, V/V) at room temperature. PMID- 29993096 TI - Recovery of Antioxidant Compounds from Aronia Filter Tea Factory by -Product: Novel Versus Conventional Extraction Approaches. AB - Black chokeberry (Aronia melanocarpa L.) by-product from filter tea factory underwent subcritical water extraction (SWE) in order to recover polyphenolics and determine its antioxidant potential. In the current study Box-Behnken design was applied for optimization. Independent variables used in experimental design were temperature (T, 120-200 degrees C), extraction time (t, 15-35 min) and hydrochloride concentration (c, 0-1.5%). Experimental results were fitted to a second-order polynomial model where multiple regression analysis and analysis of variance were used to determine fitness of the model and optimal conditions. The optimized SWE conditions for maximum responses of total phenols (TP), total flavonoids (TF) and monomeric anthocyanins (MA) contents, and minimum response of IC50 were temperature of 120.4 degrees C, extraction time of 15.2 min and absence of acidifier. The predicted values of TP, TF, MA and IC50 at these conditions were: 32.8863 mg GAE/g, 23.5164 mg CE/g, 0.5124 mg C3G/g and 0.0055 mg/mL, respectively. PMID- 29993097 TI - Interaction of HF, HBr, HCl and HI Molecules with Carbon Nanotubes. AB - The present work applies the density functional theory (DFT) to study the interactions between armchair (n,n) single walled carbon nanotubes (SWCNTs) and hydrogen halides confined along the nanotube axis and perpendicular to it. Calculations are performed using the CAM-B3LYP functional. According to the hydrogen halides orientation and the internal diameter of CNTs hollow space, HF, HCl, HBr and HI behave differently. The nanoconfinement alters the charge distribution and the dipolar moment. The encapsulated hydrogen fluoride (HF) molecule is stable along and perpendicular to the nanotubes (5,5) and (6,6) axis. The hydrogen chloride (HCl), hydrogen bromide (HBr) and hydrogen iodide (HI) form stable systems inside the nanotube (6,6) only at the perpendicular orientation. In addition, other phenomena are observed such as leaving the nanotube or decreasing the bond length of the molecule and even the creation of covalent bind between the guest molecule and the host nanotube. PMID- 29993098 TI - Phase Equilibria in the Tl4PbTe3-Tl9SmTe6-Tl9BiTe6 Section of the Tl-Pb-Bi-Sm-Te System. AB - Phase equilibria in the section Tl4PbTe3-Tl9SmTe6-Tl9BiTe6 of the Tl-Pb-Bi-Sm-Te system were determined by combination of differential thermal analysis, powder X ray diffraction methods as well as microhardness measurements. The phase diagrams of the boundary systems Tl4PbTe3-Tl9SmTe6, Tl9SmTe6-Tl9BiTe6, isothermal section at 820 and 840 K, some isopleth sections and as well as liquidus and solidus surfaces projections, were plotted. Unlimited solid solutions, which crystallize in Tl5Te3 structure type were found in the system at the solidus temperatures and below. PMID- 29993099 TI - Biological Significance of Hetero-Scaffolds Based Gold(III) Complexes. AB - Synthesized ligands and complexes, [Au(Ln)Cl2]Cl, have been characterized by various techniques such as elemental analysis, LC-MS, FT-IR, UV-Vis, 1H and 13C NMR spectroscopy, conductance measurement and magnetic moments measurement. The experimental results show that complexes exhibit higher antibacterial activity against Gram(+ve) and Gram(-ve) microorganisms than free ligands. The in vitro cytotoxicity and cellular level cytotoxicity suggest that Au(III) complexes show better activity than corresponding ligands. The DNA interaction study has been evaluated using absorption titration. The experimental evidence indicates (Kb = 1.08-3.44 * 105 M-1) that all the complexes have been bind to HS-DNA by intercalation mode. To further verify the nature of interaction viscosity measurement and molecular modeling have been carried out which suggest the intercalation binding between complex and DNA. The Schizosaccharomyces pombe cell DNA cleavage has been performed using agarose gel and their photographic images of complexes show smearing of DNA due to DNA cleavage from the nucleus. PMID- 29993100 TI - Thin-Layer Chromatography: an Efficient Technique for the Optimization of Dispersive Liquid-Liquid Microextraction. AB - Thin-layer chromatography (TLC) is an often omitted analytical technique due to its lower sensitivity and separation capacity. Even in the era of high performance liquid chromatography (HPLC), thin-layer chromatography still offers many advantages, such as simplicity, rapidity, and cost-effectiveness, which predict TLC to be the first-choice method for the laborious optimization process requiring analysis of numerous samples. In this work, a thin-layer chromatography method with chemical and densitometric detection was used to optimize a dispersive liquid-liquid microextraction (DLLME) process for the extraction and preconcentration of estradiol in human urine. The chromatographic system consisted of silica gel plates as the stationary phase and toluene-ethanol (9:1; v/v) mixture as the developing solvent. The plates were dyed with 10% phosphomolybdic acid reagent and sequentially evaluated densitometrically at lambda = 430 nm. In the context of DLLME optimization, parameters including the type and volume of extraction and dispersive solvents, centrifugation, salt addition and extraction time, were studied. The proposed DLLME-TLC method was successfully applied to the determination of estradiol in real human urine samples. PMID- 29993101 TI - Capsicum annuum Fruit Extract: A Novel Reducing Agent for the Green Synthesis of ZnO Nanoparticles and Their Multifunctional Applications. AB - A simple, efficient and convenient method for the preparation of zinc oxide (ZnO) nanoparticle was described. Several parameters like size and morphology of the prepared nanoparticles were characterized thorough a variety of analytical techniques such as XRD, FT-IR, UV-Vis, SEM, and EDX. The prepared ZnO nanoparticles were successfully used as catalyst for the formylation of amino acid esters and biodiesel synthesis. Further, the synthesized formamide esters were well characterized through HRMS, 1H NMR and 13C NMR analysis and subjected for the in vitro antibacterial and antifungal tests and the results indicated that some of them showed promising activity against targeted bacterial pathogens. PMID- 29993102 TI - Interaction Between the Rubidium Cation and [2.2.2]Paracyclophane: Experimental and Theoretical Study. AB - By means of electrospray ionization mass spectrometry (ESI-MS), it was evidenced experimentally that the rubidium cation (Rb+) reacts with the electroneutral [2.2.2]paracyclophane ligand (C24H24) to form the cationic complex [Rb(C24H24)]+. Moreover, applying quantum chemical calculations, the most probable conformation of the proven [Rb(C24H24)]+ complex was solved. In the complex [Rb(C24H24)]+ having a symmetry very close to C3, the "central" cation Rb+, fully located in the cavity of the parent [2.2.2]paracyclophane ligand, is coordinated to all three benzene rings of [2.2.2]paracyclophane via cation-pi interaction. Finally, the binding energy, E(int), of the considered cation-pi complex [Rb(C24H24)]+ was evaluated as -99.3 kJ/mol, confirming the formation of this fascinating complex species as well. This means that the [2.2.2]paracyclophane ligand can be considered as a receptor for the rubidium cation in the gas phase. PMID- 29993103 TI - Solvothermal Synthesis and Photocatalytic Activity of BiOBr Microspheres with Hierarchical Morphologies. AB - BiOBr microspheres with hierarchical morphologies (BiOBr-MicSphe) has potential application in heterogeneous photocatalysis for decontamination of water and air. For this reason, the synthesis, characterization an evaluation of photocatalytic activity of these materials become important. In this article, BiOBr-MicSphe were synthesized using different ranges of reaction temperature (120-200 degrees C) and reaction time (12 h - 24 h). Samples grown at 145 degrees C and 18 h showed the higher photocatalytic activity on gallic acid degradation. Morphological properties, chemical composition and structural analysis revealed that sample with higher photocatalytic activity exhibited a microspherical morphology with pure BiOBr tetragonal phase. Besides, adsorption-desorption analysis showed a smaller pore diameter for sample grown at 145 degrees C and 18 hrs. The results showed that the reaction temperature has a strong influence on the different properties of the material, affecting the photocatalytic activity. PMID- 29993104 TI - The Antioxidant Response System in Wheat Exposed to Pesticides and its Combined induced Oxidative Damage. AB - The aim of the present study was to analyze the alterations in the, antioxidant enzyme activities (such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and level of glutathione (GSH) and lipid peroxidation (LPO) of wheat acutely treated with CP and DM treatments at low, high doses and their combination. CP and DM were administered to wheat in different doses of 1, 1.5, 5 and 35 mg kg-1 given alone and combination. After 3 weeks, antioxidant enzyme activities, and the level of GSH and LPO were recorded and analyzed. Antioxidative defense mechanisms and LPO in wheat display different responses depending on different pesticide treatments and doses. Biochemical analysis showed that exposure of the CP and DM cause plant tissue damage. It is suggested that appropriate ecotoxicological risk assessment should be made in the areas where DM is proposed to be used in pest control when compared to CP. In the present study, we also concluded that the effect of the combined of CP and DM on the oxidative stress may be synergistic. PMID- 29993105 TI - DFT Study of the Reaction Mechanism of N-(Carbomylcarbamothioyl) Benzamide. AB - The reaction mechanism for the formation of N-(carbomylcarbamothioyl)benzamide has been successfully computed with the B3LYP/6-31g(d) functional and basis set and compared with 1H NMR monitoring of the progress of the reaction with time. The reaction is proposed to proceed through two transition states: Ts1 (the rate determining step) with highly unstable species (with a requisite orientation for the reaction to proceed), and Ts2 with a lower energy leading to the product. Computation of the reaction pathway was also carried out using the B3PW91/6 31G(d), M06/6-31G(d) and Wb97XD/6- 31G(d) functionals and basis set. These results do not present a clear reaction pathway compared to that given by the B3LYP/6-31G(d). PMID- 29993106 TI - The Accuracy of Macro-Submicro-Symbolic Language of Future Chemistry Teachers. AB - The present study is focused on the examination of language accuracy of future chemistry teachers in the macro-submicro-symbolic domain. Since the knowledge at the submicroscopic level is crucial for the understanding of chemical concepts and ideas, the aim of this study was to examine the accuracy of the language of future chemistry teachers while delivering chemical contents at this level. Within this objective, it was examined whether future chemistry teachers make a distinction between submicroscopic and macroscopic levels, as well as between submicroscopic and symbolic levels in their speech. Using qualitative methods of analysis, it was found that the majority of surveyed future chemistry teachers did not have the expected and necessary language accuracy within the examined domain. Most worrying were the attitudes of future chemistry teachers, who perceived the accurate expressions in the macro-submicro-symbolic domain as a redundant complication rather than a necessity. PMID- 29993107 TI - Possibility of C38 and Si19Ge19 Nanocages in Anode of Metal Ion Batteries: Computational Examination. AB - In this study, the potential of C38 and Si19Ge19 as anode electrodes of Li-ion, Na-ion and K-ion batteries via density functional theory was investigated. Obtained results showed that Si19Ge19 as anode electrode in metal-ion batteries has higher potential than C38 ca 0.18 V. Calculated results illustrated that K ion battery has higher cell voltage and higher performance than Li-ion and Na-ion batteries ca 0.15 and 0.31 V, respectively. Results showed that halogen adoption increased the cell voltage of studied metal-ion batteries ca 1.5-2.2 V. Results show that, Vcell values of studied metal-ion batteries in water are higher than gas phase ca 0.46 V. Finally it can be concluded that F-doped Si18Ge19 as anode electrode in K-ion battery has the highest performance and it can be proposed as novel metal-ion batteries with high performance. PMID- 29993108 TI - Solvothermal Synthesis of ZnO-Nitrogen Doped Graphene Composite and its Application as Catalyst for Photodegradation of Organic Dye Methylene Blue. AB - A facile one step solvothermal method is designed for the synthesis of visible light-sensitive ZnO-nitrogen doped graphene (ZNG) nano photocatalysts using ethylene glycol as a solvent as well as an agent to prevent aggregation of graphene layers. The deposition of ZnO nanoparticles onto the NG layers was confirmed by high resolution transmission electron microscope (HR-TEM), scanning electron microscope (SEM), powder X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). UV-Vis spectroscopy (UV-Vis) was used to study the enhanced photocatalytic activity, which shows the red-shift of the band-edge as compared to ZnO nano particles. The enhancement in photocatalytic activity is possibly due to the synergistic effect of improved adsorptivity of dyes, enhanced visible light absorption and effective charge separation. PMID- 29993109 TI - Polypropylene Blends with m-EPR Copolymers: Mechanical and Rheological Properties. AB - The effects of two metallocene ethylene-propylene-based elastomers (m-EPR1 and m EPR2) differing in molecular mass and viscosity on mechanical, rheological and interfacial properties were compared. The m-EPR elastomers were added to iPP in 2.5, 5, 10, 15, and 20 vol.%. Torque values, elongation at break and impact strength measured of the iPP/m-EPR1 blends were higher than the iPP/m-EPR2 blends due to higher molten viscosity of m-EPR1 than m-EPR2 copolymer. Slight differences in Young moduli as well as in tensile strength at yield and at break might indicate that tensile properties of iPP/m-EPR blends were not significantly affected by difference in viscosity or molecular mass, miscibility and spherulite size. Optimization diagrams indicated the metallocene m-EPR copolymers are efficient impact modifiers for polypropylene and showed good balancing of mechanical properties in iPP/m-EPR blends. PMID- 29993110 TI - Complex Formation in a Liquid-Liquid Extraction System Containing Vanadium(IV/V), 2,3-Dihydroxynaphtahlene and Thiazolyl Blue. AB - Liquid-liquid extraction systems for VIV/V containing 2,3-dihydroxynaphtahlene (DN) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (thiazolyl blue, MTT) were studied. The optimum conditions for VIV and VV extraction were found. VIV is extracted in chloroform as a 1:2:2 complex (V:DN:MTT) with lmax = 570 nm and e570 = 2.9'104 dm3 mol-1 cm-1. However, this wavelength was found unsuitable for precise spectrophotometric measurements due to time dependent absorbance changes. VV forms predominantly a 1:1:1 complex with lmax = 335 nm. The calibration graph for this oxidation state is linear in the range of 0.06-1.5 mg cm-3. The molar absorptivity, Sandell's sensitivity and limit of detection were calculated to be 1.6 ' 104 dm3 mol-1 cm-1, 3.2 ng cm-2 and 0.02 mg cm-3, respectively. The ground-state equilibrium geometries of the anionic parts of the extracted ion-associates, [VIVO(DN2-)2]2-and [VVO2(DN2-)]-, were optimized at the BLYP/6-31++G* level of theory. PMID- 29993111 TI - Synthesis, X-ray Structural Characterization, and DFT Calculations of Mononuclear Nickel(II) Complexes Containing Diamine and Methacrylate Ligands. AB - The mononuclear Ni(II) complexes [Ni(en)2(H2O)2](MAA)2 (1) and [Ni(pn)2(MAA)2] (2), where MAA, en and pn are methacrylate, ethylendiamine and 1,3 propylendiamine, respectively, have been synthesized and characterized by elemental analysis, FT-IR and UV?Vis spectroskopy. Structures of the complexes have been determined by single-crystal X-ray diffraction analyses. In the nickel(II) complexes 1 and 2 nickel(II) ion is six-coordinate and has a distorted octahedral geometry. Ni(II) is bonded to four nitrogen atoms of the two diamines and additionally to two oxygen atoms of aqua ligand in 1, and two oxygen atoms of methacrylate ligands in 2. The theoretical geometries of the studied compounds have been calculated by means of density functional theory (DFT) at the B3LYP/6 311+G(d,p)/LanL2DZ level and considering effective core potential (ECP). The comparison of the results indicates that the employed DFT method yields good agreement with experimental data. PMID- 29993112 TI - Simultaneous Sensitive Detection of Lead(II), Mercury(II) and Silver Ions Using a New Nucleic Acid-Based Fluorescence Sensor. AB - A new nucleic acid-based fluorescence sensor is reported for simultaneous detection of Pb2+, Ag+, and Hg2+ based on the specific catalytic activity of Pb2+ for a particular DNAzyme, specific regulation of Ag+ on "C-Ag+-C" complex, and stable complex formed by Hg2+ and rhodamine B isothiocyanate (RBITC). Three fluorescence dyes, aminomethylcoumarin acetic acid (AMCA), 5-carboxyfluorescein (FAM), and RBITC, were modified on the probes and served as fluorescent donors. Upon DNA interaction with these metal ions and AuNP fluorescence quenching effect on the fluorescence dyes,the fluorescencerecovery of RBITC and the fluorescencequenching of AMCA and FAM were monitored to detect Hg2+, Pb2+, and Ag+, separately, without the need of using any masking reagents. This sensor exhibited high sensitivity and selectivity. The limit of detection (LOD) is 0.48 nM for Pb2+, 0.23 nM for Ag+, and 0.17 nM for Hg2+. Finally, this sensor was successfully applied for simultaneous detection of Pb2+, Ag+, and Hg2+ in real sample. PMID- 29993113 TI - Hydrothermal Synthesis of Novel Magnetic Plate-Like Bi2O2CO3/CoFe2O4 Hybrid Nanostructures and Their Catalytic Performance for the Reduction of Some Aromatic Nitrocompounds. AB - Novel magnetically separable Bi2O2CO3/CoFe2O4 nanocomposites were fabricated by a feasible hydrothermal route. Fourier transform infrared (FT-IR) spectroscopy, X ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X ray spectroscopy (EDX), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), vibrating sample magnetometer (VSM), and N2 adsorption-desorption analysis were employed to examine the structure, morphology, particle size, phase composition, optical and magnetic properties of the as-synthesized nanocomposites. The results of the findings showed demonstrated the successful coupling of spherical CoFe2O4 nanoparticles and plate-like Bi2O2CO3 nanostructures. The catalytic performance of magnetic Bi2O2CO3/CoFe2O4 nanocamposites was evaluated in the reduction of some aromatic nitrocompounds such as nitrophenols and nitroanilines by using sodium borohydride (NaBH4) aqueous solution at room temperature. The Bi2O2CO3/CoFe2O4 nanocamposite with 30 %wt. CoFe2O4 exhibited the best performance in the reduction of aromatic nitrocompounds with 100% conversion into the corresponding amino compounds within 15-30 min with rate constant of 0.10 0.24 min-1. The effect of catalyst dosage was also investigated on the efficiency of reduction process. Furthermore, magnetic Bi2O2CO3/CoFe2O4 nanocomposite could be easily removed by an external magnet from the reaction system. PMID- 29993114 TI - Theoretical Study of Ability of Boron Nitride Nanocone to Oxidation of Sulfur Monoxide. AB - In recent years, the discovery of suitable catalyst to oxidation of sulfur monoxide (SO) in normal temperature is a major concern in the industry. In this study, in first step; the boron nitride nanocone (BNNC) with Ge were doped and the surface of Ge-BNNC by using of the O2 molecule were activated. In second step; oxidation of SO on surface of Ge-BNNC through the Langmuir Hinshelwood (LH) and Eley Rideal (ER) mechanisms was investigated. Calculated data reveal that surface of O2-Ge-BNNC oxide the SO molecule with Ge-BNNC-O-O* + SO -> Ge-BNNC-O O*-SO -> Ge-BNNC-O* + SO2 and Ge-BNNC-O* + SO -> Ge-BNNC + SO2 reactions. It can be concluded, the energy barrier of LH mechanism to oxidation of SO on Ge-BNNC is lower than ER mechanism. Finally, the Ge-BNNC is acceptable catalyst with low price and high performance to oxidation of SO in normal temperature. PMID- 29993115 TI - Type 1 diabetes mellitus induced low bone turnover in ovariectomized rats. AB - To investigate type 1 diabetes mellitus (T1DM) affecting bone remodeling in the context of menopause in female rats. The animals were subjected to either ovariectomy (OVX) which was performed to mimic postmenopausal estrogen deficiency, and/or type 1 diabetes mellitus which was established by the intra abdominal administration of 50 mg/kg streptozotocin (STZ). Single-loaded groups were the OVX group and the STZ group, while the combined group was the OVX+STZ group. Bone histomorphometry was performed on the tibial metaphysis by Micro-CT scanning. Immunohistochemistry was used to assess the activity of osteoblast and osteoclast by counteracting with antibodies against their respective specific marker enzymes. The gene expression of key molecules involved in osteoblastic and osteoclastic signaling pathways were analyzed by RT-qPCR. The results showed a significant bone volume decrease in both single-loaded groups and combined group with the combined group suffering greatest bone loss and bone structural deterioration (p<0.001). Immunohistochemical staining and RT-qPCR revealed an increase in osteoblastic (p<0.001) and osteoclastic (p<0.01) activities in OVX rats while there was a decrease (p<0.05) in those of STZ rats. When OVX and STZ were combined, the rats exhibited a further decrease in osteoblastic activity (p<0.001) and a similar level of osteoclastic activity (p>0.05) compared to their STZ counterparts. These results demonstrated that STZ-induced T1DM reverses OVX associated high bone turnover osteoporosis to the type of low bone turnover, leading to greater bone loss and structural defect. PMID- 29993116 TI - CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms are associated with heavy smoking, lung cancer, and chronic obstructive pulmonary disease in a mexican population. AB - BACKGROUND AND PURPOSE: Smoking is a major public health problem worldwide. Polymorphisms in CHRNA3, CHRNA5, and CHRNB4 receptors play a critical role in nicotine dependence, lung cancer (LC) risk, and chronic obstructive pulmonary disease (COPD). This study characterized the CHRNA3 rs1051730 and CHRNA5 rs16969968 polymorphisms in a Mexican population and its association with nicotine dependence, LC, and COPD. METHODS: The study included 312 healthy individuals, 74 LC cases and 117 COPD cases. Genotyping was performed using TaqMan probes, and the data were analyzed using logistic regression adjusted for covariates. RESULTS: The polymorphism CHRNA3 rs1051730 and CHRNA5 rs16969968 were in the Hardy-Weinberg equilibrium and the allelic frequency of the A allele was 0.15, for both polymorphisms. The smokers were stratified in heavy smokers and moderate/light smokers, and we found in A alleles an OR = 2.86 (P = 0.01) to CHRNA3 rs1051730 and OR = 3.12 (P = 0.03) to CHRNA5 rs16969968. In addition, the A alleles in CHRNA3 rs1051730 and CHRNA5 rs16969968 were associated with the risk for LC (OR = 1.66, P = 0.07 and OR = 1.57, P = 0.1, respectively) and for COPD (OR = 2.04, P = 0.01 and OR = 1.91, P = 0.02, respectively). CONCLUSION: CHRNA3/5 polymorphisms are associated with nicotine dependence, LC, and COPD in Mexicans. PMID- 29993117 TI - Anticoagulation for perioperative thromboprophylaxis in people with cancer. AB - BACKGROUND: The choice of the appropriate perioperative thromboprophylaxis for people with cancer depends on the relative benefits and harms of different anticoagulants. OBJECTIVES: To systematically review the evidence for the relative efficacy and safety of anticoagulants for perioperative thromboprophylaxis in people with cancer. SEARCH METHODS: This update of the systematic review was based on the findings of a comprehensive literature search conducted on 14 June 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL, 2018, Issue 6), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) that enrolled people with cancer undergoing a surgical intervention and assessed the effects of low-molecular weight heparin (LMWH) to unfractionated heparin (UFH) or to fondaparinux on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, and thrombocytopenia. DATA COLLECTION AND ANALYSIS: Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interest included all-cause mortality, PE, symptomatic venous thromboembolism (VTE), asymptomatic DVT, major bleeding, minor bleeding, postphlebitic syndrome, health related quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook). MAIN RESULTS: Of 7670 identified unique citations, we included 20 RCTs with 9771 randomized people with cancer receiving preoperative prophylactic anticoagulation. We identified seven reports for seven new RCTs for this update.The meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.63 to 1.07; risk difference (RD) 9 fewer per 1000, 95% CI 19 fewer to 4 more; moderate-certainty evidence), PE (RR 0.49, 95% CI 0.17 to 1.47; RD 3 fewer per 1000, 95% CI 5 fewer to 3 more; moderate-certainty evidence), symptomatic DVT (RR 0.67, 95% CI 0.27 to 1.69; RD 3 fewer per 1000, 95% CI 7 fewer to 7 more; moderate-certainty evidence), asymptomatic DVT (RR 0.86, 95% CI 0.71 to 1.05; RD 11 fewer per 1000, 95% CI 23 fewer to 4 more; low-certainty evidence), major bleeding (RR 1.01, 95% CI 0.69 to 1.48; RD 0 fewer per 1000, 95% CI 10 fewer to 15 more; moderate-certainty evidence), minor bleeding (RR 1.01, 95% CI 0.76 to 1.33; RD 1 more per 1000, 95% CI 34 fewer to 47 more; moderate-certainty evidence), reoperation for bleeding (RR 0.93, 95% CI 0.57 to 1.50; RD 4 fewer per 1000, 95% CI 22 fewer to 26 more; moderate-certainty evidence), intraoperative transfusion (mean difference (MD) 35.36 mL, 95% CI -253.19 to 182.47; low-certainty evidence), postoperative transfusion (MD 190.03 mL, 95% CI -23.65 to 403.72; low-certainty evidence), and thrombocytopenia (RR 3.07, 95% CI 0.32 to 29.33; RD 6 more per 1000, 95% CI 2 fewer to 82 more; moderate-certainty evidence). LMWH was associated with lower incidence of wound hematoma (RR 0.70, 95% CI 0.54 to 0.92; RD 26 fewer per 1000, 95% CI 39 fewer to 7 fewer; moderate-certainty evidence). The meta-analyses found the following additional results: outcomes intraoperative blood loss (MD -6.75 mL, 95% CI -85.49 to 71.99; moderate-certainty evidence); and postoperative drain volume (MD 30.18 mL, 95% CI -36.26 to 96.62; moderate-certainty evidence).In addition, the meta-analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with Fondaparinux for the following outcomes: any VTE (DVT or PE, or both; RR 2.51, 95% CI 0.89 to 7.03; RD 57 more per 1000, 95% CI 4 fewer to 228 more; low-certainty evidence), major bleeding (RR 0.74, 95% CI 0.45 to 1.23; RD 8 fewer per 1000, 95% CI 16 fewer to 7 more; low-certainty evidence), minor bleeding (RR 0.83, 95% CI 0.34 to 2.05; RD 8fewer per 1000, 95% CI 33 fewer to 52 more; low-certainty evidence), thrombocytopenia (RR 0.35, 95% CI 0.04 to 3.30; RD 14 fewer per 1000, 95% CI 20 fewer to 48 more; low-certainty evidence), any PE (RR 3.13, 95% CI 0.13 to 74.64; RD 2 more per 1000, 95% CI 1 fewer to 78 more; low-certainty evidence) and postoperative drain volume (MD 20.00 mL, 95% CI -114.34 to 74.34; low-certainty evidence) AUTHORS' CONCLUSIONS: We found no difference between perioperative thromboprophylaxis with LMWH versus UFH and LMWH compared with fondaparinux in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in people with cancer. There was a lower incidence of wound hematoma with LMWH compared to UFH. PMID- 29993118 TI - An approach to estimate bidirectional mediation effects with application to body mass index and fasting glucose. AB - Obesity and type 2 diabetes are major public health issues with known interdependence. Genetic variants have been associated with obesity, type 2 diabetes, or both; thus, we hypothesize that some single nucleotide polymorphisms (SNPs) associated with both conditions may be mediated through obesity to affect type 2 diabetes or vice versa. We propose a framework for bidirectional mediation analyses. Simulations show that this approach accurately estimates the parameters, whether the mediation is unidirectional or bidirectional. In many scenarios, when the mediator is regressed on the initial variable and the outcome is regressed on the mediator and the initial variable, the resulting residuals are correlated because of other unmeasured covariates not in the model. We show that the proposed model provides accurate estimates in this scenario, too. We applied the proposed approach to investigate the mediating effects of SNPs associated with type 2 diabetes and obesity using genetic data from the Multi Ethnic Study of Atherosclerosis cohort. Specifically, we used body mass index (BMI) as a measure for obesity and fasting glucose as a measure for type 2 diabetes. We evaluated the top 6 SNPs associated with both BMI and fasting glucose. Two SNPs (rs3752355 and rs6087982) had indirect effects on BMI mediated through fasting glucose [0.2677; 95% confidence interval (CI) (0.0007, 0.6548) and 0.3301; 95% CI (0.0881, 0.8544), respectively]. The remaining four SNPs (rs7969190, rs4869710, rs10201400, and rs12421620) directly affect BMI and fasting glucose without mediating effects. PMID- 29993119 TI - Mirror therapy for improving motor function after stroke. AB - BACKGROUND: Mirror therapy is used to improve motor function after stroke. During mirror therapy, a mirror is placed in the person's midsagittal plane, thus reflecting movements of the non-paretic side as if it were the affected side. OBJECTIVES: To summarise the effectiveness of mirror therapy compared with no treatment, placebo or sham therapy, or other treatments for improving motor function and motor impairment after stroke. We also aimed to assess the effects of mirror therapy on activities of daily living, pain, and visuospatial neglect. SEARCH METHODS: We searched the Cochrane Stroke Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, AMED, PsycINFO and PEDro (last searched 16 August 2017). We also handsearched relevant conference proceedings, trials and research registers, checked reference lists, and contacted trialists, researchers and experts in our field of study. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and randomised cross-over trials comparing mirror therapy with any control intervention for people after stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials based on the inclusion criteria, documented the methodological quality, assessed risks of bias in the included studies, and extracted data. We assessed the quality of the evidence using the GRADE approach. We analysed the results as standardised mean differences (SMDs) or mean differences (MDs) for continuous variables, and as odds ratios (ORs) for dichotomous variables. MAIN RESULTS: We included 62 studies with a total of 1982 participants that compared mirror therapy with other interventions. Of these, 57 were randomised controlled trials and five randomised cross-over trials. Participants had a mean age of 59 years (30 to 73 years). Mirror therapy was provided three to seven times a week, between 15 and 60 minutes for each session for two to eight weeks (on average five times a week, 30 minutes a session for four weeks).When compared with all other interventions, we found moderate-quality evidence that mirror therapy has a significant positive effect on motor function (SMD 0.47, 95% CI 0.27 to 0.67; 1173 participants; 36 studies) and motor impairment (SMD 0.49, 95% CI 0.32 to 0.66; 1292 participants; 39 studies). However, effects on motor function are influenced by the type of control intervention. Additionally, based on moderate-quality evidence, mirror therapy may improve activities of daily living (SMD 0.48, 95% CI 0.30 to 0.65; 622 participants; 19 studies). We found low-quality evidence for a significant positive effect on pain (SMD -0.89, 95% CI -1.67 to -0.11; 248 participants; 6 studies) and no clear effect for improving visuospatial neglect (SMD 1.06, 95% CI -0.10 to 2.23; 175 participants; 5 studies). No adverse effects were reported. AUTHORS' CONCLUSIONS: The results indicate evidence for the effectiveness of mirror therapy for improving upper extremity motor function, motor impairment, activities of daily living, and pain, at least as an adjunct to conventional rehabilitation for people after stroke. Major limitations are small sample sizes and lack of reporting of methodological details, resulting in uncertain evidence quality. PMID- 29993120 TI - Extent of lymph node dissection in patients with gallbladder cancer. AB - BACKGROUND: Definitions of regional lymph nodes for gallbladder cancer differ according to staging system. Hence, the appropriate extent of lymph node dissection has not yet been standardized. METHODS: Pathological stages and disease-specific survival (DSS) of patients who had undergone surgical resection of gallbladder cancer between 1990 and 2016 were reviewed. Patients with nodal metastases limited to the hepatoduodenal ligament or common hepatic artery, extending to the posterosuperior pancreatic head lymph nodes (PSPLNs), or in nodes along the coeliac axis or superior mesenteric vessels were grouped as having Na, Nb and Nc disease respectively. Metastases beyond these regions were defined as distant metastases (M1). Absence of distant metastasis was expressed as M0. RESULTS: A total of 259 patients were evaluated. There were 74, 31 and nine patients respectively in the Na, Nb and Nc groups. Twenty-five, nine and four patients in the respective groups had M1 disease (P = 0.682). The 5-year DSS rate was comparable between patients with Na M0 and those with Nb M0 disease (36 versus 34 per cent respectively; P = 0.950), whereas the rate in patients with Nc M0 status (0 per cent) was worse than that of patients with Nb M0 (P = 0.017) and comparable to that of patients with M1 disease (14 per cent; P = 0.590). Among 22 patients with Nb M0 disease, the 5-year DSS rate did not differ between those who had undergone pancreatoduodenectomy and those who had had dissection of PSPLNs without pancreatoduodenectomy (50 versus 30 per cent respectively; P = 0.499). CONCLUSION: PSPLNs and nodes along the hepatoduodenal ligament and hepatic artery should be considered regional nodes for gallbladder cancer, and should be resected. PMID- 29993121 TI - Pemphigus foliaceus associated with imatinib therapy in a patient with gastrointestinal stromal tumor. PMID- 29993122 TI - Regulation of synaptic release-site Ca2+ channel coupling as a mechanism to control release probability and short-term plasticity. AB - Synaptic transmission relies on the rapid fusion of neurotransmitter-containing synaptic vesicles (SVs), which happens in response to action potential (AP) induced Ca2+ influx at active zones (AZs). A highly conserved molecular machinery cooperates at SV-release sites to mediate SV plasma membrane attachment and maturation, Ca2+ sensing, and membrane fusion. Despite this high degree of conservation, synapses - even within the same organism, organ or neuron - are highly diverse regarding the probability of APs to trigger SV fusion. Additionally, repetitive activation can lead to either strengthening or weakening of transmission. In this review, we discuss mechanisms controlling release probability and this short-term plasticity. We argue that an important layer of control is exerted by evolutionarily conserved AZ scaffolding proteins, which determine the coupling distance between SV fusion sites and voltage-gated Ca2+ channels (VGCC) and, thereby, shape synapse-specific input/output behaviors. We propose that AZ-scaffold modifications may occur to adapt the coupling distance during synapse maturation and plastic regulation of synapse strength. PMID- 29993123 TI - Characterization and synergistic action of a tetra-modular lytic polysaccharide monooxygenase from Bacillus cereus. AB - Lytic polysaccharide monooxygenases (LPMOs) contribute to enzymatic conversion of recalcitrant polysaccharides such as chitin and cellulose and may also play a role in bacterial infections. Some LPMOs are multimodular, the implications of which remain only partly understood. We have studied the properties of a tetra modular LPMO from the food poisoning bacterium Bacillus cereus (named BcLPMO10A). We show that BcLPMO10A, comprising an LPMO domain, two fibronectin-type III (FnIII)-like domains, and a carbohydrate-binding module (CBM5), is a powerful chitin-active LPMO. While the role of the FnIII domains remains unclear, we show that enzyme functionality strongly depends on the CBM5, which, by promoting substrate binding, protects the enzyme from inactivation. BcLPMO10A enhances the activity of chitinases during the degradation of alpha-chitin. PMID- 29993124 TI - Stabilizing selection, mutational bias, and the evolution of sex. AB - Stabilizing selection around a fixed phenotypic optimum is expected to disfavor sexual reproduction, since asexually reproducing organisms can maintain a higher fitness at equilibrium, while sex disrupts combinations of compensatory mutations. This conclusion rests on the assumption that mutational effects on phenotypic traits are unbiased, that is, mutation does not tend to push phenotypes in any particular direction. In this article, we consider a model of stabilizing selection acting on an arbitrary number of polygenic traits coded by bialellic loci, and show that mutational bias may greatly reduce the mean fitness of asexual populations compared with sexual ones in regimes where mutations have weak to moderate fitness effects. Indeed, mutation and drift tend to push the population mean phenotype away from the optimum, this effect being enhanced by the low effective population size of asexual populations. In a second part, we present results from individual-based simulations showing that positive rates of sex are favored when mutational bias is present, while the population evolves toward complete asexuality in the absence of bias. We also present analytical (QLE) approximations for the selective forces acting on sex in terms of the effect of sex on the mean and variance in fitness among offspring. PMID- 29993125 TI - Best-practice care pathway for improving management of mastitis and breast abscess. AB - BACKGROUND: Surgical subspecialization has resulted in mastitis and breast abscesses being managed with unnecessary admission to hospital, prolonged inpatient stay, variable antibiotic prescribing, incision and drainage rather than percutaneous aspiration, and loss to specialist follow-up. The objective was to evaluate a best-practice algorithm with the aim of improving management of mastitis and breast abscesses across a multisite NHS Trust. The focus was on uniformity of antibiotic prescribing, ultrasound assessment, admission rates, length of hospital stay, intervention by aspiration or incision and drainage, and specialist follow-up. METHODS: Management was initially evaluated in a retrospective cohort (phase I) and subsequently compared with that in two prospective cohorts after introduction of a breast abscess and mastitis pathway. One prospective cohort was analysed immediately after introduction of the pathway (phase II), and the second was used to assess the sustainability of the quality improvements (phase III). The overall impact of the pathway was assessed by comparing data from phase I with combined data from phases II and III; results from phases II and III were compared to judge sustainability. RESULTS: Fifty three patients were included in phase I, 61 in phase II and 80 in phase III. The management pathway and referral pro forma improved compliance with antibiotic guidelines from 34 per cent to 58.2 per cent overall (phases II and III) after implementation (P = 0.003). The improvement was maintained between phases II and III (54 and 61 per cent respectively; P = 0.684). Ultrasound assessment increased from 38 to 77.3 per cent overall (P < 0.001), in a sustained manner (75 and 79 per cent in phases II and III respectively; P = 0.894). Reductions in rates of incision and drainage (from 8 to 0.7 per cent overall; P = 0.007) were maintained (0 per cent in phase II versus 1 per cent in phase III; P = 0.381). Specialist follow-up improved consistently from 43 to 95.7 per cent overall (P < 0.001), 92 per cent in phase II and 99 per cent in phase III (P = 0.120). Rates of hospital admission and median length of stay were not significantly reduced after implementation of the pathway. CONCLUSION: A standardized approach to mastitis and breast abscess reduced undesirable practice variation, with sustained improvements in process and patient outcomes. PMID- 29993126 TI - Eccrine hamartoma with spectrum of histologic findings associated with limb deformity. PMID- 29993128 TI - Reaching for the stars: Iranian nurses' perceptions of career success. AB - AIM: The aim was to explore nurses' perceptions of career success. INTRODUCTION: Career success is a concept which leads to improving professional behaviours. Research that focused on conceptualizing career success found it to be a complex, value-driven construct likely to be perceived differently across work and cultural contexts. It is not yet clear what constitutes career success, and how it is perceived by nurses in Iran. More comprehensive exploration of this concept in nursing is needed, so research and policymaking can advance in informed, data driven manner. METHOD: This is a qualitative descriptive study. The setting was teaching hospitals of Iran. Twenty-seven nurses participated in face-to-face interviews, and six field notes were collected. Data were analysed using conventional content analysis. FINDINGS: Analyses identified five themes of career success: providing high-quality care, being exemplary employee, embarking on career growth, having positive personal attributes and being internally satisfied. CONCLUSION: Findings confirmed that career success in Iranian nurses was a multidimensional concept that represented five internally and externally driven dimensions set within its cultural and religious context. Policymakers and clinical educators can now plan interventions aimed at fostering career success in nursing staff. IMPLICATIONS FOR EDUCATION, NURSING AND HEALTH POLICIES: Future nurses could use these finding to reflect on their developed attributes throughout their studies and clinical placements and adjust their career preparation and learning to bridge any identified gaps. Organizational values and intervention for nursing staff could also be redesigned to align with the aspects of career success. PMID- 29993127 TI - Biochemical and structural insights into an allelic variant causing the lysosomal storage disorder - aspartylglucosaminuria. AB - : Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by defects of the hydrolase glycosylasparaginase (GA). Previously, we showed that a Canadian AGU mutation disrupts an obligatory intramolecular autoprocessing with the enzyme trapped as an inactive precursor. Here, we report biochemical and structural characterizations of a model enzyme corresponding to a Finnish AGU allele, the T234I variant. Unlike the Canadian counterpart, the Finnish variant is capable of a slow autoprocessing to generate detectible hydrolyzation activity of the natural substrate of GA. We have determined a 1.6 A-resolution structure of the Finnish AGU model and built an enzyme-substrate complex to provide a structural basis for analyzing the negative effects of the point mutation on KM and kcat of the mature enzyme. ENZYME: Glycosylasparaginase or aspartylglucosaminidase, EC3.5.1.26. PMID- 29993129 TI - Paraffinoma, siliconoma and Co: Disastrous consequences of failed penile augmentation-A single-centre successful surgical management of a challenging entity. AB - The purpose of this study was to present our series of patients with disastrous consequences of failed penile self-augmentation and suggested surgical reconstruction. Ten patients with median age of 23 years and a variety of penile and scrotal deformities due to injections of several substances had undergone successful surgical reconstruction of external genitalia. The injections were self-performed in nine cases and the patients reported from 4 to 20 substance injections throughout the penile shaft. Three patients presented with fibrotic scirrhous masses in their scrotum, although they did not report any injections in scrotal area. All patients underwent extended penile-shaft skin excision, while all palpable scrotal lesions were removed in one-by-one fashion, as an attempt to destroy the less possible scrotal tissue. All patients were discharged on first post-operative day and reassessed at 2 months post-operatively. As a result, penile self-augmentation with injected substances may cause severe complications. Our proposed single-staged procedure seems safe and effective. PMID- 29993130 TI - A comparative study of various modalities in the treatment of keloids. AB - INTRODUCTION: Treatment of keloids is a challenge as a result of paucity of effective treatment modalities, significant side effects, and their recurrent nature. In this study, various treatment modalities were compared to search for a treatment option with maximum efficacy and minimum side effects. METHODS: One hundred patients were recruited into five treatment groups of 20 patients in each. Intralesional triamcinolone acetonide, intralesional triamcinolone acetonide with hyaluronidase, intralesional verapamil hydrochloride, intralesional radiofrequency, and intralesional radiofrequency with triamcinolone acetonide were the different modalities received. The treatment in groups 1, 2, and 3 were given at 3-week intervals for 8 times or till complete flattening, whichever was earlier. In groups 4 and 5, treatment was given at six weekly intervals for 4 times or till complete flattening. For statistical comparison, all patients were followed up at three weekly intervals. RESULTS: In total, 16, 16, 15, 17, and 16 patients completed the study in groups 1, 2, 3, 4, and 5, respectively. Treatment modalities in groups 1, 2, and 5 were more or less equally efficacious with clearance rate of 75, 68.75, and 75% respectively, whereas groups 3 and 4 had clearance rate of 0 and 11.76%, respectively (P value <0.01, Chi-square test). CONCLUSION: Intralesional triamcinolone acetonide, intralesional triamcinolone acetonide with hyaluronidase, and intralesional radiofrequency with triamcinolone acetonide are effective modalities for the treatment of keloids. However, intralesional triamcinolone acetonide with hyaluronidase fares better than other two as far as safety is concerned with least side effects. PMID- 29993131 TI - Effect of adjuvant drug therapy after varicocelectomy on fertility outcome in males with varicocele-associated infertility: Systematic review and meta analysis. AB - Varicocele is one of the common correctable causes of male infertility. Recent studies have demonstrated varicocelectomy in males with abnormal semen parameters was associated with better fertility outcome, but the effect of adjuvant drug therapy after varicocelectomy on fertility outcome in patients with varicocele associated infertility remains undefined. Hence, the present meta-analysis was performed to assess the efficacy of adjuvant drug therapy after varicocelectomy. The protocol was registered with PROSPERO (No. CRD42018093749). Ten randomised controlled trails containing 533 patients with adjuvant drug therapy after varicocelectomy and 368 patients with no medical treatment after varicocelectomy were included. Our analysis revealed that the improvement in pregnancy rate after adjuvant drug therapy was insignificant. (OR = 1.70, 95%CI = 0.99-2.91), but resulted in significant improvements in sperm concentration (MD = 13.71, 95%CI = 5.80-21.63) and motility (MD = 4.77, 95%CI = 3.98-5.56) at 3 months, sperm DNA integrity (SMD = 3.13, 95%CI = 1.50-4.75) and serum FSH level (MD = -1.02, 95%CI = -1.79 to -0.24). Therefore, compared to no medical treatment, the adjuvant drug therapy, especially the use of antioxidants seems to be associated with better fertility outcome. However, more evidences with high-quality studies are necessary to conform its benefits. PMID- 29993132 TI - Cross-group friendships and psychological well-being: A dual pathway through social integration and empowerment. AB - This study investigated the associations between cross-group friendships and psychological well-being among a sample of physically disabled adults. A total of 269 disabled people (Mage = 39.13, SD = 13.80; 114 females, 152 males, 3 unknown) completed questionnaires including the quality of their friendships with non-disabled people, perceived majority group's attitudes towards the minority group, collective self-esteem, collective action tendencies, own outgroup attitudes, and psychological well-being. Findings demonstrated that disabled people's cross-group friendships were directly and indirectly associated with higher levels of psychological well-being via two routes: one by promoting perceived majority attitudes which consequently led to more positive own outgroup attitudes (well-being through social integration hypothesis) and the other by leading to higher levels of collective self-esteem which enhanced collective action tendencies (well-being through empowerment hypothesis). Findings offer important insights into the study of cross-group friendships in relation to the psychological well-being of stigmatized minority group members. PMID- 29993133 TI - Pharmacokinetics of Sijunzi decoction in rat plasma after oral administration using ultra-high-performance liquid chromatography electrospray ionization quadrupole-time of flight mass spectrometry. AB - Sijunzi decoction (SJZD) is one of the most well-known traditional Chinese herbal formulations. This study elucidates the pharmacokinetics of SJZD in rat plasma after the administration of a single oral dose of 3 mL/kg using ultra-high performance liquid chromatography electrospray ionization quadrupole-time of flight mass spectrometry (UHPLC-ESI-Q-TOF/MS) with bergapten as an internal standard. The separation was performed on an Agilent Zorbax Eclipse Plus C18 column (2.1 * 50 mm, 1.8 MUm) by elution with acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.3 mL/min. Electrospray ionization in positive and negative ion modes was used to quantify six compounds, with monitored ion m/z values of 249.1397 [M + H]+ and 529.3857 [M + H]+ for atractylenolide III (ATL-III) and pachymic acid (PA), respectively, and m/z of 1107.6638 [M - H]- , 991.5746 [M - H + HCOO]- , 821.3714 [M - H]- , 469.3315 [M - H]- for ginsenoside Rb1, Re, glycyrrhizic acid (GL), and glycyrrhetinic acid (GA), respectively. The calibration curves for ginsenoside Rb1 , Re, ATL-III, PA, GL and GA were 0.0015-0.75, 0.001-0.5, 0.0004-0.2, 0.003-0.9, 0.0015-0.3 and 0.001-1.5 MUg/mL, respectively. The intra- and inter-day precisions (RSD) were <14.3%. The rapid, sensitive and specific UHPLC-ESI-Q-TOF/MS method developed and validated in this study was successfully applied to the simultaneous determination of the six components of SJZD using rat plasma for pharmacokinetic studies after oral administration. PMID- 29993134 TI - Exploring the putative role of kallikrein-6, calpain-1 and cathepsin-D in the proteolytic degradation of alpha-synuclein in multiple system atrophy. AB - AIMS: There is evidence that accumulation of alpha-synuclein (alpha-syn) in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) results from impaired removal of alpha-syn rather than its overproduction. Kallikrein-6 (KLK6), calpain-1 (CAPN1) and cathepsin-D (CTSD) are among a small number of proteases that cleave alpha-syn and are dysregulated in PD and DLB. Our aim in this study was to determine whether protease activity is altered in another alpha synucleinopathy, multiple system atrophy (MSA), and might thereby modulate the regional distribution of alpha-syn accumulation. METHODS: mRNA and protein level and/or activity of KLK6, CAPN1 and CTSD were measured and assessed in relation to alpha-syn load in multiple brain regions (posterior frontal cortex, caudate nucleus, putamen, occipital cortex, pontine base and cerebellar white matter), in MSA (n = 20) and age-matched postmortem control tissue (n = 20). RESULTS: CTSD activity was elevated in MSA in the pontine base and cerebellar white matter. KLK6 and CAPN1 levels were elevated in MSA in the putamen and cerebellar white matter. However, the activity or level of these proteolytic enzymes did not correlate with the regional distribution of alpha-syn. CONCLUSIONS: Accumulation of alpha-syn in MSA is not due to reduced activity of the proteases we have studied. We suggest that their upregulation is likely to be a compensatory response to increased alpha-syn in MSA. PMID- 29993135 TI - Erratum. PMID- 29993136 TI - Genetic diversity, population structure and phylogenetic relationships of three indigenous pig breeds from Jiangxi Province, China, in a worldwide panel of pigs. AB - Dongxiang Spotted, Pingxiang Two-End-Black and Yushan Black pigs are three indigenous breeds in Jiangxi Province, China, that have been listed in the national conservation program for Chinese indigenous livestock germplasm. Here, we investigated the genetic diversity and population structure of the nucleus populations of these three breeds in a worldwide context of European and Chinese pigs using Illumina Porcine 60K chips. Our data indicate that Dongxiang Spotted and Yushan Black pigs have recently experienced severe inbreeding. The two breeds show large runs-of-homozygosity values, long-range extents of linkage disequilibrium and reduced observed heterozygosity. In contrast, Pingxiang Two End-Black pigs are rich in genetic diversity and have few inbred individuals. Both phylogenetic and admixture analyses illustrate that Dongxiang Spotted and Yushan Black pigs are genetically close to their geographical neighbors in East China and that Pingxiang Two-End-Black pigs have a close relationship with three other Two-End-Black breeds in central China. Finally, we reconstructed the family structures of the three breeds and propose a reliable breeding strategy to better conserve these breeds. PMID- 29993137 TI - Comorbidity of mental illness and chronic physical illness: A diagnostic and treatment conundrum. PMID- 29993138 TI - Overexpression of Fra-1, c-Jun and c-Fos in odontogenic keratocysts: potential correlation with proliferative and anti-apoptotic activity. AB - AIMS: The purpose of this study was to explore the potential involvement of Fra 1, c-Jun and c-Fos, three vital members of the AP-1 complex, in the pathogenesis of odontogenic keratocysts (OKCs). METHODS AND RESULTS: Tissue samples, containing 10 normal oral mucosa (OM), 10 dentigerous cysts (DC) and 32 OKC specimens, were applied to investigate the expression levels of Fra-1, c-Jun and c-Fos by immunohistochemistry and real-time-quantitative polymerase chain reaction (RT-qPCR). The association between Fra-1, c-Jun and c-Fos expression levels and markers of proliferation [Ki-67, proliferating cell nuclear antigen (PCNA)], anti-apoptosis (Bcl-2) was then investigated in the OKC serial tissue sections. The results showed that Fra-1, c-Jun and c-Fos expression levels were increased significantly in OKCs compared to these in OM and DC tissue samples. Meanwhile, the expression levels of Fra-1, c-Jun and c-Fos were associated positively with the expression levels of Ki-67, PCNA and Bcl-2, as confirmed further by double-labelling immunofluorescence analysis and hierarchical analysis. CONCLUSIONS: This study revealed for the first time that Fra-1, c-Jun and c-Fos were overexpressed in OKCs and had a close correlation with proliferation and anti-apoptosis potential of OKCs. PMID- 29993139 TI - The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases. AB - AIMS: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. METHODS AND RESULTS: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (>=20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). CONCLUSIONS: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC. PMID- 29993140 TI - Oral health status of long-term care residents in Canada: Results of a national cross-sectional study. AB - OBJECTIVE: To describe the oral health and oral prosthetic status of long-term care residents in four Canadian provinces. BACKGROUND: Oral health can have significant impact on the health and quality of life of older adults. Seniors in long-term care are highly dependent on care staff for basic activities of daily living and are at risk for poor oral health. MATERIALS AND METHODS: Five hundred and fifty-nine randomly selected residents were examined from thirty-two long term care homes in Alberta, Manitoba, Ontario and New Brunswick, Canada. Four experienced registered dental hygienists, one in each province, completed a standardised oral health examination with each participant, examining lip health, breath odour, saliva appearance, natural teeth count, gingival inflammation, tooth and jaw pain, denture status, mucosal status and oral health abnormalities. RESULTS: Of the examined residents, 57.6% were dentate, with an average of 16.4 (SD = 8.0) teeth. Most dentate residents had moderate or severe inflammation on at least one tooth (79.6%). Sixty per cent of residents wore dentures, and 43.2% of edentulous residents had poor hygiene of their dentures. Nine per cent of residents required urgent dental treatment for oral health problems such as broken teeth, infection, severe decay and ulcers. CONCLUSION: This study provides an estimate of the prevalence of oral health problems in residents living in long term care homes across Canada and indicates that improvement in oral health care is needed. Future work on development strategies aimed at optimising oral health for long-term care residents is required. PMID- 29993141 TI - Feed and reproductive efficiency differences between divergently selected lines for birthweight environmental variability in mice. AB - Sustainability has come to play an important role in agricultural production. A way to combine efficiency with sustainability might be by searching for robust animals that can be selected for the homogeneity of certain traits. Furthermore, the optimization of feed efficiency is one of the challenges to improve livestock genetics programmes, but this might compromise reproductive efficiency. Animals from two divergent mouse lines, regarding variability of birthweight, were used to check whether homogeneity was also related to both feed and reproductive efficiency. The objective of this study was to use these divergent lines of mice to compare them with their feed efficiency and the reproductive capacity. Animal weight, weight gain, feed intake, relative intake and cumulated transformation index were considered as feed efficiency traits. Animals from the low line had both lower weight and feed intake from 21 to 56 days. They had a worse transforming index in the three last weeks when litter size was fitted as an effect of the model, but the lines become similar if the higher litter size of the low line was not included. Reproductively, the low line performed better considering the number of females having parturitions, the number of parturitions, and with higher litter size and survival in both parturitions. Hence, the low variability line was preferred because of reproductive efficiency without seriously affecting its feed efficiency. Homogeneity seemed to be related to robustness with similar feed efficiency but higher reproductive efficiency. PMID- 29993142 TI - Synovial GATA1 mediates rheumatoid arthritis progression via transcriptional activation of NOS2 signaling. AB - Transcriptional regulation of inducible nitric oxide synthase (iNOS) is critically involved in the pathogenesis and progression of rheumatoid arthritis (RA); however, the specific transcription factors that control this process remain largely unidentified. In the present study, it was discovered that expression of the key erythroid factor, globin transcription factor 1 (GATA1), is significantly greater in human RA synovial tissues than in osteoarthritis (OA) tissues. IL 6 was found to induce synovial GATA1 expression in a signal transducer and activator of transcription 3-dependent manner. Functionally, knockdown of GATA1 expression using specific small interfering RNA treatment was found to compromise immunoreaction-elicited expression of proinflammatory cytokines and thus impair invasiveness of the human fibroblast-like synovial cell line MH7A, whereas introduction of exogenous GATA1 was found to promote production of proinflammatory cytokines, leading to greater aggressiveness of MH7A cells. Mechanistically, GATA1 acts as the transcriptional coactivator of NOS2 (the gene encoding iNOS) transcription. Collectively, these data suggest that synovial GATA1 is an essential contributor to development and exacerbation of RA, presumably by inducing NOS2 transcription. PMID- 29993143 TI - Evaluation of the antinociceptive activities of several sodium channel blockers using veratrine test in mice. AB - An important role of voltage-gated sodium channels (VGSCs) in many different pain states has been established in animal models and humans wherein sodium channel blockers partially ameliorate pain. However, behavioral tests for screening analgesics that exhibit pharmacologic action by acting on VGSCs are rarely reported, and there are no studies on antinociception using veratrine as a nociceptive agent. The aim of the present study was to examine the amount of nociceptive behavior evoked by subcutaneous administration of veratrine into the hind paw and investigate whether veratrine can be used as a VGSC agonist to test the pharmacological properties of candidate analgesics via sodium channel blockade. We report for the first time that intraplantar injection of veratrine produced a reproducible nociceptive response in mice. Furthermore, several sodium channel blockers, namely carbamazepine, valproate, mexiletine, and the selective Nav1.7 inhibitor PF-04856264, but not flecainide or pilsicainide, reduced veratrine-induced nociception. In contrast, calcium channel blockers gabapentin and ethosuximide did not change veratrine-induced nociception. The veratrine test in mice might be a useful tool, at least in part, to evaluate the potential analgesic effect of sodium channel blockers. PMID- 29993144 TI - Increased risk of incident psoriasis in end-stage renal disease patients on chronic hemodialysis: A nationwide population-based cohort study. AB - Patients with end-stage renal disease (ESRD) on chronic hemodialysis (HD) experience chronic inflammation and immune dysregulation; whether these affect the development of chronic inflammatory disease such as psoriasis is unknown. We aimed to investigate the impact of ESRD on the development of psoriasis. We performed a retrospective cohort study using records between 1999 and 2013 from Taiwan's National Health Insurance Research Database. Among 74 916 patients with ESRD on chronic HD and the control group comprising 74 916 sex and age group matched patients, 165 and 81 incident psoriasis developed after a mean follow up of 2.4 and 2.9 years, respectively. The incidence rates of psoriasis in HD patients and the control group were 91.7 and 37.1 per 100 000 person-years, respectively (difference between groups, P < 0.001). HD patients had a shorter time to psoriasis diagnosis than the control group (P < 0.05). Cox proportional hazard adjustment showed the hazard ratio (HR) for psoriasis in HD patients as 2.09 (95% confidence interval [CI], 1.49-2.94; P < 0.001) than that of the control group. Younger HD patients had relatively higher risk of psoriatic development (age <60 years; adjusted HR, 3.68; 95% CI, 1.93-7.02; P < 0.001). The relative risk of psoriatic arthritis was not increased in HD patients compared with the control group. In conclusion, patients with ESRD on chronic HD had a greater risk of developing psoriasis. Physicians should be aware of the predisposition to psoriasis in patients with ESRD on chronic HD. PMID- 29993145 TI - Sensitivity of the breeding values for growth rate and worm egg count to environmental worm burden in Australian Merino sheep. AB - The objective of this study was to explore the sensitivity of breeding values for growth rate and worm egg count (WEC, cube root transformed) to environmental worm burden, measured as the average WEC for each contemporary group (CGWEC). Growth rate and WEC were measured on 7,818 naturally infected Merino lambs in eight flocks across Australia, linked through common use of AI sires. Through bivariate analysis, genetic correlations of 0.55 +/- 0.23 and 0.30 +/- 0.16 were found for growth rate and WEC between low and high CGWEC, respectively. In a second analysis, breeding values for growth rate and WEC were regressed on CGWEC with a random regression model. The heritability for growth rate varied from 0.23 to 0.16 from low to high CGWEC, and the heritability for WEC varied from 0.25 to 0.36. Results suggest that breeding values for both growth rate and WEC are sensitive to environmental worm burden. Animals expressed less genetic variation for growth rate and more genetic variation for WEC in high CGWEC than in low CGWEC. This form of genotype-by-environment interaction should therefore be considered in genetic evaluation of both growth rate and WEC, to increase the efficiency of selection for animals that are more parasite resistant and more resilient to environmental worm challenge. PMID- 29993146 TI - Comparison of efficacy of aminolaevulinic acid photodynamic therapy vs. adapalene gel plus oral doxycycline for treatment of moderate acne vulgaris-A simple, blind, randomized, and controlled trial. AB - BACKGROUND: Although progress has been made in the study of photodynamic therapy for acne, studies using current recommended therapies as active comparators are lacking. METHODS: Randomized, controlled trial involving 46 patients with moderate inflammatory facial acne, 23 patients received two sessions of PDT separated by 2 weeks (ALA 20% incubated 1.5 hours before red light irradiation with 37 J/cm2 fluence) and 23 patients received doxycycline 100 mg/d plus adapalene gel 0.1%. In both groups, from the sixth week, we started adapalene gel 0.1% as maintenance therapy until 12 weeks of follow-up. Primary end point was the reduction of acne lesions at the 6-week follow-up, which was evaluated by 2 investigators blinded to the intervention. RESULTS: The median percent reductions in noninflammatory lesion count (P = 0.013) and total lesions (P = 0.038) at 6 weeks was found to be significantly higher in the group receiving PDT. At 12 weeks there was a greater reduction of inflammatory lesions in PDT group with 84% vs. 74% for group who received doxycycline plus adapalene (P = 0.020) as well as in reducing total lesions with 79% vs. 67% respectively (P = 0.026). No severe side-effects were observed for either therapy. CONCLUSIONS: ALA-PDT offers promise as an alternative treatment for moderately severe inflammatory acne that has a higher effectiveness than the combination of doxycycline and adapalene gel in reducing noninflammatory and total lesions at 6 weeks. There were significantly superior reductions at 12 weeks in the combination of PDT group followed by adapalene gel in total, inflammatory, and noninflammatory lesions. PMID- 29993147 TI - 90 Y-ibritumomab-tiuxetan as a therapeutic alternative for follicular lymphoma (FL): A single-center experience. AB - BACKGROUND: Follicular lymphoma (FL) is the most frequent indolent lymphoma subtype in adults. Maintenance therapy with rituximab is frequently applied to FL patients with complete or partial response following initial chemoimmunotherapy. However, radioimmunotherapy with 90 Y-ibritumomab-tiuxetan represents a therapeutic alternative. METHODS: To compare the clinical and the prognostic impact of both therapies, a study collective of n = 56 patients diagnosed with indolent B-cell lymphoma was retrospectively investigated. The study collective was subdivided into two groups: n = 36 patients treated with rituximab maintenance therapy vs n = 20 patients treated with 90 Y-ibritumomab-tiuxetan. RESULTS: No prognostic differences for performance status, FLIPI score, gender, or B-symptoms were found for 90 Y-ibritumomab-tiuxetan or rituximab maintenance therapy. Overall survival rates and progression-free survival did not differ between both maintenance therapies. CONCLUSION: Our retrospective single-center analysis of two patient groups without major differences in prognostic parameters revealed similar outcome with two different maintenance therapies. Hence, 90 Y ibritumomab-tiuxetan therapy might offer a valuable alternative treatment option for FL patients with partial response. However, large prospective trials are needed to confirm the reported findings. PMID- 29993148 TI - Standardized Morinda citrifolia L. and Morinda elliptica L. leaf extracts alleviated fatigue by improving glycogen storage and lipid/carbohydrate metabolism. AB - The antifatigue properties of Morinda elliptica (ME) leaf were compared with Morinda citrifolia (MC) leaf extracts. Sixty Balb/C mice were administered (N = 10): control water, standardized green tea extract (positive control 200 mg/kg body weight [BW]), either 200 or 400 mg MC/kg BW, or either 200 or 400 mg ME/kg BW). The mice performances, biochemical, and mRNA expressions were evaluated. After 6 weeks, the weight-loaded swimming time to exhaustion in the mice consuming 400 mg MC/kg, were almost five times longer than the control mice. The gene expressions analysis suggested the extracts enhanced performance by improving lipid catabolism, carbohydrate metabolism, electron transport, antioxidant responses, energy production, and tissue glycogen stores. The MC and ME extracts enhanced stamina by reducing blood lactate and blood urea nitrogen levels, increasing liver and muscle glycogen reserve through augmenting the glucose metabolism (glucose transporter type 4 and pyruvate dehydrogenase kinase 4), lipid catabolism (acyl-Coenzyme A dehydrogenases and fatty acid translocase), antioxidant (superoxide dismutase 2) defence responses, electron transport (COX4I2), and energy production (PGC1alpha, NRF1, NRF2, cytochrome C electron transport, mitochondrial transcription factor A, UCP1, and UCP3) biomarkers. The MC (containing scopoletin and epicatechin) was better than ME (containing only scopoletin) or green tea (containing epicatechin and GT catechins) for alleviating fatigue. PMID- 29993149 TI - Satisfaction with care of hospitalised patients with advanced cancer in the Netherlands. AB - We aimed to assess the level of satisfaction with hospital care of patients with advanced cancer and its association with quality of life and other patient characteristics. Eligible patients were asked to fill out the EORTC INPATSAT-32 questionnaire, measuring patient satisfaction, and the EORTC QLQ-C15-PAL, measuring quality of life. Factor analysis was performed to identify underlying patterns in satisfaction. Multivariable regression analyses were used to assess associations of quality of life and other patient characteristics with satisfaction. A total of 105 patients participated in the study. The mean general satisfaction score was 72 (SD 21). Factor analysis identified three underlying dimensions: satisfaction with nurses (explaining 62.1% of the total variance), satisfaction with physicians (7.7%) and satisfaction with hospital services (5.3%). Associations were found between global health and general satisfaction (beta = 0.35, p = 0.01), and between emotional functioning and satisfaction with hospital services (beta = 0.016, p < 0.01). Further, diagnosis of breast cancer was associated with satisfaction with physicians (beta = 1.06, p < 0.01) and dyspnoea with satisfaction with hospital services (beta = 0.007, p = 0.03). Patients with advanced cancer are reasonably satisfied with hospital care. The INPATSAT-32 mainly measures satisfaction with nurses. Satisfaction with care and quality of life seems to represent distinct outcomes of hospital care in patients with advanced cancer. PMID- 29993150 TI - Development and preliminary testing of a brief clinical tool to enable daily monitoring of chemotherapy toxicity: The Daily Chemotherapy Toxicity self Assessment Questionnaire. AB - Close monitoring of chemotherapy toxicity can be instrumental in ensuring prompt symptom management and quality care. Our aim was to develop a brief clinical tool to enable daily assessment of chemotherapy toxicity and investigate/establish its content validity, feasibility/applicability, internal consistency and stability. Development of the Daily Chemotherapy Toxicity self-Assessment Questionnaire (DCTAQ) was based on an initial item pool created from two scoping reviews. Expert panel review (n = 15) and cognitive debriefing with patients with cancer (n = 7) were used to establish content validity. Feasibility/acceptability, applicability (self-report vs. interview-like administration), internal consistency (KR-20) and test-retest reliability (at 1-hr intervals) of the DCTAQ were field-tested with 82 patients with breast or colorectal cancer receiving active chemotherapy at eight hospitals. Initial development/content validity stages enabled item revisions and re-wording that led to a final, 11-item DCTAQ version with 10 core symptom items plus one open-ended "any other symptom" item. Feasibility and acceptability were demonstrated through the absence of participant withdrawals, absence of missing data and no complaints about tool length. The DCTAQ was found to have modest internal consistency (KR-20 = 0.56), but very good test-retest reliability. The DCTAQ is a brief clinical tool that allows for rapid and accurate daily assessments of chemotherapy toxicity in clinical practice. PMID- 29993151 TI - The Deep Sea Osmolyte Trimethylamine N-Oxide and Macromolecular Crowders Rescue the Antiparallel Conformation of the Human Telomeric G-Quadruplex from Urea and Pressure Stress. AB - Organisms are thriving in the deep sea at pressures up to the 1 kbar level, which imposes severe stress on the conformational dynamics and stability of their biomolecules. The impact of osmolytes and macromolecular crowders, mimicking intracellular conditions, on the effect of pressure on the conformational dynamics of a human telomeric G-quadruplex (G4) DNA is explored in this study employing single-molecule Forster resonance energy transfer (FRET) experiments. In neat buffer, pressurization favors the parallel/hybrid state of the G4-DNA over the antiparallel conformation at ~400 bar, finally leading to unfolding beyond 1000 bar. High-pressure NMR data support these findings. The folded topological conformers have different solvent accessible surface areas and cavity volumes, leading to different volumetric properties and hence pressure stabilities. The deep-sea osmolyte trimethylamine N-oxide (TMAO) and macromolecular crowding agents are able to effectively rescue the G4-DNA from unfolding in the whole pressure range encountered on Earth. PMID- 29993152 TI - Combination of 177 Lu-lilotomab with rituximab significantly improves the therapeutic outcome in preclinical models of non-Hodgkin's lymphoma. AB - OBJECTIVES: To investigate the therapeutic potential of the next-generation anti CD37 radioimmunoconjugate 177 Lu-lilotomab satetraxetan (177 Lu-lilotomab) in combination with the anti-CD20 antibody rituximab for treatment of mice with non Hodgkin's lymphoma (NHL) xenografts. METHODS: Nude mice with subcutaneous (s.c.) Burkitt's lymphoma Daudi xenografts and SCID mice intravenously (i.v.) injected with Mantle cell lymphoma Rec-1 cells were treated with either 177 Lu-lilotomab or rituximab alone or with the combination of both treatments. Tumour volume, body weight, blood counts and clinical status were monitored. CD20 expression was measured using flow cytometry with fluorescence-labelled rituximab. RESULTS: The combination of 177 Lu-lilotomab and rituximab was synergistic for treatment of nude mice with s.c. Daudi xenografts while it was additive for treatment of SCID mice with i.v. injected Rec-1 cells. Binding of rituximab to NHL cells in-vitro was increased by pretreatment with 177 Lu-lilotomab. CONCLUSIONS: Treatment of mice with NHL xenografts with 177 Lu-lilotomab synergistically increased tumour suppression of subsequent anti-CD20 immunotherapy and improved survival. If the same effect is confirmed in a recently started clinical study, it could change the way radioimmunotherapy and CD20 immunotherapy would be used in the future. PMID- 29993153 TI - The impact of informal leader nurses on patient satisfaction. AB - BACKGROUND: The relationship between informal leaders, i.e., highly competent individuals who have influence over peers without holding formal leadership positions, and organisational outcomes has not been adequately assessed in health care. AIMS: We evaluated the relationships between informal leaders and experience, job satisfaction and patient satisfaction, among hospital nurses. METHODS: Floor nurses in non-leadership positions participated in an online survey and rated colleagues' leadership behaviours. Nurses identified as informal leaders took an additional survey to determine their leadership styles via the Multifactor Leadership QuestionnaireTM . Six months of patient satisfaction data were linked to the nursing units. RESULTS: A total of 3,456 (91%) nurses received peer ratings and 628 (18%) were identified as informal leaders. Informal leaders had more experience (13.2 +/- 10.9 vs. 8.4 +/- 9.7 years, p < 0.001) and higher job satisfaction than their counterparts (4.8 +/- 1.2 vs. 4.5 +/- 1.1, p = 0.007). Neither the proportion of informal leaders on a unit nor leadership style was associated with patient satisfaction (p = 0.53, 0.46, respectively). CONCLUSION: While significant relationships were not detected between patient satisfaction and styles/proportion of informal leaders, we found that informal leaders had more years of experience and higher job satisfaction. More work is needed to understand the informal leaders' roles in achieving organisational outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse informal leaders are unique resources and health care organisations should utilise them for optimal outcomes. PMID- 29993154 TI - 'Always say something positive about the child' T. Berry Brazelton 1918-2018. PMID- 29993155 TI - Vibrating Sharp-edge Spray Ionization (VSSI) for voltage-free direct analysis of samples using mass spectrometry. AB - RATIONALE: The development of miniaturized and field portable mass spectrometers could not succeed without a simple, compact, and robust ionization source. Here we present a voltage-free ionization method, Vibrating Sharp-edge Spray Ionization (VSSI), which can generate a spray of liquid samples using only one standard microscope glass slide to which a piezoelectric transducer is attached. Compared with existing ambient ionization methods, VSSI eliminates the need for a high electric field (~5000 V.cm-1 ) for spray generation, while sharing a similar level of simplicity and flexibility with the simplest direct ionization techniques currently available such as paper spray ionization (PSI) and other solid substrate-based electrospray ionization methods. METHODS: The VSSI device was fabricated by attaching a piezoelectric transducer onto a standard glass microscope slide using epoxy glue. Liquid sample was aerosolized by either placing a droplet onto the vibrating edge of the glass slide or touching a wet surface with the glass edge. Mass spectrometric detection was achieved by placing the VSSI device 0.5-1 cm from the inlet of the mass spectrometer (Q-Exactive, ThermoScientific). RESULTS: VSSI is demonstrated to ionize a diverse array of chemical species, including small organic molecules, carbohydrates, peptides, proteins, and nucleic acids. Preliminary sensitivity experiments show that high quality mass spectra of acetaminophen can be obtained by consuming 100 femtomoles of the target. The dual spray of VSSI was also demonstrated by performing in droplet denaturation of ubiquitin. Finally, due to the voltage-free nature and the direct-contact working mode of VSSI, it has been successfully applied for the detection of chemicals directly from human fingertips. CONCLUSIONS: Overall, we report a compact ionization method based on vibrating sharp-edges. The simplicity and voltage-free nature of VSSI make it an attractive option for field portable applications or analyzing biological samples that are sensitive to high voltage or difficult to access by conventional ionization methods. PMID- 29993156 TI - Evaluation of micromilling/conventional isotope ratio mass spectrometry and secondary ion mass spectrometry of delta18 O values in fish otoliths for sclerochronology. AB - RATIONALE: Stable oxygen isotope ratios (delta18 O values) measured in fish otoliths can provide valuable detailed information on fish life history, fish age determination, and ocean thermography. Traditionally, otoliths are sampled by micromilling followed by isotope ratio mass spectrometry (IRMS), but direct analysis by secondary ion mass spectrometry (SIMS) is becoming more common. However, these two methods have not been compared to determine which, if either, is better for fish age validation studies. Hence, the goals were to: (1) determine if the delta18 O signatures from the two different methods are similar, (2) determine which method is better for fish age validation studies, and (3) examine biogeographic and migration history. METHODS: Both analytical techniques, micromilling/IRMS and SIMS, were used to measure delta18 O values in six Pacific cod (Gadus macrocephalus) otoliths. A series of measurements was made from the center of each otolith to its edge to develop a life-history delta18 O signature for each fish. RESULTS: The sampling resolution of SIMS analyses was 2-3 times greater than that obtained by micromilling/IRMS. We found an offset between SIMS and micromilling/IRMS delta18 O values, about 0.50/00 on average, with SIMS yielding lower values. However, the delta18 O patterns from both methods (i.e., the number of delta18 O maxima) correspond to the estimated age determined by otolith growth-zone counts, validating fish age determination methods. CONCLUSIONS: Both techniques resolved delta18 O life-history signatures and showed patterns consistent with seasonal variation in temperatures and changes due to fish migration. When otoliths are large, micromilling/IRMS can provide adequate resolution for fish age validation. However, SIMS is the better option if greater sampling resolution is required, such as when otoliths are small or specimens are longer lived and have compact growth zones. PMID- 29993157 TI - Magnesium Stung by Nonclassical Scorpionate Ligands: Synthesis and Cone-Angle Calculations. AB - A series of tris(pyrazolyl)alkane (RCTp) scorpionate ligands of the type RCTp3-R' (R=Me, nBu, SiMe3 ; R'=H, Me, Ph, iPr, tBu) were synthesized and their ability to coordinate methylmagnesium moieties was examined. The reaction of Mg(AlMe4 )2 with neutral proligands HCTp3-Ph or Me3 SiCTp3-Me , containing a non-innocent backbone methine moiety, led to deprotonation/rearrangement and SiMe3 /AlMe3 exchange to afford [(Me3 AlCTp3-Ph )2 Mg] and [(Me3 AlCTp3-Me )Mg(AlMe4 )], respectively, with monoanionic tripodal ligands. Treatment of sterically less demanding RCTp3-R' with Mg(AlMe4 )2 produced isostructural dicationic "metal-in-a box" complexes of the type [(RCTp3-R' )2 Mg][AlMe4 ]2 (R=Me, nBu; R'=H, Me). Utilization of the superbulky ligands MeCTp3-Ph and MeCTp3-tBu gave monocationic complexes [(MeCTp3-Ph )MgMe][AlMe4 ] and [(MeCTp3-tBu )MgMe][Al2 Me7 ] as separated ion pairs. The reaction of Mg(AlMe4 )2 with nBuCTp3-Ph led to the formation of the dimagnesium complex [{(nBuCTp3-Ph )Mg(AlMe4 )}2 (MU-CH3 )], which features a bridging methyl moiety and terminal eta1 -coordinated tetramethylaluminato ligands. Isopropyl-substituted ligand MeCTp3-iPr emerged from further fine-tuning of the steric and electronic parameters and, upon reaction with Mg(AlMe4 )2 , gave (MeCTp3-iPr )Mg(AlMe4 )2 ; this represents the first example of a magnesium bis(alkyl) complex with an intact RCTp3-R' ligand. The exact ligand cone angles Theta degrees of all magnesium complexes were determined according to the mathematical analysis developed by Allen et al. [J. Comput. Chem. 2013, 34, 1189-1197]. PMID- 29993158 TI - Dynamic changes in chromatin and microtubules at the first cell cycle in SCNT or IVF goat embryos. AB - We investigated the dynamic changes in chromatin and microtubules at the first cell cycle in goat somatic cell nuclear transfer (SCNT)-derived and in vitro fertilization (IVF)-derived embryos. Stage-dependent and characteristic changes to chromatin and microtubules occurred in SCNT-derived embryos at different times after activation. About half donor nuclei underwent premature chromosome condensation (PCC) at 1 h post activation, and furtherly reached telophase at 2 h after activation. However, we discovered that the separated chromosomes reaggregated, not keeping two independent nuclei; and formed one pronucleus at 2.5 h after activation. One pronucleus was found in all reconstructed oocytes except other no nucleus oocytes from 3 to 22 h after activation. Reconstructed oocytes reached the first mitotic metaphase at 23 h post activation, which was later than that of IVF-derived embryos at 16 h after insemination. SCNT-derived embryos showed significantly higher abnormalities in the first mitotic metaphase spindle, compared with IVF-derived embryos. Abnormal spindles included multi polar and half spindles. SCNT-derived embryos began to cleave at 24 h after activation, which was later than that of IVF-derived embryos at 21 h after insemination. SCNT-derived embryos showed delayed conversion from telophase to interphase than IVF-derived embryos during cleavage. These might lead to poor development in SCNT-derived embryos. PMID- 29993159 TI - Pragmatic competence and its relationship with the linguistic and cognitive profile of young adults with dyslexia. AB - The study assessed the pragmatic skills of 19 well-compensated Italian-speaking young adults with dyslexia compared with controls. A comprehensive pragmatic assessment tool was employed, targeting production and comprehension (Assessment of Pragmatic Abilities and Cognitive Substrates [APACS]). Participants were also administered a series of standardized tests to assess verbal and non-verbal cognitive abilities, including executive functions and social cognition tests. Data were analysed with the aim of understanding whether pragmatic abilities are compromised in dyslexia and of exploring associations between pragmatic performance and other cognitive domains. The performance of the dyslexia group was poorer than that of the control group in both expressive and receptive modalities. Data showed diffuse problems across several domains, with the greatest challenge posed by inferring nonliteral meanings, which indicates that pragmatic inefficiency is an important aspect of the linguistic and communicative profile of dyslexia in adulthood. Explorative correlations highlighted a relation between pragmatic performance and reading and vocabulary abilities, as well as between pragmatics and working memory. This suggests that pragmatic difficulties are strongly tied to the most distinctive aspects of dyslexia, namely, phonological awareness, verbal short-term memory, pseudo-word repetition, whereas the link with high-level executive functions and Theory of Mind is negligible. PMID- 29993161 TI - Transforming growth factor-beta1 increases C-C chemokine ligand 11 production in interleukin 4-stimulated human periodontal ligament cells. AB - Transforming growth factor (TGF)-beta1 is a multifunctional cytokine, which can control certain functions of various kinds of cells. However, it is unclear whether TGF-beta1 affects T-cell migration in periodontal lesions. The aim of this study was to examine the effects of TGF-beta1 on the production of C-C chemokine ligand (CCL)11, which is a T-helper 2-type chemokine, in human periodontal ligament cells (HPDLC). Interleukin (IL)-4 induced CCL11 production, but TGF-beta1 did not, in HPDLC. However, TGF-beta1 enhanced CCL11 production in IL-4-stimulated HPDLC. Western blot analysis showed that the signal transducer and activator of transcription 6 (STAT6) pathway was highly activated in HPDLC that had been stimulated with both IL-4 and TGF-beta1. Mitogen-activated protein kinase activation did not differ between the HPDLC treated with a combination of IL-4 and TGF-beta1 and those treated with IL-4 or TGF-beta1 alone. Moreover, a STAT6 inhibitor significantly inhibited CCL11 production in HPDLC that had been stimulated with IL-4 and TGF-beta1. The current study clearly demonstrated that TGF-beta1 enhanced IL-4-induced CCL11 production in HPDLC. The STAT6 pathway is important for CCL11 production in IL-4- and TGF-beta1-treated HPDLC. PMID- 29993160 TI - Double-negative feedback interaction between DNA methyltransferase 3A and microRNA-145 in the Warburg effect of ovarian cancer cells. AB - Ovarian cancer is the most lethal gynecological malignancy because of its poor prognosis. The Warburg effect is one of the key mechanisms mediating cancer progression. Molecules targeting the Warburg effect are therefore of significant therapeutic value for the treatment of cancers. Many microRNAs (miR) are dysregulated in cancers, and aberrant miR expression patterns have been suggested to correlate with the Warburg effect in cancer cells. In our study, we found that miR-145 negatively correlated with DNA methyltransferase (DNMT)3A expression at cellular/histological levels. miR-145 inhibited the Warburg effect by targeting HK2. Luciferase reporter assays confirmed that miR-145-mediated downregulation of DNMT3A occurred through direct targeting of its mRNA 3'-UTRs, whereas methylation specific PCR (MSP) assays found that knockdown of DNMT3A increased mRNA level of miR-145 and decreased methylation levels of promoter regions in the miR-145 precursor gene, thus suggesting a crucial crosstalk between miR-145 and DNMT3A by a double-negative feedback loop. DNMT3A promoted the Warburg effect through miR 145. Coimmunoprecipitation assays confirmed no direct binding between DNMT3A and HK2. In conclusion, a feedback loop between miR-145 and DNMT3A is a potent signature for the Warburg effect in ovarian cancer, promising a potential target for improved anticancer treatment. PMID- 29993162 TI - Disease state changes and safety of long-term donepezil hydrochloride administration in patients with Alzheimer's disease: Japan-Great Outcome of Long term trial with Donepezil (J-GOLD). AB - BACKGROUND: A long-term, large-scale study of donepezil hydrochloride in patients with Alzheimer's disease (AD) was conducted. Previously, two interim reports were published during this study. We have now completed the study and herein present our analysis of the final results. METHODS: The subjects of this study included AD patients who received the drug for the first time (newly treated patients), as well as AD patients who were already receiving the drug at the start of the study (continuously treated patients). The observation period was 48 months. Changes in cognitive function and severity of dementia associated with the drug administration and its safety were assessed. RESULTS: Cognitive function decreased significantly after 24 months in newly treated patients and after 6 months in continuously treated patients, compared with baseline. The percentages of patients whose dementia severity improved or remained the same compared with baseline were 59.27% at 48 months in the newly treated patients and 57.09% at 48 months in the continuously treated patients. There were no major safety problems with the drug. CONCLUSIONS: We conducted a large-scale study of AD patients in Japan. Here, we present our analysis of the final results and describe current clinical practice with the drug, changes in cognitive function and dementia severity associated with long-term administration of the drug, and the drug's safety. PMID- 29993163 TI - Acute cholinergic syndrome in a patient with Alzheimer's disease taking the prescribed dose of galantamine. PMID- 29993164 TI - Late relapse of hepatitis C virus in patients with sustained virological response after daclatasvir and asunaprevir therapy. AB - The optimal term of follow-up for patients who achieve sustained virological responses (SVR) is an important topic because of the widespread use of direct acting antivirals (DAA), which achieve a high SVR rate. Investigations of long term follow-up among patients with SVR after interferon (IFN) therapy have reported that approximately 80%-100% of patients maintained SVR. However, the long-term durability of SVR to DAA treatment is unknown. The aim of this study was to evaluate the incidence of late relapse in patients who achieved SVR with daclatasvir (DCV) and asunaprevir (ASV). Four hundred and thirteen patients infected with hepatitis C virus (HCV) genotype 1b who completed ASV and DCV treatment and achieved SVR were selected. Patients who were persistently negative for serum HCV RNA at 24 weeks after withdrawal of DCV and ASV were considered to have SVR24. Mean follow-up period was 21.5 months (range, 4.8-30.3 months) after SVR24. Four patients redeveloped HCV RNA in serum at 6, 12, 12 and 26 months, respectively, after achieving SVR24. Results of molecular analysis by phylogenetic tree of HCV nonstructural protein 3 and 5A regions from late relapse indicated that the same strain was present at pretreatment and late relapse. In conclusion, late relapse by the original HCV strain was confirmed by direct sequencing in 4 of 413 patients with SVR to ASV and DCV. Although a few patients may develop late relapse, SVR achieved with all oral DAA therapy is as durable as that with IFN therapy. PMID- 29993165 TI - Pathological diagnosis of combined Alzheimer's disease and argyrophilic grain dementia in a very elderly man who presented with advanced behavioural and psychological symptoms. AB - This case report describes a Japanese man who presented with slowly progressive memory disturbances that began at the age of 79 years. The man also displayed conspicuous behaviour and psychological symptoms in the early stage of dementia. Computed tomography revealed atrophy of the amygdala and severe hippocampal deterioration, particularly in the anterior portion. Lateral ventricular dilatation, mainly affecting the anterior and inferior horns, was also observed. Interestingly, cerebral neocortical atrophy in the frontal and temporal lobes was considerably mild for the patient's age. Apolipoprotein E gene analysis showed epsilon 3 homozygosity. The patient died at the age of 96 years, and his clinical diagnosis was Alzheimer's disease with severe behavioural and psychological symptoms of dementia. In addition to indicating considerable hippocampal atrophy, an autopsy revealed numerous neurofibrillary tangles and argyrophilic grains in the brain, as well as extensive senile plaques. Cerebral amyloid angiopathy was also recognized. The pathological findings were suggestive of both Alzheimer's disease and argyrophilic grain dementia; other neurodegenerative disorders were not apparent. The clinicopathologic findings of the present case suggest significant consideration should be made when determining the clinical diagnosis and pathogenesis of senile dementia. PMID- 29993166 TI - Trends and variations in per capita expenditure on adult intellectual disabilities health and social care across Scotland, and by urban/rural class. AB - BACKGROUND: Following the global financial crisis in 2007/08, the UK implemented an austerity programme which may impact on services. Scotland comprises both densely populated urban conurbations and highly dispersed remote rural and island communities. METHOD: Expenditure data were extracted from Scottish Government statistics. Per capita expenditure was calculated using adjusted Scotland's 2011 census data. RESULTS: There was a 3.41% decrease in real term expenditure on adult intellectual disabilities services between 2012/13 and 2014/15 (>L32 million). In 2014/15, per capita expenditure on adult intellectual disabilities health care ranged from L1,211 to L17,595; social care from L21,147 to L83,831; and combined health and social care expenditures from L37,703 to L85,929. Per capita expenditure on combined health and social care was greater in rural areas, with more on intellectual disabilities social care, though less on health care. CONCLUSIONS: Scottish expenditure on adult intellectual disabilities services has not kept abreast of rising living costs. It varies considerably across the country: a postcode lottery. PMID- 29993167 TI - Leishmania parasitophorous vacuole membranes display phosphoinositides that create conditions for continuous Akt activation and a target for miltefosine in Leishmania infections. AB - Miltefosine is an important drug for the treatment of leishmaniasis; however, its mechanism of action is still poorly understood. In these studies, we tested the hypothesis that like in cancer cells, miltefosine's efficacy in leishmaniasis is due to its inhibition of Akt activation in host cells. We show using pharmacologic agents that block Akt activation by different mechanisms and also using an inducible knockdown approach that miltefosine loses its efficacy when its access to Akt1 is limited. Interestingly, limitation of Akt activation results in clearance of established Leishmania infections. We then show, using fluorophore-tagged probes that bind to phosphoinositides, that Leishmania parasitophorous vacuole membranes (LPVMs) display the relevant phosphoinositides to which Akt can be recruited and activated continuously. Taken together, we propose that the acquisition of PI(4) P and the display of PI (3,4)P2 on LPVMs initiate the machinery that supports continuous Akt activation and sensitivity to miltefosine. PMID- 29993168 TI - Why is change a challenge in acute mental health wards? A cross-sectional investigation of the relationships between burnout, occupational status and nurses' perceptions of barriers to change. AB - Changes in UK psychiatric wards have been difficult to implement. Specific areas of nursing staff resistance remain unclear. Previous healthcare research suggests that burnout is common and that managers' regard changes more positively than direct care staff. We will therefore examine whether burnout and workforce characteristics influence psychiatric nurses' perceptions of barriers to change. Psychiatric nurses (N = 125) completed perceptions measures of 'barriers to change' (VOCALISE: subscales included 'powerlessness, confidence and demotivation'); and 'burnout' (Maslach Burnout Inventory: subscales included 'emotional exhaustion, personal accomplishment and depersonalization '). Staff characteristics, such as length of employment, occupational status, education, ethnicity, gender and age, were also collected. Correlations between these measures informed random-effects regression models, which were conducted to predict the barriers to change score and to explore differential effects in the subscales of VOCALISE. Perceptions of barriers to change (VOCALISE) were correlated with burnout (r = 0.39), occupational status (r = -0.18) and age (r = 0.22). Burnout (Coef. beta: 10.52; P > 0.001) and occupational status (Coef. beta: -4.58; P = 0.05) predicted VOCALISE. Emotional exhaustion (Coef. beta: 0.18; P < 0.001) and low personal accomplishment (Coef. beta: 0.21; P = 0.001) predicted powerlessness. Emotional exhaustion predicted low motivation regarding changes (Coef. beta: 0.11; P = 0.005). Low confidence predicted high levels of depersonalization (Coef beta: 0.23; P = 0.01). Direct care staff expressed significantly more powerlessness (Coef. beta: -2.60; P = 0.02) and significantly less confidence (Coef. beta: -3.07; P = 0.002) than managers. For changes to be successful in psychiatric wards, burnout will need to be addressed. Future change strategies may consider involving direct care staff to improve perceptions of barriers to change. PMID- 29993169 TI - Effects of Electric Fields on Multiple Exciton Generation. AB - Unique properties of lead chalcogenides have enabled multiple exciton generation (MEG) in their nanocrystals that can be beneficial in enhancing the efficiency of third-generation solar cells. Although the intrinsic electric field plays an imperative role in a solar cell, its effect on the multiple exciton generation (MEG) has been overlooked, so far. Using EOM-CCSD as a many-body approach, we show that any electric field can affect the absorptivity spectra of the lead chalcogenide nanocrystals (Pb4 Te4 , Pb4 Se4 , and Pb4 S4 ). The same electric field, however, has insignificant effects on the MEG quantum probabilities and the thresholds in these nanocrystals. Furthermore, simulations show that Pb4 Te4 , among the aforementioned nanocrystals, has the lowest MEG threshold and the strongest absorptivity peak that is located in the multi-excitation window, irrespective of the field strength, making it the most suitable candidate for MEG applications. Simulations also demonstrate that an electric field affects the MEG characteristics in the Pb4 Te4 nanocrystal, in general, less than it perturbs MEG characteristics in Pb4 Se4 and Pb4 S4 nanocrystals. Our results can have a great impact in designing optoelectronic devices whose performance can be significantly influenced by MEG. PMID- 29993170 TI - Perceptions of anger and aggression in rural adolescent Australian males. AB - Problematic anger is often the outward manifestation and expression of deeper mental health issues in young men with strong links to depression, aggression, and suicide. Few studies have explored adolescent anger and aggression from the perspective of adolescent males and even fewer studies focus specifically on a rural context. This research aimed to understand the role of anger and aggression from the perspective of Australian rural adolescent males. Mental health nurses can build upon this knowledge to promote more adaptive ways of coping with anger therefore identifying specific interventions for the prevention of violence and promotion of mental health in this cohort. One hundred and eighty-seven rural adolescent males participated in focus groups that were conducted during their participation in the Rock and Water Program (RWP). Participants identified a number of factors they felt contributed to the aggression they both witnessed and experienced with eight themes emerging in response to the research questions. Four themes related to personological factors, that is racism, homophobia, family influences, and media influence. A further four themes related to situational factors, that is alcohol, territorialism, school context, and peer pressure. The study identified that racist and homophobic attitudes and beliefs were evident and clearly contributed to aggressive scripts as did family and media messages that normalized aggressive behaviour by way of endorsing stereotypical images of an aggressive masculinity. Situational factors such as alcohol use, territorialism, school context, and peer pressure were directly linked by participants to aggressive incidents embedded within their notions of masculinity. PMID- 29993171 TI - Ghanaian traditional and faith healers' explanatory models of intellectual disability. AB - BACKGROUND: The use of traditional/alternative medicine for health care in Africa has been examined for various conditions. However, there is limited research about traditional/alternative health care for intellectual disability. The present authors explored the explanatory models (EMs) of intellectual disability held by traditional/faith healers in Ghana. METHODS: Using a case vignette, the present authors conducted semi-structured interviews with 36 traditional/faith healers in Accra, Ghana. Using the EMs of illness framework as a guide, participants were asked questions to examine their beliefs about the nature, causes, course and recommended treatment of intellectual disability. RESULTS: The healers' causal explanations included maternal negligence during pregnancy and spiritual factors. They also believed that intellectual disability was a congenital, lifelong condition which could not be cured. CONCLUSIONS: Unlike other conditions which traditional healers claimed to cure, participants admitted that intellectual disability was not curable. The present authors suggest that the findings highlight opportunities that exist for collaboration between biomedicine and traditional medicine. PMID- 29993172 TI - Cardiovascular and metabolic comorbidities in patients with Alzheimer's disease and vascular dementia compared to a psychiatric control cohort. AB - BACKGROUND: Multimorbidity in dementia is associated with an increased risk of complications and a higher need for care. Having knowledge of cardiovascular and metabolic comorbidities is crucial when making decisions about diagnostic procedures and therapies. We compared the prevalence of comorbidities in hospitalized patients with Alzheimer's disease (AD), vascular dementia, and psychiatric diseases other than dementia. Additionally, we compared clinically relevant health-care indicators (length of hospital stay, rate of re hospitalization) between these groups. METHODS: We used information from a database of treatment-relevant indicators from psychiatric and psychosomatic hospitals throughout Germany. This database contains routinely recorded data collected from 85 German hospitals from 2011 to 2015. In total, 14 411 AD cases, 7156 vascular dementia cases, and 34 534 cases involving non-demented psychiatric patients (used as controls) were included. To analyze comorbidities and health care indicators, chi2 tests and t-tests were used. RESULTS: Diabetes mellitus, lipoprotein disorders, coronary artery diseases, cardiac arrhythmia and insufficiency, and atherosclerosis were significantly more prevalent in patients with vascular dementia than in those with AD and psychiatric controls. Hypertension and coronary artery diseases were less frequently associated with AD than with non-demented psychiatric controls (P < 0.001). Additionally, dementia patients with cardiovascular or metabolic diseases exhibited longer hospital stays (+ 1.4 days, P < 0.001) and were more often re-hospitalized within 3 weeks (P < 0.001) and 1 year (P < 0.001) compared to dementia patients without these comorbidities. CONCLUSIONS: Awareness of somatic comorbidities in patients with dementia is crucial to avoid complications during inpatient treatment. The occurrence of comorbid disorders was associated with longer and more frequent hospital stays, which potentially lead to higher health-care costs. Further studies should evaluate the causative association between somatic comorbidities and inpatient costs in dementia patients. PMID- 29993173 TI - Multiphase-Assembly of Siloxane Oligomers with Improved Mechanical Strength and Water-Enhanced Healing. AB - Healable silicone materials have great technical impact in coatings, smart actuators, and flexible electronics, however, current healable silicone materials lack mechanical tunability. Herein, we designed and synthesized a new type of healable silicone through hydrogen-bond assisted multiphase assembly of siloxane oligomers. Besides the enhanced mechanical strength, unique water-enhanced healing was observed in the polymer network which is due to the reversible dissociation/association of multivalent hydrogen bonds in the presence of water. PMID- 29993174 TI - alpha-Blockers for uncomplicated ureteric stones: a clinical practice guideline. AB - OBJECTIVE: To develop an evidence-based recommendation concerning the use of alpha-blockers for uncomplicated ureteric stones based on an up-to-date Cochrane review, as the role of medical expulsive therapy for uncomplicated ureteric stones remains controversial in the light of new contradictory trial evidence. METHODS: We applied the Rapid Recommendations approach to guideline development, which represents an innovative approach by an international collaborative network of clinicians, researchers, methodologists and patient representatives seeking to rapidly respond to new, potentially practice-changing evidence with recommendations developed according to standards for trustworthy guidelines. RESULTS: The panel suggests the use of alpha-blockers in addition to standard care over standard care alone in patients with uncomplicated ureteric stones (weak recommendation based on low-quality evidence). The panel judged that the net benefit of alpha-blockers was small and that there was considerable uncertainty about patients' values and preferences. This means that the panel expects that most patients would choose treatment with alpha-blockers but that a substantial proportion would not. This recommendation applies to both patients in whom the presence of ureteric stones is confirmed by imaging, as well as patients in whom the diagnosis is made based on clinical grounds only. CONCLUSION: The Rapid Recommendations panel suggests the use of alpha-blockers for patients with ureteric stones. Shared decision-making is emphasised in making the final choice between the treatment options. PMID- 29993175 TI - Physical activity levels of children and adolescents with moderate-to-severe intellectual disability. AB - BACKGROUND: Regular participation of children and adolescents with intellectual disabilites in physical activity is important to maintain good health and to acquire motor skills. The aim of this study was to investigate the habitual physical activity in these children. METHODS: Sixty-eight children and adolescents (2-18 years) with a moderate-to-severe intellectual disability were included in the analyses. They wore an accelerometer on eight consecutive days. Data was analysed by use of descriptive statistics and multiple linear regression analyses. RESULTS: The participants took on average 6,677 +/- 2,600 steps per day, with intensity of 1,040 +/- 431 counts per minute. In total, 47% of the participants were meeting physical activity recommendations. Low motor development was associated with low physical activity. CONCLUSIONS: As more than half of the participants were not meeting the recommendations, family and caregivers of these children should focus on supporting and motivating them to explore and expand their physical activities. PMID- 29993176 TI - To prescribe, or not to prescribe: decision making in HIV-1 post-exposure prophylaxis. AB - OBJECTIVES: We investigated the trend in usage of post-exposure prophylaxis (PEP) after HIV-1 risk exposure and evaluated PEP prescription decision making of physicians according to guidelines. METHODS: All PEP consultations from January 2014 to December 2016 in patients presenting at the University Hospital of Cologne (Germany) were retrospectively analysed. HIV risk contacts included sexual and occupational exposure. The European AIDS Clinical Society (EACS) Guidelines for HIV PEP (version 9.0, 2017) were used for assessment. RESULTS: A total of 649 patients presented at the emergency department (ED) or the clinic for infectious diseases (IDC) for PEP consultations. A continuous increase in the number of PEP requests was recorded: 189 in 2014, 208 in 2015 and 252 in 2016. PEP consultations in men who have sex with men (MSM) showed a remarkable increase in 2016 (2014, n = 96; 2015, n = 101; 2016, n = 152). Decisions taken by physicians with a specialization in infectious diseases (n = 547) included 61 (11%) guideline-discordant prescriptions [2014: 14% (n = 22); 2015: 9% (n = 16); 2016: 11% (n = 23)]. Among these, sexual exposure accounted for 45 (74%) cases, including 15 cases of nonconsensual sex, while occupational exposure accounted for 14 (23%) cases and other exposure two cases (3%). The main reason for guideline-discordant PEP prescriptions was emotional stress of the patient (n = 37/61). CONCLUSIONS: PEP prescriptions are increasing and decision making is influenced by patients' emotional stress, but PEP prescriptions should be strictly administered according to risk assessment. PMID- 29993177 TI - Advances in Selective Carbon-Heteroatom Coupling Reactions. AB - Most of compounds containing more than one reactive groups may produce several byproducts during the coupling process. Selective carbon-heteroatom coupling reactions, which have merits of high synthetic efficiency and step economy, are the best choice to resolve the problem. Although they have made great progress, they deserve further exploration. This review discusses their recent advances and intend to inspire the research in the future. It is organized on the basis of selective carbon-heteroatom coupling reaction types, including selective C-N and C-N, C-N and C-O, C-O and C-O, C-C and C-N coupling reactions. PMID- 29993178 TI - A German version of the Three-Dimensional Work Fatigue Inventory (3D-WFI): Factor structure, internal consistency, and correlates. AB - Work fatigue represents an essential construct for understanding employee health and safety. In this study, we developed and explored the psychometric properties of a German version of the Three-Dimensional Work Fatigue Inventory and examined a set of hypothesized correlates of work fatigue. Data came from a sample of 439 German workers. Consistent with the original measure, confirmatory factor analyses supported a three-factor solution (physical, mental, and emotional work fatigue), and estimates of internal consistency reliability exceeded .90 for each dimension of work fatigue. The measure demonstrated a meaningful pattern of associations with predictors (time pressure, job control, psychological detachment, relaxation, and trait negative and positive affect) and an important outcome (work engagement). The German Three-Dimensional Work Fatigue Inventory will encourage research on an essential construct for employee health and safety using broader populations of workers. PMID- 29993179 TI - Plant-made E2 glycoprotein single-dose vaccine protects pigs against classical swine fever. AB - Classical Swine Fever Virus (CSFV) causes classical swine fever, a highly contagious hemorrhagic fever affecting both feral and domesticated pigs. Outbreaks of CSF in Europe, Asia, Africa and South America had significant adverse impacts on animal health, food security and the pig industry. The disease is generally contained by prevention of exposure through import restrictions (e.g. banning import of live pigs and pork products), localized vaccination programmes and culling of infected or at-risk animals, often at very high cost. Current CSFV-modified live virus vaccines are protective, but do not allow differentiation of infected from vaccinated animals (DIVA), a critical aspect of disease surveillance programmes. Alternatively, first-generation subunit vaccines using the viral protein E2 allow for use of DIVA diagnostic tests, but are slow to induce a protective response, provide limited prevention of vertical transmission and may fail to block viral shedding. CSFV E2 subunit vaccines from a baculovirus/insect cell system have been developed for several vaccination campaigns in Europe and Asia. However, this expression system is considered expensive for a veterinary vaccine and is not ideal for wide-spread deployment. To address the issues of scalability, cost of production and immunogenicity, we have employed an Agrobacterium-mediated transient expression platform in Nicotiana benthamiana and formulated the purified antigen in novel oil-in-water emulsion adjuvants. We report the manufacturing of adjuvanted, plant-made CSFV E2 subunit vaccine. The vaccine provided complete protection in challenged pigs, even after single-dose vaccination, which was accompanied by strong virus neutralization antibody responses. PMID- 29993180 TI - Gypenosides improve diabetic cardiomyopathy by inhibiting ROS-mediated NLRP3 inflammasome activation. AB - NLRP3 inflammasome activation plays an important role in diabetic cardiomyopathy (DCM), which may relate to excessive production of reactive oxygen species (ROS). Gypenosides (Gps), the major ingredients of Gynostemma pentaphylla (Thunb.) Makino, have exerted the properties of anti-hyperglycaemia and anti-inflammation, but whether Gps improve myocardial damage and the mechanism remains unclear. Here, we found that high glucose (HG) induced myocardial damage by activating the NLRP3 inflammasome and then promoting IL-1beta and IL-18 secretion in H9C2 cells and NRVMs. Meanwhile, HG elevated the production of ROS, which was vital to NLRP3 inflammasome activation. Moreover, the ROS activated the NLRP3 inflammasome mainly by cytochrome c influx into the cytoplasm and binding to NLRP3. Inhibition of ROS and cytochrome c dramatically down-regulated NLRP3 inflammasome activation and improved the cardiomyocyte damage induced by HG, which was also detected in cells treated by Gps. Furthermore, Gps also reduced the levels of the C-reactive proteins (CRPs), IL-1beta and IL-18, inhibited NLRP3 inflammasome activation and consequently improved myocardial damage in vivo. These findings provide a mechanism that ROS induced by HG activates the NLRP3 inflammasome by cytochrome c binding to NLRP3 and that Gps may be potential and effective drugs for DCM via the inhibition of ROS-mediated NLRP3 inflammasome activation. PMID- 29993181 TI - Rho GTPases are involved in S1P-enhanced glomerular endothelial cells activation with anti-myeloperoxidase antibody positive IgG. AB - Sphingosine-1-phosphate (S1P) is a crucial regulator in vascular inflammation. Our recent study found that under pathophysiological concentration in active anti neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), S1P participated in MPO-ANCA-positive IgG-induced glomerular endothelial cell (GEnC) activation via a S1P receptor (S1PR)-dependent way. However, the downstream signalling pathways are not fully clear yet. In this study, we demonstrated that Rho guanosine triphosphatases (GTPases) signalling pathways, RhoA and Rac1 in particular, were implicated in MPO-ANCA-positive IgG-mediated GEnCs activation enhanced by pathophysiological concentration of S1P in AAV. These results provide mechanistic insights into vascular barrier dysfunction in AAV, which may facilitate the development of effective therapies. PMID- 29993183 TI - Distinct roles for IkappaB kinases alpha and beta in regulating pulmonary endothelial angiogenic function during late lung development. AB - Pulmonary angiogenesis is essential for alveolarization, the final stage of lung development that markedly increases gas exchange surface area. We recently demonstrated that activation of the nuclear factor kappa-B (NFkappaB) pathway promotes pulmonary angiogenesis during alveolarization. However, the mechanisms activating NFkappaB in the pulmonary endothelium, and its downstream targets are not known. In this study, we sought to delineate the specific roles for the NFkappaB activating kinases, IKKalpha and IKKbeta, in promoting developmental pulmonary angiogenesis. Microarray analysis of primary pulmonary endothelial cells (PECs) after silencing IKKalpha or IKKbeta demonstrated that the 2 kinases regulate unique panels of genes, with few shared targets. Although silencing IKKalpha induced mild impairments in angiogenic function, silencing IKKbeta induced more severe angiogenic defects and decreased vascular cell adhesion molecule expression, an IKKbeta regulated target essential for both PEC adhesion and migration. Taken together, these data show that IKKalpha and IKKbeta regulate unique genes in PEC, resulting in differential effects on angiogenesis upon inhibition, and identify IKKbeta as the predominant regulator of pulmonary angiogenesis during alveolarization. These data suggest that therapeutic strategies to specifically enhance IKKbeta activity in the pulmonary endothelium may hold promise to enhance lung growth in diseases marked by altered alveolarization. PMID- 29993184 TI - Bone marrow mesenchymal stem cells reduce ureteral stricture formation in a rat model via the paracrine effect of extracellular vesicles. AB - With no effective therapy to prevent or treat ureteral stricture (US), a multifactorial fibrotic disease after iatrogenic injury of the ureter, the need for new therapies is urgent. Mesenchymal stem cells (MSCs) have been widely studied for treating tissue defects and excessive fibrosis, and recent studies established that one of the main therapeutic vectors of MSCs is comprised in their secretome and represented by extracellular vesicles (EVs). Thus, we have determined to explore the specific role of MSCs-derived EVs (MSC-EVs) treatment in a pre-clinical model of US. The results firstly showed that either a bolus dose of MSCs or a bolus dose of MSC-EVs (administration via renal-arterial) significantly ameliorated ureteral fibrosis and recuperated ureter morphological development in a US rat model. We confirmed our observations through MSCs or MSC EVs treatment alleviated hydronephrosis, less renal dysfunction and blunted transforming growth factor-beta1 induced fibration. Due to MSC-EVs are the equivalent dose of MSCs, and similar curative effects of transplantation of MSCs and MSC-EVs were observed, we speculated the curative effect of MSCs in treating US might on account of the release of EVs through paracrine mechanisms. Our study demonstrated an innovative strategy to counteract ureteral stricture formation in a rat model of US. PMID- 29993185 TI - Triggering of cancer cell cycle arrest by a novel scorpion venom-derived peptide Gonearrestide. AB - In this study, a novel scorpion venom-derived peptide named Gonearrestide was identified in an in-house constructed scorpion venom library through a combination of high-throughput NGS transcriptome and MS/MS proteome platform. In total, 238 novel peptides were discovered from two scorpion species; and 22 peptides were selected for further study after a battery of functional prediction analysis. Following a series of bioinformatics analysis alongside with in vitro biological functional screenings, Gonearrestide was found to be a highly potent anticancer peptide which acts on a broad spectrum of human cancer cells while causing few if any observed cytotoxic effects on epithelial cells and erythrocytes. We further investigated the precise anticancer mechanism of Gonearrestide by focusing on its effects on the colorectal cancer cell line, HCT116. NGS RNA sequencing was employed to obtain full gene expression profiles in HCT116 cells, cultured in the presence and absence of Gonearrestide, to dissect signalling pathway differences. Taken together the in vitro, in vivo and ex vivo validation studies, it was proven that Gonearrestide could inhibit the growth of primary colon cancer cells and solid tumours by triggering cell cycle arrest in G1 phase through inhibition of cyclin-dependent kinases 4 (CDK4) and up regulate the expression of cell cycle regulators/inhibitors-cyclin D3, p27, and p21. Furthermore, prediction of signalling pathways and potential binding sites used by Gonearrestide are also presented in this study. PMID- 29993186 TI - Theabrownin triggers DNA damage to suppress human osteosarcoma U2OS cells by activating p53 signalling pathway. AB - Osteosarcoma becomes the second leading cause of cancer death in the younger population. Current outcomes of chemotherapy on osteosarcoma were unsatisfactory to date, demanding development of effective therapies. Tea is a commonly used beverage beneficial to human health. As a major component of tea, theabrownin has been reported to possess anti-cancer activity. To evaluate its anti-osteosarcoma effect, we established a xenograft model of zebrafish and employed U2OS cells for in vivo and in vitro assays. The animal data showed that TB significantly inhibited the tumour growth with stronger effect than that of chemotherapy. The cellular data confirmed that TB-triggered DNA damage and induced apoptosis of U2OS cells by regulation of Mki67, PARP, caspase 3 and H2AX, and Western blot assay showed an activation of p53 signalling pathway. When P53 was knocked down by siRNA, the subsequent downstream signalling was blocked, indicating a p53 dependent mechanism of TB on U2OS cells (p53 wt). Using osteosarcoma cell lines with p53 mutations (HOS, SAOS-2 and MG63), we found that TB exerted stronger inhibitory effect on U2OS cells than that on p53-mut cell lines, but it also exerted obvious effect on SAOS-2 cells (p53 null), suggesting an activation of p53-independent pathway in the p53-null cells. Interestingly, theabrownin was found to have no toxicity on normal tissue in vivo and could even increase the viability of p53-wt normal cells. In sum, theabrownin could trigger DNA damage and induce apoptosis on U2OS cells via a p53-dependent mechanism, being a promising candidate for osteosarcoma therapy. PMID- 29993187 TI - Levamisole suppresses adipogenesis of aplastic anaemia-derived bone marrow mesenchymal stem cells through ZFP36L1-PPARGC1B axis. AB - Aplastic anaemia (AA) is a life-threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM-derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM-MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM-MSCs through lentivirus mediated ZFP36L1 knock-down and overexpression assay. Peroxisome proliferator activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3'-untranslated region bears adenine-uridine-rich elements was verified as a direct downstream target of ZFP36L1, and knock-down of PPARGC1B impaired the adipogenesis of AA BM MSCs. Collectively, our work demonstrated that ZFP36L1-mediated post transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM-MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy. PMID- 29993188 TI - The chaperone-like sodium phenylbutyrate improves factor IX intracellular trafficking and activity impaired by the frequent p.R294Q mutation. AB - : Essentials Missense mutations often impair protein folding, and thus intracellular trafficking and secretion. Cellular models of severe type I hemophilia B were challenged with chaperone-like compounds. Sodium phenylbutyrate improved intracellular trafficking and secretion of the frequent p.R294Q. The increased coagulant activity levels (~3%) of p.R294Q would ameliorate the bleeding phenotype. SUMMARY: Background Missense mutations often impair protein folding and intracellular processing, which can be improved by small compounds with chaperone-like activity. However, little has been done in coagulopathies, where even modest increases of functional levels could have therapeutic implications. Objectives To rescue the expression of factor IX (FIX) variants affected by missense mutations associated with type I hemophilia B (HB) through chaperone-like compounds. Methods Expression studies of recombinant (r)FIX variants and evaluation of secreted levels (ELISA), intracellular trafficking (immunofluorescence) and activity (coagulant assays) before and after treatment of cells with chaperone-like compounds. Results As a model we chose the most frequent HB mutation (p.R294Q, ~100 patients), compared with other recurrent mutations associated with severe/moderate type I HB. Immunofluorescence studies revealed retention of rFIX variants in the endoplasmic reticulum and negligible localization in the Golgi, thus indicating impaired intracellular trafficking. Consistently, and in agreement with coagulation phenotypes in patients, all missense mutations resulted in impaired secretion (< 1% wild-type rFIX). Sodium phenylbutyrate (NaPBA) quantitatively improved trafficking to the Golgi and dose dependently promoted secretion (from 0.3 +/- 0.1% to 1.5 +/- 0.3%) only of the rFIX-294Q variant. Noticeably, this variant displayed a specific coagulant activity that was higher (~2.0 fold) than that of wild-type rFIX in all treatment conditions. Importantly, coagulant activity was concurrently increased to levels (3.0 +/- 0.9%) that, if achieved in patients, would ameliorate the bleeding phenotype. Conclusions Altogether, our data detail molecular mechanisms underlying type I HB and candidate NaPBA as affordable 'personalized' therapeutics for patients affected by the highly frequent p.R294Q mutation, and with reduced access to substitutive therapy. PMID- 29993189 TI - Study of the chromatographic parameters of ultra-high-performance supercritical fluid chromatography and method development using a design of experiments approach for the quantification of pesticides in lettuce. AB - We examine the potential of ultra-high-performance supercritical fluid chromatography for multiresidue quantification of ten pesticides commonly applied to lettuce and compares it to ultra-high-performance liquid chromatography. Initially, a thorough study of the stationary and mobile phase composition and injection solvent was carried out. In a second step, a chemometric approach based on design of experiments was used to simultaneously study the influence of temperature, pressure, and percentage of ethanol on the retention, resolution and symmetry of the peaks. Using this approach, it was possible to obtain the Design Space, a robust region where complete separation of the analytes was achieved, with acceptable peak shape. Both methods were validated according to the figures of merit: selectivity, linearity, quantification limit, accuracy (in terms of recovery), and precision (repeatability and intermediate precision) and used to quantify the pesticides in lettuce samples. Comparing both techniques, it was concluded that the limits of quantification, accuracy, and precision were similar. However, in supercritical fluid chromatography, a reduced volume of organic solvent was used, the method was faster and generated lower amounts of residues. PMID- 29993190 TI - Environmental drivers and genomic architecture of trait differentiation in fire adapted Banksia attenuata ecotypes. AB - Trait divergence between populations is considered an adaptive response to different environments, but to what extent this response is accompanied by genetic differentiation is less clear since it may be phenotypic plasticity. In this study, we analyzed phenotypic variation between two Banksia attenuata growth forms, lignotuberous (shrub) and epicormic resprouting (tree), in fire-prone environments to identify the environmental factors that have driven this phenotypic divergence. We linked genotype with phenotype and traced candidate genes using differential gene expression analysis. Fire intervals determined the phenotypic divergence between growth forms in B. attenuata. A genome-wide association study identified 69 single nucleotide polymorphisms, putatively associated with growth form, whereas no growth form- or phenotype-specific genotypes were identified. Genomic differentiation between the two growth forms was low (Fst = 0.024). Differential gene expression analysis identified 37 genes/transcripts that were differentially expressed in the two growth forms. A small heat-shock protein gene, associated with lignotuber presence, was differentially expressed in the two forms. We conclude that different fire regimes induce phenotypic polymorphism in B. attenuata, whereas phenotypic trait divergence involves the differential expression of a small fraction of genes that interact strongly with the disturbance regime. Thus, phenotypic plasticity among resprouters is the general strategy for surviving varying fire regimes. PMID- 29993191 TI - Poly[(2-(acryloyloxy) ethyl]trimethylammonium chloride-co-ethylene dimethacrylate monolith on-line solid-phase extraction coupled with liquid chromatography and tandem mass spectrometry for the fast determination of salicylic acid in foodstuffs. AB - We report the fabrication of an anion-exchange monolithic column in a stainless steel chromatographic column (10 mm * 2.1 mm i.d.) using [2-(acryloyloxy) ethyl]trimethylammonium chloride as the monomer and ethylene dimethacrylate as the crosslinker. The prepared monolith was developed as the adsorbent for the on line solid-phase extraction of salicylic acid in various animal-origin foodstuffs combined with liquid chromatography and tandem mass spectrometry. The monolith was characterized by using Fourier transform infrared spectroscopy, scanning electron microscopy, nitrogen adsorption analysis, and elemental analysis. Potential factors affecting the on-line solid-phase extraction and liquid chromatography with tandem mass spectrometry analysis were studied in detail. Under the optimized conditions, the total analysis time including cleanup and liquid chromatography with tandem mass spectrometry separation was 17 min. The developed method gave the linear range of 15-750 MUg/kg, detection limits (S/N = 3) of 5 MUg/kg, and quantification limits (S/N = 10) of 15 MUg/kg. The recoveries obtained by spiking 10, 20, and 100 MUg/kg of salicylic acid in the animal-origin food samples were in the range of 85.2-98.4%. In addition, the monolith was stable enough for 550 extraction cycles with the precision of peak area <=11.6%. PMID- 29993192 TI - Modelling cadmium-induced cardiotoxicity using human pluripotent stem cell derived cardiomyocytes. AB - Cadmium, a highly ubiquitous toxic heavy metal, has been widely recognized as an environmental and industrial pollutant, which confers serious threats to human health. The molecular mechanisms of the cadmium-induced cardiotoxicity (CIC) have not been studied in human cardiomyocytes at the cellular level. Here we showed that human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) can recapitulate the CIC at the cellular level. The cadmium-treated hPSC-CMs exhibited cellular phenotype including reduced cell viability, increased apoptosis, cardiac sarcomeric disorganization, elevated reactive oxygen species, altered action potential profile and cardiac arrhythmias. RNA-sequencing analysis revealed a differential transcriptome profile and activated MAPK signalling pathway in cadmium-treated hPSC-CMs, and suppression of P38 MAPK but not ERK MAPK or JNK MAPK rescued CIC phenotype. We further identified that suppression of PI3K/Akt signalling pathway is sufficient to reverse the CIC phenotype, which may play an important role in CIC. Taken together, our data indicate that hPSC-CMs can serve as a suitable model for the exploration of molecular mechanisms underlying CIC and for the discovery of CIC cardioprotective drugs. PMID- 29993194 TI - Solid-phase extraction treatment is required for measurement of active glucagon like peptide-1 by enzyme-linked immunosorbent assay kit affected by heterophilic antibodies. AB - AIMS/INTRODUCTION: It is reported that interfering substances in the blood might influence the value for measurement of active glucagon-like peptide-1 (GLP-1) in human plasma. Solid phase extraction (SPE) pretreatment is recommended to reduce their influence, but it requires a lot of cost and time. However, there is little investigation about causative inhibitory substances and about methods that can replace solid phase extraction. In the present study, we aimed to seek the candidate of the substances that might interfere with an active GLP-1 enzyme linked immunosorbent assay (ELISA). MATERIALS AND METHODS: Two kinds of active GLP-1 ELISA kits using different antibodies, plural extraction carriers and elution solutions were used to evaluate the SPE method. Active GLP-1 concentration was compared with or without SPE, and with or without a heterophilic blocking tube. RESULTS: Active GLP-1 values were often higher without SPE compared with those with SPE pretreatment. This difference was eliminated by pretreatment with a heterophilic blocking tube or ELISA kits that did not use a mouse monoclonal antibody, and was independent of SPE. CONCLUSIONS: Substances absorbed to a heterophilic blocking tube carrier might interfere with an active GLP-1 immunoassay. Solid-phase extraction treatment is required for measurement of active GLP-1 by an ELISA kit affected by heterophilic antibodies. PMID- 29993193 TI - Calycosin alleviates allergic contact dermatitis by repairing epithelial tight junctions via down-regulating HIF-1alpha. AB - Calycosin, a bioactive component derived from Astragali Radix (AR; Huang Qi), has been shown to have an effect of anti-allergic dermatitis with unknown mechanism. This study aims to investigate the mechanism of calycosin related to tight junctions (TJs) and HIF-1alpha both in FITC-induced mice allergic contact dermatitis and in IL-1beta stimulated HaCaT keratinocytes. Th2 cytokines (IL-4, IL-5 and IL-13) were detected by ELISA. The epithelial TJ proteins (occludin, CLDN1 and ZO-1), initiative key cytokines (TSLP and IL-33) and HIF-1alpha were assessed by Western blot, real-time PCR, immunohistochemistry or immunofluorescence. Herein, we have demonstrated that allergic inflammation and the Th2 cytokines in ACD mice were reduced significantly by calycosin treatment. Meanwhile, calycosin obviously decreased the expression of HIF-1alpha and repaired TJs both in vivo and in vitro. In HaCaT keratinocytes, we noted that IL 1beta induced the deterioration of TJs, as well as the increased levels of TSLP and IL-33, which could be reversed by silencing HIF-1alpha. In addition, administration of 2-methoxyestradiolin (2-ME), a HIF-1alpha inhibitor,significantly repaired the TJs and alleviated the allergic inflammation in vivo. Furthermore, TJs were destroyed by DMOG or by overexpressing HIF-1alpha in HaCaT keratinocytes, and simultaneously, calycosin down-regulated the expression of HIF-1alpha and repaired the TJs in this process. These results revealed that calycosin may act as a potential anti-allergy and barrier-repair agent via regulating HIF-1alpha in AD and suggested that HIF-1alpha and TJs might be possible therapy targets for allergic dermatitis. PMID- 29993195 TI - Utility of thermographic measurements of laterality of body surface temperature to prevent misdiagnosis of acute Wallenberg's syndrome. AB - INTRODUCTION: Acute Wallenberg's syndrome (WS) is sometimes misdiagnosed as a nonstroke disease including auditory vertigo, and careful neurological examination is required for a precise diagnosis. Lateral difference of body surface temperature (BST) had been reported as a symptom of WS, although further details of this symptom are currently lacking. Our aim was to investigate the laterality of BST of patients with acute WS using thermography and the usefulness of thermography to detect acute WS. METHODS: Nine consecutive patients with new onset acute WS and nine patients with acute pontine infarction, intended for a comparison, were enrolled. Using thermography, the BST of patients was measured and initially evaluated visually. Detailed BSTs were measured using dedicated software. We examined the relationship between BST and other clinical factors, including first diagnosis, clinical symptoms, and MRI findings. RESULTS: Four patients with WS (44.44%) were misdiagnosed with nonstroke disease and did not receive a thermography assessment at their first visit; in contrast, all acute pontine infarction patients were diagnosed with brain infarction. Eight patients with WS (89%) showed a laterality of BST at multiple sites, and three of eight patients showed a whole-body laterality of BST; in contrast, only two pontine infarction patients showed laterality of BST at one or two sites. These lateral BST differences were easily observed visually using thermography within two minutes. The BST laterality gradually decreased over time in almost all patients with WS. The infarction size in the WS patients with whole-body laterality of BST was craniocaudally larger than in the other patients, and the size was smallest in the patient showing no BST laterality. CONCLUSIONS: In contrast to acute pontine infarction patients, almost all patients with acute WS showed lateral BST differences, which was easily detected with thermography. Thermography may thus be a useful tool to prevent misdiagnosis of acute WS. PMID- 29993196 TI - A treatment algorithm for healthy young men with erectile dysfunction. AB - OBJECTIVES: To assess baseline characteristics of a cohort of young men with erectile dysfunction (ED) but no identifiable organic cause and to evaluate the efficacy of our treatment algorithm. PATIENTS AND METHODS: We retrospectively reviewed the charts of men aged <40 years referred to our tertiary care centre for evaluation and treatment of their ED between March 2010 and August 2016. Of 185 men reviewed, we included 73 men who were identified as having no identifiable organic cause for their ED and had successfully completed a detailed questionnaire regarding their medical and sexual history at the initial consultation. The questionnaire was used to obtain baseline patient characteristics and identify comorbid conditions which may predispose to ED. For these men, our standard treatment comprised a daily low-dose phosphodiesterase type 5-inhibitor along with a referral for psychosexual therapy, with the option of more invasive treatment if this initial approach failed. After a minimum of 6 months of treatment, patients were asked to complete a follow-up questionnaire via phone or e-mail. Thirty-three men successfully completed the follow-up questionnaire. Pre- and post-treatment questionnaires were compared to determine treatment adherence and efficacy. RESULTS: The mean (range) age of the study cohort was 31.9 (22-39) years. At the initial consultation, 85% of men (n = 62) reported problems obtaining an erection. After a minimum of 6 months of treatment, only 42% reported the same problem (n = 14), with 58% (n = 19) satisfied with their erectile function. Post-treatment International Index of Erectile Function (IIEF) scores showed a significant improvement in erectile function (18.8 vs 13.3; P < 0.01), orgasmic function (7.7 vs 6.2; P = 0.01) and overall satisfaction (6.1 vs 4.5; P < 0.01). No statistically significant improvement was noted in sexual desire or intercourse satisfaction. CONCLUSIONS: Our proposed treatment approach for men with ED aged < 40 years without an identifiable organic aetiology appears to be a reasonable and effective first line approach, as demonstrated by significantly improved post-treatment IIEF scores and patient-reported outcomes. This algorithm can provide urologists with a useful framework for managing these potentially challenging patients. PMID- 29993197 TI - Young children with significant developmental delay differentiate home observed attachment behaviour towards their parents. AB - BACKGROUND: The hallmark of attachment is that contact, proximity and relief from stress are sought from specific individuals, laying important groundwork for healthy socioemotional functioning. This study investigated the extent to which differentiated attachment behaviour can be observed in young children with significant developmental delay (DD). METHOD: Video-taped observations of the parent-child and stranger-child interaction were conducted at home and complemented with questionnaires in 20 families with a child with significant DD (age 2-7 years with an average DD of 49 months). RESULTS: Children displayed more intense and persistent contact-seeking, contact-maintaining and resistant behaviour in the episodes with their parent compared to the episodes with the stranger. Parent-reported secure attachment behaviour was slightly more characteristic towards mother compared to father. CONCLUSIONS: Even children with significant DD develop differentiated attachment behaviour. Detailed observations may support parents in identifying the interactions that make the attachment relationship with their child special. PMID- 29993198 TI - Direct medical cost of diabetes in rural China using electronic insurance claims data and diabetes management data. AB - AIMS/INTRODUCTION: To evaluate the annual direct medical cost attributable to type 2 diabetes mellitus according to socioeconomic factors, medical conditions and complications categories. MATERIALS AND METHODS: We created uniquely detailed data from merging datasets of the local diabetes management system and the social security system in Tongxiang, China. We calculated the type 2 diabetes mellitus related total cost and out-of-pocket cost for inpatient admissions and outpatient visits, and compared the cost for patients with or without complications by different healthcare items. RESULTS: A total of 16,675 patients were eligible for analysis. The type 2 diabetes mellitus-related cost accounted for 40.6% of the overall cost. The cost per patient was estimated to be a median of 1,067 Chinese Yuan, 7,114 Chinese Yuan and 969 Chinese Yuan for inpatient and outpatient cost, respectively. The median total cost for hospital-based care was 3.69-fold higher than that for primary care. The median cost of patients with complications was 3.46-fold higher than that of those without complications. The median cost for a patient with only macrovascular, only microvascular or both macrovascular and microvascular complications were 3.13-, 3.79- and 10.95-fold higher than that of patients without complications. Pharmaceutical expenditure accounted for 51.8 and 79.7% of the total cost for patients with or without complications, respectively. CONCLUSIONS: Although the type 2 diabetes mellitus-related cost per patient was relatively low, it accounted for a great proportion of the overall cost. Complications obviously aggravated the economic burden of type 2 diabetes mellitus. Proper management and the prevention of diabetes and its complications are urgently required to curtail the economic burden. PMID- 29993199 TI - The oncogenic potentials and diagnostic significance of long non-coding RNA LINC00310 in breast cancer. AB - Recent studies have revealed that long non-coding RNAs (lncRNAs) are involved in different physiological processes and human diseases. However, to date, the function and overall clinical significance of the vast majority of lncRNAs in breast cancer remain largely unexplored. Here, we focused on LINC00310 by interrogating the breast invasive carcinoma data set of the Cancer Genome Atlas (TCGA). The results showed that LINC00310 was increased as breast cancer progressed, and the deregulation of LINC00310 was significantly associated with patients' survival. Experiments with knockout (KO) approach by CRISPR/Cas9 system and the subsequent rescue experiments revealed that LINC00310 promoted cell proliferation by regulating c-Myc expression in vitro. Nude mouse xenograft assay demonstrated that LINC00310 KO significantly suppressed tumour growth in vivo. Furthermore, we found that serum LINC00310 expression was significantly up regulated in patients with breast cancer, and receiver operating characteristic (ROC) curve analysis indicated that LINC00310 had a powerful capability of distinguishing patients with breast cancer from healthy individuals (the area under curve 0.828). Taken together, these results provide a more intuitive approach to explore the clinical relevance and functional roles of lncRNAs. As a result, lncRNAs, such as LINC00310, may be used in clinical applications as circulating markers for breast cancer. PMID- 29993200 TI - Lower birthweight and left-/mixed-handedness are associated with intensified age related sex steroid decline in men. Findings from the Men's Health 40+ Study. AB - In males, age-related decline in free testosterone (T) and dehydroepiandrosterone (DHEA) by 2-3% per year has been reported. Estradiol (E2) and progesterone (P) seem to decrease as well, but to a lesser extent. Lower sex steroid levels in men have been related to physical and mental symptoms. Low birthweight and left /mixed-handedness (L/MH) are indicators of an adverse fetal environment during pregnancy, and both have been linked to morbidity in later life. The aim of this study is to examine the relationship between lower birthweight as well as L/MH and age-related sex steroid decline. In a cross-sectional study design, saliva samples were collected under standardized conditions from healthy men for subsequent steroid hormone analysis using standard luminescence immunoassays. T (M = 67.57 pg/mL), DHEA (M = 247.91 pg/mL), E2 (M = 1.29 pg/mL), and P (M = 28.20 pg/mL) have been quantified leading to a final sample of 256 men providing complete data on sex hormones (MAge =57.8; SDAge = 10.8). Information on participants' birthweight was obtained from birth reports (N = 134), and participants were asked about their handedness (right-handed, left-handed, mixed handed) (N = 256). Multivariate-adjusted linear regression models relating each sex hormone individually and the principal component of declining steroid hormones (DSH)-an integrated hormonal parameter-with handedness and birthweight did not identify significant associations except for handedness and E2. Moderation analysis using robust regression accounting for bias due to influential data points detected a significant association between age and DSH for handedness (beta = -0.0314, p = 0.040) but only a trend for birthweight (beta = 0.0309, p = 0.073). For lower birthweight, a trend toward intensified age related sex steroid decline in men was observed, while for L/MH, a significant association with intensified age-related sex steroid decline was identified. These results indicate that L/MH and potentially also lower birthweight might be considered as early risk factors for endocrine health in later life. PMID- 29993201 TI - Dynamin-related protein 1-mediated mitochondrial fission contributes to IR-783 induced apoptosis in human breast cancer cells. AB - IR-783 is a kind of heptamethine cyanine dye that exhibits imaging, cancer targeting and anticancer properties. A previous study reported that its imaging and targeting properties were related to mitochondria. However, the molecular mechanism behind the anticancer activity of IR-783 has not been well demonstrated. In this study, we showed that IR-783 inhibits cell viability and induces mitochondrial apoptosis in human breast cancer cells. Exposure of MDA-MB 231 cells to IR-783 resulted in the loss of mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) depletion, mitochondrial permeability transition pore (mPTP) opening and cytochrome c (Cyto C) release. Furthermore, we found that IR-783 induced dynamin-related protein 1 (Drp1) translocation from the cytosol to the mitochondria, increased the expression of mitochondrial fission proteins mitochondrial fission factor (MFF) and fission-1 (Fis1), and decreased the expression of mitochondrial fusion proteins mitofusin1 (Mfn1) and optic atrophy 1 (OPA1). Moreover, knockdown of Drp1 markedly blocked IR-783-mediated mitochondrial fission, loss of MMP, ATP depletion, mPTP opening and apoptosis. Our in vivo study confirmed that IR-783 markedly inhibited tumour growth and induced apoptosis in an MDA-MB-231 xenograft model in association with the mitochondrial translocation of Drp1. Taken together, these findings suggest that IR-783 induces apoptosis in human breast cancer cells by increasing Drp1-mediated mitochondrial fission. Our study uncovered the molecular mechanism of the anti breast cancer effects of IR-783 and provided novel perspectives for the application of IR-783 in the treatment of breast cancer. PMID- 29993203 TI - The effect of ageism on older people and implications for nursing practice. AB - Ageism has numerous negative effects on the lives of older people, including their health and well-being. In this reflective account a nursing student explores these effects in the context of an incident where she was inadvertently ageist. She considers what she has learned from this incident and the implications for nursing practice. PMID- 29993202 TI - Sustainability of Pain Relief After Corneal Collagen Cross-Linking in Eyes With Bullous Keratopathy. AB - PURPOSE: This study aimed to examine the efficiency and sustainability of pain relief produced by corneal collagen cross-linking (CXL) in eyes with bullous keratopathy (BK) and to explore the histopathological changes in the stroma by using in vivo confocal microscopy. DESIGN: Prospective observational case series. METHODS: Fourteen eyes of 14 consecutive BK patients were treated with CXL with dehydration of the corneal stroma and followed up for 1 year after treatment. The best-corrected visual acuity (BCVA), intraocular pressure, and central corneal thickness (CCT) were examined before the treatments and up to 1 year after. The intensity and frequency of pain were graded on a scale from 0 (minimum) to 10 (maximum). At 1 year after CXL, the corneal stroma was observed using confocal microscopy at depths of 100 and 200 MUm. RESULTS: The BCVA and CCT did not change significantly. The mean pain intensity and frequency scores were 5.6 and 4.6, respectively, before treatment. The intensity score significantly decreased at 1 week and onward, and the frequency score significantly decreased over 6 months after treatment. The confocal microscopy images showed that keratocytes and nerve fibers were rare and sparsely distributed in the stroma 1 year after CXL. CONCLUSIONS: The CXL efficiently relieved pain due to BK for 1 year after treatment. The in vivo confocal microscopy observations and unchanged CCT demonstrated that the persistence of pain relief was due to the inadequate regeneration of nerve fibers in the corneal stroma. PMID- 29993204 TI - The Complex Needs of Medicaid Expansion Enrollees with Very Low Incomes. AB - Issue: Access to health care, use of services, and patient outcomes can be complicated by many medical and nonmedical factors. People facing complex challenges such as mental illness, housing insecurity, or substance use, however, are not a homogeneous group; different individuals have different needs. Goals: To understand the needs of people with very low income--no more than 75 percent of the federal poverty level--who enrolled in Medicaid under Minnesota's expansion of the program prior to the Affordable Care Act. Methods: The authors analyzed data on nondisabled, childless adults in the Minneapolis-St. Paul region who enrolled in Medicaid between 2011 and 2013. Findings and Conclusions: Early Medicaid expansion enrollees in urban Minnesota were largely nonwhite, male, and unmarried and had low educational attainment. In this very poor population, rates of homelessness, substance use, and mental illness were very high. More than 25 percent of adults dealt with two or more of these challenges, while 10 percent experienced all three. Providing access to a range of highly integrated health and social services may be the best way to help these individuals. PMID- 29993206 TI - Regulating Rare Disease: Safely Facilitating Access to Orphan Drugs. AB - While approximately one in ten Americans suffers from a rare disease, only 5 percent of rare diseases have a U.S. Food and Drug Administration (FDA) approved treatment. Congressional and regulatory efforts to stimulate the development of rare-disease treatments, while laudable, have not resolved the fundamental issues surrounding rare-disease treatment development. Indeed, small patient populations, incomplete scientific understanding of rare diseases, and high development costs continually limit the availability of rare-disease treatments. To illustrate the struggle of developing and approving safe rare-disease treatments, this Note begins by discussing the approval of Eteplirsen, the first drug approved for treating a rare disease called Duchenne muscular dystrophy. After exploring the current drug regulation system and how this impacts the availability of rare-disease treatments, this Note examines the 21st Century Cures Act's patient experience data provisions and the currently pending Trickett Wendler Right to Try Act. Ultimately, the unmet therapeutic needs of rare-disease patients can be met while protecting patient safety. This Note reasons that, if carefully implemented, the 21st Century Cures Act and the Trickett Wendler Right to Try Act could work in tandem to safely facilitate patient access to rare disease treatments. PMID- 29993205 TI - Designing a Medicare Help at Home Benefit: Lessons from Maryland's Community First Choice Program. PMID- 29993207 TI - Points & Pearls: Emergency department management of dyspnea in the dying patient AB - Dyspnea is one of the most distressing symptoms experienced by dying patients, and it is a common reason for such patients to seek care in the emergency department. Many underlying disease states and acute illnesses cause shortness of breath at the end of life, and management tends to be symptomatic rather than diagnostic, particularly in those for whom comfort is the most important goal. Opioids are the most effective and widely studied agents available for palliation of dyspnea in this population, while adjuvant therapies such as oxygen, noninvasive positive pressure ventilation, and hand-held fans may also be used. Benzodiazepines may also be helpful in select patients. The early involvement of palliative medicine specialists and/or hospice services for dying patients can facilitate optimal symptom management and transitions of care. [Points & Pearls is a digest of Emergency Medicine Practice.] PMID- 29993208 TI - The Protection of Patients Under the Clayton Act. AB - The vast consolidation among health-care providers in the aftermath of the Affordable Care Act's enactment has led to much debate over the benefits of mergers in the health-care industry. In 2016, the Federal Trade Commission filed motions in federal court to enjoin three hospital mergers in various parts of the country. This amounted to more challenges to hospital mergers in a single year than any year in recent history. Though two of these motions succeeded at the district court level, both were overturned on appeal, which led many to wonder what the effect of these decisions would be on future health-care mergers. While many fear that hospital mergers lead to higher prices for consumers, there are also those who contend that mergers lead to efficiencies, which allow merging parties to utilize resources more effectively, increase the quality of patient care and coordination, and potentially save lives. This Note argues that the possibility of quality-enhancing or life-saving efficiencies is worth the risk that consumers see increased prices. To allow mergers that may realize these types of efficiencies, antitrust enforcement agencies and courts must begin placing greater weight on merging parties' efficiency arguments by easing the current standard. Additionally, in light of new research suggesting that cross market health-care mergers, or mergers between providers in different geographic markets, affect bargaining dynamics between providers and insurers, this Note argues that parties' relative bargaining power must be considered in agencies' and courts' analyses of the competitive landscape relevant to a merger. PMID- 29993209 TI - Points & Pearls: Recognition and management of pediatric thyroid emergencies in the emergency department AB - The wide range and vague nature of clinical presentations of thyroid emergencies make accurate and timely diagnosis challenging. Patients with a variety of thyroid conditions present to the emergency department, and appropriate suspicion can reduce unnecessary delay and expense in determining the correct diagnosis. This issue reviews the current evidence for presentation, evaluation, and treatment for emergencies of thyroid function and anatomy including hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid trauma. Complications of thyroid dysfunction are also considered, as well as recommendations for disposition and follow-up. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice.] PMID- 29993210 TI - Divergent Responses in the Gap Prepulse Inhibition of the Acoustic Startle Reflex in Two Different Guinea Pig Colonies. AB - Animal models of tinnitus rely on interpretation of behavioural or reflexive tests to determine the presence of this phantom perception. A commonly used test is the gap prepulse inhibition of acoustic startle (GPIAS), which is often combined with prepulse inhibition (PPI) to ensure that reduced GPIAS suppression is not due to hearing loss caused by the acoustic trauma commonly used to trigger tinnitus development. In our laboratory GPIAS and PPI are routinely used on two colonies of outbred tri-colour guinea pigs. However, our results show that these colonies show divergent results even before any tinnitus-inducing treatment, which impacts their suitability in tinnitus models. Although colony 1 and 2 show similar results in PPI (~95% of animals showing significant suppression), only ~30% of colony 2 also shows significant suppression in GPIAS compared to ~75% of colony 1. Cochlear sensitivity measured using compound action potentials showed no significant differences between colonies. Therefore, peripheral threshold loss was excluded as a possible factor. Our results show that similar strains of laboratory animals can show highly divergent results and GPIAS testing for tinnitus will not work for every animal strain. In addition, our data support the notion that PPI and GPIAS responses may rely on different neural circuitry. PMID- 29993211 TI - Hyperacusis in Children: A Preliminary Study on the Effects of Hypersensitivity to Sound on Speech and Language. AB - There is a growing awareness that children may experience hyperacusis, a condition that is often associated with behavioral and developmental disorders. This preliminary study was aimed to investigate the effects of hyperacusis alone on various components of speech and language in children without developmental disorders. This study was conducted on 109 children aged between 4 and 7 years attending kindergarten and primary school. Hyperacusis was assessed through behavioral observation of children and questionnaires for parents. Different components of speech and language were assessed through specific tests. Hyperacusis was diagnosed in fifteen children (13.8%); ten (66.7%) were attending primary school and five (33.3%) kindergarten. A significant difference between children with and without hyperacusis was found for tests evaluating the average number of words in a sentence and phonemic fluency; older children appeared to have more difficulties. Several differences in education profiles were found: parents of children with hyperacusis spent less time with their children compared to parents of children without hyperacusis. Our preliminary results suggest some difficulties in lexical access and the use of shorter sentences by children with hypersensitivity to sound; however, the small size of our sample and the largely unknown interactions between hyperacusis and developmental disorders suggest caution when interpreting these results. Further studies on larger samples are necessary to gain additional knowledge on the effects of hyperacusis on speech and language in children without developmental disorders. PMID- 29993212 TI - Bilateral Deafness as a Complication of the Vaccination-A Case Report. AB - The vaccination has much profit for an infectious disease. On the other hand, there is little frequency, side effects may appear. It includes severe complication. We reported the case that resulted in bilateral acute profound hearing loss after mumps alone and measles and rubella (MR) vaccination. The case was a 5 years old girl. She inoculated mumps alone and MR vaccine. After 18days later, both sides profound hearing loss occurred in her. The hearing loss was not improved by the intravenous feeding of the steroid. Three months later, cochlea implantation was carried out to her right ear. She got hearing again. As for the hearing loss, mumps vaccine was considered as a cause from a latency period until the onset. The bilateral profound hearing loss that was a very rare complication was occurred by vaccination. The care of the hearing is important, but the mental care of an affected child and the parent is important, too. PMID- 29993213 TI - Transadaptation and Standardization of Tinnitus Primary Function Questionnaire in Hindi. AB - The term tinnitus is derived from the Latin word tinnire, meaning to ring. Although it is often referred to as "ringing in the ears, tinnitus can be perceived as many different sounds including hissing, clicking or whistling. India being a multilingual country needs to develop and standardize tinnitus questionnaire in Indian language. There are no significant test materials available with respect to Indian context based on Hindi, which can be routinely used by the professionals to assess the primary effect of tinnitus in patients. Thus, a need was felt to develop instrument in Hindi that can be used as per the ICF (International Classification of Functioning, Disability and Health) classification system in all over the country. The study aims to evaluate the impact of tinnitus on quality of life of clients having tinnitus with and without hearing loss by using primary function questionnaire (TPF-Hindi). The present study attempts to transadapt and standardize Tinnitus Primary function Questionnaire in Hindi. And administer both the questionnaires (TPFQ-H vs THQ-H) on the tinnitus clients with and without hearing loss and compare the impact of tinnitus in terms of quality of life in subjects with tinnitus with hearing loss and without hearing loss. A 12-item questionnaire was administered to 50 patients (tinnitus with hearing loss and without hearing loss) and compared between two questionnaires Tinnitus Primary Function Questionnaire and Tinnitus Handicapped Questionnaire (TPFQ-H & THQ-H). The results of the current study were analysed by using Statistical Package for the Social Sciences (SPSSv 20.0). Scores were positively correlated with the Tinnitus Handicap Questionnaire. There is significant correlation between both the scales and reliability between the scales is also good. PMID- 29993214 TI - Relationship between Otological Symptoms and TMD. AB - BACKGROUND: Patients with any type of temporomandibular disorder (TMD) may have several symptoms in their temporomandibular joints, masticatory muscles and associated structures, and may have otological symptoms such as tinnitus, ear fullness, ear pain, hearing loss, hyperacusis, and vertigo, which may be due to the anatomical proximity between the temporomandibular joint, muscles innervated by the trigeminal nerve, and ear structures. Objective: This study found a prevalence of ear complaints described in the medical records of patients (n = 485) at the Center for Diagnosis and Treatment of the Temporomandibular Joint and Dental-Facial Functional Alterations at Tuiuti University of Parana (CDATM/UTP), with TMD evaluated by the Research Diagnostic Criteria/Temporomandibular Disorders (RDC/ TMD). METHOD: After approval by the ethics committee were examined 485 medical records of patients of the CDATM/UTP, of both sexes a period of 2 years. The data analyzed were gender, age and the presence of reported otologic symptoms. The data were organized and subjected to statistical analysis using SPSS (IBM Statistic 20.0). RESULTS: The results showed a higher number of female patients between 41 and 50 years old. There was a prevalence of otological symptoms (tinnitus, deafness, dizziness, imbalance, and ear fullness) in 87% of TMD cases, regardless of sex and age. Tinnitus was the symptom with the highest prevalence (42%), followed by the ear fullness (39%). CONCLUSION: These data support the correlation between temporomandibular disorders and otological symptoms, even without being caused directly by the ear. PMID- 29993215 TI - The Diagnostic Value of Color Doppler Ultrasonography in Predicting Thyroid Nodules Malignancy. AB - BACKGROUND AND OBJECTIVE: Thyroid nodules are common medical and surgical problems. Although ultrasound has been proposed for evaluation of these nodules by many studies, but there is no consensus regarding its diagnostic accuracy and discriminatory cutoffs. We aimed to investigate the diagnostic value of Gray scale and Color Doppler US in predicting thyroid nodules malignancy. METHOD: This is an analytical cross-sectional study which was conducted on 63 patients with thyroid nodules. The patients with nodular goiter were evaluated by Color Doppler and Gray scale US, fine needle aspiration and surgery was performed in all the subjects. The sensitivity, specificity, positive predictive value, and negative predictive value of the finding in US and their cut offs were calculated. Data were analyzed by Chi-square and Mann Whitney U test in SPSS19. P-value less than 0.05 considered as statistically significant. RESULTS: 63 patients consisting of 55 (87.3%) female and 8 (12.7%) male patients with the age range of 20-70 years were enrolled in this study. 14% of nodules were reported as malignant in pathology. Singularity, hypo echogenicity, irregular margin, and micro calcification were significantly correlated with malignancy in nodules (p<0.05). Micro calcification and hypo echogenicity of the nodule were the most and the least discriminator of malignancy in nodules (sensitivity 77%, specificity 76% vs. 24%, PPV 41% vs., 14% and NPV 94% vs. 86%) respectively. Pulsatility Index and Mean Systolic Velocity were the most and the least predictor factors of thyroid malignancy (PPV 62% vs. 23% and NPV 100% vs. 91%, respectively). There was a significant association between Resistive Index and Pulsatility Index with malignancy with a cutoff of RI >= 0.715 (P=0.005) and PI >= 0.945 (P=0.007), respectively. The combination of calcification, RI >= 0.715 with PI >= 0.945 had a very diagnostic yield for diagnose of malignancy (PPV 66.6% and NPV 98.4%). CONCLUSION: According to results, it seems that Grayscale US combined with Color Doppler are valuable modalities for evaluating thyroid nodules and can be used as a para-clinical method in order to assess the risk of malignancy in the patient with thyroid nodules. PMID- 29993216 TI - Transtympanic Injections of N-acetylcysteine and Dexamethasone for Prevention of Cisplatin-Induced Ototoxicity: Double Blind Randomized Clinical Trial. AB - OBJECTIVE: Cisplatin is a potent chemotherapeutic agent that is used against a variety of tumors. The most common side effect of cisplatin is ototoxicity. This dose-related hearing impairment is high frequency, bilateral, and permanent. Unfortunately, there is no prophylactic protocol, and, in current clinical practice, the treatment of cancer with cisplatin is interrupted when ototoxicity develops or the resulting hearing impairment is tolerated as an acceptable side effect of cancer treatment. The aim of this study is to compare transtympanic injections of N-acetylcysteine and dexamethasone (both of which have shown substantial otoprotective activity) for the prevention of cisplatin-induced ototoxicity. METHODS: A double blind randomised clinical trial study of 60 cisplatin-treated patients was performed in Shahid Sadoughi Hospital in 2016 2017. Transtympanic injection of N-acetylcysteine (10%) and dexamethasone was performed. Hearing acuity was evaluated by an audiologist blinded to the treated ears before each cycle with pure tone audiometry (PTA) and six months later. RESULTS: Altogether, 114 transtympanic infusions were performed (57 in each group). The data were analyzed by the Fisher test and chi-squared. In the ears with N-acetylcysteine, no significant changes in auditory thresholds were recorded. In the ears with dexamethasone, cisplatin induced a significant decrease of auditory thresholds at the 8000 Hz frequency band (P = 0.001). CONCLUSION: Transtympanic injections of N-acetylcysteineas a safe and inexpensive antioxidant agent seem to be an effective otoprotective strategy for the prevention of cisplatin-induced ototoxicity and for increasing the quality of life, especially in children. PMID- 29993217 TI - The Clinician Managing Tinnitus Distress: A Preliminary Study in Clinical Engagement. AB - BACKGROUND: Tinnitus affects 10% of the population. It has been linked with depression, anxiety, insomnia and suicide. Because tinnitus is a symptom input from a multidisciplinary team of specialized clinicians is required and includes medical, allied health and mental health professionals. The study launched an enquiry into the knowledge, skills and attitudes of professionals dealing with clients with bothersome tinnitus. METHODS AND FINDINGS: Through an interpretive phenomenological lens, the life world of six participants, representing audiology (3), psychology (2) and otolaryngology (1) were chronicled. Participants were interviewed about their theoretical framework, the skills they employ, and the attitudes they bring to clinical encounters. The interview concluded with participants sharing a meaningful case. Data reached saturation and the analysis revealed four themes, centered on the value of connection, highlighting activities of reassurance and empowerment, while exposing clinician control and inter-professional criticism. The case studies appeared confessional. CONCLUSIONS: The participants' decision to not put shine and polish on a difficult encounter, but to strip away the barriers of learnedness and competence to reveal the fear, vulnerability and genuine care underneath, is an honest barometer of the clinical landscape for these dedicated clinicians. The critical need for ongoing professional support to clinicians, and further research into the clinician experience were stated. PMID- 29993218 TI - Evaluation of Adding Lidocaine to Dexamethasone in the Intra-tympanic Injection for Management of Tinnitus: A Prospective, Randomized, Controlled Double-blinded Trial. AB - OBJECTIVES: Assessment of adding lidocaine to dexamethasone in the intratympanic injections for the treatment of subjective idiopathic tinnitus (SIT). METHOD: A prospective, controlled, randomized, double-blind study of forty-four patients with SIT diagnosed in the Department of Otolaryngology, Tanta University Hospital, a tertiary academic medical centre from March 2015 to October 2016. 44 patients were recruited in the study and were categorized into two groups; (A) included 22 patients managed with ITLD, and (B) included 22 patients managed with intratympanic postoperative ITD injection. Intratympanic injections were double blind performed three times with one weak interval. After three and six months, the tinnitus improvement was studied using the following parameters: Arabic tinnitus questionnaires (ATQ), loudness matching test and Tinnitus handicap index (THI). RESULTS: The effectiveness rates of ITLD for idiopathic tinnitus reported in the ATQ, THI, and in the loudness matching test were 74.5% in the ITDL group and 50.0%, 50.5%, and 40.0% in the ITD group, respectively. Statistically, there was a significant difference between both groups in 6 months duration. CONCLUSION: ITLD seems to be effective for SIT than ITD alone. The indication of ITLD for tinnitus needs to be limited to specific cases of resistant medical treatment. PMID- 29993219 TI - Preschool Children Hearing Impairment: Prevalence, Diagnosis and Management in a Developing Country. AB - OBJECTIVES: Preschool children hearing impairment is a common otologic diseases worldwide. The burdens of this preventable condition can be reduced in developing country. This study was carried out to determine the prevalence, diagnosis and management of hearing impairment among children less than 5 years seen in our center. METHOD: This was a prospective hospital based study of preschool children with complaints of hearing impairment in Ekiti state university teaching hospital, Nigeria. This study was conducted over a period of two years (February 2016 to January 2018). Data was obtained from consented patients by using pretested interviewers assisted questionnaire. Data obtained was collated and analyzed by using SPSS software version 18.0. D escriptive statistics was used to present and expressed the data as simple tables and charts. RESULTS: The prevalence of hearing impairment in this study was 5.9% with peak value of 37.6% at preschool age 3 years. There were 42.6% males and 57.4% females. Majority (51.5%) of the patients were urban dwellers. The aetiologic factors of hearing impairment include; 15.8% neonatal jaundice, 13.9% febrile illness, 12.9% otitis media and 11.9% birth asphyxia. Prelingual presentation was commonest in 57.4%. Common clinical features includes yet to speak, restlessness/stubborn and not responding to command in 60.4%, 48.5% and 46.5% respectively. Commonest type of hearing impairment was sensorineural hearing loss is 61.4%. Type A tympanometry (normal) was the commonest findings in 82.2%. CONCLUSION: Preschool children hearing impairment with late presentation is a common otologic diseases burden to parent and otorhinolaryngologist in our center. The common causes were preventable with resulting permanent auditory damage. PMID- 29993220 TI - Characteristics and Management of Childhood Tinnitus in a Developing Country. AB - OBJECTIVES: Tinnitus is a commonly neglected otologic symptom among children in developing country. This study aimed at determining the prevalence, clinical characteristics, diagnosis and management of childhood tinnitus in a developing country. METHOD: This prospective hospital based study of patients' age 18 years and below with complaints of tinnitus was conducted in Ear, Nose and Throat Department of Ekiti state UniversityTeaching Hospital,Ado Ekiti,Nigeria between April 2016 to March 2018. The parents/guardians/patients were briefed about the scope of the study. After getting oral consent, pretested interviewers assisted questionnaire was administered to collect data. Data obtained were collated and analyzed using SPSS software version 18.0 and was expressed in simple tables and charts. RESULTS: Prevalence of tinnitus in this study was 6.2%. There were 56.1% males and male to female ratio was 1.5:1. Majority 55.3% had single episode of tinnitus and long duration (>3 months) was commonest form of tinnitus in 59.1%. Bilateral tinnitus was recorded in 68.9% while subjective tinnitus constituted 93.9%. Discrete tinnitus was commoner in 67.4%. Major causes of tinnitus were febrile illnesses, otitis media, noise exposure, unknown (idiopathic), earwax impaction and ototoxicity in 19.7%, 16.7%, 15.9%, 14.4%, 12.9% and 9.8% respectively. A commonest tympanometric finding was type A in 72.7% of patients. Commonly affected quality of life were anxiety, depression and attention problem in 51.5%, 43.2% and 40.2% respectively. Associated comorbid illnesses in this study were 50.8% sleeping disorders, 42.4% concentration disorders and 31.1% headache. Referrals were mainly from paediatrician in 44.7%. Prehospital treatment was mainly medication in 62.1%. All the patients were counselled (assured). Other treatments given were conservative treatment, surgery, ear syringing and hearing aids in 56.1%, 15.9%, 12.9% and 9.1% patients respectively. CONCLUSION: Childhood tinnitus is caused by preventable diseases. At presentation there were associated hearing impairment, comorbid illnesses and affectation of quality of life. PMID- 29993221 TI - A Review of a Steady State Coherent Bio-modulator for Tinnitus Relief and Summary of Efficiency and Safety Data from the Clinical Study Program and Post Market Clinical Follow-up. AB - OBJECTIVES: To evaluate a non-energy consuming light bio-modulator patch creating coherency for tinnitus relief. MATERIALS AND METHODS: Three independent clinical studies and continuous post market clinical follow up have been performed during the year 2012 to 2018. The first study was a limited interventional investigation with 10 patients, the second was a larger interventional study with finally 48 patients further investigated, and the third a randomized, placebo-controlled, double-blind study with 82 patients. In the clinical studies patch performance evaluated with questionnaires related to tinnitus, quality-of-life, and safety were assessed prior, during and after the end of treatment. In all studies the treatment time was 3 weeks and the patches were placed behind one year. RESULTS: The first study indicated a relief with half of the patients at the end of the treatment. Still two years after the study one third reported tinnitus relief. However, the numbers of patients were low. The second study showed a responder relief in 58% directly after end of treatment and 60% one month after. The third study showed that the biomodulator patch had statistical significant three times more responders than placebo one month after end of treatment, measured as a decrease from baseline in at least 2 points in tinnitus annoyance visual analogue scale as a minimal clinical significant difference. Tinnitus handicap inventory was improved by mean-16 points significantly for the active responder group, but with no statistically significant changes for the placebo group or between the groups. The biomodulator patch was safe and well-tolerated in all three studies. The post market clinical follow up has shown a 30% reported relief and with no new risks or unexpected issues affecting the effectiveness or safety. CONCLUSION: Taken under consideration the lack of easy-to-use alternative and the low risk profile, this patch device could highly be recommended to try for tinnitus relief as a conclusion based on the clinical studies and post market surveys. Further studies of how this bio-modulator more specific act on the auditory system, how long this may sustain and if there can be subgroups of patients or variations in the treatment time, delayed onset, number of patches, and frequency for more efficiency needs to be considered. PMID- 29993222 TI - Demographic Variations in Tinnitus Subjects with and without Hearing Loss: A Study of 175 Subjects. AB - OBJECTIVES: This research was conducted to investigate the presenting features of tinnitus in subjects with normal hearing thresholds as compared to the ones with hearing loss. METHODOLOGY: Sample population comprised of 175 subjects with tinnitus, in the age range of 18 to 55 years, segregated into two groups: G1 (75 subjects) having normal hearing with tinnitus and G2 (100 subjects) having hearing loss with tinnitus. All the subjects underwent conventional audiometric testing along with a thorough evaluation of all the parameters of tinnitus. RESULTS AND CONCLUSION: Significantly large number of males reported with tinnitus as compared to females. Tinnitus was most prevailing in left ear and these subjects sought intervention earlier than right tinnitus subjects. G1 subjects reported earlier as compared to G2 subjects. Males looked out for specialist's advice earlier than females in both the groups. Large number of subjects in both groups reported with sudden onset and continuous tinnitus. PMID- 29993223 TI - Effects of Spirulina on GABA Receptor Gene Expression in Salicylate-Induced Tinnitus. AB - OBJECTIVES: The function of gamma-amino butyric acid receptor (GR) was related with tinnitus. But, the effects of Spirulina platensis water extract (SP) on the mRNA expression of GRAbeta3 in mice with tinnitus were still unclear. METHOD: Eighteen SAMP8 mice were divided into the control group (intraperitoneal injection of saline, once per day), the tinnitus group (intraperitoneal injection of salicylate, 300 mg/kg body weight once per day), and the spirulina group [intraperitoneal injection of salicylate, 300 mg/kg body weight and oral SP supplementation (1000 mg/kg body weight) once per day]. Effects of SP on the mRNA expression of GRAbeta3 in the cochlea and brain of mice were studied for 4 days. RESULTS: Compared to the control group, the tinnitus group had significantly higher tinnitus scores and lower mRNA expression of GRAbeta3 gene in the cochlear, brainstem, hippocampus and parahippocampus, temporal lobes, and the frontal lobes. On the other hand, the spirulina group had significantly lower tinnitus scores and higher GRAbeta3 gene expression than the tinnitus group in all tested areas. CONCLUSION: SP could reduce salicylate-induced tinnitus possibly via increasing the salicylate-induced down-regulation of GRAbeta3 gene expression. PMID- 29993224 TI - Effect of ESS on Olfactory Threshold of Patients with CRS without Nasal Polyps. AB - OBJECTIVES: Chronic rhinosinusitis (CRS) is characterized by a long-time inflammatory disease of nasal and sinus mucosa. Olfactory dysfunction is common among CRS patients with a prevalence ranging from 48% to 83%. We aimed to assess the effect of ESS on olfactory function of patients with chronic rhinosinusitis without nasal polyps. METHOD: This randomized clinical trial was conducted on 30 patients with chronic rhinosinusitis without nasal polyps. Patients were randomly allocated to two intervention and control groups; patients in intervention group underwent endoscopic sinus surgery by a single surgeon and control group continued standard treatment with nasal irrigation of normal saline (4 times daily) and nasal corticosteroids (one puff in each nostril daily). Olfactory threshold was evaluated using smell threshold test (STT) before, one month and three months after intervention. RESULTS: Eventually 33 patients with a mean age of 42.70 +/- 15.50 years in intervention and 43.12 +/- 11.50 years in control group underwent analysis (p value=0.930). Mean olfactory threshold was 2.79 +/- 0.73 in intervention and 2.67 +/- 1.05 in control group prior to intervention (p value=0.345). Mean change of olfactory threshold was 0.30 +/- 0.79 in intervention and 0.38+/-1.09 in control group one month after intervention (p value=0.214). Mean change of olfactory threshold was 0.13 +/- 0.94 in ESS and 0.33 +/- 0.60 in control group three months after intervention (p value=0.196). CONCLUSION: Our study revealed that changes in olfactory threshold were not significantly different between two ESS and standard medical therapy groups one and three months after intervention. PMID- 29993225 TI - United States v. Caronia: Off-Label Drug Promotion and First Amendment Balancing. AB - Off-label drug promotion is commonplace in the United States, but it is not without its dangers. While the Food, Drug, and Cosmetic Act does not explicitly ban off-label promotion, the Food & Drug Administration (FDA)--in order to protect consumers from unsafe and ineffective drugs--has taken steps to regulate it. The FDA does so through its intended-use regulation, which lists the types of evidence the FDA can consider in determining whether a drug is misbranded. It is a crime to sell a misbranded drug into interstate commerce or to conspire to do so. On September 25, 2015, the FDA proposed an amendment to the regulation, which has drawn opposition from various industry groups due to its potential to restrict the type of speech that is often used in off-label promotion. The First Amendment challenge to the proposed amendment rests on United States v. Caronia, in which the FDA was prevented from using truthful, nonmisleading speech to convict a pharmaceutical representative of a conspiracy to sell a misbranded drug. This Note examines whether the amendment to the regulation is permissible under Caronia. It first contends that the regulation does not facially violate the First Amendment. It further argues that the rule is constitutional and does not pose the same First Amendment issue as was seen in Caronia as long as the FDA implements it with care. This Note concludes by exploring various ways that the FDA can constitutionally regulate off-label drug promotion under the proposed rule. PMID- 29993226 TI - Race and Assisted Reproduction: Implications for Population Health. AB - This Article emerges from Fordham Law Reviews Symposium on the fiftieth anniversary of Loving v. Virginia, the case that found antimiscegenation laws unconstitutional. Inspired by the need to interrogate the regulation of race in the context of family, this Article examines the diffuse regulatory environment around assisted reproductive technology (ART) that shapes procreative decisions and the inequalities that these decisions may engender. ART both centers biology and raises questions about how we imagine our racial futures in the context of family, community, and nation. Importantly, ART demonstrates how both the state and private actors shape family formation along racial lines. By placing a discussion about race and ART in the context of access to new health technologies, this Article argues that assisted reproduction has population-level effects that mirror broader racial disparities in health. In turn, this Article intervenes in a bioethics debate that frequently ignores inequalities in access when thinking through the consequences of ART. Part I presents a case study of the Sperm Bank of California (SBC) to demonstrate how ART represents a new mode of governing the family that facilitates and encourages the formation and creation of monoracial families. Part II borrows a public health analytic, the 'burdens of disease," to explain how the (re)production of monoracial families has consequences for health at the population level, especially when placed in the context of racially disparate access to ART services. Ultimately, this Article concludes that ART, as it is currently accessed and utilized, maintains racial orders with regard to health given the inequality in access to these services. PMID- 29993227 TI - Civil Rights--Eighth Amendment--Third Circuit Holds Parents of Mentally Ill Young Man Held in Solitary Confinement Stated Claims of Cruel and Unusual Punishment.- Palakovic v. Wetzel, 854 F.3d 209 (3d Cir. 2017). PMID- 29993228 TI - The Incidental Fertility Effects of School Condom Distribution Programs. AB - While the fertility effects of improving teenagers' access to contraception are theoretically ambiguous, most empirical work has shown that access decreases teen fertility. In this paper, we consider the fertility effects of access to condoms- a method of contraception not considered in prior work. We exploit variation across counties and across time in teenagers' exposure to condom distribution programs in schools. We find that access to condoms in schools increases teen fertility by about 12 percent. The results suggest that the effects of condom access varied significantly across different programs; the positive fertility estimates are driven by communities where condoms are provided without mandated counseling. Programs that mandated counseling have zero or negative fertility effects, but estimates on these counties are less robust across specifications. PMID- 29993229 TI - The Impact of Insurance Coverage on Utilization of Prescription Contraceptives: Evidence from the Affordable Care Act. AB - The Affordable Care Act (ACA) mandates that prescription contraceptives be covered by private health insurance plans with no cost sharing. Using medical and prescription claims from a large national insurer, I estimate individual claim rates and out-of-pocket (OOP) costs of prescription contraceptives for 329,642 women aged 13 to 45 who were enrolled in private health insurance between January 2008 and December 2013. I find that OOP spending on contraceptives has decreased sharply since the implementation of the ACA mandate. Using a difference-in difference model that leverages employer level variation in compliance with the mandate, I estimate the effect of the mandate on use of both short- and long-term methods of prescription birth control. I find that the mandate has increased insurance claims for short-term contraceptive methods (the pill, patch, ring, shot, diaphragms/cervical caps, and prescription emergency contraception) by 4.8 percent and increased initiation of long-term methods (intrauterine devices, implant, or sterilization) by 15.8 percent. Using data from a national survey of reproductive age women during this same time period, a back-of-the-envelope calculation suggests that the mandate increased total use of any method of prescription contraceptive use by 2.95 percentage points among privately insured women in 2013, or a 6.57 percent relative increase. These increases in use of prescription contraceptives among privately insured women in the United States as a result of the ACA mandate have important potential implications for fertility rates, health care spending, and economic outcomes for women and their families. PMID- 29993230 TI - State-Based Marketplaces Outperform Federally-Facilitated Marketplaces. AB - In response to regulatory changes at the federal level, states that run their own marketplaces have taken steps to stabilize their individual markets. In this comparison of state-based and federally-facilitated marketplaces from 2016-2018, we find that SBMs had slower premium increases (43% vs. 75%), and fewer carrier exits, than FFMs. The total population participating in FFMs declined by 10%, while the enrolled population in SBMs remained largely stable, increasing by 2%. We find that the performance of the ACA marketplaces varies by state and appears to cluster around marketplace types. PMID- 29993231 TI - Highly Sensitive Wearable Pressure Sensors Based on Three-Scale Nested Wrinkling Microstructures of Polypyrrole Films. AB - Pressure sensors have a variety of applications including wearable devices and electronic skins. To satisfy the practical applications, pressure sensors with a high sensitivity, a low detection limit, and a low-cost preparation are extremely needed. Herein, we fabricate highly sensitive pressure sensors based on hierarchically patterned polypyrrole (PPy) films, which are composed of three scale nested surface wrinkling microstructures through a simple process. Namely, double-scale nested wrinkles are generated via in situ self-wrinkling during oxidative polymerization growth of PPy film on an elastic poly(dimethylsiloxane) substrate in the mixed acidic solution. Subsequent heating/cooling processing induces the third surface wrinkling and thus the controlled formation of three scale nested wrinkling microstructures. The multiscale nested microstructures combined with stimulus-responsive characteristic and self-adaptive ability of wrinkling morphologies in PPy films offer the as-fabricated piezoresistive pressure sensors with a high sensitivity (19.32 kPa-1), a low detection limit (1 Pa), an ultrafast response (20 ms), and excellent durability and stability (more than 1000 circles), these comprehensive sensing properties being higher than the reported results in literature. Moreover, the pressure sensors have been successfully applied in the wearable electronic fields (e.g., pulse detection and voice recognition) and microcircuit controlling, as demonstrated here. PMID- 29993232 TI - Electrospraying Electrospun Nanofiber Segments into Injectable Microspheres for Potential Cell Delivery. AB - Nanofiber microspheres have attracted a lot of attention for biomedical applications because of their injectable and biomimetic properties. Herein, we report for the first time a new method for fabrication of nanofiber microspheres by combining electrospinning and electrospraying and explore their potential applications for cell therapy. Electrospraying of aqueous dispersions of electrospun nanofiber segments with desired length obtained by either cryocutting or homogenization into liquid nitrogen followed by freeze-drying and thermal treatment can form nanofiber microspheres. The microsphere size can be controlled by varying the applied voltage during the electrospray process. A variety of morphologies were achieved including solid, nanofiber, porous and nanofiber microspheres, and hollow nanofiber microspheres. Furthermore, a broad range of polymer and inorganic bioactive glass nanofiber-based nanofiber microspheres could be fabricated by electrospraying of their short nanofiber dispersions, indicating a comprehensive applicability of this method. A higher cell carrier efficiency of nanofiber microspheres as compared to solid microspheres was demonstrated with rat bone marrow-derived mesenchymal stem cells, along with the formation of microtissue-like structures in situ, when injected into microchannel devices. Also, mouse embryonic stem cells underwent neural differentiation on the nanofiber microspheres, indicated by positive staining of beta-III-tubulin and neurite outgrowth. Taken together, we developed a new method for generating nanofiber microspheres that are injectable and have improved viability and maintenance of stem cells for potential application in cell therapy. PMID- 29993233 TI - Tellurium/Bovine Serum Albumin Nanocomposites Inducing the Formation of Stress Granules in a Protein Kinase R-Dependent Manner. AB - The effect of nanoparticles (NPs) on cellular stress responses is important to the understanding of nanotoxicities and developing safe therapies. Although the relationship between NPs and cellular stress responses has been preliminarily investigated, stress responses to NPs remain unclear. Here, tellurium/bovine serum albumin (Te/BSA) nanocomposites were prepared using sodium tellurite, BSA, and glutathione as precursors. The as-prepared Te/BSA nanocomposites, with particle size similar to that of many viruses, are found to induce the formation of stress granules (SGs), a kind of cytoplasmic RNA granule formed under various stresses. The SGs in Te/BSA nanocomposite-treated cells are composed of T-cell internal antigen 1 (TIA1), TIA1-related protein, and eukaryotic initiation factor 3eta. Using chemical inhibitors and small interfering RNA-mediated silencing, protein kinase R (PKR) is identified as the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha)-kinase activated upon Te/BSA nanocomposite incubation, which is also the dominant kinase responsible for eIF2alpha activation under virus infection. Mechanistically, PKR is activated in a heparin dependent manner. This study reveals a biological effect of Te/BSA nanocomposites on stress responses, providing a preliminary basis for further research on viruslike particles and the application of NPs in biology. PMID- 29993235 TI - Nature Builds Macrocycles and Heterocycles into Its Antimicrobial Frameworks: Deciphering Biosynthetic Strategy. AB - Natural products with anti-infective activity are largely of polyketide or peptide origin. The nascent scaffolds typically undergo further enzymatic morphing to produce mature active structures. Two kinds of common constraints during maturation of immature scaffolds to active end point metabolites are macrocyclizations and hetrocyclizations. Each builds compact architectures characteristic of many high affinity, specific ligands for therapeutic targets. The chemical logic and enzymatic machinery for macrolactone and macrolactam formations are analyzed for antibiotics such as erythromycins, daptomycin, polymyxins, and vancomycin. In parallel, biosynthetic enzymes build small ring heterocycles, including epoxides, beta-lactams, and beta-lactones, cyclic ethers such as tetrahydrofurans and tetrahydropyrans, thiazoles, and oxazoles, as well as some seven- and eight-member heterocyclic rings. Combinations of fused heterocyclic scaffolds and heterocycles embedded in macrocycles reveal nature's chemical logic for building active molecular frameworks in short efficient pathways. PMID- 29993234 TI - Polymeric Nanomedicine with "Lego" Surface Allowing Modular Functionalization and Drug Encapsulation. AB - Surface functionalization of nanoparticles (NPs) is of pivotal importance in nanomedicine. However, current strategies often require covalent conjugation that involves laborious design and synthesis. Herein, cucurbit[7]uril (CB[7]) decorated poly(lactic acid) (PLA)/poly(lactic-co-glycolic acid) (PLGA) NPs are developed and exploited for the first time as a novel, biocompatible, and versatile drug delivery platform with a noncovalently tailorable surface. CB[7] on the surface of NPs, acting as a "Lego" base block, allowed facile, modular surface modification with a variety of functional moieties or tags that are linked with amantadine (a complementary "Lego" piece to the base block), including amantadine-conjugated folate, polyethylene glycol, and fluorescein isothiocyanate. In addition, surface CB[7] also provided an opportunity for encapsulation of a secondary drug, such as oxaliplatin, into the cavity of the base block CB[7], in addition to a primary drug (e.g., paclitaxel) loaded into PLA/PLGA NPs, for a possible synergistic chemotherapy. This proof of concept not only provides the first versatile PLA/PLGA nanomedicine platform with "Lego" surface for modular functionalization and improved drug delivery but also offers new insights into the design and development of novel nanomedicine with a modular surface. PMID- 29993236 TI - Solvent-Free CO2 Capture Using Membrane Capacitive Deionization. AB - Capture of CO2, originating from both fossil fuels, such as coal combustion, and from renewables, such as biogas, appears to be one of the greatest technological challenges of this century. In this study, we show that membrane capacitive deionization (MCDI) can be used to capture CO2 as bicarbonate and carbonate ions produced from the reaction of CO2 with water. This novel approach allows capturing CO2 at room temperature and atmospheric pressure without the use of chemicals. In this process, the adsorption and desorption of bicarbonate ions from the deionized water solution drive the CO2(g) absorption-desorption from the gas phase. In this work, the effects of the current density and the CO2 partial pressure were studied. We found that between 55 and 75% of the electrical charge of the capacitive electrodes can be directly used to absorb CO2 gas. The energy requirement of such a system was found to be ~40 kJ mol-1 at 15% CO2 and could be further improved by reducing the ohmic and non-ohmic energy losses of the MCDI cell. PMID- 29993237 TI - High Resolution Capillary Isoelectric Focusing Mass Spectrometry Analysis of Peptides, Proteins, And Monoclonal Antibodies with a Flow-through Microvial Interface. AB - Capillary isoelectric focusing directly coupled to high resolution mass spectrometry (cIEF-MS) provides information on amphoteric molecules, including isoelectric point and accurate mass, which enables structural interrogation of biopolymer pI variants. The coupling of cIEF with MS was facilitated by a flow through microvial interface, made by stainless steel with high chemical resistance and mechanical robustness. Two on-column electrolyte configurations of cIEF-MS were demonstrated using peptide and protein pI markers. The pI resolution was 0.02 pH unit in the pH range of 5.5 to 7.0, with no anticonvective reagent (glycerol) added. High resolution Orbitrap detector provides mass spectra for midsized proteins (<30 kDa), enabling deconvolution with high accuracy for IEF focused low abundance species. Charge heterogeneity of therapeutic monoclonal antibodies (mAb) is one of the most important attributes in the biopharmaceutical industry, and it is routinely monitored by IEF and fractionation-based methods. As a proof of concept, the commercial formulation of infliximab was directly analyzed using cIEF-MS for separation and online identification of mAb charge variants. The main intact antibody species along with two basic and one acidic variants were observed, and their accurate molecular weights ( Mw) recorded by MS detector readily revealed the structural differences of these variants. Variants with 0.1 unit in pI difference and 1 Da difference in molecular weight were readily resolved. The deconvoluted intact Mw values showed ppm level accuracy compared to theoretical predictions. PMID- 29993238 TI - Integrated Antibody with Catalytic Metal-Organic Framework for Colorimetric Immunoassay. AB - Enzyme-linked immunosorbent assay has been widely used as a gold standard in biomedical field, but some inevitable drawbacks still exist in its practical applications, especially the laborious preparation of enzyme-antibody conjugates by a covalent linkage. In this work, we proposed a new strategy to prepare enzyme antibody conjugate by integrating antibody with catalytic metal-organic framework (MOF) to form dual-functional MOF/antibody composite. As models, rabbit antimouse immunoglobulin G antibody (RIgG) and Cu-MOF with peroxidase-like activity were used to fabricate RIgG@Cu-MOF composite for colorimetric immunoassay. It was found that Cu-MOF as a host not only has no influence on the original capture ability of RIgG to its corresponding antigen (mIgG), but also can shield RIgG against long-term storage, high temperature, and biological degradation. More importantly, upon the formation of sandwiched immunocomplex between RIgG@Cu-MOF and capture antibody, Cu-MOF can serve as a signal amplification unit to perform colorimetric immunoassay. The detection limit of RIgG@Cu-MOF toward mIgG was obtained at 0.34 ng/mL, which is 3-fold lower than that of horseradish peroxidase labeled RIgG. Furthermore, the successful determination of mIgG in serum sample demonstrates the applicability of RIgG@Cu-MOF in detecting real sample. Therefore, it is highly anticipated that this study can offer a new way to prepare enzyme-antibody conjugates, facilitating the exploration of MOF composites in biomedical field. PMID- 29993239 TI - The Impact of Carbon Source as Electron Donor on Composition and Concentration of Dissolved Organic Nitrogen in Biosorption-Activated Media for Stormwater and Groundwater Co-Treatment. AB - Eutrophication has been a long-term issue in aquatic environments, where dissolved organic nitrogen (DON) recalcitrance is important. Bioavailable nitrogen qualification and quantification for effluents from stormwater and wastewater are always a challenge. The information in this study deepens the understanding of the interactions between carbon addition and DON decomposition through linear-ditch best management practices for stormwater and groundwater cotreatment. By running a laboratory-scale column study for nitrogen removal using green sorption media, the variation in composition and concentration of DON can be further linked to the population dynamics of microbial species that dominate the nitrification and denitrification processes. With the varying levels of influent total nitrogen concentration, the efficacy of nitrogen removal via biosorption activated media may be realized at the molecular level with ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry. PMID- 29993240 TI - Rear-Surface Passivation by Melaminium Iodide Additive for Stable and Hysteresis less Perovskite Solar Cells. AB - Surface passivation of perovskite grains is one of the promising methods to reduce recombination and improve stability of perovskite solar cells (PSCs). We herein report the effect of a melaminium iodide additive on the photovoltaic performance of PSCs based on (FAPbI3)0.875(CsPbBr3)0.125 perovskite. Cyclic -C?N- and primary amine in melamine are a good hydrogen bond acceptor and Lewis base, which can interact with both the organic cation and Lewis acidic lead iodide in the perovskite film. Melaminium iodide is synthesized and added to the precursor solution, which is directly spin-coated to form the perovskite film. The presence of melaminium iodide additive reduces the trap density from 1.02 * 1016 to 0.645 * 1016 cm-3, which leads to the reduction of nonradiative recombination and thereby improving the mean open-circuit voltage and the fill factor from 1.054 to 1.095 V and from 0.693 to 0.725 V, receptively. In addition, photocurrent-voltage hysteresis is reduced by the melaminium iodide additive, which results in an enhanced average power conversion efficiency, obtained from reverse and forward scanned data, from 15.86 to 17.32%. Time-resolved photoluminescence confirms that melaminium iodide plays a more important role in passivating the rear surface of the perovskite layer contacting the hole transporting spiro-MeOTAD layer. An aging test under a relative humidity of 65% reveals that melaminium iodide improves stability because of the suppression of the defect evolved by moisture. PMID- 29993241 TI - MOF-808: A Metal-Organic Framework with Intrinsic Peroxidase-Like Catalytic Activity at Neutral pH for Colorimetric Biosensing. AB - Natural enzyme mimetics with high catalytic activity at nearly neutral pH values are highly desired for their applications in biological systems. Herein for the first time a stable MOF, namely MOF-808, has been shown to possess high intrinsic peroxidase-like catalytic activity under acidic, neutral, and alkaline conditions. As a novel peroxidase mimetic, MOF-808 can effectively catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine when H2O2 serves as oxidant, accompanied by a significant color variation in the solution. The catalytic activity and the color variation were greatly dependent on H2O2 concentration, and thus MOF-808 can be applied to the colorimetric sensing of H2O2. The H2O2 detection limit is 4.5 MUM, and the linear range is 10 MUM to 15 mM. In view of the significant inhibition effect produced by ascorbic acid, a facile and sensitive approach for colorimetric sensing of ascorbic acid was successfully established. The AA detection limit is 15 MUM, and the linear range is 30-1030 MUM. Further investigation found that the catalytic activity of MOF-808 could be mainly ascribed to the Zr-OH(OH2) groups. Such active Zr-OH(OH2) groups can be effectively shielded by gluconic acid, and subsequently the catalytic activity of MOF-808 was significantly suppressed. With these findings, a facile and selective colorimetric assay for glucose sensing has been successfully explored via combination of the glucose oxidation with the TMB oxidation. The glucose detection limit is 5.7 MUM, and the linear range is 5.7-1700 MUM. MOF-808 is one of the best colorimetric biosensors among the peroxidase mimics reported for H2O2, AA, and glucose detection. PMID- 29993242 TI - ColDock: Concentrated Ligand Docking with All-Atom Molecular Dynamics Simulation. AB - We propose a simple but efficient and accurate method to generate protein-ligand complex structures, called Concentrated ligand Docking (ColDock). This method consists of multiple independent molecular dynamics simulations in which ligands are initially distributed randomly around a protein at relatively high concentration (~100 mM). This condition significantly increases the probability of the ligand exploring the protein surface, which induces spontaneous ligand binding to the correct binding sites within a 100 ns MD. After clustering of the protein-bound ligand poses, representatives of the populationally dominant clusters are considered as predicted ligand poses. We applied ColDock to four cases starting from holo protein structures and showed that ColDock can generate "correct" ligand poses very similar to the crystal complex structures. Correct ligand poses are also well reproduced in three out of four cases started from apo structures, with the exception being a case with an initially closed binding pocket. The results indicate that ColDock can be used as a protein-ligand docking as long as the ligand binding pocket is initially open. Plausible protein-ligand complex structures can be easily generated by conducting the ColDock procedure using standard MD simulation software. PMID- 29993244 TI - Selective Synthesis of 2-Substituted and 1,2-Disubstituted Benzimidazoles Directly from Aromatic Diamines and Alcohols Catalyzed by Molecularly Defined Nonphosphine Manganese(I) Complex. AB - Herein, we present a selective synthesis of 2-substituted and 1,2-disubstituted benzimidazoles by acceptorless dehydrogenative coupling of aromatic diamine with primary alcohols. The reaction is catalyzed by a phosphine-free tridentate NNS ligand-derived manganese(I) complex. PMID- 29993243 TI - Role of NH3 in the Heterogeneous Formation of Secondary Inorganic Aerosols on Mineral Oxides. AB - In this work, a relationship between the role of NH3 and the properties of mineral oxides (alpha-Fe2O3, alpha-Al2O3, CaO, and MgO) in the evolution of NO3-, SO42-, and NH4+ has been established. It was found that the promotion effect of NH3 was more favorable for the formation of NO3- (or SO42-) and NH4+ on acidic alpha-Fe2O3 and alpha-Al2O3 due to acid-base interactions between NO2 with NH3 or between SO2 and NH3, while this effect was weaker on basic CaO and MgO possibly due to their basic nature. The acid-base interaction (NO2/SO2 with NH3) overpowered the redox reaction (SO2 with NO2) on Fe2O3 owing to its unique redox chemistry. However, the opposite was found on basic CaO and MgO for the formation of SO42- and NO3-. Under equivalent concentration conditions, the two synergistic effects did not further strengthen on Fe2O3, CaO and MgO due to a competition effect. In NH3-rich situation, a synchronous increase of SO42-, NO3-, and NH4+ occurred on Fe2O3. On acidic Al2O3, the favorable adsorption of NH3 on the surface as well as the existence of NO2 with an oxidizing capability synergistically promoted the formation of SO42-, NO3-, and NH4+. PMID- 29993245 TI - AgSbF6-Mediated Selective Thiolation and Selenylation at C-4 Position of Isoquinolin-1(2 H)-ones. AB - A new and facile AgSbF6-mediated protocol for the construction of C-4 thiolated or selenylated isoquinolin-1(2 H)-ones via a radical pathway was established. This reaction proceeded efficiently with excellent regioselectivity, a broad substrate scope, and good functional group tolerance. A radical reaction mechanism involving thiyl radicals as key intermediates is proposed for the present transformation. PMID- 29993246 TI - Frustration vs Prenucleation: Understanding the Surprising Stability of Supersaturated Sodium Thiosulfate Solutions. AB - Gibbs classical nucleation theory predicts that a supersaturated solution will have transient nuclei that flitter in and out of existence. Only when one of these nuclei becomes larger than a critical size, will the solution crystalize. Recently, nonclassical nucleation theories have invoked the presence of prenuclei possibly associated with a liquid-liquid phase separation. However, there are few experimental observations of such prenuclei. Here, we use ultrafast optical Kerr effect spectroscopy to measure the temperature-dependent low-frequency (sub gigahertz to terahertz) anisotropic Raman spectra of supersaturated aqueous sodium thiosulfate solutions. Clear evidence of clusters is obtained in the spectra. However, on the basis of the inferred stability of these clusters, it appears that they frustrate rather than promote the formation of crystals. This would explain the surprising stability of supersaturated sodium thiosulfate and similar solutions. PMID- 29993247 TI - Kinetics and Product Yields of the OH Initiated Oxidation of Hydroxymethyl Hydroperoxide. AB - Hydroxymethyl hydroperoxide (HMHP), formed in the reaction of the C1 Criegee intermediate with water, is among the most abundant organic peroxides in the atmosphere. Although reaction with OH is thought to represent one of the most important atmospheric removal processes for HMHP, this reaction has been largely unstudied in the laboratory. Here, we present measurements of the kinetics and products formed in the reaction of HMHP with OH. HMHP was oxidized by OH in an environmental chamber; the decay of the hydroperoxide and the formation of formic acid and formaldehyde were monitored over time using CF3O- chemical ionization mass spectrometry (CIMS) and laser-induced fluorescence (LIF). The loss of HMHP by reaction with OH is measured relative to the loss of 1,2-butanediol [ k1,2 butanediol+OH = (27.0 +/- 5.6) * 10-12 cm3 molecule-1s-1]. We find that HMHP reacts with OH at 295 K with a rate coefficient of (7.1 +/- 1.5) * 10-12 cm3 molecule-1s-1, with the formic acid to formaldehyde yield in a ratio of 0.88 +/- 0.21 and independent of NO concentration (3 * 1010 - 1.5 * 1013 molecules cm-3). We suggest that, exclusively, abstraction of the methyl hydrogen of HMHP results in formic acid, while abstraction of the hydroperoxy hydrogen results in formaldehyde. We further evaluate the relative importance of HMHP sinks and use global simulations from GEOS-Chem to estimate that HMHP oxidation by OH contributes 1.7 Tg yr-1 (1-3%) of global annual formic acid production. PMID- 29993248 TI - Organocatalytic Asymmetric Synthesis of 3,3'-Pyrrolidinyl-bispirooxindoles via Michael/ N-Hemiketalization Cascade Reaction between 3-Aminooxindoles and Isatin Derived beta,gamma-Unsaturated alpha-Keto Esters. AB - A novel strategy for the construction of 3,3'-pyrrolidinyl-bispirooxindoles through a Michael/ N-hemiketalization cascade reaction of 3-aminooxindoles and isatin-derived beta,gamma-unsaturated alpha-keto esters was developed. Under mild conditions, a series of 3,3'-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereo- and enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. This work represents the first example using the 3-aminooxindoles for the construction of 3,3' pyrrolidinyl-bispirooxindoles. PMID- 29993250 TI - Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal Cell Carcinoma to Topotecan. AB - Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction. PMID- 29993249 TI - Molecular Dynamics Simulations Revealed the Regulation of Ligands to the Interactions between Androgen Receptor and Its Coactivator. AB - The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF 3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa. PMID- 29993251 TI - AC Stark Effect Observed in a Microwave-Millimeter/Submillimeter Wave Double Resonance Experiment. AB - Microwave-millimeter/submillimeter wave double-resonance spectroscopy has been developed with the use of technology typically employed in chirped pulse Fourier transform microwave spectroscopy and fast-sweep direct absorption (sub)millimeter wave spectroscopy. This technique offers the high sensitivity provided by millimeter/submillimeter fast-sweep techniques with the rapid data acquisition offered by chirped pulse Fourier transform microwave spectrometers. Rather than detecting the movement of population as is observed in a traditional double resonance experiment, instead we detected the splitting of spectral lines arising from the AC Stark effect. This new technique will prove invaluable when assigning complicated rotational spectra of complex molecules. The experimental design is presented along with the results from the double-resonance spectra of methanol as a proof-of-concept for this technique. PMID- 29993252 TI - Simultaneous Observation of the Orientation and Activity of Surface-Immobilized Enzymes. AB - Surface immobilized enzymes have been widely used in many applications such as biosensors, biochips, biofuel production, and biofuel cell construction. Many factors dictate how enzymes' structure, activity, and stability may change when immobilized, including surface functionalization, immobilization chemistry, nature of the solid support, and enzyme surface density. To better understand how immobilization affects enzyme structure and activity, we have developed a method to measure both surface-sensitive protein vibrational spectra and enzymatic activity simultaneously. To accomplish this, an optical/fluorescence microscope was incorporated into a sum frequency generation (SFG) spectrometer. Using beta glucosidase (beta-Glu) as a model system, enzymes were covalently tethered to a self-assembled monolayer surface using cysteine-maleimide chemistry. Their orientations were determined by SFG spectroscopy, with a single native cysteine residue oriented toward the functionalized surface, and activity measured simultaneously using a fluorogenic substrate resorufin beta-d-glucopyranoside, with a loss of activity of 53% as compared to comparable solution measurements. Measuring beta-Glu activity and orientation simultaneously provides more accurate information for designing and further improving enzymatic activity of surface bound enzymes. PMID- 29993253 TI - Monodisperse Oil-in-Water Emulsions Stabilized by Proteins: How To Master the Average Droplet Size and Stability, While Minimizing the Amount of Proteins. AB - Hexadecane-in-water emulsions were fabricated by means of a microfluidizer using two types of protein stabilizers, sodium caseinate (NaCAS) and beta-lactoglobulin (BLG). A study of the dependence of the mean droplet diameter and protein coverage on protein concentration was performed. At low protein concentrations, the emulsions were monodispersed and their mean droplet size was governed by the so-called limited-coalescence process. In this regime, the interfacial coverage was constant and was deduced from the linear evolution of the total interfacial area as a function of the amount of adsorbed proteins. In emulsions based on NaCAS, almost all of the initial protein contents were adsorbed at the interfaces. Emulsions formulated at very low protein content underwent unlimited coalescence after prolonged storage or when submitted to centrifugation. Additional NaCAS was incorporated in the continuous phase, right after the emulsification process, as a means of ensuring kinetic stability. The interfacial coverage increased after protein addition. Other strategies including acidification and salt addition were also probed to gain stability. Instead, in emulsions based on BLG, only partial adsorption of the initial protein content was observed. The corresponding emulsions remained kinetically stable against coalescence, and no further addition of protein was required after emulsification. Our approach allows to obtain monodisperse, kinetically stable emulsions and to master their average droplet size, while minimizing the amount of proteins. PMID- 29993254 TI - Chemoproteomics Reveals the Antiproliferative Potential of Parkinson's Disease Kinase Inhibitor LRRK2-IN-1 by Targeting PCNA Protein. AB - LRRK2-IN-1, one of the first selective inhibitors of leucine-rich repeat kinase 2 (LRRK2), was serendipitously found to exhibit potent antiproliferative activity in several types of human cancer cells. In this study, we employed a chemoproteomic strategy utilizing a photoaffinity probe to identify the cellular target(s) of LRRK2-IN-1 underlying its anticancer activity. LRRK2-IN-1 was found to induce cell cycle arrest as well as cancer cell death by specifically binding to human proliferating cell nuclear antigen (PCNA) in cancer cells. Our current findings suggest the potential of LRRK2-IN-1 as a novel pharmacological molecule for scrutinizing cell physiology and furnish a logical foundation for the future development of therapeutic reagents for cancer. PMID- 29993255 TI - Herbal Medicines for Cold Hypersensitivity in the Hands and Feet: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Cold hypersensitivity in the hands and feet (CHHF) and Raynaud's phenomenon (RP) are prevalent among Asian populations, especially among women, who exhibit a higher rate of cold hypersensitivity that may be associated with gynecological problems. In several countries, herbal medicine has effectively treated cold hypersensitivity symptoms. This systematic review and meta-analysis of the literature was undertaken to evaluate the efficacy of herbal medicine for the treatment of CHHF in adults. DESIGN: Through March 31, 2018, comprehensive databases were searched, including MEDLINE, EMBASE, Cochrane Library, Chinese Academic Journal, and Japanese National Institute of Informatics, to identify relevant studies and extract data. OUTCOME MEASURES: Primary: total effective rate (TER); secondary: skin temperature, peripheral blood flow, adverse events. RESULTS: Fourteen randomized controlled trials (n = 974) were included. Thirteen studies with dichotomous values showed a significant reduction in CHHF and RP (risk ratio 0.31, 0.24-0.40) when comparing herbal medicine with/without Western medicine, and no treatment or Western medicine alone. Reductions in CHHF and RP were also observed between herbal medicine plus Western medicine and Western medicine alone (risk ratio 0.45, 0.24-0.86), as well as between herbal medicine and Western medicine alone (risk ratio 0.30, 0.21-0.41). In the only study using a placebo arm, herbal medicine was found to be superior to placebo in increasing skin temperature and peripheral blood flow. Six participants exhibited minor adverse drug reactions. Herbal medicine showed a superior TER, especially when combined with Western medicine, to Western medicine alone or placebo. However, there was a high risk of bias within all studies. CONCLUSION: Although herbal medicine shows potential to be a safe and effective treatment for CHHF and RP, the high risk of bias in all studies prevents definitive conclusions; thus, higher quality studies must be performed. PMID- 29993256 TI - Processing methods for reducing alpha-galactosides in pulses. AB - Pulses are an excellent source of protein and dietary fiber and are consumed around the world. Their consumption has been recommended as part of a healthy diet. However, they contain various antinutrients such as tannins and trypsin inhibitors, as well as indigestible carbohydrates called alpha-galactosides. These oligosaccharides are fermented by the microorganisms in the gut, producing gas and causing flatulence in healthy individuals. While this flatulence is undesirable (and results in their low acceptance in the Western diet), alpha galactosides have also been hypothesized to increase susceptibility to bowel diseases, and their presence in the gut worsens the symptoms of patients with irritable bowel syndrome. The elimination of alpha-galactosides by breeding is difficult as they play a vital role in maintaining seed viability through periods of drought and cold. There is a critical need to evaluate the various post harvest processing methods, and their effect on alpha-galactoside removal to facilitate commercialization. This paper reviews the effectiveness of methods and processing conditions in alpha-galactoside removal from a variety of pulses. PMID- 29993257 TI - High-Dose Rifampin: Shall We Be Bolder? PMID- 29993258 TI - The target cells of anthocyanins in metabolic syndrome. AB - Metabolic syndrome develops to several related chronic diseases, such as obesity, cardiovascular disease, hypertension, diabetes, fatty liver disease. Diseases are outcomes of various cells dysfunction, which are especially acting with a network in metabolic syndrome. Anthocyanins are natural edible pigments widely existed in dark-colored fruits, vegetables, and grains. Epidemiological investigation and nutritional intervention of anthocyanins have exhibited broad-spectrum biological effects that benefit patients with metabolic syndrome related chronic diseases. Whereas the underlying mechanisms and the effects of anthocyanins on critical cells in chronic metabolic diseases are complex and elusive. Therefore, this review summarizes the studies about the effects of anthocyanins on various metabolism related chronic diseases, and mainly focuses on the effects and underlying molecular mechanisms on critical cells. We confirmed that anthocyanins are efficient on adipocytes, endothelial cells, inflammatory cells, hepatocytes, intestinal cells and gut microbiota, but lack of evidence on platelets, skeletal muscle cells, hepatic stellate cells and pancreatic beta cells. Additionally, we discussed the structure-function relationship of anthocyanins and the metabolites. This review summarizes the development of studies on anthocyanins with its target cells in metabolic syndrome, and discusses the unclear aspects of the anthocyanins research work, which is necessary for the future clinical application. PMID- 29993259 TI - Preoperative Administration of Jidabokuippo, a Kampo Medicine, Alleviates Postoperative Pain after Tooth Extraction with Mandible Bone Removal under General Anesthesia: A Prospective, Single-blind, Randomized Controlled Trial. AB - OBJECTIVE: This study aimed to determine the efficacy of preoperative administration of Jidabokuippo (JDI), a Kampo medicine, in treating postoperative pain after tooth extraction with mandible bone removal. DESIGN: This single blind, randomized controlled study was conducted among two groups of adult patients who were scheduled to undergo tooth extraction with mandible bone removal under general anesthesia. Patients were randomly assigned to either the JDI or control group. INTERVENTION: Before surgery, the JDI group received JDI (7.5 g), whereas the control group did not receive any treatment. Patients and the evaluator were blinded to the treatment status. At 0, 1, 3, and 24 h after anesthesia recovery, an investigator recorded the severity of postoperative pain and nausea using a numeric rating scale (0, no pain or nausea; 10, worst imaginable pain or nausea). The number of patients who requested nonsteroidal anti-inflammatory drug (NSAID) and that of additional NSAID administration within 24 h from anesthesia recovery, and the time to the first NSAID request from anesthesia recovery was also measured. RESULTS: The severity of postoperative pain was significantly lower in the JDI group compared with the control group at 3 and 24 h after anesthesia recovery (p < 0.001 each). Both the number of patients requesting NSAID and additional NSAID administration after anesthesia recovery were significantly smaller in the JDI group than in the control group (p = 0.006, p < 0.001). The time to first NSAID request from anesthesia recovery was significantly longer in the JDI group compared with control group (p < 0.001). The severity of nausea did not differ significantly between the groups. No significant side effects related to JDI were noted during the trial. CONCLUSIONS: JDI administration before general anesthesia effectively decreased the severity of postoperative pain after anesthesia recovery in patients who underwent tooth extraction with mandible bone removal. PMID- 29993260 TI - Self-Reported Cognitive Failures in Everyday Life: A Closer Look at Their Relation to Personality and Cognitive Performance. AB - A recent review concluded that the Cognitive Failures Questionnaire is the most widely used instrument to assess cognitive failures. Our aims were to place cognitive failures self-reported with the Cognitive Failures Questionnaire into their nomological network by conceptually replicating known relations to the Big Five and by extending this knowledge through testing their relations with latent cognitive abilities (Study 1, N = 158, age 20-86 years) and theoretically relevant Big Five subfacets (Study 2, N = 176, age 19-39 years). Cognitive failures were unrelated to objective cognitive performance (processing speed, memory, and inhibition), but reliably related to the personality domains conscientiousness, neuroticism, and almost all their subfacets. Thus, self reported cognitive failures do not qualify as a proxy for objective cognitive performance tasks. They are rather useful as illustration of behavioral manifestations related to personality domains. PMID- 29993261 TI - Strong/Weak Feature Recognition of Promoters Based on Position Weight Matrix and Ensemble Set-Valued Models. AB - In this article, we propose a method to recognize the strong/weak property of the promoters based on the nucleotide sequence. To the best of our knowledge, it is the first time to predict the strong/weak property of the promoters. First, position weight matrix (PWM) is used to evaluate the contributions of the nucleotides to the promoter strength. Then, the set-valued model is used to describe the relation between the nucleotide sequence and the strength. Considering the small-sample and imbalance features of the promoter data, we propose an ensemble approach to predict the strong/weak property of the promoters. The proposed method is used to recognize 60 [Formula: see text] promoters of Escherichia coli. The results show the effectiveness of the proposed method. This article provides a simple way for a biologist to evaluate the strong/weak feature of promoters from the nucleotide sequence. PMID- 29993262 TI - Dietary polyphenols and type 2 diabetes: Human Study and Clinical Trial. AB - Significant evidence from epidemiological investigations showed that dietary polyphenols might manage and prevent type 2 diabetes (T2D). This review summarizes human studies and clinical trials of polyphenols as anti-diabetic agents. Polyphenols from coffee, guava tea, whortleberry, olive oil, propolis, chocolate, red wine, grape seed, and cocoa have been reported to show anti diabetic effects in T2D patients through increasing glucose metabolism, improving vascular function as well as reducing insulin resistance and HbA1c level. However, individual flavonoid or isoflavonoid compounds appear to have no therapeutic effect on diabetes, based on the limited clinical data. Preliminary clinical trials provided evidence that resveratrol had anti-diabetic activity in humans by improving glycemic control in subjects with insulin resistance. Besides, anthocyanins exhibited anti-diabetic properties by reducing blood glucose and HbA1c levels or the improvement of insulin secretion and resistance. The structure-activity relationship of polyphenols as anti-diabetic agents in humans has been rarely reported. PMID- 29993263 TI - Probiotics interaction with foodborne pathogens: a potential alternative to antibiotics and future challenges. AB - Antibiotics are a key tool used nowadays in health care industry to fight against bacterial infections; however, repeated antibiotic use or misuses, have led to bacterial resistance, causing significant threats for many people with common bacterial infections. The use of probiotics to enhance gastrointestinal health has been proposed for many years. In recent years, there has been an increasing interest in the use of probiotic bacteria as alternatives for antibiotics for preventing or treating various intestinal infections. Several important underlying mechanisms responsible for the antagonistic effects of probiotics on different microorganisms include: (1) competitive exclusion for adhesion sites and nutritional sources; (2) secretion of antimicrobial substances; (3) enhancement of intestinal barrier function; and (4) immunomodulation. However, their mode of action is not very well understood and therefore a clearer understanding of these mechanisms is necessitated. This will enable appropriate probiotic strains to be selected for particular applications and may reveal new probiotic functions. The goal of this review was to highlight some studies from literature describing the probiotic interaction with several major foodborne pathogens, as well as explore the mechanisms for such probiotic-pathogen interaction. The review will conclude by presenting future perspective and challenges of probiotic application in food products. PMID- 29993264 TI - Progress in high-sensitivity hybrid LC-MS/MS methods for the bioanalysis of protein drugs and performance tests for their validation. PMID- 29993265 TI - Effects of EPA and DHA on blood pressure and inflammatory factors: a meta analysis of randomized controlled trials. AB - The present study aimed to clarify whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on blood pressure and inflammatory mediators. A systematic literature search was conducted in PubMed and Scopus updated to Apr. 2018. The mean changes in risk factors of chronic diseases were calculated as weighted mean difference (WMD) by using a random effects model. Twenty randomized controlled trials (RCTs) were included. The summary estimate showed that EPA intervention significantly reduced systolic blood pressure (SBP) (-2.6 mmHg; 95%confident interval (CI): -4.6, -0.5 mmHg), especially in subjects with dyslipidemia (-3.8 mmHg; 95%CI: -6.7, -0.8 mmHg). The pooled effect indicated that supplemental DHA exerted a significant reduction in diastolic blood pressure (DBP) in subjects with dyslipidemia (-3.1 mmHg; 95%CI: 5.9, -0.2 mmHg). Both EPA (-0.56 mg/L; 95%CI: -1.13, 0.00) and DHA (-0.5 mg/L; 95%CI: -1.0, -0.03) significantly reduced the concentrations of C-reactive protein (CRP), respectively, especially in subjects with dyslipidemia and higher baseline CRP concentrations. Given that limited trials have focused on EPA or DHA intervention on concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, further RCTs should be explored on these inflammatory factors. The present meta-analysis provides substantial evidence that EPA and DHA have independent (blood pressure) and shared (CRP concentration) effects on risk factors of chronic diseases, and high-quality RCTs with multi-center and large simple-size should be performed to confirm the present findings. PMID- 29993266 TI - Novel approaches for chemical and microbiological shelf life extension of cereal crops. AB - Economic losses due to post-harvest fungal spoilage and mycotoxin contamination of cereal crops is a frequently encountered issue. Typically, chemical preservatives are used to reduce the initial microbial load and the environmental conditions during storage are controlled to prevent microbial growth. However, in recent years the consumers' desire for more naturally produced foods containing less chemical preservatives has grown increasingly stronger. This article reviews the latest advances in terms of novel approaches for chemical decontamination, namely application cold atmospheric pressure plasma and electrolyzed water, and their suitability for preservation of stored cereal crops. In addition, the alternative use of bio-preservatives, such as starter cultures or purified antimicrobial compounds, to prevent the growth of spoilage organisms or remove in field accumulated mycotoxins is evaluated. All treatments assessed here show potential for inhibition of microbial spoilage. However, each method encounters draw-backs, making industrial application difficult. Even under optimized processing conditions, it is unlikely that one single treatment can reduce the natural microbial load sufficiently. It is evident that future research needs to examine the combined application of several treatments to exploit their synergistic properties. This would enable sufficient reduction in the microbial load and ensure microbiological safety of cereal crops during long-term storage. PMID- 29993267 TI - Hybrid assays: the next big thing? PMID- 29993268 TI - Biological Treatments for Eosinophilic Asthma Enter the Airways. PMID- 29993269 TI - Parallel Tiled Codes Implementing the Smith-Waterman Alignment Algorithm for Two and Three Sequences. AB - The Smith-Waterman (SW) algorithm explores all the possible alignments between two or more sequences and as a result it returns the optimal local alignment. However, the computational cost of this algorithm is very high, and the exponential growth of computation makes SW unrealistic for searching similarities in large sets of sequences. Fortunately, the dynamic programming kernel of the SW algorithm involves mathematical operations over affine control loops whose iteration space can be represented by the polyhedral model. This allows us to apply polyhedral compilation techniques to optimize the studied SW dense array code. In this article, we present an approach to generate efficient SW implementations for two and three sequences by using the transitive closure of a dependence graph and loop skewing. Generated programs are represented with parallel tiled loop nests, which expose significantly higher performance than that of programs obtained with closely related compilers. The approach is able to tile all loops of original loop nests as opposed to well-known affine transformation techniques. Furthermore, it allows for code optimization of three sequence alignment. Such a code cannot be generated by means of state-of-the-art automatic optimizing compilers. We demonstrate that an under-approximation of transitive closure (instead of exact transitive closure) can be used to generate valid parallel tiled code. This considerably reduces the computational complexity of the approach. Generated codes were run on cores of a modern Intel multiprocessor and they expose high speedup and good scalability on this platform. PMID- 29993270 TI - Recurrent Cardiology Evaluation for Innocent Heart Murmur: Echocardiogram Utilization. AB - We conducted a retrospective study to identify electrocardiogram (ECG) and echocardiogram utilization among patients presenting for a follow-up cardiology evaluation with innocent heart murmur between 2012 and 2014. The 2014 echocardiogram Appropriate Use Criteria was applied. We observed high rates of ordering ECGs and echocardiograms on follow-up visits (79% and 36%); only 1 patient had an appropriate indication for echocardiogram while the rest had rarely appropriate indication. Having had an ECG done did not affect echocardiogram ordering behavior. Older patient age was the only factor associated with a higher likelihood for ordering echocardiograms on follow-up visit (odds ratio = 1.016, P = .021). In this small sample study, we noticed high rates of test utilization and low-probability utilization of echocardiogram in the recurrent evaluation of children with innocent heart murmur. A larger, multicenter prospective study to investigate patterns and drivers of test utilization in children with innocent heart murmur presenting for a follow-up cardiology visit is needed. PMID- 29993271 TI - Developments of mathematical models for simulating vacuum cooling processes for food products - a review. AB - Vacuum cooling is a rapid cooling method widely used in cooling some food products. Simulating the vacuum cooling process with mathematical models helps to acquire a more intuitive understanding and optimize the whole cooling process. However, there is no review summarizing the mathematical models of vacuum cooling. In this review, heat and mass transfer process during vacuum cooling, types of mathematical models for vacuum cooling, and numerical methods including finite difference method, finite element method and finite volume method used for process simulation are introduced in details. The food products used in numerical simulation study of vacuum cooling generally include liquid food, vegetables and cooked meat. The ranges of application of various numerical methods are also discussed. Moreover, heat and mass transfer coefficients have a great influence on the accuracy of the model, and are generally provided by the literature. The investigations presented in this review invariably demonstrate that mathematical modeling can provide good prediction of key information of vacuum cooling process, and has a great potential to improve vacuum cooling process in the food industry. However, more efforts are still needed to realize the industrial translation of laboratory results. PMID- 29993272 TI - Prevention of 7-ketocholesterol-induced side effects by natural compounds. AB - Cholesterol oxidation products, also named oxysterols, can be formed either by cholesterol auto-oxidation, enzymatically or both. Among these oxysterols, 7 ketocholesterol (7KC) is mainly formed during radical attacks that take place on the carbon 7 of cholesterol. As increased levels of 7KC have been found in the tissues, plasma and/or cerebrospinal fluid of patients with major diseases, especially age-related diseases (cardiovascular diseases, eye diseases, neurodegenerative diseases), some cancers, and chronic inflammatory diseases, it is suspected that 7KC, could contribute to their development. Since 7KC, provided by the diet or endogenously formed, is not or little efficiently metabolized, except in hepatic cells, its cellular accumulation can trigger numerous side effects including oxidative stress, inflammation and cell death. To counteract 7KC-induced side effects, it is necessary to characterize the metabolic pathways activated by this oxysterol to identify potential targets for cytoprotection and geroprotection. Currently, several natural compounds (tocopherols, fatty acids, polyphenols, etc) or mixtures of compounds (oils) used in traditional medicine are able to inhibit the deleterious effects of 7KC. The different molecules identified could be valued in different ways (functional foods, recombinant molecules, theranostic) to prevent or treat diseases associated with 7KC. PMID- 29993273 TI - Innovative processing techniques for altering the physicochemical properties of wholegrain brown rice (Oryza sativa L.) - opportunities for enhancing food quality and health attributes. AB - Rice is a globally important staple consumed by billions of people, and recently there has been considerable interest in promoting the consumption of wholegrain brown rice (WBR) due to its obvious advantages over polished rice in metabolically protective activities. This work highlights the effects of innovative processing technologies on the quality and functional properties of WBR in comparison with traditional approaches; and it is aimed at establishing a quantitative and/or qualitative link between physicochemical changes and high efficient processing methods. Compared with thermal treatments, applications of innovative nonthermal techniques, such as high hydrostatic pressure (HHP), pulsed electric fields (PEF), ultrasound and cold plasma, are not limited to modifying physicochemical properties of WBR grains, since improvements in nutritional and functional components as well as a reduction in anti-nutritional factors can also be achieved through inducing related biochemical transformation. Much information about processing methods and parameters which influence WBR quality changes has been obtained, but simultaneously achieving the product stabilization and functionality of processed WBR grains requires a comprehensive evaluation of all the quality changes induced by different processing procedures as well as quantitative insights into the relationship between the changes and processing variables. PMID- 29993274 TI - The Association Between Vitamin D Binding Protein Polymorphisms and Vitamin D Level on Epilepsy in China. AB - Accumulating studies suggest the potential association between epilepsy and vitamin D (VD) in recent years. Vitamin D binding protein (VDBP) is the main VD carrier and can affect the availability of VD and its metabolites. Thus, this study aimed to investigate the association between VDBP polymorphisms and VD level on epilepsy. A total of 220 epilepsy patients and 210 health controls were enrolled and polymorphisms of VDBP (rs4588, rs7041, rs2298849, and rs2282679) genotype were detected using the PCR-ligase detection reaction method. The circulating status of VD metabolites, 25(OH)D and 24,25(OH)2D, was detected by a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) method, and the VD metabolite ratio (VMR), 24,25(OH)2D:25(OH)D, was then calculated. The frequency of rs4588(C>A) and rs2282679(A>C) genotype with AC was significantly lower among the patients relative to the controls [odds ratio, OR = 0.597, 95% confidence interval, CI = 0.401-0.890, p = 0.011 for rs4588(C>A); OR = 0.611, 95% CI = 0.409-0.912, p = 0.016 for rs2282679(A>C), respectively]. For rs7041 genotype distribution, VMR level was significantly higher in patients with GG genotype than in those carrying TT and TG genotype (p = 0.008). Our study demonstrated that the polymorphisms of VDBP rs4588 and rs2282679 may play a potentially important role in epilepsy susceptibility in Chinese Han population. PMID- 29993277 TI - Removal of urea by electro-oxidation in a miniature dialysis device: a study in awake goats. AB - BACKGROUND: The key to success in developing a wearable dialysis device is a technique to safely and efficiently regenerate and re-use a small volume of dialysate in a closed-loop system. In a hemodialysis model in goats, we explored whether urea removal by electro-oxidation (EO) could be effectively and safely applied in vivo. METHODS: A miniature dialysis device was built, containing 1 or 2 'EO unit(s)', each with 10 graphite electrodes, with a cumulative electrode surface of 585 cm2/unit. The units also contained poly(styrene-divinylbenzene) sulfonate beads, FeOOH beads and activated carbon for respective potassium, phosphate and chlorine removal. Urea, potassium and phosphate were infused to create 'uremic' conditions. RESULTS: Urea removal depended on total electrode surface area (removal of 8+/-1 and 16+/-2 mmol/h and clearance of 12+/-1 and 20+/ 3 mL/min with 1 and 2 EO units, respectively) and plasma urea concentration, but not on flow rate. Extrapolating urea removal with 2 EO units to 24 h would suffice to remove daily urea production, but for intermittent dialysis additional units would be required. EO had practically no effects on potassium and phosphate removal or electrolyte balance. However, slight ammonium release was observed and some chlorine release at higher dialysate flow rates. Minor effects on acid-base balance were observed, possibly partly due to infusion of chloride. Mild hemolysis occurred, which seemed related to urea infusion. CONCLUSIONS: In conclusion, clinically relevant urea removal was achieved in vivo by electro oxidation. Efficacy and safety testing in a large animal model with uremia is now indicated. PMID- 29993276 TI - H+-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. AB - The vacuolar-type H+-ATPase B1 subunit is heavily expressed in the intercalated cells of the collecting system, where it contributes to H+ transport, but has also been described in other segments of the renal tubule. This study aimed to determine the localization of the B1 subunit of the vacuolar-type H+-ATPase in the early distal nephron, encompassing thick ascending limbs (TAL) and distal convoluted tubules (DCT), in human kidney and determine whether the localization differs between rodents and humans. Antibodies directed against the H+-ATPase B1 subunit were used to determine its localization in paraffin-embedded formalin fixed mouse, rat, and human kidneys by light microscopy and in sections of Lowicryl-embedded rat kidneys by electron microscopy. Abundant H+-ATPase B1 subunit immunoreactivity was observed in the human kidney. As expected, intercalated cells showed the strongest signal, but significant signal was also observed in apical membrane domains of the distal nephron, including TAL, macula densa, and DCT. In mouse and rat, H+-ATPase B1 subunit expression could also be detected in apical membrane domains of these segments. In rat, electron microscopy revealed that the H+-ATPase B1 subunit was located in the apical membrane. Furthermore, the H+-ATPase B1 subunit colocalized with other H+-ATPase subunits in the TAL and DCT. In conclusion, the B1 subunit is expressed in the early distal nephron. The physiological importance of H+-ATPase expression in these segments remains to be delineated in detail. The phenotype of disease causing mutations in the B1 subunit may also relate to its presence in the TAL and DCT. PMID- 29993275 TI - Angiotensin receptor and tumor necrosis factor-alpha activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. AB - Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-alpha (TNF-alpha) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-alpha inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation. PMID- 29993278 TI - In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules. AB - Phosphate homeostasis is primarily maintained in the renal proximal tubules where the expression of sodium/phosphate co-transporters (Npt2a and Npt2c) is modified by the endocrine actions of both FGF23 and PTH. However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule specific deletion of the FGF23 co-receptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho (PT-PTH1R-/- and PT-PTH1R/KL-/-, respectively). PT-PTH1R /- mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with Control mice. In contrast, PT-PTH1R/KL-/- mice displayed hyperphosphatemia and increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While, serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to severe disturbance, including hyperphosphatemia with increased sodium/phosphate co-transporters expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules. PMID- 29993279 TI - Activated natural killer T cells in mice induce acute kidney injury with hematuria through possibly common mechanisms shared by human CD56+ T cells. AB - Although activation of mouse natural killer T (NKT) cells by alpha galactosylceramide (alpha-GalCer) causes failure of multiple organs, including the kidneys, the precise mechanisms underlying kidney injury remain unclear. Here, we showed that alpha-GalCer-activated mouse NKT cells injured both kidney vascular endothelial cells and tubular epithelial cells in vitro, causing acute kidney injury (AKI) with hematuria in middle-aged mice. The perforin-mediated pathway was mainly involved in glomerular endothelial cell injury, whereas the TNF-alpha/Fas ligand pathway played an important role in the injury of tubular epithelial cells. Kidney injury in young mice was mild but could be significantly exacerbated if NKT cells were strongly activated by NK cell depletion alone or in combination with IL-12 pretreatment. When stimulated by a combination of IL-2 and IL-12, human CD56+ T cells, a functional counterpart of mouse NKT cells, also damaged both glomerular endothelial cells and tubular epithelial cells, with the former being affected in a perforin-dependent manner. These data suggest that both mouse NKT cells and human CD56+ T cells are integral to the processes that mediate AKI. Targeting CD56+ T cells may, therefore, be a promising approach to treat AKI. PMID- 29993280 TI - NMR-based urine metabolic profiling and immunohistochemistry analysis of nephron changes in a mouse model of hypoxia-induced acute kidney injury. AB - Acute kidney injury can be caused by multiple factors, including sepsis, respiratory failure, heart failure, trauma, or nephrotoxic medications, among others. Here, a mouse model was used to investigate potential urinary metabolic biomarkers of hypoxia-induced AKI. Urine metabolic profiles of 48 Swiss Webster mice were assessed using nuclear magnetic resonance spectroscopy (NMR) for 7 days following 72 h exposure to a hypoxic 6.5% oxygen environment. Histological analyses indicated a lack of gross nephron structural changes in the aftermath of hypoxia. Immunohistochemical (IHC) analyses, however, indicated elevated expression of protein injury biomarkers in distal and proximal tubules but not glomeruli. Kidney injury molecule-1 levels peaked in distal tubules at 72 h and were still increasing in proximal tubules at 7 days posthypoxia, whereas cystatin C levels were elevated at 24 h but decreased thereafter, and were elevated and still increasing in proximal tubules at 7 days posthypoxia. Neutrophil gelatinase associated lipocalin levels were modestly elevated from 24 h to 7 days posthypoxia. NMR-based metabolic profiling revealed that urine metabolites involved in energy metabolism and associated biosynthetic pathways were initially decreased at 24 h posthypoxia, consistent with metabolic suppression as a mechanism for cell survival, but were significantly elevated at 48 and 72 h posthypoxia, indicating a burst in organism metabolism associated with reactivation of cellular energetics during recovery after cessation of hypoxia and return to a normoxic environment. The IHC results indicated that kidney injury persists long after plasma and urine biomarkers of hypoxia return to normal values. PMID- 29993281 TI - MixProTool: A Powerful and Comprehensive Web Tool for Analyzing and Visualizing Multigroup Proteomics Data. AB - Deciphering and visualizing proteomics data are a big challenge for high throughput proteomics research. In this work, we develop a free interactive web software platform, MixProTool, for processing multigroup proteomics data sets. This tool provides integrated data analysis workflow, including quality control assessment, normalization, soft independent modeling of class analogy, statistics, gene ontology enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. This software is also highly compatible with the identification and quantification results of various frequently used search engines, such as MaxQuant, Proteome Discoverer, or Mascot. Moreover, all analyzed results can be visualized as vector graphs and tables for further analysis. MixProTool can be conveniently operated by users, even those without bioinformatics training, and it is extremely useful for mining the most relevant features among different samples. MixProTool is deployed at the public shinyapps io server. PMID- 29993283 TI - The intake of potassium-rich food by the potassium-requiring heart disease patients and potential mechanism. PMID- 29993284 TI - Changes in Quality and Microbial Succession of Lightly Salted and Sugar-Salted Blunt Snout Bream ( Megalobrama amblycephala) Fillets Stored at 4 degrees C. AB - The effect of a low concentration of salt and sugar on the quality and microbial succession in blunt snout bream ( Megalobrama amblycephala) fillets was assessed by sensory analysis, total volatile basic nitrogen, biogenic amines, K value, total viable counts, 16S rRNA gene analysis, and Illumina MiSeq PE300 high throughput sequencing. Fish samples were left untreated (control), treated with 1.8% salt (T1), or treated with 1.8% salt plus 0.9% sugar (T2). Consequently, salted and sugar-salted treatments extended the shelf life of bream fillets by 2 days, which retarded the increase of total volatile basic nitrogen, putrescine, cadaverine, and total viable counts. The putrescine and cadaverine concentrations of T2 were significantly ( P < 0.05) higher than T1 after day 10. Brachybacterium was the major initial microbiota of bream fillets. As storage time progressed, Pseudomonas and Shewanella were major genera in the spoiled control group. Pseudomonas, Shewanella, and Pseudoalteromonas became the main spoilers in the T1 and T2 groups. PMID- 29993282 TI - Marinobufagenin and left ventricular mass in young adults: The African-PREDICT study. AB - Background The endogenous steroidal inhibitor of sodium-potassium-dependent adenosine triphosphate and natriuretic hormone, marinobufagenin, plays a physiological role in ionic homeostasis. Animal models suggest that elevated marinobufagenin adversely associates with cardiac and renal, structural and functional alterations. It remains uncertain whether marinobufagenin relates to the early stages of target organ damage development, especially in young adults without cardiovascular disease. We therefore explored whether elevated 24-hour urinary marinobufagenin excretion was related to indices of subclinical target organ damage in young healthy adults. Design This cross-sectional study included 711 participants from the African-PREDICT study (black 51%, men 42%, 24.8 +/- 3.02 years). Methods We assessed cardiac geometry and function by two-dimensional echocardiography and pulse wave Doppler imaging. 24-Hour urinary marinobufagenin and sodium excretion were measured, and the estimated glomerular filtration rate determined. Results Across marinobufagenin excretion quartiles, left ventricular mass ( P < 0.001), end diastolic volume ( P < 0.001), stroke volume ( P = 0.004) and sodium excretion ( P < 0.001) were higher within the fourth compared with the first quartile. Partial regression analyses indicated that left ventricular mass ( r = 0.08, P = 0.043), end diastolic volume ( r = 0.10, P = 0.010) and stroke volume ( r = 0.09, P = 0.022) were positively related to marinobufagenin excretion. In multivariate-adjusted regression analysis, left ventricular mass associated positively with marinobufagenin excretion only in the highest marinobufagenin excretion quartile (adjusted R2 = 0.20; beta = 0.15; P = 0.043). This relationship between left ventricular mass and marinobufagenin excretion was evident in women (adjusted R2 = 0.06; beta = 0.127; P = 0.015) but not in men (adjusted R2 = 0.06; beta = 0.007; P = 0.92). Conclusions Left ventricular mass positively and independently associates with marinobufagenin excretion in young healthy adults with excessively high marinobufagenin excretion. Women may be more sensitive to the effects of marinobufagenin on early structural cardiac changes. PMID- 29993285 TI - Biocontrol of Salmonella Typhimurium in Raw Salmon Fillets and Scallop Adductors by Using Bacteriophage SLMP1. AB - The aim of this study was to evaluate the effectiveness of bacteriophage (phage) SLMP1 to reduce Salmonella Typhimurium on contaminated raw salmon fillets and scallop adductors as a function of Salmonella inoculum level, phage dose, storage temperature, and storage time. Samples were inoculated with 102 and 104 CFU/g Salmonella and then treated with different concentrations of phage SLMP1, followed by incubation at 4, 15, and 25 degrees C, respectively. The results showed that 108 PFU/g was the optimal concentration of phage for the control of Salmonella, which was applied in the following storage experiments over a 7-day period at 4 degrees C, a 4-day period at 15 degrees C, and a 2-day period at 25 degrees C. For the salmon fillets samples, 102 CFU/g Salmonella could be reduced below the detection limit at all three temperatures, whereas 104 CFU/g Salmonella was first decreased and then increased at 15 and 25 degrees C. For the scallop adductors samples, 102 CFU/g Salmonella could be reduced below the detection limit first and then increased after a certain period at 15 and 25 degrees C. The variation trends of 104 CFU/g Salmonella in scallop adductors were similar to those in salmon fillets. The results also showed that the Salmonella counts of both inoculum levels on samples could be reduced below the detection limit or maintained at a low level by phage SLMP1 during storage at 4 degrees C. Phage SLMP1 remained stable on raw salmon fillets and scallop adductors. This study indicated that phage SLMP1 has potential effectiveness as a biocontrol agent of Salmonella in seafood. PMID- 29993286 TI - Pollicization of Biphalangeal Index Finger for Type IV Thumb Hypoplasia: A Case Report Describing Preoperative Planning, Intraoperative Decision-Making, and Technical Modifications. AB - BACKGROUND: Index finger (IF) pollicization is the standard treatment for severe congenital thumb hypoplasia. The procedure requires a supple and anatomically normal IF. No guidelines exist for IF pollicization in patients who have concomitantly underdeveloped IF, specifically when the digit has only 2 phalanges and 1 interphalangeal joint. METHODS: We present a case of a 20-month-old boy with congenital type IV thumb hypoplasia who also had biphalangeal IF. We proposed an IF pollicization operation that required significant modifications to the traditional procedure. RESULTS: Preoperative planning and intraoperative execution are described. The modifications to the traditional procedure included: (1) removal of proximal third of IF metacarpal; (2) creation of a de novo thumb carpometacarpal (CMC) joint by fibrous union whereby the IF CMC joint cartilaginous components are maintained and the remaining distal IF metacarpal is translocated down and secured to this cartilage (in contrast to the traditional use of IF metacarpophalangeal joint as a de novo thumb CMC joint); (3) preservation of IF joints at their "natural" position and function; (4) maintenance of intrinsic muscles at their original distal insertion sites; and (5) important adjustments to skin incision. CONCLUSIONS: Pollicization of biphalangeal IF can be executed in a safe and efficient manner. Early recovery has shown promising signs. Long-term results, including the de novo thumb CMC joint function, remain to be evaluated. PMID- 29993287 TI - Lobe-Specific Gene Vector Delivery to Rat Lungs Using a Miniature Bronchoscope. AB - For respiratory research utilizing gene vector delivery to the lung, the size of rodent models has typically necessitated relatively "blind" dosing via the nose, via an endotracheal tube, or through a surgical incision into the trachea. This commonly results in a limited ability to dose specific small regions of the lung reliably, and contributes to high levels of transduction variability between animals. The resultant poor reliability, reproducibility, and high variability compromises statistical capability, and so demands greater animal sample sizes than should be feasible. The first reliable targeted gene vector dosing of small regions in rat lungs has been designed and successfully implemented using a miniature rigid bronchoscope containing a working channel. Using this setup, this technique can currently access airway branches down to at least the fourth generation in the lungs of rats >200 g in body weight, allowing dosing and re dosing of specific lobes via airway branch points in the lung tree. Here, the protocol for performing this minimally invasive technique is reported, along with the effect of delivering vesicular stomatitis virus G pseudotyped lentivirus to selected lung lobes. Examples of other applications, such as delivery of agar beads, are also shown. It is expected that the availability of this technique will substantially enhance gene vector studies in rat models for a range of lung diseases. PMID- 29993288 TI - Cerebrospinal fluid and vitreous body exposure to orally administered tafamidis in hereditary ATTRV30M (p.TTRV50M) amyloidosis patients. AB - Hereditary transthyretin (TTR) amyloidosis associated with the TTRV30M (p.TTRV50M) mutation presents predominantly as an axonal polyneuropathy, with variable involvement of other organs. Serious central nervous system (CNS) and eye manifestations, including stroke, dementia, vitreous opacities and glaucoma, have been reported in untreated V30M TTR amyloidosis patients, and in these patients after treatment with liver transplantation (LT). Distinct therapies for V30M TTR amyloidosis developed during the last decade exhibit promising results in slowing the peripheral and autonomic nervous system pathology. However, the effect of these therapies on the CNS and eye manifestations of V30M TTR amyloidosis is not known. Herein, we show that in a small cohort of patients taking tafamidis orally (20 mg tafamidis meglumine daily) we could detect this small molecule in the cerebrospinal fluid (CSF) and the vitreous body. In the CSF, the ratio of TTR tetramer to tafamidis was ~2:1, leading to a moderate kinetic stabilization of TTR in the CSF of these patients. Our data suggest that tafamidis can cross the CSF-blood and eye-blood barriers. Future studies comparing CNS and eye manifestations in patients treated with LT, kinetic stabilizers or TTR lowering drugs are essential to understand the clinical effect of our observations. PMID- 29993289 TI - Bone Marrow-Derived Mesenchymal Stem Cell-Mediated Dual-Gene Therapy for Glioblastoma. AB - Bone-marrow mesenchymal stem cells (BMSCs) have been used for systemic delivery of therapeutic genes to solid tumors. However, the optimal treatment time post BMSC implantation and the assessment of the long-term fate of therapeutic BMSCs post-tumor treatment are critical if such promising therapies are to be translated into clinical practice. An efficient BMSC-based therapeutic strategy has been developed that simultaneously allows killing of tumor cells, inhibiting of tumor angiogenesis, and assessment and eradication of implanted BMSCs after treatment of glioblastoma. BMSCs were engineered to co-express the angiogenesis inhibitor kringle 5 (K5) of human plasminogen, under the control of the cytomegalovirus promoter (CMV) and the human sodium-iodide symporter (NIS), involved in uptake of radioisotopes, under the control of early growth response factor 1 (Egr1), a radiation-activated promoter. A significant decrease in tumor growth and tumor angiogenesis and a subsequent increase in survival were observed when mice bearing glioblastoma were treated with 188Re post-therapeutic intravenous BMSC implantation. Furthermore, the systemic administration of 188Re post-tumor treatment selectively eliminated therapeutic BMSCs expressing NIS, which was monitored in real time by 125I micro single photon emission computed tomography/computed tomography imaging. Meanwhile, the Egr1 promoter induced a 188Re radiation positive feedback effect absorbed by NIS. After intravenous BMSC implantation, BMSCs levels in the tumor and lung both peaked on day 10 and decreased to the lowest levels on days 24 and 17, respectively. These findings suggest that day 17 post-BMSC implantation could be an optimal time for 188Re treatment. These results provide a new adjuvant therapy mediated by BMSCs for glioblastoma treatment. PMID- 29993290 TI - Commentary on Modarresi, A. et al (2018) N-acetylcysteine decreases urinary level of neutrophil gelatinase associated lipocalin in deceased-donor renal transplant recipients: a randomized clinical trial. PMID- 29993291 TI - PCC0208009 enhances the anti-tumor effects of temozolomide through direct inhibition and transcriptional regulation of indoleamine 2,3-dioxygenase in glioma models. AB - Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in human glioblastoma and involved in tumor immune escape and resistance to chemotherapy, is clinically correlated with tumor progression and poor clinical outcomes, and is a promising therapeutic target for glioblastoma. IDO inhibitors are marginally efficacious as single-agents; therefore, combination with other therapies holds promise for cancer therapy. The aim of this study was to investigate the anti tumor effects and mechanisms of the IDO inhibitor PCC0208009 in combination with temozolomide. The effects of PCC0208009 on IDO activity inhibition, and mRNA and protein expression in HeLa cells were observed. In the mouse glioma GL261 heterotopic model, the effects of PCC0208009 on l-kynurenine/tryptophan (Kyn/Trp), tumor growth, flow cytometry for T cells within tumors, and immunohistochemistry for IDO and Ki67 were examined. In the rat glioma C6 orthotopic model, animal survival, flow cytometry for T cells within tumors, and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and IDO were examined. The results show that PCC0208009 is a highly effective IDO inhibitor, not only directly inhibiting IDO activity but also participating in the gene regulation of IDO expression at the transcription and translation levels. PCC0208009 significantly enhanced the anti-tumor effects of temozolomide in GL261 and C6 models, by increasing the percentages of CD3+, CD4+, and CD8+ T cells within tumors and suppressing tumor proliferation. These findings indicate that PCC0208009 can potentiate the anti-tumor efficacy of temozolomide and suggest that combination of IDO inhibitor-based immunotherapy with chemotherapy is a potential strategy for brain tumor treatment. PMID- 29993293 TI - Multilingual English-Mandarin-Malay phonological error patterns: An initial cross sectional study of 2 to 4 years old Malaysian Chinese children. AB - Child multilingual phonological errors are under-explored. Cross-linguistic studies suggest monolingual children make phonological errors that are subject to effects of language universality and ambient language characteristics. Bilingual Chinese children were observed to use not only typical, but also atypical phonological errors compared to monolingual peers acquiring similar languages. Atypical errors are a result of specific bilingual pair effects. Close-language relatedness (Cantonese-Mandarin) is claimed to be responsible for the nonexistence of atypical errors in both languages, whilst distant-language relatedness (Cantonese-English) is observed to cause atypical errors in both languages. The present novel cross-sectional study investigated phonological acquisition in three typologically distant languages: English-Mandarin-Malay by 64 multilingual Chinese children aged 21/2-41/2. The present research aimed to explore if multilingual Chinese children exhibit phonological errors which commensurate to that of monolingual and bilingual Chinese children acquiring similar languages as described in the literature. The single-word phonological test results revealed that the multilinguals exhibited typical and atypical phonological patterns which largely commensurate with the monolinguals and bilinguals. Similar to bilingual children, the multilingual children showed more atypical errors in English than in Mandarin, demonstrating effects of individual language irrespective of potential interaction with additional languages. The present result did not fully support the link between closeness in typology of languages and the absence of atypical errors. Rare atypical errors were found in Mandarin and Malay, two typologically different languages, and both were also interacting with English, another typologically different language. The present findings provided useful preliminary multilingual speech norms for the use of speech therapists. PMID- 29993292 TI - New HPLC instrument performance evaluation in HbA1c determination and comparison with capillary electrophoresis. AB - Glycated hemoglobin (HbA1c) measurement provides the most important medium to long-term marker of time-averaged glycemic status. Its relationship to clinical outcome in diabetes has been convincingly demonstrated for both type 1 and type 2 diabetes. The main HbA1c measurement methods for clinical routine are as follows: ion-exchange chromatography; affinity chromatography, capillary electrophoresis, immunoassay and enzymatic methods. In this study, we evaluated the analytical performances of a new HPLC instrument (Tosoh HLC-723 G11 in the VAR mode) in HbA1c analysis and compared it with a capillary electrophoresis instrument (Sebia Capillarys 2 Flex Piercing). HbA1c analysis was performed in parallel by both methods for 250 samples randomly chosen from healthy and diabetic subjects at 'Tor Vergata' University Hospital of Rome. Tosoh HLC-723 G11 showed good reproducibility for 10 days both in quality controls and in samples analyzed (%CV < 2%). We found good linearity for HbA1c values ranging from 15 mmol/mol (3.5%) to 178 mmol/mol (18.5%), with a correlation coefficient R2 = 1. In a comparison between Tosoh HLC-723 G11 and Capillarys 2FP a good correlation (r = 0.99) was found; however, Tosoh HLC-723 G11 showed higher values in the low range of HbA1c and lower in the high range (Tosoh HLC-723 G11 = 4.3043 + 0.913 Capillarys 2FP; p < 0.001). Tosoh HLC-723 G11 showed good repeatability, reproducibility, accuracy and automated simplicity, and it seemed suitable for routine use in clinical chemistry laboratories. PMID- 29993294 TI - A narrative review of problems with medicines use in people with dementia. AB - INTRODUCTION: People with dementia may be particularly susceptible to medication related problems for various reasons. They include progressive cognitive decline, high sensitivity to the effect of medications on cognition and memory, and increased likelihood of comorbidities. Areas covered: This paper aimed to review current literature on the frequency and the types of medication-related problems, and their contribution to hospital admission in people with dementia. Literature searches were conducted using key search terms of dementia and medication-related problems. Studies investigating any medication-related problems in people with dementia or cognitive impairment were included. Expert opinion: Previous research showed a high prevalence of medication-related problems in people with dementia. However, no single category of medication-related problems was reported consistently as the most frequent type across studies. The available studies also showed that medication-related hospitalization was common among people with dementia. These findings underline the need for effective medication management services to reduce the risk of these problems in people with dementia and cognitive impairment. Further work is required to characterize medication-related problems comprehensively in this vulnerable patient group across settings of care. Future research should take a holistic approach in the identification of medication-related problems. PMID- 29993295 TI - The effect of consecutive transmeridian flights on alertness, sleep-wake cycles and sleepiness: A case study. AB - Travel across time zones disrupts circadian rhythms causing increased daytime sleepiness, impaired alertness and sleep disturbance. However, the effect of repeated consecutive transmeridian travel on sleep-wake cycles and circadian dynamics is unknown. The aim of this study was to investigate changes in alertness, sleep-wake schedule and sleepiness and predict circadian and sleep dynamics of an individual undergoing demanding transmeridian travel. A 47-year old healthy male flew 16 international flights over 12 consecutive days. He maintained a sleep-wake schedule based on Sydney, Australia time (GMT + 10 h). The participant completed a sleep diary and wore an Actiwatch before, during and after the flights. Subjective alertness, fatigue and sleepiness were rated 4 hourly (08:00-00:00), if awake during the flights. A validated physiologically based mathematical model of arousal dynamics was used to further explore the dynamics and compare sleep time predictions with observational data and to estimate circadian phase changes. The participant completed 191 h and 159 736 km of flying and traversed a total of 144 time-zones. Total sleep time during the flights decreased (357.5 min actigraphy; 292.4 min diary) compared to baseline (430.8 min actigraphy; 472.1 min diary), predominately due to restricted sleep opportunities. The daily range of alertness, sleepiness and fatigue increased compared to baseline, with heightened fatigue towards the end of the flight schedule. The arousal dynamics model predicted sleep/wake states during and post travel with 88% and 95% agreement with sleep diary data. The circadian phase predicted a delay of only 34 min over the 16 transmeridian flights. Despite repeated changes in transmeridian travel direction and flight duration, the participant was able to maintain a stable sleep schedule aligned with the Sydney night. Modelling revealed only minor circadian misalignment during the flying period. This was likely due to the transitory time spent in the overseas airports that did not allow for resynchronisation to the new time zone. The robustness of the arousal model in the real-world was demonstrated for the first time using unique transmeridian travel. PMID- 29993296 TI - Mesoporous silica-coated gold nanostars with drug payload for combined chemo photothermal cancer therapy. AB - Combined chemo-photothermal therapy is attracting increasing attention in the treatment of cancers. In this work, PEGylated mesoporous SiO2-coated gold nanostars (GNS@mSiO2-PEG) were synthesised without using the cytotoxic surfactant cetyltrimethylammonium bromide as the template. Mesoporous nanostructures were obtained by poly(vinylpyrrolidone) protection of the outer silica shell and NaOH etching of the inner shell. GNS@mSiO2-PEG exhibited good dispersity in medium and excellent photothermal effects. Loading capacity for the anticancer drug doxorubicin (DOX) was ~17.9%, and the drug release profile was pH- and light responsive. In vitro studies revealed that the as-prepared nanocomposites featured good biocompatibility. Furthermore, the nanocomposites were readily internalised by cancer cells, and a combined chemo-photothermal therapy assay revealed that DOX-loaded GNS@mSiO2-PEG have a higher therapeutic efficiency than individual therapies, demonstrating suitable synergistic effects. PMID- 29993297 TI - The importance of insight, avoidance behavior, not-just-right perception and personality traits in pediatric obsessive-compulsive disorder (OCD): a naturalistic clinical study. AB - PURPOSE: The primary aim of the present explorative naturalistic study was to examine the association of poor insight, avoidance behavior, and not-just-right sensation with baseline parameters including obsessive-compulsive disorder (OCD) symptoms, baseline severity scores, comorbidity, and personality traits. A second aim was to examine how insight, avoidance and not-just-right sensation influence treatment outcome. MATERIALS AND METHODS: In total, 317 medical records from children and adolescents with OCD referred to a specialized OCD clinic in Denmark were recorded for baseline parameters and treatment outcome. All information was used. RESULTS: Avoidance behavior and poor insight were associated with an increased baseline severity, whereas not-just-right perception was not. Avoidance behavior was associated with the contamination/cleaning subtype, and a not-just right sensation with the hoarding/symmetry subtype. Lower insight and avoidance behavior were associated with comorbid conditions. At post-treatment, not-just right perception was associated with a risk of relapse, whereas lower insight was negatively associated with gaining remission. Avoidance behavior reduced the probability of remission and increased the number of offered sessions as well as and the likelihood of having SRI prescribed. Different personality traits were associated with treatment outcome. CONCLUSION: Insight, avoidance behavior, and not-just-right perceptions seem important for baseline severity and post treatment outcome. Baseline examination should include a systematic description, which could guide treatment. The present study is an explorative study describing a naturalistic clinical population. Therefore, a number of limitations should be taken into consideration when interpreting the results. More systematic studies on the importance of insight, avoidance behavior and not-just-right perceptions are warranted. PMID- 29993298 TI - Circadian rhythms may not influence the outcomes of thrombolysis in patients with ischemic stroke: A study from China. AB - Circadian rhythms can affect physical or mental activities as well as the time of stroke onset. The impact of circadian rhythms on acute ischemic stroke (AIS) patients treated by recombinant alteplase (rt-PA) is still incongruent. This study aims to consider whether the outcomes of thrombolysis differ depending on stroke onset time and rt-PA infusion time in patients with AIS. A total of 447 AIS patients, who underwent rt-PA intravenous infusion within 4.5 hours after stroke onset, were enrolled in this study consecutively from June 2010 through December 2016. All of the patients were grouped based on the stroke onset time and rt-PA infusion time into two exact 12-hour intervals as daytime (06:01-18:00) and nighttime (18:01-06:00) and further divided into four subgroups at 6-hour time intervals (00:01-06:00, 06:01-12:00, 12:01-18:00 and 18:01-24:00). Major neurological improvement at 1 hour, 24 hours and 7 days, 7-day mortality rate and 24-hour hemorrhage transformation was recorded. The results showed that a total of 295 patients (66.4%) appeared with AIS and 252 (56.4%) were treated during daytime. Higher NIHSS at admission was observed when stroke occurred in nighttime, especially during 00:01-06:00. Patients with stroke onset in nighttime especially during 18:01-24:00 had a significant shorter onset-door time and onset needle time. No differences of the major neurological improvement at 1 hour, 24 hours and 7 days, 24-hour hemorrhagic transformation and 7-day fatality rate were found among either 12-hour time frames or 6-hour time frames according to the time of stroke onset or rt-PA infusion. In conclusion, there was no evidence to predict that circadian rhythms could influence the outcomes of AIS patients treated with rt-PA in China, although stroke onset during nighttime might aggravate neurological impairment before treatment. Further, multicenter and prospective clinical trials with larger number of subjects are still needed to draw more reliable conclusions. PMID- 29993299 TI - Influence of shift type on sleep quality of female nurses working monthly rotating shifts with cortisol awakening response as mediating variable. AB - When shift nurses change shifts, it is likely to affect the cortisol patterns of their bodies and sleep quality. The objectives of this study was to verify the influence of monthly rotating day, evening and night shifts on the sleep quality of female nurses and determine whether the cortisol awakening response (CAR) mediates this relationship. A total of 132 female shift nurses were recruited, and ultimately 128 complete questionnaires and samples were obtained (subject loss rate = 3.0%) from 45 day-shift nurses, 44 evening-shift nurses and 39 night shift nurses at a teaching hospital in Northern Taiwan. The Pittsburgh sleep quality index served as the research instrument that nurses used to collect saliva samples at home every day after waking and 30 min after waking so as to calculate the net increases in cortisol levels (CARi). Hierarchical multiple regression was employed to examine the influence of shift type on the sleep quality of the female nurses and the mediating effect of CARi. The results of this study indicate that shift type significantly influenced CARi (F = 19.66, p < 0.001) and that the regression coefficients of evening versus day shifts and night versus day shifts are both negative. Shift type also significantly influenced sleep quality (F = 15.13, p < 0.001), and the regression coefficients of evening versus day shifts and night versus day shifts are both positive. After controlling for the influence of shift type, CARi remained significantly correlated with sleep quality (DeltaF = 5.17, p = 0.025). The results show that female evening-shift or night-shift nurses display significantly lower CARi and experience significantly poorer sleep quality than day-shift nurses. A greater CARi in the female shift nurses represents better sleep quality. Furthermore, the results prove that CARi is a mediating variable influencing the sleep quality of female shiftwork nurses. PMID- 29993300 TI - Endogenous Fungal Endophthalmitis Associated with Genitourinary Procedures. AB - PURPOSE: To summarize the characteristics of endogenous fungal endophthalmitis (EFE) after genitourinary procedures. METHODS: Medical records of patients diagnosed with EFE after genitourinary procedures from a single center during a 6 year period were reviewed. RESULTS: Nineteen eyes of 15 patients were included. The interval time between procedure to symptom was 3.6 +/- 3.6 weeks. As the initial treatment, 9/19 eyes underwent primary vitrectomy and 10/19 eyes underwent intravitreal antifungal injection . Candida albicans was the pathogen in 15 of 19 eyes. Systemic treatment with itraconazole was used in all patients. LogMAR best corrected visual acuity improved from 2.2 +/- 0.9 to 0.9 +/- 1.2 after treatment (p = 0.002) in 15 eyes that were followed-up for an average of 4.9 +/- 2.1 years. CONCLUSION: Genitourinary procedure is a predisposing factor for EFE. Candida albicans is the predominant pathogen. Normative systemic and local antifungal treatments improved the final visual outcome. PMID- 29993301 TI - Circadian clock rhythms in different adipose tissue model systems. AB - Circadian clock-controlled 24-h oscillations in adipose tissues play an important role in the regulation of energy homeostasis, thus representing a potential drug target for prevention and therapy of metabolic diseases. For pharmacological screens, scalable adipose model systems are needed that largely recapitulate clock properties observed in vivo. In this study, we compared molecular circadian clock regulation in different ex vivo and in vitro models derived from murine adipose tissues. Explant cultures from three different adipose depots of PER2::LUC circadian reporter mice revealed stable and comparable rhythms of luminescence ex vivo. Likewise, primary pre- and mature adipocytes from these mice displayed stable luminescence rhythms, but with strong damping in mature adipocytes. Stable circadian periods were also observed using Bmal1-luc and Per2 luc reporters after lentiviral transduction of wild-type pre-adipocytes. SV40 immortalized adipocytes of murine brown, subcutaneous and epididymal adipose tissue origin showed rhythmic mRNA expression of the core clock genes Bmal1, Per2, Dbp and REV-erbalpha in pre- and mature adipocytes, with a maturation associated increase in overall mRNA levels and amplitudes. A comparison of clock gene mRNA rhythm phases revealed specific changes between in vivo and ex vivo conditions. In summary, our data indicate that adipose culture systems to a large extent mimic in vivo tissue clock regulation. Thus, both explant and cell systems may be useful tools for large-scale screens for adipose clock regulating factors. PMID- 29993302 TI - Effect of senescence on morphological, functional and oxidative features of fresh and cryopreserved canine sperm. AB - The present research aimed to compare the hormonal profile, sperm quality and freezability of young and senile dogs. Dogs were assigned into Young Group (n = 11) and Senile Group (n = 11), additionally divided into Fresh Semen Group and Cryopreserved Semen Group. Males were evaluated for libido score and blood estrogen and testosterone assay. Sperm morphofunctional evaluations were performed based on Computer Assisted Sperm Analysis, morphology, mitochondrial activity, mitochondrial membrane potential, plasma and acrosomal membrane integrity, and DNA fragmentation. Sperm oxidative features were: protein oxidation, lipid peroxidation and production of advanced glycation end-products. Young dogs had higher libido score, sperm velocity average pathway, linearity of motility and mitochondrial activity index and lower percentage of major defects, total defects and proximal cytoplasmic droplet, despite the lack of difference between hormone profile of aged dogs. Fresh semen of senile dogs had increased percentage of spermatozoa with high mitochondrial membrane potential compared to young dogs and to cryopreserved sperm. Cryopreserved semen of young dogs had higher acrosomal membrane integrity compared to the Senile Group. In conclusion, sperm of aged dogs have reduced quality, signaled by higher morphological defects, ultimately altering sperm mitochondrial function and sperm kinetics. Furthermore, spermatozoa from senile dogs are more sensible to cryoinjury. PMID- 29993303 TI - Clinical Manifestations and Pathogenesis of Uveitis in Ebola Virus Disease Survivors. AB - In the wake of the international Ebola virus disease (EVD) outbreak from 2014 to 2016, thousands of EVD survivors are at-risk of ophthalmic manifestations, as well as systemic sequelae including arthralgias, abdominal pain, psychosocial stressors, and risk of viral persistence in immune-privileged organs. Ophthalmic manifestations in EVD survivors include a spectrum of disease ranging from anterior uveitis to panuveitis, which confers a high risk of vision impairment and blindness, particularly given the access and resource limitations for ophthalmic subspecialty care in West Africa. Clinical studies in EVD survivors, animal models of EVD and translational investigation, have provided early insight into eye disease pathogenesis. Specifically, ocular inflammation recently observed in EVD survivors is thought to involve direct viral infection, inflammation, and tissue edema. Future research is needed to understand the timing of uveitis onset and management strategies, including the role of antiviral and anti-inflammatory therapies. PMID- 29993304 TI - Macrophages: The Bridge between Inflammation Resolution and Tissue Repair? PMID- 29993305 TI - Successful application and timing of a remote network for intraoperative objective measurements during cochlear implantation surgery. AB - OBJECTIVE: To determine the time needed to remotely perform a set of intraoperative measurements during cochlear implantation surgery and to compare it to the time needed to perform the same measurements in theatre. DESIGN: Prospective two-arm study comparing a local with a remote measurement setting. Three intraoperative measurements (Impedance Field Telemetry (IFT), evoked compound action potential (ECAP) and evoked stapedius reflex test (eSRT)) were performed with the audiologist present in the operating theatre (i.e. locally) or with the audiologist in his/her office (i.e. remotely). The time needed to complete the measurements, in total and individually, were measured and compared. STUDY SAMPLE: Fifty cochlear implant recipients, aged 0.7-48 years Results: IFT, ECAP and eSRT were performed successfully in all participants. Comparing locally and remotely performed measurements, IFT did not differ significantly, ECAP threshold or slope did not differ significantly differ in any single channel and eSRT measurements did not differ significantly except for in one of six channels. Remote measurements took 8.6 min less to perform than did local measurements (10.04 vs. 18.64 min); a significant difference (p < 0.001). CONCLUSIONS: Using a remote network connection for intraoperative objective measurements is an efficient and safe way to perform measurements during cochlear implantation surgery. PMID- 29993306 TI - Diagnostic Challenges in Granulomatous Uveitis: Tuberculosis or Sarcoidosis? AB - PURPOSE: To emphasize the challenge in the diagnosis of granulomatous uveitis, distinguishing clinical, laboratory, and histological features of tuberculosis, sarcoidosis, and borderline entities. METHODS: Case report. RESULTS: A patient coming from tuberculosis endemic area with granulomatous uveitis and generalized lymphadenopathy was first diagnosed with possible intraocular tuberculosis, based on the presence of suggestive clinical signs, caseous central necrosis in lymph node biopsy, and documented exposure to TB. Lack of response to antitubercular therapy together with laboratory test results, radiological and histological findings and negative biopsies for Mycobacterium tuberculosis led to the diagnosis of tuberculous-sarcoidosis. CONCLUSIONS: The diagnosis and correct therapeutic strategy of entities that fall in between tuberculosis and sarcoidosis still remains challenging, especially in patients coming from endemic areas. PMID- 29993307 TI - Examining the relationship and clinical management between traumatic brain injury and pain in military and civilian populations. AB - In this review, we discuss the comorbidity of traumatic brain injury (TBI) and pain among civilians and military members, the common causes of pain resulting from TBI, and offer insight about the therapeutic management of TBI symptoms and pain. Traumatic brain injury (TBI) is a debilitating health problem and one of the most common post-TBI symptoms is pain, which can contribute to psychological issues such as Post-traumatic stress disorder (PTSD) and depression. Headache pain appears to be the most common type of pain that results from TBI, yet pain can also be more widespread. Managing TBI symptoms and pain simultaneously is difficult because extensive randomized control and clinical studies assessing the effectiveness of therapeutic approaches are lacking. Pharmacological agents such as antidepressants and Triptans and nonpharmacological therapies such as cognitive rehabilitation and physical therapies are commonly used yet it is unknown how effective these therapies are in the long-term. A combination of pharmacological and non-pharmacological therapies is often more effective for managing TBI symptoms and pain than either treatment alone. However, future research is needed to determine the most therapeutic approaches for managing the comorbidity of pain and TBI symptoms in the long term. This review offers suggestions for such future studies. PMID- 29993308 TI - Perceptions and use of computer-assisted surgery (CAS) in the orbit. AB - Computer-assisted surgery (CAS) plays a prominent role in certain surgical disciplines. We investigated the current perceptions and use of this technology for orbital surgery. An online survey was emailed to members of the American Society of Ophthalmic Plastic and Reconstructive Surgery, Canadian Society of Oculoplastic Surgery, and British Oculoplastic Surgery Society. Respondents were asked to describe their practice type and seniority, their frequency of orbital surgery, experience, use, and accessibility of CAS, and their opinion on the technology. There were a total of 151 responses across the societies. 105 respondents (69.5%) had been in attending/consultant practice for over 10 years, with over half (54.7%) working in academic/teaching hospitals. The majority (66.7%) had superficial or no experience with CAS. In total, 84.8% of respondents rarely or never use CAS for orbital surgery (n = 128). Posterior orbital surgery (64.2%) and orbital decompression (49.0%) were the two most useful reasons to implement CAS. Longer operating time (58.3%) and cost (54.8%) were the two most selected weaknesses for CAS, whereas improved accuracy in attaining surgical end point(s) (80.8%) and patient safety (63.6%) were the principal advantages. Type of practice was significantly associated with CAS availability/accessibility (p < 0.05). Proportion of orbital surgery performed in practice was significantly associated with both CAS experience and use (p < 0.05). Our study confirms an expected variation in the perception and use of CAS for orbital surgery. Demonstrated patient benefit and integration of refined and cost-effective CAS systems into operating room environments may influence its future role. PMID- 29993309 TI - Julius von Sachs' forgotten 1897-article: sexuality and gender in plants vs. humans. AB - One hundred and fifty years ago, Julius von Sachs' (1832-1897) monumental Lehrbuch der Botanik (Textbook of Botany) was published, which signified the origin of physiological botany and its integration with evolutionary biology. Sachs regarded the physiology of photoautotrophic organisms as a sub-discipline of botany, and introduced a Darwinian perspective into the emerging plant sciences. Here, we summarize Sachs' achievements and his description of sexuality with respect to the cellular basis of plant and animal biparental reproduction. We reproduce and analyze a forgotten paper (Gutachten) of Sachs dealing with Die Akademische Frau (The Academic Woman), published during the year of his death on the question concerning gender equality in humans. Finally, we summarize his endorsement of woman's rights to pursue academic studies in the natural sciences at the University level, and conclude that Sachs was a humanist as well as a great scientist. PMID- 29993310 TI - Design, selection and optimization of an anti-TRAIL-R2/anti-CD3 bispecific antibody able to educate T cells to recognize and destroy cancer cells. AB - Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or TRAIL-receptor agonistic monoclonal antibodies promote apoptosis in most cancer cells, and the differential expression of TRAIL-R2 between tumor and normal tissues allows its exploitation as a tumor-associated antigen. The use of these antibodies as anticancer agents has been extensively studied, but the results of clinical trials were disappointing. The observed lack of anticancer activity could be attributed to intrinsic or acquired resistance of tumor cells to this type of treatment. A possible strategy to circumvent drug resistance would be to strike tumor cells with a second modality based on a different mechanism of action. We therefore set out to generate and optimize a bispecific antibody targeting TRAIL-R2 and CD3. After the construction of different bispecific antibodies in tandem-scFv or single-chain diabody formats to reduce possible immunogenicity, we selected a humanized bispecific antibody with very low aggregates and long-term high stability and functionality. This antibody triggered TRAIL-R2 in an agonistic manner and its anticancer activity proved dramatically potentiated by the redirection of cytotoxic T cells against both sensitive and resistant melanoma cells. The results of our study show that combining the TRAIL-based antitumor strategy with an immunotherapeutic approach in a single molecule could be an effective addition to the anticancer armamentarium. PMID- 29993311 TI - Theranostic niosomes for direct intratumoral injection: marked enhancement in tumor retention and anticancer efficacy. AB - AIM: For simultaneous bioimaging and drug delivery via direct intratumoral injection, doxorubicin and Ag2S quantum dots co-loaded multifunctional niosomes were prepared and fully characterized. MATERIALS & METHODS: Various theranostic niosomes were prepared and investigated regarding cytotoxicity, in vivo imaging, drug accumulation in breast cancer tumor and antitumor activity. RESULTS: Niosomes composed of Tween-60, Tween-80 or Span 60 produced strong and more durable detectable fluorescence signals. Despite a higher accumulation of Tween 60 niosomes in tumor, the Span 60 formulation showed the highest antitumor efficacy when compared with the free drug (71.7 and 20.3% inhibition in tumor growth, respectively). CONCLUSION: Direct intratumoral injection of theranostic niosomes with appropriate composition could be a powerful tool for combined multimodal imaging and therapy. PMID- 29993312 TI - Resolving Macrophages Counter Osteolysis by Anabolic Actions on Bone Cells. AB - Progression of inflammatory osteolytic diseases, including rheumatoid arthritis and periodontitis, is characterized by increased production of proinflammatory mediators and matrix-degrading enzymes by macrophages and increased osteoclastic activity. Phenotypic changes in macrophages are central to the healing process in virtually all tissues. Using a murine model of periodontitis, we assessed the timing of macrophage phenotypic changes and the impact of proresolving activation during inflammatory osteolysis and healing. Proinflammatory macrophage activation and TNF-alpha overproduction within 3 wk after induction of periodontitis was associated with progressing bone loss. Proresolving activation within 1 wk of stimulus removal and markers of resolving macrophages (IL-10, TGF-beta, and CD206) correlated strongly with bone levels. In vivo macrophage depletion with clodronate liposomes prevented bone resorption but impaired regeneration. Induction of resolving macrophages with rosiglitazone, a PPAR-gamma agonist, led to reduced bone resorption during inflammatory stimulation and increased bone formation during healing. In vitro assessment of primary bone marrow-derived macrophages activated with either IFN-gamma and LPS (proinflammatory activation) or IL-4 (proresolving activation) showed that IL-4-activated cells have enhanced resolving functions (production of anti-inflammatory cytokines; migration and phagocytosis of aged neutrophils) and exert direct anabolic actions on bone cells. Cystatin C secreted by resolving but not inflammatory macrophages explained, in part, the macrophage actions on osteoblasts and osteoclasts. This study supports the concept that therapeutic induction of proresolving functions in macrophages can recouple bone resorption and formation in inflammatory osteolytic diseases. PMID- 29993314 TI - Trichinella britovi in Game Meat Linked to Human Trichinellosis Outbreak in Serbia. AB - After a human trichinellosis outbreak in Zlatibor District, Serbia, in 2016, Trichinella larvae were found in wild boar ( Sus scrofa) meat products. One hundred and fourteen people were infected during the outbreak. The larvae were determined to be Trichinella britovi using the polymerase chain reaction method. Trichinella britovi has previously been identified in Serbia, but this is the first case of the species being confirmed in food samples linked to human trichinellosis. The results of the study confirmed that the T. britovi is able to affect human health. In addition, this study suggests the role of wild boars as reservoirs of T. britovi in Serbia. PMID- 29993313 TI - Lateral root growth in Arabidopsis is controlled by short and long distance signaling through the LRR RLKs XIP1/CEPR1 and CEPR2. AB - Plants rely on lateral roots to explore their soil environment and to maximize their uptake of essential minerals and water. Here we present evidence that the receptor kinases XIP1/CEPR1 and CEPR2 regulate both the initiation of lateral root primordia and emergence of lateral roots locally in the root, while also controlling lateral root extension in response to shoot-derived sucrose in Arabidopsis plants. In addition, mutation of both of these receptors prevents seedlings from responding to sucrose in the media, resulting in longer lateral roots. These results, combined with previous data, establish XIP1/CEPR1 and CEPR2 dependent roles in short- and long-distance pathways regulating different stages of lateral root growth. PMID- 29993315 TI - What Can Diabetes-Associated Genetic Variation in TCF7L2 Teach Us About the Pathogenesis of Type 2 Diabetes? AB - Type 2 diabetes mellitus (T2DM) is a polygenic metabolic disorder characterized by hyperglycemia occurring as a result of impaired insulin secretion and/or insulin resistance. Among the various genetic factors associated with T2DM, a common genetic variant within the transcription factor 7-like 2 locus (TCF7L2) confers the greatest genetic risk for development of the disease. However, the mechanism(s) by which TCF7L2 predisposes to diabetes remain uncertain. Here we review the current literature pertaining to the potential mechanisms by which TCF7L2 confers risk of T2DM, using genetic variation as a probe to understand the pathogenesis of the disease. PMID- 29993317 TI - Selective Antegrade Biliary Stenting Aids Emergency Laparoscopic Cholecystectomy. AB - BACKGROUND: Symptomatic gall stone disease requires early emergency treatment to prevent complications. This early treatment is often delayed due to difficulty in the diagnosis and management of concomitant choledocholithiasis. Intervention with preoperative endoscopic retrograde cholangiopancreatography (ERCP) is associated with complications and known to be unnecessary in most cases. We follow a strategy of providing early cholecystectomy with selective utility of antegrade stent in cases of choledocholithiasis. Our main aim is to present our technique and results. METHOD: We conducted a 3-year (January 2014 to January 2017) review of a prospectively maintained database of our practice of performing routine intraoperative cholangiogram (IOC) during laparoscopic cholecystectomy (LC) and when choledocholithiasis is encountered on IOC; a transcystic antegrade biliary stent is inserted to decompress the common bile ducts (CBD) and facilitate postoperative ERCP at later date. RESULTS: Of the 411 cholecystectomies performed, 77.3% were females with mean age of 48 years. Seventy-four patients were found to have CBD stones (CBDS) on IOC. Antegrade stents were successfully deployed in 69 cases. Even though Antegrade stents were done more frequently in emergency admissions (P = .001); this did not increase the length of hospital stay (LOHS) (P = .752) or the rate of complications (P = .171). However, doing a preoperative ERCP significantly increased LOHS (P = .001), and 67% of these needed two or more ERCP for complete clearance of CBD and had more complications. Nine (15.2%) out of 59 patients with pancreatitis had CBDS on IOC and were successfully managed with antegrade stent. CONCLUSION: This strategy can be followed by general surgeons, enabling them to perform LC in the presence of choledocholithiasis during acute admissions including pancreatitis. It does not require any specialist skills in CBD exploration and also eliminates unnecessary preoperative ERCP and avoids its potential complications. PMID- 29993316 TI - Immunization and media coverage in Italy: an eleven-year analysis (2007-17). AB - Immunization polices in Italy has recently reached important milestones, including the approval of the National Immunization Prevention Plan and of a new law mandatory immunization; this stimulating a lively debate at the scientific, political and societal-level, reflected on the media. We applied a model previously published to quantitatively and qualitatively assess media coverage on vaccines and immunization-related topics on the most read Italian newspaper, "Corriere della Sera", over an 11-year study period (2007-2017). We retrieved relevant key words and articles, reported on included articles' topic, position, approach to immunization and on other selected indicators' summary statistics, temporal trends and correspondence with key epidemiological and policy events. Over the study period the quote "vaccin*" was mentioned on average 325 times per year; with an increase of 150% after the approval of the new law on mandatory immunization in 2017. In the same year, on average, two first-page articles per week were published on the topic. We report a clear association between key events (i.e the H1N1 influenza pandemic, the "Fluad case", the approval of the new law on mandatory immunization) and their media coverage. Overall, 84% of articles had a positive attitude towards immunization, this share decreasing to 79% when only considering articles published after the approval of the law on mandatory vaccination. Media play a crucial role in channelling health-related information and significantly influence health behaviours. We urge public institutions, health authorities and the scientific community not to underestimate the opportunity to monitor media coverage on key healthcare topics and to convey evidence-based health education messages through the media. PMID- 29993319 TI - Combination Therapies for Obesity. AB - The objective of this review is to examine advances in the development of combination therapies for the treatment of obesity beyond diet or lifestyle interventions. Experimental combination pharmacotherapies include combinations of pramlintide and phentermine as well as amylin and bupropion-naltrexone. Incretin and pancreatic hormones generally inhibit upper gastrointestinal motor functions, and combinations showing efficacy in obesity are coadministration of glucagon like peptide-1 (GLP-1) with glucagon, a unimolecular dual incretin of PEGylated GLP-1/GIP coagonist, the combination of GLP-1 and PYY3-36, and, in proof of concept studies, combined infusions of GLP-1, peptide YY, and oxyntomodulin. Among bariatric procedures, repeat intragastric balloon (IGB) treatments are more efficacious than IGB plus diet, and endoscopic intervention can enhance the effects of Roux-en-Y gastric bypass when weight regain occurs. A first trial has provided promising results with combination of IGB plus the GLP-1 analog, liraglutide, compared to the balloon alone. Thus, combination therapies for the treatment of obesity hold promise for introduction into clinical practice. PMID- 29993318 TI - Examining HPA-axis functioning as a mediator of the relationship between depression and cognition across the adult lifespan. AB - Altered HPA-axis functioning is a hypothesized mechanism for worsened cognition in depression. The current study examines the indirect effects of depression on processing speed, executive functioning, and memory as a function of the HPA axis. 38 individuals with a depression diagnosis and 50 healthy controls (HCs) aged 18-86 underwent neuropsychological testing and at-home diurnal salivary cortisol collection. Depression was assessed via structured clinical interviews and rating scales. Cognitive composite scores were derived from factor analysis. Daytime cortisol exposure was estimated using area under the curve (AUC). Depression was associated with higher cortisol levels and slower processing speed . A significant suppression effect of AUC was present on the relationship between depression and processing speed. Limitations include the cross-sectional design and limited sample heterogeneity. Though poorly modulated HPA-axis is one proposed mechanism of cognitive alterations in depression, our results did not support this conclusion for processing speed. Alternative mechanisms should be considered to inform interventions to target cognitive alterations in depression. PMID- 29993321 TI - The Perception and Production of Word-Initial Korean Stops by Native Speakers of Japanese. AB - Previous studies have shown that non-native speakers of Korean not only have difficulty producing the word-initial three-way stop contrast, but also exhibit a wide range of production patterns. Because these studies have only investigated native (L1) speakers of English and Mandarin and given the overall paucity of research on non-native Korean, it is not yet clear how dependent these findings are on the particular native language under investigation. The current paper reinforces our empirical grounding via extension to L1 speakers of Japanese. It is shown that although naive Japanese listeners consistently perceive Korean fortis stops as voiced, and Korean lenis and aspirated stops as voiceless, novice second language learners do not produce any significant difference among the three stop categories, despite producing clear differences between their native Japanese stop categories. Unlike in previous studies of L1 speakers of English and Mandarin, there was very little inter-speaker variation, and all speakers produced all Korean stops with long lag voice onset time. PMID- 29993320 TI - Impact of age on early outcomes and long-term survival of patients undergoing aortic repair with Stanford A dissection. AB - OBJECTIVES:: Stanford A acute aortic dissection (AAD) is a life-threatening emergency, typically occurring in older patients and requiring immediate surgical repair. The aim of this study was to evaluate early outcome and short- and long term survival of patients under and above 65 years of age. METHODS:: Two hundred and forty patients with Stanford A AAD underwent aortic surgical repair from January 2006 to April 2015 in our center. After statistical analysis and logistic regression analysis, Kaplan-Meier survival estimation was performed, with up to 9 year follow-up, comprising patients under and above 65 years of age. RESULTS:: The proportion of patients above 65 years of age suffering from Stanford A AAD was 50% (n=120). The group of patients above 65 years of age compared to the group under 65 years of age showed statistically significant differences in terms of higher odds ratios (OR) for hypertension (p=0.012), peripheral vascular disease (p=0.026) and tachyarrhythmia absoluta (p=0.004). Patients over 65 years of age also showed significantly poorer short- and long-term survival. Our subgroup analysis revealed that male patients (Breslow p=0.001, Log-Rank p=0.001) and patients suffering with hypertension (Breslow p=0.003, Log-Rank p=0.001) were reasonable for these results whereas younger and older female patients showed similar short- and long-term outcome (Breslow p=0.926, Log-Rank p=0.724). After stratifying all patients into 4 age groups (<45; 55-65; 65-75; >75years), short term survival of the patients appeared to be significantly poorer with increasing age (Breslow p=0.026, Log-Rank p=0.008) whereas long-term survival of patients free from cerebrovascular events (Breslow p=0.0494, Log-Rank p=0.489) remained similar. CONCLUSIONS:: All patients referred to our hospital for repair of Stanford A AAD with higher age had poorer short- and long-term survival, caused by male patients and patients suffering from hypertension, whereas survival of women and survival free from cerebrovascular events of the entire patient cohort was similar, irrespective of age. PMID- 29993322 TI - Microbiological monitoring of heater-cooler unit to keep free of Mycobacterium chimaera infection. AB - INTRODUCTION: The association of Mycobacterium chimaera infection in patients undergoing cardiopulmonary bypass (CPB) with the use of heater-cooler units (HCU) has been reported in various literature. We described microbiological monitoring and the extent of microbiological contamination of HCUs utilized in our centre and strategies employed to reduce the high microbial load. METHODS: Since August 2016, we have been following the new Instructions for Use from the manufacturer for the cleaning and disinfection of three units of Stockert 3T and four units of Stockert 1T HCU at the National Heart Centre Singapore. Microbiological monitoring began in January 2017 and included acid-fast bacilli (AFB) culture, Pseudomonas aeruginosa, total colony and total coliform count. Methods, such as increasing disinfection frequency and making the HCU inactive by keeping it empty in storage, were used to reduce the high colony count. RESULTS: All three units of Stockert 3T and two units of Stockert 1T were contaminated with Mycobacterium chimaera. Pseudomonas aeruginosa and total coliform count were consistently <1 colony-forming unit (CFU)/100 mL in every water sample of each HCU. High colony counts were encountered initially in all units. Step-up frequency of disinfection was found to be not as effective as keeping the HCU inactive in bringing the total colony count to an acceptable level. CONCLUSIONS: All monitoring and maintenance measures of HCUs need to be established and maintained to mitigate potential infection risks to patients. Strict adherence to all cleaning and disinfection processes and keeping the HCU inactive maintained the water quality of the HCU at acceptable levels. PMID- 29993323 TI - The magnitude and correlates of geriatric depression using Geriatric Depression Scale (GDS-15) - a Bahrain perspective for the WHO 2017 campaign 'Depression - let's talk'. AB - AIMS: Amid no current estimates or correlates of geriatric depression in Bahrain and support WHO campaign 2017 'Depression-let's talk', we aimed to assess the magnitude of geriatric depression and explore its association with socio demographic and health characteristics among the Bahrainis. METHODS: A cross sectional survey was carried out among the geriatric Bahrainis attending the 12 community congregations of the ministry of labor and social development in Bahrain, as well as in the community, by a convenient sampling method using a validated, shorter, Arabic version of the Geriatric Depression Scale (GDS-15 items) which is a self-report instrument to screen for clinical depression. Univariate analysis followed by a multivariate ordinal logistic regression was employed to test the associations between socio-demographic and health characteristics for geriatric depression. RESULTS: Of the 517 participants, 85% had the history of illness and polypharmacy. The prevalence of depression was 50.6% with a mean score of 5.23; mild, moderate, and severe depression was 30.8%, 12.4%, and 7.3%, respectively. Among the significant socio-demographic and health characteristics, the ordinal regression showed that lower depressive scores were observed for those currently married, educated, and who had not been hospitalized in the last year, with higher scores for financially dependent/income < BD 200(~L377). CONCLUSION: The high prevalence of geriatric depression using the screening tool of GDS-15 demands further diagnostic assessment by mental health professionals. Lower levels of education linked to low income or financial dependency, widowed or separated, and recent hospitalization were the factors associated with depression. We recommend targeted interventions of proactive screening and treatment options, cognitive behavioral therapy, and interpersonal therapy. PMID- 29993324 TI - Chronic White Matter Degeneration, But No Tau Pathology at One-Year Post Repetitive Mild Traumatic Brain Injury in a Tau Transgenic Model. AB - Tau pathology associated with chronic traumatic encephalopathy has been documented in the brains of individuals with a history of repetitive mild traumatic brain injury (r-mTBI). At this stage, the pathobiological role of tau in r-mTBI has not been extensively explored in appropriate pre-clinical models. Here, we describe the acute and chronic behavioral and histopathological effects of single and repetitive mild TBI (five injuries given at 48 h intervals) in young adult (3 months old) hTau mice that express all six isoforms of hTau on a null murine tau background. Animals exposed to r-mTBI showed impaired visuospatial learning in the Barnes maze test that progressively worsened from two weeks to 12 months post-injury, which was also accompanied by significant deficits in visuospatial memory consolidation at 12 months post-injury. In contrast, only marginal changes were observed in visuospatial learning at six and 12 months after single mTBI. Histopathological analyses revealed that hTau mice developed axonal injury, thinning of the corpus callosum, microgliosis and astrogliosis in the white matter at acute and chronic time points after injury. Tau immunohistochemistry and enzyme-linked immunosorbent assay data suggest, however, only transient, injury-dependent increases in phosphorylated tau in the cerebral cortex beneath the impact site and in the CA1/CA3 subregion of the hippocampus after single or r-mTBI. This study implicates white matter degeneration as a prominent feature of survival from mTBI, while the role of tau pathology in the neuropathological sequelae of TBI remains elusive. PMID- 29993325 TI - The Cynical Genius Illusion: Exploring and Debunking Lay Beliefs About Cynicism and Competence. AB - Cynicism refers to a negative appraisal of human nature-a belief that self interest is the ultimate motive guiding human behavior. We explored laypersons' beliefs about cynicism and competence and to what extent these beliefs correspond to reality. Four studies showed that laypeople tend to believe in cynical individuals' cognitive superiority. A further three studies based on the data of about 200,000 individuals from 30 countries debunked these lay beliefs as illusionary by revealing that cynical (vs. less cynical) individuals generally do worse on cognitive ability and academic competency tasks. Cross-cultural analyses showed that competent individuals held contingent attitudes and endorsed cynicism only if it was warranted in a given sociocultural environment. Less competent individuals embraced cynicism unconditionally, suggesting that-at low levels of competence-holding a cynical worldview might represent an adaptive default strategy to avoid the potential costs of falling prey to others' cunning. PMID- 29993326 TI - Progressive Ventricles Enlargement and Cerebrospinal Fluid Volume Increases as a Marker of Neurodegeneration in Patients with Spinal Cord Injury: A Longitudinal Magnetic Resonance Imaging Study. AB - Next to gray and white matter atrophy, cerebrospinal fluid (CSF) volume and ventricular dilation may be surrogate biomarkers for brain atrophy in spinal cord injury (SCI). We therefore aimed to track brain atrophy by means of CSF volume changes and ventricular enlargements over two years after SCI. Fifteen patients with SCI and 18 healthy controls underwent a series of T1-weighted scans during five time points over two years. Changes of CSF/intracranial volume (CSF/ICV) ratio, CSF volume, and ventricular enlargement rate over time were determined. Sample sizes with 80% power and 5% significance were calculated to detect a range of treatment effects for a two-armed trial. There was a significant cross sectional increased CSF/ICV ratio in patients compared with controls at each time point (p < 0.02). The rate of CSF/ICV changes, however, was not significantly different between groups over time. CSF volume increased linearly over bilateral sensorimotor cortices (left: p = 0.002, right: p = 0.042) and in the supracerebellar space (p < 0.001) within two years. An acceleration of the enlargement within the third (p = 0.017) and the fourth (p = 0.006) ventricles was observed in patients over time. Sample size estimation for six-month trials with CSF volume requires 25 patients per treatment arm to detect a hypothetical treatment effect in terms of slowing of atrophy rate of 30%. This study shows that SCI-induced changes in CSF/ICV ratio and ventricular expansion rate provide additional information on the neurodegenerative processes after injury. The sensitivity to scoring treatment effects speaks to its potential to serve as a sensitive biomarker in addition to local atrophy measures. PMID- 29993327 TI - Reports of lower respiratory tract infection following dose 1 of RotaTeq and Rotarix vaccines to the Vaccine Adverse Event Reporting System (VAERS), 2008 2016. AB - A 2018 manufacturer post-licensure safety study identified a possible association between Rotarix (RV1) rotavirus vaccine and lower respiratory tract infections (LRTI) in infants within 0-6 days following receipt of RV1 dose 1. We reviewed reports to the Vaccine Adverse Event Reporting System (VAERS) of LRTI occurring 0 6 days and 0-29 days post vaccination following RotaTeq (RV5) or Rotarix (RV1) vaccinations in conjunction with either Prevnar (PCV7) or Prevnar 13 (PCV13), in infants aged 6 to 15 weeks. There was no significant difference in LRTI reports to VAERS in the 0-6 days and 0-29 days following receipt of either RV5 or RV1 given with either pneumococcal vaccine. PMID- 29993328 TI - Reprogramming of Extraembryonic Trophoblast Stem Cells into Embryonic Pluripotent State by Fusion with Embryonic Stem Cells. AB - Pluripotential reprogramming has been examined using various technologies, including nuclear transfer, cell fusion, and direct reprogramming. Many studies have used differentiated cells for reprogramming experiments, and nearly all type of somatic cells can acquire pluripotency. However, within the embryo, other cells types are present in addition to somatic cells. The blastocyst stage embryo consists of two main types of cells, inner cell mass and trophectoderm (TE). TE cells are the first differentiated form of the totipotent zygote and differ from epiblast cells. Thus, we examined whether extraembryonic cells can be reprogrammed using a cell-cell fusion method. Trophoblast stem cells (TSCs), which can be obtained from the TE, are known to acquire pluripotency by transcription factor Oct4 overexpression or somatic cell nuclear transfer. In this study, we demonstrated that TSCs can acquire pluripotent properties by cell fusion with embryonic stem cells (ESCs). TSC-ESC hybrids reactivated Oct4-GFP and displayed self-renewal properties. They expressed the pluripotency markers Oct4 and Nanog, whereas the expression of Cdx2 and Tead4, trophoblast lineage markers, was diminished. Moreover, these cells developed into three germ layers similarly to other pluripotent stem cells. RNA-seq analysis showed that global gene expression patterns of TSC-ESC hybrids are more similar to ESCs than TSCs. Thus, we demonstrated that TSCs successfully complete reprogramming and acquire pluripotency by cell fusion-induced reprogramming. PMID- 29993329 TI - Does the structure of working memory in EL children vary across age and two language systems? AB - This study examined the cross-sectional structure of working memory (WM) among elementary school English learners (ELs). A battery of WM tasks was administered in Spanish (L1) and English (L2) within five age groups (ages 6, 7, 8, 9, & 10). Confirmatory factor analysis showed a three-factor structure of WM emerged in both L1 and L2 administrations for each age group. The important findings, however, were: (1) the separation between the executive component and storage component (phonological loop) structure of WM increased as a function of age within both language systems, (2) the structure of WM supported a domain general phonological storage component and a domain general executive system across both language systems, and (3) the visual-spatial WM system shared minimal variance with the executive system. Taken together, the findings support Baddeley's multicomponent model (e.g., Baddeley & Logie, 1999. The multiple-component model. In A. Miyake & P. Shah (Eds.), Models of working memory: Mechanisms of active maintenance and executive control (pp. 28-61). Cambridge: Cambridge University Press) as a good fit to the structure of WM in EL children's English and Spanish language system. PMID- 29993330 TI - Persistence of immune memory among adults with normal and high antibody response to primary hepatitis B vaccination: Results from a five-year follow-up study in China. AB - Immune memory after hepatitis B vaccination among adults is still under investigation. In this study, adults who had normal and high antibody response to the primary series of hepatitis B vaccination (HepB) were followed up at 5 years after the primary immunization. A booster dose was given to those who had low hepatitis B surface antibody (anti-HBs) titers, defined as anti-HBs levels < 10 mIU/mL. Blood samples were collected at two weeks after the booster and anti-HBs levels were measured. We assumed those with ant-HBs levels > = 10 mIU/mL after the booster had anamnestic response. In total, 242 persons completed the booster and the anti-HBs test. The anamnestic response rate was 99.59% (241/242) and geometric mean concentration (GMC) of anti-HBs after the booster was 2989 mIU/mL (95% CI: 255, 35085). Anti-HBs titer after the booster dose had a positive correlation with anti-HBs titers measured right after the primary immunization as well as anti-HBs titers 5 years later just before the booster. After the booster, no significant difference was found in anti-HBs titers between participants who were immunized with the 10MUg HepB vaccine and those with the 20MUg vaccine. Multivariable analysis showed that 1) vaccine brand used for the primary vaccination, 2) anti-HBs titers after primary vaccination and 3) anti-HBs titers before the booster dose were independently associated with the anti-HBs titers after the booster 1) beta = -0.21, 95% CI: -0.33, -0.09, P = 0.001; 2) beta = 0.07, 95% CI: 0.05, 0.09, P < 0.001; 3) beta = 0.04, 95% CI: 0.02, 0.07, P < 0.001). In summary, anamnestic response exists among almost all adults at five years after HepB primary immunization. Vaccine brand used for primary vaccination, initial anti-HBs titers after primary immunization and anti-HBs titers before the booster were the independent predictive factors of HepB anamnestic response titers. PMID- 29993331 TI - Effect of filling pressure in jetting dispenser on the performance of blood glucose test strips using immersion gold-plated printed circuit board. AB - To ensure accurate glucose readings when dispensing glucose oxidase enzyme solution from a jetting dispenser onto glucose test strips fabricated from an immersion gold-plated printed circuit board, every drop of the enzyme solution needs to have nearly the same weight and to be dispensed on the reaction zone of the test strips. Experimental results in this study show that the filling pressure in the fluid reservoir containing the glucose enzyme solution to dispense onto the test strips significantly affect the glucose test results. A filling pressure of 12 psi produces test strips with lower coefficient of variation and standard deviation than 10 and 14 psi. Proper filling pressure for dispensing glucose enzyme onto glucose test strips needs to be determined for any enzyme compound formulation. PMID- 29993332 TI - Hymenogaster macmurphyi and Splanchnomyces behrii are sequestrate species of Xerocomellus from the western United States. AB - Hymenogaster is an ectomycorrhizal genus of brown-spored sequestrate fungi that is related to the mushroom-forming genera Hebeloma and Alnicola (Agaricales). However, because of difficulties in morphological taxonomy of sequestrate fungi, Hymenogaster has become a polyphyletic repository for a variety of unrelated brown-spored sequestrate species. During studies of ectomycorrhizal ecology and sequestrate fungal evolution in the western USA, we encountered specimens of a morphologically unique species. It was originally described as Hymenogaster macmurphyi, but our morphological and molecular analyses indicate that it is not closely related to Hymenogaster. Phylogenetic analyses of multiple gene regions indicate that H. macmurphyi is actually a member of the Boletineae (Boletales, Basidiomycota) and is nested within the epigeous genus Xerocomellus, distantly related to any of the other known genera of sequestrate Boletales. While examining additional herbarium collections, we came upon isotype material of Splanchnomyces behrii, which represents a closely related species. Here we document the morphology and phylogenetic affinities of these unusual sequestrate Boletineae and transfer both species to Xerocomellus as X. macmurphyi and X. behrii. During our study, we also noted that the sequestrate taxon Rhopalogaster transversarius is nested within the epigeous genus Suillus. PMID- 29993333 TI - Sex-Specific Gene Expression Differences Are Evident in Human Embryonic Stem Cells and During In Vitro Differentiation of Human Placental Progenitor Cells. AB - The placenta is a short-lived tissue required for embryonic growth and survival, and it is fetal derived. Fetal sex influences gestation, and many sexual dimorphic diseases have origins in utero. There is sex-biased gene expression in third-trimester human placentas, yet the origin of sex-specific expression is unknown. Here, we used an in vitro differentiation model to convert human embryonic stem cells (hESCs) into trophoblastic progenitor cells of the first trimester placenta, which will eventually become mature extravillous trophoblasts and syncytiotrophoblasts. We observed significant sex differences in transcriptomic profiles of hESCs and trophoblastic progenitors, and also with the differentiation process itself. Male cells had higher dosage of X/Y gene pairs relative to female samples, supporting functions for Y-linked genes beyond spermatogenesis in the hESCs and in the early placenta. Female-specific differentiation altered the expression of several thousand genes compared with male cells, and female cells specifically upregulated numerous autosomal genes with known roles in trophoblast function. Sex-biased upregulation of cellular pathways during trophoblast differentiation was also evident. This study is the first to identify sex differences in trophoblastic progenitor cells of the first trimester human placenta, and reveal early origins for sexual dimorphism. PMID- 29993335 TI - Successful Therapeutic Hypothermia in a Propofol-Related Cardiac Arrest Case: A Case Report and Literature Review. AB - Targeted temperature management (therapeutic hypothermia) is a treatment method used to prevent potential complications that can develop in relation to the increased temperature in the brain as a result of cardiac arrest. Due to costs and various health policies there is no comprehensive study in the world that has been able to guide the relevant literature on therapeutic hypothermia. We have presented a 25-year-old female patient in our study who developed cardiac arrest after the administration of propofol for sedation before undergoing a diagnostic upper gastroscopy procedure and received a successful therapeutic hypothermia therapy following a resuscitation of 19 minutes. PMID- 29993334 TI - A Method for Identifying Mouse Pancreatic Ducts. AB - Proper identification of pancreatic ducts is a major challenge for researchers performing partial duct ligation (PDL), because pancreatic ducts, which are covered with acinar cells, are translucent and thin. Although damage to pancreatic ducts may activate quiescent ductal stem cells, which may allow further investigation into ductal stem cells for therapeutic use, there is a lack of effective techniques to visualize pancreatic ducts. In this study, we report a new method for identifying pancreatic ducts. First, we aimed to visualize pancreatic ducts using black, waterproof fountain pen ink. We injected the ink into pancreatic ducts through the bile duct. The flow of ink was observed in pancreatic ducts, revealing their precise architecture. Next, to visualize pancreatic ducts in live animals, we injected fluorescein-labeled bile acid, cholyl-lysyl-fluorescein into the mouse tail vein. The fluorescent probe clearly marked not only the bile duct but also pancreatic ducts when observed with a fluorescent microscope. To confirm whether the pancreatic duct labeling was successful, we performed PDL on Neurogenin3 (Ngn3)-GFP transgenic mice. As a result, acinar tissue is lost. PDL tail pancreas becomes translucent almost completely devoid of acinar cells. Furthermore, strong activation of Ngn3 expression was observed in the ligated part of the adult mouse pancreas at 7 days after PDL. PMID- 29993336 TI - Identification and Characterization of Skeletal Muscle Stem Cells from Human Orbicularis Oculi Muscle. AB - Skeletal muscle stem cell (SMSC) transplantation has shown great therapeutical potential in repairing muscle loss and dysfunction, but the muscle acquisition is usually a traumatic procedure causing pain and morbidity to the donor. In this study, we investigated the feasibility of isolating SMSCs from human orbicularis oculi muscle (OOM), which is routinely removed and discarded during ophthalmic cosmetic surgeries. OOM fragments were harvested from 18 female healthy donors undergoing upper eyelid plasties. Plastic-adherent cells were isolated from the muscles using a two-step plating method combined with collagenase digestion. A total of 15 cell cultures were successfully established from the muscle samples. These adherent cells were positive for the specific markers of SMSCs and could be directed toward the osteogenic, adipogenic, chondrogenic, and myogenic phenotypes in the presence of lineage-specific inductive media. Moreover, after cultured in the myogenic inductive medium for 3 weeks, the muscle cells were injected into the tibialis anterior muscles of nude mice and the cell fate was detected using a DiI-labeling technique. In vivo myogenesis was evidenced by the expression of DiI fluorescence after cell transplantation. The donor cells could be found in the satellite cell position and incorporated into the host myofibers. Our results demonstrated that human OOM represents a novel source of myogenic precursors with stem cell-like properties, which may provide a foundation for the SMSC-based therapeutics of skeletal muscle diseases. PMID- 29993337 TI - Biogenic iron oxides for phosphate removal. AB - Biogenic iron oxides (BioFeO) formed by Leptothrix sp. and Gallionella sp. were compared with chemically formed iron oxides (ChFeO) for their suitability to remove and recover phosphate from solutions. The ChFeO used for comparison included a commercial iron-based adsorbent (GEH) and chemically oxidized iron precipitates from groundwater. Despite contrary observations in earlier studies, the batch experiments showed that BioFeO do not have superior phosphate adsorption capacities compared to ChFeO. However, it seems multiple mechanisms are involved in phosphate removal by BioFeO which make their overall phosphate removal capacity higher than that of ChFeO. The overall phosphate removal capacity of Leptothrix sp. deposits was 26.3 mg P/g d.s., which could be attributed to multiple mechanisms. This included adsorption on the solid phase (6.4 mg P/g d.s.) as well as removal via precipitation and/or adsorption onto suspended complexes released from the BioFeO of Leptothrix sp. (19.6 mg P/g d.s.). Only a very small part of phosphorus (0.3 mg P/g d.s.) was retained in the Leptothrix sp. sheats during bacterial growth. Deposits of Gallionella sp. had an overall phosphate removal capacity of 39.6 mg P/g d.s. Significant amounts of phosphate were apparently incorporated into the Gallionella sp. stalks during their growth (31.0 mg P/g d.s.) and only one-fifth of the total phosphate removal can be related to adsorption (8.6 mg P/g d.s.). Their overall ability to immobilize large quantities of phosphate from solutions indicates that BioFeO could play an important role in environmental and engineered systems for removal of contaminants. PMID- 29993338 TI - Supporting the UN's Sustainable Development Goals: reconceptualising a 'sustainable development assessment tool' for the health and care system in England. AB - AIM: As one of the biggest organisations in the world, the National Health Service (NHS) in England can contribute considerably to the United Nations' Sustainable Development Goals (UN's SDGs). In order to optimise this, this study evaluated and reconceptualised a sustainable development assessment tool for health and care settings in England. METHODS: A quantitative survey and user/expert discussion panels were conducted to evaluate and reconceptualise the existing sustainable development assessment tool used by the NHS in England, the so-called 'Good Corporate Citizenship Assessment Tool', including potential improvements such as the integration of the UN's SDGs. RESULTS: A reconceptualised self-assessment tool integrating the UN's SDGs was developed and implemented online as the 'Sustainable Development Assessment Tool' (SDAT). Further improvements included a process-oriented redesign and the creation of new modules and cross-sections aligning them with the leads responsible for the implementation of key initiatives in NHS organisations, which would contribute to achieving the targets of the SDGs. CONCLUSION: User/expert involvement has enabled an informed approach to a reconceptualisation of a sustainable assessment tool for health and care settings. The tool will support organisations to build their mandatory Sustainable Development Management Plans, as part of the National Public Health Outcomes Framework. Alignment of the tool to the UN's SDGs provides an opportunity for health and care organisations to demonstrate accountability and progress against the UN's set of transformational goals. Furthermore, the tool could be adapted to other public service providers. PMID- 29993339 TI - Using step counters to promote physical activity and exercise capacity in patients with chronic obstructive pulmonary disease: a meta-analysis. AB - BACKGROUND: Although step counters are popularly employed for physical rehabilitation in chronic obstructive pulmonary disease (COPD) patients, their effectiveness is inconsistent and even questioned. This meta-analysis aimed to investigate whether step counter use increases physical activity or improves exercise capacity in COPD patients. METHODS: Electronic databases were searched for randomized controlled trials that assessed the efficacy of step counter use in increasing physical activity or in improving exercise capacity. Data were aggregated using a random-effects model to get the overall effect sizes [standard mean difference (SMD) with 95% confidence interval (CI)], and subgroup analyses were performed. RESULTS: A total of 15 trials enrolling 1316 patients with moderate to severe COPD were included. Step counter use increased physical activity compared with controls (SMD = 0.57, 95% CI 0.31-0.84), which is equal to a magnitude of 1026 steps/day in daily steps. It also enhanced exercise capacity with an effect size of 0.30 (95% CI 0.16-0.45), approximating to a magnitude of 11.6 m in the 6-min walking distance. Step counter use could augment physical activity (SMD = 0.64, 95% CI 0.19-1.08) and exercise capacity (SMD = 0.32, 95% CI 0.01-0.62) for patients receiving pulmonary rehabilitation. Yet it cannot enhance physical activity or exercise capacity in patients with severe COPD or among studies with intervention durations ?6 months (both p > 0.50). CONCLUSIONS: Step counter use increases physical activity and improves exercise capacity in COPD patients, at least in the short term, which supports the notion of recommending step counter use in COPD management. PMID- 29993341 TI - Mini-Sheet Injection for Cultured Corneal Endothelial Transplantation. AB - Corneal endothelium is a single layer of hexagonal cells that maintains the corneal transparency and thickness through its barrier and pump function. For the treatment of corneal endothelial dysfunction, the transplantation of tissue engineered corneal endothelium and direct injection of cultured corneal endothelial cells were developed because of the severe shortage of donor cornea worldwide. However, the technique difficulty or safety risk still remained. In this study, we report a novel mini-sheet injection for the cultured corneal endothelial cell transplantation and compare with the effects of single-cell injection in rabbit model. Compared with the reported single-cell injection, mini sheets promoted the adhesion and tight junction formation after injection. Rabbit corneal clarity and thickness were rapidly recovered after 7 days of mini-sheet injection, compared with 14 days of single-cell injection. Moreover, typical endothelial morphology was observed as early as 7 days after the mini-sheet injection, whereas until 21 days after the single-cell injection. These results demonstrate that the novel mini-sheet injection of corneal endothelial cells exhibited rapid adhesion, tight junction formation, and corneal clarity recovery, which may represent a more efficient method for the transplantation of cultured corneal endothelial cells. PMID- 29993340 TI - Serum chitotriosidase: a circulating biomarker in polycythemia vera. AB - OBJECTIVES: Serum chitotriosidase activity (CHIT1) is a biomarker of macrophage activation with an important role in inflammation-induced tissue remodeling and fibrosis. Macrophages have been described to play a crucial role in regulating pathological erythropoiesis in polycythemia vera (PV). The aim of this study was to evaluate CHIT1 in patients diagnosed with Philadelphia-negative myeloproliferative neoplasms (MPNs). METHODS: Using fluorometric assay, we measured CHIT1 in 28 PV, 27 essential thrombocythemia (ET), 17 primary myelofibrosis (PMF), 19 patients with secondary myelofibrosis and in 25 healthy controls. RESULTS: CHIT1 was significantly higher in PV (p < .001) and post-PV myelofibrosis (MF) transformation (post-PV MF) (p = .020), but not in ET (p = .080), post-ET MF transformation (p = .086), and PMF patients (p = .287), when compared to healthy controls. CHIT1 in PV was positively correlated with hemoglobin (p = .026), hematocrit (p = .012), absolute basophil count (p = .030) and the presence of reticulin fibrosis in the bone marrow (p = .023). DISCUSSION: A positive correlation between CHIT1 and these distinct laboratory PV features might imply macrophages closely related to clonal erythropoiesis as cells of CHIT1 origin. In addition, a positive association between CHIT1 and reticulin fibrosis might indicate its potential role in PV progression. CONCLUSION: CHIT1 might be considered as a circulating biomarker in PV. Additional studies are needed to clarify the role of CHIT1 in promoting disease progression and bone marrow fibrosis in PV. PMID- 29993342 TI - Polymorphisms in the TGF-beta1 (rs1982037) and IL-2 (rs2069762, rs4833248) genes are not associated with inhibitor development in Iranian patients with hemophilia A. AB - Objectives Development of neutralizing antibodies against factor VIII is the major complication in hemophilia care which makes replacement therapies ineffective. The reports showed that inflammatory cytokines play an important role in inhibitor production. In the present study, the relationship between inhibitor development and the polymorphisms of two cytokine genes was studied in severe hemophiliac patients from Iran. Methods In this case-control study, three polymorphisms of immune regulatory genes [TGF-beta (rs1982037) and IL-2 (rs2069762, rs4833248)] were analyzed in 100 Iranian hemophilia A patients divided into 55 inhibitor positive and 45 inhibitor negative patients using Tetra primer ARMS PCR, and DNA sequencing. Results The analysis of polymorphisms in the TGF-beta and IL-2 genes showed no association between the genotypes and the production of inhibitors (p > 0.05). Also, comparison of allele frequencies for TGF-beta and IL-2 genes between two groups indicated no significant differences associated with the development of FVIII inhibitors (p > 0.05). Discussion In contrast with some reports involving the correlation between polymorphisms of the TGF-beta1 and IL-2 genes and inhibitor development in the world, no statistically significant differences in analysis of the alleles and genotypes for TGF-beta and IL-2 genes were found between the inhibitor and non-inhibitor Iranian patients. Thus, other genetic markers influencing the immune response to replacement therapy in patients with hemophilia should be identified. Conclusions Regarding our results in molecular predisposition for inhibitor development, further studies of effective genetic markers are required as a prerequisite for the development of novel immunogenic therapeutic approaches in the future. PMID- 29993343 TI - The association between wet-bulb globe temperature and other thermal indices (DI, MDI, PMV, PPD, PHS, PSI and PSIhr): a field study. AB - The current study aimed at comparing the correlation coefficients between wet bulb globe temperature (WBGT) and a number of parameters, including the discomfort index (DI), modified discomfort index (MDI), predicted mean vote (PMV), predicted percentage of dissatisfaction (PPD), predicted heat strain (PHS), physiological strain index (PSI) and physiological strain index heart rate (PSIhr). In total, 30 workers of a pelletizing factory participated in this study. Environmental parameters and workers' physiological parameters were measured in 10 working stations. The results showed that effective WBGT (WBGTeff) strongly correlates with DI, MDI, PMV, PPD, PHS, PSI and PSIhr. WBGTeff had the highest correlation coefficients with PMV, MDI, PHS and PSIhr. Based on the obtained results, it was concluded that heat stress exceeded the standard limit for a number of indices in some of the working stations. Thus, some controlling measures should be taken to reduce heat stress in these stations. PMID- 29993344 TI - Enhanced fluoride adsorption of aluminum humate and its resistance on fluoride accumulation in tea leaves. AB - Tea trees (Camellia sinensis) can take in fluorine from soil and the content of fluorine in tea increases with maturity, leading to high content of fluoride in tea leaves and tea products. Long-term consumption of high fluoride tea products could result in chronic fluoride intoxication. Confining the fluoride in the earth with absorbents to reduce the fluoride accumulation of the tea trees during the growth period which could radically control the fluoride level in tea product. Humic acid (HA), a kind of organic matter in the earth was used as raw material to prepare adsorbent aluminum humate (HAA) by aluminum modification. The HAA absorbent presented excellent absorption performance to the fluoride in a wide pH range (4-10), and the maximum adsorptive capacity can reach to 62.5 mg/g. The absorption isotherm demonstrated the adsorption of fluoride was the monomolecular adsorption and the absorption was in accordance with the pseudo second order kinetic equation. Fluoride content in real soil solution decreased significantly by 53.03% by using the HAA absorbent. The utilization of HAA adsorbent in the culture and field plots experiments also obviously adsorb the soluble fluoride in solution and soil, which could significantly suppress the fluoride accumulation in tea leaves. In September, the fluoride accumulation in tea leaves has been reduced 74.29% in the field plots experiments. PMID- 29993345 TI - Assessing operational performance benefits of a Water Safety Plan implemented in Southwestern France. AB - AIMS: The World Health Organization (WHO) has recommended Water Safety Plans (WSPs) since 2004 as a means to reduce drinking water contamination and risks to human health. These risk management programs have shown promise across several potential areas of evaluation, such as economic benefits and regulatory compliance. Since WSPs are largely carried out by people who interact with water treatment equipment and processes, operational performance indicators may be key to understanding the mechanisms behind desirable WSP impacts such as water quality and public health improvement. METHOD: This study reports performance measures collected at a WSP implementation location in southwestern France over several years. RESULTS: Quantitative assessment of performance measures supported qualitative reports from utility managers. Results indicate significantly reduced duration of low-chlorine events at one production facility and a significant decrease in customer complaints related to water quality, manifesting reported improvements in operational performance and the customer service culture. CONCLUSION: The findings demonstrate some success stories and potential areas of future performance tracking. Cyclical iteration of the WSP can help to achieve continuous quality improvement. Successfully applied evaluation criteria such as the number of water quality complaints or alarm resolution time might be useful across other locations. PMID- 29993346 TI - Mitochondrial ferritin expression in erythroid cells from patients with alpha thalassaemia. AB - BACKGROUND: Patients with thalassaemia who received regular transfusions had increased iron accumulation, leading to iron overload, which was associated with oxidative stress. Mitochondrial ferritin, encoded by the FTMT gene is an iron storage protein in the mitochondria. The aim of this work was to investigate the expression levels of FTMT in the reticulocytes of patients with alpha thalassaemia who were regularly transfused and rarely transfused compared with healthy controls and to evaluate the relationships of the levels of FTMT mRNA with malondialdehyde (MDA) and ferritin in these patients. METHODS: The levels of FTMT mRNA in the reticulocytes of patients (30 regularly transfused and 30 rarely transfused) and 30 healthy individuals were assessed by quantitative reverse transcription-polymerase chain reaction. The levels of ferritin and MDA were analysed by ELISA and by a thiobarbituric acid reactive substance assay, respectively. RESULTS: The levels of FTMT mRNA, ferritin and MDA in both groups of patients were significantly increased compared with those in the healthy controls. In addition, the levels of FTMT mRNA, ferritin and MDA in the regularly transfused patients were significantly higher than those in the rarely transfused patients. Furthermore, the relative expression levels of FTMT in patients correlated with those of MDA and ferritin. CONCLUSION: These results suggest that the elevation of expression levels of FTMT in the reticulocytes of patients with alpha-thalassaemia may be associated with iron loading and oxidative stress. PMID- 29993347 TI - Coexisting driver mutations in MPN: clinical and molecular characteristics of a series of 11 patients. AB - OBJECTIVES: CML, PV, ET and PMF are so called classical MPN with distinct clinical phenotypes. The discovery of the BCR-ABL1 translocation and mutations in driver genes JAK2, MPL and CALR has provided novel insights in their pathogenesis. While these mutations are thought to be mutually exclusive, rare cases of MPN with coexisting driver mutations have been reported. However, little is known about the clinical, biological and molecular characteristics of these patients and the interaction of the neoplastic clones. METHODS: We retrospectively studied 11 MPN patients with coexisting driver mutations (JAK2 V617F + BCR-ABL1: n = 8; CALR type 2 + BCR-ABL1: n = 1; JAK2 V617F + MPL W515: n = 1; JAK2 V617F + CALR type 1: n = 1). To assess possible associated molecular aberrations, we analysed DNA of six patients using NGS. RESULTS: In four CML patients, decreasing BCR-ABL1 transcript levels with increasing JAK2 V617F allele burden under TKI were observed. This strongly suggests that the coexistence of driver mutations originates from two different clones growing independently. Additional somatic mutations were detected in 5 out of 6 (83%) patients affecting 4 different genes, confirming the heterogeneity of this study cohort. Suboptimal response to TKI was observed with a higher frequency (4/8 patients) than reported in conventional series of CML and the overall tolerance of treatment with hydroxyurea and/or imatinib in our series was poor. CONCLUSION: Given the emergence of NGS in clinical practice, more similar cases will be identified in the coming years. The optimal treatment strategy for this rare group of patients is uncertain and toxicity of combination treatment may have to be considered. PMID- 29993348 TI - Parental occupational pesticide exposure and nonsyndromic orofacial clefts. AB - Nonsyndromic orofacial clefts are common birth defects. Reported risks for orofacial clefts associated with parental occupational pesticide exposure are mixed. To examine the role of parental pesticide exposure in orofacial cleft development in offspring, this study compared population-based case-control data for parental occupational exposures to insecticides, herbicides, and fungicides, alone or in combinations, during maternal (1 month before through 3 months after conception) and paternal (3 months before through 3 months after conception) critical exposure periods between orofacial cleft cases and unaffected controls. Multivariable logistic regression was used to estimate odds ratios, adjusted for relevant covariables, and 95% confidence intervals for any (yes, no) and cumulative (none, low [=median exposure level in controls]) occupational pesticide exposures and cleft lip +/- cleft palate and cleft palate. Associations for cleft lip +/- cleft palate tended to be near unity for maternal or paternal occupational pesticide exposures, except for low paternal exposure to any pesticide, which produced a statistically significant inverse association with this subtype. Associations for cleft palate tended to be near unity for maternal exposures and mostly positive, but non significant, for paternal exposures; a significant positive association was observed between paternal low exposure to insecticide + herbicide + fungicide and cleft palate. Combined parental exposure produced non-significant associations near or below unity for all orofacial cleft cases combined and cleft lip +/- cleft palate and positive, but non-significant, associations for cleft palate. This study observed associations mostly near unity between maternal occupational pesticide exposure and orofacial clefts. Associations for paternal occupational pesticide exposures were mostly near or below unity for cleft lip +/- cleft palate, and mostly positive for cleft palate. However, due to the limitations of this study, these subtype-specific results should be interpreted cautiously. Future research examining parental occupational pesticide exposure and orofacial clefts should attempt to improve exposure assessment and increase sample size to better facilitate risk estimation. PMID- 29993349 TI - Structured evaluation of food loss and waste prevention and avoidable impacts: A simplified method. AB - Interest in life-cycle assessment (LCA) for foodstuffs has increased over recent years. In the same period, there could also be noticed an increased focus on food losses and waste (FLW); hence the need for guidance or a method that assesses the environmental impacts of FLW when analyzing agrifood systems with the use of LCA. This study introduces a method of assessing FLW in the context of supply chain LCA through: i) calculating the impacts of the food supply chain with the associated FLW, in order to account for the overall environmental impacts; and ii) assessing the benefits of FLW prevention strategies. After the method is presented, a practical application follows. The results of this study show that this method is able to aid LCA practitioners to include FLW on their LCA for food studies so as not to underestimate the impacts. Furthermore, the method is able to aid decision makers to assess the benefits of implementing a FLW prevention action in comparison to a baseline scenario. This method has some limitations: the attributional approach, lack of guidelines on how to estimate prevention potentials, as well as lack of guidelines to estimate additional impacts due to prevention actions. PMID- 29993350 TI - Gender, power and intimate relationships over the life course among Ethiopian female peer educators living with HIV. AB - Historically, Ethiopian women have faced numerous challenges to gender equity at the individual, relational and community levels; such inequalities can lead to increased risk of HIV acquisition. Over the past two decades, some progress has been made towards changing policies and norms to reduce gender inequality. We sought to understand the ways in which marriage and other romantic/sexual relationships of a group of Ethiopian women living with HIV had been impacted by gender norms, relational power dynamics and HIV status over the life course. We conducted in-depth interviews with 19 women living with HIV who were working as peer educators at a large clinic in Addis Ababa, Ethiopia. Reflecting on their early lives, participants often described traumatic prior relationships characterised by rape, forced marriage and HIV nondisclosure. In the aftermath of being diagnosed with HIV, participants' more recent relationships embodied a more egalitarian dynamic characterised by mutual support for HIV care engagement and open communication. Participants' narratives illustrate encouraging examples of ways in which HIV-positive women can form and maintain equitable and satisfying personal relationships even in the context of obstacles at multiple levels. PMID- 29993351 TI - Decision-making about motherhood among women living with HIV in Canada: a negotiation of multidimensional risks. AB - Little research in Canada has examined the perspectives of women living with HIV on decision-making across the stages of motherhood. In 2004-2005, semi-structured interviews were conducted with 42 African, Caucasian and Haitian HIV-positive women recruited in Montreal. All were or wished to be biological mothers. Transcripts underwent thematic analysis organised by three culturally informed models of motherhood described by the participants, which influenced decision making and perceived risks. For women who saw motherhood as 'self-fulfilment and completeness', vertical HIV transmission was a primary concern. It threatened their identity as a 'good mother', which also meant adhering to antiretrovirals. For women who viewed motherhood as a 'social realisation' (all African or Haitian), fears of compromised fertility dominated. Not becoming pregnant threatened their social status and presumed health within their community. Antiretrovirals were abandoned after delivery, fearing they would reveal their HIV status. For women endorsing a 'personal growth' model of motherhood (all Caucasian), threats to personal health were paramount. Pregnancy meant purifying body and soul. Antiretrovirals, seen as pollutants, were stopped after delivery. These findings can inform current research and sensitise health providers to the complex biological, psychological, social and spiritual risks that HIV-positive women negotiate in motherhood-related decision-making, towards more patient centred care. PMID- 29993352 TI - Updating the SAPRC Maximum Incremental Reactivity (MIR) scale for the United States from 1988 to 2010. AB - Ozone reactivity scales play an important role in selecting which chemical compounds are used in products ranging from gasoline to pesticides to hairspray in California, across the United States and around the world. The California Statewide Air Pollution Research Center (SAPRC) box model that calculates ozone reactivity uses a representative urban atmosphere to predict how much additional ozone forms for each kilogram of compound emission. This representative urban atmosphere has remained constant since 1988, even though more than 25 years of emissions controls have greatly reduced ambient ozone concentrations across the United States during this time period. Here we explore the effects of updating the representative urban atmosphere used for ozone reactivity calculations from 1988 to 2010 conditions by updating the meteorology, emission rates, concentration of initial conditions, concentration of background species, and composition of volatile organic compound (VOC) profiles. Box model scenarios are explored for 39 cities across the United States to calculate the Maximum Incremental Reactivity (MIR) scale for 1,233 individual compounds and compound mixtures. Median MIR values across the cities decreased by approximately 20.3% when model conditions were updated. The decrease is primarily due to changes in atmospheric composition ultimately attributable to emissions control programs between 1998 and 2010. Further effects were caused by changes in meteorological variables stemming from shifting seasons for peak ozone events (summer versus early fall). Lumped model species with the highest MIR values in 1988 experienced the greatest decrease in MIR values when conditions were updated to 2010. Despite the reduction in the absolute reactivity in the updated 2010 atmosphere, the relative ranking of the VOCs according to their reactivity did not change strongly compared to the original 1988 atmosphere. These findings indicate that past decisions about ozone control programs remain valid today, and the ozone reactivity scale continues to provide relevant guidance for future policy decisions even as new products are developed. Implications: Updating the representative urban atmosphere used for the Maximum Incremental Reactivity (MIR) scale from 1988 to 2010 conditions caused the reactivity of 1223 individual compounds and combined mixtures to decrease by an average of 20.3% but the relative ranking of the VOCs was not strongly affected. This means that previous guidance about preferred chemical formulations to reduce ozone formation in cities across the United States remain valid today, and the MIR scale continues to provide relevant guidance for future policy decisions even as new products are developed. PMID- 29993354 TI - Hypoglycemia Following Pancreas Transplant: A Diagnostic Challenge in the Immediate Posttransplant Setting. AB - Few studies have described glucose metabolism in the immediate posttransplant period. Here, we report a 37-year-old female patient who had transient hypoglycemia after combined pancreas and kidney transplant for poorly controlled type 1 diabetes and renal failure. Although the patient's blood sugar decreased from 420 to less than 120 mg/dL and the kidney demonstrated graft function immediately posttransplant, at 19 hours after transplant, the patient's blood glucose decreased to below the normal range at a nadir of 59 mg/dL. When treated with intravenous dextrose, her blood glucose levels increased over 7 hours to 119 mg/dL but then again declined, appearing to follow a circadian rhythm, with hypoglycemia shown during early morning hours and then improving during the afternoon. This prompted treatment with a continuous infusion of 5% dextrose on day 2, resulting in blood sugar levels returning to normal by day 4 and discharge on day 6. She has since remained euglycemic. The differential diagnosis of hypoglycemia immediately after kidney-pancreas transplant is wide. Indeed, after we excluded ischemia-reperfusion injury, impaired renal clearance, insulin associated antibodies, and lack of pancreatic innervation, we believe that cause was most likely due to impairment of early glucose counterregulatory responses or delayed alpha cell function. PMID- 29993355 TI - A Late Complication Occurring Due to Tacrolimus After Liver Transplant: Posterior Reversible Encephalopathy Syndrome. AB - Posterior reversible encephalopathy syndrome is a rare condition of the central nervous system that may occur in adults as well as in children. Clinically, it presents with mental status changes, visual loss, headaches, seizures, or coma. The diagnosis of posterior reversible encephalopathy syndrome is based on the typical appearance in occipital and parietal lobes in radiologic imaging studies, such as computed tomography or magnetic resonance imaging of the brain, which exhibit the typical appearance due to vasogenic edema. Causative factors include hypertensive encephalopathy, renal failure, preeclampsia, autoimmune conditions, and the use of cytotoxic or immunosuppressive agents. Rare cases of posterior reversible encephalopathy syndrome due to treatment with tacrolimus, an immunosuppressive agent commonly used after organ transplant, have been reported. In these patients, the tacrolimus dose is reduced or discontinued. In transplant patients with neurologic symptoms, the possibility of posterior reversible encephalopathy syndrome should be kept in mind. PMID- 29993353 TI - Unique antioxidant effects of herbal leaf tea and stem tea from Moringa oleifera L. especially on superoxide anion radical generation systems. AB - This study aimed to investigate the unique antioxidative effects of Japanese moringa products, herbal leaf tea and stem tea, using established free radical assays, focusing on superoxide anion (O2-) radical generation systems. Hot-water extracts from moringa teas resulted in different but lower scavenging activities than Trolox in four synthetic free radical models. Interestingly, these extracts further showed higher O2- radical scavenging effects than Trolox in the phenazine methosulfate-NADH-nitroblue tetrazolium and xanthine oxidase assay systems. Incubating human neutrophils in the presence of these tea extracts rather than Trolox effectively suppressed cellular O2- radical generation. Among the eight known phenolic constituents of moringa leaves, caffeic acid and chlorogenic acid may be responsible for the O2-specific radical scavenging capacity stronger than that of Trolox. These results suggest that moringa herbal teas are a good source of natural antioxidants for preventing O2- radical-mediated disorders. Abbreviations: O2-: superoxide anion; ROS: reactive oxygen species; H2O2: hydrogen peroxide; XOD: xanthine oxidase; DPPH: 1,1-diphenyl-2-picrylhydrazyl; ABTS+: 2,2'-azinobis(2-ethylbenzothiazoline-6-sulfonic acid) cation; CPZ+: chlorpromazine cation; PMS: phenazine methosulfate; NBT: nitroblue tetrazolium; PMA: phorbol 12-myristate 13-acetate. PMID- 29993357 TI - Retransplant of the Liver: 12-Year Experience of the Shiraz Organs Transplantation Center. AB - OBJECTIVES: Liver transplant is the most effective treatment modality for patients with end-stage liver disease, metabolic disorders, hepatic malignancy, and acute liver failure. When a graft fails after primary liver transplant, retransplant of the liver remains the only option. Here, we report the past 12 year experience of the Shiraz Transplant Center regarding liver retransplant. MATERIALS AND METHODS: This is a retrospective cohort study of a 12-year period (2004-2015) of the Shiraz Center in Iran. RESULTS: Of the 3107 patients who had a liver transplant during the study period, 58 retransplants were performed (1.86%) in 57 patients. The leading cause of retransplant was primary nonfunction in 24 patients (41.4% of retransplant cases and 0.77% of all liver transplant cases). The second leading cause of retransplant was vascular complications in 25 patients (23 with hepatic artery thrombosis and 2 with portal vein thrombosis), accounting for 43.1% of retransplant cases and 0.80% of all liver transplant cases. In addition, 5 patients (8.6%) had retransplant for rejection, which accounted for 0.16% of all liver transplant cases. Four patients with retransplant (6.9%) had recurrence of primary disease, which accounted for 0.12% of all liver transplant cases. Most liver retransplants occurred early (<= 30 days after primary transplant) at the Shiraz Transplant Center. Five-year survival rate after retransplant was 35%, and retransplant for hepatic artery thrombosis was more common in children. CONCLUSIONS: Because most patients required retransplants in the early period after primary transplant, the decision for retransplant must be considered carefully with full multidisciplinary evaluation and only in skilled hands. Retransplant in subgroups of patients with little chance of a successful outcome should be avoided. PMID- 29993356 TI - Efficacy of the Sonoelastography Method for Diagnosis of Fibrosis in Renal Transplant Patients. AB - OBJECTIVES: Although biopsy is the most important method for diagnosing the cause of renal allograft dysfunction, sonoelastography, a new ultrasonography method, can be used to distinguish between the soft or hard nature of lesions. In this study, our aim was to investigate whether sonoelastography could diagnose fibrosis in renal transplant patients. MATERIALS AND METHODS: In this prospective study, we included patients over 18 years old who were recommended for clinical biopsy. Sonoelastographic evaluation was made by conducting acoustic radiation force impulse measurements for each patient after they were admitted to the clinic for biopsy. Measurements were performed just before the biopsy procedure. All results were examined by 2 experienced radiologists using the Siemens S3000 Ultrasound Machine (Erlangen, Germany). Comparisons of ultrasonographic values with biopsy results were made with SPSS software (SPSS: An IBM Company, version 20, IBM Corporation, Armonk, NY, USA). RESULTS: Of the 65 patients included in this study, pathology showed acute T-cell-mediated rejection in 37 patients. There was a significant correlation between the pathologic Banff scores and the sonographic acoustic radiation force impulse values (P = .002), where the degree of Banff increased as the mean acoustic radiation force impulse values elevated. A rise in mean impulse values correlated with increased degree of interstitial fibrosis in renal allografts. Renal parenchymal echogenicity of patients significantly differed by sex (P = .009), with an average renal echogenicity of grade 1 in women and grade 0 in men. Also, a statistically significant difference was found between age of the renal transplant recipient and resistive index values. CONCLUSIONS: Our study showed a significant correlation between Banff degree and the acoustic radiation force impulse values of renal transplant patients. In addition to biopsy, sonoelastography can be beneficial for the diagnosis of fibrosis in renal transplant patients. PMID- 29993358 TI - Mce2R/Rv0586 of Mycobacterium tuberculosis is the functional homologue of FadRE. coli. AB - Lipid metabolism is critical to Mycobacterium tuberculosis survival and infection. Unlike Escherichia coli, which has a single FadR, the M. tuberculosis genome encodes five proteins of the FadR sub-family. While the role of E. coli FadR as a regulator of fatty acid metabolism is well known, the definitive functions of M. tuberculosis FadR proteins are still under investigation. An interesting question about the M. tuberculosis FadRs remains open: which one of these proteins is the functional homologue of E. coli FadR? To address this, we have applied two different approaches. The first one was the bioinformatics approach and the second one was the classical molecular genetic approach involving complementation studies. Surprisingly, the results of these two approaches did not agree. Among the five M. tuberculosis FadRs, Rv0494 shared the highest sequence similarity with FadRE. coli and Rv0586 was the second best match. However, only Rv0586, but not Rv0494, could complement E. coli ?fadR, indicating that Rv0586 is the M. tuberculosis functional homologue of FadRE. coli. Further studies showed that both regulators, Rv0494 and Rv0586, show similar responsiveness to LCFA, and have conserved critical residues for DNA binding. However, analysis of the operator site indicated that the inter palindromic distance required for DNA binding differs for the two regulators. The differences in the binding site selection helped in the success of Rv0586 binding to fadB upstream over Rv0494 and may have played a critical role in complementing E. coli ?fadR. Further, for the first time, we report the lipid-responsive nature of Rv0586. PMID- 29993359 TI - Cinnamaldehyde disrupts biofilm formation and swarming motility of Pseudomonas aeruginosa. AB - Bacterial biofilms can cause serious health care complications associated with increased morbidity and mortality. There is an urge to discover and develop new biofilm inhibitors from natural products or by modifying natural compounds or understanding the modes of action of existing compounds. Cinnamaldehyde (CAD), one of the major components of cinnamon oil, has been demonstrated to act as an antimicrobial agent against a number of Gram-negative and Gram-positive pathogens, including Pseudomonas aeruginosa, Helicobacter pylori and Listeria monocytogenes. Despite the mechanism of action of CAD against the model organism P. aeruginosa being undefined, based on its antimicrobial properties, we hypothesized that it may disrupt preformed biofilms of P. aeruginosa. The minimum inhibitory concentration (MIC) of CAD for planktonic P. aeruginosa was determined to be 11.8 mM. Membrane depolarization assays demonstrated disruption of the transmembrane potential of P. aeruginosa. CAD at 5.9 mM (0.5 MIC) disrupted preformed biofilms by 75.6 % and 3 mM CAD (0.25 MIC) reduced the intracellular concentrations of the secondary messenger, bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), which controls P. aeruginosa biofilm formation. The swarming motility of P. aeruginosa was also reduced by CAD in a concentration dependent manner. Collectively, these findings show that sub-MICs of CAD can disrupt biofilms and other surface colonization phenotypes through the modulation of intracellular signalling processes. PMID- 29993360 TI - Short-term Outcomes in Patients with Carcinoma of the Esophagus and Gastroesophageal Junction Receiving Neoadjuvant Chemotherapy or Chemoradiation before Surgery. A Prospective Study. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) and neoadjuvant chemoradiotherapy (NACRT) have been demonstrated to improve survival compared to surgery alone in esophageal carcinoma, but the evidence is scarce on which of these therapies is more beneficial, particularly with regard to resectability rates, postoperative morbidity and mortality, and histological responses. OBJECTIVE: This study compares the resectability, pathological response rates, and short-term surgical outcomes in patients with carcinoma of the esophagus or gastroesophageal junction receiving NACT or NACRT prior to surgery. METHODS: Patients with resectable carcinoma of the esophagus or gastroesophageal junction adenocarcinoma, squamous cell carcinoma, and adenosquamous histologies were enrolled in this well-matched prospective non-randomized study. Thirty-five patients were given NACT, and 35 NACRT. In the NACT group, 25 patients received three cycles of three-weekly carboplatin and paclitaxel, and 10 received three cycles of cisplatin/5 fluorouracil, while all the patients in the NACRT group received 41.4 Gy of radiotherapy concomitant with five cycles of weekly paclitaxel and carboplatin based chemotherapy. RESULTS: Twenty-two patients in the NACT group and 33 patients in NACRT group had resection (P value = 0.0027). The percentage of microscopically margin-negative resection (R0 resection) was similar in both the groups (86% versus 88%). The incidences of surgical and non-surgical complications were similar in both the groups (P=0.34). There was no 30-day mortality. There was a trend toward more pathological complete regression in the NACRT group (P=0.067). The percentage of patients achieving complete tumor regression at the primary site (pT0) was significantly higher in the NACRT group. The down-staging effect on nodal status was similar in both the groups (P=0.55). There was a statistically significant reduction in tumor size in the NACRT group. The median numbers of nodes harvested and positive nodes were similar in both the groups. CONCLUSION: Patients receiving NACRT had better resectability rates and pathological response rates, but similar postoperative morbidity compared to the NACT group. PMID- 29993361 TI - Comparison of Clinical Characteristics and Prognosis in Patients with Right- and Left-sided Infective Endocarditis. AB - OBJECTIVE: Right-sided endocarditis (RSE) accounts for 5%-10% of all cases of infective endocarditis (IE) and frequently has different etiological, pathogenetic, and clinical presentations compared with left-sided endocarditis (LSE). The aims of this study were to evaluate the epidemiologic and clinical characteristics and prognosis of RSE patients and to compare them with those of LSE patients. This study's importance relates to the local understanding of RSE and LSE, since Israeli demographics are different compared to the Unites States and Europe with regard to intravenous drug abuse and rheumatic valvular disease prevalence. MATERIAL AND METHODS: A retrospective cohort study of 215 patients with infective endocarditis was performed. The primary outcome was in-hospital mortality. The secondary outcomes were duration of hospitalization, recurrent hospitalization, recurrent infective endocarditis, and one-year mortality. RESULTS: Of the 215 patients in the study, 176 had LSE and 39 had RSE. The RSE patients were younger than the LSE patients (48.1+/-18.9 years versus 61.8+/-17.0 years, P<0.001). The most common pathogen in both groups was Staphylococcus aureus, which occurred more in the RSE group (51%) versus the LSE group (19%). In hospital mortality was lower among patients with RSE (2.6% versus 17%, P<0.037). CONCLUSIONS: Our study demonstrated an increasing percentage of RSE compared to LSE among patients with IE. Pacemaker lead infection has become the leading cause of RSE in intravenous drug users (IVDU), although less common in Southern Israel. The etiological and clinical differences between RSE and LSE are noteworthy. Patients with RSE have a better prognosis than those with LSE. PMID- 29993362 TI - Highly multiplexed immunofluorescence imaging of human tissues and tumors using t CyCIF and conventional optical microscopes. AB - The architecture of normal and diseased tissues strongly influences the development and progression of disease as well as responsiveness and resistance to therapy. We describe a tissue-based cyclic immunofluorescence (t-CyCIF) method for highly multiplexed immuno-fluorescence imaging of formalin-fixed, paraffin embedded (FFPE) specimens mounted on glass slides, the most widely used specimens for histopathological diagnosis of cancer and other diseases. t-CyCIF generates up to 60-plex images using an iterative process (a cycle) in which conventional low-plex fluorescence images are repeatedly collected from the same sample and then assembled into a high-dimensional representation. t-CyCIF requires no specialized instruments or reagents and is compatible with super-resolution imaging; we demonstrate its application to quantifying signal transduction cascades, tumor antigens and immune markers in diverse tissues and tumors. The simplicity and adaptability of t-CyCIF makes it an effective method for pre clinical and clinical research and a natural complement to single-cell genomics. PMID- 29993363 TI - The reliability of LERI's sign in L4 and L3 radiculalgia. AB - Although not as frequent as sciatica, cruralgia remains one of the most frequent reasons why people consult a neurosurgeon. It should be kept in mind, however, that every anterior leg pain is not cruralgia and thus several diagnoses must be discarded, such as of musculoskeletal diseases of hip, pelvis and femur. In the last years of the 19th century, Andre Leri, a French neurologist, described Leri's sign as it is used widely even today in everyday clinical practice. We studied retrospectively files of those patients who were seen in Neurosurgery by the authors for L3 and L4 nerve root compression to evaluate the reliability and accuracy of this sign. Between October 1998 and September 2017, 38,654 patients were examined in our department of Neurosurgery. Among them, 1698 patients presented pain as cruralgia and meralgia. In total, 1545 patients were included in the study. The data analysis showed that the sensitivity of LS was 0.9333 and the specificity 0.7974. The results of the study show a reliable diagnostic accuracy of Leri's sign. PMID- 29993365 TI - Maximum Velocity Estimation in Coronary Arteries Using 3-D Tracking Doppler. AB - Several challenges currently prevent the use of Doppler echocardiography to assess blood flow in the coronary arteries. Due to the anatomy of the coronary tree, out-of-plane flow and high beam-to-flow angles easily occur. Transit-time broadening in regions with high velocities leads to overestimation of the maximum velocity envelope, which is a standard clinical parameter for flow quantification. In this paper, a commercial ultrasound system was locally modified to perform trans-thoracic, 3-D high frame-rate imaging of the coronary arteries. The imaging sequence was then combined with 3-D tracking Doppler for retrospective estimation of maximum velocities. Results from simulations showed that 3-D tracking Doppler delivers sonograms with better velocity resolution and spectral SNR compared to conventional pulsed wave (PW) Doppler. Results were confirmed using in vitro recordings. Further simulations based on realistic coronary flow data showed that 3-D tracking Doppler can provide improved performance compared to PW Doppler, suggesting a potential benefit to patients. In vivo feasibility of the method was also shown in a healthy volunteer. PMID- 29993364 TI - Ultrasound Open Platforms for Next-Generation Imaging Technique Development. AB - Open platform (OP) ultrasound systems are aimed primarily at the research community. They have been at the forefront of the development of synthetic aperture, plane wave, shear wave elastography, and vector flow imaging. Such platforms are driven by a need for broad flexibility of parameters that are normally preset or fixed within clinical scanners. OP ultrasound scanners are defined to have three key features including customization of the transmit waveform, access to the prebeamformed receive data, and the ability to implement real-time imaging. In this paper, a formative discussion is given on the development of OPs from both the research community and the commercial sector. Both software- and hardware-based architectures are considered, and their specifications are compared in terms of resources and programmability. Software based platforms capable of real-time beamforming generally make use of scalable graphics processing unit architectures, whereas a common feature of hardware based platforms is the use of field-programmable gate array and digital signal processor devices to provide additional on-board processing capacity. OPs with extended number of channels (>256) are also discussed in relation to their role in supporting 3-D imaging technique development. With the increasing maturity of OP ultrasound scanners, the pace of advancement in ultrasound imaging algorithms is poised to be accelerated. PMID- 29993366 TI - Measurements of the Relationship Between CT Hounsfield Units and Acoustic Velocity and How It Changes With Photon Energy and Reconstruction Method. AB - Transcranial magnetic resonance-guided focused ultrasound continues to gain traction as a noninvasive treatment option for a variety of pathologies. Focusing ultrasound through the skull can be accomplished by adding a phase correction to each element of a hemispherical transducer array. The phase corrections are determined with acoustic simulations that rely on speed of sound estimates derived from CT scans. While several studies have investigated the relationship between acoustic velocity and CT Hounsfield units (HUs), these studies have largely ignored the impact of X-ray energy, reconstruction method, and reconstruction kernel on the measured HU, and therefore the estimated velocity, and none have measured the relationship directly. In this paper, 91 ex vivo human skull fragments from two skulls are imaged by 80 CT scans with a variety of energies and reconstruction methods. The average HU from each fragment is found for each scan and correlated with the speed of sound measured using a through transmission technique in that fragment. As measured by the -squared value, the results show that CT is able to account for 23%-53% of the variation in velocity in the human skull. Both the X-ray energy and the reconstruction technique significantly alter the -squared value and the linear relationship between HU and speed of sound in bone. Accounting for these variations will lead to more accurate phase corrections and more efficient transmission of acoustic energy through the skull. PMID- 29993368 TI - Signal Coherence and Image Amplitude With the Filtered Delay Multiply and Sum Beamformer. AB - The filtered delay multiply and sum (F-DMAS) beamformer has recently been presented in the context of medical ultrasound image formation. This nonlinear beamformer produces images with improved contrast resolution and noise rejection when compared with the delay and sum (DAS) beamformer. In an attempt to better understand the origin of the improved image quality, this paper shows a theoretical study of the image amplitude statistics backed up by numerical simulations. The results show that the difference in image amplitude using the DAS or F-DMAS beamformers can be partly explained by the way signal coherence influences both beamformers. When using the F-DMAS compared with the DAS beamformer, the image amplitude is shown to be more dependent on the signal coherence. Experimental ultrasound images of a phantom confirm our findings. PMID- 29993367 TI - Phase-Inverted Multifrequency HIFU Transducer for Lesion Expansion: A Simulation Study. AB - It has been well known that the treatment time of high-intensity focused ultrasound (HIFU) surgery can be reduced by expanding the focal area per sonication. Previously, a dual-concentric transducer using phase-inverted signals was proposed to axially extend the focal area, but it has suffered from the deep notch point between two focal lobes. In this paper, we propose the improved HIFU transducer with dual-concentric aperture driven by phase-inverted multifrequency signals based on an inversion layer technique. The proposed transducer can generate the expanded focal zone with a significantly reduced level of the notch point between two focal lobes in the axial direction. The performance of the proposed transducer was investigated using finite element analysis simulation. The electrical impedance, one-way impulse response, and acoustic field of the transducer were simulated. Subsequently, the lesion volume was investigated by heat transfer simulation. In the proposed method, the level of the notch point was increased above -6 dB due to various phase interactions between the fundamental and harmonic frequency combinations and the inverted and noninverted frequency combinations. The -6-dB depth of field related to the necrotic lesion size was increased by 141% compared with the conventional single element transducer. Thus, the proposed transducer can be a potential way to enlarge coagulated lesion size resulting in a reduced overall treatment time of HIFU surgery. PMID- 29993369 TI - Compressed Sensing Based Synthetic Transmit Aperture for Phased Array Using Hadamard Encoded Diverging Wave Transmissions. AB - Previously, we proposed compressed sensing based synthetic transmit aperture (CS STA) to improve the contrast and frame rate of STA while maintaining its spatial resolution in linear array by choosing uniform random matrix as the measurement matrix and transmitting the plane waves (PWs). In this paper, to extend CS-STA for phased array imaging and further improve its performance, we design four types of CS-STA implementations with different combinations of measurement matrices (i.e., uniform random and Hadamard matrices) and transmitted waves [i.e., PW and diverging wave (DW)]. Through simulations and phantom experiments with a 3 MHz, 64-element phased array, we find that type-IV CS-STA with the combination of a Hadamard matrix and DW outperforms the other three implementations including the previously proposed type-I CS-STA in terms of image quality and reconstruction time. Specifically, PW transmission produces visible discontinuity and the reconstruction time with uniform random matrix is about 100 fold longer than that with the Hadamard matrix. Compared with STA, with eightfold higher frame rate, type-IV CS-STA achieves 8.2 and 12.3 dB higher contrast-to noise ratio and signal-to-noise ratio in the simulations, respectively. These improvements are slightly lower in the phantom experiments, which are 6.2 and 6.6 dB, respectively. In addition, CS-STA does not deteriorate the spatial resolution of STA, with the maximum deterioration being smaller than 1/8 wavelength. These results demonstrate that type-IV CS-STA can achieve phased array imaging with high image quality at high frame rate and may be beneficial to cardiac imaging. PMID- 29993370 TI - Microbeamforming With Error Compensation. AB - One of the main issues in the development of 2-D arrays is the high system complexity due to the requirement for a large number of elements. The 2-D array systems suffer from high system complexity. The microbeamforming (MBF) method has been proposed to reduce the system complexity; however, distortions of MBF approach such as focusing errors of postbeamforming process result in broadening the main lobe and increasing the sidelobe and grating-lobe levels, which together degrade the image quality. As the presteered radio frequency (RF) data can be estimated from MBF data at the digital back end, better postbeamforming can be performed and higher image quality can be achieved. In this paper, a compensation approach is proposed to estimate the presteered RF data from MBF data by utilizing additional headers and compensation factors. The compensation factors and headers are estimated at the probe front end and then applied to the back-end digital system to reconstruct the required presteered RF data. As the absolute values of the MBF errors are modeled as a single-sided Gaussian distribution, the theoretical mean square error with the proposed method is approximately 2.75 times lower than that of its counterpart without compensation; this implies better reconstruction of presteered RF data can be achieved with the proposed method. The simulation results showed that the main lobe is improved, and the sidelobe and grating-lobe levels in both the lateral and elevation directions were improved by 11.73 and 19.12 dB, respectively, while the peak signal-to-noise ratios improved by 6-9 dB with the proposed method. The contrast-to-noise ratios also are enhanced by 0.5 dB when using the proposed method. Analog circuits are presented to demonstrate that this novel compensation method can be realized in practice. The reduction of cables and analog-to-digital converters are about seven-fold compared to fully sampled 2-D array systems as 4 by 4 channels are grouped for the proposed method as well. PMID- 29993371 TI - Simultaneous Vascular Strain and Blood Vector Velocity Imaging Using High Frequency Versus Conventional-Frequency Plane Wave Ultrasound: A Phantom Study. AB - Plaque strain and blood vector velocity imaging of stenosed arteries are expected to aid in diagnosis and prevention of cerebrovascular disease. Ultrafast plane wave imaging enables simultaneous strain and velocity estimation. Multiple ultrasound vendors are introducing high-frequency ultrasound probes and systems. This paper investigates whether the use of high-frequency ultrafast ultrasound is beneficial for assessing blood velocities and strain in arteries. The performance of strain and blood flow velocity estimation was compared between a high frequency transducer (MS250, fc = 21 MHz) and a clinically utilized transducer (L12-5, fc = 9 MHz). Quantitative analysis based on straight tube phantom experiments revealed that the MS250 outperformed the L12-5 in the superficial region: low velocities near the wall were more accurately estimated and wall strains were better resolved. At greater than 2-cm echo depth, the L12-5 performed better due to the high attenuation of the MS250 probe. Qualitative comparison using a perfused patient-specific carotid bifurcation phantom confirmed these findings. Thus, in conclusion, for strain and blood velocity estimation for depths up to ~2 cm, a high-frequency probe is recommended. PMID- 29993372 TI - Curvilinear 3-D Imaging Using Row-Column-Addressed 2-D Arrays With a Diverging Lens: Phantom Study. AB - A double-curved diverging lens over the flat row-column-addressed (RCA) 2-D array can extend its inherent rectilinear 3-D imaging field of view (FOV) to a curvilinear volume region, which is necessary for applications such as abdominal and cardiac imaging. Two concave lenses with radii of 12.7 and 25.4 mm were manufactured using RTV664 silicone. The diverging properties of the lenses were evaluated based on simulations and measurements on several phantoms. The measured FOV for both lenses in contact with tissue mimicking phantom was less than 15% different from the theoretical predictions, i.e., a curvilinear FOV of and for the 12.7- and 25.4-mm radii lenses. A synthetic aperture imaging sequence with single-element transmissions was designed for imaging down to 140 mm at a volume rate of 88 Hz. The performance was evaluated in terms of signal-to-noise ratio, FOV, and full-width at half-maximum (FWHM) of a focused beam. The penetration depths in a tissue mimicking phantom with 0.5-dB/(cm MHz) attenuation were 100 and 125 mm for the lenses with radii of 12.7 and 25.4 mm. The azimuth, elevation, and radial FWHM at 43-mm depth were (5.8, 5.8, 1) and (6, 6, 1) . The results of this study confirm that the proposed lens approach is an effective method for increasing the FOV, when imaging with RCA 2-D arrays. PMID- 29993373 TI - Real-Time 2-D Phased Array Vector Flow Imaging. AB - Echocardiography examination of the blood flow is currently either restricted to 1-D techniques in real-time or experimental offline 2-D methods. This paper presents an implementation of transverse oscillation for real-time 2-D vector flow imaging (VFI) on a commercial BK Ultrasound scanner. A large field-of-view (FOV) sequence for studying flow dynamics at 11 frames per second (fps) and a sequence for studying peak systolic velocities (PSVs) with a narrow FOV at 36 fps were validated. The VFI sequences were validated in a flow rig with continuous laminar parabolic flow and in a pulsating flow pump system before being tested in vivo, where measurements were obtained on two healthy volunteers. Mean PSV from 11 cycles was 155 cms-1 with a precision of +/-9.0% for the pulsating flow pump. In vivo, PSV estimated in the ascending aorta was 135 cms-1 +/- 16.9% for eight cardiac cycles. Furthermore, in vivo flow dynamics of the left ventricle and in the ascending aorta were visualized. In conclusion, angle independent 2-D VFI on a phased array has been implemented in real time, and it is capable of providing quantitative and qualitative flow evaluations of both the complex and fully transverse flow. PMID- 29993374 TI - Enhanced Ultrasonic Flaw Detection Using an Ultrahigh Gain and Time-Dependent Threshold. AB - In an attempt to improve the ultrasonic testing capability of a conventional C scan system, a flaw detection method using an ultrahigh gain is developed in this paper. A time-dependent threshold for image segmentation is applied to identify automatically material anomalies present in the sample. A singly scattered response model is used with extreme value statistics to calculate the confidence bounds of grain noise. The result is a time-dependent threshold associated with the grain noise that can be used for segmentation. Ultrasonic imaging experiments show that the presented method has advantages over a traditional fixed threshold approach with respect to false positives and missed flaws. The results also show that a low gain is adverse to the detection of microflaws with subwavelength dimensions. The forward model is expected to serve as an effective tool for the probability of detection of flaws and the inspection of coarse-grained materials in the future. PMID- 29993375 TI - Ultrasonic Wave-Speed Diffraction Tomography With Undersampled Data Using Virtual Transducers. AB - Ultrasonic diffraction tomography offers a way to achieve high-resolution imaging of the wave-speed map, and hence, has strong potential applications in medical diagnosis and nondestructive evaluation. Ideal images can be obtained with a complete array of sensors surrounding the scatterer, provided that the measurement data are fully sampled in space, obeying the Nyquist criterion. Spatial undersampling causes the image to be distorted and introduce unwanted circular artifacts. In this paper, we propose an iteration approach using virtual transducers to achieve high-resolution tomographic imaging with undersampled measurements. At each iteration stage, the extent constraint estimated from the shape of the object of interest is applied on the image space to obtain a regularized image, based on which the ultrasonic measurement data at virtual transducers are calculated using a forward model. The full data set composed of original and virtual measurements is then used for tomography in the next stage. A final image with sufficiently high resolution is obtained only after a few iterations. The new imaging method yields improvements in the robustness and accuracy of ultrasonic tomography with undersampled data. We present numerical results using complicated wave-speed maps from realistic corrosion profiles. In addition, an experiment using guided ultrasonic waves is performed to further evaluate the imaging method. PMID- 29993376 TI - Mode Selectivity of SH Guided Waves by Dual Excitation and Reception Applied to Mode Conversion Analysis. AB - Shear horizontally (SH) guided waves, generated by periodic permanent magnet arrays, have been used previously in nondestructive evaluation of metal plates and pipes. When an SH guided wave interacts with a defect or a change in sample thickness, the incident SH wave may undergo mode conversion. Analysis of mode conversion is complicated, due to the interference of several propagating modes in the received signal that can often temporally overlap. This paper proposes a mode selection technique to help understand the interaction of SH guided waves with changes in sample thickness. Using an understanding of the propagation characteristics of the guided waves, SH guided waves are sequentially generated and detected on both surfaces of the plate, capturing four distinct waveforms. By superposition of the detected signals, symmetric modes can be clearly separated from antisymmetric modes in the processed received signals. For this method to work well, the transducers used should have very similar responses and be precisely positioned on exactly opposite positions either side of the plate. Finite element simulations are also performed, mirroring the experimental measurements, and the results correlate well with the experimental observations made on an 8-mm-thick plate with a region of simulated wall thinning machined into the sample. PMID- 29993377 TI - High-Temperature Ultrasound Attenuation in Langasite and Langatate. AB - The ultrasound attenuation in langasite crystals increases rapidly at about 800 K with increasing temperature for reasons that are not well understood. In this paper, the attenuation quantified as of the langasite-type materials La3Ga5SiO14 (LGS) and La3Ta0.5Ga5.5O14 (LGT) was studied from room temperature to 1653 and 1608 K, respectively, using resonant ultrasound spectroscopy. Two to three attenuation peaks can be seen. A change of the magnitudes of the largest two attenuation peaks in LGT was correlated with the changing color of an LGT sample, which is related to its oxygen vacancy concentration. Thus, the attenuation likely involves oxygen vacancies. The observed can be explained well by a model based on the anelastic relaxation of two to three noninteracting point defects causing Debye peak-like attenuation maxima. The activation energies of the largest two relaxation peaks match the activation energies for different conductivity mechanisms in LGS and LGT. Thus, the oxygen movement-based conductivity and the relaxation processes seem to involve the exchange of ions and vacancies on the same positions. The largest two attenuation peaks are probably caused by the movement of ions induced by two different phenomena, the deformation of the lattice (point-defect relaxation) on the one hand and the electric field via the piezoelectric effect (piezoelectric/carrier relaxation) on the other hand. PMID- 29993380 TI - Anisotropy Factors and Electromechanical Coupling in Lead-Free 1-3-Type Composites. AB - The effective electromechanical properties and anisotropy factors of novel lead free 1-3-type composites are studied to demonstrate their large piezoelectric anisotropy and considerable level of electromechanical coupling. The composites studied contain two single-crystal (SC) components and a polymer component. The first piezoactive component is a domain-engineered [001]-poled SC based on ferroelectric alkali niobates-tantalates, and this component is in the form of a system of long rods that are parallel to the poling axis . The second SC component is a system of spheroidal piezoelectric Li2B4O7 inclusions aligned in a continuous and relatively large polymer matrix. The SC rods are surrounded by an SC/polymer matrix, and the connectivity of the composite is 1-0-3. It is shown that the conditions , which indicates a large degree of anisotropy of the piezoelectric coefficients, and and , which indicate a large anisotropy of the electromechanical coupling factors (ECFs), can be achieved simultaneously in specific ranges of the component volume fractions and inclusion aspect ratios. Moreover, in the same volume-fraction and aspect-ratio ranges, large ECFs ( -0.9) are also achieved. In this context, the important role of the elastic properties of the continuous anisotropic matrix is discussed. The properties and anisotropy factors of the lead-free 1-3-type composites are compared to the similar parameters of conventional lead-containing piezoelectric materials, and the advantages of the composite system studied are described. PMID- 29993379 TI - Influence of Compositional Variation on the Electrical Properties of [Pb(Zn1/3Nb2/3)O3]-[Pb(Zr,Ti)O3] Ceramics and Their Transducer Application. AB - The ternary system of x[Pb(Zn1/3Nb2/3O3. ( )[Pb(ZryTi1-y)O3] composition with " " varying from 0.1 to 0.6 with interval of 0.1 and " " varying from 0.46 to 0.52 with interval of 0.01 was studied. The main objective was to maximize the dielectric and electromechanical properties through compositional variation and then to establish the full property matrix of the optimized composition for further analysis and device applications. Ceramics with pure perovskite phase have been produced in the entire compositional range that was investigated. The highest ferroelectric and electromechanical properties were obtained at the 0.4[Pb(Zn1/3Nb2/3)O3-0.6[Pb(Zr0.48Ti0.52)O3]-(0.4 PZN-0.6 PZT) composition with remanent polarization ( ) of /cm2, piezoelectric charge coefficient (d33) of 465 pC/N, and electromechanical coupling coefficients ( , , and ) of 0.67, 0.52, and 0.77, respectively. Full property matrix for 0.4 PZN-0.6 PZT was obtained and was used as input in the finite-elements analysis of ceramics in disc and hemispherical shell form. Hollow spherical omnidirectional transducers were fabricated from the lead zinc niobate-lead zirconate titanate (PZN-PZT) ceramics as a device prototype, and underwater characteristics have been determined and reported for these transducers. PMID- 29993378 TI - Numerical Modeling of Ultrasound Propagation in Weakly Heterogeneous Media Using a Mixed-Domain Method. AB - A mixed-domain method (MDM) is presented in this paper for modeling one-way linear/nonlinear wave propagation in biological tissue with arbitrary heterogeneities, in which sound speed, density, attenuation coefficients, and nonlinear coefficients are all spatial varying functions. The present method is based on solving an integral equation derived from a Westervelt-like equation. One-dimensional problems are first studied to verify the MDM and to reveal its limitations. It is shown that this method is accurate for cases with small variation of sound speed. A 2-D case is further studied with focused ultrasound beams to validate the application of the method in the medical field. Results from the MATLAB toolbox k-Wave are used as the benchmark. Normalized root-mean square (rms) error estimated at the focus of the transducer is 0.0133 when the coarsest mesh (1/3 of the wavelength) is used in the MDM. Fundamental and second harmonic fields throughout the considered computational domains are compared and good agreement is observed. Overall, this paper demonstrates that the MDM is a computationally efficient and accurate method when used to model wave propagation in biological tissue with relatively weak heterogeneities. PMID- 29993381 TI - Long Haul Time and Frequency Distribution in Different DWDM Systems. AB - In this paper, we have presented the possibility of time and frequency (T&F) distribution in two generations of dense wavelength-division-multiplexing (DWDM) networks: the older one, equipped with dispersion compensation fiber (DCF) modules, and the newest, without in-line chromatic dispersion compensation (dedicated for coherent signals). The experiments were performed in a 1500-km loop arranged in the PIONIER production network, with T&F signals regarded as so called "alien wavelength" network service. In the newest DWDM version, we observed very good stability of delivered signals: modified Allan deviation approach 10-16 for averaging longer than 104 s (for 10-MHz frequency signal), and time deviation below 15 ps for averaging up to 105 s for 1 PPS time signal. These results show that the DWDM alien wavelength service can be used for high demanding applications like cesium fountains comparisons. Results achieved for the former version of DWDM were about one magnitude worse for a long-term comparison, but it can still be useful for less demanding applications. We found that the main reason for relatively poor results observed in the older generation of DWDM is the impact of the DCFs used in this DWDM approach. PMID- 29993382 TI - Reducing Cavity-Pulling Shift in Ramsey-Operated Compact Clocks. AB - We describe a method to stabilize the amplitude of the interrogating microwave field in compact atomic clocks working in a Ramsey approach. In this technique, we take advantage of the pulsed regime to use the atoms themselves as microwave amplitude discriminators. Specifically, in addition to the dependence on the microwave detuning, the atomic signal after the Ramsey interrogation acquires a dependence on the microwave pulse area (amplitude times duration) that can be exploited to implement an active stabilization of the microwave field amplitude, in a similar way in which the Ramsey clock signal is used to lock the local oscillator frequency to the atomic reference. The stabilization allows us to reduce the microwave field-amplitude fluctuations, which in turn impact the clock frequency through cavity pulling. The proposed technique has shown to be effective to improve our clock frequency stability on medium and long term. We demonstrate the method for a vapor-cell clock working with a hot sample of atoms, but it can be extended to cold-atom compact clocks. PMID- 29993383 TI - Information-Theoretic Approach and Fundamental Limits of Resolving Two Closely Timed Neuronal Spikes in Mouse Brain Calcium Imaging. AB - OBJECTIVE: Although optical imaging of neurons using fluorescent genetically encoded calcium sensors has enabled large-scale in vivo experiments, the sensors' slow dynamics often blur closely timed action potentials into indistinguishable transients. While several previous approaches have been proposed to estimate the timing of individual spikes, they have overlooked the important and practical problem of estimating interspike interval (ISI) for overlapping transients. METHODS: We use statistical detection theory to find the minimum detectable ISI under different levels of signal-to-noise ratio (SNR), model complexity, and recording speed. We also derive the Cramer-Rao lower bounds (CRBs) for the problem of ISI estimation. We use Monte-Carlo simulations with biologically derived parameters to numerically obtain the minimum detectable ISI and evaluate the performance of our estimators. Furthermore, we apply our detector to distinguish overlapping transients from experimentally obtained calcium imaging data. RESULTS: Experiments based on simulated and real data across different SNR levels and recording speeds show that our algorithms can accurately distinguish two fluorescence signals with ISI on the order of tens of milliseconds, shorter than the waveform's rise time. Our study shows that the statistically optimal ISI estimators closely approached the CRBs. CONCLUSION: Our work suggests that full analysis using recording speed, sensor kinetics, SNR, and the sensor's stochastically distributed response to action potentials can accurately resolve ISIs much smaller than the fluorescence waveform's rise time in modern calcium imaging experiments. SIGNIFICANCE: Such analysis aids not only in future spike detection methods, but also in future experimental design when choosing sensors of neuronal activity. PMID- 29993384 TI - Multiple Instance Dictionary Learning for Beat-to-Beat Heart Rate Monitoring From Ballistocardiograms. AB - A multiple instance dictionary learning approach, dictionary learning using functions of multiple instances (DL-FUMI), is used to perform beat-to-beat heart rate estimation and to characterize heartbeat signatures from ballistocardiogram (BCG) signals collected with a hydraulic bed sensor. DL-FUMI estimates a "heartbeat concept" that represents an individual's personal ballistocardiogram heartbeat pattern. DL-FUMI formulates heartbeat detection and heartbeat characterization as a multiple instance learning problem to address the uncertainty inherent in aligning BCG signals with ground truth during training. Experimental results show that the estimated heartbeat concept obtained by DL FUMI is an effective heartbeat prototype and achieves superior performance over comparison algorithms. PMID- 29993385 TI - A Quasi-Static Boundary Element Approach With Fast Multipole Acceleration for High-Resolution Bioelectromagnetic Models. AB - OBJECTIVE: We develop a new accurate version of the boundary element fast multipole method for transcranial magnetic stimulation (TMS) related problems. This method is based on the surface-charge formulation and is using the highly efficient fast multipole accelerator along with analytical computations of neighbor surface integrals. RESULTS: The method accuracy is demonstrated by comparison with the proven commercial finite-element method (FEM) software ANSYS Maxwell 18.2 2017 operating on unstructured grids and with adaptive mesh refinement. Five realistic high-definition head models from the Population Head Repository (IT'IS Foundation, Switzerland) have been acquired and augmented with a commercial TMS coil model (MRi-B91, MagVenture, Denmark). For each head model, simulations with our method and simulations with the FEM software ANSYS Maxwell 18.2 2017 have been performed. These simulations have been compared with each other and an excellent agreement was established in every case. SIGNIFICANCE: At the same time, our new method runs approximately 500 times faster than the ANSYS FEM, finishes in about 200 s on a standard server, and naturally provides a submillimeter field resolution, which is justified using mesh refinement. CONCLUSIONS: Our method can be applied to modeling of brain stimulation and recording technologies such as TMS and magnetoencephalography, and has the potential to become a real-time high-resolution simulation tool. PMID- 29993386 TI - Electroencephalogram Based Detection of Deep Sedation in ICU Patients Using Atomic Decomposition. AB - OBJECTIVE: This study was performed to evaluate how well states of deep sedation in ICU patients can be detected from the frontal electroencephalogram (EEG) using features based on the method of atomic decomposition (AD). METHODS: We analyzed a clinical dataset of 20 min of EEG recordings per patient from 44 mechanically ventilated adult patients receiving sedatives in an intensive care unit (ICU) setting. Several features derived from AD of the EEG signal were used to discriminate between awake and sedated states. We trained support vector machine (SVM) classifiers using AD features and compared the classification performance with SVM classifiers trained using standard spectral and entropy features using leave-one-subject-out validation. The potential of each feature to discriminate between awake and sedated states was quantified using area under the receiver operating characteristic curve (AUC). RESULTS: The sedation level classification system using AD was able to reliably discriminate between sedated and awake states achieving an average AUC of 0.90, which was significantly better () than performance achieved using spectral (AUC = 0.86) and entropy (AUC = 0.81) domain features. A combined feature set consisting of AD, entropy, and spectral features provided better discrimination (AUC = 0.91, ) than any individual feature set. CONCLUSIONS: Features derived from the atomic decomposition of EEG signals provide useful discriminative information about the depth of sedation in ICU patients. SIGNIFICANCE: With further refinement and external validation, the proposed system may be able to assist clinical staff with continuous surveillance of sedation levels in mechanically ventilated critically ill ICU patients. PMID- 29993387 TI - Microbubble Localization for Three-Dimensional Superresolution Ultrasound Imaging Using Curve Fitting and Deconvolution Methods. AB - Superresolution algorithms in ultrasound imaging are attracting the interest of researchers recently due to the ability of these methods to enable enhanced vascular imaging. In this study, two superresolution imaging methods are compared for postprocessing images of microbubbles generated using passive acoustic mapping (PAM) methods with a potential application of three-dimensional (3-D) brain vascular imaging. The first method is based on fitting single bubble images one at a time with a 3-D Gaussian profile to localize the microbubbles and a superresolution image is then formed using the uncertainty of the localization as the standard deviation of the Gaussian profile. The second superresolution method is based on image deconvolution that processes multiframe resolution-limited images iteratively and estimates the intensity at each pixel of the superresolution image without the need for localizing each microbubble. The point spread function is approximated by a Gaussian curve which is similar to the beam response of the hemispherical transducer array used in our experimental setup. The Cramer-Rao Bounds of the two estimation techniques are derived analytically and the performance of these techniques is compared through numerical simulations based on experimental PAM images. For linear and sinusoidal traces, the localization errors between the estimated peaks by the fitting-based method and the actual source locations were 220 10 m and 210 5 m, respectively, as compared to 74 10 m and 59 8 m with the deconvolution-based method. However, in terms of the running time and the computational costs, the curve fitting technique outperforms the deconvolution-based approach. PMID- 29993388 TI - Video Magnification Applied in Ultrasound. AB - GOAL: This paper describes a method to enhance, visualize and reveal subtle motion that can be present in medical images. As proposed in vision applications, the principle is to magnify displacement applied, in this case, to cardiovascular tissues (carotid). METHODS: In the example presented, ultrasound data were acquired at a high frame rate and 2D motion was estimated, amplified and reapplied in ultrasound carotid sequences. RESULTS: Video magnification makes fast and complex phenomena of human tissue visible. In fact, pulse and reflected wave, but also global radial and longitudinal motion in the example presented, are visible with video magnification. CONCLUSION: Video magnification can be used in medical imaging for subtle motion visualization. One of the many possible applications is direct visualization of a local modification in terms of stiffness of a tissue (due to local necrosis, for instance) from acquisition. Moreover, video magnification can be executed with any type of imaging modality. SIGNIFICANCE: Video magnification could be a new tool for physicians to highlight new pathology indicators or for long-term disease monitoring. PMID- 29993389 TI - Noninvasive Ultrasonic Neuromodulation in Freely Moving Mice. AB - Neuromodulation is a fundamental method for obtaining basic information about neuronal circuits for use in treatments for neurological and psychiatric disorders. Ultrasound stimulation has become a promising approach for noninvasively inducing neuromodulation in animals and humans. However, the previous investigations were subject to substantial limitations, due to most of them involving anesthetized and fixed small-animal models. Studies of awake and freely moving animals are needed, but the currently used ultrasound devices are too bulky to be applied to a freely moving animal. This study is the first time to design and fabricate a miniature and lightweight head-mounted ultrasound stimulator for inducing neuromodulation in freely moving mice. The main components of the stimulator include a miniature piezoelectric ceramic, a concave epoxy acoustic lens, and housing and connection components. The device was able to induce action potentials recorded and evoke head-turning behaviors by stimulating the primary somatosensory cortex barrel field of the mouse. These findings indicate that the proposed method can be used to induce noninvasive neuromodulation in freely moving mice. This novel method could potentially lead to the application of ultrasonic neuromodulation in more-extensive neuroscience investigations. PMID- 29993390 TI - Deep Residual Learning for Accelerated MRI Using Magnitude and Phase Networks. AB - OBJECTIVE: Accelerated magnetic resonance (MR) image acquisition with compressed sensing (CS) and parallel imaging is a powerful method to reduce MR imaging scan time. However, many reconstruction algorithms have high computational costs. To address this, we investigate deep residual learning networks to remove aliasing artifacts from artifact corrupted images. METHODS: The deep residual learning networks are composed of magnitude and phase networks that are separately trained. If both phase and magnitude information are available, the proposed algorithm can work as an iterative k-space interpolation algorithm using framelet representation. When only magnitude data are available, the proposed approach works as an image domain postprocessing algorithm. RESULTS: Even with strong coherent aliasing artifacts, the proposed network successfully learned and removed the aliasing artifacts, whereas current parallel and CS reconstruction methods were unable to remove these artifacts. CONCLUSION: Comparisons using single and multiple coil acquisition show that the proposed residual network provides good reconstruction results with orders of magnitude faster computational time than existing CS methods. SIGNIFICANCE: The proposed deep learning framework may have a great potential for accelerated MR reconstruction by generating accurate results immediately. PMID- 29993391 TI - Deformable Image Registration Using a Cue-Aware Deep Regression Network. AB - SIGNIFICANCE: Analysis of modern large-scale, multicenter or diseased data requires deformable registration algorithms that can cope with data of diverse nature. OBJECTIVE: We propose a novel deformable registration method, which is based on a cue-aware deep regression network, to deal with multiple databases with minimal parameter tuning. METHODS: Our method learns and predicts the deformation field between a reference image and a subject image. Specifically, given a set of training images, our method learns the displacement vector associated with a pair of reference-subject patches. To achieve this, we first introduce a key-point truncated-balanced sampling strategy to facilitate accurate learning from the image database of limited size. Then, we design a cue-aware deep regression network, where we propose to employ the contextual cue, i.e., the scale-adaptive local similarity, to more apparently guide the learning process. The deep regression network is aware of the contextual cue for accurate prediction of local deformation. RESULTS AND CONCLUSION: Our experiments show that the proposed method can tackle various registration tasks on different databases, giving consistent good performance without the need of manual parameter tuning, which could be applicable to various clinical applications. PMID- 29993392 TI - Cuffless Estimation of Blood Pressure: Importance of Variability in Blood Pressure Dependence of Arterial Stiffness Across Individuals and Measurement Sites. AB - OBJECTIVE: Measuring arterial pulse transit time (PTT) to estimate blood pressure (BP) without conventional brachial cuff-based measurement is not new, but is a focus of current wearable technologies research. Much research pertains to efficient, accurate sensing of artery-related waveforms, yet the relationship between PTT and BP receives less attention despite being key for accurate BP estimation. This study investigated BP/PTT calibration by quantifying anatomical site variability (n = 10, 3 female, age 30 9 years) and individual variability ( n = 103, 50 female, age 53 22 years). METHODS: BP and pulse wave velocity (PWV) were measured in both seated and supine. Carotid-femoral PWV (cfPWV), carotid radial PWV (crPWV), and carotid-finger-volume PWV (cvPWV) were measured with the wrist and hand positioned at the level of the upper thigh to achieve the same hydrostatic pressure effect across all measurements. RESULTS: The postural change invoked a small (4 7 mmHg) change in brachial diastolic BP with an additional 27 2 mmHg change in hydrostatic pressure. cfPWV decreased in the supine position (1.75 0.17 m s-1, p < 0.001), but crPWV and cvPWV were more variable. The calibration term (BP/PWV) across the sample population varied from 6.6 to 98.3 mmHg sm-1 (mean 22 14 mmHg sm-1) and was correlated with age, heart rate, diastolic and pulse pressure, and weight. These variables did not explain the majority of the variability (R2 = 0.248). CONCLUSION: There is anatomical site and between-individual variability in the calibration term for BP estimation from PTT. SIGNIFICANCE: Using and accurately calculating hydrostatic changes in BP within the individual may be one method to increase the accuracy of this calibration term. PMID- 29993393 TI - Learning Patterns of Pivoting Neuromuscular Control Training- Towards a Learning Model for Therapy Scheduling. AB - OBJECTIVE: The goal of this study was to investigate the learning patterns in leg pivoting neuromuscular control performance over six-week pivoting neuromuscular control training (POINT) and to estimate how many sessions at beginning are needed to estimate the overall pivoting neuromuscular control learning curve. METHODS: Twenty subjects (10 females, 10 males) participated in 18 sessions of POINT (three sessions per week for six weeks) program using an off-axis elliptical trainer. Performance measures including pivoting instability and stepping speed were quantified for each study session during a stepping task while subjects were asked to control pivoting movements under a slippery condition. Learning curve relating the pivoting instability to training sessions was quantified by the power law and by the exponential curve as a function of sessions or days with three parameters: the limit of learning, rate of learning, and learning capacity. RESULTS: The power and exponential learning models characterized the learning curves similarly with no differences in R2. No significant sex differences were found in the limit of learning, rate of learning, and learning capacity. Based on R2 and RMSE, data from the first three study sessions might be enough to estimate the pivoting neuromuscular performance over the whole training period. CONCLUSION: The findings showed that subjects' motor skills to improve pivoting instability followed the learning curve models. SIGNIFICANCE: The findings and models can potentially be used to develop more effective subject-specific therapy scheduling. PMID- 29993394 TI - An uncontrolled manifold analysis of arm joint variability in virtual planar position and orientation tele-manipulation. AB - OBJECTIVE: In teleoperated robot-assisted tasks, the user interacts with manipulators to finely control remote tools. Manipulation of robotic devices, characterized by specific kinematic and dynamic proprieties, is a complex task for the human sensorimotor system due to the inherent biomechanical and neuronal redundancies that characterize the human arm and its control. We investigate how master devices with different kinematics structures and how different task constraints influence users capabilities in exploiting arm redundancy. METHODS: A virtual teleoperation workbench was designed and the arm kinematics of seven users was acquired during the execution of two planar virtual tasks, involving either the control of position only or position-orientation of a tool. Using the UnControlled Manifold Analysis of arm joint variability we estimated the logarithmic ratio between task irrelevant and the task relevant manifolds (Rv). RESULTS: The Rv values obtained in the position-orientation task were higher than in the position only task while no differences were found between the master devices. A modulation of Rv was found through the execution of the position task and a positive correlation was found between task performance and redundancy exploitation. CONCLUSION: Users exploited additional portions of arm redundancy when dealing with the tool orientation. The Rv modulation seems influenced by the task constraints and by the users possibility of reconfiguring the arm position. SIGNIFICANCE: This work advances the general understanding of the exploitation of arm redundancy in complex tasks, and can improve the development of future robotic devices. PMID- 29993395 TI - Out-of-plane Rotation Control of Biological Cells with a Robot-Tweezers Manipulation System for Orientation-based Cell Surgery. AB - In many cell surgery applications, cell must be oriented properly such that the micro-surgery tool can access the target components with minimum damage to the cell. In this paper, a scheme for out of image plane orientation control of suspended biological cells using robotic controlled optical tweezers is presented for orientation-based cell surgery. Based on our previous work on planar cell rotation using optical tweezers, the dynamic model of cell out-of-plane orientation control is formulated by using the T-matrix approach. Vision-based algorithms are developed to extract the cell out of image plane orientation angles, based on 2D image slices obtained under optical microscope. A robust feedback controller is then proposed to achieve cell out-of-plane rotation. Experiments of automated out of image plane rotational control for cell nucleus extraction surgery are performed to demonstrate the effectiveness of the proposed approach. This approach advances robot-aided single cell manipulation and produces impactful benefits to cell surgery applications such as nucleus transplantation and organelle biopsy in precision medicine. PMID- 29993396 TI - Joint Segment-Level and Pixel-Wise Losses for Deep Learning Based Retinal Vessel Segmentation. AB - OBJECTIVE: Deep learning based methods for retinal vessel segmentation are usually trained based on pixel-wise losses, which treat all vessel pixels with equal importance in pixel-to-pixel matching between a predicted probability map and the corresponding manually annotated segmentation. However, due to the highly imbalanced pixel ratio between thick and thin vessels in fundus images, a pixel wise loss would limit deep learning models to learn features for accurate segmentation of thin vessels, which is an important task for clinical diagnosis of eye-related diseases. METHODS: In this paper, we propose a new segment-level loss which emphasizes more on the thickness consistency of thin vessels in the training process. By jointly adopting both the segment-level and the pixel-wise losses, the importance between thick and thin vessels in the loss calculation would be more balanced. As a result, more effective features can be learned for vessel segmentation without increasing the overall model complexity. RESULTS: Experimental results on public data sets demonstrate that the model trained by the joint losses outperforms the current state-of-the-art methods in both separate-training and cross-training evaluations. CONCLUSION: Compared to the pixel-wise loss, utilizing the proposed joint-loss framework is able to learn more distinguishable features for vessel segmentation. In addition, the segment level loss can bring consistent performance improvement for both deep and shallow network architectures. SIGNIFICANCE: The findings from this study of using joint losses can be applied to other deep learning models for performance improvement without significantly changing the network architectures. PMID- 29993397 TI - Estimating Brain Connectivity With Varying-Length Time Lags Using a Recurrent Neural Network. AB - OBJECTIVE: Computer-aided estimation of brain connectivity aims to reveal information propagation in brain automatically, which has great potential in clinical applications, e.g., epilepsy foci diagnosis. Granger causality is an effective tool for directional connection analysis in multivariate time series. However, most existing methods based on Granger causality assume fixed time lags in information transmission, while the propagation delay between brain signals is usually changing constantly. METHODS: We propose a Granger causality estimator based on the recurrent neural network, called RNN-GC, to deal with the multivariate brain connectivity detection problem. Our model takes input of time series signals with arbitrary length of transmission time lags and learns the information flow from the data using the gated RNN model, i.e., long short-term memory (LSTM). The LSTM model can sequentially update the gates in memory cells to determine how many preceding points should be considered for prediction. Therefore, the LSTM-based RNN-GC estimator works well on varying-length time lags and shows effectiveness even on very long transmission delays. RESULTS: Experiments are carried out in comparison with other methods using both simulation data and epileptic electroencephalography signals. The RNN-GC estimator achieves superior performance in brain connectivity estimation and shows robustness in modeling multivariate connections with varying-length time lags. CONCLUSION: The RNN-GC method is capable of modeling nonlinear and varying length lagged information transmission and effective in directional brain connectivity estimation. SIGNIFICANCE: The proposed method is promising to serve as a robust brain connection analysis tool in clinical applications. PMID- 29993398 TI - Heart Sound Segmentation-An Event Detection Approach Using Deep Recurrent Neural Networks. AB - OBJECTIVE: In this paper, we accurately detect the state-sequence first heart sound (S1)-systole-second heart sound (S2)-diastole, i.e., the positions of S1 and S2, in heart sound recordings. We propose an event detection approach without explicitly incorporating a priori information of the state duration. This renders it also applicable to recordings with cardiac arrhythmia and extendable to the detection of extra heart sounds (third and fourth heart sound), heart murmurs, as well as other acoustic events. METHODS: We use data from the 2016 PhysioNet/CinC Challenge, containing heart sound recordings and annotations of the heart sound states. From the recordings, we extract spectral and envelope features and investigate the performance of different deep recurrent neural network (DRNN) architectures to detect the state sequence. We use virtual adversarial training, dropout, and data augmentation for regularization. RESULTS: We compare our results with the state-of-the-art method and achieve an average score for the four events of the state sequence of ${?bf F}_{1}?approx 96$% on an independent test set. CONCLUSION: Our approach shows state-of-the-art performance carefully evaluated on the 2016 PhysioNet/CinC Challenge dataset. SIGNIFICANCE: In this work, we introduce a new methodology for the segmentation of heart sounds, suggesting an event detection approach with DRNNs using spectral or envelope features. PMID- 29993399 TI - Slow-wave recordings from micro-sized neural clusters using multi-well type microelectrode arrays. AB - : The use of microelectrode array (MEA) recordings is a very effective neurophysiological method, because it is able to continuously and noninvasively obtain the spatiotemporal information of electrical activity from many neurons constituting a neural network. Very recently, studies have been published that the measurement of a low-frequency component of electrical activity as an indicator of diverse activity of cultured neurons using MEAs. Although the occurrence of low-frequency activities has electrophysiological information that does not include the information from fast spikes, however, there is no in experimental model suitable for measuring the low-frequency activities ('slow waves') for further study. : The neural clusters consisting of dozens of neurons were placed directly on each electrode of an MEA, from which fast spikes and slow waves were measured. : We obtained sufficient data on the early development patterns of the slow-waves and the spikes measured from the many independent neural clusters, confirming that the slow-waves first occurred before the emergence of spikes in the neural clusters. We also showed that changes in the occurrence frequency of the slow-waves for synaptic blockers were measured from a large number of independent cultures. : Microsized neural cluster arrays, which can be combined with conventional MEAs, are suitable for multiple simultaneous recording the slow-waves. : Our technology provides a simple but useful method to study the generation of a low-frequency component of the electrical activity in cultured neural networks that are not yet well known, as well as to expand the use of conventional MEAs. PMID- 29993400 TI - Model-based Feature Augmentation for Cardiac Ablation Target Learning from Images. AB - GOAL: We present a model-based feature augmentation scheme to improve the performance of a learning algorithm for the detection of cardiac radio-frequency ablation (RFA) targets with respect to learning from images alone. METHODS: Initially, we compute image features from delayed-enhanced MRI (DE-MRI) to describe local tissue heterogeneities and feed them into a machine learning framework with uncertainty assessment for the identification of potential ablation targets. Next, we introduce the use of a patient-specific image-based model derived from DE-MRI coupled with the Mitchell-Schaeffer electrophysiology model for the simulation of intracardiac electrograms (EGM). Relevant features are extracted from these simulated signals which serve as a feature augmentation scheme for the learning algorithm. We assess the classifier's performance when using only image features and with model-based feature augmentation. RESULTS: We obtained average classification scores of 97.2% accuracy, 82.4% sensitivity and 95.0% positive predictive value (PPV) by using a model-based feature augmentation scheme. Preliminary results also show that training the algorithm on the closest patient from the database, instead of using all the patients, improves the classification results. CONCLUSION: We presented a feature augmentation scheme based on biophysical cardiac electrophysiology modeling to increase the prediction scores of a machine learning framework for the RFA target prediction. SIGNIFICANCE: The results derived from this study are a proof of concept that the use of model-based feature augmentation strengthens the performance of a purely image driven learning scheme for the prediction of cardiac ablation targets. PMID- 29993401 TI - A Smart Capsule With a Hydrogel-Based pH-Triggered Release Switch for GI-Tract Site-Specific Drug Delivery. AB - In this paper, we present a smart capsule that can release its payload after a predetermined/adjustable delay subsequent to passing from the stomach into the small intestine. The described capsule (9 mm * 22 mm) comprises a pH-sensitive hydrogel-based switch, an electronic compartment containing a capacitor charged to 2.7 V, and a drug reservoir capped by a taut fusible thread intertwined with a nichrome wire. The nichrome wire, capacitor, and pH-responsive electrical switch are connected in series. The pH transition the capsule encounters when it enters the small intestine triggers controlled swelling of the pH-responsive hydrogel, which pushes a conductive elastic membrane to close an electrical switch. This initiates a sequence of events, i.e., the discharge of the capacitor, heating the nichrome wire, breakage of the fusible thread, and release of the payload stored in the capsule reservoir through the unlatched cap. The time lag between initiation of hydrogel swelling (by the near-neutral pH of the small intestine) and payload release is controlled by the deflection of the conductive elastic membrane and the gap separating the contacts. The release time can be set to within +/-5 min after one hour in the small intestine (start of the swelling) increasing to +/-40 min after 4 h. PMID- 29993402 TI - Distortion Distribution of Neural Spike Train Sequence Matching With Optogenetics. AB - OBJECTIVE: This paper uses a simple optogenetic model to compare the timing distortion between a randomly-generated target spike sequence and an externally stimulated neuron spike sequence. Optogenetics is an emerging field of neuroscience where neurons are genetically modified to express light-sensitive receptors that enable external control when the neurons fire. METHODS: Two different measures are studied to determine the timing distortion. The first measure is the delay in externally-stimulated spikes. The second measure is the root-mean-square-error between the filtered outputs of the target and stimulated spike sequences. RESULTS: The mean and the distribution of the distortion are derived in closed form when the target sequence generation rate is sufficiently low. The derived results are verified with simulations. CONCLUSION: The proposed model and distortion measures can be used to measure the deviation between neuron spike sequences that are prescribed and what can be achieved via external stimulation. SIGNIFICANCE: Given the prominence of neuronal signaling within the brain and throughout the body, optogenetics has significant potential to improve the understanding of the nervous system and to develop treatments for neurological diseases. This work is a step towards an analytical model to predict whether different spike trains were observed from the same external stimulus, and the broader goal of understanding the quantity and reliability of information that can be carried by neurons. PMID- 29993403 TI - Ex Vivo Modeling of Perioperative Air Leaks in Porcine Lungs. AB - OBJECTIVE: A novel ex vivo model is described to advance the understanding of prolonged air leaks, one of the most common postoperative complications following thoracic resection procedures. METHODS: As an alternative to in vivo testing, an ex vivo model simulating the various physiologic environments experienced by an isolated lung during the perioperative period was designed and built. Isolated porcine lungs were perfused and ventilated during open chest and closed chest simulations, mimicking intra and postoperative ventilation conditions. To assess and validate system capabilities, nine porcine lungs were tested by creating a standardized injury to create an approximately 250 cc/min air leak. Air leak rates, physiologic ventilation, and perfusion parameters were continuously monitored, while gas transfer analysis was performed on selected lungs. Segmental ventilation was monitored using electrical impedance tomography. RESULTS: The evaluated lungs produced flow-volume and pressure-volume loops that approximated standard clinical representations under positive (mechanical) and negative (physiological) pressure ventilation modalities. Leak rate was averaged across the ventilation phases, and sharp increases in leak rate were observed between positive and negative pressure phases, suggesting that differences or changes in ventilation mechanics may strongly influence leak development. CONCLUSION: The successful design and validation of a novel ex vivo lung model was achieved. Model output paralleled clinical observations. Pressure modality may also play a significant role in air leak severity. SIGNIFICANCE: This work provides a foundation for future studies aimed at increasing the understanding of air leaks to better inform means of mitigating the risk of air leaks under clinically relevant conditions. PMID- 29993404 TI - Magnetomotive Displacement of the Tympanic Membrane Using Magnetic Nanoparticles: Toward Enhancement of Sound Perception. AB - OBJECTIVE: A novel hearing-aid scheme using magnetomotive nanoparticles (MNPs) as transducers in the tympanic membrane (TM) is proposed, aiming to noninvasively and directly induce a modulated vibration on the TM. METHODS: In this feasibility study, iron oxide (Fe3O4) nanoparticles were applied on ex vivo rat TM tissues and allowed to diffuse over ~2 h. Subsequently, magnetic force was exerted on the MNP-laden TM via a programmable electromagnetic solenoid to induce the magnetomotion. Optical coherence tomography (OCT), along with its phase-sensitive measurement capabilities, was utilized to visualize and quantify the nanometer scale vibrations generated on the TM tissues. RESULTS: The magnetomotive displacements induced on the TM were significantly greater than the baseline vibration of the TM without MNPs. In addition to a pure frequency tone, a chirped excitation and the corresponding spectroscopic response were also successfully generated and obtained. Finally, visualization of volumetric TM dynamics was achieved. CONCLUSION: This study demonstrates the effectiveness of magnetically inducing vibrations on TMs containing iron oxide nanoparticles, manipulating the amplitude and the frequency of the induced TM motions, and the capability of assessing the magnetomotive dynamics via OCT. SIGNIFICANCE: The results demonstrated here suggest the potential use of this noninvasive magnetomotive approach in future hearing aid applications. OCT can be utilized to investigate the magnetomotive dynamics of the TM, which may either enhance sound perception or magnetically induce the perception of sound without the need for acoustic speech signals. PMID- 29993406 TI - Image-based methods for phase estimation, gating and temporal super-resolution of cardiac ultrasound. AB - OBJECTIVE: Ultrasound is an effective tool for rapid non-invasive assessment of cardiac structure and function. Determining the cardiorespiratory phases of each frame in the ultrasound video and capturing the cardiac function at a much higher temporal resolution is essential in many applications. Fulfilling these requirements is particularly challenging in preclinical studies involving small animals with high cardiorespiratory rates, requiring cumbersome and expensive specialized hardware. METHODS: We present a novel method for the retrospective estimation of cardiorespiratory phases directly from the ultrasound videos. It transforms the videos into a univariate time-series preserving the evidence of periodic cardiorespiratory motion, decouples the signatures of cardiorespiratory motion with a trend extraction technique, and estimates the cardiorespiratory phases using a Hilbert transform approach. We also present a robust nonparametric regression technique for respiratory gating and a novel kernel-regression model for reconstructing images at any cardiac phase facilitating temporal super resolution. RESULTS: We validated our methods using 2D echocardiography videos and electrocardiogram (ECG) recordings of 6 mice. Our cardiac phase estimation method provides accurate phase estimates with a mean-phase-error-range of 3-6% against ECG derived phase and outperforms three previously published methods in locating ECG's R-wave peak frames with a mean-frame-error-range of 0.73-1.36. Our kernel-regression model accurately reconstructs images at any cardiac phase with a mean-normalized-correlation-range of 0.81-0.85 over 50 leave-one-out-cross validation rounds. CONCLUSION AND SIGNIFICANCE: Our methods can enable tracking of cardiorespiratory phases without additional hardware and reconstruction of respiration-free single cardiac-cycle videos at a much higher temporal resolution. PMID- 29993405 TI - Sleep-Dependent Directional Coupling of Cardiorespiratory System in Patients With Obstructive Sleep Apnea. AB - OBJECTIVE: Cardiorespiratory interactions have been widely investigated in different physiological states and conditions. Various types of coupling characteristics have been observed in the cardiorespiratory system; however, it is difficult to identify and quantify details of their interaction. In this study, we investigate directional coupling of the cardiorespiratory system in different physiological states (sleep stages) and conditions, i.e., severity of obstructive sleep apnea (OSA). METHODS: Directionality analysis is performed using the evolution map approach with heartbeats acquired from electrocardiogram and abdominal respiratory effort measured from the polysomnographic data of 39 healthy individuals and 24 mild, 21 moderate, and 23 severe patients with OSA. The mean phase coherence is used to confirm the weak and strong coupling of cardiorespiratory system. RESULTS: We find that unidirectional coupling from the respiratory to the cardiac system increases during wakefulness (average value of 0.61) and rapid eye movement sleep (-0.55). Furthermore, unidirectional coupling between the two systems significantly decreases during light (-0.52) and deep sleep, which is further decreased in deep sleep (-0.46), approaching bidirectional coupling. In addition, unidirectional coupling from the respiratory to the cardiac system also significantly increases according to the severity of OSA. CONCLUSION: These coupling characteristics in different states and conditions are believed to be linked with autonomic nervous modulation. SIGNIFICANCE: Our approach could provide an opportunity to understand how integrated systems cooperate for physiological functions under internal and external environmental changes, and how abnormality in one physiological system could develop to increase the risk of other systemic dysfunctions and/or disorders. PMID- 29993407 TI - A Multistage Algorithm for ECG Rhythm Analysis during Piston Driven Mechanical Chest Compressions. AB - OBJECTIVE: An accurate rhythm analysis during cardiopulmonary resuscitation (CPR) would contribute to increase survival from out-of-hospital cardiac arrest. Piston driven mechanical compression devices are frequently used to deliver CPR. The objective of this work was to design a method to accurately diagnose the rhythm during compressions delivered by a piston-driven device. METHODS: Data was gathered from 230 out-of-hospital cardiac arrest patients treated with the LUCAS 2 mechanical CPR device. The dataset comprised 201 shockable and 844 nonshockable ECG segments, whereof 270 were asystole (AS) and 574 organized rhythm (OR). A multistage algorithm (MSA) was designed, which included two artifact filters based on a recursive least squares algorithm, a rhythm analysis algorithm from a commercial defibrillator, and an ECG-slope based rhythm classifier. Data was partitioned randomly and patient-wise into training (60%) and test (40%) for optimization and validation, and statistically meaningful results were obtained repeating the process 500 times. RESULTS: The mean (standard deviation) sensitivity (SE) for shockable rhythms, specificity (SP) for nonshockable rhythms, and total accuracy of the MSA solution were: 91.7 (6.0), 98.1 (1.1) and 96.9 (0.9), respectively. The SP for AS and OR were 98.0 (1.7) and 98.1 (1.4), respectively. CONCLUSIONS: The SE/SP were above the 90/95% values recommended by the American Heart Association for shockable and nonshockable rhythms other than sinus rhythm, respectively. PMID- 29993408 TI - Movement Symmetry Assessment by Bilateral Motion Data Fusion. AB - OBJECTIVE: A new approach, named bilateral motion data fusion, was proposed for the analysis of movement symmetry, which takes advantage of cross-information between both sides of the body and processes the unilateral motion data at the same time. METHODS: This was accomplished using canonical correlation analysis and joint independent component analysis. It should be noted that human movements include many categories, that cannot be enumerated one by one. Therefore, the gait rhythm fluctuations of the healthy subjects and patients with neurodegenerative diseases were employed as an example for method illustration. In addition, our model explains the movement data by latent parameters in the time and frequency domains, respectively, which were both based on bilateral motion data fusion. RESULTS: They show that our method not only reflects the physiological correlates of movement but also obtains the differential signatures of movement asymmetry in diverse neurodegenerative diseases. Furthermore, the latent variables also exhibit the potentials for sharper disease distinctions. CONCLUSION: We have provided a new perspective on movement analysis, which may prove to be a promising approach. SIGNIFICANCE: This method exhibits the potentials for effective movement feature extractions, which might contribute to many research fields such as rehabilitation, neuroscience, biomechanics, kinesiology and so on. PMID- 29993409 TI - Transfer Learning from Simulations on a Reference Anatomy for ECGI in Personalised Cardiac Resynchronization Therapy. AB - GOAL: Non-invasive cardiac electrophysiology (EP) model personalisation has raised interest for instance in the scope of predicting EP cardiac resynchronization therapy (CRT) response. However, the restricted clinical applicability of current methods is due in particular to the limitation to simple situations and the important computational cost. METHODS: We propose in this manuscript an approach to tackle these two issues. First, we analyse more complex propagation patterns (multiple onsets and scar tissue) using relevance vector regression and shape dimensionality reduction on a large simulated database. Second, this learning is performed offline on a reference anatomy and transferred onto patient-specific anatomies in order to achieve fast personalised predictions online. RESULTS: We evaluated our method on a dataset composed of 20 dyssynchrony patients with a total of 120 different cardiac cycles. The comparison with a commercially available electrocardiographic imaging (ECGI) method shows a good identification of the cardiac activation pattern. From the cardiac parameters estimated in sinus rhythm, we predicted 5 different paced patterns for each patient. The comparison with the body surface potential mappings (BSPM) measured during pacing} and the ECGI method indicates a good predictive power. CONCLUSION: We showed that learning offline from a large simulated database on a reference anatomy was able to capture the main cardiac EP characteristics from non-invasive measurements for fast patient-specific predictions. SIGNIFICANCE: The fast CRT pacing predictions are a step forward to a non-invasive CRT patient selection and therapy optimisation, to help clinicians in these difficult tasks. PMID- 29993410 TI - Myoelectric Pattern Recognition for Controlling a Robotic Hand: A Feasibility Study in Stroke. AB - OBJECTIVE: Myoelectric pattern recognition has been successfully applied as a human-machine interface to control robotic devices such as prostheses and exoskeletons, significantly improving the dexterity of myoelectric control. This study investigates the feasibility of applying myoelectric pattern recognition for controlling a robotic hand in stroke patients. METHODS: Myoelectric pattern recognition of six hand motion patterns was performed using forearm electromyogram (EMG) signals in paretic side of 8 stroke subjects. Both the random cross validation (RCV) and the chronological handout validation (CHV) were applied to assess the offline myoelectric pattern recognition performance. Experiments on real-time myoelectric pattern recognition control of an exoskeleton robotic hand were also performed. RESULTS: An average classification accuracy of 84.1% (the mean value from two different classifiers) and individual subject differences were observed in the offline myoelectric pattern recognition analysis using the RCV, while the accuracy decreased to 65.7% when the CHV was used. The stroke subjects achieved an average accuracy of 61.3-20.9% for controlling the robotic hand. However, our study did not reveal a clear correlation between the real-time control accuracy and the offline myoelectric pattern recognition performance, or any specific characteristics of the stroke subjects. CONCLUSION: The findings suggest that it is feasible to apply myoelectric pattern recognition to control the robotic hand in some but not all of the stroke patients. Each stroke subject should be individually online tested for the feasibility of applying myoelectric pattern recognition control for robot assisted rehabilitation. PMID- 29993411 TI - Cardiac Propagation Pattern Mapping with Vector Field for Helping Tachyarrhythmias Diagnosis with Clinical Tridimensional Electro-Anatomical Mapping Tools. AB - Ventricular (VT) and atrial (AT) tachycardias are some of the most common clinical cardiac arrhythmias. For ablation of tachycardia substrates, two clinical diagnosis methods are used: invasive electro-anatomical mapping for an accurate diagnosis using electrograms (EGMs) acquired with intra-cardiac catheters, and localized on the surface mesh of the studied cavities; and non invasive electrocardiographic imaging (ECGi) for a global view of the arrhythmia, with EGMs mathematically reconstructed from body surface electrocardiograms using 3-D cardio-thoracic surface meshes obtained from CT-scans. In clinics, VT and AT are diagnosed by studying activation time maps that depict the propagation of the activation wavefront on the cardiac mesh. Nevertheless, slow conduction areas - a well-known pro-arrhythmic feature for tachycardias - and tachycardia specific propagation patterns are not easily identifiable with these maps. Therefore, local characterization of the activation wavefront propagation can be helpful for improving VT and AT diagnoses. The purpose of this study is to develop a method to locally characterize the activation wavefront propagation for clinical data. For this, a conduction velocity (CV) vector field is estimated and analyzed using divergence and curl mathematical operators. The workflow was first validated on a simulated database from computer models, and then applied to a clinical database obtained from ECGi to improve AT diagnosis. The results show the relevancy and the efficacy of the proposed method to guide ablation of tachyarrhythmias. PMID- 29993412 TI - Representing Medical Images With Encoded Local Projections. AB - This paper introduces the "encoded local projections" (ELP) as a new dense sampling image descriptor for search and classification problems. The gradient changes of multiple projections in local windows of gray-level images are encoded to build a histogram that captures spatial projection patterns. Using projections is a conventional technique in both medical imaging and computer vision. Furthermore, powerful dense-sampling methods, such as local binary patterns and the histogram of oriented gradients, are widely used for image classification and recognition. Inspired by many achievements of such existing descriptors, we explore the design of a new class of histogram-based descriptors with particular applications in medical imaging. We experiment with three public datasets (IRMA, Kimia Path24, and CT Emphysema) to comparatively evaluate the performance of ELP histograms. In light of the tremendous success of deep architectures, we also compare the results with deep features generated by pretrained networks. The results are quite encouraging as the ELP descriptor can surpass both conventional and deep descriptors in performance in several experimental settings. PMID- 29993413 TI - An EOG-based Human Machine Interface to Control a Smart Home Environment for Patients with Severe Spinal Cord Injuries. AB - OBJECTIVE: This paper presents an asynchronous EOG-based human machine interface (HMI) for smart home environmental control with the purpose of providing daily assistance for severe spinal cord injury (SCI) patients. METHODS: The proposed HMI allows users to interact with a smart home environment through eye blinking. Specifically, several buttons, each corresponding to a control command, randomly flash on a graphical user interface. Each flash of the buttons functions as a visual cue for the user to blink. To issue a control command, the user can blink synchronously with the flashes of the corresponding button. Through detecting blinks based on the recorded EOG signal, the target button and its corresponding control command are determined. Seven SCI patients participated in an online experiment, during which the patients were required to control a smart home environment including household electrical appliances, an intelligent wheelchair as well as a nursing bed via the proposed HMI. RESULTS: The average false operation ratio in the control state was 4.1%, whereas during the idle state, no false operations occurred. CONCLUSION: All SCI patients were able to control the smart home environment using the proposed EOG-based HMI with satisfactory performance in terms of the false operation ratio in both the control and the idle states. SIGNIFICANCE: The proposed HMI offers a simple and effective approach for patients with severe SCIs to control a smart home environment. Therefore, it is promising to assist severe SCI patients in their daily lives. PMID- 29993414 TI - The Ability to Reproducibly Record Cardiac Action Potentials from Multiple Anatomic Locations: Endocardially and Epicardially, In Situ and In Vitro. AB - OBJECTIVE: For cardiac arrhythmia mapping and ablation procedures, the ability to record focal cardiac action potentials could aid in precisely identifying lesions, scarred tissue, and/or arrhythmic foci. Our study objective was to validate the electrophysiologic properties of a routinely employed large mammalian in vitro working heart model. METHODS: Monophasic action potentials (MAPs) were recorded from 18 swine hearts during viable hemodynamic function both in situ (post-median sternotomy) and in vitro (using Visible Heart' methodologies). We placed specially designed mapping catheters in epicardial and endocardial locations. High-quality MAP signals were recorded for up to 2 hours, and MATLAB was utilized to evaluate relative duration and temporal/regional changes in waveform morphology. RESULTS: MAPs were reproducibly recorded from both epicardial and endocardial locations in situ and in vitro. No significant differences were noted in right atrial endocardial, right ventricular endocardial, right ventricular epicardial, or left atrial epicardial waveforms, when baseline recordings were compared to all other in situ and in vitro time points. Further, MAP duration between right ventricular endocardial and epicardial waveforms was not significantly different, in situ or in vitro. CONCLUSION: The use of in vitro models like the Visible Heart' is considered invaluable for the study of cardiac arrhythmias, the development of novel therapies, and/or preclinical testing of future cardiac mapping catheters and systems. SIGNIFICANCE: Preclinical studies assessing in situ and/or in vitro recorded cardiac monophasic action potentials could be critical for the future development and validation of cardiac devices. PMID- 29993415 TI - Dry-Contact Electrode Ear-EEG. AB - OBJECTIVE: Ear-EEG is a recording method where EEG signals are acquired from electrodes placed on an earpiece inserted into the ear. Thereby, ear-EEG provides a non-invasive and discreet way of recording EEG, and has the potential to be used for long-term brain monitoring in real-life environments. Whereas previously reported ear-EEG recordings have been performed with wet electrodes, the objective of this study was to develop and evaluate dry-contact electrode ear EEG. METHODS: To achieve a well-functioning dry-contact interface, a new ear-EEG platform was developed. The platform comprised actively shielded and nano structured electrodes embedded in an individualized soft-earpiece. The platform was evaluated in a study of 12 subjects and four EEG paradigms: auditory steady state response, steady-state visual evoked potential, mismatch negativity, and alpha band modulation. RESULTS: Recordings from the prototyped dry-contact ear EEG platform was compared to conventional scalp EEG recordings. When all electrodes were referenced to a common scalp electrode (Cz), the performance was on par with scalp EEG measured close to the ear. With both the measuring electrode and the reference electrode located within the ear, statistically significant (p<0.05) responses were measured for all paradigms, although for mismatch negativity it was necessary to use a reference located in the opposite ear, to obtain a statistically significant response. CONCLUSION: The study demonstrated that dry-contact electrode ear-EEG is a feasible technology for EEG recording. SIGNIFICANCE: The prototyped dry-contact ear-EEG platform represents an important technological advancement of the method in terms of user friendliness because it eliminates the need for gel in the electrode-skin interface. PMID- 29993416 TI - Cell patterning method on a clinically ubiquitous culture dish using acoustic pressure generated from resonance vibration of a disk-shaped ultrasonic transducer. AB - Cell patterning methods have been previously reported for cell culture. However, these methods use inclusions or devices that are not used in general cell culture and that might affect cell functionality. Here we report a cell patterning method that can be conducted on a general cell culture dish without any inclusions by employing a resonance vibration of a disk-shaped ultrasonic transducer located under the dish. A resonance vibration with a single nodal circle patterned C2C12 myoblasts into a circular shape on the dish with 10-min exposure of the vibration with maximum peak-peak amplitude of 10 MUm. Furthermore, the relationship between the amplitude distribution of the transducer and the cell density in the patterned sample could be expressed as a linear function, and there was a clear threshold of amplitude for cell adhesion. To evaluate the cell function of the patterned cells, we conducted proliferation and protein assays at 120-h culture after patterning. Our results showed that the cell proliferation rate did not decrease and the expression of cellular proteins was unchanged. Thus we conclude this method can successfully pattern cells in the clinically ubiquitous culture dish while maintaining cell functionality. PMID- 29993417 TI - A Novel Method for Low-Volume Measurement of Lithium in Human Blood to use in Personalized Monitoring of Lithium Treatment. AB - GOAL: Lithium preparations are considered the most reliable mood stabilizers for patients with Bipolar Disorder (BD), and are the most effective at reducing the risk of suicide. However, maintaining blood lithium concentration within the narrow therapeutic range of 0.4-1.2 mEq is crucial but extremely difficult. The aim of this work is to develop a personal lithium blood level analyzer using a novel method of combined optical and electrical impedance spectroscopy to test micro volumes of spiked samples of human blood. RESULTS: Impedance measurements alone showed a limit of detection of less than 0.1 mEq within the therapeutic range, whereas optical measurements could verify the presence of lithium and provide a degree of lithium content. Optical specificity to lithium was further verified in qualitative assessment of lithium spiked blood samples with varying concentrations of sodium. Moreover, analysis of multiple linear regression yielded a prediction model of R2 = 0.322716 and RMSEP =0.223602 for optical measurements only using feature wavelengths, which were found to appear at minima 560 and 605 nm. Combined with impedance measurements, prediction of lithium concentration in samples with unknown lithium content was significantly increased to R2 = 0.876438, and RMSEP = 0.513554. CONCLUSION: The combination of optical and impedance modalities for determinations of blood lithium resulted in significant improvement to the sensitivity and accuracy of measurement. SIGNIFICANCE: Results are complementary of the proposed opto-impedance method, and future work will now focus on the technical development of an integrated and miniaturized system for measurement of lithium levels in blood with a high level of accuracy and sensitivity. PMID- 29993418 TI - The Performance of Higher-Frequency Microwave Ablation in the Presence of Perfusion. AB - OBJECTIVE: In this paper, we investigate the impact of perfusion on the performance of microwave ablation across a large frequency range. METHODS: We designed multiple microwave ablation antennas to operate in liver tissue at discrete frequencies in the range 1.9-18 GHz. We performed electromagnetic simulations to calculate microwave power absorption patterns. Five-minute, 25 W ablation experiments were performed at each frequency in perfused and non perfused ex vivo porcine livers, and thermal lesion dimensions were measured. RESULTS: The volume of greatest microwave power absorption shrinks by two orders of magnitude as frequency is increased from 1.9 to 18 GHz. Mean thermal lesion volumes are consistent across the frequency range for a given perfusion state, and are about three times smaller under active perfusion. Typical thermal lesion diameters (perpendicular to the antenna axis) were 24 mm and 16 mm for non perfused and perfused ablations, respectively. No significant differences in axial ratio were observed among different frequency groups in active-perfusion experiments. CONCLUSION: Higher-frequency microwave ablation produces thermal lesions with volumes comparable to those achieved at lower frequencies, even in strongly perfused environments. SIGNIFICANCE: Higher-frequency microwave ablation is appealing because it allows for more flexibility in antenna design. A critical issue concerning the feasibility of higher-frequency microwave ablation, considering its strong dependence on heat diffusion to grow thermal lesions, is its performance in strongly perfused environments. This work shows that higher frequency microwave ablation achieves thermal lesions comparable to those from microwave ablation performed at conventional frequencies in both non- and strongly perfused environments. PMID- 29993419 TI - Multivariate Regression with Gross Errors on Manifold-valued Data. AB - We consider the topic of multivariate regression on manifold-valued output, that is, for a multivariate observation, its output response lies on a manifold. Moreover, we propose a new regression model to deal with the presence of grossly corrupted manifold-valued responses, a bottleneck issue commonly encountered in practical scenarios. Our model first takes a correction step on the grossly corrupted responses via geodesic curves on the manifold, then performs multivariate linear regression on the corrected data. This results in a nonconvex and nonsmooth optimization problem on Riemannian manifolds. To this end, we propose a dedicated approach named PALMR, by utilizing and extending the proximal alternating linearized minimization techniques for optimization problems on Euclidean spaces. Theoretically, we investigate its convergence property, where it is shown to converge to a critical point under mild conditions. Empirically, we test our model on both synthetic and real diffusion tensor imaging data, and show that our model outperforms other multivariate regression models when manifold-valued responses contain gross errors, and is effective in identifying gross errors. PMID- 29993420 TI - Unsupervised Deep Hashing with Similarity-Adaptive and Discrete Optimization. AB - Recent vision and learning studies show that learning compact hash codes can facilitate massive data processing with significantly reduced storage and computation. Particularly, learning deep hash functions has greatly improved the retrieval performance, typically under the semantic supervision. In contrast, current unsupervised deep hashing algorithms can hardly achieve satisfactory performance due to either the relaxed optimization or absence of similarity sensitive objective. In this work, we propose a simple yet effective unsupervised hashing framework, named Similarity-Adaptive Deep Hashing (SADH), which alternatingly proceeds over three training modules: deep hash model training, similarity graph updating and binary code optimization. The key difference from the widely-used two-step hashing method is that the output representations of the learned deep model help update the similarity graph matrix, which is then used to improve the subsequent code optimization. In addition, for producing high-quality binary codes, we devise an effective discrete optimization algorithm which can directly handle the binary constraints with a general hashing loss. Extensive experiments validate the efficacy of SADH, which consistently outperforms the state-of-the-arts by large gaps. PMID- 29993421 TI - Wavelet p-Leader Non Gaussian Multiscale Expansions for Heart Rate Variability Analysis in Congestive Heart Failure Patients. AB - OBJECTIVE: Numerous indices were devised for the statistical characterization of temporal dynamics of heart rate variability (HRV) with aim to discriminate between healthy subjects and non healthy patients. Elaborating on the concepts of (multi)fractal and non linear analyses, the present contribution defines and studies formally novel non Gaussian multiscale representations. METHODS: A methodological framework for non Gaussian multiscale representations constructed on wavelet p-leaders is developed, relying a priori neither on exact scale-free dynamics nor on pre-defined forms of departure from Gaussianity. Its versatility in quantifying the strength and nature of departure from Gaussian is analyzed theoretically and numerically. The ability of the representations to discriminate between healthy subjects and congestive heart failure (CHF) patients, and between survivors and non survivor CHF patients, is assessed on a large cohort of 198 subjects. RESULTS: The analysis leads to conclude that i) scale-free and multifractal dynamics are observed, both for healthy subjects and CHF patients, for time scales shorter than 170s; ii) a circadian evolution of multifractal and non Gaussian properties of HRV is evidenced for healthy subjects, but not for CHF patients; iii) non Gaussian multiscale indices possess high discriminative abilities between survivor and non survivor CHF patients, at specific time scales (~20s and ~85s). CONCLUSIONS: The non Gaussian multiscale representations provide evidence for the existence of short-term cascade-type multifractal mechanisms underlying HRV for both healthy and CHF subjects. A circadian evolution of this mechanism is only evidenced for the healthy group, suggesting an alteration of the sympathetic-parasympathetic balance for CHF patients. SIGNIFICANCE: Results obtained for a large cohort of subjects suggest that the novel non Gaussian indices might robustly quantify crucial information for clinical risk stratification in CHF patients. PMID- 29993422 TI - Multi-Snapshot Imaging for Chromatographic Peak Analysis. AB - OBJECTIVE: Snapshot imaging has several advantages in automated gel electrophoresis compared with the finish-line method in capillary electrophoresis; this comes at the expense of resolution. A novel signal processing algorithm is proposed enabling a multi-snapshot imaging (MSI) modality whose objective is to substantially improve resolution. MSI takes multiple captures in time as macromolecules are electrophoresed. Peaks from latter snapshots have high resolution but low signal-to-noise ratio (SNR), while earlier snapshots have low resolution but high SNR. METHODS: Signals at different capture times are related by a scale-in-separation, shift-in-separation, and amplitude gain. The proposed method realigns the multiple captures using least-squares and fuses them. The algorithm accounts for the partial waveforms observed as the chromatic peaks exit the sensor's field-of-view. RESULTS: MSI improves resolution by approximately 10% on average per minute of additional electrophoresis. CONCLUSIONS: Comprehensive analysis of the resolution are quantified on several datasets demonstrate the effectiveness of MSI. SIGNIFICANCE: MSI can double the resolution compared with traditional snapshot imaging over a typical set of captures. PMID- 29993423 TI - EEG Spectral Coherence Analysis in Nocturnal Epilepsy. AB - OBJECTIVE: Electroencephalography (EEG) is widely employed in the study of sleep disorders. This paper exploits the identification of cyclic alternating patterns (CAPs), a periodic ubiquitous phenomenon nested in the sleep stages, to analyze the EEG spectral coherence in subjects affected by nocturnal frontal lobe epilepsy (NFLE) and healthy controls. METHODS: For each EEG recording, we extracted several CAP A1 subtype 4 s time series. We analyze the coherence between each pair of electrodes for each individual to obtain its distribution for each frequency range of interest to investigate differences between cases and controls. In addition, the imaginary and real parts of the spectral coherence were calculated and plotted to assess their likelihood of segregation into different classes and anatomical regions. RESULTS: The results of this study suggest a relevant frontal-temporal neural circuitry difference between individuals affected by epilepsy and controls. CONCLUSION: This supports the observation that, though highly variable, a broad range of executive, cognitive and attentional deficit observed in subjects affected by NFLE might depend on frontal-temporal altered networking. SIGNIFICANCE: The investigation of EEG activity in the domain of the complex sleep architecture represents a challenging topic in neurophysiology and needs new methods to explore the manifold aspects of sleep. This work aims to provide a simple method to distinguish NFLE from healthy subjects from a functional connectivity point of view and to explore the possibility of using a smaller EEG channel set to support diagnosis. PMID- 29993424 TI - Cardiac Motion Evolution Model for Analysis of Functional Changes Using Tensor Decomposition and Cross-Sectional Data. AB - Cardiac disease can reduce the ability of the ventricles to function well enough to sustain long-term pumping efficiency. Recent advances in cardiac motion tracking have led to improvements in the analysis of cardiac function. We propose a method to study cohort effects related to age with respect to cardiac function. The proposed approach makes use of a recent method for describing cardiac motion of a given subject using a polyaffine model, which gives a compact parameterization that reliably and accurately describes the cardiac motion across populations. Using this method, a data tensor of motion parameters is extracted for a given population. The partial least squares method for higher order arrays is used to build a model to describe the motion parameters with respect to age, from which a model of motion given age is derived. Based on the cross-sectional statistical analysis with the data tensor of each subject treated as an observation along time, the left ventricular motion over time of Tetralogy of Fallot patients is analysed to understand the temporal evolution of functional abnormalities in this population compared to healthy motion dynamics. PMID- 29993426 TI - Brain-wide Genome-wide Association Study for Alzheimer's Disease via Joint Projection Learning and Sparse Regression Model. AB - In this paper, a Brain-Wide and Genome-Wide Association (BW-GWA) study is presented to identify the associations between the brain imaging phenotypes (i.e., regional volumetric measures) and the genetic variants (i.e., Single Nucleotide Polymorphism (SNP)) in Alzheimer's Disease (AD). The main challenges of this study include the data heterogeneity, complex phenotype-genotype associations, high-dimensional data (e.g., thousands of SNPs), and the existence of phenotype outliers. Previous BW-GWA studies, while addressing some of these challenges, did not consider the diagnostic label information in their formulations, thus limiting their clinical applicability. To address these issues, we present a novel joint projection and sparse regression model to discover the associations between the phenotypes and genotypes. Specifically, to alleviate the negative influence of data heterogeneity, we first map the genotypes to an intermediate imaging-phenotype-like space. Then, to better reveal the complex phenotype-genotype associations, we project both the mapped genotypes and the original imaging phenotypes to a diagnostic-label-guided joint feature space, where the intra-class projected points are constrained to be close to each other. In addition, we use L2,1-norm minimization on both the regression loss function and the transformation coefficient matrices, to reduce the effect of phenotype outliers, and to encourage sparse feature selections of both the genotypes and phenotypes. We evaluate our method using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and the results show that the proposed method outperforms several state-of-the-art methods in term of average Root-Mean Square Error (RMSE) of genome-to-phenotype predictions. Besides, the associated SNPs and brain regions found in this study have also been shown AD-related in previously studies, thus verifying the effectiveness and potential of the proposed method in AD pathogenesis study. PMID- 29993425 TI - Three-Dimensional Model of Electroretinogram Field Potentials in the Rat Eye. AB - OBJECTIVE: The information derived from the electroretinogram (ERG), especially with regard to local areas of retinal dysfunction or therapeutic rescue, can be enhanced by an increased understanding of the relationship between local retinal current sources and local ERG potentials measured at the cornea. A critical step in this direction is the development of a robust bioelectric field model of the ERG. METHODS: A finite-element model was created to simulate ERG potentials at the cornea resulting from physiologically relevant transretinal currents. A magnetic resonance image of a rat eye was segmented to define all major ocular structures, tissues were assigned conductivity values from the literature. The model was optimized to multi-electrode ERG (meERG) data recorded in healthy rat eyes, and validated with meERG data from eyes with experimental lesions in peripheral retina. RESULTS: Following optimization, the simulated distribution of corneal potentials was in good agreement with measured values; residual error was comparable to the average difference of individual eyes from the measured mean. The model predicted the corneal potential distribution for eight eyes with experimental lesions with similar accuracy, and a measure of pre- to post-lesion changes in corneal potential distribution was well correlated with the location of the lesion. CONCLUSION: An eye model with high anatomical accuracy was successfully validated against a robust dataset. SIGNIFICANCE: This model can now be used for optimization of ERG electrode design, and to support functional mapping of the retina from meERG data via solving the inverse bioelectric source problem. PMID- 29993427 TI - A Coupled Magnetoelastic Strain Sensor Array for Guiding and Monitoring Hernia Repairs. AB - OBJECTIVE: Ventral hernia repairs using mesh prosthetics suffer from high recurrence rates, with 10-20% of repairs failing within three years. Uneven distribution of stress within the implanted mesh prosthetic is thought to contribute to the high recurrence rate. We propose a method for providing quantitative guidance and monitoring of hernia repairs using an array of magnetoelastic strain sensors. METHODS: The magnetoelastic strain sensors presented here are based on a coupled design to achieve measurements with higher signal-to-noise ratio (SNR). A first magnetoelastic element (the transducer) is bonded to the mesh prosthetic and is characterized by a strain-dependent magnetic field. The resonance frequency of a second magnetoelastic element (the resonator) encased in a rigid casing is biased by the transducer element's magneticity and can be measured non-invasively using an external interrogation coil. The coupled magnetoelastic strain sensors are assembled using a combination of photochemical machining, patterning, and heat sealing. RESULTS: The dynamic range of the coupled sensors can be tuned by altering the transducer geometry. Additional spring elements are integrated onto the transducer element to achieve high dynamic range measurements saturating at 74 millistrains. CONCLUSION: A coupled magnetoelastic strain sensor combines a transducer with an encased resonator element to measure strain with high SNR on an implantable flexible hernia mesh substrate. SIGNIFICANCE: This work provides surgeons and researchers with a clinically relevant tool to quantify the strain distributions within implanted mesh prosthetics, with the ultimate goal of reducing the recurrence rate of ventral hernia repairs. PMID- 29993428 TI - Biomarkers for Alzheimer's Disease Defined by a Novel Brain Functional Network Measure. AB - OBJECTIVE: This paper aims to explore affordable biomarkers of Alzheimer's disease (AD) based on noninvasive, low-cost and portability electroencephalography (EEG) signals. METHODS: By combining multiscale analysis and embedding space theory, a novel strategy was developed for constructing brain functional network inferred from generalized composite multiscale entropy vector (GCMSEV). Functional network analysis and seed analysis were used for comparing AD pattern vs. control pattern. Machine learning methods were employed for proving the effectiveness of our method. RESULTS: AD patients exhibited hypo connectivity over the whole scalp, especially for long-range connections. Significant decreased connections between frontal and other regions reveals that the transmission of signals related to frontal hub is indeed damage due to AD. The predictors consist of inter-frontal and left frontal-right occipital connections led to a good performance for distinguishing AD patients and normal subjects with over 96% classification accuracy and 0.98 parametric AUC. CONCLUSION: Above findings demonstrated the superior power of the EEG markers quantified by our GCMSEV-network, as the indicator of abnormal functional connectivity in the brain of AD patients. SIGNIFICANCE: This work develops a novel EEG-based strategy for functional connectivity quantification and enriches the topographical biomarkers used for neurophysiological assessment. PMID- 29993429 TI - Heartbeats Based Biometric Random Binary Sequences Generation to Secure Wireless Body Sensor Networks. AB - Heartbeats based random binary sequences (RBSs) are the backbone for several security aspects in wireless body sensor networks (WBSNs). However, current heartbeats based methods require a lot of processing time (~25-30 s) to generate 128-bit RBSs in real-time healthcare applications. In order to improve time efficiency, a biometric RBSs generation technique using interpulse intervals (IPIs) of heartbeats is developed in this study. The proposed technique incorporates a finite monotonic increasing sequences generation mechanism of IPIs and a cyclic block encoding procedure that extracts a high number of entropic bits from each IPI. To validate the proposed technique, 89 ECG recordings including 25 healthy individuals in a laboratory environment, 20 from MIT-BIH Arrhythmia Database, and 44 cardiac patients from the clinical environment are considered. By applying the proposed technique on the ECG signals, at most 16 random bits can be extracted from each heartbeat to generate 128-bit RBSs via concatenation of eight consecutive IPIs. And the randomness and distinctiveness of generated 128-bit RBSs are measured based on the National Institute of Standards and Technology statistical tests and hamming distance, respectively. From the experimental results, the generated 128-bit RBSs from both healthy subjects and patients can potentially be used as keys for encryption or entity identifiers to secure WBSNs. Moreover, the proposed approach is examined to be up to four times faster than the existing heartbeat-based RBSs generation schemes. Therefore, the developed technique necessitates less processing time (0-8 s) in real-time health monitoring scenarios to construct 128-bit RBSs in comparisons with current methods. PMID- 29993430 TI - An Optimization-Based Algorithm for the Construction of Cardiac Purkinje Network Models. AB - OBJECTIVE: This work presents a new algorithm for the construction of a model for the Purkinje network (PN) of the heart. METHODS: The algorithm is based on a method called constructive constrained optimization (CCO), which was reformulated for the specific case of automatic PN generation. The proposed optimization-based algorithm is referred to as constructive optimization (CO). The CO method iteratively constructs the PN by minimizing the total length of the generated PN tree. In addition, it can take into account some important topological information of the PN, such as the location of the Purkinje-muscle junctions and the average bifurcation angle found in the literature. RESULTS: To validate the model, the new method was compared with the classical L-system method for generating PN models and to a recently proposed image-based technique. CONCLUSION: The results show that the CO is able to construct PNs with geometric features and activation times that are in good agreement with those reported in the literature and to those obtained by the other aforementioned alternatives. PMID- 29993431 TI - Registration Accuracy of Patient-Specific, 3D Printed Prostate Molds for Correlating Pathology with Magnetic Resonance Imaging. AB - OBJECTIVE: This investigation was performed to evaluate the registration accuracy between magnetic resonance imaging (MRI) and pathology using three-dimensional (3D) printed molds. METHODS: Tissue-mimicking prostate phantoms were manufactured with embedded fiducials. The fiducials were used to measure and compare target registration error (TRE) between phantoms that were sliced by hand versus phantoms sliced within 3D-printed molds. Subsequently, 10 radical prostatectomy specimens were placed inside molds, scanned with MRI, and then sliced. The ex vivo scan was used to assess the true location of whole mount (WM) slides relative to in vivo MRI. The TRE between WM and in vivo MRI was measured using anatomic landmarks. RESULTS: Manually sliced phantoms had a 4.1 mm mean TRE, whereas mold-sliced phantoms had a 1.9 mm mean TRE. Similarly, mold-assisted slicing reduced mean angular misalignment around the left-right (LR) anatomic axis from 10.7 to 4.5 degrees. However, ex vivo MRI revealed that excised prostates were misaligned within molds, including a mean 14-degree rotation about the LR axis. The mean in-plane TRE was 3.3 mm using molds alone, and 2.2 mm after registration was corrected with ex vivo MRI. CONCLUSION: Patient-specific molds improved accuracy relative to manual slicing techniques in a phantom model. However, the registration accuracy of surgically resected specimens was limited by their imperfect fit within molds. This limitation can be overcome with the addition of ex vivo imaging. SIGNIFICANCE: The accuracy of 3D printed molds was characterized, quantifying their utility for facilitating MRI-pathology registration. PMID- 29993432 TI - Ultra-Wideband, Stable Normal and Cancer Skin Tissue Phantoms for Millimeter-Wave Skin Cancer Imaging. AB - This work introduces new, stable, and broadband skin-equivalent semisolid phantoms for mimicking interactions of millimeter waves with the human skin and skin tumors. Realistic skin phantoms serve as an invaluable tool for exploring the feasibility of new technologies and improving design concepts related to millimeter-wave skin cancer detection methods. Normal and malignant skin tissues are separately mimicked by using appropriate mixtures of deionized water, oil, gelatin powder, formaldehyde, TX-150 (a gelling agent, widely referred to as "super stuff"), and detergent. The dielectric properties of the phantoms are characterized over the frequency band of 0.5-50 GHz using a precision slim-form open-ended coaxial probe in conjunction with a millimeter-wave vector network analyzer. The measured permittivity results show excellent match with ex-vivo, fresh skin (both normal and malignant) permittivities determined in our prior work over the entire frequency range. This work results in the closest match among all phantoms reported in the literature to surrogate human skin tissues. The stability of dielectric properties over time is also investigated. The phantoms demonstrate long-term stability (up to 7 months was investigated). In addition, the penetration depth of millimeter waves into normal and malignant skin phantoms is calculated. It is determined that millimeter waves penetrate the human skin deep enough (0.6 mm on average at 50 GHz) to affect the majority of the epidermis and dermis skin structures. PMID- 29993433 TI - Removal of High-Voltage Brain Stimulation Artifacts from Simultaneous EEG Recordings. AB - OBJECTIVE: Noninvasive electrical brain stimulation (NEBS) can modulate brain dynamics and be used to induce changes in target brain areas. Because high voltage stimulation artifacts tend to completely dominate the simultaneously recorded EEG and vary slightly trial-by-trial in both amplitude and phase, the majority of studies to date have simply compared post-stimulation and pre stimulation periods. Here, we propose the use of a modified joint blind source separation (JBSS) approach for removing stimulation artifacts when the same stimulus is applied in multiple epochs. METHODS: Quadrature regression and subsequent independent vector analysis (q-IVA) was applied to simulated and real EEG data sets recorded from 10 subjects who received theta-band galvanic vestibular stimulation (GVS). RESULTS: In simulations, q-IVA and JBSS approaches significantly improved the relative root-mean-squared error, correlation coefficient, and power deviation between the original and recovered EEG compared to conventional methods. In the real EEG data, after removing the artifacts with q-IVA, the power spectra during stimulation demonstrated significantly enhanced beta and gamma power compared to pre-stimulation, becoming similar to that seen in immediate post-stimulation periods. In addition, we demonstrate that increased alpha power (8-13 Hz) in occipital regions with eye closure could be reliably detected in the cleaned EEG data after applying q-IVA. CONCLUSION: q-IVA and JBSS approaches outperform conventional artifact removal methods in both time and frequency domains. SIGNIFICANCE: Our results provide a promising way to effectively isolate stimulation artifacts in EEG, paving the way for future studies attempting to uncover ongoing modulation of brain activity during NEBS. PMID- 29993434 TI - Detecting Regions of Maximal Divergence for Spatio-Temporal Anomaly Detection. AB - Automatic detection of anomalies in space- and time-varying measurements is an important tool in several fields, e.g., fraud detection, climate analysis, or healthcare monitoring. We present an algorithm for detecting anomalous regions in multivariate spatio-temporal time-series, which allows for spotting the interesting parts in large amounts of data, including video and text data. In opposition to existing techniques for detecting isolated anomalous data points, we propose the "Maximally Divergent Intervals" (MDI) framework for unsupervised detection of coherent spatial regions and time intervals characterized by a high Kullback-Leibler divergence compared with all other data given. In this regard, we define an unbiased Kullback-Leibler divergence that allows for ranking regions of different size and show how to enable the algorithm to run on large-scale data sets in reasonable time using an interval proposal technique. Experiments on both synthetic and real data from various domains, such as climate analysis, video surveillance, and text forensics, demonstrate that our method is widely applicable and a valuable tool for finding interesting events in different types of data. PMID- 29993435 TI - On the Reconstruction of Face Images from Deep Face Templates. AB - State-of-the-art face recognition systems are based on deep (convolutional) neural networks. Therefore, it is imperative to determine to what extent face templates derived from deep networks can be inverted to obtain the original face image. In this paper, we study the vulnerabilities of a state-of-the-art face recognition system based on template reconstruction attack. We propose a neighborly de-convolutional neural network (?textit{NbNet}) to reconstruct face images from their deep templates. In our experiments, we assumed that no knowledge about the target subject and the deep network are available. To train the NbNet reconstruction models, we augmented two benchmark face datasets (VGG Face and Multi-PIE) with a large collection of images synthesized using a face generator. The proposed reconstruction was evaluated using type-I (comparing the reconstructed images against the original face images used to generate the deep template) and type-II (comparing the reconstructed images against a different face image of the same subject) attacks. Given the images reconstructed from NbNets, we show that for verification, we achieve TAR of 95.20% (58.05%) on LFW under type-I (type-II) attacks @ FAR of 0.1%. Besides, 96.58% (92.84%) of the images reconstructed from templates of partition fa (fb) can be identified from partition fa in color FERET. PMID- 29993436 TI - Aggregating Randomized Clustering-Promoting Invariant Projections for Domain Adaptation. AB - Unsupervised domain adaptation aims to leverage the labeled source data to learn with the unlabeled target data. Previous methods tackle it by seeking a low dimensional projection to extract the invariant features and building a classifier on source data. However, they merely concentrate on minimizing the cross-domain distribution divergence, while ignoring the intra-domain structure especially for the target domain. Even after projection, possible risk factors like imbalanced data distribution may still hinder the performance of target label inference. In this paper, we propose a simple yet effective domain invariant projection ensemble approach to tackle these two issues together. Specifically, we seek the optimal projection via a novel relaxed domain irrelevant clustering-promoting term that jointly bridges the cross-domain semantic gap and increases the intra-class compactness in both domains. To further enhance the target label inference, we first develop a 'sampling-and fusion' framework, under which multiple projections are independently learned based on various randomized coupled domain subsets. Subsequently, aggregating models such as majority voting are utilized to leverage multiple projections and classify unlabeled target data. Extensive experimental results on four visual benchmarks including object, face, and digit images, demonstrate that the proposed methods gain remarkable margins over state-of-the-art unsupervised domain adaptation methods. PMID- 29993437 TI - Occlusion-aware Method for Temporally Consistent Superpixels. AB - A wide variety of computer vision applications rely on superpixel or supervoxel algorithms as a preprocessing step. This underlines the overall importance that these approaches have gained in recent years. However, most methods show a lack of temporal consistency or fail in producing temporally stable superpixels. In this paper, we present an approach to generate temporally consistent superpixels for video content. Our method is formulated as a contour-evolving expectation maximization framework, which utilizes an efficient label propagation scheme to encourage the preservation of superpixel shapes and their relative positioning over time. By explicitly detecting the occlusion of superpixels and the disocclusion of new image regions, our framework is able to terminate and create superpixels whose corresponding image region becomes hidden or newly appears. Additionally, the occluded parts of superpixels are incorporated in the further optimization. This increases the compliance of the superpixel flow with the optical flow present in the scene. Using established benchmark suites, we show the performance of our approach in comparison to state-of-the-art supervoxel and superpixel algorithms for video content. PMID- 29993438 TI - Imbalanced Deep Learning by Minority Class Incremental Rectification. AB - Model learning from class imbalanced training data is a long-standing and significant challenge for machine learning. In particular, existing deep learning methods consider mostly either class balanced data or moderately imbalanced data in model training, and ignore the challenge of learning from significantly imbalanced training data. To address this problem, we formulate a class imbalanced deep learning model based on batch-wise incremental minority (sparsely sampled) class rectification by hard sample mining in majority (frequently sampled) classes during model training. This model is designed to minimise the dominant effect of majority classes by discovering sparsely sampled boundaries of minority classes in an iterative batch-wise learning process. To that end, we introduce a Class Rectification Loss (CRL) function that can be deployed readily in deep network architectures. Extensive experimental evaluations are conducted on three imbalanced person attribute benchmark datasets (CelebA, X-Domain, DeepFashion) and one balanced object category benchmark dataset (CIFAR-100). These experimental results demonstrate the performance advantages and model scalability of the proposed batch-wise incremental minority class rectification model over the existing state-of-the-art models for addressing the problem of imbalanced data learning. PMID- 29993439 TI - Dynamic Clustering Algorithms via Small-Variance Analysis of Markov Chain Mixture Models. AB - Bayesian nonparametrics are a class of probabilistic models in which the model size is inferred from data. A recently developed methodology in this field is small-variance asymptotic analysis, a mathematical technique for deriving learning algorithms that capture much of the flexibility of Bayesian nonparametric inference algorithms, but are simpler to implement and less computationally expensive. Past work on small-variance analysis of Bayesian nonparametric inference algorithms has exclusively considered batch models trained on a single, static dataset, which are incapable of capturing time evolution in the latent structure of the data. This work presents a small variance analysis of the maximum a posteriori filtering problem for a temporally varying mixture model with a Markov dependence structure, which captures temporally evolving clusters within a dataset. Two clustering algorithms result from the analysis: D-Means, an iterative clustering algorithm for linearly separable, spherical clusters; and SD-Means, a spectral clustering algorithm derived from a kernelized, relaxed version of the clustering problem. Empirical results from experiments demonstrate the advantages of using D-Means and SD-Means over contemporary clustering algorithms, in terms of both computational cost and clustering accuracy. PMID- 29993440 TI - Sensitivity of the projected subtraction approach to mesh degeneracies and its impact on the forward problem in EEG. AB - OBJECTIVE: Subtraction-based techniques are known for being theoretically rigorous and accurate methods for solving the forward problem in EEG (EEG-FP) by means of the finite element method. Within them, the projected subtraction (PS) approach is generally adopted because of its computational efficiency. Although this technique received the attention of the community, its sensitivity to degenerated elements is still poorly understood. In this paper, we investigate the impact of low quality tetrahedra on the results computed with the PS approach. METHODS: We derived upper bounds on the relative error of the element source vector as a function of geometrical features describing the tetrahedral discretisation of the domain. These error bounds were then utilised for showing the instability of the PS method with regards to the mesh quality. To overcome this issue, we proposed an alternative technique, coined projected gradient subtraction (PGS) approach, that exploits the stability of the corresponding bounds. RESULTS: Computer simulations showed that the PS method is extremely sensitive to the mesh shape and size, leading to unacceptable solutions of the EEG-FP in case of using suboptimal tessellations. This was not the case of the PGS approach, which led to stable and accurate results in a comparable amount of time. CONCLUSION: Solutions of the EEG-FP computed with the PS method are highly sensitive to degenerated elements. Such errors can be mitigated by the PGS approach, which showed better performance than the PS technique. SIGNIFICANCE: The PGS is an efficient method for computing high-quality lead field matrices even in the presence of degenerated elements. PMID- 29993441 TI - Electrical Impedance to Assess Facial Nerve Proximity during Robotic Cochlear Implantation. AB - Reported studies pertaining to needle guidance suggest that tissue impedance available from neuromonitoring systems can be used to discriminate nerve tissue proximity. In this pilot study, the existence of a relationship between intraoperative electrical impedance and tissue density, estimated from computer tomography (CT) images, is evaluated in the mastoid bone of in-vivo sheep. In five subjects, nine trajectories were drilled using an image-guided surgical robot. Per trajectory, five measurement points near the facial nerve were accessed and electrical impedance was measured ( 1 KHz) using a multipolar electrode probe. Micro-CT was used postoperatively to measure the distances from the drilled trajectories to the facial nerve. Tissue density was determined from co-registered preoperative CT images and, following sensitivity field modelling of the measuring tip, tissue resistivity was calculated. The relationship between impedance and density was determined for 29 trajectories passing or intersecting the facial nerve. A monotonic decrease in impedance magnitude was observed in all trajectories with a drill axis intersecting the facial nerve. Mean tissue densities intersecting with the facial nerve (971-1161 HU) were different (p < 0.01) from those along safe trajectories passing the nerve (1194-1449 HU). However, mean resistivity values of trajectories intersecting the facial nerve (14-24 MUm) were similar to those of safe passing trajectories (17-23 MUm). The determined relationship between tissue density and electrical impedance during neuromonitoring of the facial nerve suggests that impedance spectroscopy may be used to increase the accuracy of tissue discrimination, and ultimately improve nerve safety distance assessment in the future. PMID- 29993442 TI - ECG-Based Concentration Recognition with Multi-Task Regression. AB - OBJECTIVE: Recognition of human activities and mental states using wearable sensors and smartphones has attracted considerable attention recently. In particular, prediction of the stress level of a subject using an electrocardiogram (ECG) sensor has been studied extensively. In this paper, we attempt to predict the degree of concentration by using heart-rate features. However, due to strong diversity in individuals and high sampling costs, building an accurate prediction model is still highly challenging. METHOD: To overcome these difficulties, we propose to use a multi-task learning (MTL) technique for effectively sharing information among similar individuals. RESULT: Through experiments with eighteen healthy subjects performing daily office works such as writing reports, we demonstrate that the proposed method significantly improves the accuracy of concentration prediction in small sample situations. CONCLUSION: The performance of the MTL method is shown to be stable across different subjects, which is an important advantage over conventional models. SIGNIFICANCE: This improvement has significant impact in real-world concentration recognition because the data collection burden of each user can be drastically mitigated. PMID- 29993443 TI - Uncertainty-Aware Organ Classification for Surgical Data Science Applications in Laparoscopy. AB - OBJECTIVE: Surgical data science is evolving into a research field that aims to observe everything occurring within and around the treatment process to provide situation-aware data-driven assistance. In the context of endoscopic video analysis, the accurate classification of organs in the field of view of the camera proffers a technical challenge. Herein, we propose a new approach to anatomical structure classification and image tagging that features an intrinsic measure of confidence to estimate its own performance with high reliability and which can be applied to both RGB and multispectral imaging (MI) data. METHODS: Organ recognition is performed using a superpixel classification strategy based on textural and reflectance information. Classification confidence is estimated by analyzing the dispersion of class probabilities. Assessment of the proposed technology is performed through a comprehensive in vivo study with seven pigs. RESULTS: When applied to image tagging, mean accuracy in our experiments increased from 65% (RGB) and 80% (MI) to 90% (RGB) and 96% (MI) with the confidence measure. CONCLUSION: Results showed that the confidence measure had a significant influence on the classification accuracy, and MI data are better suited for anatomical structure labeling than RGB data. SIGNIFICANCE: This paper significantly enhances the state of art in automatic labeling of endoscopic videos by introducing the use of the confidence metric, and by being the first study to use MI data for in vivo laparoscopic tissue classification. The data of our experiments will be released as the first in vivo MI dataset upon publication of this paper. PMID- 29993444 TI - Inertial Sensing for Gait Event Detection and Transfemoral Prosthesis Control Strategy. AB - OBJECTIVE: This paper presents a method for walking gait event detection using a single inertial measurement unit (IMU) mounted on the shank. METHODS: Experiments were conducted to detect heel strike (HS) and toe off (TO) gait events of 10 healthy subjects and 5 transfemoral amputees walking at various speeds and slopes on an instrumented treadmill. The performance of three different algorithms [thresholding (THR), linear discriminant analysis, and quadratic discriminant analysis] was evaluated on both timing and frequency of gait event detections compared to data collected using force plates. RESULTS: Though all algorithms could be used reliably (within 8.2% stride temporal error and 0.2% frequency error), THR was the most accurate, detecting 100% of gait events within an average of 2% stride for both the healthy subjects and the amputees. Furthermore, universal parameters could be used across all speeds and slopes within each demographic. CONCLUSION: HS and TO for walking gait can be reliably detected in healthy and transfemoral amputee subjects using a single IMU. SIGNIFICANCE: This work provides a robust, simple, and inexpensive method of gait event detection that does not rely on a load cell and could be easily implemented in a lower-limb prosthesis. PMID- 29993445 TI - Medical Image Synthesis with Deep Convolutional Adversarial Networks. AB - Medical imaging plays a critical role in various clinical applications. However, due to multiple considerations such as cost and radiation dose, the acquisition of certain image modalities may be limited. Thus, medical image synthesis can be of great benefit by estimating a desired imaging modality without incurring an actual scan. In this paper, we propose a generative adversarial approach to address this challenging problem. Specifically, we train a fully convolutional network (FCN) to generate a target image given a source image. To better model a nonlinear mapping from source to target and to produce more realistic target images, we propose to use the adversarial learning strategy to better model the FCN. Moreover, the FCN is designed to incorporate an image-gradient-difference based loss function to avoid generating blurry target images. Long-term residual unit is also explored to help the training of the network. We further apply Auto Context Model to implement a context-aware deep convolutional adversarial network. Experimental results show that our method is accurate and robust for synthesizing target images from the corresponding source images. In particular, we evaluate our method on three datasets, to address the tasks of generating CT from MRI and generating 7T MRI from 3T MRI images. Our method outperforms the state-of-the-art methods under comparison in all datasets and tasks. PMID- 29993446 TI - Pathogen Detection Using Frequency Domain Fluorescent Lifetime Measurements. AB - OBJECTIVE: Inflammation of the meninges is a source of severe morbidity and therefore is an important health concerns worldwide. The conventional clinical microbiology approaches used today to identify pathogens suffer from several drawbacks and frequently provide false results. This research describes a fast method to detect the presence of pathogens using the frequency domain (FD) fluorescence lifetime (FLT) imaging microscopy (FLIM) system. METHODS: The study included 43 individuals divided into 4 groups: 9 diagnosed with different types of bacteria; 16 diagnosed with different types of viruses; 5 healthy samples served as a control; and 12 samples were negative to any pathogen, although presenting related symptoms. All samples contained leukocytes that were extracted from the cerebrospinal fluid (CSF) and were subjected to nuclear staining by 4', 6-diamidino-2-phenylindole (DAPI) and FLT analyses based on phase and amplitude crossing point (CRPO). RESULTS: Using notched boxplots, we found differences in 95% probability between the first three groups through different notch ranges (NR). Pathogen samples presented a longer median FLT (3.28 ns with NR of 3.24 3.32 ns in bacteria and 3.18 ns with NR of 3.16-3.21 ns in viruses) compared to the control median FLT (2.65 ns with NR of 2.63-2.67 ns). Furthermore, we found that the undetected forth group was divided into two types: a relatively normal median FLT (2.72 ns with NR of 2.68-2.76 ns) and a prolonged FLT (3.22 ns with NR of 3.17-3.27 ns). CONCLUSION: FLT measurements can differentiate between control and pathogen by the CRPO method. SIGNIFICANCE: The FD-FLIM system can provide a high throughput diagnostic technique that does not require a physician. PMID- 29993447 TI - Detecting Vascular Age Using the Analysis of Peripheral Pulse. AB - : Vascular ageing is known to be accompanied by arterial stiffening and vascular endothelial dysfunction, and represents an independent factor contributing to the development of cardiovascular disease. The microvascular pulse is affected by the biomechanical alterations of the circulatory system, and has been the focus of studies aiming at the development of non-invasive methods able to extract physiologically relevant features. OBJECTIVE: proposing an approach for the assessment of vascular ageing based on a support vector machine (SVM) learning from features of the pulse contour. METHODS: the supervised classifier was trained and validated over 20935 models of pulse wave, obtained with a multi Gaussian decomposition algorithm, applied to laser Doppler flowmetry signals of 54 healthy, non-smoker subjects. RESULTS: the multi-Gaussian model showed a mean R2 of 0.98 and an average normalized root mean square error of 0.90, demonstrating the ability to reconstruct the pulse shape. Over 30 training and validation experiments, the SVM showed a mean Pearson's r of 0.808 between the rate of waves classified as old and the age of the subjects, along with an average area under the ROC curve of 0.953. CONCLUSION: the SVM showed the capability to discriminate differently aged individuals. SIGNIFICANCE: the proposed method might detect the ageing-related modifications of the vascular tree; furthermore, since diabetes promotes vascular alterations comparable to ageing, this approach may be also suitable for the screening of diabetic angiopathy. PMID- 29993448 TI - Assessment of Quadratic Nonlinear Cardiorespiratory Couplings During Tilt Table Test by Means of Real Wavelet Biphase. AB - OBJECTIVE: In this paper a method for assessment of Quadratic Phase Coupling (QPC) between respiration and Heart Rate Variability (HRV) is presented. METHODS: First, a method for QPC detection is proposed named Real Wavelet Biphase (RWB). Then, a method for QPC quantification is proposed based on the Normalized Wavelet Biamplitude (NWB). A simulation study has been conducted to test the reliability of RWB to identify QPC, even in the presence of constant delays between interacting oscillations, and to discriminate it from Quadratic Phase Uncoupling. Significant QPC was assessed based on surrogate data analysis. Then, quadratic cardiorespiratory couplings were studied during a tilt table test protocol of 17 young healthy subjects. RESULTS: Simulation study showed that RWB is able to detect even weak QPC with delays in the range of 0 2 s, which are usual in the Autonomic Nervous System (ANS) control of heart rate. Results from the database revealed a significant reduction (p<0.05) of NWB between respiration and both low and high frequencies of HRV in head-up tilt position compared to early supine. CONCLUSION: The proposed technique detects and quantifies robustly QPC and is able to track the coupling between respiration and various HRV components during ANS changes. SIGNIFICANCE: The proposed method can help to assess alternations of nonlinear cardiorespiratory interactions related to ANS dysfunction and physiological regulation of HRV in cardiovascular diseases. PMID- 29993449 TI - Is EMG a Viable Alternative to BCI for Detecting Movement Intention in Severe Stroke? AB - OBJECTIVE: In light of the shortcomings of current restorative brain-computer interfaces (BCI), this study investigated the possibility of using EMG to detect hand/wrist extension movement intention to trigger robot-assisted training in individuals without residual movements. METHODS: We compared movement intention detection using an EMG detector with a sensorimotor rhythm based EEG-BCI using only ipsilesional activity. This was carried out on data of 30 severely affected chronic stroke patients from a randomized control trial using an EEG-BCI for robot-assisted training. RESULTS: The results indicate the feasibility of using EMG to detect movement intention in this severely handicapped population; probability of detecting EMG when patients attempted to move was higher (p 0.001) than at rest. Interestingly, 22 out of 30 (or 73%) patients had sufficiently strong EMG in their finger/wrist extensors. Furthermore, in patients with detectable EMG, there was poor agreement between the EEG and EMG intent detectors, which indicates that these modalities may detect different processes. CONCLUSION: A substantial segment of severely affected stroke patients may benefit from EMG-based assisted therapy. When compared to EEG, a surface EMG interface requires less preparation time, which is easier to don/doff, and is more compact in size. SIGNIFICANCE: This study shows that a large proportion of severely affected stroke patients have residual EMG, which yields a direct and practical way to trigger robot-assisted training. PMID- 29993450 TI - RF Channel Modeling for Implant-to-Implant Communication and Implant to Subcutaneous Implant Communication for Future Leadless Cardiac Pacemakers. AB - Propagation of radio-frequency signals inside human body is demanding to analyze as it is a highly complex medium consisting of different frequency-dependent lossy materials of varying thickness. Moreover, experimental analyses are also unfeasible because that requires probes to be placed inside a human body to collect the signals. This paper focuses on in-body to in-body implant communication for future multinodal capsule-like leadless cardiac pacemaker technology. The frequency range of 0.3-3 GHz is analyzed using very detailed numerical simulations of digital human models. The results show that the Industrial, Scientific, and Medical radio band of the frequency range of 2.4-2.5 GHz is optimal, having the least attenuation of signals considering the size constraints of the implant antenna. Furthermore, the placement of an additional subcutaneous implant transceiver is studied. The analysis shows that the abdominal wall is the optimal position for the placement of the implant compared to shoulder and lateral side of the body. This result is further validated by an in vivo experiment on an adult pig. The other novelty of the study is the investigation of the channel behavior based on ventricular blood volume of the heart to find out the appropriate timing of the transmission of signals between the implants. The results show that the attenuation of the signal increases with the increase in blood volume inside the heart. PMID- 29993451 TI - Wireless thermometry for real-time temperature recording on thousand-cell level. AB - OBJECTIVE: A wireless, multi-channel system for realtime measurement of the cellular-temperature response to drugs is developed. METHODS: The acquisition system applies a highprecision reference resistor and a low real-time measurement current (below or equal to 0.14 mA) to reduce self-heating via the intermittent measurement. Cells of a small volume cell fluid are cultured on the surface of the platinum thermal resistor and subsequently measured in the incubator. RESULTS: The resistor resolution of the circuit exhibits 20 mMU, which corresponds to no more than 0.01 degrees C. The resistance deviations of each channel are corrected with software compensation. The linearity between the temperature and resistance of the sensors lies above 0.999 in the applied temperature range (30 MUC 42 degrees C). Observations with the scanning electron microscope (SEM) show that the cells grow well on the sensor surface. The latter is composed of a glass glaze, which is nontoxic for organisms. The cell population temperature measurements under norepinephrine action present an obvious temperature rise, which can be the result of the drug binding to the receptors on cell membrane thus promoting a cationic inflow. CONCLUSION: The platinum sensor and multi-channel acquisition system can be used to determine the temperature changes of cells in their original state. SIGNIFICANCE: The wireless, real-time, highthroughput temperature detection method is particularly suitable to evaluate the thermogenic ability of growing cells that interact with other matter or organisms. The proposed method can help to explore thermal changes in cell populations, intercellular connections, and social connections of cells. PMID- 29993452 TI - Fast Multiway Partial Least Squares Regression. AB - Multiway array decomposition has been successful in providing a better understanding of the structure underlying data and in discovering potentially hidden feature dependencies serving high-performance decoder applications. However, the computational cost of multi-way algorithms can become prohibitive, especially when considering large data sets, rendering them unsuitable for time critical applications. We propose a multi-way regression model for large-scale tensors with optimized performance in terms of time complexity, called fast Higher-Order Partial Least Squares (fHOPLS). We compare fHOPLS with its native version, Higher-Order Partial Least Squares (HOPLS), the state-of-the-art in multilinear regression, under different noise conditions and tensor dimensionalities using synthetic data. We also compare their performance when used for predicting scalp-recorded electroencephalography (EEG) signals from invasively-recorded electrocorticography (ECoG) signals in an oddball experiment. For the sake of exposition, we evaluated the performance of standard unfolded Partial Least Squares- (PLS) and linear regression. Our results show that fHOPLS is significantly faster than HOPLS in particular for big data. In addition, the regression performances of fHOPLS and HOPLS are comparable and outperform both unfolded PLS and linear regression. Another interesting result is that multiway array decoding yields more accurate results than epoch-based averaging procedures traditionally used in the brain computer interfacing (BCI) community. PMID- 29993454 TI - Numerical Study of Particle-fluid Two-phase Flow under AC Electrokinetics in Electrode-multilayered Microfluidic Device. AB - A particle-fluid two-phase flow under alternating current (AC) electrokinetics was numerically simulated to investigate the three-dimensional (3D) particle motion in a complex electric field of a high conductivity medium generated by an electrode-multilayered microfluidic device. The simulation model coupling thermal fluid-electrical and dispersed particle problems incorporates three AC electrokinetics (ACEK) phenomena: the AC electrothermal effect (ACET), thermal buoyancy (TB) and dielectrophoresis (DEP). The electrode-multilayered microfluidic device was fabricated with forty electrodes exposed at the flow channel sidewalls in five cross sections. The governing equations of the simulation model are solved by the Eulerian-Lagrangian method with finite volume discretization. Fluid flow simulations in three cases with or without consideration of ACET and TB are performed to clarify the contributions of these phenomena. The fluid flow is found to be composed of short-range vortices due to ACET and long-range circulation due to TB based on the features of the electrode multilayered microfluidic device. The 3D particle trajectory influenced by the fluid flow is compared with four values of the real part of the Clausius-Mossotti (CM) factor to evaluate the DEP phenomenon. The simulation model is validated by experiments using a cell suspension. The pattern of cell trajectories in the upper part of the flow channel measured by Particle Tracking Velocimetry agrees with the simulated pattern. By comparison of the simulation and experiment, it is found that the cells moving straight away from the electrode on the focal plane are decelerated within the region of 60 MUm from the electrode by positive-DEP with Re[K(omega)] = 0.10-0.14. Furthermore, the 3D DEP-effective region and the ACET and TB dominant region for the cells is predicted by evaluating the slip velocity due to DEP force with Re[K(omega)] = 0.13. Consequently, the flow mechanism and dominant region of each ACEK phenomenon in the device are clarified from the 3D simulation validated by the experiments. PMID- 29993453 TI - Robotic Immobilization of Motile Sperm for Clinical Intracytoplasmic Sperm Injection. AB - OBJECTIVE: In clinical intracytoplasmic sperm injection (ICSI), a motile sperm must be immobilized before insertion into an oocyte. This paper aims to develop a robotic system for automated tracking, orientation control, and immobilization of motile sperms for clinical ICSI applications. METHODS: We adapt the probabilistic data association filter by adding sperm head orientation into state variables for robustly tracking the sperm head and estimating sperm tail positions under interfering conditions. The robotic system also utilizes a motorized rotational microscopy stage and a new visual servo control strategy that predicts and compensates for sperm movements to actively adjust sperm orientation for immobilizing a sperm swimming in any direction. RESULTS: The system robustly tracked sperm head with a tracking success rate of 96.0% and estimated sperm tail position with an accuracy of 1.08 MUm under clinical conditions where the occlusion of the target sperm and interference from other sperms occur. Experimental results from robotic immo bilization of 400 sperms confirmed that the system achieved a consistent immobilization success rate of 94.5%, independent of sperm velocity or swimming direction. CONCLUSION: Our adapted tracking algorithm effectively distinguishes the target sperm from interfering sperms. Predicting and compensating for sperm move ments significantly reduce the positioning error during sperm orientation control. These features make the robotic system suitable for automated sperm immobilization. SIGNIFICANCE: The robotic system eliminates stringent skill requirements in manual sperm immobilization. It is capable of manipulating sperms swimming in an arbitrary direction with a high success rate. PMID- 29993455 TI - Combined multi-wavelength photoacoustic and plane-wave ultrasound imaging for probing dynamic phase-change contrast agents. AB - OBJECTIVE: The purpose of this study was to introduce combined multi-wavelength photoacoustic (PA) and plane-wave ultrasound (US) imaging referred to as mwPA/pwUS imaging capable of probing the rapid dynamic behavior of optically activated phase-change contrast agents. METHODS: A dedicated mwPA/pwUS imaging sequence was developed based on a programmable US system synchronized with a tunable laser to irradiate tissue with laser pulses at desired optical wavelengths and to acquire post-laser-pulse PA images followed by ultrafast plane wave US images. To evaluate the mwPA/pwUS imaging, a capillary filled with optically responsive perfluorohexane nanodroplets (PFHnDs) containing a dye with the peak absorption at 760 nm was imaged with optical wavelengths ranging from 700 nm to 940 nm. In addition, the differences between post-laser ultrafast US images (i.e., differential US (US)) were taken to visualize the recondensation dynamics of PFHnDs at each wavelength. Furthermore, US images were acquired as a function of both time and optical wavelength. RESULTS: PA images of PFHnDs obtained showed higher contrast at near 760 nm, corresponding to the peak absorption of the optical dye inside the nanodroplets. Moreover, the US signals immediately after 760 nm pulsed-laser irradiation were also higher due to the increased ultrasound contrast associated with vaporized PFHnDs. CONCLUSION: The mwPA/pwUS imaging allowed for the US-based optical spectroscopic characterization of PFHnDs and their dynamics. SIGNIFICANCE: The introduced mwPA/pwUS imaging sequence can be used in various clinical applications where both spectroscopic PA imaging of endogenous and/or exogenous chromophores and ultrafast ultrasound imaging of optically triggered nanodroplets are desired. PMID- 29993456 TI - A Single-stimulus, Multi-target BCI Based on Retinotopic Mapping of Motion-Onset VEPs. AB - OBJECTIVE: We present a new type of brain-computer interface (BCI) that utilizes the retinotopic mapping of motion-onset visual evoked potentials (mVEP) to accomplish four control channels using a single motion stimulus. METHODS: Participants selected a BCI command by fixating one of four target locations around a centrally presented visual motion stimulus. A template-matching method was employed to recognize the users' intention by decoding the position of the motion stimulus in the peripheral visual field, and classification performances were evaluated in an offline manner. The motion stimulus eccentricity between the targets and the visual motion stimulus varied among 5.1 degrees , 6.7 degrees , 9.8 degrees , and 13.0 degrees . RESULTS: Distinct N200 spatial patterns were elicited when participants directed attention overtly to the target locations. A four-class classification accuracy of 72.2 5.05% was achieved with a distance of 5.1 degrees visual angle between the targets and the visual motion stimulus. The classification accuracies decreased with increasing motion stimulus eccentricities but remained separable well above the chance level at 13.0 degrees (47.3 8.54%). CONCLUSION: Our results support the feasibility of a single stimulus, multi-target mVEP BCI. SIGNIFICANCE: The proposed system can simplify the visual stimulation of mVEP BCIs, improve user experience and pave the way for simple yet efficient BCI communication. PMID- 29993457 TI - Model of impedance changes in unmyelinated nerve fibres. AB - OBJECTIVE: Currently there is no imaging method which is able to distinguish the functional activity inside nerves. Such a method would be essential for understanding peripheral nerve physiology and would allow precise neuromodulation of organs these nerves supply. Electrical Impedance Tomography (EIT) is a method which produces images of electrical impedance change (dZ) of an object by injecting alternating current and recording surface voltages. It has been shown to be able to image fast activity in the brain and large peripheral nerves. To image inside small autonomic nerves, mostly containing unmyelinated fibres, it is necessary to maximise SNR and optimize the EIT parameters. An accurate model of the nerve is required to identify these optimal parameters as well as to validate data obtained in the experiments. METHODS: In this study, we developed two 3D models of unmyelinated fibres: Hodgkin-Huxley (HH) squid giant axon (single and multiple) and mammalian C-nociceptor. A coupling feedback system was incorporated into the models to simulate direct (DC) and alternating current (AC) application and simultaneously record external field during action potential propagation. RESULTS: Parameters of the developed models were varied to study their influence on the recorded impedance changes; the optimal parameters were identified. The negative dZ was found to monotonically decrease with frequency for both HH and C fibre models, in accordance with the experimental data. CONCLUSION AND SIGNIFICANCE: The accurate realistic model of unmyelinated nerve allows optimisation of EIT parameters and matches literature and experimental results. PMID- 29993458 TI - Automatic Croup Diagnosis Using Cough Sound Recognition. AB - OBJECTIVE: Croup, a respiratory tract infection common in children, causes an inflammation of the upper airway restricting normal breathing and producing cough sounds typically described as seal-like "barking cough". Physicians use the existence of barking cough as the defining characteristic of croup. This work aims to develop automated cough sound analysis methods to objectively diagnose croup. METHODS: In automating croup diagnosis, we propose the use of mathematical features inspired by the human auditory system. In particular, we utilize the cochleagram for feature extraction, a time-frequency representation where the frequency components are based on the frequency selectivity property of the human cochlea. Speech and cough share some similarities in the generation process and physiological wetware used. As such, we also propose the use of mel-frequency cepstral coefficients which has been shown to capture the relevant aspects of the short-term power spectrum of speech signals. Feature combination and backward sequential feature selection are also experimented with. Experimentation is performed on cough sound recordings from patients presenting various clinically diagnosed respiratory tract infections divided into croup and non-croup. The dataset is divided into training and test sets of 364 and 115 patients, respectively, with automatically segmented cough sound segments. RESULTS: Croup and non-croup patient classification on the test dataset with the proposed methods achieve a sensitivity and specificity of 92.31% and 85.29%, respectively. CONCLUSION: Experimental results show significant improvement in automatic croup diagnosis against earlier methods. SIGNIFICANCE: This work has the potential to automate croup diagnosis based solely on cough sound analysis. PMID- 29993459 TI - A Portable Passive Rehabilitation Robot for Upper-Extremity Functional Resistance Training. AB - OBJECTIVE: Loss of arm function is common in individuals with neurological damage, such as stroke or cerebral palsy. Robotic devices that address muscle strength deficits in a task-specific manner can assist in the recovery of arm function; however, current devices are typically large, bulky, and expensive to be routinely used in the clinic or at home. This study sought to address this issue by developing a portable planar passive rehabilitation robot, PaRRo. METHODS: We designed PaRRo with a mechanical layout that incorporated kinematic redundancies to generate forces that directly oppose the user's movement. Cost efficient eddy current brakes were used to provide scalable resistances. The lengths of the robot's linkages were optimized to have a reasonably large workspace for human planar reaching. We then performed theoretical analysis of the robot's resistive force generating capacity and steerable workspace using MATLAB simulations. We also validated the device by having a subject move the end effector along different paths at a set velocity using a metronome while simultaneously collecting surface electromyography (EMG) and end-effector forces felt by the user. RESULTS: Results from simulation experiments indicated that the robot was capable of producing sufficient end-effector forces for functional resistance training. We also found the endpoint forces from the user were similar to the theoretical forces expected at any direction of motion. EMG results indicated that the device was capable of providing adjustable resistances based on subjects' ability levels, as the muscle activation levels scaled with increasing magnet exposures. CONCLUSION: These results indicate that PaRRo is a feasible approach to provide functional resistance training to the muscles along the upper extremity. SIGNIFICANCE: The proposed robotic device could provide a technological breakthrough that will make rehabilitation robots accessible for small outpatient rehabilitation centers and in-home therapy. PMID- 29993460 TI - A Multi-Threshold Iterative DBIM-Based Algorithm for the Imaging of Heterogeneous Breast Tissues. AB - Microwave imaging (MWI) represents a well-known tool for quantitatively retrieving unknown objects in a nondestructive way. Microwave radiation is non ionizing, which suggests that MWI can be also attractive for medical diagnostics applications. This work proposes a novel MWI multi-frequency technique, which combines compressive sensing (CS) with the well-known distorted Born iterative method (DBIM). CS strategies are emerging as a promising tool in MWI applications, which can improve reconstruction quality and/or reduce the number of data samples. The proposed approach is based on iterative shrinkage thresholding algorithm (ISTA), which has been modified to include an automatic and adaptive selection of multithreshold values. This adaptive multi-threshold ISTA (AMTISTA) implementation is applied in reconstruction of two-dimensional (2 D) numerical heterogeneous breast phantoms, where it outerperforms the standard thresholding implementation. We show that our approach is also successful in three-dimensional (3-D) simulations of a realistic imaging experiment, despite the mismatch between the data and our algorithm's forward model. These results suggest that the proposed algorithm is a promising tool for medical MWI applications. PMID- 29993461 TI - Antidepressant-like Effect of Low-intensity Transcranial Ultrasound Stimulation. AB - OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a noninvasive neuromodulation technique with good spatial resolution and deep penetration. This study aims to investigate whether TUS has antidepressant-like effect to depressed rats. METHODS: Rats were divided into five groups, including two groups (ST-Ctr and ST-Res) for evaluating the short-term impact of restraint stress and three groups (LT-Ctr-ShamTUS, LT-Res-ShamTUS and LT-Res-TUS) for studying the long-term effects of restraint and TUS stimulation. The TUS-treated rats were subjected to 15 min TUS stimulation to the prelimbic cortex every day for 2 weeks after the restraint. Then depressive symptoms related behavioral outcomes were estimated in ST-Ctr and ST-Res groups (1 week after restraint), as well as in the other three groups (3 weeks after restraint). RESULTS: The 48-hour-restraint stress could lead to long lasting reduction of exploratory behavior (1 and 3 weeks after restraint) and protracted anhedonia (only observed 3 weeks after restraint). TUS application successfully reversed the core depressive phenotype, anhedonia, indicated by significantly higher sucrose preference index in LT-Res-TUS group (88.8%2.5%, n=16) than LT-Res-ShamTUS group (72.8%7.2%, n=16) (p=0.046). Furthermore, the BDNF expression in left hippocampus was significantly promoted in LT-Res-TUS group (1.530.096, n=5) compared to LT-Res-ShamTUS group (0.790.054, n=5) (p=0.009). In addition, the histologic results of H&E staining showed no TUS induced brain tissue injury. CONCLUSION: These results demonstrated that low intensity TUS had antidepressant-like effect. SIGNIFICANCE: TUS has been speculated to have therapeutic effect in depression. This study provide evidence for the antidepressant-like effects of TUS in rats for the first time. PMID- 29993462 TI - A Cascaded Deep Convolutional Neural Network for Joint Segmentation and Genotype Prediction of Brainstem Gliomas. AB - GOAL: Automatic segmentation of brainstem gliomas and prediction of genotype (H3 K27M) mutation status based on magnetic resonance (MR) images are crucial but challenging tasks for computer-aided diagnosis in neurosurgery. In this paper, we present a novel cascaded deep convolutional neural network (CNN) to address these two challenging tasks simultaneously. METHODS: Our novel segmentation task contains two feature-fusion modules: the Gaussian-pyramid multiscale input features-fusion technique and the brainstem-region feature enhancement. The aim is to resolve very difficult problems in brainstem glioma segmentation. Our prediction model combines CNN features and support-vector-machine classifier to automatically predict genotypes without region-of-interest labeled-MR images and is learned jointly with the segmentation task. First, Gaussian-pyramid multiscale input feature fusion is added to our glioma-segmentation task to solve the problems of size variety and weak brainstem-gliomas boundaries. Second, the two feature-fusion modules provide both local and global contexts to retain higher frequency details for sharper tumor boundaries, handling the problem of the large variation of tumor shape, and volume resolution. RESULTS AND CONCLUSION: Experiments demonstrate that our cascaded CNN method achieves not only a good tumor segmentation result with a high Dice similarity coefficient of 77.03%, but also a competitive genotype prediction result with an average accuracy of 94.85% upon fivefold cross-validation. PMID- 29993463 TI - Automated Detection of Convulsive Seizures Using a Single Wrist-Worn Accelerometer Device. AB - Epileptic seizure detection requires specialized approaches such as video/electroencephalography monitoring. However, these approaches are restricted mainly to hospital setting and requires video/EEG analysis by experts, which makes these approaches resource- and labor-intensive. In contrast, we aim to develop a wireless, remote monitoring system using a single wrist-worn accelerometer sensor, which is sensitive to multiple types of convulsive seizures and is capable of detecting seizures with short duration. Simple time domain features including a new set of Poincare plot based features were extracted from the active movement events recorded using a wrist-worn accelerometer sensor. The best features were then selected using the area under the ROC curve analysis. Kernelized support vector data description (SVDD) was then used to classify non seizure and seizure events. The proposed algorithm was evaluated on 5,576h of recordings from 79 patients and detected 40 (86.95%) of 46 convulsive seizures (generalized tonic-clonic (GTCS), psychogenic non-epileptic (PNES), and complex partial seizures (CPS)) from twenty patients with a total of 270 false alarms (1.16/24h). Furthermore, the algorithm showed a comparable performance (sensitivity 95.23% and false alarm rate 0.64/24h) with respect to existing unimodal and multi-modal methods for GTCS detection. The promising results shows the potential to build an ambulatory monitoring convulsive seizure detection system. A wearable accelerometer based seizure detection system would aid in continuous assessment of convulsive seizures in a timely and non-invasive manner. PMID- 29993464 TI - Sparse Ultrasound Image Reconstruction From a Shape-Sensing Single-Element Forward-Looking Catheter. AB - OBJECTIVE: Minimally invasive procedures, such as intravascular and intracardiac interventions, may benefit from guidance with forward-looking (FL) ultrasound. In this work, we investigate FL ultrasound imaging using a single-element transducer integrated in a steerable catheter, together with an optical shape sensing (OSS) system. METHODS: We tested the feasibility of the proposed device by imaging the surface of a tissue-mimicking (TM) phantom and an ex vivo human carotid plaque. While manually steering the catheter tip, ultrasound A-lines are acquired at 60 Hz together with the catheter shape from the OSS system, resulting in a two dimensional sparse and irregularly sampled data set. We implemented an adaptive Normalized Convolution (NC) algorithm to interpolate the sparse data set by applying an anisotropic Gaussian kernel that is rotated according to the local direction of the catheter scanning pattern. To choose the Gaussian widths tangential ( ${?sigma _t}$) and normal ( ${?sigma _n}$) to the scanning pattern, an exhaustive search was implemented based on RMSE computation on simulated data. RESULTS: Simulations showed that the sparse data set contains only 5% of the original information. The chosen widths, ${?sigma _n} = ?text{250}?;?mu {?textrm{m}}$ and ${?sigma _t} = ?text{100}?;?mu{?textrm{m}}$, are used to successfully reconstruct the surface of the phantom with a contrast ratio of 0.9. The same kernel is applied successfully to the carotid plaque data. CONCLUSION: The proposed approach enables FL imaging with a single ultrasound element, mounted on a steerable device. SIGNIFICANCE: This principle may find application in a variety of image-guided interventions, such as chronic total occlusion (CTO) recanalization. PMID- 29993465 TI - Real-time Visualisation and Analysis of Clinicians' Performance during Palpation in Physical Examinations. AB - OBJECTIVE: Motivated by the fact that palpation skills are challenging to learn and teach, particularly during Digital Rectal Examinations (DRE), and the lack of understanding of what constitutes adequate performance, we present a visualisation and analysis system that uses small position and pressure sensors located on the examining finger, allowing the quantitative analysis of duration, steps and pressure applied. METHODS: The system is first described, followed by an experimental study of twenty experts from four clinical specialties performing ten DREs each on a benchtop model using the proposed system. Analysis of the constitutive steps was conducted to improve understanding of the examination. A Markov model representing executed tasks and analysis of pressure applied is also introduced. RESULTS: The proposed system successfully allowed the visualisation and analysis during the experimental study. General Practitioners and Nurses were found to execute more tasks compared to Urologists and Colorectal Surgeons. Urologists executed the least number of tasks and were the most consistent group compared to others. CONCLUSION: The ability to "see through" allowed us to better characterise the performance of experts when conducting a DRE on a benchtop model, comparing the performance of relevant specialties, and studying executed tasks and the pressure applied. The Markov model presented summarises task execution of experts and could be used to compare performance of novices against that of experts. SIGNIFICANCE: This approach allows for the analysis of performance based on continuous sensor data recording that can be easily extended to real subjects and other types of physical examinations. PMID- 29993466 TI - Experimental Comparisons of Sparse Dictionary Learning and Independent Component Analysis for Brain Network Inference from fMRI Data. AB - Independent Component Analysis (ICA) has been one of the most popular methods for inferring functional brain networks from fMRI data. Recently, sparse dictionary learning (SDL) has been shown to be an alternative, effective approach to inferring functional networks based on fMRI data. However, there have been little experimental comparisons between ICA and SDL in the literature so far. In this work, we conduct comprehensive comparisons between four variants of ICA methods and three variants of SDL methods by using synthesized fMRI data with ground truth. Our results showed that ICA methods perform very well and slightly better than SDL methods when functional networks' spatial overlaps are minor, but ICA methods have difficulty in differentiating functional networks with moderate or significant spatial overlaps. In contrast, the SDL algorithms perform consistently well no matter how functional networks spatially overlap, and importantly, SDL methods are significantly better than ICA methods when spatial overlaps between networks are moderate or severe. This work offers empirical better understanding of ICA and SDL algorithms in inferring functional networks from fMRI data, and provides new guidelines and caveats when constructing and interpreting functional networks in the era of fMRI-based connectomics. PMID- 29993467 TI - Synthetic Ultra-High-Resolution Millimeter-Wave Imaging for Skin Cancer Detection. AB - This work introduces, for the first time, a millimeter-wave imaging system with a "synthetic" ultra-wide imaging bandwidth of 98 GHz to provide the ultra-high resolutions required for early-stage skin cancer detection. The proposed approach consists of splitting the required ultra-wide imaging bandwidth into four sub bands, and assigning each sub-band to a separate imaging element, i.e. an antenna radiator. Each of the sub-band antennas transmits and receives signals only at its corresponding sub-band. The captured signals are then combined and processed to form the image of the target. For each sub-band, a Vivaldi tapered slot antenna (TSA) fed with a combination of substrate-integrated waveguide (SIW) and coplanar waveguide (CPW) is designed and micro-fabricated. Design techniques are also provided for the four similarly-shaped sub-band antennas for achieving excellent impedance matches (S11 < -10 dB) and nearly constant gains of 10 dBi over the entire 12-110-GHz bandwidth. The design procedure is validated by comparing the simulated results with measurements performed on the fabricated prototypes. Excellent agreements are obtained between simulations and measurements. Finally, the feasibility of detecting early-stage skin tumors in three dimensions is experimentally verified by employing the sub-band antennas in a synthetic ultra-wideband imaging system with a bandwidth of 98 GHz. Two separate setups, each comprising of a dispersive skin-mimicking phantom as well as two dispersive spherical tumors are constructed for imaging experiments. Lateral and axial resolutions of 200 MUm are confirmed, and a successful reconstruction of the spherical tumors is achieved in both cases. PMID- 29993468 TI - Separation of subcutaneous fat from muscle in surface electrical impedance myography measurements using model component analysis. AB - OBJECTIVE: Electrical impedance myography (EIM) is a relatively new technique to assess neuromuscular disorders (NMD). Although the application of EIM using surface electrodes (sEIM) has been adopted by the neurology community in recent years to evaluate NMD status, sEIM's sensitivity as a biomarker of skeletal muscle condition is impacted by subcutaneous fat (SF) tissue. Here, we develop a method able to remove the contribution of SF from sEIM data. METHODS: We evaluate independent component analysis (ICA) and principal component analysis (PCA) for this purpose. Then, we introduce the so-called model component analysis (MCA). All methods are validated with numerical simulations using impedivity data from SF and muscle tissues. The methods are then tested with measurements performed in diseased individuals (n=3). RESULTS: Simulations demonstrate that MCA is the most accurate method at separating the impedivity of SF and muscle tissues with the accuracy being 99.2%, followed by ICA with 51.4%, and finally PCA with 38.5%. Experimental results from sEIM data measured on the triceps brachii of patients are consistent with muscle gray scale level values obtained using ultrasound imaging. CONCLUSION: MCA can be used to separate the impedivity of SF and muscle tissues from sEIM data, thus increasing the sensitivity to detect changes in the muscle. SIGNIFICANCE: MCA can make sEIM technique a better diagnostic tool and biomarker of disease progression and response to therapy by removing the confounding effect of SF tissue in NMD patients with excess subcutaneous fat tissue for any reason. PMID- 29993469 TI - A Radiomics Approach With CNN for Shear-Wave Elastography Breast Tumor Classification. AB - This paper proposes a segmentation-free radiomics method to classify malignant and benign breast tumors with shear-wave elastography (SWE) data. The method is targeted to integrate the advantage of both SWE in providing important elastic with morphology information and convolutional neural network (CNN) in automatic feature extraction and accurate classification. Compared to traditional methods, the proposed method is designed to directly extract features from the dataset without the prerequisite of segmentation and manual operation. This can keep the peri-tumor information, which is lost by segmentation-based methods. With the proposed model trained on 540 images (318 of malignant breast tumors and 222 of benign breast tumors, respectively), an accuracy of 95.8%, a sensitivity of 96.2%, and a specificity of 95.7% was obtained for the final test. The superior performances compared to the existing state-of-the-art methods and its automatic nature both demonstrate that the proposed method has a great potential to be applied to clinical computer-aided diagnosis of breast cancer. PMID- 29993470 TI - Robust Methods for Automated Selection of Cardiac Signals After Blind Source Separation. AB - OBJECTIVE: Novel minimum-contact vital signs monitoring techniques like textile or capacitive electrocardiogram (ECG) provide new opportunities for health monitoring. These techniques are sensitive to artifacts and require handling of unstable signal quality. Spatio-temporal blind source separation (BSS) is capable of processing suchlike multichannel signals. However, BSS's permutation indeterminacy requires the selection of the cardiac signal (i.e., the component resembling the electric cardiac activity) after its separation from artifacts. This study evaluates different concepts for solving permutation indeterminacy. METHODS: Novel automated component selection routines based on heartbeat detections are compared with standard concepts, as using higher order moments or frequency-domain features, for solving permutation indeterminacy in spatio temporal BSS. BSS was applied to a textile and a capacitive ECG dataset of healthy subjects performing a motion protocol, and to the MIT-BIH Arrhythmia Database. The performance of the subsequent component selection was evaluated by means of the heartbeat detection accuracy (ACC) using an automatically selected single component. RESULTS: The proposed heartbeat-detection-based selection routines significantly outperformed the standard selectors based on Skewness, Kurtosis, and frequency-domain features, especially for datasets containing motion artifacts. For arrhythmia data, beat analysis by sparse coding outperformed simple periodicity tests of the detected heartbeats. CONCLUSION: Component selection routines based on heartbeat detections are capable of reliably selecting cardiac signals after spatio-temporal BSS in case of severe motion artifacts and arrhythmia. SIGNIFICANCE: The availability of robust cardiac component selectors for solving permutation indeterminacy facilitates the usage of spatio-temporal BSS to extract cardiac signals in artifact-sensitive minimum contact vital signs monitoring techniques. PMID- 29993471 TI - Classification of Pre-Clinical Seizure States Using Scalp EEG Cross-Frequency Coupling Features. AB - OBJECTIVE: This work proposes a machine-learning based system for a scalp EEG that flags an alarm in advance of a clinical seizure onset. METHODS: EEG recordings from 12 patients with drug resistant epilepsy were marked by an expert neurologist for clinical seizure onset. Scalp EEG recordings consisted of 56 seizures and 9.67 h of interictal periods. Data from six patients were reserved for testing, and the rest was split into training and testing sets. A global spatial average of a cross-frequency coupling (CFC) index, , was extracted in 2 s windows, and used as the feature for the machine learning. A multistage state classifier (MSC) based on random forest algorithms was trained and tested on these data. Training was conducted to classify three states: interictal baseline, and segments prior to and following EG onset. Classifier performance was assessed using a receiver-operating characteristic (ROC) analysis. RESULTS: The MSC produced an alarm 45 16 s in advance of a clinical seizure onset across seizures from the 12 patients. It performed with a sensitivity of 87.9%, a specificity of 82.4%, and an area-under-the-ROC of 93.4%. On patients for whom it received training, performance metrics increased. Performance metrics did not change when the MSC used reduced electrode ring configurations. CONCLUSION: Using the scalp , the MSC produced an alarm in advance of a clinical seizure onset for all 12 patients. Patient-specific training improved the specificity of classification. SIGNIFICANCE: The MSC is noninvasive, and demonstrates that CFC features may be suitable for use in a home-based seizure monitoring system. PMID- 29993472 TI - A Lumped Parameter Model to Study Atrioventricular Valve Regurgitation in Stage 1 and Changes Across Stage 2 Surgery in Single Ventricle Patients. AB - GOAL: This manuscript evaluates atrioventric-ular valve regurgitation (AVVR) in babies born with an already very challenging heart condition, i.e., with single ventricle physiology. Although the second surgery that single ventricle patients undergo is thought to decrease AVVR, there is much controversy in the clinical literature about AVVR treatment. METHODS: The effect of AVVR on Stage 1 haemodynamics and resulting acute changes from conversion to Stage 2 circulation in single ventricle patients are analyzed through lumped parameter models. Several degrees of AVVR severity are analyzed, for two types of valve regurgitation: incomplete leaflet closure and valve prolapse. RESULTS: The models show that increasing AVVR in Stage 1 induces the following effects: first, higher stroke volume and associated decrease in ventricular end-systolic volume; second, increase in atrial volumes with V-loop enlargement in pressure-volume curves; third, pulmonary venous hypertension. The Stage 2 surgery results in volume unloading of the ventricle, thereby, driving a decrease in AVVR. However, this effect is offset by an increase in ventricular pressures resulting in a net increase in regurgitation fraction (RF) of approximately 0.1 (for example, in severe AVVR, the preoperative RF increases from 60% to 70% postoperatively). Moreover, despite some improvements to sarcomere function early after Stage 2 surgery, it may deteriorate in cases of severe AVVR. CONCLUSION: In patients with moderate to severe AVVR, restoration of atrioventricular valve competence prior to, or at the time of, Stage 2 surgery would likely lead to improved haemodynamics and clinical outcome as the models suggest that uncorrected AVVR can worsen across Stage 2 surgery. This was found to be independent of the AVVR degree and mechanisms. PMID- 29993473 TI - A Benchmark Dataset and Evaluation for Non-Lambertian and Uncalibrated Photometric Stereo. AB - Classic photometric stereo is often extended to deal with real-world materials and work with unknown lighting conditions for practicability. To quantitatively evaluate non-Lambertian and uncalibrated photometric stereo, a photometric stereo image dataset containing objects of various shapes with complex reflectance properties and high-quality ground truth normals is still missing. In this paper, we introduce the 'DiLiGenT' dataset with calibrated Directional Lightings, objects of General reflectance with different shininess, and 'ground Truth' normals from high-precision laser scanning. We use our dataset to quantitatively evaluate state-of-the-art photometric stereo methods for general materials and unknown lighting conditions, selected from a newly proposed photometric stereo taxonomy emphasizing on non-Lambertian and uncalibrated methods. The dataset and evaluation results are made publicly available, and we hope it can serve as a benchmark platform that inspires future research. PMID- 29993474 TI - Hierarchical Scene Parsing by Weakly Supervised Learning with Image Descriptions. AB - This paper investigates a fundamental problem of scene understanding: how to parse a scene image into a structured configuration (i.e., a semantic object hierarchy with object interaction relations). We propose a deep architecture consisting of two networks: i) a convolutional neural network (CNN) extracting the image representation for pixel-wise object labeling and ii) a recursive neural network (RsNN) discovering the hierarchical object structure and the inter object relations. Rather than relying on elaborative annotations (e.g., manually labeled semantic maps and relations), we train our deep model in a weakly supervised learning manner by leveraging the descriptive sentences of the training images. Specifically, we decompose each sentence into a semantic tree consisting of nouns and verb phrases, and apply these tree structures to discover the configurations of the training images. Once these scene configurations are determined, then the parameters of both the CNN and RsNN are updated accordingly by back propagation. The entire model training is accomplished through an Expectation-Maximization method. Extensive experiments show that our model is capable of producing meaningful scene configurations and achieving more favorable scene labeling results on two benchmarks (i.e., PASCAL VOC 2012 and SYSU-Scenes) compared with other state-of-the-art weakly-supervised deep learning methods. In particular, SYSU-Scenes contains more than 5000 scene images with their semantic sentence descriptions, which is created by us for advancing research on scene parsing. PMID- 29993475 TI - Robust and Globally Optimal Manhattan Frame Estimation in Near Real Time. AB - Most man-made environments, such as urban and indoor scenes, consist of a set of parallel and orthogonal planar structures. These structures are approximated by the Manhattan world assumption, of which notion can be represented as a Manhattan Frame (MF). Given a set of inputs such as surface normals or vanishing points, we pose an MF estimation problem as a consensus set maximization that maximizes the number of inliers over the rotation search space. Conventionally this problem can be solved by a branch-and-bound framework which mathematically guarantees global optimality. However, the computational time of the conventional branch-and-bound algorithms is rather far from real-time. In this paper, we propose a novel bound computation method on an efficient measurement domain for MF estimation, i.e., the extended Gaussian image (EGI). By relaxing the original problem, we can compute the bound with a constant complexity, while preserving global optimality. Furthermore, we quantitatively and qualitatively demonstrate the performance of the proposed method for various synthetic and real-world data. We also show the versatility of our approach through three different applications: extension to multiple MF estimation, 3D rotation based video stabilization and vanishing point estimation (line clustering). PMID- 29993476 TI - FCSS: Fully Convolutional Self-Similarity for Dense Semantic Correspondence. AB - We present a descriptor, called fully convolutional self-similarity (FCSS), for dense semantic correspondence. Unlike traditional dense correspondence for estimating depth or optical flow, semantic correspondence estimation poses additional challenges due to intra-class appearance and shape variations among different instances within the same object or scene category. To robustly match points across semantically similar images, we formulate FCSS using local self similarity (LSS), which is inherently insensitive to intra-class appearance variations. LSS is incorporated through a proposed convolutional self-similarity (CSS) layer, where the sampling patterns and the self-similarity measure are jointly learned in an end-to-end and multi-scale manner. Furthermore, to address shape variations among object instances, we propose a convolutional affine transformer (CAT) layer that estimates explicit affine transformation fields at each pixel to transform the sampling patterns and corresponding receptive fields. As training data for semantic correspondence is rather limited, we propose to leverage object candidate priors provided in most existing datasets and also correspondence consistency between object pairs to enable weakly-supervised learning. Experiments demonstrate that FCSS significantly outperforms conventional handcrafted descriptors and CNN-based descriptors on various benchmarks. PMID- 29993477 TI - Constant-time Calculation of Zernike Moments for Detection with Rotational Invariance. AB - We construct a set of special complex-valued integral images and an algorithm that allows to calculate Zernike moments fast, namely in constant time. The technique is suitable for dense detection procedures, where the image is scanned by a sliding window at multiple scales, and where rotational invariance is required at the level of each window. We assume no preliminary image segmentation. Owing to the proposed integral images and binomial expansions, the extraction of each feature does not depend on the number of pixels in the window and thereby is an calculation. We analyze algorithmic properties of the proposition, such as: number of needed integral images, complex-conjugacy of integral images, number of operations involved in feature extraction, speed-up possibilities based on lookup tables. We also point out connections between Zernike and orthogonal Fourier--Mellin moments in the context of computations backed with integral images. Finally, we demonstrate three examples of detection tasks of varying difficulty. Detectors are trained on the proposed features by the RealBoost algorithm. When learning, the classifiers get acquainted only with examples of target objects in their upright position or rotated within a limited range. At the testing stage, generalization onto the full 360 degrees angle takes place automatically. PMID- 29993478 TI - Self Paced Deep Learning for Weakly Supervised Object Detection. AB - In a weakly-supervised scenario object detectors need to be trained using image level annotation alone. Since bounding-box-level ground truth is not available, most of the solutions proposed so far are based on an iterative, Multiple Instance Learning framework in which the current classifier is used to select the highest-confidence boxes in each image, which are treated as pseudo-ground truth in the next training iteration. However, the errors of an immature classifier can make the process drift, usually introducing many of false positives in the training dataset. To alleviate this problem, we propose in this paper a training protocol based on the self-paced learning paradigm. The main idea is to iteratively select a subset of images and boxes that are the most reliable, and use them for training. While in the past few years similar strategies have been adopted for SVMs and other classifiers, we are the first showing that a self paced approach can be used with deep-network-based classifiers in an end-to-end training pipeline. Our method is built on the fully-supervised Fast-RCNN architecture and can be applied to similar architectures which represent the input image as a bag of boxes. We show state-of-the-art results on Pascal VOC 2007-2010 and ILSVRC 2013. On ILSVRC 2013 our results based on a low-capacity AlexNet network outperform even those weakly-supervised approaches which are based on much higher-capacity networks. PMID- 29993479 TI - Tensor Based Method for Residual Water Suppression in H Magnetic Resonance Spectroscopic Imaging. AB - OBJECTIVE: Magnetic resonance spectroscopic imaging (MRSI) signals are often corrupted by residual water and artifacts. Residual water suppression plays an important role in accurate and efficient quantification of metabolites from MRSI. A tensor-based method for suppressing residual water is proposed. METHODS: A third-order tensor is constructed by stacking the Lowner matrices corresponding to each MRSI voxel spectrum along the third mode. A canonical polyadic decomposition (CPD) is applied on the tensor to extract the water component, and to subsequently remove it from the original MRSI signals. RESULTS: The proposed method applied on both simulated and in-vivo MRSI signals showed good water suppression performance. CONCLUSION: The tensor-based Lowner method has better performance in suppressing residual water in MRSI signals as compared to the widely-used subspace-based Hankel singular value decomposition (HSVD) method. SIGNIFICANCE: A tensor method suppresses residual water simultaneously from all the voxels in the MRSI grid and helps in preventing the failure of the water suppression in single voxels. PMID- 29993480 TI - Prediction of Abdominal Aortic Aneurysm Growth using Dynamical Gaussian Process Implicit Surface. AB - An Abdominal Aortic Aneurysm (AAA) is a form of vascular disease causing focal enlargement of the abdominal aorta. It affects a large part of the population, and in case of rupture, has up to 90% mortality rate. Recent clinical recom- mendations suggest that people with small aneurysms should be examined 3-36 months depending on the size, to monitor morphological changes. While advances in biomechanics provide state-of-the-art spatial estimates of stress distributions of AAAs, there are still limitations in modeling its time evolution and uncertainty qualification. To date, there are a few biomechanical frameworks that utilize longitudinal medical images, which would aid physicians in detecting small aneurysms with high risk of rupture. In this study, we use longitudinal computer tomography (CT) scans of AAAs that are captured at different times to predict the spatio-temporal evolution of AAAs' shape in future time. We consider a surface of 3D AAA as a manifold embedded in a scalar field over the three dimensional space. The changes of the scalar field propagate into the changes in the surface. For this formulation, we develop our Dynamical Gaussian Process Implicit Surface (DGPIS) model based on observed surfaces of 3D AAAs as visible variables while the scalar fields are hidden fields. First of all, we utilize the concept of the implicit surface field as a parameterization-free framework to describe a 3D shape. We then use Gaussian process regression to construct the field as an observation model from CT training image data. Furthermore, we propose a dynamic model to represent the evolution of the field. Finally, we derive the predicted surface from the predicted field. Our model is deployed on a real medical data set, which indicates its effectiveness. In addition, we discuss our prediction results with respect to ones from conventional analysis techniques. PMID- 29993481 TI - On the Relevance of Computing a Local Version of Sample Entropy in Cardiovascular Control Analysis. AB - OBJECTIVE: Traditional definition of sample entropy (SampEn), here referred to as global SampEn (GSampEn), provides a conditional entropy estimate that blurs the local statistical properties of the time series. We hypothesized that a local version of SampEn (LSampEn) might be more powerful in presence of determinism than GSampEn. METHODS: LSampEn was computed by calculating the probability of the current sample conditioned on each reference pattern and averaging it over all reference patterns. The improved ability of LSampEn compared to GSampEn was demonstrated by simulating deterministic periodic, deterministic chaotic and linear stochastic dynamics corrupted by additive noise and over real cardiovascular variability series recorded from 16 healthy subjects (max-min age range: 22-58 years) during incremental bicycle ergometer exercise. RESULTS: We found that: i) LSampEn is more robust in describing deterministic periodic or nonlinear features in presence of additive noise than GSampEn; ii) in association with a surrogate approach LSampEn is more powerful in detecting nonlinear dynamics than GSampEn; iii) LSampEn and GSampEn are equivalent in presence of stochastic linear dynamics; iv) only LSampEn can detect the decrease of complexity of heart period variability during bicycle exercise being a likely hallmark of sympathetic activation. CONCLUSION: LSampEn preserves the GSampEn capability in characterizing the complexity of short sequences but improves its reliability in presence of deterministic patterns featuring sharp state transitions and nonlinear dynamics. SIGNIFICANCE: Variations of complexity can be measured with a greater statistical power over short series using LSampEn especially when nonlinear features are present. PMID- 29993482 TI - In-Vivo Evaluation of Microultrasound and Thermometric Capsule Endoscopes. AB - Clinical endoscopy and colonoscopy are commonly used to investigate and diagnose disorders in the upper gastrointestinal tract and colon respectively. However, examination of the anatomically remote small bowel with conventional endoscopy is challenging. This and advances in miniaturization led to the development of video capsule endoscopy (VCE) to allow small bowel examination in a non-invasive manner. Available since 2001, current capsule endoscopes are limited to viewing the mucosal surface only due to their reliance on optical imaging. To overcome this limitation with submucosal imaging, work is under way to implement microultrasound (MUUS) imaging in the same form as VCE devices. This paper describes two prototype capsules, termed Sonocap and Thermocap, which were developed respectively to assess the quality of MUUS imaging and the maximum power consumption that can be tolerated for such a system. The capsules were tested in vivo in the oesophagus and small bowel of porcine models. Results are presented in the form of MUUS B-scans and safe temperature readings observed up to 100 mW in both biological regions. These results demonstrate that acoustic coupling and MUUS imaging can be achieved in vivo in the lumen of the bowel and the maximum power consumption that is possible for miniature MUUS systems. PMID- 29993483 TI - Sensory Stimulation Training for BCI System based on Somatosensory Attentional Orientation. AB - In this study, we propose a sensory stimulation training (SST) approach to improve the performance of a brain-computer interface (BCI) based on somatosensory attentional orientation (SAO). In this BCI, subjects imagine the tactile sensation and maintain the attention on the corresponding hand as if there was a tactile stimulus on the wrist skin. Twenty BCI naive subjects were recruited and randomly divided into a Control-Group and an SST-Group. In the Control-Group, subjects performed left hand and right hand SAO tasks in six consecutive runs (with 40 trials in each run), divided into three blocks with each having two runs. For the SST-Group, two runs included real tactile stimulation to the left or right hand (SST training block), between the first two (Pre-SST block) and the last two SAO runs (Post-SST block). Results showed that the SST-Group had a significantly improved performance of 9.4% between the last block and the first block after SST training (F(2,18) =11.11, p=0.0007); in contrast, no significant difference was found in the Control-Group between the first, second and the last block (F(2,18) = 2.07, p=0.1546), indicating no learning effect. The tactile sensation-induced oscillatory dynamics were similar to those induced by SAO. In the SST-Group, R2 discriminative information was enhanced around the somatosensory cortex due to the real sensory stimulation as compared with that in the Control-Group. Since the SAO mental task is inherently an internal process, the proposed SST method is meant as an adjuvant to SAO to facilitate subjects in achieving an initial SAO-based BCI control. PMID- 29993484 TI - Ultrasonic Micro-Elastography to Assess Biomechanical Properties of the Cornea. AB - OBJECTIVE: to both qualitatively and quantitatively investigate corneal biomechanical properties through an ultrasonic micro-elastography imaging system, which is potentially useful in diagnosis of diseases such as keratoconus, post refractive keratectasia and tracking treatment such as cross-linking surgery. METHODS: our imaging system has a dual frequency configuration, including a 4.5 MHz ring transducer to push the tissue and a confocally aligned 40 MHz needle transducer to track micron-level displacement. 2D/3D acoustic radiation force impulse (ARFI) imaging and the Young's modulus in the region of interest were performed on ex vivo porcine corneas that were either cross-linked using formalin solution or preloaded with IOPs from 5 mmHg to 30 mmHg. RESULTS: the increase of corneal stiffness and the change in cross-linked volume following formalin crosslinking could be precisely observed in the ARFI images and reflected by the reconstructed Young's modulus while the B-mode structural images remained almost unchanged. In addition, the relationship between the stiffness of the cornea and IOPs was investigated among twelve porcine corneas. The corneal stiffness is significantly different at various IOPs and has a tendency to become stiffer with increasing IOP. CONCLUSION: Our results demonstrate the principle of using ultrasonic micro-elastography techniques to image the biomechanical properties of the cornea. Integrating high-resolution ARFI imaging labelled with reconstructed Young's modulus and structural imaging of the cornea can potentially lead to a routinely performed imaging modality in the field of ophthalmology. PMID- 29993485 TI - Electrophysiological Muscle Classification Using Multiple Instance Learning and Unsupervised Time and Spectral Domain Analysis. AB - OBJECTIVE: Electrophysiological muscle classification (EMC) is a crucial step in the diagnosis of neuromuscular disorders. Existing quantitative techniques are not sufficiently robust and accurate to be reliably clinically used. Here, EMC is modeled as a multiple instance learning (MIL) problem and a system to infer unsupervised motor unit potential (MUP) labels and create supervised muscle classifications is presented. METHODS: The system has five main steps: MUP representation using morphological, stability, and near fiber parameters as well as spectral features extracted from wavelet coefficients; MUP feature selection using unsupervised Laplacian scores; MUP clustering using neighborhood distance entropy consistency to find representations of MUP normality and abnormality; muscle representation by embedding its MUP cluster associations in a feature vector; and muscle classification using support vector machines or random forests. RESULTS: The evaluation data consist of 63, 83, 93, and 84 sets of MUPs recorded in deltoid, vastus medialis, first dorsal interosseous, and tibialis anterior muscles, respectively. The proposed system discovered representations of normal, myopathic, and neurogenic MUPs for each specific muscle type and resulted in an average classification accuracy of 98%, which is higher than in previous works. CONCLUSION: Modeling EMC as an instance of the MIL solves the traditional problem of characterizing MUPs without full supervision. Furthermore, finding representations of MUP normality and abnormality using morphological, stability, near fiber, and spectral features improve muscle classification. SIGNIFICANCE: The proposed method is able to characterize MUPs with respect to disease categories, with no a priori information. PMID- 29993486 TI - Cellular Obstruction Clearance in Proximal Ventricular Catheters Using Low Voltage Joule Heating. AB - OBJECTIVE: Proximal obstruction due to cellular material is a major cause of shunt failure in hydrocephalus management. The standard approach to treat such cases involves surgical intervention which unfortunately is accompanied by inherent surgical risks and a likelihood of future malfunction. We report a prototype design of a proximal ventricular catheter capable of noninvasively clearing cellular obstruction. Methods: In-vitro cell-culture methods show that low-intensity ac signals successfully destroy a cellular layer in a localized manner by means of Joule heating induced hyperthermia. A detailed electrochemical model for determining the temperature distribution and ionic current density for an implanted ventricular catheter supports our experimental observations. RESULTS: In-vitro experiments with cells cultured in a plate as well as cells seeded in mock ventricular catheters demonstrated that localized heating between 43 degrees C and 48 degrees C caused cell death. This temperature range is consistent with hyperthermia. The electrochemical model verified that Joule heating due to ionic motion is the primary contributor to heat generation. CONCLUSION: Hyperthermia induced by Joule heating can clear cellular material in a localized manner. This approach is feasible to design a noninvasive self clearing ventricular catheter system. SIGNIFICANCE: A shunt system capable of clearing cellular obstruction could significantly reduce the need for future surgical interventions, lower the cost of disease management, and improve the quality of life for patients suffering from hydrocephalus. PMID- 29993487 TI - On the Feasibility of Automated Mechanical Ventilation Control Through EIT. AB - OBJECTIVE: This paper aims to demonstrate the feasibility of coupling electrical impedance tomography (EIT) with models of lung function in order to recover parameters and inform mechanical ventilation control. METHODS: A compartmental ordinary differential equation model of lung function is coupled to simulations of EIT, assuming accurate modeling and movement tracking, to generate time series values of bulk conductivity. These values are differentiated and normalized against the total air volume flux to recover regional volumes and flows. These ventilation distributions are used to recover regional resistance and elastance properties of the lung. Linear control theory is used to demonstrate how these parameters may be used to generate a patient-specific pressure mode control. RESULTS: Ventilation distributions are shown to be recoverable, with Euclidean norm errors in air flow below 9% and volume below 3%. The parameters are also shown to be recoverable, although errors are higher for resistance values than elastance. The control constructed is shown to have minimal seminorm resulting in bounded magnitudes and minimal gradients. CONCLUSION: The recovery of regional ventilation distributions and lung parameters is feasible with the use of EIT. These parameters may then be used in model based control schemes to provide patient-specific care. SIGNIFICANCE: For pulmonary-intensive-care patients mechanical ventilation is a life saving intervention, requiring careful calibration of pressure settings. Both magnitudes and gradients of pressure can contribute to ventilator induced lung injury. Retrieving regional lung parameters allows the design of patient-specific ventilator controls to reduce injury. PMID- 29993488 TI - Microwave Breast Imaging: Clinical Advances and Remaining Challenges. AB - OBJECTIVE: Microwave breast imaging has seen significant academic and commercial development in recent years, with four new operational microwave imaging systems used with patients since 2016. In this paper, a comprehensive review of these recent clinical advances is presented, comparing patient populations and study outcomes. For the first time, the designs of operational microwave imaging systems are compared in detail. METHODS: First, the current understanding of dielectric properties of human breast tissues is reviewed, considering evidence from operational microwave imaging systems and from dielectric properties measurement studies. Second, design features of operational microwave imaging systems are discussed in terms of advantages and disadvantages during clinical operation. RESULTS: Reported results from patient imaging trials are compared, contrasting the principal results from each trial. Additionally, clinical experience from each trial is highlighted, identifying desirable system design features for clinical use. CONCLUSIONS: Increasingly, evidence from patient imaging studies indicate that a contrast in dielectric properties between healthy and cancerous breast tissues exists. However, despite the significant and encouraging results from patient trials, variation still exists in the microwave imaging system design. SIGNIFICANCE: This study seeks to define the current state of the art in microwave breast imaging, and identify suitable design characteristics for ease of clinical use. PMID- 29993489 TI - Epileptic Seizure Detection in Long-Term EEG Recordings by Using Wavelet-Based Directed Transfer Function. AB - GOAL: The accurate automatic detection of epileptic seizures is very important in long-term electroencephalogram (EEG) recordings. In this study, the wavelet decomposition and the directed transfer function (DTF) algorithm were combined to present a novel wavelet-based directed transfer function (WDTF) method for the patient-specific seizure detection. METHODS: First, five subbands were extracted from 19-channel EEG signals by using wavelet decomposition in a sliding window. Second, the information flow characteristics of five subbands and full frequency band of EEG signals were calculated by the DTF method. The intensity of the outflow information was then used to reduce the feature dimensionality. Finally, all features were combined to identify interictal and ictal EEG segments by the support vector machine classifier. RESULTS: By using fivefold cross validation, the proposed method had achieved excellent performance with the average accuracy of 99.4%, the average selectivity of 91.1%, the average sensitivity of 92.1%, the average specificity of 99.5%, and the average detection rate of 95.8%. CONCLUSION: The WDTF method is able to enhance seizure detection results in long term EEG recordings of focal epilepsy patients. SIGNIFICANCE: This study may lead to the development of seizure detection system with high performance, thus reducing the workload of epileptologists and facilitating to take corresponding steps promptly after the seizure onset. The high-frequency activity in the epilepsy brain may be of great importance for investigating the pathological mechanism and treatment of seizure. PMID- 29993490 TI - Force Closure Mechanism Modeling for Musculoskeletal Multibody Simulation. AB - OBJECTIVE: Neuro-musculoskeletal multibody simulation (NMBS) seeks to optimize decision-making for patients with neuro-musculoskeletal disorders. In clinical practice, however, the inter-subject variability and the inaccessibility for experimental testing impede the reliable model identification. These limitations motivate the novel modeling approach termed as force closure mechanism modeling (FCM2). METHODS: FCM 2 expresses the dynamics between mutually articulating joint partners with respect to instantaneous screw axes (ISA) automatically reconstructed from their relative velocity state. Thereby, FCM2 reduces arbitrary open-chain multibody topologies to force closure n-link pendulums. Within a computational validation study on the human knee joint with implemented contact surfaces, we examine FCM2 as an underlying inverse dynamic model for computed muscle control. We evaluate predicted tibiofemoral joint quantities, i.e., kinematics and contact forces along with muscle moment arms, during muscle induced knee motion against the classic hinge joint model and experimental studies. RESULTS: Our NMBS study provided the proof-of-principle of the novel modeling approach. FCM2 freed us from assuming a certain joint formulation while correctly predicting the joint dynamics in agreement with the established methods. Although experimental results were closely predicted, owing to noise in the ISA estimation, muscle moment arms were overestimated (RISA = 0.84 < RHINGE = 0.97, RMSEISA = 13.18 mm > RMSEHINGE = 6.54 mm), identifying the robust ISA estimation as key to FCM2. CONCLUSION: FCM2 automatically derives the equations of motion in closed form. Moreover, it captures subject-specific joint function and, thereby, minimizes modeling and parameterization efforts. SIGNIFICANCE: Model derivation becomes driven by quantitative data available in clinical settings so that FCM2 yields a promising framework toward subject-specific NMBS. PMID- 29993491 TI - A Time-Reversal Imaging System for Breast Screening: Theory and Initial Phantom Results. AB - In this paper, a working ultrawideband (UWB) microwave imaging (MI) system using basic techniques is proposed to detect and localize a tumor model. The system harnesses the time reversal-decomposition of time reversal operator (DORT) signal processing method. We suggest a modified background Green's function and suitable spiral antennas for time reversal imaging of a breast cancer tumor. In this method, scatterings from a breast phantom are measured. Then, reflected signals are processed using the decomposition of time reversal (TR), known under French acronym DORT, algorithm. In a conventional TR imaging method, free-space Green's function is used for detection. However, in the present method, we employ cylindrical Green's functions of a two-layer medium. This makes a better model of the background medium for TR-DORT imaging. Also, the performance of TR-DORT detector against signal to clutter ratio, and its ability to detect and localize different shapes, sizes, and permittivity values of breast tumor are discussed. Furthermore, a fatty tissue phantom model is used to verify the results experimentally. The MI system is tested to localize a tumor within the breast Debye phantom at the frequency range of 3.1-10.6 GHz. The experimental results show the validity of our proposed system. PMID- 29993492 TI - A model for estimating the blood flow of the POLVAD pulsatile ventricular assist device. AB - OBJECTIVE: The aim of this work was to model the blood flow rate of the POLVAD MEV pulsatile ventricular assist device (VAD). An adequate flow rate is crucial to restore physiological cardiac output. Unfortunately, during clinical heart support, neither blood flows nor pressures can be measured within the device. In general, the flow rate depends on the control parameters and patient conditions. However, the patient's hemodynamic parameters are not constantly monitored. Therefore, blood flow must be evaluated based on the standard measurements from the device control unit. METHODS: The model identification data were taken from a research stand consisting of a VAD connected to a hybrid cardiovascular simulator. The studies were conducted under different work and control conditions. A compound model of a ventricular assist device was proposed. First, the driving pressure waveform for an idle run of the supply unit is modeled. Next, the blood flow is estimated based on the difference between the measured value of driving pressure and the modeled value for an idle run. RESULTS: The quality of the developed model is good (R=0.92) and similar for all tested cases, confirming the high versatility of the proposed solution. CONCLUSION: The blood flow rate is estimated based on standard signals from the device control unit; therefore, no additional measurements are necessary. SIGNIFICANCE: The developed model application in the VAD control unit will aid the selection of control parameters and might be useful for development of adaptive control system. A preliminary version of this work was reported at the [1]. PMID- 29993493 TI - Dielectric Properties of Ex Vivo Porcine Liver Tissue Characterized at Frequencies Between 5 and 500 kHz When Heated at Different Rates. AB - OBJECTIVE: The released energy during radio frequency thermal ablation therapy changes the dielectric properties of biological tissues. Understanding changes of dielectric properties of biological tissues during heating is fundamental to suitably model the medical procedure. The aim of this work is to obtain the thermal dependences of conductivity and permittivity of ex vivo porcine liver tissue at six frequencies from 5 to 500 kHz, during heating from 37 degrees C to 100 degrees C at three heating rates of approximately 0.1, 3, and 10 degrees C/min. METHODS: Two experimental setups using different heating sources and a four-needle electrode connected to an impedance analyzer were developed to evaluate the thermal dependencies. RESULTS: The results at a body temperature of 37 degrees C show a good agreement with the data reported in the literature. The conductivity initially shows an increase followed by a decrease, whereas the permittivity increases before a subsequent sharp decrease. Above 60 degrees C, different trends are observed for the three heating rates studied. CONCLUSION: The electric conductivity and permittivity show a similar behavior at all evaluated frequencies and heating rates. The observed abrupt change of the slope near 45 degrees C at a slow heating rate may be used to identify the region of reversible changes in the tissue. SIGNIFICANCE: These results confirm the connection among tissue dielectric properties, working frequency, and exposure time with thermal damage during heating. PMID- 29993494 TI - Understanding Irregularity Characteristics of Short-Term HRV Signals Using Sample Entropy Profile. AB - Sample entropy (), a popularly used "regularity analysis" tool, has restrictions in handling short-term segments (largely ) of heart rate variability (HRV) data. For such short signals, the estimate either remains undefined or fails to retrieve "accurate" regularity information. These limitations arise due to the extreme dependence of on its functional parameters, in particular the tolerance . Evaluating at a single random choice of parameter is a major cause of concern in being able to extract reliable and complete regularity information from a given signal. Here, we hypothesize that, finding a complete profile of (in contrast to a single estimate) corresponding to a data specific set of values may facilitate enhanced information retrieval from short-term signals. We introduce a novel and computationally efficient concept of profiling in order to eliminate existing inaccuracies seen in the case of estimation. Using three different HRV datasets from the PhysioNet database-first, real and simulated, second, elderly and young, and third, healthy and arrhythmic; we demonstrate better definiteness and classification performance of profile based estimates ( and ) when compared to conventional and estimates. Our novelty is to identify the importance of reliability in short-term signal regularity analysis, and our proposed approach aims to enhance both quality and quantity of information from any short-term signal. PMID- 29993495 TI - Automatic Early-Onset Free Flap Failure Detection for Implantable Biomedical Devices. AB - OBJECTIVE: Up to 10% of free flap cases are compromised, and without prompt intervention, amputation and even death can occur. Hourly monitoring improves salvage rates, but the gold standard for monitoring requires experienced personnel to operate and suffers from high false-positive rates as high as 31% that result in costly and unnecessary surgeries. In this paper, we investigate free flap patency monitoring using automatic hardware-only classification systems that eliminate the need for experienced personnel. The expected flow ranges of the antegrade and retrograde veins for breast reconstruction are studied using a syringe pump to create the laminar flow seen in veins. METHODS: Feature data extracted from the Doppler blood flow signals are analyzed for sensitivity, specificity, and false-positive rates. Hardware is built to perform the classification automatically in real-time and output a decision at the end of the observation period. RESULTS: Experimental results using the hardware-only classifier for a 50 ms window size show high sensitivity (96.75%), specificity (90.20%), and low false-positive rate (9.803%). The experimental and theoretical classification results show close agreement. CONCLUSION: This work indicates that automatic hardware-only classifiers can eliminate the need for experienced personnel to monitor free flap patency. SIGNIFICANCE: The hardware-only classification is amenable to a monolithic implementation and future studies should study a totally implantable wirelessly-powered blood flow classifier. The high classifier performance in a short window period indicates that duty-cycled powering can be used to extend the safe operational depth of an implant. This is particularly relevant for the difficult buried free flap applications. PMID- 29993496 TI - An Algorithm for Heart Rate Extraction from Acoustic Recordings at the Neck. AB - Heart rate is an important physiological parameter to assess the cardiac condition of an individual and is traditionally determined by attaching multiple electrodes on the chest of a subject to record the electrical activity of the heart. The installation and handling complexities of such systems does not prove feasible for a user to undergo a long-term monitoring in the home settings. A small-sized, battery-operated wearable monitoring device is placed on the suprasternal notch at neck to record acoustic signals containing information about breathing and cardiac sounds. The heart sounds obtained are heavily corrupted by the respiratory cycles and other external artifacts. This paper presents a novel algorithm for reliably extracting the heart rate from such acoustic recordings, keeping in mind the constraints posed by the wearable technology. The methodology constructs the Hilbert energy envelope of the signal by calculating its instantaneous characteristics to segment and classify a cardiac cycle into S1 and S2 sounds using their timing characteristics. The algorithm is tested on a dataset consisting of 13 subjects with an approximate data length of 75 hours and achieves an accuracy of 94.34%, an RMS error of 3.96 bpm and a correlation coefficient of 0.93 with reference to a commercial device in use. PMID- 29993498 TI - OxiMA: A Frequency-Domain Approach to Address Motion Artifacts in Photoplethysmograms for Improved Estimation of Arterial Oxygen Saturation and Pulse Rates. AB - OBJECTIVE: The purpose of this manuscript is to demonstrate that a new algorithm for estimating arterial oxygen saturation can be effective even with data corrupted by motion artifacts (MAs). METHODS: OxiMA, an algorithm based on the time-frequency components of a photoplethysmogram (PPG), was evaluated using 22 minute datasets recorded from 10 subjects during voluntarily-induced hypoxia, with and without subject-induced MAs. A Nellcor OxiMax transmission sensor was used to collect an analog PPG while reference oxygen saturation and pulse rate (PR) were collected simultaneously from an FDA-approved Masimo SET' Radical RDS-1 pulse oximeter. RESULTS: The performance of our approach was determined by computing the mean relative error between the PR/oxygen saturation estimated by OxiMA and the reference Masimo oximeter. The average estimation error using OxiMA was 3 beats/minute for PR and 3.24% for oxygen saturation, respectively. CONCLUSION: The results show that OxiMA has great potential for improving the accuracy of PR and oxygen saturation estimation during MAs. SIGNIFICANCE: This is the first study to demonstrate the feasibility of a reconstruction algorithm to improve oxygen saturation estimates on a dataset with MAs and concomitant hypoxia. PMID- 29993497 TI - Intraoperative robotic-assisted large-area high-speed microscopic imaging and intervention. AB - OBJECTIVE: Probe-based confocal endomicroscopy is an emerging high-magnification optical imaging technique that provides in-vivo and in-situ cellular-level imaging for real-time assessment of tissue pathology. Endomicroscopy could potentially be used for intraoperative surgical guidance, but it is challenging to assess a surgical site using individual microscopic images due to the limited field-of-view and difficulties associated with manually manipulating the probe. METHODS: In this paper, a novel robotic device for large-area endomicroscopy imaging is proposed, demonstrating a rapid, but highly accurate, scanning mechanism with image-based motion control which is able to generate histology like endomicroscopy mosaics. The device also includes, for the first time in robotic-assisted endomicroscopy, the capability to ablate tissue without the need for an additional tool. RESULTS: The device achieves pre-programmed trajectories with positioning accuracy of less than 30um, the image-based approach demonstrated that it can suppress random motion disturbances up to 1.25mm/s. Mosaics are presented from a range of ex-vivo human and animal tissues, over areas of more than 3mm, scanned in approximate 10s. CONCLUSION: This work demonstrates the potential of the proposed instrument to generate large-area, high-resolution microscopic images for intraoperative tissue identification and margin assessment. SIGNIFICANCE: This approach presents an important alternative to current histology techniques, significantly reducing the tissue assessment time, while simultaneously providing the capability to mark and ablate suspicious areas intraoperatively. PMID- 29993499 TI - Noninvasive magnetogastrography detects erythromycin-induced effects on the gastric slow wave. AB - OBJECTIVE: The prokinetic action of erythromycin is clinically useful in conditions associated with gastrointestinal hypomotility. Although erythromycin is known to affect the electrogastrogram, no studies have examined the effects that erythromycin has on gastric slow wave magnetic fields. METHODS: In this study, gastric slow wave activity was assessed simultaneously using non-invasive magnetogastrogram, electrogastrogram, and mucosal electromyogram recordings. Recordings were obtained for 30 minutes prior to and 60 minutes after intravenous administration of erythromycin at dosages of 3 mg/kg and 6 mg/kg. RESULTS: Magnetogastrogram (MGG) recordings showed significant changes in the percentage power distribution of gastric signal after infusion of both 3 mg/kg and 6 mg/kg erythromycin at t=1-5 min that persisted for 31-40 min after infusion. These changes agree with changes observed in the electromyogram. We did not observe any statistically significant difference in MGG amplitude before or after injection of either 3 mg/kg or 6 mg/kg erythromycin. Both 3 mg/kg and 6 mg/kg erythromycin infusion showed retrograde propagation with a statistically significant decrease in slow wave propagation velocity 11-20 min after infusion. Propagation velocity started returning towards baseline values after approximately 21-30 min for the 3 mg/kg dosage and after 31-40 min for a dosage of 6 mg/kg. CONCLUSION: Our results showed that the magnetic signatures were sensitive to disruptions in normal slow wave activity induced by pharmacological and prokinetic agents such as erythromycin. SIGNIFICANCE: This study shows that repeatable noninvasive bio electro-magnetic techniques can objectively characterize gastric dysrhythmias and may quantify treatment efficacy in patients with functional gastric disorders. PMID- 29993500 TI - Fast Forward-Dynamics Tracking Simulation: Application to Upper Limb and Shoulder Modeling. AB - OBJECTIVE: Musculoskeletal simulation can be used to estimate muscle forces in clinical movement studies. However, such simulations typically only target movement measurements and are not applicable to force exertion tasks which are commonly used in rehabilitation therapy. Simulations can also produce non physiological joint forces or be too slow for real-time clinical applications, such as rehabilitation with real-time feedback. The objective of this study is to propose and evaluate a new formulation of forward-dynamics assisted tracking simulation that incorporates measured reaction forces as targets or constraints without any additional computational cost. METHODS: We illustrate our method with idealized proof-of-concept models and evaluate it with two upper limb cases: tracking of hand reaction forces during an isometric force-generation task and constraining glenohumeral joint reaction forces for stability during arm elevation. RESULTS: We show that the addition of reaction force optimization terms within our simulations generates plausible muscle force predictions for these tasks, which are strongly related to reaction forces in addition to movement. Execution times for all models tested were not different when run with or without the reaction force optimization term, ensuring that the simulations are fast enough for real-time clinical applications. CONCLUSION: Our novel reaction force optimization term leads to more realistic shoulder reaction forces, without any additional computational costs. SIGNIFICANCE: Our formulation is not only valuable for shoulder simulations, but could be used in various clinical situations (e.g. for different joints and rehabilitation therapy tasks) where the direction and/or magnitude of reaction forces are of interest. PMID- 29993501 TI - Automated Detection of Convulsive Seizures Using a Wearable Accelerometer Device. AB - Epileptic seizure detection requires specialized approaches such as video/electroencephalography monitoring. However, these approaches are restricted mainly to hospital setting and requires video/EEG analysis by experts, which makes these approaches resource- and labor-intensive. In contrast, we aim to develop a wireless remote monitoring system based on a single wrist-worn accelerometer device, which is sensitive to multiple types of convulsive seizures and is capable of detecting seizures with short duration. Simple time domain features including a new set of Poincar'e plot based features were extracted from the active movement events recorded using a wrist-worn accelerometer device. The best features were then selected using the area under the ROC curve analysis. Kernelized support vector data description (SVDD) was then used to classify non seizure and seizure events. The proposed algorithm was evaluated on 5;576h of recordings from 79 patients and detected 40 (86:95%) of 46 convulsive seizures (generalized tonic-clonic (GTCS), psychogenic non-epileptic (PNES), and complex partial seizures (CPS)) from twenty patients with a total of 270 false alarms (1:16=24h). Furthermore, the algorithm showed a comparable performance (sensitivity 95:23% and false alarm rate 0:64=24h) with respect to existing unimodal and multi-modal methods for GTCS detection. The promising results shows the potential to build an ambulatory monitoring convulsive seizure detection system. A wearable accelerometer based seizure detection system would aid in continuous assessment of convulsive seizures in a timely and non-invasive manner. PMID- 29993502 TI - An Intracardiac Flow Based Electromagnetic Energy Harvesting Mechanism for Cardiac Pacing. AB - Contemporary cardiac implantable electronic devices such as pacemakers or event recorders are powered by primary batteries. Device replacement due to battery depletion may cause complications and is costly. The goal of energy harvesting devices is to power the implant with energy from intra-corporeal power sources such as vibrations and blood flow. By replacing primary batteries with energy harvesters, re-interventions can be avoided and the size of the total device might be reduced. This paper introduces a device with a lever which is deflected by the blood stream within right ventricular outflow tract (RVOT), an attractive site for cardiac pacing. The resulting torque is converted to electrical energy by an electromagnetic mechanism. The blood flow harvester weighs 6.4 g and has a volume of 2 cm$^{3}$, making the harvester small enough for catheter implantation. It was tested in an experimental setup mimicking flow conditions in the RVOT. The blood flow harvester generated a mean power of 14.39 8.38 W at 60 bpm (1 Hz) and up to 82.64 17.14 W at 200 bpm (3.33 Hz) during bench experiments at 1 m/s peak flow velocity. Therefore, it presents a viable alternative to power batteryless and leadless cardiac pacemakers. PMID- 29993503 TI - Computer-Aided Diagnostic System for Early Detection of Acute Renal Transplant Rejection Using Diffusion-Weighted MRI. AB - OBJECTIVE: Early diagnosis of acute renal transplant rejection (ARTR) is critical for accurate treatment. Although the current gold standard, diagnostic technique is renal biopsy, it is not preferred due to its invasiveness, long recovery time (1-2 weeks), and potential for complications, e.g., bleeding and/or infection. METHODS: This paper presents a computer-aided diagnostic (CAD) system for early ARTR detection using (3D + b-value) diffusion-weighted (DW) MRI data. The CAD process starts from kidney tissue segmentation with an evolving geometric (level set-based) deformable model. The evolution is guided by a voxel-wise stochastic speed function, which follows from a joint kidney-background Markov-Gibbs random field model accounting for an adaptive kidney shape prior and on-going kidney background visual appearances. A B-spline-based 3D data alignment is employed to handle local deviations due to breathing and heart beating. Then empirical cumulative distribution functions of apparent diffusion coefficients of the segmented DW-MRI at different b-values are collected as discriminatory transplant status features. Finally, a deep-learning-based classifier with stacked non negative constrained auto-encoders is employed to distinguish between rejected and non-rejected renal transplants. RESULTS: In our initial "leave-one-subject out" experiment on 100 subjects, 97.0% of the subjects were correctly classified. The subsequent four-fold and 10-fold cross-validations gave the average accuracy of 96.0% and 94.0%, respectively. CONCLUSION: These results demonstrate the promise of this new CAD system to reliably diagnose renal transplant rejection. SIGNIFICANCE: The technology presented here can significantly impact the quality of care of renal transplant patients since it has the potential to replace the gold standard in kidney diagnosis, biopsy. PMID- 29993504 TI - Fractional Wavelet Scattering Network and Applications. AB - OBJECTIVE: The present study introduces a fractional wavelet scattering network (FrScatNet), which is a generalized translation invariant version of the classical wavelet scattering network (ScatNet). METHODS: In our approach, the FrScatNet is constructed based on the fractional wavelet transform (FRWT). The fractional scattering coefficients are iteratively computed using FRWTs and modulus operators. The feature vectors constructed by fractional scattering coefficients are usually used for signal classification. In this work, an application example of FrScatNet is provided in order to assess its performance on pathological images. Firstly, the FrScatNet extracts feature vectors from patches of the original histological images under different orders. Then we classify those patches into target (benign or malignant) and background groups. And the FrScatNet property is analyzed by comparing error rates computed from different fractional orders respectively. Based on the above pathological image classification, a gland segmentation algorithm is proposed by combining the boundary information and the gland location. RESULTS: The error rates for different fractional orders of FrScatNet are examined and show that the classification accuracy is significantly improved in fractional scattering domain. We also compare the FrScatNet based gland segmentation method with those proposed in the 2015 MICCAI Gland Segmentation Challenge and our method achieves comparable results. CONCLUSION: The FrScatNet is shown to achieve accurate and robust results. More stable and discriminative fractional scattering coefficients for different are obtained by the FrScatNet in this work. SIGNIFICANCE: The added fractional order parameter is then able to analyze the signal in the fractional scattering domain. PMID- 29993505 TI - The Stabilizing Function of Superficial Shoulder Muscles Changes Between Single Plane Elevation and Reaching Tasks. AB - OBJECTIVE: The goal of the current study was to determine whether and how much the stabilizing role of the shoulder muscles changes as a function of humeral elevation and the plane of elevation. METHODS: A musculoskeletal model, comprising a personalized scapulohumeral rhythm, was used to calculate the ratio of shear over compressive force (stability ratio) of three rotator cuff muscles (supraspinatus, infraspinatus, subscapularis) and three superficial shoulder muscles (middle deltoid, clavicular part of pectoralis major, latissimus dorsi) during abduction, flexion and reaching movements. RESULTS: The range of the stability ratios was [+/-0.5] for the rotator cuff muscles compared to [+5,-2] for the superficial shoulder muscles. In the superior-inferior direction, the stability ratios of all muscles changed with humeral elevation and for infraspinatus, subscapularis, latissimus dorsi and deltoid also with the plane of elevation. In the anterior-posterior direction, the stability ratios of all muscles changed with humeral elevation, except for the deltoid, and with the plane of elevation, except for the supraspinatus. CONCLUSION: The rotator cuff muscles provide greater compression than shear forces during all tasks. The stabilizing function of the superficial shoulder muscles examined in this study varies during tasks. SIGNIFICANCE: The findings can be used to predict in which movements the shoulder joint becomes more unstable and can be applied to understand how shear and compressive forces change in populations with abnormal shoulder motion. PMID- 29993506 TI - Sockets for Limb Prostheses: A Review of Existing Technologies and Open Challenges. AB - In the prosthetics field, one of the most important bottlenecks is still the human-machine interface, namely the socket. Indeed, a large number of amputees still rejects prostheses or points out a low satisfaction level, due to a sub optimal interaction between the socket and the residual limb tissues. The aim of this paper is to describe the main parameters (displacements, stress, volume fluctuations and temperature) affecting the stump-socket interface and reducing the comfort/stability of limb prostheses. In this review, a classification of the different socket types proposed in the literature is reported, together with an analysis of advantages and disadvantages of the different solutions, from multiple viewpoints. The paper then describes the technological solutions available to face an altered distribution of stresses on the residual limb tissues, volume fluctuations affecting the stump overtime and temperature variations affecting the residual tissues within the socket. The open challenges in this research field are highlighted and the possible future routes are discussed, towards the ambitious objective of achieving an advanced socket able to self-adapt in real-time to the complex interplay of factors affecting the stump, during both static and dynamic tasks. PMID- 29993507 TI - Design and Development of Surgeon Augmented Endovascular Robotic System. AB - OBJECTIVE: Inadequate visual and force feedback while navigating surgical tools elevate the risk of endovascular procedures. It also poses occupational hazard due to repeated exposure to X-rays. A teleoperated robotic system that augments surgeon's actions is a solution. METHOD: We have designed and developed an endovascular robotic system that augments surgeon's actions using conventional surgical tools, as well as generates feedback in order to ensure safety during the procedure. The reaction force from vasculature is estimated from motor current that drives the surgical tool. Calibration required for force estimation is based on bilevel optimization. Input shaping is used in conjunction with a cascaded controller to avoid large responses due to faster inputs and to track tool position. The design, realization, and testing of our system are presented. RESULTS: The responses of the system in comparison with the dynamics model is similar vis-a-vis the same input commands. Any error in the position tracking is reduced by the cascaded controller. Phase-portrait analysis of the system showed that the system is stable. The reaction force estimation is validated against load cell measurements. The safety mechanism in the events of excessive reaction forces while interacting with vasculature is demonstrated. CONCLUSION AND SIGNIFICANCE: Our system is a step toward intelligent robots that can assist surgeons during endovascular procedures by monitoring and alerting the surgeons regarding detrimental parameters. It arrests any unintended excursions of the surgical tools or surgeon's actions. This will also eliminate the need for surgeons to be in radiation environment. PMID- 29993508 TI - Shared and Subject-Specific Dictionary Learning (ShSSDL) Algorithm for Multisubject fMRI Data Analysis. AB - OBJECTIVE: Analysis of functional magnetic resonance imaging (fMRI) data from multiple subjects is at the heart of many medical imaging studies, and approaches based on dictionary learning (DL) are recently noted as promising solutions to the problem. However, the DL-based methods for fMRI analysis proposed to date do not naturally extend to multisubject analysis. In this paper, we propose a DL algorithm for multisubject fMRI data analysis. METHODS: The proposed algorithm [named shared and subject-specific dictionary learning (ShSSDL)] is derived based on a temporal concatenation, which is particularly attractive for the analysis of multisubject task-related fMRI datasets. It differs from existing DL algorithms in both its sparse coding and dictionary update stages and has the advantage of learning a dictionary shared by all subjects as well as a set of subject-specific dictionaries. RESULTS: The performance of the proposed DL algorithm is illustrated using simulated and real fMRI datasets. The results show that it can successfully extract shared as well as subject-specific latent components. CONCLUSION: In addition to offering a new DL approach, when applied on multisubject fMRI data analysis, the proposed algorithm generates a group level as well as a set of subject-specific spatial maps. SIGNIFICANCE: The proposed algorithm has the advantage of learning simultaneously multiple dictionaries providing us with a shared as well discriminative source of information about the analyzed fMRI datasets. PMID- 29993509 TI - Model-Based Assessment of f-Wave Signal Quality in Patients With Atrial Fibrillation. AB - OBJECTIVE: The detection and analysis of atrial fibrillation (AF) in the ECG is greatly influenced by signal quality. The present study proposes and evaluates a model-based f-wave signal quality index (SQI), denoted , for use in the QRST cancelled ECG signal. METHODS: is computed using a harmonic f-wave model, allowing for variation in frequency and amplitude. The properties of are evaluated on both f-waves and P-waves using 378 12-lead ECGs, 1875 single-lead ECGs, and simulated signals. RESULTS: decreases monotonically when noise is added to f-wave signals, even for noise which overlaps spectrally with f-waves. Moreover, is shown to be closely associated with the accuracy of AF frequency estimation, where implies accurate estimation. When is used as a measure of f wave presence, AF detection performance improves: the sensitivity increases from 97.0% to 98.1% and the specificity increases from 97.4% to 97.8% when compared to the reference detector. CONCLUSION: The proposed SQI represents a novel approach to assessing f-wave signal quality, as well as to determining whether f-waves are present. SIGNIFICANCE: The use of improves the detection of AF and benefits the analysis of noisy ECGs. PMID- 29993510 TI - A Novel Approach for Real-Time Recognition of Epileptic Seizures Using Minimum Variance Modified Fuzzy Entropy. AB - OBJECTIVE: Validation of epileptic seizures annotations from long-term electroencephalogram (EEG) recordings is a tough and tedious task for the neurological community. It is a well-known fact that computerized qualitative methods thoroughly assess the complex brain dynamics toward seizure detection and proven as one of the acceptable clinical indicators. METHODS: This research study suggests a novel approach for real-time recognition of epileptic seizure from EEG recordings by a technique referred as minimum variance modified fuzzy entropy (MVMFzEn). Multichannel EEG recordings of 4.36 h of epileptic seizures and 25.74 h of normal EEG were considered. Signal processing techniques such as filters and independent component analysis were appropriated to reduce noise and artifacts. Unlike, the predefined fuzzy membership function, the modified fuzzy entropy utilizes relative energy as a membership function followed by scaling operation to obtain the feature. RESULTS: Results revealed that MVMFzEn drops abruptly during an epileptic activity and this fact was used to set a threshold. An automated threshold derived from MVMFzEn assesses the classification efficiency of the given data during validation. It was observed from the results that the proposed method yields a classification accuracy of 100% without the use of any classifier. CONCLUSION: The graphical user interface was designed in MATLAB to automatically label the normal and epileptic segments in the long-term EEG recordings. SIGNIFICANCE: The ground truth clinical validation using validation specificity and validation sensitivity confirms the suitability of the proposed technique for automated annotation of epileptic seizures in real time. PMID- 29993511 TI - Tensor Sparse Representation for 3-D Medical Image Fusion Using Weighted Average Rule. AB - OBJECTIVE: The technique of fusing multimodal medical images into single image has a great impact on the clinical diagnosis. The previous works mostly concern the two-dimensional (2-D) image fusion performed on each slice individually, that may destroy the 3-D correlation across adjacent slices. To address this issue, this paper proposes a novel 3-D image fusion scheme based on Tensor Sparse Representation (TSR). METHODS: First, each medical volume is arranged as a three order tensor, and represented by TSR with learned dictionaries. Second, a novel "weighted average" rule, calculated from the tensor sparse coefficients using 3-D local-to-global strategy. The weights are then employed to combine the multimodal medical volumes through weighted average. RESULTS: The visual and objective comparisons show that the proposed method is competitive to the existing methods on various medical volumes in different imaging modalities. CONCLUSION: The TSR based 3-D fusion approach with weighted average rule can preserve the 3-D structure of medical volume, and reduce the low contrast and artifacts in fused product. SIGNIFICANCE: The designed weights offer the effective assigned weights and accurate salience levels measure, which can improve the performance of fusion approach. PMID- 29993512 TI - Passive wrist stiffness: The influence of handedness. AB - OBJECTIVE: This paper reports on the quantification of passive wrist joint stiffness and investigates the potential influence of handedness and gender on stiffness estimates. METHODS: We evaluated the torque-angle relationship during passive wrist movements in 2 degrees of freedom (into flexion-extension and radial-ulnar deviation) in thirteen healthy subjects using a wrist robot. Experimental results determined intra-subject differences between dominant and non-dominant wrist and inter-subject differences between male and female participants. RESULTS: We found differences in the magnitude of passive stiffness of left and right-hand dominant males and right-hand dominant females suggesting that the dominant hand tends to be stiffer than the non-dominant hand. Left hand stiffness magnitude was found to be 37% higher than the right-hand stiffness magnitude in the left-handed male group and the right-hand stiffness magnitude was 11% and 40% higher in the right-handed male and female groups respectively. Other joint stiffness features such as the orientation and the anisotropy of wrist stiffness followed the expected pattern from previous studies. CONCLUSION: The observed difference in wrist stiffness between the dominant and non-dominant limb is likely due to biomechanical adaptations to repetitive asymmetric activities (such as squash, tennis, basketball or activities of daily living such as writing, teeth brushing, etc.). SIGNIFICANCE: Understanding and quantifying handedness influence on stiffness may have critical implication for the optimization of surgical and rehabilitative interventions. PMID- 29993513 TI - Non-invasive Treatment Efficacy Evaluation for HIFU Therapy Based on Magneto Acousto-Electrical Tomography. AB - OBJECTIVE: As a novel non-invasive modality of oncotherapy or stroke treatment, high intensity focused ultrasound (HIFU) has drawn more and more attention in the past decades. Whereas, real-time temperature monitoring and treatment efficacy evaluation are still the key issues for HIFU therapy. METHODS: Based on the temperature-conductivity relation of tissues with a sharp conductivity variation of irreversible thermocoagulation at 69 degrees C, a non-invasive method of treatment efficacy evaluation for HIFU ablation using the magneto-acousto electrical tomography (MAET) technology is theoretically studied. By applying the nonlinear Khokhlov-Zabolotskaya-Kuznetsov equation and Pennes equation, a cylindrical model is established to simulate the distributions of pressure, temperature and conductivity with the consideration of harmonic components. RESULTS: The MAET signals are simulated to analyze the characteristics of the peak amplitude and the axial interval of the two clusters generated by the conductivity boundary of HIFU ablation. CONCLUSION: The axial interval can be used as the indictor to evaluate the size of HIFU ablation with the minimum axial width of one wavelength. SIGNIFICANCE: The favorable results demonstrate the feasibility of real-time treatment efficacy evaluation for HIFU therapy using the MAET technology and suggest potential applications in clinical practice. PMID- 29993514 TI - An Entropy-regularized Framework for Detecting Copy Number Variants. AB - The detection of DNA copy number variants (CNVs) is essential for the diagnosis and prognosis of multiple diseases including cancer. Array-based comparative genomic hybridization (aCGH) is a technique to find these aberrations. The available methods for CNV discovery are often predicated on several critical assumptions based on which various regularizations are employed. However, most of the resulting problems are not differentiable and finding their optimums needs massive computations. This paper addresses a new entropic regularization which is significantly fast and robust against various types of noise. The proposed problem takes advantage of the quadratic Renyi's entropy estimation which is not convex, but the half-quadratic programming gives an efficient solution with guaranteed convergence. We further theoretically prove that minimizing the Renyi's entropy estimation would induce the sparsity and smoothness, two salient and desired features for recovered aCGH profiles. Extensive experimental results on simulated and real datasets illustrate the robustness and speed of the proposed method in comparison to the state-of-the-art algorithms. PMID- 29993515 TI - Predicting Athlete Ground Reaction Forces and Moments from Spatio-temporal Driven CNN Models. AB - The accurate prediction of 3D ground reaction forces and moments (GRF/Ms) outside the laboratory setting would represent a watershed for on-field biomechanical analysis. To extricate the biomechanist's reliance on ground embedded force plates, this study sought to improve on an earlier Partial Least Squares (PLS) approach by using deep learning to predict 3D GRF/Ms from legacy marker-based motion capture sidestepping trials, ranking multivariate regression of GRF/Ms from five convolutional neural network (CNN) models. In a possible first for biomechanics, tactical feature engineering techniques were used to compress space time and facilitate fine-tuning from three pre-trained CNNs, from which a model derivative of ImageNet called 'CaffeNet' achieved the strongest average correlation to ground truth GRF/Ms r(Fmean) 0.9881 and r(Mmean) 0.9715 (rRMSE 4.31 and 7.04 %). These results demonstrate the power of CNN models to facilitate real-world multivariate regression with practical application for spatio-temporal sports analytics. PMID- 29993516 TI - Tensor Based Temporal and Multi-layer Community Detection for Studying Brain Dynamics During Resting State fMRI. AB - OBJECTIVE: In recent years, resting state fMRI has been widely utilized to understand the functional organization of the brain for healthy and disease populations. Recent studies show that functional connectivity during resting state is a dynamic process. Studying this temporal dynamics provides a better understanding of the human brain compared to static network analysis. METHODS: In this paper, a new tensor based temporal and multi-layer community detection algorithm is introduced to identify and track the brain network community structure across time and subjects. The framework studies the temporal evolution of communities in fMRI connectivity networks constructed across different regions of interests (ROIs). The proposed approach relies on determining the subspace that best describes the community structure using Tucker decomposition of the tensor. RESULTS: The brain dynamics are summarized into a set of functional connectivity states that are repeated over time and subjects. The dynamic behavior of the brain is evaluated in terms of consistency of different subnetworks during resting state. The results illustrate that some of the networks, such as the default mode, cognitive control and bilateral limbic networks, have low consistency over time indicating their dynamic behavior. CONCLUSION: The results indicate that the functional connectivity of the brain is dynamic and the detected community structure experiences smooth temporal evolution. SIGNIFICANCE: The work in this paper provides evidence for temporal brain dynamics during resting state through dynamic multi-layer community detection which enables us to better understand the behavior of different subnetworks. PMID- 29993517 TI - Cross-Frequency Transfer Entropy Characterize Coupling of Interacting Nonlinear Oscillators in Complex Systems. AB - The purpose of this study is to introduce a method in quantifying cross-frequency information transfer to characterize directional couplers between irregular oscillations in complex systems. Importantly, the method should be able to reflect the intrinsic mechanism of interacting oscillations faithfully. Six types of interacting oscillators, including phase-amplitude, amplitude-amplitude, and component-amplitude cross-frequency transfer entropy as well as their inverse transfer entropies, are within our scope in untangling the brain connectivity. Challenges with nonlinear and nonstationary patterns are designed to validate the robustness of the proposed method. We suggest this approach could be effective in identifying driving and responding elements of interacting oscillators across different time scales. Meanwhile, an atlas of interacting oscillators in sleep is constructed. High-frequency amplitude can inversely drive low-frequency phase stronger than the standard phase-amplitude coupling, and the low-frequency amplitude can be the driving force to the high-frequency amplitude in addition to the low-frequency phase. Unlike the standard phase-amplitude coupling, the proposed cross-frequency transfer entropy is applicable to quantify the interactions across phases, amplitudes or even the components without methodological adjustments. Meanwhile, the exploration of causal relationship enables the identification of the driving force of information flow. PMID- 29993518 TI - Detecting Abnormal Pattern of Epileptic Seizures via Temporal Synchronization of EEG Signals. AB - OBJECTIVE: Synchronization phenomena of epileptic electroencephalography (EEG) have long been studied. In this study, we aim at investigating the spatial temporal synchronization pattern in epileptic human brains using the spectral graph theoretic features extracted from scalp EEG and developing an efficient multivariate approach for detecting seizure onsets in real-time. METHODS: A complex network model is used for representing the recurrence pattern of EEG signals, based on which the temporal synchronization patterns are quantified using spectral graph theoretic features. Furthermore, a statistical control chart is applied to the extracted features over time for monitoring the transits from normal to epileptic states in multivariate EEG systems. RESULTS: Our method is tested on 23 patients from CHB-MIT Scalp EEG database. The results show that the graph theoretic feature yields a high sensitivity (98%) and low latency (6 seconds) on average, and seizure onsets in 18 patients are 100% detected. CONCLUSION: Our approach validates the increased temporal synchronization in epileptic EEG and achieves a comparable detection performance to previous studies. SIGNIFICANCE: We characterize the temporal synchronization patterns of epileptic EEG using network structures. In addition, the significant changes in temporal synchronization enable a patient-specific approach for real-time seizure detection, which is applicable for personalized diagnosis and treatment purposes. PMID- 29993519 TI - Model-Based Analysis of Electrode Placement and Pulse Amplitude for Hippocampal Stimulation. AB - OBJECTIVE: The ideal form of a neural-interfacing device is highly dependent upon the anatomy of the region with which it is meant to interface. Multiple-electrode arrays provide a system that can be adapted to various neural geometries. Computational models of stimulating systems have proven useful for evaluating electrode placement and stimulation protocols, but have yet to be adequately adapted to the unique features of the hippocampus. METHODS: As an approach to understanding potential memory restorative devices, an admittance method-NEURON model was constructed to predict the direct and synaptic response of a region of the rat dentate gyrus to electrical stimulation of the perforant path. RESULTS: A validation of estimated local field potentials against experimental recordings is performed and results of a bilinear electrode placement and stimulation amplitude parameter search are presented. CONCLUSION: The parametric analysis presented herein suggests that stimulating electrodes placed between the lateral and medial perforant path, near the crest of the dentate gyrus, yield a larger relative population response to given stimuli. SIGNIFICANCE: Beyond deepening understanding of the hippocampal tissue system, establishment of this model provides a method to evaluate candidate stimulating devices and protocols. PMID- 29993520 TI - Reducing the Computational Complexity of EEG Source Localization With Cortical Patch Decomposition and Optimal Electrode Selection. AB - OBJECTIVE: Real-time implementation of EEG source localization can be employed in a broad area of applications such as clinical diagnosis of neurologic diseases and brain-computer interface. However, a power-efficient, low-complexity, and real-time implementation of EEG source localization is still challenging due to extensive iterations in the solutions. In this study, two techniques are introduced to reduce the computational burden of the subspace-based MUltiple SIgnal Classification (MUSIC) algorithm. METHODS: To shrink the exhaustive search inherent in MUSIC, the cortex is parsed into cortical regions. A novel nomination procedure involving a dictionary learning step will pick a number of regions to be searched for the active sources. In addition, a new electrode selection algorithm based on the Cramer-Rao bound of the errors is introduced to pick the best set of an arbitrary number of electrodes out of the total. RESULTS: The performance of the proposed techniques were evaluated using simulated EEG signal under variation of different parameters such as the number of nominated regions, the signal to noise ratio, and the number of electrodes. The proposed techniques can reduce the computational complexity by up to $90?%$. Furthermore, the proposed techniques were tested on EEG data from an auditory oddball experiment. CONCLUSION: A good concordance was observed in the comparison of the topographies and the localization errors derived from the proposed technique and regular MUSIC. SIGNIFICANCE: Such reduction can be exploited in the real-time, long-run, and mobile monitoring of cortical activity for clinical diagnosis and research purposes. PMID- 29993521 TI - Automatic Identification of Reentry Mechanisms and Critical Sites During Atrial Tachycardia by Analyzing Areas of Activity. AB - OBJECTIVE: Atrial tachycardia (AT) still poses a major challenge in catheter ablation. Although state-of-the-art electroanatomical mapping systems allow to acquire several thousand intracardiac electrograms (EGMs), algorithms for diagnostic analysis are mainly limited to the amplitude of the signal (voltage map) and the local activation time (LAT map). We applied spatio-temporal analysis of EGM activity to generate maps indicating reentries and diastolic potentials, thus identifying and localizing the driving mechanism of AT. METHODS: First, the time course of active surface area ASA is determined during one basic cycle length (BCL). The chamber cycle length coverage cCLC reflects the relative duration within one BCL for which activity was present in each individual atrium. A local cycle length coverage lCLC is computed for circular subareas with 20 mm diameter. The simultaneous active surface area sASA is determined to indicate the spatial extent of depolarizing tissue. RESULTS: Combined analysis of these spatial scales allowed to correctly identify and localize the driving mechanism: cCLC values of 100% were indicative for atria harbouring a reentrant driver. lCLC could detect micro reentries within an area of 1.65 $?pm$ 1.28 cm $^2$ in simulated data and differentiate them against focal sources. Middiastolic potentials, being potential targets for catheter ablation, were identified as areas showing confined activity based on sASA values. CONCLUSION: The concept of spatio-temporal activity analysis proved successful and correctly indicated the tachycardia mechanism in 20 simulated AT scenarios and three clinical data sets. SIGNIFICANCE: Automatic interpretation of intracardiac mapping data could help to improve the treatment strategy in complex cases of AT. PMID- 29993522 TI - Mortality Prediction in Severe Congestive Heart Failure Patients with Multifractal Point-Process Modeling of Heartbeat Dynamics. AB - Multifractal analysis of human heartbeat dynamics has been demonstrated to provide promising markers of Congestive Heart Failure (CHF). Yet, it crucially builds on the interpolation of RR intervals series, which has been generically performed with limited links to CHF pathophysiology. We devise a novel methodology estimating multifractal autonomic dynamics from heartbeat-derived series defined in the continuous time. We hypothesize that markers estimated from our novel framework are also effective for mortality prediction in severe CHF. We merge multifractal analysis within a methodological framework based on inhomogeneous point process models of heartbeat dynamics. Specifically, wavelet coefficients and wavelet leaders are computed over measures extracted from instantaneous statistics of probability density functions characterizing and predicting the time until the next heartbeat event occurs. The proposed approach is tested on data from 94 CHF patients, aiming at predicting survivor and non survivor individuals as determined after a 4 years follow up. Instantaneous markers of vagal and sympatho-vagal dynamics display power-law scaling for a large range of scales, from s to s. Using standard SVM algorithms, the proposed inhomogeneous point-process representation based multifractal analysis achieved the best CHF mortality prediction accuracy of 79.11 % (sensitivity 90.48%, specificity 67.74%). Our results suggest that heartbeat scaling and multifractal properties in CHF patients are not generated at the sinus-node level, but rather by the intrinsic action of vagal short-term control and of sympatho-vagal fluctuations associated with circadian cardiovascular control, especially within the VLF band. These markers might provide critical information in devising a clinical tool for individualized prediction of survivor and non-survivor CHF patients. PMID- 29993524 TI - Viscosity Prediction in a Physiologically Controlled Ventricular Assist Device. AB - OBJECTIVE: We present a novel machine learning model to accurately predict the blood-analog viscosity during support of a pathological circulation with a rotary ventricular assist device (VAD). The aim is the continuous monitoring of the hematocrit (HCT) of VAD patients with the benefit of a more reliable pump flow estimation and a possible early detection of adverse events, such as bleeding or pump thrombosis. METHODS: A large dataset was generated with a blood pump connected to a hybrid mock circulation by varying the pump speed, the physiological requirements of the modeled circulation, and the viscosity of the blood-analog. The inlet pressure and the intrinsic signals of the pump were considered as inputs for the model. Gaussian process yielded models with the best performance, which were then combined using a variant of stacked generalization to derive the final model. The final model was evaluated with unseen testing data from the dataset created. RESULTS: For these data, the model yielded a mean absolute deviation of 1.81% from the true HCT, while it proved to correctly predict the direction of the HCT change. It showed to be independent of the set speed and of the condition of the simulated cardiovascular circulation. CONCLUSION: The accuracy of the prediction model allows an improvement of the quality of flow estimators and the detection of adverse events at an early stage. The evaluation of this approach with blood is suggested for further validation. SIGNIFICANCE: Its clinical application could provide the clinicians with reliable and important hemodynamic information of the patient and, thus, enhance patient monitoring and supervision. PMID- 29993523 TI - Ballistocardiogram-Based Approach to Cuffless Blood Pressure Monitoring: Proof of Concept and Potential Challenges. AB - OBJECTIVE: The goal was to propose and establish the proof of concept of an ultraconvenient cuffless blood pressure monitoring approach based on the ballistocardiogram. METHODS: The proposed approach monitors blood pressure by exploiting two features in the whole-body head-to-foot ballistocardiogram measured using a force plate: the time interval between the first ("I") and second ("J") major waves ("I-J interval") for diastolic pressure and the amplitude between the J and third major ("K") waves ("J-K amplitude") for pulse pressure. The efficacy of the approach was examined in 22 young healthy volunteers by investigating the diastolic pressure monitoring performance of pulse transit time, pulse arrival time, and ballistocardiogram's I-J interval, and the systolic pressure monitoring performance of pulse transit time and I-J interval in conjunction with ballistocardiogram's J-K amplitude. RESULTS: The I-J interval was comparable to pulse transit time and pulse arrival time in monitoring diastolic pressure, and the J-K amplitude could provide meaningful improvement to pulse transit time and I-J interval in monitoring systolic pressure. CONCLUSION: The ballistocardiogram may contribute toward ultraconvenient and more accurate cuffless blood pressure monitoring. SIGNIFICANCE: The proposed approach has potential to complement the pulse transit time technique for cuffless blood pressure monitoring in two ways. First, it may be integrated with pulse transit time to enable independent monitoring of diastolic and systolic pressures via the J-K amplitude. Second, it may even enable diastolic and systolic pressure monitoring from the ballistocardiogram alone. PMID- 29993525 TI - Conductivity Anisotropy Influence on Acoustic Sources for Magnetoacoustic Tomography With Magnetic Induction. AB - OBJECTIVE: As the multi-physics imaging approach, magnetoacoustic tomography with magnetic induction (MAT-MI) attracts more and more attentions, focusing on image reconstruction for conductivity isotropic tissues. METHODS: By introducing vector analyses to electromagnetic stimulation and magnetoacoustic excitation for a single-layer cylindrical conductivity anisotropic model, the acoustic source strength (ASS) of MAT-MI is derived in explicit formula and the influence of the anisotropic conductivity tensor is also analyzed. RESULTS: Theoretical and numerical studies demonstrate that the ASS generated at the tissue boundary is composed of an alternating current (AC) fluctuation and a direct current (DC) bias, where the distribution of the AC fluctuation with respect to the spatial angle exhibits a double-period cosine function, and the DC bias remains constant at each angle. The dependences of the AC fluctuation and the DC bias on the anisotropic component ratio (ACR) and the conductivity tensor are proved by numerical results, which are also verified by the special cases of the zero AC fluctuation for the conductivity isotropic medium and the negative DC bias of the low-conductivity medium. CONCLUSION: With the measurements of the ASS around the model, the anisotropic conductivity tensor can be reconstructed by the amplitudes of the AC fluctuation and the DC bias with the conductivity of the isotropic surrounding medium. SIGNIFICANCE: The favorable results provide a new method for anisotropic conductivity measurement, and suggest the application potential of MAT-MI in biomedical imaging and nondestructive testing for conductivity anisotropic tissues. PMID- 29993526 TI - Using Machine Learning and a Combination of Respiratory Flow, Laryngeal Motion, and Swallowing Sounds to Classify Safe and Unsafe Swallowing. AB - OBJECTIVE: The aim of this research was to develop a swallowing assessment method to help prevent aspiration pneumonia. The method uses simple sensors to monitor swallowing function during an individual's daily life. METHODS: The key characteristics of our proposed method are as follows. First, we assess swallowing function by using respiratory flow, laryngeal motion, and swallowing sound signals recorded by simple sensors. Second, we classify whether the recorded signals correspond to healthy subjects or patients with dysphagia. Finally, we analyze the recorded signals using both a feature extraction method (linear predictive coding) and a machine learning method (support vector machine). RESULTS: Based on our experimental results for 140 healthy subjects (54.5 32.5 years old) and 52 patients with dysphagia (75.5 20.5 years old), our proposed method could achieve 82.4% sensitivity and 86.0% specificity. CONCLUSION: Although 20% of testing sample sets were erroneously classified, we conclude that our proposed method may facilitate screening examinations of swallowing function. SIGNIFICANCE: In combination with the portable sensors, our proposed method is worth utilizing for noninvasive swallowing assessment. PMID- 29993527 TI - Hap-Pro: a wearable haptic device for proprioceptive feedback. AB - OBJECTIVE: Myolectric hand prostheses have reached a considerable technological level and gained an increasing attention in assistive robotics. However, their abandonment rate remains high, with unintuitive control and lack of sensory feedback being major causes. Among the different types of sensory information, proprioception, e.g. information on hand aperture, is crucial to successfully perform everyday actions. Despite the many attempts in literature to restore and convey this type of feedback, much remains to be done to close the action perception loop in prosthetic devices. METHODS: With this as motivation, in this work we introduce HapPro, a wearable, non-invasive haptic device that can convey proprioceptive information for a prosthetic hand. The device was used with an under-actuated, simple to control anthropomorphic robotic hand, providing information on the level of hand aperture by mapping it to the position of a wheel that can run on the user's forearm. Tests with 43 able bodied subjects and one amputee subject were conducted in order to quantify the effectiveness of HapPro as a feedback device. RESULTS: HapPro provided a good level of accuracy for item discrimination. Participants also reported the device to be intuitive and effective in conveying proprioceptive cues. Similar results were obtained in the proof-of-concept experiment with an amputee subject. CONCLUSIONS: Results show that HapPro is able to convey information on the opening of a prosthetic hand in a non-invasive way. SIGNIFICANCE: Using this device for proprioceptive feedback could improve usability of myoelectric prostheses, potentially reducing abandonment and increasing quality of life for their users. PMID- 29993528 TI - Model-based Sparse-to-dense Image Registration for Realtime Respiratory Motion Estimation in Image-guided Interventions. AB - OBJECTIVE: Intra-interventional respiratory motion estimation is becoming a vital component in modern radiation therapy delivery or high intensity focused ultrasound systems. The treatment quality could tremendously benefit from more accurate dose delivery using realtime motion tracking based on magnetic-resonance (MR) or ultrasound (US) imaging techniques. However, current practice often relies on indirect measurements of external breathing indicators, which has an inherently limited accuracy. In this work, we present a new approach that is applicable to challenging realtime capable imaging modalities like MR-Linac scanners and 3D-US by employing contrast-invariant feature descriptors. METHODS: We combine GPU-accelerated image-based realtime tracking of sparsely distributed feature points and a dense patient-specific motion-model for regularisation and sparse-to-dense interpolation within a unified optimisation framework. RESULTS: We achieve highly accurate motion predictions with landmark errors of approximately 1 mm for MRI (and approximately 2 mm for US) and substantial improvements over classical template tracking strategies. CONCLUSION: Our technique can model physiological respiratory motion more realistically and deals particularly well with the sliding of lungs against the rib cage. SIGNIFICANCE: Our model-based sparse-to-dense image registration approach allows for accurate and realtime respiratory motion tracking in image-guided interventions. PMID- 29993529 TI - Proposal and Validation of a Knee Measurement System for Patients with Osteoarthritis. AB - OBJECTIVE: Currently, most measurements of knee joint function are obtained through observation and patient-reported outcomes. This paper proposes an implementation and validation of a knee monitor to measure quantitative joint data in multiple degrees of freedom. The proposed system is configurable with minimal patient interaction and no frame-alignment calibration procedure is required for measurement after visually placing/replacing sensors on patients. METHODS: A mobile software system was developed using a method of extracting clinical knee angles based on attitude estimations from independent wearable sensors. Validation was performed using a robot phantom and results were compared with a gold standard motion capture system. Two instrumentation placements (lateral and posterior) were examined. RESULTS: A posterior sensor placement was determined to provide the most repeatable results through multiple degrees of freedom and measurement accuracy approached a gold standard motion capture technology with low root mean square error (flexion: 3.34 degrees , internal/external rotation: 2.18 degrees , varus/valgus: 1.44 degrees ). CONCLUSION: The proposed system is simple to use and convenient for use in ambulatory or unsupervised environments for joint measurement, however, it was shown that accuracy can be sensitive to sensor placement. SIGNIFICANCE: This system would be beneficial for obtaining quantitative patient data or tracking functional activity in variable environments, providing clinicians with indications of how patients' knees function during activity, potentially permitting more individualized care and recommendations. PMID- 29993530 TI - Closed-Loop Lumped Parameter Modeling of Hemodynamics During Cirrhogenesis in Rats. AB - OBJECTIVE: Cirrhosis is the common end stage of any given chronic liver disease, developing after persistent destruction and regeneration of parenchymal liver cells. The associated architectural distortion increases the intrahepatic vascular resistance, leading to portal hypertension and systemic circulatory disorders. This study investigates the impact of the changing vascular resistances on the hepatic and global circulation hemodynamics during cirrhogenesis. METHODS: Cirrhogenesis was revisited using the thioacetamide rat model (N = 20). Rats were sacrificed at weeks 0, 6, 12, and 18. For each time point, three-dimensional vascular geometries were created by combining hepatic vascular corrosion casting with MUCT imaging. Morphological quantification of the trees branching topology provided the input for a lobe-specific lumped parameter model of the liver that was coupled to a closed-loop model of the entire circulation of the rat. Hemodynamics was simulated in physiological and pathological circumstances. RESULTS: The simulations showed the effect of the liver vascular resistances (driven by the hepatic venous resistance increase) on liver hemodynamics with portal hypertension observed after 12 weeks. The closed loop model was further adapted to account for systemic circulatory compensation mechanisms and disorders frequently observed in cirrhosis and simulated their impact on the hepatic, systemic, and pulmonary hemodynamics. CONCLUSION: The simulations explain how vascular changes due to cirrhosis severely disrupt both hepatic and global hemodynamics. SIGNIFICANCE: This study is a priori the first to model the rat's entire blood circulation during cirrhogenesis. Since it is able to simulate cirrhosis main characteristics, the model may be translated to humans for the assessment of liver interventions. PMID- 29993531 TI - Topological Properties of the Structural Brain Network in Autism via epsilon Neighbor Method. AB - OBJECTIVE: Topological characteristics of the brain can be analyzed using structural brain networks constructed by diffusion tensor imaging (DTI). When a brain network is constructed by the existing parcellation method, the structure of the network changes depending on the scale of parcellation and arbitrary thresholding. To overcome these issues, we propose to construct brain networks using the improved $?varepsilon $-neighbor construction, which is a parcellation free network construction technique. METHODS: We acquired DTI from 14 control subjects and 15 subjects with autism. We examined the differences in topological properties of the brain networks constructed using the proposed method and the existing parcellation between the two groups. RESULTS: As the number of nodes increased, the connectedness of the network decreased in the parcellation method. However, for brain networks constructed using the proposed method, connectedness remained at a high level even with an increase in the number of nodes. We found significant differences in several topological properties of brain networks constructed using the proposed method, whereas topological properties were not significantly different for the parcellation method. CONCLUSION: The brain networks constructed using the proposed method are considered as more realistic than a parcellation method with respect to the stability of connectedness. We found that subjects with autism showed the abnormal characteristics in the brain networks. These results demonstrate that the proposed method may provide new insights to analysis in the structural brain network. SIGNIFICANCE: We proposed the novel brain network construction method to overcome the shortcoming in the existing parcellation method. PMID- 29993532 TI - DeepIGeoS: A Deep Interactive Geodesic Framework for Medical Image Segmentation. AB - Accurate medical image segmentation is essential for diagnosis, surgical planning and many other applications. Convolutional Neural Networks (CNNs) have become the state-of-the-art automatic segmentation methods. However, fully automatic results may still need to be refined to become accurate and robust enough for clinical use. We propose a deep learning-based interactive segmentation method to improve the results obtained by an automatic CNN and to reduce user interactions during refinement for higher accuracy. We use one CNN to obtain an initial automatic segmentation, on which user interactions are added to indicate mis-segmentations. Another CNN takes as input the user interactions with the initial segmentation and gives a refined result. We propose to combine user interactions with CNNs through geodesic distance transforms, and propose a resolution-preserving network that gives a better dense prediction. In addition, we integrate user interactions as hard constraints into a back-propagatable Conditional Random Field. We validated the proposed framework in the context of 2D placenta segmentation from fetal MRI and 3D brain tumor segmentation from FLAIR images. Experimental results show our method achieves a large improvement from automatic CNNs, and obtains comparable and even higher accuracy with fewer user interventions and less time compared with traditional interactive methods. PMID- 29993533 TI - Distributed Very Large Scale Bundle Adjustment by Global Camera Consensus. AB - The increasing scale of Structure-from-Motion is fundamentally limited by the conventional optimization framework for the all-in-one global bundle adjustment. In this paper, we propose a distributed approach to coping with this global bundle adjustment for very large scale Structure-from-Motion computation. First, we derive the distributed formulation from the classical optimization algorithm ADMM, Alternating Direction Method of Multipliers, based on the global camera consensus. Then, we analyze the conditions under which the convergence of this distributed optimization would be guaranteed. In particular, we adopt over relaxation and self-adaption schemes to improve the convergence rate. After that, we propose to split the large scale camera-point visibility graph in order to reduce the communication overheads of the distributed computing. The experiments on both public large scale SfM data-sets and our very large scale aerial photo sets demonstrate that the proposed distributed method clearly outperforms the state-of-the-art method in efficiency and accuracy. PMID- 29993534 TI - Wasserstein CNN: Learning Invariant Features for NIR-VIS Face Recognition. AB - Heterogeneous face recognition (HFR) aims at matching facial images acquired from different sensing modalities with mission-critical applications in forensics, security and commercial sectors. However, HFR presents more challenging issues than traditional face recognition because of the large intra-class variation among heterogeneous face images and the limited availability of training samples of cross-modality face image pairs. This paper proposes the novel Wasserstein convolutional neural network (WCNN) approach for learning invariant features between near-infrared (NIR) and visual (VIS) face images (i.e., NIR-VIS face recognition). The low-level layers of the WCNN are trained with widely available face images in the VIS spectrum, and the high-level layer is divided into three parts: the NIR layer, the VIS layer and the NIR-VIS shared layer. The first two layers aim at learning modality-specific features, and the NIR-VIS shared layer is designed to learn a modality-invariant feature subspace. The Wasserstein distance is introduced into the NIR-VIS shared layer to measure the dissimilarity between heterogeneous feature distributions. W-CNN learning is performed to minimize the Wasserstein distance between the NIR distribution and the VIS distribution for invariant deep feature representations of heterogeneous face images. To avoid the over-fitting problem on small-scale heterogeneous face data, a correlation prior is introduced on the fully-connected WCNN layers to reduce the size of the parameter space. This prior is implemented by a low-rank constraint in an end-to-end network. The joint formulation leads to an alternating minimization for deep feature representation at the training stage and an efficient computation for heterogeneous data at the testing stage. Extensive experiments using three challenging NIR-VIS face recognition databases demonstrate the superiority of the WCNN method over state-of-the-art methods. PMID- 29993535 TI - Feedback Convolutional Neural Network for Visual Localization and Segmentation. AB - Feedback is a fundamental mechanism existing in the human visual system, but has not been explored deeply in designing computer vision algorithms. In this paper, we claim that feedback plays a critical role in understanding convolutional neural networks (CNNs), e.g., how a neuron in CNN describes an object's pattern, and how a collection of neurons form comprehensive perception to an object. To model the feedback in CNNs, we propose a novel model named Feedback CNN and develop two new processing algorithms, i.e., neural pathway pruning and pattern recovering. We have mathematically proven that the proposed method can reach local optimum. Note that Feedback CNN belongs to weakly supervised methods and can be trained only using category-level labels. But it possesses powerful capability to accurately localize and segment category-specific objects. We conduct extensive visualization analysis, and the results reveal the close relationship between neurons and object parts in Feedback CNN. Finally, we evaluate the proposed Feedback CNN over the tasks of weakly supervised object localization and segmentation, and the experimental results on ImageNet and Pascal VOC show that our method remarkably outperforms the state-of-the-art ones. PMID- 29993536 TI - Error Backprojection Algorithms for Non-Line-of-Sight Imaging. AB - Recent advances in computer vision and inverse light transport theory have resulted in several non-line-of-sight imaging techniques. These techniques use photon time-of-flight information encoded in light after multiple, diffuse reflections to reconstruct a three-dimensional scene. In this paper, we propose and describe two iterative backprojection algorithms, the additive error backprojection (AEB) and multiplicative error backprojection (MEB), whose goal is to improve the reconstruction of the scene under investigation over non-iterative backprojection algorithms. We evaluate the proposed algorithms' performance applied to simulated and real data (gathered from an experimental setup where the system needs to reconstruct an unknown scene). Results show that the proposed iterative algorithms are able to provide better reconstruction than the unfiltered, non-iterative backprojection algorithm for both simulated and physical scenes, however are more sensitive to errors in the light transport model. PMID- 29993537 TI - NOVIFAST: A Fast Algorithm for Accurate and Precise VFA MRI Mapping. AB - In quantitative magnetic resonance mapping, the variable flip angle (VFA) steady state spoiled gradient recalled echo (SPGR) imaging technique is popular as it provides a series of high resolution weighted images in a clinically feasible time. Fast, linear methods that estimate maps from these weighted images have been proposed, such as DESPOT1 and iterative re-weighted linear least squares. More accurate, non-linear least squares (NLLS) estimators are in play, but these are generally much slower and require careful initialization. In this paper, we present NOVIFAST, a novel NLLS-based algorithm specifically tailored to VFA SPGR mapping. By exploiting the particular structure of the SPGR model, a computationally efficient, yet accurate and precise map estimator is derived. Simulation and in vivo human brain experiments demonstrate a twenty-fold speed gain of NOVIFAST compared with conventional gradient-based NLLS estimators while maintaining a high precision and accuracy. Moreover, NOVIFAST is eight times faster than the efficient implementations of the variable projection (VARPRO) method. Furthermore, NOVIFAST is shown to be robust against initialization. PMID- 29993538 TI - Unsupervised Reverse Domain Adaptation for Synthetic Medical Images via Adversarial Training. AB - To realize the full potential of deep learning for medical imaging, large annotated datasets are required for training. Such datasets are difficult to acquire due to privacy issues, lack of experts available for annotation, underrepresentation of rare conditions, and poor standardization. The lack of annotated data has been addressed in conventional vision applications using synthetic images refined via unsupervised adversarial training to look like real images. However, this approach is difficult to extend to general medical imaging because of the complex and diverse set of features found in real human tissues. We propose a novel framework that uses a reverse flow, where adversarial training is used to make real medical images more like synthetic images, and clinically relevant features are preserved via self-regularization. These domain-adapted synthetic-like images can then be accurately interpreted by networks trained on large datasets of synthetic medical images. We implement this approach on the notoriously difficult task of depth-estimation from monocular endoscopy which has a variety of applications in colonoscopy, robotic surgery, and invasive endoscopic procedures. We train a depth estimator on a large data set of synthetic images generated using an accurate forward model of an endoscope and an anatomically-realistic colon. Our analysis demonstrates that the structural similarity of endoscopy depth estimation in a real pig colon predicted from a network trained solely on synthetic data improved by 78.7% by using reverse domain adaptation. PMID- 29993539 TI - Convective-Dispersion Modeling in 3D Contrast-Ultrasound Imaging for the Localization of Prostate Cancer. AB - Despite being the solid tumor with the highest incidence in western men, prostate cancer (PCa) still lacks reliable imaging solutions that can overcome the need for systematic biopsies. Dynamic contrast-enhanced ultrasound imaging (DCE-US) allows us to quantitatively characterize the vascular bed in the prostate, due to its ability to visualize an intravenously administered bolus of contrast agents. Previous research has demonstrated that DCE-US parameters related to the vascular architecture are useful markers for the localization of PCa lesions. In this paper, we propose a novel method to assess the convective dispersion (D) and velocity (v) of the contrast bolus spreading through the prostate from three dimensional (3D) DCE-US recordings. By assuming that D and v are locally constant, we solve the convective-dispersion equation by minimizing the corresponding regularized least-squares problem. 3D multiparametric maps of D and v were compared with 3D histopathology retrieved from the radical prostatectomy specimens of six patients. With a pixel-wise area under the receiver operating characteristic curve of 0.72 and 0.80, respectively, the method shows diagnostic value for the localization of PCa. PMID- 29993540 TI - Development of an MRI-Compatible High-Intensity Focused Ultrasound Phased Array Transducer Dedicated for Breast Tumor Treatment. AB - High-intensity focused ultrasound (HIFU) under magnetic resonance imaging (MRI) guidance can achieve a noninvasive and precise ablation of the solid tumor. In the study, an MRI-compatible 1-MHz 16-channel ring-shaped transducer was developed to minimize the burn risk of breast skin and perform volumetric ablation for short treatment time. The measured electroacoustic conversion efficiency of the transducer was 50.90% +/- 5. The transducer could produce a point and a quasi-hollow-cylinder lesion in a thermal-sensitive phantom or an ex vivo pork by tuning the phase of each element. It may achieve volumetric ablation of 1.5 cm3 when the point lesion is located inside the hollow lesion. Ex vivo ablation experiments showed that the transducer could cause a coagulative necrosis in the pork from the surrounded subcutaneous fat by 5 mm without fat damage. The temperature and region of the pork ablation were quantified by MRI technique. There was no MRI interference from HIFU and vice versa while both systems operated concurrently. PMID- 29993542 TI - Coupling myocardium and vortex dynamics in diverging-wave echocardiography. AB - Echocardiography is widely used to provide critical left ventricular indices describing myocardial motion and blood inflow velocity. Tissue motion and blood flow are strongly connected and interdependent in the ventricle. During cardiac relaxation, rapid filling leads to the formation of a vortical blood flow pattern. In this work, we introduce a high-frame-rate method to track vortex dynamics alongside myocardium motion, in a single heartbeat. Cardiac triplex imaging (B-mode + tissue Doppler + color Doppler) was obtained by insonating the left ventricle with diverging waves. We used coherent compounding with integrated motion compensation to obtain high-quality Bmode images. Tissue Doppler was retrieved and the septal and lateral velocities of the mitral annulus were deduced. A rate of ~80 triplex images/s was obtained. Vortex dynamics was analyzed by Doppler vortography. BVS (blood vortex signature) maps were used to track the vortex and compute core vorticities. The sequence was implemented in a Verasonics scanner with a 2.5 MHz phased array, and tested in vivo in 12 healthy volunteers. Two main peaks appeared on the vorticity curves. These peaks were synchronized with the mitral inflow velocities, with a small delay. We observed a relationship between the tissue and vortex waveforms, though also with a delay, which denoted the lag between the wall and the flow motion. Clinical diastolic indices combining basal and mitral inflow velocities (E/A ratio and E/e' ratio) were determined and compared with those measured using a conventional ultrasound scanner; a good correlation was obtained (r 2 = 0:96). High-frame-rate Doppler echocardiography enabled us to retrieve time-resolved dynamics of the myocardium and vortex flow within the same cardiac cycle. Coupling wallflow analysis could be of clinical relevance for early diagnosis of filling impairment. PMID- 29993541 TI - Effect of Model Thrombus Volume and Elastic Modulus on Magnetomotive Ultrasound Signal Under Pulsatile Flow. AB - Direct ultrasonic imaging of arterial and venous thrombi could aid in diagnosis and treatment planning by providing rapid and cost-effective measurements of thrombus volume and elastic modulus. Toward this end, it was demonstrated that open-air magnetomotive ultrasound (MMUS) provides specific contrast to superparamagnetic iron oxide-labeled model thrombi embedded in gelatin-based blood vessel-mimicking flow phantoms. MMUS was performed on model thrombi in the presence of pulsatile flow that mimics cardiac-induced motion found in real vasculature. The MMUS signal and contrast-to-noise ratio (CNR) were measured across a range of physiologically relevant thrombus volumes and elastic moduli. Model thrombus volumes as small as 0.5 ml were shown to be detectable (CNR > 1) over the entire range of elastic moduli tested (3.5-40 kPa). It was also found that MMUS signal and CNR are increased with increasing thrombus volume ( ) and decreasing elastic modulus ( ), while variations in pulsatile flow rate had little effect. These findings demonstrate that MMUS has promise as a direct in vivo thrombosis imaging modality for quantifying thrombus volume and stiffness. PMID- 29993544 TI - Nonlinear Frequency-Sweep Correction of Tunable Electromagnetic Sources. AB - Tunable electromagnetic (EM) sources, such as voltage-controlled oscillators, micro-electromechanical systems, or diode lasers are often required to be linear during frequency-sweep modulation. In many cases, it might also be sufficient that the degree of the nonlinearity can be well controlled. Without further efforts, these conditions are rarely achieved using free-running sources. Based on a predistortion voltage ramp, we develop in this paper a simple and universal method that minimizes the nonlinear frequency response of tunable EM sources. Using a current-driven quantum cascade laser as an example, we demonstrate that the nonlinearity can easily be reduced by a factor of ten when using a single distortion parameter . In the investigation of the IR absorption spectrum of ozone at 10 , an even better reduction of the frequency-scale error by two orders of magnitude is obtained by using the predistortion method to generate an essentially purely quadratic sweep frequency dependence that can be inverted easily to retrieve precise molecular line positions. After having tested our method on a variety of EM sources, we anticipate a wide range of applications in a variety of fields. PMID- 29993543 TI - Plane-Wave Imaging Improves Single-Track Location Shear Wave Elasticity Imaging. AB - Single-track location shear wave elasticity imaging (STL-SWEI) is immune to speckle bias, but the quality of the images is depth dependent. We hypothesize that plane-wave imaging can reduce the depth dependence of STL-SWEI. To test this hypothesis, we developed a novel technique known as plane-wave STL-SWEI (pSTL SWEI). To evaluate the pSTL-SWEI's potential, we performed studies on phantoms and excised murine pancreatic tumors. The mean shear wave speeds measured with STL-SWEI and pSTL-SWEI were similar. However, the elastographic signal-to-noise ratio (SNRe) of pSTL-SWEI elastograms was noticeably higher than that produced with STL-SWEI. Specifically, we observed an improvement in SNRe ranging from 39.9%-55.1%, depending on tissue stiffness. The spatial resolution of pSTL-SWEI elastograms was 2.7%-12.1% lower than that produced with STL-SWEI. pSTL-SWEI elastograms displayed higher contrast-to-noise ratio (CNRe) than those produced with STL-SWEI, especially when imaging was performed with low push pulse intensities and low pulse durations. PMID- 29993545 TI - A +/-0.3 ppm Oven-Controlled MEMS Oscillator Using Structural Resistance-Based Temperature Sensing. AB - This paper presents a 77.7-MHz silicon microelectromechanical-systems oven controlled oscillator (MEMS OCXO) that uses the structural resistance ( ) of the resonator as an embedded temperature sensor. The exhibits a large temperature coefficient of resistance and is used as a self-temperature sensor to accurately and locally monitor the temperature of the resonator. A high-Q capacitive cross sectional Lame-mode resonator fabricated using the nanogap high aspect-ratio combined poly- and single-crystal silicon process (HARPSS) is used as the frequency selective element. A silicon resistor micro-oven is implemented on the MEMS die adjacent to the resonator and the ensemble is wafer-level packaged in vacuum to yield a 2 mm mm MEMS die. The micro-oven resistor is automatically controlled by the analog loop to provide active temperature stabilization for the resonator. A resistance temperature detector (RTD) circuit, high-gain loop filter, and heater amplifier are implemented as the analog micro-oven control loop. To further boost the frequency stability, a digital feedforward calibration path which uses the digitized RTD output to fine tune the phase shift of the sustaining amplifier is added to the system. The silicon MEMS OCXO achieves +/ 0.3-ppm frequency stability from -25 degrees C to 85 degrees C. The microresonator is interfaced with a sustaining amplifier implemented in Taiwan Semiconductor Manufacturing Company 0.35-s CMOS process, consuming 16 mA from a 3.2-V supply. PMID- 29993546 TI - Barometric Effect in Vapor-Cell Atomic Clocks. AB - Vapor-cell atomic clocks are compact and high-performance frequency references employed in various applications ranging from telecommunication to global positioning systems. Environmental sensitivities are often the main sources of long-term instabilities of the clock frequency. Among these sensitivities, the environmental pressure shift describes the clock frequency change with respect to the environmental pressure variations. We report here on our theoretical and experimental analysis of the environmental pressure shift on rubidium atomic frequency standards (RAFSs) operated under open atmosphere. By using an unsealed high-performance laser-pumped rubidium standard, we demonstrate that the deformation of the vapor-cell volume induced by the environmental pressure changes (i.e., barometric effect) is the dominant environmental pressure shift in a standard laboratory environment. An experimental barometric coefficient of /hPa is derived, in good agreement with theory and with previously reported measurements of frequency shifts of RAFS operated when transiting to vacuum. PMID- 29993547 TI - Mutual Learning Between Saliency and Similarity: Image Cosegmentation via Tree Structured Sparsity and Tree Graph Matching. AB - This paper proposes a unified mutual learning framework based on image hierarchies, which integrates structured sparsity with tree-graph matching to conquer the problem of weakly supervised image cosegmentation. We focus on the interaction between two common-object properties: saliency and similarity. Most existing cosegmentation methods only pay emphasis on either of them. The proposed method realizes the learning of the prior knowledge for structured sparsity with the help of treegraph matching, which is capable of generating object-oriented salient regions. Meanwhile, it also reduces the searching space and computational complexity of tree-graph matching with the attendance of structured sparsity. We intend to thoughtfully exploit the hierarchically geometrical relationships of coherent objects. Experimental results compared with the state-of-thearts on benchmark datasets confirm that the mutual learning framework are capable of effectively delineating co-existing object patterns in multiple images. PMID- 29993548 TI - Interacting Tracklets for Multi-object Tracking. AB - In this paper, we propose to exploit the interactions between non-associable tracklets to facilitate multi-object tracking. We introduce two types of tracklet interactions, close interaction and distant interaction. The close interaction imposes physical constraints between two temporally overlapping tracklets and more importantly, allows us to learn local classifiers to distinguish targets that are close to each other in the spatiotemporal domain. The distant interaction, on the other hand, accounts for the higher-order motion and appearance consistency between two temporally isolated tracklets. Our approach is modeled as a binary labeling problem and solved using the efficient Quadratic Pseudo-Boolean Optimization (QPBO). It yields promising tracking performance on the challenging PETS09 and MOT16 dataset. Our code will be made publicly available upon the acceptance of the manuscript. PMID- 29993549 TI - Eye Fixation Assisted Video Saliency Detection via Total Variation-based Pairwise Interaction. AB - As human visual attention is naturally biased towards foreground objects in a scene, it can be used to extract salient objects in video clips. In this work, we proposed a weakly supervised learning based video saliency detection algorithm utilizing eye fixations information from multiple subjects. Our main idea is to extend eye fixations to saliency regions step by step. First, visual seeds are collected using multiple color space geodesic distance based seed region mapping with filtered and extended eye fixations. This operation helps raw fixation points spread to the most likely salient regions, namely, visual seed regions. Second, in order to seize the essential scene structure from video sequences, we introduce the total variance based pairwise interaction model to learn the potential pairwise relationship between foreground and background within a frame or across video frames. In this vein, visual seed regions eventually grow into salient regions. Compared with previous approaches the generated saliency maps has two most outstanding properties: integrity and purity, which are conductive to segment the foreground and significant to the follow-up tasks. Extensive quantitative and qualitative experiments on various video sequences demonstrate that the proposed method outperforms state-of-theart image and video saliency detection algorithms. PMID- 29993550 TI - Context-Aware Asset Search for Graphic Design. AB - Graphic design tools provide powerful controls for expert-level design creation, but the options can often be overwhelming for novices. This paper proposes Context-Aware Asset Search tools that take the current state of the user's design into account, thereby providing search and selections that are compatible with the current design and better fit the user's needs. In particular, we focus on image search and color selection, two tasks that are central to design. We learn a model for compatibility of images and colors within a design, using crowdsourced data. We then use the learned model to rank image search results or color suggestions during design. We found counterintuitive behavior using conventional training with pairwise comparisons for image search, where models with and without compatibility performed similarly. We describe a data collection procedure that alleviates this problem. We show that our method outperforms baseline approaches in quantitative evaluation, and we also evaluate a prototype interactive design tool. PMID- 29993551 TI - Visual Analytics in Deep Learning: An Interrogative Survey for the Next Frontiers. AB - Deep learning has recently seen rapid development and received significant attention due to its state-of-the-art performance on previously-thought hard problems. However, because of the internal complexity and nonlinear structure of deep neural networks, the underlying decision making processes for why these models are achieving such performance are challenging and sometimes mystifying to interpret. As deep learning spreads across domains, it is of paramount importance that we equip users of deep learning with tools for understanding when a model works correctly, when it fails, and ultimately how to improve its performance. Standardized toolkits for building neural networks have helped democratize deep learning; visual analytics systems have now been developed to support model explanation, interpretation, debugging, and improvement. We present a survey of the role of visual analytics in deep learning research, which highlights its short yet impactful history and thoroughly summarizes the state-of-the-art using a human-centered interrogative framework, focusing on the Five W's and How (Why, Who, What, How, When, and Where). We conclude by highlighting research directions and open research problems. This survey helps researchers and practitioners in both visual analytics and deep learning to quickly learn key aspects of this young and rapidly growing body of research, whose impact spans a diverse range of domains. PMID- 29993552 TI - Data-Adaptive Spatiotemporal ERP Cleaning for Single-Trial BCI Implementation. AB - This paper presents a data-adaptive approach to enhance the discriminative information of event-related potential (ERP) for the implementation of a brain computer interface (BCI). The use of single-trial ERP in a real-time BCI application is challenging, due to its inherent noise contamination. Usually, multiple-trial ERPs are averaged to derive discriminative features of different classes by reducing their noise effects. Time-domain filtering is implemented here using an array wavelet transform. Sometimes, several channels can carry the signals, which are irrelevant to actual EPR information against the respective stimuli. A spatial filtering method based on clustering is introduced, to suppress such channels if any. Hence, the single-trial ERP is filtered in both the spatial and temporal domains to improve its discriminative features. The spatial-temporal discriminate analysis is employed to derive the features leading to the performance of target and non-target classification by using linear discriminant analysis. The proposed method is validated using a data set recorded from our experiments. The experimental results show that the performance of the proposed method is superior to that of the recently developed algorithms for single-trial ERP classification. PMID- 29993553 TI - XGBFEMF: An XGBoost-Based Framework for Essential Protein Prediction. AB - Essential proteins as a vital part of maintaining the cells' life play an important role in the study of biology and drug design. With the generation of large amounts of biological data related to essential proteins, an increasing number of computational methods have been proposed. Different from the methods which adopt a single machine learning method or an ensemble machine learning method, this paper proposes a predicting framework named by XGBFEMF for identifying essential proteins, which includes a SUB-EXPAND-SHRINK method for constructing the composite features with original features and obtaining the better subset of features for essential protein prediction, and also includes a model fusion method for getting a more effective prediction model. We carry out experiments on Yeast data to assess the performance of the XGBFEMF with ROC analysis, accuracy analysis, and top analysis. Meanwhile, we set up experiments on E. coli data for the validation of performance. The test results show that the XGBFEMF framework can effectively improve many essential indicators. In addition, we analyze each step in the XGBFEMF framework; our results show that both each step of the SUB-EXPAND-SHRINK method as well as the step of multi-model fusion can improve prediction performance. PMID- 29993554 TI - Exploring the Robustness of the Parsimonious Reconciliation Method in Host Symbiont Cophylogeny. AB - The aim of this paper is to explore the robustness of the parsimonious host symbiont tree reconciliation method under editing or small perturbations of the input. The editing involves making different choices of unique symbiont mapping to a host in the case where multiple associations exist. This is made necessary by the fact that the tree reconciliation model is currently unable to handle such associations. The analysis performed could however also address the problem of errors. The perturbations are re-rootings of the symbiont tree to deal with a possibly wrong placement of the root specially in the case of fast-evolving species. In order to do this robustness analysis, we introduce a simulation scheme specifically designed for the host-symbiont cophylogeny context, as well as a measure to compare sets of tree reconciliations, both of which are of interest by themselves. PMID- 29993555 TI - ChromStruct 4: A Python Code to Estimate the Chromatin Structure from Hi-C Data. AB - A method and a stand-alone Python(TM) code to estimate the 3D chromatin structure from chromosome conformation capture data are presented. The method is based on a multiresolution, modified-bead-chain chromatin model, evolved through quaternion operators in a Monte Carlo sampling. The solution space to be sampled is generated by a score function with a data-fit part and a constraint part where the available prior knowledge is implicitly coded. The final solution is a set of 3D configurations that are compatible with both the data and the prior knowledge. The iterative code, provided here as additional material, is equipped with a graphical user interface and stores its results in standard-format files for 3D visualization. We describe the mathematical-computational aspects of the method and explain the details of the code. Some experimental results are reported, with a demonstration of their fit to the data. PMID- 29993556 TI - 3gClust: Human Protein Cluster Analysis. AB - We present a human protein cluster analysis by combining: 1) n-gram based amino acid frequency features, 2) optimal feature selection, 3) hierarchical clustering and 4) advanced partitioning techniques. Our method qualitatively and quantitatively groups proteins with increasing sequence similarity into similar clusters by calculating the frequency model of amino acids using n-grams. We experiment with , i.e., unigrams, i.e., bigrams and finally , i.e., trigrams for optimal selection of features to design the 3gClust algorithm. The benchmarking results on 20,105 manually curated human proteins show that 3gClust ensures better cluster compactness in the case of proteins with similar functional groups, biological processes, structural alignment and shared domains (e.g. aquaporins, keratins). Quantitative analysis of non-singleton clusters shows significant improvement in their compactness in comparison to other state-of-the art methodologies. 3gClust is available at https://sites.google.com/site/bioinfoju/projects/3gclust for academic use along with supplementary materials and datasets. PMID- 29993557 TI - Efficient Algorithms for Finding the Closest l-mers in Biological Data. AB - With the advances in the next generation sequencing technology, huge amounts of data have been and get generated in biology. A bottleneck in dealing with such datasets lies in developing effective algorithms for extracting useful information from them. Algorithms for finding patterns in biological data pave the way for extracting crucial information from the voluminous datasets. In this paper we focus on a fundamental pattern, namely, the closest -mers. Given a set of biological strings and an integer , the problem of interest is that of finding an -mer from each string such that the distance among them is the least. I.e., we want to find -mers such that is an -mer in (for ) and the Hamming distance among these -mers is the least (from among all such possible -mers). This problem has many applications including motif search. Algorithms for finding the closest mers have been used in solving the -motif search problem (see e.g., ?cite{PeSz00,DBR07}). In this paper novel algorithms are proposed for this problem for the case of . A comprehensive experimental evaluation is performed for , along with a further empirical study of and . PMID- 29993558 TI - Towards Ultrasound Everywhere: A Portable 3D Digital Back-End Capable of Zone and Compound Imaging. AB - Ultrasound imaging is a ubiquitous diagnostic technique, but does not fit the requirements of the telemedicine approach, because it relies on the real-time manipulation and image recognition skills of a trained expert, called sonographer. Sonographers are only available in hospitals and clinics, negating or at least delaying access to ultrasound scans in many locales-rural areas, developing countries-as well as in medical rescue operations. Telesonography would require an advanced imager that supports three-dimensional (3-D) acquisition; this would allow untrained operators to acquire broad scans and upload them remotely for diagnosis. Such advanced imagers do exist, but do not meet several other requirements for telesonography, such as being portable, inexpensive, and sufficiently low power to enable battery operation. In this work, we present our prototype of the first portable 3-D digital ultrasound back end system. The prototype is implemented in a single midrange Xilinx field programmable gate array (FPGA), for an estimated power consumption of 5 W. The device supports up to 1024 input channels, which is state of the art and could be scaled further, and supports multiple image reconstruction modes. We evaluate the resource utilization of the FPGA and provide various quality metrics to ascertain the output image quality. PMID- 29993559 TI - A Multichannel High-Frequency Power-Isolated Neural Stimulator With Crosstalk Reduction. AB - In neuroprostheses applications requiring simultaneous stimulations on a multielectrode array, electric crosstalk, the spatial interaction between electric fields from various electrodes is a major limitation to the performance of multichannel stimulation. This paper presents a multichannel stimulator design that combines high-frequency current stimulation (using biphasic charge-balanced chopped pulse profile) with a switched-capacitor power isolation method. The approach minimizes crosstalk and is particularly suitable for fully integrated realization. A stimulator fabricated in a 0.6 MUm CMOS high-voltage technology is presented. It is used to implement a multichannel, high-frequency, power-isolated stimulator. Crosstalk reduction is demonstrated with electrodes in physiological media while the efficacy of the high-frequency stimulator chip is proven in vivo. The stimulator provides fully independent operation on multiple channels and full flexibility in the design of neural modulation protocols. PMID- 29993560 TI - Adaptive Learning-Based -Nearest Neighbor Classifiers With Resilience to Class Imbalance. AB - The classification accuracy of a -nearest neighbor ( NN) classifier is largely dependent on the choice of the number of nearest neighbors denoted by . However, given a data set, it is a tedious task to optimize the performance of NN by tuning . Moreover, the performance of NN degrades in the presence of class imbalance, a situation characterized by disparate representation from different classes. We aim to address both the issues in this paper and propose a variant of NN called the Adaptive NN (Ada- NN). The Ada- NN classifier uses the density and distribution of the neighborhood of a test point and learns a suitable point specific for it with the help of artificial neural networks. We further improve our proposal by replacing the neural network with a heuristic learning method guided by an indicator of the local density of a test point and using information about its neighboring training points. The proposed heuristic learning algorithm preserves the simplicity of NN without incurring serious computational burden. We call this method Ada- NN2. Ada- NN and Ada- NN2 perform very competitive when compared with NN, five of NN's state-of-the-art variants, and other popular classifiers. Furthermore, we propose a class-based global weighting scheme (Global Imbalance Handling Scheme or GIHS) to compensate for the effect of class imbalance. We perform extensive experiments on a wide variety of data sets to establish the improvement shown by Ada- NN and Ada- NN2 using the proposed GIHS, when compared with NN, and its 12 variants specifically tailored for imbalanced classification. PMID- 29993561 TI - Enhanced Robot Speech Recognition Using Biomimetic Binaural Sound Source Localization. AB - Inspired by the behavior of humans talking in noisy environments, we propose an embodied embedded cognition approach to improve automatic speech recognition (ASR) systems for robots in challenging environments, such as with ego noise, using binaural sound source localization (SSL). The approach is verified by measuring the impact of SSL with a humanoid robot head on the performance of an ASR system. More specifically, a robot orients itself toward the angle where the signal-to-noise ratio (SNR) of speech is maximized for one microphone before doing an ASR task. First, a spiking neural network inspired by the midbrain auditory system based on our previous work is applied to calculate the sound signal angle. Then, a feedforward neural network is used to handle high levels of ego noise and reverberation in the signal. Finally, the sound signal is fed into an ASR system. For ASR, we use a system developed by our group and compare its performance with and without the support from SSL. We test our SSL and ASR systems on two humanoid platforms with different structural and material properties. With our approach we halve the sentence error rate with respect to the common downmixing of both channels. Surprisingly, the ASR performance is more than two times better when the angle between the humanoid head and the sound source allows sound waves to be reflected most intensely from the pinna to the ear microphone, rather than when sound waves arrive perpendicularly to the membrane. PMID- 29993562 TI - Depth-Camera-Based System for Estimating Energy Expenditure of Physical Activities in Gyms. AB - Energy expenditure (EE) monitoring is crucial to tracking physical activity (PA). Accurate EE monitoring may help people engage in adequate activity and therefore avoid obesity and reduce the risk of chronic diseases. This study proposes a depth-camera-based system for EE estimation of PA in gyms. Most previous studies have used inertial measurement units for EE estimation. By contrast, the proposed system can be used to conveniently monitor subjects' treadmill workouts in gyms without requiring them to wear any devices. A total of 21 subjects were recruited for the experiment. Subjects' skeletal data acquired using the depth camera and oxygen consumption data simultaneously obtained using the K4b device was used to establish an EE predictive model. To obtain a robust EE estimation model, depth cameras were placed in the side view, rear side view, and rear view. A comparison of five different predictive models and these three camera locations showed that the multilayer perceptron model was the best predictive model and that placing the camera in the rear view provided the best EE estimation performance. The measured and predicted metabolic equivalents of task exhibited a strong positive correlation, with r = 0.94 and coefficient of determination r = 0.89. Furthermore, the mean absolute error was 0.61 MET, mean squared error was 0.67 MET, and root mean squared error was 0.76 MET. These results indicate that the proposed system is handy and reliable for monitoring user's EE when performing treadmill workouts. PMID- 29993563 TI - A Decision Support System for Diagnostics and Treatment Planning in Traumatic Brain Injury. AB - Traumatic Brain Injury (TBI) occurs when an external force causes functional or structural alterations in the brain. Clinical characteristics of TBI vary greatly from patient to patient, and a large amount of data is gathered during various phases of clinical care in these patients. It is hard for clinicians to efficiently integrate and interpret all of these data and plan interventions in a timely manner. This paper describes the technical architecture and functionality of a web-based Decision Support System (DSS), which not only provides advanced support for visualizing complex TBI data but also predicts a possible outcome by using a state-of-the-art Disease State Index machine-learning algorithm. The DSS is developed by using a three-layered architecture and by employing modern programming principles, software design patterns and using robust technologies (C#, ASP.NET MVC, HTML5, JavaScript, and Entity Framework etc.). The DSS is comprised of a patient overview module, a disease-state prediction module and an imaging module. After deploying it on a web-server, the DSS was made available to two hospitals in UK and Finland. Afterwards, we conducted a validation study to evaluate its usability in clinical settings. Initial results of the study indicate that especially less experience clinicians may benefit from this type of decision support software tool. PMID- 29993564 TI - Automatic Detection of Obstructive Sleep Apnea Using Wavelet Transform and Entropy based Features from Single-Lead ECG Signal. AB - Obstructive Sleep Apnea (OSA) is a prevalent sleep disorder, and highly affects the quality of human life. Currently, gold standard for OSA detection is Polysomnogram. Since this method is time consuming and cost inefficient, practical systems focus on the usage of electrocardiogram (ECG) signals for OSA detection. In this paper, a novel automatic OSA detection method using a single lead ECG signal has been proposed. A non-linear feature extraction using Wavelet Transform (WT) coefficients obtained by an ECG signal decomposition is employed. In addition, different classification methods are investigated. ECG signals are decomposed into 8 levels using a Symlet function as a mother Wavelet function with third-order. Then, the entropy-based features including fuzzy/approximate/sample/correct conditional entropy as well as other non-linear features including interquartile range, mean absolute deviation, variance, Poincare plot and recurrence plot are extracted from WT coefficients. The best features are chosen using the automatic sequential forward feature selection algorithm. In order to assess the introduced method, 95 single-lead ECG recordings are used. SVM classifier having a RBF kernel leads to an accuracy of 94.63% (Sens: 94.43%, Spec: 94.77%) and 95.71% (Sens: 95.83%, Spec: 95.66%) for minute-by-minute and subject-by-subject classifications, respectively. The results show that applying entropy-based features for extracting hidden information of the ECG signals outperforms other available automatic OSA detection methods. The results indicate that a highly accurate OSA detection is attained by just exploiting the single-lead ECG signals. Furthermore, due to the low computational load in the proposed method, it can easily be applied to the home monitoring systems. PMID- 29993565 TI - MR Image Super-Resolution Via Wide Residual Networks With Fixed Skip Connection. AB - Spatial resolution is a critical imaging parameter in magnetic resonance imaging (MRI). The image super-resolution (SR) is an effective and cost efficient alternative technique to improve the spatial resolution of MR images. Over the past several years, the convolutional neural networks (CNN)-based SR methods have achieved state-of-the-art performance. However, CNNs with very deep network structures usually suffer from the problems of degradation and diminishing feature reuse, which add difficulty to network training and degenerate the transmission capability of details for SR. To address these problems, in this work, a progressive wide residual network with a fixed skip connection (named FSCWRN) based SR algorithm is proposed to reconstruct MR images, which combines the global residual learning and the shallow network based local residual learning. The strategy of progressive wide networks is adopted to replace deeper networks, which can partially relax the abovementioned problems, while a fixed skip connection helps provide rich local details at high frequencies from a fixed shallow layer network to subsequent networks. The experimental results on one simulated MR image database and three real MR image databases show the effectiveness of the proposed FSCWRN SR algorithm, which achieves improved reconstruction performance compared with other algorithms. PMID- 29993566 TI - Delta Divergence: A Novel Decision Cognizant Measure of Classifier Incongruence. AB - In pattern recognition, disagreement between two classifiers regarding the predicted class membership of an observation can be indicative of an anomaly and its nuance. Since, in general, classifiers base their decisions on class a posteriori probabilities, the most natural approach to detecting classifier incongruence is to use divergence. However, existing divergences are not particularly suitable to gauge classifier incongruence. In this paper, we postulate the properties that a divergence measure should satisfy and propose a novel divergence measure, referred to as delta divergence. In contrast to existing measures, it focuses on the dominant (most probable) hypotheses and, thus, reduces the effect of the probability mass distributed over the non dominant hypotheses (clutter). The proposed measure satisfies other important properties, such as symmetry, and independence of classifier confidence. The relationship of the proposed divergence to some baseline measures, and its superiority, is shown experimentally. PMID- 29993567 TI - Physically-based Simulation of Cosmetics via Intrinsic Image Decomposition with Facial Priors. AB - We present a physically-based approach for simulating makeup in face images. The key idea is to decompose the face image into intrinsic image layers - namely albedo, diffuse shading, and specular highlights - which are each differently affected by cosmetics, and then manipulate each layer according to corresponding models of reflectance. Accurate intrinsic image decompositions for faces are obtained with the help of human face priors, including statistics on skin reflectance and facial geometry. The intrinsic image layers are then transformed in appearance according to measured optical properties of cosmetics and proposed adaptations of physically-based reflectance models. With this approach, realistic results are generated in a manner that preserves the personal appearance features and lighting conditions of the target face while not requiring detailed geometric and reflectance measurements. We demonstrate this technique on various forms of cosmetics including foundation, blush, lipstick, and eye shadow. Results on both images and videos exhibit a close approximation to ground truth and compare favorably to existing techniques. PMID- 29993568 TI - Learning and selecting confidence measures for robust stereo matching. AB - We present a robust approach for computing disparity maps with a supervised learning-based confidence prediction. This approach takes into consideration following features. First, we analyze the characteristics of various confidence measures in the random forest framework to select effective confidence measures depending on the characteristics of the training data and matching strategies, such as similarity measures and parameters. We then train a random forest using the selected confidence measures to improve the efficiency of confidence prediction and to build a better prediction model. Second, we present a confidence-based matching cost modulation scheme based on the predicted confidence values to improve the robustness and accuracy of the (semi-) global stereo matching algorithms. Finally, we apply the proposed modulation scheme to popularly used algorithms to make them robust against unexpected difficulties that could occur in an uncontrolled environment using challenging outdoor datasets. The proposed confidence measure selection and cost modulation schemes are experimentally verified from various perspectives using the KITTI and Middlebury datasets. PMID- 29993569 TI - HeadFusion: 360 Head Pose Tracking Combining 3D Morphable Model and 3D Reconstruction. AB - Head pose estimation is a fundamental task for face and social related research. Although 3D morphable model (3DMM) based methods relying on depth information usually achieve accurate results, they usually require frontal or mid-profile poses which preclude a large set of applications where such conditions can not be garanteed, like monitoring natural interactions from fixed sensors placed in the environment. A major reason is that 3DMM models usually only cover the face region. In this paper, we present a framework which combines the strengths of a 3DMM model fitted online with a prior-free reconstruction of a 3D full head model providing support for pose estimation from any viewpoint. In addition, we also proposes a symmetry regularizer for accurate 3DMM fitting under partial observations, and exploit visual tracking to address natural head dynamics with fast accelerations. Extensive experiments show that our method achieves state-of the-art performance on the public BIWI dataset, as well as accurate and robust results on UbiPose, an annotated dataset of natural interactions that we make public and where adverse poses, occlusions or fast motions regularly occur. PMID- 29993570 TI - MITT: Medical Image Tracking Toolbox. AB - Over the years, medical image tracking has gained considerable attention from both medical and research communities due to its widespread utility in a multitude of clinical applications, from functional assessment during diagnosis and therapy planning to structure tracking or image fusion during image-guided interventions. Despite the ever-increasing number of image tracking methods available, most still consist of independent implementations with specific target applications, lacking the versatility to deal with distinct end-goals without the need for methodological tailoring and/or exhaustive tuning of numerous parameters. With this in mind, we have developed the medical image tracking toolbox (MITT)-a software package designed to ease customization of image tracking solutions in the medical field. While its workflow principles make it suitable to work with 2-D or 3-D image sequences, its modules offer versatility to set up computationally efficient tracking solutions, even for users with limited programming skills. MITT is implemented in both C/C++ and MATLAB, including several variants of an object-based image tracking algorithm and allowing to track multiple types of objects (i.e., contours, multi-contours, surfaces, and multi-surfaces) with several customization features. In this paper, the toolbox is presented, its features discussed, and illustrative examples of its usage in the cardiology field provided, demonstrating its versatility, simplicity, and time efficiency. PMID- 29993571 TI - Automated Non-Invasive Measurement of Single Sperm's Motility and Morphology. AB - Measuring cell motility and morphology is important for revealing their functional characteristics. This paper presents automation techniques that enable automated, non-invasive measurement of motility and morphology parameters of single sperm. Compared to the status quo of qualitative estimation of single sperm's motility and morphology manually, the automation techniques provide quantitative data for embryologists to select a single sperm for intracytoplasmic sperm injection. An adapted joint probabilistic data association filter was used for multi-sperm tracking and tackled challenges of identifying sperms that intersect or have small spatial distances. Since the standard differential interference contrast (DIC) imaging method has side illumination effect which causes inherent inhomogeneous image intensity and poses difficulties for accurate sperm morphology measurement, we integrated total variation norm into the quadratic cost function method, which together effectively removed inhomogeneous image intensity and retained sperm's subcellular structures after DIC image reconstruction. In order to relocate the same sperm of interest identified under low magnification after switching to high magnification, coordinate transformation was conducted to handle the changes in the field of view caused by magnification switch. The sperm's position after magnification switch was accurately predicted by accounting for the sperm's swimming motion during magnification switch. Experimental results demonstrated an accuracy of 95.6% in sperm motility measurement and an error <10% in morphology measurement. PMID- 29993572 TI - Spectral Angiography Material Decomposition Using an Empirical Forward Model and a Dictionary-Based Regularization. AB - By resolving the energy of the incident X-ray photons, spectral X-ray imaging with photon counting detectors offers additional material-specific information compared to conventional X-ray imaging. This additional information can be used to improve clinical diagnosis for various applications. However, spectral imaging still faces several challenges. Amplified noise and a reduced signal-to-noise ratio on the decomposed basis material images remain a major problem, especially for low-dose applications. Furthermore, it is challenging to construct an accurate model of the spectral measurement acquisition process. In this paper, we present a novel algorithm for projection-based material decomposition. It uses an empirical polynomial model that is tuned by calibration measurements. We combine this method with a statistical model of the measured photon counts and a dictionary-based joint regularization approach. We focused on spectral coronary angiography as a potential clinical application of projection-based material decomposition with photon counting detectors. Numerical and real experiments show that spectral angiography with realistic dose levels and gadolinium contrast agent concentrations are feasible using the proposed decomposition algorithm and currently available photon-counting detector technology. PMID- 29993573 TI - Corneal Endothelial Cell Segmentation by Classifier-Driven Merging of Oversegmented Images. AB - Corneal endothelium images obtained by in vivo specular microscopy provide important information to assess the health status of the cornea. Estimation of clinical parameters, such as cell density, polymegethism, and pleomorphism, requires accurate cell segmentation. State-of-the-art techniques to automatically segment the endothelium are error-prone when applied to images with low contrast and/or large variation in cell size. Here, we propose an automatic method to segment the endothelium. Starting with an oversegmented image comprised of superpixels obtained from a stochastic watershed segmentation, the proposed method uses intensity and shape information of the superpixels to identify and merge those that constitute a cell, using support vector machines. We evaluated the automatic segmentation on a data set of in vivo specular microscopy images (Topcon SP-1P), obtaining 95.8% correctly merged cells and 2.0% undersegmented cells. We also evaluated the parameter estimation against the results of the vendor's built-in software, obtaining a statistically significant better precision in all parameters and a similar or better accuracy. The parameter estimation was also evaluated on three other data sets from different imaging modalities (confocal microscopy, phase-contrast microscopy, and fluorescence confocal microscopy) and tissue types (ex vivo corneal endothelium and retinal pigment epithelium). In comparison with the estimates of the data sets' authors, we achieved statistically significant better accuracy and precision in all parameters except pleomorphism, where a similar accuracy and precision were obtained. PMID- 29993574 TI - An Indoor Airborne Ultrasonic Wireless Communication Network. AB - There is an increasing interest in the use of modulated airborne ultrasound as a means of indoor wireless communication. By using commercially available capacitive ultrasonic transducers at 50 kHz, this paper describes the successful practical implementation of a prototype airborne ultrasonic communication network with ceiling-mounted base stations (BSs) and a mobile transceiver unit. An asynchronous ultrasonic location technique using Gold code-modulated ranging signals was chosen to optimize the modulation schemes and data transfer and offered automatic handover between different cell regions on a switch ON and OFF basis as all BSs used the same frequency bands for data transmission. The 16 quadrature amplitude modulation (QAM) based on orthogonal frequency division multiplexing (OFDM) was used to achieve an uplink data transfer rate of 37.4 kb/s, whereas the range was extended by using quadrature phase-shift keying (QPSK)-OFDM with a data rate of 18.7 kb/s. For the uplink connection, the achieved data rates using 16-QAM-OFDM and QPSK-OFDM were 36.1 and 18.1 kb/s, respectively. A more robust handover technique using received signal strength with hysteresis was also proposed to improve system efficiency when multiple mobile receivers used the service. PMID- 29993575 TI - The Role of Microbubble Echo Phase Lag in Multipulse Contrast-Enhanced Ultrasound Imaging. AB - In this paper, we assess the importance of microbubble shell composition for contrast-enhanced imaging sequences commonly used on clinical scanners. While the gas core dynamics are primarily responsible for the nonlinear harmonic response of microbubbles at diagnostic pressures, it is now understood that the shell rheology plays a dominant role in the nonlinear response of microbubbles subjected to low acoustic pressures. Of particular interest here, acoustic pressures of tens of kilopascal can cause a reversible phase transition of the phospholipid coatings from a stiff elastic organized state to a less stiff disorganized buckled state. Such a transition from elastic to buckled shell induces a steep variation of the shell elasticity, which alters the microbubble acoustic scattering properties. We demonstrate in this paper that this mechanism plays a dominant role in contrast pulse sequences that modulate the amplitude of the insonifying pulse pressure. The contrast-to-tissue ratio (CTR) for amplitude modulation (AM), pulse inversion (PI), and amplitude modulation pulse inversion (AMPI) is measured in vitro for Definity, Sonazoid, both lipid-encapsulted microbubbles, and the albumin-coated Optison. It is found that pulse sequences using AM significantly enhanced the nonlinear response of all studied microbubbles compared to PI (up to 15 dB more) when low insonation pressures under 200 kPa were used. Further investigation reveals that the origin of the hyperechoicity is a small phase lag occurring between the echoes from the full and half-amplitude driving pulses, and that the effect could be attributed to the shell softening dynamics of lipid and albumin coatings. We assess that this additional phase in microbubble ultrasound scattering can have a dominant role in the CTR achieved in contrast sequences using AM. We also show that the pressure dependent phase lag is a specific marker for microbubbles with no equivalent in tissue, which can be used to segment microbubbles from the tissue harmonics and significantly increase the CTR. PMID- 29993576 TI - An Improved Protocol for Performing Two-Way Satellite Time and Frequency Transfer Using a Satellite in an Inclined Geo-Synchronous Orbit. AB - Two-way satellite time and frequency transfer (TWSTFT) using satellites in inclined geo-synchronous orbit (IGSO) is fundamentally more difficult than using satellites in geostationary orbit (GEO), due to the fact that IGSO satellites are constantly moving relative to a ground station, which brings in large residual effects. In this paper, we designed a protocol and an algorithm to correct several factors that affect the precision of TWSTFT using IGSO satellites. We used two ground stations, each equipped with sending and receiving channels, to conduct real-time measurements of the distance and the speed of an IGSO satellite, and data collected were used to make appropriate corrections. We tested this concept by conducting TWSTFT experiments using an IGSO satellite (BEIDOU I1-S), and compared the results with that obtained using a GEO satellite (CHINASAT 12). Indeed, the individual components that contribute to the residual effects of TWSTFT measurements using the IGSO satellite were several orders of magnitude greater than that of the GEO satellite. By using our modified protocol, TWSTFT results with an IGSO satellite were well accorded with that of using a GEO satellite; the standard deviation of residuals was less than 0.4 ns, well within the limit for the measurement uncertainty of TWSTFT. Therefore, we have expanded the use of IGSO satellites for TWSTFT. In principle, it should also be applicable to medium earth orbit and other satellites. PMID- 29993577 TI - Find who to look at: Turning from action to saliency. AB - The past decade has witnessed the use of highlevel features in saliency prediction for both videos and images. Unfortunately, the existing saliency prediction methods only handle high-level static features, such as face. In fact, high-level dynamic features (also called actions), such as speaking or head turning, are also extremely attractive to visual attention in videos. Thus, in this paper, we propose a data-driven method for learning to predict the saliency of multiple-face videos, by leveraging both static and dynamic features at high level. Specifically, we introduce an eye-tracking database, collecting the fixations of 39 subjects viewing 65 multiple-face videos. Through analysis on our database, we find a set of high-level features that cause a face to receive extensive visual attention. These high-level features include the static features of face size, center-bias and head pose, as well as the dynamic features of speaking and head turning. Then, we present the techniques for extracting these high-level features. Afterwards, a novel model, namely multiple hidden Markov model (M-HMM), is developed in our method to enable the transition of saliency among faces. In our MHMM, the saliency transition takes into account both the state of saliency at previous frames and the observed high-level features at the current frame. The experimental results show that the proposed method is superior to other state-of-the-art methods in predicting visual attention on multiple-face videos. Finally, we shed light on a promising implementation of our saliency prediction method in locating the region-of-interest (ROI), for video conference compression with high efficiency video coding (HEVC). PMID- 29993578 TI - From Focal Stack to Tensor Light-Field Display. AB - We propose a method of using a focal stack, i.e., a set of differently focused images, as the input for a novel light field display called a "tensor display." Although this display consists of only a few light attenuating layers located in front of a backlight, it can be viewed from many directions (angles) simultaneously without the resolution of each viewing direction being sacrificed. Conventionally, a transmittance pattern is calculated for each layer from a light field, namely, a set of dense multi-view images (typically dozens) that are to be observed from different directions. However, preparing such a massive amount of images is often cumbersome for real objects. We developed a method that does not require a complete light field as the input; instead, a focal stack composed of only a few differently focused images is directly transformed into layer patterns. Our method greatly reduces the cost of acquiring data while also maintaining the quality of the output light field. We validated the method with experiments using synthetic light field datasets and a focal stack acquired by an ordinary camera. PMID- 29993579 TI - A frequency domain SIM reconstruction algorithm using reduced number of images. AB - Conventional two-dimensional structured illumination microscopy (SIM) requires 9 raw images to reconstruct a super-resolved image. In order to increase the frame rate of 2DSIM, attempts are being made to reduce the number of raw SIM images. However, all the proposed SIM reconstruction algorithms (SIM-RA) capable of reconstructing super-resolution (SR) image with a reduced number of raw SIM images operate in the spatial domain. Here, we present a frequency domain SIM-RA based on ordinary least squares technique, which enables reconstruction of SR image using 4 raw SIM images. Unlike the spatial domain RA, which produces the SR image through iterative convergence, the presented RA provides a single step solution. It also reveals the fundamental limitation of least number of raw images required for resolution doubling in SIM. PMID- 29993580 TI - Popup-Plots: Warping Temporal Data Visualization. AB - Visualizing temporal data is inherently difficult, due to the many aspects that need to be communicated to the users. This is an important topic in visualization, and a wide range of visualization techniques dealing with different tasks have already been designed. In this paper we propose popup-plots, a novel concept where the common interaction of 3D rotation is used to navigate through the data. This allows the users to view the data from different perspectives without having to learn and adapt to new interaction concepts. Popup plots are therefore a novel method for visualizing and interacting with dependent variables over time. We extend 2D plots with the temporal information by bending the space according to the time. The bending is calculated based on a spherical coordinates approach, which is continuously influenced by the viewing direction towards the plot. Hence, the plot can be viewed from various angles with seamless transitions in between, offering the possibility to analyze different aspects of the represented data. The temporal information is encoded into the visualization itself, resembling annual rings of a tree. We demonstrate our method by applying it to data from two different domains, and we also evaluated the usability of our solution. PMID- 29993581 TI - MfeCNN: Mixture Feature Embedding Convolutional Neural Network for Data Mapping. AB - Data mapping plays an important role in data integration and exchanges among institutions and organizations with different data standards. However, traditional rule-based approaches and machine learning methods fail to achieve satisfactory results for the data mapping problem. In this paper, we propose a novel and sophisticated deep learning framework for data mapping called mixture feature embedding convolutional neural network (MfeCNN). The MfeCNN model converts the data mapping task to a multiple classification problem. In the model, we incorporated multimodal learning and multiview embedding into a CNN for mixture feature tensor generation and classification prediction. Multimodal features were extracted from various linguistic spaces with a medical natural language processing package. Then, powerful feature embeddings were learned by using the CNN. As many as 10 classes could be simultaneously classified by a softmax prediction layer based on multiview embedding. MfeCNN achieved the best results on unbalanced data (average F1 score, 82.4%) among the traditional state of-the-art machine learning models and CNN without mixture feature embedding. Our model also outperformed a very deep CNN with 29 layers, which took free texts as inputs. The combination of mixture feature embedding and a deep neural network can achieve high accuracy for data mapping and multiple classification. PMID- 29993583 TI - Deep Learning for Drug Discovery and Cancer Research: Automated Analysis of Vascularization Images. AB - Likely drug candidates which are identified in traditional pre-clinical drug screens often fail in patient trials, increasing the societal burden of drug discovery. A major contributing factor to this phenomenon is the failure of traditional in vitro models of drug response to accurately mimic many of the more complex properties of human biology. We have recently introduced a new microphysiological system for growing vascularized, perfused microtissues that more accurately models human physiology and is suitable for large drug screens. In this work, we develop a machine learning model that can quickly and accurately flag compounds which effectively disrupt vascular networks from images taken before and after drug application in vitro. The system is based on a convolutional neural network and achieves near perfect accuracy while committing no potentially expensive false negatives. PMID- 29993582 TI - Identification and Analysis of Key Residues in Protein-RNA Complexes. AB - Protein-RNA complexes play important roles in various biological processes. The functions of protein-RNA complexes are dictated by their interactions, binding, stability, and affinity. In this work, we have identified the key residues (KRs), which are involved in both stability and binding. We found that 42 percent of considered proteins share common binding and stabilizing residues, whereas these residues are distinct in 58 percent of the proteins. Overall, 5 percent of stabilizing and 3 percent of binding residues serve as key residues. These residues are enriched with the combination of polar, charged, aliphatic, and aromatic residues. Analysis on subclasses of protein-RNA complexes based on protein structural class, function and RNA type showed that regulatory proteins, and complexes with single stranded RNA and rRNA have appreciable number of key residues. Specifically, Arg, Tyr, and Thr are preferred in most of the subclasses of protein-RNA complexes. In addition, residues with similar chemical behavior have different preferences to be KRs, such that Arg, Tyr, Val, and Thr are preferred over Lys, Trp, Ile, and Ser, respectively. Atomic level contacts revealed that charged and polar-nonpolar contacts are dominant in enzymes, polar in structural, and nonpolar in regulatory proteins. On the other hand, polar nonpolar contacts are enriched in all these classes of protein-RNA complexes. Further, the influence of sequence and structural features such as conservation score, surrounding hydrophobicity, solvent accessibility, secondary structure, and long-range order in key residues are also discussed. We envisage that the present study provides insights to understand the structural and functional aspects of protein-RNA complexes. PMID- 29993584 TI - Exploiting All Programmable SoCs in Neural Signal Analysis: A Closed-Loop Control for Large-Scale CMOS Multielectrode Arrays. AB - Microelectrode array (MEA) systems with up to several thousands of recording electrodes and electrical or optical stimulation capabilities are commercially available or described in the literature. By exploiting their submillisecond and micrometric temporal and spatial resolutions to record bioelectrical signals, such emerging MEA systems are increasingly used in neuroscience to study the complex dynamics of neuronal networks and brain circuits. However, they typically lack the capability of implementing real-time feedback between the detection of neuronal spiking events and stimulation, thus restricting large-scale neural interfacing to open-loop conditions. In order to exploit the potential of such large-scale recording systems and stimulation, we designed and validated a fully reconfigurable FPGA-based processing system for closed-loop multichannel control. By adopting a Xilinx Zynq-all-programmable system on chip that integrates reconfigurable logic and a dual-core ARM-based processor on the same device, the proposed platform permits low-latency preprocessing (filtering and detection) of spikes acquired simultaneously from several thousands of electrode sites. To demonstrate the proposed platform, we tested its performances through ex vivo experiments on the mice retina using a state-of-the-art planar high-density MEA that samples 4096 electrodes at 18 kHz and record light-evoked spikes from several thousands of retinal ganglion cells simultaneously. Results demonstrate that the platform is able to provide a total latency from whole-array data acquisition to stimulus generation below 2 ms. This opens the opportunity to design closed-loop experiments on neural systems and biomedical applications using emerging generations of planar or implantable large-scale MEA systems. PMID- 29993585 TI - Noncontact Wearable Wireless ECG Systems for Long-Term Monitoring. AB - Electrocardiography (ECG) is the most common and extensively used vital sign monitoring method in modern healthcare systems. Different designs of ambulatory ECG systems were developed as alternatives to the commonly used 12-lead clinical ECG systems. These designs primarily focus on portability and user convenience, while maintaining signal integrity and lowering power consumption. Here, a wireless ECG monitoring system is developed using flexible and dry capacitive electrodes for long-term monitoring of cardiovascular health. Our capacitive coupled dry electrodes can measure ECG signals over a textile-based interface material between the skin and electrodes. The electrodes are connected to a data acquisition system that receives the raw ECG signals from the electrodes and transmits the data using Bluetooth to a computer. A software application was developed to process, store, and display the ECG signal in real time. ECG measurements were obtained over different types of textile materials and in the presence of body movements. Our experimental results show that the performance of our ECG system is comparable to other reported ECG monitoring systems. In addition, to put this research into perspective, recent ambulatory ECG monitoring systems, ECG systems-on-chip, commercial ECG monitoring systems, and different state-of-the-art ECG systems are reviewed, compared, and critically discussed. PMID- 29993586 TI - Perceived Hardness through Actual and Virtual Damped Natural Vibrations. AB - Humans perceive the hardness of objects from damped natural vibrations by tapping their surfaces. We investigated the roles of six parameters characterizing the vibration in the virtual and real environments. The effects of some parameters differed between the two environments. This finding warns the developers of haptic applications. PMID- 29993587 TI - A Cost-Sensitive Deep Belief Network for Imbalanced Classification. AB - Imbalanced data with a skewed class distribution are common in many real-world applications. Deep Belief Network (DBN) is a machine learning technique that is effective in classification tasks. However, conventional DBN does not work well for imbalanced data classification because it assumes equal costs for each class. To deal with this problem, cost-sensitive approaches assign different misclassification costs for different classes without disrupting the true data sample distributions. However, due to lack of prior knowledge, the misclassification costs are usually unknown and hard to choose in practice. Moreover, it has not been well studied as to how cost-sensitive learning could improve DBN performance on imbalanced data problems. This paper proposes an evolutionary cost-sensitive deep belief network (ECS-DBN) for imbalanced classification. ECS-DBN uses adaptive differential evolution to optimize the misclassification costs based on the training data that presents an effective approach to incorporating the evaluation measure (i.e., G-mean) into the objective function. We first optimize the misclassification costs, and then apply them to DBN. Adaptive differential evolution optimization is implemented as the optimization algorithm that automatically updates its corresponding parameters without the need of prior domain knowledge. The experiments have shown that the proposed approach consistently outperforms the state of the art on both benchmark data sets and real-world data set for fault diagnosis in tool condition monitoring. PMID- 29993588 TI - A Highly Effective and Robust Membrane Potential-Driven Supervised Learning Method for Spiking Neurons. AB - Spiking neurons are becoming increasingly popular owing to their biological plausibility and promising computational properties. Unlike traditional rate based neural models, spiking neurons encode information in the temporal patterns of the transmitted spike trains, which makes them more suitable for processing spatiotemporal information. One of the fundamental computations of spiking neurons is to transform streams of input spike trains into precisely timed firing activity. However, the existing learning methods, used to realize such computation, often result in relatively low accuracy performance and poor robustness to noise. In order to address these limitations, we propose a novel highly effective and robust membrane potential-driven supervised learning (MemPo Learn) method, which enables the trained neurons to generate desired spike trains with higher precision, higher efficiency, and better noise robustness than the current state-of-the-art spiking neuron learning methods. While the traditional spike-driven learning methods use an error function based on the difference between the actual and desired output spike trains, the proposed MemPo-Learn method employs an error function based on the difference between the output neuron membrane potential and its firing threshold. The efficiency of the proposed learning method is further improved through the introduction of an adaptive strategy, called skip scan training strategy, that selectively identifies the time steps when to apply weight adjustment. The proposed strategy enables the MemPo-Learn method to effectively and efficiently learn the desired output spike train even when much smaller time steps are used. In addition, the learning rule of MemPo-Learn is improved further to help mitigate the impact of the input noise on the timing accuracy and reliability of the neuron firing dynamics. The proposed learning method is thoroughly evaluated on synthetic data and is further demonstrated on real-world classification tasks. Experimental results show that the proposed method can achieve high learning accuracy with a significant improvement in learning time and better robustness to different types of noise. PMID- 29993589 TI - Active Contours Based Segmentation and Lesion Periphery Analysis For Characterization of Skin Lesions in Dermoscopy Images. AB - This paper proposes a computer assisted diagnostic (CAD) system for the detection of melanoma in dermoscopy images. Clinical findings have concluded that in case of melanoma, the lesion borders exhibit differential structures such as pigment networks and streaks as opposed to normal skin spots, which have smoother borders. We aim to validate these findings by performing segmentation of the skin lesions followed by an extraction of the peripheral region of the lesion that is subjected to feature extraction and classification for detecting melanoma. For segmentation, we propose a novel active contours based method that takes an initial lesion contour followed by the usage of Kullback-Leibler divergence between the lesion and skin to fit a curve precisely to the lesion boundaries. After segmentation of the lesion, its periphery is extracted to detect melanoma using image features that are based on local binary patterns. For validation of our algorithms, we have used the publicly available PH dermoscopy dataset. An extensive experimental analysis reveals two important findings: 1). The proposed segmentation method mimics the ground truth data accurately, outperforming the other methods that have been used for comparison purposes, and 2). The most significant melanoma characteristics in the lesion actually lie on the lesion periphery. PMID- 29993590 TI - Biologically Inspired QuadTree Colour Detection in Dermoscopy Images of Melanoma. AB - This paper presents a QuadTree-based melanoma detection system inspired by dermatologists' colour perception. Clinical colour assessment in dermoscopy images is challenging because of subtle differences in shades, location-dependent colour information, poor colour contrast and wide variation among images of the same class. To overcome these challenges, colour enhancement and automatic colour identification techniques, based on QuadTree segmentation and modelled after expert colour assessments, are developed. The approach presented in this paper is shown to provide an accurate model of expert colour assessment. Specifically, the proposed model is shown to: (i) identify significantly more colours in melanomas than in benign skin lesions, (ii) identify a higher frequency in melanomas of three colours: blue-grey, black and pink, and (iii) delineate locations of melanoma colours by quintiles, specifically predilection for blue-grey and pink in the periphery and a trend for white and black in the lesion centre. Performance of the proposed method is evaluated using four classifiers. The kernel support vector machine (SVM) classifier is found to achieve the best results, with an area under the receiver operating characteristic (ROC) curve of 0.93, compared to average area under the ROC curve of 0.82 achieved by the dermatologists in this study. The results indicate that the biologically inspired method of automatic colour detection proposed in this paper has the potential to play an important role in melanoma diagnosis in the clinic. PMID- 29993591 TI - Pattern Classification for Gastrointestinal Stromal Tumors by Integration of Radiomics and Deep Convolutional Features. AB - Predicting malignant potential is one of the most critical components of a computer-aided diagnosis (CAD) system for gastrointestinal stromal tumors (GISTs). These tumors have been studied only on the basis of subjective computed tomography (CT) findings. Among various methodologies, radiomics and deep learning algorithms, specifically convolutional neural networks (CNNs), have recently been confirmed to achieve significant success by outperforming the state of-the-art performances in medical image pattern classification and have rapidly become leading methodologies in this field. However, the existing methods generally use radiomics or deep convolutional features independently for pattern classification, which tend to take into account only global or local features, respectively. In this paper, we introduce and evaluate a hybrid structure that includes different features selected with radiomics model and CNN and integrates these features to deal with GIST classification. Radiomics model and CNN architecture are constructed for global radiomics and local convolutional feature selections, respectively. Subsequently, we utilize distinct radiomics and deep convolutional features to perform pattern classification for GIST. Specifically, we propose a new pooling strategy to assemble the deep convolutional features of 54 3D patches from the same case and integrate these features with the radiomics features for independent case, followed by random forests (RF) classifier. Our method can be extensively evaluated using multiple clinical datasets. The classification performance (area under the curve (AUC): 0.882; 95% confidence interval (CI): 0.816-0.947) consistently outperforms those of independent radiomics (AUC: 0.807; 95% CI: 0.724-0.892) and CNN (AUC: 0.826; 95% CI: 0.795 0.856) approaches. PMID- 29993592 TI - Deception Decreases Brain Complexity. AB - Extensive evidence suggests the feasibility of lie detection using electroencephalograms (EEGs). However, it is largely unknown whether there are any differences in the nonlinear features of EEGs between guilty and innocent subjects. In this study, we proposed a complexity-based method to distinguish lying from truth telling. Thirty-five participants were randomly divided into two groups, and their EEG signals were recorded with 14 elec-trodes. Averages for sequential sets of five trials were first calculated for the probe responses within each subject. Next, a common wavelet entropy (WE) measure and an improved one were used to quantify complexity from each five-trial average. The results show that for both measures, the WE values in the guilty subjects are statistically lower than those in the innocent subjects for most of the 14 electrodes. More importantly, using the im-proved measure, the difference in WE between the two groups of subjects significantly increases for 11 brain regions compared with the values from the common measure. Finally, the highest balanced classification accuracy, 89.64%, is achieved when using the combined WE feature vector in 5 brain regions. Our findings indicate that the lying task elicits a more ordered brain activity in some specific brain regions than the task of telling the truth. This study not only demonstrates that improved WE measurements could be a powerful quantitative index for detecting lying but also sheds light on the brain mechanisms underlying deceptive behaviors. PMID- 29993593 TI - Spike Timing or Rate? Neurons Learn to Make Decisions for Both Through Threshold Driven Plasticity. AB - Spikes play an essential role in information transmission in central nervous system, but how neurons learn from them remains a challenging question. Most algorithms studied how to train spiking neurons to process patterns encoded with a sole assumption of either a rate or a temporal code. Is there a general learning algorithm capable of processing both codes regardless of the intense debate on them within neuroscience community? In this paper, we propose several threshold-driven plasticity algorithms to address the above question. In addition to formulating the algorithms, we also provide proofs with respect to several properties, such as robustness and convergence. The experimental results illustrate that our algorithms are simple, effective and yet efficient for training neurons to learn spike patterns. Due to their simplicity and high efficiency, our algorithms would be potentially beneficial for both software and hardware implementations. Neurons with our algorithms can also detect and recognize embedded features from a background sensory activity. With the as proposed algorithms, a single neuron can successfully perform multicategory classifications by making decisions based on its output spike number in response to each category. Spike patterns being processed can be encoded with both spike rates and precise timings. When afferent spike timings matter, neurons will automatically extract temporal features without being explicitly instructed as to which point to fire. PMID- 29993594 TI - Deep Max-Margin Discriminant Projection. AB - In this paper, a unified Bayesian max-margin discriminant projection framework is proposed, which is able to jointly learn the discriminant feature space and the max-margin classifier with different relationships between the latent representations and observations. We assume that the latent representation follows a normal distribution whose sufficient statistics are functions of the observations. The function can be flexibly realized through either shallow or deep structures. The shallow structure includes linear, nonlinear kernel-based functions, and even the convolutional projection, which can be further trained layerwisely to build a multilayered convolutional feature learning model. To take the advantage of the deep neural networks, especially their highly expressive ability and efficient parameter learning, we integrate Bayesian modeling and the popular neural networks, for example, mltilayer perceptron and convolutional neural network, to build an end-to-end Bayesian deep discriminant projection under the proposed framework, which degenerated into the existing shallow linear or convolutional projection with the single-layer structure. Moreover, efficient scalable inferences for the realizations with different functions are derived to handle large-scale data via a stochastic gradient Markov chain Monte Carlo. Finally, we demonstrate the effectiveness and efficiency of the proposed models by the experiments on real-world data, including four image benchmarks (MNIST, CIFAR-10, STL-10, and SVHN) and one measured radar high-resolution range profile dataset, with the detailed analysis about the parameters and computational complexity. PMID- 29993595 TI - A Nonparametric Deep Generative Model for Multimanifold Clustering. AB - Multimanifold clustering separates data points approximately lying on a union of submanifolds into several clusters. In this paper, we propose a new nonparametric Bayesian model to handle the manifold data structure. In our framework, we first model the manifold mapping function between Euclidean space and topological space by applying a deep neural network, and then construct the corresponding generation process of multiple manifold data. To solve the posterior approximation problem, in the optimization procedure, we apply a variational auto encoder-based optimization algorithm. Especially, as the manifold algorithm has poor performance on the real dataset where nonmanifold and manifold clusters are appearing simultaneously, we expand our proposed manifold algorithm by integrating it with the original Dirichlet process mixture model. Experimental results have been carried out to demonstrate the state-of-the-art clustering performance. PMID- 29993596 TI - An Error Transformation Approach for Connectivity-Preserving and Collision Avoiding Formation Tracking of Networked Uncertain Underactuated Surface Vessels. AB - This paper investigates a distributed connectivity-preserving and collision avoiding formation tracking problem of networked uncertain underactuated surface vessels (USVs) with heterogeneous limited communication ranges. All nonlinearities in the dynamic model are assumed to be completely unknown. Compared with the existing formation tracking results for USVs, our primary contribution is to develop a new nonlinearly transformed formation error for achieving the initial connectivity preservation, the collision avoidance, and the distributed formation tracking without switching the desired formation pattern and using any additional potential functions. In other words, these three objectives can be achieved by using only one transformed formation error surface. The local tracker design strategy using the nonlinearly transformed error is established under the direct graph topology, where the adaptive function approximation technique and the auxiliary variables are employed to compensate for uncertain nonlinearities and to deal with the underactuated problem of USVs, respectively. Finally, the Lyapunov stability analysis and simulations are performed to verify the effectiveness of the proposed theoretic result. PMID- 29993597 TI - SurfCut: Surfaces of Minimal Paths From Topological Structures. AB - We present SurfCut, an algorithm for extracting a smooth, simple surface with an unknown 3D curve boundary from a noisy image and a seed point. Our method is built on the novel observation that certain ridge curves of a function defined on a front propagated using the Fast Marching algorithm lie on the surface. Our method extracts and cuts these ridges to form the surface boundary. Our surface extraction algorithm is built on the novel observation that the surface lies in a valley of the distance from Fast Marching. We show that the resulting surface is a collection of minimal paths. Using the framework of cubical complexes and Morse theory, we design algorithms to extract these critical structures robustly. Experiments on three 3D datasets show the robustness of our method, and that it achieves higher accuracy with lower computational cost than state-of-the-art. PMID- 29993598 TI - A Dual Tissue-Doppler Optical-Flow Method for Speckle Tracking Echocardiography at High Frame Rate. AB - A coupled computational method for recovering tissue velocity vector fields from high-frame-rate echocardiography is described. Conventional transthoracic echocardiography provides limited temporal resolution, which may prevent accurate estimation of the 2-D myocardial velocity field dynamics. High-frame-rate compound echocardiography using diverging waves with integrated motion compensation has been shown to provide concurrent high-resolution B-mode and tissue Doppler imaging (TDI). In this paper, we propose a regularized least squares method to provide accurate myocardial velocities at high frame rates. The velocity vector field was formulated as the minimizer of a cost function that is a weighted sum of: 1) the ${?ell }^{{2}}$ -norm of the material derivative of the B-mode images (optical flow); 2) the ${?ell }^{{2}}$ -norm of the tissue-Doppler residuals; and 3) a quadratic regularizer that imposes spatial smoothness and well-posedness. A finite difference discretization of the continuous problem was adopted, leading to a sparse linear system. The proposed framework was validated in vitro on a rotating disk with speeds up to 20 cm/s, and compared with speckle tracking echocardiography (STE) by block matching. It was also validated in vivo against TDI and STE in a cross-validation strategy involving parasternal long axis and apical three-chamber views. The proposed method based on the combination of optical flow and tissue Doppler led to more accurate time-resolved velocity vector fields. PMID- 29993599 TI - Double Diffeomorphism: Combining Morphometry and Structural Connectivity Analysis. AB - The brain is composed of several neural circuits which may be seen as anatomical complexes composed of grey matter structures interconnected by white matter tracts. Grey and white matter components may be modeled as 3-D surfaces and curves, respectively. Neurodevelopmental disorders involve morphological and organizational alterations which cannot be jointly captured by usual shape analysis techniques based on single diffeomorphisms. We propose a new deformation scheme, called double diffeomorphism, which is a combination of two diffeomorphisms. The first one captures changes in structural connectivity, whereas the second one recovers the global morphological variations of both grey and white matter structures. This deformation model is integrated into a Bayesian framework for atlas construction. We evaluate it on a data-set of 3-D structures representing the neural circuits of patients with Gilles de la Tourette syndrome (GTS). We show that this approach makes it possible to localise, quantify, and easily visualise the pathological anomalies altering the morphology and organization of the neural circuits. Furthermore, results also indicate that the proposed deformation model better discriminates between controls and GTS patients than a single diffeomorphism. PMID- 29993600 TI - A Comparative Study of Algorithms for Realtime Panoramic Video Blending. AB - Unlike image blending algorithms, video blending algorithms have been little studied. In this paper, we investigate 6 popular blending algorithms-feather blending, multi-band blending, modified Poisson blending, mean value coordinate blending, multi-spline blending and convolution pyramid blending. We consider their application to blending realtime panoramic videos, a key problem in various virtual reality tasks. To evaluate the performances and suitabilities of the 6 algorithms for this problem, we have created a video benchmark with several videos captured under various conditions. We analyze the time and memory needed by the above 6 algorithms, for both CPU and GPU implementations (where readily parallelizable). The visual quality provided by these algorithms is also evaluated both objectively and subjectively. The video benchmark and algorithm implementations are publicly available1. PMID- 29993601 TI - HEVC-EPIC: Fast Optical Flow Estimation from Coded Video via Edge-Preserving Interpolation. AB - This paper presents a method leveraging coded motion information to obtain a fast, high quality motion field estimation. The method is inspired by a recent trend followed by a number of top-performing optical flow estimation schemes that first estimate a sparse set of features between two frames, and then use an edge preserving interpolation scheme (EPIC) to obtain a piecewise-smooth motion field that respects moving object boundaries. In order to skip the time-consuming estimation of features, we propose to directly derive motion seeds from decoded HEVC block motion; we call the resulting scheme "HEVCEPIC". We propose motion seed weighting strategies that account for the fact that some motion seeds are less reliable than others. Experiments on a large variety of challenging sequences and various bit-rates show that HEVC-EPIC runs significantly faster than EPIC flow, while producing motion fields that have a slightly lower average endpoint error (A-EPE). HEVC-EPIC opens the door of seamlessly integrating HEVC motion into video analysis and enhancement tasks. When employed as input to a framerate upsampling scheme, the average Y-PSNR of the interpolated frames using HEVC-EPIC motion slightly outperforms EPIC flow across the tested bit-rates, while running an order of magnitude faster. PMID- 29993602 TI - Exploration Strategies for Discovery of Interactivity in Visualizations. AB - We investigate how people discover the functionality of an interactive visualization that was designed for the general public. While interactive visualizations are increasingly available for public use, we still know little about how the general public discovers what they can do with these visualizations and what interactions are available. Developing a better understanding of this discovery process can help inform the design of visualizations for the general public, which in turn can help make data more accessible. To unpack this problem, we conducted a lab study in which participants were free to use their own methods to discover the functionality of a connected set of interactive visualizations of public energy data. We collected eye movement data and interaction logs as well as video and audio recordings. By analyzing this combined data, we extract exploration strategies that the participants employed to discover the functionality in these interactive visualizations. These exploration strategies illuminate possible design directions for improving the discoverability of a visualization's functionality. PMID- 29993603 TI - Lineage: Visualizing Multivariate Clinical Data in Genealogy Graphs. AB - The majority of diseases that are a significant challenge for public and individual heath are caused by a combination of hereditary and environmental factors. In this paper we introduce Lineage, a novel visual analysis tool designed to support domain experts that study such multifactorial diseases in the context of genealogies. Incorporating familial relationships between cases can provide insights on shared genomic variants that could be implicated in diseases, but also into shared environmental exposures. We introduce a data and task abstraction and argue that the problem of analyzing such diseases based on genealogical, clinical, and genetic data can be mapped to a multivariate graph visualization problem. The main contribution of our design study is a novel visual representation for tree-like, multivariate graphs, which we apply to genealogies and clinical data about the individuals in these families. We introduce data-driven aggregation methods to scale to multiple families. By designing the genealogy graph layout to align with a tabular view, we are able to incorporate extensive, multivariate attributes in the analysis of the genealogy without cluttering the graph. We validate our designs by conducting multiple case studies with our domain collaborators. PMID- 29993604 TI - Temporal Upsampling of Depth Maps Using a Hybrid Camera. AB - In recent years consumer-level depth cameras have been adopted in various applications. However, they often produce depth maps at a not very high fram-rate (around 30 frames per second), preventing them from being used for applications like digitizing human performance involving fast motion. On the other hand there are available low-cost high frame-rate video cameras. This motivates us to develop a hybrid camera that consists of a high frame-rate video camera and a low frame-rate depth camera, and to allow temporal interpolation of depth maps with the help of auxiliary color images. To achieve this we develop a novel algorithm that reconstructs intermediate depth maps and estimates scene flow simultaneously. We have tested our algorithm on various examples involving fast, non-rigid motions of single or multiple objects. Our experiments show that our scene flow estimation method is more precise than a purely tracking based method and the state-of-the-art techniques. PMID- 29993605 TI - Local Traces: An Over-Approximation of the Behavior of the Proteins in Rule-Based Models. AB - Thanks to rule-based modelling languages, we can assemble large sets of mechanistic protein-protein interactions within integrated models. Our goal would be to understand how the behavior of these systems emerges from these low-level interactions. Yet, this is a quite long term challenge and it is desirable to offer intermediary levels of abstraction, so as to get a better understanding of the models and to increase our confidence within our mechanistic assumptions. To this extend, static analysis can be used to derive various abstractions of the semantics, each of them offering new perspectives on the models. We propose an abstract interpretation of the behavior of each protein, in isolation. Given a model written in Kappa, this abstraction computes for each kind of proteins a transition system that describes which conformations this protein may take and how a protein may pass from one conformation to another one. Then, we use simplicial complexes to abstract away the interleaving order of the transformations between conformations that commute. As a result, we get a compact summary of the potential behavior of each protein of the model. PMID- 29993606 TI - Comorbidity Scoring with Causal Disease Networks. AB - In recent years, there have been studies constructing disease network with diverse sources of data. Researchers attempted to extend the usage of disease network by employing machine learning algorithms on various problems such as comorbidity prediction. The relations between diseases can be specified into causalities. When causality is laid on the edges, comorbidity prediction can be improved. However, not many algorithms have been developed to concern causality. In this study, we exploit a network based machine learning algorithm that generates comorbidity scores from a causal disease network. To find comorbid diseases, semi-supervised scoring for causal networks is proposed. It computes scores of entire nodes in the network. Each score is calculated one at a time and affects to the others along causal edges. The algorithm iterates until it converges. We compared the scoring results of the causal disease network with the association network. As a gold standard, we referenced relative risk from prevalence database. The proposed method provides clearer distinguishability between the top-ranked diseases in the list. This benefits as to choose the most significant ones on an easier fashion. To present typical use of the resulting list, comorbid diseases of Huntington disease and Pneumonia are validated via PubMed literatures. PMID- 29993607 TI - Promises and Challenges in the Use of Consumer-Grade Devices for Sleep Monitoring. AB - The market for smartphones, smartwatches, and wearable devices is booming. In recent years, individuals and researchers have used these devices as additional tools to monitor and track sleep, physical activity, and behavior. Their use in sleep research and clinical applications could address the difficulties in scaling up studies that rely on polysomnography, the gold-standard. However, the use of commercial devices for large-scale sleep studies is not without challenges. With this in mind, this paper presents an extensive review of sleep monitoring systems and the techniques used in their development. We also discuss their performance in terms of reliability and validity, and consider the needs and expectations of users, whether they are experts, patients, or the general public. Through this review, we highlight a number of challenges with current studies: a lack of standard evaluation methods for consumer-grade devices (e.g., reliability and validity assessment); limitations in the populations studied; consumer expectations of monitoring devices; constraints on the resources of consumer-grade devices (e.g., power consumption). PMID- 29993608 TI - Deep Sparse Tensor Filtering Network for Synthetic Aperture Radar Images Classification. AB - Recognizing scenes from synthetic aperture radar (SAR) images has been a challenging task due to the increasing resolution of SAR data. Extracting discriminative features from SAR images is extremely difficult for their sensitivity to target aspect. Considering the intractability of the available deep neural networks in practical implementations, in this brief, we propose a simple and efficient deep sparse tensor filtering network (DSTFN) for SAR image classification. An SAR image is first organized into a data tensor by an overlapped partition. Then, a set of dimension-inseparable geometric filters is developed from a least squares support vector machine, followed by a learned sparse filtering of tensors. Finally, the constructed sparse tensor filters are cascaded to a deep network to automatically extract the discriminative features of the image for accurate classification. Simulations are carried out to verify the effectiveness of the proposed DSTFN. PMID- 29993609 TI - Efficient Reinforcement Learning via Probabilistic Trajectory Optimization. AB - We present a trajectory optimization approach to reinforcement learning in continuous state and action spaces, called probabilistic differential dynamic programming (PDDP). Our method represents systems dynamics using Gaussian processes (GPs), and performs local dynamic programming iteratively around a nominal trajectory in Gaussian belief spaces. Different from model-based policy search methods, PDDP does not require a policy parameterization and learns a time varying control policy via successive forward-backward sweeps. A convergence analysis of the iterative scheme is given, showing that our algorithm converges to a stationary point globally under certain conditions. We show that prior model knowledge can be incorporated into the proposed framework to speed up learning, and a generalized optimization criterion based on the predicted cost distribution can be employed to enable risk-sensitive learning. We demonstrate the effectiveness and efficiency of the proposed algorithm using nontrivial tasks. Compared with a state-of-the-art GP-based policy search method, PDDP offers a superior combination of learning speed, data efficiency, and applicability. PMID- 29993610 TI - Multiview Clustering via Unified and View-Specific Embeddings Learning. AB - Multiview clustering, which aims at using multiple distinct feature sets to boost clustering performance, has a wide range of applications. A subspace-based approach, a type of widely used methods, learns unified embedding from multiple sources of information and gives a relatively good performance. However, these methods usually ignore data similarity rankings; for example, example A may be more similar to B than C, and such similarity triplets may be more effective in revealing the data cluster structure. Motivated by recent embedding methods for modeling knowledge graph in natural-language processing, this paper proposes to mimic different views as different relations in a knowledge graph for unified and view-specific embedding learning. Moreover, in real applications, it happens so often that some views suffer from missing information, leading to incomplete multiview data. Under such a scenario, the performance of conventional multiview clustering degenerates notably, whereas the method we propose here can be naturally extended for incomplete multiview clustering, which enables full use of examples with incomplete feature sets for model promotion. Finally, we demonstrate through extensive experiments that our method performs better than the state-of-the-art clustering methods. PMID- 29993612 TI - A Game-Theoretic Approach to Design Secure and Resilient Distributed Support Vector Machines. AB - Distributed support vector machines (DSVMs) have been developed to solve large scale classification problems in networked systems with a large number of sensors and control units. However, the systems become more vulnerable, as detection and defense are increasingly difficult and expensive. This paper aims to develop secure and resilient DSVM algorithms under adversarial environments in which an attacker can manipulate the training data to achieve his objective. We establish a game-theoretic framework to capture the conflicting interests between an adversary and a set of distributed data processing units. The Nash equilibrium of the game allows predicting the outcome of learning algorithms in adversarial environments and enhancing the resilience of the machine learning through dynamic distributed learning algorithms. We prove that the convergence of the distributed algorithm is guaranteed without assumptions on the training data or network topologies. Numerical experiments are conducted to corroborate the results. We show that the network topology plays an important role in the security of DSVM. Networks with fewer nodes and higher average degrees are more secure. Moreover, a balanced network is found to be less vulnerable to attacks. PMID- 29993611 TI - A Supervised Learning Algorithm for Learning Precise Timing of Multiple Spikes in Multilayer Spiking Neural Networks. AB - There is a biological evidence to prove information is coded through precise timing of spikes in the brain. However, training a population of spiking neurons in a multilayer network to fire at multiple precise times remains a challenging task. Delay learning and the effect of a delay on weight learning in a spiking neural network (SNN) have not been investigated thoroughly. This paper proposes a novel biologically plausible supervised learning algorithm for learning precisely timed multiple spikes in a multilayer SNNs. Based on the spike-timing-dependent plasticity learning rule, the proposed learning method trains an SNN through the synergy between weight and delay learning. The weights of the hidden and output neurons are adjusted in parallel. The proposed learning method captures the contribution of synaptic delays to the learning of synaptic weights. Interaction between different layers of the network is realized through biofeedback signals sent by the output neurons. The trained SNN is used for the classification of spatiotemporal input patterns. The proposed learning method also trains the spiking network not to fire spikes at undesired times which contribute to misclassification. Experimental evaluation on benchmark data sets from the UCI machine learning repository shows that the proposed method has comparable results with classical rate-based methods such as deep belief network and the autoencoder models. Moreover, the proposed method can achieve higher classification accuracies than single layer and a similar multilayer SNN. PMID- 29993613 TI - Event-Triggered Cooperative Global Robust Practical Output Regulation for Second Order Uncertain Nonlinear Multiagent Systems. AB - In this paper, we study the cooperative global robust practical output regulation problem for a class of second-order uncertain nonlinear multiagent systems via a distributed event-triggered state feedback control strategy. Compared with the existing work, one of the main challenges is that we need to design two distributed internal models to learn both the desired steady-state state and steady-state input for each agent. Moreover, to obtain a directly implementable digital control law, the two distributed internal models of each agent only depend on the sampled states of the neighboring agents and itself. As a result, the resulting augmented system is more complicated, and the control law needs to be recursively designed. To overcome the difficulty, we propose a novel distributed event-triggered control law and a novel distributed event-triggered mechanism to deal with our problem. By adjusting a design parameter in the proposed event-triggered mechanism, we show that the Zeno behavior does not happen and the ultimate bound of the tracking error can be made arbitrarily small. Our design will be illustrated by two examples. PMID- 29993614 TI - Recursive Neural Networks for Density Estimation Over Generalized Random Graphs. AB - Structured data in the form of labeled graphs (with variable order and topology) may be thought of as the outcomes of a random graph (RG) generating process characterized by an underlying probabilistic law. This paper formalizes the notions of generalized RG (GRG) and probability density function (pdf) for GRGs. Thence, a "universal" learning machine (combining the encoding module of a recursive neural network and a radial basis functions' network) is introduced for estimating the unknown pdf from an unsupervised sample of GRGs. A maximum likelihood training algorithm is presented and constrained so as to ensure that the resulting model satisfies the axioms of probability. Techniques for preventing the model from degenerate solutions are proposed, as well as variants of the algorithm suitable to the tasks of graphs classification and graphs clustering. The major properties of the machine are discussed. The approach is validated empirically through experimental investigations in the estimation of pdfs for synthetic and real-life GRGs, in the classification of images from the Caltech Benchmark data set and molecules from the Mutagenesis data set, and in clustering of images from the LabelMe data set. PMID- 29993615 TI - Optimized Backstepping for Tracking Control of Strict-Feedback Systems. AB - In this paper, a control technique named optimized backstepping is first proposed by implementing tracking control for a class of strict-feedback systems, which considers optimization as a design philosophy of the high-order system control. The basic idea is that designing the actual and virtual controls of backstepping is the optimized solutions of the corresponding subsystems so that overall control of the high-order system is optimized. In general, optimization control is designed based on the solution of Hamilton-Jacobi-Bellman equation, but solving the equation is very difficult due to the inherent nonlinearity and intractability. In order to overcome the difficulty, the neural network (NN) based reinforcement learning strategy of actor-critic architecture is used. In every backstepping step, the actor and critic NNs are constructed for executing control behavior and evaluating control performance, respectively. According to the Lyapunov stability theorem, it is proven that the desired control performance can be obtained. Finally, a simulation example is carried out to further demonstrate the effectiveness of the proposed control approach. PMID- 29993616 TI - Optimizing Kernel Machines Using Deep Learning. AB - Building highly nonlinear and nonparametric models is central to several state-of the-art machine learning systems. Kernel methods form an important class of techniques that induce a reproducing kernel Hilbert space (RKHS) for inferring non-linear models through the construction of similarity functions from data. These methods are particularly preferred in cases where the training data sizes are limited and when prior knowledge of the data similarities is available. Despite their usefulness, they are limited by the computational complexity and their inability to support end-to-end learning with a task-specific objective. On the other hand, deep neural networks have become the de facto solution for end-to end inference in several learning paradigms. In this paper, we explore the idea of using deep architectures to perform kernel machine optimization, for both computational efficiency and end-to-end inferencing. To this end, we develop the deep kernel machine optimization framework, that creates an ensemble of dense embeddings using Nystrom kernel approximations and utilizes deep learning to generate task-specific representations through the fusion of the embeddings. Intuitively, the filters of the network are trained to fuse information from an ensemble of linear subspaces in the RKHS. Furthermore, we introduce the kernel dropout regularization to enable improved training convergence. Finally, we extend this framework to the multiple kernel case, by coupling a global fusion layer with pretrained deep kernel machines for each of the constituent kernels. Using case studies with limited training data, and lack of explicit feature sources, we demonstrate the effectiveness of our framework over conventional model inferencing techniques. PMID- 29993617 TI - Complex Gaussian Processes for Regression. AB - In this paper, we propose a novel Bayesian solution for nonlinear regression in complex fields. Previous solutions for kernels methods usually assume a complexification approach, where the real-valued kernel is replaced by a complex valued one. This approach is limited. Based on the results in complex-valued linear theory and Gaussian random processes, we show that a pseudo-kernel must be included. This is the starting point to develop the new complex-valued formulation for Gaussian process for regression (CGPR). We face the design of the covariance and pseudo-covariance based on a convolution approach and for several scenarios. Just in the particular case where the outputs are proper, the pseudo kernel cancels. Also, the hyperparameters of the covariance can be learned maximizing the marginal likelihood using Wirtinger's calculus and patterned complex-valued matrix derivatives. In the experiments included, we show how CGPR successfully solves systems where the real and imaginary parts are correlated. Besides, we successfully solve the nonlinear channel equalization problem by developing a recursive solution with basis removal. We report remarkable improvements compared to previous solutions: a 2-4-dB reduction of the mean squared error with just a quarter of the training samples used by previous approaches. PMID- 29993618 TI - Deep Cascade Learning. AB - In this paper, we propose a novel approach for efficient training of deep neural networks in a bottom-up fashion using a layered structure. Our algorithm, which we refer to as deep cascade learning, is motivated by the cascade correlation approach of Fahlman and Lebiere, who introduced it in the context of perceptrons. We demonstrate our algorithm on networks of convolutional layers, though its applicability is more general. Such training of deep networks in a cascade directly circumvents the well-known vanishing gradient problem by ensuring that the output is always adjacent to the layer being trained. We present empirical evaluations comparing our deep cascade training with standard end-end training using back propagation of two convolutional neural network architectures on benchmark image classification tasks (CIFAR-10 and CIFAR-100). We then investigate the features learned by the approach and find that better, domain specific, representations are learned in early layers when compared to what is learned in end-end training. This is partially attributable to the vanishing gradient problem that inhibits early layer filters to change significantly from their initial settings. While both networks perform similarly overall, recognition accuracy increases progressively with each added layer, with discriminative features learned in every stage of the network, whereas in end-end training, no such systematic feature representation was observed. We also show that such cascade training has significant computational and memory advantages over end-end training, and can be used as a pretraining algorithm to obtain a better performance. PMID- 29993619 TI - Evolutionary ensemble learning algorithm to modeling of warfarin dose prediction for Chinese. AB - An evolutionary ensemble modeling (EEM) method is developed to improve the accuracy of warfarin dose prediction. In EEM, genetic programming (GP) evolves diverse base models, and genetic algorithm optimizes the parameters of the GP. The EEM model is assembled by using the prepared based models through a technique called "bagging." In the experiment, a dataset of 289 Chinese patients, which is provided by The First Affiliated Hospital of Soochow University, is used for training, validation, and testing. The EEM model with selected feature groups is benchmarked with four machine-learning methods and three conventional regression models. Results show that the EEM model with M2+G group, namely, age, height, weight, gender, CYP2C9, VKORC1, and amiodarone, presents the largest coefficients of determination (R2), highest percentage of predicted dose within 20% of the actual dose (20%-p), smallest mean absolute error (mae), mean squared error (mse), root-mse on the test set, and the least decrease in R2 from the training set to the test set. In conclusion, the EEM method with M2+G delivers superior performance and can therefore be a suitable prediction model of warfarin dose for clinical application. PMID- 29993620 TI - Automatic analysis of food intake and meal microstructure based on continuous weight measurements. AB - The structure of the cumulative food intake (CFI) curve has been associated with obesity and eating disorders. Scales that record the weight loss of a plate from which a subject eats food are used for capturing this curve; however, their measurements are contaminated by additive noise and are distorted by certain types of artifacts. This paper presents an algorithm for automatically processing continuous in-meal weight measurements in order to extract the clean CFI curve and in-meal eating indicators, such as total food intake and food intake rate. The algorithm relies on the representation of the weight-time series by a string of symbols that correspond to events such as bites or food additions. A context free grammar is next used to model a meal as a sequence of such events. The selection of the most likely parse tree is finally used to determine the predicted eating sequence. The algorithm is evaluated on a dataset of 113 meals collected using the Mandometer, a scale that continuously samples plate weight during eating. We evaluate the effectiveness for seven indicators, and for bite instance detection. We compare our approach with three state-of-the-art algorithms, and achieve the lowest error rates for most indicators (24 g for total meal weight). The proposed algorithm extracts the parameters of the CFI curve automatically, eliminating the need for manual data processing, and thus facilitating large-scale studies of eating behavior. PMID- 29993621 TI - Consensus of Heterogeneous Linear Multiagent Systems Subject to Aperiodic Sampled Data and DoS Attack. AB - In this paper, the robust output consensus problem for a class of heterogeneous linear multiagent systems (MASs) in presence of aperiodic sampling and random deny-of-service (DoS) attack is investigated. A novel distributed output-feedback control strategy is proposed so that the controlled MAS achieves the objective of output consensus in spite of aperiodic sampling and DoS attack. By assuming that the sampling process is nonuniform and the consecutive attack duration is upper bounded, the closed-loop control system is first described as a discrete-time switched stochastic delay system. Some sufficient conditions are then obtained for the solvability of the secure consensus problem. Furthermore, a constructive design procedure for the proposed controller is then presented. Finally, a simulation example is introduced to illustrate the effectiveness of controller design. PMID- 29993622 TI - Nonfragile Sampled-Data Control for Uncertain Networked Control Systems With Additive Time-Varying Delays. AB - This paper investigates the stabilization problem of uncertain networked control systems with additive time-varying delays by using nonfragile sampled-data control. Suitable Lyapunov-Krasovskii functional (LKF) is constructed which includes more information about the additive time-varying delays. The main aim of this paper is to design a nonfragile sampled-data control scheme which guarantees asymptotic stability of the considered system. Besides that, the Jensen's and improved integral inequalities are used for estimating the single and double integral terms in the derivative of LKFs and the sufficient conditions are expressed in terms of linear matrix inequalities. Finally, the effectiveness of proposed theoretical results are validated and compared with existing literature by numerical examples and their simulation results. PMID- 29993623 TI - Adaptive Neural Tracking Control for Interconnected Switched Systems With Non-ISS Unmodeled Dynamics. AB - The adaptive neural network tracking control problem is investigated for a class of interconnected switched systems. The considered systems are with unmodeled dynamics, some of which do not satisfy the input-to-state stable (ISS) condition. By utilizing the neural network to approximate the composite unknown nonlinear functions, the corresponding decentralized tracking controller is designed for each subsystem with the help of dynamic surface control method. Some subsystems are stable with the designed controller, while other subsystems may not be stable because of non-ISS unmodeled dynamics, but they have some special properties with the designed controller. Then, a novel switching signal scheme is established such that the interconnected switched system is stable in the sense of semi global boundedness, and the tracking errors can converge to predefined residual sets with prescribed performance index. Moreover, the switching scheme allows the number of switches to grow faster than traditional average dwell time method. Finally, a numerical example is provided to demonstrate the effectiveness of the presented results. PMID- 29993624 TI - A Multiscale Fuzzy Metric for Detecting Small Infrared Targets Against Chaotic Cloudy/Sea-Sky Backgrounds. AB - In a low signal-to-clutter ratio (SCR) small-infrared-target image with chaotic cloudy-/sea-sky background, the target has very similar thermal intensities to the background (e.g., edges of clouds). In such case, how to accurately detect small targets is crucial in infrared search and tracking applications. Conventional methods based on the local difference/mutation potentially result in high miss and/or false alarm rates. Here, we propose an effective method for detecting small infrared targets embedded in complex backgrounds through a multiscale fuzzy metric that measures the certainty of targets in images. Accordingly, the detection task is formulated as a fuzzy measure issue. The presented metric is able to eliminate substantial background clutters and noise. Especially, it significantly improves SCR values of the image. Subsequently, a simple and adaptive threshold is used to segment target. Extensive clipped and real data experiments demonstrate that the proposed algorithm not only works more robustly for different target sizes, SCR values, target and/or background types, but also has better performance regarding detection accuracy, when compared with traditional baseline methods. Moreover, the mathematical proofs are provided for understanding the proposed detection method. PMID- 29993625 TI - Anchor-Free Correlated Topic Modeling. AB - In topic modeling, identifiability of the topics is an essential issue. Many topic modeling approaches have been developed under the premise that each topic has an anchor word, which may be fragile in practice, because words and terms have multiple uses; yet it is commonly adopted because it enables identifiability guarantees. Remedies in the literature include using three- or higher-order word co-occurence statistics to come up with tensor factorization models, but identifiability still hinges on additional assumptions. In this work, we propose a new topic identification criterion using second order statistics of the words. The criterion is theoretically guaranteed to identify the underlying topics even when the anchor-word assumption is grossly violated. An algorithm based on alternating optimization, and an efficient primal-dual algorithm are proposed to handle the resulting identification problem. The former exhibits high performance and is completely parameter-free; the latter affords up to 200 times speedup relative to the former, but requires step-size tuning and a slight sacrifice in accuracy. A variety of real text copora are employed to showcase the effectiveness of the approach, where the proposed anchor-free method demonstrates substantial improvements compared to a number of anchor-word based approaches under various evaluation metrics. PMID- 29993626 TI - A graph based image interpretation method using a priori qualitative inclusion and photometric relationships. AB - This paper presents a method for recovering and identifying image regions from an initial oversegmentation using qualitative knowledge of its content. Compared to recent works favoring spatial information and quantitative techniques, our approach focuses on simple a priori qualitative inclusion and photometric relationships such as "region A is included in region B", "the intensity of region A is lower than the one of region B" or "regions A and B depict similar intensities" (photometric uncertainty). The proposed method is based on a two steps" inexact graph matching approach. The first step searches for the best subgraph isomorphism candidate between expected regions and a subset of regions resulting from the initial oversegmentation. Then, remaining segmented regions are progressively merged with appropriate already matched regions, while preserving the coherence with a priori declared relationships. Strengths and weaknesses of the method are studied on various images (grayscale and color), with various intial oversegmentation algorithms (k-means, meanshift, quickshift). Results show the potential of the method to recover, in a reasonable runtime, expected regions, a priori described in a qualitative manner. For further evaluation and comparison purposes, a Python opensource package implementing the method is provided, together with the specifically built experimental database. PMID- 29993627 TI - Recurrent Shape Regression. AB - An end-to-end network architecture, the Recurrent Shape Regression (RSR), is presented to deal with the task of facial shape detection, a crucial step in many computer vision problems. The RSR generalizes the conventional cascaded regression into a recurrent dynamic network through abstracting common latent models with stage-to-stage operations. Instead of invariant regression transformation, we construct shape-dependent dynamic regressors to attain the recurrence of regression action itself. The regressors can be stacked into a high order regression network to represent more complex shape regression. By further integrating feature learning as well as global shape constraint, the RSR becomes more controllable in entire optimization of shape regression, where the gradient computation can be efficiently back-propagated through time. To handle the possible partial occlusions of shapes, we propose a mimic virtual occlusion strategy by randomly disturbing certain point cliques without the requirement of any annotations of occlusion information or even occluded training data. Extensive experiments on five face datasets demonstrate that the proposed RSR is more competitive with the recent state-of-the-art cascaded approaches. PMID- 29993628 TI - Visual Dialog. AB - We introduce the task of Visual Dialog, which requires an AI agent to hold a meaningful dialog with humans in natural, conversational language about visual content. Specifically, given an image, a dialog history, and a question about the image, the agent has to ground the question in image, infer context from history, and answer the question accurately. Visual Dialog is disentangled enough from a specific downstream task so as to serve as a general test of machine intelligence, while being sufficiently grounded in vision to allow objective evaluation of individual responses and benchmark progress. We develop a novel two person real-time chat data-collection protocol to curate a large-scale Visual Dialog dataset (VisDial). VisDial v0.9 has been released and consists of dialog question-answer pairs from 10-round, human-human dialogs grounded in images from the COCO dataset. PMID- 29993629 TI - Graph-Based Rate Control in Pathology Imaging With Lossless Region of Interest Coding. AB - The increasing availability of digital pathology images has motivated the design of tools to foster multidisciplinary collaboration among researchers, pathologists, and computer scientists. Telepathology plays an important role in the development of collaborative tools, as it facilitates the transmission and access to pathology images by multiple users. However, the huge file size associated with pathology images usually prevents full exploitation of the collaborative telepathology system potential. Within this context, rate control (RC) is an important tool that allows meeting storage and bandwidth requirements by controlling the bit rate of the coded image. In this paper, we propose a novel graph-based RC algorithm with lossless region of interest (RoI) coding for pathology images. The algorithm, which is designed for block-based predictive transform coding methods, compresses the non-RoI in a lossy manner according to a target bit rate and the RoI in a lossless manner. It employs a graph where each node represents a constituent block of the image to be coded. By incorporating information about the coding cost similarities of blocks into the graph, a graph kernel is used to distribute a target bit budget among the non-RoI blocks. In order to increase RC accuracy, the algorithm uses a rate-lambda (R- ) model to approximate the slope of the rate-distortion curve of the non-RoI, and a graph based approach to guarantee that the target bit rate is accurately attained. The algorithm is implemented in the High-Efficiency Video Coding standard and tested over a wide range of pathology images with multiple RoIs. Evaluation results show that it outperforms the other state-of-the-art methods designed for single images by very accurately attaining the target bit rate of the non-RoI. PMID- 29993630 TI - Squeezed Trajectory Design for Peak RF and Integrated RF Power Reduction in Parallel Transmission MRI. AB - High peak RF amplitude and excessive specific absorption rate (SAR) are two critical concerns for hardware implementation and patient safety in scientific and clinical research for high field MRI using parallel transmissions (pTX). In this paper, we introduce a squeezing strategy to reduce peak RF amplitude and integrated RF power via direct reshaping of the k-space trajectory. In the existing peak RF / integrated RF power optimization methods gradient amplitude or slew rate is reduced, but the k-space trajectory remains unchanged. Unlike these traditional methods, we worked directly in the excitation k-space to reshape k space traversal by a squeezing vector in order to achieve peak RF and total RF power optimization, using a particle swarm optimization algorithm. The squeezing strategy was applied to the conventional variable density spiral (CVDS) and the variable rate selective excitation (VERSE) trajectories, dubbed SVDS (squeezed variable density spiral) and SVERSE (squeezing trajectory with VERSE), respectively, for different excitation profiles of small or large tip angles. Pulse acceleration and off-resonance effects were evaluated for an 8-ch pTX via Bloch simulation. CVDS, VERSE, SVDS, and SVERSE pulses were implemented on a 3T scanner with a 2-ch pTX. Phantom and in vivo experiments were performed for reduced FOV (rFOV) imaging. The results show that SVDS pulses simultaneously reduce integrated RF power and peak RF by about 30% on average compared to CVDS pulses for a square pattern ( $80?times80$ mm2) with flip angles of 30 degrees , 90 degrees , and 180 degrees . Compared with the VERSE method under the same peak RF constraints, the SVDS method reduces integrated RF power by an average of 20% for small tip excitations for profiles of slice, rectangular, square, and circle, and has slightly reduced excitation accuracy slightly (about 0.6%, from 6.8% to 7.4%). The SVERSE method shortens the duration of the VERSE pulse by 12.8% at large ti p angle (180 degrees ). Feasibility for rFOV imaging was demonstrated with phantom and in vivo experiments with squeezed pulses. PMID- 29993631 TI - Ferroelectric Domain Continuity Over Grain Boundaries for Tetragonal, Orthorhombic, and Rhombohedral Crystal Symmetries. AB - Domain mobility is understood to have a significant impact on ferroelectric material properties. Grain boundaries are known to inhibit ferroelectric domain wall mobility, thereby limiting the properties of polycrystalline ferroelectrics. Continuous domains across grain boundaries can change the grain boundary impact on domain wall mobility. Such microstructures have been observed since the 1950s, but their impact on properties is not well understood. This paper predicts the likelihood of domain wall continuity over grain boundaries for typical perovskite oxide ferroelectric symmetries of tetragonal, orthorhombic, and rhombohedral. Five two-grain systems are studied for domain continuity over all possible grain boundary space. Results show that rhombohedral and orthorhombic symmetries have a higher probability for domain continuity over grain boundaries as compared with tetragonal symmetry. This observation is due to the greater number of domain wall planes and polarization vectors in these symmetries. Grain boundaries probable for domain continuity can be identified in each misorientation for each symmetry. This knowledge, combined with developments in microstructural measurements and ceramic processing techniques, may be used to control domain continuity at grain boundaries, and hence, influence the final properties of the material. PMID- 29993632 TI - Enhanced Ultrasonic Flaw Detection using an Ultra-high Gain and Time-dependent Threshold. AB - In an attempt to improve the ultrasonic testing capability of a conventional C scan system, a flaw detection method using an ultra-high gain is developed in this paper. A time-dependent threshold for image segmentation is applied to identify automatically material anomalies present in the sample. A singly scattered response (SSR) model is used with extreme value statistics to calculate the confidence bounds of grain noise. The result is a time-dependent threshold associated with the grain noise that can be used for segmentation. Ultrasonic imaging experiments show that the presented method has advantages over a traditional fixed threshold approach with respect to false positives and missed flaws. The results also show that a low gain is adverse to the detection of micro flaws with subwavelength dimensions. The forward model is expected to serve as an effective tool for the probability of detection (POD) of flaws and the inspection of coarse-grained materials in the future. PMID- 29993633 TI - Deep Active Learning with Contaminated Tags for Image Aesthetics Assessment. AB - Image aesthetic quality assessment has becoming an indispensable technique that facilitates a variety of image applications, e.g., photo retargeting and non realistic rendering. Conventional approaches suffer from the following limitations: 1) the inefficiency of semantically describing images due to the inherent tag noise and incompletion, 2) the difficulty of accurately reflecting how humans actively perceive various regions inside each image, and 3) the challenge of incorporating the aesthetic experiences of multiple users. To solve these problems, we propose a novel semi-supervised deep active learning (SDAL) algorithm, which discovers how humans perceive semantically important regions from a large quantity of images partially assigned with contaminated tags. More specifically, as humans usually attend to the foreground objects before understanding them, we extract a succinct set of BING (binarized normed gradients) [60]-based object patches from each image. To simulate human visual perception, we propose SDAL which hierarchically learns human gaze shifting path (GSP) by sequentially linking semantically important object patches from each scenery. Noticeably, SDLA unifies the semantically important regions discovery and deep GSP feature learning into a principled framework, wherein only a small proportion of tagged images are adopted. Moreover, based on the sparsity penalty, SDLA can optimally abandon the noisy or redundant low-level image features. Finally, by leveraging the deeply-learned GSP features, a probabilistic model is developed for image aesthetics assessment, where the experience of multiple professional photographers can be encoded. Besides, auxiliary quality-related features can be conveniently integrated into our probabilistic model. Comprehensive experiments on a series of benchmark image sets have demonstrated the superiority of our method. As a byproduct, eye tracking experiments have shown that GSPs generated by our SDAL are about 93% consistent with real human gaze shifting paths. PMID- 29993634 TI - Minimum Spanning Forest with Embedded Edge Inconsistency Measurement Model for Guided Depth Map Enhancement. AB - Guided depth map enhancement based on Markov Random Field (MRF) normally assumes edge consistency between the color image and the corresponding depth map. Under this assumption, the low-quality depth edges can be refined according to the guidance from the high-quality color image. However, such consistency is not always true, which leads to texture-copying artifacts and blurring depth edges. In addition, the previous MRF-based models always calculate the guidance affinities in the regularization term via a non-structural scheme which ignores the local structure on the depth map. In this paper, a novel MRF-based method is proposed. It computes these affinities via the distance between pixels in a space consisting of the Minimum Spanning Trees (Forest) to better preserve depth edges. Furthermore, inside each Minimum Spanning Tree, the weights of edges are computed based on explicit edge inconsistency measurement model, which significantly mitigates texture-copying artifacts. To further tolerate the effects caused by noise and better preserve depth edges, a bandwidth adaption scheme is proposed. Our method is evaluated for depth map super-resolution and depth map completion problems on synthetic and real datasets including Middlebury, ToF-Mark and NYU. A comprehensive comparison against 16 state-of-the-art methods is carried out. Both qualitative and quantitative evaluation present the improved performances. PMID- 29993635 TI - Multispectral Image Restoration via Inter- and Intra-block Sparse Estimation based on Physically-induced Joint Spatiospectral Structures. AB - Existing low-level vision algorithms (e.g., those for superresolution, denoising, deblurring etc.) were primarily motivated and optimized for precision in spatial domain. However, high precision in spectral domain is of importance for many applications in scientific and technical fields, such as spectral analysis, recognition, and classification. In quest for both high spectral and spatial fidelity we introduce previously-unexplored, physically-induced, joint spatiospectral sparsities to improve existing methods for multispectral image restoration. The bidirectional image formation model is used to reveal that the discontinuities of a multispectral image tend to align spatially across different spectral bands; in other words, the 2D Laplacians of different bands are not only sparse each, but they also agree with one the other in significance positions. Such strongly structured sparsities give rise to a new inter-and intra-block sparse estimation approach. The estimation is performed on 3D spatiospectral sample blocks, rather than on separate 2D patches, one per spectral band or per luminance and chrominance component as in current practice. Moreover, intra-block and inter-block sparsity priors are combined via an intra-block l1,2-norm minimization term and an inter-block low rank term, strengthening the regularization of the underlying inverse problem. The new approach is tested and evaluated on two concrete applications: superresolving and denoising multispectral images; its validity and advantages over the current state of the art are established by empirical results. PMID- 29993636 TI - Robust Tracing and Visualization of Heterogeneous Microvascular Networks. AB - Advances in high-throughput imaging allow researchers to collect three dimensional images of whole organ microvascular networks. These images are extremely large, and contain networks that are highly complex. As a result, these data sets are time consuming to segment and difficult to visualize. In this paper, we present a framework for segmenting and visualizing vascular networks from terabyte-sized three-dimensional images collected using high-throughput microscopy. While these images require terabytes of storage, the volume devoted to the fiber network is of the total volume size. While the networks themselves are sparse, they are tremendously complex, interconnected, and vary widely in diameter. We describe a parallel GPU-based predictor-corrector method for tracing filaments that is robust to noise and sampling errors common in these data sets. We also propose a number of visualization techniques designed to convey the complex statistical descriptions of fibers across large tissue sections - including commonly studied microvascular characteristics, such as orientation and volume. PMID- 29993637 TI - StreamStory: Exploring Multivariate Time Series on Multiple Scales. AB - This paper presents an approach for the interactive visualization, exploration and interpretation of large multivariate time series. Interesting patterns in such datasets usually appear as periodic or recurrent behavior often caused by the interaction between variables. To identify such patterns, we summarize the data as conceptual states, modeling temporal dynamics as transitions between the states. This representation can visualize large datasets with potentially billions of examples. We extend the representation to multiple spatial granularities allowing the user to find patterns on multiple scales. The result is an interactive web-based tool called StreamStory. StreamStory couples the abstraction with several tools that map the abstractions back to domain-specific concepts using techniques from statistics and machine learning. It is aimed at users who are not experts in data analytics, minimizing the number of parameters to configure out-of-the-box. We use three real-world datasets to demonstrate how StreamStory can be used to perform three main visual analytics tasks: identify the main states of a complex system and map them back to data-specific concepts, find high-level and long-term periodic behavior and traverse the scales to identify which scales exhibit interesting phenomena. We find and interpret several known, as well as previously unknown patterns in these datasets. PMID- 29993638 TI - Multi-Normal Estimation via Pair Consistency Voting. AB - The normals of feature points, i.e., the intersection points of multiple smooth surfaces, are ambiguous and undefined. This paper presents a unified definition for point cloud normals of feature and non-feature points, which allows feature points to possess multiple normals. This definition facilitates several succeeding operations, such as feature points extraction and point cloud filtering. We also develop a feature preserving normal estimation method which outputs multiple normals per feature point. The core of the method is a pair consistency voting scheme. All neighbor point pairs vote for the local tangent plane. Each vote takes the fitting residuals of the pair of points and their preliminary normal consistency into consideration. Thus the pairs from the same subspace and relatively far off features dominate the voting. An adaptive strategy is designed to overcome sampling anisotropy. In addition, we introduce an error measure compatible with traditional normal estimators, and present the first benchmark for normal estimation, composed of 152 synthesized data with various features and sampling densities, and 288 real scans with different noise levels. Comprehensive and quantitative experiments show that our method generates faithful feature preserving normals and outperforms previous cutting edge normal estimation methods, including the latest deep learning based method. PMID- 29993639 TI - A Novel Method for LncRNA-Disease Association Prediction Based on an lncRNA disease Association Network. AB - An increasing number of studies have indicated that long-non-coding RNAs (lncRNAs) play critical roles in many important biological processes. Predicting potential lncRNAdisease associations can improve our understanding of the molecular mechanisms of human diseases and aid in finding biomarkers for disease diagnosis, treatment, and prevention. In this paper, we constructed a bipartite network based on known lncRNA-disease associations; based on this work, we proposed a novel model for inferring potential lncRNA disease associations. Specifically, we analyzed the properties of the bipartite network and found that it closely followed a power-law distribution. Moreover, to evaluate the performance of our model, a leaveone-out cross-validation (LOOCV) framework was implemented, and the simulation results showed that our computational model significantly outperformed previous state-of-the-art models, with AUCs of 0.8825, 0.9004 and 0.9292 for known lncRNAdisease associations obtained from the LncRNADisease database, Lnc2Cancer database, and MNDR database, respectively. Thus, our approach may be an excellent addition to the biomedical research field in the future. PMID- 29993640 TI - Dynamical Detection of Boundaries and Cavities in Biophysical Cell-based Simulations of Growing Tumor Tissues. AB - Cell-based lattice-free simulations of the growth of tumor tissues require the definition of geometrical and topological relations among cells and the other basic elements of the simulation (most notably the local and the global environment). This is necessary for the correct description of the biochemistry of tumor tissues, and to implement the biomechanical interactions among cells. Weak cell-cell forces and the necrosis of tumor tissues due to poor vascularization can lead to the formation of cavities -- i.e., regions without viable cells and filled with cellular debris and fluids. It is important to give an accurate geometrical/topological description of the resulting microenvironment that plays an important role in the pathology of cancer. In this paper, we concentrate on simulations of the growth of avascular solid tumors and we describe the STAR (Shape of Tumours from Algorithmic Reconstruction) algorithm that defines the shape of clusters of cells and searches for the boundary and cavities in a 3D environment. The algorithm is GPU-based and exploits the high degree of parallelism of GPUs. The final implementation achieves a 30-fold speedup with respect to a previous CPU-based version. PMID- 29993642 TI - Efficient Mining Multi-mers in a Variety of Biological Sequences. AB - Counting the occurrence frequency of each -mer in a biological sequence is a preliminary yet important step in many bioinformatics applications. However, most -mer counting algorithms rely on a given k to produce single-length -mers, which is inefficient for sequence analysis for different k. Moreover, existing -mer counters focus more on DNA and RNA sequences and less on protein ones. In practice, the analysis of -mers in protein sequences can provide substantial biological insights in structure, function and evolution. To this end, an efficient algorithm, called MulMer (Multiple-Mer mining), is proposed to mine mers of various lengths termed multi-mers via inverted-index technique, which is orders of magnitude faster than the conventional forward-index methods. Moreover, to the best of our knowledge, MulMer is the first able to mine multi-mers in a variety of sequences, including DNARNA and protein sequences. PMID- 29993641 TI - A Distributed Classifier for MicroRNA Target Prediction with Validation Through TCGA Expression Data. AB - BACKGROUND: MicroRNAs (miRNAs) are approximately 22-nucleotide long regulatory RNA that mediate RNA interference by binding to cognate mRNA target regions. Here, we present a distributed kernel SVM-based binary classification scheme to predict miRNA targets. It captures the spatial profile of miRNA-mRNA interactions via smooth B-spline curves. This is accomplished separately for various input features, such as thermodynamic and sequence-based features. Further, we use a principled approach to uniformly model both canonical and non-canonical seed matches, using a novel seed enrichment metric. Finally, we verify our miRNA-mRNA pairings using an Elastic Net-based regression model on TCGA expression data for four cancer types to estimate the miRNAs that together regulate any given mRNA. RESULTS: We present a suite of algorithms for miRNA target prediction, under the banner Avishkar, with superior prediction performance over the competition. Specifically, our final kernel SVM model, with an Apache Spark backend, achieves an average true positive rate (TPR) of more than 75 percent, when keeping the false positive rate of 20 percent, for non-canonical human miRNA target sites. This is an improvement of over 150 percent in the TPR for non-canonical sites, over the best-in-class algorithm. We are able to achieve such superior performance by representing the thermodynamic and sequence profiles of miRNA-mRNA interaction as curves, devising a novel seed enrichment metric, and learning an ensemble of miRNA family-specific kernel SVM classifiers. We provide an easy-to use system for large-scale interactive analysis and prediction of miRNA targets. All operations in our system, namely candidate set generation, feature generation and transformation, training, prediction, and computing performance metrics are fully distributed and are scalable. CONCLUSIONS: We have developed an efficient SVM-based model for miRNA target prediction using recent CLIP-seq data, demonstrating superior performance, evaluated using ROC curves for different species (human or mouse), or different target types (canonical or non-canonical). We analyzed the agreement between the target pairings using CLIP-seq data and using expression data from four cancer types. To the best of our knowledge, we provide the first distributed framework for miRNA target prediction based on Apache Hadoop and Spark. AVAILABILITY: All source code and sample data are publicly available at https://bitbucket.org/cellsandmachines/avishkar. Our scalable implementation of kernel SVM using Apache Spark, which can be used to solve large-scale non-linear binary classification problems, is available at https://bitbucket.org/cellsandmachines/kernelsvmspark. PMID- 29993643 TI - Why Deep Learning Is Changing the Way to Approach NGS Data Processing: A Review. AB - Nowadays, big data analytics in genomics is an emerging research topic. In fact, the large amount of genomics data originated by emerging next-generation sequencing (NGS) techniques requires more and more fast and sophisticated algorithms. In this context, deep learning is re-emerging as a possible approach to speed up the DNA sequencing process. In this review, we specifically discuss such a trend. In particular, starting from an analysis of the interest of the Internet community in both NGS and deep learning, we present a taxonomic analysis highlighting the major software solutions based on deep learning algorithms available for each specific NGS application field. We discuss future challenges in the perspective of cloud computing services aimed at deep learning based solutions for NGS. PMID- 29993644 TI - Review of Computational Techniques for Performance Evaluation of RF Localization inside the Human Body. AB - Location estimation within the human body by means of wireless signals is becoming popular for a variety of purposes, including wireless endoscopy using camera pills. The precision of wireless ranging in any medium is contingent upon the methodology employed. Two of the most popular wireless tracking methods are received signal strength (RSS) and time-of-arrival (TOA). The scope of this study is an assessment of the precision of TOA and RSS based ranging in the proximity of anthropomorphic tissue by means of simulation software designed to mimic signal transmission in the human body environment. Software simulations of wireless signals traveling within a human body are exceptionally challenging and require extensive computational resources. We created a rudimentary, MATLAB' script using finite difference time-domain (FDTD) method to simulate signal transmission inside and outside a human body and correlated the simulation outcomes of this script with the high end commercial finite element method (FEM) tool, ANSYS HFSS. First, we demonstrated that the FDTD modeling produces similar outcomes. Next, we employed the script to emulate the RSS and TOA of the wide bandwidth radio transmission within the human body for wireless ranging and estimated the accuracy of each technology. PMID- 29993645 TI - Detection and Automation Technologies for the Mass Production of Droplet Biomicrofluidics. AB - Droplet microfluidics utilizes two immiscible flows to generate small droplets with the diameter of a few to a few hundred micrometers. These droplets are promising tools for biomedical engineering because of the high throughput and the ease to finely tune the microenvironments. In addition to the great success of droplet biomicrofluidics in the proof-of-concept biosensing, regenerative medicine, and drug delivery, few droplet biomicrofluidic devices have a transformative impact on the industrial and clinical applications. The main issues are the low volume throughput and the lack of proper methods for quality control and automation. This review covers the methodologies for the mass production, detection, and automation of droplet generators. Recent advances in droplet mass production using parallelized devices and modified junction structures are discussed. Detection techniques, including optical and electrical detection methods, are comprehensively reviewed in detail. Newly emerged droplet closed-loop control systems are surveyed to highlight the progress in system integration and automation. Overall, with the advances in parallel droplet generation, highly sensitive detection, and robust closed-loop regulation, it is anticipated that the productivity and reliability of droplet biomicrofluidics will be significantly improved to meet the industrial and clinical needs. PMID- 29993646 TI - Prediction of Perceived Steering Wheel Operation Force by Muscle Activity. AB - Humans feel forces or weights while grasping and manipulating an object. There is a difference between the physical and perceived forces because the physical characteristics of an object and/or human psychophysical characteristics affect perceived force. Sense of effort plays an important role in deciding the movement made by humans. In this study, we propose a computational method to predict the perceived force by evaluating the muscle activity as a function of effort in the operation of a steering wheel based on a 3D musculoskeletal model simulation. We found that the perceived-force characteristics depend on the driving posture, though the applied force is the same. We evaluated the results, and showed that the mean of the absolute error is 1.78 N for the experiments conducted on four different vehicles in commercially available. PMID- 29993647 TI - Decentralized Global Optimization Based on a Growth Transform Dynamical System Model. AB - Conservation principles, such as conservation of charge, energy, or mass, provide a natural way to couple and constrain spatially separated variables. In this paper, we propose a dynamical system model that exploits these constraints for solving nonconvex and discrete global optimization problems. Unlike the traditional simulated annealing or quantum annealing-based global optimization techniques, the proposed method optimizes a target objective function by continuously evolving a driver functional over a conservation manifold, using a generalized variant of growth transformations. As a result, the driver functional asymptotically converges toward a Dirac-delta function that is centered at the global optimum of the target objective function. In this paper, we provide an outline of the proof of convergence for the dynamical system model and investigate different properties of the model using a benchmark nonlinear optimization problem. Also, we demonstrate how a discrete variant of the proposed dynamical system can be used for implementing decentralized optimization algorithms, where an ensemble of spatially separated entities (for example, biological cells or simple computational units) can collectively implement specific functions, such as winner-take-all and ranking, by exchanging signals only with its immediate substrate or environment. The proposed dynamical system model could potentially be used to implement continuous-time optimizers, annealers, and neural networks. PMID- 29993648 TI - Deep Convolutional Hashing for Low Dimensional Binary Embedding of Histopathological Images. AB - Compact binary representations of histopathology images using hashing methods provide efficient approximate nearest neighbor search for direct visual query in large-scale databases. They can be utilized to measure the probability of the abnormality of the query image based on the retrieved similar cases, thereby providing support for medical diagnosis. They also allow for efficient managing of large-scale image databases because of a low storage requirement. However, the effectiveness of binary representations heavily relies on the visual descriptors that represent the semantic information in the histopathological images. Traditional approaches with hand-crafted visual descriptors might fail due to significant variations in image appearance. Recently, deep learning architectures provide promising solutions to address this problem using effective semantic representations. In this paper, we propose a Deep Convolutional Hashing (DCH) method that can be trained "point-wise" to simultaneously learn both semantic and binary representations of histopathological images. Specifically, we propose a convolutional neural network (CNN) that introduces a latent binary encoding (LBE) layer for low dimensional feature embedding to learn binary codes. We design a joint optimization objective function that encourages the network to learn discriminative representations from the label information, and reduce the gap between the real-valued low dimensional embedded features and desired binary values. The binary encoding for new images can be obtained by forward propagating through the network and quantizing the output of the LBE layer. Experimental results on a large-scale histopathological image dataset demonstrate the effectiveness of the proposed method. PMID- 29993649 TI - DDC-Outlier: Preventing medication errors using unsupervised learning. AB - Electronic Health Records (EHR) have brought valuable improvements to hospital practices by integrating patient information. In fact, the understanding of this data can prevent mistakes that may put patients' lives at risk. Nonetheless, to the best of our knowledge, there are no previous studies addressing the automatic detection of outlier prescriptions, regarding dosage and frequency. In this paper, we propose an unsupervised method, called Density-Distance-Centrality (DDC), to detect potential outlier prescriptions. A dataset with 563 thousand prescribed medications was used to assess our proposed approach against different state-of-the-art techniques for outlier detection. In the experiments, our approach achieves better results in the task of overdose and underdose detection in medical prescriptions, compared to other methods applied to this problem. Additionally, most of the false positive instances detected by our algorithm were potential prescriptions errors. PMID- 29993650 TI - Adaptive Critic Designs for Event-Triggered Robust Control of Nonlinear Systems With Unknown Dynamics. AB - This paper develops a novel event-triggered robust control strategy for continuous-time nonlinear systems with unknown dynamics. To begin with, the event triggered robust nonlinear control problem is transformed into an event-triggered nonlinear optimal control problem by introducing an infinite-horizon integral cost for the nominal system. Then, a recurrent neural network (RNN) and adaptive critic designs (ACDs) are employed to solve the derived event-triggered nonlinear optimal control problem. The RNN is applied to reconstruct the system dynamics based on collected system data. After acquiring the knowledge of system dynamics, a unique critic network is proposed to obtain the approximate solution of the event-triggered Hamilton-Jacobi-Bellman equation within the framework of ACDs. The critic network is updated by using simultaneously historical and instantaneous state data. An advantage of the present critic network update law is that it can relax the persistence of excitation condition. Meanwhile, under a newly developed event-triggering condition, the proposed critic network tuning rule not only guarantees the critic network weights to converge to optimums but also ensures nominal system states to be uniformly ultimately bounded. Moreover, by using Lyapunov method, it is proved that the derived optimal event-triggered control (ETC) guarantees uniform ultimate boundedness of all the signals in the original system. Finally, a nonlinear oscillator and an unstable power system are provided to validate the developed robust ETC scheme. PMID- 29993651 TI - Non-Negative Matrix Factorizations for Multiplex Network Analysis. AB - Networks have been a general tool for representing, analyzing, and modeling relational data arising in several domains. One of the most important aspect of network analysis is community detection or network clustering. Until recently, the major focus have been on discovering community structure in single (i.e., monoplex) networks. However, with the advent of relational data with multiple modalities, multiplex networks, i.e., networks composed of multiple layers representing different aspects of relations, have emerged. Consequently, community detection in multiplex network, i.e., detecting clusters of nodes shared by all layers, has become a new challenge. In this paper, we propose Network Fusion for Composite Community Extraction (NF-CCE), a new class of algorithms, based on four different non-negative matrix factorization models, capable of extracting composite communities in multiplex networks. Each algorithm works in two steps: first, it finds a non-negative, low-dimensional feature representation of each network layer; then, it fuses the feature representation of layers into a common non-negative, low-dimensional feature representation via collective factorization. The composite clusters are extracted from the common feature representation. We demonstrate the superior performance of our algorithms over the state-of-the-art methods on various types of multiplex networks, including biological, social, economic, citation, phone communication, and brain multiplex networks. PMID- 29993652 TI - Quantitative Assessment of Thin-Layer Tissue Viscoelastic Properties Using Ultrasonic Micro-Elastography With Lamb Wave Model. AB - Characterizing the viscoelastic properties of thin-layer tissues with micro-level thickness has long remained challenging. Recently, several micro-elastography techniques have been developed to improve the spatial resolution. However, most of these techniques have not considered the medium boundary conditions when evaluating the viscoelastic properties of thin-layer tissues such as arteries and corneas; this might lead to estimation bias or errors. This paper aims to integrate the Lamb wave model with our previously developed ultrasonic micro elastography imaging system for obtaining accurate viscoelastic properties in thin-layer tissues. A 4.5-MHz ring transducer was used to generate an acoustic radiation force for inducing tissue displacements to produce guided wave, and the wave propagation was detected using a confocally aligned 40-MHz needle transducer. The phase velocity and attenuation were obtained from k-space by both the impulse and the harmonic methods. The measured phase velocity was fit using the Lamb wave model with the Kelvin-Voigt model. Phantom experiments were conducted using 7% and 12% gelatin and 1.5% agar phantoms with different thicknesses (2, 3, and 4 mm). Biological experiments were performed on porcine cornea and rabbit carotid artery ex vivo. Thin-layer phantoms with different thicknesses were confirmed to have the same elasticity; this was consistent with the estimates of bulk phantoms from mechanical tests and the shear wave rheological model. The trend of the measured attenuations was also confirmed with the viscosity results obtained using the Lamb wave model. Through the impulse and harmonic methods, the shear viscoelasticity values were estimated to be 8.2 kPa for $0.9~?text {Pa}{?cdot} ?text {s}$ and 9.6 kPa for $0.8~?text {Pa}{?cdot} ?text {s}$ in the cornea and 27.9 kPa for $0.1~?text {Pa}?cdot ?text {s}$ and 26.5 kPa for $0.1~?text {Pa}?cdot ?text {s}$ in the artery. PMID- 29993653 TI - Versatile Low-Cost Volumetric 3-D Ultrasound Platform for Existing Clinical 2-D Systems. AB - Ultrasound imaging has indications across many areas of medicine, but the need for training and the variability in skill and acquired image quality among 2-D ultrasound users have limited its wider adoption and utilization. Low-cost volumetric ultrasound with a known frame of reference has the potential to lower these operator-dependent barriers and enhance the clinical utility of ultrasound imaging. In this paper, we improve upon our previous research-scanner-based prototype to implement a versatile volumetric imaging platform for existing clinical 2-D ultrasound systems. We present improved data acquisition and image reconstruction schemes to increase quality, streamline workflow, and provide real time visual feedback. We present initial results using the platform on a Vimedix simulator, as well as on phantom and in vivo targets using a variety of clinical ultrasound systems and probes. PMID- 29993654 TI - 2D myocardial deformation imaging based on RF-based non-rigid image registration. AB - Myocardial deformation imaging is a well-established echocardiographic technique for the assessment of myocardial function. Although some solutions make use of speckle tracking of the reconstructed B-mode images, others apply block matching on the underlying radio-frequency (RF) data in order to increase sensitivity to small inter-frame motion and deformation. However, for both approaches, lateral motion estimation remains a challenge due to the relatively poor lateral resolution of the ultrasound image in combination with the lack of phase information in this direction. Hereto, non-rigid image registration (NRIR) of B mode images has previously been proposed as an attractive solution. However, hereby, the advantages of RF-based tracking were lost. The aim of this study was therefore to develop an NRIR motion estimator adopted to RF data sets. The accuracy of this estimator was quantified using synthetic data and was contrasted against a state of the art block matching solution. The results show that RF based NRIR outperforms BM in terms of tracking accuracy particularly, as hypothesized, in the lateral direction. Finally, this RF-based NRIR algorithm was applied clinically, illustrating its ability to estimate both in-plane velocity components in-vivo. PMID- 29993655 TI - Extracting the Principal Shape Components via Convex Programming. AB - We present a general method for extracting a region from an image (or 3D object) that can be expressed, or approximated, by taking unions and set differences from a collection of template shapes in a dictionary. We build on recent work that shows how this geometric problem can be recast in the language of linear algebra, with set operations on shapes translated into linear combinations of vectors, and solved using convex programming. This paper presents a set of sufficient conditions for which this convex program returns the "correct" shape. These conditions are robust in that they can account for the shapes that have indistinct boundaries, or model mismatch between the shapes in the dictionary and the target region in the image. We also present two different methods for solving the convex extraction program. The first method simply recasts the problem as a linear program, while the second uses the alternating direction method of multipliers with a series of easily computed proximal operators. We present a number of numerical experiments that use the framework to perform image segmentation, optical character recognition, and find multi-resolution geometrical descriptions of 3D objects. PMID- 29993656 TI - Triplet-Based Deep Hashing Network for Cross-Modal Retrieval. AB - Given the benefits of its low storage requirements and high retrieval efficiency, hashing has recently received increasing attention. In particular, cross-modal hashing has been widely and successfully used in multimedia similarity search applications. However, almost all existing methods employing cross-modal hashing cannot obtain powerful hash codes due to their ignoring the relative similarity between heterogeneous data that contains richer semantic information, leading to unsatisfactory retrieval performance. In this paper, we propose a tripletbased deep hashing (TDH) network for cross-modal retrieval. First, we utilize the triplet labels, which describes the relative relationships among three instances as supervision in order to capture more general semantic correlations between cross-modal instances. We then establish a loss function from the inter-modal view and the intra-modal view to boost the discriminative abilities of the hash codes. Finally, graph regularization is introduced into our proposed TDH method to preserve the original semantic similarity between hash codes in Hamming space. Experimental results show that our proposed method outperforms several state-of the-art approaches on two popular cross-modal datasets. PMID- 29993657 TI - Designing optimal experiments to discriminate interaction graph models. AB - Modern methods for the inference of cellular networks from experimental data often express nondeterminism through an ensemble of candidate models. To discriminate among these candidates new experiments need to be carried out. Theoretically, the number of possible experiments is exponential in the number of possible perturbations. In praxis, experiments are expensive and there exist several limiting constraints. Limiting factors exist on the combinations of perturbations that are technically possible, which components can be measured, and on the number of affordable experiments. Further, not all experiments are equally well suited to discriminate model candidates. The goal of optimal experiment design is to determine those experiments that discriminate most of the candidates while minimizing the costs. We present an approach for experiment planning with interaction graph models and sign consistency methods. This new approach can be used in combination with methods for network inference and consistency checking. We applied our method to study the Erythropoietin signal transduction in human kidney cells HEK293. We first used simulated experiment data from an ODE model to demonstrate in silico that our experimental design results in the inference of the gold standard model. Finally, we used the approach to plan in vivo experiments that discriminate model candidates for the Erythropoietin signal transduction in this cell line. PMID- 29993658 TI - Submodular generalized matching for peptide identification in tandem mass spectrometry. AB - MOTIVATION: Identification of spectra produced by a shotgun proteomics mass spectrometry experiment is commonly performed by searching the observed spectra against a peptide database. The heart of this search procedure is a score function that evaluates the quality of a hypothesized match between an observed spectrum and a theoretical spectrum corresponding to a particular peptide sequence. Accordingly, the success of a spectrum analysis pipeline depends critically upon this peptide-spectrum score function. We develop peptide-spectrum score functions that compute the maximum value of a submodular function under matroid constraints. We call this procedure a submodular generalized matching (SGM) since it generalizes bipartite matching. We use a greedy algorithm to compute maximization, which can achieve a solution whose objective is guaranteed to be at least of the true optimum. The advantage of the SGM framework is that known long-range properties of experimental spectra can be modeled by designing suitable submodular functions and matroid constraints. Experiments on four data sets from various organisms and mass spectrometry platforms show that the SGM approach leads to significantly improved performance compared to several state-of the-art methods. Supplementary information, C++ source code, and data sets can be found at https://melodi-lab.github.io/SGM. PMID- 29993659 TI - Differentiating prostate cancer from benign prostatic hyperplasia using PSAD based on machine learning: Single-center retrospective study in China. AB - The incidence of prostate cancer increases annually. Prostate cancer is an underreported and emerging problem in China. We conducted a cross-sectional study of 392 eligible patients from 710 men with prostate cancer or benign prostatic hyperplasia between 2000 and 2003. For total prostate-specific antigen, age, three diameters of prostate, prostate volume and prostate-specific antigen density seven indices, analysis of variance and t test were used to analyze the difference between the groups. A decision tree with pruning was established using the prostate-specific antigen density, age and transversal diameter of the prostate to screen the patient with prostate cancer. According to the established decision tree model, prostate-specific antigen density was the most important factor affecting the occurrence of prostate cancer. In elderly people over the age of 83 years, the transverse diameter of prostate cancer was smaller than that of benign prostatic hyperplasia, with prostate-specific antigen density less than . No additional index was introduced, and the detection rate of prostate cancer was 86.6 %.The specificity was enhanced to 78.1%. PMID- 29993660 TI - BitMapper2: a GPU-accelerated all-mapper based on the sparse q-gram index. AB - The explosive growth of next-generation sequencing (NGS) read datasets drives a need for new faster read mappers. One class of read mappers, called all-mappers, is designed to identify all mapping locations of each read. Many all-mappers have been developed over the past few years, but they are either time-consuming or memory-consuming. Here, we present BitMapper2, a GPU-accelerated read mapper that reports all mapping locations of NGS reads. To make full use of the parallel processing capability of GPUs, BitMapper2 proposes the sparse q-gram index, which reduces the memory requirement and the data transfer time between GPU and CPU. We also design the filtration part and the verification part of BitMapper2 specifically for the architecture of GPU. In addition, BitMapper2 is still time efficient and memory-efficient even if there is no GPU available. Experiments show that BitMapper2 was significantly faster than the state-of-the-art all mappers, while requiring less space. PMID- 29993661 TI - Measuring Boundedness for Protein Complex Identification in PPI Networks. AB - The problem of identifying protein complexes in Protein-Protein Interaction (PPI) networks is usually formulated as the problem of identifying dense regions in such networks. In this paper, we present a novel approach, called TBPCI, to identify protein complexes based instead on the concept of a measure of boundedness. Such a measure is defined as an objective function of a Jaccard Index-based connectedness measure which takes into consideration how much two proteins within a network are connected to each other, and an association measure which takes into consideration how much two connecting proteins are associated based on their attributes found in the Gene Ontology database. Based on the above two measures, the objective function is derived to capture how strong the proteins can be considered as bounded together and the objective value is therefore referred as the aggregated degree of boundedness. To identify protein complexes, TBPCI computes the degree of boundedness between all possible pairwise proteins. Then, TBPCI uses a Breadth-First-Search method to determine whether a protein-pair should be incorporated into the same complex. TBPCI has been tested with several real data sets and the experimental results show it is an effective approach for identifying protein complexes in PPI networks. PMID- 29993662 TI - Transfer Learning for Molecular Cancer classification using Deep Neural Networks. AB - The emergence of deep learning has impacted numerous machine learning based applications and research. The reason for its success lies in two main advantages: 1) it provides the ability to learn very complex non-linear relationships between features and 2) it allows one to leverage information from unlabeled data that does not belong to the problem being handled. This paper presents a transfer learning procedure for cancer classification, which uses feature selection and normalization techniques in conjunction with stacked sparse auto-encoders on gene expression data. While classifying any two tumor types, data of other tumor types were used in unsupervised manner to improve the feature representation. The performance of our algorithm was tested on 36 two-class benchmark datasets from the GEMLeR repository. On performing statistical tests, it is clearly ascertained that our algorithm statistically outperforms several generally used cancer classification approaches. The deep learning based molecular disease classification can be used to guide decisions made on the diagnosis and treatment of diseases, and therefore may have important applications in precision medicine. PMID- 29993663 TI - Pain-Free Blood Glucose Monitoring Using Wearable Sensors: Recent Advancements and Future Prospects. AB - Keeping track of blood glucose levels non-invasively is now possible due to diverse breakthroughs in wearable sensors technology coupled with advanced biomedical signal processing. However, each user might have different requirements and priorities when it comes to selecting a self-monitoring solution. After extensive research and careful selection, we have presented a comprehensive survey on noninvasive/pain-free blood glucose monitoring methods from the recent five years (2012-2016). Several techniques, from bioinformatics, computer science, chemical engineering, microwave technology, etc., are discussed in order to cover a wide variety of solutions available for different scales and preferences. We categorize the noninvasive techniques into nonsample- and sample based techniques, which we further grouped into optical, nonoptical, intermittent, and continuous. The devices manufactured or being manufactured for noninvasive monitoring are also compared in this paper. These techniques are then analyzed based on certain constraints, which include time efficiency, comfort, cost, portability, power consumption, etc., a user might experience. Recalibration, time, and power efficiency are the biggest challenges that require further research in order to satisfy a large number of users. In order to solve these challenges, artificial intelligence (AI) has been employed by many researchers. AI-based estimation and decision models hold the future of noninvasive glucose monitoring in terms of accuracy, cost effectiveness, portability, efficiency, etc. The significance of this paper is twofold: first, to bridge the gap between IT and medical field; and second, to bridge the gap between end users and the solutions (hardware and software). PMID- 29993664 TI - Actor-Critic Learning Control Based on -Regularized Temporal-Difference Prediction With Gradient Correction. AB - Actor-critic based on the policy gradient (PG-based AC) methods have been widely studied to solve learning control problems. In order to increase the data efficiency of learning prediction in the critic of PG-based AC, studies on how to use recursive least-squares temporal difference (RLS-TD) algorithms for policy evaluation have been conducted in recent years. In such contexts, the critic RLS TD evaluates an unknown mixed policy generated by a series of different actors, but not one fixed policy generated by the current actor. Therefore, this AC framework with RLS-TD critic cannot be proved to converge to the optimal fixed point of learning problem. To address the above problem, this paper proposes a new AC framework named critic-iteration PG (CIPG), which learns the state-value function of current policy in an on-policy way and performs gradient ascent in the direction of improving discounted total reward. During each iteration, CIPG keeps the policy parameters fixed and evaluates the resulting fixed policy by regularized RLS-TD critic. Our convergence analysis extends previous convergence analysis of PG with function approximation to the case of RLS-TD critic. The simulation results demonstrate that the -regularization term in the critic of CIPG is undamped during the learning process, and CIPG has better learning efficiency and faster convergence rate than conventional AC learning control methods. PMID- 29993665 TI - A Locally Weighted Project Regression Approach-Aided Nonlinear Constrained Tracking Control. AB - An intelligent data-driven predictive control strategy is proposed in this paper. The predictive controller is designed by combining predictive control and local weighted projection regression. The presented control strategy needs less prior knowledge and has fewer parameters that are hard to determine compared to other data-driven predictive controller, e.g., the one in dynamic partial least square (PLS) framework. Furthermore, the proposed predictive controller performs better in the control of nonlinear processes and is able to update its parameters based on the online data. The predictive model validity and intelligence of the control strategy are guaranteed by the online updating strategy to a certain degree. The control performance of the proposed predictive controller against the model predictive control (MPC) in dynamic PLS framework is illustrated through the simulation of a typical numerical example and the benchmark of a continuous stirred tank heater system. It can be observed from the simulation that the proposed MPC strategy has higher prediction precision and stronger ability in coping with nonlinear dynamic processes which are quite common in practical applications, for instance, the industrial process. PMID- 29993666 TI - Learning to Map Social Network Users by Unified Manifold Alignment on Hypergraph. AB - Nowadays, a lot of people possess accounts on multiple online social networks, e.g., Facebook and Twitter. These networks are overlapped, but the correspondences between their users are not explicitly given. Mapping common users across these social networks will be beneficial for applications such as cross-network recommendation. In recent years, a lot of mapping algorithms have been proposed which exploited social and/or profile relations between users from different networks. However, there is still a lack of unified mapping framework which can well exploit high-order relational information in both social structures and profiles. In this paper, we propose a unified hypergraph learning framework named unified manifold alignment on hypergraph (UMAH) for this task. UMAH models social structures and user profile relations in a unified hypergraph where the relative weights of profile hyperedges are determined automatically. Given a set of training user correspondences, a common subspace is learned by preserving the hypergraph structure as well as the correspondence relations of labeled users. UMAH intrinsically performs semisupervised manifold alignment with profile information for calibration. For a target user in one network, UMAH ranks all the users in the other network by their probabilities of being the corresponding user (measured by similarity in the subspace). In experiments, we evaluate UMAH on three real world data sets and compare it to state-of-art baseline methods. Experimental results have demonstrated the effectiveness of UMAH in mapping users across networks. PMID- 29993667 TI - Image-Text Surgery: Efficient Concept Learning in Image Captioning by Generating Pseudopairs. AB - Image captioning aims to generate natural language sentences to describe the salient parts of a given image. Although neural networks have recently achieved promising results, a key problem is that they can only describe concepts seen in the training image-sentence pairs. Efficient learning of novel concepts has thus been a topic of recent interest to alleviate the expensive manpower of labeling data. In this paper, we propose a novel method, Image-Text Surgery, to synthesize pseudoimage-sentence pairs. The pseudopairs are generated under the guidance of a knowledge base, with syntax from a seed data set (i.e., MSCOCO) and visual information from an existing large-scale image base (i.e., ImageNet). Via pseudodata, the captioning model learns novel concepts without any corresponding human-labeled pairs. We further introduce adaptive visual replacement, which adaptively filters unnecessary visual features in pseudodata with an attention mechanism. We evaluate our approach on a held-out subset of the MSCOCO data set. The experimental results demonstrate that the proposed approach provides significant performance improvements over state-of-the-art methods in terms of F1 score and sentence quality. An ablation study and the qualitative results further validate the effectiveness of our approach. PMID- 29993668 TI - Sensitive Finite-State Computations Using a Distributed Network With a Noisy Network Attractor. AB - We exhibit a class of smooth continuous-state neural-inspired networks composed of simple nonlinear elements that can be made to function as a finite-state computational machine. We give an explicit construction of arbitrary finite-state virtual machines in the spatiotemporal dynamics of the network. The dynamics of the functional network can be completely characterized as a "noisy network attractor" in phase space operating in either an "excitable" or a "free-running" regime, respectively, corresponding to excitable or heteroclinic connections between states. The regime depends on the sign of an "excitability parameter." Viewing the network as a nonlinear stochastic differential equation where a deterministic (signal) and/or a stochastic (noise) input is applied to any element, we explore the influence of the signal-to-noise ratio on the error rate of the computations. The free-running regime is extremely sensitive to inputs: arbitrarily small amplitude perturbations can be used to perform computations with the system as long as the input dominates the noise. We find a counter intuitive regime where increasing noise amplitude can lead to more, rather than less, accurate computation. We suggest that noisy network attractors will be useful for understanding neural networks that reliably and sensitively perform finite-state computations in a noisy environment. PMID- 29993669 TI - Classification and Recall With Binary Hyperdimensional Computing: Tradeoffs in Choice of Density and Mapping Characteristics. AB - Hyperdimensional (HD) computing is a promising paradigm for future intelligent electronic appliances operating at low power. This paper discusses tradeoffs of selecting parameters of binary HD representations when applied to pattern recognition tasks. Particular design choices include density of representations and strategies for mapping data from the original representation. It is demonstrated that for the considered pattern recognition tasks (using synthetic and real-world data) both sparse and dense representations behave nearly identically. This paper also discusses implementation peculiarities which may favor one type of representations over the other. Finally, the capacity of representations of various densities is discussed. PMID- 29993670 TI - Adaptive Neural Tracking Control of Switched Stochastic Pure-Feedback Nonlinear Systems With Unknown Bouc-Wen Hysteresis Input. AB - This paper aims to analyze the problem of adaptive neural network (NN) tracking control for a class of switched stochastic nonlinear pure-feedback systems with unknown direction hysteresis. In the light of recent studies on the hysteresis phenomenon in the field of nonlinear switched systems, this paper focuses on Bouc Wen hysteresis model with unknown parameters and direction conditions. To simplify the control design, the following procedure is applied. Prior to tackling the unknown direction hysteresis problem based on the Nussbaum function and the backstepping techniques, the pure-feedback structure difficulty is governed by the mean value theorem. Furthermore, an optimized adaptation method is utilized to cope with computational burden. Universal approximation capability of radial basis function NNs and Lyapunov function method is synthesized to develop an adaptive NN tracking control scheme. It is demonstrated that under arbitrary deterministic switching, the presented controller can guarantee that all signals in the closed-loop system are semiglobally uniformly ultimately bounded in probability and the tracking error converges to a neighborhood of the origin. Finally, two simulation examples are given to illustrate the advantages of the proposed control design approach. PMID- 29993671 TI - Speckle tracking of tendon displacement in the carpal tunnel: improved quantification using Singular Value Decomposition. AB - Ultrasound is a real-time image modality enabling the analysis of tendon dynamics for diagnosis of carpal tunnel syndrome. Automatic tendon displacement quantification algorithms based on speckle tracking generally suffer from underestimation due to stationary background present in the tendon region. We propose an improved quantification method using Singular Value Decomposition (SVD) filtering to suppress the clutter. The accuracy of our Improved Speckle Tracking (IST) method was validated against a ground truth and compared to the accuracy of our Original Block Matching (OBM) algorithm and Commercial Tissue Tracking (CTT) software. The methods were evaluated in experiments involving six human cadaver arms. The ground truth displacements were generated by tracking metal markers inserted in the tendons. The relative displacement errors with respect to the ground truth for IST were 12 +/- 16.9%, which was significantly lower than for OBM (19.7 +/- 20.8%) and for CTT (25.8 +/- 18.4%). These findings show that SVD filtering improves the tendon tracking by reducing the underestimation due to clutter. PMID- 29993672 TI - A Review of Obstructive Sleep Apnea Detection Approaches. AB - Sleep disorders are a common health condition that can affect numerous aspects of life. Obstructive sleep apnea is one of the most common disorders and is characterized by a reduction or cessation of airflow during sleep. In many countries this disorder is usually diagnosed in sleep laboratories, by a polysomnography, which is an expensive procedure involving much effort for the patient. Multiple systems have been proposed to address this situation, including performing the examination and analysis in the patient's home, using sensors to detect physiological signals that are automatically analyzed by algorithms. However, the precision of these devices is usually not enough to provide a clinical diagnosis. Therefore, the objective of this review is to analyze already existing algorithms that have not been implemented on hardware but have had their performance verified by at least one experiment which aims to detect obstructive sleep apnea, in order to show future trends. The performance of different algorithms and methods for apnea detection through the use of different sensors (pulse oximetry, electrocardiogram, respiration, sound and combined approaches) has been evaluated. A total of 84 original research articles published from 2003 to 2017, that had the potential to be promising diagnostic tools, were selected to cover multiple solutions. This review could provide valuable information for those researchers who want to carry out a hardware implementation of potential signal processing algorithms. PMID- 29993673 TI - Evaluation of Machine-Learning Approaches to Estimate Sleep Apnea Severity from at-Home Oximetry Recordings. AB - Complexity, costs, and waiting lists issues demand a simplified alternative for sleep apnea-hypopnea syndrome (SAHS) diagnosis. The blood oxygen saturation signal (SpO) carries useful information about SAHS and can be easily acquired from overnight oximetry. In this study, SpO single-channel recordings from 320 subjects were obtained at patients' home. They were used to automatically obtain statistical, spectral, non-linear, and clinical SAHS-related information. Relevant and non-redundant data from these analyses were subsequently used to train and validate four machine-learning methods with ability to classify SpO signals into one out of the four SAHS-severity degrees (no-SAHS, mild, moderate, and severe). All the models trained (linear discriminant analysis, 1-vs-all logistic regression, Bayesian multi-layer perceptron, and AdaBoost), outperformed the diagnostic ability of the conventionally-used 3% oxygen desaturation index. An AdaBoost model built with linear discriminants as base classifiers reached the highest figures. It achieved 0.479 Cohen's a in the SAHS severity classification, as well as 92.9%, 87.4%, and 78.7% accuracies in binary classification tasks using increasing severity thresholds (apnea-hypopnea index: 5, 15, and 30 events/hour, respectively). These results suggest that machine learning can be used along with SpO information acquired at patients' home to help in SAHS diagnosis simplification. PMID- 29993674 TI - Statistical detection of colors in dermoscopic images with a texton-based estimation of probabilities. AB - Color has great diagnostic significance in dermatoscopy. Several diagnosis methods are based on the colors detected within a lesion. Malignant lesions frequently show more than three colors, whereas in benign lesions, three or fewer colors are usually observed. Black, red, white and blue-gray are found more frequently in melanomas than in benign nevi. In this paper, a method to identify the colors of a lesion automatically is presented. A color label identification problem is proposed and solved by maximizing the posterior probability of a pixel to belong to a label, given its color value and the neighborhood color values. The main contribution of this work is the estimation of the different terms involved in the computation of this probability. Two evaluations are performed on a database of 200 dermoscopic images. The first one evaluates if all the colors detected in a lesion are indeed present in it. The second analyzes if each pixel within a lesion is assigned the correct color label. The results show that the proposed method performs correctly and outperforms other methods, with an average F-measure of 0.89, an accuracy of 0.90 and a Spearman correlation of 0.831. PMID- 29993675 TI - Adaptive Sliding Mode Consensus Tracking for Second-Order Nonlinear Multiagent Systems With Actuator Faults. AB - This paper investigates the consensus tracking problem of second-order nonlinear multiagent systems (MAS) with disturbance and actuator fault by the sliding mode control method. The communication topology of the MAS is directed and only part of the followers have access to the leader's information. First, a discontinuous sliding mode tracking protocol is studied for consensus tracking of the MAS. Second, to address the shortcoming of chattering and difficulty of setting the control gain in the discontinuous protocol, a continuous sliding mode tracking protocol with an adaptive mechanism is developed. The adaptive mechanism will adjust the gain of the control automatically and enable the tracking protocol to work well without prior knowledge of the MAS. Third, the performance of the adaptive sliding mode protocol for consensus tracking of the MAS in the presence of actuator faults of biased fault and partial loss of effectiveness fault is further investigated. Finally, numerical simulations are performed to illustrate the efficiency of the theoretical results. PMID- 29993676 TI - AdaSampling for Positive-Unlabeled and Label Noise Learning With Bioinformatics Applications. AB - Class labels are required for supervised learning but may be corrupted or missing in various applications. In binary classification, for example, when only a subset of positive instances is labeled whereas the remaining are unlabeled, positive-unlabeled (PU) learning is required to model from both positive and unlabeled data. Similarly, when class labels are corrupted by mislabeled instances, methods are needed for learning in the presence of class label noise (LN). Here we propose adaptive sampling (AdaSampling), a framework for both PU learning and learning with class LN. By iteratively estimating the class mislabeling probability with an adaptive sampling procedure, the proposed method progressively reduces the risk of selecting mislabeled instances for model training and subsequently constructs highly generalizable models even when a large proportion of mislabeled instances is present in the data. We demonstrate the utilities of proposed methods using simulation and benchmark data, and compare them to alternative approaches that are commonly used for PU learning and/or learning with LN. We then introduce two novel bioinformatics applications where AdaSampling is used to: 1) identify kinase-substrates from mass spectrometry-based phosphoproteomics data and 2) predict transcription factor target genes by integrating various next-generation sequencing data. PMID- 29993677 TI - Security Research on Wireless Networked Control Systems Subject to Jamming Attacks. AB - In this paper, a countermeasure for wireless networked control systems suffering from jamming attacks is studied by a variable sampling approach. A Stackelberg game framework is utilized to analyze interactions between a smart jammer and a legitimate user. The variable sampling approach is exploited to deal with data packets dropout between a sensor and a controller. Moreover, a resilient variable sampling controller is designed by a delta operator method. Besides, stability conditions are provided for systems with proposed controller. Finally, a numerical simulation is provided to validate the effectiveness of the proposed method. PMID- 29993678 TI - Graph-Theory-Based Decentralized Adaptive Output-Feedback Control for a Class of Nonlinear Interconnected Systems. AB - This paper investigates the problem of decentralized output feedback control for a class of interconnected systems with unknown state-dependent interconnections. First, we design a new form of K-filters with extra design parameters to compensate the unmeasurable states. Then by introducing a smooth function, we can design a decentralized output feedback control law by integrating the well-known backstepping framework. Furthermore, from the graph theory and Lyapunov function method, we analyze the stability and tracking property of the closed-loop systems. As an illustrative example, the proposed control scheme is applied to the controller design of a mass-spring-damper system. PMID- 29993679 TI - Evolutionary Multiobjective Clustering and Its Applications to Patient Stratification. AB - Patient stratification has a major role in enabling efficient and personalized medicine. An important task in patient stratification is to discover disease subtypes for effective treatment. To achieve this goal, the research on clustering algorithms for patient stratification has brought attention from both academia and medical community over the past decades. However, existing clustering algorithms suffer from realistic restrictions such as experimental noises, high dimensionality, and poor interpretability. In particular, the existing clustering algorithms usually determine clustering quality using only one internal evaluation function. Unfortunately, it is obvious that one internal evaluation function is hard to be fitted and robust for all datasets. Therefore, in this paper, a novel multiobjective framework called multiobjective clustering algorithm by fast search and find of density peaks is proposed to address those limitations altogether. In the proposed framework, a parameter candidate population is evolved under multiple objectives to select features and evaluate clustering densities automatically. To guide the multiobjective evolution, five cluster validity indices including compactness, separation, Calinski-Harabasz index, Davies-Bouldin index, and Dunn index, are chosen as the objective functions, capturing multiple characteristics of the evolving clusters. Multiobjective differential evolution algorithm based on decomposition is adopted to optimize those five objective functions simultaneously. To demonstrate its effectiveness, extensive experiments have been conducted, comparing the proposed algorithm with 45 algorithms including nine state-of-the-art clustering algorithms, five multiobjective evolutionary algorithms, and 31 baseline algorithms under different objective subsets on 94 datasets featuring 35 real patient stratification datasets, 55 synthetic datasets based on a real human transcription regulation network model, and four other medical datasets. The numerical results reveal that the proposed algorithm can achieve better or competitive solutions than the others. Besides, time complexity analysis, convergence analysis, and parameter analysis are conducted to demonstrate the robustness of the proposed algorithm from different perspectives. PMID- 29993680 TI - Nonrepetitive Leader-Follower Formation Tracking for Multiagent Systems With LOS Range and Angle Constraints Using Iterative Learning Control. AB - In this paper, we present a novel iterative learning control (ILC) algorithm for the leader-follower formation tracking problem of a class of nonlinear multiagent systems that are subject to actuator faults. Unlike most ILC works that require identical reference trajectories over the iteration domain, the desired line-of sight (LOS) range and angle profiles can be iteration dependent based on different tasks and environment in each iteration. Furthermore, the LOS range and angle tracking errors are subject to iteration and time dependent constraint requirements. Both parametric and nonparametric system unknowns and uncertainties, in particular the control input gain functions that are not fully known, are considered. We show that under the proposed algorithm, the formation tracking errors can converge to zero uniformly over the iteration domain beyond a certain time interval in each iteration, while the constraint requirements on the LOS range and angle will not be violated during operations. A numerical simulation involving two agents in leader-follower formation is presented in the end to demonstrate the efficacy of the proposed algorithm. PMID- 29993681 TI - Potential Game Theoretic Learning for the Minimal Weighted Vertex Cover in Distributed Networking Systems. AB - Toward the minimal weighted vertex cover (MWVC) in agent-based networking systems, this paper recasts it as a potential game and proposes a distributed learning algorithm based on relaxed greed and finite memory. With the concept of convention, we prove that our algorithm converges with probability 1 to Nash equilibria, which serve as the bridge connecting the game and the MWVC. More importantly, an additional degree of freedom is also provided for equilibrium refinement, such that increasing memory lengths and mutation probabilities contributes to the improvement of system-level objectives. Comparisons with typical methods, centralized and distributed, demonstrate the advantage of our algorithm for both weighted and unweighted versions. This paper not only provides a useful tool for the MWVC problem in decentralized environments but also paves an effective way for distributed coordination and optimization that could be modeled as potential games. PMID- 29993682 TI - Regularized Diffusion Process on Bidirectional Context for Object Retrieval. AB - Diffusion process has advanced object retrieval greatly as it can capture the underlying manifold structure. Recent studies have experimentally demonstrated that tensor product diffusion can better reveal the intrinsic relationship between objects than other variants. However, the principle remains unclear,i.e., what kind of manifold structure is captured. In this paper, we propose a new affinity learning algorithm called Regularized Diffusion Process (RDP). By deeply exploring the properties of RDP, our first yet basic contribution is providing a manifold-based explanation for tensor product diffusion. A novel criterion measuring the smoothness of the manifold is defined, which simultaneously regularizes four vertices in the affinity graph. Inspired by this observation, we further contribute two variants towards two specific goals. While ARDP can learn similarities across heterogeneous domains, HRDP performs affinity learning on tensor product hypergraph, considering the relationships between objects are generally more complex than pairwise. Consequently, RDP, ARDP and HRDP constitute a generic tool for object retrieval in most commonly-used settings, no matter the input relationships between objects are derived from the same domain or not, and in pairwise formulation or not. Comprehensive experiments on10retrieval benchmarks, especially on large scale data, validate the effectiveness and generalization of our work. PMID- 29993683 TI - Spatially Consistent Supervoxel Correspondences of Cone-Beam Computed Tomography Images. AB - Establishing dense correspondences of cone-beam computed tomography (CBCT) images is a crucial step for the attribute transfer and morphological variation assessment in clinical orthodontics. In this paper, a novel method, unsupervised spatially consistent clustering forest, is proposed to tackle the challenges for automatic supervoxel-wise correspondences of CBCT images. A complexity analysis of the proposed method with respect to the clustering hypotheses is provided with a data-dependent learning guarantee. The learning bound considers both the sequential tree traversals determined by questions stored in branch nodes and the clustering compactness of leaf nodes. A novel tree-pruning algorithm, guided by the learning bound, is also proposed to remove locally inconsistent leaf nodes. The resulting forest yields spatially consistent affinity estimations, thanks to the pruning penalizing trees with inconsistent leaf assignments and the combinational contextual feature channels used to learn the forest. A forest based metric is utilized to derive the pairwise affinities and dense correspondences of CBCT images. The proposed method has been applied to the label propagation of clinically captured CBCT images. In the experiments, the method outperforms variants of both supervised and unsupervised forest-based methods and state-of-the-art label-propagation methods, achieving the mean dice similarity coefficients of 0.92, 0.89, 0.94, and 0.93 for the mandible, the maxilla, the zygoma arch, and the teeth data, respectively. PMID- 29993684 TI - Continuation of Nesterov's Smoothing for Regression With Structured Sparsity in High-Dimensional Neuroimaging. AB - Predictive models can be used on high-dimensional brain images to decode cognitive states or diagnosis/prognosis of a clinical condition/evolution. Spatial regularization through structured sparsity offers new perspectives in this context and reduces the risk of overfitting the model while providing interpretable neuroimaging signatures by forcing the solution to adhere to domain specific constraints. Total variation (TV) is a promising candidate for structured penalization: it enforces spatial smoothness of the solution while segmenting predictive regions from the background. We consider the problem of minimizing the sum of a smooth convex loss, a non-smooth convex penalty (whose proximal operator is known) and a wide range of possible complex, non-smooth convex structured penalties such as TV or overlapping group Lasso. Existing solvers are either limited in the functions they can minimize or in their practical capacity to scale to high-dimensional imaging data. Nesterov's smoothing technique can be used to minimize a large number of non-smooth convex structured penalties. However, reasonable precision requires a small smoothing parameter, which slows down the convergence speed to unacceptable levels. To benefit from the versatility of Nesterov's smoothing technique, we propose a first order continuation algorithm, CONESTA, which automatically generates a sequence of decreasing smoothing parameters. The generated sequence maintains the optimal convergence speed toward any globally desired precision. Our main contributions are: gap to probe the current distance to the global optimum in order to adapt the smoothing parameter and the To propose an expression of the duality convergence speed. This expression is applicable to many penalties and can be used with other solvers than CONESTA. We also propose an expression for the particular smoothing parameter that minimizes the number of iterations required to reach a given precision. Furthermore, we provide a convergence proof and its rate, which is an improvement over classical proximal gradient smoothing methods. We demonstrate on both simulated and high-dimensional structural neuroimaging data that CONESTA significantly outperforms many state-of-the-art solvers in regard to convergence speed and precision. PMID- 29993685 TI - Enhancing the Image Quality via Transferred Deep Residual Learning of Coarse PET Sinograms. AB - Increasing the image quality of positron emission tomography (PET) is an essential topic in the PET community. For instance, thin-pixelated crystals have been used to provide high spatial resolution images but at the cost of sensitivity and manufacture expense. In this paper, we proposed an approach to enhance the PET image resolution and noise property for PET scanners with large pixelated crystals. To address the problem of coarse blurred sinograms with large parallax errors associated with large crystals, we developed a data-driven, single-image super-resolution (SISR) method for sinograms, based on the novel deep residual convolutional neural network (CNN). Unlike the CNN-based SISR on natural images, periodically padded sinogram data and dedicated network architecture were used to make it more efficient for PET imaging. Moreover, we included the transfer learning scheme in the approach to process cases with poor labeling and small training data set. The approach was validated via analytically simulated data (with and without noise), Monte Carlo simulated data, and pre clinical data. Using the proposed method, we could achieve comparable image resolution and better noise property with large crystals of bin sizes of thin crystals with a bin size from to . Our approach uses external PET data as the prior knowledge for training and does not require additional information during inference. Meanwhile, the method can be added into the normal PET imaging framework seamlessly, thus potentially finds its application in designing low cost high-performance PET systems. PMID- 29993686 TI - Super-resolution imaging with ultrafast ultrasound imaging of optically triggered perfluorohexane nanodroplets. AB - Super-resolution imaging with moving microbubbles has shown potential in identifying fine details of deep-lying vascular compartments. To image the extravascular targets, the current study has employed nanometer-sized, optically triggered perfluorohexane nanodroplets (PFHnDs). In response to pulsed laser irradiation, the PFHnDs repeatedly vaporize and stochastically recondense, resulting in random changes of ultrasound signals. Our previous study has shown that the stochastic recondensation of the PFHnDs can be used to isolate individual PFHnDs for super-resolution imaging. This study introduces an improved method for super-resolution imaging with ultrafast ultrasound imaging of PFHnDs. The previous method was based on subtraction of two consecutive ultrasound images to detect signals from recondensed, isolated droplets whereas our current method compounds respective multiple pre- and post-recondensation ultrafast ultrasound images prior to subtraction to improve the spatial resolution further. To evaluate the axial and lateral resolutions of our method, we repeatedly imaged a phantom containing PFHnDs using a programmable ultrasound system synchronized with a pulsed laser system. As a result, our method improved the lateral and axial resolutions by 54% and 68%, respectively, over the previous super resolution imaging approach, indicating that it can be used for localizing extravascular molecular targets with superior accuracy. PMID- 29993687 TI - 3D Randomized Connection Network with Graph-based Label Inference. AB - In this paper, a novel 3D deep learning network is proposed for brain MR image segmentation with randomized connection, which can decrease the dependency between layers and increase the network capacity. The convolutional LSTM and 3D convolution are employed as network units to capture the long-term and short-term 3D properties respectively. To assemble these two kinds of spatial-temporal information and refine the deep learning outcomes, we further introduce an efficient graph-based node selection and label inference method. Experiments have been carried out on two publicly available databases and results demonstrate that the proposed method can obtain competitive performances as compared with other state-of-the-art methods. PMID- 29993688 TI - Digital Affine Shear Filter Banks with 2-Layer Structure and Their Applications in Image Processing. AB - Digital affine shear filter banks with 2-layer structure (DAS-2 filter banks) are constructed and are shown to be with the perfect reconstruction (PR) property. The implementation of digital affine shear transforms using the transition and subdivision operators are given. The redundancy rate analysis shows that our digital affine shear transforms have redundancy rate no more than 8 and it decreases with respect to the number of directional filters. Numerical experiments on image processing demonstrate the advantage of our DAS-2 filter banks over many other state-of-the-art frame-based transforms. The connection between DAS-2 filter banks and affine shear tight frames with 2-layer structure is established. Characterizations and constructions of affine shear tight frames with 2-layer structure are provided. PMID- 29993689 TI - The Visual Word Booster: A Spatial Layout of Words Descriptor Exploiting Contour Cues. AB - Although researchers have made efforts to use the spatial information of visual words to obtain better image representations, none of the studies take contour cues into account. Meanwhile, it has been shown that contour cues are important to the perception of imagery in the literature. Inspired by these studies, we propose to use the Spatial Layout of Words (SLoW) to boost visual word based image descriptors by exploiting contour cues. Essentially, the SLoW descriptor utilises contours and incorporates different types of commonly used visual words, including hand-crafted basic contour elements (referred to as "contons"), textons and Scale-Invariant Feature Transform (SIFT) words, deep convolutional words and a special type of words: LBP (Local Binary Pattern) codes. Moreover, SLoW features are combined with Spatial Pyramid Matching (SPM) or Vector of Locally Aggregated Descriptors (VLAD) features. The SLoW descriptor and its combined versions are tested in different tasks. Our results show that they are superior to, or at least comparable to, their counterparts examined in this study. In particular, the joint use of the SLoW descriptor boosts the performance of the SPM and VLAD descriptors. We attribute these results to the fact that contour cues are important to human visual perception and, the SLoW descriptor captures not only local image characteristics but also the global spatial layout of these characteristics in a more perceptually consistent way than its counterparts. PMID- 29993690 TI - Multi-Instance Dynamic Ordinal Random Fields for Weakly-supervised Facial Behavior Analysis. AB - We propose a Multi-Instance-Learning (MIL) approach for weakly-supervised learning problems, where a training set is formed by bags (sets of feature vectors or instances) and only labels at bag-level are provided. Specifically, we consider the Multi-Instance Dynamic-Ordinal-Regression (MI-DOR) setting, where the instance labels are naturally represented as ordinal variables and bags are structured as temporal sequences. To this end, we propose Multi-Instance Dynamic Ordinal Random Fields (MI-DORF). In this framework, we treat instance-labels as temporally-dependent latent variables in an Undirected Graphical Model. Different MIL assumptions are modelled via newly introduced high-order potentials relating bag and instance-labels within the energy function of the model. We also extend our framework to address the Partially-Observed MI-DOR problems, where a subset of instance labels are available during training.We show on the tasks of weakly supervised facial behavior analysis, Facial Action Unit (DISFA dataset) and Pain (UNBC dataset) Intensity estimation, that the proposed framework outperforms alternative learning approaches. Furthermore, we show that MIDORF can be employed to reduce the data annotation efforts in this context by large-scale. PMID- 29993691 TI - Enhanced Cross-Component Linear Model for Chroma Intra-Prediction in Video Coding. AB - Cross-Component Linear Model (CCLM) for chroma intra-prediction is a promising coding tool in Joint Exploration Model (JEM) developed by the Joint Video Exploration Team (JVET). CCLM assumes a linear correlation between the luma and chroma components in a coding block. With this assumption, the chroma components can be predicted by the Linear Model (LM) mode, which utilizes the reconstructed neighbouring samples to derive parameters of a linear model by linear regression. This paper presents three new methods to further improve the coding efficiency of CCLM. First, we introduce a multi-model CCLM (MM-CCLM) approach, which applies more than one linear models to a coding block. With MM-CCLM, reconstructed neighbouring luma and chroma samples of the current block are classified into several groups, and a particular set of linear model parameters is derived for each group. The reconstructed luma samples of the current block are also classified to predict the associated chroma samples with the corresponding linear model. Second, we propose a multi-filter CCLM (MF-CCLM) technique, which allows the encoder to select the optimal down-sampling filter for the luma component with the 4:2:0 colour format. Third, we present a LM-angular prediction (LAP) method, which synthesizes the angular intra-prediction and the MM-CCLM intra prediction into a new chroma intra coding mode. Simulation results show that 0.55%, 4.66% and 5.08% BD rate savings in average on Y, Cb and Cr components respectively, are achieved for All Intra (AI) configurations with the proposed three methods. MM-CCLM and MF-CCLM have been adopted into the JEM by JVET. PMID- 29993692 TI - Protein Domain Level Cancer Drug Targets in the Network of MAPK pathways. AB - Proteins in the MAPK pathways considered as potential drug targets for cancer treatment. Considering pathways along with the cross-talks increases their scope to view them as a network of MAPK pathways. Side effect causing targeted domains act as a proxy for drug targets due to its structural similarity and frequent reuse of their variants. We proposed to identify non-repeatable protein domains as the drug targets to disrupt the signal transduction than targeting the whole protein. Network based approach is used to understand the contribution of 52 domains in non-hub, non-essential and intra-pathway cancerous nodes and to identify potential drug target domains. 34 distinct domains in the cancerous proteins are playing vital roles in making cancer as a complex disease and pose challenges to identify potential drug targets. Distribution of domain families follows the power law in the network. Single promiscuous domains are contributing to the formation of hubs like Pkinease, Pkinease Tyr, Ras. Hub nodes are positively correlated with the domain coverage and targeting them would disrupt functional properties of the proteins. EIF 4EBP, alpha Kinase, Sel1, ROKNT and KH 1 are the domains identified as potential domain targets for the disruption of the signaling mechanism involved in cancer. PMID- 29993693 TI - An efficient mixed-model for screening differentially expressed genes of breast cancer based on LR-RF. AB - To screen differentially expressed genes quickly and efficiently in breast cancer, two gene microarray datasets of breast cancer, GSE15852 and GSE45255, were downloaded from GEO. By combining the Logistic Regression and Random Forest algorithm, this paper proposed a novel method named LR-RF to select differentially expressed genes of breast cancer on microarray data by the Bonferroni test of FWER error measure. Comparing with Logistic Regression and Random Forest, our study shows that LR-FR has a great facility in selecting differentially expressed genes. The average prediction accuracy of the proposed LR-RF from replicating random test ten times surprisingly reaches 93.11% with variance as low as 0.00045. The prediction accuracy rate reaches a maximum 95.57% when threshold value in the random forest algorithm process of ranking genes importance score, and the differentially expressed genes are relatively few in number. In addition, through analyzing the gene interaction networks, most of the top 20 genes we selected were found to involve in the development of breast cancer. All of these results demonstrate the reliability and efficiency of LR-RF. It is anticipated that LR-RF would provide new knowledge and method for biologists, medical scientists, and cognitive computing researchers to identify disease-related genes of breast cancer. PMID- 29993694 TI - Phylogenetic Reconstruction for Copy-Number Evolution Problems. AB - Cancer is known for its heterogeneity and is regarded as an evolutionary process driven by somatic mutations and clonal expansions. This evolutionary process can be modeled by a phylogenetic tree and phylogenetic analysis of multiple subclones of cancer cells can facilitate the study of the tumor variants progression. Copy number aberration occurs frequently in many types of tumors in terms of segmental amplifications and deletions. In this paper, we developed a distance-based method for reconstructing phylogenies from copy-number profiles of cancer cells. We demonstrate the importance of distance correction from the edit (minimum) distance to the estimated actual number of events. Experimental results show that our approaches provide accurate and scalable results in estimating the actual number of evolutionary events between copy number profiles and in reconstructing phylogenies. PMID- 29993695 TI - SAFETY: Secure gwAs in Federated Environment Through a hYbrid solution. AB - Recent studies demonstrate that effective healthcare can benefit from using the human genomic information. Consequently, many institutions are using statistical analysis of genomic data, which are mostly based on genome-wide association studies (GWAS). GWAS analyze genome sequence variations in order to identify genetic risk factors for diseases. These studies often require pooling data from different sources together in order to unravel statistical patterns, relationships between genetic variants and diseases. Here, the primary challenge is to fulfill one major objective: accessing multiple genomic data repositories for collaborative research in a privacy-preserving manner. Due to the privacy concerns regarding the genomic data, multi-jurisdictional laws and policies of cross-border genomic data sharing are enforced among different countries. In this article, we present SAFETY, a hybrid framework, which can securely perform GWAS on federated genomic datasets using homomorphic encryption and recently introduced secure hardware component of Intel Software Guard Extensions to ensure high efficiency and privacy at the same time. Different experimental settings show the efficacy and applicability of such hybrid framework in secure conduction of GWAS. To the best of our knowledge, this hybrid use of homomorphic encryption along with Intel SGX is not proposed to this date. SAFETY is up to 4.82 times faster than the best existing secure computation technique. PMID- 29993696 TI - GLAlign: A Novel Algorithm for Local Network Alignment. AB - Networks are successfully used as a modelling framework in many application domains. For instance, Protein-Protein Interaction Networks (PPINs) model the set of interactions among proteins in a cell. A critical application of network analysis is the comparison among PPINs of different organisms to reveal similarities among the underlying biological processes. Algorithms for comparing networks (also referred to as network aligners) fall into two main classes: global aligners, which aim to compare two networks on a global scale, and local aligners that evidence single sub-regions of similarity among networks. The possibility to improve the performance of the aligners by mixing the two approaches is a growing research area. In our previous work, we started to explore the possibility to use global alignment to improve the local one. We here examine further this possibility by using topological information extracted from global alignment to guide the steps of the local alignment. Therefore, we present GLAlign (Global Local Aligner), a methodology that improves the performances of local network aligners by exploiting a preliminary global alignment. Furthermore, we provide an implementation of GLAlign. As a proof-of-principle, we evaluated the performance of the GLAlign prototype. Results show that GLAlign methodology outperforms the state-of-the-art local alignment algorithms. GLAlign is publicly available for academic use and can be downloaded here: https://sites.google.com/site/globallocalalignment/. PMID- 29993697 TI - Control of Gene Regulatory Networks using Bayesian Inverse Reinforcement Learning. AB - Control of gene regulatory networks (GRNs) to shift gene expression from undesirable states to desirable ones has received much attention in recent years. Most of the existing methods assume that the cost of intervention at each state and time point, referred to as the immediate cost function, is fully known. In this paper, we employ the Partially-Observed Boolean Dynamical System (POBDS) signal model for a time sequence of noisy expression measurement from a Boolean GRN and develop a Bayesian Inverse Reinforcement Learning (BIRL) approach to address the realistic case in which the only available knowledge regarding the immediate cost function is provided by the sequence of measurements and interventions recorded in an experimental setting by an expert. The Boolean Kalman Smoother (BKS) algorithm is used for optimally mapping the available gene expression data into a sequence of Boolean states, and then the BIRL method is efficiently combined with the Q-learning algorithm for quantification of the immediate cost function. The performance of the proposed methodology is investigated by applying a state-feedback controller to two GRN models: a melanoma WNT5A Boolean network and a p53-MDM2 negative feedback loop Boolean network, when the cost of the undesirable states, and thus the identity of the undesirable genes, is learned using the proposed methodology. PMID- 29993698 TI - DrPOCS: Drug repositioning based on projection onto convex sets. AB - Drug repositioning, i.e. identifying new indications for known drugs, has attracted a lot of attentions recently and is becoming an effective strategy in drug development. In literature, several computational approaches have been proposed to identify potential indications of old drugs based on various types of data sources. In this paper, by formulating the drug-disease associations as a low-rank matrix, we propose a novel method, namely DrPOCS, to identify candidate indications of old drugs based on projection onto convex sets (POCS). With the integration of drug structure and disease phenotype information, DrPOCS predicts potential associations between drugs and diseases with matrix completion. Benchmarking results demonstrate that our proposed approach outperforms popular existing approaches with high accuracy. In addition, a number of novel predicted indications are validated with various types of evidences, indicating the predictive power of our proposed approach. PMID- 29993699 TI - Chronic Diseases and Health Monitoring Big Data: A Survey. AB - With the advancement of technology in data science and network technology, the world has stepped into the Era of Big Data, and the medical field is rich in data suitable for analysis. Thus, in recent years, there has been much research in medical big data, mainly targeting data collection, data analysis, and visualization. However, very few works provide a full survey of the medical big data on chronic diseases and health monitoring. This review investigates recent research efforts and conducts a comprehensive overview of the work on medical big data, especially as related to chronic diseases and health monitoring. It focuses on the full cycles of the big data processing, which includes medical big data preprocessing, big data tools and algorithms, big data visualization, and security issues in big data. It also attempts to combine common big data technologies with special medical needs by analyzing in detail existing works of medical big data. To the best of our knowledge, this is the first survey that targets chronic diseases and health monitoring big data technologies. PMID- 29993700 TI - Neural-Dynamic Optimization-Based Model Predictive Control for Tracking and Formation of Nonholonomic Multirobot Systems. AB - In this paper, a neural-dynamic optimization-based nonlinear model predictive control (NMPC) is developed for the multiple nonholonomic mobile robots formation. First, a model-based monocular vision method is developed to obtain the location information of the leader. Then, a separation-bearing-orientation scheme (SBOS) control strategy is proposed. During the formation motion, the leader robot is controlled to track the desired trajectory and the desired leader follower relationship can be maintained through the SBOS method. Finally, the model predictive control (MPC) is utilized to maintain the desired leader follower relationship. To solve the MPC generated constrained quadratic programming problem, the neural-dynamic optimization approach is used to search for the global optimal solution. Compared to other existing formation control approaches, the proposed solution is that the NMPC scheme exploit prime-dual neural network for online optimization. Finally, by using several actual mobile robots, the effectiveness of the proposed approach has been verified through the experimental studies. PMID- 29993701 TI - SyMIL: MinMax Latent SVM for Weakly Labeled Data. AB - Designing powerful models able to handle weakly labeled data are a crucial problem in machine learning. In this paper, we propose a new multiple instance learning (MIL) framework. Examples are represented as bags of instances, but we depart from standard MIL assumptions by introducing a symmetric strategy (SyMIL) that seeks discriminative instances in positive and negative bags. The idea is to use the instance the most distant from the hyper-plan to classify the bag. We provide a theoretical analysis featuring the generalization properties of our model. We derive a large margin formulation of our problem, which is cast as a difference of convex functions, and optimized using concave-convex procedure. We provide a primal version optimizing with stochastic subgradient descent and a dual version optimizing with one-slack cutting-plane. Successful experimental results are reported on standard MIL and weakly supervised object detection data sets: SyMIL significantly outperforms competitive methods (mi/MI/Latent-SVM), and gives very competitive performance compared to state-of-the-art works. We also analyze the selected instances of symmetric and asymmetric approaches on weakly supervised object detection and text classification tasks. Finally, we show complementarity of SyMIL with recent works on learning with label proportions on standard MIL data sets. PMID- 29993702 TI - Automatic Detection of Aortic Valve Opening using Seismocardiography in Healthy Individuals. AB - Accurate detection of fiducial points in a seismocardiogram (SCG) is a challenging research problem for its clinical application. In this paper, an automated method for detecting aortic valve opening (AO) instants using the dorsoventral component of SCG signal is proposed. This method does not require electrocardiogram (ECG) as a reference signal. After pre-processing the SCG, multiscale wavelet decomposition is carried out to get signal components in different wavelet subbands. The subbands having possible AO peaks are selected by a newly proposed dominant multiscale kurtosis (DMK) and dominant multiscale central frequency (DMCF) based criteria. The signal is reconstructed using selected subbands, and it is emphasized using the weights derived from proposed relative squared dominant multiscale kurtosis (RSDMK). The Shannon energy (SE) followed by autocorrelation coefficients are computed for systole envelope construction. Finally, AO peaks are detected by a Gaussian derivative filtering based scheme. The robustness of the proposed method is tested using clean and noisy SCG signals from CEBS database. Evaluation results show that the method can achieve an average sensitivity (Se) of 94%, prediction rate (+P) of 90% and detection accuracy (ACC) of 86% approximately over 4585 analyzed beats. PMID- 29993703 TI - Adaptive Consensus-Based Distributed Target Tracking With Dynamic Cluster in Sensor Networks. AB - This paper is concerned with the target tracking problem over a filtering network with dynamic cluster and data fusion. A novel distributed consensus-based adaptive Kalman estimation is developed to track a linear moving target. Both optimal filtering gain and average disagreement of the estimates are considered in the filter design. In order to estimate the states of the target more precisely, an optimal Kalman gain is obtained by minimizing the mean-squared estimation error. An adaptive consensus factor is employed to adjust the optimal gain as well as to acquire a better filtering performance. In the filter's information exchange, dynamic cluster selection and two-stage hierarchical fusion structure are employed to get more accurate estimation. At the first stage, every sensor collects information from its neighbors and runs the Kalman estimation algorithm to obtain a local estimate of system states. At the second stage, each local sensor sends its estimate to the cluster head to get a fused estimation. Finally, an illustrative example is presented to validate the effectiveness of the proposed scheme. PMID- 29993704 TI - Global and Local Surrogate-Assisted Differential Evolution for Expensive Constrained Optimization Problems With Inequality Constraints. AB - For expensive constrained optimization problems (ECOPs), the computation of objective function and constraints is very time-consuming. This paper proposes a novel global and local surrogate-assisted differential evolution (DE) for solving ECOPs with inequality constraints. The proposed method consists of two main phases: 1) global surrogate-assisted phase and 2) local surrogate-assisted phase. In the global surrogate-assisted phase, DE serves as the search engine to produce multiple trial vectors. Afterward, the generalized regression neural network is used to evaluate these trial vectors. In order to select the best candidate from these trial vectors, two rules are combined. The first is the feasibility rule, which at first guides the population toward the feasible region, and then toward the optimal solution. In addition, the second rule puts more emphasis on the solution with the highest predicted uncertainty, and thus alleviates the inaccuracy of the surrogates. In the local surrogate-assisted phase, the interior point method coupled with radial basis function is utilized to refine each individual in the population. During the evolution, the global surrogate-assisted phase has the capability to promptly locate the promising region and the local surrogate-assisted phase is able to speed up the convergence. Therefore, by combining these two important elements, the number of fitness evaluations can be reduced remarkably. The proposed method has been tested on numerous benchmark test functions from three test suites and two real-world cases. The experimental results demonstrate that the performance of the proposed method is better than that of other state-of-the-art methods. PMID- 29993705 TI - Input Time Delay Margin in Event-Triggered Consensus of Multiagent Systems. AB - In this paper, the event-triggered consensus problem of multiagent systems with input time delay is investigated. First, the normal event-triggered control scheme containing the input time delay is introduced to reduce the number of communication. Then the following results are achieved: 1) the procedure of setting parameters is carefully formulated for the event-triggered control scheme; 2) the precise input time delay margin is calculated for the event triggered consensus of the multiagent systems; 3) a more general condition of constructing event-triggered functions is derived to exclude the Zeno behavior; 4) the self-triggered control scheme is further applied to avoid the continuous measurement; and 5) the observer-based control scheme is also utilized to tackle the problem of unmeasurable state. Finally, the correctness and the effectiveness of these results are demonstrated by numerical simulations. PMID- 29993706 TI - Flexible Job-Shop Rescheduling for New Job Insertion by Using Discrete Jaya Algorithm. AB - Rescheduling is a necessary procedure for a flexible job shop when newly arrived priority jobs must be inserted into an existing schedule. Instability measures the amount of change made to the existing schedule and is an important metrics to evaluate the quality of rescheduling solutions. This paper focuses on a flexible job-shop rescheduling problem (FJRP) for new job insertion. First, it formulates FJRP for new job insertion arising from pump remanufacturing. This paper deals with bi-objective FJRPs to minimize: 1) instability and 2) one of the following indices: a) makespan; b) total flow time; c) machine workload; and d) total machine workload. Next, it discretizes a novel and simple metaheuristic, named Jaya, resulting in DJaya and improves it to solve FJRP. Two simple heuristics are employed to initialize high-quality solutions. Finally, it proposes five objective-oriented local search operators and four ensembles of them to improve the performance of DJaya. Finally, it performs experiments on seven real-life cases with different scales from pump remanufacturing and compares DJaya with some state-of-the-art algorithms. The results show that DJaya is effective and efficient for solving the concerned FJRPs. PMID- 29993707 TI - 3D Reconstruction of "In-the-Wild" Faces in Images and Videos. AB - 3D Morphable Models (3DMMs) are powerful statistical models of 3D facial shape and texture, and are among the state-of-the-art methods for reconstructing facial shape from single images. With the advent of new 3D sensors, many 3D facial datasets have been collected containing both neutral as well as expressive faces. However, all datasets are captured under controlled conditions. Thus, even though powerful 3D facial shape models can be learnt from such data, it is difficult to build statistical texture models that are sufficient to reconstruct faces captured in unconstrained conditions ("in-the-wild"). In this paper, we propose the first "in-the-wild" 3DMM by combining a statistical model of facial identity and expression shape with an "in-the-wild" texture model. We show that such an approach allows for the development of a greatly simplified fitting procedure for images and videos, as there is no need to optimise with regards to the illumination parameters. We have collected three new benchmarks that combine "in the-wild" images and video with ground truth 3D facial geometry, the first of their kind, and report extensive quantitative evaluations using them that demonstrate our method is state-of-the-art. PMID- 29993708 TI - Large Scale Image Segmentation with Structured Loss based Deep Learning for Connectome Reconstruction. AB - We present a method combining affinity prediction with region agglomeration, which improves significantly upon the state of the art of neuron segmentation from electron microscopy (EM) in accuracy and scalability. Our method consists of a 3D U-net, trained to predict affinities between voxels, followed by iterative region agglomeration. We train using a structured loss based on MALIS, encouraging topologically correct segmentations obtained from affinity thresholding. Our extension consists of two parts: First, we present a quasi linear method to compute the loss gradient, improving over the original quadratic algorithm. Second, we compute the gradient in two separate passes to avoid spurious gradient contributions in early training stages. Our predictions are accurate enough that simple learning-free percentile-based agglomeration outperforms more involved methods used earlier on inferior predictions. We present results on three diverse EM datasets, achieving relative improvements over previous results of 27%, 15%, and 250%. Our findings suggest that a single method can be applied to both nearly isotropic block-face EM data and anisotropic serial sectioned EM data. The runtime of our method scales linearly with the size of the volume and achieves a throughput of ~2.6 seconds per megavoxel, qualifying our method for the processing of very large datasets. PMID- 29993709 TI - A Fast Frequent Directions Algorithm for Low Rank Approximation: (Previous Title: Sparse Frequent Directions Algorithm for Low Rank Approximation). AB - Recently a deterministic method, frequent directions (FD) is proposed to solve the high dimensional low rank approximation problem. It works well in practice, but experiences high computational cost. In this paper, we establish a fast frequent directions algorithm for the low rank approximation problem, which implants a randomized algorithm, sparse subspace embedding (SpEmb) in FD. This new algorithm makes use of FD's natural block structure and sends more information through SpEmb to each block in FD. We prove that our new algorithm produces a good low rank approximation with a sketch of size linear on the rank approximated. Its effectiveness and efficiency are demonstrated by the experimental results on both synthetic and real world datasets, as well as applications in network analysis. PMID- 29993710 TI - A Deep Network Solution for Attention and Aesthetics Aware Photo Cropping. AB - We study the problem of photo cropping, which aims to find a cropping window of an input image to preserve as much as possible its important parts while being aesthetically pleasant. Seeking a deep learning-based solution, we design a neural network that has two branches for attention box prediction (ABP) and aesthetics assessment (AA), respectively. Given the input image, the ABP network predicts an attention bounding box as an initial minimum cropping window, around which a set of cropping candidates are generated with little loss of important information. Then, the AA network is employed to select the final cropping window with the best aesthetic quality among the candidates. The two sub-networks are designed to share the same full-image convolutional feature map, and thus are computationally efficient. By leveraging attention prediction and aesthetics assessment, the cropping model produces high-quality cropping results, even with the limited availability of training data for photo cropping. The experimental results on benchmark datasets clearly validate the effectiveness of the proposed approach. In addition, our approach runs at 5 fps, outperforming most previous solutions. PMID- 29993711 TI - Joint Active Learning with Feature Selection via CUR Matrix Decomposition. AB - This paper presents an unsupervised learning approach for simultaneous sample and feature selection, which is in contrast to existing works which mainly tackle these two problems separately. In fact the two tasks are often interleaved with each other: noisy and high-dimensional features will bring adverse effect on sample selection, while informative or representative samples will be beneficial to feature selection. Specifically, we propose a framework to jointly conduct active learning and feature selection based on the CUR matrix decomposition. From the data reconstruction perspective, both the selected samples and features can best approximate the original dataset respectively, such that the selected samples characterized by the features are highly representative. In particular, our method runs in one-shot without the procedure of iterative sample selection for progressive labeling. Thus, our model is especially suitable when there are few labeled samples or even in the absence of supervision, which is a particular challenge for existing methods. As the joint learning problem is NP-hard, the proposed formulation involves a convex but non-smooth optimization problem. We solve it efficiently by an iterative algorithm, and prove its global convergence. Experimental results on publicly available datasets corroborate the efficacy of our method compared with the state-of-the-art. PMID- 29993712 TI - End-to-end policy learning for active visual categorization. AB - Visual recognition systems mounted on autonomous moving agents face the challenge of unconstrained data, but simultaneously have the opportunity to improve their performance by moving to acquire new views of test data. In this work, we first show how a recurrent neural network-based system may be trained to perform end-to end learning of motion policies suited for this "active recognition" setting. Further, we hypothesize that active vision requires an agent to have the capacity to reason about the effects of its motions on its view of the world. To verify this hypothesis, we attempt to induce this capacity in our active recognition pipeline, by simultaneously learning to forecast the effects of the agent's motions on its internal representation of the environment conditional on all past views. Results across three challenging datasets confirm both that our end-to-end system successfully learns meaningful policies for active category recognition, and that "learning to look ahead" further boosts recognition performance. PMID- 29993713 TI - 3-D Human Sperm Flagellum Tracing in Low SNR Fluorescence Images. AB - Tracing tubular structures from biomedical images is important for a wide range of applications. Particularly, the spermatozoon is an essential cell whose flagella have a tubular form. Its main function is to fertilize the egg, and the flagellum is fundamental to achieve this task which depends importantly on the dynamics of intracellular calcium ([Ca2+]i). Measuring [Ca2+]i along the flagellum in 3-D is not a simple matter since it requires: 1) sophisticated fluorescence imaging techniques dealing with low intensity and signal to noise ratio (SNR) and 2) tracing the flagellum's centerline. Most of the algorithms proposed to trace tubular structures have been developed for multi-branch structures not being adequate for single tubular structures with low SNR. Taking into account the prior knowledge that the flagellum is constituted by a single tubular structure, we propose an automatic method to trace and track multiple single tubular structures from 3-D images. First, an algorithm based on one-class classification allows enhancement of the flagellum. This enhanced 3-D image permits guiding an iterative centerline algorithm toward the flagellum's centerline. Each sperm is assigned an ID to keep track of it in 3-D . Our algorithm was quantitatively evaluated using a ground truth 564 semi-manual traces (six 3-D image stacks) comparing them to those obtained from state-of-the art tubular structure centerline extraction algorithms. The qualitative and quantitative results show that our algorithm is extracting similar traces as compared with ground truth, and it is more robust and accurate to trace the flagellum's centerline than multi-branch algorithms. PMID- 29993714 TI - Beam Hardening Correction Using Cone Beam Consistency Conditions. AB - The polychromatic X-ray spectrum and the energy-dependent attenuation coefficient of materials cause beam hardening artifacts in CT reconstructed volumes. These artifacts appear as cupping and streak artifacts depending on the material composition and the geometry of the imaged object. CT scanners employ projection linearization to transform polychromatic attenuation to monochromatic attenuation using a polynomial model. Polynomial coefficients are computed during calibration or using prior information such as X-ray spectrum and attenuation properties of the materials. In this paper, we are presenting a novel method to correct beam hardening artifacts by enforcing cone beam consistency conditions on the projection data. We used consistency conditions derived from Grangeat's fundamental relation between cone beam projection data and 3-D Radon transform. The optimal polynomial coefficients for artifact reduction are iteratively estimated by minimizing the inconsistency of a set of projection pairs. The results from simulated and real datasets show the visible reduction of artifacts. Our studies also demonstrate the robustness of the algorithm when the projections are perturbed with other physical measurement and geometrical errors. The proposed method requires neither calibration nor prior information like X-ray spectrum, attenuation properties of the materials and detector response. The algorithm can be used for beam hardening correction in clinical, pre-clinical, and industrial CT systems. PMID- 29993715 TI - Observation of Self-Bending and Focused Ultrasound Beams in the Megahertz Range. AB - Self-bending (or self-accelerating) and nondiffracting acoustic beams, such as Airy beams, have the potential to focus around obstacles that are directly in the beam path. Here, we demonstrate the self-bending and focusing properties of Airy beams in the ultrasound domain using finite difference time-domain simulations at 5.2 MHz. The phase profiles of self-bending Airy beams are determined from the Airy function. This beam is then transmitted experimentally using a linear array transducer connected to a 128 channel Vantage Verasonics operating at 5.2 MHz. The performance of self-bending beams is compared to conventional focused ultrasound beams in the presence of a strong scattering obstacle (steel rod). The ability of self-bending Airy beams to bypass obstacles is characterized in terms of their relative energy retention at peak intensity, that was found experimentally to be 50.5% for traditional focused beams whereas 71.5% for Airy beams, proving that self-bending beams performed better than conventional beams in terms of relative energy retention with no significant change in the focal profiles. However, it is observed that, in absolute terms, self-bending beams focus less energy than traditional focused beams. PMID- 29993717 TI - FFDNet: Toward a Fast and Flexible Solution for CNN based Image Denoising. AB - Due to the fast inference and good performance, discriminative learning methods have been widely studied in image denoising. However, these methods mostly learn a specific model for each noise level, and require multiple models for denoising images with different noise levels. They also lack flexibility to deal with spatially variant noise, limiting their applications in practical denoising. To address these issues, we present a fast and flexible denoising convolutional neural network, namely FFDNet, with a tunable noise level map as the input. The proposed FFDNet works on downsampled subimages, achieving a good trade-off between inference speed and denoising performance. In contrast to the existing discriminative denoisers, FFDNet enjoys several desirable properties, including (i) the ability to handle a wide range of noise levels (i.e., [0, 75]) effectively with a single network, (ii) the ability to remove spatially variant noise by specifying a non-uniform noise level map, and (iii) faster speed than benchmark BM3D even on CPU without sacrificing denoising performance. Extensive experiments on synthetic and real noisy images are conducted to evaluate FFDNet in comparison with state-of-the-art denoisers. The results show that FFDNet is effective and efficient, making it highly attractive for practical denoising applications. PMID- 29993718 TI - Supervised Mixed Norm Autoencoder for Kinship Verification in Unconstrained Videos. AB - Identifying kinship relations has garnered interest due to several applications such as organizing and tagging the enormous amount of videos being uploaded on the Internet. Existing research in kinship verification primarily focuses on kinship prediction with image pairs. In this research, we propose a new deep learning framework for kinship verification in unconstrained videos using a novel Supervised Mixed Norm regularization Autoencoder (SMNAE). This new autoencoder formulation introduces class-specific sparsity in the weight matrix. The proposed three-stage SMNAE based kinship verification framework utilizes the learned spatio-temporal representation in the video frames for verifying kinship in a pair of videos. A new kinship video (KIVI) database of more than 500 individuals with variations due to illumination, pose, occlusion, ethnicity, and expression is collected for this research. It comprises a total of 355 true kin video pairs with over 250,000 still frames. The effectiveness of the proposed framework is demonstrated on the KIVI database and six existing kinship databases. On the KIVI database, SMNAE yields video-based kinship verification accuracy of 83.18% which is at least 3.2% better than existing algorithms. The algorithm is also evaluated on six publicly available kinship databases and compared with best reported results. It is observed that the proposed SMNAE consistently yields best results on all the databases. PMID- 29993716 TI - GPU Accelerated Multilevel Lagrangian Carotid Strain Imaging. AB - A multilevel Lagrangian carotid strain imaging algorithm is analyzed to identify computational bottlenecks for implementation on a graphics processing unit (GPU). Displacement tracking including regularization was found to be the most computationally expensive aspect of this strain imaging algorithm taking about 2.2 h for an entire cardiac cycle. This intensive displacement tracking was essential to obtain Lagrangian strain tensors. However, most of the computational techniques used for displacement tracking are parallelizable, and hence GPU implementation is expected to be beneficial. A new scheme for subsample displacement estimation referred to as a multilevel global peak finder was also developed since the Nelder-Mead simplex optimization technique used in the CPU implementation was not suitable for GPU implementation. GPU optimizations to minimize thread divergence and utilization of shared and texture memories were also implemented. This enables efficient use of the GPU computational hardware and memory bandwidth. Overall, an application speedup of was obtained enabling the algorithm to finish in about 50 s for a cardiac cycle. Last, comparison of GPU and CPU implementations demonstrated no significant difference in the quality of displacement vector and strain tensor estimation with the two implementations up to a 5% interframe deformation. Hence, a GPU implementation is feasible for clinical adoption and opens opportunity for other computationally intensive techniques. PMID- 29993719 TI - Learning a Patch Quality Comparator for Single Image Dehazing. AB - In bad weather conditions like fog and haze, the particles present in the atmosphere scatter incident light in different directions. As a result, image taken under these conditions suffers from reduced visibility, lack of contrast, as a result, it appears colorless. Image dehazing method tries to recover a haze free portrayal of the given hazy image. In this paper we propose a method that dehazes a given image by comparing various output patches with the original hazy version and choosing the best one. The comparison is performed by our proposed dehazed patch quality comparator based on Convolutional Neural Network (CNN). To select the best dehazed patch we employ binary search. Quantitative and qualitative evaluations show that our method achieves good results in most of the cases, and are, on an average, comparable with state-of-the-art methods. PMID- 29993720 TI - A Semantic-based Method for Visualizing Large Image Collections. AB - Interactive visualization of large image collections is important and useful in many applications, such as personal album management and user profiling on images. However, most prior studies focus on using low-level visual features of images, such as texture and color histogram, to create visualizations without considering the more important semantic information embedded in images. This paper proposes a novel visual analytic system to analyze images in a semantic aware manner. The system mainly comprises two components: a semantic information extractor and a visual layout generator. The semantic information extractor employs an image captioning technique based on convolutional neural network (CNN) to produce descriptive captions for images, which can be transformed into semantic keywords. The layout generator employs a novel co-embedding model to project images and the associated semantic keywords to the same 2D space. Inspired by the galaxy metaphor, we further turn the projected 2D space to a multi-scale galaxy visualization of images, in which semantic keywords and images are visually encoded as stars and planets. Users can iteratively refine the visual layout by integrating their domain knowledge into the co-embedding process. Two task-based evaluations are conducted to demonstrate the effectiveness of our system. PMID- 29993721 TI - An On-Chip Trainable and the Clock-Less Spiking Neural Network With 1R Memristive Synapses. AB - Spiking neural networks (SNNs) are being explored in an attempt to mimic brain's capability to learn and recognize at low power. Crossbar architecture with highly scalable resistive RAM or RRAM array serving as synaptic weights and neuronal drivers in the periphery is an attractive option for the SNN. Recognition (akin to "reading" the synaptic weight) requires small amplitude bias applied across the RRAM to minimize conductance change. Learning (akin to "writing" or updating the synaptic weight) requires large amplitude bias pulses to produce a conductance change. The contradictory bias amplitude requirement to perform reading and writing simultaneously and asynchronously, akin to biology, is a major challenge. Solutions suggested in the literature rely on time-division multiplexing of read and write operations based on clocks, or approximations ignoring the reading when coincidental with writing. In this paper, we overcome this challenge and present a clock-less approach wherein reading and writing are performed in different frequency domains. This enables learning and recognition simultaneously on an SNN. We validate our scheme in SPICE circuit simulator by translating a two-layered feed-forward Iris classifying SNN to demonstrate software-equivalent performance. The system performance is not adversely affected by a voltage dependence of conductance in realistic RRAMs, despite departing from linearity. Overall, our approach enables direct implementation of biological SNN algorithms in hardware. PMID- 29993722 TI - Dynamic handwriting analysis for the assessment of neurodegenerative diseases: a pattern recognition perspective. AB - Neurodegenerative diseases, as for instance Alzheimer's Disease (AD) and Parkinson's Disease (PD), affect the peripheral nervous system, where nerve cells send the messages that control muscles in order to allow movements. Sick neurons cannot control muscles properly. Handwriting involves cognitive planning, coordination and execution abilities. Significant changes in the handwriting performance are a prominent feature of AD and PD. This work addresses the most relevant results obtained in the field of on-line (dynamic) analysis of handwritten trials by AD and PD patients. The survey is made from a pattern recognition point of view, so that different phases are described. Data acquisition deal not only with the device, but also with the handwriting task. Feature extraction can deal with function and parameter features. The classification problem is also discussed along with results already obtained. The paper also highlights the most profitable research direction. PMID- 29993723 TI - Modeling Semantically Multilayered Affective and Psychophysical Responses Toward Tactile Textures. AB - Subjective responses related to touch are described via perceptual and affective adjectives. Understanding relationships among such responses is useful for industrial surface design. We developed a method for investigating relationships among touch related responses by constructing multilayered adjective models without assumptions regarding model structure such as adjective hierarchy or a defnition of layers. The method consists of two processes through which a model structure and parameters are estimated. To acquire the model structure, subjectively evaluated causal relationships among adjective pairs are used. Free parameters, such as effects among adjectives, are then statistically estimated through sensory evaluation and structural equation modeling. To validate the method, two models with different levels of details were developed using 29 adjective pairs and 46 texture samples. For example, the model with three layers,which we categorized into psychophysical, affective, and hedonic layers, was constructed. Moreover, a detailed model with four layers was provided, which was more complex than previously reported models. The present method helps advance our understanding and design of connections among subjective surface ratings. PMID- 29993724 TI - Design and Adaptive Control for an Upper Limb Robotic Exoskeleton in Presence of Input Saturation. AB - This paper addresses the control design for an upper limb exoskeleton in the presence of input saturation. An adaptive controller employing the neural network technology is proposed to approximate the uncertain robotic dynamics. Also, an auxiliary system is designed to deal with the effect of input saturation. Furthermore, we develop both the state feedback and the output feedback control strategies, which effectively estimates the uncertainties online from the measured feedback errors, instead of the model-based control. In addition to the proposed control, a disturbance observer is designed to reject the unknown disturbance online for achieving the trajectory tracking. The method requires a minimal amount of a priori knowledge of system dynamics. Subsequently, the principle of Lyapunov synthesis ensures the stability of the closed-loop system. Finally, the experimental studies are carried out on this robotic exoskeleton. PMID- 29993725 TI - Multiple-Model Adaptive Estimation for 3-D and 4-D Signals: A Widely Linear Quaternion Approach. AB - Quaternion state estimation techniques have been used in various applications, yet they are only suitable for dynamical systems represented by a single known model. In order to deal with model uncertainty, this paper proposes a class of widely linear quaternion multiple-model adaptive estimation (WL-QMMAE) algorithms based on widely linear quaternion Kalman filters and Bayesian inference. The augmented second-order quaternion statistics is employed to capture complete second-order statistical information in improper quaternion signals. Within the WL-QMMAE framework, a widely linear quaternion interacting multiple-model algorithm is proposed to track time-variant model uncertainty, while a widely linear quaternion static multiple-model algorithm is proposed for time-invariant model uncertainty. A performance analysis of the proposed algorithms shows that, as expected, the WL-QMMAE reduces to semiwidely linear QMMAE for Ceta-improper signals and further reduces to strictly linear QMMAE for proper signals. Simulation results indicate that for improper signals, the proposed WL-QMMAE algorithms exhibit an enhanced performance over their strictly linear counterparts. The effectiveness of the proposed recursive performance analysis algorithm is also validated. PMID- 29993726 TI - Optimal Synchronization Control of Multiagent Systems With Input Saturation via Off-Policy Reinforcement Learning. AB - In this paper, we aim to investigate the optimal synchronization problem for a group of generic linear systems with input saturation. To seek the optimal controller, Hamilton-Jacobi-Bellman (HJB) equations involving nonquadratic input energy terms in coupled forms are established. The solutions to these coupled HJB equations are further proven to be optimal and the induced controllers constitute interactive Nash equilibrium. Due to the difficulty to analytically solve HJB equations, especially in coupled forms, and the possible lack of model information of the systems, we apply the data-based off-policy reinforcement learning algorithm to learn the optimal control policies. A byproduct of this off policy algorithm is shown that it is insensitive to probing noise that is exerted to the system to maintain persistence of excitation condition. In order to implement this off-policy algorithm, we employ actor and critic neural networks to approximate the controllers and the cost functions. Furthermore, the estimated control policies obtained by this presented implementation are proven to converge to the optimal ones under certain conditions. Finally, an illustrative example is provided to verify the effectiveness of the proposed algorithm. PMID- 29993727 TI - Extraction and Automatic Grouping of Joint and Individual Sources in Multi Subject fMRI Data Using Higher Order Cumulants. AB - The joint analysis of multiple datasets to extract their interdependency information has wide applications in biomedical and health informatics. In this paper, we propose an algorithm to extract joint and individual sources of multi subject datasets by using a deflation based procedure, which is referred to as joint/individual thin independent component analysis (JI-ThICA). The proposed algorithm is based on two cost functions utilizing higher order cumulants to extract joint and individual sources. Joint sources are discriminated by fusing signals of all subjects, whereas individual sources are extracted separately for each subject. Furthermore, JI-ThICA algorithm estimates the number of joint sources by applying a simple and efficient strategy to determine the type of sources (joint or individual). The algorithm also categorizes similar sources automatically across datasets through an optimization process. The proposed algorithm is evaluated by analyzing simulated functional Magnetic Resonance Imaging (fMRI) multi-subject datasets, and its performance is compared with existing alternatives. We investigate clean and noisy fMRI signals and consider two source models. Our results reveal that the proposed algorithm outperforms its alternatives in terms of the mean joint Signal to Interference Ratio (jSIR). We also apply the proposed algorithm on a public-available real fMRI multi-subject dataset, which was acquired during naturalistic auditory experience. The extracted results are in accordance with the previous studies on naturalistic audio listening and results of a recent study investigated this dataset, which demonstrates that the JI-ThICA algorithm can be applied to extract reliable and meaningful information from multi-subject fMRI data. PMID- 29993728 TI - An ARIMA Model with Adaptive Orders for Predicting Blood Glucose Concentrations and Hypoglycemia. AB - The Continuous Glucose Monitoring System (CGMS) is an effective tool which enables the users to monitor their blood glucose (BG) levels. Based on the CGM data, we aim at predicting future BG levels so that appropriate actions can be taken in advance to prevent hyperglycemia or hypoglycemia. Due to the time varying non-stationarity of CGM data, verified by Augmented Dickey-Fuller (ADF) test and Analysis of Variance (ANOVA), an Autoregressive Integrated Moving Average (ARIMA) model with an adaptive identification algorithm of model orders is proposed in the prediction framework. Such identification algorithm adaptively determines the model orders and simultaneously estimates the corresponding parameters using Akaike Information Criterion (AIC) and least square estimation (LSE). A case study is conducted with the CGM data of diabetics under daily living conditions to analyze the prediction performance of the proposed model together with the early hypoglycemic alarms. Results show that the proposed model outperforms the adaptive univariate model and ARIMA model. PMID- 29993729 TI - Adaptive Sojourn Time HSMM for Heart Sound Segmentation. AB - Heart sounds are difficult to interpret due to events with very short temporal onset between them (tens of millisec- onds) and dominant frequencies that are out of the human audi- ble spectrum. Computer assisted decision systems may help but they require robust signal processing algorithms. In this paper, we propose a new algorithm for heart sound segmentation using a hidden semi-Markov model. The proposed algorithm infers more suitable sojourn time parameters than those currently suggested by the state-of-art, through a maximum likelihood approach. We test our approach over three different datasets, including the publicly available PhysioNet and Pascal datasets. We also release a pediatric dataset composed of 29 heart sounds. In contrast with any other dataset available online, the annotations of the heart sounds in the released dataset contain information about the beginning and the ending of each heart sound event. Annotations were made by two cardiopulmonologists. The proposed algorithm is compared with the current state- of-the-art. The results show a significant increase in segmen- tation performance, regardless the dataset or the methodology presented. E.g.: when using the PhysioNet dataset to train and to evaluate the HSMMs, our algorithm achieved average an F-score of 92% compared to 89% achieved by the algorithm described in [1]. In this sense, the proposed approach to adapt sojourn time parameters represents an effective solution for heart sound segmentation problems, even when the training data does not perfectly express the variability of the testing data. PMID- 29993730 TI - Describing Video With Attention-Based Bidirectional LSTM. AB - Video captioning has been attracting broad research attention in the multimedia community. However, most existing approaches heavily rely on static visual information or partially capture the local temporal knowledge (e.g., within 16 frames), thus hardly describing motions accurately from a global view. In this paper, we propose a novel video captioning framework, which integrates bidirectional long-short term memory (BiLSTM) and a soft attention mechanism to generate better global representations for videos as well as enhance the recognition of lasting motions in videos. To generate video captions, we exploit another long-short term memory as a decoder to fully explore global contextual information. The benefits of our proposed method are two fold: 1) the BiLSTM structure comprehensively preserves global temporal and visual information and 2) the soft attention mechanism enables a language decoder to recognize and focus on principle targets from the complex content. We verify the effectiveness of our proposed video captioning framework on two widely used benchmarks, that is, microsoft video description corpus and MSR-video to text, and the experimental results demonstrate the superiority of the proposed approach compared to several state-of-the-art methods. PMID- 29993731 TI - SG-FCN: A Motion and Memory-Based Deep Learning Model for Video Saliency Detection. AB - Data-driven saliency detection has attracted strong interest as a result of applying convolutional neural networks to the detection of eye fixations. Although a number of image-based salient object and fixation detection models have been proposed, video fixation detection still requires more exploration. Different from image analysis, motion and temporal information is a crucial factor affecting human attention when viewing video sequences. Although existing models based on local contrast and low-level features have been extensively researched, they failed to simultaneously consider interframe motion and temporal information across neighboring video frames, leading to unsatisfactory performance when handling complex scenes. To this end, we propose a novel and efficient video eye fixation detection model to improve the saliency detection performance. By simulating the memory mechanism and visual attention mechanism of human beings when watching a video, we propose a step-gained fully convolutional network by combining the memory information on the time axis with the motion information on the space axis while storing the saliency information of the current frame. The model is obtained through hierarchical training, which ensures the accuracy of the detection. Extensive experiments in comparison with 11 state of-the-art methods are carried out, and the results show that our proposed model outperforms all 11 methods across a number of publicly available datasets. PMID- 29993732 TI - Fuzzy Finite Time Control for Switched Systems via Adding a Barrier Power Integrator. AB - This paper concentrates on the study of finite time control for nonlinear switched systems. Based on a newly introduced adding a barrier integrator technique, a novel adaptive fuzzy control strategy is proposed for a class of nonlinear switched systems. Compared with the existing adaptive control methods, the proposed method has several distinguishing features. Finite time control: the proposed adaptive control method can solve the exact finite time control problem for the stabilization and some types of tracking issues. Namely, the errors will converge to zero in finite time. For a general tracking problem, the practical finite time control can be achieved. More general systems: the proposed method is suitable for high order nonlinear switched systems with arbitrary switching and unknown control gains. Some strict assumptions on the system dynamics are relaxed. Full state constraints: the proposed method can be utilized to deal with the full state constraints problem. Simple controller structure: the ''explosion of the complexity'' in the backstepping design is avoided. Singularity free design: the singularity problem is carefully handled during the whole design procedure. Examples are presented to illustrate the effectiveness of the proposed method. PMID- 29993733 TI - Interval Type-2 Fuzzy Neural Networks for Chaotic Time Series Prediction: A Concise Overview. AB - Chaotic time series widely exists in nature and society (e.g., meteorology, physics, economics, etc.), which usually exhibits seemingly unpredictable features due to its inherent nonstationary and high complexity. Thankfully, multifarious advanced approaches have been developed to tackle the prediction issues, such as statistical methods, artificial neural networks (ANNs), and support vector machines. Among them, the interval type-2 fuzzy neural network (IT2FNN), which is a synergistic integration of fuzzy logic systems and ANNs, has received wide attention in the field of chaotic time series prediction. This paper begins with the structural features and superiorities of IT2FNN. Moreover, chaotic characters identification and phase-space reconstruction matters for prediction are presented. In addition, we also offer a comprehensive review of state-of-the-art applications of IT2FNN, with an emphasis on chaotic time series prediction and summarize their main contributions as well as some hardware implementations for computation speedup. Finally, this paper trends and extensions of this field, along with an outlook of future challenges are revealed. The primary objective of this paper is to serve as a tutorial or referee for interested researchers to have an overall picture on the current developments and identify their potential research direction to further investigation. PMID- 29993734 TI - A Multiobjective Evolutionary Algorithm Based on Coordinate Transformation. AB - In this paper, a novel multiobjective evolutionary algorithm (MOEA/CT) is proposed to better manage convergence and distribution of solutions when MOEAs are used for solving multiobjective optimization problems. The coordinate transformation strategy, an external archive update strategy, and a diversity maintenance strategy are proposed in MOEA/CT. The coordinate transformation strategy in the objective space is designed to find more efficient solutions that can accelerate the convergence process. Based on the coordinate transformation strategy, a novel update strategy and diversity maintenance approach for selecting nondominated solutions from the external archive set are integrated in MOEA/CT for getting better distribution of the solutions. The proposed MOEA/CT is compared with eight state-of-art algorithms on six biobjective and seven tri objective test problems. In terms of four performance metrics, the comparative experimental results demonstrate that MOEA/CT outperforms the other eight competitors and it can achieve solutions with better distribution and better convergence to the Pareto front. In addition, parameter sensitivity analysis is provided to investigate the effect of a key parameter in MOEA/CT; the proposed three strategies are also studied individually to investigate their contribution to MOEA/CT; the performance analysis along with the capacity of external archive is given to clearly make the influence in MOEA/CT; finally, the scalability performance of MOEA/CT is investigated and compared with five notable many objective evolutionary algorithms on the DTLZ and WFG test suites with 5, 8, 10, and 15 objectives. PMID- 29993735 TI - Towards Personalized Image Captioning via Multimodal Memory Networks. AB - We address personalized image captioning, which generates a descriptive sentence for a user's image, accounting for prior knowledge such as her active vocabularies or writing style in her previous documents. As applications of personalized image captioning, we solve two post automation tasks in social networks: hashtag prediction and post generation. The hashtag prediction predicts a list of hashtags for an image, while the post generation creates a natural post text consisting of normal words, emojis, and even hashtags. We propose a novel personalized captioning model named Context Sequence Memory Network (CSMN). Its unique updates over existing memory networks include (i) exploiting memory as a repository for multiple types of context information, (ii) appending previously generated words into memory to capture long-term information, and (iii) adopting CNN memory structure to jointly represent nearby ordered memory slots for better context understanding. For evaluation, we collect a new dataset InstaPIC-1.1M, comprising 1.1M Instagram posts from 6.3K users. We further use the benchmark YFCC100M dataset to validate the generality of our approach. With quantitative evaluation and user studies via Amazon Mechanical Turk, we show that the three novel features of the CSMN help enhance the performance of personalized image captioning over state-of-the-art captioning models. PMID- 29993736 TI - Online Data Thinning via Multi-Subspace Tracking. AB - In an era of ubiquitous large-scale streaming data, the availability of data far exceeds the capacity of expert human analysts. In many settings, such data is either discarded or stored unprocessed in data centers. This paper proposes a method of online data thinning, in which large-scale streaming datasets are winnowed to preserve unique, anomalous, or salient elements for timely expert analysis. At the heart of this proposed approach is an online anomaly detection method based on dynamic, low-rank Gaussian mixture models. Specifically, the high dimensional covariances matrices associated with the Gaussian components are associated with low-rank models. According to this model, most observations lie near a union of subspaces. The low-rank modeling mitigates the curse of dimensionality associated with anomaly detection for high-dimensional data, and recent advances in subspace clustering and subspace tracking allow the proposed method to adapt to dynamic environments. Furthermore, the proposed method allows subsampling, is robust to missing data, and uses a mini-batch online optimization approach. The resulting algorithms are scalable, efficient, and are capable of operating in real time. Experiments on wide-area motion imagery and e-mail databases illustrate the efficacy of the proposed approach. PMID- 29993737 TI - Composite Quantization. AB - This paper studies the compact coding approach to approximate nearest neighbor search. We introduce a composite quantization framework. It uses the composition of several () elements, each of which is selected from a different dictionary, to accurately approximate a -dimensional vector, thus yielding accurate search, and represents the data vector by a short code composed of the indices of the selected elements in the corresponding dictionaries. Our key contribution lies in introducing a near-orthogonality constraint, which makes the search efficiency is guaranteed as the cost of the distance computation is reduced to from through a distance table lookup scheme. The resulting approach is called near-orthogonal composite quantization. We theoretically justify the equivalence between near orthogonal composite quantization and minimizing an upper bound of a function formed by jointly considering the quantization error and the search cost according to a generalized triangle inequality. We empirically show the efficacy of the proposed approach over several benchmark datasets. In addition, we demonstrate the superior performances in other three applications: combination with inverted multi-index, inner-product similarity search, and query compression for mobile search. PMID- 29993738 TI - DRINet for Medical Image Segmentation. AB - Convolutional neural networks (CNNs) have revolutionized medical image analysis over the past few years. The U-Net architecture is one of the most well-known CNN architectures for semantic segmentation and has achieved remarkable successes in many different medical image segmentation applications. The U-Net architecture consists of standard convolution layers, pooling layers, and upsampling layers. These convolution layers learn representative features of input images and construct segmentations based on the features. However, the features learned by standard convolution layers are not distinctive when the differences among different categories are subtle in terms of intensity, location, shape, and size. In this paper, we propose a novel CNN architecture, called Dense-Res-Inception Net (DRINet), which addresses this challenging problem. The proposed DRINet consists of three blocks, namely a convolutional block with dense connections, a deconvolutional block with residual inception modules, and an unpooling block. Our proposed architecture outperforms the U-Net in three different challenging applications, namely multi-class segmentation of cerebrospinal fluid on brain CT images, multi-organ segmentation on abdominal CT images, and multi-class brain tumor segmentation on MR images. PMID- 29993739 TI - Development of low frequency (20-100 kHz) clinically viable ultrasound applicator for chronic wound treatment. AB - This paper details the systematic approach used to develop a viable clinical prototype of a therapeutic ultrasound applicator and discusses the rationale and deliberations that led to the design strategy. The applicator was specifically devised to treat chronic wounds and - to the best of the author's knowledge - is the first truly wearable device with a proven record of reducing healing time, directly translating to a reduction of healthcare costs. The prototype operates in the kHz (20-100) range of frequencies and uses non-cavitational and non thermal levels of ultrasound energy. Hence, in the absence of inertial cavitation and temperature elevation, the tissue-ultrasound interaction is considered to be dependent on stable cavitation (if any) and radiation force. The peak acoustic output pressure amplitude is limited to 55 kPa, corresponding to a spatial peak temporal peak intensity of 100 mW/cm2. This level of intensity is considered to be safe to apply for extended (up to four hours) periods of time. The patch-like applicator design is suitable to be embedded in wound dressing. With its light weight (<20g) and circular (40 mm dia) disk shape architecture, the applicator is well suited for chronic wound treatment. A small (n=8) pilot study on the effects of the applicator on diabetic ulcers healing time is presented. The average time to wound closure was 4.7 weeks for subjects treated with the active ultrasound applicator, compared to 12 weeks for subjects treated with a sham applicator, suggesting that patients with diabetic ulcers may benefit from the proposed treatment. PMID- 29993740 TI - Discriminative Transfer Learning for General Image Restoration. AB - Recently, several discriminative learning approaches have been proposed for effective image restoration, achieving convincing trade-off between image quality and computational efficiency. However, these methods require separate training for each restoration task (e.g., denoising, deblurring, demosaicing) and problem condition (e.g., noise level of input images). This makes it time-consuming and difficult to encompass all tasks and conditions during training. In this paper, we propose a discriminative transfer learning method that incorporates formal proximal optimization and discriminative learning for general image restoration. The method requires a single-pass discriminative training and allows for reuse across various problems and conditions while achieving an efficiency comparable to previous discriminative approaches. Furthermore, after being trained, our model can be easily transferred to new likelihood terms to solve untrained tasks, or be combined with existing priors to further improve image restoration quality. PMID- 29993741 TI - Moire Photo Restoration Using Multiresolution Convolutional Neural Networks. AB - Digital cameras and mobile phones enable us to conveniently record precious moments. While digital image quality is constantly being improved, taking high quality photos of digital screens still remains challenging because the photos are often contaminated with moire patterns, a result of the interference between the pixel grids of the camera sensor and the device screen. Moire patterns can severely damage the visual quality of photos. However, few studies have aimed to solve this problem. In this paper, we introduce a novel multiresolution fully convolutional network for automatically removing moire patterns from photos. Since a moire pattern spans over a wide range of frequencies, our proposed network performs a nonlinear multiresolution analysis of the input image before computing how to cancel moire artefacts within every frequency band. We also create a large-scale benchmark dataset with 100,000+ image pairs for investigating and evaluating moire pattern removal algorithms. Our network achieves state-of-the-art performance on this dataset in comparison to existing learning architectures for image restoration problems. PMID- 29993742 TI - Improved Random Forest for Classification. AB - We propose an improved random forest classifier that performs classification with minimum number of trees. The proposed method iteratively removes some unimportant features. Based on the number of important and unimportant features, we formulate a novel theoretical upper limit on the number of trees to be added to the forest to ensure improvement in classification accuracy. Our algorithm converges with a reduced but important set of features. We prove that further addition of trees or further reduction of features does not improve classification performance. The efficacy of the proposed approach is demonstrated through experiments on benchmark datasets. We further use the proposed classifier to detect mitotic nuclei in the histopathological datasets of breast tissues. We also apply our method on the industrial dataset of dual phase steel microstructures to classify different phases. Results of our method on different datasets show significant reduction in average classification error compared to a number of competing methods. PMID- 29993743 TI - Perceptual Adversarial Networks for Image-to-Image Transformation. AB - In this paper, we propose Perceptual Adversarial Networks (PAN) for image-to image transformations. Different from existing application driven algorithms, PAN provides a generic framework of learning to map from input images to desired images (Fig. 1), such as a rainy image to its de-rained counterpart, object edges to photos, semantic labels to a scenes image, etc. The proposed PAN consists of two feed-forward convolutional neural networks (CNNs): the image transformation network T and the discriminative network D. Besides the generative adversarial loss widely used in GANs, we propose the perceptual adversarial loss, which undergoes an adversarial training process between the image transformation network T and the hidden layers of the discriminative network D. The hidden layers and the output of the discriminative network D are upgraded to constantly and automatically discover the discrepancy between the transformed image and the corresponding ground-truth, while the image transformation network T is trained to minimize the discrepancy explored by the discriminative network D. Through integrating the generative adversarial loss and the perceptual adversarial loss, D and T can be trained alternately to solve image-to-image transformation tasks. Experiments evaluated on several image-to-image transformation tasks (e.g., image de-raining, image inpainting, etc) demonstrate the effectiveness of the proposed PAN and its advantages over many existing works. PMID- 29993744 TI - Fast Texture Mapping Adjustment via Local/Global Optimization. AB - This paper deals with the texture mapping of a triangular mesh model given a set of calibrated images. Different from the traditional approach of applying projective texture mapping with model parameterizations, we develop an image space texture optimization scheme that aims to reduce visible seams or misalignment at texture or depth boundaries. Our novel scheme starts with an efficient local (and parallel) texture adjustment scheme at these boundaries, followed by a global correction step to rectify potential texture distortions caused by the local movement. Our phased optimization scheme achieves 50~100 times speedup on GPU (or 6x on CPU) compared to previous state-of-the-art methods. Experiments on a variety of models showed that we achieve this significant speedup without sacrificing texture quality. Our approach significantly improves resilience to modeling and calibration errors, thereby allowing fast and fully automatic creation of textured models using commodity depth sensors by untrained users. PMID- 29993745 TI - Surface Motion Capture Animation Synthesis. AB - We propose to generate novel animations from a set of elementary examples of video-based surface motion capture, under user-specified constraints. 4D surface capture animation is motivated by the increasing demand from media production for highly realistic 3D content. To this aim, data driven strategies that consider video-based information can produce animation with real shapes, kinematics and appearances. Our animations rely on the combination and the interpolation of textured 3D mesh data, which requires examining two aspects: (1) shape geometry and (2) appearance. First, we propose an animation synthesis structure for the shape geometry, the Essential graph, that outperforms standard Motion graphs in optimality with respect to quantitative criteria, and we extend optimized interpolated transition algorithms to mesh data. Second, we propose a compact view-independent representation for the shape appearance. This representation encodes subject appearance changes due to viewpoint and illumination, and due to inaccuracies in geometric modelling independently. In addition to providing compact representations, such decompositions allow for additional applications such as interpolation for animation. PMID- 29993746 TI - Simulation of Textile Stains. AB - Studies on virtual textile have long been an appealing topic in computer graphics and most of the efforts were paid to their distinctive appearances or physically based simulation. However, stain as one of the most commonly seen phenomena has received little attention so far. This paper introduces techniques for simulating the stain effect on fabric. Based on the microstructure of yarns, we propose a triple-layer model (TLM) to handle the liquid-yarn interaction for the wetting and wicking computation, and we formalize the liquid spreading in woven cloth into two typical actions, the in-yarn diffusion and the cross-yarn diffusion. The dye diffusion is driven by the liquid diffusion and the concentration distribution of pigments. The warp-weft anisotropy is handled by simulation of the yarn's structure in the two directions. Experimental results demonstrate that a wide range of fabric stain phenomenon on different textile materials, such as the water ring effect, the high saturate stain contour, and the dynamic wash away effect, can be simulated effectively without loss of visual realism. The realism of our simulation results is comparable to the pictures taken from the real world. PMID- 29993747 TI - Turbulent Micropolar SPH Fluids with Foam. AB - In this paper we introduce a novel micropolar material model for the simulation of turbulent inviscid fluids. The governing equations are solved by using the concept of Smoothed Particle Hydrodynamics (SPH). SPH fluid simulations suffer from numerical diffusion which leads to a lower vorticity, a loss in turbulent details and finally in less realistic results. To solve this problem we propose a micropolar fluid model. The micropolar fluid model is a generalization of the classical Navier-Stokes equations, which are typically used in computer graphics to simulate fluids. In contrast to the classical Navier-Stokes model, micropolar fluids have a microstructure and therefore consider the rotational motion of fluid particles. In addition to the linear velocity field these fluids have a field of microrotation which represents existing vortices and provides a source for new ones. Our novel micropolar model can generate realistic turbulences, is linear and angular momentum conserving, can be easily integrated in existing SPH simulation methods and its computational overhead is negligible. Another important visual feature of turbulent liquids is foam. Therefore, we present a post-processing method which considers microrotation in the foam generation. It works completely automatic and requires only one user-defined parameter to control the amount of foam. PMID- 29993748 TI - A Voxel-based Rendering Pipeline for Large 3D Line Sets. AB - We present a voxel-based rendering pipeline for large 3D line sets that employs GPU ray-casting to achieve scalable rendering including transparency and global illumination effects. Even for opaque lines we demonstrate superior rendering performance compared to GPU rasterization of lines, and when transparency is used we can interactively render amounts of lines that are infeasible to be rendered via rasterization. We propose a direction-preserving encoding of lines into a regular voxel grid, along with the quantization of directions using face-to-face connectivity in this grid. On the regular grid structure, parallel GPU ray casting is used to determine visible fragments in correct visibility order. To enable interactive rendering of global illumination effects like low-frequency shadows and ambient occlusions, illumination simulation is performed during ray casting on a level-of-detail (LoD) line representation that considers the number of lines and their lengths per voxel. In this way we can render effects which are very difficult to render via GPU rasterization. A detailed performance and quality evaluation compares our approach to rasterization-based rendering of lines. PMID- 29993749 TI - Low Rank Subspace Clustering via Discrete Constraint and Hypergraph Regularization for Tumor Molecular Pattern Discovery. AB - Tumor clustering is a powerful approach for cancer class discovery which is crucial to the effective treatment of cancer. Many traditional clustering methods such as NMF-based models, have been widely used to identify tumors. However, they cannot achieve satisfactory results. Recently, subspace clustering approaches have been proposed to improve the performance by dividing the original space into multiple low-dimensional subspaces. Among them, low rank representation is becoming a popular approach to attain subspace clustering. In this paper, we propose a novel Low Rank Subspace Clustering model via Discrete Constraint and Hypergraph Regularization (DHLRS). The proposed method learns the cluster indicators directly by using discrete constraint, which makes the clustering task simple. For each subspace, we adopt Schatten -norm to better approximate the low rank constraint. Moreover, Hypergraph Regularization is adopted to infer the complex relationship between genes and intrinsic geometrical structure of gene expression data in each subspace. Finally, the molecular pattern of tumor gene expression data sets is discovered according to the optimized cluster indicators. Experiments on both synthetic data and real tumor gene expression data sets prove the effectiveness of proposed DHLRS. PMID- 29993751 TI - Learning-Based Predictive Control for Discrete-Time Nonlinear Systems With Stochastic Disturbances. AB - In this paper, a learning-based predictive control (LPC) scheme is proposed for adaptive optimal control of discrete-time nonlinear systems under stochastic disturbances. The proposed LPC scheme is different from conventional model predictive control (MPC), which uses open-loop optimization or simplified closed loop optimal control techniques in each horizon. In LPC, the control task in each horizon is formulated as a closed-loop nonlinear optimal control problem and a finite-horizon iterative reinforcement learning (RL) algorithm is developed to obtain the closed-loop optimal/suboptimal solutions. Therefore, in LPC, RL and adaptive dynamic programming (ADP) are used as a new class of closed-loop learning-based optimization techniques for nonlinear predictive control with stochastic disturbances. Moreover, LPC also decomposes the infinite-horizon optimal control problem in previous RL and ADP methods into a series of finite horizon problems, so that the computational costs are reduced and the learning efficiency can be improved. Convergence of the finite-horizon iterative RL algorithm in each prediction horizon and the Lyapunov stability of the closed loop control system are proved. Moreover, by using successive policy updates between adjoint time horizons, LPC also has lower computational costs than conventional MPC which has independent optimization procedures between two different prediction horizons. Simulation results illustrate that compared with conventional nonlinear MPC as well as ADP, the proposed LPC scheme can obtain a better performance both in terms of policy optimality and computational efficiency. PMID- 29993750 TI - A Deep Learning Approach for Targeted Contrast-Enhanced Ultrasound Based Prostate Cancer Detection. AB - The important role of angiogenesis in cancer development has driven many researchers to investigate the prospects of noninvasive cancer diagnosis based on the technology of contrast-enhanced ultrasound (CEUS) imaging. This paper presents a deep learning framework to detect prostate cancer in the sequential CEUS images. The proposed method uniformly extracts features from both the spatial and the temporal dimensions by performing three-dimensional convolution operations, which captures the dynamic information of the perfusion process encoded in multiple adjacent frames for prostate cancer detection. The deep learning models were trained and validated against expert delineations over the CEUS images recorded using two types of contrast agents, i.e. the anti-PSMA based agent targeted to prostate cancer cells and the non-targeted blank agent. Experiments showed that the deep learning method achieved over 91% specificity and 90% average accuracy over the targeted CEUS images for prostate cancer detection, which was superior () than previously reported approaches and implementations. PMID- 29993752 TI - A New Correntropy-Based Conjugate Gradient Backpropagation Algorithm for Improving Training in Neural Networks. AB - Mean square error (MSE) is the most prominent criterion in training neural networks and has been employed in numerous learning problems. In this paper, we suggest a group of novel robust information theoretic backpropagation (BP) methods, as correntropy-based conjugate gradient BP (CCG-BP). CCG-BP algorithms converge faster than the common correntropy-based BP algorithms and have better performance than the common CG-BP algorithms based on MSE, especially in nonGaussian environments and in cases with impulsive noise or heavy-tailed distributions noise. In addition, a convergence analysis of this new type of method is particularly considered. Numerical results for several samples of function approximation, synthetic function estimation, and chaotic time series prediction illustrate that our new BP method is more robust than the MSE-based method in the sense of impulsive noise, especially when SNR is low. PMID- 29993753 TI - Radial Basis Functions With Adaptive Input and Composite Trend Representation for Portfolio Selection. AB - We propose a set of novel radial basis functions with adaptive input and composite trend representation (AICTR) for portfolio selection (PS). Trend representation of asset price is one of the main information to be exploited in PS. However, most state-of-the-art trend representation-based systems exploit only one kind of trend information and lack effective mechanisms to construct a composite trend representation. The proposed system exploits a set of RBFs with multiple trend representations, which improves the effectiveness and robustness in price prediction. Moreover, the input of the RBFs automatically switches to the best trend representation according to the recent investing performance of different price predictions. We also propose a novel objective to combine these RBFs and select the portfolio. Extensive experiments on six benchmark data sets (including a new challenging data set that we propose) from different real-world stock markets indicate that the proposed RBFs effectively combine different trend representations and AICTR achieves state-of-the-art investing performance and risk control. Besides, AICTR withstands the reasonable transaction costs and runs fast; hence, it is applicable to real-world financial environments. PMID- 29993754 TI - Neural Network-Based Model-Free Adaptive Near-Optimal Tracking Control for a Class of Nonlinear Systems. AB - In this paper, the receding horizon near-optimal tracking control problem about a class of continuous-time nonlinear systems with fully unknown dynamics is considered. The main challenges of this problem lie in two aspects: 1) most existing systems only restrict their considerations to the state feedback part while the input channel parameters are assumed to be known. This paper considers fully unknown system dynamics in both the state feedback channel and the input channel and 2) the optimal control of nonlinear systems requires the solution of nonlinear Hamilton-Jacobi-Bellman equations. Up to date, there are no systematic approaches in the existing literature to solve it accurately. A novel model-free adaptive near-optimal control method is proposed to solve this problem via utilizing the Taylor expansion-based problem relaxation, the universal approximation property of sigmoid neural networks, and the concept of sliding mode control. By making approximation for the performance index, it is first relaxed to a quadratic program, and then, a linear algebraic equation with unknown terms. An auxiliary system is designed to reconstruct the input-to-output property of the control systems with unknown dynamics, so as to tackle the difficulty caused by the unknown terms. Then, by considering the property of the sliding-mode surface, an explicit adaptive near-optimal control law is derived from the linear algebraic equation. Theoretical analysis shows that the auxiliary system is convergent, the resultant closed-loop system is asymptotically stable, and the performance index asymptomatically converges to optimal. An illustrative example and experimental results are presented, which substantiate the efficacy of the proposed method and verify the theoretical results. PMID- 29993755 TI - Adaptive Neural Control of Pure-Feedback Nonlinear Systems With Event-Triggered Communications. AB - This paper is concerned with the adaptive event-triggered control problem for a class of pure-feedback nonlinear systems. Unlike the existing results where the control execution is periodic, the new proposed scheme updates the controller and the neural network weights only when desired control specifications cannot be guaranteed. Clearly, this can largely reduce the amount of transmission data. Besides, since the event-trigger error is discontinuous because of the event triggering mechanism, the stability analysis in the classical sense may not be guaranteed. To solve this problem, we formulate the event-triggered network control systems as a nonlinear impulsive dynamical system, and a novel Lyapunov theorem is used to show the stability properties of the closed-loop systems. Finally, two simulation examples are given to illustrate the effectiveness of the theoretical results. PMID- 29993756 TI - PathEmb: Random Walk based Document Embedding for Global Pathway Similarity Search. AB - Pathway analysis is a cornerstone of system biology. In particular, pathway similarity search plays a key role in establishing structural, functional, and evolutionary relationships between different biological entities. Given a query pathway as well as a database, a pathway similarity search aims to identify novel pathways that are homologous to the query pathway. Unfortunately, the pathway similarity search is computationally inefficient due to the NP-complete graph isomorphism problem. In this current study, we introduce a novel algorithmic framework for pathway similarity search, named PathEmb (Pathway Embedding), which is analogous to the Skip-gram model where each pathway is represented as a "document". PathEmb exploits a second order random walk strategy to explore diverse pathway patterns. All signaling paths traversed from random walks are regarded as "sentences", which are constituted as a "document" afterwards. Then, the "document" pattern for the individual pathway is mapped into a low dimensional feature space for downstream tasks. Furthermore, PathEmb is a topology-free pathway similarity search algorithm, which is feasible to handle any pathway with arbitrary structure. We have extensively evaluated PathEmb and other cutting-edge methods on three pathway datasets. The experimental results demonstrate that PathEmb outperforms the existing methods in terms of computational efficiency and search accuracy. The source codes of PathEmb are freely available online https://github.com/zhangjiaobxy/PathEmb. PMID- 29993757 TI - Proposal for an eHealth Based Ecosystem Serving National Healthcare. AB - The European Union (EU)'s keen concern about citizens' health and well-being protection and advancement has been expressed at all levels. It has been understood that at present, it can only be achieved through coordinated actions at the individual member states' level based on EU directives, as well as through promoting and funding quadruple helix R&D and expanding the use of eHealth technologies. Despite the diversities and particularities among member states, common values such as universal access to good quality healthcare, equity and solidarity have been widely accepted across EU. That demanded the adoption of policies and follow directives, which streamlined actions to bridge healthcare gaps, and facilitate cross-border healthcare. This paper articulates a framework for deriving a national healthcare system, based on interoperable Electronic Health Record (EHR) with safeguarding healthcare quality, enabling quadruple helix driven R&D and guided by a patient-centered approach. A methodology to develop an integrated EHR at National level is proposed as a prerequisite for eHealth and put into perspective. Recommendations are given for the steps needed, from the managerial, legal, technical and financial concerns in developing an open access, patient-centered national healthcare system based on the context and constraints of a country. The example of a small country to apply the proposed methodology is demonstrated. Stakeholders, including citizens, healthcare professionals, academia and the industry are mobilized, enabled, and incentivized for implementing the methodology. Experiences are aspired to be offered as lessons learned for other countries to adapt on their environment. PMID- 29993758 TI - Learning to Detect Blue-white Structures in Dermoscopy Images with Weak Supervision. AB - We propose a novel approach to identify one of the most significant dermoscopic criteria in the diagnosis of cutaneous Melanoma: the blue-whitish structure (BWS). In this paper, we achieve this goal in a Multiple Instance Learning (MIL) framework using only image-level labels indicating whether the feature is present or not. To this aim, each image is represented as a bag of (non-overlapping) regions where each region may or may not be identified as an instance of BWS. A probabilistic graphical model [1] is trained (in MIL fashion) to predict the bag (image) labels. As output, we predict the classification label for the image (i.e., the presence or absence of BWS in each image) and as well we localize the feature in the image. Experiments are conducted on a challenging dataset with results outperforming state-of-the-art techniques, with BWS detection besting competing methods in terms of performance. This study provides an improvement on the scope of modelling for computerized image analysis of skin lesions. In particular, it propounds a framework for identification of dermoscopic local features from weakly-labelled data. PMID- 29993759 TI - Toward a Model for Personal Health Records Interoperability. AB - Health information technology, applied to electronic health record (EHR), has evolved with the adoption of standards for defining patient health records. However, there are many standards for defining such data, hindering communication between different healthcare providers. Even with adopted standards, patients often need to repeatedly provide their health information when they are taken care of at different locations. This problem hinders the adoption of personal health record (PHR), with the patients' health records under their own control. Therefore, the purpose of this work is to propose an interoperability model for PHR use. The methodology consisted prototyping an application model named OmniPHR, to evaluate the structuring of semantic interoperability and integration of different health standards, using a real database from anonymized patients. We evaluated health data from a hospital database with 38,645 adult patients' medical records processed using different standards, represented by openEHR, HL7 FHIR, and MIMIC-III reference models. OmniPHR demonstrated the feasibility to provide interoperability through a standard ontology and artificial intelligence with natural language processing (NLP). Although the first executions reached a 76.39% F1-score and required retraining of the machine-learning process, the final score was 87.9%, presenting a way to obtain the original data from different standards on a single format. Unlike other models, OmniPHR presents a unified, structural semantic and up-to-date vision of PHR for patients and healthcare providers. The results were promising and demonstrated the possibility of subsidizing the creation of inferences rules about possible patient health problems or preventing future problems. PMID- 29993760 TI - Scene Categorization Using Deeply Learned Gaze Shifting Kernel. AB - Accurately recognizing sophisticated sceneries from a rich variety of semantic categories is an indispensable component in many intelligent systems, e.g., scene parsing, video surveillance, and autonomous driving. Recently, there have emerged a large quantity of deep architectures for scene categorization, wherein promising performance has been achieved. However, these models cannot explicitly encode human visual perception toward different sceneries, i.e., the sequence of humans sequentially allocates their gazes. To solve this problem, we propose deep gaze shifting kernel to distinguish sceneries from different categories. Specifically, we first project regions from each scenery into the so-called perceptual space, which is established by combining color, texture, and semantic features. Then, a novel non-negative matrix factorization algorithm is developed which decomposes the regions' feature matrix into the product of the basis matrix and the sparse codes. The sparse codes indicate the saliency level of different regions. In this way, the gaze shifting path from each scenery is derived and an aggregation-based convolutional neural network is designed accordingly to learn its deep representation. Finally, the deep representations of gaze shifting paths from all the scene images are incorporated into an image kernel, which is further fed into a kernel SVM for scene categorization. Comprehensive experiments on six scenery data sets have demonstrated the superiority of our method over a series of shallow/deep recognition models. Besides, eye tracking experiments have shown that our predicted gaze shifting paths are 94.6% consistent with the real human gaze allocations. PMID- 29993761 TI - Ant Colony Stream Clustering: A Fast Density Clustering Algorithm for Dynamic Data Streams. AB - A data stream is a continuously arriving sequence of data and clustering data streams requires additional considerations to traditional clustering. A stream is potentially unbounded, data points arrive online and each data point can be examined only once. This imposes limitations on available memory and processing time. Furthermore, streams can be noisy and the number of clusters in the data and their statistical properties can change over time. This paper presents an online, bio-inspired approach to clustering dynamic data streams. The proposed ant colony stream clustering (ACSC) algorithm is a density-based clustering algorithm, whereby clusters are identified as high-density areas of the feature space separated by low-density areas. ACSC identifies clusters as groups of micro clusters. The tumbling window model is used to read a stream and rough clusters are incrementally formed during a single pass of a window. A stochastic method is employed to find these rough clusters, this is shown to significantly speeding up the algorithm with only a minor cost to performance, as compared to a deterministic approach. The rough clusters are then refined using a method inspired by the observed sorting behavior of ants. Ants pick-up and drop items based on the similarity with the surrounding items. Artificial ants sort clusters by probabilistically picking and dropping micro-clusters based on local density and local similarity. Clusters are summarized using their constituent micro clusters and these summary statistics are stored offline. Experimental results show that the clustering quality of ACSC is scalable, robust to noise and favorable to leading ant clustering and stream-clustering algorithms. It also requires fewer parameters and less computational time. PMID- 29993762 TI - An Open Framework for Constructing Continuous Optimization Problems. AB - Many artificial benchmark problems have been proposed for different kinds of continuous optimization, e.g., global optimization, multimodal optimization, multiobjective optimization, dynamic optimization, and constrained optimization. However, there is no unified framework for constructing these types of problems and possible properties of many problems are not fully tunable. This will cause difficulties for researchers to analyze strengths and weaknesses of an algorithm. To address these issues, this paper proposes a simple and intuitive framework, which is able to construct different kinds of problems for continuous optimization. The framework utilizes the k-d tree to partition the search space and sets a certain number of simple functions in each subspace. The framework is implemented into global/multimodal optimization, dynamic single objective optimization, multiobjective optimization, and dynamic multiobjective optimization, respectively. Properties of the proposed framework are discussed and verified with traditional evolutionary algorithms. PMID- 29993763 TI - Tensor Completion via Nonlocal Low-Rank Regularization. AB - Tensor completion (TC), aiming to recover original high-order data from its degraded observations, has recently drawn much attention in hyperspectral images (HSIs) domain. Generally, the widely used TC methods formulate the rank minimization problem with a convex trace norm penalty, which shrinks all singular values equally, and may generate a much biased solution. Besides, these TC methods assume the whole high-order data is of low-rank, which may fail to recover the detail information in high-order data with diverse and complex structures. In this paper, a novel nonlocal low-rank regularization-based TC (NLRR-TC) method is proposed for HSIs, which includes two main steps. In the first step, an initial completion result is generated by the proposed low-rank regularization-based TC (LRR-TC) model, which combines the logarithm of the determinant with the tensor trace norm. This model can more effectively approximate the tensor rank, since the logarithm function values can be adaptively tuned for each input. In the second step, the nonlocal spatial spectral similarity is integrated into the LRR-TC model, to obtain the final completion result. Specifically, the initial completion result is first divided into groups of nonlocal similar cubes (each group forms a 3-D tensor), and then the LRR-TC is applied to each group. Since similar cubes within each group contain similar structures, each 3-D tensor should have low-rank property, and thus further improves the completion result. Experimental results demonstrate that the proposed NLRR-TC method outperforms state-of-the-art HSIs completion techniques. PMID- 29993764 TI - Weighted General Group Lasso for Gene Selection in Cancer Classification. AB - Relevant gene selection is crucial for analyzing cancer gene expression datasets including two types of tumors in cancer classification. Intrinsic interactions among selected genes cannot be fully identified by most existing gene selection methods. In this paper, we propose a weighted general group lasso (WGGL) model to select cancer genes in groups. A gene grouping heuristic method is presented based on weighted gene co-expression network analysis. To determine the importance of genes and groups, a method for calculating gene and group weights is presented in terms of joint mutual information. To implement the complex calculation process of WGGL, a gene selection algorithm is developed. Experimental results on both random and three cancer gene expression datasets demonstrate that the proposed model achieves better classification performance than two existing state-of-the-art gene selection methods. PMID- 29993765 TI - A New Approach to Stabilization of Chaotic Systems With Nonfragile Fuzzy Proportional Retarded Sampled-Data Control. AB - This paper is concerned with the problem of stabilization of chaotic systems via nonfragile fuzzy proportional retarded sampled-data control. Compared with existing sampled-data control schemes, a more practical nonfragile fuzzy proportional retarded sampled-data controller is designed, which involves not only a signal transmission delay but also uncertainties. Based on the Wirtinger inequality, a new discontinuous Lyapunov-Krasovskii functional (LKF), namely, Wirtinger-inequality-based time-dependent discontinuous (WIBTDD) LKF, is the first time to be proposed for sampled-data systems. With the WIBTDD LKF approach and employing the developed estimation technique, a less conservative stabilization criterion is established. The desired fuzzy proportional retarded sampled-data controller can be obtained by solving a set of linear matrix inequalities. Finally, numerical examples are given to demonstrate the effectiveness and advantages of the proposed results. PMID- 29993766 TI - Odometry-Vision-Based Ground Vehicle Motion Estimation With SE(2)-Constrained SE(3) Poses. AB - This paper focuses on the motion estimation problem of ground vehicles using odometry and monocular visual sensors. While the keyframe-based batch optimization methods become the mainstream approach in mobile vehicle localization and mapping, the keyframe poses are usually represented by SE(3) in vision-based methods or SE(2) in methods based on range scanners. For a ground vehicle, this paper proposes a new SE(2)-constrained SE(3) parameterization of its poses, which can be easily achieved in the batch optimization framework using specially formulated edges. Utilizing such a parameterization of poses, a complete odometry-vision-based motion estimation system is developed. The system is designed in a commonly used structure of graph optimization, providing high modularity and flexibility for further implementation or adaptation. Its superior performance in terms of accuracy on a ground vehicle platform is validated by real-world experiments in industrial indoor environments. PMID- 29993767 TI - From Social to Individuals: a Parsimonious Path of Multi-level Models for Crowdsourced Preference Aggregation. AB - In crowdsourced preference aggregation, it is often assumed that all the annotators are subject to a common preference or social utility function which generates their comparison behaviors in experiments. However, in reality annotators are subject to variations due to multi-criteria, abnormal, or a mixture of such behaviors. In this paper, we propose a parsimonious mixed-effects model, which takes into account both the fixed effect that the majority of annotators follows a common linear utility model, and the random effect that some annotators might deviate from the common significantly and exhibit strongly personalized preferences. The key algorithm in this paper establishes a dynamic path from the social utility to individual variations, with different levels of sparsity on personalization. The algorithm is based on the Linearized Bregman Iterations, which leads to easy parallel implementations to meet the need of large-scale data analysis. In this unified framework, three kinds of random utility models are presented, including the basic linear model with loss, Bradley Terry model, and Thurstone-Mosteller model. The validity of these multi-level models are supported by experiments with both simulated and real-world datasets, which shows that the parsimonious multi-level models exhibit improvements in both interpretability and predictive precision compared with traditional HodgeRank. PMID- 29993768 TI - Multi-Task Structure-aware Context Modeling for Robust Keypoint-based Object Tracking. AB - In the fields of computer vision and graphics, keypoint-based object tracking is a fundamental and challenging problem, which is typically formulated in a spatio temporal context modeling framework. However, many existing keypoint trackers are incapable of effectively modeling and balancing the following three aspects in a simultaneous manner: temporal model coherence across frames, spatial model consistency within frames, and discriminative feature construction. To address this problem, we propose a robust keypoint tracker based on spatio-temporal multi task structured output optimization driven by discriminative metric learning. Consequently, temporal model coherence is characterized by multi-task structured keypoint model learning over several adjacent frames; spatial model consistency is modeled by solving a geometric verification based structured learning problem; discriminative feature construction is enabled by metric learning to ensure the intra-class compactness and inter-class separability. To achieve the goal of effective object tracking, we jointly optimize the above three modules in a spatio-temporal multi-task learning scheme. Furthermore, we incorporate this joint learning scheme into both single-object and multi-object tracking scenarios, resulting in robust tracking results. Experiments over several challenging datasets have justified the effectiveness of our single-object and multi-object trackers against the state-of-the-art. PMID- 29993769 TI - Automated Latent Fingerprint Recognition. AB - Latent fingerprints are one of the most important and widely used evidence in law enforcement and forensic agencies worldwide. Yet, NIST evaluations show that the performance of state-of-the-art latent recognition systems is far from satisfactory. An automated latent fingerprint recognition system with high accuracy is essential to compare latents found at crime scenes to a large collection of reference prints to generate a candidate list of possible mates. In this paper, we propose an automated latent fingerprint recognition algorithm that utilizes Convolutional Neural Networks (ConvNets) for ridge flow estimation and minutiae descriptor extraction, and extract complementary templates (two minutiae templates and one texture template) to represent the latent. The comparison scores between the latent and a reference print based on the three templates are fused to retrieve a short candidate list from the reference database. Experimental results show that the rank-1 identification accuracies are 64.7% for the NIST SD27 and 75.3% for the WVU latent databases, against a reference database of 100K rolled prints. By score-level (rank-level) fusion of our system with the commercial off-the-shelf (COTS) latent AFIS, the overall rank-1 identification performance can be improved from 64.7% and 75.3% to 73.3% (74.4%) and 76.6% (78.4%) on NIST SD27 and WVU latent databases, respectively. PMID- 29993770 TI - Semi-Supervised Video Object Segmentation with Super-Trajectories. AB - We introduce a semi-supervised video segmentation approach based on an efficient video representation, called as "super-trajectory". A super-trajectory corresponds to a group of compact point trajectories that exhibit consistent motion patterns, similar appearances, and close spatiotemporal relationships. We generate the compact trajectories using a probabilistic model, which enables handling of occlusions and drifts effectively. To reliably group point trajectories, we adopt a modified version of the density peaks based clustering algorithm that allows capturing rich spatiotemporal relations among trajectories in the clustering process. We incorporate two intuitive mechanisms for segmentation, called as reverse-tracking and object re-occurrence, for robustness and boosting the performance. Building on the proposed video representation, our segmentation method is discriminative enough to accurately propagate the initial annotations in the first frame onto the remaining frames. Our extensive experimental analyses on three challenging benchmarks demonstrate that, given the annotation in the first frame, our method is capable of extracting the target objects from complex backgrounds, and even reidentifying them after prolonged occlusions, producing high-quality video object segments. PMID- 29993771 TI - Patchmatch-based Robust Stereo Matching under Radiometric Changes. AB - In the real world, the two challenges of stereo vision system include a robust system under various radiometric changes and real-time process. To extract depth information from stereoscopic images, this paper proposes Patchmatch-based robust and fast stereo matching under radiometric changes. For this, a cost function was designed and minimized for estimating an accurate disparity map. Specifically, we used a prior probability to minimize the occlusion region and a smoothness term that considers convexity of objects to extract a fine disparity map. For evaluating the performance of the proposed scheme, we used Middlebury stereo data sets with radiometric changes. The experimental result showed that the proposed method outperforms state-of-the-art methods by up to 3.35% better and a range of 4.71 - 27.24 times faster result in terms of bad pixel error and processing time, respectively. Therefore, we believe that the proposed scheme can be a useful tool for computer vision-based applications. PMID- 29993772 TI - Memory Efficient Max Flow for Multi-label Submodular MRFs. AB - Multi-label submodular Markov Random Fields (MRFs) have been shown to be solvable using max-flow based on an encoding of the labels proposed by Ishikawa, in which each variable is represented by nodes (where is the number of labels) arranged in a column. However, this method in general requires edges for each pair of neighbouring variables. This makes it inapplicable to realistic problems with many variables and labels, due to excessive memory requirement. In this paper, we introduce a variant of the max-flow algorithm that requires much less storage. Consequently, our algorithm makes it possible to optimally solve multi-label submodular problems involving large numbers of variables and labels on a standard computer. PMID- 29993773 TI - Accurate 3D Reconstruction from Small Motion Clip for Rolling Shutter Cameras. AB - Structure from small motion has become an important topic in 3D computer vision as a method for estimating depth, since capturing the input is so user-friendly. However, major limitations exist with respect to the form of depth uncertainty, due to the narrow baseline and the rolling shutter effect. In this paper, we present a dense 3D reconstruction method from small motion clips using commercial hand-held cameras, which typically cause the undesired rolling shutter artifact. To address these problems, we introduce a novel small motion bundle adjustment that effectively compensates for the rolling shutter effect. Moreover, we propose a pipeline for a fine-scale dense 3D reconstruction that models the rolling shutter effect by utilizing both sparse 3D points and the camera trajectory from narrow-baseline images. In this reconstruction, the sparse 3D points are propagated to obtain an initial depth hypothesis using a geometry guidance term. Then, the depth information on each pixel is obtained by sweeping the plane around each depth search space near the hypothesis. The proposed framework shows accurate dense reconstruction results suitable for various sought-after applications. Both qualitative and quantitative evaluations show that our method consistently generates better depth maps compared to state-of-the-art methods. PMID- 29993774 TI - Calibration-Free Relaxation-Based Multi-Color Magnetic Particle Imaging. AB - Magnetic particle imaging (MPI) is a novel imaging modality with important potential applications, such as angiography, stem cell tracking, and cancer imaging. Recently, there have been efforts to increase the functionality of MPI via multi-color imaging methods that can distinguish the responses of different nanoparticles, or nanoparticles in different environmental conditions. The proposed techniques typically rely on extensive calibrations that capture the differences in the harmonic responses of the nanoparticles. In this paper, we propose a method to directly estimate the relaxation time constant of the nanoparticles from the MPI signal, which is then used to generate a multi-color relaxation map. The technique is based on the underlying mirror symmetry of the adiabatic MPI signal when the same region is scanned back and forth. We validate the proposed method via simulations, and via experiments on our in-house magnetic particle spectrometer setup at 10.8 kHz and our in-house MPI scanner at 9.7 kHz. Our results show that nanoparticles can be successfully distinguished with the proposed technique, without any calibration or prior knowledge about the nanoparticles. PMID- 29993775 TI - Solving 3-D PDEs by Tensor B-Spline Methodology: A High Performance Approach Applied to Optical Diffusion Tomography. AB - Solutions of 3-D elliptic PDEs form the basis of many mathematical models in medicine and engineering. Solving elliptic PDEs numerically in 3-D with fine discretization and high precision is challenging for several reasons, including the cost of 3-D meshing, the massive increase in operation count, and memory consumption when a high-order basis is used, and the need to overcome the "curse of dimensionality." This paper describes how these challenges can be either overcome or relaxed by a Tensor B-spline methodology with the following key properties: 1) the tensor structure of the variational formulation leads to regularity, separability, and sparsity, 2) a method for integration over the complex domain boundaries eliminates meshing, and 3) the formulation induces high performance and memory-efficient computational algorithms. The methodology was evaluated by application to the forward problem of Optical Diffusion Tomography (ODT), comparing it with the solver from a state-of-the-art Finite-Element Method (FEM)-based ODT reconstruction framework. We found that the Tensor B-spline methodology allows one to solve the 3-D elliptic PDEs accurately and efficiently. It does not require 3-D meshing even on complex and non-convex boundary geometries. The Tensor B-spline approach outperforms and is more accurate than the FEM when the order of the basis function is > 1, requiring fewer operations and lower memory consumption. Thus, the Tensor B-spline methodology is feasible and attractive for solving large elliptic 3-D PDEs encountered in real-world problems. PMID- 29993776 TI - Benchmark Dataset and Method for Depth Estimation from Light Field Images. AB - Convolutional Neural Networks (CNN) have performed extremely well for many image analysis tasks. However, supervised training of deep CNN architectures requires huge amounts of labelled data which is unavailable for light field images. In this paper, we leverage on synthetic light field images and propose a two stream CNN network that learns to estimate the disparities of multiple correlated neighbourhood pixels from their Epipolar Plane Images (EPI). Since the EPIs are unrelated except at their intersection, a two stream network is proposed to learn convolution weights individually for the EPIs and then combine the outputs of the two streams for disparity estimation. The CNN estimated disparity map is then refined using the central RGB light field image as a prior in a variational technique. We also propose a new real world dataset comprising light field images of 19 objects captured with the Lytro Illum camera in outdoor scenes and their corresponding 3D pointclouds, as ground truth, captured with the 3dMD scanner. This dataset will be made public to allow more precise 3D pointcloud level comparison of algorithms in the future which is currently not possible. Experiments on the synthetic and real world datasets show that our algorithm outperforms existing state-of-the-art for depth estimation from light field images. PMID- 29993777 TI - Vehicle Tracking in Wide Area Motion Imagery via Stochastic Progressive Association Across Multiple Frames (SPAAM). AB - Vehicle tracking in Wide Area Motion Imagery (WAMI) relies on associating vehicle detections across multiple WAMI frames to form tracks corresponding to individual vehicles. The temporal window length, i.e., the number M of sequential frames, over which associations are collectively estimated poses a trade-off between accuracy and computational complexity. A larger M improves performance because the increased temporal context enables the use of motion models and allows occlusions and spurious detections to be handled better. The number of total hypotheses tracks, on the other hand, grows exponentially with increasing M, making larger values of M computationally challenging to tackle. In this paper, we introduce SPAAM an iterative approach that progressively grows M with each iteration to improve estimated tracks by exploiting the enlarged temporal context while keeping computation manageable through two novel approaches for pruning association hypotheses. First, guided by a road network, accurately co-registered to the WAMI frames, we disregard unlikely associations that do not agree with the road network. Second, as M is progressively enlarged at each iteration, the related increase in association hypotheses is limited by revisiting only the subset of association possibilities rendered open by stochastically determined dis-associations for the previous iteration. The stochastic disassociation at each iteration maintains each estimated association according to an estimated probability for confidence, obtained via a probabilistic model. Associations at each iteration are then estimated globally over the M frames by (approximately) solving a binary integer programming problem for selecting a set of compatible tracks. Vehicle tracking results obtained over test WAMI datasets indicate that our proposed approach provides significant performance improvements over state of the art alternatives. PMID- 29993778 TI - Intrinsic Motion Stability Assessment For Video Stabilization. AB - This paper presents a novel algorithm for assessing the motion stability of a video after stabilization. The assessment works in a non-reference manner that directly measures the intrinsic smoothness of the video motion path. Specially, the motion path is cast as a curve embedded in the Lie group of homographies, and its smoothness is mathematically characterized by the intrinsic geodesic curvature. A bundle of paths are adopted to handle spatially variant motions through the frames. Then, we compute the weighted curvature for a holistic assessment on the motion stability. Other factors related to video stabilization, e.g., distortion and cropping, are also investigated as supplement. We collect 160 shaky video clips and their stabilized results for verification, and the experimental evidence shows the effectiveness of our algorithm in good correlation with human subjective judgements. PMID- 29993779 TI - Bas-Relief Modeling from Normal Layers. AB - Bas-relief is characterized by its unique presentation of intrinsic shape properties and/or detailed appearance using materials raised up in different degrees above a background. However, many bas-relief modeling methods could not manipulate scene details well. We propose a simple and effective solution for two kinds of bas-relief modeling (i.e., structure-preserving and detail-preserving), which is different from the prior tone mapping alike methods. Our idea originates from an observation on typical 3D models which are decomposed into a piecewise smooth base layer and a detail layer in normal field. Proper manipulation of the two layers contributes to both structure-preserving and detail-preserving bas relief modeling. We solve the modeling problem in a discrete geometry processing setup that uses normal-based mesh processing as a theoretical foundation. Specifically, using the two-step mesh smoothing mechanism as a bridge, we transfer the bas-relief modeling problem into a discrete space, and solve it in a least-squares manner. Experiments and comparisons to other methods show that (i) geometry details are better preserved in the scenario with high compression ratios, and (ii) structures are clearly preserved without shape distortion and interference from details. PMID- 29993780 TI - Compressed Animated Light Fields with Real-time View-dependent Reconstruction. AB - We propose an end-to-end solution for presenting movie quality animated graphics to the user while still allowing the sense of presence afforded by free viewpoint head motion. By transforming offline rendered movie content into a novel immersive representation, we display the content in real-time according to the tracked head pose. For each frame, we generate a set of cubemap images per frame (colors and depths) using a sparse set of of cameras placed in the vicinity of the potential viewer locations. The cameras are placed with an optimization process so that the rendered data maximise coverage with minimum redundancy, depending on the lighting environment complexity. We compress the colors and depths separately, introducing an integrated spatial and temporal scheme tailored to high performance on GPUs for Virtual Reality applications. A view-dependent decompression algorithm decodes only the parts of the compressed video streams that are visible to users. We detail a real-time rendering algorithm using multi view ray casting, with a variant that can handle strong view dependent effects such as mirror surfaces and glass. Compression rates of 150:1 and greater are demonstrated with quantitative analysis of image reconstruction quality and performance. PMID- 29993781 TI - Projective Motion Correction with Contact Optimization. AB - When motion capture data is applied to virtual characters, the applied motion often exhibits geometric and physical errors, which necessitates a cumbersome refinement process. We present a novel framework to efficiently obtain a corrected motion as well as its supporting contact information from multi-contact motion capture data. To this end, first, we present a projective dynamics-based method for optimizing character motions. By carefully defining objective functions and constraints using differential representation of motions, we develop a highly efficient motion optimizer that can create geometrically and dynamically adjusted motions given reference motion data and contact information. Second, we develop a contact optimizer that finds a set of contacts that allows the motion optimizer to generate a motion that best follows the reference motion under dynamic and geometric constraints. This is achieved by iteratively improving the hypothesis on the best set of contacts by getting feedback from the motion optimizer. We demonstrate that our method significantly improves the naturalness of a wide range of motion capture data, from walking to rolling. PMID- 29993782 TI - Constructing Disease Similarity Networks Based on Disease Module Theory. AB - Quantifying the associations between diseases is now playing an important role in modern biology and medicine, as discovering associations between diseases could help us gain deeper insights into pathogenic mechanisms of complex diseases, thus could lead to improvements in disease diagnosis, drug repositioning and drug development. Due to the growing body of high-throughput biological data, a number of methods have been developed for computing similarity between diseases during the past decade. However, these methods rarely consider the interconnections of genes related to each disease in protein-protein interaction network (PPIN). Recently, the disease module theory has been proposed, which states that disease related genes or proteins tend to interact with each other in the same neighborhood of a PPIN. In this study, we propose a new method called ModuleSim to measure associations between diseases by using disease-gene association data and PPIN data based on disease module theory. The experimental results show that by considering the interactions between disease modules and each module's modularity, the disease similarity calculated by ModuleSim has a significant correlation with disease classification of Disease Ontology (DO). Furthermore, ModuleSim outperforms other four popular methods which are all using disease-gene association data and PPIN data. In addition, MoudleSim also is capable of finding potential associations between diseases. PMID- 29993783 TI - High-Order Convolutional Neural Network Architecture for Predicting DNA-Protein Binding Sites. AB - Although Deep learning algorithms have outperformed conventional methods in predicting the sequence specificities of DNA-protein binding, they lack to consider the dependencies among nucleotides and the diverse binding lengths for different transcription factors (TFs). To address the above two limitations simultaneously, in this paper, we propose a high-order convolutional neural network architecture (HOCNN), which employs a high-order encoding method to build high-order dependencies among nucleotides, and a multi-scale convolutional layer to capture the motif features of different lengths. The experimental results on real ChIP-seq datasets show that the proposed method outperforms the state-of-the art deep learning method (DeepBind) in the motif discovery task. In addition, we provide further insights about the importance of introducing additional convolutional kernels and the degeneration problem of importing high-order in the motif discovery task. PMID- 29993784 TI - A Systematic Review of Multilateral Teleoperation Systems. AB - While conventional bilateral Single-Master/Single-Slave (SM/SS) teleoperation systems have received considerable attention during the past several decades, multilateral teleoperation is only recently being studied. Unlike an SM/SS system, which consists of one master-slave set, multilateral teleoperation frameworks involve a minimum of three agents in order to remotely perform a task. This paper presents an overview of multilateral teleoperation systems and classifies the existing state-of-the-art architecture based on topologies, applications, and closed-loop stability analysis. For each category, the review discusses control strategies used for various architectures as well as control challenges (e.g., closed-loop instability as a result of a delay in the communication network) for each methodology. PMID- 29993785 TI - Adaptive Critic Design for Pure-Feedback Discrete-Time MIMO Systems Preceded by Unknown Backlashlike Hysteresis. AB - This paper concentrates on the adaptive critic design (ACD) issue for a class of uncertain multi-input multioutput (MIMO) nonlinear discrete-time systems preceded by unknown backlashlike hysteresis. The considered systems are in a block triangular pure-feedback form, in which there exist nonaffine functions and couplings between states and inputs. This makes that the ACD-based optimal control becomes very difficult and complicated. To this end, the mean value theorem is employed to transform the original systems into input-output models. Based on the reinforcement learning algorithm, the optimal control strategy is established with an actor-critic structure. Not only the stability of the systems is ensured but also the performance index is minimized. In contrast to the previous results, the main contributions are: 1) it is the first time to build an ACD framework for such MIMO systems with unknown hysteresis and 2) an adaptive auxiliary signal is developed to compensate the influence of hysteresis. In the end, a numerical study is provided to demonstrate the effectiveness of the present method. PMID- 29993786 TI - Synchronization of Nonlinearly and Stochastically Coupled Markovian Switching Networks via Event-Triggered Sampling. AB - This paper studies the exponential synchronization problem for a new array of nonlinearly and stochastically coupled networks via events-triggered sampling (ETS) by self-adaptive learning. The networks include the following features: 1) a Bernoulli stochastic variable is introduced to describe the random structural coupling; 2) a stochastic variable with positive mean is used to model the coupling strength; and 3) a continuous time homogeneous Markov chain is employed to characterize the dynamical switching of the coupling structure and pinned node sets. The proposed network model is capable to capture various stochastic effect of an external environment during the network operations. In order to reduce networks' workload, different ETS strategies for network self-adaptive learning are proposed under continuous and discrete monitoring, respectively. Based on these ETS approaches, several sufficient conditions for synchronization are derived by employing stochastic Lyapunov-Krasovskii functions, the properties of stochastic processes, and some linear matrix inequalities. Numerical simulations are provided to demonstrate the effectiveness of the theoretical results and the superiority of the proposed ETS approach. PMID- 29993787 TI - Inferring MicroRNA Targets based on Restricted Boltzmann Machines. AB - Predicting the miRNA-target interactions (MTIs) is a critical task for elucidating mechanistic roles of miRNAs in pathophysiology. However, most existing techniques have a higher false positive because the precise miRNA target mechanisms are poorly known. Considering that ensemble methods can take advantage of the complementary knowledge in different methods, we propose an alternative optimization framework, IMTRBM (Inferring MiRNA Targets based on Restricted Boltzmann Machines), to enhance the accuracy of previous prediction results. Firstly, the proposed method directly constructs a weighted miRNA-target interaction network though the results predicted by individual methods and each miRNA target pair is weighted based on the frequency appearing in these results. Secondly, we transform the miRNA-target prediction problem into a complete bipartite graph model, named restricted Boltzmann machine, and utilize a practical learning procedure to train our model and make predictions. Our results show that the algorithm outperforms individual miRNA-target prediction approach in the number of validated miRNA targets at cutoffs of top list. Moreover, our framework can tolerate the decrease and increase of predicted miRNA target interactions and even discover new miRNA targets which have been a challenge to predict for any individual methods. Finally, for the miRNAs that are not appearing in IMTRBM, we design a new method to supplement IMTRBM based on the intuition that similar miRNAs have similar functions, which also achieves a comparable result. The source code of IMTRBM is available at https://github.com/liuying201705/IMTRBM. PMID- 29993788 TI - A Novel Blaschke Unwinding Adaptive Fourier Decomposition based Signal Compression Algorithm with Application on ECG Signals. AB - This paper presents a novel signal compression algorithm based on the Blaschke unwinding adaptive Fourier decomposition (AFD). The Blaschke unwinding AFD is a newly developed signal decomposition theory. It utilizes the Nevanlinna factorization and the maximal selection principle in each decomposition step, and achieves a faster convergence rate with higher fidelity. The proposed compression algorithm is applied to the electrocardiogram signal. To assess the performance of the proposed compression algorithm, in addition to the generic assessment criteria, we consider the less discussed criteria related to the clinical needs - for the heart rate variability analysis purpose, how accurate the R peak information is preserved is evaluated. The experiments are conducted on the MIT BIH arrhythmia benchmark database. The results show that the proposed algorithm performs better than other state-of-theart approaches. Meanwhile, it also well preserves the R peak information. PMID- 29993789 TI - A Noncontact Breathing Disorder Recognition System Using 2.4-GHz Digital-IF Doppler Radar. AB - In this paper, a noncontact breathing disorder recognition system has been proposed for identifying irregular breathing patterns. The proposed system consists of a Doppler radar-based sensor module and a machine-learning-based breathing disorder recognition module. A custom-designed 2.4-GHz continuous wave (CW) digital-IF Doppler radar is utilized as the radar sensor module to accurately capture the time-domain breathing waveform. Then a recognition module is designed with selected features and optimized classifiers. Four sets of experiments have been carried out to evaluate the proposed system comprehensively. In which, for the laboratorial experiments, the proposed system achieves 94.7 % classification accuracy using the linear SVM classifier with seven selected features. Results of clinical experiments demonstrate the feasibility of long-term breathing disorder recognition with good accuracy and robustness, and illustrate the potential of the proposed solution for the auxiliary diagnosis of diseases. PMID- 29993790 TI - Automatic Screening of Sleep Apnea Patients Based on the SpO Signal. AB - This paper presents a methodology to automatically screen for sleep apnea based on the detection of apnea and hypopnea events in the blood oxygen saturation (SpO) signal. It starts by detecting all desaturations in the SpO signal. From these desaturations, a total of 143 time-domain features are extracted. After feature selection, the six most discriminative features are used to construct classifiers to predict if desaturations are caused by respiratory events. From these, a random forest classifier yielded the best classification performance. The number of desaturations, classified as caused by respiratory events per hour of recording can then be used as an estimate of the apnea-hypopnea index (AHI), and to predict if a patient suffers from sleep apnea-hypopnea syndrome (SAHS) or not. All classifiers were developed based on a subset of 500 subjects of the Sleep Heart Health Study (SHHS) and tested on three different datasets, containing 8052 subjects in total. An averaged desaturation classification accuracy of 82.8 % was achieved over the different test sets. Subjects having SAHS with an AHI larger than 15 can be detected with an average accuracy of 87.6 %. The achieved SAHS screening outperforms SpO methods from the literature on the SHHS test dataset. Moreover, the robustness of the method was shown when tested on different independent test sets. These results show that an algorithm based on simple features of SpO desaturations can outperform more elaborate methods in the detection of apneic events and the screening of SAHS patients. PMID- 29993791 TI - Semantic Segmentation of Pathological Lung Tissue with Dilated Fully Convolutional Networks. AB - Early and accurate diagnosis of interstitial lung diseases (ILDs) is crucial for making treatment decisions, but can be challenging even for experienced radiologists. The diagnostic procedure is based on the detection and recognition of the different ILD pathologies in thoracic CT scans, yet their manifestation often appears similar. In this study, we propose the use of a deep purely convolutional neural network for the semantic segmentation of ILD patterns, as the basic component of a computer aided diagnosis (CAD) system for ILDs. The proposed CNN, which consists of convolutional layers with dilated filters, takes as input a lung CT image of arbitrary size and outputs the corresponding label map. We trained and tested the network on a dataset of 172 sparsely annotated CT scans, within a cross-validation scheme. The training was performed in an end-to end and semi-supervised fashion, utilizing both labeled and non-labeled image regions. The experimental results show significant performance improvement with respect to the state of the art. PMID- 29993792 TI - Robust Activity Recognition for Aging Society. AB - Human activity recognition (HAR) is widely applied to many industrial applications. In the context of Industry 4.0, driven by the same demand of machines' self-organizing ability, HAR can also be adopted in elderly healthcare. However, HAR should be adaptive to the application scenarios in elderly healthcare. In this paper, we propose a nonintrusive activity recognition method that can be applied to long-term and unobtrusive monitoring for elderlies. The method is robust to obstruction and nontarget object interference. Skeleton sequence is estimated from RGB images. Based on two activity continuity metrics, an interframe matching algorithm is proposed to filter nontarget objects. In order to make full use of spatial-temporal information, we propose a novel activity encoding method based on the interframe joints distances. A convolutional neural network is used to learn the distinguishing features automatically. A specific data augmentation method is designed to avoid the overfitting problem on small-scale datasets. The experiments are performed on two public activity datasets and a newly released noisy activity dataset (NAD). The NAD contains obstruction, nontarget object interference. The experimental results show that the proposed method achieves the state-of-the-art performance while only using one ordinary camera. The proposed method is robust to a realistic environment. PMID- 29993793 TI - A Two-Stage Model to Predict Surgical Patients' Lengths of Stay from an Electronic Patient Database. AB - Soaring healthcare costs and the growing demand for services require us to use healthcare resources more efficiently. Randomness in resource requirements makes the care delivery process less efficient. Our aim is to reduce the uncertainty in patients' resource requirements, and we achieve that objective by classifying patients into similar resource user groups. In this article, we develop a two stage classification model to classify patients into lower variability resource user groups. There are various statistical tools for classifying patients into lower variability resource user groups. However, classification and regression tree (CART) analysis is a more suitable method for analyzing healthcare data because it has some distinct features. For example, it can handle the interaction between predictor variables naturally, it is non-parametric in nature, and it is relatively insensitive to the curse of dimensionality. We found that the CART analysis is also useful for determining the patient attributes that can explain the variability in resource requirements. Furthermore, we observed that some of the covariates, such as the principal prescribed procedure code, the admission point, and the operating surgeon, were able to explain up to 53.43% of the variability in patients' lengths of stay (LoS). Reducing the uncertainty in patients' LoS predictions helps us manage patient flow efficiently and subsequently obtain a better throughput. PMID- 29993794 TI - Quantized Control of Markov Jump Nonlinear Systems Based on Fuzzy Hidden Markov Model. AB - This paper considers the problem of asynchronous guaranteed cost control (GCC) for nonlinear Markov jump systems with stochastic quantization. Hidden Markov model is used to describe the nonsynchronous controller and the random quantization phenomenon. Based on Takagi-Sugeno fuzzy technique and Lyapunov function approach, a sufficient condition is obtained, which can not only ensure the asymptotic stability of the closed-loop system and existence of the desired controller, but also can yield the minimal upper bound of GCC performance. Finally, two examples are provided to demonstrate the correctness and reliability of our developed approaches. PMID- 29993795 TI - Self-Triggered Leader-Following Consensus for High-Order Nonlinear Multiagent Systems via Dynamic Output Feedback Control. AB - This paper investigates the event-based leader-following consensus problem for high-order nonlinear multiagent systems whose dynamics are in strict feedback forms and satisfy Lipschitz condition. By using self-triggered control scheme and dynamic output feedback control method in combination, a new class of distributed self-triggered consensus protocols is proposed based only on the relative output measurements of neighboring agents. It is noted that the proposed protocols only require the output information of neighboring agents to be shared and the designed self-triggered algorithm can avoid continuous communication among neighboring agents, thus the communication cost is reduced significantly. Sufficient conditions in terms of matrix inequalities are derived to guarantee the exponential leader-following consensus. The effectiveness of the theoretical results is illustrated through a simulation example. PMID- 29993796 TI - Deep Attention-Based Spatially Recursive Networks for Fine-Grained Visual Recognition. AB - Fine-grained visual recognition is an important problem in pattern recognition applications. However, it is a challenging task due to the subtle interclass difference and large intraclass variation. Recent visual attention models are able to automatically locate critical object parts and represent them against appearance variations. However, without consideration of spatial dependencies in discriminative feature learning, these methods are underperformed in classifying fine-grained objects. In this paper, we present a deep attention-based spatially recursive model that can learn to attend to critical object parts and encode them into spatially expressive representations. Our network is technically premised on bilinear pooling, enabling local pairwise feature interactions between outputs from two different convolutional neural networks (CNNs) that correspond to distinct region detection and relevant feature extraction. Then, spatial long short term memory (LSTMs) units are introduced to generate spatially meaningful hidden representations via the long-range dependency on all features in two dimensions. The attention model is leveraged between bilinear outcomes and spatial LSTMs for dynamic selection on varied inputs. Our model, which is composed of two-stream CNN layers, bilinear pooling, and spatial recursive encoding with attention, is end-to-end trainable to serve as the part detector and feature extractor whereby relevant features are localized, extracted, and encoded spatially for recognition purpose. We demonstrate the superiority of our method over two typical fine-grained recognition tasks: fine-grained image classification and person re-identification. PMID- 29993797 TI - Multiple psi$-Type Stability and Its Robustness for Recurrent Neural Networks With Time-Varying Delays. AB - In this paper, the psi-type stability and robustness of recurrent neural networks are investigated by using the differential inequality. By utilizing psi-type functions combined with the inequality techniques, some sufficient conditions ensuring psi-type stability and robustness are derived for linear neural networks with time-varying delays. Then, by choosing appropriate Lipschitz coefficient in subregion, some algebraic criteria of the multiple psi-type stability and robust boundedness are established for the delayed neural networks with time-varying delays. For special cases, several criteria are also presented by selecting parameters with easy implementation. The derived results cover both psi-type mono stability and multiple psi-type stability. In addition, these theoretical results contain exponential stability, polynomial stability, and MU-stability, and they also complement and extend some previous results. Finally, two numerical examples are provided to illustrate the effectiveness of the proposed criteria. PMID- 29993798 TI - Quantized Consensus of Multi-Agent Networks With Sampled Data and Markovian Interaction Links. AB - This paper investigates the joint effect of quantization, sampled data, and general Markovian interaction links on consensus networks with a leader under directed graphs. The diversity of edges formed by all the followers and the leader is also considered. Each agent in the network possesses continuous-time general linear dynamics. Each agent's state is measured only at sampling time instants, which is encoded before transmission. Subsequently, the encoded state is transmitted through noiseless digital communication links with Markovian switching rates. For this problem, a sufficient condition is derived to guarantee the convergence of the encoded states, based on which a necessary and sufficient condition is obtained to achieve consensus tracking in the mean-square sense. In addition, two sufficient conditions on coupling gain, one of which is fully distributed, are provided by proposing an optimal linear quadratic regulator based gain matrix to ensure consensus tracking and then, the analysis of consensus region is presented. Finally, a numerical example is presented for illustrating the effectiveness of the theoretical results. PMID- 29993799 TI - Adaptive Structure Discovery for Multimedia Analysis Using Multiple Features. AB - Multifeature learning has been a fundamental research problem in multimedia analysis. Most existing multifeature learning methods exploit graph, which must be computed beforehand, as input to uncover data distribution. These methods have two major problems confronted. First, graph construction requires calculating similarity based on nearby data pairs by a fixed function, e.g., the RBF kernel, but the intrinsic correlation among different data pairs varies constantly. Therefore, feature learning based on such predefined graphs may degrade, especially when there is dramatic correlation variation between nearby data pairs. Second, in most existing algorithms, each single-feature graph is computed independently and then combine them for learning, which ignores the correlation between multiple features. In this paper, a new unsupervised multifeature learning method is proposed to make the best utilization of the correlation among different features by jointly optimizing data correlation from multiple features in an adaptive way. As opposed to computing the affinity weight of data pairs by a fixed function, the weight of affinity graph is learned by a well-designed optimization problem. Additionally, the affinity graph of data pairs from different features is optimized in a global level to better leverage the correlation among different channels. In this way, the adaptive approach correlates the features of all features for a better learning process. Experimental results on real-world datasets demonstrate that our approach outperforms the state-of-the-art algorithms on leveraging multiple features for multimedia analysis. PMID- 29993800 TI - What do different evaluation metrics tell us about saliency models? AB - How best to evaluate a saliency model's ability to predict where humans look in images is an open research question. The choice of evaluation metric depends on how saliency is defined and how the ground truth is represented. Metrics differ in how they rank saliency models, and this results from how false positives and false negatives are treated, whether viewing biases are accounted for, whether spatial deviations are factored in, and how the saliency maps are pre-processed. In this paper, we provide an analysis of 8 different evaluation metrics and their properties. With the help of systematic experiments and visualizations of metric computations, we add interpretability to saliency scores and more transparency to the evaluation of saliency models. Building off the differences in metric properties and behaviors, we make recommendations for metric selections under specific assumptions and for specific applications. PMID- 29993801 TI - MonoCap: Monocular Human Motion Capture using a CNN Coupled with a Geometric Prior. AB - Recovering 3D full-body human pose is a challenging problem with many applications. It has been successfully addressed by motion capture systems with body worn markers and multiple cameras. In this paper, we address the more challenging case of not only using a single camera but also not leveraging markers: going directly from 2D appearance to 3D geometry. Deep learning approaches have shown remarkable abilities to discriminatively learn 2D appearance features. The missing piece is how to integrate 2D, 3D and temporal information to recover 3D geometry and account for the uncertainties arising from the discriminative model. We introduce a novel approach that treats 2D joint locations as latent variables whose uncertainty distributions are given by a deep fully convolutional neural network. The unknown 3D poses are modeled by a sparse representation and the 3D parameter estimates are realized via an Expectation Maximization algorithm, where it is shown that the 2D joint location uncertainties can be conveniently marginalized out during inference. Extensive evaluation on benchmark datasets shows that the proposed approach achieves greater accuracy over state-of-the-art baselines. Notably, the proposed approach does not require synchronized 2D-3D data for training and is applicable to "in the-wild" images, which is demonstrated with the MPII dataset. PMID- 29993802 TI - FDR-Corrected Sparse Canonical Correlation Analysis With Applications to Imaging Genomics. AB - Reducing the number of false discoveries is presently one of the most pressing issues in the life sciences. It is of especially great importance for many applications in neuroimaging and genomics, where data sets are typically high dimensional, which means that the number of explanatory variables exceeds the sample size. The false discovery rate (FDR) is a criterion that can be employed to address that issue. Thus it has gained great popularity as a tool for testing multiple hypotheses. Canonical correlation analysis (CCA) is a statistical technique that is used to make sense of the cross-correlation of two sets of measurements collected on the same set of samples (e.g., brain imaging and genomic data for the same mental illness patients), and sparse CCA extends the classical method to high-dimensional settings. Here, we propose a way of applying the FDR concept to sparse CCA, and a method to control the FDR. The proposed FDR correction directly influences the sparsity of the solution, adapting it to the unknown true sparsity level. Theoretical derivation as well as simulation studies show that our procedure indeed keeps the FDR of the canonical vectors below a user-specified target level. We apply the proposed method to an imaging genomics data set from the Philadelphia Neurodevelopmental Cohort. Our results link the brain connectivity profiles derived from brain activity during an emotion identification task, as measured by functional magnetic resonance imaging, to the corresponding subjects' genomic data. PMID- 29993803 TI - Nonlinear Low-Rank Matrix Completion for Human Motion Recovery. AB - Human motion capture data has been widely used in many areas, but it involves a complex capture process and the captured data inevitably contains missing data due to the occlusions caused by the actor's body or clothing. Motion recovery, which aims to recover the underlying complete motion sequence from its degraded observation, still remains as a challenging task due to the nonlinear structure and kinematics property embedded in motion data. Low-rank matrix completion based methods have shown promising performance in short-time-missing motion recovery problems. However, low-rank matrix completion, which is designed for linear data, lacks the theoretic guarantee when applied to the recovery of nonlinear motion data. To overcome this drawback, we propose a tailored nonlinear matrix completion model for human motion recovery. Within the model, we first learn a combined low-rank kernel via multiple kernel learning. By exploiting the learned kernel, we embed the motion data into a high dimensional Hilbert space where motion data is of desirable low-rank and we then use the low-rank matrix completion to recover motions. In addition, we add two kinematic constraints to the proposed model to preserve the kinematics property of human motion. Extensive experiment results and comparisons with five other state-of-the-art methods demonstrate the advantage of the proposed method. PMID- 29993804 TI - IPST: Incremental Pictorial Structures for Model-free Tracking of Deformable Objects. AB - Model-free tracking is a well-studied task in computer vision. Typically, a rectangular bounding box containing a single object is provided in the first (few) frame(s) and then the method tracks the object in the rest frames. However, for deformable objects (e.g. faces, bodies) the single bounding box scenario is sub-optimal; a part-based approach would be more effective. The current state-of the-art part-based approach is incrementally trained discriminative Deformable Part Models (DPM). Nevertheless, training discriminative DPMs with one or a few examples poses a huge challenge. We argue that a generative model is a better fit for the task. We utilise the powerful pictorial structures, which we augment with incremental updates to account for object adaptations. Our proposed incremental pictorial structures, which we call IPST, are experimentally validated in different scenarios. In a thorough experimentation we demonstrate that IPST outperforms the existing model-free methods in facial landmark tracking, body tracking, animal tracking (newly introduced to verify the strength in ad hoc cases). PMID- 29993805 TI - Deep Spatiality: Unsupervised Learning of Spatially-Enhanced Global and Local 3D Features by Deep Neural Network with Coupled Softmax. AB - The discriminability of Bag-of-Words representations can be increased via encoding the spatial relationship among virtual words on 3D shapes. However, this encoding task involves several issues, including arbitrary mesh resolutions, irregular vertex topology, orientation ambiguity on 3D surface, invariance to rigid and non-rigid shape transformations. To address these issues, a novel unsupervised spatial learning framework based on deep neural network, deep spatiality (DS), is proposed. Specifically, DS employs two novel components: spatial context extractor and deep context learner. Spatial context extractor extracts the spatial relationship among virtual words in a local region into a raw spatial representation. Along a consistent circular direction, a directed circular graph is constructed to encode relative positions between pairwise virtual words in each face ring into a relative spatial matrix. By decomposing each relative spatial matrix using SVD, the raw spatial representation is formed, from which deep context learner conducts unsupervised learning of global and local features. Deep context learner is a deep neural network with a novel model structure to adapt the proposed coupled softmax layer, which encodes not only the discriminative information among local regions but also the one among global shapes. Experimental results show that DS outperforms state-of-the-art methods. PMID- 29993806 TI - SVD-based Tensor-Completion Technique for Background Initialization. AB - Extracting the background from a video in the presence of various moving patterns is the focus of several background-initialization approaches. To model the scene background using rank-one matrices, this paper proposes a background initialization technique that relies on the singular-value decomposition (SVD) of spatiotemporally extracted slices from the video tensor. The proposed method is referred to as spatiotemporal slice-based SVD (SS-SVD). To determine the SVD components that best model the background, a depth analysis of the computation of the left/right singular vectors and singular values is performed, and the relationship with tensor-tube fibers is determined. The analysis proves that a rank-1 matrix extracted from the first left and right singular vectors and singular value represents an efficient model of the scene background. The performance of the proposed SS-SVD method is evaluated using 93 complex video sequences of different challenges, and the method is compared with state-of-the art tensor/matrix completion-based methods, statistical-based methods, search based methods, and labeling-based methods. The results not only show better performance over most of the tested challenges, but also demonstrate the capability of the proposed technique to solve the background-initialization problem in a less computational time and with fewer frames. PMID- 29993807 TI - KAVAGait: Knowledge-Assisted Visual Analytics for Clinical Gait Analysis. AB - In 2014, more than 10 million people in the US were affected by an ambulatory disability. Thus, gait rehabilitation is a crucial part of health care systems. The quantification of human locomotion enables clinicians to describe and analyze a patient's gait performance in detail and allows them to base clinical decisions on objective data. These assessments generate a vast amount of complex data which need to be interpreted in a short time period. We conducted a design study in cooperation with gait analysis experts to develop a novel Knowledge-Assisted Visual Analytics solution for clinical Gait analysis (KAVAGait). KAVAGait allows the clinician to store and inspect complex data derived during clinical gait analysis. The system incorporates innovative and interactive visual interface concepts, which were developed based on the needs of clinicians. Additionally, an explicit knowledge store (EKS) allows externalization and storage of implicit knowledge from clinicians. It makes this information available for others, supporting the process of data inspection and clinical decision making. We validated our system by conducting expert reviews, a user study, and a case study. Results suggest that KAVAGait is able to support a clinician during clinical practice by visualizing complex gait data and providing knowledge of other clinicians. PMID- 29993808 TI - An Exploratory Framework for Cyclone Identification and Tracking. AB - Analyzing depressions plays an important role in meteorology, especially in the study of cyclones. In particular, the study of the temporal evolution of cyclones requires a robust depression tracking framework. To cope with this demand we propose a pipeline for the exploration of cyclones and their temporal evolution. This entails a generic framework for their identification and tracking. The fact that depressions and cyclones are not well-defined objects and their shape and size characteristics change over time makes this task especially challenging. Our method combines the robustness of topological approaches and the detailed tracking information from optical flow analysis. At first cyclones are identified within each time step based on well-established topological concepts. Then candidate tracks are computed from an optical flow field. These tracks are clustered within a moving time window to distill dominant coherent cyclone movements, which are then forwarded to a final tracking step. In contrast to previous methods our method requires only a few intuitive parameters. An integration into an exploratory framework helps in the study of cyclone movement by identifying smooth, representative tracks. Multiple case studies demonstrate the effectiveness of the method in tracking cyclones, both in the northern and southern hemisphere. PMID- 29993809 TI - Correlation Judgment and Visualization Features: A Comparative Study. AB - Recent visualization research efforts have incorporated experimental techniques and perceptual models from the vision science community. Perceptual laws such as Weber's law, for example, have been used to model the perception of correlation in scatterplots. While this thread of research has progressively refined the modeling of the perception of correlation in scatterplots, it remains unclear as to why such perception can be modeled using relatively simple functions, e.g., linear and log-linear. In this paper, we investigate a longstanding hypothesis that people use visual features in a chart as a proxy for statistical measures like correlation. For a given scatterplot, we extract 49 candidate visual features and evaluate which best align with existing models and participant judgments. The results support the hypothesis that people attend to a small number of visual features when discriminating correlation in scatterplots. We discuss how this result may account for prior conflicting findings, and how visual features provide a baseline for future model-based approaches in visualization evaluation and design. PMID- 29993810 TI - Efficient and Anti-aliased Trimming for Rendering Large NURBS Models. AB - In Computer-Aided Design (CAD), Non-Uniform Rational B-Splines (NURBS) are a common model representation for export, simulation and visualization. In this paper, we present a direct rendering method for trimmed NURBS models based on their parametric description. Our approach builds on a novel trimming method and a three-pass pipeline which both allow for a sub-pixel precise visualization. The rendering pipeline bypasses tessellation limitations of current hardware using a feedback mechanism. In contrast to existing work, our trimming method scales well with a large number of trim curves and estimates the trimmed surface's footprint in screen-space which allows for an anti-aliasing with minimal performance overhead. Fragments with trimmed edges are routed into a designated off-screen buffer for subsequent blending with background faces. The evaluation of the presented algorithms shows that our rendering system can handle CAD models with ten thousands of trimmed NURBS surfaces. The suggested two-level data structure used for trimming outperforms state-of-the-art methods while being more precise and memory efficient. Our curve coverage estimation used for anti-aliasing provides an efficient trade-off between quality and performance compared to multisampling or screen-space anti-aliasing approaches. PMID- 29993811 TI - A Generative Model for Volume Rendering. AB - We present a technique to synthesize and analyze volume-rendered images using generative models. We use the Generative Adversarial Network (GAN) framework to compute a model from a large collection of volume renderings, conditioned on (1) viewpoint and (2) transfer functions for opacity and color. Our approach facilitates tasks for volume analysis that are challenging to achieve using existing rendering techniques such as ray casting or texture-based methods. We show how to guide the user in transfer function editing by quantifying expected change in the output image. Additionally, the generative model transforms transfer functions into a view-invariant latent space specifically designed to synthesize volume-rendered images. We use this space directly for rendering, enabling the user to explore the space of volume-rendered images. As our model is independent of the choice of volume rendering process, we show how to analyze volume-rendered images produced by direct and global illumination lighting, for a variety of volume datasets. PMID- 29993812 TI - ANTENNA, a Multi-Rank, Multi-Layered Recommender System for Inferring Reliable Drug-Gene-Disease Associations: Repurposing Diazoxide as a Targeted Anti-Cancer Therapy. AB - Existing drug discovery process follows a reductionist model of "one-drug-one gene-one-disease," which is inadequate to tackle complex diseases involving multiple malfunctioned genes. The availability of big omics data offers opportunities to transform drug discovery process into a new paradigm of systems pharmacology that focuses on designing drugs to target molecular interaction networks instead of a single gene. Here, we develop a reliable multi-rank, multi layered recommender system, ANTENNA, to mine large-scale chemical genomics and disease association data for prediction of novel drug-gene-disease associations. ANTENNA integrates a novel tri-factorization based dual-regularized weighted and imputed One Class Collaborative Filtering (OCCF) algorithm, tREMAP, with a statistical framework based on Random Walk with Restart and assess the reliability of specific predictions. In the benchmark, tREMAP clearly outperforms the single-rank OCCF. We apply ANTENNA to a real-world problem: repurposing old drugs for new clinical indications without effective treatments. We discover that FDA-approved drug diazoxide can inhibit multiple kinase genes responsible for many diseases including cancer and kill triple negative breast cancer (TNBC) cells efficiently (). TNBC is a deadly disease without effective targeted therapies. Our finding demonstrates the power of big data analytics in drug discovery and developing a targeted therapy for TNBC. PMID- 29993813 TI - Identification of local clusters of mutation hotspots in cancer-related genes and their biological relevance. AB - Mutation hotspots are either solitary amino acid residues or stretches of amino acids that show elevated mutation frequency in cancer-related genes, but their prevalence and biological relevance are not completely understood. Here, we developed a Smith-Waterman algorithm-based mutation hotspot discovery method, MutClustSW, to identify mutation hotspots of either single or clustered amino acid residues. We identified 181 missense mutation hotspots from COSMIC and TCGA mutation databases. In addition to 77 single amino acid residue hotspots (42.5%) including well-known mutation hotspots such as IDH1 (p.R132) and BRAF (p.V600), we identified 104 mutation hotspots (57.5%) as clusters or stretches of multiple amino acids, and the hotspots on MUC2, EPPK1, KMT2C, and TP53 were larger than 50 amino acids. Twelve of 27 nonsense mutation hotspots (44.4%) were observed in four cancer-related genes, TP53, ARID1A, CDKN2A, and PTEN, suggesting that truncating mutations on some tumor suppressor genes are not randomly distributed as previously assumed. We also show that hotspot mutations have higher mutation allele frequency than non-hotspots, and the hotspot information can be used to prioritize the cancer drivers. Together, the proposed algorithm and the mutation hotspot information can serve as valuable resources in the selection of functional driver mutations and associated genes. PMID- 29993814 TI - A MODEL for DISTRIBUTED PROCESSING and ANALYSES of NGS DATA under MAP-REDUCE PARADIGM. AB - Massively parallel sequencing technique, introduced by NGS technology, has resulted in an exponential growth of sequencing data, with greatly reduced cost and increased throughput. This huge explosion of data has introduced new challenges in regard to its storage, integration, processing and analyses. In this paper, we have proposed a novel distributed model under Map-Reduce paradigm to address the NGS big data problem. The architecture of the model involves Map Reduce based modularized approach involving 3 different phases that support various analytical pipelines. The first phase will generate detailed base level information of various individual genomes, by granulating the alignment data. The other 2 phases independently process this base level information in parallel. One of these 2 phases will provide an integrated DNA profile of multiple individuals, whereas the other phase will generate contigs with similar features in an individual. Each of these 2 phases will generate a repository of genomic information that will facilitate other analytical pipelines. A simulated and real experimental prototypes has been provided as results to show the effectiveness of the model and its superiority over a few existing popular models and tools. A detailed description of the scope of applications of this model is also included in this article. PMID- 29993815 TI - Computational prediction of sigma-54 promoters in bacterial genomes by integrating motif finding and machine learning strategies. AB - Sigma factor, as a unit of RNA polymerase holoenzyme, is a critical factor in the process of gene transcriptional regulation. It recognizes the specific DNA sites and brings the core enzyme of RNA polymerase to the upstream regions of target genes. Therefore, the prediction of the promoters for a particular sigma factor is essential for interpreting functional genomic data and observation. This paper develops a new method to predict sigma-54 promoters in bacterial genomes. The new method organically integrates motif finding and machine learning strategies to capture the intrinsic features of sigma-54 promoters. The experiments on E. coli benchmark test set show that our method has good capability to distinguish sigma 54 promoters from surrounding or randomly selected DNA sequences. The applications of other three bacterial genomes indicate the potential robustness and applicative power of our method on a large number of bacterial genomes. The source code of our method can be freely downloaded at https://github.com/maqin2001/PromotePredictor. PMID- 29993816 TI - Scaffolding of Ancient Contigs and Ancestral Reconstruction in a Phylogenetic Framework. AB - Ancestral genome reconstruction is an important task to analyze the evolution of genomes. Recent progress in sequencing ancient DNA led to the publication of so called paleogenomes and allows the integration of this sequencing data in genome evolution analysis. However, the de novo assembly of ancient genomes is usually fragmented due to DNA degradation over time among others. Integrated phylogenetic assembly addresses the issue of genome fragmentation in the ancient DNA assembly while aiming to improve the reconstruction of all ancient genomes in the phylogeny simultaneously. The fragmented assembly of the ancient genome can be represented as an assembly graph, indicating contradicting ordering information of contigs. In this setting, our approach is to compare the ancient data with extant finished genomes. We generalize a reconstruction approach minimizing the Single-Cut-or-Join rearrangement distance towards multifurcating trees and include edge lengths to improve the reconstruction in practice. This results in a polynomial time algorithm that includes additional ancient DNA data at one node in the tree, resulting in consistent reconstructions of ancestral genomes. PMID- 29993817 TI - EBWS: Essential Bioinformatics Web Services for Sequence Analyses. AB - The Essential Bioinformatics Web Services (EBWS) are implemented on a new PHP based server that provides useful tools for analyses of DNA, RNA, and protein sequences applying a user-friendly interface. Nine Web-based applets are currently available on the Web server. They include reverse complementary DNA and random DNA/RNA/peptide oligomer generators, a pattern sequence searcher, a DNA restriction cutter, a prokaryotic ORF finder, a random DNA/RNA mutation generator. It also includes calculators of melting temperature (TM) of DNA/DNA, RNA/RNA, and DNA/RNA hybrids, a guide RNA (gRNA) generator for the CRISPR/Cas9 system and an annealing temperature calculator for multiplex PCR. The pattern searching applet has no limitations in the number of motif inputs and applies a toolbox of Regex quantifiers that can be used for defining complex sequence queries of RNA, DNA, and protein sequences. The DNA enzyme digestion program utilizes a large database of 1502 restriction enzymes. The gRNA generator has a database of 25 bacterial genomes searchable for gRNA target sequences and has an option for searching in any genome sequence given by the user. All programs are permanently available online at http://penchovsky.atwebpages.com/applications.php without any restrictions. PMID- 29993818 TI - Introducing Whole Finger Effects in Surface Haptics: An Extended Stick-Slip Model Incorporating Finger Stiffness. AB - The kinematic serial chain configuration of a finger modulates the frictional properties during tactile exploration tasks. This paper analyzes and subsequently models the effects of the entire finger during sliding operations on a surface. Qualitative and quantitative study of finger movement patterns with postures, sliding directions, and contact angles first indicate the effect of finger stiffness on contact mechanics. A "stiffness ellipse" is subsequently modeled to incorporate finger pose effects, and then coupled with the lumped mass-spring damper model of the finger pad to estimate resultant contact forces. The performance of the proposed model is verified by comparing with experimental results obtained from ten subjects. The proposed model could estimate the general tendencies of contact forces with change in postures (Extended and Flexed), sliding directions (proximal and distal), and contact angles (20 degrees , 40 degrees and 60 degrees ). The experimental results indicate that finger stiffness significantly modulates the contact forces, stick-slip frequency, preloading duration and initial spike during sliding. Introduction of finger posture effects could explain the change in finger normal force during tactile exploration tasks. The proposed haptic rendering model can be used to give a more natural user feedback in virtual fingertip-surface interactions. PMID- 29993819 TI - MR-Compatible Haptic Display of Membrane Puncture in Robot-Assisted Needle Procedures. AB - Multilayer electroactive polymer films actuate a small hand-held device that can display tool tip forces during MR-guided interventions. The display produces localized skin stretch at the thumb and index fingertips. Tests confirm that the device does not significantly affect MR imaging and produces detectable stimuli in response to forces measured by a biopsy needle instrumented with optical fibers. Tests with human subjects explored robotic and teleoperated paradigms to detect when the needle contacted a membrane embedded at variable depth in a tissue phantom that approximated the properties of porcine liver. In the first case, naive users detected membranes with a 98.9% success rate as the needle was driven at fixed speed. In the second case, users with experience in needle-based procedures controlled the needle insertion and detected membranes embedded in tissue phantoms with a 98% success rate. In the second experiment, some users detected membranes with very light contact forces, but there was greater subject to-subject variation. PMID- 29993820 TI - Ristretto: A Framework for Empirical Study of Resource-Efficient Inference in Convolutional Neural Networks. AB - Convolutional neural networks (CNNs) have led to remarkable progress in a number of key pattern recognition tasks, such as visual scene understanding and speech recognition, that potentially enable numerous applications. Consequently, there is a significant need to deploy trained CNNs to resource-constrained embedded systems. Inference using pretrained modern deep CNNs, however, requires significant system resources, including computation, energy, and memory space. To enable efficient implementation of trained CNNs, a viable approach is to approximate the network with an implementation-friendly model with only negligible degradation in classification accuracy. We present Ristretto, a CNN approximation framework that enables empirical investigation of the tradeoff between various number representation and word width choices and the classification accuracy of the model. Specifically, Ristretto analyzes a given CNN with respect to numerical range required to represent weights, activations, and intermediate results of convolutional and fully connected layers, and subsequently, it simulates the impact of reduced word width or lower precision arithmetic operators on the model accuracy. Moreover, Ristretto can fine-tune a quantized network to further improve its classification accuracy under a given number representation and word width configuration. Given a maximum classification accuracy degradation tolerance of 1%, we use Ristretto to demonstrate that three ImageNet networks can be condensed to use 8-bit dynamic fixed point for network weights and activations. Ristretto is available as a popular open-source software project and has already been viewed over 1,000 times on Github as of the submission of this brief. PMID- 29993821 TI - Latent Topic Text Representation Learning on Statistical Manifolds. AB - The explosive growth of text data requires effective methods to represent and classify these texts. Many text learning methods have been proposed, like statistics-based methods, semantic similarity methods, and deep learning methods. The statistics-based methods focus on comparing the substructure of text, which ignores the semantic similarity between different words. Semantic similarity methods learn a text representation by training word embedding and representing text as the average vector of all words. However, these methods cannot capture the topic diversity of words and texts clearly. Recently, deep learning methods such as CNNs and RNNs have been studied. However, the vanishing gradient problem and time complexity for parameter selection limit their applications. In this paper, we propose a novel and efficient text learning framework, named Latent Topic Text Representation Learning. Our method aims to provide an effective text representation and text measurement with latent topics. With the assumption that words on the same topic follow a Gaussian distribution, texts are represented as a mixture of topics, i.e., a Gaussian mixture model. Our framework is able to effectively measure text distance to perform text categorization tasks by leveraging statistical manifolds. Experimental results on text representation and classification, and topic coherence demonstrate the effectiveness of the proposed method. PMID- 29993822 TI - Output Reachable Set Estimation and Verification for Multilayer Neural Networks. AB - In this brief, the output reachable estimation and safety verification problems for multilayer perceptron (MLP) neural networks are addressed. First, a conception called maximum sensitivity is introduced, and for a class of MLPs whose activation functions are monotonic functions, the maximum sensitivity can be computed via solving convex optimization problems. Then, using a simulation based method, the output reachable set estimation problem for neural networks is formulated into a chain of optimization problems. Finally, an automated safety verification is developed based on the output reachable set estimation result. An application to the safety verification for a robotic arm model with two joints is presented to show the effectiveness of the proposed approaches. PMID- 29993823 TI - Kidney Detection in 3D Ultrasound Imagery Via Shape to Volume Registration Based on Spatially Aligned Neural Network. AB - This paper introduces a computer-aided kidney shape detection method suitable for volumetric (3D) ultrasound images. Using shape and texture priors, the proposed method automates the process of kidney detection, which is a problem of great importance in computer-assisted trauma diagnosis. This paper introduces a new complex-valued implicit shape model which represents the multi-regional structure of the kidney shape. A spatially aligned neural network classifiers with complex valued output is designed to classify voxels into background and multi-regional structure of the kidney shape. The complex values of the shape model and classification outputs are selected and incorporated in a new similarity metric such the shape-to-volume registration process only fits the shape model on the actual kidney shape in input ultrasound volumes. The algorithm's accuracy and sensitivity are evaluated using both simulated and actual 3D ultrasound images, and it is compared against the performance of the state-of-the-art. The results support the claims about accuracy and robustness of the proposed kidney detection method, and statistical analysis validates its superiority over state-of-the-art. PMID- 29993824 TI - Funneled Bayesian Optimization for Design, Tuning and Control of Autonomous Systems. AB - In this paper, we tackle several problems that appear in robotics and autonomous systems: algorithm tuning, automatic control, and intelligent design. All those problems share in common that they can be mapped to global optimization problems where evaluations are expensive. Bayesian optimization (BO) has become a fundamental global optimization algorithm in many problems where sample efficiency is of paramount importance. BO uses a probabilistic surrogate model to learn the response function and reduce the number of samples required. Gaussian processes (GPs) have become a standard surrogate model for their flexibility to represent a distribution over functions. In a black-box settings, the common assumption is that the underlying function can be modeled with a stationary GP. In this paper, we present a novel kernel function specially designed for BO, that allows nonstationary behavior of the surrogate model in an adaptive local region. This kernel is able to reconstruct nonstationarity even with the irregular sampling distribution that arises from BO. Furthermore, in our experiments, we found that this new kernel results in an improved local search (exploitation), without penalizing the global search (exploration) in many applications. We provide extensive results in well-known optimization benchmarks, machine learning hyperparameter tuning, reinforcement learning, and control problems, and UAV wing optimization. The results show that the new method is able to outperform the state of the art in BO both in stationary and nonstationary problems. PMID- 29993825 TI - Global Anti-Synchronization of Complex-Valued Memristive Neural Networks With Time Delays. AB - This paper formulates a class of complex-valued memristive neural networks as well as investigates the problem of anti-synchronization for complex-valued memristive neural networks. Under the concept of drive-response, several sufficient conditions for guaranteeing the anti-synchronization are given by employing suitable Lyapunov functional and some inequality techniques. The proposed results of this paper are less conservative than existing literatures due to the characteristics of memristive complex-valued neural networks. Moreover, the proposed results are easy to be validated with the parameters of system itself. Finally, two examples with numerical simulations are showed to demonstrate the efficiency of our theoretical results. PMID- 29993826 TI - Robust Reconstruction of Fluorescence Molecular Tomography Based on Sparsity Adaptive Correntropy Matching Pursuit Method for Stem Cell Distribution. AB - Fluorescence molecular tomography (FMT), as a promising imaging modality in preclinical research, can obtain the three-dimensional (3-D) position information of the stem cell in mice. However, because of the ill-posed nature and sensitivity to noise of the inverse problem, it is a challenge to develop a robust reconstruction method, which can accurately locate the stem cells and define the distribution. In this paper, we proposed a sparsity adaptive correntropy matching pursuit (SACMP) method. SACMP method is independent on the noise distribution of measurements and it assigns small weights on severely corrupted entries of data and large weights on clean ones adaptively. These properties make it more suitable for in vivo experiment. To analyze the performance in terms of robustness and practicability of SACMP, we conducted numerical simulation and in vivo mice experiments. The results demonstrated that the SACMP method obtained the highest robustness and accuracy in locating stem cells and depicting stem cell distribution compared with stagewise orthogonal matching pursuit and sparsity adaptive subspace pursuit reconstruction methods. To the best of our knowledge, this is the first study that acquired such accurate and robust FMT distribution reconstruction for stem cell tracking in mice brain. This promotes the application of FMT in locating stem cell and distribution reconstruction in practical mice brain injury models. PMID- 29993827 TI - Pulsed-Laser Deposited 35 Bi(Mg1/2Ti1/2) O3-65 PbTiO3 Thin Films-Part I: Influence of Processing on Composition, Microstructure, and Ferroelectric Hysteresis. AB - 35 Bi(Mg1/2Ti1/2)O3 - 65 PbTiO3 (35 BiMT-65 PT) is a potential candidate material for a high-temperature nonvolatile ferroelectric memory. For pulsed-laser deposited 35 BiMT-65 PT films with the perovskite structure, it was found that as the chamber pressure during deposition decreased, the Mg and Pb contents in as deposited films drop, while the concentration of Bi increases. Concurrently with the change in composition, the remanent polarization $P_{r}$ increases 64% to $?approx 21~?mu ?text{C}$ /cm2 and the polarization-electric field loops rotated counterclockwise as the deposition pressure increases. Decreasing the seed layer thickness from 36 to 16 nm led to a decrease in $P_{r}$ to $?approx 14~?mu ?text{C}$ /cm2. Adjusting the target composition allowed the deposition of films which had near-stoichiometric Bi and Mg concentrations, but in all cases, the grown films were lead deficient. These films had remanent polarizations of 18- $20~?mu ?text{C}$ /cm2. If the lead content of the target was increased too far, the remanent polarization decreased, possibly due to the need to evolve more PbO from defective growth layers. Finally, the deposition rate showed no substantial effect on the film composition, but did have a significant impact on the ferroelectric properties. As the deposition rate decreased, the $P_{r}$ increased to $?approx 22~?mu ?text{C}$ /cm2 due to enhanced crystalline quality. At laser frequencies of 5 Hz, a Mg-rich pyrochlore phase begins to form and films showed a maximum $P_{r} ?approx 22~?mu ?text{C}$ /cm2. The processing-composition behavior is explained via preferential adsorption of Bi on the A-site, which results in lead vacancies. PMID- 29993828 TI - Pulsed-Laser Deposited 35 Bi(Mg1/2Ti1/2)O3-65 PbTiO3 Thin Films-Part II: Influence of A-Site Deficiency and Thickness Scaling on Electric Properties. AB - 35 Bi(Mg1/2Ti1/2)O3-65 PbTiO3 (35 BiMT-65 PT) thin films with varying levels of A site deficiency were investigated as a potential candidate for high-temperature nonvolatile ferroelectric memories. PbTiO3 seed layers utilized to nucleate the perovskite phase in A-site deficient films induced a thickness dependence to the ferroelectric hysteresis and dielectric permittivity. Adjusting for this, the dielectric response of the 35 BiMT-65 PT films is $?approx 960$ . The maximum dielectric permittivity was 430 degrees C at 1 MHz for A-site deficient films. The transition temperature is independent of film thickness to 85 nm. Tan( $?delta$ ) remains less than 15% at 1 MHz regardless of film thickness and temperature up to 585 degrees C. High-temperature polarization-electric field hysteresis measurements show charge injection with increasing temperature, while positive-up-negative-down measurements show little temperature dependence of $P_{r}$ up to temperatures of 200 degrees C. Poole-Frenkel emission dominated the high field leakage behavior. The refractive index measured by ellipsometry is 2.58 at 633 nm. All samples show significant retention loss. As the stoichiometry improves, retention improves such that >40% of the initial $?Delta P$ is retained over $?approx 280$ min. PMID- 29993829 TI - Evaluation of a Three Hydrophones Method for 2-Dimensional Cavitation Localization. AB - Cavitation is a critical parameter in various therapeutic applications involving ultrasound (US) such as histotrispy, lithothripsy, drug delivery, and cavitation enhanced hyperthermia. A cavitation exposure outside the region of interest may lead to suboptimal treatment efficacy or in a worse case, to safety issues. Current methods of localizing cavitation are based on imaging approaches, such as beamforming the cavitation signals received passively by a US imager. These methods, although efficient, require expensive equipment, which may discourage potential future developments. We propose a threehydrophone method to localize the cavitation cloud source. Firstly, the delays between the three receptors are measured by detecting the maximum of their inter-correlations. Then, the position of the source is calculated by either minimizing a cost function or solving hyperbolic equations. After a numerical validation, the method was assessed experimentally. This method was able to track a source displacement with accuracy similar to the size of the cavitation cloud (2-4 millimeters). This light and versatile method provides interesting perspectives since localization can be executed in real time and the extension to three-dimensional localization seems straightforward. PMID- 29993830 TI - Paxel: A Generic Framework to Superimpose High-Frequency Print Patterns using Projected Light. AB - In this paper, we propose Paxel, a generic framework for modeling the interaction between a projector and a high-frequency pattern surface. Using this framework, we present two different application setups (cf. Fig. 1a): a novel colorchanging effect, created with a single projected image and only when the projection surface is changed from a pattern surface to a uniform white surface. The observed effect relies on the spatially different reflectance properties of these two surfaces. Using this approach, one can alter color proprieties of the projected image such as hue or chroma. Furthermore, for a specific color range, defined by an full color-changing sub-gamut, one can embed two completely different images, within a single static projection, from which either one will be revealed depending on the surface. The second application allows the creation of color images using a single channel projector. For this application, we present a full color projection created using a 365 nm ultraviolet (UV) projector in combination with fluorescent pigments (cf. Fig. 1b), enabling new display possibilities, such as projection through participating media, e.g. fog, while hiding the scattering of the projection light outside of the visible spectrum. Both presented approaches create effects that might be striking to the observer, making this framework useful for art exhibitions, advertisements, entertainment and visual cryptography. Finally, in Sec. VI, we provide an in-depth analysis of the reproducible colors based on input parameters, used in the presented algorithm, such as: pattern layout, dot size of the pattern and the number of the clusters formed by k-means algorithm (IV-B). PMID- 29993831 TI - TextBoxes++: A Single-Shot Oriented Scene Text Detector. AB - Scene text detection is an important step of scene text recognition system and also a challenging problem. Different from general object detection, the main challenges of scene text detection lie on arbitrary orientations, small sizes, and significantly variant aspect ratios of text in natural images. In this paper, we present an end-to-end trainable fast scene text detector, named TextBoxes++, which detects arbitrary-oriented scene text with both high accuracy and efficiency in a single network forward pass. No post-processing other than an efficient non-maximum suppression is involved. We have evaluated the proposed TextBoxes++ on four public datasets. In all experiments, TextBoxes++ outperforms competing methods in terms of text localization accuracy and runtime. More specifically, TextBoxes++ achieves an f-measure of 0.817 at 11.6fps for 1024 * 1024 ICDAR 2015 Incidental text images, and an f-measure of 0.5591 at 19.8fps for 768 * 768 COCO-Text images. Furthermore, combined with a text recognizer, TextBoxes++ significantly outperforms the stateof-the-art approaches for word spotting and end-to-end text recognition tasks on popular benchmarks. PMID- 29993832 TI - Permuted Coordinate-wise Optimizations Applied to Lp-regularized Image Deconvolution. AB - Image deconvolution is an ill-posed problem that usually requires prior knowledge for regularizing the feasible solutions. In literature, iterative methods estimate an intrinsic image, minimizing a cost function regularized by specific prior information. However, it is difficult to directly minimize the constrained cost function, if a nondifferentiable regularization (e.g., the sparsity constraint) is employed. In this paper, we propose a nonderivative image deconvolution algorithm that solves the under-constrained problem (i.e., a non blind image deconvolution) by successively solving the permuted subproblems. The subproblems, arranged in permuted sequences, directly minimize the nondifferentiable cost functions. Various Lp-regularized (0 < p <= 1, p = 2) objective functions are utilized to demonstrate the pixel-wise optimization, in which the projection operator generates simplified, low-dimensional subproblems for estimating each pixel. The subproblems, after projection, are dealt with in the corresponding hyperplanes containing the adjacent pixels of each image coordinate. Furthermore, successively solving the subproblems can accelerate the deconvolution process with a linear speed-up, by parallelizing the subproblem sequences. The image deconvolution results with various regularization functionals are presented and the linear speed-up is also demonstrated with a parallelized version of the proposed algorithm. Experimental results demonstrate that the proposed method outperforms the conventional methods in terms of the improved-signal-to-noise ratio and structural similarity index measure. PMID- 29993833 TI - Visualizing a Thinker's Life. AB - This paper presents a visualization framework that aids readers in understanding and analyzing the contents of medium-sized text collections that are typical for the opus of a single or few authors.We contribute several document-based visualization techniques to facilitate the exploration of the work of the German author Bazon Brock by depicting various aspects of its texts, such as the TextGenetics that shows the structure of the collection along with its chronology. The ConceptCircuit augments the TextGenetics with entities - persons and locations that were crucial to his work. All visualizations are sensitive to a wildcard-based phrase search that allows complex requests towards the author's work. Further development, as well as expert reviews and discussions with the author Bazon Brock, focused on the assessment and comparison of visualizations based on automatic topic extraction against ones that are based on expert knowledge. PMID- 29993834 TI - Biomarker Identification for Cancer Disease Using Biclustering Approach: An Empirical Study. AB - This paper presents an exhaustive empirical study to identify biomarkers using two approaches: frequency-based and network-based, over seventeen different biclustering algorithms and six different cancer expression datasets. To systematically analyze the biclustering algorithms, we perform enrichment analysis, subtype identification and biomarker identification. Biclustering algorithms such as C&C, SAMBA and Plaid are useful to detect biomarkers by both approaches for all datasets except prostate cancer. We detect a total of 102 gene biomarkers using frequency-based method out of which 19 are for blood cancer, 36 for lung cancer, 25 for colon cancer, 13 for multi-tissue cancer and 9 for prostate cancer. Using the network-based approach we detect a total of 41 gene biomarkers of which 15 are from blood cancer, 12 from lung cancer, 6 from colon cancer, 7 from multi-tissue cancer and 1 from prostate cancer dataset. We further extend our network analysis over some biclusters and detect some gene biomarkers not detected earlier by both frequency-based or network-based approach. We expand our work on breast cancer miRNA expression data to evaluate the performance of the biclustering algorithms. We detect 19 breast cancer biomarkers by frequency based method and 5 by network-based method for the miRNA dataset. PMID- 29993835 TI - A novel cluster-based computational method to identify miRNA regulatory modules. AB - The identification of miRNA regulatory modules can help decipher miRNAs combinatorial regulation effects on the pathogenesis underlying complex diseases, especially in cancer. By integrating miRNA/mRNA expression profiles and sequence based predicted target site information, we develop a novel cluster-based computational method named CoModule for identifying miRNA regulatory modules (MRMs). The ultimate goal of CoModule is to detect the MRMs, in which the miRNAs in each module are expected to present cooperative mechanisms in regulating their targets mRNAs. Here, the co-expression of miRNAs are believed to present cooperative regulatory relationship, therefore, the critical step of CoModule is firstly to partition the miRNAs with similar expression into a cluster by employing rough set clustering. After gaining credible miRNA clusters, the targets of regulator are naturally added into corresponding clusters to produce the final miRNA regulatory modules. We apply this present method to ovarian cancer datasets and make comparison with other two existing prominent approaches. The results indicate that the modules identified by CoModule perform better than other two methods ranging from the topological aspects to the biological function. Survival analysis detects a number of prognostic modules with statistical significance, which can help reveal the potential diagnostic for ovarian cancer. PMID- 29993836 TI - Machine Vision System for 3D Plant Phenotyping. AB - Machine vision for plant phenotyping is an emerging research area for producing high throughput in agriculture and crop science applications. Since 2D based approaches have their inherent limitations, 3D plant analysis is becoming state of the art for current phenotyping technologies. We present an automated system for analyzing plant growth in indoor conditions. A gantry robot system is used to perform scanning tasks in an automated manner throughout the lifetime of the plant. A 3D laser scanner mounted as the robot's payload captures the surface point cloud data of the plant from multiple views. The plant is monitored from the vegetative to reproductive stages in light/dark cycles inside a controllable growth chamber. An efficient 3D reconstruction algorithm is used, by which multiple scans are aligned together to obtain a 3D mesh of the plant, followed by surface area and volume computations. The whole system, including the programmable growth chamber, robot, scanner, data transfer and analysis is fully automated in such a way that a naive user can, in theory, start the system with a mouse click and get back the growth analysis results at the end of the lifetime of the plant with no intermediate intervention. As evidence of its functionality, we show and analyze quantitative results of the rhythmic growth patterns of the dicot Arabidopsis thaliana(L.), and the monocot barley (Hordeum vulgare L.) plants under their diurnal light/dark cycles. PMID- 29993837 TI - A probabilistic framework for molecular network structure inference by means of mechanistic modeling. AB - Ordinary differential equations (ODEs) provide a powerful formalism to model molecular networks mechanistically. However, inferring the model structure, given a set of time course measurements and a large number of alternative molecular mechanisms, is a challenging and open research question. Existing search heuristics are designed only for finding a single best model configuration and cannot account for the uncertainty in selecting the network components. In this study, we present a novel Markov chain Monte Carlo approach for performing Bayesian model structure inference over ODE models. We formulate a Metropolis algorithm that explores the model space efficiently and is suitable for obtaining probabilistic inferences about the network structure. The method and its special parallelization possibilities are demonstrated using simulated data. Furthermore, we apply the method to a time course RNA sequencing data set to infer the structure of the transiently evolving core regulatory network that steers the T helper 17 (Th17) cell differentiation. Our results are in agreement with the earlier finding that the Th17 lineage-specific differentiation program evolves in three sequential phases. Further, the analysis provides us with probabilistic predictions on the molecular interactions that are active in different phases of Th17 cell differentiation. PMID- 29993838 TI - Robust Gene Circuit Control Design for Time-delayed Genetic Regulatory Networks without SUM Regulatory Logic. AB - This paper investigates the gene circuit control design problem of time-delayed genetic regulatory networks. In the genetic regulatory networks, the time delays are unknown constants, and the genetic regulatory is not conventional SUM regulatory logic and can be modeled to be an unknown nonlinear function of the time-delayed states of the other genes in a cell. By Lyapunov stability, a novel adaptive gene circuit control design approach is proposed for the genetic regulatory networks, where the unknown time delays are estimated online by adaptive algorithms and the unknown regulatory functions are approximated by neural networks. The design approach in this paper is delay-dependent and has less conservatism than the delay-independent approach. From theoretical analysis, the closed-loop system is asymptotically stable and all the signals in the system converge to an adjustable neighborhood of the origin. Finally, a numerical example is given to show the effectiveness of the new design approach. PMID- 29993839 TI - Inferring large-scale gene regulatory networks using a randomized algorithm based on singular value decomposition. AB - Reconstructing large-scale gene regulatory networks (GRNs) is a challenging problem in the field of computational biology. Various methods for inferring GRNs have been developed, but they fail to accurately infer GRNs with a large number of genes. Additionally, the existing evaluation indexes for evaluating the constructed networks have obvious disadvantages because GRNs in most biological systems are sparse. In this paper, we develop a new method for inferring GRNs based on randomized singular value decomposition (RSVD) and ordinary differential equation (ODE)-based optimization, denoted as IGRSVD, from large-scale time series data with noise. The three major contributions of this paper are as follows. First, the IGRSVD algorithm uses the RSVD to handle the noise and reduce the original large-scale data into small-scale problems. Second, we propose two new evaluated indexes, the expected value accuracy (EVA) and the expected value error (EVE), to evaluate the performance of inferred networks by considering the sparse features in the network. Finally, the proposed IGRSVD algorithm is compared with the existing SVD algorithm and PCA_CMI algorithm using four subsets from E. coli and datasets from DREAM challenge. The experimental results demonstrate that the IGRSVD algorithm is effective and more suitable for reconstructing large-scale networks. PMID- 29993840 TI - Hydrogels for Advanced Stem Cell Therapies: A Biomimetic Materials Approach for Enhancing Natural Tissue Function. AB - Stem cell-based therapy is a promising approach for the treatment of a myriad of diseases and injuries. However, the low rate of cell survival and the uncontrolled differentiation of the injected stem cells currently remain as the key challenges in advancing stem cell therapeutics. Hydrogels are biomaterials that are potentially highly effective candidates for scaffold systems for stem cells and other molecular encapsulation approaches to target in vivo delivery. Hydrogel-based strategies can potentially address several current challenges in stem cell therapy. In the current review, we present a concise overview of the recent advances in applications of hydrogels in stem cell therapies, with a focus particularly on the recent advances in the design and approaches for application of hydrogels in tissue engineering. The capability of hydrogels to either enhance the function of the transplanted stem cells by promoting their controlled differentiation or enhance the recruitment of endogenous adult stem cells to the injury site for repair is also reviewed. Finally, the importance of impacts and the desired relationship between the scaffold system and the encapsulated stem cells are discussed. PMID- 29993841 TI - A Standard Methodology to Characterize the Intrinsic Material Properties of Compliant Test Stimuli. AB - Understanding how we perceive differences in material compliance, or 'softness,' is a central topic in the field of haptics. The intrinsic elasticity of an object is the primary factor thought to influence our perceptual estimates. Therefore, most studies test and report the elasticity of their stimuli, typically as stiffness or modulus. However, many reported estimates are of very high magnitude for silicone-elastomers, which may be due to artifacts in characterization technique. This makes it very difficult to compare the perceptual results between the studies. The work herein defines a standardized and easy-to-implement way to characterize test stimuli. The procedure involves the unconstrained, uniaxial compression of a plate into cylindrical substrates 10 mm tall by 10 mm diameter. The resultant force-displacement data are straightforwardly converted into stress strain data, from which a modulus is readily derived. This procedure was used to re-characterize stimuli from prior studies. The revised results from the validated method herein are 200-1,100% lower than modulus values either reported and/or approximated from stiffness. This is practically significant when differences of 10-15% are perceptually discriminable. The re-characterized estimates are useful in comparing prior studies and designing new studies. Furthermore, this characterization methodology may help more readily bridge studies on perception with those designing technology. PMID- 29993842 TI - Neural-Learning-Based Control for a Constrained Robotic Manipulator With Flexible Joints. AB - Nowadays, the control technology of the robotic manipulator with flexible joints (RMFJ) is not mature enough. The flexible-joint manipulator dynamic system possesses many uncertainties, which brings a great challenge to the controller design. This paper is motivated by this problem. In order to deal with this and enhance the system robustness, the full-state feedback neural network (NN) control is proposed. Moreover, output constraints of the RMFJ are achieved, which improve the security of the robot. Through the Lyapunov stability analysis, we identify that the proposed controller can guarantee not only the stability of flexible-joint manipulator system but also the boundedness of system state variables by choosing appropriate control gains. Then, we make some necessary simulation experiments to verify the rationality of our controllers. Finally, a series of control experiments are conducted on the Baxter. By comparing with the proportional-derivative control and the NN control with the rigid manipulator model, the feasibility and the effectiveness of NN control based on flexible joint manipulator model are verified. PMID- 29993843 TI - Low-Complexity Approximate Convolutional Neural Networks. AB - In this paper, we present an approach for minimizing the computational complexity of the trained convolutional neural networks (ConvNets). The idea is to approximate all elements of a given ConvNet and replace the original convolutional filters and parameters (pooling and bias coefficients; and activation function) with an efficient approximations capable of extreme reductions in computational complexity. Low-complexity convolution filters are obtained through a binary (zero and one) linear programming scheme based on the Frobenius norm over sets of dyadic rationals. The resulting matrices allow for multiplication-free computations requiring only addition and bit-shifting operations. Such low-complexity structures pave the way for low power, efficient hardware designs. We applied our approach on three use cases of different complexities: 1) a "light" but efficient ConvNet for face detection (with around 1000 parameters); 2) another one for hand-written digit classification (with more than 180 000 parameters); and 3) a significantly larger ConvNet: AlexNet with million matrices. We evaluated the overall performance on the respective tasks for different levels of approximations. In all considered applications, very low complexity approximations have been derived maintaining an almost equal classification performance. PMID- 29993844 TI - Simultaneous Spectral Data Embedding and Clustering. AB - Spectral clustering is often carried out by combining spectral data embedding and -means clustering. However, the aims, dimensionality reduction and clustering, are usually not performed jointly. In this brief, we propose a novel approach to finding an optimal spectral embedding for identifying a partition of the set of objects; it iteratively alternates spectral embedding and clustering. In doing so, we show that our model can learn a low-dimensional representation more suited to clustering. Compared with classical spectral clustering methods, the proposed algorithm is not costly and outperforms not only these methods but also other nonnegative matrix factorization variants. PMID- 29993845 TI - A Weightedly Uniform Detectability for Sensor Networks. AB - In this brief, we study the detectability issues in the context of distributed state estimation problems for a class of locally undetectable sensor networks. First, we introduce a novel detectability condition, i.e., weightedly uniform detectability (WUD), which is a sufficient condition to prove that the error covariances of the consensus filtering are uniformly bounded even though the local sensor nodes are undetectable. Different from the existing detectability (or observability) conditions, our condition includes the interacting weights which could further optimize the lower detectability Gramian bound. Hence, a new weights selection method is derived in term of the criterion of WUD. This new rule of selecting weights provides a new framework for distributed state estimation. The advantages of this approach lead to a better performance in estimation without extra computational burden to the filtering process. Finally, an example shows the effectiveness of the proposed method. PMID- 29993846 TI - Learning and Guaranteed Cost Control With Event-Based Adaptive Critic Implementation. AB - This paper focuses on the event-triggered guaranteed cost control design of nonlinear systems via a self-learning technique. In brief, an event-based guaranteed cost control strategy of nonlinear systems subjects to matched uncertainties is developed, thereby balancing the performance of guaranteed cost and the actuality of limited communication resource. The original control design is transformed into an optimal control problem with an event-based mechanism, where the relationship of guaranteed cost performance compared to the time-based formulation is discussed. A critic neural network is constructed for implementing the event-based optimal control design with stability guarantee. Simulation experiments are carried out to verify the theoretical results in detail. PMID- 29993847 TI - Beyond Bilinear: Generalized Multimodal Factorized High-Order Pooling for Visual Question Answering. AB - Visual question answering (VQA) is challenging, because it requires a simultaneous understanding of both visual content of images and textual content of questions. To support the VQA task, we need to find good solutions for the following three issues: 1) fine-grained feature representations for both the image and the question; 2) multimodal feature fusion that is able to capture the complex interactions between multimodal features; and 3) automatic answer prediction that is able to consider the complex correlations between multiple diverse answers for the same question. For fine-grained image and question representations, a "coattention" mechanism is developed using a deep neural network (DNN) architecture to jointly learn the attentions for both the image and the question, which can allow us to reduce the irrelevant features effectively and obtain more discriminative features for image and question representations. For multimodal feature fusion, a generalized multimodal factorized high-order pooling approach (MFH) is developed to achieve more effective fusion of multimodal features by exploiting their correlations sufficiently, which can further result in superior VQA performance as compared with the state-of-the-art approaches. For answer prediction, the Kullback-Leibler divergence is used as the loss function to achieve precise characterization of the complex correlations between multiple diverse answers with the same or similar meaning, which can allow us to achieve faster convergence rate and obtain slightly better accuracy on answer prediction. A DNN architecture is designed to integrate all these aforementioned modules into a unified model for achieving superior VQA performance. With an ensemble of our MFH models, we achieve the state-of-the-art performance on the large-scale VQA data sets and win the runner-up in VQA Challenge 2017. PMID- 29993848 TI - Novel Radiomic Features based on Joint Intensity Matrices for Predicting Glioblastoma Patient Survival Time. AB - This paper presents a novel set of image texture features, generalizing standard grey-level co-occurrence matrices (GLCM) to multi-modal image data through joint intensity matrices (JIMs). These are used to predict the survival of glioblastoma multiforme (GBM) patients from multi-modal MRI data. The scans of 73 GBM patients from the Cancer Imaging Archive are used in our study. Necrosis, active tumor and edema/invasion sub-regions of GBM phenotypes are segmented using the co registration of contrast enhanced T1-weighted (CET1) images and its corresponding fluid-attenuated inversion recovery (FLAIR) images. Texture features are then computed from the JIM of these GBM sub-regions, and a random forest model employed to classify patients into short or long survival groups. Our survival analysis identified JIM features in necrotic (e.g., entropy and inverse-variance) and edema (e.g., entropy and contrast) sub-regions that are moderately correlated with survival time (i.e., Spearman rank correlation of 0.35). Moreover, 9 features were found to be associated with GBM survival, with a Hazard-ratio range of 0.382.1 and a significance level of p < 0.05 following Holm-Bonferroni correction. These features also led to the highest accuracy in a univariate analysis for predicting the survival group of patients, with AUC values in the range of 68- 70%. Considering multiple features for this task, JIM features led to significantly higher AUC values than those based on standard GLCMs and gene expression. Furthermore, an AUC of 77.56% with p=0.003 was achieved when combining JIM, GLCM and gene expression features into a single radiogenomic signature. In summary, our study demonstrated the usefulness of modeling the joint intensity characteristics of CE-T1 and FLAIR images for predicting the prognosis of patients with GBM. PMID- 29993849 TI - Accurate segmentation and registration of skin lesion images to evaluate lesion change. AB - Skin cancer is a major health problem. There are several techniques to help diagnose skin lesions from a captured image. Computer-aided diagnosis (CAD) systems operate on single images of skin lesions, extracting lesion features to further classify them and help the specialists. Accurate feature extraction, which further depends on precise lesion segmentation, is key for the performance of these systems. In this paper, we present a skin lesion segmentation algorithm based on a novel adaptation of superpixels techniques and achieving the best reported results for the ISIC 2017 challenge dataset. Additionally, CAD systems have paid little attention to a critical criterion in skin lesion diagnosis: the lesion's evolution. This requires operating on two or more images of the same lesion, captured at different times but with a comparable scale, orientation and point of view; in other words, an image registration process should first be performed. We also propose in this work an image registration approach that outperforms top image registration techniques. Combined with the proposed lesion segmentation algorithm, this allows for the accurate extraction of features to assess the evolution of the lesion. We present a case-study with the lesion-size feature, paving the road for the development of automatic systems to easily evaluate skin lesion evolution. PMID- 29993850 TI - Semi-Supervised Salient Object Detection Using a Linear Feedback Control System Model. AB - To overcome the challenging problems in saliency detection, we propose a novel semi-supervised classifier which makes good use of a linear feedback control system (LFCS) model by establishing a relationship between control states and salient object detection. First, we develop a boundary homogeneity model to estimate the initial saliency and background likelihoods, which are regarded as the labeled samples in our semi-supervised learning procedure. Then in order to allocate an optimized saliency value to each superpixel, we present an iterative semi-supervised learning framework which integrates multiple saliency cues and image features using an LFCS model. Via an innovative iteration method, the system gradually converges an optimized stable state, which is associating with an accurate saliency map. This paper also covers comprehensive simulation study based on public datasets, which demonstrates the superiority of the proposed approach. PMID- 29993852 TI - Nonuniform State Space Reconstruction for Multivariate Chaotic Time Series. AB - State space reconstruction is the foundation of chaotic system modeling. Selection of reconstructed variables is essential to the analysis and prediction of multivariate chaotic time series. As most existing state space reconstruction theorems deal with univariate time series, we have presented a novel nonuniform state space reconstruction method using information criterion for multivariate chaotic time series. We derived a new criterion based on low dimensional approximation of joint mutual information for time delay selection, which can be solved efficiently through the use of an intelligent optimization algorithm with low computation complexity. The embedding dimension is determined by conditional entropy, after which the reconstructed variables have relatively strong independence and low redundancy. The scheme, which integrates nonuniform embedding and feature selection, results in better reconstructions for multivariate chaotic systems. Moreover, the proposed nonuniform state space reconstruction method shows good performance in forecasting benchmark and actual multivariate chaotic time series. PMID- 29993851 TI - Small-Gain Technique-Based Adaptive NN Control for Switched Pure-Feedback Nonlinear Systems. AB - This paper focuses on the problem of adaptive neural networks (NNs) tracking control for a class of completely nonaffine switched pure-feedback uncertain nonlinear systems with switched reference model. A sufficient and necessary condition for the control problem to be solvable is derived by exploiting the common Lyapunov function (CLF) method, backstepping, input-to-state stability analysis, and the small-gain technique. Also, a small-gain technique-based adaptive NN control scheme is provided to avoid the designed difficulty caused by the construction of an overall CLF for the switched closed-loop system, which is usually required when studying the switched pure-feedback system. Adaptive NN controllers of individual subsystems are constructed to guarantee that all of the signals in the closed-loop system are semi-globally uniformly ultimately bounded under arbitrary switchings, and the tracking error converges to a small neighborhood of the origin. Two examples, which include a continuously stirred tank reactor system, are presented to demonstrate the effectiveness of the proposed design approach. PMID- 29993853 TI - Domain Space Transfer Extreme Learning Machine for Domain Adaptation. AB - Extreme learning machine (ELM) has been applied in a wide range of classification and regression problems due to its high accuracy and efficiency. However, ELM can only deal with cases where training and testing data are from identical distribution, while in real world situations, this assumption is often violated. As a result, ELM performs poorly in domain adaptation problems, in which the training data (source domain) and testing data (target domain) are differently distributed but somehow related. In this paper, an ELM-based space learning algorithm, domain space transfer ELM (DST-ELM), is developed to deal with unsupervised domain adaptation problems. To be specific, through DST-ELM, the source and target data are reconstructed in a domain invariant space with target data labels unavailable. Two goals are achieved simultaneously. One is that, the target data are input into an ELM-based feature space learning network, and the output is supposed to approximate the input such that the target domain structural knowledge and the intrinsic discriminative information can be preserved as much as possible. The other one is that, the source data are projected into the same space as the target data and the distribution distance between the two domains is minimized in the space. This unsupervised feature transformation network is followed by an adaptive ELM classifier which is trained from the transferred labeled source samples, and is used for target data label prediction. Moreover, the ELMs in the proposed method, including both the space learning ELM and the classifier, require just a small number of hidden nodes, thus maintaining low computation complexity. Extensive experiments on real-world image and text datasets are conducted and verify that our approach outperforms several existing domain adaptation methods in terms of accuracy while maintaining high efficiency. PMID- 29993854 TI - Synchronization Control for A Class of Discrete Time-Delay Complex Dynamical Networks: A Dynamic Event-Triggered Approach. AB - This paper is concerned with the synchronization control problem for a class of discrete time-delay complex dynamical networks under a dynamic event-triggered mechanism. For the efficiency of energy utilization, we make the first attempt to introduce a dynamic event-triggering strategy into the design of synchronization controllers for complex dynamical networks. A new discrete-time version of the dynamic event-triggering mechanism is proposed in terms of the absolute errors between control input updates. By constructing an appropriate Lyapunov functional, the dynamics of each network node combined with the introduced event triggering mechanism are first analyzed, and a sufficient condition is then provided under which the synchronization error dynamics is exponentially ultimately bounded. Subsequently, a set of the desired synchronization controllers is designed by solving a matrix inequality. Finally, a simulation example is provided to verify the effectiveness of the proposed dynamic event triggered synchronization control scheme. PMID- 29993855 TI - A Scalar Projection and Angle-Based Evolutionary Algorithm for Many-Objective Optimization Problems. AB - In decomposition-based multiobjective evolutionary algorithms, the setting of search directions (or weight vectors), and the choice of reference points (i.e., the ideal point or the nadir point) in scalarizing functions, are of great importance to the performance of the algorithms. This paper proposes a new decomposition-based many-objective optimizer by simultaneously using adaptive search directions and two reference points. For each parent, binary search directions are constructed by using its objective vector and the two reference points. Each individual is simultaneously evaluated on two fitness functions which are motivated by scalar projections-that are deduced to be the differences between two penalty-based boundary intersection (PBI) functions, and two inverted PBI functions, respectively. Solutions with the best value on each fitness function are emphasized. Moreover, an angle-based elimination procedure is adopted to select diversified solutions for the next generation. The use of adaptive search directions aims at effectively handling problems with irregular Pareto-optimal fronts, and the philosophy of using the ideal and nadir points simultaneously is to take advantages of the complementary effects of the two points when handling problems with either concave or convex fronts. The performance of the proposed algorithm is compared with seven state-of-the-art multi-/many-objective evolutionary algorithms on 32 test problems with up to 15 objectives. It is shown by the experimental results that the proposed algorithm is flexible when handling problems with different types of Pareto-optimal fronts, obtaining promising results regarding both the quality of the returned solution set and the efficiency of the new algorithm. PMID- 29993856 TI - Consensus Control of a Class of Uncertain Nonlinear Multiagent Systems via Gradient-Based Algorithms. AB - This paper is concerned with the distributed optimization problem for a class of minimum-phase nonlinear multiagent systems with second relative degree. The target is to minimize a cost function composed of a group of convex local functions of the outputs in a cooperative manner. Novel state feedback control laws are first proposed and the consensus subject to the optimization constraint is achieved when the communication graph is directed. By replacing the derivatives of the outputs in the state feedback control laws with their estimations, the output feedback control laws are constructed and proved to achieve exponential consensus under the undirected graph. The effectiveness of the proposed control laws is validated by some simulations. PMID- 29993857 TI - Data-Driven Distributed Optimal Consensus Control for Unknown Multiagent Systems With Input-Delay. AB - This paper is concerned with data-driven distributed optimal consensus control for unknown multiagent systems (MASs) with input delays. The input-delayed MAS model is first converted into a delay-free form using a model reduction method. By establishing an equivalent relationship on the predesigned performance indices of the two MASs, optimal consensus control of input-delayed MAS can be fully transformed to that of delay-free MAS. Based on the coupled Hamilton-Jacobi equations and Bellman's optimality principle, optimal consensus control policies are derived for the transformed delay-free MAS. Then a policy iteration algorithm based on distributed asynchronous update mechanism is proposed to learn the coupled Hamilton-Jacobi-Bellman equations online. To perform the proposed data driven adaptive dynamic programming algorithm, we adopt the measured data-based critic-actor neural networks to approximate the value functions and the control policies, respectively. Finally, a simulation example is given to illustrate the effectiveness of the proposed method. PMID- 29993858 TI - Adaptive Fault Estimation for T-S Fuzzy Interconnected Systems Based on Persistent Excitation Condition via Reference Signals. AB - This paper is concerned with the fault estimation (FE) problem for a class of interconnected nonlinear systems described by Takagi-Sugeno fuzzy models. Different from the existing FE approaches, where the reference inputs are always viewed as external disturbances, the considered reference signals are injected directly in the controller to excite the system states to ensure persistent excitation condition. Within this framework, a bank of distributed adaptive observers are then designed to effectively estimate the actuator fault parameters even in the presence of nonlinear interconnections. Moreover, in the disturbance free case, by employing graph theory, a global Lyapunov function is constructed such that the corresponding fault parameter estimate errors are proved to be asymptotically convergent provided that the interconnected strengths are less than a given constant. Finally, two simulation examples are provided to demonstrate the validity of the presented FE scheme. PMID- 29993859 TI - Finite-Time Hinfinity Filtering for Nonlinear Singular Systems With Nonhomogeneous Markov Jumps. AB - This paper addresses the finite-time Hinfinity filtering for a class of nonlinear singular nonhomogeneous Markov jump systems by T-S fuzzy approximation approach, where the transition probabilities (TPs) are time-varying and unknown. First, by considering a stochastic Lyapunov functional and rendering the time-varying TPs inside a polytope, a sufficient condition on singular stochastic Hinfinity finite time boundedness (SSHinfinityFTB) for the filtering error systems is given. Then, by using the matrix inequality decoupling technique, a novel linear matrix inequality (LMI) condition on the existence of the finite-time Hinfinity fuzzy filter is presented. The fuzzy filter is developed in terms of LMIs ensuring the filtering error system is SSHinfinityFTB. Compared with the previous ones, the proposed design method in this paper has more freedom, leading to less conservative results. A tunnel diode circuit is provided to illustrate the effectiveness and advantage of the design approach proposed in this paper. PMID- 29993860 TI - Finite/Fixed-Time Pinning Synchronization of Complex Networks With Stochastic Disturbances. AB - This brief proposes a unified theoretical framework to investigate the finite/fixed-time synchronization of complex networks with stochastic disturbances. By designing a common pinning controller with different ranges of power parameters, both the goals of finite-time and fixed-time synchronization in probability for the network topology containing spanning trees can be achieved. Moveover, with the help of finite-time stochastic stability theory, two types of explicit expressions of finite/fixed (dependent/independent on the initial values) settling times are calculated as well. One numerical example is finally presented to demonstrate the effectiveness of the theoretical analysis. PMID- 29993861 TI - Recursive nearest agglomeration (ReNA): fast clustering for approximation of structured signals. AB - In this work, we revisit fast dimension reduction approaches, as with random projections and random sampling. Our goal is to summarize the data to decrease computational costs and memory footprint of subsequent analysis. Such dimension reduction can be very efficient when the signals of interest have a strong structure, such as with images. We focus on this setting and investigate feature clustering schemes for data reductions that capture this structure. An impediment to fast dimension reduction is then that good clustering comes with large algorithmic costs. We address it by contributing a linear-time agglomerative clustering scheme, Recursive Nearest Agglomeration (ReNA). Unlike existing fast agglomerative schemes, it avoids the creation of giant clusters. We empirically validate that it approximates the data as well as traditional variance-minimizing clustering schemes that have a quadratic complexity. In addition, we analyze signal approximation with feature clustering and show that it can remove noise, improving subsequent analysis steps. As a consequence, data reduction by clustering features with ReNA yields very fast and accurate models, enabling to process large datasets on budget. Our theoretical analysis is backed by extensive experiments on publicly-available data that illustrate the computation efficiency and the denoising properties of the resulting dimension reduction scheme. PMID- 29993862 TI - Deeply Supervised Salient Object Detection with Short Connections. AB - Recent progress on salient object detection is substantial, benefiting mostly from the explosive development of Convolutional Neural Networks (CNNs). Semantic segmentation and salient object detection algorithms developed lately have been mostly based on Fully Convolutional Neural Networks (FCNs). There is still a large room for improvement over the generic FCN models that do not explicitly deal with the scale-space problem. Holistically-Nested Edge Detector (HED) provides a skip-layer structure with deep supervision for edge and boundary detection, but the performance gain of HED on saliency detection is not obvious. In this paper, we propose a new salient object detection method by introducing short connections to the skip-layer structures within the HED architecture. Our framework takes full advantage of multi-level and multi-scale features extracted from FCNs, providing more advanced representations at each layer, a property that is critically needed to perform segment detection. Our method produces state-of the-art results on 5 widely tested salient object detection benchmarks, with advantages in terms of efficiency (0.08 seconds per image), effectiveness, and simplicity over the existing algorithms. Beyond that, we conduct an exhaustive analysis on the role of training data on performance. Our experimental results provide a more reasonable and powerful training set for future research and fair comparisons. PMID- 29993863 TI - Multi-Pass Fast Watershed for Accurate Segmentation of Overlapping Cervical Cells. AB - The task of segmenting cell nuclei and cytoplasm in pap smear images is one of the most challenging tasks in automated cervix cytological analysis due to specifically the presence of overlapping cells. This paper introduces a multi pass fast watershed-based method (MPFW) to segment both nucleus and cytoplasm from large cell masses of overlapping cervical cells in three watershed passes. The first pass locates the nuclei with barrier-based watershed on the gradient based edge map of a pre-processed image. The next pass segments the isolated, touching, and partially overlapping cells with a watershed transform adapted to the cell shape and location. The final pass introduces mutual iterative watersheds separately applied to each nucleus in the largely overlapping clusters to estimate the cell shape. In MPFW, the line-shaped contours of the watershed cells are deformed with ellipse fitting and contour adjustment to give a better representation of cell shapes. The performance of the proposed method has been evaluated using synthetic, real extended depth-of-field, and multi-layers cervical cytology images provided by the first and second overlapping cervical cytology image segmentation challenges in ISBI 2014 and ISBI 2015. The experimental results demonstrate superior performance of the proposed MPFW in terms of segmentation accuracy, detection rate, and time complexity, compared with recent peer methods. PMID- 29993864 TI - MR Performance in the Presence of a Radio Frequency-Penetrable Positron Emission Tomography (PET) Insert for Simultaneous PET/MRI. AB - Despite the great promise of integrated positron emission tomography (PET)/magnetic resonance (MR) imaging to add molecular information to anatomical and functional MR, its potential impact in medicine is diminished by a very high cost, limiting its dissemination. An RF-penetrable PET ring that can be inserted into any existing MR system has been developed to address this issue. Employing optical signal transmission along with battery power enables the PET ring insert to electrically float with respect to the MR system. Then, inter-modular gaps of the PET ring allow the RF transmit field from the standard built-in body coil to penetrate into the PET fields-of-view (FOV) with some attenuation that can be compensated for. MR performance, including RF noise, magnetic susceptibility, RF penetrability through and $B_{1}$ uniformity within the PET insert, and MR image quality, were analyzed with and without the PET ring present. The simulated and experimentally measured RF field attenuation factors with the PET ring present were -2.7 and -3.2 dB, respectively. The magnetic susceptibility effect (0.063 ppm) and noise emitted from the PET ring in the MR receive channel were insignificant. $B_{1}$ homogeneity of a spherical agar phantom within the PET ring FOV dropped by 8.4% and MR image SNR was reduced by 3.5 and 4.3 dB with the PET present for gradient-recalled echo and fast-spin echo, respectively. This paper demonstrates, for the first time, an RF-penetrable PET insert comprising a full ring of operating detectors that achieves simultaneous PET/MR using the standard built-in body coil as the RF transmitter. PMID- 29993865 TI - A Bayesian Approach to Eigenspectra Optoacoustic Tomography. AB - The quantification of hemoglobin oxygen saturation (sO2) with multispectral optoacoustic (OA) (photoacoustic) tomography (MSOT) is a complex spectral unmixing problem, since the OA spectra of hemoglobin are modified with tissue depth due to depth (location) and wavelength dependencies of optical fluence in tissue. In a recent work, a method termed eigenspectra MSOT (eMSOT) was proposed for addressing the dependence of spectra on fluence and quantifying blood sO2 in deep tissue. While eMSOT offers enhanced sO2 quantification accuracy over conventional unmixing methods, its performance may be compromised by noise and image reconstruction artifacts. In this paper, we propose a novel Bayesian method to improve eMSOT performance in noisy environments. We introduce a spectral reliability map, i.e., a method that can estimate the level of noise superimposed onto the recorded OA spectra. Using this noise estimate, we formulate eMSOT as a Bayesian inverse problem where the inversion constraints are based on probabilistic graphical models. Results based on numerical simulations indicate that the proposed method offers improved accuracy and robustness under high noise levels due the adaptive nature of the Bayesian method. PMID- 29993866 TI - Training Very Deep CNNs for General Non-Blind Deconvolution. AB - Non-blind image deconvolution is an ill-posed problem. The presence of noise and band-limited blur kernels makes the solution of this problem non-unique. Existing deconvolution techniques produce a residual between the sharp image and the estimation that is highly correlated with the sharp image, the kernel, and the noise. In most cases, different restoration models must be constructed for different blur kernels and different levels of noise, resulting in low computational efficiency or highly redundant model parameters. Here we aim to develop a single model that handles different types of kernels and different levels of noise: general non-blind deconvolution. Specifically, we propose a very deep convolutional neural network that predicts the residual between a pre deconvolved image and the sharp image rather than the sharp image. The residual learning strategy makes it easier to train a single model for different kernels and different levels of noise, encouraging high effectiveness and efficiency. Quantitative evaluations demonstrate the practical applicability of the proposed model for different blur kernels. The model also shows state-of-the-art performance on synthesized blurry images. PMID- 29993867 TI - Action-Attending Graphic Neural Network. AB - The motion analysis of human skeletons is crucial for human action recognition, which is one of the most active topics in computer vision. In this paper, we propose a fully end-to-end action-attending graphic neural network (A2GNN) for skeleton-based action recognition, in which each irregular skeleton is structured as an undirected attribute graph. To extract high-level semantic representation from skeletons, we perform the local spectral graph filtering on the constructed attribute graphs like the standard image convolution operation. Considering not all joints are informative for action analysis, we design an actionattending layer to detect those salient action units (AUs) by adaptively weighting skeletal joints. Herein the filtering responses are parameterized into a weighting function irrelevant to the order of input nodes. To further encode continuous motion variations, the deep features learnt from skeletal graphs are gathered along consecutive temporal slices and then fed into a recurrent gated network. Finally, the spectral graph filtering, action-attending and recurrent temporal encoding are integrated together to jointly train for the sake of robust action recognition as well as the intelligibility of human actions. To evaluate our A2GNN, we conduct extensive experiments on four benchmark skeletonbased action datasets, including the large-scale challenging NTU RGB+D dataset. The experimental results demonstrate that our network achieves the state-of-the-art performances. PMID- 29993868 TI - Supervised Polarimetric SAR Image Classification Using Tensor Local Discriminant Embedding. AB - Feature extraction is a very important step for polarimetric synthetic aperture radar (PolSAR) image classification. Many dimensionality reduction (DR) methods have been employed to extract features for supervised PolSAR image classification. However, these DR-based feature extraction methods only consider each single pixel independently and thus fail to take into account the spatial relationship of the neighboring pixels, so their performance may not be satisfactory. To address this issue, we introduce a novel tensor local discriminant embedding (TLDE) method for feature extraction for supervised PolSAR image classification. The proposed method combines the spatial and polarimetric information of each pixel by characterizing the pixel with the patch centered at this pixel. Then each pixel is represented as a third-order tensor, of which the first two modes indicate the spatial information of the patch (i.e. the row and the column of the patch) and the third mode denotes the polarimetric information of the patch. Based on the label information of samples and the redundance of the spatial and polarimetric information, a supervised tensor-based dimensionality reduction technique, called TLDE, is introduced to find three projections which project each pixel, that is, the third-order tensor into the low-dimensional feature. Finally, classification is completed based on the extracted features using the nearest neighbor (NN) classifier and the support vector machine (SVM) classifier. The proposed method is evaluated on two real PolSAR data sets and the simulated PolSAR data sets with various number of looks. The experimental results demonstrate that the proposed method not only improves the classification accuracy greatly, but also alleviates the influence of speckle noise on classification. PMID- 29993869 TI - A Skinned Tetrahedral Mesh for Hair Animation and Hair-Water Interaction. AB - We propose a novel framework for hair animation as well as hair-water interaction that supports millions of hairs. First, we develop a hair animation framework that embeds hair into a tetrahedralized volume mesh that we kinematically skin to deform and follow the exterior of an animated character. Creating a copy of the tetrahedral mesh, endowing it with springs, and attaching it to the kinematically skinned mesh creates more dynamic behavior. Notably, the springs can be quite weak and thus efficient to simulate because they are structurally supported by the kinematic mesh. If independent simulation of individual hairs or guide hairs is desired, they too benefit from being anchored to the kinematic mesh dramatically increasing efficiency as weak springs can be used while still supporting interesting and dramatic hairstyles. Furthermore, we explain how to embed these dynamic simulations into the kinematically deforming skinned mesh so that they can be used as part of a blendshape system where an artist can make many subsequent iterations without requiring any additional simulation. We discuss hair-water interaction as well, how porosities are stored in the kinematic mesh, how the kinematically deforming mesh can be used to apply drag and adhesion forces to the water, etc. PMID- 29993870 TI - A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling. AB - Tumor-treating fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (~100-500 kHz) and low intensity (1-3 V/cm) to disrupt cell division. TTFields are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth. TTFields therapy is U.S. Food and Drug Administration approved for the treatment of glioblastoma multiforme, the most common and aggressive primary human brain cancer. Clinical trials testing the safety and efficacy of TTFields for other solid tumor types are underway. The objective of this paper is to review computational approaches used to characterize TTFields. The review covers studies of the macroscopic spatial distribution of TTFields generated in the human head, and of the microscopic field distribution in tumor cells. In addition, preclinical and clinical findings related to TTFields and principles of its operation are summarized. Particular emphasis is put on outlining the potential clinical value inferred from computational modeling. PMID- 29993871 TI - A Block EM Algorithm for Multivariate Skew Normal and Skew -Mixture Models. AB - Finite mixtures of skew distributions provide a flexible tool for modeling heterogeneous data with asymmetric distributional features. However, parameter estimation via the Expectation-Maximization (EM) algorithm can become very time consuming due to the complicated expressions involved in the E-step that are numerically expensive to evaluate. While parallelizing the EM algorithm can offer considerable speedup in time performance, current implementations focus almost exclusively on distributed platforms. In this paper, we consider instead the most typical operating environment for users of mixture models-a standalone multicore machine and the R programming environment. We develop a block implementation of the EM algorithm that facilitates the calculations on the E- and M-steps to be spread across a number of threads. We focus on the fitting of finite mixtures of multivariate skew normal and skew distributions, and show that both the E- and M steps in the EM algorithm can be modified to allow the data to be split into blocks. Our approach is easy to implement and provides immediate benefits to users of multicore machines. Experiments were conducted on two real data sets to demonstrate the effectiveness of the proposed approach. PMID- 29993872 TI - New Discrete-Time ZNN Models for Least-Squares Solution of Dynamic Linear Equation System With Time-Varying Rank-Deficient Coefficient. AB - In this brief, a new one-step-ahead numerical differentiation rule called six instant -cube finite difference (6I CFD) formula is proposed for the first-order derivative approximation with higher precision than existing finite difference formulas (i.e., Euler and Taylor types). Subsequently, by exploiting the proposed 6I CFD formula to discretize the continuous-time Zhang neural network model, two new-type discrete-time ZNN (DTZNN) models, namely, new-type DTZNNK and DTZNNU models, are designed and generalized to compute the least-squares solution of dynamic linear equation system with time-varying rank-deficient coefficient in real time, which is quite different from the existing ZNN-related studies on solving continuous-time and discrete-time (dynamic or static) linear equation systems in the context of full-rank coefficients. Specifically, the corresponding dynamic normal equation system, of which the solution exactly corresponds to the least-squares solution of dynamic linear equation system, is elegantly introduced to solve such a rank-deficient least-squares problem efficiently and accurately. Theoretical analyses show that the maximal steady-state residual errors of the two new-type DTZNN models have an pattern, where denotes the sampling gap. Comparative numerical experimental results further substantiate the superior computational performance of the new-type DTZNN models to solve the rank deficient least-squares problem of dynamic linear equation systems. PMID- 29993873 TI - A Unifying Objective Function of Independent Component Analysis for Ordering Sources by Non-Gaussianity. AB - The independent component analysis (ICA) is a widely used method for solving blind separation problems. The ICA assumes that the sources are independent of each other and extracts them by maximizing their non-Gaussianity as the objective function. There are the two types of non-Gaussianity of the sources (the super Gaussian type with the positive kurtosis and the sub-Gaussian one with the negative kurtosis). In this paper, we propose a new objective function unifying the two types of non-Gaussianity naturally, which is derived by applying the Gaussian approximation to the distribution of sources in the second-order polynomial feature space. The proposed objective function [called the adaptive ICA function (AIF)] is a simple form given as a summation of weighted fourth order statistics, where the weights are adaptively estimated by the current kurtoses. The first practical advantage of the AIF is that it can extract the sources one by one in the descending order of the criterion of non-Gaussianity. It can solve the permutation ambiguity problem. The second and more important advantage is that it can estimate the number of non-Gaussian sources by the Akaike information criterion irrespective of the specific form of their distributions. In order to utilize the above-mentioned advantages of the AIF, we construct a new algorithm named the ordering ICA by extending the fast ICA. Experimental results verify that the ordering ICA can estimate the number of non Gaussian sources correctly in both artificial and real data sets. PMID- 29993874 TI - Band-Limited Stokes Large Deformation Diffeomorphic Metric Mapping. AB - The class of registration methods proposed in the framework of Stokes Large Deformation Diffeomorphic Metric Mapping is a particularly interesting family of physically meaningful diffeomorphic registration methods. Stokes-LDDMM methods are formulated as constrained variational problems, where the different physical models are imposed using the associated partial differential equations as hard constraints. The most significant limitation of Stokes-LDDMM framework is its huge computational complexity. The objective of this work is to promote the use of Stokes-LDDMM in Computational Anatomy applications with an efficient approximation of the original variational problem. Thus, we propose a novel method for efficient Stokes-LDDMM diffeomorphic registration. Our method poses the constrained variational problem in the space of band-limited vector fields and it is implemented in the GPU. The performance of Band-Limited Stokes-LDDMM has been compared and evaluated with original Stokes-LDDMM, EPDiff-LDDMM, and Band-Limited EPDiff-LDDMM. The evaluation has been conducted in 3D with the Non Rigid Image Registration Evaluation Project database. Since the update equation in Stokes-LDDMM involves the action of low-pass filters, the computational complexity has been greatly alleviated with a modest accuracy lose. We have obtained a competitive performance for some method configurations. Overall, our proposed method may make feasible the extensive use of novel physically meaningful Stokes-LDDMM methods in different Computational Anatomy applications. In addition, our results reinforce the usefulness of band-limited vector fields in diffeomorphic registration methods involving the action of low-pass filters in the optimization, even in algorithmically challenging environments such as Stokes LDDMM. PMID- 29993875 TI - Tracking Control of a Class of Cyber-Physical Systems via a FlexRay Communication Network. AB - Due to properties of flexibility, adaptiveness, error tolerance, and time determinism performance, the FlexRay communication protocol has been widely used to investigate robot systems and new generation of automobiles. In this paper, with the FlexRay communication protocol, the tracking problem of a class of cyber physical systems are investigated by developing a general hybrid model, in which an emulation controller is utilized. Based on the proposed hybrid model, some sufficient conditions are established to guarantee the convergence of tracking errors. Then, the maximum allowable transmission interval (MATI) of the static/dynamic segment is obtained with a more general formula than the ones in some the previous works. The obtained MATI over the FlexRay communication network can be adjusted via the appropriate length of the static/dynamic segment, which reflects the flexibility of FlexRay. Finally, the results are verified by considering the tracking problem of a single-link robot arm system as well as the stabilization of a batch reactor system. PMID- 29993876 TI - An Adaptive Framework to Tune the Coordinate Systems in Nature-Inspired Optimization Algorithms. AB - The performance of many nature-inspired optimization algorithms (NIOAs) depends strongly on their implemented coordinate system. However, the commonly used coordinate system is fixed and not well suited for different function landscapes, NIOAs thus might not search efficiently. To overcome this shortcoming, in this paper we propose a framework, named ACoS, to adaptively tune the coordinate systems in NIOAs. In ACoS, an Eigen coordinate system is established by making use of the cumulative population distribution information, which can be obtained based on a covariance matrix adaptation strategy and an additional archiving mechanism. Since the population distribution information can reflect the features of the function landscape to some extent, NIOAs in the Eigen coordinate system have the capability to identify the modality of the function landscape. In addition, the Eigen coordinate system is coupled with the original coordinate system, and they are selected according to a probability vector. The probability vector aims to determine the selection ratio of each coordinate system for each individual, and is adaptively updated based on the collected information from the offspring. ACoS has been applied to two of the most popular paradigms of NIOAs, i.e., particle swarm optimization and differential evolution, for solving 30 test functions with 30D and 50D at the 2014 IEEE Congress on Evolutionary Computation. The experimental studies demonstrate its effectiveness. PMID- 29993877 TI - Evolutionary Optimization of Expensive Multiobjective Problems With Co-Sub-Pareto Front Gaussian Process Surrogates. AB - This paper proposes a Gaussian process (GP) based co-sub-Pareto front surrogate augmentation strategy for evolutionary optimization of computationally expensive multiobjective problems. In the proposed algorithm, a multiobjective problem is decomposed into a number of subproblems, the solution of each of which is used to approximate a portion or sector of the Pareto front (i.e., a subPF). Thereafter, a multitask GP model is incorporated to exploit the correlations across the subproblems via joint surrogate model learning. A novel criterion for the utility function is defined on the surrogate landscape to determine the next candidate solution for evaluation using the actual expensive objectives. In addition, a new management strategy for the evaluated solutions is presented for model building. The novel feature of our approach is that it infers multiple subproblems jointly by exploiting the possible dependencies between them, such that knowledge can be transferred across subPFs approximated by the subproblems. Experimental studies under several scenarios indicate that the proposed algorithm outperforms state-of the-art multiobjective evolutionary algorithms for expensive problems. The parameter sensitivity and effectiveness of the proposed algorithm are analyzed in detail. PMID- 29993878 TI - LRR for Subspace Segmentation via Tractable Schatten-$p$ Norm Minimization and Factorization. AB - Recently, nuclear norm-based low rank representation (LRR) methods have been popular in several applications, such as subspace segmentation. However, there exist two limitations: one is that nuclear norm as the relaxation of rank function will lead to the suboptimal solution since nuclear norm-based minimization subproblem tends to the over-relaxations of singular value elements and treats each of them equally; the other is that solving LRR problems may cause more time consumption due to involving singular value decomposition of the large scale matrix at each iteration. To overcome both disadvantages, this paper mainly considers two tractable variants of LRR: one is Schatten-p norm minimization based LRR (i.e., SpNM_LRR) and the other is Schatten-p norm factorization-based LRR (i.e., SpNFLRR) for p=1, 2/3 and 1/2. By introducing two or more auxiliary variables in the constraints, the alternating direction method of multiplier (ADMM) with multiple updating variables can be devised to solve these variants of LRR. Furthermore, both computational complexity and convergence property are given to evaluate nonconvex multiblocks ADMM algorithms. Several experiments finally validate the efficacy and efficiency of our methods on both synthetic data and real world data. PMID- 29993879 TI - What Makes Objects Similar: A Unified Multi-Metric Learning Approach. AB - Linkages are essentially determined by similarity measures that may be derived from multiple perspectives. For example, spatial linkages are usually generated based on localities of heterogeneous data. Semantic linkages, however, can come from even more properties, such as different physical meanings behind social relations. Many existing metric learning models focus on spatial linkages but leave the rich semantic factors unconsidered. We propose a Unified Multi-Metric Learning framework to exploit multiple types of metrics with respect to overdetermined similarities between linkages. In , a type of combination operator is introduced for distance characterization from multiple perspectives, and thus can introduce flexibilities for representing and utilizing both spatial and semantic linkages. Besides, we propose a uniform solver for , and the theoretical analysis reflects the generalization ability of as well. Extensive experiments on diverse applications exhibit the superior classification performance and comprehensibility of . Visualization results also validate its ability on physical meanings discovery. PMID- 29993880 TI - Unsupervised Deep Learning of Compact Binary Descriptors. AB - Binary descriptors have been widely used for efficient image matching and retrieval. However, most existing binary descriptors are designed with hand-craft sampling patterns or learned with label annotation provided by datasets. In this paper, we propose a new unsupervised deep learning approach, called DeepBit, to learn compact binary descriptor for efficient visual object matching. We enforce three criteria on binary descriptors which are learned at the top layer of the deep neural network: 1) minimal quantization loss, 2) evenly distributed codes and 3) transformation invariant bit. Then, we estimate the parameters of the network through the optimization of the proposed objectives with a back propagation technique. Extensive experimental results on various visual recognition tasks demonstrate the effectiveness of the proposed approach. We further demonstrate our proposed approach can be realized on the simplified deep neural network, and enables efficient image matching and retrieval speed with very competitive accuracies. PMID- 29993881 TI - Evaluation and Stability Analysis of Video-Based Navigation System for Functional Endoscopic Sinus Surgery on In Vivo Clinical Data. AB - Functional endoscopic sinus surgery (FESS) is one of the most common outpatient surgical procedures performed in the head and neck region. It is used to treat chronic sinusitis, a disease characterized by inflammation in the nose and surrounding paranasal sinuses, affecting about 15% of the adult population. During FESS, the nasal cavity is visualized using an endoscope, and instruments are used to remove tissues that are often within a millimeter of critical anatomical structures, such as the optic nerve, carotid arteries, and nasolacrimal ducts. To maintain orientation and to minimize the risk of damage to these structures, surgeons use surgical navigation systems to visualize the 3-D position of their tools on patients' preoperative Computed Tomographies (CTs). This paper presents an image-based method for enhanced endoscopic navigation. The main contributions are: (1) a system that enables a surgeon to asynchronously register a sequence of endoscopic images to a CT scan with higher accuracy than other reported solutions using no additional hardware; (2) the ability to report the robustness of the registration; and (3) evaluation on in vivo human data. The system also enables the overlay of anatomical structures, visible, or occluded, on top of video images. The methods are validated on four different data sets using multiple evaluation metrics. First, for experiments on synthetic data, we observe a mean absolute position error of 0.21mm and a mean absolute orientation error of 2.8 degrees compared with ground truth. Second, for phantom data, we observe a mean absolute position error of 0.97mm and a mean absolute orientation error of 3.6 degrees compared with the same motion tracked by an electromagnetic tracker. Third, for cadaver data, we use fiducial landmarks and observe an average reprojection distance error of 0.82mm. Finally, for in vivo clinical data, we report an average ICP residual error of 0.88mm in areas that are not composed of erectile tissue and an average ICP residual error of 1.09mm in areas that are composed of erectile tissue. PMID- 29993882 TI - Effect of Spectral Degradation and Spatio-Energy Correlation in X-Ray PCD for Imaging. AB - Charge sharing, scatter, and fluorescence events in a photon counting detector can result in counting of a single incident photon in multiple neighboring pixels, each at a fraction of the true energy. This causes energy distortion and correlation of data across energy bins in neighboring pixels (spatio-energy correlation), with the severity depending on the detector pixel size and detector material. If a "macro-pixel" is formed by combining the counts from multiple adjacent small pixels, it will exhibit correlations across its energy bins. Understanding these effects can be crucial for detector design and for model based imaging applications. This paper investigates the impact of these effects in basis material and effective monoenergetic estimates using the Cramer-Rao Lower Bound. To do so, we derive a correlation model for the multi-counting events. CdTe detectors with grids of pixels with side length of $250~?mu ?text{m}$ , $500~?mu ?text{m}$ , and 1 mm were compared, with binning of $4?times4$ , $2?times2$ , and $1?times1$ pixels, respectively, to keep the same net 1 mm2 aperture constant. The same flux was applied to each. The mean and covariance matrix of measured photon counts were derived analytically using spatio-energy response functions precomputed from Monte Carlo simulations. Our results show that a 1 mm2 macro-pixel with $250?times 250?,?,?mu ?text{m}^{?textsf {2}}$ sub-pixels shows 35% higher standard deviation than a single 1 mm2 pixel for material-specific imaging, while the penalty for effective monoenergetic imaging is <10% compared with a single 1 mm $^{?textsf {2}}$ pixel. Potential benefits of sub-pixels (higher spatial resolution and lower pulse pile up effects) are important but were not investigated here. PMID- 29993883 TI - Extracting Blood Vessels From Full-Field OCT Data of Human Skin by Short-Time RPCA. AB - Recent advances in optical coherence tomography (OCT) lead to the development of OCT angiography to provide additional helpful information for diagnosis of diseases like basal cell carcinoma. In this paper, we investigate how to extract blood vessels of human skin from full-field OCT (FF-OCT) data using the robust principal component analysis (RPCA) technique. Specifically, we propose a short time RPCA method that divides the FF-OCT data into segments and decomposes each segment into a low-rank structure representing the relatively static tissues of human skin and a sparse matrix representing the blood vessels. The method mitigates the problem associated with the slow-varying background and is free of the detection error that RPCA may have when dealing with FF-OCT data. Both short time RPCA and RPCA methods can extract blood vessels from FF-OCT data with heavy speckle noise, but the former takes only half the computation time of the latter. We evaluate the performance of the proposed method by comparing the extracted blood vessels with the ground truth vessels labeled by a dermatologist and show that the proposed method works equally well for FF-OCT volumes of different quality. The average F-measure improvements over the correlation-mapping OCT method, the modified amplitude-decorrelation OCT angiography method, and the RPCA method, respectively, are 0.1835, 0.1032, and 0.0458. PMID- 29993884 TI - Micro-beamforming with Error Compensation. AB - One of the main issues in the development of 2D arrays is the high system complexity due to the requirement for a large number of elements. 2D array systems suffer from high system complexity. Micro-beamforming (MBF) method has been proposed to reduce the system complexity; however, distortions of MBF approach such as focusing errors of post-beamforming process results in broadening the main lobe and increasing the side-lobe and grating-lobe levels, which together degrade the image quality. As the pre-steered radio-frequency (RF) data can be estimated from MBF data at the digital back end, better post beamforming can be performed and higher image quality can be achieved. In this study, a compensation approach is proposed to estimate the pre-steered RF data from MBF data by utilizing additional headers and compensation factors. The compensation factors and headers are estimated at the probe front end and then applied to the back-end digital system to reconstruct the required pre-steered RF data. As the absolute values of the MBF errors are modeled as a single-sided Gaussian distribution, the theoretical mean square error (MSE) with the proposed method is approximately 2.75 times lower than that of its counterpart without compensation; this implies better reconstruction of pre-steered RF data can be achieved with the proposed method. The simulation results showed that the main lobe is improved, and the side-lobe and grating-lobe levels in both the lateral and elevation directions were improved by 11.73 dB and 19.12 dB, respectively, while the peak signal-to-noise ratios improved by 6-9 dB with the proposed method. The contrast-to-noise ratios also are enhanced by 0.5 dB when using the proposed method. Analog circuits are presented to demonstrate that this novel compensation method can be realized in practice. The reduction of cables and analog-to-digital converters (ADCs) are about 7-fold compared to fully-sampled 2D array systems as 4 by 4 channels are grouped for the proposed method as well. PMID- 29993885 TI - Visual Saliency Prediction Using a Mixture of Deep Neural Networks. AB - Visual saliency models have recently begun to incorporate deep learning to achieve predictive capacity much greater than previous unsupervised methods. However, most existing models predict saliency without explicit knowledge of global scene semantic information. We propose a model (MxSalNet) that incorporates global scene semantic information in addition to local information gathered by a convolutional neural network. Our model is formulated as a mixture of experts. Each expert network is trained to predict saliency for a set of closely related images. The final saliency map is computed as a weighted mixture of the expert networks' output, with weights determined by a separate gating network. This gating network is guided by global scene information to predict weights. The expert networks and the gating network are trained simultaneously in an end-toend manner. We show that our mixture formulation leads to improvement in performance over an otherwise identical nonmixture model that does not incorporate global scene information. Additionally, we show that our model achieves better performance than several other visual saliency models. PMID- 29993886 TI - Real-time External Labeling of Ghosted Views. AB - We present a new algorithm for calculating the external labeling of ghosted views of moderately complex 3D models. The algorithm uses multiple criteria decision making, based on fuzzy logic, to optimize positions of the labels associated with different parts of the input model. The proposed method can be used with various existing algorithms for creating ghosted views from 3D models. The method operates in real-time, which allows the user to acquire a good understanding of the structure of the input model by studying the model and its labels from different viewpoints. We have conducted a user study to evaluate label layouts produced by our algorithm and those created by humans. The results show that the proposed method can significantly improve user understanding of labeled ghosted views of complicated 3D models, and its label layouts are comparable with label layouts created by humans. PMID- 29993887 TI - Bridging Text Visualization and Mining: A Task-Driven Survey. AB - Visual text analytics has recently emerged as one of the most prominent topics in both academic research and the commercial world. To provide an overview of the relevant techniques and analysis tasks, as well as the relationships between them, we comprehensively analyzed 263 visualization papers and 4,346 mining papers published between 1992-2017 in two fields: visualization and text mining. From the analysis, we derived around 300 concepts (visualization techniques, mining techniques, and analysis tasks) and built a taxonomy for each type of concept. The co-occurrence relationships between the concepts were also extracted. Our research can be used as a stepping-stone for other researchers to 1) understand a common set of concepts used in this research topic; 2) facilitate the exploration of the relationships between visualization techniques, mining techniques, and analysis tasks; 3) understand the current practice in developing visual text analytics tools; 4) seek potential research opportunities by narrowing the gulf between visualization and mining techniques based on the analysis tasks; and 5) analyze other interdisciplinary research areas in a similar way. We have also contributed a web-based visualization tool for analyzing and understanding research trends and opportunities in visual text analytics. PMID- 29993888 TI - A Composite Mode Differential Gene Regulatory Architecture based on Temporal Expression Profiles. AB - Exploring the complex interactive mechanism in a Gene Regulatory Network (GRN) developed using transcriptome data obtained from standard microarray and/or RNA seq experiments helps us to understand the triggering factors in cancer research. The Transcription Factor (TF) genes generate protein complexes which affect the transcription of various target genes. However, considering the mode of regulation in a time frame such transcriptional activities are dependent on some specific activation time points only. It is also crucial to check whether the regulating capabilities are uniform across varied conditions, especially when periodicity is a big issue. In this context, we propose an algorithm called RIFT which helps to monitor the temporal differential regulatory pattern of a Differentially Expressed (DE) target gene either by a TF gene or a group of TF genes from a large time series (TS) data. We have tested our algorithm on HeLa cell cycle data and compared the result with its most advanced state of the art counterpart proposed so far. As our algorithm yields up stringent mode and target specific significant valid TF genes for a DE gene, we can expect to have new forms of genetic interactions. PMID- 29993889 TI - A distributed feature selection algorithm based on distance correlation with an application to microarrays. AB - DNA microarray datasets are characterized by a large number of features with very few samples, which is a typical cause of overfitting and poor generalization in the classification task. Here we introduce a novel feature selection (FS) approach which employs the distance correlation (dCor) as a criterion for evaluating the dependence of the class on a given feature subset. The dCor index provides a reliable dependence measure among random vectors of arbitrary dimension, without any assumption on their distribution. Moreover, it is sensitive to the presence of redundant terms. The proposed FS method is based on a probabilistic representation of the feature subset model, which is progressively refined by a repeated process of model extraction and evaluation. A key element of the approach is a distributed optimization scheme based on a vertical partitioning of the dataset, which alleviates the negative effects of its unbalanced dimensions. The proposed method has been tested on several microarray datasets, resulting in quite compact and accurate models obtained at a reasonable computational cost. PMID- 29993890 TI - Identifying Candidate Genetic Associations with MRI-derived AD-related ROI via Tree-guided Sparse Learning. AB - Imaging genetics has attracted significant interests in recent studies. Traditional work has focused on univariate statistical approaches that identify important single nucleotide polymorphisms (SNPs) associated with quantitative traits (QTs). Recently, to address the problem of multiple comparison and weak detection, multivariate analysis methods such as Lasso are often used for selecting the most relevant SNPs associated with QTs. However, one problem of Lasso based feature selection methods for imaging genetics is that priori information, i.e., the hierarchical structure among SNPs are rarely used for designing powerful model. In this paper, we propose to identify the associations between candidate genetic features (i.e., SNPs) and MRI-derived measures using a tree-guided sparse learning (TGSL) method. The advantage of our method is that it explicitly models the complex hierarchical structure among the SNPs. Specifically, motivated by the biological phenomenon, the hierarchical structures involving gene groups, LD blocks and individual SNPs are imposed as a tree-guided regularization term in TGSL model. Experimental results on simulation and the ADNI database studies show that our method not only achieves better predictions than competing methods on the MRI-derived measures of AD-related ROIs, but also identifies sparse SNP patterns at the block level to better guide the biological interpretation. PMID- 29993891 TI - Identifying gene network rewiring by combining gene expression and gene mutation data. AB - Understanding how gene dependency networks rewire between different disease states is an important task in genomic research. Although many computational methods have been proposed to undertake this task via differential network analysis, most of them are designed for a predefined data type. With the development of the high throughput technologies, gene activity measurements can be collected from different aspects (e.g., mRNA expression and DNA mutation). Different data types might share some common characteristics and include certain unique properties. New methods are needed to explore the similarity and difference between differential networks estimated from different data types. In this study, we develop a new differential network inference model which identifies gene network rewiring by combining gene expression and gene mutation data. Similarity and difference between different data types are learned via a group bridge penalty function. Simulation studies have demonstrated that our method consistently outperforms the competing methods. We also apply our method to identify gene network rewiring associated with ovarian cancer platinum resistance. There are certain differential edges common to both data types and some differential edges unique to individual data types. Hub genes in the differential networks inferred by our method play important roles in ovarian cancer drug resistance. PMID- 29993892 TI - Estimation of the Cardiac Field in the Esophagus Using a Multipolar Esophageal Catheter. AB - The rapid progress of invasive therapeutic options for cardiac arrhythmias increases the need for accurate diagnostics. The surface electrocardiogram (ECG) is still the standard of noninvasive diagnostics but lacks atrial signal resolution. By contrast, esophageal electrocardiography (EECG) yields atrial signals of high amplitude and with a high signal-to-noise ratio. Esophageal electrocardiography has become fast and safe, but the mechanical constraints of esophageal measuring catheters and the "random" motion of the catheter inside the subject's esophagus limit the spatial resolution of EECG signals. In this paper, we propose a method to estimate the electrical field projected onto the esophagus with an increased spatial resolution, using commonly available esophageal catheters. In a first step, we estimate the time-varying catheter position, and in a second step, we estimate the projected electrical field with enhanced spatial resolution. The proposed algorithm comprises several consecutive optimization steps, where each intermediate step produces not just a single point estimate, but a cost function over multiple solutions, which reduces the information loss at each processing step. We conclude with examples from a clinical trial, where the fields of cardiac arrhythmias are presented as two dimensional contour plots. PMID- 29993893 TI - A Real-Time QRS Detection System With PR/RT Interval and ST Segment Measurements for Wearable ECG Sensors Using Parallel Delta Modulators. AB - This paper presents a real-time electrocardiogram (ECG) monitoring system for wearable devices. The system is based on the proposed parallel delta modulator architecture with local maximum point and local minimum point algorithms to detect QRS and PT waves. Therefore, using the proposed system and algorithm, real time PR and RT intervals, and ST segment measurements can be achieved in long term wearable ECG recording. The algorithm is tested with the MIT-BIH Arrhythmia Database for QRS complex detection and with the QT Database for the P and T wave detections. The simulation result shows that the algorithm achieves above 99%, 91%, and 98% accuracy in the QRS complex, P wave, and T wave detections, respectively. Experimental results are presented from the system prototype, in which the parallel delta modulator circuits are fabricated in IBM 0.13 $?mu ?text{m}$ standard CMOS technology and the algorithms are implemented in a Xilinx Spartan-6 field programmable gate array (FPGA). The parallel delta modulators consume 720 nW at 1 kHz sampling rate with $?pm$0.6 V power supply. The proposed system has the potential to be applied in future long-term wearable ECG recording devices. PMID- 29993894 TI - Online Obstructive Sleep Apnea Detection on Medical Wearable Sensors. AB - Obstructive Sleep Apnea (OSA) is one of the main under-diagnosed sleep disorder. It is an aggravating factor for several serious cardiovascular diseases, including stroke. There is, however, a lack of medical devices for long-term ambulatory monitoring of OSA since current systems are rather bulky, expensive, intrusive, and cannot be used for long-term monitoring in ambulatory settings. In this paper, we propose a wearable, accurate, and energy efficient system for monitoring obstructive sleep apnea on a long-term basis. As an embedded system for Internet of Things, it reduces the gap between home health-care and professional supervision. Our approach is based on monitoring the patient using a single-channel electrocardiogram signal. We develop an efficient time-domain analysis to meet the stringent resources constraints of embedded systems to compute the sleep apnea score. Our system, for a publicly available database (PhysioNet Apnea-ECG), has a classification accuracy of up to 88.2% for our new online and patient-specific analysis, which takes the distinct profile of each patient into account. While accurate, our approach is also energy efficient and can achieve a battery lifetime of 46 days for continuous screening of OSA. PMID- 29993895 TI - Editorial Special Issue on Deep Reinforcement Learning and Adaptive Dynamic Programming. AB - The sixteen papers in this special section focus on deep reinforcement learning and adaptive dynamic programming (deep RL/ADP). Deep RL is able to output control signal directly based on input images, which incorporates both the advantages of the perception of deep learning (DL) and the decision making of RL or adaptive dynamic programming (ADP). This mechanism makes the artificial intelligence much closer to human thinking modes. Deep RL/ADP has achieved remarkable success in terms of theory and applications since it was proposed. Successful applications cover video games, Go, robotics, smart driving, healthcare, and so on. However, it is still an open problem to perform the theoretical analysis on deep RL/ADP, e.g., the convergence, stability, and optimality analyses. The learning efficiency needs to be improved by proposing new algorithms or combined with other methods. More practical demonstrations are encouraged to be presented. Therefore, the aim of this special issue is to call for the most advanced research and state-of-the-art works in the field of deep RL/ADP. PMID- 29993896 TI - Observability of Boolean Control Networks Using Parallel Extension and Set Reachability. AB - This brief reviews various definitions of observability for Boolean control networks (BCNs) and proposes a new one: output-feedback observability. This new definition applies to all BCNs whose initial states can be identified from the history of output measurements. A technique called parallel extension is then proposed to facilitate observability analysis. Furthermore, a technique called state transition graph reconstruction is proposed for analyzing the set reachability of BCNs, based on which new criteria for observability, single-input sequence observability, and arbitrary-input observability, are obtained. Using the proposed techniques, this brief proves that the problem of output-feedback observability can be recast as that of stabilizing a logic dynamical system with output feedback. Then, a necessary and sufficient condition for static output feedback observability is proposed. The relationships between the different definitions of observability are discussed, and the main results are illustrated with examples. PMID- 29993897 TI - Postboosting Using Extended G-Mean for Online Sequential Multiclass Imbalance Learning. AB - In this paper, a novel learning method called postboosting using extended G-mean (PBG) is proposed for online sequential multiclass imbalance learning (OS-MIL) in neural networks. PBG is effective due to three reasons. 1) Through postadjusting a classification boundary under extended G-mean, the challenging issue of imbalanced class distribution for sequentially arriving multiclass data can be effectively resolved. 2) A newly derived update rule for online sequential learning is proposed, which produces a high G-mean for current model and simultaneously possesses almost the same information of its previous models. 3) A dynamic adjustment mechanism provided by extended G-mean is valid to deal with the unresolved challenging dense-majority problem and two dynamic changing issues, namely, dynamic changing data scarcity (DCDS) and dynamic changing data diversity (DCDD). Compared to other OS-MIL methods, PBG is highly effective on resolving DCDS, while PBG is the only method to resolve dense-majority and DCDD. Furthermore, PBG can directly and effectively handle unscaled data stream. Experiments have been conducted for PBG and two popular OS-MIL methods for neural networks under massive binary and multiclass data sets. Through the analyses of experimental results, PBG is shown to outperform the other compared methods on all data sets in various aspects including the issues of data scarcity, dense majority, DCDS, DCDD, and unscaled data. PMID- 29993898 TI - First-Spike-Based Visual Categorization Using Reward-Modulated STDP. AB - Reinforcement learning (RL) has recently regained popularity with major achievements such as beating the European game of Go champion. Here, for the first time, we show that RL can be used efficiently to train a spiking neural network (SNN) to perform object recognition in natural images without using an external classifier. We used a feedforward convolutional SNN and a temporal coding scheme where the most strongly activated neurons fire first, while less activated ones fire later, or not at all. In the highest layers, each neuron was assigned to an object category, and it was assumed that the stimulus category was the category of the first neuron to fire. If this assumption was correct, the neuron was rewarded, i.e., spike-timing-dependent plasticity (STDP) was applied, which reinforced the neuron's selectivity. Otherwise, anti-STDP was applied, which encouraged the neuron to learn something else. As demonstrated on various image data sets (Caltech, ETH-80, and NORB), this reward-modulated STDP (R-STDP) approach has extracted particularly discriminative visual features, whereas classic unsupervised STDP extracts any feature that consistently repeats. As a result, R-STDP has outperformed STDP on these data sets. Furthermore, R-STDP is suitable for online learning and can adapt to drastic changes such as label permutations. Finally, it is worth mentioning that both feature extraction and classification were done with spikes, using at most one spike per neuron. Thus, the network is hardware friendly and energy efficient. PMID- 29993899 TI - Consensus Problems Over Cooperation-Competition Random Switching Networks With Noisy Channels. AB - In this paper, distributed iterative algorithms for consensus problems are considered for multiagent networks. Each agent randomly contacts with other agents at each instant and receives corrupted information due to the noisy channel from its neighborhood. Neighbors of each agent are cooperative or competitive, i.e., the elements in the adjacent weight matrix may be positive or negative. In such a framework, asymptotic consensus and mean square consensus problems are investigated, based on random graph theory and stochastic stability theory. The control gains have been designed such that cooperation-competition random multiagent networks can reach almost sure consensus and mean square consensus. Simulation examples are finally given to illustrate the effectiveness of the obtained results. PMID- 29993900 TI - Transfer Hashing: From Shallow to Deep. AB - One major assumption used in most existing hashing approaches is that the domain of interest (i.e., the target domain) could provide sufficient training data, either labeled or unlabeled. However, this assumption may be violated in practice. To address this so-called data sparsity issue in hashing, a new framework termed transfer hashing with privileged information (THPI) is proposed, which marriages hashing and transfer learning (TL). To show the efficacy of THPI, we propose three variants of the well-known iterative quantization (ITQ) as a showcase. The proposed methods, ITQ+, LapITQ+, and deep transfer hashing (DTH), solve the aforementioned data sparsity issue from different aspects. Specifically, ITQ+ is a shallow model, which makes ITQ achieve hashing in a TL manner. ITQ+ learns a new slack function from the source domain to approximate the quantization error on the target domain given by ITQ. To further improve the performance of ITQ+, LapITQ+ is proposed by embedding the geometric relationship of the source domain into the target domain. Moreover, DTH is proposed to show the generality of our framework by utilizing the powerful representative capacity of deep learning. To the best of our knowledge, this could be one of the first DTH works. Extensive experiments on several popular data sets demonstrate the effectiveness of our shallow and DTH approaches comparing with several state-of the-art hashing approaches. PMID- 29993901 TI - Data-driven predictive models of diffuse low-grade gliomas under chemotherapy. AB - Diffuse Low-Grade Gliomas (DLGG) are brain tumors of young adults. They affect the quality of life of the inflicted patients and, if untreated, they evolve into higher grade tumors where the patient's life is at risk. Therapeutic management of DLGGs includes chemotherapy, and tumor diameter is particularly important for the follow-up of DLGG evolution. In fact, the main clinical basis for deciding whether to continue chemotherapy is tumor diameter growth rate. In order to reliably assist the doctors in selecting the most appropriate time to stop treatment, we propose a novel clinical decision support system. Based on two mathematical models, one linear and one exponential, we are able to predict the evolution of tumor diameter under Temozolomide chemotherapy as a first treatment and thus offer a prognosis on when to end it. We present the results of an implementation of these models on a database of 42 patients from Nancy and Montpellier University Hospitals. In this database, 38 patients followed the linear model and four patients followed the exponential model. From a training dataset of a minimal size of five, we are able to predict the next tumor diameter with high accuracy. Thanks to the corresponding prediction interval, it is possible to check if the new observation corresponds to the predicted diameter. If the observed diameter is within the prediction interval, the clinician is notified that the trend is within a normal range. Otherwise, the practitioner is alerted of a significant change in tumor diameter. PMID- 29993902 TI - Accurate Pelvis and Femur Segmentation in Hip CT With a Novel Patch-based Refinement. AB - Due to bone deformation and joint space narrowing in diseased hips, accurate segmentation for pelvis and femur from hip computed tomography (CT) images remains a challenging task. Therefore, the paper presents a fully automatic segmentation framework for the pelvis and femur in both of healthy and diseased hips. The framework involves three steps: preprocessing, coarse segmentation and refinement. It starts with a preprocessing procedure to extract the volume of interest (VOI) from original CT images. Then, a coarse segmentation of bone has been got by classifying the VOI as bone and non-bone parts based on conditional random field (CRF) model. Lastly, the bone are further divided into the pelvis and femur using a patch-based refinement method. The innovation of this study is the novel patch-based refinement method that is particularly suitable for diseased hips. The refinement method starts from the boundary of coarse segmentation, and propagates to the neighbors only when the label is not consistent with the label of CRF-based classification, it increases the reliability of segmentation for diseased hips with bone deformation. We incorporate neighborhood information to label fusion so that final label estimation is more accurate and robust for diseased hips with joint space narrowing. 60 CT datasets which included 78 healthy hemi-hips and 42 diseased hemi-hips were used, and 3-fold cross validations were carried out. Compared to two state-of-the-art methods, our method achieved significantly increased segmentation accuracy for the diseased hemi-hips, and is, therefore, more suited for automatic segmentation of diseased hips. PMID- 29993903 TI - Improving patient safety and clinician workflow in the general care setting with enhanced surveillance monitoring. AB - Clinical monitoring systems have been implemented in the inpatient hospital setting for decades, with little attention given to systems analysis or assessment of impact on clinician workflow or patient care. This study provides an example of how system-level design and analysis can be applied in this domain, with specific focus on early detection of patient deterioration to mitigate failure to rescue events. Wireless patient sensors and pulse oximetry-based surveillance system monitors with advanced display and information systems capabilities were introduced to 71 general care beds in two units. Nursing workflow was redesigned to integrate use of the new system and its features into patient assessment activities. Patient characteristics, vital sign documentation, monitor alarm, workflow, and system utilization data were collected and analyzed for the period five months before and five months after implementation. Comparison unit data were also collected and analyzed for the same periods. A survey pertaining to staff satisfaction and system performance was administered after implementation. Statistical analysis was performed to examine differences in the before and after data for the target and control units. The enhanced monitoring system received high staff satisfaction ratings and significantly improved key clinical elements related to early recognition of changes in patient state, including reducing average vital signs data collection time by 28%, increasing patient monitoring time (rate ratio 1.22), and availability and accuracy of patient information. Impact on clinical alarms was mixed, with no significant increase in clinical alarms per monitored hour. PMID- 29993904 TI - Neural Networks Enhanced Adaptive Admittance Control of Optimized Robot Environment Interaction. AB - In this paper, an admittance adaptation method has been developed for robots to interact with unknown environments. The environment to be interacted with is modeled as a linear system. In the presence of the unknown dynamics of environments, an observer in robot joint space is employed to estimate the interaction torque, and admittance control is adopted to regulate the robot behavior at interaction points. An adaptive neural controller using the radial basis function is employed to guarantee trajectory tracking. A cost function that defines the interaction performance of torque regulation and trajectory tracking is minimized by admittance adaptation. To verify the proposed method, simulation studies on a robot manipulator are conducted. PMID- 29993905 TI - Discriminative Optimization: Theory and Applications to Computer Vision. AB - Many computer vision problems are formulated as the optimization of a cost function. This approach faces two main challenges: designing a cost function with a local optimum at an acceptable solution, and developing an efficient numerical method to search for this optimum. While designing such functions is feasible in the noiseless case, the stability and location of local optima are mostly unknown under noise, occlusion, or missing data. In practice, this can result in undesirable local optima or not having a local optimum in the expected place. On the other hand, numerical optimization algorithms in high-dimensional spaces are typically local and often rely on expensive first or second order information to guide the search. To overcome these limitations, we propose Discriminative Optimization (DO), a method that learns search directions from data without the need of a cost function. DO explicitly learns a sequence of updates in the search space that leads to stationary points that correspond to the desired solutions. We provide a formal analysis of DO and illustrate its benefits in the problem of 3D registration, camera pose estimation, and image denoising. We show that DO outperformed or matched state-of-the-art algorithms in terms of accuracy, robustness, and computational efficiency. PMID- 29993906 TI - Visual Kinship Recognition of Families in the Wild. AB - We present the largest database for visual kinship recognition, Families In the Wild (FIW), with over 13,000 family photos of 1,000 family trees with 4-to-38 members. It took only a small team to build FIW with efficient labeling tools and work-flow. To extend FIW, we further improved upon this process with a novel semi automatic labeling scheme that used annotated faces and unlabeled text metadata to discover labels, which were then used, along with existing FIW data, for the proposed clustering algorithm that generated label proposals for all newly added data-both processes are shared and compared in depth, showing great savings in time and human input required. Essentially, the clustering algorithm proposed is semi-supervised and uses labeled data to produce more accurate clusters. We statistically compare FIW to related datasets, which unarguably shows enormous gains in overall size and amount of information encapsulated in the labels. We benchmark two tasks, kinship verification and family classification, at scales incomparably larger than ever before. Pre-trained CNN models fine-tuned on FIW outscores other conventional methods and achieved state-of-the art on the renowned KinWild datasets. We also measure human performance on kinship recognition and compare to a fine-tuned CNN. PMID- 29993907 TI - Robust 3D Human Pose Estimation from Single Images or Video Sequences. AB - We propose a method for estimating 3D human poses from single images or video sequences. The task is challenging because: (a) many 3D poses can have similar 2D pose projections which makes the lifting ambiguous, and (b) current 2D joint detectors are not accurate which can cause big errors in 3D estimates. We represent 3D poses by a sparse combination of bases which encode structural pose priors to reduce the lifting ambiguity. This prior is strengthened by adding limb length constraints. We estimate the 3D pose by minimizing an norm measurement error between the 2D pose and the 3D pose because it is less sensitive to inaccurate 2D poses. We modify our algorithm to output 3D pose candidates for an image, and for videos, we impose a temporal smoothness constraint to select the best sequence of 3D poses from the candidates. We demonstrate good results on 3D pose estimation from static images and improved performance by selecting the best 3D pose from the proposals. Our results on video sequences also show improvements (over static images) of roughly 15%. PMID- 29993908 TI - Hedging Deep Features for Visual Tracking. AB - Convolutional Neural Networks (CNNs) have been applied to visual tracking with demonstrated success in recent years. Most CNN-based trackers utilize hierarchical features extracted from a certain layer to represent the target. However, features from a certain layer are not always effective for distinguishing the target object from the backgrounds especially in the presence of complicated interfering factors (e.g., heavy occlusion, background clutter, illumination variation, and shape deformation). In this work, we propose a CNN based tracking algorithm which hedges deep features from different CNN layers to better distinguish target objects and background clutters. Correlation filters are applied to feature maps of each CNN layer to construct a weak tracker, and all weak trackers are hedged into a strong one. For robust visual tracking, we propose a hedge method to adaptively determine weights of weak classifiers by considering both the difference between the historical as well as instantaneous performance, and the difference among all weak trackers over time. In addition, we design a siamese network to define the loss of each weak tracker for the proposed hedge method. Extensive experiments on large benchmark datasets demonstrate the effectiveness of the proposed algorithm against the state-of-the art tracking methods. PMID- 29993909 TI - Deep Mixture of Diverse Experts for Large-Scale Visual Recognition. AB - A deep mixture of diverse experts algorithm is developed by seamlessly combining a set of base deep CNNs (convolutional neural networks) with diverse but overlapped task spaces (outputs) to generate a mixture network with larger outputs, e.g., these base deep CNNs are trained to recognize different subsets of tens of thousands of atomic object classes. One particular base deep CNNs with outputs is learned for each task group to recognize M atomic object classes and identify one special class of "not-in-group", where the network structure of the well-designed deep CNNs is directly used to configure such base deep CNNs. For M semantically-related atomic object classes in the same task group, a deep multi task learning algorithm is developed to leverage their inter-class visual similarities to learn more discriminative base deep CNNs and multi-task softmax for enhancing their separability. All these base deep CNNs with diverse but overlapped task spaces are seamlessly combined to build a mixture network with larger outputs for recognizing tens of thousands of atomic object classes. Our experimental results have demonstrated that our deep mixture of diverse experts algorithm can achieve very competitive results on large-scale visual recognition. PMID- 29993910 TI - Learning Support Correlation Filters for Visual Tracking. AB - For visual tracking methods based on kernel support vector machines (SVMs), data sampling is usually adopted to reduce the computational cost in training. In addition, budgeting of support vectors is required for computational efficiency. Instead of sampling and budgeting, recently the circulant matrix formed by dense sampling of translated image patches has been utilized in kernel correlation filters for fast tracking. In this paper, we derive an equivalent formulation of a SVM model with the circulant matrix expression and present an efficient alternating optimization method for visual tracking. We incorporate the discrete Fourier transform with the proposed alternating optimization process, and pose the tracking problem as an iterative learning of support correlation filters (SCFs). In the fully-supervision setting, our SCF can find the globally optimal solution with real-time performance. For a given circulant data matrix with samples of pixels, the computational complexity of the proposed algorithm is whereas that of the standard SVM-based approaches is at least . In addition, we extend the SCF-based tracking algorithm with multi-channel features, kernel functions, and scale-adaptive approaches to further improve the tracking performance. Experimental results on a large benchmark dataset show that the proposed SCF-based algorithms perform favorably against the state-of-the-art tracking methods in terms of accuracy and speed. PMID- 29993911 TI - A Fusion Framework for Camouflaged Moving Foreground Detection in the Wavelet Domain. AB - Detecting camouflaged moving foreground objects has been known to be difficult due to the similarity between the foreground objects and the background. Conventional methods cannot distinguish the foreground from background due to the small differences between them and thus suffer from underdetection of the camouflaged foreground objects. In this paper, we present a fusion framework to address this problem in the wavelet domain. We first show that the small differences in the image domain can be highlighted in certain wavelet bands. Then the likelihood of each wavelet coefficient being foreground is estimated by formulating foreground and background models for each wavelet band. The proposed framework effectively aggregates the likelihoods from different wavelet bands based on the characteristics of the wavelet transform. Experimental results demonstrated that the proposed method significantly outperformed existing methods in detecting camouflaged foreground objects. Specifically, the average F-measure for the proposed algorithm was 0.87, compared to 0.71 to 0.8 for the other stateof- the-art methods. PMID- 29993912 TI - Fast Ray-Scene Intersection for Interactive Shadow Rendering with Thousands of Dynamic Lights. AB - We present a method for constant time approximation of the intersection between a ray and the geometry of a scene. The scene geometry is simplified with a 2D array of voxelizations computed from different directions, sampling the space of all possible directions. The 2D array of voxelizations is compressed using a vector quantization approach. The ray-scene intersection is approximated using the voxelization whose rows are most closely aligned with the ray. The voxelization row that contains the ray is looked up, the row is truncated to the extent of the ray using bit operations, and a truncated row with non-zero bits indicates that the ray intersects the scene. We support dynamic scenes with rigidly moving objects by building a separate 2D array of voxelizations for each type of object, and by using the same 2D array of voxelizations for all instances of an object type. We support complex dynamic scenes and scenes with deforming geometry by computing and rotating a single voxelization on the fly. We demonstrate the benefits of our method in the context of interactive rendering of scenes with thousands of moving lights, where we compare our method to ray tracing, to conventional shadow mapping, and to imperfect shadow maps. PMID- 29993913 TI - Robust and High Fidelity Mesh Denoising. AB - This paper presents a simple and effective two-stage mesh denoising algorithm, where in the first stage, face normal filtering is done by using bilateral normal filtering in a robust statistics framework. Tukey's bi-weight function is used as similarity function in the bilateral weighting, which is a robust estimator and stops the diffusion at sharp edges to retain features and removes noise from flat regions effectively. In the second stage, an edge-weighted Laplace operator is introduced to compute a differential coordinate. This differential coordinate helps the algorithm to produce a high-quality mesh without any face normal flips and makes the method robust against high-intensity noise. PMID- 29993914 TI - A Multi-Laplacian Prior and Augmented Lagrangian Approach to the Exploratory Analysis of Time-Varying Gene and Transcriptional Regulatory Networks for Gene Microarray Data. AB - This paper proposes a novel multi-Laplacian prior (MLP) and augmented Lagrangian method (ALM) approach for gene interactions and putative transcription factors (TFs) identification from time-course gene microarray data. It employs a non linear time-varying auto-regressive (N-TVAR) model and the Maximum-A-Posteriori Probability method for incorporating the multi-Laplacian prior and the continuity constraint. The MLP allows connections to/from a gene to be better preserved for putative TF identification in non-stationarity gene regulatory network as compared with conventional L1-based penalties. Moreover, the ALM allows the resultant non-smooth L1-based penalties to be decoupled from the remaining smooth terms, so that the former and latter can be efficiently solved using a low complexity proximity operator and smooth optimization technique respectively. Synthetic and real time-course gene microarray datasets are tested to evaluate the performance of the proposed method. Experimental results show that the proposed method gives better accuracy and higher computational speed than our previous work using smoothed approximation. Moreover, its performance, without the use of ChIP-chip data, is found to be highly comparable with other state-of the-art methods integrating both ChIP-chip and gene microarray data. It suggests that the proposed method may serve as a useful exploratory tool for putative TF identification with reduced experimental cost. PMID- 29993915 TI - Dynamical and Static Multisynchronization of Coupled Multistable Neural Networks via Impulsive Control. AB - This paper investigates the dynamical multisynchronization and static multisynchronization problem for delayed coupled multistable neural networks with fixed and switching topologies. To begin with, a class of activation functions as well as several sufficient conditions are introduced to ensure that every subnetwork has multiple equilibrium states. By constructing an appropriate Lyapunov function and by employing impulsive control theory and the average impulsive interval method, several sufficient conditions for multisynchronization in terms of linear matrix inequalities (LMIs) are obtained. Moreover, a unified impulsive controller is designed by means of the established LMIs. Finally, a numerical example is presented to demonstrate the effectiveness of the presented impulsive control strategy. PMID- 29993916 TI - Rank-Constrained Spectral Clustering With Flexible Embedding. AB - Spectral clustering (SC) has been proven to be effective in various applications. However, the learning scheme of SC is suboptimal in that it learns the cluster indicator from a fixed graph structure, which usually requires a rounding procedure to further partition the data. Also, the obtained cluster number cannot reflect the ground truth number of connected components in the graph. To alleviate these drawbacks, we propose a rank-constrained SC with flexible embedding framework. Specifically, an adaptive probabilistic neighborhood learning process is employed to recover the block-diagonal affinity matrix of an ideal graph. Meanwhile, a flexible embedding scheme is learned to unravel the intrinsic cluster structure in low-dimensional subspace, where the irrelevant information and noise in high-dimensional data have been effectively suppressed. The proposed method is superior to previous SC methods in that: 1) the block diagonal affinity matrix learned simultaneously with the adaptive graph construction process, more explicitly induces the cluster membership without further discretization; 2) the number of clusters is guaranteed to converge to the ground truth via a rank constraint on the Laplacian matrix; and 3) the mismatch between the embedded feature and the projected feature allows more freedom for finding the proper cluster structure in the low-dimensional subspace as well as learning the corresponding projection matrix. Experimental results on both synthetic and real-world data sets demonstrate the promising performance of the proposed algorithm. PMID- 29993917 TI - Unified Simultaneous Clustering and Feature Selection for Unlabeled and Labeled Data. AB - This paper proposes a novel feature selection method, namely, unified simultaneous clustering feature selection (USCFS). A regularized regression with a new type of target matrix is formulated to select the most discriminative features among the original features from labeled or unlabeled data. The regression with -norm regularization allows the projection matrix to represent an effective selection of discriminative features. For unsupervised feature selection, the target matrix discovers label-like information not from the original data points but rather from projected data points, which are of a reduced dimensionality. Without the aid of an affinity graph-based local structure learning method, USCFS allows the target matrix to capture latent cluster centers via orthogonal basis clustering and to simultaneously select discriminative features guided by latent cluster centers. When class labels are available, the target matrix is also able to find latent class labels by regarding the ground-truth class labels as an approximate guide. Hence, supervised feature selection is realized using these latent class labels, which may differ from the ground-truth class labels. Experimental results demonstrate the effectiveness of the proposed method. Specifically, the proposed method outperforms the state-of-the-art methods on diverse real-world data sets for both the supervised and the unsupervised feature selection. PMID- 29993918 TI - Cooperative Differential Evolution Framework for Constrained Multiobjective Optimization. AB - This paper presents a cooperative differential evolution framework (CCMODE) for constrained multiobjective optimization, and two instantiations of the CCMODE framework are implemented. The proposed framework has (M+1) populations, including M subpopulations for constrained single-objective optimization and an archive population for constrained M-objective optimization. Each subpopulation performs its own constrained single-objective differential evolution to optimize the assigned constrained single-objective optimization problem. For the archive population, the constraint handling techniques (CHTs) are modified for constrained multiobjective optimization. The proposed framework takes the advantage of existing effective constrained single-objective optimization algorithms, and extends them to deal with constrained multiobjective optimization problems. In two instantiations, two CHTs are implemented in CCMODE framework, respectively. Experiment results on several sets of benchmark problems with two, three, and many objectives show that the proposed algorithm is better than existing state-of-the-art constrained multiobjective evolutionary algorithms. The effectiveness of the subpopulations is also discussed. PMID- 29993919 TI - A Two-Stage Multiobjective Evolutionary Algorithm for Multiobjective Multidepot Vehicle Routing Problem With Time Windows. AB - This paper proposes a multiobjective multidepot vehicle routing problem with time windows and designs some real-world test instances. It develops a two-stage multiobjective evolutionary algorithm (TS-MOEA) for dealing with the problem. Stage I of our proposed algorithm focuses on finding extreme solutions, and forms a coarse Pareto front, while stage II extends the found extreme solutions for approximating the whole Pareto front. The two-stage strategy provides a new method to balance convergence and diversity. Moreover, a hybrid neighborhood structure is designed for solution improvement. Experimental result shows that TS MOEA significantly outperforms two other representative algorithms. PMID- 29993920 TI - Aggregation of Classifiers: A Justifiable Information Granularity Approach. AB - In this paper, we introduced a new approach of combining multiple classifiers in a heterogeneous ensemble system. Instead of using numerical membership values when combining, we constructed interval membership values for each class prediction from the meta-data of observation by using the concept of information granule. In the proposed method, the uncertainty (diversity) of the predictions produced by the base classifiers is quantified by the interval-based information granules. The decision model is then generated by considering both bound and length of the intervals. Extensive experimentation using the UCI datasets has demonstrated the superior performance of our algorithm over other algorithms including six fixed combining methods, one trainable combining method, AdaBoost, bagging, and random subspace. PMID- 29993921 TI - Hinfinity Consensus for Linear Heterogeneous Multiagent Systems Based on Event Triggered Output Feedback Control Scheme. AB - In this paper, the Hinfinity consensus problem for linear heterogeneous multiagent systems (LHMAS) based on event-triggered output feedback control is investigated. Two novel event-triggered control schemes including nonperiodic and periodic event-triggered control approaches are provided to make the LHMAS with external unknown disturbance achieve Hinfinity consensus. Therein, the nonperiodic event-triggered control method is designed by combining the event triggered approach with time-triggered scheme, which can make the sampled instants be decided by the event-triggered condition and provide a fixed lower bound of sampled interval to avoid the Zeno-behavior. Then, based on this approach, the periodic event-triggered control scheme has a further improvement that only the information at fixed periodic interval is used for the event triggered condition, which means that this method avoids the continuous-time information transfer. Besides, both schemes take output feedback control, which means that only the output information of each agent and leader is needed in this paper. Finally, a numerical example is given to support our results. PMID- 29993922 TI - Real-Time Neuromorphic System for Large-Scale Conductance-Based Spiking Neural Networks. AB - The investigation of the human intelligence, cognitive systems and functional complexity of human brain is significantly facilitated by high-performance computational platforms. In this paper, we present a real-time digital neuromorphic system for the simulation of large-scale conductance-based spiking neural networks (LaCSNN), which has the advantages of both high biological realism and large network scale. Using this system, a detailed large-scale cortico-basal ganglia-thalamocortical loop is simulated using a scalable 3-D network-on-chip (NoC) topology with six Altera Stratix III field-programmable gate arrays simulate 1 million neurons. Novel router architecture is presented to deal with the communication of multiple data flows in the multinuclei neural network, which has not been solved in previous NoC studies. At the single neuron level, cost-efficient conductance-based neuron models are proposed, resulting in the average utilization of 95% less memory resources and 100% less DSP resources for multiplier-less realization, which is the foundation of the large-scale realization. An analysis of the modified models is conducted, including investigation of bifurcation behaviors and ionic dynamics, demonstrating the required range of dynamics with a more reduced resource cost. The proposed LaCSNN system is shown to outperform the alternative state-of-the-art approaches previously used to implement the large-scale spiking neural network, and enables a broad range of potential applications due to its real-time computational power. PMID- 29993923 TI - Multiobjective Semisupervised Classifier Ensemble. AB - Classification of high-dimensional data with very limited labels is a challenging task in the field of data mining and machine learning. In this paper, we propose the multiobjective semisupervised classifier ensemble (MOSSCE) approach to address this challenge. Specifically, a multiobjective subspace selection process (MOSSP) in MOSSCE is first designed to generate the optimal combination of feature subspaces. Three objective functions are then proposed for MOSSP, which include the relevance of features, the redundancy between features, and the data reconstruction error. Then, MOSSCE generates an auxiliary training set based on the sample confidence to improve the performance of the classifier ensemble. Finally, the training set, combined with the auxiliary training set, is used to select the optimal combination of basic classifiers in the ensemble, train the classifier ensemble, and generate the final result. In addition, diversity analysis of the ensemble learning process is applied, and a set of nonparametric statistical tests is adopted for the comparison of semisupervised classification approaches on multiple datasets. The experiments on 12 gene expression datasets and two large image datasets show that MOSSCE has a better performance than other state-of-the-art semisupervised classifiers on high-dimensional data. PMID- 29993924 TI - Asynchronous and Resilient Filtering for Markovian Jump Neural Networks Subject to Extended Dissipativity. AB - The problem of asynchronous and resilient filtering for discrete-time Markov jump neural networks subject to extended dissipativity is investigated in this paper. The modes of the designed resilient filter are assumed to run asynchronously with the modes of original Markov jump neural networks, which accord well with practical applications and are described through a hidden Markov model. Due to the fluctuation of the filter parameters, a resilient filter taking into account parameter uncertainty is adopted. Being different from the norm-bound type of uncertainty which has been studied in a considerable number of the existing literatures, the interval type of uncertainty is introduced so as to describe uncertain phenomenon more accurately. By means of convex optimal method, the gains of filter are derived to guarantee the stochastic stability and extended dissipativity of the filtering error system under the wave of the filter parameters. Considering the limited computing power of MATLAB solver, a relatively simple simulation is exploited to verify the effectiveness and merits of the theoretical findings where the relationships among optimal performance index, uncertain parameter sigma, and asynchronous rate are revealed. PMID- 29993925 TI - Robust Spatio-Temporal Clustering and Reconstruction of Multiple Deformable Bodies. AB - In this paper we present an approach to reconstruct the 3D shape of multiple deforming objects from a collection of sparse, noisy and possibly incomplete 2D point tracks acquired by a single monocular camera. Additionally, the proposed solution estimates the camera motion and reasons about the spatial segmentation (i.e., identifies each of the deforming objects in every frame) and temporal clustering (i.e., splits the sequence into motion primitive actions). This advances competing work, which mainly tackled the problem for one single object and non-occluded tracks. In order to handle several objects at a time from partial observations, we model point trajectories as a union of spatial and temporal subspaces, and optimize the parameters of both modalities, the non observed point tracks, the camera motion, and the time-varying 3D shape via augmented Lagrange multipliers. The algorithm is fully unsupervised and does not require any training data at all. We thoroughly validate the method on challenging scenarios with several human subjects performing different activities which involve complex motions and close interaction. We show our approach achieves state-of-the-art 3D reconstruction results, while it also provides spatial and temporal segmentation. PMID- 29993926 TI - Hyperspectral Light Field Stereo Matching. AB - In this paper, we describe how scene depth can be extracted using a hyperspectral light field capture (H-LF) system. Our H-LF system consists of a array of cameras, with each camera sampling a different narrow band in the visible spectrum. There are two parts to extracting scene depth. The first part is our novel cross-spectral pairwise matching technique, which involves a new spectral invariant feature descriptor and its companion matching metric we call bidirectional weighted normalized cross correlation (BWNCC). The second part, namely, H-LF stereo matching, uses a combination of spectral-dependent correspondence and defocus cues that rely on BWNCC. These two new cost terms are integrated into a Markov Random Field (MRF) for disparity estimation. Experiments on synthetic and real H-LF data show that our approach can produce high-quality disparity maps. We also show that these results can be used to produce the complete plenoptic cube in addition to synthesizing all-focus and defocused color images under different sensor spectral responses. PMID- 29993927 TI - Real-time 3D Hand Pose Estimation with 3D Convolutional Neural Networks. AB - In this paper, we present a novel method for real-time 3D hand pose estimation from single depth images using 3D Convolutional Neural Networks (CNNs). Image based features extracted by 2D CNNs are not directly suitable for 3D hand pose estimation due to the lack of 3D spatial information. Our proposed 3D CNN-based method, taking a 3D volumetric representation of the hand depth image as input and extracting 3D features from the volumetric input, can capture the 3D spatial structure of the hand and accurately regress full 3D hand pose in a single pass. In order to make the 3D CNN robust to variations in hand sizes and global orientations, we perform 3D data augmentation on the training data. To further improve the estimation accuracy, we propose applying the 3D deep network architectures and leveraging the complete hand surface as intermediate supervision for learning 3D hand pose from depth images. Extensive experiments on three challenging datasets demonstrate that our proposed approach outperforms baselines and state-of-the-art methods. A cross-dataset experiment also shows that our method has good generalization ability. Furthermore, our method is fast as our implementation runs at over 91 frames per second on a standard computer with a single GPU. PMID- 29993928 TI - Multi-Atlas Segmentation of MR Tumor Brain Images Using Low-Rank Based Image Recovery. AB - We introduce a new multi-atlas segmentation (MAS) framework for MR tumor brain images. The basic idea of MAS is to register and fuse label information from multiple normal brain atlases to a new brain image for segmentation. Many MAS methods have been proposed with success. However, most of them are developed for normal brain images, and tumor brain images usually pose a great challenge for them. This is because tumors cause difficulties in registration of normal brain atlases to the tumor brain image. To address this challenge, in the first step of our MAS framework, a new low-rank method is used to get the recovered image of normal-looking brain from the MR tumor brain image based on the information of normal brain atlases. Different from conventional low-rank methods that produce the recovered image with distorted normal brain regions, our low-rank method harnesses a spatial constraint to get the recovered image with preserved normal brain regions. Then in the second step, normal brain atlases can be registered to the recovered image without influence from tumors. These two steps are iteratively proceeded until convergence, for obtaining the final segmentation of the tumor brain image. During the iteration, both the recovered image and the registration of normal brain atlases to the recovered image are gradually refined. We have compared our proposed method with state-of-the-art methods by using both synthetic and real MR tumor brain images. Experimental results show that our proposed method can get effectively recovered images and also improves segmentation accuracy. PMID- 29993929 TI - Maximum velocity estimation in coronary arteries using 3D tracking Doppler. AB - Several challenges currently prevent the use of Doppler echocardiography to assess blood flow in the coronary arteries. Due to the anatomy of the coronary tree, out-of-plane flow and high beam-to-flow angles easily occur. Transit time broadening in regions with high velocities leads to overestimation of the maximum velocity envelope, which is a standard clinical parameter for flow quantification. In this work, a commercial ultrasound system was locally modified to perform trans-thoracic, 3D high frame-rate imaging of the coronary arteries. The imaging sequence was then combined with 3D tracking Doppler for retrospective estimation of maximum velocities. Results from simulations showed that 3D tracking Doppler delivers sonograms with better velocity resolution and spectral SNR compared to conventional PW Doppler. Results were confirmed using in vitro recordings. Further simulations based on realistic coronary flow data showed that 3D tracking Doppler can provide improved performance compared to PW Doppler, suggesting a potential benefit on patients. In vivo feasibility of the method was also shown in a healthy volunteer. PMID- 29993930 TI - Predicting Hospital Readmission via Cost-sensitive Deep Learning. AB - Early readmission prediction enables early intervention, which is essential to preventing serious or life-threatening events, and act as a substantial contributor to reduce healthcare costs. Existing works on predicting readmission often focus on certain vital signs and diseases by extracting statistical features. They also fail to consider skewness of class labels in medical data and different costs of misclassification errors. In this paper, we recur to the merits of convolutional neural networks (CNN) to automatically learn features from time series of vital sign, and categorical feature embedding to effectively encode feature vectors with heterogeneous clinical features. Then, both learnt features via CNN and statistical features via feature embedding are fed into a multilayer perceptron (MLP) for prediction. We use a cost-sensitive formulation to train MLP during prediction to tackle the imbalance and skewness challenge. We validate the proposed approach on two real medical datasets from Barnes-Jewish Hospital. We find that early prediction of readmission is possible and when compared with state-of-the-art existing methods used by hospitals, our methods perform significantly better. Based on these results, a system is being deployed in hospital settings with the proposed forecasting algorithms to support treatment. PMID- 29993931 TI - MH-Pen: A Pen-type Multi-mode Haptic Interface for Touch Screens Interaction. AB - Touch screen technology supplies a new approach to interact with virtual environments. For haptic interaction on a touch screen, haptic devices that are capable of simultaneously conveying tactile and force information to users are highly desired for enhancing the sense of reality and immersion. To this end, a prototype haptic interface, called MH-Pen, was developed and fabricated to display the virtual interactive information through multi-mode haptic feedback. The MH-Pen is a self-contained system that provides vibrotactile feedback and precise force feedback by integrating three types of actuators. In this paper, MH Pen's design, specifications and working principle are described. Subsequently, to accurately display the interaction force, a hybrid actuator was designed by combining a piston-type magnetorheological (MR) actuator and a voice coil motor (VCM), and a closed-loop control scheme was built to manage the hybrid actuator. Finally, we objectively and subjectively evaluated the force feedback performance and the effect of multi-mode haptic display of the MH-Pen through physical measurements and psychophysical experiments of virtual surface stiffness display. The results show that improving the precision of force feedback and using multi mode haptic display are both useful and necessary to enhance the sense of human computer interaction realism. PMID- 29993932 TI - Robust Regression Estimation Based on Low-Dimensional Recurrent Neural Networks. AB - The robust Huber's M-estimator is widely used in signal and image processing, classification, and regression. From an optimization point of view, Huber's M estimation problem is often formulated as a large-sized quadratic programming (QP) problem in view of its nonsmooth cost function. This paper presents a generalized regression estimator which minimizes a reduced-sized QP problem. The generalized regression estimator may be viewed as a significant generalization of several robust regression estimators including Huber's M-estimator. The performance of the generalized regression estimator is analyzed in terms of robustness and approximation accuracy. Furthermore, two low-dimensional recurrent neural networks (RNNs) are introduced for robust estimation. The two RNNs have low model complexity and enhanced computational efficiency. Finally, the experimental results of two examples and an application to image restoration are presented to substantiate superior performance of the proposed method over conventional algorithms for robust regression estimation in terms of approximation accuracy and convergence rate. PMID- 29993933 TI - A Three-Layered Mutually Reinforced Model for Personalized Citation Recommendation. AB - Fast-growing scientific papers pose the problem of rapidly and accurately finding a list of reference papers for a given manuscript. Citation recommendation is an indispensable technique to overcome this obstacle. In this paper, we propose a citation recommendation approach via mutual reinforcement on a three-layered graph, in which each paper, author or venue is represented as a vertex in the paper layer, author layer, and venue layer, respectively. For personalized recommendation, we initiate the random walk separately for each query researcher. However, this has a high computational complexity due to the large graph size. To solve this problem, we apply a three-layered interactive clustering approach to cluster related vertices in the graph. Personalized citation recommendations are then made on the subgraph, generated by the clusters associated with each researcher's needs. When evaluated on the ACL anthology network, DBLP, and CiteSeer ML data sets, the performance of our proposed model-based citation recommendation approach is comparable with that of other state-of-the-art citation recommendation approaches. The results also demonstrate that the personalized recommendation approach is more effective than the nonpersonalized recommendation approach. PMID- 29993934 TI - Contrast-Oriented Deep Neural Networks for Salient Object Detection. AB - Deep convolutional neural networks (CNNs) have become a key element in the recent breakthrough of salient object detection. However, existing CNN-based methods are based on either patchwise (regionwise) training and inference or fully convolutional networks. Methods in the former category are generally time consuming due to severe storage and computational redundancies among overlapping patches. To overcome this deficiency, methods in the second category attempt to directly map a raw input image to a predicted dense saliency map in a single network forward pass. Though being very efficient, it is arduous for these methods to detect salient objects of different scales or salient regions with weak semantic information. In this paper, we develop hybrid contrast-oriented deep neural networks to overcome the aforementioned limitations. Each of our deep networks is composed of two complementary components, including a fully convolutional stream for dense prediction and a segment-level spatial pooling stream for sparse saliency inference. We further propose an attentional module that learns weight maps for fusing the two saliency predictions from these two streams. A tailored alternate scheme is designed to train these deep networks by fine-tuning pretrained baseline models. Finally, a customized fully connected conditional random field model incorporating a salient contour feature embedding can be optionally applied as a postprocessing step to improve spatial coherence and contour positioning in the fused result from these two streams. Extensive experiments on six benchmark data sets demonstrate that our proposed model can significantly outperform the state of the art in terms of all popular evaluation metrics. PMID- 29993935 TI - Practical Time-Varying Formation Tracking for Second-Order Nonlinear Multiagent Systems With Multiple Leaders Using Adaptive Neural Networks. AB - Practical time-varying formation tracking problems for second-order nonlinear multiagent systems with multiple leaders are investigated using adaptive neural networks (NNs), where the time-varying formation tracking error caused by time varying external disturbances can be arbitrarily small. Different from the previous work, there exists a predefined time-varying formation formed by the states of the followers and the formation tracks the convex combination of the states of the leaders with unknown control inputs. Besides, the dynamics of each agent has both matched/mismatched heterogeneous nonlinearities and disturbances simultaneously. First, a practical time-varying formation tracking protocol using adaptive NNs is proposed, which is constructed using only local neighboring information. The proposed control protocol can process not only the matched/mismatched heterogeneous nonlinearities and disturbances, but also the unknown control inputs of the leaders. Second, an algorithm with three steps is introduced to design the practical formation tracking protocol, where the parameters of the protocol are determined, and the practical time-varying formation tracking feasibility condition is given. Third, the stability of the closed-loop multiagent system is proven by using the Lyapunov theory. Finally, a simulation example is showed to illustrate the effectiveness of the obtained theoretical results. PMID- 29993936 TI - Global Bandits. AB - Multiarmed bandits (MABs) model sequential decision-making problems, in which a learner sequentially chooses arms with unknown reward distributions in order to maximize its cumulative reward. Most of the prior works on MAB assume that the reward distributions of each arm are independent. But in a wide variety of decision problems-from drug dosage to dynamic pricing-the expected rewards of different arms are correlated, so that selecting one arm provides information about the expected rewards of other arms as well. We propose and analyze a class of models of such decision problems, which we call global bandits (GB). In the case in which rewards of all arms are deterministic functions of a single unknown parameter, we construct a greedy policy that achieves bounded regret, with a bound that depends on the single true parameter of the problem. Hence, this policy selects suboptimal arms only finitely many times with probability one. For this case, we also obtain a bound on regret that is independent of the true parameter; this bound is sublinear, with an exponent that depends on the informativeness of the arms. We also propose a variant of the greedy policy that achieves worst case and parameter-dependent regret. Finally, we perform experiments on dynamic pricing and show that the proposed algorithms achieve significant gains with respect to the well-known benchmarks. PMID- 29993937 TI - Modeling and Quantification of Impact of Psychological Factors on Rehabilitation of Stroke Patients. AB - The brain damage could lead to the loss of the central nervous system, so a stroke patient may lose the function of dominating his/her body. The rehabilitation aims to maximize the potential to restore a patient who has an impairment. Traditional rehabilitation is to train a patient's muscles and joints under the guide of doctors to improve the strength of muscles and restore the motor function of joints. However, stroke patients are usually depressed, lonely and irritable, and they might easily generate negative emotions during a rehabilitation process. With a sole goal of helping patients restore their body functions from the physiology perspective, the traditional rehabilitation took little consideration on the impact of rehabilitation, which is reflected and measured from the perspective of emotions. Therefore, we suggest adding affective regulation to the stroke rehabilitation; in such a way, the patients' exercise could be completed with high intrinsic motivation, and the performance of the rehabilitation process can be enhanced. Two main contributions in the presented works are (1) the expanded emotional model to represent the status of stroke patients where the impact of psychological factors can be taken into consideration, (2) the quantifiable measurement of rehabilitation performance as well as the corresponding design of experiments (DoE) to verify the positive impact of psychological adjustment on human subjects. Note that due to the limited conditions, the experimental verification was performed on healthy college students. Since our work focused on modeling and quantification of psychological factors, it is reasonable to expend our work to other human subjects including stoke patients. PMID- 29993938 TI - A Sequentially Truncated Higher Order Singular Value Decomposition-Based Algorithm for Tensor Completion. AB - The problem of recovering missing data of an incomplete tensor has drawn more and more attentions in the fields of pattern recognition, machine learning, data mining, computer vision, and signal processing. Researches on this problem usually share a common assumption that the original tensor is of low-rank. One of the important ways to capture the low-rank structure of the incomplete tensor is based on tensor factorization. For the traditional tensor factorization algorithms, the tensor ranks should be specified ahead, which is not reasonable in real applications. To overcome this drawback, an adaptive algorithm is first presented based on sequentially truncated higher order singular value decomposition (ST-HOSVD) for fast low-rank approximation of complete tensor, in which the tensor ranks can be obtained adaptively. Then for tensor with missing data, we use adaptive ST-HOSVD and the average operator of low-rank approximation to improve the accuracy of the fulfilled tensor. Convergence analysis of the proposed algorithm is also given in this paper. The experimental results on 14 image datasets and three video datasets show that the proposed method outperforms the state-of-the-art methods in terms of running time and the accuracy. PMID- 29993939 TI - Two New Discrete-Time Neurodynamic Algorithms Applied to Online Future Matrix Inversion With Nonsingular or Sometimes-Singular Coefficient. AB - In this paper, a high-precision general discretization formula using six time instants is first proposed to approximate the first-order derivative. Then, such a formula is studied to discretize two continuous-time neurodynamic models, both of which are derived by applying the neurodynamic approaches based on neural networks (i.e., zeroing neurodynamics and gradient neurodynamics). Originating from the general six-instant discretization (6ID) formula, a specific 6ID formula is further presented. Subsequently, two new discrete-time neurodynamic algorithms, i.e., 6ID-type discrete-time zeroing neurodynamic (DTZN) algorithm and 6ID-type discrete-time gradient neurodynamic (DTGN) algorithm, are proposed and investigated for online future matrix inversion (OFMI). In addition to analyzing the usual nonsingular situation of the coefficient, this paper investigates the sometimes-singular situation of the coefficient for OFMI. Finally, two illustrative numerical examples, including an application to the inverse-kinematic control of a PUMA560 robot manipulator, are provided to show respective characteristics and advantages of the proposed 6ID-type DTZN and DTGN algorithms for OFMI in different situations, where the coefficient matrix to be inverted is always-nonsingular or sometimes-singular during time evolution. PMID- 29993940 TI - Adaptive Fuzzy State/Output Feedback Control of Nonstrict-Feedback Systems: A Direct Compensation Approach. AB - Issues of adaptive fuzzy direct compensation-based state/output feedback control for nonstrict-feedback systems are presented. The key to its feasibility is the differentiation-free feature, which is achieved in two steps. First, with the nominal adaptive fuzzy virtual controllers as the inputs, a set of low-pass filters are constructed to avoid the explosion of complexity and the algebraic loop problems. Second, via using sufficiently small time constants, the boundedness of the filters' errors is ensured without the calculation of the filter error dynamics, which otherwise would incur another loop problem. In particular, by including a supervisory linear high-gain control component, both the state/output feedback control schemes ensure the semi-global practical tracking stability without relying on the all-time validity of the fuzzy approximation. In particular, the stability criteria of the proposed state and output feedback designs are much easier to fulfill than those based on the variable-separation-based method. Simulation are then carried out to validate the proposed schemes. PMID- 29993941 TI - Observer-Based Output Feedback MPC for T-S Fuzzy System With Data Loss and Bounded Disturbance. AB - This paper investigates the output feedback model predictive control (OFMPC) for Takagi-Sugeno fuzzy networked control systems with bounded disturbance, where data quantization and data loss occur simultaneously. The quantization error is treated as sector bound uncertainties by using the sector bound approach and the data loss process is modeled as a time-homogeneous Markov chain. Invoking S procedure and the notion of quadratic boundedness which can specify closed-loop stability for system with disturbance, the state observer is offline designed and the networked output feedback model predictive controller is provided which explicitly considers the satisfaction of input constraints. Two online synthesis algorithms of OFMPC are presented, one parameterizing the infinite horizon control moves into a single feedback law, the other into one free control move followed by the single feedback law based on the state observer. A new formula is introduced to refresh the ellipsoidal bound of estimation error which can guarantee the recursive feasibility of optimization problem. An example is given to demonstrate the effectiveness of the proposed new design techniques. PMID- 29993942 TI - Transfer Independently Together: A Generalized Framework for Domain Adaptation. AB - Currently, unsupervised heterogeneous domain adaptation in a generalized setting, which is the most common scenario in real-world applications, is under insufficient exploration. Existing approaches either are limited to special cases or require labeled target samples for training. This paper aims to overcome these limitations by proposing a generalized framework, named as transfer independently together (TIT). Specifically, we learn multiple transformations, one for each domain (independently), to map data onto a shared latent space, where the domains are well aligned. The multiple transformations are jointly optimized in a unified framework (together) by an effective formulation. In addition, to learn robust transformations, we further propose a novel landmark selection algorithm to reweight samples, i.e., increase the weight of pivot samples and decrease the weight of outliers. Our landmark selection is based on graph optimization. It focuses on sample geometric relationship rather than sample features. As a result, by abstracting feature vectors to graph vertices, only a simple and fast integer arithmetic is involved in our algorithm instead of matrix operations with float point arithmetic in existing approaches. At last, we effectively optimize our objective via a dimensionality reduction procedure. TIT is applicable to arbitrary sample dimensionality and does not need labeled target samples for training. Extensive evaluations on several standard benchmarks and large-scale datasets of image classification, text categorization and text-to-image recognition verify the superiority of our approach. PMID- 29993943 TI - Resilient State Estimation for 2-D Time-Varying Systems With Redundant Channels: A Variance-Constrained Approach. AB - This paper investigates the state estimation problem for a class of 2-D time varying systems with error variance constraints, where the implemented estimator gain is subject to stochastic perturbations. Redundant channels are utilized as a protocol to strengthen the transmission reliability and the channels' packet dropout rates are described by mutually uncorrelated Bernoulli distributions. The objective of the addressed problem is to design a resilient estimator such that an upper bound on the estimation error variance is first guaranteed and then minimized at each time step, where the considered gain perturbations are characterized by their statistical properties. By employing the induction method and the variance-constrained approach, an upper bound on the estimation error variance is first constructed by means of the solutions to two Riccati-like difference equations and, subsequently, a locally minimal upper bound is achieved by appropriately designing the gain parameter. Then, an effective algorithm is proposed for designing the desired estimator, which is in a recursive form suitable for online applications. Finally, a numerical simulation is provided to demonstrate the usefulness of the proposed estimation scheme. PMID- 29993944 TI - Adaptive Control for Rendezvous Problem of Networked Uncertain Euler-Lagrange Systems. AB - This paper further improves the results for the leader-following rendezvous problem for multiple uncertain Euler-Lagrange systems. Based on a self-tuning adaptive observer, which can work under the more relaxed assumption that the information of the leader system is only available to informed followers in the rendezvous network, a full state distributed control law, depending only on the neighbor's information, is first proposed to preserve the connectivity of the initially connected rendezvous network, as well as to achieve the asymptotic tracking of leader's signal. And then such full state control strategy is further improved to be independent of the relative velocity of two neighboring agents by introducing an additional time-varying nonlinear term, determined by potential function. At the same time, dynamic gains are also introduced to make control parameter independent of system dynamics. PMID- 29993945 TI - Generalized Hidden-Mapping Transductive Transfer Learning for Recognition of Epileptic Electroencephalogram Signals. AB - Electroencephalogram (EEG) signal identification based on intelligent models is an important means in epilepsy detection. In the recognition of epileptic EEG signals, traditional intelligent methods usually assume that the training dataset and testing dataset have the same distribution, and the data available for training are adequate. However, these two conditions cannot always be met in practice, which reduces the ability of the intelligent recognition model obtained in detecting epileptic EEG signals. To overcome this issue, an effective strategy is to introduce transfer learning in the construction of the intelligent models, where knowledge is learned from the related scenes (source domains) to enhance the performance of model trained in the current scene (target domain). Although transfer learning has been used in EEG signal identification, many existing transfer learning techniques are designed only for a specific intelligent model, which limit their applicability to other classical intelligent models. To extend the scope of application, the generalized hidden-mapping transductive learning method is proposed to realize transfer learning for several classical intelligent models, including feedforward neural networks, fuzzy systems, and kernelized linear models. These intelligent models can be trained effectively by the proposed method even though the data available are insufficient for model training, and the generalization abilities of the trained model is also enhanced by transductive learning. A number of experiments are carried out to demonstrate the effectiveness of the proposed method in epileptic EEG recognition. The results show that the method is highly competitive or superior to some existing state-of-the-art methods. PMID- 29993946 TI - Synchronization Conditions for a Multirate Kuramoto Network With an Arbitrary Topology and Nonidentical Oscillators. AB - This paper presents methods to find a positively invariant set (PIS) and derive conditions on the edge weights for a multirate Kuramoto oscillator network to achieve synchronization. These methods can be applied to a network with an arbitrary topology and nonidentical oscillators. The proposed methods are based on the construction of energy functions for this type of network. Two different conditions on the edge weights are provided by using graph spectral properties, or alternatively by analyzing a path set of a graph. These methods provide flexibility in checking the edge weight conditions. We further improve the estimate of the PIS for the multirate Kuramoto network when its damping coefficients are greater than a certain value. The effectiveness and conservativeness of the proposed methods are demonstrated by simulation studies. A comparison with another method from the existing literature shows that our method gives less conservative estimate of the PIS. PMID- 29993947 TI - Robust PCA Based on Incoherence with Geometrical Interpretation. AB - Robust Principal Component Analysis (RPCA), which extracts low-dimensional data from high-dimensional data, can also be regarded as a source separation problem of the sparse error matrix and the low-rank matrix. Until recently, various methods have attempted to precisely predict the discrete rank function by assigning a weight to the nuclear norm. However, if the weights are not in ascending order, the algorithms will diverge and exhibit high computational complexity. Moreover, from the viewpoint of source separation, these methods overlook the fact that two components must be sufficiently different for accurate demixing. In this paper, we employ the incoherence term with convex shape, which considers that components must appear different from one another for boosting separability. Since it is intractable to directly exploit mutual incoherence defined in linear algebra, we guarantee the incoherence by indirectly making the sparse matrix lack the low-rank property by using the duality norm principle. This approach can also be associated with the null space. To analyze the results of the proposed algorithm geometrically, we measure the geodesic distance between the tangent spaces of the manifolds of two separate components. As this distance increases, the degree of dissimilarity of the two components is adequately assured; thus, separation succeeds. Furthermore, this paper is the first to provide insights into the relationship between source separation conditions and the derivatives of the nuclear norm and L1 norm. Experiments are conducted on still image separation and background subtraction to confirm the superiority of the proposed methods both qualitatively and quantitatively. PMID- 29993948 TI - Real-Time Action Recognition with Deeply-Transferred Motion Vector CNNs. AB - The two-stream CNNs prove very successful for video based action recognition. However the classical two-stream CNNs are time costly, mainly due to the bottleneck of calculating optical flows. In this paper, we propose a two-stream based real-time action recognition approach by using motion vector to replace optical flow. Motion vectors are encoded in video stream and can be extracted directly without extra calculation. However directly training CNN with motion vectors degrades accuracy severely due to the noise and the lack of fine details in motion vectors. In order to relieve this problem, we propose four training strategies which leverage the knowledge learned from optical flow CNN to enhance the accuracy of motion vector CNN. Our insight is that motion vector and optical flow share inherent similar structures which allows us to transfer knowledge from one domain to another. To fully utilize the knowledge learned in optical flow domain, we develop deeply transferred motion vector CNN. Experimental results on various datasets show the effectiveness of our training strategies. Our approach is significantly faster than optical flow based approaches and achieves processing speed of 390.7 frames per second, surpassing real-time requirement. We release our model and code to facilitate further research. PMID- 29993949 TI - Graph Thumbnails: Identifying and Comparing Multiple Graphs at a Glance. AB - We propose Graph Thumbnails, small icon-like visualisations of the high-level structure of network data. Graph Thumbnails are designed to be legible in small multiples to support rapid browsing within large graph corpora. Compared to existing graph-visualisation techniques our representation has several advantages: (1) the visualisation can be computed in linear time; (2) it is canonical in the sense that isomorphic graphs will always have identical thumbnails; and (3) it provides precise information about the graph structure. We report the results of two user studies. The first study compares Graph Thumbnails to node-link and matrix views for identifying similar graphs. The second study investigates the comprehensibility of the different representations. We demonstrate the usefulness of this representation for summarising the evolution of protein-protein interaction networks across a range of species. PMID- 29993950 TI - ProtDet-CCH: Protein remote homology detection by combining Long Short-Term Memory and ranking methods. AB - As one of the most challenging tasks in sequence analysis, protein remote homology detection has been extensively studied. Methods based on discriminative models and ranking approaches have achieved the state-of-the-art performance, and these two kinds of methods are complementary. In this study, three LSTM models have been applied to construct the predictors for protein remote homology detection, including ULSTM, BLSTM, and CNN-BLSTM. They are able to automatically extract the local and global sequence order information. Combined with PSSMs, the CNN-BLSTM achieved the best performance among the three LSTM-based models. We named this method as CNN-BLSTM-PSSM. Finally, a new method called ProtDet-CCH was proposed by combining CNN-BLSTM-PSSM and a ranking method HHblits. Tested on a widely used SCOP benchmark dataset, ProtDet-CCH achieved an ROC score of 0.998, and an ROC50 score of 0.982, significantly outperforming other existing state-of the-art methods. Experimental results on two updated SCOPe independent datasets showed that ProtDet-CCH can achieve stable performance. Furthermore, our method can provide useful insights for studying the features and motifs of protein families and superfamilies. It is anticipated that ProtDet-CCH will become a very useful tool for protein remote homology detection. PMID- 29993951 TI - GapReduce: a gap filling algorithm based on partitioned read sets. AB - With the advances in technologies of sequencing and assembly, draft sequences of more and more genomes are available. However, there commonly exist gaps in these draft sequences which influence various downstream analysis of biological studies. Gap filling methods can shorten the length of gaps and improve the completion of these draft sequences of genomes. Although some gap filling tools have been developed, their effectiveness and accuracy need to be improved. In this study, we develop a novel tool, called GapReduce, which can fill the gaps using the paired reads. For a gap, GapReduce selects the reads whose mate reads are aligned on the left or the right flanking region, and partitions the reads to two sets. Then GapReduce adopts different values and frequency thresholds to iteratively construct De Bruijn graphs, which are used for finding the correct path to fill the gap. For overcoming the branching problems caused by repetitive regions and sequencing errors in the procedure of path selection, GapReduce designs a novel approach that simultaneously considers frequency and distribution of paired reads based on the partitioned read sets. We compare the performance of GapReduce with current popular gap filling tools. The experimental results demonstrate that GapReduce can produce satisfactory gap filling results, especially for long insert size datasets. GapReduce is publicly available for downloading at https://github.com/bioinfomaticsCSU/GapReduce. PMID- 29993952 TI - A Unified Model for Joint Normalization and Differential Gene Expression Detection in RNA-Seq data. AB - The RNA-sequencing (RNA-seq) is becoming increasingly popular for quantifying gene expression levels. Since the RNA-seq measurements are relative in nature, between-sample normalization of counts is an essential step in differential expression (DE) analysis. The normalization of existing DE detection algorithms is ad hoc and performed once for all prior to DE detection, which may be suboptimal since ideally normalization should be based on non-DE genes only and thus coupled with DE detection. We propose a unified statistical model for joint normalization and DE detection of log-transformed RNA-seq data. Sample-specific normalization factors are modeled as unknown parameters in the gene-wise linear models and jointly estimated with the regression coefficients. By imposing sparsity-inducing L1 penalty (or mixed L1/L2 penalty for multiple treatment conditions) on the regression coefficients, we formulate the problem as a penalized least-squares regression problem and apply the augmented lagrangian method to solve it. Simulation studies show that the proposed model and algorithms perform better than or comparably to existing methods in terms of detection power and false-positive rate. The performance gain increases with increasingly larger sample size or higher signal to noise ratio, and is more significant when a large proportion of genes are differentially expressed in an asymmetric manner. PMID- 29993953 TI - Fast Algorithms for Computing Path-Difference Distances. AB - Tree comparison metrics are an important tool for the study of phylogenetic trees. Path-difference distances measure the dissimilarity between two phylogenetic trees (on the same set of taxa) by comparing their path-length vectors. Various norms can be applied to this distance. Three important examples are the -, , and -norms. The previous best algorithms for computing path difference distances all have running time. In this paper, we show how to compute the l_1-norm path-difference distance in time and how to compute the - and -norm path-difference distances in time. By extending the presented algorithms, we also show that the -norm path-difference distance can be computed in time for any positive integer . In addition, when the integer is even, we show that the distance can be computed in time as well. PMID- 29993954 TI - Cross-Modal Metric Learning for AUC Optimization. AB - Cross-modal metric learning (CML) deals with learning distance functions for cross-modal data matching. The existing methods mostly focus on minimizing a loss defined on sample pairs. However, the numbers of intraclass and interclass sample pairs can be highly imbalanced in many applications, and this can lead to deteriorating or unsatisfactory performances. The area under the receiver operating characteristic curve (AUC) is a more meaningful performance measure for the imbalanced distribution problem. To tackle the problem as well as to make samples from different modalities directly comparable, a CML method is presented by directly maximizing AUC. The method can be further extended to focus on optimizing partial AUC (pAUC), which is the AUC between two specific false positive rates (FPRs). This is particularly useful in certain applications where only the performances assessed within predefined false positive ranges are critical. The proposed method is formulated as a log-determinant regularized semidefinite optimization problem. For efficient optimization, a minibatch proximal point algorithm is developed. The algorithm is experimentally verified stable with the size of sampled pairs that form a minibatch at each iteration. Several data sets have been used in evaluation, including three cross-modal data sets on face recognition under various scenarios and a single modal data set, the Labeled Faces in the Wild. Results demonstrate the effectiveness of the proposed methods and marked improvements over the existing methods. Specifically, pAUC optimized CML proves to be more competitive for performance measures such as Rank 1 and verification rate at FPR = 0.1%. PMID- 29993955 TI - A Systematic Study of Online Class Imbalance Learning With Concept Drift. AB - As an emerging research topic, online class imbalance learning often combines the challenges of both class imbalance and concept drift. It deals with data streams having very skewed class distributions, where concept drift may occur. It has recently received increased research attention; however, very little work addresses the combined problem where both class imbalance and concept drift coexist. As the first systematic study of handling concept drift in class imbalanced data streams, this paper first provides a comprehensive review of current research progress in this field, including current research focuses and open challenges. Then, an in-depth experimental study is performed, with the goal of understanding how to best overcome concept drift in online learning with class imbalance. PMID- 29993956 TI - Concept Drift Adaptation by Exploiting Historical Knowledge. AB - Incremental learning with concept drift has often been tackled by ensemble methods, where models built in the past can be retrained to attain new models for the current data. Two design questions need to be addressed in developing ensemble methods for incremental learning with concept drift, i.e., which historical (i.e., previously trained) models should be preserved and how to utilize them. A novel ensemble learning method, namely, Diversity and Transfer based Ensemble Learning (DTEL), is proposed in this paper. Given newly arrived data, DTEL uses each preserved historical model as an initial model and further trains it with the new data via transfer learning. Furthermore, DTEL preserves a diverse set of historical models, rather than a set of historical models that are merely accurate in terms of classification accuracy. Empirical studies on 15 synthetic data streams and 5 real-world data streams (all with concept drifts) demonstrate that DTEL can handle concept drift more effectively than 4 other state-of-the-art methods. PMID- 29993957 TI - Sparse Simultaneous Recurrent Deep Learning for Robust Facial Expression Recognition. AB - Facial expression recognition is a challenging task that involves detection and interpretation of complex and subtle changes in facial muscles. Recent advances in feed-forward deep neural networks (DNNs) have offered improved object recognition performance. Sparse feature learning in feed-forward DNN models offers further improvement in performance when compared to the earlier handcrafted techniques. However, the depth of the feed-forward DNNs and the computational complexity of the models increase proportional to the challenges posed by the facial expression recognition problem. The feed-forward DNN architectures do not exploit another important learning paradigm, known as recurrency, which is ubiquitous in the human visual system. Consequently, this paper proposes a novel biologically relevant sparse-deep simultaneous recurrent network (S-DSRN) for robust facial expression recognition. The feature sparsity is obtained by adopting dropout learning in the proposed DSRN as opposed to usual handcrafting of additional penalty terms for the sparse representation of data. Theoretical analysis of S-DSRN shows that the dropout learning offers desirable properties such as sparsity, and prevents the model from overfitting. Experimental results also suggest that the proposed method yields better performance accuracy, requires reduced number of parameters, and offers reduced computational complexity than that of the previously reported state-of-the-art feed-forward DNNs using two of the most widely used publicly available facial expression data sets. Furthermore, we show that by combining the proposed neural architecture with a state-of-the-art metric learning technique significantly improves the overall recognition performance. Finally, a graphical processing unit (GPU)-based implementation of S-DSRN is obtained for real-time applications. PMID- 29993958 TI - Multiview Spectral Clustering via Structured Low-Rank Matrix Factorization. AB - Multiview data clustering attracts more attention than their single-view counterparts due to the fact that leveraging multiple independent and complementary information from multiview feature spaces outperforms the single one. Multiview spectral clustering aims at yielding the data partition agreement over their local manifold structures by seeking eigenvalue-eigenvector decompositions. Among all the methods, low-rank representation (LRR) is effective, by exploring the multiview consensus structures beyond the low rankness to boost the clustering performance. However, as we observed, such classical paradigm still suffers from the following stand-out limitations for multiview spectral clustering of overlooking the flexible local manifold structure, caused by aggressively enforcing the low-rank data correlation agreement among all views, and such a strategy, therefore, cannot achieve the satisfied between-views agreement; worse still, LRR is not intuitively flexible to capture the latent data clustering structures. In this paper, first, we present the structured LRR by factorizing into the latent low-dimensional data cluster representations, which characterize the data clustering structure for each view. Upon such representation, second, the Laplacian regularizer is imposed to be capable of preserving the flexible local manifold structure for each view. Third, we present an iterative multiview agreement strategy by minimizing the divergence objective among all factorized latent data-cluster representations during each iteration of optimization process, where such latent representation from each view serves to regulate those from other views, and such an intuitive process iteratively coordinates all views to be agreeable. Fourth, we remark that such data-cluster representation can flexibly encode the data clustering structure from any view with an adaptive input cluster number. To this end, finally, a novel nonconvex objective function is proposed via the efficient alternating minimization strategy. The complexity analysis is also presented. The extensive experiments conducted against the real-world multiview data sets demonstrate the superiority over the state of the arts. PMID- 29993959 TI - Modeling of Agent Cognition in Extensive Games via Artificial Neural Networks. AB - The decision-making process, which is regarded as cognitive and ubiquitous, has been exploited in diverse fields, such as psychology, economics, and artificial intelligence. This paper considers the problem of modeling agent cognition in a class of game-theoretic decision-making scenarios called extensive games. We present a novel framework in which artificial neural networks are incorporated to simulate agent cognition regarding the structure of the underlying game and the goodness of the game situations therein. An algorithmic procedure is investigated to describe the process for solving games with cognition, and then, a new equilibrium concept is proposed as a refinement of the classical one-subgame perfect equilibrium-by involving players' cognitive reasoning. Moreover, a series of results concerning the computational complexity, soundness, and completeness of the algorithm, as well as the existence of an equilibrium solution, is obtained. This framework, which is shown to be general enough to model the way in which AlphaGo plays Go, may offer a means for bridging the gap between theoretical models and practical problem-solving. PMID- 29993960 TI - A Two-Layer Mixture Model of Gaussian Process Functional Regressions and Its MCMC EM Algorithm. AB - The mixture of Gaussian processes (GPs) is capable of learning any general stochastic process based on a given set of (sample) curves for the regression and prediction problems. However, it is ineffective for curve clustering and prediction, when the sample curves are derived from different stochastic processes as independent sources linearly mixed together. In this paper, we propose a two-layer mixture model of GP functional regressions (GPFRs) to describe such a mixture of general stochastic processes or independent sources, especially for curve clustering and prediction. Specifically, in the lower layer, the mixture of GPFRs (MGPFRs) is developed for a cluster (or class) of curves within the input space. In the higher layer, the mixture of MGPFRs is further established to divide the curves into clusters according to its components in the output space. For the parameter estimation of the two-layer mixture of GPFRs, we develop a Monte Carlo EM algorithm based on a Monte Carlo Markov chain (MCMC) method, in short, the MCMC EM algorithm. We validate the hierarchical mixture of GPFRs and MCMC EM algorithm using synthetic and real-world data sets. Our results show that our new model outperforms the conventional mixture models in curve clustering and prediction. PMID- 29993961 TI - An Adaptive Self-Stabilizing Algorithm for Minor Generalized Eigenvector Extraction and Its Convergence Analysis. AB - Generalized eigendecomposition, which extracts the generalized eigenvector from a matrix pencil, is a powerful tool and has been widely used in many fields, such as data classification and blind source separation. First, to extract the minor generalized eigenvector (MGE), we propose a deterministic discrete-time (DDT) system. Unlike some existing systems, the proposed DDT system does not need to normalize the weight vector in each iteration, since the weight vectors in the proposed DDT system are self-stabilizing. Second, we propose an adaptive algorithm corresponding to the proposed DDT system. Moreover, we study the dynamic behavior and convergence properties of the proposed DDT system and prove that the weight vector must converge to the direction of the MGE of a matrix pencil under some mild conditions. Numerical simulations show that the proposed algorithm has a better performance in terms of convergence speed and estimation accuracy than some existing algorithms. Finally, we conduct two experiments on real data sets to demonstrate its practicability. PMID- 29993962 TI - Local Regression and Global Information-Embedded Dimension Reduction. AB - A large family of algorithms for unsupervised dimension reduction is based on both the local and global structures of the data. A fundamental step in these methods is to model the local geometrical structure of the data. However, the previous methods mainly ignore two facts in this step: 1) the dimensionality of the data is usually far larger than the number of local data, which is a typical ill-posed problem and 2) the data might be polluted by noise. These facts normally may lead to an inaccurate learned local structure and may degrade the final performance. In this paper, we propose a novel unsupervised dimension reduction method with the ability to address these problems effectively while also preserving the global information of the input data. Specifically, we first denoise the local data by preserving their principal components and we then apply a regularization term to the local modeling function to solve the illposed problem. Then, we use a linear regression model to capture the local geometrical structure, which is demonstrated to be insensitive to the parameters. Finally, we propose two criteria to simultaneously model both the local and the global information. Theoretical analyses for the relations between the proposed methods and some classical dimension-reduction methods are presented. The experimental results from various databases demonstrate the effectiveness of our methods. PMID- 29993963 TI - Multiple-criteria decision analysis-based multifactor dimensionality reduction for detecting gene-gene interactions. AB - Gene-gene interactions (GGIs) are important markers for determining susceptibility to a disease. Multifactor dimensionality reduction (MDR) is a popular algorithm for detecting GGIs and primarily adopts the correct classification rate (CCR) to assess the quality of a GGI. However, CCR measurement alone may not successfully detect certain GGIs because of potential model preferences and disease complexities. In this study, multiple-criteria decision analysis (MCDA) based on MDR was named MCDA-MDR and proposed for detecting GGIs. MCDA facilitates MDR to simultaneously adopt multiple measures within the two-way contingency table of MDR to assess GGIs; the CCR and rule utility measure were employed. Cross-validation consistency was adopted to determine the most favorable GGIs among the Pareto sets. Simulation studies were conducted to compare the detection success rates of the MDR-only-based measure and MCDA-MDR, revealing that MCDA-MDR had superior detection success rates. The Wellcome Trust Case Control Consortium dataset was analyzed using MCDA-MDR to detect GGIs associated with coronary artery disease, and MCDA-MDR successfully detected numerous significant GGIs (p < .001). MCDA-MDR performance assessment revealed that the applied MCDA successfully enhanced the GGI detection success rate of the MDR-based method compared with MDR alone. PMID- 29993964 TI - Sliding Trend Fuzzy Approximate Entropy as a Novel Descriptor of Heart Rate Variability in Obstructive Sleep Apnea. AB - Obstructive sleep apnea (OSA) is a common sleep disorder that is often associated with reduced heart rate variability (HRV), thus reflecting modulation of the autonomic system. Sliding trend fuzzy approximate entropy (SlTr-fApEn), which is based on the empirical mode decomposition (EMD) method, has been proposed as a novel index for analyzing HRV with OSA. This study included 60 electrocardiogram recordings from the PhysioNet database (40 OSA recordings and 20 healthy recordings) with apnea or no apnea in 5-minute segments. HRV indices obtained by sliding trend analysis were compared to those obtained by time-frequency domain analysis. Among all indices, the ratio of low-frequency power and high-frequency power (LF/HF) and sliding trend indices could significantly differentiate OSA recordings from normal recordings (p<0.05). The OSA screening accuracy of SlTr fApEn (85%) was higher than that of LF/HF (80%). Disease state analysis showed significant differences in SlTr-fApEn among the control group, normal OSA group, and apnea OSA group (p<0.05). Therefore, SlTr-fApEn can reflect the complexity of autonomic changes during a short time period. PMID- 29993965 TI - DroidFusion: A Novel Multilevel Classifier Fusion Approach for Android Malware Detection. AB - Android malware has continued to grow in volume and complexity posing significant threats to the security of mobile devices and the services they enable. This has prompted increasing interest in employing machine learning to improve Android malware detection. In this paper, we present a novel classifier fusion approach based on a multilevel architecture that enables effective combination of machine learning algorithms for improved accuracy. The framework (called DroidFusion), generates a model by training base classifiers at a lower level and then applies a set of ranking-based algorithms on their predictive accuracies at the higher level in order to derive a final classifier. The induced multilevel DroidFusion model can then be utilized as an improved accuracy predictor for Android malware detection. We present experimental results on four separate datasets to demonstrate the effectiveness of our proposed approach. Furthermore, we demonstrate that the DroidFusion method can also effectively enable the fusion of ensemble learning algorithms for improved accuracy. Finally, we show that the prediction accuracy of DroidFusion, despite only utilizing a computational approach in the higher level, can outperform stacked generalization, a well-known classifier fusion method that employs a meta-classifier approach in its higher level. PMID- 29993966 TI - Facial Attribute Recognition by Recurrent Learning With Visual Fixation. AB - This paper presents a recurrent learning-based facial attribute recognition method that mimics human observers' visual fixation. The concentrated views of a human observer while focusing and exploring parts of a facial image over time are generated and fed into a recurrent network. The network makes a decision concerning facial attributes based on the features gleaned from the observer's visual fixations. Experiments on facial expression, gender, and age datasets show that applying visual fixation to recurrent networks improves recognition rates significantly. The proposed method not only outperforms state-of-the-art recognition methods based on static facial features, but also those based on dynamic facial features. PMID- 29993968 TI - Effects of Target Signal Shape and System Dynamics on Feedforward in Manual Control. AB - The human controller (HC) in manual control of a dynamical system often follows a visible and predictable reference path (target). The HC can adopt a control strategy combining closed-loop feedback and an open-loop feedforward response. The effects of the target signal waveform shape and the system dynamics on the human feedforward dynamics are still largely unknown, even for common, stable, vehicle-like dynamics. This paper studies the feedforward dynamics through computer model simulations and compares these to system identification results from human-in-the-loop experimental data. Two target waveform shapes are considered, constant velocity ramp segments and constant acceleration parabola segments. Furthermore, three representative vehicle-like system dynamics are considered: 1) a single integrator (SI); 2) a second-order system; and 3) a double integrator. The analyses show that the HC utilizes a combined feedforward/feedback control strategy for all dynamics with the parabola target, and for the SI and second-order system with the ramp target. The feedforward model parameters are, however, very different between the two target waveform shapes, illustrating the adaptability of the HC to task variables. Moreover, strong evidence of anticipatory control behavior in the HC is found for the parabola target signal. The HC anticipates the future course of the parabola target signal given extensive practice, reflected by negative feedforward time delay estimates. PMID- 29993967 TI - Adapting Stochastic Block Models to Power-Law Degree Distributions. AB - Stochastic block models (SBMs) have been playing an important role in modeling clusters or community structures of network data. But, it is incapable of handling several complex features ubiquitously exhibited in real-world networks, one of which is the power-law degree characteristic. To this end, we propose a new variant of SBM, termed power-law degree SBM (PLD-SBM), by introducing degree decay variables to explicitly encode the varying degree distribution over all nodes. With an exponential prior, it is proved that PLD-SBM approximately preserves the scale-free feature in real networks. In addition, from the inference of variational E-Step, PLD-SBM is indeed to correct the bias inherited in SBM with the introduced degree decay factors. Furthermore, experiments conducted on both synthetic networks and two real-world datasets including Adolescent Health Data and the political blogs network verify the effectiveness of the proposed model in terms of cluster prediction accuracies. PMID- 29993969 TI - Networked Estimation of a Class of Fuzzy Stochastic Hybrid Systems With Variable Rates of Packet Losses. AB - This paper focuses on the state estimator design problem for a class of Takagi Sugeno fuzzy stochastic hybrid systems with intermittent measurements in discrete time domain. The hybrid systems are characterized with the stochastic switching among a set of subsystems, and the switching is supposed to be governed by a semi Markov process with finite sojourn time. The random packet dropouts are modeled by a Bernoulli distributed sequence, and the packet dropout rate, which is considered to be variable, is described by the semi-Markov stochastic process that governs the switching dynamics of the fuzzy stochastic hybrid system. A more general class of Lyapunov functions that not only depends on the system modes, but also on the time that the current mode has been in since the last mode switching, is employed to analyze the stability and Hinfinity performance of the estimation error system. Then, numerically testable conditions on the existence of a desired fuzzy mode-dependent state estimator are presented such that the estimation error system approaches to be mean square stable to an adjustable level and achieves a prescribed Hinfinity disturbance attenuation index. Finally, an illustrative example of a single-link robotic arm system is provided to demonstrate the effectiveness and the superiority of the design method of state estimator. PMID- 29993970 TI - Error Correcting Input and Output Hashing. AB - Most learning-based hashing algorithms leverage sample-to-sample similarities, such as neighborhood structure, to generate binary codes, which achieve promising results for image retrieval. This type of methods are referred to as instance level encoding. However, it is nontrivial to define a scalar to represent sample to-sample similarity encoding the semantic labels and the data structure. To address this issue, in this paper, we seek to use a class-level encoding method, which encodes the class-to-class relationship, to take the semantic information of classes into consideration. Based on these two encodings, we propose a novel framework, error correcting input and output (EC-IO) coding, which does class level and instance-level encoding under a unified mapping space. Our proposed model contains two major components, which are distribution preservation and error correction. With these two components, our model maps the input feature of samples and the output code of classes into a unified space to encode the intrinsic structure of data and semantic information of classes simultaneously. Under this framework, we present our hashing model, EC-IO hashing (EC-IOH), by approximating the mapping space with the Hamming space. Extensive experiments are conducted to evaluate the retrieval performance, and EC-IOH exhibits superior and competitive performances comparing with popular supervised and unsupervised hashing methods. PMID- 29993971 TI - Observer-Based Adaptive Fuzzy Fault-Tolerant Optimal Control for SISO Nonlinear Systems. AB - This paper investigates adaptive fuzzy output feedback fault-tolerant optimal control problem for a class of single-input and single-output nonlinear systems in strict feedback form. The considered nonlinear systems contain unknown nonaffine nonlinear faults and unmeasured states. Fuzzy logic systems are used to approximate cost function and unknown nonlinear functions, respectively. It is assumed that the states of the systems to be controlled are unmeasurable, thus an adaptive state observer is developed. To solve the nonaffine nonlinear fault control design problem, filtered signals are introduced into the adaptive backstepping control design procedures, and in the framework of adaptive critic technique and fault-tolerant control technique, a novel adaptive fuzzy fault tolerant optimal control scheme is developed. The stability of the closed-loop system is proved by using Lyapunov stability theory. The simulation results verify the effectiveness of the proposed control strategy. PMID- 29993972 TI - Two-Layer Distributed Formation-Containment Control of Multiple Euler-Lagrange Systems by Output Feedback. AB - This paper addresses the distributed formation-containment (DFC) problem for multiple Euler-Lagrange systems with model uncertainties via output feedback in both constant and time-varying formation cases. First, a novel definition of the DFC problem is proposed using a two-layer framework. Since only parts of the followers can acquire the states of the dynamic leader, we design a distributed finite-time sliding-mode estimator to obtain accurate estimations of the desired position and velocity for each agent. Next, to deal with the absence of velocity sensors, we propose two DFC control laws combined with the high-gain observer for the leaders and the followers, respectively, while the time-varying formation in the first layer and the leader-based containment in the second layer can be achieved. Further, the adaptive neural networks are applied to deal with the model uncertainties due to their superior approximation capability. The uniform ultimate boundedness of all the state errors can be guaranteed by Lyapunov stability theory. In addition, a unified framework is given which can be transformed to four other basic distributed problems. Finally, simulation examples are presented to illustrate the feasibility of the theoretical results. PMID- 29993973 TI - Consensus of Leader-Following Multiagent Systems: A Distributed Event-Triggered Impulsive Control Strategy. AB - This paper investigates the leader-following consensus problem of multiagent systems using a distributed event-triggered impulsive control method. For each agent, the controller is updated only when some state-dependent errors exceed a tolerable bound. The control inputs will be carried out by actor only at event triggering impulsive instants. According to the Lyapunov stability theory and impulsive method, several sufficient criteria for leader-following consensus are derived. Also, it is shown that continuous communication of neighboring agents can be avoided, and Zeno-behavior can be excluded in our schema. The results are illustrated through several numerical simulation examples. PMID- 29993974 TI - Multiview Learning With Generalized Eigenvalue Proximal Support Vector Machines. AB - Generalized eigenvalue proximal support vector machines (GEPSVMs) are a simple and effective binary classification method in which each hyperplane is closest to one of the two classes and as far as possible from the other class. They solve a pair of generalized eigenvalue problems to obtain two nonparallel hyperplanes. Multiview learning considers learning with multiple feature sets to improve the learning performance. In this paper, we propose multiview GEPSVMs (MvGSVMs) which effectively combine two views by introducing a multiview co-regularization term to maximize the consensus on distinct views, and skillfully transform a complicated optimization problem to a simple generalized eigenvalue problem. We also propose multiview improved GEPSVMs (MvIGSVMs), which use the minus instead of ratio in MvGSVMs to measure the differences of the distances between the two classes and the hyperplane and lead to a simpler eigenvalue problem. Linear MvGSVMs and MvIGSVMs are generalized to the nonlinear case by the kernel trick. Experimental results on multiple data sets show the effectiveness of our proposed approaches. PMID- 29993975 TI - Multiscale Amplitude Feature and Significance of Enhanced Vocal Tract Information for Emotion Classification. AB - In this paper, a novel multiscale amplitude feature is proposed using multiresolution analysis (MRA) and the significance of the vocal tract is investigated for emotion classification from the speech signal. MRA decomposes the speech signal into number of sub-band signals. The proposed feature is computed by using sinusoidal model on each sub-band signal. Different emotions have different impacts on the vocal tract. As a result, vocal tract responds in a unique way for each emotion. The vocal tract information is enhanced using pre emphasis. Therefore, emotion information manifested in the vocal tract can be well exploited. This may help in improving the performance of emotion classification. Emotion recognition is performed using German emotional EMODB database, interactive emotional dyadic motion capture database, simulated stressed speech database, and FAU AIBO database with speech signal and speech with enhanced vocal tract information (SEVTI). The performance of the proposed multiscale amplitude feature is compared with three different types of features: 1) the mel frequency cepstral coefficients; 2) the Teager energy operator (TEO) based feature (TEO-CB-Auto-Env); and 3) the breathinesss feature. The proposed feature outperforms the other features. In terms of recognition rates, the features derived from the SEVTI signal, give better performance compared to the features derived from the speech signal. Combination of the features with SEVTI signal shows average recognition rate of 86.7% using EMODB database. PMID- 29993976 TI - Improved Space Forest: A Meta Ensemble Method. AB - The performance of the ensemble algorithms is related with the individual accuracy of the base learners and their results diversity. Individual accuracy of a base learner is directly related to the similarity between the original training set and the base learner's training set. When a modified training set by randomly selecting features/classes/samples is given to the base learners, the diversity is created but the individual accuracy is decreased. From this point of view, different ensemble algorithms can be seen as a selection between having more accurate but less diverse base learners and having more diverse but less accurate base learners. We propose a meta ensemble method named as improved space forest which adds generated and (hopefully) more accurate features to the original features. The new features are obtained from randomly selected original features. When the new features are more distinctive than the original ones, they are selected by the learners. So, the ensemble may have more accurate base learners. However, a different improved space is generated for each learner to create diversity. The proposed method can be used with different ensemble methods. We compared original and improved space versions of bagging, random forest, and rotation forest algorithms. Improved space versions have generally better or comparable results than the original ones. We also present a theoretical framework to analyze the individual accuracies and diversities of the base learners. PMID- 29993977 TI - Transferring Knowledge Fragments for Learning Distance Metric from A Heterogeneous Domain. AB - The goal of transfer learning is to improve the performance of target learning task by leveraging information (or transferring knowledge) from other related tasks. In this paper, we examine the problem of transfer distance metric learning (DML), which usually aims to mitigate the label information deficiency issue in the target DML. Most of the current Transfer DML (TDML) methods are not applicable to the scenario where data are drawn from heterogeneous domains. Some existing heterogeneous transfer learning (HTL) approaches can learn target distance metric by usually transforming the samples of source and target domain into a common subspace. However, these approaches lack flexibility in real-world applications, and the learned transformations are often restricted to be linear. This motivates us to develop a general flexible heterogeneous TDML (HTDML) framework. In particular, any (linear/nonlinear) DML algorithms can be employed to learn the source metric beforehand. Then the pre-learned source metric is represented as a set of knowledge fragments to help target metric learning. We show how generalization error in the target domain could be reduced using the proposed transfer strategy, and develop novel algorithm to learn either linear or nonlinear target metric. Extensive experiments on various applications demonstrate the effectiveness of the proposed method. PMID- 29993978 TI - Navigator-Free EPI Ghost Correction With Structured Low-Rank Matrix Models: New Theory and Methods. AB - Structured low-rank matrix models have previously been introduced to enable calibrationless MR image reconstruction from sub-Nyquist data, and such ideas have recently been extended to enable navigator-free echo-planar imaging (EPI) ghost correction. This paper presents a novel theoretical analysis which shows that, because of uniform subsampling, the structured low-rank matrix optimization problems for EPI data will always have either undesirable or non-unique solutions in the absence of additional constraints. This theory leads us to recommend and investigate problem formulations for navigator-free EPI that incorporate side information from either image-domain or k-space domain parallel imaging methods. The importance of using nonconvex low-rank matrix regularization is also identified. We demonstrate using phantom and in vivo data that the proposed methods are able to eliminate ghost artifacts for several navigator-free EPI acquisition schemes, obtaining better performance in comparison with the state-of the-art methods across a range of different scenarios. Results are shown for both single-channel acquisition and highly accelerated multi-channel acquisition. PMID- 29993979 TI - Improved Bilateral Texture Filtering with Edge-aware Measurement. AB - Texture filtering depends on high-quality texture measurement to separate structures from textures. However, the existing methods employ axis-aligned box windows for texture measurement, which may cover different texture regions, and so lowering the measurement quality because structure edges are not always parallel to the axes. Additionally, the existing texture measurements consider intensity contrast at the pixel level and do not account for the linear characteristics of structure edges in filtering windows; thus, their measurement effectiveness is limited. This results in a dilemma for texture filtering. Large scale textures are not smoothed using smaller windows, while small structures are removed using larger windows. In this paper, we present edge-aware measures to improve texture measurement. Edge-aware windows are constructed such that each window is inside a texture region to the greatest extent possible, and the linear characteristics of structure edges are accounted for in the texture measurement. Furthermore, we use large box windows for texture filtering and long and narrow edge-aware small windows for texture measurement to filter out large-scale textures while preserving small structures. The experimental results show improved texture filtering with our method compared with existing methods. PMID- 29993980 TI - Depth Super-Resolution on RGB-D Video Sequences with Large Displacement 3D Motion. AB - To enhance the resolution and accuracy of depth data, some video-based depth super-resolution methods have been proposed which utilizes its neighboring depth images in the temporal domain. They often consist of two main stages: motion compensation of temporally neighboring depth images and fusion of compensated depth images. However, large displacement 3D motion often leads to compensation error, and the compensation error is further introduced into the fusion. A video based depth super-resolution method with novel motion compensation and fusion approaches is proposed in this paper. We claim that, 3D Nearest Neighboring Field (NNF) is a better choice than using positions with true motion displacement for depth enhancements. To handle large displacement 3D motion, the compensation stage utilized 3D NNF instead of true motion used in previous methods. Next, the fusion approach is modeled as a regression problem to predict the super resolution result efficiently for each depth image by using its compensated depth images. A new deep convolutional neural network architecture is designed for fusion, which is able to employ a large amount of video data for learning the complicated regression function. We comprehensively evaluate our method on various RGB-D video sequences to show its superior performance. PMID- 29993981 TI - Cubature Split Covariance Intersection Filter-based Point Set Registration. AB - Point set registration is a basic but still open problem in numerous computer vision tasks. In general, there are more than one type of error sources for registration, for example, noise, outliers and false initialization may exist simultaneously. These errors could influence the registration independently and dependently. Previous works usually test performance under one of the two types of errors at one time, or they do not perform well under some extreme situations with both of the error sources. This work presents a robust point set registration algorithm under a filtering framework, which aims to be robust under various types of errors simultaneously. The point set registration problem can be cast into a non-linear state space model. We use a split covariance intersection filter (SCIF) to capture the correlation between the state transition and the observation (moving point set). The two above-mentioned types of errors can be represented as dependent and independent parts in the SCIF. The covariance of the two types of errors will be updated every iteration. Meanwhile, the non-linearity of the observation model is approximated by a cubature transformation. First, the recursive cubature split covariance intersection filter is derived based on the non-linear state space model. Then, we use this algorithm to solve the point set registration problem. This algorithm can approximate non-linearity by a third order term and consider correlations between the process model and the observation model. Compared to other filtering-based methods, this algorithm is more robust and precise. Tests on both public datasets and experiments validate the precision and robustness of this algorithm to outliers and noise. Comparison experiments show that this algorithm outperforms state-of-the-art point set registration algorithms in certain respects. PMID- 29993982 TI - Static/Dynamic Filtering for Mesh Geometry. AB - The joint bilateral filter, which enables feature-preserving signal smoothing according to the structural information from a guidance, has been applied for various tasks in geometry processing. Existing methods either rely on a static guidance that may be inconsistent with the input and lead to unsatisfactory results, or a dynamic guidance that is automatically updated but sensitive to noises and outliers. Inspired by recent advances in image filtering, we propose a new geometry filtering technique called static/dynamic filter, which utilizes both static and dynamic guidances to achieve state-of-the-art results. The proposed filter is based on a nonlinear optimization that enforces smoothness of the signal while preserving variations that correspond to features of certain scales. We develop an efficient iterative solver for the problem, which unifies existing filters that are based on static or dynamic guidances. The filter can be applied to mesh face normals followed by vertex position update, to achieve scale aware and feature-preserving filtering of mesh geometry. It also works well for other types of signals defined on mesh surfaces, such as texture colors. Extensive experimental results demonstrate the effectiveness of the proposed filter for various geometry processing applications such as mesh denoising, geometry feature enhancement, and texture color filtering. PMID- 29993983 TI - PaperCraft3D: Paper-Based 3D Modeling and Scene Fabrication. AB - A 3D modeling system with all-inclusive functionality is too demanding for a casual 3D modeler to learn. There has been a shift towards more approachable systems, with easy-to-learn, intuitive interfaces. However, most modeling systems still employ mouse and keyboard interfaces, despite the ubiquity of tablet devices and the benefits of multi-touch interfaces. We introduce an alternative 3D modeling and fabrication paradigm using developable surfaces, inspired by traditional papercrafting, and we implement it as a complete system designed for a multi-touch tablet, allowing a user to fabricate 3D scenes. We demonstrate the modeling and fabrication process of assembling complex 3D scenes from a collection of simpler models, in turn shaped through operations applied to virtual paper. Our fabrication method facilitates the assembly of the scene with real paper by automatically converting scenes into a series of cutouts with appropriately added fiducial markers and supporting structures. Our system assists users in creating occluded supporting structures to help maintain the spatial and rigid properties of a scene without compromising its aesthetic qualities. We demonstrate several 3D scenes modeled and fabricated in our system, and evaluate the faithfulness of our fabrications relative to their virtual counterparts and 3D-printed fabrications. PMID- 29993984 TI - A fast exact functional test for directional association and cancer biology applications. AB - Directional association measured by functional dependency can answer important questions on relationships between variables, for example, in discovery of molecular interactions in biological systems. However, when one has no prior information about the functional form of a directional association, there is not a widely established statistical procedure to detect such an association. To address this issue, here we introduce an exact functional test for directional association by examining the strength of functional dependency. It is effective in promoting functional patterns by reducing statistical power on non-functional patterns. We designed an algorithm to carry out the test using a fast branch-and bound strategy, which achieved a substantial speedup over brute-force enumeration. On data from an epidemiological study of liver cancer, the test identified the hepatitis status of a subject as the most influential risk factor among others for the cancer phenotype. On human lung cancer transcriptome data, the test selected 1049 transcription start sites of putative noncoding RNAs directionally associated with lung cancers, stronger than 95% of 589 curated cancer genes. These predictions include non-monotonic interaction patterns, to which other routine tests were insensitive. Complementing symmetric (non directional) association methods such as Fisher's exact test, the exact functional test is a unique exact statistical test for evaluating evidence for causal relationships. PMID- 29993985 TI - Flexible Non-negative Matrix Factorization to Unravel Disease-related Genes. AB - Recently, non-negative matrix factorization (NMF) has been shown perform well in the analysis of omics data. NMF assumes that the expression level of one gene is a linear additive composition of metagenes. The elements in metagene matrix represent the regulation effects and are restricted to non-negativity. However, according to the real biological meaning, there are two kinds of regulation effects, i.e., up-regulation and down-regulation. Few methods based on NMF have considered this biological meaning. Therefore, we designed a flexible non negative matrix factorization (FNMF) algorithm by further considering the biological meaning of gene expression data. It allows negative numbers in the metagene matrix, and negative numbers represent down-regulation effects. We separated gene expression data into disease-driven gene expression and background gene expression. Subsequently, we computed disease-driven gene relative expression, and a ranked list of genes was obtained. The top ranked genes are considered to be involved in some disease-related biological processes. Experimental results on two real-world gene expression data demonstrate the feasibility and effectiveness of FNMF. Compared with conventional disease-related gene identification algorithms, FNMF has superior performance in analyzing gene expression data of diseases with complex pathology. PMID- 29993986 TI - Predicting FAD Interacting Residues with Feature Selection and Comprehensive Sequence Descriptors. AB - The function of a flavoprotein is determined to a great extent by the binding sites on its surface that interacts with flavin adenine dinucleotide (FAD). Malfunction or dysregulation of FAD binding leads to a series of diseases. Therefore, accurately identifying FAD interacting residues (FIRs) provides insights into the molecular mechanisms of flavoprotein-related biological processes and disease progression. In this paper, a new computational method is proposed for identifying FIRs from protein sequences. Various sequence-derived discriminative features are explored. We analyze the distinctions of these features between FIRs and non-FIRs. We also investigate the predictive capabilities of both individual features and combinations of features. A relief algorithm followed by incremental feature selection (relief-IFS) is then adopted to search the optimal features. Finally, a random forest (RF) module is used to predict FIRs based on the optimal features. Using a 5-fold cross-validation test, the proposed method performs well, with a sensitivity of 0.847, a specificity of 0.933, an accuracy of 0.890, and a Matthews correlation coefficient (MCC) of 0.782, thereby outperforming previous methods. These results indicate that our method is relatively successful at predicting FIRs. PMID- 29993987 TI - A 36 MUW 1.1 mm2 Reconfigurable Analog Front-End for Cardiovascular and Respiratory Signals Recording. AB - This paper presents a 1.2 V 36 MUW reconfigurable analog front-end (R-AFE) as a general-purpose low-cost IC for multiple-mode biomedical signals acquisition. The R-AFE efficiently reuses a reconfigurable preamplifier, a current generator (CG), and a mixed signal processing unit, having an area of 1.1 mm2 per R-AFE while supporting five acquisition modes to record different forms of cardiovascular and respiratory signals. The R-AFE can interface with voltage-, current-, impedance-, and light-sensors and hence can measure electrocardiography (ECG), bio-impedance (BioZ), photoplethysmogram (PPG), galvanic skin response (GSR), and general purpose analog signals. Thanks to the chopper preamplifier and the low-noise CG utilizing dynamic element matching, the R-AFE mitigates ${?text{1}}?text{/}f$ noise from both the preamplifier and the CG for improved measurement sensitivity. The IC achieves competitive performance compared to the state-of-the-art dedicated readout ICs of ECG, BioZ, GSR, and PPG, but with approximately 1.4* 5.3* smaller chip area per channel. PMID- 29993989 TI - Runtime Programmable and Memory Bandwidth Optimized FPGA-Based Coprocessor for Deep Convolutional Neural Network. AB - The deep convolutional neural network (DCNN) is a class of machine learning algorithms based on feed-forward artificial neural network and is widely used for image processing applications. Implementation of DCNN in real-world problems needs high computational power and high memory bandwidth, in a power-constrained environment. A general purpose CPU cannot exploit different parallelisms offered by these algorithms and hence is slow and energy inefficient for practical use. We propose a field-programmable gate array (FPGA)-based runtime programmable coprocessor to accelerate feed-forward computation of DCNNs. The coprocessor can be programmed for a new network architecture at runtime without resynthesizing the FPGA hardware. Hence, it acts as a plug-and-use peripheral for the host computer. Caching is implemented for input features and filter weights using on chip memory to reduce the external memory bandwidth requirement. Data are prefetched at several stages to avoid stalling of computational units and different optimization techniques are used to efficiently reuse the fetched data. Dataflow is dynamically adjusted in runtime for each DCNN layer to achieve consistent computational throughput across a wide range of input feature sizes and filter sizes. The coprocessor is prototyped using Xilinx Virtex-7 XC7VX485T FPGA-based VC707 board and operates at 150 MHz. Experimental results show that our implementation is energy efficient than highly optimized CPU implementation and achieves consistent computational throughput of more than 140 G operations/s for a wide range of input feature sizes and filter sizes. Off-chip memory transactions decrease by due to the use of the on-chip cache. PMID- 29993988 TI - Computationally Efficient Data-Driven Higher Order Optimal Iterative Learning Control. AB - Based on a nonlifted iterative dynamic linearization formulation, a novel data driven higher order optimal iterative learning control (DDHOILC) is proposed for a class of nonlinear repetitive discrete-time systems. By using the historical data, additional tracking errors and control inputs in previous iterations are used to enhance the online control performance. From the online data, additional control inputs of previous time instants within the current iteration are utilized to improve transient response. The data-driven property of the proposed method implies that no model information except for the I/O data is utilized. The computational complexity is reduced by avoiding matrix inverse operation in the proposed DDHOILC approach due to the nonlifted linear formulation of the original model. The asymptotic convergence is proved rigorously. Furthermore, the convergence property is analyzed and evaluated via three performance indexes. By elaborately selecting the higher order factors, the higher order learning control law outperforms the lower order one in terms of convergence performance. Simulation results verify the effectiveness of the proposed approach. PMID- 29993990 TI - Weakly Supervised Object Detection via Object-Specific Pixel Gradient. AB - Most existing object detection algorithms are trained based upon a set of fully annotated object regions or bounding boxes, which are typically labor-intensive. On the contrary, nowadays there is a significant amount of image-level annotations cheaply available on the Internet. It is hence a natural thought to explore such "weak" supervision to benefit the training of object detectors. In this paper, we propose a novel scheme to perform weakly supervised object localization, termed object-specific pixel gradient (OPG). The OPG is trained by using image-level annotations alone, which performs in an iterative manner to localize potential objects in a given image robustly and efficiently. In particular, we first extract an OPG map to reveal the contributions of individual pixels to a given object category, upon which an iterative mining scheme is further introduced to extract instances or components of this object. Moreover, a novel average and max pooling layer is introduced to improve the localization accuracy. In the task of weakly supervised object localization, the OPG achieves a state-of-the-art 44.5% top-5 error on ILSVRC 2013, which outperforms competing methods, including Oquab et al. and region-based convolutional neural networks on the Pascal VOC 2012, with gains of 2.6% and 2.3%, respectively. In the task of object detection, OPG achieves a comparable performance of 27.0% mean average precision on Pascal VOC 2007. In all experiments, the OPG only adopts the off-the shelf pretrained CNN model, without using any object proposals. Therefore, it also significantly improves the detection speed, i.e., achieving three times faster compared with the state-of-the-art method. PMID- 29993991 TI - Intelligent Mortality Reporting With FHIR. AB - One pressing need in the area of public health is timely, accurate, and complete reporting of deaths and the diseases or conditions leading up to them. Fast Healthcare Interoperability Resources (FHIR) is a new HL7 interoperability standard for electronic health record, while Sustainable Medical Applications and Reusable Technologies (SMART)-on-FHIR enables third-party app development that can work "out of the box." This paper demonstrates the feasibility of developing SMART-on-FHIR applications that enables medical professionals to perform timely and accurate death reporting within multiple different USA State jurisdictions. We explored how the information on a standard certificate of death can be mapped to resources defined in the FHIR standard Draft Standard for Trial Use Version 2 and common profiles. We also demonstrated analytics for potentially improving the accuracy and completeness of mortality reporting data. PMID- 29993992 TI - Prediction of Adverse Glycemic Events from Continuous Glucose Monitoring Signal. AB - The most important objective of any diabetes therapy is to maintain the blood glucose concentration within the euglycemic range, avoiding or at least mitigating critical hypo/hyperglycemic episodes. Modern Continuous Glucose Monitoring (CGM) devices bear the promise of providing the patients with an increased and timely awareness of glycemic conditions as these get dangerously near to hypo/hyperglycemia. The challenge is to detect, with reasonable advance, the patterns leading to risky situations, allowing the patient to make therapeutic decisions on the basis of future (predicted) glucose concentration levels. We underline that a technically sound performance comparison of the approaches that have been proposed in recent years is still missing, and is thus unclear which one is to be preferred. The aim of this study is to fill this gap, by carrying out a comparative analysis among the most common methods for glucose event prediction. Both regression and classification algorithms have been implemented and analyzed, including static and dynamic training approaches. The dataset consists of 89 CGM time series measured in diabetic subjects for 7 subsequent days. Performance metrics, specifically defined to assess and compare the event prediction capabilities of the methods, have been introduced and analyzed. Our numerical results show that a static training approach exhibits better performance, in particular when regression methods are considered. However, classifiers show some improvement when trained for a specific event category, such as hyperglycemia, achieving performance comparable to the regressors, with the advantage of predicting the events sooner. PMID- 29993993 TI - An enhanced device-transparent real-time teleconsultation environment for radiologists. AB - This paper describes a novel web-based platform promoting real-time advanced teleconsultation services on medical imaging. Principles of heterogeneous Workflow Management Systems (WFMSs) and state-of-the-art technologies such as the microservices architectural pattern, peer-to-peer networking and the Single-Page Application (SPA) concept are combined to build a platform to aid collaboration among geographically distributed healthcare professionals. The real time communication capabilities are based on the webRTC protocol. The paper discusses the conceptual and technical details of the system, emphasizing on its innovative elements. The operation of the system in practice along with some initial results are also presented. PMID- 29993994 TI - 7-Point Checklist and Skin Lesion Classification using Multi-Task Multi-Modal Neural Nets. AB - We propose a multi-task deep convolutional neural network, trained on multi-modal data (clinical and dermoscopic images, and patient meta-data), to classify the 7 point melanoma checklist criteria and perform skin lesion diagnosis. Our neural network is trained using several multi-task loss functions, where each loss considers different combinations of the input modalities, which allows our model to be robust to missing data at inference time. Our final model classifies the 7 point checklist and skin condition diagnosis, produces multi-modal feature vectors suitable for image retrieval, and localizes clinically discriminant regions. We benchmark our approach using 1011 lesion cases, and report comprehensive results over all 7-point criteria and diagnosis. We also make our dataset (images and metadata) publicly available online at http://derm.cs.sfu.ca. PMID- 29993995 TI - Distributed Graph Hashing. AB - Recently, hashing-based approximate nearest neighbors search has attracted considerable attention, especially in big data applications, due to its low computation cost and fast retrieval speed. In the literature, most of the existing hashing algorithms are centralized. However, in many large-scale applications, the data are often stored or collected in a distributed manner. In this situation, the centralized hashing methods are not suitable for learning hash functions. In this paper, we consider the distributed learning to hash problem. We propose a novel distributed graph hashing model for learning efficient hash functions based on the data distributed across multiple agents over network. The graph hashing model involves a graph matrix, which contains the similarity information in the original space. We show that the graph matrix in the proposed distributed hashing model can be decomposed into multiple local graph matrices, and each local graph matrix can be constructed by a specific agent independently, with moderate communication and computation cost. Then, the whole objective function of the distributed hashing model can be represented by the sum of local objective functions of multiple agents, and the hashing problem can be formulated as a nonconvex constrained distributed optimization problem. For tractability, we transform the nonconvex constrained distributed optimization problem into an equivalent bi-convex distributed optimization problem. Then we propose two algorithms based on the idea of alternating direction method of multipliers to solve this problem in a distributed manner. We show that the proposed two algorithms have moderate communication and computational complexities, and both of them are scalable. Experiments on benchmark datasets are given to demonstrate the effectiveness of the proposed methods. PMID- 29993997 TI - Automated 3-D Neuron Tracing With Precise Branch Erasing and Confidence Controlled Back Tracking. AB - The automatic reconstruction of single neurons from microscopic images is essential to enable large-scale data-driven investigations in neuron morphology research. However, few previous methods were able to generate satisfactory results automatically from 3-D microscopic images without human intervention. In this paper, we developed a new algorithm for automatic 3-D neuron reconstruction. The main idea of the proposed algorithm is to iteratively track backward from the potential neuronal termini to the soma centre. An online confidence score is computed to decide if a tracing iteration should be stopped and discarded from the final reconstruction. The performance improvements comparing with the previous methods are mainly introduced by a more accurate estimation of the traced area and the confidence controlled back-tracking algorithm. The proposed algorithm supports large-scale batch-processing by requiring only one user specified parameter for background segmentation. We bench tested the proposed algorithm on the images obtained from both the DIADEM challenge and the BigNeuron challenge. Our proposed algorithm achieved the state-of-the-art results. PMID- 29993996 TI - Pulmonary Artery-Vein Classification in CT Images Using Deep Learning. AB - Recent studies show that pulmonary vascular diseases may specifically affect arteries or veins through different physiologic mechanisms. To detect changes in the two vascular trees, physicians manually analyze the chest computed tomography (CT) image of the patients in search of abnormalities. This process is time consuming, difficult to standardize, and thus not feasible for large clinical studies or useful in real-world clinical decision making. Therefore, automatic separation of arteries and veins in CT images is becoming of great interest, as it may help physicians to accurately diagnose pathological conditions. In this paper, we present a novel, fully automatic approach to classify vessels from chest CT images into arteries and veins. The algorithm follows three main steps: first, a scale-space particles segmentation to isolate vessels; then a 3-D convolutional neural network (CNN) to obtain a first classification of vessels; finally, graph-cuts' optimization to refine the results. To justify the usage of the proposed CNN architecture, we compared different 2-D and 3-D CNNs that may use local information from bronchus- and vessel-enhanced images provided to the network with different strategies. We also compared the proposed CNN approach with a random forests (RFs) classifier. The methodology was trained and evaluated on the superior and inferior lobes of the right lung of 18 clinical cases with noncontrast chest CT scans, in comparison with manual classification. The proposed algorithm achieves an overall accuracy of 94%, which is higher than the accuracy obtained using other CNN architectures and RF. Our method was also validated with contrast-enhanced CT scans of patients with chronic thromboembolic pulmonary hypertension to demonstrate that our model generalizes well to contrast enhanced modalities. The proposed method outperforms state-of-the-art methods, paving the way for future use of 3-D CNN for artery/vein classification in CT images. PMID- 29993998 TI - Investigation on Third-Order Intermodulation Distortions Due to Material Nonlinearities in TC-SAW Devices. AB - Nonlinearity can give rise to intermodulation distortions in surface acoustic wave (SAW) devices operating at high input power levels. To understand such undesired effects, a finite element method (FEM) simulation model in combination with a perturbation theory is applied to find out the role of different materials and higher order nonlinear tensor data for the nonlinearities in such acoustic devices. At high power, the SAW devices containing metal, piezoelectric substrate, and temperature compensating (TC) layers are subject to complicated geometrical, material, and other nonlinearities. In this paper, third-order nonlinearities in TC-SAW devices are investigated. The materials used are LiNbO3 rot128YX as the substrate and copper electrodes covered with a SiO2 film as the TC layer. An effective nonlinearity constant for a given system is determined by comparison of nonlinear P-matrix simulations to third-order intermodulation measurements of test filters in a first step. By employing these constants from different systems, i.e., different metallization ratios, in nonlinear periodic P matrix simulations, a direct comparison to nonlinear periodic FEM-simulations yields scaling factors for the materials used. Thus, the contribution of the different materials to the nonlinear behavior of TC-SAW devices is obtained and the role of metal electrodes, substrate, and TC film are discussed in detail. PMID- 29993999 TI - On the Effects of Spatial Sampling Quantization in Super-Resolution Ultrasound Microvessel Imaging. AB - Ultrasound super-resolution (SR) microvessel imaging technologies are rapidly emerging and evolving. The unprecedented combination of imaging resolution and penetration promises a wide range of preclinical and clinical applications. This study concerns spatial quantization error in SR imaging, a common issue that involves a majority of current SR imaging methods. While quantization error can be alleviated by the microbubble localization process (e.g., via upsampling or parametric fitting), it is unclear to what extent the localization process can suppress the spatial quantization error induced by discrete sampling. It is also unclear when low spatial sampling frequency will result in irreversible quantization errors that cannot be suppressed by the localization process. This study had two goals: 1) to systematically investigate the effect of quantization in SR imaging and establish principles of adequate SR imaging spatial sampling that yield minimal quantization error with proper localization methods; 2) to compare the performance of various localization methods and study the level of tolerance of each method to quantization. We conducted experiments on a small wire target and on a microbubble flow phantom. We found that Fourier analysis of an oversampled spatial profile of the microbubble signal could provide reliable guidance for selecting beamforming spatial sampling frequency. Among various localization methods, parametric Gaussian fitting and centroid-based localization on upsampled data had better microbubble localization performance and were less susceptible to quantization error than peak intensity-based localization methods. When spatial sampling resolution was low, parametric Gaussian fitting-based localization had the best performance in suppressing quantization error, and could produce acceptable SR microvessel imaging with no significant quantization artifacts. The findings from this paper can be used in practice to help intelligently determine the minimum requirement of spatial sampling for robust microbubble localization to avoid adding or even reduce the burden of computational cost and data storage that are commonly associated with SR imaging. PMID- 29994000 TI - Plenoptic Image Coding using Macropixel-based Intra Prediction. AB - The plenoptic image in a super high resolution is composed of a number of macropixels recording both spatial and angular light radiance. Based on the analysis of spatial correlations of macropixel structure, this paper proposes a macropixel-based intra prediction method for plenoptic image coding. After applying an invertible image reshaping method to the plenoptic image, the macropixel structures are aligned with the coding unit grids of a block-based video coding standard. The reshaped and regularized image is compressed by the video encoder comprising the proposed macropixel-based intra prediction, which includes three modes: multi-block weighted prediction mode (MWP), co-located single-block prediction mode (CSP), and boundary matching based prediction mode (BMP). In the MWP mode and BMP mode, the predictions are generated by minimizing spatial Euclidean distance and boundary error among the reference samples, respectively, which can fully exploit spatial correlations among the pixels beneath the neighboring microlens. The proposed approach outperforms HEVC by an average of 47.0% bitrate reduction. Compared with other state-of-the-art methods, like pseudo-video based on tiling and arrangement method (PVTA), intra block copy (IBC) mode, and locally linear embedding (LLE) based prediction, it can also achieve 45.0%, 27.7% and 22.7% bitrate savings on average, respectively. PMID- 29994001 TI - Task-Based Effectiveness of Basic Visualizations. AB - Visualizations of tabular data are widely used; understanding their effectiveness in different task and data contexts is fundamental to scaling their impact. However, little is known about how basic tabular data visualizations perform across varying data analysis tasks. In this paper, we report results from a crowdsourced experiment to evaluate the effectiveness of five small scale (5-34 data points) two-dimensional visualization types---Table, Line Chart, Bar Chart, Scatterplot, and Pie Chart---across ten common data analysis tasks using two datasets. We found the effectiveness of these visualization types significantly varies across task, suggesting that visualization design would benefit from considering context-dependent effectiveness. Based on our findings, we derive recommendations on which visualizations to choose based on different tasks. PMID- 29994002 TI - Robust Non-Rigid Registration with Reweighted Position and Transformation Sparsity. AB - Non-rigid registration is challenging because it is ill-posed with high degrees of freedom and is thus sensitive to noise and outliers. We propose a robust non rigid registration method using reweighted sparsities on position and transformation to estimate the deformations between 3-D shapes. We formulate the energy function with position and transformation sparsity on both the data term and the smoothness term, and define the smoothness constraint using local rigidity. The double sparsity based non-rigid registration model is enhanced with a reweighting scheme, and solved by transferring the model into four alternately optimized subproblems which have exact solutions and guaranteed convergence. Experimental results on both public datasets and real scanned datasets show that our method outperforms the state-of-the-art methods and is more robust to noise and outliers than conventional non-rigid registration methods. PMID- 29994003 TI - Effects of AR Display Context Switching and Focal Distance Switching on Human Performance. AB - In augmented reality (AR) environments, information is often distributed between real- world and virtual contexts, and often appears at different distances from the user. Therefore, to integrate the information, users must repeatedly switch context and refocus the eyes. To focus at different distances, the user's eyes must accommodate, which when done repeatedly can cause eyestrain and degrade task performance. An experiment was conducted that examined switching context and focal distance between a real and an AR environment, using a text-based visual search task and a monocular optical see-through AR display. Both context switching and focal distance switching resulted in significantly reduced performance. In addition, repeatedly performing the task caused visual fatigue to steadily increase. Performance was particularly poor for virtual text presented at optical infinity, and for target letters that participants tried to read before their eyes had completely accommodated to a new focal distance. The results show that context switching and focal distance switching are important AR user interface design issues. PMID- 29994004 TI - A Scalable Hybrid Scheme for Ray-Casting of Unstructured Volume Data. AB - We present an algorithm for parallel volume rendering that is a hybrid between classical object order and image order techniques. The algorithm operates on unstructured grids (and structured ones), and thus can deal with block boundaries interleaving in complex ways. It also deals effectively with cases that are prone to load imbalance, i.e., cases where cell sizes differ dramatically, either because of the nature of the input data, or because of the effects of the camera transformation. The algorithm divides work over resources such that each phase of its processing is bounded in the amount of computation it can perform. We demonstrate its efficacy through a series of studies, varying over camera position, data set size, transfer function, image size, and processor count. At its biggest, our experiments scaled up to 8,192 processors and operated on data sets with more than one billion cells. In total, we find that our hybrid algorithm performs well in all cases. This is because our algorithm naturally adapts its computation based on workload, and can operate like either an object order technique or an image order technique in scenarios where those techniques are efficient. PMID- 29994005 TI - SecureLR: Secure Logistic Regression Model via a Hybrid Cryptographic Protocol. AB - Machine learning applications are intensively utilized in various science fields, and increasingly the biomedical and healthcare sector. Applying predictive modeling to biomedical data introduces privacy and security concerns requiring additional protection to prevent accidental disclosure or leakage of sensitive patient information. Significant advancements in secure computing methods have emerged in recent years, however, many of which require substantial computational and/or communication overheads, which might hinder their adoption in biomedical applications. In this work, we propose SecureLR, a novel framework allowing researchers to leverage both the computational and storage capacity of Public Cloud Servers to conduct learning and predictions on biomedical data without compromising data security or efficiency. Our model builds upon homomorphic encryption methodologies with hardware-based security reinforcement through Software Guard Extensions (SGX), and our implementation demonstrates a practical hybrid cryptographic solution to address important concerns in conducting machine learning with public clouds. PMID- 29994006 TI - Advances in Automation Technologies for Lower Extremity Neurorehabilitation: A Review and Future Challenges. AB - The world is experiencing an unprecedented, enduring, and pervasive aging process. With more people who need walking assistance, the demand for lower extremity gait rehabilitation has increased rapidly over the years. The current clinical gait rehabilitative training requires heavy involvement of both medical doctors and physical therapists, and thus, are labor intensive, subjective, and expensive. To address these problems, advanced automation techniques, especially along with the proliferation of smart sensing and actuation devices and big data analytics platforms, have been introduced into this field to make the gait rehabilitation convenient, efficient, and personalized. This survey paper provides a comprehensive review on recent technological advances in wearable sensors, biofeedback devices, and assistive robots. Empowered by the emerging networking and computing technologies in the big data era, these devices are being interconnected into smart and connected rehabilitation systems to provide nonintrusive and continuous monitoring of physical and neurological conditions of the patients, perform complex gait analysis and diagnosis, and allow real-time decision making, biofeedback, and control of assistive robots. For each technology category, a detailed comparison among the existing solutions is provided. A thorough discussion is also presented on remaining open problems and future directions to further improve the safety, efficiency, and usability of the technologies. PMID- 29994007 TI - Behavioral Learning in a Cognitive Neuromorphic Robot: An Integrative Approach. AB - We present here a learning system using the iCub humanoid robot and the SpiNNaker neuromorphic chip to solve the real-world task of object-specific attention. Integrating spiking neural networks with robots introduces considerable complexity for questionable benefit if the objective is simply task performance. But, we suggest, in a cognitive robotics context, where the goal is understanding how to compute, such an approach may yield useful insights to neural architecture as well as learned behavior, especially if dedicated neural hardware is available. Recent advances in cognitive robotics and neuromorphic processing now make such systems possible. Using a scalable, structured, modular approach, we build a spiking neural network where the effects and impact of learning can be predicted and tested, and the network can be scaled or extended to new tasks automatically. We introduce several enhancements to a basic network and show how they can be used to direct performance toward behaviorally relevant goals. Results show that using a simple classical spike-timing-dependent plasticity (STDP) rule on selected connections, we can get the robot (and network) to progress from poor task-specific performance to good performance. Behaviorally relevant STDP appears to contribute strongly to positive learning: "do this" but less to negative learning: "don't do that." In addition, we observe that the effect of structural enhancements tends to be cumulative. The overall system suggests that it is by being able to exploit combinations of effects, rather than any one effect or property in isolation, that spiking networks can achieve compelling, task-relevant behavior. PMID- 29994008 TI - Discriminative Deep Quantization Hashing for Face Image Retrieval. AB - This paper proposes a new discriminative deep quantization hashing (DDQH) approach for large-scale face image retrieval by learning discriminative and compact binary codes. It jointly explores the discrete code learning, batch normalization quantization (BNQ) module, and end-to-end learning in one unified framework, which can guarantee the optimal compatibility of hash coding and feature learning. To learn multiscale and robust facial features, a deep network properly stacking several convolution-pooling layers and pooling layers is designed, and the facial features are obtained by fusing the outputs of the last convolutional layer and the last pooling layer. Besides, the prediction errors of the learned binary codes are minimized to learn discriminative binary codes of images. To obtain higher retrieval accuracies, a BNQ module is utilized to control quantization at a moderate level. Experiments are conducted on two widely used data sets, and the proposed DDQH method achieves encouraging improvements over some state-of-the-art hashing approaches. PMID- 29994009 TI - Exclusive Sparsity Norm Minimization With Random Groups via Cone Projection. AB - Many practical applications such as gene expression analysis, multitask learning, image recognition, signal processing, and medical data analysis pursue a sparse solution for the feature selection purpose and particularly favor the nonzeros evenly distributed in different groups. The exclusive sparsity norm has been widely used to serve to this purpose. However, it still lacks systematical studies for exclusive sparsity norm optimization. This paper offers two main contributions from the optimization perspective: 1) we provide several efficient algorithms to solve exclusive sparsity norm minimization with either smooth loss or hinge loss (nonsmooth loss). All algorithms achieve the optimal convergence rate . ( is the iteration number.) To the best of our knowledge, this is the first time to guarantee such convergence rate for the general exclusive sparsity norm minimization and 2) when the group information is unavailable to define the exclusive sparsity norm, we propose to use the random grouping scheme to construct groups and prove that if the number of groups is appropriately chosen, the nonzeros (true features) would be grouped in the ideal way with high probability. Empirical studies validate the efficiency of the proposed algorithms, and the effectiveness of random grouping scheme on the proposed exclusive support vector machine formulation. PMID- 29994010 TI - Neuro-Adaptive Control With Given Performance Specifications for Strict Feedback Systems Under Full-State Constraints. AB - In this paper, we investigate the tracking control problem for a class of strict feedback systems with pregiven performance specifications as well as full-state constraints. Our focus is on developing a feasible neural network (NN)-based control method that is able to, under full-state constraints, force the tracking error to converge into a prescribed region within preset finite time and further reduce the error to a smaller and adjustable residual set, while confining the overshoot within predefined small level. Based on two consecutive error transformations governed by two auxiliary functions, named with behavior-shaping function and asymmetric scaling function, respectively, a novel approach to achieve given performance specifications is developed under certain bound condition on the transformed error, such condition, along with the full-stated constraints, is guaranteed by imbedding barrier Lyapunov function (BLF) into the back-stepping design. Furthermore, asymmetric output constraints are maintained with a single symmetric BLF, simplifying the procedure of stability analysis. All internal signals including the stimulating inputs to the NN unit are ensured to be bounded. Both theoretical analysis and numerical simulation verify the effectiveness and the benefits of the design. PMID- 29994011 TI - Noncontact In-Bed Measurements of Physiological and Behavioral Signals Using an Integrated Fabric-Sheet Sensing Scheme. AB - Home monitoring requires measuring the physiological and behavioral signals without impairing a subject's everyday life. This research presents an integrated and noncontact approach for obtaining simultaneous physiological and behavioral signals of recumbent humans in beds using a home-monitoring application. In the proposed approach, a fabric-sheet unified sensing electrode (FUSE) obtains physiological signals by recording the electrocardiogram (ECG), chest and abdominal respiratory movements (RMs), and ballistocardiogram (BCG). The FUSE also detects the behavioral signals of body proximity (BPx) and lateral/supine lying postures. A prototype system with FUSE was validated in a short-term experiment and 6-h overnight measurements on two different groups composed of seven lying subjects. The results confirmed that the approach senses each signal independently and records the ECG, RMs, BCG, and BPx signals simultaneously. The mean sensitivities of the R and T waves of the ECG during sleep were 86.1% and 88.0%, respectively, whereas those of the chest and abdominal RMs were 90.7% and 90.1%, respectively. Although our prototype system has room for improvement, the results suggest that our approach enables the unconstrained, nocturnal monitoring of the physiological and behavioral signals in recumbent humans. The at-home monitoring of the physiological and behavioral signals is expected to contribute to cost-effective personalized healthcare in the future. This noncontact and easy to-install system for in-bed measurements can facilitate a new era of home monitoring. PMID- 29994012 TI - Unobtrusive Activity Recognition of Elderly People Living Alone Using Anonymous Binary Sensors and DCNN. AB - Elderly population (over the age of 60) is predicted to be 1.2 billion by 2025. Most of the elderly people would like to stay alone in their own house due to the high eldercare cost and privacy invasion. Unobtrusive activity recognition is the most preferred solution for monitoring daily activities of the elderly people living alone rather than the camera and wearable devices based systems. Thus, we propose an unobtrusive activity recognition classifier using Deep Convolutional Neural Network (DCNN) and anonymous binary sensors (PIR sensors and door sensors). The real world long-term fully annotated Aruba open dataset collected by binary sensors has been employed for the training and evaluation of the classifier. First, ten basic daily activities, namely: Bed_to_Toilet, Eating, Meal_Preparation, Relax, Sleeping, Work, Housekeeping, Wash_Dishes, Enter_Home, and Leave_Home are segmented with different sliding window sizes, and then converted into binary activity images. Next, the activity images are employed for training the DCNN classifiers with different parameters. Finally, the trained classifiers are evaluated with the 10-fold cross validation method, and the results show that the best DCNN classifier gives 0.79 and 0.951 of F1-score for all 10 activities and eight activities (excluding Leave_Home and Wash_Dishes), respectively. PMID- 29994013 TI - Early detection of mild cognitive impairment with in-home monitoring technologies using functional measures: A systematic review. AB - INTRODUCTION: The aging of the world population is accompanied by a substantial increase in neurodegenerative disorders such as dementia. Early detection of dementia, i.e. at the mild cognitive impairment (MCI) stage, could be an essential condition for slowing down the loss of autonomy and quality of life caused by the disease, as it would provide a critical window for the implementation of early pharmacological and non-pharmacological interventions. However, the current assessments for MCI have several limitations. In this context, approaches involving smart home technologies offer many attractive advantages, including the continuous measurement of functional abilities in ecological environments. OBJECTIVE: This systematic review aims to investigate the current state of knowledge on the effectiveness of smart home technologies for the early detection of MCI through the monitoring of everyday life activities. METHODS: A systematic search of publications in Medline, EMBASE, CINAHL was conducted. RESULTS: Sixteen studies were included in this review. Twelve studies were based on real-life monitoring, with several sensors installed in participants' actual homes, and four studies included scenario-based evaluations in which the participants had to complete various tasks in a research lab apartment. In real-life monitoring, the most used indicators of MCI were walking speed and activity/motion in the house. In scenario-based evaluation, time of completion, quality of activity completion, number of errors, amount of assistance needed, and task-irrelevant behaviors during the performance of everyday activities predicted MCI in participants. DISCUSSION: Despite technological limitations and the novelty of the field, smart home technologies represent a promising potential for the early screening of MCI and could support clinicians in geriatric care. PMID- 29994014 TI - Deep Self-Taught Hashing for Image Retrieval. AB - Hashing algorithm has been widely used to speed up image retrieval due to its compact binary code and fast distance calculation. The combination with deep learning boosts the performance of hashing by learning accurate representations and complicated hashing functions. So far, the most striking success in deep hashing have mostly involved discriminative models, which require labels. To apply deep hashing on datasets without labels, we propose a deep self-taught hashing algorithm (DSTH), which generates a set of pseudo labels by analyzing the data itself, and then learns the hash functions for novel data using discriminative deep models. Furthermore, we generalize DSTH to support both supervised and unsupervised cases by adaptively incorporating label information. We use two different deep learning framework to train the hash functions to deal with out-of-sample problem and reduce the time complexity without loss of accuracy. We have conducted extensive experiments to investigate different settings of DSTH, and compared it with state-of-the-art counterparts in six publicly available datasets. The experimental results show that DSTH outperforms the others in all datasets. PMID- 29994015 TI - Adaptive Formation Control of Cooperative Teleoperators With Intermittent Communications. AB - Most research so far in teleoperation control has assumed that all information is transmitted continuously. Unfortunately, the damaged and electromagnetic interfered line cause communication link failure. In addition, the unreliable link further leads to port data congestion. The data packet will be discarded when the buffer overflows. Consequently, it is unknown whether stability of the teleoperator could be guaranteed in the presence of intermittent communications. In order to overcome these drawbacks, in this paper, we provide a solution to the formation control problem of a single-master-multislave teleoperator in the situation where each robot is allowed to communicate with its neighbors only at some irregular discrete time instants. The relationship among control gains, topology, and maximum-allowable connected interval is presented. Simulations are performed to show the validity of our proposed approach. PMID- 29994016 TI - Distributed Algorithms for Searching Generalized Nash Equilibrium of Noncooperative Games. AB - In this paper, the distributed Nash equilibrium (NE) searching problem is investigated, where the feasible action sets are constrained by nonlinear inequalities and linear equations. Different from most of the existing investigations on distributed NE searching problems, we consider the case where both cost functions and feasible action sets depend on actions of all players, and each player can only have access to the information of its neighbors. To address this problem, a continuous-time distributed gradient-based projected algorithm is proposed, where a leader-following consensus algorithm is employed for each player to estimate actions of others. Under mild assumptions on cost functions and graphs, it is shown that players' actions asymptotically converge to a generalized NE. Simulation examples are presented to demonstrate the effectiveness of the theoretical results. PMID- 29994017 TI - Neural Networks-Based Adaptive Finite-Time Fault-Tolerant Control for a Class of Strict-Feedback Switched Nonlinear Systems. AB - This paper concentrates upon the problem of finite-time fault-tolerant control for a class of switched nonlinear systems in lower-triangular form under arbitrary switching signals. Both loss of effectiveness and bias fault in actuator are taken into account. The method developed extends the traditional finite-time convergence from nonswitched lower-triangular nonlinear systems to switched version by designing appropriate controller and adaptive laws. In contrast to the previous results, it is the first time to handle the fault tolerant problem for switched system while the finite-time stability is also necessary. Meanwhile, there exist unknown internal dynamics in the switched system, which are identified by the radial basis function neural networks. It is proved that under the presented control strategy, the system output tracks the reference signal in the sense of finite-time stability. Finally, an illustrative simulation on a resistor-capacitor-inductor circuit is proposed to further demonstrate the effectiveness of the theoretical result. PMID- 29994018 TI - An Efficient and Fast Quantum State Estimator With Sparse Disturbance. AB - A pure or nearly pure quantum state can be described as a low-rank density matrix, which is a positive semidefinite and unit-trace Hermitian. We consider the problem of recovering such a low-rank density matrix contaminated by sparse components, from a small set of linear measurements. This quantum state estimation task can be formulated as a robust principal component analysis (RPCA) problem subject to positive semidefinite and unit-trace Hermitian constraints. We propose an efficient and fast inexact alternating direction method of multipliers (I-ADMM), in which the subproblems are solved inexactly and hence have closed form solutions. We prove global convergence of the proposed I-ADMM, and the theoretical result provides a guideline for parameter setting. Numerical experiments show that the proposed I-ADMM can recover state density matrices of 5 qubits on a laptop in 0.69 s, with 6 x 10-4 accuracy (99.38% fidelity) using 30% compressive sensing measurements, which outperforms existing algorithms. PMID- 29994019 TI - Model-Based Edge-Event-Triggered Containment Control Under Directed Topologies. AB - This paper investigates the containment control problem of multiagent systems with double integrator dynamics under directed topologies. A model-based edge event-triggered control protocol is proposed, in which the control input to each agent only contains edge information and its own velocity information. Continuous detection is avoided by the establishment of a predictive model and each controller is only updated at its own event time instants. The theoretical results show that, under our control protocol, the containment control problem can be solved and the Zeno behavior is excluded. The effectiveness is further illustrated by simulation results. PMID- 29994020 TI - Variational Bayesian Approach for Causality and Contemporaneous Correlation Features Inference in Industrial Process Data. AB - In this paper, a hybrid model is proposed to simultaneously mine causal connections and features responsible for contemporaneous correlations in a multivariate process. The model is developed by combining the vector auto regressive exogenous model and the factor analysis model. The parameters of the resulting model are regularized using the hierarchical prior distributions for pruning insignificant/irrelevant ones from the model. It is then estimated under the variational Bayesian expectation maximization framework. The estimation is initiated with a complex model which is then systematically reduced to a simpler model that retains only the parameters corresponding to significant causal connections and contemporaneous correlations. Model reduction is carried out through a series of deterministic jumps from complex models to simpler models using a relevance criterion. The approach is illustrated with a number of simulated examples and an industrial case study. PMID- 29994021 TI - Network-Based T-S Fuzzy Dynamic Positioning Controller Design for Unmanned Marine Vehicles. AB - This paper is concerned with a Takagi-Sugeno (T-S) fuzzy dynamic positioning controller design for an unmanned marine vehicle (UMV) in network environments. Network-based T-S fuzzy dynamic positioning system (DPS) models for the UMV are first established. Then, stability and stabilization criteria are derived by taking into consideration an asynchronous difference between the normalized membership function of the T-S fuzzy DPS and that of the controller. The proposed stabilization criteria can stabilize states of the UMV. The dynamic positioning performance analysis verifies the effectiveness of the networked modeling and the controller design. PMID- 29994022 TI - Efficient Registration of High-Resolution Feature Enhanced Point Clouds. AB - We present a novel framework for rigid point cloud registration. Our approach is based on the principles of mechanics and thermodynamics. We solve the registration problem by assuming point clouds as rigid bodies consisting of particles. Forces can be applied between both particle systems so that they attract or repel each other. These forces are used to cause rigid-body motion of one particle system toward the other, until both are aligned. The framework supports physics-based registration processes with arbitrary driving forces, depending on the desired behaviour. Additionally, the approach handles feature enhanced point clouds, e.g. by colours or intensity values. Our framework is freely accessible for download. In contrast to already existing algorithms, our contribution is to precisely register high-resolution point clouds with nearly constant computational effort and without the need for pre-processing, subsampling or pre-alignment. At the same time, the quality is up to 28% higher than for state-of-the-art algorithms and up to 49% higher when considering feature-enhanced point clouds. Even in the presence of noise, our registration approach is one of the most robust, on par with state-of-the-art implementations. PMID- 29994023 TI - Deep D-Bar: Real-Time Electrical Impedance Tomography Imaging With Deep Neural Networks. AB - The mathematical problem for electrical impedance tomography (EIT) is a highly nonlinear ill-posed inverse problem requiring carefully designed reconstruction procedures to ensure reliable image generation. D-bar methods are based on a rigorous mathematical analysis and provide robust direct reconstructions by using a low-pass filtering of the associated nonlinear Fourier data. Similarly to low pass filtering of linear Fourier data, only using low frequencies in the image recovery process results in blurred images lacking sharp features, such as clear organ boundaries. Convolutional neural networks provide a powerful framework for post-processing such convolved direct reconstructions. In this paper, we demonstrate that these CNN techniques lead to sharp and reliable reconstructions even for the highly nonlinear inverse problem of EIT. The network is trained on data sets of simulated examples and then applied to experimental data without the need to perform an additional transfer training. Results for absolute EIT images are presented using experimental EIT data from the ACT4 and KIT4 EIT systems. PMID- 29994024 TI - Reducing Navigators in Free-Breathing Abdominal MRI via Temporal Interpolation Using Convolutional Neural Networks. AB - Navigated 2-D multi-slice dynamic magnetic resonance imaging (MRI) acquisitions are essential for MR guided therapies. This technique yields time-resolved volumetric images during free-breathing, which are ideal for visualizing and quantifying breathing induced motion. To achieve this, navigated dynamic imaging requires acquiring multiple navigator slices. Reducing the number of navigator slices would allow for acquiring more data slices in the same time, and hence, increasing through-plane resolution or alternatively the overall acquisition time can be reduced while keeping resolution unchanged. To this end, we propose temporal interpolation of navigator slices using convolutional neural networks (CNNs). Our goal is to acquire fewer navigators and replace the missing ones with interpolation. We evaluate the proposed method on abdominal navigated dynamic MRI sequences acquired from 14 subjects. Investigations with several CNN architectures and training loss functions show favorable results for cost and a simple feed-forward network with no skip connections. When compared with interpolation by non-linear registration, the proposed method achieves higher interpolation accuracy on average as quantified in terms of root mean square error and residual motion. Analysis of the differences shows that the better performance is due to more accurate interpolation at peak exhalation and inhalation positions. Furthermore, the CNN-based approach requires substantially lower execution times than that of the registration-based method. At last, experiments on dynamic volume reconstruction reveal minimal differences between reconstructions with acquired and interpolated navigator slices. PMID- 29994025 TI - NIMA: Neural Image Assessment. AB - Automatically learned quality assessment for images has recently become a hot topic due to its usefulness in a wide variety of applications such as evaluating image capture pipelines, storage techniques and sharing media. Despite the subjective nature of this problem, most existing methods only predict the mean opinion score provided by datasets such as AVA [1] and TID2013 [2]. Our approach differs from others in that we predict the distribution of human opinion scores using a convolutional neural network. Our architecture also has the advantage of being significantly simpler than other methods with comparable performance. Our proposed approach relies on the success (and retraining) of proven, state-of-the art deep object recognition networks. Our resulting network can be used to not only score images reliably and with high correlation to human perception, but also to assist with adaptation and optimization of photo editing/enhancement algorithms in a photographic pipeline. All this is done without need for a "golden" reference image, consequently allowing for single-image, semantic- and perceptually-aware, no-reference quality assessment. PMID- 29994026 TI - Visualization of Cultural Heritage Collection Data: State of the Art and Future Challenges. AB - After decades of digitization, large cultural heritage collections have emerged on the web, which contain massive stocks of content from galleries, libraries, archives, and museums. This increase in digital cultural heritage data promises new modes of analysis and increased levels of access for academic scholars and casual users alike. Going beyond the standard representations of search-centric and grid-based interfaces, a multitude of approaches has recently started to enable visual access to cultural collections, and to explore them as complex and comprehensive information spaces by the means of interactive visualizations. In contrast to conventional web interfaces, we witness a widening spectrum of innovative visualization types specially designed for rich collections from the cultural heritage sector. This new class of information visualizations gives rise to a notable diversity of interaction and representation techniques while lending currency and urgency to a discussion about principles such as serendipity, generosity, and criticality in connection with visualization design. With this survey, we review information visualization approaches to digital cultural heritage collections and reflect on the state of the art in techniques and design choices. We contextualize our survey with humanist perspectives on the field and point out opportunities for future research. PMID- 29994027 TI - MIMOSA: Algorithms for Microbial Profiling. AB - A significant goal of the study of metagenomes obtained from an environment is to find the microbial diversity and the abundance of each organism in the community. Phylotyping and binning methods which address this problem generally operate using either marker sequences or by classifying each genome fragment individually. However, these approaches might not use all the information contained in the metagenome. PMID- 29994028 TI - Robust Microbial Markers for Non-Invasive Inflammatory Bowel Disease Identification. AB - Inflammatory Bowel Disease (IBD) is an umbrella term for a group of inflammatory diseases of the gastrointestinal tract, including Crohn's Disease and ulcerative colitis. Changes to the intestinal microbiome, the community of micro-organisms that resides in the human gut, have been shown to contribute to the pathogenesis of IBD. IBD diagnosis is often delayed due its non-specific symptoms and because an invasive colonoscopy is required for confirmation, which leads to poor growth in children and worse treatment outcomes. Feature selection algorithms are often applied to microbial communities to identify bacterial groups that drive disease. It has been shown that aggregating Ensemble Feature Selection (EFS) can improve the robustness of feature selection algorithms, which is defined as the variation of feature selector output caused by small changes to the dataset. In this work we apply a two-step filter and an EFS process to generate robust feature subsets that can non-invasively predict IBD subtypes from high-resolution microbiome data. The predictive power of the robust feature subsets is the highest reported in literature to date. Furthermore, we identify five biologically plausible bacterial species that have not previously been implicated in IBD aetiology. PMID- 29994030 TI - An Exact Algorithm for Sorting by Weighted Preserving Genome Rearrangements. AB - The preserving Genome Sorting Problem (pGSP) asks for a shortest sequence of rearrangement operations that transforms a given gene order into another given gene order by using rearrangement operations that preserve common intervals, i.e., groups of genes that form an interval in both given gene orders. The wpGSP is the weighted version of the problem were each type of rearrangement operation has a weight and a minimum weight sequence of rearrangement operations is sought. An exact algorithm - called CREx2 - is presented, which solves the wpGSP for arbitrary gene orders and the following types of rearrangement operations: inversions, transpositions, inverse transpositions, and tandem duplication random loss operations. CREx2 has a (worst case) exponential runtime, but a linear runtime for problem instances where the common intervals are organized in a linear structure. The efficiency of CREx2 and its usefulness for phylogenetic analysis is shown empirically for gene orders of fungal mitochondrial genomes. PMID- 29994029 TI - Modelling Microbial Fuel Cells using lattice Boltzmann methods. AB - An accurate modelling of bio-electrochemical processes that govern Microbial Fuel Cells (MFCs) and mapping their behaviour according to several parameters will enhance the development of MFC technology and enable their successful implementation in well defined applications. The geometry of the electrodes is among key parameters determining efficiency of MFCs due to the formation of a biofilm of anodophilic bacteria on the anode electrode, which is a decisive factor for the functionality of the device. We simulate the bio-electrochemical processes in an MFC while taking into account the geometry of the electrodes. Namely, lattice Boltzmann methods are used to simulate the fluid dynamics and the advection-diffusion phenomena in the anode compartment. The model is verified on voltage and current outputs of a single MFC derived from laboratory experiments under continuous flow. Conclusions can be obtained from a parametric analysis of the model concerning the design of the geometry of the anode compartment, the positioning and microstructure of the anode electrode, in order to achieve more efficient overall performance of the system. An example of such a parametric analysis is presented here, taking into account the positioning of the electrode in the anode compartment. PMID- 29994031 TI - An integrative framework for protein interaction network and methylation data to discover epigenetic modules. AB - DNA methylation is a critical epigenetic modification that plays an important role in cancers. The available algorithms fail to fully characterize epigenetic modules. To address this issue, we first characterize the epigenetic module as a group of well-connected genes in the protein interaction network and are also co methylated based on gene methylation profiles. Then, the epigenetic module discovery problem is transformed into an optimization problem. Then, a regularized nonnegative matrix factorization algorithm for methylation modules (RNMF-MM) is presented, where the co-methylation constraint is treated as a regularizer. Using the artificial networks with known module structure, we demonstrate that the proposed algorithm outperforms state-of-the-art approaches in terms of accuracy. On the basis of breast cancer methylation data and protein interaction network, the RNMF-MM algorithm discovers methylation modules that are significantly more enriched by the known pathways than those obtained by other algorithms. These modules serve as biomarkers for predicting cancer stages and estimating survival time of patients. The proposed model and algorithm provide an effective way for the integrative analysis of protein interaction network and methylation data. PMID- 29994032 TI - Hardness of Covering Alignment: Phase Transition in Post-Sequence Genomics. AB - Covering alignment problems arise from recent developments in genomics; so called pan-genome graphs are replacing reference genomes, and advances in haplotyping enable full content of diploid genomes to be used as basis of sequence analysis. In this paper, we show that the computational complexity will change for natural extensions of alignments to pan-genome representations and to diploid genomes. More broadly, our approach can also be seen as a minimal extension of sequence alignment to labelled directed acyclic graphs (labeled DAGs). Namely, we show that finding a covering alignment of two labeled DAGs is NP-hard even on binary alphabets. A covering alignment asks for two paths (red) and (green) in DAG and two paths (red) and (green) in DAG that cover the nodes of the graphs and maximize the sum of the global alignment scores: , where is the concatenation of labels on the path P. Pair-wise alignment of haplotype sequences forming a diploid chromosome can be converted to a two-path coverable labelled DAG, and then the covering alignment models the similarity of two diploids over arbitrary recombinations. Reduction to the other direction shows that problem NP-hard on alphabets of size 3. PMID- 29994033 TI - Psychophysical Evaluation of Change in Friction on an Ultrasonically-Actuated Touchscreen. AB - To render haptic cues on a touchscreen by friction modulation, it is important to understand how human perceive a change in friction. In this study, we investigate the relations between perceived change in friction on an ultrasonically actuated touchscreen and parameters involved in contact between finger and its surface. We first estimate the perceptual thresholds to detect rising and falling friction while finger is sliding on the touch surface. Then, we conduct magnitude estimation experiments and investigate the effect of finger sliding velocity, normal force, and transition time on the perceived magnitude of change in friction. In order to better understand the role of contact mechanics, we also look into the correlations between the perceived magnitudes of subjects and several parameters involved in contact. The results of our experiments show that the contrast and rate of change in tangential force were best correlated with the magnitude estimates. The subjects perceived rising friction more strongly than falling friction, particularly at higher tangential force contrast. We argue that this is due to hysteresis and viscoelasticity of fingertip deformation under tangential loading. The results also showed that finger velocity did not affect the perception while transition time and normal force have a significant effect on our tactile perception. PMID- 29994034 TI - Nonconvulsive Epileptic Seizure Detection in Scalp EEG Using Multiway Data Analysis. AB - Nonconvulsive status epilepticus is a condition where the patient is exposed to abnormally prolonged epileptic seizures without evident physical symptoms. Since these continuous seizures may cause permanent brain damage, it constitutes a medical emergency. This paper proposes a method to detect nonconvulsive seizures for a further nonconvulsive status epilepticus diagnosis. To differentiate between the normal and seizure electroencephalogram (EEG), a K-Nearest Neighbor, a Radial Basis Support Vector Machine, and a Linear Discriminant Analysis classifier are used. The classifier features are obtained from the Canonical Polyadic Decomposition (CPD) and Block Term Decomposition (BTD) of the EEG data represented as third order tensor. To expand the EEG into a tensor, Wavelet or Hilbert-Huang transform are used. The algorithm is tested on a scalp EEG database of 139 seizures of different duration. The experimental results suggest that a Hilbert-Huang tensor representation and the CPD analysis provide the most suitable framework for nonconvulsive seizure detection. The Radial Basis Support Vector Machine classifier shows the best performance with sensitivity, specificity, and accuracy values over 98%. A rough comparison with other methods proposed in the literature shows the superior performance of the proposed method for nonconvulsive epileptic seizure detection. PMID- 29994035 TI - Iterative Learning Control for a Flapping Wing Micro Aerial Vehicle Under Distributed Disturbances. AB - This paper addresses a flexible micro aerial vehicle (MAV) under spatiotemporally varying disturbances, which is composed of a rigid body and two flexible wings. Based on Hamilton's principle, a distributed parameter system coupling in bending and twisting, is modeled. Two iterative learning control (ILC) schemes are designed to suppress the vibrations in bending and twisting, reject the distributed disturbances and regulate the displacement of the rigid body to track a prescribed constant trajectory. At the basis of composite energy function, the boundedness and the learning convergence are proved for the closed-loop MAV system. Simulation results are provided to illustrate the effectiveness of the proposed ILC laws. PMID- 29994036 TI - Feature Learning Using Spatial-Spectral Hypergraph Discriminant Analysis for Hyperspectral Image. AB - Hyperspectral image (HSI) contains a large number of spatial-spectral information, which will make the traditional classification methods face an enormous challenge to discriminate the types of land-cover. Feature learning is very effective to improve the classification performances. However, the current feature learning approaches are most based on a simple intrinsic structure. To represent the complex intrinsic spatial-spectral of HSI, a novel feature learning algorithm, termed spatial-spectral hypergraph discriminant analysis (SSHGDA), has been proposed on the basis of spatial-spectral information, discriminant information, and hypergraph learning. SSHGDA constructs a reconstruction between class scatter matrix, a weighted within-class scatter matrix, an intraclass spatial-spectral hypergraph, and an interclass spatial-spectral hypergraph to represent the intrinsic properties of HSI. Then, in low-dimensional space, a feature learning model is designed to compact the intraclass information and separate the interclass information. With this model, an optimal projection matrix can be obtained to extract the spatial-spectral features of HSI. SSHGDA can effectively reveal the complex spatial-spectral structures of HSI and enhance the discriminating power of features for land-cover classification. Experimental results on the Indian Pines and PaviaU HSI data sets show that SSHGDA can achieve better classification accuracies in comparison with some state-of-the-art methods. PMID- 29994037 TI - Dual-Environmental Particle Swarm Optimizer in Noisy and Noise-Free Environments. AB - Particle swarm optimizer (PSO) is a population-based optimization technique applied to a wide range of problems. In the literature, many PSO variants have been proposed to deal with noise-free or noisy environments, respectively. While in real-life applications, noise emerges irregularly and unpredictably. As a result, PSO for a noise-free environment loses its accuracy when noise exists, while PSO for a noisy environment wastes its resampling resource when noise does not exist. To handle such scenario, a PSO variant that can work well in both noise-free and noisy environments is required, which does, to the authors' best knowledge, not exist yet. To fill such gap, this work proposes a novel PSO variant named as dual-environmental PSO (DEPSO). It uses a weighted search center based on top-k elite particles to guide the swarm. It averages their positions rather than resampling fitness values of particles to achieve noise reduction, which challenges the indispensable role of the resampling method in a noisy environment and adapts to a noise-free environment as well. Two theoretical analyses are presented for noise reduction and finer local optimization capabilities. Experimental results performed on CEC2013 benchmark functions indicate that DEPSO outperforms state-of-the-art PSO variants in both noise-free and noisy environments. PMID- 29994039 TI - Consensus Maneuvering for a Class of Nonlinear Multivehicle Systems in Strict Feedback Form. AB - In this paper, a consensus maneuvering problem for nonlinear multivehicle systems in strict-feedback form is investigated. The consensus maneuvering problem includes a geometric task and a dynamic task. The geometric task means that all trajectories of follower vehicles converge to a parameterized path. The dynamic task is to drive the system to satisfy a desired dynamic assignment. A consensus maneuvering controller is developed for each vehicle based on a modular design approach. First, an estimator module is designed based on an echo state network, which is used to estimate uncertain nonlinearities. Then, a controller module is designed based on a modified dynamic surface control method through the use of a second-order nonlinear tracking differentiator. Finally, a path update law is designed based on a distributed maneuvering error feedback and a filtering scheme. The proposed controller is distributed in the sense that the path information is accessed by a small number of follower vehicles only. The stability of the closed-loop system cascaded by the estimator module and the controller module is analyzed based on input-to-state stability theory and cascade theory. Simulation results are provided to demonstrate the efficacy of the proposed consensus maneuvering controllers for uncertain nonlinear strict feedback systems. PMID- 29994038 TI - Adaptive -Learning for Data-Based Optimal Output Regulation With Experience Replay. AB - In this paper, the data-based optimal output regulation problem of discrete-time systems is investigated. An off-policy adaptive -learning (QL) method is developed by using real system data without requiring the knowledge of system dynamics and the mathematical model of utility function. By introducing the function, an off-policy adaptive QL algorithm is developed to learn the optimal function. An adaptive parameter in the policy evaluation is used to achieve tradeoff between the current and future -functions. The convergence of adaptive QL algorithm is proved and the influence of the adaptive parameter is analyzed. To realize the adaptive QL algorithm with real system data, the actor-critic neural network (NN) structure is developed. The least-squares scheme and the batch gradient descent method are developed to update the critic and actor NN weights, respectively. The experience replay technique is employed in the learning process, which leads to simple and convenient implementation of the adaptive QL method. Finally, the effectiveness of the developed adaptive QL method is verified through numerical simulations. PMID- 29994040 TI - Hybrid Regularized Echo State Network for Multivariate Chaotic Time Series Prediction. AB - Multivariate chaotic time series prediction is a hot research topic, the goal of which is to predict the future of the time series based on past observations. Echo state networks (ESNs) have recently been widely used in time series prediction, but there may be an ill-posed problem for a large number of unknown output weights. To solve this problem, we propose a hybrid regularized ESN, which employs a sparse regression with the L1/2 regularization and the L2 regularization to compute the output weights. The L1/2 penalty shows many attractive properties, such as unbiasedness and sparsity. The L2 penalty presents appealing ability on shrinking the amplitude of the output weights. After the output weights are calculated, the input weights, internal weights, and output weights are fine-tuning by a Hessian-free optimization method--conjugate gradient backpropagation algorithm. The fine-tuning helps to bubble up the input information toward the output layer. Besides, the largest Lyapunov exponent is used to calculate the predictable horizon of a chaotic time series. Experimental results on benchmark and real-world datasets show that our proposed method is superior to other ESN-based models, as sparser, smaller-absolute-value, and more informative output weights are obtained. All of the predictions within the predictable horizon of the proposed model are accurate. PMID- 29994041 TI - Secure Estimation for Cyber-Physical Systems via Sliding Mode. AB - This paper is concerned with the problem of secure state reconstruction for cyber physical systems (CPSs). CPSs are more vulnerable to the cyber world yet to attackers, who can attack any sensor of the considered systems and modify values of attacked sensors to be arbitrary ones. In the design process, both malicious attacks on sensors and unknown input are taken into consideration. First, a linear discrete-time state-space model is utilized to describe such systems, and then a sparse vector is adopted to model attacks. By collecting sensor measurements and using an iterative approach, a new model in descriptor form is obtained, which paves the way for estimating system states under an unknown input situation. Second, the problem of secure state estimation is transformed into an optimal version. A novel sliding-mode observer is proposed to estimate system states from collected sensor measurements corrupted by malicious attacks. In order to guarantee the estimations to be sparse, a projection operator is designed. Third, a projected sliding-mode observer-based estimation algorithm is developed to reconstruct system states, where an event-triggered scheme is integrated to save limited computational resource. In addition to propose such an algorithm, the effectiveness of both projection operator and sliding-mode observer is analyzed. Furthermore, the convergence of the proposed secure estimation algorithm is proved. Finally, some simulation results are given to demonstrate the effectiveness of the proposed algorithm. PMID- 29994042 TI - Growing Super Stable Tensegrity Frameworks. AB - This paper discusses methods for growing tensegrity frameworks akin to what are now known as Henneberg constructions (HCs), which apply to bar-joint frameworks. In particular, this paper presents tensegrity framework versions of the three key HCs of vertex addition, edge splitting, and framework merging (where separate frameworks are combined into a larger framework). This is done for super stable tensegrity frameworks in an ambient 2-D or 3-D space. We start with the operation of adding a new vertex to an original super stable tensegrity framework, named vertex addition. We prove that the new tensegrity framework can be super stable as well if the new vertex is attached to the original framework by an appropriate number of members, which include struts or cables, with suitably assigned stresses. Edge splitting can be secured in R2 (R3) by adding a vertex joined to three (four) existing vertices, two of which are connected by a member, and then removing that member. This procedure, with appropriate selection of struts or cables, preserves super-stability. In d-dimensional ambient space, merging two super stable frameworks sharing at least d+1 vertices that are in general positions, we show that the resulting tensegrity framework is still super stable. Based on these results, we further investigate the strategies of merging two super stable tensegrity frameworks in Rd, (d ? {2,3}) that share fewer than d+1 vertices, and show how they may be merged through the insertion of struts or cables as appropriate between the two structures, with a super stable structure resulting from the merge. PMID- 29994044 TI - Image Projective Invariants. AB - In this paper, we have proved the existence of projective moment invariants of images using finite combinations of weighted moments, with relative projective differential invariants as weight functions. We have given some instances constructed in that way, and analyzed possible issues could affect the performance. Some procedures are taken to estimate partial derivatives of discrete images, and a new method is designed to normalize the number of pixels for discrete images to minimize the changes before and after the projective transformation. We have carried out experiments using popular image databases and real images to test the performance. And the results show that the invariants proposed in this paper have better stability and discriminability than other previously used moment invariants in image retrieval and classification. Users can directly extract invariant features of images for a given planar object from different viewpoints without knowing the parameters of the 2D projective transformations. Therefore, the projective moment invariant could be potentially useful for planar object recognition, image description and classification. PMID- 29994043 TI - Adaptive Estimated Inverse Output-Feedback Quantized Control for Piezoelectric Positioning Stage. AB - Focusing on the piezoelectric positioning stage, this paper proposes an adaptive estimated inverse output-feedback quantized control scheme. First, the quantized issue due to the use of computer is addressed by introducing a linear time varying quantizer model where the quantizer parameters can be estimated on-line. Second, by using the fuzzy approximator, the developed controller can avoid the identification of the parameters in the piezoelectric positioning stage. Third, by constructing the estimated inverse compensator of the hysteresis, the hysteresis nonlinearities in the piezoelectric actuator are mitigated; Fourth, the states observer is designed to avoid the measurements of the velocity and acceleration signals. The analysis of stability shows all the signals in the piezoelectric positioning stage are uniformly ultimately bounded and the prespecified tracking performance of the quantized control system is achieved by employing the error transformed function. Finally, a computer controlled experiments for the piezoelectric positioning stage is conducted to show the effectiveness of the proposed quantized controller. PMID- 29994045 TI - Egocentric Meets Top-View. AB - Thanks to the availability of wearable devices such as GoPro cameras, smart phones, and glasses, we have now access to a plethora of videos captured from the first person perspective. Surveillance cameras and Unmanned Aerial Vehicles (UAVs) also offer tremendous amounts of video data recorded from top and oblique view points. Egocentric and surveillance vision have been studied extensively but separately in the computer vision community. The relationship between these two domains, however, remains unexplored. In this study, we make the first attempt in this direction by addressing two basic yet challenging questions. First, having a set of egocentric videos and a top-view video, does the top-view video contain all or some of the egocentric viewers? In other words, have these videos been shot in the same environment at the same time? Second, if so, how can we identify the egocentric viewers in the top-view video? These problems can become even more challenging when videos are not temporally aligned. We model each view using a graph, and compute the assignment and time-delays in an iterative-alternative fashion using spectral graph matching and time delay estimation. Such an approach handles the temporal misalignment between the egocentric videos and the top-view video. PMID- 29994046 TI - Learning to Deblur Images with Exemplars. AB - Human faces are one interesting object class with numerous applications. While significant progress has been made in the generic deblurring problem, existing methods are less effective for blurry face images. The success of the state-of the-art image deblurring algorithms stems mainly from implicit or explicit restoration of salient edges for kernel estimation. However, existing methods are less effective as only few edges can be restored from blurry face images for kernel estimation. In this paper, we address the problem of deblurring face images by exploiting facial structures. We propose a deblurring algorithm based on an exemplar dataset without using coarse-to-fine strategies or heuristic edge selections. In addition, we develop a convolutional neural network to restore sharp edges from blurry face images for deblurring. Extensive experiments against the state-of-the-art methods demonstrate the effectiveness of the proposed algorithms for deblurring face images. In addition, we show the proposed algorithms can be applied to image deblurring for other object classes. PMID- 29994047 TI - Multiscale Frame-Based Kernels for Large Deformation Diffeomorphic Metric Mapping. AB - We present a set of multiscale frame-based kernels that can be used to construct diffeomorphic transformation in the large deformation diffeomorphic metric mapping (LDDMM) framework. We construct multiscale kernels via compact wavelet frames that are equipped with the hierarchical multiresolution analysis. We show that these kernels under certain conditions can form reproducing kernel Hilbert spaces of smooth velocity fields and hence can be used to generate multiscale diffeomorphic transformation for LDDMM. As a proof of concept, we incorporate these kernels in the LDDMM framework. We show the improvement of whole brain mapping accuracy using the LDDMM with frame-based kernels in comparison to that obtained using the LDDMM with Gaussian kernels. Moreover, we evaluate whole brain mapping accuracy of the LDDMM with frame-based kernels against that obtained from the 14 brain mapping methods given by Klein et al.. Our results suggest that the LDDMM with frame-based kernels has the potential to outperform the 14 brain mapping methods for whole brain mapping. PMID- 29994048 TI - Influence of Coupling Between Rayleigh and SH SAWs on Rotated -Cut LiNbO3 to Their Propagations. AB - This paper investigates the influence of coupling between Rayleigh and shear horizontal (SH) surface acoustic waves (SAWs) on rotated Y-cut LiNbO3 to their electromechanical coupling. For the purpose, a coupling-of-mode (COM) model including the coupling between two SAWs is developed, and the coupling influences to their excitation in addition to electromechanical coupling factors are discussed. Then, its validity is confirmed by comparison of its results with the finite-element method analysis. Comparing with the conventional COM shows this extended COM model could fit the complex value area much better in the dispersion curve analysis. After that, variation of COM parameters with the device design is discussed. Then, all COM parameters are fit by polynomial equations and the procedures to find the optimal rotation angle are obtained in terms of the SH mode suppression. It indicates that the optimal angle changes rapidly at certain Cu thickness, which is due to decoupling between two SAW modes. At last, structure based on the low-cut LiNbO3 is discussed and the validity of this COM model is further confirmed. PMID- 29994049 TI - A Sampling Approach to Generating Closely Interacting 3D Pose-pairs from 2D Annotations. AB - We introduce a data-driven method to generate a large number of plausible, closely interacting 3D human pose-pairs, for a given motion category, e.g., wrestling or salsa dance. With much difficulty in acquiring close interactions using 3D sensors, our approach utilizes abundant existing video data which cover many human activities. Instead of treating the data generation problem as one of reconstruction, either through 3D acquisition or direct 2D-to-3D data lifting from video annotations, we present a solution based on Markov Chain Monte Carlo (MCMC) sampling. With a focus on efficient sampling over the space of close interactions, rather than pose spaces, we develop a novel representation called interaction coordinates (IC) to encode both poses and their interactions in an integrated manner. Plausibility of a 3D pose-pair is then defined based on the ICs and with respect to the annotated 2D pose-pairs from video. We show that our sampling-based approach is able to efficiently synthesize a large volume of plausible, closely interacting 3D pose-pairs which provide a good coverage of the input 2D pose-pairs. PMID- 29994050 TI - Resource Cut, a New Bounding Procedure to Algorithms for Enumerating Tree-like Chemical Graphs. AB - Enumerating chemical compounds with given structural properties plays an important role in structure elucidation, with applications such as drug design. We focus on the problem of enumerating tree-like chemical graphs specified by upper and lower bounds on feature vectors, where chemical graphs represent compounds, and a feature vector characterizes frequencies of finite paths in a graph. Building on the branch-and-bound algorithm proposed in earlier work, we propose a new bounding procedure, called RESOURCE CUT, to speed up the enumeration process. Tree-like chemical graphs are modeled as vertex-colored trees, colors representing chemical elements. The algorithm is based on a scheme of generating each unique colored tree with n vertices. A colored tree is constructed by repeatedly appending vertices. Given a set R of n colored vertices, we found that the algorithm often constructs trees that cannot be extended to a unique representation of a colored tree no matter how the remaining unused colored vertices in the set R are appended. We derive a mathematical condition to detect and discard such trees. Experimental results show that RESOURCE CUT significantly reduces the search space. We have been able to obtain exact numbers of chemical graphs with up to 17 vertices excluding hydrogen atoms. PMID- 29994051 TI - Computational drug repositioning with random walk on a heterogeneous network. AB - Drug repositioning is an efficient and promising strategy to identify new indications for existing drugs, which can improve the productivity of traditional drug discovery and development. Rapid advances in high-throughput technologies have generated various types of biomedical data over the past decades, which lay the foundations for furthering the development of computational drug repositioning approaches. Although many researches have tried to improve the repositioning accuracy by integrating information from multiple sources and different levels, it is still appealing to further investigate how to efficiently exploit valuable data for drug repositioning. In this study, we propose an efficient approach, RWHNDR (Random Walk on a Heterogeneous Network for Drug Repositioning), to prioritize candidate drugs for diseases. First, an integrated heterogeneous network is constructed by combining multiple sources including drugs, drug targets, diseases and disease genes data. Then, a random walk model is developed to capture the global information of the heterogeneous network. RWHNDR takes advantage of drug targets and disease genes data more comprehensively for drug repositioning. The experiment results show that our approach achieves well improved performance, compared with other state-of-the-art approaches which prioritized candidate drugs based on multi-source data. PMID- 29994052 TI - Kurtosis-Based CRTRL Algorithms for Fully Connected Recurrent Neural Networks. AB - In this paper, kurtosis-based complex-valued real-time recurrent learning (KCRTRL) and kurtosis-based augmented CRTRL (KACRTRL) algorithms are proposed for training fully connected recurrent neural networks (FCRNNs) in the complex domain. These algorithms are designed by minimizing the cost functions based on the kurtosis of a complex-valued error signal. The KCRTRL algorithm exploits the circularity properties of the complex-valued signals, and this algorithm not only provides a faster convergence rate but also results in a lower steady-state error. However, the KCRTRL algorithm is suboptimal in the processing of noncircular (NC) complex-valued signals. On the other hand, the KACRTRL algorithm contains a complete second-order information due to the augmented statistics, thus considerably improves the performance of the FCRNN in the processing of NC complex-valued signals. Simulation results on the one-step-ahead prediction problems show that the proposed KCRTRL algorithm significantly enhances the performance for only circular complex-valued signals, whereas the proposed KACRTRL algorithm provides more superior performance than existing algorithms for NC complex-valued signals in terms of the convergence rate and the steady-state error. PMID- 29994053 TI - Fully Convolutional Neural Networks to Detect Clinical Dermoscopic Features. AB - The presence of certain clinical dermoscopic features within a skin lesion may indicate melanoma, and automatically detecting these features may lead to more quantitative and reproducible diagnoses. We reformulate the task of classifying clinical dermoscopic features within superpixels as a segmentation problem, and propose a fully convolutional neural network to detect clinical dermoscopic features from dermoscopy skin lesion images. Our neural network architecture uses interpolated feature maps from several intermediate network layers, and addresses imbalanced labels by minimizing a negative multi-label Dice-F1 score, where the score is computed across the mini-batch for each label. Our approach ranked first place in the 2017 ISIC-ISBI Part 2: Dermoscopic Feature Classification Task challenge over both the provided validation and test datasets, achieving a 0.895% area under the receiver operator characteristic curve score. We show how simple baseline models can outrank state-of-the-art approaches when using the official metrics of the challenge, and propose to use a fuzzy Jaccard Index that ignores the empty set (i.e., masks devoid of positive pixels) when ranking models. Our results suggest that (i) the classification of clinical dermoscopic features can be effectively approached as a segmentation problem, and (ii) the current metrics used to rank models may not well capture the efficacy of the model. We plan to make our trained model and code publicly available. PMID- 29994054 TI - Quantitative Assessment for Self-Tracking of Acute Stress based on Triangulation Principle in a Wearable Sensor System. AB - Due to the variation in factors surrounding humans, the physiological impact of stress is reported to be different for each individual. Thus, an efficient stress monitoring system needs to assess both the physiological and psychological impact of stress on individual basis and translate these assessments into an accurate quantitative metric that is of value to the individual. Therefore, this study proposed a logistic regression based model that integrates data from psychological (Stress Response Inventory, SRI), biochemical (salivary cortisol), and physiological (HRV measures) domains via a principle of triangulation for achieving high reliability and consistency during stress assessment. With the proposed model, a mental stress index (MSI) based on the correlation between salivary cortisol and HRV time-/frequency-domain features were established. A total of 30 college students were recruited to verify the feasibility of proposed method by identifying targeted stressful event. The obtained results reveal that MSI values were sensitive to acute stress, and could predict the association level of normal individual to a stress group with approximately 97% accuracy. Findings from this study could provide potential insight on self-tracking and training of individual's stress with adoption of wearable sensor system in a dynamic setting. PMID- 29994055 TI - Sparse Group Representation Model for Motor Imagery EEG Classification. AB - A potential limitation of a motor imagery (MI) based brain-computer interface (BCI) is that it usually requires a relatively long time to record sufficient EEG data for robust classifier training. The calibration burden during data acquisition phase will most probably cause a subject to be reluctant to use a BCI system. To alleviate this issue, we propose a novel sparse group representation model (SGRM) for improving the efficiency of MI-based BCI by exploiting the inter subject information. Specifically, preceded by feature extraction using common spatial pattern, a composite dictionary matrix is constructed with training samples from both the target subject and other subjects. By explicitly exploiting within-group sparse and group-wise sparse constraints, the most compact representation of a test sample of the target subject is then estimated as a linear combination of columns in the dictionary matrix. Classification is implemented by calculating the class-specific representation residual based on the significant training samples corresponding to the nonzero representation coefficients. Accordingly, the proposed SGRM method effectively reduces the required training samples from the target subject due to auxiliary data available from other subjects. With two public EEG datasets, extensive experimental comparisons are carried out between SGRM and other state-of-the-art approaches. Superior classification performance of our method using 40 trials of the target subject for model calibration (Averaged accuracy = 78.2%, Kappa = 0.57 and Averaged accuracy = 77.7%, Kappa = 0.55 for the two datasets, respectively) indicates its promising potential for improving the practicality of MI-based BCI. PMID- 29994056 TI - A Hierarchical Bayesian Model for Personalized Survival Predictions. AB - We study the problem of personalizing survival estimates of patients in heterogeneous populations for clinical decision support. The desiderata are to improve predictions by making them personalized to the patient-at-hand, to better understand diseases and their risk factors, and to provide interpretable model outputs to clinicians. To enable accurate survival prognosis in heterogeneous populations we propose a novel probabilistic survival model which flexibly captures individual traits through a hierarchical latent variable formulation. Survival paths are estimated by jointly sampling the location and shape of the individual survival distribution resulting in patient-specific curves with quantifiable uncertainty estimates. An understanding of model predictions is paramount in medical practice where decisions have major social consequences. We develop a "personalized interpreter" that can be used to test the effect of covariates on each individual patient, in contrast to traditional methods that focus on population average effects. We extensively validated the proposed approach in various clinical settings, with a special focus on cardiovascular disease. PMID- 29994057 TI - PhysOnline: An Online Feature Extraction and Machine Learning Pipeline for Real Time Analysis of Streaming Physiological Data. AB - Real-time analysis of streaming physiological data to identify earlier abnormal conditions is an important aspect of precision medicine. However, open-source systems supporting this workflow are lacking. In this paper, we present PhysOnline, a pipeline built on the open-source Apache Spark platform to ingest streaming physiological data for online feature extraction and machine learning. We consider scalability factors for horizontal deployment to support growing analysis requirements. We further integrate real-time feature extraction, including pattern recognition methods as well as descriptive statistical components to identify temporal characteristics of waveform signals. These generated features are then used for machine learning and for real-time classification of abnormal conditions. As a case study, we present the online classification of electrocardiography (ECG) recordings for screening Paroxysmal Atrial Fibrillation (PAF) and demonstrate that our pipeline can predict persons developing PAF at least 45 minutes before an episode of that condition. This pipeline can be applied in domains where pattern matching, temporal abstractions, and morphological characteristics can be used for real-time classification of streaming time-series data. PMID- 29994058 TI - Hidden-Markov-Model-Based Asynchronous Filter Design of Nonlinear Markov Jump Systems in Continuous-Time Domain. AB - This paper addresses the dissipative asynchronous filtering problem for a class of Takagi-Sugeno fuzzy Markov jump systems in the continuous-time domain. The hidden Markov model is applied to describe the asynchronous situation between the designed filter and the original system. Based on the stochastic Lyapunov function, a sufficient condition is developed to guarantee the stochastic stability of the filtering error systems with a given dissipative performance. Two different methods for the existence of desired filter are established. Due to the Finsler's lemma, the second approach has fewer variables to decide and brings less conservatism than the first one. Finally, an example is provided to demonstrate the correctness and advantage of the proposed approaches. PMID- 29994059 TI - A Systematic Evaluation and Benchmark for Person Re-Identification: Features, Metrics, and Datasets. AB - Person re-identification (re-id) is a critical problem in video analytics applications such as security and surveillance. The public release of several datasets and code for vision algorithms has facilitated rapid progress in this area over the last few years. However, directly comparing re-id algorithms reported in the literature has become difficult since a wide variety of features, experimental protocols, and evaluation metrics are employed. In order to address this need, we present an extensive review and performance evaluation of single- and multi-shot re-id algorithms. The experimental protocol incorporates the most recent advances in both feature extraction and metric learning. To ensure a fair comparison, all of the approaches were implemented using a unified code library that includes 11 feature extraction algorithms and 22 metric learning and ranking techniques. All approaches were evaluated using a new large-scale dataset that closely mimics a real-world problem setting, in addition to 16 other publicly available datasets: VIPeR, GRID, CAVIAR, DukeMTMC4ReID, 3DPeS, PRID, V47, WARD, SAIVT-SoftBio, CUHK01, CHUK02, CUHK03, RAiD, iLIDSVID, HDA+ and Market1501. The evaluation codebase and results will be made publicly available for community use. PMID- 29994060 TI - Beyond Sharing Weights for Deep Domain Adaptation. AB - The performance of a classifier trained on data coming from a specific domain typically degrades when applied to a related but different one. While annotating many samples from the new domain would address this issue, it is often too expensive or impractical. Domain Adaptation has therefore emerged as a solution to this problem; It leverages annotated data from a source domain, in which it is abundant, to train a classifier to operate in a target domain, in which it is either sparse or even lacking altogether. In this context, the recent trend consists of learning deep architectures whose weights are shared for both domains, which essentially amounts to learning domain invariant features. Here, we show that it is more effective to explicitly model the shift from one domain to the other. To this end, we introduce a two-stream architecture, where one operates in the source domain and the other in the target domain. In contrast to other approaches, the weights in corresponding layers are related but not shared. We demonstrate that this both yields higher accuracy than state-of-the-art methods on several object recognition and detection tasks and consistently outperforms networks with shared weights in both supervised and unsupervised settings. PMID- 29994061 TI - ASAP: Super-Contrast Vasculature Imaging Using Coherence Analysis and High Frame Rate Contrast Enhanced Ultrasound. AB - The very high frame rate afforded by ultrafast ultrasound, combined with microbubble contrast agents, opens new opportunities for imaging tissue microvasculature. However, new imaging paradigms are required to obtain superior image quality from the large amount of acquired data while allowing real-time implementation. In this paper, we report a technique-acoustic sub-aperture processing (ASAP)-capable of generating very high contrast/signal-to-noise ratio (SNR) images of macro-and microvessels, with similar computational complexity to classical power Doppler (PD) imaging. In ASAP, the received data are split into subgroups. The reconstructed data from each subgroup are temporally correlated over frames to generate the final image. As signals in subgroups are correlated but the noise is not, this substantially reduces the noise floor compared to PD. Using a clinical imaging probe, the method is shown to visualize vessels down to $200~?mu ?text{m}$ with a SNR of 10 dB higher than PD and to resolve microvascular flow/perfusion information in rabbit kidneys noninvasively in vivo at multiple centimeter depths. With careful filter design, the technique also allows the estimation of flow direction and the separation of fast flow from tissue perfusion. ASAP can readily be implemented into hardware/firmware for real time imaging and can be applied to contrast enhanced and potentially noncontrast imaging and 3-D imaging. PMID- 29994062 TI - Improving the Automated Detection of Calcifications Using Adaptive Variance Stabilization. AB - In this paper, we analyze how stabilizing the variance of intensity-dependent quantum noise in digital mammograms can significantly improve the computerized detection of microcalcifications (MCs). These lesions appear on mammograms as tiny deposits of calcium smaller than 20 pixels in diameter. At this scale, high frequency image noise is dominated by quantum noise, which in raw mammograms can be described with a square-root noise model. Under this assumption, we derive an adaptive variance stabilizing transform (VST) that stabilizes the noise to unitary standard deviation in all the images. This is achieved by estimating the noise characteristics from the image at hand. We tested the adaptive VST as a preprocessing stage for four existing computerized MC detection methods on three data sets acquired with mammographic units from different manufacturers. In all the test cases considered, MC detection performance on transformed mammograms was statistically significantly higher than on unprocessed mammograms. Results were also superior in comparison with a "fixed" (nonparametric) VST previously proposed for digital mammograms. PMID- 29994063 TI - Direct-Write Laser Greyscale Lithography for Multi-Layer Lead Zirconate Titanate Thin Films. AB - Direct-write laser greyscale lithography has been used to facilitate a single step patterning technique for multi-layer lead zirconate titanate (PZT) thin films. A 2.55 MUm thick photoresist was patterned with a direct-write laser. The intensity of the laser was varied to create both tiered and sloped structures that are subsequently transferred into multi-layer PZT(52/48) stacks using a single Ar ion mill etch. Traditional processing requires a separate photolithography step and an ion mill etch for each layer of the substrate, which can be costly and time consuming. The novel process allows access to buried electrode layers in the multi-layer stack in a single photolithography step. The greyscale process was demonstrated on three 150 mm diameter Si substrates configured with a 0.5 MUm thick SiO2 elastic layer, a base electrode of Pt/TiO2, and a stack of four PZT(52/48) thin films of either 0.25 MUm thickness per layer or 0.50 MUm thickness per layer, and using either Pt or IrO2 electrodes above and below each layer. Stacked capacitor structures were patterned and results will be reported on the ferroelectric and electromechanical properties using various wiring configurations and compared to comparable single layer PZT configurations. PMID- 29994064 TI - Hallucinating Face Image by Regularization Models in High-Resolution Feature Space. AB - In this paper, we propose two novel regularization models in patch-wise and pixel wise respectively, which are efficient to reconstruct high-resolution (HR) face image from low-resolution (LR) input. Unlike the conventional patch-based models which depend on the assumption of local geometry consistency in LR and HR spaces, the proposed method directly regularizes the relationship between the target patch and corresponding training set in the HR space. It avoids to deal with the tough problem of preserving local geometry in various resolutions. Taking advantage of kernel function in efficiently describing intrinsic features, we further conduct the patch-based reconstruction model in the high-dimensional kernel space for capturing nonlinear characteristics. Meanwhile, a pixel-based model is proposed to regularize the relationship of pixels in the local neighborhood, which can be employed to enhance the fuzzy details in the target HR face image. It privileges the reconstruction of pixels along the dominant orientation of structure, which is useful for preserving high-frequency information on complex edges. Finally, we combine the two reconstruction models into a unified framework. The output HR face image can be finally optimized by performing an iterative procedure. Experimental results demonstrate that the proposed face hallucination method produces superior performance than the state of-the-art methods. PMID- 29994065 TI - P2T: Part-to-Target Tracking via Deep Regression Learning. AB - Most existing part based tracking methods are part-to-part trackers, which usually have two separated steps including part matching and target localization. Different from existing methods, in this paper, we propose a novel part-totarget (P2T) tracker in a unified fashion by inferring target location from parts directly. To achieve this goal, we propose a novel deep regression model for part to target regression in an end-to-end framework via Convolutional Neural Networks. The proposed model is able to not only exploit part context information to preserve object spatial layout structure, but also learn part reliability to emphasize part importance for robust part to target regression. We evaluate the proposed tracker on 4 challenging benchmark sequences, and extensive experimental results demonstrate that our method performs favorably against state-of-the-art trackers because of the powerful capacity of the proposed deep regression model. PMID- 29994066 TI - A MAP-Based Approach for Hyperspectral Imagery Super-resolution. AB - In this study, we propose a novel single image Bayesian super-resolution (SR) algorithm where the hyperspectral image (HSI) is the only source of information. The main contribution of the proposed approach is to convert the ill-posed SR reconstruction (SRR) problem in the spectral domain to a quadratic optimization problem in the abundance map domain. In order to do so, Markov Random Field (MRF) based energy minimization approach is proposed and proved that the solution is quadratic. The proposed approach consists of five main steps. First, the number of endmembers in the scene is determined using virtual dimensionality. Second, the endmembers and their low resolution abundance maps are computed using simplex identification via the splitted augmented Lagrangian (SISAL) and fully constrained least squares (FCLS) algorithms. Third, high resolution (HR) abundance maps are obtained using our proposed maximum a posteriori (MAP) based energy function. This energy function is minimized subject to smoothness, unity and boundary constraints. Fourth, the HR abundance maps are further enhanced with texture preserving methods. Finally, HR HSI is reconstructed using the extracted endmembers and the enhanced abundance maps. The proposed method is tested on three real HSI datasets; namely the Cave, Harvard and Hyperspectral Remote Sensing Scenes (HRSS) and compared to state-of-the-art alternative methods using peak signal to noise ratio, structural similarity, spectral angle mapper and relative dimensionless global error in synthesis metrics. It is shown that the proposed method outperforms the state of the art methods in terms of quality while preserving the spectral consistency. PMID- 29994067 TI - Towards Optimization of Gaze-Controlled Human-Computer Interaction: Application to Hindi Virtual Keyboard for Stroke Patients. AB - Virtual keyboard applications and alternative communication devices provide new means of communication to assist disabled people. To date, virtual keyboard optimization schemes based on script-specific information along with multimodal input access facility are limited. In this work, we propose a novel method for optimizing the position of the displayed items for gaze-controlled tree-based menu selection systems by considering a combination of letter frequency and command selection time. The optimized graphical user interface (GUI) layout has been designed for a Hindi language virtual keyboard based on a menu wherein 10 commands provide access to type 88 different characters along with additional text editing commands. The system can be controlled in two different modes: eye tracking alone and eye-tracking with an access soft-switch. Five different keyboard layouts have been presented and evaluated with ten healthy participants. Further, the two best performing keyboard layouts have been evaluated with eye tracking alone on ten stroke patients. The overall performance analysis demonstrated significantly superior typing performance, high usability (87% SUS score), and low workload (NASA TLX with 17 scores) for the letter frequency and time-based organization with script specific arrangement design. This work represents the first optimized gaze-controlled Hindi virtual keyboard, which can be extended to other languages. PMID- 29994068 TI - Identifying gene network rewiring by integrating gene expression and gene network data. AB - Exploring the rewiring pattern of gene regulatory networks between different pathological states is an important task in bioinformatics. Although a number of computational approaches have been developed to infer differential networks from high-throughput data, most of them only focus on gene expression data. The valuable static gene regulatory network data accumulated in recent biomedical researches are neglected. In this study, we propose a new Gaussian graphical model-based method to infer differential networks by integrating gene expression and static gene regulatory network data. We first evaluate the empirical performance of our method by comparing with the state-of-the-art methods using simulation data. We also apply our method to The Cancer Genome Atlas data to identify gene network rewiring between ovarian cancers with different platinum responses, and rewiring between breast cancers of luminal A subtype and basal like subtype. Hub genes in the estimated differential networks rediscover known genes associated with platinum resistance in ovarian cancer and signatures of the breast cancer intrinsic subtypes. PMID- 29994069 TI - Estimating energy parameters for RNA secondary structure predictions using both experimental and computational data. AB - Computational RNA secondary structure prediction depends on a large number of nearest-neighbor free-energy parameters, including 10 parameters for Watson-Crick stacked base pairs that were estimated from experimental measurements of the free energies of 90 RNA duplexes. These experimental data are provided by time consuming and cost-intensive experiments. In contrast, various modified nucleotides in RNAs, which would affect not only their structures but also functions, have been found, and rapid determination of energy parameters for a such modified nucleotides is needed. To reduce the high cost of determining energy parameters, we propose a novel method to estimate energy parameters from both experimental and computational data, where the computational data are provided by a recently developed molecular dynamics simulation protocol. We evaluate our method for Watson-Crick stacked base pairs, and show that parameters estimated from 10 experimental data items and 10 computational data items can predict RNA secondary structures with accuracy comparable to that using conventional parameters. The results indicate that the combination of experimental free-energy measurements and molecular dynamics simulations is capable of estimating the thermodynamic properties of RNA secondary structures at lower cost. PMID- 29994070 TI - Secure Wavelet Matrix: Alphabet-Friendly Privacy-Preserving String Search for Bioinformatics. AB - Biomedical data often includes personal information, and the technology is demanded that enables to search such a sensitive data while protecting privacy. We consider a case in which a server has a text database and a user searches the database to find substring matches. The user wants to conceal his/her query and the server wants to conceal the database except for the search results. The previous approach for this problem is based on a linear-time algorithm in terms of alphabet size , and it cannot search on the database of large alphabet such as biomedical documents.We present a novel algorithm that can search a string in logarithmic time of . In our algorithm, named secure wavelet matrix (sWM), we use an additively homomorphic encryption to build an efficient data structure called a wavelet matrix.In an experiment using a simulated string of length 10,000 whose alphabet size ranges from 4 to 1024, the run time of the sWM was up to around two orders of magnitude faster than that of the previous method.sWM enables to search a private database efficiently and thus it will facilitate utilizing sensitive biomedical information. PMID- 29994071 TI - Stage-Dependent Gene Expression Profiling in Colorectal Cancer. AB - Temporal gene expression profiles have been widely considered to uncover the mechanism of cancer development and progression. Gene expression patterns, however, have been analyzed for limited stages with small samples, without proper data pre-processing, in many cases. With those approaches, it is difficult to unveil the mechanism of cancer development over time. In this study, we analyzed gene expression profiles of two independent colorectal cancer sample datasets, each of which contains 556 and 566 samples, respectively. To find specific gene expression changes according to cancer stage, we applied the linear mixed-effect regression model (LMER) that controls other clinical variables. Based on this methodology, we found two types of gene expression patterns: continuously increasing and decreasing genes as cancer develops. We found that continuously increasing genes are related to the nervous and developmental system, whereas the others are related to the cell cycle and metabolic processes. We further analyzed connected sub-networks related to the two types of genes. From these results, we suggest that the gene expression profile analysis can be used to understand underlying the mechanisms of cancer development such as cancer growth and metastasis. Furthermore, our approach can provide a good guideline for advancing our understanding of cancer developmental processes. PMID- 29994072 TI - Systematic Inspection of the Clinical Relevance of TP53 Missense Mutations in Gastric Cancer. AB - The "guardian of the genome," TP53, is one of the most frequently mutated genes of all cancers. Despite the important biological roles of TP53, the clinical relevance of TP53 mutations, in gastric cancer (GC), remains largely unknown. Here, we systematically assessed clinical relevance, in terms of TP53 mutation positions, finding substantial variability. Thus, we hypothesized that the position of the TP53 mutation might affect clinical outcomes in GC. We systematically inspected missense mutations in TP53, from a TCGA (The Cancer Genome Atlas) GC dataset in UCSC Xena repository. Specifically, we examined five aspects of each mutational position: (1) the whole gene body; (2) known hot spots; (3) the DNA-binding domain; (4) the secondary structure of the domain; and (5) individual mutation positions. We then analyzed the clinical outcomes for each aspect. These results showed that, in terms of secondary structure, patients with mutations in turn regions showed poor prognosis, compared to those with mutations in beta strand regions (log rank p = 0.043). Also, in terms of individual mutation positions, patients having mutations at R248 showed poorer survival than other patients having mutations at different TP53 positions (log rank p = 0.035). PMID- 29994073 TI - ParaCells: A GPU Architecture for Cell-Centered Models in Computational Biology. AB - In computational biology, the hierarchy of biological systems requires the development of flexible and powerful computational tools. Graphics processing unit (GPU) architecture has been a suitable device for parallel computing in simulating multi-cellular systems. However, in modeling complex biological systems, scientists often face two tasks, mathematical formulation and skillful programming. In particular, specific programming skills are needed for GPU programming. Therefore, the development of an easy-to-use computational architecture, which utilizes GPU for parallel computing and provides intuitive interfaces for simple implementation, is needed so that general scientists can perform GPU simulations without knowing much about the GPU architecture. Here, we introduce ParaCells, a cell-centered GPU simulation architecture for NVIDIA compute unified device architecture (CUDA). ParaCells was designed as a versatile architecture that connects the user logic (in C++) with NVIDIA CUDA runtime and is specific to the modeling of multi-cellular systems. An advantage of ParaCells is its object-oriented model declaration, which allows it to be widely applied to many biological systems through the combination of basic biological concepts. We test ParaCells with two applications. Both applications are significantly faster when compared with sequential as well as parallel OpenMP and OpenACC implementations. Moreover, the simulation programs based on ParaCells are cleaner and more readable than other versions. PMID- 29994074 TI - Prediction of Protein Backbone Torsion Angles Using Deep Residual Inception Neural Networks. AB - Prediction of protein backbone torsion angles (Psi and Phi) can provide important information for protein structure prediction and sequence alignment. Existing methods for Psi-Phi angle prediction have significant room for improvement. In this paper, a new deep residual inception network architecture, called DeepRIN, is proposed for the prediction of Psi-Phi angles. The input to DeepRIN is a feature matrix representing a composition of physico-chemical properties of amino acids, a 20-dimensional position-specific substitution matrix (PSSM) generated by PSI-BLAST, a 30-dimensional hidden Markov Model sequence profile generated by HHBlits, and predicted eight-state secondary structure features. DeepRIN is designed based on inception networks and residual networks that have performed well on image classification and text recognition. The architecture of DeepRIN enables effective encoding of local and global interatcions between amino acids in a protein sequence to achieve accruacte prediction. Extensive experimental results show that DeepRIN outperformed the best existing tools significantly. Compared to the recently released state-of-the-art tool, SPIDER3, DeepRIN reduced the Psi angle prediction error by more than 5 degrees and the Phi angle prediction error by more than 2 degrees on average. The executable tool of DeepRIN is available for download at http://dslsrv8.cs.missouri.edu/~cf797/MUFoldAngle/. PMID- 29994075 TI - Learning Temporal Information for Brain-Computer Interface Using Convolutional Neural Networks. AB - Deep learning (DL) methods and architectures have been the state-of-the-art classification algorithms for computer vision and natural language processing problems. However, the successful application of these methods in motor imagery (MI) brain-computer interfaces (BCIs), in order to boost classification performance, is still limited. In this paper, we propose a classification framework for MI data by introducing a new temporal representation of the data and also utilizing a convolutional neural network (CNN) architecture for classification. The new representation is generated from modifying the filter bank common spatial patterns method, and the CNN is designed and optimized accordingly for the representation. Our framework outperforms the best classification method in the literature on the BCI competition IV-2a 4-class MI data set by 7% increase in average subject accuracy. Furthermore, by studying the convolutional weights of the trained networks, we gain an insight into the temporal characteristics of EEG. PMID- 29994076 TI - Adaptive Neural Control for Robotic Manipulators With Output Constraints and Uncertainties. AB - This paper investigates adaptive neural control methods for robotic manipulators, subject to uncertain plant dynamics and constraints on the joint position. The barrier Lyapunov function is employed to guarantee that the joint constraints are not violated, in which the Moore-Penrose pseudo-inverse term is used in the control design. To handle the unmodeled dynamics, the neural network (NN) is adopted to approximate the uncertain dynamics. The NN control based on full-state feedback for robots is proposed when all states of the closed loop are known. Subsequently, only the robot joint is measurable in practice; output feedback control is designed with a high-gain observer to estimate unmeasurable states. Through the Lyapunov stability analysis, system stability is achieved with the proposed control, and the system output achieves convergence without violation of the joint constraints. Simulation is conducted to approve the feasibility and superiority of the proposed NN control. PMID- 29994077 TI - Concept Drift and Anomaly Detection in Graph Streams. AB - Graph representations offer powerful and intuitive ways to describe data in a multitude of application domains. Here, we consider stochastic processes generating graphs and propose a methodology for detecting changes in stationarity of such processes. The methodology is general and considers a process generating attributed graphs with a variable number of vertices/edges, without the need to assume a one-to-one correspondence between vertices at different time steps. The methodology acts by embedding every graph of the stream into a vector domain, where a conventional multivariate change detection procedure can be easily applied. We ground the soundness of our proposal by proving several theoretical results. In addition, we provide a specific implementation of the methodology and evaluate its effectiveness on several detection problems involving attributed graphs representing biological molecules and drawings. Experimental results are contrasted with respect to suitable baseline methods, demonstrating the effectiveness of our approach. PMID- 29994078 TI - Hierarchical Deep Reinforcement Learning for Continuous Action Control. AB - Robotic control in a continuous action space has long been a challenging topic. This is especially true when controlling robots to solve compound tasks, as both basic skills and compound skills need to be learned. In this paper, we propose a hierarchical deep reinforcement learning algorithm to learn basic skills and compound skills simultaneously. In the proposed algorithm, compound skills and basic skills are learned by two levels of hierarchy. In the first level of hierarchy, each basic skill is handled by its own actor, overseen by a shared basic critic. Then, in the second level of hierarchy, compound skills are learned by a meta critic by reusing basic skills. The proposed algorithm was evaluated on a Pioneer 3AT robot in three different navigation scenarios with fully observable tasks. The simulations were built in Gazebo 2 in a robot operating system Indigo environment. The results show that the proposed algorithm can learn both high performance basic skills and compound skills through the same learning process. The compound skills learned outperform those learned by a discrete action space deep reinforcement learning algorithm. PMID- 29994079 TI - Unification of MAP Estimation and Marginal Inference in Recurrent Neural Networks. AB - Numerous experimental data show that human brain can represent probability distributions and perform Bayesian inference. However, it remains unclear how the brain implements probabilistic inference in the form of neural circuits. Several models have been proposed that aim at explaining how the network of neurons carry out maximum a posterior inference (MAP) estimation and marginal inference, but they are all task specific in that they treat MAP estimation and marginal inference separately. In this brief, we propose that human brain could implement MAP estimation and marginal inference in the same network of neurons. We illustrate our result in hidden Markov models and prove that a recurrent neural network (RNN) implementation of belief propagation can be tuned to perform approximate Bayesian inference (to provide posterior or conditional distribution over the latent causes of observations) or identify the MAP or peak of the joint distribution. The key tuning parameter is a temperature parameter that controls the precision of probability distributions that are optimized. Theoretical analyses and experimental results demonstrate that RNNs can carry out near optimal MAP estimation and marginal inference. PMID- 29994080 TI - An Online Minimax Optimal Algorithm for Adversarial Multiarmed Bandit Problem. AB - We investigate the adversarial multiarmed bandit problem and introduce an online algorithm that asymptotically achieves the performance of the best switching bandit arm selection strategy. Our algorithms are truly online such that we do not use the game length or the number of switches of the best arm selection strategy in their constructions. Our results are guaranteed to hold in an individual sequence manner, since we have no statistical assumptions on the bandit arm losses. Our regret bounds, i.e., our performance bounds with respect to the best bandit arm selection strategy, are minimax optimal up to logarithmic terms. We achieve the minimax optimal regret with computational complexity only log-linear in the game length. Thus, our algorithms can be efficiently used in applications involving big data. Through an extensive set of experiments involving synthetic and real data, we demonstrate significant performance gains achieved by the proposed algorithm with respect to the state-of-the-art switching bandit algorithms. We also introduce a general efficiently implementable bandit arm selection framework, which can be adapted to various applications. PMID- 29994081 TI - Reduced-Order Filtering of Delayed Static Neural Networks With Markovian Jumping Parameters. AB - The reduced-order filtering problems are investigated in this paper for static neural networks with Markovian jumping parameters and mode-dependent time-varying delays. By fully making use of integral inequalities, the designs of reduced order and filters are discussed. The proper gain matrices of filters and the optimal performance indices are efficiently obtained by resolving corresponding convex optimization problems with the constraints of linear matrix inequalities. It is verified that the computational complexity for the reduced-order filter design is significantly reduced when compared with the full-order one. Furthermore, the nonfragile reduced-order filtering problems are also resolved in this paper. Two examples with simulation results are presented to demonstrate the feasibility and application of the established results. PMID- 29994082 TI - Personalised Adaptive CBR Bolus Recommender System for Type 1 Diabetes. AB - Type 1 Diabetes Mellitus (T1DM) is a chronic disease. Those who have it must administer themselves with insulin to control their blood glucose level. It is difficult to estimate the correct insulin dosage due to the complex glucose metabolism, which can lead to less than optimal blood glucose levels. This paper presents PepperRec, a case-based reasoning (CBR) bolus insulin recommender system capable of dealing with an unrestricted number of situations in which T1DM persons can find themselves. PepperRec considers several factors that affect glucose metabolism, such as data about the physical activity of the user, and can also cope with missing values for these factors. Based on CBR methodology, PepperRec uses new methods to adapt past recommendations to the current state of the user, and retains updated historical patient information to deal with slow and gradual changes in the patient over time (concept drift). The proposed approach is tested using the UVA/PADOVA simulator with 33 virtual subjects and compared with other methods in the literature, and with the default insulin therapy of the simulator. The achieved results demonstrate that PepperRec increases the amount of time the users are in their target glycaemic range, reduces the time spent below it, while maintaining, or even reducing, the time spent above it. PMID- 29994083 TI - Look into Person: Joint Body Parsing & Pose Estimation Network and a New Benchmark. AB - Human parsing and pose estimation have recently received considerable interest due to their substantial application potentials. However, the existing datasets have limited numbers of images and annotations and lack a variety of human appearances and coverage of challenging cases in unconstrained environments. In this paper, we introduce a new benchmark named "Look into Person (LIP)" that provides a significant advancement in terms of scalability, diversity, and difficulty, which are crucial for future developments in human-centric analysis. This comprehensive dataset contains over 50,000 elaborately annotated images with 19 semantic part labels and 16 body joints, which are captured from a broad range of viewpoints, occlusions, and background complexities. Using these rich annotations, we perform detailed analyses of the leading human parsing and pose estimation approaches, thereby obtaining insights into the successes and failures of these methods. To further explore and take advantage of the semantic correlation of these two tasks, we propose a novel joint human parsing and pose estimation network to explore efficient context modeling, which can simultaneously predict parsing and pose with extremely high quality. Furthermore, we simplify the network to solve human parsing by exploring a novel self supervised structure-sensitive learning approach, which imposes human pose structures into the parsing results without resorting to extra supervision. The datasets, code and models are available at http://www.sysu-hcp.net/lip/. PMID- 29994084 TI - Image Reconstruction in Electrical Impedance Tomography Based on Structure-Aware Sparse Bayesian Learning. AB - Electrical impedance tomography (EIT) is developed to investigate the internal conductivity changes of an object through a series of boundary electrodes, and has become increasingly attractive in a broad spectrum of applications. However, the design of optimal tomography image reconstruction algorithms has not achieved the adequate level of progress and matureness. In this paper, we propose an efficient and high-resolution EIT image reconstruction method in the framework of sparse Bayesian learning. Significant performance improvement is achieved by imposing structure-aware priors on the learning process to incorporate the prior knowledge that practical conductivity distribution maps exhibit clustered sparsity and intra-cluster continuity. The proposed method not only achieves high resolution estimation and preserves the shape information even in low signal-to noise ratio scenarios but also avoids the time-consuming parameter tuning process. The effectiveness of the proposed algorithm is validated through comparisons with state-of-the-art techniques using extensive numerical simulation and phantom experiment results. PMID- 29994085 TI - Dictionary-Free MRI PERK: Parameter Estimation via Regression with Kernels. AB - This paper introduces a fast, general method for dictionary-free parameter estimation in quantitative magnetic resonance imaging (QMRI) parameter estimation via regression with kernels (PERK). PERK first uses prior distributions and the nonlinear MR signal model to simulate many parameter-measurement pairs. Inspired by machine learning, PERK then takes these parameter-measurement pairs as labeled training points and learns from them a nonlinear regression function using kernel functions and convex optimization. PERK admits a simple implementation as per voxel nonlinear lifting of MRI measurements followed by linear minimum mean squared error regression. We demonstrate PERK for $ {?textit {T}_{1}}, {?textit {T}_{2}}$ estimation, a well-studied application where it is simple to compare PERK estimates against dictionary-based grid search estimates and iterative optimization estimates. Numerical simulations as well as single-slice phantom and in vivo experiments demonstrate that PERK and other tested methods produce comparable $ {?textit {T}_{1}}, {?textit {T}_{2}}$ estimates in white and gray matter, but PERK is consistently at least $140?times $ faster. This acceleration factor may increase by several orders of magnitude for full-volume QMRI estimation problems involving more latent parameters per voxel. PMID- 29994086 TI - Whole-Slide Mitosis Detection in H&E Breast Histology Using PHH3 as a Reference to Train Distilled Stain-Invariant Convolutional Networks. AB - Manual counting of mitotic tumor cells in tissue sections constitutes one of the strongest prognostic markers for breast cancer. This procedure, however, is time consuming and error-prone. We developed a method to automatically detect mitotic figures in breast cancer tissue sections based on convolutional neural networks (CNNs). Application of CNNs to hematoxylin and eosin (H&E) stained histological tissue sections is hampered by: (1) noisy and expensive reference standards established by pathologists, (2) lack of generalization due to staining variation across laboratories, and (3) high computational requirements needed to process gigapixel whole-slide images (WSIs). In this paper, we present a method to train and evaluate CNNs to specifically solve these issues in the context of mitosis detection in breast cancer WSIs. First, by combining image analysis of mitotic activity in phosphohistone-H3 (PHH3) restained slides and registration, we built a reference standard for mitosis detection in entire H&E WSIs requiring minimal manual annotation effort. Second, we designed a data augmentation strategy that creates diverse and realistic H&E stain variations by modifying the hematoxylin and eosin color channels directly. Using it during training combined with network ensembling resulted in a stain invariant mitosis detector. Third, we applied knowledge distillation to reduce the computational requirements of the mitosis detection ensemble with a negligible loss of performance. The system was trained in a single-center cohort and evaluated in an independent multicenter cohort from The Cancer Genome Atlas on the three tasks of the Tumor Proliferation Assessment Challenge (TUPAC). We obtained a performance within the top-3 best methods for most of the tasks of the challenge. PMID- 29994087 TI - 3-D Consistent and Robust Segmentation of Cardiac Images by Deep Learning With Spatial Propagation. AB - We propose a method based on deep learning to perform cardiac segmentation on short axis Magnetic resonance imaging stacks iteratively from the top slice (around the base) to the bottom slice (around the apex). At each iteration, a novel variant of the U-net is applied to propagate the segmentation of a slice to the adjacent slice below it. In other words, the prediction of a segmentation of a slice is dependent upon the already existing segmentation of an adjacent slice. The 3-D consistency is hence explicitly enforced. The method is trained on a large database of 3078 cases from the U.K. Biobank. It is then tested on the 756 different cases from the U.K. Biobank and three other state-of-the-art cohorts (ACDC with 100 cases, Sunnybrook with 30 cases, and RVSC with 16 cases). Results comparable or even better than the state of the art in terms of distance measures are achieved. They also emphasize the assets of our method, namely, enhanced spatial consistency (currently neither considered nor achieved by the state of the art), and the generalization ability to unseen cases even from other databases. PMID- 29994088 TI - Automatic Segmentation of Acute Ischemic Stroke From DWI Using 3-D Fully Convolutional DenseNets. AB - Acute ischemic stroke is recognized as a common cerebral vascular disease in aging people. Accurate diagnosis and timely treatment can effectively improve the blood supply of the ischemic area and reduce the risk of disability or even death. Understanding the location and size of infarcts plays a critical role in the diagnosis decision. However, manual localization and quantification of stroke lesions are laborious and time-consuming. In this paper, we propose a novel automatic method to segment acute ischemic stroke from diffusion weighted images (DWIs) using deep 3-D convolutional neural networks (CNNs). Our method can efficiently utilize 3-D contextual information and automatically learn very discriminative features in an end-to-end and data-driven way. To relieve the difficulty of training very deep 3-D CNN, we equip our network with dense connectivity to enable the unimpeded propagation of information and gradients throughout the network. We train our model with Dice objective function to combat the severe class imbalance problem in data. A DWI data set containing 242 subjects (90 for training, 62 for validation, and 90 for testing) with various types of acute ischemic stroke was constructed to evaluate our method. Our model achieved high performance on various metrics (Dice similarity coefficient: 79.13%, lesionwise precision: 92.67%, and lesionwise F1 score: 89.25%), outperforming the other state-of-the-art CNN methods by a large margin. We also evaluated the model on ISLES2015-SSIS data set and achieved very competitive performance, which further demonstrated its generalization capacity. The proposed method is fast and accurate, demonstrating a good potential in clinical routines. PMID- 29994089 TI - A Mixed-Effects Model for Detecting Disrupted Connectivities in Heterogeneous Data. AB - The human brain is an amazingly complex network. Aberrant activities in this network can lead to various neurological disorders such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, and autism. functional magnetic resonance imaging has emerged as an important tool to delineate the neural networks affected by such diseases, particularly autism. In this paper, we propose a special type of mixed-effects model together with an appropriate procedure for controlling false discoveries to detect disrupted connectivities for developing a neural network in whole brain studies. Results are illustrated with a large data set known as autism brain imaging data exchange which includes 361 subjects from eight medical centers. PMID- 29994090 TI - Convolutional Regression for Visual Tracking. AB - Recently, discriminatively learned correlation filters (DCF) has attracted much attention in visual object tracking community. The success of DCF is potentially attributed to the fact that a large number of samples are utilized to train the ridge regression model and predict the location of an object. To solve the regression problem in an efficient way, these samples are all generated by circularly shifting from a searching patch. However, these synthetic samples also induce some negative effects which weaken the robustness of DCF based trackers. In this paper, we propose a new approach to learn the regression model for visual tracking with single convolutional layer. Instead of learning the linear regression model in a closed form, we try to solve the regression problem by optimizing a onechannel- output convolution layer with gradient descent (GD). In particular, the kernel size of the convolution layer is set to the size of the object. Contrary to DCF, it is possible to incorporate all "real" samples clipped from the whole image. A critical issue of the GD approach is that most of the convolutional samples are negative and the contribution of positive samples will be suppressed. To address this problem, we propose a novel objective function to eliminate easy negatives and enhance positives. We perform extensive experiments on four widely-used datasets: OTB-100, OTB-50, TempleColor, and VOT-2016. The results show that the proposed algorithm achieves outstanding performance and outperforms most of the existing DCF based algorithms. PMID- 29994092 TI - Learning Temporal Dynamics for Video Super-Resolution: A Deep Learning Approach. AB - Video super-resolution (SR) aims at estimating a high-resolution (HR) video sequence from a low-resolution (LR) one. Given that deep learning has been successfully applied to the task of single image SR, which demonstrates the strong capability of neural networks for modeling spatial relation within one single image, the key challenge to conduct video SR is how to efficiently and effectively exploit the temporal dependency among consecutive LR frames other than the spatial relation. However, this remains challenging because complex motion is difficult to model and can bring detrimental effects if not handled properly. We tackle the problem of learning temporal dynamics from two aspects. First, we propose a temporal adaptive neural network that can adaptively determine the optimal scale of temporal dependency. Inspired by the Inception module in GoogLeNet [1], filters of various temporal scales are applied to the input LR sequence before their responses are adaptively aggregated, in order to fully exploit the temporal relation among consecutive LR frames. Second, we decrease the complexity of motion among neighboring frames using a spatial alignment network that can be end-to-end trained with the temporal adaptive network and has the merit of increasing the robustness to complex motion and the efficiency compared to competing image alignment methods. We provide a comprehensive evaluation of the temporal adaptation and the spatial alignment modules. We show the temporal adaptive design considerably improve SR quality over its plain counterparts, and the spatial alignment network is able to attain comparable SR performance with the sophisticated optical flow based approach, but requires much less running time. Overall our proposed model with learned temporal dynamics is shown to achieve state-of-the-art SR results in terms of not only spatial consistency but also temporal coherence on public video datasets. More information can be found in. PMID- 29994093 TI - Novel Efficient 3D Short-range Imaging Algorithms for a Scanning 1D-MIMO Array. AB - Recently, millimeter-wave (MMW) 3D holography techniques employing a scanning 1D multiple input multiple output (MIMO) array have shown several superiorities for short-range applications than traditional single input single output (SISO) ones. However, current imaging algorithms for this emerging regime are not satisfied, either too slow as a back projection (BP) manner is used or of poor quality since several steps of approximations are introduced. In this paper, two fast fully focused imaging algorithms are developed towards fixing these drawbacks. Both algorithms are based on the assumption that the receivers are evenly distributed. The first algorithm further hypothesizes that the transmitters are also evenly located, while the second algorithm needs looser restrictions that the transmitters can be arbitrarily positioned. The frequency domain expressions of the modified Kirchhoff method are also derived and used to promote the precision of the proposed algorithms. In addition, several implementation issues including resolution, sampling criteria and computational complexity are discussed. Finally, both simulation and experimental results validate the effectiveness of the proposed methods on reconstruction quality and computational efficiency. PMID- 29994091 TI - Region-adaptive Deformable Registration of CT/MRI Pelvic Images via Learning based Image Synthesis. AB - Registration of pelvic CT and MRI is highly desired as it can facilitate effective fusion of two modalities for prostate cancer radiation therapy, i.e., using CT for dose planning and MRI for accurate organ delineation. However, due to the large inter-modality appearance gaps and the high shape/appearance variations of pelvic organs, the pelvic CT/MRI registration is highly challenging. In this paper, we propose a region-adaptive deformable registration method for multi-modal pelvic image registration. Specifically, to handle the large appearance gaps, we first perform both CT-to-MRI and MRI-to-CT image synthesis by multi-target regression forest (MT-RF). Then, to use the complementary anatomical information in the two modalities for steering the registration, we select key points automatically from both modalities and use them together for guiding correspondence detection in the region-adaptive fashion. That is, we mainly use CT to establish correspondences for bone regions, and use MRI to establish correspondences for soft tissue regions. The number of key points is increased gradually during the registration, to hierarchically guide the symmetric estimation of the deformation fields. Experiments for both intra-subject and inter-subject deformable registration show improved performances compared with state-of-the-art multi-modal registration methods, which demonstrate the potentials of our method to be applied for the routine prostate cancer radiation therapy. PMID- 29994095 TI - An Adaptive Robust Control Strategy in a Cancer Tumor-Immune System under Uncertainties. AB - We propose an adaptive robust control for a second order nonlinear model of the interaction between cancer and immune cells of the body to control the growth of cancer and maintain the number of immune cells in an appropriate level. Most of the control approaches are based on minimizing the drug dosage based on an optimal control structure. However, in many cases, measuring the exact quantity of the model parameters is not possible. This is due to limitation in measuring devices, variational and undetermined characteristics of micro-environmental factors. It is of great importance to present a control strategy that can deal with these unknown factors in a nonlinear model. PMID- 29994094 TI - Precision Risk Analysis of Cancer Therapy with Interactive Nomograms and Survival Plots. AB - We present the design and evaluation of an integrated problem solving environment for cancer therapy analysis. The environment intertwines a statistical martingale model and a K Nearest Neighbor approach with visual encodings, including novel interactive nomograms, in order to compute and explain a patient's probability of survival as a function of similar patient results. A coordinated views paradigm enables exploration of the multivariate, heterogeneous and few-valued data from a large head and neck cancer repository. A visual scaffolding approach further enables users to build from familiar representations to unfamiliar ones. Evaluation with domain experts show how this visualization approach and set of streamlined workflows enable the systematic and precise analysis of a patient prognosis in the context of cohorts of similar patients. We describe the design lessons learned from this successful, multi-site remote collaboration. PMID- 29994096 TI - Bioimage Classification with Handcrafted and Learned Features. AB - Bioimage classification is increasingly becoming more important in many biological studies including those that require accurate cell phenotype recognition, subcellular localization, and histopathological classification. In this paper, we present a new General Purpose (GenP) bioimage classification method that can be applied to a large range of classification problems. The GenP system we propose is an ensemble that combines multiple texture features (both handcrafted and learned descriptors) for superior and generalizable discriminative power. Our ensemble obtains a boosting of performance by combining local features, dense sampling features, and deep learning features. Each descriptor is used to train a different Support Vector Machine that is then combined by sum rule. We evaluate our method on a diverse set of bioimage classification tasks each represented by a benchmark database, including some of those available in the IICBU 2008 database. Each bioimage classification task represents a typical subcellular, cellular, and tissue level classification problem. Our evaluation on these datasets demonstrates that the proposed GenP bioimage ensemble obtains state-of-the-art performance without any ad-hoc dataset tuning of the parameters (thereby avoiding any risk of overfitting/overtraining). To reproduce the experiments reported in this paper, the MATLAB code of all the descriptors is available at https://github.com/LorisNanni and https://www.dropbox.com/s/bguw035yrqz0pwp/ElencoCode.docx?dl=0. PMID- 29994097 TI - Controllability Analysis of A Gene Network for Arabidopsis thaliana Reveals Characteristics of Functional Gene Families. AB - Based on structural controllability of complex networks and a constructed gene network with 9241 nodes for Arabidopsis thaliana, we classified nodes into five categories via their roles in control or node deletion, including indispensable, neutral, dispensable, driver and critical driver nodes. The indispensable nodes can increase the number of drivers after deletion, which are never drivers or critical drivers. About 10% nodes are indispensable. However, more than 60% nodes are neutral ones. More than 62% nodes are drivers, and indicates the gene network is very difficult to be fully controlled. Gene Ontology (GO) enrichment analysis reveals that different sets of nodes have preferred biological functions and processes.The indispensable nodes are significantly enriched as essential genes, drought responsive and abscisic acid (ABA) independent genes, transcriptional factors (TFs), core cell cycle genes, ABA and Gibberellin (GA) related genes. The critical drivers are enriched as receptor kinase-like genes, while shorted in WRKY TFs and functional genes that are enriched in the indispensable nodes. Robustness analysis based on node and edge additions, edge rewiring indicate the obtained conclusions are robust to network perturbations. Our investigations clarify control roles of some gene families and provide potential implications for identifying functional genes in other plant species, such as drought responsive genes and TFs. PMID- 29994098 TI - A new algorithm for counting independent motifs in probabilistic networks. AB - Biological networks provide great potential to understand how cells function. Motifs are topological patterns which are repeated frequently in a specific network. Network motifs are key structures through which biological networks operate. However, counting independent (i.e. non-overlapping) instances of a specific motif remains to be a computationally hard problem. Motif counting problem becomes computationally even harder for biological networks as biological interactions are uncertain events. The main challenge behind this problem is that different embeddings of a given motif in a network can share edges. Such edges can create complex computational dependencies between different instances of the given motif when considering uncertainty of those edges. In this paper, we develop a novel algorithm for counting independent instances of a specific motif topology in probabilistic biological networks. We present a novel mathematical model to capture the dependency between each embedding and all the other embeddings, which it overlaps with. We prove the correctness of this model. We evaluate our model on real and synthetic networks with different probability, and topology models as well as reasonable range of network sizes. Our results demonstrate that our method counts non-overlapping embeddings in practical time for a broad range of networks. PMID- 29994099 TI - A Collaborative Neurodynamic Approach to Multiobjective Optimization. AB - There are two ultimate goals in multiobjective optimization. The primary goal is to obtain a set of Pareto-optimal solutions while the secondary goal is to obtain evenly distributed solutions to characterize the efficient frontier. In this paper, a collaborative neurodynamic approach to multiobjective optimization is presented to attain both goals of Pareto optimality and solution diversity. The multiple objectives are first scalarized using a weighted Chebyshev function. Multiple projection neural networks are employed to search for Pareto-optimal solutions with the help of a particle swarm optimization (PSO) algorithm in reintialization. To diversify the Pareto-optimal solutions, a holistic approach is proposed by maximizing the hypervolume (HV) using again a PSO algorithm. The experimental results show that the proposed approach outperforms three other state-of-the-art multiobjective algorithms (i.e., HMOEA/D, MOEA/DD, and NSGAIII) most of times on 37 benchmark datasets in terms of HV and inverted generational distance. PMID- 29994100 TI - Swarming Behavior of Multiple Euler-Lagrange Systems With Cooperation-Competition Interactions: An Auxiliary System Approach. AB - In this paper, the swarming behavior of multiple Euler-Lagrange systems with cooperation-competition interactions is investigated, where the agents can cooperate or compete with each other and the parameters of the systems are uncertain. The distributed stabilization problem is first studied, by introducing an auxiliary system to each agent, where the common assumption that the cooperation-competition network satisfies the digon sign-symmetry condition is removed. Based on the input-output property of the auxiliary system, it is found that distributed stabilization can be achieved provided that the cooperation subnetwork is strongly connected and the parameters of the auxiliary system are chosen appropriately. Furthermore, as an extension, a distributed consensus tracking problem of the considered multiagent systems is discussed, where the concept of equi-competition is introduced and a new pinning control strategy is proposed based on the designed auxiliary system. Finally, illustrative examples are provided to show the effectiveness of the theoretical analysis. PMID- 29994101 TI - An Event-Triggered Pinning Control Approach to Synchronization of Discrete-Time Stochastic Complex Dynamical Networks. AB - This paper is concerned with the synchronization analysis and control problems for a class of nonlinear discrete-time stochastic complex dynamical networks (CDNs) consisting of identical nodes. The discrete-time stochastic dynamical networks under consideration are quite general that account for asymmetric coupling configuration, nonlinear inner coupling structures as well as nonidentical exogenous disturbances. By resorting to both the error bound and the synchronization probability, a notion of quasi-synchronization in probability is first introduced to assess the synchronization performance of the addressed CDNs. An event-triggered pinning feedback control strategy is adopted to control a small fraction of the network nodes with hope to reduce the frequency of updating and communication in the control process while preserving the desired dynamical behaviors of the controlled networks. By using the Lyapunov function method and the stochastic analysis techniques, a general framework is established within which the problems of dynamics analysis and controller synthesis are solved for the closed-loop stochastic dynamical networks. Two numerical examples and their simulations are presented to illustrate the effectiveness and the usefulness of our theoretical results. PMID- 29994102 TI - Sparse Temporal Encoding of Visual Features for Robust Object Recognition by Spiking Neurons. AB - Robust object recognition in spiking neural systems remains a challenging in neuromorphic computing area as it needs to solve both the effective encoding of sensory information and also its integration with downstream learning neurons. We target this problem by developing a spiking neural system consisting of sparse temporal encoding and temporal classifier. We propose a sparse temporal encoding algorithm which exploits both spatial and temporal information derived from an spike-timing-dependent plasticity-based HMAX feature extraction process. The temporal feature representation, thus, becomes more appropriate to be integrated with a temporal classifier based on spiking neurons rather than with nontemporal classifier. The algorithm has been validated on two benchmark data sets and the results show the temporal feature encoding and learning-based method achieves high recognition accuracy. The proposed model provides an efficient approach to perform feature representation and recognition in a consistent temporal learning framework, which is easily adapted to neuromorphic implementations. PMID- 29994103 TI - The Use of A Finger-Worn Accelerometer for Monitoring of Hand Use in Ambulatory Settings. AB - Objective assessment of stroke survivors' upper limb movements in ambulatory settings can provide clinicians with important information regarding the real impact of rehabilitation outside the clinic and help establish individually tailored therapeutic programs. This paper explores a novel approach to monitor the amount of hand use, which is relevant to the purposeful, goal-directed use of the limbs, based on a body networked sensor system composed of miniaturized finger- and wrist-worn accelerometers. The main contributions of this paper are two-fold. First, this paper introduces and validates a new benchmark measurement of the amount of hand use based on data recorded by a motion capture system, the gold standard for human movement analysis. Second, this paper introduces a machine learning-based analytic pipeline that estimates the amount of hand use using data obtained from the wearable sensors and validates its estimation performance against the aforementioned benchmark measurement. Based on data collected from 18 neurologically intact individuals performing 11 motor tasks resembling various activities of daily living, the analytic results presented herein that our new benchmark measure is reliable and responsive, and that the proposed wearable system can yield an accurate estimation of the amount of hand use (normalized root mean square error of 0.11 and average Pearson correlation of 0.78). This study has the potential to open up new research and clinical opportunities for monitoring hand function in ambulatory settings, ultimately enabling evidence-based, patient-centered rehabilitation and healthcare. PMID- 29994104 TI - Empirical Mode Decomposition and Monogenic Signal based Approach for Quantification of Myocardial Infarction from MR Images. AB - Quantification of myocardial infarction on Late Gadolinium Enhancement cardiovascular magnetic resonance (LGE-CMR) images into heterogeneous infarct periphery (or gray zone) and infarct core plays an important role in cardiac diagnosis, especially in identifying patients at high risk of cardiovascular mortality. However, quantification task is challenging due to noise corrupted in cardiac MR images, the contrast variation, and limited resolution of images. In this study, we propose a novel approach for automatic myocardial infarction quantification, termed DEMPOT, which consists of three key parts: DEcomposition of image into intrinsic modes, Monogenic Phase performing on combined dominant modes, and multi-level Otsu Thresholding on the phase. In particular, inspired by the Hilbert-Huang transform, we perform the multi-dimensional Ensemble Empirical Mode Decomposition and 2D generalization of the Hilbert transform known as the Riesz transform on the MR image to obtain the monogenic phase that is robust to noise and contrast variation. Then, a two-stage algorithm using multilevel Otsu thresholding is accomplished on the monogenic phase to automatically quantify the myocardium into healthy, gray zone, and infarct core regions. Experiments on LGE CMR images with myocardial infarction from 82 patients show the superior performance of the proposed approach in terms of reproducibility, robustness, and effectiveness. PMID- 29994105 TI - Local Motion Intensity Clustering (LMIC) Model for Segmentation of Right Ventricle in Cardiac MRI Images. AB - Analysis of the morphology and function of the right ventricle (RV) can be used for the prediction and diagnosis of cardiovascular disease. Accurate description of the structure and function of heart can be provided by analyzing cardiac magnetic resonance imaging (MRI) images. Noise interference and intensity inhomogeneity of MRI images can be addressed by using a Local Intensity Clustering (LIC) model. However, the segmentation of the RV in MRI images still remains a challenge mainly due to its ill-defined borders. To address such a challenge, an algorithm for segmenting the RV based on a local motion intensity clustering (LMIC) model is proposed in this paper. The LMIC model combines the LIC model with the motion intensity information, due to cardiac motion and blood flow. The motion intensity is calculated by using the Lucas Kanade (LK) optical flow method and utilized in the LMIC model as an energy parameter. Because the motion intensity of the RV region is stronger than other areas, the RV can be accurately segmented by this approach. Experimental results demonstrate that the LMIC model is able to address the challenge of the ill-defined RV borders in cardiac MRI images and improved RV segmentation accuracy over existing methods. PMID- 29994106 TI - Adaptive Compensation for Nonlinear Time-Varying Multiagent Systems With Actuator Failures and Unknown Control Directions. AB - This paper investigates a problem of designing an adaptive asymptotic cooperative control scheme for nonlinear time-varying multiagent systems, which can simultaneously tolerate unknown actuator failures and unknown control directions. To address such the problem, we propose a conditional inequality, which allows multiple piecewise Nussbaum functions to acquire the control robustness. Benefiting from this robustness, a part of failure uncertainties and system errors are compensated for, while the remaining parts are handled by adaptive control technique. Moreover, structural properties of the proposed adaptive laws are utilized so that Barbalat's lemma is applicable to make all the followers asymptotically converge to the leader based on the neighborhood information. PMID- 29994107 TI - Resilience Analysis of Critical Infrastructures: A Cognitive Approach Based on Granular Computing. AB - A great impetus for the study of resilience in critical infrastructures (CIs) is found in the large number of initiatives and international research programmes from U.S., EU, and Asia. Politicians, decision makers, and citizens are now aware of the drastic consequences that can have the cascading effects of an adverse event in these large scale infrastructures. However, the study of resilience in CIs is challenging for several reasons, among which their large scale and interdependencies. We have to consider also that adverse events, e.g., attacks, natural hazards, or man-made disasters, suddenly occur and evolve rapidly, giving us little time to take decisions and react to them. Approximate reasoning and rapid decision making have to be considered requirements for resilience analysis of CIs. The main result presented in this paper relates to a systemic integration of granular computing (GrC) and resilience analysis for CIs. Each phase of our approach presents distinctive aspects but, overall, we argue the merit of this paper consists in the originality of the study, being this the first work that combines GrC and resilience analysis of CIs. This paper reports an illustrative example that shows how to apply our results, and a discussion on the necessary contextualizations and extensions of the GrC results to be better adapted for CIs resilience. PMID- 29994108 TI - Filtering for Switched T-S Fuzzy Systems With Persistent Dwell Time. AB - The Hinfinity filter design for a class of switched Takagi-Sugeno (T-S) fuzzy systems with persistent dwell time (PDT) is investigated in this paper. The considered switched fuzzy systems contain a limited number of subsystems and each local subsystem is represented by the well-known T-S fuzzy model. Compared with the dwell time (DT) switching or average DT switching that attracted quantities of interests over the last decade, the PDT switching considered in this paper is known to be more general. The stability and L2-gain analysis for switched systems with PDT switching are derived first, based on which a set of full-order Hinfinity filter is designed to guarantee the global uniform asymptotic stability with a prescribed nonweighted Hinfinity noise attenuation performance for the resulting filtering error system. Finally, the effectiveness of the provided method is illustrated with an example. PMID- 29994109 TI - Globally-Optimal Inlier Set Maximisation for Camera Pose and Correspondence Estimation. AB - Estimating the 6-DoF pose of a camera from a single image relative to a 3D point set is an important task for many computer vision applications. Perspective-n point solvers are routinely used for camera pose estimation, but are contingent on the provision of good quality 2D-3D correspondences. However, finding cross modality correspondences between 2D image points and a 3D point-set is non trivial, particularly when only geometric information is known. Existing approaches to the simultaneous pose and correspondence problem use local optimisation, and are therefore unlikely to find the optimal solution without a good pose initialisation, or introduce restrictive assumptions. Since a large proportion of outliers and many local optima are common for this problem, we instead propose a robust and globally-optimal inlier set maximisation approach that jointly estimates the optimal camera pose and correspondences. Our approach employs branch-and-bound to search the 6D space of camera poses, guaranteeing global optimality without requiring a pose prior. The geometry of SE(3) is used to find novel upper and lower bounds on the number of inliers and local optimisation is integrated to accelerate convergence. The algorithm outperforms existing approaches on challenging synthetic and real datasets, reliably finding the global optimum, with a GPU implementation greatly reducing runtime. PMID- 29994110 TI - On Detection, Data Association and Segmentation for Multi-target Tracking. AB - In this work, we propose a tracker that differs from most existing multi-target trackers in two major ways. Firstly, our tracker does not rely on a pre-trained object detector to get the initial object hypotheses. Secondly, our tracker's final output is the fine contours of the targets rather than traditional bounding boxes. Therefore, our tracker simultaneously solves three main problems: detection, data association and segmentation. This is especially important because the output of each of those three problems are highly correlated and the solution of one can greatly help improve the others. The proposed algorithm consists of two main components: structured learning and Lagrange dual decomposition. Our structured learning based tracker learns a model for each target and infers the best locations of all targets simultaneously in a video clip. The inference of our structured learning is achieved through a new Target Identity-aware Network Flow (TINF). The second component is Lagrange dual decomposition, which combines the structured learning tracker with a multi-label Conditional Random Field (CRF) based segmentation algorithm. This leads to more accurate segmentation results and also helps better resolve typical difficulties in multiple target tracking, such as occlusion handling, ID-switch and track drifting. PMID- 29994111 TI - Safe Classification With Augmented Features. AB - With the evolution of data collection methods, it is possible to produce abundant data described by multiple feature sets. Previous studies show that including more features does not necessarily bring positive effects. How to prevent the augmented features from worsening classification performance is crucial but rarely studied. In this paper, we study this challenging problem by proposing a safe classification approach, whose accuracy is never degenerated when exploiting augmented features. We propose two ways to achieve the safeness of our method named as SAfe Classification (SAC). Firstly, to leverage augmented features, we learn various types of classifiers and adapt them by employing a specially designed robust loss. It provides various candidate classifiers to meet the assumption of safeness operation. Secondly, we search for a safe prediction by integrating all candidate classifiers. Under a mild assumption, the integrated classifier has theoretical safeness guarantee. Several new optimization methods have been developed to accommodate the problems with proved convergence. Besides evaluating SAC on 16 data sets, we also apply SAC in the application of diagnostic classification of schizophrenia since it has vast application potentiality. Experimental results demonstrate the effectiveness of SAC in both tackling safeness problem and discriminating schizophrenic patients from healthy controls. PMID- 29994112 TI - High-Resolution X-Ray Phase-Contrast 3-D Imaging of Breast Tissue Specimens as a Possible Adjunct to Histopathology. AB - Histopathological analysis is the current gold standard in breast cancer diagnosis and management, however, as imaging technology improves, the amount of potential diagnostic information that may be demonstrable radiologically should also increase. We aimed to evaluate the potential clinical usefulness of 3-D phase-contrast micro-computed tomography (micro-CT) imaging at high spatial resolutions as an adjunct to conventional histological microscopy. Ten breast tissue specimens, 2 mm in diameter, were scanned at the SYRMEP beamline of the Elettra Synchrotron using the propagation-based phase-contrast micro-tomography method. We obtained pixel size images, which were analyzed and compared with corresponding histological sections examined under light microscopy. To evaluate the effect of spatial resolution on breast cancer diagnosis, scans with four different pixel sizes were also performed. Our comparative analysis revealed that high-resolution images can enable, at a near-histological level, detailed architectural assessment of tissue that may permit increased breast cancer diagnostic sensitivity and specificity when compared with current imaging practices. The potential clinical applications of this method are also discussed. PMID- 29994113 TI - 3-D Subject-Specific Shape and Density Estimation of the Lumbar Spine From a Single Anteroposterior DXA Image Including Assessment of Cortical and Trabecular Bone. AB - Dual Energy X-ray Absorptiometry (DXA) is the standard exam for osteoporosis diagnosis and fracture risk evaluation at the spine. However, numerous patients with bone fragility are not diagnosed as such. In fact, standard analysis of DXA images does not differentiate between trabecular and cortical bone; neither specifically assess of the bone density in the vertebral body, which is where most of the osteoporotic fractures occur. Quantitative computed tomography (QCT) is an alternative technique that overcomes limitations of DXA-based diagnosis. However, due to the high cost and radiation dose, QCT is not used for osteoporosis management. We propose a method that provides a 3-D subject-specific shape and density estimation of the lumbar spine from a single anteroposterior (AP) DXA image. A 3-D statistical shape and density model is built, using a training set of QCT scans, and registered onto the AP DXA image so that its projection matches it. Cortical and trabecular bone compartments are segmented using a model-based algorithm. Clinical measurements are performed at different bone compartments. Accuracy was evaluated by comparing DXA-derived to QCT-derived 3-D measurements for a validation set of 180 subjects. The shape accuracy was 1.51 mm at the total vertebra and 0.66 mm at the vertebral body. Correlation coefficients between DXA and QCT-derived measurements ranged from 0.81 to 0.97. The method proposed offers an insightful 3-D analysis of the lumbar spine, which could potentially improve osteoporosis and fracture risk assessment in patients who had an AP DXA scan of the lumbar spine without any additional examination. PMID- 29994114 TI - Assessment of CT Image Quality Using a Bayesian Framework. AB - In computed tomography, there is a tradeoff between the quality of the reconstructed image and the radiation dose received by the patient. In order to find an appropriate compromise between the image quality of the reconstructed images and the radiation dose, it is important to have reliable methods for evaluating the quality of the reconstructed images. A successful family of methods for the assessment of image quality is task-based image quality assessment, which often involves the use of model observers, and which assesses the quality of the image reconstruction by deriving a figure of merit. Here, we present a Bayesian framework that can be used in task-based image quality assessment. Our framework is applicable to binary classification problems with normally distributed observations, and we make the additional assumption that the covariance matrix is the same in both image classes. We choose a particular non informative prior for the parameters of our model, which allows us to derive an expression for the Bayes factor for the binary classification problem which to the best of our knowledge is novel. We introduce a novel model observer based on this Bayes factor. Further, we have developed a methodology for estimating the posterior distribution of the figure of merit for this type of classification problem. Compared with classical statistical approaches, our Bayesian approach has the advantage that it provides a full characterization of the uncertainty of the figure of merit. Our choice of prior allows us to design a simple Monte Carlo algorithm to efficiently sample the posterior of the figure of merit of the ideal observer, in contrast to common Bayesian procedures which rely on computationally expensive Markov chain Monte Carlo sampling. We have shown that for training samples of sufficient size, our estimated credible intervals for the figure of merit have coverage probabilities close to their credibility, so that our approach can reasonably be used within a classical statistical framework as well. PMID- 29994115 TI - Structured AutoEncoders for Subspace Clustering. AB - Existing subspace clustering methods typically employ shallow models to estimate underlying subspaces of unlabeled data points and cluster them into corresponding groups. However, due to the limited representative capacity of the employed shallow models, those methods may fail in handling realistic data without the linear subspace structure. To address this issue, we propose a novel subspace clustering approach by introducing a new deep model-Structured AutoEncoder (StructAE). The StructAE learns a set of explicit transformations to progressively map input data points into nonlinear latent spaces while preserving the local and global subspace structure. In particular, to preserve local structure, the StructAE learns representations for each data point by minimizing reconstruction error w.r.t. itself. To preserve global structure, the StructAE incorporates a prior structured information by encouraging the learned representation to preserve specified reconstruction patterns over the entire data set. To the best of our knowledge, StructAE is one of first deep subspace clustering approaches. Extensive experiments show that the proposed StructAE significantly outperforms 15 state-of-the-art subspace clustering approaches in terms of five evaluation metrics. PMID- 29994116 TI - USEAQ: Ultra-fast Superpixel Extraction via Adaptive Sampling from Quantized Regions. AB - We present a novel and highly efficient superpixel extraction method called USEAQ to generate regular and compact superpixels in an image. To reduce the computational cost of iterative optimization procedures adopted in most recent approaches, the proposed USEAQ for superpixel generation works in a one-pass fashion. It firstly performs joint spatial and color quantizations and groups pixels into regions. It then takes into account the variations between regions, and adaptively samples one or a few superpixel candidates for each region. It finally employs maximum a posteriori (MAP) estimation to assign pixels to the most spatially consistent and perceptually similar superpixels. It turns out that the proposed USEAQ is quite efficient, and the extracted superpixels can precisely adhere to boundaries of objects. Experimental results show that USEAQ achieves better or equivalent performance compared to the stateof- the-art superpixel extraction approaches in terms of boundary recall, undersegmentation error, achievable segmentation accuracy, the average miss rate, average undersegmentation error, and average unexplained variation, and it is significantly faster than these approaches. PMID- 29994117 TI - MIO-TCD: A new benchmark dataset for vehicle classification and localization. AB - The ability to train on a large dataset of labeled samples is critical to the success of deep learning in many domains. In this paper, we focus on motor vehicle classification and localization from a single video frame and introduce the "MIOvision Traffic Camera Dataset" (MIO-TCD) in this context. MIO-TCD is the largest dataset for motorized traffic analysis to date. It includes 11 traffic object classes such as cars, trucks, buses, motorcycles, bicycles, pedestrians. It contains 786,702 annotated images acquired at different times of the day and different periods of the year by hundreds of traffic surveillance cameras deployed across Canada and the United States. The dataset consists of two parts: a "localization dataset", containing 137,743 full video frames with bounding boxes around traffic objects, and a "classification dataset", containing 648,959 crops of traffic objects from the 11 classes. We also report results from the 2017 CVPR MIO-TCD Challenge, that leveraged this dataset, and compare them with results for state-of-the-art deep learning architectures. These results demonstrate the viability of deep learning methods for vehicle localization and classification from a single video frame in real-life traffic scenarios. The topperforming methods achieve both accuracy and Kappa score above 96% on the classification dataset and mean-average precision of 77% on the localization dataset. We also identify scenarios in which state-of-the-art methods still fail and we suggest avenues to address these challenges. Both the dataset and detailed results are publicly available on-line [1]. PMID- 29994118 TI - Detecting 3D Points of Interest Using Multiple Features and Stacked Auto-encoder. AB - Considering the fact that points of interest on 3D shapes can be discriminated from a geometric perspective, it is reasonable to map the geometric signature of a point to a probability value encoding to what degree is a point of interest, especially for a specific class of 3D shapes. Based on the observation, we propose a three-phase algorithm for learning and predicting points of interest on 3D shapes by using multiple feature descriptors. Our algorithm requires two separate deep neural networks (stacked auto-encoders) to accomplish the task. During the first phase, we predict the membership of the given 3D shape according to a set of geometric descriptors using a deep neural network. After that, we train the other deep neural network to predict a probability distribution defined on the surface representing the possibility of a point being a point of interest. Finally, we use a manifold clustering technique to extract a set of points of interest as the output. Experimental results show superior detection performance of the proposed method over the previous state-of-the-art approaches. PMID- 29994119 TI - Realtime Hand-Object Interaction using Learned Grasp Space for Virtual Environments. AB - We present a realtime virtual grasping algorithm to model interactions with virtual objects. Our approach is designed for multi-fingered hands and makes no assumptions about the motion of the user's hand or the virtual objects. Given a model of the virtual hand, we use machine learning and particle swarm optimization to automatically pre-compute stable grasp configurations for that object. The learning pre-computation step is accelerated using GPU parallelization. At runtime, we rely on the pre-computed stable grasp configurations, and dynamics/non-penetration constraints along with motion planning techniques to compute plausible looking grasps. In practice, our realtime algorithm can perform virtual grasping operations in less than 20ms for complex virtual objects, including high genus objects with holes. We have integrated our grasping algorithm with Oculus Rift HMD and Leap Motion controller and evaluated its performance for different tasks corresponding to grabbing virtual objects and placing them at arbitrary locations. Our user evaluation suggests that our virtual grasping algorithm can increase the user's realism and participation in these tasks and offers considerable benefits over prior interaction algorithms, such as pinch grasping and raycast picking. PMID- 29994120 TI - Sparse Coding and Compressive Sensing for Overlapping Neural Spike Sorting. AB - Spike sorting is one of the key techniques to understand brain activity. With the development of modern electrophysiology technology, some recent multi-electrode technologies have been able to record the activity of thousands of neuronal spikes simultaneously. In this scenario, however, the recorded activity may be the overlap of multi-neuron spikes, which will degrade the sorting performance of existing cluster-based algorithms. In this paper, we introduce methods for overlapping spike sorting. The introduced methods start from a convolution model, where a sparse vector could be obtained via sparse coding or compressive sensing. Then, we use a maximum a posteriori estimate to optimize the sparse vector, which makes the overlapped spike sorting completed successfully. The advantage of the introduced method is that it performs better than traditional methods when the waveforms of the spikes are similar. In experiments, some synthetic and real spike data are used to testify the methods. The experiment results show that the introduced methods' average sorting detection, defined as the ratio of successfully sorted spikes to the total spikes is nearly 4% higher than the traditional methods, under the condition of the experimental data with similar waveforms. PMID- 29994121 TI - Intelligent Object Grasping With Sensor Fusion for Rehabilitation and Assistive Applications. AB - This paper presents the design and control of the intelligent sensing and force feedback exoskeleton robotic glove to create a system capable of intelligent object grasping initiated by detection of the user's intentions through motion amplification. Using a combination of sensory feedback streams from the glove, the system has the ability to identify and prevent object slippage, as well as adapting grip geometry to the object properties. The slip detection algorithm provides updated inputs to the force controller to prevent an object from being dropped, while only requiring minimal input from a user who may have varying degrees of functionality in their injured hand. This paper proposes the use of a high dynamic range, low cost conductive elastomer sensor coupled with a negative force derivative trigger that can be leveraged in order to create a controller that can intelligently respond to slip conditions through state machine architecture, and improve the grasping robustness of the exoskeleton. The improvements to the previous design are described while the details of the controller design and the proposed assistive and rehabilitative applications are explained. Experimental results confirming the validity of the proposed system are presented. Finally, this paper concludes with topics for future exploration. PMID- 29994122 TI - A Novel Framework for Quantitatively Connecting the Mechanical Design of Passive Prosthetic Feet to Lower Leg Trajectory. AB - This paper presents a novel framework that quantitatively connects the mechanical design of a prosthetic foot to its anticipated biomechanical performance. The framework uses kinetic inputs (ground reaction forces and center of pressure) to predict kinematic outputs of the lower leg segment by knowing the geometry and stiffness of the foot. The error between the predicted and target kinematics is evaluated using a root-mean-square error function called the Lower Leg Trajectory Error (LLTE). Using physiological kinetic inputs and kinematic targets, three model foot architectures were optimized to minimize the LLTE. The resulting predicted lower leg kinematics were compared to those of the same foot architectures optimized for physiological roll-over geometry. The feet with minimized LLTE had lower leg kinematics closer to physiological than those optimized for roll-over geometry. A prosthetic foot that exactly mimics physiological roll-over geometry may result in gait kinematics that differ greatly from physiological, as roll-over geometry omits information about the foot-ground contact constraint, lower leg orientation, and temporal progression of a step. The LLTE-based framework is agnostic to specific foot designs provided their constitutive behavior can be characterized, and it can accept alternate inputs and targets depending on what performance and clinical objectives are desired. PMID- 29994123 TI - A Multi-Class BCI Based on Somatosensory Imagery. AB - In this paper, we investigated the performance of a multi-class brain-computer interface (BCI). The BCI system is based on the concept of somatosensory attentional orientation (SAO), in which the user shifts and maintains somatosensory attention by imagining the sensation of tactile stimulation of a body part. At the beginning of every trial, a vibration stimulus (200 ms) informed the subjects to prepare for the task. Four SAO tasks were performed following randomly presented cues: SAO of the left hand (SAO-LF), SAO of the right hand (SAO-RT), bilateral SAO (SAO-BI), and SAO suppressed or idle state (SAO-ID). Analysis of the event-related desynchronization and synchronization (ERD/ERS) in the EEG indicated that the four SAO tasks had different somatosensory cortical activation patterns. SAO-LF and SAO-RT exhibited stronger contralateral ERD, whereas bilateral ERD activation was indicative of SAO-BI, and bilateral ERS activation was associated with SAO-ID. By selecting the frequency bands and/or optimal classes, classification accuracy of the system reached 85.2%+/-11.2% for two classes, 69.5%+/-16.2% for three classes, and 55.9%+/-15.8% for four classes. The results validated a multi-class BCI system based on SAO, on a single trial basis. Somatosensory attention to different body parts induces diverse oscillatory dynamics within the somatosensory area of the brain, and the proposed SAO paradigm provided a new approach for a multiple-class BCI that is potentially stimulus independent. PMID- 29994124 TI - Prediction of Optimal Facial Electromyographic Sensor Configurations for Human Machine Interface Control. AB - Surface electromyography (sEMG) is a promising computer access method for individuals with motor impairments. However, optimal sensor placement is a tedious task requiring trial-and-error by an expert, particularly when recording from facial musculature likely to be spared in individuals with neurological impairments. We sought to reduce the sEMG sensor configuration complexity by using quantitative signal features extracted from a short calibration task to predict human-machine interface (HMI) performance. A cursor control system allowed individuals to activate specific sEMG-targeted muscles to control an onscreen cursor and navigate a target selection task. The task was repeated for a range of sensor configurations to elicit a range of signal qualities. Signal features were extracted from the calibration of each configuration and examined via a principle component factor analysis in order to predict the HMI performance during subsequent tasks. Feature components most influenced by the energy and the complexity of the EMG signal and muscle activity between the sensors were significantly predictive of the HMI performance. However, configuration order had a greater effect on performance than the configurations, suggesting that non experts can place sEMG sensors in the vicinity of usable muscle sites for computer access and healthy individuals will learn to efficiently control the HMI system. PMID- 29994125 TI - iGlu-Lys: A Predictor for Lysine Glutarylation Through Amino Acid Pair Order Features. AB - As one of the new posttranslational modification, lysine glutarylation has been identified in both prokaryotic and eukaryotic cells. These glutarylated proteins are involved in various cellular functions, such as translation, metabolism, and exhibited diverse subcellular localizations. Experimental identification of lysine glutarylation sites was founded in 2014 and also identified its deglutarylase sirturn 5(SIRT 5). Computational prediction of lysine glutarylation could be a complementary way to the experimental technique. In this work, the lysine glutarylation predictor iGlu-Lys has been developed based on the machine learning scheme. We have selected the best feature scheme which took the amino acid pair order and special-position information into account from four constructions. The machine learning algorithm support vector machine has been adopted and its performance has been measured for different window length of peptides. In the 10-fold cross-validation with window length 19, the AUC and MCC were 0.8944 and 0.5098, respectively. Different ROC curves in 6-, 8-, and 10-fold cross-validations were very close which illustrated the robustness of our predictor. The results of iGLu-Lys were better than the existing method GlutPred. Meanwhile, a free webserver for iGlu-Lys is accessible at http://app.aporc.org/iGlu-Lys/. PMID- 29994126 TI - An Integrated Reconciliation Framework for Domain, Gene, and Species Level Evolution. AB - The majority of genes in eukaryotes consist of one or more protein domains that can be independently lost or gained during evolution. This gain and loss of protein domains, through domain duplications, transfers, or losses, has important evolutionary and functional consequences. Yet, even though it is well understood that domains evolve inside genes and genes inside species, there do not exist any computational frameworks to simultaneously model the evolution of domains, genes, and species and account for their inter-dependency. Here, we develop an integrated model of domain evolution that explicitly captures the interdependence of domain-, gene-, and species-level evolution. Our model extends the classical phylogenetic reconciliation framework, which infers gene family evolution by comparing gene trees and species trees, by explicitly considering domain-level evolution and decoupling domain-level events from gene-level events. In this paper, we (i) introduce the new integrated reconciliation framework, (ii) prove that the associated optimization problem is NP-hard, (iii) devise an efficient heuristic solution for the problem, (iv) apply our algorithm to a large biological dataset, and (v) demonstrate the impact of using our new computational framework compared to existing approaches. The implemented software is freely available from http://compbio.engr.uconn.edu/software/seadog/. PMID- 29994127 TI - A branch point on differentiation trajectory is the bifurcating event revealed by dynamical network biomarker analysis of single-cell data. AB - The advance in single-cell profiling technologies and the development in computational algorithms provide the opportunity to reconstruct pseudo temporal trajectory with branch point of cellular development. On the other hand, theories such as dynamical network biomarkers (DNB) theory have been recently proposed to characterize the pre-transition state in biological systems. Few studies have validated whether the branch point identified in pseudo time is the critical point in dynamical system. In this study, the dynamical behavior of the branch point on the pseudo trajectory has been investigated. We study the pseudo temporal trajectories reconstructed by Wishbone and diffusion pseudotime analysis (DPT) algorithms, as well as the simulated trajectory. DNB theory is applied to justify the bifurcating event on the pseudo trajectories. Our results demonstrate that the branch point recovered by Wishbone and DPT algorithms is confirmed as a transition state in cell differentiation process by DNB theory. Furthermore, we show that an appropriate DNB group will amplify the comprehensive index of critical event as defined in DNB theory. Our study provides biological insights on pseudo trajectory with branch point in a dynamical view and also indicates that DNB theory may serve as a benchmark to check the validity of branch point. PMID- 29994128 TI - Comparison of computational methods for imputing single-cell RNA-sequencing data. AB - Single-cell RNA-sequencing (scRNA-seq) is a recent breakthrough technology, which paves the way for measuring RNA levels at single cell resolution to study precise biological functions. One of the main challenges when analyzing scRNA-seq data is the presence of zeros or dropout events, which may mislead downstream analyses. To compensate the dropout effect, several methods have been developed to impute gene expression since the first Bayesian-based method being proposed in 2016. However, these methods have shown very diverse characteristics in terms of model hypothesis and imputation performance. Thus, largescale comparison and evaluation of these methods is urgently needed now. To this end, we compared eight imputation methods, evaluated their power in recovering original real data, and performed broad analyses to explore their effects on clustering cell types, detecting differentially expressed genes, and reconstructing lineage trajectories in the context of both simulated and real data. Simulated datasets and case studies highlight that there are no one method performs the best in all the situations. Some defects of these methods such as scalability, robustness and unavailability in some situations need to be addressed in future studies. PMID- 29994129 TI - Deep Learning for Plant Species Classification using Leaf Vein Morphometric. AB - Automated plant species identification system could help botanists and layman in identifying plant species rapidly. Deep learning is robust for feature extraction as it is superior in providing deeper information of images. In this research, a new CNN-based method named D-Leaf was proposed. The leaf images were pre processed and the features were extracted by using three different Convolutional Neural Network (CNN) models namely pre-trained AlexNet, fine-tuned AlexNet and D Leaf. These features were then classified by using five machine learning techniques, namely, Support Vector Machine (SVM), Artificial Neural Network (ANN), k-Nearest-Neighbour (k-NN), Naive-Bayes (NB) and CNN. A conventional morphometric method computed the morphological measurements based on the Sobel segmented veins was employed for benchmarking purposes. The D-Leaf model achieved a comparable testing accuracy of 94.88% as compared to AlexNet (93.26%) and fine tuned AlexNet (95.54%) models. In addition, CNN models performed better than the traditional morphometric measurements (66.55%). The features extracted from the CNN are found to be fitted well with the ANN classifier. D-Leaf can be an effective automated system for plant species identification as shown by the experimental results. PMID- 29994130 TI - Multi-factored gene-gene proximity measures exploiting biological knowledge extracted from Gene Ontology : application in gene clustering. AB - To describe the cellular functions of proteins and genes, a potential dynamic vocabulary is Gene Ontology (GO), which comprises of three sub-ontologies namely, Biological-process, Cellular-component and Molecular-function. It has several applications in the field of bioinformatics like annotating/measuring gene-gene or protein-protein semantic similarity, identifying genes/proteins by their GO annotations for disease gene and target discovery etc. To determine semantic similarity between genes, several semantic measures have been proposed in literature, which involve information content of GO-terms, GO tree structure or the combination of both. But most of the existing semantic similarity measures do not consider different topological and information theoretic aspects of GO-terms collectively. Inspired by this fact, in this article, we have first proposed three novel semantic similarity/distance measures for genes covering different aspects of GO-tree. These are further implanted in the frameworks of well-known multi-objective and single-objective based clustering algorithms to determine functionally similar genes. For comparative analysis, ten popular existing GO based semantic similarity/distance measures and tools are also considered. Experimental results on Mouse genome, Yeast and Human genome datasets evidently demonstrate the supremacy of multi-objective clustering algorithms in association with proposed multi-factored similarity/distance measures. Clustering outcomes are further validated by conducting some biological/statistical significance tests. PMID- 29994131 TI - Stepwise Tikhonov Regularisation: Application to the Prediction of HIV-1 Drug Resistance. AB - This paper focuses on constructing genotypic predictors for antiretroviral drug susceptibility of HIV. To this end, a method to recover the largest elements of an unknown vector in a least squares problem is developed. The proposed method introduces two novel ideas. The first idea is a novel forward stepwise selection procedure based on the magnitude of the estimates of the candidate variables. To implement this newly introduced procedure, we revise Tikhonov regularisation from a sparse representations' perspective. This analysis leads us to the second novel idea in the paper, which is the development of a new method to recover the largest elements of the unknown vector in the least squares problem. The method implements a sequence of Tikhonov regularisation problems which aim to recover the largest of the remaining elements of the unknown vector. Additionally, we derive sufficient conditions that ensure the recovery of the largest elements of the unknown vector. We perform numerical studies using simulated data and data from the Stanford HIV resistance database. The performance of the proposed method is compared against a state-of-the-art method. PMID- 29994132 TI - Spiking Optical Flow for Event-Based Sensors Using IBM's TrueNorth Neurosynaptic System. AB - This paper describes a fully spike-based neural network for optical flow estimation from dynamic vision sensor data. A low power embedded implementation of the method, which combines the asynchronous time-based image sensor with IBM's TrueNorth Neurosynaptic System, is presented. The sensor generates spikes with submillisecond resolution in response to scene illumination changes. These spike are processed by a spiking neural network running on TrueNorth with a 1-ms resolution to accurately determine the order and time difference of spikes from neighbouring pixels, and therefore infer the velocity. The spiking neural network is a variant of the Barlow Levick method for optical flow estimation. The system is evaluated on two recordings for which ground truth motion is available, and achieves an average endpoint error of 11% at an estimated power budget of under 80 mW for the sensor and computation. PMID- 29994133 TI - Scaling Up Kernel SVM on Limited Resources: A Low-Rank Linearization Approach. AB - Kernel support vector machines (SVMs) deliver state-of-the-art results in many real-world nonlinear classification problems, but the computational cost can be quite demanding in order to maintain a large number of support vectors. Linear SVM, on the other hand, is highly scalable to large data but only suited for linearly separable problems. In this paper, we propose a novel approach called low-rank linearized SVM to scale up kernel SVM on limited resources. Our approach transforms a nonlinear SVM to a linear one via an approximate empirical kernel map computed from efficient kernel low-rank decompositions. We theoretically analyze the gap between the solutions of the approximate and optimal rank-k kernel map, which in turn provides guidance on the sampling scheme of the Nystrom approximation. Furthermore, we extend it to a semisupervised metric learning scenario in which partially labeled samples can be exploited to further improve the quality of the low-rank embedding. Our approach inherits rich representability of kernel SVM and high efficiency of linear SVM. Experimental results demonstrate that our approach is more robust and achieves a better tradeoff between model representability and scalability against state-of-the-art algorithms for large-scale SVMs. PMID- 29994134 TI - Optimized Neural Network Parameters Using Stochastic Fractal Technique to Compensate Kalman Filter for Power System-Tracking-State Estimation. AB - Tracking-state estimation uses previous state vector and recent measurement data to give real-time update on the state of the power system noniteratively during the subsequent time sampling. This paper discusses Kalman filtering enhanced by optimized neural network parameters-based stochastic fractals search technique (KF-MLP-based SFS). Both KF gain (mismodeling error) and measurement noise were replaced by optimized multilayer perceptron (MLP-SFS). This optimized MLP-based SFS could suppress filter divergence and improve the accuracy. The proposed method was used to detect and identify anomalies exhibited in normal operation where loads fluctuate linearly, bad data condition, sudden loss of loads, generators, and transmission lines. The application of the proposed technique (KF MLP-based SFS) is illustrated on the IEEE 57-bus system. Results of the presented approach are compared to the true state vector (load flow), KF standalone, and KF compensated by radial basis function. PMID- 29994135 TI - Exploring Correlations Among Tasks, Clusters, and Features for Multitask Clustering. AB - Multitask clustering methods are proposed to improve performances of related tasks concurrently, because they explore the relationship among tasks via exploiting the coefficient matrix or the shared feature matrix. However, divergent effects of features in learning this relationship are seldom considered. To further improve performances, we propose a new multitask clustering approach through exploring correlations among tasks, clusters, and features based on effects of features on clusters. First, a Feature-Cluster (FeaCluster) matrix is introduced to capture the similarity and the distinct task feature information simultaneously for each task. With the FeaCluster matrix, two affinities are calculated to constitute the interdependencies among tasks: the former is the graphical affinity based on feature-task and task-cluster correlations, while the latter is the reconstructive affinity. Here, the feature task correlation considers effects of features on tasks, and the task-cluster correlation considers the overall effects of features on clusters. The reconstructive affinity is obtained by minimizing the reconstruction error when representing the FeaCluster matrix for a given task with a linear combination of others. The interdependencies among tasks allow transferring asymmetric shared information, exploring significant features and preserving key information when mapping data into the subspace. The experimental results on multiple data sets reveal that the proposed approach outperforms the state-of-the-art clustering methods in terms of accuracy and normal mutual information. PMID- 29994136 TI - Design and Evaluation of a Motorized Robotic Bed Mover With Omnidirectional Mobility for Patient Transportation. AB - Patient transportation in hospitals faces many challenges, including the limited manpower, work-related injuries, and low efficiency of current bed pushing methods. This paper presents a new motorized robotic bed mover with omnidirectional mobility to address this problem. This device is composed of an omnidirectional mobility unit, a force sensing-based human-machine interface, and control hardware with batteries and electronics. The proposed bed mover can be attached to the bottom of a manual hospital stretcher, transforming it into a powered omnidirectional bed (OmniBed) that can be used only by one person. The function of the OmniBed is compared with that of a conventional powered bed, which only provides forward assistance with a fifth powered wheel. We perform a pilot study with 14 subjects to evaluate the performance of this OmniBed and benefits for hospital application. The experimental results show that the OmniBed can half the manpower while decreasing back muscle activities, revealing the potential health benefits for older staffs. The OmniBed also shows the promising signs of high precision and handling in small spaces with its one-step "parallel parking" ability. This device is more ergonomic, more effective, and safer than the conventional powered bed. PMID- 29994137 TI - Sparse Multiview Task-Centralized Ensemble Learning for ASD Diagnosis Based on Age- and Sex-Related Functional Connectivity Patterns. AB - Autism spectrum disorder (ASD) is an age- and sex-related neurodevelopmental disorder that alters the brain's functional connectivity (FC). The changes caused by ASD are associated with different age- and sex-related patterns in neuroimaging data. However, most contemporary computer-assisted ASD diagnosis methods ignore the aforementioned age-/sex-related patterns. In this paper, we propose a novel sparse multiview task-centralized (Sparse-MVTC) ensemble classification method for image-based ASD diagnosis. Specifically, with the age and sex information of each subject, we formulate the classification as a multitask learning problem, where each task corresponds to learning upon a specific age/sex group. We also extract multiview features per subject to better reveal the FC changes. Then, in Sparse-MVTC learning, we select a certain central task and treat the rest as auxiliary tasks. By considering both task-task and view-view relationships between the central task and each auxiliary task, we can learn better upon the entire dataset. Finally, by selecting the central task, in turn, we are able to derive multiple classifiers for each task/group. An ensemble strategy is further adopted, such that the final diagnosis can be integrated for each subject. Our comprehensive experiments on the ABIDE database demonstrate that our proposed Sparse-MVTC ensemble learning can significantly outperform the state-of-the-art classification methods for ASD diagnosis. PMID- 29994138 TI - Improving Speech Related Facial Action Unit Recognition by Audiovisual Information Fusion. AB - It is challenging to recognize facial action unit (AU) from spontaneous facial displays, especially when they are accompanied by speech. The major reason is that the information is extracted from a single source, i.e., the visual channel, in the current practice. However, facial activity is highly correlated with voice in natural human communications. Instead of solely improving visual observations, this paper presents a novel audiovisual fusion framework, which makes the best use of visual and acoustic cues in recognizing speech-related facial AUs. In particular, a dynamic Bayesian network is employed to explicitly model the semantic and dynamic physiological relationships between AUs and phonemes as well as measurement uncertainty. Experiments on a pilot audiovisual AU-coded database have demonstrated that the proposed framework significantly outperforms the state of-the-art visual-based methods in terms of recognizing speech-related AUs, especially for those AUs whose visual observations are impaired during speech, and more importantly is also superior to audio-based methods and feature-level fusion methods, which employ low-level audio features, by explicitly modeling and exploiting physiological relationships between AUs and phonemes. PMID- 29994139 TI - A Knowledge-Based Semisupervised Hierarchical Online Topic Detection Framework. AB - Topic models have achieved big success in recent years. To detect topics in a text stream, various online topic models have been proposed in the literature. The limitations of these works include that: 1) most of them run with fixed topic numbers and 2) the overlaps between the topics may enlarge in the evolving process. Hierarchical topic model is a candidate solution to these problems since it can reveal many useful relationships between the topics. These relationships can help to find high quality topics and reduce topic overlaps. In this paper, a knowledge-based semisupervised hierarchical online topic detection framework is proposed. The proposed framework can detect topics in an online hierarchical way. In addition, it has been proven that introducing external knowledge can improve the performance of text mining. Therefore, the knowledge from external knowledge sources and human experts are also integrated in the proposed framework. Experiments are conducted to evaluate the proposed framework with different metrics. The results show that compared with the baseline methods, our framework can achieve better performance with competitive time efficiency. PMID- 29994140 TI - A Consistency and Consensus-Based Goal Programming Method for Group Decision Making With Interval-Valued Intuitionistic Multiplicative Preference Relations. AB - Interval-valued intuitionistic multiplicative preference relations (IVIMPRs) form a suitable conceptual framework to represent and process simultaneously uncertain preferred and nonpreferred judgments of decision makers (DMs). The focus of this paper is on group decision-making (GDM) problems realized with IVIMPRs. First, a consistency index is introduced to evaluate the consistency degree for intuitionistic multiplicative preference relations (IMPRs), and a consistency optimization approach is presented to jointly improve the consistency degrees of several IMPRs that do not satisfy the predefined consistency threshold. Then, a consistency definition and an acceptable consistency definition for IVIMPRs are established by splitting an IVIMPR into two IMPRs. For several IVIMPRs with unacceptable consistency, a goal program-based approach is proposed to simultaneously improve their consistency. Subsequently, by minimizing the degree to which the opinions of individual DMs deviate from those of the group, a maximum consensus-based goal program is established to determine the DMs' weights. Furthermore, an aggregation approach is applied to integrate individual IVIMPRs into a collective one. A linear program is then built to determine the interval-valued intuitionistic multiplicative priority weights of alternatives coming from the collective IVIMPR. A consistency-based GDM algorithm is proposed. Finally, a practical example is offered to show the application of the new algorithm, and a comparative analysis is presented to highlight the advantages of the new method. PMID- 29994141 TI - Multidirectional Prediction Approach for Dynamic Multiobjective Optimization Problems. AB - Various real-world multiobjective optimization problems are dynamic, requiring evolutionary algorithms (EAs) to be able to rapidly track the moving Pareto front of an optimization problem once an environmental change occurs. To this end, several methods have been developed to predict the new location of the moving Pareto set (PS) so that the population can be reinitialized around the predicted location. In this paper, we present a multidirectional prediction strategy to enhance the performance of EAs in solving a dynamic multiobjective optimization problem (DMOP). To more accurately predict the moving location of the PS, the population is clustered into a number of representative groups by a proposed classification strategy, where the number of clusters is adapted according to the intensity of the environmental change. To examine the performance of the developed algorithm, the proposed prediction strategy is compared with four state of-the-art prediction methods under the framework of particle swarm optimization as well as five popular EAs for dynamic multiobjective optimization. Our experimental results demonstrate that the proposed algorithm can effectively tackle DMOPs. PMID- 29994142 TI - Quantized Feedback Control of Fuzzy Markov Jump Systems. AB - This paper addresses the problem of quantized feedback control of nonlinear Markov jump systems (MJSs). The nonlinear plant is represented by a class of fuzzy MJSs with time-varying delay based on a Takagi-Sugeno fuzzy model. The quantized signal is utilized for control purpose and the sector bound approach is exploited to deal with quantization errors. By constructing a Lyapunov function which depends both on mode information and fuzzy basis functions, the reciprocally convex approach is used to derive the criterion which is able to ensure the stochastic stability with a predefined l2-linfinity performance of the resulting closed-loop system. The design of the quantized feedback controller is then converted to a convex optimization problem, which can be handled through the linear matrix inequality technique. Finally, a simulation example is presented to verify the effectiveness and practicability of the proposed new design techniques. PMID- 29994143 TI - Pinning Controllers for Activation Output Tracking of Boolean Network Under One Bit Perturbation. AB - This paper studies pinning controllers for activation output tracking (AOT) of Boolean network under one-bit perturbation, based on the semitensor product of matrices. First, the definition of AOT with respect to an activation number is presented, where the activation number means the number of active outputs whose logical variables are 1 s. Then, several criteria are established for AOT issue. Further, the impact of one-bit perturbation on AOT is studied, where one-bit perturbation means that only one logical function has one-bit change of its truth table by flipping the value from 1 to 0 or 0 to 1. In addition, if a one-bit perturbation is a valid perturbation on AOT, an output feedback pinning control is designed to recover AOT. The obtained results are effectively illustrated by a D. melanogaster segmentation polarity gene network and a reduced signal transduction network. PMID- 29994144 TI - Fuzzy-Model-Based Sliding Mode Control of Nonlinear Descriptor Systems. AB - This paper addresses the problem of sliding mode control (SMC) for a type of uncertain time-delay nonlinear descriptor systems represented by T-S fuzzy models. One crucial contributing factor is to put forward a novel integral fuzzy switching manifold involved with time delay. Compared with previous results, the key benefit of the new manifold is that the input matrices via different subsystems are permitted to be diverse, and thus much more applicability will be achieved. By resorting to Frobenius' theorem and double orthogonal complement, the existence condition of the fuzzy manifold is presented. The admissibility conditions of sliding motion with a strictly dissipative performance are further provided. Then, the desired fuzzy SMC controller is synthesized by analyzing the reachability of the manifold. Moreover, an adaptive fuzzy SMC controller is also proposed to adapt the input saturation and the matched uncertainty with unknown upper bounds. The feasibility and virtue of our theoretical findings are demonstrated by a fuzzy SMC controller implementation for a practical system about the pendulum. PMID- 29994145 TI - Evaluating the Group Detection Performance: The GRODE Metrics. AB - The detection of groups of individuals is attracting the attention of many researchers in diverse fields, from automated surveillance to human-computer interaction, with a growing number of approaches published every year. Unexpectedly, the evaluation metrics for this problem are not consolidated, with some measures inherited from different fields, other designed specifically for a particular approach, thus lacking in generalization and making the comparisons between different approaches difficult. Moreover, most of the existent metrics are scarcely expressive, addressing groups as atomic entities, ignoring that they may have different cardinalities, and that group detection approaches may fail in capturing the exact number of individuals that compose it. This paper fills this gap presenting the GROup DEtection (GRODE) metrics, which formally define precision and recall on the groups, including the group cardinality as a variable. This gives the possibility to investigate aspects never considered so far, such as the tendency of a method of over- or under-segmenting, or of better dealing with specific group cardinalities. The GRODE metrics have been evaluated first on controlled scenarios, where the differences with alternative metrics are evident, as well as on public datasets, providing a fresh-new panorama of the state-of-the-art. PMID- 29994146 TI - High-Speed Hyperspectral Video Acquisition By Combining Nyquist and Compressive Sampling. AB - We propose a novel hybrid imaging system to acquire 4D high-speed hyperspectral (HSHS) videos with high spatial and spectral resolution. The proposed system consists of two branches: one branch performs Nyquist sampling in the temporal dimension while integrating the whole spectrum, resulting in a high-frame-rate panchromatic video; the other branch performs compressive sampling in the spectral dimension with longer exposures, resulting in a low-frame-rate hyperspectral video. Owing to the high light throughput and complementary sampling, these two branches jointly provide reliable measurements for recovering the underlying HSHS video. Moreover, the panchromatic video can be used to learn an over-complete 3D dictionary to represent each band-wise video sparsely, thanks to the inherent structural similarity in the spectral dimension. Based on the joint measurements and the self-adaptive dictionary, we further propose a simultaneous spectral sparse (3S) model to reinforce the structural similarity across different bands and develop an efficient computational reconstruction algorithm to recover the HSHS video. Both simulation and hardware experiments validate the effectiveness of the proposed approach. To the best of our knowledge, this is the first time that hyperspectral videos can be acquired at a frame rate up to 100fps with commodity optical elements and under ordinary indoor illumination. PMID- 29994147 TI - CColor and Vector Flow Imaging in Parallel Ultrasound with Sub-Nyquist Sampling. AB - RF acquisition with a high-performance multi-chan-nel ultrasound system generates massive datasets in short periods of time, especially in "ultrafast" ultrasound when digital receive beamforming is required. Sampling at a rate four times the carrier frequency is the standard procedure since this rule complies with the Nyquist-Shannon sampling theorem and simplifies quadrature sampling. Bandpass sampling (or undersampling) outputs a band-pass signal at a rate lower than the maximal frequency without harmful aliasing. Advantages over Nyquist sampling are reduced storage volumes and data workflow, and simplified digital signal processing tasks. We used RF undersampling in color flow imag-ing (CFI) and vector flow imaging (VFI) to decrease data volume significantly (factor of 3 to 13 in our configurations). CFI and VFI with Nyquist and sub-Nyquist samplings were compared in vitro and in vivo. The estimate errors due to undersampling were small or marginal, which illustrates that Doppler and vector Doppler im-ages can be correctly computed with a drastically reduced amount of RF samples. Undersampling can be a method of choice in CFI and VFI to avoid information overload and reduce data transfer and storage. PMID- 29994148 TI - Road Surface 3D Reconstruction Based on Dense Subpixel Disparity Map Estimation. AB - Various 3D reconstruction methods have enabled civil engineers to detect damage on a road surface. To achieve the millimetre accuracy required for road condition assessment, a disparity map with subpixel resolution needs to be used. However, none of the existing stereo matching algorithms are specially suitable for the reconstruction of the road surface. Hence in this paper, we propose a novel dense subpixel disparity estimation algorithm with high computational efficiency and robustness. This is achieved by first transforming the perspective view of the target frame into the reference view, which not only increases the accuracy of the block matching for the road surface but also improves the processing speed. The disparities are then estimated iteratively using our previously published algorithm where the search range is propagated from three estimated neighbouring disparities. Since the search range is obtained from the previous iteration, errors may occur when the propagated search range is not sufficient. Therefore, a correlation maxima verification is performed to rectify this issue, and the subpixel resolution is achieved by conducting a parabola interpolation enhancement. Furthermore, a novel disparity global refinement approach developed from the Markov Random Fields and Fast Bilateral Stereo is introduced to further improve the accuracy of the estimated disparity map, where disparities are updated iteratively by minimising the energy function that is related to their interpolated correlation polynomials. The algorithm is implemented in C language with a near real-time performance. The experimental results illustrate that the absolute error of the reconstruction varies from 0.1 mm to 3 mm. PMID- 29994149 TI - External Prior Guided Internal Prior Learning for Real-World Noisy Image Denoising. AB - Most of existing image denoising methods learn image priors from either external data or the noisy image itself to remove noise. However, priors learned from external data may not be adaptive to the image to be denoised, while priors learned from the given noisy image may not be accurate due to the interference of corrupted noise. Meanwhile, the noise in real-world noisy images is very complex, which is hard to be described by simple distributions such as Gaussian distribution, making real-world noisy image denoising a very challenging problem. We propose to exploit the information in both external data and the given noisy image, and develop an external prior guided internal prior learning method for real-world noisy image denoising. We first learn external priors from an independent set of clean natural images. With the aid of learned external priors, we then learn internal priors from the given noisy image to refine the prior model. The external and internal priors are formulated as a set of orthogonal dictionaries to efficiently reconstruct the desired image. Extensive experiments are performed on several real-world noisy image datasets. The proposed method demonstrates highly competitive denoising performance, outperforming state-of-the art denoising methods including those designed for real-world noisy images. PMID- 29994150 TI - Minimizing Reconstruction Bias Hashing via Joint Projection Learning and Quantization. AB - Hashing, a widely-studied solution to the approximate nearest neighbor (ANN) search, aims to map data points in the high-dimensional Euclidean space to the low-dimensional Hamming space while preserving the similarity between original points. As directly learning binary codes can be NP-hard due to discrete constraints, a two-stage scheme, namely "projection and quantization", has already become a standard paradigm for learning similarity-preserving hash codes. However, most existing hashing methods typically separate these two stages and thus fail to investigate complementary effects of both stages. In this paper, we systematically study the relationship between "projection and quantization", and propose a novel minimal reconstruction bias hashing (MRH) method to learn compact binary codes, in which the projection learning and quantization optimizing are jointly performed. By introducing a lower bound analysis, we design an effective ternary search algorithm to solve the corresponding optimization problem. Furthermore, we conduct some insightful discussions on the proposed MRH approach, including the theoretical proof, and computational complexity. Distinct from previous works, MRH can adaptively adjust the projection dimensionality to balance the information loss between projection and quantization. The proposed framework not only provides a unique perspective to view traditional hashing methods but also evokes some other researches, e.g., guiding the design of the loss functions in deep networks. Extensive experiment results have shown that the proposed MRH significantly outperforms a variety of state-of-the-art methods over eight widely used benchmarks. PMID- 29994151 TI - MCast: High-Quality Linear Video Transmission with Time and Frequency Diversities. AB - Uncoded linear video transmission has recently attracted people's attention due to its capacity to provide robust and scalable transmission. However, in reality, with the fluctuation of the wireless channels, the received quality may not be good enough. In such a case, the data may need to be transmitted multiple times to exploit both the time and frequency diversities to improve the received quality. Such a problem has never been investigated in the literature of uncoded video transmission. To resolve the problem, in this paper, we propose a framework, named MCast, to utilize the time and frequency diversities to achieve high-quality linear video transmission. We study how to optimally allocate the power and assign the channels at each time slot to the source data such that the overall performance is maximized. Specifically, we first derive a closed-form optimal power allocation solution for any given channel assignment. With the optimal power allocation, we then propose a suboptimal channel assignment scheme, where we sort the channels with their gains and assign the channels one-by-one to the corresponding block that can reduce the most reconstruction error. Finally, we compare MCast system with four other systems that are based on Softcast and Parcast, and simulation results show that MCast system can achieve better performance in terms of both PSNR performance and visual quality. PMID- 29994152 TI - ColorMapND: A Data-Driven Approach and Tool for Mapping Multivariate Data to Color. AB - A wide variety of color schemes have been devised for mapping scalar data to color. We address the challenge of color-mapping multivariate data. While a number of methods can map low-dimensional data to color, for example, using bilinear or barycentric interpolation for two or three variables, these methods do not scale to higher data dimensions. Likewise, schemes that take a more artistic approach through color mixing and the like also face limits when it comes to the number of variables they can encode. Our approach does not have these limitations. It is data driven in that it determines a proper and consistent color map from first embedding the data samples into a circular interactive multivariate color mapping display (ICD) and then fusing this display with a convex (CIE HCL) color space. The variables are arranged in terms of their similarity and mapped to the ICD's boundary. Using this layout, the color of a sample is obtained via modified generalized barycentric coordinate interpolation. The system we devised has facilities for contrast and feature enhancement, supports both regular and irregular grids, can deal with multi-field as well as multispectral data, and can produce heat maps, choropleth maps, and diagrams such as scatterplots. PMID- 29994153 TI - Smart Brushing for Parallel Coordinates. AB - The Parallel Coordinates plot is a popular tool for the visualization of high dimensional data. One of the main challenges when using parallel coordinates is occlusion and overplotting resulting from large data sets. Brushing is a popular approach to address these challenges. Since its conception, limited improvements have been made to brushing both in the form of visual design and functional interaction. We present a set of novel, smart brushing techniques that enhance the standard interactive brushing of a parallel coordinates plot. We introduce two new interaction concepts: Higher-order, sketch-based brushing, and smart, data-driven brushing. Higher-order brushes support interactive, flexible, n dimensional pattern searches involving an arbitrary number of dimensions. Smart, data-driven brushing provides interactive, real-time guidance to the user during the brushing process based on derived meta-data. In addition, we implement a selection of novel enhancements and user options that complement the two techniques as well as enhance the exploration and analytical ability of the user. We demonstrate the utility and evaluate the results using a case study with a large, high-dimensional, real-world telecommunication data set and we report domain expert feedback from the data suppliers. PMID- 29994154 TI - Surface reconstruction from discrete indicator functions. AB - This paper introduces a procedure for the calculation of the vertex positions in Marching-Cubes-like surface reconstruction methods, when the surface to reconstruct is characterised by a discrete indicator function. Linear or higher order methods for the vertex interpolation problem require a smooth input function. Therefore, the interpolation methodology to convert a discontinuous indicator function into a triangulated surface is non-trivial. Analytical formulations for this specific vertex interpolation problem have been derived for the 2D case by Manson et al. [Eurographics (2011) 30, 2] and the straightforward application of their method to a 3D case gives satisfactory visual results. A rigorous extension to 3D, however, requires a least-squares problem to be solved for the discrete values of a symmetric neighbourhood. It thus relies on an extra layer of information, and comes at a significantly higher cost. This paper proposes a novel vertex interpolation method which yields second-order-accurate reconstructed surfaces in the general 3D case, without altering the locality of the method. The associated errors are analysed and comparisons are made with linear vertex interpolation and the analytical formulations of Manson et al. [Eurographics (2011) 30, 2]. PMID- 29994155 TI - Unified Mathematical Model for Multilayer-Multiframe Compressive Light Field Displays Using LCDs. AB - We propose a unified mathematical model for multilayer-multiframe compressive light field displays that supports both attenuation-based and polarization-based architectures. We show that the light field decomposition of such a display can be cast as a bound constrained nonlinear matrix optimization problem. Efficient light field decomposition algorithms are developed using the limited-memory BFGS (L-BFGS) method for automultiscopic displays with high resolution and high image fidelity. In addition, this framework is the first to support multilayer polarization-based compressive light field displays with time multiplexing. This new architecture significantly reduces artifacts compared with attenuation-based multilayer-multiframe displays; thus, it can allow the requirements regarding the number of layers or the refresh rate to be relaxed. We verify the proposed methods by constructing two 3-layer prototypes using high-speed LCDs, one based on the attenuation architecture and one based on the polarization architecture. Moreover, an efficient CUDA-based program is implemented. Our displays can produce images with higher spatial resolution with thinner form factors compared with traditional automultiscopic displays in both simulations and experiments. PMID- 29994156 TI - Chromatin 3D reconstruction from chromosomal contacts using a genetic algorithm. AB - Recent epigenetics research has demonstrated that chromatin conformation plays an important role in various aspects of gene regulation. Chromosome Conformation Capture (3C) technology makes it possible to analyze the spatial organization of chromatin in a cell. Several algorithms for three-dimensional reconstruction of chromatin structure from 3C experimental data have been proposed. Compared to other algorithms, ShRec3D, one of the most advanced algorithms, can reconstruct a chromatin model in the shortest time for high-resolution whole-genome experimental data. However, ShRec3D employs a graph shortest path algorithm, which introduces errors in the resulting model. We propose an improved algorithm that optimizes shortest path distances using a genetic algorithm approach. The proposed algorithm and ShRec3D were compared using in silico 3C experimental data. Compared to ShRec3D, the proposed algorithm demonstrated significant improvement relative to the similarity between the algorithm's output and the original model with a reasonable increase to calculation time. PMID- 29994157 TI - Automated ICD-9 Coding via A Deep Learning Approach. AB - ICD-9 (the Ninth Revision of International Classification of Diseases) is widely used to describe a patient's diagnosis. Accurate automated ICD-9 coding is important because manual coding is expensive, time-consuming and inefficient. Inspired by the recent successes of deep learning, in this study, we present a deep learning framework called DeepLabeler to automatically assign ICD-9 codes. DeepLabeler combines the convolutional neural network with the 'Document to Vector' technique to extract and encode local and global features. Our proposed DeepLabeler demonstrates its effectiveness by achieving state-of-the-art performance, i.e., 0.335 micro F-measure on MIMIC-II dataset and 0.408 micro F measure on MIMIC-III dataset. It outperforms classical hierarchy-based SVM and flat-SVM both on these two datasets by at least 14%. Furthermore, we analyze the deep neural network structure to discover the vital elements in the success of DeepLabeler. We find that the convolutional neural network is the most effective component in our network and the 'Document to Vector' technique is also necessary for enhancing classification performance since it extracts well-recognized global features. Extensive experimental results demonstrate that the great promise of deep learning techniques in the field of text multi-label classification and automated medical coding. PMID- 29994158 TI - Exploring Feature-Based Learning for Data-Driven Haptic Rendering. AB - In this work we extend ideas of machine learning to the domain of data-driven haptic rendering. The proposed approach facilitates the processing of high dimensional haptic interaction signals, which so far proved too difficult for existing data-driven methods. The key idea is to construct a compact feature space in the frequency domain which allows for efficient data reduction via a feature selection process. First, in a recording stage, extensive force and displacement datasets are acquired in automated measurements on deformable sample objects. These data are then transformed into a dimensionally reduced, compact frequency space representation. Next, feature-based learning is carried out in this feature space to significantly reduce the size of the original dataset. Based on this, time-domain haptic models capable of real-time performance are finally generated to encode the forces arising from bimanual object interactions. The presented processing chain is generally applicable and extendable to more complex interactions with even higher-dimensional data. The resulting haptic models are directly usable for data-driven haptic rendering. We illustrate the improved performance in comparison with previously existing data-processing approaches. PMID- 29994159 TI - Collaborative Deconvolutional Neural Networks for Joint Depth Estimation and Semantic Segmentation. AB - Semantic segmentation and single-view depth estimation are two fundamental problems in computer vision. They exploit the semantic and geometric properties of images, respectively, and are thus complementary in scene understanding. In this paper, we propose a collaborative deconvolutional neural network (C-DCNN) to jointly model these two problems for mutual promotion. The C-DCNN consists of two DCNNs, of which each is for one task. The DCNNs provide a finer resolution reconstruction method and are pretrained with hierarchical supervision. The feature maps from these two DCNNs are integrated via a pointwise bilinear layer, which fuses the semantic and depth information and produces higher order features. Then, the integrated features are fed into two sibling classification layers to simultaneously learn for semantic segmentation and depth estimation. In this way, we combine the semantic and depth features in a unified deep network and jointly train them to benefit each other. Specifically, during network training, we process depth estimation as a classification problem where a soft mapping strategy is proposed to map the continuous depth values into discrete probability distributions and the cross entropy loss is used. Besides, a fully connected conditional random field is also used as postprocessing to further improve the performance of semantic segmentation, where the proximity relations of pixels on position, intensity, and depth are jointly considered. We evaluate our approach on two challenging benchmarks: NYU Depth V2 and SUN RGB-D. It is demonstrated that our approach effectively utilizes these two kinds of information and achieves state-of-the-art results on both the semantic segmentation and depth estimation tasks. PMID- 29994160 TI - Efficient Cluster-Based Boosting for Semisupervised Classification. AB - Semisupervised classification (SSC) consists of using both labeled and unlabeled data to classify unseen instances. Due to the large number of unlabeled data typically available, SSC algorithms must be able to handle large-scale data sets. Recently, various ensemble algorithms have been introduced with improved generalization performance when compared to single classifiers. However, existing ensemble methods are not able to handle typical large-scale data sets. We propose efficient cluster-based boosting (ECB), a multiclass SSC algorithm with cluster based regularization that avoids generating decision boundaries in high-density regions. A semisupervised selection procedure reduces time and space complexities by selecting only the most informative unlabeled instances for the training of each base learner. We provide evidences to demonstrate that ECB is able to achieve good performance with small amounts of selected data and a relatively small number of base learners. Our experiments confirmed that ECB scales to large data sets while delivering comparable generalization to state-of-the-art methods. PMID- 29994161 TI - Segmentation of Intra-Retinal Cysts from Optical Coherence Tomography Images using a Fully Convolutional Neural Network Model. AB - Optical Coherence Tomography (OCT) is an imaging modality that is used extensively for ophthalmic diagnosis, near-histological visualization and quantification of retinal abnormalities such as cysts, exudates, retinal layer disorganization, etc. Intra-retinal cysts (IRCs) occur in several macular disorders such as, diabetic macular edema, retinal vascular disorders, age related macular degeneration, and inflammatory disorders. Automated segmentation of IRCs poses challenges owing to variations in the acquisition system scan intensities, speckle noise, and imaging artifacts. Several segmentation methods have been proposed in the literature for IRC segmentation on vendor-specific OCT images that lack generalizability across imaging systems. In this work, we propose a fully convolutional network (FCN) model for vendor-independent IRC segmentation. The proposed method counteracts image noise variabilities and trains FCN models on OCT sub-images from the OPTIMA cyst segmentation challenge dataset (with four different vendor-specific images, namely, Cirrus, Nidek, Spectralis, and Topcon). Further, optimal data augmentation and model hyper parametrization is shown to prevent over-fitting for IRC area segmentation. The proposed method is evaluated on the test data set with a recall/precision rate of 0.66/0.79 across imaging vendors. The Dice correlation coefficient of the proposed method outperforms that of the published algorithms in the OPTIMA cyst segmentation challenge with a Dice rate of 0.71 across the vendors. PMID- 29994162 TI - A New Unsupervised Approach for Segmenting and Counting Cells in High-Throughput Microscopy Image Sets. AB - New technological advances in automated mi- croscopy have given rise to large volumes of data, which have made human-based analysis infeasible, heightening the need for automatic systems for high-throughput microscopy applications. In particular, in the field of fluorescence microscopy, automatic tools for image analysis are making an essential contribution in order to increase the statistical power of the cell analysis process. The development of these automatic systems is a difficult task due to both the diversification of the staining patterns and the local variability of the images. In this paper, we present an unsupervised approach for automatic cell segmentation and counting, namely CSC, in high-throughput microscopy images. The segmentation is performed by dividing the whole image into square patches that undergo a gray level clustering followed by an adaptive thresholding. Subsequently, the cell labeling is obtained by detecting the centers of the cells, using both distance transform and curvature analysis, and by applying a region growing process. The advantages of CSC are manifold. The foreground detection process works on gray levels rather than on individual pixels, so it proves to be very efficient. Moreover, the combination of distance transform and curvature analysis makes the counting process very robust to clustered cells. A further strength of the CSC method is the limited number of parameters that must be tuned. Indeed, two different versions of the method have been considered, CSC-7 and CSC-3, depending on the number of parameters to be tuned. The CSC method has been tested on several publicly available image datasets of real and synthetic images. Results in terms of standard metrics and spatially-aware measures show that CSC outperforms the current state of the art techniques. PMID- 29994163 TI - Fully Distributed Adaptive Consensus Control of a Class of High-Order Nonlinear Systems With a Directed Topology and Unknown Control Directions. AB - In this paper, we investigate the adaptive consensus control for a class of high order nonlinear systems with different unknown control directions where communications among the agents are represented by a directed graph. Based on backstepping technique, a fully distributed adaptive control approach is proposed without using global information of the topology. Meanwhile, a novel Nussbaum type function is proposed to address the consensus control with unknown control directions. It is proved that boundedness of all closed-loop signals and asymptotically consensus tracking for all the agents' outputs are ensured. In simulation studies, a numerical example is illustrated to show the effectiveness of the control scheme. PMID- 29994164 TI - Constructive Neural Network Learning. AB - In this paper, we aim at developing scalable neural network-type learning systems. Motivated by the idea of constructive neural networks in approximation theory, we focus on constructing rather than training feed-forward neural networks (FNNs) for learning, and propose a novel FNNs learning system called the constructive FNN (CFN). Theoretically, we prove that the proposed method not only overcomes the classical saturation problem for constructive FNN approximation, but also reaches the optimal learning rate when the regression function is smooth, while the state-of-the-art learning rates established for traditional FNNs are only near optimal (up to a logarithmic factor). A series of numerical simulations are provided to show the efficiency and feasibility of CFN. PMID- 29994165 TI - A Software Level Calibration Based on Bayesian Regression for a Successive Stochastic Approximation Analog-to-Digital Converter System. AB - Recently, a novel low-power high-precision analog-to-digital converter (ADC) called the successive stochastic approximation ADC has been proposed which has two kinds of outputs from different modes, and which requires a software-level error correction method of combining them into a high-precision total output. From the practical viewpoint, we propose an error correction method based on the Bayesian regression with an incremental learning, in which additional data are successively selected according to the uncertainty of the corresponding predictive total output, and the uncertainty is approximately estimated by evaluating the upper bound of the standard deviations of the Bayesian predictive distributions of the outputs in each block of a partition of the all data set. Through numerical experiments, we verify the performance of the proposed method. PMID- 29994169 TI - Some Properties of Interpolations Using Mathematical Morphology. AB - The problem of interpolation of images is defined as - given two images at time t = 0 and t = T, one must find the series of images for the intermediate time. This problem is not well posed, in the sense that without further constraints, there are many possible solutions. The solution is thus usually dictated by the choice of the constraints/assumptions, which in turn relies on the domain of application. In this article we follow the approach of obtaining a solution to the interpolation problem using the operators from Mathematical Morphology (MM). These operators have an advantage of preserving structures since the operators are defined on sets. In this work we explore the solutions obtained using MM, and provide several results along with proofs which corroborates the validity of the assumptions, provide links among existing methods and intuition about them. We also summarize few possible extensions and prospective problems of current interest. PMID- 29994168 TI - EAC-Net: Deep Nets with Enhancing and Cropping for Facial Action Unit Detection. AB - In this paper, we propose a deep learning based approach for facial action unit (AU) detection by enhancing and cropping regions of interest of face images. The approach is implemented by adding two novel nets (a.k.a. layers): the enhancing layers and the cropping layers, to a pretrained convolutional neural network (CNN) model. For the enhancing layers (noted as E-Net), we have designed an attention map based on facial landmark features and apply it to a pretrained neural network to conduct enhanced learning. For the cropping layers (noted as C Net ), we crop facial regions around the detected landmarks and design individual convolutional layers to learn deeper features for each facial region. We then combine the E-Net and the C-Net to construct a so-called Enhancing and Cropping Net (EAC-Net), which can learn both features enhancing and region cropping functions effectively. The EAC-Net integrates three important elements, i.e., learning transfer, attention coding, and regions of interest processing, making our AU detection approach more efficient and more robust to facial position and orientation changes. Our approach shows a significant performance improvement over the state-of-the-art methods when tested on the BP4D and DISFA AU datasets. The EAC-Net with a slight modification also shows its potentials in estimating accurate AU intensities. We have also studied the performance of the proposed EAC Net under two very challenging conditions: (1) faces with partial occlusion and (2) faces with large head pose variations. Experimental results show that (1) the EAC-Net learns facial AUs correlation effectively and predicts AUs reliably even with only half of a face being visible, especially for the lower half; (2) Our EAC-Net model also works well under very large head poses, which outperforms significantly a compared baseline approach. It further shows that the EAC-Net works much better without a face frontalization than with face frontalization through image warping as pre-processing, in terms of computational efficiency and AU detection accuracy. PMID- 29994171 TI - Stain Formation on Deforming Inelastic Cloth. AB - We propose a novel approach to simulating the formation and evolution of stains on cloths in motion. We accurately capture the diffusion of a pigmented solution over a complex knitted or woven fabric through homogenization of its inhomogeneous and/or anisotropic properties into bulk anisotropic diffusion tensors. Secondary effects such as absorption, adsorption and evaporation are also accounted for through physically-based modeling. Finally, the influence of the cloth motion on the shape and evolution of the stain is captured by evaluating the inertial (e.g., centrifugal and Coriolis) forces experienced by the solution. The governing equations of motion are integrated in time directly on a deforming triangle mesh discretizing the inelastic cloth for efficiency and robustness. The deformation of the cloth can be precomputed or integrated through simplified two-way coupling, by using off-the-shell cloth simulations. Finally, numerical experiments demonstrate the plausibility of our results in practical applications by reproducing the usual shape and behavior of stains on various fabrics. PMID- 29994167 TI - Information Dropout: Learning Optimal Representations Through Noisy Computation. AB - The cross-entropy loss commonly used in deep learning is closely related to the defining properties of optimal representations, but does not enforce some of the key properties. We show that this can be solved by adding a regularization term, which is in turn related to injecting multiplicative noise in the activations of a Deep Neural Network, a special case of which is the common practice of dropout. We show that our regularized loss function can be efficiently minimized using Information Dropout, a generalization of dropout rooted in information theoretic principles that automatically adapts to the data and can better exploit architectures of limited capacity. When the task is the reconstruction of the input, we show that our loss function yields a Variational Autoencoder as a special case, thus providing a link between representation learning, information theory and variational inference. Finally, we prove that we can promote the creation of optimal disentangled representations simply by enforcing a factorized prior, a fact that has been observed empirically in recent work. Our experiments validate the theoretical intuitions behind our method, and we find that Information Dropout achieves a comparable or better generalization performance than binary dropout, especially on smaller models, since it can automatically adapt the noise to the structure of the network, as well as to the test sample. PMID- 29994172 TI - Estimation of the Spatial Chromatin Structure Based on a Multiresolution Bead Chain Model. AB - We present a method to infer 3D chromatin configurations from Chromosome Conformation Capture data. Quite a few methods have been proposed to estimate the structure of the nuclear DNA in homogeneous populations of cells from this kind of data. Many of them transform contact frequencies into Euclidean distances between pairs of chromatin fragments, and then reconstruct the structure by solving a distance-to-geometry problem. To avoid inconsistencies, our method is based on a score function that does not require any frequency-to-distance translation. We propose a multiscale chromatin model where the chromatin fibre is suitably partitioned at each scale. The partial structures are estimated independently, and connected to rebuild the whole fibre. Our score function consists in a data-fit part and a penalty part, balanced automatically at each scale and each subchain. The penalty part enforces "soft" geometric constraints. As many different structures can fit the data, our sampling strategy produces a set of solutions with similar scores. The procedure contains a few parameters, independent of both the scale and the genomic segment treated. The partition of the fibre, along with intrinsically parallel parts, make this method computationally efficient. Results from human genome data support the biological plausibility of our solutions. PMID- 29994170 TI - Light Field inpainting propagation via Low Rank Matrix completion. AB - Building up on the advances in low rank matrix completion, this article presents a novel method for propagating the inpainting of the central view of a light field to all the other views. After generating a set of warped versions of the inpainted central view with random homographies, both the original light field views and the warped ones are vectorized and concatenated into a matrix. Because of the redundancy between the views, the matrix satisfies a low rank assumption enabling us to fill the region to inpaint with low rank matrix completion. To this end, a new matrix completion algorithm, better suited to the inpainting application than existing methods, is also developed in this paper. In its simple form, our method does not require any depth prior, unlike most existing light field inpainting algorithms. The method has then been extended to better handle the case where the area to inpaint contains depth discontinuities. In this case, a segmentation map of the different depth layers of the inpainted central view is required. This information is used to warp the depth layers with different homographies. Our experiments with natural light fields captured with plenoptic cameras demonstrate the robustness of the low rank approach to noisy data as well as large color and illumination variations between the views of the light field. PMID- 29994173 TI - Motivated Optimal Developmental Learning for Sequential Tasks Without Using Rigid Time-Discounts. AB - Many methods for reinforcement learning use symbolic representations-nonemergent such as Q-learning. We use emergent representations here, without human handcrafted symbolic states (i.e., each state corresponds to a different location). This paper models reinforcement learning for hidden neurons in emergent networks for sequential tasks. In this paper, their influences on sequential tasks (e.g., robot navigation in different scenarios) are investigated where the learned value and results of a behavior rely on not only the current experience just like in a pattern recognition (episodic) but also the prediction of future experiences (e.g., delayed rewards) and environments (e.g., previously learned navigational trajectories). We show that this new model of motivated learning amounts to the computation of the maximum-likelihood estimate through "life" where punishment and reward have increased weights. This new formulation avoids the greediness of time-discount in Q-learning. Its complex nonlinear sequential optimization has been solved in a closed-form procedure under the condition of the limited computational resources and limited learning experience so far, because we convert it into a simpler problem of incremental and linear estimation. The experimental results showed that the serotonin and dopamine systems speed up learning for sequential tasks, because not all events are equally important. As far as we know, this is the first work that studies the influences of reinforcers (via serotonin and dopamine) on hidden neurons (Y neurons) for sequential tasks in dynamic scenarios using emergent representations. PMID- 29994179 TI - Depth from a Light Field Image with Learning-based Matching Costs. AB - One of the core applications of light field imaging is depth estimation. To acquire a depth map, existing approaches apply a single photo-consistency measure to an entire light field. However, this is not an optimal choice because of the non-uniform light field degradations produced by limitations in the hardware design. In this paper, we introduce a pipeline that automatically determines the best configuration for photo-consistency measurement, which leads to the most reliable depth label from the light field. We analyzed the practical factors affecting degradation in lenslet light field cameras, and designed a learning based framework that can retrieve the best cost measure and optimal depth label. To enhance the reliability of our method, we augmented an existing light field benchmark to simulate realistic source dependent noise, aberrations, and vignetting artifacts. The augmented dataset was used for the training and validation of the proposed approach. Our method was competitive with several state-of-the-art methods for the benchmark and real-world light field datasets. PMID- 29994180 TI - Submodular Trajectories for Better Motion Segmentation in Videos. AB - We propose a new trajectory clustering method using submodular optimization for better motion segmentation in videos. A small number of representative trajectories are first selected by submodular maximization automatically. Then all the initial trajectories can be segmented into fragments with the representative trajectories as centers of fragments. At last, fragments are merged into clusters by a two-stage bottom-up clustering method, and each cluster shows the motion of one moving object. The submodular energy function integrates the quality of all trajectories and their correlations. As a result, thousands of initial trajectories are replaced by only dozens of representative trajectories, which will reduce the negative influence of inaccurate initial trajectories on motion segmentation. The representative trajectories will have larger weights while extracting color or texture information of each moving entity at the step of motion segmentation. Experimental results demonstrate that our method can divide trajectories into more accurate clusters. The final motion segmentation results also illustrate that our method outperforms state-of-the-art motion segmentation methods based on trajectory clustering. PMID- 29994177 TI - A Geometric Approach to Second-Order Consensus of Heterogeneous Networked Systems. AB - This paper investigates second-order consensus of networked systems with heterogeneous intrinsic nonlinear dynamics via a geometrical method, in which the nonlinear dynamics are governed by both velocity and position. First, two necessary conditions are deduced for the existence of consensus solutions by analyzing the inherent nonlinear dynamics of isolated nodes. Then a closed invariant set is constructed via geometrical methods. The nonempty of the set implies the existence of consensus solution. Assuming that the primary and the second dimension about the above invariant set are the same linear subspace, the system can be divided into two simple subsystems through a linear transformation. In addition, some sufficient conditions are proposed for reaching the global consensus based on matrix theory and Lyapunov method. Finally, numerical simulation results are provided to illustrate the validity of theoretical analysis. PMID- 29994181 TI - Transportation Spherical Watermarking. AB - During the past twenty years, there has been a great interest in the study of spread spectrum (SS) watermarking. However, it is still a challenging task to design a secure and robust SS watermarking method. In this paper, we first define a family of secure SS watermarking methods, named as spherical watermarking (SW). The watermarked correlation of SW is defined to be uniformly distributed on a spherical surface, and this makes SW be key-secure against the watermarked-only attack. Then, we propose an implementation of SW, called transportation SW (TSW), which is designed to decrease embedding distortion in a recursive manner using the transportation theory, meanwhile keeping the security of SW. Moreover, we present a theoretical analysis of the embedding distortion and robustness of the proposed method. Finally, extensive experiments are conducted on simulated signals and real images. The experimental results show that TSW is more robust than existing secure SS watermarking methods. PMID- 29994166 TI - Optimal Output Consensus of High-Order Multiagent Systems With Embedded Technique. AB - In this paper, we study an optimal output consensus problem for a multiagent network with agents in the form of multi-input multioutput minimum-phase dynamics. Optimal output consensus can be taken as an extended version of the existing output consensus problem for higher-order agents with an optimization requirement, where the output variables of agents are driven to achieve a consensus on the optimal solution of a global cost function. To solve this problem, we first construct an optimal signal generator, and then propose an embedded control scheme by embedding the generator in the feedback loop. We give two kinds of algorithms based on different available information along with both state feedback and output feedback, and prove that these algorithms with the embedded technique can guarantee the solvability of the problem for high-order multiagent systems under standard assumptions. PMID- 29994174 TI - Speckle Removal Using Diffusion Potential for Optical Coherence Tomography Images. AB - We propose a fast and accurate solution to speckle reduction targeted specifically at optical coherence tomography images. The proposed speckle removing filter is designed using a novel potential function based on the gradient of the local variance of intensity. After filtering, the spatially neighboring pixels with close values of intensities converge to uniform gray values while the edges remain intact. This filtering process results in removal of speckle without destroying the edges of the desired object. The proposed filter also prevents the generation of any false edges. Detailed experimental analysis shows at least 1 dB improvement in peak signal-to-noise ratio for spectral domain optical coherence tomography images. The method also shows superior edge preservation, contrast and speed compared to the state-of-the-art in speckle removing filters. PMID- 29994178 TI - Metric Learning for Multi-output Tasks. AB - Multi-output learning with the task of simultaneously predicting multiple outputs for an input has increasingly attracted interest from researchers due to its wide application. The k nearest neighbor (kNN) algorithm is one of the most popular frameworks for handling multi-output problems. The performance of kNN depends crucially on the metric used to compute the distance between different instances. However, our experiment results show that the existing advanced metric learning technique cannot provide an appropriate distance metric for multi-output tasks. This paper systematically studies how to learn an appropriate distance metric for multi-output problems. In particular, we present a novel large margin metric learning paradigm for multi-output tasks, which projects both the input and output into the same embedding space and then learns a distance metric to discover output dependency such that instances with very different multiple outputs will be moved far away. Several strategies are then proposed to speed up the training and testing time. Moreover, we study the generalization error bound of our method, which shows that our method is able to tighten the excess risk bounds. Experiments on three multi-output learning tasks (multi-label classification, multi-target regression, and multi-concept retrieval) validate the effectiveness and scalability of the proposed method. PMID- 29994175 TI - Anatomical Landmark Based Deep Feature Representation for MR Images in Brain Disease Diagnosis. AB - Most automated techniques for brain disease diagnosis utilize hand-crafted (e.g., voxel-based or region-based) biomarkers from structural magnetic resonance (MR) images as feature representations. However, these hand-crafted features are usually high-dimensional or require regions-of-interest defined by experts. Also, because of possibly heterogeneous property between the hand-crafted features and the subsequent model, existing methods may lead to sub-optimal performances in brain disease diagnosis. In this paper, we propose a landmark-based deep feature learning (LDFL) framework to automatically extract patch-based representation from MRI for automatic diagnosis of Alzheimer's disease. We first identify discriminative anatomical landmarks from MR images in a data-driven manner, and then propose a convolutional neural network for patch-based deep feature learning. We have evaluated the proposed method on subjects from three public datasets, including the Alzheimer's disease neuroimaging initiative (ADNI-1), ADNI-2, and the minimal interval resonance imaging in alzheimer's disease (MIRIAD) dataset. Experimental results of both tasks of brain disease classification and MR image retrieval demonstrate that the proposed LDFL method improves the performance of disease classification and MR image retrieval. PMID- 29994176 TI - Longitudinally Guided Super-Resolution of Neonatal Brain Magnetic Resonance Images. AB - Neonatal magnetic resonance (MR) images typically have low spatial resolution and insufficient tissue contrast. Interpolation methods are commonly used to upsample the images for the subsequent analysis. However, the resulting images are often blurry and susceptible to partial volume effects. In this paper, we propose a novel longitudinally guided super-resolution (SR) algorithm for neonatal images. This is motivated by the fact that anatomical structures evolve slowly and smoothly as the brain develops after birth. We propose a strategy involving longitudinal regularization, similar to bilateral filtering, in combination with low-rank and total variation constraints to solve the ill-posed inverse problem associated with image SR. Experimental results on neonatal MR images demonstrate that the proposed algorithm recovers clear structural details and outperforms state-of-the-art methods both qualitatively and quantitatively. PMID- 29994182 TI - Deep-learning-assisted Volume Visualization. AB - Designing volume visualizations showing various structures of interest is critical to the exploratory analysis of volumetric data. The last few years have witnessed dramatic advances in the use of convolutional neural networks for identification of objects in large image collections. Whereas such machine learning methods have shown superior performance in a number of applications, their direct use in volume visualization has not yet been explored. In this paper, we present a deep-learning-assisted volume visualization to depict complex structures, which are otherwise challenging for conventional approaches. A significant challenge in designing volume visualizations based on the high dimensional deep features lies in efficiently handling the immense amount of information that deep-learning methods provide. In this paper, we present a new technique that uses spectral methods to facilitate user interactions with high dimensional features. We also present a new deep-learning-assisted technique for hierarchically exploring a volumetric dataset. We have validated our approach on two electron microscopy volumes and one magnetic resonance imaging dataset. PMID- 29994183 TI - Stable IL-1-Activation in an Inflammasome Signalling Model Depends on Positive and Negative Feedbacks and Tight Regulation of Protein Production. AB - INTRODUCTION: NLRP3-dependent inflammasome signalling is a key pathway during inflammatory processes and its deregulation is implicated in several diseases. NLRP3-inflammasome pathway activation leads to the rapid, hosphorylation-driven NFB-pathway signalling, subsequently proceeds via lower transcription/translation process for producing pro-enzymes, and finally leads to the medium-speed enzymatic activation of the central inflammatory ediator IL-1 [1]. We here were interested how the timing of the rate-limiting step of transcription/translation and the presence of a positive and negative auto-regulation would pose conditions for meaningful and stable IL-1-activation. METHODS: We extracted the essential topology of the inflammasome pathway network using a linear chain of first order reaction and a second order reaction for inhibitory feedback. We then performed an analytical treatment of the resulting ODE set to obtain closed-form formulae. We therefore looked for the steady states and characterised their stability by using a Jacobian-based, local analysis. We employed the Small Gain Theorem from Control Theory as recently applied by us [2] and the Gershgorin Circle Theorem to obtain mathematically exact conditions for a positive on state and stabilities for on and off steady states. RESULTS: We identified an on- and one off- steady state whose properties we characterised in terms of the kinetic parameters by closed-form formulae. We found that under the assumption of a first-order information flow through the network the existence of a biologically reasonable ON steady state required the simultaneous presence of the positive and the negative feedback. Assuming non-competitivity between IL-1 entities binding to different receptors, we found that a minimum kinetics for protein production is required to sustain a steady state with IL-1 activation. Assuming competitivity between IL-1 entities introduced additional restrictions on the maximum protein production speed to guarantee a biologically reasonable ON steady state. Finally, for both models we ruled out bistability, suggesting that IL- 1 activation would undergo a smooth change upon alterations of its parameters. CONCLUSION: Exemplified by the core pathway of NLRP3-inflammasome signalling, we here demonstrate that a mostly linear activation cascade containing an intermediate rate limiting step poses kinetic restrictions on this step and requires positive and negative autoregulation for obtaining a meaningful ON steady state. Due to the generality of our framework, our results are important for a wide class of receptor mediated-pathways, where a fast initial phosphorylation cascade is followed by a (slower) transcriptional response and subsequent autoregulation. Our results may further provide important design principles for synthetic biological networks involving biochemical activation and transcription/translation, by relating timing considerations and autoregulation to stable pathway activation. PMID- 29994184 TI - Event-Triggered Stabilization of Neural Networks With Time-Varying Switching Gains and Input Saturation. AB - This paper investigates the event-triggered stabilization of neural networks (NNs) subject to input saturation. The main core lies in the design of a novel controller with time-varying switching gains and the associated switching event triggered condition (ETC). The ETC is essentially a switching between the aperiodic sampling and continuous event trigger. The control gains of the designed controller are composed of an exponentially decaying term and two gain matrices. The two gain matrices are required to be switched when the switching between the aperiodic sampling and continuous event trigger is met. By employing the generalized sector condition and switching Lyapunov function, several sufficient conditions that ensure the local exponential stability of the NNs are formulated in terms of linear matrix inequalities (LMIs). Both the exponentially decaying term and switching gains improve the feasible region of LMIs, and then they are helpful to enlarge the set of admissible initial conditions, the threshold in ETC, and the average waiting time. Together with several optimization problems, two numerical examples are employed to validate the effectiveness of our results. PMID- 29994186 TI - Wearable Heading Estimation for Motion Tracking in Health Care by Adaptive Fusion of Visual-Inertial Measurementsments. AB - The increasing demand for health informatics has become a far-reaching trend in the ageing society. The utilization of wearable sensors enables monitoring senior people daily activities in free-living environments, conveniently and effectively. Among the primary health-care sensing categories, the wearable visual-inertial modality for human motion tracking gradually exerts promising potentials. In this paper, we present a novel wearable heading estimation strategy to track the movements of human limbs. It adaptively fuses inertial measurements with visual features following locality constraints. Body movements are classified into two types: general motion (which consists of both rotation and translation). or degenerate motion (which consists of only rotation). A specific number of feature correspondences between camera frames are adaptively chosen to satisfy both the feature descriptor similarity constraint and the locality constraint. The selected feature correspondences and inertial quaternions are employed to calculate the initial pose, followed by the coarse-to fine procedure to iteratively remove visual outliers. Eventually, the ultimate heading is optimized using the correct feature matches. The proposed method has been thoroughly evaluated on the straight-line, rotatory and ambulatory movement scenarios. As the system is lightweight and requires small computational resources, it enables effective and unobtrusive human motion monitoring, especially for the senior citizens in the long-term rehabilitation. PMID- 29994185 TI - A Multi Rate Marginalized Particle Extended Kalman Filter for P and T Wave Segmentation in ECG Signals. AB - The marginalized particle extended Kalman filter (MP-EKF) has been known as an effective model-based nonlinear Bayesian framework in the field of electrocardiogram (ECG) signal denoising. In this paper, we reveal another potential capability of MP-EKF and propose a multi rate MP-EKF based framework for P and T wave segmentation in ECG signals. The proposed multi rate implementation of MP-EKF leads to better estimation of states and avoids unwanted errors in estimation procedure. The behavior of particles in the multi rate MP EKF is controlled by a novel particle weighting strategy that helps the particles adapt themselves with respect to ECG signal trajectory. After ECG filtering, a novel morphology based algorithm uses the estimates of multi rate MP-EKF to determine the P and T wave fiducial points. This algorithm is a combination of well-known morphological operators such as 'opening', closing, 'top-hat' and 'bottom-hat' transforms. The segmentation performance of the proposed algorithm was evaluated on QT database and it showed promising results in comparison to other Bayesian frameworks such as partially collapsed Gibbs sampler (PCGS) and extended Kalman filter (EKF). PMID- 29994187 TI - Bifurcation and Oscillatory Dynamics of Delayed Cyclic Gene Networks Including Small RNAs. AB - It has been demonstrated in a large number of experimental results that small RNAs (sRNAs) play a vital role in gene regulation processes. Thus, the gene regulation process is dominated by sRNAs in addition to messenger RNAs and proteins. However, the regulation mechanism of sRNAs is not well understood and there are few models considering the effect of sRNAs. So it is of realistic biological background to include sRNAs when modeling gene networks. In this paper, sRNAs are incorporated into the process of gene expression and a new differential equation model is put forward to describe cyclic genetic regulatory networks with sRNAs and multiple delays. We mainly investigate the stability and bifurcation criteria for two cases: 1) positive cyclic genetic regulatory networks and 2) negative cyclic genetic regulatory networks. For a positive cyclic genetic regulatory network, it is revealed that there may exist more than one equilibrium and the multistability can appear. Sufficient conditions are established for the delay-independent stability and fold bifurcations. It is found that the dynamics of positive cyclic gene networks has no bearing on time delays, but depends on the biochemical parameters, the Hill coefficient and the equilibrium itself. For a negative cyclic genetic regulatory network, it is proved that there exists a unique equilibrium. Delay-dependent conditions for the stability are derived, and the existence of Hopf bifurcations is examined. Different from the delay-independent stability of positive gain networks, the stability of equilibrium is determined not only by the biochemical parameters, the Hill coefficient and the equilibrium itself, but also by the total delay. At last, three illustrative examples are provided to validate the major results. PMID- 29994188 TI - Large-Scale Robust Semisupervised Classification. AB - Semisupervised learning aims to leverage both labeled and unlabeled data to improve performance, where most of them are graph-based methods. However, the graph-based semisupervised methods are not capable for large-scale data since the computational consumption on the construction of graph Laplacian matrix is huge. On the other hand, the substantial unlabeled data in training stage of semisupervised learning could cause large uncertainties and potential threats. Therefore, it is crucial to enhance the robustness of semisupervised classification. In this paper, a novel large-scale robust semisupervised learning method is proposed in the framework of capped l2,p-norm. This strategy is superior not only in computational cost because it makes the graph Laplacian matrix unnecessary, but also in robustness to outliers since the capped l2,p-norm used for loss measurement. An efficient optimization algorithm is exploited to solve the nonconvex and nonsmooth challenging problem. The complexity of the proposed algorithm is analyzed and discussed in theory detailedly. Finally, extensive experiments are conducted over six benchmark data sets to demonstrate the effectiveness and superiority of the proposed method. PMID- 29994189 TI - Multiobjective Learning in the Model Space for Time Series Classification. AB - A well-defined distance is critical for the performance of time series classification. Existing distance measurements can be categorized into two branches. One is to utilize handmade features for calculating distance, e.g., dynamic time warping, which is limited to exploiting the dynamic information of time series. The other methods make use of the dynamic information by approximating the time series with a generative model, e.g., Fisher kernel. However, previous distance measurements for time series seldom exploit the label information, which is helpful for classification by distance metric learning. In order to attain the benefits of the dynamic information of time series and the label information simultaneously, this paper proposes a multiobjective learning algorithm for both time series approximation and classification, termed multiobjective model-metric (MOMM) learning. In MOMM, a recurrent network is exploited as the temporal filter, based on which, a generative model is learned for each time series as a representation of that series. The models span a non Euclidean space, where the label information is utilized to learn the distance metric. The distance between time series is then calculated as the model distance weighted by the learned metric. The network size is also optimized to learn parsimonious representations. MOMM simultaneously optimizes the data representation, the time series model separation, and the network size. The experiments show that MOMM achieves not only superior overall performance on uni/multivariate time series classification but also promising time series prediction performance. PMID- 29994191 TI - Adaptive Fuzzy Containment Control of Nonlinear Systems With Unmeasurable States. AB - The adaptive fuzzy containment control problem is discussed for high-order systems with unknown nonlinear dynamics and unmeasurable states guided by multiple dynamic leaders. A high gain observer is introduced to reconstruct the system states. Then, utilizing fuzzy logic systems to model followers' dynamics, an observer-based adaptive fuzzy containment control approach is presented using only the relative position of the neighbors. It is shown that the uniformly ultimately bounded containment control is realized under the condition that, each follower can obtain the information from at least one leader through a directed path. As an extension, an observer-based containment control with prescribed performance is developed, which guarantees the relative position error to be bounded by a specified bound. The obtained theoretical results are validated by simulation examples. PMID- 29994190 TI - Taste Recognition in E-Tongue Using Local Discriminant Preservation Projection. AB - Electronic tongue (E-Tongue), as a novel taste analysis tool, shows a promising perspective for taste recognition. In this paper, we constructed a voltammetric E Tongue system and measured 13 different kinds of liquid samples, such as tea, wine, beverage, functional materials, etc. Owing to the noise of system and a variety of environmental conditions, the acquired E-Tongue data shows inseparable patterns. To this end, from the viewpoint of algorithm, we propose a local discriminant preservation projection (LDPP) model, an under-studied subspace learning algorithm, that concerns the local discrimination and neighborhood structure preservation. In contrast with other conventional subspace projection methods, LDPP has two merits. On one hand, with local discrimination it has a higher tolerance to abnormal data or outliers. On the other hand, it can project the data to a more separable space with local structure preservation. Further, support vector machine, extreme learning machine (ELM), and kernelized ELM (KELM) have been used as classifiers for taste recognition in E-Tongue. Experimental results demonstrate that the proposed E-Tongue is effective for multiple tastes recognition in both efficiency and effectiveness. Particularly, the proposed LDPP based KELM classifier model achieves the best taste recognition performance of 98%. The developed benchmark data sets and codes will be released and downloaded in http://www.leizhang.tk/tempcode.html. PMID- 29994192 TI - Few-Example Object Detection with Model Communication. AB - In this paper, we study object detection using a large pool of unlabeled images and only a few labeled images per category, named "few-example object detection". The key challenge consists in generating trustworthy training samples as many as possible from the pool. Using few training examples as seeds, our method iterates between model training and high-confidence sample selection. In training, easy samples are generated first and, then the poorly initialized model undergoes improvement. As the model becomes more discriminative, challenging but reliable samples are selected. After that, another round of model improvement takes place. To further improve the precision and recall of the generated training samples, we embed multiple detection models in our framework, which has proven to outperform the single model baseline and the model ensemble method. Experiments on PASCAL VOC'07, MS COCO'14, and ILSVRC'13 indicate that by using as few as three or four samples selected for each category, our method produces very competitive results when compared to the state-of-the-art weakly-supervised approaches using a large number of image-level labels. PMID- 29994193 TI - Predicting the Driver's Focus of Attention: the DR(eye)VE Project. AB - In this work we aim to predict the driver's focus of attention. The goal is to estimate what a person would pay attention to while driving, and which part of the scene around the vehicle is more critical for the task. To this end we propose a new computer vision model based on a multi-branch deep architecture that integrates three sources of information: raw video, motion and scene semantics. We also introduce DR(eye)VE, the largest dataset of driving scenes for which eye-tracking annotations are available. This dataset features more than 500,000 registered frames, matching ego-centric views (from glasses worn by drivers) and car-centric views (from roof-mounted camera), further enriched by other sensors measurements. Results highlight that several attention patterns are shared across drivers and can be reproduced to some extent. The indication of which elements in the scene are likely to capture the driver's attention may benefit several applications in the context of human-vehicle interaction and driver attention analysis. PMID- 29994194 TI - Density-Preserving Hierarchical EM Algorithm: Simplifying Gaussian Mixture Models for Approximate Inference. AB - We propose an algorithm for simplifying a finite mixture model into a reduced mixture model with fewer mixture components. The reduced model is obtained by maximizing a variational lower bound of the expected log-likelihood of a set of virtual samples. We develop three applications for our mixture simplification algorithm: recursive Bayesian filtering using Gaussian mixture model posteriors, KDE mixture reduction, and belief propagation without sampling. For recursive Bayesian filtering, we propose an efficient algorithm for approximating an arbitrary likelihood function as a sum of scaled Gaussian. Experiments on synthetic data, human location modeling, visual tracking, and vehicle self localization show that our algorithm can be widely used for probabilistic data analysis, and is more accurate than other mixture simplification methods. PMID- 29994196 TI - lp-Box ADMM: A Versatile Framework for Integer Programming. AB - This paper revisits the integer programming (IP) problem, which plays a fundamental role in many computer vision and machine learning applications. The literature abounds with many seminal works that address this problem, some focusing on continuous approaches (e.g., linear program relaxation), while others on discrete ones (e.g., min-cut). However, since many of these methods are designed to solve specific IP forms, they cannot adequately satisfy the simultaneous requirements of accuracy, feasibility, and scalability. To this end, we propose a novel and versatile framework called -box ADMM, which is based on two main ideas. (1) The discrete constraint is equivalently replaced by the intersection of a box and an -norm sphere. (2) We infuse this equivalence into the ADMM (Alternating Direction Method of Multipliers) framework to handle the continuous constraints separately and to harness its attractive properties. More importantly, the ADMM update steps can lead to manageable sub-problems in the continuous domain. To demonstrate its efficacy, we apply it to an optimization form that occurs often in computer vision and machine learning, namely binary quadratic programming (BQP). In this case, the ADMM steps are simple, computationally efficient. Moreover, we present the theoretic analysis about the global convergence of the -box ADMM through adding a perturbation with the sufficiently small factor to the original IP problem. Specifically, the globally converged solution generated by -box ADMM for the perturbed IP problem will be close to the stationary and feasible point of the original IP problem within . We demonstrate the applicability of -box ADMM on three important applications: MRF energy minimization, graph matching, and clustering. Results clearly show that it significantly outperforms existing generic IP solvers both in runtime and objective. It also achieves very competitive performance to state-of-the-art methods designed specifically for these applications. PMID- 29994197 TI - Efficient Learning-Free Keyword Spotting. AB - In this article, a method for segmentation-based learning-free Query by Example (QbE) keyword spotting on handwritten documents is proposed. The method consists of three steps, namely preprocessing, feature extraction and matching, which address critical variations of text images (e.g. skew, translation, different writing styles). During the feature extraction step, a sequence of descriptors is generated using a combination of a zoning scheme and a novel appearance descriptor, referred as modified Projections of Oriented Gradients. The preprocessing step, which includes contrast normalization and main-zone detection, aims to overcome the shortcomings of the appearance descriptor. Moreover, an uneven zoning scheme is introduced by applying a denser zoning only on query images for a more detailed representation. This leads to a significant reduction in storage requirements of a document collection. The distance between the query and word sequences is efficiently computed by the proposed Selective Matching algorithm. This algorithm is further extended to handle an augmented set of images originating from a single query image. The efficiency of the proposed method is demonstrated by experimentation conducted on seven publicly available datasets. In these experiments, the proposed method significantly outperforms all state-of-the-art learning-free techniques. PMID- 29994198 TI - Design of a Quadrature 1H/31P Coil Using Bent Dipole Antenna and Four-Channel Loop at 3T MRI. AB - MRI using nuclei other than protons is of clinical interest due to the important role of these nuclei in cellular processes. Phosphorous-31 (31P), for example, plays an important role in energy metabolism. However, measurement of 31P can be challenging, as the receive signal is weak compared with that of proton (1H). Consequently, it is often necessary to integrate 1H elements for localizations and B0 shimming in RF coils intended for 31P measurements. Good decoupling between the 1H and the 31P elements is therefore essential. In this paper, bent dipole antennas tuned to 1H were integrated with a four channel 31P loop coil array, in a manner providing strong geometric decoupling between dipoles and loops. As the physical length of a resonant dipole antenna is too long at 3T, the dipole antennas were bent around the load. The loss of 31P elements due to the presence of the dipole antennas was evaluated by measuring scattering parameters and comparing the SNR of 31P spectra with and without the presence of the dipole antennas. The performance of the bent dipole antenna was evaluated by simulation and sensitivity measurement. The Q-factors and the SNR of the four-loop array were reduced by less than 5% when the bent dipole antennas were introduced. The measured sensitivity of the bent dipole was higher (15%) than that of dual-tuned birdcage. The combined bent dipole and loop array is therefore a promising design for 1H/31P applications at 3T. PMID- 29994200 TI - FiloGen: A Model-Based Generator of Synthetic 3-D Time-Lapse Sequences of Single Motile Cells With Growing and Branching Filopodia. AB - The existence of diverse image datasets accompanied by reference annotations is a crucial prerequisite for an objective benchmarking of bioimage analysis methods. Nevertheless, such a prerequisite is hard to satisfy for time lapse, multidimensional fluorescence microscopy image data, manual annotations of which are laborious and often impracticable. In this paper, we present a simulation system capable of generating 3-D time-lapse sequences of single motile cells with filopodial protrusions of user-controlled structural and temporal attributes, such as the number, thickness, length, level of branching, and lifetime of filopodia, accompanied by inherently generated reference annotations. The proposed simulation system involves three globally synchronized modules, each being responsible for a separate task: the evolution of filopodia on a molecular level, linear elastic deformation of the entire cell with filopodia, and the synthesis of realistic, time-coherent cell texture. Its flexibility is demonstrated by generating multiple synthetic 3-D time-lapse sequences of single lung cancer cells of two different phenotypes, qualitatively and quantitatively resembling their real counterparts acquired using a confocal fluorescence microscope. PMID- 29994199 TI - 4-D Intracardiac Ultrasound Vector Flow Imaging-Feasibility and Comparison to Phase-Contrast MRI. AB - In vivo characterization of intracardiac blood velocity vector fields may provide new clinical information but is currently not available for bedside evaluation. In this paper, 4-D vector flow imaging for intracardiac flow assessment is demonstrated using a clinical ultrasound (US) system and a matrix array transducer, without the use of contrast agent. Two acquisition schemes were developed, one for full volumetric coverage of the left ventricle (LA) at 50 vps and a 3-D thick-slice setup with continuous frame acquisition (4000 vps), both utilizing ECG-gating. The 3-D vector velocity estimates were obtained using a novel method combining phase and envelope information. In vitro validation in a rotating tissue-mimicking phantom revealed velocity estimates in compliance with the ground truth, with a linear regression slope of 0.80, 0.77, and 1.03 for the , , and velocity components, and with standard deviations of 2.53, 3.19, and 0.95 cm/s, respectively. In vivo measurements in a healthy LV showed good agreement with PC-MRI. Quantitative analysis of energy loss (EL) and kinetic energy (KE) further showed similar trends, with peak KE at 1.5 and 2.4 mJ during systole and 3.6 and 3.1 mJ for diastole for US and PC-MRI. Similar for EL, 0.15- 0.2 and 0.7 mW was found during systole and 0.6 and 0.7 mW during diastole, for US and PC MRI, respectively. Overall, a potential for US as a future modality for 4D cardiac vector flow imaging was demonstrated, which will be further evaluated in clinical studies. PMID- 29994201 TI - H-DenseUNet: Hybrid Densely Connected UNet for Liver and Tumor Segmentation From CT Volumes. AB - Liver cancer is one of the leading causes of cancer death. To assist doctors in hepatocellular carcinoma diagnosis and treatment planning, an accurate and automatic liver and tumor segmentation method is highly demanded in the clinical practice. Recently, fully convolutional neural networks (FCNs), including 2-D and 3-D FCNs, serve as the backbone in many volumetric image segmentation. However, 2 D convolutions cannot fully leverage the spatial information along the third dimension while 3-D convolutions suffer from high computational cost and GPU memory consumption. To address these issues, we propose a novel hybrid densely connected UNet (H-DenseUNet), which consists of a 2-D DenseUNet for efficiently extracting intra-slice features and a 3-D counterpart for hierarchically aggregating volumetric contexts under the spirit of the auto-context algorithm for liver and tumor segmentation. We formulate the learning process of the H DenseUNet in an end-to-end manner, where the intra-slice representations and inter-slice features can be jointly optimized through a hybrid feature fusion layer. We extensively evaluated our method on the data set of the MICCAI 2017 Liver Tumor Segmentation Challenge and 3DIRCADb data set. Our method outperformed other state-of-the-arts on the segmentation results of tumors and achieved very competitive performance for liver segmentation even with a single model. PMID- 29994203 TI - Development of Dual-Frequency Oblong-Shaped-Focused Transducers for Intravascular Ultrasound Tissue Harmonic Imaging. AB - Tissue harmonic imaging (THI), an essential mode of commercial ultrasound imaging scanners, can provide images with high spatial and contrast resolutions. For THI, the frequency spectrum of a transducer is generally divided for the transmission of fundamental signal and the reception of its second harmonic. Therefore, it is difficult to use the THI mode for intravascular ultrasound (IVUS) imaging because typical IVUS transducers have a narrow -6-dB fractional bandwidth of about 50%. Due to its small aperture (about 0.5 mm) and the strength of IVUS being too weak, it is difficult to construct a high-quality tissue harmonic image. In this paper, we report a recently developed dual-frequency oblong-shaped-focused IVUS transducer for high-quality intravascular THI; the transducer consists of three elements arranged side by side in the horizontal (i.e., elevation) direction. The two outer elements with a center frequency of 35 MHz are responsible for ultrasound transmission and the center element has a center frequency of 70 MHz for the reception of the second-harmonic signals. All three elements have a spherical shape with a radius of 3 mm to efficiently generate harmonics in the region of interest. This configuration of the developed IVUS transducer was determined to facilitate high-quality THI, which was based on the results of Field II simulation and finite-element analysis. The images of wires and a tissue mimicking phantom indicated that the tissue harmonic images produced by the developed transducer have not only a high spatial resolution but also a deep imaging depth, compared to the 35- and 70-MHz fundamental images. PMID- 29994195 TI - Light Field Reconstruction Using Convolutional Network on EPI and Extended Applications. AB - In this paper, a novel convolutional neural network (CNN)-based framework is developed for light field reconstruction from a sparse set of views. We indicate that the reconstruction can be efficiently modeled as angular restoration on an epipolar plane image (EPI). The main problem in direct reconstruction on the EPI involves an information asymmetry between the spatial and angular dimensions, where the detailed portion in the angular dimensions is damaged by undersampling. Directly upsampling or super-resolving the light field in the angular dimensions causes ghosting effects. To suppress these ghosting effects, we contribute a novel "blur-restoration-deblur" framework. First, the "blur" step is applied to extract the low-frequency components of the light field in the spatial dimensions by convolving each EPI slice with a selected blur kernel. Then, the "restoration" step is implemented by a CNN, which is trained to restore the angular details of the EPI. Finally, we use a non-blind "deblur" operation to recover the spatial high frequencies suppressed by the EPI blur. We demonstrate the high performance and robustness of the proposed framework compared with state-of-the-art algorithms. We further show extended applications, including depth enhancement and interpolation for unstructured input. PMID- 29994205 TI - Trapped-Energy Thickness-Extensional Mode of a Partially Electroded ZnO Thin-Film Resonator. AB - Free and forced vibration analysis of ZnO thin-film resonator operating with trapped-energy thickness-extensional (TE) mode is performed based on the dispersion curves for both the unbounded fully electroded and unelectroded films. The thickness solutions to the free vibration problem consist of the mode branches of the dispersion curves for the electroded and the unelectroded regions, respectively. The mode branches in the unelectroded region that carry energy away from the vibration zone are neglected because this effective energy loss corresponds to a complex frequency in the frequency spectrum. Since the thickness solutions in each region have satisfied the differential equations and the boundary conditions on the major surfaces exactly, the substitution of the thickness solutions into the modified Hamilton variational principle derived by Tiersten gives an approximate continuity condition in the form of integral over the thickness of the resonator at the interface between the electroded and unelectroded regions. The stationary condition of the integral continuity condition leads to a system of homogeneous linear equations, which determines the frequency spectrum ranging from the first TE cutoff frequency of the fully electroded film to that of the unelectroded film where the conventional trapped energy vibration occurs. Forced vibration analysis of ZnO thin film driven into TE mode by applying a voltage to the top and bottom electrodes is also performed, which further verifies the validity of the obtained results from the free vibration analysis. PMID- 29994207 TI - Grid-Free Localization Algorithm Using Low-rank Hankel Matrix for Super Resolution Microscopy. AB - Localization microscopy, such as STORM / PALM, can reconstruct super-resolution images with a nanometer resolution through the iterative localization of fluorescence molecules. Recent studies in this area have focused mainly on the localization of densely activated molecules to improve temporal resolutions. However, higher density imaging requires an advanced algorithm that can resolve closely spaced molecules. Accordingly, sparsitydriven methods have been studied extensively. One of the major limitations of existing sparsity-driven approaches is the need for a fine sampling grid or for Taylor series approximation which may result in some degree of localization bias toward the grid. In addition, prior knowledge of the point-spread function (PSF) is required. To address these drawbacks, here we propose a true grid-free localization algorithm with adaptive PSF estimation. Specifically, based on the observation that sparsity in the spatial domain implies a low rank in the Fourier domain, the proposed method converts source localization problems into Fourier-domain signal processing problems so that a truly gridfree localization is possible. We verify the performance of the newly proposed method with several numerical simulations and a live-cell imaging experiment. PMID- 29994204 TI - Electromechanical Characteristics of Radially Layered Piezoceramic/Epoxy Cylindrical Composite Transducers: Theoretical Solution, Numerical Simulation, and Experimental Verification. AB - This paper derives theoretical solutions for three radially layered piezoceramic/epoxy cylindrical composite transducers, which are composed of a solid epoxy disk, two axially polarized piezoceramic rings, and two epoxy rings. Two piezoceramic rings are the functional components, which can actuate and adjust the composite's performance. According to different functions, three typical transducers are developed. The first one involves both of the two piezoceramic rings acting as actuating elements with parallel connections electrically. The other two involve only one piezoceramic ring as an actuating element, while the other ring that is connected to a resistor acts as a sensing element to adjust the electromechanical characteristics. Based on the plane stress assumption, theoretical solutions of these three transducers in radial vibration are derived, and performance differences of their electromechanical characteristics are analyzed and discussed. Furthermore, the solutions are validated by comparing with the ANSYS simulation results and the experimental data. The simulated and the measured first resonance and antiresonance frequencies are in a good agreement with the theoretical results, which validates the accuracy of the directed solution. This paper contributes to a comprehensive understanding of the proposed cylindrical composite's electromechanical performance, which is helpful for further application in underwater sound and ultrasonic fields. PMID- 29994209 TI - Edge information diffusion based reconstruction (EIDR) for cone beam computed laminography. AB - Computed laminography (CL) is a prospective nondestructive testing technique for flat object inspection in industrial applications. However, CL image reconstruction is a challenging task because incomplete projection data are acquired from the CL scan. When a conventional computed tomography (CT) reconstruction method is applied to cone beam CL data, the vertical edges (singularities in the z-direction) in the reconstructed image would be blurred. On the contrary, the horizontal edges (singularities within slices) can be quite accurately reconstructed. Based on this key observation, an edge information diffusion method is developed, which fixes the horizontal edges and propagates their values within the slices. An effective CL reconstruction method is then proposed for flat object inspection by combining the edge information diffusion procedure, which plays the role of regularization, with conventional CT image reconstruction algorithms. Experiments on both simulated data and real data are performed to verify the effectiveness of the proposed method. The results show that the proposed method can effectively suppress the inter-slice aliasing and blurring caused by incompleteness of the CL scan data, and that it outperforms other state-of-the-art methods. PMID- 29994208 TI - LAPSE: Low-Overhead Adaptive Power Saving and Contrast Enhancement for OLEDs. AB - Organic Light Emitting Diode (OLED) display panels are becoming increasingly popular especially in mobile devices; one of the key characteristics of these panels is that their power consumption strongly depends on the displayed image. In this paper we propose LAPSE, a new methodology to concurrently reduce the energy consumed by an OLED display and enhance the contrast of the displayed image, that relies on image-specific pixel-by-pixel transformations. Unlike previous approaches, LAPSE focuses specifically on reducing the overheads required to implement the transformation at runtime. To this end, we propose a transformation that can be executed in real time, either in software, with low time overhead, or in a hardware accelerator with a small area and low energy budget. Despite the significant reduction in complexity, we obtain comparable results to those achieved with more complex approaches in terms of power saving and image quality. Moreover, our method allows to easily explore the full quality versus-power tradeoff by acting on a few basic parameters; thus, it enables the runtime selection among multiple display quality settings, according to the status of the system. PMID- 29994202 TI - Temperature-Dependent Evolution of Crystallographic and Domain Structures in (K,Na,Li)(Ta,Nb)O3 Piezoelectric Single Crystals. AB - (K,Na)NbO3-based ferroelectric single crystals have recently undergone a substantial development, resulting in improved crystal quality and large piezoelectric coefficients, exceeding 700 pC/N, over a broad temperature range. However, further development necessitates a detailed understanding of the mechanisms defining the domain structure and its temperature evolution. This paper presents the investigation into the crystallographic structure and domain configurations of a (K,Na,Li)(Ta,Nb)O3 single crystal over a broad temperature range. The crystal was grown by the submerged-seed solution growth technique and investigated using in situ transmission electron microscopy, X-ray diffraction, dielectric measurements, and polarized light microscopy. The lattice distortion, structural phase transitions, and domain configurations are reported. A transition from the lamellar orthorhombic to the rectangular tetragonal domain structure is observed upon heating. Moreover, the milky optical appearance of the crystal was investigated and found to result from the presence of regions with different domain configurations and domain sizes. The formation of these regions is related to the growth defects, which govern the domain formation when cooling below the Curie temperature. PMID- 29994206 TI - High Frame Rate Contrast-Enhanced Ultrasound for Velocimetry in the Human Abdominal Aorta. AB - Treatment of abdominal aortic (AA) aneurysms and stenotic lesions may be improved by analyzing their associated blood flow patterns. Angle-independent blood flow patterns in the AA can be obtained by combining echo-particle image velocimetry (ePIV) with high frame rate contrast-enhanced ultrasonography. However, ePIV performance is affected by ultrasound contrast agent (UCA) concentration, microbubble stability and tissue clutter. In this study we assessed the influence of acoustic pressure and UCA concentration on image quality for ePIV analysis. We also compared amplitude modulation (AM) and singular value decomposition (SVD) as tissue suppression strategies for ePIV. Fourteen healthy volunteers were imaged in the region of the distal AA. We tested four different UCA bolus volumes (0.25, 0.5, 0.75 and 1.5 ml) and four different acoustic output pressures (mechanical indices: 0.01, 0.03, 0.06 and 0.09). As image quality metrics, we measured contrast-to-background ratio, bubble disruption ratio and maximum normalized cross-correlation value during ePIV. At mechanical indices >= 0.06, we detected severe bubble destruction, suggesting that very low acoustic pressures should be used for ePIV. SVD was able to suppress tissue clutter better than AM. The maximum tracking correlation was affected by both UCA concentration and flow rate, where at high flow rates, lower UCA concentrations resulted in slightly higher correlation values but more signal drop-outs during late diastole. High frame rate ePIV was successfully performed in the AA of healthy volunteers and shows promise for future studies in patients. PMID- 29994210 TI - Leveraging expert feature knowledge for predicting image aesthetics. AB - The ability to rank images based on their appearance finds many real-world applications such as image retrieval or image album creation. Despite the recent dominance of deep learning methods in computer vision which often result in superior performance, they are not always the methods of choice because they lack interpretability. In this work, we investigate the possibility of improving image aesthetic inference of convolutional neural networks with hand-designed features that rely on domain expertise in various fields. We perform a comparison of hand crafted feature sets in their ability to predict fine-grained aesthetics scores on two image aesthetics datasets. We observe that even feature sets published earlier are able to compete with more recently published algorithms and, by combining the algorithms together, one can obtain a significant improvement in predicting image aesthetics. By using a tree-based learner, we perform feature elimination to understand the best performing features overall and across different image categories. Only roughly 15 % and 8 % of the features are needed to achieve full performance in predicting a fine-grained aesthetic score and binary classification respectively. By combining hand-crafted features with meta features that predict the quality of an image based on CNN features, the model performs better than a baseline VGG16 model. One can, however, achieve more significant improvement in both aesthetics score prediction and binary classification by fusing the hand-crafted features and the penultimate layer activations. Our experiments indicate an improvement up to 2.2 % achieving current state-of-the-art binary classification accuracy on the AVA dataset when the hand-designed features are fused with activation from VGG16 and ResNet50 networks. PMID- 29994212 TI - Optimized Pre-Compensating Compression. AB - In imaging systems, following acquisition, an image/ video is transmitted or stored and eventually presented to human observers using different and often imperfect display devices. While the resulting quality of the output image may severely be affected by the display, this degradation is usually ignored in the preceding compression. In this paper we model the sub-optimality of the display device as a known degradation operator applied on the decompressed image/video. We assume the use of a standard compression path, and augment it with a suitable pre-processing procedure, providing a compressed signal intended to compensate the degradation without any post-filtering. Our approach originates from an intricate rate-distortion problem, optimizing the modifications to the input image/video for reaching best end-to-end performance. We address this seemingly computationally intractable problem using the alternating direction method of multipliers (ADMM) approach, leading to a procedure in which a standard compression technique is iteratively applied. We demonstrate the proposed method for adjusting HEVC image/video compression to compensate post-decompression visual effects due to a common type of displays. Particularly, we use our method to reduce motion-blur perceived while viewing video on LCD devices. The experiments establish our method as a leading approach for preprocessing high bit rate compression to counterbalance a postdecompression degradation. PMID- 29994213 TI - Dynamic Match Kernel With Deep Convolutional Features for Image Retrieval. AB - For image retrieval methods based on bag of visual words, much attention has been paid to enhancing the discriminative powers of the local features. Although retrieved images are usually similar to a query in minutiae, they may be significantly different from a semantic perspective, which can be effectively distinguished by convolutional neural networks (CNN). Such images should not be considered as relevant pairs. To tackle this problem, we propose to construct a dynamic match kernel by adaptively calculating the matching thresholds between query and candidate images based on the pairwise distance among deep CNN features. In contrast to the typical static match kernel which is independent to the global appearance of retrieved images, the dynamic one leverages the semantical similarity as a constraint for determining the matches. Accordingly, we propose a semantic-constrained retrieval framework by incorporating the dynamic match kernel, which focuses on matched patches between relevant images and filters out the ones for irrelevant pairs. Furthermore, we demonstrate that the proposed kernel complements recent methods, such as hamming embedding, multiple assignment, local descriptors aggregation, and graph-based re-ranking, while it outperforms the static one under various settings on off-the-shelf evaluation metrics. We also propose to evaluate the matched patches both quantitatively and qualitatively. Extensive experiments on five benchmark data sets and large-scale distractors validate the merits of the proposed method against the state-of-the-art methods for image retrieval. PMID- 29994211 TI - Embedding Visual Hierarchy with Deep Networks for Large-Scale Visual Recognition. AB - In this paper, a layer-wise mixture model (LMM) is developed to support hierarchical visual recognition, where a Bayesian approach is used to automatically adapt the visual hierarchy to the progressive improvements of the deep network along the time. Our LMM algorithm can provide an end-to-end approach for jointly learning: (a) the deep network for achieving more discriminative deep representations for object classes and their inter-class visual similarities; (b) the tree classifier for recognizing large numbers of object classes hierarchically; and (c) the visual hierarchy adaptation for achieving more accurate assignment and organization of large numbers of object classes. By learning the tree classifier, the deep network and the visual hierarchy adaptation jointly in an end-to-end manner, our LMM algorithm can achieve higher accuracy rates on hierarchical visual recognition. Our experiments are carried on ImageNet1K and ImageNet10K image sets, which have demonstrated that our LMM algorithm can achieve very competitive results on the accuracy rates as compared with the baseline methods. PMID- 29994221 TI - Suppression of Multimodality in Inter-Spike Interval Distribution: Role of External Damped Oscillatory Input. AB - A theoretical model based on the generalized neuronal model with distributed delay (GNMDD) is proposed to generate multimodal/bimodal inter-spike interval (ISI) distribution. The distributed delay is assumed to be general in the sense that it is a linear combination of gamma distributed weak and strong memory kernels. It is found that the expected membrane potential in the subthreshold regime exhibits damped oscillatory behavior. This causes the ISI pattern to become bimodal/multimodal. Furthermore, the effect of external damped oscillatory current in the GNMDD model is investigated. Based on extensive simulation study of a set of coupled stochastic differential equations in the presence of a threshold, a vast amount of spiking data are generated. Using the non-parametric modeling approach, the optimal bin width of the histogram is obtained by using the Freedman-Diaconis rule. It is to be noted that, with the increasing amplitude of the damped oscillatory current, the multimodal ISI distribution changes to unimodal ISI distribution when the magnitude of external current reaches a critical value. It is found that the entropy also shows a sudden transition around the critical point. This phenomenon is akin to a phase transition. PMID- 29994222 TI - Discovering Patterns From Sequences Using Pattern-Directed Aligned Pattern Clustering. AB - Functional region identification is of fundamental importance for protein sequences analysis. Such knowledge provides better scientific understanding and could assist drug discovery. Up-to-date, domain annotation is one approach, but it needs to leverage existing databases. For de novo discovery, motif discovery locates and aligns locally homologous sub-sequences to obtain a position-weight matrix (PWM), which is a fixed-length representation model, whereas protein functional region size varies. It thus requires computational expensive exhaustive search to obtain a PWM with width of optimal range. This paper presents a new method known as pattern-directed aligned pattern clustering (PD APCn) to discover and align patterns in conserved protein functional regions. It adopts aligned pattern cluster (APC) with patterns of variable length and strong support to direct the incremental APC expansion. It allows substitution and frame shift mutations until a robust termination condition is reached. The concept of breakpoint gap is introduced to identify spots of mutations, such as substitution and frame shifts. Experiments on synthetic data sets with different sizes and noise levels showed that PD-APCn outperforms MEME with much higher recall and Fmeasure and computational speed 665 times faster that MEME. When applying to Cytochrome C and Ubiquitin families, it found all key binding sites within the APCs. PMID- 29994214 TI - 3D Face Reconstruction with Geometry Details from a Single Image. AB - 3D face reconstruction from a single image is a classical and challenging problem, with wide applications in many areas. Inspired by recent works in face animation from RGBD or monocular video inputs, we develop a novel method for reconstructing 3D faces from unconstrained 2D images, using a coarse-to-fine optimization strategy. First, a smooth coarse 3D face is generated from an example-based bilinear face model, by aligning the projection of 3D face landmarks with 2D landmarks detected from the input image. Afterwards, using local corrective deformation fields, the coarse 3D face is refined using photometric consistency constraints, resulting in a medium face shape. Finally, a shape-from-shading method is applied on the medium face to recover fine geometric details. Our method outperforms stateof- the-art approaches in terms of accuracy and detail recovery, which is demonstrated in extensive experiments using real world models and publicly available datasets. PMID- 29994217 TI - Catfish Taguchi-Based Binary Differential Evolution Algorithm for Analyzing Single Nucleotide Polymorphism Interactions in Chronic Dialysis. AB - Single-nucleotide polymorphism (SNP)-SNP interactions are crucial for understanding the association between disease-related multifactorials for disease analysis. Existing statistical methods for determining such interactions are limited by the considerable computation required for evaluating all potential associations between disease-related multifactorials. Identifying SNP-SNP interactions is thus a major challenge in genetic association studies. This paper proposes a catfish Taguchi-based binary differential evolution (CT-BDE) algorithm for identifying SNP-SNP interactions. In the search space, the catfish effect prevents the premature convergence of the population, and the Taguchi method improves the search ability of the BDE algorithm. Hence, the proposed algorithm enables obtaining a favorable solution regarding the identification of high-order SNP-SNP interactions. Additionally, the proposed algorithm applies an effective fitness function derived from a multifactor dimensionality reduction (MDR) operation to evaluate the solutions from BDE-based algorithms. Simulated and real data sets were used to evaluate the ability of several BDE-based algorithms in identifying specific SNP-SNP interactions. We compared the fitness function derived from the MDR operation with that derived according to the difference between cases and controls, by using the different BDE-based algorithms. The results showed that the proposed CT-BDE algorithm applying the fitness function derived from the MDR operation exhibited a superior ability in identifying SNP SNP interactions compared with the other BDE-based algorithms. PMID- 29994224 TI - Robust Inductive Matrix Completion Strategy to Explore Associations between LincRNAs and Human Disease Phenotypes. AB - Over the past few years, it has been established that a number of long intergenic non-coding RNAs (lincRNAs) are linked to a wide variety of human diseases. The relationship among many other lincRNAs still remains as puzzle. Validation of such link between the two entities through biological experiments is expensive. However, piles of information about the two are becoming available, thanks to the High Throughput Sequencing (HTS) platforms, Genome Wide Association Studies (GWAS), etc, thereby opening opportunity for cutting-edge machine learning and data mining approaches. However, there are only a few in silico lincRNA-disease association inference tools available to date, and none of these utilizes side information of both the entities. The recently developed Inductive Matrix Completion (IMC) technique provides a recommendation platform among two entities considering respective side information. But, the formulation of IMC is incapable of handling noise and outliers that may present in the dataset, while data sparsity consideration is another issue with the standard IMC method. Thus, a robust version of IMC is needed that can solve these two issues. As a remedy, in this paper, we propose Robust Inductive Matrix Completion (RIMC) using norm loss function as well as norm based regularization. We applied RIMC to the available association data between human lincRNAs and OMIM disease phenotypes as well as a diverse set of side information about the lincRNAs and the diseases. Our method performs better than the state-of-the-art methods in terms of and at the top- disease prioritization to the subject lincRNAs. We also demonstrate that RIMC is equally effective for querying about novel lincRNAs, as well as predicting rank of a newly known disease for a set of well-characterized lincRNAs. PMID- 29994215 TI - Fight Recognition in video using Hough Forests and 2D Convolutional Neural Network. AB - While action recognition has become an important line of research in computer vision, the recognition of particular events such as aggressive behaviors, or fights, has been relatively less studied. These tasks may be extremely useful in several video surveillance scenarios such as psychiatric wards, prisons or even in personal camera smartphones. Their potential usability has led to a surge of interest in developing fight or violence detectors. One of the key aspects in this case is efficiency, that is, these methods should be computationally fast. "Handcrafted" spatiotemporal features that account for both motion and appearance information can achieve high accuracy rates, albeit the computational cost of extracting some of those features is still prohibitive for practical applications. The deep learning paradigm has been recently applied for the first time to this task too, in the form of a 3D Convolutional Neural Network that processes the whole video sequence as input. However, results in human perception of other's actions suggest that, in this specific task, motion features are crucial. This means that using the whole video as input may add both redundancy and noise in the learning process. In this work, we propose a hybrid "handcrafted/learned" feature framework which provides better accuracy than the previous feature learning method, with similar computational efficiency. The proposed method is compared to three related benchmark datasets. The method outperforms the different state-of-the-art methods in two of the three considered benchmark datasets. PMID- 29994220 TI - Fully Automatic Multiresolution Idealization for Filtered Ion Channel Recordings: Flickering Event Detection. AB - We propose a new model-free segmentation method, JULES, which combines recent statistical multiresolution techniques with local deconvolution for idealization of ion channel recordings. The multiresolution criterion takes into account scales down to the sampling rate enabling the detection of flickering events, i.e., events on small temporal scales, even below the filter frequency. For such small scales the deconvolution step allows for a precise determination of dwell times and, in particular, of amplitude levels, a task which is not possible with common thresholding methods. This is confirmed theoretically and in a comprehensive simulation study. In addition, JULES can be applied as a preprocessing method for a refined hidden Markov analysis. Our new methodology allows us to show that gramicidin A flickering events have the same amplitude as the slow gating events. JULES is available as an R function jules in the package clampSeg. PMID- 29994226 TI - Leader-Following Practical Cluster Synchronization for Networks of Generic Linear Systems: An Event-Based Approach. AB - In network systems, a group of nodes may evolve into several subgroups and coordinate with each other in the same subgroup, i.e., reach cluster synchronization, to cope with the unanticipated situations. To this end, the leader-following practical cluster synchronization problem of networks of generic linear systems is studied in this paper. An event-based control algorithm that can largely reduce the amount of communication is first proposed over directed communication topologies. In the proposed algorithm, each node decides itself when to transmit its current state to its neighbors and how to update its controller according to the estimations of the states of it and its neighbors. Then, the Lyapunov method is utilized to perform the convergence analysis. It shows that the practical cluster synchronization can be ensured by choosing appropriate parameters no matter what kind of estimation for the state is applied. Furthermore, the Zeno behavior is also excluded for each node under some mild assumptions. Besides, three kinds of common estimations for the states including zero-order hold model, first-order approximate model, and high-order model-based estimations are, respectively, analyzed from the perspective of the exclusion of Zeno behavior. Finally, the validity of the proposed algorithm is demonstrated, the effects of the concerned parameters are simply presented, and the effects of the three estimations are also compared through several simulations. PMID- 29994216 TI - Biorthogonal wavelet transforms and applications based on generalized progressive Catmull-Clark subdivision with shape control. AB - In recent years, some biorthogonal Catmull-Clark subdivision wavelets constructed via lifting scheme have been proposed to speed up processing of geometric models. Thanks to the idea of progressive interpolation, the compression qualities and noise-filtering effects have been improved significantly. However, the reconstruction precision fails to be improved further because many model details are removed and the noise-filtering performance decreases greatly while the noise intensity increases gradually. To deal with this dilemma, a unified Catmull-Clark subdivision based biorthogonal wavelet construction with shape control parameters is presented to process 3D models with sharp-feature constraints. By customizing its local orthogonalizing coefficients for different vertex valences of quadrilateral patches, the novel scheme can greatly strengthen the capability of the model's shape control that is vital for data compression, noise-filtering, etc. Combined with the local and in-place lifting operations, the proposed wavelet transform can dramatically decrease the memory consumption and computation complexity. Both theoretical analysis and experiments show that, compared with the state-of-the-art lifting-based solutions, the proposed wavelet transform achieves higher compression ratio, more stable noise-filtering effects and better progressive transmission quality, not only decreasing Bits/vertex of 3D meshes and improving PSNR of reconstruction models, but also reducing the time costs of coding and decoding. PMID- 29994218 TI - Development of Amoxicillin-Loaded Electrospun Polyurethane/Chitosan/ $?beta$ Tricalcium Phosphate Scaffold for Bone Tissue Regeneration. AB - Biocompatible nanocomposite electrospun fibers containing Polyurethane/Chitosan/ $?beta $ -Tri calcium phosphate with diverse concentrations were designed and produced through the electrospinning process for bone tissue engineering applications. After the production process, density measurement, viscosity, electrical conductivity, and tensile strength measurement tests were carried out as physical analyses of blended solutions. The chemical structural characterization was scrutinized using Fourier transform infrared spectrometer (FTIR), and scanning electron microscopy (SEM) was used to observe the morphological details of developed electrospun scaffolds. Cell viability, attachment, and proliferation were performed using a L929 fibroblast cell line. Based on the physical, SEM, FTIR analysis, and cell culture studies, preferable nanofiber composition was selected for further studies. Amoxicillin (AMX) was loaded to that selected nanofiber composition for examination of the drug release. In comparison with other studies on similar AMX controlled products, higher drug loading and encapsulation efficiencies were obtained. It has been clearly found that the developed nanofiber composites have potential for bone tissue engineering applications. PMID- 29994219 TI - Classification of Whole Mammogram and Tomosynthesis Images Using Deep Convolutional Neural Networks. AB - Mammography is the most popular technology used for the early detection of breast cancer. Manual classification of mammogram images is a hard task because of the variability of the tumor. It yields a noteworthy number of patients being called back to perform biopsies, ensuring no missing diagnosis. The convolutional neural network (CNN) has succeeded in a lot of image classification challenges during the recent years. In this paper, we proposed an approach of mammogram and tomosynthesis classification based on CNNs. We had acquired more than 3000 mammograms and tomosynthesis data with approval from an institutional review board at the University of Kentucky. Different models of CNNs were built to classify both the 2-D mammograms and 3-D tomosynthesis, and every classifier was assessed with respect to truth-values generated by histology results from the biopsy and two-year negative mammogram follow-up confirmed by expert radiologists. Our outcomes demonstrated that CNN-based models we had built and optimized utilizing transfer learning and data augmentation have good potential for automatic breast cancer detection based on the mammograms and tomosynthesis data. PMID- 29994225 TI - Semisupervised Learning Based on a Novel Iterative Optimization Model for Saliency Detection. AB - In this paper, we propose a novel iterative optimization model for bottom-up saliency detection. By exploring bottom-up saliency principles and semisupervised learning approaches, we design a high-performance saliency analysis method for wide ranging scenes. The proposed algorithm consists of two stages: 1) we develop a boundary homogeneity model to characterize the general position and the contour of the salient objects and 2) we propose a novel iterative optimization model, termed gradual saliency optimization, for further performance improvement. Our main contribution falls on the second stage, where we propose an iterative framework with self-repairing mechanisms for refining saliency maps. In this framework, we further develop a more comprehensive optimization function applying a novel semisupervised learning scheme to enhance the traditional saliency measure. More elaborately, the iterative method can gradually improve the output in each iteration and finally converge to high-quality saliency maps. Based on our experiments on four different public data sets, it can be demonstrated that our approach significantly outperforms the state-of-the-art methods. PMID- 29994223 TI - Using Emulation to Engineer and Understand Simulations of Biological Systems. AB - Modeling and simulation techniques have demonstrated success in studying biological systems. As the drive to better capture biological complexity leads to more sophisticated simulators, it becomes challenging to perform statistical analyses that help translate predictions into increased understanding. These analyses may require repeated executions and extensive sampling of high dimensional parameter spaces: analyses that may become intractable due to time and resource limitations. Significant reduction in these requirements can be obtained using surrogate models, or emulators, that can rapidly and accurately predict the output of an existing simulator. We apply emulation to evaluate and enrich understanding of a previously published agent-based simulator of lymphoid tissue organogenesis, showing an ensemble of machine learning techniques can reproduce results obtained using a suite of statistical analyses within seconds. This performance improvement permits incorporation of previously intractable analyses, including multi-objective optimization to obtain parameter sets that yield a desired response, and Approximate Bayesian Computation to assess parametric uncertainty. To facilitate exploitation of emulation in simulation focused studies, we extend our open source statistical package, spartan, to provide a suite of tools for emulator development, validation, and application. Overcoming resource limitations permits enriched evaluation and refinement, easing translation of simulator insights into increased biological understanding. PMID- 29994227 TI - Filippov Hindmarsh-Rose Neuronal Model With Threshold Policy Control. AB - A Filippov system of Hindmarsh-Rose (HR) neuronal model with threshold policy control is proposed, membrane potential has been taken as the threshold and the corresponding switching function is also established. We first discuss the existence and stability of the equilibria for the two Filippov subsystems based on the 2-D HR model. Subsequently, the sliding dynamics of HR model including the sliding segments, sliding regions, and various equilibria under the Filippov framework are studied. Then, we further consider the equilibria and the sliding bifurcation set of the Filippov system, and find there exist the bistable equilibria and several sliding bifurcation phenomena, such as boundary-node bifurcation, pseudosaddle-node bifurcation, the emergence and disappearance of limit cycles on the sliding line, and so on. Finally, we study the Filippov system of the 3-D HR model, and provide a phase diagram of the system that generates the sliding spiking and the sliding bursting, which lie on the sliding line. PMID- 29994228 TI - On the Duality Between Belief Networks and Feed-Forward Neural Networks. AB - This paper addresses the duality between the deterministic feed-forward neural networks (FF-NNs) and linear Bayesian networks (LBNs), which are the generative stochastic models representing probability distributions over the visible data based on a linear function of a set of latent (hidden) variables. The maximum entropy principle is used to define a unique generative model corresponding to each FF-NN, called projected belief network (PBN). The FF-NN exactly recovers the hidden variables of the dual PBN. The large-$N$ asymptotic approximation to the PBN has the familiar structure of an LBN, with the addition of an invertible nonlinear transformation operating on the latent variables. It is shown that the exact nature of the PBN depends on the range of the input (visible) data details for the three cases of input data range are provided. The likelihood function of the PBN is straightforward to calculate, allowing it to be used as a generative classifier. An example is provided in which a generative classifier based on the PBN has comparable performance to a deep belief network in classifying handwritten characters. In addition, several examples are provided that demonstrate the duality relationship, for example, by training networks from either side of the duality. PMID- 29994229 TI - Exploiting Combination Effect for Unsupervised Feature Selection by l2,0 Norm. AB - In learning applications, exploring the cluster structures of the high dimensional data is an important task. It requires projecting or visualizing the cluster structures into a low dimensional space. The challenges are: 1) how to perform the projection or visualization with less information loss and 2) how to preserve the interpretability of the original data. Recent methods address these challenges simultaneously by unsupervised feature selection. They learn the cluster indicators based on the k nearest neighbor similarity graph, then select the features highly correlated with these indicators. Under this direction, many techniques, such as local discriminative analysis, nonnegative spectral analysis, nonnegative matrix factorization, etc., have been successfully introduced to make the selection more accurate. In this paper, we focus on enhancing the unsupervised feature selection in another perspective, namely, making the selection exploit the combination effect of the features. Given the expected feature amount, previous works operate on the whole features then select those of high coefficients one by one as the output. Our proposed method, instead, operates on a group of features initially then update the selection when a better group appears. Compared to the previous methods, the proposed method exploits the combination effect of the features by l2,0 norm. It improves the selection accuracy where the cluster structures are strongly related to a group of features. We conduct the experiments on six open access data sets from different domains. The experimental results show that our proposed method is more accurate than the recent methods which do not specially consider the combination effect of the features. PMID- 29994235 TI - Hierarchical Consensus Problem via Group Information Exchange. AB - This paper presents a hierarchical structure to solve the consensus problem of multiagent systems. The new scheme divides the agents into several groups, with each group containing a value concerning all of the intragroup agents' states, which we call group information. For each single agent, it receives not only the agent information from its intragroup neighbors, but also the group information from its neighboring groups. It is then shown that global consensus can be achieved under the proposed scheme in both discrete time and continuous time. Moreover, a sufficient condition to achieve average consensus is provided. This hierarchical model can be well used in the PageRank algorithm to reduce the communication loads, and to reveal the attractors for Boolean networks by reducing the computational complexity. PMID- 29994233 TI - Automated Region of Interest Detection Method in Scintigraphic Glomerular Filtration Rate Estimation. AB - The glomerular filtration rate (GFR) is a crucial index to measure renal function. In daily clinical practice, the GFR can be estimated using the Gates method, which requires the clinicians to define the region of interest (ROI) for the kidney and the corresponding background in dynamic renal scintigraphy. The manual placement of ROIs to estimate the GFR is subjective and labor-intensive, however, making it an undesirable and unreliable process. This work presents a fully automated ROI detection method to achieve accurate and robust GFR estimations. After image preprocessing, the ROI for each kidney was delineated using a shape prior constrained level set (spLS) algorithm and then the corresponding background ROIs were obtained according to the defined kidney ROIs. In computer simulations, the spLS method had the best performance in kidney ROI detection compared with the previous threshold method (Threshold) and the Chan Vese level set (cvLS) method. In further clinical applications, 223 sets of 99mTc diethylenetriaminepentaacetic acid (99mTc-DTPA) renal scintigraphic images from patients with abnormal renal function were reviewed. Compared with the former ROI detection methods (Threshold and cvLS), the GFR estimations based on the ROIs derived by the spLS method had the highest consistency and correlations (r=0.98, p<0.001) with the reference estimated by experienced physicians. The results indicate that the proposed automated ROI detection method has great potential in automated ROI detection for accurate and robust GFR estimation in dynamic renal scintigraphy. PMID- 29994236 TI - Multirobot Exploration While Building Power-Efficient Sensor Networks in Three Dimensions. AB - An information (sensor) network can be used to monitor various 3-D environments, such as underwater environments. To build an information network in 3-D environments, we use multiple robots deploying information nodes. Our 3-D networking strategy results in the network without coverage holes and does not require the global localization of a node or a robot. We assume that as the size of each sensor coverage decreases, the power consumption of the sensor decreases. Thus, once the 3-D network is built by multiple robots, each node searches for the smallest size of its sensing coverage while assuring that there is no hole in the global coverage. In this way, we save the power consumption while preserving the global coverage. Note that each node searches for its optimal sensing coverage by accessing the relative positions of its neighbors only once. This implies that energy consumption of searching for the optimal coverage is very low. Using MATLAB simulations, we verify the scalability and effectiveness of our strategies in 3-D environments. PMID- 29994230 TI - Groupwise multi-channel image registration. AB - Multi-channel image registration is an important challenge in medical image analysis. Multi-channel images result from modalities such as dual-energy CT or multispectral microscopy. Besides, multi-channel feature images can be derived from acquired images, for instance, by applying multi-scale feature banks to the original images to register. Multi-channel registration techniques have been proposed, but most of them are applicable to only two multi-channel images at a time. In the present study, we propose to formulate multi-channel registration as a groupwise image registration problem. In this way, we derive a method that allows the registration of two or more multi-channel images in a fully symmetric manner (i.e. all images play the same role in the registration procedure), and therefore has transitive consistency by definition. The method that we introduce is applicable to any number of multi-channel images, any number of channels per image, and it allows to take into account correlation between any pair of images and not just corresponding channels. In addition, it is fully modular in terms of dissimilarity measure, transformation model, regularisation method, and optimisation strategy. For two multimodal datasets, we computed feature images from the initially acquired images, and applied the proposed registration technique to the newly created sets of multi-channel images. MIND descriptors were used as feature images, and we chose total correlation as groupwise dissimilarity measure. Results show that groupwise multi-channel image registration is a competitive alternative to the pairwise multi-channel scheme, in terms of registration accuracy and insensitivity towards registration reference spaces. PMID- 29994241 TI - Distributed Impulsive Quasi-Synchronization of Lur'e Networks With Proportional Delay. AB - This paper investigates the exponential synchronization of nonidentically coupled Lur'e dynamical networks with proportional delay. Since the heterogeneities existed in different Lur'e systems, quasi-synchronization rather than complete synchronization is thus discussed. Different from general time delay, the proportional delay is a type of unbounded time-varying delay, which tremendously increases the requirements on network synchronization. Based on distributed impulsive pinning control protocol and different roles that impulsive effects play, the criteria for quasi-synchronization of nonidentically coupled Lur'e dynamical networks are derived by jointly applying the delayed impulsive comparison principle, the extended formula for the variation of parameters, and the definition of an average impulsive interval. Moreover, synchronization errors for different impulsive effects with different functions are evaluated and simultaneously, the corresponding exponential convergence rates are obtained. In addition, three numerical examples are presented to illustrate the validity of the control scheme and the theoretical analysis. PMID- 29994243 TI - Distributed Optimization Based on a Multiagent System Disturbed by General Noise. AB - A distributed optimization problem based on a continuous-time multiagent system (MAS) disturbed by general noise is considered in this paper. The general noise, under some relaxed assumptions, which may be a stationary process, is proposed to describe the disturbance among agents more accurately. The noise-to-state (NOS) stability of the concerned MAS is analyzed based on an improved theoretical result of random differential equations. Furthermore, the relative sufficient conditions in the form of linear matrix inequality are developed with less conservatism, from which the minimum estimation error between the optimal solution and the NOS stable state of the proposed MAS with general noise can be obtained by choosing some appropriate distributed optimization parameters. One example is used to verify the effectiveness of the proposed approach. PMID- 29994244 TI - Framework of Randomized Distribution Features for Visual Representation and Categorization. AB - This paper introduces a framework to deal with the distribution of descriptive features, which preserves the advantages of the vectorial representation and computational efficiency of histogram-based techniques, and inherits the rigorous theoretical guarantee and competitive performance of metric-based ones. The methods developed under this framework describe the underlying distribution of a set of features as a vectorial feature by utilizing random features. Moreover, the proposed methods asymptotically converge to metric-based methods in terms of the similarity and distance and, depending on a specific kernel function, reduce to histogram-based methods. The experimental results show the benefits of a comparable performance on categorization tasks compared to conventional metric based methods at a significantly reduced computational cost. PMID- 29994234 TI - A Survey of Feature Extraction in Dermoscopy Image Analysis of Skin Cancer. AB - Dermoscopy image analysis (DIA) is a growing field, with works being published every week. This makes it difficult not only to keep track of all the contributions, but also for new researchers to identify relevant information and new directions to be explored. Several surveys have been written in the past decade, but these tend to cover all of the steps of a CAD system, which can be overwhelming. Moreover, in these works, each of the steps is briefly discussed due to lack of space. Among the different blocks of the CAD system, the most relevant is the one devoted to feature extraction. This is also the block where existing works exhibit the most variability. Therefore, we believe that it is important to review the state-of-the-art on this matter. This work thoroughly explores the several types of features that have been used in DIA. A discussion on their relevance and limitations, as well as suggestions for future research are provided. PMID- 29994239 TI - Admissibility Analysis for Interval Type-2 Fuzzy Descriptor Systems Based on Sliding Mode Control. AB - This paper is concerned with the sliding mode control of nonlinear singular systems in terms of the interval type-2 (IT2) fuzzy model. To better approximate the nonlinear systems, the modeling errors are considered in the IT2 fuzzy model. The uncertainties in membership functions are expressed based on their boundedness. Admissibility conditions are obtained via a linear matrix inequalities approach. A new reaching law-based sliding controller is presented by choosing a typical sliding surface to analyze the sliding motion, such that all of the input gains are allowed to be different and the chattering of the system can be minimized with a guaranteed Hinfinity performance. The feasibility of the proposed control method is verified by simulation results. PMID- 29994231 TI - Sleep Apnea Detection Based on Rician Modeling of Feature Variation in Multi-band EEG Signal. AB - Sleep apnea, a serious sleep disorder affecting a large population, causes disruptions in breathing during sleep. In this paper, an automatic apnea detection scheme is proposed using single lead electroencephalography (EEG) signal to discriminate apnea patients and healthy subjects as well as to deal with the difficult task of classifying apnea and non-apnea events of an apnea patient. A unique multi-band sub-frame based feature extraction scheme is developed to capture the feature variation pattern within a frame of EEG data, which is shown to exhibit significantly different characteristics in apnea and non-apnea frames. Such within-frame feature variation can be better represented by some statistical measures and characteristic probability density functions. It is found that use of Rician model parameters along with some statistical measures can offer very robust feature qualities in terms of standard performance criteria, such as Bhattacharyya distance and geometric separability index. For the purpose of classification, proposed features are used in KNN. From extensive experimentations and analysis on three different publicly available databases it is found that the proposed method offers superior classification performance in terms of sensitivity, specificity and accuracy. PMID- 29994238 TI - Full Representation Data Embedding via Nonoverlapping Historical Features. AB - Data recycling, which reuses the historical data to assist the present data to achieve better performance, is an emerging and important research topic. A common case is that historical examples only have features from one source while presently have more data collection ways and extract different types of features simultaneously for new examples. Previous studies assume that either historical data appear in all sources, or at least there is one type of representations for all data. In this paper, we study the challenging problem in the above common case and propose a novel semisupervised approach by leveraging nonoverlapping historical features (NHFs). It learns full representations of both historical features and present features in a latent subspace. We utilize the intrinsic geometrical structure of all data and add the label information of historical data as a hard constraint to discover a latent subspace. Then, the classification will be performed with these new representations. Moreover, we provide an efficient algorithm to solve the formulated optimization problem with proved convergence behavior, together with some insightful discussions about parameter determination. Experimental results on real-world data sets are provided to examine the effectiveness of our algorithm. Furthermore, we have also evaluated our method in face recognition. They all demonstrate the effectiveness of our proposed approach on recycling NHFs. PMID- 29994237 TI - Energy-to-Peak State Estimation for Static Neural Networks With Interval Time Varying Delays. AB - This paper is concerned with energy-to-peak state estimation on static neural networks (SNNs) with interval time-varying delays. The objective is to design suitable delay-dependent state estimators such that the peak value of the estimation error state can be minimized for all disturbances with bounded energy. Note that the Lyapunov-Krasovskii functional (LKF) method plus proper integral inequalities provides a powerful tool in stability analysis and state estimation of delayed NNs. The main contribution of this paper lies in three points: 1) the relationship between two integral inequalities based on orthogonal and nonorthogonal polynomial sequences is disclosed. It is proven that the second order Bessel-Legendre inequality (BLI), which is based on an orthogonal polynomial sequence, outperforms the second-order integral inequality recently established based on a nonorthogonal polynomial sequence; 2) the LKF method together with the second-order BLI is employed to derive some novel sufficient conditions such that the resulting estimation error system is globally asymptotically stable with desirable energy-to-peak performance, in which two types of time-varying delays are considered, allowing its derivative information is partly known or totally unknown; and 3) a linear-matrix-inequality-based approach is presented to design energy-to-peak state estimators for SNNs with two types of time-varying delays, whose efficiency is demonstrated via two widely studied numerical examples. PMID- 29994240 TI - Fisher Information Matrix of Unipolar Activation Function-Based Multilayer Perceptrons. AB - The multilayer perceptrons (MLPs) are widely used in many fields, however, singularities in the parameter space may seriously influence the learning dynamics of MLPs and cause strange learning behaviors. Given that the singularities are the subspaces of the parameter space where the Fisher information matrix (FIM) degenerates, the FIM plays a key role in the study of the singular learning dynamics of the MLPs. In this paper, we obtain the analytical form of the FIM for unipolar activation function-based MLPs where the input subjects to the Gaussian distribution with general covariance matrix and the unipolar error function is chosen as the activation function. Then three simulation experiments are taken to verify the validity of the obtained results. PMID- 29994242 TI - Robust Hinfinity Adaptive Fuzzy Tracking Control for MIMO Nonlinear Stochastic Poisson Jump Diffusion Systems. AB - Recently, stochastic Poisson jump diffusion system has attracted much attention in stochastic control. Poisson jump process has been used to model the random discontinuous jump behavior of the intrinsic discontinuous perturbation in stochastic system. Wiener process also called diffusion process represents the continuous random fluctuation to the system. In this paper, a robust adaptive control is introduced for multi-input multi-output (MIMO) nonlinear stochastic Poisson jump diffusion system with continuous and discontinuous random fluctuations to achieve the Hinfinity tracking performance with a prescribed disturbance attenuation level. The system structure is of a strict-feedback form. Based on the backstepping design technique and Hinfinity control theory, a robust adaptive control law is constructed for MIMO nonlinear stochastic Poisson jump diffusion system to achieve the Hinfinity tracking performance with a prescribed attenuation level of external disturbance, despite of fuzzy approximation error and the effect of continuous and discontinuous random fluctuations. The proposed Hinfinity adaptive control law combines both merits of Hinfinity tracking control and adaptive control scheme to sufficiently solve the robust Hinfinity adaptive tracking control problem for MIMO stochastic nonlinear systems with continuous and discontinuous random fluctuations. In addition, the uniformly positive definite assumption of control coefficient matrix is relaxed for the proposed MIMO adaptive control as well. A stochastic quadrotor trajectory tracking control simulation is provided to show the effectiveness of the proposed Hinfinity robust adaptive control law. PMID- 29994245 TI - Differential Geometry in Edge Detection: accurate estimation of position, orientation and curvature. AB - The vast majority of edge detection literature has aimed at improving edge recall and precision, with relatively few addressing the accuracy of edge orientation estimates which are often based on gradient. We show that first-order estimates of orientation can have significant error and this can be remedied by employing Third-Order estimates. This paper aims at estimating differential geometry attributes of an edge, namely, localization, orientation, and curvature, as well as edge topology, and develop robust numerical techniques in gray-scale and color images, applicable to a variety of popular edge detectors, such as gradient based, gPb and SE. Second, a combinatorial model of edge grouping in a small neighborhood is developed to capture all geometrically consistent grouping called curvelets, which establish: (i) edge topology in the form of potential links between an edge and other edges; (ii) an accurate curvature estimate for each possible grouping, whose performance is comparable to methods which use global and multi-scale methods; (iii) a more accurate localization of an edge. These have been evaluated using four distinct methodologies (i) traditional human annotated datasets; (ii) using coherence measure; (iii) stability analysis under visual perturbation, and (iv) utilitarian evaluation, and show meaningful improvements. PMID- 29994232 TI - Blood Triglyceride Monitoring with Smartphone as Electrochemical Analyzer for Cardiovascular Disease Prevention. AB - Nowadays, cardiovascular diseases have become one of the most risks threating human being's life in the world. The early screening and efficient management of cardiovascular diseases are critically important to extend the patients' life. Blood lipid level is a key biochemical factor used to estimate the cardiovascular disease in clinical situation. Triglyceride as one important blood lipid plays an indispensable role in the blood test. On the other hand, smartphone has unprecedentedly large scale users since the last decade, which paves the wide avenue for the dissemination of smartphone-associated medical devices. In this letter, we integrated the smartphone with the Triglyceride (TG) sensory module to monitor the finger pricked whole blood TG at the point of care scale. The miniaturized electrochemical analyzer was immobilized on the main board of the smartphone which enables the smartphone work as the blood TG analyzer incorporating with the disposable electrochemical TG test strip. The blood TG measured by the medical smartphone was compared to the results obtained from the conventional bulky biochemical analyzer with acceptable accuracy, which demonstrated that the proposed medical smartphone is capable of providing a point of care analytical device for blood TC monitoring at the medical level. Its potential in cardiovascular disease prevention and management was believed to be great, since the proposed system is ultra-compact, smart, cost effective, reliable and flexible with medical data acquisition. PMID- 29994247 TI - Salient Object Detection with Recurrent Fully Convolutional Networks. AB - Deep networks have been proved to encode high-level features with semantic meaning and delivered superior performance in salient object detection. In this paper, we take one step further by developing a new saliency detection method based on recurrent fully convolutional networks (RFCNs). Compared with existing deep network based methods, the proposed network is able to incorporate saliency prior knowledge for more accurate inference. In addition, the recurrent architecture enables our method to automatically learn to refine the saliency map by iteratively correcting its previous errors, yielding more reliable final predictions. To train such a network with numerous parameters, we propose a pre training strategy using semantic segmentation data, which simultaneously leverages the strong supervision of segmentation tasks for effective training and enables the network to capture generic representations to characterize category agnostic objects for saliency detection. Extensive experimental evaluations demonstrate that the proposed method compares favorably against state-of-the-art saliency detection approaches. Additional validations are also performed to study the impact of the recurrent architecture and pre-training strategy on both saliency detection and semantic segmentation, which provides important knowledge for network design and training in the future research. PMID- 29994250 TI - The Main Lateral Mode Approximation of a Film Bulk Acoustic Resonator With Perfect Metal Electrodes. AB - Using first principles and the constitutive equations of a piezoelectric crystal, we solve the 2-D problem inside a three-layer film bulk acoustic resonator (FBAR) in order to study the dispersion and parasitic lateral modes' characteristic of the structure. In our main lateral mode approximation, described here in detail, we construct the acoustic wave by combining the ideal "piston" mode and the main dispersion branch lateral mode. By limiting our analysis to the practical range of frequencies near the series resonance of the stack, where the lateral component $k_{x}$ of the ${k}$ vector is small, we find analytical expressions for the FBAR acoustic wave and for the dispersion of the three-layer stack. When lateral boundary conditions are added to the acoustic problem of a laterally finite resonator, we employ our theory to estimate the amplitude and the propagation of the lateral modes and then compare the theoretical predictions with the measurements of fabricated FBARs and finite-element simulation results. We are able to distinguish between a "clamped" and a "quasi-free" lateral interface by comparing the amplitude strength of the lateral modes produced, and we discuss how optimum lateral boundaries can be engineered with perimeter frames for realistic resonators. PMID- 29994249 TI - Regularization Analysis and Design for Prior-Image-Based X-Ray CT Reconstruction. AB - Prior-image-based reconstruction (PIBR) methods have demonstrated great potential for radiation dose reduction in computed tomography applications. PIBR methods take advantage of shared anatomical information between sequential scans by incorporating a patient-specific prior image into the reconstruction objective function, often as a form of regularization. However, one major challenge with PIBR methods is how to optimally determine the prior image regularization strength which balances anatomical information from the prior image with data fitting to the current measurements. Too little prior information yields limited improvements over traditional model-based iterative reconstruction, while too much prior information can force anatomical features from the prior image not supported by the measurement data, concealing true anatomical changes. In this paper, we develop quantitative measures of the bias associated with PIBR. This bias exhibits as a fractional reconstructed contrast of the difference between the prior image and current anatomy, which is quite different from traditional reconstruction biases that are typically quantified in terms of spatial resolution or artifacts. We have derived an analytical relationship between the PIBR bias and prior image regularization strength and illustrated how this relationship can be used as a predictive tool to prospectively determine prior image regularization strength to admit specific kinds of anatomical change in the reconstruction. Because bias is dependent on local statistics, we further generalized shift-variant prior image penalties that permit uniform (shift invariant) admission of anatomical changes across the imaging field of view. We validated the mathematical framework in phantom studies and compared bias predictions with estimates based on brute force exhaustive evaluation using numerous iterative reconstructions across regularization values. The experimental results demonstrate that the proposed analytical approach can predict the bias regularization relationship accurately, allowing for prospective determination of the prior image regularization strength in PIBR. Thus, the proposed approach provides an important tool for controlling image quality of PIBR methods in a reliable, robust, and efficient fashion. PMID- 29994252 TI - Frequency-Temperature Compensated Cuts of Crystalline-Quartz Acoustic Cavity Within the Cryogenic Range [4 K, 15 K]. AB - New temperature coefficients of quartz elastic coefficients particularly relevant at liquid-helium temperature have been reported recently. Based on this result, frequency-temperature compensated cuts are predicted by calculation and then demonstrated by experiment. Such compensated cuts can definitely fix the issue of remaining temperature sensitivity of crystalline-quartz acoustic cavities unbeatable for their extremely low mechanical loss, as low as $10^{-9}$ , when operated at liquid-He temperature. PMID- 29994253 TI - Electrical Evidence of the Tunable Electrical Bragg Bandgaps in Piezoelectric Plates. AB - A piezoelectric plate, poled along its thickness and supporting on its top and bottom surfaces a periodic grating of electrodes, is considered. An analytical model allowing band structure calculation is derived for the first symmetrical mode propagating along the length of the plate. Analytical results show that an electrical Bragg (EB) bandgap can be observed for this mode, depending on the electrical boundary conditions applied on the electrodes. This "EB bandgap" is associated with a discontinuity of the electric field between two successive unit cells. These results are validated with the numerical simulations based on the finite element method. Analytical and numerical results prove that the EB bandgap is highly tunable and can be optimized by changing the crystallographic orientation of the material. A simple tunable filter exploiting this bandgap is designed and fabricated. Experimental results of electrical impedance and electrical potential at the output together with a scanning laser vibrometer analysis are presented, which confirm the theoretical predictions. PMID- 29994246 TI - Fine-tuning CNN Image Retrieval with No Human Annotation. AB - Image descriptors based on activations of Convolutional Neural Networks (CNNs) have become dominant in image retrieval due to their discriminative power, compactness of representation, and search efficiency. Training of CNNs, either from scratch or fine-tuning, requires a large amount of annotated data, where a high quality of annotation is often crucial. In this work, we propose to fine tune CNNs for image retrieval on a large collection of unordered images in a fully automated manner. Reconstructed 3D models obtained by the state-of-the-art retrieval and structure-from-motion methods guide the selection of the training data. We show that both hard-positive and hard-negative examples, selected by exploiting the geometry and the camera positions available from the 3D models, enhance the performance of particular-object retrieval. CNN descriptor whitening discriminatively learned from the same training data outperforms commonly used PCA whitening. We propose a novel trainable Generalized-Mean (GeM) pooling layer that generalizes max and average pooling and show that it boosts retrieval performance. Applying the proposed method to the VGG network achieves state-of the-art performance on the standard benchmarks: Oxford Buildings, Paris, and Holidays datasets. PMID- 29994258 TI - Multidimensional Projection for Visual Analytics: Linking Techniques with Distortions, Tasks, and Layout Enrichment. AB - Visual analysis of multidimensional data requires effective ways to reduce data dimensionality to encode them visually. Multidimensional projections (MDP) figure among the most important visualization techniques in this context, transforming multidimensional data into scatter plots where patterns reflect some notion of similarity in the data. However, MDP come with distortions that make visual patterns not trustworthy. Moreover, the patterns present in scatter plots might not be enough to allow an understanding of multidimensional data, motivating the development of layout enrichment methodologies that operate with MDP. This survey attempts to cover the main aspects of MDP as a visualization and visual analytic tool, providing detailed analysis and taxonomies taht organize MDP techniques according to their main properties and traits. The survey also approaches the different types of distortions that can result from MDP mappings while overviewing existing mechanisms to quantitatively evaluate such distortions. A qualitative analysis of the impact of distortions on the different analytic tasks is also presented, providing guidelines for users to choose a proper MDP for an intended. Finally, layout enrichment schemes to debunk MDP distortions and/or reveal relevant information not directly inferable from the scatter plot are reviewed and discussed in the light of new taxonomies. PMID- 29994251 TI - A Design Approach for High-Q FBARs With a Dual-Step Frame. AB - This paper presents a new approach for the design of film bulk acoustic resonators (FBARs) with high-quality factor ${Q}_{a}$ at antiresonant frequency ${f}_{a}$ . Lamb waves are among the main contributors to the loss of energy at ${f}_{a}$ and the deterioration of ${Q}_{a}$ . The targeted approach is an optimization process of a dual-step frame structure to alleviate the problem with Lamb waves at ${f}_{a}$ . Such a frame is a combination of two neighboring steps that have different acoustic impedances reflecting the two Lamb modes that carry the largest amount of energy. The dimensions of these steps are computed using the diffraction grating method. To do so, the dispersion curves of Lamb waves and their associated power flows are calculated using a global matrix method and the acoustic Poynting's Theorem. This results in an enhancement in ${Q}_{a}$ of nearly 82% for an FBAR with a dual-step frame in comparison with an FBAR with no frame, as well as a smoother electrical response, at frequencies above ${f}_{a}$ but below the resonant frequency ${f}_{r}$ spurious resonances are moderately increased. PMID- 29994260 TI - ELF: Extract Landmark Features by optimizing topology maintenance, redundancy, and specificity. AB - Feature selection is the process of selecting a subset of landmark features for model construction when there are many features and a comparatively few samples. The far-reaching development technologies such as biological sequencing at single cell level make feature selection a more challenging work. The difficulty lies in four facts: those features measured are in high dimension and with noise; dropouts make the data much sparse; many features are either redundant or irrelevant; and samples are not well-labeled in the experiments. Here, we propose a new model called ELF (Extract Landmark Features) to address the above challenges. ELF aims to simultaneously maximize topology maintenance to keep the pairwise relationships among samples, minimize feature redundancy to diversify the features, and maximize feature specificity to make every selected features more representative. This makes ELF a nonlinear combinatorial optimization. To solve this difficult problem, we propose a heuristic algorithm based on greedy strategy. We show ELF's outstanding performance on two single cell RNA-seq datasets. One is the direct reprogramming from mouse embryonic fibroblasts to induced neuron and the other is hepatoblast differentiation. ELF is able to choose only hundreds of landmark genes to maintain the cells' correlativity. Topology maintenance, redundancy removal, and specificity each plays its important role in selecting landmark features and revealing cells' biological functions. In addition, ELF can be generally applied in other scenarios. We demonstrate that ELF can reveal pivotal pixels in writing region and human face in two public image datasets. We believe that ELF is a useful tool to obtain more interpretable results by revealing key features while clustering the samples well. PMID- 29994254 TI - Imaging-Guided Dual-Target Neuromodulation of the Mouse Brain Using Array Ultrasound. AB - Neuromodulation is an important method for investigating neural circuits and treating neurological and psychiatric disorders. Multiple-target neuromodulation is considered an advanced technology for the flexible optimization of modulation effects. However, traditional methods such as electrical and magnetic stimulations are not convenient for multiple-target applications due to their disadvantages of invasiveness or poor spatial resolution. Ultrasonic neuromodulation is a new noninvasive method that has gained wide attention in the field of neuroscience, and it is potentially able to support multiple-target stimulation by allocating multiple focal points in the brain using an array transducer. However, there are no reports in the literature of the efficacy of this technical concept, and an imaging tool for localizing the stimulation area for evaluating the neural effects in vivo has been lacking. In this study, we designed and fabricated a new system specifically for imaging-guided dual-target neuromodulation. The design of the array transducer and overall system is described in detail. The stimulation points were selectable on a B-mode image. In vivo experiments were carried out in mice, in which forelimbs shaking responses and electromyography outcomes were induced by changing the stimulation targets. The system could be a valuable tool for imaging-guided multiple-target stimulation in various neuroscience applications. PMID- 29994259 TI - Sum Rate of MISO Neuro-Spike Communication Channel With Constant Spiking Threshold. AB - Communication among neurons, known as neuro-spike communication, is the most promising technique for realization of a bio-inspired nanoscale communication paradigm to achieve biocompatible nanonetworks. In neuro-spike communication, the information, encoded into spike trains, is communicated to various brain regions through neuronal network. An output neuron needs to receive signal from multiple input neurons to generate a spike. Hence, in this paper, we aim to quantify the information transmitted through the multiple-input single-output (MISO) neuro spike communication channel by considering models for axonal propagation, synaptic transmission, and spike generation. Moreover, the spike generation and propagation in each neuron requires opening and closing of numerous ionic channels on the cell membrane, which consumes considerable amount of ATP molecules called metabolic energy. Thus, we evaluate how applying a constraint on available metabolic energy affects the maximum achievable mutual information of this system. To this aim, we derive a closed form equation for the sum rate of the MISO neuro-spike communication channel and analyze it under the metabolic cost constraints. Finally, we discuss the impacts of changes in number of pre synaptic neurons on the achievable rate and quantify the tradeoff between maximum achievable sum rate and the consumed metabolic energy. PMID- 29994255 TI - Investigation of Piezoelectricity and Curie Temperature of Pb(Mg1/3, Nb2/3)O3 PbTiO3 Epitaxial Thin Film on Si Prepared by Sputter Deposition With Fast Cooling. AB - This paper reports on an abnormally high Curie temperature ( $T_{c}$ ) of a Pb(Mg1/3, Nb2/3)O3-PbTiO3 (PMN-PT) epitaxial thin film on Si prepared by sputter deposition with fast cooling. This deposition method was previously applied to Pb(Mn, Nb)O3-Pb(Zr, Ti)O3, and a c-axis-oriented epitaxial film with high $T_{c}$ was obtained. Using the same method, a crack-free 2- $?mu ?text{m}$ -thick PMN-PT thin film was epitaxially grown on a Si substrate covered with buffer layers. The piezoelectricity, $?vert ?text{e}_{31,f}?vert $ , was as large as 18~19 C/m2 under an electric field ranging from 25 to 75 kV/cm. The temperature characteristics of the dielectric constant and crystalline structure were significantly different from those of a bulk single crystal of PMN-PT, and suggested $T_{c}$ higher than 500 degrees C. The enhanced $T_{c}$ was possibly caused by thermally induced compressive strain received from the Si substrate. This approach can be an effective method for breaking the well-known tradeoff relationship between piezoelectricity and $T_{c}$ of a piezoelectric thin film. 0. PMID- 29994262 TI - HetRCNA: a novel method to identify recurrent copy number alternations from heterogeneous tumor samples based on matrix decomposition framework. AB - A common strategy to discovering cancer associated copy number aberrations (CNAs) from a cohort of cancer samples is to detect recurrent CNAs (RCNAs). Although the previous methods can successfully identify communal RCNAs shared by nearly all tumor samples, detecting subgroup-specific RCNAs and their related subgroup samples from cancer samples with heterogeneity is still invalid for these existing approaches. In this paper, we introduce a novel integrated method called HetRCNA, which can identify statistically significant subgroup-specific RCNAs and their related subgroup samples. Based on matrix decomposition framework with weight constraint, HetRCNA can successfully measure the subgroup samples by coefficients of left vectors with weight constraint and subgroup-specific RCNAs by coefficients of the right vectors and significance test. When we evaluate HetRCNA on simulated dataset, the results show that HetRCNA gives the best performances among the competing methods and is robust to the noise factors of the simulated data. When HetRCNA is applied on a real breast cancer dataset, our approach successfully identifies a bunch of RCNA regions and the result is highly correlated with the results of the other two investigated approaches. Notably, the genomic regions identified by HetRCNA harbor many breast cancer related genes reported by previous researches. PMID- 29994256 TI - Reducing Complexity of HEVC: A Deep Learning Approach. AB - High Efficiency Video Coding (HEVC) significantly reduces bit-rates over the preceding H.264 standard but at the expense of extremely high encoding complexity. In HEVC, the quad-tree partition of coding unit (CU) consumes a large proportion of the HEVC encoding complexity, due to the brute-force search for rate-distortion optimization (RDO). Therefore, this paper proposes a deep learning approach to predict the CU partition for reducing the HEVC complexity at both intra-and inter-modes, which is based on convolutional neural network (CNN) and long-and short-term memory (LSTM) network. First, we establish a large-scale database including substantial CU partition data for HEVC intra-and inter-modes. This enables deep learning on the CU partition. Second, we represent the CU partition of an entire coding tree unit (CTU) in the form of a hierarchical CU partition map (HCPM). Then, we propose an early-terminated hierarchical CNN (ETH CNN) for learning to predict the HCPM. Consequently, the encoding complexity of intra-mode HEVC can be drastically reduced by replacing the brute-force search with ETH-CNN to decide the CU partition. Third, an early-terminated hierarchical LSTM (ETH-LSTM) is proposed to learn the temporal correlation of the CU partition. Then, we combine ETH-LSTM and ETH-CNN to predict the CU partition for reducing the HEVC complexity at inter-mode. Finally, experimental results show that our approach outperforms other state-of-the-art approaches in reducing the HEVC complexity at both intra-and inter-modes. PMID- 29994263 TI - Arrhythmia Recognition and Classification Using ECG Morphology and Segment Feature Analysis. AB - In this work, arrhythmia appearing with the presence of abnormal heart electrical activity is efficiently recognized and classified. A novel method is proposed for accurate recognition and classification of cardiac arrhythmias. Firstly, P-QRS-T waves is segmented from ECG waveform; secondly, morphological features are extracted from P-QRS-T waves, and ECG segment features are extracted from the selected ECG segment by using PCA and dynamic time warping(DTW); finally, SVM is applied to the features and automatic diagnosis results is presented. ECG data set used is derived from the MIT-BIH in which ECG signals are divided into the four classes: normal beats(N), supraventricular ectopic beats (SVEBs), ventricular ectopic beats (VEBs) and fusion of ventricular and normal (F). Our proposed method can distinguish N, SVEBs, VEBs and F with an accuracy of 97.80%. The sensitivities for the classes N, SVEBs, VEBs and F are 99.27%, 87.47%, 94.71%, and 73.88% and the positive predictivities are 98.48%, 95.25%,95.22% and 86.09% respectively. The detection sensitivity of SVEBs and VEBs has a better performance by combining proposed features than by using the ECG morphology or ECG segment features separately. The proposed method is compared with four selected peer algorithms and delivers solid results. PMID- 29994265 TI - Bioinformatic workflow extraction from scientific texts based on word sense disambiguation and relation extraction. AB - This paper introduces a method for automatic workflow extraction from texts using Process-Oriented Case-Based Reasoning (POCBR). While the current workflow management systems implement mostly different complicated graphical tasks based on advanced distributed solutions (e.g. cloud computing and grid computation), workflow knowledge acquisition from texts using case-based reasoning represents more expressive and semantic cases representations. We propose in this context, an ontology-based workflow extraction framework to acquire processual knowledge from texts. Our methodology extends classic NLP techniques to extract and disambiguate tasks and relations in texts. Using a graph-based representation of workflows and a domain ontology, our extraction process uses a context-aware approach to recognize workflow components: data and control flows. We applied our framework in a technical domain in bioinformatics: i.e. phylogenetic analyses. An evaluation based on workflow semantic similarities on a gold standard proves that our approach provides promising results in the process extraction domain. Both data and implementation of our framework are available in: http://labo.bioinfo.uqam.ca/tgrowler. PMID- 29994257 TI - Exploiting Color Volume and Color Difference for Salient Region Detection. AB - Foreground and background cues can assist humans in quickly understanding visual scenes. In computer vision, however, it is difficult to detect salient objects when they touch the image boundary. Hence, detecting salient objects robustly under such circumstances without sacrificing precision and recall can be challenging. In this paper, we propose a novel model for salient region detection, namely, the foreground-center-background (FCB) saliency model. Its main highlights as follows. First, we use regional color volume as the foreground, together with perceptually uniform color differences within regions to detect salient regions. This can highlight salient objects robustly, even when they touched the image boundary, without greatly sacrificing precision and recall. Second, we employ center saliency to detect salient regions together with foreground and background cues, which improves saliency detection performance. Finally, we propose a novel and simple yet efficient method that combines foreground, center, and background saliency. Experimental validation with three well-known benchmark data sets indicates that the FCB model outperforms several state-of-the-art methods in terms of precision, recall, F-measure, and particularly, the mean absolute error. Salient regions are brighter than those of some existing state-of-the-art methods. PMID- 29994248 TI - Evaluation of Single-Chip, Real-Time Tomographic Data Processing on FPGA SoC Devices. AB - A novel approach to tomographic data processing has been developed and evaluated using the Jagiellonian positron emission tomography scanner as an example. We propose a system in which there is no need for powerful, local to the scanner processing facility, capable to reconstruct images on the fly. Instead, we introduce a field programmable gate array system-on-chip platform connected directly to data streams coming from the scanner, which can perform event building, filtering, coincidence search, and region-of-response reconstruction by the programmable logic and visualization by the integrated processors. The platform significantly reduces data volume converting raw data to a list-mode representation, while generating visualization on the fly. PMID- 29994261 TI - Detection of Driver Modules with Rarely Mutated Genes in Cancers. AB - Identifying driver modules or pathways is a key challenge to interpret the molecular mechanisms and pathogenesis underlying cancer. An increasing number of studies suggest that rarely mutated genes are important for the development of cancer. However, the driver modules consisting of mutated genes with low frequency driver mutations are not well characterized. To identify driver modules with rarely mutated genes, we propose a functional similarity index to quantify the functional relationship between rarely mutated genes and other ones in the same module. Then, we develop a method to detect Driver Modules with Rarely mutated Genes (DMRG) by incorporating the functional similarity, coverage and mutual exclusivity. By applying DMRG on TCGA cancer dataset on three networks: HINT+HI2012, iRefIndex and MultiNet, we detect driver modules intersecting with the well-known signalling pathways and protein complexes, such as the cell cycle pathway and the mediator complex. DMRG can also detect driver modules effectively with 20%, 40%, 60% and 80% of samples by random selection. When compared with HotNet2, DMRG detects more rarely mutated cancer genes and has higher pathway enrichment. Overall, DMRG provides an effective method for the identification of driver modules with rarely mutated genes. PMID- 29994267 TI - An Analog Front End ASIC for Cardiac Electrical Impedance Tomography. AB - In this paper, an end-to-end CMOS application specific integrated circuit (ASIC) for readout channel in a cardiac electrical impedance tomography system is presented. The ASIC consists of an integrated current driver for current injection, an instrumentation amplifier, variable gain amplifier at the analog front end for voltage readout from electrodes, and an on-chip 10-bit successive approximation register analog to digital converter with serial peripheral interface. The ASIC is fabricated in the CMOS 0.18 $?mu$ m process with a supply voltage of 3.3 V. Amplitude and phase extraction of the voltages is performed in the digital domain with a matched filter. A fully integrated solution for use in multiple electrode system is demonstrated. The readout chain in the ASIC achieves a minimum signal-to-noise ratio of 71 dB over the frequency range of 500 Hz-700 kHz, while maintaining an average accuracy of 99.7 $?%$. Frame rates of 21 frames per second for a 32 electrode system is feasible, and the ASIC has an overall power consumption of 11.8 mW. PMID- 29994264 TI - Quantifying direct dependencies in biological networks by multiscale association analysis. AB - Partial correlation (PC) or conditional mutual information (CMI) is widely used in detecting direct dependencies between the observed variables in biological networks by eliminating indirect correlations/associations, but it fails whenever there are some strong correlations in a network. In this paper, we theoretically develop a multiscale association analysis to overcome this flaw. We propose a new measure, partial association (PA), based on the multiscale conditional mutual information. We show that linear PA and nonlinear PA have clear advantages over PC and CMI from both theoretical and computational aspects. Both simulated models and real omics datasets demonstrate that PA is superior to PC and CMI in terms of accuracy, and is a powerful tool to identify the direct associations or reconstruct molecular networks based on the observed data. Survival and functional analyses of the hub genes in the gene networks reconstructed from TCGA data for different cancers also validated the effectiveness of our method. PMID- 29994266 TI - Noise Model of Capacitive and Textile Capacitive Noncontact Electrodes for Bioelectric Applications. AB - In this paper, a comprehensive model for the electronic noise properties and frequency-dependent responses of printed circuit board (PCB)-based as well as textile noncontact capacitive electrodes is presented. For bioelectric diagnostics, noncontact capacitive electrodes provide an interesting alternative to classical galvanically coupled electrodes, since such a low-cost diagnostic system can be applied without preparation time and in mobile wireless environments. For even higher user comfort, textile capacitive electrodes are preferable. This paper provides a thorough study of the influence of the electrical components of capacitive electrodes and textile capacitive electrodes, as well as their surface area and circumferences on the resulting noise properties of the electrode by independently measuring the corresponding noise spectra. Consequently, the equivalent noise model is developed. The most important noise source is the high input bias resistance, which, in combination with the involved capacitance, results in an apparent $1/f^2$-power noise spectrum. By comparing the noise measurements with the noise model of the electrode, we conclude that the surface of the electrode contributes to an additional $1/f$ -power noise in the noise spectrum. We also found that the highest possible coupling capacitance is most favorable for low-noise behavior. Therefore, electrodes with electrically conducting fabric surfaces are investigated. Due to this, it is possible to enlarge the surface of the electrode and maintain a small distance between the body and the surface of the electrode. We show that with the use of textile capacitive electrodes, it is possible to reduce the noise characteristics considerably. Our findings in this paper provide a necessary source for further optimization of capacitive electrodes for bioelectric measurement applications. PMID- 29994273 TI - A Semisupervised Classification Approach for Multidomain Networks With Domain Selection. AB - Multidomain network classification has attracted significant attention in data integration and machine learning, which can enhance network classification or prediction performance by integrating information from different sources. Despite the previous success, existing multidomain network learning methods usually assume that different views are available for the same set of instances, and thus, they seek a consistent classification result for all domains. However, in many real-world problems, each domain has its specific instance set, and one instance in one domain may correspond to multiple instances in another domain. Moreover, due to the rapid growth of data sources, different domains may not be relevant to each other, which asks for selecting domains relevant to the target/focused domain. A key challenge under this setting is how to achieve accurate prediction by integrating different data representations without losing data information. In this paper, we propose a semisupervised classification approach for a multidomain network based on label propagation, i.e., multidomain classification with domain selection (MCS), which can deal with the cross-domain information and different instance sets in domains. In particular, with sparse weight properties, the proposed MCS can automatically identify those domains relevant to our target domain by assigning them higher weights than the other irrelevant domains. This not only significantly improves a classification accuracy but also helps to obtain optimal network partition for the target domain. From the theoretical viewpoint, we equivalently decompose MCS into two simpler subproblems with analytical solutions, which can be efficiently solved by their computational procedures. Extensive experimental results on both synthetic and real-world data sets empirically demonstrate the advantages of the proposed approach in terms of both prediction performance and domain selection ability. PMID- 29994276 TI - Blind Denoising Autoencoder. AB - The term ''blind denoising'' refers to the fact that the basis used for denoising is learned from the noisy sample itself during denoising. Dictionary learning- and transform learning-based formulations for blind denoising are well known. But there has been no autoencoder-based solution for the said blind denoising approach. So far, autoencoder-based denoising formulations have learned the model on a separate training data and have used the learned model to denoise test samples. Such a methodology fails when the test image (to denoise) is not of the same kind as the models learned with. This will be the first work, where we learn the autoencoder from the noisy sample while denoising. Experimental results show that our proposed method performs better than dictionary learning (K-singular value decomposition), transform learning, sparse stacked denoising autoencoder, and the gold standard BM3D algorithm. PMID- 29994275 TI - Augmented Real-Valued Time-Delay Neural Network for Compensation of Distortions and Impairments in Wireless Transmitters. AB - A digital predistorter, modeled by an augmented real-valued time-delay neural network (ARVTDNN), has been proposed and found suitable to mitigate the nonlinear distortions of the power amplifier (PA) along with modulator imperfections for a wideband direct-conversion transmitter. The input signal of the proposed ARVTDNN consists of Cartesian in-phase and quadrature phase (I/Q) components, as well as envelope-dependent terms. Theoretical analysis shows that the proposed model is able to produce a richer basis function containing both the desired odd- and even order terms, resulting in improved modeling capability and distortion mitigation. Its actual performance has been validated through extensive simulations and experiments. The results show that the compensation and hardware impairment mitigation capabilities of the ARVTDNN are superior to the existing state-of-the art real-valued focused time-delay neural network (RVFTDNN) by 3-4 dB for the adjacent channel power ratio and by 2-3 dB in terms of the normalized mean square error. Other important features of the proposed model are its reduced complexity, in terms of the number of parameters and floating-point operations, and its improved numerical stability compared to the RVFTDNN model. PMID- 29994269 TI - A Novel Neural Networks Ensemble Approach for Modeling Electrochemical Cells. AB - Accurate modeling of electrochemical cells is nowadays mandatory for achieving effective upgrades in the fields of energetic efficiency and sustainable mobility. Indeed, these models are often used for performing accurate State-of Charge (SoC) estimations in energy storage systems used in microgrids or powering pure electric and hybrid cars. To this aim, a novel neural networks ensemble approach for modeling electrochemical cells is proposed in this paper. Herein, the system identification has been faced by means of a gray box technique, in which different and specialized neural networks are used for identifying the unknown internal behaviors of the cell. In particular, the a priori knowledge on the system dynamic is used for defining the network architecture. Specifically, each nonlinear function appearing in the system equations is approximated by a distinct neural network. The proposed model has been validated upon three different data sets both in terms of model accuracy and effectiveness in the SoC estimation task. The achieved performances have been compared with those of other computational intelligence approaches proposed in the literature. The results prove the effectiveness of the gray box scheme, achieving very promising performances in both the system identification accuracy and the SoC estimation task. PMID- 29994270 TI - Deep CNN-Based Blind Image Quality Predictor. AB - Image recognition based on convolutional neural networks (CNNs) has recently been shown to deliver the state-of-the-art performance in various areas of computer vision and image processing. Nevertheless, applying a deep CNN to no-reference image quality assessment (NR-IQA) remains a challenging task due to critical obstacles, i.e., the lack of a training database. In this paper, we propose a CNN based NR-IQA framework that can effectively solve this problem. The proposed method--deep image quality assessor (DIQA)--separates the training of NR-IQA into two stages: 1) an objective distortion part and 2) a human visual system-related part. In the first stage, the CNN learns to predict the objective error map, and then the model learns to predict subjective score in the second stage. To complement the inaccuracy of the objective error map prediction on the homogeneous region, we also propose a reliability map. Two simple handcrafted features were additionally employed to further enhance the accuracy. In addition, we propose a way to visualize perceptual error maps to analyze what was learned by the deep CNN model. In the experiments, the DIQA yielded the state-of-the-art accuracy on the various databases. PMID- 29994278 TI - Protein-protein Interactions Prediction via Multimodal Deep Polynomial Network and Regularized Extreme Learning Machine. AB - Predicting the protein-protein interactions (PPIs) has played an important role in many applications. Hence, a novel computational method for PPIs prediction is highly desirable. PPIs endow with protein amino acid mutation rate and two physicochemical properties of protein (e.g., hydrophobicity, and hydrophilicity). Deep polynomial network (DPN) is well-suited to integrate these modalities since it can represent any function on a finite sample dataset via the supervised deep learning algorithm. We propose a multimodal DPN (MDPN) algorithm to effectively integrate these modalities to enhance prediction performance. MDPN consists of a two-stage DPN, the first stage feeds multiple protein features into DPN encoding to obtain high-level feature representation while the second stage fuses and learns features by cascading three types of high-level features in the DPN encoding. We employ a regularized extreme learning machine (RELM) to predict PPIs. The proposed method is tested on the public dataset of H. pylori, Human, and Yeast and achieves average accuracies of 97.87%, 99.90%, and 98.11%, respectively. The proposed method also achieves good accuracies on other datasets. Furthermore, we test our method on three kinds of PPI networks and obtain superior prediction results. PMID- 29994268 TI - Active Perception With Dynamic Vision Sensors. Minimum Saccades With Optimum Recognition. AB - Vision processing with dynamic vision sensors (DVSs) is becoming increasingly popular. This type of a bio-inspired vision sensor does not record static images. The DVS pixel activity relies on the changes in light intensity. In this paper, we introduce a platform for the object recognition with a DVS in which the sensor is installed on a moving pan-tilt unit in a closed loop with a recognition neural network. This neural network is trained to recognize objects observed by a DVS, while the pan-tilt unit is moved to emulate micro-saccades. We show that performing more saccades in different directions can result in having more information about the object, and therefore, more accurate object recognition is possible. However, in high-performance and low-latency platforms, performing additional saccades adds latency and power consumption. Here, we show that the number of saccades can be reduced while keeping the same recognition accuracy by performing intelligent saccadic movements, in a closed action-perception smart loop. We propose an algorithm for smart saccadic movement decisions that can reduce the number of necessary saccades to half, on average, for a predefined accuracy on the N-MNIST dataset. Additionally, we show that by replacing this control algorithm with an artificial neural network that learns to control the saccades, we can also reduce to half the average number of saccades needed for the N-MNIST recognition. PMID- 29994272 TI - UCFTS: A Unilateral Coupling Finite-Time Synchronization Scheme for Complex Networks. AB - Improving universality and robustness of the control method is one of the most challenging problems in the field of complex networks (CNs) synchronization. In this paper, a special unilateral coupling finite-time synchronization (UCFTS) method for uncertain CNs is proposed for this challenging problem. Multiple influencing factors are considered, so that the proposed method can be applied to a variety of situations. First, two kinds of drive-response CNs with different sizes are introduced, each of which contains two types of nonidentical nodes and time-varying coupling delay. In addition, the node parameters and topological structure are unknown in drive network. Then, an effective UCFTS control technique is proposed to realize the synchronization of drive-response CNs and identify the unknown parameters and topological structure. Second, the UCFTS of uncertain CNs with four types of nonidentical nodes is further studied. Moreover, both the networks are of unknown parameters, time-varying coupling delay and uncertain topological structure. Through designing corresponding adaptive updating laws, the unknown parameters are estimated successfully and the weight of uncertain topology can be automatically adapted to the appropriate value with the proposed UCFTS. Finally, two experimental examples show the correctness of the proposed scheme. Furthermore, the method is compared with the other three synchronization methods, which shows that our method has a better control performance. PMID- 29994274 TI - Variational Random Function Model for Network Modeling. AB - Link prediction is a fundamental problem in network modeling. A family of link prediction approaches is to treat network data as an exchangeable array whose entries can be explained by random functions (e.g., block models and Gaussian processes) over latent node factors. Despite their powerful ability in modeling missing links, these models tend to have a large computational complexity and thus are hard to deal with large networks. To address this problem, we develop a novel variational random function model by defining latent Gaussian processes on exchangeable arrays. This model not only inherits the ability of Gaussian process to describe the nonlinear interactions between nodes, but also enjoys significant reduction on computational complexity. To further make the model scalable to large network data, we develop an efficient key-value-free strategy under the map reduce framework to tremendously reduce the inference time. Experimental results on large network data have demonstrated both the efficacy and efficiency of the proposed method over state-of-the-arts methods in network modeling. PMID- 29994271 TI - Local Adaptive Projection Framework for Feature Selection of Labeled and Unlabeled Data. AB - Most feature selection methods first compute a similarity matrix by assigning a fixed value to pairs of objects in the whole data or to pairs of objects in a class or by computing the similarity between two objects from the original data. The similarity matrix is fixed as a constant in the subsequent feature selection process. However, the similarities computed from the original data may be unreliable, because they are affected by noise features. Moreover, the local structure within classes cannot be recovered if the similarities between the pairs of objects in a class are equal. In this paper, we propose a novel local adaptive projection (LAP) framework. Instead of computing fixed similarities before performing feature selection, LAP simultaneously learns an adaptive similarity matrix and a projection matrix with an iterative method. In each iteration, is computed from the projected distance with the learned and W is computed with the learned . Therefore, LAP can learn better projection matrix by weakening the effect of noise features with the adaptive similarity matrix. A supervised feature selection with LAP (SLAP) method and an unsupervised feature selection with LAP (ULAP) method are proposed. Experimental results on eight data sets show the superiority of SLAP compared with seven supervised feature selection methods and the superiority of ULAP compared with five unsupervised feature selection methods. PMID- 29994281 TI - A Discrete Multiobjective Particle Swarm Optimizer for Automated Assembly of Parallel Cognitive Diagnosis Tests. AB - Parallel test assembly has long been an important yet challenging topic in educational assessment. Cognitive diagnosis models (CDMs) are a new class of assessment models and have drawn increasing attention for being able to measure examinees' ability in detail. However, few studies have been devoted to the parallel test assembly problem in CDMs (CDM-PTA). To fill the gap, this paper models CDM-PTA as a subset-based bi-objective combinatorial optimization problem. Given an item bank, it aims to find a required number of tests that achieve optimal but balanced diagnostic performance, while satisfying important practical requests in the aspects of test length, item type distribution, and overlapping proportion. A set-based multiobjective particle swarm optimizer based on decomposition (S-MOPSO/D) is proposed to solve the problem. To coordinate with the property of CDM-PTA, S-MOPSO/D utilizes an assignment-based representation scheme and a constructive learning strategy. Through this, promising solutions can be built efficiently based on useful assignment patterns learned from personal and collective search experience on neighboring scalar problems. A heuristic constraint handling strategy is also developed to further enhance the search efficiency. Experimental results in comparison with three representative approaches validate that the proposed algorithm is effective and efficient. PMID- 29994277 TI - Neurons With Paraboloid Decision Boundaries for Improved Neural Network Classification Performance. AB - In mathematical terms, an artificial neuron computes the inner product of a d dimensional input vector x with its weight vector w, compares it with a bias value w0 and fires based on the result of this comparison. Therefore, its decision boundary is given by the equation wTx+w0=0. In this paper, we propose replacing the linear hyperplane decision boundary of a neuron with a curved, paraboloid decision boundary. Thus, the decision boundary of the proposed paraboloid neuron is given by the equation (hTx+h0)2-||x-p||22 = 0, where h and h0 denote the parameters of the directrix and p denotes the coordinates of the focus. Such paraboloid neural networks are proven to have superior recognition accuracy in a number of applications. PMID- 29994282 TI - Synchronization of Multiple Reaction-Diffusion Neural Networks With Heterogeneous and Unbounded Time-Varying Delays. AB - The synchronization problem of multiple/coupled reaction-diffusion neural networks with time-varying delays is investigated. Differing from the existing considerations, state delays among distinct neurons and coupling delays among different subnetworks are included in the proposed model, the assumptions posed on the arisen delays are very weak, time-varying, heterogeneous, even unbounded delays are permitted. To overcome the difficulties from this kind of delay as well as diffusion effects, a comparison-based approach is applied to this model and a series of algebraic criteria are successfully obtained to verify the global asymptotical synchronization. By specifying the existing delays, some M-matrix based criteria are derived to justify the power-rate synchronization and exponential synchronization. In addition, new criterion on synchronization of general connected neural networks without diffusion effects is also given. Finally, two simulation examples are given to verify the effectiveness of the obtained theoretical results and provide a comparison with the existing criterion. PMID- 29994279 TI - A Clinical Decision Support Framework for Heterogeneous Data Sources. AB - To keep pace with the developments in medical informatics, health medical data is being collected continually. But, owing to the diversity of its categories and sources, medical data has become so complicated in many hospitals that it now needs a clinical decision support (CDS) system for its management. To effectively utilize the accumulating health data, we propose a CDS framework that can integrate heterogeneous health data from different sources such as laboratory test results, basic information of patients, and health records into a consolidated representation of features of all patients. Using the electronic health medical data so created, multilabel classification was employed to recommend a list of diseases and thus assist physicians in diagnosing or treating their patients' health issues more efficiently. Once the physician diagnoses the disease of a patient, the next step is to consider the likely complications of that disease, which can lead to more diseases. Previous studies reveal that correlations do exist among some diseases. Considering these correlations, a k nearest neighbors algorithm is improved for multilabel learning by using correlations among labels (CML-kNN). The CML- kNN algorithm first exploits the dependence between every two labels to update the origin label matrix and then performs multilabel learning to estimate the probabilities of labels by using the integrated features. Finally, it recommends the top N diseases to the physicians. Experimental results on real health medical data establish the effectiveness and practicability of the proposed CDS framework. PMID- 29994284 TI - Synchronization Analysis of Two-Time-Scale Nonlinear Complex Networks With Time Scale-Dependent Coupling. AB - In this paper, a time-scale-dependent coupling scheme for two-time-scale nonlinear complex networks is proposed. According to this scheme, the inner coupling matrices are related to the fast dynamics of individual subsystems, but are no longer time-scale-independent. Designing time-scale-dependent inner coupling matrices is motivated by the fact that the difference of time scales is an essential feature of modular architecture of two-time-scale systems. Under the novel coupling framework, the previous assumption on individual two-time-scale subsystems that the fast dynamics must be exponentially stable can be removed. The idea of time-scale separation is employed to analyze the stability of synchronization error systems via weighted epsilon-dependent Lyapunov functions. For a given upper bound of the singular perturbation parameter epsilon, it is proved that the exponential decay rate of the synchronization error can be guaranteed to be independent of the value of epsilon. In this way, criteria for local and global exponential synchronization are established. The allowable upper bound of epsilon such that the synchronizability of the considered two-time-scale network is retained can be obtained by solving a set of epsilon-dependent matrix inequalities. Finally, the efficiency of the proposed time-scale-dependent coupling strategy is demonstrated through numerical simulations. PMID- 29994285 TI - Mixed Supervised Object Detection with Robust Objectness Transfer. AB - In this paper, we consider the problem of leveraging existing fully labeled categories to improve the weakly supervised detection (WSD) of new object categories, which we refer to as mixed supervised detection (MSD). Different from previous MSD methods that directly transfer the pre-trained object detectors from existing categories to new categories, we propose a more reasonable and robust objectness transfer approach for MSD. In our framework, we first learn domain invariant objectness knowledge from the existing fully labeled categories. The knowledge is modeled based on invariant features that are robust to the distribution discrepancy between the existing categories and new categories; therefore the resulting knowledge would generalize well to new categories and could assist detection models to reject distractors (e.g., object parts) in weakly labeled images of new categories. Under the guidance of learned objectness knowledge, we utilize multiple instance learning (MIL) to model the concepts of both objects and distractors and to further improve the ability of rejecting distractors in weakly labeled images. Our robust objectness transfer approach outperforms the existing MSD methods, and achieves state-of-the-art results on the challenging ILSVRC2013 detection dataset and the PASCAL VOC datasets. PMID- 29994280 TI - Predictor-Based Extended-State-Observer Design for Consensus of MASs With Delays and Disturbances. AB - In this paper, we study output feedback leader-follower consensus problem for multiagent systems subject to external disturbances and time delays in both input and output. First, we consider the linear case and a novel predictor-based extended state observer is designed for each follower with relative output information of the neighboring agents. Then, leader-follower consensus protocols are proposed which can compensate the delays and disturbances efficiently. In particular, the proposed observer and controller do not contain any integral term of the past control input and hence are easy to implement. Consensus analysis is put in the framework of Lyapunov-Krasovskii functionals and sufficient conditions are derived to guarantee that the consensus errors converge to zero asymptotically. Then, the results are extended to nonlinear multiagent systems with nonlinear disturbances. Finally, the validity of the proposed design is demonstrated through a numerical example of network-connected unmanned aerial vehicles. PMID- 29994286 TI - Ordinal Constraint Binary Coding for Approximate Nearest Neighbor Search. AB - Binary code learning, a.k.a. hashing, has been successfully applied to the approximate nearest neighbor search in largescale image collections. The key challenge lies in reducing the quantization error from the original real-valued feature space to a discrete Hamming space. Recent advances in unsupervised hashing advocate the preservation of ranking information, which is achieved by constraining the binary code learning to be correlated with pairwise similarity. However, few unsupervised methods consider the preservation of ordinal relations in the learning process, which serves as a more basic cue to learn optimal binary codes. In this paper, we propose a novel hashing scheme, termed Ordinal Constraint Hashing (OCH), which embeds the ordinal relation among data points to preserve ranking into binary codes. The core idea is to construct an ordinal graph via tensor product, and then train the hash function over this graph to preserve the permutation relations among data points in the Hamming space. Subsequently, an in-depth acceleration scheme, termed Ordinal Constraint Projection (OCP), is introduced, which approximates the n-pair ordinal graph by L pair anchor-based ordinal graph, and reduce the corresponding complexity from Finally, to make the optimization tractable, we further relax the discrete constrains and design a customized stochastic gradient decent algorithm on the Stiefel manifold. Experimental results on serval large-scale benchmarks demonstrate that the proposed OCH method can achieve superior performance over the state-of-the-art approaches. PMID- 29994287 TI - Interactive Partitioning of 3D Models into Printable Parts. AB - In this paper, we present an easy, flexible and interactive tool for partitioning a 3D model, which is larger than 3D-printers working volume, into printable parts in an intuitive way. Our presented tool is based on the elegant partitioning optimization framework Chopper. Our tool aims at improving Chopper by providing users three easy-to-use interactive operations: no-go region painting, cutting plane specification and components re-union. With these operations, we show that (1) exhaustive search in the BSP tree --- the most time-consuming step in Chopper --- can be avoided, (2) more flexible geometric configurations can be provided, (3) users design intention is considered naturally and efficiently, and customized 3D partitioning results can be obtained. We test our tool on a wide range of 3D models and observe promising results. A preliminary user study also demonstrates its effectiveness and efficiency. PMID- 29994283 TI - Dynamic Boundary Fuzzy Control Design of Semilinear Parabolic PDE Systems With Spatially Noncollocated Discrete Observation. AB - The problem of dynamic boundary fuzzy control design is investigated in this paper for nonlinear parabolic partial differential equation (PDE) systems with spatially noncollocated discrete observation. Two cases of noncollocated discrete observation in space (i.e., pointwise observation in space and local piecewise uniform observation in space) are considered, respectively. The spatially noncollocated discrete observation makes the control design very difficult. Such design difficulty can be surmounted by an observer-based feedback control technique. It is assumed that the semilinear PDEs are accurately represented by a Takagi-Sugeno fuzzy PDE model. On the basis of the obtained fuzzy PDE model, a fuzzy Luenberger-type PDE state observer with above two cases of noncollocated discrete observation in space is first proposed for exponential estimation of the PDE system state. An observer-based dynamic fuzzy controller is then constructed such that the resulting closed-loop system is exponentially stable. Sufficient conditions on existence of such fuzzy controller are developed by Lyapunov technique with variations of vector-valued Poincare-Wirtinger inequality, and presented in terms of linear matrix inequalities. Finally, extensive numerical simulation results of two examples are provided to support the proposed design method. PMID- 29994292 TI - Distributed Online One-Class Support Vector Machine for Anomaly Detection Over Networks. AB - Anomaly detection has attracted much attention in recent years since it plays a crucial role in many domains. Various anomaly detection approaches have been proposed, among which one-class support vector machine (OCSVM) is a popular one. In practice, data used for anomaly detection can be distributively collected via wireless sensor networks. Besides, as the data usually arrive at the nodes sequentially, online detection method that can process streaming data is preferred. In this paper, we formulate a distributed online OCSVM for anomaly detection over networks and get a decentralized cost function. To get the decentralized implementation without transmitting the original data, we use a random approximate function to replace the kernel function. Furthermore, to find an appropriate approximate dimension, we add a sparse constraint into the decentralized cost function to get another one. Then we minimize these two cost functions by stochastic gradient descent and derive two distributed algorithms. Some theoretical analysis and experiments are performed to show the effectiveness of the proposed algorithms. Experimental results on both synthetic and real datasets reveal that both of the proposed algorithms achieve low misdetection rates and high true positive rates. Compared with other state-of-the-art anomaly detection methods, the proposed distributed algorithms not only show good anomaly detection performance, but also require relatively short running time and low CPU memory consumption. PMID- 29994288 TI - Non-Contact Thermo-Visual Augmentation by IR-RGB Projection. AB - This paper presents an approach for non-contact haptic augmentation with spatial augmented reality (SAR). We construct a thermo-visual projection system by combining a standard RGB projector and a fabricated infrared (IR) projector. The primary contribution of this paper is that we conduct thorough psychophysical experiments to investigate a design guideline for spatiotemporal projection patterns for both RGB and IR projectors to render a warm object with high presence. We develop application systems to evaluate the validity of the proposed system and design guideline. The evaluation results demonstrate that the proposed system can render warm objects with significantly higher presence than a standard SAR system. PMID- 29994289 TI - Haptic Augmentation for Teleoperation through Virtual Grasping Points. AB - Future challenges in teleoperation arise from a new complexity of tasks and from constraints in unstructured environments. In industrial applications as nuclear research facilities, the operator has to manipulate large objects whereas medical robotics requires extremely high precision. In the last decades, research optimized the transparency in teleoperation setups through accurate hardware, higher sampling rates, and improved sensor technologies. To further enhance the performance in telemanipulation, the idea of haptic augmentation has been briefly introduced in [Panzirsch et al., IEEE ICRA, 2015, pp. 312-317]. Haptic augmentation provides supportive haptic cues to the operator that promise to ease the task execution and increase the control accuracy. Therefore, an additional haptic interface can be added into the control loop. The present paper introduces the stability analysis of the resulting multilateral framework and equations for multi-DoF coupling and time delay control. Furthermore, a detailed analysis via experiments and a user study is presented. The control structure is designed in the network representation and based on passive modules. Through this passivity based modular design, a high adaptability to new tasks and setups is achieved. The results of the user study indicate that the bimanual control brings large benefits especially in improving rotational precision. PMID- 29994290 TI - A Comprehensive Look at Coding Techniques on Riemannian Manifolds. AB - Core to many learning pipelines is visual recognition such as image and video classification. In such applications, having a compact yet rich and informative representation plays a pivotal role. An underlying assumption in traditional coding schemes [e.g., sparse coding (SC)] is that the data geometrically comply with the Euclidean space. In other words, the data are presented to the algorithm in vector form and Euclidean axioms are fulfilled. This is of course restrictive in machine learning, computer vision, and signal processing, as shown by a large number of recent studies. This paper takes a further step and provides a comprehensive mathematical framework to perform coding in curved and non Euclidean spaces, i.e., Riemannian manifolds. To this end, we start by the simplest form of coding, namely, bag of words. Then, inspired by the success of vector of locally aggregated descriptors in addressing computer vision problems, we will introduce its Riemannian extensions. Finally, we study Riemannian form of SC, locality-constrained linear coding, and collaborative coding. Through rigorous tests, we demonstrate the superior performance of our Riemannian coding schemes against the state-of-the-art methods on several visual classification tasks, including head pose classification, video-based face recognition, and dynamic scene recognition. PMID- 29994293 TI - Adaptive Bi-Weighting Toward Automatic Initialization and Model Selection for HMM Based Hybrid Meta-Clustering Ensembles. AB - Temporal data clustering can provide underpinning techniques for the discovery of intrinsic structures, which proved important in condensing or summarizing information demanded in various fields of information sciences, ranging from time series analysis to sequential data understanding. In this paper, we propose a novel hidden Markov model (HMM)-based hybrid meta-clustering ensemble with bi weighting scheme to solve the problems of initialization and model selection associated with temporal data clustering. To improve the performance of the ensemble techniques, the proposed bi-weighting scheme adaptively examines the partition process and hence optimizes the fusion of consensus functions. Specifically, three consensus functions are used to combine the input partitions, generated by HMM-based K-models under different initializations, into a robust consensus partition. An optimal consensus partition is then selected from the three candidates by a normalized mutual information-based objective function. Finally, the optimal consensus partition is further refined by the HMM-based agglomerative clustering algorithm in association with dendrogram-based similarity partitioning algorithm, leading to the advantage that the number of clusters can be automatically and adaptively determined. Extensive experiments on synthetic data, time series, and real-world motion trajectory datasets illustrate that our proposed approach outperforms all the selected benchmarks and hence providing promising potentials for developing improved clustering tools for information analysis and management. PMID- 29994291 TI - Physical Activity Classification for Elderly People in Free Living Conditions. AB - Physical activity is strongly linked with mental and physical health in the elderly population and accurate monitoring of activities of daily living (ADLs) can help improve quality of life and well-being. This study presents and validates an inertial sensors-based physical activity classification system developed with older adults as the target population. The dataset was collected in free living conditions without placing constraints on the way and order of performing ADLs. Four sensor locations (chest, lower back, wrist, and thigh) were explored to obtain the optimal number and combination of sensors by finding the best tradeoff between the system's performance and wearability. Several feature selection techniques were implemented on the feature set obtained from acceleration and angular velocity signals to classify four major ADLs (sitting, standing, walking, and lying). Support vector machine was used for the classification of the ADLs. The findings show the potential of different solutions (single-sensor or multi-sensor) to correctly classify the ADLs of older people in free living conditions. Considering a minimal set-up of a single sensor, the sensor worn at the L5 achieved the best performance. A two-sensor solution (L5 + thigh) achieved a better performance with respect to a single sensor solution. On the other hand, considering more than two sensors did not provide further improvements. Finally, we evaluated the computational cost of different solutions and it was shown that a feature selection step can reduce the computational cost of the system and increase the system performance in most cases. This can be helpful for real-time applications. PMID- 29994294 TI - Low-Rank 2-D Neighborhood Preserving Projection for Enhanced Robust Image Representation. AB - 2-D neighborhood preserving projection (2DNPP) uses 2-D images as feature input instead of 1-D vectors used by neighborhood preserving projection (NPP). 2DNPP requires less computation time than NPP. However, both NPP and 2DNPP use the L2 norm as a metric, which is sensitive to noise in data. In this paper, we proposed a novel NPP method called low-rank 2DNPP (LR-2DNPP). This method divided the input data into a component part that encoded low-rank features, and an error part that ensured the noise was sparse. Then, a nearest neighbor graph was learned from the clean data using the same procedure as 2DNPP. To ensure that the features learned by LR-2DNPP were optimal for classification, we combined the structurally incoherent learning and low-rank learning with NPP to form a unified model called discriminative LR-2DNPP (DLR-2DNPP). By encoding the structural incoherence of the learned clean data, DLR-2DNPP could enhance the discriminative ability for feature extraction. Theoretical analyses on the convergence and computational complexity of LR-2DNPP and DLR-2DNPP were presented in details. We used seven public image databases to verify the performance of the proposed methods. The experimental results showed the effectiveness of our methods for robust image representation. PMID- 29994295 TI - A Fast Distributed Variational Bayesian Filtering for Multisensor LTV System With Non-Gaussian Noise. AB - For multisensor linear time-varying system with non-Gaussian measurement noise, how to design distributed robust estimator to increase the accuracy and robustness to outliers at a relatively low computation and communication cost is a fundamental task. This paper proposes a fast distributed variational Bayesian (VB) filtering algorithm to recursively estimate the state and noise distribution over three conventional sensor networks: 1) incremental-based; 2) diffusion based; and 3) consensus-based. To be specific, the non-Gaussian measurement noise of each sensor is modeled as Student-t distribution, and the system state and the parameters of the distribution are estimated via VB approach in each iteration step. An interaction scheme is then added to obtain the global optimal parameter by fusing the local optimal parameters over incremental, diffusion, and consensus communication topology. An efficient sensor selection criterion under these topologies based on the Cramer-Rao lower bound is proposed to reduce the communication and computation burden. Compared with the existing centralized VB filtering algorithms, the proposed algorithm in this paper can extensively increase the robustness to node or link failure at a lower computation cost with acceptable estimation performance and communication load. The theoretic results and simulation results are given to show the efficiency of our proposed algorithm. PMID- 29994296 TI - Reliable Control Policy of Cyber-Physical Systems Against a Class of Frequency Constrained Sensor and Actuator Attacks. AB - This paper is concerned with reliable control problems of cyber-physical systems against a class of frequency-constrained sensor and actuator attacks. We consider a continuous-time linear physical system equipped with an observer-based abnormal detector, and it is assumed that control signals and partial sensor outputs transmitted via network layers are vulnerable to cyber attacks. With the use of detection mechanisms of the abnormal monitor, an upper bound of the worst stealthy attacks is obtained, which is composed of the information of the detector's threshold, the attack's structure, and frequency characteristic. By exploiting the bound information, a novel attack compensator, which can stabilize the system with a nearly desired system performance, is proposed for a situation where an attack may occur without triggering an alarm. Finally, the effectiveness of the proposed control policy is verified by a numerical example. PMID- 29994297 TI - CNN-based Real-time Dense Face Reconstruction with Inverse-rendered Photo realistic Face Images. AB - With the powerfulness of convolution neural networks (CNN), CNN based face reconstruction has recently shown promising performance in reconstructing detailed face shape from 2D face images. The success of CNN-based methods relies on a large number of labeled data. The state-of-the-art synthesizes such data using a coarse morphable face model, which however has difficulty to generate detailed photo-realistic images of faces (with wrinkles). This paper presents a novel face data generation method. Specifically, we render a large number of photo-realistic face images with different attributes based on inverse rendering. Furthermore, we construct a fine-detailed face image dataset by transferring different scales of details from one image to another. We also construct a large number of video-type adjacent frame pairs by simulating the distribution of real video data. With these nicely constructed datasets, we propose a coarse-to-fine learning framework consisting of three convolutional networks. The networks are trained for real-time detailed 3D face reconstruction from monocular video as well as from a single image. Extensive experimental results demonstrate that our framework can produce high-quality reconstruction but with much less computation time compared to the state-of-the-art. Moreover, our method is robust to pose, expression and lighting due to the diversity of data. PMID- 29994298 TI - Video Object Segmentation Without Temporal Information. AB - Video Object Segmentation, and video processing in general, has been historically dominated by methods that rely on the temporal consistency and redundancy in consecutive video frames. When temporal smoothness is suddenly broken, such as when an object is occluded, the result of these methods can deteriorate significantly. This paper explores the orthogonal approach of processing each frame independently, i.e. disregarding temporal information. In particular, it tackles the task of semi-supervised video object segmentation: the separation of an object from the background in a video, given its mask in the first frame. We present Semantic One-Shot Video Object Segmentation (OSVOS ), based on a fully convolutional neural network architecture that is able to successively transfer generic semantic information, learned on ImageNet, to the task of foreground segmentation, and finally to learning the appearance of a single annotated object of the test sequence (hence one shot). We show that instance-level semantic information, when combined effectively, can dramatically improve the results of our previous method, OSVOS. We perform experiments on two recent single-object video segmentation databases, which show that OSVOS is both the fastest and most accurate method in the state of the art. Experiments on multi-object video segmentation show that OSVOS obtains competitive results. PMID- 29994299 TI - Content Aware Image Pre-Compensation. AB - The goal of image pre-compensation is to process an image such that after being convolved with a known kernel, will appear close to the sharp reference image. In a practical setting, the pre-compensated image has significantly higher dynamic range than the latent image. As a result, some form of tone mapping is needed. In this paper, we show how global tone mapping functions affect contrast and ringing in image pre-compensation. We further enhance contrast and reduce ringing by considering the visual saliency. Specifically, we prioritize contrast preservation in salient regions while tolerating more blurriness elsewhere. For quantitative analysis, we design new metrics to measure the contrast of an image with ringing. Specifically, we set out to find its "equivalent ringing-free" image that matches its intensity histogram and uses its contrast as the measure. We illustrate our approach on projector defocus compensation and visual acuity enhancement. Compared with the state-of-the-art, our approach significantly improves the contrast. We also perform user studies to demonstrate that our method can effectively improve the viewing experience for users with impaired vision. PMID- 29994300 TI - Monocular Depth Estimation using Multi-Scale Continuous CRFs as Sequential Deep Networks. AB - Depth cues have been proved very useful in various computer vision and robotic tasks. This paper addresses the problem of monocular depth estimation from a single still image. Inspired by the effectiveness of recent works on multi-scale convolutional neural networks (CNN), we propose a deep model which fuses complementary information derived from multiple CNN side outputs. Different from previous methods using concatenation or weighted average schemes, the integration is obtained by means of continuous Conditional Random Fields (CRFs). In particular, we propose two different variations, one based on a cascade of multiple CRFs, the other on a unified graphical model. By designing a novel CNN implementation of mean-field updates for continuous CRFs, we show that both proposed models can be regarded as sequential deep networks and that training can be performed end-to-end. Through an extensive experimental evaluation, we demonstrate the effectiveness of the proposed approach and establish new state of the art results for the monocular depth estimation task on three publicly available datasets, i.e. NYUD-V2, Make3D and KITTI. PMID- 29994301 TI - Piecewise Flat Embedding for Image Segmentation. AB - We propose a new multi-dimensional nonlinear embedding -- Piecewise Flat Embedding (PFE) -- for image segmentation. Based on the theory of sparse signal recovery, piecewise flat embedding with diverse channels attempts to recover a piecewise constant image representation with sparse region boundaries and sparse cluster value scattering. The resultant piecewise flat embedding exhibits interesting properties such as suppressing slowly varying signals, and offers an image representation with higher region identifiability which is desirable for image segmentation or high-level semantic analysis tasks. We formulate our embedding as a variant of the Laplacian Eigenmap embedding with an - regularization term to promote sparse solutions. First, we devise a two-stage numerical algorithm based on Bregman iterations to compute L1,1-regularized piecewise flat embeddings. We further generalize this algorithm through iterative reweighting to solve the general L1,p-regularized problem. To demonstrate its efficacy, we integrate PFE into two existing image segmentation frameworks, segmentation based on clustering and hierarchical segmentation based on contour detection. Experiments on four major benchmark datasets, BSDS500, MSRC, Stanford Background Dataset, and PASCAL Context, show that segmentation algorithms incorporating our embedding achieve significantly improved results. PMID- 29994302 TI - Deep Learning Techniques for Automatic MRI Cardiac Multi-Structures Segmentation and Diagnosis: Is the Problem Solved? AB - Delineation of the left ventricular cavity, myocardium, and right ventricle from cardiac magnetic resonance images (multi-slice 2-D cine MRI) is a common clinical task to establish diagnosis. The automation of the corresponding tasks has thus been the subject of intense research over the past decades. In this paper, we introduce the "Automatic Cardiac Diagnosis Challenge" dataset (ACDC), the largest publicly available and fully annotated dataset for the purpose of cardiac MRI (CMR) assessment. The dataset contains data from 150 multi-equipments CMRI recordings with reference measurements and classification from two medical experts. The overarching objective of this paper is to measure how far state-of the-art deep learning methods can go at assessing CMRI, i.e., segmenting the myocardium and the two ventricles as well as classifying pathologies. In the wake of the 2017 MICCAI-ACDC challenge, we report results from deep learning methods provided by nine research groups for the segmentation task and four groups for the classification task. Results show that the best methods faithfully reproduce the expert analysis, leading to a mean value of 0.97 correlation score for the automatic extraction of clinical indices and an accuracy of 0.96 for automatic diagnosis. These results clearly open the door to highly accurate and fully automatic analysis of cardiac CMRI. We also identify scenarios for which deep learning methods are still failing. Both the dataset and detailed results are publicly available online, while the platform will remain open for new submissions. PMID- 29994303 TI - A Dedicated 36-Channel Receive Array for Fetal MRI at 3T. AB - Due to a lack of fetal imaging coils, the standard commercial abdominal coil is often used for fetal imaging, the performance of which is limited by its insufficient coverage, element number, and Signal-to-noise ratio (SNR). In this paper, a dedicated 36-channel coil array, of which size can best fit the body sizes of pregnancy gestation from 20 to 37+ weeks, was designed for fetal imaging at 3T. SNR with full phase encoding and G-factor denoted as noise amplification for parallel imaging were quantitatively evaluated by phantom studies. Compared with a commercial abdominal coil array, the proposed 36-channel fetal array provides not only SNR improvements in full phase encoding (with 10% in the region where the whole fetal body was located, and up to 40% in the edge region where the fetal brain and heart may appear) but also an augmented parallel imaging capability and remarkable SNR improvements at high acceleration factors. PMID- 29994304 TI - High-Volume-Rate 3-D Ultrasound Imaging Based on Synthetic Aperture Sequential Beamforming With Chirp-Coded Excitation. AB - Three-dimensional (3-D) ultrasound imaging is a promising modality for many medical applications. Unfortunately, it generates voluminous data in the front end, making it unattractive for high-volume-rate portable medical applications. We apply synthetic aperture sequential beamforming (SASB) to greatly compress the front-end receive data. Baseline 3-D SASB has a low volume rate, because subapertures fire one by one. In this paper, we propose to increase the volume rate of 3-D SASB without degrading imaging quality through: 1) transmitting and receiving simultaneously with four subapertures and 2) using linear chirps as the excitation waveform to reduce interference. We design four linear chirps that operate on two overlapped frequency bands with chirp pairs in each band having opposite chirp rates. Direct implementation of this firing scheme results in grating lobes. Therefore, we design a sparse array that mitigates the grating lobe levels through optimizing the locations of transducer elements in the bin based random array. Compared with the baseline 3-D SASB, the proposed method increases the volume rate from 8.56 to 34.2 volumes/s without increasing the front-end computation requirement. Field-II-based cyst simulations show that the proposed method achieves imaging quality comparable with baseline 3-D SASB in both shallow and deep regions. PMID- 29994305 TI - AlN/ZnO/LiNbO3 Packageless Structure as a Low-Profile Sensor for Potential On Body Applications. AB - Surface acoustic wave sensors find their application in a growing number of fields. This interest stems in particular from their passive nature and the possibility of remote interrogation. Still, the sensor package, due to its size, remains an obstacle for some applications. In this regard, packageless solutions are very promising. This paper describes the potential of the AlN/ZnO/LiNbO3 structure for packageless acoustic wave sensors. This structure, based on the waveguided acoustic wave principle, is studied numerically and experimentally. According to the COMSOL simulations, a wave, whose particle displacement is similar to a Rayleigh wave, is confined within the structure when the AlN film is thick enough. This result is confirmed by comprehensive experimental tests, thus proving the potential of this structure for packageless applications, notably temperature sensing. PMID- 29994306 TI - Computer-Aided Theragnosis Based on Tumor Volumetric Information in Breast Cancer. AB - OBJECTIVE: A computer-assisted technology has recently been proposed for the assessment of therapeutic responses to neoadjuvant chemotherapy in patients with locally advanced breast cancer (LABC). The system, however, extracted features from individual scans in a tumor irrespective of its relation to the other scans of the same patient, ignoring the volumetric information. This study addresses this problem by introducing a novel engineered texton-based method in order to account for volumetric information in the design of textural descriptors to represent tumor scans. METHODS: A noninvasive computer-aided-theragnosis (CAT) system was developed by employing multiparametric QUS spectral and backscatter coefficient maps. The proceeding was composed of two subdictionaries: one built on the "pretreatment" and another on "week " scans, where was 1, 4, or 8. The learned dictionary of each patient was subsequently used to compute the model (histogram of textons) for each scan of the patient. Advanced machine learning techniques including a kernel-based dissimilarity measure to estimate the distances between "pretreatment" and "mid-treatment" scans as an indication of treatment effectiveness, learning from imbalanced data, and supervised learning were subsequently employed on the texton-based features. RESULTS: The performance of the CAT system was tested using statistical tests of significance and leave one-subject-out (LOSO) classification on 56 LABC patients. The proposed texton based CAT system indicated significant differences in changes between the responding and nonresponding patient populations and achieved high accuracy, sensitivity, and specificity in discriminating between the two patient groups early after the start of treatment, i.e., on weeks 1 and 4 of several months of treatment. Specifically, the CAT system achieved the area under curve of 0.81, 0.83, and 0.85 on weeks 1, 4, and 8, respectively. CONCLUSION: The proposed texton-based CAT system accounted for the volumetric information in "pretreatment" and "mid-treatment" scans of each patient. It was demonstrated that this attribute of the CAT system could boost its performance compared to the cases that the features were extracted from solely individual scans. PMID- 29994307 TI - Compact Intrinsically Switchable FBAR Filters Utilizing Ferroelectric BST. AB - Intrinsically switchable thin film bulk acoustic resonator (FBAR) filters based on ferroelectric barium strontium titanate (BST) are presented. A 1.5-stage network intrinsically switchable FBAR filter unit cell with a 3-dB fractional bandwidth of 3% at 2 GHz is systematically designed, simulated, and fabricated. The minimum insertion loss (IL) for the filter unit cell is 2.25 dB, representing the lowest IL reported for BST bulk acoustic wave filters to date, which is mainly due to its high BST resonators. Two 1.5-stage filter unit cells are connected in series to form a 2.5-stage filter, providing more than 25 dB of out of-band rejection and OFF-state isolation between the input and the output ports. The measured input third-order intercept point (IIP3) of the 2.5-stage filter is 47 dBm. Furthermore, the footprint of the fabricated filters is notably small, due to the high permittivity of BST. PMID- 29994308 TI - An Unsupervised Game-Theoretic Approach to Saliency Detection. AB - We propose a novel unsupervised game-theoretic salient object detection algorithm that does not require labeled training data. First, saliency detection problem is formulated as a non-cooperative game, hereinafter referred to as Saliency Game, in which image regions are players who choose to be "background" or "foreground" as their pure strategies. A payoff function is constructed by exploiting multiple cues and combining complementary features. Saliency maps are generated according to each region's strategy in the Nash equilibrium of the proposed Saliency Game. Second, we explore the complementary relationship between color and deep features and propose an Iterative Random Walk algorithm to combine saliency maps produced by the Saliency Game using different features. Iterative random walk allows sharing information across feature spaces, and detecting objects that are otherwise very hard to detect. Extensive experiments over 6 challenging datasets demonstrate the superiority of our proposed unsupervised algorithm compared to several state of the art supervised algorithms. PMID- 29994309 TI - Landmark Free Face Attribute Prediction. AB - Face attribute prediction in the wild is important for many facial analysis applications yet it is very challenging due to ubiquitous face variations. In this paper, we address face attribute prediction in the wild by proposing a novel method, lAndmark Free Face AttrIbute pRediction (AFFAIR). Unlike traditional face attribute prediction methods that require facial landmark detection and face alignment, AFFAIR uses an endto- end learning pipeline to jointly learn a hierarchy of spatial transformations that optimize facial attribute prediction with no reliance on landmark annotations or pre-trained landmark detectors. AFFAIR achieves this through simultaneously 1) learning a global transformation which effectively alleviates negative effect of global face variation for the following attribute prediction tailored for each face, 2) locating the most relevant facial part for attribute prediction and 3) aggregating the global and local features for robust attribute prediction. Within AFFAIR, a new competitive learning strategy is developed that effectively enhances global transformation learning for better attribute prediction. We show that with zero information about landmarks, AFFAIR achieves state-of-the-art performance on three face attribute prediction benchmarks, which simultaneously learns the face-level transformation and attribute-level localization within a unified framework. PMID- 29994310 TI - Classification of Blood Flow Patterns in Cerebral Aneurysms. AB - We present a Cerebral Aneurysm Vortex Classification (CAVOCLA) that allows to classify blood flow in cerebral aneurysms. Medical studies assume a strong relation between the progression and rupture of aneurysms and flow patterns. To understand how flow patterns impact the vessel morphology, they are manually classified according to predefined classes. However, manual classifications are time-consuming and exhibit a high inter-observer variability. In contrast, our approach is more objective and faster than manual methods. The classification of integral lines, representing steady or unsteady blood flow, is based on a mapping of the aneurysm surface to a hemisphere by calculating polar-based coordinates. The lines are clustered and for each cluster a representative is calculated. Then, the polar-based coordinates are transformed to the representative as basis for the classification. Classes are based on the flow complexity. The classification results are presented by a detail-on-demand approach using a visual transition from the representative over an enclosing surface to the associated lines. Based on seven representative datasets, we conduct an informal interview with five domain experts to evaluate the system. They confirmed that CAVOCLA allows for a robust classification of intra-aneurysmal flow patterns. The detail-on-demand visualization enables an efficient exploration and interpretation of flow patterns. PMID- 29994311 TI - 3D Tooth Segmentation and Labeling using Deep Convolutional Neural Networks. AB - In this paper, we present a novel approach for 3D dental model segmentation via deep Convolutional Neural Networks (CNNs). Traditional geometry-based methods tend to receive undesirable results due to the complex appearance of human teeth (e.g., missing/rotten tooth, feature-less regions, crowding teeth, extra medical attachments, etc.). To address these issues, we propose to learn a generic and robust segmentation model by exploiting deep neural networks, namely NNs. To this end, we extensively experiment with various network structures, and eventually arrive at a two-level hierarchical CNNs structure for tooth segmentation: one for teeth-gingiva labelling and the other for inter-teeth labelling. Further, we propose a novel boundary-aware tooth simplification method to significantly improve efficiency in the stage of feature extraction. After CNNs prediction, we do graph-based label optimization and further refine the boundary with an improved version of fuzzy clustering. The accuracy of our mesh labelling method exceeds that of the state-of-art geometry-base methods, reaching 99.06% measured by area which is directly applicable in orthodontic CAD systems. It is also robust to any possible foreign matters on model surface, e.g., air bubbles, dental accessories, and many more. PMID- 29994312 TI - Myoelectric Control Based on A Generic Musculoskeletal Model: Towards A Multi User Neural-Machine Interface. AB - This study aimed to develop a novel electromyography (EMG)-based neural-machine interface (NMI) that is user-generic for continuously predicting coordinated motion between metacarpophalangeal (MCP) and wrist flexion/extension. The NMI requires a minimum calibration procedure that only involves capturing maximal voluntary muscle contraction for the monitored muscles for individual users. At the center of the NMI is a user-generic musculoskeletal model based on the experimental data collected from 6 able-bodied (AB) subjects and 9 different upper limb postures. The generic model was evaluated on-line on both AB subjects and a transradial amputee. The subjects were instructed to perform a virtual hand/wrist posture matching task with different upper limb postures. The on-line performance of the generic model was also compared with that of the musculoskeletal model customized to each individual user (called "specific model"). All subjects accomplished the assigned virtual tasks while using the user-generic NMI, although the AB subjects produced better performance than the amputee subject. Interestingly, compared to the specific model, the generic model produced comparable completion time, a reduced number of overshoots, and improved path efficiency in the virtual hand/wrist posture matching task. The results suggested that it is possible to design an EMG-driven NMI based on a musculoskeletal model that could fit multiple users, including upper limb amputees, for predicting coordinated MCP and wrist motion. The present new method might address the challenges of existing advanced EMG-based NMI that require frequent and lengthy customization and calibration. Our future research will focus on evaluating the developed NMI for powered prosthetic arms. PMID- 29994313 TI - Reshaping Movement Distributions With Limit-Push Robotic Training. AB - High-cost situations need to be avoided. However, occasionally, cost may only be learned by experience. Here, we tested whether an artificially induced unstable and invisible high-cost region, a "limit-push" force field, might reshape people's motion distributions. Healthy and neurologically impaired (chronic stroke) populations attempted 600 interceptions of a projectile while holding a robot handle that could render forces to the hand. The "limit-push," in the middle of the study, pushed the hand outward unless the hand stayed within a box shaped region. Both healthy and some stroke survivors adapted through selection of safer actions, avoiding the high-cost regions (outside the box); they stayed more inside and even kept a greater distance from the box's boundaries. This was supported by other measures that showed subjects distributed their hand movements within the box more uniformly. These effects lasted a very short time after returning to the no-force condition. Although most robotic teaching approaches focus on shifting the mean, this limit-push treatment demonstrates how both mean and variance might be reshaped in motor training and neurorehabilitation. PMID- 29994314 TI - A Fungus Spores Dataset and a Convolutional Neural Network Based Approach for Fungus Detection. AB - Fungus is enormously notorious for food, human health, and archives. Fungus sign and symptoms in medical science are non-specific and asymmetrical for extremely large areas resulting into a challenging task of fungal detection. Various traditional and computer vision techniques were applied to meet the challenge of early fungus detection. On the other hand, features learned through the convolutional neural network (CNN) provided state-of-the-art results in many other applications of object detection and classification. However, the large amount of data is an essential prerequisite for its effective application. In pursuing this idea, we present a novel fungus dataset of its kind, with the goal of advancing the state of the art in fungus classification by placing the question of fungus detection. This is achieved by gathering various images of complex fungal spores by extracting samples from contaminated fruits, archives, and laboratory-incubated fungus colonies. These images primarily consisted of five different types of fungus spores and dirt. An optical sensor system was utilized to obtain these images, which were further annotated to mark fungal spores as a region of interest using specially designed graphical user interface. As a result, 40,800 labeled images were used to develop the fungus dataset to aid in precise fungus detection and classification. The other main objective of this research was to develop a CNN-based approach for the detection of fungus and distinguish different types of fungus. A CNN architecture was designed, and it showed the promising results with an accuracy of 94.8%. The obtained results proved the possibility of early detection of several types of fungus spores using CNN and could estimate all possible threats due to fungus. PMID- 29994315 TI - Single-Trial Classification of fNIRS Signals in Four Directions Motor Imagery Tasks Measured From Prefrontal Cortex. AB - As a promising non-invasive technique, functional near-infrared spectroscopy (fNIRS) can easily detect the hemodynamic responses of cortical brain activities. This paper investigated the multiclass classification of motor imagery (MI) based on fNIRS; ten healthy individuals were recruited to move an object using their imagination. A multi-channel continuous-wave fNIRS equipment was applied to obtain the signals from the prefrontal cortex. A combination of ensemble empirical mode decomposition and independent component analysis method was used to solve the signal-noise frequency spectrum aliasing issues caused by the Mayer wave (0.1 Hz), then the signal means features were extracted as an input of linear discriminant analysis and support vector machine (SVM) classifier. The SVM classifier shows better classification results, and the average accuracies of four directions, up-down and left-right were 40.55%, 73.05%, and 70.7%, respectively, using oxygenated hemoglobin (8-21 s). This paper demonstrated that Brodmann area 4 was activated, which is consistent with previous conclusions. Furthermore, we found that the orbitofrontal cortex is also involved in MI and O2sat can also serve as a classified index. PMID- 29994316 TI - A Novel Method to Predict Knee Osteoarthritis Progression on MRI Using Machine Learning Methods. AB - This paper explored the hidden biomedical information from knee magnetic resonance (MR) images for osteoarthritis (OA) prediction. We have computed the cartilage damage index (CDI) information from 36 informative locations on tibiofemoral cartilage compartment from 3-D MR imaging and used principal component analysis (PCA) analysis to process the feature set. Four machine learning methods (artificial neural network (ANN), support vector machine, random forest, and naive Bayes) were employed to predict the progression of OA, which was measured by the change of Kellgren and Lawrence (KL) grade, Joint Space Narrowing on Medial compartment (JSM) grade, and Joint Space Narrowing on Lateral compartment (JSL) grade. To examine the different effects of medial and lateral informative locations, we have divided the 36-D feature set into a 18-D medial feature set and a 18-D lateral feature set and run the experiment on four classifiers separately. Experiment results showed that the medial feature set generated better prediction performance than the lateral feature set, while using the total 36-D feature set generated the best. PCA analysis is helpful in feature space reduction and performance improvement. For KL grade prediction, the best performance was achieved by ANN with AUC = 0.761 and F-measure = 0.714. For JSM grade prediction, the best performance was achieved by random forest with AUC = 0.785 and F-measure = 0.743, while for JSL grade prediction, the best performance was achieved by ANN with AUC = 0.695 and F-measure = 0.796. As experiment results showing that the informative locations on medial compartment provide more distinguishing features than informative locations on the lateral compartment, it could be considered to select more points from the medial compartment while reducing the number of points from the lateral compartment to improve clinical CDI design. PMID- 29994317 TI - Microaneurysm Detection Using Principal Component Analysis and Machine Learning Methods. AB - Diabetic retinopathy (DR) is an eye abnormality caused by long-term diabetes and it is the most common cause of blindness before the age of 50. Microaneurysms (MAs), resulting from leakage from retinal blood vessels, are early indicators of DR. In this paper, we analyzed MA detectability using small 25 by 25 pixel patches extracted from fundus images in the DIAbetic RETinopathy DataBase - Calibration Level 1 (DIARETDB1). Raw pixel intensities of extracted patches served directly as inputs into the following classifiers: random forest (RF), neural network, and support vector machine. We also explored the use of two techniques (principal component analysis and RF feature importance) for reducing input dimensionality. With traditional machine learning methods and leave-10 patients-out cross validation, our method outperformed a deep learning-based MA detection method, with AUC performance improved from 0.962 to 0.985 and F-measure improved from 0.913 to 0.926, using the same DIARETDB1 database. Furthermore, we validated our method on a different dataset-retinopathy online challenge (ROC) data set. The performance of the three classifiers and the pattern with different percentage of principal components are consistent on the two data sets. Especially, we trained the RF on DIARETDB1 and applied it to ROC; the performance is very similar to that of the RF trained and tested using cross validation on ROC data set. This result indicates that our method has the potential to generalize to different datasets. PMID- 29994318 TI - Systematic relations between affective and sensory material dimensions in touch. AB - Participants manually explored 47 solid, fluid and granular materials and rated them according to a list of sensory and affective attributes. In principal component analyses (PCA) of sensory ratings, we extracted six dimensions: Fluidity, Roughness, Deformability, Fibrousness, Heaviness, Granularity. PCAs on affective ratings revealed Valence, Arousal, and Dominance. PCAs explained 87% of variance or more. We found sensory dimensions beyond the surface characteristics on which many previous studies had focused, and the affective dimension of Dominance which previously had not been reported-probably due to our wide range of materials. Experiment 1 investigated a single sample, Experiment 2 distinguished between participants with more versus less outdoor experience during childhood. High correlations between scores of the two groups suggested that group differences were small. Across different experiments and groups greater Arousal was associated with more Fluidity, greater Dominance with increasing Heaviness and decreasing Deformability, and greater Granularity with more positive Valence. Participants with more outdoor experience associated fluid materials with unpleasant feelings, whereas participants with less outdoor experience rated rough materials as being unpleasant. Overall, we demonstrate that the range of affective responses to touched material is broader than previously assumed, and suggests systematic associations between specific affective and sensory dimensions. PMID- 29994319 TI - Improving Haptic Transparency for Uncertain Virtual Environments using Adaptive Control and Gain-Scheduled Prediction. AB - The realism or transparency of haptic interfaces is becoming more critical as they are applied to training in fields like minimally invasive surgery (MIS). Surgical training simulators must provide a transparent virtual environment (VE) at a high update rate. Complex, deformable, cuttable tissue models have nonlinear dynamics and are computationally expensive, making it difficult to provide sufficient update rates. The objective of this work is to improve the transparency for this type of VE by formulating the unknown nonlinear dynamics as a quasi-linear parameter varying (LPV) system and designing a predictor to provide an output at a much higher update rate. An adaptive controller based on gain-scheduled prediction is considered for a nonlinear haptic device and a nonlinear, delayed and sampled VE. The predictor uses feedback from the more accurate but slow-updating VE to update a simplified dynamic model. The predictor is designed based on numerical solutions to a linear matrix inequality derived using Lyapunov-based methods. Experimental results demonstrate the effectiveness of the gain-scheduled predictor approach and compare it to previous work using a constant-gain predictor. The gain-scheduled predictor results in significant performance improvements compared to a haptic system without prediction, but less significant improvement compared to the constant-gain approach. PMID- 29994320 TI - Mining Markov Blankets Without Causal Sufficiency. AB - Markov blankets (MBs) in Bayesian networks (BNs) play an important role in both local causal discovery and large-scale BN structure learning. Almost all existing MB discovery algorithms are designed under the assumption of causal sufficiency, which states that there are no latent common causes for two or more of the observed variables in data. However, latent common causes are ubiquitous in many applications, and hence, this assumption is often violated in practice. Thus, developing algorithms for discovering MBs without assuming causal sufficiency is of practical significance, and it is crucial for causal structure learning in real-world data. In this paper, we focus on addressing this problem. Specifically, we adopt a maximal ancestral graph (MAG) model to represent latent common causes and the concept of MBs without assuming causal sufficiency. Then, we propose an effective and efficient algorithm to discover the MB of a target variable in an MAG. Using benchmark and real-world data sets, the experiments validate the algorithm proposed in this paper. PMID- 29994321 TI - Finite-Time Passivity-Based Stability Criteria for Delayed Discrete-Time Neural Networks via New Weighted Summation Inequalities. AB - In this paper, we study the problem of finite-time stability and passivity criteria for discrete-time neural networks (DNNs) with variable delays. The main objective is how to effectively evaluate the finite-time passivity conditions for NNs. To achieve this, some new weighted summation inequalities are proposed for application to a finite-sum term appearing in the forward difference of a novel Lyapunov-Krasovskii functional, which helps to ensure that the considered delayed DNN is passive. The derived passivity criteria are presented in terms of linear matrix inequalities. A numerical example is given to illustrate the effectiveness of the proposed results. PMID- 29994322 TI - Metric Learning-Guided Least Squares Classifier Learning. AB - For a multicategory classification problem, discriminative least squares regression (DLSR) explicitly introduces an -dragging technique to enlarge the margin between the categories, yielding superior classification performance from a margin perspective. In this brief, we reconsider this classification problem from a metric learning perspective and propose a framework of metric learning guided least squares classifier (MLG-LSC) learning. The core idea is to learn a unified metric matrix for the error of LSR, such that such a metric matrix can yield small distances for the same category, while large ones for the different categories. As opposed to the -dragging in DLSR, we call this the error-dragging (e-dragging). Different from DLSR and its related variants, our MLG-LSC implicitly carries out the e-dragging and can naturally reflect the roughly relative distance relationships among the categories from a metric learning perspective. Furthermore, our optimization objective functions are strictly (geodesically) convex and thus can obtain their corresponding closed-form solutions, resulting in higher computational performance. Experimental results on a set of benchmark data sets indicate the validity of our learning framework. PMID- 29994323 TI - Supervised Saliency Map Driven Segmentation of Lesions in Dermoscopic Images. AB - Lesion segmentation is the first step in most automatic melanoma recognition systems. Deficiencies and difficulties in dermoscopic images such as color inconstancy, hair occlusion, dark corners and color charts make lesion segmentation an intricate task. In order to detect the lesion in the presence of these problems, we propose a supervised saliency detection method tailored for dermoscopic images based on the discriminative regional feature integration (DRFI). DRFI method incorporates multi-level segmentation, regional contrast, property, background descriptors, and a random forest regressor to create saliency scores for each region in the image. In our improved saliency detection method, mDRFI, we have added some new features to regional property descriptors. Also, in order to achieve more robust regional background descriptors, a thresholding algorithm is proposed to obtain a new pseudo-background region. Findings reveal that mDRFI is superior to DRFI in detecting the lesion as the salient object in dermoscopic images. The proposed overall lesion segmentation framework uses detected saliency map to construct an initial mask of the lesion through thresholding and post-processing operations. The initial mask is then evolving in a level set framework to fit better on the lesion's boundaries. The results of evaluation tests on three public datasets show that our proposed segmentation method outperforms the other conventional state-of-the-art segmentation algorithms and its performance is comparable with most recent approaches that are based on deep convolutional neural networks. PMID- 29994324 TI - Detecting Alzheimer's Disease on Small Dataset: A Knowledge Transfer Perspective. AB - Computer-aided diagnosis (CAD) is an attractive topic in Alzheimer's disease (AD) research. Many algorithms are based on a relatively large training dataset. However, small hospitals are usually unable to collect sufficient training samples for robust classification. Although data sharing is expanding in scientific research, it is unclear whether a model based on one dataset is well suited for other data sources. Using a small dataset from a local hospital and a large shared dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we conducted a heterogeneity analysis and found that different functional magnetic resonance imaging (fMRI) data sources show different sample distributions in feature space. In addition, we proposed an effective knowledge transfer method to diminish the disparity among different datasets and improve the classification accuracy on datasets with insufficient training samples. The accuracy increased by approximately 20% compared with that of a model based only on the original small dataset. The results demonstrated that the proposed approach is a novel and effective method for CAD in hospitals with only small training datasets. It solved the challenge of limited sample size in detection of AD, which is a common issue but lack of adequate attention. Furthermore, the paper sheds new light on effective use of multi-source data for neurological disease diagnosis. PMID- 29994325 TI - Fault Diagnosis of Tennessee-Eastman Process Using Orthogonal Incremental Extreme Learning Machine Based on Driving Amount. AB - Fault diagnosis is important to the industrial process. This paper proposes an orthogonal incremental extreme learning machine based on driving amount (DAOI ELM) for recognizing the faults of the Tennessee-Eastman process (TEP). The basic idea of DAOI-ELM is to incorporate the Gram-Schmidt orthogonalization method and driving amount into an incremental extreme learning machine (I-ELM). The case study for the 2-D nonlinear function and regression problems from the UCI dataset results show that DAOI-ELM can obtain better generalization ability and a more compact structure of ELM than I-ELM, convex I-ELM (CI-ELM), orthogonal I-ELM (OI ELM), and bidirectional ELM. The experimental training and testing data are derived from the simulations of TEP. The performance of DAOI-ELM is evaluated and compared with that of the back propagation neural network, support vector machine, I-ELM, CI-ELM, and OI-ELM. The simulation results show that DAOI-ELM diagnoses the TEP faults better than other methods. PMID- 29994326 TI - p-Laplacian Regularization for Scene Recognition. AB - The explosive growth of multimedia data on the Internet makes it essential to develop innovative machine learning algorithms for practical applications especially where only a small number of labeled samples are available. Manifold regularized semi-supervised learning (MRSSL) thus received intensive attention recently because it successfully exploits the local structure of data distribution including both labeled and unlabeled samples to leverage the generalization ability of a learning model. Although there are many representative works in MRSSL, including Laplacian regularization (LapR) and Hessian regularization, how to explore and exploit the local geometry of data manifold is still a challenging problem. In this paper, we introduce a fully efficient approximation algorithm of graph p-Laplacian, which significantly saving the computing cost. And then we propose p-LapR (pLapR) to preserve the local geometry. Specifically, p-Laplacian is a natural generalization of the standard graph Laplacian and provides convincing theoretical evidence to better preserve the local structure. We apply pLapR to support vector machines and kernel least squares and conduct the implementations for scene recognition. Extensive experiments on the Scene 67 dataset, Scene 15 dataset, and UC-Merced dataset validate the effectiveness of pLapR in comparison to the conventional manifold regularization methods. PMID- 29994327 TI - Retinal Vessel Segmentation Using Minimum Spanning Superpixel Tree Detector. AB - The retinal vessel is one of the determining factors in an ophthalmic examination. Automatic extraction of retinal vessels from low-quality retinal images still remains a challenging problem. In this paper, we propose a robust and effective approach that qualitatively improves the detection of low-contrast and narrow vessels. Rather than using the pixel grid, we use a superpixel as the elementary unit of our vessel segmentation scheme. We regularize this scheme by combining the geometrical structure, texture, color, and space information in the superpixel graph. And the segmentation results are then refined by employing the efficient minimum spanning superpixel tree to detect and capture both global and local structure of the retinal images. Such an effective and structure-aware tree detector significantly improves the detection around the pathologic area. Experimental results have shown that the proposed technique achieves advantageous connectivity-area-length (CAL) scores of 80.92% and 69.06% on two public datasets, namely, DRIVE and STARE, thereby outperforming state-of-the-art segmentation methods. In addition, the tests on the challenging retinal image database have further demonstrated the effectiveness of our method. Our approach achieves satisfactory segmentation performance in comparison with state-of-the art methods. Our technique provides an automated method for effectively extracting the vessel from fundus images. PMID- 29994328 TI - Deep Neuro-Cognitive Co-Evolution for Fuzzy Attribute Reduction by Quantum Leaping PSO With Nearest-Neighbor Memeplexes. AB - Attribute reduction with many patterns and indicators has been regarded as an important approach for large-scale data mining and machine learning tasks. However, it is extremely difficult for researchers to inadequately extract knowledge and insights from multiple overlapping and interdependent fuzzy datasets from the current changing and interconnected big data sources. This paper proposes a deep neuro-cognitive co-evolution for fuzzy attribute reduction (DNCFAR) that contains a combination of quantum leaping particle swarm optimization with nearest-neighbor memeplexes. A key element of DNCFAR resides in its deep neuro-cognitive cooperative co-evolution structure, which is explicitly permitted to identify interdependent variables and adaptively decompose them in the same neuro-subpopulation, with minimizing the complexity and nonseparability of interdependent variables among different fuzzy attribute subsets. Next DNCFAR formalizes to the different types of quantum leaping particles with nearest neighbor memeplexes to share their respective solutions and deeply cooperate to evolve the assigned fuzzy attribute subsets. The experimental results demonstrate that DNCFAR can achieve competitive performance in terms of average computational efficiency and classification accuracy while reinforcing noise tolerance. Furthermore, it can be well applied to clearly identify different longitudinal surfaces of infant cerebrum regions, which indicates its great potential for brain disorder prediction based on fMRI. PMID- 29994329 TI - Polya Urn Latent Dirichlet Allocation: a doubly sparse massively parallel sampler. AB - Latent Dirichlet Allocation (LDA) is a topic model widely used in natural language processing and machine learning. Most approaches to training the model rely on iterative algorithms, which makes it difficult to run LDA on big corpora that are best analyzed in parallel and distributed computational environments. Indeed, current approaches to parallel inference either don't converge to the correct posterior or require storage of large dense matrices in memory. We present a novel sampler that overcomes both problems, and we show that this sampler is faster, both empirically and theoretically, than previous Gibbs samplers for LDA. We do so by employing a novel Polya-urn-based approximation in the sparse partially collapsed sampler for LDA. We prove that the approximation error vanishes with data size, making our algorithm asymptotically exact, a property of importance for large-scale topic models. In addition, we show, via an explicit example, that -- contrary to popular belief in the topic modeling literature -- partially collapsed samplers can be more efficient than fully collapsed samplers. We conclude by comparing the performance of our algorithm with that of other approaches on well-known corpora. PMID- 29994330 TI - Unifying Visual Attribute Learning with Object Recognition in a Multiplicative Framework. AB - Attributes are mid-level semantic properties of objects. Recent research has shown that visual attributes can benefit many typical learning problems in computer vision community. However, attribute learning is still a challenging problem as the attributes may not always be predictable directly from input images and the variation of visual attributes is sometimes large across categories. In this paper, we propose a unified multiplicative framework for attribute learning, which tackles the key problems. Specifically, images and category information are jointly projected into a shared feature space, where the latent factors are disentangled and multiplied to fulfil attribute prediction. The resulting attribute classifier is category-specific instead of being shared by all categories. Moreover, our model can leverage auxiliary data to enhance the predictive ability of attribute classifiers, which can reduce the effort of instance-level attribute annotation to some extent. By integrated into an existing deep learning framework, our model can both accurately predict attributes and learn efficient image representations. Experimental results show that our method achieves superior performance on both instance-level and category level attribute prediction. For zero-shot learning based on visual attributes and human-object interaction recognition, our method can improve the state-of-the-art performance on several widely used datasets. PMID- 29994331 TI - Mask R-CNN. AB - We present a conceptually simple, flexible, and general framework for object instance segmentation. Our approach efficiently detects objects in an image while simultaneously generating a high-quality segmentation mask for each instance. The method, called Mask R-CNN, extends Faster R-CNN by adding a branch for predicting an object mask in parallel with the existing branch for bounding box recognition. Mask R-CNN is simple to train and adds only a small overhead to Faster R-CNN, running at 5 fps. Moreover, Mask R-CNN is easy to generalize to other tasks, ?eg, allowing us to estimate human poses in the same framework. We show top results in all three tracks of the COCO suite of challenges, including instance segmentation, bounding-box object detection, and person keypoint detection. Without bells and whistles, Mask R-CNN outperforms all existing, single-model entries on every task, including the COCO 2016 challenge winners. We hope our simple and effective approach will serve as a solid baseline and help ease future research in instance-level recognition. Code has been made available at: https://github.com/facebookresearch/Detectron. PMID- 29994333 TI - Constitutive Equations of Piezoelectric Layered Beams With Interdigitated Electrodes. AB - This paper establishes the constitutive equations, or linear two-port models, of piezoelectric layered beams with interdigital electrodes (IDEs). The effect of the nontrivial field on the transduction is analyzed. Based on conformal mapping techniques, we derive new analytic expressions for the capacitance, the electric field, and the electromechanical coupling factor of an anisotropic dielectric with the IDE configuration on top. The IDE capacitance with an anisotropic permittivity can be treated as the one with an isotropic permittivity. The complex expression for the nonuniform field is simplified to a quadratic form. A correction is required for the transducer's coupling constant. All modifications are expressed analytically. The analytic models are verified against the finite element method. Finally, the two-port models help to compare the devices with other electrode configurations, such as beams with a top and bottom electrode. PMID- 29994332 TI - Spatio-Temporally Constrained Reconstruction for Hyperpolarized Carbon-13 MRI Using Kinetic Models. AB - We present a method of generating spatial maps of kinetic parameters from dynamic sequences of images collected in hyperpolarized carbon-13 magnetic resonance imaging (MRI) experiments. The technique exploits spatial correlations in the dynamic traces via regularization in the space of parameter maps. Similar techniques have proven successful in other dynamic imaging problems, such as dynamic contrast enhanced MRI. In this paper, we apply these techniques for the first time to hyperpolarized MRI problems, which are particularly challenging due to limited signal-to-noise ratio (SNR). We formulate the reconstruction as an optimization problem and present an efficient iterative algorithm for solving it based on the alternation direction method of multipliers. We demonstrate that this technique improves the qualitative appearance of parameter maps estimated from low SNR dynamic image sequences, first in simulation then on a number of data sets collected in vivo. The improvement this method provides is particularly pronounced at low SNR levels. PMID- 29994334 TI - Efficiently Detecting Protein Complexes from Protein Interaction Networks via Alternating Direction Method of Multipliers. AB - Protein complexes are crucial in improving our understanding of the mechanisms employed by proteins. Various computational algorithms have thus been proposed to detect protein complexes from protein interaction networks. However, given massive protein interactome data obtained by high-throughput technologies, existing algorithms, especially those with additionally consideration of biological information of proteins, either have low efficiency in performing their tasks or suffer from limited effectiveness. For addressing this issue, this work proposes to detect protein complexes from a protein interaction network with high efficiency and effectiveness. To do so, the original detection task is first formulated into an optimization problem according to the intuitive properties of protein complexes. After that, the framework of alternating direction method of multipliers is applied to decompose this optimization problem into several subtasks, which can be subsequently solved in a separate and parallel manner. An algorithm for implementing this solution is then developed. Experimental results on five large protein interaction networks demonstrated that compared to state-of the-art protein complex detection algorithms, our algorithm outperformed them in terms of both effectiveness and efficiency. Moreover, as number of parallel processes increases, one can expect an even higher computational efficiency for the proposed algorithm with no compromise on effectiveness. PMID- 29994335 TI - Perception of ultrasonic switches involves large discontinuity of the mechanical impedance. AB - The distinct tactile feedback provided by mechanical keyboards notifies users that their actions have been successfully recorded. The presence of these subtle yet informative tactile cues is one of the reasons why mechanical keyboards are still preferred to their virtual counterparts. An artificial sensation of pressing a mechanical switch can be produced by varying the coefficient of friction as the user is pressing down on a glass surface using ultrasonic vibration. We examined the factors involved in producing a vivid sensation of a stimulus by measuring the mechanical impedance, the frictional behavior of the fingertip and the perceptual thresholds. Subjects who experienced weaker sensations also showed a weaker sensitivity to friction modulation, which may in turn be attributable to the presence of a larger or a smaller than average impedance. In the second experiment, the user's finger impedance was measured during the click, and it was observed that the successful detection of the stimulus was correlated with the presence of considerable discontinuity in the mechanical impedance added to the plate by the finger. This discontinuity in the evolution of the impedance supports the idea that the skin is being reconfigured towards a new equilibrium state after the change in friction. PMID- 29994336 TI - Quantized Sampled-Data Control for Synchronization of Inertial Neural Networks With Heterogeneous Time-Varying Delays. AB - This paper is concerned with the problem of synchronization for inertial neural networks (INNs) with heterogeneous time-varying delays (HTVDs) through quantized sampled-data control. The control scheme, which takes the communication limitations of quantization and variable sampling into account, is first employed for tackling the synchronization of INNs. A novel Lyapunov-Krasovskii functional (LKF) is constructed for synchronizing an error system. Compared with existing LKFs by the largest upper bound of all HTVDs, the proposed LKF is superior, since it can make full use of the information on the lower and upper bounds of each HTVD. Based on the LKF and a new integral inequality technique, less conservative synchronization criteria are derived. The desired quantized sampled-data controller is designed by solving a set of linear matrix inequalities. Finally, a numerical example is given to illustrate the effectiveness and conservatism reduction of the proposed results. PMID- 29994337 TI - Reconstructible Nonlinear Dimensionality Reduction via Joint Dictionary Learning. AB - This paper presents a parametric low-dimensional (LD) representation learning method that allows to reconstruct high-dimensional (HD) input vectors in an unsupervised manner. Under the assumption that the HD data and its LD representation share the same or similar local sparse structure, the proposed method achieves reconstructible dimensionality reduction via jointly learning dictionaries in both the original HD data space and its LD representation space. By regarding the sparse representation as a smooth function with respect to a specific dictionary, we construct an encoding-decoding block for learning LD representations from sparse coefficients of HD data. It is expected that this learning process preserves the desirable structure of HD data in the LD representation space, and simultaneously allows a reliable reconstruction from the LD space back to the original HD space. In addition, the proposed single layer encoding-decoding block can be easily extended to deep learning structures. Numerical experiments on both synthetic data sets and real images show that the proposed method achieves strongly competitive and robust performance in data DR, reconstruction, and synthesis, even on heavily corrupted data. The proposed method can be used as an alternative approach to compressive sensing (CS); however, it can outperform the traditional CS methods in: 1) task-driven learning problems, such as 2-D/3-D data visualization, and 2) data reconstruction at a lower dimensional space. PMID- 29994338 TI - A Discrete-Time Projection Neural Network for Sparse Signal Reconstruction With Application to Face Recognition. AB - This paper deals with sparse signal reconstruction by designing a discrete-time projection neural network. Sparse signal reconstruction can be converted into an L1-minimization problem, which can also be changed into the unconstrained basis pursuit denoising problem. To solve the L1-minimization problem, an iterative algorithm is proposed based on the discrete-time projection neural network, and the global convergence of the algorithm is analyzed by using Lyapunov method. Experiments on sparse signal reconstruction and several popular face data sets are organized to illustrate the effectiveness and performance of the proposed algorithm. The experimental results show that the proposed algorithm is not only robust to different levels of sparsity and amplitude of signals and the noise pixels but also insensitive to the diverse values of scalar weight. Moreover, the value of the step size of the proposed algorithm is close to 1/2, thus a fast convergence rate is potentially possible. Furthermore, the proposed algorithm achieves better classification performance compared with some other algorithms for face recognition. PMID- 29994339 TI - Domain-Weighted Majority Voting for Crowdsourcing. AB - Crowdsourcing labeling systems provide an efficient way to generate multiple inaccurate labels for given observations. If the competence level or the ''reputation,'' which can be explained as the probabilities of annotating the right label, for each crowdsourcing annotators is equal and biased to annotate the right label, majority voting (MV) is the optimal decision rule for merging the multiple labels into a single reliable one. However, in practice, the competence levels of annotators employed by the crowdsourcing labeling systems are often diverse very much. In these cases, weighted MV is more preferred. The weights should be determined by the competence levels. However, since the annotators are anonymous and the ground-truth labels are usually unknown, it is hard to compute the competence levels of the annotators directly. In this paper, we propose to learn the weights for weighted MV by exploiting the expertise of annotators. Specifically, we model the domain knowledge of different annotators with different distributions and treat the crowdsourcing problem as a domain adaptation problem. The annotators provide labels to the source domains and the target domain is assumed to be associated with the ground-truth labels. The weights are obtained by matching the source domains with the target domain. Although the target-domain labels are unknown, we prove that they could be estimated under mild conditions. Both theoretical and empirical analyses verify the effectiveness of the proposed method. Large performance gains are shown for specific data sets. PMID- 29994340 TI - Unsupervised Bayesian Inference to Fuse Biosignal Sensory Estimates for Personalising Care. AB - With the increase in volume of wearable sensors, there exists the possibility of personalising patient care, employing automated algorithms. However, automated algorithms are typically less reliable than gold-standard expert labels; the latter are scarce and expensive. In real-life applications, expert labels are not available, and algorithms for processing sensor data must be relied upon, without access to the "ground truth". It is therefore difficult to choose which algorithms to trust or discard at any point in time, where different algorithms may be optimal for different patients. We propose two fully-Bayesian generative models for fusing labels from (i) independent and (ii) potentially-correlated algorithms. They aggregate outputs of the algorithms in an unsupervised manner, to estimate jointly the assumed bias and precision of each algorithm without access to the ground truth. The latter fused estimate may then be used to infer the underlying ground truth. For the first time in the biomedical context, we show that modelling correlations between annotators, and fusing information concerning task difficulty (i.e., quality of the data), improves these estimates. Also, we adopt a strongly-Bayesian approach to inference using Gibbs sampling to improve estimates over the existing state-of-the-art. Our proposed models were applied to simulated and two publicly-available biomedical datasets, and showed that they outperform all existing approaches recreated from the literature. Our models are robust when dealing with missing values, and are suitably efficient for use in real-time biomedical applications, thereby providing the basis for the reliable use of sensors for personalising the care of the individual. PMID- 29994342 TI - A Clustering-Based Adaptive Evolutionary Algorithm for Multiobjective Optimization With Irregular Pareto Fronts. AB - Existing multiobjective evolutionary algorithms (MOEAs) perform well on multiobjective optimization problems (MOPs) with regular Pareto fronts in which the Pareto optimal solutions distribute continuously over the objective space. When the Pareto front is discontinuous or degenerated, most existing algorithms cannot achieve good results. To remedy this issue, a clustering-based adaptive MOEA (CA-MOEA) is proposed in this paper for solving MOPs with irregular Pareto fronts. The main idea is to adaptively generate a set of cluster centers for guiding selection at each generation to maintain diversity and accelerate convergence. We investigate the performance of CA-MOEA on 18 widely used benchmark problems. Our results demonstrate the competitiveness of CA-MOEA for multiobjective optimization, especially for problems with irregular Pareto fronts. In addition, CA-MOEA is shown to perform well on the optimization of the stretching parameters in the carbon fiber formation process. PMID- 29994341 TI - Binary Classification Using Neural and Clinical Features: An Application in Fibromyalgia with Likelihood based Decision Level Fusion. AB - Among several features used for clinical binary classification, behavioral performance, questionnaire scores, test results and physical exam reports can be counted. Attempts to include neuroimaging findings to support clinical diagnosis are scarce due to difficulties in collecting such data, as well as problems in integration of neuroimaging findings with other features. The binary classification method proposed here aims to merge small samples from multiple sites so that a large cohort which better describes the features of the disease can be built. We implemented a simple and robust framework for detection of fibromyalgia, using likelihood during decision level fusion. This framework supports sharing of classifier applications across clinical sites and arrives at a decision by fusing results from multiple classifiers. If there are missing opinions from some classifiers due to inability to collect their input features, such degradation in information is tolerated. We implemented this method using fNIRS data collected from fibromyalgia patients across three different tasks. Functional connectivity maps are derived from these tasks as features. In addition, self-reported clinical features are also used. Five classifiers are trained using kNN, LDA and SVM. Fusion of classification opinions from multiple classifiers based on log likelihood outperformed other fusion methods reported in the literature for detection of FM. When 2, 3, 4 and 5 classifers are fused, sensitivity and specificity figures of 100% could be obtained based on the choice of the classifier set. PMID- 29994343 TI - Multiobjective Sparse Non-Negative Matrix Factorization. AB - Non-negative matrix factorization (NMF) is becoming increasingly popular in many research fields due to its particular properties of semantic interpretability and part-based representation. Sparseness constraints are usually imposed on the NMF problems in order to achieve potential features and sparse representation. These constrained NMF problems are usually reformulated as regularization models to solve conveniently. However, the regularization parameters in the regularization model are difficult to tune and the frequently used sparse-inducing terms in the regularization model generally have bias effects on the induced matrix and need an extra restricted isometry property (RIP). This paper proposes a multiobjective sparse NMF paradigm which refrains from the regularization parameter issues, bias effects, and the RIP condition. A novel multiobjective memetic algorithm is also proposed to generate a set of solutions with diverse sparsity and high factorization accuracy. A masked projected gradient local search scheme is specially designed to accelerate the convergence rate. In addition, a priori knowledge is also integrated in the algorithm to reduce the computational time in discovering our interested region in the objective space. The experimental results show that the proposed paradigm has better performance than some regularization algorithms in producing solutions with different degrees of sparsity as well as high factorization accuracy, which are favorable for making the final decisions. PMID- 29994344 TI - Spectral Clustering of Customer Transaction Data With a Two-Level Subspace Weighting Method. AB - Finding customer groups from transaction data is very important for retail and e commerce companies. Recently, a ''Purchase Tree'' data structure is proposed to compress the customer transaction data and a local PurTree spectral clustering method is proposed to cluster the customer transaction data. However, in the PurTree distance, the node weights for the children nodes of a parent node are set as equal and the differences between different nodes are not distinguished. In this paper, we propose a two-level subspace weighting spectral clustering (TSW) algorithm for customer transaction data. In the new method, a PurTree subspace metric is proposed to measure the dissimilarity between two customers represented by two purchase trees, in which a set of level weights are introduced to distinguish the importance of different tree levels and a set of sparse node weights are introduced to distinguish the importance of different tree nodes in a purchase tree. TSW learns an adaptive similarity matrix from the local distances in order to better uncover the cluster structure buried in the customer transaction data. Simultaneously, it learns a set of level weights and a set of sparse node weights in the PurTree subspace distance. An iterative optimization algorithm is proposed to optimize the proposed model. We also present an efficient method to compute a regularization parameter in TSW. TSW was compared with six clustering algorithms on ten benchmark data sets and the experimental results show the superiority of the new method. PMID- 29994345 TI - UUV's Hierarchical DE-Based Motion Planning in a Semi Dynamic Underwater Wireless Sensor Network. AB - This paper describes a reflexive multilayered mission planner with a mounted energy efficient local path planner for unmanned underwater vehicle's (UUV) navigation throughout complex subsea volume in a time variant semi-dynamic operation network. The UUV routing protocol in underwater wireless sensor network is generalized with a homogeneous dynamic knapsack-traveler salesman problem emerging with an adaptive path planning mechanism to address UUV's long-duration missions on dynamically changing subsea volume. The framework includes a base layer of global path planning, an inner layer of local path planning and an environmental sublayer. Such a multilayer integrated structure facilitates the framework to adopt any algorithm with real-time performance. The evolutionary technique known as differential evolution (DE) algorithm is employed by both base and inner layers to examine the performance of the framework in efficient mission timing and its resilience against the environmental disturbances. Relying on reactive nature of the framework and fast computational performance of the DE algorithm, the simulations show promising results and this new framework guarantees a safe and efficient deployment in a turbulent uncertain marine environment passing through a proper sequence of stations considering various constraint in a complex environment. PMID- 29994346 TI - Observer-Based Event-Triggered Control for Nonlinear Systems With Mixed Delays and Disturbances: The Input-to-State Stability. AB - In this paper, the input-to-state stabilization problem is investigated for a class of nonlinear delayed systems with exogenous disturbances. The model under consideration is general that covers for both mixed time-delays and Lipschitz type nonlinearities. An observer-based controller is designed such that the closed-loop system is stable under an event-triggered mechanism. Two separate event-triggered strategies are proposed in sensor-to-observer (S/O) and controller-to-actuator (C/A) channels, respectively, in order to reduce the updating frequencies of the sensor and the controller with guaranteed performance requirements. The notion of input-to-state practical stability is introduced to characterize the performance of the controlled system that caters for the influence from both disturbances and event-triggered schemes. The estimates of the upper bounds of the delayed states and two measurement errors are employed to analyze and further exclude the Zeno behavior resulting from the proposed event triggered schemes in S/O and C/A channels. The controller gain matrices and the event-trigger parameters are co-designed in terms of the feasibility of certain matrix inequalities. A numerical simulation example is provided to illustrate the effectiveness of theoretical results. PMID- 29994347 TI - Data-Driven Methods for Stealthy Attacks on TCP/IP-Based Networked Control Systems Equipped With Attack Detectors. AB - Most of the existing stealthy attack schemes for cyber-physical systems (CPSs) are presented under the assumption that the model parameters of CPS are known to attackers. Presently, there are only a few model-independent stealthy attack approaches, which, however, need the assumption that attackers know sensor measurements and can modify them. This paper aims to remove the aforementioned conservative assumptions and give a stealthy attack methodology for closed-loop CPS with reference signals, that is, transmission control protocol/Internet protocol (TCP/IP)-based networked control systems. To this end, under the condition that the model parameters of the CPS are unknown, a benchmark platform (consisting of an attack detector and a TCP/IP-based networked dc servo system) used for testing the stealthy attack technology is constructed via data-driven methods. A plan is made, which is utilized for eavesdropping the information of the TCP/IP-based CPS. On this basis, an approach to blocking network communications and injecting the false sensor data into the CPS is explored. A closed-loop recursive identification strategy for the dynamic characteristic matrix of the CPS is designed. By employing all of the above-obtained results, a data-driven stealthy attack scheme for the CPS is proposed and, subsequently, its effectiveness and practicability are validated by experiment. PMID- 29994348 TI - Fixed-Time Stochastic Synchronization of Complex Networks via Continuous Control. AB - This paper investigates the fixed-time synchronization (FDTS) of complex networks with stochastic perturbations. A new control scheme is designed to realize the synchronization goal. Moreover, the designed controller without sign function is continuous, which means the chattering phenomenon in some previous results can be avoided. By constructing Lyapunov functionals, using the properties of the Weiner process as well as applying a designed comparison system, several FDTS criteria are obtained. Synchronization criteria of this paper are very general and can be utilized in directed and undirected weighted networks. Numerical simulations are given to illustrate the theoretical results. PMID- 29994349 TI - Input-to-State Stabilization in Probability for Nonlinear Stochastic Systems Under Quantization Effects and Communication Protocols. AB - In this paper, the observer-based stabilization problem is investigated for a class of discrete-time nonlinear stochastic networked control systems (NCSs) with exogenous disturbances. The signal transmission from the sensors to the observer is implemented via a shared digital network, in which both uniform quantization effect and stochastic communication protocol (SCP) are taken into account to reflect several network-induced constraints. The notion of input-to-state stability in probability is introduced to describe the dynamical behaviors of the closed-loop stochastic NCS that is effectively characterized by a general nonlinear stochastic difference equation with Markovian jumping parameters. A theoretical framework is first established to felicitate the dynamics analysis of the closed-loop system in virtue of the switched Lyapunov function method and the stochastic analysis techniques. By making full use of the quantized measurement output under the scheduling of the SCP, the existence conditions for an observer based controller are established under which the closed-loop system is input-to state stable in probability. Then, the explicit expression of the gain matrices of the desired controller is given by resorting to a set of feasible solutions of certain matrix inequalities. The effectiveness of the theoretical results is demonstrated by a numerical simulation example. PMID- 29994350 TI - Learning Two-Branch Neural Networks for Image-Text Matching Tasks. AB - Image-language matching tasks have recently attracted a lot of attention in the computer vision field. These tasks include image-sentence matching, i.e., given an image query, retrieving relevant sentences and vice versa, and region-phrase matching or visual grounding, i.e., matching a phrase to relevant regions. This paper investigates two-branch neural networks for learning the similarity between these two data modalities. We propose two network structures that produce different output representations. The first one, referred to as an embedding network, learns an explicit shared latent embedding space with a maximum-margin ranking loss and novel neighborhood constraints. Compared to standard triplet sampling, we perform improved neighborhood sampling that takes neighborhood information into consideration while constructing mini-batches. The second network structure, referred to as a similarity network, fuses the two branches via element-wise product and is trained with regression loss to directly predict a similarity score. Extensive experiments show that our networks achieve high accuracies for phrase localization on the Flickr30K Entities dataset and for bi directional image-sentence retrieval on Flickr30K and MSCOCO datasets. PMID- 29994351 TI - Multimodal Machine Learning: A Survey and Taxonomy. AB - Our experience of the world is multimodal - we see objects, hear sounds, feel texture, smell odors, and taste flavors. Modality refers to the way in which something happens or is experienced and a research problem is characterized as multimodal when it includes multiple such modalities. In order for Artificial Intelligence to make progress in understanding the world around us, it needs to be able to interpret such multimodal signals together. Multimodal machine learning} aims to build models that can process and relate information from multiple modalities. It is a vibrant multi-disciplinary field of increasing importance and with extraordinary potential. Instead of focusing on specific multimodal applications, this paper surveys the recent advances in multimodal machine learning itself and presents them in a common taxonomy. We go beyond the typical early and late fusion categorization and identify broader challenges that are faced by multimodal machine learning, namely: representation, translation, alignment, fusion, and co-learning. This new taxonomy will enable researchers to better understand the state of the field and identify directions for future research. PMID- 29994352 TI - Reformulating Level Sets as Deep Recurrent Neural Network Approach to Semantic Segmentation. AB - Variational Level Set (LS) has been a widely used method in medical segmentation. However, it is limited when dealing with multi-instance objects in the real world. In addition, its segmentation results are quite sensitive to initial settings and highly depend on the number of iterations. To address these issues and boost the classic variational LS methods to a new level of the learnable deep learning approaches, we propose a novel definition of contour evolution named Recurrent Level Set (RLS) 1 to employ Gated Recurrent Unit under the energy minimization of a variational LS functional. The curve deformation process in RLS is formed as a hidden state evolution procedure and updated by minimizing an energy functional composed of fitting forces and contour length. By sharing the convolutional features in a fully end-to-end trainable framework, we extend RLS to Contextual RLS (CRLS) to address semantic segmentation in the wild. The experimental results have shown that our proposed RLS improves both computational time and segmentation accuracy against the classic variational LS-based method whereas the fully end-to-end system CRLS achieves competitive performance compared to the state-of-the-art semantic segmentation approaches. PMID- 29994353 TI - A Perceptually Weighted Rank Correlation Indicator for Objective Image Quality Assessment. AB - In the field of objective image quality assessment (IQA), Spearman's rho and Kendall's tau, which straightforwardly assign uniform weights to all quality levels and assume that each pair of images is sortable, are the two most popular rank correlation indicators. These indicators can successfully measure the average accuracy of an IQA metric for ranking multiple processed images. However, two important perceptual properties are ignored. First, the sorting accuracy (SA) of high-quality images is usually more important than that of poor-quality images in many real-world applications, where only top-ranked images are pushed to the users. Second, due to the subjective uncertainty in making judgments, two perceptually similar images are usually barely sortable, and their ranks do not contribute to the evaluation of an IQA metric. To more accurately compare different IQA algorithms, in this paper, we explore a perceptually weighted rank correlation indicator, which rewards the capability of correctly ranking high quality images and suppresses the attention towards insensitive rank mistakes. Specifically, we focus on activating a 'valid' pairwise comparison of images whose quality difference exceeds a given sensory threshold (ST). Meanwhile, each image pair is assigned a unique weight that is determined by both the quality level and rank deviation. By modifying the perception threshold, we can illustrate the sorting accuracy with a sophisticated SA-ST curve rather than a single rank correlation coefficient. The proposed indicator offers new insight into interpreting visual perception behavior. Furthermore, the applicability of our indicator is validated for recommending robust IQA metrics for both degraded and enhanced image data. PMID- 29994354 TI - A Coloring Algorithm for Disambiguating Graph and Map Drawings. AB - Drawings of non-planar graphs always result in edge crossings. When there are many edges crossing at small angles, it is often difficult to follow these edges, because of the multiple visual paths resulted from the crossings that slow down eye movements. In this paper we propose an algorithm that disambiguates the edges with automatic selection of distinctive colors. Our proposed algorithm computes a near optimal color assignment of a dual collision graph, using a novel branch-and bound procedure applied to a space decomposition of the color gamut. We give examples demonstrating this approach in real world graphs and maps, as well as a user study to establish its effectiveness and limitations. PMID- 29994355 TI - Safely Filling Gaps with Partial Solutions Common to All Solutions. AB - Gap filling has emerged as a natural sub-problem of many de novo genome assembly projects. The gap filling problem generally asks for an path in an assembly graph whose length matches the gap length estimate. Several methods have addressed it, but only few have focused on strategies for dealing with multiple gap filling solutions and for guaranteeing reliable results. Such strategies include reporting only unique solutions, or exhaustively enumerating all filling solutions and heuristically creating their consensus. Our main contribution is a new method for reliable gap filling: filling gaps with those sub-paths common to all gap filling solutions. We call these partial solutions safe, following the framework of (Tomescu and Medvedev, RECOMB 2016). We give an efficient safe algorithm running in time and space, where is the gap length estimate and is the number of edges of the assembly graph. To show the benefits of this method, we implemented this algorithm for the problem of filling gaps in scaffolds. Our experimental results on bacterial and on conservative human assemblies show that, on average, our method can retrieve over 73% more safe and correct bases as compared to previous methods, with a similar precision. PMID- 29994356 TI - A Survey of Graph Cuts/Graph Search Based Medical Image Segmentation. AB - Medical image segmentation is a fundamental and challenging problem for analyzing medical images. Among different existing medical image segmentation methods, graph-based approaches are relatively new and show good features in clinical applications. In the graph-based method, pixels or regions in the original image are interpreted into nodes in a graph. By considering Markov random field to model the contexture information of the image, the medical image segmentation problem can be transformed into a graph-based energy minimization problem. This problem can be solved by the use of minimum s-t cut/ maximum flow algorithm. This review is devoted to cut-based medical segmentation methods, including graph cuts and graph search for region and surface segmentation. Different varieties of cut based methods, including graph-cuts-based methods, model integrated graph cuts methods, graph-search-based methods, and graph search/graph cuts based methods, are systematically reviewed. Graph cuts and graph search with deep learning technique are also discussed. PMID- 29994357 TI - Wearable Heading Estimation for Motion Tracking in Health Care by Adaptive Fusion of Visual-Inertial Measurements. AB - The increasing demand for health informatics has become a far-reaching trend in the ageing society. The utilization of wearable sensors enables monitoring senior people daily activities in free-living environments, conveniently and effectively. Among the primary health-care sensing categories, the wearable visual-inertial modality for human motion tracking gradually exerts promising potentials. In this paper, we present a novel wearable heading estimation strategy to track the movements of human limbs. It adaptively fuses inertial measurements with visual features following locality constraints. Body movements are classified into two types: general motion (which consists of both rotation and translation). or degenerate motion (which consists of only rotation). A specific number of feature correspondences between camera frames are adaptively chosen to satisfy both the feature descriptor similarity constraint and the locality constraint. The selected feature correspondences and inertial quaternions are employed to calculate the initial pose, followed by the coarse-to fine procedure to iteratively remove visual outliers. Eventually, the ultimate heading is optimized using the correct feature matches. The proposed method has been thoroughly evaluated on the straight-line, rotatory and ambulatory movement scenarios. As the system is lightweight and requires small computational resources, it enables effective and unobtrusive human motion monitoring, especially for the senior citizens in the long-term rehabilitation. PMID- 29994358 TI - Autonomic Nervous System Measurement in Hyperbaric Environments using ECG and PPG signals. AB - The main aim of this work was to characterise the Autonomic Nervous System (ANS) response in hyperbaric environments using electrocardiogram (ECG) and pulse photoplethysmogram (PPG) signals. To that end, 26 subjects were introduced into a hyperbaric chamber and five stages with different atmospheric pressures (1 atm; descent to 3 and 5 atm; ascent to 3 and 1 atm) were recorded. Respiratory information was extracted from the ECG and PPG signals and a combined respiratory rate was studied. This information was also used to analyse Heart Rate Variability (HRV) and Pulse Rate Variability (PRV). The database was cleaned by eliminating those cases where the respiratory rate dropped into the low frequency band (LF: 0.04-0.15 Hz) and those in which there was a discrepancy between the respiratory rates estimated using the ECG and PPG signals. Classical temporal and frequency indices were calculated in such cases. The ECG results showed a time related dependency, with the heart rate and sympathetic markers (normalised power in LF and LF/HF ratio) decreasing as more time was spent inside the hyperbaric environment. A dependency between the atmospheric pressure and the parasympathetic response, as reflected in the high frequency band power (HF: 0.15 0.40 Hz), was also found, with power increasing with atmospheric pressure. The combined respiratory rate also reached a maximum in the deepest stage, thus highlighting a significant difference between this stage and the first one. The PPG data gave similar findings and also allowed the oxygen saturation to be computed, therefore we propose the use of this signal for future studies in hyperbaric environments. PMID- 29994359 TI - Smart Home-Based Prediction of Multidomain Symptoms Related to Alzheimer's Disease. AB - As members of an increasingly aging society, one of our major priorities is to develop tools to detect the earliest stage of age-related disorders such as Alzheimer's Disease (AD). The goal of this paper is to evaluate the possibility of using unobtrusively collected activity-aware smart home behavior data to detect the multimodal symptoms that are often found to be impaired in AD. After gathering longitudinal smart home data for 29 older adults over an average duration of 2 years, we automatically labeled the data with corresponding activity classes and extracted time-series statistics containing ten behavioral features. Mobility, cognition, and mood were evaluated every six months. Using these data, we created regression models to predict symptoms as measured by the tests and a feature selection analysis was performed. Classification models were built to detect reliable absolute changes in the scores predicting symptoms and SmoteBOOST and wRACOG algorithms were used to overcome class imbalance where needed. Results show that all mobility, cognition, and depression symptoms can be predicted from activity-aware smart home data. Similarly, these data can be effectively used to predict reliable changes in mobility and memory skills. Results also suggest that not all behavioral features contribute equally to the prediction of every symptom. Future work therefore can improve model sensitivity by including additional longitudinal data and by further improving strategies to extract relevant features and address class imbalance. The results presented herein contribute toward the development of an early change detection system based on smart home technology. PMID- 29994360 TI - An Efficient Nondominated Sorting Algorithm for Large Number of Fronts. AB - Nondominated sorting is a key operation used in multiobjective evolutionary algorithms (MOEA). Worst case time complexity of this algorithm is O(MN2), where N is the number of solutions and M is the number of objectives. For stochastic algorithms like MOEAs, it is important to devise an algorithm which has better average case performance. In this paper, we propose a new algorithm that makes use of faster scalar sorting algorithm to perform nondominated sorting. It finds partial orders of each solution from all objectives and use these orders to skip unnecessary solution comparisons. We also propose a specific order of objectives that reduces objective comparisons. The proposed method introduces a weighted binary search over the fronts when the rank of a solution is determined. It further reduces total computational effort by a large factor when there is large number of fronts. We prove that the worst case complexity can be reduced to Theta(MNCmaxlog2(F+1)), where the number of fronts is F and the maximum number of solutions per front is Cmax; however, in general cases, our worst case complexity is still O(MN2). Our best case time complexity is O(MNlogN). We also achieve the best case complexity O(MNlogN+N2), when all solutions are in a single front. This method is compared with other state-of-the-art algorithms--efficient nondomination level update, deductive sort, corner sort, efficient nondominated sort and divide-and-conquer sort--in four different datasets. Experimental results show that our method, namely, bounded best order sort, is computationally more efficient than all other competing algorithms. PMID- 29994361 TI - Dimension Reduction for Non-Gaussian Data by Adaptive Discriminative Analysis. AB - High-dimensional non-Gaussian data are ubiquitous in many real applications. Face recognition is a typical example of such scenarios. The sampled face images of each person in the original data space are more closely located to each other than to those of the same individuals due to the changes of various conditions like illumination, pose variation, and facial expression. They are often non Gaussian and differentiating the importance of each data point has been recognized as an effective approach to process the high-dimensional non-Gaussian data. In this paper, to embed non-Gaussian data well, we propose a novel unified framework named adaptive discriminative analysis (ADA), which combines the sample's importance measurement and subspace learning in a unified framework. Therefore, our ADA can preserve the within-class local structure and learn the discriminative transformation functions simultaneously by minimizing the distances of the projected samples within the same classes while maximizing the between-class separability. Meanwhile, an efficient method is developed to solve our formulated problem. Comprehensive analyses, including convergence behavior and parameter determination, together with the relationship to other related approaches, are as well presented. Systematical experiments are conducted to understand the work of our proposed ADA. Promising experimental results on various types of real-world benchmark data sets are provided to examine the effectiveness of our algorithm. Furthermore, we have also evaluated our method in face recognition. They all validate the effectiveness of our method on processing the high-dimensional non-Gaussian data. PMID- 29994363 TI - Lorentz-symmetry test at Planck-scale suppression with a spin-polarized 133 Cs cold atom clock. AB - We present the results of a Local Lorentz Invariance (LLI) test performed with the 133Cs cold atom clock FO2 [1], hosted at SYRTE. Such test, relating the frequency shift between 133Cs hyperfine Zeeman substates to the Lorentz violating coefficients of the Standard Model Extension (SME), has already been realized in [2] and led to state-of-the-art constraints on several SME proton coefficients. In this second analysis we used an improved model, based on a second order Lorentz transformation and a SCRMF nuclear model, which enables us to extend the scope of the analysis from purely proton to both proton and neutron coefficients. We have also become sensitive to the isotropic coefficient ~cTT, another SME coefficient that was not constrained in [2]. The resulting limits on SME coefficients improve by up to 13 orders of magnitude the present maximal sensitivities for laboratory tests and reach the generally expected suppression scales at which signatures of Lorentz violation could appear [3]. PMID- 29994364 TI - Using Dashboard Networks to Visualize Multiple Patient Histories: A Design Study on Post-operative Prostate Cancer. AB - In this design study, we present a visualization technique that segments patients' histories instead of treating them as raw event sequences, aggregates the segments using criteria such as the whole history or treatment combinations, and then visualizes the aggregated segments as static dashboards that are arranged in a dashboard network to show longitudinal changes. The static dashboards were developed in nine iterations, to show 15 important attributes from the patients' histories. The final design was evaluated with five non experts, five visualization experts and four medical experts, who successfully used it to gain an overview of a 2,000 patient dataset, and to make observations about longitudinal changes and differences between two cohorts. The research represents a step-change in the detail of large-scale data that may be successfully visualized using dashboards, and provides guidance about how the approach may be generalized. PMID- 29994362 TI - Deep Learning for Quantification of Epicardial and Thoracic Adipose Tissue From Non-Contrast CT. AB - Epicardial adipose tissue (EAT) is a visceral fat deposit related to coronary artery disease. Fully automated quantification of EAT volume in clinical routine could be a timesaving and reliable tool for cardiovascular risk assessment. We propose a new fully automated deep learning framework for EAT and thoracic adipose tissue (TAT) quantification from non-contrast coronary artery calcium computed tomography (CT) scans. The first multi-task convolutional neural network (ConvNet) is used to determine heart limits and perform segmentation of heart and adipose tissues. The second ConvNet, combined with a statistical shape model, allows for pericardium detection. EAT and TAT segmentations are then obtained from outputs of both ConvNets. We evaluate the performance of the method on CT data sets from 250 asymptomatic individuals. Strong agreement between automatic and expert manual quantification is obtained for both EAT and TAT with median Dice score coefficients of 0.823 (inter-quartile range (IQR): 0.779-0.860) and 0.905 (IQR: 0.862-0.928), respectively; with excellent correlations of 0.924 and 0.945 for EAT and TAT volumes. Computations are performed in <6 s on a standard personal computer for one CT scan. Therefore, the proposed method represents a tool for rapid fully automated quantification of adipose tissue and may improve cardiovascular risk stratification in patients referred for routine CT calcium scans. PMID- 29994365 TI - A Simplified Description of Child Tables for Sequence Similarity Search. AB - Finding related nucleotide or protein sequences is a fundamental, diverse, and incompletely-solved problem in bioinformatics. It is often tackled by seed-and extend methods, which first find "seed" matches of diverse types, such as spaced seeds, subset seeds, or minimizers. Seeds are usually found using an index of the reference sequence(s), which stores seed positions in a suffix array or related datastructure. A child table is a fundamental way to achieve fast lookup in an index, but previous descriptions have been overly complex. This paper aims to provide a more accessible description of child tables, and demonstrate their generality: they apply equally to all the above-mentioned seed types and more. We also show that child tables can be used without LCP (longest common prefix) tables, reducing the memory requirement. PMID- 29994366 TI - A Comparative Study of Network Motifs in the Integrated Transcriptional Regulation and Protein Interaction Networks of Shewanella. AB - The Shewanella species shows a remarkable respiratory versatility with a great variety of extracellular electron acceptors (termed Extracellular Electron Transfer, EET). To explore relevant mechanisms from the network motif view, we constructed the integrated networks that combined transcriptional regulation interactions (TRIs) and protein-protein interactions (PPIs) for 13 Shewanella species, identified and compared the network motifs in these integrated networks. We found that the network motifs were evolutionary conserved in these integrated networks. The functional significance of the highly conserved motifs was discussed, especially the important ones that were potentially involved in the Shewanella EET processes. More importantly, we found that: 1) the motif co regulated PPI took a role in the standby mode of protein utilization, which will be helpful for cells to rapidly response to environmental changes; and 2) the type II cofactors, which involved in the motif TRI interacting with a third protein, mainly carried out a signalling role in Shewanella oneidensis MR-1. PMID- 29994367 TI - Organisation-Oriented Coarse Graining and Refinement of Stochastic Reaction Networks. AB - Chemical organisation theory is a framework developed to simplify the analysis of long-term behaviour of chemical systems. In this work, we build on these ideas to develop novel techniques for formal quantitative analysis of chemical reaction networks, using discrete stochastic models represented as continuous-time Markov chains. We propose methods to identify organisations, and to study quantitative properties regarding movements between these organisations. We then construct and formalise a coarse-grained Markov chain model of hierarchic organisations for a given reaction network, which can be used to approximate the behaviour of the original reaction network. As an application of the coarse-grained model, we predict the behaviour of the reaction network systems over time via the master equation. Experiments show that our predictions can mimic the main pattern of the concrete behaviour in the long run, but the precision varies for different models and reaction rule rates. Finally, we propose an algorithm to selectively refine the coarse-grained models and show experiments demonstrating that the precision of the prediction has been improved. PMID- 29994368 TI - Computational Modeling of Wound Suture: A Review. AB - Suturing is an acquired skill which is based on a surgeon's experience. To date, no two sutures are the same with respect to the type of knot, tension, or suture material. With advancement in medical technologies, robotic suturing is becoming more and more important to operate on complex and difficult to reach internal surgical sites. While it is very difficult to translate a surgeon's suturing expertise to an automated environment, computational models could be employed to estimate baseline suture force requirements for a given wound shape, size, and suture material, which could be subsequently processed by a robot. In the literature, there have been few attempts to characterize wound closure and suture mechanics using simple two- and three-dimensional computational models. Single and multiple skin layers (epidermis, dermis, and hypodermis) and tissues with different wound geometries and sizes have been simulated under simple wound flap displacements to estimate suture force requirements. Also, recently, sutures were modeled to simulate a realistic wound closure via suture pulling, and skin prestress effect due to the natural tension of skin was incorporated in a few models to understand its effects on wound closure mechanics. An extensive review of this literature on computational modeling of wound suture would provide valuable insights into the areas in which further research work is required. Discussion of various computational challenges in modeling sutures in a numerical environment will help in better understanding the roadblocks and the required advancements in suture modeling. PMID- 29994369 TI - An experimental setup to test dual-joystick directional responses to vibrotactile stimuli. AB - In this paper we investigate the influence of the location of vibrotactile stimulation in triggering the response made using two handheld joysticks. In particular, we compare performance with stimuli delivered either using tactors placed on the palm or on the back of the hand and with attractive (move toward the vibration) or repulsive prompts (move away from the vibration). The experimental set-up comprised two joysticks and two gloves, each equipped with four pager motors along the cardinal directions. In different blocks, fifty-three volunteers were asked to move the joysticks as fast as possible either towards or away with respect to the direction specified by a set of vibrating motors. Results indicate that participants performed better with attractive prompts (i.e. responses were faster and with fewer errors in conditions where participants were asked to move the joysticks in the direction of the felt vibration) and that the stimulation delivered on the back of the hand from the gloves gives better results than the stimulation on the palm delivered by the joysticks. Finally, we analyse the laterality, the relation between correct responses and reaction times, the direction patterns for wrong responses and we perform an analysis on the Stimulus-Response Compatibility and on the training effect. PMID- 29994370 TI - Learning Shared Control by Demonstration for Personalized Wheelchair Assistance. AB - An emerging research problem in assistive robotics is the design of methodologies that allow robots to provide personalized assistance to users. For this purpose, we present a method to learn shared control policies from demonstrations offered by a human assistant. We train a Gaussian process (GP) regression model to continuously regulate the level of assistance between the user and the robot, given the user's previous and current actions and the state of the environment. The assistance policy is learned after only a single human demonstration, i.e. in one-shot. Our technique is evaluated in a one-of-a-kind experimental study, where the machine-learned shared control policy is compared to human assistance. Our analyses show that our technique is successful in emulating human shared control, by matching the location and amount of offered assistance on different trajectories. We observed that the effort requirement of the users were comparable between human-robot and human-human settings. Under the learned policy, the jerkiness of the user's joystick movements dropped significantly, despite a significant increase in the jerkiness of the robot assistant's commands. In terms of performance, even though the robotic assistance increased task completion time, the average distance to obstacles stayed in similar ranges to human assistance. PMID- 29994371 TI - A Vibrotactile Alarm System for Pleasant Awakening. AB - There has been a vast development of personal informatics devices combining sleep monitoring with alarm systems, in order to find an optimal time to awaken a sleeping person in a pleasant way. Most of these systems implement auditory feedback, which is not always pleasant and may disturb other sleepers. We present an adaptive alarm system that detects sleeping cycles and triggers alarm signal during shallow sleep, to minimize sleep inertia. Since tactile sensation is associated with positive valence, vibrotactile stimulation is investigated as a silent alarm to enhance pleasant awakening. Three modulation techniques to render the tactile stimuli for pleasant awakening are considered, namely simultaneous, continuous, and successive stimulation. Two experimental studied are conducted. Experiment 1 studied exogenous attention towards tactile stimulation in a multimodal scenario (involving visual and haptic interactions) with fully awake individuals. Results from the attention task and the subjective valence rating suggest that the vibrotactile stimulation should be based on the continuous modulation, since this not only is very perceivable but also associated with positive attention. Experiment 2 evaluated the user experience with tactile stimulation patterns during sleep. Results confirmed the findings of experiment 1. Continuous modulation was rated highest for pleasant yet arousing sleep-awake transition. PMID- 29994372 TI - Fuzzy Neural Network Control of a Flexible Robotic Manipulator Using Assumed Mode Method. AB - In this paper, in order to analyze the single-link flexible structure, the assumed mode method is employed to develop the dynamic model. Based on the discrete dynamic model, fuzzy neural network (NN) control is investigated to track the desired trajectory accurately and to suppress the flexible vibration maximally. To ensure the stability rigorously as the goal, the system is proved to be uniform ultimate boundedness by Lyapunov's stability method. Eventually, simulations verify that the proposed control strategy is effective, and the control performance is compared with the proportion derivative control. The experiments are implemented on the Quanser platform to further demonstrate the feasibility of the proposed fuzzy NN control. PMID- 29994373 TI - Remote Estimator Design for Time-Delay Neural Networks Using Communication State Information. AB - This paper investigates the estimator design for the neural networks, where distributed delays and imperfect measurements are included. A randomly occurred neuron-dependent nonlinearity is used to describe the uncertain measurements disturbed by neurons. The measurements are transmitted over multiple transmission channels, and Markov chains are introduced to model packet dropouts of these channels. A one-to-one map is constructed to transform $m$ independent Markov chains to an augmented one to facilitate system analysis. A new variable called channel state is defined based on the cases of packet dropouts, and the channel state-dependent estimator is designed to trade off between the number and the performance of the estimator. Sufficient conditions are established to guarantee that the augmented system is stochastically stable and satisfies the strict $(Q, S, R)-?gamma -$ dissipativity. The estimator gains are derived using linear matrix methods. Finally, an example is applied to illustrate the effectiveness of the developed methods. PMID- 29994374 TI - Theoretical Study of Oscillator Neurons in Recurrent Neural Networks. AB - Neurons in a network can be both active or inactive. Given a subset of neurons in a network, is it possible for the subset of neurons to evolve to form an active oscillator by applying some external periodic stimulus? Furthermore, can these oscillator neurons be observable, that is, is it a stable oscillator? This paper explores such possibility, finding that an important property: any subset of neurons can be intermittently co-activated to form a stable oscillator by applying some external periodic input without any condition. Thus, the existing of intermittently active oscillator neurons is an essential property possessed by the networks. Moreover, this paper shows that, under some conditions, a subset of neurons can be fully co-activated to form a stable oscillator. Such neurons are called selectable oscillator neurons. Necessary and sufficient conditions are established for a subset of neurons to be selectable oscillator neurons in linear threshold recurrent neuron networks. It is proved that a subset of neurons forms selectable oscillator neurons if and only if the real part of each eigenvalue of the associated synaptic connection weight submatrix of the network is not larger than one. This simple condition makes the concept of selectable oscillator neurons tractable. The selectable oscillator neurons can be regarded as memories stored in the synaptic connections of networks, which enables to find a new perspective of memories in neural networks, different from the equilibrium-type attractors. PMID- 29994375 TI - Improved Stability Criterion for Recurrent Neural Networks With Time-Varying Delays. AB - In this brief, the problem of delay-dependent stability of recurrent neural networks with time-varying delays is studied. A newly augmented Lyapunov Krasovskii functional (LKF) that considers the information of the nonzero lower bound of time-varying delays is developed. Moreover, the information of the delayed state terms is not considered as elements of augmented vectors when constructing the LKF. An improved stability criterion with the framework of linear matrix inequalities is derived by employing the integral inequality and reciprocally convex combination. With the comparison to the existing ones, the developed stability criterion for neural networks has less conservatism and complexity. Finally, two widely used numerical examples are given to show the effectiveness and superiority of the obtained stability criterion. PMID- 29994376 TI - Matrix Factorization From a Few Dominators. AB - The Pareto principle states that most effects are the result of a few dominating causes. This principle also fits most matrix completion problems. In practice, most real-world data sets exhibit nonuniformly distributed observations. Unfortunately, most existing algorithms are designed based on uniformly distributed observations. In this brief, we propose a matrix factorization approach to recover a large-scale matrix from a dominating submatrix that is composed of a few most important rows and columns from the original matrix. The method for evaluating the importance of a row or column is inspired by the term frequency-inverse document frequency in natural language processing. The selected submatrix is recovered using an existing base matrix factorization algorithm. Then, factors of the completed submatrix are used to retrieve the factors of the whole matrix via a linear regression model. Numerical experiments demonstrate the effectiveness of our approach for recovering the matrix from nonuniformly distributed observations. In addition, our framework is naturally applicable for parallel and distributed computing, which is very encouraging for massive-sized data sets. PMID- 29994377 TI - Approximate Low-Rank Projection Learning for Feature Extraction. AB - Feature extraction plays a significant role in pattern recognition. Recently, many representation-based feature extraction methods have been proposed and achieved successes in many applications. As an excellent unsupervised feature extraction method, latent low-rank representation (LatLRR) has shown its power in extracting salient features. However, LatLRR has the following three disadvantages: 1) the dimension of features obtained using LatLRR cannot be reduced, which is not preferred in feature extraction; 2) two low-rank matrices are separately learned so that the overall optimality may not be guaranteed; and 3) LatLRR is an unsupervised method, which by far has not been extended to the supervised scenario. To this end, in this paper, we first propose to use two different matrices to approximate the low-rank projection in LatLRR so that the dimension of obtained features can be reduced, which is more flexible than original LatLRR. Then, we treat the two low-rank matrices in LatLRR as a whole in the process of learning. In this way, they can be boosted mutually so that the obtained projection can extract more discriminative features. Finally, we extend LatLRR to the supervised scenario by integrating feature extraction with the ridge regression. Thus, the process of feature extraction is closely related to the classification so that the extracted features are discriminative. Extensive experiments are conducted on different databases for unsupervised and supervised feature extraction, and very encouraging results are achieved in comparison with many state-of-the-arts methods. PMID- 29994378 TI - Surrogate-assisted Retinal OCT Image Classification Based on Convolutional Neural Networks. AB - Optical Coherence Tomography (OCT) is becoming one of the most important modalities for the noninvasive assessment of retinal eye diseases. As the number of acquired OCT volumes increases, automating the OCT image analysis is becoming increasingly relevant. In this paper, we propose a surrogate-assisted classification method to classify retinal OCT images automatically based on convolutional neural networks (CNNs). Image denoising is first performed to reduce the noise. Thresholding and morphological dilation are applied to extract the masks. The denoised images and the masks are then employed to generate a lot of surrogate images, which are used to train the CNN model. Finally, The prediction for a test image is determined by the average of the outputs from the trained CNN model on the surrogate images. The proposed method has been evaluated on different databases. The results (AUC of 0.9783 in the local database and AUC of 0.9856 in the Duke database) show that the proposed method is a very promising tool for classifying the retinal OCT images automatically. PMID- 29994379 TI - Automatic Retinal Layer Segmentation of OCT Images with Central Serous Retinopathy. AB - In this paper, an automatic method is reported for simultaneously segmenting layers and fluid in the retina from 3D OCT retinal images of subjects suffering from central serous retinopathy. Dark-to-bright or bright-to-dark transition is often kept in OCT images. To enhance the contrast between certain layers and the adjacent ones, multi-scale bright and dark layer detection filters are proposed. Due to the appearance of serous fluid or pigment epithelial detachment caused fluid, the contrast between adjacent layers is often reduced, and also large morphological changes are caused. In addition, in order to reduce the influence of fluid, twenty four features are designed for the random forest classifiers. Then, eight coarse surfaces of the retina are obtained based on the trained random forest classifiers. Finally, a hyper graph is constructed based on the smoothed image and the layer structure detection responses. A modified live wire algorithm is proposed to accurately detect surfaces between retinal layers even though OCT images with fluids are of low contrast and layer boundaries are blurred. The proposed method was evaluated on 48 spectral domain OCT images with central serous retinopathy. The experimental results showed that the proposed method outperformed the state-of-art methods with regard to layers and fluid segmentation. PMID- 29994380 TI - SetSVM: An Approach to Set Classification in Nuclei-based Cancer Detection. AB - Due to the importance of nuclear structure in cancer diagnosis, several predictive models have been described for diagnosing a wide variety of cancers based on nuclear morphology. In many computer-aided diagnosis (CAD) systems, cancer detection tasks can be generally formulated as set classification problems, which can't be directly solved by classifying single instances. In this paper, we propose a novel set classification approach SetSVM to build a predictive model by considering any nuclei set as a whole without specific assumptions. SetSVM features highly discriminative power in cancer detection challenges in the sense that it not only optimizes the classifier decision boundary but also transfers discriminative information to set representation learning. During model training, these two process are unified in the support vector machine (SVM) maximum separation margin problem. Experiment results show that SetSVM provides significant improvements compared with five commonly used approaches in cancer detection tasks utilizing 260 patients in total across three different cancer types, namely thyroid cancer, liver cancer and melanoma. In addition, we show that SetSVM enables visual interpretation of discriminative nuclear characteristics representing the nuclei set. These features make SetSVM a potentially practical tool in building accurate and interpretable CAD systems for cancer detection. PMID- 29994381 TI - A New Varying-Parameter Recurrent Neural-Network for Online Solution of Time Varying Sylvester Equation. AB - Solving Sylvester equation is a common algebraic problem in mathematics and control theory. Different from the traditional fixed-parameter recurrent neural networks, such as gradient-based recurrent neural networks or Zhang neural networks, a novel varying-parameter recurrent neural network, [called varying parameter convergent-differential neural network (VP-CDNN)] is proposed in this paper for obtaining the online solution to the time-varying Sylvester equation. With time passing by, this kind of new varying-parameter neural network can achieve super-exponential performance. Computer simulation comparisons between the fixed-parameter neural networks and the proposed VP-CDNN via using different kinds of activation functions demonstrate that the proposed VP-CDNN has better convergence and robustness properties. PMID- 29994382 TI - Fixed-Time Leader-Follower Output Feedback Consensus for Second-Order Multiagent Systems. AB - This paper addresses the fixed-time leader-follower consensus problem for second order multiagent systems without velocity measurement. A new continuous fixed time distributed observer-based consensus protocol is developed to achieve consensus in a bounded finite time fully independent of initial condition. A rigorous stability proof of the multiagent systems by output feedback control is presented based on the bi-limit homogeneity and the Lyapunov technique. Finally, the efficiency of the proposed methodology is illustrated by numerical simulation. PMID- 29994383 TI - R1-2-DPCA and Face Recognition. AB - 2-D principal component analysis (2-DPCA) is one of the successful dimensionality reduction approaches for image classification and representation. However, 2-DPCA is not robust to outliers. To tackle this problem, we present an efficient robust method, namely R1-2-DPCA for feature extraction. R1-2-DPCA aims to seek the projection matrix such that the projected data have the maximum variance, which is measured by R1-norm. Compared with most existing robust 2-DPCA methods, our model is not only robust to outliers but also helps encode discriminant information. Accordingly, we develop a nongreedy iterative algorithm, which has not only a closed-form solution in each iteration but also a good convergence, to solve our model. Moreover, to further improve classification performance, we employ nuclear norm as the distance metric in the classification phase. Extensive experiments on several face databases illustrate that our proposed method is superior to most existing robust 2-DPCA methods. PMID- 29994384 TI - EmotionMeter: A Multimodal Framework for Recognizing Human Emotions. AB - In this paper, we present a multimodal emotion recognition framework called EmotionMeter that combines brain waves and eye movements. To increase the feasibility and wearability of EmotionMeter in real-world applications, we design a six-electrode placement above the ears to collect electroencephalography (EEG) signals. We combine EEG and eye movements for integrating the internal cognitive states and external subconscious behaviors of users to improve the recognition accuracy of EmotionMeter. The experimental results demonstrate that modality fusion with multimodal deep neural networks can significantly enhance the performance compared with a single modality, and the best mean accuracy of 85.11% is achieved for four emotions (happy, sad, fear, and neutral). We explore the complementary characteristics of EEG and eye movements for their representational capacities and identify that EEG has the advantage of classifying happy emotion, whereas eye movements outperform EEG in recognizing fear emotion. To investigate the stability of EmotionMeter over time, each subject performs the experiments three times on different days. EmotionMeter obtains a mean recognition accuracy of 72.39% across sessions with the six-electrode EEG and eye movement features. These experimental results demonstrate the effectiveness of EmotionMeter within and between sessions. PMID- 29994386 TI - A Hybrid Intelligent Approach for Co-Scheduling of Cascaded Locks With Multiple Chambers. AB - A complex and typical scheduling problem in waterway transportation: co scheduling of cascaded locks with multiple chambers (CCLM) is studied. Based on in-depth analysis of the problem properties, the CCLM is handled by separating it into three interconnected subproblems, each with a simpler structure and higher flexibility to be handled. The outer layer and inner layer concerns the sum of lockage number and ship placement, respectively. The interlayer as a connection bridge between the other two refers to lockage direction combination and timetable optimization which is a high-dimensional mixed integer optimization problem. To solve the CCLM problem, a hybrid approach based on iteration which mainly combines quantum inspired binary gravitational search algorithm and modified moth-flame optimization algorithm is proposed. In addition, two different scheduling rules which are usually concerned in practice, the area utilization maximization and first-come-first-served (FCFS) rule, are also tested in the CCLM problem. Experiments are conducted on instances that are extracted from real world data. The scheduling and comparison results verify that the CCLM problem can be well handled by the proposed method. PMID- 29994385 TI - 3-D Fully Convolutional Networks for Multimodal Isointense Infant Brain Image Segmentation. AB - Accurate segmentation of infant brain images into different regions of interest is one of the most important fundamental steps in studying early brain development. In the isointense phase (approximately 6-8 months of age), white matter and gray matter exhibit similar levels of intensities in magnetic resonance (MR) images, due to the ongoing myelination and maturation. This results in extremely low tissue contrast and thus makes tissue segmentation very challenging. Existing methods for tissue segmentation in this isointense phase usually employ patch-based sparse labeling on single modality. To address the challenge, we propose a novel 3-D multimodal fully convolutional network (FCN) architecture for segmentation of isointense phase brain MR images. Specifically, we extend the conventional FCN architectures from 2-D to 3-D, and, rather than directly using FCN, we intuitively integrate coarse (naturally high-resolution) and dense (highly semantic) feature maps to better model tiny tissue regions, in addition, we further propose a transformation module to better connect the aggregating layers; we also propose a fusion module to better serve the fusion of feature maps. We compare the performance of our approach with several baseline and state-of-the-art methods on two sets of isointense phase brain images. The comparison results show that our proposed 3-D multimodal FCN model outperforms all previous methods by a large margin in terms of segmentation accuracy. In addition, the proposed framework also achieves faster segmentation results compared to all other methods. Our experiments further demonstrate that: 1) carefully integrating coarse and dense feature maps can considerably improve the segmentation performance; 2) batch normalization can speed up the convergence of the networks, especially when hierarchical feature aggregations occur; and 3) integrating multimodal information can further boost the segmentation performance. PMID- 29994387 TI - Neural Networks-Based Adaptive Control for Nonlinear State Constrained Systems With Input Delay. AB - This paper addresses the problem of adaptive tracking control for a class of strict-feedback nonlinear state constrained systems with input delay. To alleviate the major challenges caused by the appearances of full state constraints and input delay, an appropriate barrier Lyapunov function and an opportune backstepping design are used to avoid the constraint violation, and the Pade approximation and an intermediate variable are employed to eliminate the effect of the input delay. Neural networks are employed to estimate unknown functions in the design procedure. It is proven that the closed-loop signals are semiglobal uniformly ultimately bounded, and the tracking error converges to a compact set of the origin, as well as the states remain within a bounded interval. The simulation studies are given to illustrate the effectiveness of the proposed control strategy in this paper. PMID- 29994388 TI - Generalized State Estimation for Markovian Coupled Networks Under Round-Robin Protocol and Redundant Channels. AB - In this paper, the problem of generalized state estimation for an array of Markovian coupled networks under the round-Robin protocol (RRP) and redundant channels is investigated by using an extended dissipative property. The randomly varying coupling of the networks under consideration is governed by a Markov chain. With the aid of using the RRP, the transmission order of nodes is availably orchestrated. In this case, the probability of occurrence data collisions through a shared constrained network may be reduced. The redundant channels are also used in the signal transmission to deal with the frangibility of networks caused by a single channel in the networks. The network induced phenomena, that is, randomly occurring packet dropouts and randomly occurring quantization are fully considered. The main purpose of the research is to find a desired estimator design approach such that the extended (Omega1,Omega2,Omega3) - gamma-stochastic dissipativity property of the estimation error system is guaranteed. In terms of the Lyapunov-Krasovskii methodology, the Kronecker product and an improved matrix decoupling approach, sufficient conditions for such an addressed problem are established by means of handling some convex optimization problems. Finally, the serviceability of the proposed method is explained by providing an illustrated example. PMID- 29994389 TI - Decentralized Fault Prognosis of Discrete-Event Systems Using State-Estimate Based Protocols. AB - We investigate the problem of decentralized fault prognosis in the context of discrete-event systems. In this problem, the system is monitored by a set of local agents; each of them sends its local information to a coordinator in order to issue a fault alarm before the occurrence of fault. Two new decentralized protocols are proposed by exploiting the state-estimate of each local agent. For each protocol, a necessary and sufficient condition for its correctness is proposed; they are termed as positive state-estimate-prognosability and negative state-estimate prognosability. Verification algorithms for the necessary and sufficient conditions are also provided. We show that the proposed new protocols are incomparable with any of the existing protocols in the literature. Therefore, they provide new opportunities for correctly predicting the fault when all existing protocols fail. PMID- 29994390 TI - Analysis and Pinning Control for Output Synchronization and Hinfinity Output Synchronization of Multiweighted Complex Networks. AB - The output synchronization and Hinfinity output synchronization problems for multiweighted complex network are discussed in this paper. First, we analyze the output synchronization of multiweighted complex network by exploiting Lyapunov functional and Barbalat's lemma. In addition, some nodes- and edges-based pinning control strategies are developed to ensure the output synchronization of multiweighted complex network. Similarly, the Hinfinity output synchronization problem of multiweighted complex network is also discussed. Finally, two numerical examples are presented to verify the correctness of the obtained results. PMID- 29994391 TI - Deep Collaborative Embedding for Social Image Understanding. AB - In this work, we investigate the problem of learning knowledge from the massive community-contributed images with rich weakly-supervised context information, which can benefit multiple image understanding tasks simultaneously, such as social image tag refinement and assignment, content-based image retrieval, tag based image retrieval and tag expansion. Towards this end, we propose a Deep Collaborative Embedding (DCE) model to uncover a unified latent space for images and tags. The proposed method incorporates the end-to-end learning and collaborative factor analysis in one unified framework for the optimal compatibility of representation learning and latent space discovery. A nonnegative and discrete refined tagging matrix is learned to guide the end-to end learning. To collaboratively explore the rich context information of social images, the proposed method integrates the weakly-supervised image-tag correlation, image correlation and tag correlation simultaneously and seamlessly. The proposed model is also extended to embed new tags in the uncovered space. To verify the effectiveness of the proposed method, extensive experiments are conducted on two widely-used social image benchmarks for multiple social image understanding tasks. The encouraging performance of the proposed method over the state-of-the-art approaches demonstrates its superiority. PMID- 29994392 TI - Distance Encoded Product Quantization for Approximate K-Nearest Neighbor Search in High-Dimensional Space. AB - Approximate K-nearest neighbor search is a fundamental problem in computer science. The problem is especially important for high-dimensional and large-scale data. Recently, many techniques encoding high-dimensional data to compact codes have been proposed. The product quantization and its variations that encode the cluster index in each subspace have been shown to provide impressive accuracy. In this paper, we explore a simple question: is it best to use all the bit-budget for encoding a cluster index? We have found that as data points are located farther away from the cluster centers, the error of estimated distance becomes larger. To address this issue, we propose a novel compact code representation that encodes both the cluster index and quantized distance between a point and its cluster center in each subspace by distributing the bit-budget. We also propose two distance estimators tailored to our representation. We further extend our method to encode global residual distances in the original space. We have evaluated our proposed methods on benchmarks consisting of GIST, VLAD, and CNN features. Our extensive experiments show that the proposed methods significantly and consistently improve the search accuracy over other tested techniques. This result is achieved mainly because our methods accurately estimate distances. PMID- 29994393 TI - Automatic Multiorgan Segmentation via Multiscale Registration and Graph Cut. AB - We propose an automatic multiorgan segmentation method for 3-D radiological images of different anatomical contents and modalities. The approach is based on a simultaneous multilabel graph cut optimization of location, appearance, and spatial configuration criteria of target structures. Organ location is defined by target-specific probabilistic atlases (PA) constructed from a training dataset using a fast (2+1)D SURF-based multiscale registration method involving a simple four-parameter transformation. PAs are also used to derive target-specific organ appearance models represented as intensity histograms. The spatial configuration prior is derived from shortest-path constraints defined on the adjacency graph of structures. Thorough evaluations on Visceral project benchmarks and training dataset, as well as comparisons with the state-of-the-art confirm that our approach is comparable to and often outperforms similar approaches in multiorgan segmentation, thus proving that the combination of multiple suboptimal but complementary information sources can yield very good performance. PMID- 29994394 TI - Mosaic-Based Color-Transform Optimization for Lossy and Lossy-to-Lossless Compression of Pathology Whole-Slide Images. AB - The use of whole-slide images (WSIs) in pathology entails stringent storage and transmission requirements because of their huge dimensions. Therefore, image compression is an essential tool to enable efficient access to these data. In particular, color transforms are needed to exploit the very high degree of inter component correlation and obtain competitive compression performance. Even though state-of-the-art color transforms remove some redundancy, they disregard important details of the compression algorithm applied after the transform. Therefore, their coding performance is not optimal.We propose an optimization method called Mosaic Optimization for designing irreversible and reversible color transforms simultaneously optimized for any given WSI and the subsequent compression algorithm. Mosaic Optimization is designed to attain reasonable computational complexity and enable continuous scanner operation. Exhaustive experimental results indicate that, for JPEG 2000 at identical compression ratios, the optimized transforms yield images more similar to the original than other state-of-the-art transforms. Specifically, irreversible optimized transforms outperform the Karhunen-Lo'eve Transform (KLT) in terms of PSNR (up to 1.1 dB), the HDR-VDP-2 visual distortion metric (up to 3.8 dB) and accuracy of computer-aided nuclei detection tasks (F1 score up to 0.04 higher). Additionally, reversible optimized transforms achieve PSNR, HDR-VDP-2 and nuclei detection accuracy gains of up to 0.9 dB, 7.1 dB and 0.025, respectively, when compared to the reversible color transform (RCT) in lossy-to-lossless compression regimes. PMID- 29994395 TI - Hierarchical Cascading Algorithm for 2-D FEM Simulation of Finite SAW Devices. AB - Application of the finite-element method (FEM) for the simulation of surface acoustic wave (SAW) devices has been constrained by the large number of degrees of freedom required, resulting in large memory usage and long computation times. We propose a new 2-D algorithm that takes advantage of the periodic structure typical of SAW devices. The device is partitioned into small, repeatedly occurring building blocks. Only unique building blocks are simulated with FEM. The device geometry is presented as a hierarchical tree of cascading operations, where smaller blocks are combined into larger blocks. This is equivalent to the full FEM simulation of the device, implying the drastic reduction of memory consumption and simulation time for structures with a high degree of periodicity. The method is verified against FEM/BEM-based software. To ensure accurate and efficient simulation, the boundary conditions should be chosen according to the anisotropy of the substrate crystal. PMID- 29994396 TI - Loss Mechanisms Determining the Quality Factors in Quartz Tuning Forks Vibrating at the Fundamental and First Overtone Modes. AB - Quartz tuning forks (QTFs) are piezo-transducers that have been implemented for numerous applications, such as chemical gas sensing, atomic force microscopy, rheology, and industrial process control. The most important parameter for QTFs' sensing application is the resonance quality factor (Q-factor). An experimental investigation and theoretical analysis of the influence of QTFs' geometries on the Q-factor of the flexural fundamental and first overtone resonance modes are reported. The resonance frequencies and related Q-factors for five different QTFs have been measured. The QTF response was recorded at different air pressures to investigate the influence of the surrounding medium on the Q-factor. A data analysis demonstrated that air viscous damping is the dominant energy dissipation mechanism for both flexural modes. Thermoelastic and support losses are additional contributions that depend on the QTF geometry. A study of the QTF damping mechanism dependence upon the prong geometry is also provided. PMID- 29994397 TI - Modality-specific Cross-modal Similarity Measurement with Recurrent Attention Network. AB - Nowadays, cross-modal retrieval plays an important role to flexibly find useful information across different modalities of data. Effectively measuring the similarity between different modalities of data is the key of cross-modal retrieval. Different modalities such as image and text have imbalanced and complementary relationship, and they contain unequal amount of information when describing the same semantics. For example, images often contain more details that cannot be demonstrated by textual descriptions and vice versa. Existing works based on Deep Neural Network (DNN) mostly construct one common space for different modalities, to find the latent alignments between them, which lose their exclusive modality-specific characteristics. Therefore, we propose modality specific cross-modal similarity measurement (MCSM) approach by constructing the independent semantic space for each modality, which adopts an endto- end framework to directly generate modality-specific crossmodal similarity without explicit common representation. For each semantic space, modality-specific characteristics within one modality are fully exploited by recurrent attention network, while the data of another modality is projected into this space with attention based joint embedding, which utilizes the learned attention weights for guiding the fine-grained cross-modal correlation learning, and captures the imbalanced and complementary relationship between different modalities. Finally, the complementarity between the semantic spaces for different modalities is explored by adaptive fusion of the modality-specific cross-modal similarities to perform cross-modal retrieval. Experiments on the widely-used Wikipedia, Pascal Sentence, MS-COCO datasets as well as our constructed large-scale XMediaNet dataset verify the effectiveness of our proposed approach, outperforming 9 stateof- the-art methods. PMID- 29994398 TI - Adaptive curvature-guided image filtering for structure + texture image decomposition. AB - A preliminary structure + texture image decomposition is very useful for a number of digital image processing tasks, as different strategies are supposed to be employed for processing the structure and texture image components. In this paper, a new variational structure + texture image decomposition method is developed. The main ingredients of the proposed approach are: (1) using a low pass filtered level-set curvature of the input image as a guidance image; (2) texture suppressing by minimizing a variable exponent energy, where the variable exponent is learned from the result of the curvature-guided image filtering. Numerical experiments demonstrate that the method is competitive with the current state of the art in structure + texture image decomposition. Several applications are considered. PMID- 29994399 TI - Average Vector Field Integration for St. Venant-Kirchhoff Deformable Models. AB - We propose Average Vector Field (AVF) integration for simulation of deformable solids in physics-based animation. Our method achieves exact energy conservation for the St. Venant-Kirchhoff material without any correction steps or extra parameters. Exact energy conservation implies that our resulting animations 1) cannot explode and 2) do not suffer from numerical damping, which are two common problems with previous numerical integration techniques. Our method produces lively motion even with large time steps as typically used in physics-based animation. Our implicit update rules can be formulated as a minimization problem and solved in a similar way as optimization-based backward Euler, with only a mild computing overhead. Our approach also supports damping and collision response models, making it easy to deploy in practical computer animation pipelines. PMID- 29994400 TI - Mathematical Modeling for Description of Oscillation Suppression Induced by Deep Brain Stimulation. AB - A mathematical modeling for description of oscillation suppression by deep brain stimulation (DBS) is explored in this paper. High-frequency DBS introduced to the basal ganglia network can suppress pathological neural oscillations that occur in the Parkinsonian state. However, selecting appropriate stimulation parameters remains a challenging issue due to the limited understanding of the underlying mechanisms of the Parkinsonian state and its control. In this paper, we use a describing function analysis to provide an intuitive way to select the optimal stimulation parameters based on a biologically plausible computational model of the Parkinsonian neural network. By the stability analysis using the describing function method, effective DBS parameter regions for inhibiting the pathological oscillations can be predicted. Additionally, it is also found that a novel sinusoidal-shaped DBS may become an alternative stimulation pattern and expends less energy, but with a different mechanism. This paper provides new insight into the possible mechanisms underlying DBS and a prediction of optimal DBS parameter settings, and even suggests how to select novel DBS wave patterns for the treatment of movement disorders, such as Parkinson's disease. PMID- 29994401 TI - Assessing Wrist Movement With Robotic Devices. AB - Robotic devices have been proposed to meet the rising need for high intensity, long duration, and goal-oriented therapy required to regain motor function after neurological injury. Complementing this application, exoskeletons can augment traditional clinical assessments through precise, repeatable measurements of joint angles and movement quality. These measures assume that exoskeletons are making accurate joint measurements with a negligible effect on movement. For the coupled and coordinated joints of the wrist and hand, the validity of these two assumptions cannot be established by characterizing the device in isolation. To examine these assumptions, we conducted three user-in-the-loop experiments with able-bodied participants. First, we compared robotic measurements to an accepted modality to determine the validity of joint- and trajectory-level measurements. Then, we compared those movements to movements without the device to investigate the effects of device dynamic properties on wrist movement characteristics. Last, we investigated the effect of the device on coordination with a redundant, coordinated pointing task with the wrist and hand. For all experiments, smoothness characteristics were preserved in the robotic kinematic measurement and only marginally impacted by robot dynamics, validating the exoskeletons for use as assessment devices. Stemming from these results, we propose design guidelines for exoskeletal assessment devices. PMID- 29994402 TI - Feedback Control of Functional Electrical Stimulation for 2-D Arm Reaching Movements. AB - Functional electrical stimulation (FES) can be used as a neuroprosthesis in which muscles are stimulated by electrical pulses to compensate for the loss of voluntary movement control. Modulating the stimulation intensities to reliably generate movements is a challenging control problem. This paper introduces a feedback controller for a multi-muscle FES system to control hand movements in a 2-D (table-top) task space. This feedback controller is based on a recent human motor control model, which uses muscle synergies to simplify its calculations and improve the performance. This synergy-based controller employs direct relations between the muscle synergies and the produced hand force, therefore allowing for the real-time calculation of six muscle stimulation levels required to reach an arbitrary target. The experimental results show that this control scheme can perform arbitrary point-to-point reaching tasks in the 2-D task space in real time, with an average of ~2 cm final hand position error from the specified targets. The success of this prototype demonstrates the potential of the proposed method for the feedback control of functional tasks with FES. PMID- 29994403 TI - Detection of Cell Morphological Changes of Ischemic Rabbit Liver Tissue Using Bioimpedance Spectroscopy. AB - Bioimpedance spectroscopy is a promising method for tissue ischemia monitoring; it is used in this research to study ischemia and cell morphology using bioimpedance measurements of rabbit liver tissue. This paper presents the evolution of Cole parameters and cell parameters with time and establishes a relation between cellular morphological changes during cell ischemia with bioimpedance measurements at different frequencies. The general behavior of ischemic liver tissue has been analyzed. Evolution of Cole parameters was extrapolated from BIS measurements, and their behavior was studied with respect to time. Then, cell parameters were estimated from Cole parameters. A detailed analysis of the changes of cell parameters was done in parallel with explanations for these changes depending on the physiological mechanism of ischemia and necrosis bioprocess. These explanations give a confirmation of the established relation between cell morphological changes and the corresponding BIS measurements. PMID- 29994404 TI - Hemodynamic Sensing of 3-D Fingertip Force by Using Nonpulsatile and Pulsatile Signals in the Proximal Part. AB - This study proposed a novel sensing method of 3-D contact force at a fingertip by using a photoplethysmogram (PPG) device on the proximal part of a finger. The proposed system detects nonpulsatile and pulsatile components of PPG signals from both sides of the proximal part, extracts 16 feature values related to the contact force, and estimates the 3-D force by using a multiple linear regression model. In the validation experiments, the participants wore a PPG device at the proximal parts of their index fingers and applied a contact force at the fingertips for the 11 types of touch actions. The results indicated that satisfactory agreements are observed between the system outputs and the reference forces by the calibrated force sensor. Moreover, the results revealed that the most effective number of feature values corresponded to six for the higher reproducible sensing. Although the development of the effective calibration method is expected to increase robustness, we realized that the proposed method can potentially be used for a 3-D input user interface. PMID- 29994405 TI - Current and Emerging Diagnostic Imaging-Based Techniques for Assessment of Osteoporosis and Fracture Risk. AB - Osteoporosis is a metabolic bone disorder characterized by low bone mass, degradation of bone micro-architecture and susceptibility to fracture. It is a growing major health concern across the world, especially in the elderly population. Osteoporosis can cause hip or spinal fractures that may lead to high morbidity and socio-economic burden. Therefore, there is a need for early diagnosis of osteoporosis and prediction of fragility fracture risk. In this paper, state-of-the-art and recent advances in imaging techniques for diagnosis of osteoporosis and fracture risk assessment have been explored. A review of segmentation methods used to segment the regions of interest and texture analysis methods used for classification of healthy and osteoporotic subjects are also presented. Furthermore, challenges posed by the current diagnostic tools have been studied and feasible solutions to circumvent the limitations are discussed. Early diagnosis of osteoporosis and prediction of fracture risk requires the development of highly precise and accurate low-cost diagnostic techniques that would help the elderly population in low economies. PMID- 29994406 TI - Deep Ensemble Machine for Video Classification. AB - Video classification has been extensively researched in computer vision due to its wide spread applications. However, it remains an outstanding task because of the great challenges in effective spatial-temporal feature extraction and efficient classification with high-dimensional video representations. To address these challenges, in this paper, we propose an end-to-end learning framework called deep ensemble machine (DEM) for video classification. Specifically, to establish effective spatio-temporal features, we propose using two deep convolutional neural networks (CNNs), i.e., vision and graphics group and C3-D to extract heterogeneous spatial and temporal features for complementary representations. To achieve efficient classification, we propose ensemble learning based on random projections aiming to transform high-dimensional features into a set of lower dimensional compact features in subspaces; an ensemble of classifiers is trained on the subspaces and combined with a weighting layer during the backpropagation. To further enhance the performance, we introduce rectified linear encoding (RLE) inspired from error-correcting output coding to encode the initial outputs of classifiers, followed by a softmax layer to produce the final classification results. DEM combines the strengths of deep CNNs and ensemble learning, which establishes a new end-to-end learning architecture for more accurate and efficient video classification. We show the great effectiveness of DEM by extensive experiments on four data sets for diverse video classification tasks including action recognition and dynamic scene classification. Results have shown that DEM achieves high performance on all tasks with an improvement of up to 13% on CIFAR10 data set over the baseline model. PMID- 29994407 TI - Neural-Response-Based Extreme Learning Machine for Image Classification. AB - This paper proposes a novel and simple multilayer feature learning method for image classification by employing the extreme learning machine (ELM). The proposed algorithm is composed of two stages: the multilayer ELM (ML-ELM) feature mapping stage and the ELM learning stage. The ML-ELM feature mapping stage is recursively built by alternating between feature map construction and maximum pooling operation. In particular, the input weights for constructing feature maps are randomly generated and hence need not be trained or tuned, which makes the algorithm highly efficient. Moreover, the maximum pooling operation enables the algorithm to be invariant to certain transformations. During the ELM learning stage, elastic-net regularization is proposed to learn the output weight. Elastic net regularization helps to learn more compact and meaningful output weight. In addition, we preprocess the input data with the dense scale-invariant feature transform operation to improve both the robustness and invariance of the algorithm. To evaluate the effectiveness of the proposed method, several experiments are conducted on three challenging databases. Compared with the conventional deep learning methods and other related ones, the proposed method achieves the best classification results with high computational efficiency. PMID- 29994408 TI - Ensemble Prediction of Synergistic Drug Combinations Incorporating Biological, Chemical, Pharmacological and Network Knowledge. AB - Combinatorial therapy may reduce drug side effects and improve drug efficacy, making combination therapy a promising strategy to treat complex diseases. However, in the existing computational methods, the natural properties and network knowledge of drugs have not been adequately and simultaneously considered, making it difficult to identify effective drug combinations. Computational methods that incorporate multiple sources of information (biological, chemical, pharmacological and network knowledge) offer more opportunities to screen synergistic drug combinations. Therefore, we developed a novel Ensemble Prediction framework of Synergistic Drug Combinations (EPSDC) to accurately and efficiently predict drug combinations by integrating information from multiple-sources. EPSDC constructs feature vector of drug pair by concatenating different types of drug similarities, and then uses these groups in a feature-based base predictor. Next, transductive learning is applied on heterogeneous drug-target networks to achieve a network-based score for the drug pair. Finally, two types of ensemble rules are introduced to combine the feature based score and the network-based score, and then potential drug combinations are prioritized. To demonstrate the effect of the ensemble rule, comprehensive experiments were conducted to compare single models and ensemble models. The experimental results indicated that our method outperformed the state-of-the-art method in five-fold cross validation and de novo prediction tests on the two benchmark datasets. We further analyzed the effect of maximum length of the meta path and the impacts of different types of features. Moreover, the practical usefulness of our method was confirmed in the predicted novel drug combinations. The source code of EPSDC is available at https://github.com/KDDing/EPSDC. PMID- 29994409 TI - User Profiling in Elderly Healthcare Services in China: Scalper Detection. AB - Driven by the automation technologies and health informatics of Industry 4.0, hospitals in China have deployed a complete automation system/platform for healthcare services accessing. Without much more Internet knowledge, elderlies usually seek the third-party to assist them to get healthcare services from Web or APPs, it consequently results in an unexpected situation that scalpers could grab all healthcare services booking by unrighteous means in order to resell to elderlies for a much higher price. Moreover, it is hard for physicians to identify the scalpers due to the complexity, ad-hoc, and multiscenario nature of healthcare processes. In this paper, a novel method is proposed for the identification and creation of user groups of scalpers in mobile healthcare services. The approach utilizes and extends state of the art data analysis approaches in the event-logs of the mobile system to identify user groups. Based on the user groups, user profiles are extracted by identifying representative eventcases from hierarchical user-event clusters. A comprehensive evaluation is conducted in a selected test-set from the event-logs of a mobile healthcare APP. The result shows its accuracy and effectiveness in scalper detection in mobile healthcare APP. Further, a complete case study is deployed in a real word hospital to ensure its utility, efficacy, and reliability. PMID- 29994410 TI - RACE-net: A Recurrent Neural Network for Biomedical Image Segmentation. AB - The level set based deformable models (LDM) are commonly used for medical image segmentation. However, they rely on a handcrafted curve evolution velocity that needs to be adapted for each segmentation task. The Convolutional Neural Networks (CNN) address this issue by learning robust features in a supervised end-to-end manner. However, CNNs employ millions of network parameters which require a large amount of training data to prevent over-fitting and also increases its memory requirement and computation time during testing. Moreover, since CNNs pose segmentation as a region-based pixel labeling, they cannot explicitly model the high-level dependencies between the points on the object boundary to preserve its overall shape, smoothness or the regional homogeneity within and outside the boundary. We present a Recurrent Neural Network (RNN) based solution called the RACE-net to address the above issues. RACE-net models a generalized LDM evolving under a constant and mean curvature velocity. At each time-step, the curve evolution velocities are approximated using a feed-forward architecture inspired by the multi-scale image pyramid. RACE-net allows the curve evolution velocities to be learned in an end-to-end manner while minimizing the number of network parameters, computation time and memory requirements. The RACE-net was validated on three different segmentation tasks: Optic disc and cup in color fundus images, cell nuclei in histopathological images and the left atrium in cardiac MRI volumes. Assessment on public datasets was seen to yield high Dice values between 0.87 and 0.97 which illustrates its utility as a generic, off-the-shelf architecture for biomedical segmentation. PMID- 29994411 TI - Unsupervised Learning For Cell-level Visual Representation with Generative Adversarial Networks. AB - The visual attributes of cells, such as the nuclear morphology and chromatin openness, are critical for histopathology image analysis. By learning cell-level visual representation, we can obtain a rich mix of features that are highly reusable for various tasks, such as cell-level classification, nuclei segmentation, and cell counting. In this paper, we propose a unified generative adversarial networks architecture with a new formulation of loss to perform robust cell-level visual representation learning in an unsupervised setting. Our model is not only label-free and easily trained but also capable of cell-level unsupervised classification with interpretable visualization, which achieves promising results in the unsupervised classification of bone marrow cellular components. Based on the proposed cell-level visual representation learning, we further develop a pipeline that exploits the varieties of cellular elements to perform histopathology image classification, the advantages of which are demonstrated on bone marrow datasets. PMID- 29994412 TI - Multi-task Cascade Convolution Neural Networks for Automatic Thyroid Nodule Detection and Recognition. AB - Thyroid ultrasonography is a widely-used clinical technique for nodule diagnosis in thyroid regions. However, it remains difficult to detect and recognize the nodules due to low contrast, high noise, and diverse appearance of nodules. In today's clinical practice, senior doctors could pinpoint nodules by analyzing global context features, local geometry structure, and intensity changes, which would require rich clinical experience accumulated from hundreds and thousands of nodule case studies. To alleviate doctors' tremendous labor in the diagnosis procedure, we advocate a machine learning approach to the detection and recognition tasks in this paper. In particular, we develop a multi-task cascade convolution neural network framework (MC-CNN) to exploit the context information of thyroid nodules. It may be noted that, our framework is built upon a large number of clinically-confirmed thyroid ultrasound images with accurate and detailed ground truth labels. Other key advantages of our framework result from a multi-task cascade architecture, two stages of carefully-designed deep convolution networks in order to detect and recognize thyroid nodules in a pyramidal fashion, and capturing various intrinsic features in a global-to-local way. Within our framework, the potential regions of interest after initial detection are further fed to the spatial pyramid augmented CNNs to embed multi scale discriminative information for fine-grained thyroid recognition. Experimental results on clinical ultrasound images have indicated that, our MC CNN is accurate and effective for both thyroid nodules detection and recognition. For the correct diagnosis rate of malignant and benign thyroid nodules, its mAP performance can achieve up to 98.2% accuracy, which outperforms the common CNNs by % on average. In addition, we conduct rigorous user studies to confirm that our MC-CNN outperforms experienced doctors, yet only consuming roughly 2% (1/48) of doctors' examination time on average. Therefore, the accuracy and efficiency of our new method exhibit its great potential in clinical applications. PMID- 29994413 TI - Near-Optimal Resilient Control Strategy Design for State-Saturated Networked Systems Under Stochastic Communication Protocol. AB - In this paper, the near-optimal resilient control strategy design problem is investigated for a class of discrete time-varying system in simultaneous presence of stochastic communication protocols (SCPs), gain perturbations, state saturations, and additive nonlinearities. In the sensor-to-controller network, only one sensor is permitted to get access to the communication media so as to avoid possible data collisions. Described by a Markov chain, the SCP is employed to determine which sensor should obtain the access to the network at a certain time. Furthermore, two kinds of well-recognized complexities (i.e., state saturations and additive nonlinearities) are considered in the system model and the phenomenon of controller gain perturbation is also taken into special consideration. Accordingly, the resilient control strategy is designed by: 1) deriving a certain upper bound on the associate cost function of underlying systems and 2) minimizing such an upper bound through the utilization of the completing-the-square technique and the Moore-Penrose pseudo inverse. The resilient control strategy is obtained in an iterative manner by solving a set of coupled backward Riccati-like recursions. Furthermore, based on the proposed control strategies, the infinite horizon case is considered and the corresponding upper bound of the cost function is explicitly provided. Finally, numerical simulations are carried out on power systems in order to verify the validity of the proposed resilient control algorithms. PMID- 29994414 TI - Fault Tolerant Nonrepetitive Trajectory Tracking for MIMO Output Constrained Nonlinear Systems Using Iterative Learning Control. AB - Most works on iterative learning control (ILC) assume identical reference trajectories for the system state over the iteration domain. This fundamental assumption may not always hold in practice, where the desired trajectories or control objectives may be iteration dependent. In this paper, we relax this fundamental assumption, by introducing a new way of modifying the reference trajectories. The concept of modifier functions has been introduced for the first time in the ILC literature. This proposed approach is also a unified framework that can handle other common types of initial conditions in ILC. Multi-input multi-output nonlinear systems are considered, which can be subject to the actuator faults. Time and iteration dependent constraint requirements on the system output can be effectively handled. Backstepping design and composite energy function approach are used in the analysis. We show that in the closed loop analysis, the proposed control scheme can guarantee uniform convergence on the full state tracking error over the iteration domain, beyond a small initial time interval in each iteration, while the constraint requirements on the system output are never violated. In the end two simulation examples are shown to illustrate the efficacy of the proposed ILC algorithm. PMID- 29994415 TI - Evolutionary Multitasking via Explicit Autoencoding. AB - Evolutionary multitasking (EMT) is an emerging research topic in the field of evolutionary computation. In contrast to the traditional single-task evolutionary search, EMT conducts evolutionary search on multiple tasks simultaneously. It aims to improve convergence characteristics across multiple optimization problems at once by seamlessly transferring knowledge among them. Due to the efficacy of EMT, it has attracted lots of research attentions and several EMT algorithms have been proposed in the literature. However, existing EMT algorithms are usually based on a common mode of knowledge transfer in the form of implicit genetic transfer through chromosomal crossover. This mode cannot make use of multiple biases embedded in different evolutionary search operators, which could give better search performance when properly harnessed. Keeping this in mind, this paper proposes an EMT algorithm with explicit genetic transfer across tasks, namely EMT via autoencoding, which allows the incorporation of multiple search mechanisms with different biases in the EMT paradigm. To confirm the efficacy of the proposed EMT algorithm with explicit autoencoding, comprehensive empirical studies have been conducted on both the single- and multi-objective multitask optimization problems. PMID- 29994416 TI - Stereo Video Object Segmentation Using Stereoscopic Foreground Trajectories. AB - We present an unsupervised segmentation framework for stereo videos using stereoscopic trajectories. The proposed stereo trajectory shows favorable properties for modeling the long-term motion information through the whole sequence and explicitly capturing the corresponding relationships between two stereo views. The stereo prior is important for inferring the desired object and guarantees the consistent spatial-temporal segmentation, which contributes to an enjoyable stereo experience. We start by deriving stereo trajectories from left and right views simultaneously, which are represented via a graph structure. Then we detect object-like stereo trajectories via the graph structure to efficiently infer the desired object. Finally, an energy optimization function is proposed to produce the stereo segmentation results via leveraging the object information from stereo trajectories. To benefit potential research, we collected a new stereoscopic video benchmark, which consists of a total of 50 stereo video clips and includes many challenges in segmentation. Extensive experimental results demonstrate that our stereo segmentation method achieves higher performance and preserves better stereo structures, compared with prevailing competitors. The source code and results are available at: https://github.com/shenjianbing/StereoSeg. PMID- 29994417 TI - Memetic Search for Identifying Critical Nodes in Sparse Graphs. AB - Critical node problems (CNPs) involve finding a set of critical nodes from a graph whose removal results in optimizing a predefined measure over the residual graph. As useful models for a variety of practical applications, these problems are computationally challenging. In this paper, we study the classic CNP and introduce an effective memetic algorithm for solving CNP. The proposed algorithm combines a double backbone-based crossover operator (to generate promising offspring solutions), a component-based neighborhood search procedure (to find high-quality local optima), and a rank-based pool updating strategy (to guarantee a healthy population). Extensive evaluations on 42 synthetic and real-world benchmark instances show that the proposed algorithm discovers 24 new upper bounds and matches 15 previous best-known bounds. We also demonstrate the relevance of our algorithm for effectively solving a variant of the classic CNP, called the cardinality-constrained CNP. Finally, we investigate the usefulness of each key algorithmic component. PMID- 29994418 TI - Analysis of Spatio-temporal Representations for Robust Footstep Recognition with Deep Residual Neural Networks. AB - Human footsteps can provide a unique behavioural pattern for robust biometric systems. We propose spatio-temporal footstep representations from floor-only sensor data in advanced computational models for automatic biometric verification. Our models deliver an artificial intelligence capable of effectively differentiating the fine-grained variability of footsteps between legitimate users (clients) and impostor users of the biometric system. The methodology is validated in the largest to date footstep database, containing nearly 20,000 footstep signals from more than 120 users. The database is organized by considering a large cohort of impostors and a small set of clients to verify the reliability of biometric systems. We provide experimental results in 3 critical data-driven security scenarios, according to the amount of footstep data made available for model training: at airports security checkpoints (smallest training set), workspace environments (medium training set) and home environments (largest training set). We report state-of-the-art footstep recognition rates with an optimal equal false acceptance and false rejection rate of 0.7% (equal error rate), an improvement ratio of 371% from previous state-of the-art. We perform a feature analysis of deep residual neural networks showing effective clustering of client's footstep data and provide insights of the feature learning process. PMID- 29994419 TI - Efficient Encrypted Images Filtering and Transform Coding with Walsh-Hadamard Transform and Parallelization. AB - Since homomorphic encryption operations have high computational complexity, image applications based on homomorphic encryption are often time consuming, which makes them impractical. In this paper, we study efficient encrypted image applications with the encrypted domain Walsh-Hadamard transform (WHT) and parallel algorithms. We first present methods to implement real and complex WHTs in the encrypted domain. We then propose a parallel algorithm to improve the computational efficiency of the encrypted domain WHT. To compare the WHT with the discrete cosine transform (DCT), integer DCT, and Haar transform in the encrypted domain, we conduct theoretical analysis and experimental verification, which reveal that the encrypted domain WHT has the advantages of lower computational complexity and a shorter running time. Our analysis shows that the encrypted WHT can accommodate plaintext data of larger values. We propose two encrypted image applications using the encrypted domain WHT. To accelerate the practical execution, we present two parallelization strategies for the proposed applications. The experimental results show that the speedup of the homomorphic encrypted image application exceeds 12. PMID- 29994420 TI - Joint Separable and Non-Separable Transforms for Next-Generation Video Coding. AB - Throughout the past few decades, the separable Discrete Cosine Transform (DCT), particularly the DCT type II, has been widely used in image and video compression. It is well known that, under first-order stationary Markov conditions, DCT is an efficient approximation of the optimal Karhunen-Loeve transform. However, for natural image and video sources, the adaptivity of a single separable transform with fixed core is rather limited for the highly dynamic image statistics, e.g., textures and arbitrarily directed edges. It is also known that non-separable transforms can achieve better compression efficiency for images with directional texture patterns, yet they are computationally complex, especially when the transform size is large. In order to achieve higher transform coding gains with relatively low-complexity implementations, we propose a joint separable and non-separable transform. The proposed separable primary transform, named Enhanced Multiple Transform (EMT), applies multiple transform cores from a pre-defined subset of sinusoidal transforms, and the transform selection is signaled in a joint block level manner. Moreover, a Non-Separable Secondary Transform (NSST) method is proposed to operate in conjunction with EMT. Unlike the existing non-separable transform schemes which require excessive amounts of memory and computation, the proposed NSST efficiently improves coding gain with much lower complexity. Extensive experimental results show that the proposed methods, in a state-of-the-art video codec, such as HEVC, can provide significant coding gains (average 6.9% and 4.5% bitrate reductions for intra and random-access coding, respectively). PMID- 29994421 TI - Animation Plans for Before-and-After Satellite Images. AB - Before-and-after image pairs show how entities in a given region have evolved over a specific period of time. Satellite images are a major source of such data, that capture how natural phenomena or human activity impact a geographical area. These images are used both for data analysis and to illustrate the resulting findings to diverse audiences. The simple techniques used to display them, including juxtaposing, swapping and monolithic blending, often fail to convey the underlying phenomenon in a meaningful manner. We introduce Baia, a framework to create advanced animated transitions, called animation plans, between before-and after images. Baia relies on a pixel-based transition model that gives authors much expressive power, while keeping animations for common types of changes easy to create thanks to predefined animation primitives. We describe our model, the associated animation editor, and report on two user studies. In the first study, advanced transitions enabled by Baia were compared to monolithic blending, and perceived as more realistic and better at focusing viewer's attention on a region of interest than the latter. The second study aimed at gathering feedback about the usability of Baia's animation editor. PMID- 29994422 TI - MultiStream: A Multiresolution Streamgraph Approach to Explore Hierarchical Time Series. AB - Multiple time series are a set of multiple quantitative variables occurring at the same interval. They are present in many domains such as medicine, finance, and manufacturing for analytical purposes. In recent years, streamgraph visualization (evolved from ThemeRiver) has been widely used for representing temporal evolution patterns in multiple time series. However, streamgraph as well as ThemeRiver suffer from scalability problems when dealing with several time series. To solve this problem, multiple time series can be organized into a hierarchical structure where individual time series are grouped hierarchically according to their proximity. In this paper, we present a new streamgraph-based approach to convey the hierarchical structure of multiple time series to facilitate the exploration and comparisons of temporal evolution. Based on a focus+context technique, our method allows time series exploration at different granularities (e.g., from overview to details). To illustrate our approach, two usage examples are presented. PMID- 29994423 TI - Learning to Refine Expansion Terms for Biomedical Information Retrieval using Semantic Resources. AB - With the rapid development of biomedicine, the number of biomedical articles has increased accordingly, which presents a great challenge for biologists trying to keep up with the latest research. Information retrieval technologies seek to meet this challenge by searching among a large number of articles based on a given query and providing the most relevant ones to fulfill information needs. As an effective information retrieval technique, query expansion has some room for improvement to achieve the desired performance when directly applied for biomedical information retrieval because there exist many domain-related terms both in users' queries and in related articles. To solve this problem, we propose a biomedical query expansion framework based on learning-to-rank methods, in which we refine the candidate expansion terms by training term-ranking models to select the most relevant terms for enriching the original query. To train the term-ranking models, we first propose a pseudo-relevance feedback method based on MeSH to select candidate expansion terms and then represent the candidate terms as feature vectors by defining both the corpus-based term features and the resource-based term features. Experimental results obtained for TREC genomics datasets show that our method can capture more relevant terms to expand the original query and effectively improve biomedical information retrieval performance. PMID- 29994424 TI - Nonfragile State Estimation of Quantized Complex Networks With Switching Topologies. AB - This paper considers the nonfragile $H_?infty $ estimation problem for a class of complex networks with switching topologies and quantization effects. The network architecture is assumed to be dynamic and evolves with time according to a random process subject to a sojourn probability. The coupled signal is to be quantized before transmission due to power and bandwidth constraints, and the quantization errors are transformed into sector-bounded uncertainties. The concept of nonfragility is introduced by inserting randomly occurred uncertainties into the estimator parameters to cope with the unavoidable small gain variations emerging from the implementations of estimators. Both the quantizers and the estimators have several operation modes depending on the switching signal of the underlying network structure. A sufficient condition is provided via a linear matrix inequality approach to ensure the estimation error dynamic to be stochastically stable in the absence of external disturbances, and the $H_?infty $ performance with a prescribed index is also satisfied. Finally, a numerical example is presented to clarify the validity of the proposed method. PMID- 29994425 TI - Sequential Independent Component Analysis Density Estimation. AB - A problem of multivariate probability density function estimation by exploiting linear independent components analysis (ICA) is addressed. Historically, ICA density estimation was initially proposed under the name projection pursuit density estimation (PPDE) and two basic methods, named forward and backward, were published. We derive a modification of the forward PPDE method, which avoids a computationally demanding optimization involving Monte Carlo sampling of the original method. The results of the experiments show that the proposed method presents an attractive choice for density estimation, which is pronounced for a small number of training observations. Under such conditions, our method usually outperforms model-based Gaussian mixture model. We also found that our method obtained better results than the backward PPDE methods in the situation of nonfactorizable underlying density functions. The proposed method has demonstrated a competitive performance compared with the support vector machine and the extreme learning machine in some real classification tasks. PMID- 29994426 TI - Experimental Study of Artificial Neural Networks Using a Digital Memristor Simulator. AB - This paper presents a fully digital implementation of a memristor hardware (HW) simulator, as the core of an emulator, based on a behavioral model of voltage controlled threshold-type bipolar memristors. Compared to other analog solutions, the proposed digital design is compact, easily reconfigurable, demonstrates very good matching with the mathematical model on which it is based, and complies with all the required features for memristor emulators. We validated its functionality using Altera Quartus II and ModelSim tools targeting low-cost yet powerful field programmable gate array families. We tested its suitability for complex memristive circuits as well as its synapse functioning in artificial neural networks, implementing examples of associative memory and unsupervised learning of spatiotemporal correlations in parallel input streams using a simplified spike timing-dependent plasticity. We provide the full circuit schematics of all our digital circuit designs and comment on the required HW resources and their scaling trends, thus presenting a design framework for applications based on our HW simulator. PMID- 29994427 TI - F-SVM: Combination of Feature Transformation and SVM Learning via Convex Relaxation. AB - The generalization error bound of the support vector machine (SVM) depends on the ratio of the radius and margin. However, conventional SVM only considers the maximization of the margin but ignores the minimization of the radius, which restricts its performance when applied to joint learning of feature transformation and the SVM classifier. Although several approaches have been proposed to integrate the radius and margin information, most of them either require the form of the transformation matrix to be diagonal, or are nonconvex and computationally expensive. In this paper, we suggest a novel approximation for the radius of the minimum enclosing ball in feature space, and then propose a convex radius-margin-based SVM model for joint learning of feature transformation and the SVM classifier, i.e., F-SVM. A generalized block coordinate descent method is adopted to solve the F-SVM model, where the feature transformation is updated via the gradient descent and the classifier is updated by employing the existing SVM solver. By incorporating with kernel principal component analysis, F SVM is further extended for joint learning of nonlinear transformation and the classifier. F-SVM can also be incorporated with deep convolutional networks to improve image classification performance. Experiments on the UCI, LFW, MNIST, CIFAR-10, CIFAR-100, and Caltech101 data sets demonstrate the effectiveness of F SVM. PMID- 29994428 TI - Permutation Jaccard Distance-Based Hierarchical Clustering to Estimate EEG Network Density Modifications in MCI Subjects. AB - In this paper, a novel electroencephalographic (EEG)-based method is introduced for the quantification of brain-electrical connectivity changes over a longitudinal evaluation of mild cognitive impaired (MCI) subjects. In the proposed method, a dissimilarity matrix is constructed by estimating the coupling strength between every pair of EEG signals, Hierarchical clustering is then applied to group the related electrodes according to the dissimilarity estimated on pairs of EEG recordings. Subsequently, the connectivity density of the electrodes network is calculated. The technique was tested over two different coupling strength descriptors: wavelet coherence (WC) and permutation Jaccard distance (PJD), a novel metric of coupling strength between time series introduced in this paper. Twenty-five MCI patients were enrolled within a follow up program that consisted of two successive evaluations, at time T0 and at time T1, three months later. At T1, four subjects were diagnosed to have converted to Alzheimer's Disease (AD). When applying the PJD-based method, the converted patients exhibited a significantly increased PJD (p < 0.05), i.e., a reduced overall coupling strength, specifically in delta and theta bands and in the overall range (0.5-32 Hz). In addition, in contrast to stable MCI patients, converted patients exhibited a network density reduction in every subband (delta, theta, alpha, and beta). When WC was used as coupling strength descriptor, the method resulted in a less sensitive and specific outcome. The proposed method, mixing nonlinear analysis to a machine learning approach, appears to provide an objective evaluation of the connectivity density modifications associated to the MCI-AD conversion, just processing noninvasive EEG signals. PMID- 29994429 TI - Learning From Multiple Imperfect Instructors in Sensor Networks. AB - This paper presents a sequential learning framework for sensors in a network, where a few sensors assume the role of an instructor to train other sensors in the network. The instructors provide estimated labels for measurements of new sensors. These labels are possibly noisy, because a classifier of the instructor may not be perfect. A recursive density estimator is proposed to obtain the true measurement model (i.e., the observation density conditioned on the label) in spite of the training with noisy labels. Specifically, this paper answers the question "Can a sensor train other sensors?", provides necessary conditions for sensors to act as instructors, presents a sequential learning framework using recursive nonparametric kernel density estimation, and provides a convergence rate for the expected error in an observation density. The underlying concepts are illustrated and validated with simulation results. PMID- 29994430 TI - Progressive Stochastic Learning for Noisy Labels. AB - Large-scale learning problems require a plethora of labels that can be efficiently collected from crowdsourcing services at low cost. However, labels annotated by crowdsourced workers are often noisy, which inevitably degrades the performance of large-scale optimizations including the prevalent stochastic gradient descent (SGD). Specifically, these noisy labels adversely affect updates of the primal variable in conventional SGD. To solve this challenge, we propose a robust SGD mechanism called progressive stochastic learning (POSTAL), which naturally integrates the learning regime of curriculum learning (CL) with the update process of vanilla SGD. Our inspiration comes from the progressive learning process of CL, namely learning from "easy" tasks to "complex" tasks. Through the robust learning process of CL, POSTAL aims to yield robust updates of the primal variable on an ordered label sequence, namely, from "reliable" labels to "noisy" labels. To realize POSTAL mechanism, we design a cluster of "screening losses," which sorts all labels from the reliable region to the noisy region. To sum up, POSTAL using screening losses ensures robust updates of the primal variable on reliable labels first, then on noisy labels incrementally until convergence. In theory, we derive the convergence rate of POSTAL realized by screening losses. Meanwhile, we provide the robustness analysis of representative screening losses. Experimental results on UCI1 simulated and Amazon Mechanical Turk crowdsourcing data sets show that the POSTAL using screening losses is more effective and robust than several existing baselines.1UCI is the abbreviation of University of California Irvine. PMID- 29994431 TI - Identifying Resting-state Multi-Frequency Biomarkers via Tree-Guided Group Sparse Learning for Schizophrenia Classification. AB - The fractional amplitude of low-frequency fluctuations (fALFF) has been widely used as potential clinical biomarkers for resting-state functional magnetic resonance imaging based schizophrenia diagnosis. However, previous studies usually measure the fALFF with specific bands from 0.01-0.08 Hz, which cannot fully delineate the complex variations of spontaneous fluctuations in the resting state brain. As we konow, fALFF data is intrinsically constrained by the brain structure, but most of the traditional methods have not consider it in feature selection. For addressing these problems, we propose a model to classify schizophrenia in multi-frequency bands with tree-guided group sparse learning. In detail, we first acquire the fALFF data in multi-frequency bands (i.e., slow 5:0.01-0.027 Hz, slow-4:0.027-0.073 Hz, slow-3:0.073-0.198 Hz and slow-2:0.198 0.25 Hz). Then, we divide the whole brain into different candidate patches, and select those significant patches related to schizophrenia using random forest based importancescore. Moreover, we use tree-structured sparse learning method for feature selection with above patches spatial constraint. Finally, considering biomarkers from multi-frequency bands can reflect complementary information among multiple frequency bands, we adopt the multi-kernel learning (MKL) method to combine features of multi-frequency bands for classification. Our experimental results show that these biomarkers from multi-frequency bands can achieve a classification accuracy of 91.1% on 17 schizophrenia patients and 17 healthy controls, further demonstrating the multi-frequency bands analysis can better account for classification of schizophrenia. PMID- 29994432 TI - Robust Detection of Audio-Cough Events using local Hu moments. AB - Telehealth has shown potential to improve access to health-care cost-effectively in respiratory illness. However, it has failed to live up to expectation, in part because of poor objective measures of symptoms such as cough events, which could lead to early diagnosis or prevention. Considering the burden that these conditions constitute for national health systems, an effort is needed to foster telehealth potential by developing low cost technology for efficient monitoring and analysis of cough events. This paper, proposes the use of local Hu moments as a robust feature set for automatic cough detection in smartphone-acquired audio signals. The final system feeds a k-Nearest Neighbors classifier with the extracted features. To properly evaluate the system in a diversity of noisy backgrounds, we contaminated real cough audio data with a variety of sounds including noise from both indoor and outdoor environments, and non-cough events (sneeze, laugh, speech, etc.). The created database allows flexible settings of Signal to Noise Ratio (SNR) levels between background sounds and events (cough and non-cough). This evaluation was complemented using real patient data from an outpatient clinic. The system is able to detect cough events with high sensitivity (up to 88.51%) and specificity (up to 99.77%) in a variety of noisy environments, overcoming other state-of-the-art audio features. Our proposal paves the way for ubiquitous cough monitoring with minimal disruption in daily activities. PMID- 29994433 TI - Multiagent Rendezvous With Shortest Distance to Convex Regions With Empty Intersection: Algorithms and Experiments. AB - This paper presents both algorithms and experimental results to solve a distributed rendezvous problem with shortest distance to convex regions. In a multiagent network, each agent is assigned to a certain convex region and has information about only its own region. All these regions might not have an intersection. Through local interaction with their neighbors, multiple agents collectively rendezvous at an optimal location that is a priori unknown to each agent and has the shortest total squared distance to these regions. First, a distributed time-varying algorithm is introduced, where a corresponding condition is given to guarantee that all agents rendezvous at the optimal location asymptotically for bounded convex regions. Then a distributed tracking algorithm combined with a distributed estimation algorithm is proposed. It is first shown that for general possibly unbounded convex regions, all agents rendezvous in finite time and then collectively slide to the optimal location asymptotically. Then it is shown that for convex regions with certain projection compressibility, all agents collectively rendezvous at the optimal location in finite time, even when the regions are time varying. The algorithms are experimentally implemented on multiple ground robots to illustrate the obtained theoretical results. PMID- 29994434 TI - Reach-Avoid Games With Two Defenders and One Attacker: An Analytical Approach. AB - This paper considers a reach-avoid game on a rectangular domain with two defenders and one attacker. The attacker aims to reach a specified edge of the game domain boundary, while the defenders strive to prevent that by capturing the attacker. First, we are concerned with the barrier, which is the boundary of the reach-avoid set, splitting the state space into two disjoint parts: 1) defender dominance region (DDR) and 2) attacker dominance region (ADR). For the initial states lying in the DDR, there exists a strategy for the defenders to intercept the attacker regardless of the attacker's best effort, while for the initial states lying in the ADR, the attacker can always find a successful attack strategy. We propose an attack region method to construct the barrier analytically by employing Voronoi diagram and Apollonius circle for two kinds of speed ratios. Then, by taking practical payoff functions into considerations, we present optimal strategies for the players when their initial states lie in their winning regions, and show that the ADR is divided into several parts corresponding to different strategies for the players. Numerical approaches, which suffer from inherent inaccuracy, have already been utilized for multiplayer reach-avoid games, but computational complexity complicates solving such games and consequently hinders efficient on-line applications. However, this method can obtain the exact formulation of the barrier and is applicable for real-time updates. PMID- 29994435 TI - Increasing Interpretation of Web Topic Detection via Prototype Learning From Sparse Poisson Deconvolution. AB - Organizing webpages into interesting topics is one of the key steps to understand the trends from multimodal Web data. The sparse, noisy, and less-constrained user generated content results in inefficient feature representations. These descriptors unavoidably cause that a detected topic still contains a certain number of the false detected webpages, which further make a topic be less coherent, less interpretable, and less useful. In this paper, we address this problem from a viewpoint interpreting a topic by its prototypes, and present a two-step approach to achieve this goal. Following the detection-by-ranking approach, a sparse Poisson deconvolution is proposed to learn the intratopic similarities between webpages. To find the prototypes, leveraging the intratopic similarities, top-k diverse yet representative prototype webpages are identified from a submodularity function. Experimental results not only show the improved accuracies for the Web topic detection task, but also increase the interpretation of a topic by its prototypes on two public datasets. PMID- 29994436 TI - A Novel Deep Learning-Based Collaborative Filtering Model for Recommendation System. AB - The collaborative filtering (CF) based models are capable of grasping the interaction or correlation of users and items under consideration. However, existing CF-based methods can only grasp single type of relation, such as restricted Boltzmann machine which distinctly seize the correlation of user-user or item-item relation. On the other hand, matrix factorization explicitly captures the interaction between them. To overcome these setbacks in CF-based methods, we propose a novel deep learning method which imitates an effective intelligent recommendation by understanding the users and items beforehand. In the initial stage, corresponding low-dimensional vectors of users and items are learned separately, which embeds the semantic information reflecting the user user and item-item correlation. During the prediction stage, a feed-forward neural networks is employed to simulate the interaction between user and item, where the corresponding pretrained representational vectors are taken as inputs of the neural networks. Several experiments based on two benchmark datasets (MovieLens 1M and MovieLens 10M) are carried out to verify the effectiveness of the proposed method, and the result shows that our model outperforms previous methods that used feed-forward neural networks by a significant margin and performs very comparably with state-of-the-art methods on both datasets. PMID- 29994437 TI - A Two-Phase Meta-Heuristic for Multiobjective Flexible Job Shop Scheduling Problem With Total Energy Consumption Threshold. AB - Flexible job shop scheduling problem (FJSP) has been extensively considered; however, multiobjective FJSP with energy consumption threshold is seldom investigated, the goal of which is to minimize makespan and total tardiness under the constraint that total energy consumption does not exceed a given threshold. Energy constraint is not always met and the threshold is difficult to be decided in advance. These features make it more difficult to solve the problem. In this paper, a two-phase meta-heuristic (TPM) based on imperialist competitive algorithm (ICA) and variable neighborhood search (VNS) is proposed. In the first phase, the problem is converted into FJSP with makespan, total tardiness and total energy consumption and the new FJSP is solved by an ICA, which uses some new methods to build initial empires and do imperialist competition. In the second phase, new strategies are provided for comparing solutions and updating the nondominated set of the first phase and a VNS is used for the original problem. The current solution of VNS is periodically replaced with member of the set $Omega$ to improve solution quality. An energy consumption threshold is obtained by optimization. Extensive experiments are conducted to test the performance of TPM finally. The computational results show that TPM is a very competitive algorithm for the considered FJSP. PMID- 29994438 TI - Empirical Bayesian Light-Field Stereo Matching by Robust Pseudo Random Field Modeling. AB - Light-field stereo matching problems are commonly modeled by Markov Random Fields (MRFs) for statistical inference of depth maps. Nevertheless, most previous approaches did not adapt to image statistics but instead adopted fixed model parameters. They explored explicit vision cues, such as depth consistency and occlusion, to provide local adaptability and enhance depth quality. However, such additional assumptions could end up confining their applicability, e.g. algorithms designed for dense view sampling are not suitable for sparse one. In this paper, we get back to MRF fundamentals and develop an empirical Bayesian framework-Robust Pseudo Random Field-to explore intrinsic statistical cues for broad applicability. Based on pseudo-likelihoods with hidden soft-edge priors, we apply soft expectation-maximization (EM) for good model fitting and perform hard EM for robust depth estimation. We introduce novel pixel difference models to enable such adaptability and robustness simultaneously. Accordingly, we devise a stereo matching algorithm to employ this framework on dense, sparse, and even denoised light fields. It can be applied to both true-color and grey-scale pixels. Experimental results show that it estimates scene-dependent parameters robustly and converges quickly. In terms of depth accuracy and computation speed, it also outperforms state-of-the-art algorithms constantly. PMID- 29994439 TI - Fully Convolutional Architectures for Multiclass Segmentation in Chest Radiographs. AB - The success of deep convolutional neural networks (NNs) on image classification and recognition tasks has led to new applications in very diversified contexts, including the field of medical imaging. In this paper, we investigate and propose NN architectures for automated multiclass segmentation of anatomical organs in chest radiographs (CXRs), namely for lungs, clavicles, and heart. We address several open challenges including model overfitting, reducing number of parameters, and handling of severely imbalanced data in CXR by fusing recent concepts in convolutional networks and adapting them to the segmentation problem task in CXR. We demonstrate that our architecture combining delayed subsampling, exponential linear units, highly restrictive regularization, and a large number of high-resolution low-level abstract features outperforms state-of-the-art methods on all considered organs, as well as the human observer on lungs and heart. The models use a multiclass configuration with three target classes and are trained and tested on the publicly available Japanese Society of Radiological Technology database, consisting of 247 X-ray images the ground-truth masks for which are available in the segmentation in CXR database. Our best performing model, trained with the loss function based on the Dice coefficient, reached mean Jaccard overlap scores of 95% for lungs, 86.8% for clavicles, and 88.2% for heart. This architecture outperformed the human observer results for lungs and heart. PMID- 29994440 TI - Prospective Respiration Detection in Magnetic Resonance Imaging by a Non Interfering Noise Navigator. AB - Passive monitoring of the thermal noise variances of the channels of a receive array was shown to reveal respiratory motion of the underlying anatomy, a so called "noise navigator". There is, however, an inevitable trade off between the accuracy and temporal resolution of the noise navigator due to its passive nature. A temporal filter has to be added to the noise navigator to accurately reveal respiration and retain temporal resolution. For real-time applications of the noise navigator, e.g., prospective motion correction or motion tracking, the added filter must be prospective. Thus a prospective Kalman filter was designed to predict respiration from the noise navigator without a temporal delay. The performance of the noise navigator enhanced by this prospective Kalman filter was explored and the robustness of the proposed method was assessed on healthy volunteers. The respiratory signal could be measured by the noise navigator independent of magnetic resonance acquisition. The calculated respiratory signal was qualitatively compared with the respiratory bellows. In addition, a strong linear relationship was found between the prospective noise navigator and a quantitative 2-D image navigator for measurements, including free and tasked breathing. PMID- 29994441 TI - Deep Neural Networks for Ultrasound Beamforming. AB - We investigate the use of deep neural networks (DNNs) for suppressing off-axis scattering in ultrasound channel data. Our implementation operates in the frequency domain via the short-time Fourier transform. The inputs to the DNN consisted of the separated real and imaginary components (i.e. in-phase and quadrature components) observed across the aperture of the array, at a single frequency and for a single depth. Different networks were trained for different frequencies. The output had the same structure as the input and the real and imaginary components were combined as complex data before an inverse short-time Fourier transform was used to reconstruct channel data. Using simulation, physical phantom experiment, and in vivo scans from a human liver, we compared this DNN approach to standard delay-and-sum (DAS) beamforming and an adaptive imaging technique that uses the coherence factor. For a simulated point target, the side lobes when using the DNN approach were about 60 dB below those of standard DAS. For a simulated anechoic cyst, the DNN approach improved contrast ratio (CR) and contrast-to-noise (CNR) ratio by 8.8 dB and 0.3 dB, respectively, compared with DAS. For an anechoic cyst in a physical phantom, the DNN approach improved CR and CNR by 17.1 dB and 0.7 dB, respectively. For two in vivo scans, the DNN approach improved CR and CNR by 13.8 dB and 9.7 dB, respectively. We also explored methods for examining how the networks in this paper function. PMID- 29994442 TI - Effective Sequential Classifier Training for SVM-Based Multitemporal Remote Sensing Image Classification. AB - The explosive availability of remote sensing images has challenged supervised classification algorithms such as Support Vector Machines (SVM), as training samples tend to be highly limited due to the expensive and laborious task of ground truthing. The temporal correlation and spectral similarity between multitemporal images have opened up an opportunity to alleviate this problem. In this study, a SVM-based Sequential Classifier Training (SCT-SVM) approach is proposed for multitemporal remote sensing image classification. The approach leverages the classifiers of previous images to reduce the required number of training samples for the classifier training of an incoming image. For each incoming image, a rough classifier is firstly predicted based on the temporal trend of a set of previous classifiers. The predicted classifier is then fine tuned into a more accurate position with current training samples. This approach can be applied progressively to sequential image data, with only a small number of training samples being required from each image. Experiments were conducted with Sentinel-2A multitemporal data over an agricultural area in Australia. Results showed that the proposed SCT-SVM achieved better classification accuracies compared with two state-of-the-art model transfer algorithms. When training data are insufficient, the overall classification accuracy of the incoming image was improved from 76.18% to 94.02% with the proposed SCT-SVM, compared with those obtained without the assistance from previous images. These results demonstrate that the leverage of a priori information from previous images can provide advantageous assistance for later images in multitemporal image classification. PMID- 29994443 TI - Region-Aware Reflection Removal with Unified Content and Gradient Priors. AB - Removing the undesired reflections in images taken through the glass is of broad application to various image processing and computer vision tasks. Existing single image based solutions heavily rely on scene priors such as separable sparse gradients caused by different levels of blur, and they are fragile when such priors are not observed. In this paper, we notice that strong reflections usually dominant a limited region in the whole image, and propose a Region-aware Reflection Removal (R3) approach by automatically detecting and heterogeneously processing regions with and without reflections. We integrate content and gradient priors to jointly achieve missing contents restoration as well as background and reflection separation in a unified optimization framework. Extensive validation using 50 sets of real data shows that the proposed method outperforms state-of-the-art on both quantitative metrics and visual qualities. PMID- 29994444 TI - A Novel Computational Approach for Global Alignment for Multiple Biological Networks. AB - Due to the rapid progress of biological networks for modeling biological systems, a lot of biomolecular networks have been producing more and more protein-protein interaction (PPI) data. Analyzing protein-protein interaction (PPI) networks aims to find regions of topological and functional (dis)similarities between molecular networks of different species. The study of PPI networks has the potential to teach us as much about life process and diseases at the molecular level. Although few methods have been developed for multiple PPI network alignment and thus, new network alignment methods are of a compelling need. In this paper, we propose a novel algorithm for a global alignment of multiple protein-protein interaction (PPI) networks called MAPPIN. The latter relies on information available for the proteins in the networks, such as sequence, function and network topology. Our algorithm is perfectly designed to exploit current multi-core CPU architectures, and has been extensively tested on a real data (eight species). Our experimental results show that MAPPIN significantly outperforms NetCoffee in terms of coverage. Nevertheless, MAPPIN is handicapped by the time required to load the gene annotation file. An extensive comparison versus the pioneering PPI methods also show that MAPPIN is often efficient in terms of coverage, mean entropy or mean normalized. PMID- 29994445 TI - Sequential Emboli Detection from Ultrasound Outpatient Data. AB - This paper addresses the detection of emboli from signals acquired with a new miniaturized and portable transcranial Doppler ultrasound device. The use of this device enables outpatient monitoring but increases the number of artifacts. These artifacts usually come from the patient voice and motion and can be superimposed to emboli. For this reason and because of the scarcity of emboli compared to artifacts, reliably detect emboli is a challenging task. As an example, the 11809 s of signal used in this study contained 0.06 % of embolic events and 10.14 % of artifacts. Herein, we propose an automatic and sequential approach. The method is based on sequential determination of high intensity transient signal. We also define efficient features to describe emboli in the time frequency representation. On our database, the number of artifacts detected as emboli is divided by more than 10 compared to the other algorithms reported in the literature. PMID- 29994446 TI - SDI+: a Novel Algorithm for Segmenting Dermoscopic Images. AB - Malignant skin lesions are among the most common types of cancer, and automated systems for their early detection are of fundamental importance. We propose SDI+, an unsupervised algorithm for the segmentation of skin lesions in dermoscopic images. It is articulated into three steps, aimed at extracting preliminary information on possible confounding factors, accurately segmenting the lesion, and post-processing the result. The overall method achieves high accuracy on dark skin lesions and can handle several cases where confounding factors could inhibit a clear understanding by a human operator. We present extensive experimental results and comparisons achieved by the SDI+ algorithm on the ISIC 2017 dataset, highlighting the advantages and disadvantages. PMID- 29994447 TI - Multiple Intentional Delays Can Facilitate Fast Consensus and Noise Reduction in a Multiagent System. AB - We investigate the use of a derivative-free control scheme called the multiple delay proportional-retarded (PR) protocol to achieve fast consensus in a large scale multiagent system. The delays are intentionally introduced in the PR with the purpose of creating derivative-like controllers that rely only on position measurements, thus mitigating undesirable noise effects. The main result places the spectral abscissa of the consensus dynamics at a desired locus and also achieves a user-defined spectral ''separation,'' both of which directly influence convergence to consensus. Design rules and limitations arising from analytical derivations to achieve these results are laid out. Case studies are provided to demonstrate the concepts. PMID- 29994448 TI - Clustering Homogeneous Granular Data: Formation and Evaluation. AB - In this paper, we develop a comprehensive conceptual and algorithmic framework to cope with a problem of clustering homogeneous information granules. While there have been several approaches to coping with granular (viz. non-numeric) data, the origin of granular data themselves considered there is somewhat unclear and, as a consequence, the results of clustering start lacking some full-fledged interpretation. In this paper, we offer a holistic view at clustering information granules and an evaluation of the results of clustering. We start with a process of forming information granules with the use of the principle of justifiable granularity (PJG). With this regard, we discuss a number of parameters used in this development of information granules as well as quantify the quality of the granules produced in this manner. In the sequel, Fuzzy C-Means is applied to cluster the derived information granules, which are represented in a parametric manner and associated with weights resulting from the usage of the PJG. The quality of clustering results is evaluated through the use of the reconstruction criterion (quantifying the concept of information granulation and degranulation). A suite of experiments using synthetic and publicly available datasets is reported to quantify the performance of the proposed approach and highlight its key features. PMID- 29994449 TI - Distributed Event-Triggered Cooperative Control for Frequency and Voltage Stability and Power Sharing in Isolated Inverter-Based Microgrid. AB - The distributed cooperative control for frequency and voltage stability and power sharing in microgrid considering the limitation of communication network is concerned in this paper. Two types of novel event-triggered mechanism with distributed architecture are first proposed, which can greatly reduce the communication burdens among power source inverters. Based on the event-triggered schemes, distributed restoration mechanism is constructed, which can restore the frequency and voltage magnitude of microgrid and realize the fair utilization of all power sources with comparative less requirements for the transmission data. Simulation is carried out to verify the effectiveness of the proposed method. PMID- 29994450 TI - Double-Loop Stability for High Frequency Networked Control Systems Subject to Actuator Saturation. AB - This paper generalizes stability for a high frequency networked control system (NCS) subject to actuator saturation via integral quadratic constraints. A delta operator system with a high frequency constraint is used to model the high frequency NCS. Double-loop stability is treated via outer-loop and interloop feedback configurations for the high frequency NCS. Stability criteria are derived with the high frequency constraint and actuator saturation by a generalized Kalman-Yakubovich-Popov lemma. Numerical results are provided to demonstrate the effectiveness of the proposed techniques in this paper. PMID- 29994451 TI - Incentive Stackelberg Games for Stochastic Linear Systems With Hinfinity Constraint. AB - In this paper, incentive Stackelberg games with one leader and multiple followers are investigated for a class of stochastic linear systems with external disturbance. Unlike the existing ordinary Stackelberg games, the leader is required to design an incentive Stackelberg strategy set that can lead to the leader's team-optimal solution and the follower's Nash equilibrium, and attenuate the external disturbance in the system simultaneously. It is shown that the incentive Stackelberg strategy set is obtained by solving a set of the cross coupled stochastic Riccati differential equations in a finite-horizon case and a set of the cross-coupled stochastic algebraic Riccati equations in an infinite horizon case. Numerical examples are solved to demonstrate the effectiveness of the proposed incentive Stackelberg strategy set. PMID- 29994452 TI - HARD-PnP: PnP Optimization Using a Hybrid Approximate Representation. AB - This paper proposes a Hybrid Approximate Representation (HAR) based on unifying several efficient approximations of the generalized reprojection error (which is known as the gold standard for multiview geometry). The HAR is an over parameterization scheme where the approximation is applied simultaneously in multiple parameter spaces. A joint minimization scheme "HAR-Descent" can then solve the PnP problem efficiently, while remaining robust to approximation errors and local minima. The technique is evaluated extensively, including the synthetic benchmark protocols introduced by both [1] and [2]. Additionally, the real-world data evaluations of [2], [3] and [4] are all examined. The proposed technique was found to have runtime complexity comparable to the fastest techniques, and up to 10 times faster than current state of the art minimization approaches. In addition, the accuracy exceeds that of all 9 previous techniques tested, providing definitive state of the art performance on the benchmarks, across all 90 of the experiments in the paper and supplementary material. PMID- 29994454 TI - Local Deep-Feature Alignment for Unsupervised Dimension Reduction. AB - This paper presents an unsupervised deep-learning framework named Local Deep Feature Alignment (LDFA) for dimension reduction. We construct neighbourhood for each data sample and learn a local Stacked Contractive Auto-encoder (SCAE) from the neighbourhood to extract the local deep features. Next, we exploit an affine transformation to align the local deep features of each neighbourhood with the global features. Moreover, we derive an approach from LDFA to map explicitly a new data sample into the learned low-dimensional subspace. The advantage of the LDFA method is that it learns both local and global characteristics of the data sample set: the local SCAEs capture local characteristics contained in the data set, while the global alignment procedures encode the interdependencies between neighbourhoods into the final lowdimensional feature representations. Experimental results on data visualization, clustering and classification show that the LDFA method is competitive with several well-known dimension reduction techniques, and exploiting locality in deep learning is a research topic worth further exploring. PMID- 29994453 TI - 3-D Reconstruction in Canonical Co-Ordinate Space From Arbitrarily Oriented 2-D Images. AB - Limited capture range, and the requirement to provide high quality initialization for optimization-based 2-D/3-D image registration methods, can significantly degrade the performance of 3-D image reconstruction and motion compensation pipelines. Challenging clinical imaging scenarios, which contain significant subject motion, such as fetal in-utero imaging, complicate the 3-D image and volume reconstruction process. In this paper, we present a learning-based image registration method capable of predicting 3-D rigid transformations of arbitrarily oriented 2-D image slices, with respect to a learned canonical atlas co-ordinate system. Only image slice intensity information is used to perform registration and canonical alignment, no spatial transform initialization is required. To find image transformations, we utilize a convolutional neural network architecture to learn the regression function capable of mapping 2-D image slices to a 3-D canonical atlas space. We extensively evaluate the effectiveness of our approach quantitatively on simulated magnetic resonance imaging (MRI), fetal brain imagery with synthetic motion and further demonstrate qualitative results on real fetal MRI data where our method is integrated into a full reconstruction and motion compensation pipeline. Our learning based registration achieves an average spatial prediction error of 7 mm on simulated data and produces qualitatively improved reconstructions for heavily moving fetuses with gestational ages of approximately 20 weeks. Our model provides a general and computationally efficient solution to the 2-D/3-D registration initialization problem and is suitable for real-time scenarios. PMID- 29994455 TI - IsoTree: A New Framework for De novo Transcriptome Assembly from RNA-seq Reads. AB - High-throughput sequencing of mRNA has made the deep and efficient probing of transcriptome more affordable. However, the vast amounts of short RNA-seq reads make de novo transcriptome assembly an algorithmic challenge. In this work, we present IsoTree, a novel framework for transcripts reconstruction in the absence of reference genomes. Unlike most of de novo assembly methods that build de Bruijn graph or splicing graph by connecting which are sets of overlapping substrings generated from reads, IsoTree constructs splicing graph by connecting reads directly. For each splicing graph, IsoTree applies an iterative scheme of mixed integer linear program to build a prefix tree, called isoform tree. Each path from the root node of the isoform tree to a leaf node represents a plausible transcript candidate which will be pruned based on the information of paired-end reads. Experiments showed that in most cases IsoTree performs better than other leading transcriptome assembly programs. IsoTree is available at https://github.com/Jane110111107/IsoTree. PMID- 29994456 TI - Nonparametric Bayesian Correlated Group Regression With Applications to Image Classification. AB - Sparse Bayesian learning has emerged as a powerful tool to tackle various image classification tasks. The existing sparse Bayesian models usually use independent Gaussian distribution as the prior knowledge for the noise. However, this assumption often contradicts to the practical observations in which the noise is long tail and pixels containing noise are spatially correlated. To handle the practical noise, this paper proposes to partition the noise image into several 2 D groups and adopt the long-tail distribution, i.e., the scale mixture of the matrix Gaussian distribution, to model each group to capture the intragroup correlation of the noise. Under the nonparametric Bayesian estimation, the low rank-induced prior and the matrix Gamma distribution prior are imposed on the covariance matrix of each group, respectively, to induce two Bayesian correlated group regression (BCGR) methods. Moreover, the proposed methods are extended to the case with unknown group structure. Our BCGR method provides an effective way to automatically fit the noise distribution and integrates the long-tail attribute and structure information of the practical noise into model. Therefore, the estimated coefficients are better for reconstructing the desired data. We apply BCGR to address image classification task and utilize the learned covariance matrices to construct a grouped Mahalanobis distance to measure the reconstruction residual of each class in the design of a classifier. Experimental results demonstrate the effectiveness of our new BCGR model. PMID- 29994457 TI - Biologically Inspired Intensity and Depth Image Edge Extraction. AB - In recent years, artificial vision research has moved from focusing on the use of only intensity images to include using depth images, or RGB-D combinations due to the recent development of low-cost depth cameras. However, depth images require a lot of storage and processing requirements. In addition, it is challenging to extract relevant features from depth images in real time. Researchers have sought inspiration from biology in order to overcome these challenges resulting in biologically inspired feature extraction methods. By taking inspiration from nature, it may be possible to reduce redundancy, extract relevant features, and process an image efficiently by emulating biological visual processes. In this paper, we present a depth and intensity image feature extraction approach that has been inspired by biological vision systems. Through the use of biologically inspired spiking neural networks, we emulate functional computational aspects of biological visual systems. The results demonstrate that the proposed bioinspired artificial vision system has increased performance over existing computer vision feature extraction approaches. PMID- 29994458 TI - Deep Hyperspectral Image Sharpening. AB - Hyperspectral image (HSI) sharpening, which aims at fusing an observable low spatial resolution (LR) HSI (LR-HSI) with a high spatial resolution (HR) multispectral image (HR-MSI) of the same scene to acquire an HR-HSI, has recently attracted much attention. Most of the recent HSI sharpening approaches are based on image priors modeling, which are usually sensitive to the parameters selection and time-consuming. This paper presents a deep HSI sharpening method (named DHSIS) for the fusion of an LR-HSI with an HR-MSI, which directly learns the image priors via deep convolutional neural network-based residual learning. The DHSIS method incorporates the learned deep priors into the LR-HSI and HR-MSI fusion framework. Specifically, we first initialize the HR-HSI from the fusion framework via solving a Sylvester equation. Then, we map the initialized HR-HSI to the reference HR-HSI via deep residual learning to learn the image priors. Finally, the learned image priors are returned to the fusion framework to reconstruct the final HR-HSI. Experimental results demonstrate the superiority of the DHSIS approach over existing state-of-the-art HSI sharpening approaches in terms of reconstruction accuracy and running time. PMID- 29994459 TI - Improved False Positive Reduction by Novel Morphological Features for Computer Aided Polyp Detection in CT Colonography. AB - Computer-aided detection (CAD) systems can assist radiologists in reducing the interpretation time and improving the detection results in computed tomographic colonography (CTC). However, existing false positives (FPs) impair the advantages of CAD systems. This study aims to develop new morphological features for FP reduction while maintaining high detection sensitivity. Volumetric feature maps are computed for each polyp candidate by using 3D geodesic distance transformation, circular transformation (CcT), and quantized convergence index (QCI) filters. Then, new morphological features are developed based on the curvature, fractal dimension, and volumetric feature maps. To the best of our knowledge, we are also the first to develop 3D CcT and QCI filters specifically for colonic polyps. The new morphological features were evaluated to reduce FPs by using 456 oral contrast-enhanced CT scans from 228 patients with 130 polyps MU5 mm. For comparison, the well-defined features from our previous work were used to generate a baseline reference. The additional use of the new morphological features reduced the FP rate from 4.2 to 2.0 FPs per scan (i.e., 52.4% FP reduction percentage) at 96.2% by-polyp sensitivity and from 4.5 to 2.1 FPs per scan (i.e., 53.3% FP reduction percentage) at 93.9% per-scan sensitivity for polyps MU5 mm. Experimental results indicate that the new morphological features can effectively reduce the FP rate without sacrificing detection sensitivity. We believe that the newly developed morphological features would advance the CAD systems to assist radiologists in interpreting CTC images. PMID- 29994460 TI - Deep Learning for Fall Detection: 3D-CNN Combined with LSTM on Video Kinematic Data. AB - Fall detection is an important public healthcare problem. Timely detection could enable instant delivery of medical service to the injured. A popular non intrusive solution for fall detection is based on videos obtained through ambient camera, and the corresponding methods usually require a large dataset to train a classifier and are inclined to be influenced by the image quality. However, it is hard to collect fall data and instead simulated falls are recorded to construct the training dataset, which is restricted to limited quantity. To address these problems, a three-dimensional convolutional neural network (3D CNN) based method for fall detection is developed which only uses video kinematic data to train an automatic feature extractor and could circumvent the requirement for large fall dataset of deep learning solution. 2D CNN could only encode spatial information, and the employed 3D convolution could extract motion feature from temporal sequence, which is important for fall detection. To further locate the region of interest in each frame, a LSTM (Long Short-Term Memory) based spatial visual attention scheme is incorporated. Sports dataset Sports-1M with no fall examples is employed to train the 3D CNN, which is then combined with LSTM to train a classifier with fall dataset. Experiments have verified the proposed scheme on fall detection benchmark with high accuracy as 100%. Superior performance has also been obtained on other activity databases. PMID- 29994461 TI - Barrier Lyapunov Function Based Learning Control of Hypersonic Flight Vehicle With AOA Constraint and Actuator Faults. AB - This paper investigates a fault-tolerant control of the hypersonic flight vehicle using back-stepping and composite learning. With consideration of angle of attack (AOA) constraint caused by scramjet, the control laws are designed based on barrier Lyapunov function. To deal with the unknown actuator faults, a robust adaptive allocation law is proposed to provide the compensation. Meanwhile, to obtain good system uncertainty approximation, the composite learning is proposed for the update of neural weights by constructing the serial-parallel estimation model to obtain the prediction error which can dynamically indicate how the intelligent approximation is working. Simulation results show that the controller obtains good system tracking performance in the presence of AOA constraint and actuator faults. PMID- 29994462 TI - Adaptive Robust Tracking Control for Multiple Unknown Fractional-Order Nonlinear Systems. AB - By applying the fractional Lyapunov direct method, we investigate the robust consensus tracking problem for a class of uncertain fractional-order multiagent systems with a leader whose input is unknown and bounded. More specifically, multiple fractional-order systems with heterogeneous unknown nonlinearities and external disturbances are considered in this paper, which include the second order multiagent systems as its special cases. First, a discontinuous neural network-based (NN-based) distributed robust adaptive algorithm is designed to guarantee the consensus tracking error exponentially converges to zero under a fixed topology. Also the derived results are further extended to the case of switching topology by appropriately choosing multiple Lyapunov functions. Second, a continuous NN-based distributed robust adaptive algorithm is further proposed to eliminate the undesirable chattering phenomenon of the discontinuous controller, where the consensus tacking error is uniformly ultimately bounded and can be reduced as small as desired. It is worth noting that all the proposed NN based robust adaptive algorithms are independent of any global information and thus are fully distributed. Finally, numerical simulations are provided to validate the correctness of the proposed algorithms. PMID- 29994463 TI - New Stability Criterion for Continuous-Time Takagi-Sugeno Fuzzy Systems With Time Varying Delay. AB - In this technical paper, a new Lyapunov-Krasovskii functional (LKF) is designed to study the stability of continuous-time Takagi-Sugeno fuzzy systems with time varying delay. The integrand of the LKF depends on integral variable and time t which can help to reduce the number of linear matrix inequalities (LMIs). Then, a new stability criterion is derived by analyzing the sign of the time derivatives of membership functions. Compared with the existing results, larger delay bounds can be obtained by applying the new criterion. In the end, two examples show the effectiveness of the conclusions. PMID- 29994464 TI - Image Representation and Learning With Graph-Laplacian Tucker Tensor Decomposition. AB - Tucker tensor decomposition (TD) is widely used for image representation, reconstruction, and learning tasks. Compared to principal component analysis (PCA) models, tensor models retain more 2-D characteristics of images whereas PCA models linearize images. However, traditional TD involves attribute information only and thus does not consider the pairwise similarity information between images. In this paper, we propose a graph-Laplacian tucker tensor decomposition (GLTD) which explores both attributes and pairwise similarity information simultaneously. Generally, GLTD has three main benefits: 1) GLTD reconstruction shows clear robustness against image occlusions/outliers. We provide analysis to show that Laplacian regularization is mainly responsible to this robustness via an out-of-sample GLTD model. To the best of our knowledge, this Laplacian regularization induced robustness of TD has not been studied or emphasized before; 2) GLTD representation performs more regularity, which improves both unsupervised and supervised learning results; and 3) an effective algorithm is derived to solve GLTD problem. Although GLTD is a noncovex problem, the proposed algorithm is shown experimentally to provide a stable/unique solution starting from different random initializations. Experimental results on image reconstruction, data clustering, and classification tasks show the benefits of GLTD. PMID- 29994465 TI - New Results on Sliding-Mode Control for Takagi-Sugeno Fuzzy Multiagent Systems. AB - This paper investigates the sliding-mode control (SMC) problem of Takagi-Sugeno (T-S) fuzzy multiagent systems (MASs). A cooperative fuzzy-based dynamical sliding-mode (SM) controller is designed and the overall closed-loop T-S fuzzy MAS is constructed. A new model transformation method for T-S fuzzy MASs is presented to transform the fuzzy weighting matrix into a set of fuzzy weighting scalars. By applying the method of linear matrix inequality, a general stability analysis approach for T-S fuzzy MASs is proposed. Moreover, the energy-cost constraint problem is studied by using the linear quadratic regulator method. Finally, numerical examples are provided to illustrate the effectiveness of the proposed theoretical approaches and the improved performance compared to existing results. PMID- 29994466 TI - Deep Metric Learning with BIER: Boosting Independent Embeddings Robustly. AB - Learning similarity functions between image pairs with deep neural networks yields highly correlated activations of embeddings. In this work, we show how to improve the robustness of such embeddings by exploiting the independence within ensembles. To this end, we divide the last embedding layer of a deep network into an embedding ensemble and formulate the task of training this ensemble as an online gradient boosting problem. Each learner receives a reweighted training sample from the previous learners. Further, we propose two loss functions which increase the diversity in our ensemble. These loss functions can be applied either for weight initialization or during training. Together, our contributions leverage large embedding sizes more effectively by significantly reducing correlation of the embedding and consequently increase retrieval accuracy of the embedding. Our method works with any differentiable loss function and does not introduce any additional parameters during test time. We evaluate our metric learning method on image retrieval tasks and show that it improves over state-of the-art methods on the CUB-200-2011, Cars-196, Stanford Online Products, In-Shop Clothes Retrieval and VehicleID datasets. Therefore, our findings suggest that by dividing deep networks at the end into several smaller and diverse networks, we can significantly reduce overfitting. PMID- 29994467 TI - ASTER: An Attentional Scene Text Recognizer with Flexible Rectification. AB - A challenging aspect of scene text recognition is to handle text with distortions or irregular layout. In particular, perspective text and curved text are common in natural scenes and are difficult to recognize. In this work, we introduce ASTER, an end-to-end neural network model that comprises a rectification network and a recognition network. The rectification network adaptively transforms an input image into a new one, rectifying the text in it. It is powered by a flexible Thin-Plate Spline transformation which handles a variety of text irregularities and is trained without human annotations. The recognition network is an attentional sequence-to-sequence model that predicts a character sequence directly from the rectified image. The whole model is trained end to end, requiring only images and their groundtruth text. Through extensive experiments, we verify the effectiveness of the rectification and demonstrate the state-of-the art recognition performance of ASTER. Furthermore, we demonstrate that ASTER is a powerful component in end-to-end recognition systems, for its ability to enhance the detector. PMID- 29994468 TI - Revisiting Projective Structure for Motion: A Robust and Efficient Incremental Solution. AB - This paper presents a solution to the Projective Structure from Motion (PSfM) problem able to deal efficiently with missing data, outliers and, for the first time, large scale 3D reconstruction scenarios. By embedding the projective depths into the projective parameters of the points and views, we decrease the number of unknowns to estimate and improve computational speed by optimizing standard linear Least Squares systems instead of homogeneous ones. In order to do so, we show that an extension of the linear constraints from the Generalized Projective Reconstruction Theorem can be transferred to the projective parameters, ensuring also a valid projective reconstruction in the process. We use an incremental approach that, starting from a solvable sub-problem, incrementally adds views and points until completion with a robust, outliers free, procedure. Experiments with simulated data shows that our approach is performing well, both in term of the quality of the reconstruction and the capacity to handle missing data and outliers with a reduced computational time. Finally, results on real datasets shows the ability of the method to be used in medium and large scale 3D reconstruction scenarios with high ratios of missing data (up to 98?%). PMID- 29994469 TI - PsyPhy: A Psychophysics Driven Evaluation Framework for Visual Recognition. AB - By providing substantial amounts of data and standardized evaluation protocols, datasets in computer vision have helped fuel advances across all areas of visual recognition. But even in light of breakthrough results on recent benchmarks, it is still fair to ask if our recognition algorithms are doing as well as we think they are. The vision sciences at large make use of a very different evaluation regime known as Visual Psychophysics to study visual perception. Psychophysics is the quantitative examination of the relationships between controlled stimuli and the behavioral responses they elicit in experimental test subjects. Instead of using summary statistics to gauge performance, psychophysics directs us to construct item-response curves made up of individual stimulus responses to find perceptual thresholds, thus allowing one to identify the exact point at which a subject can no longer reliably recognize the stimulus class. In this article, we introduce a comprehensive evaluation framework for visual recognition models that is underpinned by this methodology. Over millions of procedurally rendered 3D scenes and 2D images, we compare the performance of well-known convolutional neural networks. Our results bring into question recent claims of human-like performance, and provide a path forward for correcting newly surfaced algorithmic deficiencies. PMID- 29994470 TI - Corrections to "Direct Patlak Reconstruction From Dynamic PET Data Using the Kernel Method With MRI Information Based on Structural Similarity". AB - In the above paper [1], there are typos in Algorithm 1 table. The correct version of Algorithm 1 is given below. PMID- 29994471 TI - Deep Recurrent Neural Networks for Prostate Cancer Detection: Analysis of Temporal Enhanced Ultrasound. AB - Temporal enhanced ultrasound (TeUS), comprising the analysis of variations in backscattered signals from a tissue over a sequence of ultrasound frames, has been previously proposed as a new paradigm for tissue characterization. In this paper, we propose to use deep recurrent neural networks (RNN) to explicitly model the temporal information in TeUS. By investigating several RNN models, we demonstrate that long short-term memory (LSTM) networks achieve the highest accuracy in separating cancer from benign tissue in the prostate. We also present algorithms for in-depth analysis of LSTM networks. Our in vivo study includes data from 255 prostate biopsy cores of 157 patients. We achieve area under the curve, sensitivity, specificity, and accuracy of 0.96, 0.76, 0.98, and 0.93, respectively. Our result suggests that temporal modeling of TeUS using RNN can significantly improve cancer detection accuracy over previously presented works. PMID- 29994472 TI - A Model-Based Approach to Investigate the Effect of a Long Bone Fracture on Ultrasound Strain Elastography. AB - The mechanical behavior of long bones and fractures has been under investigation for many decades due to its complexity and clinical relevance. In this paper, we report a new subject-specific methodology to predict and analyze the mechanical behavior of the soft tissue at a bone interface with the intent of identifying the presence and location of bone abnormalities with high accuracy, spatial resolution, and contrast. The proposed methodology was tested on both intact and fractured rabbit femur samples with finite element-based 3-D simulations, created from actual femur computed tomography data, and ultrasound elastography experiments. The results included in this study demonstrate that elastographic strains at the bone/soft tissue interface can be used to differentiate fractured femurs from the intact ones on a distribution level. These results also demonstrate that coronal plane axial shear strain creates a unique contrast mechanism that can be used to reliably detect fractures (both complete and incomplete) in long bones. Kruskal-Wallis test further demonstrates that the contrast measure for the fracture group (simulation: 2.1286+/-0.2206; experiment: 2.7034 +/- 1.0672) is significantly different from that for the intact group (simulation: 0 +/- 0; experiment: 1.1540+/-0.6909) when using coronal plane axial shear strain elastography ( < 0.01). We conclude that: 1) elastography techniques can be used to accurately identify the presence and location of fractures in a long bone and 2) the proposed model-based approach can be used to predict and analyze strains at a bone fracture site and to better interpret experimental elastographic data. PMID- 29994473 TI - 3-D Single Breath-Hold Shear Strain Estimation for Improved Breast Lesion Detection and Classification in Automated Volumetric Ultrasound Scanners. AB - Automated breast volume scanner (ABVS) is an ultrasound imaging modality used in breast cancer screening. It has high sensitivity but limited specificity as it is hard to discriminate between benign and malignant lesions by echogenic properties. Specificity might be improved by shear strain imaging as malignant lesions, firmly bonded to its host tissue, show different shear patterns compared to benign lesions, often loosely bonded. Therefore, 3-D quasi-static elastography was implemented in an ABVS-like system. Plane wave instead of conventional focused transmissions were used to reduce scan times within a single breath hold. A 3-D strain tensor was obtained and shear strains were reconstructed in phantoms containing firmly and loosely bonded lesions. Experiments were also simulated in finite-element models (FEMs). Experimental results, confirmed by FEM-results, indicated that loosely bonded lesions showed increased maximal shear strains (~2.5%) and different shear patterns compared to firmly bonded lesions (~0.9%). To conclude, we successfully implemented 3-D elastography in an ABVS-like system to assess lesion bonding by shear strain imaging. PMID- 29994474 TI - Effect of the Chloride Anions on the Formation of Self-Assembled Diphenylalanine Peptide Nanotubes. AB - Self-assembled peptide nanostructures are being intensively investigated due to their potential applications such as biosensors, piezotransducers, and microactuators. It was predicted that their formation and hence piezoelectric property strongly depend on the water content and acidity of the stock solution. In this paper, simple diphenylalanine (FF) tubular structures were fabricated from the solutions with added hydrochloric acid in order to understand the influence of chloride ions on the self-assembly process and resulting piezoelectricity. Low-frequency Raman scattering, atomic, and piezoresponse force microscopies were used to characterize both the morphology and piezoelectric properties of the grown samples. The mechanism of chloride anions' effect on the formation of self-assembled peptide nanostructures is discussed based on the acquired Raman data and quantum-chemical modeling. It is shown that the addition of chloride anions causes a significant reduction of the dipole moments of FF tubes accompanied with the concomitant decrease of tube dimensions and apparent shear piezoelectric coefficients. PMID- 29994475 TI - Efficient Recovery of Essential Matrix From Two Affine Correspondences. AB - We propose a method to estimate the essential matrix using two affine correspondences for a pair of calibrated perspective cameras. Two novel, linear constraints are derived between the essential matrix and a local affine transformation. The proposed method is also applicable to the over-determined case. We extend the normalization technique of Hartley to local affinities and show how the intrinsic camera matrices modify them. Even though perspective cameras are assumed, the constraints can straightforwardly be generalized to arbitrary camera models since they describe the relationship between local affinities and epipolar lines (or curves). Benefiting from the low number of exploited points, it can be used in robust estimators, e.g. RANSAC, as an engine, thus leading to significantly less iterations than the traditional point-based methods. The algorithm is validated both on synthetic and publicly available data sets and compared with the state-of-the-art. Its applicability is demonstrated on two-view multi-motion fitting, i.e., finding multiple fundamental matrices simultaneously, and outlier rejection. PMID- 29994477 TI - Single Image Dehazing With Depth-aware Non-local Total Variation Regularization. AB - Single image dehazing can benefit many computer vision applications hence has attracted much more attention in recent years. However, it still remains a challenging task due to its double uncertainty of scene transmission and scene radiance. The existing image dehazing methods usually impair edges in the estimated transmission which leads to halo effects in the dehazing results. Besides, most existing methods suffer from noise and artifacts amplification in dense haze region after dehazing. To address these challenges, we propose a transmission adaptive regularized image recovery method for high quality single image dehazing. An initial transmission map is first obtained by a boundary constraint on the haze model. Then it is refined by applying a non-local total variation (NLTV) regularization to keep depth structures while smoothing excessive details. Noticing that the artifacts amplification effect depends on scene transmission, a transmission adaptive regularized recovery method based on NLTV is proposed to simultaneously suppress visual artifacts and preserve image details in the final dehazing result. An efficient alternating optimization algorithm is also proposed to solve the regularization model. Thorough experimental results demonstrate that the proposed method can effectively suppress visual artifacts for degraded hazy images, and yields high-quality results comparative to the state-of-the-art dehazing methods both quantitatively and qualitatively. PMID- 29994476 TI - Context-Dependent Random Walk Graph Kernels and Tree Pattern Graph Matching Kernels with Applications to Action Recognition. AB - Graphs are effective tools for modeling complex data. Setting out from two basic substructures, random walks and trees, we propose a new family of context dependent random walk graph kernels and a new family of tree pattern graph matching kernels. In our context-dependent graph kernels, context information is incorporated into primary random walk groups. A multiple kernel learning algorithm with a proposed l1,2-norm regularization is applied to combine context dependent graph kernels of different orders. This improves the similarity measurement between graphs. In our tree-pattern graph matching kernel, a quadratic optimization with a sparse constraint is proposed to select the correctly matched tree-pattern groups. This augments the discriminative power of the tree-pattern graph matching. We apply the proposed kernels to human action recognition, where each action is represented by two graphs which record the spatiotemporal relations between local feature vectors. Experimental comparisons with state-of-the-art algorithms on several benchmark datasets demonstrate the effectiveness of the proposed kernels for recognizing human actions. It is shown that our kernel based on tree-pattern groups, which have more complex structures and exploit more local topologies of graphs than random walks, yields more accurate results but requires more runtime than the context-dependent walk graph kernel. PMID- 29994478 TI - A Model of Spatial Directness in Interactive Visualization. AB - We discuss the concept of directness in the context of spatial interaction with visualization. In particular, we propose a model that allows practitioners to analyze and describe the spatial directness of interaction techniques, ultimately to be able to better understand interaction issues that may affect usability. To reach these goals, we distinguish between different types of directness. Each type of directness depends on a particular mapping between different spaces, for which we consider the data space, the visualization space, the output space, the user space, the manipulation space, and the interaction space. In addition to the introduction of the model itself, we also show how to apply it to several real world interaction scenarios in visualization, and thus discuss the resulting types of spatial directness, without recommending either more direct or more indirect interaction techniques. In particular, we will demonstrate descriptive and evaluative usage of the proposed model, and also briefly discuss its generative usage. PMID- 29994479 TI - Lifetime Improvement of a Multiple Transmitter Local Drug Delivery System Based on Diffusive Molecular Communication. AB - In this paper, a multiple transmitter local drug delivery system associated with encapsulated drug transmitters is investigated. One of the limitations of drug delivery systems is the reservoir capacity. In order to improve the lifetime of drug transmitting nanomachines, and, hence, the longevity of drug delivery scenario, the system is associated with encapsulated drug transmitters. Encapsulated drugs are incapable of reaction with the environment unless they are unpacked in a drug transmitter nanomachine. Therefore, far-reaching transmitters do not have harmful effects on the healthy parts of the body. The advantage of this protocol is to increase the time interval between consecutive administrations without increased toxicity. As a result, it improves the mental health of patients and reduces the costs of treatment. The lifetime of this drug delivery system depends on the distribution and topology of encapsulated drug transmitters rather than their rates. Finally, a lower bound is derived on the expected lifetime of a Poisson distributed random network of nanomachines. PMID- 29994480 TI - Multi-domain Networks Association for Biological Data Using Block Signed Graph Clustering. AB - Multi-domain biological network association and clustering have attracted a lot of attention in biological data integration and understanding. In many problems, different domains may have different cluster structures. Due to growth of data collection from different sources, some domains may be strongly or weakly associated with the other domains. A key challenge is how to determine the degree of association among different domains, and to achieve accurate clustering results by data integration. In this paper, we propose an unsupervised learning approach for multi-domain network association by using block signed graph clustering. In particular, with consistency weights calculation, the proposed algorithm automatically identify domains relevant to each other strongly (or weakly) by assigning them larger (or smaller) weights. This approach not only significantly improve clustering accuracy but also understand multi-domain networks association. In each iteration of the proposed algorithm, we update consistency weights based on cluster structure of each domain, and then make use of different sets of eigenvectors to obtain different cluster structures in each domain. Experimental results on both synthetic data sets and real data sets (neuron activity data and gene expression data) empirically demonstrate the effectiveness of the proposed algorithm in clustering performance and in domain association capability. PMID- 29994481 TI - Drug Selection via Joint Push and Learning to Rank. AB - Selecting the right drugs for the right patients is a primary goal of precision medicine. In this manuscript, we consider the problem of cancer drug selection in a learning-to-rank framework. We have formulated the cancer drug selection problem as to accurately predicting 1). the ranking positions of sensitive drugs and 2). the ranking orders among sensitive drugs in cancer cell lines based on their responses to cancer drugs. We have developed a new learning-to-rank method, denoted as pLETORg, that predicts drug ranking structures in each cell line via using drug latent vectors and cell line latent vectors. The pLETORg method learns such latent vectors through explicitly enforcing that, in the drug ranking list of each cell line, the sensitive drugs are pushed above insensitive drugs, and meanwhile the ranking orders among sensitive drugs are correct. Genomics information on cell lines is leveraged in learning the latent vectors. Our experimental results on a benchmark cell line-drug response dataset demonstrate that the new pLETORg significantly outperforms the state-of-the-art method in prioritizing new sensitive drugs. PMID- 29994482 TI - Identifying "Many-to-Many" Relationships Between Gene-Expression Data and Drug Response Data Via Sparse Binary Matching. AB - Identifying gene-drug patterns is a critical step in pharmacology for unveiling disease mechanisms and drug discovery. The availability of high-throughput technologies accumulates massive large-scale pharmacological and genomic data, and thus provides a new substantial opportunity to deeply understand how the oncogenic genes and the therapeutic drugs relate to each other. However, most previous studies merely used the pharmacological and genomic datasets without any prior knowledge to infer the gene-drug patterns. Here, we proposed a novel network-guided sparse binary matching model (NSBM) to decode these relationships hidden in the datasets. Not only the large-scale gene-expression data and drug response data are jointly analyzed in our method, but also the additional prior information of genes and drugs are integrated into the form of network-based regularization. The essential structure of the NSBM model is a convex quadratic minimization problem with network-based penalties. It was demonstrated to achieve superior when compared with two benchmark methods through extensive experiments on both synthetic and empirical data. Posterior validation, including gene ontology and enrichment analysis, confirmed the effectiveness of NSBM in revealing gene-drug patterns on a large-scale heterogeneous data source. PMID- 29994483 TI - A Slice-based 13C-detected NMR Spin System Forming and Resonance Assignment Method. AB - Nuclear magnetic resonance (NMR) spectroscopy is attracting more attention in the field of computational structural biology. Till recently, 1H-detected experiments are the dominant NMR technique used due to the high sensitivity of 1H nuclei. However, the current availability of high magnetic fields and cryogenically cooled probe heads allow researchers to overcome the low sensitivity of 13C nuclei. Consequently, 13C-detected experiments have become a popular technique in different NMR applications especially resonance assignment and structure determination of large proteins. In this paper, we propose the first spin system forming method for 13C-detected NMR spectra. Our method is able to accurately form spin systems based on as few as two 13C-detected spectra, CBCACON and CBCANCO. Our method picks slices from the more trusted spectrum and uses them as feedback to direct the slice picking in the less trusted one. This feedback leads to picking the accurate slices that consequently helps to form better spin systems. We tested our method on a real dataset of 'Ubiquitin' and a benchmark simulated dataset consisting of 12 proteins. We fed our spin systems as inputs to a genetic algorithm to generate the chemical shift assignment, and obtained 92% correct chemical shift assignment for Ubiquitin. For the simulated dataset, we obtained an average recall of 86% and an average precision of 88%. Finally, our chemical shift assignment of Ubiquitin was given as an input to CS-ROSETTA server that generated structures close to the experimentally determined structure. PMID- 29994484 TI - Computing the Diameter of the Space of Maximum Parsimony Reconciliations in the Duplication-Transfer-Loss Model. AB - Phylogenetic tree reconciliation is widely used in the fields of molecular evolution, cophylogenetics, parasitology, and biogeography to study the evolutionary histories of pairs of entities. In these contexts, reconciliation is often performed using maximum parsimony under the DTL (Duplication-Transfer-Loss) event model. In general, the number of maximum parsimony reconciliations (MPRs) can grow exponentially with the size of the trees. While a number of previous efforts have been made to count the number of MPRs, find representative MPRs, and compute the frequencies of events across the space of MPRs, little is known about the structure of MPR space. In particular, how different are MPRs in terms of the events that they comprise? PMID- 29994485 TI - Nature-Inspired Multiobjective Epistasis Elucidation from Genome-Wide Association Studies. AB - In recent years, the detection of epistatic interactions of multiple genetic variants on the causes of complex diseases brings a significant challenge in genome-wide association studies (GWAS). However, most of the existing methods still suffer from algorithmic limitations such as single-objective optimization, intensive computational requirement, and premature convergence. In this paper, we propose and formulate an epistatic interaction multi-objective artificial bee colony algorithm based on decomposition (EIMOABC/D) to address those problems for genetic interaction detection in genome-wide association studies. Firstly, to direct the genetic interaction detection, two objective functions are formulated to characterize various epistatic models; rank probability model is proposed to sort each population into different nondomination levels based on the fast nondominated sorting approach. After that, the mutual information based local search algorithm is proposed to guide the population search for disease model evaluations in an unbiased manner. To validate the effectiveness of EIMOABC/D, we compare EIMOABC/D against seven state-of-the-art methods on 79 epistatic models including eight small-scale epistatic models with marginal effects, eight large scale epistatic models with marginal effects, sixty large-scale epistatic models without any marginal effect, and one case study. The experimental results indicate that our proposed algorithm EIMOABC/D outperforms seven state-of-the-art methods on those epistatic models. Furthermore, time complexity analysis and parameter analysis are conducted to demonstrate various properties of our proposed algorithm. PMID- 29994486 TI - Natural Language Processing for EHR-Based Computational Phenotyping. AB - This article reviews recent advances in applying natural language processing (NLP) to Electronic Health Records (EHRs) for computational phenotyping. NLP based computational phenotyping has numerous applications including diagnosis categorization, novel phenotype discovery, clinical trial screening, pharmacogenomics, drug-drug interaction (DDI) and adverse drug event (ADE) detection, as well as genome-wide and phenome-wide association studies. Significant progress has been made in algorithm development and resource construction for computational phenotyping. Among the surveyed methods, well designed keyword search and rule-based systems often achieve good performance. However, the construction of keyword and rule lists requires significant manual effort, which is difficult to scale. Supervised machine learning models have been favored because they are capable of acquiring both classification patterns and structures from data. Recently, deep learning and unsupervised learning have received growing attention, with the former favored for its performance and the latter for its ability to find novel phenotypes. Integrating heterogeneous data sources have become increasingly important and have shown promise in improving model performance. Often better performance is achieved by combining multiple modalities of information. Despite these many advances, challenges and opportunities remain for NLP-based computational phenotyping, including better model interpretability and generalizability, and proper characterization of feature relations in clinical narratives. PMID- 29994487 TI - Are My EHRs Private Enough? - Event-level Privacy Protection. AB - Privacy is a major concern in sharing human subject data to researchers for secondary analyses. A simple binary consent (opt-in or not) may significantly reduce the amount of sharable data, since many patients might only be concerned about a few sensitive medical conditions rather than the entire medical records. We propose event-level privacy protection, and develope a feature ablation method to protect event-level privacy in electronic medical records. Using a list of 13 sensitive diagnoses, we evaluate the feasibility and the efficacy of the proposed method. As feature ablation progresses, the identifiability of a sensitive medical condition decreases with varying speeds on different diseases. We find that these sensitive diagonoses can be divided into 3 categories: (1) 5 diseases have fast declining identifiability (AUC below 0.6 with less than 400 features excluded); (2) 7 diseases with progressively declining identifiability (AUC below 0.7 with between 200 and 700 features excluded); and (3) 1 disease with slowly declining identifiability (AUC above 0.7 with 1000 features excluded). The fact that the majority (12 out of 13) of the sensitive diseases fall into the first two categories suggests the potential of the proposed feature ablation method as a solution for event-level record privacy protection. PMID- 29994488 TI - Self-Paced Learning-Based Probability Subspace Projection for Hyperspectral Image Classification. AB - In this paper a self-paced learning-based probability subspace projection (SL PSP) method is proposed for hyperspectral image classification. First, a probability label is assigned for each pixel, and a risk is assigned for each labeled pixel. Then, two regularizers are developed from a self-paced maximum margin and a probability label graph, respectively. The first regularizer can increase the discriminant ability of features by gradually involving the most confident pixels into the projection to simultaneously push away heterogeneous neighbors and pull inhomogeneous neighbors. The second regularizer adopts a relaxed clustering assumption to make avail of unlabeled samples, thus accurately revealing the affinity between mixed pixels and achieving accurate classification with very few labeled samples. Several hyperspectral data sets are used to verify the effectiveness of SL-PSP, and the experimental results show that it can achieve the state-of-the-art results in terms of accuracy and stability. PMID- 29994489 TI - Weakly-supervised biomedical image segmentation by reiterative learning. AB - Recent advances in deep learning have produced encouraging results for biomedical image segmentation; however, outcomes rely heavily on comprehensive annotation. In this paper, we propose a neural network architecture and a new algorithm, known as overlapped region forecast, for the automatic segmentation of gastric cancer images. To the best of our knowledge, this report describes the first time that deep learning has been applied to the segmentation of gastric cancer images. Moreover, a reiterative learning framework that achieves superior performance without pre-training or further manual annotation is presented to train a simple network on weakly annotated biomedical images. We customize the loss function to make the model converge faster while avoiding becoming trapped in local minima. Patch boundary errors were eliminated by our overlapped region forecast algorithm. By studying the characteristics of the model trained using two different patch extraction methods, we train iteratively and integrate predictions and weak annotations to improve the quality of the training data. Using these methods, a mean Intersection over Union coefficient (IoU) of 0.883 and a mean accuracy of 91.09% were achieved on the partially labeled dataset, thereby securing a win in the 2017 China Big Data and Artificial Intelligence Innovation and Entrepreneurship Competition. PMID- 29994490 TI - Unified Fine-grained Access Control for Personal Health Records in Cloud Computing. AB - Attribute-based encryption has been a promising encryption technology to secure personal health records (PHRs) sharing in cloud computing. PHRs consist of the patient data often collected from various sources including hospitals and general practice centres. Different patients' access policies have a common access sub policy. In this paper, we propose a novel attribute-based encryption scheme for fine-grained and flexible access control to PHRs data in cloud computing. The scheme generates shared information by the common access sub-policy which is based on different patients' access policies. Then the scheme combines the encryption of PHRs from different patients. Therefore, both time consumption of encryption and decryption can be reduced. Medical staff require varying levels of access to PHRs. The proposed scheme can also support multi-privilege access control so that medical staff can access the required level of information while maximizing patient privacy. Through implementation and simulation, we demonstrate that the proposed scheme is efficient in terms of time. Moreover, We prove the security of the proposed scheme based on security of the ciphertext-policy attribute-based encryption scheme. PMID- 29994491 TI - Constrained Multiobjective Nonlinear Optimization: A User Preference Enabling Method. AB - A novel user preference enabling (UPE) method is developed to solve general constrained nonlinear multiple objective optimization (MOO) problems. User wish lists on the preferred range of each objective function are introduced and incorporated into the MOO formulation to form a user-preferred (UP) MOO problem. A theoretical foundation of the UP feasible region of MOO problems is developed. The developed theoretical work leads to the development of a UPE method for effectively solving the UP-MOO problems. Distinguishing features of the proposed method include its ability to compute a targeted Pareto solution and to serve as a complement to existing MOO methods, in the sense that the proposed method assists the existing MOO methods in computing the Pareto front by providing feasible solutions and UP feasible solutions. Both proposed UPE method and derived theoretical developments are evaluated on several test systems with promising results. PMID- 29994492 TI - Abdominal-Waving Control of Tethered Bumblebees Based on Sarsa With Transformed Reward. AB - Cyborg insects have attracted great attention as the flight performance they have is incomparable by micro aerial vehicles and play a critical role in supporting extensive applications. Approaches to construct cyborg insects consist of two major issues: 1) the stimulating paradigm and 2) the control policy. At present, most cyborg insects are constructed based on invasive methods, requiring the implantation of electrodes into neural or muscle systems, which would harm the insects. As the control policy is basically manual control, the shortcomings of which lie in the requirement of excessive amount of experiments and focused attention. This paper presents the design and implementation of a noninvasive and much safer cyborg insect system based on visual stimulation. The tethered paradigm is adopted here and we look at controlling the flight behavior of bumblebees, especially the abdominal-waving behavior, in the context of a model free reinforcement learning problem. The problem is formulated as a finite and deterministic Markov decision process, where the agent is designed to change the abdominal-waving behavior from the initial state to the target state. Sarsa with transformed reward function which can speed up the learning process is employed to learn the optimal control policy. Learned policies are compared to the stochastic one by evaluating the results of ten bumblebees, demonstrating that abdominal-waving state can be modulated to approximate the target state quickly with small deviation. PMID- 29994493 TI - Learning Neural Representations for Network Anomaly Detection. AB - This paper proposes latent representation models for improving network anomaly detection. Well-known anomaly detection algorithms often suffer from challenges posed by network data, such as high dimension and sparsity, and a lack of anomaly data for training, model selection, and hyperparameter tuning. Our approach is to introduce new regularizers to a classical autoencoder (AE) and a variational AE, which force normal data into a very tight area centered at the origin in the nonsaturating area of the bottleneck unit activations. These trained AEs on normal data will push normal points toward the origin, whereas anomalies, which differ from normal data, will be put far away from the normal region. The models are very different from common regularized AEs, sparse AE, and contractive AE, in which the regularized AEs tend to make their latent representation less sensitive to changes of the input data. The bottleneck feature space is now used as a new data representation. A number of one-class learning algorithms are used for evaluating the proposed models. The experiments testify that our models help these classifiers to perform efficiently and consistently on high-dimensional and sparse network datasets, even with relatively few training points. More importantly, the models can minimize the effect of model selection on these classifiers since their performance is insensitive to a wide range of hyperparameter settings. PMID- 29994494 TI - Lifelong Metric Learning. AB - The state-of-the-art online learning approaches are only capable of learning the metric for predefined tasks. In this paper, we consider a lifelong learning problem to mimic ''human learning,'' i.e., endowing a new capability to the learned metric for a new task from new online samples and incorporating the previous experiences. Therefore, we propose a new metric learning framework: lifelong metric learning (LML), which only utilizes the data of the new task to train the metric model while preserving the original capabilities. More specifically, the proposed LML maintains a common subspace for all learned metrics, named lifelong dictionary, transfers knowledge from the common subspace to learn each new metric learning task with task-specific idiosyncrasy, and redefines the common subspace over time to maximize performance across all metric tasks. For model optimization, we apply online passive aggressive optimization algorithm to achieve lifelong metric task learning, where the lifelong dictionary and task-specific partition are optimized alternatively and consecutively. Finally, we evaluate our approach by analyzing several multitask metric learning datasets. Extensive experimental results demonstrate effectiveness and efficiency of the proposed framework. PMID- 29994495 TI - Serendipitous Recommendation in E-Commerce Using Innovator-Based Collaborative Filtering. AB - Collaborative filtering (CF) algorithms have been widely used to build recommender systems since they have distinguishing capability of sharing collective wisdoms and experiences. However, they may easily fall into the trap of the Matthew effect, which tends to recommend popular items and hence less popular items become increasingly less popular. Under this circumstance, most of the items in the recommendation list are already familiar to users and therefore the performance would seriously degenerate in finding cold items, i.e., new items and niche items. To address this issue, in this paper, a user survey is first conducted on the online shopping habits in China, based on which a novel recommendation algorithm termed innovator-based CF is proposed that can recommend cold items to users by introducing the concept of innovators. Specifically, innovators are a special subset of users who can discover cold items without the help of recommender system. Therefore, cold items can be captured in the recommendation list via innovators, achieving the balance between serendipity and accuracy. To confirm the effectiveness of our algorithm, extensive experiments are conducted on the dataset provided by Alibaba Group in Ali Mobile Recommendation Algorithm Competition, which is collected from the real e-commerce environment and covers massive user behavior log data. PMID- 29994496 TI - Multiview Clustering Based on Non-Negative Matrix Factorization and Pairwise Measurements. AB - As we all know, multiview clustering has become a hot topic in machine learning and pattern recognition. Non-negative matrix factorization (NMF) has been one popular tool in multiview clustering due to its competitiveness and interpretation. However, the existing multiview clustering methods based on NMF only consider the similarity of intra-view, while neglecting the similarity of inter-view. In this paper, we propose a novel multiview clustering algorithm, named multiview clustering based on NMF and pairwise measurements, which incorporates pairwise co-regularization and manifold regularization with NMF. In the proposed algorithm, we consider the similarity of the inter-view via pairwise co-regularization to obtain the more compact representation of multiview data space. We can also obtain the part-based representation by NMF and preserve the locally geometrical structure of the data space by utilizing the manifold regularization. Furthermore, we give the theoretical proof that the objective function of the proposed algorithm is convergent for multiview clustering. Experimental results show that the proposed algorithm outperforms the state-of the-arts for multiview clustering. PMID- 29994497 TI - Learning Pose-Aware Models for Pose-Invariant Face Recognition in the Wild. AB - We propose a method designed to push the frontiers of unconstrained face recognition in the wild with an emphasis on extreme out-of-plane pose variations. Existing methods either expect a single model to learn pose invariance by training on massive amounts of data or else normalize images by aligning faces to a single frontal pose. Contrary to these, our method is designed to explicitly tackle pose variations. Our proposed Pose-Aware Models (PAM) process a face image using several pose-specific, deep convolutional neural networks (CNN). 3D rendering is used to synthesize multiple face poses from input images to both train these models and to provide additional robustness to pose variations at test time. Our paper presents an extensive analysis on the IJB-A benchmark, evaluating the effects that landmark detection accuracy, CNN layer selection, and pose model selection all have on the performance of the recognition pipeline. It further provides comparative evaluations on the IARPA Janus Benchmarks A (IJB-A) and the PIPA dataset. These tests show that our approach outperforms existing methods, even surprisingly matching the accuracy of methods that were specifically fine-tuned to the target dataset. Parts of this work previously appeared in [1] and [2]. PMID- 29994498 TI - Model-based learning of local image features for unsupervised texture segmentation. AB - Features that capture well the textural patterns of a certain class of images are crucial for the performance of texture segmentation methods. The manual selection of features or designing new ones can be a tedious task. Therefore, it is desirable to automatically adapt the features to a certain image or class of images. Typically, this requires a large set of training images with similar textures and ground truth segmentation. In this work, we propose a framework to learn features for texture segmentation when no such training data is available. The cost function for our learning process is constructed to match a commonly used segmentation model, the piecewise constant Mumford-Shah model. This means that the features are learned such that they provide an approximately piecewise constant feature image with a small jump set. Based on this idea, we develop a two-stage algorithm which first learns suitable convolutional features and then performs a segmentation. We note that the features can be learned from a small set of images, from a single image, or even from image patches. The proposed method achieves a competitive rank in the Prague texture segmentation benchmark, and it is effective for segmenting histological images. PMID- 29994499 TI - Modelling and Control of Gene Regulatory Networks for Perturbation Mitigation. AB - Synthetic Biologists are increasingly interested in the idea of using synthetic feedback control circuits for the mitigation of perturbations to gene regulatory networks that may arise due to disease and/or environmental disturbances. Models employing Michaelis-Menten kinetics with Hill-type nonlinearities are typically used to represent the dynamics of gene regulatory networks. Here, we identify some fundamental problems with such models from the point of view of control system design, and argue that an alternative formalism, based on so-called S System models, is more suitable. Using tools from system identification, we show how to build S-System models that capture the key dynamics of an example gene regulatory network, and design a genetic feedback controller with the objective of rejecting an external perturbation. Using a sine sweeping method, we show how the S-System model can be approximated by a linear transfer function and, based on this transfer function, we design our controller. Simulation results using the full nonlinear S-System model of the network show that the synthetic control circuit is able to mitigate the effect of external perturbations. Our study is the first to highlight the usefulness of the S-System modelling formalism for the design of synthetic control circuits for gene regulatory networks. PMID- 29994500 TI - Fast QRS detection and ECG compression based on signal structural analysis. AB - OBJECTIVE: This paper presents a fast approach to detect QRS complexes based on a simple analysis of the temporal ECG structure. METHODS: The ECG is processed through several steps involving noise removal, feature detection and feature analysis. The obtained feature set, which holds most of the ECG information while requiring low data storage, constitutes a lossy compressed version of the ECG. RESULTS: The experiments, performed using 12 different ECG databases, emphasize the advantages of our proposal. For example, 130 minute ECG recordings are processed in average in 0.77 s. Also, sensitivities and positive predictions surpass 99.9% in some databases and a global data saving of 90.35% is achieved. CONCLUSION AND SIGNIFICANCE: When compared to other approaches, this study offers a parameterless and computationally efficient alternative for QRS complex detection and lossy ECG compression. Moreover, some of the presented techniques are general enough to be used by other ECG analysis tools. Finally, the documented source code corresponding to this study is publicly available. PMID- 29994501 TI - Segmentation of retinal cysts from Optical Coherence Tomography volumes via selective enhancement. AB - Automated and accurate segmentation of cystoid structures in Optical Coherence Tomography (OCT) is of interest in the early detection of retinal diseases. It is, however, a challenging task. We propose a novel method for localizing cysts in 3D OCT volumes. The proposed work is biologically inspired and based on selective enhancement of the cysts, by inducing motion to a given OCT slice. A Convolutional Neural Network (CNN) is designed to learn a mapping function that combines the result of multiple such motions to produce a probability map for cyst locations in a given slice. The final segmentation of cysts is obtained via simple clustering of the detected cyst locations. The proposed method is evaluated on two public datasets and one private dataset. The public datasets include the one released for the OPTIMA Cyst segmentation challenge (OCSC) in MICCAI 2015 and the DME dataset. After training on the OCSC train set, the method achieves a mean Dice Coefficient (DC) of 0.71 on the OCSC test set. The robustness of the algorithm was examined by cross-validation on the DME and AEI (private) datasets and a mean DC values obtained were 0.69 and 0.79, respectively. Overall, the proposed system outperforms all benchmarks. These results underscore the strengths of the proposed method in handling variations in both data acquisition protocols and scanners. PMID- 29994502 TI - Decentralized Adaptive Fuzzy Secure Control for Nonlinear Uncertain Interconnected Systems Against Intermittent DoS Attacks. AB - Cyber-physical systems (CPSs) are naturally highly interconnected and complexly nonlinear. This paper investigates the problem of decentralized adaptive output feedback control for CPSs subject to intermittent denial-of-service (DoS) attacks. The considered CPSs are modeled as a class of nonlinear uncertain strict feedback interconnected systems. When a DoS attack is active, all the state variables become unavailable and standard backstepping cannot be applied. To overcome this difficulty, a switching-type adaptive state estimator is constructed. Based on an improved average dwell time method incorporated by frequency and duration properties of DoS attacks, convex design conditions of controller parameters are derived in term of solving a set of linear matrix inequalities. The proposed controller guarantees that all closed-loop signals remain bounded, while the error signals converge to a small neighborhood of the origin. As an illustrative example, the proposed control scheme is applied to a power network system. PMID- 29994503 TI - Distributed Hinfinity State Estimation Over a Filtering Network With Time-Varying and Switching Topology and Partial Information Exchange. AB - This paper is concerned with the distributed Hinfinity state estimation for a discrete-time target linear system over a filtering network with time-varying and switching topology and partial information exchange. Both filtering network topology switching and partial information exchange between filters are simultaneously considered in the filter design. The topology under consideration evolves not only over time but also by an event switch which is assumed to be subject to a nonhomogeneous Markov chain. The probability transition matrix of the nonhomogeneous Markov chain is time-varying. In the filter information exchange, partial state estimation information and channel noise are simultaneously considered. In order to design such a switching filtering network with partial information exchange, stochastic Markov stability theory is developed. The switching topology-dependent filters are derived to guarantee an optimal Hinfinity disturbance rejection attenuation level for the estimation disagreement of the filtering network. It is shown that the addressed Hinfinity state estimation problem is turned into a switching topology-dependent optimal problem. The distributed filtering problem with complete information exchanges from its neighbors is also investigated. An illustrative example is given to show the applicability of the obtained results. PMID- 29994504 TI - A Threshold-Parameter-Dependent Approach to Designing Distributed Event-Triggered Hinfinity Consensus Filters Over Sensor Networks. AB - This paper is concerned with distributed event-triggered Hinfinity consensus filtering for a discrete-time linear system over a sensor network. Different from some existing event-triggered communication schemes (ETCSs), a new distributed ETCS is first developed to reduce the communication frequency of neighboring sensors, where the threshold parameter in an event triggering condition is time varying with attainable upper and lower bounds. Then a threshold-parameter dependent approach is proposed to derive criteria for designing the desired Hinfinity consensus filters and the ETCS such that the resultant filtering error system is asymptotically stable with the prescribed Hinfinity performance while maintaining satisfactory resource efficiency. Furthermore, a polytope-like transformation with regard to time-varying threshold parameters is performed and a recursive algorithm is presented to determine the threshold-parameter-dependent filter matrix sequences and event triggering weighting matrix sequence. Two illustrative examples are employed to show the effectiveness of the developed approach. PMID- 29994505 TI - Recurrent Face Aging with Hierarchical AutoRegressive Memory. AB - Modeling the aging process of human faces is important for cross-age face verification and recognition. In this paper, we propose a Recurrent Face Aging (RFA) framework which takes as input a single image and automatically outputs a series of aged faces. The hidden units in the RFA are connected autoregressively allowing the framework to age the person by referring to the previous aged faces. Due to the lack of labeled face data of the same person captured in a long range of ages, traditional face aging models split the ages into discrete groups and learn a one-step face transformation for each pair of adjacent age groups. Since human face aging is a smooth progression, it is more appropriate to age the face by going through smooth transitional states. In this way, the intermediate aged faces between the age groups can be generated. Towards this target, we employ a recurrent neural network whose recurrent module is a hierarchical triple-layer gated recurrent unit which functions as an autoencoder. The bottom layer of the module encodes the input to a latent representation, and the top layer decodes the representation to a corresponding aged face. The experimental results demonstrate the effectiveness of our framework. PMID- 29994506 TI - Searching for Representative Modes on Hypergraphs for Robust Geometric Model Fitting. AB - In this paper, we propose a simple and effective geometric model fitting method to fit and segment multi-structure data even in the presence of severe outliers. We cast the task of geometric model fitting as a representative mode-seeking problem on hypergraphs. Specifically, a hypergraph is firstly constructed, where the vertices represent model hypotheses and the hyperedges denote data points. The hypergraph involves higher-order similarities (instead of pairwise similarities used on a simple graph), and it can characterize complex relationships between model hypotheses and data points. In addition, we develop a hypergraph reduction technique to remove "insignificant" vertices while retaining as many "significant" vertices as possible in the hypergraph. Based on the simplified hypergraph, we then propose a novel mode-seeking algorithm to search for representative modes within reasonable time. Finally, the proposed mode seeking algorithm detects modes according to two key elements, i.e., the weighting scores of vertices and the similarity analysis between vertices. Overall, the proposed fitting method is able to efficiently and effectively estimate the number and the parameters of model instances in the data simultaneously. Experimental results demonstrate that the proposed method achieves significant superiority over several state-of-the-art model fitting methods on both synthetic data and real images. PMID- 29994507 TI - Improving Shadow Suppression for Illumination Robust Face Recognition. AB - 2D face analysis techniques, such as face landmarking, face recognition and face verification, are reasonably dependent on illumination conditions which are usually uncontrolled and unpredictable in the real world. An illumination robust preprocessing method thus remains a significant challenge in reliable face analysis. In this paper we propose a novel approach for improving lighting normalization through building the underlying reflectance model which characterizes interactions between skin surface, lighting source and camera sensor, and elaborates the formation of face color appearance. Specifically, the proposed illumination processing pipeline enables the generation of Chromaticity Intrinsic Image (CII) in a log chromaticity space which is robust to illumination variations. Moreover, as an advantage over most prevailing methods, a photo realistic color face image is subsequently reconstructed which eliminates a wide variety of shadows whilst retaining the color information and identity details. Experimental results under different scenarios and using various face databases show the effectiveness of the proposed approach to deal with lighting variations, including both soft and hard shadows, in face recognition. PMID- 29994508 TI - Bayesian Bistatic ISAR Imaging for Targets with Complex Motion under Low SNR Condition. AB - This paper proposes a novel bistatic inverse synthetic aperture radar (ISAR) imaging algorithm for the target with complex motion under low signal to noise ratio (SNR) condition. Note the bistatic ISAR system generally suffers from a lower SNR than the monostatic one because of its non-mirror reflection geometry. A de-noising method, therefore, is proposed to improve SNR of range profiles, which accumulates the aligned range profiles non-coherently to obtain a window for noise suppression. Additionally, since the complex motion of target induces nonstationary Doppler, which is destructive to ISAR imaging, an optimal coherent processing interval (CPI) selection algorithm is further proposed to find out the interval where the Doppler is relatively stationary, so as to produce well focused ISAR images. It utilizes the reassigned time-frequency (TF) method to obtain the high resolution instantaneous Doppler spectrum, and the minimum entropy criterion to select the optimal CPI, respectively. Note the selected CPI often contains too limited pulses to produce ISAR images with high resolution. A sparse aperture ISAR imaging method within the Bayesian framework is further proposed, which introduces the Laplacian scale mixture (LSM) model as the sparse prior, so as to reconstruct well-focused ISAR images with high resolution and low side lobes from the limited data. Compared with the traditional sparse Bayesian learning method, the proposed LSM based ISAR imaging performs superiorly on resolution improvement and noise reduction. Experimental results based on both simulated and measured data validate the effectiveness of the proposed algorithms. PMID- 29994509 TI - Underlying Connections Between Algorithms For Nongreedy LDA-L1. AB - To solve the essential objective of LDA-L1, NLDA-L1 proposes a nongreedy algorithm by constructing an auxiliary function. In this correspondence, we show that essentially, this algorithm directly solves the objective using a gradient ascending procedure, meaning that the auxiliary function may be not necessary. Then, we further show that NLDA-L1 is a special case of ILDA-L1, which applies the same iterative procedure of ILDA-L1. PMID- 29994510 TI - DeepDemosaicking: Adaptive Image Demosaicking via Multiple Deep Fully Convolutional Networks. AB - Convolutional neural networks are currently the state-of-the-art solution for a wide range of image processing tasks. Their deep architecture extracts low and high-level features from images, thus, improving the model's performance. In this paper, we propose a method for image demosaicking based on deep convolutional neural networks. Demosaicking is the task of reproducing full color images from incomplete images formed from overlaid color filter arrays on image sensors found in digital cameras. Instead of producing the output image directly, the proposed method divides the demosaicking task into an initial demosaicking step and a refinement step. The initial step produces a rough demosaicked image containing unwanted color artifacts. The refinement step then reduces these color artifacts using deep residual estimation and multi-model fusion producing a higher quality image. Experimental results show that the proposed method outperforms several existing and state-of-the-art methods in terms of both subjective and objective evaluations. PMID- 29994511 TI - Urban Weathering: Interactive Rendering of Polluted Cities. AB - Weathering effects are ubiquitous phenomena in cities. Buildings age and deteriorate over time as they interact with the environment. Pollution accumulating on facades is a particularly visible consequence of this. Even though relevant work has been done to produce impressive images of virtual urban environments including weathering effects, so far, no technique using a global approach has been proposed to deal with weathering effects. Here, we propose a technique based on a fast physically-inspired approach, that focuses on modeling the changes in appearance due to pollution soiling on an urban scale. We consider pollution effects to depend on three main factors: wind, rain and sun exposure, and we take into account three intervening steps: deposition, reaction and washing. Using a low-cost pre-computation, we evaluate the pollution distribution throughout the city. Based on this and the use of screen-space operators, our method results in an efficient approach able to generate realistic images of urban scenes by combining the intervening factors at interactive rates. In addition, the pre-computation demands a reduced amount of memory to store the resulting pollution map and, as it is independent from scene complexity, it can suit large and complex models by adapting the map resolution. PMID- 29994512 TI - Tensor Decompositions for Integral Histogram Compression and Look-Up. AB - Histograms are a fundamental tool for multidimensional data analysis and processing, and many applications in graphics and visualization rely on computing histograms over large regions of interest (ROI). Integral histograms (IH) greatly accelerate the calculation in the case of rectangular regions, but come at a large extra storage cost. Based on the tensor train decomposition model, we propose a new compression and approximate retrieval algorithm to reduce the overall IH memory usage by several orders of magnitude at a user-defined accuracy. To this end we propose an incremental tensor decomposition algorithm that allows us to compress integral histograms of hundreds of gigabytes. We then encode the borders of any desired rectangular ROI in the IH tensor-compressed domain and reconstruct the target histogram at a high speed which is independent of the region size. We furthermore generalize the algorithm to support regions of arbitrary shape rather than only rectangles, as well as histogram field computation, i.e. recovering many histograms at once. We test our method with several multidimensional data sets and demonstrate that it radically speeds up costly histogram queries while avoiding storing massive, uncompressed IHs. PMID- 29994513 TI - Feature Preserving Mesh Denoising Based on Graph Spectral Processing. AB - The increasing interest for reliable generation of large scale scenes and objects has facilitated several real-time applications. Although the resolution of the new generation geometry scanners are constantly improving, the output models, are inevitably noisy, requiring sophisticated approaches that remove noise while preserving sharp features. Moreover, we no longer deal exclusively with individual shapes, but with entire scenes resulting in a sequence of 3D surfaces that are affected by noise with different characteristics due to variable environmental factors (e.g., lighting conditions, orientation of the scanning device). In this work, we introduce a novel coarse-to-fine graph spectral processing approach that exploits the fact that the sharp features reside in a low dimensional structure hidden in the noisy 3D dataset. In the coarse step, the mesh is processed in parts, using a model based Bayesian learning method that identifies the noise level in each part and the subspace where the features lie. In the feature-aware fine step, we iteratively smooth face normals and vertices, while preserving geometric features. Extensive evaluation studies carried out under a broad set of complex noise patterns verify the superiority of our approach as compared to the state-of-the-art schemes, in terms of reconstruction quality and computational complexity. PMID- 29994514 TI - Shadow Accrual Maps: Efficient Accumulation of City-Scale Shadows over Time. AB - Large scale shadows from buildings in a city play an important role in determining the environmental quality of public spaces. They can be both beneficial, such as for pedestrians during summer, and detrimental, by impacting vegetation and by blocking direct sunlight. Determining the effects of shadows requires the accumulation of shadows over time across different periods in a year. In this paper, we propose a simple yet efficient class of approach that uses the properties of sun movement to track the changing position of shadows within a fixed time interval. We use this approach to extend two commonly used shadowing techniques, shadow maps and ray tracing, and demonstrate the efficiency of our approach. Our technique is used to develop an interactive visual analysis system, Shadow Profiler, targeted at city planners and architects that allows them to test the impact of shadows for different development scenarios. We validate the usefulness of this system through case studies set in Manhattan, a dense borough of New York City. PMID- 29994515 TI - 6-DoF Haptic Rendering of Static Coulomb Friction Using Linear Programming. AB - Simulating frictional contact between objects with complex geometry is important for 6-DoF haptic rendering applications. For example, friction determines whether components can be navigated past narrow clearances in virtual assembly. State-of the-art haptic rendering of frictional contact either augments penalty contact with frictional penalty springs, which do not prevent sliding and cannot render correct static friction, or uses constraint-based methods that are difficult to meet the stringent haptic loop computation time requirements for complex geometry. We give a 6-DoF Coulomb friction haptic rendering algorithm for distributed contact between rigid objects with complex geometry. Our algorithm is compatible with the fast point vs implicit function penalty-based contact method such as the Voxmap-PointShell method. Our algorithm incorporates the maximal dissipation principle and produces correct static friction, all the while inheriting the speed of penalty-based methods. We demonstrate our algorithm on several challenging 6-DoF haptic rendering examples. PMID- 29994516 TI - Adaptive Neural Dynamic Surface Control for Nonstrict-Feedback Systems With Output Dead Zone. AB - This paper focuses on the problem of adaptive output-constrained neural tracking control for uncertain nonstrict-feedback systems in the presence of unknown symmetric output dead zone and input saturation. A Nussbaum-type function-based dead-zone model is introduced such that the dynamic surface control approach can be used for controller design. The variable separation technique is employed to decompose the unknown function of entire states in each subsystem into a series of smooth functions. Radial basis function neural networks are utilized to approximate the unknown black-box functions derived from Young's inequality. With the help of auxiliary first-order filters, the dimensions of neural network input are reduced in each recursive design. A main advantage of the proposed method is that for an -order nonlinear system, only one adaptation parameter needs to be tuned online. It is rigorously shown that the proposed output-constrained controller guarantees that all the closed-loop signals are semiglobal uniformly ultimately bounded and the tracking error never violates the output constraint. PMID- 29994517 TI - Cell Segmentation Based on FOPSO Combined with Shape Information Improved Intuitionistic FCM. AB - For image segmentation, fuzzy c-means (FCM) clustering algorithms have been proved to be effective. However, FCM clustering algorithms are sensitive to noises and initialization. They cannot effectively segment cell images with inhomogeneous gray value distributions and complex touching cells. Aiming to overcome these disadvantages, this paper proposes a cell image segmentation algorithm using fractional-order velocity based particle swarm optimization (FOPSO) combined with shape information improved intuitionistic fuzzy c-means (SI IFCM) clustering. Iterations are carried out between FOPSO and SI-IFCM to achieve final cell segmentation. Experimental results demonstrate that the proposed algorithm has advantages on cell image segmentation, with the highest PCD (90.25%) and lowest PFA (0.28%) compared with the state-of-the-art algorithms. PMID- 29994518 TI - Sampled-Data Control for the Synchronization of Boolean Control Networks. AB - In this paper, we investigate the sampled-data state feedback control (SDSFC) for the synchronization of Boolean control networks (BCNs) under the configuration of drive-response coupling. Necessary and sufficient conditions for the complete synchronization of BCNs are obtained by the algebraic representations of logical dynamics. Based on the analysis of the sampling periods, we establish an algorithm to guarantee the synchronization of drive-response coupled BCNs by SDSFC. An example is given to illustrate the significance of the obtained results. PMID- 29994519 TI - Fast Large-Scale Spectral Clustering via Explicit Feature Mapping. AB - We propose an efficient spectral clustering method for large-scale data. The main idea in our method consists of employing random Fourier features to explicitly represent data in kernel space. The complexity of spectral clustering thus is shown lower than existing Nystrom approximations on large-scale data. With m training points from a total of n data points, Nystrom method requires O(nmd+m3+nm2) operations, where d is the input dimension. In contrast, our proposed method requires O(nDd+D3+n'D2), where n' is the number of data points needed until convergence and D is the kernel mapped dimension. In large-scale datasets where n' << n hold true, our explicitly mapping method can significantly speed up eigenvector approximation and benefit prediction speed in spectral clustering. For instance, on MNIST (60,000 data points), the proposed method is similar in clustering accuracy to Nystrom methods while its speed is twice as fast as Nystrom. PMID- 29994520 TI - 3-D Contrast Source Inversion-Electrical Properties Tomography. AB - Contrast source inversion-electrical properties tomography (CSI-EPT) is an iterative reconstruction method to retrieve the electrical properties (EPs) of tissues from magnetic resonance data. The method is based on integral representations of the electromagnetic field and has been shown to allow EP reconstructions of small structures as well as tissue boundaries with compelling accuracy. However, to date, the CSI-EPT has been implemented for 2-D configurations only, which limits its applicability. In this paper, a full 3-D extension of the CSI-EPT method is presented, to enable CSI-EPT to be applied to realistic 3-D scenarios. Here, we demonstrate a proof-of-principle of 3-D CSI-EPT and present the reconstructions of a 3-D abdominal body section and a 3-D head model using different settings of the transmit coil. Numerical results show that the full 3-D approach yields accurate reconstructions of the EPs, even at tissue boundaries and is most accurate in regions where the absolute value of the electric field is highest. PMID- 29994521 TI - Robust Reconstruction of Elasticity Using Ultrasound Imaging and Multi-Frequency Excitations. AB - Biomedical parameters of tissue can be important indicators for clinical diagnosis. One such parameter that reflects tissue stiffness is elasticity, the imaging of which is called elastography. In this paper, we use displacements from harmonic excitations to solve the inverse problem of elasticity based on a finite element method (FEM) formulation. This leads to iterative solution of nonlinear and nonconvex problems. In this paper, we show the importance and selection of viable initializations in numerical simulation studies and propose techniques for the fusion of multiple initializations for ideal reconstructions of unknown tissue as well as combining information from excitations at multiple frequencies. Results show that our method leads up to 76% decrease in root-mean-squared error (RMSE) and 9.9 dB increase in contrast-to-noise ratio (CNR) in simulations with noise, when compared to conventional iterative FEM without multiple initializations and frequencies. As the wave patterns in individually selected frequencies may introduce artifacts, a joint inverse-problem solution of multi frequency excitations is introduced as a robust solution, where CNR improvements of up to 11.9 dB are observed. We also present the methods on a tissue-mimicking gelatin phantom study using mechanical excitation and ultrafast plane-wave ultrasound imaging, where the RMSE was improved by up to 51%. An experiment of ablation via heating an ex-vivo bovine liver shows that reconstruction artifacts are reduced with our proposed method. PMID- 29994522 TI - Structure-Preserving Guided Retinal Image Filtering and Its Application for Optic Disk Analysis. AB - Retinal fundus photographs have been used in the diagnosis of many ocular diseases such as glaucoma, pathological myopia, age-related macular degeneration, and diabetic retinopathy. With the development of computer science, computer aided diagnosis has been developed to process and analyze the retinal images automatically. One of the challenges in the analysis is that the quality of the retinal image is often degraded. For example, a cataract in human lens will attenuate the retinal image, just as a cloudy camera lens which reduces the quality of a photograph. It often obscures the details in the retinal images and posts challenges in retinal image processing and analyzing tasks. In this paper, we approximate the degradation of the retinal images as a combination of human lens attenuation and scattering. A novel structure-preserving guided retinal image filtering (SGRIF) is then proposed to restore images based on the attenuation and scattering model. The proposed SGRIF consists of a step of global structure transferring and a step of global edge-preserving smoothing. Our results show that the proposed SGRIF method is able to improve the contrast of retinal images, measured by histogram flatness measure, histogram spread, and variability of local luminosity. In addition, we further explored the benefits of SGRIF for subsequent retinal image processing and analyzing tasks. In the two applications of deep learning-based optic cup segmentation and sparse learning based cup-to-disk ratio (CDR) computation, our results show that we are able to achieve more accurate optic cup segmentation and CDR measurements from images processed by SGRIF. PMID- 29994523 TI - CMOS High-Voltage Analog 1-64 Multiplexer/Demultiplexer for Integrated Ultrasound Guided Breast Needle Biopsy. AB - Ultrasound guided needle biopsy is an important method for collection of breast cancer tissue. In this paper, we report on the design and testing of a high voltage 1 to 64 Multiplexer/Demultiplexer (MUX/De-MUX) integrated circuit (IC) for ultrasound-guided breast biopsy applications implemented in a high-voltage CMOS process. The IC is intended to be incorporated inside the breast biopsy needle and is designed to fit inside the needle inner diameter of 2.38 mm. The MUX/De-MUX electronics are made up of three parts, including a low-voltage 6 to 64 decoder, a level shifter to convert from low voltage to high voltage, and analog high-voltage switches. Experimental results show a -3-dB bandwidth of over 70 MHz, Rds (on) of , -2.279-dB insertion loss, and -17.5-dB off isolation at 70 MHz with low-voltage input. Finally, we present results obtained via synthetic aperture imaging using the fabricated MUX/De-Mux device and a high-frequency ultrasound array. This device and technique hold promise for high-frequency imaging probes where a limited number of elements are used and the depth of penetration is short such as in breast biopsy and intravascular applications. PMID- 29994524 TI - Improved Performance of -Mode Needle-Actuating Transducer With PMN-PT Piezocrystal. AB - Prototypes of a PZT-based ultrasound needle-actuating device have shown the ability to reduce needle penetration force and enhance needle visibility with color Doppler imaging during needle insertion for tissue biopsy and regional anesthesia. However, the demand for smaller, lighter devices and the need for high performance transducers have motivated investigation of a different configuration of needle-actuation transducer, utilizing the -mode of PZT4 piezoceramic, and exploration of further improvement in its performance using relaxor-type piezocrystal. This paper outlines the development of the -mode needle actuation transducer design from simulation to fabrication and demonstration. Full characterization was performed on transducers for performance comparison. The performance of the proposed smaller, lighter -mode transducer is comparable with that of previous -mode transducers. Furthermore, it has been found to be much more efficient when using PMN-PT piezocrystal rather than piezoceramic. PMID- 29994525 TI - AlN Ultrasound Sensor for Photoacoustic Lamb Wave Detection in a High-Temperature Environment. AB - In this paper, we present an ultrasound nondestructive testing (NDT) method for high-temperature (HT) applications using laser-generated Lamb waves and aluminum nitride (AlN) sensors. Lamb waves were introduced to a stainless steel plate by the Nd:YAG pulsed laser at one point and detected by an AlN receiver at a distant position. The fundamental symmetric ( ) and antisymmetric ( ) Lamb waves generated by the pulsed laser were successfully detected by the AlN sensor. This detection was done on a stainless steel plate at temperatures ranging from room temperature to about 800 degrees C, with a signal-to-noise ratio of higher than 20 dB. Based on the time-of-flights analysis, the ability of this NDT method to localize the defect at an HT (~800 degrees C) has been demonstrated. PMID- 29994526 TI - Learning Depth from Single Images with Deep Neural Network Embedding Focal Length. AB - Learning depth from a single image, as an important issue in scene understanding, has attracted a lot of attention in the past decade. The accuracy of the depth estimation has been improved from conditional Markov random fields, non parametric methods, to deep convolutional neural networks most recently. However, there exist inherent ambiguities in recovering 3D from a single 2D image. In this paper, we first prove the ambiguity between the focal length and monocular depth learning, and verify the result using experiments, showing that the focal length has a great influence on accurate depth recovery. In order to learn monocular depth by embedding the focal length, we propose a method to generate synthetic varying-focal-length dataset from fixed-focal-length datasets, and a simple and effective method is implemented to fill the holes in the newly generated images. For the sake of accurate depth recovery, we propose a novel deep neural network to infer depth through effectively fusing the middle-level information on the fixed-focal-length dataset, which outperforms the state-of-the-art methods built on pretrained VGG. Furthermore, the newly generated varying-focallength dataset is taken as input to the proposed network in both learning and inference phases. Extensive experiments on the fixed- and varying-focal-length datasets demonstrate that the learned monocular depth with embedded focal length is significantly improved compared to that without embedding the focal length information. PMID- 29994527 TI - Segmentation in Weakly Labeled Videos via a Semantic Ranking and Optical Warping Network. AB - Weakly supervised video object segmentation (WSVOS) focuses on generating pixel level object masks for videos only tagged with class labels, which is an essential yet challenging task. For WSVOS, the algorithm is just aware of rough category information rather than the concrete object size and location cues, besides it lacks reliable annotated exemplars to learn temporal evolution in the investigated videos. Basically, there are three challenging factors which may influence the performance of WSVOS: foreground object discovery in each frame, coarse object semantic consistency within each video, and fine-grained segmentation smoothness within neighbor frames. In this paper, we establish a semantic ranking and optical warping network (SROWN) to simultaneously solve these three challenges in a unified framework. For the first challenge, we apply the still image saliency detection method and discover the foreground object for each frame via a segmentation network. Due to the huge discrepancies between the image saliency and the video object segmentation, we step further and propose two subnetworks to solve the other two challenges. For the second one, we propose an attentive semantic ranking subnetwork to mine video-level tags, which can learn discriminative features for semantic ranking and lead to semantic consistent segmentation masks. For the third one, we propose an optical flow warping subnetwork to constrain fine-grained segmentation smoothness within neighbor frames, which can suppress the large deformation and thus obtain smooth object boundaries for adjacent frames. Experiments on two benchmark datasets, i.e., DAVIS dataset and YouTube-Objects dataset, demonstrate the effectiveness of the proposed approach for segmenting out video objects under weak supervision. PMID- 29994528 TI - Superpixel Segmentation Using Gaussian Mixture Model. AB - Superpixel segmentation partitions an image into perceptually coherent segments of similar size, namely, superpixels. It is becoming a fundamental preprocessing step for various computer vision tasks because superpixels significantly reduce the number of inputs and provide a meaningful representation for feature extraction. We present a pixel-related Gaussian mixture model (GMM) to segment images into superpixels. GMM is a weighted sum of Gaussian functions, each one corresponding to a superpixel, to describe the density of each pixel represented by a random variable. Different from previously proposed GMMs, our weights are constant, and Gaussian functions in the sums are subsets of all the Gaussian functions, resulting in segments of similar size and an algorithm of linear complexity with respect to the number of pixels. In addition to the linear complexity, our algorithm is inherently parallel and allows fast execution on multicore systems. During the expectation-maximization iterations of estimating the unknown parameters in the Gaussian functions, we impose two lower bounds to truncate the eigenvalues of the covariance matrices, which enables the proposed algorithm to control the regularity of superpixels. Experiments on a wellknown segmentation dataset show that our method can efficiently produce superpixels that adhere to object boundaries better than the current state-of-the-art methods. PMID- 29994529 TI - Heteroscedastic Max-min Distance Analysis for Dimensionality Reduction. AB - Max-min distance analysis (MMDA) performs dimensionality reduction by maximizing the minimum pairwise distance between classes in the latent subspace under the homoscedastic assumption, which can address the class separation problem caused by the Fisher criterion, but is incapable of tackling heteroscedastic data properly. In this paper, we propose two heteroscedastic MMDA (HMMDA) methods to employ the differences of class covariances. Whitened HMMDA (WHMMDA) extends MMDA by utilizing the Chernoff distance as the separability measure between classes in the whitened space. Orthogonal HMMDA (OHMMDA) incorporates the maximization of the minimal pairwise Chernoff distance and the minimization of class compactness into a trace quotient formulation with an orthogonal constraint of the transformation, which can be solved by bisection search. Two variants of OHMMDA further encode the margin information by using only neighboring samples to construct the intra-class and inter-class scatters. Experiments on several UCI datasets and two face databases demonstrate the effectiveness of the HMMDA methods. PMID- 29994530 TI - Image Super-resolution with Parametric Sparse Model Learning. AB - Recovering a high-resolution (HR) image from its low-resolution (LR) version is an ill-posed inverse problem. Learning accurate prior of HR images is of great importance to solve this inverse problem. Existing super-resolution (SR) methods either learn a non-parametric image prior from training data (a large set of LR/HR patch pairs) or estimate a parametric prior from the LR image analytically. Both methods have their limitations: the former lacks flexibility when dealing with different SR settings; while the latter often fails to adapt to spatially varying image structures. In this paper, we propose to take a hybrid approach toward image SR by combining those two lines of ideas - that is, a parametric sparse prior of HR images is learned from the training set as well as the input LR image. By exploiting the strengths of both worlds, we can more accurately recover the sparse codes and therefore HR image patches than conventional sparse coding approaches. Experimental results show that the proposed hybrid SR method significantly outperforms existing model-based SR methods and is highly competitive to current state-of-the-art learning-based SR methods in terms of both subjective and objective image qualities. PMID- 29994531 TI - Isotropic Surface Remeshing without Large and Small Angles. AB - We introduce a novel algorithm for isotropic surface remeshing which progressively eliminates obtuse triangles and improves small angles. The main novelty of the proposed approach is a simple vertex insertion scheme that facilitates the removal of large angles, and a vertex removal operation that improves the distribution of small angles. In combination with other standard local mesh operators, e.g., connectivity optimization and local tangential smoothing, our algorithm is able to remesh efficiently a low-quality mesh surface. Our approach can be applied directly or used as a post-processing step following other remeshing approaches. Our method has a similar computational efficiency to the fastest approach available, i.e., real-time adaptive remeshing [1]. In comparison with state-of-the-art approaches, our method consistently generates better results based on evaluations using different metrics. PMID- 29994532 TI - P Systems-Based Computing Polynomials With Integer Coefficients: Design and Formal Verification. AB - Automatic design of mechanical procedures solving abstract problems is a relevant scientific challenge. In particular, automatic design of membranes systems performing some prefixed tasks is an important and useful research topic in the area of Natural Computing. In this context, deterministic membrane systems were designed in order to capture the values of polynomials with natural numbers coefficients. Following that work, this paper extends the previous result to polynomials with integer numbers coefficients. Specifically, a deterministic transition P system using priorities in the weak interpretation, associated with an arbitrary such kind polynomial, is presented. The configuration of the unique computation of the system will be encoded by means of two distinguished objects, the values of the polynomial for natural numbers. The descriptive computational resources required by the designed membrane system are also analyzed. PMID- 29994533 TI - Managing Complex Workflows in Bioinformatics: An Interactive Toolkit With GPU Acceleration. AB - Bioinformatics research continues to advance at an increasing scale with the help of techniques such as next-generation sequencing and the availability of tool support to automate bioinformatics processes. With this growth, a large amount of biological data gets accumulated at an unprecedented rate, demanding high performance and high-throughput computing technologies for processing such datasets. Use of hardware accelerators, such as graphics processing units (GPUs) and distributed computing, accelerates the processing of big data in high performance computing environments. They enable higher degrees of parallelism to be achieved, thereby increasing the throughput. In this paper, we introduce BioWorkflow, an interactive workflow management system to automate the bioinformatics analyses with the capability of scheduling parallel tasks with the use of GPU-accelerated and distributed computing. This paper describes a case study carried out to evaluate the performance of a complex workflow with branching executed by BioWorkflow. The results indicate the gains of $?times 2.89$ magnitude by utilizing GPUs and gains in speed by average $?times 2.832$ magnitude (over $n = 5$ scenarios) by parallel execution of graph nodes during multiple sequence alignment calculations. Combined speed-ups are achieved $?times 1.71$ times for complex workflows. This confirms the expected higher speed-ups when having parallelism through GPU-acceleration and concurrent execution of workflow nodes than the mainstream sequential workflow execution. The tool also provides a comprehensive user interface with better interactivity for managing complex workflows; a system usability scale score of 82.9 is confirmed high usability for the system. PMID- 29994534 TI - Deep Patient Similarity Learning for Personalized Healthcare. AB - Predicting patients' risk of developing certain diseases is an important research topic in healthcare. Accurately identifying and ranking the similarity among patients based on their historical records is a key step in personalized healthcare. The electric health records (EHRs), which are irregularly sampled and have varied patient visit lengths, cannot be directly used to measure patient similarity due to the lack of an appropriate representation. Moreover, there needs an effective approach to measure patient similarity on EHRs. In this paper, we propose two novel deep similarity learning frameworks which simultaneously learn patient representations and measure pairwise similarity. We use a convolutional neural network (CNN) to capture local important information in EHRs and then feed the learned representation into triplet loss or softmax cross entropy loss. After training, we can obtain pairwise distances and similarity scores. Utilizing the similarity information, we then perform disease predictions and patient clustering. Experimental results show that CNN can better represent the longitudinal EHR sequences, and our proposed frameworks outperform state-of the-art distance metric learning methods. PMID- 29994535 TI - Impacts of Spike Shape Variations on Synaptic Communication. AB - Understanding the communication theoretical capabilities of information transmission among neurons, known as neuro-spike communication, is a significant step in developing bio-inspired solutions for nanonetworking. In this paper, we focus on a part of this communication known as synaptic transmission for pyramidal neurons in the Cornu Ammonis area of the hippocampus location in the brain and propose a communication-based model for it that includes effects of spike shape variation on neural calcium signaling and the vesicle release process downstream of it. For this aim, we find impacts of spike shape variation on opening of voltage-dependent calcium channels, which control the release of vesicles from the pre-synaptic neuron by changing the influx of calcium ions. Moreover, we derive the structure of the optimum receiver based on the Neyman Pearson detection method to find the effects of spike shape variations on the functionality of neuro-spike communication. Numerical results depict that changes in both spike width and amplitude affect the error detection probability. Moreover, these two factors do not control the performance of the system independently. Hence, a proper model for neuro-spike communication should contain effects of spike shape variations during axonal transmission on both synaptic propagation and spike generation mechanisms to enable us to accurately explain the performance of this communication paradigm. PMID- 29994536 TI - Phenotype Extraction Based on Word Embedding to Sentence Embedding Cascaded Approach. AB - As a significant determinant in the development of named entity recognition, phenotypic descriptions are normally presented differently in biomedical literature with the use of complicated semantics. In this paper, a novel approach has been proposed to identify plant phenotypes by adopting word embedding to sentence embedding cascaded approach. We make use of a word embedding method to find high-frequency phenotypes with original sentences used as input in a sentence embedding method. In doing so, a variety of complicated phenotypic expressions can be recognized accurately. Besides, the state-of-the-art word representation models have been compared and among them, skip-gram with negative sampling was selected with the best performance. To evaluate the performance of our approach, we applied it to the dataset composed of 56 748 PubMed abstracts of model organism Arabidopsis thaliana. The experiment results showed that our approach yielded the best performance, as it achieved a 2.588-fold increase in terms of the number of new phenotypic descriptions when compared to the original phenotype ontology. PMID- 29994537 TI - A Parametric Targetability Evaluation Approach for Vitiligo Proteome extracted through Integration of Gene Ontologies and Protein Interaction Topologies. AB - Vitiligo is a well - known skin disorder with complex etiology. Vitiligo pathogenesis is multifaceted with many ramifications. A computational systemic path was designed to first propose candidate disease proteins by merging properties from protein interaction networks and gene ontology terms. All in all 109 proteins were identified and suggested to be involved in the onset of disease or its progression. Later, a composite approach was employed to prioritize vitiligo disease proteins by comparing and benchmarking the properties against standard target identification criteria. This includes sequence-based, structural, functional, essentiality, protein-protein interaction, vulnerability, secretability, assayability and druggability information. The existing information was seamlessly integrated into efficient pipelines to propose a novel protocol for assessment of targetability of disease proteins. Using the online data resources and the scripting, an illustrative list of 68 potential drug targets was generated for vitiligo. While this list is broadly consistent with the research community's current interest in certain specific proteins, and suggests novel target candidates that may merit further study, it can still be modified to correspond to a user - specific environment, either by adjusting the weights for chosen criteria (i.e. a quantitative approach) or by changing the considered criteria (i.e. a qualitative approach). PMID- 29994538 TI - Parallel Computation of the Burrows-Wheeler Transform of Short Reads Using Prefix Parallelism. AB - The Burrows-Wheeler transform (BWT) of shortread data has unexplored potential utilities, such as for efficient and sensitive variation analysis against multiple reference genome sequences, because it does not depend on any particular reference genome sequence, unlike conventional mappingbased methods. However, since the amount of read data is generally much larger than the size of the reference sequence, computation of the BWT of reads is not easy, and this hampers development of potential applications. For the alleviation of this problem, a new method of computing the BWT of reads in parallel is proposed. The BWT, corresponding to a sorted list of suffixes of reads, is constructed incrementally by successively including longer and longer suffixes. The working data is divided into more than ten thousand "blocks" corresponding to sublists of suffixes with the same prefixes. Thousands of groups of blocks can be processed in parallel while making exclusive writes and concurrent reads into a shared memory. Reads and writes are basically sequential, and the read concurrency is limited to two. Thus, a fine-grained parallelism, referred to as prefix parallelism, is expected to work efficiently. The time complexity for processing reads of length is . On actual biological DNA sequence data of about 100 Gbp with a read length of 100 bp (base pairs), a tentative implementation of the proposed method took less than an hour on a singlenode computer; i.e., it was about three times faster than one of the fastest programs developed so far. PMID- 29994539 TI - Enhancement of Protein beta-sheet Topology Prediction using Maximum Weight Disjoint Path Cover. AB - Predicting beta-sheet topology (beta-topology) is one of the most critical intermediate steps towards protein structure and function prediction. The beta topology prediction problem is defined as the determination of the optimal arrangement of beta-strand interactions within protein beta-sheets. Significant efforts have been made to predict beta-topologies. However, due to the inaccurate determination of interactions among beta-strands and the huge topological space of proteins with a large number of beta-strands, more efficient methods are required to improve both the accuracy and speed of beta-topology prediction. In order to attain higher accuracy, the current paper introduces a bidirectional strand-strand interaction graph and considers all possible orientations (parallel and antiparallel) and orders of beta-strand pairwise interactions. For the first time, the beta-topology prediction is transformed into a maximum weight disjoint path cover solution by conserving all potential topologies. Moreover, to manage the computation time, a set of candidate beta-sheets is generated and an optimization process is applied to select a subset of maximum score disjoint beta sheets as a predicted beta-topology. The proposed method is comprehensively compared with state-of-the-art methods. The experimental results on the BetaSheet916 and BetaSheet1452 datasets reveal that the current study's approach enhances performance measurements as well as reduces the runtime. PMID- 29994540 TI - Combining Context and Knowledge Representations for Chemical-disease Relation Extraction. AB - Automatically extracting the relationships between chemicals and diseases is significantly important to various areas of biomedical research and health care. Biomedical experts have built many large-scale knowledge bases (KBs) to advance the development of biomedical research. KBs contain huge amounts of structured information about entities and relationships, therefore plays a pivotal role in chemical-disease relation (CDR) extraction. However, previous researches pay less attention to the prior knowledge existing in KBs. This paper proposes a neural network-based attention model (NAM) for CDR extraction, which makes full use of context information in documents and prior knowledge in KBs. For a pair of entities in a document, an attention mechanism is employed to select important context words with respect to the relation representations learned from KBs. Experiments on the BioCreative V CDR dataset show that combining context and knowledge representations through the attention mechanism, could significantly improve the CDR extraction performance while achieve comparable results with state-of-the-art systems. PMID- 29994541 TI - Grip Stabilization of Novel Objects using Slip Prediction. AB - Controlling contact with arbitrary, unknown objects defines a fundamental problem for robotic grasping and in-hand manipulation. In real-world scenarios, where robots interact with a variety of objects, the sheer number of possible contact interactions prohibits acquisition of the necessary models for all objects of interest. As an alternative to traditional control approaches that require accurate models, predicting the onset of slip can enable controlling contact interactions without explicit model knowledge. In this article, we propose a grip stabilization approach for novel objects based on slip prediction. Using tactile information, such as applied pressure and fingertip deformation, our approach predicts the onset of slip and modulates the contact forces accordingly. We formulate a supervised-learning problem to predict the future onset of slip from high-dimensional tactile information provided by a BioTac sensor. This slip mapping generalizes across objects, including objects absent during training. We evaluate how different input features, slip prediction time horizons, and available tactile information channels, impact prediction accuracy. By mounting the sensor on a PA-10 robotic arm, we show that employing prediction in a controller's feedback loop yields an object grip stabilization controller that can successfully stabilize multiple, previously unknown objects by counteracting slip events. PMID- 29994542 TI - Optimizing Top- Multiclass SVM via Semismooth Newton Algorithm. AB - Top- performance has recently received increasing attention in large data categories. Advances, like a top- multiclass support vector machine (SVM), have consistently improved the top- accuracy. However, the key ingredient in the state of-the-art optimization scheme based upon stochastic dual coordinate ascent relies on the sorting method, which yields complexity. In this paper, we leverage the semismoothness of the problem and propose an optimized top- multiclass SVM algorithm, which employs semismooth Newton algorithm for the key building block to improve the training speed. Our method enjoys a local superlinear convergence rate in theory. In practice, experimental results confirm the validity. Our algorithm is four times faster than the existing method in large synthetic problems; Moreover, on real-world data sets it also shows significant improvement in training time. PMID- 29994543 TI - Estimation of Graphlet Counts in Massive Networks. AB - Graphlets are induced subgraphs of a large network and are important for understanding and modeling complex networks. Despite their practical importance, graphlets have been severely limited to applications and domains with relatively small graphs. Most previous work has focused on exact algorithms; however, it is often too expensive to compute graphlets exactly in massive networks with billions of edges, and finding an approximate count is usually sufficient for many applications. In this paper, we propose an unbiased graphlet estimation framework that is: (a) fast with large speedups compared to the state of the art; (b) parallel with nearly linear speedups; (c) accurate with less than 1% relative error; (d) scalable and space efficient for massive networks with billions of edges; and (e) effective for a variety of real-world settings as well as estimating global and local graphlet statistics (e.g., counts). On 300 networks from 20 domains, we obtain <1% relative error for all graphlets. This is vastly more accurate than the existing methods while using less data. Moreover, it takes a few seconds on billion edge graphs (as opposed to days/weeks). These are by far the largest graphlet computations to date. PMID- 29994544 TI - Adaptive Asymptotic Neural Network Control of Nonlinear Systems With Unknown Actuator Quantization. AB - In this paper, we propose an adaptive neural-network-based asymptotic control algorithm for a class of nonlinear systems subject to unknown actuator quantization. To this end, we exploit the sector property of the quantization nonlinearity and transform actuator quantization control problem into analyzing its upper bounds, which are then handled by a dynamic loop gain function-based approach. In our adaptive control scheme, there is only one parameter required to be estimated online for updating weights of neural networks. Within the framework of Lyapunov theory, it is shown that the proposed algorithm ensures that all the signals in the closed-loop system are ultimately bounded. Moreover, an asymptotic tracking error is obtained by means of introducing Barbalat's lemma to the proposed adaptive law. PMID- 29994545 TI - Incomplete-Data Oriented Multiview Dimension Reduction via Sparse Low-Rank Representation. AB - For dimension reduction on multiview data, most of the previous studies implicitly take an assumption that all samples are completed in all views. Nevertheless, this assumption could often be violated in real applications due to the presence of noise, limited access to data, equipment malfunction, and so on. Most of the previous methods will cease to work when missing values in one or multiple views occur, thus an incomplete-data oriented dimension reduction becomes an important issue. To this end, we mathematically formulate the above mentioned issue as sparse low-rank representation through multiview subspace (SRRS) learning to impute missing values, by jointly measuring intraview relations (via sparse low-rank representation) and interview relations (through common subspace representation). Moreover, by exploiting various subspace priors in the proposed SRRS formulation, we develop three novel dimension reduction methods for incomplete multiview data: 1) multiview subspace learning via graph embedding; 2) multiview subspace learning via structured sparsity; and 3) sparse multiview feature selection via rank minimization. For each of them, the objective function and the algorithm to solve the resulting optimization problem are elaborated, respectively. We perform extensive experiments to investigate their performance on three types of tasks including data recovery, clustering, and classification. Both two toy examples (i.e., Swiss roll and -curve) and four real-world data sets (i.e., face images, multisource news, multicamera activity, and multimodality neuroimaging data) are systematically tested. As demonstrated, our methods achieve the performance superior to that of the state-of-the-art comparable methods. Also, the results clearly show the advantage of integrating the sparsity and low-rankness over using each of them separately. PMID- 29994546 TI - Stability of Singular Discrete-Time Neural Networks With State-Dependent Coefficients and Run-to-Run Control Strategies. AB - In this brief, sustaining and intermittent run-to-run controllers are designed to achieve the stability of singular discrete-time neural networks with state dependent coefficients. The controllers are designed for two reasons: 1) it is very difficult and almost impossible to only measure the in situ feedback information for the controllers and 2) the controllers may not always exist at any time. The stability is then established for singular discrete-time neural networks with state-dependent coefficients. Finally, numerical simulations are shown to illustrate the usefulness of the obtained criteria. PMID- 29994547 TI - Adaptive Human-Machine Interactive Behavior Analysis With Wrist-Worn Devices for Password Inference. AB - The pervasiveness of wearable devices furnished with state-of-the-art sensors has shown the powerful capability in context-aware applications. However, embedded sensors also become targets for adversaries to launch potential side-channel attacks. In this paper, we present a self-adaptive and pretraining-independent pattern attack that infers a graphical password by recovering the victim's hand movement trajectory via motion sensors of a wrist-worn smart device. With the adaptive pattern inference algorithm, the discovered attack can be launched remotely without requiring previous training data from victims or the prior knowledge about the keyboard input settings. Toward the proposed attack, we create a method to detect the sliding behavior that draws a graphical password on the screen. We also propose an inference algorithm to generate password candidates from hand movement trajectories for different keypad input settings. We implement the discovered attack on a smartwatch and conduct experiments to evaluate the impact of this attack. The evaluation results show that for complex graphical patterns, with a single try, the attack can infer the passwords at a success rate as high as 80%, and the success rate can be further boosted to over 90% within five attempts, which reveals the overlooked privacy information threat caused by sensor data leakage. PMID- 29994548 TI - Dynamic Affinity Graph Construction for Spectral Clustering Using Multiple Features. AB - Spectral clustering (SC) has been widely applied to various computer vision tasks, where the key is to construct a robust affinity matrix for data partitioning. With the increase in visual features, conventional SC methods are facing two challenges: 1) how to effectively generate an affinity matrix based on multiple features? and 2) how to deal with high-dimensional visual features which could be redundant? To address these issues mentioned earlier, we present a new approach to: 1) learn a robust affinity matrix using multiple features, allowing us to simultaneously determine optimal weights for each feature; and 2) decide a set of optimal projection matrixes, one for each feature, that decide the lower dimensional space, as well as the optimal affinity weight of each data pair in the lower dimensional space. There are two major advantages of our new approach over the existing clustering techniques. First, our approach assigns affinity weights for data points on a per-data-pair basis. The learning procedure avoids the explicit specification of the size of the neighborhood in the affinity matrix, and the bandwidth parameter required to compute the Gaussian kernel, both of which are sensitive and yet difficult to determine beforehand. Second, the affinity weights are based on the distances in a lower dimensional space, while the low-dimensional space is inferred according to the optimized affinity weights. Both variables are jointly optimized so as to leverage mutual benefits. The experimental results outperform the compared alternatives, which indicate that the proposed method is effective in simultaneously learning the affinity graph and feature fusion, resulting in better clustering results. PMID- 29994549 TI - Feature Selection Based on the Neighborhood Entropy. AB - In feature selection, a measure that captures nonlinear relationships between features and class is the mutual information (MI), which is based on how information in the features reduces the uncertainty in the output. In this paper, we propose a new measure that is related to MI, called neighborhood entropy, and a novel filter method based on its minimization in a greedy procedure. Our algorithm integrates sequential forward selection with approximated nearest neighbors techniques and locality-sensitive hashing. Experiments show that the classification accuracy is usually higher than that of other state-of-the-art algorithms, with the best results obtained with problems that are highly unbalanced and nonlinearly separable. The order by which the features are selected is also better, leading to a higher accuracy for fewer features. The experimental results indicate that our technique can be employed effectively in offline scenarios when one can dedicate more CPU time to achieve superior results and more robustness to noise and to class imbalance. PMID- 29994550 TI - Pairwise Constraint Propagation-Induced Symmetric Nonnegative Matrix Factorization. AB - As a variant of nonnegative matrix factorization (NMF), symmetric NMF (SNMF) has shown to be effective for capturing the cluster structure embedded in the graph representation. In contrast to the existing SNMF-based clustering methods that empirically construct the similarity matrix and rigidly introduce the supervisory information to the assignment matrix, in this paper, we propose a novel SNMF based semisupervised clustering method, namely, pairwise constraint propagation induced SNMF (PCPSNMF). By formulating a single-constrained optimization problem, PCPSNMF is capable of learning the similarity and assignment matrices adaptively and simultaneously, in which a small amount of supervisory information in the form of pairwise constraints is introduced in a flexible way to guide the construction of the similarity matrix, and the two matrices communicate with each other to achieve mutual refinement until convergence. In addition, we propose an efficient alternating iterative algorithm to solve the optimization problem, whose convergence is theoretically proven. Experimental results over several benchmark image data sets demonstrate that PCPSNMF is less sensitive to initialization and produces higher clustering performance, compared with the state-of-the-art methods. PMID- 29994551 TI - Exponential Stability Analysis for Delayed Semi-Markovian Recurrent Neural Networks: A Homogeneous Polynomial Approach. AB - This paper investigates the exponential stability analysis issue for a class of delayed recurrent neural networks (RNNs) with semi-Markovian parameters. By constructing a stochastic Lyapunov functional and using some zoom techniques to estimate its weak infinitesimal operator, the exponential mean square stability criteria have been proposed for the Markovian neural networks with certain transition probabilities. We then generalize the homogeneous polynomial approach for the delayed Markovian RNNs with uncertain transition probabilities during the stability analysis. Theoretical results have obtained by introducing an appropriate technique for dealing with a large number of complex homogeneous polynomial matrix inequalities. Finally, numerical examples are provided to demonstrate the effectiveness of the proposed technique. PMID- 29994552 TI - A Novel Multi-Standard Compliant Hand Function Assessment Method Using an Infrared Imaging Device. AB - Many post-stroke patients suffer varying degrees of hand function and fine motor skills impairment. Both passive and active hand rehabilitation training are beneficial in improving the strength and dexterity of the hands. However, hand rehabilitation programs should be prescribed based on an accurate assessment of hand function. In this paper, we propose a novel method for hand function assessment which can accurately measure multiple joint angles of a hand simultaneously using a portable infrared based imaging device. Different from traditional assessment methods that are often based on a clinician's subjective observations and ordinal charts, this method provides an accurate, fast, and objective evaluation using infrared imaging sensors. Performance evaluation and benchmarking for the proposed measurement system were carried out using the correlation coefficient (CC) method and the percentage residual difference method (PRD). A clinical trial involving 25 participants resulted in a higher correlation with CC of 0.9672 and PRD of 8.8 % which indicated that the developed assessment framework is compliant with multiple assessment standards such as Swanson impairment evaluation and Fugl-Meyer assessment very well. This new hand function assessment method can be used to replace the widely used traditional methods for fine hand function modeling and assessment in rehabilitation medicine and can play an important role in precision post-stroke function analysis. PMID- 29994553 TI - Neural-Network-Based Output-Feedback Control Under Round-Robin Scheduling Protocols. AB - The neural-network (NN)-based output-feedback control is considered for a class of stochastic nonlinear systems under round-Robin (RR) scheduling protocols. For the purpose of effectively mitigating data congestions and saving energies, the RR protocols are implemented and the resulting nonlinear systems become the so called protocol-induced periodic ones. Taking such a periodic characteristic into account, an NN-based observer is first proposed to reconstruct the system states where a novel adaptive tuning law on NN weights is adopted to cater to the requirement of performance analysis. In addition, with the established boundedness of the periodic systems in the mean-square sense, the desired observer gain is obtained by solving a set of matrix inequalities. Then, an actor critic NN scheme with a time-varying step length in adaptive law is developed to handle the considered control problem with terminal constraints over finite horizon. Some sufficient conditions are derived to guarantee the boundedness of estimation errors of critic and actor NN weights. In view of these conditions, some key parameters in adaptive tuning laws are easily determined via elementary algebraic operations. Furthermore, the stability in the mean-square sense is investigated for the discussed issue in infinite horizon. Finally, a simulation example is utilized to illustrate the applicability of the proposed control scheme. PMID- 29994554 TI - Visual Servoing of Wheeled Mobile Robots Without Desired Images. AB - This paper proposes a novel monocular visual servoing strategy, which can drive a wheeled mobile robot to the desired pose without a prerecorded desired image. Compared with existing methods that adopt the teaching pattern for visual regulation, this scheme can still work well in the situation that the desired image has not been previously acquired. Thus, with the aid of this method, it is more convenient for mobile robots to execute visual servoing tasks. Specifically, to deal with nonexistence of the desired image, the reference frame is craftily defined by taking advantage of visual targets and the planar motion constraint, and the pose estimation algorithm is designed for the mobile robot with respect to the reference frame. Then, an adaptive visual regulation controller is developed to drive the mobile robot to the intermediate frame, where the parameter updating law is constructed for the unknown feature height based on the concurrent learning framework. Stability analysis shows that regulation errors and height identification error can converge simultaneously. Afterwards, the mobile robot is driven to the metric desired pose with the identified feature height. Both simulation and experimental results are provided to validate the performance of this strategy. PMID- 29994555 TI - Similarity Measure-Based Possibilistic FCM With Label Information for Brain MRI Segmentation. AB - Magnetic resonance imaging (MRI) is extensively applied in clinical practice. Segmentation of the MRI brain image is significant to the detection of brain abnormalities. However, owing to the coexistence of intensity inhomogeneity and noise, dividing the MRI brain image into different clusters precisely has become an arduous task. In this paper, an improved possibilistic fuzzy c-means (FCM) method based on a similarity measure is proposed to improve the segmentation performance for MRI brain images. By introducing the new similarity measure, the proposed method is more effective for clustering the data with nonspherical distribution. Besides that, the new similarity measure could alleviate the ''cluster-size sensitivity'' problem that most FCM-based methods suffer from. Simultaneously, the proposed method could preserve image details as well as suppress image noises via the use of local label information. Experiments conducted on both synthetic and clinical images show that the proposed method is very effective, providing mitigation to the cluster-size sensitivity problem, resistance to noisy images, and applicability to data with more complex distribution. PMID- 29994556 TI - Multiobjective Cloud Workflow Scheduling: A Multiple Populations Ant Colony System Approach. AB - Cloud workflow scheduling is significantly challenging due to not only the large scale of workflow but also the elasticity and heterogeneity of cloud resources. Moreover, the pricing model of clouds makes the execution time and execution cost two critical issues in the scheduling. This paper models the cloud workflow scheduling as a multiobjective optimization problem that optimizes both execution time and execution cost. A novel multiobjective ant colony system based on a co evolutionary multiple populations for multiple objectives framework is proposed, which adopts two colonies to deal with these two objectives, respectively. Moreover, the proposed approach incorporates with the following three novel designs to efficiently deal with the multiobjective challenges: 1) a new pheromone update rule based on a set of nondominated solutions from a global archive to guide each colony to search its optimization objective sufficiently; 2) a complementary heuristic strategy to avoid a colony only focusing on its corresponding single optimization objective, cooperating with the pheromone update rule to balance the search of both objectives; and 3) an elite study strategy to improve the solution quality of the global archive to help further approach the global Pareto front. Experimental simulations are conducted on five types of real-world scientific workflows and consider the properties of Amazon EC2 cloud platform. The experimental results show that the proposed algorithm performs better than both some state-of-the-art multiobjective optimization approaches and the constrained optimization approaches. PMID- 29994557 TI - Coordinated Optimization for the Descent Gradient of Technical Index in the Iron Removal Process. AB - In the iron removal process, which is composed of four cascaded reactors, outlet ferrous ion concentration (OFIC) is an important technical index for each reactor. The descent gradient of OFIC indicates the reduced degree of ferrous ions in each reactor. Finding the optimal descent gradient of OFIC is tightly close to the effective iron removal and the optimal operation of the process. This paper proposes a coordinated optimization strategy for setting the descent gradient of OFIC. First, an optimal setting module is established to determine the initial set-points of the descent gradient. The oxygen utilization ratio (OUR), an important parameter in this module, cannot be measured online. Therefore, a self-adjusting RBF (SARBF) neural network with an adaptive learning rate is developed to estimate the OUR. The convergence of the SARBF neural network is discussed. Then, a coordinated optimization strategy is proposed to adjust the set-points of the descent gradient when the measured OFICs drift away from their desired set-pints. If the final OFIC does not satisfy the process requirements, a compensation mechanism is developed to provide a compensation for the set-points of the descent gradient. Finally, industrial experiments in the largest zinc hydrometallurgy plant validate the effectiveness of the proposed coordinated optimization strategy. Our strategy improves the qualified ratio of the OFIC and the quality of the goethite precipitate. More profit is created to the iron removal process after our strategy is applied. PMID- 29994558 TI - Subspace Clustering by Block Diagonal Representation. AB - This paper studies the subspace clustering problem. Given some data points approximately drawn from a union of subspaces, the goal is to group these data points into their underlying subspaces. Many subspace clustering methods have been proposed and among which sparse subspace clustering and low-rank representation are two representative ones. Despite the different motivations, we observe that many existing methods own the common block diagonal property, which possibly leads to correct clustering, yet with their proofs given case by case. In this work, we consider a general formulation and provide a unified theoretical guarantee of the block diagonal property. The block diagonal property of many existing methods falls into our special case. Second, we observe that many existing methods approximate the block diagonal representation matrix by using different structure priors, e.g., sparsity and low-rankness, which are indirect. We propose the first block diagonal matrix induced regularizer for directly pursuing the block diagonal matrix. With this regularizer, we solve the subspace clustering problem by Block Diagonal Representation (BDR), which uses the block diagonal structure prior. The BDR model is nonconvex and we propose an alternating minimization solver and prove its convergence. Experiments on real datasets demonstrate the effectiveness of BDR. PMID- 29994559 TI - Dynamic Structure Embedded Online Multiple-Output Regression for Streaming Data. AB - Online multiple-output regression is an important machine learning technique for modeling, predicting, and compressing multi-dimensional correlated data streams. In this paper, we propose a novel online multiple-output regression method, called MORES, for streaming data. MORES can dynamically learn the structure of the regression coefficients to facilitate the model's continuous refinement. Considering that limited expressive ability of regression models often leading to residual errors being dependent, MORES intends to dynamically learn and leverage the structure of the residual errors to improve the prediction accuracy. Moreover, we introduce three modified covariance matrices to extract necessary information from all the seen data for training, and set different weights on samples so as to track the data streams' evolving characteristics. Furthermore, an efficient algorithm is designed to optimize the proposed objective function, and an efficient online eigenvalue decomposition algorithm is developed for the modified covariance matrix. Finally, we analyze the convergence of MORES in certain ideal condition. Experiments on two synthetic datasets and three real world datasets validate the effectiveness and efficiency of MORES. In addition, MORES can process at least 2,000 instances per second (including training and testing) on the three real-world datasets, more than 12 times faster than the state-of-the-art online learning algorithm. PMID- 29994560 TI - Semi-Supervised Discriminative Classification Robust to Sample-Outliers and Feature-Noises. AB - Discriminative methods commonly produce models with relatively good generalization abilities. However, this advantage is challenged in real-world applications (e.g., medical image analysis problems), in which there often exist outlier data points (sample-outliers) and noises in the predictor values (feature noises). Methods robust to both types of these deviations are somewhat overlooked in the literature. We further argue that denoising can be more effective, if we learn the model using all the available labeled and unlabeled samples, as the intrinsic geometry of the sample manifold can be better constructed using more data points. In this paper, we propose a semi-supervised robust discriminative classification method based on the least-squares formulation of linear discriminant analysis to detect sample-outliers and feature-noises simultaneously, using both labeled training and unlabeled testing data. We conduct several experiments on a synthetic, some benchmark semi-supervised learning, and two brain neurodegenerative disease diagnosis datasets (for Parkinson's and Alzheimer's diseases). Specifically for the application of neurodegenerative diseases diagnosis, incorporating robust machine learning methods can be of great benefit, due to the noisy nature of neuroimaging data. Our results show that our method outperforms the baseline and several state-of the-art methods, in terms of both accuracy and the area under the ROC curve. PMID- 29994561 TI - Compressive Binary Patterns: Designing a Robust Binary Face Descriptor with Random-Field Eigenfilters. AB - A binary descriptor typically consists of three stages: image filtering, binarization, and spatial histogram. This paper first demonstrates that the binary code of the maximum-variance filtering responses leads to the lowest bit error rate under Gaussian noise. Then, an optimal eigenfilter bank is derived from a universal assumption on the local stationary random field. Finally, compressive binary patterns (CBP) is designed by replacing the local derivative filters of local binary patterns (LBP) with these novel random-field eigenfilters, which leads to a compact and robust binary descriptor that characterizes the most stable local structures that are resistant to image noise and degradation. A scattering-like operator is subsequently applied to enhance the distinctiveness of the descriptor. Surprisingly, the results obtained from experiments on the FERET, LFW, and PaSC databases show that the scattering CBP (SCBP) descriptor, which is handcrafted by only 6 optimal eigenfilters under restrictive assumptions, outperforms the state-of-the-art learning-based face descriptors in terms of both matching accuracy and robustness. In particular, on probe images degraded with noise, blur, JPEG compression, and reduced resolution, SCBP outperforms other descriptors by a greater than 10% accuracy margin. PMID- 29994562 TI - Missing Surface Estimation Based on Modified Tikhonov Regularization: Application for Destructed Dental Tissue. AB - Estimation of missing digital information is mostly addressed by one or two dimensional signal processing methods; however, this problem can emerge in multi dimensional data including 3D images. Examples of 3D images dealing with missing edge information are often found using dental micro-CT, where the natural contours of dental enamel and dentine are partially dissolved or lost by caries. In this paper, we present a novel sequential approach to estimate the missing surface of an object. First, an initial correct contour is determined interactively or automatically, for the starting slice. This contour information defines the local search area and provides the overall estimation pattern for the edge candidates in the next slice. The search for edge candidates in the next slice is performed in the perpendicular direction to the obtained initial edge in order to find and label the corrupted edge candidates. Subsequently, the location information of both initial and nominated edge candidates are transformed and segregated into two independent signals (X-coordinates and Y-coordinates) and the problem is changed into error concealment. In the next step, the missing samples of these signals are estimated using a modified Tikhonov regularization model with two new terms. One term contributes in the denoising of the corrupted signal by defining an estimation model for a group of mildly destructed samples, and the other term contributes in the estimation of the missing samples with the highest similarity to the samples of the obtained signals from the previous slice. Finally, the reconstructed signals are transformed inversely to edge pixel representation. The estimated edges in each slice are considered as initial edge information for the next slice and this procedure is repeated slice by slice until the entire contour of the destructed surface is estimated. The visual results as well as quantitative results (using both contour-based and area-based metrics) for seven image datasets of tooth samples with considerable destruction of the dentin-enamel junction (DEJ) demonstrates that the proposed method can accurately interpolate the shape and the position of the missing surfaces in computed tomography images in both two and three dimensions (e.g. 14.87 +/-3.87 MU m of mean distance (MD) error for the proposed method versus 7.33 +/-0.27 MUm of MD error between human experts and 1.25 +/-~0 % error rate (ER) of the proposed method versus 0.64 +/-~0 % of ER between human experts (~1% difference)). PMID- 29994563 TI - Smooth, Efficient, and Interruptible Zooming and Panning. AB - This paper introduces a novel technique for smooth and efficient zooming and panning based on dynamical systems in hyperbolic space. Unlike the technique of van Wijk and Nuij, the animations produced by our technique are smooth at the endpoints and when interrupted by a change of target. To analyze the results of our technique, we introduce world/screen diagrams, a novel technique for visualizing zooming and panning animations. PMID- 29994564 TI - Electrical Stimulation and Bone Healing: A Review of Current Technology and Clinical Applications. AB - Pseudarthrosis is an exceedingly common, costly, and morbid complication in the treatment of long bone fractures and after spinal fusion surgery. Electrical bone growth stimulation (EBGS) presents a unique approach to accelerate healing and promote fusion success rates. Over the past three decades, increased experience and widespread use of EBGS devices has led to significant improvements in stimulation paradigms and clinical outcomes. In this paper, we comprehensively review the literature and examine the history, scientific evidence, available technology, and clinical applications for EBGS. We summarize indications, limitations, and provide an overview of cost-effectiveness and future directions of EBGS technology. Various models of electrical stimulation have been proposed and marketed as adjuncts for spinal fusions and long bone fractures. Clinical studies show variable safety and efficacy of EBGS under different conditions and clinical scenarios. While the results of clinical trials do not support indiscriminate EBGS utilization for any bone injury, the evidence does suggest that EBGS is desirable and cost efficient for certain orthopedic indications, especially when used in combination with standard, first-line treatments. This review should serve as a reference to inform practicing clinicians of available treatment options, facilitate evidence-based decision making, and provide a platform for further research. PMID- 29994565 TI - Aerial Vibrotactile Display Based on MultiUnit Ultrasound Phased Array. AB - In this paper, we report on an airborne vibrotactile display with a multiunit ultrasound phased array synthetic aperture. The system generates an ultrasound field with a location-tunable focus in the air, which exerts time-variant acoustic radiation pressure on the user's skin, resulting in perceivable localized vibrotactile stimuli. The paper contains three major new contributions from previous related works. The first is an experimental validation of large aperture focusing with improved synchronization offering an enlarged workspace in which sufficient acoustic power concentration is guaranteed. From the experiments, it is expected that perceivable vibrotactile focus can be generated 1 m away from a four-unit array system. The second is an experimental evaluation of the presented pressure for producing a broad variety of tactile perception, which shows that the generated ultrasound focus can serve as an vibrotactile actuator that has flat frequency characteristics in the domain of perceptual stimuli. The third is a psychophysical result of the detection threshold curve for sinusoidal stimuli offered by the system. The obtained curve shows similarity with conventionally known results, which have minimum values at approximately 200 Hz. PMID- 29994566 TI - SGD-Based Adaptive NN Control Design for Uncertain Nonlinear Systems. AB - In this paper, a stochastic gradient descent (SGD)-based adaptive neural network (NN) control scheme is presented for a class of uncertain nonlinear systems. The introduction of the SGD algorithm results in a better tracking performance compared with some other adaptive NN methods without using SGD. This is because the proposed SGD-based adaptive NN control strategy provides optimization algorithms for the weights, the widths, and the centers of the NNs, which can achieve a good function approximation performance. In order to implement the proposed method, extended differentiators are introduced to get the differential estimations of error signals, such that the loss function of the optimization algorithm can be constructed approximatively. Moreover, adaptive laws are designed to reduce the overall approximation errors, such that the tracking performance is further improved. By using the Lyapunov stability theory, it can be proved that the target signal is tracked by the system output within a small error. Finally, simulation and comparison results are given to show the effectiveness and advantages of the proposed method. PMID- 29994567 TI - Providing Healthcare-as-a-Service Using Fuzzy Rule Based Big Data Analytics in Cloud Computing. AB - With advancements in information and communication technology, there is a steep increase in the remote healthcare applications in which patients can get treatment from the remote places also. The data collected about the patients by remote healthcare applications constitute big data because it varies with volume, velocity, variety, veracity, and value. To process such a large collection of heterogeneous data is one of the biggest challenges which requires a specialized approach. To address this challenge, a new fuzzy rule based classifier is presented in this paper with an aim to provide Healthcare-as-a-Service. The proposed scheme is based upon the initial cluster formation, retrieval, and processing of the big data in cloud environment. Then, a fuzzy rule based classifier is designed for efficient decision making for data classification in the proposed scheme. To perform inferencing from the collected data, membership functions are designed for fuzzification and defuzzification processes. The proposed scheme is evaluated on various evaluation metrics, such as average response time, accuracy, computation cost, classification time, and false positive ratio. The results obtained confirm the effectiveness of the proposed scheme with respect to various performance evaluation metrics in cloud computing environment. PMID- 29994568 TI - Virtual M-Mode for Echocardiography: A New Approach for the Segmentation of the Anterior Mitral Leaflet. AB - Rheumatic heart disease can result from repeated episodes of acute rheumatic fever, which damages the heart valves and reduces their functionality. Early manifestations of heart valve damage are visible in echocardiography in the form of valve thickening, shape changing and mobility reduction. The quantification of these features is important for a precise diagnosis and it is the main motivation for this work. The first step to make this quantification is to accurately identify and track the anterior mitral leaflet throughout the cardiac cycle. An accurate segmentation and tracking with minimum user interaction is still an open problem in literature due to low image quality, speckle noise, signal dropout and non-rigid deformations. In this work, we propose a novel approach for the identification of the anterior mitral valve leaflet in all frames. The method requires a single user-specified point on the posterior wall of the aorta as input, in the first frame. The echocardiography videos are converted into a new image space, the Virtual M-mode, which samples the original echocardiography image over automatically estimated scanning lines. This new image space not only provides the motion pattern of the posterior wall of the aorta, the anterior wall of the aorta and the posterior wall of the left atrium, but also provides the location of the structures in each frame. The location information is then used to initialize the localized active contours, followed by segmenting the anterior mitral leaflet. Results shown that the new image space has robustly identified the anterior mitral valve leaflet, without any failure. The median modified Hausdorff distance error of the proposed method was 2.3 mm, with a recall of 0.94. PMID- 29994569 TI - Transductive Zero-Shot Learning With a Self-Training Dictionary Approach. AB - As an important and challenging problem in computer vision, zero-shot learning (ZSL) aims at automatically recognizing the instances from unseen object classes without training data. To address this problem, ZSL is usually carried out in the following two aspects: 1) capturing the domain distribution connections between seen classes data and unseen classes data and 2) modeling the semantic interactions between the image feature space and the label embedding space. Motivated by these observations, we propose a bidirectional mapping-based semantic relationship modeling scheme that seeks for cross-modal knowledge transfer by simultaneously projecting the image features and label embeddings into a common latent space. Namely, we have a bidirectional connection relationship that takes place from the image feature space to the latent space as well as from the label embedding space to the latent space. To deal with the domain shift problem, we further present a transductive learning approach that formulates the class prediction problem in an iterative refining process, where the object classification capacity is progressively reinforced through bootstrapping-based model updating over highly reliable instances. Experimental results on four benchmark datasets (animal with attribute, Caltech-UCSD Bird2011, aPascal-aYahoo, and SUN) demonstrate the effectiveness of the proposed approach against the state-of-the-art approaches. PMID- 29994570 TI - Tooth-Marked Tongue Recognition Using Multiple Instance Learning and CNN Features. AB - Tooth-marked tongue or crenated tongue can provide valuable diagnostic information for traditional Chinese Medicine doctors. However, tooth-marked tongue recognition is challenging. The characteristics of different tongues are multiform and have a great amount of variations, such as different colors, different shapes, and different types of teeth marks. The regions of teeth mark only appear along the lateral borders. Most existing methods make use of concave regions information to classify the tooth-marked tongue which leads to inconstant performance when the region of teeth mark is not concave. In this paper, we try to solve these problems by proposing a three-stage approach which first makes use of concavity information to propose the suspected regions, then use a convolutional neural network to extract deep features and at last use a multiple instance classifier to make the final decision. Experimental results demonstrate the effectiveness of the proposed method. PMID- 29994571 TI - Distributed Adaptive Event-Triggered Fault-Tolerant Consensus of Multiagent Systems With General Linear Dynamics. AB - In this paper, the distributed adaptive event-triggered fault-tolerant consensus of general linear multiagent systems (MASs) is considered. First, in order to deal with multiplicative fault, a distributed event-triggered consensus protocol is designed. Using distributed adaptive online updating strategies, the computation of the minimum eigenvalue of Laplacian matrix is avoided. Second, some adaptive parameters are introduced in trigger function to improve the self regulation ability of event-triggered mechanism. The new trigger threshold is both state-dependent and time-dependent, which is independent of the number of agents. Then sufficient conditions are derived to guarantee the leaderless and leader-following consensus. On the basis of this, the results are extended to the case of actuator saturation. It is proved the Zeno-behavior of considered event triggered mechanism is avoided. At last, the effectiveness of the proposed methods are demonstrated by three simulation examples. PMID- 29994572 TI - Spatial-Temporal Recurrent Neural Network for Emotion Recognition. AB - In this paper, we propose a novel deep learning framework, called spatial temporal recurrent neural network (STRNN), to integrate the feature learning from both spatial and temporal information of signal sources into a unified spatial temporal dependency model. In STRNN, to capture those spatially co-occurrent variations of human emotions, a multidirectional recurrent neural network (RNN) layer is employed to capture long-range contextual cues by traversing the spatial regions of each temporal slice along different directions. Then a bi-directional temporal RNN layer is further used to learn the discriminative features characterizing the temporal dependencies of the sequences, where sequences are produced from the spatial RNN layer. To further select those salient regions with more discriminative ability for emotion recognition, we impose sparse projection onto those hidden states of spatial and temporal domains to improve the model discriminant ability. Consequently, the proposed two-layer RNN model provides an effective way to make use of both spatial and temporal dependencies of the input signals for emotion recognition. Experimental results on the public emotion datasets of electroencephalogram and facial expression demonstrate the proposed STRNN method is more competitive over those state-of-the-art methods. PMID- 29994573 TI - Data-Driven Distributed Output Consensus Control for Partially Observable Multiagent Systems. AB - This paper is concerned with a class of optimal output consensus control problems for discrete linear multiagent systems with the partially observable system state. Since the optimal control policy depends on the full system state which is not accessible for a partially observable system, traditionally, distributed observers are employed to recover the system state. However, in many situations, the accurate model of a real-world dynamical system might be difficult to obtain, which makes the observer design infeasible. Furthermore, the optimal consensus control policy cannot be analytically solved without system functions. To overcome these challenges, we propose a data-driven adaptive dynamic programming approach that does not require the complete system inner state. The key idea is to use the input and output sequence as an equivalent representation of the underlying state. Based on this representation, an adaptive dynamic programming algorithm is developed to generate the optimal control policy. For the implementation of this algorithm, we design a neural network-based actor-critic structure to approximate the local performance indices and the control polices. Two numerical simulations are used to demonstrate the effectiveness of our method. PMID- 29994574 TI - Prescribed-Time Consensus and Containment Control of Networked Multiagent Systems. AB - In this paper, we present a new prescribed-time distributed control method for consensus and containment of networked multiple systems. Different from both regular finite-time control (where the finite settling time is not uniform in initial conditions) and the fixed-time control (where the settling time cannot be preassigned arbitrarily), the proposed one is built upon a novel scaling function, resulting in prespecifiable convergence time (the settling time can be preassigned as needed within any physically allowable range). Furthermore, the developed control scheme not only ensures that all the agents reach the average consensus in prescribed finite time under undirected connected topology, but also ensures that all the agents reach a prescribed-time consensus with the root's state being the group decision value under the directed topology containing a spanning tree with the root as the leader. In addition, we extend the result to prescribed-time containment control involving multiple leaders under directed communication topology. Numerical examples are provided to verify the effectiveness and the superiority of the proposed control. PMID- 29994575 TI - Game-Based Memetic Algorithm to the Vertex Cover of Networks. AB - The minimum vertex cover (MVC) is a well-known combinatorial optimization problem. A game-based memetic algorithm (GMA-MVC) is provided, in which the local search is an asynchronous updating snowdrift game and the global search is an evolutionary algorithm (EA). The game-based local search can implement (k,l) exchanges for various numbers of k and l to remove k vertices from and add l vertices into the solution set, thus is much better than the previous (1,0) exchange. Beyond that, the proposed local search is able to deal with the constraint, such that the crossover operator can be very simple and efficient. Degree-based initialization method is also provided which is much better than the previous uniform random initialization. Each individual of the GMA-MVC is designed as a snowdrift game state of the network. Each vertex is treated as an intelligent agent playing the snowdrift game with its neighbors, which is the local refinement process. The game is designed such that its strict Nash equilibrium (SNE) is always a vertex cover of the network. Most of the SNEs are only local optima of the problem. Then an EA is employed to guide the game to escape from those local optimal Nash equilibriums to reach a better Nash equilibrium. From comparison with the state of the art algorithms in experiments on various networks, the proposed algorithm always obtains the best solutions. PMID- 29994576 TI - Event-Triggered Coordination for Formation Tracking Control in Constrained Space With Limited Communication. AB - In this paper, the formation tracking control is studied for a multiagent system (MAS) with communication limitations. The objective is to control a group of agents to track a desired trajectory while maintaining a given formation in nonomniscient constrained space. The role switching triggered by the detection of unexpected spatial constraints facilitates efficiency of event-triggered control in communication bandwidth, energy consumption, and processor usage. A coordination mechanism is proposed based on a novel role ''coordinator'' to indirectly spread environmental information among the whole communication network and form a feedback link from followers to the leader to guarantee the formation keeping. A formation scaling factor is introduced to scale up or scale down the given formation size in the case that the region is impassable for MAS with the original formation size. Controllers for the leader and followers are designed and the adaptation law is developed for the formation scaling factor. The conditions for asymptotic stability of MAS are discussed based on the Lyapunov theory. Simulation results are presented to illustrate the performance of proposed approaches. PMID- 29994577 TI - Heterogeneous Ensemble-Based Infill Criterion for Evolutionary Multiobjective Optimization of Expensive Problems. AB - Gaussian processes (GPs) are the most popular model used in surrogate-assisted evolutionary optimization of computationally expensive problems, mainly because GPs are able to measure the uncertainty of the estimated fitness values, based on which certain infill sampling criteria can be used to guide the search and update the surrogate model. However, the computation time for constructing GPs may become excessively long when the number of training samples increases, which makes it inappropriate to use them as surrogates in evolutionary optimization. To address this issue, this paper proposes to use ensembles as surrogates and infill criteria for model management in evolutionary optimization. A heterogeneous ensemble consisting of a least square support vector machine and two radial basis function networks is constructed to enhance the reliability of ensembles for uncertainty estimation. In addition to the original decision variables, a selected subset of the decision variables and a set of transformed variables are used as inputs of the heterogeneous ensemble to further promote the diversity of the ensemble. The proposed heterogeneous ensemble is compared with a GP and a homogeneous ensemble for infill sampling criteria in evolutionary multiobjective optimization. Experimental results demonstrate that the heterogeneous ensemble is competitive in performance compared with GPs and much more scalable in computational complexity to the increase in search dimension. PMID- 29994578 TI - Finite-Time Formation Control of Under-Actuated Ships Using Nonlinear Sliding Mode Control. AB - A novel nonlinear sliding mode control approach dealing with the formation control of under-actuated ships is presented in this paper. To avoid the singularity problem, state space of the system is partitioned into two regions, with one region bounded for terminal sliding mode control and its complement singular for that. And a linear auxiliary sliding mode controller is designed for system trajectories starting from the complement region. With the application of nonlinear sliding mode control approach and finite-time stability theory, a distributed controller is designed for individual under-actuated ship to achieve the given formation pattern within a finite time. Finally, two simulation examples are provided to verify the effectiveness and performance of the proposed approach. PMID- 29994579 TI - Learning Hyperedge Replacement Grammars for Graph Generation. AB - The discovery and analysis of network patterns is central to the scientific enterprise. In the present work we developed and evaluated a new approach that learns the building blocks of graphs that can be used to understand and generate new realistic graphs. Our key insight is that a graph's clique tree encodes robust and precise information. We show that a Hyperedge Replacement Grammar (HRG) can extracted from the clique tree, and we develop a fixed-size graph generation algorithm that can be used to produce new graphs of a specified size. In experiments on large real-world graphs, we show that graphs generated from the HRG approach exhibit a diverse range of properties that are similar to those found in the original networks. In addition to graph properties like degree or eigenvector centrality, what a graph "looks like" ultimately depends on small details in local graph substructures that are difficult to define at a global level. We show that the HRG model can also preserve these local substructures when generating new graphs. PMID- 29994580 TI - Recurrent Convolutional Shape Regression. AB - The mainstream direction in face alignment is now dominated by cascaded regression methods. These methods start from an image with an initial shape and build a set of shape increments based on features with respect to the current estimated shape. These shape increments move the initial shape to the desired location. Despite the advantages of the cascaded methods, they all share two major limitations: (i) shape increments are learned independently from each other in a cascaded manner, (ii) the use of standard generic computer vision features such SIFT, HOG, does not allow these methods to learn problem-specific features. In this work, we propose a novel Recurrent Convolutional Shape Regression (RCSR) method that overcomes these limitations. We formulate the standard cascaded alignment problem as a recurrent process and learn all shape increments jointly, by using a recurrent neural network with a gated recurrent unit. Importantly, by combining a convolutional neural network with a recurrent one we avoid hand crafted features, widely adopted in the literature and thus we allow the model to learn task-specific features. Besides, we employ the convolutional gated recurrent unit which takes as input the feature tensors instead of flattened feature vectors. Therefore, the spatial structure of the features can be better preserved in the memory of the recurrent neural network. Moreover, both the convolutional and the recurrent neural networks are learned jointly. Experimental evaluation shows that the proposed method has better performance than the state of-the-art methods, and further supports the importance of learning a single end to-end model for face alignment. PMID- 29994581 TI - Isotropic Reconstruction of MR Images Using 3D Patch-Based Self-Similarity Learning. AB - Isotropic three-dimensional (3D) acquisition is a challenging task in magnetic resonance imaging (MRI). Particularly in cardiac MRI, due to hardware and time limitations, current 3D acquisitions are limited by low-resolution, especially in the through-plane direction, leading to poor image quality in that dimension. To overcome this problem, super-resolution (SR) techniques have been proposed to reconstruct a single isotropic 3D volume from multiple anisotropic acquisitions. Previously, local regularization techniques such as total variation have been applied to limit noise amplification while preserving sharp edges and small features in the images. In this paper, inspired by the recent progress in patch based reconstruction, we propose a novel isotropic 3D reconstruction scheme that integrates non-local and self-similarity information from 3D patch neighborhoods. By grouping 3D patches with similar structures, we enforce the natural sparsity of MR images, which can be expressed by a low-rank structure, leading to robust image reconstruction with high signal-to-noise ratio efficiency. An Augmented Lagrangian formulation of the problem is proposed to efficiently decompose the optimization into a low-rank volume denoising and a SR reconstruction. Experimental results in simulations, brain imaging and clinical cardiac MRI, demonstrate that the proposed joint SR and self-similarity learning framework outperforms current state-of-the-art methods. The proposed reconstruction of isotropic 3D volumes may be particularly useful for cardiac applications, such as myocardial infarction scar assessment by late gadolinium enhancement MRI. PMID- 29994582 TI - Multi-Label Nonlinear Matrix Completion With Transductive Multi-Task Feature Selection for Joint MGMT and IDH1 Status Prediction of Patient With High-Grade Gliomas. AB - The O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase 1 (IDH1) mutation in high-grade gliomas (HGG) have proven to be the two important molecular indicators associated with better prognosis. Traditionally, the statuses of MGMT and IDH1 are obtained via surgical biopsy, which has limited their wider clinical implementation. Accurate presurgical prediction of their statuses based on preoperative multimodal neuroimaging is of great clinical value for a better treatment plan. Currently, the available data set associated with this study has several challenges, such as small sample size and complex, nonlinear (image) feature-to-(molecular) label relationship. To address these issues, we propose a novel multi-label nonlinear matrix completion (MNMC) model to jointly predict both MGMT and IDH1 statuses in a multi-task framework. Specifically, we first employ a nonlinear random Fourier feature mapping to improve the linear separability of the data, and then use transductive multi-task feature selection (performed in a nonlinearly transformed feature space) to refine the imputed soft labels, thus alleviating the overfitting problem caused by small sample size. We further design an optimization algorithm with a guaranteed convergence ability based on a block prox-linear method to solve the proposed MNMC model. Finally, by using a single center, multimodal brain imaging and molecular pathology data set of HGG, we derive brain functional and structural connectomics features to jointly predict MGMT and IDH1 statuses. Results demonstrate that our proposed method outperforms the previously widely used single- and multi-task machine learning methods. This paper also shows the promise of utilizing brain connectomics for HGG prognosis in a non-invasive manner. PMID- 29994583 TI - Real-Time FEM-Based Registration of 3-D to 2.5-D Transrectal Ultrasound Images. AB - We present a novel technique for real-time deformable registration of 3-D to 2.5 D transrectal ultrasound (TRUS) images for image-guided, robot-assisted laparoscopic radical prostatectomy (RALRP). For RALRP, a pre-operatively acquired 3-D TRUS image is registered to thin-volumes comprised of consecutive intra operative 2-D TRUS images, where the optimal transformation is found using a gradient descent method based on analytical first and second order derivatives. Our method relies on an efficient algorithm for real-time extraction of arbitrary slices from a 3-D image deformed given a discrete mesh representation. We also propose and demonstrate an evaluation method that generates simulated models and images for RALRP by modeling tissue deformation through patient-specific finite element models (FEM). We evaluated our method on in-vivo data from 11 patients collected during RALRP and focal therapy interventions. In the presence of an average landmark deformation of 3.89 and 4.62 mm, we achieved accuracies of 1.15 and 0.72 mm, respectively, on the synthetic and in-vivo data sets, with an average registration computation time of 264 ms, using MATLAB on a conventional PC. The results show that the real-time tracking of the prostate motion and deformation is feasible, enabling a real-time augmented reality-based guidance system for RALRP.]. PMID- 29994584 TI - Exploring Variability within Ensembles of Decadal Climate Predictions. AB - Ensemble simulations are used in climate research to account for natural variability. For medium-term decadal predictions, each simulation run is initialized with real observations from a different day resulting in a set of possible climatic futures. Understanding the variability and the predictive power in this wealth of data is still a challenging task. In this paper, we introduce a visual analytics system to explore variability within ensembles of decadal climate predictions. We propose a new interactive visualization technique (clustering timeline) based on the Sankey diagram, which conveys a concise summary of data similarity and its changes over time. We augment the system with two additional visualizations, filled contour maps and heatmaps, to provide analysts with additional information relating the new diagram to raw data and automatic clustering results. The usefulness of the technique is demonstrated by case studies and user interviews. PMID- 29994585 TI - Calculating the Unrooted Subtree Prune-and-Regraft Distance. AB - The subtree prune-and-regraft (SPR) distance metric is a fundamental way of comparing evolutionary trees. It has wide-ranging applications, such as to study lateral genetic transfer, viral recombination, and Markov chain Monte Carlo phylogenetic inference. Although the rooted version of SPR distance can be computed relatively efficiently between rooted trees using fixed-parameter tractable maximum agreement forest (MAF) algorithms, no MAF formulation is known for the unrooted case. Correspondingly, previous algorithms are unable to compute unrooted SPR distances larger than 7. PMID- 29994586 TI - A robust simulator for physiologically structured population models. AB - A framework to simulate physiologically structured population (PSP) models on high performance compute (HPC) infrastructure is built. Based on the model of a single cell, billions of cells can be simulated in an efficient way, allowing fast simulation of the interaction of an entire organ with other body parts. Trough combination of three state-of-the-art algorithms, the simulation time is decreased with multiple orders of magnitude. First: PSP modelling exploits the fact that a lot of the cells act the same at the same time which results in multiple orders of magnitude speed-up. Secondly, speed-up is achieved by using an unconditionally stable, partial differential equation solver which allows to trade speed for precision and allows big time stepping. Third speed-up is due to the fact that the framework is designed with HPC cluster use in mind. The PSP simulator is mathematically derived to have maximal stability.Simulation results are validated and simulation speed and accuracy are measured. PMID- 29994587 TI - Inference Attacks and Controls on Genotypes and Phenotypes for Individual Genomic Data. AB - The rapid growth of DNA-sequencing technologies motivates more personalized and predictive genetic-oriented services, which further attract individuals to increasingly release their genome information to learn about personalized medicines, disease predispositions, genetic compatibilities, etc. Individual genome information is notoriously privacy-sensitive and highly associated with relatives. In this paper, we present an inference attack algorithm to predict target genotypes and phenotypes based on belief propagation in factor graphs. With this algorithm, an attacker can effectively predict the target genotypes and phenotypes of target individuals based on genome information shared by individuals or their relatives, and genotype and phenotype association from genome-wide association study (GWAS). To address the privacy threats resulted from such inference attacks, we elaborate the metrics to evaluate data utility and privacy and then present a data sanitization method. We evaluate our inference attack algorithm and data sanitization method on real GWAS dataset: Age related macular degeneration (AMD) case/control dataset. The evaluation results show that our work can effectively defense against genome threats while guaranteeing data utility. PMID- 29994588 TI - Microarray Missing Value Imputation: A Regularized Local Learning Method. AB - Microarray experiments on gene expression inevitably generate missing values, which impedes further downstream biological analysis. Therefore, it is key to estimate the missing values accurately. Most of the existing imputation methods tend to suffer from the over-fitting problem. In this study, we propose two regularized local learning methods for microarray missing value imputation. Motivated by the grouping effect of L2 regularization, after selecting the target gene, we train an L2 Regularized Local Least Squares imputation model (RLLSimpute_L2) on the target gene and its neighbors to estimate the missing values of the target gene. Furthermore, RLLSimpute_L2 imputes the missing values in an ascending order based on the associated missing rate with each target gene. This contributes to fully utilizing the previously estimated values. Besides L2, we further explore L1 regularization and propose an L1 Regularized Local Least Squares imputation model (RLLSimpute_L1). To evaluate their effectiveness, we conducted extensive experimental studies on six benchmark datasets covering both time series and non-time series cases. Nine state-of-the-art imputation methods are compared with RLLSimpute_L2 and RLLSimpute_L1 in terms of three performance metrics. The comparative experimental results indicate that RLLSimpute_L2 outperforms its competitors by achieving smaller imputation errors and better structure preservation of differentially expressed genes. PMID- 29994589 TI - Review on Otological Robotic Systems: Toward Microrobot-Assisted Cholesteatoma Surgery. AB - Otologic surgical procedures over time have become minimally invasive due to the development of medicine, microtechniques, and robotics. This trend then provides an expected reduction in the patient's recovery time and improvement in the accuracy of diagnosis and treatment. One of the most challenging difficulties that such techniques face are precise control of the instrument and supply of an ergonomic system to the surgeon. The objective of this literature review is to present requirements and guidelines for a surgical robotic system dedicated to middle ear surgery. This review is particularly focused on cholesteatoma surgery (diagnosis and surgical tools), which is one of the most frequent pathologies that urge for an enhanced treatment. This review also presents the current robotic systems that are implemented for otologic applications. PMID- 29994590 TI - A Review of Signal Processing Techniques for Electrocardiogram Signal Quality Assessment. AB - Electrocardiogram (ECG) signal quality assessment (SQA) plays a vital role in significantly improving the diagnostic accuracy and reliability of unsupervised ECG analysis systems. In practice, the ECG signal is often corrupted with different kinds of noises and artifacts. Therefore, numerous SQA methods were presented based on the ECG signal and/or noise features and the machine learning classifiers and/or heuristic decision rules. This paper presents an overview of current state-of-the-art SQA methods and highlights the practical limitations of the existing SQA methods. Based upon past and our studies, it is noticed that a lightweight ECG noise analysis framework is highly demanded for real-time detection, localization, and classification of single and combined ECG noises within the context of wearable ECG monitoring devices which are often resource constrained. PMID- 29994591 TI - Stable Physical Human-Robot Interaction Using Fractional Order Admittance Control. AB - In the near future, humans and robots are expected to perform collaborative tasks involving physical interaction in various environments, such as homes, hospitals, and factories. Robots are good at precision, strength, and repetition, while humans are better at cognitive tasks. The concept, known as physical human-robot interaction (pHRI), takes advantage of these abilities and is highly beneficial by bringing speed, flexibility, and ergonomics to the execution of complex tasks. Current research in pHRI focuses on designing controllers and developing new methods which offer a better tradeoff between robust stability and high interaction performance. In this paper, we propose a new controller, fractional order admittance controller, for pHRI systems. The stability and transparency analyses of the new control system are performed computationally with human-in the-loop. Impedance matching is proposed to map fractional order control parameters to integer order ones, and then the stability robustness of the system is studied analytically. Furthermore, the interaction performance is investigated experimentally through two human subject studies involving continuous contact with linear and nonlinear viscoelastic environments. The results indicate that the fractional order admittance controller can be made more robust and transparent than the integer order admittance controller and the use of fractional order term can reduce the human effort during tasks involving contact interactions with environment. PMID- 29994592 TI - Accounting for Label Uncertainty in Machine Learning for Detection of Acute Respiratory Distress Syndrome. AB - When training a machine learning algorithm for a supervised-learning task in some clinical applications, uncertainty in the correct labels of some patients may adversely affect the performance of the algorithm. For example, even clinical experts may have less confidence when assigning a medical diagnosis to some patients because of ambiguity in the patient's case or imperfect reliability of the diagnostic criteria. As a result, some cases used in algorithm training may be mis-labeled, adversely affecting the algorithm's performance. However, experts may also be able to quantify their diagnostic uncertainty in these cases. We present a robust method implemented with Support Vector Machines to account for such clinical diagnostic uncertainty when training an algorithm to detect patients who develop the acute respiratory distress syndrome (ARDS). ARDS is a syndrome of the critically ill that is diagnosed using clinical criteria known to be imperfect. We represent uncertainty in the diagnosis of ARDS as a graded weight of confidence associated with each training label. We also performed a novel time-series sampling method to address the problem of inter-correlation among the longitudinal clinical data from each patient used in model training to limit overfitting. Preliminary results show that we can achieve meaningful improvement in the performance of algorithm to detect patients with ARDS on a hold-out sample, when we compare our method that accounts for the uncertainty of training labels with a conventional SVM algorithm. PMID- 29994593 TI - Small Fault Detection for a Class of Closed-Loop Systems via Deterministic Learning. AB - In this paper, based on the deterministic learning (DL) theory, an approach for detection for small faults in a class of nonlinear closed-loop systems is proposed. First, the DL-based neural control approach and identification approach are employed to extract the knowledge of the control effort that compensates the fault dynamics (change of the control effort) and the fault dynamics (the change of system dynamics due to fault). Second, two types of residuals are constructed. One is to measure the change of system dynamics, another one is to measure change of the control effort. By combining these residuals, an enhanced residual is generated, in which the fault dynamics and the control effort are combined to diagnose the fault. It is shown that the major fault information is compensated by the control, and the major fault information is double in the enhanced residual. Therefore, the fault information in the diagnosis residual is enhanced. Finally, an analysis of the fault detectability condition of the diagnosis scheme is given. Simulation studies are included to demonstrate the effectiveness of the approach. PMID- 29994594 TI - Multiobject Tracking by Submodular Optimization. AB - In this paper, we propose a new multiobject visual tracking algorithm by submodular optimization. The proposed algorithm is composed of two main stages. At the first stage, a new selecting strategy of tracklets is proposed to cope with occlusion problem. We generate low-level tracklets using overlap criteria and min-cost flow, respectively, and then integrate them into a candidate tracklets set. In the second stage, we formulate the multiobject tracking problem as the submodular maximization problem subject to related constraints. The submodular function selects the correct tracklets from the candidate set of tracklets to form the object trajectory. Then, we design a connecting process which connects the corresponding trajectories to overcome the occlusion problem. Experimental results demonstrate the effectiveness of our tracking algorithm. Our source code is available at https://github.com/shenjianbing/submodulartrack. PMID- 29994595 TI - Robust Graph-Based Semisupervised Learning for Noisy Labeled Data via Maximum Correntropy Criterion. AB - Semisupervised learning (SSL) methods have been proved to be effective at solving the labeled samples shortage problem by using a large number of unlabeled samples together with a small number of labeled samples. However, many traditional SSL methods may not be robust with too much labeling noisy data. To address this issue, in this paper, we propose a robust graph-based SSL method based on maximum correntropy criterion to learn a robust and strong generalization model. In detail, the graph-based SSL framework is improved by imposing supervised information on the regularizer, which can strengthen the constraint on labels, thus ensuring that the predicted labels of each cluster are close to the true labels. Furthermore, the maximum correntropy criterion is introduced into the graph-based SSL framework to suppress labeling noise. Extensive image classification experiments prove the generalization and robustness of the proposed SSL method. PMID- 29994596 TI - Desktop Action Recognition From First-Person Point-of-View. AB - Desktop action recognition from first-person view (egocentric) video is an important task due to its omnipresence in our daily life, and the ideal first person viewing perspective for observing hand-object interactions. However, no previous research efforts have been dedicated on the benchmark of the task. In this paper, we first release a dataset of daily desktop actions recorded with a wearable camera and publish it as a benchmark for desktop action recognition. Regular desktop activities of six participants were recorded in egocentric video with a wide-angle head-mounted camera. In particular, we focus on five common desktop actions in which hands are involved. We provide original video data, action annotations at frame-level, and hand masks at pixel-level. We also propose a feature representation for the characterization of different desktop actions based on the spatial and temporal information of hands. In experiments, we illustrate the statistical information about the dataset, and evaluate the action recognition performance of different features as a baseline. The proposed method achieves promising performance for five action classes. PMID- 29994597 TI - Consensus via Time-Varying Feedback for Uncertain Stochastic Nonlinear Multiagent Systems. AB - This paper focuses on the almost sure consensus via time-varying feedback for a class of uncertain stochastic nonlinear multiagent systems. A remarkable feature of the systems is that the nonlinearities allow serious unknowns and time variations. Moreover, there exists no known bound for the unknown control coefficients. To handle the unknowns and time-variations, a time-varying consensus scheme is developed. The main idea of the scheme is to incorporate a delicate function of time into consensus protocols such that the unknowns and time-variations can be compensated as time increases. Based on the proposed protocols, the almost sure leaderless consensus and almost sure leader-following consensus are achieved. Finally, two simulation examples are provided to illustrate the effectiveness of the theoretical results. PMID- 29994598 TI - Learning Multi-task Correlation Particle Filters for Visual Tracking. AB - We propose a multi-task correlation particle filter (MCPF) for robust visual tracking. We first present the multi-task correlation filter (MCF) that takes the interdependencies among different object parts and features into account to learn the correlation filters jointly. The proposed MCPF is introduced to exploit and complement the strength of a MCF and a particle filter. Compared with existing tracking methods based on correlation filters and particle filters, the proposed MCPF enjoys several merits. First, it exploits the interdependencies among different features to derive the correlation filters jointly, and makes the learned filters complement and enhance each other to obtain consistent responses. Second, it handles partial occlusion via a part-based representation, and exploits the intrinsic relationship among local parts via spatial constraints to preserve object structure and learn the correlation filters jointly. Third, it effectively handles large scale variation via a sampling scheme by drawing particles at different scales for target object state estimation. Fourth, it shepherds the sampled particles toward the modes of the target state distribution via the MCF, and effectively covers object states well using fewer particles than conventional particle filters. Extensive experimental results odemonstrate that the proposed MCPF tracking algorithm performs favorably against the state-of-the art methods. PMID- 29994599 TI - Robust Structural Sparse Tracking. AB - Sparse representations have been applied to visual tracking by finding the best candidate region with minimal reconstruction error based on a set of target templates. However, most existing sparse trackers only consider holistic or local representations and do not make full use of the intrinsic structure among and inside target candidate regions, thereby making them less effective when similar objects appear at close proximity or under occlusion. In this paper, we propose a novel structural sparse representation, which not only exploits the intrinsic relationships among target candidate regions and local patches to learn their representations jointly, but also preserves the spatial structure among the local patches inside each target candidate region. For robust visual tracking, we take outliers resulting from occlusion and noise into account when searching for the best target region. Constructed within a Bayesian filtering framework, we show that the proposed algorithm accommodates most existing sparse trackers with respective merits. The formulated problem can be efficiently solved using an accelerated proximal gradient method that yields a sequence of closed form updates. Qualitative and quantitative evaluations on challenging benchmark datasets demonstrate that the proposed tracking algorithm performs favorably against several state-of-the-art methods. PMID- 29994600 TI - Online Localization and Prediction of Actions and Interactions. AB - This paper proposes a person-centric and online approach to the challenging problem of localization and prediction of actions and interactions in videos. Typically, localization or recognition is performed in an offline manner where all the frames in the video are processed together. This prevents timely localization and prediction of actions and interactions - an important consideration for many tasks including surveillance and human-machine interaction. PMID- 29994601 TI - Single-Scan Dual-Energy CT Using Primary Modulation. AB - Compared with conventional computed tomography (CT), dual-energy CT (DECT) provides better material differentiation but requires projection data acquired with two different effective x-ray spectra, limiting DECT applications to specialized scanners. We propose a hardware-based method, known as PM-DECT, which utilizes primary beam modulation to enable single-scan DECT on a conventional CT scanner. PM-DECT inserts an attenuation sheet with a spatially varying pattern primary beam modulator-between the x-ray source and imaged object. During a CT scan, the modulator selectively hardens the x-ray beam, thereby increasing the average photon energy at specific detector pixel locations. Thus, PM-DECT simultaneously acquires high and low energy data at each projection angle. From the sparse projection data, high and low energy CT images are jointly reconstructed and simultaneously decomposed into basis materials via an iterative CT reconstruction algorithm with gradient weighting and an improved version of similarity based regularization. Studies on Catphan 600 and anthropomorphic head phantoms demonstrate that PM-DECT retains a high level of spatial resolution compared with conventional CT scans. Electron density values calculated from decomposed images indicate a limited error of 1.12% for PM-DECT. Comparison against a two-scan DECT technique shows that PM-DECT's image reconstruction from sparse data sets contributes only 0.66% error. By granting the opportunity for high-quality single-scan DECT on conventional CT scanners via limited hardware modification, PM-DECT has the potential to liberate DECT from specialized scanners, extending clinical availability, and implementation. PMID- 29994602 TI - Domain Regeneration for Cross-Database Micro-Expression Recognition. AB - Recently, micro-expression recognition has attracted lots of researchers' attention due to its potential value in many practical applications, e.g., lie detection. In this paper, we investigate an interesting and challenging problem in micro-expression recognition, i.e., cross-database micro-expression recognition, in which the training and testing samples come from different micro expression databases. Under this problem setting, the consistent feature distribution between the training and testing samples originally existing in conventional micro-expression recognition would be seriously broken and hence the performance of most current well-performing micro-expression recognition methods may sharply drop. In order to overcome it, we propose a simple yet effective framework called Domain Regeneration (DR) in this paper. DR framework aims at learning a domain regenerator to regenerate the micro-expression samples from source and target databases respectively such that they can abide by the same or similar feature distributions. Thus, we are able to use the classifier learned based on the labeled source micro-expression samples to predict the label information of the unlabeled target micro-expression samples. To evaluate the proposed DR framework, we conduct extensive cross-database micro-expression recognition experiments designed based on SMIC and CASME II databases. Experimental results show that compared with recent state-of-the-art cross database emotion recognition methods, the proposed DR framework has more promising performance. PMID- 29994603 TI - Efficient Local Statistical Analysis via Point-Wise Histograms in Tetrahedral Meshes and Curvilinear Grids. AB - histograms (i.e., point-wise histograms computed from local regions of mesh vertices) have been used in many data analysis and visualization applications. Previous methods for computing local histograms are mainly for regular or rectilinear grids. In this paper, we develop theory and novel algorithms for computing local histograms in tetrahedral meshes and curvilinear grids. Our algorithms are theoretically sound and efficient, and work effectively and fast in practice. Our main focus is on scalar fields, but the algorithms also work for vector fields as a by-product with small, easy modifications. Our methods can benefit information theoretic and other distribution-driven analysis. The experiments demonstrate the efficacy of our new techniques, including a utility case study on tetrahedral vector field visualization. PMID- 29994604 TI - Altering indispensable proteins in controlling directed human protein interaction network. AB - The numerous interconnections within complex systems enable us to control networks towards a desired state through a few suitable selected nodes, which are called driver nodes. Recent works analyzed directed human Protein-Protein Interaction (PPI) network based on structural control theory. They found that indispensable proteins, whose removal increase the number of driver nodes, are the primary targets of human viruses and drugs. However, the human PPI network is usually incomplete and may include many false-positive or false-negative interactions. That prompts us to ask whether these indispensable proteins are stable to possible structural changes. Here, we present a method to alter the type of indispensable proteins and thereby investigate the stability of indispensable proteins. By comparing the sets of indispensable proteins before and after structural changes to the network, we find that very few added or removed interactions can change the type of many indispensable nodes. Furthermore, some indispensable proteins are very sensitive to structural changes have is significantly lower interactions than the other indispensable proteins. The results indicate that indispensable proteins are sensitive to structural changes. Therefore, approaches based on structural control theory should be used with caution because of the incomplete nature of these networks. PMID- 29994605 TI - Structural Target Controllability of Linear Networks. AB - Computational analysis of the structure of intra-cellular molecular interaction networks can suggest novel therapeutic approaches for systemic diseases like cancer. Recent research in the area of network science has shown that network control theory can be a powerful tool in the understanding and manipulation of such bio-medical networks. In 2011, Liu et al. developed a polynomial time algorithm computing the size of the minimal set of nodes controlling a linear network. In 2014, Gao et al. generalized the problem for target control, minimizing the set of nodes controlling a target within a linear network. The authors developed a Greedy approximation algorithm while leaving open the complexity of the optimization problem. We prove here that the target controllability problem is NP-hard in all practical setups, i.e., when the control power of any individual input is bounded by some constant. We also show that the algorithm provided by Gao et al. fails to provide a valid solution in some special cases, and an additional validation step is required. We fix and improve their algorithm using several heuristics, obtaining in the end an up to 10-fold decrease in running time and also a decrease in the size of solutions. PMID- 29994606 TI - Quantitative MRI Brain Studies in Mild Cognitive Impairment and Alzheimer's Disease: A Methodological Review. AB - Classifying and predicting Alzheimer's disease (AD) in individuals with memory disorders through clinical and psychometric assessment is challenging, especially in mild cognitive impairment (MCI) subjects. Quantitative structural magnetic resonance imaging acquisition methods in combination with computer-aided diagnosis are currently being used for the assessment of AD. These acquisitions methods include voxel-based morphometry, volumetric measurements in specific regions of interest (ROIs), cortical thickness measurements, shape analysis, and texture analysis. This review evaluates the aforementioned methods in the classification of cases into one of the following three groups: normal controls, MCI, and AD subjects. Furthermore, the performance of the methods is assessed on the prediction of conversion from MCI to AD. In parallel, it is also assessed which ROIs are preferred in both classification and prognosis through the different states of the disease. Structural changes in the early stages of the disease are more pronounced in the medial temporal lobe, especially in the entorhinal cortex, whereas with disease progression, both entorhinal cortex and hippocampus offer similar discriminative power. However, for the conversion from MCI subjects to AD, entorhinal cortex provides better predictive accuracies rather than other structures, such as the hippocampus. PMID- 29994607 TI - Generative Kernels for Tree-Structured Data. AB - This paper presents a family of methods for the design of adaptive kernels for tree-structured data that exploits the summarization properties of hidden states of hidden Markov models for trees. We introduce a compact and discriminative feature space based on the concept of hidden states multisets and we discuss different approaches to estimate such hidden state encoding. We show how it can be used to build an efficient and general tree kernel based on Jaccard similarity. Furthermore, we derive an unsupervised convolutional generative kernel using a topology induced on the Markov states by a tree topographic mapping. This paper provides an extensive empirical assessment on a variety of structured data learning tasks, comparing the predictive accuracy and computational efficiency of state-of-the-art generative, adaptive, and syntactical tree kernels. The results show that the proposed generative approach has a good tradeoff between computational complexity and predictive performance, in particular when considering the soft matching introduced by the topographic mapping. PMID- 29994608 TI - Efficient Unsupervised Parameter Estimation for One-Class Support Vector Machines. AB - One-class support vector machines (OCSVMs) are very effective for semisupervised anomaly detection. However, their performance strongly depends on the settings of their hyperparameters, which has not been well studied. Moreover, unavailability of a clean training set that only comprises normal data in many real-life problems has given rise to the application of OCSVMs in an unsupervised manner. However, it has been shown that if the training set includes anomalies, the normal boundary created by OCSVMs is prone to skew toward the anomalies. This problem decreases the detection rate of anomalies and results in poor performance of the classifier. In this paper, we propose a new technique to set the hyperparameters and clean suspected anomalies from unlabelled training sets. The proposed method removes suspected anomalies based on a $K$ -nearest neighbors technique, which is then used to directly estimate the hyperparameters. We examine several benchmark data sets with diverse distributions and dimensionality. Our findings suggest that on the examined data sets, the proposed technique is roughly 70 times faster than supervised parameter estimation via grid-search and cross validation, and one to three orders of magnitude faster than broadly used semisupervised and unsupervised parameter estimation methods for OCSVMs. Moreover, our method statistically outperforms those semisupervised and unsupervised methods and its accuracy is comparable to supervised grid-search and cross validation. PMID- 29994609 TI - Auxiliary Demographic Information Assisted Age Estimation With Cascaded Structure. AB - Owing to the variations including both intrinsic and extrinsic factors, age estimation remains a challenging problem. In this paper, five cascaded structure frameworks are proposed for age estimation based on convolutional neural networks. All frameworks are learned and guided by auxiliary demographic information, since other demographic information (i.e., gender and race) is beneficial for age prediction. Each cascaded structure framework is embodied in a parent network and several subnetworks. For example, one of the applied framework is a gender classifier trained by gender information, and then two subnetworks are trained by the male and female samples, respectively. Furthermore, we use the features extracted from the cascaded structure frameworks with Gaussian process regression that can boost the performance further for age estimation. Experimental results on the MORPH II and CACD datasets have gained superior performances compared to the state-of-the-art methods. The mean absolute error is significantly reduced from 3.63 to 2.93 years under the same test protocol on the MORPH II dataset. PMID- 29994610 TI - Granular Data Aggregation: An Adaptive Principle of the Justifiable Granularity Approach. AB - The design of information granules assumes a central position in the discipline of Granular Computing and its applications. The principle of justifiable granularity offers a conceptually and algorithmically attractive way of designing information granule completed on a basis of some experimental evidence (especially present in the form of numeric data). This paper builds upon the existing principle and presents its significant generalization, referred here as an adaptive principle of justifiable information granularity. The method supports a granular data aggregation producing an optimal information granule (with the optimality expressed in terms of the criteria of coverage and specificity commonly used when characterizing quality of information granules). The flexibility of the method stems from an introduction of the adaptive weighting scheme of the data leading to a vector of weights used in the construction of the optimal information granule. A detailed design procedure is provided along with the required optimization vehicle (realized with the aid of the population-based optimization techniques, such as particle swarm optimization and differential evolution). Two direct application areas in which the principle becomes of direct usage include prediction of time series and prediction of spatial data. In both cases, it is advocated that the results formed by the principle are reflective of the precision (quality) of the prediction process. PMID- 29994611 TI - An Interclass Margin Maximization Learning Algorithm for Evolving Spiking Neural Network. AB - This paper presents a new learning algorithm developed for a three layered spiking neural network for pattern classification problems. The learning algorithm maximizes the interclass margin and is referred to as the two stage margin maximization spiking neural network (TMM-SNN). In the structure learning stage, the learning algorithm completely evolves the hidden layer neurons in the first epoch. Further, TMM-SNN updates the weights of the hidden neurons for multiple epochs using the newly developed normalized membrane potential learning rule such that the interclass margins (based on the response of hidden neurons) are maximized. The normalized membrane potential learning rule considers both the local information in the spike train generated by a presynaptic neuron and the existing knowledge (synaptic weights) stored in the network to update the synaptic weights. After the first stage, the number of hidden neurons and their parameters are not updated. In the output weights learning stage, TMM-SNN updates the weights of the output layer neurons for multiple epochs to maximize the interclass margins (based on the response of output neurons). Performance of TMM SNN is evaluated using ten benchmark data sets from the UCI machine learning repository. Statistical performance comparison of TMM-SNN with other existing learning algorithms for SNNs is conducted using the nonparametric Friedman test followed by a pairwise comparison using the Fisher's least significant difference method. The results clearly indicate that TMM-SNN achieves better generalization performance in comparison to other algorithms. PMID- 29994612 TI - Efficient enhancement of stereo endoscopic images based on joint wavelet decomposition and binocular combination. AB - The success of minimally invasive interventions and the remarkable technological and medical progress have made endoscopic image enhancement a very active research field. Due to the intrinsic endoscopic domain characteristics and the surgical exercise, stereo endoscopic images may suffer from different degradations which affect its quality. Therefore, in order to provide the surgeons with a better visual feedback and improve the outcomes of possible subsequent processing steps, namely a 3D organ reconstruction/registration, it would be interesting to improve the stereo endoscopic image quality. To this end, we propose in this paper two joint enhancement methods which operate in the wavelet transform domain. More precisely, by resorting to a joint wavelet decomposition, the wavelet subbands of the right and left views are simultaneously processed to exploit the binocular vision properties. While the first proposed technique combines only the approximation subbands of both views, the second method combines all the wavelet subbands yielding an inter-view processing fully adapted to the local features of the stereo endoscopic images. Experimental results, carried out on various stereo endoscopic datasets, have demonstrated the efficiency of the proposed enhancement methods in terms of perceived visual image quality. PMID- 29994613 TI - Continuous Control Monte Carlo Tree Search Informed by Multiple Experts. AB - Efficient algorithms for 3D character control in continuous control setting remain an open problem in spite of the remarkable recent advances in the field. We present a sampling-based model-predictive controller that comes in the form of a Monte Carlo tree search (MCTS). The tree search utilizes information from multiple sources including two machine learning models. This allows rapid development of complex skills such as 3D humanoid locomotion with less than a million simulation steps, in less than a minute of computing on a modest personal computer. We demonstrate locomotion of 3D characters with varying topologies under disturbances such as heavy projectile hits and abruptly changing target direction. In this paper we also present a new way to combine information from the various sources such that minimal amount of information is lost. We furthermore extend the neural network, involved in the algorithm, to represent stochastic policies. Our approach yields a robust control algorithm that is easy to use. While learning, the algorithm runs in near real-time, and after learning the sampling budget can be reduced for real-time operation. PMID- 29994614 TI - COPE: Interactive Exploration of Co-occurrence Patterns in Spatial Time Series. AB - Spatial time series is a common type of data dealt with in many domains, such as economic statistics and environmental science. There have been many studies focusing on finding and analyzing various kinds of events in time series; the term 'event' refers to significant changes or occurrences of particular patterns formed by consecutive attribute values. We focus on a further step in event analysis: finding and exploring events that frequently co-occurred with a target class of similar events having occurred repeatedly over a period of time. This type of analysis can provide important clues for understanding the formation and spreading mechanisms of events and interdependencies among spatial locations. We propose a visual exploration framework COPE (Co-Occurrence Pattern Exploration), which allows users to extract events of interest from data and detect various co occurrence patterns among them. Case studies and expert reviews were conducted to verify the effectiveness and scalability of COPE using two real-world datasets. PMID- 29994615 TI - Visualization and Visual Analysis of Ensemble Data: A Survey. AB - Over the last decade, ensemble visualization has witnessed a significant development due to the wide availability of ensemble data, and the increasing visualization needs from a variety of disciplines. From the data analysis point of view, it can be observed that many ensemble visualization works focus on the same facet of ensemble data, use similar data aggregation or uncertainty modeling methods. However, the lack of reflections on those essential commonalities and a systematic overview of those works prevents visualization researchers from effectively identifying new or unsolved problems and planning for further developments. In this paper, we take a holistic perspective and provide a survey of ensemble visualization. Specifically, we study ensemble visualization works in the recent decade, and categorize them from two perspectives: (1) their proposed visualization techniques; and (2) their involved analytic tasks. For the first perspective, we focus on elaborating how conventional visualization techniques (e.g., surface, volume visualization techniques) have been adopted to ensemble data; for the second perspective, we emphasize how analytic tasks (e.g., comparison, clustering) have been performed differently for ensemble data. From the study of ensemble visualization literature, we have also identified several research trends, as well as some future research opportunities. PMID- 29994616 TI - Viewpoint Assessment and Recommendation for Photographing Architectures. AB - This paper studies the problem of how to assess the quality of photographing viewpoints and how to choose good viewpoints for taking photographs of architectures. We achieve this by learning from photographs of world famous landmarks that are available on the Internet and their viewpoint quality ranked by online user annotation. Unlike previous efforts devoted to photo quality assessment which mainly rely on 2D image features, we show in this paper combining 2D image features extracted from images with 3D geometric features computed on the 3D models can result in more reliable evaluation of viewpoint quality. Specifically, we collect a set of photographs for each of 15 world famous architectures as well as their 3D models from the Internet. Viewpoint recovery for images is carried out through an image-model registration process, after which a newly proposed viewpoint clustering strategy is exploited to validate users' viewpoint preferences when photographing landmarks. Finally, we extract a number of 2D and 3D features for each image based on multiple visual and geometric cues and perform viewpoint recommendation by learning from both 2D and 3D features using a specifically designed SVM-2K multi-view learner, achieving superior performance over using solely 2D or 3D features. We show the effectiveness of the proposed approach through extensive experiments. The experiments also demonstrate that our system can be used to recommend viewpoints for rendering textured 3D models of buildings for the use of architectural design, in addition to viewpoint evaluation of photographs and recommendation of viewpoints for photographing architectures in practice. PMID- 29994617 TI - A Soft Exosuit for Flexible Upper-Extremity Rehabilitation. AB - For stroke survivors and many other people with upper-extremity impairment, daily life can be difficult without properly functioning arms. Some modern physical therapy exercises focus on rehabilitating people with these troubles by correcting patients' perceptions of their own body to eventually regain complete control and strength over their arms again. Augmentative wearable robots, such as the upper-extremity exoskeletons and exosuits, may be able to assist in this endeavor. A common drawback in many of these exoskeletons, however, is their inability to conform to the natural flexibility of the human body without a rigid base. We have built one such exosuit to address this challenge: Compliant Robotic Upper-extremity eXosuit (CRUX). This robot is a compliant, lightweight, multi DoF, portable exosuit that affords its wearer the ability to augment themselves in many unconventional settings (i.e. outside of a clinic). These attributes are largely achieved by using a modified tensegrity design situated according to measured lines of minimal-extension, where a network of tension members provide a foundation to apply augmentative forces via precisely placed power-lines. In this paper, we detail the design process of CRUX, the report on CRUX's prototypical composition, and describe the mimetic control algorithm used. We also discuss the results of three studies that illustrate the efficacy of CRUX's mimetic controller, CRUX's flexibility and compliance, and the metabolic cost reduction when users exercise with assistance from CRUX as opposed to without. We conclude this paper with a summary of our findings, potential use cases for this technology, and the direction of future related work. PMID- 29994618 TI - Assessing the Effectiveness of Causality Inference Methods for Gene Regulatory Networks. AB - Causality inference is the use of computational techniques to predict possible causal relationships for a set of variables, thereby forming a directed network. Causality inference in Gene Regulatory Networks (GRNs) is an important, yet challenging task due to the limits of available data and lack of efficiency in existing causality inference techniques. A number of techniques have been proposed and applied to infer causal relationships in various domains, although they are not specific to regulatory network inference. In this paper, we assess the effectiveness of methods for inferring causal GRNs. We introduce seven different inference methods and apply them to infer directed edges in GRNs. We use time-series expression data from the DREAM challenges to assess the methods in terms of quality of inference and rank them based on performance. The best method is applied to Breast Cancer data to infer a causal network. Experimental results show that Causation Entropy is best, however, highly time-consuming and not feasible to use in a relatively large network. We infer Breast Cancer GRN with the second-best method, TE. The topological analysis of the network reveals that top out-degree genes such as SLC39A5 which are considered central genes, play important role in cancer progression. PMID- 29994619 TI - Solving Partial Least Squares Regression via Manifold Optimization Approaches. AB - Partial least squares regression (PLSR) has been a popular technique to explore the linear relationship between two data sets. However, all existing approaches often optimize a PLSR model in Euclidean space and take a successive strategy to calculate all the factors one by one for keeping the mutually orthogonal PLSR factors. Thus, a suboptimal solution is often generated. To overcome the shortcoming, this paper takes statistically inspired modification of PLSR (SIMPLSR) as a representative of PLSR, proposes a novel approach to transform SIMPLSR into optimization problems on Riemannian manifolds, and develops corresponding optimization algorithms. These algorithms can calculate all the PLSR factors simultaneously to avoid any suboptimal solutions. Moreover, we propose sparse SIMPLSR on Riemannian manifolds, which is simple and intuitive. A number of experiments on classification problems have demonstrated that the proposed models and algorithms can get lower classification error rates compared with other linear regression methods in Euclidean space. We have made the experimental code public at https://github.com/Haoran2014. PMID- 29994620 TI - Multiple psi-Type Stability of Cohen-Grossberg Neural Networks With Both Time Varying Discrete Delays and Distributed Delays. AB - In this paper, multiple psi-type stability of Cohen-Grossberg neural networks (CGNNs) with both time-varying discrete delays and distributed delays is investigated. By utilizing psi-type functions combined with a new psi-type integral inequality for treating distributed delay terms, some sufficient conditions are obtained to ensure that multiple equilibrium points are psi-type stable for CGNNs with discrete and distributed delays, where the distributed delays include bounded and unbounded delays. These conditions of CGNNs with different output functions are less restrictive. More specifically, the algebraic criteria of the generalized model are applicable to several well-known neural network models by taking special parameters, and multiple different output functions are introduced to replace some of the same output functions, which improves the diversity of output results for the design of neural networks. In addition, the estimation of relative convergence rate of psi-type stability is determined by the parameters of CGNNs and the selection of psi-type functions. As a result, the existing results on multistability and monostability can be improved and extended. Finally, some numerical simulations are presented to illustrate the effectiveness of the obtained results. PMID- 29994621 TI - Neural Network Training With Levenberg-Marquardt and Adaptable Weight Compression. AB - Difficult experiments in training neural networks often fail to converge due to what is known as the flat-spot problem, where the gradient of hidden neurons in the network diminishes in value, rending the weight update process ineffective. Whereas a first-order algorithm can address this issue by learning parameters to normalize neuron activations, the second-order algorithms cannot afford additional parameters given that they include a large Jacobian matrix calculation. This paper proposes Levenberg-Marquardt with weight compression (LM WC), which combats the flat-spot problem by compressing neuron weights to push neuron activation out of the saturated region and close to the linear region. The presented algorithm requires no additional learned parameters and contains an adaptable compression parameter, which is adjusted to avoid training failure and increase the probability of neural network convergence. Several experiments are presented and discussed to demonstrate the success of LM-WC against standard LM and LM with random restarts on benchmark data sets for varying network architectures. Our results suggest that the LM-WC algorithm can improve training success by 10 times or more compared with other methods. PMID- 29994622 TI - Effects of percutaneous transluminal angioplasty of superficial femoral artery on photoplethysmographic pulse transit times. AB - We analyze the changes in upper and lower limb pulse transit times (PTT) caused by peripheral artery disease (PAD) and its treatment with percutaneous transluminal angioplasty (PTA) of the superficial femoral artery. PTTs were extracted from the photoplethysmograms (PPG) recorded from an index finger and 2nd toes. PTTs were defined between the R-peaks of the ECG and different reference points of the (PPG): foot and peak points, maxima of 1st and 2nd derivative, and by means of intersecting tangents method. Also the PTTs between the toe and finger pulses were analyzed. Our sample consists of 24 subjects examined before and after the PTA and in 1-month follow-up visit. Also 28 older than 65 years controls having normal ankle-to-brachial pressure index (ABI) and no history in cardiovascular diseases as well as 21 younger subjects were examined. The differences between the groups and pre- and post-treatment phases were analyzed by means of non-parametric statistical tests. The changes in the PTTs of upper limb and non-treated lower limb were negligible. The agreement with the reference values, ABI and toe pressures, was studied by kappa-analysis, resulting in kappa-values of 0.330.91. Differences in PTTs were found between pre treatment state of the treated limb, post-treatment state and the follow-up visit, as well as between the pre-treatment state and controls. If patients' age and systolic blood pressure were taken into consideration, the method of lower limb PTT calculation from the peak point turns out feasible in finding the markers of PAD and monitoring post- treatment vascular remodellation. PMID- 29994623 TI - Deep Endoscopic Visual Measurements. AB - Robotic endoscopic systems offer a minimally invasive approach to the examination of internal body structures, and their application is rapidly extending to cover the increasing needs for accurate therapeutic interventions. In this context, it is essential for such systems to be able to perform measurements, such as measuring the distance travelled by a wireless capsule endoscope, so as to determine the location of a lesion in the gastrointestinal (GI) tract, or to measure the size of lesions for diagnostic purposes. In this paper, we investigate the feasibility of performing contactless measurements using a computer vision approach based on neural networks. The proposed system integrates a deep convolutional image registration approach and a multilayer feed-forward neural network in a novel architecture. The main advantage of this system, with respect to the state-of-the-art ones, is that it is more generic in the sense that it is: i) unconstrained by specific models, ii) more robust to non-rigid deformations, and iii) adaptable to most of the endoscopic systems and environments, while enabling measurements of enhanced accuracy. The performance of this system is evaluated in ex-vivo conditions using a phantom experimental model and a robotically-assisted test bench. The results obtained promise a wider applicability and impact in endoscopy in the era of big data. PMID- 29994624 TI - Aberrant Brain Connectivity in Schizophrenia Detected via a Fast Gaussian Graphical Model. AB - Schizophrenia (SZ) is a chronic and severe mental disorder that affects how a person thinks, feels, and behaves. It has been proposed that this disorder is related to disrupted brain connectivity. With the development of functional magnetic resonance imaging (fMRI), further exploration of brain connectivity was made possible and this hypothesis has been verified. Region-based networks are commonly used for mapping brain connectivity. However, they fail to illustrate the connectivity within regions of interest (ROIs) and lose precise location information. Voxel-based networks provide higher precision, but are difficult to construct and interpret due to the high dimensionality of the data. In this paper, we adopt a novel high-dimensional Gaussian Graphical Model (GGM) -- learning method, which can help ease computational burden and provide more accurate inference for underlying networks. This method has been proved to be an equivalent measure of the partial correlation coefficient and thus is flexible for network comparison through statistical tests. The fMRI data we used were collected by the Mind Clinical Imaging Consortium (MCIC) using an auditory task in which there are 92 SZ patients and 116 healthy controls. We compared the networks at three different scales by using global measurements, community structure, and edge-wise comparisons within the networks. Results reveal, at the highest resolution, sets of distinct aberrant patterns for the SZ patients and more precise local structures are provided within ROIs for further investigation. PMID- 29994625 TI - Joint Learning of Multiple Differential Networks With Latent Variables. AB - Graphical models have been widely used to learn the conditional dependence structures among random variables. In many controlled experiments, such as the studies of disease or drug effectiveness, learning the structural changes of graphical models under two different conditions is of great importance. However, most existing graphical models are developed for estimating a single graph and based on a tacit assumption that there is no missing relevant variables, which wastes the common information provided by multiple heterogeneous data sets and underestimates the influence of latent/unobserved relevant variables. In this paper, we propose a joint differential network analysis (JDNA) model to jointly estimate multiple differential networks with latent variables from multiple data sets. The JDNA model is built on a penalized D-trace loss function, with group lasso or generalized fused lasso penalties. We implement a proximal gradient based alternating direction method of multipliers to tackle the corresponding convex optimization problems. Extensive simulation experiments demonstrate that JDNA model outperforms state-of-the-art methods in estimating the structural changes of graphical models. Moreover, a series of experiments on several real world data sets have been performed and experiment results consistently show that our proposed JDNA model is effective in identifying differential networks under different conditions. PMID- 29994626 TI - Multimodal Optimization Enhanced Cooperative Coevolution for Large-Scale Optimization. AB - Cooperative coevolutionary (CC) algorithms decompose a problem into several subcomponents and optimize them separately. Such a divide-and-conquer strategy makes CC algorithms potentially well suited for large-scale optimization. However, decomposition may be inaccurate, resulting in a wrong division of the interacting decision variables into different subcomponents and thereby a loss of important information about the topology of the overall fitness landscape. In this paper, we suggest an idea that concurrently searches for multiple optima and uses them as informative representatives to be exchanged among subcomponents for compensation. To this end, we incorporate a multimodal optimization procedure into each subcomponent, which is adaptively triggered by the status of subcomponent optimizers. In addition, a nondominance-based selection scheme is proposed to adaptively select one complete solution for evaluation from the ones that are constructed by combining informative representatives from each subcomponent with a given solution. The performance of the proposed algorithm has been demonstrated by comparing five popular CC algorithms on a set of selected problems that are recognized to be hard for traditional CC algorithms. The superior performance of the proposed algorithm is further confirmed by a comprehensive study that compares 17 state-of-the-art CC algorithms and other metaheuristic algorithms on 20 1000-dimensional benchmark functions. PMID- 29994627 TI - Concatenated and Connected Random Forests With Multiscale Patch Driven Active Contour Model for Automated Brain Tumor Segmentation of MR Images. AB - Segmentation of brain tumors from magnetic resonance imaging (MRI) data sets is of great importance for improved diagnosis, growth rate prediction, and treatment planning. However, automating this process is challenging due to the presence of severe partial volume effect and considerable variability in tumor structures, as well as imaging conditions, especially for the gliomas. In this paper, we introduce a new methodology that combines random forests and active contour model for the automated segmentation of the gliomas from multimodal volumetric MR images. Specifically, we employ a feature representations learning strategy to effectively explore both local and contextual information from multimodal images for tissue segmentation by using modality specific random forests as the feature learning kernels. Different levels of the structural information is subsequently integrated into concatenated and connected random forests for gliomas structure inferring. Finally, a novel multiscale patch driven active contour model is exploited to refine the inferred structure by taking advantage of sparse representation techniques. Results reported on public benchmarks reveal that our architecture achieves competitive accuracy compared to the state-of-the-art brain tumor segmentation methods while being computationally efficient. PMID- 29994628 TI - Automatic Multi-Organ Segmentation on Abdominal CT With Dense V-Networks. AB - Automatic segmentation of abdominal anatomy on computed tomography (CT) images can support diagnosis, treatment planning, and treatment delivery workflows. Segmentation methods using statistical models and multi-atlas label fusion (MALF) require inter-subject image registrations, which are challenging for abdominal images, but alternative methods without registration have not yet achieved higher accuracy for most abdominal organs. We present a registration-free deep-learning based segmentation algorithm for eight organs that are relevant for navigation in endoscopic pancreatic and biliary procedures, including the pancreas, the gastrointestinal tract (esophagus, stomach, and duodenum) and surrounding organs (liver, spleen, left kidney, and gallbladder). We directly compared the segmentation accuracy of the proposed method to the existing deep learning and MALF methods in a cross-validation on a multi-centre data set with 90 subjects. The proposed method yielded significantly higher Dice scores for all organs and lower mean absolute distances for most organs, including Dice scores of 0.78 versus 0.71, 0.74, and 0.74 for the pancreas, 0.90 versus 0.85, 0.87, and 0.83 for the stomach, and 0.76 versus 0.68, 0.69, and 0.66 for the esophagus. We conclude that the deep-learning-based segmentation represents a registration-free method for multi-organ abdominal CT segmentation whose accuracy can surpass current methods, potentially supporting image-guided navigation in gastrointestinal endoscopy procedures. PMID- 29994629 TI - Prior-Free Respiratory Motion Estimation in Rotational Angiography. AB - Rotational coronary angiography using C-arm angiography systems enables intra procedural 3-D imaging that is considered beneficial for diagnostic assessment and interventional guidance. Despite previous efforts, rotational angiography was not yet successfully established in clinical practice for coronary artery procedures due to challenges associated with substantial intra-scan respiratory and cardiac motion. While gating handles cardiac motion during reconstruction, respiratory motion requires compensation. State-of-the-art algorithms rely on 3-D / 2-D registration that requires an uncompensated reconstruction of sufficient quality. To overcome this limitation, we investigate two prior-free respiratory motion estimation methods based on the optimization of: 1) epipolar consistency conditions (ECCs) and 2) a task-based auto-focus measure (AFM). The methods assess redundancies in projection images or impose favorable properties of 3-D space, respectively, and are used to estimate the respiratory motion of the coronary arteries within rotational angiograms. We evaluate our algorithms on the publicly available CAVAREV benchmark and on clinical data. We quantify reductions in error due to respiratory motion compensation using a dedicated reconstruction domain metric. Moreover, we study the improvements in image quality when using an analytic and a novel temporal total variation regularized algebraic reconstruction algorithm. We observed substantial improvement in all figures of merit compared with the uncompensated case. Improvements in image quality presented as a reduction of double edges, blurring, and noise. Benefits of the proposed corrections were notable even in cases suffering little corruption from respiratory motion, translating to an improvement in the vessel sharpness of (6.08 +/- 4.46)% and (14.7 +/- 8.80)% when the ECC-based and the AFM-based compensation were applied. On the CAVAREV data, our motion compensation approach exhibits an improvement of (27.6 +/- 7.5)% and (97.0 +/- 17.7)% when the ECC and AFM were used, respectively. At the time of writing, our method based on AFM is leading the CAVAREV scoreboard. Both motion estimation strategies are purely image-based and accurately estimate the displacements of the coronary arteries due to respiration. While current evidence suggests the superior performance of AFM, future work will further investigate the use of ECC in the context of angiography as they solely rely on geometric calibration and projection-domain images. PMID- 29994630 TI - Metrics for Assessing the Similarity of Microwave Breast Imaging Scans of Healthy Volunteers. AB - Microwave radar imaging is promising as a complementary medical imaging modality. However, the unique nature of the images means interpretation can be difficult. As a result, it is important to understand the sources of image differences, and how much variability is inherent in the imaging system itself. To address this issue, we compare the effectiveness of six different measures of image similarity for quantifying the similarity (or difference) between two microwave radar images. The structural similarity index has become the de facto standard for image comparison, but we propose that useful information can be acquired from a measure known as the Modified Hausdorff Distance. We apply each measure to image pairs from sequential scans of both phantoms and volunteers. We find that rather than using a single value to quantify the image similarity, by computing a number of values that are designed to capture different image aspects, we can better assess the ways in which the images differ. PMID- 29994631 TI - Depth Super-resolution from RGB-D Pairs with Transform and Spatial Domain Regularization. AB - This paper proposes a depth super-resolution method with both transform and spatial domain regularization. In the transform domain regularization, nonlocal correlations are exploited via an auto-regressive model, where each patch is further sparsified with a locally-trained transform to consider intra-patch correlations. In the spatial domain regularization, we propose a multi directional total variation (MTV) prior to characterize the geometrical structures spatially orientated at arbitrary directions in depth maps. To achieve adaptive regularization, the MTV is weighted for each directional finite difference considering local characteristics of RGB-D data. We develop an accelerated proximal gradient algorithm to solve the proposed model. Quantitative and qualitative evaluations compared with state-of-the-art methods demonstrate that the proposed method achieves superior depth super-resolution performance for various configurations of magnification factors and datasets. PMID- 29994632 TI - A Multi-Region Segmentation Method for SAR Images based on the Multi-Texture Model with Level Sets. AB - Synthetic Aperture Radar (SAR) image segmentation is a difficult problem due to the presence of strong multiplicative noise. To attain multi-region segmentation for SAR images, this paper presents a parametric segmentation method based on the multi-texture model with level sets. Segmentation is achieved by solving level set functions obtained from minimizing the proposed energy functional. To fully utilize image information, edge feature and region information are both included in the energy functional. For the need of level set evolution, the Ratio of Exponentially Weighted Averages (ROEWA) operator is modified to obtain edge feature. Region information is obtained by the Improved Edgeworth Series Expansion (IESE), which can adaptively model a SAR image distribution with respect to various kinds of regions. The performance of the proposed method is verified by three high resolution SAR images. The experimental results demonstrate that SAR images can be segmented into multiple regions accurately without any speckle pre-processing steps by the proposed method. PMID- 29994633 TI - DesnowNet: Context-Aware Deep Network for Snow Removal. AB - Existing learning-based atmospheric particle-removal approaches such as those used for rainy and hazy images are designed with strong assumptions regarding spatial frequency, trajectory, and translucency. However, the removal of snow particles is more complicated because they possess additional attributes of particle size and shape, and these attributes may vary within a single image. Currently, hand-crafted features are still the mainstream for snow removal, making significant generalization difficult to achieve. In response, we have designed a multistage network named DesnowNet to in turn deal with the removal of translucent and opaque snow particles. We also differentiate snow attributes of translucency and chromatic aberration for accurate estimation. Moreover, our approach individually estimates residual complements of the snow-free images to recover details obscured by opaque snow. Additionally, a multi-scale design is utilized throughout the entire network to model the diversity of snow. As demonstrated in the qualitative and quantitative experiments, our approach outperforms state-of-the-art learning-based atmospheric phenomena removal methods and one semantic segmentation baseline on the proposed Snow100K dataset. The results indicate our network would benefit applications involving computer vision and graphics. PMID- 29994634 TI - Unified Discriminative and Coherent Semi-supervised Subspace Clustering. AB - The ubiquitous large, complex and high dimensional datasets in computer vision and machine learning generates the problem of subspace clustering, which aims to partition the data into several low dimensional subspaces. By utilizing relatively limited labeled data and sufficient unlabeled data, the semi supervised subspace clustering is more effective, practical and become more popular. In this work, we present a new regularity combing the labels and the affinity to ensure the coherence of the affinity between data points from the same subspace as well as the discrimination of cluster labels for data points from different subspaces. We combine it with the manifold smoothing term of the existing methods and the Gaussian fields and harmonic functions method to give a new unified optimization framework for semi-supervised subspace clustering. Analysis shows the proposed model fully combines the affinity and the labels to guide each other so that both are discriminative between clusters and coherent within clusters. Extensive experiments show that our method outperforms the existing state-of-the-art methods, thus suggests that the property of discriminative between clusters and coherent within clusters of our method is advantageous to semi-supervised subspace clustering. PMID- 29994635 TI - Good Features to Correlate for Visual Tracking. AB - During the recent years, correlation filters have shown dominant and spectacular results for visual object tracking. The types of the features that are employed in these family of trackers significantly affect the performance of visual tracking. The ultimate goal is to utilize robust features invariant to any kind of appearance change of the object, while predicting the object location as properly as in the case of no appearance change. As the deep learning based methods have emerged, the study of learning features for specific tasks has accelerated. For instance, discriminative visual tracking methods based on deep architectures have been studied with promising performance. Nevertheless, correlation filter based (CFB) trackers confine themselves to use the pre-trained networks which are trained for object classification problem. To this end, in this manuscript the problem of learning deep fully convolutional features for the CFB visual tracking is formulated. In order to learn the proposed model, a novel and efficient backpropagation algorithm is presented based on the loss function of the network. The proposed learning framework enables the network model to be flexible for a custom design. Moreover, it alleviates the dependency on the network trained for classification. Extensive performance analysis shows the efficacy of the proposed custom design in the CFB tracking framework. By fine tuning the convolutional parts of a state-of-the-art network and integrating this model to a CFB tracker, which is the top performing one of VOT2016, 18% increase is achieved in terms of expected average overlap, and tracking failures are decreased by 25%, while maintaining the superiority over the state-of-the-art methods in OTB-2013 and OTB-2015 tracking datasets. PMID- 29994636 TI - A Psychophysical Evaluation of Texture Compression Masking Effects. AB - Lossy texture compression is increasingly used to reduce GPU memory and bandwidth consumption. However, evaluating the quality of compressed textures is a difficult problem. Indeed using PSNR on texture images, like done in most applications, may not be a correct way to proceed. In particular, there is evidence that masking effects apply when the texture image is mapped on a surface and combined with other textures. These masking effects have to be taken into account when compressing a set of texture maps, in order to have a real understanding of the visual impact of the compression artifacts on the rendered images. We present the first psychophysical experiment investigating the perceptual impact of texture compression. We explore the influence of compression bit rate, lighting, and diffuse and normal map content on the impact of artifacts. The collected data reveal huge masking effects from normal map to diffuse map artifacts and vice versa, and reveal the weakness of PSNR for evaluating compression quality. The results allow us to also analyze the performance and failures of image quality metrics for predicting the visibility of these artifacts. We finally provide some recommendations for evaluating the quality of texture compression and show a practical application. PMID- 29994637 TI - Influence Networks Compared with Reaction Networks: Semantics, Expressivity and Attractors. AB - Biochemical reaction networks are one of the most widely used formalisms in systems biology to describe the molecular mechanisms of high-level cell processes. However, modellers also reason with influence diagrams to represent the positive and negative influences between molecular species and may find an influence network useful in the process of building a reaction network. In this paper, we introduce a formalism of influence networks with forces, and equip it with a hierarchy of Boolean, Petri net, stochastic and differential semantics, similarly to reaction networks with rates. We show that the expressive power of influence networks is the same as that of reaction networks under the differential semantics, but weaker under the discrete semantics. Furthermore, the hierarchy of semantics leads us to consider a (positive) Boolean semantics that cannot test the absence of a species, that we compare with the (negative) Boolean semantics with test for absence of a species in gene regulatory networks a la Thomas. We study the monotonicity properties of the positive semantics and derive from them an algorithm to compute attractors in both the positive and negative Boolean semantics. We illustrate our results on models of the literature about the p53/Mdm2 DNA damage repair system, the circadian clock, and the influence of MAPK signaling on cell-fate decision in urinary bladder cancer. PMID- 29994638 TI - High-scalable Collaborated Parallel Framework for Large-scale Molecular Dynamic Simulation on Tianhe-2 Supercomputer. AB - Molecular dynamics (MD) is a computer simulation method of studying physical movements of atoms and molecules that provide detailed microscopic sampling on molecular scale. With the continuous efforts and improvements, MD simulation gained popularity in materials science, biochemistry and biophysics with various application areas and expanding data scale. Assisted Model Building with Energy Refinement (AMBER) is one of the most widely used software packages for conducting MD simulations. However, the speed of AMBER MD simulations for system with millions of atoms in microsecond scale still need to be improved. In this paper, we propose a parallel acceleration strategy for AMBER on the Tianhe-2 supercomputer. The parallel optimization of AMBER is carried out on three different levels: fine grained OpenMP parallel on a single CPU, single node CPU/MIC parallel optimization and multi-node multi-MIC collaborated parallel acceleration. By the three levels of parallel acceleration strategy above, we achieved the highest speedup of 25-33 times compared with the original program. PMID- 29994639 TI - A multimodal deep neural network for human breast cancer prognosis prediction by integrating multi-dimensional data. AB - Breast cancer is a highly aggressive type of cancer with very low median survival. Accurate prognosis prediction of breast cancer can spare a significant number of patients from receiving unnecessary adjuvant systemic treatment and its related expensive medical costs. Previous work relies mostly on selected gene expression data to create a predictive model. The emergence of deep learning methods and multi-dimensional data offers opportunities for more comprehensive analysis of the molecular characteristics of breast cancer and therefore can improve diagnosis, treatment and prevention. In this study, we propose a Multimodal Deep Neural Network by integrating Multi-dimensional Data (MDNNMD) for the prognosis prediction of breast cancer. The novelty of the method lies in the design of our method's architecture and the fusion of multi-dimensional data. The comprehensive performance evaluation results show that the proposed method achieves a better performance than the prediction methods with single-dimensional data and other existing approaches. The source code implemented by TensorFlow 1.0 deep learning library can be downloaded from the Github: https://github.com/USTC HIlab/MDNNMD. PMID- 29994640 TI - Shared Predictive Cross-Modal Deep Quantization. AB - With explosive growth of data volume and ever-increasing diversity of data modalities, cross-modal similarity search, which conducts nearest neighbor search across different modalities, has been attracting increasing interest. This paper presents a deep compact code learning solution for efficient cross-modal similarity search. Many recent studies have proven that quantization-based approaches perform generally better than hashing-based approaches on single-modal similarity search. In this paper, we propose a deep quantization approach, which is among the early attempts of leveraging deep neural networks into quantization based cross-modal similarity search. Our approach, dubbed shared predictive deep quantization (SPDQ), explicitly formulates a shared subspace across different modalities and two private subspaces for individual modalities, and representations in the shared subspace and the private subspaces are learned simultaneously by embedding them to a reproducing kernel Hilbert space, where the mean embedding of different modality distributions can be explicitly compared. In addition, in the shared subspace, a quantizer is learned to produce the semantics preserving compact codes with the help of label alignment. Thanks to this novel network architecture in cooperation with supervised quantization training, SPDQ can preserve intramodal and intermodal similarities as much as possible and greatly reduce quantization error. Experiments on two popular benchmarks corroborate that our approach outperforms state-of-the-art methods. PMID- 29994641 TI - Sequential Outlier Criterion for Sparsification of Online Adaptive Filtering. AB - In this paper, we deal with the learning problem when using an adaptive filtering method. For the learning system in filtering, the knowledge is obtained and updated based on the newly acquired information that is extracted and learned from the sequential samples over time. Effective measurement on the informativeness of a sample and reasonable subsequent treatment on the sample will improve the learning performance. This paper proposes a sequential outlier criterion for sparsification of online adaptive filtering. The method is proposed to achieve effective informativeness measurement of online filtering to obtain a more accurate and more compact network in the learning process. In the proposed method, the measurement on the samples' informativeness is established based on the historical sequentially adjacent samples, and then the informative-measured samples are treated individually by the learning system based on whether the sample is informative, redundant, or abnormal. With our method, a more sensible learning process can be achieved with valid knowledge extracted, and the optimal network in the learning system can be obtained. Simulations based on static function estimation, Mackey-Glass time series prediction, and Lorenz chaotic time series prediction demonstrate that the proposed method can provide more effective classification on samples and more accurate networks in online adaptive filtering. PMID- 29994642 TI - Integrating Space, Time, and Orientation in Spiking Neural Networks: A Case Study on Multimodal Brain Data Modeling. AB - Recent progress in a noninvasive brain data sampling technology has facilitated simultaneous sampling of multiple modalities of brain data, such as functional magnetic resonance imaging, electroencephalography, diffusion tensor imaging, and so on. In spite of the potential benefits from integrating predictive modeling of multiple modality brain data, this area of research remains mostly unexplored due to a lack of methodological advancements. The difficulty in fusing multiple modalities of brain data within a single model lies in the heterogeneous temporal and spatial characteristics of the data sources. Recent advances in spiking neural network systems, however, provide the flexibility to incorporate multidimensional information within the model. This paper proposes a novel, unsupervised learning algorithm for fusing temporal, spatial, and orientation information in a spiking neural network architecture that could potentially be used to understand and perform predictive modeling using multimodal data. The proposed algorithm is evaluated both qualitatively and quantitatively using synthetically generated data to characterize its behavior and its ability to utilize spatial, temporal, and orientation information within the model. This leads to improved pattern recognition capabilities and performance along with robust interpretability of the brain data. Furthermore, a case study is presented, which aims to build a computational model that discriminates between people with schizophrenia who respond or do not respond to monotherapy with the antipsychotic clozapine. PMID- 29994643 TI - Tree2Vector: Learning a Vectorial Representation for Tree-Structured Data. AB - The tree structure is one of the most powerful structures for data organization. An efficient learning framework for transforming tree-structured data into vectorial representations is presented. First, in attempting to uncover the global discriminative information of child nodes hidden at the same level of all of the trees, a clustering technique can be adopted for allocating children into different clusters, which are used to formulate the components of a vector. Moreover, a locality-sensitive reconstruction method is introduced to model a process, in which each parent node is assumed to be reconstructed by its children. The resulting reconstruction coefficients are reversely transformed into complementary coefficients, which are utilized for locally weighting the components of the vector. A new vector is formulated by concatenating the original parent node vector and the learned vector from its children. This new vector for each parent node is inputted into the learning process of formulating vectorial representation at the upper level of the tree. This recursive process concludes when a vectorial representation is achieved for the entire tree. Our method is examined in two applications: book author recommendations and content based image retrieval. Extensive experimental results demonstrate the effectiveness of the proposed method for transforming tree-structured data into vectors. PMID- 29994644 TI - Exploring Auxiliary Context: Discrete Semantic Transfer Hashing for Scalable Image Retrieval. AB - Unsupervised hashing can desirably support scalable content-based image retrieval for its appealing advantages of semantic label independence, memory, and search efficiency. However, the learned hash codes are embedded with limited discriminative semantics due to the intrinsic limitation of image representation. To address the problem, in this paper, we propose a novel hashing approach, dubbed as discrete semantic transfer hashing (DSTH). The key idea is to directly augment the semantics of discrete image hash codes by exploring auxiliary contextual modalities. To this end, a unified hashing framework is formulated to simultaneously preserve visual similarities of images and perform semantic transfer from contextual modalities. Furthermore, to guarantee direct semantic transfer and avoid information loss, we explicitly impose the discrete constraint, bit-uncorrelation constraint, and bit-balance constraint on hash codes. A novel and effective discrete optimization method based on augmented Lagrangian multiplier is developed to iteratively solve the optimization problem. The whole learning process has linear computation complexity and desirable scalability. Experiments on three benchmark data sets demonstrate the superiority of DSTH compared with several state-of-the-art approaches. PMID- 29994645 TI - Electrode density affects the robustness of myoelectric pattern recognition system with and without electrode shift. AB - With the availability of high density (HD) electrodes technology, the electrodes used in myoelectric control can have much higher density than the current practice. In this study, we investigated the effects of electrode density on pattern recognition (PR) based myoelectric control. Four density levels were analyzed in two directions: parallel and perpendicular to muscle fibers. Their influence on PR-based myoelectric control algorithms were investigated under three conditions between training and testing data sets: no electrode shift, 10 mm shift parallel to muscle fibers and 10 mm shift perpendicular to muscle fibers. The effect of electrode density varied among the different shift conditions: 1) when there was no shift, increasing electrode density significantly improved the classification performance; 2) when the shift was in the perpendicular direction, increasing electrode density resulted in deterioration in the classification performance; 3) when the shift was the parallel direction, the effect of the electrode density was more complicated: increasing the density in the parallel direction reduced the performance, while increasing density in the perpendicular direction would initially enhance the performance, but then reduce performance. To our best knowledge, this was the first study focusing on the role of electrode density in myoelectric control with the presence of electrode shift. Its outcome would benefit the design of electrode placement for future myoelectric prostheses with high-density electrodes. PMID- 29994646 TI - Hierarchical Algorithms for Causality Retrieval in Atrial Fibrillation Intracavitary Electrograms. AB - Multi-channel intracavitary electrograms (EGMs), are acquired at the electrophysiology laboratory to guide radio frequency catheter ablation of patients suffering from atrial fibrillation (AF). These EGMs are used by cardiologists to determine candidate areas for ablation (e.g., areas corresponding to high dominant frequencies or complex fractionated electrograms). In this paper, we introduce two hierarchical algorithms to retrieve the causal interactions among these multiple EGMs. Both algorithms are based on Granger causality, but other causality measures can be easily incorporated. In both cases, they start by selecting a root node, but they differ on the way in which they explore the set of signals to determine their cause-effect relationships: either testing the full set of unexplored signals (GS-CaRe) or performing a local search only among the set of neighbor EGMs (LS-CaRe). The ensuing causal model provides important information about the propagation of the electrical signals inside the atria, uncovering wavefronts and activation patterns that can guide cardiologists towards candidate areas for catheter ablation. Numerical experiments, on both synthetic signals and annotated real-world signals, show the good performance of the two proposed approaches. PMID- 29994647 TI - Multivariate Chaotic Time Series Online Prediction Based on Improved Kernel Recursive Least Squares Algorithm. AB - Kernel recursive least squares (KRLS) is a kind of kernel methods, which has attracted wide attention in the research of time series online prediction. It has low computational complexity and updates in a recursive form. However, as data size increases, computational complexity of calculating kernel inverse matrix will raise. And it has some difficulties in accommodating time-varying environments. Therefore, we have presented an improved KRLS algorithm for multivariate chaotic time series online prediction. Approximate linear dependency, dynamic adjustment, and coherence criterion are combined with quantization to form our improved KRLS algorithm. In the process of online prediction, it can bring computational efficiency up and adjust weights adaptively in time-varying environments. Moreover, Lorenz chaotic time series, El Nino-Southern Oscillation indexes chaotic time series, yearly sunspots and runoff of the Yellow River chaotic time series online prediction are presented to prove the effectiveness of our proposed algorithm. PMID- 29994648 TI - Opinion Dynamics in the Presence of Increasing Agreement Pressure. AB - In this paper, we study a model of agent consensus in a social network in the presence increasing interagent influence, i.e., increasing peer pressure. Each agent in the social network has a distinct social stress function given by a weighted sum of internal and external behavioral pressures. We assume a weighted average update rule consistent with the classic DeGroot model and prove conditions under which a connected group of agents converge to a fixed opinion distribution, and under which conditions the group reaches consensus. We show that the update rule converges to gradient descent and explain its transient and asymptotic convergence properties. Through simulation, we study the rate of convergence on a scale-free network. PMID- 29994649 TI - Prescribed Performance for Bipartite Tracking Control of Nonlinear Multiagent Systems With Hysteresis Input Uncertainties. AB - This paper studies bipartite tracking problem of nonlinear multiagent systems over signed directed graphs. Each following agent is modeled by a higher-order nonlinear system in strict-feedback form with unknown dynamics and hysteresis input uncertainty. Both distributed state feedback and output feedback control laws are proposed to achieve bipartite tracking confined by the prescribed performance bounds. The proposed approximation-free distributed controllers only utilize error variables incorporating with performance bound functions, which lead to a low-complexity control algorithm. Moreover, the proposed control laws guarantee that all signals of the closed-loop system are uniformly ultimately bounded. PMID- 29994650 TI - User Participation in Collaborative Filtering-Based Recommendation Systems: A Game Theoretic Approach. AB - Collaborative filtering is widely used in recommendation systems. A user can get high-quality recommendations only when both the user himself/herself and other users actively participate, i.e., provide sufficient ratings. However, due to the rating cost, rational users tend to provide as few ratings as possible. Therefore, there exists a tradeoff between the rating cost and the recommendation quality. In this paper, we model the interactions among users as a game in satisfaction form and study the corresponding equilibrium, namely satisfaction equilibrium (SE). Considering that accumulated ratings are used for generating recommendations, we design a behavior rule which allows users to achieve an SE via iteratively rating items. We theoretically analyze under what conditions an SE can be learned via the behavior rule. Experimental results on Jester and MovieLens data sets confirm the analysis and demonstrate that, if all users have moderate expectations for recommendation quality and satisfied users are willing to provide more ratings, then all users can get satisfying recommendations without providing many ratings. The SE analysis of the proposed game in this paper is helpful for designing mechanisms to encourage user participation. PMID- 29994651 TI - Distributed multi-agent Gaussian regression via finite-dimensional approximations. AB - We consider the problem of distributedly estimating Gaussian processes in multi agent frameworks. Each agent collects few measurements and aims to collaboratively reconstruct a common estimate based on all data. Agents are assumed with limited computational and communication capabilities and to gather noisy measurements in total on input locations independently drawn from a known common probability density. The optimal solution would require agents to exchange all the input locations and measurements and then invert an matrix, a non scalable task. Differently, we propose two suboptimal approaches using the first orthonormal eigenfunctions obtained from the KL expansion of the chosen kernel, where typically . The benefits are that the computation and communication complexities scale with and not with , and computing the required statistics can be performed via standard average consensus algorithms. We obtain probabilistic non-asymptotic bounds that determine a priori the desired level of estimation accuracy, and new distributed strategies relying on SURE paradigms for tuning the regularization parameters and applicable to generic basis functions (thus not necessarily kernel eigenfunctions) and that can again be implemented via average consensus. The proposed estimators and bounds are finally tested on both synthetic and real field data. PMID- 29994652 TI - Binary Multi-View Clustering. AB - Clustering is a long-standing important research problem, however, remains challenging when handling large-scale image data from diverse sources. In this paper, we present a novel Binary Multi-View Clustering (BMVC) framework, which can dexterously manipulate multi-view image data and easily scale to large data. To achieve this goal, we formulate BMVC by two key components: compact collaborative discrete representation learning and binary clustering structure learning, in a joint learning framework. Specifically, BMVC collaboratively encodes the multi-view image descriptors into a compact common binary code space by considering their complementary information; the collaborative binary representations are meanwhile clustered by a binary matrix factorization model, such that the cluster structures are optimized in the Hamming space by pure, extremely fast bit-operations. For efficiency, the code balance constraints are imposed on both binary data representations and cluster centroids. Finally, the resulting optimization problem is solved by an alternating optimization scheme with guaranteed fast convergence. Extensive experiments on four large-scale multi view image datasets demonstrate that the proposed method enjoys the significant reduction in both computation and memory footprint, while observing superior (in most cases) or very competitive performance, in comparison with state-of-the-art clustering methods. PMID- 29994653 TI - Opening the Black Box: Hierarchical Sampling Optimization for Hand Pose Estimation. AB - Hand pose estimation, formulated as an inverse problem, is typically optimized by an energy function over pose parameters using a 'black box' image generation procedure, knowing little about either the relationships between the parameters or the form of the energy function. In this paper, we show significant improvement upon the black box optimization by exploiting high-level knowledge of the parameter structure and using a local surrogate energy function. Our new framework, hierarchical sampling optimization (HSO), consists of a sequence of discriminative predictors organized into a kinematic hierarchy. Each predictor is conditioned on its ancestors, and generates a set of samples over a subset of the pose parameters, with only one selected by the highly-efficient surrogate energy. The selected partial poses are concatenated to generate a full-pose hypothesis. Repeating the same process, several hypotheses are generated and the full energy function selects the best result. Under the same kinematic hierarchy, two methods based on decision forest and convolutional neural network are proposed to generate the samples and two optimization methods are studied when optimizing these samples. Experimental evaluations on three publicly available datasets show that our method is particularly impressive in low-compute scenarios where it significantly outperforms all other state-of-the-art methods. PMID- 29994654 TI - Salient Subsequence Learning for Time Series Clustering. AB - Time series has been a popular research topic over the past decade. Salient subsequences of time series that can benefit the learning task, e.g. classification or clustering, are called shapelets. Shapelet-based time series learning extracts these types of salient subsequences with highly informative features from a time series. Most existing methods for shapelet discovery must scan a large pool of candidate subsequences, which is a time-consuming process. A recent work, Grabocka:KDD14, uses regression learning to discover shapelets in a time series; however, it only considers learning shapelets from labeled time series data. This paper proposes an Unsupervised Salient Subsequence Learning (USSL) model that discovers shapelets without the effort of labeling. We developed this new learning function by integrating the strengths of shapelet learning, shapelet regularization, spectral analysis and pseudo-label to simultaneously and automatically learn shapelets to help clustering unlabeled time series better. The optimization model is iteratively solved via a coordinate descent algorithm. Experiments show that our USSL can learn meaningful shapelets, with promising results on real-world and synthetic data that surpass current state-of-the-art unsupervised time series learning methods. PMID- 29994655 TI - Bearing-based Network Localizability: A Unifying View. AB - This paper provides a unifying view and offers new insights on bearing-based network localizability, that is the problem of establishing whether a set of directions between pairs of nodes uniquely determines (up to translation and scale) the position of the nodes in d-space. If nodes represent cameras then we are in the context of global structure from motion. The contribution of the paper is theoretical: first, we rewrite and link in a coherent structure several results that have been presented in different communities using disparate formalisms; second, we derive some new localizability results within the edge based formulation. PMID- 29994656 TI - Blind Source Separation-Based Motion Detector for Imaging Super-Paramagnetic Iron Oxide (SPIO) Particles in Magnetomotive Ultrasound Imaging. AB - In magnetomotive ultrasound (MMUS) imaging, an oscillating external magnetic field displaces tissue loaded with super-paramagnetic iron oxide (SPIO) particles. The induced motion is on the nanometer scale, which makes its detection and its isolation from background motion challenging. Previously, a frequency and phase locking (FPL) algorithm was used to suppress background motion by subtracting magnetic field off ( -off) from on ( -on) data. Shortcomings to this approach include long tracking ensembles and the requirement for -off data. In this paper, a novel blind source separation-based FPL (BSS-FPL) algorithm is presented for detecting motion using a shorter ensemble length (EL) than FPL and without -off data. MMUS imaging of two phantoms containing an SPIO laden cubical inclusion and one control phantom was performed using an open-air MMUS system. When background subtraction was used, contrast and contrast to noise ratio (CNR) were, respectively, 1.20+/-0.20 and 1.56+/-0.34 times higher in BSS FPL as compared to FPL-derived images for EL < 3.5 s. However, contrast and CNR were similar for BSS-FPL and FPL for EL >= 3.5 s. When only -on data was used, contrast and CNR were 1.94 +/- 0.21 and 1.56 +/- 0.28 times higher, respectively, in BSS-FPL as compared to FPL-derived images for all ELs. Percent error in the estimated width and height was 39.30% +/- 19.98% and 110.37% +/- 6.5% for FPL and was 7.30% +/- 7.6% and 16.21% +/- 10.29% for BSS-FPL algorithm. This paper is an important step toward translating MMUS imaging to in vivo application, where long tracking ensembles would increase acquisition time and -off data may be misaligned with -on due to physiological motion. PMID- 29994657 TI - Optimized Echo Decorrelation Imaging Feedback for Bulk Ultrasound Ablation Control. AB - Feasibility of controlling bulk ultrasound (US) thermal ablation using echo decorrelation imaging was investigated in ex vivo bovine liver. The first of two ablation and control procedures used a sequence of constant-intensity sonication cycles, ceased when the minimum echo decorrelation within a control region of interest (ROI) exceeded a predetermined threshold. The second procedure used a variable-intensity sonication sequence, with spatially averaged decorrelation as the stopping criterion. US exposures and echo decorrelation imaging were performed by a linear image-ablate array. Based on preliminary experiments, control ROIs and thresholds for the minimum-decorrelation and average decorrelation criteria were specified. Controlled trials for the minimum decorrelation and average-decorrelation criteria were compared with uncontrolled trials employing 9 or 18 cycles of matching sonication sequences. Lesion dimensions, treatment times, ablation rates, and areas under receiver operating characteristic curves were statistically compared. Successfully controlled trials using both criteria required significantly shorter treatment times than corresponding 18-cycle treatments, with better ablation prediction performance than uncontrolled 9-cycle and 18-cycle treatments. Either control approach resulted in greater ablation rate than corresponding 9-cycle or 18-cycle uncontrolled approaches. A post hoc analysis studied the effect of exchanging control criteria between the two series of controlled experiments. For either group, the average time needed to exceed the alternative decorrelation threshold approximately matched the average duration of successfully controlled experimental trials. These results indicate that either approach, using minimum decorrelation or average-decorrelation criteria, is feasible for control of bulk US ablation. In addition, use of a variable-intensity sonication sequence for bulk US thermal ablation can result in larger ablated regions compared to constant-intensity sonication sequences. PMID- 29994658 TI - Plane wave contrast imaging: a radiation force point of view. AB - Radiation force is known to produce microbubble axial displacements by an amount that depends on the transmit burst frequency, amplitude and length, as well as the pulse repetition frequency (PRF). In standard focused imaging mode, the actual PRF experienced by each microbubble is low because it is of the order of the frame rate (i.e. usually tens of Hz). In plane-wave imaging mode, however, the actual PRF is considerably higher, as it is equivalent to the transmit PRF (kHz range). Furthermore, the radiation pressure is expected to be almost uniform over the field of view, and typically lower than the peak pressure experienced in focused transmit (TX) mode. We have experimentally investigated the possible effects of radiation force in plane-wave mode. Here we report on preliminary findings that show the acoustic radiation force is negligible only at lower TX levels. At higher TX amplitudes, the bubble displacements due to radiation force are comparable to those obtained for focused waves at the same PRF. In addition, the radiation force is nearly uniform over the field of view and increases as the TX burst central frequency approaches the resonance frequency of size-isolated microbubbles. PMID- 29994659 TI - Deep Blur Mapping: Exploiting High-Level Semantics by Deep Neural Networks. AB - The human visual system excels at detecting local blur of visual images, but the underlying mechanism is not well understood. Traditional views of blur such as reduction in energy at high frequencies and loss of phase coherence at localized features have fundamental limitations. For example, they cannot well discriminate flat regions from blurred ones. Here we propose that high-level semantic information is critical in successfully identifying local blur. Therefore, we resort to deep neural networks that are proficient at learning high-level features and propose the first end-to-end local blur mapping algorithm based on a fully convolutional network. By analyzing various architectures with different depths and design philosophies, we empirically show that high-level features of deeper layers play a more important role than low-level features of shallower layers in resolving challenging ambiguities for this task. We test the proposed method on a standard blur detection benchmark and demonstrate that it significantly advances the state-of-the-art (ODS F-score of 0.853). Furthermore, we explore the use of the generated blur maps in three applications, including blur region segmentation, blur degree estimation, and blur magnification. PMID- 29994660 TI - Exploratory Visual Sequence Mining Based on Pattern-Growth. AB - Sequential pattern mining finds applications in numerous diverging fields. Due to the problem's combinatorial nature, two main challenges arise. First, existing algorithms output large numbers of patterns many of which are uninteresting from a user's perspective. Second, as datasets grow, mining large number of patterns gets computationally expensive. There is, thus, a need for mining approaches that make it possible to focus the pattern search towards directions of interest. This work tackles this problem by combining interactive visualization with sequential pattern mining in order to create a "transparent box" execution model. We propose a novel approach to interactive visual sequence mining that allows the user to guide the execution of a pattern-growth algorithm at suitable points through a powerful visual interface. Our approach (1) introduces the possibility of using local constraints during the mining process, (2) allows stepwise visualization of patterns being mined, and (3) enables the user to steer the mining algorithm towards directions of interest. The use of local constraints significantly improves users' capability to progressively refine the search space without the need to restart computations. We exemplify our approach using two event sequence datasets; one composed of web page visits and another composed of individuals' activity sequences. PMID- 29994661 TI - Low-Complexity Privacy-Preserving Compressive Analysis Using Subspace-Based Dictionary for ECG Telemonitoring System. AB - Compressive sensing (CS) is attractive in long-term electrocardiography (ECG) telemonitoring to extend life-time for resource-constrained wireless wearable sensors. However, the availability of transmitted personal information has posed great concerns for potential privacy leakage. Moreover, the traditional CS-based security frameworks focus on secured signal recovery instead of privacy preserving data analytics; hence, they provide only computational secrecy and have impractically high complexities for decryption. In this paper, to protect privacy from an information-theoretic perspective while delivering the classification capability, we propose a low-complexity framework of Privacy Preserving Compressive Analysis (PPCA) based on subspace-based representation. The subspace-based dictionary is used for both encrypting and decoding the CS measurements online, and it is built by dividing signal space into discriminative and complementary subspace offline. The encrypted signal is unreconstructable even if the eavesdropper cracks the measurement matrix and the dictionary. PPCA is implemented in ECG-based atrial fibrillation detection. It can reduce the mutual information by 1.98 bits via encrypting measurements with signal-dependent noise at 1 dB, while the classification accuracy remains 96.05% with the decoding matrix. Furthermore, by decoding via matrix-vector product, rather than sparse coding, this computational complexity of PPCA is 341 times fewer compared with the traditional CS-based security. PMID- 29994662 TI - Acoustic Analog Front End for Proton Range Detection in Hadron Therapy. AB - Clinical ions beams for cancer treatment provide maximum energy deposition (Bragg peak (BP)) at the end of their range and practically no dose behind. This enables a more efficient therapeutic option comparing with classical photon-based radiotherapy where maximum energy is deposited at the body interface. Obviously, minimum-error BP detection is, thus, a key aspect of this treatment. This paper investigates a promising detection technique, based on the so-called ionoacoustic effect. The BP energy deposition causes a small (millikelvin) heating of the surrounding volume that in turn induces a pressure variation. This generates a sound signal that can be detected by an acoustic sensor placed at a certain distance from the BP point. Thus, the sound time-of-flight measure aims, with sound speed, to detect the BP position with very high accuracy (<1 mm). This paper presents the results of a complete cross-domain model that starting from proton beam energy provides the induced pressure variation in water, emulates the propagation of sound waves in the medium, and finally, returns a voltage signal whose time evolution determines BP position with an average deviation from effective position of 1% accuracy. PMID- 29994663 TI - A Parasitic Insensitive Catheter-Based Capacitive Force Sensor for Cardiovascular Diagnosis. AB - This paper presents a catheter-based capacitive force sensor interface for cardiovascular diagnosis. The force sensor is implemented on a flexible printed circuit board (FPCB) substrate with a force-sensitive polydimethylsiloxane (PDMS), and a force-induced change in a capacitance of the sensor is measured by a precision capacitive sensor interface. To recover the performance degradation caused by the large parasitic capacitance ${?rm C}_{?rm P}$ of a long catheter, we present a parasitic insensitive analog front-end (AFE) with active ${?rm C}_{?rm P}$ cancellation, which employs a charge amplifier and a negative capacitor at the virtual ground of the charge amplifier. The prototype sensor was measured with a force loader in whole blood. The proposed AFE successfully cancels ${?rm C}_{?rm P}$ of 348 pF in a 0.9-m-long sensor and measurement results show the SNR of 53.8 dB and the capacitance resolution of 16 aF, a 19.6 dB improvement by canceling nonideal effect of ${?rm C}_{?rm P}$ . This corresponds to a force resolution of 2.22 gf, which is 9.29 $?times$ reduction compared to the work without the ${?rm C}_{?rm P}$ cancellation. The proposed sensor interface is insensitive to ${?rm C}_{?rm P}$ from hundreds to 1-nF level, and the force-dependent stiffness of two different tissues has been successfully distinguished with an ex-vivo experiment. The proposed sensor interface enables the integration of capacitive force sensors in a smart catheter. PMID- 29994664 TI - A Review of Implant Communication Technology in WBAN : Progresses and Challenges. AB - Over the past six decades there has been tremendous progress made in the field of medical implant communications. A comprehensive review of the progress, current state-of-the-art and future direction is presented in this chapter. Implanted Medical Devices (IMDs) are designed mainly for the purpose of diagnostic, therapeutic and assitive applications in heathcare, active living and sports technology. The primary target of implanted medical devices (IMDs) design revolve around reliable communications, sustainable power sources, high degree of miniaturisation while maintaining bio-compatibility to surrounding tissues adhering to the human safety limits set by appropriate guidelines. The role of internet of things (IoT) and intelligent data analysis in implant device networks as future research is presented. Lastly, in addition to reviewing the state-of the art, a novel intuitive lower bound on implant size is presented. PMID- 29994665 TI - Analysis and Quantification of Repetitive Motion in Long-Term Rehabilitation. AB - Objective assessment in long-term rehabilitation under real-life recording conditions is a challenging task. We propose a data-driven method to evaluate changes in motor function under uncontrolled, long-term conditions with the low cost Microsoft Kinect Sensor. Instead of using human ratings as ground truth data, we propose kinematic features of hand motion, healthy reference trajectories derived by principal component regression, and methods from machine learning to analyze the progression of motor function. We demonstrate the capability of this approach on datasets with repetitive unrestrained bi-manual drumming movements in 3-dimensional space of stroke survivors, patients suffering of Parkinson's disease, and a healthy control group. We present processing steps to eliminate the influence of varying recording setups under real-life conditions and offer visualization methods to support clinicians in the evaluation of treatment effects. PMID- 29994666 TI - Leader-Follower Consensus of Multiagent Systems With Time Delays Over Finite Fields. AB - This paper studies the leader-follower consensus of multiagent systems with time delays and switching topology over finite fields. First, an equivalent algebraic form is established for leader-follower multiagent systems with time delays over finite fields. Second, based on the algebraic form, a necessary and sufficient condition is presented for the finite-field leader-follower consensus with time delays. Third, the switching topology case is considered, and a new criterion is presented for the finite-field leader-follower consensus with time delays and switching topology. Finally, an example is worked out to illustrate the obtained results. PMID- 29994667 TI - Temporally Constrained Sparse Group Spatial Patterns for Motor Imagery BCI. AB - Common spatial pattern (CSP)-based spatial filtering has been most popularly applied to electroencephalogram (EEG) feature extraction for motor imagery (MI) classification in brain-computer interface (BCI) application. The effectiveness of CSP is highly affected by the frequency band and time window of EEG segments. Although numerous algorithms have been designed to optimize the spectral bands of CSP, most of them selected the time window in a heuristic way. This is likely to result in a suboptimal feature extraction since the time period when the brain responses to the mental tasks occurs may not be accurately detected. In this paper, we propose a novel algorithm, namely temporally constrained sparse group spatial pattern (TSGSP), for the simultaneous optimization of filter bands and time window within CSP to further boost classification accuracy of MI EEG. Specifically, spectrum-specific signals are first derived by bandpass filtering from raw EEG data at a set of overlapping filter bands. Each of the spectrum specific signals is further segmented into multiple subseries using sliding window approach. We then devise a joint sparse optimization of filter bands and time windows with temporal smoothness constraint to extract robust CSP features under a multitask learning framework. A linear support vector machine classifier is trained on the optimized EEG features to accurately identify the MI tasks. An experimental study is implemented on three public EEG datasets (BCI Competition III dataset IIIa, BCI Competition IV datasets IIa, and BCI Competition IV dataset IIb) to validate the effectiveness of TSGSP in comparison to several other competing methods. Superior classification performance (averaged accuracies are 88.5%, 83.3%, and 84.3% for the three datasets, respectively) based on the experimental results confirms that the proposed algorithm is a promising candidate for performance improvement of MI-based BCIs. PMID- 29994668 TI - A Complex Varying-Parameter Convergent-Differential Neural-Network for Solving Online Time-Varying Complex Sylvester Equation. AB - A novel recurrent neural network, which is named as complex varying-parameter convergent-differential neural network (CVP-CDNN), is proposed in this paper for solving the time-varying complex Sylvester equation. Two kinds of CVP-CDNNs (i.e., CVP-CDNN Type I and Type II) are illustrated and proved to be effective. The proposed CVP-CDNNs can achieve super-exponential performance if the linear activation function is used. Some activation functions are considered for searching the better performance of the CVP-CDNN and the finite time convergence property of the CVP-CDNN with sign-bi-power activation function is testified. The convergence time of the CVP-CDNN with sign-bi-power activation function is shorter than complex fixed-parameter convergent-differential neural network (CFP CDNN). Moreover, compared with traditional CFP-CDNN, better convergence performances of novel CVP-CDNN are verified by computer simulation comparisons. PMID- 29994669 TI - Deep Learning Global Glomerulosclerosis in Transplant Kidney Frozen Sections. AB - Transplantable kidneys are in very limited supply. Accurate viability assessment prior to transplantation could minimize organ discard. Rapid and accurate evaluation of intra-operative donor kidney biopsies is essential for determining which kidneys are eligible for transplantation. The criterion for accepting or rejecting donor kidneys relies heavily on pathologist determination of the percent of glomeruli (determined from a frozen section) that are normal and sclerotic. This percentage is a critical measurement that correlates with transplant outcome. Inter- and intra-observer variability in donor biopsy evaluation is, however, significant. An automated method for determination of percent global glomerulosclerosis could prove useful in decreasing evaluation variability, increasing throughput, and easing the burden on pathologists. Here, we describe the development of a deep learning model that identifies and classifies non-sclerosed and sclerosed glomeruli in whole-slide images of donor kidney frozen section biopsies. This model extends a convolutional neural network (CNN) pre-trained on a large database of digital images. The extended model, when trained on just 48 whole slide images, exhibits slide-level evaluation performance on par with expert renal pathologists. Encouragingly, the model's performance is robust to slide preparation artifacts associated with frozen section preparation. The model substantially outperforms a model trained on image patches of isolated glomeruli, in terms of both accuracy and speed. The methodology overcomes the technical challenge of applying a pretrained CNN bottleneck model to whole-slide image classification. The traditional patch-based approach, while exhibiting deceptively good performance classifying isolated patches, does not translate successfully to whole-slide image segmentation in this setting. As the first model reported that identifies and classifies normal and sclerotic glomeruli in frozen kidney sections, and thus the first model reported in the literature relevant to kidney transplantation, it may become an essential part of donor kidney biopsy evaluation in the clinical setting. PMID- 29994670 TI - Keypoint Transfer for Fast Whole-Body Segmentation. AB - We introduce an approach for image segmentation based on sparse correspondences between keypoints in testing and training images. Keypoints represent automatically identified distinctive image locations, where each keypoint correspondence suggests a transformation between images. We use these correspondences to transfer label maps of entire organs from the training images to the test image. The keypoint transfer algorithm includes three steps: (i) keypoint matching, (ii) voting-based keypoint labeling, and (iii) keypoint-based probabilistic transfer of organ segmentations. We report segmentation results for abdominal organs in whole-body CT and MRI, as well as in contrast-enhanced CT and MRI. Our method offers a speed-up of about three orders of magnitude in comparison to common multi-atlas segmentation, while achieving an accuracy that compares favorably. Moreover, keypoint transfer does not require the registration to an atlas or a training phase. Finally, the method allows for the segmentation of scans with highly variable field-of-view. PMID- 29994671 TI - Phase Noise Measurements of AlN Contour-Mode Resonators With Carrier Suppression Technique. AB - In this paper, the phase noise of aluminum nitride (AlN) contour-mode resonators is investigated using a passive measurement system with carrier suppression. The purpose is to make careful measurements of the performance of AlN resonators in order to better understand and clarify previously reported frequency instability in these devices. The resonant frequencies of the resonators are around 220 MHz. The motional parameters, the thermal behavior, and the nonlinear power effect of these resonators have been evaluated. Then, the principle of the noise measurement system is reviewed, and the resonator conditioning is shown. Finally, the noise measurements of the resonators are presented and discussed. PMID- 29994672 TI - 3D velocity and volume flow measurement in vivo using speckle decorrelation and 2D high frame rate contrast-enhanced ultrasound. AB - Being able to measure 3D flow velocity and volumetric flow rate effectively in the cardiovascular system is valuable but remains a significant challenge in both clinical practice and research. Currently there has not been an effective and practical solution to the measurement of volume flow using ultrasound imaging systems due to challenges in existing 3D imaging techniques and high system cost. In this study, a new technique for quantifying volumetric flow rate from the crosssectional imaging plane of the blood vessel was developed by using speckle decorrelation, 2D high frame rate imaging with a standard 1D array transducer, microbubble contrast agents, and ultrasound imaging velocimetry (UIV). Through speckle decorrelation analysis of microbubble signals acquired with a very high frame rate and by using UIV to estimate the two in-plane flow velocity components, the third and out-of-plane velocity component can be obtained over time and integrated to estimate volume flow. The proposed technique was evaluated on a wall-less flow phantom in both steady and pulsatile flow. UIV in the longitudinal direction was conducted as a reference. The influences of frame rate, mechanical index, orientation of imaging plane, and compounding on velocity estimation were also studied. In addition, an in vivo trial on the abdominal aorta of a rabbit was conducted. The results show that the new system can estimate volume flow with an averaged error of 3.65+/-2.37% at a flow rate of 360 ml/min and a peak velocity of 0.45 m/s, and an error of 5.03+/-2.73% at a flow rate of 723 ml/min and a peak velocity of 0.8 m/s. The accuracy of the flow velocity and volumetric flow rate estimation directly depend on the imaging frame rate. With a frame rate of 6000 Hz, a velocity up to 0.8 m/s can be correctly estimated. A higher mechanical index (MI=0.42) is shown to produce greater errors (up to 21.78+/-0.49%, compared to 3.65+/-2.37% at MI=0.19). An in vivo trial, where velocities up to 1 m/s were correctly measured, demonstrated the potential of the technique in clinical applications. PMID- 29994673 TI - Ultrasound Localization Microscopy and Super-Resolution: A State of the Art. AB - Because it drives the compromise between resolution and penetration, the diffraction limit has long represented an unreachable summit to conquer in ultrasound imaging. Within a few years after the introduction of optical localization microscopy, we proposed its acoustic alter ego that exploits the micrometric localization of microbubble contrast agents to reconstruct the finest vessels in the body in-depth. Various groups now working on the subject are optimizing the localization precision, microbubble separation, acquisition time, tracking, and velocimetry to improve the capacity of ultrasound localization microscopy (ULM) to detect and distinguish vessels much smaller than the wavelength. It has since been used in vivo in the brain, the kidney, and tumors. In the clinic, ULM is bound to improve drastically our vision of the microvasculature, which could revolutionize the diagnosis of cancer, arteriosclerosis, stroke, and diabetes. PMID- 29994674 TI - Joint Subarray Coherence and Minimum Variance Beamformer for Multitransmission Ultrasound Imaging Modalities. AB - Multitransmission modalities, such as plane wave compounding and synthetic aperture imaging, are promising techniques for ultrafast ultrasound imaging. Adaptive beamformers have been proposed to improve the imaging quality. Two common categories of adaptive beamformers are the minimum variance (MV)-based beamformers and the coherence factor (CF)-based beamformers. The MV can significantly improve the resolution while lacking robustness. It is also computationally expensive for multitransmission modalities. The CF can increase the contrast while over-suppressing some desired signals. In this paper, we propose a novel beamformer for better imaging quality in multitransmission ultrasound modalities. Specifically, the MV weighting process is applied to the receiving and transmitting beamforming. The spatial smoothing technique is modified for both dimensions to enhance the robustness. Then, the CF-based weights are calculated using the MV beamformed output. The submatrix technique is also used in the CF process to avoid over-suppression. Simulations and experiments are conducted to evaluate the performance of the proposed method. The results show that it can preserve the high resolution of MV and the high contrast of CF. Compared with the traditional compounding method, the full-width at half maximum is smaller and the contrast ratio is significantly increased. Anatomic structures of an in vivo human carotid artery are more distinguishable. Because of the spatial smoothing in both dimensions, the proposed beamformer also has high robustness against the channel noise and sound velocity errors. PMID- 29994675 TI - Field Characterization and Compensation of Vibrational Nonuniformity for a 256 Element Focused Ultrasound Phased Array. AB - Multielement focused ultrasound phased arrays have been used in therapeutic applications to treat large tissue volumes by electronic steering of the focus, to target multiple simultaneous foci, and to correct aberration caused by inhomogeneous tissue pathways. There is an increasing interest in using arrays to generate more complex beam shapes and corresponding acoustic radiation force patterns for manipulation of particles such as kidney stones. Toward this end, experimental and computational tools are needed to enable accurate delivery of desired transducer vibrations and corresponding ultrasound fields. The purpose of this paper was to characterize the vibrations of a 256-element array at 1.5 MHz, implement strategies to compensate for variability, and test the ability to generate specified vortex beams that are relevant to particle manipulation. The characterization of the array output was performed in water using both element-by element measurements at the focus of the array and holography measurements for which all the elements were excited simultaneously. Both methods were used to quantify each element's output so that the power of each element could be equalized. Vortex beams generated using both compensation strategies were measured and compared to the Rayleigh integral simulations of fields generated by an idealized array based on the manufacturer's specifications. Although both approaches improved beam axisymmetry, compensation based on holography measurements had half the error relative to the simulation results in comparison to the element-by-element method. PMID- 29994676 TI - Semi-supervised Deep Domain Adaptation via Coupled Neural Networks. AB - Domain adaptation is a promising technique when addressing limited or no labeled target data by borrowing well-labeled knowledge from the auxiliary source data. Recently, researchers have exploited multi-layer structures for discriminative feature learning to reduce the domain discrepancy. However, there are limited research efforts on simultaneously building a deep structure and a discriminative classifier over both labeled source and unlabeled target. In this paper, we propose a semi-supervised deep domain adaptation framework, in which the multi layer feature extractor and a multi-class classifier are jointly learned to benefit from each other. Specifically, we develop a novel semi-supervised class wise adaptation manner to fight off the conditional distribution mismatch between two domains by assigning a probabilistic label to each target sample, i.e., multiple class labels with different probabilities. Furthermore, a multi-class classifier is simultaneously trained on labeled source and unlabeled target samples in a semi-supervised fashion. In this way, the deep structure can formally alleviate the domain divergence and enhance the feature transferability. Experimental evaluations on several standard cross-domain benchmarks verify the superiority of our proposed approach. PMID- 29994677 TI - Reversible Data Hiding under Inconsistent Distortion Metrics. AB - Recursive code construction (RCC), based on the optimal transition probability matrix (OTPM), approaching the rate-distortion bound of reversible data hiding (RDH) has been proposed. Using the existing methods, OTPM can be effectively estimated only for a consistent distortion metric, i.e., if the host elements at different positions share the same distortion metric. However, in many applications, the distortion metrics are position dependent and should thus be inconsistent. Inconsistent distortion metrics can usually be quantified as a multi-distortion metric. In this paper, we first formulate the rate-distortion problem of RDH under a multi-distortion metric and subsequently propose a general framework to estimate the corresponding OTPM, with which RCC is extended to approach the rate-distortion bound of RDH under the multi-distortion metric. We apply the proposed framework to two examples of inconsistent distortion metrics: RDH in color image and reversible steganography. The experimental results show that the proposed method can efficiently improve upon the existing techniques. PMID- 29994678 TI - Cross-View Discriminative Feature Learning for Person Re-Identification. AB - The viewpoint variability across a network of non-overlapping cameras is a challenging problem affecting person re-identification performance. In this paper, we investigate how to mitigate the cross-view ambiguity by learning highly discriminative deep features under the supervision of a novel loss function. The proposed objective is made up of two terms, the steering meta center term and the enhancing centers dispersion term, that steer the training process to mining effective intra-class and inter-class relationships in the feature domain of the identities. The effect of our loss supervision is to generate a more expanded feature space of compact classes where the overall level of the inter-identities' interference is reduced. Compared with the existing metric learning techniques, this approach has the advantage of achieving a better optimization because it jointly learns the embedding and the metric contextually. Our technique, by dismissing side-sources of performance gain, proves to enhance the CNN invariance to viewpoint without incurring increased training complexity (like in Siamese or triplet networks) and outperforms many related state-of-the-art techniques on Market-1501 and CUHK03. PMID- 29994679 TI - Decal-Lenses: Interactive Lenses on Surfaces for Multivariate Visualization. AB - We present decal-lenses, a new interaction technique that extends the concept of magic lenses to augment and manage multivariate visualizations on arbitrary surfaces. Our object-space lenses follow the surface geometry and allow the user to change the point of view during data exploration while maintaining a spatial reference to positions where one or more lenses were placed. Each lens delimits specific regions of the surface where one or more attributes can be selected or combined. Similar to 2D lenses, the user interacts with our lenses in real-time, switching between different attributes within the lens context. The user can also visualize the surface data representations from the point of view of each lens by using local cameras. To place lenses on surfaces of intricate geometry, such as the human brain, we introduce the concept of support surfaces for designing interaction techniques. Support surfaces provide a way to place and interact with the lenses while avoiding holes and occluded regions during data exploration. We further extend decal-lenses to arbitrary regions using brushing and lassoing operations. We discuss the applicability of our technique and present several examples where our lenses can be useful to create a customized exploration of multivariate data on surfaces. PMID- 29994680 TI - Transductive Joint-Knowledge-Transfer TSK FS for Recognition of Epileptic EEG Signals. AB - Intelligent recognition of electroencephalogram (EEG) signals is an important means to detect seizure. Traditional methods for recognizing epileptic EEG signals are usually based on two assumptions: 1) adequate training examples are available for model training and 2) the training set and the test set are sampled from data sets with the same distribution. Since seizures occur sporadically, training examples of seizures could be limited. Besides, the training and test sets are usually not sampled from the same distribution for generic non-patient specific recognition of EEG signals. Hence, the two assumptions in traditional recognition methods could hardly be satisfied in practice, which results in degradation of model performance. Transfer learning is a feasible approach to tackle this issue attributed to its ability to effectively learn the knowledge from the related scenes (source domains) for model training in the current scene (target domain). Among the existing transfer learning methods for epileptic EEG recognition, transductive transfer learning fuzzy systems (TTL-FSs) exhibit distinctive advantages-the interpretability that is important for medical diagnosis and the transfer learning ability that is absent from traditional fuzzy systems. Nevertheless, the transfer learning ability of TTL-FSs is restricted to a certain extent since only the discrepancy in marginal distribution between the training data and test data is considered. In this paper, the enhanced transductive transfer learning Takagi-Sugeno-Kang fuzzy system construction method is proposed to overcome the challenge by introducing two novel transfer learning mechanisms: 1) joint knowledge is adopted to reduce the discrepancy between the two domains and 2) an iterative transfer learning procedure is introduced to enhance transfer learning ability. Extensive experiments have been carried out to evaluate the effectiveness of the proposed method in recognizing epileptic EEG signals on the Bonn and CHB-MIT EEG data sets. The results show that the method is superior to or at least competitive with some of the existing state-of-art methods under the scenario of transfer learning. PMID- 29994681 TI - Drug Side-effect Profiles Prediction: From Empirical Risk Minimization to Structural Risk Minimization. AB - The identification of drug side-effects is considered to be an important step in drug design, which could not only shorten the time but also reduce the cost of drug development. In this paper, we investigate the relationship between the potential side-effects of drug candidates and their chemical structures. The preliminary Regularized Regression (RR) model for drug side-effects prediction has promising features in the efficiency of model training and the existence of a closed form solution. It performs better than other state-of-the-art methods, in terms of minimum accuracy and average accuracy. In order to dig inside how drug structure will associate with side effect, we propose weighted GTS (Generalized T Student Kernel: WGTS) SVM model from a structural risk minimization perspective. The SVM model proposed in this paper provide a better understanding of drug side effects in the process of drug development. The usefulness of the WGTS model lies in the superior performance in a cross validation setting on a 1385 side-effects profiling from SIDER database and the chemical structures of 888 approved drugs and independent side-effect profile predictions. This work is expected to shed light on intriguing studies that predict potential un-identifying side-effects and suggest how we can avoid drug side-effects by the removal of some distinguished chemical structures. PMID- 29994682 TI - Taming Asynchrony for Attractor Detection in Large Boolean Networks. AB - Boolean networks is a well-established formalism for modelling biological systems. A vital challenge for analysing a Boolean network is to identify all the attractors. This becomes more challenging for large asynchronous Boolean networks, due to the asynchronous updating scheme. Existing methods are prohibited due to the well-known state-space explosion problem in large Boolean networks. In this paper, we tackle this challenge by proposing a SCC-based decomposition method. We prove the correctness of our proposed method and demonstrate its efficiency with two real-life biological networks. PMID- 29994683 TI - Rich Chromatin Structure Prediction from Hi-C Data. AB - Recent studies involving the 3-dimensional conformation of chromatin have revealed the important role it has to play in different processes within the cell. These studies have also led to the discovery of densely interacting segments of the chromosome, called topologically associating domains. The accurate identification of these domains from Hi-C interaction data is an interesting and important computational problem for which numerous methods have been proposed. Unfortunately, most existing algorithms designed to identify these domains assume that they are non-overlapping whereas there is substantial evidence to believe a nested structure exists. We present a methodology to predict hierarchical chromatin domains using chromatin conformation capture data. Our method predicts domains at different resolutions, calculated using intrinsic properties of the chromatin data, and effectively clusters these to construct the hierarchy. At each individual level, the domains are non-overlapping in such a way that the intra-domain interaction frequencies are maximized. We show that our predicted structure is highly enriched for actively transcribing housekeeping genes and various chromatin markers, including CTCF, around the domain boundaries. We also show that large-scale domains, at multiple resolutions within our hierarchy, are conserved across cell types and species. We also provide comparisons against existing tools for extracting hierarchical domains. Our software, Matryoshka, is written in and licensed under GPL v3; it is available at https://github.com/COMBINE-lab/matryoshka. PMID- 29994684 TI - Technology-Enabled Assessment of Functional Health. AB - The maturation and adoption of pervasive computing technologies have dramatically altered the face of healthcare. With the introduction of mobile devices, body area networks, and embedded computing systems, care providers can use continuous, ecologically valid information to overcome geographic and temporal barriers and thus provide more effective and timely health assessments. In this paper, we review recent technological developments that can be harnessed to replicate, enhance, or design new methods for assessment of functional performance. Enabling technologies in wearable sensors, ambient sensors, mobile technologies and virtual reality make it possible to quantify real-time functional performance and changes in cognitive health. These technologies, their uses for functional health assessment, and their challenges for adoption are presented in this paper. PMID- 29994685 TI - Quantification of Ventricular Repolarization Variation for Sudden Cardiac Death Risk Stratification in Atrial Fibrillation. AB - OBJECTIVE: Atrial fibrillation (AF) rhythm gives rise to an irregular response in ventricular activity, preventing the use of standard ECG-derived risk markers based on ventricular repolarization heterogeneity under this particular condition. In this study we proposed new indices to quantify repolarization variations in AF patients, assessing their stratification performance in a chronic heart failure (CHF) population with AF. METHODS: We developed a method based on a selective bin averaging technique. Consecutive beats preceded by a similar RR interval were selected, from which the average variation within the ST T complex for each RR range was computed.We proposed two sets of indices: (i) the 2-beat index of ventricular repolarization variation, (I_V2), computed from pairs of stable consecutive beats; and (ii) the 3-beat indices of ventricular repolarization variation, computed in triplets of stable consecutive beats (I_V3). RESULTS: These indices showed a significant association with sudden cardiac death (SCD) outcome in the study population. In addition, risk assessment based on the combination of the proposed indices improved stratification performance compared to their individual potential. CONCLUSION: Patients with enhanced ventricular repolarization variation computed in terms of the proposed indices were successfully associated to a higher SCD incidence in our study population, evidencing their prognostic value. SIGNIFICANCE: using a simple ambulatory ECG recording, it is possible to stratify AF patients at risk of SCD, which may help cardiologists in adopting most effective therapeutic strategies, with a positive impact in both the patient and healthcare systems. PMID- 29994686 TI - Event-Based Synchronization Control for Memristive Neural Networks With Time Varying Delay. AB - In this paper, we investigate the global synchronization control problem for memristive neural networks (MNNs) with time-varying delay. A novel event triggered controller is introduced with the linear diffusive term and discontinuous sign term. In order to greatly reduce the computation cost of the controller under certain event-triggering condition, two event-based control schemes are proposed with static event-triggering condition and dynamic event triggering condition. Some sufficient conditions are derived by these control schemes to ensure the response MNN to be synchronized with the driving one. Furthermore, under certain event-triggering conditions, a positive lower bound is achieved for the interexecution time to guarantee that Zeno behavior cannot be executed. Finally, numerical simulations are provided to substantiate the effectiveness of the proposed theoretical results. PMID- 29994687 TI - A Novel Cyber Attack Detection Method in Networked Control Systems. AB - This paper is concerned with cyber attack detection in a networked control system. A novel cyber attack detection method, which consists of two steps: 1) a prediction step and 2) a measurement update step, is developed. An estimation ellipsoid set is calculated through updating the prediction ellipsoid set with the current sensor measurement data. Based on the intersection between these two ellipsoid sets, two criteria are provided to detect cyber attacks injecting malicious signals into physical components (i.e., sensors and actuators) or into a communication network through which information among physical components is transmitted. There exists a cyber attack on sensors or a network exchanging data between sensors and controllers if there is no intersection between the prediction set and the estimation set updated at the current time instant. Actuators or network transmitting data between controllers and actuators are under a cyber attack if the prediction set has no intersection with the estimation set updated at the previous time instant. Recursive algorithms for the calculation of the two ellipsoid sets and for the attack detection on physical components and the communication network are proposed. Simulation results for two types of cyber attacks, namely a replay attack and a bias injection attack, are provided to demonstrate the effectiveness of the proposed method. PMID- 29994688 TI - Adaptive Tracking Control of Surface Vessel Using Optimized Backstepping Technique. AB - In this paper, a tracking control approach for surface vessel is developed based on the new control technique named optimized backstepping (OB), which considers optimization as a backstepping design principle. Since surface vessel systems are modeled by second-order dynamic in strict feedback form, backstepping is an ideal technique for finishing the tracking task. In the backstepping control of surface vessel, the virtual and actual controls are designed to be the optimized solutions of corresponding subsystems, therefore the overall control is optimized. In general, optimization control is designed based on the solution of Hamilton-Jacobi-Bellman equation. However, solving the equation is very difficult or even impossible due to the inherent nonlinearity and complexity. In order to overcome the difficulty, the reinforcement learning (RL) strategy of actor-critic architecture is usually considered, of which the critic and actor are utilized for evaluating the control performance and executing the control behavior, respectively. By employing the actor-critic RL algorithm for both virtual and actual controls of the vessel, it is proven that the desired optimizing and tracking performances can be arrived. Simulation results further demonstrate effectiveness of the proposed surface vessel control. PMID- 29994689 TI - Noise-Induced Improvement of the Parkinsonian State: A Computational Study. AB - The benefit of noise in improving the basal ganglia (BG) dysfunctions, especially Parkinsonian state, is explored in this paper. High frequency (>=100 Hz) deep brain stimulation (DBS), as a clinical effective stimulation method, has compelling and fantastic results in alleviating the motor symptoms of Parkinson's disease (PD). However, the mechanism of DBS is still unclear. And the selection of the DBS waveform parameters faces great challenges to further optimize the stimulation effects and to reduce its energy expenditure. Considering that the desynchronization of the BG neuronal activities is benefited from the forced high frequency regular spikes driven by standard high frequency DBS, we expect to explore a novel stimulation method that has capability of restoring the BG physiological firing patterns without introducing artificial high-frequency fires. In this paper, a colored noise stimulation is used as a neuromodulation method to disrupt the firing patterns of the pathological neuronal activities. A computational model of the BG that exhibits the intrinsic properties of the BG neurons and their interactions with the thalamic (Th) cells is employed. Based on the model, we investigate the effects of noise stimulation and explore the impacts of the noise stimulation parameters on both relay reliability of the Th neurons and energy expenditure of the stimulation. By comparison, it can be found that noise stimulation does not entrain the network to an artificial high frequency firing state, but induces the pathological increased synchronous activities back to a normal physiological level. Moreover, besides the capability of restoring the neuronal state, the benefits of the noise also include its balanced waveform to avert potential tissue or electrode damage and its ability to reduce the energy expenditure to 50% less than that of the standard DBS, when the noise stimulation has low frequency (<=10 Hz) and appropriate intensity. Thus, the exploration of the optimal noise-induced improvement of the BG dysfunction is of great significance in treating symptoms of neurological disorders such as PD. PMID- 29994690 TI - Multiobjective and Interactive Genetic Algorithms for Weight Tuning of a Model Predictive Control-Based Motion Cueing Algorithm. AB - Driving simulators are effective tools for training, virtual prototyping, and safety assessment which can minimize the cost and maximize road safety. Despite the aim of a realistic motion generation for the impression of real-world driving, motion simulators are bound in a limited workspace. Motion cueing algorithms (MCAs) aim to plan an acceptable motion feeling for drivers, without infringing the simulated boundaries. Recently, model predictive control (MPC) has been widely used in MCAs; however, the tuning process for finding the best weights of the MPC optimization is still a challenge. As there are several objectives for the optimization without any standard weighting for solution evaluations, a nonbiased scalarization of solutions for the purpose of comparison is impossible. In this paper, a clear method for obtaining the best MPC weighting has been proposed. This method searches for the best tune of MPC cost function weights, reduces the user burden for weight tuning while receiving feedback from the user satisfaction. The MPC-based MCA weights are optimized using a multiobjective genetic algorithm (GA) considering objectives, such as minimization of motion inputs (linear acceleration and angular velocity), input rates, output displacements and the sensed motion errors. Any process based on trial-and-error has been omitted. The adjusted weights have to satisfy a set of predefined conditions related to maximum tolerated error and maximum displacement. The obtained Pareto-front is used for decision making via an interactive GA (IGA), aiming for maximization of the decision maker's satisfaction. A Web interface is developed to interact with the IGA and to influence the region of searching. Simulation results show the superiority of the proposed method compared with the previous empirical tuning method. The sensed motion error is minimized using the proposed method and with the same available workspace, a more realistic motion can be rendered to the driver. PMID- 29994691 TI - Model-Free Fault Tolerant Control for a Class of Complex Dynamical Networks With Derivative Couplings. AB - This paper studies the fault tolerant synchronization control for a class of derivative coupled complex dynamical networks (CDNs). Different from the existing results, each subsystem model is assumed to be completely unknown and the coupling terms are mismatched with the control input. Within this framework, a novel model-free fault tolerant controller is designed. Under the proposed control law, the synchronization errors of CDNs are proved to asymptotically converge to zero, which means that the synchronization is successfully achieved. Especially, by combining an important spectral decomposition technique and some properties of Laplacian matrix, a data-based algorithm is provided to derive the controller parameter. In addition, the proposed method is also valid for the CDNs with unknown coupling weights. Finally, examples on circuit systems are given to verify the theoretical results, and some circuit realizations of the proposed control law are implemented based on the circuit theory. PMID- 29994692 TI - Robust Point Set Registration Using Signature Quadratic Form Distance. AB - Point set registration is a problem with a long history in many pattern recognition tasks. This paper presents a robust point set registration algorithm based on optimizing the distance between two probability distributions. A major problem in point to point algorithms is defining the correspondence between two point sets. This paper follows the idea of some probability-based point set registration methods by representing the point sets as Gaussian mixture models (GMMs). By optimizing the distance between the two GMMs, rigid transformations (rotation and translation) between two point sets can be obtained without having to find a correspondence. Previous studies have used L2, Kullback Leibler, etc. distance to measure similarity between two GMMs; however, these methods have problems with robustness to noise and outliers, especially when the covariance matrix is large, or a local minimum exists. Therefore, in this paper, the signature quadratic form distance is derived to measure the distribution similarity. The contribution of this paper lies in adopting the signature quadratic form distance for the point set registration algorithm. The experimental results show the precision and robustness of this algorithm and demonstrate that it outperforms other state-of-the-art point set registration algorithms regarding factors, such as noise, outliers, missing partial structures, and initial misalignment. PMID- 29994693 TI - Multiview, Few-Labeled Object Categorization by Predicting Labels With View Consistency. AB - The categorization accuracies of objects have been greatly improved in recent years. However, large quantities of labeled images are needed. many methods fail when only few labeled images are available. To tackle the few-labeled object categorization problem, we need to represent and classify them from multiple views. In this paper, we propose a novel multiview, few-labeled object categorization algorithm by predicting the labels of images with view consistency (MVFL-VC). We use labeled images along with other unlabeled images in a unified framework. A mapping function is learned to model the correlations of images with their labels. Since there are no labeling information for unlabeled images, we simultaneously learn the mapping function and image labels by classification error minimization. We make use of multiview information for joint object categorization. Although different views represent different aspects of images, for one image, the predicted categories of multiple views should be consistent with each other. We learn the mapping function by minimizing the summed classification losses along with the discrepancy of predicted labels between different views in an alternative way. We conduct object categorization experiments on five public image datasets and compare with other semi-supervised methods. Experimental results well demonstrate the effectiveness of the proposed MVFL-VC method. PMID- 29994694 TI - Global Dynamic Nonrecursive Realization of Decentralized Nonsmooth Exact Tracking for Large-Scale Interconnected Nonlinear Systems. AB - This paper investigates a global decentralized nonsmooth tracking algorithm for a class of interconnected nonlinear systems with strongly coupled interactions. As a main contribution, a nonrecursive dynamic exact tracking control design is proposed for the decentralized control issue which facilitates an intrinsic separation of control law design and stability analysis. First, a fully decentralized extended high-gain observer is constructed to enable the dynamic controller design and performance recovery with the presence of additional disturbances. Then by integrating a nonrecursive homogeneous domination strategy, now the decentralized tracking control law can be designed in a very simple and explicit manner whereas the control gains follow the conventional pole placement approach. Moreover, the nonsmooth design framework will render a finite-time convergence rate of the output tracking which is of significance in practices. The effectiveness of the controller is demonstrated by a rigorous stability analysis and simulation verifications. PMID- 29994695 TI - Optimal Data Injection Attacks in Cyber-Physical Systems. AB - The primary goal of this paper is to analyze the dynamic response of a system under optimal data injection attacks from a control perspective. In this paper, optimal data injection attack design problems are formulated in a similar framework of optimal control. We consider a scenario, where an attacker injects false data to a healthy plant comprising many actuators distributed in different regions. For the case, where an attacker pollutes all actuators, an optimal state feedback injection law is proposed to minimize a quadratic cost functional containing two conflicting objectives. For the case, where the attacker only pollutes partial actuators within a short period, the quadratic programming is employed to solve an optimal switching data injection attack design problem using the technique of embedded transformation. A bang-bang-type solution of the quadratic programming exists on account of the minimum value of the Hamilton functional and is achieved at an extreme point of the convex set. Consequently, a switching condition is derived to obtain the optimal attack sequence. We also introduce a closed-form switching policy for data injection attacks with multiple objectives, which is shown optimal in the sense of minimizing a hybrid quadratic performance criterion. Finally, applications of our approaches to a networked dc motor and a power system are provided to illustrate the effectiveness of the proposed method. PMID- 29994696 TI - Regularized Gaussian Mixture Model for High-Dimensional Clustering. AB - Finding low-dimensional representation of high-dimensional data sets is an important task in various applications. The fact that data sets often contain clusters embedded in different subspaces poses barrier to this task. Driven by the need in methods that enable clustering and finding each cluster's intrinsic subspace simultaneously, in this paper, we propose a regularized Gaussian mixture model (GMM) for clustering. Despite the advantages of GMM, such as its probabilistic interpretation and robustness against observation noise, traditional maximum-likelihood estimation for GMMs shows disappointing performance in high-dimensional setting. The proposed regularization method finds low-dimensional representations of the component covariance matrices, resulting in better estimation of local feature correlations. The regularization problem can be incorporated in the expectation maximization algorithm for maximizing the likelihood function of a GMM, with the M-step modified to incorporate the regularization. The M-step involves a determinant maximization problem, which can be solved efficiently. The performance of the proposed method is demonstrated using several simulated data sets. We also illustrate the potential value of the proposed method in applications using four real data sets. PMID- 29994697 TI - Matching Larger Image Areas for Unconstrained Face Identification. AB - Many approaches to unconstrained face identification exploit small patches which are unaffected by distortions outside their locality. A larger area usually contains more discriminative information, but may be unidentifiable due to local appearance changes across its area, given limited training data. We propose a novel block-based approach, as a complement to existing patch-based approaches, to exploit the greater discriminative information in larger areas, while maintaining robustness to limited training data. A testing block contains several neighboring patches, each of a small size. We identify the matching training block by jointly estimating all of the matching patches, as a means of reducing the uncertainty of each small matching patch with the addition of the neighboring patch information, without assuming additional training data. We further propose a multiscale extension in which we carry out block-based matching at several block sizes, to combine complementary information across scales for further robustness. We have conducted face identification experiments using three datasets, the constrained Georgia Tech dataset to validate the new approach, and two unconstrained datasets, LFW and UFI, to evaluate its potential for improving robustness. The results show that the new approach is able to significantly improve over existing patch-based face identification approaches, in the presence of uncontrolled pose, expression, and lighting variations, using small training datasets. It is also shown that the new block-based scheme can be combined with existing approaches to further improve performance. PMID- 29994698 TI - Event-Based Practical Output Regulation for a Class of Multiagent Nonlinear Systems. AB - This paper explores a cooperative practical output regulation problem for a class of heterogeneous multiagent nonlinear systems by event-based output feedback. Specifically, we shall restrict our attention to the situation of sampled-data based local measurements. As usual, due to agents heterogeneity, we first convert the problem into a stabilization one for the so-called augmented system, composed of the agent systems and suitably designed continuous-time internal models. Then, we show that this stabilization can be solved by measurement feedback. It finally allows us to establish a valid event-based protocol, leading to a global practical stability property and meanwhile guaranteeing Zeno-free condition. PMID- 29994699 TI - Incremental Hash-Bit Learning for Semantic Image Retrieval in Nonstationary Environments. AB - Images are uploaded to the Internet over time which makes concept drifting and distribution change in semantic classes unavoidable. Current hashing methods being trained using a given static database may not be suitable for nonstationary semantic image retrieval problems. Moreover, directly retraining a whole hash table to update knowledge coming from new arriving image data may not be efficient. Therefore, this paper proposes a new incremental hash-bit learning method. At the arrival of new data, hash bits are selected from both existing and newly trained hash bits by an iterative maximization of a 3-component objective function. This objective function is also used to weight selected hash bits to re rank retrieved images for better semantic image retrieval results. The three components evaluate a hash bit in three different angles: 1) information preservation; 2) partition balancing; and 3) bit angular difference. The proposed method combines knowledge retained from previously trained hash bits and new semantic knowledge learned from the new data by training new hash bits. In comparison to table-based incremental hashing, the proposed method automatically adjusts the number of bits from old data and new data according to the concept drifting in the given data via the maximization of the objective function. Experimental results show that the proposed method outperforms existing stationary hashing methods, table-based incremental hashing, and online hashing methods in 15 different simulated nonstationary data environments. PMID- 29994700 TI - Outlier Detection for Robust Multi-dimensional Scaling. AB - Multi-dimensional scaling (MDS) plays a central role in data-exploration, dimensionality reduction and visualization. State-of-the-art MDS algorithms are not robust to outliers, yielding significant errors in the embedding even when only a handful of outliers are present. In this paper, we introduce a technique to detect and filter outliers based on geometric reasoning. We test the validity of triangles formed by three points, and mark a triangle as broken if its triangle inequality does not hold. The premise of our work is that unlike inliers, outlier distances tend to break many triangles. Our method is tested and its performance is evaluated on various datasets and distributions of outliers. We demonstrate that for a reasonable amount of outliers, e.g., under 20%, our method is effective, and leads to a high embedding quality. PMID- 29994701 TI - Passive Acoustic Mapping Using Data-Adaptive Beamforming Based on Higher Order Statistics. AB - Sources of nonlinear acoustic emissions, particularly those associated with cavitation activity, play a key role in the safety and efficacy of current and emerging therapeutic ultrasound applications, such as oncological drug delivery, blood-brain barrier opening, and histotripsy. Passive acoustic mapping (PAM) is the first technique to enable real-time and non-invasive imaging of cavitation activity during therapeutic ultrasound exposure, through the recording and passive beamforming of broadband acoustic emissions using an array of ultrasound detectors. Initial limitations in PAM spatial resolution led to the adoption of optimal data-adaptive beamforming algorithms, such as the robust capon beamformer (RCB), that provide improved interference suppression and calibration error mitigation compared to non-adaptive beamformers. However, such approaches are restricted by the assumption that the recorded signals have a Gaussian distribution. To overcome this limitation and further improve the source resolvability of PAM, we propose a new beamforming approach termed robust beamforming by linear programming (RLPB). Along with the variance, this optimization-based method uses higher-order-statistics of the recorded signals, making no prior assumption on the statistical distribution of the acoustic signals. The RLPB is found via numerical simulations to improve resolvability over time exposure acoustics and RCB. In vitro experimentation yielded improved resolvability with respect to the source-to-array distance on the order of 22% axially and 13% transversely relative to RCB, whilst successfully accounting for array calibration errors. The improved resolution and decreased dependence on accurate calibration of RLPB is expected to facilitate the clinical translation of PAM for diagnostic, including super-resolution, and therapeutic ultrasound applications. PMID- 29994702 TI - Sparse Range-Constrained Learning and Its Application for Medical Image Grading. AB - Sparse learning has been shown to be effective in solving many real-world problems. Finding sparse representations is a fundamentally important topic in many fields of science including signal processing, computer vision, genome study, and medical imaging. One important issue in applying sparse representation is to find the basis to represent the data, especially in computer vision and medical imaging where the data are not necessary incoherent. In medical imaging, clinicians often grade the severity or measure the risk score of a disease based on images. This process is referred to as medical image grading. Manual grading of the disease severity or risk score is often used. However, it is tedious, subjective, and expensive. Sparse learning has been used for automatic grading of medical images for different diseases. In the grading, we usually begin with one step to find a sparse representation of the testing image using a set of reference images or atoms from the dictionary. Then in the second step, the selected atoms are used as references to compute the grades of the testing images. Since the two steps are conducted sequentially, the objective function in the first step is not necessarily optimized for the second step. In this paper, we propose a novel sparse range-constrained learning (SRCL) algorithm for medical image grading. Different from most of existing sparse learning algorithms, SRCL integrates the objective of finding a sparse representation and that of grading the image into one function. It aims to find a sparse representation of the testing image based on atoms that are most similar in both the data or feature representation and the medical grading scores. We apply the new proposed SRCL to two different applications, namely, cup-to-disc ratio (CDR) computation from retinal fundus images and cataract grading from slit-lamp lens images. Experimental results show that the proposed method is able to improve the accuracy in CDR computation and cataract grading. PMID- 29994703 TI - Doppler-Based Motion Compensation Strategies for 3-D Diverging Wave Compounding and Multiplane-Transmit Beamforming: A Simulation Study. AB - Fast imaging of the heart has shown promise toward bringing new diagnostic information. Although most studies to date have been based on 2-D imaging technology, the ultimate diagnostic tool would enable fast 3-D echocardiography. Hereto, 3-D diverging wave compounding (DWC) and 3-D multiline-transmit (MLT) beamforming have recently been proposed. Moreover, in our recent study, a hybrid technique was proposed in which multiple planar diverging waves were transmitted [i.e., multiplane-transmit (MPT)]. The proposed 3MPT sequence was demonstrated to outperform $9 ?times 9$ DWC and 16MLT-4MLA (i.e., multiline acquisition) while imaging moving targets. However, none of the investigated beamforming techniques made use of motion compensation (MoCo) strategies. In this paper, we therefore propose Doppler-based MoCo strategies for 3-D DWC and MPT and test them via computer simulations. It is demonstrated that the MoCo strategies proposed for both DWC and MPT are effective and significantly restore image quality. Moreover, the MPT beamforming with MoCo outperforms $9 ?times 9$ DWC with MoCo in terms of contrast ratio and contrast-to-noise ratio. The proposed MPT beamforming with MoCo thus provides volumetric images with relatively high temporal resolution (~66 Hz) and high image quality that is minimally affected by motion artifacts. PMID- 29994704 TI - Simultaneous Azimuth and Fresnel Elevation Compounding: A Fast 3-D Imaging Technique for Crossed-Electrode Arrays. AB - We have developed a new, fast, and simple 3-D imaging approach referred to as Simultaneous Azimuth and Fresnel Elevation (SAFE) compounding using a bias sensitive crossed-electrode array. The principle behind this technique is to perform conventional plane-wave compounding with a back set of electrodes, while implementing a reconfigurable Fresnel elevation lens with an orthogonal set of front electrodes. While a Fresnel lens would usually result in unacceptable secondary lobe levels, these lobes can be suppressed by compounding different Fresnel patterns. The azimuthal and elevational planes can be simultaneously compounded to increase the beam quality with no loss in frame rate. A 10-MHz, $64 ?times 64$ element crossed-electrode relaxor array was fabricated on an electrostrictive one-to-three composite substrate to demonstrate the SAFE compounding approach. The electrostrictive composite array has a measured electromechanical coupling coefficient ( $k_{t}$ ) of 0.62 with a bias voltage of 90 V and a measured two-way pulse bandwidth of 60%. The electrical impedance magnitude of array elements on resonance was measured to be $90~?Omega$ with a phase angle of -35 degrees . Radiation patterns were simulated showing a -6-dB beamwidth of $330~?mu ?text{m}$ with secondary lobe levels suppressed more than 60 dB in the azimuth dimension, and a -6-dB beamwidth of $450~?mu ?text{m}$ with secondary lobe levels suppressed to -50 dB in the elevation dimension after 64 compounds. Experimental radiation patterns were collected and found to be in good agreement with simulations. Experimental 3-D images of wire phantoms were collected using a Verasonics experimental ultrasound system. PMID- 29994705 TI - White Rabbit Clock Synchronization: Ultimate Limits on Close-In Phase Noise and Short-Term Stability Due to FPGA Implementation. AB - This paper investigates the ultimate limits of White Rabbit (WR), an high accuracy time distribution system based on field-programmable gate array (FPGA). The knowledge of such limits is essential for new emerging applications that are evaluating WR. In this paper, we identify and study the key elements in the WR synchronization: the digital dual mixer time difference phase detector and the Gigabit Ethernet transceiver. The benchmarks and experimental analysis of these key elements allow us to determine the WR switch (WRS) performance limits and evaluate their evolution with newer FPGAs. The identified performance limits are achievable by the present-day generation of WRS. The ultimate limits of short term synchronization performance due to FPGA implementation have been derived through analysis and then demonstrated using the existing WRS enhanced with an additional daughterboard. This combination (WRS and daughterboard) achieves a tenfold improvement in terms of phase noise, jitter, and short-term stability with respect to the current WR performance. Both phase detectors and Gigabit transceivers have a similar phase noise contribution equal to a short-term stability of modified Allan deviation 4E-13 at $?tau = 1$ s (dominated by flicker phase modulation noise). PMID- 29994706 TI - Assessment of carotid artery plaque components with machine learning classification using homodyned-K parametric maps and elastograms. AB - Quantitative ultrasound (QUS) imaging methods including elastography, echogenicity analysis and speckle statistical modeling are available from a single ultrasound radiofrequency data acquisition. Since these ultrasound imaging methods provide complementary quantitative tissue information, characterization of carotid artery plaques may gain from their combination. Sixty-six patients with symptomatic (n=26) and asymptomatic (n=40) carotid atherosclerotic plaques were included in the study. Of these, 31 underwent magnetic resonance imaging (MRI) to characterize plaque vulnerability and quantify plaque components. Ultrasound radiofrequency data sequence acquisitions were performed on all patients and were used to compute non-invasive vascular ultrasound elastography (NIVE) and other QUS features. Additional QUS features were computed from 3 types of images: homodyned-K (HK) parametric maps, Nakagami parametric maps, and log compressed B-mode images. The following six classification tasks were performed: detection of 1) a small area of lipid; 2) a large area of lipid; 3) a large area of calcification; 4) presence of a ruptured fibrous cap; 5) differentiation of MRI-based classification of non-vulnerable carotid plaques from neovascularized or vulnerable ones; and 6) confirmation of symptomatic versus asymptomatic patients. Feature selection was firstly applied to reduce the number of QUS parameters to a maximum of 3 per classification task. A random forest machine learning algorithm was then used to perform classifications. Areas under receiver operating curves (AUC) were computed with a bootstrap method. For all tasks, statistically significant higher AUCs were achieved with features based on elastography, HK parametric maps and B-mode gray levels, when compared to elastography alone or other QUS alone (p<0.001). For detection of a large area of lipid, the combination yielding the highest AUC (0.90, 95% CI 0.80 - 0.92, p<0.001) was based on elastography, HK and B-mode gray level features. To detect a large area of calcification, the highest AUC (0.95, 95% CI 0.94 - 0.96, p<0.001) was based on HK and B-mode gray level features. For other tasks, AUCs varied between 0.79 and 0.97. None of the best combinations contained Nakagami features. This study shows the added value of combining different features computed from a single ultrasound acquisition with machine learning to characterize carotid artery plaques. PMID- 29994707 TI - Quality Assessment of Screen Content Images via Convolutional-Neural-Network Based Synthetic/Natural Segmentation. AB - The recent popularity of remote desktop software and live streaming of composited video has given rise to a growing number of applications which make use of so called screen content images that contain a mixture of text, graphics, and photographic imagery. Automatic quality assessment (QA) of screen-content images is necessary to enable tasks such as quality monitoring, parameter adaptation, and other optimizations. Although QA of natural images has been heavily researched over the last several decades, QA of screen content images is a relatively new topic. In this paper, we present a QA algorithm, called convolutional neural network (CNN) based screen content image quality estimator (CNN-SQE), which operates via a fuzzy classification of screen content images into plain-text, computergraphics/ cartoons, and natural-image regions. The first two classes are considered to contain synthetic content (text/graphics), and the latter two classes are considered to contain naturalistic content (graphics/photographs), where the overlap of the classes allows the computer graphics/cartoons segments to be analyzed by both text-based and natural-image based features. We present a CNN-based approach for the classification, an edge structurebased quality degradation model, and a region-size-adaptive quality fusion strategy. As we will demonstrate, the proposed CNN-SQE algorithm can achieve better/competitive performance as compared with other state-of-the-art QA algorithms. PMID- 29994708 TI - On GPU Connected Components and Properties: A Systematic Evaluation of Connected Component Labeling Algorithms and Their Extension for Property Extraction. AB - Connected component labeling (CCL) is a fundamental image processing problem that has been studied in many platforms, including GPUs. A common approach to CCL performance analysis is studying the total processing time as a function of abstract image features, like the number of connected components or the fraction of foreground pixels, and input data usually includes synthetic images and segmented video datasets. In this paper, we develop on these ideas and propose an evaluation methodology for GPU CCL algorithms based on synthetic image patterns, addressing the nonexistence of a standard and reliable benchmark in the literature. Our methodology, applied on two important algorithms from existing literature, uncovers their data dependency with great detail, and allows us to model their processing time in three real-world video data sets as functions of abstract, high-level image concepts. We also apply our methodology for studying the memory and performance requirements of two strategies for computing connected component properties: an existing memory-hungry approach, and a new memory preserving strategy. PMID- 29994709 TI - Deep Visual Discomfort Predictor for Stereoscopic 3D Images. AB - Most prior approaches to the problem of stereoscopic 3D (S3D) visual discomfort prediction (VDP) have focused on the extraction of perceptually meaningful handcrafted features based on models of visual perception and of natural depth statistics. Towards advancing performance on this problem, we have developed a deep learning based VDP model named Deep Visual Discomfort Predictor (DeepVDP). DeepVDP uses a convolutional neural network (CNN) to learn features that are highly predictive of experienced visual discomfort. Since a large amount of reference data is needed to train a CNN, we develop a systematic way of dividing S3D image into local regions defined as patches, and model a patch-based CNN using two sequential training steps. Since it is very difficult to obtain human opinions on each patch, instead a proxy ground-truth label that is generated by an existing S3D visual discomfort prediction algorithm called 3D-VDP is assigned to each patch. These proxy ground-truth labels are used to conduct the first stage of training the CNN. In the second stage, the automatically learned local abstractions are aggregated into global features via a feature aggregation layer. The learned features are iteratively updated via supervised learning on subjective 3D discomfort scores, which serve as ground-truth labels on each S3D image. The patchbased CNN model that has been pretrained on proxy groundtruth labels is subsequently retrained on true global subjective scores. The global S3D visual discomfort scores predicted by the trained DeepVDP model achieve state-of the-art performance as compared to previous VDP algorithms. PMID- 29994710 TI - Predicting Human Eye Fixations via an LSTM-based Saliency Attentive Model. AB - Data-driven saliency has recently gained a lot of attention thanks to the use of Convolutional Neural Networks for predicting gaze fixations. In this paper we go beyond standard approaches to saliency prediction, in which gaze maps are computed with a feed-forward network, and present a novel model which can predict accurate saliency maps by incorporating neural attentive mechanisms. The core of our solution is a Convolutional LSTM that focuses on the most salient regions of the input image to iteratively refine the predicted saliency map. Additionally, to tackle the center bias typical of human eye fixations, our model can learn a set of prior maps generated with Gaussian functions. We show, through an extensive evaluation, that the proposed architecture outperforms the current state of the art on public saliency prediction datasets. We further study the contribution of each key component to demonstrate their robustness on different scenarios. PMID- 29994711 TI - A Simple Measure for Acuity in Medical Images. AB - An automatic and objective assessment of image quality is important in an era, where large-scale processing of imaging data from multi-center studies becomes commonplace. Based on a comprehensive statistical image model that includes noise and blur, a measure for image acuity is derived here as the ratio of the maximal gradient magnitude and the intensity difference at a boundary. Acuity may be affected by the object under study, the image acquisition, reconstruction processes, and any post-processing steps. The acuity measure presented here is post-hoc, intuitive to understand, simple to compute, and easily integrates with other standard measures of image quality. Three applications in medical imaging are included where our acuity measure is useful in the objective and automatic assessment of image quality. PMID- 29994712 TI - Discrete Vibro-Tactile Feedback Prevents Object Slippage in Hand Prostheses More Intuitively Than Other Modalities. AB - In the case of a hand amputation, the affected can use myoelectric prostheses to substitute the missing limb and regain motor functionality. Unfortunately, these prostheses do not restore sensory feedback, thus users are forced to rely on vision to avoid object slippage. This is cognitively taxing, as it requires continuous attention to the task. Thus, providing functionally effective sensory feedback is pivotal to reduce the occurrence of slip events and reduce the users' cognitive burden. However, only a few studies investigated which kind of feedback is the most effective for this purpose, mostly using unrealistic experimental scenarios. Here we attempt a more realistic simulation of involuntary hand opening and subsequent recovery of a stable grasp of the slipping object using a robotic hand operated by the subjects through a standard myoelectric control interface. We compared three stimulation modalities (vision, continuous grip force feedback, and discrete slip feedback) and found that the discrete feedback allowed subjects to have higher success rates (close to 100%) in terms of objects recovered from slippage, basically requiring no learning. These results suggest that this simple yet effective feedback can be used to reduce grasp failures in prosthetic users, increasing their confidence in the device. PMID- 29994713 TI - Smartphone Allows Capture of Speech Abnormalities Associated With High Risk of Developing Parkinson's Disease. AB - Although smartphone technology provides new opportunities for the recording of speech samples in everyday life, its ability to capture prodromal speech impairment in persons with a high risk of developing Parkinson's disease (PD) has never been investigated. Speech data were acquired through a smartphone as well as a professional microphone with a linear frequency response from 50 participants with a rapid eye movement sleep behavior disorder that are at a high risk of developing PD and related neurodegenerative disorders. Additionally, recordings of 30 newly diagnosed, untreated PD patients and 30 healthy participants were evaluated. Acoustic assessment of 11 speech dimensions representing the key aspects of hypokinetic dysarthria in the early stages of PD was performed. Smartphone allowed the detection of speech abnormalities in participants with a high risk of developing PD. Acoustic measurements related to fundamental frequency variability, duration of pause intervals, and rate of speech timing extracted from spontaneous speech were sufficiently sensitive to significantly separate groups (area under curve of 0.85 between PD and controls) and showed very strong correlation and reliability between the professional microphone and the smartphone. Speech-based biomarkers collected through smartphones may have the potential to revolutionize the diagnostic process in neurodegenerative diseases and improve stratification for future neuroprotective therapy in PD. PMID- 29994714 TI - Automated Deep Brain Stimulation Programming for Tremor. AB - Deep brain stimulation (DBS) programming, the systematic selection of fixed electrical stimulation parameters that deliver maximal therapeutic benefit while limiting side effects, poses several challenges in the treatment of movement disorders. DBS programming requires the expertise of trained neurologists or nurses who assess patient symptoms according to standardized clinical rating scales and use patient reports of DBS-related side effects to adjust stimulation parameters and optimize therapy. In this paper, we describe and validate an automated software platform for DBS programming for tremor associated with Parkinson's disease and essential tremor. DBS parameters are changed automatically through a direct computer interface with implanted neurostimulators. Each tested DBS setting is ranked according to its effect on tremor, which is assessed using smartwatch inertial measurement unit data, and side effects, which are reported through a user interface. Blinded neurologist assessments showed the automated programming method performed at least as well as clinician mediated programming in selecting the optimal settings for tremor therapy. This proof of concept study describes a novel DBS programming paradigm that may improve programming efficiency and outcomes, increase access to programming outside specialty clinics, and aid in the development of adaptive and closed-loop DBS strategies. PMID- 29994715 TI - Molecular Communication: A Personal Perspective. AB - The authors of this paper have been involved in molecular communication since its conception. They describe their decade-and-a-half long personal journey of the molecular communication research and share their observations and thoughts on how the molecular communication research started and expanded to flourish. The authors also share their thoughts on research challenges that they hope the molecular communication research community addresses in the coming decade. PMID- 29994716 TI - Machine Learning Helps Identify New Drug Mechanisms in Triple-Negative Breast Cancer. AB - This paper demonstrates the ability of mach- ine learning approaches to identify a few genes among the 23,398 genes of the human genome to experiment on in the laboratory to establish new drug mechanisms. As a case study, this paper uses MDA MB-231 breast cancer single-cells treated with the antidiabetic drug metformin. We show that mixture-model-based unsupervised methods with validation from hierarchical clustering can identify single-cell subpopulations (clusters). These clusters are characterized by a small set of genes (1% of the genome) that have significant differential expression across the clusters and are also highly correlated with pathways with anticancer effects driven by metformin. Among the identified small set of genes associated with reduced breast cancer incidence, laboratory experiments on one of the genes, CDC42, showed that its downregulation by metformin inhibited cancer cell migration and proliferation, thus validating the ability of machine learning approaches to identify biologically relevant candidates for laboratory experiments. Given the large size of the human genome and limitations in cost and skilled resources, the broader impact of this work in identifying a small set of differentially expressed genes after drug treatment lies in augmenting the drug-disease knowledge of pharmacogenomics experts in laboratory investigations, which could help establish novel biological mechanisms associated with drug response in diseases beyond breast cancer. PMID- 29994717 TI - Rapid Detection of Tumor Necrosis Factor-Alpha Using Quantum Dot-Based Optical Aptasensor. AB - This paper reports an optical "TURN OFF" aptasensor, which is comprised of a deoxyribonucleic acid aptamer attached to a quantum dot on the terminus and gold nanoparticle on the terminus. The photoluminescence intensity is observed to decrease upon progressive addition of the target protein tumor necrosis factor alpha (TNF- ) to the sensor. For PBS-based TNF- samples, the beacon exhibited 19% 20% quenching at around 22 nM concentration. The photoluminescence intensity and the quenching efficiency showed a linear decrease and a linear increase, respectively, between 0 to 22.3 nM TNF- . The detection limit of the sensor was found to be 97.2 pM. Specificity test results determined that the sensor has higher selectivity toward TNF- than other control proteins such as C-reactive protein, albumin, and transferrin. The beacon successfully detected different concentrations of TNF- in human serum-based samples exhibiting around 10% quenching efficiency at 12.5 nM of the protein. PMID- 29994718 TI - Identification of differentially expressed genes to establish new Biomarker for cancer prediction. AB - The goal of human genome project is to integrate genetic information into different clinical therapies. To achieve this goal different computational algorithms are devised for identifying the biomarker genes, cause of complex diseases. However, most of the methods developed so far using DNA microarray data lack in interpreting biological findings and less accurate in disease prediction. In the paper we propose two parameters and to identify the biologically significant genes for cancer development. First we evaluate of each gene and the genes with nonzero result misclassification of data, therefore removed. Next we calculate of the remaining genes which determines confusion of a gene in prediction due to closeness of the samples in the cancer and normal classes. We apply nondominated sorting genetic algorithm (NSGA-II) to select the maximally uncorrelated differentially expressed genes in the cancer class with minimum . The proposed Gene selection explore (GSE) algorithm is compared to well established feature selection algorithms using ten microarray data with respect to sensitivity, specificity and accuracy. The identified genes appear in KEGG pathway and have several biological importance. PMID- 29994719 TI - Quadrature Synthetic Aperture Beamforming Front-End for Miniaturized Ultrasound Imaging. AB - A quadrature synthetic aperture front-end receiver for B-mode ultrasound imaging is presented. The receiver targets small-scale imaging applications such as capsule endoscopy and low-cost portable devices. System complexity, area, power consumption, and cost are minimized using synthetic aperture beamforming (SAB), whereby signals are processed in a sequential manner using only a single channel. SAB is combined with quadrature (I/Q) sampling, which further reduces the bandwidth and computational load. I/Q demodulation is carried out using a full custom analog front-end (AFE), which comprises a low-noise, variable gain preamplifier, followed by a passive mixer, programmable gain amplifier (PGA) and active lowpass filter. A novel preamplifier design is proposed, with quasi exponential time-gain control and low noise (${?text{5.42 nV}}/?sqrt{?text{Hz}}$ input-referred noise). Overall, the AFE consumes ${?text{7.8 mW}}$ (static power) and occupies ${?text{1.5}}?,?text{mm}?times {?text{1.5}}?,?text{mm}$ in AMS ${?text{0.35}}?,?mu ?text{m}$ CMOS. Real-time SAB is carried out using a Spartan 6 FPGA, which dynamically apodises and focuses the data by interpolating and applying complex phase rotations to the I/Q samples. For a frame rate of ${?text{7}}?,?text{Hz}$ , the power consumption is ${?text{3.4}}?,?text{mW}/?text{channel}$ across an aperture of 64 elements. B mode images were obtained using a database of ultrasound signals ( ${?text{2.5}}?,?text{MHz}$ center frequency) derived from a commercial ultrasound machine. The normalized root mean squared error between the quadrature SAB image and the RF reference image was ${?text{13}}?%$. Image quality/frame rate may be tuned by varying the degree of spatial compounding. PMID- 29994720 TI - Combining Full and Partial Haptic Guidance Improves Handwriting Skills Development. AB - It has been shown in previous studies that haptic guidance improves the learning outcomes of handwriting motor skills. Full and partial haptic guidance are developed and evaluated in the literature. In this paper, we present two experimental studies to examine whether combining full and partial haptic guidance is more effective for improving handwriting skills than merely full or partial guidance methods. Experiment I, with 22 participants, compares the effectiveness of merely full and partial haptic guidance methods towards improving learning outcomes of Arabic handwriting. Even though haptic guidance in general is found to be effective and pleasant by all participants, experiment I concludes that there are no statistically significant differences in the learning outcomes between full and partial haptic guidance. Experiment II investigates whether a combination of full and partial haptic guidance could further improve the learning outcomes, compared to merely full or partial haptic guidance. The learning outcomes and quality of experience are measured to evaluate each group's performance. Results from experiment II demonstrate that the combination of full and partial haptic guidance results in statistically significant improvements in the quality of handwriting, compared to mere full or partial haptic guidance. In particular, starting with partial haptic guidance at early stage of learning and then using full guidance at intermediate/advanced learning stages seemed to be the most effective. This implies that partial haptic guidance is more effective to learn the gross shape of handwriting skills (at early stages of the learning process) whereas full haptic guidance is more effective to learn the fine details of the handwriting skills (at intermediate or advanced stage of learning). Therefore, partial-then-full haptic guidance seems to be the most effective to improve learning outcomes. PMID- 29994721 TI - Hinfinity State Estimation for Discrete-Time Nonlinear Singularly Perturbed Complex Networks Under the Round-Robin Protocol. AB - This paper investigates the Hinfinity state estimation problem for a class of discrete-time nonlinear singularly perturbed complex networks (SPCNs) under the Round-Robin (RR) protocol. A discrete-time nonlinear SPCN model is first devised on two time scales with their discrepancies reflected by a singular perturbation parameter (SPP). The network measurement outputs are transmitted via a communication network where the data transmissions are scheduled by the RR protocol with hope to avoid the undesired data collision. The error dynamics of the state estimation is governed by a switched system with a periodic switching parameter. A novel Lyapunov function is constructed that is dependent on both the transmission order and the SPP. By establishing a key lemma specifically tackling the SPP, sufficient conditions are obtained such that, for any SPP <= a predefined upper bound, the error dynamics of the state estimation is asymptotically stable and satisfies a prescribed Hinfinity performance requirement. Furthermore, the explicit parameterization of the desired state estimator is given by means of the solution to a set of matrix inequalities, and the upper bound of the SPP is then evaluated in the feasibility of these matrix inequalities. Moreover, the corresponding results for linear discrete-time SPCNs are derived as corollaries. A numerical example is given to illustrate the effectiveness of the proposed state estimator design scheme. PMID- 29994722 TI - A New Approach to Stochastic Stability of Markovian Neural Networks With Generalized Transition Rates. AB - This paper investigates the stability problem of Markovian neural networks (MNNs) with time delay. First, to reflect more realistic behaviors, more generalized transition rates are considered for MNNs, where all transition rates of some jumping modes are completely unknown. Second, a new approach, namely time-delay dependent-matrix (TDDM) approach, is proposed for the first time. The TDDM approach is associated with both time delay and its time derivative. Thus, the TDDM approach can fully capture the information of time delay and would play a key role in deriving less conservative results. Third, based on the TDDM approach and applying Wirtinger's inequality and improved reciprocally convex inequality, stability criteria are derived. In comparison with some existing results, our results are not only less conservative but also involve lower calculation complexity. Finally, numerical examples are provided to show the effectiveness and advantages of the proposed results. PMID- 29994723 TI - Semisupervised Learning With Parameter-Free Similarity of Label and Side Information. AB - As for semisupervised learning, both label information and side information serve as pivotal indicators for the classification. Nonetheless, most of related research works utilize either label information or side information instead of exploiting both of them simultaneously. To address the referred defect, we propose a graph-based semisupervised learning (GSL) problem according to both given label information and side information. To solve the GSL problem efficiently, two novel self-weighted strategies are proposed based on solving associated equivalent counterparts of a GSL problem, which can be widely applied to a spectrum of biobjective optimizations. Different from a conventional technique to amalgamate must-link and cannot-link into a single similarity for convenient optimization, we derive a new parameter-free similarity, upon which intrinsic graph and penalty graph can be separately developed. Consequently, a novel semisupervised classification algorithm can be summarized correspondingly with a theoretical analysis. PMID- 29994724 TI - Online Identification of Nonlinear Stochastic Spatiotemporal System With Multiplicative Noise by Robust Optimal Control-Based Kernel Learning Method. AB - In this paper, we propose a novel kernel method for the online identification of stochastic nonlinear spatiotemporal dynamical systems using the robust control approach. By the difference method, the stochastic spatiotemporal (SST) systems driven by multiplicative noise are first transformed into a class of multi-input multi-output-partially linear kernel models (PLKMs) with heterogeneous random terms. With the help of techniques established for reproducing kernel Hilbert space, the online learning problem is reasonably considered as an output feedback control problem for a group of time varying linear dynamical systems. We develop an effective algorithm to address the learning problem of PLKM and SST systems by employing the model predictive control theory. Compared with the existing learning methods, the new one can achieve adaptive, robust, and fast convergent online modeling performance for the spatiotemporal dynamics with multiplicative noise, which greatly facilitates the characterization of physical characteristics of the system. Moreover, this investigation for the first time addresses the learning problems for SST systems with novel robust control techniques, which can provide some novel insights into the design of kernel machine learning methods from the perspective of optimal control theory. Numerical studies for benchmark systems are presented to illustrate the effectiveness and efficiency of our new method. PMID- 29994725 TI - fpgaConvNet: Mapping Regular and Irregular Convolutional Neural Networks on FPGAs. AB - Since neural networks renaissance, convolutional neural networks (ConvNets) have demonstrated a state-of-the-art performance in several emerging artificial intelligence tasks. The deployment of ConvNets in real-life applications requires power-efficient designs that meet the application-level performance needs. In this context, field-programmable gate arrays (FPGAs) can provide a potential platform that can be tailored to application-specific requirements. However, with the complexity of ConvNet models increasing rapidly, the ConvNet-to-FPGA design space becomes prohibitively large. This paper presents fpgaConvNet, an end-to-end framework for the optimized mapping of ConvNets on FPGAs. The proposed framework comprises an automated design methodology based on the synchronous dataflow (SDF) paradigm and defines a set of SDF transformations in order to efficiently navigate the architectural design space. By proposing a systematic multiobjective optimization formulation, the presented framework is able to generate hardware designs that are cooptimized for the ConvNet workload, the target device, and the application's performance metric of interest. Quantitative evaluation shows that the proposed methodology yields hardware designs that improve the performance by up to 6.65$x$ over highly optimized graphics processing unit designs for the same power constraints and achieve up to 2.94$x$ higher performance density compared with the state-of-the-art FPGA-based ConvNet architectures. PMID- 29994726 TI - Adaptive Reinforcement Learning Control Based on Neural Approximation for Nonlinear Discrete-Time Systems With Unknown Nonaffine Dead-Zone Input. AB - In this paper, an optimal control algorithm is designed for uncertain nonlinear systems in discrete-time, which are in nonaffine form and with unknown dead-zone. The main contributions of this paper are that an optimal control algorithm is for the first time framed in this paper for nonlinear systems with nonaffine dead zone, and the adaptive parameter law for dead-zone is calculated by using the gradient rules. The mean value theory is employed to deal with the nonaffine dead zone input and the implicit function theory based on reinforcement learning is appropriately introduced to find an unknown ideal controller which is approximated by using the action network. Other neural networks are taken as the critic networks to approximate the strategic utility functions. Based on the Lyapunov stability analysis theory, we can prove the stability of systems, i.e., the optimal control laws can guarantee that all the signals in the closed-loop system are bounded and the tracking errors are converged to a small compact set. Finally, two simulation examples demonstrate the effectiveness of the design algorithm. PMID- 29994727 TI - Deep Convolutional Identifier for Dynamic Modeling and Adaptive Control of Unmanned Helicopter. AB - Helicopters are complex high-order and time-varying nonlinear systems, strongly coupling with aerodynamic forces, engine dynamics, and other phenomena. Therefore, it is a great challenge to investigate system identification for dynamic modeling and adaptive control for helicopters. In this paper, we address the system identification problem as dynamic regression and propose to represent the uncertainties and the hidden states in the system dynamic model with a deep convolutional neural network. Particularly, the parameters of the network are directly learned from the real flight data of aerobatic helicopter. Since the deep convolutional model has a good performance for describing the dynamic behavior of the hidden states and uncertainties in the flight process, the proposed identifier manifests strong robustness and high accuracy, even for untrained aerobatic maneuvers. The effectiveness of the proposed method is verified by various experiments with the real-world flight data from the Stanford Autonomous Helicopter Project. Consequently, an adaptive flight control scheme including a deep convolutional identifier and a backstepping-based controller is presented. The stability of the flight control scheme is rigorously proved by the Lyapunov theory. It reveals that the tracking errors for both the position and attitude of unmanned helicopter asymptotic converge to a small neighborhood of the origin. PMID- 29994728 TI - Unified Low-Rank Matrix Estimate via Penalized Matrix Least Squares Approximation. AB - Low-rank matrix estimation arises in a number of statistical and machine learning tasks. In particular, the coefficient matrix is considered to have a low-rank structure in multivariate linear regression and multivariate quantile regression. In this paper, we propose a method called penalized matrix least squares approximation (PMLSA) toward a unified yet simple low-rank matrix estimate. Specifically, PMLSA can transform many different types of low-rank matrix estimation problems into their asymptotically equivalent least-squares forms, which can be efficiently solved by a popular matrix fast iterative shrinkage thresholding algorithm. Furthermore, we derive analytic degrees of freedom for PMLSA, with which a Bayesian information criterion (BIC)-type criterion is developed to select the tuning parameters. The estimated rank based on the BIC type criterion is verified to be asymptotically consistent with the true rank under mild conditions. Extensive experimental studies are performed to confirm our assertion. PMID- 29994729 TI - Temporal Self-Organization: A Reaction-Diffusion Framework for Spatiotemporal Memories. AB - Self-organizing maps (SOMs) find numerous applications in learning, clustering, and recalling spatial input patterns. The traditional approach in learning spatiotemporal patterns is to incorporate time on the output space of a SOM along with heuristic update rules that work well in practice. Inspired by the pioneering work of Alan Turing, who used reaction-diffusion equations to explain spatial pattern formation, we develop an analogous theoretical model for a spatiotemporal memory to learn and recall temporal patterns. The contribution of the paper is threefold: 1) using coupled reaction-diffusion equations, we develop a theory from first principles for constructing a spatiotemporal SOM and derive an update rule for learning based on the gradient of a potential function; 2) we analyze the dynamics of our algorithm and derive conditions for optimally setting the model parameters; and 3) we mathematically quantify the temporal plasticity effect observed during recall in response to the input dynamics. The simulation results show that the proposed algorithm outperforms the SOM with temporal activity diffusion, neural gas with temporal activity diffusion and spatiotemporal map formation based on a potential function in the presence of correlated noise for the same data set and similar training conditions. PMID- 29994730 TI - Online Active Learning Ensemble Framework for Drifted Data Streams. AB - In practical applications, data stream classification faces significant challenges, such as high cost of labeling instances and potential concept drifting. We present a new online active learning ensemble framework for drifting data streams based on a hybrid labeling strategy that includes the following: 1) an ensemble classifier, which consists of a long-term stable classifier and multiple dynamic classifiers (a multilevel sliding window model is used to create and update the dynamic classifiers to effectively process both the gradual drift type and sudden drift type data stream) and 2) active learning, which takes a nonfixed labeling budget, supports on-demand request labeling, and adopts an uncertainty strategy and random strategy to label instances. The decision threshold of the uncertainty strategy is adjusted dynamically, i.e., when concept drift occurs, the threshold is gradually reduced to query the most uncertain instances in priority to reduce the request expense as much as possible. Experiments on synthetic and real data sets show that precise prediction accuracy can be obtained by the proposed method without increasing the total cost of labeling, and that the labeling cost can be dynamically allocated according to the concept drift. PMID- 29994731 TI - Variational Bayesian Learning for Dirichlet Process Mixture of Inverted Dirichlet Distributions in Non-Gaussian Image Feature Modeling. AB - In this paper, we develop a novel variational Bayesian learning method for the Dirichlet process (DP) mixture of the inverted Dirichlet distributions, which has been shown to be very flexible for modeling vectors with positive elements. The recently proposed extended variational inference (EVI) framework is adopted to derive an analytically tractable solution. The convergency of the proposed algorithm is theoretically guaranteed by introducing single lower bound approximation to the original objective function in the EVI framework. In principle, the proposed model can be viewed as an infinite inverted Dirichlet mixture model that allows the automatic determination of the number of mixture components from data. Therefore, the problem of predetermining the optimal number of mixing components has been overcome. Moreover, the problems of overfitting and underfitting are avoided by the Bayesian estimation approach. Compared with several recently proposed DP-related methods and conventional applied methods, the good performance and effectiveness of the proposed method have been demonstrated with both synthesized data and real data evaluations. PMID- 29994732 TI - Hierarchical Decision and Control for Continuous Multitarget Problem: Policy Evaluation With Action Delay. AB - This paper proposes a hierarchical decision-making and control algorithm for the shepherd game, the seventh mission in the International Aerial Robotics Competition (IARC). In this game, the agent (a multirotor aerial robot) is required to contact targets (ground vehicles) sequentially and drive them to a certain boundary to earn score. During the game of 10 min, the agent should be fully autonomous without any human interference. Regarding the lower-level controller and dynamics of the agent, each action takes a duration of time to accomplish. Denoted as an action delay, in this paper, this action duration is nonconstant and is related to the final reward. Therefore, the challenging point is making the agent ''aware of time'' when applying a certain action. We solve this problem by two approaches: deep Q-networks and lookup table. The action delay predictor in the decision-level is fitted by a lower-level controller. Through simulations by the example of the shepherd game, the effectiveness and efficiency of this approach are validated. This paper helps our team winning the first prize in IARC 2017, and keeps the best record of this mission since it was released in 2013. PMID- 29994733 TI - Optimization of Distributions Differences for Classification. AB - In this paper, we introduce a new classification algorithm called the optimization of distribution differences (ODD). The algorithm aims to find a transformation from the feature space to a new space where the instances in the same class are as close as possible to one another, whereas the gravity centers of these classes are as far as possible from one another. This aim is formulated as a multiobjective optimization problem that is solved by a hybrid of an evolutionary strategy and the quasi-Newton method. The choice of the transformation function is flexible and could be any continuous space function. We experiment with a linear and a nonlinear transformation in this paper. We show that the algorithm can outperform eight other classification methods, namely naive Bayes, support vector machines, linear discriminant analysis, multilayer perceptrons, decision trees, and k-nearest neighbors, and two recently proposed classification methods, in 12 standard classification data sets. Our results show that the method is less sensitive to the imbalanced number of instances compared with these methods. We also show that ODD maintains its performance better than other classification methods in these data sets and hence offers a better generalization ability. PMID- 29994734 TI - A Column-Row-Parallel Ultrasound Imaging Architecture for 3D Plane-wave Imaging and Tx 2nd-Order Harmonic Distortion (HD2) Reduction. AB - We propose a Column-Row-Parallel imaging frontend architecture for integrated and low-power 3D medical ultrasound imaging. The Column-Row-Parallel architecture offers linear-scaling interconnection, acquisition and programming time with row by-row or column-by-column operations, while supporting volumetric imaging functionality and fault-tolerance against possible transducer element defects with per-element controls. The combination of column-parallel selection logic, row-parallel selection logic, and per-element selection logic reaches a balance between flexible imaging aperture definition and manageable imaging data / control interface to a 2D array. A 16*16 CMUT-ASIC Column-Row-Parallel prototype is fabricated and assembled with a flip-chip bonding process. It facilitates the 3D plane-wave coherent compounding algorithm for volumetric imaging with a fast frame rate of 62.5 Hz and 46% improved lateral resolution with 10-angle compounding and a field of view volume of 2.3mm in both azimuth and elevation, 8.5mm in depth. At a hypothetically scaled up 64x64 array size, the frame rate can still be kept at 31.2 Hz for a volume of 40mm in both azimuth and elevation, 150mm in depth. An interleaved checker board pattern with in-phase (I) and quadrature (Q) excitations is also demonstrated for reducing CMUT second harmonic distortion (HD2) emission by up to 25 dB at the loss of 3 dB fundamental energy reduction. The method reduces nonlinear effects from both transducers and circuits and is a wide band technique that is applicable to arbitrary pulse shapes. PMID- 29994735 TI - Temporally Coherent 3D Point Cloud Video Segmentation in Generic Scenes. AB - Video segmentation is an important building block for high level applications such as scene understanding and interaction analysis. While outstanding results are achieved in this field by state-of-the-art learning and model based methods, they are restricted to certain types of scenes or require a large amount of annotated training data to achieve object segmentation in generic scenes. On the other hand, RGBD data, widely available with the introduction of consumer depth sensors, provides actual world 3D geometry compared to 2D images. The explicit geometry in RGBD data greatly helps in computer vision tasks, but the lack of annotations in this type of data may also hinder the extension of learning based methods to RGBD. In this paper, we present a novel generic segmentation approach for 3D point cloud video (stream data) thoroughly exploiting the explicit geometry in RGBD. Our proposal is only based on low level features, such as connectivity and compactness. We exploit temporal coherence by representing the rough estimation of objects in a single frame with a hierarchical structure, and propagating this hierarchy along time. The hierarchical structure provides an efficient way to establish temporal correspondences at different scales of object connectivity, and to temporally manage the splits and merges of objects. This allows updating the segmentation according to the evidence observed in the history. The proposed method is evaluated on several challenging datasets, with promising results for the presented approach. PMID- 29994736 TI - Using Machine Learning to Improve the Prediction of Functional Outcome in Ischemic Stroke Patients. AB - Ischemic stroke is a leading cause of disability and death worldwide among adults. The individual prognosis after stroke is extremely dependent on treatment decisions physicians take during the acute phase. PMID- 29994737 TI - Semisupervised Negative Correlation Learning. AB - Negative correlation learning (NCL) is an ensemble learning algorithm that introduces a correlation penalty term to the cost function of each individual ensemble member. Each ensemble member minimizes its mean square error and its error correlation with the rest of the ensemble. This paper analyzes NCL and reveals that adopting a negative correlation term for unlabeled data is beneficial to improving the model performance in the semisupervised learning (SSL) setting. We then propose a novel SSL algorithm, Semisupervised NCL (SemiNCL) algorithm. The algorithm considers the negative correlation terms for both labeled and unlabeled data for the semisupervised problems. In order to reduce the computational and memory complexity, an accelerated SemiNCL is derived from the distributed least square algorithm. In addition, we have derived a bound for two parameters in SemiNCL based on an analysis of the Hessian matrix of the error function. The new algorithm is evaluated by extensive experiments with various ratios of labeled and unlabeled training data. Comparisons with other state-of-the-art supervised and semisupervised algorithms confirm that SemiNCL achieves the best overall performance. PMID- 29994738 TI - A Generalized Model for Robust Tensor Factorization With Noise Modeling by Mixture of Gaussians. AB - The low-rank tensor factorization (LRTF) technique has received increasing attention in many computer vision applications. Compared with the traditional matrix factorization technique, it can better preserve the intrinsic structure information and thus has a better low-dimensional subspace recovery performance. Basically, the desired low-rank tensor is recovered by minimizing the least square loss between the input data and its factorized representation. Since the least square loss is most optimal when the noise follows a Gaussian distribution, -norm-based methods are designed to deal with outliers. Unfortunately, they may lose their effectiveness when dealing with real data, which are often contaminated by complex noise. In this paper, we consider integrating the noise modeling technique into a generalized weighted LRTF (GWLRTF) procedure. This procedure treats the original issue as an LRTF problem and models the noise using a mixture of Gaussians (MoG), a procedure called MoG GWLRTF. To extend the applicability of the model, two typical tensor factorization operations, i.e., CANDECOMP/PARAFAC factorization and Tucker factorization, are incorporated into the LRTF procedure. Its parameters are updated under the expectation-maximization framework. Extensive experiments indicate the respective advantages of these two versions of MoG GWLRTF in various applications and also demonstrate their effectiveness compared with other competing methods. PMID- 29994739 TI - Multistability Analysis of Quaternion-Valued Neural Networks With Time Delays. AB - This paper addresses the multistability issue for quaternion-valued neural networks (QVNNs) with time delays. By using the inequality technique, sufficient conditions are proposed for the boundedness and the global attractivity of delayed QVNNs. Based on the geometrical properties of the activation functions, several criteria are obtained to ensure the existence of equilibrium points, of which are locally stable. Two numerical examples are provided to illustrate the effectiveness of the obtained results. PMID- 29994740 TI - Learning Rates of Regularized Regression With Multiple Gaussian Kernels for Multi Task Learning. AB - This paper considers a least square regularized regression algorithm for multi task learning in a union of reproducing kernel Hilbert spaces (RKHSs) with Gaussian kernels. It is assumed that the optimal prediction function of the target task and those of related tasks are in an RKHS with the same but with unknown Gaussian kernel width. The samples for related tasks are used to select the Gaussian kernel width, and the sample for the target task is used to obtain the prediction function in the RKHS with this selected width. With an error decomposition result, a fast learning rate is obtained for the target task. The key step is to estimate the sample errors of related tasks in the union of RKHSs with Gaussian kernels. The utility of this algorithm is illustrated with one simulated data set and four real data sets. The experiment results illustrate that the underlying algorithm can result in significant improvements in prediction error when few samples of the target task and more samples of related tasks are available. PMID- 29994741 TI - A Neural Controller for Image-Based Visual Servoing of Manipulators With Physical Constraints. AB - Main issues in visual servoing of manipulators mainly include rapid convergence of feature errors to zero and the safety of joints regarding joint physical limits. To address the two issues, in this paper, an image-based visual servoing scheme is proposed for manipulators with an eye-in-hand configuration. Compared with existing schemes, the proposed one does not require performing pseudoinversion for the image Jacobian matrix or inversion for the Jacobian matrix associated with the forward kinematics of the manipulators. Theoretical analysis shows that the proposed scheme not only guarantees the asymptotic convergence of feature errors to zero but also the compliance with joint angle and velocity limits of the manipulators. Besides, simulation results based on a PUMA560 manipulator with a camera mounted on the end effector verify the theoretical conclusions and the efficacy of the proposed scheme. PMID- 29994742 TI - Kalman smoothing for objective and automatic preprocessing of glucose data. AB - A method for preprocessing a time series of glucose measurements based on Kalman smoothing is presented. Given a glucose data time series that may be irregularly sampled, the method outputs an interpolated time series of glucose estimates with mean and variance. The method can provide homogenization of glucose data collected from different devices by using separate measurement noise parameters for differing glucose measurement equipment. We establish a link between the ISO 15197 standard and the measurement noise variance used by the Kalman smoother for Self Monitoring of Blood Glucose (SMBG) measurements. The method provides phaseless smoothing, and it can automatically correct errors in the original datasets like small fallouts and erroneous readings when surrounding data allows. The estimated variance can be used for deciding at which times the data are trustworthy. The method can be used as a preprocessing step in many kinds of glucose data processing and analysis tasks, such as computing the Mean Absolute Relative Deviation (MARD) between measurement systems, or estimating the plasma to-interstital fluid glucose dynamics of continuous glucose monitor (CGM) or Flash Glucose Monitor (FGM) signals. The method is demonstrated on SMBG and FGM glucose data from a clinical study. PMID- 29994743 TI - Low-Rank Preserving Projection Via Graph Regularized Reconstruction. AB - Preserving global and local structures during projection learning is very important for feature extraction. Although various methods have been proposed for this goal, they commonly introduce an extra graph regularization term and the corresponding regularization parameter that needs to be tuned. However, tuning the parameter manually not only is time-consuming, but also is difficult to find the optimal value to obtain a satisfactory performance. This greatly limits their applications. Besides, projections learned by many methods do not have good interpretability and their performances are commonly sensitive to the value of the selected feature dimension. To solve the above problems, a novel method named low-rank preserving projection via graph regularized reconstruction (LRPP_GRR) is proposed. In particular, LRPP_GRR imposes the graph constraint on the reconstruction error of data instead of introducing the extra regularization term to capture the local structure of data, which can greatly reduce the complexity of the model. Meanwhile, a low-rank reconstruction term is exploited to preserve the global structure of data. To improve the interpretability of the learned projection, a sparse term with l2,1 norm is imposed on the projection. Furthermore, we introduce an orthogonal reconstruction constraint to make the learned projection hold main energy of data, which enables LRPP_GRR to be more flexible in the selection of feature dimension. Extensive experimental results show the proposed method can obtain competitive performance with other state-of the-art methods. PMID- 29994744 TI - Differential Evolution With Underestimation-Based Multimutation Strategy. AB - As we know, the performance of differential evolution (DE) highly depends on the mutation strategy. However, it is difficult to choose a suitable mutation strategy for a specific problem or different running stages. This paper proposes an underestimation-based multimutation strategy (UMS) for DE. In the UMS, a set of candidate offsprings are simultaneously generated for each target individual by utilizing multiple mutation strategies. Then a cheap abstract convex underestimation model is built based on some selected individuals to obtain the underestimation value of each candidate offspring. According to the quality of each candidate offspring measured by the underestimation value, the most promising candidate solution is chosen as the offspring. Compared to the existing probability-based multimutation techniques, no mutation strategies are lost during the search process as each mutation strategy has the same probability to generate a candidate solution. Moreover, no extra function evaluations are produced because the candidate solutions are filtered by the underestimation value. The UMS is integrated into some DE variants and compared with their original algorithms and several advanced DE approaches over the CEC 2013 and 2014 benchmark sets. Additionally, a well-known real-world problem is employed to evaluate the performance of the UMS. Experimental results show that the proposed UMS can improve the performance of the advanced DE variants. PMID- 29994745 TI - Approximating Dunn's Cluster Validity Indices for Partitions of Big Data. AB - Dunn's internal cluster validity index is used to assess partition quality and subsequently identify a ''best'' crisp partition of n objects. Computing Dunn's index (DI) for partitions of n p-dimensional feature vector data has quadratic time complexity O(pn2), so its computation is impractical for very large values of n. This note presents six methods for approximating DI. Four methods are based on Maximin sampling, which identifies a skeleton of the full partition that contains some boundary points in each cluster. Two additional methods are presented that estimate boundary points associated with unsupervised training of one class support vector machines. Numerical examples compare approximations to DI based on all six methods. Four experiments on seven real and synthetic data sets support our assertion that computing approximations to DI with an incremental, neighborhood-based Maximin skeleton is both tractable and reliably accurate. PMID- 29994746 TI - Multi Line Transmit Beamforming Combined With Adaptive Apodization. AB - Increased frame rate is of high importance to cardiac diagnostic imaging as it enables examination of fast events during the cardiac cycle and improved quantitative analysis, such as speckle tracking. Multi-line transmission (MLT) is one of the methods proposed for this purpose. In contrast to the single-line transmission (SLT), where one focused beam is sent in each direction, MLT beams are simultaneously transmitted and focused in several (2,4,6..) directions improving the framerate accordingly. The simultaneous transmission is known to cause cross-talk artifacts due to the interference between the main-lobes and the side-lobes of the transmitted and received beams. Usually, the artifacts are attenuated using a Tukey window apodization, but the lateral resolution is degraded. Several other methods, such as minimum variance beamforming and filtered delay multiply and sum beamforming were proposed to deal with these artifacts.The assumption examined in this study is that a receive apodization can be chosen adaptively from a number of apodization windows in order to provide better artifact rejection and to increase the spatial resolution. The entire study was performed on experimental MLT dataset including wire and tissue mimicking phantoms, as well as in vivo cardiac data. The results demonstrate that application of a predefined apodization bank outperforms Tukey windowing alone, in terms of both resolution and receive crosstalk artifact rejection. Moreover, the achieved spatial resolution is superior to the non-apodized SLT, as measured from wire phantoms. The proposed method can also be combined with wider transmit beams, suitable for multi line acquisition. PMID- 29994747 TI - Learning a Deep Single Image Contrast Enhancer from Multi-Exposure Images. AB - Due to the poor lighting condition and limited dynamic range of digital imaging devices, the recorded images are often under-/over-exposed and with low contrast. Most of previous single image contrast enhancement (SICE) methods adjust the tone curve to correct the contrast of an input image. Those methods, however, often fail in revealing image details because of the limited information in a single image. On the other hand, the SICE task can be better accomplished if we can learn extra information from appropriately collected training data. In this work, we propose to use the convolutional neural network (CNN) to train a SICE enhancer. One key issue is how to construct a training dataset of low-contrast and high-contrast image pairs for end-to-end CNN learning. To this end, we build a large-scale multi-exposure image dataset, which contains 589 elaborately selected high-resolution multi-exposure sequences with 4,413 images. Thirteen representative multi-exposure image fusion and stack-based high dynamic range imaging algorithms are employed to generate the contrast enhanced images for each sequence, and subjective experiments are conducted to screen the best quality one as the reference image of each scene. With the constructed dataset, a CNN can be easily trained as the SICE enhancer to improve the contrast of an under-/over exposure image. Experimental results demonstrate the advantages of our method over existing SICE methods with a significant margin. PMID- 29994748 TI - Midair Ultrasound Fragrance Rendering. AB - We propose a system that controls the spatial distribution of odors in an environment by generating electronically steerable ultrasound-driven narrow air flows. The proposed system is designed not only to remotely present a preset fragrance to a user, but also to provide applications that would be conventionally inconceivable, such as: 1) fetching the odor of a generic object placed at a location remote from the user and guiding it to his or her nostrils, or 2) nullifying the odor of an object near a user by carrying it away before it reaches his or her nostrils (Fig. 1). These are all accomplished with an ultrasound-driven air stream serving as an airborne carrier of fragrant substances. The flow originates from a point in midair located away from the ultrasound source and travels while accelerating and maintaining its narrow cross sectional area. These properties differentiate the flow from conventional jet- or fan-driven flows and contribute to achieving a midair flow. In our system, we employed a phased array of ultrasound transducers so that the traveling direction of the flow could be electronically and instantaneously controlled. In this paper, we describe the physical principle of odor control, the system construction, and experiments conducted to evaluate remote fragrance presentation and fragrance tracking. PMID- 29994749 TI - Prediction of Hot Regions in PPIs Based on Improved Local Community Structure Detecting. AB - The hot regions in PPIs are some assembly regions which are composed of the tightly packed HotSpots. The discovery of hot regions helps to understand life activities and has very important value for biological applications. The identification of hot regions is the basis for protein design and cancer prevention. The existing algorithms of predicting hot regions often have some defects, such as low accuracy and unstability. This paper proposes a novel hot region prediction method based on diverse biological characteristics. First, feature evaluation is employed by using an impoved mRMR method. Then, SVM is adopted to create cassification model based on the features selected. In addition, a new clustering algorithm, namely LCSD (Local community structure detecting), is developed to detect and analyze the conformation of hot regions. In the clustering process, the link similarity of protein residues is introduced to handle the boundary nodes. This algorithm can effectively deal with the missing residue nodes and control the local community boundaries. The results indicate that the spatial structure of hot regions can be obtained more effectively, and that our method is more effective than previous methods for precise identification of hot regions. PMID- 29994750 TI - On the Generalization Ability of Online Gradient Descent Algorithm Under the Quadratic Growth Condition. AB - Online learning has been successfully applied in various machine learning problems. Conventional analysis of online learning achieves a sharp generalization bound with a strongly convex assumption. In this paper, we study the generalization ability of the classic online gradient descent algorithm under the quadratic growth condition (QGC), a strictly weaker condition than strong convexity. Under some mild assumptions, we prove that the excess risk converges no worse than $O(?log T/T)$ when the data are independently and identically distributed (i.i.d.). When the data are generated from a $?phi $ -mixing process, we achieve the excess risk bound $O(?log T /T+?phi (?tau))$ , where $?phi (?tau)$ is the mixing coefficient capturing the non-i.i.d. attribute. Our key technique is based on the combination of the QGC and the martingale concentrations. Our results indicate that the strong convexity is not necessary to achieve the sharp $O(?log {T}/T)$ convergence rate in online learning. We verify our theories on both synthetic and real-world data. PMID- 29994751 TI - Containment Control of Linear Multiagent Systems With Aperiodic Sampling and Measurement Size Reduction. AB - The containment control problem for generally linear multiagent systems with aperiodic sampling intervals and measurement size reduction is considered in this paper. Under the assumption that the sampling interval changes from a finite set, an improved protocol is proposed, such that a larger sampling interval can be obtained to achieve containment. By using the properties of Laplacian matrix and the newly developed protocol, the containment control problem is transformed into the stability problem of a discrete-time switched linear system. A sufficient condition is obtained that ensures all the followers converge to the convex hull formed by the state of leaders, and such a sufficient condition is presented in terms of linear matrix inequalities, which are independent of the node of network. To further reduce the communication among agents, a switching-type measurement size reduction scheme is introduced. An optimization problem is proposed for the corresponding controller design. Finally, two simulation studies are conducted to show the effectiveness and advantage of the proposed control algorithms. PMID- 29994752 TI - Spatial and Temporal Downsampling in Event-Based Visual Classification. AB - As the interest in event-based vision sensors for mobile and aerial applications grows, there is an increasing need for high-speed and highly robust algorithms for performing visual tasks using event-based data. As event rate and network structure have a direct impact on the power consumed by such systems, it is important to explore the efficiency of the event-based encoding used by these sensors. The work presented in this paper represents the first study solely focused on the effects of both spatial and temporal downsampling on event-based vision data and makes use of a variety of data sets chosen to fully explore and characterize the nature of downsampling operations. The results show that both spatial downsampling and temporal downsampling produce improved classification accuracy and, additionally, a lower overall data rate. A finding is particularly relevant for bandwidth and power constrained systems. For a given network containing 1000 hidden layer neurons, the spatially downsampled systems achieved a best case accuracy of 89.38% on N-MNIST as opposed to 81.03% with no downsampling at the same hidden layer size. On the N-Caltech101 data set, the downsampled system achieved a best case accuracy of 18.25%, compared with 7.43% achieved with no downsampling. The results show that downsampling is an important preprocessing technique in event-based visual processing, especially for applications sensitive to power consumption and transmission bandwidth. PMID- 29994753 TI - Frame-Based Variational Bayesian Learning for Independent or Dependent Source Separation. AB - Variational Bayesian (VB) learning has been successfully applied to instantaneous blind source separation. However, the traditional VB learning is restricted to the separation of independent source signals. Moreover, it has the difficulty to recover source signals with a sizable number of samples because of its rapidly increasing computational requirement. To overcome such shortcomings, frame-based VB (FVB) learning is proposed to address both independent and dependent source separation with a large number of samples in this paper. Specifically, a Gaussian process (GP) is employed to model independent or dependent source signals. To our knowledge, GP has been only used to model each of independent source signals. For dependent source signals, this paper proposes a novel modeling process: initial source signals are zigzag concatenated into a long serial and GP is then used to model it. In order to obtain a reliable covariance function for GP, first, we apply singular value decomposition to give initial estimated source signals and then we select an appropriate covariance function with which GP can perfectly fit them. In order to alleviate the computational burden of VB learning, we split observed signals into frames, and then model and infer source signals for each frame. Compared with the state-of-the-art algorithms, the experimental results show that the FVB learning has potential to provide improvement in separation performance not only for independent source signals but also for dependent ones, especially for long data records. PMID- 29994754 TI - Modified Sparse Linear-Discriminant Analysis via Nonconvex Penalties. AB - This paper considers the linear-discriminant analysis (LDA) problem in the undersampled situation, in which the number of features is very large and the number of observations is limited. Sparsity is often incorporated in the solution of LDA to make a well interpretation of the results. However, most of the existing sparse LDA algorithms pursue sparsity by means of the $?ell _{1}$ -norm. In this paper, we give elaborate analysis for nonconvex penalties, including the $?ell _{0}$ -based and the sorted $?ell _{1}$ -based LDA methods. The latter one can be regarded as a bridge between the $?ell _{0}$ and $?ell _{1}$ penalties. These nonconvex penalty-based LDA algorithms are evaluated on the gene expression array and face database, showing high classification accuracy on real-world problems. PMID- 29994755 TI - Matrix-Regularized Multiple Kernel Learning via (r,p) Norms. AB - This paper examines a matrix-regularized multiple kernel learning (MKL) technique based on a notion of (r,p) norms. For the problem of learning a linear combination in the support vector machine-based framework, model complexity is typically controlled using various regularization strategies on the combined kernel weights. Recent research has developed a generalized lp-norm MKL framework with tunable variable p(p>=1) to support controlled intrinsic sparsity. Unfortunately, this ''1-D'' vector lp-norm hardly exploits potentially useful information on how the base kernels ''interact.'' To allow for higher order kernel-pair relationships, we extend the ''1-D'' vector lp-MKL to the ''2-D'' matrix (r,p) norms (1 <= r,p < infinity). We develop a new formulation and an efficient optimization strategy for (r,p)-MKL with guaranteed convergence. A theoretical analysis and experiments on seven UCI data sets shed light on the superiority of (r,p)-MKL over lp-MKL in various scenarios. PMID- 29994756 TI - Stochastic Training of Neural Networks via Successive Convex Approximations. AB - This paper proposes a new family of algorithms for training neural networks (NNs). These are based on recent developments in the field of nonconvex optimization, going under the general name of successive convex approximation techniques. The basic idea is to iteratively replace the original (nonconvex, highly dimensional) learning problem with a sequence of (strongly convex) approximations, which are both accurate and simple to optimize. Different from similar ideas (e.g., quasi-Newton algorithms), the approximations can be constructed using only first-order information of the NN function, in a stochastic fashion, while exploiting the overall structure of the learning problem for a faster convergence. We discuss several use cases, based on different choices for the loss function (e.g., squared loss and cross-entropy loss), and for the regularization of the NN's weights. We experiment on several medium-sized benchmark problems and on a large-scale data set involving simulated physical data. The results show how the algorithm outperforms the state-of-the art techniques, providing faster convergence to a better minimum. Additionally, we show how the algorithm can be easily parallelized over multiple computational units without hindering its performance. In particular, each computational unit can optimize a tailored surrogate function defined on a randomly assigned subset of the input variables, whose dimension can be selected depending entirely on the available computational power. PMID- 29994757 TI - Feature Selection With $?ell_{2,1-2}$ Regularization. AB - Feature selection aims to select a subset of features from high-dimensional data according to a predefined selecting criterion. Sparse learning has been proven to be a powerful technique in feature selection. Sparse regularizer, as a key component of sparse learning, has been studied for several years. Although convex regularizers have been used in many works, there are some cases where nonconvex regularizers outperform convex regularizers. To make the process of selecting relevant features more effective, we propose a novel nonconvex sparse metric on matrices as the sparsity regularization in this paper. The new nonconvex regularizer could be written as the difference of the $?ell _{2,1}$ norm and the Frobenius ( $?ell _{2,2}$ ) norm, which is named the $?ell _{2,1-2}$ . To find the solution of the resulting nonconvex formula, we design an iterative algorithm in the framework of ConCave-Convex Procedure (CCCP) and prove its strong global convergence. An adopted alternating direction method of multipliers is embedded to solve the sequence of convex subproblems in CCCP efficiently. Using the scaled cluster indictors of data points as pseudolabels, we also apply $?ell _{2,1-2}$ to the unsupervised case. To the best of our knowledge, it is the first work considering nonconvex regularization for matrices in the unsupervised learning scenario. Numerical experiments are performed on real-world data sets to demonstrate the effectiveness of the proposed method. PMID- 29994758 TI - Left Atrial Appendage Segmentation Using Fully Convolutional Neural Networks and Modified Three-Dimensional Conditional Random Fields. AB - Thrombosis has become a global disease threatening human health. The left atrial appendage (LAA) is a major source of thrombosis in patients with atrial fibrillation (AF). Positive correlation exists between LAA volume and AF risk. LAA morphology has been suggested to influence thromboembolic risk in AF patients and to help predict thromboembolic events in low-risk patient groups. Automatic segmentation of LAA can greatly help physicians diagnose AF. In consideration of the large anatomical variations of the LAA, we proposed a robust method for automatic LAA segmentation on computed tomographic angiography (CTA) data using fully convolutional neural networks with three-dimensional (3-D) conditional random fields (CRFs). After manual localization of ROI of LAA, we adopted the FCN in natural image segmentation and transferred their learned models by fine-tuning the networks to segment each 2-D LAA slice. Subsequently, we used a modified dense 3-D CRF that accounts for the 3-D spatial information and larger contextual information to refine the segmentations of all slices. Our method was evaluated on 150 sets of CTA data using five-fold cross validation. Compared with manual annotation, we obtained a mean dice overlap of and a mean volume overlap of with a computation time of less than 40 s per volume. Experimental results demonstrated the robustness of our method in dealing with large anatomical variations and computational efficiency for adoption in a daily clinical routine.). PMID- 29994759 TI - Super-Fine Attributes with Crowd Prototyping. AB - Recognising human attributes from surveillance footage is widely studied for attribute-based re-identification. However, most works assume coarse, expertly defined categories, ineffective in describing challenging images. Such brittle representations are limited in descriminitive power and hamper the efficacy of learnt estimators. We aim to discover more relevant and precise subject descriptions, improving image retrieval and closing the semantic gap. Inspired by fine-grained and relative attributes, we introduce super-fine attributes, which now describe multiple, integral concepts of a single trait as multi-dimensional perceptual coordinates. Crowd prototyping facilitates efficient crowdsourcing of super-fine labels by pre-discovering salient perceptual concepts for prototype matching. We re-annotate gender, age and ethnicity traits from PETA, a highly diverse (19K instances, 8.7K identities) amalgamation of 10 re-id datasets including VIPER, CUHK and TownCentre. Employing joint attribute regression with the ResNet-152 CNN, we demonstrate substantially improved ranked retrieval performance with super-fine attributes in direct comparison to conventional binary labels, reporting up to a 11.2% and 14.8% mAP improvement for gender and age, further surpassed by ethnicity. We also find our 3 super-fine traits to outperform 35 binary attributes by 6.5% mAP for subject retrieval in a challenging zero-shot identification scenario. PMID- 29994760 TI - Simultaneous Estimation of Corneal Topography, Pachymetry, and Curvature. AB - Identification of objective criteria to correctly diagnose ectatic diseases of the cornea or to detect early stages of corneal ectasia is of great interest in ophthalmology and optometry. Metrics for diagnosis typically employed are curvature maps (axial/sagittal, tangential); elevation map of the anterior surface of the cornea with respect to a reference sphere; and pachymetry (thickness) map of the cornea. We present evidence that currently used curvature maps do not represent the actual curvatures (principal or mean) in a human cornea. A novel contribution of this paper is the computation of the true mean curvature over every point of a central region of the cornea. We show that the true mean curvature can accurately identify the location of the ectasia. We present a quartic smoothing spline algorithm for the simultaneous computation of elevation maps for anterior and posterior corneal surfaces, pachymetry, and true mean curvature. The input to the algorithm is data from a single measurement from imaging devices such as an anterior segment optical coherence tomographer or a Scheimpflug imager. We show that a different combination of metrics is useful for the diagnosis of existing ectasia (true mean curvature and anterior elevation map) as opposed to subclinical ectasia (pachymetry and posterior elevation map). We compare our results with existing algorithms, and present applications to a normal cornea, a forme fruste keratoconic cornea, and an advanced keratoconic cornea. PMID- 29994761 TI - A Stacked Sparse Autoencoder-Based Detector for Automatic Identification of Neuromagnetic High Frequency Oscillations in Epilepsy. AB - High-frequency oscillations (HFOs) are spontaneous magnetoencephalography (MEG) patterns that have been acknowledged as a putative biomarker to identify epileptic foci. Correct detection of HFOs in the MEG signals is crucial for the accurate and timely clinical evaluation. Since the visual examination of HFOs is time-consuming, error-prone, and with poor inter-reviewer reliability, an automatic HFOs detector is highly desirable in clinical practice. However, the existing approaches for HFOs detection may not be applicable for MEG signals with noisy background activity. Therefore, we employ the stacked sparse autoencoder (SSAE) and propose an SSAE-based MEG HFOs (SMO) detector to facilitate the clinical detection of HFOs. To the best of our knowledge, this is the first attempt to conduct HFOs detection in MEG using deep learning methods. After configuration optimization, our proposed SMO detector is outperformed other classic peer models by achieving 89.9% in accuracy, 88.2% in sensitivity, and 91.6% in specificity. Furthermore, we have tested the performance consistency of our model using various validation schemes. The distribution of performance metrics demonstrates that our model can achieve steady performance. PMID- 29994762 TI - A Monte Carlo Model of a Benchtop X-Ray Fluorescence Computed Tomography System and Its Application to Validate a Deconvolution-Based X-Ray Fluorescence Signal Extraction Method. AB - In this study, we developed and validated a Geant4-based Monte Carlo (MC) model of an experimental benchtop X-ray fluorescence (XRF) computed tomography (XFCT) system for quantitative imaging of metallic nanoparticles such as gold nanoparticles (GNPs) injected into small animals for preclinical testing of various NP-based diagnostic and therapeutic approaches. Detailed hardware components of the current benchtop XFCT system, including the X-ray source, excitation beam collimation and filtration, custom imaging phantoms with GNP solutions, and single/ring/linear array detectors with custom collimation, were incorporated into the MC model. In conjunction with a known CdTe detector response function, a deconvolution-based XRF signal extraction method was also developed in this study, which enabled complete separation of gold K-shell XRF peaks even when they almost overlapped and facilitated extraction of XRF signals from a broadband Compton scattered photon background. The extracted signal-to background ratios were comparable with those expected using an ideal detector with high enough energy resolution (e.g., 0.1 keV full-width at half-maximum). Once convoluted with the CdTe detector response function, the MC-calculated spectra for excitation beams or emitted photons and XFCT image spatial resolutions agreed well with those measured experimentally. Thus, the current MC model can be used to optimize the beam/imaging parameters (e.g., beam geometry, excitation X-ray beam energy, and X-ray filter material) as well as the design of critical hardware components (e.g., detector collimators) within the current benchtop XFCT system. Also, the current XRF signal extraction method can relax the usual stringent requirement of detector energy resolution while not degrading the sensitivity of benchtop XFCT. PMID- 29994763 TI - Detecting and Locating Gastrointestinal Anomalies Using Deep Learning and Iterative Cluster Unification. AB - This paper proposes a novel methodology for automatic detection and localization of gastrointestinal (GI) anomalies in endoscopic video frame sequences. Training is performed with weakly annotated images, using only image-level, semantic labels instead of detailed, and pixel-level annotations. This makes it a cost effective approach for the analysis of large videoendoscopy repositories. Other advantages of the proposed methodology include its capability to suggest possible locations of GI anomalies within the video frames, and its generality, in the sense that abnormal frame detection is based on automatically derived image features. It is implemented in three phases: 1) it classifies the video frames into abnormal or normal using a weakly supervised convolutional neural network (WCNN) architecture; 2) detects salient points from deeper WCNN layers, using a deep saliency detection algorithm; and 3) localizes GI anomalies using an iterative cluster unification (ICU) algorithm. ICU is based on a pointwise cross feature-map (PCFM) descriptor extracted locally from the detected salient points using information derived from the WCNN. Results, from extensive experimentation using publicly available collections of gastrointestinal endoscopy video frames, are presented. The data sets used include a variety of GI anomalies. Both anomaly detection and localization performance achieved, in terms of the area under receiver operating characteristic (AUC), were >80%. The highest AUC for anomaly detection was obtained on conventional gastroscopy images, reaching 96%, and the highest AUC for anomaly localization was obtained on wireless capsule endoscopy images, reaching 88%. PMID- 29994764 TI - Disc-Aware Ensemble Network for Glaucoma Screening From Fundus Image. AB - Glaucoma is a chronic eye disease that leads to irreversible vision loss. Most of the existing automatic screening methods first segment the main structure and subsequently calculate the clinical measurement for the detection and screening of glaucoma. However, these measurement-based methods rely heavily on the segmentation accuracy and ignore various visual features. In this paper, we introduce a deep learning technique to gain additional image-relevant information and screen glaucoma from the fundus image directly. Specifically, a novel disc aware ensemble network for automatic glaucoma screening is proposed, which integrates the deep hierarchical context of the global fundus image and the local optic disc region. Four deep streams on different levels and modules are, respectively, considered as global image stream, segmentation-guided network, local disc region stream, and disc polar transformation stream. Finally, the output probabilities of different streams are fused as the final screening result. The experiments on two glaucoma data sets (SCES and new SINDI data sets) show that our method outperforms other state-of-the-art algorithms. PMID- 29994765 TI - The Signal Projection Method: A General Approach to Active Imaging With Arrays. AB - Using a generic model of how active array imaging systems operate, a formal definition of the image as a projection of the reflected wave field onto the wave field emitted to probe the medium is proposed. This definition is applied to the case of imaging in homogeneous and isotropic media to which, by using the frequency-domain solution of the wave equation, the relationship between the calculated image, the emitted and received signals, the positions of the transducers, the speed of the waves used, and the reflectivity of the medium is shown at each point. Then, a general algorithm for the formation of images of a region in this kind of media is derived. Finally, using real and simulated ultrasound signals, images obtained with the proposed signal projection method are compared with those produced by the "de facto" standard delay and sum-based algorithms. PMID- 29994766 TI - Fourier Domain Depth Migration for Plane-Wave Ultrasound Imaging. AB - Plane-wave (PW) ultrasound imaging allows for ultrafast image acquisition rates, thus enabling new biomedical applications, such as ultrasound-based blood flow and tissue motion characterization. We propose two novel Fourier domain techniques for PW ultrasound image reconstruction that can be used as an alternative to conventional delay-and-sum beamforming. In particular, we show how to modify two classic algorithms used for geophysical data processing (namely, Stolt's and slant-stack depth migration under zero-offset constant-velocity assumptions), so that their new versions can be used for PW ultrasound data processing. To demonstrate the merits and limitations of our approach, we provide qualitative and quantitative comparisons with other Fourier domain methods reported in the ultrasound literature. Our evaluation results are based on the image resolution, contrast, and similarity metrics obtained for several public domain experimental benchmark data sets. PMID- 29994767 TI - Fusing Hyperspectral and Multispectral Images via Coupled Sparse Tensor Factorization. AB - Fusing a low spatial resolution hyperspectral image (LR-HSI) with a high spatial resolution multispectral image (HR-MSI) to obtain a high spatial resolution hyperspectral image (HR-HSI) has attracted increasing interest in recent years. In this paper, we propose a coupled sparse tensor factorization (CSTF) based approach for fusing such images. In the proposed CSTF method, we consider an HR HSI as a three-dimensional tensor and redefine the fusion problem as the estimation of a core tensor and dictionaries of the three modes. The high spatial spectral correlations in the HR-HSI are modeled by incorporating a regularizer which promotes sparse core tensors. The estimation of the dictionaries and the core tensor are formulated as a coupled tensor factorization of the LR-HSI and of the HR-MSI. Experiments on two remotely sensed HSIs demonstrate the superiority of the proposed CSTF algorithm over current state-of-the-art HSI-MSI fusion approaches. PMID- 29994768 TI - Composing Semantic Collage for Image Retargeting. AB - Image retargeting has been applied to display images of any size via devices with various resolutions (e.g., cell phone, TV monitors). To fit an image with the target resolution, certain unimportant regions need to be deleted or distorted and the key problem is to determine the importance of each pixel. Existing methods predict pixel-wise importance in a bottom-up manner via eye fixation estimation or saliency detection. In contrast, the proposed algorithm estimates the pixel-wise importance based on a top-down criterion where the target image maintains the semantic meaning of the original image. To this end, several semantic components corresponding to foreground objects, action contexts, and background regions are extracted. The semantic component maps are integrated by a classification guided fusion network. Specifically, the deep network classifies the original image as object or scene-oriented, and fuses the semantic component maps according to classification results. The network output, referred to as the semantic collage with the same size as the original image, is then fed into any existing optimization method to generate the target image. Extensive experiments are carried out on the RetargetMe dataset and S-Retarget database developed in this work. Experimental results demonstrate the merits of the proposed algorithm over the state-of-the-art image retargeting methods. PMID- 29994769 TI - Deep Monocular Depth Estimation via Integration of Global and Local Predictions. AB - Recent works on machine learning have greatly advanced the accuracy of single image depth estimation. However, the resulting depth images are still over smoothed and perceptually unsatisfying. This paper casts depth prediction from single image as a parametric learning problem. Specifically, we propose a deep variational model that effectively integrates heterogeneous predictions from two convolutional neural networks (CNNs), named global and local networks. They have contrasting network architecture and are designed to capture depth information with complementary attributes. These intermediate outputs are then combined in the integration network based on the variational framework. By unrolling the optimization steps of Split Bregman (SB) iterations in the integration network, our model can be trained in an end-to-end manner. This enables one to simultaneously learn an efficient parameterization of the CNNs and hyper parameter in the variational method. Finally, we offer a new dataset of 0.22 million RGB-D images captured by Microsoft Kinect v2. Our model generates realistic and discontinuity-preserving depth prediction without involving any low level segmentation or superpixels. Intensive experiments demonstrate the superiority of the proposed method in a range of RGB-D benchmarks including both indoor and outdoor scenarios. PMID- 29994770 TI - Arbitrary View Action Recognition via Transfer Dictionary Learning on Synthetic Training Data. AB - Human action recognition is crucial to many practical applications, ranging from human-computer interaction to video surveillance. Most approaches either recognize the human action from a fixed view or require the knowledge of view angle, which is usually not available in practical applications. In this paper, we propose a novel end-to-end framework to jointly learn a view-invariance transfer dictionary and a view-invariant classifier. The result of the process is a dictionary that can project real-world 2D video into a view-invariant sparse representation, as well as a classifier to recognize actions with an arbitrary view. The main feature of our algorithm is the use of synthetic data to extract view-invariance between 3D and 2D videos during the pre-training phase. This guarantees the availability of training data, and removes the hassle of obtaining real-world videos in specific viewing angles. Additionally, for better describing the actions in 3D videos, we introduce a new feature set called the 3D dense trajectories to effectively encode extracted trajectory information on 3D videos. Experimental results on the IXMAS, N-UCLA, i3DPost and UWA3DII datasets show improvements over existing algorithms. PMID- 29994771 TI - Computational Models for Trapping Ebola Virus Using Engineered Bacteria. AB - The outbreak of Ebola virus in recent years has resulted in numerous research initiatives to seek new solutions to contain the virus. A number of approaches that have been investigated include new vaccines to boost the immune system. An alternative post-exposure treatment is presented in this paper. The proposed approach for clearing Ebola virus can be developed through a microfluidic attenuator, which contains the engineered bacteria that traps Ebola flowing through the blood onto its membrane. The paper presents the analysis of the chemical binding force between the virus and a genetically engineered bacterium considering the opposing forces acting on the attachment point, including hydrodynamic tension and drag force. To test the efficacy of the technique, simulations of bacterial motility within a confined area to trap the virus were performed. More than 60% of the displaced virus could be collected within 15 minutes. While the proposed approach currently focuses on in vitro environments for trapping the virus, the system can be further developed into the future for treatment whereby blood can be cycled out of the body into a microfluidic device that contains the engineered bacteria to trap viruses. PMID- 29994772 TI - Compact Lensless Fluorescence Counting System for Single Molecular Assay. AB - In digital enzyme-linked immunosorbent assay, which is used for biomarker detection and diagnosis, the concentration of target biomarkers is estimated by counting the number of fluorescence chambers in the microchamber array. We propose a compact system for counting fluorescent chambers. Our system consists of three components: a micro-reaction chamber array, an absorption filter for attenuating excitation light, and a photodetector. The absorption filter has a micro-light-pipe array (m-LPA) structure. A stacked photodiode CMOS image sensor (CIS), which can discriminate color, is applied as a photodetector. This paper describes the fabrication process enabling thin m-LPA chips. The unique low-noise characteristics of the stacked photodiode CIS that attains high sensitivity by adopting the 4T-APS configuration are explained. Furthermore, a detection method using the photobleaching phenomenon is proposed for high-sensitivity fluorescence detection. This method suggests that fluorescence by a single molecular enzyme can be detected within 30 min of the start of the fluorescence reaction. PMID- 29994773 TI - Towards Characterization and Adaptive Compensation of Backlash in a Novel Robotic Catheter System for Cardiovascular Interventions. AB - Despite the success and prospects of the robotic catheter system for the cardiovascular access, loss of vision, and haptics have limited its global adoption. A direct implication is the great difficulty posed when trying to eliminate the backlash in catheters during vascular cannulations. As a result, physicians and patients end up been exposed to high radiation for a long period of time. Existing control systems proposed for such interventional robots have not fully consider the hysteretic (backlash) behavior. In this study, a novel robotic catheter system is designed for accessing the human cardiac area through the radial vasculature, while single factor descriptive analysis is employed to characterize the backlash behavior during axial motions of the interventional robot. Based on the descriptive analysis, an adaptive system is proposed for the backlash compensation during the cardiovascular access. The adaptive system consists of a neuro-fuzzy module that predicts a backlash gap based on bounded motion signals, and contact force modulated from a modified error-based force control model. The proposed system is implemented in MATLAB and visual C++. Finally, an in vitro experiment with a human tubular model, shows that the proposed adaptive compensation system can minimize the backlash occurrence during cardiovascular access. PMID- 29994775 TI - A Photoplethysmographic Signal Isolated From an Additive Motion Artifact by Frequency Translation. AB - Acquiring a precise percentage of oxygen saturation (SpO2) from a finger-probe pulse oximeter is dependent on both artifact-free red and infrared photoplethysmoghaphic (PPG) signals. Nonetheless, in real-life situations, these PPG signals are corrupted by a motion artifact (MA) signal that is generated from either finger or hand movement. To resolve this MA interference, the cause of the adulteration of PPG signals by the MA signal is examined. The MA signal is found to behave like an additive noise. Additionally, the frequency responses of the MA and PPG signals show that these signals are in the same frequency band. Hence, instead of direct current, a sinusoidal wave alternating current is proposed to drive an LED source in order to shift the PPG frequency band away from the MA frequency band. Experimentally, a commercial finger-probe pulse oximeter is employed. To determine the performance of the presented scheme, the resulting PPG signals are compared with those from employing the old-fashioned LED-driving method. In addition, the accuracy is verified by computing the SpO2 value. The results reveal that the proposed approach successfully retains the fundamental morphologies of the PPG structures when motion occurs. Moreover, the calculated SpO2 values from the proposed technique provide an average error of approximately 1.4%, whereas the conventional method yields a mean error approximately 4.2%. PMID- 29994774 TI - A Bidirectional-Current CMOS Potentiostat for Fast-Scan Cyclic Voltammetry Detector Arrays. AB - A potentiostat circuit for the application of bipolar electrode voltages and detection of bidirectional currents using a microelectrode array is presented. The potentiostat operates as a regulated-cascode amplifier for positive input currents, and as an active-input regulated-cascode mirror for negative input currents. This topology enables constant-potential amperometry and fast-scan cyclic voltammetry (FSCV) at microelectrode arrays for parallel recording of quantal release events, electrode impedance characterization, and high-throughput drug screening. A 64-channel FSCV detector array, fabricated in a 0.5-$?mu$m, 5-V CMOS process, is also demonstrated. Each detector occupies an area of 45 $?mu$m $?times$ 30 $?mu$m and consists of only 14 transistors and a 50-fF integrating capacitor. The system was validated using prerecorded input stimuli from actual FSCV measurements at a carbon-fiber microelectrode. PMID- 29994776 TI - Development of Novel Hearing Aids by Using Image Recognition Technology. AB - Speech is easily affected by different background noise in real environment to reduce the speech intelligibility, in particular, for hearing impaired listeners. In order to improve the above issue, several hearing aids have been developed to enhance the speech signal in noisy environment. Most of current hearing aids were designed to enhance the component of speech and suppress the component of noise. However, it is difficult to separate other speech sources. Adaptive signal enhancement (ASE) with the beamforming technique might improve the above issue. However, how to distinguish the location of the desired speaker effectively is still a difficult challenge for adaptive beamforming method. A novel concept of hearing aid was proposed in this study. Different from the beamforming-based hearing aids which use the cross-correlation-coefficient method to estimate time difference of arrival (TDOA), an image recognition technology was used to estimate the location of the desired speaker to obtain the more precise TDOA. An adaptive signal enhancement was also used to enhance the noisy speech sound. From the experimental results, the proposed system could provide a smaller absolute error of TDOA less than 1.25 10 ms, and a clear speech sound from the target speaker who the user wants to listen to. PMID- 29994777 TI - Non-rigid image registration using spatially region-weighted correlation ratio and GPU-acceleration. AB - OBJECTIVE: Non-rigid image registration with high accuracy and efficiency is still a challenging task for medical image analysis. In this work, we present the spatially region-weighted correlation ratio (SRWCR) as a novel similarity measure to improve the registration performance. METHODS: SRWCR is rigorously deduced from a three-dimension joint probability density function combining the intensity channels with an extra spatial information channel. SRWCR estimates the optimal functional dependence between the intensities for each spatial bin, in which the spatial distribution modeled by a cubic B-spline function is used to differentiate the contribution of voxels. We also analytically derive the gradient of SRWCR with respect to the transformation parameters and optimize it using a quasi-Newton approach. Furthermore, we propose a GPU-based parallel mechanism to accelerate the computation of SRWCR and its derivatives. RESULTS: The experiments on synthetic images, public 4-D thoracic computed tomography (CT) dataset, retinal optical coherence tomography (OCT) data, and clinical CT and positron emission tomography (PET) images confirm that SRWCR significantly outperforms some state-of-the-art techniques such as spatially encoded mutual information and Robust PaTch-based cOrrelation Ration. CONCLUSION: This study demonstrates the advantages of SRWCR in tackling the practical difficulties due to distinct intensity changes, serious speckle noise, or different imaging modalities. SIGNIFICANCE: The proposed registration framework might be more reliable to correct the non-rigid deformations and more potential for clinical applications. PMID- 29994778 TI - Remote Nonlinear State Estimation With Stochastic Event-Triggered Sensor Schedule. AB - This paper concentrates on the remote state estimation problem for nonlinear systems over a communication-limited wireless sensor network. Because of the non Gaussian property caused by nonlinear transformation, the unscented transformation technique is exploited to obtain approximate Gaussian probability distributions of state and measurement. To reduce excessive data transmission, uncontrollable and controllable stochastic event-triggered scheduling schemes are developed to decide whether the current measurement should be transmitted. Compared with some existing deterministic event-triggered scheduling schemes, the newly developed ones possess a potential superiority in maintaining Gaussian property of innovation process. Under the proposed schemes, two nonlinear state estimators are designed based on the unscented Kalman filter. Stability and convergence conditions of these two estimators are established by analyzing behaviors of estimation error and error covariance. It is shown that an expected compromise between communication rate and estimation quality can be achieved by properly tuning event-triggered parameter matrix. Numerical examples are provided to testify the validity of the proposed results. PMID- 29994779 TI - Nonfragile Near-Optimal Control of Stochastic Time-Varying Multiagent Systems With Control- and State-Dependent Noises. AB - In this paper, the near-optimal nonfragile consensus control design problem is investigated for a class of discrete time-varying multiagent systems (MASs) with control- and state-dependent noises. A decentralized observer-based control protocol is proposed by using the relative output measurements. The gain perturbations/variations of the controller as well as the state- and control dependent noises are simultaneously taken into consideration, which could better reflect the complexities in reality. The corresponding time-varying observer based nonfragile near-optimal consensus protocol is designed for the underlying MASs over a finite horizon. To be specific, a certain upper bound is first derived for the associate cost function for the MASs. Then, such an upper bound is minimized by using the completing-the-square technique and Moore-Penrose pseudo inverse. The parameters of the time-varying observer/controller are obtained in terms of the solutions to the Riccati-like recursion. In virtue of the matrix partitioning technique, the explicit expressions of the control/observer parameters are presented. Finally, based on the derived consensus protocol, an upper bound of the associate cost function is provided as time goes to infinity. Some numerical simulations are conducted to demonstrate the validity of the proposed methodology. PMID- 29994780 TI - Data-Based Reinforcement Learning for Nonzero-Sum Games With Unknown Drift Dynamics. AB - This paper is concerned about the nonlinear optimization problem of nonzero-sum (NZS) games with unknown drift dynamics. The data-based integral reinforcement learning (IRL) method is proposed to approximate the Nash equilibrium of NZS games iteratively. Furthermore, we prove that the data-based IRL method is equivalent to the model-based policy iteration algorithm, which guarantees the convergence of the proposed method. For the implementation purpose, a single critic neural network structure for the NZS games is given. To enhance the application capability of the data-based IRL method, we design the updating laws of critic weights based on the offline and online iterative learning methods, respectively. Note that the experience replay technique is introduced in the online iterative learning, which can improve the convergence rate of critic weights during the learning process. The uniform ultimate boundedness of the critic weights are guaranteed using the Lyapunov method. Finally, the numerical results demonstrate the effectiveness of the data-based IRL algorithm for nonlinear NZS games with unknown drift dynamics. PMID- 29994781 TI - Visual Classification With Multikernel Shared Gaussian Process Latent Variable Model. AB - Multiview learning methods often achieve improvement compared with single-view based approaches in many applications. Due to the powerful nonlinear ability and probabilistic perspective of Gaussian process (GP), some GP-based multiview efforts were presented. However, most of these methods make a strong assumption on the kernel function (e.g., radial basis function), which limits the capacity of the real data modeling. In order to address this issue, in this paper, we propose a novel multiview approach by combining a multikernel and GP latent variable model. Instead of designing a deterministic kernel function, multiple kernel functions are established to automatically adapt various types of data. Considering a simple way of obtaining latent variables at the testing stage, a projection from the observed space to the latent space as a back constraint has also been simultaneously introduced into the proposed method. Additionally, different from some existing methods which apply the classifiers off-line, a hinge loss is embedded into the model to jointly learn the classification hyperplane, encouraging the latent variables belonging to the different classes to be separated. An efficient algorithm based on the gradient decent technique is constructed to optimize our method. Finally, we apply the proposed approach to three real-world datasets and the associated results demonstrate the effectiveness and superiority of our model compared with other state-of-the-art methods. PMID- 29994782 TI - High-Order Temporal Correlation Model Learning for Time-Series Prediction. AB - Time-series prediction has become a prominent challenge, especially when the data are described as sequences of multiway arrays. Because noise and redundancy may exist in the tensor representation of a time series, we focus on solving the problem of high-order time-series prediction under a tensor decomposition framework and develop two novel multilinear models: 1) the multilinear orthogonal autoregressive (MOAR) model and 2) the multilinear constrained autoregressive (MCAR) model. The MOAR model is designed to preserve as much information as possible from the original tensorial data under orthogonal constraints. The MCAR model is an enhanced version that is developed by replacing orthogonal constraints with an inverse decomposition error term. For both models, we project the original tensor into subspaces spanned by basis matrices to facilitate the discovery of the intrinsic temporal structure embedded in the original tensor. To build connections among consecutive slices of the tensor, we generalize a traditional autoregressive model to tensor form to better preserve the temporal smoothness. Experiments conducted on four publicly available datasets demonstrate that our proposed methods converge within a small number of iterations during the training stage and achieve promising results compared with state-of-the-art methods. PMID- 29994783 TI - BULDP: Biomimetic Uncorrelated Locality Discriminant Projection for Feature Extraction in Face Recognition. AB - This paper develops a new dimensionality reduction method, named Biomimetic Uncorrelated Locality Discriminant Projection (BULDP), for face recognition. It is based on unsupervised discriminant projection and two human bionic characteristics: principle of homology continuity and principle of heterogeneous similarity. With these two human bionic characteristics, we propose a novel adjacency coefficient representation, which does not only capture the category information between different samples, but also reflects the continuity between similar samples and the similarity between different samples. By applying this new adjacency coefficient into the unsupervised discriminant projection, it can be shown that we can transform the original data space into an uncorrelated discriminant subspace. A detailed solution of the proposed BULDP is given based on singular value decomposition. Moreover, we also develop a nonlinear version of our BULDP using kernel functions for nonlinear dimensionality reduction. The performance of the proposed algorithms is evaluated and compared with the state of-the-art methods on four public benchmarks for face recognition. Experimental results show that the proposed BULDP method and its nonlinear version achieve much competitive recognition performance. PMID- 29994784 TI - Adaptive RGB Image Recognition by Visual-Depth Embedding. AB - Recognizing RGB images from RGB-D data is a promising application, which significantly reduces the cost while can still retain high recognition rates. However, existing methods still suffer from the domain shifting problem due to conventional surveillance cameras and depth sensors are using different mechanisms. In this paper, we aim to simultaneously solve the above two challenges: 1) how to take advantage of the additional depth information in the source domain? 2) how to reduce the data distribution mismatch between the source and target domains? We propose a novel method called adaptive Visual- Depth Embedding (aVDE) which learns the compact shared latent space between two representations of labeled RGB and depth modalities in the source domain first. Then the shared latent space can help the transfer of the depth information to the unlabeled target dataset. At last, aVDE models two separate learning strategies for domain adaptation (feature matching and instance reweighting) in a unified optimization problem, which matches features and reweights instances jointly across the shared latent space and the projected target domain for an adaptive classifier. We test our method on five pairs of datasets for object recognition and scene classification, the results of which demonstrates the effectiveness of our proposed method. PMID- 29994785 TI - Time-of-Flight Range Measurement in Low-sensing Environment: Noise Analysis and Complex-domain Non-local Denoising. AB - In this work, we deal with the problem of denoising 3D scene range measurements acquired by Time-of-flight (ToF) range sensors and composed in the form of 2D image-like depth maps. We address the specific case of ToF low-sensing environment (LSE). Such environment is set by low-light sensing conditions, low power hardware requirements, and low-reflectivity scenes. We demonstrate that data captured by a device in such mode can be effectively post-processed in order to reach the same measurement accuracy as if the device was working in normal operating mode. In order to achieve this, we first present an elaborated analysis of noise properties of ToF data sensed in LSE and verify the derived noise models by empirical measurements. Then, we develop a related novel non-local denoising approach working in complex domain and demonstrate its superiority against the state of the art for data acquired by an off-the-shelf ToF device. PMID- 29994786 TI - A Review on Accelerometry-Based Gait Analysis and Emerging Clinical Applications. AB - Gait analysis continues to be an important technique for many clinical applications to diagnose and monitor certain diseases. Many mental and physical abnormalities cause measurable differences in a person's gait. Gait analysis has applications in sport, computer games, physical rehabilitation, clinical assessment, surveillance, human recognition, modeling, and many other fields. There are established methods using various sensors for gait analysis, of which accelerometers are one of the most often employed. Accelerometer sensors are generally more user friendly and less invasive. In this paper, we review research regarding accelerometer sensors used for gait analysis with particular focus on clinical applications. We provide a brief introduction to accelerometer theory followed by other popular sensing technologies. Commonly used gait phases and parameters are enumerated. The details of selecting the papers for review are provided. We also review several gait analysis software. Then we provide an extensive report of accelerometry-based gait analysis systems and applications, with additional emphasis on trunk accelerometry. We conclude this review with future research directions. PMID- 29994787 TI - Admissible Delay Upper Bounds for Global Asymptotic Stability of Neural Networks With Time-Varying Delays. AB - This paper is concerned with global asymptotic stability of a neural network with a time-varying delay, where the delay function is differentiable uniformly bounded with delay-derivative bounded from above. First, a general reciprocally convex inequality is presented by introducing some slack vectors with flexible dimensions. This inequality provides a tighter bound in the form of a convex combination than some existing ones. Second, by constructing proper Lyapunov Krasovskii functional, global asymptotic stability of the neural network is analyzed for two types of the time-varying delays depending on whether or not the lower bound of the delay derivative is known. Third, noticing that sufficient conditions on stability from estimation on the derivative of some Lyapunov Krasovskii functional are affine both on the delay function and its derivative, allowable delay sets can be refined to produce less conservative stability criteria for the neural network under study. Finally, two numerical examples are given to substantiate the effectiveness of the proposed method. PMID- 29994788 TI - DermaKNet: Incorporating the knowledge of dermatologists to Convolutional Neural Networks for skin lesion diagnosis. AB - Traditional approaches to automatic diagnosis of skin lesions consisted of classifiers working on sets of hand-crafted features, some of which modeled lesion aspects of special importance for dermatologists. Recently, the broad adoption of Convolutional Neural Networks(CNNs)in most computer vision tasks has brought about a great leap forward in terms of performance. Nevertheless, with this performance leap, the CNN-based Computer Aided Diagnosis (CAD) systems have also brought a notable reduction of the useful insights provided by hand-crafted features. This paper presents DermaKNet, a CAD system based on CNNs that incorporates specific subsystems modeling properties of skin lesions that are of special interest to dermatologists, aiming to improve the interpretability of its diagnosis. Our results prove that the incorporation of these subsystems not only improves the performance, but also enhances the diagnosis by providing more interpretable outputs. PMID- 29994789 TI - A Hybrid Level Set With Semantic Shape Constraint for Object Segmentation. AB - This paper presents a hybrid level set method for object segmentation. The method deconstructs segmentation task into two procedures, i.e., shape transformation and curve evolution, which are alternately optimized until convergence. In this framework, only one shape prior encoded by shape context is utilized to estimate a transformation allowing the curve to have the same semantic expression as shape prior, and curve evolution is driven by an energy functional with topology preserving and kernelized terms. In such a way, the proposed method is featured by the following advantages: 1) hybrid paradigm makes the level set framework possess the ability of incorporating other shape-related techniques about shape descriptor and distance; 2) shape context endows one single prior with semanticity, and hence leads to the competitive performance compared to the ones with multiple shape priors; and 3) additionally, combining topology-preserving and kernelization mechanisms together contributes to realizing a more reasonable segmentation on textured and noisy images. As far as we know, we propose a hybrid level set framework and utilize shape context to guide curve evolution for the first time. Our method is evaluated with synthetic, healthcare, and natural images, as a result, it shows competitive and even better performance compared to the counterparts. PMID- 29994790 TI - Event-Driven Continuous STDP Learning With Deep Structure for Visual Pattern Recognition. AB - Human beings can achieve reliable and fast visual pattern recognition with limited time and learning samples. Underlying this capability, ventral stream plays an important role in object representation and form recognition. Modeling the ventral steam may shed light on further understanding the visual brain in humans and building artificial vision systems for pattern recognition. The current methods to model the mechanism of ventral stream are far from exhibiting fast, continuous, and event-driven learning like the human brain. To create a visual system similar to ventral stream in human with fast learning capability, in this paper, we propose a new spiking neural system with an event-driven continuous spike timing dependent plasticity (STDP) learning method using specific spiking timing sequences. Two novel continuous input mechanisms have been used to obtain the continuous input spiking pattern sequence. With the event driven STDP learning rule, the proposed learning procedure will be activated if the neuron receive one pre- or post-synaptic spike event. The experimental results on MNIST database show that the proposed method outperforms all other methods in fast learning scenarios and most of the current models in exhaustive learning experiments. PMID- 29994791 TI - Decentralized Adaptive Event-Triggered Hinfinity Filtering for a Class of Networked Nonlinear Interconnected Systems. AB - This paper focuses on the issue of designing an adaptive event-triggered scheme to the decentralized filtering for a class of networked nonlinear interconnected system. A novel adaptive event-triggered condition is proposed by constructing an adaptive law for the threshold. This new type of threshold mainly depends on the error between the states at the current sampling instant and the latest releasing instant, by which the data release rate is adapted to the variation of the system. The limitation of network bandwidth is alleviated on account of a large amount of ''unnecessary'' packets being dropped out before accessing the network. Sufficient conditions are derived such that the overall filtering error system under the proposed adaptive data-transmitting scheme is asymptotically stable with a prescribed disturbance attenuation level. An example is given to show the effectiveness of the proposed scheme. PMID- 29994792 TI - Efficacy of Compression Gloves in the Rehabilitation of Distal Radius Fractures: Randomized Controlled Study. AB - OBJECTIVE: The aim of this study was to examine the outcomes of wearing made-to measure compression gloves after distal radius fracture. DESIGN: In a randomized controlled trial, adults who were about 6 wks post distal radius fracture were recruited and divided into a comparison control group (n = 15), who received standard rehabilitation twice a week for half an hour, and an intervention group (n = 17), who additionally used compression gloves. All treatments were conducted at a single rehabilitation clinic. Outcomes assessed were wrist and finger range of motion, grip strength, swelling, pain, and activities of daily living (using the Patient Rating Wrist Evaluation). The intervention group underwent additional objective dynamic assessments of range of motion with and without the gloves. RESULTS: The intervention group demonstrated reduced swelling, pain, and analgesic use; increased wrist range of motion; better scores for specific hand functions; and greater participation in activities of daily living compared with the comparison group. CONCLUSION: This randomized controlled trial shows that using compression gloves during the rehabilitation phase after distal radius fracture improves daily functioning and reduces adverse symptoms. These improvements, which are important in their own right, are also expected to aid in preventing the development of chronic conditions and disability. EVIDENCE LEVEL II: Un-blinded prospective comparative study. PMID- 29994793 TI - Relation Between Memory Impairment and the Fornix Injury in Patients With Mild Traumatic Brain Injury: A Diffusion Tensor Tractography Study. AB - OBJECTIVE: We investigated the relation between memory impairment and the fornix injury in patients with mild traumatic brain injury, using diffusion tensor tractography. DESIGN: Eighty-six chronic patients with mild traumatic brain injury and 50 normal control subjects were recruited. Fractional anisotropy and fiber volume were measured for each reconstructed fornix. The patients were classified according to the following three types: type A (47 patients), intact integrity of both fornical crura; type B (27 patients), showed a discontinuation in either fornical crus; and type C (12 patients), discontinuations in both fornical crura. The Memory Assessment Scale was used for evaluation of memory function. RESULTS: Fractional anisotropy and fiber volume showed weak positive correlations with global memory of Memory Assessment Scale, respectively (r = 0.303, P = 0.006; r = 0.271, P = 0.014). Significant difference in the global memory of Memory Assessment Scale was observed between type A and B and between type A and C without difference between type B and C (P < 0.05). CONCLUSION: It seems that the diffusion tensor tractography parameters of the fornix and the integrity of fornical crus can be used as a biomarker for axonal injury of the fornix in patients with mild traumatic brain injury. PMID- 29994795 TI - Comment on: Efficacy of Armeo(r) Robotic Therapy Versus Conventional Therapy on Upper Limb Function in Children with Hemiplegic Cerebral Palsy. PMID- 29994794 TI - Mechanical In-Exsufflation-Expiratory Flows as Indication for Tracheostomy Tube Decannulation: Case Studies. AB - Mechanical insufflation exsufflation-expiratory flows (MIE-EF) correlate with upper airway patency. Patients dependent on continuous noninvasive ventilatory support (CNVS) with severe spinal muscular atrophy type 1, now over 20 years old, have used MIE sufficiently effectively along with CNVS to avoid tracheotomy indefinitely. While MIE-EF can apparently decrease in amyotrophic lateral sclerosis to necessitate tracheotomy, they can increase over time and remain effective in all spinal muscular atrophy types. Two cases demonstrate an association between increasing MIE-EF and ultimately successful decannulation of a continuous tracheostomy mechanical ventilation dependent patient with spinal muscular atrophy type 2 and a patient with obesity hypoventilation syndrome. Only when MIE-EF increased to exceed 200 L/m did the decannulations succeed. Definitive noninvasive management (CNVS) of these patients may only be possible when MIE is effective and the greater the MIE-EF, the greater its effectiveness. Thus, increasing MIE-EF can signal resolution of upper airway obstruction sufficiently to permit decannulation whether a patient is ventilator dependent or not. PMID- 29994796 TI - How Does Smoking Cessation Affect Disease Activity, Function Loss, and Quality of Life in Smokers With Ankylosing Spondylitis? AB - BACKGROUND: Ankylosing spondylitis (AS) is a chronic systemic inflammatory disease that can progressively restrict spinal mobility. OBJECTIVE: This study aimed to investigate how smoking cessation by AS patients affects disease activity and their psychological state, physical mobility, lung function, and quality of life. MATERIALS AND METHODS: This was a prospective, single-blind, controlled, and observational study on 92 AS patients. Pulmonary function test, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, chest expansion, Short-Form 36, and Ankylosing Spondylitis Quality of Life were evaluated. The patients were divided into smokers (group 1 = 54) and nonsmokers (group 2 = 38). The smokers were divided further into subgroups of those who quit smoking (group 1a = 17) and those who did not (group 1b = 37). Groups 1a and 1b patients were compared in terms of their baseline data and data 6 months after smoking cessation. In addition, group 1a patients' baseline data and data 6 months after smoking cessation were compared statistically. RESULTS: There was no statistically significant difference between groups 1a and 1b after 6 months in terms of the evaluated parameters, except for BASDAI. Bath Ankylosing Spondylitis Disease Activity Index was significantly lower in group 1a than group 1b (P = 0.02), indicating that. When the baseline data and data after 6 months of group 1a were compared, a significant improvement was found in BASDAI (P = 0.001), Bath Ankylosing Spondylitis Functional Index (P = 0.001), chest expansion (P = 0.001), ankylosing spondylitis quality of life (P = 0.003), and subparameters physical function (P = 0.015), physical role strength (P = 0.05), power/live/vitality (P = 0.025), social functioning (P = 0.039), pain (P = 0.036), and general health perception (P = 0.05) of Short-Form 36, as well as forced expiratory volume in the first second (P = 0.003) and forced vital capacity (P = 0.007). CONCLUSIONS: We observed significant improvements in disease activity, physical mobility, and quality of life in AS patients who quit smoking. PMID- 29994797 TI - Analgesic Use in Dutch Patients With Osteoarthritis: Frequent But Low Doses. AB - OBJECTIVE: The aim of this study was to examine which analgesics are used by patients with osteoarthritis (OA)-related pain and how the analgesics are used in the preceding month. In addition, their beliefs about (pain) medication and the rationale of those declining to use analgesics were explored. METHODS: An online cross-sectional survey was sent to 1521 patients participating in the panel of the Dutch Arthritis Foundation. Descriptive analyses and logistic regression were used to analyze data. RESULTS: Of the 842 participants (56%) with OA that responded, 70% had generalized OA, 26% had concomitant fibromyalgia, and 34% had another musculoskeletal morbidity. Of all participants, 71% used analgesics, and 34% used more than 1 type. Analgesics were used for more than 14 days in the preceding month by most participants, with paracetamol being used most frequently (51%). Doses used were predominantly lower than the daily defined dose: 58.2% for paracetamol, 31.2% for nonsteroidal anti-inflammatory drugs/cyclooxygenase-2 inhibitors, and 75.7% for weak opioids. Compared with participants with concomitant fibromyalgia or other musculoskeletal morbidities, participants with OA alone significantly more frequently declined to use analgesics (P < 0.01) and significantly less frequently used 2 or 3 types of analgesics (P < 0.05). CONCLUSIONS: In this population with generalized OA and musculoskeletal comorbidities, medication use was high, and more than 1 type of analgesic was frequently used. Patients with concomitant fibromyalgia or other musculoskeletal morbidities more frequently used 2 or 3 types of analgesics; however, this use was often intermittent and in low doses. Medication use on a daily basis and at higher doses may lead to improved analgesic effect. PMID- 29994798 TI - Renal Sarcoidosis With Multiple Organ Involvement. PMID- 29994799 TI - Expression of Peripheral Node Addressins by Plasmacytic Plaque of Children, APACHE, TRAPP, and Primary Cutaneous Angioplasmacellular Hyperplasia. AB - High-endothelial venules are a common feature of 3 types of cutaneous pseudolymphomas: pretibial lymphoplasmacytic plaque (PLP) of children, acral pseudolymphomatous angiokeratoma of children (APACHE), and T-cell rich angiomatoid polypoid pseudolymphoma (TRAPP). In addition, primary cutaneous angioplasmacellular hyperplasia (PCAH) overlaps with these other 3 conditions. We intend to study the expression of peripheral node addressins in PLP, APACHE, TRAPP, and PCAH. We studied 1 case of PLP, 2 cases of APACHE, 2 cases of TRAPP, and 2 cases of PCAH. Immunostainings for MECA-79 and WT-1 were obtained in all cases. All cases showed a dense lymphohistiocytic dermal inflammatory infiltrate with abundant plasma cells. In addition, HEV were prominent in all cases. Cases of PLP, APACHE, and TRAPP expressed MECA-1. Cases of PCAH did not express MECA-1. Although PLP, APACHE, and TRAPP seem to fall under the same morphologic spectrum with different clinical representations, PCAH seems to be a different entity, with histopathologic peculiarities and a different immunophenotype. PMID- 29994800 TI - From Static Spinal Alignment to Dynamic Body Balance: Utilizing Motion Analysis in Spinal Deformity Surgery. PMID- 29994801 TI - Treatment of Basilar Thumb Arthritis: A Critical Analysis Review. PMID- 29994802 TI - The anticancer effects of pharmacological inhibition of autophagy in acute erythroid leukemia cells. AB - Although recent studies have reported different aspects of autophagy, from pro survival to pro-death roles of this process in malignant cells, the underlying mechanisms by which autophagy inhibitors contribute toward the induction of programmed cell death in cancerous cells are still unclear. In the present study, we have attempted to explore some of the molecular features of pharmacological inhibition of autophagy in TF-1 cells (an acute erythroid leukemia model). Our findings indicated that ara-C induces autophagy (with alteration of LC3B, p62, and Beclin-1) in the cells; however, targeting autophagy by 3-methyladenine and chloroquine significantly increased caspase-dependent apoptosis and the sub-G1 compartment in ara-C-treated cells. Moreover, cell cycle analysis showed that 3 MA, as an early-stage autophagy inhibitor, could elevate the cell population in the G0/G1 cell cycle phase, which was associated with upregulation of p21 and p27 expressions. Interestingly, autophagy inhibition was also accompanied by downregulation of c-Myc gene and protein expression levels and upregulated levels of Bax and Bak gene expressions. In addition, following inhibition of autophagy, the levels of tumor-suppressive miRNA (i.e. miR-204) increased, whereas the values of oncogenic miRNAs (including miR-21, miR-221, miR-30a, and miR-17) decreased. Overall, our experiments indicate that autophagy inhibitors (especially chloroquine) seem to be promising agents for combination therapy in acute erythroid leukemia. PMID- 29994803 TI - Validity and Reliability of the Korean Version of the Dialysis Symptom Index for Hemodialysis Patients. AB - BACKGROUND: Hemodialysis patients experience physical and psychosocial symptoms caused by comorbid illnesses, treatment-related side effects, lifestyle alteration, and the psychosocial impacts of living with end-stage renal disease. The Dialysis Symptom Index (DSI) is the most frequently used instrument to assess symptoms of chronic kidney disease and end-stage renal disease in patients. PURPOSE: The aims of this study were to develop the Korean version of the DSI, to verify the reliability and validity of the developed tool, and to use the tool to evaluate the symptoms of hemodialysis patients in Korea. METHODS: A methodological study was performed on 230 hemodialysis patients from three hospitals who agreed to participate in the study from October 1 to 30, 2015. The Symptom Checklist-90-Revised was used to verify the convergent validity, whereas the total score of Kidney Disease Quality of Life Questionnaire-Short Form, Version 1.3, was used to verify the divergent validity. Data were analyzed using descriptive analysis, Cronbach's alpha, confirmatory factor analysis, and Pearson's correlation analysis. RESULTS: The internal consistency reliability of the Korean DSI assessed by Cronbach's alpha was .90. The Korean DSI showed a high positive correlation coefficient of .80 with symptom severity using the Symptom Checklist-90-Revised, which confirmed the convergent validity. Finally, the correlation coefficient with the quality of life of the participants using the Kidney Disease Quality of Life Questionnaire-Short Form, Version 1.3, was -.68, which confirmed the divergent validity. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study developed the Korean version of the DSI and verified its validity and reliability. The Korean version of the DSI showed good properties and may be used to assess the symptoms of hemodialysis patients. Nurses may use this self-report tool to better understand and help relieve the prevalence and severity of symptoms in hemodialysis patients in Korea. PMID- 29994804 TI - Diabetes and multivessel disease: coronary artery bypass grafting remains king. AB - PURPOSE OF REVIEW: Review the recently published scientific evidence to support the decision-making process of revascularization strategy in patients with diabetes mellitus (DM) and multivessel coronary artery disease (MVD). RECENT FINDINGS: Recently published observational analyses have proven the superiority of coronary artery bypass grafting (CABG) in patients presenting with other comorbidities together with DM, such as renal disease or heart failure. SUMMARY: Significant challenges and controversies surrounded the choice of the appropriate revascularization method in patients with DM and MVD over the last decades. FREEDOM trial was the first adequately powered randomized study to directly compare percutaneous coronary intervention (PCI) versus CABG in the DM population, showing the superiority of CABG in the long-term follow-up. Subsequently, other studies confirmed that CABG is also preferable over PCI in diabetic patients with particular comorbidities, such as renal failure and left ventricular dysfunction, and also in patients with type 1 DM and in the setting of an early acute coronary syndrome. Finally, in 2018, an individual level data meta-analysis reported an expressive reduction in all-cause mortality when comparing CABG versus PCI in patients with DM and MVD enrolled in the most recent clinical trials (hazard ratio 1.44, 95% confidence interval 1.20-1.74, P = 0.0001). PMID- 29994806 TI - What is the state of hybrid coronary revascularization in 2018? AB - PURPOSE OF REVIEW: Hybrid coronary revascularization (HCR) combines minimally invasive surgical bypass with percutaneous coronary intervention (PCI) using drug eluting stents, the goal being to leverage the strengths of each approach. Here we provide an update on HCR from the past 12 months. RECENT FINDINGS: HCR represents a minority of surgical revascularization cases from a small number of highly experienced surgical centers. Most single-center observational series show no differences in major cardiovascular outcomes comparing HCR and coronary artery bypass graft (CABG) or HCR and PCI. The 5-year results of the first randomized study comparing HCR to CABG reported no difference in all-cause mortality, myocardial infarction, and repeat revascularization. Comparing HCR with multivessel PCI, a large, prospective observational study reported no difference in risk-adjusted major adverse cardiovascular events at 12 months. The Hybrid Coronary Revascularization Trial is an international, multicenter, randomized controlled trial to compare HCR versus PCI for patients with proximal left anterior descending disease or left main disease. This trial is currently recruiting patients. SUMMARY: HCR is a potentially attractive alternative to both surgical revascularization and multivessel PCI when performed in experienced centers for highly selected patients. The results of a large, multicenter, prospective trial will provide greater clarity on the clinical role and optimal coronary anatomy for this third revascularization option. PMID- 29994805 TI - Altered branched chain amino acid metabolism: toward a unifying cardiometabolic hypothesis. AB - PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (CVD) and type II diabetes (T2D) share common etiologic pathways that may long precede the development of clinically evident disease. Early identification of risk markers could support efforts to individualize risk prediction and improve the efficacy of primary prevention, as well as uncover novel therapeutic targets. RECENT FINDINGS: Altered metabolism of branched-chain amino acids (BCAAs), and their subsequent accumulation in circulation, may precede the development of insulin resistance and clinically manifest cardiometabolic diseases. BCAAs - the essential amino acids leucine, isoleucine and valine - likely promote insulin resistance through activation of mammalian target of rapamycin complex 1. Epidemiologic studies demonstrate robust associations between BCAAs and incident T2D, and Mendelian randomization supports a potentially causal relationship. More recently, there is emerging evidence that BCAAs are also associated with incident atherosclerotic CVD, possibly mediated by the development of T2D. SUMMARY: In this article, we review the biochemistry of BCAAs, their potential contribution to cardiometabolic risk, the available evidence from molecular epidemiologic studies to date, and, finally, consider future research and clinical directions. Overall, BCAAs represent a promising emerging target for risk stratification and possible intervention, to support efforts to mitigate the burden of cardiometabolic disease in the population. PMID- 29994807 TI - Women's heart health: a focus on nurses' physical activity and sedentary behaviour. AB - PURPOSE OF REVIEW: This review focuses on recent literature examining and targeting the physical activity and sedentary behaviour of nurses. The role of physical activity and sedentary behaviour in preventing and managing cardiovascular disease (CVD) in women is also discussed. RECENT FINDINGS: Nurses (most of whom are women) represent the largest professional group within the health care workforce and many present with risk factors for CVD (e.g. physical inactivity, sedentary behaviour, overweight/obesity, hypertension, dyslipidemia, diabetes, smoking, depression, anxiety). Several studies have measured the physical activity and sedentary behaviour of nurses and found low levels of physical activity (i.e. most do not meet physical activity guidelines) and high levels of sedentary behaviour (50-60% of the day). Nurses working rotating shifts, 12-h shifts and/or working full-time or part-time (vs. casual) may be at greater risk of physical inactivity; however, the opposite has been observed for sedentary behaviour. Few interventions targeting nurses' physical activity levels have shown promise, but those that have used activity monitors with behavioural strategies; no studies, to date, have evaluated the impact of sedentary behaviour interventions in nurses. SUMMARY: Improving the physical activity levels and reducing the sedentary behaviour of nurses is important for nurses' cardiovascular health. There is a need for interventions to address low physical activity and high sedentary behaviour among nurses. PMID- 29994808 TI - New biomarker strategies to enable precision cardiovascular medicine. AB - PURPOSE OF REVIEW: Precision medicine is the concept of disease treatment and prevention using an individual's genomic profile in addition to personal and environmental factors. This review outlines examples of new biomarker strategies that enable the practice of precision cardiovascular medicine. RECENT FINDINGS: Although commonly attributed to identifying causative genetic variants, mono genetic causes of cardiovascular diseases (CVD) are not common and largely focused on lipoprotein analyses. Nevertheless, rare clinical presentations in families with extreme phenotypes can sometimes identify novel pathways that can serve as therapeutic targets, such as the discovery of PCSK9 inhibitors for familial hypercholesterolemia or small molecular inhibitors of myosin ATPase activities for hypertrophic cardiomyopathy. Polygenetic risks scores can also identify high-risk cohorts before their clinical manifestations. Novel metabolomic insights can also lead to unexpected modulators of CVD susceptibility, such as nutrient-induced gut microbiota-derived metabolic pathways. SUMMARY: Adequate knowledge systems and data infrastructure are necessary for clinicians to take into account both genetic and environmental factors to operationalize precision medicine and to prevent CVD. PMID- 29994809 TI - Should functional assessment of lesion severity be used to guide coronary bypass? AB - PURPOSE OF REVIEW: The purpose of this article is to investigate the potential role of fractional flow reserve (FFR) to guide surgical revascularization. RECENT FINDINGS: Coronary artery bypass is planned and executed primarily based on angiographic coronary anatomy. FFR is the most well-established tool for functional assessment of coronary lesions. Randomized trials have demonstrated the benefit of FFR-guided percutaneous coronary intervention (PCI) to determine the ischemic burden of intermediate lesions. Surgically, FFR is predominantly used to determine the functional severity of intermediate lesions of the left anterior descending (LAD) coronary artery to establish candidacy for multivessel coronary bypass. The broader use of FFR will likely downgrade a proportion of coronary lesions, which may alter the overall management plan. Whether this will improve clinical outcomes remains to be seen. Importantly, bypass of functionally nonsignificant lesions predicts graft failure. However, graft failure in the context of sufficient native coronary flow may not impact negatively on clinical outcome. Thus, at this time, there are insufficient data to support the wider use of FFR to guide surgical grafting of non-LAD targets. It remains to be seen whether FFR can be used to optimize the use of arterial grafts or to guide complex revascularization strategies such as hybrid coronary revascularization. SUMMARY: FFR has become an invaluable tool for decision making for PCI in patients with stable ischemic heart disease. Beyond its use to assess an intermediate LAD lesion to establish candidacy for coronary bypass, at present there are insufficient data to support its wider use to guide surgical revascularization. PMID- 29994810 TI - Spinal cord stimulation postconditioning reduces microglial activation through down-regulation of ERK1/2 phosphorylation during spinal cord ischemic reperfusion in rabbits. AB - Microglial activation plays a critical role in spinal cord ischemic reperfusion injury. Spinal cord stimulation preconditioning and postconditioning has shown spinal cord protection in ischemic reperfusion injury in animal studies. However, whether spinal cord stimulation could reduce microglial activation is still unclear. In this study, rabbits experienced 28-min infrarenal aorta occlusion and reperfusion for 8 h, 1, 3, and 7 days correspondingly. Immediately after reperfusion, rabbits received spinal cord stimulation of 2 or 50 Hz for 30 min and daily for a week. The results showed that spinal cord stimulation of 2 Hz reduced microglial activation. Microglial activation was accompanied with up regulated p-ERK1/2, and microglial inhibition by 2 Hz spinal cord stimulation was associated with down-regulated p-ERK1/2. Spinal cord stimulation increased the expression of IL-1beta. Our results revealed, for the first time, that spinal cord stimulation postconditioning suppresses microglial activation during spinal cord ischemic reperfusion by down-regulation of p-ERK1/2, which may be the protective mechanism of spinal cord stimulation. PMID- 29994811 TI - Golgi-specific DHHC type zinc finger protein is decreased in neurons of intractable epilepsy patients and pentylenetetrazole-kindled rats. AB - Golgi-specific DHHC type zinc finger protein (GODZ) is a member of the DHHC protein family, and its enzymatic activity is regulated by fibroblast growth factor or Src kinase-mediated tyrosine phosphorylation. In cultured neurons, GODZ affects the numbers of calcium ions channels, alpha-amino-3-hydroxy-5-methyl-4 isoxazole-propionic acid receptors, N-methy-D-aspartate receptors, and gamma aminobutyric acid A receptors on postsynaptic membrane by palmitoylation, thus modulating synaptic plasticity. As the change in synaptic plasticity plays a role in epilepsy, GODZ may play roles in epilepsy. However, the expression of GODZ has never been investigated in brain tissues in vivo, and its change during epilepsy is still unclear. In this study, the cellular distribution of GODZ in brain tissues of both patients and rats was determined using double-labeled immunofluorescence and the levels of GODZ protein and mRNA among intractable epilepsy patients, pentylenetetrazole (PTZ)-kindled rats, and controls were measured using immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction. GODZ expression was identified on cytomembranes and in the cytoplasm of neurons in the temporal neocortex of intractable epilepsy patients and in the hippocampus and the adjacent temporal cortex of PTZ-kindled rats, but not in astrocytes. Decreased GODZ protein and mRNA were identified in brain tissues of intractable epilepsy patients and PTZ-kindled rats compared with the controls. In conclusion, GODZ is expressed in neurons, but not astrocytes, and epilepsy may reduce the protein and mRNA levels of GODZ, indicating a possible role of GODZ in the pathogenesis or the pathophysiology of epilepsy. PMID- 29994812 TI - Hypercholesterolemia impairs contextual fear conditioning memory formation in female mice: evidence for cholinergic dysfunction. AB - The present study evaluated the effects of hypercholesterolemia in response to conditioned aversive stimuli in mice. Specifically, (a) young (3 months old) and aged (24 months old) female C57Bl/6 mice were fed daily for 4 weeks with a standard rodent diet or an enriched cholesterol diet (ECD) and then subjected to the contextual fear conditioning test. In another experimental set, 3-month-old C576Bl/6 female mice, fed daily during the 4 weeks with the standard rodent diet or ECD, were subjected to the contextual fear conditioning test and received vehicle or scopolamine (0.37 mg/kg; intraperitoneally) immediately after the training session. (b) 12-month-old C576Bl/6 and low-density lipoprotein receptor knockout mice (LDLr) female mice were subjected to the contextual fear conditioning test. In another experimental set, they were subjected to the contextual fear conditioning test and received vehicle or donepezil (3.0 mg/kg; intraperitoneally) immediately after the training session. The present results show that (a) the ECD specifically impaired retrieval of contextual fear memory in aged mice; (b) an ineffective dose of scopolamine impaired fear memory consolidation in young mice fed the ECD; (c) LDLr mice presented impaired contextual fear memory retrieval; and (d) boosting cholinergic neurotransmission with a single donepezil administration at the consolidation window led to improved fear memory consolidation in LDLr mice. These findings suggest that high levels of cholesterol induced by either an ECD or a genetic deletion of LDLr decreased freezing behavior on the contextual fear conditioning test, which seemed to involve dysfunction of the cholinergic system. PMID- 29994813 TI - Wandering by Children with Autism Spectrum Disorder: Key Clinical Factors and the Role of Schools and Pediatricians. AB - OBJECTIVE: To examine the clinical characteristics associated with wandering in children with autism spectrum disorder (ASD), the impact on families, and how medical and educational professionals address wandering. METHODS: An anonymous, online questionnaire was distributed through autism-related organizations to parents of children with ASD. The questionnaire asked about demographics, developmental diagnoses, past wandering behavior, and impact of wandering on parents. It also asked about the use of electronic tracking devices, requested Individualized Education Program (IEP) modifications, use of restraints and/or seclusion to prevent wandering at school, and receipt of guidance about wandering. Parents were included if they lived in the United States and had a child aged 4 to 18 years with ASD who had previously wandered. RESULTS: A total of 1454 parents who completed the questionnaire met the inclusion criteria. It was found that 22.4% of the children wandered from their home or yard and 24.6% from a public place more than monthly. Wandering concerns affected 73.3% of parents' decisions to let their child spend time with friends or family in their absence. Furthermore, 48.6% and 58.7% of parents were moderately/very worried about their child wandering from home or yard or a public place, respectively. Over half of the parents (54.9%) parents requested IEP changes to address wandering. Only 33.3% of parents had previously received any counseling about wandering. CONCLUSION: Children with ASD and a history of elopement wandered at a fairly high frequency. Wandering concerns increased worry and anxiety for parents and negatively impacted household routines. The medical community is not adequately educating families about these risks. Pediatricians must become more aware of available prevention and mitigation strategies. PMID- 29994814 TI - Effectiveness of Animal-Assisted Therapy in the Pediatric Population: Systematic Review and Meta-Analysis of Controlled Studies. AB - OBJECTIVE: To synthesize the results of controlled studies evaluating the effectiveness of animal-assisted therapy (AAT) in children. METHODS: Eleven databases were searched following the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement recommendations, and references from included studies and previous reviews were examined. No date or language filters were applied. Only controlled study designs, including those using wait-list controls, that studied a specific condition or illness were included. Study quality was assessed using the Cochrane Risk of Bias Tool. RESULTS: Twenty-six studies that met the inclusion criteria were retrieved. Nine were conducted in children with autism spectrum disorders, 10 in cerebral palsy (CP), 2 in Down syndrome, 3 in pain, and 2 in other conditions. Qualitative synthesis showed a small but significant contribution of AAT to the management of these conditions. Meta analysis showed a mean difference in improvement in the Gross Motor Function Measure-66 scale in children with CP of 1.61 (95% confidence interval [CI] -2.00 to 5.23) and a mean difference for 5-point pain scales of -0.81 (95% CI -1.32 to 0.30), both favoring AAT. CONCLUSION: Animal-assisted therapy may be useful as a complementary intervention in the management of children with CP and pain. Although results are in general positive for the management of children with Down syndrome and autism, the diversity of scales used to measure outcomes makes it difficult to establish true effectiveness. The application of simple corrective measures in the randomization process would greatly improve the quality of evidence. It is necessary to reach a consensus between AAT researchers regarding appropriate instruments to provide higher-quality evidence in further studies. PMID- 29994815 TI - International Society for the Study of Vulvovaginal Disease Recommendations Regarding Female Cosmetic Genital Surgery. AB - Female genital cosmetic surgeries (FGCSs) and procedures are increasingly being advertised as common, simple, and complication-free, capable of not only improving aesthetic appearance but also increasing self-esteem and sexual pleasure.Guidelines for physicians and clear, scientifically correct information for patients must be made available, to minimize the number of ineffective or deleterious procedures.The International Society for the Study of Vulvovaginal Disease positions/recommendations regarding FGCS are as follows:1. There is a wide variation regarding genital normalcy; providers must be able to explain this to women.2. There are no data supporting FGCS including, G-spot augmentation, hymenoplasty, vulvar and perianal bleaching/whitening, vaginal tightening procedures, and other procedures aimed at increasing sexual function.3. Women should not be offered FGCS before the age of 18 years.4. Women undergoing FGCS should be evaluated by a provider with expertise in vulvovaginal diseases, including attention to their psychological, social, and sexual context. Evaluation by an experienced mental health provider should be considered when the motivation for seeking surgery and/or expectations are not clear or realistic.5. Female genital cosmetic surgery is not exempt from complications.6. Informed consent must always be obtained.7. Surgeons performing FGCS should refrain from solicitous advertising or promoting procedures without scientific basis, including on Web sites.8. Surgeons should not perform surgery that they do not agree with and explain their rationale/position when pressured by patients.9. The genital surgeon must be adequately trained in performing FGCS including knowledge of the anatomy, physiology and pathophysiology of the vulva, vagina and adjacent organs. PMID- 29994816 TI - Classic and Hypertrophic Vulvar Lichen Planus. AB - OBJECTIVES: Three types of lichen planus (LP) occur on the vulva: erosive, classic, and hypertrophic. The latter 2 occur on keratinized skin and little is known about their clinicopathologic appearance. MATERIALS AND METHODS: Vulvar biopsies of keratinized skin reported as LP or "lichenoid" between 2011 and 2017 were reviewed. Inclusion required age of older than 18 years, a lichenoid tissue reaction, and insufficient abnormal dermal collagen to diagnose lichen sclerosus. Clinical and histopathologic data were collected and cases were categorized as hypertrophic, classic, or nonspecific lichenoid dermatosis. Descriptive statistics were performed and groups were compared with the Fisher exact test. RESULTS: Sixty-three cases met criteria for inclusion. Twenty-nine (46%) cases were categorized as hypertrophic LP, 21 (33%) as classic LP, and 13 (21%) as nonspecific lichenoid dermatosis. There were no significant differences in age, primary symptom, biopsy location, or duration of disease between the 3 groups. When compared with classic and nonspecific disease, hypertrophic LP was less likely to have comorbid dermatoses and more likely to be red, diffuse, have scale crust, and contain plasma cells in the infiltrate. Nonspecific disease had similar clinical features to classic LP but was less likely than the other 2 categories to have a dense lymphocytic infiltrate and exocytosis. CONCLUSIONS: Vulvar LP on keratinized skin has a diversity of appearances and presents a clinicopathologic challenge. Further research is required to understand the natural history of hypertrophic LP and the underlying diagnosis of nonspecific lichenoid cases. PMID- 29994817 TI - Understanding the Types and Effects of Clinical Interruptions and Distractions Recorded in a Multihospital Patient Safety Reporting System. AB - OBJECTIVES: Interruptions and distractions have been shown to be a frequent occurrence across health care and have been linked to negative outcomes that create potential patient safety risks. Although observational studies have catalogued interruption frequency and source, the impact of an interruption is difficult to observe. We analyzed patient safety event (PSE) reports related to interruptions to identify clinical processes reported to be frequently interrupted and the reported outcomes of those interruptions. METHODS: We retrospectively analyzed PSE reports entered by frontline staff between January 2013 and January 2016. Of 79,428 total PSEs entered, 220 reports were identified using keyword matching and subsequent manual review as being directly related to a clinical interruption. Categories were developed to identify the cause of the interruption, task being interrupted, and the result of the interruption. Percentages were calculated. RESULTS: Nurses were most often reported to be interrupted in the PSEs (50%). General distractions (43.2%) or high workload (18.6%) were most commonly noted to interrupt the individual's work. The interrupted activity was most often a medication task (50.9%), frequently in the administration phase (24.1%), or the ordering phase (16.8%). The most common medication error was wrong dose administration (14.4% of total medication-related errors). Laboratory processes were reported to be disturbed by interruptions in 22.7% of reports, and this frequently resulted in mislabeling of specimens (75% of laboratory-related errors). CONCLUSIONS: This retrospective review of PSE reports involving interruptions of clinical activities reveals that interruptions affect a variety of aspects of patient care and can help to guide future work on interruption management. PMID- 29994818 TI - Preoperative Anticoagulation Management in Everyday Clinical Practice: An International Comparative Analysis of Work-as-Done Using the Functional Resonance Analysis Method. AB - OBJECTIVES: Preoperative anticoagulation management (PAM) is a complex, multidisciplinary process important to patient safety. The Functional Resonance Analysis Method (FRAM) is a novel method to study how complex processes usually go right at the frontline (labeled Safety-II) and how this relates to predefined procedures. This study aimed to assess PAM in everyday practice and explore the usability and utility of FRAM. METHODS: The study was conducted at an Australian and European Cardiothoracic Surgery Department. A FRAM model of work-as-imagined was developed using (inter)national guidelines. Semistructured interviews with 18 involved professionals were used to develop models reflecting work-as-done at both sites, which were presented to staff for validation. Workload in hours was estimated per process step. RESULTS: In both centers, work-as-done differed from work-as-imagined, such as in the division of tasks among disciplines (e.g., nurses/registrars rather than medical specialists), but control mechanisms had been developed locally to ensure safe care (e.g., crosschecking with other clinicians). Centers had organized the process differently, revealing opportunities for improvement regarding patient information and clustering of clinic visits. Presenting FRAM models to staff initiated discussion on improvement of functions in the model that are vital for success. Overall workload was estimated at 47 hours per site. CONCLUSIONS: This FRAM analysis provided insight into PAM from the perspective of frontline clinicians, revealing essential functions, interdependencies and variability, and the relation with guidelines. Future studies are warranted to study the potential of FRAM, such as for guiding improvements in complex systems. PMID- 29994819 TI - How to Identify Organizational High-Alert Medications. AB - OBJECTIVES: High-alert medications may cause significant patient harm when used in error. Hospital-specific safety data should be used to customize high-alert medication lists to fit the local context. The aim of this study was to identify organizational high-alert medications by evaluating university hospital's data on adverse drug reaction (ADR) and medication error (ME). METHODS: The Anatomical Therapeutic Chemical (ATC) codes and top active substances in ADR (n = 401) and ME (n = 11,668) reports of Helsinki University Hospital from 2015-2016 were analyzed and compared with hospitals' drug consumption and the Institute for Safe Medication Practices' (ISMP) list of high-alert medications. RESULTS: The top ATC groups and active substances in ADR and ME reports were not similar. The most numerous ATC groups were L, antineoplastic and immunomodulating agents (30%) in ADRs and N, nervous system (26%) in MEs. According to ADR and ME reports, several high-alert medications from Institute for Safe Medication Practices' lists, such as antineoplastic agents, antithrombotics, opioids, and insulins, should be considered high-alert medications also in Helsinki University Hospital. Although no ADR reports of amphotericin B existed, it had the highest number of MEs causing severe/moderate harm or unexpected reactions relative to its consumption. CONCLUSIONS: To identify organizational high-alert medications, both drug safety information and medication safety information should be used. Adverse drug reaction and ME data are needed to recognize high-alert medications, but these should also be combined with a literature search and local expert opinions. PMID- 29994820 TI - ACSM Clinician Profile. PMID- 29994821 TI - Caffeine Powder, Placebos for Athletes, and Muscle Breakdowns. PMID- 29994822 TI - Sport and Hemophilia in Italy: An Obstacle Course. PMID- 29994823 TI - Physical Effects of Anabolic-androgenic Steroids in Healthy Exercising Adults: A Systematic Review and Meta-analysis. AB - Many athletes use anabolic-androgenic steroids (AAS) for physical enhancement but the magnitude of these gains and associated adverse effects has not been rigorously quantified. MEDLINE, EMBASE, Cochrane, SPORTDiscus, and PsycINFO were searched to identify randomized placebo-controlled trials of AAS in healthy exercising adults that reported one of the following outcomes: muscular strength, body composition, cardiovascular endurance, or power. Two authors appraised abstracts to identify studies for full-text retrieval; these were reviewed in duplicate to identify included studies. Study quality was assessed using the Cochrane method. Data were extracted in duplicate and pooled using the DerSimonian and Laird random effects model and to calculate the ratio of mean outcome improvement where possible. Pooled standardized mean difference (SMD) in muscle strength between AAS and placebo was 0.27 (95% confidence interval, 0.07 0.47; I = 12.7%; 21 studies). Change in strength was 52% greater in the AAS group compared to placebo. The SMD for change in lean mass between AAS and placebo was 0.62 (95% confidence interval, 0.35-0.89; I = 26%; 14 studies). Due to missing data, fat mass, cardiovascular endurance, power, and adverse effects were summarized qualitatively. Only 13 of 25 studies reported adverse effects including increased low density lipoprotein (LDL), decreased high density lipoprotein (HDL), irritability, and acne. In healthy exercising adults, AAS use is associated with a small absolute increase in muscle strength and moderate increase in lean mass. However, the transparency and completeness of adverse effect reporting varied, most studies were of short duration, and doses studied may not reflect actual use by athletes. PMID- 29994824 TI - Applying the Science of Nutrient Timing and Distribution On-and-Off the Soccer Pitch: Sports Nutritionist's Experience. PMID- 29994825 TI - Exertional Heat Stroke, the Return to Play Decision, and the Role of Heat Tolerance Testing: A Clinician's Dilemma. AB - Exertional heat stroke (EHS) is a leading cause of preventable morbidity and mortality among both athletes and warfighters. Since current evidence suggests that the history of a prior event is an important risk factor for an EHS event, sports medicine providers can find post-EHS return to play/duty (RTP/D) decisions challenging. Heat tolerance testing is a tool that can help with such decisions by exposing the subject to a given heat load under controlled conditions to assess the presence or absence of heat tolerance. This special communication explores the challenge of the RTP/D after an EHS event and the potential role of heat tolerance testing in making this clinical decision. PMID- 29994826 TI - Supplement Introduction: Accelerating Children's HIV/AIDS Treatment (ACT) Initiative: Using What We Learned to Maintain the Pace to Close the Pediatric HIV Treatment Gap. PMID- 29994827 TI - ACTing in Partnership to Accelerate Impact. AB - Partnership between funders plays a vital role in tackling the AIDS epidemic and can help partners deliver "more than the sum of their parts." But how do partnerships form? How is value leveraged and maximized? How can partnerships achieve policy change? This article addresses these questions through the example of the Accelerating Children's HIV/AIDS Treatment Initiative, an ambitious $200 million public private partnership with a goal of doubling the number of children living with HIV on treatment in 9 priority African countries over a 2-year period. It describes how the partnership formed between the US President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF), and the differing styles, vision, and resources each organization contributed. It also gives examples of policy influence at global level and policy change at national level. Finally, the article considers whether working in partnership was more or less effective than independent funding, with reflections on the value and challenges of collaboration. PMID- 29994828 TI - Multimonth Prescription of Antiretroviral Therapy Among Children and Adolescents: Experiences From the Baylor International Pediatric AIDS Initiative in 6 African Countries. AB - BACKGROUND: To reach 90-90-90 targets, differentiated approaches to care are necessary. We describe the experience of delivering multimonth prescription (MMP) schedules of antiretroviral therapy (ART) to youth at centers of excellence in 6 African countries. METHODS: We analyzed data from electronic medical records of patients aged 0-19 years started on ART. Patients were eligible to transition from monthly prescribing to MMP when clinically stable [improving CD4, viral load (VL) suppression, or minimal HIV-associated morbidity] and ART adherent (pill count 95%-105%). Patients were classified as transitioned to MMP after 3 consecutive visits at intervals of >56 days. We used survival analysis to describe death and lost to follow-up. We described adherence and acceptable immunologic response by CD4 using 6-month and VL suppression (<400 copies per milliliter) using 12-month intervals. RESULTS: Twenty-two thousand six hundred fifty-eight patients aged 0-19 years received ART and 14,932 (66%) transitioned to MMP between 2003 and 2015. Of these 2.6% were lost to follow-up and 2.0% died. Median duration of MMP was 3.9 (interquartile range: 2.2-5.9) years. There were significant differences in survival (P < 0.0001) between age groups, worst among those younger than 1 year and 15-19 years. The frequency of favorable clinical endpoints was high throughout the first 5 years of MMP, by year ranging from 87% to 94% acceptable immunologic response, 75% to 80% adherent, and 79% to 85% VL suppression. CONCLUSIONS: These analyses from 6 African countries demonstrate that youth on ART who transitioned to MMP overall maintained favorable outcomes in terms of death, retention, adherence, immunosuppression, and viral suppression. These results reassure that children and adolescents, who are clinically stable and ART adherent, can do well with reduced visit frequencies and extended ART refills. PMID- 29994829 TI - Community-Based Interventions to Reach 95-95-95 for Children and Adolescents: An Exploratory Programmatic Review From Lesotho. AB - BACKGROUND: Viral suppression is the desired outcome for children and adolescents with HIV. In this article, data from districts supporting community interventions (implementation districts) were reviewed and compared with data from districts without community interventions (nonimplementation districts) to explore a potential correlation between community interventions and clinical outcomes. SETTING: The study was based on data collected from facilities in 6 districts in Lesotho. METHODS: Twelve-month retention, viral load coverage, and viral suppression data from patients with ART between ages 5 and 24 from facilities in both district types were collected retrospectively. RESULTS: Implementation districts showed retention rates of 75%, with 5365 patients (47% of all patients on ART) having documented viral load results and 4641 (87%) being virally suppressed. Retention comparison demonstrated significantly higher rates in implementation districts (73%) as compared to (63%) in nonimplementation districts (P = 0.023). Viral load coverage and suppression comparison found that implementation district hospitals reported 632 (37% of total on ART) patients with a documented viral load, with 539 (85%) virally suppressed, whereas nonimplementation district hospitals reported 220 (31%) patients with viral load results, of whom 181 (82%) were suppressed. CONCLUSIONS: Overall, retention rates in the implementation districts were reasonable and were significantly better than the rates in the nonimplementation districts. PMID- 29994830 TI - Family Testing: An Index Case Finding Strategy to Close the Gaps in Pediatric HIV Diagnosis. AB - Despite significant advances in pediatric HIV treatment, too many children remain undiagnosed and thus without access to lifesaving antiretroviral therapy. It is critical to identify these children and initiate antiretroviral therapy as early as possible. Although the children of HIV-infected adults are at higher risk of infection, few access HIV testing services because of missed opportunities in existing case finding programs. Family testing is an index case finding strategy through which HIV-infected patients are systematically screened to identify family members with unknown HIV status. By specifically targeting a high-risk population, family testing is a pragmatic, high-yield, and efficient approach to identify previously undiagnosed HIV-infected children and link them to care before they become symptomatic. Despite this, incorporation of family testing into national guidelines and implementation of this case finding approach is variable. In this article, we review the evidence base for family testing, describe its challenges, and provide guidance and sample tools for program managers aiming to integrate family testing into existing health systems. PMID- 29994831 TI - Strategies for Identifying and Linking HIV-Infected Infants, Children, and Adolescents to HIV Treatment Services in Resource Limited Settings. AB - Many children living with HIV in resource-limited settings remain undiagnosed and at risk for HIV-related mortality and morbidity. This article describes 5 key strategies for strengthening HIV case finding and linkage to treatment for infants, children, and adolescents. These strategies result from lessons learned during the Accelerating Children's HIV/AIDS Treatment Initiative, a public private partnership between the President's Emergency Plan for AIDS Relief (PEPFAR) and the Children's Investment Fund Foundation (CIFF). The 5 strategies include (1) implementing a targeted mix of HIV case finding approaches (eg, provider-initiated testing and counseling within health facilities, optimization of early infant diagnosis, index family testing, and integration of HIV testing within key population and orphan and vulnerable children programs); (2) addressing the unique needs of adolescents; (3) collecting and using data for program improvement; (4) fostering a supportive political and community environment; and (5) investing in health system-strengthening activities. Continued advocacy and global investments are required to eliminate AIDS-related deaths among children and adolescents. PMID- 29994832 TI - Beyond Early Infant Diagnosis: Changing the Approach to HIV-Exposed Infants. AB - Despite dramatic global progress with implementing prevention of mother-to-child HIV transmission (PMTCT) programs, there were 160,000 new pediatric HIV infections in 2016. More than 50% of infant HIV infections now occur in the postpartum period, reflecting the relatively high coverage of interventions in the antenatal period and the need for greater attention to the breastfeeding mother and her HIV-exposed infant (HEI). Early diagnosis and treatment are critical to prevent morbidity and mortality in HIV-infected children; however, early infant HIV testing rates remain low in most high HIV-burden countries. Furthermore, systematic retention and follow-up of HEI in the postpartum period and ascertainment of final HIV status remain major program gaps. Despite multiple calls to action to improve infant HIV testing rates, progress has been marginal due to a lack of focus on the critical health care needs of HEI coupled with health system barriers that result in fragmented services for HIV-infected mothers and their families. In this paper, we describe the available evidence on the health outcomes of HEI, define a comprehensive care package for HEI that extends beyond early HIV testing, and describe successful examples of integrated services for HEI. PMID- 29994833 TI - Zvandiri-Bringing a Differentiated Service Delivery Program to Scale for Children, Adolescents, and Young People in Zimbabwe. AB - Since 2004, there has been a dramatic shift in the HIV response for children, adolescents, and young people in low resource settings. Previous programs and services were largely orientated to adults. This is now changing, but there is limited evidence on how to take services for children, adolescents, and young people living with HIV (CAYPLHIV) to scale. Zvandiri is a theoretically grounded, multicomponent-differentiated service delivery model for children, adolescents, and young people in Zimbabwe that integrates peer-led, community interventions within government health services. Africaid analyzed routine program and other data from November 2004 to October 2017 to document Zvandiri scale-up, framed by the World Health Organization framework for scaling up interventions. Since 2004, Zvandiri has evolved from one support group in Harare into a comprehensive model, combining community- and clinic-based health services and psychosocial support for CAYPLHIV. Zvandiri was scaled up across Zimbabwe through phased expansion into 51 of 63 districts, reaching 40,213 CAYPLHIV. Evidence indicates that this approach improved uptake of HIV testing services, adherence, and retention in care. The environment and strategic choices were critical when taking the model to scale, particularly nesting the program within existing services, and capacity strengthening of service providers working jointly with trained, mentored CAYPLHIV. The results provide a firm foundation for programming and from which to build evidence of sustainable impact. Formal impact evaluation is needed and underway. These program data contribute to the essential evidence base on strategic approaches to assist in planning services for this relatively neglected group. PMID- 29994834 TI - The Case For Family-Centered Differentiated Service Delivery for HIV. AB - Differentiated care, or differentiated service delivery (DSD), is increasingly being promoted as one of the possible ways to address and improve access, quality, and efficiency of HIV prevention, care, and treatment. Family-centered care has long been promoted within the provision of HIV services, but the full benefits have not necessarily been realized. In this article, we bring together these two approaches and make the case for how family-centered DSD can offer benefits to both people affected by HIV and the health system. Family-centered DSD approaches are presented for HIV testing and antiretroviral therapy (ART) delivery, referencing policies, best practice examples, and evidence from the field. With differentiated family-centered ART delivery, the potential efficiencies gained by extending ART refills can both benefit clients by reducing the frequency and intensity of contact with the health service and lead to health system gains by not requiring multiple providers to care for one family. A family centered DSD approach should also be leveraged along the HIV care cascade in the provision of prevention technologies and mobilizing family members to receive regular HIV testing. Furthermore, a family-centered lens should be applied wherever DSD is implemented to ensure that, for example, adolescents who are pregnant receive an adapted package of quality care. PMID- 29994835 TI - Getting Treatment and Care Services Right for Children and Adolescents to Reach High Viral Suppression. AB - In August 2014, PEPFAR and the Children's Investment Fund Foundation launched the Accelerating Children's HIV/AIDS Treatment (ACT) initiative with the aim of doubling the number of children on antiretroviral treatment in 9 African countries. Increasing rates of pretreatment drug resistance and use of suboptimal treatment regimens and formulations result in poor adherence and high rates of viral failure. Supporting adherence and ensuring appropriate treatment monitoring are needed to maximize duration of first-line treatment and enable timely sequencing to subsequent lines of antiretroviral treatment. Although timely antiretroviral treatment is the core of clinical care for infants, children and adolescents living with HIV, ensuring a broader package of biomedical and non biomedical interventions is also required to address highly prevalent comorbidities among children living with HIV. Providing such a comprehensive package has been challenging for health care workers who lack the necessary skills and confidence to care for pediatric populations. Efforts to simplify clinical management and specific training and mentorship are needed to address these challenges. In this article, we review the progress made during the ACT initiative and the persistent challenges in achieving and maintaining virological suppression across the age spectrum. We identify innovations needed to build on the success of the ACT initiative. Despite the challenges, achieving high levels of virological suppression in children and adolescents is possible. The complexity of pediatric HIV treatment can be offset as antiretroviral regimens become more effective, tolerable, and easier to prescribe and administer. Meanwhile, basic programmatic elements to address comorbidities as well as support health care workers remain critical. In this article we review the progress made through the ACT initiative, as well as identify innovations needed to address persistent challenges to viral suppression across the age spectrum. PMID- 29994836 TI - Pediatric HIV Treatment Gaps in 7 East and Southern African Countries: Examination of Modeled, Survey, and Routine Program Data. AB - BACKGROUND: Remarkable success in the prevention and treatment of pediatric HIV infection has been achieved in the past decade. Large differences remain between the estimated number of children living with HIV (CLHIV) and those identified through national HIV programs. We evaluated the number of CLHIV and those on treatment in Lesotho, Malawi, Swaziland, Tanzania, Uganda, Zambia, and Zimbabwe. METHODS: We assessed the total number of CLHIV, CLHIV on antiretroviral treatment (ART), and national and regional ART coverage gaps using 3 data sources: (1) Joint United Nations Programme on HIV/AIDS model-based estimates and national program data used as input values in the models, (2) population-based HIV impact surveys (PHIA), and (3) program data from the President's Emergency Plan for AIDS Relief (PEPFAR)-supported clinics. RESULTS: Across the 7 countries, HIV prevalence among children aged 0-14 years ranged from 0.4% (Uncertainty Bounds (UB) 0.2%-0.6%) to 2.8% (UB: 2.2%-3.4%) according to the PHIA surveys, resulting in estimates of 520,000 (UB: 460,000-580,000) CLHIV in 2016-2017 in the 7 countries. This compared with Spectrum estimates of pediatric HIV prevalence ranging from 0.5% (UB: 0.5%-0.6%) to 3.5% (UB: 3.0%-4.0%) representing 480,000 (UB: 390,000-550,000) CLHIV. CLHIV not on treatment according to the PEPFAR, PHIA, and Spectrum for the countries stood at 48% (UB: 25%-60%), 49% (UB: 37% 50%), and 38% (UB: 24%-47%), respectively. Of 78 regions examined across 7 countries, 33% of regions (PHIA data) or 41% of regions (PEPFAR data) had met the ART coverage target of 81%. CONCLUSIONS: There are substantial gaps in the coverage of HIV treatment in CLHIV in the 7 countries studied according to all sources. There is continued need to identify, engage, and treat infants and children. Important inconsistencies in estimates across the 3 sources warrant in depth investigation. PMID- 29994837 TI - Sustainability and Accelerating Children's HIV/AIDS Treatment (ACT) Initiative: Lessons for the Next Treatment Surge. AB - The Accelerating Children's HIV/AIDS Treatment (ACT) Initiative was an ambitious joint donor initiative to increase the number of HIV-positive children and adolescents on treatment over a 2-year period from 2014 to 2016. The funding was provided by the US Government's President's Emergency Plan for AIDS Relief (PEPFAR) and the private Children's Investment Fund Foundation (CIFF). Great gains were achieved across the 9 ACT focus countries in pediatric treatment coverage. This article assesses the status of sustainability in the ACT countries after the pediatric treatment surge using PEPFAR sustainability data and a CIFF independent evaluation of sustainability. Although a focus on treatment is critical for pediatric HIV and HIV broadly, there is also a need to support the host country ability to maintain the progress gained once donor funds and initiatives transition. It uses the case of the ACT Initiative to argue that although surge activities are successful in rapidly scaling treatment results, there are concerns related to the health system's ability to maintain the progress along the full cascade. It shares important lessons for planning for and management of transition to support future donor efforts in pediatric HIV, overall HIV programming, and broader global health initiatives. PMID- 29994838 TI - Editorial introduction. PMID- 29994839 TI - Relevance of human fat distribution on lipid and lipoprotein metabolism and cardiovascular disease risk. AB - PURPOSE OF REVIEW: Upper body abdominal and lower body gluteofemoral fat depot masses display opposing associations with plasma lipid and lipoprotein and cardiovascular disease (CVD) risk profiles. We review developments on adipose tissue fatty acid metabolism in the context of body fat distribution and how that might be related to adverse lipid and lipoprotein profiles and CVD risk. RECENT FINDINGS: Recent data have confirmed the paradoxical relationship of upper abdominal and lower body gluteofemoral adiposity and CVD risk. Mechanistically, this is likely to reflect the different ways fat depots handle lipid storage and release, which impacts directly and indirectly on lipid and lipoprotein metabolism. The upper body enhances immediate fat storage pathway with rapid uptake of dietary-derived fatty acids, whereas the lower body fat depot has a reduced lipid turnover accommodating a slower fat redistribution. Body fat distribution and the fat depots' ability to undergo appropriate expansion when fat storage is required, rather than overall body fatness, appear as the important determinant of metabolic health. SUMMARY: A focus on fat distribution in overweight people, preferably using precise imaging methods, rather than quantifying total body fatness, is likely to provide the medical community with better tools to stratify and treat patients with obesity-related complications. PMID- 29994840 TI - Pleiotropic effects of proprotein convertase subtilisin/kexin type 9 inhibitors? AB - PURPOSE OF REVIEW: Current data suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may affect many metabolic pathways beyond lowering LDL cholesterol. The aim of the present manuscript is to present these so-called pleiotropic effects of PCSK9 inhibitors. RECENT FINDINGS: PCSK9 may affect the activity of other receptors beyond LDL receptors (LDLR), such as cluster of differentiation 36 (CD36), very-low-density-lipoprotein (VLDL) receptors, apolipoprotein (Apo) E receptors, LDLR-related protein 1 (LRP-1) and ATP-Binding Cassette Transporter (ABCA1). Thus, a role of PCSK9 in the development of atherosclerosis, in vascular wall inflammation and in platelet function has been suggested. Additionally, PCSK9 inhibitors may affect lipid variables beyond LDL cholesterol, carbohydrate variables, as well as they may affect brain and kidney function. Additionally, a controversial role of PCSK9 in sepsis, hepatitis C infection and Alzheimer's disease has been suggested. SUMMARY: These possible pleiotropic effects of PCSK9 inhibitors need further research, as they may affect cardiovascular risk and provide further insights in the development of atherosclerosis and other diseases such as Alzheimer's disease or chronic viral infection and sepsis. PMID- 29994841 TI - Paths to progress on protective dietary patterns. PMID- 29994842 TI - Therapy and clinical trials. PMID- 29994843 TI - Facial Implants: Controversies and Criticism. A Comprehensive Review of the Current Literature. AB - BACKGROUND: Polyethylene (Medpor) and silicone are two of the most popular materials used today for facial skeleton implantation. Previous studies have identified common complications with the use of these implants, but patient follow-up has been short. This review of the literature examines complications and patient follow-up in cases using Medpor and silicone implants for reconstructive and aesthetic operations of the mid and lower face over the past 20 years. METHODS: A literature search was conducted through the PubMed database. Keywords used were as follows: ("mandible implants" or "malar implants" or "chin implants") AND ("reconstruction" or "augmentation") AND ("Medpor" or "silicone"). RESULTS: There were nine studies with 626 patients in the Medpor group and five studies with 365 patients in the silicone group. The silicone group had a higher incidence of infections and displacements. The Medpor group showed a higher incidence of prominence problems. Exposure/extrusion rates were low for both implant types. Chin and mandibular implants were the safest, whereas malar implants had a high incidence of prominence problems. The average follow-up for Medpor was 36.6 months and 24 months for silicone. There were wide ranges of follow-up times, from 2 weeks up to 15 years. A limited number of articles included an averaged time within their ranges. Reported follow-up times were not linked to specific complications. CONCLUSIONS: Medpor implantation is more common than silicone. Complication rates are low with the use of both materials. Patient follow-up is deficient and has not improved in the past 20 years, raising questions on the reliability of complication rates. PMID- 29994844 TI - Increasing Nerve Autograft Length Increases Senescence and Reduces Regeneration. AB - BACKGROUND: Nerve grafting with an autograft is considered the gold standard. However, the functional outcomes of long (>3 cm) nerve autografting are often poor. The authors hypothesized that a factor contributing to these outcomes is the graft microenvironment, where long compared to short autografts support axon regeneration to different extents. METHODS: A rat sciatic nerve defect model was used to compare regeneration in short (2 cm) and long (6 cm) isografts. Axon regeneration and cell populations within grafts were assessed using histology, retrograde labeling of neurons regenerating axons, immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction, and electron microscopy at 4 and/or 8 weeks. RESULTS: At 8 weeks, for distances of both 1 and 2 cm from the proximal coaptation (equivalent regenerative distance), long isografts had reduced numbers of regenerated fibers compared with short isografts. Similarly, the number of motoneurons regenerating axons was reduced in the presence of long isografts compared with short isografts. Considering the regenerative microenvironments between short and long isografts, cell densities and general populations within both short and long isografts were similar. However, long isografts had significantly greater expression of senescence markers, which included senescence-associated beta-galactosidase, p21, and p16, and distinct chromatin changes within Schwann cells. CONCLUSIONS: This study shows that axon regeneration is reduced in long compared with short isografts, where long isografts contained an environment with an increased accumulation of senescent markers. Although autografts are considered the gold standard for grafting, these results demonstrate that we must continue to strive for improvements in the autograft regenerative environment. PMID- 29994845 TI - Outcomes of Corticosteroid Treatment for Trigger Finger by Stage. AB - BACKGROUND: Although steroid injection remains a common first-line treatment of trigger finger, clinical experience suggests that not all cases of trigger finger respond the same. The purpose of this study was to use a classification system for trigger finger that is simple and reproducible, and produces clearly definable, clinically relevant cutoff points to determine whether responsiveness to steroid injection correlates to clinical staging. METHODS: The authors conducted a prospectively collected longitudinal study of trigger finger patients separated into four stages of severity. Each subject received a single injection of 6 mg of dexamethasone acetate. One-month outcomes were analyzed to evaluate the efficacy of steroid injection. These outcomes were further stratified based on baseline characteristics and stage of triggering. RESULTS: A total of 99 digits and 69 subjects were included. Two variables were found to be significant in predicting response to initial injection: (1) multiple affected digits and (2) stage severity. Patients with multiple involved fingers were 5.8 times more likely to have no resolution of symptoms compared with those with a single affected finger. For every level of stage increase, the odds doubled for having no resolution of symptoms. CONCLUSIONS: Steroid injection remains a viable first line option for patients presenting with mild triggering (stage 1 and 2). For more severe triggering (stage 3 and 4) or multiple affected digits, the success of steroid injection is significantly lower at 1 month. For the latter patients, surgery may be a more reasonable initial treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 29994846 TI - Treatment of Apert Hand Syndrome: Strategies for Achieving a Five-Digit Hand. AB - BACKGROUND: Apert hand reconstruction requires complex surgical planning. The purpose of this study was to describe the authors' 8-year surgical experience with Apert syndrome hand reconstruction, and provide specific surgical strategies for achieving a five-digit hand in Upton type I and II hands. METHODS: A retrospective analysis of consecutive Apert syndrome patients who underwent web space releases between 2007 and 2015 was performed. Demographic, surgical, and outcome data were verified through medical records, clinical photographs, radiographic images, and patient interviews. RESULTS: A total of 41 Apert syndrome patients [23 boys (56.1 percent) and 18 girls (43.9 percent)] have been treated at our hospital since 2007. A five-digit hand was achieved in all patients (100 percent) with Upton type I and II hands, and in eight patients (72.7 percent) with Upton type III hands. A four-digit hand was obtained in three of 11 patients (27.3 percent) with Upton type III hands. Four of 20 patients (25 percent) with Upton type I hands, three of 10 patients (30 percent) with Upton type II hands, and six of 11 patients (54.5 percent) with Upton type III hands required subsequent revision for aesthetic reasons. CONCLUSIONS: Upton type III hands have demonstrated higher revision rates than type I and II hands, regardless of whether a four- or five-digit hand is obtained. Treatment strategies for Apert syndrome hands based on hand type are offered to guide four web-space release in all patients with Upton type I and II hands. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29994847 TI - Aesthetic Comparison of Two Different Types of Web-Space Reconstruction for Finger Syndactyly. AB - BACKGROUND: Syndactyly reconstruction incorporates techniques of applying skin grafts or dorsal advancement flaps without the use of skin grafts. Comparative outcome studies of these two approaches are lacking. The authors' study compares the long-term aesthetic outcomes of these two flap techniques. METHODS: Forty five patients were included in the authors' study. The methods of reconstruction used were a dorsally based rectangular flap with skin graft from the groin and a dorsal pentagonal advancement flap without skin grafting. Eighteen independent raters completed a visual analogue scale and a unique classification scale to subjectively assess aesthetic outcomes. The authors used univariate analyses to determine which variables significantly influenced the outcome score. The authors then used multivariable regression models to compare the two flap types. RESULTS: Dorsally based rectangular flaps with skin graft had statistically significantly better visual analogue scale scores and greater odds of receiving an "excellent" rating compared with dorsal pentagonal advancement flaps. CONCLUSIONS: Despite the use of skin grafting, with its associated donor-site morbidity, dorsal rectangular flaps may offer better overall aesthetic outcomes for patients. Future comparative studies should incorporate functional and patient-reported outcomes to better assess the optimal reconstruction type. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29994848 TI - Reestablishment of Lymphatic Drainage after Vascularized Lymph Node Transfer in a Rat Model. AB - BACKGROUND: Vascularized lymph node transfer has recently received attention as a potential surgical treatment for lymphedema. Despite good results in some series, the mechanism and benefits of vascularized lymph node transfer have yet to be fully understood. This study aimed to investigate the reestablishment of drainage into transferred lymph nodes following vascularized lymph node transfer in a rat model. METHODS: Seven rats underwent vascularized lymph node transfer. The operation performed on each rat consisted of two parts. First, the left groin lymph node basin with superficial epigastric vessels was harvested as a free flap. Second, the flap was reattached in the left groin of the rat by means of end-to-end microvascular anastomoses. Anastomosis patency was assessed immediately postoperatively and at the time of animal sacrifice. The rats were evaluated for reestablishment of lymphatic flow into the transplanted nodes at 1 month intervals for at least 6 months postoperatively. This was accomplished noninvasively by injecting the rats in their flanks with fluorescent indocyanine green, which was detected using a Photodynamic Eye infrared camera. RESULTS: Anastomoses were patent in all seven rats immediately postoperatively. No indocyanine green uptake was seen in the transplanted lymph node basins in the first 2 months postoperatively in any of the rats. In five of seven rats, however, indocyanine green uptake was demonstrated in the transplanted lymph node basin by 6 months (average, 13 weeks). CONCLUSION: The authors report uptake of indocyanine green in five of seven rats at an average of 13 weeks after lymph node transplantation, consistent with the reestablishment of lymphatic drainage into the transplanted nodes. PMID- 29994849 TI - Cardiac Involvement in Systemic Sclerosis: Diagnostic Tools and Evaluation Methods. AB - The heart is one of the major organs commonly involved in systemic sclerosis. Myocardial fibrosis has been identified in a high percentage of these patients. Most systemic sclerosis patients with cardiac involvement are subclinical, especially early on in the course of their disease. To accurately identify cardiac involvement and improve diagnosis and treatment, imaging techniques should be implemented on a regular basis following diagnosis. In this review, we discuss the up-to-date pathophysiologic basis of cardiac involvement, the cardiac manifestations, and the diagnostic methods which have been published in the literature.Recent studies have shown that tissue Doppler imaging is a promising evaluation technique in the bedside detection of cardiac involvement. Cardiovascular magnetic resonance is an operator-independent method used for detecting systemic sclerosis cardiac involvement. It is an especially useful tool in the early stages of the disease when patients may be asymptomatic. At present, it is the most promising imaging technique for the diagnosis, follow-up and response to therapy in clinical practice. PMID- 29994850 TI - Conditional recurrence-free survival in patients with primary stage I-II cutaneous malignant melanoma - a population-based study. AB - Conditional survival in patients with localized primary cutaneous malignant melanoma (CMM) is well described. However, conditional recurrence-free survival (RFS) has not been investigated before. The aim of this study was to determine conditional RFS and test for time dependency in prognostic factors in patients with localized stage I-II CMM. This study included 1437 CMM patients registered in one region of Sweden during 1999-2012 followed up through 31 December 2012. To identify first recurrence of CMM disease, data from a care data warehouse, the pathology and radiology department registries were used. Patients were also followed through a Census Register and the National Cause of Death Register. The time-dependent risk of recurrence was analysed in a Cox's proportional hazard regression. The 5-year conditional RFS increased from 86% (95% confidence interval: 84-88) at diagnosis to 96% (95% confidence interval: 94-98) at 5 years after diagnosis. Women showed a 60% lower risk of recurrence than men and this effect was stable over time (P=0.39). Patients aged greater than or equal to 65 years had a 40% higher risk of recurrence than patients aged less than 65 years, and this effect was stable over time (P=0.65). Patients with tumour ulceration showed a 70% higher risk of recurrence than nonulcerated patients, but this effect disappeared after 2 years (P=0.04). For patients with T3-T4 CMM, the hazard ratios decreased over time and were similar to hazard ratio of patients with T2 CMM after 2 years and later. The decreasing impact of tumour thickness and ulceration over time could have important implications for CMM patients in terms of counselling and follow-up. PMID- 29994851 TI - Botulinum toxin injection and tear production. AB - PURPOSE OF REVIEW: In 1980, botulinum toxin type A (BTX-A) was introduced for the treatment of strabismus and benign essential blepharospasm. Since then, a number of additional indications have been introduced, which continue to expand, providing less invasive solutions in managing different ophthalmic conditions. RECENT FINDINGS: Successful trials of BTX-A injection into the lacrimal gland have been reported for the treatment of epiphora caused by primary lacrimal gland hyperlacrimation, functional tearing, gustatory tearing, and lacrimal outflow obstruction. This is achieved through blockage of the cholinergic receptors by BTX-A at the glandular level. Interestingly, BTX-A has also been found to be useful in treating patients with dry eyes by compromising the tear drainage from the eye through injection of BTX-A in the medial part of the lower eyelid. BTX-A may help provide effective relief for patients who have two different ophthalmic comorbidities such as benign essential blepharospasm and dry eye. SUMMARY: Better understanding of the mechanism of BTX-A action in the treatment of the growing applications in ophthalmology helps provide relatively noninvasive solutions for patients. Full awareness of possible side effects of BTX-A and the optimal way to manage them is vital for the success of this treatment option. PMID- 29994852 TI - Infection following strabismus surgery. AB - PURPOSE OF REVIEW: To provide the most up to date information on postoperative infection associated with strabismus surgery, its diagnosis, management, and prevention. RECENT FINDINGS: Recent studies show that topical povidone-iodide is effective in reducing the bacteria colony count at the incision site and preventing contamination during strabismus surgery. Repeating povidone-iodide 5% drops after surgical preparation and presoaking the sutures in povidone-iodide reduces bacterial contamination further. There is no single postoperative day that would be best to detect the onset of a postoperative infection. Infection can follow a normal postoperative visit. SUMMARY: Infection continues to be a concerning complication of strabismus surgery. Early detection and treatment is needed to obtain a good outcome. Patients and their families should be educated on the early signs and symptoms of postoperative infection and to contact their ophthalmologist if any occur. PMID- 29994853 TI - Physical therapy for facial nerve palsy: applications for the physician. AB - PURPOSE OF REVIEW: The aim of this study was to describe the current state of physical therapy for facial nerve palsy, the evidence basis for these interventions and how therapy can be integrated with other medical and surgical interventions for facial nerve palsy, as it applies to ophthalmologists, oculoplastic surgeons and other specialists. RECENT FINDINGS: Many studies indicate that physical therapy is effective for the rehabilitation of patients with facial nerve palsy and can be used synergistically with interventions administered by physicians, such as targeted botulinum toxin injections. The field is limited by a relative paucity of high-quality randomized controlled trials. Alternative therapies including Brief Electrical Stimulation continue to be studied; however, they lack a scientific rationale and, anecdotally, appear to cause more problems in cases of incomplete facial nerve recovery. SUMMARY: Physical therapy, specifically neuromuscular retraining, is a useful intervention for treating facial nerve palsy. Care for these patients is best delivered in a multidisciplinary setting in which physical therapy and medical or surgical interventions can be closely integrated. Further study aimed at standardizing physical therapy and optimizing the integration of this with other treatments for facial nerve palsy are needed. PMID- 29994855 TI - Context for Practice: Clinically Meaningful Versus Statistically Significant Differences: Why You Should Care. PMID- 29994854 TI - Current concepts in convergence insufficiency. AB - PURPOSE OF REVIEW: As the majority of our patients are spending significant time using computers and reading, it is important to understand any disease process that can affect one's near vision. Convergence insufficiency, not an uncommon condition, is still not screened for by most eyecare professionals. This review aims to report the current screening methods and diagnostic criteria, and to summarize the current treatment of convergence insufficiency. RECENT FINDINGS: The current literature shows that convergence insufficiency has a prevalence of 2 17% in the general population and an even higher rate, up to 49%, in patients who have suffered a traumatic brain injury. Although the measurement is still not standardized, near point of convergence and patient symptomatology appear to be an appropriate screen for convergence insufficiency. Further study is needed to establish standardization of diagnostic criteria. It is now well recognized that orthoptic/vergence therapy provides excellent improvement in the clinical measurements and symptoms associated with convergence insufficiency. SUMMARY: Convergence insufficiency is a condition that causes a significant impact on near vision. Treatment with orthoptic/vergence therapy can reduce symptomatology and greatly improve one's quality of life. Further study is needed to provide an evidence-based definition that encompasses all cases of convergence insufficiency, research possible subtypes of the disease and establish the efficacy of home-based computer therapy as compared to office-based orthoptic/vergence therapy. PMID- 29994856 TI - Statistical Comments on "The Effect of Foot Exercise on Wound Healing in Type 2 Diabetes Patients With a Foot Ulcer". PMID- 29994857 TI - Authors' Response to Letter to the Editor Re: The Effect of Foot Exercises on Wound Healing in Type 2 Diabetic Patients With a Foot Ulcer: A Randomized Control Study. PMID- 29994858 TI - Patient-Reported Outcome After Ostomy Surgery for Chronic Constipation. AB - PURPOSE: The purpose of this study was to describe experiences of and evaluate psychosocial and health-related quality of life of individuals undergoing ostomy surgery for severe, chronic constipation. METHODS: A search of the local ostomy archive and the electronic hospital episode statistics database was performed in a large tertiary referral center. Study outcomes were evaluated retrospectively using clinical notes and prospectively via administration of the City of Hope Ostomy Quality of Life questionnaire, Medical Outcomes Study Short Form-36, Hospital Anxiety and Depression tool, and a specially designed ostomy-specific questionnaire. Questionnaires were mailed and returned via post. RESULTS: Twenty four patients, with a median age of 44 years (interquartile range [IQR] = 31-56), who underwent ileostomy (n = 20) and colostomy (n = 4) over a 13-year period participated in the study. The vast majority of respondents (91%; n = 22) were female. Ten (41%) underwent laparoscopic surgery, 13 (54%) underwent open procedures, and 1 was converted from laparoscopic to open surgery. The mean length of stay (5.5 days vs 5.4 days) and the rate of complication did not differ between the 2 approaches. Fourteen patients (13 females, median age = 47.5 years; IQR = 23-70 years) responded to the postal questionnaires (58.3%). Adverse effects on health-related quality of life in the physical and social well-being domains were reported, and a further 86% of respondents reported psychological morbidity related to their ostomy. However, more than 70% were satisfied (median follow-up = 17 months; IQR = 0.16-8 years) with their quality of life despite a 20% reoperation rate. CONCLUSIONS: An ostomy is a justified last-resort treatment option in selected individuals with severe, chronic constipation. Patients should be warned of the negative effects on health-related quality of life and the risk of complications. We advocate using an algorithm presented in this article. PMID- 29994859 TI - Clinical Practice Guidelines for the Nursing Management of Percutaneous Endoscopic Gastrostomy and Jejunostomy (PEG/PEJ) in Adult Patients: An Executive Summary. AB - Enteral nutrition (EN) is the introduction of nutrients into the gastrointestinal tract through a tube placed in a natural or artificial stoma. Tubes may be passed into the stomach (gastrostomy) or the jejunum (jejunostomy) in patients who cannot obtain adequate nourishing via oral feeding. Following placement, nurses are typically responsible for management of gastrostomy or other enteral tube devices in both the acute and home care settings. This article summarizes guidelines developed for nursing management of percutaneous endoscopic gastrostomy or jejunostomy (PEG/PEJ) and gastrojejunostomy (PEGJ) tubes, developed by the Italian Association of Stoma care Nurses (AIOSS-Associazione Italiana Operatori Sanitari di Stomaterapia) in collaboration with the Italian Association of Endoscopic Operators (ANOTE-Associazione Nazionale Operatori Tecniche Endoscopiche) and the Italian Association of Gastroenterology Nurses and Associates (ANIGEA-Associazione Nazionale Infermieri di Gastroenterologia e Associati). The guidelines do not contain recommendations about EN through nasogastric tubes, indications for PEG/PEJ/PEGJ positioning, composition of EN, selection of patients, type of tube, modality of administration of the EN, and gastrointestinal complications. PMID- 29994860 TI - Clinical Practice Guidelines for the Nursing Management of Percutaneous Endoscopic Gastrostomy and Jejunostomy (PEG/PEJ) in Adult Patients: An Executive Summary. PMID- 29994861 TI - Development and Validation of an Instrument Measuring Self-Care in Persons With a Fecal Ostomy. AB - PURPOSE: The purpose of this study was to describe development of the Specific Self-Care for Ostomized Patients Questionnaire (CAESPO) instrument and evaluate its construct validity, internal reliability, and test-retest reliability (temporal stability). DESIGN: Prospective evaluation of psychometric properties of the instrument. SUBJECTS AND SETTING: The study sample comprised 125 persons (n = 89, 71.2% men) with a temporary (n = 42, 33.6%) and permanent (n = 83, 66.4%) colostomy (n = 102, 81.6%) and ileostomy (n = 23, 18.4%). Their mean age was 66.72 years; all had undergone ostomy surgery at least 3 months prior to study participation. Participants were drawn from 4 acute care facilities in the province of Castellon, Spain. INSTRUMENT: The CAESPO Questionnaire is completed by a nurse or health care provider. It comprises 3 sections: the first queries sociodemographic data, the second queries pertinent clinical data, and the third contains 58 scored items with 4 ordinal responses. Possible cumulative scores ranged from 58 to 232 points; scores are reported based on a derived percentage score that varies from 0 to 100, where a score of 0 indicates lower self-care and 100 indicates a high level of self-care. METHODS: Data were collected at baseline and retesting was completed 6 months later. Internal consistency of the CAESPO was evaluated using the Cronbach alpha coefficient; temporal stability (test retest reliability) was evaluated using the test-retest procedure; confirmatory factor analysis based on conceptually hypothesized factor structure was performed to evaluate construct validity. RESULTS: Initial assessment of the construct validity of the CAESPO using confirmatory factory analysis revealed a poor fit, resulting in removal of multiple items from each of the subscales owing to low factor loading values. The final model comprised 58 scored items; it was found to have a good fit based on standard indices (chi= 43.132, P < .001; root mean square error of approximation = 0.155 [0.107-0.204]; Bentler-Bonett normed fit index = 0.957; comparative fit index = 0.967; incremental fit index = 0.968), indicating adequate construct validity. The internal consistency of the CAESPO total score was acceptable at alpha = 0.889. Test-retest reliability (temporal stability) was deemed excellent (alpha = 0.987). CONCLUSIONS: Psychometric tests indicate that the CAESPO is a valid and reliable instrument for measuring self care in persons living with a fecal ostomy. PMID- 29994862 TI - The Impact of Microclimate on Skin Health With Absorbent Incontinence Product Use: An Integrative Review. AB - This integrative review considers the role of skin occlusion and microclimate in incontinence-associated dermatitis (IAD), with a particular focus on disposable, body-worn, absorbent incontinence products. Although the mechanisms are not fully understood, the primary causes of IAD are well-established: occluded skin, in prolonged contact with urine and/or feces and exposed to abrasive forces, is more likely to be affected, and each of these factors can be influenced by wearing absorbent incontinence products. Studies comparing the effect of various absorbent products on skin health have been hindered by the many differences between compared products, making it difficult to clearly attribute any differences in performance to particular materials or design features. Nevertheless, the large and significant differences that have sometimes been found invite further work. Breathable back sheets can significantly reduce the temperature of occluded skin and the humidity of the adjacent air, and several treatments for nonwoven top sheet materials (used next to the skin) have been shown to impart antimicrobial properties in the laboratory, but an impact on IAD incidence or severity has yet to be demonstrated directly. Recent work to introduce sensing technology into absorbent incontinence products to reduce the exposure of skin to urine and feces, by encouraging prompt product changing, seems likely to yield measurable benefits in terms of reducing incidents of IAD as the technology develops. Published work to date suggests that there is considerable potential for products to be engineered to play a significant role in the reduction of IAD among users. PMID- 29994863 TI - Incontinence, Incontinence-Associated Dermatitis, and Pressure Injuries in a Health District in Australia: A Mixed-Methods Study. AB - PURPOSE: This purpose of this study was to measure the prevalence of incontinence, incontinence-associated dermatitis (IAD), and pressure injuries (PIs) in a local health district in Australia. We also aimed to determine associated evidence-into-practice gaps. DESIGN: Multisite mixed-methods study. SUBJECTS AND SETTINGS: The sample comprised 250 adult patients in 12 units across 4 hospitals; their mean age was 73 years. Nurses caring for the patient at the time of the audit were questioned on nursing practice for patients with incontinence. METHODS: A 2-page audit tool was developed and used to capture demographic data, continence and mobility status, IAD and PI, incontinence products, nursing practice observations, and nurses' comments. Each patient was assessed by 2 senior nurses. Quantitative analysis included descriptive statistics and bivariate analysis using a chi test to examine the association between mobility and incontinence and a Fisher exact test to examine the association between IAD and PI. Content analysis was used to analyze qualitative data and develop themes. RESULTS: Almost half of patients had incontinence (n = 111/250), 20.7% of patients with incontinence (n = 23/111) had IAD, and 6.3% (n = 7/111) had hospital-acquired PI. There was a significant association between incontinence and mobility, and between IAD and PIs. In addition, 22.3% of patients who were continent (31/139) were wearing an incontinence product. Analysis of qualitative data found that both incontinence management and language used to refer to incontinence pads were incompatible with current best practices. CONCLUSION: The prevalence of incontinence among patients observed in this study was similar to rates reported internationally, but the prevalence of IAD was slightly lower. The association between IAD and PIs, as well as incontinence and mobility, was statistically and clinically significant. Nurses commonly used interventions with little or no evidence. Hospitals should put measures in place to improve nurses' knowledge of incontinence, IAD, and PI practices. PMID- 29994864 TI - Using Alternative Light Source Technology to Enhance Visual Inspection of the Skin. AB - BACKGROUND: The identification of deep tissue pressure injury (DTPI) in the early stages of evolution presents a challenge, as skin compromise is only visually apparent when evidence of damage reaches its outer layers. CASE DESCRIPTION: We describe use of an alternative light source (ALS) to enhance visual skin assessment in 3 cases. Case 1 was a 47-year-old African American man with a hyperpigmented inner buttocks and a mixture of partial- and shallow full thickness skin loss from incontinence-associated dermatitis and friction. Case 2 was a 62-year-old African American woman with a gluteal cleft DTPI. Case 3 was a 57-year-old African American woman with a stage 3 pressure injury of the right buttock. CONCLUSION: The ALS enabled visualization of skin nuances not visible to the unaided eye. Based on this experience, we conclude that use of an ALS provided additional visual details when compared to traditional visual inspection. We found that as the ALS interplays with skin layers, penetrating and absorbing at differing depths, compromised skin appeared darker and more distinct when compared to adjacent, intact skin. Additional research is needed to determine whether the ALS enables earlier pressure injury detection, timelier and more effective intervention, decreased morbidity, and cost savings. PMID- 29994866 TI - Getting Ready for Continence Certification: Challenges of Functional Incontinence. PMID- 29994865 TI - Biological Approach for Managing Severe Gunshot Wounds: A Case Report. AB - BACKGROUND: Autologous formulations rich in bioactive proteins promote cutaneous tissue regeneration. This case report describes our experiences with a platelet based autologous formulation in the management of a hard-to-heal and severe gunshot wound. CASE: A healthy, 34-year-old man suffered an accidental gunshot wound of his right foot. After cleansing with saline and application of vacuum assisted closure therapy for a period of 5 weeks, the resulting full-thickness wound had a surface area of 20 cm and did not show progress toward closure despite ongoing treatment. Plasma-rich growth factor (PRGF) therapy was used in order to promote tissue regeneration. The patient's own blood was drawn, centrifuged, and platelet-rich plasma was obtained. Intradermal injections of freshly activated platelet-rich plasma were administered into the wound edges, and a fibrin membrane was applied on the wound bed. Afterward, a novel topical ointment based on the patient's own growth factors was used as a daily therapy over the affected tissue. RESULTS: This full-thickness wound healed after 16 weeks of autologous growth factor therapy. The patient was able to walk without pain. CONCLUSION: Plasma-rich growth factor therapy successfully healed this full thickness wound that did not respond to a period of 5 weeks with negative pressure wound therapy using a vacuum-assisted device. Healing occurred after 16 weeks of treatment, and he was able to resume walking without pain or functional deficits. PMID- 29994867 TI - WOCN(r)-Accredited Professional Education Programs. PMID- 29994868 TI - Accuracy of Administrative Health Data for Surveillance of Traumatic Brain Injury: A Bayesian Latent Class Analysis. AB - BACKGROUND: Traumatic brain injury surveillance provides information for allocating resources to prevention efforts. Administrative data are widely available and inexpensive but may underestimate traumatic brain injury burden by misclassifying cases. Moreover, previous studies evaluating the accuracy of administrative data surveillance case definitions were at risk of bias by using imperfect diagnostic definitions as reference standards. We assessed the accuracy (sensitivity/specificity) of traumatic brain injury surveillance case definitions in administrative data, without using a reference standard, to estimate incidence accurately. METHODS: We used administrative data from a 25% random sample of Montreal residents from 2000 to 2014. We used hierarchical Bayesian latent class models to estimate the accuracy of widely used traumatic brain injury case definitions based on the International Classification of Diseases, or on head radiologic examinations, covering the full injury spectrum in children, adults, and the elderly. We estimated measurement error-adjusted age- and severity specific incidence. RESULTS: The adjusted traumatic brain injury incidence was 76 (95% CrI = 68, 85) per 10,000 person-years (underestimated as 54 [95% CrI = 54, 55] per 10,000 without adjustment). The most sensitive case definitions were radiologic examination claims in adults/elderly (0.48; 95% CrI = 0.43, 0.55 and 0.66; 95% CrI = 0.54, 0.79) and emergency department claims in children (0.45; 95% CrI = 0.39, 0.52). The most specific case definitions were inpatient claims and discharge abstracts (0.99; 95% CrI = 0.99, 1.00). We noted strong secular trends in case definition accuracy. CONCLUSIONS: Administrative data remain a useful tool for conducting traumatic brain injury surveillance and epidemiologic research when measurement error is adjusted for. PMID- 29994869 TI - Securing the Appendiceal Stump During Emergency Appendicectomy: Options and Influencing Factors in Current UK Surgical Practice. AB - INTRODUCTION: The aim of our study was to identify the most commonly employed methods and influencing factors for securing the appendiceal stump in current NHS practice. METHODS: An electronic survey of the Scottish Surgical Research Group network, invitation extended to the UK National Research Collaborative. RESULTS: A total of 111 responses were received from 32 surgical centers; 28 (25.2%) consultants, 66 (59.5%) specialty trainees and 12 (10.8%) core trainees. Endoscopic ligatures were the preferred method in 96 (86.5%) with no difference in those with the greatest operative experience (P=0.79), 12 (10.8%) preferred polymeric clips. Ease of application (70.3%) and severity of stump inflammation (65.8%) had the greatest influence on the method chosen. Cost was a factor in 36.0%. CONCLUSIONS: The preferred method for securing the appendiceal stump in UK practice is endoscopic ligatures regardless of operative experience. Factors with the greatest influence on the method employed include the ease of application and severity of stump inflammation. Our findings are likely to be representative of current NHS practice in Scotland. PMID- 29994871 TI - Osteopetrosis-Anesthetic Considerations for Total Knee Arthroplasty: A Case Report. AB - Autosomal dominant or benign osteopetrosis is a rare genetic disorder of osteoclasts that results in dense but brittle bone structures. Patients with osteopetrosis may be scheduled for total knee arthroplasty to treat painful and functionally limiting osteoarthrosis. A search of the published literature produced no citation concerning anesthesia for patients with autosomal dominant osteopetrosis undergoing total knee arthroplasty. We present a case report detailing our experience and discuss considerations for the care of future patients with autosomal dominant osteopetrosis. PMID- 29994870 TI - A case of diencephalic syndrome presenting with isolated lipodystrophy. AB - Diencephalic syndrome is a disorder characterized by severe emaciation during childhood. The rarity of the disorder coupled with nonspecific symptomology means that there is often a protracted diagnostic journey. Here, we report a child who was referred to a clinical genetics service for investigation of lipodystrophy and failure to thrive. A broad range of genetic differential diagnoses were considered and investigated before a mass lesion was identified in the hypothalamus, confirming diencephalic syndrome. In the context of this case, we consider the relevant differentials and appropriate workup of a child with lipodystrophy presenting to a genetics service. This report also highlights the importance of considering diencephalic syndrome in cases such as this. PMID- 29994872 TI - Refeeding syndrome in the gastroenterology practice: how concerned should we be? AB - Clinical nutrition is emerging as a major area in gastroenterology practice. Most gastrointestinal disorders interfere with digestive physiology and compromise nutritional status. Refeeding syndrome (RS) may increase morbidity and mortality in gastroenterology patients. Literature search using the keywords "Refeeding Syndrome", "Hypophosphatemia", "Hypomagnesemia" and "Hypokalemia". Data regarding definition, pathophysiology, clinical manifestations, risk factors, management and prevention of RS were collected. Most evidence comes from case reports, narrative reviews and scarse observational trials. RS results from the potentially fatal shifts in fluid and electrolytes that may occur in malnourished patients receiving nutritional therapy. No standard definition is established and epidemiologic data is lacking. RS is characterized by hypophosphatemia, hypomagnesemia, hypokalemia, vitamin deficiency and abnormal glucose metabolism. Oral, enteral and parenteral nutrition may precipitate RS. Awareness and risk stratification using NICE criteria is essential to prevent and manage malnourished patients. Nutritional support should be started using low energy replacement and thiamine supplementation. Correction of electrolytes and fluid imbalances must be started before feeding. Malnourished patients with inflammatory bowel disease, liver cirrhosis, chronic intestinal failure and patients referred for endoscopic gastrostomy due to prolonged dysphagia present high risk of RS, in the gastroenterology practice. RS should be considered before starting nutritional support. Preventive measures are crucial, including fluid and electrolyte replacement therapy, vitamin supplementation and use of hypocaloric regimens. Gastroenterology patients must be viewed as high risk patients but the impact of RS in the outcome is not clearly defined in current literature. PMID- 29994873 TI - Esophageal varices are not predictive of patient prognosis after surgical resection of hepatocellular carcinoma. AB - OBJECTIVE: The predictive value of esophageal varices (EV) in determining the patient outcome in hepatocellular carcinoma (HCC) remains unresolved. We aimed to assess the impact of EV on the prognosis of HCC patients after surgical resection. MATERIALS AND METHODS: We consecutively enrolled 446 treatment-naive HCC patients who underwent surgical resection and esophagogastroduodenoscopy from 2003 to 2015. Prognostic factors were analyzed using the Cox proportional hazards model and a propensity score matching analysis. RESULTS: A total of 89 (20.0%) HCC patients presented with EV. Compared with those without EV, patients with EV had poorer preservation of liver function and higher rates of cirrhosis in the nontumor part of liver specimens. After a median follow-up period of 34.6 months (25-75 percentiles; 12.8-59.3 months), 130 patients had died. The cumulative 5 year overall survival (OS) rates were 62.3 and 70.6% in patients with and without EV, respectively (P=0.102). A multivariate analysis showed that serum albumin level less than or equal to 4 g/dl (P=0.020), alpha-fetoprotein level greater than 20 ng/ml (P<0.001), as well as the presence of vascular invasion (P<0.001), but not the presence of EV, were independent risk factors associated with poor OS. Moreover, 67 patients were matched in each group using the one-to-one nearest neighbor matching method. After matching, the OS rates were comparable between HCC patients with and without EV. CONCLUSION: EV is not an independent risk factor predictive of poor prognosis for HCC patients after resection surgery if they have well-preserved liver function. PMID- 29994874 TI - Outcome and adverse events in patients with chronic hepatitis C treated with direct-acting antivirals: a clinical randomized study. AB - OBJECTIVE: New potent direct-acting antiviral (DAA) regimens against hepatitis C virus have been approved in recent years. However, information about the rate of adverse events (AEs) across different DAA regimens is limited. We aimed to evaluate differences in AEs and treatment efficacy in patients with chronic hepatitis C (CHC), genotype (GT) 1 or 3, randomized to two different treatment arms, correspondingly. PATIENTS AND METHODS: We randomly assigned 96 patients in a 1 : 1 ratio, to treatment for 12 weeks with either paritaprevir/ombitasvir/ritonavir/dasabuvir/ribavirin (RBV) or ledipasvir/sofosbuvir (SOF)/RBV if infected with GT1 (72 patients) or to daclatasvir/SOF/RBV for 12 weeks or SOF/RBV for 24 weeks, if infected with GT3 (24 patients). Data on AEs were collected throughout the entire study period. RESULTS: A total of 70 (97%) patients with CHC with GT1 and 20 (83%) patients with GT3 achieved cure. The GT3 treatment arm was prematurely terminated, owing to change in national treatment guidelines. Thus, only AEs for GT1 patients are described. AEs occurred in 70 (97%) GT1 patients, and most common AEs were anemia (n=56/78%), fatigue (n=53/74%), and headache (n=33/46%). No difference was observed in relation to treatment group (P=1.0), anemia (P=1.0), or liver cirrhosis (P=0.53). In seven (11%) patients, AEs assessed by the investigator to be possibly related to the DAA regimen were still present 12 weeks after treatment. CONCLUSIONS: We found no difference in AEs possibly related to the DAA regimen in patients with CHC, but surprisingly, AEs possibly related to the DAA regimen persisted in a significant number of patients after treatment. This finding can be of importance for clinicians in relation to patient information concerning AEs possibly related to DAA treatment. PMID- 29994875 TI - Quantification of Chronic Lymphedema in a Revised Mouse Model. AB - BACKGROUND: Lymphedema is a common and debilitating complication following cancer treatment with surgical lymph node excision and radiotherapy. Currently there are no curative treatments for lymphedema. Animal models that intended to replicate the disease have been inadequate, making a troublesome transition from experimental therapeutic studies into the clinic. It is therefore imperative to establish an experimental animal model that can reliably replicate clinical lymphedema. METHODS: To discover the optimal method of lymphedema induction, surgical lymph ablation and irradiation or silicone splint emplacement were combined in 8 experimental groups (n = 4). In total, 32 mice served in this study and were followed for 8 weeks after surgery. Outcomes included micro-computed tomography hind limb volumetry, lymphatic clearance measured with technetium Tc 99m (Tc) human serum albumin lymphoscintigraphy and lymph vessel ectasia quantified with LYVE-1 immunohistochemistry. RESULTS: All trialed models but one resulted in only transient lymphedema or lasting lymphedema with adverse morbidity. Combined surgical lymph obstruction with 2 fractions of 10-Gy irradiation successfully induced lasting lymphedema without adverse events. Over the 8 weeks' follow-up, limb volumes were significantly increased at all time points (P < 0.001), lymph drainage was impaired (P < 0.001), and lymph vessels were ectatic (P < 0.001), when compared with the unoperated limbs. CONCLUSIONS: The presented model of acquired lymphedema is a reduction and refinement of previous works and can transpose to future observational and interventional studies. In addition, it is shown how Tc-HSA lymphoscintigraphy can quantify lymphatic clearance, which can prove insightful in therapeutic studies aiming to enhance lymphatic drainage. PMID- 29994876 TI - Using a Bilobed Trapezius Myocutaneous Flap and a Scapula Osteomyocutaneous Flap to Reconstruct Through-and-Through Defects of the Hemimandible After Debridement of Advanced Mandibular Osteoradionecrosis. AB - OBJECTIVE: The purpose of this study was to evaluate the outcomes of reconstructing through-and-through defects of the hemimandible after debridement of advanced mandibular osteoradionecrosis (ORN) with bilobed trapezius myocutaneous flaps and scapula osteomyocutaneous flaps. METHODS: Six patients with grade III mandibular ORN were treated with debridement of lesions. Type IIb soft tissue and type H hemimandible defects after surgery were reconstructed using bilobed trapezius myocutaneous flaps and scapula osteomyocutaneous flaps including the acromion, spine, and part of the medial scapular border based on the transverse cervical vessels. RESULTS: No flap failure occurred. Two patients experienced minor complications; one showed wound dehiscence at the donor site, and one showed minor plate exposure. No patient required nasogastric tube feeding or a permanent tracheotomy. The appearance of the face and neck was satisfactory or acceptable in all patients. No patient showed severely limited range of motion in the upper limb. The patients were followed for 8 to 22 months; at the end of follow-up, all patients were living with no recurrence evidence of mandibular ORN or nasopharyngeal carcinoma. CONCLUSIONS: The bilobed trapezius myocutaneous flap and scapula osteomyocutaneous flap based on transverse cervical vessels may be an effective approach to reconstruct through-and-through defects of the hemimandible and to provide satisfactory or acceptable functional and esthetic outcomes after debridement of advanced mandibular ORN. PMID- 29994877 TI - Medial Plantar Flap for Hand Reconstruction: A Systematic Literature Review and Its Application for Post-Sarcoma Excision. AB - The reconstruction of soft tissue defects on the volar aspect of the hand represents a special challenge for the hand surgeon. Even though local and regional options have been described, in some cases because of their complexity, a free flap is preferred. The medial plantar free flap offers a unique reconstructive alternative by providing glabrous skin resurfacing for the palm and digits. The aim of this article is to present a systematic literature review on the use of the medial plantar free flap for hand surgery and a case report in which this flap was used for reconstructing a thenar eminence defect after sarcoma excision. Twenty-five relevant articles were found, and their findings are included in our study. The fasciocutaneous medial plantar flap and its musculocutaneous, flow-through, venous, perforator, and chimeric variants offer a wide range of reconstructive options for complex hand injuries. PMID- 29994878 TI - Does Bowstringing Affect Hand Function in Patients Treated With A1 Pulley Release for Trigger Fingers?: Comparison Between Percutaneous Versus Open Technique. AB - We aimed to inspect bowstringing after percutaneous and open release of the A1 pulley for trigger digits and its influence on hand function. Sixty-two patients with a resistant trigger digit were randomized to undergo either open release or percutaneous release of the A1 pulley. We quantified bowstringing of the digit using ultrasonography preoperatively and at 12 and 24 weeks after surgery. Pain on a visual analog scale; Disabilities of the Arm, Shoulder, and Hand questionnaire; pinch power; and grip strength were assessed. Bowstringing was significantly increased at 12 weeks after surgery in both groups, and the mean value of the open release group was significantly greater than that of the percutaneous group (2.30 +/- 0.58 mm vs 1.46 +/- 0.51 mm, respectively; P = 0.035). However, the bowstringing was decreased at 24 weeks without showing significant difference between the 2 groups. The clinical outcomes of each cohort improved significantly, with no difference between the groups at final follow-up. No association was found between bowstringing and any clinical outcome measure. Bowstringing occurred by A1 pulley release with either the percutaneous or open technique does not affect clinical hand function in patients with trigger fingers. PMID- 29994879 TI - Successful Relief of a Male Breast Lymphedema by Supermicrosurgical Lymphaticovenular Anastomosis. AB - BACKGROUND: Breast lymphedema is a common issue after breast cancer surgery but remains understudied because it is difficult to be quantified. Untreated breast lymphedema may lead to severe form of delayed breast cellulitis. Supermicrosurgical lymphaticovenular anastomosis is one option for the treatment of breast cancer-related lymphedema but has not been described for the treatment of breast lymphedema. METHODS: This report presented a rare case of male breast lymphedema secondary to axillary lymph node dissection for the treatment of a forearm melanoma. Deep lymphatic vessels and adjacent venules were individualized under high magnification in the periareolar area. Six lymphaticovenular anastomoses were performed using supermicrosurgical techniques. A clinical examination and a volume assessment under magnetic resonance imaging were used to assess the efficiency of surgery. RESULTS: Postoperative outcome was uneventful. The patient was followed-up during 1 year. Swelling relief was clinically significant 3 months postoperatively. The pinch test reduction was 2 cm after 12 months. The breast volume reduction rate was 47.2%. CONCLUSIONS: Supermicrosurgical lymphaticovenular anastomosis may be efficient for the treatment of postoperative breast lymphedema, even in male patients. PMID- 29994880 TI - Outcome of the Modified Meek Technique in the Management of Major Pediatric Burns. AB - INTRODUCTION: The modified Meek micrografting technique has been used in the treatment of severely burned patients and a number of articles have examined the use of the modified Meek technique in adults and in mixed-age groups. However, there is a paucity of research pertaining to the outcome in the pediatric age group. The aim of this study is to present our favorable outcome in pediatric major burns using the modified Meek technique. METHODS: A retrospective review of burn cases in Hospital Universiti Sains Malaysia from 2010 to 2015 was conducted. Cases of major burns among pediatric patients grafted using the Meek technique were examined. RESULTS: Twelve patients were grafted using the Meek technique. Ten (91.7%) patients were male, whereas 2 (8.3%) were female. The average age of patients was 6 years (range, 2-11 years). The average total body surface area was 35.4% (range, 15%-75%). Most burn mechanisms were due to flame injury (66.7%) as compared with scalds injury (16.7%) and chemical injury (16.7%). There was no mortality. All patients were completely grafted with a good donor site scar. The average graft take rate was 82.3%, although 8 cases had positive tissue cultures from the Meek-grafted areas. The average follow-up duration was 3.6 years (range, 1.1-6.7 years). Only 1 case developed contracture over minor joint. CONCLUSIONS: The Meek technique is useful when there is a paucity of donor site in the pediatric group. The graft take is good, contracture formation is low, and this technique is cost-effective. PMID- 29994881 TI - Cadaver Study of Combined Neurovascular Sensate Flaps to Create Vaginal Erogenous Sensation During Male-to-Female Genital Confirmation Surgery: The Pedicle "O" Flap. AB - PURPOSE: The lack of erogenous sensitivity in the neovagina is one of the major shortcomings for patients undergoing male-to-female genital confirmation surgery. Remnant fibers of the dorsal nerve of the penis (DNP) after clitroplasty can potentially be used for a second neurovascular pedicle flap for intravaginal erogenous sensation. METHODS: An anatomic dissection of the DNP was performed in 10 male frozen pelvises to identify major trunks and their branches. Lateral branches of DNP were preserved for a sensate "O" pedicle flap for the vagina. The number of main branches in the lateral dorsal aspect of the penis was calculated to ensure sufficient erogenous innervation to the vagina. Cross sections of the penis were used for histological analysis. Optimal width and length of the new sensate flap were described. RESULTS: There were 1, 2, and 3 main branches in the lateral compartment in 2 (20%), 6 (30.7%), and 2 (42.8%) cadavers, respectively. A sensate pedicle flap from the lateral aspect of the glans penis with a mean width of 1.14 cm (range, 0.9-1.28 cm) ensured at least one main branch of the DNP for erogenous sensitivity of the vagina. This sensate vaginal flap and its neurovascular pedicle had a mean length of 9.8 cm (range, 8.7-10.3 cm) allowing its inset into the anterior vaginal canal. CONCLUSION: Lateral branches of the DNP can be preserved for a pedicle sensate flap to the vagina, which can provide patients with an erogenous vaginal "spot" during male-to-female confirmation surgery. PMID- 29994882 TI - Validation and Clinical Evaluation of a Method for Double-Blinded Blood Pressure Target Investigation in Intensive Care Medicine. AB - OBJECTIVES: No double-blinded clinical trials have investigated optimal mean arterial pressure targets in the ICU. The aim of this study was to develop and validate a method for blinded investigation of mean arterial pressure targets in patients monitored with arterial catheter in the ICU. DESIGN: Prospective observational study (substudy A) and prospective, randomized, controlled clinical study (substudy B). SETTING: ICU, Department of Cardiology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark. PATIENTS: Adult patients resuscitated from out-of-hospital cardiac arrest. INTERVENTIONS: Standard blood pressure measuring modules were offset to display 10% lower or higher blood pressure values. We then: 1) confirmed this modification in vivo by comparing offset to standard modules in 22 patients admitted to the ICU. Thereafter we 2) verified the method in two randomized, clinical trials, each including 50 out-of hospital cardiac arrest patients, where the offset of the blood pressure module was blinded to the treating staff. MEASUREMENTS AND MAIN RESULTS: Substudy A showed that the expected separation of blood pressure measurements was achieved with an excellent correlation of the offset and standard modules (R = 0.997). Bland-Altman plots showed no bias of modified modules over a clinically relevant range of mean arterial pressure. The primary endpoint of the clinical trials was between-group difference of norepinephrine dose needed to achieve target mean arterial pressure. Trial 1 aimed at a 10% difference between groups in mean arterial pressure (targets: 65 and 72 mm Hg, respectively) and demonstrated a separation of 5 +/- 1 mm Hg (p < 0.001). The difference in norepinephrine dose was not significantly different (0.03 +/- 0.03 ug/kg/min; p = 0.42). Trial 2 aimed at a 20% difference between groups in mean arterial pressure (targets: 63 and 77 mm Hg, respectively). Separation was 12 +/- 1 mm Hg (p < 0.01) in mean arterial pressure and 0.07 +/- 0.03 ug/kg/min (p < 0.01) in norepinephrine dose. CONCLUSIONS: The present method is feasible and robust and provides a platform for double-blinded comparison of mean arterial pressure targets in critically ill patients. PMID- 29994884 TI - Reading disorders and dyslexia: Erratum. PMID- 29994885 TI - Incorporating Innovative Simulation Activities Into Campus Lab to Enhance Skill Competence and Critical Thinking of Second-Semester Associate Degree Nursing Students. AB - Decreasing access to clinical sites, inconsistency in student learning experiences, and lack of faculty have compelled nursing schools to incorporate more simulation into their curricula. Professional organizations, regulating bodies, and schools of nursing support its use. The Nursing 2 Challenge simulation activity was designed to give second-semester nursing students an opportunity to improve skill competence and critical thinking utilizing a systematic, preplanned station rotation format in the safe setting of the nursing campus lab. Each station required the students to apply clinical decision-making and nursing skills to complete interventions aligned with course objectives. PMID- 29994886 TI - Peer Mentoring as a Successful Retention Strategy for a Baccalaureate Nursing Program in a Historically Black College and University. AB - A university-based, student-run nursing organization improved cultural awareness, academic environment, and performance for members of the organization. The International Student Nursing Organization sponsored cultural events and a peer mentoring program. Members who participated in the peer mentoring program were randomly matched as mentors (seniors) or mentees (juniors); mentors were awarded service hours. Statistical data was tracked over two semesters for the first cohort of students. Mentors had a higher aggregate score on their comprehensive exit and nursing licensure exams when compared to their graduating class as a whole. A collegial and learning environment was created that promoted students' professional and leadership skills. PMID- 29994887 TI - School Counselors' Perceptions of Necessary Attributes of Middle and High School Students Interested in a Career in Nursing. AB - AIM: The focus of this study was to examine which attributes school counselors perceive as necessary for middle and high school students interested in a career in nursing. BACKGROUND: School counselors play a pivotal role in secondary students' career development but were found to have limited knowledge about the need for increased academic rigor in nursing. METHOD: A national sample of 204 school counselors responded to a web-based survey that examined perceptions of necessary attributes of prospective nursing students. RESULTS: This is the first national study to identify school counselors' perceived attributes of prospective nursing students. Results included trustworthiness and caring; academic attributes ranked lower. CONCLUSION: School counselors in this study perceived nursing as a caring profession but not necessarily an academic one. Early intervention in middle school may alter preconceived images of nursing as exclusively female and caring but also as a profession that requires much academic preparation. PMID- 29994888 TI - Failing to Fail in Undergraduate Nursing: Understanding the Phenomenon. AB - AIM: The aim of the study was to explore and understand the phenomenon of "failing to fail." BACKGROUND: Phase 1 of a mixed-methods study suggested faculty in clinical settings instructed students that should not have passed preceding placements; students in didactic settings also passed exams that merited a fail. Phase 2 explored this phenomenon. METHOD: A multisite qualitative case study targeted baccalaureate and community college faculty to support analysis using replication logic. Data collection was conducted via semistructured interview. RESULTS: Eighteen demographically diverse cases were recruited (including age, experience, and full-/part-time status). Factors supporting failing to fail included being good enough, clinical/didactic dichotomy, team grading, and being the bad guy. CONCLUSION: The consistency of enabling factors suggests a collective approach is required to address failing to fail, including pedagogical preparation and cross-school mechanisms for ensuring grading parity. Effort must address integrity and teaching excellence in all aspects of nursing education. PMID- 29994889 TI - Budget Friendly Simulation for Clinical Nursing Education: Putting It All Together. AB - Clinical simulation in nursing has become increasingly valuable in helping students learn tasks and assessments in a nonthreatening environment. Evaluating student assessments can promote collegiality among faculty. This article focuses on three tips for faculty used by one university to objectively capture a clinical snapshot in a cost-effective manner: 1) write one's own scenarios, 2) create assessment forms using Word, and 3) employ bar scanning with quick response code readers. PMID- 29994890 TI - Missed Nursing Care as a Quality Indicator During Transition to a Dedicated Education Unit Model. AB - This pilot study compared the implementation of the innovative dedicated education unit (DEU) clinical model on quality of care with the traditional clinical model using missed nursing care as a quality indicator. A university and academic medical center partnered to conduct this quasiexperimental study, which is the first to use missed nursing care as a quality indicator when assessing transition to the DEU model. Evidence suggests that quality of care was maintained during DEU implementation. PMID- 29994891 TI - Using Motion Picture Films to Teach Nursing Theory in Graduate Nursing Education. AB - Teaching strategies that use pedagogy of inquiry and contextualization are needed to ensure that nursing students will be well prepared to manage increasingly complex patient information. The rationale for using motion pictures to teach theoretical thinking is explained, and an assignment that uses motion pictures is described. Film scene assignments facilitate learning theoretical thinking skills, reading clinical situations, and understanding how theory can be useful to problem-solve ambiguous clinical situations. Motion pictures present a text-in motion that can be studied and analyzed in a repeatable, objective, and collaborative way. PMID- 29994892 TI - An Innovative Approach to Onboarding and Supporting Adjunct Faculty in Nursing. AB - In recent years, online graduate nursing programs throughout the United States have seen unprecedented growth that has resulted in a greater need for adjunct faculty who can adequately teach in an online format. Frequently, adjunct faculty are not prepared to teach online as they are not offered the necessary continued support in their roles. Through the development of an onboarding program, barriers for teaching online were eliminated. The program is supported by a faculty learning community and continuous professional development workshops. These resources support adjunct faculty at various stages of their professional development and allow for collaborative exchange. PMID- 29994893 TI - Social Marketing Campaigns as a Teaching Strategy for Health Promotion. AB - Current nursing students are more technologically adept than past generations; they are accustomed to using technology in their everyday life. Proficiency in technology is a major asset, and as such, nursing education should provide for opportunities with technology that will support future practice. This article reports on a group project effectively used to capitalize on this skill while encouraging active engagement in learning about health promotion. Student groups created a social marketing campaign consisting of a summary of their campaign, one infogram, and one 30-second video focused on a topic area from Healthy People 2020. PMID- 29994894 TI - Using Personalized Music Playlists for Patients With Dementia as a Teaching Innovation. AB - Nursing students need innovative educational approaches to bridge generational and cultural differences and improve communication skills with patients who are cognitively impaired. An individualized music and memory intervention for older adults with dementia and communication issues was implemented. A review of weekly student journals provided information regarding the use of the approach as an alternative therapy and benefit for students. The usefulness of the music and memory program as an innovative learning tool has widespread applicability to various health care settings. PMID- 29994895 TI - Concordance Within an RN to BSN Program: Standardized Writing Assessment Rubrics. AB - A standardized rubric for writing assessment can improve concordance in expectations across a nurse educator community; however, standardization may also pose a perceived threat to faculty academic freedom. To improve assessment consistency while retaining academic freedom, an innovative rubric system that offers a compromise is proposed; it includes both standardized objective areas of assessment as well as areas of assessment for individualized instructor determination. In creating a hybrid standardized rubric, a community of nurse educators can retain academic freedom while better serving students with consistent expectations for writing skills. PMID- 29994897 TI - Tolerance induction in hemophilia: innovation and accomplishments. AB - PURPOSE OF REVIEW: Hemophilia is an X-linked blood coagulation genetic disorder, which can cause significant disability. Replacement therapy for coagulation factor VIII (hemophilia A) or factor IX (hemophilia B) may result in the development of high-affinity alloantibodies ('inhibitors') to the replacement therapy, thus making it ineffective. Therefore, there is interest in directing immunological responses towards tolerance to infused factors. RECENT FINDINGS: In this review, we will discuss latest advancements in the development of potentially less immunogenic replacement clotting factors, optimization of current tolerance induction protocols (ITI), preclinical and clinical data of pharmacological immune modulation, hepatic gene therapy, and the rapidly advancing field of cell therapies. We will also evaluate publications reporting data from preclinical studies on oral tolerance induction using chloroplast transgenic (transplastomic) plants. SUMMARY: Until now, no clinical prophylactic immune modulatory protocol exists to prevent inhibitor formation to infused clotting factors. Recent innovative technologies provide hope for improved eradication and perhaps even prevention of inhibitors. PMID- 29994896 TI - Fibrinogen and factor XIII: newly recognized roles in venous thrombus formation and composition. AB - PURPOSE OF REVIEW: In spite of significant morbidity and mortality associated with venous thromboembolism, the underlying pathogenesis remains poorly understood. RECENT FINDINGS: Clues to operant pathogenic mechanisms are found in the unique morphology and composition of these thrombi, which have substantial red blood cell and fibrin content. Recent studies have revealed biochemical and biophysical mechanisms that dictate fibrin structure in venous thrombi and promote retention of red blood cells within the contracted clots. These mechanisms include newly recognized contributions of fibrin network structure and factor XIII(a)-mediated fibrin crosslinking to venous thrombus composition, size, and stability. SUMMARY: Continued work to elucidate mechanisms by which fibrin(ogen), factor XIII, and red blood cells contribute to venous thrombus formation, structure, and stability may expose novel molecular targets and strategies for reducing thrombosis and thrombotic complications in certain at risk patients. PMID- 29994898 TI - Multiple protein disulfide isomerases support thrombosis. AB - PURPOSE OF REVIEW: The present review provides an overview of recent findings on new members of the protein disulfide isomerase (PDI) family required for thrombosis. RECENT FINDINGS: Twenty years ago PDI was shown to mediate platelet aggregation, and 10 years ago PDI was shown to support thrombosis in vivo. Subsequently, other members of this endoplasmic reticulum family of enzymes, ERp57 and ERp5, were demonstrated to support thrombosis. A fourth member, ERp72, was recently shown to be required for platelet accumulation and fibrin deposition in vivo. None of these enzymes can individually support these processes. Moreover, aggregation of platelets deficient in a specific PDI is only recovered by the PDI that is missing. This implies that each PDI has a distinct role in activation of the alphaIIbbeta3 fibrinogen receptor and platelet aggregation. Free thiols can be labeled in both subunits of alphaIIbbeta3, suggesting cysteine based reactions are involved in relaying conformational changes from the cytoplasmic tails to the integrin headpiece of this integrin. SUMMARY: Multiple members of the PDI family support platelet function, and hemostasis and thrombosis with distinct roles in these processes. The individual cysteine targets of each enzyme and how these enzymes are integrated into a network that supports hemostasis and thrombosis remain to be elucidated. PMID- 29994899 TI - Factor XII in inflammation and wound healing. AB - PURPOSE OF REVIEW: This review describes the contribution of coagulation factor XII (FXII) in sterile inflammation and wound healing, focusing on recently identified roles for zymogen FXII in neutrophil functions. RECENT FINDINGS: Recent studies have identified an important role for FXII in neutrophil trafficking. In particular, following neutrophil activation, autocrine FXII signals through the urokinase plasminogen activator receptor (uPAR) on the neutrophil surface to upregulate neutrophil functions. The sum of these activities leads to neutrophil adhesion, chemotaxis, and neutrophil extracellular (NET) formation. Downregulating FXII-mediated signaling in neutrophils is associated with improved wound healing. SUMMARY: These recent findings show the sophisticated role of FXII in vivo and create new opportunities for research on the treatment of chronic inflammatory diseases. PMID- 29994900 TI - Immunotherapy-based combinations: an update. AB - PURPOSE OF REVIEW: The advent of immunotherapy significantly improved clinical outcomes in cancer patients, although immune checkpoint blockade (ICB) still lack of efficacy in a consistent proportion of treated patients. The purpose of this article is to review the most innovative and clinically promising ICB-based combinations designed to improve the efficacy of cancer immunotherapy. RECENT FINDINGS: First-line combinatorial treatment with ipilimumab and nivolumab has recently shown to be superior to the standard of care in a subset of metastatic nonsmall cell lung cancer (NSCLC) and renal cell carcinoma (RCC). The combination of programmed cell death protein 1 (PD-1)/PD-L1 blockade with antiangiogenics has demonstrated a consistent clinical efficacy, especially for the combination of bevacizumab and atezolizumab as first-line therapy in metastatic RCC. The sequential combination of definitive chemoradiotherapy followed by durvalumab maintenance in advanced, unresectable NSCLC became the new standard of care, while the addition of pembrolizumab to first-line chemotherapy in metastatic NSCLC significantly improves overall survival. Despite promising results for the combination of ICBs with v-raf murine sarcoma viral oncogene homolog B/MAPK/ERK kinase inhibitors or epidermal growth factor receptor inhibitors, especially in melanoma and NSCLC, safety concerns slowed down the development of such strategies. SUMMARY: Immunotherapy-based combinations are becoming the standard of care for cancer treatment, in particularly for advanced melanoma, NSCLC and RCC. PMID- 29994901 TI - Hodgkin lymphoma in elderly patients. AB - PURPOSE OF REVIEW: We aim to summarize the current knowledge on the treatment of elderly Hodgkin lymphoma patients with a focus on evidence from clinical trials and novel drugs. RECENT FINDINGS: For elderly Hodgkin lymphoma patients above 60 years without precluding comorbidities a curative treatment approach is warranted. Early favorable stage patients should receive two cycles of multiagent chemotherapy followed by 20 Gy localized radiotherapy. Early unfavorable stage patients should receive four cycles of multiagent chemotherapy followed by 30 Gy localized radiotherapy. For advanced stage patients six cycles of multiagent chemotherapy can be recommended and should be followed by localized radiotherapy on residual disease manifestations. Relapsed or refractory patients should be treated in an individually tailored approach that considers both the patient's objectives and comorbidities. The antibody-drug conjugate brentuximab vedotin is a very effective option for elderly patients with a high response rate albeit limited durability. Anti-programed cell death protein 1 antibodies might also be effective in elderly Hodgkin lymphoma patients with a mechanism of action distinct from chemotherapy. SUMMARY: In conclusion, the goal of treatment in newly diagnosed elderly Hodgkin lymphoma patients is curative whenever possible and prospective and retrospective evidence has shown that this is feasible for all disease stages with a variety of multiagent chemotherapy regimen. Relapsed and refractory elderly Hodgkin lymphoma patients can mostly only be treated with the goal of palliation. However, it remains to be seen if novel substances and new combination regimen are able to change that. PMID- 29994902 TI - The management of locally advanced cervical cancer. AB - PURPOSE OF REVIEW: Cervical cancer is still a major cause of morbidity and mortality among women worldwide. Surgery and chemoradiation are widely utilized treatments for cervical cancer. Despite the available standard treatment of choice, outcome is suboptimal among patients with LACC. It is vital to integrate the evidence generated from high-quality research work for effective management of these cases. This review intends to critically evaluate the latest evidence supporting the available treatment modalities and to provide a comprehensive overview of recent advances and ongoing research in the management of LACC. RECENT FINDINGS: Research advances in imaging and radiotherapy technologies, incorporating imaging into brachytherapy planning, use of newer targeted agents, chemotherapy intensification and immunotherapy are some of the new therapeutic options that have been in the forefront of research to improve the outcome of patients with LACC. SUMMARY: Advanced imaging modalities are increasingly being utilized to tailor treatments. Neoadjuvant chemotherapy followed by surgery does not improve outcomes in FIGO Stage IB2-IIB. Although cisplatin-based concurrent chemoradiation is the standard of care, more aggressive systemic therapies (neoadjuvant or adjuvant chemotherapy and chemoradiation) and use of newer agents, still remains investigational. PMID- 29994903 TI - Targeting CD47 as a cancer therapeutic strategy: the cutaneous T-cell lymphoma experience. AB - PURPOSE OF REVIEW: To describe the relevance of CD47 in the tumor microenvironment and summarize data on anti-CD47 therapies, including its role in cutaneous T-cell lymphoma (CTCL). RECENT FINDINGS: CD47 is expressed on all normal cells and targets SIRPalpha on the surface of myeloid cells. However, CD47 is found to be overexpressed on cancer cells. CD47-SIRPalpha interaction inhibits macrophage phagocytosis, allowing cancer cells to escape immune surveillance. Current focus in immunotherapy has been targeted toward inhibiting CD47-SIRPalpha interaction via anti-CD47 antibodies. This activates innate immunity, promoting cancer cell destruction by macrophages. It also activates adaptive immunity resulting in antigen-presentation, mostly by dendritic cells, leading to antitumor cytotoxic reactions. Current CD47 antagonists undergoing clinical trials include Hu5F9 (an anti-CD47 antibody that directly inhibits the CD47 SIRPalpha interaction) and TTI-621, (a fusion protein composed of CD47 binding domain of human SIRPalpha and linked to the Fc region of IgG1). These agents have continued to show strong efficacy against solid and hematological tumors. SUMMARY: In the CTCL tumor microenvironment, increased immune checkpoint inhibition expression via CD47 bound to SIRPalpha correlates with a more advanced disease state. Continued success in treating these patients requires further studies on CD47 antagonists, specifically when combined with other antibodies. PMID- 29994904 TI - Targeting cancer metabolism through synthetic lethality-based combinatorial treatment strategies. AB - PURPOSE OF REVIEW: Targeting cancer metabolism for therapy has received much attention over the last decade with various small molecule inhibitors entering clinical trials. The present review highlights the latest strategies to target glucose and glutamine metabolism for cancer therapy with a particular emphasis on novel combinatorial treatment approaches. RECENT FINDINGS: Inhibitors of glucose, lactate, and glutamine transport and the ensuing metabolism are in preclinical to clinical trial stages of investigation. Recent advances in our understanding of cell-intrinsic and cell-extrinsic factors that dictate dependence on these targets have informed the development of rational, synthetic lethality-based strategies to exploit these metabolic vulnerabilities. SUMMARY: Cancer cells exhibit a number of metabolic alterations with functional consequences beyond that of sustaining cellular energetics and biosynthesis. Elucidating context specific metabolic dependencies and their connections to oncogenic signaling and epigenetic programs in tumor cells represents a promising approach to identify new metabolic drug targets for cancer therapy. PMID- 29994905 TI - INTERNAL LIMITING MEMBRANE PEELING DURING PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT: Cost Analysis, Review of the Literature, and Meta-analysis. AB - PURPOSE: To evaluate the visual and potential economic impact of primary internal limiting membrane (ILM) peeling in primary treatment of rhegmatogenous retinal detachment. METHODS: A PubMed search was performed to extract data regarding the rate of epiretinal membrane formation and the rate of secondary pars plana vitrectomy with membrane peel after repair of rhegmatogenous retinal detachment with or without ILM peeling. Data were aggregated and analyzed in a meta analysis. This information was used to perform a cost analysis to determine the economic ramifications of primary ILM peeling. RESULTS: Six included studies compared the outcomes of eyes receiving pars plana vitrectomy for rhegmatogenous retinal detachment repair with and without primary ILM peel. The cumulative rate of epiretinal membrane formation was 29% (86/295) in the eyes without ILM peel and 3% (8/289) in the eyes with ILM peel. The cumulative rate of secondary pars plana vitrectomy/membrane peel was 16% (22/141) in the eyes without ILM peel and 0% (0/158) in the eyes with ILM peel. The weighted summary point estimate odds ratio was 0.083 (95% confidence interval 0.042-0.164), indicating a statistically significant protective effect across the 6 studies of ILM peeling and the development of epiretinal membrane. Based on published data, the average dollars saved by conducting a primary ILM peel was $615 in a facility setting and $364 in an ambulatory surgical center. CONCLUSION: Published, mainly retrospective, data suggest that primary ILM peel in rhegmatogenous retinal detachment repair may have a significant reduction in the rate of postoperative epiretinal membrane and may lessen the need for secondary pars plana vitrectomy/membrane peel. Furthermore, from an economic perspective, the reduction in the need for secondary surgery may justify the higher cost with primary ILM peel. PMID- 29994906 TI - FLEXIBLE POLYPROPYLENE IRIS RETRACTORS MADE BY CAUTERY THERMOPLASTICITY: An Instant Intraoperative Solution for Small Pupil Vitrectomy. PMID- 29994907 TI - A Proposal for a Classification for Recurrent Endometrial Cancer: Analysis of a French Multicenter Database From the FRANCOGYN Study Group. AB - OBJECTIVE: Endometrial cancer (EC) recurrences are relatively common with no standardized way of describing them. We propose a new classification for them called locoregional, nodal, metastasis, carcinomatosis recurrences (rLMNC). PATIENTS AND METHODS: The data of 1230 women with EC who were initially treated by primary surgery were included in this French multicenter retrospective study. Recurrences were classified based on dissemination pathways: (1) locoregional recurrence (rL); (2) nodal recurrence (rN) for lymphatic pathway; (3) distant organ recurrence (rM) for hematogenous pathway; and (4) carcinomatosis recurrence (rC) for peritoneal pathway. These pathways were further divided into subgroups. We compared recurrence free survival and overall survival (OS) between the 4 groups (rL/rN/rM/rC). RESULTS: The median follow-up was 35.6 months (range, 1.70 167.60). One hundred ninety-eight women (18.2%) experienced a recurrence: 150 (75.8%) experienced a single-pathway recurrence and 48 (24.2%) a multiple-pathway recurrence. The 5-year OS was 34.1% (95% confidence interval [CI], 27.02%-43.1%), and the median time to first recurrence was 18.9 months (range, 0-152 months). The median survival after recurrence was 14.8 months (95% CI, 11.7-18.8). Among women with single pathway of recurrence, a difference in 5-year OS (P < 0.001) and survival after recurrence (P < 0.01) was found between the 4 rLNMC groups. The carcinomatosis group had the worst prognosis compared with other single recurrence pathways. Women with multiple recurrences had poorer 5-year OS (P < 0.001) and survival after recurrence (P < 0.01) than those with single metastasis recurrence, other than women with peritoneal carcinomatosis. CONCLUSIONS: This easy-to-use and intuitive classification may be helpful to define EC recurrence risk groups and develop guidelines for the management of recurrence. Its prognosis value could also be a tool to select homogenous populations for further trials. PMID- 29994908 TI - The Effect of Body Mass Index and Weight Change on Late Gastrointestinal Toxicity in Locally Advanced Cervical Cancer Treated With Intensity-modulated Radiotherapy. AB - OBJECTIVE: To evaluate the effects of body mass index (BMI) and weight change during radiotherapy on the development of toxicity in patients with locally advanced cervical cancer (LACC) treated with intensity-modulated radiotherapy (IMRT). METHODS: A total of 245 patients were analyzed after undergoing definitive IMRT treatment between 2004 and 2015 for stage IB2 to stage IVA LACC. The patients were divided into 3 groups: underweight (BMI <18.5 kg/m), normal weight (BMI 18.5-24.9 kg/m), and overweight (BMI >=25.0 kg/m). The relationships between toxicity, clinical factors, and the bowel dose-volume histogram were analyzed. V45 indicated the bowel volume that received a radiation dose of 45 Gy. RESULTS: The median follow-up period was 63 months. The V45 was similar among the 3 groups. The 5-year rates of grade 3 or higher late gastrointestinal toxicities were 18.6%, 4.0%, and 4.2% for the underweight, normal weight, and overweight groups, respectively (P = 0.002). In the multivariable analysis, underweight (hazard ratio, 13.99; 95% confidence interval, 3.22-60.82; P < 0.001) and weight loss (> -5%) (hazard ratio, 5.91; 95% confidence interval, 1.75-19.98; P = 0.004) were significant predictors of grade 3 or higher-grade late gastrointestinal toxicities. CONCLUSION: A BMI of less than 18.5 kg/m and weight loss (> -5%) were associated with a higher risk of grade >=3 or higher late gastrointestinal toxicity in patients with LACC treated with definitive IMRT. Future research on the development of a standardized and structured approach to improve the therapeutic ratio for the supportive care of patients with LACC is needed. PMID- 29994909 TI - Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Advanced Cervical Carcinoma: The Advantage of Perfusion Parameters From the Peripheral Region in Predicting the Early Response to Radiotherapy. AB - OBJECTIVE: This study aimed to investigate the importance of perfusion parameters from the peripheral region in predicting the early response to radiotherapy for advanced cervical carcinoma by using dynamic contrast-enhanced (DCE) perfusion magnetic resonance imaging (MRI). METHODS: One hundred eight patients with advanced cervical carcinoma were enrolled into this study. Dynamic contrast enhanced perfusion MR examinations were performed for all the patients before radiotherapy. Perfusion parameters were obtained from the central region and the peripheral region of tumor respectively. After radiotherapy, the patients were classified into responders and nonresponders according to tumor shrinkage on the basis of follow-up MRI examination. The mean follow-up time lasted 12 months. The perfusion parameters were compared between the 2 groups. The relationship between perfusion parameters from 2 different regions of tumor and treatment effect was analyzed. RESULTS: The mean value of volume transfer constant (K), rate constant (Kep) or extravascular extracellular volume fraction (Ve) from the peripheral region was higher than that from the central region of tumor, respectively (P = 0.01, 004, 0.03). Responders had higher Kperipheral (K from the peripheral region) and Kcentral (K from the central region) values than nonresponders (P = 0.04, 0.01). Responders had higher Kepperipheral (Kep from the peripheral region) than nonresponders (P = 0.03). Responders had lower Veperipheral (Ve from the peripheral region) than nonresponders (P = 0.04). At logistic regression analysis, the perfusion parameters that had predicting value were Kperipheral, Veperipheral, Kepperipheral and Kcentral according to diagnostic potency. CONCLUSIONS: Compared with perfusion parameters from the central region of tumor, perfusion parameters from the peripheral region are more valuable in predicting the early response to radiotherapy for advanced cervical carcinoma. PMID- 29994910 TI - Tumor Grade Correlation Between Preoperative Biopsy and Final Surgical Specimen in Endometrial Cancer: The Use of Different Diagnostic Methods and Analysis of Associated Factors. AB - OBJECTIVE: This study aimed to identify the correlation between histology tumor grade of the preoperative biopsy using dilatation and curettage (D&C), Pipelle, or hysteroscopy and final surgical specimen in women with endometrioid endometrial cancer. MATERIALS AND METHODS: Patients on whom a preoperative biopsy was performed between 2009 and 2016 were reviewed and cases with apparent early stage endometrioid endometrial cancer were included in the study. The accuracy of preoperative biopsy performed before hysterectomy using D&C, Pipelle, or hysteroscopy was compared. RESULTS: A total of 332 patients were included. The diagnostic method was D&C in 43 cases (13%), Pipelle in 102 (31%), and hysteroscopy in 187 (56%). The preoperative diagnosis included G1 tumors in 177 cases (53.3%), G2 in 103 (31%), and G3 in 52 (15.6%). The surgical specimen confirmed endometrioid endometrial tumor in 309 patients (93%).The accuracy rates of preoperative biopsy and surgical specimen were 74.69%, 73.19%, and 89.75% for G1, G2, and G3, respectively. Hysteroscopy showed better kappa index (kappa = 0.551) than did D&C (kappa = 0.392) and Pipelle (kappa = 0.430). Tumor diameter greater than 30 mm was the only factor independently associated with absence of correlation between preoperative and postoperative tumor grade (odds ratio [95% confidence interval], 1.959 [1.096-3.504], P = 0.023). CONCLUSIONS: Preoperative biopsy, regardless of the method, has its limitations in predicting the tumor grade compared with final surgical specimen in women with endometrioid endometrial cancer at an apparent early stage. Concordance between the biopsy and hysterectomy specimen is less likely to happen in the case of preoperative G1 or G2 tumors, as well as in big tumors. Although hysteroscopy was associated with the highest tumor grade agreement, no differences in correlation between the 3 methods (D&C, Pipelle, and hysteroscopy) were found. PMID- 29994911 TI - Predictive Value of Kanagawa Cancer Center Scoring System for Lymph Node Metastasis and Need for Lymphadenectomy in Patients With Endometrial Cancer: A Validation Study. AB - OBJECTIVES: The objective of this study was to determine the predictive value of Kanagawa Cancer Center (KCC) scoring system for lymph node metastasis and need for lymphadenectomy in patients with endometrial cancer. METHODS: This cross sectional study was conducted during a 2-year period in a gynecologic oncology referral center in Southern Iran. We included a total number of 94 patients with endometrial cancer. Preoperative assessment included tumor volume, myometrium invasion, histology, and CA125. The KCC was calculated for all the patients. All the patients underwent total abdominal hysterectomy and bilateral salpingo oophorectomy along with dissection of pelvic and para-aortic lymph nodes. The histopathology of the dissected lymph nodes was considered as criterion standard, and the predictive value of KCC was evaluated accordingly. RESULTS: The mean +/- SD age of the patients was 56.8 +/- 10.2 years. Overall, 26 patients (27.7%) tested positive for lymph node involvement. The sensitivity, specificity, positive predictive value, and negative predictive value of KCC for lymph node involvement was found to be 35.3%, 100%, 100%, and 64.7%, respectively. Overall, the predictive value according to the area under the curve measured by receiver operating characteristic curve was found to be 0.890 (0.823-0.956) indicative of moderate accuracy. Lymph node involvement was associated with higher Federation of Gynecology and Obstetrics stage (P < 0.001), higher tumor volume (P = 0.003), higher histological subtype (P < 0.001), positive CA125 (P < 0.001), and higher KCC score (P < 0.001). CONCLUSIONS: The KCC scoring system has a moderate accuracy for predicting the lymph node involvement in patients with endometrial cancer. PMID- 29994912 TI - Ensuring Children and Adolescents Are Not Left Behind. PMID- 29994913 TI - Setting Global Research Priorities in Pediatric and Adolescent HIV Using the Child Health and Nutrition Research Initiative (CHNRI) Methodology. AB - BACKGROUND: WHO and the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) of the International AIDS Society (IAS) led a collaborative process to set global prioritized research agendas, aiming to focusing future research, funding, and stakeholder's efforts. This study describes the methodology used to establish the research agendas. METHODS: The Child Health and Nutrition Research Initiative methodology was adapted in parallel exercises on pediatric and adolescent HIV. After definition of scope by an expert working group, priority questions were collected from stakeholders through an online survey. Submitted questions were coded, analyzed, and collated. The same respondents were asked to score the collated lists through a second online survey. The top 10 ranked questions per thematic area (testing, treatment, and service delivery) were reviewed and priority themes developed with consideration of existing policy, systematic reviews, and planned, ongoing, and recently published research. RESULTS: A total of 375 respondents submitted 1735 priority research questions. The majority of respondents were from Africa; 55% self identified as researchers. The final collated lists included 51 and 61 research questions for pediatric and adolescent HIV, respectively. The response rate for the second survey was 48%. The final research agendas include 5 priority research themes per area, discussed in 2 separate publications. CONCLUSIONS: To date, this is the largest example of the Child Health and Nutrition Research Initiative method in pediatric and adolescent HIV in terms of stakeholders reached, and the first to incorporate top thematic areas based on current evidence. Its impact on improving outcomes for these populations will require strong political and financial commitment. PMID- 29994914 TI - A Global Research Agenda for Pediatric HIV. AB - BACKGROUND: Despite progress, 2016 still saw 160,000 new infections and 120,000 AIDS-related deaths among children. Evidence gaps on how to best diagnose, treat, and deliver services to children living with HIV remain. A global research prioritization exercise was undertaken by WHO and CIPHER to focus research efforts in the context of diminishing resources. METHODS: The Child Health and Nutrition Research Initiative methodology was adapted and used, as described by Irvine et al. Outcomes were reviewed by an expert group and 5 priority themes identified for testing, antiretroviral treatment, and service delivery, accounting for existing policies, published literature and ongoing research. RESULTS: A total of 749 questions were submitted by 269 individuals from 62 countries. For HIV testing, priority themes included strategies and interventions to improve access, uptake and linkage to care, including with novel diagnostic tools and entry points beyond antenatal care. For treatment, priorities included strategies to improve adherence, short- and long-term outcomes and management of coinfections, optimal drug formulations, and early ART. For service delivery, priorities included strategies or interventions to improve access, uptake and retention in care, including psychosocial and family support and approaches to HIV disclosure and reduction of stigma and discrimination. CONCLUSIONS: This is the largest Child Health and Nutrition Research Initiative exercise undertaken in HIV. The results provide guidance to focus future research in pediatric HIV for impact. Global commitment to support priority research, adequate investment, and strong leadership is urgently needed to improve the health and well-being of children living with and affected by HIV. PMID- 29994915 TI - A Global Research Agenda for Adolescents Living With HIV. AB - BACKGROUND: Despite growing interest in undertaking research in adolescent HIV, the current pace of interventional research in particular remains very low compared with the needs of adolescents living with HIV (ALHIV). More robust evidence is needed to inform innovative and targeted interventions that bridge research gaps, inform policy, and improve outcomes for adolescents. A global research prioritization exercise was undertaken by WHO and CIPHER to focus efforts on priority research in the context of diminishing resources. METHODS: The Child Health and Nutrition Research Initiative (CHNRI) methodology was adapted and used. Outcomes were reviewed by an expert group and 5 priority themes identified for testing, treatment, and service delivery, accounting for existing policies, published literature, and ongoing research. RESULTS: A total of 986 research questions were submitted by 323 individuals from 67 countries. For HIV testing, priority themes included strategies and interventions to improve access, uptake, and linkage to care, and self-testing, particularly for key populations. For treatment, priorities included strategies to monitor and improve adherence, novel drug delivery systems, preventions and management of coinfections, optimal drug sequencing, and short- and long-term outcomes. For service delivery, priorities included service delivery models across the cascade, strategies to improve retention in care and sexual and reproductive health, support for pregnant ALHIV, and the provision of psychosocial support. CONCLUSIONS: This prioritized research agenda assists in focusing future research in ALHIV and will help to fill critical knowledge gaps. Key stakeholders, donors, program managers, and researchers should all support these priority questions and themes to collaboratively drive the adolescent HIV research agenda forward. PMID- 29994916 TI - Using Observational Data to Inform HIV Policy Change for Children and Youth. AB - Observational data characterizing the pediatric and adolescent HIV epidemics in real-world settings are critical to informing clinical guidelines, governmental HIV programs, and donor prioritization. Global expertise in curating and analyzing these data has been expanding, with increasingly robust collaborations and the identification of gaps in existing surveillance capacity. In this commentary, we describe existing sources of observational data for children and youth living with HIV, focusing on larger regional and global research cohorts, and targeted surveillance studies and programs. Observational data are valuable resources to cross-validate other research and to monitor the impact of changing HIV program policies. Observational studies were among the first to highlight the growing population of children surviving perinatal HIV and transitioning to adolescence and young adulthood, and have raised serious concerns about high rates of treatment failure, loss to follow-up, and death among older perinatally infected youth. The use of observational data to inform modeling of the current global epidemic, predict future patterns of the youth cascade, and facilitate antiretroviral forecasting are critical priorities and key end products of observational HIV research. Greater investments into data infrastructure are needed at the local level to improve data quality and at the global level to faciliate reliable interpretation of the evolving patterns of the pediatric and youth epidemics. Although this includes harmonized data forms, use of unique patient identifiers to allow for data linkages across routine data sets and electronic medical record systems, and competent data managers and analysts are essential to make optimal use of the data collected. PMID- 29994917 TI - Nothing About Us Without RIGHTS-Meaningful Engagement of Children and Youth: From Research Prioritization to Clinical Trials, Implementation Science, and Policy. AB - This article presents a new agenda for the meaningful engagement of youth in guiding research and policy. It has been codeveloped with youth, adolescents, and children who are living with and affected by HIV. We set out 6 basic requirements (we call them RIGHTS) that hold across clinical trials, observational studies, implementation science, service delivery, and policy development. These requirements are based on a literature review and in-depth consultations with children, adolescents, and youth, which have taken place over a decade in the HIV/AIDS epidemic. Youth engagement must be adequately Resourced with time, training, technical support, and funds. It must be Impactful, with youth informed of how their inputs have been directly used in research, policy, and programming. It must be Genuine, with youth understanding the intentions of the project and choosing to take part. It is essential that we ensure that participation is Harmless, and that it is responsive to the emotional and mental health needs of youth. Processes of participation should be Teen friendly, designed to be enjoyable and relevant to youth priorities. Finally, regarding Skills building, participation should allow for the competencies and skills developed to be recognized in youth education and career experience (without advertising the HIV aspect if this is inappropriate for young people). We propose that these 6 basic requirements be endorsed by all research organizations, and that they become a core component of research in the HIV response. PMID- 29994918 TI - Propelling the Pediatric HIV Therapeutic Agenda With Science, Innovation, and Collaboration. AB - BACKGROUND: A number of well-described obstacles to the pediatric therapeutic agenda have resulted in substantial delays in the introduction of new medications, formulations, strategies, and approaches to treat infants, children, and adolescents living with HIV. SETTING: Global landscape. METHODS: The authors will provide a summary of current and emerging initiatives to accelerate the pediatric therapeutic agenda including illustrative case studies of innovations and scientific discovery in diagnosis and treatment of very young children with HIV infection. RESULTS: The challenges posed by rapid physiologic and developmental changes that characterize the trajectory of childhood as well as the complex regulatory and fiscal milieu of HIV therapeutics have hampered pediatric HIV therapeutic research. Recent efforts to accelerate this agenda include prioritizing agents and formulations, defining dosing by weight bands, applying innovative study designs, synergizing work across research networks to achieve common goals, and the establishment of a global prioritized research agenda. A case study of initiatives to diagnose and effectively treat newborns and infants will illustrate the critical role of basic science research and novel approaches to study design and implementation that are informing global efforts to end AIDS. CONCLUSIONS: A pediatric therapeutic agenda informed by basic science and achieved through innovation and global cooperation is essential to achieve an AIDS-free generation. PMID- 29994919 TI - Optimizing Clinical Trial Design to Maximize Evidence Generation in Pediatric HIV. AB - For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis. PMID- 29994920 TI - Simulation Modeling and Metamodeling to Inform National and International HIV Policies for Children and Adolescents. AB - OBJECTIVE AND APPROACH: Computer-based simulation models serve an important purpose in informing HIV care for children and adolescents. We review current model-based approaches to informing pediatric and adolescent HIV estimates and guidelines. FINDINGS: Clinical disease simulation models and epidemiologic models are used to inform global and regional estimates of numbers of children and adolescents living with HIV and in need of antiretroviral therapy, to develop normative guidelines addressing strategies for diagnosis and treatment of HIV in children, and to forecast future need for pediatric and adolescent antiretroviral therapy formulations and commodities. To improve current model-generated estimates and policy recommendations, better country-level and regional-level data are needed about children living with HIV, as are improved data about survival and treatment outcomes for children with perinatal HIV infection as they age into adolescence and adulthood. In addition, novel metamodeling and value of information methods are being developed to improve the transparency of model methods and results, as well as to allow users to more easily tailor model-based analyses to their own settings. CONCLUSIONS: Substantial progress has been made in using models to estimate the size of the pediatric and adolescent HIV epidemic, to inform the development of guidelines for children and adolescents affected by HIV, and to support targeted implementation of policy recommendations to maximize impact. Ongoing work will address key limitations and further improve these model-based projections. PMID- 29994922 TI - Game analysis and clinical use of the Xbox-Kinect for stroke rehabilitation. AB - Whole-body movement is required to interact (play) with Microsoft Xbox with the 3D Kinect sensor (Xbox-Kinect) and, therefore, may be suitable for encouraging and practicing movements as part of stroke rehabilitation. We aimed to describe (i) game analysis, (ii) clinical use, and (iii) to characterize the Xbox-Kinect game experience with individuals with chronic stroke. Four therapists played the Xbox-Kinect games and then carried out a games analysis on the basis of the categories suggested by Deutsch. Eleven participants (age 29-69 years) with chronic stroke and varying motor deficits played Xbox-Kinect games for 4-22 sessions as part of a video-game group intervention and the clinical use was documented. The game experience of 'Bowling' (Kinect-Sport) and '20 000 leaks' (Kinect Adventures) was characterized by self-report questionnaires. Detailed tables of game analysis are provided. The clinical use of the console with the participants is presented. Participants reported high enjoyment and 'somewhat high' perceived exertion after playing the two games and stated that overall the console suited their therapeutic goals. This information can assist clinicians with their clinical reasoning and decision-making for incorporating the Xbox Kinect into stroke rehabilitation. Potentially, the Xbox-Kinect could be used as an on-going tool to facilitate whole-body movement and physical activity of individuals with chronic stroke. PMID- 29994921 TI - Making Implementation Science Work for Children and Adolescents Living With HIV. AB - The global HIV response is leaving children and adolescents behind. Because of a paucity of studies on treatment and care models for these age groups, there are gaps in our understanding of how best to implement services to improve their health outcomes. Without this evidence, policymakers are left to extrapolate from adult studies, which may not be appropriate, and can lead to inefficiencies in service delivery, hampered uptake, and ineffective mechanisms to support optimal outcomes. Implementation science research seeks to investigate how interventions known to be efficacious in study settings are, or are not, routinely implemented within real-world programmes. Effective implementation science research must be a collaborative effort between government, funding agencies, investigators, and implementers, each playing a key role. Successful implementation science research in children and adolescents requires clearer policies about age of consent for services and research that conform to ethical standards but allow for rational modifications. Implementation research in these age groups also necessitates age appropriate consultation and engagement of children, adolescents, and their caregivers. Finally, resource, systems, technology, and training must be prioritized to improve the availability and quality of age-/sex-disaggregated data. Implementation science has a clear role to play in facilitating understanding of how the multiple complex barriers to HIV services for children and adolescents prevent effective interventions from reaching more children and adolescents living with HIV, and is well positioned to redress gaps in the HIV response for these age groups. This is truer now more than ever, with urgent and ambitious 2020 global targets on the horizon and insufficient progress in these age groups to date. PMID- 29994923 TI - Is physical rehabilitation effective for Wernicke-Korsakoff syndrome? A case report. AB - Wernicke-Korsakoff syndrome is a type of brain disorder caused by the lack of thiamine, most commonly because of chronic alcohol misuse. It consists of two separate conditions including Wernicke's encephalopathy and Korsakoff syndrome. Various levels of cognitive impairments are associated with the severity of the syndrome. Although the effectiveness of thiamine replacement in the early phases of the syndrome is proven, the efficacy of subsequent treatments, which mainly include rehabilitation protocols after the development of Korsakoff syndrome, is not clear. This is the first report showing the positive effects of physical rehabilitation in a 48-year-old male patient with Wernicke-Korsakoff syndrome. PMID- 29994925 TI - Validation of the Omron HBP-1300 in pregnancy for medium-arm and large-arm circumferences according to the British Hypertension Society protocol. AB - OBJECTIVE: The aim of this study was to validate the Omron HBP-1300 oscillometric blood pressure (BP) device according to the British Hypertension Society validation protocol, in pregnant women of both medium-arm and large-arm circumferences. PARTICIPANTS AND METHODS: BP was measured sequentially in 72 women of any gestation requiring the use of a large-size (N=36, arm circumference >=33 cm) or medium-size cuff (N=36, arm circumference <33 cm) alternating between a mercury sphygmomanometer and the Omron HBP-1300 device. RESULTS: The Omron HBP 1300 is accurate in pregnancy with a mean device-observer difference of 3+/-6 and 1+/-6 mmHg for systolic BP and 2+/-5 and 3+/-6 mmHg for diastolic BP in women requiring the use of the medium and large cuff, respectively. CONCLUSION: The Omron HBP-1300-automated BP device can be recommended for use in pregnant women with medium-arm or large-arm circumferences. PMID- 29994924 TI - Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a tibia fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. METHODS: Three weeks after tibia fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. RESULTS: At 7 weeks postfracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postfracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). CONCLUSIONS: Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after tibia fracture. PMID- 29994927 TI - Comments on "Higher Recurrence Rate After Endoscopic Totally Extraperitoneal (TEP) Inguinal Hernia Repair With Ultrapro Lightweight Mesh: 5-Year Results of a Randomized Controlled Trial (TULP-trial)." PMID- 29994928 TI - Don't Calculate Post-hoc Power Using Observed Estimate of Effect Size. PMID- 29994926 TI - The blood pressure variability and baroreflex sensitivity in healthy participants are not determined by sex or cardiorespiratory fitness. AB - BACKGROUND: Heart rate (HR) and blood pressure (BP) autonomic modulation and baroreflex sensitivity (BRS) are important indexes of cardiovascular homeostasis. However, methodological errors are often observed, such as joint analysis of men and women. Another important aspect is that we still do not know whether cardiorespiratory fitness influences these autonomic parameters in healthy individuals. OBJECTIVES: This study aimed to investigate whether sex can affect BRS, autonomic modulation of HR and BP variabilities (HRV and BPV, respectively), as well as the influence of cardiorespiratory fitness on these autonomic parameters. METHODS: Healthy men and women (N=120) were assigned to groups according to the peak oxygen consumption (VO2 peak) obtained in the cardiorespiratory test: low cardiorespiratory fitness (VO2 peak: 22-38 ml/kg/min), moderate cardiorespiratory fitness (VO2 peak: 38-48 ml/kg/min), and high cardiorespiratory fitness (VO2 peak>48 ml/kg/min). HRV and BPV evaluations were performed for all groups in the frequency domain by spectral analysis. Spontaneous BRS was assessed using the sequence method. RESULTS: Women presented lower BP values compared with men. HR did not differ between sexes, but showed an inverse relationship with cardiorespiratory performance. The HRV analysis showed greater sympathetic modulation for men and greater vagal modulation for women. Men and women presented similar results for systolic BPV and BRS, and cardiorespiratory performance did not influence any of the autonomic parameters evaluated. CONCLUSION: Cardiorespiratory fitness does not interfere with HRV and BPV autonomic modulation or BRS. However, the cardiac modulatory balance differs between sexes, with a greater influence of the autonomic vagal component in women and the sympathetic component in men. PMID- 29994929 TI - Successful Development and Implementation of a Surgical Response Team for Emergent Surgical Cases. AB - : At our institution, we recognized a need for a standardized, efficient approach to safely evaluate, prepare, and transport patients in need of emergent surgery. With the establishment of an Emergency Surgery Transport and Assessment Team, we were able to substantially reduce our median transport time to the OR. We believe other institutions can establish an efficient team using existing resources to expedite care of the emergent surgical patient. PMID- 29994930 TI - Long-term Quality of Life in Neonatal Surgical Disease. AB - OBJECTIVE: This prospective observational study was designed to assess Pediatric Quality of Life (PedsQL) after surgical treatment for congenital diaphragmatic hernia (CDH), esophageal atresia/tracheoesophageal fistula (EA/TEF), Hirschsprung disease (HD), gastroschisis (GAS), omphalocele (OMP), and necrotizing enterocolitis (NEC). SUMMARY OF BACKGROUND DATA: Improvements in neonatal and surgical care have led to increased survival for many newborn conditions. Quality of life in these patients is seldom explored in a longitudinal manner. We hypothesized that age-adjusted physical and psychosocial scores would improve over time, but with diagnosis-dependent variation. METHODS: Data were collected from 241 patients (CDH = 52; EA/TEF = 62; HD = 46; GAS = 32; OMP = 26; NEC = 23) in an institutional Clinical Outcomes Registry (COR) from 2012 to 2017. Aggregate physical, psychosocial, and overall PedsQL scores were determined for each diagnosis. Spline regression models were created to model scores as a function of age. RESULTS: Physical scores trended up for all diagnoses except CDH and NEC beyond age 10. Psychosocial scores trended up for all diagnoses except NEC and EA/TEF beyond age 10. Beyond age 12, CDH, GAS, and HD patients had overall scores within the normal range, while NEC, OMP, and EA/TEF patients had scores similar to children with chronic medical illness. CONCLUSION: Variation exists in long term PedsQL scores after neonatal surgery for selected, complex disease. Beyond age 12, quality of life is significantly impaired in NEC, moderately impaired in OMP and EA/TEF, and within normal range for CDH, HD, and GAS patients at the population level. These data are relevant to prenatal and perioperative discussions with patients and families. PMID- 29994931 TI - Evidence for the Role of the Cecal Microbiome in Maintenance of Immune Regulation and Homeostasis. AB - OBJECTIVE (S): Our objective was to investigate alterations in the cecal microbial composition during the development of type 1 diabetes (T1D) with or without IgM therapy, and correlate these alterations with the corresponding immune profile. METHODS: (1) Female nonobese diabetic (NOD) mice treated with IgM or saline (n = 20/group) were divided into 5-week-old nondiabetic; 9 to 12-week old prehyperglycemic stage-1; >=13-week-old prehyperglycemic stage-2; and diabetic groups. 16S rRNA libraries were prepared from bacterial DNA and deep sequenced. (2) New-onset diabetic mice were treated with IgM (200 MUg on Days 1, 3, and 5) and their blood glucose monitored for 2 months. RESULTS: Significant dysbiosis was observed in the cecal microbiome with the progression of T1D development. The alteration in microbiome composition was characterized by an increase in the bacteroidetes:firmicutes ratio. In contrast, IgM conserved normal bacteroidetes:firmicutes ratio and this effect was long-lasting. Furthermore, oral gavage using cecal content from IgM-treated mice significantly diminished the incidence of diabetes compared with controls, indicating that IgM specifically affected mucosa-associated microbes, and that the affect was causal and not an epiphenomenon. Also, regulatory immune cell populations (myeloid derived suppressor cells and regulatory T cells) were expanded and insulin autoantibody production diminished in the IgM-treated mice. In addition, IgM therapy reversed hyperglycemia in 70% of new-onset diabetic mice (n = 10) and the mice remained normoglycemic for the entire post-treatment observation period. CONCLUSIONS: The cecal microbiome appears to be important in maintaining immune homeostasis and normal immune responses. PMID- 29994933 TI - Novel Sternal Reconstruction With Custom Three-Dimensional-Printed Titanium PoreStar Prosthesis. AB - Resection of sternal tumors can leave large defects, which exposes major mediastinal structures, and can affect respiratory mechanics. If feasible, resection is potentially a complex reconstructive challenge to restore normal and functional anatomy using conventional techniques. We report the first Australian use of a three-dimensional-printed titanium and PoreStar prosthesis in a 39-year old woman for reconstruction after major surgical resection of the sternum for metastatic breast cancer. The patient successfully underwent excision of the sternum and costal cartilages as well as implantation of the prosthesis. We conclude that three-dimensional-printed prostheses are technically feasible to deliver excellent cosmetic result. PMID- 29994932 TI - Lutetium-177 tin colloid radiosynovectomy in patients with inflammatory knee joint conditions intractable to prevailing therapy. AB - OBJECTIVE: To evaluate the treatment response of lutetium-177 tin colloid radiosynovectomy (Lu-RSV) in patients with inflammatory knee joint conditions refractory to conventional treatment. PATIENTS AND METHODS: Overall, 29 knee joints in 29 patients with chronic synovitis caused by various inflammatory knee joint diseases refractory to conventional therapy were included in this prospective study. All patients were assessed clinically for pain, tenderness, joint swelling, mobility, analgesic intake, and blood pool activity on bone scan. Different scores were assigned to all these parameters. RSV of knee joint was done using intra-articular injection of Lu tin colloid. Response was assessed at 3 months using various clinical parameter scores and blood pool bone scan as mentioned before and categorized as responders and nonresponders on the basis of change in percentage of cumulative scores. RESULTS: Of the 29 joints, 21 were responders and eight were nonresponders at 3 months after RSV. There was a statistically significant reduction in clinical parameters cumulative scores at follow-up when compared with baseline (P<0.0001). Blood pool scintigraphy also showed decrease in blood pool activity compared with the baseline. There was statistically significant association between the responder group and absence of radiological abnormality. CONCLUSION: Lu tin colloid synovectomy is a useful treatment modality in patients with chronic inflammatory knee joint conditions refractory to conventional treatment. Patients with shorter duration of disease and normal or minor radiographic findings are better candidates for RSV. PMID- 29994934 TI - Message From the Editor. PMID- 29994935 TI - Screening Peter to Save Paul: The Population-Level Effects of Screening Men Who Have Sex With Men for Gonorrhea and Chlamydia. PMID- 29994936 TI - Survey of Obstetrician-Gynecologists in the United States about Trichomoniasis, 2016. AB - PURPOSE: Trichomoniasis is the most prevalent non-viral sexually transmitted infection in the United States. It can present with vaginitis in women and urethritis in men, but is most often asymptomatic or occurs with minimal symptoms. It is associated with other sexually transmitted infections (STIs), adverse pregnancy outcomes and pelvic inflammatory disease. For these reasons, healthcare provider awareness of trichomoniasis is of public health importance. METHODS: To assess practitioner knowledge, attitudes, and practices concerning trichomoniasis management, the American College of Obstetricians and Gynecologists (ACOG) conducted an online survey in 2016 of its members, and we analyzed results from 230 respondents. RESULTS: We note discrepancies between practice and recommendations amongst surveyed providers: a minority of respondents routinely screen HIV positive patients for trichomoniasis (10.7% "most of the time" 95% confidence interval [CI]: 6.7-15.8, 33.0% "always" 95% CI: 26.5%-40.0%), treat trichomoniasis in HIV positive patients with the recommended dose of metronidazole 500 mg twice a day for 7 days (25.8% 95% CI: 20.0%-32.3%), or retest patients diagnosed with trichomoniasis 3 months after treatment (9.6% 95% CI: 6.1%-14.3R). Only 29.0% (95% CI: 23.0%-35.5%) retreat with metronidazole 500 mg twice a day for 7 days in patients who have failed prior treatment. CONCLUSIONS: Screening for and treatment of trichomoniasis in HIV positive patients, as well as retesting and retreatment for trichomoniasis in the general population appear to be suboptimal. Continuing education for providers is needed for this common but "neglected" STI. PMID- 29994937 TI - Is epidural analgesia still a viable option for enhanced recovery after abdominal surgery. AB - PURPOSE OF REVIEW: Although thoracic epidural analgesia (TEA) is considered often as gold standard in multimodal analgesia with regard to major abdominal surgery, there is an ongoing debate if it is still a viable option for enhanced recovery because of its potential severe complications. RECENT FINDINGS: In addition to the unsurpassed analgesic quality, a TEA offers several advantages. Studies have shown that a TEA does have a positive effect on perioperative morbidity and mortality, bowel function, the occurrence of ileus and patient mobility. Furthermore, TEA can reduce opioid-induced side effects, cardiac arrhythmias and pneumonia. When it is embedded into a multimodal fast-track program, it also shortens intensive care and hospital stay. SUMMARY: TEA provides superior pain control with a handful of important advantages if used sensibly and with caution. Because of associated risks for severe neurological complications, clear contraindications should be ruled out. Special attention needs be paid to potential hypotension in the setting of epidural analgesia. If these key points are considered, a TEA still represents a viable option for enhanced recovery after major abdominal surgery. PMID- 29994938 TI - Anesthesia for awake craniotomy. AB - PURPOSE OF REVIEW: The current review reports on current trends in the anesthetic management of awake craniotomy, including preoperative preparation, sedation schemes, pain management, and prevention of intraoperative complications. RECENT FINDINGS: Both approaches for anesthesia for awake craniotomy, asleep-awake asleep and monitored anesthesia care (MAC), have shown equal efficacy for performing intraoperative brain mapping. Choice of the appropriate scheme is currently based mainly on the preferences of the particular anesthesiologist. Dexmedetomidine has demonstrated high efficacy and safety in MAC for awake craniotomy and has become a rational alternative to propofol. Despite the high efficacy of scalp block and opioids, pain remains a common compliant in awake craniotomy. Appropriate surgical tactics can reduce pain and even prevent postoperative neurological complications. Although the efficacy of prophylaxis of intraoperative seizures with anticonvulsants remains doubtful, levetiracetam can be superior to other drugs for this purpose. SUMMARY: Following a great deal of progress in anesthetic management, awake craniotomy, which had been a relatively rare approach, is now a commonly performed procedure for neurosurgical intervention. Modern anesthesia techniques can provide for successful brain mapping in almost any patient. Management of awake craniotomy in high-risk patients is a central task for future research. PMID- 29994939 TI - Genetics and genomics in postoperative pain and analgesia. AB - PURPOSE OF REVIEW: The review describes recent advances in genetics and genomics of postoperative pain, the association between genetic variants and the efficacy of analgesics, and the role of pharmacogenomics in the selection of appropriate analgesic treatments for postoperative pain. RECENT FINDINGS: Recent genetic studies have reported associations of genetic variants in catechol-O methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), voltage-gated channel alpha subunit 11 (SCN11A) and MU-opioid receptor (OPRM1) genes with postoperative pain. The recent pharmacogenetics studies revealed an association of the organic cation transporter 1 (OCT1) and ATP-binding cassette C3 (ABCC3) polymorphisms with morphine-related adverse effects, an effect of polymorphisms in cytochrome P450 gene CYP2D6 on the analgesic efficacy of tramadol and no effect of CYP2C8 and CYP2C9 variants on efficacy of piroxicam. SUMMARY: Genetic variants associate with inter-individual variability in drug responses and they can affect pain sensitivity and intensity of postoperative pain. Despite the recent progress in genetics and genomics of postoperative pain, it is still not possible to precisely predict the patients who are genetically predisposed to have severe postoperative pain or who develop chronic postoperative pain. PMID- 29994940 TI - The road to accreditation for fellowship training in regional anesthesiology and acute pain medicine. AB - PURPOSE OF REVIEW: The purpose of this review is to provide the background and rationale for pursuing accreditation of regional anesthesiology and acute pain medicine (RAAPM) fellowships, explain specific steps and challenges in the process, and forecast the future of fellowship training. RECENT FINDINGS: In 2016, the first fellowship program in RAAPM was able to apply for accreditation from the Accreditation Council for Graduate Medical Education (ACGME). The establishment of this newly accredited subspecialty fellowship and the announcement of the first accredited programs represented a tremendous achievement in anesthesiology training and medical education in general and was the culmination of nearly 4 years of dedicated effort. SUMMARY: Programs with initial ACGME accreditation are on a 2-year term and will be reviewed to evaluate adherence to the program requirements and the quality of fellowship training. Deficiencies identified will need to be resolved or face loss of accreditation. However, a program's maintenance of accreditation represents a commitment to its fellows to provide a training experience that can be held as a benchmark for all programs. PMID- 29994941 TI - Recent developments in ultrasound imaging for neuraxial blockade. AB - PURPOSE OF REVIEW: Recent research has shed further light on the place of ultrasound imaging in neuraxial blockade in routine clinical practice, its use in thoracic epidurals, and real-time ultrasound-guided techniques. RECENT FINDINGS: Compared with the conventional technique of surface landmark palpation, preprocedural ultrasound imaging minimizes technical difficulty associated with lumbar neuraxial blockade in patients with poor-quality surface landmarks. Novice practitioners are able to learn to employ the technique effectively. Safety benefits include a reduction in postprocedural back pain associated with fewer needle passes and a lower risk of procedure-associated bleeding. The advantage of ultrasound is minimal however in patients with easily discernible surface landmarks, especially if the practitioner is highly experienced. Recent trials show that preprocedural ultrasound scanning for thoracic epidural insertion reduces needle punctures and increases early analgesic efficacy compared with the palpation technique. Real-time ultrasound-guided techniques, while feasible, remain challenging and may not offer significant benefit over preprocedural imaging in lumbar neuraxial blockade. Their role in thoracic epidural insertion requires further investigation. SUMMARY: Ultrasound imaging of the spine is a valuable technique that, while not indicated for routine use, should be part of the skillset of any practitioner that regularly performs lumbar and thoracic neuraxial blockade. PMID- 29994942 TI - Opioid-free anesthesia: a different regard to anesthesia practice. AB - PURPOSE OF REVIEW: In the past two decades, opioids have been prescribed increasingly for the treatment of various chronic pain conditions and during the perioperative period. Perioperative opioid administration is associated with well known adverse effects and recently to long-term use and poor surgical outcomes. In this context, the anesthesiologists have to face their responsibilities. The review discusses the neurophysiological basis of opioid-free anesthesia (OFA), the rational supporting its use in perioperative medicine as well as barriers and future challenges in the field. RECENT FINDINGS: OFA has gained in popularity as a way to enhance early recovery and to spare opioids for the postoperative period. Whether it is possible to deliver safe and stable anesthesia without intraoperative opioids to many patients undergoing various surgical procedures, OFA still raises questions. Accurate monitoring to measure intraoperative nociception and guide the use of adjuvants are not available. There is a need for the development of procedure-specific strategies as well as indications and contraindications to the technique. Finally, objective assessment of OFA use on patient outcomes should be recorded in large multicenter studies. SUMMARY: OFA stands as a new paradigm, which questions anesthesiology practice and might help to rationalize perioperative opioids use. PMID- 29994943 TI - Anesthesia for electroconvulsive therapy. AB - PURPOSE OF REVIEW: Electroconvulsive therapy (ECT) is a well established and effective therapy in treatment-resistant depression. It is performed under general anesthesia, but no consensus exists regarding the optimal anesthetic drugs. A growing interest in optimizing adjunctive medication regimes in ECT anesthesia has emerged in recent years. Moreover different methods of seizure induction have been evaluated. RECENT FINDINGS: Pretreatment with dexmedetomidine eased the propofol injection pain and reduced the hyperdynamic response to ECT, but prolonged recovery. Remifentanil exhibited no proconvulsive effect and had no effect on seizure quality. Ketamine showed an antidepressive effect but was associated with cardiovascular side effects and an increased recovery time. A bispectral index-guided anesthesia or a time delay between anesthesia and seizure induction resulted in a better seizure quality presumably by avoiding high concentrations of (anticonvulsive) hypnotics. Seizure induction by magnetism seems to be an alternative to ECT, as the former is associated with less cognitive side effects but comparable antidepressive efficacy. SUMMARY: The current practice of anesthesia for ECT should not be modified, as the evidence of studies is either too low or the results are inconsistent. Some approaches are promising but require validation in further studies with a higher number of participants. PMID- 29994944 TI - Education in neuroanesthesia and neurocritical care: trends, challenges and advancements. AB - PURPOSE OF REVIEW: We summarize the latest evidence in neuroanesthesia and neurocritical care (NCC) training. In addition, we describe the newer advancements that clinical educators face in these subspecialties. Lastly, we highlight educational approaches that may lead to an enhanced learning experience and development of necessary skills for neurosciences trainees. RECENT FINDINGS: Current neuroanesthesia and NCC training requires acquisition of specific skills for increasing complex surgical cases, specialized neurosurgical practice and new perioperative technologies. Furthermore, there is increasing international interest for standardization and accreditation of neuroanesthesia fellowship programs. Recent evidence has demonstrated that well structured training using high-fidelity simulation improves cognitive and technical skills in acute neurological crises. SUMMARY: High-fidelity simulation in perioperative care of neurosurgical patients can be part of formal neuroanesthesia and NCC curricula, and potentially impact trainees' proficiency. A research agenda is needed to validate the assessment of most effective educational interventions in neurosciences trainees with diverse medical backgrounds. Creative combinations of cost-effective interventions including traditional teaching, specific technical skills workshops, low and high-fidelity simulation deserve to be assessed in future studies. PMID- 29994945 TI - Introducing Fresh Voices: Commentaries from the Medical Care Blog. PMID- 29994946 TI - Repair of a Large Sternal Notch Defect. PMID- 29994947 TI - Biochemistry, Physiology, and Tissue Interactions of Contemporary Biodegradable Injectable Dermal Fillers. AB - BACKGROUND: Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions. OBJECTIVE: To review and describe the biochemistry, physiology, and tissue interactions of the most commonly used contemporary biodegradable dermal fillers. METHODS: A thorough review of the literature was performed with additional review of pertinent clinical cases and corresponding histopathology. RESULTS: This article provides a comprehensive review of the biochemistry, physiology, and potential tissue interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described. CONCLUSION: Understanding of the innate differences in the physical properties, and physiologic responses to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events. PMID- 29994948 TI - Commentary on Patient Preferences for the Treatment of Basal Cell Carcinoma and Squamous Cell Carcinoma: A Mapping Review of Discrete Choice Experiments. PMID- 29994949 TI - Review of the Evaluation and Treatment of Vasovagal Reactions in Outpatient Procedures. AB - BACKGROUND: A vasovagal reaction is a commonly encountered event in outpatient procedures. There is a paucity of discussion on vasovagal reactions (VVRs) in the dermatologic surgery literature. However, recent investigations in the physiology, evaluation, and treatment of VVRs have been reported in other specialties. OBJECTIVE: A comprehensive review of the physiology, evaluation, treatment, and prevention of VVRs. MATERIALS AND METHODS: A search as performed using the PubMed/MEDLINE databases. Search terms included "vasovagal," "vasovagal reaction," "syncope," "reflex syncope," "neurocardiogenic syncope," and "fainting." RESULTS: Studies demonstrate greater understanding in the physiology of a vasovagal reaction. Although permanent sequelae are uncommon, it is important to respond in a prompt manner. A variety of treatment and prevention options are presented. CONCLUSION: Vasovagal reactions should be carefully evaluated. Additional studies may provide greater data in understanding and managing vasovagal reactions. PMID- 29994950 TI - Cosmetic and Functional Outcomes of Second Intention Healing for Mohs Defects of the Lips. AB - BACKGROUND: The lips are a common location for skin cancer and thus for Mohs micrographic surgery (MMS). There are few studies looking at second intention healing of Mohs defects of the lips, and none have used a scar assessment scale. OBJECTIVE: To evaluate the acceptability of second intention healing of the vermilion lips following MMS using a patient questionnaire and the Patient and Observer Assessment Scale (POSAS). METHODS: Eligible patients were found through chart review. A patient questionnaire and the patient scale of the POSAS were performed over the phone. For patients who were able to come to clinic, the observer scale of the POSAS was performed. RESULTS: Forty-seven phone interviews and 21 clinic assessments were performed. Overall, patients noted excellent functional outcomes, and good to excellent cosmetic outcomes, and were satisfied with healing time. There was not a significant difference between the patient and observer total scores (p = .63) or overall scores (p = .59). CONCLUSION: Second intention healing can have satisfactory functional and cosmetic outcomes and healing times with few complications and should be considered for surgical defects on the vermilion lips as large as 2.8 cm even when there is involvement of the cutaneous lip and muscular layer. PMID- 29994951 TI - Estimation of Prognosis in Invasive Cutaneous Melanoma: An Independent Study of the Accuracy of a Gene Expression Profile Test. AB - BACKGROUND: Cutaneous melanomas (CMs) with similar clinical and histopathologic features can harbor differing capacities for metastasis. A validated gene expression profile (GEP) test offers prognostic information by classifying CMs as low risk (Class 1A/1B) or high risk (Class 2A/2B) for metastasis. OBJECTIVE: The authors sought to perform an independent study of the predictive accuracy of the GEP test, to determine what clinical and histopathologic features predict high risk classification, and to evaluate how intermediate classes (1B & 2A) performed clinically. MATERIALS AND METHODS: Using our institution's prospectively collected melanoma registry, the authors identified patients who had been treated for CM within the last 5 years and undergone GEP testing. Clinical, histopathologic, and outcomes data were analyzed. A subcohort of patients with known metastatic disease were identified and tested. RESULTS: The GEP test accurately identified 77% of metastatic CMs as high risk (Class 2). The GEP had a negative predictive value of 99% for Class 1 CMs. Class 2 CMs were 22 times more likely to metastasize. CONCLUSION: The GEP test's performance in our independent cohort corresponded with previous industry-sponsored studies and proved to be a helpful clinical prognostic tool with the potential to direct patient care protocols. PMID- 29994952 TI - Enhancement of Photodynamic Therapy for Bowen's Disease Using Plum-Blossom Needling to Augment Drug Delivery. AB - BACKGROUND: Bowen's disease (BD) is treated effectively with 5-aminolevulinic acid (ALA)-photodynamic therapy (ALA-PDT). Plum-blossom needling (PBN) may enhance topical drug delivery. OBJECTIVE: To compare the effects of and adverse reactions to PBN and ALA-PDT of BD with those associated with ALA-PDT alone. MATERIALS AND METHODS: Forty-three lesions from 24 patients were randomly assigned to 2 groups. The PBN-ALA-PDT group underwent vertical skin tapping with PBN before applying 10% ALA cream and narrow-band light-emitting diode irradiation (lambda = 633 +/- 10 nm; 100-200 J/cm). The ALA-PDT group received ALA cream and irradiation only. RESULTS: At 6 weeks, the PBN-ALA-PDT and ALA-PDT groups achieved complete response (CR) rates of 77.78% (14/18 lesions) and 40% (7/20 lesions), respectively, (p < .05), and 2/18 and 10/20 lesions, respectively, achieved CRs after further treatment; 2.9 +/- 0.8 sessions and 3.4 +/- 0.7 sessions, respectively, were required for the lesions to achieve CRs. The PBN-ALA-PDT group required fewer treatment sessions and had higher protoporphyrin IX fluorescence levels (p < .05). CONCLUSION: Plum-blossom needling may improve the efficacy of ALA-PDT by enhancing ALA delivery for BD treatment. PMID- 29994953 TI - Hyaluronic Acid After Subcutaneous Injection-An Objective Assessment. AB - BACKGROUND: Hyaluronic acid (HA) fillers are the preferred injectable products for aesthetic correction of skin depressions and restoration of facial volume. OBJECTIVE: To investigate the subcutaneous distribution of 3, biophysically distinct, CE-marked and FDA-approved HA fillers. MATERIALS AND METHODS: BELB, JUVV, and RESL were injected ex vivo in porcine and human skin. Immediately after injection, the skin samples were snap-frozen, cross-sectioned, and visualized using stereomicroscopy and full-field optical coherence tomography. Images were compared with histological sections after hematoxylin and eosin staining. RESULTS: Hyaluronic acid fillers were distributed as homogeneous bolus in the ex vivo skin. The injection bulks were found to preserve the fibrous trabecular network, shift the fat lobules, and displace the adjacent adipocyte layers independently of the formulation injected. CONCLUSION: For the first time, the subcutaneous injection of 3 HA fillers with markedly different biophysical properties was systematically investigated by complementary visualization techniques. Despite their different properties, no difference in distribution was found after subcutaneous injection. The global preservation of the hypodermis structure observed was consistent with the good tolerability seen in clinical practice after implantation of the HA fillers in the subcutaneous skin layer. PMID- 29994954 TI - Understanding the "Scope" of the Problem. PMID- 29994955 TI - What is at the Cutting Edge of IBD? Proceedings of the European Crohn's and Colitis Organisation 2018 Congress from a Surgical Perspective. PMID- 29994956 TI - Neoadjuvant Therapy for Rectal Cancer. PMID- 29994957 TI - Expert Commentary on Neoadjuvant Therapy for Rectal Cancer. PMID- 29994958 TI - The Obese Colorectal Surgery Patient: Surgical Site Infection and Outcomes. AB - BACKGROUND: Obese patients undergoing colorectal surgery are at increased risk for adverse outcomes. It remains unclear whether these risks can be further defined with more discriminatory stratifications of obesity. OBJECTIVE: The purpose of this study was to understand the association between BMI and 30-day postoperative outcomes, including surgical site infection, among patients undergoing colorectal surgery. DESIGN: This was a retrospective cohort study. SETTINGS: The 2011-2013 American College of Surgeons National Surgical Quality Improvement Program database was used. PATIENTS: Patients included those undergoing elective colorectal surgery in 2011-2013 who were assessed by the American College of Surgeons National Surgical Quality Improvement Program. MAIN OUTCOME MEASURES: BMI was categorized into World Health Organization categories. Primary outcome was 30-day postoperative surgical site infection. Secondary outcomes included all American College of Surgeons National Surgical Quality Improvement Program-assessed 30-day postoperative complications. RESULTS: Our cohort included 74,891 patients with 4.4% underweight (BMI <18.5), 29.0% normal weight (BMI 18.5-24.9), 33.0% overweight (BMI 25.0-29.9), 19.8% obesity class I (BMI 30.0-34.9), 8.4% obesity class II (BMI 35.0-39.9), and 5.5% obesity class III (BMI >=40.0). Compared with normal-weight patients, obese patients experienced incremental odds of surgical site infection from class I to class III (I: OR = 1.5 (95% CI, 1.4-1.6); II: OR = 1.9 (95% CI, 1.7-2.0); III: OR = 2.1 (95% CI, 1.9-2.3)). Obesity class III patients were most likely to experience wound disruption, sepsis, respiratory or renal complication, and urinary tract infection. Mortality was highest among underweight patients (OR = 1.3 (95% CI, 1.0-1.8)) and lowest among overweight (OR = 0.8 (95% CI, 0.6-0.9)) and obesity class I patients (OR = 0.8 (95% CI, 0.6-1.0)). LIMITATIONS: Retrospective analysis of American College of Surgeons National Surgical Quality Improvement Program hospitals may not represent patients outside of the American College of Surgeons National Surgical Quality Improvement Program and cannot assign causation or account for interventions to improve surgical outcomes. CONCLUSIONS: Patients with increasing BMI showed an incremental and independent risk for adverse 30-day postoperative outcomes, especially surgical site infections. Strategies to address obesity preoperatively should be considered to improve surgical outcomes among this population. See Video Abstract at http://links.lww.com/DCR/A607. PMID- 29994959 TI - Acute Kidney Injury in the Age of Enhanced Recovery Protocols. AB - BACKGROUND: Acute kidney injury is a prevalent complication after abdominal surgery. With increasing adoption of enhanced recovery protocols, concern exists for concomitant increase in acute kidney injury. OBJECTIVE: This study evaluated effects of enhanced recovery on acute kidney injury through identification of risk factors. DESIGN: This was a retrospective cohort study comparing acute kidney injury rates before and after implementation of enhanced recovery protocol. SETTINGS: The study was conducted at a large academic medical center. PATIENTS: All of the patients undergoing elective colorectal surgery between 2010 and 2016, excluding patients with stage 5 chronic kidney disease, were included. MAIN OUTCOME MEASURES: Patients before and after enhanced recovery implementation were compared, with rate of acute kidney injury as the primary outcome. Acute kidney injury was defined as a rise in serum creatinine >=1.5 times baseline within 30 days of surgery. Multivariable logistic regression identified risk factors for acute kidney injury. RESULTS: A total of 900 cases were identified, including 461 before and 439 after enhanced recovery; 114 cases were complicated by acute kidney injury, including 11.93% of patients before and 13.44% after implementation of enhanced recovery (p = 0.50). Five patients required hemodialysis, with 2 cases after protocol implementation. Multivariable logistic regression identified hypertension, functional status, ureteral stents, nonsteroidal anti-inflammatory drugs, operative time >200 minutes, and increased intravenous fluid administration on postoperative day 1 as predictors of acute kidney injury. Laparoscopic surgery decreased the risk of acute kidney injury. The enhanced recovery protocol was not independently associated with acute kidney injury. LIMITATIONS: The study was limited by its retrospective and nonrandomized before-and-after design. CONCLUSIONS: No difference in rates of acute kidney injury was detected before and after implementation of a colorectal enhanced recovery protocol. Independent predictors of acute kidney injury were identified and could be used to alter the protocol in high-risk patients. Future study is needed to determine whether protocol modifications will further decrease rates of acute kidney injury in this population. See Video Abstract at http://links.lww.com/DCR/A568. PMID- 29994960 TI - Comparison of Mesenteric Lengthening Techniques in IPAA: An Anatomic and Angiographic Study on Fresh Cadavers. AB - BACKGROUND: The IPAA technique restores anal functionality in patients who have had the large intestine and rectum removed; however, 1 of the most important reasons for pouch failure is tension on the anastomosis. OBJECTIVE: The aim of this study was to compare technical procedures for mesenteric lengthening used for IPAA to reduce this tension. DESIGN: After randomization, 4 different techniques for mesenteric lengthening were performed and compared on fresh cadavers. SETTING: This was a cross-sectional cadaveric study. MAIN OUTCOME MEASURES: In the first group (n = 5), stepladder incisions were made on the visceral peritoneum of the mesentery of the small intestine. In the second and third groups, the superior mesenteric pedicle was divided, whereas the ileocolic pedicle (n = 7) or marginal vessels (n = 6) were preserved during proctocolectomy. In the fourth group (n = 7), the superior mesenteric pedicle was cut without preserving any colic vessels. Mesenteric lengthening was analyzed. Angiography was performed to visualize the blood supply of the terminal ileum and pouch after mesenteric lengthening. RESULTS: Average mesenteric lengthening was 5.72 cm (+/- 1.68 cm) in group 1, 3.63 cm (+/- 1.75 cm) in group 2, 7.03 cm (+/- 3.47 cm) in group 3, and 7.29 cm (+/- 1.73 cm) in group 4 (p = 0.011 for group 2 when compared with the others). LIMITATIONS: The study was limited by nature of being a cadaver study. CONCLUSIONS: Stepladder incisions through superior mesenteric pedicle trace are usually sufficient for mesenteric lengthening. In addition, division of the superior mesenteric pedicle with either a preserving marginal artery or without preserving ileocolic and marginal arteries leads to additional mesenteric lengthening. PMID- 29994961 TI - In Patients Undergoing Colorectal Resection, Can Preoperative Antibiotics Combined With Mechanical Bowel Preparation Compared With Mechanical Bowel Preparation Only Significantly Reduce Surgical Site Infection? PMID- 29994962 TI - Prophylactic Ureteral Stenting in Colectomy Patients: Who Is at Risk? PMID- 29994963 TI - The Authors Reply. PMID- 29994965 TI - Intraoperative Traction May Be a Viable Alternative to Anterior Surgery in Cerebral Palsy Scoliosis >=100 Degrees: Erratum. PMID- 29994966 TI - Serum androgen profiles in women with premature ovarian insufficiency: a systematic review and meta-analysis. AB - OBJECTIVE: This meta-analysis aims to investigate serum androgen profiles (testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone binding globulin) in women with premature ovarian failure and to establish if there is evidence of diminished androgen levels in these women. METHODS: Various Internet sources of PubMed, Cochrane library, and Medline were searched systematically until February, 2018. Out of a pool of 2,461 studies, after applying the inclusion/exclusion criterion, 14, 8, 10, and 9 studies were chosen for testosterone, dehydroepiandrosterone sulfate, androstenedione, and sex hormone-binding globulin, respectively, for this meta-analysis. The effect measure was the standardized mean difference with 95% confidence interval (95% CI) in a random-effects model. RESULTS: The testosterone concentrations in premature ovarian insufficiency were compared with fertile controls: stamdard mean difference (IV, random, 95% CI) -0.73 [-0.99, -0.46], P value < 0.05. The dehydroepiandrosterone sulfate concentrations in premature ovarian insufficiency compared to fertile controls: standard mean difference (IV, random, 95% CI) -0.65 [-0.92, -0.37], P value < 0.05. Androstenedione in premature ovarian insufficiency were compared with fertile controls: standard mean difference (IV, random, 95% CI) -1.09 [-1.71, -0.48], P value < 0.05. Sex hormone-binding globulin levels did not show statistical significance. The dehydroepiandrosterone sulfate levels were reduced in premature ovarian insufficiency cases, but still showed a higher level than in postmenopausal women. CONCLUSIONS: Women with premature ovarian insufficiency are at risk for decreased concentrations of testosterone, dehydroepiandrosterone sulfate, and androstenedione. Dehydroepiandrosterone sulfate levels were more reduced in postmenopausal controls when compared with premature ovarian insufficiency cases.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29994969 TI - In Reply. PMID- 29994967 TI - Postmenopausal hormone treatment alters neural pathways but does not improve verbal cognitive function. AB - OBJECTIVE: Cognitive outcomes in trials of postmenopausal hormone treatment have been inconsistent. Differing outcomes may be attributed to hormone formulation, treatment duration and timing, and differential cognitive domain effects. We previously demonstrated treatment benefits on visual cognitive function. In the present study, we describe the effects of hormone treatment on verbal outcomes in the same women, seeking to understand the effects of prior versus current hormone treatment on verbal function. METHODS: This is a cross-sectional evaluation of 57 women (38 hormone users [25 prior long-term users and 13 current users] and 19 never-users). Hormone users took identical formulations of estrogen or estrogen + progestin (0.625 mg/d conjugated equine estrogens with or without medroxyprogesterone acetate) for at least 10 years, beginning within 2 years of menopause. Women were evaluated with tests of verbal function and functional magnetic resonance imaging (fMRI) of a verbal discrimination task. RESULTS: All women scored similarly on assessments of verbal function (Hopkins Verbal Learning Test and a verbal discrimination task performed during the fMRI scanning session); however, women ever treated with hormones had more left inferior frontal (T = 3.72; P < 0.001) and right prefrontal cortex (T = 3.53; P < 0.001) activation during the verbal task. Hormone-treated women performed slightly worse on the verbal discrimination task (mean accuracy 81.72 +/- 11.57 ever-treated, 85.30 +/- 5.87 never-treated, P = 0.14), took longer to respond (mean reaction time 1.10 +/- 0.17 s ever-treated, 1.02 +/- 0.11 never-treated, P = 0.03), and remembered fewer previously viewed words (mean accuracy 62.21 +/- 8.73 ever treated, 65.45 +/- 7.49 never-treated, P = 0.18). Increased posterior cingulate activity was associated with longer response times (R = 0.323, P = 0.015) and worse delayed verbal recall (R = -0.328, P = 0.048), suggesting that increased activation was associated with less efficient cognitive processing. We did not detect between group differences in activation in the left prefrontal cortex, superior frontal cortex, thalamus, or occipital/parietal junction. CONCLUSIONS: Although current and past hormone treatment was associated with differences in neural pathways used during verbal discrimination, verbal function was not higher than never-users. PMID- 29994970 TI - The histological microstructure and in vitro mechanical properties of the human female postmenopausal perineal body. AB - OBJECTIVE: The perineal body connects muscles from the pelvic floor and is critical for support of the lower part of the vagina and proper function of the anal canal. We determined mechanical parameters and volume fractions of main components of the human female postmenopausal perineal body. METHODS: The specimens were taken from 15 fresh female cadavers (age 74 +/- 10, mean +/- standard deviation). Seventy-five specimens from five regions of the perineal body were processed histologically to assess volume fractions of tissue components using stereological point testing grid. Fifteen specimens taken from the midline region were loaded uniaxially with 6 mm/min velocity until tissue rupture to determine Young's modulus of elasticity, ultimate stresses, and strains. RESULTS: The perineal body was composed of collagen (29%), adipose cells (27%), elastin (7%), smooth muscle (11%), and skeletal muscle (3%). The residual tissue (19%) constituted mostly peripheral nerves, lumina of blood vessels, fibroblasts, and fibrocytes. Young's modulus of elasticity at midline region was 18 kPa (median) at small and 232 kPa at large deformations, respectively. The ultimate stress was 172 kPa and the ultimate strain was 1.4. CONCLUSIONS: We determined the structural and mechanical parameters of the perineal body. The resultant data could be used as input for models simulating pelvic floor prolapse or dysfunction. PMID- 29994968 TI - A prospective study of inflammatory biomarker levels and risk of early menopause. AB - OBJECTIVE: Early menopause, the cessation of ovarian function before age 45, has consequences for fertility and cardiovascular health. Evidence from studies of women with autoimmune conditions and genetic studies supports a role for inflammation in early menopause, but the association of inflammatory markers and risk has not been directly evaluated. METHODS: We assessed the relation of the soluble fraction of tumor necrosis factor alpha receptor 2 (sTNFR2), C-reactive protein, interleukin-6 (IL6) levels with incident early menopause among Nurses' Health Study II participants who provided a premenopausal blood sample in 1996 to 1999. Cases (n = 328) were women reporting natural menopause between blood collection and age 45.Controls (n = 492) included (1) 328 women with menopause after age 47, matched 1:1 with cases on age at blood collection and other factors; and (2) 164 additional women with menopause after age 45. RESULTS: In multivariable models comparing cases and n = 492 controls, we observed a significant association of sTNFR2 levels and risk of early menopause (P = 0.002). Compared with women with the lowest sTNFR2 levels, odds ratios (95% CIs) for quartiles 2 to 4 were 0.60 (0.38-0.95), 0.93 (0.61-1.43), and 1.40 (0.93-2.11). Results further adjusting for antimullerian hormone levels were similar in magnitude, as were results from sensitivity analyses of matched cases and controls (n = 328 pairs), nonsmokers, and leaner women. C-reactive protein and IL6 levels were unrelated to risk. CONCLUSIONS: The observation of lower risk of early menopause among women with moderate sTNFR2 levels compared with women with lower and higher levels warrants further prospective study. PMID- 29994971 TI - Multifactorial: pain in the menopause transition. PMID- 29994972 TI - Clinician practice: bridging what we clinically know about genitourinary syndrome of menopause and what research data report to us. PMID- 29994973 TI - The many menopauses: searching the cognitive research literature for menopause types. AB - OBJECTIVE: Recent evidence suggests that early or induced menopause increases the risk for cognitive impairment and dementia. Given the potential for different cognitive outcomes due to menopause types, it is important that present research on menopause and cognition distinguishes between types. The aim of this project was to determine to what extent research looking at cognition in postmenopausal women published in one year, 2016, accounted for menopausal type. METHODS: We searched MEDLINE, EMBASE, and PsychINFO using keywords and MeSH terms for menopause and cognition. We included any research paper reporting a cognitive outcome measure in a menopausal human population. Differentiation between the types of menopause was defined by four categories: undifferentiated, demographic differentiation (menopause type reported but not analyzed), partial differentiation (some but not all types analyzed), and full differentiation (menopause types factored into analysis, or recruitment of only one type). RESULTS: Fifty research articles were found and analyzed. Differentiation was distributed as follows: undifferentiated, 38% (19 articles); demographic differentiation, 16% (8); partial differentiation, 28% (14); and full differentiation, 18% (9). CONCLUSIONS: This review revealed that although some clinical studies differentiated between the many menopauses, most did not. This may limit their relevance to clinical practice. We found that when menopause types are distinguished, the differing cognitive outcomes of each type are clarified, yielding the strongest evidence, which in turn will be able to inform best clinical practice for treating all women.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29994974 TI - Postmenopausal hormone therapy is accompanied by elevated risk for uterine prolapse. AB - OBJECTIVE: Receptors for estrogen and progesterone are present in the pelvic floor, and therefore, postmenopausal hormone therapy may affect its function. We compared the former use of estradiol-progestogen postmenopausal hormone therapy in nonhysterectomized women with a uterine prolapse surgery (N = 12,072) and control women (N = 33,704). METHODS: The women with a history of uterine prolapse operation were identified from the Finnish National Hospital Discharge Register, and the control women from the Finnish Central Population Register. The use of hormone therapy was traced from the national drug reimbursement register, and the odd ratios with 95% CIs for prolapse were calculated by using the conditional logistic regression analysis. RESULTS: The women with uterine prolapse had used hormone therapy more often than control women (N = 4,127; 34.2% vs N = 9,189; 27.3%; P < 0.005). The use of hormone therapy was accompanied by significant (23% 53%) elevations in the risk for prolapse, being higher with longer exposure. The risk elevations (33%-23%) were comparable between sole norethisteroneacetate estradiol and sole medroxyprogesteroneacetate-estradiol therapy. The use of estradiol in combination with a levonorgestrel releasing intrauterine device was accompanied by a 52% elevation. CONCLUSIONS: The postmenopausal use of estradiol in combination with various progestogen regimens may weaken the pelvic floor, resulting in uterine prolapse. This data should be incorporated into the information given to the users of estradiol-progestogen hormone therapy. PMID- 29994975 TI - Physical activity and weight gain after smoking cessation in postmenopausal women. AB - OBJECTIVE: Weight gain frequently occurs after smoking cessation. The objective of this study was to examine whether weight gain after smoking cessation was attenuated by physical activity (PA) in postmenopausal women. METHODS: A total of 4,717 baseline smokers from the Women's Health Initiative were followed for 3 years. One thousand two hundred eighty-two women quit smoking, and 3,435 continued smoking. Weight was measured at baseline and at the year 3 visit. PA was assessed at both times by self-report, summarized as metabolic equivalent task-hours per week. Multiple linear regression models were used to assess the association between PA and postcessation weight gain, adjusting for potential confounding factors. RESULTS: Compared with continuing smokers, quitters gained an average of 3.5 kg (SD = 5.6) between the baseline and year 3 visit. Quitters with decreased PA had the highest amount of weight gain (3.88 kg, 95% CI: 3.22 4.54); quitters with increased PA (>=15 metabolic equivalent task-hours /week) had the lowest weight gain (2.55 kg, 95% CI: 1.59-3.52). Increased PA had a stronger beneficial association for postcessation weight gain for women with obesity compared to normal weight women. Quitters who had low PA at baseline and high PA at year 3 and were also enrolled in a dietary modification intervention had nonsignificant weight gain (1.88 kg, 95% CI: -0.21-3.96) compared with continuing smokers. CONCLUSIONS: Our data demonstrate that even a modest increase in PA (equivalent to current recommendations) can attenuate weight gain after quitting smoking among postmenopausal women, especially in combination with improved diet. PMID- 29994976 TI - Ovariectomy and obesity have equal impact in causing mitochondrial dysfunction and impaired skeletal muscle contraction in rats. AB - OBJECTIVE: Previous studies have demonstrated that either an obese-insulin resistance condition or a condition involving loss of estrogen impaired skeletal muscle function as indicated by a decrease in muscle contraction. The differing effects of combined estrogen deficiency over obese-insulin resistance on skeletal muscle function have, however, not yet been determined. Our hypothesis was that estrogen deficiency aggravates skeletal muscle dysfunction in obese-insulin resistant rats, via increased muscle oxidative stress and mitochondrial dysfunction. METHODS: Twenty-four female Wistar rats were divided into 2 groups and animals in each group were fed either a normal diet (ND) or a high-fat diet (HFD) for 24 weeks. At week 13, rats in each group were subdivided into 2 subgroups: sham-operated or ovariectomized (n = 6/subgroup). At the end of the experimental period the contraction of the gastrocnemius muscles was tested before the rats were sacrificed. Skeletal muscle was removed to assess oxidative stress and mitochondrial function. RESULTS: We found that an obese-insulin resistant condition was observed in sham-operated HFD-fed rats, ovariectomized ND fed rats, and ovariectomized HFD-fed rats. Skeletal muscle contractile function (peak-force ratio [g/g]; 25.40 +/- 2.03 [ovariectomized ND-fed rats], 22.44 +/- 0.85 [sham-operated HFD-fed rats] and 25.06 +/- 0.61 [ovariectomized HFD-fed rats]), skeletal muscle mitochondrial function, and oxidative stress were equally significantly impaired in all 3 groups, when compared with those of sham-operated ND-fed rats (31.12 +/- 1.88 g/g [NDS]; P < 0.05). Surprisingly, loss of estrogen did not aggravate these dysfunctions of skeletal muscles in HFD-fed rats. CONCLUSIONS: These findings suggest that skeletal muscle dysfunction may occur due to increased muscle oxidative stress and mitochondrial dysfunction as a result of ovariectomy and obese-insulin resistance. Loss of estrogen, however, did not aggravate these impairments in the muscle of rats with obese-insulin resistant condition. PMID- 29994978 TI - Outcomes of Pancreas Transplant Recipients with de novo Donor Specific Antibodies. AB - BACKGROUND: Development of denovo donor-specific antibodies (dnDSA) has detrimental effects on graft survival in several types of solid organ transplants. But limited information exists about the effect of dnDSA on pancreas transplant graft survival. METHODS: We report our experience with pancreas recipients transplanted between 01/01/2005 and 08/31/2017. RESULTS: We identified 541 pancreas transplant recipients, of which 121 developed dnDSA and 420 did not. 32% developed dnDSA against HLA class I antigens, 56% developed against class II antigens and 12% developed against both. 52% of the patients in the dnDSA+ and 24% in the dnDSA- group underwent pancreas biopsy, mainly due to a rise in pancreatic enzymes. Rejection was found in 42% of the dnDSA+ group, and 20% of the dnDSA- group(p<0.001). There were 36% uncensored graft failures in the dnDSA+ group and 17% uncensored failures in the dnDSA- group(p<0.001). A similar trend was seen in death-censored graft failure between the groups. In univariate Cox regression analyses, male gender, older age, and recipients of simultaneous pancreas and kidney transplant were found to be protective for death-censored graft failure; multiple transplants, dnDSA, requirement for pancreas biopsy and presence of pancreas rejection were associated with increased risk of graft failure. In multivariate analysis, only older age and dnDSA were significantly associated with death-censored graft failure. CONCLUSION: Our findings suggest that dnDSA in pancreas transplant recipients are associated with increased rates of rejection and graft failure. Timely detection of dnDSA through regular screening and early treatment of pancreas rejection may ultimately improve graft outcomes. PMID- 29994979 TI - gammadelta T Cells in Transplantation: Friend and Foe. PMID- 29994977 TI - Deciphering the Contribution of gammadelta T Cells to Outcomes in Transplantation. AB - gammadelta T cells are a subpopulation of lymphocytes expressing heterodimeric T cell receptors composed of gamma and delta chains. They are morphologically and functionally heterogeneous, innate yet also adaptive in behavior, and exhibit diverse activities spanning immunosurveillance, immunomodulation, and direct cytotoxicity. The specific responses of gammadelta T cells to allografts are yet to be fully elucidated with evidence of both detrimental and tolerogenic roles in different settings. Here we present an overview of gammadelta T-cell literature, consider ways in which their functional heterogeneity contributes to the outcomes after transplantation, and reflect on methods to harness their beneficial properties. PMID- 29994980 TI - Impact of Donor Core Body Temperature on Graft Survival After Heart Transplantation. AB - BACKGROUND: A previous donor intervention trial found that induction of mild therapeutic hypothermia in the brain-dead donor reduced the dialysis requirement after kidney transplantation. Consequences on the performance of cardiac allografts after transplantation were not explored to date. METHODS: Cohort study investigating 3-year heart allograft survival according to spontaneous core body temperature (CBT) assessed on the day of organ procurement. The study is nested in the database of the randomized trial of donor pretreatment with low-dose dopamine (ClinicalTrials.gov identifier: NCT000115115). RESULTS: Ninety-nine heart transplant recipients who had received a cardiac allograft from a multiorgan donor enrolled in the dopamine trial were grouped by tertiles of the donor's CBT assessed by a mere temperature reading 4 to 20 hours before procurement (lowest, 32.0-36.2 degrees C; middle, 36.3-36.8 degrees C; highest, 36.9-38.8 degrees C). Baseline characteristics considering demographics of donors and recipients, concomitant donor treatments, donor hemodynamic, and respiratory parameters as well as underlying cardiac diseases in recipients, pretransplant hemodynamic assessments, including pretransplant inotropic/mechanical support, urgency, and waiting time were similar. A lower CBT was associated with inferior heart allograft survival (hazard ratio, 0.53; 95% confidence interval, 0.31-0.93, per tertile; P = 0.02, and hazard ratio, 0.68; 95% confidence interval, 0.50-0.93 degrees C; P = 0.02) when CBT was included as continuous explanatory variable in the Cox regression analysis. CONCLUSIONS: A lower CBT in the brain-dead donor before procurement may associate with an unfavorable clinical course after heart transplantation. More research is required, before therapeutic hypothermia can routinely be used in multiorgan donors when a cardiac transplantation is intended. PMID- 29994981 TI - Recurrent or De Novo Allograft Steatosis and Long-Term Outcomes After Liver Transplantation. AB - BACKGROUND: Hepatic steatosis is strongly associated with cardiovascular disease in the general population. Whether recurrent or de novo, it can occur in the allograft but the impact on survival and long term clinical outcomes remains unclear. In this study, we aim to determine both the frequency and impact of allograft steatosis on long term posttransplant outcomes. METHODS: A retrospective review of 588 adult liver transplant (LT) recipients (1999-2006) was performed. Cox regression analysis (time dependent) was used to evaluate differences in time to steatosis post-LT, patient survival and cardiovascular outcomes. RESULTS: Mean age 51.9+/-10.6 years, 64.6% males, underlying NASH (9.4%), previous tobacco (52%), pre-LT diabetes mellitus (30.3%), pre-LT hypertension (23.2%), and known cardiovascular disease (9.7%). Overall, 254 recipients developed allograft steatosis (at 10 years: 77.6% NASH recipients, 44.7% Non-NASH recipients). Risk factors for allograft steatosis were female gender (hazard ratio [HR] 1.47, 95% confidence interval [CI] 1.09-2.00, p=0.014), HCV diagnosis (HR 2.49, 95% CI 1.77-3.94, p<0.001) and time dependent BMI (per unit: HR 1.08, 95% CI 1.05-1.10, p<0.001). Allograft steatosis was not associated with post-LT survival (p=0.25) nor cardiovascular events (HR1.08, (0.73-1.59), p=0.70). Underlying NASH associated with cardiovascular events (HR 2.04, (1.37 3.04), p<0.001). CONCLUSION: Allograft steatosis is common, but not associated with survival or cardiovascular events in this study. Larger prospective studies are needed to better define the natural history of allograft steatosis. PMID- 29994982 TI - Cold Storage Injury to Rat Small-bowel Transplants-Beneficial Effect of a Modified HTK Solution. AB - BACKGROUND: The small bowel is prone to ischemic injury during transport before transplantation, an injury that endangers the recipient patient. The small-bowel mucosal microcirculation in particular appears to be highly sensitive to injury. Current preservation solutions such as histidine-tryptophan-ketoglutarate (HTK) solution provide some protection to the graft. However, these were developed decades ago and do not address several critical processes, such as hypoxia induced membrane pores and free radical-mediated hypothermic injury. METHODS: To protect the graft from cold ischemic injury, we implemented a modified HTK solution here, including glycine, alanine, and iron chelators in a heterotopic, syngeneic small-bowel transplantation model of the rat. The effects of the modified solution and its major components were compared against the conventional HTK solution using intravital microscopy in the early reperfusion period. RESULTS: The amino acid glycine, added to HTK solution, slightly improved mucosal perfusion. Both, the modified base solution (without iron chelators) and iron chelators increased functional capillary density of the mucosa during the early reperfusion period. The complete modified solution (with glycine, alanine, and iron chelators) significantly increased the perfusion index, functional capillary density of the mucosa, and red blood cell velocity in the grafts after reperfusion in comparison with the grafts preserved with HTK. CONCLUSIONS: The modified preservation solution improved the microcirculation of the transplants and needs detailed evaluation in further models of small-bowel transplantation. PMID- 29994983 TI - Gender differences in medication adherence among adolescent and young adult kidney transplant recipients. AB - BACKGROUND: Among kidney transplant recipients, gender differences in medication adherence may contribute to the higher graft failure risks observed in girls and young women compared with boys and young men. Our aim was to determine whether adherence differs by gender, and whether gender differences vary by age in adolescent and young adult kidney transplant recipients. METHODS: We examined data from the 3-month run-in period (no intervention) of the randomized TAKE-IT trial. Adherence was monitored using electronic pillboxes in 136 patients (11-24 y) followed in 8 transplant centers in Canada and USA. We used ordinal logistic regression with generalized estimating equations to estimate the association between gender and each of daily taking (proportion of prescribed doses taken) and timing (proportion of prescribed doses taken on time) adherence, considering effect modification by age (11-16 vs. 17-24 years). RESULTS: No difference in taking adherence was observed by gender among participants 11-16 years (OR=0.92 (95%CI 0.55-1.54)), whereas among participants 17-24 years, women had significantly greater odds of higher taking adherence scores (OR=3.03 (95%CI 1.20 7.66)) than men. Results were similar for timing adherence, with no difference among participants 11-16 years (OR=1.03 (95%CI 0.65-1.63)) but a greater odds of higher timing adherence scores in women than in men among participants 17-24 years (OR=3.26 (95%CI 1.43-7.45)). There were no differences in adherence assessed by self-report or SD of tacrolimus trough levels. CONCLUSIONS: Gender differences in adherence vary by age. Whereas younger adolescents show no adherence differences by gender, young women show much better adherence than young men. PMID- 29994985 TI - Therapeutic Drug Monitoring of Methotrexate in Plasma Using Ultra High Performance Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry: Necessary After Administration of Glucarpidase in Methotrexate Intoxications. AB - High-dose methotrexate (HD-MTX) is used to treat a variety of cancers. In all patients receiving HD-MTX, plasma MTX levels are monitored mainly to anticipate rescue therapy to prevent adverse events. We present 2 children treated with HD MTX and afterward treated with glucarpidase at different time-points after their HD-MTX infusions. After the administration of glucarpidase, a nontoxic metabolite of MTX cross-reacts with MTX in the standard immunoassay (Abbott Diagnostics, Hoofddorp, the Netherlands) resulting in an artificially elevated MTX level. An artificially elevated MTX level results in unnecessarily long folinic acid administration, which decreases the effectivity of MTX. This grand round highlights the importance of measuring plasma MTX levels after the administration of glucarpidase with an ultra high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method instead of with an immunoassay. PMID- 29994984 TI - Evolutionary Distance Predicts Recurrence After Liver Transplantation in Multifocal Hepatocellular Carcinoma. AB - BACKGROUND: Liver transplantation (LTx) is a potentially curative treatment option for hepatocellular carcinoma (HCC) in cirrhosis. However, patients, where HCC is already a systemic disease, LTx may be individually harmful and has a negative impact on donor organ usage. Thus, there is a need for improved selection criteria beyond nodule morphology to select patients with a favorable outcome for LTx in multifocal HCC. Evolutionary distance measured from genome wide single-nucleotide polymorphism data between tumor nodules and the cirrhotic liver may be a prognostic marker of survival after LTx for multifocal HCC. METHODS: In a retrospective multicenter study, clinical data and formalin-fixed paraffin-embedded specimens of the liver and 2 tumor nodules were obtained from explants of 30 patients in the discovery and 180 patients in the replication cohort. DNA was extracted from formalin-fixed paraffin-embedded specimens followed by genome wide single-nucleotide polymorphism genotyping. RESULTS: Genotype quality criteria allowed for analysis of 8 patients in the discovery and 17 patients in the replication set. DNA concentrations of a total of 25 patients fulfilled the quality criteria and were included in the analysis. Both, in the discovery (P = 0.04) and in the replication data sets (P = 0.01), evolutionary distance was associated with the risk of recurrence of HCC after transplantation (combined P = 0.0002). In a univariate analysis, evolutionary distance (P = 7.4 * 10) and microvascular invasion (P = 1.31 * 10) were significantly associated with survival in a Cox regression analysis. CONCLUSIONS: Evolutionary distance allows for the determination of a high-risk group of recurrence if preoperative liver biopsy is considered. PMID- 29994986 TI - Development and Validation of an Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Method for the Concurrent Measurement of Gabapentin, Lamotrigine, Levetiracetam, Monohydroxy Derivative of Oxcarbazepine, and Zonisamide Concentrations in Serum in a Clinical Setting. AB - BACKGROUND: Therapeutic drug monitoring of antiepileptic drugs (AEDs) is often necessary to prevent associated destructive toxicities. Tandem mass spectrometry (MS/MS) with stable-isotope-labeled internal standards is considered the gold standard for the measurement of AEDs. This study presents the development and validation of a clinical ultra-performance liquid chromatography-MS/MS method for the concurrent measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative of oxcarbazepine, and zonisamide in human serum. METHODS: To determine the optimal assay analyte range, one year of AED therapeutic drug monitoring results (n = 1825) were evaluated. Simple protein precipitation with acetonitrile containing isotopically labeled internal standards was used. Reverse-phase ultra performance liquid chromatography chromatographic separation was used, having a total run time of 3 minutes. Quantification of analytes was accomplished using electrospray ionization in positive ion mode and collision-induced dissociation MS. Assay parameters were evaluated per Food and Drug Administration bioanalytical guidelines. RESULTS: After evaluating internal patient data, the analytical measuring range (AMR) of the assay was established as 0.1-100 mcg/mL. All AEDs were linear across the AMR, with R values ranging from 0.9988 to 0.9999. Imprecision (% coefficient of variation) and inaccuracy (% difference) were calculated to be <20% for the lower limit of quantitation and <15% for the low, mid, and high levels of quality controls across the AMR. All AEDs demonstrated acceptable assay parameters for carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency. In addition, the assay displayed acceptable concordance to results obtained from a national reference laboratory, with Deming regression R of 0.99 and slope values ranging from 0.89 to 1.17. CONCLUSIONS: A simple, cost-effective, and robust ultra-performance liquid chromatography-tandem mass spectrometry method for monitoring multiple AEDs was developed and validated to address the clinical needs of patients at our institution. PMID- 29994987 TI - Validation of an Isavuconazole High-Performance Liquid Chromatography Assay in Plasma for Routine Therapeutic Drug Monitoring Applications. AB - BACKGROUND: Isavuconazole is a triazole antifungal agent for treatment of invasive aspergillosis and mucormycosis. At present, it is unclear whether a therapeutic drug monitoring (TDM) of isavuconazole would be necessary. The aim of the investigation was to validate a high-performance liquid chromatography (HPLC) assay for routine applications. METHODS: An HPLC assay for routine determination of isavuconazole in plasma has been adapted and validated. The assay used the reagents and HPLC column provided by the ChromSystems HPLC Kit for TDM of itraconazole, posaconazole, and voriconazole. Isocratic flow rate was set at 1.0 mL/min. Detection was performed using a fluorescence detector with excitation wavelength set at 261 nm and emission wavelength set at 366 nm. RESULTS: The assay was linear between 0.15 and 10 mg/L with intraday and interday imprecision and accuracy <10% (<20% at lower limit of quantification). The method was applied to routine TDM of 7 patients after hematopoietic stem cell transplantation (n = 31 samples). In these patients, trough levels ranged from 0.45 to 3.06 mg/L (median 1.44 mg/L). CONCLUSIONS: A robust and simple HPLC assay of isavuconazole in plasma for routine TDM applications is presented. PMID- 29994988 TI - Analgesic effects of a novel pH-dependent MU-opioid receptor agonist in models of neuropathic and abdominal pain. AB - Recently, (+/-)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a newly designed MU-opioid receptor (MOR) agonist with a low pKa, has been shown to produce injury-restricted analgesia in models of inflammatory and postoperative pain, without exhibiting typical opioid side effects. Here, we investigated MOR binding of NFEPP in brain and dorsal root ganglia, pH in injured tissues, and the analgesic efficacy of NFEPP compared with fentanyl in a chronic constriction injury model of neuropathic pain, and in the acetic acid-induced abdominal writhing assay in rats. Binding experiments revealed significantly lower affinity of NFEPP compared with fentanyl at pH 7.4. In vivo, pH significantly dropped both at injured nerves after chronic constriction injury and in the abdominal cavity after acetic acid administration. Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid-induced abdominal constrictions. In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity. Our results indicate that NFEPP exerts peripheral opioid receptor-mediated analgesia exclusively in damaged tissue in models of neuropathic and abdominal pain. PMID- 29994989 TI - Dynamic pain connectome functional connectivity and oscillations reflect multiple sclerosis pain. AB - Pain is a prevalent and debilitating symptom of multiple sclerosis (MS); yet, the mechanisms underlying this pain are unknown. Previous studies have found that the functional relationships between the salience network (SN), specifically the right temporoparietal junction a SN node, and other components of the dynamic pain connectome (default mode network [DMN], ascending and descending pathways) are abnormal in many chronic pain conditions. Here, we use resting-state functional magnetic resonance imaging and measures of static and dynamic functional connectivity (sFC and dFC), and regional BOLD variability to test the hypothesis that patients with MS have abnormal DMN-SN cross-network sFC, dFC abnormalities in SN-ascending and SN-descending pathways, and disrupted BOLD variability in the dynamic pain connectome that relates to pain inference and neuropathic pain (NP). Thirty-one patients with MS and 31 controls completed questionnaires to characterize pain and pain interference, and underwent a resting-state functional magnetic resonance imaging scan from which measures of sFC, dFC, and BOLD variability were compared. We found that (1) ~50% of our patients had NP features, (2) abnormalities in SN-DMN sFC were driven by the mixed-neuropathic subgroup, (3) in patients with mixed NP, dFC measures showed that there was a striking change in how the SN was engaged with the ascending nociceptive pathway and descending modulation pathway, (4) BOLD variability was increased in the DMN, and (5) the degrees of sFC and BOLD variability abnormalities were related to pain interference. We propose that abnormal SN-DMN cross-network FC and temporal dynamics within and between regions of the dynamic pain connectome reflect MS pain features. PMID- 29994991 TI - Complex regional pain syndrome: intradermal injection of phenylephrine evokes pain and hyperalgesia in a subgroup of patients with upregulated alpha1 adrenoceptors on dermal nerves. AB - The aim of this study was to determine whether upregulated cutaneous expression of alpha1-adrenoceptors (alpha1-AR) is a source of pain in patients with complex regional pain syndrome (CRPS). Immunohistochemistry was used to identify alpha1 AR on nerve fibres and other targets in the affected and contralateral skin of 90 patients, and in skin samples from 38 pain-free controls. The distribution of alpha1-AR was compared between patients and controls, and among subgroups of patients defined by CRPS duration, limb temperature asymmetry, and diagnostic subtype (CRPS I vs CRPS II). In addition, alpha1-AR expression was investigated in relation to pain and pinprick hyperalgesia evoked by intradermal injection of the alpha1-AR agonist phenylephrine. Expression of alpha1-AR on nerve bundles in the CRPS-affected limb was greater in patients who reported prolonged pain and pinprick hyperalgesia around the phenylephrine injection site than in patients with transient pain after the injection. In addition, alpha1-AR expression in nerve bundles was greater in patients with CRPS II than CRPS I, and was greater in acute than more long-standing CRPS. Although less clearly associated with the nociceptive effects of phenylephrine, alpha1-AR expression was greater on dermal nerve fibres in the painful than contralateral limb. Together, these findings are consistent with nociceptive involvement of cutaneous alpha1-AR in CRPS. This involvement may be greater in acute than chronic CRPS, and in CRPS II than CRPS I. PMID- 29994990 TI - Anti-nerve growth factor does not change physical activity in normal young or aging mice but does increase activity in mice with skeletal pain. AB - Anti-nerve growth factor (anti-NGF) therapy has shown significant promise in attenuating several types of skeletal pain. However, whether anti-NGF therapy changes the level of physical activity in individuals with or without skeletal pain is largely unknown. Here, automated day/night activity boxes monitored the effects of anti-NGF treatment on physical activity in normal young (3 months old) and aging (18-23 months old) mice and mice with bone fracture pain. Although aging mice were clearly less active and showed loss of bone mass compared with young mice, anti-NGF treatment had no effect on any measure of day/night activity in either the young or aging mice. By contrast, in mice with femoral fracture pain, anti-NGF treatment produced a clear increase (10%-27%) in horizontal activity, vertical rearing, and velocity of travel compared with the Fracture + Vehicle group. These results suggest, just as in humans, mice titrate their level of physical activity to their level of skeletal pain. The level of skeletal pain may in part be determined by the level of free NGF that seems to rise after injury but not normal aging of the skeleton. In terms of bone healing, animals that received anti-NGF showed an increase in the size of calcified callus but no increase in the number of displaced fractures or time to cortical union. As physical activity is the best nondrug treatment for many patients with skeletal pain, anti-NGF may be useful in reducing pain and promoting activity in these patients. PMID- 29994992 TI - Do post-traumatic pain and post-traumatic stress symptomatology mutually maintain each other? A systematic review of cross-lagged studies. AB - After traumatic exposure, individuals are at risk of developing symptoms of both pain and post-traumatic stress disorder (PTSD). Theory and research suggest a complex and potentially mutually maintaining relationship between these symptomatologies. However, findings are inconsistent and the applied methods are not always well suited for testing mutual maintenance. Cross-lagged designs can provide valuable insights into such temporal associations, but there is a need for a systematic review to assist clinicians and researchers in understanding the nature of the relationship. Thus, the aim of this systematic review was to identify, critically appraise, and synthesize results from cross-lagged studies on pain and PTSD symptomatology to assess the evidence for longitudinal reciprocity and potential mediators. Systematic searches resulted in 7 eligible studies that were deemed of acceptable quality with moderate risk of bias using the cohort study checklist from Scottish Intercollegiate Guidelines Network. Furthermore, synthesis of significant pathways in the cross-lagged models showed inconsistent evidence of both bidirectional and unidirectional interaction patterns between pain and PTSD symptomatology across time, hence not uniformly supporting the theoretical framework of mutual maintenance. In addition, the synthesis suggested that hyperarousal and intrusion symptoms may be of particular importance in these cross-lagged relationships, while there was inconclusive evidence of catastrophizing as a mediator. In conclusion, the findings suggest an entangled, but not necessarily mutually maintaining relationship between pain and PTSD symptomatology. However, major variations in findings and methodologies complicated synthesis, prompting careful interpretation and heightening the likelihood that future high-quality studies will change these conclusions. PMID- 29994993 TI - Electrophysiological characterisation of central sensitisation in canine spontaneous osteoarthritis. AB - In man, central sensitisation (CS) contributes to the pain of osteoarthritis (OA). Dogs with spontaneous OA may also exhibit CS. Electrophysiological reflex measurements are more objective than behavioural assessments and can be used to evaluate CS in preclinical and clinical studies. It was hypothesised that dogs suffering from OA would exhibit electrophysiological characteristics indicative of CS, associated with reduced diffuse noxious inhibitory controls (DNICs). One hundred and seventeen client-owned dogs were recruited to the study. Hind limb nociceptive withdrawal reflex thresholds, stimulus response, and temporal summation characteristics were recorded, during alfaxalone anaesthesia, from 46 OA dogs, 29 OA dogs receiving nonsteroidal anti-inflammatory drugs (OANSAIDs), and 27 breed- and weight-matched control dogs. Efficacy of DNIC was evaluated in 12 control and 11 of the OA dogs, by application of a mechanical conditioning stimulus to the contralateral forelimb. Nociceptive withdrawal reflex thresholds were higher in OA compared with control dogs (P = 0.02). Stimulus response characteristics demonstrated an augmented response in OANSAID dogs compared with OA (P < 0.001) and control (P < 0.001) dogs. Temporal summation demonstrated exaggerated C-fibre-mediated responses in both OA (P < 0.001) and OANSAID (P = 0.005) groups, compared with control animals. Conditioning stimulus application resulted in inhibition of test reflex responses in both OA and control animals (P < 0.001); control animals demonstrated greater inhibition compared with OA (P = 0.0499). These data provide evidence of neurophysiological changes consistent with CS in dogs with spontaneous OA and demonstrate that canine OA is associated with reduced DNIC. PMID- 29994994 TI - Adelta and not C fibers mediate thermal hyperalgesia to short laser stimuli after burn injury in man. AB - It remains unclear which nerve fibers are responsible for mediating hyperalgesia after skin injury. Here, we examined the role of Adelta and C fibers in inflammatory hyperalgesia after a first-degree burn injury. A CO2 laser delivered ultrafast short constant-temperature heat pulses to the upper part of the lower leg to stimulate selectively the relatively fast-conducting thinly myelinated Adelta and the slowly conducting unmyelinated C fibers. Participants were asked to respond as fast as possible whenever they detected a thermal stimulus. Thresholds and reaction times to selective Adelta and C fiber activations were measured in the conditioned and the surrounding intact skin, at pre-injury, and 1 hour and 24 hours after injury. First-degree burn injury caused a significant decrease in Adelta fiber detection thresholds and a significant increase in the proportion of Adelta-fiber-mediated responses in the inflamed area 24 hours, but not 1 hour, after burn injury. No changes in heat perception were observed in the intact skin surrounding the injury. No group differences in C-fiber-mediated sensations were observed. Our findings indicate that quickly adapting Adelta fibers but not quickly adapting C fibers are sensitized when activated by short and ultrafast heat stimuli after skin burn injury. Our results further show that this change occurs between 1 hour and 24 hours after injury and that it does not extend to the skin surrounding the injury. PMID- 29994996 TI - BILATERAL ENDOGENOUS ENDOPHTHALMITIS FROM STREPTOCOCCUS PNEUMONIAE. AB - PURPOSE: To report a case of bilateral endogenous endophthalmitis from Streptococcus pneumoniae with devastating sequelae. METHODS: Interventional case report. RESULTS: A 56-year-old man presented with acute bilateral blurred vision and floaters with fever and hemodynamic instability. Previously, he was diagnosed with acute otitis externa and reported manually extracting several of his own teeth. He underwent a vitreous tap and intravitreal antibiotic injections. Blood and vitreous cultures were positive for S. pneumoniae. The patient later developed life-threatening medical sequelae. His final visual acuity was no light perception in the right eye and 20/25 in the left eye. CONCLUSION: Diagnosing endogenous endophthalmitis early is essential to initiating a systemic evaluation for potentially life-threatening medical conditions, including sepsis, endocarditis, and osteomyelitis. A high degree of suspicion, expeditious treatment, and interdisciplinary collaboration are essential to maximizing patient outcomes.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29994997 TI - GROWTH OF PRESUMED CHOROIDAL NEVUS INTO MELANOMA OVER 4 YEARS IN BAP1 TUMOR PREDISPOSITION SYNDROME. AB - PURPOSE: To report a case of presumed choroidal nevus that eventually grew into melanoma in a patient with family history of choroidal melanoma and germline BAP1 mutation. METHODS: Case report. RESULTS: A 55-year-old healthy white woman with a family history of uveal melanoma in her father, paternal aunt, and paternal cousin was referred for evaluation of an asymptomatic small pigmented choroidal lesion in her right eye, measuring 2 mm * 2 mm in basal diameter and 1 mm in thickness. There were no clinical risk factors. The patient was advised routine monitoring but returned 4 years later with intermittent photopsia. The choroidal mass demonstrated growth and suggestive of transformation into melanoma, measuring 9 mm * 6 mm in basal diameter and 2.5 mm in thickness with overlying orange lipofuscin pigment and no associated subretinal fluid. Fine-needle aspiration biopsy disclosed Chromosome 3 mosaic monosomy and Chromosomes 6 and 8 disomy. Iodine 125 plaque radiotherapy was provided. Based on growth to melanoma and strong family history of uveal melanoma, BAP1 germline mutation testing was performed, and the results were positive. CONCLUSION: This case demonstrates growth of a presumed choroidal nevus into melanoma in the setting of underlying germline BAP1 mutation. We suggest that small pigmented choroidal lesions be monitored closely in patients with germline BAP1 mutation or with family history of uveal melanoma, even in the absence of known local risk factors predictive of tumor growth. PMID- 29994995 TI - Peripherally administered calcitonin gene-related peptide induces spontaneous pain in mice: implications for migraine. AB - Migraine is the third most common disease in the world (behind dental caries and tension-type headache) with an estimated global prevalence of 15%, yet its etiology remains poorly understood. Recent clinical trials have heralded the potential of therapeutic antibodies that block the actions of the neuropeptide calcitonin gene-related peptide (CGRP) or its receptor to prevent migraine. Calcitonin gene-related peptide is believed to contribute to trigeminal nerve hypersensitivity and photosensitivity in migraine, but a direct role in pain associated with migraine has not been established. In this study, we report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. These indicators of discomfort were completely blocked by preadministration of a monoclonal anti-CGRP-blocking antibody. However, the nonsteroidal anti-inflammatory drug meloxicam failed to block the effect of CGRP. Interestingly, an apparent sex-specific response to treatment was observed with the antimigraine drug sumatriptan partially blocking the CGRP response in male, but not female mice. These results demonstrate that CGRP can induce spontaneous pain, even in the absence of light, and that the squint response provides an objective biomarker for CGRP-induced pain that is translatable to humans. PMID- 29994998 TI - Influencing the Binge-Drinking Culture on a College Campus. AB - BACKGROUND: The college years are a time of transition in which students experiment with behaviors including use of alcohol. Nursing students can be instrumental in supporting positive health behaviors and influencing the drinking culture. PURPOSE: This article describes the findings of a collaborative nursing student-faculty research project about alcohol use with a focus on binge drinking. METHODS: Using a nursing student-faculty collaborative model, a longitudinal design was used to evaluate a mass media campaign with social norming messages and education to influence the drinking culture on a college campus. RESULTS: Students in Greek life and athletics engaged in binge drinking significantly more than other students. Students observed the mass media messages, with 81.9% viewing posters. A significant decrease in binge drinking was reported. CONCLUSIONS: The nursing student-faculty team implemented a mass media campaign, which was effective at influencing the drinking culture on a college campus. PMID- 29994999 TI - Gaze Performance Adjustment During Needlestick Application: Can We Reduce Harm? AB - BACKGROUND: Novice health care students suffer more needlestick injuries (NSIs) than experts. NSIs may be prevented by learning experts' behavior during this procedure. Eye tracking offers the possibility to study both experts' and novices' eye behavior during this task. PURPOSE: The aim of this study was to offer novel information about the understanding of eye behavior in human errors during handling needles. METHODS: A group of third-year nursing students performed 3 subcutaneous injections in a simulated abdominal pad while their eye behavior was recorded. Similarly, the gaze patterns of experts were recorded and then compared with the novices. RESULTS: Total task time for experts was faster than that for novices (P < .001), but both groups showed similar accuracy (P = .959). However, novices demonstrated gazing longer at the syringe rather than the abdominal pad compared with experts (P = .009). Finally, experts demonstrated fewer attention switches than novices (P = .002). CONCLUSION: Novices demonstrated more tool-tracking eye behaviors with longer dwelling time and attentional switches than did experts, which may translate into errors in clinical performance with needles. PMID- 29995000 TI - Characteristics of Autonomic Activity and Reactivity During Rest and Emotional Processing and Their Clinical Correlations in Somatic Symptom Disorder. AB - OBJECTIVE: Altered autonomic nervous system activity is considered to be involved in the pathophysiology of somatic symptom disorder (SSD). This study aimed to investigate whether patients with SSD have disturbed autonomic activity during rest and reactivity to emotional processing and whether altered autonomic nervous system correlates with clinical characteristics and interoceptive accuracy in SSD. METHODS: We recruited 23 patients with SSD and 20 healthy controls. Heart rate variability (HRV) was assessed during recording at rest and during performance of an emotional face dot-probe task. Alpha-amylase responses were also assessed. Patients with SSD completed a self-assessment survey and heart beat perception task, which reflects interoceptive awareness. RESULTS: Patients with SSD had lower low-frequency HRV, high-frequency HRV, standard deviation of normal to normal R-R intervals (SDNN), and proportion of successive R-R intervals greater than 50 milliseconds (pNN50) at rest (p < .05). The reactivity scores (during-task activity minus resting activity) for SDNN and pNN50 were significantly different between patients with SSD and controls (SDNN: p = .013; pNN50: p = .008). In addition, resting HRV parameters (low-frequency, high frequency, SDNN, pNN50) correlated with heart beat perception error (p < .01) in patients with SSD. No significant differences in alpha-amylase activity were found. CONCLUSIONS: Our findings showed that patients with SSD have altered resting-state autonomic activity and reactivity to emotional processing, and the resting-state autonomic activity correlated with their interoceptive awareness. These findings suggest that disturbed interactions between the autonomic nervous, affective, and interoceptive systems may be involved in the pathophysiology of SSD. PMID- 29995001 TI - Hearing Changes After Intratympanic Steroids for Secondary (Salvage) Therapy of Sudden Hearing Loss: A Meta-Analysis Using Mathematical Simulations of Drug Delivery Protocols. AB - OBJECTIVE: The use of glucocorticoids for secondary (salvage/rescue) therapy of idiopathic sudden hearing loss (ISSHL), including controlled and uncontrolled studies with intratympanic injections or continuous, catheter mediated applications, were evaluated by means of a meta-analysis in an attempt to define optimal local drug delivery protocols for ISSHL. STUDY DESIGN: A total of 30 studies with 33 treatment groups between January 2000 and June 2014 were selected based on sufficiently detailed description of application protocols. Cochlear drug levels were calculated by a validated computer model of drug dispersion in the inner ear fluids based on the concentration and volume of glucocorticoids applied, the time drug remained in the middle ear, and on the specific timing of injections. Various factors were compared with hearing outcome, including baseline data, individual parameters of the application protocols, calculated peak concentration (Cmax), and total dose (area under the curve, AUC). RESULTS: There was no dependence of hearing outcome on individual parameters of the application protocol, Cmax or AUC. Hearing gain and final hearing thresholds were independent of treatment delay. CONCLUSION: Based on the available data from uncontrolled and controlled randomized and non-randomized studies no clear recommendation can be made so far for a specific application protocol for either primary or secondary (salvage) intratympanic steroid treatment in patients with ISSHL. For meta-analyses, change in pure tone average (PTA) may not be an adequate outcome parameter to assess effectiveness of the intervention especially with inhomogeneity of patient populations. Final PTA might provide a better outcome parameter. PMID- 29995002 TI - Tablet-based Hearing Screening in Children Aged 5 to 17 in Rural Dominican Republic. AB - OBJECTIVE: The principal aim of this study was to examine the feasibility of hearing screening using tablet audiometry among a cohort of school-aged children in rural Dominican Republic. The authors hypothesized that the tablet audiometer would serve as an expeditious means for hearing loss screening in various remote locations. STUDY DESIGN: Cross-sectional. SETTING: Twenty-three remote locations in and around the city of La Romana, Dominican Republic. The quietest location available in each site was used for testing. PATIENTS: Inclusion criteria comprised children aged 5 to 17 currently residing in the testing location. Children aged <5 years or >18 years were excluded. INTERVENTION: Screening. MAIN OUTCOME MEASURES: For each subject, air conduction thresholds were obtained bilaterally at 500, 1000, 2000, and 4000 Hz; testing duration was also measured. Hearing loss was suspected if any threshold measured >=30 dB. RESULTS: In this cohort of 423 subjects, 44 (10.4%) failed the screening protocol. The mean thresholds for 500, 1000, 2000, and 4000 Hz frequencies were 26.05, 22.73, 17.57, and 17.15 dB, respectively. Of the 658 thresholds obtained at >=30 dB, the majority were at 500 or 1000 Hz. The mean testing duration was 494 seconds. CONCLUSIONS: These results suggest that children living in remote communities can be screened quickly for hearing loss using a tablet audiometer. However, significant background noise during testing negatively impacted the low-frequency measurements, thus compromising test reliability. Despite extending the reach of existing audiological services, the value of tablet audiometry is not entirely clear in rural environments with uncontrollable background noise. PMID- 29995003 TI - Round Window Occlusion Affects Bone Conduction in Cadaver Heads. AB - OBJECTIVE: To explore the feasibility of ear mold glue in the molding of round window occlusion (RWO) in cadaver heads and to study the effect on bone conduction (BC). METHODS: Ten cadaver heads were selected to establish RWO model. Ear mold glue was used to immobilize round window niche. The vibration properties of the stapes footplate (VST) in response to the acoustic stimulation, and the vibration properties of the stapes footplate and cochlear promontory (VCP) in response to the B-71 stimulation were assessed by laser Doppler vibrometer in both pre-RWO and post-RWO. RESULTS: The mean velocities of the stapes footplate in response to the acoustic stimulation in post-RWO were decreased significantly beyond 14 dB for frequency from 0.5k to 3k Hz and decreased beyond 11 dB for frequency above 4 kHz compared with pre-RWO (p<0.05). The stapes footplate relative velocity (VST/VCP) for pre-RWO and post-RWO conditions showed almost no difference (the difference was around 0.5 dB for 0.5k, 1k, 2k, 5k, 6k, and 7k Hz frequencies), except a slight decrease of around 1.5 dB at 3k and 8k Hz frequencies in post-RWO. However, the VST/VCP was a significant decrease of 1.7 dB at 4k Hz in post-RWO compared with Pre-RWO (p<0.05). CONCLUSION: Ear mold glue was available for the immobilization of round window niche in cadaver heads. The RWO have an impact on the BC hearing threshold. The effect of RWO on the BC was similar to that of otosclerosis, but the feature frequency for the depressed BC threshold at 4k Hz. PMID- 29995004 TI - Evaluation of Intraoperative Testing During Cochlear Implantation From a Time and Cost Perspective: A Single-Center Experience in the United States. AB - OBJECTIVE: To measure the time spent performing intraoperative testing during cochlear implantation (CI) and determine the impact on hospital charges. STUDY DESIGN: Prospective study. SETTING: Tertiary referral hospital. PATIENTS: Twenty two children (7 mo-18 yr) who underwent a total of 22 consecutive primary and/or revision CIs by a single surgeon from December 2016 to July 2017. INTERVENTION: The time spent performing intraoperative testing, including evoked compound action potentials (ECAP) and electrical impedances (EI), was recorded for each case. The audiologist performing the testing was unaware of the time measurement and subsequent evaluations with regard to cost data. Billing information was used to determine if the testing contributed to increased operative charges to the patient. OUTCOME MEASURES: Whether intraoperative testing had an impact on operative charges to the patient. RESULTS: The average time spent in testing (ECAPs/EIs in all cases) was 6.7 minutes (range, 2-26 min). No correlation was found between testing time and preoperative computed tomography findings, the audiologist performing testing, or the electrode type used (p > 0.05). Based on billing data, including time spent in the operating room (OR), 5/22 (23%) cases incurred greater charges than if intraoperative testing had not been performed. CONCLUSION: Our data suggest that intraoperative testing increases time in the OR and can contribute to increased hospital charges for CI patients. By using testing selectively, costs incurred by patients and hospitals may be reduced. This is of interest in a healthcare environment that is increasingly focused on cost, quality, and outcomes. PMID- 29995005 TI - The Early Postoperative Effects of Cochlear Implantation on Horizontal Semicircular Canal Function. AB - OBJECTIVES: To use video head impulse testing to examine the effect of cochlear implantation (CI) on horizontal SCC vestibulo-ocular reflex (VOR) gain early after surgery, and to relate outcomes to subjective imbalance. STUDY DESIGN: Prospective cohort study. SETTING: Academic tertiary referral center. PATIENTS: Thirty-seven (23F:14M) adult cochlear implant recipients (mean age, 55; age range, 20-80). INTERVENTION: Cochlear implantation. MAIN OUTCOME MEASURE: The VOR of the horizontal semicircular canal of both the operated and non-operated ears was examined using video head impulse testing before surgery and at days 1, 7, and 28 following surgery. VOR gain, VOR gain asymmetry, and the change in VOR gain from preoperative baseline where the primary outcome measures. Subjective imbalance was assessed using a structured questionnaire. RESULTS: VOR gain value for the operated ear was 0.88 +/- 0.21. Mean VOR gain on day 1 postoperatively was 0.86 +/- 0.19; on day 7, 0.87 +/- 0.17, and on day 30, 0.91 +/- 0.21. Before surgery median asymmery was -5.50%, on day 1 it was -5.30%, at day 7, -6.44%, and at day 30 it was -2.61%. There was no significant difference between these measures for the cohort across the four time points. Thirteen of 37 (35%) of patients experienced imbalance in the follow-up period, but this was not correlated to changes in VOR gain. CONCLUSION: Horizontal semicircular canal function is preserved in the immediate and early postoperative period. This suggests that horizontal semicircular canal impairment is not likely to be responsible for postoperative imbalance. PMID- 29995006 TI - Successful Cochlear Implantation of a Split Electrode Array in a Patient With Far advanced Otosclerosis Assisted by Electromagnetic Navigation: A Case Report. AB - BACKGROUND: Incomplete electrode insertion is frequent when implanting ossified cochleae with conventional linear electrodes. If split electrode arrays (SEA) are used, this complication occurs less frequently resulting in improved audiological performance (AP). Additional implementation of electromagnetic navigation systems (EMNS) may add additional safety to this procedure and may further improve AP. However, previously performed SEA cochlea implantations rarely implemented EMNS. The few cases reported a laborious approach with customized, three-dimensional printed microstereotactic headframes, which limited clinical feasibility. Moreover, no postoperative AP was reported. In this case report a more feasible approach, using a commercially available EMNS, is described and postoperative AP is reported. PATIENT: A 70-year-old man with far-advanced otosclerosis was referred because of unsatisfactory speech intelligibility (monosyllabic word score of 0% at 75 dB sound pressure level) after cochlear implantation of a conventional linear electrode. Preoperative computed tomography revealed subtotal cochlear ossification and incomplete electrode insertion. INTERVENTION: Four titanium screws were inserted into the petrous bone for computed tomography-based registration using an EMNS. The previous mastoidectomy was expanded, the misplaced conventional linear electrode extracted and a manual, free-handed superior cochleostomy at the level of the tendon of the tensor tympani muscle was performed. The location and course of the drill-out procedure for the SEA was planned and verified with EMNS. RESULTS: Full electrode insertion for both electrode arrays of the SEA was achieved without any nerve dysfunction. Monosyllabic word score, determined 207 days after surgery, improved to 50 and 60% at 65 and 75 dB sound pressure level respectively. CONCLUSION: The implementation of EMNS in SEA cochlear implantation added additional safety to the procedure, which resulted in full electrode insertion and superior AP. Yet, outcome in cochlear implantation may vary. Larger case series to confirm this observation are required. The approach proposed for EMNS-guided SEA in this case report, using commercially available EMNS, may lead to a more frequent implementation in clinical routine due to its good clinical feasibility. Thus, larger case series may be generated. PMID- 29995007 TI - The Association Between Modiolar Base Anomalies and Intraoperative Cerebrospinal Fluid Leakage in Patients With Incomplete Partition Type-II Anomaly: A Classification System and Presentation of 73 Cases. AB - OBJECTIVE: Modiolus and modiolar base abnormalities in patients with incomplete partition-II anomaly (IP-II) increase the risk of intraoperative cerebrospinal fluid (CSF) leakage. This study aimed to classify modiolar abnormalities and define objective radiological measures for preoperatively evaluating intraoperative CSF leakage risk. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: The study included 73 patients with IP-II that underwent cochlear implant surgery between 2002 and 2017. INTERVENTION: Analysis of preoperative temporal bone computed tomography (CT) scans and surgical records. MAIN OUTCOME MEASURES: Preoperative CT modiolar anomalies and intraoperative CSF leakage status. RESULTS: Among the 73 patients (41 men and 32 women), mean age at cochlear implant surgery was 11.4 (range, 0 42) years. Preoperative CT-based modiolar base anomaly classification was as follows: grade 1 (complete modiolus, n = 1), grade 2 (thin plate of bone in the modiolar base + partial modiolus, n = 14); grade 3 (thin plate of bone in the modiolar base, n = 53); grade 4 (total modiolar base defect, n = 5). The gusher rate was 8%. All patients with grade 4 anomaly had an intraoperative gusher. Patients with grade 3 anomaly accounted for 86% of oozing cases. Oozing, pulsation, and no CSF leakage rates were similar in those with grade 2 anomaly. CONCLUSIONS: The modiolus and modiolar base must be carefully evaluated in patients with IP-II. Gushers primarily occur in IP-II patients with grade 4 anomaly. A thin plate of bone in the modiolar base most commonly prevents gushers. PMID- 29995009 TI - Temporary Explant of a Transcutaneous Bone Conduction Hearing Implant for Imaging of the Pituitary Gland. AB - OBJECTIVE: Clinical report on feasibility and outcome of a surgical procedure. PATIENT: Nine-year-old child, supplied with a transcutaneous bone conduction hearing implant, requiring magnetic resonance imaging of the head to exclude a tumor of the pituitary gland. INTERVENTION: Temporal removal and subsequent reimplantation of the implant in a single surgical procedure. MAIN OUTCOME MEASURE: Postoperative audiometric results. CONCLUSION: Under specific clinical circumstances, temporary removal of the transcutaneous bone conduction implant described, is technically accomplishable. PMID- 29995010 TI - Low Concentration Intra-Tympanic Gentamicin Treatment for Meniere's Disease: A Long-Term Follow Up. AB - BACKGROUND: Intra-tympanic injections of gentamicin (ITG), a known ototoxic agent, have been proven to be effective in controlling Meniere's disease (MD) symptoms, in patients who did not respond to conservative therapy, although its safety was questionable. OBJECTIVES: To study whether low-concentration ITG, in refractory MD, had an effect on the ipsilateral hearing, in comparison to the contralateral ear, and to study the effectiveness of such treatment. METHODS: A comparative, retrospective cohort study was conducted between 2003 and 2015, and compared the change in the hearing level between the injected ear and the contralateral, untreated ear. OUTCOMES: In 20 of 27 patients (74.1%), one course of ITG treatment was considered as successful. In the short-term, there was improvement of hearing level at 1000 Hz (p = 0.014), and deterioration of hearing level at 8000 Hz (p = 0.039), both in comparison to the control ear. In the long term and after confounders adjustment, we found there were no differences in the hearing levels between the treated ear and the untreated contralateral ear. CONCLUSIONS: A high success rates of treating vertigo attacks with low concentration ITG in refractory unilateral MD patients is herein reported, while a significant difference was not observed in the hearing threshold compared with the healthy contralateral ear. PMID- 29995008 TI - Minimally Invasive Ponto Surgery Versus the Linear Incision Technique With Soft Tissue Preservation for Bone Conduction Hearing Implants: A Multicenter Randomized Controlled Trial. AB - OBJECTIVE: To compare the surgical outcomes of the Minimally Invasive Ponto Surgery (MIPS) technique with those of the linear incision technique with soft tissue preservation for bone-anchored hearing systems (BAHS). DESIGN: Sponsor initiated multicenter, open, randomized, controlled clinical trial. SETTING: Maastricht University Medical Centre, Ziekenhuisgroep Twente and Medisch Centrum Leeuwarden, all situated in The Netherlands. PARTICIPANTS: Sixty-four adult patients eligible for unilateral BAHS surgery.Interventions Single-stage BAHS surgery with 1:1 randomization to the linear incision technique with soft-tissue preservation (control) or the MIPS (test) group. PRIMARY AND SECONDARY OUTCOME MEASUREMENTS: Primary objective: compare the incidence of inflammation (Holgers Index >= 2) during 12 weeks' follow-up after surgery. Secondary objectives: skin dehiscence, pain scores, loss of sensibility around the implant, soft-tissue overgrowth, skin sagging, implant extrusion, cosmetic results, surgical time, wound healing and Implant Stability Quotient measurements. RESULTS: Sixty-three subjects were analyzed in the intention-to-treat population. No significant difference was found for the incidence of inflammation between groups. Loss of skin sensibility, cosmetic outcomes, skin sagging, and surgical time were significantly better in the test group. No statistically significant differences were found for dehiscence, pain, and soft-tissue overgrowth. A nonsignificant difference in extrusion was found for the test group. The Implant Stability Quotient was statistically influenced by the surgical technique, abutment length, and time. CONCLUSION: No significant differences between the MIPS and the linear incision techniques were observed regarding skin inflammation. MIPS results in a statistically significant reduction in the loss of skin sensibility, less skin sagging, improved cosmetic results, and reduced surgical time. Although nonsignificant, the implant extrusion rate warrants further research. PMID- 29995011 TI - Validation of Posturographic Measurements in Adolescents. AB - OBJECTIVE: The objectives of the present study were to validate the test-retest reliability of static posturography in healthy adolescents aged 13 to 16 years, to identify the most reliable and least variable measurements. PATIENTS: Thirty two healthy pupils from Skade Skole participated in this study. INTERVENTION: Static posturography. OUTCOME MEASURES: Subjects were tested for 32 seconds in eight trials (eyes open/eyes closed, on stable ground/foam pads, head neutral/head turned) by using a Tetrax platform. Testing included two rounds of trials and postural regulation was assessed by measuring sway during the eight trials. RESULTS: We found statistically significant lower sway scores during round two in position NO; a similar trend was seen for position NC, PO, HR, HL, and HB, but was not statistically significant. For position PC and HF an increase was seen, but not statistically significant. CONCLUSION: The most reliable and least variable measurements include position NO, NC, PO, and PC. Influence of all three systems involved in maintaining balance is tested in these positions. Static posturography can easily be implemented in a clinical setting as the equipment does not take up much space and is easy to use and instruct the test subjects about. Finally, the costs related to the static posturography are considerably lower compared with dynamic posturography equipment. However, static posturography might not be challenging enough when testing athletic individuals. PMID- 29995012 TI - Maximizing Exposure of the Internal Auditory Canal Via the Retrosigmoid Approach: An Anatomical, Radiological, and Surgical Study. AB - OBJECTIVE: The purpose of this study was to identify anatomic landmarks and surgical techniques that maximize bone removal for exposure of the distal internal auditory canal (IAC) to avoid labyrinthine injury during retrosigmoid removal of tumors within the IAC. STUDY DESIGN: Anatomic dissection, radiological assessment and retrospective case series. SETTING: Tertiary referral center. METHODS: On the basis of previously conducted temporal bone anatomic dissections of the temporal bone, the authors performed intraoperative measurement of the undissected distal IAC, performed pre- and postoperative radiological assessment of vestibular schwannoma (VS) patients. The surgical and anatomic information was used to determine the anatomic limits of labyrinth sparing bone dissection and the landmarks most critical to maximal IAC exposure. The authors describe surgical techniques using these data. An edited video of representative surgery highlights important principles. Review of 251 patients requiring IAC bony dissection for tumor removal from January 2005 through October 2017 is described. RESULTS: Achieving complete exposure of the IAC fundus is not possible, without labyrinthine injury, via retrosigmoid approach. Anatomic dissection, intraoperative photography, and postoperative radiographs demonstrate that bone removal within 2 to 3 mm of the fundus is routinely possible. The endolymphatic sac and duct is the optimal landmark for optimizing IAC exposure. CONCLUSION: The course of the endolymphatic sac and duct in the posterior petrous bone is the most important landmark determining the lateral limit of bony removal during IAC exposure for tumor resection. Surgical techniques based on these anatomic findings facilitate tumor resection while preserving the labyrinth. PMID- 29995013 TI - Preliminary Results With Image-guided Cochlear Implant Insertion Techniques. AB - HYPOTHESIS: Using patient-customized cochlear measurements obtained from preoperative computed tomography (CT) scans to guide insertion of cochlear implant (CI) electrode arrays will lead to more optimal intracochlear positioning. BACKGROUND: Cochlear duct length is highly variable ranging from 25.26 to 35.46 mm, yet CI electrode arrays are treated as one size fits most. We sought to investigate the impact of patient-customized insertion plans on final location of electrode arrays. METHODS: Twenty cadaveric temporal bone specimens were CT scanned and randomly divided into groups A and B. Group A specimens had an optimal customized insertion plan generated including entry site (e.g., round window versus extended round window), entry vector based on anatomical landmarks (e.g., hug posterior aspect of facial recess and angle 1 mm inferior to stapes), depth to begin advancing off stylet, and final insertion depth. Suboptimal plans were chosen for group B by selecting an approach that was normal yet predicted to result in poor final electrode location. One surgeon, blinded as to group, carried out the CI insertions following which the electrode array was fixed using superglue and the specimen CT scanned to allow assessment of final electrode location. RESULTS: Average perimodiolar distances for groups A and B were 0.51 and 0.60 mm, respectively. For group A, full scala tympani insertion was achieved in all specimens while in group B, 4 of 10 specimens had scalar translocation. CONCLUSION: Patient customized cochlear implant insertion techniques achieved better positioning of electrode arrays in this study and have potential for improving electrode positioning in patients. PMID- 29995014 TI - Targeted PCR Array Analysis of Genes in Innate Immunity and Glucocorticoid Signaling Pathways in Mice Cochleae Following Acoustic Trauma. AB - AIM: To comprehensively analyze cochlear gene expressions related to innate immunity and glucocorticoid signaling at onset of acute noise-induced hearing loss (NIHL). BACKGROUND: Recent studies suggested innate immunity is involved in the cochlear pathology of NIHL. Glucocorticoids may modulate immune actions in cochleae. METHODS: Mice were exposed to 120 dB-octave band noise for 2 hours. Twelve hours later, a targeted PCR array analyzed cochlear expressions of 84 key genes in inflammation and immune pathways and 84 genes in the glucocorticoid signaling pathway. Real-time RT-PCR was used to analyze expression of two immune related genes, Ccl12 and Glycam1, in noise-exposed cochleae with or without dexamethasone. RESULT: In inflammatory and immune gene pathways, 31.0% (26/84 genes) were significantly upregulated (>2-fold change) or downregulated (<0.5 fold change) (p < 0.05) in noise-exposed cochleae compared with controls. Sixteen of these differentially expressed genes (DEGs) encoded chemokines. DEGs included Ccl12, Ccl2, Ccl4, Ccl7, Cxcl1, Cxcl10, and Ptgs2 (upregulated genes), and Ccr7, Cxcr2, Kng1, Ltb, and Tnfsf14 (downregulated genes). In the glucocorticoid signaling pathway, 92.9% (78/84 genes) were unchanged in noise-exposed cochleae without dexamethasone administration. Cochlear expressions of Ccl12 and Glycam1 were significantly upregulated by noise and downregulated by dexamethasone. CONCLUSION: The targeted PCR array demonstrated that several dozen genes involved in innate immunity are actively regulated in cochleae with NIHL. The glucocorticoid signaling pathway was not endogenously regulated at 12 hours post noise trauma. Systemic dexamethasone downregulated Ccl12 and Glycam1, which are upregulated in noise-exposed cochleae. These data may provide a basis for genomic medicine treatment of acute sensorineural hearing loss. PMID- 29995015 TI - New Seizures in a Patient With History of Head Trauma. PMID- 29995016 TI - Mercury-induced Oxidative Stress May Adversely Affect Pregnancy Outcome among Dental Staff: A Cohort Study. AB - BACKGROUND: Dental staff may be at increased risk of adverse pregnancy outcome secondary to their chronic exposure to mercury. OBJECTIVE: To investigate obstetric outcome among dental staff and explore the oxidative stress induced by mercury exposure. METHODS: A cohort of 64 pregnant dental staff (exposed group) and 60 pregnant employees (non-exposed group) were studied. Urinary mercury level and blood antioxidant activity were measured. Participants were followed to assess their obstetric outcome. RESULTS: The exposed group had a higher mean urinary mercury level and a lower blood antioxidant activity during the three trimesters compared to non-exposed group (p<0.001). Women in the exposed group were experienced more frequently spontaneous abortion and pre-eclampsia (p<0.05). Babies born to the women in the exposed group tended to be smaller for gestational age compared to those of non-exposed group (p<0.001). CONCLUSION: Pregnant dental staff suffered higher odds of developing spontaneous abortion and pre-eclampsia and giving birth to babies smaller for gestational age. This may be linked to oxidative stress induced by exposure to mercury. PMID- 29995017 TI - Dose-response of Cotton Dust Exposure with Lung Function among Textile Workers: MultiTex Study in Karachi, Pakistan. AB - BACKGROUND: Cotton dust exposure among textile mill workers lead to impaired lung function. However, only few studies have investigated the dose-response relationship between cotton dust and lung function. OBJECTIVE: To determine the dose-response relationship between cotton dust exposure and lung function among textile workers. METHODS: This cross-sectional survey was conducted from January to March 2016 and included 303 adult male textile workers from spinning and weaving sections of 5 mills in Karachi, Pakistan. We collected data through a translated version of the American Thoracic Society respiratory questionnaire (ATS-DLD-78A) and using spirometry. Mill-level airborne cotton dust was measured over an 8-12-hour shift through UCB-PATS (University of California, Berkeley Particle, and Temperature Monitoring System). Multiple linear regression was used to determine the association between cotton dust exposure and lung function assessed through the 3 indices: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and their ratio (FEV1/FVC). RESULTS: The mean age of the workers was 32.5 (SD 10.5) years. The mean spirometry indices expressed in percent predicted values were FEV1 82.6 (SD 14.0); FVC 90.3 (14.7), and FEV1/FVC 94.9 (10.5). The median cotton dust concentration was 0.61 (IQR 0.2 to 1.3) mg/m3. The frequency of respiratory symptoms was 15% for cough, 20% for phlegm, and 20% for wheezing. After adjustment for covariates, every mg/m3 increase in dust concentration was associated with 5.4% decline in FEV1. CONCLUSION: This study quantifies the exposure-dependent relationship between cotton dust and lung function; which has implications for regulations and standards in the textile industry in Pakistan and similar cotton-processing countries. PMID- 29995018 TI - Association between the Increase in Body Mass Index and Medical Absenteeism in a Peruvian Mining Population. AB - BACKGROUND: Obesity and overweight are associated with work absenteeism of medical cause. However, there is little knowledge on the relationship between incremental body mass index (BMI) and absenteeism. OBJECTIVE: To assess the effect of annual increase in BMI on amount of prolonged absenteeism. METHODS: Data from a longitudinal historical cohort of workers of a mining camp in Peru between 2006 and 2014 were used for the analysis. Prolonged absenteeism of 30 days or more in one year was chosen as the dependent variable; annual increase in BMI was considered as the explanatory variable. Regression analysis with generalized estimating equation was used to determine the relative risk adjusted for age, sex and type of work. RESULTS: There were 1347 cases of medical leave reported with a median of 6 days. Of all cases of medical leave, 11% of those who had an annual increase in BMI and 6% of those who maintained their BMI were cases of prolonged absenteeism. Prolonged absenteeism significantly increased in workers who had an annual increment in BMI (adj RR 1.16, 95% CI 1.05 to 1.29). CONCLUSION: The annual increase in BMI was marginally associated with prolonged absenteeism. Temporal increment in BMI, regardless of the baseline BMI, may be an independent determinant of the work absenteeism of medical cause. PMID- 29995019 TI - Pesticide Exposure and Thyroid Function in Elementary School Children Living in an Agricultural Area, Brebes District, Indonesia. AB - BACKGROUND: Children living in agricultural areas are at risk of exposure to pesticides due to their involvement in agricultural activities. Pesticides are one of the chemicals classified as endocrine disrupting chemicals. OBJECTIVE: To examine the association between exposure to organophosphate pesticides and the occurrence of thyroid dysfunction in children. METHODS: This cross-sectional study was conducted on 66 children in two elementary schools located in an agricultural area in Brebes District, Indonesia, in 2015. To determine the pesticide exposure history, we analyzed urine samples and completed a questionnaire. Meanwhile, thyroid function tests were performed. RESULTS: Organophosphate pesticide metabolites were detected in urine samples of 15 (23%) of 66 children. Thyroid stimulating hormone (TSH) levels >4.5 MUIU/mL were detected in 24 (36%) children. Free thyroxine (FT4) levels of all participants were normal. The mean TSH level in children with positive urinary organophosphate pesticide metabolites (7.74 MUIU/ mL) was significantly (p=0.005) higher than that in those who were negative (4.34 MUIU/mL). The prevalence of hypothyroidism in children with positive urinary organophosphate pesticide metabolites (67%) was significantly higher than that in those who were negative (27%; PR 2.4, 95% CI 1.4 to 4.3). CONCLUSION: A history of pesticide exposure could be used as a risk factor for the occurrence of thyroid dysfunction in children living in agricultural areas. PMID- 29995020 TI - Aberrant DNA Methylation of Two Tumor Suppressor Genes, p14ARF and p15INK4b, after Chronic Occupational Exposure to Low Level of Benzene. AB - BACKGROUND: Exposure to benzene would be associated with many diseases including leukemia. Epigenetic alterations seem to be among the main mechanisms involved. OBJECTIVE: To determine if chronic occupational exposure to low level of benzene would be associated with DNA methylation. METHODS: Global DNA methylation and promoter-specific methylation of the two tumor suppressor genes, p14ARF and p15INK4b, were assessed employing methylation-specific PCR using the DNA extracted from 40 petrochemical workers exposed to ambient benzene levels of <1 ppm, and 31 office workers not exposed to benzene or its derivatives. RESULTS: While an increase in global DNA methylation of 5% in p14ARF (p=0.501) and 28% in p15INK4b (p=0.02) genes was observed in the exposed group, no hypermethylation in either of the studied genes was observed in the unexposed group. No significant association was found between the frequency of aberrant methylation and either of age, work experience, and smoking habit in the exposed group. CONCLUSION: Chronic occupational exposure to lower than the permissible exposure limit of benzene may still result in DNA methylation of tumor suppressor genes that may ultimately lead to development of cancer. PMID- 29995021 TI - Outbreak of Mushroom Poisoning in Iran: April-May, 2018. AB - From April 28 to May 28, 2018, more than 1200 patients with impression of mushroom poisoning were referred to hospital emergency departments in 13 west and northwestern provinces, Iran; 112 (8.9%) patients were hospitalized and 19 were expired (ie, a fatality rate of 1.5%). The outbreak began in Kermanshah province with increasing number of patients presenting with severe abdominal pain, nausea, vomiting, and diarrhea soon after consumption of wild mushrooms. Lepiota brunneioncarnata, Hypholoma fascicalare, and Coprinopsis atramentaria have been involved in this outbreak. To prevent similar outbreaks, raising public awareness about risky behaviors of collecting and consuming wild self-picked mushrooms is of paramount importance. Herein, we present our experience with this outbreak. PMID- 29995022 TI - Comments on the Measurement of Lung Cancer Tumor Markers in Workers of a Glass Wool Company. PMID- 29995023 TI - Authors' Reply. PMID- 29995024 TI - Thermally stable core-shell Ni/nanorod-CeO2@SiO2 catalyst for partial oxidation of methane at high temperatures. AB - During partial oxidation of methane (POM), the greatest challenge is to maintain the thermal stability of the catalyst at high temperatures. One of the most effective ways to improve thermal stability is to construct core-shell structure. Herein, using a microemulsion method, we synthesized a core-shell Ni/nanorod CeO2@SiO2 catalyst, in which the Ni nanoparticles were supported on the CeO2 nanorods and encapsulated by SiO2 shells. Based on a series of characterizations, we found that the Ni particles are of nanosize (2.2 nm) and the thickness of the SiO2 shell is about 8 nm in the core-shell catalyst. Moreover, the Ni/nanorod CeO2@SiO2 catalyst can perfectly maintain rod-like structures of the CeO2 support and enhance interaction between the metal Ni and CeO2, significantly reducing the sintering of metal Ni particles at high temperatures. Therefore, the as-prepared Ni/nanorod-CeO2@SiO2 catalyst shows high catalytic activity and good thermal stability during the POM reaction. PMID- 29995025 TI - Long circulatory liposomal maduramicin inhibits the growth of Plasmodium falciparum blood stages in culture and cures murine models of experimental malaria. AB - Malaria continues to be one of the deadliest infectious diseases and a global health menace. The emergence and spread of drug-resistant strains of malaria parasites have further made the process of disease management grimmer. Thus, there is an urgent need to identify promising antimalarial strategies that can target the blood stages as well as block parasite transmission. Maduramicin is one such ionophore selected out of a recent screen of gametocytocidal compounds that exhibit potent antiplasmodial activity. However, maduramicin's strong hydrophobic nature and associated toxicity restrict its application in chemotherapy. To alleviate this problem, we have developed a liposomal formulation loaded with the ionophore maduramicin for the treatment of chloroquine sensitive and resistant Plasmodium infections. Here, we show that maduramicin in PEGylated liposomal formulations displayed enhanced antiplasmodial activity in vitro compared to free maduramicin. Significantly, four consecutive doses of 1.5 mg kg-1 body weight of PEGylated maduramicin loaded lipid vesicles completely cured cerebral and chloroquine resistant murine models of malaria without any obvious toxic effects and suppressed the key inflammatory markers associated with the progression of the disease. PEGylated liposomal maduramicin also exhibited a prolonged plasma clearance rate, implying a greater chance of interaction and uptake by infected RBCs. Furthermore, we also provide evidence that the detrimental effect of liposomal maduramicin on parasite survival is mediated by increased ROS generation and subsequent perturbation of parasite mitochondrial membrane potential. This study presents the first report to demonstrate the potent antimalarial efficacy of maduramicin liposomes, a strategy that holds promise for the development of successful therapeutic intervention against malaria in humans. PMID- 29995028 TI - Interface-induced nucleation and growth: a new route for fabricating ordered silver nanohole arrays. AB - Metal nanohole arrays exhibit fascinating optical properties originating from the excitation of surface plasmons, and have been demonstrated to be of great potential in many applications. However, the fabrication of large-area ordered metal nanohole arrays with a tunable optical response is still highly desired. Herein, a novel interface-induced vapor phase growth method is developed to achieve hexagonally arranged silver nanohole arrays with a centimeter-scale area, in which an interface is introduced via an ordered template and used to induce Ag selective nucleation and growth. The adhesive force of the template with the substrate is found to be crucial in the determination of the nucleation sites and the resulting nanostructures. The plasmonic responses of the nanohole arrays are regulated by controlling their structural features, which are realized through simply changing the template parameters and the Ag deposition thickness. The Ag nanohole array exhibits more than 20-fold Raman enhancement compared to a rough Ag film when its localized surface plasmon resonance (LSPR) is tuned to an optimized range, which indicates its potential in biochemical sensing applications. The present method for the preparation of large-area metal nanohole arrays may open up a new avenue to fabricate novel metal nanostructures and develop high-performance plasmonic devices. PMID- 29995029 TI - Sterically shielded tetrazoles for a fluorogenic photoclick reaction: tuning cycloaddition rate and product fluorescence. AB - A panel of sterically shielded tetrazoles with different N-aryl groups were synthesized and subsequently evaluated in the photoinduced tetrazole-alkene cycloaddition reaction. It was found that increase in the HOMO energy of the corresponding nitrile imines leads to a faster cycloaddition reaction along with a red shift in the fluorescence emission of the pyrazoline cycloadduct. PMID- 29995030 TI - Enzymatic film formation of nature-derived phenolic amines. AB - An enzyme-instructed method is developed for material-independent, cytocompatible coating of phenolic amines, inspired by melanogenesis found in nature. Tyrosinase based film formation proceeds smoothly in an aqueous solution at neutral pH, and can use various phenolic amines including catecholamines, such as tyrosine, tyramine, dopamine, norepinephrine, and DOPA, as a coating precursor. Compared with polydopamine coating, the method is fast and efficient, and forms uniform films. Its high cytocompatibility is advantageously applied to cell-surface engineering, where chemically labile Jurkat cells are coated individually without any noticeable decrease in viability. Considering the huge potential of polyphenolic-based coatings, the strategy developed herein will provide an advanced tool for manipulating biological entities, including living cells, in biomedical and medicinal applications. PMID- 29995031 TI - Thermochemiluminescent semiconducting polymer dots as sensitive nanoprobes for reagentless immunoassay. AB - Thermochemiluminescence (TCL) is a potentially simple and sensitive detection principle, as the light emission is simply elicited by thermally-triggered decomposition of a molecule to produce a singlet excited-state product. Here we report about TCL semiconductive polymer dots (TCL-Pdots) obtained by doping fluorescent cyano-polyphenylene vinylene (CN-PPV) Pdots with an acridine 1,2 dioxetane derivative. The TCL-Pdots showed remarkable stability over time and minimum leaching of the thermo-responsive species. Furthermore, detectability of TCL-Pdots was improved by taking advantage of both the high number of 1,2 dioxetanes entrapped in each nanoparticle (about 20 molecules per Pdot) and the 5 fold enhancement of TCL emission due to energy transfer from 1,2-dioxetane to the polymer matrix, which itself acted as an energy acceptor. Indeed, upon heating the TCL-Pdots to 110 degrees C, 1,2-dioxetane decomposes generating an acridanone product in its electronically excited state. The latter transfers its energy to the surrounding CN-PPV chains via the Forster mechanism (phiFRET about 80%), resulting in intense yellow light emission (550 nm wavelength). We next conjugated streptavidin onto the surface of these TCL-Pdots and demonstrated their suitability for use in biological studies. In particular, we used TCL-Pdots as labels in a model non-competitive immunoassay for IgG detection, which showed a LOD of 13 nM IgG and a dynamic range extending up to 230 nM. By combining the biocompatibility, brightness and tunability of Pdot fluorescence emission with the thermally-triggered reagentless light generation from TCL 1,2-dioxetanes, a broad panel of ultrabright TCL nanosystems could be designed for a variety of bioscience applications, even in multiplexed formats. PMID- 29995032 TI - Enhancement of two-photon absorption photoresponse based on whispering gallery modes. AB - Nonlinear multiphoton absorption technology is crucial for developing novel optoelectronic devices and nanophotonics. The large enhancement of two-photon absorption (TPA) photoresponse by a high Q-factor whispering gallery mode (WGM) resonance based on a single-microwire (MW) self-formed hexagonal cavity was investigated comprehensively in this paper. The typical quadratic relationship of photocurrent as a function of incident power indicated that excited carriers resulted from a third-order nonlinear mechanism. Moreover, the photocurrent response had a dramatic dependence on the spatial location of the focus spot of the incident photons. It was demonstrated that the TPA photocurrent response in the resonant WGM mode was one-order of magnitude larger than the response in the Fabry-Perot mode. Furthermore, the photoresponse characteristics of TPA detection exhibited sensitive dependence on the incident laser polarization direction. PMID- 29995035 TI - 2D SnSe-based vdW heterojunctions: tuning the Schottky barrier by reducing Fermi level pinning. AB - Two-dimensional (2D) SnSe is a very promising material for semiconducting devices due to its novel properties. However, the contact behavior between a 2D SnSe sheet and a three-dimensional (3D) metal surface shows an un-tunable Schottky barrier because of the metallization of the SnSe sheet induced by strong Fermi level pinning at the contact interface. In this work, we use graphene rather than 3D metals as the metal electrode which comes into contact with a single-layer SnSe sheet to form a van der Waals (vdW) heterojunction. Based on state-of-the art theoretical calculations, we find that the intrinsic properties of the SnSe sheet are preserved and the Fermi level pinning is weakened because of the vdW interaction between the SnSe sheet and graphene. We further demonstrate that an Ohmic contact can be realized by doping graphene with boron or nitrogen atoms or using other high-work-function 2D metals such as ZT-MoSe2, ZT-MoS2, or H-NbS2 sheet as the electrode to reduce the Fermi level pinning, leading to a spontaneous hole injection from the electrode to the channel material. This study sheds light on how to tune the Schottky barrier height for better device performance. PMID- 29995039 TI - A supramolecular host-guest complex for heparin binding and sensing. AB - Heparin is an anionic polysaccharide widely used in clinics as an anticoagulant. However, heparin usage requires an antidote and sensors for safe operation during and after surgeries. In this study, a host-guest complex capable of selective heparin binding and sensing is presented. Heparin binding affinity was studied in solution with a variety of polycationic macrocyclic hosts, a pillar[5]arene and multiple resorcin[4]arenes, by dynamic light scattering, dye displacement assay, isothermal titration calorimetry, and anti-Xa assay. The measurements reveal the significant importance of multivalency in electrostatic host-heparin binding in competitive, application-relevant media. Additionally, to monitor the heparin concentration, a host-guest indicator displacement assay was performed by following the free and bound state of the methyl orange dye in UV-Vis spectroscopic experiments. Furthermore, this colorimetric sensing based on the tertiary host-guest-heparin supramolecular assembly was utilized in the construction of a calibration curve in a range of blood plasma concentrations. PMID- 29995040 TI - Exploring the hidden potential of a benzothiazole-based Schiff-base exhibiting AIE and ESIPT and its activity in pH sensing, intracellular imaging and ultrasensitive & selective detection of aluminium (Al3+). AB - In this article, we tried to redefine the unexplored potential of a benzothiazole type of Schiff-base (OM), which was identified as an AIE-active molecule that exhibits excited-state intramolecular proton transfer (ESIPT). Interestingly, this compound shows ultra-sensitivity and selectivity in the detection of Al(iii) (12 pM; 456 ppt). The OM was capable of pH sensing and was also tested for internalization in cancerous cells for intracellular imaging. Computational modeling was performed and the results were in good agreement with the experimental UV-Vis spectrum and the energy gap obtained in basic and acidic media. PMID- 29995042 TI - Copper molybdenum sulfide anchored nickel foam: a high performance, binder-free, negative electrode for supercapacitors. AB - Herein, we are demonstrating the use of a binder-free electrode based on copper molybdenum-sulfide nanostructures grown on nickel foam (CMS/Ni) as a novel negative electrode for supercapacitors. The cyclic voltammetry and charge discharge analyses reveal the pseudocapacitive nature of the CMS/Ni electrode with a high specific capacity of 633 mAh g-1 (~20-fold higher than the binder based CMS electrode) which is mainly due to their superior electronic conductivity and short ion transport pathways. Furthermore, the fabricated symmetric supercapacitor using the CMS/Ni electrode delivered a high device capacitance (265.62 F g-1), high energy density (23.61 Wh kg-1) and long cycle life. The results ensure that the CMS/Ni binder-free electrode will be a promising negative electrode for high-performance supercapacitors. PMID- 29995044 TI - Microwave-assisted dry-gel conversion-a new sustainable route for the rapid synthesis of metal-organic frameworks with solvent re-use. AB - Microwave-assisted dry-gel conversion (MW-DGC) combines the advantages of concentrated reactants in DGC with fast heating by microwave irradiation. This novel combination allows drastically decreasing the amount of solvent needed for synthesis and reaction times with the energy needed. Furthermore, MW-DGC allows for the recovery and re-use of the reaction solvent and thereby can significantly reduce the overall solvent waste in the syntheses of the four important MOFs MIL 100(Fe) (Basolite F300), UiO-66, MIL-140A and aluminium fumarate (Alfum, Basolite A520). All the MOF products obtained from MW-DGC showed satisfying yields, crystallinity and porosity in comparison with the industrial benchmarks Basolite F300 and Basolite A520. Moreover, MW-DGC also advantageously leads to a hierarchical micro-mesoporous Alfum material different to that from other synthesis methods. PMID- 29995046 TI - ProTide generated long-acting abacavir nanoformulations. AB - Abacavir pronucleotide nanoformulations (NM3ABC) were prepared as a novel long acting slow effective release antiretroviral therapy. Single NM3ABC treatment of human monocyte-derived macrophages produced sustained intracellular carbovir triphosphate and antiretroviral activities for up to 30 days. PMID- 29995047 TI - Redox-responsive cisplatin nanogels for anticancer drug delivery. AB - Inspired by cisplatin's deactivation by glutathione (GSH) in cancer, a GSH responsive nanogel loaded with doxorubicin (Dox) was prepared using hyaluronan as a matrix and cisplatin as a crosslinker. The elevated GSH depletes the cisplatin crosslinker in the nanogel, enhances Dox release and boosts cytotoxicity, thus providing a new GSH responsive platform to reverse cisplatin resistance. PMID- 29995048 TI - Modulation of gut microbiota by mulberry fruit polysaccharide treatment of obese diabetic db/db mice. AB - Increasing evidence indicates that gut microbiota is an important factor in mediating the development of metabolic disorders, especially type 2 diabetes. Herein, we investigated the protective effects of polysaccharides from mulberry fruit on diabetic db/db mice. We observed an inhibition in the body weight increase, a decrease in the blood glucose levels, and an improvement in glucose tolerance. Furthermore, our data showed increased enzymatic activities as evidenced by parameters such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). In addition, high density lipoprotein cholesterol (HDL-C) increased, while total cholesterol (TC), triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), lipid peroxide content malonaldehyde (MDA), and free fatty acid (FFA) levels decreased, accompanied by the recovery from damage to the liver, kidneys and pancreas. Meanwhile, metformin and polysaccharide similarly shifted the abundance of the main gut microbiota, Bacteroidetes and Firmicutes, in diabetic mice toward levels observed in healthy mice. Especially at the genus level, the enrichment of some key bacteria like Bacteroidales, Lactobacillus, Allobaculum, Bacteroides, and Akkermansia was observed. Taken together, our findings suggest that polysaccharides from the mulberry fruit modulate gut microbiota, including enriching functional bacteria and reducing microbial diversity, which may contribute to their antidiabetic effects. PMID- 29995051 TI - Spontaneous valley splitting and valley pseudospin field effect transistors of monolayer VAgP2Se6. AB - Valleytronics has attracted much attention due to its potential applications in the information processing industry. Creation of permanent valley polarization (PVP), i.e. unbalanced occupation at different valleys, is a vital requirement for practical devices in valleytronics. However, the development of an appropriate material with PVP remains a main challenge. Here we used first principles calculations to predict that the spin-orbit coupling and magnetic ordering allow spontaneous valley Zeeman-type splitting in the pristine monolayer of VAgP2Se6. After suitable doping of VAgP2Se6, the Zeeman-type valley splitting results in a PVP, similar to the effect of spin polarization in spintronics. The VAgP2Se6 monolayer has nonequivalent valleys which can emit or absorb circularly polarized photons with opposite chirality. It thus shows great potential to be used as a photonic chirality filter and a circularly polarized light source. We then designed a valley pseudospin field effect transistor (VPFET) based on the monolayer VAgP2Se6, akin to the spin field effect transistors. In contrast to the current common transistors, VPFETs carry information of not only the electrons but also the valley pseudospins, far beyond common transistors. PMID- 29995052 TI - Single-stranded templates as railroad tracks for hierarchical assembly of DNA origami. AB - DNA origami is one of the most effective tools for bottom-up construction of novel objects and devices at the nanometer-scale. However, many applications require larger structures than can be obtained with the conventional single stranded scaffold, typically 7249 nucleotides. Here, we address this limitation by developing custom-made single-stranded scaffolds that bind pre-assembled origami tiles and induce their one-dimensional organization in high yields. Our synthetic method allows the conversion of multiple repetitive and unique sequences into correctly assembled, large backbones, and to finely tune the position and frequency of each building block. Granted with these regions, three and five origami tiles were successfully arranged in 1-D with the aid of one or two scaffolds, forming a nano-"railroad track". This new method increases length scale in DNA origami without increasing cost and complexity, and is anticipated to increase the yield of other approaches aiming to assemble large origami structures. PMID- 29995053 TI - High-yield fabrication of Ti3C2Tx MXene quantum dots and their electrochemiluminescence behavior. AB - Ti3C2Tx MXene Quantum Dots (MQDs) were obtained with high yield (60%) from two dimensional MXene via a facile reflux strategy. These green luminescent MQDs possess indisputable and stable annihilation electrochemiluminescence (ECL) and coreactant (TPrA) enhanced (~29-fold) anode ECL. PMID- 29995054 TI - On the alcoholysis of alkyl-aluminum(iii) alkoxy-NHC derivatives: reactivity of the Al-carbene Lewis pair versus Al-alkyl. AB - The reaction of a bifunctional hydroxy N-heterocyclic carbene (NHC-OH) ligand with alkyl-aluminum(iii) derivatives appears to be dependent on the precursor used. The expected alkoxy-NHC metallated product is indeed obtained with Al(iBu)3. In contrast, the sterically hindered [Al(iBu)(OAr)2] (OAr = 2,6-di-tert butyl-4-methylphenoxy) displays reactivity at the carbene and affords an imidazolium-aluminate zwitterion. The non-innocence of the Al-NHC motif is further highlighted by the heterolytic cleavage of the phenol O-H bond across the Al-CNHC bond from Al(O-NHC)X2 derivatives (X = iBu, OAr). PMID- 29995055 TI - Solid-state sensors based on Eu3+-containing supramolecular polymers with luminescence colour switching capability. AB - Polymers that exhibit changes of their luminescence colour in response to external stimuli are attractive candidates for sensing systems. We herein report the preparation of europium-based metallosupramolecular polymers, which can be processed into films and coatings that display readily detectable luminescence colour changes in response to various types of analytes. PMID- 29995056 TI - Highly improved photoelectrocatalytic efficiency and stability of WO3 photoanodes by the facile in situ growth of TiO2 branch overlayers. AB - The development of highly efficient and stable visible-light-responsive photoanode materials is essential for practical photoelectrocatalytic (PEC) applications. In this work, a novel method was proposed to enhance the PEC efficiency and stability of WO3 photoanodes by the facile in situ growth of TiO2 branch overlayers on WO3 nanoplates (TWNP) based on the lattice match between monoclinic WO3 and anatase TiO2. The WO3 nanoplates (WNP) with a fluted body and a thickness of 160 nm were first prepared on tungsten foil by a hydrothermal method. Then, numerous 001-oriented anatase TiO2 branches were directly grown in situ on the WNP with an average thickness of 50 nm and a length of 35 +/- 5 nm. TWNP exhibited a photocurrent of ~2.37 mA cm-2, which is 157% of that of WNP, and showed no obvious decay over 100 h continuous testing, compared to only 11.8% that remained for WNP. During the PEC degradation of phenol, the rate constant was 0.322 h-1 for TWNP while it was only 0.131 h-1 for WNP, and the activity of TWNP remained at 97.2% after 10 repeat tests compared to only 67.4% for WNP. According to the transient photovoltage and transient photocurrent measurements, these improvements can be attributed to the TiO2 branches which enhanced the charge separation efficiency and surface reaction kinetics, and hindered the inactivation of TWNP by providing an atomic-level protective cover. Overall, the in situ wet chemical growth of the TiO2 branches is a meaningful way to overcome WO3's drawbacks, i.e., sluggish surface reaction kinetics, rapid charge recombination and gradual loss of photoactivity, to improve the PEC activity and stability of WO3 photoanodes. PMID- 29995057 TI - Supramolecular alternate donor-acceptor copolymers mediated by PtPt metal-metal interactions and their photocatalytic applications. AB - Precise arrangement of the aromatic donor-acceptor units is of paramount importance to dictate the performance of multi-component pi-functional materials. Herein a novel strategy has been developed toward alternate donor-acceptor copolymers, by incorporating Pt(ii)Pt(ii) metal-metal interactions for the hetero complexation process. The proximity of Pt atoms endows the resulting supramolecular copolymers with metal-metal-to-ligand charge-transfer transitions in the visible/NIR region. The signals have been further applied for low-energy visible-light photo-catalysis that is unattainable for the individual species. More interestingly, "on-demand" photo-catalytic efficiency can be achieved by manipulating the reversibility of the supramolecular copolymerization process. Hence, the current work demonstrates the efficiency of fabricating multi component pi-functional materials via the elaborate manipulation of non-covalent driving forces. PMID- 29995061 TI - Erratum: Active compounds and derivatives of camellia sinensis responding to erosive attacks on dentin. Braz Oral Res. 2018;32:e40. AB - [This corrects the article doi: 10.1590/1807-3107bor-2018.vol32.0040]. PMID- 29995062 TI - Comparative effectiveness of photobiomodulation and manual therapy alone or combined in TMD patients: a randomized clinical trial. AB - The effectiveness of photobiomodulation (PBM) and manual therapy (MT), alone or combined (CT), were evaluated in pain intensity, mandibular movements, psychosocial aspects, and anxiety symptoms of temporomandibular disorder (TMD) patients. Fifty-one TMD patients were randomly assigned to three groups: the PBM group (n = 18), which received PBM with 808 nm, 100 mW, 13.3 J/cm2, and 4 J per point; the MT group (n=16) for 21 minutes each session on masticatory muscles and temporomandibular joint TMJ; and the CT group (n = 17), applied during twelve sessions. Seven evaluations were performed in different moments using visual analogue scale (VAS), Research Diagnosis Criteria for Temporomandibular Disorders (RDC/TMD) Axis I and II, and Beck anxiety inventory (BAI). All groups demonstrated reductions in pain and improvement in jaw movements during treatment and at follow-up (< 0.001). The assessment of psychosocial aspects of TMD, comparing baseline and follow-up in all treatment groups, revealed that treatment did not promote modification in the intensity of chronic pain (p > 0.05). However, depression symptoms showed a reduction in PBM and CT groups (p<=0.05). All treatments promoted reduction in physical symptoms with and without pain and enhancement of jaw disabilities (p <= 0.05). MT promotes improvement in 5 functions, PBM in 2, and CT in 1 (p < 0.001). BAI analysis revealed that all treatments lead to a reduction in anxiety symptoms (p<=0.05). All protocols tested were able to promote pain relief, improve mandibular function, and reduce the negative psychosocial aspects and levels of anxiety in TMD patients. However, the combination of PBM and MT did not promote an increase in the effectiveness of both therapies alone. PMID- 29995063 TI - Stability and bone loss around submerged and non-submerged implants in diabetic and non-diabetic patients: a 7-year follow-up. AB - To evaluate peri-implant bone loss (PIBL) and stability around submerged and non submerged dental implants in patients with and without type 2 diabetes mellitus (T2DM). Thirty-five T2DM and non-diabetic (NT2DM) patients were included in this study. Demographic data were recorded using a questionnaire and PIBL was measured on digital radiographs. Resonance frequency analysis (RFA) was carried out for each implant at the time of fixture placement and at 3 months in both groups. P values less than 0.05 were considered statistically significant. One hundred and eighteen dental implants with a mean height of 10 to 12 mm and 3.3 to 4.1 mm in diameter were placed. The comparison of the mean RFA values at baseline and at 3 months was statistically significant (p = 0.008) in T2DM patients. The inter group mean RFA values at baseline and at 3 months were not significant (p > 0.05). PIBL was significantly high in T2DM as compared to NT2DM patients at each follow-up (p < 0.05). At 2, 3, and 7 years, non-submerged dental implants showed significantly high PIBL in T2DM patients as compared to NT2DM individuals (p<0.05). The results of the present clinical study demonstrate increased PIBL around non-submerged single-tooth implant-supported restorations in T2DM patients, which may be due to the immune inflammatory status. PMID- 29995064 TI - A comparison of different bone graft materials in peri-implant guided bone regeneration. AB - The aim of this study was to compare the effects of hydroxyapatite (HA), deproteinized bovine bone (DPB), human-derived allogenic bone (HALG), and calcium sulfate (CAP) graft biomaterials used with titanium barriers for bone augmentation to treat peri-implant defects in rat calvarium treated by guided bone regeneration (GBR). Thirty-two female Sprague-Dawley rats were divided into four groups: DPB, HALG, HA, and CAP. One titanium barrier was fixed to each rat's calvarium after the titanium implants had been fixed. In total, 32 titanium implants and barriers were used. Ninety days after the surgical procedure, all the barriers were removed. After decalcification of bone tissue, the titanium implants were removed gently, and new bone regeneration in the peri-implant area was analyzed histologically. Immunohistochemical staining of vascular endothelial growth factor (VEGF) was also performed. There were no statistically significant between-group differences in new bone regeneration or VEGF expression after 3 months. According to the results of the histological and immunohistochemical analyses, none of the grafts used in this study showed superiority with respect to new bone formation. PMID- 29995065 TI - Accuracy of visual and image-based ICDAS criteria compared with a micro-CT gold standard for caries detection on occlusal surfaces. AB - The aim of this study was to check the in vitro accuracy of ICDAS criteria on digital images compared to visual examination for the diagnosis of occlusal caries against a micro-CT gold standard. ICDAS was scored in 40 extracted permanent molars by means of visual inspection and stereomicroscopic images. Visual examinations were performed in duplicate and at a one-week interval by three different calibrated examiners. The analysis of digital images by ICDAS criteria was also performed in duplicate, 1 month after visual examinations. The detection methods were compared by means of sensitivity, specificity, area under the curve, predictive positive and negative values, and accuracy for two different thresholds (1- sound vs. carious teeth; 2- tooth requiring operative vs. non-operative treatment). Sensitivity and accuracy values for threshold 1 in the visual ICDAS and image-based ICDAS methods were high for sensitivity (0.93 and 0.97) and for accuracy (0.83 and 0.85), but low for specificity (0.55 for both methods). Specificity values for threshold 2 were 0.77 and 0.82, while sensitivity was 0.33 and 0.28 for each method. Spearman's rank correlation coefficient was 0.53 and 0.43 (p<0.05) for visual and image-based ICDAS compared to the gold standard scores. Both visual and image-based ICDAS scores were similar to each other in terms of diagnostic accuracy when compared to the micro CT gold standard. Low specificity for the presence of caries and sensitivity for the detection of caries requiring operative treatment were found. PMID- 29995066 TI - The role of contextual and individual factors on periodontal disease in Uruguayan adults. AB - The present study aimed at understanding the relationship between periodontitis and socio-contextual and individual determinants of health. Data from "The First Uruguayan Oral Health Survey, 2011", which included 223 and 455 individuals with 35-44 and 65-74 years old respectively, were used. A stratified, multistage cluster sampling design was adopted (cities with >= 20.000 residents). Periodontitis was assessed using the modified Community Periodontal Index (CPI) and clinical attachment loss (CAL) (periodontal pocket and CAL >= 4 mm). Independent variables included contextual socioeconomic status (SES) measured by proportion of houses with Unsatisfied Basic Needs (UBN) and individual demographic and behavioral factors. Logistic regression multilevel models were generated. Living in contexts with a higher UBN was associated with higher odds for periodontitis in both age groups, even when adjusting for individual level variables (odds ratio [OR] = 1.51, 95%CI = 1.42-1.60 and 1.31, 95%CI = 1.21-1.42, respectively). Being male or heavy smoker increased the odds of periodontitis in this population for both age groups. Social structure impacts periodontal disease by modifying individual socioeconomic situations: in better socioeconomic context, UBN acts increasing the protector role of socioeconomic situation but in a poverty context the role is attenuated. Conclusions for this study are that periodontitis varies across contextual socio-demographic groups being higher in the population with a lower SES, challenging health authorities to integrate oral health into national non-communicable diseases programs. PMID- 29995067 TI - School environment and individual factors influence oral health related quality of life in Brazilian children. AB - The aim of this study was to verify the influence of school environment and individual factors on oral health related quality of life (OHRQoL) in a representative sample of Brazilian schoolchildren. A cross-sectional study was conducted with 1,134 12-year-old schoolchildren from Santa Maria, Southern Brazil. Clinical variables were obtained from examinations carried out by calibrated individuals. In addition, parents/guardians answered a semi-structured questionnaire about sociodemographic characteristics. Contextual variables were obtained from the city's official database, including the mean income of the neighborhood in which the school was located and the Basic School's Development Index (IDEB) of the school. The Brazilian version of the Child Perception Questionnaire (CPQ11-14) was used to access OHRQoL. Data analysis was conducted using multilevel Poisson regression. Children studying in schools with a higher classification on the IDEB presented a lower CPQ11-14 mean score (rate ratio 0.80, 95%CI 0.74-0.88) than those studying in schools with a lower IDEB. Regarding individual variables, children with carious cavities, malocclusion, and gingival bleeding presented higher CPQ11-14 mean values than their counterparts. The same was observed in children from families with low socioeconomic status. School environment, and individual clinical and socioeconomic factors were associated with schoolchildren's OHRQoL. PMID- 29995068 TI - Physical accessibility in primary healthcare: a step towards the embracement. AB - OBJECTIVE: To assess the physical accessibility from the front desk of primary healthcare units. METHOD: Descriptive and quantitative research to map the accessibility of the physical space in 157 health units, between August 2014 and May 2015, in the region of Baturite, Ceara, Brazil. The data were collected using a checklist instrument type, and absolute and relative frequencies, binomial and verisimilitude tests for statistical analysis, with statistical significance of p <0.05 were used. RESULTS: Of the analyzed items, stairs (24.8%), ramps (47.1%) and floors (75.8%) were inaccessible in most health units. Comparing urban and rural areas, circulation area (0.7x, p=0.293), counter (0.4x, p=0.010), seat (0.7x, p=0.758) and drinking fountain (0.7x, p=0.736) were more inaccessible in the urban area. CONCLUSION: The access of persons with physical disabilities to primary care should be seen as a priority. There are physical, architectural and furniture barriers that compromise the full embracement of the user. PMID- 29995069 TI - V diagram as a tool for analytical integration of theoretical, conceptual, and methodological knowledge in health care. AB - OBJECTIVE: To produce a reflection on the ability of the V diagram to integrate theoretical, conceptual, and methodological knowledge obtained from complex, non explicitly identifiable systems, models, and theories. METHODS: Reflection study with an analytical characteristic. RESULTS: The V Diagram is presented as an instrument that can ensure an integrated analysis between theoretical and conceptual knowledge (worldview and philosophy, theories, principles, constructs, and concepts), and the analysis or production of methodological knowledge (data records, transformations, knowledge assertions, and value assertions). Examples are related to the Unified Health System (SUS), and care in Psychosocial Care Centers for Alcohol and Drugs. CONCLUSIONS: V diagram is an instrument capable of producing an integrated analysis of the knowledge contained in productions linked to complex and non-explicitly identifiable models and theories as a theoretical model, theory or framework applying deductive and inductive procedures. PMID- 29995070 TI - Gender violence: knowledge and professional conduct of the family health strategy. AB - OBJECTIVE: To evaluate the knowledge and behaviors of health professionals of units of the Strategies Family opposite gender violence. METHODS: This descriptive study with 53 seven of units of the family health strategy professionals from March to July 2015. Data were collected through a self administered instrument and analyzed in Excel 2007. RESULTS: It was observed that the knowledge of professionals about definitions, epidemiology and management of violence ranged from reasonable to good, despite knowing little about the prevalence of violence during pregnancy. Regarding the conduct was evident difficulty in questioning women about violence and its notification. Professionals with shorter assistance and who received training were more assertive results regarding conduct. CONCLUSIONS: It is suggested that educational actions in service be carried out in order to provide subsidies for the professionals' action against cases of gender violence. PMID- 29995071 TI - Webquest and blog as educational strategies in school health. AB - OBJECTIVE: To describe health education strategy on healthy eating using WebQuest and blog with elementary school students from a public school. METHOD: To report the health education activity carried out in 2014 with fourteen students from the 8th year of public school. The "Healthy Food Blog" was developed by the students using the WebQuest methodology guided by the nurse during four periods of the science discipline. RESULTS: In three work groups, the students performed the WebQuest made available on the website with the introduction, task, process and resource stages. The blog was written in a free website in response to WebQuest questions. The students' evaluation highlighted the positives, difficulties and recommendations for future activities. CONCLUSION: This technology makes the search for knowledge participatory and active, besides being a space for integration of health professionals in the school environment. PMID- 29995072 TI - Single Therapeutic Project and Nursing Process from an interdisciplinary care perspective. AB - OBJECTIVE: To analyze the single therapeutic project and the nursing process regarding its specificities and intersection points from the interdisciplinary care perspective. METHODIntegrative review of the literature from articles available in the Lilacs, SciELO, MEDLINE and PubMed databases, published in Portuguese, English and Spanish from 2005 to 2015. RESULTS: It was identified 23 articles. From these, 17 on the nursing process, six on the single therapeutic project and one about multiprofessional residency. From the analysis, their specificities and intersection points that describe the alignment and similarities between them were identified in the primary and mental health cares. CONCLUSIONS: The single therapeutic project and the nursing process are aligned in health practices in primary and mental health cares. The multiprofessional residency allows this alignment among them, and the nurse contributes to the interdisciplinary care with the nursing process. PMID- 29995073 TI - Cross-cultural adaptation methods of instruments in the nursing area. AB - OBJECTIVE: To analyze scientific publications in order to identify the cross cultural adaptation methods of instruments that are mainly applied in nursing. METHOD: Integrative review, in the electronic sources Medline - Pubmed, Cinahl, Lilacs, Scopus and Web of Science. 96 peer-reviewed papers, published between 2010 and 2015 were selected. RESULTS: The articles that composed the sample were published in 59 different journals, 15.2% were Brazilian. The largest number of publications was concentrated in 2015 (31.2%), 28 countries appeared on the list which is led by Brazil (33.3%), followed by China (10.4%). It was used 26 different guidelines, however the one proposed by Beaton and their collaborators was mentioned in 47 (49.0%) articles and the Brislin's in 12 (12.5%). CONCLUSION: This review does not allow us to define the most appropriate method, however all methods applied agreed on the use of back translation. In addition, many studies in different languages and countries showed the international acceptability of the method developed by Beaton et al. PMID- 29995074 TI - Vulnerabilities, depression, and religiosity in the elderly hospitalised in an emergency unit. AB - OBJECTIVES: To identify vulnerabilities and the association between religiosity and depressive signs in the elderly hospitalised in an emergency unit. METHODS: This cross-sectional study was conducted with 140 elderly patients admitted to a public hospital in the Federal District, Brazil, between May and October 2016. Data were collected using a semi-structured health questionnaire, the Duke University Religion Scale (DUREL), and the Geriatric Depression Scale (GDS). RESULTS: The elderly patients were vulnerable in terms of schooling, place of residence, and life habits, and 37.3% exhibited signs of depression. A weak association was found between religiosity and the development of depressive signs (p <= 0, R = 0.12; p = 0.02 and r = 0.06). CONCLUSION: The results showed isolated religiosity is not an effective protective factor, but it strengthens resilience in the face of disease and serves as a support network for the elderly. PMID- 29995075 TI - Psychosocial rehabilitation in the west network of the municipality of Sao Paulo: potentialities and challenges. AB - OBJECTIVE: To describe the strategies of the Psychosocial Rehabilitation conducted in the Network of Psychosocial Care of the western region of the municipality of Sao Paulo. METHODOLOGY: Descriptive qualitative study, carried out with 123 professionals, from September 2015 to July 2016. Data processed by the software Alceste and analyzed in light of the analytical category Psychosocial Rehabilitation of Benedetto Saraceno and complementary literature. RESULTS: Three classes emerged that address the potential and scarcity of therapeutic residential services as a space to resume the daily life; importance of cultural activities for the exchange of identities and care beyond the scope of health; the potential of projects to generate work and income to regain the contractual power. CONCLUSION: The strategies contribute to the construction of subjectivity and the resumption of the citizenship. In order to sustain the Psychosocial Rehabilitation it is necessary to overcome the weaknesses of human, physical and structural resources. Still, there is potential in the collaborative work and accountability of the teams. PMID- 29995076 TI - Meaning of nursing care to brain dead potential organ donors. AB - OBJECTIVE: To understand the meanings of care to brain dead potential organ donors for nurses, and construct a theoretical model. METHOD: Qualitative study based on the Grounded Theory approach. Data were collected through open interviews with 12 nurses, distributed in three sample groups in a university hospital in northeastern Brazil, from December 2010 to June 2011. RESULTS: The phenomenon Unveiling multiple relationships and interactions of nurses in the complexity of patient care in brain dead potential donors is supported by the interrelationship of five categories and results from the need to organize care practices in the context of the intensive care unit, considering the factors involved in the relationship between nurses, staff and family and reveals challenges for nurses imposed by the complexity of the care process. CONCLUSIONS: The meaning of care to brain dead potential donors involves understanding the complexity of this patient who can save somebody's life through organ donation. PMID- 29995077 TI - Perfusion index for assessing microvascular reactivity in septic shock after fluid resuscitation. AB - OBJECTIVE: Microcirculation disturbances are implicated in the prognosis of septic shock. Microvascular hyporesponsiveness can be assessed by an oximetry derived perfusion index and reactive hyperemia. Using this perfusion index, we investigated reactive hyperemia and its relationship with peripheral perfusion and clinical-hemodynamic parameters in septic shock. METHODS: Eighty-two patients were evaluated: 47 with septic shock and 35 controls. Tests were performed within 24 hours after admission. The perfusion index was evaluated before and after a 3 min blood flow occlusion using a time-response analysis for 5 min. The perfusion index was also evaluated in the hyperemic phases and was mainly derived by mechanosensitive (DeltaPI0-60) and metabolic mechanisms (DeltaPI60-120). Correlation tests were performed between reactive hyperemia and clinical hemodynamic data. RESULTS: Reactive hyperemia measured by the perfusion index was significantly lower in patients with septic shock, but this was only observed for the first 45 seconds after cuff-deflation. In the remaining period, there were no statistical differences between the groups. The peaks in the perfusion index were similar between groups, although the peak was reached more slowly in the septic group. Values of DeltaPI0-60 were lower in shock [01% (-19% - -40%) versus 39% (6% - 75%); p = 0.001]. However, DeltaPI60-120 was similar between the groups [43% (18% - 93%) versus 48% (18% - 98%); p = 0.58]. The time-to-peak of the perfusion index was correlated positively with the SOFA scores and negatively with C-reactive protein; the peak of the perfusion index was positively correlated with vasopressor doses; and the DeltaPI60-120 values were positively correlated with C-reactive protein and vasopressor doses. No other significant correlations occurred. CONCLUSIONS: This perfusion index-based study suggests that septic shock promotes initial peripheral vascular hyporesponsiveness and preserves posterior vascular reactivity to a considerable degree. These results demonstrate a time-dependent peripheral hyperemic response and a significant ischemic reserve in septic shock. PMID- 29995078 TI - Sizing the lung in dogs: the inspiratory capacity defines the tidal volume. AB - OBJECTIVE: To evaluate a novel physiological approach for setting the tidal volume in mechanical ventilation according to inspiratory capacity, and to determine if it results in an appropriate mechanical and gas exchange measurements in healthy and critically ill dogs. METHODS: Twenty healthy animals were included in the study to assess the tidal volume expressed as a percentage of inspiratory capacity. For inspiratory capacity measurement, the mechanical ventilator was set as follows: pressure control mode with 35cmH2O of inspired pressure and zero end-expiratory pressure for 5 seconds. Subsequently, the animals were randomized into four groups and ventilated with a tidal volume corresponding to the different percentages of inspiratory capacity. Subsequently, ten critically ill dogs were studied. RESULTS: Healthy dogs ventilated with a tidal volume of 17% of the inspiratory capacity showed normal respiratory mechanics and presented expected PaCO2 values more frequently than the other groups. The respiratory system and transpulmonary driving pressure were significantly higher among the critically ill dogs but below 15 cmH2O in all cases. CONCLUSIONS: The tidal volume based on the inspiratory capacity of each animal has proven to be a useful and simple tool when setting ventilator parameters. A similar approach should also be evaluated in other species, including human beings, if we consider the potential limitations of tidal volume titration based on the calculated ideal body weight. PMID- 29995079 TI - Prognostic factors among critically ill patients with community-acquired acute bacterial meningitis and acute kidney injury. AB - OBJECTIVE: To investigate prognostic factors among critically ill patients with community-acquired bacterial meningitis and acute kidney injury. METHODS: A retrospective study including patients admitted to a tertiary infectious disease hospital in Fortaleza, Brazil diagnosed with community-acquired bacterial meningitis complicated with acute kidney injury. Factors associated with death, mechanical ventilation and use of vasopressors were investigated. RESULTS: Forty one patients were included, with a mean age of 41.6 +/- 15.5 years; 56% were males. Mean time between intensive care unit admission and acute kidney injury diagnosis was 5.8 +/- 10.6 days. Overall mortality was 53.7%. According to KDIGO criteria, 10 patients were classified as stage 1 (24.4%), 18 as stage 2 (43.9%) and 13 as stage 3 (31.7%). KDIGO 3 significantly increased mortality (OR = 6.67; 95%CI = 1.23 - 36.23; p = 0.028). Thrombocytopenia was not associated with higher mortality, but it was a risk factor for KDIGO 3 (OR = 5.67; 95%CI = 1.25 - 25.61; p = 0.024) and for mechanical ventilation (OR = 6.25; 95%CI = 1.33 - 29.37; p = 0.02). Patients who needed mechanical ventilation by 48 hours from acute kidney injury diagnosis had higher urea (44.6 versus 74mg/dL, p = 0.039) and sodium (138.6 versus 144.1mEq/L; p = 0.036). CONCLUSION: Mortality among critically ill patients with community-acquired bacterial meningitis and acute kidney injury is high. Acute kidney injury severity was associated with even higher mortality. Thrombocytopenia was associated with severer acute kidney injury. Higher urea was an earlier predictor of severer acute kidney injury than was creatinine. PMID- 29995080 TI - Reducing malnutrition in critically ill pediatric patients. AB - OBJECTIVE: To compare the prevalence of malnutrition during two time periods in a pediatric intensive care unit. METHODS: This was a retrospective cross-sectional study of patients admitted to the pediatric intensive care unit of a university hospital during two one-year periods with an interval of four years between them. Nutritional evaluation was conducted based on weight and height measured at admission. The body mass index-for-age was the parameter chosen to evaluate nutritional status, as classified according to the World Health Organization, according to age group. RESULTS: The total sample size was 881 (406 in the contemporary sample and 475 in the historical sample). There was a significant reduction in malnutrition in the contemporary sample (p = 0.03). Malnourishment in patients in the historical sample was significantly associated with mortality and length of stay, while malnourishment in patients in the contemporary sample was not associated with worse outcomes. CONCLUSION: There was a significant reduction in malnutrition among patients in the same pediatric intensive care unit when comparing the two time periods. Our findings of a change in nutritional profile in critically ill patients corroborate the nutritional status data of children and adolescents worldwide. PMID- 29995081 TI - Predictors of de novo atrial fibrillation in a non-cardiac intensive care unit. AB - OBJECTIVE: To assess the predictors of de novo atrial fibrillation in patients in a non-cardiac intensive care unit. METHODS: A total of 418 hospitalized patients were analyzed between January and September 2016 in a non-cardiac intensive care unit. Clinical characteristics, interventions, and biochemical markers were recorded during hospitalization. In-hospital mortality and length of hospital stay in the intensive care unit were also evaluated. RESULTS: A total of 310 patients were included. The mean age of the patients was 61.0 +/- 18.3 years, 49.4% were male, and 23.5% presented de novo atrial fibrillation. The multivariate model identified previous stroke (OR = 10.09; p = 0.016) and elevated levels of pro-B type natriuretic peptide (proBNP, OR = 1.28 for each 1,000pg/mL increment; p = 0.004) as independent predictors of de novo atrial fibrillation. Analysis of the proBNP receiver operating characteristic curve for prediction of de novo atrial fibrillation revealed an area under the curve of 0.816 (p < 0.001), with a sensitivity of 65.2% and a specificity of 82% for proBNP > 5,666pg/mL. There were no differences in mortality (p = 0.370), but the lengths of hospital stay (p = 0.002) and stay in the intensive care unit (p = 0.031) were higher in patients with de novo atrial fibrillation. CONCLUSIONS: A history of previous stroke and elevated proBNP during hospitalization were independent predictors of de novo atrial fibrillation in the polyvalent intensive care unit. The proBNP is a useful and easy- and quick-access tool in the stratification of atrial fibrillation risk. PMID- 29995082 TI - Assessment of the neuropsychomotor development in the first year of life of premature infants with and without bronchopulmonary dysplasia. AB - OBJECTIVE: To compare the neuropsychomotor development in the first year of life of premature infants with and without bronchopulmonary dysplasia. METHODS: A cross-sectional retrospective study was conducted between January 1, 2014, and December 30, 2015, with premature infants weighing < 1,500g at birth and diagnosed with bronchopulmonary dysplasia at the corrected ages of 6 and 9 months, assessed using the DENVER II Developmental Screening Test. Quantitative variables were described as the means, medians and standard deviations. Variables with normal distribution were tested using Student's t test; otherwise, the Mann Whitney test was used, considering significance at p-value < 0.05. Qualitative variables were expressed as frequencies and percentages. Logistic regression was used with odds ratio analysis to evaluate the effects of other variables as risk factors for changes in neuropsychomotor development. RESULTS: Infants with bronchopulmonary dysplasia showed greater developmental delay compared with those without bronchopulmonary dysplasia (p-value = 0.001). The factors associated with a higher incidence of changes in neuropsychomotor development, in addition to bronchopulmonary dysplasia, were antenatal steroid, gender, birth weight, 5 minute Apgar score, Score for Neonatal Acute Physiology-Perinatal Extension, duration of oxygen therapy, duration of mechanical ventilation and length of hospital stay. Other variables may also have influenced the result, such as drug use by mothers of infants with bronchopulmonary dysplasia. CONCLUSION: Bronchopulmonary dysplasia associated with other pre- and postnatal factors may be considered a risk factor for delayed neuropsychomotor development in the first year of life in premature infants born weighing less than 1,500g. PMID- 29995083 TI - APACHE IV score in postoperative kidney transplantation. AB - OBJECTIVES: To evaluate the calibration and discrimination of APACHE IV in the postoperative period after kidney transplantation. METHODS: This clinical cohort study included 986 hospitalized adult patients in the immediate postoperative period after kidney transplantation, in a single center in southern Brazil. RESULTS: Kidney transplant patients who died in hospital had significantly higher APACHE IV values and higher predicted mortality. The APACHE IV score showed adequate calibration (H-L 11.24 p = 0.188) and a good discrimination ROC curve of 0.738 (95%CI 0.643 - 0.833, p < 0.001), although SMR overestimated mortality (SMR = 0.73; 95%CI: 0.24 - 1.42, p = 0.664). CONCLUSIONS: The APACHE IV score showed adequate performance for predicting hospital outcomes in the postoperative period for kidney transplant recipients. PMID- 29995084 TI - Clinical attitudes and perceived barriers to early mobilization of critically ill patients in adult intensive care units. AB - OBJECTIVE: To investigate the knowledge of multi-professional staff members about the early mobilization of critically ill adult patients and identify attitudes and perceived barriers to its application. METHODS: A cross-sectional study was conducted during the second semester of 2016 with physicians, nursing professionals and physical therapists from six intensive care units at two teaching hospitals. Questions were answered on a 5-point Likert scale and analyzed as proportions of professionals who agreed or disagreed with statements. The chi-square and Fisher's exact tests were used to investigate differences in the responses according to educational/training level, previous experience with early mobilization and years of experience in intensive care units. RESULTS: The questionnaire was answered by 98 out of 514 professionals (response rate: 19%). The acknowledged benefits of early mobilization were maintenance of muscle strength (53%) and shortened length of mechanical ventilation (83%). Favorable attitudes toward early mobilization included recognition that its benefits for patients under mechanical ventilation exceed the risks for both patients and staff, that early mobilization should be routinely performed via nursing and physical therapy protocols, and readiness to change the parameters of mechanical ventilation and reduce sedation to facilitate the early mobilization of patients. The main barriers mentioned were the unavailability of professionals and time to mobilize patients, excessive sedation, delirium, risk of musculoskeletal self injury and excessive stress at work. CONCLUSION: The participants were aware of the benefits of early mobilization and manifested attitudes favorable to its application. However, the actual performance of early mobilization was perceived as a challenge, mainly due to the lack of professionals and time, excessive sedation, delirium, risk of musculoskeletal self-injury and excessive stress at work. PMID- 29995085 TI - Translation and cross-cultural adaptation of the Cornell Assessment of Pediatric Delirium scale for the Portuguese language. AB - OBJECTIVE: This study sought to translate the Cornell Assessment of Pediatric Delirium from English into Brazilian Portuguese and cross-culturally adapt it for use in Brazil. METHODS: Following the authorization granted by its main author, the processes of translation and cross-cultural adaptation were performed with regard to the Cornell Assessment of Pediatric Delirium in accordance with the following internationally recommended steps: translation of the original into Portuguese by two native speakers of the target language; synthesis of the translated versions; back-translation by two native speakers of the original language; review and harmonization of the back-translation; a review of the Portuguese version of the Cornell Assessment of Pediatric Delirium by an expert panel composed of specialists; pretesting including assessments of clarity, comprehensibility, and acceptability of the translated version using a sample of the target population; and finishing modifications to achieve the final version. RESULTS: The translation and cross-cultural adaptation of the Cornell Assessment of Pediatric Delirium followed international recommendations. The linguistic and semantic issues that emerged during the process were discussed by the expert panel, which unanimously agreed to slight modifications. During pretesting, the Cornell Assessment of Pediatric Delirium was administered to 30 eligible children, twice per day; the final version was easy to understand, could be completed quickly, and showed a high inter-rater correlation coefficient (0.955). CONCLUSIONS: The translation of the Cornell Assessment of Pediatric Delirium into Brazilian Portuguese and its cross-cultural adaptation were successful and preserved the linguistic and semantic properties of the original instrument. The Cornell Assessment of Pediatric Delirium proved to be easy to understand and could be completed quickly. Additional studies are needed to test the validity and psychometric properties of this version in Brazil. PMID- 29995086 TI - Organ donation: the reality of an intensive care unit in Portugal. AB - OBJECTIVE: To clinically and demographically characterize potential organ donors admitted to a general intensive care unit and analyze data on donated organs. METHODS: This retrospective study was conducted from 2010 to 2015 and analyzed demographic and clinical variables and the number of harvested organs and tissues. RESULTS: A total of 92 potential organ donors were identified, of whom eight were non-effective donors and 84 were effective donors (59.5% were expanded criteria donors). The mean age of the potential donors was 60.7 years, and the majority were men. Hemorrhagic stroke accounted for 55.4% of brain deaths. The most common blood type among the donors was A Rh+ (43.5%), and the most common comorbidity was arterial hypertension (43.3%). The most frequently collected organs were the kidneys (84.5%) and liver (66.7%). The average number of organs harvested per donor was 2.8, and this ratio was smaller for donors with expanded criteria compared to other donors. CONCLUSION: In most cases, potential organ donors died of brain death, were older than middle age, were male and were victims of a hemorrhagic stroke. The majority of the donors were expanded criteria donors and donated an average of two to three organs. The organs donated most frequently were the kidneys and liver. PMID- 29995087 TI - Chest wall effect on the monitoring of respiratory mechanics in acute respiratory distress syndrome. AB - The respiratory system mechanics depend on the characteristics of the lung and chest wall and their interaction. In patients with acute respiratory distress syndrome under mechanical ventilation, the monitoring of airway plateau pressure is fundamental given its prognostic value and its capacity to assess pulmonary stress. However, its validity can be affected by changes in mechanical characteristics of the chest wall, and it provides no data to correctly titrate positive end-expiratory pressure by restoring lung volume. The chest wall effect on respiratory mechanics in acute respiratory distress syndrome has not been completely described, and it has likely been overestimated, which may lead to erroneous decision making. The load imposed by the chest wall is negligible when the respiratory system is insufflated with positive end-expiratory pressure. Under dynamic conditions, moving this structure demands a pressure change whose magnitude is related to its mechanical characteristics, and this load remains constant regardless of the volume from which it is insufflated. Thus, changes in airway pressure reflect changes in the lung mechanical conditions. Advanced monitoring could be reserved for patients with increased intra-abdominal pressure in whom a protective mechanical ventilation strategy cannot be implemented. The estimates of alveolar recruitment based on respiratory system mechanics could reflect differences in chest wall response to insufflation and not actual alveolar recruitment. PMID- 29995088 TI - Safety of neuromuscular electrical stimulation among critically ill patients: systematic review. AB - OBJECTIVE: To review the evidence on the safety of neuromuscular electrical stimulation when used in the intensive care unit. METHODS: A systematic review was conducted; a literature search was performed of the MEDLINE (via PubMed), PEDro, Cochrane CENTRAL and EMBASE databases, and a further manual search was performed among the references cited in randomized studies. Randomized clinical trials that compared neuromuscular electrical stimulation to a control or placebo group in the intensive care unit and reporting on the technique safety in the outcomes were included. Hemodynamic variables and information on adverse effects were considered safety parameters. Articles were independently analyzed by two reviewers, and the data analysis was descriptive. RESULTS: The initial search located 1,533 articles, from which only four randomized clinical trials were included. Two studies assessed safety based on hemodynamic variables, and only one study reported an increase in heart rate, respiratory rate and blood lactate, without clinical relevance. The other two studies assessed safety based on reported adverse effects. In one, 15% of patients described a prickling sensation, without any clinically relevant abnormalities. In the other, one patient suffered a superficial burn due to improper parameter configuration. CONCLUSION: Neuromuscular electrical stimulation is safe for critically ill patients; however, it should be applied by duly trained professionals and with proper evidence-based parameters. PMID- 29995089 TI - Difficult decisions in pediatric practice and moral distress in the intensive care unit. AB - In an ethical dilemma, there is always an option that can be identified as the best one to be chosen. When it is impossible to adopt such option, the situation can lead professionals to experience moral distress. This review aims to define the issue of moral distress and propose coping strategies. Systematic searches in the MEDLINE/PubMed and SciELO databases were conducted using the keywords "moral distress" and "moral suffering" in articles published between 2000 and 2017. This review was non-exhaustive and contextual, with a focus on definitions, etiologies and methods of resolution for moral distress. In the daily practice of intensive care, moral distress was commonly related to the prolongation of patients' suffering and feelings of helplessness, as well as difficulties in communication among team members. Coping strategies for moral distress included organizational, personal and administrative actions. Actions such as workload management, mutual support among professionals and the development of techniques to cultivate open communication, reflection and questioning within the multidisciplinary team were identified. In clinical practice, health professionals need to be recognized as moral agents, and the development of moral courage was considered helpful to overcome ethical dilemmas and interprofessional conflicts. Both in pediatric and adult intensive care, professionals are challenged by questions about their practice, and they may experience moral distress. This suffering can be minimized and solved by understanding that the focus is always on the patient and acting with moral courage and good communication in an environment of mutual respect. PMID- 29995090 TI - Use of extracorporeal membrane oxygenation for treating acute cardiomyopathy after liver transplantation: a case report. AB - We report the case of a female patient, 58 years of age, without known heart disease, who underwent liver transplantation without complications. On the second postoperative day, the patient developed cardiogenic shock secondary to stress induced cardiomyopathy (Takotsubo-like syndrome). The patient was successfully managed with veno-arterial peripheral extracorporeal membrane oxygenation for 6 days, with complete recovery of cardiac function and of the hepatic graft. Coronary syndrome and acute myocarditis were excluded as the causes of the shock. The use of extracorporeal membrane oxygenation in this scenario is possible and safe, considering its specialized protocols and treatment. PMID- 29995091 TI - Paroxysmal sympathetic hyperactivity syndrome caused by fat embolism syndrome. AB - Paroxysmal sympathetic hyperactivity represents an uncommon and potentially life threatening complication of severe brain injuries, which are most commonly traumatic. This syndrome is a clinical diagnosis based on the recurrent occurrence of tachycardia, hypertension, diaphoresis, tachypnea, and occasionally high fever and dystonic postures. The episodes may be induced by stimulation or may occur spontaneously. Underdiagnosis is common, and delayed recognition may increase morbidity and long-term disability. Trigger avoidance and pharmacological therapy can be very successful in controlling this complication. Fat embolism syndrome is a rare but serious complication of long bone fractures. Neurologic signs, petechial hemorrhages and acute respiratory failure constitute the characteristic presenting triad. The term cerebral fat embolism is used when the neurological involvement predominates. The diagnosis is clinical, but specific neuroimaging findings can be supportive. The neurologic manifestations include different degrees of alteration of consciousness, focal deficits or seizures. Management is supportive, but good outcomes are possible even in cases with very severe presentation. We report two cases of paroxysmal sympathetic hyperactivity after cerebral fat embolism, which is a very uncommon association. PMID- 29995092 TI - Periodontal disease and bronchoaspiration in a neurovegetative patient. PMID- 29995093 TI - Analgosedation and delirium in intensive care units in Brazil: current status. ASDUTI study. PMID- 29995094 TI - Infective endocarditis of the tricuspid valve. PMID- 29995095 TI - To: The Epimed Monitor ICU Database(r): a cloud-based national registry for adult intensive care unit patients in Brazil. PMID- 29995096 TI - Experimental studies in the gestational period: an overview of scientific production. AB - OBJECTIVE: Describing the current panorama on the production of experimental studies related to the gestational period. METHOD: A bibliometric descriptive study using a quantitative approach. The data collection was performed in the International Clinical Trials Registry Platform in the month of October 2016. A descriptive statistical analysis was conducted after reading the abstracts and summarizing the material. RESULTS: The sample consisted of 33 studies registered in the period from 2007 to 2016. The Southeast Region concentrated 48.5% of the studies. Regarding the subjects covered, 33.1% of the total refer to physical activities during pregnancy and to perineal exercises to strengthen the pelvic floor musculature. CONCLUSION: The study showed us the panorama of the experimental studies focused on the gestational period, serving as support and incentive for performing further studies with a high level of evidence, which can impact the care provided to this population. PMID- 29995097 TI - Serum Paraoxonase, Arylesterase, and Glutathione-S-Transferase Activities and Oxidative Stress Levels in Patients with Mushroom Poisoning. AB - OBJECTIVES: Consumption of toxic species of mushrooms may have detrimental effects and increase oxidative stress. Paraoxonase, arylesterase and glutathione S-transferase are antioxidants that resist oxidative stress. In this study, we analyzed the changes in these enzymes during intoxication due to mushrooms. METHODS: The study enrolled 49 adult patients with a diagnosis of mushroom poisoning according to clinical findings and 49 healthy volunteers as the control group. The patients with mild clinical findings were hospitalized due to the possibility that the patient had also eaten the mushrooms and due to clinical findings in the late period, which could be fatal. Paraoxonase, arylesterase, and glutathione-S-transferase concentrations, as well as total antioxidant and oxidant status, were determined in the 49 patients and 49 healthy volunteers by taking blood samples in the emergency department. RESULTS: While paraoxonase, arylesterase, and total antioxidant status were significantly decreased in the patient group (p<0.05), glutathione-S-transferase, total oxidant status and the oxidative stress index were significantly higher (p<0.05). There was a positive correlation between the hospitalization time and the oxidative stress index (r=0.752, p<0.001), whereas a negative correlation was found with glutathione-S transferase (r=-0.420, p=0.003). CONCLUSION: We observed a significant decrease in paraoxonase and arylesterase and an increase in glutathione-S-transferase and oxidative stress indexes in patients with mushroom poisoning, indicating that these patients had an oxidative status. In particular, a low total antioxidant status and high oxidative stress index may gain importance in terms of the assessment of hospitalization duration. PMID- 29995098 TI - Expression of tumor suppressors miR-195 and let-7a as potential biomarkers of invasive breast cancer. AB - OBJECTIVE: MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the posttranscriptional level. Some miRNAs, including let-7a and miR-195, have been described as tumor suppressors. However, the roles of these microRNAs in breast cancer progression remain controversial. The aim of this study is to evaluate miR-195 and let-7a expression as potential biomarkers of invasive breast cancer. METHODS: In the present study, 200 individuals were separated into three groups: (i) 72 women constituting the control group who were selected according to rigorous and well-established criteria; (ii) 56 patients with benign breast tumors; and (iii) 72 patients with malignant breast cancers of different clinical stages. The miR-195 and let-7a expression levels in serum were evaluated by real-time PCR. The results were assessed alone and in combination, and the analysis included an estimation of sensitivity and specificity in ROC curves. RESULTS: Compared with the benign and control groups, both microRNAs were downregulated in the malignant breast cancer patient group. Compared with the malignant group, the combination of both biomarkers in the control and benign groups showed good sensitivity and specificity in the serum with AUCs of 0.75 and 0.72, respectively. The biomarker combination for the control group versus the malignant group exhibited a better sensitivity and specificity than for the benign group versus the malignant group. CONCLUSION: These findings support the evidence that the analysis of miR-195 and let-7a can be used as a non-invasive biomarker for breast cancer detection. PMID- 29995099 TI - Current management of biliary atresia based on 35 years of experience at a single center. AB - OBJECTIVE: The prognosis of patients with biliary atresia undergoing Kasai portoenterostomy is related to the timing of the diagnosis and the indication for the procedure. The purpose of the present study is to present a practical flowchart based on 257 children who underwent Kasai portoenterostomy. METHODS: We conducted a retrospective cohort study of patients who underwent Kasai portoenterostomy between 1981 and 2016. RESULTS: During the first period (1981 to 2009), 230 infants were treated, and the median age at the time of surgery was 84 days; jaundice was resolved in 77 patients (33.5%). During the second period, from 2010 to 2016, a new diagnostic approach was adopted to shorten the wait time for portoenterostomy; an ultrasonography examination suggestive of the disease was followed by primary surgical exploration of the biliary tract without complementary examination or liver biopsy. Once the diagnosis of biliary atresia was confirmed, a portoenterostomy was performed during the same surgery. During this period, 27 infants underwent operations; the median age at the time of surgery was 66 days (p<0.001), and jaundice was resolved in 15 patients (55.6% - p=0.021), with a survival rate of the native liver of 66.7%. CONCLUSION: Primary surgical exploration of the biliary tract without previous biopsy was effective at improving the prognostic indicators of patients with biliary atresia undergoing Kasai portoenterostomy. PMID- 29995101 TI - Rapid Monitoring of Vaccination to prevent measles in Ceara State, Brazil, 2015. AB - OBJECTIVE: to describe the results of Rapid Monitoring Vaccination monitoring conducted with the aim of interrupting the measles outbreak in the State of Ceara, Brazil, in 2015. METHODS: this was a descriptive study using data taken from 52,216 vaccination cards of children aged from 6 months to less than 5 years and data on vaccination coverage, homogeneity, and reasons for non-vaccination extracted from the National Immunization Program Information System (SI-PNI). RESULTS: vaccination coverage against measles reached 96.7% in Ceara; of the 21 Regional Health Offices in the State, four did not reach minimum coverage of 95% for the first dose, and two for the second dose; 836 children (1.6%) were not vaccinated and 1,388 vaccine doses were not used. CONCLUSION: Measles vaccination campaigns enabled the immunization coverage goal in the State of Ceara to be surpassed, despite the considerable number of unvaccinated children found. PMID- 29995100 TI - Simple but not simpler: a systematic review of Markov models for economic evaluation of cervical cancer screening. AB - The aim of this study was to critically evaluate the quality of the models used in economic evaluations of screening strategies for cervical cancer prevention. We systematically searched multiple databases, selecting model-based full economic evaluations (cost-effectiveness analyses, cost-utility analyses, and cost-benefit analyses) of cervical cancer screening strategies. Two independent reviewers screened articles for relevance and performed data extraction. Methodological assessment of the quality of the models utilized formal checklists, and a qualitative narrative synthesis was performed. Thirty-eight articles were reviewed. The majority of the studies were conducted in high-income countries (82%, n=31). The Pap test was the most used screening strategy investigated, which was present in 86% (n=33) of the studies. Half of the studies (n=19) used a previously published Markov model. The deterministic sensitivity analysis was performed in 92% (n=35) of the studies. The mean number of properly reported checklist items was 9 out of the maximum possible 18. Items that were better reported included the statement of decision problem, the description of the strategies/comparators, the statement of time horizon, and information regarding the disease states. Compliance with some items of the checklist was poor. The Markov models for economic evaluation of screening strategies for cervical cancer varied in quality. The following points require improvement: 1) assessment of methodological, structural, heterogeneity, and parameter uncertainties; 2) model type and cycle length justification; 3) methods to account for heterogeneity; and 4) report of consistency evaluation (through calibration and validation methods). PMID- 29995102 TI - Outbreak of Guillain-Barre syndrome possibly related to prior Zika virus infection, Metropolitan Region of Recife, Pernambuco, Brazil, 2015. AB - OBJETIVO: to investigate the occurrence of GBS in the Metropolitan Region of Recife, PE, Brazil, 2015. METHODS: this was a descriptive study using data from the Hospital Information System, National Pharmaceutical Services Management System and interviews; GBS cases were classified according to Brighton criteria and prior infection according to laboratory and clinical criteria. RESULTS: in 2015, the number of GBS hospitalizations had a threefold increase in comparison to 2014. We investigated 44 confirmed or probable GBS cases, of which 18 had symptoms of Zika infection up to 35 days before the occurrence of GBS, mainly rash; one case was laboratory-confirmed for Zika virus infection and one death was registered. CONCLUSION: the findings reinforce a possible relationship between GBS and Zika infection, given the absence of increased GBS occurrence in previous dengue epidemic years, absence of chikungunya transmission records, presence of clinical manifestations compatible with infection and a laboratory confirmation. PMID- 29995103 TI - Data Integation Process: an information management model for multiple databases on traffic accidents in Brazil. AB - OBJECTIVE: to describe the management process for multiple traffic accident database integration applied in five state capital cities piloting the Life in the Traffic. METHODS: This is a descriptive study presenting the integration of traffic accident data for the year 2012 provided by multiple institutions and linked with data from the Mortality Information System Information and the Hospital Information System. RESULTS: integration of data from multiple institutions, creation of a single list of traffic accident victims and reclassification of accidents as serious or fatal. There was also an average increase of 87% in relation to the total number of victims counted before the use of the integration process. CONCLUSION: the results suggest that the Data Integration Process provides good results and can be adopted by other cities that need reliable information about traffic accidents to inform the planning, monitoring and evaluation of road safety actions. PMID- 29995104 TI - Magnitude and distribution of deaths due to hantavirus in Brazil, 2007-2015. AB - OBJECTIVE: to describe the magnitude and temporal and spatial distribution of hantavirus cases and deaths in Brazil between 2007 and 2015. METHODS: descriptive study with data from the Notifiable Diseases Information System (SINAN). RESULTS: 1,060 cases and 410 deaths were reported in the period; hantavirus lethality was 39.0%, varying according to month (from 28.6% in November to 50.7% in December), sex (37.4% in males and 42.6% in females), age (higher lethality in the elderly and children) and Brazilian regions (46.2% in the North, 32.9% in the South); most of the individuals who died lived in urban areas (58.3%) and were infected in rural area (70.2%). CONCLUSION: high lethality in certain population groups, months of the year and regions of Brazil point to low clinical suspicion of the disease in groups with low exposure, which may compromise proper case management. PMID- 29995105 TI - Dengue incidence and associated costs in the periods before (2000-2008) and after (2009-2013) the construction of the hydroelectric power plants in Rondonia, Brazil. AB - OBJECTIVE: to describe the incidence of dengue cases and associated costs in the period before and after the construction of the Jirau and Santo Antonio hydroelectric power plants (HPP), in Rondonia State, Brazil. METHODS: economic evaluation study, based on data from the Notifiable Diseases Information System (SINAN) and the National Hospital Information System (SIH/SUS); dengue direct costs were calculated and segmented regression analysis was carried out. RESULTS: dengue incidence mean was higher in the period after HPP construction (880.29/100,000 inhabitants) than before them (356.34/100,000 inhabitants) (p<=0.05); direct costs were estimated at US$3.47 million in the pre-construction period and US$7.1 million in the post-construction period. CONCLUSION: there was an increase in the incidence and direct costs of dengue after HPP construction; the environmental licensing process should include more detailed health impact assessments. PMID- 29995106 TI - Health education and promotion actions among teams of the National Primary Care Access and Quality Improvement Program, Rio Grande do Sul state, Brazil. AB - OBJETIVO: to investigate the provision of health education and promotion actions in primary care, and their association with demographic characteristics and Family Health Strategy (FHS) coverage in Rio Grande do Sul state, Brazil. METHODS: this is a cross-sectional study conducted with 816 teams that adhered to the 2012 Primary Care Access and Quality Improvement Program. RESULTS: the most frequent actions were directed towards people with diabetes (91.2%), hypertension (90.8%) as well as antenatal and postnatal care (84.6%). The least frequent were directed to wards crack, alcohol and other drug users (32.4%), anxiolytic/benzodiazepine users (20.3%), people with tuberculosis (31.4%) and leprosy (21.0%). The greatest provision of health promotion and education actions occurred in smaller municipalities and with greater Family Health coverage. CONCLUSION: actions aimed at the reproductive period and chronic morbidities were the focus of primary care. FHS implementation strengthens health promotion. PMID- 29995107 TI - Imbalance of gammadeltaT17/gammadeltaTreg cells in the pathogenesis of allergic asthma induced by ovalbumin. AB - We aimed to explore the imbalance between the T helper 17 gammadeltaT cells (gammadeltaT17) and the regulatory gammadeltaT cells (gammadeltaTreg) in asthmatic mice. Male Balb/c mice were randomly divided into the normal control group and the asthmatic model group. The asthmatic model group mice were intraperitoneally injected with the mixture of ovalbumin (OVA)/Al(OH)3 and then activated by exposure of the animals to OVA atomization. Airway hyperresponsiveness (AHR) was determined by a non-invasive lung function machine. Hematoxylin and eosin and Alcian blue-periodic acid Schiff staining were done for histopathological analysis. Interleukin (IL)-17 and IL-35 levels in bronchoalveolar lavage fluid were detected by ELISA. The percentage of IL-17+ gammadeltaT cells and Foxp3+ gammadeltaT cells in spleen cells suspension were detected and the transcription levels of RORgammat and Foxp3 in the lung tissue were determined. Compared with the normal control, the severity of airway inflammation and AHR were higher in the asthmatic mice. Furthermore, mice in the asthmatic group displayed significant increases of IL-17+ gammadeltaT cells, expression of IL-17A, and RORgammat, whereas control mice displayed marked decreases of Foxp3+ gammadeltaT cells, expression of IL-35, and transcription factor Foxp3. In addition, the mRNA expression of RORgammat was positively correlated with the percentage of IL-17+gammadeltaT cells, and the mRNA level of Foxp3 was positively correlated with the percentage of Foxp3+ gammadeltaT cells. The imbalance of gammadeltaT17/gammadeltaTreg in the asthmatic mice may contribute to the pathogenesis of OVA-induced asthma. PMID- 29995108 TI - Strontium ranelate inhibits wear particle-induced aseptic loosening in mice. AB - The imbalance between bone formation and osteolysis plays a key role in the pathogenesis of aseptic loosening. Strontium ranelate (SR) can promote bone formation and inhibit osteolysis. The aim of this study was to explore the role and mechanism of SR in aseptic loosening induced by wear particles. Twenty wild type (WT) female C57BL/6j mice and 20 sclerostin-/- female C57BL/6j mice were used in this study. Mice were randomly divided into four groups: WT control group, WT SR group, knockout (KO) control group, and KO SR group. We found that SR enhanced the secretion of osteocalcin (0.72+/-0.007 in WT control group, 0.98+/-0.010 in WT SR group, P=0.000), Runx2 (0.34+/-0.005 in WT control group, 0.47+/-0.010 in WT SR group, P=0.000), beta-catenin (1.04+/-0.05 in WT control group, 1.22+/-0.02 in WT SR group, P=0.000), and osteoprotegerin (OPG) (0.59+/ 0.03 in WT control group, 0.90+/-0.02 in WT SR group, P=0.000). SR significantly decreased the level of receptor activator for nuclear factor-kappaB ligand (RANKL) (1.78+/-0.08 in WT control group, 1.37+/-0.06 in WT SR group, P=0.000) and improved the protein ratio of OPG/RANKL, but these effects were not observed in sclerostin-/- mice. Our findings demonstrated that SR enhanced bone formation and inhibited bone resorption in a wear particle-mediated osteolysis model in wild-type mice, and this effect relied mainly on the down-regulation of sclerostin levels to ameliorate the inhibition of the canonical Wnt pathway. PMID- 29995109 TI - Genome sequence of a multidrug-resistant Corynebacterium striatum isolated from bloodstream infection from a nosocomial outbreak in Rio de Janeiro, Brazil. AB - Multidrug-resistant (MDR) Corynebacterium striatum has been cited with increased frequency as pathogen of nosocomial infections. In this study, we report the draft genome of a C. striatum isolated from a patient with bloodstream infection in a hospital of Rio de Janeiro, Brazil. The isolate presented susceptibility only to tetracycline, vancomycin and linezolid. The detection of various antibiotic resistance genes is fully consistent with previously observed multidrug-resistant pattern in Corynebacterium spp. A large part of the pTP10 plasmid of MDR C. striatum M82B is present in the genome of our isolate. A SpaDEF cluster and seven arrays of CRISPR-Cas were found. PMID- 29995110 TI - Structural insights into Plasmodium falciparum nicotinamide mononucleotide adenylyltransferase: oligomeric assembly. AB - The biochemical pathways involved in nicotinamide adenine dinucleotide (NAD) biosynthesis converge at the enzymatic step catalysed by nicotinamide mononucleotide adenylyltransferase (NMNAT, EC: 2.7.7.1). The majority of NMNATs are assembled into homo-oligomeric states that comprise 2-6 subunits. Recently, the NMNAT of Plasmodium falciparum (PfNMNAT) has been identified as a pharmacological target. The enzymatic characterisation, cellular location, and tertiary structure of the PfNMNAT protein have been reported. Nonetheless, its quaternary structure remains to be explored. The present study describes the oligomeric assembly of the 6 x His-PfNMNAT recombinant protein using immobilised metal affinity chromatography coupled with size exclusion chromatography (SEC) and native protein electrophoresis combined with Ferguson plot graphing. These chromatographic approaches resulted in the elution of an active monomer from the SEC column, whereas the Ferguson plot indicated a dimeric assembly of the 6 x His PfNMNAT protein. PMID- 29995111 TI - Frugivorous Flies (Diptera: Lonchaeidae) Hosts in the State of Bahia, Brazil and registers of new bitrophic interactions. PMID- 29995112 TI - Assessment of serotonergic system in formation of memory and learning. AB - We evaluated the involvement of the serotonergic system on memory formation and learning processes in healthy adults Wistar rats. Fifty-seven rats of 5 groups had one serotonergic nuclei damaged by an electric current. Electrolytic lesion was carried out using a continuous current of 2mA during two seconds by stereotactic surgery. Animals were submitted to learning and memory tests. Rats presented different responses in the memory tests depending on the serotonergic nucleus involved. Both explicit and implicit memory may be affected after lesion although some groups showed significant difference and others did not. A damage in the serotonergic nucleus was able to cause impairment in the memory of Wistar. The formation of implicit and explicit memory is impaired after injury in some serotonergic nuclei. PMID- 29995113 TI - Cadmium tolerance of Typha domingensis Pers. (Typhaceae) as related to growth and leaf morphophysiology. AB - Typha domingensis (cattail) is a native macrophyte known by its capacity to tolerate several heavy metals effects and the potential use for phytoremediation. However, in despite that cadmium (Cd) is one of the most toxic pollutants; its effects in T. domingensis biology remain uninvestigated. Thus, the objective of this study was to study the tolerance of T. domingensis to cadmium contamination by evaluating its growth, Cd uptake, leaf anatomy and gas exchange. The experiment was designed using three cadmium concentrations (0, 10 and 50 uM) and ten replicates for 90 days. The cadmium uptake, growth, gas exchange, chlorophyll content and leaf anatomy were evaluated. Data was submitted to ANOVA and Scott Knott test for P<0.05. Typha domingensis accumulates Cd proportionally to its concentration on the solution and the content of this metal was higher in roots as compared to shoots. Plants showed no significant modifications on growth parameters such as the biomass production, number of leaves, number of clones and the biomass allocation to organs. The photosynthesis, transpiration and chlorophyll content were not modified by Cd. Most anatomical traits evaluated were not modified by the metal but the stomatal density and the proportion of vascular tissues were reduced under 50 uM of Cd. In despite, the leaf anatomy showed no toxicity evidences for any Cd level. The absence of growth reduction and the stability of anatomical and physiological traits give insight about the Cd tolerance of this species. Therefore, T. domingensis is able to overcome Cd toxicity and shows potential for phytoremediation. PMID- 29995114 TI - Metazoan parasites of the lambari Astyanax altiparanae collected in the Batalha River, State of Sao Paulo, Brazil. AB - Here we conduct a qualitative and quantitative analysis of ectoparasites and endoparasites of Astyanax altiparanae (Garutti & Britski, 2000), popularly known as lambari-do-rabo-amarelo collected from the Batalha River, State of Sao Paulo, Brazil. Of the 67 specimens of A. altiparanae, 52 were parasitized by at least one parasitic metazoan species. The following metazoan parasites were found: Monogenea, Digenea and Nematoda. The monogenetic Diaphorocleidus sp. was the predominant species, presenting a higher frequency of dominance, prevalence and mean abundance. However, the monogenean Trinigyrus sp. was the one with the highest mean intensity value. All parasites showed aggregate distribution pattern. The parasitic community of A. altiparanae was characterized by low diversity, low richness and low uniformity. The digenetic Rhipidocotyle santanaensis is recorded for the first time in A. altiparanae, in the same way, this parasite is being registered for the first time in the Batalha River. PMID- 29995115 TI - Understanding mammary activity in red-rumped agouti and implications for management and conservation of this Neotropical game species. AB - The red-rumped agouti (Dasyprocta leporina) produces precocial young and is the most hunted and farmed game species in several Neotropical countries. An understanding of the reproductive biology, including the relationship between litter size and teat functionality is crucial for conservation management of this animal. In precocial mammals, as the red-rumped agouti, maintaining maternal contact to learn foraging patterns may be more important than the energy demands and nutritional constraints during lactation and suckling may not play important roles when compared to altricial mammals. Therefore, in this study we evaluated the relationship between mammary functionality with litter size, litter birth weight, and parturition number in captive red-rumped agouti. Functionality was assessed by manual palpation of teats from un-sedated females (N=43). We compared the average birth weight of all newborns, male newborns and female newborns among agoutis with different litter sizes and different parturitions by one way ANOVA's, while Pearson's Chi-squared tests were used to detect relationships between teat functionality, litter size, and parturition number. Parturition number had no effect on the mean birth weight of all young (F0.822, P > 0.05), male young (F0.80, P > 0.05) or female young (F0.66, P > 0.05) in the litters. We found (i) no significant correlations (P > 0.05) between teat functionality and litter size and (ii) no significant correlations (P > 0.05) between teat functionality and parturition number. This suggests that whilst all teat pairs were functional, functionality was a poor indicator of litter size; suggesting that female agouti young may not have a high dependency on maternal nutrition; an possible evolutionary strategy resulting in large wild populations; hence its popularity as a game species. PMID- 29995116 TI - Occasional release of guppy, Poecilia reticulata (Cyprinodontiformes, Poeciliidae) in Upper Paraguay River Basin, Mato Grosso State: a new threat to rivers forming the Brazilian Pantanal? PMID- 29995117 TI - Creation of a childhood glaucoma registry database. AB - PURPOSE: The aim is creation of a database to register patients diagnosed with childhood glaucoma. Information collection and storage will utilize a digital platform that permits multiple centers to register patients. This registry will be an important tool to evaluate and group patient profiles, thus allowing identification of risk factors, estimating prevalence, and recruiting participants in future studies. METHODS: An online form was designed at the Department of Ophthalmology and Visual Sciences of the Federal University of Sao Paulo to create a registry of patients diagnosed with congenital glaucoma. In addition, a pilot study was conducted in the same institution to validate the Google Forms platform that comprises the registry questionnaire. RESULTS: Data can be entered online and stored in the cloud. The database allows the acquisition and storage of epidemiological and clinical data, detection of patterns, and evaluation of the current treatment of children with childhood glaucoma. The data from multiple centers can be combined as collection in online and storage is in the cloud. The form is comprehensive and includes social data, gestational history, family history, clinical data on entering the center, and the treatment received. CONCLUSIONS: Google Forms is a useful tool for collecting and analyzing statistical data, facilitating the process of registering patients, and analyzing information. Using the online questionnaire, it will be possible to create a multicenter online database that allows identification of risk factors and evaluation of the outcome of interventions and treatment. PMID- 29995118 TI - Peripapillary choroidal thickness in contralateral eyes after evisceration of diseased eyes. AB - PURPOSE: To evaluate peripapillary choroidal thickness changes in contralateral eyes of patients who had undergone evisceration of their diseased eyes. METHODS: In this retrospective study, peripapillary choroidal thickness parameters in 34 eyes of 34 patients who had undergone diseased-eye evisceration between March 2014 and May 2016 were evaluated using spectral domain optical coherence tomography. The scans were manually delineated to identify the principal surfaces of Bruch's membrane, the Bruch's membrane opening, and the anterior sclera. Peripapillary choroidal thickness was measured between the Bruch's membrane and the anterior sclera at increasing distance away from the Bruch's membrane opening. The mean peripapillary choroidal thickness values in the contralateral eyes of the patients and those of the control group were compared. RESULTS: The mean peripapillary choroidal thickness was higher in the contralateral eyes of the patients compared with that of normal eyes at all distances from the Bruch's membrane opening. CONCLUSION: Increased peripapillary choroidal thickness was noted in the contralateral eyes of the patients, potentially resulting in a thicker choroid. Although further investigation is required to determine the cause, these findings indicate the presence of a compensatory factor in the contralateral eyes. PMID- 29995119 TI - Surgical outcomes of rhegmatogenous retinal detachment associated with ocular toxoplasmosis. AB - PURPOSE: To evaluate the anatomical and functional outcomes of surgical treatment of retinal detachment secondary to ocular toxoplasmosis. METHODS: A retrospective analysis of data from patients who had undergone vitreoretinal surgery for retinal detachment secondary to ocular toxoplasmosis was conducted. The parameters that were analyzed include surgical procedures, anatomical outcomes, visual acuity, and postoperative complications. RESULTS: This study included 22 patients, of which 13 were female (59.1%). The mean age was 28.5 years (SD +/- 14.5, range 12-78 years) and the follow-up period varied from 1 to 163 months (mean 64 months). The mean baseline best-corrected visual acuity (BCVA) was 2.0 logMAR (SD +/- 1.0). A total of 31 surgeries were performed, and the retina was reattached in 15 patients (68.2%) immediately after the first surgery and in 20 patients (90.9%) at a later point. The mean postoperative BCVA improved to 1.3 logMAR (SD +/- 0.9) (p<0.05). Nineteen patients (86.4%) underwent cataract surgery with intraocular lens implant, and 12 patients (60.0%) underwent silicone oil removal. Five patients (22.7%) exhibited elevated intraocular pressure, and 1 patient (4.5%) developed hypotonia. CONCLUSION: Surgical treatment of retinal detachment secondary to ocular toxoplasmosis resulted in considerable anatomical and functional improvement. Although PPV with silicone oil injection demonstrated the best outcomes, it is not reasonable to conclude that this is the best surgical approach given the small number of patients included in this study. PMID- 29995120 TI - Frequency of ocular diseases among recipients of disability benefits in the metropolitan region of Recife, Brazil. AB - PURPOSE: To identify the frequency of ocular diseases among recipients of disability benefits in the metropolitan region of Recife, Brazil. METHODS: A review was performed of 217,221 cases of disability benefits granted between 2010 and 2015 by the executive managerial department of the Brazilian National Institute of Social Security (Instituto Nacional do Seguro Social [INSS]) in Recife, which encompasses 14 municipalities of the metropolitan region, including the capital. The frequencies of the identified cases of ocular morbidity were then determined according to their group in the International Classification of Diseases, 10th Revision (ICD-10), their cause, the age, sex, and income of the recipient, and the type and duration of the benefit. RESULTS: Of all disability benefits granted, 5,324 (2.5%) were due to ocular disease, the majority (91.1%) consisting of sick pay. Most of the beneficiaries (64.6%) were males, were 20 to 59 years of age, and 61.2% earned the minimum wage or less. The principal ocular diseases for which sick pay benefits were granted were cataract (24.5%), conjunctivitis (21.1%), and pterygium (8.8%). Blindness and low vision were the principal ocular diseases in cases of accident indemnity and disability retirement. CONCLUSIONS: The results highlight the magnitude of the problem of ocular diseases to the social security system, with serious economic and social losses, and emphasize the need for measures aimed at their prevention. Moreover, integration between the national departments of health and social security needs to be improved. PMID- 29995121 TI - Comparison of the efficacy of 0.03% tacrolimus eye drops diluted in olive oil and linseed oil for the treatment of keratoconjunctivitis sicca in dogs. AB - OBJECTIVE: To compare the efficacy of 0.03% tacrolimus eye drops diluted in two different vehicles (linseed oil and olive oil) for the treatment of keratoconjunctivitis sicca (KCS) in dogs. METHODS: This study included 60 dogs. Of this group, 20 were healthy and allocated to the control group, and 40 were diagnosed with bilateral KCS and randomly allocated to either the TO (tacrolimus in olive oil) or the TL (tacrolimus in linseed oil) groups. Ophthalmic examinations, Schirmer Tear Test-1 (STT-1), Tear Film Break-up Time (TBUT) and Fluorescein Test (FT) were carried out monthly, along with cytological and histopathological examinations at the beginning and end of the study. RESULTS: The clinical signs, corneal ulcers, Schirmer Tear Test-1 values, and Tear Film Break-up Time values improved in both groups after one month of treatment. Cytological examination at the end of the study showed decreased lymphocytes, neutrophil, metaplastic, and squamous cell counts in both groups, while the histopathological analysis showed decreases in lymphocytes and neutrophils and an increase in goblet cell density (cells/mm2). The decreases in neutrophil count were more significant (p<0.05) in the TL group for both types of examination. CONCLUSION: In sum, 0.03% tacrolimus eye drops diluted in olive oil and linseed oil were effective in the treatment of keratoconjunctivitis sicca. None of the evaluated parameters differed significantly between the two groups, except for neutrophil count which was significantly lower in the TL group. Thus, linseed oil may be considered as an alternative diluent for tacrolimus eye drops. PMID- 29995122 TI - A new surgical technique for scleral fixation using a "knot ball" for scleral fixated intraocular lenses: impact on clinical outcomes. AB - PURPOSE: Scleral fixation surgery is a pivotal procedure that depends on the availability of robust and innovative surgical fixation methods. There continues to be a need for innovation in suture fixation techniques, particularly for intraocular lens implantation. METHODS: We conceived and designed a "knot ball" scleral fixation technique for suture burial in a retrospective sample of 108 patients with primary (n=40) or secondary (n=68) scleral-fixated intraocular lens. Importantly, our technique did not require additional scleral flap or tunnel procedures. We evaluated pre- and postoperative best-corrected visual aquity (BCVA) and postoperative complications. All data were analyzed and compared between groups. RESULTS: The preoperative mean BCVA improved significantly in both groups using the "knot ball" fixation technique (p<0.01). The extent of the improvement in the best-corrected visual acuity and late complications one month post-surgery were not significantly different between the groups (p>0.05). These clinical outcomes were consistent with those described in the ophthalmology literature. CONCLUSION: A "knot ball" scleral fixation technique is reported; to the best of our knowledge, this is the first report of such a technique, which offers a less invasive and simplified surgical procedure for transscleral fixation of scleral-fixated intraocular lenses. Moreover, the technique appears to display similar effectiveness and safety compared with existing scleral fixation techniques. We suggest that the "knot ball" technique warrants further research focus and clinical evaluation in future studies. PMID- 29995123 TI - Corneoscleral contact lenses fitting on irregular corneas after laser-assisted in situ keratomileusis. AB - PURPOSE: We aimed to describe the outcomes of corneoscleral contact lens fitting with multi-aspherical geometry designs in patients with irregular corneas after laser-assisted in situ keratomileusis (LASIK). METHODS: This was a retrospective series of 18 patients (age, 26-38 years) selected from an eye clinic database. Participants were required to have unsatisfactory visual acuity with their current contact lenses or spectacles after LASIK for myopia correction. All patients were fitted with corneoscleral contact lenses designed to correct corneal surface irregularities. A diagnostic trial set was used for fitting, and assessments were performed according to a standardized methodology. Subjective comfort, visual acuity, central corneal thickness, endothelial cell count, and corneal-compensated intraocular pressure were evaluated. The follow-up period was one year. RESULTS: Contact lens use was discontinued in 3 patients, thus leaving 24 eyes from 8 females and 7 males for analysis. The fitting characteristics were optimal in terms of lens position and movement. Statistically significant improvements were found in the best spectacle-corrected vision from before fitting to the visual acuity after fitting (p<0.001). Moreover, the patients reported high subjective comfort ratings and usage times (12.98 +/- 2.3 hours/day). After one year of wear, visual acuity, subjective comfort, and usage time were maintained. No statistically significant adverse changes developed in the corneas over this period. CONCLUSION: Corneoscleral contact lenses with a multi-aspherical geometry design provide optimal visual acuity, improved comfort, and prolonged usage times in patients with irregular corneas after LASIK. PMID- 29995124 TI - Antiscarring effect of intraoperative bevacizumab in experimental glaucoma filtration surgery. AB - PURPOSE: To determine the effects of bevacizumab and mitomycin C alone and in combination on intraocular pressure and the scarring process after modified glaucoma filtration surgery in rabbits. METHODS: The rabbits underwent modified glaucoma filtration surgery and were allocated into three groups to receive intraoperative treatment with subconjunctival bevacizumab (group A), mitomycin C and subconjunctival bevacizumab (group B), or mitomycin C (group C). Intraocular pressure was measured immediately preoperatively and on postoperative days 8, 14, 17, 21, 26, and 30. The scarring process was assessed 30 days after surgery by tissue section using hematoxylin and eosin, Masson's trichrome, and picrosirius. Expression of vascular endothelial growth factor (VEGF) was assessed by immunohistochemical analyses. All analyses were performed by a masked observer. RESULTS: Animals in group A had higher intraocular pressure than those in groups B and C (p<0.01). Intraocular pressure did not differ significantly between groups B and C. The amount of fibrosis was similar with all stains used: group A had the highest level of fibrosis compared with groups B and C (p>0.05). There was less VEGF expression in group A than in groups B and C (p<0.01). Groups B and C did not differ in VEGF expression. CONCLUSION: Mean intraocular pressure and fibrosis were lower in animals receiving bevacizumab in combination with mitomycin C but did not differ from values in animals receiving mitomycin C alone. Inhibition of VEGF was greater when bevacizumab was used alone than when bevacizumab was combined with mitomycin C. PMID- 29995125 TI - Effects of sub-Tenon's triamcinolone injections in patients with uveitis. AB - PURPOSE: To evaluate the response to sub-Tenon's triamcinolone injection in patients with uveitis. METHODS: We studied 28 eyes with macular edema associated with controlled uveitis. We administered sub-Tenon's injection of triamcinolone and followed the patients for 180 days to analyze the positive effects (improvement of macular edema and visual acuity) and monitor the possible adverse effects. This prospective study was conducted at the Department of Ophthalmology, Hospital de Clinicas de Porto Alegre, Brazil. RESULTS: We observed improvement in macular edema in 86% of patients. The mean central macular thickness at each time point of assessment was 432.22, 298.80, 286.37, 267.49, 253.87, and 253.49 mm at baseline (before sub-Tenon's injection of triamcinolone), 15 days after the procedure, at 30 days, at 60 days, at 90 days, and at 180 days, respectively. The mean reduction in retinal thickness was 30.8%, 33.7%, 38.11%, 41.2%, and 41.35% at 15, 30, 60, 90, and 180 days of follow-up, respectively. Visual acuity also improved in 85.7% of patients, with a mean improvement of 1.36, 1.93, 2.23, 2.26, and 2.30 lines gained on the Early Treatment Diabetic Retinopathy Study chart at 15, 30, 60, 90, and 180 days of follow-up, respectively. No statistically significant increases in intraocular pressure and conjunctival abnormalities were caused by the procedure, and no other adverse effects were observed. Overall, the results of this study were similar to those described in the literature. CONCLUSIONS: Sub-Tenon's injection of triamcinolone provides reduced macular thickness and improvement in visual acuity with no significant adverse effects and is therefore an effective and safe procedure for the treatment of sequelae of uveitis. PMID- 29995126 TI - Scleral necrosis in patients with posterior uveal melanomas evaluated by transcleral fine needle aspiration biopsy and treated by 125I plaque. AB - PURPOSE: To evaluate the incidence, potential correlation with transcleral fine needle aspiration biopsy, and treatment of scleral necrosis in patients with posterior uveal melanomas treated by 125I plaque radiotherapy and assessed by transcleral fine needle aspiration biopsy. METHODS: We per-formed a retrospective review of posterior uveal melanoma treated by 125I plaque radiotherapy at a single academic institution between July 2006 and July 2013. Consecutive patients diagnosed with a posterior uveal melanoma during the study period that had an anterior margin at or anterior to the equator who were evaluated by transcleral fine needle aspiration biopsy prior to 125I plaque radiotherapy were included. The main outcome measure was development of scleral necrosis, and the secondary outcome was treatment of this complication. Statistical analysis included computation of conventional descriptive statistics, cross-tabulation and chi square tests of potential factors related to the development of scleral necrosis, and summarizing of treatment approaches and results. The incidence of treatment of scleral necrosis was calculated using the Kaplan-Meier method. RESULTS: During the 7-year study period, 87 posterior uveal melanomas were evaluated by transcleral fine needle aspiration biopsy and treated by 125I plaque radiotherapy. The median largest basal diameter of the tumor was 13.3 mm, and the median thickness was 6.8 mm. Eight patients (9.2%) developed scleral necrosis during follow-up. Thicker tumors (> 6.5 mm) were more likely to develop scleral necrosis (n=7) than thinner tumors (p=0.05). The median interval between 125I plaque radiotherapy and detection of scleral necrosis was 19.1 months. The overall cumulative probability of scleral necrosis was 6.2% at 6 months and 14.3% at 24 months, subsequently remaining stable. For thicker tumors, the probability of scleral necrosis was 23.5% at 45.4 months. Five patients were treated by scleral patch graft (62.5%) and three by observation (37.5%). One patient underwent enucleation after two failed scleral patch attempts and recurrent scleral necrosis. The mean follow-up period for patients with scleral necrosis was 34.5 months. CONCLUSIONS: Thicker posterior uveal melanomas are more likely to develop scleral necrosis after 125I plaque radiotherapy and transcleral fine needle aspiration biopsy. While observation is sufficient for managing limited scleral necrosis, scleral patch graft is a viable alternative for eye preservation in extensive scleral necrosis. PMID- 29995127 TI - Classic homocystinuria and keratoconus: a case report. AB - Homocystinuria is one of a group of genetic disorders called inborn errors of metabolism. It is characterized by a deficiency of the enzyme that converts homocysteine to cystathionine. Keratoconus is an ophthalmologic condition characterized by thinning of the corneal stroma, which causes the cornea to assume a conical shape. There is little information in the scientific literature about the association between keratoconus and homocystinuria. We believe that a collagen cross-linking defect may be the key to understand the connection between these two conditions. This case report describes a 38-year-old male patient with a diagnosis of classical homocystinuria since age 13. At the age of 16, he received a diagnosis of asymmetrical keratoconus when referred for lensectomy with vitrectomy of his left eye. To the best of our knowledge, this is the first report of a patient with simultaneous homocystinuria and keratoconus. PMID- 29995128 TI - Pseudomonas aeruginosa-induced bilateral endophthalmitis after bilateral simultaneous cataract surgery: case report. AB - Bilateral simultaneous cataract surgery (BSCS) has gained popularity among eye surgeons in many countries. This study examines the case of a 77-year-old patient who developed bilateral Pseudomonas aeruginosa endophthalmitis following bilateral simultaneous cataract surgery. Immediate bilateral vitrectomy and intravitreal antibiotics injection were performed. Ultimately, both eyes were eviscerated due to pain refractory to treatment and no light perception. PMID- 29995129 TI - Chronic lacrimal canaliculitis - the answer to a three-year history of red eye. AB - Chronic lacrimal canaliculitis is a rare infection of the lacrimal system, and can lead to misdiagnosis due to its overlapping presentation to other common entities. The authors report a case of lacrimal canaliculitis with a three-year history of recurrent unilateral red eye and mucopurulent discharge. Here, we describe the clinical course, surgical details, and microbial analysis of canaliculitis infection. PMID- 29995130 TI - Focal phototherapeutic keratectomy for the treatment of apical leucoma syndrome. AB - The following report describes a case of apical leucoma syndrome after hyperopic photorefractive keratectomy following hyperopic laser in situ keratomileusis and the subsequent treatment of this complication with focal phototherapeutic keratectomy. The patient underwent focal transepithelial phototherapeutic keratectomy of 70 mm ablation and 1.5 mm diameter after pupil and ablation offset correction. After 1 year, significant improvement in vision was observed and only slight residual opacity remained on biomicroscopy and optical coherence tomography. Focal phototherapeutic keratectomy was effective and safe for the treatment of this complication. PMID- 29995131 TI - Anticoagulants and antiplatelet drugs during cataract surgery. AB - Patients undergoing cataract surgery are generally elderly, and many take drugs with systemic effects. The surgeon must be aware of the risks of continuing or discontinuing such medications perioperatively. Antiplatelet drugs and anticoagulants, prescribed to reduce the incidence of thromboembolic events, are often used in this population. This paper aims to review the perioperative use of antiplatelet and anticoagulant drugs in the setting of cataract surgery. Topical or intracameral anesthesia is preferred over anesthesia injected with needles. Aspirin can be safely continued in patients undergoing cataract surgery. Warfarin has been extensively studied, and the risk of hemorrhage associated with cataract surgery is low if the international normalized ratio is in the therapeutic range. Only a few studies of direct oral anticoagulants are available, and therefore no definite recommendations regarding those agents can be made at this time. Anesthesia in cataract surgery carries a low risk, even for patients taking anticoagulant or antiplatelet drugs. The discontinuation of this class of drugs before cataract surgery may increase the risk of thromboembolism. PMID- 29995132 TI - Effective dose of bevacizumab for the treatment of retinopathy of prematurityResponse: effective dose of bevacizumab for the treatment of retinopathy of prematurityComputer-assisted digital image analysis of plus disease in retinopathy of prematurityRetinopathy of prematurityWhich dose of bevacizumab is more effective for the treatment of aggressive posterior retinopathy of prematurity: lower or higher dose? PMID- 29995133 TI - From ARVO 2018. PMID- 29995134 TI - Occurrence of aborted seeds in the cleistogamous flowers of Janusia guaranitica (A.St.-Hil.) A.Juss. (Malpighiaceae). PMID- 29995135 TI - Identification and mapping of real acupoints in the anatomical topography of Boa constrictor. AB - Acupuncture is a therapy of the traditional Chinese medicine technique, which over the years has been widespread in the West. Defined as a needle-point treatment technique (acupoints), exactly preconfigured in the body to produce a specific physiological reaction to restore the balance between the function of conflicting states and homeostasis, alternating states of energy and thus maintain the ideal organ and body organization. Thus, the objective of this study was to map and describe the main points of acupuncture in the species Boa constrictor , and their indications to promote the balance of this species. The unprecedented result of the mapping was the discovery of specific acupoints with individual location indications without distribution in specific meridians and dispersedly distributed in the body. PMID- 29995136 TI - Owlet moths (Lepidoptera: Noctuoidea) associated with Bt and non- Bt soybean in the brazilian savanna. AB - The use of GMO expressing Bt toxin in soybean production has increased significantly in the last years in Brazil in order to manage the damage caused by lepidopteran pests. In this study, we compared the richness and abundance of owlet moths (Noctuoidea) associated with Bt and non-Bt soybean. We determined the temporal variations as a function of phenology, and correlated the population variations of the most common species with meteorological variables. The research was conducted at the experimental area of Embrapa Cerrados. The collection method used was differentiated being suppressive and absolute. A total of 13 species were collected, of which eight occurred on Bt soybeans. The most representative taxa were Chrysodeixis includens (72.87%), Anticarsia gemmatalis (18.17%) and Spodoptera spp (5.22%). The number of larvae belonging to species targeted by the Bt technology was 10 times lower on Bt than on non-Bt soybeans. Utetheisa ornatrix and Elaphria deltoides were recorded on soybean for the first time, observing larvae of both species in non-Bt soybean and those of U. ornatrix also in Bt soybean. Only A. gemmatalis larvae correlated (p <0.05) negatively with precipitation. This study provided field information on the abundance and species richness of owlet moths on non-Bt soybeans, associated with the effects of Bt soybean. When considering the different levels of infestation between cultivars as a criterion, larvae monitoring is of substantial importance in order to develop the lost control program. PMID- 29995137 TI - COLOSTRUM FAT AND ENERGY CONTENT: EFFECT OF GESTATIONAL AGE AND FETAL GROWTH. AB - OBJECTIVE: To determine whether fat content and energy value change in colostrum according to gestational age and fetal growth. METHODS: Cross-sectional study with mothers of preterm and term infants born in a tertiary center in 2015-2016. Inclusion criteria: single pregnancy, absence of diabetes, chorioamnionitis and mastitis, no use of illicit drugs or alcohol, without fetal congenital malformation or infection. Four groups were formed according to gestational age and fetal growth: preterm infants small for gestational age (PT-SGA; n=33) and appropriate for gestational age (PT-AGA; n=60), term infants small for gestational age (T-SGA; n=59) and appropriate for gestational age (T-AGA; control, n=73). Colostrum was collected between 24-72 hours postpartum. Gestational and birth variables were analyzed. Outcome variables were: fat content in colostrum (evaluated by crematocrit method) and estimated energy value. Chi-square or Fisher exact tests, ANOVA, and multivariable linear regression were used for comparison among groups. RESULTS: Mean gestational age was 34 weeks in preterm infants and 39 weeks in term neonates. Crematocrit did not differ between groups, with mean values varying between 3.3 and 4.0%; estimated energy value was 52 to 56 kcal/dL. Crematocrit >=4% was more frequent in the T-SGA group. Only in the PT-SGA group there was a correlation between crematocrit and body mass index of the mother. CONCLUSIONS: The fat content and energy value of colostrum did not change according to gestational age or fetal growth. PMID- 29995139 TI - LEUKOENCEPHALOPATHY WITH EVANESCENT WHITE MATTER: A CASE REPORT. AB - OBJECTIVE: To describe the case of a child diagnosed with leukoencephalopathy with vanishing white matter (LVWM), a rare genetic disease with autosomal recessive inheritance pattern. CASE DESCRIPTION: A 5-month-old male child started to refuse breast-feeding, showing somnolence and signs of dehydration,with dry mouth, increasing body temperature and adipsy. As days went by, the symptoms got worse. The infant was very sleepy and was transferred to the intensive care unit, where he stayed for one week. At this time, a signal alteration with hyper attenuated T2 predominance was identified in the magnetic resonance imaging, compromising the white matter, which had diffuse and symmetrical aspect. At this time, the infant started to present seizures. When the infant was 11 months old, he was diagnosed with tonsillitis and presented recurrent fever peaks and extreme sleepiness. After hospital admission, the infant progressed to a comatose state and died. The diagnosis of LVWM was confirmed in examinations performed after death. As a late diagnosis, a genetic disease was identified with a mutation in one of the five genes responsible for the codification of complex eukaryotic translation initiation factor 2B (eIF2B), involved with the control of the protein translation and which is described as pathogenic in individuals with LVWM. COMMENTS: LVWM is a hereditary brain disease that occurs primarily in children. The disease is chronic and progressive, with additional episodes of rapid deterioration, as shown in the present case report. PMID- 29995138 TI - ASSOCIATION BETWEEN PERCEPTION OF SLEEP QUALITY AND ASSIMILATION OF CONTENT COVERED IN CLASS. AB - OBJECTIVE: To analyze the association between self-perception of sleep quality and assimilation of content covered in classes by adolescents. METHODS: Epidemiological cross-sectional study conducted with 481 high-school students (14 to 19 years), both genders, enrolled in public schools in the city of Caruaru, Pernambuco, and selected by random cluster sampling strategy. Analyses were conducted using the Chi-square test and binary logistic regression. RESULTS: 44.1% of the adolescents reported learning difficulties during classes, 77.1% slept less than eight hours per day, and 28.9% had a bad perception of their sleep quality. Young people who studied at least one extra hour per day out of school had less difficulty in assimilating class content (OR=0.34; 95%CI 0.19 0.58). We also found that participants who reported a bad perception of sleep quality were more likely to have learning difficulties at school (OR=1.73; 95%CI 1.13-2.65) regardless of gender, age, school shift, study time out of school, and sleeping hours. CONCLUSIONS: Perception of sleep quality was associated with learning difficulties at school regardless of the number of sleeping and study hours. PMID- 29995140 TI - GRANULOMATOUS PERIORAL DERMATITIS WITH EXTRA-FACIAL INVOLVEMENT IN CHILDHOOD: GOOD THERAPEUTIC RESPONSE WITH ORAL AZITHROMYCIN. AB - OBJECTIVE: To present a case of granulomatous perioral dermatitis (GPD) with extra-facial involvement and good response to short-term treatment with oral macrolide. CASE DESCRIPTION: A 9-year-old girl presented with exuberant GPD with extra-facial involvement. During follow-up, she received multiple ineffective therapies, but showed significant improvement of the lesions after the use of azithromycin for five days. COMMENTS: GPD is an inflammatory dermatological condition represented by papulo-erythematous eruptions on perioral, nasal and periorbital regions, more prevalent in children and adolescents. It rarely extends to the genital region, trunk, and extremities, which characterizes its extra-facial manifestation. Its etiology is unknown, but it seems to have a correlation with the use of topical corticosteroids and other agents. PMID- 29995141 TI - THE BABY-LED WEANING METHOD (BLW) IN THE CONTEXT OF COMPLEMENTARY FEEDING: A REVIEW. AB - OBJECTIVE: To review the scientific findings on the baby-led weaning method (BLW) in the context of complementary feeding. DATA SOURCES: Two independent examiners searched the Medical Literature Analysis and Retrieval System Online (MEDLINE)/PubMed database in August 2016. No time-period was defined for the publication dates. The following descriptors were used: "baby-led weaning" OR "baby-led" OR "BLW". Inclusion criteria were: original studies that were available in English, and which addressed the BLW method. Exclusion criteria were: references in other languages, opinion articles and literature reviews, editorials and publications that did not elaborate on the intended subject. Of the 97 references identified, 13 were included in the descriptive synthesis. DATA SYNTHESIS: The BLW group of babies, when compared to the traditional eating group, were less prone to being overweight, less demanding of food, and ate the same foods as the family. The number of choking episodes did not differ between groups. Mothers who opted for the implementation of BLW had higher levels of schooling, held managerial positions at work, and were more likely to have breastfed until the sixth month of the child's life. Concerns were raised about messes made during meals, wasting food, and choking, but most of the mothers recommended adopting the method. Health professionals were hesitant to indicate this method. CONCLUSIONS: BLW was recommended by mothers who followed the method with their own children. However, concerns have been reported, which, coupled with professionals' fears about the inability of infants to self-feed, reflect a lack of knowledge about the method. PMID- 29995142 TI - CLINICAL AND EPIDEMIOLOGICAL CHARACTERISTICS AND SURVIVAL OUTCOMES OF CHILDREN WITH NEUROBLASTOMA: 21 YEARS OF EXPERIENCE AT THE INSTITUTO DE ONCOLOGIA PEDIATRICA, IN SAO PAULO, BRAZIL. AB - OBJECTIVE: To describe the clinical and epidemiological characteristics and survival outcomes of children with neuroblastoma (NB) treated at a pediatric oncology center from 1991 to 2012. METHODS: A retrospective study with clinical and epidemiological data from 258 patients with neuroblastoma treated at a pediatric oncology center from 1991 to 2012, using medical records. RESULTS: The average age of the children at diagnosis was 40.5+/-46.4 months with a median age of 28.9 months (interquartile range 42.2). The male:female ratio was 1.3:1, and 1% of the patients were asymptomatic. The most frequent manifestations were: fever (25%), abdominal pain (22%), abdominal mass (19%), and bone pain (19%). The mean time from symptom onset to diagnosis was 3.0+/-4.8 months. The most common location of the tumor was the abdomen (63%). Metastases occurred in the bone marrow (37%) and in the bone (33%). Overall survival (OS) and event-free survival (EFS) in five years were 62 and 52%, respectively. The main cause of death was the progression of the disease (72%). CONCLUSIONS: The clinical features of children with neuroblastoma are variable and mostly nonspecific, which makes clinical recognition difficult and, in general, too late. In children less than 5 years old, with an abdominal mass and/or bone pain, irritability, and a fever from an unknown cause, neuroblastoma should be considered as a possible diagnosis. PMID- 29995143 TI - HIGH-FLOW NASAL CANNULA POST-TRACHEAL EXTUBATION IN A CHILD WITH UPPER AIRWAY OBSTRUCTION: CASE REPORT. AB - OBJECTIVE: To report a case of a patient who required tracheal intubation in a pediatric emergency department due to acute laryngitis and that, after the planned extubation, has successfully used the high-flow nasal cannula, which possibly prevented extubation failure. CASE DESCRIPTION: A male 8-month-old child was admitted to the pediatric emergency room with acute respiratory distress due to a high airway obstruction secondary to severe acute laryngitis. He was immediately intubated and referred to the pediatric intensive care unit. He presented extubation failure due to a significant laryngeal edema evidenced by bronchoscopy. In the second attempt to extubate, he presented respiratory distress, but, after the use of the high-flow nasal cannula, he became stable, reducing the heart and respiratory frequencies, and the extubation was successful. COMMENTS: The use of the high-flow nasal cannula was effective and presented good response in this patient with acute laryngitis, suggesting that it is a possible adjuvant for the treatment, avoiding worsening respiratory conditions and the need for reintubation. PMID- 29995144 TI - COMPARISON OF TWO INHALATIONAL TECHNIQUES FOR BRONCHODILATOR ADMINISTRATION IN CHILDREN AND ADOLESCENTS WITH ACUTE ASTHMA CRISIS: A META-ANALYSIS. AB - OBJECTIVE: To compare the efficacy of pediatric asthma treatment by nebulizer and metered-dose inhaler with the use of a spacer (MDI-spacer) in rescue techniques for asthmatic patients assisted at pediatric emergency units. DATA SOURCES: A systematic review was conducted to identify the most relevant randomized controlled trials comparing the administration of a bronchodilator (beta-2 agonist) by two inhalation techniques (nebulization and MDI-spacer) to treat asthma in children at pediatric emergency units. The following databases were searched: PubMed, Scientific Electronic Library Online (SciELO), and ScienceDirect. Two researchers independently applied the eligibility criteria, and only randomized controlled trials that compared both inhalation techniques (nebulization and MDI-spacer) for asthma treatment at pediatric emergency units were included. DATA SYNTHESIS: 212 articles were pre-selected, of which only nine met the eligibility criteria and were included in meta-analysis. Results show no differences between inhalation techniques for any of the four outcomes analyzed: heart rate (difference - Df: 1.99 [95% confidence interval - 95%CI -2.01-6.00]); respiratory rate (Df: 0.11 [95%CI -1.35-1.56]); O2 saturation (Df: -0.01 [95%CI 0.50-0.48]); and asthma score (Df: 0.06 [95%CI -0,26-0.38]). CONCLUSIONS: The findings demonstrate no differences in cardiorespiratory frequency, O2 saturation, and asthma scores upon administration of beta-2 agonist by both inhalation techniques (nebulization and MDI-spacer) to asthmatic patients assisted at pediatric emergency units. PMID- 29995145 TI - Daily melatonin administration improves osseointegration in pinealectomized rats. AB - INTRODUCTION: The hypothesis of this study was that the peri-implant bone healing of the group of pinealectomized rats would differ from the control group. The samples were subjected to immunohistochemical, microtomographic (total porosity and connectivity density), and fluorochrome (mineralized surface) analyses. OBJECTIVES: The goal of this study was to investigate the cellular changes and bone remodeling dynamics along the bone/implant interface in pinealectomized rats. MATERIAL AND METHODS: The total of 18 adult male rats (Rattus norvegicus albinus, Wistar) was divided into three groups (n=6): control (CO), pinealectomized without melatonin (PNX) and pinealectomized with melatonin (PNXm). All animals were submitted to the first surgery (pinealectomy), except the CO group. Thirty days after the pinealectomy without melatonin, the second surgery was conducted, in which all animals received an implant in each tibia (36 titanium implants with surface treatment were installed - Implalife(r) Sao Paulo, SP, Brazil). By gavage, the rats of the PNX group received the vehicle solution, and the procedure. RESULTS: Immunohistochemical analysis for runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteopontin (OP) and osteocalcin (OC) showed that the bone repair process in the PNXm group was similar to that of the CO group, whereas the PNX group showed a delay. The microtomographic parameters of total porosity [Po(tot)] and bone surface (BS) showed no statistically significant differences, whereas for the connective density (Conn.Dn) a statistical difference was found between the CO and PNXm groups. Fluorochrome analysis of the active mineralized surface showed statistically significant difference between the CO and PNX and between the CO and PNXm groups. CONCLUSION: The absence of the pineal gland impaired the bone repair process during osseointegration, however the daily melatonin replacement was able to restore this response. PMID- 29995146 TI - Immunohistochemical and mRNA expression of RANK, RANKL, OPG, TLR2 and MyD88 during apical periodontitis progression in mice. AB - OBJECTIVE: To evaluate and correlate, in the same research, the mRNA expression and the staining of RANK, RANKL, OPG, TLR2 and MyD88 by immunohistochemistry in the apical periodontitis (AP) progression in mice. MATERIAL AND METHODS: AP was induced in the lower first molars of thirty-five C57BL/6 mice. They were assigned to four groups according to their euthanasia periods (G0, G7, G21 and G42). The jaws were removed and subjected to histotechnical processing, immunohistochemistry and real-time reverse transcription-PCR (qRT-PCR). Data were analyzed with parametric and nonparametric tests (alpha=0.05). RESULTS: An increase of positive immunoreactivity for RANK, RANKL, OPG, TLR2 and MyD88 was observed over time (p<0.05). The RANKL expression was different between the groups G0 and G42, G21 and G42 (p=0.006), with G42 presenting the higher expression in both comparations. The OPG expression was statistically different between the groups G0 and G7, G7 and G21 and G7 and G42 (p<0.001), with G7 presenting higher expression in all the time points. The TLR2 expression was different between the groups G0 and G42 (p=0.03), with G42 showing the higher expression. The MyD88 expression presented a statistical significant difference between groups G7, G21 and G42 compared with G0 (p=0.01), with G0 presenting the smallest expression in all the comparisons. The Tnfrsf11/Tnfrsf11b (RANKL/OPG) ratio increased with the AP progression (p=0.002). A moderate positive correlation between MyD88 and RANKL (r=0.42; p=0.03) and between MyD88 and TLR2 (r=0.48; p<0.0001) was observed. CONCLUSION: The expression of the RANK, RANKL, OPG, MyD88 and TLR2 proteins as well as the ratio Tnfrsf11/Tnfrsf11b (RANKL/OPG) increased with AP progression. There was also a moderate positive correlation between the expression Myd88-Tnfrsf11 and Tlr2-Myd88, suggesting the relevance of Tlr2-Myd88 in bone loss due to bacterial infection. PMID- 29995147 TI - Successful and failed mini-implants: microbiological evaluation and quantification of bacterial endotoxin. AB - OBJECTIVES: Using two groups of mini-implants (successful and failed) the objectives of this in vivo study were: to evaluate the microbial contamination by the checkerboard DNA-DNA hybridization technique and to quantify the bacterial endotoxin by the limulus amebocyte lysate assay. MATERIAL AND METHODS: The 15 successful and 10 failed mini-implants (1.6 mm diameter * 7.0 or 9.0 mm long), placed in the maxilla and/or mandible, were obtained from 15 patients undergoing orthodontic treatment. Data were analyzed statistically by the Wilcoxon rank-sum test using the SAS software (a=0.05). RESULTS: All 40 microbial species were detected in both groups of mini-implants, with different frequencies. No differences were observed between the groups with respect to microbial complexes (blue, purple, yellow, green, orange, red and other species) and endotoxin quantification (p>0.05). CONCLUSION: Neither microbial contamination nor endotoxin quantification was determinant for the early loss of stability of the mini-implants. PMID- 29995148 TI - ERRATUM: Neurosensory analysis of tooth sensitivity during at-home dental bleaching: a randomized clinical trial. AB - [This corrects the article doi: 10.1590/1678-7757-2017-0284]. PMID- 29995149 TI - Effects of platelet-rich plasma on human gingival fibroblast proliferation and migration in vitro. AB - OBJECTIVE: This study evaluated the influence of platelet-rich plasma (PRP) on the behaviour of human gingival fibroblasts (hGFs), including fibroblast proliferation, migration and colony formation. METHODS: PRP was obtained from the human peripheral blood of a healthy volunteer and then was diluted into platelet concentrations of 1%, 2% and 5%. The proliferation of hGFs was determined by two methods: (1) Cell-number counting with a haemocytometer method at days 1, 3, 5 and 7; (2) Colony-forming unit-fibroblast (CFU-F) assay at 2 weeks. The migration of hGFs was evaluated with scratch assay, then recorded digital images were analysed by Image-Analysis J 1.51j8 software to compare the remaining artificial wound areas between PRP groups at 0, 24 and 48 hours. RESULTS: All hGFs that were cultivated in media with 1%, 2% and 5% PRP showed their ability to proliferate and migrate. Cell numbers incubated with 1% PRP increased significantly during the first three days and peaked at day 5, tending to be similar to their proliferation in complete medium. With concentrations of 2% and 5% PRP, hGFs outgrew and peaked at day 3, which was faster than with those in medium with 1% PRP. Especially, hGFs in the group 5% PRP proliferated with higher cell numbers than those in the other remaining groups at day 3. The hGF colony number that was formed in the group 5% PRP was significantly higher than those in the groups 1% and 2% PRP. Scratch assay showed hGFs in the groups 2% and 5% PRP almost filled the artificial wound and migrated more effectively than in the group 1% PRP at 24 hours, which was significant. CONCLUSION: In this study, perhaps the medium with 5% PRP is the dominant option, promoting the abilities of hGFs to heal wounds, because of its fast and effective impact on cell proliferation, colony formation and migration. PMID- 29995151 TI - Expression of epidermal growth factor receptor (EGFR) in cholangiocarcinomas: predictive factors and survival. AB - OBJECTIVE: to evaluate the expression of the epithelial growth factor receptor (EGFR) by immunohistochemistry, and to verify its association with prognostic factors and survival of patients operated by cholangiocarcinoma. METHODS: we verified the immunohistochemical expression of EGFR in 35 surgical specimens of cholangiocarcinoma (CCA). We obtained survival curves with the Kaplan-Meier method. RESULTS: we found significant EGFR expression in ten (28.6%) of the 35 CCAs, eight with score 3 and two with score 2. Advanced stages (III and IV) presented higher EGFR expression (p=0.07). The clinical characteristics that were most associated with positive EGFR expression were female gender (p=0.06) and absence of comorbidities (p=0.06). Overall survival at 12, 24, 36 and 48 months was 100%, 82.5%, 59% and 44.2%, respectively. The survival of EGFR positive patients at 12, 24, 36 and 48 months was 100%, 75%, 50% and 0%, whereas for negative EGFR patients it was 100%, 87.5%, 65.6% and 65.6%, respectively. CONCLUSION: EGFR expression occurred in 28.6% of the cases studied and was associated with lower survival. PMID- 29995150 TI - Effects of hyperbaric oxygen treatment on implant osseointegration in experimental diabetes mellitus. AB - OBJECTIVE: To evaluate whether hyperbaric oxygen (HBO) treatment has a favorable effect on implant osseointegration in diabetic rabbits. MATERIAL AND METHODS: An experimental diabetes model was induced in 32 New Zealand rabbits through IV injection of alloxan. After the state of diabetes had been confirmed, one dental implant was placed in the metaphysical region of each animal's tibia. After the implants' placements, the animals were divided into two groups. Half of the animals underwent HBO treatment, while the other group did not receive HBO treatment and served as the control group. The animals were euthanized at the 4th and 8th weeks. The osseointegration of the implants were compared by histomorphometry and resonance frequency analysis (RFA). RESULTS: The Bone Implant Contact (BIC) values were significantly higher in the HBO group than in the control group at the 4th week. There was no difference in the BIC values between the groups at the 8th week. There was no significant difference in the RFA scores between the groups both at the 4th and 8th weeks after the operation. CONCLUSION: Histomorphometry findings suggest that HBO has positive effect on implant osseointegration in the early healing period in diabetic rabbits. However, implant stability is not affected by HBO treatment. PMID- 29995152 TI - Should splenic autotransplantation be considered after total splenectomy due to trauma? AB - Trauma is a public health problem and the most common cause of death in people under the age of 45. In blunt abdominal trauma, the spleen is the most commonly injured organ. Splenectomy remains the most common treatment, especially in high grade lesions, despite increased nonoperative treatment. Removal of the spleen leads to increased susceptibility to infections due to its role in the immune function. Postsplenectomy sepsis is an important complication and presents a high mortality rate. Patients undergoing splenectomy should be immunized for encapsulated germs, as these are the agents most commonly associated with such infections. Splenic autotransplantation is a simple procedure, which can be an alternative to reduce infection rates consequent to total splenectomy, and reduce costs related to hospitalizations. This review aims to provide evidence-based information on splenic autotransplantation and its impact on the prognosis of patients undergoing total splenectomy. We searched the Cochrane Library, Medline/PubMed, SciELO and Embase, from January 2017 to January 2018 and selected articles in English and Portuguese, dated from 1919 to 2017. We found that the adjusted risk of death in splenectomized patients is greater than that of the general population, and when total splenectomy is performed, splenic autotransplantation is the only method capable of preserving splenic function, avoiding infections, especially postsplenectomy sepsis. Health professionals should be familiar with the consequences of the method chosen to manage the patient suffering from splenic trauma. PMID- 29995153 TI - Choledochal cyst in the pediatric population: experience of 13 laparoscopic procedures in two years at a single institution. AB - OBJECTIVE: to describe the first 13 cases of laparoscopic correction of common bile duct cyst in the Pequeno Principe Hospital, Curitiba, Parana, Brazil. METHODS: we performed a retrospective analysis of medical records of cases of choledochal cyst operated by laparoscopy between March 2014 and September 2016. RESULTS: of the 13 patients, eight were female and the mean age at surgery was 7.8 years. The most common symptom was abdominal pain. The hepaticoduodenal anastomosis was the most used reconstruction technique, in 84.6% of the cases. There was no conversion to laparotomy or intraoperative complications. Only one patient presented anastomotic fistula and was reoperated by laparotomy. All patients were followed up in an outpatient clinic, were asymptomatic and had no episode of cholangitis after surgery, with a mean follow-up of 16 months. CONCLUSION: laparoscopy is a safe method to correct choledochal cysts, even in younger children, with low rates of complications and low rates of conversion to open surgery when performed by well trained surgeons. PMID- 29995154 TI - Reliability, validity, and factorial structure of the World Health Organization-5 Well-Being Index (WHO-5) in Iranian psychiatric outpatients. AB - INTRODUCTION: The association between psychological well-being and physical and mental health has been shown in the literature. Psychological well-being is a multifaceted concept. The World Health Organization-5 Well-Being Index (WHO-5) is a 5-item instrument used to screen for depression. However, the validity of the WHO-5 has not been investigated in Iranian psychiatric or psychological settings. OBJECTIVE: To investigate the validation of the Farsi version of the WHO-5 in a sample of Iranian psychiatric outpatients. METHODS: A cross-sectional study was conducted with a convenience sample of 116 Iranian volunteer psychiatric outpatients selected from the psychiatric and psychological clinics at the School of Behavioral Sciences and Mental Health - Tehran Institute of Psychiatry, Iran University of Medical Sciences. Patients completed the WHO-5, the Patient Health Questionnaire-9 (PHQ-9), the Patient Health Questionnaire-15 (PHQ-15), and the short form of the Beck Depression Inventory-13 (BDI-13). RESULTS: The mean score of the WHO-5 was 8.95 (standard deviation [SD] = 5.49). Cronbach's alpha for the WHO-5 was 0.91. The WHO-5 negatively correlated with PHQ-9 (-0.358), PHQ-15 ( 0.328), and BDI-13 (-0.475), indicating good validity. Factor analysis of the WHO 5 items identified one factor labeled psychological well-being. CONCLUSIONS: The WHO-5 has a single dimensional structure and acceptable psychometric parameters. The results of this study suggest that WHO-5 can be used in a clinical context in Iran. PMID- 29995155 TI - Investigation of the clinical functioning of the Dimensional Clinical Personality Inventory 2 criticism avoidance dimension. AB - OBJECTIVE: To investigate the clinical functioning of the criticism avoidance dimension from the Dimensional Clinical Personality Inventory 2 (Inventario Dimensional Clinico da Personalidade 2 [IDCP-2]), establishing a clinically relevant cut-off for the typical traits of avoidant personality disorder (AvPD) for screening purposes. METHODS: We administered the IDCP-2 to a sample of 2,276 subjects aged 18 to 90 years (mean = 26.95, standard deviation = 9.71). Of the total sample, 1,650 were women (67%) and most were college students (72.7%). The sample was divided into psychiatric patients diagnosed with other personality disorders (PDs) (n = 53), patients diagnosed with AvPD without comorbidities (n = 10), patients with AvPD with comorbidities (n=42) and those without a known diagnosis of PD (nonpsychiatric patients; n=2,171). RESULTS: We checked for psychometric properties, assessed the adequacy of psychometric assumptions, and proceeded to focus analyses. The Wright item-person map showed the predominance of patients with AvPD in high levels of the scale. Analysis of variance (ANOVA) post hoc comparisons pointed to significant and expressive differences for almost all the comparisons; in the receiver operating characteristic (ROC) curve, we observed a sensitivity of 79% and a specificity of 87%. CONCLUSION: We found a suitable cut-off for the dimension, and results suggest that the dimension may help clinicians discriminate between patients with and without high levels in the symptoms of AvPD. PMID- 29995156 TI - Psychometric properties of the World Health Organization Quality of Life Instrument-Abbreviated version in Portuguese-speaking adults from three different countries. AB - OBJECTIVE: To evaluate the validity, reliability and invariance of the World Health Organization Quality of Life Instrument-Abbreviated version (WHOQOL-Bref) in Portuguese-speaking adults from three different countries. METHODS: A total of 4,020 Brazilian, Portuguese, and Mozambican individuals participated in the study. The total sample was divided into four samples: Brazilian patients (n = 1,120), Brazilian students (n = 1,398), Portuguese students (n = 1,165) and Mozambican students (n = 337). Factorial validity of the WHOQOL-Bref was assessed by confirmatory factor analysis. The convergent and discriminant validities of the instrument were assessed using the average variance extracted (AVE) and the square of Pearson's correlational coefficient (r2), respectively. Composite reliability and ordinal alpha were used as measures of reliability. The metric, scalar, and strict invariance of WHOQOL-Bref was evaluated by multi-group analysis in independent subsamples (within each sample) and only between Brazil and Portugal (transnational invariance), because the configural model of Mozambique was different. RESULTS: The original model of the WHOQOL-Bref did not show a good fit for the samples. Different items were excluded to fit the instrument in each sample (different models for WHOQOL-Bref among Brazilian, Portuguese, and Mozambican samples). AVE and r2 were not adequate; however, the reliability of the WHOQOL-Bref was good, except in the Mozambican sample. Invariance was observed only in independent subsamples. CONCLUSION: The WHOQOL Bref fitted models showed adequate factorial validity and invariance in independent subsamples. The transnational non-invariance of the WHOQOL-Bref shows the influence of culture on the operationalization of the quality of life construct. PMID- 29995157 TI - The Farsi translation, reliability and validity of the Death Concern Scale. AB - INTRODUCTION: Death concern is a conscious contemplation of the reality of death combined with a negative evaluation of that reality. The Death Concern Scale (DCS) is related to thinking, and death fear or anxiety about death. The aim of the present study was to develop a Farsi version of the DCS and to explore its psychometric properties in a sample of Iranian nurses. METHODS: A cross-sectional study was conducted to investigate the reliability, validity, and factorial structure of the Farsi version of the DCS in a convenience sample of 106 Iranian nurses in two hospitals in Tehran, Iran. The nurses completed the DCS, the Collett-Lester Fear of Death Scale (CLFDS), the Death Anxiety Scale (DAS), the Reasons for Death Fear Scale (RDFS), the Death Depression Scale (DDS), and the Death Obsession Scale (DOS). RESULTS: For the DCS, Cronbach's alpha was 0.77, the Spearman-Brown coefficient 0.63, the Guttman split-half coefficient 0.62, and two week test-retest reliability 0.77. The DCS correlated at 0.51 with the CLFDS, 0.52 with the DAS, 0.34 with the RDFS, 0.40 with the DDS, and 0.48 with the DOS, indicating good construct and criterion-related validity. The results of an exploratory factor analysis for the DCS identified seven factors, accounting for 64.30% of the variance and indicating considerable heterogeneity in the content of the items. CONCLUSIONS: The Farsi version of the DCS has good validity and reliability, and it can be used in clinical, educational, and research settings to assess death concerns in the Iranian society. PMID- 29995158 TI - A structural model of well-being, spontaneity and self-efficacy: Italian validation between adolescents and young adults. AB - INTRODUCTION: The passage from adolescence to young adulthood introduces many challenges and chances aimed at promoting independence, financial self sufficiency, assumption of responsibilities and separation from parents. Literature shows that in the continuum between these two phases of life, many factors intervene, producing significant differentiations. METHODS: This study considered three dimensions - well-being, measured through the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM); spontaneity, measured through the Spontaneity Assessment Inventory-Revised (SAI-R); and self-efficacy, measured through the General Self-Efficacy scale (GSE). The study involved two groups of Italian participants: 495 adolescents, aged between 13 and 19 years, selected at a high school; and 368 young adults, aged between 18 and 30 years, recruited by snowball sampling. RESULTS: Results of confirmatory factor analysis for each instrument in each group indicate the validity of the three instruments for both age groups. No significant differences were found between adolescents and young adults on total or subtotal scores of the CORE-OM, except for the risk factor. Conversely, the mean scores obtained with SAI-R and GSE were very different between adolescents and young adults. CONCLUSIONS: The results of path analysis show a significant mediation of spontaneity in the link between self-efficacy and all specific psychological distress domains for adolescents. Instead, there is a significant mediation of spontaneity between self-efficacy and all specific psychological distress domains except the risk domain for young adults. PMID- 29995159 TI - Reliability and validity of the Farsi version of the Patient Health Questionnaire 9 (PHQ-9) with Iranian psychiatric outpatients. AB - INTRODUCTION: The Patient Health Questionnaire-9 (PHQ-9) is a brief screening and diagnostic tool for depression. It has been used in research and clinical practice in primary care and other clinical and non-clinical settings. The PHQ-9 has not had its validity examined in psychiatric and psychological settings in Iran. METHODS: A cross-sectional study was conducted to investigate the validation of the Farsi version of the PHQ-9. A convenience sample of 130 Iranian volunteer psychiatric outpatients was selected from psychiatric and psychological clinics. They completed the PHQ-9, the Patient Health Questionnaire-15 (PHQ-15), the World Health Organization-five Well-Being Index (WHO-5), and the short form of the Beck Depression Inventory-13 (BDI-13). Data were analyzed by descriptive statistics, Cronbach's alpha, Pearson correlation coefficient, principal component analysis, exploratory factor analysis, and confirmatory factor analysis. RESULTS: Mean score of the PHQ-9 was 12.83 (standard deviation = 6.25), indicating moderately severe depression in the sample. Cronbach's alpha coefficient for PHQ-9 was 0.88, and one-week test-retest reliability 0.79. The PHQ-9 correlated 0.64 with PHQ-15, -0.35 with WHO-5, and 0.70 with BDI-13, indicating good construct and criterion-related validity. The results of the factor analysis of PHQ-9 items identified and confirmatory factor analysis confirmed a single factor labeled general depression. CONCLUSIONS: The PHQ-9 appears to have a unidimensional structure, adequate validity and reliability, and can be useful in epidemiological/research settings. Based on previous literature and on the present findings, the PHQ-9 may have applicability to other contexts in the studied population, but this needs to be confirmed by other studies. PMID- 29995160 TI - Psychometric properties of the Brazilian version of the Cognitive Emotion Regulation Questionnaire. AB - INTRODUCTION: The Cognitive Emotion Regulation Questionnaire (CERQ) was developed to measure nine cognitive strategies referring to what someone thinks after the experience of threatening or stressful events. The main purpose of this study was to evaluate the validity of the Brazilian version of the CERQ. METHODS: The adaptation process included translation, backtranslation, expert committee evaluation, and test on 30 participants from the target population. A sample of 445 university students completed the Portuguese version of the CERQ, a sociodemographic questionnaire, the Life Events Checklist (LEC-5), and the Positive and Negative Affect Schedule (PANAS) on an on-line research platform. Validity was assessed through confirmatory factor analysis of two models - a nine factor model and a second-order model. Internal consistency was assessed through Cronbach's alpha analysis and correlations with affective variables measured by the PANAS. RESULTS: The analyses showed that the nine-factor model of the CERQ has good factorial validity and high reliability, with Cronbach's alpha values ranging between 0.71 and 0.88. The second-order model did not have a good fit to the data. CONCLUSION: The results obtained in this study are similar to the ones found previously, indicating that the Brazilian version of the CERQ is a valid and reliable tool for assessing cognitive emotion regulation strategies, but that grouping them according to their adaptability is not recommended. PMID- 29995161 TI - Validity and reliability of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) in Brazilian bipolar patients. AB - INTRODUCTION: In Brazil, there is no valid instrument to measure subjective cognitive dysfunction in bipolar disorder. The present study analyzed the psychometric properties of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) in Brazilian bipolar patients. We further investigated the relationship between the COBRA, objective cognitive measures, and illness course variables. METHODS: The total sample (N=150) included 85 bipolar disorder patients and 65 healthy controls. The psychometric properties of the COBRA (e.g., internal consistency, concurrent validity, discriminative validity, factor analyses, ROC curve, and feasibility) were analyzed. RESULTS: The COBRA showed a one-factor structure with very high internal consistency (Cronbach's alpha=0.890). Concurrent validity was indicated by a strong correlation with the cognitive domain of the FAST (r=0.811, p<0.001). Bipolar patients experienced greater cognitive complaints (mean=14.69; standard deviation [SD]=10.03) than healthy controls (mean=6.78; SD=5.49; p<0.001), suggesting discriminative validity of the instrument. No significant correlations were found between the COBRA and objective cognitive measures. Furthermore, higher COBRA scores were associated with residual depressive (r=0.448; p<0.001) and manic (r=0.376; p<0.001) symptoms, number of depressive episodes (r=0.306; p=0.011), number of total episodes (r=0.256; p=0.038), and suicide attempts (r=0.356; p=0.003). CONCLUSION: The COBRA is a valid instrument to assess cognitive complaints, and the combined use of subjective-objective cognitive measures enables the correct identification of cognitive dysfunctions in bipolar disorder. PMID- 29995162 TI - Patient goal achievement 2 years after a tension-free vaginal tape operation. AB - INTRODUCTION AND HYPOTHESIS: The primary aim of this study was to investigate long-term patient-reported goals after a tension-free vaginal tape (TVT) operation for stress urinary incontinence (SUI). METHODS: In this prospective study involving 67 women, patients completed the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) preoperatively and stated three goals for the operation. Postoperatively, a visual analog scale (VAS) ranging from zero (none) to ten (worst) estimated the extent to which goals were achieved. Goals were divided into five groups: symptoms, quality of life (QoL) (physical), QoL (emotional), sexual function, avoidance, and others. Short-term achievement of goal was estimated after 3 months and long-term achievement of goals after a mean of 28.2 months. RESULTS: A total of 201 goals were stated, most of which (38%) were in the group concerning QoL in physical domains. Mean VAS score for all goals was 9.1 after 3 months and 8.5 at long-term follow-up. ICIQ-UI SF preoperatively was mean 14.9; 3 months' postoperatively mean 1.4; and at long-term 3.8. The small rise in ICIQ-UI SF at long-term follow-up was statistically insignificant and due to urge urinary incontinence (UUI). CONCLUSIONS: Our study showed that patients achieved their goals to a high degree and maintained them at long-term follow-up. Most goals concerned QoL in physical domains. Although a proportion of women experienced episodes of UUI at the long-term follow-up, VAS score was not significantly changed. PMID- 29995163 TI - National BSUG audit of stress urinary incontinence surgery in England. AB - INTRODUCTION AND HYPOTHESIS: The aim of the British Society of Urogynaecology (BSUG) 2013 audit for stress urinary incontinence (SUI) surgery was to conduct a national clinical audit looking at the intra- and postoperative complications and provide outcomes for these procedures. This audit was supported by the Healthcare Quality Improvement Partnership (HQIP) and National Health Service (NHS) England. METHODS: Data were collected for all continence procedures performed in 2013 through the BSUG database. All clinicians in England performing SUI surgery were invited to submit data to a central database. Outcomes data for the different continence procedures were collected and included intraoperative and postoperative complications and the change in continence scores at postoperative follow-up Changing trends in stress incontinence surgery were also assessed. RESULTS: We recorded 4993 urinary incontinence procedures from 177 consultants at 110 centres in England: 94.6% were midurethral slings; 86.7% (4331) were submitted by BSUG members with the remaining 13.3% submitted by non-BSUG members. Postoperative follow-up data were available for 3983 (80%) patients: 92.3% (3676) were very much better/much better postoperatively, and 4806 (96.3%) proceeded with no reported complications. There were 187 cases (3.7%) in which a perioperative complication was recorded. Pain persisting >30 days was reported in 1.9% of all patients. CONCLUSIONS: Surgery for SUI has good outcomes in the short term. Midurethral synthetic slings have been shown to be safe and effective as a treatment option, with >90% being very much/much better at their postoperative follow-up. PMID- 29995164 TI - Commentary to "Defining normal apical vaginal support: a relook at the POSST study". PMID- 29995165 TI - Bony landmarks with tibial cutting surface are useful to avoid rotational mismatch in total knee arthroplasty. AB - PURPOSE: The purpose of this study was to define various anteroposterior axes of the tibial component as references and to evaluate their accuracy and variability using virtual surgery. It was hypothesized that (1) Akagi's Line could result in high accuracy and low variability in varus osteoarthritic knees; (2) anteroposterior axes defined by using the tibial bony cutting surface as a landmark might be good substitutes for Akagi's Line; and (3) extra-articular bony landmarks might influence the variability of the anteroposterior axis. METHODS: Three-dimensional bone models were reconstructed from the preoperative computed tomography data of 111 osteoarthritic knees with varus deformities. Seven different anteroposterior axes of the tibial component were defined: Akagi's Line, Axis MED, Axis 1/6MED, Axis 1/3MED, Axis of Oval Shape, Axis of Anterior Crest, and Axis Second Metatarsus. The rotational mismatch angle was measured between the tibial anteroposterior axis and the line perpendicular to the transepicondylar axis projected on the cutting surface (positive value: external rotation of the tibial anteroposterior axis). RESULTS: The average rotational mismatch angles (referring to the projected anatomical/surgical epicondylar axes) were - 2.7 degrees +/- 5.8 degrees /1.0 degrees +/- 6.0 degrees (Akagi's Line), - 4.2 degrees +/- 7.7 degrees /- 0.5 degrees +/- 7.8 degrees , 2.9 degrees +/- 7.2 degrees /6.6 degrees +/- 7.2 degrees , 9.8 degrees +/- 7.0 degrees /13.5 degrees +/- 6.8 degrees (Axis MED, Axis 1/6MED, Axis 1/3MED), - 5.1 degrees +/- 7.9 degrees /- 1.4 degrees +/- 7.8 degrees (Axis of Oval Shape), and 19.3 +/- 9.5 degrees /23.0 degrees +/- 9.6 degrees , - 2.0 degrees +/- 11.3 degrees /1.7 degrees +/- 11.4 degrees (Axis Anterior Crest, Axis Second Metatarsus), respectively. CONCLUSIONS: Akagi's Line provided the best accuracy and least variability in varus osteoarthritic knees. Axis 1/6MED and Axis MED are good substitutes for Akagi's Line due to the difficulty of identifying the attachment site of the posterior cruciate ligament after the proximal tibia has been cut. Extra-articular bony landmarks should not be used for alignment due to their high variability. This study will aid surgeons in choosing the proper anteroposterior axis of the tibial component to reduce rotational mismatch and thus achieve good clinical knee outcomes. LEVELS OF EVIDENCE: III. PMID- 29995166 TI - Short lateral posterior condyle is associated with trochlea dysplasia and patellar dislocation. AB - PURPOSE: Surgeons mainly consider the anterior anatomy of the distal femur in the treatment of patellar instability (PI) with trochlear dysplasia (TD). Through this research, the idea was to analyse the posterior femoral condyle length in TD. The research team posited the presence of morphological differences in the posterior part of the femoral epiphysis in TD compared to a control group. They also postulated that the posterior bicondylar angle (PCA), in the axial plane, was increased in TD. METHODS: This is a single-centre morphological study of 100 patients who had a computed tomography (CT) using the same protocol. 50 patients with PI (25 dysplasias A and 25 B-C-D according to the Dejour classification), and 50 controls were included. All patients presenting a clinical PI were considered for the study. None of these patients had undergone a surgical treatment prior to imaging. Demographic characteristics, BMI, and laterality were comparable in all patients. 20 pilot CT scans were used to establish the methodology. The following measurements were performed: anterior bicondylar angle, PCA, and condylar lengths with respect to the surgical transepicondylar axis. Ratios were calculated in relation to the femoral width. TD was classified according to the Dejour classification in grade A or grades B-C-D. An analysis of variance and a linear model were performed within some groups to investigate which parameters correlated with the classification's grade. RESULTS: This study showed a link between TD and the PCA: control group (1.4 +/- 0.2 degrees ), type A group (1.6 +/- 0.3 degrees ), and types B, C, D group (2.6 +/- 0.3 degrees ) (p = 0.01). The difference between the control group and types B, C, D TD group was significant (p = 0.002). In groups B, C, D, the PCA was more important, which proves that in these groups the posterior part of the lateral condyle was relatively shorter compared to the medial condyle. The greater the dysplasia, the longer the medial condyle was in the anterior posterior (p = 0.02). CONCLUSIONS: This study shows not only an anterior but also a posterior anomaly in PI with TD. There is a correlation between the severity of the anterior deformation and the PCA: in other words, the knee is placed in valgus in flexure which promotes the external dislocation of the patella. This anatomical study could open a field of research on the development of surgical treatments based on the correction of posterior condylar femoral anomalies in PI. LEVEL OF EVIDENCE: III. PMID- 29995167 TI - Virtual reality hip arthroscopy simulator demonstrates sufficient face validity. AB - PURPOSE: To test the face validity of the hip diagnostics module of a virtual reality hip arthroscopy simulator. METHODS: A total of 25 orthopaedic surgeons, 7 faculty members and 18 orthopaedic residents, performed diagnostic supine hip arthroscopies of a healthy virtual reality hip joint using a 70 degrees arthroscope. Twelve specific targets were visualised within the central compartment; six via the anterior portal, three via the anterolateral portal and three via the posterolateral portal. This task was immediately followed by a questionnaire regarding the realism and training capability of the system. This consisted of seven questions addressing the verisimilitude of the simulator and five questions addressing the training environment of the simulator. Each question consisted of a statement stem and 10-point Likert scale. Following similar work in surgical simulators, a rating of 7 or above was considered an acceptable level of realism. RESULTS: The diagnostic hip arthroscopy module was found to have an acceptable level of realism in all domains apart from the tactile feedback received from the soft tissue. 23 out of 25 participants (92%) felt the simulator provided a non-threatening learning environment and 22 participants (88%) stated they enjoyed using the simulator. It was most frequently agreed that the level of trainees who would benefit most from the simulator were registrars and fellows (22 participants; 88%). Additionally, 21 of the participants (84%) agreed that this would be a beneficial training modality for foundation and core trainees, and 20 participants (80%) agreed that his would be beneficial for consultants. CONCLUSIONS: This VR hip arthroscopy simulator was demonstrated to have a sufficient level of realism, thus establishing its face validity. These results suggest this simulator has sufficient realism for use in the acquisition of basic arthroscopic skills and supports its use in orthopaedics surgical training. LEVEL OF EVIDENCE: I. PMID- 29995168 TI - Presence of Oil Mineral Aggregates (OMAs) in Surface Sediments from Mexico's Exclusive Economic Zone, NW Gulf of Mexico. AB - We assessed the presence and distribution of oil mineral aggregates (OMAs) in surficial sediments of Mexican waters in the NW Gulf of Mexico, their potential sources and their correlation with polycyclic aromatic hydrocarbons (PAH). In summer of 2010, OMAs were detected in three shallow sites. In winter of 2011, OMAs were observed in ten sites, two of them in the northernmost area at > 1500 m depth. These particles were possibly advected from the north Gulf and Mississippi area following the deep-water currents of the zone. The OMAs from shallower sites may reflect local pollution sources. PAHs displayed low concentrations in both surveys (from 0.01 to 0.7 ug g-1 in summer, and from 0.01 to 0.51 ug g-1 in winter), and showed rather a local origin. The expansion of the oil and port industry in the region is accountable for most of the OMAs detected. PMID- 29995169 TI - Pain and disability after first-time spinal fusion for lumbar degenerative disorders: a systematic review and meta-analysis. AB - PURPOSE: Lumbar spinal fusion (LSF) is frequently and increasingly used in lumbar degenerative disorders despite conflicting results and recommendations. A thorough understanding of patient outcomes after LSF is required to inform decisions regarding surgery and to improve post-surgery management. The current study aims to evaluate the course of pain and disability in patients with degenerative disorders of the lumbar spine after first-time LSF. METHODS: A systematic review and meta-analysis of pain and disability outcomes in prospective cohort studies up to 31 March 2017 is identified in four electronic databases. Two independent researchers determined study eligibility, extracted data, and assessed risk of bias (modified Quality in Prognostics tool). A random effects model (maximum likelihood) was used to calculate means and 95% confidence intervals. The primary analysis was performed on complete data, and a sensitivity analysis was performed on all data. RESULTS: Twenty-five studies (n = 1777 participants) were included. The mean (95% confidence interval) Visual Analogue Scale (VAS) back pain (n = 9 studies) decreased from 64 (57-71) pre-surgery to 20 (16-24) at 24-month follow-up. Leg pain (n = 9 studies) improved from VAS 70 (65 74) pre-surgery to 17 (12-23) at 24-month interval. Disability (n = 12 studies), measured with the Oswestry Disability Index, decreased from 44.8 (40.1-49.4) pre surgery to 17.3 (11.9-22.8) at 24-month follow-up. The sensitivity analysis yielded similar results. CONCLUSION: There is a substantial improvement in pain and disability after first-time LSF for degenerative disorders. However, long term outcomes indicate that leg pain might be more reduced and for a longer period of time than axial back pain and disability. Registration PROSPERO CRD42015026922. These slides can be retrieved under Electronic Supplementary Material. PMID- 29995170 TI - Does the META score evaluating osteoporotic and metastatic vertebral fractures have enough agreement to be used by orthopaedic surgeons with different levels of training? AB - PURPOSE: Differentiating osteoporotic vertebral fractures (OVF) from metastatic vertebral fractures (MVF) is difficult. A magnetic resonance imaging (MRI)-based score (META score) aiming to differentiate OVF and MVF was recently published; however, an independent agreement assessment is required before the score is used. We performed such independent agreement evaluation, including raters with different levels of training. METHODS: Sixty-four patients with confirmed OVF or MVF were evaluated by six raters (three spine surgeons and three orthopaedic residents) using the META score. We used the intra-class correlation coefficient (ICC) to evaluate inter- and intra-observer agreement and the kappa statistic (kappa) to determine the agreement for individual score criteria. We calculated the area under the receiver-operating characteristic curve (AUC) to establish the score accuracy. RESULTS: The inter-observer agreement was poor [ICC = 0.22 (0.12 0.33)]; spine surgeons [ICC = 0.75 (0.66-0.83)] had better agreement than that of residents [ICC = 0.06 (- 0.07 to 0.23)]. The intra-observer agreement was poor [ICC = 0.15 (- 0.04 to 0.30)]; both spine surgeons [ICC = 0.21 (0.05-0.41)] and residents exhibited poor agreement [ICC = - 0.06 (- 0.40 to 0.20)]. The agreement for each specific criterion varied from kappa = 0.24 to kappa = 0.38. The AUC was 0.57 (0.64 for spine surgeons and 0.51 for residents, p < 0.01). CONCLUSION: The inter-observer agreement using the META score was adequate for spine surgeons but not for residents; the intra-observer agreement was poor. These results do not support the standard use of the META score to differentiate OVF and MVF. These slides can be retrieved under Electronic Supplementary Material. PMID- 29995171 TI - Aging is associated with a mild acidification in neocortical human neurons in vitro. AB - The intracellular pH (pHi) in the cytosol of mammalian central neurons is tightly regulated and small pHi-fluctuations are deemed to modulate inter-/intracellular signaling, excitability, and synaptic plasticity. The resting pHi of young rodent hippocampal pyramidal neurons is known to decrease alongside aging for about 0.1 pH-units. There is no information about the relationship between age and pHi of human central neurons. We addressed this knowledge gap using 26 neocortical slices from 12 patients (1-56-years-old) who had undergone epilepsy surgery. For fluorometric recordings, the slice-neurons were loaded with the pHi-sensitive dye BCECF-AM. We found that the pyramidal cells' resting pHi (n = 26) descended linearly alongside aging (r = - 0.71, p < 0.001). This negative relationship persisted, when the sample was confined to specific brain regions (i.e., middle temporal gyrus, 23 neurons, r = - 0.68, p < 0.001) or pathologies (i.e., hippocampus sclerosis, 8 neurons, r = - 0.78, p = 0.02). Specifically, neurons (n = 9, pHi 7.25 +/- 0.12) from young children (1.5 +/- 0.46-years-old) were significantly more alkaline than neurons from adults (n = 17, 38.53 +/- 12.38 years old, pHi 7.08 +/- 0.07, p < 0.001). Although the samples were from patients with different pathologies the results were in line with those from the rodent hippocampal pyramidal neurons. Like a hormetin, the age-related mild pHi-decrease might contribute to neuroprotection, e.g., via limiting excitotoxicity. On the other hand, aging cortical neurons could become more vulnerable to metabolic overstress by a successive pHi-decrease. Certainly, its impact for the dynamics in short and long-term synaptic plasticity and, ultimately, learning and memory provides a challenge for further research. PMID- 29995172 TI - Human tyrosine hydroxylase in Parkinson's disease and in related disorders. AB - Parkinson's disease (PD) is an aging-related movement disorder mainly caused by a deficiency of neurotransmitter dopamine (DA) in the striatum of the brain and is considered to be due to progressive degeneration of nigro-striatal DA neurons. Most PD is sporadic without family history (sPD), and there are only a few percent of cases of young-onset familial PD (fPD, PARKs) with the chromosomal locations and the genes identified. Tyrosine hydroxylase (TH), tetrahydrobiopterin (BH4)-dependent and iron-containing monooxygenase, catalyzes the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is the initial and rate-limiting step in the biosynthesis of catecholamines (DA, noradrenaline, and adrenaline). PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD. However, this decrease in TH is thought to be secondary due to neurodegeneration of DA neurons caused by some as yet unidentified genetic and environmental factors, and thus, TH deficiency may not play a direct role in PD. This manuscript provides an overview of the role of human TH in the pathophysiology of PD, covering the following aspects: (1) structures of the gene and protein of human TH in relation to PD; (2) similarity and dissimilarity between the phenotypes of aging-related sPD and those of young-onset fPD or DOPA responsive dystonia due to DA deficiency in the striatum with decreased TH activity caused by mutations in either the TH gene or GTP cyclohydrolase I (GCH1) gene; and (3) genetic variants of the TH gene (polymorphisms, rare variants, and mutations) in PD, as discovered recently by advanced genome analysis. PMID- 29995173 TI - Perforated sigmoid diverticulitis: Hartmann's procedure or resection with primary anastomosis-a systematic review and meta-analysis of randomised control trials. AB - INTRODUCTION: The surgical management of perforated sigmoid diverticulitis and generalised peritonitis is challenging. Surgical resection is the established standard of care. However, there is debate as to whether a primary anastomosis (PA) or a Hartmann's procedure (HP) should be performed. The aim of the present study was to perform a review of the literature comparing HP to PA for the treatment of perforated sigmoid diverticulitis with generalised peritonitis. METHODS: A systematic literature search was performed for articles published up to March 2018. We considered only randomised control trials (RCTs) comparing the outcomes of sigmoidectomy with PA versus HP in adults with perforated sigmoid diverticulitis and generalised peritonitis (Hinchey III or IV). Primary outcomes were mortality and permanent stoma rate. Outcomes were pooled using a random effects model to estimate the risk ratio and 95% confidence intervals. RESULTS: Of the 1,204 potentially relevant articles, 3 RCTs were included in the meta analysis with 254 patients in total (116 and 138 in the PA and HP groups, respectively). All three RCTs had significant limitations including small size, lack of blinding and possible selection bias. There was no statistically significant difference in mortality or overall morbidity. Although 2 out of the 3 trials reported a lower permanent stoma rate in the PA arm, the difference in permanent stoma rates was not statistically significant (RR = 0.40, 95% CI 0.14 1.16). The incidence of anastomotic leaks, including leaks after stoma reversal, was not statistically different between PA and HP (RR = 1.42, 95% CI 0.41-4.87, p = 0.58) while risk of a postoperative intra-abdominal abscess was lower after PA than after HP (RR = 0.34, 95% CI 0.12-0.96, p = 0.04). CONCLUSIONS: PA and HP appear to be equivalent in terms of most outcomes of interest, except for a lower intra-abdominal abscess risk after PA. The latter finding needs further investigation as it was not reported in any of the individual trials. However, given the limitations of the included RCTs, no firm conclusion can be drawn on which is the best surgical option in patients with generalised peritonitis due to diverticular perforation. PMID- 29995174 TI - Transcriptome-Guided Identification of Carbohydrate Active Enzymes (CAZy) from the Christmas Island Red Crab, Gecarcoidea natalis and a Vote for the Inclusion of Transcriptome-Derived Crustacean CAZys in Comparative Studies. AB - The Christmas Island red crab, Gecarcoidea natalis, is an herbivorous land crab that consumes mostly fallen leaf litter. In order to subsist, G. natalis would need to have developed specialised digestive enzymes capable of supplying significant amounts of metabolisable sugars from this diet. To gain insights into the carbohydrate metabolism of G. natalis, a transcriptome assembly was performed, with a specific focus on identifying transcripts coding for carbohydrate active enzyme (CAZy) using in silico approaches. Transcriptome sequencing of the midgut gland identified 70 CAZy-coding transcripts with varying expression values. At least three newly discovered putative GH9 endo-beta-1,4 glucanase ("classic cellulase") transcripts were highly expressed in the midgut gland in addition to the previously characterised GH9 and GH16 (beta-1,3 glucanase) transcripts, and underscoring the utility of whole transcriptome in uncovering new CAZy-coding transcripts. A highly expressed transcript coding for GH5_10 previously missed by conventional screening of cellulase activity was inferred to be a novel endo-beta-1,4-mannase in G. natalis with in silico support from homology modelling and amino acid alignment with other functionally validated GH5_10 proteins. Maximum likelihood tree reconstruction of the GH5_10 proteins demonstrates the phylogenetic affiliation of the G. natalis GH5_10 transcript to that of other decapods, supporting endogenous expression. Surprisingly, crustacean-derived GH5_10 transcripts were near absent in the current CAZy database and yet mining of the transcriptome shotgun assembly (TSA) recovered more than 100 crustacean GH5_10s in addition to several other biotechnological relevant CAZys, underscoring the unappreciated potential of the TSA database as a valuable resource for crustacean CAZys. PMID- 29995175 TI - Nitric Oxide Participates in the Brain Ischemic Tolerance Induced by Intermittent Hypobaric Hypoxia in the Hippocampal CA1 Subfield in Rats. AB - Previous studies have shown that intermittent hypobaric hypoxia (IH) preconditioning protected neurons survival from brain ischemia. However, the mechanism remains to be elucidated. The present study explored the role of nitric oxide (NO) in the process by measuring the expression of NO synthase (NOS) and NO levels. Male Wistar rats (100) were randomly assigned into four groups: sham group, IH + sham group, ischemia group and IH + ischemia group. Rats for IH preconditioning were exposed to hypobaric hypoxia mimicking 5000 m high-altitude (PB = 404 mmHg, PO2 = 84 mmHg) 6 h/day, once daily for 28 days. Global brain ischemia was established by four-vessel occlusion that has been created by Pulsinelli. Rats were sacrificed at 7th day after the ischemia for neuropathological evaluation by thionin stain. In addition, the expression of neuronal NOS (nNOS), inducible NOS (iNOS), and NO content in the hippocampal CA1 subfield were measured at 2nd day and 7th day after the ischemia. Results revealed that global brain ischemia engendered delayed neuronal death (DND), both nNOS and iNOS expression up-regulated, and NO content increased in the hippocampal CA1 subfield. IH preconditioning reduced neuronal injury induced by the ischemia, and prevented the up-regulation of NOS expression and NO production. In addition, L-NAME + ischemia group was designed to detect whether depressing NO production could alleviate the DND. Pre-administration of L-NAME alleviated DND induced by the ischemia. These results suggest that IH preconditioning plays a protective role by inhibiting the over expression of NOS and NO content after brain ischemia. PMID- 29995176 TI - Prognostic value of NUSAP1 in progression and expansion of glioblastoma multiforme. AB - Nucleolar and spindle-associated protein (NUSAP1) is a microtubule and chromatin binding protein that stabilizes microtubules to prevent depolymerization, maintains spindle integrity. NUSAP1 could cross-link spindles into aster-like structures, networks and fibers. It has also been found to play roles in progression of several cancers. However, the potential correlation between NUSAP1 and clinical outcome in patients with glioblastoma multiforme (GBM) remains largely unknown. In the current study, we demonstrated that NUSAP1 was significantly up-regulated in GBM tissues compared with adult non-tumor brain tissues both in a validated cohort and a TCGA cohort. In addition, Kaplan-Meier analysis indicated that patients with high NUSAP1 expression had significantly lower OS (P = 0.0027). Additionally, in the TCGA cohort, NUSAP1 expression was relatively lower in GBM patients within the neural and mesenchymal subtypes compared to other subtypes, and associated with the status of several genetic aberrations such as PTEN deletion and wild type IDH1. The present study provides new insights and evidence that NUSAP1 over-expression was significantly correlated with progression and prognosis of GBM. Furthermore, knockdown of NUSAP1 revealed its regulation on G2/M progression and cell proliferation (both in vitro and in vivo). These data demonstrate that NUSAP1 could serve as a novel prognostic biomarker and a potential therapeutic target for GBM. PMID- 29995177 TI - Avatrombopag: First Global Approval. AB - Avatrombopag (Doptelet(r)) is an orally bioavailable, small molecule thrombopoietin receptor agonist that has been developed by Dova Pharmaceuticals for the treatment of thrombocytopenic disorders. In May 2018 avatrombopag received its first global approval, in the USA, for use in the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure. A Marketing Authorization Application for use of avatrombopag in this indication was submitted to the EMA in April 2018. Clinical development of avatrombopag in the treatment of other thrombocytopenic disorders, including immune thrombocytopenic purpura and chemotherapy-induced thrombocytopenia, is ongoing. This article summarizes the milestones in the development of avatrombopag leading to this first approval for the treatment of thrombocytopenia in adult patients with CLD. PMID- 29995178 TI - Hemiarthroplasty for proximal humerus fractures with conservation of the whole humeral head as autograft: does it improve greater tuberosity healing? AB - PURPOSE: Hemiarthroplasty (HA) for proximal humerus fracture (PHF) is associated with tuberosity complications like migration, non-union, and resorption. In order to improve the rate of consolidation of the greater tuberosity (GT), we have developed a hollow humeral head prosthesis in which the whole humeral head is inserted and used as autograft. This study is designed to evaluate the consolidation rate of the GT with this device. METHOD: Twenty-two patients at mean age of 68 were treated between 2015 and 2017 for four-part fractures, fracture-dislocations, and head-split fractures with HA including the bony humeral head. The humeral prosthesis device comprises a prosthetic cephalic cup in which the detached humeral head is inserted and a cementless adjustable humeral stem which works like a jack. Mean follow-up was 14 months. The consolidation of GT was followed on X-rays. As comparison, 15 published series were selected and analyzed. RESULTS: There were two mechanical complications related to GT consolidation (9.1%). In the 20 other cases, the GT was radiologically consolidated without displacement. While the raw proportion of complications observed in the present series was lower than that reported in each of the 15 comparative series, the proportion of complications observed in the present series was significantly different from that observed only in seven out of the 15 previous series. CONCLUSION: Whole conservation of the humeral head as an autograft along with proper surgical technique yielded in 20 consolidations of GT without displacement in 22 cases of PHF treated with hemiarthroplasty. PMID- 29995179 TI - Molecular Classification and Management of Rare Pediatric Embryonal Brain Tumors. AB - PURPOSE OF REVIEW: Malignant embryonal brain tumors (EBTs) of childhood span a wide clinical spectrum but can share remarkably similar morphologic features. This overlap presents significant diagnostic challenges, particularly for tumor entities that are rarely encountered in clinical practice and for which diagnostic criteria were poorly defined. This review will provide an update on the evolving characterization and treatment of rare EBTs. RECENT FINDINGS: Rapid advances in genomic tools have led to the discovery of robust molecular markers, and identification of novel tumor types and subtypes for almost all major categories of pediatric brain tumors. These developments have had significant impact on improving the diagnostic classification of the rare EBTs, particularly for tumors with newly recognized C19MC alterations, central nervous system primitive neuroectodermal tumors (CNS-PNET), and pineoblastoma (PB). These important developments in the clinical and molecular understanding of rare EBTs are paving the way for novel therapeutic strategies and improved clinical management. PMID- 29995180 TI - Growth performance and blood profile of West African Dwarf (WAD) goats fed varying levels of treated sweet orange peels. AB - Fifteen West African Dwarf grower bucks of about 6-8 months of age and average weights of 8.39 kg were used in a 70-day study to assess the intake and blood profile of West African Dwarf (WAD) goats fed diets containing graded levels of treated sweet orange peel meal (TSOPM), in a completely randomized design. Sweet orange peels were collected from sweet orange retailers within Makurdi, Benue State, Nigeria. The peels were packed into synthetic bags, compressed, and allowed to ferment for 12 h before sun-drying. The sun-dried peels were crushed into a meal and used to compound four treatments diets which consisted of 0, 60, and 80% TSOPM, designated diets A, B, and C respectively. Results showed that there were no significant differences (P > 0.05) among the treatments in all the performance parameters except in the total forage intake values in which treatment A (19.74 kg) was significantly lower (P < 0.05) than treatment B (21.77 kg) and treatment C (21.96 kg). But between treatment B and treatment C, there was no difference. Effect of treatments was also not apparent on the haematological indices measured, but the serum biochemical parameters showed significant difference (P < 0.05) among the treatments for total protein values. The total protein value for treatment C (8.02 g/dl) was significantly higher (P < 0.05) than treatments A (7.10 g/dl) and B (6.62 g/dl). The study showed that treated sweet orange peel meal can be used up to 80% level to replace maize offal in the diets of goats without adverse effects on the performance blood indices. PMID- 29995181 TI - Evaluation of a new method of oral health education in children with cleft lip and palate. AB - AIM: To evaluate the efficacy of an oral health educational programme in children with cleft lip and palate. METHODS: The sample comprised 38 children with cleft lip and palate: Group 1-dental prophylaxis; Group 2-education and motivation instructions in oral health and plaque control. Children were evaluated during six appointments, at 30-day intervals. The Patient Hygiene Performance (PHP) index was used to assess plaque control. To evaluate the knowledge on oral health a questionnaire was used. Baseline and 6-month PHP scores were compared through Mann-Whitney and Wilcoxon tests. The questionnaire scores were analysed through t test and paired-t test. RESULTS: Baseline PHP indexes between Groups exhibited no statistically significant differences, while the 6-month PHP indices between Groups showed statistically differences (p < 0.001). Group 2 showed statistically significant differences between baseline and 6-month PHP index (p < 0.001). The comparison of Groups questionnaire scores showed no statistically significant differences neither at baseline nor after 6 months. In Group 1, the level of knowledge between baseline and 6-month periods did not show statistically differences, while Group 2 did. CONCLUSIONS: The oral health educational programme improved the plaque control of children with cleft lip and palate. PMID- 29995182 TI - Gastroesophageal Reflux Disease Might Induce Certain-Supposedly Adaptive-Changes in the Esophagus: A Hypothesis. AB - BACKGROUND: The increasing prevalence of GERD has become a major concern due to its major health and economic impacts. Beyond the typical unpleasant symptoms, reflux can also be the source of severe, potentially life-threatening complications, such as aspiration. AIM: Our aim was to support our hypothesis that the human body may in some cases develop various protective mechanisms to prevent these conditions. METHODS: Based on our experiences and review of the literature, we investigated the potential adaptive nature of seven reflux complications (hypertensive lower esophageal sphincter, achalasia, hypertensive upper esophageal sphincter, Zenker's diverticulum, Schatzki's ring, esophageal web, and Barrett's esophagus). RESULTS: Patients with progressive GERD may develop diverse structural and functional esophageal changes that narrow the lumen of the esophagus and therefore reduce the risk of regurgitation and protect the upper aerodigestive tract from aspiration. The functional changes (hypertensive lower esophageal sphincter, achalasia, hypertensive upper esophageal sphincter) seem to be adaptive reactions aimed at easing the unpleasant symptoms and reducing acid regurgitation. The structural changes (Schatzki's ring, esophageal web) result in very similar outcomes, but we consider these are rather secondary consequences and not real adaptive mechanisms. Barrett's esophagus is a special form of adaptive protection. In these cases, patients report significant relief of their previous heartburn as Barrett's esophagus develops because of the replacement of the normal squamous epithelium of the esophagus by acid-resistant metaplastic epithelium. CONCLUSION: We believe that GERD may induce different self-protective reactions in the esophagus that result in reduced acid regurgitation or decreased reflux symptoms. PMID- 29995183 TI - Stool Microbiota Composition Differs in Patients with Stomach, Colon, and Rectal Neoplasms. AB - BACKGROUND: Microbial ecosystems that inhabit the human gut form central component of our physiology and metabolism, regulating and modulating both health and disease. Changes or disturbances in the composition and activity of this gut microbiota can result in altered immunity, inflammation, and even cancer. AIM: To compare the composition and diversity of gut microbiota in stool samples from patient groups based on the site of neoplasm in the gastrointestinal tract (GIT) and to assess the possible contribution of the bacterial composition to tumorigenesis. METHODS: We studied gut microbiota by16S RNA gene sequencing from stool DNA of 83 patients, who were diagnosed with different GIT neoplasms, and 13 healthy individuals. RESULTS: As compared to healthy individuals, stools of patients with stomach neoplasms had elevated levels of Enterobacteriaceae, and those with rectal neoplasms had lower levels of Bifidobacteriaceae. Lower abundance of Lactobacillaceae was seen in patients with colon neoplasms. Abundance of Lactobacillaceae was higher in stools of GIT patients sampled after cancer treatment compared to samples collected before start of any treatment. In addition to site-specific differences, higher abundances of Ruminococcus, Subdoligranulum and lower abundances of Lachnoclostridium and Oscillibacter were observed in overall GIT neoplasms as compared to healthy controls CONCLUSION: Our study demonstrates that the alterations in gut microbiota vary according to the site of GIT neoplasm. The observed lower abundance of two common families, Lactobacillaceae and Bifidobacteriaceae, and the increased abundance of Enterobacteriaceae could provide indicators of compromised gut health and potentially facilitate GIT disease monitoring. PMID- 29995184 TI - Placebo Rates in Randomized Controlled Trials of Pouchitis Therapy. AB - BACKGROUND: Approximately half of the patients with ulcerative colitis (UC) who undergo restorative proctocolectomy develop pouchitis within 10 years of surgery. Currently, there are no approved pouchitis treatments. It is important to quantify, and ultimately minimize, placebo rates to design and conduct efficient pouchitis trials. AIMS: To quantify the placebo rate observed in pouchitis randomized controlled trials (RCTs) in meta-analysis. METHODS: Embase, MEDLINE, and the Cochrane Library were searched from inception to November 3, 2017, for placebo-controlled RCTs enrolling adult UC patients with, or at risk for developing, pouchitis. A fixed-effect binomial-normal model was used to pool placebo rates on the log-odds (logit) scale. Proportions and 95% confidence intervals were reported. Outcomes of interest included development of pouchitis, induction of remission/response, and maintenance of remission/response. The Cochrane risk of bias tool was used to evaluate study quality. RESULTS: Twelve trials (five prevention, five induction, and two maintenance) enrolling a total of 229 placebo patients were eligible for inclusion. The pooled placebo rates for development of pouchitis and induction of response were 47% (95% CI 39-56%) and 24% (95% CI 14-37%), respectively. An insufficient number of trials prevented additional data pooling and meta-regression analysis and no consistent definitions of outcome were identified. CONCLUSIONS: No consistent methods for measuring pouchitis disease activity or defining response and remission were identified, highlighting the need for standardized definitions of outcomes for use in pouchitis trials. Additional high-quality trials are required to evaluate existing and novel therapies in this area. PMID- 29995185 TI - Admission Serum Calcium Level as a Prognostic Marker for Intracerebral Hemorrhage. AB - BACKGROUND: Prognostic significance of serum calcium level in patients with intracerebral hemorrhage is not well studied. The aim of the study was to identify if a relationship between admission serum calcium level and prognosis exists in patients with intracerebral hemorrhage. METHODS: A total of 1262 confirmed intracerebral hemorrhage patients were included. Demographic data, medical history, medicine history, laboratory data, imaging data, clinical score, and progress note were collected from their medical records. All images of head computed tomography were reanalyzed. Ninety-day prognosis was recorded, and poor outcome was defined as death or major disability caused by intracerebral hemorrhage. RESULTS: During the 90-day follow-up period, 504 patients died and 226 patients suffered from major disability. Death and major disability were combined as poor prognosis. The remaining 532 patients showed good prognosis. Admission serum calcium level was lower in the patients with poor prognosis than in the patients with good prognosis (2.41 +/- 0.23 mmol/l, 2.55 +/- 0.26 mmol/l, P < 0.001). Admission INR and hematoma volume were higher in the patients with poor prognosis than in the patients with good prognosis (INR: 1.74 +/- 0.29, 1.70 +/- 0.29, P = 0.029; hematoma volume: 11.6 +/- 4.4 ml, 10.7 +/- 4.1 ml, P < 0.001). There was no difference in admission APTT level between the two prognosis groups (28.4 +/- 5.6 s, 27.8 +/- 5.4 s, P = 0.056). A multivariate COX regression analysis reported that admission serum calcium level <= 2.41 mmol/l was associated with the increased risk of poor prognosis (death or major disability) in the patients (HR 1.45, 95% CI 1.32-1.60). In addition, there was a significant linear association of serum calcium level with coagulation function markers and hematoma volume on admission (APTT: r = - 0.091, P = 0.001; INR: r = - 0.063, P = 0.025; hematoma volume: r = -0.108, P < 0.001). CONCLUSIONS: Admission serum calcium level might be a prognostic marker for intracerebral hemorrhage. Potential mechanism involved calcium-induced coagulation function abnormality. PMID- 29995186 TI - Two multicenter Phase I randomized trials to compare the bioequivalence and safety of a generic doxorubicin hydrochloride liposome injection with Doxil(r) or Caelyx(r) in advanced ovarian cancer. AB - PURPOSE: To compare the pharmacokinetic bioequivalence and safety of a generic pegylated liposomal doxorubicin formulation (SPIL DXR hydrochloride liposome injection) with that of the reference products, Caelyx or Doxil. METHODS: Two open-label, two-way reference crossover studies were conducted in patients with ovarian cancer. Cmax, AUC0 - t, and AUC0-infinity, Vd, and Cl for total, free, and encapsulated DXR were evaluated in 18 blood samples taken pre-dose (t = 0), at increasing time intervals over the following 14 days. A washout period of 28 days was observed before crossing over. RESULTS: Studies 1 and 2 were completed by 24/29 and 41/60 patients, respectively. Pharmacokinetic data from 24 patients from each study established bioequivalence for free DXR in study 2, and for total and encapsulated DXR in both studies. Data from 29 and 54 patients, respectively, were included in the safety evaluation. Of these, 37 patients experienced 81 post dose adverse events (40 related to the test product and 41 related to the reference product). In study 1, four patients were withdrawn owing to adverse events. Eleven patients experienced serious adverse events and one death occurred in study 2. CONCLUSIONS: Bioequivalence between the test and the reference products was established for total and encapsulated DXR in both studies, and for free DXR in the study with the larger sample size (study 2). There were no significant differences between the safety profiles of the generic formulation and the reference products. No correlation was found between drug level and adverse events. TRIAL REGISTRATION: Study 1 was registered retrospectively; registration number is NCT03055143, dated February 15, 2017. Study 2 registration number is NCT00862355, dated March 13, 2009. PMID- 29995187 TI - A multi-detector chromatographic approach for characterization and quantitation of botanical constituents to enable in silico safety assessments. AB - An approach has been developed to characterize the individual chemical constituents of botanicals. The challenge was to identify and quantitate the significant analytes in these complex mixtures, largely in the absence of authentic standards. The data-rich information content generated by this three detector configuration was specifically intended to be used to conduct safety and/or quality evaluations for complex botanical mixtures, on a chemical constituent basis. The approach utilized a broad gradient UHPLC chromatographic separation. Following the chromatographic separation and UV detection, the eluent was split and sent into a charged aerosol detector (CAD), for quantitation, and a quadrupole/time-of-flight high-resolution mass spectrometer for component identification. The known bias of the otherwise universal CAD response, for organic solvent composition of the mobile phase, was compensated by the addition of an inverse gradient make-up stream. This approach and the orthogonal information content from the chromatography and three different detectors was specifically designed to enable in-silico safety assessments. These guide, minimize, or even eliminate the need for in vivo and in vitro safety assessments. The methodology was developed and demonstrated using standardized extracts of Ginkgo biloba. Results from the development of this novel approach and the characterization example reported here demonstrate the suitability of this instrumental configuration for enabling in-silico safety assessments and proving general quality assessments of botanicals. PMID- 29995188 TI - Dissolved oxygen-mediated enrichment of quorum-sensing phenomenon in the bacterial community to combat oxidative stress. AB - Microbial community with their plasticity follows a course of changes that allow adaptation and survival in a particular habitat. In this study perturbations in microbial flora dwelling in two reactors with phenol as a carbon source under the limiting nitrogen and phosphorus conditions were monitored for 3 months with alterations of dissolved oxygen (DO). With the time, the shift in diversity and abundance of bacteria were observed with simultaneous increase in biofilm-forming bacteria like Pseudomonas, Escherichia, etc. Functional level screening revealed that the abundance of core metabolic genes were not much altered, however, the regulated level of increase in quorum sensing genes (acyl-homoserine lactone), biofilm-forming genes, catalase and ferroxidase enzymes at high DO suggest the survival mechanism of the community. This study sheds light on survival route followed by the bacterial community with abiotic stress, such as an increase in DO. PMID- 29995189 TI - Putah Creek hydrology affecting riparian cottonwood and willow tree survival. AB - Creating or recruiting new riparian forests to improve Lower Putah Creek (LPC) ecosystem functions is challenging under the modified stream flow regime developed after historic gravel mining and installation of Monticello Dam upstream. Hydrologic connectivity between riparian trees, shallow groundwater, and the low flow channel is essential towards maintaining these forests and related habitats through the annual summer and multi-year drought periods typical in this Sacramento Valley region of California. Despite increased average summer flows, significant mature cottonwood and willow tree mortality along the LPC riparian areas below the Putah Creek diversion dam in 2014 raised concerns over the soil and hydrologic factors affecting riparian vegetation survival. A forensic analysis was conducted combining annual canopy coverage fractions and tree ring studies with daily soil-water balances, low flow records, and available groundwater level Information from the past few decades to determine the key hydrologic factors affecting riparian tree survival along the LPC. The 2011-2016 drought was linked with greater than prior average soil-water deficits in 2012 2015 and lower initial soil-water storage on March 1 of 2012 and 2014 that would be expected to stress the trees. However, such stress was not apparent in decreased tree ring spacing during this period from mature (40-50 years old), deceased, and living trees. Tree canopy coverage declined dramatically (by as much as 50% as compared to the previous decade average) only in the summer of the 2014 despite a ~ 35% increase in average summer flows from 2011 to 2014. However, the regional water table aquifer levels declined at an average rate of ~ 35 mm/day in 2014 (as compared to ~ 17 mm/day in previous decade) and by several meters overall between 2011 and 2016 suggesting that deceased trees lacked access to the water table aquifer or lateral stream seepage. The increased rates of water table decline and overall depth may be associated with a large increase in adjacent irrigated almond orchard areas in 2014-2016. Knowledge of the dynamic hydrologic factors controlling sustainability of riparian trees should better inform and guide future tree restoration efforts along the LPC. PMID- 29995190 TI - Infer the in vivo point of departure with ToxCast in vitro assay data using a robust learning approach. AB - The development and application of high throughput in vitro assays is an important development for risk assessment in the twenty-first century. However, there are still significant challenges to incorporate in vitro assays into routine toxicity testing practices. In this paper, a robust learning approach was developed to infer the in vivo point of departure (POD) with in vitro assay data from ToxCast and Tox21 projects. Assay data from ToxCast and Tox21 projects were utilized to derive the in vitro PODs for several hundred chemicals. These were combined with in vivo PODs from ToxRefDB regarding the rat and mouse liver to build a high-dimensional robust regression model. This approach separates the chemicals into a majority, well-predicted set; and a minority, outlier set. Salient relationships can then be learned from the data. For both mouse and rat liver PODs, over 93% of chemicals have inferred values from in vitro PODs that are within +/- 1 of the in vivo PODs on the log10 scale (the target learning region, or TLR) and R2 of 0.80 (rats) and 0.78 (mice) for these chemicals. This is comparable with extrapolation between related species (mouse and rat), which has 93% chemicals within the TLR and the R2 being 0.78. Chemicals in the outlier set tend to also have more biologically variable characteristics. With the continued accumulation of high throughput data for a wide range of chemicals, predictive modeling can provide a valuable complement for adverse outcome pathway based approach in risk assessment. PMID- 29995191 TI - Fluorometric determination of microRNA-155 in cancer cells based on carbon dots and MnO2 nanosheets as a donor-acceptor pair. AB - A fluorometric method is presented for sensitive deternination of microRNA. It is making use of carbon dots (C-dots) loaded with a DNA probe as fluorophore and MnO2 nanosheets as the quenching agent. The blue-green fluorescence of the DNA loaded C-dots is quenched by the MnO2 nanosheets, but restored on binding target microRNA-155. The maximum excitation wavelength and the maximum emission wavelength of C-dots are at 360 nm and 455 nm, respectively. Fluorescence correlates linearly with the log of the microRNA-155 concentration in two ranges, viz. from 0.15 to 1.65 aM and from 1.65 to 20 aM. The detection limit is as low as 0.1 aM. The assay can discriminate between fully complementary and single-base mismatch microRNA. The assay displayed high specificity when used to detect MCF-7 breast cancer cells which can be detected in concentrations from 1000 to 45,000 cells.mL-1, with a 600 cells.mL-1 detection limit. The method was applied to the analysis of serum samples spiked with microRNA, and satisfactory results were acquired. Graphical abstract Schematic of a fluorometric sensing platform for miRNA-155. The method relies on a FRET process between C-dots and MnO2 nanosheets. This strategy has a practical application for detection of miRNA in cell lines and biological fluids. PMID- 29995192 TI - Salar del Hombre Muerto, source of lithium-tolerant bacteria. AB - The Salar del Hombre Muerto is a flat salt with great microbial activity despite the existing extreme conditions like high altitude, lack of water, low level of oxygen, high radiation and high concentration of sodium and lithium chloride. Despite these unfavorable conditions, we found microbial diversity with the presence of fungi, algae, and bacteria. From aqueous solutions and soil samples, a total of 238 bacteria were isolated and 186 of them were able to grow in the presence of salt. About 30% of the strains showed the ability to grow in solid medium proximally to a LiCl solution close to saturation (636 g/L). These isolates were characterized taking into account the morphology, Gram stain, ability to form biofilms and to produce pigments, and mainly according to the tolerance against lithium chloride. Bacillus was predominant among the most tolerant 26 microorganisms found, followed by Micrococcus and Brevibacterium. Members of the genera Kocuria, Curtobacterium and Halomonas were also represented among the bacteria with tolerance to 30 and 60 g/L of LiCl in defined liquid medium. All the capacities found in these microorganisms make them extremely interesting for biotechnological applications. PMID- 29995193 TI - Streptomyces lutosisoli sp. nov., a novel actinomycete isolated from muddy soil. AB - A novel Gram-stain positive, spore-forming, aerobic actinomycete, designated strain NEAU-QTH3-11T, was isolated from muddy soil collected from a stream in Qitaihe, Heilongjiang Province, northeast China and characterised using a polyphasic approach. The 16S rRNA gene sequence analysis showed that strain NEAU QTH3-11T belongs to the genus Streptomyces and is closely related to Streptomyces rhizosphaerihabitans NBRC 109807T (99.38%) and Streptomyces mirabilis JCM 4791T (99.03%). Phylogenetic analysis based on the 16S rRNA gene sequences indicated that the strain formed a cluster with S. rhizosphaerihabitans NBRC 109807T and Streptomyces siamensis NBRC 108799T (98.62%). The menaquinones were identified as MK-9(H8), MK-9(H6) and MK-9(H4). The phospholipid profile was found to consist of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, an unidentified phospholipid and an unidentified lipid. The major fatty acids were identified as anteiso-C15:0, iso-C16:0, C16:0 and C15:0. However, multilocus sequence analysis based on five house-keeping genes (atpD, gyrB, rpoB, recA and trpB), low DNA-DNA hybridization results and some phenotypic, physiological and biochemical properties could differentiate the strain from its close relatives in the genus Streptomyces. Therefore, strain NEAU-QTH3-11T is considered to represent a novel species of the genus Streptomyces, for which the name Streptomyces lutosisoli sp. nov. is proposed, with NEAU-QTH3-11T (=DSM 42165T=CGMCC 4.7198T) as the type strain. PMID- 29995194 TI - MP2-IQA: upscaling the analysis of topologically partitioned electron correlation. AB - When electronic correlation energy is partitioned topologically, a detailed picture of its distribution emerges, both within atoms and between any two atoms. This methodology allows one to study dispersion beyond its more narrow definition in long-range Rayleigh-Schrodinger perturbation theory. The interacting quantum atoms (IQA) method was applied to MP2/6-31G(d,p) (uncontracted) wave functions of a wide variety of systems: glycine...water (hydration), the ethene dimer (pi-pi interactions), benzene (aromaticity), cyclobutadiene (antiaromaticity), and NH3BH3 (dative bond). Through the study of molecular complexes it turns out that dispersion energy is either important to a system's stabilization (for the C2H4 dimer) or not important (for Gly...H2O). We have also discovered that the delocalization in benzene lowers the strength of Coulomb repulsion in the bonds, which has been quantified for the first time through IQA. Finally, we showed that the nature of the dative bond is much different from that of a regular covalent bond as it is not destabilized by electronic correlation. Finally, the conclusions obtained for these archetypical systems have implications for the future of the quantum topological force field FFLUX in the simulation of larger systems. Graphical abstract Atomic and bond dynamic correlation energies are now available thanks to IQA. Larger molecules can now be accessed to include resonance and solvation of FFLUX force field. PMID- 29995195 TI - Visual function and inner retinal structure correlations in aquaporin-4 antibody positive optic neuritis. AB - PURPOSE: To investigate the correlation between visual function and thinning of the retinal nerve fiber layer (RNFL) and the macular ganglion cell-inner plexiform layer (GCIPL) as measured by optical coherence tomography (OCT) in eyes with aquaporin-4 IgG-positive optic neuritis (AQP4-IgG-positive ON). STUDY DESIGN: Prospective study. METHODS: Patients with a history of ON were categorized into 2 groups: the AQP4-IgG-positive group and the AQP4-IgG-negative group. Patients with multiple sclerosis were excluded. All patients underwent ophthalmologic examination and OCT imaging at least 6 months after the last episode of acute ON. Visual function and inner retinal structure correlations were analyzed using Pearson correlation and regression analyses. RESULTS: Thirty one previous ON eyes of 17 AQP4-IgG-positive patients and 21 previous ON eyes of 15 AQP4-IgG-negative patients were registered. Visual function, especially the visual field, was better correlated with RNFL than with macular GCIPL. The best correlation between visual function and RNFL was the linear model, whereas the best correlation between visual function and GCIPL was the nonlinear model (inverse regression). Regression models revealed worse visual function in AQP4 IgG-positive ON than in AQP4-IgG-negative ON, whereas no differences in RNFL and GCIPL were found between the 2 groups. CONCLUSIONS: RNFL measured by OCT can be a useful retinal structure for estimating and monitoring visual field loss in AQP4 IgG-positive ON patients, particularly in patients whose visual field cannot be quantitated. The correlation between visual function and the inner retinal structure of eyes with AQP4-IgG is unique and differs from that of eyes without AQP4-IgG. PMID- 29995196 TI - Limited Approaches to Calcaneal Fractures. AB - PURPOSE OF REVIEW: To review literature published in the last 3 years related to minimally invasive approaches to calcaneal fracture fixation. RECENT FINDINGS: Numerous randomized control trials, cohort studies, and meta-analyses have been done in the last 3 years comparing surgical treatment of calcaneus fractures. These studies indicate minimally invasive procedures decrease wound complication rates and achieve similar radiographic and clinical outcomes to open reduction internal fixation. In comparing different surgical treatment methods to non operative treatment, operative management has increased complication rates but may lead to better functional outcomes in certain patient populations. Optimal treatment for displaced intra-articular calcaneus fractures continues to be debated. Current literature would suggest that the decision to operate be based on patient and fracture characteristics and surgeon capabilities. Minimally invasive techniques aim to improve patient reported outcomes and quality of life while decreasing complications and offer another option for surgeons in the treatment of displaced intra-articular calcaneal fractures. PMID- 29995197 TI - Association between serum somatostatin levels and glucose-lipid metabolism in the Jino ethnic minority and Han Chinese population. AB - We aim to investigate the relationship between serum somatostatin (SST) levels and glucose-lipid metabolism at various stages of glucose tolerance in the Jino ethnic minority (n=111) and Han population (n=113) of Yunnan Province, southwest China. Anthropometric parameters and biochemical traits were measured. Serum SST and plasma glucagon levels were tested. Participants were divided into three subgroups: isolated fasting hyperglycemia (IFH), isolated post challenge hyperglycemia (IPH) and normal glucose tolerance (NGT). SST levels were found lower while glucagon levels were significantly higher in the Jino ethnic with IPH (P=0.0026 and P=0.0069, respectively). Fasting glucose and high density lipoprotein-cholesterol (HDL-C) levels were higher (P=0.0055 and P=0.0021, respectively) and fasting insulin levels and homeostasis model assessments beta cell function were lower (P=0.0479 and P=0.0007, respectively) in the Jino population. After adjusting for confounding factors, the serum SST level was associated with glucagon (P<0.0001) in both populations. The SST level was correlated with fasting Cpeptide (P=0.0267) in Jino and HDL-C levels in Han (P=0.0079). Our findings suggest that serum SST levels and plasma glucagon levels may vary in subjects with IPH between two ethnics. PMID- 29995198 TI - Genomic characterizations of H4 subtype avian influenza viruses from live poultry markets in Sichuan province of China, 2014-2015. PMID- 29995199 TI - Grapevine virus T is relatively widespread in Slovakia and Czech Republic and genetically diverse. AB - A recently described putative foveavirus, grapevine virus T (GVT), was detected in a Slovak grapevine accession (SK704) using high-throughput sequencing, prompting further studies. Full-length genome sequence of isolate GVT-SK704 was determined. Analyses revealed 86.1% nucleotide identity with the Italian GVT isolate, currently the only available nearly complete sequence of GVT in GenBank. A virus-specific RT-PCR assay was developed, which enabled a survey of GVT incidence in grapevine samples from Slovakia and Czech Republic. Unexpectedly, GVT was present in ~ 30% of tested samples. Analysis of complete CP gene sequences of 20 Slovak and Czech GVT isolates detected in the survey revealed relatively high intra-species variability (up to 11.2% nucleotide divergence), suggesting multiple introductions from different sources, possibly over an extended period of time. PMID- 29995200 TI - "It ain't what you do, it's the way that you do it": does obesity affect perceptual motor control ability of adults on the speed and accuracy of a discrete aiming task? AB - The ability to control speed and accuracy of goal directed aiming tasks underpins many activities of daily living. Recent evidence has begun to suggest that obesity can affect the control of movement. This study evaluated perceptual motor control of 183 normal weight, overweight, and obese participants using a discrete Fitts' task on a digital tablet. In addition, we manipulated tablet orientation to determine whether tablet orientation influences task difficulty with the view to increase the task's constraints. Our study found that the traditional relationship between target distance and target width hold true for each of the three weight groups in both tablet orientations. Interestingly, no significant differences were found for movement time between the groups, while movement kinematics differed between weight groups. Obese participants demonstrated significantly higher peak acceleration values in the horizontal tablet orientation when compared to their normal weight and overweight counterparts. Further to this, obese participants made significantly more errors than normal weight and overweight groups. These findings suggest that obese individuals have altered control strategies compared to their normal weight peers. PMID- 29995201 TI - Burden of Illness in Acid Sphingomyelinase Deficiency: A Retrospective Chart Review of 100 Patients. AB - Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease caused by the deficiency of the enzyme acid sphingomyelinase (ASM) resulting in accumulation of sphingomyelin in target tissues. Little is known regarding predictors of disease-related morbidity, healthcare use, and lifestyle impact in adults with chronic disease. A multinational retrospective study collected data on the burden of illness and healthcare resource use for 100 patients across the clinical spectrum of ASMD, including those with rapidly progressive infantile neurovisceral disease (n = 13) and those with the more slowly progressive chronic neurovisceral (n = 6) and chronic visceral (n = 81) disease. Growth was subnormal throughout childhood for all patients with chronic neurovisceral disease and for 50% of patients with chronic visceral disease. Developmental delay, regression, and/or learning disabilities were reported in 40% of patients with chronic neurovisceral ASMD and 21% of patients with chronic visceral ASMD. Outpatient therapy or home healthcare was required for 50% of patients with chronic neurovisceral disease and 12% of patients with chronic visceral disease. Disease-related disability for patients with chronic disease resulted in need for home schooling for 16% of patients and compromised work ability for 22% of patients. Grade school was the highest level of education for 22% of patients older than 13 years of age. PMID- 29995202 TI - The Second Case of Saposin A Deficiency and Altered Autophagy. AB - Krabbe disease is a lysosomal storage disease caused by galactosylceramidase deficiency, resulting in neurodegeneration with a rapid clinical downhill course within the first months of life in the classic infantile form. This process may be triggered by the accumulation of galactosylceramide (GalCer) in nervous tissues. Both the enzyme galactosylceramidase and its in vivo activator molecule, saposin A, are essential during GalCer degradation. A clinical manifestation almost identical to Krabbe disease is observed when, instead of the galactosylceramidase protein, the saposin A molecule is defective. Saposin A results from posttranslational processing of the precursor molecule, prosaposin, encoded by the PSAP gene. Clinical and neuroimaging findings in a 7-month-old child strongly suggested Krabbe disease, but this condition was excluded by enzymatic and genetic testing. However, at whole exome sequencing, the previously undescribed homozygous, obviously pathogenic PSAP gene NM_002778.3:c.209T>G(p.Val70Gly) variant was determined in the saposin A domain of the PSAP gene. Fibroblast studies showed GalCer accumulation and the activation of autophagy for the first time in a case of human saposin A deficiency. Our patient represents the second known case in the literature and provides new information concerning the pathophysiology of saposin A deficiency and its intralysosomal effects. PMID- 29995203 TI - Heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A1) can cause transient adrenal insufficiency and life-threatening failure to thrive. AB - The first and rate-limited step of steroidogenesis in all steroidogenic tissues is the conversion of cholesterol to pregnenolone, catalysed by P450scc side-chain cleavage enzyme (CYP11A1 gene-SCC). SCC deficiency has been characterised as an autosomal recessive disorder, although it may also be inherited as an autosomal dominant trait in humans. Here, we describe a family of three members carrying the same novel heterozygous CYP11A1 mutation, a c.235G > A missense variant in exon 1: pVal79Ile. A 46 XY boy (P1) was presented at the age of 3 months with early onset adrenal insufficiency and life-threatening failure to thrive, with low adrenal androgens but normal external genitalia. Five years later, the parents had twin girls, one of whom (P2) presented acute adrenal crisis a few hours after birth. The father (P3), born at term, was reported as having suffered from failure to thrive during the neonatal period, though not his only male sibling. This report of severe early adrenal insufficiency caused by a heterozygous mutation of the CYP11A1 gene clearly demonstrates that SCC deficiency may be inherited as an autosomal dominant trait in humans. PMID- 29995204 TI - Framework of Computer Aided Diagnosis Systems for Cancer Classification Based on Medical Images. AB - Early detection of cancer can increase patients' survivability and treatment options. Medical images such as Mammogram, Ultrasound, Magnetic Resonance Imaging, and microscopic images are the common method for cancer diagnosis. Recently, computer-aided diagnosis (CAD) systems have been used to help physicians in cancer diagnosis so that the diagnosis accuracy can be improved. CAD can help in decreasing missed cancer lesions due to physician fatigue, reducing the burden of workload and data overloading, and decreasing variability of inter- and intra-readers of images. In this research, a framework of CAD systems for cancer diagnosis based on medical images has been proposed. The proposed work helps physicians in detection of suspicion regions using different medical images modalities and in classifying the detected suspicious regions as normal or abnormal with the highest possible accuracy. The proposed framework of CAD system consists of four stages which are: preprocessing, segmentation of regions of interest, feature extraction and selection, and finally classification. In this research, the framework has been applied on blood smear images to diagnose the cases as normal or abnormal for Acute Lymphoblastic Leukemia (ALL) cases. Ant Colony Optimization (ACO) has been used to select the subsets of features from the features extracted from segmented cell parts which can maximize the classification performance as possible. Different classifiers which are Decision Tree (DT), K-nearest neighbor (K-NN), Naive Bayes (NB), and Support Vector Machine (SVM) have been applied. The framework has been yielding promising results which reached 96.25% accuracy, 97.3% sensitivity, and 95.35% specificity using decision tree classifier. PMID- 29995205 TI - Negotiating Control of HIV: A Qualitative Analysis of HIV-Positive Latino MSM in North Carolina. AB - The majority of HIV disease management happens outside of clinical encounters. As such, understanding how HIV fits into the lives of patients is key to improving HIV outcomes. The concept of control is a vital part of the social context within which health is managed. This qualitative study explores how a sample of Latino men who have sex with men living with HIV in North Carolina (n = 16) conceptualize and negotiate control in the context of living with HIV. We found that participants use a range of strategies to exert control over their lives including: understanding their infection, engaging with health care, and developing relationships with health professionals. By considering how individuals make sense of their HIV diagnosis and integrate it into their lives, HIV providers can direct efforts at strategic points of control decision-making and advanced clinicians can prioritize issues to address during clinical encounters. PMID- 29995206 TI - Level of Alcohol Use Associated with HIV Care Continuum Targets in a National U.S. Sample of Persons Living with HIV Receiving Healthcare. AB - We evaluated associations between levels of alcohol use and HIV care continuum components using national Veterans Aging Cohort Study data for all patients with HIV and AUDIT-C screening (2/1/2008-9/30/2014). Poisson regression models evaluated associations between alcohol use levels (non-drinking, low-, medium-, high-, and very high-level drinking) and: (1) engagement with care (documented CD4 cells/ul or viral load copies/ml labs), (2) ART treatment (>= 1 prescription), and (3) viral suppression (HIV RNA < 500 copies/ml) within one year. Among 33,224 patients, alcohol use level was inversely associated with all care continuum outcomes (all p < 0.001). Adjusted prevalence of care engagement ranged from 77.8% (95% CI 77.1-78.4%) for non-drinking to 69.1% (66.6-71.6%) for high-level drinking. The corresponding range for ART treatment was 74.0% (73.3 74.7%) to 60.1% (57.3-62.9%) and for viral suppression was 57.3% (56.5-58.1%) to 38.3% (35.6-41.1%). Greater alcohol use is associated with suboptimal HIV treatment across the HIV care continuum. PMID- 29995207 TI - Flavonoids of Rosa roxburghii Tratt offers protection against radiation induced apoptosis and inflammation in mouse thymus. AB - The present study evaluated the protective effect of the natural compound flavonoids of Rosa roxburghii Tratt (FRT) against gamma-radiation-induced apoptosis and inflammation in mouse thymus cells in vivo and in vitro. Thymus cells and mice were exposed to 60Co gamma-ray at a dose of 6 Gy. The radiation treatment induced significant cell apoptosis and inflammation. Radiation increased the expressions of cleaved caspase 3/8-10, AIF, and PARP-1, and FRT could mitigate their activation and inhibit subsequent apoptosis in the thymus both in vitro or in vivo. Irradiation increased the mRNA expression of ICAM 1/VCAM-1, IL-1alpha/IL-6 and TNF-alpha/NF-kappaB. Our results also indicated that FRT alleviated gene expression of some inflammatory factors such as ICAM-1/VCAM 1, TNF-alpha/NF-kappaB, but not IL-1alpha/IL-6. Irradiation increased the protein expression levels of ICAM-1/VCAM-1, IL-1alpha/IL-6 and TNF-alpha/NF-Kappab, and our results also indicated that FRT alleviated protein level expression of certain inflammatory factors such as ICAM-1, IL-1alpha/IL-6, TNF-alpha/NF-kappaB, but not VCAM-1. Our results suggested that FRT enhanced radioprotection at least partially by regulating caspase 3/8-10, AIF, and PARP-1 to reduce apoptosis and by regulating ICAM-1, IL-1alpha/IL-6, TNF-alpha/NF-kappaB to reduce inflammation. PMID- 29995208 TI - Host and Viral Factors Influencing Interplay between the Macrophage and HIV-1. AB - HIV-1 persists in cellular reservoirs that cannot be eliminated by antiretroviral therapy (ART). The major reservoir in infected individuals on effective ART is composed of resting memory CD4+ T cells that harbor proviral cDNA, and undergo a state of latency in which viral gene expression is minimal to absent. The CD4+ T cell reservoir has been extensively characterized. However, other HIV-1 permissive cells may contribute to HIV-1 persistence. Lentiviruses have a long recognized association with macrophages. However, the role, if any, played by macrophages in HIV-1 persistence is not well understood. Macrophages are resistant to cell death upon HIV-1 infection, and can survive for long periods of time, making them ideal host cells in which the virus might persist. Studying macrophages is challenging, as these cells reside in nearly all tissues. Moreover, detecting viral DNA or RNA in macrophages does not necessarily indicate that these cells will produce replication-competent viral particles. Currently, the gold standard assay to detect cellular reservoirs is the ex vivo quantitative viral outgrowth assay (QVOA), which requires a patient blood draw. However, macrophages reside deep within tissues that are inaccessible in living subjects, such as the central nervous system (CNS). Therefore, tools other than QVOA must be developed to identify cellular reservoirs that reside in the tissues. In this review, we will focus on the main aspects involved in HIV-1 persistence, including the molecular mechanisms of viral evasion, the main cell types responsible for harboring persistent HIV-1 and the tissue compartments that are likely to be reservoirs for HIV-1. PMID- 29995209 TI - Increasing grassland degradation stimulates the non-growing season CO2 emissions from an alpine meadow on the Qinghai-Tibetan Plateau. AB - The alpine meadow ecosystem is one of the major vegetation biomes on the Qinghai Tibetan Plateau, which hold substantial quantities of soil organic carbon. Pronounced grassland degradations (induced by overgrazing/climate change and further exacerbated by the subterranean rodent activities) that have widely occurred in this ecosystem may significantly alter the non-growing season carbon turnover processes such as carbon dioxide (CO2) efflux, but little is known about how the non-growing season CO2 emissions respond to the degradation (particularly the exacerbated degradations by plateau zokor), as most previous studies have focused primarily on the growing season. In this study, the effects of four degradation levels (i.e., the healthy meadow (HM), degraded patches (DP), 2-year old zokor mounds (ZM2), and current-year zokor mounds (ZM1)) on CO2 emissions and corresponding environmental and agronomic variables were investigated over the two non-growing seasons under contrasting climatic conditions (a normal season in 2013-2014 and a "warm and humid" season in 2014-2015). The temporal variation in the non-growing season CO2 emissions was mainly regulated by soil temperature, while increasing degradation levels reduced the temperature sensitivity of CO2 emissions due to a reduction in soil water content. The cumulative CO2 emissions across the non-growing season were 587-1283 kg C ha-1 for all degradation levels, which varied significantly (p < 0.05) interannually. The degradation of alpine meadows significantly (p < 0.05) reduced the vegetation cover and aboveground net primary productivity as well as the belowground biomass, which are typically thought to decrease soil CO2 emissions. However, the non-growing season CO2 emissions for the degraded meadow, weighted by the areal extent of the DP, ZM2, and ZM1, were estimated to be 641-1280 kg C ha-1, which was significantly higher (p < 0.05) as compared with the HM in the warm and humid season of 2014-2015 but not in the normal season of 2013-2014. Additionally, grassland degradation substantially increased the productivity-scaled non-growing season CO2 emissions, which showed an exponential trend with increasing degradation levels. These results suggest that there is a strong connection between grassland degradation and soil carbon loss, e.g., in the form of CO2 release, pointing to the urgent need to manage degraded grassland restoration that contributes to climate change mitigation. PMID- 29995211 TI - Some new angles on the magic angle: what MSK radiologists know and don't know about this phenomenon. AB - PURPOSE: Magic angle effects (MAE) are well-recognized in musculoskeletal (MSK) MRI. With short TE acquisitions, the signal intensity of tendons, ligaments, and menisci depend on their orientation relative to the main magnetic field (B0). An interactive resident physics teaching module simulating MR imaging of a tendon forced us to identify and correct several misconceptions we had about MAE. We suspected these misconceptions were shared by other MSK radiologists. MATERIALS AND METHODS: We surveyed members of the Society of Academic Bone Radiologists (SABR) regarding which pulse sequences, acquisition parameters, tissues and angles relative to B0 were most likely to produce MAE. RESULTS: Survey respondents knew that MAE strongly depend on TE and commonly appear on T1W, FSE and PD sequences, but were less aware that MAE may also appear on T2W, STIR and DWI sequences. They knew of MAE effects in tendons, ligaments and cartilage, but were less aware of those in entheses, peripheral nerves and intervertebral discs. Respondents underestimated the wide angular range (full-width at half-maximum ~ 40?) over which significant MAE can be seen with short TE. CONCLUSIONS: Collagen containing tissues with parallel molecular alignment exhibit increased signal intensity when oriented at 55? relative to B0. Experienced MSK radiologists were found to underestimate the combinations of image parameters, pulse sequences, tissues and collagen orientations in which significant MAE may be seen. Our survey results highlight the need for ongoing MR physics education for practicing radiologists. PMID- 29995210 TI - Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons. AB - alpha-Synuclein (alphaSyn) histopathology defines several neurodegenerative disorders, including Parkinson's disease, Lewy body dementia, and Alzheimer's disease (AD). However, the functional link between soluble alphaSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted alphaSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by alphaSyn. Overexpression of human wild-type alphaSyn in APP animals markedly reduced amyloid deposition but, counter-intuitively, exacerbated deficits in spatial memory. It also increased extracellular amyloid-beta oligomers (AbetaOs), alphaSyn oligomers, exacerbated tau conformational and phosphorylation variants associated with AD, and enhanced neuronal cell cycle re entry (CCR), a frequent prelude to neuron death in AD. Conversely, ablation of the SNCA gene encoding for alphaSyn in APP mice improved memory retention in spite of increased plaque burden. Reminiscent of the effect of MAPT ablation in APP mice, SNCA deletion prevented premature mortality. Moreover, the absence of alphaSyn decreased extracellular AbetaOs, ameliorated CCR, and rescued postsynaptic marker deficits. In summary, this complementary, bidirectional genetic approach implicates alphaSyn as an essential mediator of key phenotypes in AD and offers new functional insight into alphaSyn pathophysiology. PMID- 29995212 TI - Influenza: Underestimated in Children Below 2 Years of Age. AB - Children under 2 years of age may receive antiviral therapy when influenza is suspected. Signs of influenza are frequently unclear and testing is indicated. The aim of the study was to assess the usefulness of clinical signs and the rapid influenza diagnostic test (RIDT) in diagnosing influenza and in choosing the appropriate treatment. In the 2015-2016 influenza season, 89 children under 2 years of age (56.7% of 157 children diagnosed with influenza) were hospitalized. There were 74 RIDT and 70 reverse transcription polymerase chain reactions (RT PCR) performed for the purpose of diagnosis, either test per child. Eighty-three percent of children (74/89) presented with fever, 55.1% (49/89) with cough, and 39.3% (35/89) with both cough and fever. The RIDT was positive in 31.1% (23/74) of cases. The highest percentage of positive RIDT was within the first 24 h of disease, decreasing dramatically thereafter (70% vs.13-17%, respectively). The RIDT shortened the time to diagnosis by 43.8 h/patient (an average ?149 gain in treatment costs). The mean delay for RT-PCR-based diagnosis was 33.5 h/patient (an average ?114 loss in treatment costs). We conclude that clinical signs have a low diagnostic sensitivity in children under 2 years of age. Likewise, RIDT is of low sensitivity, being diagnostically useful only in the first 24 h. The PCR is recommended for the diagnosis, but that requires a constant access to the method. PMID- 29995213 TI - Knowledge Regarding Influenza and Influenza Vaccination in General Population: Results of a National Survey in Poland. AB - For the past 10 years, influenza vaccination coverage rate in Poland remains at a low 3% threshold. This low rate may be related to the unsatisfactory knowledge of vaccination, influenza, and misperception of health risks in the general population. To examine these issues, we used an online questionnaire consisting of 12 closed questions. The basic knowledge on influenza and vaccination was examined. The questionnaire was completed by 1669 persons, mostly young women. Generally, 73% of respondents passed the threshold of 70% correct answers, but important gaps in their knowledge were identified concerning the persons at risk of developing the infection (7.9% of correct answers) and the timing of vaccination (8.4% of correct answers). Although most respondents did identify the etiologic agent correctly (91.1% knew influenza is caused by a virus), only 12.3% knew that the vaccines registered in Poland contain fragments of viruses or its antigens, while 63.1% thought the vaccines contain live bacteria. In conclusion, the knowledge on influenza vaccination is deficient in the general population. Education on immunization should be prioritized to increase vaccination coverage rate in Poland. PMID- 29995214 TI - Decreasing incidence of pharmacologically and non-pharmacologically treated type 2 diabetes in Norway: a nationwide study. AB - AIMS/HYPOTHESIS: This study aimed to examine recent time trends in the incidence and prevalence of type 2 diabetes in Norway. METHODS: In this Norwegian nationwide cohort study, we linked data from national registries with prospectively collected data on diabetes medication and diabetes diagnoses for all residents in Norway aged 30 to 89 years (>3.2 million people). We analysed trends in incidence and prevalence of type 2 diabetes from 2009 to 2014 by type of treatment, sex, age, education level and place of birth. RESULTS: During 15,463,691 person-years of follow-up from 2009 to 2014, we identified 75,496 individuals with new-onset type 2 diabetes. Of these, 36,334 (48%) were treated with blood-glucose-lowering drugs within 6 months of diagnosis. A low education level and being born in Asia, Africa or South America were significant risk factors for incident type 2 diabetes. While the prevalence of type 2 diabetes increased from 4.9% to 6.1% during the study period, the incidence decreased significantly from 609 cases per 100,000 person-years in 2009 to 398 cases per 100,000 in 2014, an annual reduction of 10.1% (95% CI -10.5, -9.6). A declining incidence was seen for both pharmacologically and non-pharmacologically treated type 2 diabetes, and in all subgroups defined by sex, age group, education level and place of birth. CONCLUSIONS/INTERPRETATIONS: This nationwide study shows that, despite a decreasing incidence of type 2 diabetes in Norway, the prevalence continues to rise, probably due to diagnosis at a younger age and increased longevity. PMID- 29995216 TI - Flow-mediated dilation and heart failure: a review with implications to physical rehabilitation. AB - Endothelial dysfunction plays as an important role on mismatch responses that occur during exercise in patients with congestive heart failure (CHF). However, cardiac rehabilitation, a core component of management of CHF patients, can improve endothelial function, contributing to reduce the morbidity and mortality of these patients. The primary aims of this review were to describe the importance of flow-mediated dilatation (FMD) as a non-invasive validation tool to assess endothelial dysfunction and to highlight the relevance of scientific studies that evaluated the effects of exercise interventions on peripheral vascular endothelial function as measured by FMD in patients with CHF with both preserved and reduced ejection fraction. PMID- 29995215 TI - Emerging Approaches in Surveillance of Type 1 Diabetes. AB - PURPOSE OF REVIEW: Surveillance of type 1 diabetes provides an opportunity to address public health needs, inform etiological research, and plan health care services. We present issues in type 1 diabetes surveillance, review previous and current methods, and present new initiatives. RECENT FINDINGS: Few diabetes surveillance systems distinguish between type 1 and type 2 diabetes. Most worldwide efforts have focused on registries and ages < 15 years, resulting in limited information among adults. Recently, surveillance includes use of electronic health information and national health surveys. However, distinguishing by diabetes type remains a challenge. Enhancing and improving surveillance of type 1 diabetes across all age groups could include validating questions for use in national health surveys. In addition, validated algorithms for classifying diabetes type in electronic health records could further improve surveillance efforts and close current gaps in our understanding of the epidemiology of type 1 diabetes. PMID- 29995217 TI - A randomized trial of mailed HPV self-sampling for cervical cancer screening among ethnic minority women in South Florida. AB - PURPOSE: HPV self-sampling has previously been shown to increase cervical cancer screening among ethnic minority and immigrant women. We conducted a randomized pragmatic trial to examine the effectiveness of HPV self-sampling delivered via in-person versus by US mail for medically underserved Hispanic, Haitian, and non Hispanic Black women living in South Florida. METHODS: We randomized women aged 30-65 who had not completed Pap smear screening in the past 3 years into two groups: (1) HPV self-sampling delivered in-person (IP) by a community health worker (CHW; IP + SS) or (2) HPV self-sampling delivered via US mail (SS + Mail). Our primary outcome was HPV self-sampling completion by 6-month post-study enrollment. RESULTS: We enrolled 600 women. Approximately 65% were Hispanic and 35% were Haitian or non-Hispanic Black. Nearly half (43%) had an income of less than $20,000/year and 67% were uninsured. In intent-to-treat analyses, 71.6% of participants in the SS + Mail group and 81.0% of participants in the IP + SS group completed HPV self-sampling. CONCLUSION: Mailed HPV self-sampling is an effective strategy to increase cervical cancer screening among underserved immigrant and ethnic minority women. PMID- 29995218 TI - LMU Munich: platelet inhibition novel aspects on platelet inhibition and function. AB - A core research area in the Department of Cardiology at Ludwig-Maximilians University (LMU) Munich focuses on antiplatelet therapy, its translational aspects, and its underlying mechanism with respect to platelet physiology. We are conducting a broad range of investigator-initiated clinical trials (phase II-IV) and preclinical studies on the topic of antithrombotic therapy for percutaneous coronary intervention patients, platelet activation, and reactivity as well as on novel inhibitors of platelet adhesion. Just recently, we completed the large multi-centre investigator-initiated TROPICAL-ACS trial on guided early de escalation of antiplatelet treatment in acute coronary syndrome (ACS) patients (Sibbing et al. in Lancet 390:1747-1757, 2017; Sibbing et al. in Thromb Haemost 117:1240-1248), done at 33 sites in Europe. Furthermore, besides other ongoing clinical studies, we initiated and are currently recruiting patients for the multi-centre randomized APixaban versus PhenpRocoumon in Patients With ACS and AF: APPROACH-ACS-AF study as well as for the multi-centre phase II randomized, double-blind, placebo-controlled study of revacept in Patients With Stable Coronary Artery Disease (Revacept/CAD/02) trial. PMID- 29995219 TI - Parathyroid hormone is a determinant of serum Dickkopf-1 levels in ankylosing spondylitis. AB - Available studies reported contradictory results about serum levels Dickkopf-1 (DKK1), an inhibitor of Wnt signaling in patients with ankylosing spondylitis (AS). In previous studies, we observed in other conditions that parathyroid hormone (PTH) serum levels were an important determinant of DKK1 serum levels. The aim of the present study was to investigate it in patients with AS. We recruited 71 patients diagnosed with AS. Levels of C-reactive protein (CRP), DKK1, PTH, 25OH-vitamin D, and bone turnover markers (intact N-propeptide of type I collagen, P1NP, and C-terminal telopeptide of type I collagen, CTX) were measured and compared to healthy controls (HC). Dual X-ray absorptiometry at lumbar spine and proximal femoral site was used for bone mineral density (BMD) assessment and spine X-rays were also performed. PTH serum levels were found to be significantly higher in AS patients than in HC (33.8 +/- 14.11 vs 24.8 +/- 13 pg/ml, p = 0.002), while mean DKK1 serum levels were lower than in HC (23.3 +/- 13.1 vs 29.8 +/- 15.9 pmol/l, p = 0.009). A positive correlation between DKK1 and PTH (correlation coefficient + 0.25, p = 0.03) was observed; it remained significant in a multivariate analysis. In patients with longer disease duration, DKK1 was also positively correlated with CTX (coefficient 0.42, p = 0.01), and PTH was higher in those patients with low BMD (Z-score <= - 1) at any site (p = 0.04). Also in AS, PTH is an important determinant of DKK1 serum levels and should be evaluated in studies on DKK1. PTH might have a role in bone involvement in AS, also through the Wnt pathway. PMID- 29995220 TI - Regulation and Interaction of Multiple Types of Synaptic Plasticity in a Purkinje Neuron and Their Contribution to Motor Learning. AB - There are multiple types of plasticity at both excitatory glutamatergic and inhibitory GABAergic synapses onto a cerebellar Purkinje neuron (PN). At parallel fiber to PN synapses, long-term depression (LTD) and long-term potentiation (LTP) occur, while at molecular layer interneuron to PN synapses, a type of LTP called rebound potentiation (RP) takes place. LTD, LTP, and RP seem to contribute to motor learning. However, each type of synaptic plasticity might play a different role in various motor learning paradigms. In addition, defects in one type of synaptic plasticity could be compensated by other forms of synaptic plasticity, which might conceal the contribution of a particular type of synaptic plasticity to motor learning. The threshold stimulation for inducing each type of synaptic plasticity and the induction conditions are different for different plasticity mechanisms, and they change depending on the state of an animal. Facilitation and/or saturation of synaptic plasticity occur after certain behavioral experiences or in some transgenic mice. Thus, the regulation and roles of synaptic plasticity are complicated. Toward a comprehensive understanding of the respective roles of each type of synaptic plasticity and their possible interactions during motor learning processes, I summarize induction conditions, modulations, interactions, and saturation of synaptic plasticity and discuss how multiple types of synaptic plasticity in a PN might work together in motor learning processes. PMID- 29995222 TI - The cost and quality of life outcomes in developing a robotic lobectomy program. AB - The use of the robotic platform is increasingly being utilized for lung resections. Our aim was to compare outcomes of thoracoscopic (VATS) versus robotic-assisted thoracoscopic (RATS) lobectomy early in a program's adoption of robotic surgery, including perioperative outcomes, cost, and long-term quality of life. A prospective database was retrospectively reviewed for all patients undergoing minimally invasive lobectomy by either VATS or RATS techniques from 2010 to 2012. Patients' operative, post-operative complications, cost (operating room and hospital) and quality of life were compared between the two resection techniques. Long-term follow-up including assessment using the European Organization for Research and Treatment of Cancer quality of life questionnaire was documented. During the first 25 RATS lobectomies, there were 73 VATS lobectomies performed, for a total of 98 cases. There was no significant difference in cancer stage, operative time, estimated blood loss, lymph node count, or hospital length of stay. The RATS resections had significantly higher operative and total hospital cost (p < 0.0001 and p < 0.05). At a median of 65 month follow-up, 29 patients (9 robotic; 20 VATS) completed the EORTC questionnaire. The global health status and symptom scale median scores were similar to the general population and did not significantly differ between groups. While transitioning from thoracoscopic to robotic lobectomy incurs increased operative and total hospital cost, equivalent operative outcomes, length of hospitalization, and long-term quality of life can be maintained during this transition. With increasing patient and surgeon interest in robotic resection, it appears both safe and feasible to adopt this approach while maintaining outcomes. PMID- 29995223 TI - Robotic-assisted right posterior segmentectomies for liver lesions: single-center experience of an evolutional method in left semi-lateral position. AB - Despite the popularity of minimally invasive surgery (MIS) for hepatectomy, limitations in the approach of the right posterior section of the liver remain. Although skills and approach techniques have been developed for hepatectomy of lesions in the posterior segments of the liver, most are performed laparoscopically and are limited to few experienced hands using rigid laparoscopic instruments. In this study, we tried a different approach area via the aid of a flexible robotic system. Since 2012, we have successfully completed more than 200 robotic hepatectomy procedures in our institution. Two different patient settings have been applied for right posterior segment lesions, including supine position as general setting in early cases and left semi-lateral decubitus setting in our later cases. The demographic data and perioperative outcomes between the two groups were analyzed in regard to different positioning. A total of 25 patients with right posterior segment lesions underwent robotic-assisted resection, 13 were placed in supine position and 12 in left semi-lateral position. The left semi-lateral group had significantly shorter operation time (306.0 versus 416.8 min, p = 0.023), less blood loss (203.9 versus 1092.3 mL, p = 0.030), and lower transfusion rates (0 versus 46.2%, p = 0.015). We described an evolutionary technique for robotic right posterior segmentectomies with the patient placed in left semi-lateral position. This method can be applied for most patients easily and is demonstrated as a safe and feasible approach in selected patients owing to its ability to overcome the difficulty of MIS hepatectomy for right posterior lesions. PMID- 29995221 TI - A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rbeta1 Deficiency. AB - PURPOSE: Inborn errors of IFN-gamma immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rbeta1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rbeta1 deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rbeta1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variations by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rbeta1-deficient patients with a complete loss of IL-12Rbeta1 expression on phytohemagglutinin-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL 12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, either in the homozygous state (n = 1) or in trans (n = 4) with a single-nucleotide variation (n = 3) or a small indel (n = 1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rbeta1 deficiency. PMID- 29995224 TI - Molecular Genotyping of Candida parapsilosis Species Complex. AB - BACKGROUND: The Candida parapsilosis complex species has emerged as an important cause of human disease. The molecular identification of C. parapsilosis isolates at the species level can be helpful for epidemiological studies and then for the establishment of appropriate therapies and prophylactic measures. METHODS: The present study was undertaken to analyze 13 short tandem repeat (STR) markers (7 minisatellites and 6 microsatellites) in a global set of 182 C. parapsilosis complex isolates from different origins including invasive and superficial clinical sites. RESULTS: Upon the analysis of 182 strains of C. parapsilosis complex species, 10-17 haplotypes were detected for each minisatellite marker. The combination of 7 minisatellite markers yielded 121 different genotypes with a 0.995 D value. Upon the analysis of 114 isolates (68 from invasive infections and 46 from superficial infections), 21-32 genotypes were detected for each microsatellite marker. The combination of all 13 markers yielded 96 different genotypes among 114 isolates with a high degree of discrimination (0.997 D value). The same multilocus genotype was shared by isolates recovered from some patients and from the hand of theirs correspondent healthcare worker. For another patient, the same multilocus genotype of C. metapsilosis was detected in blood and skin confirming that candidemia usually arises as an endogenous infection following prior colonization. CONCLUSIONS: These STR markers are a valuable tool for the differentiation of C. parapsilosis complex strains, to support epidemiological investigations especially studies of strain relatedness and pathways of transmission. PMID- 29995226 TI - A tribute to my supervisor Professor Zhengyi Wu. PMID- 29995225 TI - Venous Obstruction in Cardiac Rhythm Device Therapy. AB - PURPOSE OF REVIEW: A variety of complex vascular pathologies arise following the implantation of electronic cardiac devices. Pacemaker and defibrillator lead insertion may cause proximal venous obstruction, resulting in symptomatic venous congestion and the compromise of potential future access sites for cardiac rhythm lead management. RECENT FINDINGS: Various innovative techniques to recanalize the vein and establish alternate venous access have been pioneered over the past few years. A collaborative team of electrophysiologists and vascular specialists strategically integrate the patient's vascular disease into the planning of electrophysiology procedures. When vascular complications occur after device implantation, the same team effectively manages both the resulting vascular sequelae and related cardiac rhythm device challenges. This review will outline the various vascular challenges related to device therapy and offer an effective strategy for their management. PMID- 29995228 TI - A Novel Bridging Strategy for Patients Undergoing Emergent Non-Cardiac Surgery with a Recent Coronary Stent. AB - INTRODUCTION: Not infrequently, patients undergoing dual antiplatelet therapy for a recent cardiac stent develop a need for a non-cardiac surgery. Most of these surgeries can be delayed while the antiplatelet treatment is stopped and normal platelet function returns in order to avoid potential surgical complications and excessive bleeding. However, there are a number of patients who require urgent surgery where the procedure cannot be postponed. To date, no agents have been proven to bridge the patient off dual-antiplatelet therapy. METHODS: A 46-year old man was admitted to the hospital with an acute anterior wall myocardial infarction. He was urgently taken to the catheterization lab where he was found to have a totally occluded proximal left anterior descending coronary artery (LAD). He was successfully stented with a drug-eluting stent of the LAD, but subsequently developed a sarcoma 2 months later that required urgent surgery. The novel direct-acting, reversible P2Y12 receptor inhibitor cangrelor was used to bridge this patient followed by ongoing antiplatelet treatment, allowing surgery for the removal of a soft tissue sarcoma. RESULTS: Cangrelor was successfully used to bridge a patient with a recent stent placement and current antiplatelet treatment undergoing the removal of a soft tissue sarcoma. CONCLUSION: This case report demonstrates the use of a novel, now currently available, short-acting antiplatelet agent that can be used for bridging patients undergoing non-cardiac surgery who had a recent myocardial infarction and stent placement. PMID- 29995229 TI - Abnormal sperm concentration and motility as well as advanced paternal age compromise early embryonic development but not pregnancy outcomes: a retrospective study of 1266 ICSI cycles. AB - PURPOSE: To investigate the effect of sperm concentration, motility and advanced paternal age on reproductive outcomes. METHODS: A retrospective analysis of 1266 intracytoplasmic sperm injection (ICSI) cycles between 2013 and 2017. The cohort was divided into four groups according to semen concentration based on the WHO criteria (2010): group A (conc. <1 M/ml), group B (1 <= conc. <5 M/ml), group C (5 <= conc. < 15 M/ml) and the control group D (conc. >=15 M/ml). The primary outcome investigated was the blastulation rate. Secondary outcomes were fertilization rate, top quality blastocyst formation rate and ongoing pregnancy rate. RESULTS: After adjustment for maternal age and number of oocytes recovered, a significant difference was observed between group A and group D on the rate of fertilized oocytes [66.7 (40.0-80.0) vs 75.0 (57.1-90.2), adjusted p < 0.001] and the blastocyst formation rate [50.0 (33.3-66.3) vs 55.6 (40.0-75.0), adjusted p < 0.05]. However, the male factor did not affect the top quality blastocyst formation rate nor the ongoing pregnancy rate. Considering the age of the male partner as confounding factor, at the increase of each year of age, a reduction of 0.3% on the fertilization rate was observed but no other outcome was impacted. A negative correlation was also observed between sperm motility and fertilization rate in the group with a motility <5%. CONCLUSION: Male factor infertility and advanced paternal age may compromise fertilization and blastulation rates but not top quality blastocyst formation rate or the establishment of pregnancy in ICSI cycles. PMID- 29995227 TI - Determining the potential sites of neural adaptation to cross-education: implications for the cross-education of muscle strength. AB - Cross-education describes the strength gain in the opposite, untrained limb following a unilateral strength training program. Since its discovery in 1894, several studies now confirm the existence of cross-education in contexts that involve voluntary dynamic contractions, eccentric contraction, electrical stimulation, whole-body vibration and, more recently, following mirror feedback training. Although many aspects of cross-education have been established, the mediating neural mechanisms remain unclear. Overall, the findings of this review show that the neural adaptations to cross-education of muscle strength most likely represent a continuum of change within the central nervous system that involves both structural and functional changes within cortical motor and non motor regions. Such changes are likely to be the result of more subtle changes along the entire neuroaxis which include, increased corticospinal excitability, reduced cortical inhibition, reduced interhemispheric inhibition, changes in voluntary activation and new regions of cortical activation. However, there is a need to widen the breadth of research by employing several neurophysiological techniques (together) to better understand the potential mechanisms mediating cross-education. This fundamental step is required in order to better prescribe targeted and effective guidelines for the clinical practice of cross-education. There is a need to determine whether similar cortical responses also occur in clinical populations where, perhaps, the benefits of cross-education could be best observed. PMID- 29995230 TI - The rice white green leaf 2 gene causes defects in chloroplast development and affects the plastid ribosomal protein S9. AB - BACKGROUND: Plastid ribosomal proteins (PRPs) play important roles in the translation of key proteins involved in chloroplast development and photosynthesis. PRPs have been widely studied in many plant species; however, few studies have investigated their roles in rice. RESULT: In the present study, we used ethyl methane sulfonate mutagenesis and obtained a novel rice mutant called white green leaf 2 (wgl2). The wgl2 mutants exhibited an albino phenotype from germination through the three-leaf stage, and then gradually transitioned to green through the later developmental stages. Consistent with this albino phenotype, wgl2 mutants had abnormal chloroplasts and lower levels of photosynthetic pigments. Map-based cloning and DNA sequencing analyses of wgl2 revealed a single-nucleotide substitution (G to T) in the first exon of LOC_Os03g55930, which resulted in a substitution of glycine 92 to valine (G92 V). WGL2 encodes a conserved ribosomal protein, which localizes to the chloroplast. Complementation and targeted deletion experiments confirmed that the point mutation in WGL2 is responsible for the wgl2 mutant phenotype. WGL2 is preferentially expressed in the leaf, and mutating WGL2 led to obvious changes in the expression of genes related to chlorophyll biosynthesis, photosynthesis, chloroplast development, and ribosome development compared with wild-type. CONCLUSIONS: WGL2 encodes a conserved ribosomal protein, which localizes to the chloroplast. WGL2 is essential for early chloroplast development in rice. These results facilitate research that will further uncover the molecular mechanism of chloroplast development. PMID- 29995231 TI - Three renal failure cases successfully treated with ombitasvir/paritaprevir/ritonavir for genotype 1b hepatitis C virus reinfection after liver transplantation. AB - We report three cases of genotype 1b hepatitis C virus (HCV) reinfection after liver transplantation. When antiviral treatment was considered, all three patients had renal dysfunction and had been treated with immunosuppressive agents for a long time; one with tacrolimus (TAC) and the others with cyclosporine A (CyA). Therefore, the possible antiviral regimens among direct-acting antivirals (DAA) were limited and so we treated all three patients with ombitasvir/paritaprevir/ritonavir (OBV/PTV/r). Because ritonavir is known to markedly increase the blood concentration of TAC and CyA through drug-drug interactions, close monitoring of blood concentrations of TAC or CyA and dose adjustments of immunosuppressive agents were needed. Sustained virus response was achieved in all the patients treated, and there were no adverse effects or transplant rejection. OBV/PTV/r might be a useful DAA regimen for patients with genotype 1 HCV reinfection in the setting of renal dysfunction. PMID- 29995233 TI - Sub-muscular Breast Augmentation Using Tumescent Local Anesthesia. AB - BACKGROUND: Tumescent local anesthesia (TLA) consists of infiltration of saline solution with lidocaine and epinephrine into the tissues to obtain regional anesthesia and vasoconstriction. The use of TLA in augmentation mammoplasty has been described for sub-glandular positioning. We describe a modified TLA technique for primary sub-muscular breast augmentation reporting our experience during the past 7 years. METHODS: From 2010 to 2017, 300 patients underwent bilateral primary sub-muscular breast augmentation under TLA and conscious sedation. The tumescent solution was prepared with 25 mL of 2% lidocaine, 8 mEq of sodium bicarbonate, and 1 mL of epinephrine (1 mg/1 mL) in 1000 mL of 0.9% saline solution. Firstly, the solution was infiltrated between the pectoral fascia and the mammary gland, secondarily, during surgery, under the pectoralis major muscle. RESULTS: The average amount of tumescent solution infiltrated while performing TLA was 740 mL per breast. No signs of adrenaline or lidocaine toxicity were reported and conversion to general anesthesia was never required. In all patients, no pain nor discomfort was reported during the pre-operating infiltration and surgical procedure. We reported a major complication rate of 3.3% (4 hematomas and 6 seromas) and a minor complication rate of 6.0% (8 implant dislocation and 10 dystrophic scars formation). CONCLUSIONS: TLA represents a safe and efficacious technique for performing breast augmentation surgery with sub-muscular implant positioning. This technique guarantees good pain control during and after surgery and has low incidence of postoperative side effects. Patients subjected to sub-muscular breast augmentation with TLA were satisfied. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29995232 TI - Health Behaviors and Preventive Healthcare Utilization Among African-American Attendees at a Faith-Based Public Health Conference: Healthy Churches 2020. AB - Unhealthy eating habits and physical inactivity along with lack of access to quality healthcare contribute to the marked health disparities in chronic diseases among African-Americans. Faith-based public health conferences offer a potential opportunity to improve health literacy and change health behaviors through health promotion within this population, thereby reducing health disparities. This study examined the self-reported health behaviors and preventive healthcare utilization patterns of 77 participants at a predominantly African-American faith-based public health conference, Healthy Churches 2020. A self-administered questionnaire was distributed to a sample of attendees to assess their health behaviors (diet and physical activity), preventive healthcare utilization (annual healthcare provider visits), and health-promoting activities at their places of worship. The results indicate that attendees of a faith-based public health conference have adequate preventive healthcare utilization, but suboptimal healthy behaviors. Our findings support the need for ongoing health promoting activities with an emphasis on diet and physical activity among this population. PMID- 29995234 TI - [Clostridium difficile in the intensive care unit]. AB - Clostridium difficile infections (CDI) are encountered in about 1-2% of patients in the intensive care unit (ICU) and pose a special challenge to those who provide care. Only little data regarding severity and management of CDI in ICU patients in Europe are available. Extrapolation of results from one patient population to another is often difficult. The comorbidities of those patients often limit the application of general recommendations concerning diagnosis and therapy. In addition, there are a relevant percentage of patients (10-20%) with asymptomatic C. difficile colonization. The relevance for the patient and for the risk of patient to patient infection is not yet fully understood. Based on available data, we give an overview of current challenges in the diagnosis, assessment of disease course, primary management options, and alternatives in special cases and treatment failures of CDI. We also discuss prevention of new CDI in the intensive care unit. PMID- 29995235 TI - [Diaries for intensive care unit patients reduce the risk for psychological sequelae : Systematic literature review and meta-analysis]. AB - BACKGROUND: Diaries are written for patients on intensive care units (ICU) by clinicians and relatives to reduce the risk of psychological complications such as posttraumatic stress disorder (PTSD), anxiety, and depression. The authors of a Cochrane Review on this topic published in 2015, included studies with PTSD diagnoses based on interviews carried out by qualified personnel, and concluded that there is inadequate evidence to support the thesis that ICU diaries reduce the risk of psychological complications. METHODS: The present study replicated the design of the Cochrane Review with identical search algorithms, but included additional outcomes data from validated methods of diagnosing psychological complications that were not considered in the original Cochrane Review. The primary outcome was PTSD in patients or relatives with ICU diaries. Secondary outcomes were anxiety and/or depression symptoms. Study quality was evaluated using the Cochrane risk of bias assessment. RESULTS: The replicated search produced 3179 citations, of which there were 6 eligible studies from which 605 patients and 145 relatives could be included in the meta-analysis. Studies ratings ranged from low to good. The meta-analyses of the PTSD outcome demonstrated the following: (a) for ICU patients (4 studies, n = 569 patients) a non-significant reduction (odds ratio [OR] 0.58, 95% confidence interval [CI]: 0.24-1.42, p = 0.23), and (b) for relatives' PTSD (2 studies, n = 145 relatives) a significant reduction (OR 0.17, 95%CI: 0.08-0.38, p < 0.0001). The symptoms anxiety and depression in ICU patients (2 studies each, n = 88 patients) were significantly reduced (OR 0.23, 95%CI: 0.07-0.77, p = 0.02; OR 0.27, 95%CI: 0.09 0.77, p = 0.01, respectively). Heterogeneity was between 0 and 54%. CONCLUSION: ICU diaries may reduce the risk of psychological complications in patients and relatives after ICU stays. PMID- 29995236 TI - Fulminant onset of insulin-dependent diabetes with positive anti-GAD antibody titers during treatment with nivolumab in a patient with NSCLC. AB - Programmed cell death-1 (PD-1) and programmed cell death-ligand-1 (PD-L1) inhibitors have been highlighted in the field of cancer treatment. The interaction between PD-1 and PD-L1 is thought to play an important role in the regulation of the self-immune tolerance mechanism, so blocking these molecules may cause serious immune-related adverse events (IrAE), including fulminant insulin-dependent (type 1) diabetes. Here, we describe a patient with fulminant type 1 diabetes induced by nivolumab, an anti-PD-1 antibody. The patient, a 78 year-old man, was being treated with nivolumab as a third-line treatment for squamous cell carcinoma of the lung. After three cycles, he experienced an abrupt flare-up of the blood glucose within half a day. His blood glucose further increased without clinical symptoms until his hospital visit. Laboratory data showed the complete exhaustion of intrinsic insulin and the elevation of serum antibody titer to glutamic acid decarboxylase (GAD). Although the patient was previously diagnosed with non-insulin-dependent (type 2) diabetes, his disease activity had been well controlled with oral medication and low-dose insulin therapy until just before the flare-up. Because of the laboratory findings and the extremely rapid onset of hyperglycemia, a diagnosis of fulminant, rather than the rapid onset, type 1 diabetes related to nivolumab therapy was strongly suspected. Our case study indicates that fulminant hyperglycemia can occur extremely rapidly. The blood glucose of patients receiving PD-1 antibody therapy should be closely monitored. PMID- 29995237 TI - [Peri-implant femoral fracture following hip arthrodesis in adolescence]. AB - This article presents the case of an 83-year-old woman with a peri-implant femoral fracture after hip arthrodesis in adolescence. Due to the rarity of such operations, there is no standardized approach for these cases. In order to secure the treatment goal of rapid pain-adapted full weight bearing despite reduced bone quality, it was decided to perform a new osteosynthesis with a retrograde femoral nail after removal of some fixation screws of the existing arthrodesis plate. Due to this type of treatment, the preservation of activity and independence of an older trauma patient could be sustainably secured despite operative challenges. Taking an extended osteoporosis treatment into consideration, a bony fracture consolidation and complete convalescence of activity and autonomy were ultimately achieved. PMID- 29995238 TI - [Gudden's diagnosis on Louis II from a contemporary and current psychiatric perspective]. AB - BACKGROUND: Not only the circumstances of the simultaneous death of King Louis II and his psychiatrist Bernhard von Gudden on Pentecost 1886 are still the subject of controversial discussion but also the nature of Louis' mental illness and the expert report that formed the basis for removing Louis from power. RESULTS: When one considers the psychiatric knowledge of the time, however, it becomes clearer how the four experts who assessed Louis reached a diagnosis of paranoia (madness). Gudden left behind no textbook. Nevertheless, a comparison of the structure and symptom weighting of the expert report with the classification system used in the Compendium, the first edition of the textbook published in 1883 by Gudden's long-time pupil Emil Kraepelin, provides insight into Gudden's school of thought. The experts' interpretation of Louis' illness is an outstanding document in the history of psychiatry. Even after the death of Louis and Gudden, the three remaining experts did not change their views before the parliamentary committees investigating the incident. CONCLUSION: If we use the knowledge of the time as the basis for our assessment, there is no justification for claiming that Gudden and his fellow experts wrongly diagnosed Louis. PMID- 29995239 TI - Endometrial Cancer MRI staging: Updated Guidelines of the European Society of Urogenital Radiology. AB - OBJECTIVES: To update the 2009 ESUR endometrial cancer guidelines and propose strategies to standardize image acquisition, interpretation and reporting for endometrial cancer staging with MRI. METHODS: The published evidence-based data and the opinion of experts were combined using the RAND-UCLA Appropriateness Method and formed the basis for these consensus guidelines. The responses of the experts to 81 questions regarding the details of patient preparation, MR imaging protocol, image interpretation and reporting were collected, analysed and classified as "RECOMMENDED" versus "NOT RECOMMENDED" (if at least 80% consensus among experts) or uncertain (if less than 80% consensus among experts). RESULTS: Consensus regarding patient preparation, MR image acquisition, interpretation and reporting was determined using the RAND-UCLA Appropriateness Method. A tailored MR imaging protocol and a standardized report were recommended. CONCLUSIONS: These consensus recommendations should be used as a guide for endometrial cancer staging with MRI. KEY POINTS: * MRI is recommended for initial staging of endometrial cancer. * MR imaging protocol should be tailored based on the risk of lymph node metastases. * Myometrial invasion is best assessed using combined axial-oblique T2WI, DWI and contrast-enhanced imaging. * The mnemonic "Clinical and MRI Critical TEAM" summarizes key elements of the standardized report. PMID- 29995240 TI - Weak-noise-induced transitions with inhibition and modulation of neural oscillations. AB - We analyze the effect of weak-noise-induced transitions on the dynamics of the FitzHugh-Nagumo neuron model in a bistable state consisting of a stable fixed point and a stable unforced limit cycle. Bifurcation and slow-fast analysis give conditions on the parameter space for the establishment of this bi-stability. In the parametric zone of bi-stability, weak-noise amplitudes may strongly inhibit the neuron's spiking activity. Surprisingly, increasing the noise strength leads to a minimum in the spiking activity, after which the activity starts to increase monotonically with an increase in noise strength. We investigate this inhibition and modulation of neural oscillations by weak-noise amplitudes by looking at the variation of the mean number of spikes per unit time with the noise intensity. We show that this phenomenon always occurs when the initial conditions lie in the basin of attraction of the stable limit cycle. For initial conditions in the basin of attraction of the stable fixed point, the phenomenon, however, disappears, unless the timescale separation parameter of the model is bounded within some interval. We provide a theoretical explanation of this phenomenon in terms of the stochastic sensitivity functions of the attractors and their minimum Mahalanobis distances from the separatrix isolating the basins of attraction. PMID- 29995241 TI - Secondary metabolite production by cereal-associated penicillia during cultivation on cereal grains. AB - Cereals are vulnerable substrates for fungal growth and subsequent mycotoxin contamination. One of the major fungal genera to colonize the ecosystem of stored grain is Penicillium, especially species in the series of Viridicata and Verrucosa. Culturing these species on grains, we hoped to induce the production of relevant secondary metabolites produced by these fungi in the early stage of cereal breakdown. In a multivariate setup six different cereal grains (wheat, rye, barley, oat, rice, and maize), one kind of white beans, and two standard fungal media, Yeast Extract Sucrose agar (YES agar) and Czapek Yeast Autolysate agar (CYA agar), were inoculated with the ten most important cereal-associated species from Penicillium (P. aurantiogriseum, P. cyclopium, P. freii, P. melanoconidium, P. neoechinulatum, P. polonicum, P. tricolor, P. viridicatum, P. hordei, and P. verrucosum). P. nordicum is a meat-associated species, which was included due to its chemical association with P. verrucosum, in addition to see if a substrate change would alter the profile of known chemistry. We found that cereals function very well as substrates for secondary metabolite production, but did not present significantly different secondary metabolite profiles, concerning known chemistry, as compared to standard laboratory agar media. However, white beans altered the semi-quantitative secondary metabolite profiles for several species. Correlations between substrates and certain metabolites were observed, as illuminated by principal component analysis. Many bioactive secondary metabolites were observed for the first time in the analyzed fungal species, including ergot type alkaloids in P. hordei. PMID- 29995242 TI - SGLT2 Inhibitors and Cardiovascular Outcomes: Current Perspectives and Future Potentials. AB - PURPOSE OF REVIEW: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to exert benefit on cardiac outcomes. In this review, we provide updates on available clinical data, studies on potential mechanisms for the CV effects, as well as discuss potential clinical implications of these new findings. RECENT FINDINGS: Since the publications of the EMPA-REG and CANVAS trials, large multi national cohort studies have further shown the cardioprotective effects of SGLT2i. Moreover, new studies examining SGLT2i action on sodium-hydrogen exchanger proteins in both the heart and the kidney, on myocardial energetics and impact on inflammation and atherosclerosis continue to shed light on the multitude of pleotropic effects of these agents. Though more data is needed to substantiate the safety and efficacy, SGLT2i should be considered as a valuable therapy to help reduce CV risk in patients with diabetes. Ultimately, SGLT2i may have utility in preventing progression to diabetes or providing CV protection in patients who do not have diabetes. PMID- 29995244 TI - Medicine Administration in People with Parkinson's Disease in New Zealand: An Interprofessional, Stakeholder-Driven Online Survey. AB - Medicine administration errors are twice as frequent in people with dysphagia than in those without. Medicine administration is particularly critical for people with Parkinson's disease where late, or missed doses reduce medicine effectiveness and impact on the quality of life. The aim of this study was to explore the current medicine administration practices of people with Parkinson's disease in New Zealand. A self-administered online survey was developed by an interprofessional group including people with Parkinson's disease (the primary stakeholders), speech-language pathologists and pharmacists. The survey was administered using a cross-sectional study design and asked respondents about self-reported swallowing difficulties [using Eating Assessment Tool (EAT-10)], medicine regimes and strategies used to swallow medicines. Seventy-one people with Parkinson's disease responded to the survey (69% male, mean age 72 years, mean years with Parkinson's disease 9 years). Respondents reported complex daily multi-medicine consumption (mean no. of pills 11, range 2-25). Analyses showed that 57% of respondents scored outside the normal range for EAT-10 (> 3) with 57% complaining of difficulties with pills. Many respondents admitted to missing medicines and requiring external reminders. Multiple strategies for swallowing pills were described including crushing tablets, using yoghurt or fruit juice, and swallowing strategies (such as head tilt, effortful swallow, chin down and altered pill placement in the mouth). Medicine administration is complex and challenging for people with Parkinson's disease. The development of educational packages for people with Parkinson's disease, their carers and health professionals is much needed. PMID- 29995243 TI - Screening for Barrett's Esophagus: Are New High-Volume Methods Feasible? AB - New improved methods are required for the early detection of esophageal adenocarcinoma in order to reduce mortality from this aggressive cancer. In this review we discuss different screening methods which are currently under evaluation ranging from image-based methods to cell collection devices coupled with biomarkers. As Barrett's esophagus is a low prevalence disease, potential screening tests must be applied to an enriched population to reduce the false positive rate and improve the cost-effectiveness of the program. PMID- 29995245 TI - Association study of dietary non-enzymatic antioxidant capacity (NEAC) and colorectal cancer risk in the Spanish Multicase-Control Cancer (MCC-Spain) study. AB - PURPOSE: Studies attempting to link dietary non-enzymatic antioxidant activity (NEAC) and colorectal cancer (CRC) risk have reported mixed results. We examined this association in the Spanish Multicase-Control Study considering the likely influence of coffee and other dietary factors. METHODS: 1718 CRC cases and 3312 matched-controls provided information about diet through a validated 140-item food frequency questionnaire. Dietary NEAC was estimated for three methods [total radical-trapping antioxidant parameters (TRAP), ferric reducing/antioxidant power (FRAP) and TEAC-ABTS] using published values of NEAC content in food, with and without coffee's NEAC. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated through unconditional logistic regression models adjusted for lifestyle and dietary factors. RESULTS: Overall dietary intake of NEAC was significantly lower in cases compared to controls and associated with a significantly reduced CRC risk, in both men (ORQ5vsQ1 = 0.67, 95% CI 0.47-0.96 for FRAP) and women (ORQ5vsQ1 = 0.53, 95% CI 0.32-085 for FRAP), in multivariate models with and without the antioxidant contribution from coffee. The effect was similar for all the NEAC methods evaluated and for both colon and rectum. The association between dietary NEAC and CRC risk became non-significant when adjusting for fiber intake. However, intakes of NEAC and fiber were correlated. CONCLUSION: This study indicates that intake of an antioxidant-rich plant-based diet, both with and without NEAC from coffee, is associated with decreased CRC risk. PMID- 29995246 TI - [Exposure therapy for chronic back pain]. AB - Exposure therapy is an economical and promising psychological method for the treatment of chronic back pain, although little research has been done and its evidence needs further clarification. Exposure therapy has so far been little used in practice, which is partly due to the few published studies on this topic and partly to the uncertainty of the practitioners as to whether exposure therapy can be carried out without risk. Exposure therapy can be classified as a "tailored treatment" approach, in which patients with certain profiles (here: increased fear of movement) receive specific treatments. In this review article, the theoretical principles of exposure therapy are presented. Subsequently, possibilities for the identification of those patients suitable for exposure treatment are explained. The practical procedure is presented using a case study. The four randomized controlled trials available to date are described in detail and discussed. PMID- 29995247 TI - Effect of Site-Specific Intermolecular Lysine-Tryptophan Interactions on the Aggregation of Gramicidin-Based Peptides Leading to Pore Formation in Lipid Membranes. AB - In contrast to the parent pentadecapeptide gramicidin A (gA), some of its cationic analogs have been shown previously to form large-diameter pores in lipid membranes. These pores are permeable to fluorescent dyes, which allows one to monitor pore formation by using the fluorescence de-quenching assay. According to the previously proposed model, the gA analog with lysine substituted for alanine at position 3, [Lys3]gA, forms pores by a homopentameric assembly of gramicidin double-stranded beta-helical dimers. Here, we studied the newly synthesized analogs of [Lys3]gA with single, double and triple substitutions of isoleucines for tryptophans at positions 9, 11, 13, and 15. Replacement of any of the tryptophans of [Lys3]gA with isoleucine resulted in suppression of the pore forming activity of the peptide, the effect being significantly dependent on the position of tryptophans. In particular, the peptide with a single substitution of tryptophan 13 showed much lower activity than the analogs with single substitutions at positions 9, 11, or 15. Of the peptides with double substitutions, the strongest suppression of the leakage was observed with tryptophans 13 and 15. In the case of triple substitutions, only the peptide retaining tryptophan 11 exhibited noticeable activity. It is concluded that tryptophans 11 and 13 contribute most to pore stabilization in the membrane, whereas tryptophan 9 is not so important for pore formation. Cation-pi interactions between the lysine and tryptophan residues of the peptide are suggested to be crucial for the formation of the [Lys3]gA pore. PMID- 29995248 TI - [Human genetics in atypical hemolytic uremic syndrome-its role in diagnosis and treatment]. AB - The atypical hemolytic uremic syndrome (aHUS), one of the three major forms of thrombotic microangiopathy, is characterized by genetic alterations in the area of the complement cascade, which can be detected in 40%-60% of all patients with aHUS. Mutations in over 10 different genes have now been identified. The most frequent and clinically relevant of these are mutations that result in a decreased or absent function of factor H, the formation of hybrid genes, or the formation of autoantibodies against factor H. Although genetics are not required for the diagnosis of aHUS, it is of great importance for the decision on how long to treat with the C5 inhibitor eculizumab. Also, knowledge of genetic alterations is absolutely essential if a living related donor is considered, in order to protect the living donor and recipient from developing aHUS. PMID- 29995249 TI - [From symptom to syndrome using modern software support]. AB - Diagnosing rare diseases can be challenging for clinicians. This article gives an overview on novel approaches, which enable automated phenotype-driven analyses of differential diagnoses for rare diseases as well as genomic variation data of affected individuals. The focus lies on reliable methods for collating clinical phenotypic data and new algorithms for precise and robust assessment of the similarity between phenotypic profiles. The Human Phenotype Ontology project (HPO; www.human-phenotype-ontology.org ) provides an ontology for collating symptoms and clinical phenotypic abnormalities. Using ontologies makes it possible to capture these data in a precise and comprehensive fashion as well as to apply reliable and robust automated analyses. Tools, such as the Phenomizer, enable the algorithmic calculation of similarity values amongst patients or between patients and disease descriptions. Such digital tools represent a solid foundation for differential diagnostic applications. Many rare diseases have a strong genetic component but the analysis of the coding DNA variants in rare disease patients is an enormously complex procedure, which often impedes successful molecular diagnostics. In this situation a combined analysis of the patients HPO-coded phenotypic features and the genomic characteristics of the variants can be of substantial help. In this case the HPO project and the associated algorithms are helpful: it is therefore an important component for phenotype-driven translational research and prioritization of disease-relavant genomic variations. PMID- 29995250 TI - [Substitution with thyroid hormones in the elderly : Goals and risks]. AB - Substitution with thyroid hormones is indicated in elderly patients with overt hypothyroidism, especially, when they present with typical symptoms of hypothyroidism. In light of the current study situation, the use of levothyroxine to treat clinical hypothyroidism in elderly patients is still controversial. In a recent double-blind, randomized, placebo-controlled study, levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. The impact of levothyroxine therapy in patients with subclinical hypothyroidism on cardiovascular risk is not completely clear. Levothyroxine treatment is safe and free of side effects, when the thyroid-stimulating hormone (TSH) levels remain within the normal range. Prescription of levothyroxine in patients with only slightly elevated TSH levels often leads to overtreatment, which is associated with an increased risk of fractures, neurological and psychological symptoms, and atrial fibrillation. The recommendations of the European Thyroid Association is to treat elderly patients only when the TSH value is greater than 10 mU/l and the patient is symptomatic or the patient has a high cardiovascular risk. The therapeutic TSH range in elderly patients in the case of levothyroxine treatment should be 1.0-5.0 mU/l. Follow-up of the TSH level is mandatory in order to not oversee a developing overt hypothyroidism and to avoid overtreatment in case of levothyroxine treatment. PMID- 29995251 TI - Removal of malachite green from aqueous solution using pulverized teak leaf litter: equilibrium, kinetic and thermodynamic studies. AB - The removal of malachite green (MG) from aqueous solution using teak leaf litter powder (TLLP) was investigated. The process was influenced by initial concentration, pH and temperature of dye solution as well as TLLP dosage. Optimum removal of MG per gram of TLLP occurred at 2 g/L and at pH 6-8. Dubinin Radushkevich and Freundlich isotherm models fit the batch adsorption data better than Langmuir isotherm. The monolayer capacity of TLLP was 333.33 mg/g at 293-313 K. The mean free energy of 7.07 kJ/mol implied physical adsorption. The pseudo second order model fit the kinetic data better than the pseudo-first order model. Both intraparticle diffusion and film diffusion mechanisms jointly influenced the adsorption process but the latter was the rate-controlling step. Thermodynamic data indicated that the process was endothermic, spontaneous and feasible. Therefore, TLLP could be an important low-cost adsorbent for removal of MG from aqueous solution. PMID- 29995254 TI - Locoregional control and survival after lymph node SBRT in oligometastatic disease. AB - Stereotactic body radiotherapy (SBRT) has emerged as an effective option in oligo metastatic cancer patients affected by lymph node metastases, but its use might be questioned due to risk of regional and distant dissemination through the lymph node chain. The primary aim of our study was to assess the loco-regional control following SBRT in this setting. Ninety-one patients undergoing SBRT for at least one lymph node metastasis from miscellaneous primary tumors were retrospectively evaluated for patterns of failure and toxicity. locoregional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS) at 4 years were 79 and 44%. Repeated use of local therapy after progression resulted in a median interval of 17 months until allocation to systemic therapy or supportive care. Forty-three percent of patients were alive at 4 years. Local failure, occurring in 15% of patients, was the only predictor of poor survival (HR: 3.06). Tumor diameter >= 30 mm and urothelial primary tumor predicted for impaired local control (HR: 4.59 and 5.43, respectively). Metastases from pulmonary cancer showed a significant earlier distant dissemination (HR: 3.53). Only acute and late grade 1-2 toxicities were reported except for 1 case of G3 dysphagia. Loco regional failure risk is low (18%) and justifies the use of local therapies for patients with oligometastatic disease. Durable disease remission can be achieved by iterative use of local approaches. Local control is correlated to improved OS. Diameter and primary tumor type may affect response to SBRT and risk for early metastatic dissemination. PMID- 29995252 TI - Neighborhood Environments and Diabetes Risk and Control. AB - PURPOSE OF REVIEW: The objective of this review is to highlight the evidence on the association between contextual characteristics of residential environments and type 2 diabetes, to provide an overview of the methodological challenges and to outline potential topics for future research in this field. RECENT FINDINGS: The link between neighborhood socioeconomic status or deprivation and diabetes prevalence, incidence, and control is robust and has been replicated in numerous settings, including in experimental and quasi-experimental studies. The association between characteristics of the built environment that affect physical activity, other aspects of the built environment, and diabetes risk is robust. There is also evidence for an association between food environments and diabetes risk, but some conflicting results have emerged in this area. While the evidence base on the association of neighborhood socioeconomic status and built and physical environments and diabetes is large and robust, challenges remain related to confounding due to neighborhood selection. Moreover, we also outline five paths forward for future research on the role of neighborhood environments on diabetes. PMID- 29995255 TI - A rare mechanism of delayed splenic rupture following the nonoperative management of blunt splenic injury in a child. AB - BACKGROUND: Nonoperative management (NOM) has been established as the standard treatment for isolated blunt organ injury in hemodynamically stable pediatric patients. Although delayed splenic rupture or bleeding is a rare complication in NOM, it is an issue that many pediatric surgeons are greatly concerned about. We herein report a rare pediatric case concerning the mechanisms involved in delayed splenic rupture after NOM. CASE PRESENTATION: A 9-year-old boy with severe abdominal pain was transferred to our hospital. Twenty-one hours before the admission, he had been kicked in the region of his left lateral abdomen. Contrast enhanced abdominal computed tomography revealed a severe intra-parenchymal hematoma and multiple lacerations of the spleen with a large amount of hemoperitoneum without active bleeding. His condition was diagnosed as a grade III injury on the AAST splenic injury scale. After fluid resuscitation, his vital signs became stable. The patient was treated with NOM in our intensive care unit. However, suddenly after defecation (72 h after the injury), he started complaining of severe abdominal pain and left shoulder pain. His blood pressure dropped to 70/35 mmHg, and he started to lose consciousness. Abdominal ultrasonography (US) revealed increased ascites. Fluid resuscitation and blood transfusion were performed. His symptoms and abdominal US findings suggested that splenic re-bleeding had caused delayed splenic rupture to occur. Emergency splenectomy was performed. The resected spleen was enlarged with a large parenchymal hematoma. The posterior-lateral side of the splenic capsule was ruptured. CONCLUSIONS: The mechanism of delayed splenic rupture in our case was considered to be the result of a tear in the subcapsular hematoma caused by stretching the splenocolic ligament related to a bowel movement during defecation. Although delayed splenic rupture or bleeding is unpredictable, it is very important to understand the mechanisms and to educate the family of the children with splenic injuries of the warning signs of delayed rupture or bleeding. PMID- 29995256 TI - Cortical Neurotoxic Astrocytes with Early ALS Pathology and miR-146a Deficit Replicate Gliosis Markers of Symptomatic SOD1G93A Mouse Model. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) loss. Recent evidences highlight astrocytes as important players in MN death, but the mechanism-based neurotoxicity is still unknown. It is also unclear whether activation of astrocytes in ALS occurs differently in the cerebral cortex and spinal cord. We investigated glial and neuronal alterations in the cortex of SOD1G93A (mSOD1) mice in pre-symptomatic and symptomatic stages. We also characterized astrocytes isolated from the cortex of 7-day-old mSOD1 mice for their aberrancy and MN-induced degenerative effects. In the early stage, we identified a reduction of cell proliferation, NF-kB expression, and of vimentin and micro(miR)-146a expression, suggesting a restrained cortical inflammatory status. However, increased NF-kB expression, cell proliferation, and gene expression of HMGB1, connexin 43 and S100B were distinctive of the symptomatic stage, together with MN loss, downregulated unfold protein response, and decreased expression of synaptic proteins, together with that of miR-125b, miR-21, miR-146a, GFAP, and glutamate transporters. Astrocytes cultured for 13 days in vitro showed comparable NF-kB expression and cell proliferation increase, as well as similar microRNA and gene/protein expression profiles (decreased miR-21, miR-146a, GLT-1 and GFAP, and upregulated HMGB1, S100B and connexin-43), thus sustaining astrocytes as the major contributors of cortical homeostasis deregulation in the symptomatic stage. These reactive astrocytes reduced neurite length and synaptophysin expression in NSC-34/hSOD1WT MN-like cells, and induced mitochondria dysfunction, PSD-95 downregulation, metalloproteinase-9 activation, and late apoptosis in NSC-34/hSOD1G93A cells. Data indicate that astrocytes in mSOD1 mice model acquire early phenotypic aberrancies and highlight downregulated miR-146a as a biomarker and drug target in ALS. PMID- 29995258 TI - Virtual Thorough QT (TQT) Trial-Extrapolation of In Vitro Cardiac Safety Data to In Vivo Situation Using Multi-Scale Physiologically Based Ventricular Cell-wall Model Exemplified with Tolterodine and Fesoterodine. AB - QT interval prolongation typically assessed with dedicated clinical trials called thorough QT/QTc (TQT) studies is used as surrogate to identify the proarrhythmic risk of drugs albeit with criticism in terms of cost-effectiveness in establishing the actual risk of torsade de pointes (TdP). Quantitative systems toxicology and safety (QSTS) models have potential to quantitatively translate the in vitro cardiac safety data to clinical level including simulation of TQT trials. Virtual TQT simulations have been exemplified with use of two related drugs tolterodine and fesoterodine. The impact of bio-relevant concentration in plasma versus estimated heart tissue exposure on predictions was also assessed. Tolterodine and its therapeutically equipotent metabolite formed via CYP2D6 pathway, 5-HMT, inhibit multiple cardiac ion currents (IKr, INa, ICaL). The QSTS model was able to accurately simulate the QT prolongation at therapeutic and supra-therapeutic dose levels of tolterodine well within 95% confidence interval limits of observed data. The model was able to predict the QT prolongation difference between CYP2D6 extensive and poor metaboliser subject groups at both dose levels thus confirming the ability of the model to account for electrophysiologically active metabolite. The QSTS model was able to simulate the negligible QT prolongation observed with fesoterodine establishing that the 5-HMT does not prolong QT interval even though it is a blocker of hERG channel. With examples of TOL and FESO, we demonstrated the utility of the QSTS approaches to simulate virtual TQT trials, which in turn could complement and reduce the clinical studies or help optimise clinical trial designs. PMID- 29995259 TI - Green as a cbemcuru: modal as well as amodal color cues can help to solve anagrams. AB - Embodied cognition theories have been getting much support in recent years from studies showing that multimodal experiential traces are activated during language comprehension. However, there are almost no studies examining this influence in the opposite direction. Here, we investigated the influence of modal (physical color patch) and amodal (color word) cues on anagram solving times. We manipulated the association between the color cue and the solution word's referent color (e.g., finding the solution word "cucumber" for the anagram "cmrbucue" should be facilitated by the word "green" or a green color patch). In a third experiment, both cues were combined: a color word was presented inside a color patch before the anagram appeared. We indeed observed priming effects: anagrams were solved faster when the preceding color patch or color word matched the solution word's referent compared to a mismatching color patch or color word. When combining these cues, a priming effect only was found when both color word and color patch matched the solution word's referent. These results further strengthen the notion that multimodal experiential traces play an important role in language comprehension and expand upon the results of earlier studies on anagram solution tasks. PMID- 29995257 TI - Is Allergen Immunotherapy in Children Disease Modifying? A Review of the Evidence. AB - PURPOSE OF REVIEW: Although evidence supports a beneficial effect of allergen immunotherapy on the symptoms of allergic respiratory disease and food allergy, it is not clear whether immunotherapy modifies the natural history of these conditions. RECENT FINDINGS: In aeroallergen immunotherapy, studies suggest that prevention of asthma can be attained. Less evident is the ability of immunotherapy to prevent new allergen sensitizations and more studies are needed to test whether immunotherapy can continue suppressing airway symptoms after treatment discontinuation. In food allergen immunotherapy, there is evidence that unresponsiveness to a food challenge can be sustained in some treatment recipients, but little knowledge exists as to the dose and duration of treatment that can optimize this effect. Suggestive evidence exists that allergen immunotherapy can modify allergic disease in children, but definitive studies are lacking. More research in the field is required. PMID- 29995260 TI - Survival models and health sequences: discussion. PMID- 29995261 TI - Linoleate-enriched diet increases both linoleic acid esterified to omega hydroxy very long chain fatty acids and free ceramides of canine stratum corneum without effect on protein-bound ceramides and skin barrier function. AB - Few studies have investigated the influence of increased amounts of dietary linoleic acid on the epidermal lipid biochemistry and TEWL in healthy subject. The influence of dietary linoleic acid on canine stratum corneum (SC) lipids was studied by feeding two groups of five dogs differential amounts of linoleic acid (LA) for three months. SC was harvested by tape stripping and lipids were analyzed by thin-layer chromatography and mass spectrometry. The dogs that were fed the higher concentration of LA showed high increases in the contents of both linoleic acid and free ceramides in the SC, whereas the protein-bound ceramide content was unchanged. Acylacids that represent the esterified form of linoleic acid in omega hydroxy very long chain fatty acids (omega-OH VLCFA) accounted for most of the elevation of LA, whereas the concentration of the free form was not significantly changed. Corroborating the absence of change in the protein-bound ceramides content of healthy dogs SC, TEWL was nearly unaffected by the linoleic acid-enriched diet. PMID- 29995262 TI - Alkali-metal-adsorbed g-GaN monolayer: ultralow work functions and optical properties. AB - The electronic and optical properties of alkali-metal-adsorbed graphene-like gallium nitride (g-GaN) have been investigated using density functional theory. The results denote that alkali-metal-adsorbed g-GaN systems are stable compounds, with the most stable adsorption site being the center of the hexagonal ring. In addition, because of charge transfer from the alkali-metal atom to the host, the g-GaN layer shows clear n-type doping behavior. The adsorption of alkali metal atoms on g-GaN occurs via chemisorption. More importantly, the work function of g GaN is substantially reduced following the adsorption of alkali-metal atoms. Specifically, the Cs-adsorbed g-GaN system shows an ultralow work function of 0.84 eV, which has great potential application in field-emission devices. In addition, the alkali-metal adsorption can lead to an increase in the static dielectric constant and extend the absorption spectrum of g-GaN. PMID- 29995263 TI - Simulation model of the relationship between cesarean section rates and labor duration. AB - Cesarean delivery is the most common major abdominal surgery in many parts of the world, and it accounts for nearly one-third of births in the United States. For a patient who requires a C-section, allowing prolonged labor is not recommended because of the increased risk of infection. However, for a patient who is capable of a successful vaginal delivery, performing an unnecessary C-section can have a substantial adverse impact on the patient's future health. We develop two stochastic simulation models of the delivery process for women in labor; and our objectives are (i) to represent the natural progression of labor and thereby gain insights concerning the duration of labor as it depends on the dilation state for induced, augmented, and spontaneous labors; and (ii) to evaluate the Friedman curve and other labor-progression rules, including their impact on the C-section rate and on the rates of maternal and fetal complications. To use a shifted lognormal distribution for modeling the duration of labor in each dilation state and for each type of labor, we formulate a percentile-matching procedure that requires three estimated quantiles of each distribution as reported in the literature. Based on results generated by both simulation models, we concluded that for singleton births by nulliparous women with no prior complications, labor duration longer than two hours (i.e., the time limit for labor arrest based on the Friedman curve) should be allowed in each dilation state; furthermore, the allowed labor duration should be a function of dilation state. PMID- 29995265 TI - Anti-neuroinflammatory effects of galangin in LPS-stimulated BV-2 microglia through regulation of IL-1beta production and the NF-kappaB signaling pathways. AB - Neuroinflammation resulting from microglial activation is involved in the pathogenesis of neurodegenerative diseases, including Parkinson's diseases. Microglial activation plays an important role in neuroinflammation and contributes to several neurological disorders. Hence, inhibition of both microglial activation and the generation of pro-inflammatory cytokines may lead to an effective treatment for neurodegenerative diseases. In the present study, the anti-neuroinflammatory effects of galangin were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Galangin significantly decreased the generation of nitric oxide, interleukin-1beta, and inducible nitric oxide synthase in LPS-stimulated BV-2 microglial cells. In addition, galangin inhibited the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase 1/2. Furthermore, it was observed that activation of both IkappaB-alpha and nuclear factor kappa B (NF-kappaB) was significantly increased following LPS stimulation, and this effect was suppressed by galangin treatment. In conclusion, galangin displayed an anti-neuroinflammatory activity in LPS stimulated BV-2 microglial cells. Galangin inhibited LPS-induced neuroinflammation via the MAPK and NF-kappaB signaling pathways and might act as a natural therapeutic agent for the treatment of various neuroinflammatory conditions. PMID- 29995266 TI - Are sleep hygiene practices related to the incidence, persistence and remission of insomnia? Findings from a prospective community study. AB - The purpose was to examine whether sleep hygiene practices are associated with the course of insomnia (incidence, persistence and remission) over 1 year in the general population. This longitudinal study was carried out in the general population. After excluding anyone with other primary sleep disorder than insomnia, 1638 participants returned a baseline and a 1-year follow-up survey. Questions regarding sleep hygiene practices were administered at baseline, and the status of insomnia was assessed at baseline (T1) and at the 1-year follow-up (T2). Age, gender, mental ill-health, and pain were used as covariates in the analyses. Nicotine use, mental ill-health and pain were independently associated with an increased risk for concurrent insomnia at T1, while mental ill-health was the only risk factor for incident insomnia at T2. Relative to not reporting insomnia at the two time-points, nicotine use, light or noise disturbance, mental ill-health, and pain significantly increased the risk for persistent insomnia over 1 year. In comparison with those whose insomnia had remitted at the follow up, reporting an irregular sleep schedule was a significant risk factor for persistent insomnia. Of the nine sleep hygiene practices examined in this study, only three were independently linked to concurrent and future insomnia, respectively; using nicotine late in the evening, light or noise disturbance, and having an irregular sleep schedule. This may have implications for the conceptualization and management of insomnia as well as for future research. PMID- 29995264 TI - Effects of preemptive interferon-alpha monotherapy in acute leukemia patients with relapse tendency after allogeneic hematopoietic stem cell transplantation: a case-control study. AB - Interferon-alpha (IFN-alpha) inhibits tumor growth and mimics graft-versus leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the current case-control study, we compared treatment responses in acute leukemia patients with relapse tendency post-allo-HSCT receiving preemptive IFN-alpha after withdrawal of immunosuppressants (n = 31) vs. receiving no IFN-alpha (n = 67). In the IFN-alpha group, 25 patients responded to the treatment without progressing to hematological relapse. In the non-IFN-alpha group, only 22 patients responded to the treatment. The response rate differed significantly (80.6 vs. 32.8%, P < 0.001). The 2-year cumulative incidence of relapse was 31.6 and 61.2% in the IFN-alpha and the non-IFN groups, respectively (P = 0.006). The 2-year leukemia-free survival and overall survival rate was 57.4 vs. 28.4% (P < 0.001) and 67.6 vs. 32.9% (P = 0.001), respectively. Among the 31 patients in the IFN-alpha group, 18 patients (58.1%) developed graft-versus-host disease (GVHD): 6 acute and 12 limited chronic GVHD. Patients who developed GVHD had higher treatment response rate than patients without GVHD (88.9 vs. 53.8%, P = 0.022). In conclusion, preemptive IFN-alpha therapy is a safe and effective treatment to prevent disease progression in high-risk patients with relapse tendency post-allo HSCT. PMID- 29995267 TI - Neuroendoscopic lavage for the treatment of CSF infection with hydrocephalus in children. AB - OBJECTIVE: The treatment of infectious CSF condition with ventriculitis and hydrocephalus in children is an interdisciplinary challenge. Conventional surgical treatment includes external ventricular drain (EVD) and systemic antibiotic therapy. However, infectious contamination of large ventricles combined with CSF protein overload often requires long treatment regimens. We retrospectively investigated neuroendoscopic lavage as a new option for clearance of CSF in children with hydrocephalus and active CSF infection. PATIENTS AND METHODS: A database review identified 50 consecutive patients treated for CSF infection with hydrocephalus at our institution. Twenty-seven patients (control group, CG) were treated conventionally between 2004 and 2010, while 23 patients (neuroendoscopic group, NEG) underwent neuroendoscopic lavage for removal of intraventricular debris between 2010 and 2015. Clinical data, microbiology, laboratory measures, shunt dependency, and shunt revision rate were evaluated retrospectively. RESULTS: The patient groups did not differ regarding basic clinical characteristics. Patients in NEG received neuroendoscopic lavage at mean of 1.6 +/- 1times (1-4). No immediate postoperative complications were observed in NEG patients. Shunt rate in NEG patients was 91% as compared 100% in CG patients (p = 0.109). Within 24 months after shunt implantation, incidence of shunt revision was higher in CG (23/27) compared to NEG (5/23; p < 0.001). Reinfection was observed more often in CG (n = 17) compared to one patient in NEG (p < 0.001). CONCLUSIONS: We experienced that neuroendoscopic lavage is a safe and effective treatment for hydrocephalus in children with infectious conditions. Neuroendoscopic lavage resulted in a decreased number of overall shunt revisions in shunt-depended patients as well as a lower number of recurrent infections. PMID- 29995269 TI - An ancient Caria Village: Comakdag Kizilagac in Mylasa, Turkey. PMID- 29995268 TI - Infections in the immunocompromised child. AB - Prevention and management of opportunistic infections in children is particularly relevant in an era demonstrating an increased prevalence of immunocompromising conditions. The presence of an unusual organism which results in serious infection in a child should therefore always raise the consideration of immune compromise. The more common opportunistic infections have become easier to recognize in recent times due to improved awareness and more refined diagnostic testing. Targeted treatment is usually followed by long-term prophylactic medication. The impact of these conditions on patient outcome is of clear significance and certainly warrants further discussion. PMID- 29995270 TI - Machine learning algorithm-based risk prediction model of coronary artery disease. AB - In view of high mortality associated with coronary artery disease (CAD), development of an early predicting tool will be beneficial in reducing the burden of the disease. The database comprising demographic, conventional, folate/xenobiotic genetic risk factors of 648 subjects (364 cases of CAD and 284 healthy controls) was used as the basis to develop CAD risk and percentage stenosis prediction models using ensemble machine learning algorithms (EMLA), multifactor dimensionality reduction (MDR) and recursive partitioning (RP). The EMLA model showed better performance than other models in disease (89.3%) and stenosis prediction (82.5%). This model depicted hypertension and alcohol intake as the key predictors of CAD risk followed by cSHMT C1420T, GCPII C1561T, diabetes, GSTT1, CYP1A1 m2, TYMs 5'-UTR 28 bp tandem repeat and MTRR A66G. MDR and RP models are in agreement in projecting increasing age, hypertension and cSHMTC1420T as the key determinants interacting in modulating CAD risk. Receiver operating characteristic curves exhibited clinical utility of the developed models in the following order: EMLA (C = 0.96) > RP (C = 0.83) > MDR (C = 0.80). The stenosis prediction model showed that xenobiotic pathway genetic variants i.e. CYP1A1 m2 and GSTT1 are the key determinants of percentage of stenosis. Diabetes, diet, alcohol intake, hypertension and MTRR A66G are the other determinants of stenosis. These eleven variables contribute towards 82.5% stenosis. To conclude, the EMLA model exhibited higher predictability both in terms of disease prediction and stenosis prediction. This can be attributed to higher number of iterations in EMLA model that can increase the prediction accuracy. PMID- 29995272 TI - Molecular generative model based on conditional variational autoencoder for de novo molecular design. AB - We propose a molecular generative model based on the conditional variational autoencoder for de novo molecular design. It is specialized to control multiple molecular properties simultaneously by imposing them on a latent space. As a proof of concept, we demonstrate that it can be used to generate drug-like molecules with five target properties. We were also able to adjust a single property without changing the others and to manipulate it beyond the range of the dataset. PMID- 29995273 TI - Carbon Materials from Technical Lignins: Recent Advances. AB - Lignin, a major component of lignocellulosic biomass, is generated in enormous amounts during the pulp production. It is also a major coproduct of second generation biofuels. The effective utilization of lignin is critical for the accelerated development of the advanced cellulosic biorefinery. Low cost and availability of lignin make it attractive precursor for preparation of a range of carbon materials, including activated carbons, activated carbon fibers (CF), structural CF, graphitic carbons or carbon black that could be used for environmental protection, as catalysts, in energy storage applications or as reinforcing components in advanced composite materials. Technical lignins are very diverse in terms of their molecular weight, structure, chemical reactivity, and chemical composition, which is a consequence of the different origin of the lignin and the various methods of lignin isolation. The inherent heterogeneity of lignin is the main obstacle to the preparation of high-performance CF. Although lignin-based CF still do not compete with polyacrylonitrile-derived CF in mechanical properties, they nevertheless provide new markets through high availability and low production costs. Alternatively, technical lignin could be used for production of carbon adsorbents, which have very high surface areas and pore volumes comparable to the best commercial activated carbons. These porous carbons are useful for purifying gas and aqueous media from organic pollutants or adsorption of heavy metal ions from aqueous solutions. They also could be used as catalysts or electrodes in electrochemical applications. PMID- 29995271 TI - Endotypes of Chronic Rhinosinusitis Across Ancestry and Geographic Regions. AB - PURPOSE OF REVIEW: Preliminary studies have suggested differences in endotypes of chronic rhinosinusitis (CRS) across ancestry/ethnic groups. Eosinophilic CRS (ECRS) is the predominant subtype for Western/European ancestry CRS patients and non-eosinophilic CRS (nECRS) for Asian patients. This review aims to re-analyze CRS endotypes across ancestry populations using one consistent criteria to existing data. RECENT FINDINGS: Although tissue eosinophilia is the most commonly used criterion for ECRS, various cut-off points are suggested. Surrogate markers have been extensively studied. Sixty-six cohorts with study criteria were included with a total of 8557 patients. Raw data from 11 studies 544 patients were re-analyzed using number of tissue eosinophils. At lower cut-off values of >= 5 and >= 10 cells/HPF, most patients of Asian and Western/European ancestry were classified as ECRS without difference. In contrast, at cut-off points of >= 70 and >= 120 cells/HPF, the majority of both groups became reclassified as nECRS. After applying one consistent criteria to existing data, differences across ancestry and geographic populations in endotypes of CRS were no longer evident. PMID- 29995274 TI - Enhancing theory of mind in behavioural variant frontotemporal dementia with transcranial direct current stimulation. AB - Behavioural variant frontotemporal dementia (bvFTD) is a form of frontotemporal degeneration characterized by early changes in personality, emotional blunting, and/or loss of empathy. Recent research has highlighted that these features may be at least partially explained by impairments in the theory of mind (ToM; i.e., the ability to understand and predict other people's behaviour by attributing independent mental states to them). The aim of this randomized, double-blind, placebo-controlled study was to test the hypothesis that transcranial direct current stimulation (tDCS) over the medial frontal cortex (MFC) selectively enhances communicative intention processing, a specific ToM ability. Using a single-session online design, we administered a ToM task that measures the ability to represent other people's private and communicative intentions during active or sham tDCS to 16 bvFTD patients. To assess the impact of dementia on performance on the ToM task, we included 16 age-matched healthy volunteers who were asked to perform the entire experimental ToM task. BvFTD is characterized by an impairment in the comprehension of both communicative and private intentions relative to a healthy control group and by a disproportional impairment in communicative intention compared with private intention processing. Significant and selective accuracy improvement in the comprehension of communicative intentions after active stimulation was observed in patients with bvFTD. This is the first study that analyses ToM ability in patients with bvFTD using tDCS stimulation. Our findings could potentially contribute to the development of an effective, noninvasive brain stimulation treatment of ToM impairments in patients with bvFTD. PMID- 29995276 TI - Choir Boy: Trans Vocal Performance and the De-Pathologization of Transition. AB - This paper will examine Choir Boy (2005), a trans coming-of-age novel by Charlie Anders, to disrupt historically rooted medical narratives of gender transition. Through a disability studies lens, this paper locates vocal performance as a means of speaking back to gatekeeping practices held in place by medical authorities since the inception of transsexuality as a classificatory category. Offering imaginative alternatives to "wrong body" diagnostics, this analysis places cultural texts in conversation with disability theory to reframe the trans self as a singing body that cannot be reduced to normalizing biomedical practices. Choir Boy frames vocal performance as a mode of gender expression and as a survival strategy against violence. The trans counter-narratives offered by Anders resist the medicalization of trans bodies and the classification of some bodies as not "trans enough" to qualify for transition. Choir Boy locates vocal performance and not binary gender identification as impetus for transition, thereby advocating for trans self-determination over medical access. PMID- 29995275 TI - Spinal Cord Stimulation Frequency Influences the Hemodynamic Response in Patients with Disorders of Consciousness. AB - Spinal cord stimulation (SCS) is a promising technique for treating disorders of consciousness (DOCs). However, differences in the spatio-temporal responsiveness of the brain under varied SCS parameters remain unclear. In this pilot study, functional near-infrared spectroscopy was used to measure the hemodynamic responses of 10 DOC patients to different SCS frequencies (5 Hz, 10 Hz, 50 Hz, 70 Hz, and 100 Hz). In the prefrontal cortex, a key area in consciousness circuits, we found significantly increased hemodynamic responses at 70 Hz and 100 Hz, and significantly different hemodynamic responses between 50 Hz and 70 Hz/100 Hz. In addition, the functional connectivity between prefrontal and occipital areas was significantly improved with SCS at 70 Hz. These results demonstrated that SCS modulates the hemodynamic responses and long-range connectivity in a frequency specific manner (with 70 Hz apparently better), perhaps by improving the cerebral blood volume and information transmission through the reticular formation thalamus-cortex pathway. PMID- 29995277 TI - Genetics of and pathogenic mechanisms in arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease, associated with a high risk of sudden cardiac death. ARVC has been termed a 'disease of the desmosome' based on the fact that in many cases, it is caused by mutations in genes encoding desmosomal proteins at the specialised intercellular junctions between cardiomyocytes, the intercalated discs. Desmosomes maintain the structural integrity of the ventricular myocardium and are also implicated in signal transduction pathways. Mutated desmosomal proteins are thought to cause detachment of cardiac myocytes by the loss of cellular adhesions and also affect signalling pathways, leading to cell death and substitution by fibrofatty adipocytic tissue. However, mutations in desmosomal proteins are not the sole cause for ARVC as mutations in non-desmosomal genes were also implicated in its pathogenesis. This review will consider the pathology, genetic basis and mechanisms of pathogenesis for ARVC. PMID- 29995278 TI - Excretion kinetics of three dominant organochlorine compounds in human milk within the first 6 months postpartum. AB - Breastfeeding is a specific and important way for women to eliminate harmful substances accumulated in body. Hexachlorobenzene (HCB), beta hexachlorocyclohexane (beta-HCH), and 2,2-bis(p-chlorophenyl)-1,1-dichloroethene (p,p'-DDE) are dominant organochlorine compounds(OCCs) and persistent organic pollutants (POPs) accumulated in human being. Although a 6-month breastfeeding was suggested by the World Health Organization (WHO), the excretion characteristics of OCCs in human milk during the first 6-month lactation remain controversial. The main purpose of this study was to continuously monitor the three dominant OCC concentrations and reveal their elimination characteristic in human milk within the first 6-month lactation. To do that, with one sample per month, during their first 6-month lactation, human milk samples were continuously collected from 40 mothers after their first birth. The result showed that the concentrations of the three OCCs in human milk during the lactation continuously decreased from 51.7 to 39.9 MUg/kg milk lipids for HCB, from 136.5 to 84.8 MUg/kg milk lipids for beta-HCH, and from 307.3 to 192 MUg/kg milk lipids, respectively. The excretion kinetics of each compound in milk lipids fitted zero-order kinetics during the 6-month lactation. The excretion rate of the three OCCs was approximately 3% per month for HCB and 7% per month for the other two compounds during the lactation, with tdec 1/2 of 13 months for HCB, 7.5 months for beta HCH, and 8 months for p,p'-DDE. The excretion rate of the target compounds depended on initial deposited levels, compound properties, and exposure or input source. PMID- 29995281 TI - Geography and Urban Health. PMID- 29995279 TI - Stevia rebaudiana Bertoni and Its Effects in Human Disease: Emphasizing Its Role in Inflammation, Atherosclerosis and Metabolic Syndrome. AB - PURPOSE OF REVIEW: Stevia rebaudiana Bertoni is a perennial shrub with zero calorie content that has been increasing in popularity for its potential use as an adjuvant in the treatment of obesity. The level of evidence supporting general benefits to human health is insufficient. We conducted a review of the literature summarizing the current knowledge and role in human disease. RECENT FINDINGS: Despite stevia's minimal systemic absorption, studies have been promising regarding its potential benefits against inflammation, carcinogenesis, atherosclerosis glucose control, and hypertension. On the other hand, the growing popularity of artificial sweeteners does not correlate with improved trends in obesity. An increased intake of artificial non-caloric sweeteners may not be associated with decreased intake of traditional sugar-sweetened beverages and foods. The effects of Stevia on weight change have been linked to bacteria in the intestinal microbiome, mainly by affecting Clostridium and Bacteroides sp. POPULATIONS: A growing body of evidence indicates that Stevia rebaudiana Bertoni is protective against malignant conversion by inhibition of DNA replication in human cancer cell growth in vitro. Consumption of Stevia has demonstrated to be generally safe in most reports. Further clinical studies are warranted to determine if regular consumption brings sustained benefits for human health. PMID- 29995282 TI - Cardiac Arrhythmias and Pregnancy. AB - PURPOSE OF REVIEWS: In this review, the challenges of managing cardiac arrhythmias and syncope in the setting of pregnancy will be discussed. RECENT FINDINGS: Arrhythmias in pregnancy are increasing, as diagnostic and therapeutic options have advanced and women are older at the time of gestation. Atrial fibrillation has become the most common arrhythmia in pregnancy. Inherited arrhythmia has become a more common entity, with advances in treatments and genetic testing, and require specialized treatments in pregnancy. The majority of arrhythmias in pregnancy are benign. The potential risk of increased cardiac morbidity and mortality exists for mother and fetus, especially in women with structural heart disease, which is becoming increasingly common. Early evaluation, diagnosis, and appropriate treatment are necessary to achieve optimal outcomes for both mother and fetus. PMID- 29995283 TI - Lethal Effect and Behavioral Responses of Leaf-Cutting Ants to Essential Oil of Pogostemon cablin (Lamiaceae) and Its Nanoformulation. AB - Leaf-cutting ants belonging to the genus Atta (Formicidae: Myrmicinae) are important pests in agricultural and forest environments. In the present study, we evaluated the formicidal activity of the essential oil of Pogostemon cablin and its nanoformulation on the leaf-cutting ants: Atta opaciceps (Borgmeier, 1939), Atta sexdens (Linnaeus, 1758), and Atta sexdens rubropilosa Forel, 1908. The nanoformulation was developed by magnetic stirring using polyoxyethylene (36%), pure ethanol (36%), essential oil of P. cablin (18%), and water (10%). Bioassays of acute toxicity by fumigation and behavioral bioassays in treated arenas, with and without choice, were performed. The essential oil of P. cablin and its nanoformulation demonstrated efficient insecticidal activity and irritability to ant species. The concentration required to kill 50% of workers varied from 1.06 to 2.10 MUL L-1, with a mean time to death of less than or equal to 42 h. The essential oil of P. cablin and its nanoformulation reduced the displacement and velocity speed of the workers of A. opaciceps and A. sexdens rubropilosa in totally treated arenas. In the bioassays with choices, the three species of ants walked less and at a greater speed on the treated side of arena. This work demonstrates the potential of the essential oil of P. cablin and its nanoformulation to the generation of new formicidal products. PMID- 29995284 TI - Resting Heart Rate Variability (HRV) in Adolescents and Young Adults from a Genetically-Informed Perspective. AB - Reduced heart rate variability (HRV) is associated with cardiac morbidity, mortality, and negative psychopathology. Most research concerning genetic influences on HRV has focused on adult populations, with fewer studies investigating the developmental period of adolescence and emerging adulthood. The current study estimated the genetic and environmental contributions to resting HRV in a sample of twins using various HRV time domain metrics to assess autonomic function across two different time measurement intervals (2.5- and 10 min). Five metrics of resting HRV [mean interbeat interval (IBI), the standard deviation of normal IBIs (SDNN), root square mean of successive differences between IBIs (RMSSD), cardiac vagal index (CVI), and cardiac sympathetic index (CSI)] were assessed in 421 twin pairs aged 14-20 during a baseline electrocardiogram. This was done for four successive 2.5-min intervals as well as the overall 10-min interval. Heritability (h2) appeared consistent across intervals within each metric with the following estimates (collapsed across time intervals): mean IBI (h2 = 0.36-0.46), SDNN (h2 = 0.23-0.30), RMSSD (h2 = 0.36 0.39), CVI (h2 = 0.37-0.42), CSI (h2 = 0.33-0.46). Beyond additive genetic contributions, unique environment also was an important influence on HRV. Within each metric, a multivariate Cholesky decomposition further revealed evidence of genetic stability across the four successive 2.5-min intervals. The same models showed evidence for both genetic and environmental stability with some environmental attenuation and innovation. All measures of HRV were moderately heritable across time, with further analyses revealing consistent patterns of genetic and environmental influences over time. This study confirms that in an adolescent sample, the time interval used (2.5- vs. 10-min) to measure HRV time domain metrics does not affect the relative proportions of genetic and environmental influences. PMID- 29995285 TI - Role Reversal: The Influence of Slot Machine Gambling on Subsequent Alcohol Consumption. AB - Experimental studies examining the relationship between alcohol use and gambling have focused predominantly on alcohol's influence on gambling behavior. There has been little consideration of the reverse pathway: whether gambling influences subsequent alcohol use. Two experiments examined whether gambling and gambling outcomes (i.e. profits during a gambling session) influenced subsequent alcohol consumption. Experiment 1 (n = 53) used an ad libitum consumption test, in which participants could request beverages during a 30 min window. Experiment 2 (n = 29) used a beer taste test procedure, in which participants were asked to rate a series of beers. In both studies, male regular gamblers were assigned to watch a television show or play a modern slot machine for 30 min, before being provided with access to alcohol. On the ad libitum procedure, gambling significantly increased the number of alcoholic drinks ordered, the volume of alcohol consumed, the participants' speed of drinking, and their intention to drink alcohol. These effects were not corroborated using the taste test procedure. Across both studies, gambling outcomes were not associated with alcohol consumption. In conjunction with prior findings, the observation that gambling can promote alcohol consumption under certain conditions highlights a possible feedback loop whereby gambling and alcohol reinforce one another. However, the divergent results between the ad libitum and taste test experiments point to boundary conditions for the effect and raise methodological considerations for future work measuring alcohol consumption in gambling environments. PMID- 29995286 TI - A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. AB - Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade >= 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. PMID- 29995287 TI - Phase I study of resminostat, an HDAC inhibitor, combined with S-1 in patients with pre-treated biliary tract or pancreatic cancer. AB - Resminostat is an oral hydroxamate inhibitor of class I, IIb, and IV histone deacetylases. S-1 is widely used to treat biliary tract cancer and pancreatic cancer in Japan. We performed a phase I study of resminostat combined with S-1 as second-line or later therapy in Japanese patients with biliary tract or pancreatic cancer. A total of 27 patients were enrolled. We determined the optimal regimen for resminostat/S-1 therapy in part 1, and investigated its safety and efficacy in part 2. In part 1, 17 patients were enrolled. One DLT (anorexia and stomatitis, respectively) occurred with each of regimens 2 and 3. In part 2, an additional 10 patients received regimen 3, which was selected in part 1. Regimen 3 was resminostat (200 mg/day on Days 1 to 5 and Days 8 to 12: 5 days on/2 days off) plus S-1 (80-120 mg/day according to body surface area on Days 1 to 14) repeated every 21 days. A total of 16 patients (13 with biliary tract cancer and 3 with pancreatic cancer) received regimen 3 and it was well tolerated. The most frequent treatment-related adverse events were thrombocytopenia and anorexia (11 patients each, 69%). The disease control rate was 81.3% (84.6% for biliary tract cancer and 66.7% for pancreatic cancer, respectively). Median progression-free survival was 3.1 months (5.5 and 2.3 months), while median overall survival was 8.8 months (10.2 and 4.7 months). In conclusion, regimen 3 was well tolerated by patients with pre-treated biliary tract or pancreatic cancer. PMID- 29995288 TI - Human parechovirus type 6 and Guillain-Barre syndrome: a case report. AB - A previously healthy 6-year-old boy was admitted to hospital with hypotonia and hyposthenia of lower limbs. Electromyography and slow motor nerve conduction velocity test identified a lower limb acute motor axonal neuropathy. Brain and spinal cord magnetic resonance imaging demonstrated multifocal cortical gray matter lesions in both cerebral hemispheres consistent with gray matter acute disseminated encephalitis otherwise with viral/Mycoplasma pneumoniae encephalitis, and signs of involvement of anterior nerve roots of the cauda equina consistent with Guillain-Barre syndrome. The patient resulted negative to routinely bacterial and viral investigations but positive to human parechovirus that sequence analyses confirmed as type 6. Intravenous immunoglobulins and methylprednisolone treatment were administered but did not relieve the symptoms of Guillain-Barre syndrome. The disease improved gradually over the next 3-month follow-up with a complete remission of both central and peripheral nervous system symptoms. PMID- 29995289 TI - Complex Systems Approaches to Understand Drivers of Mental Health and Inform Mental Health Policy: A Systematic Review. AB - We conducted a systematic review of studies employing complex systems approaches (i.e., agent based and system dynamics models) to understand drivers of mental health and inform mental health policy. We extracted key data (e.g., purpose, design, data) for each study and provide a narrative synthesis of insights generated across studies. The studies investigated drivers and policy intervention strategies across a diversity of mental health outcomes. Based on these studies and the extant literature, we propose a typology of mental health research and policy areas that may benefit from complex systems approaches. PMID- 29995290 TI - Correction to: Influences to ADHD Problem Recognition: Mixed-Method Investigation and Recommendations to Reduce Disparities for Latino Youth. AB - The original version of this article unfortunately contained a mistake. The co author, Dr. Araujo's name and the affiliation for Dr. Pfiffner was incorrect in the original version of the article. The correct information is given below. PMID- 29995291 TI - Extrapyramidal deficits in ALS: a combined biomechanical and neuroimaging study. AB - INTRODUCTION: Extrapyramidal deficits are poorly characterised in amyotrophic lateral sclerosis (ALS) despite their contribution to functional disability, increased fall risk and their quality-of-life implications. Given the concomitant pyramidal and cerebellar degeneration in ALS, the clinical assessment of extrapyramidal features is particularly challenging. OBJECTIVE: The comprehensive characterisation of postural instability in ALS using standardised clinical assessments, gait analyses and computational neuroimaging tools in a prospective study design. METHODS: Parameters of gait initiation in the anticipatory postural adjustment phase (APA) and execution phase (EP) were evaluated in ALS patients with and without postural instability and healthy controls. Clinical and gait analysis parameters were interpreted in the context of brain imaging findings. RESULTS: ALS patients with postural instability exhibit impaired gait initiation with an altered APA phase, poor dynamic postural control and significantly decreased braking index. Consistent with their clinical profile, "unsteady" ALS patients have reduced caudate and brain stem volumes compared to "steady" ALS patients. INTERPRETATION: Our findings highlight that the ALS functional rating scale (ALSFRS-r) does not account for extrapyramidal deficits, which are major contributors to gait impairment in a subset of ALS patients. Basal ganglia degeneration in ALS does not only contribute to cognitive and behavioural deficits, but also adds to the heterogeneity of motor disability. PMID- 29995292 TI - Relationship between episodic memory and volume of the brain regions of two functional cortical memory systems in multiple sclerosis. AB - BACKGROUND/OBJECTIVE: Two functional networks are proposed as neuronal support for the complex processes of memory: the anterior temporal and the medial posterior systems. We examined the atrophy of hippocampus (HC) and of those areas constituting the two functional memory systems in multiple sclerosis (MS) patients with low disability. METHODS: Episodic memory (EM) was assessed in 88 relapsing MS patients and in 40 healthy controls using Wechsler Memory Scale III (Spanish adaptation). FreeSurfer software was used to calculate normalized volume of total cortex, grey matter, white matter, subcortical grey matter (thalamus and striatum), HC and both the anterior temporal (entorhinal, ventral temporopolar, lateral orbitofrontal, amygdala) and posterior medial systems (thalamus, parahippocampal, posterior cingulate, precuneus, lateral parietal and medial prefrontal). Linear regression analysis was used to identify predictors of memory performance. RESULTS: Total grey matter and cortex volumes correlated with all subtypes of EM, and the precuneus volume correlated with overall, immediate and delayed memories. Univariant regression analysis identified an association between the volumes of the posterior medial memory network regions and EM scores. The volume of the left precuneus area was the unique and independent predictor for all EM subtypes except for visual memory, for which left HC volume was also an independent predictor. CONCLUSION: Left precuneus volume was the best predictor of memory in relapsing MS patients with low disability and mild deficits in EM. PMID- 29995293 TI - One Anastomosis (Mini) Gastric Bypass Is Now an Established Bariatric Procedure: a Systematic Review of 12,807 Patients. AB - The One Anastomosis (Mini) Gastric Bypass is rapidly gaining acceptance. This review reports cumulative results of 12,807 procedures in obese patients with a mean age of 41.18 years and BMI of 46.6 kg/m2. The overall mortality was 0.10% and the leak rate was 0.96%. The follow-up duration ranged from 6 months to 12 years. A marginal ulceration rate of 2.7% and an anaemia rate of 7.0% were reported. Approximately 2.0% of patients reported postoperative gastro oesophageal reflux and 0.71% developed malnutrition. Excess weight loss at 6, 12, 24 and 60 months was 60.68, 72.56, 78.2 and 76.6% respectively. Type 2 diabetes mellitus and hypertension resolved in 83.7 and 66.94% respectively. We conclude that there is now sufficient evidence to include MGB-OAGB as a mainstream bariatric procedure. PMID- 29995295 TI - Thyroid-Like Low-Grade Nasopharyngeal Papillary Adenocarcinoma. AB - Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is a rare entity. Patients often present with complaints of nasal fullness, obstruction, and epistaxis. It may be confused with metastatic papillary thyroid carcinoma due to its histologic similarity and overlapping immunohistochemical studies, but it is important to distinguish between the two because of differing treatment modalities and prognosis. A significant difference between the two is that despite both entities demonstrating TTF-1 positivity, TL-LGNPPA usually does not stain for thyroglobulin. TL-LGNPPA exhibits indolent growth, with no incidence of metastasis or recurrence after surgical excision. PMID- 29995294 TI - Fructose-1,6-Bisphosphate Prevents Bleomycin-Induced Pulmonary Fibrosis in Mice and Inhibits the Proliferation of Lung Fibroblasts. AB - Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer. PMID- 29995296 TI - Title V Maternal and Child Health Services Block Grant Priority Needs and Linked Performance Measures: Current Patterns and Trends (2000-2015). AB - Objective As part of the Title V Maternal and Child Health (MCH) Services Block Grant, administered by the Health Resources and Services Administration's (HRSA's) Maternal and Child Health Bureau (MCHB), states are required to conduct a comprehensive needs assessment identifying MCH priorities every 5 years. The most current needs assessment (2015) occurred after a transformation of the program, in which a new performance measurement framework was created. This analysis examined current patterns and trends in state MCH priorities and selected performance measures to identify changing needs and inform technical support. Methods Multiple coders categorized: (1) state priority needs from 2000 to 2015 into focus areas and subcategories for examination of current, diminishing, and emerging needs; and (2) the selection of linked national and state performance measures in 2015 for all 59 states and jurisdictions. Results Between 2000 and 2015, the proportion of states with a need around pre- and inter conception care increased from 19% to 66%. More states had needs in the breastfeeding subcategory (42%) compared with 20% of states or less in previous years. Fewer states had needs around data capacity than in past years. Emerging needs included supporting families/relationships. The most commonly selected national performance measures (NPMs) were around breastfeeding and well-woman visits. The state performance measures (SPMs) analysis also emphasized assets, with measures around community/context and positive development. Teen births and postpartum depression were areas where multiple states had SPMs. Conclusions for practice Increasing and emerging needs may help to inform technical assistance and future national measures for the Title V program. PMID- 29995297 TI - Examining the Association Between Maternal Smoking During Pregnancy and Child Behavior Problems Using Quality-Adjusted Life Years. AB - Objectives Examining the association between maternal smoking and losses in childhood health-related quality of life due to behavior problems provides parents and policymakers another tool for the valuation of smoking cessation during pregnancy. Methods Using the National Longitudinal Survey of Youth 1979 Child and Young Adult data, this study retrospectively examined a cohort of 4114 women and 8668 children. In addition to questions focusing on maternal smoking and general demographics, each survey included the Behavior Problems Index (BPI), a 28-item questionnaire with six subscales measuring childhood behavior problems (antisocial behavior, anxiousness/depression, headstrongness, hyperactivity, immature dependency, and peer conflict/social withdrawal). Responses to the BPI, completed by mothers with children ages 4-14, were summarized on a QALY scale using published preference weights. Results Children whose mothers smoked during pregnancy experience additional QALY losses of 0.181, on average, per year due to increased behavior problems. Boys suffered larger QALY losses associated with maternal smoking (0.242) compared to girls (0.119; p value = .021), regardless of age. Moreover, heavier smoking during pregnancy (i.e., 1 or more packs/day) was associated with larger QALY losses (0.282; p-value < .001). Conclusions for Practice These findings illustrate the burden of maternal smoking during pregnancy on child health, namely behavioral problems. The losses in QALYs may be incorporated into economic evaluations for smoking cessation interventions during pregnancy. Future research will investigate how maternal smoking following childbirth is associated with child QALYs. PMID- 29995298 TI - Evaluation of a Training for Health and Social Service Providers on Abortion Referral-Making. AB - Purpose Engaging trusted care providers and empowering them with information and skills about abortion is a critical opportunity to improve coordination of care for women seeking abortion, if and when these services are needed. Description Provide, a nonprofit that works in partnership with health and social service providers to build a health system that is equipped to respond to women's health care needs around abortion, launched a referrals training program in 2013. To assess the effectiveness of this training program, we conducted an evaluation of satisfaction with training and the impact of the intervention on provider knowledge of safety of abortion, self-efficacy to provide abortion referrals, and intention to provide pregnancy options counseling and referrals in the future. Assessment Approximately 90% of participants were "very satisfied" with their training experience. Results show significant increase in intention to provide non-judgmental pregnancy options counseling and referrals for abortion care after participants went through training. Post-training, significantly more reported that they would present all pregnancy options without judgment or bias (94 vs. 82%, p < .0001), provide a referral for abortion care if needed (80 vs. 50%, p < .0001), and follow-up with the client (71 vs. 39%, p < .0001). Further, more also reported they would refer a client for prenatal care if the client requested it (78 vs. 67%, p < .0001). Conclusion Our results suggest that abortion referrals training hold potential to build the capacity of health and social service providers' ability to meet client needs related to pregnancy and could be implemented at a larger scale. PMID- 29995299 TI - Enhanced Energetic Performances Based on Integration with the Al/PTFE Nanolaminates. AB - Integrating energetic materials on a chip has received great attention for its widely potential applications in the microscale energy consumption system, including electric initiation device. In this article, reactive Al/PTFE nanolaminates with periodic layer structure are prepared by magnetron sputtering, which consists of fuel Al, oxidant PTFE, and inert layer Al-F compound in a metastable system. The as-deposited Al/PTFE nanolaminates exhibit a significantly high energy output, and the onset temperature and the heat of reaction are 410 degrees C and 3034 J/g, respectively. Based on these properties, an integrated film bridge is designed and fabricated via integrating Al/PTFE nanolaminates with a Cu exploding foil, which exhibits enhanced energetic performances with more violent explosion phenomenon, larger quantities of ejected product, and higher plasma temperature in comparison with the Cu film bridge. The kinetic energy of flyers derived from the expansion of the Cu film bridge is also increased around 29.9% via integration with the Al/PTFE nanolaminates. Overall, the energetic performances can be improved substantially through a combination of the chemical reaction of Al/PTFE nanolaminates with the electric explosion of the Cu film bridge. PMID- 29995300 TI - Enhanced Safety Surveillance of Seasonal Quadrivalent Influenza Vaccines in English Primary Care: Interim Analysis. AB - INTRODUCTION: The European Medicines Agency (EMA) requires vaccine manufacturers to conduct enhanced safety surveillance (ESS) of seasonal influenza vaccines including a near real-time evaluation of collected data. The objective was to identify whether the use of passive surveillance or active surveillance provides different results of reported adverse events of interest (AEIs) by specified age strata and AEI type. We report the weekly incidence rates of AEIs within 7 days following seasonal influenza vaccination using passive and active surveillance. METHODS: AEIs were collected within 7 days of vaccination from ten general practices predominantly administering inactivated quadrivalent influenza vaccine (IIV4, Fluarix Tetra, GSK). Vaccinees completed an adverse drug reaction (ADR) card. ADR card and medically attended AEIs data were recorded in practice electronic health records. We report the outcome of the first 5 weeks of safety surveillance (September 12, 2016-October 16, 2016); in an exploratory analysis, rates of AEI for IIV4 are compared to those passively reported through a sentinel network. RESULTS: Practices vaccinated 13.1% (12,864/98,091) of their registered population; 5.6% (95% CI 5.20-6.00) of them reported AEIs, none serious. The most frequent were respiratory 2.60% (95% CI 2.33-2.88), musculoskeletal 1.82% (95% CI 1.59-2.05) and neurological 1.05% (95% CI 0.88-1.23). AEIs were more frequently reported for adults than for children; 5.91% (95% CI 5.49-6.34) compared to 1.49% (95% CI 0.69-2.29); 47.18% of the adults reported AEI using the ADR card, none were returned for subjects < 18 years old. The frequency of AEIs reporting was higher, 6.88% (95% CI 6.35-7.42) vs. 3.30% (95% CI 2.68-3.96, 100/3028, p < 0.000), through ESS than passive surveillance. CONCLUSION: The ESS did not reveal any safety signal and we demonstrated the feasibility of conducting ESS following EMA recommendations. The use of a customised ADR card led to a doubling of AEIs reports over passive surveillance in adults. FUNDING: GlaxoSmithKline Biologicals SA, Wavre, Belgium. PMID- 29995301 TI - Total Joint Arthroplasty in Patients with Inflammatory Rheumatic Diseases. AB - Since its introduction, total joint arthroplasty (TJA) has improved the quality of life of patients with degenerative joint disorders. In the last decades, a number of conventional and biological disease-modifying antirheumatic drugs have become available for the treatment of patients with inflammatory rheumatic diseases (IRD), leading to a reduction in the need to undergo TJA. However, TJA is still frequently performed in IRD patients. Both rheumatologists and orthopedics should be aware that patients with IRD have a peculiar perioperative risk profile due to disease-related, patient-related, and surgery-related risk factors. On the basis of current evidence, TJA is a safe procedure for IRD patients as long as an accurate risk stratification and a multidisciplinary approach are applied. We here describe the current strategies for an appropriate surgical management of osteoarthritis in IRD patients and the fascinating opening perspectives that surgeons and clinicians may expect in the future. PMID- 29995302 TI - Simulation in children's conscious recursive reasoning. AB - When do children acquire the ability to understand recursion-that is, repeated loops of actions, as in cookery recipes or computer programs? Hitherto, studies have focused either on unconscious recursions in language and vision or on the difficulty of conscious recursions-even for adults-when learning to program. In contrast, we examined 10- to 11-year-old fifth-graders' ability to deduce the consequences of loops of actions in informal algorithms and to create such algorithms for themselves. In our experiments, the children tackled problems requiring the rearrangement of cars on a toy railway with a single track and a siding-an environment that in principle allows for the execution of any algorithm that is, it has the power of a universal Turing machine. The children were not allowed to move the cars, so each problem's solution called for them to envision the movements of cars on the track. We describe a theory of recursive thinking, which is based on kinematic simulations and which we have implemented in a computer program embodying mental models of the cars and track. Experiment 1 tested children's ability to deduce rearrangements of the cars in a train from descriptions of algorithms containing a single loop of actions. Experiment 2 assessed children's spontaneous creation of similar sorts of algorithms. The results showed that fifth-grade children with no training in computer programming have systematic abilities to deduce from and to create informal recursive algorithms. PMID- 29995303 TI - Public Libraries: A Community-Level Resource to Advance Population Health. AB - Policy makers and public health practitioners rarely consider public libraries to be part of the health system, even though they possess several characteristics that suggest unrealized potential to advance population health. This scoping review uses an adapted social determinants framework to categorize current health related work conducted by public libraries in the United States and to discuss libraries' potential as 'meso-level' community resources to improve population health. Our discussion of libraries contributes to scholarship on place-based health disparities, by emphasizing the potential impact of institutions that are modifiable through social policy-e.g., parks, community centers, schools-and which have a conceptually clear or empirically documented relationship to health. PMID- 29995304 TI - Graphenide Solutions: A Chemical Platform for Nanoparticle-Nanocarbon Composites. AB - Graphenide solutions, comprising charged graphene layers in aprotic organic solutions, are exploited as a chemical platform to graft transition-metal oxide nanoparticles, namely nickel, manganese, copper, and cobalt oxide, onto the carbon framework. The reduction process is driven and controlled by the graphenide solution yielding nanoparticles with comparable sizes for all studied metal salts, well below 10 nm. The synthesis is generic and is not limited by the type of metal salt, because the reduced graphene layers serve simultaneously as both substrates and reducing agents. This reaction is reliable, reproducible, and versatile, generating materials for catalytic purposes without requiring any kind of stabilization or capping agents. PMID- 29995305 TI - Chiral Bambusurils for Enantioselective Recognition of Carboxylate Anion Guests. AB - Synthesis of the first enantiomerically pure chiral bambusurils is reported. The bambusurils were prepared on the gram scale without using any chromatography techniques. The bambusurils formed supramolecular complexes with all tested chiral carboxylates including amino acids and drug molecules with the enantioselectivity ranging from 1.1 to 3.2. PMID- 29995306 TI - Adipokine dysregulation and adipose tissue inflammation in human obesity. AB - Obesity, a worldwide epidemic, confers increased risk for multiple serious conditions, including type 2 diabetes, cardiovascular diseases, nonalcoholic fatty liver disease and cancer. Adipose tissue is considered one of the largest endocrine organs in the body as well as an active tissue for cellular reactions and metabolic homeostasis rather than an inert tissue for energy storage. The functional pleiotropism of adipose tissue relies on its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins and growth and vasoactive factors, collectively termed adipokines that influence a variety of physiological and pathophysiological processes. In the obese state, excessive visceral fat accumulation causes adipose tissue dysfunctionality that strongly contributes to the onset of obesity-related comorbidities. The mechanisms underlying adipose tissue dysfunction include adipocyte hypertrophy and hyperplasia, increased inflammation, impaired extracellular matrix remodelling and fibrosis together with an altered secretion of adipokines. This review describes how adipose tissue becomes inflamed in obesity and summarizes key players and molecular mechanisms involved in adipose inflammation. PMID- 29995307 TI - The effect of presymptomatic hypertension in posterior reversible encephalopathy syndrome. AB - OBJECTIVE: The effect of blood pressure (BP) on the lesion distribution of posterior reversible encephalopathy syndrome (PRES) is controversial. The aim of this study was to identify the relationship between brain lesion distribution patterns and BP. METHODS: Sixty-five patients with PRES were selected from the database. Data regarding brain MRI findings, clinical symptoms, medical conditions, and BP at the presymptomatic period (24 hr before the symptom onset) and at the symptom onset were collected. The brain lesion distribution degree was numerically calculated (lesion scoring point [LSP]) and compared with BP and medical conditions. RESULTS: Mean onset-MAP was higher than mean pre-MAP. Pre-MAP correlated with onset-MAP. The LSP was significantly correlated with pre-MAP (p = 0.009, correlation coefficient [cc] = 0.323), whereas no significant correlation was found between LSP and onset-MAP (p = 0.159, cc = 0.177). Similarly, when patients were grouped by mean MAP values, LSP was significantly higher in the patients with high MAP at the presymptomatic period (p = 0.004), whereas no difference was found in the LSP value between patients with low MAP and high MAP at the symptom onset (p = 0.272). CONCLUSION: The patient with PRES who has relatively higher BP in the presymptomatic period would be more likely to have wider lesion distribution than the patient with lower BP. BP elevation during presymptomatic period may be a heralding sign of impending PRES and a factor affecting the severity of PRES although BP was not investigated at earlier time points. PMID- 29995308 TI - Novel dual regulators of Pseudomonas aeruginosa essential for productive biofilms and virulence. AB - Gene regulation network in Pseudomonas aeruginosa is complex. With a relatively large genome (6.2 Mb), there is a significant portion of genes that are proven or predicted to be transcriptional regulators. Many of these regulators have been shown to play important roles in biofilm formation and maintenance. In this study, we present a novel transcriptional regulator, PA1226, which modulates biofilm formation and virulence in P. aeruginosa. Mutation in the gene encoding this regulator abolished the ability of P. aeruginosa to produce biofilms in vitro, without any effect on the planktonic growth. This regulator is also essential for the in vivo fitness and pathogenesis in both Drosophila melanogaster and BALB/c mouse lung infection models. Transcriptome analysis revealed that PA1226 regulates many essential virulence genes/pathways, including those involved in alginate, pili, and LPS biosynthesis. Genes/operons directly regulated by PA1226 and potential binding sequences were identified via ChIP-seq. Attempts to confirm the binding sequences by electrophoretic mobility shift assay led to the discovery of a co-regulator, PA1413, via co-immunoprecipitation assay. PA1226 and PA1413 were shown to bind collaboratively to the promoter regions of their regulons. A model is proposed, summarizing our finding on this novel dual regulation system. PMID- 29995309 TI - Helicenes Grafted with 1,1,4,4-Tetracyanobutadiene Moieties: pi-Helical Push-Pull Systems with Strong Electronic Circular Dichroism and Two-Photon Absorption. AB - Enantiopure P- and M-carbo[6]helicenes substituted with one or two tetracyanobutadiene moieties at positions 2 and 15 have been prepared. Grafting of these electron-accepting groups onto the pi-helical core resulted in strong charge-transfer effects, which greatly affected the UV/Vis, electronic circular dichroism (ECD), and two-photon absorption (TPA) responses. The ECD signal was found to be reversibly switched by applying a redox stimulus. PMID- 29995311 TI - Tanner Awards for the Most-Cited Articles of 2015. PMID- 29995310 TI - Dynamic High-Pressure Microfluidization Treatment of Rice Bran: Effect on Pb(II) Ions Adsorption In Vitro. AB - : Insoluble dietary fiber from rice bran (RBIDF) was treated with dynamic high pressure microfluidization (DHPM). The influence of pressure on the adsorption of Pb(II) capacity of RBIDF was explored in a simulation of the gastrointestinal environment. RBIDF (pH 7.0) displayed the maximal binding capacity (420.74 +/- 13.12 MUmol/g), at the level of 150 MPa, which was as 1.36 times as the untreated sample. DHPM-treated RBIDF demonstrated a higher ability to adsorb cholesterol and sodium cholate. Meanwhile, the treatment changed the morphology but did not alter the primary structure. The adsorption capacity is linear to the physicochemical properties of the total negative charges. The adsorption kinetics fit the pseudo-second-order model, Pb(II) adsorption mainly occur on the surface of the fiber particulate, this process includes natural physical adsorption and chemical reaction. This study provides a feasible approach for improving the adsorption capacity of RBIDF, especially the adsorption of Pb(II). PRACTICAL APPLICATION: Dynamic high-pressure microfluidization can modify biomass adsorption materials effectively as a physically modification. The pretreatment dietary fiber can be used as a low-cost absorbing heavy metal biosorbent, and can be develop the functional food ingredients in the food industry. PMID- 29995313 TI - Pregnancy intention and opioid use disorder treatment retention in the MOTHER study. AB - BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) during pregnancy challenges public health. This study examines how pregnancy intention affects OUD treatment. METHODS: The primary exposure and outcome were pregnancy intention and treatment duration among MOTHER (Maternal Opioid Treatment: Human Experimental Research) participants (N = 175). RESULTS: Treatment durations were longer (21.3 vs. 16.3 weeks; p = .01) among intended (n = 29) compared to unintended (n = 146) pregnancy participants, but this was not significant in adjusted analyses. DISCUSSION AND CONCLUSIONS: Unintended pregnancies intersect with OUD and may modify one's treatment outcomes. SCIENTIFIC SIGNIFICANCE: OUD treatment may be a setting to help women implement informed family planning choices. (Am J Addict 2018;XX:1-3). PMID- 29995314 TI - Phylogeny, evolution, and biogeographic history of Calandrinia (Montiaceae). AB - PREMISE OF THE STUDY: Calandrinia are small, succulent herbs that vary broadly in habitat, morphology, life history, and photosynthetic metabolism. The lineage is placed within the Montiaceae, which in turn is sister to the rest of the Portulacineae (Caryophyllales). Calandrinia occupy two distinct biogeographic regions, one in the Americas (~14 species), and one in Australia (~74 species). Past analyses of the Montiaceae present conflicting hypotheses for the phylogenetic placement and monophyly of Calandrinia, and to date, there has been no molecular phylogenetic analysis of the Australian species. METHODS: Using a targeted gene enrichment approach, we sequenced 297 loci from multiple gene families across the Montiaceae, including all named and 16 putative new species of Australian Calandrinia, and the enigmatic monotypic genus Rumicastrum. KEY RESULTS: All data sets and analyses reject the monophyly of Calandrinia, with Australian and New World Calandrinia each comprising distinct and well-supported clades, and Rumicastrum nested within Australian Calandrinia. We provide the first well-supported phylogeny for Australian Calandrinia, which includes all named species and several phrase-named taxa. CONCLUSIONS: This study brings much needed clarity to relationships within Montiaceae and confirms that New World and Australian Calandrinia do not form a clade. Australian Calandrinia is a longtime resident of the continent, having diverged from its sister lineage ~30 Ma, concurrent with separation of Australia from Antarctica. Most diversification occurred during the middle Miocene, with lowered speciation and/or higher extinction rates coincident with the establishment of severe aridity by the late Miocene. PMID- 29995315 TI - Biomimetic Tissue Engineering: Tuning the Immune and Inflammatory Response to Implantable Biomaterials. AB - Regenerative medicine technologies rely heavily on the use of well-designed biomaterials for therapeutic applications. The success of implantable biomaterials hinges upon the ability of the chosen biomaterial to negotiate with the biological barriers in vivo. The most significant of these barriers is the immune system, which is composed of a highly coordinated organization of cells that induce an inflammatory response to the implanted biomaterial. Biomimetic platforms have emerged as novel strategies that aim to use the principle of biomimicry as a means of immunomodulation. This principle has manifested itself in the form of biomimetic scaffolds that imitate the composition and structure of biological cells and tissues. Recent work in this area has demonstrated the promising potential these technologies hold in overcoming the barrier of the immune system and, thereby, improve their overall therapeutic efficacy. In this review, a broad overview of the use of these strategies across several diseases and future avenues of research utilizing these platforms is provided. PMID- 29995316 TI - PcrX, an sRNA derived from the 3'- UTR of the Rhodobacter sphaeroides puf operon modulates expression of puf genes encoding proteins of the bacterial photosynthetic apparatus. AB - Facultative phototrophic bacteria like Rhodobacter sphaeroides can produce ATP by anoxygenic photosynthesis, which is of advantage under conditions with limiting oxygen. However, the simultaneous presence of pigments, light and oxygen leads to the generation of harmful singlet oxygen. In order to avoid this stress situation, the formation of photosynthetic complexes is tightly regulated by light and oxygen signals. In a complex regulatory network several regulatory proteins and the small non-coding RNA PcrZ contribute to the balanced expression of photosynthesis genes. With PcrX this study identifies a second sRNA that is part of this network. The puf operon encodes pigment binding proteins of the light-harvesting I complex (PufBA) and of the reaction center (PufLM), a protein regulating porphyrin flux (PufQ), and a scaffolding protein (PufX). The PcrX sRNA is derived from the 3' UTR of the puf operon mRNA by RNase E-mediated cleavage. It targets the pufX mRNA segment, reduces the half-life of the pufBALMX mRNA and as a consequence affects the level of photosynthetic complexes. By its action PcrX counteracts the increased expression of photosynthesis genes that is mediated by protein regulators and is thus involved in balancing the formation of photosynthetic complexes in response to external stimuli. PMID- 29995317 TI - Signaling pathways governing iron homeostasis in budding yeast. AB - Iron is an essential element for eukaryotes as it participates as a redox-active co-factor in many biological processes. Since iron is also potentially toxic, iron levels are carefully regulated. In the yeast Saccharomyces cerevisiae, iron homeostasis is maintained by the transcriptional control of the iron acquisition systems (iron regulon), mainly by the iron-responsive transcriptional factors Aft1p and Yap5p. Intracellular iron is stored in the vacuole, mobilized for other locations when necessary, particularly for the mitochondria, the major site of iron-utilizing pathways. Mitochondria also play an additional role as a sensor for the regulation of cellular iron acquisition and intracellular distribution. Mounting evidence suggest that iron acquisition systems are not only responsive to iron levels but also to signaling pathways. The most recognized is the activation of the iron regulon at the diauxic shift, oppositely regulated by PKA and SNF1 kinases, major regulators of glucose signaling. Hog1p, a MAP kinase involved in stress responses, also negatively regulates iron uptake by phosphorylating Aft1p. In this review, we address organellar signaling and signal transduction pathways that play a major role in the coordination of iron homeostasis with cell growth and division. PMID- 29995318 TI - Clinical value of hepatitis C virus core antigen levels in monitoring acute hepatitis C spontaneous clearance or treatment-induced clearance. AB - BACKGROUND AND AIM: To observe the clinical value of hepatitis C virus (HCV) core antigen (HCcAg) levels in monitoring acute HCV infection in patients with spontaneous clearance (SC) or clearance induced by antiviral therapy. METHODS: Patients with iatrogenic HCV infection (n = 104) were enrolled at the Shengjing Hospital, China Medical University, between 5 February 2013 and 3 April 2013. All cases were diagnosed with acute HCV infection, enrolled within 90 days of infection, and followed for 12 to 16 weeks. Blood was collected every month. HCV RNA and HCcAg levels were detected. From week 16, patients without SC were treated with pegylated-interferon and the HCV RNA and HCcAg levels were observed monthly. Follow-up was 7.5 (5.0 to 10.4) months. The Spearman correlation analysis was performed to determine the correlation between HCV RNA and HCcAg. Logistic regression analysis was used to determine the association of baseline HCV RNA and HCcAg levels with SC. RESULTS: Ten patients (9.62%) showed SC, with a negative conversion time of 57 (14 to 143) days. During follow-up, HCV RNA and HCcAg expression levels were positively correlated for each patient (except on the sixth month), but the levels of HCV RNA and HCcAg were not associated with HCV infection SC. CONCLUSIONS: HCcAg levels could be of value for monitoring the course early HCV infection, but could not predict SC of HCV infection. PMID- 29995319 TI - Reciprocal enhancement of gene expression between the phz and prn operon in Pseudomonas chlororaphis G05. AB - In previous studies with Pseudomonas chlororaphis G05, two operons (phzABCDEFG and prnABCD) were confirmed to respectively encode enzymes for biosynthesis of phenazine-1-carboxylic acid and pyrrolnitrin that mainly contributed to suppression of some fungal phytopathogens. Although some regulators were identified to govern their expression, it is not known how two operons coordinately interact. By constructing the phz- or/and prn- deletion mutants, we found that in comparison with the wild-type strain G05, phenazine-1-carboxylic acid production in the mutant G05Deltaprn obviously decreased in GA broth in the absence of prn, and pyrrolnitrin production in the mutant G05Deltaphz remarkably declined in the absence of phz. By generating the phzA and prnA transcriptional and translational fusions with a truncated lacZ on shuttle vector or on the chromosome, we found that expression of the phz or prn operon was correspondingly increased in the presence of the prn or phz operon at the post-transcriptional level, not at the transcriptional level. These results indicated that the presence of one operon would promote the expression of the other one operon between the phz and prn. This reciprocal enhancement would keep the strain G05 producing more different antifungal compounds coordinately and living better with growth suppression of other microorganisms. PMID- 29995320 TI - Sphingosine-1-phosphate reduces atresia of primordial follicles occurring during slow-freezing and thawing of human ovarian cortical strips. AB - We aimed in this study to explore if sphingosine-1-phosphate (S1P) reduces apoptosis of primordial follicles during cryopreservation of human ovarian cortical samples. Ovarian cortical tissue fragments obtained from young patients who underwent laparoscopic excision of benign ovarian cysts were used for the experiments. The samples were slow-frozen and thawed with and without S1P at 200 and 400 MUM, cultured for 1 day, and then were fixed and processed for both histomorphological assessment and detection of apoptosis with immunohistochemistry using apoptosis marker cleaved caspase-3. Follicle counts were expressed as the mean number of follicles per mm2 . The mean number of primordial follicles and in vitro estradiol (E2) and anti-mullerian hormone (AMH) production of the slow-frozen and thawed samples were significantly reduced compared with fresh unfrozen samples. S1P treatment at 400 MUM but not 200 MUM concentration resulted in a significant increase in the number of surviving primordial follicles and in vitro E2 and AMH productions of the samples compared with their counterparts slow-frozen without S1P. We found that that there was a significant decrease in the number of primordial follicles with their oocytes stained positive for cleaved caspase-3 in the slow-frozen samples S1P 400 MUM in comparison with the samples slow-frozen without S1P. These results suggest that S1P may ameliorate follicle atresia occurring in human ovarian cortical samples during cryopreservation. PMID- 29995321 TI - Tolerance traits related to climate change resilience are independent and polygenic. AB - The resilience of organisms to climate change through adaptive evolution is dependent on the extent of genetically based variation in key phenotypic traits and the nature of genetic associations between them. For aquatic animals, upper thermal tolerance and hypoxia tolerance are likely to be a important determinants of sensitivity to climate change. To determine the genetic basis of these traits and to detect associations between them, we compared naturally occurring populations of two subspecies of Atlantic killifish, Fundulus heteroclitus, that differ in both thermal and hypoxia tolerance. Multilocus association mapping demonstrated that 47 and 35 single nucleotide polymorphisms (SNPs) explained 43.4% and 51.9% of variation in thermal and hypoxia tolerance, respectively, suggesting that genetic mechanisms underlie a substantial proportion of variation in each trait. However, no explanatory SNPs were shared between traits, and upper thermal tolerance varied approximately linearly with latitude, whereas hypoxia tolerance exhibited a steep phenotypic break across the contact zone between the subspecies. These results suggest that upper thermal tolerance and hypoxia tolerance are neither phenotypically correlated nor genetically associated, and thus that rates of adaptive change in these traits can be independently fine tuned by natural selection. This modularity of important traits can underpin the evolvability of organisms to complex future environmental change. PMID- 29995322 TI - Photothermal Control of Heat-Shock Protein Expression at the Single Cell Level. AB - Laser heating of individual cells in culture recently led to seminal studies in cell poration, fusion, migration, or nanosurgery, although measuring the local temperature increase in such experiments remains a challenge. Here, the laser induced dynamical control of the heat-shock response is demonstrated at the single cell level, enabled by the use of light-absorbing gold nanoparticles as nanosources of heat and a temperature mapping technique based on quadriwave lateral shearing interferometry (QLSI) measurements. As it is label-free, this approach does not suffer from artifacts inherent to previously reported fluorescence-based temperature-mapping techniques and enables the use of any standard fluorescent labels to monitor in parallel the cell's response. PMID- 29995323 TI - Natural course of persistent hepatitis B virus infection in hepatitis B e antigen positive and hepatitis B e antigen-negative cohorts in Japan based on the Markov model. AB - This population-based study examined the natural course of hepatitis B e antigen (HBeAg)-positive or HBeAg-negative persistent hepatitis B virus (HBV) infection, adjusted by age and liver disease states using a Markov model. Using 12 417 person-years data (n = 862), annual transition probabilities were estimated, and age-adjusted cumulative incidence and natural history of persistent HBV infection were simulated in both sexes of groups 1 (HBeAg-negative status with HBV DNA level <4.0 log IU/mL at entry) and 2 (persistent HBeAg-positive status throughout the study). In group 1, 15.26% of 30-years old men with chronic hepatitis (CH) were expected to remain in the same state at age 65 years, 28.32% subsided into an hepatitis B surface antigen (HBsAg)-negative state, and 13.20% developed hepatocellular carcinoma (HCC). The expectations for 40-years old men in group 1 were 21.43%, 19.86%, and 15.04%, respectively. The expectations for 30 years women in group 1 were 30.57%, 21.15%, and 4.08%, respectively. These results suggest that HBeAg positivity caused a higher risk of HCC onset in persistent HBV infection after adjustments for age, sex, and liver disease state. HCC was likely to develop, but unlikely to subside into HBsAg clearance, remaining in a CH state with aging, regardless of HBeAg state. Furthermore, both HCC development and HBsAg clearance occurred more frequently in men than in women, irrespective of HBeAg status. PMID- 29995324 TI - Roles of PIP2 in the membrane binding of MIM I-BAR: insights from molecular dynamics simulations. AB - In order to probe the roles of PIP2 in the interactions between MIM I-BAR and model membranes, we performed a series of 10 MUs-scale coarse-grained molecular dynamics simulations. Our results indicate that PIP2 plays predominant roles in the membrane binding of MIM I-BAR in a concentration-dependent manner and via electrostatic interactions. Besides, we find that the occurrence of the membrane curvature may induce the re-distribution of lipids in the membrane and result in the local enrichment of PIP2 at negatively curved membrane areas. Combining these roles of PIP2 in the membrane binding of MIM I-BAR helps explain how MIM I-BAR senses negative curvature and, thus, contributes to maintaining membrane protrusions. PMID- 29995325 TI - Genetic inactivation of synaptosomal-associated protein 25 (SNAP-25) in adult hippocampal neural progenitors impairs pattern discrimination learning but not survival or structural maturation of newborn dentate granule cells. AB - Adult neurogenesis is necessary for proper cognition and behavior, however, the mechanisms that underlie the integration and maturation of newborn neurons into the pre-existing hippocampal circuit are not entirely known. In this study, we sought to determine the role of action potential (AP)-dependent synaptic transmission by adult-generated dentate granule cells (DGCs) in their survival and function within the existing circuitry. We used a triple transgenic mouse (NestinCreERT2 :Snap25fl/fl : tdTomato) to inducibly inactivate AP-dependent synaptic transmission within adult hippocampal progenitors and their progeny. Behavioral testing in a hippocampal-dependent A/B contextual fear-discrimination task revealed impaired discrimination learning in mice harboring SNAP-25 deficient adult-generated dentate granule cells (DGCs). Despite poor performance on this neurogenesis-dependent task, the production and survival of newborn DGCs was quantitatively unaltered in tamoxifen-treated NestinCreERT2 :Snap25fl/fl : tdTomato SNAP compared to tamoxifen-treated NestinCreERT2 :Snap25wt/wt : tdTomato control mice. Although SNAP-25-deficient adult DGCs displayed a small but statistically significant enhancement in proximal dendritic branching, their overall dendritic length and distal branching complexity was unchanged. SNAP-25 deficient newborn DGCs also displayed robust efferent mossy fiber output to CA3, with normal linear density of large mossy fiber terminals (LMTs). These studies suggest that AP-dependent neurotransmitter release by newborn DGCs is not essential for their survival or rudimentary structural maturation within the adult hippocampus. PMID- 29995326 TI - Personalized Boosters After a Computerized Intervention Targeting College Drinking: A Randomized Controlled Trial. AB - BACKGROUND: Problematic drinking among emerging adult college students is extensive. Computer-delivered interventions (CDIs) have strong appeal because they can be quickly delivered to large numbers of students. Although they are efficacious in the short term, CDIs are not as efficacious as in-person interventions longer term. This study examined the utility of emailed boosters containing personalized feedback after a CDI to enhance and extend reductions among emerging adult college drinkers. Sex and age were explored as potential moderators. METHODS: Participants were 537 college students (67.4% female) aged 18 to 24 years (M age = 19.65, SD = 1.67) who consumed at least 1 alcoholic drink in the past 2 weeks. They were randomly assigned to CDI-only, CDI + booster email, or an assessment-only control condition, and were assessed up to 9 months postintervention. A booster email with personalized feedback was sent to the CDI + booster email group 2 weeks after completion of the CDI. RESULTS: Moderation findings for age revealed that the booster may be an effective means to strengthen and extend intervention effects for emerging adults who are of legal drinking age. However, effects were negligible for underage drinkers. Although the booster effect for the overall sample demonstrated a trend in the expected direction, it failed to reach significance. Booster effects were not significantly moderated by sex. Intervention effects were not moderated by either age or sex. CONCLUSIONS: The present investigation contributes to a limited body of research on boosters to augment main intervention effects in college drinkers. Our study demonstrated that a brief CDI plus a simple email booster with personalized feedback resulted in significant reductions in drinking outcomes for emerging adults of legal drinking age. Efforts to further develop and refine intervention booster strategies represent a promising future direction to minimize harmful drinking among college students. PMID- 29995327 TI - Distribution of norovirus and sapovirus genotypes with emergence of NoV GII.P16/GII.2 recombinant strains in Chiang Mai, Thailand. AB - Norovirus (NoV) and sapovirus (SaV) are recognized as the causative agents of acute gastroenteritis, and NoV is one of the leading pathogens reported worldwide. This study reports on the distribution of NoV and SaV genotypes in children hospitalized with acute gastroenteritis in Chiang Mai, Thailand, from January 2015 to February 2017. From a total of 843 stool samples, 170 (20.2%) and 16 (1.9%) were identified as having NoV and SaV infections, respectively. Two samples (0.2%) were positive for both NoV and SaV. Of these, NoV GII.4 (57.2%) was the dominant genotype, followed by GII.2, GII.3, GII.17, GII.6, GII.7, GII.13, GII.14, GII.15, GII.21, GI.6, and GI.5. Among the NoV GII.4 variants, Sydney 2012 was the dominant variant during the period 2015-2016, while the other variants detected in this study were Asia 2003 and New Orleans 2009. Interestingly, an increase of NoV GII.2 was observed in 2016 and 2017. Characterization of partial RNA-dependent RNA polymerase and VP1 nucleotide sequences of GII.2 strains revealed that more than half of the GII.2 strains circulating in 2016 and 2017 were recombinant strains of GII.P16/GII.2. For SaV, the majority of strains belonged to GI.1 (55.6%) and GI.2 (33.3%), while GII.5 accounted for 11.1%. In conclusion, this study demonstrates the diversity of NoV and SaV, and the emergence of NoV GII.P16/GII.2 recombinant strains in 2016 and 2017 in Chiang Mai, Thailand. PMID- 29995328 TI - Boron Embedded in Metal Iron Matrix as a Novel Anode Material of Excellent Performance. AB - Boron, the most ideal lithium-ion battery anode material, demonstrates highest theoretical capacity up to 12 395 mA h g-1 when forming Li5 B. Furthermore, it also exhibits promising features such as light weight, considerable reserves, low cost, and nontoxicity. However, boron-based materials are not in the hotspot list because Li5 B may only exist when B is in atomically isolated/dispersed form, while the aggregate material can barely be activated to store/release Li. At this time, an ingenious design is demonstrated to activate the inert B to a high specific capacity anode material by dispersing it in a Fe matrix. The above material can be obtained after an electrochemical activation of the precursors Fe2 B/Fe and B2 O3 /Fe. The latter harvests the admirable capacity, ultrahigh tap density of 2.12 g cm-3 , excellent cycling stability of 3180 mA h cm-3 at 0.1 A g 1 (1500 mA h g-1 ) after 250 cycles, and superlative rate capability of 2650 mA h cm-3 at 0.5 A g-1 , 2544 mA h cm-3 at 1.0 A g-1 , and 1696 mA h cm-3 at 2.0 A g-1 . Highly conductive matrix promoted reversible Li storage of boron-based materials might open a new gate for advanced anode materials. PMID- 29995329 TI - Araucaria lefipanensis (Araucariaceae), a new species with dimorphic leaves from the Late Cretaceous of Patagonia, Argentina. AB - PREMISE OF THE STUDY: We describe a new araucarian species, Araucaria lefipanensis, from the Late Cretaceous flora of the Lefipan Formation, in Patagonia (Argentina) based on reproductive and vegetative remains, with a combination of characters that suggest mosaic evolution in the Araucaria lineage. METHODS: The studied fossils were found at the Canadon del Loro locality. Specimens were separated into two leaf morphotypes, and their morphological differences were tested with MANOVA. KEY RESULTS: The new species Araucaria lefipanensis is erected based on the association of dimorphic leaves with cuticle remains and isolated cone scale complexes. The reproductive morphology is characteristic of the extant section Eutacta, whereas the vegetative organs resemble those of the sections Intermedia, Bunya, and Araucaria (the broad-leaved clade). CONCLUSIONS: The leaf dimorphism of A. lefipanensis is similar to that of extant A. bidwillii, where dimorphism is considered to be related to seasonal growth. The leaf dimorphism in A. lefipanensis is consistent with the paleoclimatic and paleoenvironmental reconstructions previously suggested for the Lefipan Formation, which is thought to have been a seasonal subtropical forest. The new species shows evidence of mosaic evolution, with cone scale complexes morphologically similar to section Eutacta and leaves similar to the sections of the broad-leaved clade, constituting a possible transitional form between these two well-defined lineages. More complete plant concepts, especially those including both reproductive and vegetative remains are necessary to understand the evolution of ancient plant lineages. This work contributes to this aim by documenting a new species that may add to the understanding of the early evolution of the sections of Araucaria. PMID- 29995330 TI - Record Efficiency Stable Flexible Perovskite Solar Cell Using Effective Additive Assistant Strategy. AB - Even though the power conversion efficiency (PCE) of rigid perovskite solar cells is increased to 22.7%, the PCE of flexible perovskite solar cells (F-PSCs) is still lower. Here, a novel dimethyl sulfide (DS) additive is developed to effectively improve the performance of the F-PSCs. Fourier transform infrared spectroscopy reveals that the DS additive reacts with Pb2+ to form a chelated intermediate, which significantly slows down the crystallization rate, leading to large grain size and good crystallinity for the resultant perovskite film. In fact, the trap density of the perovskite film prepared using the DS additive is reduced by an order of magnitude compared to the one without it, demonstrating that the additive effectively retards transformation kinetics during the thin film formation process. As a result, the PCE of the flexible devices increases to 18.40%, with good mechanical tolerance, the highest reported so far for the F PSCs. Meanwhile, the environmental stability of the F-PSCs significantly enhances by 1.72 times compared to the device without the additive, likely due to the large grain size that suppresses perovskite degradation at grain boundaries. The present strategy will help guide development of high efficiency F-PSCs for practical applications. PMID- 29995331 TI - Lost in virtual gaming worlds: Grit and its prognostic value for online game addiction. AB - BACKGROUND AND OBJECTIVES: The personality construct grit is defined as the ability to be persistent in pursuit of long-term goals in spite of challenges or obstacles. Grit is an emerging concept in positive psychology and has gained much attention because of its relevance for success and well-being across different domains. The aim of the present study was to examine the prognostic value of grit for online game addiction. METHODS: We surveyed German speaking online gamers (N = 305: 193 males and 112 females, Mage = 28.44 years, SDage = 8.88) in an online cross-sectional self-report study. We measured grit with the German version of the Short Grit Scale (BISS-8), online game addiction with the short version of the Game Addiction Scale (GAS), and participants' age and gender. RESULTS: Structural equation modeling supported the higher-order factor structure of grit in our sample (chi2 [18] = 29.31, p < .05; CFI = .980; TLI = .969; RMSEA = .045; SRMR = .038). A logistic regression revealed that both grit (OR = 0.62, 95%CI [.42; .89], p < .05) as well as age (OR = .92, 95%CI [.88; .97], p < .01) significantly reduced the likelihood of being addicted to online games. DISCUSSION AND CONCLUSIONS: In line with previous research on grit in patients with substance use disorders, we found grit to be a protective factor against online game addiction. We concluded that higher grit scores and older ages decrease the likelihood of being addicted to online games. SCIENTIFIC SIGNIFICANCE: This study provides initial support for the clinical relevance of grit for online game addiction. (Am J Addict 2018;XX:1-6). PMID- 29995332 TI - DPFGSE-MDEC-J-resolved COSY: An efficient method for selectively measuring proton proton spin coupling constants of the multiplet signals. AB - Natural products such as polyketides often possess various spin systems, consisting of a methine group directly bonded to a methyl group (e.g., ?CHA ?CHB (CH3 )?CHC ?). The methine proton HB splits into a broadened multiplet by coupling with several vicinal protons, rendering analysis difficult of n JH-H with respect to HB in double-quantum filtered COSY or exclusive COSY. For the purpose of measuring n JH-H in the aforesaid spin system, we have developed new techniques, named multifrequency homo-decoupling (MDEC)-J-resolved COSY and DPFGSE-MDEC-J-resolved COSY. This method incorporates MDEC pulse scheme into J resolved COSY for the selective decouple of individual methyl groups, avoiding decoupling of the target protons resonating in methyl region. Determinations of n JH-H of the multiplet signals can easily be performed using the proposed pulse sequence. PMID- 29995333 TI - Picturing the Membrane-assisted Choreography of Cytochrome P450 with Lipid Nanodiscs. AB - Cytochrome P450, a family of monooxygenase enzymes, is organized as a catalytic metabolon, and requires enzymatic partners as well as environmental factors that tune its complex dynamic activity. P450 and its reducing counterparts are membrane-bound proteins which are believed to dynamically interact to form functional complexes. Increasing experimental evidence signifies the role (s) of protein-lipid interactions in P450's catalytic function and efficiency. The challenges posed by the membrane have severely limited high-resolution understanding of the molecular interfaces of these interactions. Nevertheless, recent NMR studies have provided piercing insights into the dynamic structural interactions that enable the function of P450. In this review, we will discuss different biomimetic approaches relevant to unveil molecular interplays at the membrane, focusing on our recent work on lipid-nanodiscs. We also highlight the need to expand the use of nanodiscs, and the power of a combination of cutting edge solution and solid-state NMR techniques, to study the dynamic structures of P450 as well as other membrane-proteins. PMID- 29995334 TI - Light-Activated, Multi-Semiconductor Hybrid Microswimmers. AB - Using a dynamic fabrication process, hybrid, photoactivated microswimmers made from two different semiconductors, titanium dioxide (TiO2 ) and cuprous oxide (Cu2 O) are developed, where each material occupies a distinct portion of the multiconstituent particles. Structured light-activated microswimmers made from only TiO2 or Cu2 O are observed to be driven in hydrogen peroxide and water most vigorously under UV or blue light, respectively, whereas hybrid structures made from both of these materials exhibit wavelength-dependent modes of motion due to the disparate responses of each photocatalyst. It is also found that the hybrid particles are activated in water alone, a behavior which is not observed in those made from a single semiconductor, and thus, the system may open up a new class of fuel-free photoactive colloids that take advantage of semiconductor heterojunctions. The TiO2 /Cu2 O hybrid microswimmer presented here is but an example of a broader method for inducing different modes of motion in a single light-activated particle, which is not limited to the specific geometries and materials presented in this study. PMID- 29995335 TI - Combatting Infections with Nanomedicine. PMID- 29995336 TI - Phylogeny and diversification history of the large Neotropical genus Philodendron (Araceae): Accelerated speciation in a lineage dominated by epiphytes. AB - PREMISE OF THE STUDY: Philodendron is a large genus of ~560 species and among the most conspicuous epiphytic components of Neotropical forests, yet its phylogenetic relationships, timing of divergence, and diversification history have remained unclear. We present a comprehensive phylogenetic study for Philodendron and investigate its diversification, including divergence-time estimates and diversification rate shift analyses. METHODS: We performed the largest phylogenetic reconstruction for Philodendron to date, including 125 taxa with a combined dataset of three plastid regions (petD, rpl16, and trnK/matK). We estimated divergence times using Bayesian evolutionary analysis sampling trees and inferred shifts in diversification rates using Bayesian analysis of macroevolutionary mixtures. KEY RESULTS: We found that Philodendron, its three subgenera, and the closely related genus Adelonema are monophyletic. Within Philodendron subgenus Philodendron, 12 statistically well-supported clades are recognized. The genus Philodendron originated ~25 mya and a diversification rate upshift was detected at the origin of subgenus Philodendron ~12 mya. CONCLUSIONS: Philodendron is a species-rich Neotropical lineage that diverged from Adelonema during the late Oligocene. Within Philodendron, the three subgenera currently accepted are recovered in two lineages: one contains the subgenera Meconostigma and Pteromischum and the other contains subgenus Philodendron. The lineage containing subgenera Meconostigma and Pteromischum underwent a consistent diversification rate. By contrast, a diversification rate upshift occurred within subgenus Philodendron ~12 mya. This diversification rate upshift is associated with the species radiation of the most speciose subgenus within Philodendron. The sections accepted within subgenus Philodendron are not congruent with the clades recovered. Instead, the clades are geographically defined. PMID- 29995337 TI - EEMCO-European group on efficacy measurement and evaluation of cosmetics and other products. PMID- 29995338 TI - Assessing ICSI outcome by combining non-invasive indicators: Early time-lapse morphokinetics and apoptosis in associated cumulus cells among women with the polycystic ovarian syndrome. AB - Cumulus cells features and embryo developmental events can be considered as noninvasive indicators for embryo selection and clinical outcomes. A combination of time-lapse morphokinetic parameters and cumulus cell apoptosis in women with polycystic ovarian syndrome (PCOS) was evaluated for predicting pregnancy outcome. We assessed a total of 547 embryos from 100 intracytoplasmic sperm injection (ICSI) cycles. Time-lapse records were interpreted in time to pronuclear fading (tPNf), time to 2 to 8 cells (t2-t8), direct cleavage, reverse cleavage, and also for the presence of multinucleation. Percentages of apoptosis were identified in 100 associated cumulus cell samples using the TDT-mediated dUTP-biotin nick end-labeling assay. The significant decrease of apoptotic cumulus cells was detected in patients with chemical and clinical pregnancies as well as live birth among patients PCOS and in the tubal infertility group (p > 0.05). Furthermore, significantly higher implantation rate and also significantly lower cases of early pregnancy loss were observed in the group of oocytes with less apoptotic cumulus cells. Multivariate logistic regression analysis showed that tPNf together with cumulus cell apoptosis were independent prognostic factors of chemical pregnancy, clinical pregnancy rate, and live birth. Time lapse embryo parameters may not reflect the cumulus cell apoptosis rate. However, the rate of apoptotic cumulus cells is significantly associated with ICSI outcome using Day 3 embryo transfer. PMID- 29995339 TI - Effect of the anther-smut fungus Microbotryum on the juvenile growth of its host Silene latifolia. AB - PREMISE OF THE STUDY: Plant pathogens that form persistent systemic infections within plants have the potential to affect multiple plant life history traits, yet we tend to focus only on visible symptoms. Anther smut of Silene latifolia caused by the fungus Microbotryum lychnidis-dioicae induces the anthers of its host to support fungal spore production instead of pollen, and the pathogen is primarily transmitted among flowering plants by pollinators. Nevertheless, most of its life cycle is spent in the asymptomatic vegetative phase, and spores falling on seedlings or nonflowering plants can also infect the host. The purpose of this study was to ask whether the fungus also had an effect on its host plant in the juvenile vegetative phase before flowering as this is important for the disease dynamics in species where infection of seedlings is commonplace. METHODS: Leaf length and leaf number of inoculated and uninoculated juvenile plants were compared in greenhouse experiments, and in one experiment, disease status of the plants at flowering was determined. KEY RESULTS: Inoculated plants had shorter but more leaves, and reduced root mass at the early juvenile (preflowering) stage. Some of these effects were detectable in plants that were inoculated but showed no disease symptoms at flowering. CONCLUSIONS: These results show that pathogenic fungi can have endophyte-like effects even in the total absence of their typical and more charismatic symptoms, and conversely that the assessment of endophyte effects on the fitness of their hosts should include all stages of the host life cycle. PMID- 29995340 TI - Evidence-based farriery - does it exist? PMID- 29995341 TI - Metal-Free Direct C-H Cyanation of Alkenes. AB - A metal-free and direct alkene C-H cyanation is described. Directing groups are not required and the mechanism involves electrophilic activation of the alkene by a cyano iodine(III) species generated in situ from a [bis(trifluoroacetoxy)iodo]arene and trimethylsilyl cyanide as the cyanide source. This C-H functionalization can be conducted on gram scale, and for noncyclic 1,1- and 1,2-disubstuted alkenes high stereoselectivity is achieved, thus rendering the method highly valuable. PMID- 29995343 TI - The impact of DNA methylation in Alphaproteobacteria. AB - Alphaproteobacteria include bacteria with very different modes of life, from free living to host-associated and pathogenic bacteria. Their genomes vary in size and organization from single circular chromosomes to multipartite genomes and are often methylated by one or more adenine or cytosine methyltransferases (MTases). These include MTases that are part of restriction/modification systems and so called orphan MTases. The development of novel technologies accelerated the analysis of methylomes and revealed the existence of epigenetic patterns in several Alphaproteobacteria. This review describes the known functions of DNA methylation in Alphaproteobacteria and also discusses its potential drawbacks through the accidental deamination of methylated cytosines. Particular emphasis is given to the strong connection between the cell cycle-regulated orphan MTase CcrM and the complex network that controls gene expression and cell cycle progression in Alphaproteobacteria. PMID- 29995342 TI - Comparison of Siriraj liquid-based solution and standard transport media for the detection of high-risk human papillomavirus in cervical specimens. AB - PURPOSE: To evaluate the performance of Siriraj liquid-based solution for human papillomavirus (HPV) DNA testing compared with standard transport media. METHODS: This cross-sectional study enrolled 217 women aged 30 years or older who attended for cervical cancer screening or had abnormal cervical cytology, or were diagnosed with cervical cancer at the Department of Obstetrics-Gynecology, Siriraj Hospital from March 2015 to January 2016. We excluded patients with a history of any cervical procedures, hysterectomy, or previous treatment with pelvic irradiation or chemotherapy. Two cervical specimens were collected from each participant. The standard Cervi-Collect Specimen Collection Kit was used to preserve the first sample, and Siriraj liquid-based solution was used for the second one. All samples were sent for HPV DNA testing using the same standard high-risk HPV assay. HPV test results were recorded and statistically analyzed. RESULTS: The results showed agreement between standard transport media and Siriraj liquid-based solution for HPV DNA testing, at a kappa value of 0.935 (P < 0.001). We found no discorrelation for the detection of HPV 16, which accounts for approximately 50% of cervical cancers. The relative sensitivity of Siriraj liquid-based solution and standard transport media in patients with high-grade cervical intraepithelial neoplasia or worse (CIN2+) is 98% (50/51). The relative specificity of Siriraj liquid-based solution and standard transport media in patients with non-CIN2+ is 98.1% (102/104). CONCLUSION: Siriraj liquid-based solution showed almost perfect agreement with the standard transport media for HPV DNA testing. This solution, costing 2 to 3 times less than the commercially available standard media, may be an alternative option for HPV DNA testing. PMID- 29995345 TI - Differentiation of the granulosa layer from hen prehierarchal follicles associated with follicle-stimulating hormone receptor signaling. AB - Recruitment of a single follicle into the preovulatory hierarchy of the domestic hen ovary occurs from a small cohort of prehierarchal follicles measuring 6-8 mm in diameter. We have previously reported that granulosa cells (GCs) collected from prehierarchal follicles express highest levels of membrane-localized follicle-stimulating hormone receptor (FSHR) during follicle development, yet fail to initiate signaling via cAMP following short-term incubation with FSH. Consequently, GC from prehierarchal follicles remain in an undifferentiated state and lack the capacity for steroidogenesis due to a deficiency of cAMP-dependent STAR protein and CYP11A1 gene expression. The present studies investigate FSH responsiveness in GC before and after the transition from undifferentiated to a differentiated state at follicle recruitment. Before recruitment focus is directed toward the inhibition of FSHR-signaling by beta-ARRESTIN (betaARR). Specifically, knockdown of betaARR messenger RNA in cultured, undifferentiated GC using small interfering RNA facilitated FSH-induced cAMP formation, STAR expression, and progesterone production. Furthermore, overexpression of bovine betaARR1 and G-protein-coupled receptor kinase2 in actively differentiating GC significantly decreased cAMP accumulation and progesterone production following a challenge with FSH. We propose that a betaARR-mediated mechanism maintains FSHR unresponsiveness in undifferentiated GC from prehierarchal follicles, and as a result prevents GC differentiation until the time of follicle recruitment. PMID- 29995344 TI - In Vitro Culturing and Screening of Candida albicans Biofilms. AB - Candida albicans is a normal member of the human microbiota that asymptomatically colonizes healthy individuals, however it is also an opportunistic pathogen that can cause severe infections, especially in immunocompromised individuals. The medical impact of C. albicans depends, in part, on its ability to form biofilms, communities of adhered cells encased in an extracellular matrix. Biofilms can form on both biotic and abiotic surfaces, such as tissues and implanted medical devices. Once formed, biofilms are highly resistant to antifungal agents and the host immune system, and can act as a protected reservoir to seed disseminated infections. Here, we present several in vitro biofilm protocols, including protocols that are optimized for high-throughput screening of mutant libraries and antifungal compounds. We also present protocols to examine specific stages of biofilm development and protocols to evaluate interspecies biofilms that C. albicans forms with interacting microbial partners. (c) 2018 by John Wiley & Sons, Inc. PMID- 29995346 TI - Postfire nitrogen balance of Mediterranean shrublands: Direct combustion losses versus gaseous and leaching losses from the postfire soil mineral nitrogen flush. AB - Fire is a major factor controlling global carbon (C) and nitrogen (N) cycling. While direct C and N losses caused by combustion have been comparably well established, important knowledge gaps remain on postfire N losses. Here, we quantified both direct C and N combustion losses as well as postfire gaseous losses (N2 O, NO and N2 ) and N leaching after a high-intensity experimental fire in an old shrubland in central Spain. Combustion losses of C and N were 9.4 Mg C/ha and 129 kg N/ha, respectively, representing 66% and 58% of initial aboveground vegetation and litter stocks. Moreover, fire strongly increased soil mineral N concentrations by several magnitudes to a maximum of 44 kg N/ha 2 months after the fire, with N largely originating from dead soil microbes. Postfire soil emissions increased from 5.4 to 10.1 kg N ha-1 year-1 for N2 , from 1.1 to 1.9 kg N ha-1 year-1 for NO and from 0.05 to 0.2 kg N ha-1 year-1 for N2 O. Maximal leaching losses occurred 2 months after peak soil mineral N concentrations, but remained with 0.1 kg N ha-1 year-1 of minor importance for the postfire N mass balance. 15 N stable isotope labelling revealed that 33% of the mineral N produced by fire was incorporated in stable soil N pools, while the remainder was lost. Overall, our work reveals significant postfire N losses dominated by emissions of N2 that need to be considered when assessing fire effects on ecosystem N cycling and mass balance. We propose indirect N gas emissions factors for the first postfire year, equalling to 7.7% (N2 -N), 2.7% (NO-N) and 5.0% (N2 O-N) of the direct fire combustion losses of the respective N gas species. PMID- 29995347 TI - Dirac Semimetal Heterostructures: 3D Cd3 As2 on 2D Graphene. AB - Dirac semimetal is an emerging class of quantum matters, ranging from 2D category, such as, graphene and surface states of topological insulator to 3D category, for instance, Cd3 As2 and Na3 Bi. As 3D Dirac semimetals typically possess Fermi-arc surface states, the 2D-3D Dirac van der Waals heterostructures should be promising for future electronics. Here, graphene-Cd3 As2 heterostructures are fabricated through direct layer-by-layer stacking. The electronic coupling results in a notable interlayer charge transfer, which enables us to modulate the Fermi level of graphene through Cd3 As2 . A planar graphene p-n-p junction is achieved by selective modification, which demonstrates quantized conductance plateaus. Moreover, compared with the bare graphene device, the graphene-Cd3 As2 hybrid device presents large nonlocal signals near the Dirac point due to the charge transfer from the spin-polarized surface states in the adjacent Cd3 As2 . The results enrich the family of van der Waals heterostructure and should inspire more studies on the application of Dirac/Weyl semimetals in spintronics. PMID- 29995348 TI - Efficacy of probiotics on anxiety-A meta-analysis of randomized controlled trials. AB - BACKGROUND: The concept "psychobiotics" claims potential beneficial effect of probiotics on anxiety, whereas findings from clinical trials are inconsistent. Thus, a meta-analysis is needed to clarify the effect of probiotics on anxiety. METHODS: Randomized controlled trials (RCTs) assessing the effect of probiotics on anxiety were systematically retrieved from online databases and manually screened for references of relevant published literature through September 1, 2017. Standardized mean difference in change from baseline of anxiety rating scales between probiotics groups and placebo groups was selected as the main effect index. Subgroup analyses were conducted with respect to overall health status of the sample, existence of gastrointestinal symptoms, strains of flora, trial duration, and risk of bias assessment. Publication bias was evaluated by funnel plot and Egger's test. The reliability of the result was assessed by leave one-out sensitivity analysis. RESULTS: Twelve studies with 1,551 subjects (871 in probiotics group and 680 in control group) were included. All the studies were rated as low or moderate risk of bias. The meta-analysis and subgroup analyses all showed no significant difference between probiotics and placebo in alleviating anxiety symptoms. The Egger's test revealed no evidence of significant publication bias. Sensitivity analysis showed that leaving out one study would result in marginal significance. CONCLUSIONS: The evidence for the efficacy of probiotics in alleviating anxiety, as presented in currently published RCTs, is insufficient. More reliable evidence from clinical trials is needed before a case can be made for promoting the use of probiotics for alleviating anxiety. PMID- 29995349 TI - An external review of the conclusions regarding the peak direct training module. AB - Promoting the Emergence of Advanced Knowledge-Direct Training Module (PEAK-DTM) is a commercially available assessment and curriculum for individuals whose language skills are not developmentally adequate. In their review of PEAK-DTM, Reed and Luiselli (2016) analyzed the extant literature on PEAK-DTM and concluded that it has a sound and growing body of empirical support on its efficacy, usability, and psychometric properties. Similar conclusions are mirrored in the PEAK-DTM literature and promotional material. I review these conclusions and contend that many overrate the research that backs them. Suggestions for a more rigorous research agenda on PEAK-DTM and its related modules are provided. PMID- 29995350 TI - Hop-family Helicobacter outer membrane adhesins form a novel class of Type 5-like secretion proteins with an interrupted beta-barrel domain. AB - The human stomach pathogen Helicobacter pyloriattaches to healthy and inflamed gastric tissue through members of a paralogous family of 'Helicobacter outer membrane proteins' (Hops), including adhesins BabA, SabA, HopQ, LabA and HopZ. Hops share a conserved 25 kDa C-terminal region that is thought to form an autotransporter-like transmembrane domain. Instead, our results show that Hops contain a non-continuous transmembrane domain, composed of seven predicted beta strands at the C-terminus and one at the N-terminus. Folding and outer membrane localization of the C-terminal beta-domain critically depends on a predicted transmembrane beta-strand within the first 16 N-terminal residues. The N-terminus is shown to reside in the periplasm, and our crystal and small angle X-ray scattering structures for the SabA extracellular domain reveal a conserved coiled coil stem domain that connects to transmembrane beta-strand 1 and 2. Taken together, our data show that Hop adhesins represent a novel outer membrane protein topology encompassing an OmpA-like 8-stranded beta-barrel that is interrupted by a 15-108 kDa domain inserted inside the first extracellular loop. The insertion of large, folded domains in an extracellular loop is unprecedented in bacterial outer membrane proteins and is expected to have important consequences on how these proteins reach the cell surface. PMID- 29995351 TI - Superior explicit memory despite severe developmental amnesia: In-depth case study and neural correlates. AB - The acquisition of new semantic memories is sometimes preserved in patients with hippocampal amnesia. Robust evidence for this comes from case reports of developmental amnesia suggesting that low-to-normal levels of semantic knowledge can be achieved despite compromised episodic learning. However, it is unclear whether this relative preservation of semantic memory results from normal acquisition and retrieval or from residual episodic memory, combined with effortful repetition. Furthermore, lesion studies have mainly focused on the hippocampus itself, and have seldom reported the state of structures in the extended hippocampal system. Preserved components of this system may therefore mediate residual episodic abilities, contributing to the apparent semantic preservation. We report an in-depth study of Patient KA, a 27-year-old man who had severe hypoxia at birth, in which we carefully explored his residual episodic learning abilities. We used novel speeded recognition paradigms to assess whether KA could explicitly acquire and retrieve new context-free memories. Despite a pattern of very severe amnesia, with a 44-point discrepancy between his intelligence and memory quotients, KA exhibited normal-to-superior levels of knowledge, even under strict time constraints. He also exhibited normal-to superior recognition memory for new material, again under strict time constraints. Multimodal neuroimaging revealed an unusual pattern of selective atrophy within each component of the extended hippocampal system, contrasting with the preservation of anterior subhippocampal cortices. A cortical thickness analysis yielded a pattern of thinner but also thicker regional cortices, pointing toward specific temporal lobe reorganization following early injury. We thus report the first case of superior explicit learning and memory in a severe case of amnesia, raising important questions about how such knowledge can be acquired. PMID- 29995352 TI - Different miniaturized extraction methodologies followed by GC-MS/MS analysis for the determination of UV filters in beach sand. AB - Four different miniaturized methodologies were developed and applied to the analysis of 11 UV filters in sand samples. These approaches were based on ultrasound and vortex extractions, on-column lixiviation, and ultrasound extraction followed by solid-phase microextraction. Gas chromatography with tandem mass spectrometry was used for quantitative analysis. The analytical performance provided by the four methods was evaluated in terms of linearity, accuracy, precision, and limits of quantification. Lixiviation was discarded since it provided the lowest recoveries and the highest limits of quantification. In contrast, ultrasound and vortex extractions, and ultrasound extraction followed by solid-phase microextraction were suitable, with recoveries in general >85% and limits of quantification at the low ng/g level. Moreover, ultrasound extraction followed by solid-phase microextraction allowed using external calibration with aqueous standards and it provided higher sensitivity, with limits of quantification in general one order of magnitude lower than those achieved with the other techniques. The methodologies were applied for the analysis of four marine sand samples, and the results were statistically compared performing an analysis of variance. Eight out of the eleven target UV filters were detected. Octocrylene was found at very high concentrations (up to 1000 ng/g) followed by ethylhexyl salicylate, 4-methylbenzylidene camphor, homosalate, and 2-ethylhexyl methoxycinnamate. PMID- 29995353 TI - Rational Design of Redox-Responsive and P-gp-Inhibitory Lipid Nanoparticles with High Entrapment of Paclitaxel for Tumor Therapy. AB - An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy is recognized as important obstacles in tumor treatment. Herein, novel lipid nanoparticles (LNPs) with redox-responsive properties based on disulfide bond-contained, quercetin (Qu)-grafted glyceryl caprylate-caprate (Gcc) are introduced (Qu-SS-Gcc LNPs). Qu-SS-Gcc LNPs show good entrapment of paclitaxel (PTX) due to pi-pi stacking between the aromatic rings of Qu and PTX. In vitro experiments indicate that Qu-SS-Gcc LNPs can selectively respond to high levels of reducing substances by breakdown of disulfide bonds, thus achieving rapid and efficient drug release, and only dissociate rapidly in tumor cells rather than in normal cells. Meanwhile, the Qu released concomitantly with the breakdown of disulfide bonds combines with P-gp and inhibits the drug efflux triggered by P-gp. Using an orthotopic 4T1 mouse mammary tumor model in BALB/c mice, PTX/Qu-SS-Gcc LNPs exhibit superior antitumor efficacy compared to Taxol, in addition better biosafety and inhibition of chemotherapy-triggered P-gp overexpression are achieved. Taken together, this work designs and implements redox-responsive drug release and drug efflux inhibition in tumor cells via modified LNPs, which not only leads to efficient drug release but also solves the problem of drug efflux that exists in stimulus-responsive systems. PMID- 29995354 TI - Fluorescence Blinking Beyond Nanoconfinement: Spatially Synchronous Intermittency of Entire Perovskite Microcrystals. AB - Abrupt fluorescence intermittency or blinking is long recognized to be characteristic of single nano-emitters. Extended quantum-confined nanostructures also undergo spatially heterogeneous blinking; however, there is no such precedent in dimensionally unconfined (bulk) materials. Herein, we report multi level blinking of entire individual organo-lead bromide perovskite microcrystals (volume=0.1-3 MUm3 ) under ambient conditions. Extremely high spatiotemporal correlation (>0.9) in intracrystal emission intensity fluctuations signifies effective communication amongst photogenerated carriers at distal locations (up to ca. 4 MUm) within each crystal. Fused polycrystalline grains also exhibit this intriguing phenomenon, which is rationalized by correlated and efficient migration of carriers to a few transient nonradiative traps, the nature and population of which determine blinking propensity. Observation of spatiotemporally correlated emission intermittency in bulk semiconductor crystals opens the possibility of designing novel devices involving long-range (mesoscopic) electronic communication. PMID- 29995355 TI - Predicting Initial Specialist Mental Health Care Use in Adolescence Using Self-, Parent-, and Teacher-Reported Problem Behavior: A Prospective Community-Based Record-Linkage Study. AB - OBJECTIVE: The aim of this study was to determine the relative importance of self , parent-, and teacher-reported problem behavior for initial specialist mental health care use in adolescence and the extent to which the relative importance of each informant changes over time. METHODS: Data from the Dutch community-based cohort study TRacking Adolescents' Individual Lives Survey (TRAILS) were linked to administrative records of specialist mental health care organizations. Self-, parent-, and teacher-reported internalizing and externalizing problems were assessed at ages 11, 13, and 16 years, with self-reported problems also assessed at age 19 years. The study included 1,478 adolescents, of whom 19.8% had administrative records between January 2000 (age 9 years) and December 2011 (age 21 years). RESULTS: After effects of internalizing and externalizing problems were adjusted for each other and for sociodemographic correlates, internalizing problems, but not externalizing problems, predicted initial specialist mental health care use. Teacher reports mainly predicted initial specialist care between the ages of 11 and 13 years (hazard ratio [HR] = 1.57; 95% confidence interval [CI], 1.22-2.02; P < .001), parent reports mainly predicted initial specialist care between the ages of 13 and 16 years (HR = 1.47; 95% CI, = 1.13-1.91; P = .004), and self-reports mainly predicted initial specialist care between the ages of 16 and 19 years (HR = 1.61; 95% CI, = 1.25-2.08; P < .001) and between the ages 19 and 21 years (HR = 1.50; 95% CI, 1.10-2.05; P = .011). CONCLUSIONS: Teachers, parents, and adolescents are the driving force behind initial specialist care at consecutive phases in adolescence. Future research should assess whether improving the problem recognition of teachers in secondary education and educating young adults about mental health problems are effective ways of reducing the treatment gap. PMID- 29995356 TI - Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo Controlled Study. AB - OBJECTIVE: To determine if adjunctive treatment with a standardized extract of Withania somnifera (WSE), with known anti-inflammatory and immunomodulating properties, improves psychopathology and stress in patients with schizophrenia or schizoaffective disorder (DSM-IV-TR). METHODS: Patients experiencing an exacerbation of symptoms were assigned to WSE (1,000 mg/d) or placebo for 12 weeks, added to their antipsychotic medication, in a random-assignment, double blind, placebo-controlled study conducted from April 2013 to July 2016. Primary outcomes were change from baseline to end of treatment on the Positive and Negative Syndrome Scale (PANSS total, positive, negative, and general symptoms) between treatment groups. Secondary outcomes evaluated stress and inflammatory indices using the Perceived Stress Scale (PSS), S100 calcium-binding protein B (S100B), and C-reactive protein (CRP). RESULTS: Sixty-six randomized patients (n = 33 per group) provided efficacy data. Beginning at 4 weeks and continuing to the end of treatment, WSE produced significantly greater reductions in PANSS negative, general, and total symptoms (Cohen d: 0.83, 0.76, 0.83), but not positive symptoms, when compared to placebo. PSS scores improved significantly with WSE treatment compared to placebo (Cohen d: 0.58). CRP and S100B declined more in the WSE group but were not significantly different from placebo. Adverse events were mild to moderate and transient; somnolence, epigastric discomfort, and loose stools were more common with WSE. No significant between-treatment differences were noted in body weight, vital signs, or laboratory measures, which remained stable. CONCLUSIONS: This early study suggests that adjunctive treatment with a standardized extract of Withania somnifera provides significant benefits, with minimal side effects, for negative, general, and total symptoms and stress in patients with recent exacerbation of schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01793935. PMID- 29995357 TI - Modes of Resting Functional Brain Organization Differentiate Suicidal Thoughts and Actions: A Preliminary Study. AB - OBJECTIVE: A major target in suicide prevention is interrupting the progression from suicidal thoughts to action. Use of complex algorithms in large samples has identified individuals at very high risk for suicide. We tested the ability of data-driven pattern classification analysis of brain functional connectivity to differentiate recent suicide attempters from patients with suicidal ideation. METHODS: We performed a cross-sectional study using resting-state functional magnetic resonance imaging in depressed inpatients and outpatients of both sexes recruited from a university hospital between March 2014 and June 2016: recent suicide Attempters within 3 days of an attempt (n = 10), Suicidal Ideators (n = 9), Depressed Non-Suicidal Controls (n = 17), and Healthy Controls (n = 18). All depressed patients fulfilled DSM-IV-TR criteria for major depressive episode and either major depressive disorder, bipolar disorder, or depression not otherwise specified. A subset of suicide attempters (n = 7) were rescanned within 7 days. We used a support vector machine data-driven neural pattern classification analysis of resting-state functional connectivity to characterize recent suicide attempters and then tested the classifier's specificity. RESULTS: A binary classifier trained to discriminate patterns of resting-state functional connectivity robustly differentiated Suicide Attempters from Suicidal Ideators (mean accuracy = 0.788, signed rank test: P = .002; null hypothesis: area under the curve = 0.5), with distinct functional connectivity between the default mode and the limbic, salience, and central executive networks. The classifier did not discriminate stable Suicide Attempters from Suicidal Ideators (mean accuracy = 0.58, P = .33) or presence from absence of lifetime suicidal behavior (mean accuracy = 0.543, P = .348) and was not improved by modeling clinical variables (mean accuracy = 0.736, P = .002). CONCLUSIONS: Measures of intrinsic brain organization may have practical value as objective measures of suicide risk and its underlying mechanisms. Further incorporation of serum or cognitive markers and use of a prospective study design are needed to validate and refine the clinical relevance of this candidate biomarker of suicide risk. PMID- 29995358 TI - Longitudinal Epidemiologic Study of Poor Mental Health Status in Japanese Adolescents: Incidence of Predictive Lifestyle Factors. AB - OBJECTIVE: To clarify the incidence of predictive risk factors for poor mental health status in Japanese adolescents. METHODS: In 2010, baseline surveys of first-year junior and senior high school students were conducted at 10 randomly selected junior high schools and 14 senior high schools in Japan. After 2 years, follow-up surveys were conducted on the same students. For both surveys, a self administered questionnaire about mental health status and lifestyle, General Health Questionnaire-12 (GHQ-12), was provided to the students. RESULTS: In total, 1,304 junior and 4,383 senior high school students were enrolled at the start of the study, and 776 junior and 2,697 senior high school students responded to both surveys. The new incidence of poor mental health status (GHQ-12 >= 4 points), determined by changes between the baseline and follow-up surveys, was 17.1% (95% CI, 13.9% to 20.3%) of junior high school students and 22.6% (95% CI, 20.5% to 24.7%) of senior high school students. According to the multiple logistic regression analysis, in junior high school students, factors associated with the onset of poor mental health were not participating in sports activities (adjusted odds ratio, 3.13; P = .035) and spending >= 2 hours per day studying outside of school (2.18; P = .010). In senior high school students, factors associated with the onset of poor mental health were female sex (2.51; P < .001), difficulty initiating sleep (3.38; P < .001), poor sleep quality (1.83; P = .034), poor appetite (3.43; P = .011), spending less than 2 hours per day watching television (1.37; P = .038), being a victim of bullying (2.46; P = .011), and not having a sympathetic supporter (1.72; P = .006). CONCLUSIONS: The findings of this study are valuable for formulating approaches aimed at addressing adolescent mental health. PMID- 29995359 TI - Efficacy of Tianeptine 25-50 mg in Elderly Patients With Recurrent Major Depressive Disorder: An 8-Week Placebo- and Escitalopram-Controlled Study. AB - OBJECTIVE: The present placebo-controlled study evaluated the efficacy and safety of 8 weeks of treatment with tianeptine 25-50 mg/d in elderly patients suffering from major depressive disorder (MDD) according to DSM-IV-TR. Escitalopram 5-10 mg/d was used as an active comparator. METHODS: Elderly outpatients aged at least 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD were recruited by psychiatrists in 44 clinical centers in 10 countries from October 2013 to January 2016. Patients were randomly assigned to receive tianeptine (n = 105), placebo (n = 107), or escitalopram (n = 99) for 8 weeks. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. RESULTS: Tianeptine improved depressive symptoms, as evaluated by the HDRS17 total score in terms of absolute change from baseline (week 0) to week 8 (placebo-tianeptine difference [SE] of 3.84 [0.85] points, P < .001, using a last-observation-carried-forward approach) and response to treatment (tianeptine: 46.7%; placebo: 34.0%, estimate [SE] = 12.70% [6.70], P = .06). A sensitivity analysis using a mixed model for repeated measures confirmed the main results on HDRS total score. The placebo-tianeptine difference (SE) was 0.66 (0.15) for Clinical Global Impressions-Severity of Illness (95% CI, 0.37 to 0.96; P < .001) and 0.57 (0.14) for Clinical Global Impressions- Improvement (95% CI, 0.30 to 0.83; P < .001). Positive results were also obtained with the active control escitalopram (HDRS17 total score placebo-escitalopram difference of 4.09 +/- 0.86 points, P < .001), therefore validating the sensitivity of the studied population. Tianeptine was well tolerated, with only minimal differences in tolerability from placebo. CONCLUSIONS: The present study provides robust evidence that an 8-week treatment period with tianeptine 25-50 mg is efficacious and well tolerated in depressed patients aged 65 years or older. TRIAL REGISTRATION: EudraCT identifier: 2012-005612-26. PMID- 29995360 TI - Repetitive Transcranial Magnetic Stimulation: The Magic Bullet for Managing Treatment-Resistant Obsessive-Compulsive Disorder in a Congenitally Deaf and Mute Woman. PMID- 29995361 TI - Electroconvulsive Therapy for Catatonia With Deep Venous Thrombosis: A Case Series. AB - Objective: Catatonia is a motor dysregulation syndrome often accompanied by deep vein thrombosis (DVT) and pulmonary embolism (PE). Although electroconvulsive therapy (ECT) is effective for catatonia, it is unknown whether ECT contributes to the onset of a PE from a residual DVT. The objective of this case series is to examine and propose safety methods for ECT in catatonia patients with a DVT. Methods: Data were obtained retrospectively via chart review for 5 psychiatric inpatients diagnosed with catatonia based on DSM-IV-TR or DSM-5 criteria from April 2010 to March 2017 who underwent ECT after developing a DVT. Results: All 5 patients received anticoagulation therapy after the onset of DVT and underwent subsequent ECT. Three patients had distal DVT (thromboses located below the knee in the calf veins) before ECT, which did not result in an onset of PE in the course of ECT. One had a proximal DVT (thromboses in the popliteal vein and above), and the ECT session was completed without the occurrence of PE. In the fifth patient, a proximal DVT developed into a PE after an ECT session. Conclusions: These results suggest that it is important to determine the location of a DVT and to continue anticoagulation therapy until a proximal DVT disappears before ECT is performed. PMID- 29995369 TI - [MicroRNA Expression Profiles of Porcine Kidney 15 Cell Line Infected with Porcine Epidemic Diahorrea Virus]. AB - To explore the effect of porcine epidemic diarrhea virus(PEDV)on microRNA expression profiles of porcine kidney 15cell(PK-15),total RNA was isolated from PK-15 cells with or without PEDV infection. Then, we obtained the miRNAs by using solexa sequencing technology and analyzed these differentially expressed miRNAs. Heatmap cluster analysis and GO (ontology, GO) (Gene function, MF, Molecular) analysis was performed on the significant differences in expression of the miRNA, and 10 significant differences in expression of miRNA were selected by RT-qPCR. The result showed 214 kinds of microRNAs (miRNAs) expression levels were significantly different in PEDV-infected cells, compared with normal PK-15 cells. Among of them,175 kinds of miRNAs were significantly up-regulated while 39 kinds of miRNAs were significantly down-regulated. Furthermore, qPCR results of the expression trends of miRNA were similar with that of solexa sequencing. Heatmap cluster analysis showed that the vast majority of the viral groups were differentially expressed in miRNA compared with the control group, Go analysis showed that miRNAs are widely involved in combination, binding protein, protein kinase activity, transfer enzyme activity, phosphorus containing radicals transfer, phosphotransferase enzyme activity and other biological effects. The expression trends of RT-qPCR verified by miRNA were consistent with the high throughput sequencing results. The results showed that the swine epidemic diarrhea virus infection had a significant impact on the level of miRNA expression in PK-15 cells, thus providing a new idea for the further study of the miRNA preparation for the treatment of PEDV. PMID- 29995370 TI - [Expression and Purification of M Protein of RV in Baculovirus and Preparation of Its Polyclonal Antibody]. AB - The purpose of this study was to express the matrix protein of rabies virus in baculovirus expression system and prepare its polyclonal antibody. Using the total RNA of RABV strain BD06 as a template, RT-PCR technique was utilized to amplify the sequence of M gene, which were then inserted into shuttle vector pFastbac I to construct the recombinant vector pFastbac I-M. After identification using the double restriction endonuclease cleavage method, the recombinant vector pFastbac I-M were transformed into the competent E. coli DH10 Bac to construct the recombinant expression vector Bacmid-M, which were transfected into Sf9 cells mediated by lipofectamine 2000 to obtain the recombinant baculovirus AcMNPV-M. The mice anti-His monoclonal antibody, rabbit anti-RV positive serum and canine anti-RV positive serum were used in Western Blot assays to identify the expression and reactogenicity of the recombinant. The recombinant M protein were purified under denaturing conditions using the nickel iron affinity chromatography column, then used to immunize the New Zealand White rabbit to prepare its polyclonal antibody. Western Blot assay and FAVN assay were used to validate the polyclonal antibody. Our results showed that the M protein of RABV were successfully expressed in baculovirus expression system,of which molecular weight was of about 25kD;the recombinant M protein has a good reactogenicity and immunogenicity; the rabbit polyclonal antibody prepared by purification of M protein could react with the M protein of RABV strain BD06,SRV 9,CVS 24,ERA,PV2061 and aG. Undoubtedly, the successfully preparation of both recombinant M protein and its polyclonal antibody support a material foundation for further study on the properties of M protein of RABV. PMID- 29995371 TI - [Detection and Molecular Epidemiology of Norovirus, Rotavirus and Human Astrovirus in Domestic Sewage]. AB - To assess the significance of environmental surveillance in the control and prevention of viral gastroenteritis, we analyzed the molecular characteristics of norovirus (NoV), rotavirus(RV),and human astrovirus (HAstV), sequences detected in domestic sewage. Environmental sewage monitoring sites were set up in three cities in Shandong, China. RNA was extracted from seven sewage samples collected each year from 2009 to 2015.RT-PCR detection of norovirus, rotavirus, and human astrovirus was performed. Positive PCR segments were cloned into a T-vector, transformed and sequenced, and genotyping and phylogenic analysis performed. A total of 210 viral sequences belonging to 6NoV I,4NoV II,3RV G,3RV P and 4HAstV were obtained.GI.2,GII.4,G9,P[8],and HAstV-1were the most frequently detected types. Phylogenetic analysis revealed multiple transmission chains in the genotypes of GI.3,GI.6,GII.4,G9,P[8],HAstV-1,and HAstV-4.The results showed not only that sewage contains dramatic information regarding gastroenteritis viruses, but also that environmental surveillance is an important approach in monitoring the regional circulation of specific viruses. PMID- 29995372 TI - [Risk Assessment and Genotyping of Hepatitis A Virus in Fruit and Vegetable Products]. AB - This study explored risk assessment and genotyping of hepatitis A virus(HAV)in fruit and vegetable products. Two hundred and sixteen samples of fruit and vegetable products were examined by real-time RT-PCR. Six samples tested positive for hepatitis A virus, including frozen strawberries, frozen blueberries, frozen diced potatoes, frozen diced apple and frozen raspberries, accounting for 2.8% of the total samples tested. These six HAV isolates were genotyped by nested RT-PCR amplification, and a single band was detected in isolates from frozen diced apple(210-1999)and frozen blueberries(210-2002).These two isolates belong to the HAV IB subtype, based on analysis of evolution and homology. This study provides HAV risk information for fruit and vegetable enterprises and food safety management departments. Furthermore, it lays a foundation for HAV traceability, and provides technical support to ensure product safety for enterprises at critical control points including planting, harvest, processing and packaging. These results provide reliable data for epidemiological diagnosis. PMID- 29995373 TI - [The Establishment of The Chronic Bee Paralysis Virus by Semi Nested PCR Detection]. AB - According to the published chronic bee paralysis virus(CBPV)gene sequences, three specific primers were designed. Establish CBPV semi nested PCR detection method, the outer primer annealing temperatures(52,54,56 and 58C),the Inner primer annealing temperatures(48,50,52 and 54C),primer concentrations(0.1,0.2and 0.4 mmol/L)and volume of ExTaq enzyme (0.25,0.5and 1MUL) for semi nested PCR were optimized, and the optimized method was verified for specificity and sensitivity. At the same time, Twenty clinical samples were tested by the developed semi nested PCR. The results show that the semi nested PCR outer primer annealing temperature, inner primer annealing temperature, primer concentration and volume of ExTaq enzyme were 56C,50C,0.2mmol/L and 0.25MUL;no cross reactions with the cDNAs of healthy, CBPV, ABPV, CSBV, BQCV, DWV were observed by the developed semi nested PCR, with a minimun detection limit of 10-3 pg;4samples were positive from the 20 clinical samples. The established semi nested PCR detection was proved to be rapid, sensitive, specific, etc, which enable it a promising clinical diagnostic and epidemiological investigation method. PMID- 29995374 TI - [Novel Research Progress of the Recombinant Vaccine for MERS-CoV]. AB - Respiratory syndrome coronavirus in the Middle East (MERS-Co V) has caused wide attention since it was discovered, and the design of effective vaccines for MERS Co V becomes a hot area at present. Therefore, this review is aimed at novel research progress of the recombinant vaccine for MERS-Co V, including selection and improvement of animal model for vaccine test,construction and optimization of recombinant subunit vaccine, attempts at recombinant live vector vaccine based on varies of vectors, as well as the advantages of pseudovirus. In conclusion, we make a summary about the novel research progress of the recombinant vaccine for MERS-Co V and a promising prospect of its development in terms of both safety and effectiveness verification in the future will be demonstrated. PMID- 29995375 TI - Vapor-Infiltration Approach toward Selenium/Reduced Graphene Oxide Composites Enabling Stable and High-Capacity Sodium Storage. AB - Emerging sodium-selenium batteries suffer from volume expansion of the selenium cathode and shuttling effects of soluble intermediates. Confining selenium within the carbon matrix is the most adopted strategy to address these two issues, which is generally realized via a melt-infusion method. Herein, we developed a vapor infiltration method to fabricate selenium/carbon composites that are advantageous over the melt-infusion route in terms of several aspects: it relieves the requirement of intensive mechanical mixing and simplifies the ratio optimization between selenium and carbon; it avoids selenium aggregation and makes it possible to utilize all of the surface and pores of the carbon host. Utilizing this method, we fabricated a selenium/graphene composite from thermally reduced graphene oxide with a selenium loading equal to 71 wt %, thus approaching the record value. The obtained composite achieved the highest reported to date initial Coulombic efficiency of 88% among various selenium cathodes, with superior rate and cycle performance (410 and 367 mA h g-1 at 0.1 and 1 A g-1; capacity decay <10% after 800 cycles at 2 A g-1) enabled by the supporting graphene framework and the use of the ether electrolyte. In view of the distinct advantages of the vapor-infiltration method and the significant influence of the ether electrolyte on both initial Coulombic efficiency and cyclability of the batteries, we believe the introduced approach will be frequently adopted to incorporate selenium into various host materials, and the ether electrolyte will be widely considered for selenium-based electrodes. PMID- 29995376 TI - Analog and Digital Bipolar Resistive Switching in Solution-Combustion-Processed NiO Memristor. AB - In this study, a NiO-based resistive memristor was manufactured using a solution combustion method. In this device, both analog and digital bipolar resistive switching were observed. They are dependent on the stressed bias voltage. Prior to the electroforming, the analog bipolar resistive switching was realized through the change of the Schottky barrier at p-type NiO/Ag junction by the local migration of the oxygen ion in the interface. On the basis of the analog resistive switching, several synaptic functions were demonstrated, such as nonlinear transmission characteristics, spike-rate-dependent plasticity, long term/short-term memory, and "learning-experience" behavior. In addition, once the electroforming operation was carried out using a high applied voltage, the resistive switching was changed from analog to digital. The formation and rupture of the oxygen vacancy filaments is dominant. This novel memristor with the multifunction of analog and digital resistive switching is expected to decrease the manufacturing complexity of the electrocircuits containing analog/digital memristors. PMID- 29995377 TI - Plasmon-Triggered Hot-Spot Excitation on SERS Substrates for Bacterial Inactivation and in Situ Monitoring. AB - Bacterial sensing and inactivating is one of the key steps to prevent bacterial propagation and transfer. Here, using Ag nanoparticle-grafted tungsten oxide films (WO3/Ag), we developed a multifunctional platform that may act as a surface enhanced Raman spectroscopy substrate for sensitively capturing and counting bacteria. Moreover, we demonstrated that the use of photon-triggered surface plasmon resonance of Ag on the WO3 surface resulted in a significantly improved photocatalytic activity under visible light (638 nm). The photogenerated reactive oxygen species have been shown to be efficient in the inactivation of bacteria, and the bacteria inactivation process could be monitored in situ by Raman spectroscopy. On the basis of the obtained Raman results and fluorescence measurements of green fluorescence protein expressing bacteria, the active species triggered by hot spots was demonstrated to account for broken cell walls. The bacterial cell contents subsequently leaked out, leading to cell degradation. Potentially, our work may provide a promising strategy for capturing and monitoring the bactericidal process at low concentration and, specifically, may help in the investigation of related inactivation approaches and mechanisms. PMID- 29995378 TI - Ultrafast Heat Flow in Heterostructures of Au Nanoclusters on Thin Films: Atomic Disorder Induced by Hot Electrons. AB - We study the ultrafast structural dynamics, in response to electronic excitations, in heterostructures composed of size-selected Au nanoclusters on thin-film substrates with the use of femtosecond electron diffraction. Various forms of atomic motion, such as thermal vibrations, thermal expansion, and lattice disordering, manifest as distinct and quantifiable reciprocal-space observables. In photoexcited supported nanoclusters, thermal equilibration proceeds through intrinsic heat flow between their electrons and their lattice and extrinsic heat flow between the nanoclusters and their substrate. For an in depth understanding of this process, we have extended the two-temperature model to the case of 0D/2D heterostructures and used it to describe energy flow among the various subsystems, to quantify interfacial coupling constants and to elucidate the role of the optical and thermal substrate properties. When lattice heating of Au nanoclusters is dominated by intrinsic heat flow, a reversible disordering of atomic positions occurs, which is absent when heat is injected as hot substrate phonons. The present analysis indicates that hot electrons can distort the lattice of nanoclusters, even if the lattice temperature is below the equilibrium threshold for surface premelting. Based on simple considerations, the effect is interpreted as activation of surface diffusion due to modifications of the potential energy surface at high electronic temperatures. We discuss the implications of such a process in structural changes during surface chemical reactions. PMID- 29995379 TI - Solvent- and Wavelength-Dependent Photoluminescence Relaxation Dynamics of Carbon Nanotube sp3 Defect States. AB - Photoluminescent sp3 defect states introduced to single wall carbon nanotubes (SWCNTs) through low-level covalent functionalization create new photophysical behaviors and functionality as a result of defect sites acting as exciton traps. Evaluation of relaxation dynamics in varying dielectric environments can aid in advancing a more complete description of defect-state relaxation pathways and electronic structure. Here, we exploit helical wrapping polymers as a route to suspending (6,5) SWCNTs covalently functionalized with 4-methoxybenzene in solvent systems including H2O, D2O, methanol, dimethylformamide, tetrahydrofuran, and toluene, spanning a range of dielectric constants from 80 to 3. Defect-state photoluminescence decays were measured as a function of emission wavelength and solvent environment. Emission decays are biexponential, with short lifetime components on the order of 65 ps and long components ranging from around 100 to 350 ps. Both short and long decay components increase as emission wavelength increases, while only the long lifetime component shows a solvent dependence. We demonstrate that the wavelength dependence is a consequence of thermal detrapping of defect-state excitons to produce mobile E11 excitons, providing an important mechanism for loss of defect-state population. Deeper trap states (i.e., those emitting at longer wavelengths) result in a decreased rate for thermal loss. The solvent-independent behavior of the short lifetime component is consistent with its assignment as the characteristic time for redistribution of exciton population between bright and dark defect states. The solvent dependence of the long lifetime component is shown to be consistent with relaxation via an electronic to vibrational energy transfer mechanism, in which energy is resonantly lost to solvent vibrations in a complementary mechanism to multiphonon decay processes. PMID- 29995380 TI - Invariance of Water Permeance through Size-Differentiated Graphene Oxide Laminates. AB - Laminates made of graphene oxide nanosheets have been shown to exhibit high water permeance and salt rejection and, therefore, have generated immense interest from the scientific community due to their potential in separation applications. However, there is no clear consensus on the water-transport pathways through such laminates. In this study, we synthesized chemically identical graphene oxide nanosheets with 2 orders of magnitude difference in lateral sizes and measured water permeance through laminates of different thicknesses fabricated by pressure assisted deposition of these nanosheets. Our results reveal that water permeance through these laminates is nearly the same despite such massive difference in lateral sheet size. Furthermore, we simulated fluid flow through laminates using an interconnected nanochannel network model for comparison with experiments. The simulations in combination with the experimental data show that it is unlikely that the dominant fluid transport pathway is a circuitous, lateral pathway around individual sheets, as has been proposed in some studies. Rather, nonideal factors including trans-sheet flow through pinhole defects in sheet interiors and/or flow through regions arising from imperfect stacking in the laminates can significantly affect the fluid transport pathways. The presence of such nonidealities is also supported by thickness- and time-dependent measurements of permeance and by infrared spectroscopy, which indicates that water predominantly adopts a bulk-like structure in the laminates. These analyses are significant steps toward understanding water transport through graphene oxide laminates and provide further insight toward the structure of water inside these materials, which could have immense potential in next-generation separation applications. PMID- 29995381 TI - Organometallic Precursor-Derived SnO2/Sn-Reduced Graphene Oxide Sandwiched Nanocomposite Anode with Superior Lithium Storage Capacity. AB - Benefiting from the reversible conversion reaction upon delithiation, nanosized SnO2, with its theoretical capacity of 1494 mA h g-1, has gained special attention as a promising anode material. Here, we report a self-assembled SnO2/Sn reduced graphene oxide (rGO) sandwich nanocomposite developed by organometallic precursor coating and in situ transformation. Ultrafine SnO2 nanoparticles with an average diameter of 5 nm are sandwiched within the rGO/carbonaceous network, which not only greatly alleviates the volume changes upon lithiation and aggregation of SnO2 nanoparticles but also facilitates the charge transfer and reaction kinetics of SnO2 upon lithiation/delithiation. As a result, the SnO2/Sn rGO nanocomposite exhibited a superior lithium storage capacity with a reversible capacity of 1307 mA h g-1 at a current density of 80 mA g-1 in the potential window of 0.01-2.5 V versus Li+/Li and showed a reversible capacity of 767 mA h g 1 over 200 cycles at a current density of 400 mA g-1. When cycling at a higher current density of 1600 mA g-1, the SnO2/Sn-rGO nanocomposite showed a highly stable capacity of 449 mA g-1 without obvious decay after 400 cycles. PMID- 29995382 TI - Pressure Insensitive Strain Sensor with Facile Solution-Based Process for Tactile Sensing Applications. AB - Tactile sensors that can mechanically decouple, and therefore differentiate, various tactile inputs are highly important to properly mimic the sensing capabilities of human skin. Herein, we present an all-solution processable pressure insensitive strain sensor that utilizes the difference in structural change upon the application of pressure and tensile strain. Under the application of strain, microcracks occur within the multiwalled carbon nanotube (MWCNT) network, inducing a large change in resistance with gauge factor of ~56 at 70% strain. On the other hand, under the application of pressure to as high as 140 kPa, negligible change in resistance is observed, which can be attributed to the pressure working primarily to close the pores, and hence minimally changing the MWCNT network conformation. Our sensor can easily be coated onto irregularly shaped three-dimensional objects (e.g., robotic hand) via spray coating, or be attached to human joints, to detect bending motion. Furthermore, our sensor can differentiate between shear stress and normal pressure, and the local strain can be spatially mapped without the use of patterned electrode array using electrical impedance tomography. These demonstrations make our sensor highly useful and important for the future development of high performance tactile sensors. PMID- 29995383 TI - Comb-Like Fluorophilic-Lipophilic-Hydrophilic Polymers for Nanocapsules as Ultrasound Contrast Agents. AB - Imaging the enhanced permeation and retention effect by ultrasound is hindered by the large size of commercial ultrasound contrast agents (UCAs). To obtain nanosized UCAs, triblock copolymers of poly(ethylene glycol)-polylactide-poly(1 H,1 H,2 H,2 H-heptadecafluorodecyl methacrylate) (PEG-PLA-PFMA) with distinct numbers of perfluorinated pendant chains (5, 10, or 20) are synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. Nanocapsules (NCs) containing perfluorooctyl bromide (PFOB) intended as UCAs are obtained with a 2-fold increase in PFOB encapsulation efficiency in fluorinated NCs as compared with plain PEG-PLA NCs thanks to fluorous interactions. NC morphology is strongly influenced by the number of perfluorinated chains and the amount of polymer used for formulation, leading to peculiar capsules with several PFOB cores at high PEG-PLA-PFMA20 amount and single-cored NCs with a thinner shell at low fluorinated polymer amount, as confirmed by small-angle neutron scattering. Finally, fluorinated NCs yield higher in vitro ultrasound signal compared with PEG-PLA NCs, and no in vitro cytotoxicity is induced by fluorinated polymers and their degradation products. Our results highlight the benefit of adding comb-like fluorinated blocks in PEG PLA polymers to modify the nanostructure and enhance the echogenicity of nanocapsules intended as UCAs. PMID- 29995384 TI - Orbital Ordering of the Mobile and Localized Electrons at Oxygen-Deficient LaAlO3/SrTiO3 Interfaces. AB - Interfacing different transition-metal oxides opens a route to functionalizing their rich interplay of electron, spin, orbital, and lattice degrees of freedom for electronic and spintronic devices. Electronic and magnetic properties of SrTiO3-based interfaces hosting a mobile two-dimensional electron system (2DES) are strongly influenced by oxygen vacancies, which form an electronic dichotomy, where strongly correlated localized electrons in the in-gap states (IGSs) coexist with noncorrelated delocalized 2DES. Here, we use resonant soft-X-ray photoelectron spectroscopy to prove the eg character of the IGSs, as opposed to the t2g character of the 2DES in the paradigmatic LaAlO3/SrTiO3 interface. We furthermore separate the d xy and d xz/d xz orbital contributions based on deeper consideration of the resonant photoexcitation process in terms of orbital and momentum selectivity. Supported by a self-consistent combination of density functional theory and dynamical mean field theory calculations, this experiment identifies local orbital reconstruction that goes beyond the conventional eg- vs t2g band ordering. A hallmark of oxygen-deficient LaAlO3/SrTiO3 is a significant hybridization of the eg and t2g orbitals. Our findings provide routes for tuning the electronic and magnetic properties of oxide interfaces through "defect engineering" with oxygen vacancies. PMID- 29995385 TI - Microprobe for the Thermal Analysis of Crude Oil Coupled to Photoionization Fourier Transform Mass Spectrometry. AB - We present the simple microprobe for the investigation of crude oil by a thermal desorption photoionization coupled to Orbitrap mass spectrometry. The droplet of crude oil was placed on the heating element with controllable temperature. The temperature was linearly increased, and crude oil vapors were ionized by a vacuum ultraviolet (VUV) lamp and detected by Orbitrap mass spectrometer. Use of modified Orbitrap allowed introduction of the heating element and VUV lamp directly into the ion funnel and performing experiment not only at atmosphere pressure but also at 20, 10, and 5 torr. We observed that at high pressure protonated CHN compounds dominate in the spectrum, while at the low pressure CH compounds dominate. Similar to previously reported thermogravimetry coupled to photoionization or chemical ionization mass spectrometry systems we were able to separate compounds with different desorption energy and reliably detect low abundant compounds. Also, we were able to determine the desorption temperature for each compound of the crude oil. We found that temperature of desorption increases linearly with m/ z for compounds that belong to the same homology series (same Kendrick mass defect). This may serve as indirect evidence that such compounds differ only by the length of aliphatic chains attached to some basic structure. PMID- 29995386 TI - Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro: A Case Study with Cyproconazole. AB - Adverse outcome pathways (AOPs) describe causal relationships between molecular perturbation and adverse cellular effects and are being increasingly adopted for linking in vitro mechanistic toxicology to in vivo data from regulatory toxicity studies. In this work, a case study was performed by developing a bioassay toolbox to assess key events in the recently proposed AOP for chemically induced liver steatosis. The toolbox is comprised of in vitro assays to measure nuclear receptor activation, gene and protein expression, lipid accumulation, mitochondrial respiration, and formation of fatty liver cells. Assay evaluation was performed in human HepaRG hepatocarcinoma cells exposed to the model compound cyproconazole, a fungicide inducing steatosis in rodents. Cyproconazole dose dependently activated RARalpha and PXR, two molecular initiating events in the steatosis AOP. Moreover, cyproconazole provoked a disruption of mitochondrial functions and induced triglyceride accumulation and the formation of fatty liver cells as described in the AOP. Gene and protein expression analysis, however, showed expression changes different from those proposed in the AOP, thus suggesting that the current version of the AOP might not fully reflect the complex mechanisms linking nuclear receptor activation and liver steatosis. Our study shows that cyproconazole induces steatosis in human liver cells in vitro and demonstrates the utility of systems-based approaches in the mechanistic assessment of molecular and cellular key events in an AOP. AOP-driven in vitro testing as demonstrated can further improve existing AOPs, provide insight regarding molecular mechanisms of toxicity, and inform predictive risk assessment. PMID- 29995387 TI - Chemical Denaturation and Protein Precipitation Approach for Discovery and Quantitation of Protein-Drug Interactions. AB - Described here is a mass spectrometry-based proteomics approach for the large scale analysis of protein-drug interactions. The approach involves the evaluation of ligand-induced protein folding free energy changes (DeltaDelta Gf) using chemical denaturation and protein precipitation (CPP) to identify the protein targets of drugs and to quantify protein-drug binding affinities. This is accomplished in a chemical denaturant-induced unfolding experiment where the folded and unfolded protein fractions in each denaturant containing buffer are quantified by the amount of soluble or precipitated protein (respectively) that forms upon abrupt dilution of the chemical denaturant and subsequent centrifugation of the sample. In the proof-of-principle studies performed here, the CPP technique was able to identify the well-known protein targets of cyclosporin A and geldanamycin in a yeast. The technique was also used to identify protein targets of sinefungin, a broad-based methyltransferase inhibitor, in a human MCF-7 cell lysate. The CPP technique also yielded dissociation constant ( Kd) measurements for these well-studied drugs that were in general agreement with previously reported Kd or IC50 values. In comparison to a similar energetics-based technique, termed stability of proteins from rates of oxidation (SPROX), the CPP technique yielded significantly better (~50% higher) proteomic coverage and a largely reduced false discovery rate. PMID- 29995388 TI - Tough Magnetic Chitosan Hydrogel Nanocomposites for Remotely Stimulated Drug Release. AB - As one of important biomaterials for localized drug delivery system, chitosan hydrogel still suffer several challenges, including poor mechanical properties, passive drug release behavior and lack of remote stimuli response. To address these challenges, a facile in situ hybridization method was reported for fabricate tough magnetic chitosan hydrogel (MCH), which remotely switched drug release from passive release to pulsatile release under a low frequency alternating magnetic field (LAMF). The in situ hybridization method avoided the aggregation of magnetic nanoparticles (MNPs) in hydrogel, which simultaneously brings 416% and 265% increase in strength and elastic modulus, respectively. The mechanical property enhancement was contributed by the physical crosslinking of in situ synthesized MNPs. When a LAMF with 15 min ON-15 min OFF cycles was applied to MCH, the fraction release showed zigzag shape and pulsatile release behavior with quick response. The cumulative release and fraction release of drug from MCH were improved by 67.2% and 31.9%, respectively. MTT results and cell morphology indicated that the MCH have excellent biocompatibility and no acute adverse effect on MG-63 cells. The developed tough MCH system holds great potential for applications in smart drug release system with noninvasive characteristics and magnetic field stimulated drug release behavior. PMID- 29995389 TI - Water Flow and Biofilm Cover Influence Environmental DNA Detection in Recirculating Streams. AB - The increasing use of environmental DNA (eDNA) for determination of species presence in aquatic ecosystems is an invaluable technique for both ecology as a field and for the management of aquatic ecosystems. We examined the degradation dynamics of fish eDNA using an experimental array of recirculating streams, also using a "nested" primer assay to estimate degradation among eDNA fragment sizes. We introduced eDNA into streams with a range of water velocities (0.1-0.8 m s-1) and substrate biofilm coverage (0-100%) and monitored eDNA concentrations over time (~10 d) to assess how biophysical conditions influence eDNA persistence. We found that the presence of biofilm significantly increased initial decay rates relative to previous studies conducted in nonflowing microcosms, suggesting important differences in detection and persistence in lentic vs lotic systems. Lastly, by using a nested primer assay that targeted different size eDNA fragments, we found that fragment size altered both the estimated rate constant coefficients, as well as eDNA detectability over time. Larger fragments (>600 bp) were quickly degraded, while shorter fragments (<100 bp) remained detectable for the entirety of the experiment. When using eDNA as a stream monitoring tool, understanding environmental factors controlling eDNA degradation will be critical for optimizing eDNA sampling strategies. PMID- 29995390 TI - Interplay between Dopant Species and a Spin-Crossover Host Lattice during Light Induced Excited-Spin-State Trapping Probed by Electron Paramagnetic Resonance Spectroscopy. AB - Q-band electron paramagnetic resonance (EPR) data conclusively demonstrate that the iron and cobalt centers in the solid solution [Fe(bpp)2]0.97[Co(terpy)2]0.03[BF4]2 (bpp = 2,6-dipyrazol-1-ylpyridine) undergo allosteric spin-state switching during light-induced excited-spin-state trapping (LIESST) at 20 K and thermal relaxation around 80 K. EPR of [Cu(terpy)2]2+ and [Cu(bpp)2]2+, doped into the same host lattice, also indicates expansion of the copper coordination sphere during LIESST excitation. PMID- 29995391 TI - Thyroid Hormone-Disrupting Potentials of Major Benzophenones in Two Cell Lines (GH3 and FRTL-5) and Embryo-Larval Zebrafish. AB - Benzophenones (BPs) have been widely used in personal care products (PCPs) such as UV protectants. Sex endocrine-disrupting effects have been documented for some BPs, but, significant knowledge gaps are present for their thyroid-disrupting effects. To investigate the thyroid-disrupting potential of BPs, a rat pituitary (GH3) and thyroid follicle (FRTL-5) cell line were employed on six BPs, i.e., benzophenone (BP), benzophenone-1 (BP-1), benzophenone-2 (BP-2), benzophenone-3 (BP-3), benzophenone-4 (BP-4), and benzophenone-8 (BP-8). Subsequently, zebrafish ( Danio rerio) embryo exposure was conducted for three potent BPs that were identified based on the transcriptional changes observed in the cells. In GH3 cells, all BPs except BP-4 down-regulated the Tshbeta, Trhr, and Trbeta genes. In addition, some BPs significantly up-regulated the Nis and Tg genes while down regulating the Tpo gene in FRTL-5 cells. In zebrafish embryo assay conducted for BP-1, BP-3, and BP-8, significant decreases in whole-body T4 and T3 level were observed at 6 day postfertilization (dpf). The up-regulation of the dio1 and ugt1ab genes in the fish suggests that decreased thyroid hormones are caused by changing metabolism of the hormones. Our results show that these frequently used BPs can alter thyroid hormone balances by influencing the central regulation and metabolism of the hormones. PMID- 29995392 TI - Full Color Luminescence Tuning in Bi3+/Eu3+-Doped LiCa3MgV3O12 Garnet Phosphors Based on Local Lattice Distortion and Multiple Energy Transfers. AB - In the pursuit of high-quality W-LED lighting, the precise control of emission color of phosphor materials is indispensable. Herein we report a series of single composition Bi3+-doped LiCa3MgV3O12 garnet-structure phosphors, whose emission colors under n-UV excitation could be tuned from bluish green (480 nm) to yellow (562 nm) on the basis of local lattice distortion and VO43- -> Bi3+ energy transfer. Furthermore, full-color luminescence tuning from bluish green to orangish red across the warm white light region was successfully achieved by designing VO43- -> Bi3+ -> Eu3+ energy transfers. More interestingly, the thermal stabilities of as-prepared samples were gradually enhanced through designing VO43 /Bi3+ -> Eu3+ energy transfers. This work provides a new perspective for color tuning originating from simultaneous local lattice distortion and multiple energy transfers. PMID- 29995393 TI - Changes in the Soil to Brown Rice Concentration Ratio of Radiocaesium before and after the Fukushima Daiichi Nuclear Power Plant Accident in 2011. AB - Radiocaesium (RCs) mobility in soil is initially relatively high when the nuclide first comes into contact with soil, after which the mobile fraction decreases with time due to RCs fixation to soil particles (aging effect). Consequently, the RCs activity concentration in plants grown in soil was expected to decrease with time after the Fukushima Daiichi nuclear power plant accident in 2011. In this study, we collated data on concentration ratios (CR) of RCs between brown rice grain and paddy soil and compared CR values reported for periods before and after the accident. For this purpose, soil and rice data were collected after the accident specifically from paddy fields that did not have additional potassium fertilizer added (for remediation purposes). The geometric mean rice/soil CR of RCs for all types of soil was 1.2 * 10-2 in 2011 ( n = 62) and by 2013 the value had declined to 3.5 * 10-3 ( n = 32), which was similar to that for 1995-2007 of 3.4 * 10-3 ( n = 120). The comparison suggests that the mean soil-to-rice grain concentration ratio had returned to that prevailing before the accident after less than three years. It was also confirmed that CR values for rice sampled from paddy fields were lower than those obtained from pot experiments. PMID- 29995394 TI - Synthesis, Structure, and Electrical Properties of the Single Crystal Ba8Cu16As30. AB - Single crystals of clathrate-I Ba8Cu16As30 have been synthesized and their structure and electronic properties determined using synchrotron-based X-ray diffraction and first-principles calculations. The structure is confirmed to be Pm3 n (No. 223), with lattice parameter a = 10.4563(3) A, and defined by a tetrahedrally bonded network of As and Cu that forms two distinct coordination polyhedra, with Ba residing inside these polyhedra. All crystallographic positions are fully occupied with no vacancies or superstructure with the Cu atoms, while occupying all framework sites in the network, exhibiting a preference for the 6c site. Agreement between the experimental and theoretically predicted structures was achieved after accounting for spin-orbit coupling. Our calculated Fermi surface, electron localization, and charge transfer, as well as a comparison with the results for elemental As46, provide insight into the fundamental properties of this clathrate-I material. PMID- 29995395 TI - Real-Time Imaging Revealed That Exoelectrogens from Wastewater Are Selected at the Center of a Gradient Electric Field. AB - Exoelectrogens acclimated from the environment are the key to energy recovery from waste in bioelectrochemical systems. However, it is still unknown how these bacteria are selectively enriched on the electrode. Here we confirmed for the first time that the electric field (EF) intensity selects exoelectrogens from wastewater using an integrated electrovisual system with a gradient EF. Under the operating conditions ( I = 3 * 10-3A), the EF intensity on the working electrode ranged from 6.00 V/cm at the center to 1.08 V/cm at the edge. A thick biofilm (88.9 MUm) with spherical pink aggregates was observed at the center, while the color became gray at the edge (33.8 MUm). The coverage of the biofilm also increased linearly with EF intensity from 0.42 at the edge (12 mm to the center) to 0.78 at the center. The biofilm at the center contained 76% Geobacter, which was 25% higher than that at the edge (60%). Geobacter anodireducens was the main species induced by the EF (50% at the center vs 24% at the edge). These results improve our fundamental knowledge of exoelectrogen acclimation and mixed electroactive biofilm formation, which has broader implications for energy recovery from waste and general understanding of microbial ecology. PMID- 29995396 TI - Tuning the Electron-Phonon and Superconducting Coupling in InPb Bimetallic Alloys. AB - Electron-phonon coupling is a fundamental inelastic interaction in solid-state physics and superconductors. Here we probe electron-phonon and superconducting coupling strength by tuning the indium composition in In qPb1- q superconducting bimetallic alloys. A crossover from weak to strong coupling strength was observed through the analysis of crystal structure and superconducting phase diagrams. The hole-doped Pb solid solution showed suppressed TC and subverted coupling strength due to decreased density of state N(0) and hardened phonons, while the electron doped In solid solution revealed enhanced TC and stronger coupling strength because of increased N(0) and softened phonons. Our results are in agreement with the Ginzburg-Landau theory calculations regarding the dirty limits and are well described by the Allen and Dynes formula within the framework of the McMillan formalism. PMID- 29995397 TI - Acetylcholinesterase Is a Potential Biomarker for a Broad Spectrum of Organic Environmental Pollutants. AB - Acetylcholinesterase (AChE, EC 3.1.1.7) is a classical biomarker for monitoring contamination and intoxication of organophosphate (OP) and carbamate pesticides. In addition to these classical environmental AChE inhibitors, other organic toxic substances have been found to alter AChE activity in various species. These emerging organic AChE disruptors include certain persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs), and wildly used chemicals, most of which have received considerable public health concern in recent years. It is necessary to re-evaluate the environmental significances of AChE in terms of these toxic substances. Therefore, the present review is aiming to summarize correlations of AChE activity of certain organisms with the level of the contaminants in particular habitats, disruptions of AChE activity upon treatment with the emerging disruptors in vivo and in vitro, and action mechanisms underlying the effects on AChE. Over 40 chemicals belonging to six main categories were reviewed, including 12 POPs listed in the Stockholm Convention. AChE activity in certain organisms has been found to be well correlated with the contamination level of certain persistent pesticides and PAHs in particular habitats. Moreover, it has been documented that most of the listed toxic chemicals could inhibit AChE activity in diverse species ranging from invertebrates to mammals. Besides directly inactivating AChE, the mechanisms in terms of interference with the biosynthesis have been recognized for some emerging AChE disruptors, particularly for dioxins. The collected evidence suggests that AChE could serve as a potential biomarker for a diverse spectrum of organic environmental pollutants. PMID- 29995398 TI - Simultaneous Opto- and Spectro-Electrochemistry: Reactions of Individual Nanoparticles Uncovered by Dark-Field Microscopy. AB - Despite the frequent use of silver nanoparticles in consumer products and medical treatments, their reactivity and degradation in aqueous suspensions are still under debate. Here we elucidate this reactivity by an in situ opto- and spectro electrochemical approach. Using dark-field microscopy coupled to a spectrophotometer and to an electrochemical cell, redox reactions of individual silver nanoparticles are studied in the presence of chloride. The intensity and spectral position of the plasmon resonance of an individual particle are tracked simultaneously in real time during cyclic voltammetry. They both change almost instantaneously with the detected current in a chemically reversible way. Thus, it is evidenced that the intensity decrease of the optical signal at the silver peak position is caused by the reversible formation of silver chloride and not by dissolution of silver. Moreover, at large positive potentials, further transformation to silver oxide or chlorite is revealed spectroscopically, although the electrochemical current is hidden by water and chloride oxidation. Thus, the combination of electrochemistry with dark-field microscopy and hyperspectral imaging is introduced as a new tool for real-time analysis of (electro-)chemical reactions of nanoparticles on a single-entity level. PMID- 29995399 TI - Synthesis and Characterization of the Aurivillius Phase CoBi2O2F4. AB - The new CoBi2O2F4 compound was synthesized by a hydrothermal method at 230 degrees C. Single-crystal X-ray diffraction data were used to determine the crystal structure. The compound is layered and belongs to the Aurivillius family of compounds. The present compound is the first oxo-fluoride Aurivillius phase containing Co2+. Inclusion of a d-block cation with such a low oxidation state as 2+ was achieved by partially replacing O2- with F- ions. The crystal structure is best described in the tetragonal noncentrosymmetric space group I4 with unit-cell parameters a = 3.843(2) A and c = 16.341(8) A. The crystal structure consists of two main building units: [BiO4F4] distorted cubes and [CoF6] octahedra. Interestingly, since the octahedra [CoF6] tilt between four equivalent positions, the F atoms occupy a 4-fold split position at room temperature. For the investigation of the structural disorder, Raman scattering data were collected in the range from 10 K to room temperature. As the temperature decreases, sharper phonon peaks appear and several modes clearly appear, which indicates a reduction of the disorder. Magnetic susceptibility and heat capacity measurements evidence long-range antiferromagnetic ordering below the Neel temperature of ~50 K. The magnetic susceptibility is in agreement with the Curie-Weiss law above 75 K with a Curie-Weiss temperature of thetaCW = -142(2) K. PMID- 29995400 TI - Design of a Novel Series of Donor-Acceptor Frameworks via Superalkali Superhalogen Assemblage to Improve the Nonlinear Optical Responses. AB - Presently, many researches are directed toward the design of novel superatoms with high nonlinear optical responses. Inspired by a fascinating finding of superatoms which were designed by bonding superhalogen (Al13 nanocluster) with superalkalis (M3O, M = Na and K), we suggest an effective strategy to form a series of typical donor-acceptor frameworks with high nonlinear optical responses via bonding the superalkalis M3O (Li3O, Na3O, K3O, Li2NaO, Li2KO, Na2LiO, Na2KO, K2LiO, K2NaO, and LiNaKO) with low ionization potential to the superhalogen Al13 with large electron affinity. The ionization potential, electronic spatial extent, electric field gradient tensors of 17O nuclei, and natural bond orbital charge values of the superalkalis M3O were also calculated. We found that the M ligands have the remarkable effect on the ionization potential as well as 17O nuclear quadrupole resonance parameters of the superalkalis M3O. Our results also represented that the bonding superalkalis can efficiently narrow wide HOMO-LUMO gap and considerably enhance first hyperpolarizability of the pristine Al13, due to electron transfer in this type of superatom. Also, the effect of oriented external electric fields on the nonlinear optical responses of the superatoms M3O Al13 has been systematically explored. We found that the first hyperpolarizability of the superatom compounds can be gradually increased by increasing the imposed oriented external electric field from zero to the critical external electric field along the charge transfer direction (M3O -> Al13). In this respect, this work reveals an effective approach to gradually enhance the nonlinear optical responses of the superatoms through applying oriented external electric fields. PMID- 29995401 TI - Chiral Aldehyde Catalysis for the Catalytic Asymmetric Activation of Glycine Esters. AB - Chiral aldehyde catalysis is uniquely suitable for the direct asymmetric alpha functionalization of N-unprotected amino acids, because aldehydes can reversibly form imines. However, there have been few successful reports of these transformations. In fact, only chiral aldehyde catalyzed aldol reactions of amino acids and alkylation of 2-amino malonates have been reported with good chiral induction. Here, we report a novel type of chiral aldehyde catalyst based on face control of the enolate intermediates. The resulting chiral aldehyde is the first efficient nonpyridoxal-dependent catalyst that can promote the direct asymmetric alpha-functionalization of N-unprotected glycine esters. Possible transition states and the proton transfer process were investigated by density functional theory calculations. PMID- 29995402 TI - Enzymatic Assemblies Disrupt the Membrane and Target Endoplasmic Reticulum for Selective Cancer Cell Death. AB - The endoplasmic reticulum (ER) is responsible for the synthesis and folding of a large number of proteins, as well as intracellular calcium regulation, lipid synthesis, and lipid transfer to other organelles, and is emerging as a target for cancer therapy. However, strategies for selectively targeting the ER of cancer cells are limited. Here we show that enzymatically generated crescent shaped supramolecular assemblies of short peptides disrupt cell membranes and target ER for selective cancer cell death. As revealed by sedimentation assay, the assemblies interact with synthetic lipid membranes. Live cell imaging confirms that the assemblies impair membrane integrity, which is further supported by lactate dehydrogenase (LDH) assays. According to transmission electron microscopy (TEM), static light scattering (SLS), and critical micelle concentration (CMC), attaching an l-amino acid at the C-terminal of a d tripeptide results in the crescent-shaped supramolecular assemblies. Structure activity relationship suggests that the crescent-shaped morphology is critical for interacting with membranes and for controlling cell fate. Moreover, fluorescent imaging indicates that the assemblies accumulate on the ER. Time dependent Western blot and ELISA indicate that the accumulation causes ER stress and subsequently activates the caspase signaling cascade for cell death. As an approach for in situ generating membrane binding scaffolds (i.e., the crescent shaped supramolecular assemblies), this work promises a new way to disrupt the membrane and to target the ER for developing anticancer therapeutics. PMID- 29995403 TI - Spatial Isolation of Carbon and Silica in a Single Janus Mesoporous Nanoparticle with Tunable Amphiphilicity. AB - Like surfactants with tunable hydrocarbon chain length, Janus nanoparticles also possess the ability to stabilize emulsions. The volume ratio between the hydrophilic and hydrophobic domains in a single Janus nanoparticle is very important for the stabilization of emulsions, which is still a great challenge. Herein, dual-mesoporous Fe3O4@mC&mSiO2 Janus nanoparticles with spatial isolation of hydrophobic carbon and hydrophilic silica at the single-particle level have successfully been synthesized for the first time by using a novel surface-charge mediated selective encapsulation approach. The obtained dual-mesoporous Fe3O4@mC&mSiO2 Janus nanoparticles are made up of a pure one-dimensional mesoporous SiO2 nanorod with tunable length (50-400 nm), ~100 nm wide and ~2.7 nm mesopores and a closely connected mesoporous Fe3O4@mC magnetic nanosphere (~150 nm diameter, ~10 nm mesopores). As a magnetic "solid amphiphilic surfactant", the hydrophilic/hydrophobic ratio can be precisely adjusted by varying the volume ratio between silica and carbon domains, endowing the Janus nanoparticles surfactant-like emulsion stabilization ability and recyclability under a magnetic field. Owing to the total spatial separation of carbon and silica, the Janus nanoparticles with an optimized hydrophilic/hydrophobic ratio show spectacular emulsion stabilizing ability, which is crucial for improving the biphasic catalysis efficiency. By selectively anchoring catalytic active sites into different domains, the fabricated Janus nanoparticles show outstanding performances in biphasic reduction of 4-nitroanisole with 100% conversion efficiency and 700 h-1 high turnover frequency for biphasic cascade synthesis of cinnamic acid. PMID- 29995404 TI - Exploring the Structure-Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug-Resistant Cancer Cells. AB - Multidrug resistance (MDR) is one major barrier in cancer management, which urges for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (the CXL series) demonstrate increased antiproliferative activity toward MDR acute-myeloid-leukemia (AML) cells. The structure-activity relationship (SAR) of the antiproliferative potency has been partly characterized, whereas the structural determinants contributing to selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells. The results not only confirmed previous SAR studies but also, for the first time, provided structural insights into the selectivity for MDR HL60/MX2 cells. Using the lead compounds as probes, we demonstrated that their modulation of intracellular-calcium homeostasis results in their antiproliferative potency and selectivity. Three candidates also demonstrate excellent in vitro safety profiles between cancer cells and normal cells, which will be evaluated in vivo in future studies. PMID- 29995405 TI - Identification of a Selective, Non-Prostanoid EP2 Receptor Agonist for the Treatment of Glaucoma: Omidenepag and its Prodrug Omidenepag Isopropyl. AB - EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2 selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3 ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2). Low doses of omidenepag isopropyl (OMDI), a prodrug of 13ax, lowered intraocular pressure (IOP) in ocular normotensive monkeys. OMDI was selected as a clinical candidate for the treatment of glaucoma. PMID- 29995406 TI - Carbene-Catalyzed Tandem [1,2]-Phospha-Brook/[1,4]-Phosphate Rearrangement: Access to alpha-Ketophosphates via Controlled Cross-Acyloin Condensation. AB - The first N-heterocyclic carbene (NHC)-organocatalytic tandem [1,2]-phospha Brook/[1,4]-phosphate rearrangement is reported. Acyl phosphonates, unlike acyl silanes that are well-exploited, make entry as the acyl anion precursors under NHC catalysis. The reactions proceed with absolute chemoselectivity via cross acyloin condensation between acyl phosphonates and aldehydes giving the products alpha-ketophosphates in good to excellent yields. The challenging (enolizable) aliphatic-aliphatic substrates coupling also furnished the desired product in a good yield. PMID- 29995407 TI - Borneol and Luteolin from Chrysanthemum morifolium Regulate Ubiquitin Signal Degradation. AB - Targeting the two degradation systems, ubiquitin proteasome pathway and ubiquitin signal autophagy lysosome system, plays an important function in cancer prevention. Borneol is called an "upper guiding drug". Luteolin has demonstrated anticancer activity. The fact that borneol regulates luteolin can be sufficient to serve as an alternative strategy. Borneol activates luteolin to inhibit E1 and 20S activity (IC50 = 118.8 +/- 15.7 MUM) and perturb the 26S proteasome structure in vitro. Borneol regulates luteolin to inhibit 26S activity (IC50 = 157 +/- 19 MUM), induces apoptosis (LC50 = 134 +/- 4 MUM), and causes pre-G1 and G0/G1 arrest in HepG2 cells. Borneol regulates luteolin to induce ubiquitin signal autophagic degradation, resulting in induction of E1, reduction of USP47, and accumulation of p62 in HepG2 reporter cells. Interestingly, luteolin decreased Ub conjugates, while borneol increased the accumulation of Ub conjugates in HepG2 reporter cells. E1, p62, and ubiquitin levels were downregulated in borneol treated HepG2 reporter cells at 24 h. These observations suggest a potential autophagic inhibitor of borneol that may guide luteolin in the ubiquitin proteasome pathway and the ubiquitin signal autophagic degradation. PMID- 29995408 TI - Identification of the 4-Position of 3-Alkynyl and 3-Heteroaromatic Substituted Pyridine Methanamines as a Key Modification Site Eliciting Increased Potency and Enhanced Selectivity for Cytochrome P-450 2A6 Inhibition. AB - Cigarette smoking causes nearly one in every five deaths in the United States. The development of a specific inhibitor of cytochrome P450 2A6 (CYP2A6), the major nicotine-metabolizing enzyme in humans, which could be prescribed for the cessation of cigarette smoking, has been undertaken. To further refine the structure activity relationship of CYP2A6, previously synthesized 3-alkynyl and 3 heteroaromatic substituted pyridine methanamines were used as lead compounds. Isosteric pyridine replacement and appendage of all available positions around the pyridine ring with a methyl group was performed to identify a modification that would increase CYP2A6 inhibition potency, which led to 4g (IC50 = 0.055 mM) as a primary analogue. Potent compounds were evaluated for CYP selectivity, human liver microsomal half-life, and compliance with the rules of five. Top compounds (i.e., 6i, IC50 = 0.017 mM, >120 min half-life) are poised for further development as treatments for smoking and tobacco use cessation. PMID- 29995409 TI - Bifidenone: Structure-Activity Relationship and Advanced Preclinical Candidate. AB - Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure-activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues. Compounds 45b and 46b were found to demonstrate promising efficacy in murine xenograft experiments, and 46b had significantly more potent in vitro antiproliferative activity against taxane-resistant cell lines compared to that of paclitaxel. PMID- 29995410 TI - Spectroscopy of Reactive Complexes and Solvated Clusters: A Bottom-Up Approach Using Cryogenic Ion Traps. AB - In this paper, applications of cryogenic ion traps for forming reaction intermediates and solvated clusters from precursor ions generated by electrospray ionization are presented and discussed. These studies are motivated by the aim of spectroscopically probing isolated complexes that exhibit higher levels of complexity in chemical compositions and intermolecular interactions, which make them more closely resemble the systems existing in real-world environments. Illustrative examples are provided to highlight the current capabilities, showcase the detailed information available in the spectroscopic results, and outline general future directions. PMID- 29995411 TI - Theoretical Insights into D-D-pi-A Sensitizers Employing N-Annulated Perylene for Dye-Sensitized Solar Cells. AB - This paper reports new D-D-pi-A dyes based on N-annulated perylene, emphasizing the enhanced dye-to-semiconductor charge-transfer mechanism. A series of DFT calculations for new tPA-perylene-based dyes was conducted, starting from the systematic selection of DFT methods by reproducing the experimentally obtained properties of known perylene-based sensitizers. Accordingly, using the LC omegaPBE xc functional with 6-31+G(d) basis set for the time-dependent calculations of the excitation energies, a damping parameter of omega = 0.150 Bohr-1 was found to be most appropriate for dyes having spatial orbital overlap value of 0.21 <= LambdaHL <= 0.38, while omega = 0.175 Bohr-1 is suitable for analogues with 0.43 <= LambdaHL <= 0.57. Moreover, the mPWHandHPW91/6-31G(d) method gave high accuracy in GSOP calculations. The comparison between the properties of tPA-based donor groups has revealed that the semirigid tPA-based D4 unit is an effective donor group for perylene-based dye. Initial screening of the acceptor designs resulted in PLz4 dye with promising charge-transfer mechanism and highly favorable dye-TiO2 interaction based on the calculated dipole moment of the dye and dye-TiO2 complex. The attachment of the substituted-hydroacridine donor unit (D4) to PLz4 afforded a bathochromically shifted absorbance and improved molar absorptivity signifying its effective electron-donating ability. Among the D-D-pi-A dyes, DP46 is expected to render a relatively high Voc and Jsc supported by the calculated optical properties, oxidation potentials, ionization potential, and electron affinity values. PMID- 29995412 TI - On the Binding Free Energy and Molecular Origin of Sickle Cell Hemoglobin Aggregation. AB - Protein aggregation is associated with various diseases, including Alzheimer and Parkinson as well as sickle cell disease (SCD). From a molecular point of view, protein aggregation depends on a complex balance of electrostatic and hydrophobic interactions mediated by water. An impressive manifestation of the importance of this balance concerns the human hemoglobin (HbA) mutant, HbS (sickle cell Hb), where a single substitution at the 6th position of HbA beta-chains, from glutamic acid to valine, causes the polymerization of deoxygenated HbS (deoxy-HbS), responsible for SCD. HbS polymerization is believed to occur via a double nucleation mechanism initiated by the formation of HbS fibers (homogeneous nucleation), followed by fiber growth. Furthermore, it was proposed that homogeneous nucleation proceeds through a two-step mechanism, where metastable dense clusters play the role of nucleation precursors. Thus, hindering or delaying the formation of such precursors could represent a potential SCD therapeutic route. Here, we study, through molecular dynamics, the binding free energy and protein-protein contacts involved in the deoxy-HbS dimer aggregation and stabilization process. A binding free energy of ~-14.0 +/- 1 kcal/mol is estimated from a one-dimensional potential of mean force. Analysis of protein protein interactions shows that both electrostatic and van der Waals interactions play an important role on the aggregation of HbS. With respect to the former, our results indicate that aggregation is largely favored by the formation of salt bridges (SB), mostly, Lys-Glu, Lys-Asp, and Heme-Lys SB, which outweigh electrostatic repulsions involving similar residues. Thus, our results suggest that a potential antisickling drug could be one with the ability to weaken or hinder the formation of a few SB between carboxylate and ammonium groups. PMID- 29995413 TI - Correction to "Theoretical Investigations of the Role of Mutations in Dynamics of Kinesin Motor Proteins". PMID- 29995414 TI - Predicting Q-Speciation in Binary Phosphate Glasses Using Statistical Mechanics. AB - Predicting the compositional evolution of the atomic-scale structure of oxide glasses is important for developing quantitative composition-property models. In binary phosphate glasses, the addition of network modifiers generally leads to depolymerization of the networks as described by the Q-speciation, where Q n denotes PO4 tetrahedra with n number (between 0 and 3) of bridging P-O-P linkages per tetrahedron. Upon the initial creation of nonbridging oxygens and thus partly depolymerized Q species, a variety of network former-modifier interactions exist. Here, on the basis of 31P magic angle spinning nuclear magnetic resonance spectroscopy data from the literature, we present a statistical description of the compositional evolution of Q-speciation in these glasses by accounting for the relative enthalpic and entropic contributions to the bonding preferences. We show that the entire glass structure evolution can be predicted based on experimental structural information for only a few glass compositions in each series. The model also captures the differences in bonding preferences in glasses with different field strengths (charge-to-size ratio) of the modifier cations. PMID- 29995415 TI - Effect of Imidazolium-Based Ionic Liquids on the Structure and Stability of Stem Bromelain: Concentration and Alkyl Chain Length Effect. AB - In the present work, changes in the structure and stability of stem bromelain (BM) are observed in the presence of a set of four imidazolium-based ionic liquids (ILs) such as 1-ethyl-3-methylimidazolium chloride ([Emim][Cl]), 1-butyl 3-methylimidazolium chloride ([Bmim][Cl]), 1-hexyl-3-methylimidazolium chloride ([Hmim][Cl]), and 1-decyl-3-methylimidazolium chloride ([Dmim][Cl]), using various biophysical techniques. Fluorescence spectroscopy is used to observe the changes taking place in the microenvironment around the tryptophan (Trp) residues of BM and its thermal stability because of its interactions with the ILs at different concentrations. Near-UV circular dichroism results showed that the native structure of BM remained preserved only at lower concentrations of ILs. In agreement with these results, dynamic light scattering revealed the formation of large aggregates of BM at higher concentrations of ILs, indicating the unfolding of BM. In addition to this, the results also show that higher alkyl chain length imidazolium-based ILs have a more denaturing effect on the BM structure as compared to the lower alkyl chain length ILs because of the increased hydrophobic interaction between the ILs and the BM structure. Interestingly, it is noted that low concentrations (0.01-0.10 M) of short alkyl chain ILs only alter the structural arrangement of the protein without any significant effect on its stability. However, high concentrations of all five ILs are found to disrupt the structural stability of BM. PMID- 29995416 TI - Stretchable Fiber Biofuel Cell by Rewrapping Multiwalled Carbon Nanotube Sheets. AB - The fiber-type biofuel cell is attractive as an implantable energy source because the fiber can modify various structures and the wound can be stitched like a suture. In addition, in daily life, the biofuel cell is forced by human motion, and stretchability is a critical requirement for real applications. Therefore, we introduce a new type of highly stretchable, stable, soft fiber biofuel cell with microdiameter dimensions as an energy harvester. The completed biofuel cell operated well in fluids similar to human fluids, such as 20 mM phosphate-buffered 0.14 M NaCl solution (39.5 mW/cm2) and human serum (36.6 MUW/cm2). The fiber-type biofuel cell can be reversibly stretched up to 100% in tensile direction while producing sustainable electrical power. In addition, the unique rewrapping structure, which traps the enzyme between multiwalled carbon nanotube sheets, enormously enhanced the stability of the biofuel cell when the biofuel cell was repeatedly stretched (the power density retention increased from 63 to 99%) and operated in human serum (the power density retention increased from 29 to 86%). The fiber can be easily woven into various structures, such as McKibben braid yarn, and scaled up by series and parallel connections. PMID- 29995417 TI - Resolving the Multiple Emission Centers in Carbon Dots: From Fluorophore Molecular States to Aromatic Domain States and Carbon-Core States. AB - Despite many efforts focused on the emission origin of carbon dots (CDs), it is still a topic of debate. This is mainly due to the complex structure of these nanomaterials. Here, we developed an innovative method to evaluate the number and spectral characterizations of various emission centers in CDs. We monitored the photostability of a series of column-separated CDs under UV irradiation to obtain three-dimensional data sets and resolve them using multivariate decomposition methods. The obtained results clearly revealed the presence of three different types of emission centers in CDs, including molecular states, aromatic domain states, and carbon-core states so that their single or coexisting appearance was found to be deeply dependent on the reaction temperature. Furthermore, density functional theory and time-dependent density functional theory were used to investigate the electronic and optical properties of some different aza polycyclic and corannulene molecules as possible polycyclic aromatic hydrocarbons responsible for the above-mentioned aromatic domain states. PMID- 29995418 TI - Therapeutic Efficacy-Potentiated and Diseased Organ-Targeting Nanovesicles Derived from Mesenchymal Stem Cells for Spinal Cord Injury Treatment. AB - Human mesenchymal stem cell (hMSC)-derived exosomes have been spotlighted as a promising therapeutic agent for cell-free regenerative medicine. However, poor organ-targeting ability and insufficient therapeutic efficacy of systemically injected hMSC-exosomes were identified as critical limitations for their further applications. Therefore, in this study we fabricated iron oxide nanoparticle (IONP)-incorporated exosome-mimetic nanovesicles (NV-IONP) from IONP-treated hMSCs and evaluated their therapeutic efficacy in a clinically relevant model for spinal cord injury. Compared to exosome-mimetic nanovesicles (NV) prepared from untreated hMSCs, NV-IONP not only contained IONPs which act as a magnet-guided navigation tool but also carried greater amounts of therapeutic growth factors that can be delivered to the target cells. The increased amounts of therapeutic growth factors inside NV-IONP were attributed to IONPs that are slowly ionized to iron ions which activate the JNK and c-Jun signaling cascades in hMSCs. In vivo systemic injection of NV-IONP with magnetic guidance significantly increased the amount of NV-IONP accumulating in the injured spinal cord. Accumulated NV-IONP enhanced blood vessel formation, attenuated inflammation and apoptosis in the injured spinal cord, and consequently improved spinal cord function. Taken together, these findings highlight the development of therapeutic efficacy potentiated extracellular nanovesicles and demonstrate their feasibility for repairing injured spinal cord. PMID- 29995419 TI - Ballistic One-Dimensional Holes with Strong g-Factor Anisotropy in Germanium. AB - We report experimental evidence of ballistic hole transport in one-dimensional quantum wires gate-defined in a strained SiGe/Ge/SiGe quantum well. At zero magnetic field, we observe conductance plateaus at integer multiples of 2 e2/ h. At finite magnetic field, the splitting of these plateaus by Zeeman effect reveals largely anisotropic g-factors with absolute values below 1 in the quantum well plane, and exceeding 10 out-of-plane. This g-factor anisotropy is consistent with a heavy-hole character of the propagating valence-band states, which is in line with a predominant confinement in the growth direction. Remarkably, we observe quantized ballistic conductance in device channels up to 600 nm long. These findings mark an important step toward the realization of novel devices for applications in quantum spintronics. PMID- 29995420 TI - Ultrafast Charge Transfer at a Quantum Dot/2D Materials Interface Probed by Second Harmonic Generation. AB - Hybrid quantum dot (QD)/transition metal dichalcogenide (TMD) heterostructures are attractive components of next generation optoelectronic devices, which take advantage of the spectral tunability of QDs and the charge and exciton transport properties of TMDs. Here, we demonstrate tunable electronic coupling between CdSe QDs and monolayer WS2 using variable length alkanethiol ligands on the QD surface. Using femtosecond time-resolved second harmonic generation (SHG) microscopy, we show that electron transfer from photoexcited CdSe QDs to single layer WS2 occurs on ultrafast (50 fs to 1 ps) time scales. Moreover, in the samples exhibiting the fastest charge transfer rates (<=50 fs) we observed oscillations in the time-domain signal corresponding to an acoustic phonon mode of the donor QD, which coherently modulates the SHG response of the underlying WS2 layer. These results reveal surprisingly strong electronic coupling at the QD/TMD interface and demonstrate the usefulness of time-resolved SHG for exploring ultrafast electronic-vibrational dynamics in TMD heterostructures. PMID- 29995421 TI - Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM HER3 in Comparison with a Monoclonal Antibody, Seribantumab. AB - Human epidermal growth factor receptor type 3 (HER3) is recognized to be involved in resistance to HER-targeting therapies. A number of HER3-targeting monoclonal antibodies are under clinical investigation as potential cancer therapeutics. Smaller high-affinity scaffold proteins are attractive non-Fc containing alternatives to antibodies. A previous study indicated that anti-HER3 affibody molecules could delay the growth of xenografted HER3-positive tumors. Here, we designed a second-generation HER3-targeting construct (TAM-HER3), containing two HER3-specific affibody molecules bridged by an albumin-binding domain (ABD) for extension of blood circulation. Receptor blocking activity was demonstrated in vitro. In mice bearing BxPC-3 xenografts, the therapeutic efficacy of TAM-HER3 was compared to the HER3-specific monoclonal antibody seribantumab (MM-121). TAM HER3 inhibited heregulin-induced phosphorylation in a panel of HER3-expressing cancer cells and was found to be equally as potent as seribantumab in terms of therapeutic efficacy in vivo and with a similar safety profile. Median survival times were 60 days for TAM-HER3, 54 days for seribantumab, and 41 days for the control group. No pathological changes were observed in cytopathological examination. The multimeric HER3-binding affibody molecule in fusion to ABD seems promising for further evaluation as candidate therapeutics for treatment of HER3 overexpressing tumors. PMID- 29995422 TI - RXRalpha Nitro-ligand Z-10 and Its Optimized Derivative Z-36 Reduce beta-amyloid Plaques in AD Mouse Model. AB - Bexarotene, an agonist of retinoid X receptor alpha (RXRalpha), has been shown to increase the expression of apoE, ABCA1 and ABCG1 by activating RXR/LXR and RXR/PPAR heterodimers, resulting in amyloid beta (Abeta)-protein clearance in the brain of an Alzheimer's Disease (AD) mouse model and reversal of mouse cognitive deficits. Nitrostyrene derivative Z-10 is the first identified nitro-ligand of RXRalpha. We hypothesized that Z-10 and its derivatives have the similar effect as bexarotene. A series of Z-10 derivatives were synthesized by introducing methyl, hydroxyl, and methoxy groups in 2- or 4- position of naphthalene ring, respectively. Our reporter gene assays showed that the derivatives with substituted groups of methyl and methoxy in position 2 were more potent to activate Gal4-DBD/RXRalpha-LBD and RXRalpha homodimer as well as RXRalpha heterodimers than the corresponding 4-substituted derivatives. The derivatives with hydroxyl substitution in either 2- or 4- position failed to activate RXRalpha. Consistently, the derivatives with stronger potency of RXRalpha activation had higher RXRalpha binding affinity. Z-10 and its 2-ethyoxyl substituted derivative Z-36 reduced Abeta plaques in both hippocampus and cortex of AD mouse model significantly, of which Z-36 had stronger efficacy. This may due to the stronger ability of Z-36 than Z-10 in activating RXR/LXR and RXR/PPAR heterodimers and inducing ABCA1 and ABCG1 expressions. Thus, the 2- rather than 4 position was the better site for Z-10 modification as to RXRalpha transactivation, and Z-36 is an optimized derivative of Z-10 as to reducing Abeta plaques in AD mouse model. PMID- 29995423 TI - Automated in Vivo Nanosensing of Breath-Borne Protein Biomarkers. AB - Toxicology and bedside medical condition monitoring is often desired to be both ultrasensitive and noninvasive. However, current biomarker analyses for these purposes are mostly offline and fail to detect low marker quantities. Here, we report a system called dLABer (detection of living animal's exhaled breath biomarker) that integrates living rats, breath sampling, microfluidics, and biosensors for the automated tracking of breath-borne biomarkers. Our data show that dLABer could selectively detect (online) and report differences (of up to 103-fold) in the levels of inflammation agent interleukin-6 (IL-6) exhaled by rats injected with different ambient particulate matter (PM). The dLABer system was further shown to have an up to 104 higher signal-to-noise ratio than that of the enzyme-linked immunosorbent assay (ELISA) when analyzing the same breath samples. In addition, both blood-borne IL-6 levels analyzed via ELISA in rats injected with different PM extracts and PM toxicity determined by a dithiothreitol (DTT) assay agreed well with those determined by the dLABer system. Video recordings further verified that rats exposed to PM with higher toxicity (according to a DTT assay and as revealed by dLABer) appeared to be less physically active. All the data presented here suggest that the dLABer system is capable of real-time, noninvasive monitoring of breath-borne biomarkers with ultrasensitivity. The dLABer system is expected to revolutionize pollutant health effect studies and bedside disease diagnosis as well as physiological condition monitoring at the single-protein level. PMID- 29995424 TI - Photoinduced Anomalous Coulomb Blockade and the Role of Triplet States in Electron Transport through an Irradiated Molecular Transistor. AB - In this study, we explore photoinduced electron transport through a molecule weakly coupled to two electrodes by combining first-principles quantum chemistry calculations with a Pauli master equation approach that accounts for many electron states. In the incoherent limit, we demonstrate that energy-level alignment of triplet and charged states plays a crucial role, even when the rate of intersystem crossing is much smaller than the rate of fluorescence. Furthermore, the field intensity dependence and an upper bound to the photoinduced electric current can be analytically derived in our model. Under an optical field, the conductance spectra (charge stability diagrams) exhibit unusual Coulomb diamonds, which are associated with molecular excited states, and their widths can be expressed in terms of energies of the molecular electronic states. This study offers new directions for exploring optoelectronic response in nanoelectronics. PMID- 29995425 TI - Connecting Composition-Driven Faceting with Facet-Driven Composition Modulation in GaAs-AlGaAs Core-Shell Nanowires. AB - Ternary III-V alloys of tunable bandgap are a foundation for engineering advanced optoelectronic devices based on quantum-confined structures including quantum wells, nanowires, and dots. In this context, core-shell nanowires provide useful geometric degrees of freedom in heterostructure design, but alloy segregation is frequently observed in epitaxial shells even in the absence of interface strain. High-resolution scanning transmission electron microscopy and laser-assisted atom probe tomography were used to investigate the driving forces of segregation in nonplanar GaAs-AlGaAs core-shell nanowires. Growth-temperature-dependent studies of Al-rich regions growing on radial {112} nanofacets suggest that facet dependent bonding preferences drive the enrichment, rather than kinetically limited diffusion. Observations of the distinct interface faceting when pure AlAs is grown on GaAs confirm the preferential bonding of Al on {112} facets over {110} facets, explaining the decomposition behavior. Furthermore, three dimensional composition profiles generated by atom probe tomography reveal the presence of Al-rich nanorings perpendicular to the growth direction; correlated electron microscopy shows that short zincblende insertions in a nanowire segment with predominantly wurtzite structure are enriched in Al, demonstrating that crystal phase engineering can be used to modulate composition. The findings suggest strategies to limit alloy decomposition and promote new geometries of quantum confined structures. PMID- 29995426 TI - Monitoring the Opening and Recovery of the Blood-Brain Barrier with Noninvasive Molecular Imaging by Biodegradable Ultrasmall Cu2- xSe Nanoparticles. AB - The reversible and controllable opening and recovery of the blood-brain barrier (BBB) is crucial for the treatment of brain diseases, and it is a big challenge to noninvasively monitor these processes. In this article, dual-modal photoacoustic imaging and single-photon-emission computed tomography imaging based on ultrasmall Cu2- xSe nanoparticles (3.0 nm) were used to noninvasively monitor the opening and recovery of the BBB induced by focused ultrasound in living mice. The ultrasmall Cu2- xSe nanoparticles were modified with poly(ethylene glycol) to exhibit a long blood circulation time. Both small size and long blood circulation time enable them to efficiently penetrate into the brain with the assistance of ultrasound, which resulted in a strong signal at the sonicated site and allowed for photoacoustic and single-photon emission computed tomography imaging monitoring the recovery of the opened BBB. The results of biodistribution, blood routine examination, and histological staining indicate that the accumulated Cu2- xSe nanoparticles could be excreted from the brain and other major organs after 15 days without causing side effects. By the combination of the advantages of noninvasive molecular imaging and focused ultrasound, the ultrasmall biocompatible Cu2- xSe nanoparticles holds great potential for the diagnosis and therapeutic treatment of brain diseases. PMID- 29995427 TI - Neurite Guidance on Laser-Scribed Reduced Graphene Oxide. AB - This paper describes a one-step, chemical-free method to generate micropatterned in vitro neuronal networks on chemically unmodified reduced graphene oxide. The suggested method relies on infrared-based photothermal reduction of graphene oxide, which concurrently leads to the formation of submicrometer-scale surface roughness that promotes neuronal adhesion and guides neurite outgrowth. A commercially available laser source (LightScribe DVD drive) controlled by a computer software can be used to reduce graphene oxide (GO), and its repetitive scribing to a GO film brings about gradual increase and decrease in electrical conductivity and neurite guiding ability of the scribed regions, respectively. Our results also indicate that the observed adhesion-promoting and neurite guiding effect originate from the contrast in surface nanotopography, but not that in conductivity. This method is readily applicable to diverse graphene-based biomedical devices. PMID- 29995428 TI - Radiative Pumping and Propagation of Plexcitons in Diffractive Plasmonic Crystals. AB - Strong coupling between plasmons and excitons leads to the formation of plexcitons: quasiparticles that combine nanoscale energy confinement and pronounced optical nonlinearities. In addition to these localized modes, the enhanced control over the dispersion relation of propagating plexcitons may enable coherent and collective coupling of distant emitters. Here, we experimentally demonstrate strong coupling between carbon nanotube excitons and spatially extended plasmonic modes formed via diffractive coupling of periodically arranged gold nanoparticles (nanodisks, nanorods). Depending on the light-matter composition, the rather long-lived plexcitons (>100 fs) undergo highly directional propagation over 20 MUm. Near-field energy distributions calculated with the finite-difference time-domain method fully corroborate our experimental results. The previously demonstrated compatibility of this plexcitonic system with electrical excitation opens the path to the realization of a variety of ultrafast active plasmonic devices, cavity-assisted energy transport and low-power optoelectronic components. PMID- 29995429 TI - Fluorogenic Sydnone-Modified Coumarins Switched-On by Copper-Free Click Chemistry. AB - The synthesis, photophysical characterization, and biochemical application of sydnone-modified coumarins, a novel class of fluorogenic clickable reagents, are reported. The sydnone moiety, a stable aromatic 1,3-dipole, efficiently quenched the fluorescence of coumarin, which could be restored, with a 132-fold enhancement, upon cycloadditions with cyclooctynes, thereby expanding the fluorogenic click toolbox. TD-DFT calculations suggest that the fluorescence quenching of the sydnone-modified coumarins is likely due to the presence of an energetically low-lying nonemissive charge-separated state. PMID- 29995430 TI - Ultrascaled Germanium Nanowires for Highly Sensitive Photodetection at the Quantum Ballistic Limit. AB - We report an experimental study on quasi-one-dimensional Al-Ge-Al nanowire (NW) heterostructures featuring unmatched photoconductive gains exceeding 107 and responsivities as high as 10 A/MUW in the visible wavelength regime. Our observations are attributed to the presence of GeO x related hole-trapping states at the NW surface and can be described by a photogating effect in accordance with previous studies on low-dimensional nanostructures. Utilizing an ultrascaled photodetector device operating in the quantum ballistic transport regime at room temperature we demonstrate for the first time that individual current channels can be addressed directly by laser irradiation. The resulting quantization of the photocurrent represents the ultimate limit of photodetectors, allowing for advanced concepts including highly resolved imaging, light effect transistors and single photon detectors with practically zero off-state current. PMID- 29995431 TI - Supply and Demand: Micro(vascular) Economics of the Right Ventricle in Pulmonary Hypertension. PMID- 29995432 TI - Of Mice and Men . . . and Microbes: Conclusions and Cautions from a Murine Study of the Lung Microbiome and Microbiome-Immune Interactions. PMID- 29995433 TI - A Multivariable Prediction Model for Pneumocystis jirovecii Pneumonia in Hematology Patients with Acute Respiratory Failure. AB - RATIONALE: The incidence of Pneumocystis jirovecii pneumonia (PjP) is rising. Longer time to treatment is associated with higher mortality. OBJECTIVES: to develop a multivariable risk prediction model for PjP diagnosis. METHODS: In a prospective multicentre cohort of intensive-care-unit patients with hematological malignancies and ARF, factors associated with documented PjP were identified. The risk prediction model was tested in an independent prospective multicentre cohort. We assessed discrimination (by areas under the ROC curves [AUCs]), and goodness-of-fit (by Hosmer-Lemeshow statistic). Model performance was assessed using 30 sets of imputed datasets. MEASUREMENTS AND MAIN RESULTS: Among the 1330 patients, 134/1092 (12.3%) had proven PjP in the derivation cohort and 15/238 (6.3%) in the validation cohort. The model included age, lymphoproliferative disease, anti-Pneumocystis prophylaxis, respiratory symptom duration, shock, chest radiograph pattern, and pleural effusion. Median [IQR] score was 3.5 [1.5 5.0] (range, -3.5 to 8.5) in the derivation cohort and 1.0 [0-2.0] (range, -3.5 to 6.0) in the validation cohort. Scores >3 had 73% sensitivity and 88% specificity for PjP. The negative predictive value was 97% (PjP prevalence, 10%). The score had excellent calibration (goodness of fit, -0.75) and discrimination in the derivation cohort (mean AUC, 0.87) and validation cohort (mean AUC, 0.83). CONCLUSIONS: The PjP score for hematology patients with ARF can be computed at admission based on readily available variables. Potential clinical benefits of using this score deserve assessment. PMID- 29995434 TI - Sirtuin 1: A New Potential Therapeutic Target for Rhinosinusitis? Who "Nose"? PMID- 29995435 TI - Association of Height Growth in Puberty with Lung Function: A Longitudinal Study. AB - RATIONALE: Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. OBJECTIVES: To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. METHODS: Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated SuperImposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders. MEASUREMENTS AND MAIN RESULTS: Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC. CONCLUSIONS: Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth. PMID- 29995436 TI - Reproductive Governance and the (Re)definition of Human Rights in Poland. AB - Reproductive rights struggles have continued to dominate public debates in Poland since the political resurgence of the Catholic church in 1989. In 2015, the state passed a landmark "In Vitro Policy" to regulate assisted reproductive technologies. Its religiously based compromises may jeopardize other reproductive rights. I argue that the new policy negotiations demonstrate how versions of competing human rights claims are central to reproductive governance and struggles in the new Polish "ethical order." These negotiations reveal a reciprocal and temporal effect between infertility and abortion laws, in which previously enacted abortion restrictions are used to limit and define "In Vitro" rights. PMID- 29995437 TI - Digital Images in Academic Plastic Surgery: A Novel and Secure Methodology for Use in Clinical Practice and Research. AB - BACKGROUND: Digital photographs have become an integral part in plastic and reconstructive surgery. They are significant in clinical research and outcome evaluation. There is a need for effective and secure methods to store, search, and retrieve those photographs. We developed a Health Insurance Portability and Accountability Act compliant searchable database to archive and index clinical information for clinical and research purposes. METHODS: At our craniofacial clinic, digital media (2-D, 3-D, and 4-D photographs) are obtained on a regular basis to evaluate and document treatment outcomes. In addition, patients are asked to enroll in our institutional review board (IRB)-approved imaging database. Daily, we link all digital photographs to the patient encounter through EPIC's Media Manager. This allows us to automatically identify and extract new digital media, patient demographics, diagnosis codes, relevant providers, and the text of the clinic notes to our digital database. To search our extensive database, we employed the VIEW search engine. RESULTS: To date, our database contains more than 277 000 images of 11 000 patients where more than 1900 patients are enrolled in the IRB study. This search engine allows full-text search with query response time between 2 and 5 seconds. The search engine displays the returned through a web page interface, which includes image thumbnails and the relevant part of the clinic note. In addition, a patient specific chart allows the user to examine all patient notes and photographs. CONCLUSION: Our solution allows providers and researchers to retrieve all digital media securely and efficiently. PMID- 29995438 TI - Managing Our Older Population: The Challenges Ahead. PMID- 29995439 TI - Recent developments with immunotherapy for hepatocellular carcinoma. AB - INTRODUCTION: Immunotherapy is on the way to become the new standard of care for advanced hepatocellular carcinoma (HCC) worldwide. With higher rates of objective responses, and overall less side effects compared to tyrosine-kinase inhibitors (TKIs) immunotherapeutics will probably replace sorafenib from standard first line treatment. Areas covered: This review covers recent clinical data on systemic agents and ongoing trials in patients with advanced HCC focusing on immunotherapy. Expert opinion: In unselected patients with advanced HCC immunotherapeutics, namely the programmed cell death-1 (PD-1) antibodies, nivolumab and pembrolizumab have shown promising efficacy in therapy-naive, as well as pre-treated patients with advanced HCC. However, only 10-20 percent of treated patients show an objective and durable response to the indicated therapeutics. Therefore, combination therapies including different immunotherapeutics, e.g. PD-1/programmed cell death 1 ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies, or combinations of immunotherapeutics and small molecules, or bifunctional antibodies will be needed to improve response rates. ABBREVIATIONS: HCC: hepatocellular carcinoma; TKI: tyrosine-kinase inhibitors; PD-1: programmed death receptor-1; PD-L1: programmed cell death 1 ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated Protein 4; CAR-T: chimeric T cell receptors; TACE: transarterial chemoembolization; SIRT: selective internal radiation therapy; SBRT: stereotactic body radiation therapy; VEGF: vascular endothelial growth factor; MEK: mitogen activated protein kinase kinase; NK cell: natural killer cell; TGFbeta: transforming growth factor-beta; OV: Oncolytic viruses; PFU: plaque-forming unit. PMID- 29995440 TI - Unraveling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation. AB - Aurora kinases are critical mitotic serine/threonine kinases and are often implicated in tumorigenesis. Recent studies of the interphase functions for aurora kinase (Aurk)A have considerably expanded our understanding of its role beyond mitosis. To identify the unknown targets of AurkA, we used peptide array based screening and found E2F4 to be a novel substrate. Phosphorylation of E2F4 by AurkA at Ser75 regulates its DNA binding and subcellular localization. Because E2F4 plays an important role in skeletal muscle differentiation, we attempted to gain insight into E2F4 phosphorylation in this context. We observed that a block in E2F4 phosphorylation retained it better within the nucleus and inhibited muscle differentiation. RNA sequencing analysis revealed a perturbation of the gene network involved in the process of muscle differentiation and mitochondrial biogenesis. Collectively, our findings establish a novel role of AurkA in the process of skeletal muscle differentiation.-Dhanasekaran, K., Bose, A., Rao, V. J., Boopathi, R., Shankar, S. R., Rao, V. K., Swaminathan, A., Vasudevan, M., Taneja, R., Kundu, T. K. Unravelling the role of aurora A beyond centrosomes and spindle assembly: implications in muscle differentiation. PMID- 29995441 TI - Musculoskeletal and Cognitive Effects of a Movement Intervention During Prolonged Standing for Office Work. AB - OBJECTIVE: To investigate whether use of a movement intervention when undertaking prolonged standing affected discomfort and cognitive function. BACKGROUND: Alternate work positions to break up prolonged sitting for office workers are being trialed, such as standing. Prolonged standing has potential negative health implications, including low back and lower limb discomfort, and may influence cognitive function. Introducing movement during standing may provide a healthy and productive alternative work posture. METHOD: Twenty adult participants undertook a laboratory study of 2 hr of standing and standing with movement (using a footrest) while performing computer work. Changes in discomfort and cognitive function, with muscle fatigue, low back angle, pelvis movement, lower limb swelling, and mental state, were investigated. RESULTS: Discomfort increased significantly over time across all body regions. Ankle/foot differed between conditions (incident rate ratio [95% confidence interval]: 1.89 [1.10-3.23]), with higher discomfort during standing with movement. Creative problem-solving errors increased during standing with movement and decreased during standing (Time * Condition: beta = 0.64 [0.10-1.18]), with no other cognitive function measure differences. Mental state deteriorated over time for both conditions, greater during standing with movement (Time * Condition: beta = 2.44 [0.23 4.66]). No significant interaction effects were found for the other outcome variables. CONCLUSION: Standing with movement provided no advantage in discomfort or cognitive function. There were some negative effects for ankle/foot discomfort and creative problem solving. An alternate footrest design and protocol for use may yield more favorable results. APPLICATION: Based on the results from this study, footrest use to raise alternative foot for forced 5-min intervals would not be recommended to assist with managing discomfort while prolonged standing in workplaces. PMID- 29995442 TI - Internal Fixation of Unstable Osteochondritis Dissecans: Do Open Growth Plates Improve Healing Rate? AB - BACKGROUND: Osteochondritis dissecans (OCD) is a disorder of unknown origin that can affect knees in skeletally mature and immature patients. Surgical management is an important cornerstone of treatment for unstable OCD lesions. PURPOSE: To determine the (1) healing rate after internal fixation of unstable OCD between skeletally immature and mature knees, (2) risk factors for failure, and (3) patient-reported outcomes among healed patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A multicenter retrospective cohort study was conducted with patients who underwent internal fixation of unstable knee OCD lesions from 2000 to 2015. Skeletal immaturity was defined as open or partially open physes. Healing was assessed through clinical findings and imaging. Definitive reoperation for the same OCD lesion was classified as failure. RESULTS: Among 87 patients included, 66 (76%) had healed lesions at >=2 years postoperatively, while 21 (24%) failed. Skeletal maturity made no significant difference in failure rate (risk ratio, 0.68; 95% CI, 0.29-1.72; P = .40). For skeletally immature patients, lateral versus medial condylar location conferred an increased hazard of 18.2 (95% CI, 1.76-188.07; P < .01). Multivariate analysis factoring in skeletal maturity showed that lateral condylar location was an independent risk factor for failure (hazard ratio, 4.25; 95% CI, 1.47-19.85; P < .01). Mean patient-reported outcome scores (International Knee Documentation Committee [IKDC] and Knee injury and Osteoarthritis Outcome Score [KOOS]) increased significantly after surgery, except the KOOS symptoms score for the skeletally mature group. Final scores (mean +/- SD) were as follows at a mean follow-up of 60 months (range, 24-166): IKDC, 83.5 +/- 20.2; KOOS pain, 89.7 +/- 14.1; KOOS symptoms, 87.4 +/- 18.4; KOOS activities of daily living, 93.9 +/- 12.7; KOOS sports, 80.7 +/- 25.9; KOOS quality of life, 78.9 +/- 23.1. CONCLUSION: Skeletally immature and mature patients heal at comparable rates after internal fixation of OCD lesions, resulting in functional and subjective improvement. Lateral femoral condylar lesion location is an independent risk factor for failure. PMID- 29995443 TI - You only have one chance for a first impression! Impact of Patients' First Impression on the Global Quality Assessment of Doctors' Communication Approach. AB - Patients' first impressions obtained during early contacts with doctors represent the basis for relationship building processes. Aim of this study was to verify how patients' first impression of doctors' communication approach influences patients' global assessment of doctors' performance. This cross-sectional study was part of a larger, multicenter observational study aiming to assess lay people's preferences regarding patient-doctor communication. All participants (N = 136) were equally distributed over two selected Italian and Dutch recruitment centers as well as for gender and age. In each center, panels of 6-9 persons each watched the same set of eight videotaped Objective Structured Clinical Examination consultations. Participants performed different tasks as to pick up salient communication elements while watching the videos and to rate doctors' global communicative performances on a 10-point Likert scale. We performed a mediation analysis to assess direct and indirect effects of participants' first impression on participants' global assessment. Among the 439 collected first impressions, 284(65%) were positive. When the first impression was positive, the mean value of the global assessment of doctors' performance was significantly higher (M = 7.4, SD = 1.5) than when the first impression was negative (M = 6.0, SD = 1.6); t(437) = 9.0 p < .001. According to the mediation analysis, this difference was due to a direct (c' = 0.53) and an indirect effect (ab = 0.86) deriving from the total effect of first impressions on the global assessment of doctors' performances (c = 1.39). In conclusion, the first impression has a strong impact on positive and negative judgments on doctors' communication approach and may facilitate or inhibit all further interactions. PMID- 29995444 TI - Confirmatory Testing Prior to Treating Toenail Onychomycosis Is Recommended in Canada. PMID- 29995445 TI - Cost-effectiveness of Confirmatory Testing and Empirical Therapy for Onychomycosis in Canada. PMID- 29995446 TI - Habit Tic Nail Deformity. PMID- 29995447 TI - Right Forearm Eruption Associated With Playing Minecraft: A Case of Contact Dermatitis Related to Computer Gaming. AB - This submission highlights the importance of careful history taking along with a strong index of suspicion for an exogenous cause of dermatitis. In particular, it highlights the importance of being aware of the latest trends and exposure risks for contact dermatitis. PMID- 29995448 TI - Revolution-"Speak With Your Pens" / Prenez la plume pour participer a une revolution. PMID- 29995449 TI - Measuring and Mitigating the Costs of Attentional Switches in Active Network Monitoring for Cybersecurity. AB - OBJECTIVE: The authors seek to characterize the behavioral costs of attentional switches between points in a network map and assess the efficacy of interventions intended to reduce those costs. BACKGROUND: Cybersecurity network operators are tasked with determining an appropriate attentional allocation scheme given the state of the network, which requires repeated attentional switches. These attentional switches may result in temporal performance decrements, during which operators disengage from one attentional fixation point and engage with another. METHOD: We ran two experiments where participants identified a chain of malicious emails within a network. All interactions with the system were logged and analyzed to determine if users experienced disengagement and engagement delays. RESULTS: Both experiments revealed significant costs from attentional switches before (i.e., disengagement) and after (i.e., engagement) participants navigated to a new area in the network. In our second experiment, we found that interventions aimed at contextualizing navigation actions lessened both disengagement and engagement delays. CONCLUSION: Attentional switches are detrimental to operator performance. Their costs can be reduced by design features that contextualize navigations through an interface. APPLICATION: This research can be applied to the identification and mitigation of attentional switching costs in a variety of visual search tasks. Furthermore, it demonstrates the efficacy of noninvasive behavioral monitoring for inferring cognitive events. PMID- 29995450 TI - Full Factorial Microfluidic Designs and Devices for Parallelizing Human Pluripotent Stem Cell Differentiation. AB - Human pluripotent stem cells (hPSCs) are promising therapeutic tools for regenerative therapies and disease modeling. Differentiation of cultured hPSCs is influenced by both exogenous factors added to the cultures and endogenously secreted molecules. Optimization of protocols for the differentiation of hPSCs into different cell types is difficult because of the many variables that can influence cell fate. We present microfluidic devices designed to perform three- and four-factor, two-level full factorial experiments in parallel for investigating and directly optimizing hPSC differentiation. These devices feature diffusion-isolated, independent culture wells that allow for control of both exogenous and endogenous cellular signals and that allow for immunocytochemistry (ICC) and confocal microscopy in situ. These devices are fabricated by soft lithography in conjunction with 3D-printed molds and are operable with a single syringe pump, eliminating the need for specialized equipment or cleanroom facilities. Their utility was demonstrated by on-chip differentiation of hPSCs into the auditory neuron lineage. More broadly, these devices enable multiplexing for experimentation with any adherent cell type or even multiple cell types, allowing efficient investigation of the effects of medium conditions, pharmaceuticals, or other soluble reagents. PMID- 29995451 TI - Immune-checkpoint inhibitors to treat cancers in specific immunocompromised populations: a critical review. AB - INTRODUCTION: Because of their efficacy against numerous cancers, immune checkpoint inhibitors (ICIs), anti-cytotoxic T-lymphocyte antigen-4, and anti programmed cell death monoclonal antibodies are being used ever more often in oncology. However, some patients were excluded from clinical trials because of their comorbidities despite their potentially higher cancer frequencies, as is the case for immunocompromised patients. Areas covered: We analyzed reported preclinical and clinical information and evaluated the risk/benefit ratio for four immunocompromised populations: people living with human immunodeficiency virus (PLHs), solid-organ transplant recipients, recipients of hematopoietic stem cell allografts, and patients with autoimmune diseases. Expert commentary: Information available in the literature is fragmentary and scarce, making it difficult to evaluate the risk/benefit ratio. It can, nonetheless, be noted that ICI use in PLHs seems possible. For solid-organ transplant recipients, the risk for the graft seems elevated. For the other two populations, it is difficult to conclude at this time. PMID- 29995452 TI - Development and Characterization of Quantitative, High-Throughput-Compatible Assays for Proteolytic Degradation of Glucagon. AB - Glucagon is a vital peptide hormone involved in the regulation of blood sugar under fasting conditions. Although the processes underlying glucagon production and secretion are well understood, far less is known about its degradation, which could conceivably be manipulated pharmacologically for therapeutic benefit. We describe here the development of novel assays for glucagon degradation, based on fluoresceinated and biotinylated glucagon (FBG) labeled at the N- and C-termini, respectively. Proteolysis at any peptide bond within FBG separates the fluorescent label from the biotin tag, which can be quantified in multiple ways. In one method requiring no specialized equipment, intact FBG is separated from the cleaved fluoresceinated fragments using NeutrAvidin agarose beads, and hydrolysis is quantified by fluorescence. In an alternative, high-throughput compatible method, the degree of hydrolysis is quantified using fluorescence polarization after addition of unmodified avidin. Using a known glucagon protease, we confirm that FBG is cleaved at similar sites as unmodified glucagon and use both methods to quantify the kinetic parameters of FBG degradation. We show further that the fluorescence polarization-based assay performs exceptionally well ( Z'-factor values >0.80) in a high-throughput, mix-and measure format. PMID- 29995453 TI - First Nonphosphorylated Inhibitors of Phosphoglucose Isomerase Identified by Chemical Library Screening. AB - Human African trypanosomiasis, Chagas disease, and leishmaniasis are human infections caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania. Besides their severity and global impact, treatments are still challenging. Currently available drugs have important limitations, highlighting the urgent need to develop new drugs. Phosphoglucose isomerase (PGI) is considered a promising target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis. Herein, we describe the identification of new nonphosphorylated inhibitors of Leishmania mexicana PGI ( LmPGI), with the potential for the development of antiparasitic drugs. A fluorescence-based high-throughput screening (HTS) assay was developed by coupling the activities of recombinant LmPGI with glucose-6-phosphate dehydrogenase and diaphorase. This coupled assay was used to screen 42,720 compounds from ChemBridge and TimTec commercial libraries. After confirmatory assays, selected LmPGI inhibitors were tested against homologous Trypanosoma cruzi and humans. The PGI hits are effective against trypanosomatid PGIs, with IC50 values in the micromolar range, and also against the human homologous enzyme. A computational analysis of cavities present on PGI's crystallographic structure suggests a potential binding site for the proposed mixed-type inhibition mechanism. PMID- 29995454 TI - Signals in Stem Cell Differentiation on Fluorapatite-Modified Scaffolds. AB - Previously, we reported that the fluorapatite (FA)-modified polycaprolactone (PCL) nanofiber could be an odontogenic/osteogenic inductive tissue-engineering scaffold by inducing stem cell differentiation and mineralization. The present study aimed to explore which of the signal pathways affected this differentiation and mineralization process. The Human Signal Transduction PathwayFinder RT2 Profiler PCR Array was used to analyze the involvement of potential signal transduction pathways during human dental pulp stem cell (DPSCs) osteogenic differentiation induced by FA-modified PCL nanofiber scaffolds. Based on the results, perturbation studies of the signaling pathways hedgehog, insulin, and Wnt were performed. Moreover, the autophagy process was studied, as indicated by the expression of the microtubule-associated protein 1 light chain 3A/B-II (LC3 II) and the cell osteogenic phenotypic changes. In a comparison of the cells grown on PCL + FA scaffolds and those on PCL-only scaffolds, the transcript expression of BMP2, BMP4, FOXA2, PTCH1, WNT1, and WNT2 (PCR array-labeled signal proteins of the hedgehog pathway); CEBPB, FASN, and HK2 (PCR array-labeled signal proteins of the insulin pathway); and CCND1, JUN, MYC, TCF7, and WISP1 (PCR array labeled signal proteins of the Wnt pathway) doubled at day 14 when obvious cell osteogenic differentiation occurred. Phenotypically, in all the perturbation groups at day 14, ALP activity, OPN, and autophagy marker LC3-II expression were coincidently decreased. Consistently, no positive alizarin red staining or von Kossa staining was observed in the specimens from these perturbation groups at day 28. The results showed that when obvious cell differentiation occurred at day 14 on PCL + FA control groups, the inhibition of the hedgehog, insulin, and Wnt pathways significantly decreased DPSC osteogenic differentiation and mineralization. The osteogenic differentiation of DPSCs grown on FA-modified PCL scaffolds appeared to be positively modulated by the hedgehog, insulin, and Wnt signal pathways, which were coordinated with and/or mediated by the cell autophagy process. PMID- 29995455 TI - Evaluation of the cost-effectiveness of rifaximin-alpha for the management of patients with hepatic encephalopathy in the United Kingdom. AB - OBJECTIVE: Rifaximin-alpha 550 mg twice daily plus lactulose has demonstrated efficacy in reducing recurrence of episodes of overt hepatic encephalopathy (OHE) and the risk of hepatic encephalopathy (HE)-related hospitalizations compared with lactulose alone. This analysis estimated the cost effectiveness of rifaximin alpha 550 mg twice daily plus lactulose versus lactulose alone in United Kingdom (UK) cirrhotic patients with OHE. METHOD: A Markov model was built to estimate the incremental cost-effectiveness ratio (ICER). The perspective was that of the UK National Health Service (NHS). Clinical data was sourced from a randomized controlled trial (RCT) and an open-label maintenance study in cirrhotic patients in remission from recurrent episodes of OHE. Health-related utility was estimated indirectly from disease-specific quality of life RCT data. Resource use data describing the impact of rifaximin-alpha on hospital admissions and length of stay for cirrhotic patients with OHE was from four single-center UK audits. Costs (2012) were derived from published sources; costs and benefits were discounted at 3.5%. The base-case time horizon was 5 years. RESULTS: The average cost per patient was L22,971 in the rifaximin-alpha plus lactulose arm and L23,545 in the lactulose arm, a saving of L573. The corresponding values for benefit were 2.35 quality adjusted life years (QALYs) and 1.83 QALYs per person, a difference of 0.52 QALYs. This translated into a dominant base-case ICER. Key parameters that impacted the ICER included number of hospital admissions and length of stay. CONCLUSION: Rifaximin-alpha 550 mg twice daily in patients with recurrent episodes of OHE was estimated to generate cost savings and improved clinical outcomes compared to standard care over 5 years. PMID- 29995456 TI - MEF2 as upstream regulator of the transcriptome signature in human skeletal muscle during unloading. AB - Our understanding of skeletal muscle structural and functional alterations during unloading has increased in recent decades, yet the molecular mechanisms underpinning these changes have only started to be unraveled. The purpose of the current investigation was to assess changes in skeletal muscle gene expression after 21 days of bed rest, with a particular focus on predicting upstream regulators of muscle disuse. Additionally, the association between differential microRNA expression and the transcriptome signature of bed rest were investigated. mRNAs from musculus vastus lateralis biopsies obtained from 12 men before and after the bed rest were analyzed using a microarray. There were 54 significantly upregulated probesets after bed rest, whereas 103 probesets were downregulated (false discovery rate 10%; fold-change cutoff >=1.5). Among the upregulated genes, transcripts related to denervation-induced alterations in skeletal muscle were identified, e.g., acetylcholine receptor subunit delta and perinatal myosin. The most downregulated transcripts were functionally enriched for mitochondrial genes and genes involved in mitochondrial biogenesis, followed by a large number of contractile fiber components. Upstream regulator analysis identified a robust inhibition of the myocyte enhancer factor-2 (MEF2) family, in particular MEF2C, which was suggested to act upstream of several key downregulated genes, most notably peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha)/peroxisome proliferator-activated receptors (PPARs) and CRSP3. Only a few microRNAs were identified as playing a role in the overall transcriptome picture induced by sustained bed rest. Our results suggest that the MEF2 family is a key regulator underlying the transcriptional signature of bed rest and, hence, ultimately also skeletal muscle alterations induced by systemic unloading in humans. PMID- 29995458 TI - Differential influence of vitamin C on the peripheral and cerebral circulation after diving and exposure to hyperoxia. AB - We examined if the diving-induced vascular changes in the peripheral and cerebral circulation could be prevented by oral antioxidant supplementation. Fourteen divers performed a single scuba dive to eighteen meter sea water for 47 min. Twelve of the divers participated in a follow-up study involving breathing 60% of oxygen at ambient pressure for 47 min. Before both studies, participants ingested vitamin C (2 g/day) or a placebo capsule for 6 days. After a 2-wk washout, the study was repeated with the different condition. Endothelium-dependent vasodilator function of the brachial artery was assessed pre- and postintervention using the flow-mediated dilation (FMD) technique. Transcranial Doppler ultrasound was used to measure intracranial blood velocities pre- and 90 min postintervention. FMD was reduced by ~32.8% and ~21.2% postdive in the placebo and vitamin C trial and posthyperoxic condition in the placebo trial by ~28.2% ( P < 0.05). This reduction in FMD was attenuated by ~10% following vitamin C supplementation in the hyperoxic study ( P > 0.05). Elevations in intracranial blood velocities 30 min after surfacing from diving were reduced in the vitamin C study compared with the placebo trial ( P < 0.05). O2 breathing had no postintervention effects on intracranial velocities ( P > 0.05). Prophylactic ingestion of vitamin C effectively abrogated peripheral vascular dysfunction following exposure to 60% O2 but did not abolish the postdive decrease in FMD. Transient elevations of intracranial velocities postdive were reduced by vitamin C. These findings highlight the differential influence of vitamin C on peripheral and cerebral circulations following scuba diving, which are only partly mediated via hyperoxia. PMID- 29995457 TI - Impact of age on the development of fatigue during large and small muscle mass exercise. AB - To examine the impact of aging on neuromuscular fatigue following cycling (CYC; large active muscle mass) and single-leg knee-extension (KE; small active muscle mass) exercise, 8 young (25 +/- 4 years) and older (72 +/- 6 years) participants performed CYC and KE to task failure at a given relative intensity (80% of peak power output). The young also matched CYC and KE workload and duration of the old (iso-work comparison). Peripheral and central fatigue were quantified via pre /postexercise decreases in quadriceps twitch torque (?Qtw, electrical femoral nerve stimulation) and voluntary activation (?VA). Although young performed 77% and 33% more work during CYC and KE, respectively, time to task failure in both modalities was similar to the old (~9.5 min; P > 0.2). The resulting DeltaQtw was also similar between groups (CYC ~40%, KE ~55%; P > 0.3); however, ?VA was, in both modalities, approximately double in the young (CYC ~6%, KE ~9%; P < 0.05). While causing substantial peripheral and central fatigue in both exercise modalities in the old, ?Qtw in the iso-work comparison was not significant (CYC; P = 0.2), or ~50% lower (KE; P < 0.05) in the young, with no central fatigue in either modality ( P > 0.4). Based on iso-work comparisons, healthy aging impairs fatigue resistance during aerobic exercise. Furthermore, comparisons of fatigue following exercise at a given relative intensity mask the age-related difference observed following exercise performed at the same workload. Finally, although active muscle mass has little influence on the age-related difference in the rate of fatigue at a given relative intensity, it substantially impacts the comparison during exercise at a given absolute intensity. PMID- 29995459 TI - Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer. AB - Obstructive sleep apnea (OSA) is common and linked to a variety of poor health outcomes. A key modulator of this disease is nocturnal intermittent hypoxia. There is striking epidemiological evidence that patients with OSA have higher rates of cancer and cancer mortality. Small-animal models demonstrate an important role for systemic intermittent hypoxia in tumor growth and metastasis, yet the underlying mechanisms are poorly understood. Emerging data indicate that intermittent hypoxia activates the hypoxic response and inflammatory pathways in a manner distinct from chronic hypoxia. However, there is significant heterogeneity in published methods for modeling hypoxic conditions, which are often lacking in physiological relevance. This is particularly important for studying key transcriptional mediators of the hypoxic and inflammatory responses such as hypoxia-inducible factor (HIF) and NF-kappaB. The relationship between HIF, the molecular clock, and circadian rhythm may also contribute to cancer risk in OSA. Building accurate in vitro models of intermittent hypoxia reflective of OSA is challenging but necessary to better elucidate underlying molecular pathways. PMID- 29995460 TI - The First Decade of Web-Based Sports Injury Surveillance: Descriptive Epidemiology of Injuries in US High School Girls' Field Hockey (2008-2009 Through 2013-2014) and National Collegiate Athletic Association Women's Field Hockey (2004-2005 Through 2013-2014). AB - CONTEXT: : The advent of Web-based sports injury surveillance via programs such as the High School Reporting Information Online system and the National Collegiate Athletic Association Injury Surveillance Program has aided the acquisition of data for girls' and women's field hockey injuries. OBJECTIVE: : To describe the epidemiology of injuries sustained in high school girls' field hockey in the 2008-2009 through 2013-2014 academic years and collegiate women's field hockey in the 2004-2005 through 2013-2014 academic years using Web-based sports injury surveillance. DESIGN: : Descriptive epidemiology study. SETTING: : Online injury surveillance from field hockey teams in high school girls (annual average = 61) and collegiate women (annual average = 14). PATIENTS OR OTHER PARTICIPANTS: : Girls' and women's field hockey players who participated in practices and competitions during the 2008-2009 through 2013-2014 high school academic years and the 2004-2005 through 2013-2014 collegiate academic years. MAIN OUTCOME MEASURE(S): : Athletic trainers collected time-loss (>=24 hours) injury and exposure data. Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (IRRs) with 95% confidence intervals (CIs), and injury proportions by body site and diagnosis were calculated. RESULTS: : The High School Reporting Information Online system documented 983 time-loss injuries during 569 551 AEs; the National Collegiate Athletic Association Injury Surveillance Program documented 996 time-loss injuries during 185 984 AEs. The injury rate from 2008 2009 through 2013-2014 was higher in college than in high school (3.25 versus 1.73/1000 AEs; IRR = 1.89; 95% CI = 1.63, 2.18). Most injuries occurred during practices in high school (52.0%) and college (60.7%). Injury rates were higher during competitions than practices in high school (IRR = 2.00; 95% CI = 1.76, 2.26) and college (IRR = 1.96; 95% CI = 1.73, 2.23). At both levels, injuries most commonly occurred to the lower extremity and head/face and resulted in muscle/tendon strains and contusions. However, injury patterns varied between practices and competitions. CONCLUSIONS: : Injury rates and patterns varied across age groups and between practices and competitions, highlighting the need for development of targeted injury-prevention strategies at both levels of play. PMID- 29995463 TI - Calculating Versus Estimating Causal Effects. PMID- 29995461 TI - Getting Back on the Horse: Sport-Specific Return to Play in Rodeo Athletes After Concussion Injury. AB - CONTEXT: Despite a high incidence of injury in their sport, rodeo athletes have been underrepresented in the concussion literature. No standard postconcussion protocols are available across rodeo organizations for evaluating fitness to return to competition. OBJECTIVE: To review the literature on concussion in rodeo, examine published guidelines, and offer an active return-to-play (RTP) protocol specific to rodeo athletes. BACKGROUND: Unique barriers complicate the management and treatment of rodeo athletes with concussion, such as the solo nature of the sport, lack of consistent access to health care professionals, and athletic conditioning that often occurs outside of a traditional gym-based exercise regimen. In addition, the rodeo culture encourages a swift return to competition after injury. DESCRIPTION: Best practices for managing concussion are removal from activity, proper diagnostic evaluation, and gradual return to sport, with medical clearance when an athlete is symptom free and able to tolerate cognitive and physical exertion. An RTP protocol for rodeo events needs to capture the distinctive features and challenges of the sport and its athletes. CLINICAL ADVANTAGES: Rodeo athletes would benefit from an RTP protocol that can be initiated by an athletic trainer or medical professional in the acute stage of injury, integrates exercise into activities of daily living, and is appropriate for athletes who travel frequently. At the organizational sport level, a formal RTP protocol could enhance consistency in medical-clearance techniques among providers responsible for the return to sport of rodeo athletes. CONCLUSIONS: Rodeo athletes represent a sport population that has received little formal guidance on the diagnosis, management, and RTP after concussion. A sport-specific RTP protocol sensitive to the particular culture of these athletes is an important first step in protecting the health and safety of rodeo athletes after a concussive injury. PMID- 29995462 TI - Balance- and Strength-Training Protocols to Improve Chronic Ankle Instability Deficits, Part II: Assessing Patient-Reported Outcome Measures. AB - CONTEXT: Assessing global, regional, and fear-of-reinjury outcomes in individuals with chronic ankle instability (CAI) is critical to understanding the effectiveness of clinical interventions. OBJECTIVE: To determine the improvement of patient-reported outcomes after balance- and strength-training and control protocols among participants with CAI. DESIGN: Randomized controlled clinical trial. SETTING: Athletic training research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-nine volunteers with CAI who scored 11 or greater on the Identification of Functional Ankle Instability questionnaire were randomly assigned to 1 of 3 groups: balance-training protocol (7 males, 6 females; age = 23.5 +/- 6.5 years, height = 175.0 +/- 8.5 cm, mass = 72.8 +/- 10.9 kg), strength training protocol (8 males, 5 females; age = 24.6 +/- 7.7 years, height = 173.2 +/- 9.0 cm, mass = 76.0 +/- 16.2 kg), or control (6 males, 7 females; age = 24.8 +/- 9.0 years, height = 175.5 +/- 8.4 cm, mass = 79.1 +/- 16.8 kg). INTERVENTION(S): Each group met for 20 minutes, 3 times each week, for 6 weeks. The control group completed a mild to moderately strenuous bicycle workout. MAIN OUTCOME MEASURE(S): Global patient-reported outcomes, regional ankle function, and perceived instability were measured using the Disablement in the Physically Active Scale, the Fear-Avoidance Beliefs Questionnaire, the Foot and Ankle Ability Measure, and a visual analog scale for perceived instability. Participants completed the questionnaires at pretest and 6 weeks posttest. A multivariate repeated-measures analysis of variance with follow-up univariate analysis was conducted. The alpha level was set a priori at .05. RESULTS: No time-by-group interaction was found ( P = .78, eta2 = 0.09). However, we observed a main effect for time ( P = .001, eta2 = 0.49). Follow-up univariate analyses revealed differences between the pretest and posttest for the Disablement in the Physically Active Scale ( P = .02, eta2 = 0.15), Fear-Avoidance Beliefs Questionnaire ( P = .001, eta2 = 0.27), Foot and Ankle Ability Measure-Activities of Daily Living subscale ( P = .003, eta2 = 0.22), Foot and Ankle Ability Measure Sport subscale ( P = .001, eta2 = 0.36), and visual analog scale ( P = .008, eta2 = 0.18). CONCLUSIONS: Statistically, after the 6-week intervention, all groups improved in global and regional health-related quality of life. Clinicians should compare patient-reported outcomes with clinical measures to have a better understanding of progression during rehabilitation. PMID- 29995465 TI - Social Impact Bonds: A Promising Public-Private Partnership Model for Public Health. PMID- 29995464 TI - A Clarification on Causal Questions: We Ask Them More Often Than We Realize. PMID- 29995466 TI - Katz et al. Respond. PMID- 29995467 TI - Short-Term Adverse Effects of Austerity Policies on Mortality Rates: What Could Their Real Magnitude Be? PMID- 29995468 TI - The US Virgin Islands: The Ninth Ward of 2017? PMID- 29995469 TI - Tuckson Responds. PMID- 29995470 TI - Repositioning Social Work Into Population Health. PMID- 29995471 TI - Bachman Responds. PMID- 29995472 TI - Noam Chomsky (1928-), Fierce and Formidable Critic of the Vietnam War. PMID- 29995473 TI - Making the Invisible Causes of Population Health Visible: A Public Health of Consequence, August 2018. PMID- 29995474 TI - Austerity Policies and Mortality in Spain After the Financial Crisis of 2008. AB - OBJECTIVES: To analyze mortality in Spain and the United States before and after these countries implemented divergent policies in response to the financial crisis of 2008. METHODS: We examined mortality statistics in both countries in the years 2000 to 2015. Spain started austerity policies in 2010. We compared differences in mortality ratios, on the basis of trends and effect size analysis. RESULTS: During 2000 to 2010, overall mortality rates (r = 0.98; P < .001; Cohen's d = -0.228) decreased in both countries. In 2011, this trend changed abruptly in Spain, where observed mortality surpassed expected mortality by 29% in 2011 and by 41% in 2015. By contrast, observed mortality surpassed expected mortality in the United States by only 8% in 2015. As the mortality statistics diverged, the effect size greatly increased (d = 7.531). During this 5-year period, there were 505 559 more deaths in Spain than the expected number, while in the United States the difference was 431 501 more deaths despite the 7-fold larger population in the United States compared with Spain. CONCLUSIONS: The marked excess mortality in 2011 to 2015 in Spain is attributable to austerity policies. PMID- 29995475 TI - Subsidized Housing and Health: Time for a Multidisciplinary Approach. PMID- 29995476 TI - Venturing Beyond the Binary Sexual Health Interview. PMID- 29995477 TI - The Responsibility of Intellectuals. PMID- 29995480 TI - Nonsuicidal Self-Injury: A Neglected Public Health Problem Among Adolescents. PMID- 29995481 TI - Baltimore Citywide Engagement of Emergency Departments to Combat the Opioid Epidemic. PMID- 29995483 TI - AJPH Global News. PMID- 29995482 TI - Could Social Bots Pose a Threat to Public Health? PMID- 29995484 TI - Extending the Sunshine Act From Physicians to Patient Advocacy Organizations. PMID- 29995485 TI - The Story Behind the Sharp Decline in US Tanning Bed Rates. PMID- 29995486 TI - Preventing Risk for "Deaths of Despair" Among American Indian Youths: Unanswered Questions for Future Research. PMID- 29995487 TI - Substance Use Among Lesbian, Gay, Bisexual, and Questioning Adolescents in the United States, 2015. AB - OBJECTIVES: To provide current national estimates of lesbian, gay, bisexual, and questioning (LGBQ) adolescents' (grades 9-12) substance use risks. METHODS: The 2015 national Youth Risk Behavior Survey included questions for 19 substance use outcomes covering 15 substances. LGBQ adolescents' substance use was described and their risk relative to heterosexual adolescents was estimated after controlling for sociodemographic confounders. RESULTS: In controlled analyses, we found that LGBQ adolescents were 1.12 (95% confidence interval [CI] = 1.06, 1.19) times as likely as heterosexual adolescents to report any lifetime and 1.27 (95% CI = 1.14, 1.41) times as likely to report past 30-day substance use. LGBQ adolescents were at significantly greater risk for all but 1 studied substance, including alcohol, cigarettes, cigars, cocaine, ecstasy, electronic vapor usage ("vaping"), hallucinogens, heroin, inhalants, marijuana, methamphetamine, prescription drugs (without physician direction), steroids, and synthetic marijuana. CONCLUSIONS: LGBQ adolescents are at substantially greater risk for substance use. Public Health Implications. Policymakers should invest in prevention and early intervention resources to address substance use risks among LGBQ adolescents. PMID- 29995488 TI - Long-Acting Reversible Contraception: A Silver Bullet Solution for Unintended Pregnancy? PMID- 29995489 TI - Identifying and Ameliorating Lesbian, Gay, Bisexual, and Transgender Health Disparities in the Criminal Justice System. PMID- 29995490 TI - History Lesson: Vaccine Trials in the Classroom. PMID- 29995491 TI - Wanted: Less Prevalence of and More Data on Early Childhood Caries. PMID- 29995492 TI - Racial Inequities in Drug Arrests: Treatment in Lieu of and After Incarceration. PMID- 29995493 TI - News From The Nation's Health. PMID- 29995494 TI - Construction of a Preoperative Radiologic-Risk Signature for Predicting the Pathologic Status of Prostate Cancer at Radical Prostatectomy. AB - OBJECTIVE: We developed a radiologic-risk signature (RRS) that serves as a surrogate for the pathologic status of prostate cancer (PCA) and investigated its ability to predict disease-free survival. MATERIALS AND METHODS: This study included 631 patients with localized PCA who underwent prostatic multiparametric MRI before prostatectomy. Images from 426 training datasets were structurally interpreted and correlated to a postoperative Memorial Sloan Kettering Cancer Center (MSKCC) score by a stepwise partial least-squares regression analysis. The developed RRS, compared with a preoperative Kattan nomogram, was validated in a cohort of 205 patients with 3-year follow-up data after prostatectomy in terms of calibration, discrimination, and clinical usefulness. Statistical tests were performed by AUC analysis, Kaplan-Meier test, and decision curve analysis. RESULTS: The RRS, which consists of 12 preoperative variables, faithfully represented postoperative MSKCC score in 426 training (r = 0.75; p < 0.001) and 205 validation (r = 0.79; p < 0.001) datasets. For patients in the validation group, RRS showed better discriminative power (C-index, 0.859; 95% CI, 0.779 0.939; p = 0.013) than did the preoperative Kattan nomogram (C-index, 0.780; 95% CI, 0.701-0.859) for predicting 3-year biochemical recurrence and showed higher net benefits for a probability threshold of greater than 10%. CONCLUSION: Characteristics of RRS can faithfully represent the tumor pathologic status and predict accurately the disease postoperative outcome before prostatectomy. PMID- 29995495 TI - ADC Metrics From Multiparametric MRI: Histologic Downgrading of Gleason Score 9 or 10 Prostate Cancers Diagnosed at Nontargeted Transrectal Ultrasound-Guided Biopsy. AB - OBJECTIVE: The purpose of this study was to evaluate quantitative apparent diffusion coefficient (ADC) metrics for the downgrading of Gleason score (GS) 9 or 10 prostate cancer (PCa) diagnosed by means of nontargeted transrectal ultrasound-guided biopsy. MATERIALS AND METHODS: Between 2012 and 2015, 30 men with a diagnosis of GS 9 or 10 PCa at nontargeted transrectal ultrasound-guided biopsy underwent 3-T multiparametric MRI before radical prostatectomy (RP). Two radiologists blinded to the histopathologic results independently assessed multiparametric MR images using Prostate Imaging Reporting and Data System (PI RADS) version 2. Whole-lesion ADC mean, centile, and texture features were extracted from coregistered ADC and RP maps by a third blinded radiologist. Comparisons were performed by chi-square, multivariable logistic regression, and ROC analysis. RESULTS: Tumors were downgraded to intermediate risk (GS 4 + 3 [n = 7] and GS 3 + 4 [n = 2]) PCa in 30.0% (9/30) of men after RP. There were no statistically significant differences between groups with respect to age (p = 0.028), prostate-specific antigen level (p = 0.018), or clinical stage (p = 0.021). PI-RADS version 2 scores did not differ between groups (p = 0.035, p = 0.091) with moderate agreement (kappa = 0.48). There were no differences in mean or centile ADC (p = 0.269-0.634) between the two groups. ADC entropy was significantly lower in downgraded tumors (5.542 +/- 0.721 [SD] vs 8.089 +/- 1.237, p < 0.001) with no difference in kurtosis or skewness (p = 0.133, p = 0.296). The ROC AUC for the diagnosis of downgrading was 0.93 (95% CI, 0.84-1.00) with sensitivity of 85.7% and specificity of 88.9% when entropy was less than 6.31. CONCLUSION: ADC entropy was significantly lower in GS 9 and 10 tumors diagnosed by means of nontargeted transrectal ultrasound-guided biopsy that were eventually downgraded to intermediate risk (GS 7) after RP. ADC texture analysis may be useful for further risk stratification of PCa diagnosed at biopsy. PMID- 29995496 TI - Hallmarks of Cancer in the Reading Room: A Guide for Radiologists. AB - OBJECTIVE: The hallmarks of cancer are mechanisms that cells develop to undergo malignant transformation. The targeting of these hallmarks by newer cancer therapies results in new mechanisms of response, toxicity, and resistance. The purpose of this article is to review these hallmarks, their associated targeted therapies, imaging features of responses, and toxicities. CONCLUSION: Ten hallmarks, among them proliferative signaling, angiogenesis, immune response, and genome instability, are reviewed. Molecular targeted therapies, including antiangiogenic factors and immune checkpoint inhibitors, target these hallmarks. PMID- 29995497 TI - MRI Features Predictive of Invasive Placenta With Extrauterine Spread in High Risk Gravid Patients: A Prospective Evaluation. AB - OBJECTIVE: The objective of our study was to evaluate MRI diagnostic ability in predicting invasive placenta with extrauterine spread in high-risk gravid patients. SUBJECTS AND METHODS: Between March 2016 and June 2017, 49 patients (mean age, 35.7 years; mean gestational age, 32.5 weeks) with sonographically confirmed placenta previa underwent dedicated MRI. All MRI examinations were reviewed by two experienced radiologists prospectively. Intraoperative and pathologic findings were the standard of reference. Kappa values were calculated to assess the agreement between MRI findings and histologic results as well as interrater reliability. ROC curve analysis was used to test the discriminative ability of MRI features for invasive placenta with extrauterine spread. Stepwise multiple logistic regression analysis was performed to identify any MRI findings predictive of invasive placenta and of bladder and parametrial involvement. RESULTS: MRI exhibited significant overall accuracy (AUC = 0.77, p = 0.006) in identifying invasive placenta with 100% sensitivity and negative predictive values; it was highly specific (100%) in identifying placental extension to both bladder and parametrial tissues. Lumpy tapering of the placental edges, intraplacental dark T2 bands, prominent intraplacental vascularity, and serosal hypervascularity were independently associated with an increased risk for invasive placenta. Serosal hypervascularity and vesicouterine space hypervascularity were independent predictors of bladder invasion; abnormal vascularization within the parametrial fat was significant for parametrial invasion. CONCLUSION: MRI is highly accurate in depicting placental extrauterine spread. The presence of abnormal vessels at the uterine serosa was the most important MRI feature for identifying invasive placenta. An abnormal vascular network within the vesicouterine space or parametrium was the most reliable MRI sign for detecting bladder or parametrial involvement. PMID- 29995498 TI - Prediction of Posthepatectomy Liver Failure: MRI With Hepatocyte-Specific Contrast Agent Versus Indocyanine Green Clearance Test. AB - OBJECTIVE: The objective of our study was to identify whether quantitative measurements from gadoxetic acid-enhanced MRI are useful for predicting posthepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC) compared with and in combination with future remnant liver volume (FRLV) and an indocyanine green (ICG) clearance test. MATERIALS AND METHODS: Preoperative gadoxetic acid-enhanced MR images were retrospectively evaluated in 73 patients who underwent anatomic liver resection for HCC between 2011 and 2013. For quantitative measurement of hepatocyte function, relative liver enhancement (RLE) and remnant hepatocyte uptake index (rHUI) were measured using hepatobiliary phase MR images. FRLV was determined using measurements from preoperative CT scans. Univariate and multivariate analyses of measurements from gadoxetic acid-enhanced MRI, ICG clearance tests, and FRLV for finding predictors of PHLF were performed. To compare the diagnostic performance of predictors, ROC analyses were also performed. RESULTS: Eighteen (25%) of 73 patients met the criteria for PHLF. Univariate analysis revealed that all measurements related to MRI including RLE, rHUI, ICG clearance, and FRLV were significantly associated with PHLF. Multivariate analysis showed that RLE, FRLV, ICG-plasma disappearance rate (ICG-PDR), rHUI, and rHUI corrected for body weight (rHUI-BW) were independent predictors of PHLF (p = 0.011, p = 0.034, p = 0.003, p < 0.001, and p = 0.001, respectively). In ROC analyses, AUCs of rHUI and rHUI-BW were larger than those of other independent predictors; the differences were statistically significant (for rHUI-BW vs RLE, ICG-PDR, and FRLV, p = 0.016, 0.007, and 0.046, respectively; for rHUI vs RLE and ICG-PDR, p = 0.045 and 0.016, respectively). CONCLUSION: Measurements from gadoxetic acid-enhanced MRI predicted PHLF better than the ICG clearance test in patients with HCC who underwent hepatectomy. PMID- 29995499 TI - MRI Findings After MRI-Guided Focal Laser Ablation of Prostate Cancer. AB - OBJECTIVE: The purpose of this study is to describe the quantitative and qualitative findings of multiparametric prostate MRI performed after MRI-guided focal laser ablation of prostate cancer. MATERIALS AND METHODS: A total of 27 consenting patients met the study inclusion criteria, which included but were not limited to the presence of clinical category T1c-T2a prostate cancer with a Gleason score of 7 or less, having undergone prostate biopsy before and after focal laser ablation, and having undergone MRI before ablation, immediately after ablation, and 3 and 12 months after ablation. Signal changes were evaluated both qualitatively and quantitatively and were then correlated with the results of subsequent biopsy performed at 3 and 12 months after ablation. RESULTS: MRI performed immediately after ablation revealed a hypovascular defect in the ablation zone, with patchy or bandlike decreased T2 signal most commonly noted at 3 months (in 66.7% of ablated lesions) and T2 scarring observed in most lesions (66.7%) at 12 months. Patchy or bandlike decreased apparent diffusion coefficient signal and scarlike changes were most prevalent at 3 months after ablation (50.0% of lesions), and these features remained the most commonly observed findings at 12 months after ablation (27.8% of lesions). At 12 months after ablation, 10 patients were found to have recurrent tumor, with three patients found to have persistent cancer when biopsy was performed at the ablation site. All postablation biopsy cases with positive results showed suspicious T2 and apparent diffusion coefficient characteristics, which were considered to be a well-defined nodular intermediate signal on both of these sequences. Two of the patients for whom positive biopsy findings were noted had focal enhancement of the ablation zone. A significant reduction in the forward volume transfer constant after ablation was found at the ablation site on follow-up examination. CONCLUSION: Multiparametric MRI can reveal postablation changes in the prostate and can be a valuable tool for monitoring patients who have undergone MRI-guided focal laser ablation. PMID- 29995500 TI - Liver MR Elastography at 3 T: Agreement Across Pulse Sequences and Effect of Liver R2* on Image Quality. AB - OBJECTIVE: The objectives of our study were to compare MR elastography (MRE) based on gradient-recalled echo (GRE) imaging with spin-echo echo-planar imaging (SEEPI) and rapid fractional (RF)-GRE MRE sequences at 3 T in terms of liver stiffness (LS) and image quality and to evaluate the effect of liver R2* on image quality. MATERIALS AND METHODS: Eighty-one patients underwent 3-T liver MRE with GRE, SE-EPI, and RF-GRE sequences performed in variable order in this study. LS and ROI areas on the LS 95% confidence maps were compared among the three sequences. The relationship between liver R2* and ROI area was investigated. RESULTS: There was no significant difference in mean LS among the three sequences (p = 0.49). Mean ROI area was significantly larger for RF-GRE (18,213 +/- 9292 [SD] mm2) than for GRE (13,196 +/- 8149 mm2) and SE-EPI (12,896 +/- 8656 mm2) (p < 0.0001). Liver R2* was significantly higher among patients with one or more failed sequences (mean +/- SD, 116 +/- 76 s-1) than for patients with no failed sequences (59 +/- 26 s-1) (p = 0.001). Technical failure rates were 10% (8/81), 4% (3/81), and 2% (2/81) for GRE, SE-EPI, and RF-GRE, respectively. Among patients with iron overload (R2* >= 100 s-1), there was a trend toward larger ROI area for SE-EPI (p = 0.09). CONCLUSION: SE-EPI-and RF-GRE-based MRE sequences provide equivalent measures of LS compared with GRE-based MRE, and both have lower technical failure rates. The RF-GRE sequence yielded the largest measurable area of LS. Among patients with iron overload, there was a trend toward larger measurable area of LS for the SE-EPI sequence. PMID- 29995501 TI - Prevalence of Solid Tumors in Incidentally Detected Homogeneous Renal Masses Measuring > 20 HU on Portal Venous Phase CT. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of solid tumors in incidental homogeneous renal masses with attenuation greater than 20 HU on portal venous phase CT images. MATERIALS AND METHODS: In this retrospective study, the records of patients with incidental indeterminate (> 20 HU) homogeneous renal masses on portal venous phase CT scans from September 11, 2007, through March 18, 2017, were identified. Adult patients were included if they had undergone follow-up ultrasound, contrast-enhanced MRI, multiphase contrast enhanced CT, or pathologic analysis alone to confirm the solid or cystic nature of the lesion. A single ROI was placed in the center of the mass, and lesions were characterized as >= 50% exophytic, < 50% exophytic, or entirely surrounded by renal parenchyma. RESULTS: There were 322 masses in 267 patients. The mean lesion size was 16.6 (SD, 9.8) mm (range, 9-45 mm). Lesions were >= 50% exophytic in 92 cases, < 50% exophytic in 111 cases, and completely surrounded by renal parenchyma in 119 cases. All nonsolid lesions were characterized as benign cysts. The numbers of solid lesions per total number of lesions in each attenuation group were: 20-30 HU (0/140), 30-40 HU (0/67), 40-50 HU (1/38), 50-60 HU (3/24), 60-70 HU (5/17), 70-80 HU (5/17), and > 80 HU (8/19). All 207 lesions in the 20- to 40-HU range were benign cysts with no solid lesions (0%; 95% CI, 0.0-1.4%). CONCLUSION: Small homogeneous renal masses measuring 20-40 HU on portal venous phase CT images are highly likely to be benign cysts. PMID- 29995502 TI - Diagnostic Accuracy of Real-Time Sonography in Differentiating Diffuse Thyroid Disease From Normal Thyroid Parenchyma: A Multicenter Study. AB - OBJECTIVE: The purpose of this multicenter study was to assess the diagnostic accuracy of real-time sonography (US) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma among radiologists blinded to patients' clinical, serologic, and imaging history and to determine the differences in diagnostic accuracy among radiologists from different institutions. MATERIALS AND METHODS: From January to March 2017, 214 patients underwent preoperative thyroid US and subsequent thyroid surgery at four participating institutions. Real-time US was performed at each institution by an attending radiologist, who classified US diagnoses into one of the following four categories based on US findings: no DTD, indeterminate, suspicious for DTD, and DTD. The outcomes of US diagnoses were compared with histopathologic results to determine the diagnostic accuracy of real-time US at each institution. RESULTS: Histopathologic results included normal thyroid parenchyma (n = 143), Hashimoto thyroiditis (n = 29), non Hashimoto lymphocytic thyroiditis (n = 37), and diffuse hyperplasia (n = 5). Normal thyroid parenchyma and DTD exhibited statistically significant differences in echogenicity, echotexture, size, glandular margin, vascularity of thyroid, and US classification. There was positive correlation between US classification and histopathologic results at all institutions for detecting DTD. The highest diagnostic indexes were obtained when the cutoff criterion was suspicious for DTD. There was favorable diagnostic accuracy, with statistically significant differences, at all institutions for the diagnosis of DTD. CONCLUSION: Real-time US can be helpful for differentiating DTD from normal thyroid parenchyma. PMID- 29995503 TI - Experiencing compassionate care in practice: a travel scholarship. AB - Alison Bunce, Director of Care at Ardgowan Hospice, Greenock, and Programme Lead for Compassionate Inverclyde ( Alison.bunce@ardhosp.co.uk ), describes her Florence Nightingale Foundation Travel Scholarship. PMID- 29995504 TI - Borrowing against the future: the response to the public consultation on the NHS bursary. AB - This paper discusses the UK Government's public consultation into the NHS bursary and the response from the Nursing and Midwifery Council. A public consultation stipulated that the current arrangements for funding, by the State, were not to be considered for discussion. Instead, the consultation only appraised views that would lead to the successful introduction of student finance loans for NHS professional education. Testimonies from nurses, midwives and nursing students expressed concern that the new funding arrangements were unaffordable, dis incentivising and biased towards the marketisation of student loans in the UK, yet the changes went ahead. The changes to NHS bursary funding resulted from the UK Government's desire for growth in student numbers (and ostensibly not growth in financial figures), and the fact that nursing (and other healthcare) students will become more fiscally indebted, despite society's moral obligation to them. PMID- 29995505 TI - Can a reset of digital literacy standards improve nursing practice? AB - Duncan Hamilton, final year adult nursing student at the University of Surrey, reflects on the questions around technology proficiency for future nurses. PMID- 29995506 TI - Prevalence of self-reported side effects in neuroendocrine tumour patients prescribed somatostatin analogues. AB - Somatostatin analogues (SSA) are a common treatment for some forms of neuroendocrine tumours (NETs). Patients report a variety of side effects after starting these drugs, so in most cases they require a lot of nutritional input. The authors used an online survey to invite responses from patients worldwide to determine the extent of reported side effects. Patients were asked which SSA they were taking and how they rated the severity of their side effects. They were provided with a list of 11 options to choose from, but not given any guidance or a definition of terms. The most commonly reported side effect was constipation (85%), with 8.6% of these respondents rating its severity as 10/10. The survey found that many self-reported side effects from the use of SSAs were experienced more frequently than previous clinical studies or the patient information leaflets reported. As this was an online survey, so the findings are limited in that first, this was a self-selected sample of patients and second, patients were able to respond more than once. PMID- 29995507 TI - Take pride in the NHS at 70. PMID- 29995508 TI - Treading carefully. PMID- 29995509 TI - Celebrating the contribution of nurses to policy and practice development. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses the contribution that nurses have made to policy and practice since the inception of the NHS 70 years ago. PMID- 29995510 TI - The importance of relationships in international collaborations. AB - Elizabeth Rosser, Acting Executive Dean, Bournemouth University, considers the human aspects of global partnerships and the sense of belonging that comes with actively engaging with others in the profession. PMID- 29995511 TI - Equality and justice are at the core of our NHS, so let's keep it that way. AB - Since its inception in 1948, the NHS has provided universal health care to millions but, suggests nurse and Labour MP for Lincoln Karen Lee, underfunding and privatisation by stealth are threatening its very existence. PMID- 29995512 TI - Birthday funding boost puts the focus on patients, research and world-class staff. AB - Excellent heathcare provision requires significant sums of money, says nurse and Conservative MP for Lewes Maria Caulfield, but she stresses that free care for all will remain the guiding principle of the NHS. PMID- 29995513 TI - Understanding alcohol-related liver disease patients' illness beliefs and views about their medicine. AB - BACKGROUND: people with alcohol-related liver disease require complex treatment plans that often include the need for medication for the rest of their lives. Between 30% and 50% of all patients do not take their treatment as prescribed, leading to a significantly increased risk of morbidity and mortality. AIM: to consider the factors which influence beliefs held by patients with alcohol related liver disease about their medication to provide an evidence base to support interventions to reduce medication non-adherence. METHOD: an observational cross-sectional patient survey. RESULTS: statistically significant associations were found between positive attitudes towards medication and the illness representation dimensions of 'illness identity' and 'illness comprehension'. CONCLUSIONS: medication adherence in patients with alcohol related liver disease is likely to be improved by an intervention that strives to improve the patient's understanding of their illness condition and their perception of their illness symptoms. PMID- 29995514 TI - Intramuscular injection CLIMAT pathway: a clinical practice guideline. AB - The intramuscular (IM) injection has been part of nursing practice since the 1960s. Over the past 60 years, the practice of aspiration during IM injection has been controversial and understudied. In 2016, a study by Thomas et al identified that blood aspiration does occur during injection. This article introduces a clinical practice guideline for safe and effective aspiration during IM injection, as a follow-up to the findings of that study. The proposed guideline acknowledges the correct practice of aspiration and identifies considerations that may make aspiration unnecessary. These practices and considerations are presented to the reader using a visual clinical pathway and a narrative clinical practice guideline. PMID- 29995515 TI - The Florence Nightingale Foundation: developing nursing's leaders. AB - Ursula Ward, Chief Executive, Florence Nightingale Foundation, chiefexec@florence nightingale-foundation.org.uk , describes the role of the foundation and its plans for the future. PMID- 29995516 TI - The Gosport inquiry and the principle of double effect. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, restates the requirements of the principle of double effect that seeks to ensure that patients in intractable pain receive the analgesia they require to manage it. PMID- 29995517 TI - Responsibility, research and reasoning: nursing through 70 years of the NHS. AB - B Gail Thomas, Emeritus Professor, and Elizabeth Rosser, Professor and Acting Executive Dean, of Bournemouth University, chart the evolution of nurses into modern autonomous professionals. erosser@bournemouth.ac.uk. PMID- 29995518 TI - The changing face of nursing: from the pioneers to the future of leadership. AB - As we celebrate the 70th birthday of the NHS, Clare Price-Dowd reflects on the pioneers of nursing and how leadership in the NHS, and in nursing, has changed over time, and shares some thoughts about the future. PMID- 29995519 TI - The robot nurses are coming to a workplace near you. AB - As robot technology rapidly encroaches into most areas of our lives, second-year Kingston and St George's universities nursing student Jack Sherry remains optimistic that he will still have a job, jsherry38@gmail.com. PMID- 29995520 TI - The National Early Warning Score: when the numbers don't add up. PMID- 29995521 TI - Help in times of trouble: supporting nurses facing hardship. AB - Paul Steiner, Communications Manager, Cavell Nurses' Trust ( PaulS@cavellnursestrust.org ), reflects on the vital work of the charity, which provides support to nurses facing financial difficulties. PMID- 29995522 TI - Surviving the challenges: the NHS at 70. AB - Sam Foster, Chief Nurse, Oxford University Hospitals, reflects on the reasons for the NHS's continued role in British life after 70 years, despite the many difficulties it has faced. PMID- 29995523 TI - The NHS and the law. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses clinical negligence trends in the NHS, from its early years to the current key concerns. PMID- 29995524 TI - The way we were.... AB - BJN editorial board member Alan Glasper has been collecting historic photos of NHS nurses for a number of years, which he shares here to celebrate NHS70. PMID- 29995525 TI - Privacy Concerns and Self-Disclosure in Private and Public Uses of Social Media. AB - The study contributes to the ongoing debate about the "privacy paradox" in the context of using social media. The presence of a privacy paradox is often declared if there is no relationship between users' information privacy concerns and their online self-disclosure. However, prior research has produced conflicting results. The novel contribution of this study is that we consider public and private self-disclosure separately. The data came from a cross national survey of 1,500 Canadians. For the purposes of the study, we only examined the subset of 545 people who had at least one public account and one private account. Going beyond a single view of self-disclosure, we captured five dimensions of self-disclosure: Amount, Depth, Polarity, Accuracy, and Intent; and two aspects of privacy concerns: concerns about organizational and social threats. To examine the collected data, we used Partial Least Squares Structural Equation Modeling. Our research does not support the presence of a privacy paradox as we found a relationship between privacy concerns from organizational and social threats and most of the dimensions of self-disclosure (even if the relationship was weak). There was no difference between patterns of self disclosure on private versus public accounts. Different privacy concerns may trigger different privacy protection responses and, thus, may interact with self disclosure differently. Concerns about organizational threats increase awareness and accuracy while reducing amount and depth, while concerns about social threats reduce accuracy and awareness while increasing amount and depth. PMID- 29995526 TI - Positive Side of Social Comparison on Social Network Sites: How Envy Can Drive Inspiration on Instagram. AB - A growing body of research finds social network sites (SNS) such as Instagram to facilitate social comparison and the emotional experience of envy in everyday life, with harmful effects for users' well-being. Yet, previous research has exclusively focused on the negative side of social comparison and envy on SNS. Thereby, it has neglected two important aspects: (a) comparison processes can also elicit a beneficial emotional reaction to other users' online self presentations (i.e., benign envy) and, thus, (b) comparisons can be motivating, with positive outcomes for well-being. The present study aims at closing this research gap by investigating how social comparisons and envy on SNS are related to inspiration, a complex motivational state. Due to its specific characteristics of a creative and aesthetic visual culture, we focus our investigation on Instagram. A structural equation modeling mediation analysis with data from N = 385 Instagram users reveals that the intensity of social comparisons on Instagram was positively related to inspiration and that this relationship was fully mediated by benign envy. Furthermore, inspiration on Instagram was related to increased positive affect. Results of this study underline that to understand the effects of SNS on well-being, we also need to consider the positive motivational side of social comparison and envy. PMID- 29995528 TI - Alcoholposts on Social Networking Sites: The Alcoholpost-Typology. AB - Young people frequently display alcohol-related posts ("alcoholposts") on social networking sites such as Facebook and Instagram. Although evidence exists that such posts may be linked with increases in alcohol consumption, hardly any studies have focused on the content of such posts. This study addresses this gap by applying and extending the alcoholpost-typology previously proposed by Hendriks, Gebhardt, and van den Putte. A content analysis assessed the extent to which alcoholposts were displayed on Facebook and/or Instagram profiles of young participants (12-30 years; N = 192), and which type of alcoholpost these posts most strongly resembled. Moderate alcoholposts (e.g., in which alcohol was in the background) were most often posted. At times, textual alcoholposts and commercial alcoholposts were also displayed; however, extreme posts (e.g., about drunk people or drinking-games) were almost nonexistent. These findings confirm the previous results by Hendriks et al. that moderate posts are more frequently posted than extreme posts. This could imply that positive associations with alcohol consumption are more visible on social media than negative associations, potentially leading to an underestimation of alcohol-related risks. PMID- 29995529 TI - PHENOSELF: Self as a Phenomenon. PMID- 29995527 TI - Exploring the Effect of Sharing Common Facebook Friends on the Sexual Risk Behaviors of Tinder Users. AB - An increasing number of young adults are using online dating sites and mobile apps. The "common connections" feature on Tinder displays mutual Facebook friends between users and might serve as an unintentional validation of a user's character. This study investigates condom use differences between partners met via mobile dating apps or in-person; and if the "common connections" feature affects the perceived sexual risk Tinder users have toward partners met online. College students who met a partner online or in-person in the past year were recruited from a large metropolitan university to complete an online survey. Participants answered questions about sexual risk behavior, condom use, Tinder use, and the effect "common connections" could have on sexual risk behaviors. The likelihood of condomless vaginal sex was no different if participants met their partner through an app or in-person. Among a subset of participants who reported using Tinder, having "common connections" with a potential date decreased the likelihood that they would talk to their date about HIV (p = 0.004) or STI testing (p = 0.001). The "common connections" feature on Tinder might influence sexual decision-making because users are able to evaluate potential dates based on their social network. Our findings suggest that Tinder users may (1) perceive partners with whom they share "common connections" as familiar or "safe," which may give users a false sense of security about the sexual health risks that a potential date may pose or (2) be hesitant to discuss sexual health matters with partners who are within their sexual network due to fear of potential gossip. Both lines of thought may reduce safer sex behaviors among sex partners who meet on Tinder. PMID- 29995530 TI - Passive and Active Social Media Use and Depressive Symptoms Among United States Adults. AB - Social media allows users to explore self-identity and express emotions or thoughts. Research looking into the association between social media use (SMU) and mental health outcomes, such as anxiety or depressive symptoms, have produced mixed findings. These contradictions may best be addressed by examining different patterns of SMU as they relate to depressive symptomatology. We sought to assess the independent associations between active versus passive SMU and depressive symptoms. For this, we conducted an online survey of adults 18-49 of age. Depressive symptoms were measured using the Patient-Reported Outcomes Measurement Information System brief depression scale. We measured active and passive SMU with previously developed items. Factor analysis was used to explore the underlying factor structure. Then, we used ordered logistic regression to assess associations between both passive and active SMU and depressive symptoms while controlling for sociodemographic covariates. Complete data were received from 702 participants. Active and passive SMU items loaded on separate factors. In multivariable analyses that controlled for all covariates, each one-point increase in passive SMU was associated with a 33 percent increase in depressive symptoms (adjusted odds ratio [AOR] = 1.33, 95 percent confidence interval [CI] = 1.17-1.51). However, in the same multivariable model, each one-point increase in active SMU was associated with a 15 percent decrease in depressive symptoms (AOR = 0.85, 95 percent CI = 0.75-0.96). To inform interventions, future research should determine directionality of these associations and investigate related factors. PMID- 29995532 TI - Has the Internet Killed Privacy, or Has Our Definition Simply Changed? PMID- 29995531 TI - Facebook Addiction Disorder in Germany. AB - This study explored the Facebook addiction disorder (FAD) in Germany. Of the 520 participants, 6.2 percent reached the critical polythetic cutoff score and 2.5 percent reached the critical monothetic cutoff score. FAD was significantly positively related to Facebook use frequency, the personality trait narcissism, as well as depression and anxiety symptoms, but also to subjective happiness. Its association with resilience was significantly negative. Furthermore, Facebook use frequency partly mediated the positive relationship between narcissism and FAD. Current results provide a first overview of FAD in Germany. They demonstrate that FAD is not only the consequence of excessive Facebook use. The positive relationship between FAD and happiness contributes to the understanding of the mechanisms that are involved in the development and maintenance of FAD, and partly explains earlier inconsistencies. Practical applications for future studies and limitations of present results are discussed. PMID- 29995533 TI - Internet Filtering and Adolescent Exposure to Online Sexual Material. AB - Early adolescents are spending an increasing amount of time online, and a significant share of caregivers now use Internet filtering tools to shield this population from online sexual material. Despite wide use, the efficacy of filters is poorly understood. In this article, we present two studies: one exploratory analysis of secondary data collected in the European Union (n = 13,176), and one preregistered study focused on British adolescents and caregivers (n = 1,004) to rigorously evaluate their utility. In both studies, caregivers were asked about their use of Internet filtering, and adolescent participants were interviewed about their recent online experiences. Analyses focused on the absolute and relative risks of young people encountering online sexual material and the effectiveness of Internet filters. Results suggested that caregiver's use of Internet filtering had inconsistent and practically insignificant links with young people reports of encountering online sexual material. Our findings underscore the need for randomized controlled trials to determine the extent to which Internet filtering and related technologies support versus thwarts young people online, and if their perceived utility justifies their financial and informational costs. PMID- 29995534 TI - Internet Use for School-Mandated and Self-Initiated Learning: Good, Bad, or Both? AB - Because delivery of school assignments and other learning materials has been migrating to online learning environments, use of the Internet for learning has become obligatory for high school students. However, research on the consequences of Internet learning remains equivocal, with some advocating benefits of such learning and others warning about its potential negative effects. In this study, we approach Internet use for learning from a motivational perspective and argue that such learning can be both positive and negative depending on whether it contributes to harmonious or obsessive Internet passion. We test how two types of Internet use for learning, school mandated and self-initiated, may relate to harmonious and obsessive Internet passion among high schoolers in the United States and Russia. The results indicate that Internet use for school-mandated learning is positively related to both harmonious and obsessive Internet passion, and these results hold in both countries. Internet use for self-initiated learning was also positively related to harmonious Internet passion in both Russia and the United States, but was unrelated to obsessive Internet passion in either country. This research not only augments the nomological network of the Internet passion construct but also informs educators on how to incorporate Internet use into the learning environment in ways that are likely to promote harmonious Internet passion and decrease obsessive Internet passion. PMID- 29995535 TI - Digital Twins: An Emerging Paradigm in Cyberpsychology Research? PMID- 29995536 TI - Low and high energy pelvic injuries. PMID- 29995538 TI - Setting goals of care in acutely unwell patients with chronic neurodisability. PMID- 29995537 TI - How not to miss major spinal pathology in neck pain. PMID- 29995539 TI - Management of oncological emergencies on the acute take. AB - In 2008, recommendations from the National Confidential Enquiry into Patient Outcome and Death identified large variations in the quality and safety of delivery of systemic anti-cancer therapy. In 49% of cases it was felt there was room for improvement and in 27% of cases treatment actually caused or hastened death. Every hospital with an emergency department and/or specialist oncology beds should therefore have a fully functioning acute oncology service to align acute oncology with urgent care. Many patients will still present via the acute take and therefore acute physicians need to be aware of the role of the acute oncology teams and management of oncology emergencies. This article discusses the role of the acute oncology team, management of acute oncology emergencies, namely neutropenic sepsis, metastatic spinal cord compression and superior vena cava obstruction, and important points for acute teams to consider. PMID- 29995541 TI - Children and young people with chronic neurodisability: reviewing quality of care. PMID- 29995540 TI - Managing side effects of cancer immunotherapy for the acute physician. AB - Immunotherapy is a novel type of anti-cancer treatment that works by upregulating the host's immune system to fight against cancer cells. Landmark immunotherapy trials have demonstrated improvements in response rates and survival compared to cytotoxic chemotherapy. Specific immunotherapies known as checkpoint inhibitors are now routinely used in a range of cancers including melanoma, lung, renal and urological cancers. Immunotherapies are associated with immune-related adverse events which are very different to those seen with traditional cytotoxic chemotherapies. This can present a new challenge to oncologists, acute physicians and the wider team of health-care professionals who look after patients receiving immunotherapy. Generally, these side effects are easily managed but some, if untreated, can be subtle and potentially life-threatening. Patients on immunotherapy may present to a wide variety of medical professionals including the emergency department, primary care and general medical admissions units. It is therefore vital that there is increased awareness and education to identify and manage side effects of immunotherapy effectively. PMID- 29995542 TI - Emergency caesarean section in a woman with myasthenia gravis and pre-eclampsia. PMID- 29995543 TI - Medicolegal issues in surgery. PMID- 29995544 TI - Outcome measures of disease activity for rare autoimmune rheumatic diseases. AB - Systemic lupus erythematosus, scleroderma, myositis and Sjogren's syndrome are rare, complex, multi-systemic rheumatic diseases associated with significant morbidity and mortality. Thorough assessments of disease activity are required to guide clinical management and assess response to new therapies in clinical trials. This article reviews the commonly used outcome measures to assess this group of diseases and discusses the limitations of their use. PMID- 29995545 TI - Injured on the front and back: dual vascular pathology from one iatrogenic vascular injury. PMID- 29995546 TI - Inclusive and person-centred leadership: creating a culture that involves everyone. AB - Contemporary leadership theory is based on the dynamic processes that occur between leaders and followers. One such theory is inclusive leadership, which is a person-centred approach that focuses on the empowerment and development of followers. It has roots in other leadership theories such as transformational leadership, but there are distinguishing features. This review discusses these features and presents a case study. Inclusive leadership is also viewed in the context of diversity, organizational culture and innovation. This is then further explored in regards to the diverse workforce of the NHS, with particular focus on the black and minority ethnic groups. PMID- 29995547 TI - 55th ERA-EDTA Congress Copenhagen, Denmark, 24-27 May. PMID- 29995548 TI - When quality improvement with clinical decision support becomes iatrogenesis. PMID- 29995549 TI - Proximal hamstring tendinopathy: pathophysiology, diagnosis and treatment. AB - Proximal hamstring tendinopathy is a chronic degenerative disease associated with progressive morbidity and functional decline. There is a growing incidence of the disease process but diagnosis is commonly delayed as patients present with vague and indolent symptoms, often without a specific precipitating injury. Treatment is also challenging as the existing literature varies in the nomenclature used for proximal hamstring tendinopathy and clinical trials use different management protocols with variable follow-up times. This review explores the existing literature on proximal hamstring tendinopathy and discusses the relevant anatomy, pathology, medical history, differential diagnosis, clinical assessment, diagnostic imaging and treatment of patients with proximal hamstring tendinopathy. This structured approach to proximal hamstring tendinopathy will enable clinicians to better understand the pathophysiology of the disease process, improve referrals to diagnostic imaging, and follow a stepwise approach to medical treatment and surgical referral. PMID- 29995550 TI - Dermatology emergencies: handy hints for the acute medical team. AB - This article will help the general physician recognize and manage acute dermatology presentations. This can be challenging for non-dermatology doctors owing partly to the difficulty in providing an extensive dermatology undergraduate education and the lack of exposure to dermatology patients. The problem is further compounded at many hospital trusts because of the lack of on site dermatology 'on-call'. The general physician must be able to recognize dermatology emergencies in order to provide initial management and maintain appropriate referrals to acute dermatology services. The emergency presentations discussed are erythroderma, life-threatening drug eruptions, cutaneous vasculitis, eczema herpeticum and bullous disorders. PMID- 29995551 TI - William Morton: pioneer of general anaesthesia. PMID- 29995552 TI - The differential diagnosis of intra-abdominal tuberculosis. PMID- 29995553 TI - Multiple finger replantations. PMID- 29995554 TI - Self-directed learning using clinical decision support: costs and outcomes. AB - It is an axiom of research into cost and value in education that the way to deliver low cost education is to save on faculty cost, as this makes up the majority of the costs in most educational programmes. Thus, any savings that can be made to faculty costs will make a significant contribution to reducing overall cost. But this may not be the case with all programmes, or with all methods of learning. In particular, it may not be the case with self-directed learning. The cost of self-directed learning can be divided up into cost categories just like any other form of learning. As such, it will be made up of faculty cost, learner costs, infrastructure and facility costs, content costs and technology costs. However, in postgraduate education, these costs are largely the same as those that account for clinical care, as postgraduate learners learn as they work. To get maximum value from self-directed learning that will support clinical decisions, learners will need to have access to excellent clinical decision support resources that will facilitate self-directed learning. PMID- 29995555 TI - Imaging mitophagy in the fruit fly. AB - Loss-of-function mutations in the genes encoding PRKN/parkin and PINK1 cause autosomal recessive Parkinson disease (PD). Seminal work in Drosophila revealed that loss of park/parkin and Pink1 causes prominent mitochondrial pathology in flight muscle and, to a lesser extent, in dopaminergic neurons. Subsequent studies in cultured mammalian cells discovered a crucial role for PRKN/PARK2 and PINK1 in selective macroautophagic removal of mitochondria (mitophagy). However, direct evidence for the existence of a PINK1-PRKN/PARK2-mediated mitophagy pathway in vivo is still scarce. Recently, we engineered Drosophila that express the mitophagy reporter mt-Keima. We demonstrated that mitophagy occurs in flight muscle cells and dopaminergic neurons in vivo and increases with aging. Moreover, this age-dependent rise depends on park and Pink1. Our data also suggested that some aspects of the mitochondrial phenotype of park- and Pink1-deficient flies are independent of the mitophagy defect, and that park and Pink1 may have multiple functions in the regulation of the integrity of these organelles. Here, we discuss implications of these findings as well as possible future applications of the mt-Keima fly model. PMID- 29995556 TI - The role of SAGA coactivator complex in snRNA transcription. AB - The general snRNA gene transcription apparatus has been extensively studied. However, the role of coactivators in this process is far from being clearly understood. Here, we have demonstrated that the Drosophila SAGA complex interacts with the PBP complex, the key component of the snRNA gene transcription apparatus, and is present at the promoter regions of the snRNA genes transcribed by both the RNA polymerase II and RNA polymerase III (U6 snRNA). We show that SAGA interacts with the Brf1 transcription factor, which is a part of the RNA polymerase III transcription apparatus and is present at promoters of a number of Pol III-transcribed genes. Mutations inactivating several SAGA subunit genes resulted in reduced snRNA levels in adult flies, indicating that SAGA is indeed the transcriptional coactivator for the snRNA genes. The transcription of the Pol II and Pol III-transcribed U genes was reduced by mutations in all tested SAGA complex subunits. Therefore, the transcription of the Pol II and Pol III transcribed U genes was reduced by the mutations in the deubiquitinase module, as well as in the acetyltransferase module of the SAGA, indicating that the whole complex is essential for their transcription. Therefore, the SAGA complex activates snRNA genes suggesting its wide involvement in the regulation of gene transcription, and consequently, in the maintenance of cellular homeostasis. PMID- 29995558 TI - Retrograde trafficking from the vacuole/lysosome membrane. AB - Membrane protein recycling is a fundamental process from yeast to humans. The lysosome (or vacuole in yeast) receives membrane proteins from the secretory, endocytic, and macroautophagy/autophagy pathways. Although some of these membrane proteins appear to be recycled, the molecular mechanisms underlying this retrograde trafficking are poorly understood. Our recent study revealed that the transmembrane autophagy protein Atg27 is recycled from the vacuole membrane using a 2-step recycling process. First, the Snx4 complex recycles Atg27 from the vacuole to the endosome. Then, the retromer complex mediates endosome-to-Golgi retrograde transport. Thus, 2 distinct protein complexes facilitate the sequential retrograde trafficking for Atg27. As far as we know, Atg27 is the first physiological substrate for the vacuole-to-endosome retrograde trafficking pathway. PMID- 29995557 TI - USP14 regulates DNA damage repair by targeting RNF168-dependent ubiquitination. AB - : Recent reports have made important revelations, uncovering direct regulation of DNA damage response (DDR)-associated proteins and chromatin ubiquitination (Ubn) by macroautophagy/autophagy. Here, we report a previously unexplored connection between autophagy and DDR, via a deubiquitnase (DUB), USP14. Loss of autophagy in prostate cancer cells led to unrepaired DNA double-strand breaks (DSBs) as indicated by persistent ionizing radiation (IR)-induced foci (IRIF) formation for gammaH2AFX, and decreased protein levels and IRIF formation for RNF168, an E3 ubiquitin ligase essential for chromatin Ubn and recruitment of critical DDR effector proteins in response to DSBs, including TP53BP1. Consistently, RNF168 associated Ubn signaling and TP53BP1 IRIF formation were reduced in autophagy deficient cells. An activity assay identified several DUBs, including USP14, which showed higher activity in autophagy-deficient cells. Importantly, inhibiting USP14 could overcome DDR defects in autophagy-deficient cells. USP14 IRIF formation and protein stability were increased in autophagy-deficient cells. Co-immunoprecipitation and colocalization of USP14 with MAP1LC3B and the UBA domain of SQSTM1 identified USP14 as a substrate of autophagy and SQSTM1. Additionally, USP14 directly interacted with RNF168, which depended on the MIU1 domain of RNF168. These findings identify USP14 as a novel substrate of autophagy and regulation of RNF168-dependent Ubn and TP53BP1 recruitment by USP14 as a critical link between DDR and autophagy. Given the role of Ubn signaling in non homologous end joining (NHEJ), the major pathway for repair of IR-induced DNA damage, these findings provide unique insights into the link between autophagy, DDR-associated Ubn signaling and NHEJ DNA repair. ABBREVIATIONS: ATG7: autophagy related 7; CQ: chloroquine; DDR: DNA damage response; DUB: deubiquitinase; HR: homologous recombination; IR: ionizing radiation; IRIF: ionizing radiation induced foci; LAMP2: lysosomal associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MIU1: motif interacting with ubiquitin; NHEJ: non homologous end-joining; PCa: prostate cancer; TP53BP1/53BP1: tumor protein p53 binding protein 1; RNF168: ring finger protein 168; SQSTM1/p62 sequestosome 1; gammaH2AFX/gammaH2AX: H2A histone family member X: phosphorylated, UBA: ubiquitin-associated; Ub: ubiquitin; Ubn: ubiquitination; USP14: ubiquitin specific peptidase 14. PMID- 29995560 TI - Prediction and diversity of tracrRNAs from type II CRISPR-Cas systems. AB - Type II CRISPR-Cas9 systems require a small RNA called the trans-activating CRISPR RNA (tracrRNA) in order to function. The prediction of these non-coding RNAs in prokaryotic genomes is challenging because they have dissimilar structures, having short stems (3-6 bp) and non-canonical base-pairs e.g. G-A. Much of the tracrRNA is involved in base-pairing interactions with the CRISPR RNA, or itself, or in RNA-protein interactions with Cas9. Here we develop a new bioinformatic tool to predict tracrRNAs. On an experimentally verified test set the algorithm achieved a high sensitivity and specificity, and a low false discovery rate (FDR) on genome analysis. Analysis of representative RefSeq genomes (5462) detected 275 tracrRNAs from 165 genera. These tracrRNAs could be grouped into 15 clusters which were used to build covariance models. These clusters included Streptococci and Staphylococci tracrRNAs from the CRISPR-Cas9 systems which are currently used for gene editing. Compensating base changes observed in the models were consistent with the experimental structures of single guide RNAs (sgRNAs). Other clusters, for which there are not yet structures available, were predicted to form novel tracrRNA folds. These clusters included a large and divergent tracrRNA set from Bacteroidetes. These computational models contribute to the understanding of CRISPR-Cas biology, and will assist in the design of further engineered CRISPR-Cas9 systems. The tracrRNA prediction software is available through a galaxy web server. PMID- 29995559 TI - Mitochondria-targeted antioxidant SkQ1 suppresses fibrosarcoma and rhabdomyosarcoma tumour cell growth. AB - : Mitochondria are important regulators of tumour growth and progression due to their specific role in cancer metabolism and modulation of apoptotic pathways. In this paper we describe that mitochondria-targeted antioxidant SkQ1 designed as a conjugate of decyl-triphenylphosphonium cation (TPP+) with plastoquinone, suppressed the growth of fibrosarcoma HT1080 and rhabdomyosarcoma RD tumour cells in culture and tumour growth of RD in xenograft nude mouse model. Under the same conditions, no detrimental effect of SkQ1 on cell growth of primary human subcutaneous fibroblasts was observed. The tumour growth suppression was shown to be a result of the antioxidant action of low nanomolar concentrations of SkQ1. We have revealed significant prolongation of mitosis induced by SkQ1 in both tumour cell cultures. Prolonged mitosis and apoptosis could be responsible for growth suppression after SkQ1 treatment in RD cells. Growth suppression in HT1080 cells was accompanied by the delay of telophase and cytokinesis, followed by multinuclear cells formation. The effects of SkQ1 on the cell cycle were proved to be at least partially mediated by inactivation of Aurora family kinases. ABBREVIATIONS: TPP+: Triphenylphosphonium cation; ROS: Reactive oxygen species; mtROS: Mitochondrial reactive oxygen species; NAC: N-acetyl-L-cysteine; DCFH-DA: Dichlorodihydrofluorescein diacetate; APC: Anaphase promoting complex; ABPs: Actin-binding proteins; DMEM: Dulbecco's modified Eagle media; SDS: sodium dodecyl sulfate; HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid. PMID- 29995561 TI - Low coverage rate and awareness of influenza vaccine among older people in Shanghai, China: A cross-sectional study. AB - BACKGROUND: Older individuals are at high risk for morbidity and mortality due to influenza, and the most effective way to prevent influenza is yearly vaccination. In China, the influenza vaccine is not covered by the national Expanded Program on Immunization, and more evidence is needed about influenza vaccine usage among older individuals. OBJECTIVE: To determine the influenza vaccination coverage and its influencing factors, and understand barriers to older adults receiving influenza vaccinations in Shanghai, China. METHODS: A cross-sectional survey was conducted with residents aged 60 and older. Vaccination status in the 2016-17 influenza season and reasons for or against vaccination were surveyed. The vaccination coverage rates were adjusted by gender, age and community distribution, and potential factors influencing vaccination uptake were determined by bivariate logistic regression. RESULTS: In total, 253 of the 4417 respondents received an influenza vaccine during the 2016-17 season, yielding an adjusted coverage rate of 5.2% (95% CI, 4.5-5.8). The frequency of receiving the vaccine was higher for older individuals living with family/friends than that for those living alone (p < 0.05), and lower among individuals with chronic respiratory diseases (p < 0.05). Among unvaccinated respondents, lack of influenza vaccine awareness was the most common reason for being unvaccinated (48.3%, 2012/4164). CONCLUSION: Influenza vaccination coverage is extremely low among older people in Shanghai, and lack of awareness of the influenza vaccine might be a potential barrier to vaccination. Our study highlights the need for an appropriate influenza vaccination strategy and program targeting the older population. PMID- 29995562 TI - Knockdown of lncRNA BDNF-AS suppresses neuronal cell apoptosis via downregulating miR-130b-5p target gene PRDM5 in acute spinal cord injury. AB - OBJECTIVE: The present study was designed to investigate the molecular mechanism and biological roles of lncRNA brain-derived neurotrophic factor antisense (lncRNA BDNF-AS) in acute spinal cord injury (ASCI). METHODS: The rat model of ASCI and hypoxic cellular model were established to detect the expression of BDNF AS, miR-130b-5p, PR (PRDI-BF1 and RIZ) domain protein 5 (PRDM5) and cleaved caspase 3 (c-caspase 3) using qRT-PCR and western blot. Basso, Beattie and Bresnahan (BBB) score was carried out to assess neurological function. Flow cytometry was used to determine the apoptosis of neuronal cells. The association among BDNF-AS, miR-130b-5p and PRDM5 were disclosed by RNA immunoprecipitation (RIP) assay, RNA pull-down assay and dual-luciferase reporter assay. RESULTS: BDNF-AS, PRDM5 and c-caspase 3 expression were significantly upregulated, while miR-130b-5p was suppressed in the ASCI group and neuronal cells following hypoxia treatment. BDNF-AS knockdown inhibited neuronal cell apoptosis. Further studies indicated that BDNF-AS functioned as a competing endogenous RNA (ceRNA) by sponging miR-130b-5p in neuronal cells. Further investigations demonstrated that PRDM5 was a target of miR-130b-5p and BDNF-AS knockdown exerted anti-apoptotic effects via miR-130b-5p/PRDM5 axis. CONCLUSION: The lncRNA BDNF-AS/miR-130b 5p/PRDM5 axis might be a promising therapeutic target for ASCI. PMID- 29995564 TI - Estimation of causal effects in clinical endpoint bioequivalence studies in the presence of intercurrent events: noncompliance and missing data. AB - In clinical endpoint bioequivalence (BE) studies, the primary analysis for assessing equivalence between a generic and an innovator product is based on the observed per-protocol (PP) population (usually completers and compliers). However, missing data and noncompliance are post-randomization intercurrent events and may introduce selection bias. Therefore, PP analysis is generally not causal. The FDA Missing Data Working Group recommended using "causal estimands of primary interest." In this paper, we propose a principal stratification causal framework and co-primary causal estimands to test equivalence, which was also recommended by the recently published ICH E9 (R1) addendum to address intercurrent events. We identify three conditions under which the current PP estimator is unbiased for one of the proposed co-primary causal estimands - the "Survivor Average Causal Effect" (SACE) estimand. Simulation shows that when these three conditions are not met, the PP estimator is biased and may inflate Type 1 error and/or change power. We also propose a tipping point sensitivity analysis to evaluate the robustness of the current PP estimator in testing equivalence when the sensitivity parameters deviate from the three identified conditions, but stay within a clinically meaningful range. Our work is the first causal equivalence assessment in equivalence studies with intercurrent events. PMID- 29995563 TI - Massive parallel screening of phage libraries for the generation of repertoires of human immunomodulatory monoclonal antibodies. AB - Immune checkpoints are emerging as novel targets for cancer therapy, and antibodies against them have shown remarkable clinical efficacy with potential for combination treatments to achieve high therapeutic index. This work aims at providing a novel approach for the generation of several novel human immunomodulatory antibodies capable of binding their targets in their native conformation and useful for therapeutic applications. We performed a massive parallel screening of phage libraries by using for the first time activated human lymphocytes to generate large collections of single-chain variable fragments (scFvs) against 10 different immune checkpoints: LAG-3, PD-L1, PD-1, TIM3, BTLA, TIGIT, OX40, 4-1BB, CD27 and ICOS. By next-generation sequencing and bioinformatics analysis we ranked individual scFvs in each collection and identified those with the highest level of enrichment. As a proof of concept of the quality/potency of the binders identified by this approach, human IgGs from three of these collections (i.e., PD-1, PD-L1 and LAG-3) were generated and shown to have comparable or better binding affinity and biological activity than the clinically validated anti-PD-1 mAb nivolumab. The repertoires generated in this work represent a convenient source of agonistic or antagonistic antibodies against the 'Checkpoint Immunome' for preclinical screening and clinical implementation of optimized treatments. PMID- 29995565 TI - Metabolomics analysis of Cajanus cajan L. seedlings unravelled amelioration of stress induced responses to salinity after halopriming of seeds. AB - Soil salinity has become a major concern for agriculture. Such constraints not only reinforce the urgent need to understand the underlying mechanisms by which plants cope during salt stress but also to develop cost-effective and farmer friendly halopriming technique to alleviate the adverse effects of salinity to some extent. Metabolomics approach was used to explore different responses to physiological metabolites and pathway variations that occur during salt stress responses in Cajanus cajan L. var. Rabi and to understand the role of halopriming in ameliorating stress at the level of metabolite. Seedlings raised from non primed and haloprimed seeds, grown in hydroponic solution, were subjected to different concentrations of NaCl. After 21 days, metabolites were extracted, derivatized and analyzed by GC-MS. The data were analysed by different multivariate analyses. Chemometric study of the identified metabolites indicated that the leaves responded most to NaCl induced stress than the stem and root with production of beta-cyano-L-alanine and also increased level of different compatible solutes. O-Acetylsalicylic was also found to increase in all the parts upon facing stress but, such upregulated metabolite production was downregulated in the leaves when the seeds were haloprimed before germination, although many of the metabolites, including beta-cyanoalanine, showed a trend of increase with increase in salt concentrations. Important metabolites produced by C. cajan seedlings in response to salinity were unravelled. Pre-germination haloprimimg of seeds resulted in amelioration of NaCl induced stress, as the levels of stress induced metabolites were lowered. PMID- 29995566 TI - Plant nucleoside diphosphate kinase 1: A housekeeping enzyme with moonlighting activity. AB - Nucleoside diphosphate kinase (NDPK) catalyzes the interconversion of nucleoside diphosphates and triphosphates using ATP as phosphate donor. This housekeeping enzyme is present in several subcellular compartments. The main isoform (NDPK1) is located in the cytosol and is highly expressed in meristems and provascular tissues. The manipulation of NDPK1 levels in transgenic potato roots demonstrates that this enzyme plays a key role in the transfer of energy between the cytosolic adenine and uridine nucleotide pools and in the distribution of carbon between starch and cellulose. Modulation of the expression of NDPK1 also alters the homeostasis of root respiration, glycolytic flux, reactive oxygen species production and growth. Herein, we propose a model summarizing the effects of the manipulation of NDPK1 levels on root metabolism. The model also accounts for G quadruplex DNA binding, a moonlighting activity recently attributed to NDPK1, which possibly contributes to the metabolic phenotype of transgenic roots. PMID- 29995567 TI - Consolidated bioprocessing for cellulosic ethanol conversion by cellulase xylanase cell-surfaced yeast consortium. AB - Consolidated bioprocessing (CBP) strategy was developed to construct a cell surface displayed consortium for heterologously expressing functional lignocellulytic enzymes. The reaction system composed of two engineered yeast strains: Y5/XynII-XylA (co-displaying two types of xylanases) and Y5/EG-CBH-BGL (co-displaying three types of cellulases). The immobilization of recombinant fusion proteins and their cell-surface accessibility of were analyzed by flow cytometry and immunofluorescence. The feasibility of consolidated bioprocessing by using pretreated corn stover (CS) as substrate for direct bioconversion was further investigated, and the synergistic activity and proximity effect between cellulases and xylanases on lignocelluloses degradation were also discussed in this work. Without any commercial enzyme addition, the combined yeast consortium produced 1.61 g/L ethanol which achieved 64.7% of the theoretical ethanol yield during 144 h from steam-exploded CS. The results indicated that the assembly of cellulases and xylanases using a synthetic consortium capable of combined displaying lignocellulytic enzymes is a promising approach for simultaneous saccharification and fermentation to ethanol from lignocellulosic biomass. PMID- 29995568 TI - Microtubules play an essential role in the survival of primary acute lymphoblastic leukemia cells advancing through G1 phase. AB - We recently reported that primary acute lymphoblastic leukemia (ALL) cells are susceptible to the microtubule depolymerizing agent vincristine (VCR) in G1 phase. This finding prompted testing another G1 phase-active compound, palbociclib (PCB), a highly selective inhibitor of cyclin-dependent kinases 4/6 (CDK4/6), alone and in combination with VCR. PCB used alone caused G1 arrest in ALL cells with no effect on cell viability, and similar results were obtained for the retinoblastoma (RB)-proficient T98G glioblastoma cell line. In contrast, HeLa cells failed to arrest in the presence of PCB, consistent with their lack of dependence on the CDK4/6-RB pathway. When ALL cells were pretreated with PCB, they became refractory to death in G1 phase induced by VCR treatment, whereas HeLa cells retained VCR sensitivity after PCB pretreatment. Immunofluorescence microscopy showed that PCB did not disrupt the microtubule network nor prevent VCR from doing so. Furthermore, ALL cells pretreated with PCB retained susceptibility to the Bcl-2/Bcl-xL inhibitor ABT-263, indicating that downstream apoptotic signaling was unaffected. When released from PCB-enforced arrest, ALL cells reinitiated cycling and regained sensitivity to VCR. ALL cells treated with cycloheximide also arrested in G1 phase and became insensitive to VCR, independently reinforcing conclusions derived from PCB-imposed arrest. Thus, primary ALL cells advancing through G1 phase are strictly dependent on functional microtubules for survival whereas microtubules are dispensable for G1-arrested cells. These findings provide novel insight into interphase microtubule function and, from a therapy standpoint, strongly caution against combining microtubule targeting agents and CDK4/6 inhibitors for ALL. PMID- 29995569 TI - Paip2 is localized to active promoters and loaded onto nascent mRNA in Drosophila. AB - Paip2 (Poly(A)-binding protein - interacting protein 2) is a conserved metazoan specific protein that has been implicated in regulating the translation and stability of mRNAs. However, we have found that Paip2 is not restricted to the cytoplasm but is also found in the nucleus in Drosophila embryos, salivary glands, testes, and tissue culture cells. Nuclear Paip2 is associated with chromatin, and in chromatin immunoprecipitation experiments it maps to the promoter regions of active genes. However, this chromatin association is indirect, as it is RNA-dependent. Thus, Paip2 is one more item in the growing list of translation factors that are recruited to mRNAs co-transcriptionally. PMID- 29995570 TI - Development of Fe3O4/Ag core/shell-based multifunctional immunomagnetic nanoparticles for isolation and detection of CD34+ stem cells. AB - Fe3O4/Ag core/shell nanoparticles functionalized with the free amino (NH2) functional groups (Fe3O4/Ag-NH2) were conjugated with fluorescent electron coupled dye (ECD)-antiCD34 antibody using the 1-ethyl-3-(3'-dimethyl-aminopropyl) carbodiimide (EDC) catalyst (ECD - Electron Coupled Dye or R Phycoerythrin-Texas Red is a fluorescent organic dye attached to the antibody). The characteristic fluorescence of ECD in the antibody was investigated and was used as a good indicator for estimating the percentage of the antibodies that were successfully conjugated with the nanoparticles. The conjugation efficiency was found to increase depending on the VNP:VAB ratio, where VNP and VAB are the volumes of the nanoparticle solution (concentration of 50 ppm) and the as-purchased antibody solution, respectively. The conjugation efficiency rapidly increased from approximately 18% to approximately 70% when VNP:VAB was increased from 2:1 to 100:1, and it gradually reached the saturated state at an efficiency of 95%, as the VNP:VAB was equal to 300:1. The bioactivity of the abovementioned conjugation product (denoted by Fe3O4/Ag-antiCD34) was evaluated in an experiment for the collection of stem cells from bone marrow samples. PMID- 29995571 TI - Connecting GCN5's centromeric SAGA to the mitotic tension-sensing checkpoint. AB - Multiple interdependent mechanisms ensure faithful segregation of chromosomes during cell division. Among these, the spindle assembly checkpoint monitors attachment of spindle microtubules to the centromere of each chromosome, whereas the tension-sensing checkpoint monitors the opposing forces between sister chromatid centromeres for proper biorientation. We report here a new function for the deeply conserved Gcn5 acetyltransferase in the centromeric localization of Rts1, a key player in the tension-sensing checkpoint. Rts1 is a regulatory component of protein phopshatase 2A, a near universal phosphatase complex, which is recruited to centromeres by the Shugoshin (Sgo) checkpoint component under low tension conditions to maintain sister chromatid cohesion. We report that loss of Gcn5 disrupts centromeric localization of Rts1. Increased RTS1 dosage robustly suppresses gcn5? cell cycle and chromosome segregation defects, including restoration of Rts1 to centromeres. Sgo1's Rts1-binding function also plays a key role in RTS1 dosage suppression of gcn5? phenotypes. Notably, we have identified residues of the centromere histone H3 variant Cse4 that function in these chromosome segregation-related roles of RTS1. Together, these findings expand the understanding of the mechanistic roles of Gcn5 and Cse4 in chromosome segregation. PMID- 29995572 TI - Human papillomavirus infection among women attending family planning clinic in Nigeria: prevalence, correlates, and co-infection with Chlamydia trachomatis. AB - Infection with high-risk genotypes of human papillomavirus (HPV) is considered the main cause of invasive cervical. A number of epidemiologic studies have suggested that HPV and Chlamydia trachomatis (CT) play a synergistic role in the etiology of cervical intraepithelial neoplasia and subsequent cervical cancer. The current study aimed to evaluate the HPV prevalence and the risk factors for co-infection with CT among women attending family planning clinic in Nigeria. Following enrolment, 90 patients were screened for IgG antibodies to virus-like proteins of HPV types 6, 8, 16, and 18. CT seropositivity was tested by enzyme linked immunosorbent assay for the detection of IgG and IgM antibodies. The prevalence of HPV IgG was 20%. Seropositivity for CT IgM was 77.8% while the IgG was 0%. A total of 10 women (11.1%) were seropositive for both CT IgM and HPV IgG antibodies. Seropositivity for HPV IgG was significantly associated with age at marriage (P < 0.001), current Chlamydia infection (P < 0.011), and number of children (P < 0.025), while seropositivty for HPV IgG and Chlamydia trahomatis IgM was significantly associated with age at coitarche (P < 0.028), number of life sex partners (P < 0.033), and history of multiple sexual partners (P < 0.002). PMID- 29995574 TI - Developing an anaerobic digester with external Zeolite filled column for enhancing methane production from swine manure - A feasibility study. AB - Development of digesters with an external zeolite column facilitates the convenient removal of the zeolite with TAN, without disturbing the continuous anaerobic digestion process. A digester with an inside zeolite bed (In-Zeo) and digester without adding zeolite (No-Zeo) were employed to compare the process performance with digester with external zeolite column (EX-Zeo). The cumulative, CH4 yields were 5% and 15% greater in the EX-Zeo, and the In-Zeo digesters respectively compared to the No-Zeo digesters. Also, the % VS reduction was 49%, 55% and 41%, respectively in the Ex-Zeo, In-Zeo and No-Zeo digesters. The results indicated that treatment with 7% zeolite during anaerobic digestion has the potential to improve biodegradation of swine manure. The addition of zeolite appeared to reduce TAN from the digestate, thereby enhancing the CH4 yield. Zeolite could be used either internally or externally to enhance CH4 production through anaerobic digestion of swine manure. PMID- 29995573 TI - Requirement for and polarized localization of integrin proteins during Drosophila wound closure. AB - Wound reepithelialization is an evolutionarily conserved process in which skin cells migrate as sheets to heal the breach and is critical to prevent infection but impaired in chronic wounds. Integrin heterodimers mediate attachment between epithelia and underlying extracellular matrix and also act in large signaling complexes. The complexity of the mammalian wound environment and evident redundancy among integrins has impeded determination of their specific contributions to reepithelialization. Taking advantage of the genetic tools and smaller number of integrins in Drosophila, we undertook a systematic in vivo analysis of integrin requirements in the reepithelialization of skin wounds in the larva. We identify alphaPS2-betaPS and alphaPS3-betaPS as the crucial integrin dimers and talin as the only integrin adhesion component required for reepithelialization. The integrins rapidly accumulate in a JNK-dependent manner in a few rows of cells surrounding a wound. Intriguingly, the integrins localize to the distal margin in these cells, instead of the frontal or lamellipodial distribution expected for proteins providing traction and recruit nonmuscle myosin II to the same location. These findings indicate that signaling roles of integrins may be important for epithelial polarization around wounds and lay the groundwork for using Drosophila to better understand integrin contributions to reepithelialization. PMID- 29995576 TI - Microbial cell disruption methods for efficient release of enzyme L-asparaginase. AB - The efficacy of a simple laboratory method for cell disruption based on the glass bead stirring, sonication, osmotic shock, freezing and grinding, or use of solvents and detergents was assessed in this study, via measurements of the release of total protein and L-asparaginase activity. Three different microbial sources of L-asparaginase were used: Escherichia coli BL21 (DE3), Leucosporidium muscorum, and Aspergillus terreus (CCT 7693). This study adjusted and identified the best procedure for each kind of microorganism. Sonication and glass bead stirring led to obtaining filamentous fungus cell-free extracts containing high concentrations of soluble proteins and specific activity; however, sonication was the best since it obtained 4.61 +/- 0.12 IU mg-1 after 3 min of operation time. Mechanical methods were also the most effective for yeast cell disruption, but sonication was the technique which yielded a higher efficiency releasing 7.3 IUtotal compared to glass bead stirring releasing 2.7 IUtotal at the same operation time. For bacterium, sonication proved to be the best procedure due to getting the highest specific activity (9.01 IU mg-1) and total enzyme activity (61.7 IU). The data presented lead to conclude that the mechanical methods appeared to be the most effective for the disintegration of the all microbial cells studies. This is the first report related to the experimental comparison of L-ASNase extraction procedures from different microorganisms, which can also be used for extracting periplasm located enzymes from other organisms. PMID- 29995575 TI - Deregulation of MADS-box transcription factor genes in a mutant defective in the WUSCHEL-LIKE HOMEOBOX gene EVERGREEN of Petunia hybrida. AB - Angiosperm inflorescences develop in two fundamentally different ways. In monopodial plants, for example in Arabidopsis thaliana, the flowers are initiated as lateral appendages of a central indeterminate inflorescence meristem. In sympodial plants, flowers arise by terminal differentiation of the inflorescence meristem, while further inflorescence development proceeds from new sympodial meristems that are generated at the flank of the terminal flower. We have used the sympodial model species Petunia hybrida to investigate inflorescence development. Here, we describe a mutant, bonsai (bns), which is defective in flower formation, inflorescence branching, and control of meristem size. Detailed microscopic analysis revealed that bns meristems retain vegetative charateristics including spiral phyllotaxis. Consistent with a block in flower formation, bns mutants exhibit a deregulated expression of various MADS-box genes. Molecular analysis revealed that the bns mutant carries a transposon insertion in the previously described EVERGREEN (EVG) gene, which belongs to the WUSCHEL-LIKE HOMEOBOX (WOX) transcription factor gene family. EVG falls in the WOX9 subfamily, which has diverse developmental functions in angiosperms. The comparison of WOX9 orthologues in five model species for flowering shows that these genes play functionally divergent roles in monopodial and sympodial plants, indicating that the WOX9 regulatory node may have played an important role in the evolution of shoot architecture. PMID- 29995577 TI - The ribonuclease activity of Csm6 is required for anti-plasmid immunity by Type III-A CRISPR-Cas systems. AB - CRISPR-Cas systems provide prokaryotes with RNA-based adaptive immunity against viruses and plasmids. A unique feature of Type III CRISPR-Cas systems is that they selectively target transcriptionally-active invader DNA, and can cleave both the expressed RNA transcripts and source DNA. The Type III-A effector crRNP (CRISPR RNA-Cas protein complex), which contains Cas proteins Csm1-5, recognizes and degrades invader RNA and DNA in a crRNA-guided, manner. Interestingly, Type III-A systems also employ Csm6, an HEPN family ribonuclease that does not stably associate with the Type III-A effector crRNP, but nevertheless contributes to defense via mechanistic details that are still being determined. Here, we investigated the mechanism of action of Csm6 in Type III-A CRISPR-Cas systems from Lactococcus lactis, Staphylococcus epidermidis, and Streptococcus thermophilus expressed in Escherichia coli. We found that L. lactis and S. epidermidis Csm6 cleave RNA specifically after purines in vitro, similar to the activity reported for S. thermophilus Csm6. Moreover, L. lactis Csm6 functions as a divalent metal-independent, single strand-specific endoribonuclease that depends on the conserved HEPN domain. In vivo, we show that deletion of csm6 or expression of an RNase-defective form of Csm6 disrupts crRNA-dependent loss of plasmid DNA in all three systems expressed in E. coli. Mutations in the Csm1 palm domain, which are known to deactivate Csm6 ribonuclease activity, also prevent plasmid loss in the three systems. The results indicate that Csm6 ribonuclease activity rather than Csm1-mediated DNase activity effects anti-plasmid immunity by the three Type III-A systems investigated. PMID- 29995578 TI - Progress toward a group B streptococcal vaccine. AB - Streptococcus agalactiae (group B Streptococcus, GBS) is a leading cause of severe invasive disease in neonate, elderly, and immunocompromised patients worldwide. Despite recent advances in the diagnosis and intrapartum antibiotic prophylaxis (IAP) of GBS infections, it remains one of the most common causes of neonatal morbidity and mortality, causing serious infections. Furthermore, recent studies reported an increasing number of GBS infections in pregnant women and elderly. Although IAP is effective, it has several limitations, including increasing antimicrobial resistance and late GBS infection after negative antenatal screening. Maternal immunization is the most promising and effective countermeasure against GBS infection in neonates. However, no vaccine is available to date, but two types of vaccines, protein subunit and capsular polysaccharide conjugate vaccines, were investigated in clinical trials. Here, we provide an overview of the GBS vaccine development status and recent advances in the development of immunoassays to evaluate the GBS vaccine clinical efficacy. PMID- 29995579 TI - Comparative aspects of early lineage specification events in mammalian embryos - insights from reverse genetics studies. AB - Within the mammalian class, formation of the blastocyst is morphologically highly conserved among different species. The molecular and cellular events during preimplantation embryo development have been studied extensively in the mouse as model organism, because multiple genetically defined strains and a plethora of reverse genetics tools are available to dissect specific gene functions and regulatory networks. However, major differences in preimplantation developmental kinetics, implantation, and placentation exist among mammalians, and recent studies in species other than mouse showed, that even regulatory mechanisms of the first lineage differentiation events and maintenance of pluripotency are not always conserved. Here, we focus on the first and the second lineage segregation in mouse and bovine embryos, when the first differentiated cell types emerge. We outline their common features and differences in the regulation of these essential events during embryonic development with a glance at further species. In addition, we show how new reverse genetics strategies aid the study of regulatory circuits in embryos of domestic species, enhancing our overall understanding of mammalian preimplantation development. PMID- 29995580 TI - Kidney atrophy vs hypertrophy in diabetes: which cells are involved? AB - One of the first structural changes in diabetic nephropathy (DN) is the renal enlargement. These changes resulted in renal hypertrophy in both glomerular and tubular cells. Shrink in the kidney size, which described as kidney atrophy resulted from the loss of nephrons or abnormal nephron function and lead to loss of the kidney function. On the other hand, increase in kidney size, which described as hypertrophy resulted from increase in proximal tubular epithelial and glomerular cells size. However overtime, tubular atrophy and tubulointerstitial fibrosis occurs as subsequent changes in tubular cell hypertrophy, which is associated with the infiltration of fibroblast cells into the tubulointerstitial space. The rate of deterioration of kidney function shows a strong correlation with the degree of tubulointerstitial fibrosis. A consequence of long-standing diabetes/hyperglycemia may lead to major changes in renal structure that occur but not specific only to nephropathy. Identifying type of cells that involves in renal atrophy and hypertrophy may help to find a therapeutic target to treat diabetic nephropathy. In summary, the early changes in diabetic kidney are mainly includes the increase in tubular basement membrane thickening which lead to renal hypertrophy. On the other hand, only renal tubule is subjected to apoptosis, which is one of the characteristic morphologic changes in diabetic kidney to form tubular atrophy at the late stage of diabetes. PMID- 29995581 TI - Autophagy-deficient tumor cells rely on extracellular amino acids to survive upon glutamine deprivation. AB - Macroautophagy/autophagy is a unique protein degradation process by which intracellular materials are recycled for energy homeostasis. However, the metabolic status and energy source of autophagy-defective tumor cells is poorly understood. Here in this study, we found ATF4-dependent amino acid transporter (AAT) gene expression and amino acid uptake were increased in autophagy-deficient cells under conditions of Gln deprivation. Notably, inhibition of amino acid uptake reduced the viability of Gln-deprived autophagy-deficient cells, but not significantly in wild-type cells, suggesting the reliance of autophagy-deficient tumor cells on extracellular amino acid uptake. PMID- 29995582 TI - Regulation of cyclin E1 expression in human pluripotent stem cells and derived neural progeny. AB - : Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells (hESCs and hiPSCs) show unique cell cycle characteristics, such as a short doubling time due to an abbreviated G1 phase. Whether or not the core cell cycle machinery directly regulates the stemness and/or the differentiation potential of hPSCs remains to be determined. To date, several scenarios describing the atypical cell cycle of hPSCs have been suggested, and therefore there is still controversy over how cyclins, master regulators of the cell cycle, are expressed and regulated. Furthermore, the cell cycle profile and the expression pattern of major cyclins in hESCs-derived neuroprogenitors (NP) have not been studied yet. Therefore, herein we characterized the expression pattern of major cyclins in hPSCs and NP. We determined that all studied cyclins mRNA expression levels fluctuate along cell cycle. Particularly, after a thorough analysis of synchronized cell populations, we observed that cyclin E1 mRNA levels increased sharply in G1/S concomitantly with cyclin E1 protein accumulation in hPSCs and NP. Additionally, we demonstrated that cyclin E1 mRNA expression levels involves the activation of MEK/ERK pathway and the transcription factors c-Myc and E2Fs in hPSCs. Lastly, our results reveal that proteasome mediates the marked down-regulation (degradation) of cyclin E1 protein observed in G2/M by a mechanism that requires a functional CDK2 but not GSK3beta activity. ABBREVIATIONS: hPSCs: human pluripotent stem cells; hESCs: human embryonic stem cells; hiPSCs: human induced pluripotent stem cells; NP: neuroprogenitors; HF: human foreskin fibroblasts; MEFs: mouse embryonic fibroblasts; iMEFs: irradiated mouse embryonic fibroblasts; CDKs: cyclindependent kinases; CKIs: CDK inhibitors; CNS: central nervous system; Oct-4: Octamer-4; EB: embryoid body; AFP: Alpha fetoprotein; cTnT: Cardiac Troponin T; MAP-2: microtubule-associated protein; TUJ 1: neuron-specific class III beta-tubulin; bFGF: basic fibroblastic growth factor; PI3K: Phosphoinositide 3-kinase; KSR: knock out serum replacement; CM: iMEF conditioned medium; E8: Essential E8 medium. PMID- 29995583 TI - CRISPR-Cas systems in multicellular cyanobacteria. AB - : Novel CRISPR-Cas systems possess substantial potential for genome editing and manipulation of gene expression. The types and numbers of CRISPR-Cas systems vary substantially between different organisms. Some filamentous cyanobacteria harbor > 40 different putative CRISPR repeat-spacer cassettes, while the number of cas gene instances is much lower. Here we addressed the types and diversity of CRISPR Cas systems and of CRISPR-like repeat-spacer arrays in 171 publicly available genomes of multicellular cyanobacteria. The number of 1328 repeat-spacer arrays exceeded the total of 391 encoded Cas1 proteins suggesting a tendency for fragmentation or the involvement of alternative adaptation factors. The model cyanobacterium Anabaena sp. PCC 7120 contains only three cas1 genes but hosts three Class 1, possibly one Class 2 and five orphan repeat-spacer arrays, all of which exhibit crRNA-typical expression patterns suggesting active transcription, maturation and incorporation into CRISPR complexes. The CRISPR-Cas system within the element interrupting the Anabaena sp. PCC 7120 fdxN gene, as well as analogous arrangements in other strains, occupy the genetic elements that become excised during the differentiation-related programmed site-specific recombination. This fact indicates the propensity of these elements for the integration of CRISPR-cas systems and points to a previously not recognized connection. The gene all3613 resembling a possible Class 2 effector protein is linked to a short repeat-spacer array and a single tRNA gene, similar to its homologs in other cyanobacteria. The diversity and presence of numerous CRISPR Cas systems in DNA elements that are programmed for homologous recombination make filamentous cyanobacteria a prolific resource for their study. ABBREVIATIONS: Cas: CRISPR associated sequences; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; C2c: Class 2 candidate; SDR: small dispersed repeat; TSS: transcriptional start site; UTR: untranslated region. PMID- 29995584 TI - A molecular model for LINC complex regulation: activation of SUN2 for KASH binding. AB - Linkers of the nucleoskeleton and cytoskeleton are key molecular complexes that span the nuclear envelope (NE) and provide a direct linkage between the nucleoskeleton and cytoskeleton. Two major components of these complexes are members of the SUN and KASH protein families that interact in the perinuclear space to allow the transmission of mechanochemical signals across the NE. Structural details of the mammalian SUN domain protein SUN2 have established that SUN2 must form a trimer to bind to KASH, and that this trimerization is mediated through two predicted coiled-coil regions of the protein, CC1 and CC2, which precede the SUN domain. Recent crystallographic data suggest that CC2-SUN formed an unexpected autoinhibited monomer unable to bind to KASH. These structural insights raise the question of how full-length SUN2 transitions from a monomer to a trimer inside the NE. In this study we used a computational approach to model a fragment of SUN2 containing CC1, CC2, and the SUN domain. We observed the dynamics of these modeled structures using ~1 MUs molecular dynamics simulations and showed that the interplay between CC1 and CC2 may be sufficient for the release of CC2-SUN2 from its autoinhibited state. Additionally, using our models and gel filtration analysis, we show the involvement of an E452 residue on CC1 in the monomer--trimer transition of SUN2. Intriguingly, mutations in this residue have been seen in muscular dystrophy-associated SUN2 variants. Finally, we propose a Ca2+-dependent monomer-trimer transition of SUN2. PMID- 29995585 TI - Fractional-Dose Yellow Fever Vaccination - Advancing the Evidence Base. PMID- 29995586 TI - ATP6AP2 functions as a V-ATPase assembly factor in the endoplasmic reticulum. AB - ATP6AP2 (also known as the [pro]renin receptor) is a type I transmembrane protein that can be cleaved into two fragments in the Golgi apparatus. While in Drosophila ATP6AP2 functions in the planar cell polarity (PCP) pathway, recent human genetic studies have suggested that ATP6AP2 could participate in the assembly of the V-ATPase in the endoplasmic reticulum (ER). Using a yeast model, we show here that the V-ATPase assembly factor Voa1 can functionally be replaced by Drosophila ATP6AP2. This rescue is even more efficient when coexpressing its binding partner ATP6AP1, indicating that these two proteins together fulfill Voa1 functions in higher organisms. Structure-function analyses in both yeast and Drosophila show that proteolytic cleavage is dispensable, while C-terminus dependent ER retrieval is required for ATP6AP2 function. Accordingly, we demonstrate that both overexpression and lack of ATP6AP2 causes ER stress in Drosophila wing cells and that the induction of ER stress is sufficient to cause PCP phenotypes. In summary, our results suggest that full-length ATP6AP2 contributes to the assembly of the V-ATPase proton pore and that impairment of this function affects ER homeostasis and PCP signaling. PMID- 29995587 TI - The moderating effect of parental support: internalizing symptoms of emerging adults exposed to community violence. AB - Evidence suggests parental support mitigates the association between community violence exposure and internalizing symptoms in adolescents. This study investigates this moderation of parental support for emerging adults and compares it with that for adolescents. Data were drawn from the Pathways to Desistence Study using community violence, parental support, and their interaction to predict internalizing symptoms in a series of regression models for adolescents and emerging adults. Results suggest that exposure to community violence during adolescence and emerging adulthood had a significant association with internalizing symptoms. Mother support during adolescence moderated this relationship. Emerging adulthood was marked by an increase in parental support; however, this support did not moderate the relationship between community violence and internalizing symptoms. Interventions, programs, and policies that leverage the parental support of emerging adults may be a useful strategy to mitigate the negative impacts of community violence. PMID- 29995588 TI - Magnetic nanocellulose hybrid nanoparticles and ionic liquid for extraction of neonicotinoid insecticides from milk samples prior to determination by liquid chromatography-mass spectrometry. AB - A simple and rapid microextraction procedure is reported on the use of ionic liquid in combination with magnetic nanocellulose hybrid nanoparticles. The procedure is ultrasound-assisted and applicable to selective preconcentration of neonicotinoid insecticides from milk samples, prior to being analysed by liquid chromatography-mass spectrometry. The extraction procedure uses small volume of organic solvents (<1 mL), and there is no need for centrifugation. In the experimental approach the ionic liquid was quickly disrupted by an ultrasonic probe and dispersed in milk samples in a cloudy form. At this stage, neonicotinoid insecticides were extracted into the fine droplets of ionic liquid. Then small amounts of magnetic nanocellulose hybrid nanoparticles were dispersed into the sample solutions to adsorb the ionic liquid containing the analytes and phase separation was completed. The ionic liquid allowed the microextraction of the analytes and a small volume of acetonitrile was used for elution. Magnetic nanocellulose favoured the adsorption of the ionic liquid with the analytes and improved the final recovery with respect to the use of simple magnetic nanoparticles as a sorbent material. Under the optimum conditions, decision capabilities were achieved in the 0.02-0.06 mg kg-1 range, with recoveries between 91.0% and 109.5%. PMID- 29995589 TI - Results from the family and coping oriented palliative homecare intervention study (FamCope)-A randomized controlled trial. AB - We tested if a family-and-coping-oriented basic palliative homecare intervention (six visits within 15 weeks) could improve quality-of-life and reduce anxiety and depression of advanced cancer patients and their closest relative, and reduce acute hospital admissions of patients. Fifty-seven families were randomized, but patient enrollment was terminated before reaching target sample due to a low recruitment rate. We found no evidence of effect of the FamCope-intervention, but further investigation of effective methods to support how families cope with advanced cancer at home is needed as levels of distress is as high in relatives as it is in patients. However, duration of interventions to support family-coping may need a considerable time-span to show effect on quality-of-life. We recommend that recruitment is undertaken in close collaboration with the hospital clinics, and that complexity of problems is used as inclusion criterion to decide when a family-coping intervention is needed based on the level of problems and distress in the family. PMID- 29995590 TI - A Rnd3/p190RhoGAP pathway regulates RhoA activity in idiopathic pulmonary fibrosis fibroblasts. AB - Idiopathic pulmonary fibrosis (IPF) is an incurable disease of the lung that is characterized by excessive deposition of extracellular matrix (ECM), resulting in disruption of normal lung function. The signals regulating fibrosis include both transforming growth factor beta (TGF-beta) and tissue rigidity and a major signaling pathway implicated in fibrosis involves activation of the GTPase RhoA. During studies exploring how elevated RhoA activity is sustained in IPF, we discovered that not only is RhoA activated by profibrotic stimuli but also that the expression of Rnd3, a major antagonist of RhoA activity, and the activity of p190RhoGAP (p190), a Rnd3 effector, are both suppressed in IPF fibroblasts. Restoration of Rnd3 levels in IPF fibroblasts results in an increase in p190 activity, a decrease in RhoA activity and a decrease in the overall fibrotic phenotype. We also find that treatment with IPF drugs nintedanib and pirfenidone decreases the fibrotic phenotype and RhoA activity through up-regulation of Rnd3 expression and p190 activity. These data provide evidence for a pathway in IPF where fibroblasts down-regulate Rnd3 levels and p190 activity to enhance RhoA activity and drive the fibrotic phenotype. PMID- 29995591 TI - Energy Spectra of Protons and Generated Secondary Electrons around the Bragg Peak in Materials of Interest in Proton Therapy. AB - The number and energy of secondary electrons generated around the trajectories of swift protons interacting with biological materials are highly relevant in proton therapy, due to the prominent role of low-energy electrons in the production of biodamage. For a given material, electron energy distributions are determined by the proton energy; and it is imperative that the distribution of proton energy at depths around the Bragg peak region be described as accurately as possible. With this objective, we simulated the energy distributions of proton beams of clinically relevant energies (50-300 MeV) at depths around the Bragg peak in liquid water and the water-equivalent polymer poly(methyl methacrylate) (PMMA). By using a simple model, this simulation has been conveniently extended to account for nuclear fragmentation reactions, providing depth-dose curves in excellent agreement with available experimental data. Special care has been taken to describe the electronic excitation spectrum of the target, taking into account its condensed phase nature. A predictive formula has been obtained for the mean value and the width of the proton energy distribution at the Bragg peak depth, quantities which are found to grow linearly with the initial energy of the beam, in good agreement with available data. To accurately characterize (in number and energy) the electrons generated around the proton paths, the energy distributions of the latter at each depth have been convoluted with the energy-dependent ionization inverse mean free paths. This results in a number of low-energy electrons around the Bragg peak larger than when only the proton beam average energy at the given depths is considered. The convoluted ionization inverse mean free path closely resembles the Bragg curve shape. The average energy of the secondary electrons is nearly constant (~55 eV for liquid water and ~43 eV for PMMA) in the plateau of the Bragg curve, independent of the proton incident energy and suddenly decaying once the Bragg peak is reached. These findings highlight the importance of a precise calculation of the proton beam energy distribution as a function of the target depth to reliably characterize the secondary electrons generated around the Bragg peak region. PMID- 29995592 TI - Multiple-Disease System in Coffee: From Crop Loss Assessment to Sustainable Management. AB - Assessment of crop loss due to multiple diseases and pests (D&P) is a necessary step in designing sustainable crop management systems. Understanding the drivers of D&P development and yield loss helps identify leverage points for crop health management. Crop loss assessment is also necessary for the quantification of D&P regulation service to identify promising systems where ecosystem service provision is optimized. In perennial crops, assessment of crop losses due to D&P is difficult, as injuries can affect yield over years. In coffee, one of the first perennials in which crop loss trials were implemented, crop losses concurrent with injuries were found to be approximately 50% lower than lagged losses that originated following the death of productive branches due to D&P. Crop losses can be assessed by field trials and surveys, where yield reduction factors such as the number of productive branches that have died are quantified, and by modeling, where damage mechanisms for each injury are considered over several years. PMID- 29995593 TI - Feasibility of using a novel algal-bacterial biofilm reactor for efficient domestic wastewater treatment. AB - Current algal-bacterial consortia require high hydraulic retention times (HRTs, 2 10 days) to efficiently remove pollutants from domestic wastewaters. A novel algal-bacterial biofilm reactor was developed for a much lower HRT. The results showed that an HRT of 12 h ensured 90% removal of organic matter and ammonium, and phosphate removal was approximately 30%. Decreasing the HRT to 8 h significantly deteriorated the reactor's pollutant removal efficiencies and increasing the HRT to 24 h did not improve these efficiencies. Illumination, which was light source for algae, was provided by a LED light. Activity tests showed that organic matter and ammonium removal rates resulting from illumination were 70% and 50%, respectively, of the rates when dissolved oxygen concentration was maintained at 2 mg/L. Chemical oxygen demand (COD) removal rates resulted from illumination and aeration were 18.63 and 25.38 mg COD/L.h, respectively. The phosphate removal rate was 0.26 and 0.43 mg/L.h when illumination and aeration were applied, respectively. The ammonium removal rates were approximately 10,390 and 5000 mg [Formula: see text] when the reactor was aerated or illuminated, respectively. These two rates were significantly higher than reported nitrification rates. Moreover, the percentage of Oscillatoria sp. increased from below 10% to over 90% under the applied organic load and temperature, while the percentage of fast growing algae, Chlorella, chroococcus sp and Scenedesmus sp., decreased from over 90% to below 10%. These results showed that an algal bacterial biofilm reactor with a low reactor footprint was developed. PMID- 29995594 TI - Life Lessons from Paul in the Face of Death. PMID- 29995596 TI - Co-metabolic substrates enhanced biological nitrogen removal from cellulosic ethanol biorefinery wastewater using aerobic granular sludges. AB - The effect of different co-metabolic substrates (glucose, acetic acid and ethanol) on aerobic granular sludge treating cellulose ethanol wastewater was investigated using sequencing batch reactors. The efficiencies of the three substrates in removing chemical oxygen demand were respectively 18.87%, 28.88% and 27.99%, all of which were remarkably higher than without co-metabolic substrates, indicating that co-metabolic substrates can promote the degradation of the refractory substances. With acetic acid as the co-metabolic substrate, the removal amount of ammonium nitrogen and nitrate nitrogen was greater than glucose and ethanol used. The nitrogen removals by the three co-metabolic substrates were 53.18%, 72.15%, 69.36%, respectively, which were 1.4, 1.8, and 1.6 times the removal without co-metabolic substrates. Fluorescence in situ hybridization results showed that the proportion of ammonium-oxidizing bacteria in the granular sludge was greater than that of nitrite-oxidizing bacteria after adding co metabolic substrates, and the order was acetic acid > ethanol > glucose. PMID- 29995595 TI - Interstitial flow promotes macrophage polarization toward an M2 phenotype. AB - Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (~3 um/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment. PMID- 29995597 TI - Automated in vivo patch clamp evaluation of extracellular multielectrode array spike recording capability. AB - Much innovation is currently aimed at improving the number, density, and geometry of electrodes on extracellular multielectrode arrays for in vivo recording of neural activity in the mammalian brain. To choose a multielectrode array configuration for a given neuroscience purpose, or to reveal design principles of future multielectrode arrays, it would be useful to have a systematic way of evaluating the spike recording capability of such arrays. We here describe an automated system that performs robotic patch clamp recording of a neuron being simultaneously recorded via an extracellular multielectrode array. By recording a patch clamp dataset from a neuron while acquiring extracellular recordings from the same neuron, we can evaluate how well the extracellular multielectrode array captures the spiking information from that neuron. To demonstrate the utility of our system, we show that it can provide data from the mammalian cortex to evaluate how the spike sorting performance of a close-packed extracellular multielectrode array is affected by bursting, which alters the shape and amplitude of spikes in a train. We also introduce an algorithmic framework to help evaluate how the number of electrodes in a multielectrode array affects spike sorting, examining how adding more electrodes yields data that can be spike sorted more easily. Our automated methodology may thus help with the evaluation of new electrode designs and configurations, providing empirical guidance on the kinds of electrodes that will be optimal for different brain regions, cell types, and species, for improving the accuracy of spike sorting. PMID- 29995598 TI - Late maturation of backward masking in auditory cortex. AB - Speech perception relies on the accurate resolution of brief, successive sounds that change rapidly over time. Deficits in the perception of such sounds, indicated by a reduced ability to detect signals during auditory backward masking, strongly relate to language processing difficulties in children. Backward masking during normal development has a longer maturational trajectory than many other auditory percepts, implicating the involvement of central auditory neural mechanisms with protracted developmental time courses. Despite the importance of this percept, its neural correlates are not well described at any developmental stage. We therefore measured auditory cortical responses to masked signals in juvenile and adult Mongolian gerbils and quantified the detection ability of individual neurons and neural populations in a manner comparable with psychoacoustic measurements. Perceptually, auditory backward masking manifests as higher thresholds for detection of a short signal followed by a masker than for the same signal in silence. Cortical masking was driven by a combination of suppressed responses to the signal and a reduced dynamic range available for signal detection in the presence of the masker. Both coding elements contributed to greater masked threshold shifts in juveniles compared with adults, but signal-evoked firing suppression was more pronounced in juveniles. Neural threshold shifts were a better match to human psychophysical threshold shifts when quantified with a longer temporal window that included the response to the delayed masker, suggesting that temporally selective listening may contribute to age-related differences in backward masking. NEW & NOTEWORTHY In children, auditory detection of backward masked signals is immature well into adolescence, and detection deficits correlate with problems in speech processing. Our auditory cortical recordings reveal immature backward masking in adolescent animals that mirrors the prolonged development seen in children. This is driven by both signal-evoked suppression and dynamic range reduction. An extended window of analysis suggests that differences in temporally focused listening may contribute to late maturing thresholds for backward masked signals. PMID- 29995599 TI - The role of intersegmental dynamics in coordination of the forelimb joints during unperturbed and perturbed skilled locomotion. AB - Joint coordination during locomotion and how this coordination changes in response to perturbations remains poorly understood. We investigated coordination among forelimb joints during the swing phase of skilled locomotion in the cat. While cats walked on a horizontal ladder, one of the cross-pieces moved before the cat reached it, requiring the cat to alter step size. Direction and timing of the cross-piece displacement were manipulated. We found that the paw was transported in space through body translation and shoulder and elbow rotations, whereas the wrist provided paw orientation required to step on cross-pieces. Kinetic analysis revealed a consistent joint control pattern in all conditions. Although passive interaction and gravitational torques were the main sources of shoulder and elbow motions for most of the movement time, shoulder muscle torque influenced movement of the entire limb at the end of the swing phase, accelerating the shoulder and causing interaction torque that determined elbow motion. At the wrist, muscle and passive torques predominantly compensated for each other. In all perturbed conditions, although all joints and the body slightly contributed to changes in the step length throughout the entire movement, the major adjustment was produced by the shoulder at the movement end. We conclude that joint coordination during the swing phase is produced mainly passively, by exploiting gravity and the limb's intersegmental dynamics, which may simplify the neural control of locomotion. The use of shoulder musculature at the movement end enables flexible responses to environmental disturbances. NEW & NOTEWORTHY This is the first study to investigate joint control during the swing phase of skilled, accuracy-dependent locomotion in the cat and how this control is altered to adapt to known and unexpected perturbations. We demonstrate that a pattern of joint control that exploits gravitational and interaction torques is used in all conditions and that movement modifications are produced mainly by shoulder muscle torque during the last portion of the movement. PMID- 29995600 TI - Using gaze behavior to parcellate the explicit and implicit contributions to visuomotor learning. AB - Successful motor performance relies on our ability to adapt to changes in the environment by learning novel mappings between motor commands and sensory outcomes. Such adaptation is thought to involve two distinct mechanisms: an implicit, error-based component linked to slow learning and an explicit, strategic component linked to fast learning and savings (i.e., faster relearning). Because behavior, at any given moment, is the resultant combination of these two processes, it has remained a challenge to parcellate their relative contributions to performance. The explicit component to visuomotor rotation (VMR) learning has recently been measured by having participants verbally report their aiming strategy used to counteract the rotation. However, this procedure has been shown to magnify the explicit component. Here we tested whether task-specific eye movements, a natural component of reach planning, but poorly studied in motor learning tasks, can provide a direct readout of the state of the explicit component during VMR learning. We show, by placing targets on a visible ring and including a delay between target presentation and reach onset, that individual differences in gaze patterns during sensorimotor learning are linked to participants' rates of learning and their expression of savings. Specifically, we find that participants who, during reach planning, naturally fixate an aimpoint rotated away from the target location, show faster initial adaptation and readaptation 24 h later. Our results demonstrate that gaze behavior cannot only uniquely identify individuals who implement cognitive strategies during learning but also how their implementation is linked to differences in learning. NEW & NOTEWORTHY Although it is increasingly well appreciated that sensorimotor learning is driven by two separate components, an error-based process and a strategic process, it has remained a challenge to identify their relative contributions to performance. Here we demonstrate that task-specific eye movements provide a direct read-out of explicit strategies during sensorimotor learning in the presence of visual landmarks. We further show that individual differences in gaze behavior are linked to learning rate and savings. PMID- 29995601 TI - Vocal learning in songbirds requires cholinergic signaling in a motor cortex-like nucleus. AB - Cholinergic inputs to cortex modulate plasticity and sensory processing, yet little is known about their role in motor control. Here, we show that cholinergic signaling in a songbird vocal motor cortical area, the robust nucleus of the arcopallium (RA), is required for song learning. Reverse microdialysis of nicotinic and muscarinic receptor antagonists into RA in juvenile birds did not significantly affect syllable timing or acoustic structure during vocal babbling. However, chronic blockade over weeks reduced singing quantity and impaired learning, resulting in an impoverished song with excess variability, abnormal acoustic features, and reduced similarity to tutor song. The demonstration that cholinergic signaling in a motor cortical area is required for song learning motivates the songbird as a tractable model system to identify roles of the basal forebrain cholinergic system in motor control. NEW & NOTEWORTHY Cholinergic inputs to cortex are evolutionarily conserved and implicated in sensory processing and synaptic plasticity. However, functions of cholinergic signals in motor areas are understudied and poorly understood. Here, we show that cholinergic signaling in a songbird vocal motor cortical area is not required for normal vocal variability during babbling but is essential for developmental song learning. Cholinergic modulation of motor cortex is thus required for learning but not for the ability to sing. PMID- 29995603 TI - A novel and fully automatic spike-sorting implementation with variable number of features. AB - The most widely used spike-sorting algorithms are semiautomatic in practice, requiring manual tuning of the automatic solution to achieve good performance. In this work, we propose a new fully automatic spike-sorting algorithm that can capture multiple clusters of different sizes and densities. In addition, we introduce an improved feature selection method, by using a variable number of wavelet coefficients, based on the degree of non-Gaussianity of their distributions. We evaluated the performance of the proposed algorithm with real and simulated data. With real data from single-channel recordings, in ~95% of the cases the new algorithm replicated, in an unsupervised way, the solutions obtained by expert sorters, who manually optimized the solution of a previous semiautomatic algorithm. This was done while maintaining a low number of false positives. With simulated data from single-channel and tetrode recordings, the new algorithm was able to correctly detect many more neurons compared with previous implementations and also compared with recently introduced algorithms, while significantly reducing the number of false positives. In addition, the proposed algorithm showed good performance when tested with real tetrode recordings. NEW & NOTEWORTHY We propose a new fully automatic spike-sorting algorithm, including several steps that allow the selection of multiple clusters of different sizes and densities. Moreover, it defines the dimensionality of the feature space in an unsupervised way. We evaluated the performance of the algorithm with real and simulated data, from both single-channel and tetrode recordings. The proposed algorithm was able to outperform manual sorting from experts and other recent unsupervised algorithms. PMID- 29995602 TI - Pupil-linked arousal modulates behavior in rats performing a whisker deflection direction discrimination task. AB - Non-luminance-mediated changes in pupil size have been widely used to index arousal state. Recent animal studies have demonstrated correlations between behavioral state-related pupil dynamics and sensory processing. However, the relationship between pupil-linked arousal and behavior in animals performing perceptual tasks has not been fully elucidated. In the present study, we trained head-fixed rats to discriminate between directions of whisker movements using a Go/No-Go discrimination paradigm while imaging their pupils. Reaction times in this discrimination task were significantly slower than in previously reported detection tasks with similar setup, suggesting that discrimination required an increased cognitive load. We found the pupils dilated for all trials following stimulus presentation. Interestingly, in correct rejection trials, where pupil dilations solely resulted from cognitive processing, dilations were larger for more difficult stimuli. Baseline pupil size before stimulus presentation strongly correlated with behavior, as perceptual sensitivity peaked at intermediate pupil baselines and reaction time was fastest at large baselines. We further explored these relationships by investigating to what extent pupil baseline was predictive of upcoming behavior and found that a Bayesian decoder had significantly greater than-chance probability in correctly predicting behavioral outcomes. Moreover, the outcome of the previous trial showed a strong correlation with behavior on present trials. Animals were more liberal and faster in responding following hit trials, whereas perceptual sensitivity was greatest following correct rejection trials. Taken together, these results suggest a tight correlation between pupil dynamics, perceptual performance, and reaction time in behaving rats, all of which are modulated by fluctuating arousal state. NEW & NOTEWORTHY In this study, we for the first time demonstrated that head-fixed rats were able to discriminate different directions of whisker movement. Interestingly, we found that the pupil dilated more when discriminating more difficult stimuli, a phenomenon reported in human subjects but not in animals. Baseline pupil size before stimulus presentation was found to strongly correlate with behavior, and a Bayesian decoder had significantly greater-than-chance probability in correctly predicting behavioral outcomes based on the baseline pupil size. PMID- 29995604 TI - The parieto-insular vestibular cortex in humans: more than a single area? AB - Here, we review the structure and function of a core region in the vestibular cortex of humans that is located in the midposterior Sylvian fissure and referred to as the parieto-insular vestibular cortex (PIVC). Previous studies have investigated PIVC by using vestibular or visual motion stimuli and have observed activations that were distributed across multiple anatomical structures, including the temporo-parietal junction, retroinsula, parietal operculum, and posterior insula. However, it has remained unclear whether all of these anatomical areas correspond to PIVC and whether PIVC responds to both vestibular and visual stimuli. Recent results suggest that the region that has been referred to as PIVC in previous studies consists of multiple areas with different anatomical correlates and different functional specializations. Specifically, a vestibular but not visual area is located in the parietal operculum, close to the posterior insula, and likely corresponds to the nonhuman primate PIVC, while a visual-vestibular area is located in the retroinsular cortex and is referred to, for historical reasons, as the posterior insular cortex area (PIC). In this article, we review the anatomy, connectivity, and function of PIVC and PIC and propose that the core of the human vestibular cortex consists of at least two separate areas, which we refer to together as PIVC+. We also review the organization in the nonhuman primate brain and show that there are parallels to the proposed organization in humans. PMID- 29995605 TI - High similarity between EEG from subcutaneous and proximate scalp electrodes in patients with temporal lobe epilepsy. AB - Subcutaneous recording using electroencephalography (EEG) has the potential to enable ultra-long-term epilepsy monitoring in real-life conditions because it allows the patient increased mobility and discreteness. This study is the first to compare physiological and epileptiform EEG signals from subcutaneous and scalp EEG recordings in epilepsy patients. Four patients with probable or definite temporal lobe epilepsy were monitored with simultaneous scalp and subcutaneous EEG recordings. EEG recordings were compared by correlation and time-frequency analysis across an array of clinically relevant waveforms and patterns. We found high similarity between the subcutaneous EEG channels and nearby temporal scalp channels for most investigated electroencephalographic events. In particular, the temporal dynamics of one typical temporal lobe seizure in one patient were similar in scalp and subcutaneous recordings in regard to frequency distribution and morphology. Signal similarity is strongly related to the distance between the subcutaneous and scalp electrodes. On the basis of these limited data, we conclude that subcutaneous EEG recordings are very similar to scalp recordings in both time and time-frequency domains, if the distance between them is small. As many electroencephalographic events are local/regional, the positioning of the subcutaneous electrodes should be considered carefully to reflect the relevant clinical question. The impact of implantation depth of the subcutaneous electrode on recording quality should be investigated further. NEW & NOTEWORTHY This study is the first publication comparing the detection of clinically relevant, pathological EEG features from a subcutaneous recording system designed for out patient ultra-long-term use to gold standard scalp EEG recordings. Our study shows that subcutaneous channels are very similar to comparable scalp channels, but also point out some issues yet to be resolved. PMID- 29995606 TI - Pursuit disorder and saccade dysmetria after caudal fastigial inactivation in the monkey. AB - The caudal fastigial nuclei (cFN) are the output nuclei by which the medio posterior cerebellum influences the production of saccadic and pursuit eye movements. We investigated the consequences of unilateral inactivation on the pursuit eye movement made immediately after an interceptive saccade toward a centrifugal target. We describe here the effects when the target moved along the horizontal meridian with a 10 or 20 degrees /s speed. After muscimol injection, the monkeys were unable to track the present location of the moving target. During contralesional tracking, the velocity of postsaccadic pursuit was reduced. This slowing was associated with a hypometria of interceptive saccades such that gaze direction always lagged behind the moving target. No correlation was found between the sizes of saccade undershoot and the decreases in pursuit speed. During ipsilesional tracking, the effects on postsaccadic pursuit were variable across the injection sessions, whereas the interceptive saccades were consistently hypermetric. Here also, the ipsilesional pursuit disorder was not correlated with the saccade hypermetria either. The lack of correlation between the sizes of saccade dysmetria and changes of postsaccadic pursuit speed suggests that cFN activity exerts independent influences on the neural processes generating the saccadic and slow eye movements. It also suggests that the cFN is one locus where the synergy between the two motor categories develops in the context of tracking a moving visual target. We explain how the different fastigial output channels can account for these oculomotor tracking disorders. NEW & NOTEWORTHY Inactivation of the caudal fastigial nucleus impairs the ability to track a moving target. The accuracy of interceptive saccades and the velocity of postsaccadic pursuit movements are both altered, but these changes are not correlated. This absence of correlation is not compatible with an impaired common command feeding the circuits producing saccadic and pursuit eye movements. However, it suggests an involvement of caudal fastigial nuclei in their synergy to accurately track a moving target. PMID- 29995608 TI - A quantitative framework for motion visibility in human cortex. AB - Despite the central use of motion visibility to reveal the neural basis of perception, perceptual decision making, and sensory inference there exists no comprehensive quantitative framework establishing how motion visibility parameters modulate human cortical response. Random-dot motion stimuli can be made less visible by reducing image contrast or motion coherence, or by shortening the stimulus duration. Because each of these manipulations modulates the strength of sensory neural responses they have all been extensively used to reveal cognitive and other nonsensory phenomena such as the influence of priors, attention, and choice-history biases. However, each of these manipulations is thought to influence response in different ways across different cortical regions and a comprehensive study is required to interpret this literature. Here, human participants observed random-dot stimuli varying across a large range of contrast, coherence, and stimulus durations as we measured blood-oxygen-level dependent responses. We developed a framework for modeling these responses that quantifies their functional form and sensitivity across areas. Our framework demonstrates the sensitivity of all visual areas to each parameter, with early visual areas V1-V4 showing more parametric sensitivity to changes in contrast and V3A and the human middle temporal area to coherence. Our results suggest that while motion contrast, coherence, and duration share cortical representation, they are encoded with distinct functional forms and sensitivity. Thus, our quantitative framework serves as a reference for interpretation of the vast perceptual literature manipulating these parameters and shows that different manipulations of visibility will have different effects across human visual cortex and need to be interpreted accordingly. NEW & NOTEWORTHY Manipulations of motion visibility have served as a key tool for understanding the neural basis for visual perception. Here we measured human cortical response to changes in visibility across a comprehensive range of motion visibility parameters and modeled these with a quantitative framework. Our quantitative framework can be used as a reference for linking human cortical response to perception and underscores that different manipulations of motion visibility can have greatly different effects on cortical representation. PMID- 29995609 TI - Synaptic drive in spinal motoneurons during scratch network activity. AB - Synaptic activity in motoneurons may provide unique insight in the relation between functional network activity and behavior. During scratch network activity in an ex-vivo preparation from red-eared turtles (Trachemys scripta elegans) excitatory and inhibitory synaptic current can be separated and quantified in voltage clamp recordings. With this technique we confirm the reciprocal synaptic excitation and inhibition in hip flexor motoneurons during ipsilateral scratching and show that out-of-phase inhibition and excitation also characterize hip extensor motoneurons during ipsi- and contralateral scratching. In contrast, inhibition precedes and partly overlaps excitation in hip flexor-like motoneurons and delays depolarization of membrane potential. We conclude that out-of-phase excitation and inhibition during rhythmic network activity is a common feature in spinal motoneurons. PMID- 29995607 TI - Neuromuscular determinants of slip-induced falls and recoveries in older adults. AB - Is there a neuromuscular basis for falls? If so, it may provide new insight into falls and their assessment and treatment. We hypothesized that falls and recoveries from a laboratory-induced slip would be characterized by differences in multimuscle coordination patterns. Using muscle synergy analysis, we identified different multimuscle coordination patterns between older adults who fell and those who recovered from a laboratory-induced "feet-forward" slip. Participants who fell recruited fewer muscle synergies than participants who recovered. This suggests that a fall may result from recruitment of an inadequate number of muscle synergies to produce the necessary mechanical functions required to maintain balance. Participants who fell also recruited different muscle synergies, including one with high levels of coactivity consistent with a startle like response. These differences in multimuscle coordination between slip outcomes were not accompanied by differences in slip difficulty or gait kinematics before or during the slip response. The differences in neuromuscular control may therefore reflect differences in sensorimotor control rather than kinematic constraints imposed by the slip, or the musculoskeletal system. Further research is required to test the robustness of these results and their interpretation with respect to additional mechanical variables (e.g., joint torques, ground reaction forces), responses to other fall types (e.g., trips), and within rather than between individuals. NEW & NOTEWORTHY Do falls and recoveries possess distinct neuromuscular features? We identified differences in neuromuscular control between older adults who fell and those who recovered from a "feet-forward" slip. Differences in neuromuscular control were not accompanied by differences in gait or slip kinematics before or during the slip response, suggesting differences in sensorimotor control rather than kinematics dictated the observed differences in neuromuscular control. An analysis of additional mechanical variables is required to confirm this interpretation. PMID- 29995610 TI - Translational Research on Stem Cells for Parkinson's Disease. PMID- 29995611 TI - WDR41 supports lysosomal response to changes in amino acid availability. AB - C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization of the protein complex containing C9orf72 and SMCR8 to lysosomes. Such lysosome localization increases in response to amino acid starvation but is not dependent on either mTORC1 inhibition or autophagy induction. Furthermore, WDR41 itself exhibits a parallel pattern of regulated association with lysosomes. This WDR41-dependent recruitment of C9orf72 to lysosomes is critical for the ability of lysosomes to support mTORC1 signaling as constitutive targeting of C9orf72 to lysosomes relieves the requirement for WDR41 in mTORC1 activation. Collectively, this study reveals an essential role for WDR41 in supporting the regulated binding of C9orf72 to lysosomes and solidifies the requirement for a larger C9orf72 containing protein complex in coordinating lysosomal responses to changes in amino acid availability. PMID- 29995612 TI - Advances in Influenza Research. PMID- 29995613 TI - Unintended Consequences of Systemic and Ablative Oncologic Therapy in the Abdomen and Pelvis. AB - Human cancers are genetically complex and diverse. Although advances in oncologic therapy aim to define and target unique steps in carcinogenesis, oncologists often rely on less discriminate anticancer therapies that have consequences for normal tissues. Even many of the so-called targeted therapies currently employed can adversely affect normal cells, leading to complications that necessitate dose reductions or cessation of specific therapies. This article explores the unintended consequences of currently employed systemic and ablative anticancer therapies that might manifest at imaging examinations of the abdomen and pelvis, including cytotoxic, molecular targeted, and immunologic agents; ablation; and hematopoietic stem cell transplant. Each of these treatments can have both major and minor unintended effects in the targeted organ(s), in local or adjacent structures, or at distant sites. Timely detection and reporting of adverse consequences of anticancer therapies by the astute imager can result in critical treatment modifications and/or lifesaving interventions; therefore, knowledge of these unintended effects is paramount for radiologists interpreting the results of imaging examinations in cancer patients. (c)RSNA, 2018. PMID- 29995614 TI - Introduction to the Technical Aspects of Computed Diffusion-weighted Imaging for Radiologists. AB - Diffusion-weighted (DW) imaging is a magnetic resonance (MR) imaging method. It is an indispensable sequence for the diagnosis of acute cerebral infarction and is recognized as a standard tool in oncologic imaging. Computed DW imaging refers to the synthesizing of arbitrary b-value DW images from a set of measured b-value images by voxelwise fitting. Computed DW imaging is advantageous because it generates DW images with a higher diffusion effect than that achievable by using the MR imaging units in use today. Additionally, computed DW imaging can reduce imaging time while producing images characterized by a higher signal-to-noise ratio than what the acquired DW images would display at the corresponding b values. By fitting input images acquired at a lower b value and correspondingly a shorter echo time, the signal intensity of the resulting computed DW image is closer to the ideal case. Computed DW images are generated by employing mathematical models that use mono-, bi-, or triexponential equations. To generate accurate computed DW images, the appropriate model must be selected, and the image parameters for the input data must be chosen accordingly. In addition, to reduce artifacts on computed DW images, the misalignment of input data must be corrected with the aid of image registration techniques. (c)RSNA, 2018. PMID- 29995615 TI - Brain Imaging Findings and Neurologic Complications after Allogenic Hematopoietic Stem Cell Transplantation in Children. AB - Hematopoietic stem cell transplantation (HSCT) is the only therapy for a subset of patients with malignant and nonmalignant diseases. Central nervous system (CNS) complications continue to be an important cause of morbidity and significantly contribute to mortality after HSCT. These complications include infections, cerebrovascular lesions, therapy-induced diseases, metabolic disturbances, and post-HSCT carcinogenesis. Following HSCT, three phases can be identified on the basis of the patient's immune status: the pre-engraftment period (<30 days after HSCT), the early postengraftment period (30-100 days after HSCT), and the late postengraftment period (>100 days after HSCT). There is a distinct relationship between the patient's degree of immunodeficiency after HSCT and the incidence of various complications that may occur. Early diagnosis of CNS complications is crucial for successful management and a good prognosis, and computed tomography and magnetic resonance imaging play an important role in achieving these goals. The global increase in the use of HSCT requires radiologists to be familiar with CNS complications, their relationship to the patient's immune status, and their imaging appearances. This article describes the clinical background of HSCT; reviews the incidence, causes, and timeline of brain complications in children who underwent allogenic HSCT; and identifies the characteristic imaging findings of these disorders. (c)RSNA, 2018. PMID- 29995616 TI - Cardiac Fibroma in an Adult AIRP Best Cases in Radiologic-Pathologic Correlation. AB - Editor's Note.-RadioGraphics continues to publish radiologic-pathologic case material selected from the American Institute for Radiologic Pathology (AIRP) "best case" presentations. The AIRP conducts a 4-week Radiologic Pathology Correlation Course, which is offered five times per year. On the penultimate day of the course, the best case presentation is held at the American Film Institute Silver Theater and Cultural Center in Silver Spring, Md. The AIRP faculty identifies the best cases from each organ system, brought by the resident attendees. One or more of the best cases from each of the five courses are then solicited for publication in RadioGraphics. These cases emphasize the importance of radiologic-pathologic correlation in the imaging evaluation and diagnosis of diseases encountered at the institute and its predecessor, the Armed Forces Institute of Pathology (AFIP). PMID- 29995617 TI - A Spectrum of Entities That May Mimic Abdominopelvic Abscesses Requiring Image guided Drainage. AB - A variety of entities may mimic drainable abscesses. This can lead to misdiagnosis of these entities, unnecessary percutaneous placement of a pigtail drainage catheter, other complications, and delay in appropriate treatment of the patient. Types of entities that may mimic drainable abscesses include neoplasms (lymphoma, gallbladder cancer, gastrointestinal stromal tumor, ovarian cancer, mesenteric fibromatosis, ruptured mature cystic teratoma, recurrent malignancy in a surgical bed), ischemia/infarction (liquefactive infarction of the spleen, infarcted splenule), diverticula (calyceal, Meckel, and giant colonic diverticula), and congenital variants (obstructed duplicated collecting system). Postoperative changes, including expected anatomy after urinary diversion or Roux en-Y gastric bypass and small bowel resection, may also pose a diagnostic challenge. Nonpyogenic infections (Mycobacterium tuberculosis, Mycobacterium avium complex, echinococcal cysts) and inflammatory conditions such as xanthogranulomatous pyelonephritis and gossypiboma could also be misinterpreted as drainable fluid collections. Appropriate recognition of these entities is essential for optimal patient care. This article exposes radiologists to a variety of entities for which percutaneous drainage may be requested, but is not indicated, and highlights important imaging findings associated with these entities to facilitate greater diagnostic accuracy and treatment in their practice. (c)RSNA, 2018. PMID- 29995618 TI - US of Pediatric Superficial Masses of the Head and Neck. AB - Superficial palpable masses of the head and neck are common in the pediatric population, with the vast majority of the lesions ultimately proven to be benign. Duplex ultrasonography (US) has emerged as the first-line imaging modality for the evaluation of superficial pediatric masses. Without utilizing radiation, iodinated contrast material, or sedation and/or anesthesia, US provides a means for quick and cost-effective acquisition of information, including the location, size, shape, internal content, and vascularity of the mass. In this review, the US findings are described for a variety of common and uncommon pediatric head and neck masses diagnosed in our practice. Specifically, the entities covered include neonatal scalp hematoma, craniosynostosis, dermoid and epidermoid cysts, Langerhans cell histiocytosis, lymph nodes and their complications, fibromatosis colli, thyroglossal duct cyst, branchial cleft cyst, cervical thymus, congenital goiter, thyroid papillary carcinoma, parathyroid adenoma, hemangioma, lymphangioma, jugular vein phlebectasia, Lemierre syndrome, acute parotitis and parotid abscess, leukemia and/or lymphoma, neurogenic tumor, and rhabdomyosarcoma. Ultimately, in situations in which the head or neck mass is too large, deep, or hyperechoic to be fully assessed within the US field of view, or if malignancy or a high-flow vascular lesion is suspected, then further evaluation with cross-sectional imaging is warranted. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29995619 TI - Sarcoidosis from Head to Toe: What the Radiologist Needs to Know. AB - Sarcoidosis is a multisystem granulomatous disorder characterized by development of noncaseating granulomas in various organs. Although the etiology of this condition is unclear, environmental and genetic factors may be substantial in its pathogenesis. Clinical features are often nonspecific, and imaging is essential to diagnosis. Abnormalities may be seen on chest radiographs in more than 90% of patients with thoracic sarcoidosis. Symmetric hilar and mediastinal adenopathy and pulmonary micronodules in a perilymphatic distribution are characteristic features of sarcoidosis. Irreversible pulmonary fibrosis may be seen in 25% of patients with the disease. Although sarcoidosis commonly involves the lungs, it can affect virtually any organ in the body. Computed tomography (CT), magnetic resonance imaging, and positron emission tomography/CT are useful in the diagnosis of extrapulmonary sarcoidosis, but imaging features may overlap with those of other conditions. Familiarity with the spectrum of multimodality imaging findings of sarcoidosis can help to suggest the diagnosis and guide appropriate management. (c)RSNA, 2018. PMID- 29995620 TI - Incomplete Cord Syndromes: Clinical and Imaging Review. AB - The ability to localize the three spinal tracts (corticospinal tract, spinothalamic tract, and dorsal [posterior] columns) involved in incomplete spinal cord syndromes at cross-sectional imaging and knowledge of the classic clinical manifestations of the various syndromes enable optimized imaging evaluation and provide clinicians with information that aids in diagnosis and treatment. The requisite knowledge for localizing these tracts is outlined. The authors review the spinal cord anatomy, blood supply, and course of these tracts and describe the various associated syndromes: specifically, dorsal cord, ventral cord, central cord, Brown-Sequard, conus medullaris, and cauda equina syndromes. In addition, they describe the anatomic basis for the clinical manifestation of each syndrome and the relevant imaging features of the classic causes of these entities. Knowledge of the anatomy and clinical findings of the spinal cord is essential for examining and treating patients with cord abnormalities. (c)RSNA, 2018. PMID- 29995621 TI - Case-based Review of Endovascular Renal Interventions: Primer for Radiology Residents and Fellows RadioGraphics Fundamentals | Online Presentation. PMID- 29995622 TI - Imaging Genomics of Embryonal Tumors of the Central Nervous System. PMID- 29995623 TI - Complications of 90Y Transarterial Radioembolization of Hepatic Tumors: Primer for Interventional Radiology Residents and Fellows RadioGraphics Fundamentals | Online Presentation. PMID- 29995624 TI - Nonepithelial Pancreatic Neoplasms: Sarcoma versus Lymphoma. PMID- 29995625 TI - Risk factors for onset of delirium after neck of femur fracture surgery: a prospective observational study. AB - BACKGROUND: Delirium is a common complication after surgery in the elderly that leads to increased length of stay and other adverse outcomes. The aim of this study was to better understand the exact causes of post-operative delirium in patients undergoing surgery for neck of femur (NOF) fractures. METHODS: We performed a prospective cohort study of 381 consecutive patients undergoing surgery for NOF fractures at a single institution. Baseline cognitive status and risk factors were recorded on admission. Post-operative cognitive status was assessed at regular intervals until discharge. Binary logistic regression was performed to identify independent predictors of delirium. RESULTS: Patients who developed post-operative delirium (n = 70) were significantly older (average age 83 vs. 78, p = 0.019) and more likely to be female (79% vs. 67%, p = 0.062) than non-affected patients. The presence of delirium was associated with increased length of stay (13 vs. 10 days, p = 0.001) and 1-year mortality (25.7% vs. 15% p = 0.03). Independent predictors of delirium included age >=65 years (Odds Ratio = 5.8), presence of anaemia (OR = 2.9), hypoxia (OR = 2.86), cardiac disease (OR = 2.8), Chronic Obstructive Pulmonary Disease (OR = 2.5), new onset electrolyte imbalance (OR = 2.2) and renal failure (OR = 1.9). CONCLUSION: Overall analysis demonstrated an increased incidence of delirium in older females with greater comorbid conditions. It was also found to be associated with increased morbidity and mortality. We recommend clinicians put greater effort into recognising risk factors of delirium and diagnosing it in a timely manner to mitigate its effects. PMID- 29995626 TI - Characteristics of the patients with delaminated rotator cuff tear. AB - PURPOSE: The purpose of this study was to analyze factors relating to delamination in full-thickness rotator cuff tears. METHODS: 126 patients with full-thickness rotator cuff tears treated by arthroscopic rotator cuff repair were the subjects of this study. There were 52 females and 74 males whose average age was 64.2 years. Fifty-three patients had history of trauma. The average duration of disorder was 29.5 weeks. Nineteen patients were diagnosed with diabetes. On types of the tears, small tear was observed in 59 patients, medium tear in 47 patients, large tear in 6 patients, and massive tear in 14 patients. The average size of tear was 1.98 cm. Delamination of the torn cuff was observed in 45 patients. Factors compared between the patients without delamination and those with delamination were as follows: gender and age of the patients, history of trauma, duration of disorder, diabetes, smoking, size and number of rotator cuff tears. RESULTS: The delamination rate of the smoking patients was significantly higher than non-smoking patients. The delamination rate of patients with more than two tendon tears was significantly higher than those with only one tendon tear. The average size of tear with delamination was significantly larger than that of tear without delamination. The other factors were not related to delamination. CONCLUSIONS: This study suggests that smoking, size of tear and number of torn cuffs are associated with delamination. The progression of torn cuff, anatomical features and nicotine of smoking affect the causes of delaminated tear of rotator cuff. PMID- 29995628 TI - Correlates of Rapid Repeat Pregnancy Among Adolescents and Young Women in Uganda. AB - CONTEXT: Short pregnancy intervals can contribute to maternal and child morbidity and mortality. No previous research has explored factors associated with short pregnancy intervals among young women in Uganda, where adolescent pregnancy and short birth intervals are common. METHODS: Data on 626 married or cohabiting women aged 15-22 with one or two previous pregnancies were drawn from the 2011 Uganda Demographic and Health Survey. Bivariate and multivariable logistic regression analyses were used to examine characteristics associated with rapid repeat pregnancy, defined in two ways: a pregnancy occurring within 24 months or 12 months of a prior pregnancy outcome. RESULTS: Among women, 74% and 37% had experienced a rapid repeat pregnancy within 24 months and 12 months, respectively. Rural women were more likely than urban women to have had a rapid repeat pregnancy within 24 months (odds ratio, 2.4). Women aged 15-17 and those 18 or older at first union were more likely than women younger than 15 to have had a rapid repeat pregnancy within 24 months (3.8 and 3.4); those whose partner had at least a secondary education had lower odds than others of the outcome (0.6). The odds of rapid repeat pregnancy increased with the number of months between marriage and first birth (1.05). Variables associated with rapid repeat pregnancy within 12 months included urban-rural residence, region, age at first union and marriage-to-birth interval. CONCLUSIONS: Efforts to reduce rapid repeat pregnancy among young women in Uganda should focus on rural areas. Strategies to reach women during antenatal care and the postpartum period after their first birth should be prioritized. PMID- 29995627 TI - Physiologically Based Pharmacokinetic (PBPK) Modeling of the Bisphenols BPA, BPS, BPF, and BPAF with New Experimental Metabolic Parameters: Comparing the Pharmacokinetic Behavior of BPA with Its Substitutes. AB - BACKGROUND: The endocrine disrupting chemical bisphenol A (BPA) has been facing stricter regulations in recent years. BPA analogs, such as the bisphenols S, F, and AF (BPS, BPF, and BPAF) are increasingly used as replacement chemicals, although they were found to exert estrogenic effects similar to those of BPA. Research has shown that only the parent compounds have affinity to the estrogen receptors, suggesting that the pharmacokinetic behavior of bisphenols (BPs) can influence their potency. OBJECTIVES: Our goal was to compare the pharmacokinetic behaviors of BPA, BPS, BPF, and BPAF for different age groups after environmentally relevant external exposures by taking into account substance specific metabolism kinetics and partitioning behavior. This comparison allowed us to investigate the consequences of replacing BPA with other BPs. METHODS: We readjusted a physiologically based pharmacokinetic (PBPK) model for peroral exposure to BPA and extended it to include dermal exposure. We experimentally assessed hepatic and intestinal glucuronidation kinetics of BPS, BPF, and BPAF to parametrize the model for these BPs and calibrated the BPS model with a biomonitoring study. We used the PBPK models to compare resulting internal exposures and focused on females of childbearing age in a two-dimensional Monte Carlo uncertainty analysis. RESULTS: Within environmentally relevant concentration ranges, BPAF and BPS were glucuronized at highest and lowest rates, respectively, in the intestine and the liver. The predominant routes of BPS and BPAF exposure were peroral and dermal exposure, respectively. The calibration of the BPS model with measured concentrations showed that enterohepatic recirculation may be important. Assuming equal external exposures, BPS exposure led to the highest internal concentrations of unconjugated BPs. CONCLUSIONS: Our data suggest that the replacement of BPA with structural analogs may not lower the risk for endocrine disruption. Exposure to both BPS and BPAF might be more critical than BPA exposure, if their respective estrogenic potencies are taken into account. https://doi.org/10.1289/EHP2739. PMID- 29995629 TI - Detection capability of quantitative faecal immunochemical tests for haemoglobin (FIT) and reporting of low faecal haemoglobin concentrations. AB - Faecal immunochemical tests for haemoglobin (FIT) are widely used in asymptomatic population screening for colorectal (bowel) cancer. FIT are also used to assist with the assessment of patients presenting with lower abdominal symptoms. Quantitative FIT allow the generation of numerical estimates of faecal haemoglobin (f-Hb) concentrations. There is now great interest in "low" f-Hb concentrations in these clinical settings: in consequence, knowledge of the detection capability is very important for f-Hb concentration examinations. There are a number of current problems associated with the reporting of low f-Hb concentrations and wide misunderstanding of the metrological aspects of examinations of f-Hb at low concentrations. These would be solved if the detectability characteristics of f-Hb concentration examinations, namely, the limit of blank (LoB), limit of detection (LoD) and limit of quantitation (LoQ), were generated, validated and used in reporting systems exactly as recommended in the EP17-A2 guideline of the Clinical Laboratory Standards Institute. LoB and LoD are statistical concepts, but the LoQ depends on definition of analytical performance specifications (APS). In this Opinion Paper proposals for interim APS are made, based on the current state of the art achieved with examinations of faecal samples. It is proposed that LoQ is determined at an examination imprecision of CV<=10% using faecal samples naturally positive for Hb rather than faeces spiked with haemolysate. Detailed proposals for reporting f-Hb data at low concentrations are also made. PMID- 29995630 TI - Clinical Chemistry and Laboratory Medicine continues to shine brightly in the constellation of laboratory medicine. PMID- 29995631 TI - High-fat diet modifies cytokine gene expression and exacerbates the effects of acute pancreatitis in the liver of rats. AB - BACKGROUND: Obese patients have a higher risk of developing different metabolic syndromes (MeS), including acute pancreatitis (AP). Although obese individuals are more prone to MeS and more susceptible to local and systemic inflammation in response to AP, thus causing long-lasting hospitalization, higher morbidity and mortality, their underlying mechanisms remain unclear. This study aimed to investigate the relationship between obesity and the outcomes of AP in the rat model of AP. METHODS: To assess the link between obesity and AP, 40 male albino rats were divided into two groups: control and those given a high-fat diet for 12 weeks. This was followed by the injection of a single dose of L-arginine (250 mg/100 gm) in half of each group to induce AP. RESULTS: Data evaluation was done using 2-way ANOVA. Values were considered significant when p<=0.05. Markers of AP were evaluated in the serum and ascitic fluid. Moreover, the systemic inflammatory markers, such as IL-6, TNF-alpha, HMGB1 and TLR4, were quantified in the liver of all groups. Results showed that the OAP group had the highest levels of liver enzymes and amylase aside from several signs of liver damage, such as fat necrosis and steatosis. CONCLUSIONS: The inflammatory cytokine levels are synchronized, creating an early responsive stage and late inflammatory stage to realize the best defense mechanism. Results also indicate that obesity is a main determinant of the severity of AP at the late stage. PMID- 29995632 TI - Sequential measurements of IGF-I serum concentrations in adolescents with Laron syndrome treated with recombinant human IGF-I (rhIGF-I). AB - Background Recombinant human insulin-like growth factor 1 (rhIGF-I) has been approved as an orphan drug for the treatment of growth failure in children and adolescents with severe primary IGF-I deficiency (SPIGFD) with little pharmacokinetic data available. Therefore, sequential measurements of serum IGF I, glucose, potassium, insulin and cortisol were performed in patients treated with rhIGF-I to evaluate their significance in safety and efficacy. Methods Repetitive blood samples were taken after meals before and 30, 60, 120, 180 and 360 min after rhIGF-I injections in two male patients with Laron syndrome at times of dose adjustments. Results Maximal IGF-I concentrations were observed 2 h after injections (495 ng/mL) and concentrations were still higher 6 h after injections than at baseline (303 ng/mL vs. 137 ng/mL). Thirteen percent of all and 33% of maximum IGF-I concentrations were greater than +2 standard deviation score (SDS) calculated for bone age (BA) (IGF-I SDS BA) rather than chronological age (CA) as BA was significantly delayed to CA by 3.2 years (p=0.0007). Height velocities correlated with individual maximum IGF-I SDS BA (rho=0.735; p<0.0001). Serum insulin, cortisol and glucose did not correlate with IGF-I concentrations, but serum potassium showed a negative correlation (rho=-0.364; p<0.0001) with IGF I concentrations. Conclusions Sequential measurements of serum IGF-I, glucose and potassium in patients with Laron syndrome may aid in optimizing and individualizing rhIGF-I treatment. IGF-I concentrations should be referenced according to BA which better reflects the biological age. The inverse correlation of IGF-I and serum potassium concentrations after injections of rhIGF-I has not been reported before and warrants further consideration. PMID- 29995633 TI - Single center experience of biotinidase deficiency: 259 patients and six novel mutations. AB - Background Biotinidase deficiency (BD) is an autosomal recessively inherited disorder of biotin recycling. It is classified into two levels based on the biotinidase enzyme activity: partial deficiency (10%-30% enzyme activity) and profound deficiency (0%-10% enzyme activity). The aims of this study were to evaluate our patients with BD, identify the spectrum of biotinidase (BTD) gene mutations in Turkish patients and to determine the clinical and laboratory findings of our patients and their follow-up period. Methods A total of 259 patients who were diagnosed with BD were enrolled in the study. One hundred and forty-eight patients were male (57.1%), and 111 patients were female (42.9%). Results The number of patients detected by newborn screening was 221 (85.3%). By family screening, 31 (12%) patients were diagnosed with BD. Seven patients (2.7%) had different initial complaints and were diagnosed with BD. Partial BD was detected in 186 (71.8%) patients, and the profound deficiency was detected in 73 (28.2%) patients. Most of our patients were asymptomatic. The most commonly found variants were p.D444H, p.R157H, c.98_104delinsTCC. The novel mutations which were detected in this study are p.D401N(c.1201G>A), p.A82G (c.245C>G), p.F128S(c.383T>C), c617_619del/TTG (p.Val207del), p.A287T(c.859G>A), p.S491H(c.1471A>G). The most common mutation was p.R157H in profound BD and p.D444H in partial BD. All diagnosed patients were treated with biotin. Conclusions The diagnosis of BD should be based on plasma biotinidase activity and molecular analysis. We determined the clinical and genetic spectra of a large group of patients with BD from Western Turkey. The frequent mutations in our study were similar to the literature. In this study, six novel mutations were described. PMID- 29995634 TI - A prospective analysis of intake and composition of mother's own milk in preterm newborns less than 32 weeks' gestational age. AB - BACKGROUND: Mothers of preterm (PT) infants have difficulty providing adequate quantities of human milk (HM) for their babies during their hospital stay. The macronutrient content in HM changes over time, varying across and within individual mothers. Research aim: To describe the intake of mothers' own milk (MOM) and its composition according to gestational (GA) and postnatal age (PNA) in infants born <32 weeks' GA and to correlate them with neonatal weight, length and morbidities. METHODS: A prospective observational study of 176 premature infants in a unit without a donor milk bank was conducted. Daily milk intake was recorded. HM macronutrients were determined by mid-infrared spectrophotometric analysis at 7, 15 and 30 days after delivery and monthly until hospital discharge. RESULTS: Intake of MOM increased during the first 2 weeks after birth and decreased steadily thereafter. Protein concentration varied inversely with PNA. Carbohydrate and lipid concentrations increased over the first few days and remained stable thereafter. A fall in weight percentiles from birth to 60 days was found. No correlation was found between total protein and calorie intakes at 3 and 15 days of life and growth velocity (GV) between 15 and 30 days, even when broken down into parenteral nutrition (PN), formula and MOM. CONCLUSION: To improve MOM feeding in PT newborns, intensive support strategies at the prenatal stage along entire hospitalization income should be encouraged. New protocols for fortification of HM should be implemented to optimize postnatal weight gain while preserving the health benefits of HM. PMID- 29995635 TI - Relationship between intercellular adhesion molecule-1 and morbidly adherent placenta. AB - Objective Morbidly adherent placenta (MAP) is a clinical condition the prevalance of which is steadily increasing. It is described as the invasion of the placenta into the uterine wall through the myometrium and beyond. Several studies have shown that intercellular adhesion molecule-1 (ICAM-1) increases the invasion capability of tumor cells and placental cells. In our study, we investigated the expression of ICAM-1 in MAP cases. Study design This is a prospective case control study. Eighty-nine patients who were diagnosed with MAP and 96 patients, without adherent placenta, as a control group were included in the study. ICAM-1 staining was examined by immuno-histochemical staining in placental samples. Results Of the 89 patients in the MAP group, 72 (80.8%) showed positive staining, while 26 (27%) did so in the control group. ICAM-1 positive staining in the MAP group was statistically significantly higher (P=0.03). Conclusion This is the first study investigating the relationship between MAP and ICAM-1 in the literature. In our study, we showed that ICAM-1 expression increased in the MAP group. PMID- 29995636 TI - Association between increased antenatal vaginal pH and preterm birth rate: a systematic review. PMID- 29995637 TI - Pain and alcohol: a comparison of two cohorts of 60 year old women and men: findings from the Good Aging in Skane study. AB - Background and aims Pain, use of painkillers and alcohol are highly prevalent in the general population. Aims of the study were to describe differences in pain, alcohol consumption and use of painkillers among two 60 year old birth cohorts stratified by gender. Methods Participants were recruited from the Skane centre of The Swedish National study on Aging and Care, a multicentre, prospective, longitudinal study. The sample comprised 60 year old men and women born between 1941 and 1943 and recruited to the study between 2001 and 2004 (n=663) and 60 year old men and women born in the period 1952-1954 and recruited to the study between 2013 and 2015 (n=924). Specially trained research staff conducted the interviews. For descriptive statistics the variables were presented in total numbers, percentages, mean and standard deviation, and 1st and 3rd quartile are also shown. The sample was divided into four groups: men and women born in the period 1941-1943, men and women born in the period 1952-1954, respectively. Results No difference in alcohol intake was detected between the two birth cohorts. All participants, regardless of pain or not, reported alcohol use below the specified risk level for both sexes. Teetotallers were more common in the 1952-1954 male cohort, 128 (29%), p<0.029. Two hundred and eighty one Men born between 1952 and 1954 reported pain (59.0%), compared to 173 men born between 1941 and 1943 (51.6%), p<0.034. There was no difference between the male cohorts in use of painkillers, p<0.062. No difference was found between the two female cohorts in terms of pain, p<0.144. One hundred and ten women in the 1941-43 cohort used painkillers (53.1%) compared to 119 women born between 1952 and 1954 (40.1%), p<0.004. When comparing men and women with pain born between 1941 and 1942, men with moderate pain use more alcohol, 157 g/month (q1 10, q3 365) than women, 44 g/month (q1 0, q3 134), p<0.001. Men with severe pain also use more alcohol, 96 g/month (q1 17, q3 324) than women, 27 g/month (q1 0, q1 118), p<0.030, and when those with pain were merged into a group, men use more alcohol, 175 g/month (q1 31, q3 356), than women, 68 g/month (q1 1, q3 207), p<0.001. This also applies to the later cohort; men, 132 g/month (q1 22, q3 270), compared to women, 76 g/month (q1 8, q3 182), p<0.001. When merging all pain into one group women use more painkillers both in the 1941-43 cohort, men (39.9%) compared to women (53.1%), p<0.010 and in the 1952-54 cohort, men (18.5%) compared to women (26.6%), p<0.003. Use of analgesics and alcohol is common but the highest percentage is among women born between 1941 and 1943, 45 (48.9%). Conclusions Pain and alcohol use are common among 60 year old women and men. A gender difference is that women use more painkillers. In the 1941-43 cohort almost every second woman with moderate pain who took painkillers also consumed alcohol. Implications It is time to alert prescribers that a large section of the population uses alcohol combined with painkillers. More research is needed to better understand the long-term perspective on health when using both painkillers and alcohol. PMID- 29995638 TI - An observational study of pain self-management strategies and outcomes: does type of pain, age, or gender, matter? AB - Background and aims Acute pain is differentiated from chronic pain by its sudden onset and short duration; in contrast, chronic pain is characterized by a duration of at least several months, typically considered longer than normal healing time. Despite differences in definition, there is little information on how types of self-management strategies or outcomes differ when pain is chronic rather than acute. Additionally, age and gender are thought to be related to types of strategies used and outcomes. However, strategies used and outcomes can be influenced by level of education, socioeconomic status, occupation, and access to the health care system, which can confound associations to type of pain, age or gender. The purpose of this study was to examine the association of strategies used for pain self-management and outcomes with type of pain, acute or chronic, age, or gender in a socioeconomically homogenous population, pharmacists. Methods Pharmacists with acute or chronic pain and a valid email completed an on-line questionnaire on demographic characteristics, pain characteristics, pharmacological and non-pharmacological strategies for managing pain, and outcomes (e.g. pain intensity). Univariate analysis was conducted by stratifying on type of pain (acute or chronic), then stratifying on gender (men vs. women) and age (younger vs. older). The a priori alpha level was 0.05. Results A total of 366 pharmacists completed the questionnaire, 212 with acute pain (average age=44+/-12.1; 36% men) and 154 with chronic pain (average age=53+/-14.0; 48% men). The chronic pain group reported substantially higher levels of pain before treatment, level of post-treatment pain, level of pain at which sleep was possible, and goal pain levels (effect sizes [ES's]=0.37-0.61). The chronic pain group were substantially more likely to use prescription non-steroidal anti inflammatory medications (NSAIDS), opioids, and non-prescription pain relievers (ES's=0.29-0.80), and non-medical strategies (ES's=0.56-0.77). Participants with chronic pain also were less confident (ES=0.54) and less satisfied (ES=0.52). In contrast, there were no differences within either the acute or chronic pain groups related to gender and outcomes. In the acute pain group, there also were no gender differences related to management strategies. However, younger age in the acute pain group was associated with use of herbal remedies and use of rest. Within the chronic pain group, men were more likely to use NSAIDS and women more likely to use hot/cold packs or massage while older participants were more likely to use massage. Variability in post-treatment level of pain and percent relief was high in all groups (coefficient of variation=25%-100%). Conclusions The differences between acute and chronic pain were substantial and included differences in demographic characteristics, pain characteristics, management strategies used, and outcomes. In contrast, few associations between age and gender with either management strategies or outcomes were identified, although the variability was high. Implications When managing or researching pain management, acute pain should be differentiated from chronic pain. Because of the substantial variability within the gender and age groups, an individual approach to pain management irrespective of age and gender may be most useful. PMID- 29995639 TI - Sub-3 mm, near-200 ps TOF/DOI-PET imaging with monolithic scintillator detectors in a 70 cm diameter tomographic setup. AB - Recently, a monolithic scintillator detector for time-of-flight (TOF)/depth-of interaction (DOI) positron emission tomography (PET) was developed. It has a detector spatial resolution of ~1.7 mm full-width-at-half-maximum (FWHM), a coincidence resolving time (CRT) of ~215 ps FWHM, and ~4.7 mm FWHM DOI resolution. Here, we demonstrate, for the first time, the imaging performance of this detector in a 70 cm diameter PET geometry. We built a tomographic setup representative of a whole-body clinical scanner, comprising two coaxially rotating arms, each carrying a detector module, and a central, rotating phantom table. The fully automated setup sequentially acquires all possible lines of response (LORs) of a complete detector ring, using a step-and-shoot acquisition approach. The modules contained 2 * 2 detectors, each detector consisting of a 32 mm * 32 mm * 22 mm LYSO crystal and a digital silicon photomultiplier (dSiPM) array. The system spatial resolution was assessed using a Na-22 point source at different radial distances in the field-of-view (FOV). Using 2D filtered back projection (2D FBP, non-TOF), tangential and radial spatial resolutions of ~2.9 mm FWHM were obtained at the center of the FOV. The use of DOI information resulted in almost uniform spatial resolution throughout the FOV up to a radial distance of 25 cm, where the radial and tangential resolution are ~3.3 mm FWHM and ~4.7 mm FWHM, respectively, whereas without DOI the resolution deteriorates to ~9 mm FWHM. Additional measurements were performed with a Na-22 filled Derenzo-like phantom at different locations within the FOV. Images reconstructed with a TOF maximum-likelihood expectation-maximization (TOF ML-EM) algorithm show that the system is able to clearly resolve 3 mm diameter hot rods up to 25 cm radial distance. The excellent and uniform spatial resolution, combined with an energy resolution of 10.2% FWHM and a CRT of ~212 ps FWHM, indicates a great potential for monolithic scintillators as practical high performance detectors in TOF/DOI-PET systems. PMID- 29995640 TI - Enhanced optical properties of Cu2O anchored on reduced graphene oxide (rGO) sheets. AB - In this report, Cu2O and Cu2O/rGO nanocomposites were successfully synthesized through chemical reduction method using glucose as a reducing agent for GO. The x ray diffraction and field emission scanning electron microscope was used to investigate the phase composition and microstructure of the as-prepared materials. The presence of different functional groups in the as-synthesized sample was analyzed by Fourier transform infrared spectroscopy. Raman spectroscopy was used to confirm structural aspects such as defects of synthesized Cu2O/rGO nanocomposites. The optical properties of the as-prepared samples were analyzed by UV-vis diffuse reflectance spectroscopy and photoluminescence spectroscopy. Urbach energy is calculated in order to find out the defects in the nanocomposites. Zeta potential analysis was done to study the surface charge and stability of the as-synthesized samples. These results show that the content of rGO introduced into nanocomposite improves the optical properties of Cu2O thereby enhancing the utilization of visible light. PMID- 29995641 TI - Comparison between electrocardiogram- and photoplethysmogram-derived features for atrial fibrillation detection in free-living conditions. AB - OBJECTIVE: Atrial fibrillation (AF) is the most commonly experienced arrhythmia and it increases the risk of stroke and heart failure. The challenge in detecting the presence of AF is the occasional and asymptomatic manifestation of the condition. Long-term monitoring can increase the sensitivity of detecting intermittent AF episodes, however it is either cumbersome or invasive and costly with electrocardiography (ECG). Photoplethysmography (PPG) is an unobtrusive measuring modality enabling heart rate monitoring, and promising results have been presented in detecting AF. However, there is still limited knowledge about the applicability of the PPG solutions in free-living conditions. The aim of this study was to compare the inter-beat interval derived features for AF detection between ECG and wrist-worn PPG in daily life. APPROACH: The data consisted of 24 h ECG, PPG, and accelerometer measurements from 27 patients (eight AF, 19 non AF). In total, seven features (Shannon entropy, root mean square of successive differences (RMSSD), normalized RMSSD, pNN40, pNN70, sample entropy, and coefficient of sample entropy (CosEn)) were compared. Body movement was measured with the accelerometer and used with three different thresholds to exclude PPG segments affected by movement. MAIN RESULTS: CosEn resulted as the best performing feature from ECG with Cohens kappa 0.95. When the strictest movement threshold was applied, the same performance was obtained with PPG (kappa = 0.96). In addition, pNN40 and pNN70 reached similar results with the same threshold (kappa = 0.95 and 0.94), but were more robust with respect to movement artefacts. The coverage of PPG was 24.0%-57.6% depending on the movement threshold compared to 92.1% of ECG. SIGNIFICANCE: The inter-beat interval features derived from PPG are equivalent to the ones from ECG for AF detection. Movement artefacts substantially worsen PPG-based AF monitoring in free-living conditions, therefore monitoring coverage needs to be carefully selected. Wrist worn PPG still provides a promising technology for long-term AF monitoring. PMID- 29995642 TI - Silk fibroin-bioactive glass based advanced biomaterials: towards patient specific bone grafts. AB - A major challenge in bone tissue engineering is to develop patient-specific, defect-site specific grafts capable of triggering specific cell signaling pathways. We could programmably fabricate the 3D printed bone constructs via direct ink writing of silk-gelatin-bioactive glass (SF-G-BG) hybrids using two different compositions of melt-derived bioactive glasses (with and without strontium) and compared against commercial 45S5 Bioglass(r). Physico-chemical characterization revealed that released ions from bioactive glasses inhibited the conformational change of Bombyx mori silk fibroin protein (from random coil to beta-sheet conformation), affecting printability of the SF-G-BG ink. In-depth molecular investigations showed that strontium containing SF-G-BG constructs demonstrated superior osteogenic differentiation of mesenchymal stem cells (TVA BMSCs) over 21 days towards osteoblastic (marked by upregulated expression of runt related transcription factor, alkaline phosphatase, osteopontin, osteonectin, integrin bone sialoprotein, osteocalcin) and osteocytic (marked by podoplanin, dentin matrix acidic phosphoprotein, sclerostin) phenotype compared to other BG compositions and silk-gelatin alone. Moreover, ionic release from bioactive glasses in the silk-gelatin ink triggered the activation of signaling pathways (BMP-2, BMP-4 and IHH), which are critical in regulating bone formation in vivo. Overall, the presence of strontium containing bioactive glass in silk gelatin matrices provided appropriate cues in regulating the development of custom-made 3D in vitro human bone constructs. PMID- 29995643 TI - Shielding of beta and bremsstrahlung radiation with transparent Bi2O3-B2O3-TeO2 glasses in therapeutic nuclear medicine. AB - High-energy beta emitters (yttrium-90, strontium-89 and phosphorus-32) are nowadays increasingly used in therapeutic nuclear medicine. Beta particles and bremsstrahlung (photons produced when beta particles interact with materials) are harmful and should be shielded in order to protect the personnel and public from their harmful effects. This work determined the radiation yield, effective atomic number and range associated with the interaction of beta particles with a transparent xBi2O3-30B2O3-(70-x)TeO2 glass system (where x = 40, 50, 60 and 70 mol%) using the ESTAR database and programme; and other relevant equations. The properties of the studied glass systems were compared with transparent lead glass, which is unwanted in the medical settings because of lead's toxicity. The result of this work showed that the studied glasses are suitable for use in making vials, syringes and other transparent materials, necessary for shielding high-energy beta particles. All the studied glass systems can replace lead glass. PMID- 29995644 TI - Structural evolution and magnetic properties of anionic clusters Cr2Ge n (n = 3 14): photoelectron spectroscopy and density functional theory computation. AB - The structural, electronic and magnetic properties of dual Cr atoms doped germanium anionic clusters, [Formula: see text] (n = 3-14), have been investigated by using photoelectron spectroscopy in combination with density functional theory calculations. The low-lying structures of [Formula: see text] are determined by DFT based genetic algorithm optimization. For [Formula: see text] with n ? 8, the structures are bipyramid-based geometries, while [Formula: see text] cluster has an opening cage-like structure, and the half encapsulated structure is gradually covered by the additional Ge atoms to form closed-cage configuration with one Cr atom interior for n = 10 to 14. Meanwhile, the two Cr atoms in [Formula: see text] clusters tend to form a Cr-Cr bond rather than be separated. Interestingly, the magnetic moment of all the anionic clusters considered is 1 MU B. Almost all clusters exhibit antiferromagnetic Cr-Cr coupling, except for two clusters, [Formula: see text] and [Formula: see text]. To our knowledge, the [Formula: see text] cluster is the first kind of transition-metal doped semiconductor clusters that exhibit relatively stable antiferromagnetism within a wide size range. The experimental/theoretical results suggest high potential to modify the magnetic behavior of semiconductor clusters through introducing different transition-metal dopant atoms. PMID- 29995645 TI - Characterization of imaging latency for real-time MRI-guided radiotherapy. AB - Hybrid MR-linac systems can use fast dynamic MR sequences for tumor tracking and adapt the radiation treatment in real-time. For this the imaging latency must be as short as possible. This work describes how different acquisition parameters influence this latency. First, the latency was measured for Cartesian readouts with phase encode orderings linear, reverse-linear, and high-low. Second, the latency was measured for radial readouts with linear and golden angle profile orderings. To reduce the latency, a spatio-temporal (k-t) filter that suppresses the k-space center of earlier acquired spokes was implemented for the golden angle sequence. For Cartesian readouts a high-low ordering achieved a three times lower latency compared to a linear ordering with our sampling parameters. For radial readouts the filter was able to reduce the acquisition latency from half the acquisition time to a quarter of the acquisition time. The filter did not compromise the signal-to-noise ratio and the artifact power. PMID- 29995646 TI - Small airway segmentation in thoracic computed tomography scans: a machine learning approach. AB - Small airway obstruction is a main cause for chronic obstructive pulmonary disease (COPD). We propose a novel method based on machine learning to extract the airway system from a thoracic computed tomography (CT) scan. The emphasis of the proposed method is on including the smallest airways that are still visible on CT. We used an optimized sampling procedure to extract airway and non-airway voxel samples from a large set of scans for which a semi-automatically constructed reference standard was available. We created a set of features which represent tubular and texture properties that are characteristic for small airway voxels. A random forest classifier was used to determine for each voxel if it belongs to the airway class. Our method was validated on a set of 20 clinical thoracic CT scans from the COPDGene study. Experiments show that our method is effective in extracting the full airway system and in detecting a large number of small airways that were missed by the semi-automatically constructed reference standard. PMID- 29995647 TI - Approaching Spine Research in an Outreach Setting: What Type of Infrastructure is Conducive for Conducting Research? AB - Organizing medical research in an outreach setting can be a challenging task, especially when it involves complex spine procedures in patients whom it is difficult to follow-up for long term. Disease severity at presentation is often advanced in outreach settings due to limited local resources, surgeon expertise, and hospital infrastructure. Case complexity can present a challenge to local and outreach surgeons alike. This article will describe what encompasses an ideal outreach program as it relates to spine, how to manage cost in an outreach setting, collection of outcome data, and maintaining long-term follow-up. As one of the criticisms of medical outreach is the relative paucity of outcome data, this article discusses methods to collect and report outcomes abroad. We also discuss the value of translating outcome questionnaires to different languages and cross-cultural comparisons. In addition, relatively rare pathologies are often seen with greater frequency abroad. These patients are ideally suited for a focused case series than can guide treatment decisions. PMID- 29995649 TI - Meal Planning Program to Reduce Barriers and Improve Diet Quality in Worksite Wellness Center Members. AB - OBJECTIVE: Many adults struggle with eating healthfully. To address this problem, dietitians and a physician at a worksite wellness center designed and implemented a healthy eating program to identify and reduce barriers and to improve nutrition knowledge, confidence, and eating habits. METHODS: A single cohort study design of members of a worksite wellness center who attended the program. RESULTS: Eight six participants demonstrated significant improvement in reducing perceived barriers (P < 0.001), improving nutritional knowledge (P = 0.001), increasing confidence (P < 0.001), and increasing the frequency of preparing healthy meals (P < 0.001) and intake of fruits and vegetables (P < 0.001). These improvements were maintained at the 6-month follow-up. CONCLUSION: These results suggest that participation in a 6-week nutrition education program at a worksite wellness center decreases barriers to healthy eating and improves dietary intake. PMID- 29995650 TI - EBUS-TBNA Cytology Specimens are Predictive of Occupational Dust Exposure in Patients With Bilateral Mediastinal and Hilar Lymphadenopathy. AB - OBJECTIVES: The aim of this study was to describe the cytological features of patients with significant occupational dust exposure presenting with benign bilateral mediastinal and hilar lymphadenopathy (BHL). METHODS: A retrospective cohort study including patients undergoing EBUS-TBNA for investigation of benign BHL. Patient characteristics, dust exposure history, radiology, and cytology samples from EBUS-TBNA were assessed. RESULTS: EBUS-TBNA cytology in patients with exposure showed a significant increase in the presence of birefringent fibers (60.7% vs 19.2%, P = 0.001) and intracellular carbon pigment (75.0% vs 28.9%, P = 0.001) compared with patients without exposure. The presence of these two features together yielded a sensitivity of 53.6% and a specificity of 88.5%. CONCLUSION: In patients with BHL and a history of occupational dust exposure, the presence of birefringent fibers and intracellular carbon pigment in EBUS-TBNA cytology samples may assist in a diagnosis of lymphadenopathy due to occupational dust exposure. PMID- 29995651 TI - Occupational Hearing Loss: What Are Some Occupations Not Commonly Considered at Risk? PMID- 29995652 TI - Expression of HPV-induced DNA Damage Repair Factors Correlates With CIN Progression. AB - Human papillomaviruses (HPVs) are DNA viruses with epithelial tropism. High-risk types of HPV are the causative agents of the majority of cervical cancers and are responsible for a number of other anogenital as well as oropharyngeal cancers. The life cycle of HPV is closely linked to the differentiation state of its host cell and is dependent on the activation of specific pathways of the DNA damage response. Several proteins from the ataxia telangiectasia mutated and the ataxia telangiectasia mutated and Rad3-related DNA repair pathways, which are essential for maintaining genomic stability in cells, are upregulated in HPV-positive cells and are required for viral replication. Our studies examine the expression of 5 such DNA repair factors-pCHK2, pCHK1, FANCD2, BRCA1, and H2AX-in cervical specimens from patients diagnosed with low-grade, intermediate-grade, or high grade lesions. The percentage of cells expressing pCHK2, pCHK1, FANCD2, and BRCA1 is significantly higher in high-grade squamous intraepithelial lesions compared with that of either low-grade squamous intraepithelial lesions or normal tissue, particularly in differentiated cell layers. In addition, the distribution of this staining throughout the epithelium is altered with increasing lesion grade. This study characterizes the expression of pCHK2, pCHK1, FANCD2, H2AX and BRCA1 during cervical cancer progression and provides additional insight into the role of these DNA damage response proteins in viral transformation. PMID- 29995653 TI - Ovarian Lipoleiomyoma: A Rare Entity. AB - Ovarian lipoleiomyoma is an extremely rare neoplasm and may pose a diagnostic challenge for clinicians, radiologists, and pathologists. It is rarely described as case reports in the literature; almost all patients are late middle aged or elderly. Hereby, we encountered a 57-yr-old postmenopausal woman who presented with abdominal pain. Radiologic investigation revealed a heterogenous nonenhancing mass in the left adnexa, suggestive of dermoid cyst. Microscopic examination showed clusters of adipocytes intersecting the fascicles of smooth muscles, diagnostic of lipoleiomyoma. The present case revisits the clinical and morphologic findings of lipoleiomyoma along with previously published cases in literature. PMID- 29995654 TI - Gradual ulnar lengthening by an Ilizarov ring fixator for correction of Masada IIb forearm deformity without tumor excision in hereditary multiple exostosis: preliminary results. AB - Bony exostoses are benign osteocartilaginous growths that start close to growth plates. Approximately 30-60% of patients have forearm deformities. The commonly encountered forearm deformities in these patients are bowing of the radius, with or without ulnar drift of the carpus, radial head dislocation, shortening of the ulna, and radial head dislocation. The current study reported on the results of management of radial head dislocation for type IIb Masada and Oho classification of forearm deformities by Ilizarov ulnar lengthening and without tumor excision. A series of 12 patients with Masada type IIb deformity were treated by Ilizarov lengthening at AlHadra University Hospital, Alexandria, Egypt, during the period from January 2008 to June 2014. There were eight males and four females; the right forearm was affected in seven patients. The mean age of the patients was 8.7 years (range: 7.5-10 years). All cases showed ulnar shortening with distal ulnar exostosis and radial head dislocation (Masada type IIb). All patients were operated on under general anesthesia, with application of the Ilizarov frame to the forearm. The frame used was assembled of two complete rings; the proximal one was fixed to the proximal ulna and the distal ring was fixed to both radius and ulna. Ulnar osteotomy was performed between the two rings, followed by ulnar lengthening 10 days postoperatively to lengthen the ulna and pull down the radius. Over a follow-up period of 33.2 months (24-48 months), all patients showed spontaneous reduction of the radial head and correction of the forearm deformity. The range of motion improved: flexion increased from 117.5 degrees (110-130 degrees ) to 145 degrees (130-160 degrees ) and extension increased to 4.6 degrees (0-10 degrees ), whereas it was 13.8 degrees (10-20 degrees ) preoperatively and the supination increased from 46.3 degrees (40-50 degrees ) preoperatively to 73.6 degrees (65-80 degrees ) postoperatively. Pronation improved from a preoperative average of 37.9 degrees (30-40 degrees ) to 70.8 degrees (60-80 degrees ) at the end of follow-up. The average amount of ulnar length was 27.9 mm (25-35) and the duration of external fixation was 103.3 days on average, with a range of 90-130. Thus, the average external fixation index was 3.7 days/mm (range: 3.6-4.0). Gradual lengthening of the ulna and pulling down the radius with an Ilizarov frame is an excellent method for correction of forearm deformity in patients with multiple hereditary exostosis (Masada IIb). Early intervention is the key to achieving spontaneous reduction of the radial head in all patients without the need for corrective osteotomy or tumor excision. Level of evidence: level IV. PMID- 29995655 TI - L-Carnitine as an additive in Tyrode's buffer during platelet storage. AB - : Platelets are stored at 22-24 degrees C for 5 days, with gentle agitation. Platelet storage lesion decreases efficacy and safety of stored platelets. L Carnitine is a nonessential amino acid. Its interference with arachidonic acid metabolism affects platelet functions and oxidative stress. Hence, our study focuses on the use of L-carnitine in storage solution and investigates its influence on platelet functions and oxidative stress. Platelets isolated from 4 month-old male Wistar rats were stored with and without L-carnitine (10, 50 and 100 mmol/l) at 22 degrees C for 12 days. Various markers were analyzed on days 0, 4, 8 and 12. Aggregation with collagen decreased in LC100 (day 12), whereas adenosine triphosphate secretion increased in all L-carnitine groups. Glucose consumption was less in L-carnitine groups and pH was maintained at 7.4 in LC50 (day 8). Conjugate dienes (day 4) and thiobarbituric acid reactive substances (day 8) increased in LC10 and LC100. Protein carbonyls were maintained in L carnitine groups. Catalase activity and total antioxidant capacity increased gradually. L-Carnitine proved to be beneficial in platelet storage solution. There was improvement in platelet metabolism, decrements in lipid peroxidation and elevations in total antioxidant capacity up to 12 days. However, pH results emphasize that platelets with L-carnitine (50 mmol/l) could be stored up to 8 days. Therefore, Tyrode's buffer with L-carnitine can be an effective storage solution for extended platelet storage. This study contributes towards the development of better storage solutions for platelets. PMID- 29995656 TI - Thromboelastographic analysis of haemostasis in preeclamptic and normotensive pregnant women. AB - : Pregnancy is a state of heightened coagulation, exacerbated in pathological conditions such as preeclampsia. We evaluated the role of thromboelastography (TEG), compared with standard haemostasis tests, in identifying in haemostatic alterations in normotensive pregnancies and pregnancies complicated with preeclampsia. Standard haemostasis tests and TEG were performed on 28 normotensive women and 31 with preeclampsia at delivery, 6 weeks and 6 months postpartum. Results were compared between patient groups, and at different collection times. Standard haemostasis tests failed to reveal consistent differences in haemostatic function between subject groups, mirroring the inconsistency described in the literature. TEG revealed increased coagulability in preeclampsia subjects compared with normotensive subjects at delivery. Haemostatic alterations were normalized by 6 weeks postpartum and remained stable at 6 months postpartum. TEG is superior to standard laboratory haemostatic tests in evaluating antenatal and postpartum haemostatic alterations associated with pregnancy complications such as preeclampsia. PMID- 29995657 TI - Wdr-1 is essential for F-actin interaction with focal adhesions in platelets. AB - : Wdr-1, an actin interacting protein, enhances cofilin's capacity to accelerate depolymerization of F-actin filaments. Wdr-1-deficient mice have impaired hemostasis due to defective inside-out integrin signaling in platelets. Here, we studied the role of Wdr-1 on outside-in signaling necessary for retraction of the clot and platelet spreading. Outside-in signaling was assessed by fibrin clot retraction assay and by adhesion and spreading of unstimulated platelets on fibrinogen substrate. The spatial distribution of actin, cofilin-1 and Wdr-1 were determined by immunofluorescence microscopy. Interaction of F-actin with focal adhesion kinase was assessed in dual-color confocal images and by immunoblotting of F-actin filaments. Clot retraction is markedly impaired in Wdr-1-deficient platelets. Wdr-1-deficient platelets adhere and spread poorly on fibrinogen substrate compared with wild-type controls. In resting platelets, Wdr-1 is colocalized with cofilin-1 in cortical actin. Following platelets spreading on fibrinogen substrate, Wdr-1 translocates to the cytoskeleton in association with cofilin-1. In Wdr-1-deficient platelets, cofilin-1 is aberrantly localized throughout the cytoplasm and there is no significant change following adhesion to fibrinogen substrate. The actin filaments formed upon spreading on fibrinogen are mostly in the periphery of the platelets and does not traverse the cytoplasm. Furthermore, there is diminished colocalization of actin filaments with focal adhesion kinase. These studies show that Wdr-1 is essential for the localization of cofilin-1 to the platelet membrane skeleton. F-actin fails to attach to focal adhesions resulting in defective reorganization of actin filaments necessary for platelet spreading and clot retraction. PMID- 29995658 TI - Ibrutinib-related bleeding: pathogenesis, clinical implications and management. AB - : Ibrutinib is the first drug of a new family of Bruton's tyrosine kinases (Btk) inhibiting agents, which have proved to be useful for the treatment of several B cell lymphoid malignancies. This drug is associated to an increased bleeding risk from initial clinical trials especially in association with warfarin. Although Btk plays an important role in platelet signalling, increased bleeding tendency in patients on ibrutinib is more complex than Btk inhibition alone and is because of several antiplatelet mechanisms, namely inhibition of Btk and Tec kinases, which play a key role in platelet activation downstream of the collagen GPVI and Glycoprotein Ib. This risk is increased by concomitant antiplatelet and anticoagulant therapy; both dual antiplatelet therapy and vitamin K antagonists are contraindicated in these patients. Potential ibrutinib users often have age associated cardiovascular risk factors or conditions and the drug itself may trigger atrial fibrillation requiring antithrombotic therapy. Aspirin and direct oral anticoagulants can be regarded as the antithrombotic therapies of choice if required. Heparin and fondaparinux have also been used in clinical trials. Therefore, the need and duration of antithrombotic therapy must be carefully evaluated and treatment individualized according to clinical circumstances. Ibrutinib withdrawal and platelet transfusion are key for the management of major bleeding not involving the central nervous system. PMID- 29995659 TI - Venous thromboembolism risk associated with ABO, F11 and FGG loci. AB - : The current study aims to evaluate, for the first time in the Portuguese population, the association with venous thromboembolism (VTE) of five well known and replicated VTE-associated single nucleotide polymorphisms (SNPs) in genes ABO, F11 and FGG. A population sample of 96 cases of VTE, without strong or moderate inherited or noninherited predisposing factors, and 148 healthy controls were analyzed for variants in genes ABO (rs2519093; rs8176719), F11 (rs2036914; rs2289252) and FGG (rs2066865). SNPs were genotyped by real-time PCR with TaqMan probes or by PCR-restriction fragment length polymorphism. Logistic regression, adjusted for age and sex, revealed nominal significant association between the ABO rs8176719 C-allele and VTE in the additive model [odds ratio (OR) 1.62; P = 0.015] and significant association in the dominant model (OR 2.68; P = 0.001). A nominal significant association with VTE was found for the FGG rs2066865 minor T allele in the dominant model (OR 1.82; P = 0.034). A genetic risk score created by using subjects who carry one or any combination of two to four risk alleles showed a cumulative effect on VTE: OR 2.31 (P = 0.025) and OR 3.23 (P = 0.0016), respectively, compared with individuals who have none of the risk alleles. Our data suggest that SNPs ABO rs8176719 and FGG rs2066865 may contribute individually to the VTE susceptibility in the Portuguese population. A genetic risk score combining the VTE-associated FGG and ABO alleles improved the risk prediction of VTE. PMID- 29995660 TI - Knee Osteoarthritis with Chronic Quadriceps Tendon Rupture Treated with Total Knee Arthroplasty and Extensor Mechanism Allograft Reconstruction: A Case Report. AB - CASE: A 51-year-old male construction worker with a history of chronic quadriceps tendon rupture presented with no active knee extension and tricompartmental knee osteoarthritis. He underwent simultaneous total knee arthroplasty and extensor mechanism allograft reconstruction. At 4 years postoperatively, the patient had pain-free knee function and active extension. CONCLUSION: The combination of a chronic quadriceps tendon rupture with lack of active knee extension and knee osteoarthritis is a rare and challenging problem. To our knowledge, this combined diagnosis and the treatment described in this case report have not been reported previously in the literature. PMID- 29995661 TI - Bilateral Inferior Angle Ossicles of the Scapula: Pain Generators in a Young Woman: A Case Report. AB - CASE: We present the case of a 16-year-old woman with refractory shoulder pain despite nonoperative treatment. The only shoulder pathology that was noted on advanced imaging was an unfused ossicle on the inferior angle of each scapula. She was successfully treated with simple excision bilaterally; as demonstrated by the shoulder scores, there was substantial improvement. CONCLUSION: In young patients with vague and refractory shoulder pain with essentially normal radiographic findings, an ossicle on the inferior angle of the scapula may be considered a pain generator. Excision of the ossicle may provide excellent definitive treatment after more common shoulder pathology has been ruled out. PMID- 29995662 TI - Snapping at the Lateral Aspect of the Elbow: A Case Report and Review of the Literature. AB - CASE: A 59-year-old man presented with snapping at the lateral aspect of the elbow and associated pain. Magnetic resonance imaging demonstrated extensor tendinopathy and thickening of the radial collateral ligament. Ultrasonography showed entrapment of a synovial fold in the radiohumeral joint. Initial arthroscopic debridement did not alleviate the snapping. Three months later, the patient underwent open excision of a thickened and partially torn annular ligament; subsequently, all of the symptoms resolved. CONCLUSION: Snapping elbow is a phenomenon that often coincides with pain and limited function. Accurate diagnosis is critical because misdiagnosis has been demonstrated to have serious consequences, including the need for repeat surgery. PMID- 29995663 TI - Chronic Carpometacarpal Dislocation of the Thumb: A Case Report and Review of the Literature. AB - CASE: We report a case of a chronic, irreducible carpometacarpal (CMC) dislocation of the thumb, which was managed with a trapeziometacarpal arthrodesis. CONCLUSION: This case demonstrates that arthrodesis is a suitable salvage procedure for chronic, irreducible CMC dislocations of the thumb. PMID- 29995664 TI - Dorsal Radiocarpal Joint Fracture-Dislocation: A Case Report. AB - CASE: A 19-year-old right-hand-dominant man sustained a right dorsal radiocarpal dislocation. He presented with instability secondary to displacement of the volar ligamentous structures and an avulsed fragment of the distal aspect of the radius within the radiocarpal articulation. The patient was treated with open reduction and internal fixation, as well as a capsuloligamentous repair. At the 18-month follow-up, he had no pain and excellent functional recovery. CONCLUSION: Our experience emphasizes the importance of looking critically at the radiographs when there is an irreducible radiocarpal fracture-dislocation. A volar distal radial fragment and attached ligamentous structures can be the main blocks to closed reduction. PMID- 29995665 TI - Osteofibrous Dysplasia with Rhabdoid Elements in a 38-Year-Old Man with Spontaneous Regression Over Five Years: A Case Report. AB - CASE: A 38-year-old man presented with multifocal, partially confluent osteolytic lesions in the proximal dia-meta-epiphyseal region of the proximal aspect of the left tibia, which had been found incidentally when a radiograph was made after a rotational knee injury. When the results of a percutaneous core needle biopsy proved inconclusive, an open biopsy was performed. Osteofibrous dysplasia (OFD) with scattered groups of plump cells with a rhabdoid phenotype, shown to express both vimentin and pan-cytokeratin, was found. Because the lesion was an incidental finding, we decided to proceed with observation. Three months after the open biopsy, imaging showed marked regression of the lesion; there was nearly complete normalization 5 years later. CONCLUSION: To our knowledge, there has been only 1 prior reported case with these pathologic features, and there have been no reports of complete spontaneous regression in an adult patient with OFD. Treatment recommendations for OFD and for OFD-like adamantinoma range from observation to aggressive resection. PMID- 29995666 TI - Articulated Hip Distraction for Impingement of the Deformed Femoral Head in a Patient with Multiple Epiphyseal Dysplasia: A Case Report. AB - CASE: A 14-year-old boy with multiple epiphyseal dysplasia (MED) presented with right hip pain and stiffness. Radiographs revealed a deep notch at the superolateral part of the femoral head, which abutted the lateral corner of the acetabulum. Articulated hip distraction (AHD) was used to reduce the femoral head and obliterate the notch. At the 4-year follow-up, the radiographs showed a well preserved joint space, and the patient had functional improvement. CONCLUSION: AHD may be an effective way to address and obliterate a superolateral femoral head notch and promote regeneration of the femoral head in a patient with MED. PMID- 29995667 TI - A Guide to Reproducibility in Preclinical Research. AB - Many have raised concerns about the reproducibility of biomedical research. In this Perspective, the authors address this "reproducibility crisis" by distilling discussions around reproducibility into a simple guide to facilitate understanding of the topic.Reproducibility applies both within and across studies. The following questions address reproducibility within studies: "Within a study, if the investigator repeats the data management and analysis will she get an identical answer?" and "Within a study, if someone else starts with the same raw data, will she draw a similar conclusion?" Contrastingly, the following questions address reproducibility across studies: "If someone else tries to repeat an experiment as exactly as possible, will she draw a similar conclusion?" and "If someone else tries to perform a similar study, will she draw a similar conclusion?"Many elements of reproducibility from clinical trials can be applied to preclinical research (e.g., changing the culture of preclinical research to focus more on transparency and rigor). For investigators, steps toward improving reproducibility include specifying data analysis plans ahead of time to decrease selective reporting, more explicit data management and analysis protocols, and increasingly detailed experimental protocols, which allow others to repeat experiments. Additionally, senior investigators should take greater ownership of the details of their research (e.g., implementing active laboratory management practices, such as random audits of raw data [or at least reduced reliance on data summaries], more hands-on time overseeing experiments, and encouraging a healthy skepticism from all contributors). These actions will support a culture where rigor + transparency = reproducibility.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29995668 TI - Toronto Addis Ababa Academic Collaboration: A Relational, Partnership Model for Building Educational Capacity Between a High- and Low-Income University. AB - Educational partnerships between academic health sciences centers in high- and low-resource settings are often formed as attempts to address health care disparities. In this Perspective, the authors describe the Toronto Addis Ababa Academic Collaboration (TAAAC), an educational partnership between the University of Toronto and Addis Ababa University. The TAAAC model was designed to help address an urgent need for increased university faculty to teach in the massive expansion of universities in Ethiopia. As TAAAC has developed and expanded, faculty at both institutions have recognized that the need to understand contextual factors and to have clarity about funding, ownership, expertise, and control are essential elements of these types of collaborative initiatives. In describing the TAAAC model, the authors aim to contribute to wider conversations and deeper theoretical understandings about these issues. PMID- 29995669 TI - Competencies, Milestones, and a Level of Supervision Scale for Entrustable Professional Activities for Scholarship. AB - PROBLEM: Scholarship is an important element of both undergraduate and graduate medical education, and scholarly activity is required for all pediatric fellows. However, despite the creation of entrustable professional activities (EPAs) for scholarship, the specific progressive levels of performance and the appropriate level of supervision for a given performance level have not been defined. The authors developed competencies and milestones for the scholarship EPA to provide a framework for assessment across the continuum; a level of supervision scale was also developed. APPROACH: The Vitae Researcher Development Framework served as a template to create the competencies and milestones for the scholarship EPA. Beginning in September 2015 and using a modified Delphi approach, three drafts were circulated to individuals with expertise in various types of scholarship until broad agreement was achieved. Then, in October 2016, the Steering Committee of the Subspecialty Pediatrics Investigator Network created a level of supervision scale, modeled after one it had previously developed. OUTCOMES: Eight competencies were identified as important in making entrustment decisions related to scholarship. For each competency, five milestone levels that span the continuum from novice to expert were created. A supervision scale with five progressive levels of entrustment was also created. NEXT STEPS: Next steps include a study to obtain validity evidence for the supervision scale and determine the correlation between milestone and supervision levels. These competencies, milestones, and supervision levels can potentially serve as a road map for trainees and junior faculty and also play a role in the assessment of physician-scientists. PMID- 29995670 TI - Preventing Exercise-Associated Collapse Using Online Runner Education: A Randomized, Controlled Trial. AB - OBJECTIVE: To determine whether online exercise-associated collapse (EAC) prevention education decreases medical tent EAC visits among first-time marathoners. DESIGN: A prospective controlled study, with age- and sex-stratified randomization, evaluated rates of medical tent diagnosed EAC among runners randomized to the intervention group and intervention participants, compared with a control group. SETTING: Grandma's Marathon Medical Tent in Duluth, MN, June 2016. PARTICIPANTS: Runners in the 2016 Grandma's Marathon who never previously ran a marathon (n = 2943), randomized into control (n = 1482) and intervention (n = 1461) groups. Intervention participants opened the EAC prevention video (n = 590). INTERVENTIONS: Online EAC education included an introductory webpage and 5 minute professional video describing EAC and prevention. MAIN OUTCOME MEASURES: Medical tent visit with EAC diagnosis. RESULTS: Intervention participants had no decreased likelihood of EAC, compared with controls [odds ratio (OR), 0.88, 95% confidence interval (CI), 0.46-1.69]. Exercise-associated collapse occurred less frequently in those with longer race times (OR, 0.58, 95% CI, 0.43-0.79). Intervention participation was associated with longer race times (OR, 1.12, 95% CI, 1.10-1.23). CONCLUSIONS: Those opening the EAC prevention video and controls had similar EAC rates. Slower running speed was associated with lower EAC rates. Video viewing was a predictor of slower running pace. PMID- 29995671 TI - Revisiting Arthroscopic Partial Meniscectomy for Degenerative Tears in Knees With Mild or No Osteoarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVE: The purpose of this systematic review and meta-analysis was to evaluate the efficacy of arthroscopic partial meniscectomy (APM) for symptomatic degenerative meniscal tear (DMT) in knees with mild or no osteoarthritis. STUDY DESIGN: A systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, and Cochrane databases were systematically searched. The inclusion criteria were as follows: (1) English language, (2) randomized controlled trial (RCT), (3) comparison between APM and other treatment modalities as a primary objective, and (4) complete DMT in knees with mild or no osteoarthritis. Mild or no arthritis was defined as Kellgren-Lawrence grade 0 to 2 or Ahlback 0 to 1 on radiography. Statistical analysis of functional activity and pain after APM and conservative treatment or sham operation was performed using R version 3.3.1. RESULTS: Five articles were included in the final analysis, and they were all RCTs. Four studies compared clinical results of APM with those for physical therapy, and one study compared APM with sham operation. The functional activity was not better in the APM group (296 cases) than in the conservative treatment or sham operation group (284 cases) (I: 0%, small level of heterogeneity). Pain was not reduced significantly in the APM group compared with that in the conservative treatment or sham operation group (I: 0~90%, high level of heterogeneity). CONCLUSIONS: This systematic review and meta-analysis of high-quality literature provides relatively strong evidence that APM did not improve functional activity or reduce pain compared with the results with conservative treatment or sham operation in knees with mild or no osteoarthritis. PMID- 29995672 TI - Effects of Proton Pump Inhibitor Coadministration on the Plasma Concentration of Erlotinib in Patients With Non-Small Cell Lung Cancer. AB - BACKGROUND: Erlotinib is used for treating non-small cell lung cancer (NSCLC). Intestinal absorption of erlotinib is impaired under gastric pH elevation; therefore, coadministration of gastric acid suppressants may provide lower blood concentration of erlotinib. We investigated the effects of erlotinib coadministration with proton pump inhibitors (PPIs) and histamine H2 receptor blockers (H2RBs) on the plasma concentration of erlotinib and erlotinib-induced adverse reaction in patients with NSCLC. METHODS: Forty-two patients receiving erlotinib therapy for NSCLC were recruited for this study. Association of adverse reactions (rash and diarrhea) with plasma concentration of erlotinib was examined. Plasma concentration-to-dose (C/D) ratios and oral clearance (CL/F), which was estimated by population pharmacokinetic analysis of plasma concentrations of erlotinib, were compared among 3 patient groups: without coadministration of gastric acid suppressants (control group), with coadministration of PPI (PPI group), and coadministration of H2RB (H2RB group). RESULTS: Patients with grade >=2 rash had higher plasma concentrations of erlotinib compared with those with grade <=1 [1.02 (0.43-2.60) versus 0.67 (0.10 1.85) mcg/mL, P < 0.01]. The C/D ratios of erlotinib in the PPI and H2RB groups were lower than that in the control group [0.39 (0.08-0.76) and 0.48 (0.33-0.81) versus 0.51 (0.28-1.28) mcg.mL.mg.kg], where statistical significance was observed between PPI and control groups (P < 0.05). The population pharmacokinetic estimated oral CL/F in the PPI and H2RB groups were higher than that in the control group [5.55 (3.36-14.52) and 4.82 (2.08-6.32) versus 3.95 (2.01-10.44) L/h], where statistical significance was observed between PPI and control groups (P < 0.05). CONCLUSIONS: Plasma concentrations of erlotinib in patients under coadministration of gastric acid suppressants were lower than those without gastric acid suppressants through drug interaction, suppressing the intestinal absorption of erlotinib. The magnitude of this drug interaction was more pronounced in the coadministration of PPI compared with H2RB. PMID- 29995674 TI - Epitope-based human leukocyte antigen matching for transplantation: a personal perspective of its future. AB - PURPOSE OF REVIEW: This study reflects my personal experience with the characterization of human leukocyte antigen (HLA) epitopes and their significance in HLA matching for transplantation. It offers a subjective assessment what further studies are needed to have this concept be applied in the clinical setting. RECENT FINDINGS: This study addresses the structural characteristics of antibody-reactive HLA epitopes determined by different methods, eplet-associated antibody analysis and acceptable mismatching for sensitized patients and eplet immunogenicity and determination of mismatch permissibility. BASIC IMPLICATIONS: for clinical practice and research consider the need for further studies of the structural basis of antibody-verified HLA epitopes determined in different techniques and their clinical relevance, the biological basis of epitope immunogenicity and determinations of permissible mismatches and a computerized clinical transplant database with an Artificial Intelligence component that can generate evidence-based information for the practical application of epitope based HLA matching. PMID- 29995675 TI - Image Fusion and Mixed Reality in Abdominal Surgery. PMID- 29995676 TI - Response: 'Mixed and Augmented Reality-Why Surgeons Should Care'. PMID- 29995677 TI - Response to Letter to the Editor Regarding Epidural Analgesia in Patients Undergoing Elective Ventral Hernia Repair. PMID- 29995679 TI - Effect of Hospital Volume With Respect to Performing Gastric Cancer Resection on Recurrence and Survival: Results from the CRITICS Trial. AB - OBJECTIVE: We examined the association between surgical hospital volume and both overall survival (OS) and disease-free survival (DFS) using data obtained from the international CRITICS (ChemoRadiotherapy after Induction chemotherapy In Cancer of the Stomach) trial. SUMMARY BACKGROUND DATA: In the CRITICS trial, patients with resectable gastric cancer were randomized to receive preoperative chemotherapy followed by adequate gastrectomy and either chemotherapy or chemoradiotherapy. METHODS: Patients in the CRITICS trial who underwent a gastrectomy with curative intent in a Dutch hospital were included in the analysis. The annual number of gastric cancer surgeries performed at the participating hospitals was obtained from the Netherlands Cancer Registry; the hospitals were then classified as low-volume (1-20 surgeries/year) or high-volume (>=21 surgeries/year) and matched with the CRITICS trial data. Univariate and multivariate analyses were then performed to evaluate the hazard ratio (HR) between hospital volume and both OS and DFS. RESULTS: From 2007 through 2015, 788 patients were included in the CRITICS trial. Among these 788 patients, 494 were eligible for our study; the median follow-up was 5.0 years. Five-year OS was 59.2% and 46.1% in the high-volume and low-volume hospitals, respectively. Multivariate analysis revealed that undergoing surgery in a high-volume hospital was associated with higher OS [HR = 0.69, 95% confidence interval (CI) = 0.50 0.94, P = 0.020] and DFS (HR = 0.73, 95% CI: 0.54-0.99, P = 0.040). CONCLUSIONS: In the CRITICS trial, hospitals with a high annual volume of gastric cancer surgery were associated with higher overall and DFS. These findings emphasize the value of centralizing gastric cancer surgeries in the Western world. PMID- 29995678 TI - Morphological Factors Related to Nodal Metastases in Neuroendocrine Tumors of the Appendix: A Multicentric Retrospective Study. AB - OBJECTIVE: The aim of this study was to evaluate clinical and morphological features related to nodal involvement in appendiceal neuroendocrine tumors (NETs), to identify patients who should be referred for oncological radicalization with hemicolectomy. BACKGROUND: Appendiceal NETs are usually diagnosed accidentally after appendectomy; the indications for right hemicolectomy are currently based on several parameters (ie, tumor size, grading, proliferative index, localization, mesoappendiceal invasion, lymphovascular infiltration). Available guidelines are based on scarce evidence inferred by small, retrospective, single-institution studies, resulting in discordant recommendations. METHODS: A retrospective analysis of a prospectively collected database was performed. Patients who underwent surgical resection of appendiceal NETs at 11 tertiary Italian centers, from January 1990 to December 2015, were included. Clinical and morphological data were analyzed to identify factors related to nodal involvement. RESULTS: Four-hundred fifty-seven patients were evaluated, and 435 were finally included and analyzed. Of them, 21 had nodal involvement. Grading G2 [odds ratio (OR) 6.04], lymphovascular infiltration (OR 10.17), size (OR 18.50), and mesoappendiceal invasion (OR 3.63) were related to nodal disease. Receiver operating characteristic curve identified >15.5 mm as the best size cutoff value (area under the curve 0.747). On multivariate analysis, grading G2 (OR 6.98), lymphovascular infiltration (OR 8.63), and size >15.5 mm (OR 35.28) were independently related to nodal involvement. CONCLUSIONS: Tumor size >15.5 mm, grading G2, and presence of lymphovascular infiltration are factors independently related to nodal metastases in appendiceal NETs. Presence of >=1 of these features should be considered an indication for oncological radicalization. Although these results represent the largest study currently available, prospective validation is needed. PMID- 29995680 TI - Surgical Delay in Nipple-sparing Mastectomy. PMID- 29995681 TI - Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for Unresectable Hepatitis B Virus-related Hepatocellular Carcinoma: A Single Center Study of 45 Patients. AB - OBJECTIVE: The aim of the study is to assess the efficacy and safety of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in patients with hepatitis B virus-related hepatocellular carcinoma (HCC). BACKGROUND: ALPSS allows curative resection of conventionally-unresectable liver tumors. However, its role in HCC is largely unknown. METHODS: Consecutive HCC patients who underwent ALPPS at our center between April 2013 and September 2017 were retrospectively studied. The oncological results were compared with patients receiving transcatheter arterial chemoembolization (TACE), and patients undergoing one-stage resection by using propensity score matching (PSM) analysis. RESULTS: The median tumor diameter was 13 cm (range: 6-22 cm) in patients with a single tumor (n = 28), whereas the median total tumor diameter was 12 cm (range: 9-31 cm) in patients with multiple tumors (n = 17). After stage-1 ALPPS, the median future liver remnant (FLR) increased by 56.8%. The stage-2 ALPPS was completed in 41 patients (91.1%) after a median of 12 days. The 90-day mortality rate was 11.1% (5/45). The overall survival (OS) rates at 1- and 3-year were 64.2% and 60.2%, whereas the disease-free survival (DFS) rates at 1 and 3 years were 47.6% and 43.9%, respectively. On PSM analysis, the long-term survival of patients undergoing ALPPS was significantly better than those receiving TACE (OS, P = 0.004; DFS, P < 0.0001) and similar to those subjected to one-stage liver resection (OS, P = 0.514; DFS, P = 0.849). CONCLUSIONS: The long-term survival after ALPPS was significantly better than TACE, and similar to those after one stage liver resection. ALPPS is a viable treatment option for patients with unresectable HCC in selected patients. PMID- 29995682 TI - Low Ligation of Inferior Mesenteric Artery in Laparoscopic Anterior Resection for Rectal Cancer Reduces Genitourinary Dysfunction: Results From a Randomized Controlled Trial (HIGHLOW Trial). AB - OBJECTIVES: The aim of the present study was to compare the incidence of genitourinary (GU) dysfunction after elective laparoscopic low anterior rectal resection and total mesorectal excision (LAR + TME) with high or low ligation (LL) of the inferior mesenteric artery (IMA). Secondary aims included the incidence of anastomotic leakage and oncological outcomes. BACKGROUND: The criterion standard surgical approach for rectal cancer is LAR + TME. The level of artery ligation remains an issue related to functional outcome, anastomotic leak rate, and oncological adequacy. Retrospective studies failed to provide strong evidence in favor of one particular vascular approach and the specific impact on GU function is poorly understood. METHODS: Between June 2014 and December 2016, patients who underwent elective laparoscopic LAR + TME in 6 Italian nonacademic hospitals were randomized to high ligation (HL) or LL of IMA after meeting the inclusion criteria. GU function was evaluated using a standardized survey and uroflowmetric examination. The trial was registered under the ClinicalTrials.gov Identifier NCT02153801. RESULTS: A total of 214 patients were randomized to HL (n = 111) or LL (n = 103). GU function was impaired in both groups after surgery. LL group reported better continence and less obstructive urinary symptoms and improved quality of life at 9 months postoperative. Sexual function was better in the LL group compared to HL group at 9 months. Urinated volume, maximum urinary flow, and flow time were significantly (P < 0.05) in favor of the LL group at 1 and 9 months from surgery. The ultrasound measured post void residual volume and average urinary flow were significantly (P < 0.05) better in the LL group at 9 months postoperatively. Time of flow worsened in both groups at 9 months compared to baseline. There was no difference in anastomotic leak rate (8.1% HL vs 6.7% LL). There were no differences in terms of blood loss, surgical times, postoperative complications, and initial oncological outcomes between groups. CONCLUSIONS: LL of the IMA in LAR + TME results in better GU function preservation without affecting initial oncological outcomes. HL does not seem to increase the anastomotic leak rate. PMID- 29995683 TI - Learning Curve Under Proctorship of Pure Laparoscopic Living Donor Left Lateral Sectionectomy for Pediatric Transplantation. AB - OBJECTIVE: To evaluate the learning curve of an expert liver transplantation surgeon approaching fully laparoscopic living donor left lateral sectionectomy (L LLS) under proctorship. BACKGROUND: Laparoscopic liver resections necessitate a long learning curve trough a stepwise fulfillment of difficulties. L-LLS requires expertise in both living donor liver transplantation and advanced laparoscopic liver surgery. There is currently no data about the learning curve of L-LLS. METHODS: A total of 72 pure L-LLS were included in this study. A Broken line model was used to identify the periods of the learning curve. A CUSUM analysis of the operative time was performed to evaluate improvements of outcomes with time. To evaluate the relationship between operative time and progressive number of procedures, a linear regression model was applied. A receiver operating characteristic (ROC) curve was carried out to identify the cutoff for completion of the learning curve. RESULTS: Operative time decreased with the progressive increase of procedures. Two cutoffs and 3 different periods were identified: cases 1 to 22, cases 23 to 55, and cases 56 to 72. A significant decrease in blood loss and operative time was noted. The CUSUM analysis showed an increase in operative time in the first period, a stable duration in the second period, and a decrease in the last. Blood loss was significantly associated with an increase in operative time (P = 0.003). According to the ROC curve, the learning curve was completed after 25 procedures. CONCLUSIONS: L-LLS is a safe procedure that can be standardized and successfully taught to surgeons with large experience in donor hepatectomy through a proctored learning curve. PMID- 29995684 TI - The Limit for Artificial Intelligence's Potentiality in Surgery Doesn't Have to Be the Surgeon. PMID- 29995685 TI - Response: Artificial Intelligence in Surgery Requires Interdisciplinary Collaboration and Understanding. PMID- 29995686 TI - Is Hepatectomy Justified for BRAF Mutant Colorectal Liver Metastases?: A Multi institutional Analysis of 1497 Patients. AB - OBJECTIVE: To analyze clinical outcomes and prognostic variables of patients undergoing hepatic resection for BRAF mutant (BRAF-mut) colorectal liver metastases (CRLM). BACKGROUND: Outcomes following hepatectomy for BRAF-mut CRLM have not been well studied. METHODS: All patients who underwent hepatectomy for CRLM with complete resection and known BRAF status during 2001 to 2016 at 3 high volume centers were analyzed. RESULTS: Of 4124 patients who underwent hepatectomy for CRLM, 1497 had complete resection and known BRAF status. Thirty-five (2%) patients were BRAF-mut, with 71% of V600E mutation. Compared with BRAF wild-type (BRAF-wt), BRAF-mut patients were older, more commonly presented with higher ASA scores, synchronous, multiple and smaller CRLM, underwent more major hepatectomies, but had less extrahepatic disease. Median overall survival (OS) was 81 months for BRAF-wt and 40 months for BRAF-mut patients (P < 0.001). Median recurrence-free survival (RFS) was 22 and 10 months for BRAF-wt and BRAF-mut patients (P < 0.001). For BRAF-mut, factors associated with worse OS were node positive primary tumor, carcinoembryonic antigen (CEA) >200 MUg/L, and clinical risk score (CRS) >=4. Factors associated with worse RFS were node-positive primary tumor, >=4 CRLM, and positive hepatic margin. V600E mutations were not associated with worse OS or RFS. A case-control matching analysis on prognostic clinicopathologic factors confirmed shorter OS (P < 0.001) and RFS (P < 0.001) in BRAF-mut. CONCLUSIONS: Patients with resectable BRAF-mut CRLM are rare among patients selected for surgery and more commonly present with multiple synchronous tumors. BRAF mutation is associated with worse prognosis; however, long-term survival is possible and associated with node-negative primary tumors, CEA <= 200 MUg/L and CRS < 4. PMID- 29995687 TI - Clinical Importance of Mean Corpuscular Volume as a Prognostic Marker After Esophagectomy for Esophageal Cancer: A Retrospective Study. AB - OBJECTIVE: To elucidate the clinical value of mean corpuscular volume (MCV) for prognostic prediction in patients with esophageal cancer who underwent radical esophagectomy. BACKGROUND: High MCV is suggested to be relevant to the incidence and prognosis of several malignancies. However, few studies investigating the correlation between MCV and survival outcome of esophageal cancer have been conducted. METHODS: This study included 570 patients with esophageal cancer who underwent radical esophagectomy between April, 2005 and December, 2017. Patients were divided into 2 groups according to the standard value of pretreatment MCV: normal (83-99 fL) and high (>99 fL) groups. Clinical backgrounds, short-term outcomes, and prognostic outcomes postesophagectomy were retrospectively compared between the groups. RESULTS: Of all patients, 410 (71.9%) had normal MCV, and 160 (28.1%) had high MCV. High MCV was significantly associated with lower body mass index, higher frequency of habitual alcohol and tobacco use, and higher incidence of multiple primary malignancies other than esophageal cancer. High MCV also correlated with higher incidence of postoperative morbidity of the Clavien-Dindo classification >=II and pulmonary morbidity. Overall survival was significantly worse in patients with high MCV. Multivariate analysis suggested that high MCV was an independent risk factor for worse survival outcome (hazard ratio 1.54, 95% confidence interval 1.098-2.151, P = 0.012). CONCLUSIONS: Patients with high MCV have various disadvantages in clinical background that can adversely affect both short-term and long-term outcomes after esophagectomy. MCV can become a predictive marker to estimate survival outcome after esophagectomy for esophageal cancer. PMID- 29995688 TI - Postoperative Complications and Health-related Quality of Life 10 Years After Esophageal Cancer Surgery. AB - OBJECTIVE: To evaluate the impact of postoperative complications on health related quality of life (HRQOL) up to 10 years after surgery for esophageal cancer. BACKGROUND: The impact of postoperative complications on HRQOL past 5 years is unknown. METHODS: Some 616 patients undergoing open esophageal cancer surgery between April 2, 2001 and December 31, 2005 in Sweden were enrolled in this population-based, nationwide, and prospective cohort study. Exposure was the occurrence of predefined postoperative complications, and the outcome was HRQOL evaluated by validated European Organization for Research and Treatment of Cancer questionnaires at 6 months, 3, 5, and 10 years after surgery. Linear mixed models, adjusted for longitudinal HRQOL in the general population and confounders, provided mean score differences (MDs) with 95% confidence intervals (CIs) for each HRQOL item and scale in patients with or without postoperative complications. RESULTS: At 10 years, 104 (17%) patients were alive and 92 (88%) answered the HRQOL questionnaires. Of these, 37 (40%) had at least 1 predefined postoperative complication. Twelve of the 25 scales and items were significantly worse in patients with postoperative complications 10 years after surgery, for example, physical function (MD -15, 95% CI -24 to -7), fatigue (MD 16, 95% CI 5 26), pain (MD 18, 95% CI 7-30), dyspnea (MD 15, 95% CI 2-27), insomnia (MD 20, 95% CI 8-32), and eating problems (MD 14, 95% CI 3-24) compared to patients without complications. CONCLUSIONS: Postoperative complications are associated with considerably impaired HRQOL up to 10 years after esophageal cancer surgery. PMID- 29995689 TI - Comparison of Acute Energy Expenditure and Rating of Perceived Exertion in Equivalent Bouts of Circuit Training and Treadmill Running. AB - Brewer, CB, Booher, BM, and Lawton, N. Comparison of acute energy expenditure and rating of perceived exertion in equivalent bouts of circuit training and treadmill running. J Strength Cond Res XX(X): 000-000, 2018-Circuit weight training (CT) maximizes exercise density, which may lead to an inaccurate perception of energy expenditure (EE). The purpose of this study was to compare acute EE indices and rating of perceived exertion (RPE) between CT and an equivalent bout of treadmill running (TR). College-aged men (n = 9) who regularly engaged in running and resistance training performed CT first. Circuit weight training that consisted of 10 resistance stations (40% of 1 repetition maximum, 15 repetitions, 60 b.min) was performed for 20 minutes. Heart rate (HR) and EE (Cosmed K4b) were monitored continuously, and RPE was assessed consistently. A 20 min TR session was performed at the average HR maintained during CT. Dependent t tests were used to assess differences in RPE, total EE (TEE, kcal), rate of EE (REE, kcal.min), and relative REE (RREE, kcal.kg.min) between CT and TR. Pearson's correlation was used to examine relationships between RPE and EE indices. Total EE was lower during CT (168.19 +/- 16.42) than TR (244.20 +/- 44.80); REE was lower during CT (8.49 +/- 0.90) than TR (12.21 +/- 2.24); and RREE was lower during CT (0.10 +/- 0.02) than TR (0.15 +/- 0.02) (all p < 0.001). Circuit weight training RPE (6.0 +/- 1.1) was greater than TR (4.1 +/- 0.6) (p < 0.001). There was no association between RPE and EE indices (p > 0.05). The average HR elicited by CT was 61% HR reserve. At equivalent HRs and duration, CT resulted in a significantly higher RPE but lower EE. It is imperative for participants engaged in CT to understand that although CT results in HR values within an aerobic training zone and feels more strenuous, it is not associated with greater acute EE. PMID- 29995690 TI - Relationships Between Eccentric and Concentric Knee Strength Capacities and Maximal Linear Deceleration Ability in Male Academy Soccer Players. AB - Harper, DJ, Jordan, AR, and Kiely, J. Relationships between eccentric and concentric knee strength capacities and maximal linear deceleration ability in male academy soccer players. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to investigate the relationships between maximal linear deceleration ability, and knee flexor (KF) and knee extensor (KE) strength. Fourteen male academy soccer players completed a 30-m linear sprint, a maximal linear deceleration test, and eccentric and concentric KF and KE contractions in both dominant leg (DL) and nondominant leg (NDL) at slower (60 degrees .s) and faster (180 degrees .s) angular velocities on an isokinetic dynamometer. Maximal linear deceleration ability was evaluated using distance-to-stop (DEC-DTS) and time-to-stop (DEC-TTS), with isokinetic peak torque representing KF and KE strength capacity. Relationships were established using Pearson's correlation coefficients (r) with magnitude-based inferences used to describe the uncertainty in the correlation. Both concentric KE and KF strength at 180 degrees .s in the NDL had the highest correlations with deceleration ability (r = -0.76 and r = 0.78, respectively). In the DL, concentric KE and KF strength at 180 degrees .s also had very likely large correlations with deceleration ability (r = -0.54 and 0.55, respectively). All correlations between eccentric KF strength and deceleration ability were unclear. At 180 degrees .s, correlations between eccentric KE strength and deceleration ability were also unclear; however, at 60 degrees .s, both DL (r = -0.63 to -0.64) and NDL (r = -0.54 to -0.55) had very likely large correlations with deceleration ability. These findings provide novel insights into the unilateral KF and KE strength capacities underpinning the ability to decelerate rapidly from high-sprint velocities. PMID- 29995691 TI - Construct Validity, Test-Retest Reliability, and Repeatability of Performance Variables Using a Flywheel Resistance Training Device. AB - Bollinger, LM, Brantley, JT, Tarlton, JK, Baker, PA, Seay, RF, and Abel, MG. Construct validity, test-retest reliability, and repeatability of performance variables using a flywheel resistance training device. J Strength Cond Res XX(X): 000-000, 2018-Power production is highly associated with physical performance; however, the ability to quantitatively measure power output during resistance exercise is lacking. The purpose of this study was to determine the validity and test-retest reliability of flywheel-based performance testing. Twelve young, resistance trained subjects completed 2 bouts of resistance exercise using a flywheel resistance training device (Exxentric kbox 4 Pro). Each session consisted of 3 sets of 3 exercise (bent-over row, Romanian deadlift, and biceps curl) with varying moments of inertia (0.050, 0.075, and 0.100 kg.m, respectively) in random order. Each set consisted of 5 maximal effort repetitions with 3-minute recovery between sets. Average power, peak concentric and eccentric power, average force, average speed, and total work for each set were recorded. Regression analysis revealed a near-perfect relationship between measured and predicted power, force, and work at given workloads. Pearson's r between trials 1 and 2 revealed good (>=0.70) to excellent (>=0.90) test-retest reliability for all outcomes with the exception of peak eccentric power for biceps curls (r = 0.69), which narrowly missed the cutoff for acceptable reliability. Bland-Altman plots revealed small (approximately 5-15%), but statistically significant bias between the 2 trials for some measures. Coefficient of repeatability for all outcomes was relatively high, indicating poor repeatability. Flywheel-based performance testing provides valid data. However, reliability varies between individual lifts and specific outcomes. Given the poor repeatability between trials, it is likely that subjects who are unaccustomed to this modality may require multiple testing sessions or a thorough familiarization period to ensure accurate measures of power, force, speed, and work during flywheel-based performance testing. PMID- 29995692 TI - Match Running Performance of Elite Soccer Players: V[Combining Dot Above]O2max and Players Position Influences. AB - Metaxas, TI. Match running performance of elite soccer players: V[Combining Dot Above]O2max and players position influences. J Strength Cond Res XX(X): 000-000, 2018-The aims of this study were (a) to assess the relationship between laboratory-measured V[Combining Dot Above]O2max with total distance covered in a soccer match, (b) to assess the relationship between laboratory-measured V[Combining Dot Above]O2max with the distance covered at a different running intensity in a soccer match, (c) to quantify different intensity running in various playing positions, and (d) to determine the differences of running performance between halves. Analyzed match running performance of the Greek elite (n = 14) soccer players using a global positioning system within the second division professional league. No correlation was found between V[Combining Dot Above]O2max and match running performance at any velocity. The players covered greater distances in the first half at all speed levels except walking. In the first half, they covered a greater distance than in the second half (1,533 vs. 1,297 m, p < 0.001; 879 vs. 708 m, p < 0.001; 433 vs. 359 m, p < 001; 185 vs. 152 m, p < 0.01; 81.4 vs. 65.5 m, p < 0.001) when jogging, running, high-intensity running, fast running, sprint and total, respectively. Wide players covered greater distances at fast running (p < 0.001) and sprint zone than the players who played at the axon of the field (348 vs. 297 and 186 vs. 113 m, respectively). In addition, midfielders covered a greater distance at high intensity running zone and at fast running zone than the defenders and forwards (1,768 vs. 1,372 m, p < 0.01 and 1,768 vs. 1,361 m, p < 0.01; 686 vs. 878 m, p < 0.01 and 709 vs. 878 m, p < 0.05, respectively). The results demonstrate that match running performance and the distance covered depends on the tactical role of each player in the team. These data provide valuable information for coaches regarding the running profile of the Greek elite soccer players that could be used to design a more effective training program. PMID- 29995693 TI - Influence of Acute Concurrent Exercise Performed in Public Fitness Facilities on Ambulatory Blood Pressure Among Older Adults in Rio de Janeiro City. AB - Cordeiro, R, Monteiro, W, Cunha, F, Pescatello, LS, and Farinatti, P. Influence of acute concurrent exercise performed in public fitness facilities on ambulatory blood pressure among older adults in Rio de Janeiro city. J Strength Cond Res 32(10): 2962-2970, 2018-The project "Third-Age Academies'" (TAAs) is a public policy providing supervised physical activities to over 40,000 seniors at open access facilities (squares etc.) in Rio de Janeiro, Brazil. We investigated whether TAA concurrent exercise circuit induced postexercise hypotension (PEH) in individuals older than 60 years. Blood pressure (BP) was measured by 24-hour ambulatory BP monitoring (ABPM) after counterbalanced CEX and nonexercise (CONT) sessions (n = 16; 66.8 +/- 1.4 years; systolic/diastolic BP (SBP/DBP): 132.5 +/- 4.3/78.0 +/- 2.8 mm Hg). For statistical analyses purposes, groups were divided as exhibiting normal SBP (<=120 mm Hg) or high SBP (>120 mm Hg), based on 24-hour ABPM after CONT. The CEX included 2 aerobic and 9 resistance exercises performed alternately in circuit order (40 minutes at 60-70% heart rate reserve using body mass or fixed loads). 24-hour ambulatory BP monitoring lowered in individuals with high BP (n = 11; medicated = 5) (SBP: -6.5 +/- 1.9 mm Hg; mean arterial pressure [MAP]: -4.3 +/- 1.5 mm Hg; p < 0.015), particularly within the first 5-6 hours after exercise (SBP: -13.5 +/- 2.6 mm Hg; DBP: -9.4 +/- 2.2 mm Hg; and MAP: -11.4 +/- 1.6 mm Hg, p < 0.05). Significant BP lowering was not detected among participants with normal BP (n = 5; medicated = 4). In conclusion, CEX provoked PEH in older adults with prehypertension to established hypertension. Because of the potential of TAAs to reach large numbers of older adults, our findings are encouraging and should be confirmed in subsequent studies. PMID- 29995694 TI - Readmission Rates and Skilled Nursing Facility Utilization After Major Inpatient Surgery. AB - BACKGROUND: There is widespread interest in reducing use of postacute care (ie, care after hospital discharge) following major surgery, provided that such reductions do not worsen quality outcomes such as readmission rates. OBJECTIVES: To describe the association between changes in skilled nursing facility (SNF) use and changes in readmission rates after surgery. RESEARCH DESIGN: This was a observational study. SUBJECTS: Fee-for-service Medicare beneficiaries undergoing coronary artery bypass grafting (CABG) or total hip replacement (THR) from 2008 to 2013. MEASURES: Primary exposure was risk-adjusted SNF use initiated 0-2 days after hospital discharge, and the primary outcome was risk-adjusted readmission rates from 3 to 30 days after discharge. RESULTS: Among 176,994 patients who underwent CABG at 804 hospitals and 233,955 patients who underwent THR at 1220 hospitals, hospital-level SNF utilization increased after CABG (16.4%-19.0%, P=0.001) and THR (40.8%-45.5%, P<0.001), from 2008 to 2013. Hospital readmission rates decreased for CABG (14.7%-12.7%, P<0.001) but did not change for THR (4.9% 4.8%, P=0.55), from 2008 to 2013. However, there was wide variation in hospital level change in readmission rates. After adjusting for hospital characteristics and baseline readmission rates, there was no statistically significant association between change in SNF use and change in readmission rates (0.017 and 0.011 percentage point increase in SNF use for every one percentage point increase in readmission rates for CABG and THR respectively, P=0.58 and 0.32). CONCLUSIONS: Changes in use of postacute care after THR and CABG have not been associated with changes in readmission rates. PMID- 29995696 TI - Overview of Prescription Opioid Deaths in the Oklahoma State Medicaid Population, 2012-2016. AB - BACKGROUND: Medicaid members are predisposed to unintentional prescription opioid overdose. However, little is known about their individual risk factors. OBJECTIVES: To describe demographic and clinical characteristics, medical utilization, opioid use, concurrent use of benzodiazepines, risk factors, and substances involved in death for Oklahoma's Medicaid members who died of unintentional prescription opioid poisoning. SUBJECTS: Decedents who were Medicaid eligible in Oklahoma during the year of death, had an opioid recorded in cause of death, and had >=1 opioid prescription claim between January 1, 2011 and June 30, 2016 were cases. Controls were living Medicaid members and were matched 3:1 to cases through propensity score matching. MEASURES: Demographics, clinical characteristics, and medical/pharmacy utilization were examined in the 12 months before the index date. RESULTS: Of 639 members with fatal unintentional prescription opioid overdoses, 321 had >=1 opioid prescription claim in the year before death; these were matched to 963 controls. Compared with controls, decedents had significantly greater proportions of nonopioid substance use disorders, opioid abuse/dependence, hepatitis, gastrointestinal bleeding, trauma not involving motor vehicle accidents, nonopioid poisonings, and mental illness disorders. Decedents had significantly higher daily morphine milligram equivalent doses (67.2+/-74.4 vs. 47.2+/-50.9 mg) and greater opioid/benzodiazepine overlap (70.4% vs. 35.9%). Benzodiazepines were involved in 29.3% of deaths. CONCLUSIONS: Several comorbidities indicative of opioid use disorder and greater exposure to opioids and concomitant benzodiazepines were associated with unintentional prescription opioid overdose fatalities. Prescribers and state agencies should be aware of these addressable patient-level factors among the Medicaid population. Targeting these factors with appropriate policy interventions and education may prevent future deaths. PMID- 29995695 TI - Defining Multimorbidity in Older Surgical Patients. AB - BACKGROUND: There are numerous definitions of multimorbidity (MM). None systematically examines specific comorbidity combinations accounting for multiple testing when exploring large datasets. OBJECTIVES: Develop and validate a list of all single, double, and triple comorbidity combinations, with each individual qualifying comorbidity set (QCS) more than doubling the odds of mortality versus its reference population. Patients with at least 1 QCS were defined as having MM. RESEARCH DESIGN: Cohort-based study with a matching validation study. SUBJECTS: All fee-for-service Medicare patients between age 65 and 85 without dementia or metastatic solid tumors undergoing general surgery in 2009-2010, and an additional 2011-2013 dataset. MEASURES: 30-day all-location mortality. RESULTS: There were 576 QCSs (2 singles, 63 doubles, and 511 triples), each set more than doubling the odds of dying. In 2011, 36% of eligible patients had MM. As a group, multimorbid patients (mortality rate=7.0%) had a mortality Mantel-Haenszel odds ratio=1.90 (1.77-2.04) versus a reference that included both multimorbid and nonmultimorbid patients (mortality rate=3.3%), and Mantel-Haenszel odds ratio=3.72 (3.51-3.94) versus only nonmultimorbid patients (mortality rate=1.6%). When matching 3151 pairs of multimorbid patients from low-volume hospitals to similar patients in high-volume hospitals, the mortality rates were 6.7% versus 5.2%, respectively (P=0.006). CONCLUSIONS: A list of QCSs identified a third of older patients undergoing general surgery that had greatly elevated mortality. These sets can be used to identify vulnerable patients and the specific combinations of comorbidities that make them susceptible to poor outcomes. PMID- 29995697 TI - Effects of additional vasodilatory or nonvasodilatory treatment on renal function, vascular resistance and oxygenation in chronic kidney disease: a randomized clinical trial. AB - AIM: Progression of chronic kidney disease (CKD) may be accelerated by tissue hypoxia due to impaired blood supply. This could be induced by small artery narrowing resulting in abnormally high intrarenal vascular resistance (RVR). We investigated whether a reduction in RVR achieved by adding vasodilating medical therapy (AVT) is superior to adding nonvasodilating medical therapy (AnonVT) regarding tissue oxygenation and preservation of kidney function. METHODS: Eighty three grade 3 and 4 CKD patients [estimated glomerular filtration rate (GFR) 34.6 ml/min per 1.73 m] were randomized to either AVT with amlodipine and/or renin angiotensin blockade or AnonVT with the nonvasodilating beta-blocker metoprolol. Investigations were performed at baseline and after 18 months of therapy. Systemic vasodilation was documented in the forearm vasculature using resting venous occlusion plethysmography. GFR was measured as Chrome-EDTA plasma clearance. Using MRI, renal artery blood flow was measured for calculation of RVR and for estimating renal oxygenation (R2*). RESULTS: AVT and AnonVT achieved as planned similar blood pressure levels throughout the study. At follow-up, resistance had decreased by 7% (P < 0.05) and RVR by 12% (P < 0.05) in the AVT group, whereas in the AnonVT group, resistance increased by 39% (P < 0.01), whereas RVR remained unchanged. At follow-up, no significant differences in cortical or medullary R2* values between AVT and AnonVT were observed, and the GFR decline was similar in the two groups (3.0 vs. 3.3 ml/min per 1.73 m). CONCLUSION: Long-term intensified vasodilation treatment reduced peripheral and RVR, but this was not associated with improvement of R2* or protection against loss of kidney function in CKD patients. PMID- 29995698 TI - Short-term blood pressure variability in nondialysis chronic kidney disease patients: correlates and prognostic role on the progression of renal disease. AB - OBJECTIVE: In chronic kidney disease (CKD), few cross-sectional studies evidenced an association between short-term BP variability (BPV) derived from ambulatory blood pressure (ABP) monitoring and renal damage. However, no study has evaluated the association of short-term BPV with the risk of CKD progression. METHODS: We performed a cohort study to assess the correlates and the predictive value for incident renal outcomes of short-term BPV in hypertensive patients with CKD stage G1-5. As measures of short-term BPV, we considered the weighted SD (W-SD), and the coefficient of variation of SBP (CV-24-h SBP). Primary outcome was a composite endpoint of ESRD (chronic dialysis or transplantation) or GFR decline of at least 50%. RESULTS: We included 465 patients (63.5 +/- 14.2 years; 54.7% men; eGFR: 44 +/- 22 ml/min per 1.73 m; proteinuria: 0.2 [0.1-0.9] g/day); W-SD, CV-24-h SBP and 24 h SBP were 12.5 +/- 3.3 mmHg, 11.1 +/- 2.8% and 127 +/- 16 mmHg, respectively. W-SD was independently associated with older age, history of cardiovascular disease, diagnosis of diabetic, hypertensive and polycystic nephropathy, and higher 24 h SBP whereas no association with eGFR and proteinuria was found. During follow-up (median, 6.4 years), 130 patients reached the renal outcome (107 ESRD and 23 GFR decline of >=50%). Higher 24 h, daytime and night time SBP robustly predicted the composite renal endpoint [1.18 (1.10-1.25) for 5 mmHg], whereas BPV as measured by the W-SD did not either when expressed as a continuous variable [hazard ratio 0.97 (95% CI 0.91-1.04)] or when categorized into tertiles [1.16 (0.70-1.92) and 0.95 (0.54-1.68) in II and III tertiles, respectively]. Similar findings were found with CV-24-h SBP. CONCLUSION: In CKD patients, short-term BPV is strongly associated with 24 h, night-time and daytime BP but is independent from the eGFR and proteinuria and does not predict CKD progression. PMID- 29995699 TI - Determinants of the aortic pulse wave velocity index in hypertensive and diabetic patients: predictive and therapeutic implications. AB - OBJECTIVE: Aortic stiffness may provide information to classical risk factors information regarding cardiovascular risk. Aortic pulse wave velocity (PWV) can be measured by applanation tonometry but also theoretical PWV was calculated according to age, blood pressure, heart rate and sex. We aim to highlight biological and hemodynamic determinants of the aortic PWV index, that is the individually calculated [(measured PWV - theoretical PWV)/theoretical PWV] difference, in hypertensive diabetic patients. METHODS: A cross-sectional study was conducted in 514 patients, involving normotensive and hypertensive patients and people with and without diabetes. Biological parameters were measured during day-hospital for cardiovascular screening. Hemodynamic parameters were determined by applanation tonometry. Multivariate regression analyses evaluated the PWV index determinants. RESULTS: Hypertensive and/or diabetic population presents higher PWV index in correlation with the presence of proteinuria (P = 0.0428) and previous cardiovascular events (P = 0.0227). Hypertensive diabetic patients present a higher PWV index than the other patients (P < 0.05). Presence of insulin therapy (P = 0.0101) and the type 1 diabetes (P = 0.0065) were positively and independently modulating PWV index in hypertensive diabetic patients. HDL cholesterol levels (P = 0.0245) and absence of carotid (P = 0.0468) plaques were independently modulating PWV index with a negative correlation in hypertensive without diabetes patients. C reactive protein levels were significantly associated with increased PWV index in hypertensive patients (P = 0.0074) and in hypertensive and/or diabetic population (P = 0.0184). CONCLUSION: PWV index was correlated with numerous cardiovascular risk factors, in addition of being a marker of age and hypertension. Therefore, this index appears as a cardiovascular risk integrator. Its use could be interesting in cardiovascular risk assessment and reduction strategies. PMID- 29995700 TI - Highlights of the September issue. PMID- 29995701 TI - Incomplete recovery of cerebral blood flow dynamics in sufficiently treated high blood pressure. AB - OBJECTIVE: Whether cerebrovascular regulation is different in patients with controlled high blood pressure (HBP) with and without small vessel disease (SVD). METHODS: Sixty-seven healthy controls (mean age +/- SD, 45 +/- 16 years; 30 women, 37 men) and 40 patients (mean age, 64 +/- 13 years; 14 women, 26 men) with HBP and different stages of SVD, underwent simultaneous recordings of the spontaneous fluctuations of BP, blood flow velocity (CBFV) in both middle cerebral arteries (MCA), and of end-tidal CO2 (ETCO2). Coherence and transfer function gain and phase between BP and CBFV were assessed in the frequency ranges of VLF (0.02-0.07 Hz), low frequency (0.07-0.15), and high frequency (>0.15). BP SD indicated BP variability (BPV). RESULTS: In controls (BP, 86 +/- 13 mmHg; ETCO2, 39 +/- 4 mmHg; BPV, 15 +/- 6 mmHg), gain, phase and coherence were not age dependent in simple or a multiple regression models. BPV correlated significantly in both MCAs with gain in low frequency and high frequency, and with phase in VLF and high frequency. In patients (BP, 91 +/- 16 mmHg, ETCO2, 39 +/- 4 mmHg, BPV 18 +/- 5 mmHg), only gain showed some differences between different SVD groups. Comparing all patients with 25 controls of similar age and sex, patients exhibited significantly (P < 0.05-P < 0.005): increased coherence and gain in VLF, decreased phase in VLF and low frequency, correlations between BPV with phase in low frequency (left) and with gain in VLF (left) and in high frequency (left and right). CONCLUSION: Phase seems an age independent autoregulatory index. In controlled HBP, CBF regulation is degraded at longlasting CBF changes; BPV effects lose their physiological bilateral distribution.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29995702 TI - Risk of Diffuse Infiltrative Lymphocytosis Syndrome in HIV-Infected Patients: A Nationwide Population-Based Cohort Study. AB - OBJECTIVE: Diffuse infiltrative lymphocytosis syndrome (DILS) is the term used for sicca syndrome in HIV patients and has similar clinical manifestations as Sjogren syndrome. In this nationwide population-based study, we aimed to determine the association between HIV infection and DILS in the Taiwanese population. METHODS: The National Health Insurance Research Database was searched for cases of DILS in HIV-infected individuals diagnosed between January 1, 2000, and December 31, 2012. The incidence of DILS and the factors associated with DILS in people living with HIV/AIDS (PLWHA) were determined. RESULTS: A total of 20,364 PLWHA were followed, and 57 (0.28%) individuals had new-onset DILS. The incidence rate of DILS in PLWHA was 0.56/1000 person-years. One (0.11%) female HIV patient with highly active antiretroviral therapy (HAART) and 24 (2.99%) without HAART had incident DILS, whereas 22 (0.17%) male HIV patients with HAART and 10 (0.17%) without HAART had incident DILS. Hypertension increased the risk of incident DILS. HAART decreased the risk of DILS, but this relationship somewhat attenuated in an adjusted model. None of the patients taking emtricitabine, raltegravir, darunavir, enfuvirtide, or tipranavir developed DILS. Lopinavir was associated with a decreased risk of DILS (adjusted hazard ratio = 0.10, 95% confidence interval: 0.01 to 0.84), whereas zalcitabine was associated with an increased risk of DILS (adjusted hazard ratio = 13.7, 95% confidence interval: 2.18 to 85.9). CONCLUSIONS: DILS is a rare disease found in PLWHA. Hypertension is a risk factor for incident DILS, and HAART could affect the pathogenesis of DILS. Zalcitabine was the only antiretroviral agent found to increase the risk of DILS. PMID- 29995703 TI - Cerebral Vasoreactivity Evaluated by the Breath-Holding Challenge Correlates With Performance on a Cognitive Screening Test in Persons Living With Treated HIV Infection in China. PMID- 29995704 TI - Simple Screening Tool to Help Identify High-Risk Children for Targeted HIV Testing in Malawian Inpatient Wards. AB - BACKGROUND: To meet global AIDS goals, pediatric HIV diagnosis must be strengthened. Provider-initiated testing and counseling, which is recommended by the WHO, faces persistent implementation challenges in low-resource settings. Alternative approaches are needed. SETTING: Malawi has achieved high coverage of HIV diagnosis and treatment, but there are gaps among pediatric populations. This study assessed the sensitivity and specificity of a brief screening tool to identify at-risk pediatric patients for targeted HIV testing in Malawi. METHODS: A tool containing 6 yes/no items was used for children (aged 1-15 years) in the inpatient pediatric wards at 12 hospitals in Malawi (July 2016-July 2017). Questions were based on an established tool, translated to Chichewa, and implemented by HIV diagnostic assistants. All participating children were provided HIV testing and counseling per Ministry of Health guidelines. Analysis estimated the tool's characteristics including sensitivity, specificity, negative, and positive predictive values. RESULTS: HIV prevalence among the 8602 participants was 1.1% (n = 90). Children with a screening tool score of 1 had double the odds of being HIV positive than those with a score of 0. Frequent sickness was the most sensitive predictor of HIV status (55.1%), and having a deceased parent was the most specific (96.7%). False classification of HIV negative status was rare (n = 14) but occurred more often among boys and younger children. CONCLUSIONS: A brief screening tool for pediatric inpatients helped target HIV testing in those most at risk in a low-pediatric-prevalence, resource constrained setting. Future research should include a direct, rigorous comparison with PITC including comparative effectiveness, efficiency, and cost effectiveness. PMID- 29995705 TI - Glucose Intolerance After Pancreatectomy Was Associated With Preoperative Hemoglobin A1c, Insulin Resistance, and Histological Pancreatic Fatty Infiltration. PMID- 29995706 TI - Same principles, different practices: the distance for geographic parity in health is not so great after all. PMID- 29995707 TI - Effectiveness of mindfulness-based arts interventions on psychological wellbeing and fatigue in adults with a physical illness: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize evidence on the effectiveness of mindfulness-based arts interventions on psychological wellbeing and fatigue in adults with a physical illness. PMID- 29995708 TI - Community-based interventions to address alcohol and drug use in Indigenous populations in Australia, New Zealand and Canada: a systematic review protocol. AB - REVIEW QUESTION: What is the effectiveness of community-based interventions designed to reduce harm associated with alcohol and other drug use in Indigenous populations in Australia, New Zealand and Canada? PMID- 29995709 TI - Effectiveness of institutional strategies to recruit and retain minority nurses: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to identify, appraise and synthesize the best available evidence on the effectiveness of institutional strategies and interventions on recruitment and retention of minority nurses. PMID- 29995710 TI - Update of the best practice dietetic management of overweight and obese children and adolescents: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: To update an existing systematic review series of randomized controlled trials (RCT) that include a dietary intervention for the management of overweight or obesity in children or adolescents.Specifically, the review questions are: In randomized controlled trials of interventions which include a dietary intervention for the management of overweight or obesity in children or adolescents. PMID- 29995711 TI - Recommendations and practices for the screening of depression and anxiety in acute coronary syndrome: a scoping review protocol. AB - OBJECTIVE: The objective of this scoping review is to identify and map current recommendations and practices for the screening of depression and anxiety in acute coronary syndrome patients in the acute care setting.Specifically, the review questions are. PMID- 29995712 TI - The association of overjet with traumatic dental injuries: a systematic review protocol. AB - REVIEW QUESTION: The objective of this review of association (etiology) is to identify the relationship between different overjet measurements and developing a traumatic dental injury (TDI) across different dentition stages. Specifically, the review will elucidate the critical level, in millimetres, at which an overjet will place an individual at an increased risk of developing a TDI within each specific dentition stage. The specific review questions are. PMID- 29995713 TI - Treatment of Madura foot: a systematic review. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review was to determine the best available evidence on the most effective treatment of Madura foot. INTRODUCTION: Madura foot or mycetoma is a chronic granulomatous soft-tissue infection that is endemic to several regions of Africa and Asia. It may be of fungal (eumycetoma) or bacterial (actinomycetoma) origin, warranting therapy with either antifungal or antibacterial medication as well as surgery. Without timely intervention, it often results in lifelong disability. However, it is unclear what regimes are most effective for treatment. INCLUSION CRITERIA: This review considered studies that included individuals of all ages with Madura foot (actinomycetoma or eumycetoma) as confirmed by microbiological or histological studies. Studies that evaluated antibiotic and antifungal regimens (any drug, dosage, frequency, duration) as well as surgical interventions (wound debridement, advanced excision or limb amputation) for Madura foot were included. Outcomes of interest were disease resolution (as determined by complete healing of mycetoma lesion after treatment), recurrence (return of mycetoma lesion after successful treatment) and mortality. Although this review considered both experimental and epidemiological study designs for inclusion, only case series and individual case reports were identified and were therefore included in the review. METHODS: A three-step search strategy, involving an initial search, a second more comprehensive search using identified keywords and a third search involving the reference lists of included articles, was utilized. Ten databases were searched. An additional 13 sources were searched for gray and/or unpublished literature. Included studies were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute. Disagreements were resolved through discussion or with a third reviewer. A data extraction tool was used to extract data on interventions, populations, study designs and outcomes of significance to the review question. Statistical pooling was not possible, therefore a narrative synthesis was performed. RESULTS: Thirty-one studies were included in the review (27 case reports and four case series). A total of 47 patients with Madura foot were analyzed. Twenty-five had eumycetoma, 21 actinomycetoma and one had both. Therapy involved varying dosages of sulfa drugs (co-trimoxazole and dapsone), amikacin and tetracyclines administered for the therapy of actinomycetoma with resolution of disease in all affected patients. The azole derivatives (itraconazole, ketoconazole, voriconazole, fluconazole and miconazole) as well as co-trimoxazole were the most commonly employed drugs for eumycetoma, with resolution of disease in 88% of included patients. Surgery was performed in a total of 21 patients with resolution of disease in all cases. The overall resolution rate following therapy was 95.7%. CONCLUSION: Therapy for Madura foot is informed by case series and case reports which provide low level evidence for practice. Antimicrobials in conjunction with surgery lead to resolution of disease. PMID- 29995714 TI - Scandinavian women's experiences with abortions on request: a systematic review. AB - REVIEW QUESTION/OBJECTIVE: The objective of the review was to explore the experiences of Scandinavian women with abortions on request, that is, before, during and after the intervention. INTRODUCTION: In Scandinavia, the primary issues surrounding the abortion debate to date have been women's legal rights to an abortion, and, to a lesser extent, how women experience an abortion on request and how society could and should support them. This systematic review investigated Scandinavian women's experiences in relation to this intervention. INCLUSION CRITERIA: The current review included all studies that focused on adult women (aged 15 and over) living in Scandinavia (Denmark, Sweden and Norway) who have experienced an abortion on request (a medically or surgically induced abortion without a medical indication for the mother or child, described here as an "abortion on request"). The phenomena of interest were Scandinavian women's experiences in relation to an abortion on request, that is, before, during and after the intervention, and self-reported psychosocial or psychological health consequences following the abortion. This systematic review focused on Scandinavian hospital or clinical environments where authorized medical personnel performed abortions on request. This review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. METHODS: A three-step search strategy was used to identify published and unpublished studies from 1973 to June 2016. The comprehensive literature search identified nine studies that met the inclusion criteria. These nine studies were assessed by two independent reviewers using the standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). Six of these studies were deemed to be of sufficient methodological quality for inclusion in this systematic review. Data were extracted from the six included studies using the standardized data extraction tool from JBI. A total of 24 qualitative research findings were pooled using JBI methodology. RESULTS: A total of six studies met the inclusion criteria, with a total of 80 participants. Twenty-four research findings were extracted and grouped into six categories that were synthesized into three synthesized findings: 1) Experiences in connection with the decision-making process; 2) Experiences in connection with the procedure; and 3) Experiences after abortion. The vast majority of participants were aged 15 to 24 years at the time of the abortion. Conclusions and recommendations for practice apply to Scandinavian women within this age group. CONCLUSIONS: This systematic review indicates that young Scandinavians consider it a woman's responsibility to obtain and use contraceptives and that young women seeking an abortion on request have little knowledge of their own bodies with respect to fertility and their menstrual cycles. Young Scandinavian women between the ages of 15 and 24 years seeking an abortion on request experience conflicted feelings. They feel both joy and shame about their pregnancies and, during the decision-making process, are torn between the possibility of motherhood and the reasonable and expected choice of abortion that is supported by their parents and friends. The majority of women experience worse-than-expected pain and discomfort in connection with the abortion procedure. The approach of healthcare staff to women's physical needs is described as good and professional, but there is little or no focus on the women's emotional and existential needs. After abortions on request, young women express ambivalence: relief that the pregnancy has been terminated, coupled with a feeling of loss. Some suffer from guilt and some express regret. PMID- 29995715 TI - Basic newborn resuscitation guidelines for healthcare providers in Maragua District Hospital: a best practice implementation project. AB - OBJECTIVE: The overall aim of this project was to assess compliance with evidence based criteria regarding newborn resuscitation among healthcare workers in the maternity units in Maragua District Hospital (a busy district hospital in Kenya). INTRODUCTION: Globally, the majority of deaths under five years are attributable to neonatal causes. Perinatal asphyxia accounts for a significant portion of these deaths, especially in developing countries. These deaths are largely preventable, and interventions geared towards assisting newborns to initiate their first breath within the first minute of life have markedly reduced mortality. METHODS: This implementation project was conducted in the maternity units of a busy district hospital. Evidence-based audit criteria were developed on the basis of an evidence summary developed by the Joanna Briggs Institute (JBI). Using the JBI Practical Application of Clinical Evidence System software (JBI PACES), a baseline audit was conducted including a sample size of 55 healthcare providers and 300 patient case notes followed by an identification of potential barriers and strategies to overcome them. A follow-up audit including a sample size of 55 healthcare providers was conducted by using the same audit criteria. RESULTS: Improvements in practice were demonstrated in all criteria. The baseline audit demonstrated that three of the five audit criteria were found to be less than 50%, indicating moderate compliance with current evidence with regards to newborn resuscitation. Following implementation of the strategies, which included a six-week education and demonstrative skills training, and updating of the protocols and equipment, there was a significant improvement in all the criteria audited, with the first four criteria achieving 100% compliance, and the fifth criteria achieving 90% compliance. CONCLUSION: On completion of the project, the participants demonstrated an increase in knowledge and skills on newborn resuscitation, which led to a significant reduction in admission of newborns with birth asphyxia to the newborn unit. PMID- 29995716 TI - Falls prevention strategies for patients over 65 years in a neurology ward: a best practice implementation project. AB - OBJECTIVES: The aim of this project was to promote evidence-based practice with regard to fall prevention and management, by implementing the recommendations from the best available evidence to reduce fall rates. INTRODUCTION: Falls are a main cause of disability in older people and the most common adverse event in all hospital patients. It is essential to implement the recommendations from evidence based interventions to reduce these events. METHODS: A pre and post implementation audit method was used in a neurology ward, which employed the Joanna Briggs Institute Practical Application of Clinical Evidence System (JBI PACES) and Getting Research Into Practice (GRiP) module. The 15-month project evaluated between 20-30 patients from a sample at each audit (baseline in April 2016 and during three follow-up cycles in December 2016, March 2017 and June 2017). The data were inputted into an informatics system from nursing records and audited according to evidence-based processes and outcomes criteria. RESULTS: The baseline outcomes identified five barriers: incomplete fall registration, lack of an established fall prevention protocol for at-risk patients, limited knowledge about the fall prevention protocol, lack of a fall risk assessment scale and lack of multifactorial individual plans for fall prevention. Strategies were carried out and implemented following GRiP and all the criteria improved from baseline. CONCLUSIONS: The project successfully increased evidence-based practice on falls and provided mechanisms for sustaining evidence-based practice changes. Further audits are needed to improve some outcomes. PMID- 29995717 TI - Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a highly prevalent disorder, representing the single most common endocrine-metabolic disorder in reproductive-aged women. Currently there are four recognized phenotypes of PCOS: 1) hyperandrogenism+oligo anovulation+polycystic ovarian morphology; 2) hyperandrogenism+oligo-anovulation; 3) hyperandrogenism+polycystic ovarian morphology; and 4) oligo anovulation+polycystic ovarian morphology, each with different long-term health and metabolic implications. Clinicians should clearly denote a patient's phenotype when making the diagnosis of PCOS. Polycystic ovary syndrome is a highly inherited complex polygenic, multifactorial disorder. Pathophysiologically abnormalities in gonadotropin secretion or action, ovarian folliculogenesis, steroidogenesis, insulin secretion or action, and adipose tissue function, among others, have been described in PCOS. Women with PCOS are at increased risk for glucose intolerance and type 2 diabetes mellitus; hepatic steatosis and metabolic syndrome; hypertension, dyslipidemia, vascular thrombosis, cerebrovascular accidents, and possibly cardiovascular events; subfertility and obstetric complications; endometrial atypia or carcinoma, and possibly ovarian malignancy; and mood and psychosexual disorders. The evaluation of patients suspected of having PCOS includes a thorough history and physical examination, assessment for the presence of hirsutism, ovarian ultrasonography, and hormonal testing to confirm hyperandrogenism and oligo-anovulation as needed and to exclude similar or mimicking disorders. Therapeutic decisions in PCOS depend on the patients' phenotype, concerns, and goals, and should focus on 1) suppressing and counteracting androgen secretion and action, 2) improving metabolic status, and 3) improving fertility. However, despite significant progress in understanding the pathophysiology and diagnosis of the disorder over the past 20 years, the disorder remains underdiagnosed and misunderstood by many practitioners. PMID- 29995718 TI - Nonobstetric Surgery During Pregnancy. AB - One percent to 2% of pregnant women undergo nonobstetric surgery during pregnancy. Historically, there has been a reluctance to operate on pregnant women based on concerns for teratogenesis, pregnancy loss, or preterm birth. However, a careful review of published data suggests four major flaws affecting much of the available literature. Many studies contain outcomes data from past years in which diagnostic testing, surgical technique, and perioperative maternal-fetal care were so different from current experience as to make these data of limited utility today. This issue is further compounded by a tendency to combine experience from vastly disparate types of surgery into a single report. In addition, reports in nonobstetric journals often focus on maternal outcomes and contain insufficient detail regarding perinatal outcomes to allow distinction between complications associated with surgical disease and those attributable to surgery itself. Finally, most series are either uncontrolled or use the general population of pregnant women as controls rather than women with surgical disease who are managed nonsurgically. Consideration of these factors as well as our own extensive experience suggests that when the risks of maternal hypotension or hypoxia are minimal, or can be adequately mitigated, indicated surgery during any trimester does not appear to subject either the mother or fetus to risks significantly beyond those associated with the disease itself or the complications of surgery in nonpregnant individuals. In some cases, reluctance to operate during pregnancy becomes a self-fulfilling prophecy in which delay in surgery contributes to adverse perinatal outcomes traditionally attributed to surgery itself. PMID- 29995719 TI - What Is New in Maternal Immunization?: Best Articles From the Past Year. AB - This month we focus on current research in maternal immunization. Dr. Jamieson discusses four recent publications, which are concluded with a "bottom line" that is a take-home message. A completed reference for each can be found in on this page along with direct links to abstracts. PMID- 29995720 TI - Connect the Dots-August 2018. PMID- 29995721 TI - A Few More Reasons to Vaccinate Against Human Papillomavirus: The Vulva and Vagina. PMID- 29995722 TI - Temporal Differences in Utilization of Intracytoplasmic Sperm Injection Among U.S. Regions. AB - OBJECTIVE: To analyze changes in intracytoplasmic sperm injection (ICSI) utilization, indications, and outcomes across U.S. regions. METHODS: We conducted a retrospective cohort study. Data sets for 2000-2014 were obtained from the Centers for Disease Control and Prevention. Clinics with 100 or greater fresh, nondonor cycles were grouped by 10 nationally recognized Department of Health and Human Services (DHHS) regions and were compared for use of ICSI, frequency of male factor infertility, preimplantation genetic therapies, pregnancy, and live birth rates per cycle among fresh in vitro fertilization cycles in women younger than 35 years of age. RESULTS: Nationwide ICSI utilization increased 52% (46.3+/ 6.1% to 70.0+/-7.1%) from 2000 to 2014, whereas pregnancy and live birth rates per cycle modestly increased by 8.5% (39.2+/-3.8% to 42.5+/-2.5%) and 7.6% (34.4+/-3.6% to 37+/-2.6%), respectively, showing a positive correlation (r=0.78, P<.001; r=0.76, P=.001) with ICSI rates per clinic. All DHHS Services regions demonstrated increases in ICSI utilization over time, although the magnitude of increase varied in different regions. Regions also had similarities in trends for pregnancy and live birth rates per cycle in women younger than 35 years. There was no correlation between male factor and ICSI rates per clinic from 2000 to 2010 (r=0.32, P=.33) or 2011 to 2014 (r=0.85, P=.068). From 2007 to 2014, ICSI and preimplantation genetic testing did not demonstrate a strong correlation (r=0.68, P=.062). CONCLUSION: From 2000 to 2014, ICSI rates per clinic significantly varied among geographic regions. Increased use of ICSI did not correlate with an increase in male factor diagnoses. These findings suggest that ICSI may be overused, because its use is not accompanied by proportionate increases in medical indications or effectiveness. PMID- 29995723 TI - Maternal Outcomes by Race for Women Aged 40 Years or Older. AB - OBJECTIVE: To clarify how race is associated with adverse maternal outcomes and risk for women aged 40 years or older. METHODS: This retrospective cohort study used the Nationwide Inpatient Sample for the years 1998-2014. Women aged 40-54 years were included. Race and ethnicity were categorized as non-Hispanic white, non-Hispanic black, Hispanic, Asian or Pacific Islander, Native American, other, and unknown. Temporal trends in severe maternal morbidity and overall comorbid risk by race in women aged 40 years or older were evaluated as were common pregnancy complications including preeclampsia, gestational diabetes, and cesarean delivery. Adjusted models were created to assess factors associated with severe morbidity. RESULTS: A total of 1,724,694 deliveries were included in this analysis. Severe maternal morbidity increased over the study period from 1.6% in 1998-2000 to 3.0% from 2013 to 2014. Black women had the highest rates of severe morbidity at both the beginning (2.4% in 1998-2000) and the end (4.9% in 2013 2014) of the study period. During this same period, comorbid risk based on medical conditions and other factors increased overall and individually by race. Black women also experienced the absolute largest increase from 1998-2003 to 2010 2014 in risk for acute renal failure, disseminated intravascular coagulation, transfusion, and hysterectomy. Pregnancy complications including preeclampsia, cesarean delivery, and gestational diabetes were more common at the end compared with the beginning of the study for black, white, and Hispanic women. The adjusted risk ratio for overall severe morbidity for black compared with white race was 1.81 (95% CI 1.76-1.87). Black women had a substantially higher risk of death than white women (risk ratio 4.71, 95% CI 3.36-6.61), and Hispanic women had more than twice the risk of death (risk ratio 2.13, 95% CI 1.48-3.07) as white women. CONCLUSION: Although black women older than 40 years were at increased risk for adverse outcomes and severe morbidity, this differential was of smaller magnitude than reported mortality risk. PMID- 29995724 TI - Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age. AB - OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534. PMID- 29995725 TI - Female Sexual Dysfunction and the Placebo Effect: A Meta-analysis. AB - OBJECTIVE: To quantify the placebo effect of various pharmacologic modalities including neuromodulators, hormonal agents, and onabotulinum toxin A for female sexual dysfunction. DATA SOURCES: Using Meta-analyses Of Observational Studies in Epidemiology guidelines, we conducted a systematic review of PubMed, EMBASE, ClinicalTrials.gov, and the Cochrane Review databases. METHODS OF STUDY SELECTION: Eleven search terms, "female sexual dysfunction" "treatment" in combination with "hypoactive sexual desire," "arousal disorder," "sexual pain disorder," "genitourinary syndrome of menopause," "orgasmic disorder," "vulvovaginal atrophy," "vaginismus," "vaginal atrophy," "vulvodynia," and "vestibulitis," were used. Studies were included if their design was randomized, included a placebo arm, and used the Female Sexual Function Index as an outcome measure. TABULATION, INTEGRATION, AND RESULTS: The placebo effect on the Female Sexual Function Index was compared with each respective study's treatment effect using inverse-variance weighting in a random-effects analysis model. Six hundred five relevant articles were retrieved. Twenty-four randomized controlled trials included a placebo arm. Of these, eight studies used the Female Sexual Function Index. Across these studies, 1,723 women with clinical pretreatment female sexual dysfunction received placebo. Two thousand two hundred thirty-six women were in the treatment arm of the respective studies and received various pharmacologic interventions including flibanserin, bupropion, onabotulinum toxin A, intravaginal prasterone, intranasal oxytocin, ospemifene, and bremelanotide. Women receiving placebo improved 3.62 (95% CI 3.29-3.94) on the Female Sexual Function Index. The treatment arm had a corresponding increase of 5.35 (95% CI 4.13-6.57). CONCLUSION: This meta-analysis of Level I evidence demonstrates that 67.7% of the treatment effect for female sexual dysfunction is accounted for by placebo. Our findings suggest that the current treatments for female sexual dysfunction are, overall, minimally superior to placebo, which emphasizes the ongoing need for more efficacious treatment for female sexual dysfunction. PMID- 29995726 TI - Prophylactic Negative Pressure Wound Therapy and Wound Complication After Cesarean Delivery in Women With Class II or III Obesity: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the occurrence of superficial surgical site infections in obese women using prophylactic negative pressure therapy with standard dressings after cesarean delivery. METHODS: We conducted a randomized controlled, nonblinded, two-center study of prophylactic negative pressure therapy compared with standard surgical dressings placed at the time of primary closure at cesarean delivery in obese women with body mass indexes (BMI) of 35 or higher (ie, class II and III obesity). Our primary outcome was occurrence of a superficial surgical site infection. We assumed a superficial surgical site infection occurrence rate of 20% and intended to recruit 400 women. However, after low enrollment of 166 women over 24 months, an interim analysis for futility was conducted and the decision was made to halt the study. RESULTS: Women were recruited between January 5, 2015, and January 7, 2017, from two sites. The mean BMI on admission was 44.9 (+/-8) for the prophylactic negative wound therapy group and 43.4 (+/-7) for the standard dressing group. There were no differences in the occurrence of observed superficial surgical site infections between women using prophylactic negative pressure wound therapy (12/80 [15%]) compared with women who received the standard dressing (8/81 [10%], P=.35, relative risk 1.52, 95% CI 0.66-3.52). There were no differences in the occurrence of composite wound complications between women using prophylactic negative pressure wound therapy (25/80 [31%]) compared with women who received the standard dressing (24/81 [30%], P=.87). CONCLUSION: In this randomized controlled trial that did not achieve full anticipated enrollment, we did not observe a decrease in superficial surgical site infections after cesarean delivery in obese women with the use of prophylactic negative pressure wound therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02390401. PMID- 29995727 TI - Massachusetts Child Psychiatry Access Program for Moms: Utilization and Quality Assessment. AB - OBJECTIVE: To describe the utilization and quality assessment of a population based program to help health care providers address mental health and substance use disorders among pregnant and postpartum women, the Massachusetts Child Psychiatry Access Program for Moms (MCPAP for Moms). METHODS: The Massachusetts Child Psychiatry Access Program for Moms builds health care providers' capacity to address perinatal mental health and substance use disorders through 1) trainings and toolkits, 2) telephonic access to perinatal psychiatric consultation, and 3) facilitating referral to community resources. Clinical encounter data were collected during telephone consultations. Focus groups were conducted with health care providers and staff from enrolled practices. In-depth interviews were conducted with patients served by the practices that participated in the focus groups. Transcribed interviews were analyzed by two researchers using an iterative, interpretive process with a grounded theory framework. RESULTS: In the first 3.5 years, MCPAP for Moms enrolled 145 obstetric practices, conducted 145 trainings for 1,174 health care providers, and served 3,699 women. Of telephone consultations provided, 42% were with obstetric care providers midwives and 16% with psychiatrists. Health care providers perceived that MCPAP for Moms facilitates health care providers detecting and addressing depression and women disclosing symptoms, seeking help, and initiating treatment. Obstetric practices reported that they need additional support to more proactively address and further improve depression care. CONCLUSION: The high volume of encounters, sustained utilization over 3.5 years, and qualitative themes identified from health care providers and patients demonstrate that MCPAP for Moms is a feasible, acceptable, and sustainable approach to increasing access to evidence-based treatments for perinatal mental health and substance use disorders on a population-based level. PMID- 29995728 TI - Factors Associated With Informative Redraw After an Initial No Result in Noninvasive Prenatal Testing. AB - OBJECTIVE: Noninvasive prenatal testing (NIPT) sometimes fails to provide a test result, usually as a result of low cell-free DNA fetal fraction. We investigated how initial fetal fraction, maternal weight, gestational age, and time between blood sampling contribute to obtaining an informative result when a redraw is performed. METHODS: We performed a retrospective data review of NIPT samples received between January and October 2016 by a commercial laboratory, where the initial blood draw did not yield a result and a second sample was drawn between 5 and 28 days after the initial sampling. We included cases with fetal fraction less than 2.8% (the threshold for "no result" in this laboratory) and those with higher fetal fraction but where the NIPT results could not be interpreted with high confidence. RESULTS: For 4,018 cases in which a redraw was recommended, a result was obtained for the second sample in 2,835 cases (70.6%) (95% CI 69.1 72.0%). For the 2,959 cases with insufficient fetal fraction, there was a result for the second sample in 1,861 cases (62.9%) (95% CI 61.1-64.6%). For this subset, the average increase in fetal fraction was 1.2% with an average interval between draws of 14 days. Informative redraw rate was strongly dependent on maternal weight and fetal fraction measured at the first draw. Gestational age was not an important determinant. Informative redraw rate increased rapidly over the first 8 days after the initial draw and more slowly thereafter. CONCLUSION: Based on fetal fraction in the initial sample, maternal weight, and interval between blood draws, women can be provided with a personalized estimate of their likelihood of a result on redraw. This should aid in the counseling of women faced with the choice of reattempting NIPT, conventional screening, or an invasive diagnostic test. PMID- 29995729 TI - Zika Virus Infection Among Pregnant Women and Their Neonates in New York City, January 2016-June 2017. AB - OBJECTIVE: To describe and compare differences in the epidemiologic, clinical, and laboratory characteristics of pregnant women with confirmed or probable Zika virus infection and to compare the risk of having a neonate with laboratory evidence of Zika virus infection with that of having a neonate without evidence of Zika virus infection by maternal characteristics. METHODS: We conducted a retrospective cohort study of women with Zika virus infection who completed pregnancy in New York City from January 1, 2016 to June 30, 2017. Confirmed Zika virus infection was defined as 1) nucleic acid amplification test-detected Zika virus, or 2) a nonnegative enzyme-linked immunosorbent assay test result and a plaque-reduction neutralization test result positive for Zika virus but negative for dengue virus, or 3) delivery of a neonate with laboratory evidence of Zika virus infection. Probable infection was defined as a nonnegative enzyme-linked immunosorbent assay test result and a positive plaque-reduction neutralization test result for Zika virus and dengue virus. RESULTS: We identified 390 women with confirmed (28%) or probable (72%) Zika virus infection. Fever, rash, arthralgia, or conjunctivitis was reported by 31% of women and were more common among women with confirmed than with probable infection (43% vs 26%, P=.001). Of 366 neonates born to these women, 295 (81%) were tested for Zika virus and 22 (7%) had laboratory-diagnosed congenital Zika virus infection. The relative risk (RR) for having a neonate with laboratory evidence of Zika virus infection was greater among women with fever (RR 4.8, 95% CI 2.1-10.7), tingling (RR 4.8, CI 1.7-13.7), or numbness (RR 6.9, CI 2.6-18.2) during pregnancy or the periconception period. However, the RR did not differ whether the mother had confirmed or probable Zika virus infection (RR 1.6, CI 0.7-4.1). CONCLUSION: In New York City, a greater proportion of women had probable Zika virus infection than confirmed infection. Women with some symptoms during pregnancy or periconceptionally were more likely to have a neonate with laboratory evidence of Zika virus infection. Neonates born to women with confirmed or probable Zika virus infection should be tested for Zika virus infection. PMID- 29995730 TI - Fatal and Nonfatal Overdose Among Pregnant and Postpartum Women in Massachusetts. AB - OBJECTIVE: To estimate fatal and nonfatal opioid overdose events in pregnant and postpartum women in Massachusetts, comparing rates in individuals receiving and not receiving pharmacotherapy for opioid use disorder (OUD). METHODS: We conducted a population-based retrospective cohort study using linked administrative and vital statistics databases in Massachusetts to identify women with evidence of OUD who delivered a liveborn neonate in 2012-2014. We described maternal sociodemographic, medical, and substance use characteristics, computed rates of opioid overdose events in the year before and after delivery, and compared overdose rates by receipt of pharmacotherapy with methadone or buprenorphine in the prenatal and postpartum periods. RESULTS: Among 177,876 unique deliveries, 4,154 (2.3%) were to women with evidence of OUD in the year before delivery, who experienced 242 total opioid-related overdose events (231 nonfatal, 11 fatal) in the year before or after delivery. The overall overdose rate was 8.0 per 100,000 person-days. Overdoses were lowest in the third trimester (3.3/100,000 person-days in the third trimester) and then increased in the postpartum period with the highest overdose rate 7-12 months after delivery (12.3/100,000 person-days). Overall, 64.3% of women with evidence of OUD in the year before delivery received any pharmacotherapy in the year before delivery. Women receiving pharmacotherapy had reduced overdose rates in the early postpartum period. CONCLUSION: Pregnant women in Massachusetts have high rates of OUD. The year after delivery is a vulnerable period for women with OUD. Additional longitudinal supports and interventions tailored to women in the first year postpartum are needed to prevent and reduce overdose events. PMID- 29995732 TI - Frequency of Opioid Dispensing After Vaginal Delivery. AB - OBJECTIVE: To describe nationwide patterns in outpatient opioid dispensing after vaginal delivery. METHODS: Using the Truven Health Analytics MarketScan database, we performed a large, nationwide retrospective cohort study of commercially insured beneficiaries who underwent vaginal delivery between 2003 and 2015 and who were opioid-naive for 12 weeks before the delivery admission. We assessed the proportion of women dispensed an oral opioid within 1 week of discharge, the associated median oral morphine milligram equivalent dose dispensed, and the frequency of opioid refills during the 6 weeks after discharge. We evaluated predictors of opioid dispensing using multivariable logistic regression. RESULTS: Among 1,345,244 women undergoing vaginal delivery, 28.5% were dispensed an opioid within 1 week of discharge. The most commonly dispensed opioids were hydrocodone (44.7%), oxycodone (34.6%), and codeine (13.1%). The odds of filling an opioid were higher among those using benzodiazepines (adjusted odds ratio [OR] 1.87, 95% CI 1.73-2.02) and antidepressants (adjusted OR 1.63, 95% CI 1.59-1.66), smokers (adjusted OR 1.44, 95% CI 1.38-1.51), and among those undergoing tubal ligation (adjusted OR 3.77, 95% CI 3.67-3.87), operative vaginal delivery (adjusted OR 1.52, 95% CI 1.49-1.54), and higher order perineal laceration (adjusted OR 2.15, 95% CI 2.11-2.18). The median (interquartile range, 10th-90th percentile) dose of opioids dispensed was 150 (113-225, 80-345) morphine milligram equivalents, equivalent to 20 tablets (interquartile range 15-30, 10th-90th percentile 11-46) of 5 mg oxycodone. Six weeks after discharge, 8.5% of women filled one or more additional opioid prescriptions. CONCLUSION: Opioid dispensing after vaginal delivery is common and often occurs at high doses. Given the frequency of vaginal delivery, this may represent an important source of overprescription of opioids in the United States. PMID- 29995731 TI - Research Gaps in Gestational Diabetes Mellitus: Executive Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. AB - The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children. PMID- 29995733 TI - Association Between Attempted External Cephalic Version and Perinatal Morbidity and Mortality. AB - OBJECTIVE: To examine whether, with fetal malpresentation at term, perinatal morbidity and mortality differ between women who undergo an external cephalic version (ECV) attempt and those who do not and are expectantly managed. METHODS: We conducted a retrospective cohort study of women with nonanomalous singleton gestations in nonvertex presentation delivering at a tertiary care institution from 2006 to 2016. Women undergoing an ECV attempt at 37 weeks of gestation or greater were compared with those with nonvertex fetuses who did not undergo an ECV attempt and delivered at 37 weeks of gestation or greater. The primary outcome was a composite of perinatal morbidity and mortality including stillbirth, neonatal death within 72 hours, Apgar score less than 5 at 5 minutes, umbilical artery pH less than 7.0, base deficit 12 mmol/L or greater, or neonatal therapeutic hypothermia. Secondary outcomes were neonatal intensive care unit admission and neonatal anemia (hemoglobin value less than 13.5 g/dL). Bivariable and multivariable analyses were performed. RESULTS: Of the 4,117 women meeting eligibility criteria, 1,263 (30.7%) attempted ECV; 509 (40.3%) of these attempts resulted in successful versions. In bivariable analyses, women who underwent attempted ECV were more likely to be non-Hispanic white and multiparous and had lower mean body mass indexes. The composite perinatal morbidity and mortality outcome did not differ significantly between women who did and did not undergo attempted ECV (2.9% vs 2.5%, P=.46). The frequencies of neonatal intensive care unit admission (3.6% vs 3.3%, P=.53) and neonatal anemia (1.6% vs 1.2%, P=.36) were also similar. There continued to be no association between ECV attempt and composite perinatal morbidity and mortality outcome after adjustment for potential confounders (adjusted odds ratio 1.02, 95% CI 0.66-1.60). CONCLUSION: Compared with expectant management, an ECV attempt at term is not associated with increased perinatal morbidity or mortality. PMID- 29995734 TI - Adverse Events After Concurrent Procedures for Gynecologic Malignancies and Pelvic Floor Disorders. AB - OBJECTIVE: To evaluate the incidence and trends of 30-day outcomes after concurrent surgeries for gynecologic cancer and pelvic floor disorders. METHODS: Using the American College of Surgeons National Quality Improvement Program database, patients who underwent surgery for gynecologic cancer with and without pelvic floor reconstruction were identified between the years 2013 and 2016. Propensity score matching was performed to ameliorate selection. Student t test and Mann-Whitney tests were used to compare continuous variables between two groups where appropriate. The chi and Fisher exact tests were used where appropriate to compare categorical variables across groups. Logistic regression models were used to evaluate factors associated with any adverse event and with postoperative transfusion specifically. RESULTS: Twenty-five thousand one hundred thirty-eight patients underwent oncologic surgery and 589 (2.3%) of these had concurrent pelvic reconstruction during the study period. After propensity matching, there were 488 combined cases; 976 oncologic-only cases were selected as controls. There were no statistically significant differences across any of the baseline characteristics between groups. Although more common in the combined than in the control cohort, the incidence of any postoperative adverse event (8.2% vs 5.5%, odds ratio [OR] 1.5, 95% CI 0.99-2.3) was not statistically significant between groups. Postoperative blood transfusions, however, were more common in the combined cohort than in the control cohort (7.2% vs 3.6%, OR 1.7, 95% CI 1.1-2.8). After logistic regression, ovarian cancer (adjusted OR 7.9, 95% CI 4.9-12.7) and prolapse surgery (adjusted OR 1.7, 95% CI 1.0-2.7) remained significantly associated with any postoperative adverse events. Similarly, ovarian cancer (adjusted OR 10.0, 95% CI 5.9-17.3) and prolapse surgery (adjusted OR 2.1, 95% CI 1.2-3.6) remained significantly associated with a higher incidence of postoperative blood transfusions. CONCLUSION: Combined reconstructive and oncologic surgery is associated with a low but statistically significant increase in the risk of any postoperative adverse event and specifically blood transfusions. PMID- 29995735 TI - Models for Predicting Recurrence, Complications, and Health Status in Women After Pelvic Organ Prolapse Surgery. AB - OBJECTIVE: To develop statistical models predicting recurrent pelvic organ prolapse, surgical complications, and change in health status 12 months after apical prolapse surgery. METHODS: Logistic regression models were developed using a combined cohort from three randomized trials and two prospective cohort studies from 1,301 participants enrolled in surgical studies conducted by the Pelvic Floor Disorders Network. Composite recurrent prolapse was defined as prolapse beyond the hymen; the presence of bothersome bulge symptoms; or prolapse reoperation or retreatment within 12 months after surgery. Complications were defined as any serious adverse event or Dindo grade III complication within 12 months of surgery. Significant change in health status was defined as a minimum important change of SF-6D utility score (+/-0.035 points) from baseline. Thirty two candidate risk factors were considered for each model and model accuracy was measured using concordance indices. All indices were internally validated using 1,000 bootstrap resamples to correct for bias. RESULTS: The models accurately predicted composite recurrent prolapse (concordance index=0.72, 95% CI 0.69 0.76), bothersome vaginal bulge (concordance index=0.73, 95% CI 0.68-0.77), prolapse beyond the hymen (concordance index=0.74, 95% CI 0.70-0.77), serious adverse event (concordance index=0.60, 95% CI 0.56-0.64), Dindo grade III or greater complication (concordance index=0.62, 95% CI 0.58-0.66), and health status improvement (concordance index=0.64, 95% CI 0.62-0.67) or worsening (concordance index=0.63, 95% CI 0.60-0.67). Calibration curves demonstrated all models were accurate through clinically useful predicted probabilities. CONCLUSION: These prediction models are able to provide accurate and discriminating estimates of prolapse recurrence, complications, and health status 12 months after prolapse surgery. PMID- 29995736 TI - Factors Influencing Young Women's Preparedness for Their First Pelvic Examination. AB - OBJECTIVE: To understand factors contributing to women's level of preparedness for their first pelvic examination. METHODS: We conducted semistructured interviews with young women, aged 18-24 years, who had undergone at least one pelvic examination. This analysis explored 1) gynecologic and health care experience before the first pelvic examination, 2) preprocedure expectations and concerns, and 3) preprocedure knowledge about the examination. Interviews were transcribed and computer-assisted content analysis was performed; salient themes are presented. RESULTS: Thirty women completed interviews. Thirteen women described feeling poorly prepared for their first pelvic examination and 17 women described feeling prepared for the examination. Factors influencing women's level of preparedness for their first pelvic examination included 1) age at first examination, 2) pre-examination knowledge of the examination, 3) medical trust or mistrust, 4) overall comfort with one's body, and 5) prior sexual experiences and trauma. CONCLUSION: Preparedness for the first pelvic examination emerges as a subjective concept shaped and determined by the interplay of many factors. Although some factors such as age and personal sexual and reproductive health history may not be modifiable by clinical practice, other factors, including information that young women receive before experiencing their first pelvic examination, may be modifiable by clinical practice. PMID- 29995737 TI - Effect of an Enhanced Recovery After Surgery Program on Opioid Use and Patient Reported Outcomes. AB - OBJECTIVE: To investigate the effect of an enhanced recovery after surgery (ERAS) program on perioperative outcomes with an emphasis on opioid consumption and patient-reported outcomes in the immediate and extended postoperative periods. METHODS: We initiated our ERAS program as part of a quality improvement initiative in November 2014. We compared clinical outcomes among a cohort of 607 women undergoing open gynecologic surgery before or after implementation of ERAS. For 293 patients, patient-reported outcomes were compared using the MD Anderson Symptom Inventory-Ovarian Cancer. RESULTS: Median age was 58 years (range 18-85 years). Median length of stay decreased by 25% for patients in the ERAS pathway (P<.001). Overall, patients in the ERAS group had a 72% reduction in median opioid consumption and 16% were opioid-free during admission up to postoperative day 3 (P<.001). There was no difference in pain scores (P=.80). Patients on ERAS reported less fatigue (P=.01), interference with walking (P=.003), and total interference (composite score of physical and affective measures) during hospitalization (P=.008). After discharge, those on the ERAS pathway demonstrated a significantly shorter median time to return to no or mild fatigue (10 vs 30 days, P=.03), mild or no interference with walking (5 vs 13 days, P=.003), and mild to no total interference (3 vs 13 days, P=.02). There were no significant differences in complications, rates of readmission, or reoperation between the pre- and post-ERAS groups. CONCLUSION: Implementation of an ERAS program was associated with significantly decreased opioid use after surgery and improvement in key patient-reported outcomes associated with functional recovery after surgery without compromising pain scores. PMID- 29995738 TI - Association of Patient Race With Surgical Practice and Perioperative Morbidity After Myomectomy. AB - OBJECTIVE: To compare surgical approach, operative time, and perioperative morbidity after myomectomy by patient race. METHODS: In this retrospective cohort study, data were abstracted from the American College of Surgeons National Surgical Quality Improvement Program database on 8,438 women undergoing myomectomy between January 1, 2012, and December 31, 2015. Myoma burden and approach to myomectomy were determined based on Current Procedural Terminology coding. Surgical approach and perioperative morbidity were examined in African American, Asian American, and Hispanic American women using non-Hispanic Caucasian women as the referent population. Adjusted means and odds ratios (ORs) with 95% CI were calculated using propensity score matching accounting for age, ethnicity, body mass index (BMI), myoma burden, preoperative anemia, hypertension, smoking, and operative time. RESULTS: Data were available for 2,533 Caucasian, 3,359 African American, 664 Asian American, and 700 Hispanic American women. Smoking, BMI, hypertension, myoma burden, and anemia varied by race (P<.001, all comparisons). In adjusted analysis, African American women were twice as likely to undergo abdominal myomectomy (adjusted OR 1.9, 95% CI 1.7 2.0), Asian American women were more than twice as likely (adjusted OR 2.3, 95% CI 1.8-2.8), and Hispanic American women were 50% more likely to undergo abdominal myomectomy (adjusted OR 1.5, 95% CI 1.2-1.9) when compared with Caucasian women. African American women were 50% more likely to experience composite morbidity after abdominal myomectomy (adjusted OR 1.5, 95% CI 1.2-1.7) and Asian American women were more than three times as likely to experience composite morbidity after laparoscopic myomectomy (adjusted OR 3.7, 95% CI 1.7 8.1) compared with Caucasian women. There were no differences in composite morbidity in other racial groups. CONCLUSION: Minority women are substantially more likely to undergo abdominal myomectomy when compared with Caucasian women. African American women had 50% increased odds of morbidity after abdominal myomectomy, and Asian American women were more than three times as likely to experience morbidity after laparoscopic myomectomy. Further examination into the etiology and prevention of these racial disparities is needed. PMID- 29995739 TI - Improving Patient Knowledge of Aneuploidy Testing Using an Educational Video: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effectiveness of an educational video explaining aneuploidy testing. METHODS: This was a randomized controlled trial of women with singleton pregnancies having aneuploidy testing at less than 14 weeks of gestation from September 2016 to March 2017 at our prenatal ultrasound center. We developed an educational video on aneuploidy testing. Participants, stratified by age younger than or 35 years or older at estimated delivery date, were randomized to either view or not view the video before their ultrasonogram. Participants 35 years or older also met with a genetic counselor at the ultrasound appointment. All participants completed a survey assessing knowledge of genetic testing (score of 0-15) at baseline and after the appointment. The primary outcome was change in knowledge score after the intervention. A sample size of 23 per group (n=92) was planned for a total of 46 women younger than 35 years of age and 46 women aged 35 years or older. Data are presented as median (interquartile range). RESULTS: Of 104 eligible women who were approached, 92 were randomized. Forty women aged younger than 35 years and 41 women aged 35 years or older completed the study. Baseline characteristics were similar across groups. In women younger than 35 years, the video group had a significant improvement in knowledge score (+2.0 [1.0-5.0]) compared with the control group (0 [-1.0 to 1.0]; P=.01) and reported better understanding of the information compared with the control group (P<.001) with no change in patient satisfaction (P=.25). In women 35 years or older, change in knowledge score was similar for the video and control groups (P=.98) with no difference in self-reported understanding (P=.49) or patient satisfaction (P=.30). CONCLUSION: A patient-centered educational video explaining aneuploidy testing options improved knowledge and self-reported understanding of the information in women younger than 35 years with no change in patient satisfaction. No difference was seen for women 35 years or older, likely as a result of genetic counseling provided to these women. PMID- 29995740 TI - Salpingectomy During Vaginal Hysterectomy: A Surgical Technique to Make It Easier. AB - BACKGROUND: Opportunistic salpingectomy at the time of hysterectomy is currently recommended to reduce the lifetime risk of ovarian cancer. The vaginal route is least invasive, but surgeons sometimes may choose to perform this procedure laparoscopically or robotically when anticipating adnexal surgery as a result of limited visibility. TECHNIQUE: We describe a surgical technique to make salpingectomy by the vaginal route easier and more feasible. Posterior rotation of the uterus provides excellent access to the tube, which can easily be removed before separation of the adnexa. EXPERIENCE: We have performed more than 60 vaginal hysterectomies using this technique. Salpingectomy was always feasible. CONCLUSION: We demonstrate a simple technique to safely perform opportunistic salpingectomy during a vaginal hysterectomy. PMID- 29995741 TI - Cumulative Financial Burden of Readmissions for Biliary Pancreatitis in Pregnant Women. AB - OBJECTIVE: To evaluate the cumulative hospitalization cost differences between routine cholecystectomy and an observational approach during index hospitalization for pregnant patients. METHODS: A retrospective cohort study of 1,245 pregnant women with biliary pancreatitis across the United States between 2010 and 2014 was performed using the Nationwide Readmissions Database. Cumulative costs and complications were compared between patients with and without cholecystectomy during both initial and subsequent hospitalizations. RESULTS: Cholecystectomy was performed at index hospitalization in 374 patients (374/1,245 [30.0%]). Those who did not undergo index cholecystectomy experienced higher 30-day readmissions (33.7% vs 5.3%, P<.01), and 24.5% eventually underwent interval cholecystectomy. Incidence of bile duct injury was exceedingly low for cholecystectomies performed during either index or subsequent hospitalizations (4/548 [0.7%] vs 12/213 [1.5%], P<.01). No significant difference in risk of premature delivery and abortion was observed (13.3% vs 13.2%, P=.98). Most common diagnoses during readmission included cholelithiasis (44.9%), acute pancreatitis (29.9%), cholecystitis (19.9%), choledocholithiasis (12.8%), chronic pancreatitis (4.2%), cholangitis (1.7%), and pancreatic pseudocyst (1.1%). Patients who underwent cholecystectomy during the index hospitalization had the lowest average cumulative hospitalization episodes, followed by patients undergoing nonoperative management; patients undergoing interval cholecystectomy experienced the highest average hospitalization episodes (1.4 vs 1.7 vs 2.9 hospitalizations, P<.01 for both comparisons). Although initial hospitalization cost was higher for patients who underwent cholecystectomy during index admission, the cumulative hospitalization cost became lower when costs for subsequent readmissions were factored in. CONCLUSION: Early cholecystectomy should be considered in pregnant patients with biliary pancreatitis to reduce readmission costs, because there were no differences in postoperative outcomes. PMID- 29995742 TI - Influence of Body Mass Index on Fetal Fraction Increase With Gestation and Cell Free DNA Test Failure. AB - OBJECTIVE: To assess the influence of body mass index (BMI) on fetal fraction increase with gestational age and on the rates of test failure. METHODS: We performed a cross-sectional study of consecutive singleton pregnancies in which cell-free DNA screening for fetal aneuploidies was performed from 10 weeks of gestation, between May 2013 and January 2018, at two fetal medicine clinics in Australia using one of two different platforms. Maternal characteristics, fetal fraction, and failure after a first attempt ("no-call") and after resampling ("test failure") were recorded. Body mass index was classified as normal (BMI less than 25.0), overweight (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity classes II and III (BMI 35.0 or greater). Fetal fraction and proportions of no-call results and test failure were compared between the groups. RESULTS: Of 14,223 singleton pregnancies included, 8,583 (60.3%) were screened with platform A and 5,640 (39.7%) with platform B. Median fetal fraction values were lower, and no-call and failure rates were higher in increased BMI groups across both platforms (P<.001 in both). When compared with women with normal BMIs, women with BMIs of 35 or greater had a significantly smaller increase in fetal fraction (0.1 vs 0.3 units/wk, P<.001, in both platforms). In this subgroup, when compared with women with normal BMIs, the odds ratios for a no-call result were 22.0 (95% CI 13.8-35.3, 16.6% vs 0.9%) and 8.0 (95% CI 4.1-15.6, 7.8% vs 1.0%) and for a failed test were 25.0 (95% CI 11.2-55.7, 6.4% vs 0.3%) and 5.8 (95% CI 2.0-17.3, 2.7% vs 0.5%) using platforms A and B, respectively. CONCLUSION: The increase in fetal fraction throughout gestation in women with BMIs of 35 or above is minimal. Postponing the test is unlikely to reduce test failure rates in this population. PMID- 29995744 TI - Ondansetron for Treatment of Nausea and Vomiting of Pregnancy and the Risk of Specific Birth Defects. AB - OBJECTIVE: To use data from two large studies of birth defects to describe time trends in ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy and to investigate associations, either previously reported or undescribed, between first-trimester ondansetron use and major birth defects. METHODS: We used data from two case-control studies, the National Birth Defects Prevention Study (1997-2011) and the Slone Birth Defects Study (1997-2014). The prevalence of ondansetron use for the treatment of first-trimester nausea and vomiting of pregnancy among control patients was calculated in 2-year intervals. Using women with untreated first-trimester nausea and vomiting of pregnancy as the reference, we calculated adjusted odds ratios (ORs) and 95% CIs for associations between first-trimester ondansetron use for treatment of nausea and vomiting of pregnancy and specific birth defects. A secondary exposure group of other prescription antiemetics was used to address confounding by indication. RESULTS: In the National Birth Defects Prevention Study and Slone Birth Defects Study, respectively, 6,751 and 5,873 control mothers and 14,667 and 8,533 case mothers who reported first-trimester nausea and vomiting of pregnancy were included in the analysis. Among women in the control group, ondansetron exposure increased from less than 1% before 2000 to 13% in 2013-2014. Ondansetron use was not associated with an increased risk for most of the 51 defect groups analyzed. Modest increases in risk were observed for cleft palate (adjusted OR 1.6, 95% CI 1.1-2.3) in the National Birth Defects Prevention Study and renal agenesis dysgenesis (adjusted OR 1.8, 95% CI 1.1-3.0) in the Birth Defects Study, although these findings may be the result of chance. CONCLUSION: Off-label use of ondansetron for the treatment of nausea and vomiting of pregnancy increased to 13% by the end of the study period. For the majority of specific birth defects investigated, there was no increased risk associated with first-trimester use of ondansetron for treatment of nausea and vomiting of pregnancy compared with no treatment, although modest associations with cleft palate and renal agenesis dysgenesis warrant further study. PMID- 29995745 TI - Damage-Control Surgery for Obstetric Hemorrhage. AB - Damage-control surgery (abdominopelvic packing followed by a period of medical stabilization in the intensive care unit) is a life-saving intervention usually reserved for critically injured patients who may not survive an attempt to achieve hemostasis and complete repair of the damage in the operating room. Most obstetricians have little or no experience in this area, although the use of damage-control surgery in selected cases may be life-saving. This approach should be considered when arterial bleeding has been controlled and persistent bleeding is deemed to be secondary to coagulopathy that is refractory to blood product replacement, particularly in the presence of hypothermia, acidosis, and vasopressor requirement. A prototypical (albeit hypothetical) case is described here in which damage-control surgery is indicated. PMID- 29995743 TI - Institutional Protocols for Vaginal Preparation With Antiseptic Solution and Surgical Site Infection Rate in Women Undergoing Cesarean Delivery During Labor. AB - OBJECTIVE: To evaluate the association of institutional protocols for vaginal preparation with antiseptic solution and the surgical site infection rate in women undergoing cesarean delivery during labor. METHODS: This is a secondary analysis of a multicenter randomized controlled trial of adjunctive azithromycin prophylaxis for cesarean delivery performed in laboring patients with viable pregnancies. The primary outcome for this analysis was the rate of superficial or deep surgical site infection within 6 weeks postpartum, as per Centers for Disease Control and Prevention criteria. Maternal secondary outcomes included a composite of endometritis, wound infection or other infections, postoperative maternal fever, length of hospital stay, and the rates of hospital readmission, unexpected office visits, and emergency department visits. RESULTS: A total of 523 women delivered in institutions with vaginal antisepsis policies before cesarean delivery and 1,490 delivered in institutions without such policies. There was no difference in superficial and deep surgical site infection rates between women with and without vaginal preparation (5.5% vs 4.1%; odds ratio [OR] 1.38, 95% CI 0.87-2.17), even after adjusting for possible confounders (adjusted OR 0.86, 95% CI 0.43-1.73). The lack of significant benefit was noted in all other maternal secondary outcomes. CONCLUSION: Institutional policies for vaginal preparation before cesarean delivery were not associated with lower rates of surgical site infection in women undergoing cesarean delivery during labor. PMID- 29995746 TI - Long-Term Cognitive Impairment After Preeclampsia: A Systematic Review and Meta analysis. AB - OBJECTIVE: To systematically review and summarize studies investigating an association between a history of preeclampsia and cognitive function later in life. DATA SOURCES: Studies published before August 2017 were identified without any language restriction or study design limits through electronic searches of 10 main databases including MEDLINE and ClinicalTrials.gov. METHODS OF STUDY SELECTION: We considered all observational studies that included preeclampsia as a clearly defined prespecified risk factor and that examined a cognition-related outcome measure including validated cognitive tests, magnetic resonance brain imaging, or a clinical diagnosis of dementia. Study quality was assessed using the New-Castle Ottawa scale. All review stages were conducted independently by two reviewers, and disagreement was resolved by a third reviewer. Where possible, data were pooled using a random-effects model. TABULATION, INTEGRATION, AND RESULTS: Of 3,126 potentially relevant studies, 13 were included in our review (1,314 women with prior preeclampsia and 289,080 women with prior normotensive pregnancy); median time since pregnancy was 6 years. A higher number of self reported deficits in perception, memory, and motor functioning on the Cognitive Failure Questionnaire was reported in women with vs without prior preeclamptic pregnancies (Cognitive Failure Questionnaire mean total score 41.5 vs 36.8 out of 100, weighted mean difference of -5.1 points [-9.4 to -0.8]). Our meta-analysis did not reveal significant differences in studies assessing attention (Digit Symbol Substitution or Coding); however, women with preeclampsia performed worse on one of two meta-analyzed tests assessing memory (Letter Number Sequencing mean total score: 10.6 vs 10.1 out of 21, weighted mean difference of 0.63 points 0.06 1.2). Pooling of cognitive outcome measures for studies assessing brain imaging or a clinical diagnosis of dementia were limited by differences in reporting and marked heterogeneity between studies. CONCLUSION: Although preeclampsia is associated with subjective cognitive symptoms, our systematic review did not demonstrate clear evidence of impairment on standard neurocognitive tests. There is a paucity of high-quality studies assessing cognitive outcomes after preeclampsia. PMID- 29995747 TI - Bazedoxifene-Conjugated Estrogens for Treating Endometriosis. AB - BACKGROUND: Endometriosis is a gynecologic disorder affecting 6-10% of reproductive-aged women. First-line therapies are progestin-based regimens; however, failure rates are high, often requiring alternative hormonal agents, each with unfavorable side effects. Bazedoxifene with conjugated estrogens is approved for treatment of menopausal symptoms, and use in animal studies has demonstrated regression of endometriotic lesions. As such, it represents a potential treatment option for endometriosis. CASE: A patient with stage III endometriosis referred for management of dysmenorrhea and cyclic pelvic pain was treated with 20 mg bazedoxifene and 0.45 mg conjugated estrogens daily for more than 6 months. She noted resolution of pelvic pain. There were no abnormal effects on hormonal, uterine, or ovarian parameters. CONCLUSION: Bazedoxifene with conjugated estrogens may be an effective alternative to traditional endometriosis treatment options. PMID- 29995748 TI - Six-Year Experience in Teaching Pelvic Floor Ultrasonography Using Pelvic Floor Phantoms. AB - OBJECTIVE: To review our 6-year experience (2009-2015) in teaching three dimensional pelvic floor ultrasonography workshops that utilized pelvic floor phantoms in the setting of an Objective Structured Assessment of Technical Skills methodology. METHODS: Four-hour Objective Structured Assessment of Technical Skills workshops were given at several society meetings and involved a didactic session, a hands-on session using the pelvic floor phantoms, and a computer station session reviewing pelvic floor pathologies. We analyzed improvement in participants' diagnostic skills using a test with 60 illustrated questions of normal and pathologic findings in live human models. RESULTS: Two hundred forty three attendees completed the 60-question test before and after attending the workshop. Paired t test showed a significant improvement in attendees' average scores after the workshop in all categories: anatomy, normal, or pathologic endovaginal imaging and normal or pathologic endoanal imaging (P<.001 for all). McNemar test showed a statistically significant increased number of correct answers in 50 of 60 (83%) questions. CONCLUSION: Our Objective Structured Assessment of Technical Skills workshops incorporating pelvic floor phantoms enhanced trainees' pelvic floor ultrasound diagnostic skills. PMID- 29995749 TI - Use of the STROBE Checklist to Evaluate the Reporting Quality of Observational Research in Obstetrics. AB - OBJECTIVE: To evaluate observational research manuscripts submitted to Obstetrics & Gynecology to determine the level of adherence to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist and highlight specific areas that could be improved. METHODS: A scoring system based on the STROBE checklist was developed and validated for consistency by volunteer medical students or doctors. Using this scoring system, we performed a cross sectional analysis on 198 observational research manuscripts submitted to Obstetrics & Gynecology from 2008 to 2016. Each manuscript was given a score based on the STROBE checklist. Comparisons were made among acceptance status, country of origin, and study type. Descriptive statistics (means, medians, and frequencies) were calculated for each manuscript category. The t test or Wilcoxon rank-sum test was used to compare differences between two groups and analysis of variance or the Kruskal-Wallis test was used to compare differences among three or more groups. RESULTS: There was a statistically significant difference between the mean score for accepted (23.2+/-2.7) compared with rejected (19.7+/-4.1) manuscripts (P<.001). This difference was not seen when comparing country of origin and study type. Poor reporting was seen among all manuscript categories for objectives, study size, missing data, study participants, and translation of risk. Additionally, rejected manuscripts had poor reporting for eligibility criteria, variables, bias and confounding, statistical methods, unadjusted and adjusted estimates, and category boundaries. CONCLUSION: Overall, accepted manuscripts show better adherence to the STROBE checklist, but there are several critical items that are poorly reported in all manuscripts. PMID- 29995750 TI - Use of epoprostenol to treat severe pulmonary vasoconstriction induced by protamine in cardiac surgery. AB - Since there were a few articles to report the treatment of severe pulmonary vasoconstriction induced by protamine in cardiac surgery, we described the use of epoprostenol to reverse this condition.A total of 5 cases of severe pulmonary vasoconstriction induced by protamine in cardiac surgery were reviewed. The demographic, clinical data and treatment process were obtained. All the patients were followed up.Severe pulmonary vasoconstriction was occurred 4 to 10 minutes after protamine infusion. The primary sign was sudden hypotension, the pulmonary artery pressure was increased gradually, the arterial oxygen partial pressure was decreased in all the patients. Epoprostenol was infused via pulmonary artery catheter at dosage of 20 to 40 ng/kg.min in all the patients, 2 patients were underwent re-cardiac pulmonary bypass assistance. The hemodynamic instability status lasted 40 to 65 minutes respectively. All the patients were recovered uneventfully.All physicians should alert to the incidence of severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Use epoprostenol through pulmonary artery catheter could treat pulmonary artery vasoconstriction effectively and safely. PMID- 29995751 TI - The procalcitonin/albumin ratio as an early diagnostic predictor in discriminating urosepsis from patients with febrile urinary tract infection. AB - Discrimination between urosepsis and febrile urinary tract infections is important in therapeutic decision-making to indicate suitable treatments to avoid sepsis-related organ failure. Accurate diagnosis is time-consuming and susceptible to false-positive results. Moreover, patient responses to urosepsis are complex and varied. Therefore, this study aimed to develop a new, early diagnostic predictor that could discriminate between patients with urosepsis and those with febrile urinary tract infections using a combination of initial procalcitonin and albumin levels.We conducted a retrospective study involving 140 patients with febrile urinary tract infections from January 2013 to December 2017. Univariate and multivariate logistic analyses were performed to identify the independent risk factors for differentiating urosepsis from febrile urinary tract infection. A receiver operating characteristic (ROC) curve analysis was conducted to compare the predictive accuracy of the procalcitonin/albumin ratio.Patients in the urosepsis group had higher procalcitonin/albumin ratios compared to those in the febrile urinary tract infection group [2.254 (0.978, 6.299) vs 0.021 (0.004, 0.095); P < .001]. Based on multivariate logistic analysis, the procalcitonin/albumin ratio [adjusted odds ratio (OR) 1.029, 95% confidence interval (CI) 1.013-1.045, P < .001] was an independent predictor of urosepsis, which allowed for differentiation from patients with febrile urinary tract infections. The area under the ROC curve (AUC) for the procalcitonin/albumin ratio was 0.937 (95% CI, 0.894-0.980); P < .001. The sensitivity and specificity of the procalcitonin/albumin ratio cut-off values (>0.44) were 84.62% and 96.00%, respectively. Moreover, in the subset of 65 patients with urosepsis, the procalcitonin/albumin ratio in the uroseptic shock group was higher than in the group of patients without uroseptic shock [5.46 (1.43, 6.58) vs 1.24 (0.63, 4.38); P = .009].Our study demonstrates that the procalcitonin/albumin ratio is an early diagnostic predictor that can discriminate between urosepsis and febrile urinary tract infection. Additionally, in patients with urosepsis, those with higher procalcitonin/albumin ratios were more prone to uroseptic shock. Our findings suggest that the procalcitonin/albumin ratio is a rapid and relatively low-cost biomarker that can be used in clinical practice. PMID- 29995752 TI - Impact of high body mass index on surgical outcomes and long-term survival among patients undergoing esophagectomy: A meta-analysis. AB - BACKGROUND: The impact of high body mass index (BMI, >23/25 kg/m) on surgical outcomes and prognosis in patients with esophageal carcinoma (EC) after undergoing esophagectomy remains controversial. We herein conducted a systematic review and meta-analysis to determine the relationship between high BMI and surgical outcomes and prognosis in patients undergoing esophagectomy for EC. METHODS: The study search was conducted by retrieving publications from the PubMed, Embase, Web of Science, and CNKI (up to September 8, 2017). Nineteen studies with 13,756 patients were included in this meta-analysis. RESULTS: We found that high BMI was closely associated with a higher incidence of wound infection (odds ratio [OR]: 1.41, 95% confidence interval [CI]: 1.02-1.97, P = .04), cardiovascular complications (OR: 2.51, 95% CI, 1.65-3.81, P < .0001), and anastomotic leakage (OR: 1.50, 95% CI, 1.21-1.84, P = .0002), but a lower incidence of chylous leakage (OR: 0.59, 95% CI, 0.40-0.88, P = .01) when compared with normal BMI. The high BMI group was not associated with better or worse overall survival (OS) (hazard ratio [HR]: 0.95, 95% CI, 0.85-1.07, P = .4) and disease-free survival (HR: 0.95, 95% CI, 0.72-1.25, P = .72) than the normal BMI group. However, in the subgroup analysis, the pooled result of HRs generated from multivariate analyses suggested that high BMI could improve OS in EC patients (HR: 0.84, 95% CI, 0.76-0.93, P < .01). CONCLUSIONS: Overweight patients with EC should not be denied surgical treatment, but intraoperative prevention and careful postoperative monitoring for several surgical complications must be stressed for this population. Besides, high BMI might be a prognostic predictor in EC patients; further studies are warranted. PMID- 29995753 TI - Effect of combined therapy with catheter-directed thrombolysis and factor Xa inhibitor for inferior vena cava thrombosis: A case report. AB - RATIONALE: Inferior vena cava (IVC) thrombosis is an under-recognized entity that is associated with a mortality rate approaching twice that of lower extremity deep venous thrombosis (DVT). Thrombolytic therapy not only results in greater lysis, but also results in higher complication rates than anticoagulation alone. Catheter-directed thrombolysis (CDT), which is effective in accomplishing local resolution whilst reducing bleeding complications, has been established as an alternative treatment for patients with extensive DVT. PATIENT CONCERNS: We report the case of a 70-year-old man who was admitted due to warmness, pain, and swelling in his left leg and a feeling of gait disturbance. DIAGNOSES: Contrast enhanced computed tomography and venous ultrasonography revealed a pulmonary embolism and extensive DVT spreading to the IVC. INTERVENTIONS: First, the patient was treated with fondaparinux. Since this was inadequate, he underwent CDT using a Fountain infusion catheter. Then, CDT was switched to direct oral anticoagulant (DOAC) treatment. OUTCOMES: Both CDT and subsequent DOAC treatments dramatically improved the DVT. His subjective symptoms have disappeared, and no recurrence of thrombosis has been identified. LESSONS: The present case showed the therapeutic effect of CDT, which preceded DOAC treatment, on an extensive DVT. PMID- 29995754 TI - Influence of subglottic secretion drainage on the microorganisms of ventilator associated pneumonia: A meta-analysis for subglottic secretion drainage. AB - BACKGROUND: The influence of the subglottic secretion drainage (SSD) on the microorganisms of ventilator associated pneumonia (VAP) is still unclear.A meta analysis focusing on the influence of the SSD on the microorganisms of VAP. METHODS: A comprehensive search was conducted through the online studies of PubMed, Embase, Cochrane Library, Google scholar, CNKI (China National Knowledge Infrastructure), and VIPI (Database for Chinese Technical Periodicals) using specific search terms.Included studies were randomized controlled trials (RCTs) that compare the microorganisms of VAP between SSD and standard endotracheal tube care in mechanically ventilated adults. RESULTS: Nine RCTs were eligible. There was no significant difference in the rate of VAP caused by nonfermentative bacteria and enterobacteria between SSD group and control group (OR = 0.73, 95%CI, 0.53-1.01; P = .06). The episodes of VAP caused by Gram-positive cocci and Haemophilus influenzae organisms were lower in the SSD group (OR = 0.29, 95%CI, 0.18-0.48; P<0.00001). Less mean volume of SSD daily was observed in VAP group (OR = -16.97, 95%CI, -29.87-4.08; P = .010). CONCLUSION: We found SSD to be associated with significant decreases in VAP caused by Gram-positive cocci and H influenzae organisms but no significant differences in VAP caused by nonfermentative bacteria and enterobacteria. Less mean volume of SSD daily was observed in VAP group. PMID- 29995755 TI - Assessment of CHA2DS2-VASc score for predicting cardiovascular and cerebrovascular outcomes in acute myocardial infarction patients. AB - Although established guidelines currently recommend the use of the CHA2DS2-VASc score for evaluating embolic risk in AF patients, few studies have evaluated the use of the CHA2DS2-VASc score for predicting cardiovascular outcomes in patients with acute myocardial infarction (AMI). The aim of this study was to determine whether CHA2DS2-VASc score is a predictor of a major adverse cardiocerebral vascular event (MACCE) in AMI patients.This study analyzed data in the Taiwan National Health Insurance Research Database from January 2008 to December 2012. Cardiovascular outcomes were analyzed according to the baseline characteristics, presence of AF, and CHA2DS2-VASc score.Twenty nine thousand four hundred fifty two patients with non-fatal AMI, 1171 patients (8.3%) were with AF. The Cox regress model showed with the exception of women sex and peripheral artery disease, all the baseline characteristics considered risks in CHA2DS2-VASc scores were independently associated with the increased incidence of MACCE within 1 year after AMI. A CHA2DS2-VASc score of <5 had negative predictive values of 93.37% for recurrent MI, 98.45% for stroke, 94.86% for HF admission, 98.83% for mortality, and 87.80% for MACCE. Regardless of the presence of AF, the CHA2DS2 VASc score was correlated with 1-year MACCE.The CHA2DS2-VASc score was correlated with 1-year MACCE in AMI patients who were discharge alive. The CHA2DS2-VASc score is useful predictor for 1 year MACCE in patients with AMI. PMID- 29995756 TI - Association of MCP-1 rs1024611 polymorphism with diabetic foot ulcers. AB - Monocyte chemotactant protein-1 (MCP-1), a pro-inflammatory cytokine, plays an important role in inflammatory process. In present study, we evaluated the association of MCP-1 gene rs1024611 polymorphism with risk and clinical characteristics of diabetic foot ulcers (DFUs).This study recruited 116 patients with DFUs, 135 patients with diabetes mellitus (DM) without complications (non DFU), and 149 healthy controls (HCs). MCP-1 gene rs1024611 polymorphism was genotyped by direct sequencing. The expression of MCP-1 was analyzed using quantitative real-time polymerase chain reaction. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assume the association strength.Individuals with rs1024611 AG and GG genotypes exhibited significantly higher susceptibility to DFUs, in the comparison with HCs (AG vs AA, OR = 2.364, 95% CI = 1.021-5.470; GG vs AA, OR = 2.686, 95% CI = 1.154-6.255). Meanwhile, G allele was associated with increased DFUs susceptibility (OR = 1.457, 95% CI = 1.014-2.093). Besides, rs1024611 SNP was slightly correlated with increased DFUs susceptibility in patients with DM. GG genotype of rs1024611 was significantly correlated with higher epidermal thickness and lower dermis thickness in patients with DFUs (P < .01). Patients with DFU exhibited upregulation of MCP-1 mRNA, and GG genotype was correlated with enhanced MCP-1 expression in DFU and non-DFU groups.Rs1024611 polymorphism was significantly associated with MCP-1 expression and individual susceptibility to DFUs. PMID- 29995757 TI - Cystic lymphangioma of pancreas: A rare case report and review of the literature. AB - RATIONALE: Lymphangiomas are benign lymphatic malformations that mostly occur in the neck and axillary regions. Abdominal lymphangioma is a rare type of this tumor, and pancreatic lymphangioma accounts for less than 1% of all lymphangiomas. In this report, we firstly reveal the application of ultrasound guided puncture drainage combined with cell morphological examination for the diagnosis of pancreatic lymphangioma. PATIENT CONCERNS: A 35-year-old male patient was admitted to our hospital with recurrent abdominal pain and general weakness for 1 week. From abdominal ultrasound (US) showed that a large cystic lesion occupied the abdomen, about 30.0cm*25.0cm, leading to suspicion of lymphatic cyst. Computed tomography (CT) was performed for further diagnosis and staging. DIAGNOSES: According to pathological findings in combination with immunohistochemical features, pancreatic lymphangioma was made. INTERVENTIONS: To relieve symptoms of discomfort in the patient, distal pancreatectomy and splenectomy was carried out 1 week after the CT scan. OUTCOMES: The patient recovered to normal status within 19 days after surgery. LESSONS: The abdominal cystic lymphangiomas are difficult to be differential diagnosed from other cystic lesions. And the origin of the tumor is also hard to be detected before operation. We should combine image and pathological examination to clarify a diagnosis. Although lymphangiomas are benign tumours, they can encroach on adjacent organs and grow to an enormous size and that, resection of these invaded organs may be required for a complete excision. PMID- 29995758 TI - Combining YESS and TESSYS techniques during percutaneous transforaminal endoscopic discectomy for multilevel lumbar disc herniation. AB - The authors retrospectively characterized the clinical outcomes of combining the Yeung endoscopic spine system (YESS) and transforaminal endoscopic surgical system (TESSYS) techniques during percutaneous transforaminal endoscopic discectomy (PTED) to treat multilevel lumbar disc herniation.PTED using both YESS and TESSYS was performed on 52 patients with multilevel lumbar disc herniations who had shown no apparent response to previous conservative treatments. Postsurgical follow-ups were conducted at weeks 1, 26, and 48. Patients' preoperative and postoperative performances were assessed by modified MacNab classification, Japanese Orthopedic Association (JOA) scores, Oswestry disability index (ODI), and visual analog scale (VAS), and compared with 34 and 45 patients who were treated only by YESS and TESSYS, respectively.The postsurgery surgeon performed assessment showed satisfactory results in 98% of the YESS + TESSYS treated cases. The average operative time was 116 +/- 23 minutes, intraoperative bleeding was 19 +/- 12 mL, and bed stay was 3 days. No complications occurred, including infection, nerve injury, or spinal canal hematoma. One week after surgery, the modified MacNab classifications of the patients were excellent in 45, good in 6, fair in 1, and poor in 0 (98% were excellent or good). JOA, ODI, and VAS scores for low back pain significantly improved relative to the preoperative assessment (P < .01) and had remained stable at 26 and 48 weeks.PTED that combined YESS and TESSYS techniques, depending on the predominant type of lumbar disc herniation at individual levels, is safe, minimally invasive, and effective. PMID- 29995759 TI - Effect of knee joint function training on joint functional rehabilitation after knee replacement. AB - This retrospective study investigated the effect of knee joint function training (KJFT) on joint functional rehabilitation after knee replacement in Chinese patients with severe knee osteoarthritis (KOA).Eighty-six eligible patients with severe KOA were included. Of those, 43 patients in the intervention group received KJFT and educational program, while the other 43 patients received educational program only. Primary outcome was measured by the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Secondary outcomes were measured by the visual analogue scale (VAS), and Knee Injury and Osteoarthritis Outcome Score (KOOS). All outcomes were assessed at baseline, 1 week before and 3 months after the surgery.Patients in the intervention group showed encouraging benefit neither at 1 week before nor 3 months after the surgery in all outcome measurements, including WOMAC, VAS, and KOOS, when compared with the patients in the control group.The results of this study did not show promising effect of KJFT for joint functional rehabilitation in Chinese patients with KOA after KJR. PMID- 29995760 TI - Whole genome sequencing and 6-year follow-up of a mother and daughter with frontometaphyseal dysplasia associated with keratitis, xerosis, poikiloderma, and acro-osteolysis: A case report. AB - RATIONALE: Frontometaphyseal dysplasia (FMD) is a dominant X-linked rare disease caused by mutations of FLNA. The distinctive features of FMD include skeletal dysplasia, facial dysmorphism, extremities anomalies, deafness, cleft palate and eye anterior segment anomalies, yet none of the complications, such as acro osteolysis, keratitis, xerosis or poikiloderma, have been reported in FMD. PATIENT CONCERNS: A 29-year-old mother and her 7-year-old daughter, both presented with congenital glaucoma, craniofacial dysmorphism, xerosis and poikiloderma, were admitted to our hospital in 2011. Additionally, the mother also suffered from acro-osteolysis, keratitis, camptodactyly of hands and metastatic cutaneous squamous cell carcinoma (SCC) which turned out to be fatal 5 years later. In 2017, keratitis and acro-osteolysis were noticed in the daughter as well. Radiography showed bowed long bones with thickening cortex, and distal phalangeal osteolysis. DIAGNOSES: Whole genome sequencing (WGS) was conducted in 2016, resulting in 71491 single-nucleotide polymorphisms and 7616 indels shared by patients while the father was taken as control. A FLNA variant was classified likely pathogenic, supporting the diagnoses of FMD. In addition, though our patients' symptoms were highly consistent with xeroderma pigmentosum variant, a mild subtype of xeroderma pigmentosum (XP) with merely accumulated UV-induced lesions like xerosis and poikiloderma limited to sun-exposure sites, higher risks of cutaneous neoplasms and absence of classical XP features, WGS didn't find supportive genetical evidence, but 2 HERC2 variants were assigned highest suspicion in both XP and SCC by bioinformatical analyses. INTERVENTIONS: Anti inflammatory treatment, sunscreens and moisturizers were administered. OUTCOMES: The daughter's cutaneous lesions developed slowly during the 6-year follow-up, but the keratitis seriously weakened her sight. LESSONS: To our knowledge, it's the first report of cases carrying FMD, keratitis, xerosis, poikiloderma and acro osteolysis simultaneously, and 3 likely pathogenic variants were identified. Whole genome/exon sequencing is recommended as a common test for patients with rare phenotypes. PMID- 29995761 TI - Single intracutaneous injection of local anesthetics and steroids alleviates acute nonspecific neck pain: A CONSORT-perspective, randomized, controlled clinical trial. AB - Acute nonspecific neck pain is one of the major public health problems lacking efficient treatments. The present study was designed to observe the analgesic effect of intracutaneous injection of local anesthestics and steroids on acute nonspecific neck pain.Thirty-six newly diagnosed with acute nonspecific neck pain patients were randomized to receive ibuprofen (IPB group) or intracutaneous injection of local anesthetics (lidocaine and bupivacaine) and steroid (methylprednisolone) (MLB group). The pain intensity was the primary outcome and evaluated with visual analog scale (VAS). Neck disability index (NDI) and patient global impression of changes (PGIC) were monitored for overall outcomes.Following treatments, patients from the 2 groups have decreased VAS scores and NDI when compared with their baseline level at 3 hours, day 1, and day 3 time points. Interestingly, the MLB group patients have lower VAS scores and NDI than IPB group. MLB patients also had a greater PGIC than IPB group.This study indicates that single intracutaneous injection of local anesthetics and steroids is sufficient to alleviate acute nonspecific neck pain. PMID- 29995762 TI - A case report of purulent pericarditis caused by Candida albicans: Delayed complication forty-years after esophageal surgery. AB - RATIONALE: Candida pericarditis is a rare condition with high mortality. Risk factors include thoracic surgery and immunosuppression. We report a case of candida pericarditis which developed forty-years after esophageal reconstruction surgery. PATIENT CONCERNS: A 42-year-old female presented with nausea, abdominal discomfort, and chest pain, and was found to have a cardiac tamponade secondary to candida pericarditis. Her notable risk factor was colonic interposition done during her infancy for esophageal atresia. DIAGNOSES: The patient underwent emergent pericardial window where 500cc of purulent fluid was drained. The pericardial fluid culture grew Candida albicans. INTERVENTIONS: Esophagram did not show any visible leak and the patient improved with surgical drainage and antifungal treatment with Caspofungin. Caspofungin was continued intravenously for a total of four weeks and was switched to fluconazole. OUTCOMES: An Echocardiogram performed one month after pericardial window revealed trivial pericardial effusion. Serum beta-D-glucan at the time was negative. LESSONS: This report highlights that candida pericarditis infection could occur as a late complication of colonic interposition. We also demonstrate the utility of using an echinocandin in treating this entity. PMID- 29995763 TI - Adjuvant pegylated interferon therapy improves the survival outcomes in patients with hepatitis-related hepatocellular carcinoma after curative treatment: A meta analysis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common cancers and the second leading cause of cancer-related deaths in men worldwide. Surgical resection of HCC remains the mainstay treatment procedure. As a result of hepatitis viral infection, the postoperative survival outcome in patients with HCC is not satisfactory. Recently, studies have reported that due to its treatment effect on hepatitis infection, pegylated interferon (Peg-IFN)-based therapy could improve the survival outcome after the treatment of hepatitis related HCC. However, the postoperative effect of this regimen on the survival outcomes in patients with hepatitis-related HCC remains debatable. The present study conducted a meta-analysis to evaluate the effects of adjuvant Peg-IFN-based therapy on the survival outcomes in patients with hepatitis-related HCC after the curative treatment. METHODS: A systematic search was conducted to identify studies on the survival outcomes in patients with hepatitis-related HCC after a curative treatment with adjuvant Peg-IFN. PubMed, EmBase, and Cochrane Library databases were searched until September 20, 2017. The retrieved studies were independently assessed by 2 reviewers, to identify the potentially eligible studies and extract data of interest. STATA software (Version 10.0, STATA Corporation, College Station, Texas) software was used for all statistical analyses. RESULTS: The pooled results showed that adjuvant Peg-IFN-based therapy improved the 3- and 5-year recurrence-free survival (RFS) rates of patients with hepatitis-related HCC (3-year RFS, HR = 0.80; 95% CI: 0.64-0.99, P = .04; P = .81 for heterogeneity; 5-year RFS, HR = 0.82; 95% CI: 0.67-0.99, P = .04; P = .84 for heterogeneity). For the 5-year overall survival (OS) outcomes of Peg-IFN therapy for hepatitis-related HCC after the curative treatment, the pooled results showed a significant difference between the 2 groups (HR = 0.67; 95% CI: 0.47-0.97, P = .03; P = .99 for heterogeneity). CONCLUSIONS: Adjuvant Peg-IFN-based therapy could improve the RFS and OS outcomes in patients after curative treatment of hepatitis-related HCC, with no severe adverse effects. PMID- 29995764 TI - Predictors of internal mammary lymph nodes (IMLN) metastasis and disease-free survival comparison between IMLN-positive and IMLN-negative breast cancer patients: Results from Western China Clinical Cooperation Group (WCCCG) database (CONSORT). AB - Limited studies performed a comprehensive assessment of risk factors for internal mammary lymph nodes (IMLN) metastasis, and disease-free survival (DFS) difference between IMLN-positive and IMLN-negative breast cancer (BC) patients undergoing IMLN dissection and systemic therapies was not clear.A retrospective study included 1977 BC patients from Western China Clinical Cooperation Group between January 2005 and December 2012. The impact of clinicopathological factors on the occurrence of IMLN metastasis was assessed in univariate and multivariate logistic regression analyses, and a nomogram (model) was constructed to predict the IMLN status. DFS difference was evaluated in univariate and multivariate Cox regression analyses between IMLN-negative and IMLN-positive patients, and univariate analysis was performed to compare DFS between individuals with high and low IMLN metastasis risk defined by proposed nomogram.Of 1977 enrolled patients, 514 cases underwent IMLN dissection and 1463 cases did not undergo IMLN irradiation or dissection. We found that initial disease symptoms and signs, mammographic calcification, tumor site, number of positive axillary lymph nodes (ALNs), American Joint Committee on Cancer pT stage, and human epidermal growth factor receptor 2 status were associated with IMLN metastasis (all P < .05). Those variables were included in nomogram, whose predictive ability was better than that of ALN classification (area under the curve: 0.82 vs 0.76, P < .001). Univariate cox proportional hazards model indicated that better DFS was observed in IMLN-negative patients than IMLN-positive group (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.05-3.34; P = .04), whereas no significant differences in DFS (HR = 0.99, 95% CI = 0.49-2.00; P = .97) were found after adjusting patient-, disease-, and treatment-related factors.Nipple inversion, mammographic calcification, larger tumor size, medial tumor site, negative HER-2 status, and more positive ALNs are independent risk factors for IMLN metastasis, and the individualized nomogram is a feasible tool to predict the status of IMLN. Equivalent DFS was found between positive and negative IMLN patients who all accepted IMLN dissection and systemic therapies. PMID- 29995765 TI - Primary malignant mixed Mullerian tumors of the fallopian tube with cervix metastasis: A rare case report and literature review. AB - RATIONALE: Primary malignant mixed mullerian tumors of the fallopian tube is very rare and has only 1 case in the current literature with cervix metastasis. PATIENT CONCERNS: We reported a 49-year-old woman sufferring from primary malignant mixed mullerian tumors of the fallopian tube with cervix metastasis, and the imaging examination found a strip of solid mass in the right fallopian tube and a nodular mass in cervical canal, which were both hyperintense on T2 weighted image (T2WI) and diffusion weighted image (DWI) and continuous moderate enhancement on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DIAGNOSES: The diagnosis was confirmed according to the specific anatomical location and pathological examination which was proved as primary malignant mixed mullerian tumors of the fallopian tube with cervix metastasis. INTERVENTIONS: The patient underwent radical hysterctomy, bilateral adnexectomy, pelvic lymph node dissection, omentum majus excision and intravenous chemotherapy. OUTCOMES: Her posttreatment condition was good. LESSONS: Primary malignant mixed mullerian tumors of the fallopian tube can be located by magnetic resonance image examination, which may also offer several diagnostic tips according to changes in signal and enhancement. When combined with pathological findings, qualitative diagnosis can be determined. Surgery and adjuvant chemotherapy are considered as effective methods. Our paper discussed its epidemiology, clinical symptoms, pathologic characters, therapeutic method as well as magnetic resonance imaging findings suggesting the diagnosis and differential diagnosis, including precontrast scan, contrast scan and diffusion weighted image and provided magnetic resonance imaging characteristics of primary malignant mixed mullerian tumors of the fallopian tube described in other literatures. PMID- 29995766 TI - Use of controlled negative pressure in management of phlegmon caused by fulminant complication of pressure wound: A case report. AB - RATIONALE: Effective wound healing depends on the adequate choice of the wound cleansing method, to enable rapid removal of necrotic tissue. Negative pressure wound therapy (NPWT) is an effective non-invasive technique for management of wounds of varied aetiology, including deep tissue injuries caused by pressure. PATIENT CONCERNS: This article discusses a case of an 82-year-old female receiving hospice care at home owing to progressing untreated thoracic spinal stenosis, bedridden for 4 years, incapable of self-care. DIAGNOSES: Three fulminant pressure wounds, 50 cm each, with signs of undermining, Stage II/IV according to National Pressure Ulcer Advisory Panel, were identified in the area of the sacrum and the right and left trochanter. Despite measures used to prevent pressure sores, and nutritional supplementation, two months later a fourth pressure ulcer involving subcutaneous tissue was identified in the area of the right sciatic tuber, accompanied with signs of systemic inflammatory response, as well as massive phlegmon and lesion in the ischial bone. INTERVENTIONS: As previously applied treatments (surgical necrectomy, biological therapy - Lucilia Sericata maggots, autolysis, pharmacological therapy) proved ineffective, NPWT was experimentally administered to evacuate exudate and to cleanse the wound. OUTCOMES: Application of negative pressure during a 42-day therapy allowed significantly faster cleansing of the wound. The pressure wounds was significantly reduced in size, and necrotic tissue was removed from the sciatic tuber, which ultimately was covered with granulation tissue. LESSONS: Controlled negative pressure can successfully be used in the process of cleansing an infected pressure wound to safely remove exudate and to minimise local inflammation. Administration of controlled negative pressure is an effective and safe method in the process of cleansing an infected pressure wound. PMID- 29995767 TI - Delayed surgery in a patient with pneumococcal peritonitis and bacteremia secondary to perforation of gastroduodenal ulcer: A case report. AB - RATIONALE: Very few cases of secondary peritonitis caused by Streptococcus pneumoniae have been described in the literature, and they have been found to occur mostly in patients with predisposing factors. Here, we report the case of an elderly patient who developed pneumococcal peritonitis secondary to perforation of gastroduodenal ulcer. PATIENT CONCERNS: An 82-year-old man was admitted to intensive care unit (ICU) for septic shock with cardiac impairment 1 day after arriving in the Emergency Department. DIAGNOSES: The patient presented with pneumococcal bacteremia and pneumococcal antigenuria. No abdominal defense was found on examination. A computed tomography scan revealed pneumoperitoneum and peritoneal effusions. INTERVENTIONS: The patient was treated with effective empiric antibiotic therapy, and delayed surgery. OUTCOMES: The patient gradually improved and was discharged from ICU on day 14. The ultimate outcome was unfavorable, with death occurring on day 28. LESSONS: This rare infection can occur in elderly patients even in the absence of other predisposing factors. Secondary peritonitis may be suspected in patients with positive pneumococcal antigenuria or unexplained pneumococcal bacteremia, especially if an asthenic form is possible. PMID- 29995768 TI - Case report: incidental parathyroid adenoma in a Chinese diabetic patient with hypercalcemia and normal parathyroid hormone levels. AB - RATIONALE: Parathyroid hormone PTH) levels are the main parameters to differentiate primary hyperparathyroidism (PHPT) from non-PTH-dependent hypercalcemia. We report a case of hypercalcemia with normal PTH levels due to a parathyroid adenoma. PATIENT CONCERNS: A 52-year-old female patient presented with 2-year history of documented sustained high-normal serum calcium and hypercalcemia (2.51-3.03 mmol/L) with normal serum intact PTH levels (21.95-40.15 pg/ mL). DIAGNOSES: A parathyroid tumor was localized by ultrasonography and 99mTc-sestamibi dual-phase fusion imaging with single-photon emission computed tomography/computed tomography. INTERVENTIONS: Parathyroidectomy was performed to excise the tumor completely. OUTCOMES: A 1.2-cm-sized parathyroid adenoma was removed surgically. The serum calcium was declined to normal level immediately after resection, as well as in 4- month follow-ups. The immunohistological diagnosis proved to be a PTH positive parathyroid adenoma. LESSONS: In case of hypercalcemia, serum intact PTH and parathyroid imaging should be monitored to evaluate the presence of parathyroid adenoma with care because PHPT could present with inappropriate normal PTH. PMID- 29995769 TI - Gastrointestinal nervous system alpha-synuclein as a potential biomarker of Parkinson disease. AB - Lewy bodies (LB) play an essential role in the development, survival, and function maintenance of midbrain dopaminergic (DA) neurons in Parkinson disease (PD). Alpha-synuclein (alpha-synuclein) is the major component of Lewy bodies and is a potential target for Parkinson's disease (PD) therapies. alpha-synuclein can be detected in the gastrointestinal (GI) nervous system, but whether there is any association between altered alpha-synuclein expression in the GI nervous system and the onset of PD is not known. The answer to this question presents the opportunity for a promising biomarker in the pre-clinical diagnosis of PD. As such, this study aimed to measure the alpha-synuclein level in the GI nervous system of Parkinson's disease patients.The protein levels of alpha-synuclein in the GI nervous system of 31 PD patients (PD group) and 32 patients without PD or Parkinsonism-plus syndrome (control group) were evaluated via immunohistochemical staining. The chi test was performed to evaluate the differences between the PD group and control group. In addition to the distribution of alpha-synuclein positive protein, regional distribution of the protein in the stomach was also evaluated across groups.Alpha synuclein overexpression was found in the GI nervous tissue of PD patients. The PD group included 17 positive results and 14 negative results. The control group exhibited 7 positive results and 24 negative results. The chi test showed that chi = 7.255, P = .01. The distribution of these positive cases in the gastrointestinal system, the chi test showed that P = .949. The 21 stomach tissues had 7 alpha-synuclein positive protein tissues, while the body of stomach (4 alpha-synuclein positive protein) was higher than in other regions.Aberrant expression of alpha-synuclein was detected in the GI tissues of PD patients, though the distribution of alpha-synuclein in the gastrointestinal tract had no specificity. Gastrointestinal mucous biopsy could be regarded as a potential opportunity for the early-stage diagnostic exploration of PD, through the detection of alpha-synuclein inclusions. PMID- 29995770 TI - Low expression of aging-related NRXN3 is associated with Alzheimer disease: A systematic review and meta-analysis. AB - BACKGROUND: Alzheimer disease (AD) is a common neurodegenerative disorder with distinct pathological features, with aging considered the greatest risk factor. We explored how aging contributes to increased AD risk, and determined concurrent and coordinate changes (including genetic and phenotypic modifications) commonly exhibited in both normal aging and AD. METHODS: Using the Gene Expression Omnibus (GEO) database, we collected 1 healthy aging-related and 3 AD-related datasets of the hippocampal region. The normal aging dataset was divided into 3 age groups: young (20-40 years old), middle-aged (40-60 years old), and elderly (>60 years old). These datasets were used to analyze the differentially expressed genes (DEGs). The Gene Ontology (GO) terms, pathways, and function network analysis of these DEGs were analyzed. RESULTS: One thousand two hundred ninety-one DEGs were found to be shared in the natural aging groups and AD patients. Among the shared DEGs, ATP6V1E1, GNG3, NDUFV2, GOT1, USP14, and NAV2 have been previously found in both normal aging individuals and AD patients. Furthermore, using Java Enrichment of Pathways Extended to Topology (JEPETTO) analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) database, we determined that changes in aging-related KEGG annotations may contribute to the aging-dependence of AD risk. Interestingly, NRXN3, the second most commonly deregulated gene identified in the present study, is known to carry a mutation in AD patients. According to functional network analysis, NRXN3 plays a critical role in synaptic functions involved in the cognitive decline associated with normal aging and AD. CONCLUSION: Our results indicate that the low expression of aging-related NRXN3 may increase AD risk, though the potential mechanism requires further clarification. PMID- 29995771 TI - Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: A observational study. AB - Epidermal growth factor receptor (EGFR) mutations for EGFR-tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients are with clinical benefits. Nevertheless, eventual resistance to EGFR-TKI is almost inevitable. In about 50% patients, EGFR-TKI develops a secondary mutation, which is often the T790 M mutation. We aimed to investigate the relationship between EGFR gene status in the peripheral blood and prognosis (progression-free survival [PFS] and overall survival [OS]) in advanced lung adenocarcinoma patients and the 20 exon 790 site mutation (T790 M) and acquired resistance to EGFR-TKI.A total of 49 patients with EGFR-TKI resistance and advanced lung cancer who visited the Shihezi University School of Medicine between 12/2013 and 12/2014 were enrolled in this study. Peripheral blood plasma DNA was isolated after EGFR-TKI resistance and the EGFR exon 20 T790 M mutation was detected using the probe amplification refractory mutation system method.The T790 M mutation rate was 30.6% (15/49). There was no association between T790 M mutation and age, gender, smoking, clinical stage, Eastern Cooperative Oncology Group rating, initial EGFR mutation, and EGFR-TKI drugs, but EGFR-TKI resistance was associated with progression (P = .009). Median progression-free survival (PFS) of patients with T790 M mutation was 9.6 months and median overall survival (OS) was 17.6 months, compared to 6.8 and 12.7 months in controls (P = .018 and P = .027). Multivariate analysis showed that T790 M mutations independently affected the PFS (risk ratio, RR = 0.653, 95% confidence interval, CI: 0.069-0.886, P = .032) and OS (RR = 0.847, 95% CI: 0.208 2.696, P = .008).T790 M mutation and EGFR-TKI resistance are independent factors to affect PFS and OS of non-small cell lung cancer patients. PMID- 29995772 TI - Association between use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs and erectile dysfunction: A systematic review. AB - OBJECTIVE: There are various etiologies of erectile dysfunction (ED), including endothelial dysfunction, atherosclerosis, and chronic inflammation. Aspirin has a protective role against endothelial dysfunction and atherosclerosis, whease all non-steroidal anti-inflammatory drugs (NSAIDs) are known for their anti inflammatory properties. However, association between the use of aspirin or non aspirin NSAIDs and ED is controversial. Therefore, we reviewed this relationship. METHODS: We systematically reviewed the pathophysiology of ED, physiological effect of prostaglandins, pharmacological action of NSAIDs, and clinical and basic research studies that evaluated the effect of aspirin or non-aspirin NSAIDs on ED. RESULTS: The research studies that assessed association between aspirin or non-aspirin NSAIDs are limited, and only 12 articles have been published. One clinical and three basic studies have claimed that aspirin or non-aspirin NSAIDs are beneficial for ED by preserving nitric oxide synthase impairment or penile blood hypercoagulability. One basic and two clinical studies considered them as risk factors because they interfered with prostaglandin production. By contrast, four clinical studies showed irrelevant results after controlling various medical indications. In addition, the mechanical effect of aspirin or non-aspirin NSAIDs on the nitric oxide pathway is still controversial. CONCLUSIONS: The available research studies revealed that association between aspirin or non-aspirin NSAIDs and ED is controversial. Considering the high frequency of drug use, further clinical and basic investigations should be conducted to clarify their exact relationship. PMID- 29995773 TI - Meta-analysis of the accuracy of transient elastography in measuring liver stiffness to diagnose esophageal varices in cirrhosis. AB - BACKGROUD: To assess the diagnostic performance of transient elastography (TE) in detecting the presence and size of esophageal varices (EV) in cirrhotic patients. METHODS: We searched PubMed, Web of Science, Wiley Online Library, Science Direct, China National Knowledge Infrastructure, WeiPu, WanFang database, and Baidu Scholar to identify studies that evaluated the diagnostic accuracy of TE in liver stiffness measurement, compared with esophagogastroduodenoscopy (EGD), for the detection of the presence and degree of EV in cirrhosis. RESULTS: We included 32 studies in the presence of any EV (grade 1-3; n = 4082), 27 studies on substantial EV (grade 2-3; n = 5221) and 5 studies on large EV (grade 3). The pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were 0.8 (95% CI, 0.78-0.86), 0.68 (95% CI, 0.62-0.74), and 10 (95% CI, 7-14) for any EV; 0.81 (95% CI, 0.77-0.85), 0.72 (95% CI, 0.66-0.77), and 11 (95% CI, 8-15) for substantial EV; and 0.92 (95% CI, 0.83-0.96), 0.78 (95% CI, 0.70-0.85), and 40 (95% CI, 15-107) for large EV. Subgroup analysis revealed that the heterogeneity among studies on any EV could potentially be explained by study location, proportion of Child A, and time interval between TE and EGD; for substantial EV, the proportion of Child A, etiology of cirrhosis, and the time interval between TE and EGD were important heterogeneity factors. Publication bias was found among studies evaluating diagnostic performance of TE for any EV. CONCLUSION: TE is a good tool for detecting the presence and degree of EV; however, in determination of the liver stiffness cutoff values means that TE is only cautiously used in clinical practice. PMID- 29995774 TI - Effect of neuromuscular electrical stimulation for fatigue management in patients with advanced laryngeal cancer receiving chemoradiotherapy. AB - This study retrospectively investigated the effect of neuromuscular electrical stimulation (NMES) for fatigue management in patients with advanced laryngeal cancer (ALC) receiving chemoradiotherapy.A total of 60 eligible patients with ALC receiving chemoradiotherapy were included. These patients were assigned equally to a treatment group and a control group. Patients in the treatment group received NMES therapy and were treated for a total of 8 weeks, while the patients in the control group did not receive NMES therapy. The primary outcome was fatigue, measured by the multidimensional fatigue inventory (MFI). The secondary outcomes included anxiety and depression, measured by the Hospital Anxiety and Depression Scale (HADS), and sleep quality, measured by the Pittsburgh Sleep Quality Index (PSQI). All outcomes were evaluated before and after 8-week NMES treatmentAfter 8-week NMES treatment, the patients in the treatment group did not exert better effect than patients in the control group in fatigue relief, measured by the MFI score, anxiety and depression decrease, assessed by HADS, and sleep quality improvement, evaluated by PSQI.The results of this study demonstrate that NMES may not benefit for fatigue relief in patients with ALC receiving chemoradiotherapy. Future studies should still focus on this topic and warrant these results. PMID- 29995775 TI - Lymphoepithelial carcinoma of the maxillary sinus: A case report and review of the literature. AB - RATIONALE: Most cases of lymphoepithelial carcinoma (LEC) occur in the nasopharynx, and LEC in the sinonasal tract is extremely rare; thus, the clinical characteristics of sinonasal LEC are not well known. PATIENT CONCERNS: A 63-year old Japanese man presented with a three-week history of left cheek pain, nasal obstruction and cheek swelling. DIAGNOSES: Enhanced CT and MRI revealed a tumor of the left maxillary sinus that invaded the left orbit and hard palate, with multiple swollen left cervical lymph nodes. Open biopsy was performed, and the specimen was diagnosed as LEC. INTERVENTIONS: Alternating chemoradiotherapy (ALCRT) followed by salvage surgery was performed. OUTCOMES: Our patient has been disease free for 5 years. LESSONS: A literature review of the epidemiology, etiology, clinical course and management of sinonasal LEC is highlighted. We believe ALCRT followed by salvage surgery to be a highly optimal treatment for sinonasal LEC from the viewpoint of a balance between quality of life and a high curative effect. PMID- 29995776 TI - Outcome of adult T-lymphoblastic lymphoma depends on ALL-type chemotherapy, prognostic factors, and performance of allogeneic hematopoietic stem cell transplantation. AB - To study the prognostic factors of adult patients with T-lymphoblastic lymphoma (T-LBL) and to evaluate therapeutic effects of acute lymphoblastic leukemia (ALL) type chemotherapy in combination with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients who achieved overall response (OR) with first line ALL-type chemotherapy.This was a retrospective study of 59 adult patients with T-LBL treated with hyper-fractionated administration of cyclophosphamide, vincristine, doxorubicin and dexamethasone/methotrexate (hyper CVAD/MA) chemotherapy alone or in combination with allo-HSCT between June 2008 and October 2015. Complete response (CR) and OR rates were evaluated after the initial chemotherapy. Clinical characteristics and the risk factors associated with prognosis and overall survival (OS) were analyzed in all patients and the effects of allo-HSCT on OS were evaluated in patients who had achieved OR after initial chemotherapy.Forty-eight patients (81.4%) achieved OR by hyper-CVAD chemotherapy, among which, 22 patients (45.8%) further received allo-HSCT. The median follow-up was 31.5 months, ranging from 11 to 97 months. The 3-year OS and progression-free survival (PFS) were 45.7% and 45.0% for patients who achieved OR after chemotherapy and both 0 for patients who did not achieve OR (both P < .001). Three year OS and PFS were higher in patients who received chemotherapy + allo-HSCT than in patients who received chemotherapy alone (3-year OS: 72.8% vs 17.5%, P = .008; PFS: 65.1% vs 27.8%, P = 0.007). Shorter survival was independently associated with elevated lactic dehydrogenase (LDH), Ki-67>=75%, pleural effusion and no OR (all P < .05) in all patients. But shorter survival was only associated with elevated LDH level, leukocytosis (>10 G/L), and chemotherapy alone in patients who achieved OR (all P < .05).The mid-term outcomes of adult patients with T-LBL are associated with response to chemotherapy (in all patients) and performance of allo-HSCT (in patients who achieved OR). Allo-HSCT could be a feasible and effective consolidation therapy for adult T-LBL. PMID- 29995777 TI - Depression and anxiety in systemic lupus erythematosus: The crosstalk between immunological, clinical, and psychosocial factors. AB - Depression and anxiety cause severe loss of quality of life for patients with systemic lupus erythematosus. The causes and factors that contribute to these psychological manifestations in lupus are difficult to disentangle. This study compared clinical, psychological, and demographic factors between lupus patients, depressed patients, and rheumatoid arthritis patients to discover lupus-specific contributors to depression. Lupus-specific manifestations of depression were also investigated.Physiological, clinical, and psychosocial data were collected from 77 patients. ELISA was used to measure cytokine levels. Univariate and Multivariate analyses were used to compare the patient populations and identify correlations between key physical and psychological indicators.The prevalence of depression in the SLE cohort was 6 times greater than the healthy control subjects. Pain, IL-6, and Pittsburgh Sleep Quality index values were all significantly higher in SLE patients compared with the healthy control group (P < .001, P = .038, and P = .005, respectively). Anxiety levels were significantly higher in SLE patients compared to healthy and RA control patients (P = .020 and .011, respectively). Serum IL-10 concentrations, relationship assessment scale, and fatigue severity scale values were found to be correlated with depression among the SLE patients (P = .036, P = .007, and P = .001, respectively). Relationship assessment and fatigue severity scale scores were found to be the best indicators of depression for the SLE patients (P = .042 and .028, respectively).Fatigue Severity, relationship satisfaction, and IL-10 concentrations are indicators of depression in lupus patients. Despite also suffering from the pain and disability that accompanies chronic autoimmune disease, the rheumatoid arthritis patients had less anxiety and better relationship scores. PMID- 29995778 TI - Migraine as a risk factor for primary open angle glaucoma: A systematic review and meta-analysis. AB - Migraine is increasingly being reported as a risk factor for primary open angle glaucoma (POAG). However, studies aimed to investigate this association yielded conflicting results. To assess the consistency of the data on the topic, we performed a systematic review and meta-analysis. A systematic literature search from Embase, Web of Science, and PubMed was performed to identify relevant studies on the relationship between migraine and POAG. Random effects models were used to estimate the pooled relative risks (RRs) with 95% confidence intervals (95% CIs) in this meta-analysis. A total of 11 studies meeting the inclusion criteria were included in this meta-analysis. Our findings showed an RR of developing POAG of 1.24 (95% CI = 1.12-1.37) in migraine patients. No evidence of significant heterogeneity was detected across studies (P = .071; I = 41.7%). This association was not modified by the glaucoma type of the included patients. A significant association was observed in case-control design studies, but not in cohort design studies. Little evidence of publication bias was found. The findings of this meta-analysis suggest that migraine can significantly increase the risk of the development of POAG. However, the cohort study design failed to identify this association. Whether migraines can significantly increase the risk of developing POAG is still controversial. PMID- 29995779 TI - Male pattern baldness and incidence of prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: The relationship between male pattern baldness and incidence of prostate cancer remains inconclusive. Hence, we performed the present meta analysis based on all eligible cohort and case-control studies. METHODS: A comprehensive literature search was performed in October 2017 based on PubMed and Web of Science databases. Pooled relative risk (RR) and its 95% confidence interval (95% CI) was calculated with a DerSimonian and Laird random-effects model. RESULTS: A total of 15 studies were included in this meta-analysis. Overall, no statistically significant association between baldness (any pattern) and prostate cancer risk was identified (RR: 1.03, 95% CI 0.96-1.11). There was obvious heterogeneity across included studies (P < .078 for heterogeneity, I = 36.4%). When subgroup analysis by types of baldness, a statistically significant association was observed for vertex baldness (RR 1.24, 95% CI 1.05-1.46) but not for other types of baldness. CONCLUSION: Individuals with vertex baldness may have an increased risk of prostate cancer. Given the obvious heterogeneity and null results in overall analysis and most of subgroup analyses, further large well-designed prospective cohort studies are warranted to confirm our preliminary findings. PMID- 29995780 TI - A meta-analysis of the association between CTLA-4 genetic polymorphism and susceptibility of asthma. AB - BACKGROUND: Numerous studies have reported an association between cytotoxic T lymphocyte associated antigen 4 gene (CTLA4) polymorphism and susceptibility to asthma, in different populations, but the results have been inconsistent. We performed a meta-analysis of 19 published case-control studies to obtain a reasonably accurate estimation of the relationship between CTLA4 polymorphism and asthma. METHODS: We searched the Pubmed, EMBASE, Chinese National Knowledge Infrastructure, and Wanfang databases and extracted data from 19 independent, eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) and Egger test were separately used to assess the strength of associations and publication bias. RESULTS: A total of 19 case-control studies involving 4831 cases and 4534 controls were identified. The combined results revealed that there was significant association between the +49A/G polymorphism and asthma (for GG + GA vs. AA: OR = 0.82, 95% CI = 0.70-0.97, P = .02). Stratification by race or age indicated a significant association between the CTLA-4 +49 GA+GG genotype and asthma in Asians (OR = 0.80, 95% CI = 0.68-0.95, P = .01) and children (OR = 0.75, 95% CI = 0.62-0.90, P = .002), but there was no association in whites (OR = 0.94, 95% CI = 0.80-1.10, P = .44) and adults (OR = 0.85, 95% CI = 0.68-1.06, P = .15). Additionally, there was a significant association with atopic asthma under the random-effects model (OR = 0.81, 95% CI = 0.67-0.98, P = .03). In addition, there was no significant association between the -318 C/T polymorphism and asthma risk. CONCLUSIONS: Our meta-analysis results suggested that the +49A/G polymorphism in CTLA-4 was an important risk factor for asthma susceptibility, especially in Asian individuals, children, and atopic patients. PMID- 29995781 TI - A meta-analysis of the relationship between environmental tobacco smoke and lung cancer risk of nonsmoker in China. AB - BACKGROUND: To investigate the association between exposure to environmental tobacco smoke (EVT) and the incidence of lung cancer (LC) in nonsmoking adults. METHOD: PubMed, Cochrane, Embase, Wanfang, CNKI, and VIP database were searched by the index words to identify the qualified case-control studies, and relevant literature sources were also searched. The latest research was done in June 2017. Odds radio (OR) along with 95% confidence interval (95% CI) were used to analyze the main outcomes. RESULT: Twenty RCTs were involved in the meta-analysis with 13,004 adults in the case group and 11,199 adults in the control group. The results indicated that compared with the nonexposure population, the risk of LC incidence was significantly higher in EVT exposure (OR: 1.64, 95% CI: 1.34-2.01), EVT male exposure (OR: 1.62, 95% CI: 1.16-2.28), EVT female exposure (OR: 1.57, 95% CI: 1.43-1.72), EVT exposure at workplace (OR: 1.78, 95% CI: 1.29-2.44), EVT exposure at home (OR: 1.53, 95% CI: 1.01-2.33), and EVT female exposure at home (OR: 1.55, 95% CI: 1.34-1.79). However, there is still no significant difference among the risk of LC incidence in EVT male exposure at workplace (OR: 1.51, 95% CI: 0.74-3.06), EVT female exposure at workplace (OR: 1.23, 95% CI: 0.99-1.53), and EVT male exposure at home (OR: 1.24, 95% CI: 0.68-2.26). CONCLUSION: EVT exposure is prospectively associated with a significantly increased risk of LC incidence. More high quality studies are required to address the association between EVT exposure and LC incidence. PMID- 29995782 TI - Charcot arthropathy of the shoulder joint as a presenting feature of basilar impression with syringomyelia: A case report and literature review. AB - RATIONALE: Charcot arthropathy, also known as Neuropathic arthropathy (NA), is an unusual chronic degenerative disease. To date, there exists a paucity of research on NA caused by syringomyelia. PATIENTS CONCERNS: A 52-year-old non-diabetic female presented with progressive swelling, pain and limited movement in her left shoulder joint combined with asthenia of her left upper extremity for three months. DIAGNOSES: Neuropathic arthropathy of the shoulder associated with the cervicothoracic syrinx and basilar impressions was diagnosed. INTERVENTIONS: The treatment is directed to its potential cause to cease its progression. A posterior fossa decompression (PFD) was conducted for this patient. OUTCOMES: Postoperatively, the patient's symptoms were relieved and the size of syrinx was reduced at the 6-month follow-up. LESSONS: Taken together with 34 previous reports identified from a PubMed search, an analysis of 35 cases of Charcot arthropathy was conducted. Surgical decompression is an effective treatment, but the optimal treatment remains controversial. Thus, the aim of this literature review was to remind us to diagnose the potential cause as early as possible and we should spare no efforts on the exploration of etiology and adjuvant therapy for this disease. PMID- 29995783 TI - Long-term outcomes and prognostic markers in gallbladder cancer. AB - Cancer-related inflammation and systemic inflammatory markers have been widely recognized as an essential part in tumor multiplication, invasion, and metastasis of tumor cells. This study aimed to estimate and compare the prognostic value of various biomarkers on overall survival (OS) in patients with gallbladder cancer patients.We performed a retrospective study of 159 patients received different therapies in West China Hospital from 2009 to 2014. The preoperative biomarker data, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), lactate dehydrogenase, and alkaline phosphatase, as well as other clinical information, were obtained from electronic record. And the receiver operating characteristic curves were used to analyze the optimal cut-off values of them. Kaplan-Meier survival analysis and Cox proportional hazard model analysis were applied to evaluate the association between markers and OS.The optimal cut-off value was 4.39 for NLR, 181.85 for PLR, 0.30 for MLR, and 3.02 for carcinoembryonic antigen (CEA). Kaplan-Meier analysis and univariate Cox analysis both demonstrated the significant prognostic value of NLR, MLR, and CEA. However, PLR failed to be a significant predictor of OS. The multivariate Cox analysis showed that preoperative NLR and CEA were independent prognostic factors for OS.Advanced tumor/node/metastasis stage, enhanced pretherapeutic NLR, and CEA were significantly associated with worse OS of gallbladder cancer patients. Furthermore, NLR was a better prognostic factor than CEA in advanced T (T3-T4) stage patients, while CEA was better for early T (T1-T2) stage, early N (N0-N1) stage, and early M (M0) stage patients. PMID- 29995784 TI - V232D mutation in patients with cystic fibrosis: Not so rare, not so mild. AB - The frequency of some Cystic Fibrosis (CF) Transmembrane Conductance Regulator gene (CFTR) mutations varies between populations. Genetic testing during newborn screening (NBS) for CF can identify less common mutations with low clinical expression in childhood and previously considered mild but not fully characterized, such as the mutation p.Val232Asp (c.695T > A). The aim of this study was to describe CF patients with the V232D mutation. We identify CF children with the V232D mutation detected by NBS and compare them with CF adults with this mutation whose diagnosis was prompted by clinical symptoms in the same period. We studied clinical, biochemical, spirometric, and prognostic features in both populations. NBS program tested 276,523 children during a period of 14 years (2003-2017) and identified 54 cases of CF. Six children (11%) had the V232D mutation. Over the same period, 5 adults (age 37.6 +/- 16.29 years old) with symptoms of CF and this mutation were also diagnosed. Follow-up duration was mean 10.1 years for adults and mean 6.5 years for children. In the adult group, lung function was impaired at diagnosis in all patients (Forced Expiratory Volume1 FEV1-67.12% +/- 13.09) and worsened in children tested during evolution (FEV1first: 113%; FEV1last: 64%). Pancreatic insufficiency was present in adult group, with recurrent pancreatitis in 1 present. Although with less clinical expression in children, V232D is associated with pulmonary and pancreatic involvement during adulthood and CF cannot be considered mild. This mutation is present in 11% of all patients diagnosed with CF in our region. Its inclusion in some NBS programs should be taken into account in order to improve the prognosis of affected children. PMID- 29995786 TI - Graft survival rate of deep anterior lamellar keratoplasty for keratoconus: A meta-analysis. AB - BACKGROUND: Deep anterior lamellar keratoplasty (DALK) is an optional treatment for patients with keratoconus, and the associated graft survival rate varies. Herein, we aimed to explore the graft survival rate of DALK in patients with keratoconus. METHODS: PubMed, Web of Science, and ProQuest databases were searched to retrieve the related articles. General data, clinical characters, and graft survival rates were obtained directly from the included studies and analyzed by meta-analysis. RESULTS: A total of 12 articles were included. The merged 1-, 3-, and 5-year graft survival rates were 100% (99.9-100%, P < .001), 92.9% (89.8-95.9%, P < .001), and 90.4% (86.0-0.948%, P < .001), respectively. Lower heterogeneity was shown in each subgroup that was divided neither according to the sample number nor number of surgeons. CONCLUSION: The survival rate slightly decreases year by year, but the overall trend seems relatively stable. Ensuring that all DALK procedures are performed by a single surgeon might be helpful to improve the graft survival rate after surgery. PMID- 29995785 TI - Parathyroid cysts: A review of 359 patients reported in the international literature. AB - BACKGROUND: Parathyroid cysts are lesions that represent 1-5% of neck masses. They are subdivided into two categories: functioning and non-functioning.The aim of the present review is to give a detailed account of all reported cases of parathyroid cysts in the literature and to analyze statistically the available data. METHODS: A bibliographic research was performed from 1905 until 2016. A database with the patients' characteristics was made and analyzed statistically. RESULTS: A total of 218 articles were found, reporting 359 cases of cysts. Mean age of patients was 49.24 y/o and the male/female ratio was 1:1.85. The most common locations were left thyroid lobe (113/358 patients, 31.6%), and superior mediastinum (69/358 patients, 19.3%), while the most common symptoms were neck mass (148/355 patients, 41.7%), compressive symptoms (73/355 patients, 206%) and hyperparathyroidism (62/355 patients, 17.5%). Non-functioning cysts were more frequent (220/357 patients, 61.6%). Regarding dimensions, mean diameter was 4.88 cm. Ultrasound and FNA are used for their diagnosis, while cystic fluid analysis may help the differential diagnosis. Recurrences were mentioned in 27/97 patients (27.8%) with available data. No deaths due to parathyroid cysts were mentioned in the literature. CONCLUSION: Parathyroid cysts should be taken into consideration in case of parathyroid dysfunction or asymptomatic neck mass. The surgeon's careful manipulations on the cyst are crucial for a definitive treatment. PMID- 29995787 TI - The application of transanal total mesorectal excision for patients with middle and low rectal cancer: A systematic review and meta-analysis. AB - BACKGROUND: Recently, in order to overcome the shortcomings of laparoscopic surgery in the treatment of low rectal cancer, a new kind of surgical procedure, transanal total mesorectal excision (TaTME), has rapidly become a research hotspot in the field of rectal cancer surgery study. Our study aimed to evaluate the efficacy and safety of transanal total mesorectal excision (TaTME) for the patients with rectal cancer. METHODS: Relevant studies were searched from the databases of the Cochrane Library, PubMed, Embase, Web of science. All relevant studies were collected to evaluate the efficacy and safety of TaTME for patients with rectal cancer. The quality of the included studies was assessed by the Newcastle-Ottawa Quality Assessment Scale (NOS) and Cochrane Library Handbook 5.1.0. Data analysis was conducted using the Review Manager 5.3 software. RESULTS: Thirteen studies including 859 patients were included in our analysis. In terms of efficacy, compared with laparoscopic total mesorectal excision (LaTME), meta-analysis showed that the rate of complete tumor resection increased and the risk of positive circumferential margins decreased in the TaTME group. For complete tumor resection and positive circumferential margins in the TaTME group, the odds ratios (ORs) and 95% confidence intervals (CIs) were 1.93 and 1.09 to 3.42 (P = .02) and 0.43 and 0.22 to 0.82 (P = .01), respectively. Concerning safety, results showed that the rates of postoperative complications were similar in the 2 groups, and differences in the risk of ileus and anastomotic leakage were not statistically significant (OR = 0.75, 95%CI = 0.51 1.09, P = .13; OR = 0.91, 95%CI = 0.46-1.78, P = .78; OR = 0.79, 95%CI = 0.45 1.38, P = .40). CONCLUSIONS: The results of this meta-analysis show that TaTME is associated with a reduced positive circumferential resection margin (CRM) rate, and could achieve complete tumor resection and improved the long-term survival in patients with mid- and low-rectal cancer. PMID- 29995788 TI - Laboratory blood test results beyond normal ranges could not be attributed to healthy aging. AB - Aging is related to a decline in the function of many organs. The results of blood tests are essential for clinical management and could change over a lifespan reflecting aging. The aim of this study was to examine serum levels of liver, kidney, and bone marrow function and to study their dynamics as a function of age and sex.The cross-sectional study conducted in Poland included 180 healthy individuals (20-90 years) divided into subgroups by sex and decade. These included subgroups of >=65 or <65 years (men and women). We investigated serum levels of creatinine, estimated glomerular filtration rate, estimated effective renal blood/plasma flow, urine pH, urine neutrophil gelatinase-associated lipocalin (NGAL) as well as serum levels of transaminases, bilirubin, total cholesterol (TC), international normalized ratio (INR), and blood morphology.All parameters were within normal range in all groups. Urine NGAL was higher in men aged >=65 years than women (25.67 +/- 53.65 vs 16.49 +/- 34.66, P = .001); serum levels of TC and platelet (PLT) count were higher in women than men aged >=65 years (221.0 +/- 41.7 vs 188.4 +/- 48.2 and 250.3 +/- 47.8 vs 202.5 +/- 57.9, P = .003 and P = .038, respectively). The INR was lower in women (0.97 +/- .06 vs 1.19 +/- 0.48, P = .03).These blood tests were normal in healthy people aged >=65 years. Higher PLT and TC and lower INR in women might indicate a higher risk of cardiovascular diseases. These changes in blood tests were not attributed to aging itself. PMID- 29995789 TI - CYP17A1 rs743572 polymorphism might contribute to endometriosis susceptibility: evidences from a case-control study. AB - This case-control study was aimed to evaluate the influence of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene rs743572 polymorphism for the susceptibility to endometriosis.Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype rs743572 polymorphism in 143 endometriosis patients and 148 healthy controls. Hardy-Weinberg equilibrium (HWE) test was utilized to detect the representativeness of the study subjects. Association strength was presented by odds ratios (ORs) with corresponding 95% confidence intervals (CIs).Genotype distribution of rs743572 polymorphism was conformed to HWE test both in case and control groups, revealing the good representativeness of our study subjects. Significantly positive association was discovered between rs743572 TT genotype and endometriosis susceptibility (P = .042, OR = 1.952, 95% CI = 1.020-3.736). Rs743572 T allele was more frequently discovered in cases than that in controls, revealing the enhanced susceptibility to endometriosis (P = .041, OR = 1.407, 95% CI = 1.014-1.951). Confounding factors (age and body mass index) were utilized to adjust the results, and then we found that the association strength had no significant changes (TT vs CC, P = .039, OR = 1.961, 95% CI = 1.023-3.742; T vs C, P = .038, OR = 1.413, 95% CI = 1.016-1.957). But we failed to find any obvious association of rs743572 genotypes with endometriosis stages and characteristics.T allele of rs743572 polymorphism might act as a risk factor for endometriosis, although it had no effects on the disease stages and basic features. PMID- 29995790 TI - Predictive value of circulating cell-free DNA in the survival of breast cancer patients: A systemic review and meta-analysis. AB - PURPOSE: Circulating cell-free DNA (cfDNA) has been reported to predict outcomes in patients with various types of cancer. However, its prognostic value in patients with breast cancer is not well established still now. In this meta analysis, we evaluated the prognostic role of cfDNA in breast cancer patients. METHODS: We performed systematic searches in electronic databases to identify studies that evaluated the prognostic value of cfDNA in breast cancer patients. The end points were progression-free survival (PFS) and overall survival (OS). The hazard ratios (HRs) and their 95% confidence intervals (95% CIs) were extracted to assess the prognostic significance of cfDNA. Subgroup analyses were also conducted. RESULTS: A total of 11 publications involving 1467 patients were included in this meta-analysis. cfDNA was shown to be significantly associated with PFS (HR 2.02, 95% CI 1.51-2.72, P < .001, I = 82%) and OS (HR 1.75, 95% CI 1.01-3.05, P < .001, I = 92%). The results of subgroup analyses also revealed that cfDNA was a good predictor of prognosis in breast cancer patients. CONCLUSION: Our meta-analysis indicated that cfDNA was associated with poor PFS and OS, thus it may help to predict outcomes of patients with breast cancer. However, further studies are needed to confirm our results. PMID- 29995791 TI - Comparison of the predictive value of scoring systems on the prognosis of cirrhotic patients with suspected infection. AB - Cirrhotic patients with infection are prone to develop sepsis or even septic shock rendering poorer prognosis. However, few methods are available to predict the prognosis of cirrhotic patients with infection although there are some scoring systems can be used to predict general patients with cirrhosis. Therefore, we aimed to explore the predictive value of scoring systems in determining the outcome of critically ill cirrhotic patients with suspected infection.This was a retrospective cohort study based on a single-center database. The prognostic accuracy of the systemic inflammatory response syndrome (SIRS) criteria, quick Sequential Organ Failure Assessment (qSOFA), chronic liver failure (CLIF)-SOFA, quick CLIF-SOFA (qCLIF-SOFA), CLIF-consortium organ failure (CLIF-C OF), Model for End-Stage Liver Disease (MELD), and Simplified Acute Physiology Score (SAPS) II were compared by using area under the receiver operating characteristic (AUROC) curve and net benefit with decision curve analysis. The primary endpoint was in-hospital mortality while the secondary endpoints were duration of hospital and intensive care unit (ICU) stay and ICU mortality.A total of 1438 cirrhotic patients with suspected infection were included in the study. Nearly half the patients (50.2%) were admitted to the ICU due to hepatic encephalopathy and the overall in-hospital mortality was 32.0%. Hospital and ICU mortality increased as the score of each scoring system increased (P < .05 for all trends). The AUROC of CLIF-SOFA (AUROC, 0.742; 95% confidence interval, CI, 0.714-0.770), CLIF-C OF (AUROC, 0.741; 95% CI, 0.713 0.769), and SAPS II (AUROC, 0.759; 95% CI, 0.733-0.786) were significantly higher than SIRS criteria (AUROC, 0.618; 95% CI, 0.590-0.647), qSOFA (AUROC, 0.612; 95% CI, 0.584-0.640), MELD (AUROC, 0.632; 95% CI, 0.601-0.662), or qCLIF-SOFA (AUROC, 0.680; 95% CI, 0.650-0.710) (P < .05 for all). In the decision curve analysis, the net benefit of implementing CLIF-SOFA and CLIF-C OF to predict the prognosis of cirrhotic patients with suspected infection were higher compared with SIRS, qSOFA, MELD, or qCLIF-SOFA.CLIF-SOFA and CLIF-C OF scores, as well as SAPS II were better tools than SIRS, qSOFA, MELD, or qCLIF-SOFA to evaluate the prognosis of critically ill cirrhotic patients with suspected infection. PMID- 29995792 TI - Electromyographic analysis of hip and knee muscles during specific exercise movements in females with patellofemoral pain syndrome: An observational study. AB - Hip muscle strengthening and knee extensor strengthening are common training exercises for patellofemoral pain syndrome (PFPS). PFPS engendered by insufficient hip abductor and external rotator muscle strength has been of interest, but these exercise movements may increase the lateral vector force of the patella warrants clarification. So, the purpose of this study was to assess muscular activations of vastus lateralis (VL), vastus medialis oblique (VMO), and gluteus medius muscles in electromyographic analysis during hip abduction and external rotator movements and open and closed kinetic chain knee extension movements.The gluteus medius, VMO, and VL muscles, in addition to the ratio of the VL and VMO muscles, were assessed through surface electromyography in 4 movements. Each muscle's amplitude expressed as a percent of maximum voluntary contraction (MVC). The differences on MVC at the terminal joint angle and during the movements were compared.Thirty female patients with PFPS were recruited. During hip abduction and external rotation movements, the MVC of the gluteus medius muscle increased, and those of the VMO and VL muscles increased in the open and closed kinetic chain knee extension movements. The MVCs of VL in the hip abduction and external rotation movements were significantly higher than those of the VMO muscle (P < .05). The ratios of the VL and VMO muscles in the open and closed kinetic chain knee extension movements approached 1, and they were significantly higher than those in the hip abduction and external rotation movements (P < .05). The highest MVC of the VMO muscle was observed at the terminal joint angle in the closed kinetic chain knee extension movement.Selective gluteus medius muscle activation was induced during the hip abduction and external rotation movements, accompanied by an increase in VL muscle activation. In open and closed kinetic chain knee movements, the ratios of the VL and VMO muscles approached 1. More selective VMO muscle activation was induced during the closed kinetic chain knee movements. PMID- 29995793 TI - Neuromuscular electrical stimulation for treating postpartum low back pain. AB - In this retrospective study, we investigated the effect of neuromuscular electrical stimulation (NMES) in patients with postpartum low back pain (PPLBP).We included 67 patients with PPLBP in this study. All patients received NMES, each session 30 minutes, 1 session weekly for a total of 4 weeks. The primary outcome was measured by the reduction in pain intensity, based on the visual analogue scale (VAS). The secondary outcomes included functional status, measured by the Roland-Morris disability questionnaire (RMDQ), and quality of life, measured by the World Health Organization Quality of Life questionnaire (WHOQOL-BREF), as well as the adverse events related to the treatment. The outcome data were evaluated at baseline and at the end of 4-week treatment.After 4-week treatment, NMES did not exert better outcomes in pain relief, measured by VAS, and functional status, measured by RMDQ compared with those before the treatment. In addition, no significant improvement in quality of life, measured by WHOQOL-BREF, compared to it before the treatment.The results of our study did not find that NMES is effective in patients with PPLBP after 4-week treatment. PMID- 29995794 TI - High- versus low-energy extracorporeal shock-wave therapy for myofascial pain syndrome of upper trapezius: A prospective randomized single blinded pilot study. AB - BACKGROUND: To compare the efficacy of high- and low-energy extracorporeal shock wave therapy (ESWT) for patients with myofascial pain syndrome (MPS) of the upper trapezius. METHODS: Thirty patients (3 men, 27 women) were randomly assigned to receive either high-energy ESWT (0.210 mJ/mm) or low-energy ESWT (0.068 mJ/mm). Both groups received 1500 pulses of ESWT once a week, for 2 weeks. Outcome measurement was assessed by verbal numeric pain scale (VNS), neck disability index (NDI), neck range of motion (ROM) (flexion, extension, rotation, lateral bending), and pressure threshold (PT). Statistical analysis was performed with significance level of P < .05. RESULTS: No statistically significant differences of demographic and clinical characteristics existed between the 2 groups. VNS, NDI, neck ROM (rotation to sound side, lateral bending to affected side, lateral bending to sound side), and PT were improved in both groups. In contrast, statistically significant improvements in neck flexion and neck extension were observed only in the high-energy group. We also found significant differences in post-treatment NDI (4.20 +/- 1.78 vs 6.47 +/- 2.48) and post-treatment neck flexion ROM (65.47 +/- 10.09 vs 55.93 +/- 11.07) between high-energy and low energy group. CONCLUSION: ESWT effectively improves VNS, NDI, neck ROM, and PT to patients with MPS of the upper trapezius. High-energy ESWT was more effective in improving NDI and neck flexion ROM compared to the low-energy ESWT, suggesting superiority in functional improvement. Further studies are required to specify the effect of ESWT by energy intensity. PMID- 29995795 TI - A meta-analysis of emotional disorders as possible risk factors for chronic periodontitis. AB - The aim of the present meta-analysis was to evaluate scientific evidence on the association between emotional disorder (depression and anxiety) and chronic periodontitis. An overall electronic literature search in PubMed, ISI Web of Science, Cochrane Library, and China National Knowledge Infrastructure was undertaken up to November 2017. Newcastle-Ottawa scale was applied to ascertain the validity of each eligible study. Stata statistical software was used to perform meta-analysis. The strength of the association between periodontitis and emotional disorder was measured by odds ratios (ORs) with their 95% confidence intervals (95% CIs). Subgroup analysis and sensitivity analysis were performed. Publication bias was assessed through funnel plots and Begger's test. A total of 14 eligible articles were included in the meta-analysis, 6 of them were focused exclusively on depression, whereas 8 studies investigated both depression and anxiety. There was significant association between emotional disorder and chronic periodontitis (OR = 1.54, 95% CI = 1.27-1.86). Sensitivity analyses confirmed the stability of the present results. No evidence of asymmetry was observed in Begger's test. This meta-analysis demonstrates significant association between emotional disorder (including anxiety and depression) and chronic periodontitis. Nevertheless, the result should be interpreted with caution because of the potential bias and confounding in the included studies. PMID- 29995796 TI - Prevalence of pulmonary hypertension in patients with systemic sclerosis and mixed connective tissue disease. AB - Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are 2 conditions in which pulmonary hypertension (PH) can develop.We retrospectively analyzed the probability of PH in case of 83 patients (69 SSc and 14 MCTD). The European Society of Cardiology/European Respiratory Society (ESC/ERS) echocardiographic guidelines of 2015 were used for the evaluation.On the basis of an echocardiography, the patients were divided into 2 subgroups: patients with elevated probability of PH (EP) (n = 16) versus the group with a low probability of PH (LP) (n = 67). Of the 16 patients in the EP group, 15 were SSc patients and 1 was an MCTD patient, respectively, that is, 21.7% and 7.1% of all patients. Of the 16 patients with EP, 10 with SSc had right-heart catheterization, which excluded PH in 7 patients; hence, PH was estimated to be 11.6% in the SSc group. The distribution of the individual causes of PH was arterial PH 2.9%, PH associated with interstitial lung disease 4.3%, PH associated with left ventricular disease 1.5%, and PH of unknown origin 2.9%. Further, there was a significant difference between EP and LP in the incidence of the right bundle branch block in standard electrocardiography, left atrial and right ventricular dimension, tricuspid annular plane systolic excursion, and Doppler-derived tricuspid lateral annular systolic velocity (S') in echocardiography.Echocardiography, particularly those evaluating the parameters included in the ESC/ERS guidelines of 2015, appears to be a useful tool in the detection of patients with a high PH probability. Additional tissue Doppler echocardiography seems to be a good option. PMID- 29995797 TI - Magnetic resonance imaging evaluation of intervertebral disc injuries can predict kyphotic deformity after posterior fixation of unstable thoracolumbar spine injuries. AB - The aim of the present study is to identify factors correlated with kyphotic deformity after thoracolumbar spine injuries. We performed a retrospective case control study with data from thoracolumbar spine fracture patients who were treated with posterior spinal fixation. Patients with a follow-up period shorter than 6 months and who experienced low-energy trauma were excluded. Intervertebral disc injuries (IDIs) were graded from 0 to 3 upon admission in accordance with Sander's classification of traumatic intervertebral disc lesions. Vertebral wedge angles (VWAs) and local kyphosis angles (LKAs) were also measured. Patients were allocated to kyphosis and control groups if they had LKA correction losses of >=10 degrees and <10 degrees , respectively. Forty-eight patients followed over a median period of 25 months were included. The median correction loss at the site of the injured vertebral body was 2.0 degrees . The median LKA correction loss was 9.0 degrees . Twenty-three and 25 patients were allocated to the kyphosis and control groups, respectively. Univariate analysis revealed that the median age was significantly lower in the kyphosis (35 years) than control group (56 years). The level of injury and IDI severity also significantly differed between groups, with a significantly greater proportion of more severe IDI cases in the kyphosis than control group. Finally, significantly more patients in kyphosis group underwent fusion (kyphosis, 19 vs control, 13) and implant removals (kyphosis, 19 vs control, 10). Multiple regression analysis revealed that IDI severity according to Sander's classification (P = .005; odds ratio, 5.263; 95% confidence interval [CI], 1.637-16.927) and implant removal (P = .011; odds ratio, 7.980; 95% CI, 1.603-39.728) were significantly associated with kyphotic deformity. IDI severity at initial magnetic resonance imaging (MRI) evaluation and implant removal are associated with kyphotic deformity after posterior fixation of thoracolumbar spine injuries. Thus, initial MRI evaluation of IDIs could be used to predict of recurrent kyphosis. PMID- 29995798 TI - Association between parity and the risk for urinary incontinence in women: A meta analysis of case-control and cohort studies. AB - Urinary incontinence (UI) is a common complaint for adult female. Cross-sectional studies suggested parity may link with UI, but the association between them was not well-established. We conducted a meta-analysis to investigate the association between parity and UI.Medline and Embase were searched for eligible case-control and cohort studies about parity and UI. Two authors screened the literature and extracted the data independently. Odds ratio (OR) was used as the measure of the effect of parity on UI. We pooled the ORs of different number of parity by a random-effect model. Subgroup analysis was conducted by a subtype of UI. Sensitivity analysis was conducted to see whether the results were stable.Thirteen studies (8 cohorts and 5 case-controls) were included in our meta analysis, with a total of 74,883 adult females. Our meta-analysis showed that compared with nulliparity, ORs of women with 1, 2, and >=3 parity were 1.43 [95% confidence interval (95% CI): 0.90-2.28; I = 81.4%; n = 4], 1.50 (95% CI: 1.02 2.20; I = 82.5%; n = 4), and 1.58 (95% CI: 1.22-2.03; I = 70.1%; n = 7) compared with nulliparity. The OR for any multiparity to nulliparity was 1.68 (95% CI: 1.39-2.03; I = 0%; n = 4). Subgroup analysis showed that parity was associated with an increased risk of stress UI (OR = 2.32, 95% CI: 1.41-3.81; I = 0%; n = 2; 1 compared with null parity) but not urgent UI; However, the definition of parity varies across studies and studies defined parity as delivery times showed higher pooled OR than those not. Sensitivity analysis showed our results were stable.Current evidence suggested that parity was associated with an increased risk of overall and stress UI but not urgency UI, though the definition of parity may differ. Higher parity may have a more significant effect on overall UI. Standardized definition of parity is needed. PMID- 29995799 TI - Matched-pair comparisons of minimally invasive esophagectomy versus open esophagectomy for resectable esophageal cancer: A systematic review and meta analysis protocol. AB - BACKGROUND: Open esophagectomy (OE) with radical lymphadenectomy is known as one of the most invasive digestive surgeries with the high rate of complications. Minimally invasive esophagectomy (MIE) has developed very rapidly and has formed several available technical approaches. This systematic review and meta-analysis is aiming at how beneficial, and to what extent MIE resection really will be. METHODS: A systematic literature search will be performed through May 31, 2018 using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and Google Scholar for relevant articles published in any language. Randomized controlled trials, prospective cohort studies, and propensity score matched comparative studies will be included. If data are sufficient, subgroup analyses will be conducted in different surgical procedures of MIE. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: This will be the first systematic review and meta-analysis using data of randomized controlled, prospective, and propensity score matched comparative studies to compare the outcomes between MIE and OE updating to May 31, 2018. PMID- 29995800 TI - Influence of SIRT1 polymorphisms for diabetic foot susceptibility and severity. AB - The present study aimed to explore the influence of sirtuin 1 (SIRT1) polymorphisms (rs12778366 and rs3758391) on diabetic foot (DF) susceptibility and severity in patients with type 2 diabetes mellitus (T2DM).This case-control study recruited 142 patients with DF, 148 patients with T2DM, and 148 healthy controls. SIRT1 gene polymorphisms were sequenced by polymerase chain reaction (PCR) and direct sequencing method. The relative expression of SIRT1 mRNA was estimated using quantitative real-time PCR (qRT-PCR) assay. Odds ratio (OR) with 95% confidence interval (95% CI) were used to represent the association of SIRT1 polymorphisms with DF susceptibility and severity. The results were adjusted using logistic regression analysis.C allele of rs12778366 polymorphism was significantly correlated with reduced DF susceptibility which deriving from healthy controls (adjusted OR = 0.364, 95% CI = 0.158-0.835) so was patients with T2DM (P = .047, OR = 0.591, 95%CI = 0.349-0.998), but the results became nonsignificant adjusted by clinical features (adjusted OR = 0.654, 95% CI = 0.391 1.094). We failed to find any significant association between rs3758391 polymorphisms and T2DM, DF susceptibility. No significant association has been discovered between SIRT1 polymorphisms and DF severity or characteristics. In addition, compared to healthy control and T2DM cases, patients with DF exhibited significant downregulation of SIRT1. The 2 studied polymorphisms had no effects on its gene expression (P > .05 for all).SIRT1 rs12778366 polymorphism C allele might act as a protective factor for DF onset. PMID- 29995801 TI - Ectopic hamartomatous thymoma (biphenotypic branchioma): A case report and review of the literature. AB - RATIONALE: Ectopic hamartomatous thymoma is a very rare soft tissue neoplasm that commonly occurs in the lower neck of adult men. PATIENT CONCERNS: A 32-year-old male presented 1-year history of the tumor lying in left supraclavicular fossa. DIAGNOSES: Initial consideration of ultrasound and computed tomography was lipoma. After the operation, the pathologist diagnosed it as Ectopic Hamartomatous Thymoma. INTERVENTIONS: A complete resection was performed. OUTCOMES: To date, the patient had no evidence of metastasis or recurrence for 26 months after the operation. LESSONS: Ectopic hamartomatous thymoma is rare. The mastery of the clinical and pathological features of the disease will contribute to the rapid diagnosis and treatment of the disease. In addition, it can be considered to update the name to "biphenotypic branchioma" in order to avoid conceptual confusion. PMID- 29995802 TI - Effect of varying external pneumatic pressure on hemolysis and red blood cell elongation index in fresh and aged blood: Randomized laboratory research. AB - BACKGROUND: External applied pneumatic pressure is usually used for rapid transfusion of red blood cells (RBCs). However, increased shear stress can cause increased hemolysis and decreased RBC elongation indices. Therefore, the purpose of this study was to measure the degree of hemolysis and the alteration of RBC elongation indices under varying external pressure in fresh and aged blood. METHODS: Venous blood samples were obtained from 20 healthy human volunteers. Each blood bag was divided into 2 subgroups (5 or 35 days of storage), and 5 levels of pressure were applied: 0, 150, 200, 250, and 300 mmHg. After infusion, a laboratory study was conducted. The percentages of irreversibly changed cells were evaluated using Bessis classification. RBC elongation indices were measured using a microfluidic ektacytometer. RESULTS: There were no significant differences in the percentage of irreversibly changed RBCs between the pressures of 0 and 300 mmHg. Moreover, there were no significant differences in laboratory test results or elongation indices among all levels of pressure. Irreversibly changed RBCs and hemolysis were increased depending on the storage period. CONCLUSION: Irreversible changes in RBCs did not occur as a result of external pressure. The hemolysis and elongation indices of fresh RBCs were not influenced by external pneumatic pressure up to 300 mmHg. Only the storage period affected the irreversible changes in RBCs and hemolysis. Therefore, the application of external pressure to RBCs in variously aged blood is likely to be a safe procedure. PMID- 29995803 TI - Treatment outcomes and HIV drug resistance of patients switching to second-line regimens after long-term first-line antiretroviral therapy: An observational cohort study. AB - To investigate the responses to switching to second-line regimens among patients who had received a long-term first-line antiretroviral therapy.Patients switching to second-line regimens from June 2008 to June 2015 were enrolled from an observational cohort. In addition, patients continuing first-line therapy and had a viral load <1000 copies/mL were included as controls in July 2012. All these patients were followed-up for 36 months or until June 2016. The virological, immunological outcomes, and drug resistance were evaluated. Virological failure was defined as viral load >=1000 copies/mL after 6 months of treatment since the start of the study.There were 304 patients switching to second-line regimens and 46 patients remaining on first-line therapy enrolled while having received first line therapy for a median of 7.6 years. Patients with plasma viral load (VL) >=1000 copies/mL before switching to second-line regimens had a sharp decline in the proportion of virological failure with 26.7%, 20.4%, and 17.0% at 12, 24, and 36 months after regimen switch, respectively (trend test, P < .001). Among these patients, individuals with drug resistance (DR) had a better virological responses as compared with those without DR after regimen switching. While patients with VL <1000 copies/mL at inclusion remained a high rate of viral suppression after switching to second-line regimens. So did patients continuing first-line therapy. Among patients with VL >=1000 copies/mL before switching to second-line regimens, the rates of drug resistance were decreased from 79.4% at inclusion to 7.5% at 36 months of regimen switch, with the proportion of NRTI- and NNRTI-related drug resistance from 67.2% and 79.4% to 5.4% and 7.5%, respectively. No PI-related resistance was found. Having self-reported missing doses within a month at follow-ups were independently associated with virological failure at 36 months of switching.HIV-infected patients had viral load >=1000 copies/mL at regimen switch after a long duration of first-line therapy had good virological responses to second-line regimens, especially those harbored drug resistant variants at regimen switch. However, patients with suppressive first line therapy did not appear to benefit virologically from switching to second line regimens. PMID- 29995804 TI - Bronchoscopic local steroid spray to prevent bronchial tuberculosis-induced cicatricial bronchial stenosis: A case series. AB - RATONALE: Cicatricial bronchial stenosis or obstruction occurring in the healing process of endobronchial tuberculosis (ET) is a problematic complication of tuberculous airway lesions. Prevention by internal medical treatment is desired. PATIENT CONCERNS: This case series describes four patients who diagnosed ET with Type IIIb (protruding ulcer-type) based on Arai's classification of bronchoscopic findings of bronchial tuberculosis. DIAGNOSES: Endobronchial tuberculosis. INTERVENTIONS: A local steroid spray was applied bronchoscopically to active protruding ulcer-type lesions (which are likely to cause cicatricial stenosis) that extended in the transverse direction and occupied one-half or more of the circumference on bronchoscopy. OUTCOMES: Cicatricial stenosis was prevented in two of four patients. Treatment was discontinued in athird patient because tolerance could not be achieved, although the patient's condition had improved. In the fourth patient, treatment was switched to systemic steroid administration because of a problem with tolerance and the broad range of the lesion; however, stenosis remained. LESSONS: Local steroid spray-applied bronchoscopically to bronchial tuberculosis lesions in the ulcer formation and granulation periods may help prevent stenosis. PMID- 29995805 TI - Benefits of an early management of palpitations. AB - Palpitations are a frequent symptom in the general population, and if cardiac arrhythmias are the most frequent etiology, their diagnosis may be uncertain. We sought to see whether a specialized management of palpitations is associated with a high diagnostic accuracy in patients presenting with palpitations.Consecutive patients addressed for isolated palpitations in our outpatient cardiac unit were prospectively included in this observational cohort study. The initial management was standardized: 12-lead electrocardiogram (ECG) as early as possible, ECG monitoring, potentially followed by an individualized management.On 688 consecutive patients prospectively included, cardiac arrhythmia as the cause of palpitations was found in 81% of cases (77% of atrial arrhythmias, 15% of junctional tachycardia, and 8% of ventricular arrhythmias). A total of 96% of diagnoses were made during initial management. Prehospital ECG (92%) and ECG at admission (67%) had the best positivity rates.A specialized management of patients presenting with lone palpitations allows the diagnostic of a cardiac arrhythmia in >80% of cases. Earliness of an ECG recording remains the key element in the diagnostic approach of these patients. PMID- 29995807 TI - A retrospective controlled clinical study of Cobb angle distribution of the main thoracic curve in adolescent idiopathic scoliosis. AB - To compare the characteristics of Cobb angle distribution of the main thoracic curve (MTC) in patients with Lenke 1 adolescent idiopathic scoliosis (AIS) and differences in fulcrum-bending flexibility, correction rate, and correction index between different segments.Included in this study were 40 consecutive patients with Lenke 1 AIS who received posterior correction and fusion with pedicle screws. Cobb angle based on the proximal (T5-T7 or T6-T8), apical (T7-T9 or T8 T10), and distal (T9-T11 or T10-T12) segments in the fulcrum-bending position was measured before and after surgery. The flexibility ([Cobb angle of each segment - residual Cobb angle on fulcrum bending]/Cobb angle of each segment * 100%), correction rate ([Cobb angle of each segment - postoperative residual Cobb angle]/Cobb angle of each segment * 100%]), and correction index (correction rate of each segment/preoperative flexibility of each segment) in different segments were calculated. Comparative analyses were conducted by variance analysis.The mean age before surgery, Cobb angle, Risser sign, and follow-up time were 14.15 +/- 2.13 years, 51.17 +/- 10.72 degrees , 2.78 +/- 1.73, and 43.75 +/- 9.82 months, respectively. MTC Cobb angle of the proximal segments was similar to that of the distal ones (12.88 +/- 4.81 vs 12.85 +/- 5.00) versus 25.45 +/- 5.90 in the middle segments (P < .001). The flexibility was higher in the distal segments than that in the proximal or apical segments (66.43 +/- 0.22% vs 43.78 +/- 0.20% or 32.55 +/- 0.17%, P < .001). One week after surgery, the correction rate in these 3 segments was 69.55 +/- 0.1%, 66.25 +/- 0.17%, and 75.28 +/- 0.16 (P = .067), and the correction index was 2.15 +/- 1.78, 3.16 +/- 3.60, and 1.53 +/- 1.93 (P = .019); the correction rate during the 3-year follow-up period was 68.06 +/- 0.19%, 69.98 +/- 0.15%, and 73.29 +/- 0.17 (P = .212); and the correction index was 2.12 +/- 1.78, 3.20 +/- 3.54, and 1.49 +/- 1.93 (P = .012), respectively.The proximal, apical, and distal segments in Lenke 1 AIS accounted for about 25%, 50%, and 25% of MTC Cobb angle, respectively. The distal segments were found to be most flexible and the apical segments most rigid. The correction rate was similar between the proximal, apical, and distal segments, and the correction index in the apical segments was higher than that in the proximal and distal segments. PMID- 29995806 TI - Socio-demographic, maternal, and child indicators of socioemotional problems in 2 year-old children: A cohort study. AB - Throughout infancy and early childhood, stable and secure relationships with caregivers are needed to promote optimal socioemotional (SE) and cognitive development.The objective is to examine socio-demographic, maternal, and child indicators of SE problems in 2-year-olds living in an urban-suburban community in the southern United States.Mother-infant pairs enrolled in a prospective pregnancy cohort study.Shelby County (Memphis), Tennessee.One thousand five hundred three women were recruited during their second trimester and followed with their children through the child's age of 2 years.Child SE development was measured by the Brief Infant-Toddler Social Emotional Assessment at 2 years of age. Mothers reported their own behavioral and mental health, temperament, parenting stress, and potential for child abuse during gestation and/or when their child was 1 year of age. Examiners measured maternal IQ during data collection at the child's age of 1 year. Child communication, cognitive development, and risk for autism spectrum disorder were assessed at 1 and 2 years of age. Multivariable regression models were developed to predict mother-reported SE problems.In bivariate analyses, multiple maternal behavioral and mental health indicators and child cognitive skills were associated with reported child SE problems at 2 years of age. Regression analyses, controlling for socio demographic, maternal, and child variables, showed the following factors were independently associated with mother-reported child SE problems: maternal education of high school or less, lower maternal IQ, higher maternal cyclothymic temperament score, greater parenting stress, greater maternal psychological distress, lower child expressive communication score, and child risk for autism spectrum disorder. Socio-demographic variables accounted for the variance often attributed to race.Since mothers in the study were medically low-risk, generalizing these findings to medically high-risk mothers is unwarranted. In addition, these SE outcomes in 2-year-old children do not reflect the trajectory of SE development throughout early childhood.Attention to independent indicators of future SE problems in children may help identify individual children and families needing intervention and target public prevention/treatment programs in communities. PMID- 29995808 TI - Treatment of pancreatic head cancer with obstructive jaundice by endoscopy ultrasonography-guided gastrojejunostomy: A case report and literature review. AB - RATIONALE: Ultrasonography-guided gastrojejunostomy (EUS-GJ) might be a safe, innovative and minimally invasive interventional treatment for patients with gastric outlet obstruction (GOO) as an alternative to the surgical approach. To date, few cases have been reported in the literature. PATIENT CONCERNS: A case of pancreatic head carcinoma with obstructive jaundice occurred in a 78-year-old man with a prior history of pancreatic head cancer. Biliary stent placement was conducted 1 year earlier. DIAGNOSES: The patient was diagnosed with pancreatic cancer, pulmonary infection, pyloric obstruction, and biliary stent implantation. INTERVENTIONS: EUS-GJ was performed. The wire and a double-balloon catheter reached the position of stenosis, then a double mushroom head bracket was released under EUS. The position was confirmed via X-ray. OUTCOMES: The symptoms of obstruction were alleviated. No recurrence of obstruction, bleeding, perforation, and other complications occurred for the following 1.5 months while he died because of whole body spread of pancreatic cancer. LESSONS: EUS-GJ may be reliable and effective for patients with GOO. PMID- 29995809 TI - Survival rate variation among different types of hospitalized traumatic cardiac arrest: A retrospective and nationwide study. AB - Studies regarding the prognostic factors for survival conditions and the proportions of survival to discharge among different types of hospitalized traumatic cardiac arrest (TCA) during the period of postresuscitation are limited.This nationwide study was designed to determine certain parameters and clarify the effect of various injuries on the survival of hospitalized TCA patients to discharge.Data were retrieved from the National Health Insurance Research Database (NHIRD) from 2007 to 2013 in Taiwan. We reviewed patients with a diagnosis of TCA using International Classification of Disease Clinical Modification, 9th revision codes (ICD-9-CM codes). Patients identified for analysis were simultaneously coded in traumatic etiology (ICD-9-CM codes: 800 999) and cardiac arrest (ICD-9-CM codes: 427.41 or 427.5). The determinants and effects of different types of injury on survival were evaluated by SPSS 22.0 (IBM, Armonk, NY).A total of 3481 cases of hospitalized TCA were selected from the NHIRD. The overall rate of survival to discharge was 22.1%. The results indicated a decreased adjusted odds ratio (aOR) of survival to discharge with higher numbers of organ failure (aOR: 0.82; 95% confidence interval [CI]: 0.73 0.92). Patients with ventricular fibrillation had a better discharge rate (aOR: 4.33; 95% CI: 3.29-5.70). Two parameters, transfer to another hospital and the number of intensive care unit beds, were positively correlated with survival. Compared with traffic accidents, different injuries associated with survival to discharge were identified; the aOR (95% CI) was 1.89 (1.12-3.19) for poisoning, 1.63 (1.13-2.36) for falls, and 2.00 (1.36-2.92) for drowning/suffocation.This study has shown that hospitalized TCA patients with multiple organ failure may be less likely to be discharged from the hospital. The presence of ventricular fibrillation rhythm on admission increased the odds of survival to discharge. In the phase of postcardiac arrest care, the number of intensive care unit beds and transfer to another hospital were positively correlated with survival. Those events attributed to traffic accidents have a much worse influence on the main outcome. PMID- 29995810 TI - Primary malignancy in giant cell tumor of thoracic vertebrae: A case report. AB - RATIONALE: Primary malignancy in giant cell tumor of bone (PMGCTB) is extremely unusual. PMGCTB in the thoracic vertebrae is particularly rare. PATIENTS CONCERNS: A 23-year-old man was admitted with a chief complaint of chest pain associated with cough for approximately 3 days. Physical examination revealed a palpable, immobile, tender, 7 cm mass in the right paravertebral area of the thoracolumbar spine. DIAGNOSIS: Computed tomography images revealed an osteolytic, expansive, and eccentric lesion on the vertebral bodies and right accessory processes with spinal cord compression in the thoracic vertebra, with right rib also having bone destruction. Magnetic resonance imaging revealed multiple fluid-fluid levels occupying more than one-third of the lesions. On the basis of the imaging and pathological findings, the final pathological diagnosis was PMGCTB with aneurysmal bone cyst. INTERVENTIONS: The patient underwent successful wide spondylectomy of T9/10 to remove the tumor, and adjuvant chemotherapy based on the protocol used for osteosarcoma. OUTCOMES: After 4 years of follow-up, there is no clinical or radiological evidence of recurrence. LESSONS: PMGCTB is difficult to distinguish from giant cell tumor of bone. PMGCTB should be considered when lesions appear with multiple fluid-fluid levels and soft tissue mass. PMID- 29995811 TI - Wilms' tumor 1 (WT1) as a prognosis factor in gynecological cancers: A meta analysis. AB - The oncogenic role of Wilms' tumor 1 (WT1) which is regarded as a promising target antigen for cancer immunotherapy has been demonstrated in many types of cancer, but the relationship between expression of WT1 and the prognosis value in gynecological cancer reminds unclear.We performed a meta-analysis with thirteen published studies including 2205 patients searched from PubMed, EMBASE, Web of Science, and Google Scholar, whose results are expressed by overall survival (OS) or disease-specific survival (DSS) or disease-free survival or relapse/recurrence free survival (RFS) or progression-free survival (PFS) in patients with gynecological cancer. The hazard ratio (HR) with its 95% confidence interval (CI) were calculated to investigate prognostic of WT1 expression in patients with gynecological cancer.Finally, the overexpression of WT1 was borderlinely associated with poor OS (metaHR = 1.51, 95% CI = 0.98-2.31) in univariate model. We found a significant association with poor DSS (metaHR = 1.61, 95% CI = 1.24 2.08) and DFS/RFS/PFS (metaHR = 2.06, 95% CI = 1.22-3.46). The subgroup analyses revealed that the expression of WT1 predicted the poor DSS (metaHR = 1.82, 95% CI = 1.42-2.73), and DFS/RFS/PFS (metaHR = 2.51, 95% CI = 1.81-3.48) in patients with ovarian cancer. In summary, WT1 overexpression indicates a poor prognosis in patients with some gynecological tumors, but more studies are needed to confirm these findings. PMID- 29995812 TI - An evaluation of impact of social support and care-giving on medication adherence of people living with HIV/AIDS: A nonrandomized community intervention study. AB - To evaluate the effect of the social support on adherence of highly active antiretroviral therapy (HAART) of people living with human immunodeficiency virus/acquired immune deficiency syndrome (PLWHA). Participants of PLWHA at Beijing, China were intervened by 1-year social support program intervention. Difference of social support scale and medication adherence scale before and after the intervention were evaluated. Our results showed that there were statistically significant difference for total score and subjective score, medication adherence between before and after intervention (t = -3.62, -2.81, 5.75, P < .05), and there were statistically significant correlation between the difference of total social support score and that of social support utilization score, and the difference of medication adherence score (r = 0.14, 0.12, all P < .05). Multifactor linear regression showed that the medication adherence score was influenced by the insurance status, the residential status, and the difference in the social support utilization score (beta = -0.14, 0.17, 0.16, all P < .05). Social support and care-giving can exert some influence and facilitate PLWHAs adherence of HAART. PMID- 29995813 TI - Autonomic influences related to frequent ventricular premature beats in patients without structural heart disease. AB - To study the possible role of autonomic influences on the occurrence of frequent premature ventricular beats (VPBs) in subjects without structural heart disease.24-hour Holter ECG recordings (>=1500 VPBs/d, sinus rhythm) of 20 symptomatic patients (9 women, 11 men, mean age 58.9 years) without structural heart disease were used for the study. The circadian distribution pattern of VPBs was studied (paired t test) by dividing the day into 3 periods (16:00-22:00-06:00 16:00), and correlations were analyzed between the absolute (ln transformed) and relative (% of total beats) average hourly numbers of VPBs and the hourly mean values of global and vagal time domain parameters of heart rate variability (Pearson correlation).No significant (P > .3 for every comparison) tendency for circadian distribution of VPBs was found. However, VPBs showed a significant correlation with rMSSD (r = 0.51 and P = .02 for the relative number), which became even stronger if VPBs were > 8000/d (r = 0.65 and P = .04 for both numbers).The significant correlation between the number of VPBs and a vagally mediated parameter underlines the triggering/permitting effect of parasympathetic tone on ventricular ectopy. This fact suggests that initiation of beta-blocker therapy could not be recommended routinely in these patients. PMID- 29995814 TI - Epidural approach to paravertebral thoracic sympathetic block as an alternative to stellate ganglion block: A case report. AB - RATIONALE: Evidence from cadaveric studies note that the sympathetic nerves from the second and third thoracic ganglia bypass the stellate ganglion in 20% of the population. We present a novel alternative technique for sympathetic blockade of upper extremity via thoracic epidural approach. PATIENT CONCERNS: The patient reported anxiety about "the placement of the needle in the front of the neck" and severe pain secondary to complex regional pain syndrome. DIAGNOSES: Complex regional pain syndrome type-1 with involvement of upper extremity. INTERVENTIONS: A patient with upper extremity complex regional pain syndrome underwent sympathetic blockade of the upper extremity via thoracic epidural approach with advancement of a catheter through neural foramen and positioning the catheter tip in the upper thoracic paravertebral space. OUTCOMES: Clinical signs of successful sympathetic blockade of upper extremity were consistently observed after each block utilizing this alternative technique multiple times in a single patient. LESSONS: Thoracic paravertebral block via thoracic epidural approach and catheter use may be an alternative technique for upper extremity sympathetic blockade. Potential advantages of this technique include complete sympathetic blockade of upper extremity for both diagnostic and therapeutic purposes, patient comfort with more effective local anesthetic administration for needle entry site, and potentially reduced risk of pneumothorax and inadvertent intravascular injection. PMID- 29995815 TI - Complete reversal of the clinical symptoms and image morphology of ketamine cystitis after intravesical hyaluronic acid instillation: A case report. AB - RATIONALE: Ketamine abuse is an emerging issue in many countries, and ketamine cystitis (KC) is a growing disease which more and more urologists may encounter with. There was no gold standard diagnostic criteria of ketamine cystits established yet, but well-accepted with the positive substance abuse history and clinical symptoms. The clinical presentation of ketamine cystitis varies and may mimic those presented in interstitial cystitis (IC), such as voiding frequency, urgency with urge incontinence, dysuria, nocturia, burning sensation during urination, post urination pain, painful hematuria, and small bladder capacity, but there are still differences that KC presented with more urgency, hematuria, pyuria and upper urinary tract involvement such as ureteral stenosis, vesico ureteric reflux, hydronephrosis and renal function impairment. PATIENT CONCERNS: We presented an interesting case with a 36-year-old man who's symptoms mimic acute prostatitis but there was no positive pathogen been cultured. The computed tomography (CT) findings revealed asymmetrical bladder wall thickening, which misleading us to the impression of bladder cancer. After the cystoscopy with bladder biopsy, the pathology revealed severe inflammation without malignancy. After that, we prescribed anticholinergic agent, beta-3 agonist and nonsteroidal anti-inflammatory drug (NSAID) for him, but in vain. DIAGNOSES: Erosive cystitis with prominent infiltration by eosinophils, lymphocytes, neutrophils and plasma cells. INTERVENTIONS: Then we introduced hyaluronic acid (HA) instillation, once a week for total 10 times. OUTCOMES: After the treatment, his urgency, frequency, nocturia improved and his bladder capacity increased from less than 100ml to 350mL per urination. The following magnetic resonance imaging (MRI) and bladder biopsy result revealed complete reversal. LESSONS: To our literature review, this is the first case of ketamine cystitis presented with asymmetrical bladder wall thickening, which may be considered as an irreversible change, but turns out complete reversal of the clinical symptoms and image morphology after merely intravesical hyaluronic acid instillation. PMID- 29995816 TI - Anti-NXP2-antibody-positive immune-mediated necrotizing myopathy associated with acute myeloid leukemia: A case report. AB - RATIONALE: Idiopathic inflammatory myopathies have been extensively reported associated with malignancy. Immune-mediated necrotizing myopathy (IMNM), however, has rarely been connected with malignancy including acute myeloid leukemia (AML). PATIENT CONCERNS: A 65-year-old woman was diagnosed with AML and received regular chemotherapy. After the 5th cycle chemotherapy, she achieved complete remission but developed severe muscle weakness and myalgia with dramatic increasing creatine kinase (CK). DIAGNOSIS: The positivity of antinuclear matrix protein 2 antibody (anti-NXP2 Ab) and muscle biopsy in together confirmed the diagnosis of IMNM. INTERVENTION: Methylprednisolone and intravenous immunoglobulin was administered. OUTCOMES: This treatment resulted in a dramatic clinical and laboratory improvement within 1 month. CK and lactate dehydrogenase levels dropped sharply to normal. Anti-NXP2 Ab was shown to disappear in a repeated test afterwards. LESSONS: The IMNM is also closely related to malignancy. We here report a case of IMNM associated with AML for the first time. Anti-NXP2 Ab may be utilized as both diagnostic and prognostic markers of paraneoplastic IMNMs. PMID- 29995817 TI - Clinical adverse effects of natalizumab: Protocol for a meta-analysis of randomized double-blind placebo-controlled clinical trails. AB - BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, which binds in both alpha4beta1 integrins and alpha4beta7 integrins, is approved for the treatment of multiple sclerosis (MS) and Crohn's disease (CD). An uncommon but serious adverse event from NAT treatment is known as progressive multifocal leukoencephalopathy (PML). However, clinical comprehensive safety evidence of NAT is limited. METHODS: We will search Medline, Embase, Cochrane library, and ClinicalTrials.gov website from inception to May 9, 2018. Double-blind, randomized placebo-controlled trials reporting safety data of NAT will be eligible for inclusion. Outcome variables will include adverse events (AEs) varying degrees and AEs occurring in >= 5% patients with NAT or placebo. STATA software (version 12, Statacorp, College Station, TX) will be utilized to assess risk of bias and synthesize data. Outcomes will be reported by weight mean difference (WMD), risk ratios (RRs), and their 95% confidence intervals (95% CIs). I statistic will be used to evaluate heterogeneity among studies. RESULTS: This systemic review and meta-analysis will evaluate serious AEs and AEs of NAT as compared to placebo. CONCLUSION: Our study will provide a comprehensive picture of AEs of NAT. PMID- 29995818 TI - Acute pulmonary edema in an obstetric intensive care unit: A case series study. AB - Acute pulmonary edema (PE) affects 0.08% to 1.5% of women during pregnancy and in the postpartum. At the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), acute PE accounts for 1.5% of admissions to the obstetric intensive care unit (ICU) and occurs in 9.3% of the patients admitted with near miss criteria. This study was conducted to describe the clinical/epidemiological profile of patients with acute PE in IMIP's obstetric ICU.A case series of 50 patients with acute PE in an obstetric ICU in northeastern Brazil between August 2012 and March 2015. Frequency distribution and measures of central tendency/dispersion were calculated using Epi Info, version 7.1.5.The mean age of the women was 27.2 years; 60% were from Recife; 50% had 8 to 11 years of schooling; 54.0% were primigravidas. Acute PE occurred antepartum (58%), postpartum (38%), or intrapartum (4.0%). Overall, 8% had had previous episodes; 6% relapsed during hospitalization; 4% died. Caesarean sections were common (78.0%), with 73.3% delivering at <37 weeks and 39.0% at <34 weeks. Etiologies were hypertensive (62%), cardiogenic (16.0%), both hypertensive and cardiogenic (20.0%) or due to fluid overload (2.0%). Irrespective of etiology, in the 24 hours preceding acute PE, fluid overload was present in 34.0%. Median time from diagnosis until resuscitation maneuvers was 5 minutes (within 30 minutes of diagnosis in 75.0% of patients). Mean ICU time was 5 days and mean hospitalization time 11 days.Acute PE is a severe disease resulting in high maternal/perinatal morbidity/mortality rates. Most commonly, it occurred antepartum and associated with hypertension. Fluid overload appears to constitute an important trigger. PMID- 29995819 TI - Migration of a foreign body to the rectum: A case report and literature review. AB - RATIONALE: Rectal foreign bodies are not an uncommon finding in outpatient departments globally. Most such objects are inserted through the anus. Occasionally, a foreign body may be ingested and may successfully pass through the entire gastrointestinal tract and be held up in the rectum. In extremely rare cases, foreign bodies in adjacent tissues or organs can penetrate the rectal wall and enter the rectal lumen. We report a rare case that the IUCD had migrated and was embedded in the rectal wall. A part of the IUCD was loosened and deformed into a metallic wire that protruded through the anus. PATIENT CONCERNS: A 45-year old woman presented with complaints of a metallic wire protruding through her anus when she used the washroom. The wire would become longer when she manually pulled it; however, this process was associated with pain in the lower abdomen, and she therefore stopped manipulating it. DIAGNOSES: A rectal foreign body secondary to intrauterine contraceptive device (IUCD) migration and rectal perforation, as well as a pelvic cyst. INTERVENTIONS: Under general anesthesia, she underwent laparoscopic removal of the rectal foreign body, pelvic adhesiolysis, pelvic cyst resection, and ileostomy combined with colonoscopy. OUTCOMES: Her postoperative recovery was uneventful. LESSONS: Foreign bodies in adjacent tissues or organs can penetrate the rectal wall and enter the rectal lumen. Regular follow-up after IUCD insertion is very important. We report this rare case that would increase awareness among clinicians regarding the differential diagnosis and treatment in such cases. PMID- 29995820 TI - Change in lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndrome. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) probably plays an important role in the development of acute coronary syndrome (ACS). However, alterations of Lp-PLA2 levels during ACS and its association with cardiovascular outcome are unclear. Our aim was to investigate the change in Lp-PLA2 and its association with cardiovascular outcome in patients with ACS.A total of 79 patients with ACS came from the coronary care unit (CCU) between June 1, 2015 and August 31, 2016 in this longitudinal study. Serum levels of Lp-PLA2, troponin I, and creatine kinase isoenzymes MB (CK-MB) were measured at admission, on the first morning (D1), on the second morning of hospitalization (D2), and on the last second morning before discharge (D4). The patients were followed up till November 30, 2016. The primary outcomes were cardiovascular death and cardiovascular rehospitalization. Kaplan-Meier analysis and Cox proportional hazard models were used to identify risk factors for poor outcome in patients with ACS.All patients were followed up for 10.6 +/- 4.7 months. The patients were divided into 2 groups according to the median of Lp-PLA2: lower Lp-PLA2 group and higher Lp-PLA2 group. Elevated levels of Lp-PLA2 significantly decreased during the early phases of ACS in higher Lp-PLA2 group. And Lp-PLA2 level increased at first and then decreased in lower Lp-PLA2 group. Kaplan-Meier analysis showed that patients with elevated Lp-PLA2 had a lower cardiovascular event-free survival (log-rank chi = 4.736, P = .030) than those with lower Lp-PLA2. Cox regression analysis indicated that high Lp-PLA2 level (hazard ratio [HR] = 1.005, 95% confidence interval [CI] = 1.002 1.008, P = .003), time delay from symptom onset to admission (HR = 1.088, 95% CI = 1.038-1.139, P < .001) independently predicted cardiovascular event in patients with ACS after adjusting for potential confounders.Serum level of Lp-PLA2 altered considerably during the early phase of ACS and increased Lp-PLA2 independently predicted cardiovascular outcome in patients with ACS after adjustment for potential confounders. PMID- 29995821 TI - Echocardiographic predictors of exercise intolerance in patients with heart failure with severely reduced ejection fraction. AB - Decreased exercise capacity (EC) is an established predictor of cardiac and all cause mortality in patients with chronic heart failure (HF). No correlation has been found between EC and left ventricular (LV) ejection fraction. Moreover, data about the effect of right ventricular (RV) function on EC in HF with severe LV dysfunction are limited and contradictory. In this study, we aimed to investigate the relationship between EC and myocardial mechanics in patients with HF with reduced ejection fraction.Consecutive patients with symptomatic HF and LV ejection fraction <=35% were prospectively assessed. All patients were evaluated with enhanced echocardiography. A symptom-limited treadmill cardiopulmonary exercise test (CPX) was performed within 24-hour interval. Patients were stratified into 4 groups according to their EC defined by Weber's classification. Prognosis of EC, expressed as oxygen uptake at peak exercise (peak VO2), was evaluated in multivariate linear regression analysis model.Sixty-seven patients with New York Heart Association classes II to III and a mean LV ejection fraction of 26 +/- 7% were enrolled. A wide range of peak VO2 was observed in CPX with patient exercise performance distributed to all classes according to Weber's classification. Significant differences were found in RV systolic and diastolic functions between groups with different classes of EC: RV peak systolic myocardial velocity (S') (P < .001), tricuspid annular plane systolic excursion (TAPSE) (P = .003), RV E' (P = .003). In patients with functional decline, systolic pulmonary artery pressure (PASP) was higher (P = .029) and TAPSE/PASP ratio was lower (P = .006). No significant differences were found in LV diameter, systolic and diastolic function, and degree of mitral regurgitation. Thirty three patients with RV systolic dysfunction showed lower peak VO2 and oxygen uptake at anaerobic threshold (P = .008, P = .006, respectively), shorter exercise time (P = .003), and lower systolic blood pressure (P = .01) than in patients with normal RV systolic function. Logistic multivariate linear regression analysis with stepwise inclusion and exclusion revealed that gender, RV S', and RV free wall strain were independent predictors of peak VO2.RV function, assessed as S' and free wall strain, was independently related to EC, measured using CPX, in patients with HF and severe LV systolic dysfunction. PMID- 29995822 TI - Factors related with osteoporosis treatment in postmenopausal women. AB - Although fractures had high mortality and morbidity, many studies proved that fracture risk might be decreased by pharmacological therapy, although a low treatment adherence rate is observed. The aim of this study was to identify factors associated with osteoporosis treatment in postmenopausal women.A cross sectional study was carried out from March to August 2013 at the primary care setting. Postmenopausal women were recruited. A standardized questionnaire was applied. Women who were using at least one of the following drugs at the moment of the survey were considered as current treatment: bisphosphonates, raloxifene, estrogen, calcitonin, teriparatide, or strontium ranelate. Women who had used any of the mentioned medications before the study were considered as past treatment.Of the 1025 women included in the study, 8% were on current treatment, 5.7% had past treatment, and 86.3% had not received treatment. Treated women (either current or past) had a higher rate of osteoarthritis, had more falls, had higher education level, presented a higher rate of private health insurance, and received more information about osteoporosis. They also had more dual-energy x ray absorptiometry (DXA) scans and were more frequently diagnosed with osteoporosis by these DXA scans. The factors independently associated with treatment in the regression analysis were the DXA scan itself, the diagnosis of osteoporosis by DXA, and information about osteoporosis.Current and past treatments of osteoporosis were associated with DXA and information. These results suggest that some measures to inform women about osteoporosis and or even the popularization of DXA scans could improve the treatment. PMID- 29995823 TI - The influence of social support on sexual mental health of female college students. AB - The aim of this study was to explore the impact of social support on female college students' sexual mental health (SMH) on the basis of realizing the current status of their SMH.A total of 627 female college students from 5 colleges and universities in Hangzhou were enrolled in the study and provided with questionnaires to evaluate their SMH and social support rating scale.The scores of SMH and social support were 2.46 +/- 0.29 and 38.29 +/- 4.37, respectively. The scores of SMH of female college students in different grades and places of origin were significantly different (P < .05). There was a negative correlation between the scores of each dimension of SMH and that of social support (r = -0.157 to -0.419, P < .01).Social support has an important influence on the SMH of female college students. Higher level of SMH is associated with greater social support. Colleges and universities can improve the social support system of female students through various measures to improve their SMH. PMID- 29995824 TI - Intracranial immature teratoma invading the nasal cavity mimicking olfactory neuroblastoma: A case report. AB - RATIONALE: Primary intracranial immature teratoma accounts for majority of congenital central nervous system germ-cell tumors, but it is extremely rare in patients older than 15 years. PATIENT CONCERNS: A 27-year-old woman was referred to our hospital for headache, nasal congestion, and decreased olfactory sensation. Imaging showed a mass measuring approximately 5 cm * 4 cm in the right frontal lobe, which also filled the right nasal cavity. Histopathologically, the intracranial tumor tissues were composed of both mature tissues, including glands and squamous epithelial cells and immature neuroectodermal components. However, the tumor tissues in the nasal cavity were mainly immature neuroectodermal components that mimicked olfactory neuroblastoma. The cells stained positively for neuron-specific enolase, Alpha Thalassemia/Mental Retardation Syndrome X Linked, and Oligodendrocyte transcription factor on immunostaining, proving a neuroectodermal differentiation. DIAGNOSES: According to these findings, the tumor was diagnosed as a primary intracranial immature teratoma that also involved the nasal cavity after excluding the metastatic tumors. INTERVENTIONS: The patient underwent 2 surgeries. The first surgery was via the subfrontal approach, followed by a second endoscopic sinus surgery performed 22 days later. OUTCOMES: The patient had no recurrence within a 6-month follow-up after the last surgery. LESSONS: When an intracranial immature teratoma involves the nasal cavity, the lesions in the nasal cavity may mimic other tumors including olfactory neuroblastoma. We suggest that thorough examination of tumor tissues and identification of variable components are critical for the appropriate diagnosis of intracranial immature teratoma, a rare tumor. PMID- 29995825 TI - Correlation between the dynamic contrast-enhanced MRI features and prognostic factors in breast cancer: A retrospective case-control study. AB - This study analyzed the correlation between the dynamic contrast-enhanced MRI (DCE-MRI) features with prognostic factors of breast cancer. Eighty-five breast cancer patients verified by pathology and immunohistochemistry underwent DCE-MRI examination. Spearman correlation analysis was used to analyze the DCE-MRI features [the strengthening types, shape, distribution, edge, internal reinforcement and the time-signal intensity curve (TIC) types] and the 4 immunohistochemical markers (ER, PR, Her-2, and Ki-67) by GraphPad InStat version 6.0 software. The enhanced morphology types, shapes, edge had significant correlation with the expression of ER (P = .001, P = .000, P = .001, respectively), PR (P = .045, P = .015, P = .000, respectively) and Ki-67 (P = .039, P = .000, P = .024, respectively), and no significant correlation with Her 2 expression (P = .906, P = .074, P = .679, respectively) was observed. There was significant correlation between internal enhancement patterns and Ki-67 expression (P = .004), and no significant correlation between internal enhancement patterns and the expression of ER, PR, and Her-2 (P = .208, P = .682, P = .437, respectively) was observed. TIC had significant correlation with ER, Ki 67 expressions (P = .022, P = .001, respectively), and no correlation with expressions of PR and Her-2 (P = .128, P = .391, respectively) was observed. The DCE-MRI features of breast cancer were well correlated with the expression of immunohistochemistry, and might also be helpful to evaluate the biological progress and prognosis. PMID- 29995826 TI - Effects of pharmacopuncture with wild ginseng complex in 2 elderly patients with obesity: Case report. AB - RATIONALE: Obesity has become a worldwide health challenge. In elderly patients, obesity induces a decrease in skeletal muscle strength and mass, which is linked to age-related sarcopenia. These are important predictors of hospitalization and death. Herein, we report on 2 elderly male patients who were treated by pharmacopuncture with wild ginseng complex (WGC). PATIENT CONCERNS: Case 1 was that of a 62-year-old man who was mainly concerned about his appearance as his abdominal fat was steadily increasing, without any changes to his body weight. He also had an aversion to any type of modern Western medicine. In addition, the patient was averse to changing his eating habits or exercise style. Case 2 was that of a 66-year-old man who was concerned about his appearance due to an increase in abdominal fat accumulation. Furthermore, he had gained 1.5 inches in waist circumference over the past 2 years. The patient wanted to lose fat in the abdomen, but not in other parts of the body. DIAGNOSES: In this study, we examined 2 elderly male patients (aged 60 years and above) with abdominal obesity and excessive visceral fat mass. Abdominal obesity is defined as a waist circumference of >= 90 cm for men and >= 80 cm for women. INTERVENTIONS: The patients received pharmacopuncture with WGC 5 times over 3 weeks on their abdomen without controlling diet and exercise. OUTCOME: After 3 weeks of pharmacopuncture with WGC and at a follow-up appointment 3 weeks later, we detected an increase in muscle mass, protein content, and basal metabolic rate in both cases. LESSONS: Although we observed only 2 cases, our results indicated that pharmacopuncture with WGC can be used as a new alternative treatment to prevent and improve abdominal obesity in elderly individuals, as well as age-related sarcopenic obesity. PMID- 29995827 TI - Prognostic role of snail in lung cancer: Protocol for a systematic review. AB - BACKGROUND: Increasing studies were performed to explore the prognostic value of snail in lung cancer (LC), however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of snail in patients with LC. METHODS: A comprehensive literature search in the PubMed, Embase, the Cochrane Library, and Web of Science databases will be conducted to identify eligible studies. Language is limited as English. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between snail expression and overall survival (OS), progression-free survival (PFS), recurrence-free survival (RFS), disease-free survival (DFS), and clinicopathological features. Meta-analysis will be performed using STATA 14.0 software. RESULTS: This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, PFS/RFS/DFS, and clinicopathological features. CONCLUSION: The study will provide updated evidence to assess whether the expression of snail is in association with poor prognosis in patients with LC. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. PROSPERO REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42018095191). PMID- 29995829 TI - Paraneoplastic limbic encephalitis associated with mixed olfactory neuroblastoma and craniopharyngioma: A case report and literature review: Erratum. PMID- 29995828 TI - Efficacy and tolerability of fluvoxamine in adults with social anxiety disorder: A meta-analysis. AB - BACKGROUND: No meta-analysis for estimating the comprehensive efficacy and tolerability of fluvoxamine in patients with social anxiety disorder (SAD) has been published. OBJECTIVE: To investigate the efficacy and tolerability of fluvoxamine in adults with SAD, trials meeting the following criteria were identified: population: >=18 years of age with a diagnosis of SAD; intervention: fluvoxamine; study design: placebo-controlled randomized controlled trials (RCTs); outcomes: efficacy and tolerability outcomes. METHODS: We conducted a comprehensive search of PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and ClinicalTrials.gov for RCTs on January 3, 2018. Review Manager 5.3 and Stata Version 12.0 software were used for all statistical analyses. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated for continuous variables, and odds ratios (ORs) with 95% CIs were calculated for dichotomous variables. Cochrane Collaboration's risk of bias tool was used to assess the likelihood of risk of bias. Efficacy was assessed by mean changes in the Liebowitz Social Anxiety scale (LSAS) total score and the Clinical Global Impression Severity of Illness (CGI-S) score as well as the response rate. Tolerability was mainly assessed by the discontinuation rate due to adverse events (AEs) and the incidence of most frequent treatment-emergent AEs (TEAEs). RESULTS: This meta-analysis included 5 RCTs. Mean changes in LSAS total and CGI-S scores were both significantly greater in patients treated with fluvoxamine than those treated with placebo (LSAS: MD = 11.90, 95% CI = 8.09-15.71, P < .001; CGI S: MD = 0.52, 95% CI = 0.33-0.72, P < .001). Response rate was higher in fluvoxamine group as compared with placebo (OR = 1.71, 95% CI = 1.30-2.24, P < .001). Additionally, mean change in the Sheehan disability scale score was significantly greater in fluvoxamine group than placebo group (OR = 2.11, 95% CI = 1.03-3.18, P < .001). The discontinuation rate due to AEs was higher in patients that received fluvoxamine compared to those received placebo (OR = 5.99, 95% CI = 2.24-15.99, P < .001), as was the incidence of overall TEAEs (any AE) (OR = 2.66, 95% CI = 1.77-4.02, P < .001). However, the incidence of serious AEs was not significantly different between the 2 groups (OR = 0.99, 95% CI = 0.25 3.89, P = .99). CONCLUSION: Fluvoxamine was found to be effective in adult patients with SAD, with acceptable tolerability. PMID- 29995830 TI - Endotoxin Tolerant Dendritic Cells Suppress Inflammatory Responses in Splenocytes via Interleukin-1 Receptor Associated Kinase (IRAK)-M and Programmed Death-Ligand 1 (PDL-1). AB - BACKGROUND Sepsis causes the highest mortality in non-cardiovascular intensive care units worldwide. Recent research has demonstrated that the late phase of sepsis, characterized as septic immunosuppression, is the central pathophysiological mechanism of immune dysfunction. Investigating the suppressive mechanism of immune cells may identify possible targets for therapy. MATERIAL AND METHODS We used LPS 2-hit model for dendritic cells (DCs) to establish endotoxin tolerance, and co-cultured with splenocytes. Co-culture responses and gene expressions were evaluated. RESULTS Endotoxin tolerant DCs showed irresponsiveness in pro-inflammatory cytokine production and expressed negative regulator genes of inflammation. When co-cultured with splenocytes, suppression of inflammatory responses and T cells apoptosis were observed with elevated expression of IRAK-M and PDL-1, and interference and neutralization of these 2 molecules led to partly reversed suppression of inflammation. CONCLUSIONS Our research found direct regulation of endotoxin tolerant DCs to other immune cells and suggested a possible mechanism via IRAK-M and PDL-1. This may inform research on septic immunosuppression and suggests possible therapeutic targets for sepsis. PMID- 29995832 TI - RNA-binding proteins in bacteria. AB - RNA-binding proteins (RBPs) are central to most if not all cellular processes, dictating the fate of virtually all RNA molecules in the cell. Starting with pioneering work on ribosomal proteins, studies of bacterial RBPs have paved the way for molecular studies of RNA-protein interactions. Work over the years has identified major RBPs that act on cellular transcripts at the various stages of bacterial gene expression and that enable their integration into post transcriptional networks that also comprise small non-coding RNAs. Bacterial RBP research has now entered a new era in which RNA sequencing-based methods permit mapping of RBP activity in a truly global manner in vivo. Moreover, the soaring interest in understudied members of host-associated microbiota and environmental communities is likely to unveil new RBPs and to greatly expand our knowledge of RNA-protein interactions in bacteria. PMID- 29995831 TI - Growth and body composition in children who are picky eaters: a longitudinal view. AB - BACKGROUND/OBJECTIVES: Picky eating may be associated with higher risk of being underweight and poor growth over time or conversely, being overweight. Our aim was to investigate if children identified as picky eaters showed differences in height, weight and body composition from their non-picky peers. SUBJECTS/METHODS: Picky eaters were identified in the Avon Longitudinal Study of Parents and Children cohort at 3 years of age. Height and weight were measured on seven occasions (age 7-17 years). Body composition was measured on five occasions by dual-energy x-ray absorptiometry (age 9-17 years). Participants were classified as thin/normal/overweight or obese at each age point using body mass index (BMI) classifications. Data were analysed with adjusted multiple regression analysis and mixed-design repeated measures ANOVA. RESULTS: There was a main effect of being a picky child on height and weight (and on BMI and lean mass index (LMI) in boys) (lower in the picky children, all p <= 0.044), but not on percentage body fat or fat mass index (and not on BMI and LMI in girls) (all p > 0.2). The mean heights, weights and BMIs of picky eaters were consistently above the 50th centiles of reference growth charts. More than two-thirds of picky eaters were not thin at any age point. However, being a picky eater was predictive of being thin at a few age points. CONCLUSIONS: The growth trajectories of children who were picky eaters were reassuring. The prevalence of thinness amongst some picky eaters is notable, suggesting that some children may need specific early identification, intervention and growth surveillance. PMID- 29995833 TI - Pivotal role of CaMK4 in podocyte injury. PMID- 29995834 TI - Hedgehog-TGFbeta signalling controls nephrogenesis. PMID- 29995835 TI - Retinal nerve fibre layer thickness - a biomarker of early dementia? PMID- 29995836 TI - What now for embolic stroke of undetermined source? PMID- 29995837 TI - Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. AB - Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning. PMID- 29995838 TI - Chemotaxis of Escherichia coli to major hormones and polyamines present in human gut. AB - The microorganisms in the gastrointestinal (GI) tract can influence the metabolism, immunity, and behavior of animal hosts. Increasing evidence suggests that communication between the host and the microbiome also occurs in the opposite direction, with hormones and other host-secreted compounds being sensed by microorganisms. Here, we addressed one key aspect of the host-microbe communication by studying chemotaxis of a model commensal bacterium, Escherichia coli, to several compounds present abundantly in the GI tract, namely catecholamines, thyroid hormones, and polyamines. Our results show that E. coli reacts to five out of ten analyzed chemicals, sensing melatonin, and spermidine as chemorepellents and showing mixed responses to dopamine, norepinephrine and 3,4-dihydroxymandelic acid. The strongest repellent response was observed for the polyamine spermidine, and we demonstrate that this response involves the low abundance chemoreceptor Trg and the periplasmic binding protein PotD of the spermidine uptake system. The chemotactic effects of the tested compounds apparently correlate with their influence on growth and their stability in the GI tract, pointing to the specificity of the observed behavior. We hypothesize that the repellent responses observed at high concentrations of chemoeffective compounds might enable bacteria to avoid harmful levels of hormones and polyamines in the gut and, more generally, antimicrobial activities of the mucous layer. PMID- 29995839 TI - Evolutionary trends in host physiology outweigh dietary niche in structuring primate gut microbiomes. AB - Over the past decade several studies have reported that the gut microbiomes of mammals with similar dietary niches exhibit similar compositional and functional traits. However, these studies rely heavily on samples from captive individuals and often confound host phylogeny, gut morphology, and diet. To more explicitly test the influence of host dietary niche on the mammalian gut microbiome we use 16S rRNA gene amplicon sequencing and shotgun metagenomics to compare the gut microbiota of 18 species of wild non-human primates classified as either folivores or closely related non-folivores, evenly distributed throughout the primate order and representing a range of gut morphological specializations. While folivory results in some convergent microbial traits, collectively we show that the influence of host phylogeny on both gut microbial composition and function is much stronger than that of host dietary niche. This pattern does not result from differences in host geographic location or actual dietary intake at the time of sampling, but instead appears to result from of differences in host physiology. These findings indicate that mammalian gut microbiome plasticity in response to dietary shifts over both the lifespan of an individual host and the evolutionary history of a given host species is constrained by host physiological evolution. Therefore, the gut microbiome cannot be considered separately from host physiology when describing host nutritional strategies and the emergence of host dietary niches. PMID- 29995840 TI - Author Correction: H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. AB - In this article, the Ponceau staining presented in Fig. 1b (right, bottom) does not follow best practices for figure preparation since itinadvertently included duplications from the Ponceau staining presented in Supplementary Fig. 1b (for which the same preparation ofnucleosomes from HeLa cells had been used). A new Fig. 1b is provided in the Author Correction. PMID- 29995842 TI - Selective inhibition of JAK1 shows promise for RA. PMID- 29995841 TI - Pachychoroid disease. AB - Pachychoroid is a relatively novel concept describing a phenotype characterized by attenuation of the choriocapillaris overlying dilated choroidal veins, and associated with progressive retinal pigment epithelium dysfunction and neovascularization. The emphasis in defining pachychoroid-related disorders has shifted away from simply an abnormally thick choroid (pachychoroid) toward a detailed morphological definition of a pathologic state (pachychoroid disease) with functional implications, which will be discussed in this review. Several clinical manifestations have been described to reside within the pachychoroid disease spectrum, including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, focal choroidal excavation, peripapillary pachychoroid syndrome. These conditions all exhibit the characteristic choroidal alterations and are believed to represent different manifestations of a common pathogenic process. This review is based on both the current literature and the clinical experience of our individual authors, with an emphasis on the clinical and imaging features, management considerations, as well as current understanding of pathogenesis of these disorders within the context of the recent findings related to pachychoroid disease. PMID- 29995843 TI - Testing the anti-osteoclastic function of biologic DMARDs. PMID- 29995845 TI - Inferring biogeographic ancestry with compound markers of slow and fast evolving polymorphisms. AB - Bio-geographic ancestry is an area of considerable interest in the medical genetics, anthropology and forensics. Although genome-wide panels are ideal as they provide dense genotyping data, small sets of ancestry informative marker provide a cost-effective way to investigate genetic ancestry and population structure. Here, we investigate the performance of a reduced marker set that combine different types of autosomal markers through haplotype analysis. In particular, recently described DIP-STR markers should offer the advantage of comprising both, low mutation rate Indels (DIPs), to study human history over longer time scale; and high mutation rate STRs, to trace relatively recent demographic events. In this study, we assessed the ability of an initial set of 23 DIP-STRs to distinguish major population groups using the HGDP-CEPH reference samples. The results obtained applying the STRUCTURE algorithm show that the discrimination capacity of the DIP-STRs is comparable to currently used small scale ancestry informative markers by approaching seven major demographic groups. Yet, the DIP-STRs show an improved success rate in assigning individuals to populations of Europe and Middle East. These data show a remarkable ability of a preliminary set of 23 DIP-STR markers to infer major biogeographic origins. A novel set of DIP-STRs preselected to contain ancestry information should lead to further improvements. PMID- 29995846 TI - Mechanism of parkin activation by PINK1. AB - Mutations in the E3 ubiquitin ligase parkin (PARK2, also known as PRKN) and the protein kinase PINK1 (also known as PARK6) are linked to autosomal-recessive juvenile parkinsonism (AR-JP)1,2; at the cellular level, these mutations cause defects in mitophagy, the process that organizes the destruction of damaged mitochondria3,4. Parkin is autoinhibited, and requires activation by PINK1, which phosphorylates Ser65 in ubiquitin and in the parkin ubiquitin-like (Ubl) domain. Parkin binds phospho-ubiquitin, which enables efficient parkin phosphorylation; however, the enzyme remains autoinhibited with an inaccessible active site5,6. It is unclear how phosphorylation of parkin activates the molecule. Here we follow the activation of full-length human parkin by hydrogen-deuterium exchange mass spectrometry, and reveal large-scale domain rearrangement in the activation process, during which the phospho-Ubl rebinds to the parkin core and releases the catalytic RING2 domain. A 1.8 A crystal structure of phosphorylated human parkin reveals the binding site of the phospho-Ubl on the unique parkin domain (UPD), involving a phosphate-binding pocket lined by AR-JP mutations. Notably, a conserved linker region between Ubl and the UPD acts as an activating element (ACT) that contributes to RING2 release by mimicking RING2 interactions on the UPD, explaining further AR-JP mutations. Our data show how autoinhibition in parkin is resolved, and suggest a mechanism for how parkin ubiquitinates its substrates via an untethered RING2 domain. These findings open new avenues for the design of parkin activators for clinical use. PMID- 29995844 TI - Molecular genetic overlap between migraine and major depressive disorder. AB - Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome wide significant association (PSNP <= 5 * 10-8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based <= 0.05) with both migraine and MDD (Pbinomial test = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome wide significance threshold (PFisher's-combined <= 3.6 * 10-6). Pathway analysis of genes with PFisher's-combined <= 1 * 10-3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD. PMID- 29995847 TI - Author Correction: Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. AB - Change history: In this Letter, the labels for splicing events A3SS and A5SS were swapped in column D of Supplementary Table 3a and b. This has been corrected online. PMID- 29995848 TI - Hominin occupation of the Chinese Loess Plateau since about 2.1 million years ago. AB - Considerable attention has been paid to dating the earliest appearance of hominins outside Africa. The earliest skeletal and artefactual evidence for the genus Homo in Asia currently comes from Dmanisi, Georgia, and is dated to approximately 1.77-1.85 million years ago (Ma)1. Two incisors that may belong to Homo erectus come from Yuanmou, south China, and are dated to 1.7 Ma2; the next oldest evidence is an H. erectus cranium from Lantian (Gongwangling)-which has recently been dated to 1.63 Ma3-and the earliest hominin fossils from the Sangiran dome in Java, which are dated to about 1.5-1.6 Ma4. Artefacts from Majuangou III5 and Shangshazui6 in the Nihewan basin, north China, have also been dated to 1.6-1.7 Ma. Here we report an Early Pleistocene and largely continuous artefact sequence from Shangchen, which is a newly discovered Palaeolithic locality of the southern Chinese Loess Plateau, near Gongwangling in Lantian county. The site contains 17 artefact layers that extend from palaeosol S15-dated to approximately 1.26 Ma-to loess L28, which we date to about 2.12 Ma. This discovery implies that hominins left Africa earlier than indicated by the evidence from Dmanisi. PMID- 29995850 TI - Hot streaks in artistic, cultural, and scientific careers. AB - The hot streak-loosely defined as 'winning begets more winnings'-highlights a specific period during which an individual's performance is substantially better than his or her typical performance. Although hot streaks have been widely debated in sports1,2, gambling3-5 and financial markets6,7 over the past several decades, little is known about whether they apply to individual careers. Here, building on rich literature on the lifecycle of creativity8-22, we collected large-scale career histories of individual artists, film directors and scientists, tracing the artworks, films and scientific publications they produced. We find that, across all three domains, hit works within a career show a high degree of temporal regularity, with each career being characterized by bursts of high-impact works occurring in sequence. We demonstrate that these observations can be explained by a simple hot-streak model, allowing us to probe quantitatively the hot streak phenomenon governing individual careers. We find this phenomemon to be remarkably universal across diverse domains: hot streaks are ubiquitous yet usually unique across different careers. The hot streak emerges randomly within an individual's sequence of works, is temporally localized, and is not associated with any detectable change in productivity. We show that, because works produced during hot streaks garner substantially more impact, the uncovered hot streaks fundamentally drive the collective impact of an individual, and ignoring this leads us to systematically overestimate or underestimate the future impact of a career. These results not only deepen our quantitative understanding of patterns that govern individual ingenuity and success, but also may have implications for identifying and nurturing individuals whose work will have lasting impact. PMID- 29995849 TI - Prespliceosome structure provides insights into spliceosome assembly and regulation. AB - The spliceosome catalyses the excision of introns from pre-mRNA in two steps, branching and exon ligation, and is assembled from five small nuclear ribonucleoprotein particles (snRNPs; U1, U2, U4, U5, U6) and numerous non-snRNP factors1. For branching, the intron 5' splice site and the branch point sequence are selected and brought by the U1 and U2 snRNPs into the prespliceosome1, which is a focal point for regulation by alternative splicing factors2. The U4/U6.U5 tri-snRNP subsequently joins the prespliceosome to form the complete pre catalytic spliceosome. Recent studies have revealed the structural basis of the branching and exon-ligation reactions3, however, the structural basis of the early events in spliceosome assembly remains poorly understood4. Here we report the cryo-electron microscopy structure of the yeast Saccharomyces cerevisiae prespliceosome at near-atomic resolution. The structure reveals an induced stabilization of the 5' splice site in the U1 snRNP, and provides structural insights into the functions of the human alternative splicing factors LUC7-like (yeast Luc7) and TIA-1 (yeast Nam8), both of which have been linked to human disease5,6. In the prespliceosome, the U1 snRNP associates with the U2 snRNP through a stable contact with the U2 3' domain and a transient yeast-specific contact with the U2 SF3b-containing 5' region, leaving its tri-snRNP-binding interface fully exposed. The results suggest mechanisms for 5' splice site transfer to the U6 ACAGAGA region within the assembled spliceosome and for its subsequent conversion to the activation-competent B-complex spliceosome7,8. Taken together, the data provide a working model to investigate the early steps of spliceosome assembly. PMID- 29995851 TI - Structures of human Patched and its complex with native palmitoylated sonic hedgehog. AB - Hedgehog (HH) signalling governs embryogenesis and adult tissue homeostasis in mammals and other multicellular organisms1-3. Whereas deficient HH signalling leads to birth defects, unrestrained HH signalling is implicated in human cancers2,4-6. N-terminally palmitoylated HH releases the repression of Patched to the oncoprotein smoothened (SMO); however, the mechanism by which HH recognizes Patched is unclear. Here we report cryo-electron microscopy structures of human patched 1 (PTCH1) alone and in complex with the N-terminal domain of 'native' sonic hedgehog (native SHH-N has both a C-terminal cholesterol and an N-terminal fatty-acid modification), at resolutions of 3.5 A and 3.8 A, respectively. The structure of PTCH1 has internal two-fold pseudosymmetry in the transmembrane core, which features a sterol-sensing domain and two homologous extracellular domains, resembling the architecture of Niemann-Pick C1 (NPC1) protein7. The palmitoylated N terminus of SHH-N inserts into a cavity between the extracellular domains of PTCH1 and dominates the PTCH1-SHH-N interface, which is distinct from that reported for SHH-N co-receptors8. Our biochemical assays show that SHH-N may use another interface, one that is required for its co-receptor binding, to recruit PTCH1 in the absence of a covalently attached palmitate. Our work provides atomic insights into the recognition of the N-terminal domain of HH (HH N) by PTCH1, offers a structural basis for cooperative binding of HH-N to various receptors and serves as a molecular framework for HH signalling and its malfunction in disease. PMID- 29995852 TI - Histidine catabolism is a major determinant of methotrexate sensitivity. AB - The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR-Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme-formimidoyltransferase cyclodeaminase-that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention. PMID- 29995853 TI - PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G protein coupling. AB - G-protein-coupled receptors (GPCRs) are involved in many physiological processes and are therefore key drug targets1. Although detailed structural information is available for GPCRs, the effects of lipids on the receptors, and on downstream coupling of GPCRs to G proteins are largely unknown. Here we use native mass spectrometry to identify endogenous lipids bound to three class A GPCRs. We observed preferential binding of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) over related lipids and confirm that the intracellular surface of the receptors contain hotspots for PtdIns(4,5)P2 binding. Endogenous lipids were also observed bound directly to the trimeric Galphasbetagamma protein complex of the adenosine A2A receptor (A2AR) in the gas phase. Using engineered Galpha subunits (mini-Galphas, mini-Galphai and mini-Galpha12)2, we demonstrate that the complex of mini-Galphas with the beta1 adrenergic receptor (beta1AR) is stabilized by the binding of two PtdIns(4,5)P2 molecules. By contrast, PtdIns(4,5)P2 does not stabilize coupling between beta1AR and other Galpha subunits (mini-Galphai or mini-Galpha12) or a high-affinity nanobody. Other endogenous lipids that bind to these receptors have no effect on coupling, highlighting the specificity of PtdIns(4,5)P2. Calculations of potential of mean force and increased GTP turnover by the activated neurotensin receptor when coupled to trimeric Galphaibetagamma complex in the presence of PtdIns(4,5)P2 provide further evidence for a specific effect of PtdIns(4,5)P2 on coupling. We identify key residues on cognate Galpha subunits through which PtdIns(4,5)P2 forms bridging interactions with basic residues on class A GPCRs. These modulating effects of lipids on receptors suggest consequences for understanding function, G-protein selectivity and drug targeting of class A GPCRs. PMID- 29995854 TI - Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations. AB - The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health. PMID- 29995855 TI - Cryo-EM structure of a fungal mitochondrial calcium uniporter. AB - The mitochondrial calcium uniporter (MCU) is a highly selective calcium channel localized to the inner mitochondrial membrane. Here, we describe the structure of an MCU orthologue from the fungus Neosartorya fischeri (NfMCU) determined to 3.8 A resolution by phase-plate cryo-electron microscopy. The channel is a homotetramer with two-fold symmetry in its amino-terminal domain (NTD) that adopts a similar structure to that of human MCU. The NTD assembles as a dimer of dimers to form a tetrameric ring that connects to the transmembrane domain through an elongated coiled-coil domain. The ion-conducting pore domain maintains four-fold symmetry, with the selectivity filter positioned at the start of the pore-forming TM2 helix. The aspartate and glutamate sidechains of the conserved DIME motif are oriented towards the central axis and separated by one helical turn. The structure of NfMCU offers insights into channel assembly, selective calcium permeation, and inhibitor binding. PMID- 29995856 TI - X-ray and cryo-EM structures of the mitochondrial calcium uniporter. AB - Mitochondrial calcium uptake is critical for regulating ATP production, intracellular calcium signalling, and cell death. This uptake is mediated by a highly selective calcium channel called the mitochondrial calcium uniporter (MCU). Here, we determined the structures of the pore-forming MCU proteins from two fungi by X-ray crystallography and single-particle cryo-electron microscopy. The stoichiometry, overall architecture, and individual subunit structure differed markedly from those described in the recent nuclear magnetic resonance structure of Caenorhabditis elegans MCU. We observed a dimer-of-dimer architecture across species and chemical environments, which was corroborated by biochemical experiments. Structural analyses and functional characterization uncovered the roles of key residues in the pore. These results reveal a new ion channel architecture, provide insights into calcium coordination, selectivity and conduction, and establish a structural framework for understanding the mechanism of mitochondrial calcium uniporter function. PMID- 29995857 TI - Cryo-EM structures of fungal and metazoan mitochondrial calcium uniporters. AB - The mitochondrial calcium uniporter (MCU) is a highly selective calcium channel and a major route of calcium entry into mitochondria. How the channel catalyses ion permeation and achieves ion selectivity are not well understood, partly because MCU is thought to have a distinct architecture in comparison to other cellular channels. Here we report cryo-electron microscopy reconstructions of MCU channels from zebrafish and Cyphellophora europaea at 8.5 A and 3.2 A resolutions, respectively. In contrast to a previous report of pentameric stoichiometry for MCU, both channels are tetramers. The atomic model of C. europaea MCU shows that a conserved WDXXEP signature sequence forms the selectivity filter, in which calcium ions are arranged in single file. Coiled coil legs connect the pore to N-terminal domains in the mitochondrial matrix. In C. europaea MCU, the N-terminal domains assemble as a dimer of dimers; in zebrafish MCU, they form an asymmetric crescent. The structures define principles that underlie ion permeation and calcium selectivity in this unusual channel. PMID- 29995858 TI - Atmosphere-soil carbon transfer as a function of soil depth. AB - The exchange of carbon between soil organic carbon (SOC) and the atmosphere affects the climate1,2 and-because of the importance of organic matter to soil fertility-agricultural productivity3. The dynamics of topsoil carbon has been relatively well quantified4, but half of the soil carbon is located in deeper soil layers (below 30 centimetres)5-7, and many questions remain regarding the exchange of this deep carbon with the atmosphere8. This knowledge gap restricts soil carbon management policies and limits global carbon models1,9,10. Here we quantify the recent incorporation of atmosphere-derived carbon atoms into whole soil profiles, through a meta-analysis of changes in stable carbon isotope signatures at 112 grassland, forest and cropland sites, across different climatic zones, from 1965 to 2015. We find, in agreement with previous work5,6, that soil at a depth of 30-100 centimetres beneath the surface (the subsoil) contains on average 47 per cent of the topmost metre's SOC stocks. However, we show that this subsoil accounts for just 19 per cent of the SOC that has been recently incorporated (within the past 50 years) into the topmost metre. Globally, the median depth of recent carbon incorporation into mineral soil is 10 centimetres. Variations in the relative allocation of carbon to deep soil layers are better explained by the aridity index than by mean annual temperature. Land use for crops reduces the incorporation of carbon into the soil surface layer, but not into deeper layers. Our results suggest that SOC dynamics and its responses to climatic control or land use are strongly dependent on soil depth. We propose that using multilayer soil modules in global carbon models, tested with our data, could help to improve our understanding of soil-atmosphere carbon exchange. PMID- 29995859 TI - Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action. AB - Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century1-3. The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools4-6. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging4. Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster7-9, which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development10. We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide resistance gene combination complements the urgent ongoing efforts to overcome weed resistance11. Our discovery demonstrates the potential of using a resistance gene-directed approach in the discovery of bioactive natural products. PMID- 29995860 TI - Evolution of a central neural circuit underlies Drosophila mate preferences. AB - Courtship rituals serve to reinforce reproductive barriers between closely related species. Drosophila melanogaster and Drosophila simulans exhibit reproductive isolation, owing in part to the fact that D. melanogaster females produce 7,11-heptacosadiene, a pheromone that promotes courtship in D. melanogaster males but suppresses courtship in D. simulans males. Here we compare pheromone-processing pathways in D. melanogaster and D. simulans males to define how these sister species endow 7,11-heptacosadiene with the opposite behavioural valence to underlie species discrimination. We show that males of both species detect 7,11-heptacosadiene using homologous peripheral sensory neurons, but this signal is differentially propagated to P1 neurons, which control courtship behaviour. A change in the balance of excitation and inhibition onto courtship promoting neurons transforms an excitatory pheromonal cue in D. melanogaster into an inhibitory cue in D. simulans. Our results reveal how species-specific pheromone responses can emerge from conservation of peripheral detection mechanisms and diversification of central circuitry, and demonstrate how flexible nodes in neural circuits can contribute to behavioural evolution. PMID- 29995862 TI - North Pacific freshwater events linked to changes in glacial ocean circulation. AB - There is compelling evidence that episodic deposition of large volumes of freshwater into the oceans strongly influenced global ocean circulation and climate variability during glacial periods1,2. In the North Atlantic region, episodes of massive freshwater discharge to the North Atlantic Ocean were related to distinct cold periods known as Heinrich Stadials1-3. By contrast, the freshwater history of the North Pacific region remains unclear, giving rise to persistent debates about the existence and possible magnitude of climate links between the North Pacific and North Atlantic oceans during Heinrich Stadials4,5. Here we find that there was a strong connection between changes in North Atlantic circulation during Heinrich Stadials and injections of freshwater from the North American Cordilleran Ice Sheet to the northeastern North Pacific. Our record of diatom delta18O (a measure of the ratio of the stable oxygen isotopes 18O and 16O) over the past 50,000 years shows a decrease in surface seawater delta18O of two to three per thousand, corresponding to a decline in salinity of roughly two to four practical salinity units. This coincided with enhanced deposition of ice rafted debris and a slight cooling of the sea surface in the northeastern North Pacific during Heinrich Stadials 1 and 4, but not during Heinrich Stadial 3. Furthermore, results from our isotope-enabled model6 suggest that warming of the eastern Equatorial Pacific during Heinrich Stadials was crucial for transmitting the North Atlantic signal to the northeastern North Pacific, where the associated subsurface warming resulted in a discernible freshwater discharge from the Cordilleran Ice Sheet during Heinrich Stadials 1 and 4. However, enhanced background cooling across the northern high latitudes during Heinrich Stadial 3 the coldest period in the past 50,000 years7-prevented subsurface warming of the northeastern North Pacific and thus increased freshwater discharge from the Cordilleran Ice Sheet. In combination, our results show that nonlinear ocean atmosphere background interactions played a complex role in the dynamics linking the freshwater discharge responses of the North Atlantic and North Pacific during glacial periods. PMID- 29995863 TI - Majorana quantization and half-integer thermal quantum Hall effect in a Kitaev spin liquid. AB - The quantum Hall effect in two-dimensional electron gases involves the flow of topologically protected dissipationless charge currents along the edges of a sample. Integer or fractional electrical conductance is associated with edge currents of electrons or quasiparticles with fractional charges, respectively. It has been predicted that quantum Hall phenomena can also be created by edge currents with a fundamentally different origin: the fractionalization of quantum spins. However, such quantization has not yet been observed. Here we report the observation of this type of quantization of the Hall effect in an insulating two dimensional quantum magnet1, alpha-RuCl3, with a dominant Kitaev interaction (a bond-dependent Ising-type interaction) on a two-dimensional honeycomb lattice2-7. We find that the application of a magnetic field parallel to the sample destroys long-range magnetic order, leading to a field-induced quantum-spin-liquid ground state with substantial entanglement of local spins8-12. In the low-temperature regime of this state, the two-dimensional thermal Hall conductance reaches a quantum plateau as a function of the applied magnetic field and has a quantization value that is exactly half of the two-dimensional thermal Hall conductance of the integer quantum Hall effect. This half-integer quantization of the thermal Hall conductance in a bulk material is a signature of topologically protected chiral edge currents of charge-neutral Majorana fermions (particles that are their own antiparticles), which have half the degrees of freedom of conventional fermions13-16. These results demonstrate the fractionalization of spins into itinerant Majorana fermions and Z2 fluxes, which is predicted to occur in Kitaev quantum spin liquids1,3. Above a critical magnetic field, the quantization disappears and the thermal Hall conductance goes to zero rapidly, indicating a topological quantum phase transition between the states with and without chiral Majorana edge modes. Emergent Majorana fermions in a quantum magnet are expected to have a great impact on strongly correlated quantum matter, opening up the possibility of topological quantum computing at relatively high temperatures. PMID- 29995861 TI - Reprogramming human T cell function and specificity with non-viral genome targeting. AB - Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells. PMID- 29995864 TI - Seabirds enhance coral reef productivity and functioning in the absence of invasive rats. AB - Biotic connectivity between ecosystems can provide major transport of organic matter and nutrients, influencing ecosystem structure and productivity1, yet the implications are poorly understood owing to human disruptions of natural flows2. When abundant, seabirds feeding in the open ocean transport large quantities of nutrients onto islands, enhancing the productivity of island fauna and flora3,4. Whether leaching of these nutrients back into the sea influences the productivity, structure and functioning of adjacent coral reef ecosystems is not known. Here we address this question using a rare natural experiment in the Chagos Archipelago, in which some islands are rat-infested and others are rat free. We found that seabird densities and nitrogen deposition rates are 760 and 251 times higher, respectively, on islands where humans have not introduced rats. Consequently, rat-free islands had substantially higher nitrogen stable isotope (delta15N) values in soils and shrubs, reflecting pelagic nutrient sources. These higher values of delta15N were also apparent in macroalgae, filter-feeding sponges, turf algae and fish on adjacent coral reefs. Herbivorous damselfish on reefs adjacent to the rat-free islands grew faster, and fish communities had higher biomass across trophic feeding groups, with 48% greater overall biomass. Rates of two critical ecosystem functions, grazing and bioerosion, were 3.2 and 3.8 times higher, respectively, adjacent to rat-free islands. Collectively, these results reveal how rat introductions disrupt nutrient flows among pelagic, island and coral reef ecosystems. Thus, rat eradication on oceanic islands should be a high conservation priority as it is likely to benefit terrestrial ecosystems and enhance coral reef productivity and functioning by restoring seabird-derived nutrient subsidies from large areas of ocean. PMID- 29995865 TI - China's response to a national land-system sustainability emergency. AB - China has responded to a national land-system sustainability emergency via an integrated portfolio of large-scale programmes. Here we review 16 sustainability programmes, which invested US$378.5 billion (in 2015 US$), covered 623.9 million hectares of land and involved over 500 million people, mostly since 1998. We find overwhelmingly that the interventions improved the sustainability of China's rural land systems, but the impacts are nuanced and adverse outcomes have occurred. We identify some key characteristics of programme success, potential risks to their durability, and future research needs. We suggest directions for China and other nations as they progress towards the Sustainable Development Goals of the United Nations' Agenda 2030. PMID- 29995866 TI - Metallic nanoparticle contacts for high-yield, ambient-stable molecular-monolayer devices. AB - Accessing the intrinsic functionality of molecules for electronic applications1 3, light emission4 or sensing5 requires reliable electrical contacts to those molecules. A self-assembled monolayer (SAM) sandwich architecture6 is advantageous for technological applications, but requires a non-destructive, top contact fabrication method. Various approaches ranging from direct metal evaporation6 over poly(3,4-ethylenedioxythiophene) polystyrene sulfonate7 (PEDOT:PSS) or graphene8 interlayers to metal transfer printing9 have been proposed. Nevertheless, it has not yet been possible to fabricate SAM-based devices without compromising film integrity, intrinsic functionality or mass fabrication compatibility. Here we develop a top-contact approach to SAM-based devices that simultaneously addresses all these issues, by exploiting the fact that a metallic nanoparticle can provide a reliable electrical contact to individual molecules10. Our fabrication route involves first the conformal and non-destructive deposition of a layer of metallic nanoparticles directly onto the SAM (itself laterally constrained within circular pores in a dielectric matrix, with diameters ranging from 60 nanometres to 70 micrometres), and then the reinforcement of this top contact by direct metal evaporation. This approach enables the fabrication of thousands of identical, ambient-stable metal-molecule metal devices. Systematic variation of the composition of the SAM demonstrates that the intrinsic molecular properties are not affected by the nanoparticle layer and subsequent top metallization. Our concept is generic to densely packed layers of molecules equipped with two anchor groups, and provides a route to the large-scale integration of molecular compounds into solid-state devices that can be scaled down to the single-molecule level. PMID- 29995867 TI - Electrically controlled water permeation through graphene oxide membranes. AB - Controlled transport of water molecules through membranes and capillaries is important in areas as diverse as water purification and healthcare technologies1 7. Previous attempts to control water permeation through membranes (mainly polymeric ones) have concentrated on modulating the structure of the membrane and the physicochemical properties of its surface by varying the pH, temperature or ionic strength3,8. Electrical control over water transport is an attractive alternative; however, theory and simulations9-14 have often yielded conflicting results, from freezing of water molecules to melting of ice14-16 under an applied electric field. Here we report electrically controlled water permeation through micrometre-thick graphene oxide membranes17-21. Such membranes have previously been shown to exhibit ultrafast permeation of water17,22 and molecular sieving properties18,21, with the potential for industrial-scale production. To achieve electrical control over water permeation, we create conductive filaments in the graphene oxide membranes via controllable electrical breakdown. The electric field that concentrates around these current-carrying filaments ionizes water molecules inside graphene capillaries within the graphene oxide membranes, which impedes water transport. We thus demonstrate precise control of water permeation, from ultrafast permeation to complete blocking. Our work opens up an avenue for developing smart membrane technologies for artificial biological systems, tissue engineering and filtration. PMID- 29995869 TI - 100 bats and a long, dark tunnel: one neuroscientist's quest to unlock the secrets of 3D navigation. PMID- 29995868 TI - Software beats animal tests at predicting toxicity of chemicals. PMID- 29995870 TI - Meteorite fragment, deadly floods and French open-access push. PMID- 29995872 TI - Nuclear respiratory factor 1 promotes spheroid survival and mesenchymal transition in mammary epithelial cells. AB - Epithelial cells aggregate into spheroids when deprived of matrix, and the proclivity for spheroid formation and survival is a hallmark of normal and tumorigenic mammary stem cells. We show here that Nuclear Respiratory Factor 1 (NRF1) is a spheroid promoter by in silico identification of this transcription factor as highly connected to top shRNA-hits deduced from re-iterative selections for shRNAs enriched in MCF10A spheroids. NRF1-promoted spheroid survival is linked to its stimulation of mitochondrial OXPHOS, cell migration, invasion, and mesenchymal transition. Conversely, NRF1 knockdown in breast cancer MDA-MB-231 cells reduced spheroids, migration, invasion, and mesenchymal marker expression. NRF1 knockdown also reduced tumor burden in mammary fat pads and lungs of orthotopic- or tail vein-transplanted mice. With the Luminal A subtype of breast cancer, higher NRF1 expression is associated with lower survival. These results show that NRF1, an activator of mitochondrial metabolism, supports mammary spheroid survival and tumor development. PMID- 29995871 TI - CPT1A-mediated fatty acid oxidation promotes colorectal cancer cell metastasis by inhibiting anoikis. AB - Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC. PMID- 29995874 TI - Directed differentiation of human induced pluripotent stem cells into mature kidney podocytes and establishment of a Glomerulus Chip. AB - Protocols have been established to direct the differentiation of human induced pluripotent stem (iPS) cells into nephron progenitor cells and organoids containing many types of kidney cells, but it has been difficult to direct the differentiation of iPS cells to form specific types of mature human kidney cells with high yield. Here, we describe a detailed protocol for the directed differentiation of human iPS cells into mature, post-mitotic kidney glomerular podocytes with high (>90%) efficiency within 26 d and under chemically defined conditions, without genetic manipulations or subpopulation selection. We also describe how these iPS cell-derived podocytes may be induced to form within a microfluidic organ-on-a-chip (Organ Chip) culture device to build a human kidney Glomerulus Chip that mimics the structure and function of the kidney glomerular capillary wall in vitro within 35 d (starting with undifferentiated iPS cells). The podocyte differentiation protocol requires skills for culturing iPS cells, and the development of a Glomerulus Chip requires some experience with building and operating microfluidic cell culture systems. This method could be useful for applications in nephrotoxicity screening, therapeutic development, and regenerative medicine, as well as mechanistic study of kidney development and disease. PMID- 29995873 TI - RNA-seq analysis identifies different transcriptomic types and developmental trajectories of primary melanomas. AB - Recent studies revealed trajectories of mutational events in early melanomagenesis, but the accompanying changes in gene expression are far less understood. Therefore, we performed a comprehensive RNA-seq analysis of laser microdissected melanocytic nevi (n = 23) and primary melanoma samples (n = 57) and characterized the molecular mechanisms of early melanoma development. Using self-organizing maps, unsupervised clustering, and analysis of pseudotime (PT) dynamics to identify evolutionary trajectories, we describe here two transcriptomic types of melanocytic nevi (N1 and N2) and primary melanomas (M1 and M2). N1/M1 lesions are characterized by pigmentation-type and MITF gene signatures, and a high prevalence of NRAS mutations in M1 melanomas. N2/M2 lesions are characterized by inflammatory-type and AXL gene signatures with an equal distribution of wild-type and mutated BRAF and low prevalence of NRAS mutations in M2 melanomas. Interestingly, N1 nevi and M1 melanomas and N2 nevi and M2 melanomas, respectively, cluster together, but there is no clustering in a stage-dependent manner. Transcriptional signatures of M1 melanomas harbor signatures of BRAF/MEK inhibitor resistance and M2 melanomas harbor signatures of anti-PD-1 antibody treatment resistance. Pseudotime dynamics of nevus and melanoma samples are suggestive for a switch-like immune-escape mechanism in melanoma development with downregulation of immune genes paralleled by an increasing expression of a cell cycle signature in late-stage melanomas. Taken together, the transcriptome analysis identifies gene signatures and mechanisms underlying development of melanoma in early and late stages with relevance for diagnostics and therapy. PMID- 29995875 TI - Publisher Correction: Carbon nanotubes as emerging quantum-light sources. AB - In the version of this Perspective originally published, the x-axis label of Fig. 1d was missing; it should have read 'Wavelength (nm)'. The units of the y axis of Fig. 3b were incorrect; they should have been meV. And the citation of Fig. 3c in the main text was incorrect; it should have been to Fig. 3b. These issues have now been corrected. PMID- 29995876 TI - An unexpected acoustic indicator of positive emotions in horses. AB - Indicators of positive emotions are still scarce and many proposed behavioural markers have proven ambiguous. Studies established a link between acoustic signals and emitter's internal state, but few related to positive emotions and still fewer considered non-vocal sounds. One of them, the snort, is shared by several perrisodactyls and has been associated to positive contexts in these species. We hypothesized that this could be also the case in horses. In this species, there is a clear need for a thorough description of non-vocal acoustic signals (snorts, snores or blows are often used interchangeably) but overall this sound produced by nostrils during expiration has up to now been mostly considered as having a hygienic function. However, observations revealed that snorts were produced more in some individuals than in others, without relationship with air conditions. We observed 48 horses living in two "extreme" conditions: restricted conditions (single stall, low roughage diet) and naturalistic conditions (stable groups in pasture). The immediate place (e.g. stall/pasture) and the behavioural/postural (behaviour performed/ears positions) contexts of snort production were observed. We additionally performed an evaluation of the welfare state, using validated behavioural (e.g. stereotypies) and postural (e.g. overall ears positions) welfare indicators. The results show that 1) snort production was significantly associated with situations known to be positive for horses (e.g. feeding in pasture) and with a positive internal state (ears in forward or sidewards positions), 2) the riding school horses produced twice as many snorts when in pasture than in stall, 3) the naturalistic population emitted significantly more snorts than riding school ones in comparable contexts, 4) the frequency of snorts was negatively correlated with the composite total chronic stress score (TCSS, reflecting compromised welfare based on the horse's rank on the different indicators): the lower the TCSS, the higher the snort rate. Snorts therefore appear as reliable indicators of positive emotions. PMID- 29995877 TI - Bio-hydrogen production by co-digestion of domestic wastewater and biodiesel industry effluent. AB - The increasing water crisis makes fresh water a valuable resource, which must be used wisely. However, with growing population and inefficient waste treatment systems, the amount of wastewater dispelled in rivers is increasing abominably. Utilizing this freely available waste-water along with biodiesel industry waste- crude glycerol for bio-hydrogen production is being reported here. The bacterial cultures of Bacillus thuringiensis strain EGU45 and Bacillus amyloliquefaciens strain CD16 produced2.4-3.0 L H2/day/L feed during a 60 days continuous culture system at hydraulic retention time of 2 days. An average H2 yield of 100-120 L/L CG was reported by the two strains. Recycling of the effluent by up to 25% resulted in up to 94% H2 production compared to control. PMID- 29995879 TI - Cryptic "royal" subfamilies in honey bee (Apis mellifera) colonies. AB - During emergency queen rearing, worker honey bees (Apis mellifera) select several otherwise worker-destined larvae to instead rear as candidates to replace their dead or failing queen. This choice is crucial as the queen is the sole reproductive in the colony and her quality is essential to its success. Because honey bee queens mate with and store sperm from multiple drones, emergency queen selection presents workers with an opportunity to increase fitness by selecting full- (0.75 relatedness), rather than half- (0.25 relatedness), sisters as new queen candidates. Through patriline analysis of colonies along with large numbers of emergency queens reared by each we affirm the purported "royal" patriline theory that, instead of competing nepotistically, workers exhibit bias towards selecting individuals from particular "royal" subfamilies during emergency queen rearing events, Further, we show that these "royal" patrilines are cryptic in honey bee colonies; occurring in such low frequency in the overall colony population that they are frequently undetected in traditional tests of queen mating number and colony composition. The identification of these cryptic "royal" subfamilies reveals that honey bee queens, already considered "hyperpolyandrous," are mating with even more males than has been previously recognized. These results alter our understanding of reproductive behavior in honey bees, raising questions about the evolutionary implications of this phenomenon. PMID- 29995878 TI - Usefulness of the frequency-volume chart over the International Prostate Symptom Score in patients with benign prostatic hyperplasia in view of global polyuria. AB - PURPOSE: We aimed to determine the usefulness of the frequency-volume chart over the International Prostate Symptom Score in patients with benign prostatic hyperplasia. Furthermore, we investigated the clinical characteristics suggesting that patients could benefit from frequency-volume chart assessment in addition to International Prostate Symptom Score assessment. METHODS: A total of 193 patients with benign prostatic hyperplasia were analyzed. The relationship between the information obtained from the frequency-volume chart and the International Prostate Symptom Score was assessed. Because the urine output per kilogram per hour was not associated with any question in the International Prostate Symptom Score questionnaire, patients were divided into 2 groups according to the presence of global polyuria, defined as urine output >40 mL.kg-1.h-1. Multivariable analysis was performed to determine the predictors of global polyuria, and the results were externally validated using 397 patients with benign prostatic hyperplasia. RESULTS: Although the other information obtained from the frequency-volume chart correlated with the International Prostate Symptom Score, the urine output was not associated with the International Prostate Symptom Score. Based on these results, patients were dichotomized into the global polyuria group (n = 19, 9.8%) and the non-global polyuria group. Although the patient characteristics did not differ between the 2 groups, the number of voids was higher in patients with global polyuria. Multivariable analysis showed that diabetes mellitus (odds ratio: 3.497, p = 0.039) and increased number of voids (odds ratio: 1.320, p < 0.001) were significant predictors of global polyuria. On external validation, the area under curve for the model was 0.723. CONCLUSIONS: Global polyuria cannot be suspected using the International Prostate Symptom Score, although it worsens the lower urinary tract symptoms of patients with benign prostatic hyperplasia. Assessment with the frequency-volume chart needs to be considered in diabetic patients with increased number of voids. PMID- 29995880 TI - Glyphosate residue concentrations in honey attributed through geospatial analysis to proximity of large-scale agriculture and transfer off-site by bees. AB - Honey taken directly from 59 bee hives on the Hawaiian island of Kaua'i was analyzed for glyphosate residue using ELISA techniques. Glyphosate residue was detected (> LOQ) in 27% of honey samples, at concentrations up to 342 ppb, with a mean = 118 ppb, S.E.M. 24 ppb. Of 15 honey samples store-purchased on Kaua'i, glyphosate was detected in 33%, with a mean concentration of 41 ppb, S.E.M. 14. Glyphosate residue was not detected in two samples from the island of Molokai but was in one of four samples from the island of Hawai'i. Presence and concentration of glyphosate residues were geospatially mapped with respect to Hawaiian land divisions. Mapping showed higher occurrence of glyphosate that was over LOQ (48%) and concentrations of glyphosate (mean = 125 ppb, S.E.M. 25 ppb; N = 15) in honey from the western, predominantly agricultural, half of Kaua'i versus the eastern half (4%, mean = 15 ppb; N = 1). Geographic Information System analysis of land use percentage was performed within a circular zone of 1 Km radius around each hive. Various land use types within each circular zone were transcribed into polygons and percent land use calculated. Only agriculture land use showed a strong positive correlation with glyphosate concentration. High glyphosate concentrations were also detected when extensive golf courses and/or highways were nearby. This suggests herbicide migration from the site of use into other areas by bees. Best management practices in use for curtailing pesticide migration are not effective and must be carefully re-assessed. PMID- 29995881 TI - Protecting contacts against privacy leaks in smartphones. AB - Due to recent developments in technologies associated with the Internet of Things (IoT), a large number of people now regularly use smart devices, such as smartwatches and smartphones. However, these devices are prone to data leaks because of security vulnerabilities. In particular, Android devices use permission-based security, which allows users to directly approve permissions requested by an app when installing it. As a result, many malicious apps can obtain and leak private user data by requesting more permissions than are needed. However, it is difficult to identify malicious apps based solely on the requested permissions. A system is hence needed to accurately identify malicious apps and protect private data from them. In this paper, we propose a system for hiding data related to a user's contacts or providing virtual data according to preconfigured policies when an Android app requests access to them. By hiding data related to the contacts, the proposed system can protect them from malicious apps. By using virtual data, it can even detect malicious apps that leak private data. The system requires less storage and provides faster access to user contacts than prevalent solutions to similar problems. PMID- 29995883 TI - The evolution of shame and guilt. AB - Shame and guilt seem to be two synonymous moral emotions but actually lead to contrasting human behaviors or behavioral tendencies. Shame drives people to hide or deny their wrongdoings while guilt drives people to amend their mistakes. How shame and guilt evolved in humans is still obscure. Here we present a computer model featured with reciprocal altruism and gregarious lifestyle for studying this question. We tested ten different strategies in our model and the pairwise contests show that shame-driven-hiding strategy can dominate the other strategies such as tit-for-tat and Pavlov in more than half of parameter combinations. The mathematical analysis of our model demonstrates that shame-driven-hiding strategy is an evolutionary stable strategy within a group as long as hiding can let an individual evade the retaliations to his wrongdoings. However, the problem of hiding is that it reduces an individual's social circle, i.e. living in a smaller group. Our analysis also shows that guilt-driven-amending strategy can outperform shame-driven-denying strategy at both individual and group levels if the cooperative behavior is sustainable within a group (b/(b-c) < T/n). Thus, we propose that shame is more adaptive at the individual level while guilt is more advantageous in the context of intergroup competition. PMID- 29995882 TI - De novo assembly of a transcriptome for the cricket Gryllus bimaculatus prothoracic ganglion: An invertebrate model for investigating adult central nervous system compensatory plasticity. AB - The auditory system of the cricket, Gryllus bimaculatus, demonstrates an unusual amount of anatomical plasticity in response to injury, even in adults. Unilateral removal of the ear causes deafferented auditory neurons in the prothoracic ganglion to sprout dendrites across the midline, a boundary they typically respect, and become synaptically connected to the auditory afferents of the contralateral ear. The molecular basis of this sprouting and novel synaptogenesis in the adult is not understood. We hypothesize that well-conserved developmental guidance cues may recapitulate their guidance functions in the adult in order to facilitate this compensatory growth. As a first step in testing this hypothesis, we have generated a de novo assembly of a prothoracic ganglion transcriptome derived from control and deafferented adult individuals. We have mined this transcriptome for orthologues of guidance molecules from four well-conserved signaling families: Slit, Netrin, Ephrin, and Semaphorin. Here we report that transcripts encoding putative orthologues of most of the candidate developmental ligands and receptors from these signaling families were present in the assembly, indicating expression in the adult G. bimaculatus prothoracic ganglion. PMID- 29995884 TI - Dance training is superior to repetitive physical exercise in inducing brain plasticity in the elderly. AB - Animal research indicates that a combination of physical activity and sensory enrichment has the largest and the only sustaining effect on adult neuroplasticity. Dancing has been suggested as a human homologue to this combined intervention as it poses demands on both physical and cognitive functions. For the present exploratory study, we designed an especially challenging dance program in which our elderly participants constantly had to learn novel and increasingly difficult choreographies. This six-month-long program was compared to conventional fitness training matched for intensity. An extensive pre/post assessment was performed on the 38 participants (63-80 y), covering general cognition, attention, memory, postural and cardio-respiratory performance, neurotrophic factors and-most crucially-structural MRI using an exploratory analysis. For analysis of MRI data, a new method of voxel-based morphometry (VBM) designed specifically for pairwise longitudinal group comparisons was employed. Both interventions increased physical fitness to the same extent. Pronounced differences were seen in the effects on brain volumes: Dancing compared to conventional fitness activity led to larger volume increases in more brain areas, including the cingulate cortex, insula, corpus callosum and sensorimotor cortex. Only dancing was associated with an increase in plasma BDNF levels. Regarding cognition, both groups improved in attention and spatial memory, but no significant group differences emerged. The latter finding may indicate that cognitive benefits may develop later and after structural brain changes have taken place. The present results recommend our challenging dance program as an effective measure to counteract detrimental effects of aging on the brain. PMID- 29995885 TI - Reduced structural complexity of the right cerebellar cortex in male children with autism spectrum disorder. AB - The cerebellum contains 80% of all neurons in the human brain and contributes prominently to implicit learning and predictive processing across motor, sensory, and cognitive domains. As morphological features of the cerebellum in atypically developing individuals remain unexplored in-vivo, this is the first study to use high-resolution 3D fractal analysis to estimate fractal dimension (FD), a measure of structural complexity of an object, of the left and right cerebellar cortex (automatically segmented from Magnetic Resonance Images using FreeSurfer), in male children with Autism Spectrum Disorders (ASD) (N = 20; mean age: 8.8 years old, range: 7.13-10.27) and sex, age, verbal-IQ, and cerebellar volume-matched typically developing (TD) boys (N = 18; mean age: 8.9 years old, range: 6.47 10.52). We focus on an age range within the 'middle and late childhood' period of brain development, between 6 and 12 years. A Mann-Whitney U test revealed a significant reduction in the FD of the right cerebellar cortex in ASD relative to TD boys (P = 0.0063, Bonferroni-corrected), indicating flatter and less regular surface protrusions in ASD relative to TD males. Consistent with the prediction that the cerebellum participates in implicit learning, those ASD boys with a higher (vs. lower) PIQ>VIQ difference showed higher, more normative complexity values, closer to TD children, providing new insight on our understanding of the neurological basis of differences in verbal and performance cognitive abilities that often characterize individuals with ASD. PMID- 29995886 TI - Forest elephant movement and habitat use in a tropical forest-grassland mosaic in Gabon. AB - Poaching of forest elephants (Loxodonta cyclotis) for ivory has decimated their populations in Central Africa. Studying elephant movement can provide insight into habitat and resource use to reveal where, when, and why they move and guide conservation efforts. We fitted 17 forest elephants with global positioning system (GPS) collars in 2015 and 2016 in the tropical forest-grassland mosaic of the Wonga Wongue Presidential Reserve (WW), Gabon. Using the location data, we quantified movement distances, home ranges, and habitat use to examine the environmental drivers of elephant movements and predict where elephants occur spatially and temporally. Forest elephants, on average, traveled 2,840 km annually and had home ranges of 713 km2, with males covering significantly larger home ranges than females. Forest elephants demonstrated both daily and seasonal movement patterns. Daily, they moved between forest and grassland at dawn and dusk. Seasonally, they spent proportionally more time in grassland than forest during the short-wet season when grasses recruit. Forest elephants also traveled faster during the short-wet season when fruit availability was greatest, likely reflecting long, direct movements to preferred fruiting tree species. Forest elephants tended to select areas with high tree and shrub density that afford cover and browse. When villages occurred in their home ranges elephants spent a disproportionate amount of time near them, particularly in the dry season, probably for access to agricultural crops and preferred habitat. Given the importance of the grassland habitat for elephants, maintenance of the forest grassland matrix is a conservation priority in WW. Law enforcement, outreach, and education should focus on areas of potential human-elephant conflict near villages along the borders of the reserve. GPS-tracking should be extended into multi-use areas in the peripheries of protected areas to evaluate the effects of human disturbance on elephant movements and to maintain connectivity among elephant populations in Gabon. PMID- 29995887 TI - The phosphoglycerate kinase 1 variants found in carcinoma cells display different catalytic activity and conformational stability compared to the native enzyme. AB - Cancer cells are able to survive in difficult conditions, reprogramming their metabolism according to their requirements. Under hypoxic conditions they shift from oxidative phosphorylation to aerobic glycolysis, a behavior known as Warburg effect. In the last years, glycolytic enzymes have been identified as potential targets for alternative anticancer therapies. Recently, phosphoglycerate kinase 1 (PGK1), an ubiquitous enzyme expressed in all somatic cells that catalyzes the seventh step of glycolysis which consists of the reversible phosphotransfer reaction from 1,3-bisphosphoglycerate to ADP, has been discovered to be overexpressed in many cancer types. Moreover, several somatic variants of PGK1 have been identified in tumors. In this study we analyzed the effect of the single nucleotide variants found in cancer tissues on the PGK1 structure and function. Our results clearly show that the variants display a decreased catalytic efficiency and/or thermodynamic stability and an altered local tertiary structure, as shown by the solved X-ray structures. The changes in the catalytic properties and in the stability of the PGK1 variants, mainly due to the local changes evidenced by the X-ray structures, suggest also changes in the functional role of PGK to support the biosynthetic need of the growing and proliferating tumour cells. PMID- 29995888 TI - Challenges of implementing Mark-recapture studies on poorly marked gregarious delphinids. AB - Population parameters of poorly marked gregarious species are difficult to estimate. This is the case for common dolphins (Delphinus sp.), a genus known for its lack of distinctive marks resulting in a low mark ratio. Furthermore, the widespread nature of common dolphins results in low recaptures. We developed reliable photo-identification protocols to ensure accurate identification of individuals in the Hauraki Gulf, New Zealand. These protocols combined the use of nicks and notches and pigmentation patterns for identification and included the development of a distinctiveness threshold. The data were further stratified by the level of distinctiveness of each individual (as distinctive or highly distinctive). Photo-identification surveys were conducted from January 2010 to December 2013. Mark-recapture techniques were implemented through a POPAN super population approach to estimate seasonal apparent survival, capture probability and abundance of dolphins. A total of 2,083 unique adult common dolphins were identified, 51.3% were classified as D1 (highly distinctive; n = 1,069) and 48.7% as D2 (distinctive; n = 1,014). Of all individuals identified, 34.3% (n = 704) were re-sighted over subsequent years. The proportion of marked dolphins (when compared to unmarked dolphins) was 26.3% for D1 and 46.4% for D1 & D2, respectively. Apparent survival was estimated at 0.767 (CI = 0.694-0.827) for D1 animals, and 0.796 (CI = 0.729-0.850) for D1 & D2 combined. For D1 only, seasonal abundance varied from 732 (CI = 460-1,177) in autumn 2010 to 5,304 (CI = 4,745 5,930) in spring 2013. While the inclusion of D2 individuals may offer a more precise estimate of total abundance, the inability to determine additional sources of bias (for example, arising from under or overestimated mark ratios) meant that estimates for D1 individuals were deemed the least biased for this population. The photo-identification protocol, stratification of the data and steps taken to eliminate potential model violations provided a useful and novel approach to estimate population parameters for common dolphins. These approaches could be implemented for other large gregarious populations (>=500 individuals) of animals with poor natural markings. PMID- 29995889 TI - Social reference managers and their users: A survey of demographics and ideologies. AB - Altmetric indicators are increasingly present in the research landscape. Among this ecosystem of heterogeneous indicators, social reference managers have been proposed as indicators of broader use of scholarly work. However, little work has been done to understand the data underlying this indicator. The present work uses a large-scale survey to study the users of two prominent social reference managers-Mendeley and Zotero. The survey examines demographic characteristics, usage of the platforms, as well as attitudes towards key issues in scholarly communication, such as open access, peer review, privacy, and the reward system of science. Results show strong differences between platforms: Mendeley users are younger and more gender-balanced; Zotero users are more engaged in social media and more likely to come from the social sciences and humanities. Zotero users are more likely to use the platform's search functions and to organize their libraries, while Mendeley users are more likely to take advantage of some of the discovery and networking features-such as browsing papers and groups and connecting with other users. We discuss the implications of using metrics derived from these platforms as impact indicators. PMID- 29995890 TI - Cyclin G and the Polycomb Repressive complexes PRC1 and PR-DUB cooperate for developmental stability. AB - In Drosophila, ubiquitous expression of a short Cyclin G isoform generates extreme developmental noise estimated by fluctuating asymmetry (FA), providing a model to tackle developmental stability. This transcriptional cyclin interacts with chromatin regulators of the Enhancer of Trithorax and Polycomb (ETP) and Polycomb families. This led us to investigate the importance of these interactions in developmental stability. Deregulation of Cyclin G highlights an organ intrinsic control of developmental noise, linked to the ETP-interacting domain, and enhanced by mutations in genes encoding members of the Polycomb Repressive complexes PRC1 and PR-DUB. Deep-sequencing of wing imaginal discs deregulating CycG reveals that high developmental noise correlates with up regulation of genes involved in translation and down-regulation of genes involved in energy production. Most Cyclin G direct transcriptional targets are also direct targets of PRC1 and RNAPolII in the developing wing. Altogether, our results suggest that Cyclin G, PRC1 and PR-DUB cooperate for developmental stability. PMID- 29995891 TI - Prevention of laparoscopic surgery induced hypothermia with warmed humidified insufflation: Is the experimental combination of a warming blanket synergistic? AB - INTRODUCTION: Maintaining normothermia during anesthesia is imperative to provide quality patient care and to prevent adverse outcomes. Prolonged laparoscopic procedures have been identified as a potential risk factor for hypothermia, due to continuous insufflation of cold and dry carbon dioxide. Perioperative hypothermia is associated with increased hospital cost and many complications including; impaired drug metabolism, impaired immune function, cardiac morbidity, shivering, coagulopathy. METHODS: In this experimental study, four pigs underwent four interventions each, resulting in 16 total trials. Using standardized general anesthesia in a randomized Latin-square sequence the four interventions include: 1. Control group without an administered pneumoperitoneum, 2. Administered standard pneumoperitoneum using 21 degrees C insufflated gas and under-body forced-air warming, 3. Administered pneumoperitoneum with insufflation of warmed/humidified carbon dioxide, 4. Administered pneumoperitoneum with insufflation of warmed/humidified carbon dioxide and under-body forced-air warming. The primary outcome was distal esophageal temperature change 4 hours after trocar insertion. RESULTS: Four hours after trocar insertion, pigs in the control group lost 2.1 +/- 0.4 degrees C; pigs with warmed and humidified insufflation lost 1.8 +/- 0.4 degrees C; pigs with forced-air warming group lost 1.3 +/- 0.9 degrees C; and pigs exposed to a combination of warmed and humidified insufflation with forced-air warming increased by 0.3 +/- 0.2 degrees C. CONCLUSION: This experimental animal study provides evidence that a combination of warmed and humidified insufflation of carbon dioxide (CO2) in conjunction with forced-air warming is an effective strategy in the prevention of perioperative hypothermia. Further clinical trials investigating humans are therefore indicated. PMID- 29995892 TI - Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex. AB - Altered glucose and lipid metabolism fuel cystic growth in polycystic kidneys, but the cause of these perturbations is unclear. Renal cysts also associate with mutations in Bicaudal C1 (Bicc1) or in its self-polymerizing sterile alpha motif (SAM). Here, we found that Bicc1 maintains normoglycemia and the expression of the gluconeogenic enzymes FBP1 and PEPCK in kidneys. A proteomic screen revealed that Bicc1 interacts with the C-Terminal to Lis-Homology domain (CTLH) complex. Since the orthologous Gid complex in S. cerevisae targets FBP1 and PEPCK for degradation, we mapped the topology among CTLH subunits and found that SAM mediated binding controls Bicc1 protein levels, whereas Bicc1 inhibited the accumulation of several CTLH subunits. Under the conditions analyzed, Bicc1 increased FBP1 protein levels independently of the CTLH complex. Besides linking Bicc1 to cell metabolism, our findings reveal new layers of complexity in the regulation of renal gluconeogenesis compared to lower eukaryotes. PMID- 29995894 TI - Efficacy of two PBO long lasting insecticidal nets against natural populations of Anopheles gambiae s.l. in experimental huts, Kolokope, Togo. AB - LLINs containing an insecticide plus the synergist, piperonyl butoxide (PBO) have been designed for increased efficacy against pyrethroid-resistant malaria vectors. In this study, two LLINs with PBO, PermaNet(r) 3.0 and Olyset(r) Plus, and a pyrethroid-only LLIN, Yorkool(r), were evaluated in experimental huts against a free-flying, wild population of Anopheles gambiae s.l. in Kolokope, a cotton cultivated area of Togo. WHO susceptibility tube tests and subsequent molecular assays determine the An. gambiae s.l. populations to be resistant to pyrethroids and DDT with both target site kdr and metabolic resistance mechanisms involved in the resistance observed. Anopheles gambiae s.s. and An. coluzzi were present in sympatry though the kdr (L1014F) mutation was observed at a higher frequency in An. gambiae s.s. The experimental hut results showed that both PermaNet(r) 3.0 and Olyset(r) Plus nets induced similar levels of deterrence, exophily, and reduced blood feeding rate against wild An. gambiae s.l. in contrast to the pyrethroid only LLIN, Yorkool(r). The proportion of wild An. gambiae s.l. killed by unwashed PermaNet(r) 3.0 was significantly higher than unwashed Olyset(r) Plus (corrected mortality 80.5% compared to 66.6%). Similar blood feeding inhibition rates were observed for unwashed PermaNet(r) 3.0 and Olyset(r) Plus; however, PermaNet(r) 3.0 washed 20 times demonstrated significantly higher blood feeding inhibition rate than Olyset(r) Plus washed 20 times (91.1% compared with 85.6% respectively). Yorkool(r) performed the worst for all the parameters evaluated. In an area of pyrethroid resistance of An. gambiae s.l involving kdr target site and metabolic resistance mechanisms, LLINs with PBO can provide additional protection in terms of reduction in blood feeding and increase in mosquito mortality compared to a pyrethroid-only net, and should be considered in malaria vector control strategies. PMID- 29995895 TI - Morphological and molecular characteristics of Parasitodiplogaster religiosae n. sp. (Nematoda: Diplogastrina) associated with Ficus religiosa in China. AB - A new nematode species of the genus Parasitodiplogaster was recovered from syconia of Ficus religiosa at the Guangxiao Temple, Guangzhou, China. It is described herein as P. religiosae n. sp. and is characterised by possessing the longest and thinnest spicule of all currently described males in the genus, an elongated laterally "epsilon-shaped" and ventrally rhomboid-like gubernaculum, a stoma without teeth, consisting of a ring-like cheilostom with indistinct anteriolateral projections, a tube-like gymnostom and a funnel-like stegostom, monodelphic with a mean vulval position of 66%. There are three pre-cloacal and six post-cloacal male genital papillae with the arrangement P1, P2, P3, (C, P4), P5, P6d, P7, P8, P9d, Ph. This new species was easily differentiated from other members of the genus by DNA sequences of partial small subunit rRNA gene (SSU) and the D2-D3 expansion segments of the large subunit rRNA gene (LSU). Phylogenetic analysis also corroborated its reasonable placement within a well supported monophyletic clade with other Parasitodiplogaster species and within the australis-group that includes P. australis and P. salicifoliae that are all associates of fig wasp pollinators (Platyscapa sp.) of figs of the subsection Urostigma. PMID- 29995893 TI - 2,4-Diaminothieno[3,2-d]pyrimidines, a new class of anthelmintic with activity against adult and egg stages of whipworm. AB - The human whipworm Trichuris trichiura is a parasite that infects around 500 million people globally, with consequences including damage to physical growth and educational performance. Current drugs such as mebendazole have a notable lack of efficacy against whipworm, compared to other soil-transmitted helminths. Mass drug administration programs are therefore unlikely to achieve eradication and new treatments for trichuriasis are desperately needed. All current drug control strategies focus on post-infection eradication, targeting the parasite in vivo. Here we propose developing novel anthelmintics which target the egg stage of the parasite in the soil as an adjunct environmental strategy. As evidence in support of such an approach we describe the actions of a new class of anthelmintic compounds, the 2,4-diaminothieno[3,2-d]pyrimidines (DATPs). This compound class has found broad utility in medicinal chemistry, but has not previously been described as having anthelmintic activity. Importantly, these compounds show efficacy against not only the adult parasite, but also both the embryonated and unembryonated egg stages and thereby may enable a break in the parasite lifecycle. PMID- 29995896 TI - Visual tuning in the flashlight fish Anomalops katoptron to detect blue, bioluminescent light. AB - Bioluminescence is a fascinating phenomenon and can be found in many different organisms including fish. It has been suggested that bioluminescence is used for example for defense, prey attraction, and for intraspecific communication to attract for example sexual partners. The flashlight fish, Anomalops katoptron (A. katoptron), is a nocturnal fish that produces bioluminescence and lives in shallow waters, which makes it ideal for laboratory studies. In order to understand A. katoptron's ability to detect bioluminescent light (480 to 490 nm) at night, we characterized the visual system adaptation of A. katoptron using phylogenetic, electrophysiological and behavioral studies. We found that the retinae of A. katoptron contain rods and sparse cones. A. katoptron retinae express two main visual pigments, rhodopsin (RH1), and to a lesser extent, rhodopsin-like opsin (RH2). Interestingly, recombinant RH1 and RH2 are maximally sensitive to a wavelength of approximately 490 nm light (lambdamax), which correspond to the spectral peak of in vivo electroretinogram (ERG) measurements. In addition, behavioral assays revealed that A. katoptron is attracted by low intensity blue but not red light. Collectively, our results suggest that the A. katoptron visual system is optimized to detect blue light in the frequency range of its own bioluminescence and residual starlight. PMID- 29995897 TI - Identification of a contact zone and hybridization for two subspecies of the American pika (Ochotona princeps) within a single protected area. AB - Genetic variation is the basis upon which natural selection acts to yield evolutionary change. In a rapidly changing environment, increasing genetic variation should increase evolutionary potential, particularly for small, isolated populations. However, the introduction of new alleles, either through natural or human-mediated processes, may have unpredictable consequences such as outbreeding depression. In this study, we identified a contact zone and limited gene flow between historically separated genetic lineages of American pikas (Ochotona princeps), representing the northern and southern Rocky Mountain subspecies, within Rocky Mountain National Park. The limited spatial extent of gene flow observed may be the result of geographic barriers to dispersal, selection against hybrid individuals, or both. Our fine-scale population genetic analysis suggests gene flow is limited but not completely obstructed by extreme topography such as glacial valleys, as well as streams including the Colorado River. The discovery of two subspecies within this single protected area has implications for monitoring and management, particularly in the light of recent analyses suggesting that the pikas in this park are vulnerable to fragmentation and local extinction under future projected climates. Future research should focus on the fitness consequences of introgression among distinct genetic lineages in this location and elsewhere, as well as within the context of genetic rescue as a conservation and management strategy for a climate sensitive species. PMID- 29995898 TI - Spatially explicit action research for coastal fisheries management. AB - We worked with artisanal fisherfolk along the Coromandel coast in two districts of Tamil Nadu and the Union Territory of Pondicherry in South India to map and quantify catch, gear and crew details for all fishing craft along 120 km. Spatially explicit fisheries data were collected to understand the distribution of fishing effort and to identify high pressure fishing zones. Approximately 7,945 square kilometres of fishing grounds were surveyed and 3,427 fishing trips were observed using nine GPS enabled echo-sounders operated by fishermen. Data were visualised and non parametric statistical analysis revealed distinct patterns in fishing effort, high density fishing zones and large overlaps in zones between traditional, motorised and mechanised craft. Existing marine fishing regulations for the respective regions were also evaluated and violations were mapped. Results were presented in each of the villages and then in district wide meetings with community leaders to spur discussions on resource based conflicts and fisheries management. Our findings suggest that the present trajectory of resource over-exploitation, the use of destructive fishing methods combined with the lack of compliance to current regulations will lead to a collapse of the small scale fishing industry and further intensify conflicts within the community. Recommendations made by fishing community leaders are presented and their role in local fisheries management is discussed. This study is the first of its kind for this region and can easily be replicated at regional scales to develop a better understanding of the spatial extent and nature of small scale fisheries, including conflict, for the purpose of fisheries management. PMID- 29995899 TI - The impact of community-based health insurance on the utilization of medically trained healthcare providers among informal workers in Bangladesh. AB - We aimed to estimate the impact of a Community-Based Health Insurance (CBHI) scheme on utilization of healthcare from medically trained providers (MTP) by informal workers. A quasi-experimental study was conducted where insured households were included in the intervention group and uninsured households in comparison group. In total 1,292 (646 insured and 646 uninsured) households were surveyed from Chandpur district comprising urban and rural areas after 1 year period of CBHI introduction. Matching of the characteristics of insured and uninsured groups was performed using a propensity score matching approach to minimize the observed baseline differences among the groups. Multilevel logistic regression model, with adjustment for individual and household characteristics was used for estimating association between healthcare utilization from the MTP and insurance enrolment. The utilization of healthcare from MTP was significantly higher in the insured group (50.7%) compared to the uninsured group (39.4%). The regression analysis demonstrated that the CBHI beneficiaries were 2.111 (95% CI: 1.458-3.079) times more likely to utilize healthcare from MTP.CBHI scheme increases the utilization of MTP among informal workers. Ensuring such healthcare for these workers and their dependents is a challenge in many low and middle income countries. The implementation and scale-up of CBHI schemes have the potential to address this challenge of universal health coverage. PMID- 29995900 TI - Reducing age bias in decision analyses of anticoagulation for patients with nonvalvular atrial fibrillation - A microsimulation study. AB - BACKGROUND: Anticoagulation decreases a patient's risk of ischemic stroke and increases the risk of hemorrhage. Decision analyses regarding anticoagulation therefore require that different outcomes be weighted in comparison to one another. Most decision analyses to date have weighted intracranial hemorrhage (ICH) as 1.5 times worse than ischemic stroke, but because death and disability have lifelong impact, the expected impact should vary by life expectancy. Therefore, a fixed weighting ratio leads to age-related bias decision analyses of anticoagulation. We aimed to quantify the relative impact of ICH and ischemic stroke and derive a ratio that allows decision analysis without microsimulation. METHODS: We created a microsimulation model to predict QALYs lost due to ICH and ischemic stroke. We then applied a meta-model to predict the ratio of QALYs lost from ICH relative to ischemic stroke. RESULTS: Previously-used weighting ratios (1.5) are close to our derived mean weighting ratio (1.60). However, the weighting ratio of QALYs lost from ICH relative to ischemic stroke is sensitive to age and discount rate. Patients at younger ages have higher mean weighting ratios, as do patients with higher discount rates. CONCLUSIONS: The ratio of QALYs lost to ICH relative to ischemic stroke varies with age and discount rate. We present a set of such ratios here for use in decision analyses that do not incorporate full microsimulation models. Use of weighting ratios that vary with age, rather than the current fixed ratios, has the potential to reduce age-based bias in decision-making regarding events with lifelong implications. In this case, use of dynamic ratios may change anticoagulation recommendations for patients with nonvalvular atrial fibrillation at relatively low stroke risk. PMID- 29995901 TI - Remotely sensed soil moisture to estimate savannah NDVI. AB - Satellite derived normalized difference vegetation index (NDVI) is a common data source for monitoring regional and global ecosystem properties. In dry lands it has contributed to estimation of inter-annual and seasonal vegetation dynamics and phenology. However, due to the spectral properties of NDVI it can be affected by clouds which can introduce missing data in the time series. Remotely sensed soil moisture has in contrast to NDVI the benefit of being unaffected by clouds due to the measurements being made in the microwave domain. There is therefore a potential in combining the remotely sensed NDVI with remotely sensed soil moisture to enhance the quality and estimate the missing data. We present a step towards the usage of remotely sensed soil moisture for estimation of savannah NDVI. This was done by evaluating the European Space Agency (ESA) Climate Change Initiative (CCI) soil moisture and three of its individual products with respect to their relative performance. The individual products are from the advance scatterometer (ASCAT), Soil Moisture and Ocean Salinity (SMOS), and the Land Parameter Retrieval Model-Advanced Microwave Scanning Radiometer-Earth Observing System (LPRM-AMSR-E). Each dataset was used to simulate NDVI, which was subsequently compared to remotely sensed NDVI from MODIS. Differences in their ability to estimate NDVI indicated that, on average, CCI soil moisture differs from its individual products by showing a higher average correlation with measured NDVI. Overall NDVI modelled from CCI soil moisture gave an average correlation of 0.81 to remotely sensed NDVI which indicates its potential to be used to estimate seasonal variations in savannah NDVI. Our result shows promise for further development in using CCI soil moisture to estimate NDVI. The modelled NDVI can potentially be used together with other remotely sensed vegetation datasets to enhance the phenological information that can be acquired, thereby, improving the estimates of savannah vegetation phenology. PMID- 29995903 TI - Ridge-furrow mulched with plastic film improves the anti-oxidative defence system and photosynthesis in leaves of winter wheat under deficit irrigation. AB - In semi-arid areas of China, the ridge-furrow mulched with plastic film (RF) cultivation system is a common water-saving agricultural technique where the shortage of water resources has become a serious problem. Therefore, we aimed to explore whether this cultivation is actually an improvement over the traditional flat planting (TF) method while testing two deficit irrigation (150, 75 mm) levels to grow winter wheat. Furthermore, we examined the responses of the anti oxidative defence system and photosynthetic capacity of winter wheat flag leaves under three simulated rainfall (275, 200 and 125 mm) conditions. The results showed that the RF system with 150 mm deficit irrigation and 200 mm simulated rainfall condition (RF2150) treatment raised soil water content (%) at the jointing and flowering stages and achieved higher net photosynthesis rates (Pn) in flag leaves. Furthermore, such improvements were due to the reduction of malondialdehyde (MDA) content and oxidative damage during different growth stages of winter wheat. The RF2150 treatment significantly increased the activities of superoxide dismutase (SOD); peroxidise (POD), catalase (CAT) and ascorbate peroxidase (APX) and the content of soluble protein (SP) during different growth stages of winter wheat. Furthermore, RF2150 treatment attained the highest value at the flowering stage, while also exhibiting significant declines in contents of proline, MDA, H2O2 and O2 in flag leaves. The higher free H2O2 and O2 scavenging capacity and better anti-oxidative enzyme activities under the RF2150 treatment were due to the lower level of lipid peroxidation, which effectively protected the photosynthetic machinery. The net photosynthetic rate of flag leaves was positively correlated with SOD, POD, CAT, APX and SP activities, and negatively correlated with proline, MDA, H2O2 and O2 contents. We concluded that the RF2150 treatment was the better water-saving management strategy because it significantly delayed flag leaf senescence and caused the increases in SWC, WUE, Pn, antioxidant enzyme activities and grain yield of winter wheat grown in semi arid regions of China. PMID- 29995904 TI - Effects of short-term, sublethal fipronil and its metabolite on dragonfly feeding activity. AB - Dragonflies, Sympetrum spp., are indispensable to agriculture and are a central element of culture in Japan. However, S. frequens populations in rice paddy fields have declined in recent decades. Dragonfly larvae are predatory aquatic insects that feed on other organisms found in habitats with slow-moving or standing water. The increasing use of fipronil and neonicotinoid insecticides in agriculture is also increasing exposure to Sympetrum spp. in larval stages through paddy soil and water. The role of fipronil insecticides in the decline of dragonflies is of concern, and we here examine the sublethal effects of this insecticide on the feeding behaviors of two Sympetrum spp. Based on the quantity of prey items consumed and the time to capture prey items, feeding inhibition was determined to be a potential mechanism of the decline of Sympetrum spp. following 48-h exposure to fipronil and fipronil sulfone. Prey consumption by S. infuscatum was significantly reduced for fipronil sulfone at all concentrations (0.01-1000 MUg/L). S. frequens exposed to 1, 10, 100 and 1000 MUg/L fipronil sulfone had significantly longer prey capture times. Fipronil sulfone was 2.8, 9.7 and 10.5 times more toxic to S. infuscatum than fipronil in terms of acute toxicity, feeding inhibition and delayed toxicity, respectively. In addition, fipronil sulfone was 6.6, 2.9 and 9.1 times more toxic, respectively, to S. frequens than fipronil. Our findings suggest that sublethal effects on feeding inhibition lead to severe mortality at realistic paddy soil and water concentrations. Our results provide the first demonstration that short-term exposure to fipronil and fipronil sulfone can consequently cause significant harm to dragonfly larvae survival due to feeding inhibition. These findings have implications for current pesticide risk assessment and dragonfly protection. PMID- 29995902 TI - Cross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men. AB - Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35-80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross sectional associations between age (beta = 0.409, p<0.001), TT (beta = 0.560, p<0.001), fT4 (beta = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (beta = -0.112, p<0.001), abdominal fat mass (beta = 0.068, p = 0.032) and E2 (beta = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (beta = 0.406, p = <0.001), TT (beta = 0.461, p = <0.001), and fT4 (beta = 0.040, p = 0.034) and negative determinants were triglycerides (beta = -0.065, p = 0.027) and abdominal fat mass (beta = -0.078, p = 0.032). Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4. PMID- 29995905 TI - pTSara-NatB, an improved N-terminal acetylation system for recombinant protein expression in E. coli. AB - N-terminal acetylation is one of the most common co- and post-translational modifications of the eukaryotic proteome and regulates numerous aspects of cellular physiology, such as protein folding, localization and turnover. In particular alpha-synuclein, whose dyshomeostasis has been tied to the pathogenesis of several neurodegenerative disorders, is completely Nalpha acetylated in nervous tissue. In this work, building on previous reports, we develop and characterize a bacterial N-terminal acetylation system based on the expression of the yeast N-terminal acetyltransferase B (NatB) complex under the control of the PBAD (L-arabinose-inducible) promoter. We show its functionality and the ability to completely Nalpha-acetylate our model substrate alpha synuclein both upon induction of the construct with L-arabinose and also by only relying on the constitutive expression of the NatB genes. PMID- 29995906 TI - Gene flow and genetic structure in Nile perch, Lates niloticus, from African freshwater rivers and lakes. AB - BACKGROUND: Geological evolution of the African continent has been subject to complex processes including uplift, volcanism, desert formation and tectonic rifting. This complex geology has created substantial biogeographical barriers, and coupled with anthropogenic introductions of freshwater fishes, has influenced the genetic diversity, connectivity and sub-structuring of the teleost fauna. Nile perch, Lates niloticus, is an iconic fish in Africa and is of high commercial importance, both in the species' native range and where it has been translocated. However, the species is in decline and there is a need to understand its population genetic structure to facilitate sustainable management of the fishery and aquaculture development. METHODOLOGY: Nile perch tissue samples were acquired from two West and four East (Lakes; Albert, Kyoga, Victoria and Turkana) African locations. Nineteen polymorphic microsatellite loci were used to study the genetic variation among populations across regions (West and East Africa), as well as between native and introduced environments within East Africa. PRINCIPAL FINDINGS AND THEIR SIGNIFICANCE: Results revealed strong and significant genetic structuring among populations across the sampled distribution (divergence across regions, FCT = 0.26, P = 0.000). STRUCTURE analysis at a broad scale revealed K = 2 clusters, the West African individuals were assigned to one cluster, while all individuals from the East African region, regardless of whether native or introduced, were assigned to another cluster. The distinct genetic clusters identified in the current study between the West and East African Nile perch, appear to have been maintained by presence of biogeographic barriers and restricted gene flow between the two regions. Therefore, any translocations of Nile perch should be carefully considered across the regions of West and East Africa. Further analysis at a regional scale revealed further structuring of up to K = 3 genetic clusters in East African Nile perch. Significantly (P < 0.05) lower genetic diversity based on analysis of allelic richness (AR) was obtained for the two translocated populations of Lake Kyoga (AR = 3.61) and Lake Victoria (AR = 3.52), compared to Nile perch populations from their putative origins of Lakes Albert (AR = 4.12) and Turkana (AR = 4.43). The lower genetic diversity in the translocated populations may be an indication of previous bottlenecks and may also indicate a difficulty for these populations to persist and adapt to climatic changes and anthropogenic pressures that are currently present in the East African region. PMID- 29995907 TI - Propofol prevents human umbilical vein endothelial cell injury from Ang II induced apoptosis by activating the ACE2-(1-7)-Mas axis and eNOS phosphorylation. AB - Angiotensin II (AngII), a vasoactive peptide that elevates arterial blood pressure and results in hypertension, has been reported to directly induce vascular endothelial cell apoptosis. Recent work has demonstrated that propofol pre-treatment attenuates angiotensin II-induced apoptosis in human coronary artery endothelial cells. However, the underlying mechanism remains largely unknown. Here, we investigated human umbilical vein endothelial cells (HUVECs) subjected to angiotensin II-induced apoptosis in the presence or absence of propofol treatment and found that angiotensin II-induced apoptosis was attenuated by propofol in a dose-dependent manner. Furthermore, ELISA assays demonstrated that the ratio of angiotensin (1-7) (Ang (1-7)) to Ang II was increased after propofol treatment. We examined the expression of ACE2, Ang (1-7) and Mas and found that the ACE2-Ang (1-7)-Mas axis was up-regulated by propofol, while ACE2 overexpression increased phosphorylated endothelial nitric oxide synthase (phosphorylated eNOS) expression and siACE2 resulted in the repression of endothelial nitric oxide synthase (eNOS) phosphorylation. In conclusion, our study revealed that propofol can inhibit endothelial cell apoptosis induced by Ang II by activating the ACE2-Ang (1-7)-Mas axis and further up-regulating the expression and phosphorylation of eNOS. PMID- 29995908 TI - Lilingostrobus chaloneri gen. et sp. nov., a Late Devonian woody lycopsid from Hunan, China. AB - Lycopsids are a minor component of current terrestrial herbaceous floras. However, lycopsid fossil diversity shows a great diversity and disparity including heterosporous woody plants, e.g. the giant isoetaleans that populated the extensive Pennsylvanian wetlands. The earliest known isoetaleans come from late Devonian localities from China. Here, we describe Lilingostrobus chaloneri gen. et sp. nov., a new isoetalean lycopsid from the Upper Devonian (Famennian) Xikuangshan Formation of China (Hunan Province, South China), which adds to the already impressive diversity of the Devonian lycopsids from China. Lilingostrobus shows an unusual combination of characters. This new plant is pseudoherbaceous, with a possible tufted habit, and consists of narrow axes with rare isotomies. The stem includes small quantities of secondary xylem. Each fertile axis bears one terminal strobilus comprising sporophylls ending in a very long upturned lamina. Microspores and putative megaspores have been found, but whether the plant has mono- or bisporangiate strobili is unknown. Importantly, our cladistic analysis identifies Lilingostrobus as a direct precursor of Isoetales, which provides new insights into the early evolution of lycopsids. PMID- 29995909 TI - Disparities by race, age, and sex in the improvement of survival for lymphoma: Findings from a population-based study. AB - OBJECTIVE: To evaluate improvement in survival of lymphoma patients from 1990 to 2014, stratified by age, sex and race using Surveillance Epidemiology and End Result Survey Program (SEER) data. STUDY DESIGN AND SETTING: We identified 113,788 incident lymphoma cases from nine SEER cancer registries were followed up for cause-specific mortality from lymphoma. Cox proportional hazard regression was used to estimate hazard ratios (HRs) and their respective 95% confidence interval (CIs) for various time periods within groups stratified by race, age and sex. RESULTS: Five-year survival for Hodgkin's lymphoma (HL) was 89% for patients 20-49 years of age. For this age group, compared to 1990-1994, survival significantly improved in 2000-2004 (HR = 0.65; 95% CI: 0.54-0.78), 2005-2009 (HR = 0.46, 95% CI: 0.38-0.57) and 2010-2014 (HR = 0.29, 95% CI: 0.20-0.41). Hodgkin's lymphoma patients aged 75-85 years had 5-year survival of 37% and in these patients, compared to 1990-1994, survival only improved from 2005 onward (HR = 0.67, 95% CI: 0.50-0.90). In patients with non-Hodgkin's Lymphoma (NHL), all age groups showed survival improvements between 1990-1994 period and 2010 2014 period. Improvements in HL and NHL survival were seen for all race categories and both genders. CONCLUSION: Survival among US lymphoma patients has improved substantially between 1990-1994 period and 2010-2014 period, though disease-specific mortality was still higher in older age groups. PMID- 29995910 TI - Isolation and characterization of two phosphate-solubilizing fungi from rhizosphere soil of moso bamboo and their functional capacities when exposed to different phosphorus sources and pH environments. AB - Phosphate-solubilizing fungi (PSF) generally enhance available phosphorus (P) released from soil, which contributes to plants' P requirement, especially in P limiting regions. In this study, two PSF, TalA-JX04 and AspN-JX16, were isolated from the rhizosphere soil of moso bamboo (Phyllostachys edulis) widely distributed in P-deficient areas in China and identified as Talaromyces aurantiacus and Aspergillus neoniger, respectively. The two PSF were cultured in potato dextrose liquid medium with six types of initial pH values ranging from 6.5 to 1.5 to assess acid resistance. Both PSF were incubated in Pikovskaya's liquid media with different pH values containing five recalcitrant P sources, including Ca3(PO4)2, FePO4, CaHPO4, AlPO4, and C6H6Ca6O24P6, to estimate their P solubilizing capacity. No significant differences were found in the biomass of both fungi grown in media with different initial pH, indicating that these fungi could grow well under acid stress. The P-solubilizing capacity of TalA-JX04 was highest in medium containing CaHPO4, followed by Ca3(PO4)2, FePO4, C6H6Ca6O24P6, and AlPO4 in six types of initial pH treatments, while the recalcitrant P solubilizing capacity of AspN-JX16 varied with initial pH. Meanwhile, the P solubilizing capacity of AspN-JX16 was much higher than TalA-JX04. The pH of fermentation broth was negatively correlated with P-solubilizing capacity (p<0.01), suggesting that the fungi promote the dissolution of P sources by secreting organic acids. Our results showed that TalA-JX04 and AspN-JX16 could survive in acidic environments and both fungi had a considerable ability to release soluble P by decomposing recalcitrant P-bearing compounds. The two fungi had potential for application as environment-friendly biofertilizers in subtropical bamboo ecosystem. PMID- 29995911 TI - Inferior long-term graft survival after end-to-side reconstruction for two renal arteries in living donor renal transplantation. AB - Living donor kidneys with two arteries can be revascularized using various techniques depending on anatomy. We hypothesized that the revascularization technique could impact long-term outcomes. We retrospectively analyzed 1714 living donor renal transplants at our institution between 1999 and 2015. Three hundred and eleven kidneys had dual arteries, and these were categorized into 5 groups; end-to-side (n = 18), inferior epigastric artery (n = 21), direct anastomosis (n = 65), side-to-side (n = 126) and ligated (n = 81). We then compared the outcomes with that of a control group (single artery, n = 1403) using Kaplan-Meier and Cox regression analyses. Cox regression was adjusted by age, sex and race/ethnicity of donor and recipient, side of kidney, transplant period and recipient surgeon. Compared to the control group, the end-to-side group had increased all-cause graft loss (10 years: 77.2% vs 24.5%, adjusted hazard ratio [aHR] 3.02, 95% confidence interval [CI] 1.30-7.03, p = 0.010) and death-censored graft loss (10 years: 82.0% vs 55.9%, aHR 4.17, 95% CI 1.63-10.68, p = 0.003), whereas the other groups did not. Our study shows that 10-year overall survival and death-censored graft survival were significantly worse for end-to-side arterial reconstruction than for other techniques. Alternative techniques to the end-to-side method should be used for accessory arteries that require revascularization. PMID- 29995912 TI - Sub-classifying patients with mild traumatic brain injury: A clustering approach based on baseline clinical characteristics and 90-day and 180-day outcomes. AB - BACKGROUND: The current classification of traumatic brain injury (TBI) into "mild", "moderate", or "severe" does not adequately account for the patient heterogeneity that still exists within each of these categories. The objective of this study was to identify "sub-groups" of mild TBI (mTBI) patients based on data available at the time of the initial post-TBI patient evaluation and to determine if the sub-grouping correlates with patient outcomes at 90 and 180 days post-TBI. METHODS: Data from patients in the TRACK-TBI Pilot dataset who had a Glasgow Coma Scale (GCS) score of 13 to 15 at arrival to the Emergency Department and a closed head injury were included. Considering 53 clinical variables that are typically available during the initial evaluation of the patient with mild TBI, sparse heirarchial clustering with cluster quality assessment was used to identify the optimal number of patient sub-groups. Patient sub-groups were then compared for ten outcomes measured at 90 or 180 days post-TBI. RESULTS: Amongst the 485 patients with mTBI, optimal clustering was based on the inclusion of 12 clinical variables that divided the patients into 5 mild TBI sub-groups. Clinical variables driving the sub-clustering included: gender, employment status, marital status, TBI due to falling, brain CT scan result, systolic blood pressure, diastolic blood pressure, administration of IV fluids in the Emergency Department, alcohol use, tobacco use, history of neurologic disease, and history of psychiatric disease. These 5 mild TBI sub-groups differed in their 90 day and 180 day outcomes within several domains including global outcomes, persistence of TBI-related symptoms, and neuropsychological impairment. CONCLUSIONS: Sub-groups of patients with mTBI can be identified according to clinical variables that are relatively easy to obtain at the time of initial patient evaluation. A patient's sub-group assignment is associated with multidimensional patient outcomes at 90 and 180 days. These findings support the notion that there are clinically meaningful subgroups of patients amongst those currently classified as having mTBI. PMID- 29995913 TI - Identification of novel diabetes impaired miRNA-transcription factor co regulatory networks in bone marrow-derived Lin-/VEGF-R2+ endothelial progenitor cells. AB - Endothelial progenitor cells (EPCs) are a group of rare cells that play an important role in the repair of injured vascular endothelial cells and assist in reperfusion of ischemic tissue. Decreased production and/or loss of function of EPCs are associated with diabetic vasculopathy. The molecular mechanisms by which diabetes impairs EPCs remain unclear. We conducted microarray experiments followed by integrative regulatory analysis on cells isolated from Akita diabetic mice (18-weeks after onset of diabetes) and age-matched non-diabetic controls. Two types of cells were isolated from mice bone marrow; Lin+ cells and Lin-/VEGF R2+ EPCs. RNA was hybridized to mouse WG-6 V2 beadchips followed by comprehensive gene network analysis and computational validation of the obtained results. In total, 80 genes were exclusively DE between non-diabetic Lin-/VEGF-R2+ EPCs and diabetic Lin-/VEGF-R2+ EPCs, of which the 3 genes Clcnka, Pik3c2a, and Ptf1a are known to be associated with diabetic complications. Further analysis led to the establishment of a TF-miRNA mediated regulatory network specific to diabetic Lin /VEGF-R2+ EPCs and to identify 11 central-hub TFs (Tbp, Ahr, Trp53, Gata1, Foxo1, Foxo4, Yy1, Max, Pparg, Myc, Cebpa), and 2 miRNAs (mir-139-5p, mir-709) that might act as putative genomic drivers of diabetic pathogenesis in Lin-/VEGF-R2+ EPCs. Moreover, we identified multiple TF-miRNA co-regulatory network motifs for which we validated their contribution to diabetic Lin-/VEGF-R2+ EPCs in terms of statistical significance and relevance to biological evidence. Our findings suggest that diabetic Lin-/VEGF-R2+ EPCs have specifically altered signature genes and miRNAs that render their capacity to proliferate and differentiate. PMID- 29995914 TI - Marijuana use and short-term outcomes in patients hospitalized for acute myocardial infarction. AB - Marijuana use is increasing worldwide, and it is ever more likely that patients presenting with acute myocardial infarctions (AMI) will be marijuana users. However, little is known about the impact of marijuana use on short-term outcomes following AMI. Accordingly, we compared in-hospital outcomes of AMI patients with reported marijuana use to those with no reported marijuana use. We hypothesized that marijuana use would be associated with increased risk of adverse outcomes in AMI patients. Hospital records from 8 states between 1994-2013 were screened for patients with a diagnosis of AMI. Clinical profiles and outcomes in patients with reported use of marijuana were compared to patients without reported marijuana use. Short-term outcomes were defined as adverse events that occurred during hospitalization for an admitting diagnosis of AMI. The composite primary outcome included death, intraaortic balloon pump placement, (IABP), mechanical ventilation, cardiac arrest, and shock. In total, 3,854 of 1,273,897 AMI patients reported use of marijuana. The marijuana cohort was younger than (47.2 vs. 57.2, respectively) and had less coronary artery disease than the non-marijuana cohort. In multivariable analysis including age, race and common cardiac risk factors, there was no association between marijuana use and the primary outcome (p = 0.53), but marijuana users were more likely to be placed on mechanical ventilation (OR (odds ratio) 1.19, p = 0.004). Interestingly, marijuana-using patients were significantly less likely to die (OR 0.79, p = 0.016), experience shock (OR 0.74, p = 0.001), or require an IABP (OR 0.80, p = 0.03) post AMI than patients with no reported marijuana use. These results suggest that, contrary to our hypothesis, marijuana use was not associated with increased risk of adverse short-term outcomes following AMI. Furthermore, marijuana use was associated with decreased in-hospital mortality post-AMI. PMID- 29995915 TI - Nitrosyl-hemoglobin formation in rodent and human venous erythrocytes reflects NO formation from the vasculature in vivo. AB - Reduced bioavailability of nitric oxide (NO) is a major feature of endothelial dysfunction characteristic of cardiovascular and metabolic diseases but the short half-life of NO precludes its easy quantification in circulating blood for early diagnosis. In erythrocytes, NO can react with hemoglobin to form an iron-nitrosyl complex (5-coordinate-alpha-HbNO) directly quantifiable by Electron Paramagnetic Resonance spectroscopy (EPR) in mouse, rat and human venous blood ex vivo. However, the sources of the nitrosylating species in vivo and optimal conditions of HbNO preservation for diagnostic use in human erythrocytes are unknown. Using EPR spectroscopy, we found that HbNO stability was significantly higher under hypoxia (equivalent to venous pO2; 12.0+/-0.2% degradation of HbNO at 30 minutes) than at room air (47.7+/-0.2% degradation) in intact erythrocytes; at 20 degrees C (15.2+/-0.3% degradation after 30 min versus 29.6+/-0.1% at 37 degrees C) and under acidic pH (31.7+/-0.8% versus 62.2+/-0.4% degradation after 30 min at physiological pH) at 50% of haematocrit. We next examined the relative contribution of NO synthase (NOS) from the vasculature or in erythrocytes themselves as a source of nitrosylating NO. We detected a NOS activity (and eNOS expression) in human red blood cells (RBC), and in RBCs from eNOS(+/+) (but not eNOS(-/-)) mice, as measured by HbNO formation and nitrite/nitrate accumulation. NO formation was increased after inhibition of arginase but abrogated upon NOS inhibition in human RBC and in RBCs from eNOS(+/+) (but not eNOS(-/-)) mice. However, the HbNO signal from freshly drawn venous RBCs was minimally sensitive to the inhibitors ex vivo, while it was enhanced upon caveolin-1 deletion in vivo, suggesting a minor contribution of erythrocyte NOS to HbNO complex formation compared with vascular endothelial NOS or other paracrine NO sources. We conclude that HbNO formation in rodent and human venous erythrocytes is mainly influenced by vascular NO sources despite the erythrocyte NOS activity, so that its measurement by EPR could serve as a surrogate for NO-dependent endothelial function. PMID- 29995916 TI - Effectiveness of corridors varies among phytosociological plant groups and dispersal syndromes. AB - In agricultural landscapes, semi-natural habitats are scarce and remaining habitat patches are largely isolated. However, linear landscape elements might facilitate dispersal of plant species through the agricultural landscape matrix. We investigated the following research questions: 1. are open linear landscape elements (LLE) effective corridors for dispersal of vascular plant species? 2. Which plant species, with respect to phytosociological group and dispersal distance class, do use LLE as corridors? 3. To which extent is floristic similarity of communities influenced by dispersal through corridors? Field work was carried out in agricultural landscapes of Northwest Germany. We sampled 50 vegetation releves on open linear landscape elements i.e. field margins (incl. road verges) and ditches, in eight 1-km2 study areas. Then, we calculated Jaccard similarities of all plot pairs within study areas using either all species or only species of certain phytosociological groups or dispersal-distance classes. We assessed the isolation of the plots from each other using both Euclidean distance and resistance distance along LLE. Resistance distance reflected the degree of connectivity of the LLE network between the plots. A stronger effect on Jaccard similarity of resistance distance compared to Euclidean distance would indicate corridor dispersal of plants through LLE. Relationships between Jaccard similarity and the two isolation measures were analysed with Generalised Linear Mixed Models. Resistance distance of LLE had a stronger negative effect on Jaccard similarity than Euclidean distance in field margins, but not in ditches. This was found for species of 'meadows and pastures' and short to medium dispersal distance. In plot pairs that were highly connected by LLE, the models suggested that roughly 20% of all species occurred in both plots due to dispersal through LLE. Other species groups did not respond more strongly to resistance distance than to Euclidean distance. We conclude that linear landscape elements in agricultural landscapes are effective corridors for dispersal of plant species that are confined to semi-natural habitats, such as traditional grasslands, and lack mechanisms of long-distance dispersal. PMID- 29995917 TI - OCR-Stats: Robust estimation and statistical testing of mitochondrial respiration activities using Seahorse XF Analyzer. AB - The accurate quantification of cellular and mitochondrial bioenergetic activity is of great interest in medicine and biology. Mitochondrial stress tests performed with Seahorse Bioscience XF Analyzers allow the estimation of different bioenergetic measures by monitoring the oxygen consumption rates (OCR) of living cells in multi-well plates. However, studies of the statistical best practices for determining aggregated OCR measurements and comparisons have been lacking. Therefore, to understand how OCR behaves across different biological samples, wells, and plates, we performed mitochondrial stress tests in 126 96-well plates involving 203 fibroblast cell lines. We show that the noise of OCR is multiplicative, that outlier data points can concern individual measurements or all measurements of a well, and that the inter-plate variation is greater than the intra-plate variation. Based on these insights, we developed a novel statistical method, OCR-Stats, that: i) robustly estimates OCR levels modeling multiplicative noise and automatically identifying outlier data points and outlier wells; and ii) performs statistical testing between samples, taking into account the different magnitudes of the between- and within-plate variations. This led to a significant reduction of the coefficient of variation across plates of basal respiration by 45% and of maximal respiration by 29%. Moreover, using positive and negative controls, we show that our statistical test outperforms the existing methods, which suffer from an excess of either false positives (within plate methods), or false negatives (between-plate methods). Altogether, this study provides statistical good practices to support experimentalists in designing, analyzing, testing, and reporting the results of mitochondrial stress tests using this high throughput platform. PMID- 29995918 TI - The influence of high-temperature heating on composition and thermo-oxidative stability of the oil extracted from Arabica coffee beans. AB - The aim of the present study was to establish the influence of high-temperature heating on the composition and thermal behavior of coffee oils obtained from Arabica green and roasted coffee beans, respectively. Morphological studies performed using scanning electron microscopy revealed the oil bodies uniformly distributed within the cells in both types of coffee beans analyzed. The obtained oils have a fatty acid composition rich in linoleic acid, palmitic acid, oleic acid, stearic acid, arachidic acid and linolenic acid. The total content of saturated fatty acids of investigated oils was 49.38 and 46.55%, the others being unsaturated fatty acids. The thermal behavior and thermo-oxidative stability of coffee oils extracted from green coffee beans and roasted coffee beans, the coffee oil high-temperature heated up to 200 degrees C, were investigated using simultaneous thermal analysis TG/DTG/DTA, in an oxidizing atmosphere. The data obtained for the analyzed samples depend mainly on the nature and compositions of fatty acids, and to a lesser extent on the roasting process of the coffee beans and the high-temperature heating process of the extracted oil. The chromatographic and TG/DTG/DTA data suggest that Arabica coffee oil has great potential for use in technological processes which require high-temperature heating (e.g. food industry or pastries). PMID- 29995919 TI - When conflict influences liking: The case of the Stroop task. AB - Research suggests that cognitive conflict is accompanied by a negative signal. Building on the demonstrated role of negative affect in attitude formation and change, the present research investigated whether the experience of cognitive conflict negatively influences subsequent evaluations of neutral stimuli. Relying on the emergence of conflict in the Stroop task, participants were presented with compatible (non-conflict) and incompatible (conflict) Stroop color words that were each followed by a neutral visual stimulus. In general, participants liked stimuli following incompatible Stroop words less than stimuli following compatible Stroop words. The results revealed similar compatibility effects in tasks in which participants actively responded to the Stroop words and in tasks in which they passively observed them. Furthermore, these effects emerged in offline and online measures of evaluation. Interestingly, the results also suggest that the compatibility effect on liking observed in the present research was to some degree driven by the positivity associated with the compatible Stroop words, and not just by the negativity associated with the incompatible Stroop words. We discuss the present findings in the context of how and when conflicting responses to events (such as in the Stroop task) can influence evaluations of stimuli associated with the conflicting events. PMID- 29995920 TI - A machine learning method to monitor China's AIDS epidemics with data from Baidu trends. AB - BACKGROUND: AIDS is a worrying public health issue in China and lacks timely and effective surveillance. With the diffusion and adoption of the Internet, the 'big data' aggregated from Internet search engines, which contain users' information on the concern or reality of their health status, provide a new opportunity for AIDS surveillance. This paper uses search engine data to monitor and forecast AIDS in China. METHODS: A machine learning method, artificial neural networks (ANNs), is used to forecast AIDS incidences and deaths. Search trend data related to AIDS from the largest Chinese search engine, Baidu.com, are collected and selected as the input variables of ANNs, and officially reported actual AIDS incidences and deaths are used as the output variable. Three criteria, the mean absolute percentage error, the root mean squared percentage error, and the index of agreement, are used to test the forecasting performance of the ANN method. RESULTS: Based on the monthly time series data from January 2011 to June 2017, this article finds that, under the three criteria, the ANN method can lead to satisfactory forecasting of AIDS incidences and deaths, regardless of the change in the number of search queries. CONCLUSIONS: Despite the inability to self detect HIV/AIDS through online searching, Internet-based data should be adopted as a timely, cost-effective complement to a traditional AIDS surveillance system. PMID- 29995921 TI - CT findings of adnexal torsion: A matched case-control study. AB - OBJECTIVE: The purpose of our study was to assess computed tomographic (CT) findings of adnexal torsion through a matched case-control analysis. MATERIALS AND METHODS: This retrospective, single-institution case-control study included 43 women with adnexal torsion and 43 age- and ovarian mass-matched control women. CT images were evaluated independently by two readers for the following: prominent peripheral follicles, uterine deviation, thickened pedicles, a whirl sign, and a navel sign. Comparisons of CT findings were performed using the Chi square test and receiver operating characteristic (ROC) curves were obtained to assess the diagnostic performance. Differences between the areas under the ROC curves (AUCs) were compared by using a Delong test. RESULTS: The CT findings significant for adnexal torsion were uterine deviation toward the side of the affected ovary (P = < .01 for reader 1 and P = .02 for reader 2) and thickened pedicles with ancillary findings including a whirl sign, a navel sign, and uterine deviation facing thickened pedicles (P < .01 for both readers). Thickened pedicles with ancillary findings had the highest diagnostic accuracy, as measured with ROC curves (AUC, 0.86 in reader 1 and 0.85 in reader 2). Combining uterine deviation toward the side of the affected ovary with thickened pedicles with ancillary findings did not increase the performance relative to that of thickened pedicles with ancillary findings alone. CONCLUSIONS: Thickened pedicles with ancillary findings including a whirl sign, a navel sign, and uterine deviation facing thickened pedicles could be helpful for the diagnosis of adnexal torsion. PMID- 29995922 TI - P-wave duration is a predictor for long-term mortality in post-CABG patients. AB - Risk stratification in secondary prevention has emerged as an unmet clinical need in order to mitigate the Number-Needed-to-Treat and make expensive therapies both clinically relevant and cost-effective. P wave indices reflect atrial conduction, which is a sensitive marker for inflammatory, metabolic, and pressure overload myocardial cell remodeling; the three stimuli are traditional mechanisms for adverse clinical evolution. Accordingly, we sought to investigate the predictive role of P-wave indices to estimate residual risk in patients with chronic coronary artery disease (CAD). The cohort included 520 post-Coronary Artery Bypass Grafting patients with a median age of 60 years who were followed for a median period of 1025 days. The primary endpoint was long-term all-cause death. Cubic spline model demonstrated a linear association between P-wave duration and incidence rate of long-term all-cause death (p = 0.023). P-wave >110ms was a marker for an average of 425 days shorter survival as compared with P-wave under 80ms (Logrank p = 0.020). The Cox stepwise regression models retained P-wave duration as independent marker (HR:1.37; 95%CI:1.05-1.79,p = 0.023). In conclusion, the present study suggests that P-wave measurement may constitute a simple, inexpensive and accessible prognostic tool to be added in the bedside risk estimation in CAD patients. PMID- 29995923 TI - Bright lights, big city: Causal effects of population and GDP on urban brightness. AB - Cities are arguably both the cause, and answer, to societies' current sustainability issues. Urbanization is the interplay between a city's physical growth and its socio-economic development, both of which consume a substantial amount of energy and resources. Knowledge of the underlying driver(s) of urban expansion facilitates not only academic research but, more importantly, bridges the gap between science, policy drafting, and practical urban management. An increasing number of researchers are recognizing the benefits of innovative remotely sensed datasets, such as nighttime lights data (NTL), as a proxy to map urbanization and subsequently examine the driving socio-economic variables in cities. We further these approaches, by taking a trans-pacific view, and examine how an array of socio-economic ind0icators of 25 culturally and economically important urban hubs relate to long term patterns in NTL for the past 21 years. We undertake a classic econometric approach-panel causality tests which allow analysis of the causal relationships between NTL and socio-economic development across the region. The panel causality test results show a contrasting effect of population and gross domestic product (GDP) on NTL in fast, and slowly, changing cities. Information derived from this study quantitatively chronicles urban activities in the pan-Pacific region and potentially offers data for studies that spatially track local progress of sustainable urban development goals. PMID- 29995925 TI - Correction: Software-aided approach to investigate peptide structure and metabolic susceptibility of amide bonds in peptide drugs based on high resolution mass spectrometry. AB - [This corrects the article DOI: 10.1371/journal.pone.0186461.]. PMID- 29995924 TI - Anthocyanins from purple corn activate free fatty acid-receptor 1 and glucokinase enhancing in vitro insulin secretion and hepatic glucose uptake. AB - The objective of this study was to evaluate the ability of anthocyanins (ANC) present in purple corn to enhance insulin secretion and hepatic glucose uptake in pancreatic cells and hepatocytes, through activation of the free fatty acid receptor-1 (FFAR1) and glucokinase (GK), respectively. Using a dual-layer cell culture with Caco-2 cells, INS-1E or HepG2 cells were treated with an anthocyanin rich extract from the pericarp of purple corn (PCW), as well as pure ANC cyanidin 3-O-glucoside (C3G), peonidin-3-O-glucoside, pelargonidin-3-O-glucoside. Delphinidin-3-O-glucoside (D3G) was used for comparative purposes. Semipurified C3G (C3G-P) and condensed forms (CF-P) isolated from PCW were also used. At 100 MUM, the pure ANC enhanced glucose-stimulated insulin secretion (GSIS) in INS-1E cells ranging from 18% to 40% (p<0.05) compared to untreated cells. PCW increased GSIS by 51%. D3G was the most effective anthocyanin activating FFAR1 (EC50: 196.6 MUM). PCW had activating potential on FFAR1 (EC50: 77 MUg/mL). PCW, as well as C3G and D3G increased the expression of FFAR1, PLC, and phosphorylation of PKD, related to the FFAR1-dependent insulin secretory pathway. The treatment with 100 MUM of P3G and C3G increased (p<0.05) glucose uptake in HepG2 cells by 19% and 31%. PCW increased the glucose uptake in HepG2 cells by 48%. It was determined that CF-P was the most effective for activating GK (EC50: 39.9 MUM) and the PCW extracts had an efficacy of EC50: 44 MUg/mL. The ANC in purple corn also reduced AMPK phosphorylation and PEPCK expression in HepG2 cells, known to be related to reduction in gluconeogenesis. It is demonstrated for the first time that dietary ANC can enhance the activity of novel biomarkers FFAR1 and GK and potentially ameliorate type-2 diabetes comorbidities. PMID- 29995926 TI - Russians are the fastest 100-km ultra-marathoners in the world. AB - OBJECTIVES: A recent study investigating the top 10 100-km ultra-marathoners by nationality showed that Japanese runners were the fastest worldwide. This selection to top athletes may lead to a selection bias and the aim of this study was to investigate from where the fastest 100-km ultra-marathoners originate by considering all finishers in 100-km ultra-marathons since 1959. METHODS: We analysed data from 150,710 athletes who finished a 100-km ultra-marathon between 1959 and 2016. To get precise estimates and stable density plots we selected only those nationalities with 900 and more finishes resulting in 24 nationalities. Histograms and density plots were performed to study the distribution of race time. Crude mean, standard deviation, median, interquartile range (IQR), mode, skewness and excess of time for each nationality were computed. A linear regression analysis adjusted by sex, age and year was performed to study the race time between the nationalities. Histograms, density and scatter plots showed that some races seemed to have a time limit of 14 hours. From the complete dataset the finishes with more than 14 hours were removed (truncated dataset) and the same descriptive plots and analysis as for the complete dataset were performed again. In addition to the linear regression a truncated regression was performed with the truncated dataset to allow conclusion for the whole sample. To study a potential difference between races at home and races abroad, an interaction term race site home/abroad with nationality was included in the model. RESULTS: Most of the finishes were achieved by runners from Japan, Germany, Switzerland, France, Italy and USA with more than 260'000 (85%) finishes. Runners from Russia and Hungary were the fastest and runners from Hong Kong and China were the slowest finishers. CONCLUSION: In contrast to existing findings investigating the top 10 by nationality, this analysis showed that ultra-marathoners from Russia, not Japan, were the fastest 100-km ultra-marathoners worldwide when considering all races held since 1959. PMID- 29995927 TI - Comparing student, instructor, and expert perceptions of learner-centeredness in post-secondary biology classrooms. AB - Learner-centered classrooms encourage critical thinking and communication among students and between students and their instructor, and engage students as active learners rather than passive participants. However, students, faculty, and experts often have distinct definitions of learner-centeredness, and the paucity of research comparing perspectives of these different groups must be resolved. In the current study, our central research question was how do student, faculty, and expert observer perceptions of learner-centeredness within biology classrooms compare to one another? We sampled 1114 students from fifteen sections of a general biology course for non-majors, and complete responses from 490 students were analyzed. Five valid and reliable tools (two faculty; two student; and one expert observer) evaluated the learner-centeredness of each participating section. Perceptions of learner-centered instructors often aligned with those of expert observers, while student perceptions tended not to align with either group. Interestingly, students perceived learner-centered instructors as less learner-centered if they taught at non-traditional times and/or in large enrollment sections, despite their focus on student learning. Perceptions of learner-centeredness in the biology classroom are complex and may be best captured with more than one instrument. Our findings encourage instructors to be cognizant that the approaches they employ in the classroom may not be interpreted as learner-centered, in the same manner, by students and external observers, particularly when additional course factors such as enrollment and scheduling may encourage negative perceptions of learner-centered practices. PMID- 29995928 TI - Ethical dilemma of identity disclosure faced by medical students in clinical clerkships: A nationwide multicenter study in China. AB - OBJECTIVE: Medical students in China are currently facing a dilemma of whether to clarify their identity as students to patients. Further investigation is needed to support policy-making. The aim was to identify factors influencing medical students' decision on whether or not to clarify their identity to patients and to examine the effects of their decision. METHODS: The study was a cross-sectional nationwide multicenter survey consisting of 947 medical students. A self-designed questionnaire was composed of 19 structured questions investigating the present situation and participants' perception of the ethical dilemma surrounding medical student identity. The questionnaires were distributed randomly in teaching hospitals affiliated with 13 medical schools across China from June 2015 to January 2016. RESULTS: A total of 947 valid questionnaires were retrieved with a valid response rate of 83.7%. Most medical students (71.4%) tended to be ambiguous about their student identity in front of patients. The frequency of encountering distrust and patients' or patient relatives' refusal to allow students to perform procedures was significantly lower for students who explicitly stated their identity than for those who were ambiguous about their identity (p<0.001). Less experience in clinical rotations (<0.5 y/0.5-1 y, OR 2.7, 95% CI 1.7-4.3; <0.5 y/>1 y, OR 3.6, 95% CI 2.0-6.5), preceptors' straightforward introduction of the students (OR 8.7, 95% CI 5.4-13.8) and students' acknowledgment of patients' right to know (OR 2.3, 95% CI 1.2-4.5) were related to students' clear self-introduction to patients. CONCLUSION: It is beneficial for medical students to clearly explain their identity to patients in order to decrease patient distrust and prevent the refusal to have certain appropriate procedures performed. Several methods, including emphasizing the role of mentors, developing curriculum for medical students, and creating clear regulations and guidelines for revealing the identity of medical students on the healthcare team can help address and ideally resolve this ethical dilemma of identity disclosure. PMID- 29995929 TI - Biomarkers and predictors for functional and anatomic outcomes for small gauge pars plana vitrectomy and peeling of the internal limiting membrane in naive diabetic macular edema: The VITAL Study. AB - PURPOSE: We aimed to investigate biomarkers and predictive factors for visual and anatomical outcome in patients with naive diabetic macular edema (DME) who underwent small gauge pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling as a first line treatment. DESIGN: Multicenter, retrospective, interventional study. PARTICIPANTS: 120 eyes from 120 patients with naive DME treated with PPV and ILM peeling with a follow up of 24 months. METHODS: Change in baseline best corrected visual acuity (BCVA) and central subfoveal thickness (CST) 1, 6, 12 and 24 months after surgery. Predictive value of baseline BCVA, CST, optical coherence tomography (OCT) features (presence of subretinal fluid (SRF) and photoreceptor damage), and time between DME diagnosis and surgery. Additional treatment for DME needed. Intra- and post-operative complications (cataract rate formation, increased intraocular pressure). MAIN OUTCOME MEASURES: The correlation between baseline characteristics and BCVA response (mean change from baseline; categorized improvement >=5 or >=10; Early Treatment Diabetic Retinopathy Study (ETDRS) letters) 12 and 24 months after surgery. RESULTS: Mean BCVA was 0.66 +/- 0.14 logMAR, 0.52 +/- 0.21 logMAR, and 0.53 +/- 0.21 logMAR (p<0.001) at baseline, 12 and 24 months, respectively. Shorter time from DME diagnosis until PPV (OR: 0.98, 95% CI: 0.97-0.99, p<0.001) was a predictor for good functional treatment response (area under the curve 0.828). For every day PPV is postponed, the patient's chances to gain >=5 letters at 24 months decrease by 1.8%. Presence of SRF was identified as an anatomical predictor of a better visual outcome, (OR: 6.29, 95% CI: 1.16-34.08, p = 0.033). Safety profile was acceptable. CONCLUSIONS: Our results reveal a significant functional and anatomical improvement of DME 24 months after primary PPV, without the need for additional treatment. Early surgical intervention and presence of SRF predict good visual outcome. These biomarkers should be considered when treatment is chosen. PMID- 29995930 TI - Epstein-Barr virus DNA modulates regulatory T-cell programming in addition to enhancing interleukin-17A production via Toll-like receptor 9. AB - Infection with the Epstein-Barr virus (EBV) has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have previously reported that DNA from this virus enhances production of the pro-autoimmune interleukin 17A (IL-17A) in mice. In this study we assessed the effect of EBV DNA on regulatory T cell programming and examined whether it mediated its effects via Toll-like receptor 9 (TLR9) in mice; moreover, we evaluated whether EBV DNA in humans had similar effects to those seen in mice. For this purpose, we assessed the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects and matched controls. A modulatory effect for the viral DNA was observed for regulatory T cell markers with an inhibitory effect observed for CTLA4 expression in the EBV DNA-treated mice. To examine whether TLR9 mediated the detection of EBV DNA and enhancement of IL-17A production, mouse peripheral blood mononuclear cells were treated with the DNA in the presence or absence of the TLR9 inhibitor ODN 2088. Subsequently, IL-17A production from these cells was assessed. Treatment with the TLR9 inhibitor resulted in a significant decrease in IL-17A production indicating that TLR9 is involved in this pathway. In human subjects, examining the linearity of the correlation between EBV DNA and IL-17A levels in RA subjects showed a propensity for linearity that was not observed in controls. Our data thus indicates that EBV DNA itself acts as a modulator of the Th17 compartment as well as that of regulatory T cell mechanisms. The involvement of TLR9 in the EBV DNA-triggered induction of IL-17A suggests therapeutic targeting of this endosomal receptor in EBV positive subjects with an autoimmune flare-up or possibly for prophylactic purposes. PMID- 29995931 TI - Positive association between moderate altitude and chronic lower respiratory disease mortality in United States counties. AB - For patients with chronic lower respiratory disease, hypobaric hypoxia at a high altitude is considered a risk factor for mortality. However, the effects of residing at moderately high altitudes remain unclear. We investigated the association between moderate altitude and chronic lower respiratory disease mortality. In particular, we examined the lower 48 United States counties for age adjusted chronic lower respiratory disease mortality rates, altitude, and socioeconomic factors, including tobacco use, per capita income, population density, sex ratio, unemployment, poverty, and education between 1979 and 1998. The socioeconomic factors were incorporated into the correlation analysis as potential covariates. Considerable positive (R = 0.235; P <0.001) and partial (R = 0.260; P <0.001) correlations were observed between altitude and chronic lower respiratory disease mortality rate. In the subgroup with high COPD prevalence subgroup, even stronger positive (R = 0.346; P <0.001) and partial (R = 0.423, P <0.001) correlations were observed. Multivariate regression analysis of all available socioeconomic factors revealed that additional knowledge on altitude improved the adjusted R2 values from 0.128 to 0.186 for all counties and from 0.301 to 0.421 for counties with high COPD prevalence. We concluded that in the lower 48 United States counties, even a moderate altitude may pose considerable risks in patients with chronic lower respiratory disease. PMID- 29995932 TI - How can a measure improve assessment and management of symptoms and concerns for people with dementia in care homes? A mixed-methods feasibility and process evaluation of IPOS-Dem. AB - BACKGROUND: Assessment of people with dementia is challenging; with undetected and under treated symptoms and concerns resulting in avoidable distress, and few evidence-based interventions to support this. We aimed to understand the mechanisms of action of a measure to support comprehensive assessment of people with dementia in care homes; and its acceptability, feasibility, and implementation requirements. METHODS: A qualitative study with an embedded quantitative component in three residential care homes, underpinned by an initial theoretical model of mechanisms of action. The measure, the Integrated Palliative care Outcome Scale for Dementia (IPOS-Dem), was introduced into the care of residents with dementia for 12 weeks. Qualitative data comprised focus groups and semi-structured interviews with family, care home staff, general practitioners and district nurses; and non-participant observations. Quantitative data comprised IPOS-Dem data. Directed content analysis for qualitative data, and descriptive statistics were used for quantitative data. FINDINGS: Key mechanisms of action were: improved observation and awareness of residents, collaborative assessment, comprehensive 'picture of the person', systematic record keeping, improved review and monitoring, care planning and changes to care provision, and facilitated multi-agency communication. Potential benefit included improved symptom management, improved comprehensive care, and increased family empowerment and engagement. IPOS-Dem was found to be acceptable and feasible. It was perceived as quick and easy to use, with proportion of overall missing data decreasing from 2.1% to 1.1% from baseline to final time points. 'Trust' in the measure was important; and leadership essential to ensure integration into care processes. CONCLUSIONS: In a population with complex care needs, with challenges to assessment and barriers to multi-agency working, a measure introduced into routine care is feasible and acceptable, and supports assessment and management of symptoms and concerns. A refined theoretical model demonstrating the likely mechanisms of action was developed. Further evaluation is required to test its effectiveness. PMID- 29995933 TI - SAP97 regulates behavior and expression of schizophrenia risk enriched gene sets in mouse hippocampus. AB - Synapse associated protein of 97KDa (SAP97) belongs to a family of scaffolding proteins, the membrane-associated guanylate kinases (MAGUKs), that are highly enriched in the postsynaptic density of synapses and play an important role in organizing protein complexes necessary for synaptic development and plasticity. The Dlg-MAGUK family of proteins are structurally very similar, and an effort has been made to parse apart the unique function of each Dlg-MAGUK protein by characterization of knockout mice. Knockout mice have been generated and characterized for PSD-95, PSD-93, and SAP102, however SAP97 knockout mice have been impossible to study because the SAP97 null mice die soon after birth due to a craniofacial defect. We studied the transcriptomic and behavioral consequences of a brain-specific conditional knockout of SAP97 (SAP97-cKO). RNA sequencing from hippocampi from control and SAP97-cKO male animals identified 67 SAP97 regulated transcripts. As large-scale genetic studies have implicated MAGUKs in neuropsychiatric disorders such as intellectual disability, autism spectrum disorders, and schizophrenia (SCZ), we analyzed our differentially expressed gene (DEG) set for enrichment of disease risk-associated genes, and found our DEG set to be specifically enriched for SCZ-related genes. Subjecting SAP97-cKO mice to a battery of behavioral tests revealed a subtle male-specific cognitive deficit and female-specific motor deficit, while other behaviors were largely unaffected. These data suggest that loss of SAP97 may have a modest contribution to organismal behavior. The SAP97-cKO mouse serves as a stepping stone for understanding the unique role of SAP97 in biology. PMID- 29995934 TI - High-density lipoprotein cholesterol as a therapeutic target for residual risk in patients with acute coronary syndrome. AB - OBJECTIVE: The current guideline recommends lowering low-density lipoprotein cholesterol (LDL-C) for the primary management of dyslipidemia in patients at high-risk of cardiovascular events. Patients who have achieved LDL-C levels below the recommended targets may still experience cardiovascular events, suggesting additional therapeutic targets beyond LDL-C. The aim of this study was to investigate whether high-density lipoprotein cholesterol (HDL-C) levels had an impact on plaque stabilization in patients with acute coronary syndrome (ACS). METHODS: This study consisted of 90 ACS patients with untreated dyslipidemia. In optical coherence tomography (OCT) analysis, a plaque with fibrous cap thickness ?160 MUm was defined as a high-risk plaque. We registered one high-risk plaque per one patient by baseline OCT imaging, and then administrated high-intensity statin. Based on the follow-up OCT results, patients whose registered plaque was no longer high-risk plaque were classified into a responder group and the remains into a non-responder group. RESULTS: No differences were observed in the baseline LDL-C and HDL-C levels between the two groups. Reduction of LDL-C levels (delta LDL-C: -53 +/- 21 mg/dL vs. -42 +/- 29 mg/dL, p = 0.036) and increase of HDL-C levels (delta HDL-C: 2.5 +/- 5.9 mg/dL vs. -0.3 +/- 6.7 mg/dL, p = 0.039) were greater in the responder group. On multivariate logistic regression analysis, delta LDL-C levels (OR: 0.956, 95% CI: 0.921-0.993; p = 0.020) and delta HDL-C levels (OR: 1.143; 95% CI: 1.005-1.300, p = 0.041) were independent contributors for plaque stabilization. CONCLUSIONS: Increase of HDL-C levels is associated with plaque stabilization in patients with ACS. HDL-C could be a therapeutic target for residual risk management. PMID- 29995935 TI - The competence-supportive and competence-thwarting role of athlete leaders: An experimental test in a soccer context. AB - The aim of this experiment was to study the growth-promoting and adverse impact of athlete leaders' competence-supportive and-thwarting behavior on the motivation and performance of team members. Male soccer players (N = 144; MAge = 14.2) were allocated to ad-hoc teams of five soccer players. These teams participated in two sessions, being randomly exposed to an athlete leader who acted either competence-supportive, competence-thwarting, or neutral during the second session. When the athlete leader was competence-supportive (versus competence-thwarting), his teammates' intrinsic motivation and performance increased (versus decreased) compared with the control condition. The leader's impact on intrinsic motivation was fully accounted for by team members' competence satisfaction. These findings recommend coaches to invest in the competence-supportive power of their athlete leaders to establish an optimally motivating and performance-enhancing team environment. PMID- 29995936 TI - Y-box-binding protein 1 supports the early and late steps of HIV replication. AB - The human immunodeficiency virus (HIV) depends on cellular proteins, so-called cofactors, to complete its replication cycle. In search for new therapeutic targets we identified the DNA and RNA binding protein Y-box-binding Protein 1 (YB 1) as a cofactor supporting early and late steps of HIV replication. YB-1 depletion resulted in a 10-fold decrease in HIV-1 replication in different cell lines. Dissection of the replication defects revealed that knockdown of YB-1 is associated with a 2- to 5-fold decrease in virion production due to interference with the viral RNA metabolism. Using single-round virus infection experiments we demonstrated that early HIV-1 replication also depends on the cellular YB-1 levels. More precisely, using quantitative PCR and an in vivo nuclear import assay with fluorescently labeled viral particles, we showed that YB-1 knockdown leads to a block between reverse transcription and nuclear import of HIV-1. Interaction studies revealed that YB-1 associates with integrase, although a direct interaction with HIV integrase could not be unambiguously proven. In conclusion, our results indicate that YB-1 affects multiple stages of HIV replication. Future research on the interaction between YB-1 and the virus will reveal whether this protein qualifies as a new antiviral target. PMID- 29995937 TI - Genome-wide identification and characterization of the CKII gene family in the cultivated banana cultivar (Musa spp. cv Tianbaojiao) and the wild banana (Musa itinerans). AB - Plant casein kinase II (CKII) plays an essential role in regulating plant growth and development, and responses to biotic and abiotic stresses. Here, we report the identification and characterization of the CKII family genes in Musa spp. cv. 'Tianbaojiao' (AAA group) and the wild banana (Musa itinerans). The 13 cDNA sequences of the CKII family members were identified both in 'Tianbaojiao' and wild banana, respectively. The differences between CKII alpha and CKII beta members are corroborated through the subcellular localizations, phosphorylation sites and gene structures. The cloning of CKII beta-like-2 gDNA sequences in wild banana and 'Tianbaojiao' and the analysis of gene structures showed MiCKIIbeta like-2b and MaCKIIbeta-like-2 are likely alternatively spliced transcripts, which were derived from the alternative splicing events that involved exon deletion. The qPCR validation showed differential expression CKII family members in response to cold stress and also in all tested tissues (leaf, pseudostem and root) of wild banana. In particular, the normal transcript MiCKIIbeta-like-2a was highly expressed in response to cold stress in wild banana; oppositely, the alternatively spliced transcript MiCKIIbeta-like-2b was quite lowly expressed. The complex origin and long-term evolution of Musa lineage might explain the alternative splicing events of CKII beta-like-2. PMID- 29995939 TI - Disrespect and abuse during childbirth in district Gujrat, Pakistan: A quest for respectful maternity care. AB - BACKGROUND: Disrespectful and abusive practices at health facilities during childbirth discourage many women to seek care at facilities. This may lead to maternal morbidity and mortalities. Despite severe impacts, such practices remain hidden and are rarely reported in developing countries. OBJECTIVES: The study was carried out to assess the prevalence and determinants of the disrespect and abuse (D & A) during child birth in rural Gujrat, Pakistan. METHODS: A cross sectional household based study was conducted in tehsil Kharian of district Gujrat. Data was collected using an interview based questionnaire from the women who had a live birth within the previous two months (n = 360). The D & A scale was based on standard Maternal and Child Health Integrated Programme indicators. Multiple logistic regression was used to find out the determinants of reported D & A. RESULTS: Almost all women experienced D & A (99.7%) during childbirth according to objective assessment "experienced D & A". However, only 27.2% reported subjective experience of D & A "reported D & A". The main determinant of reported D & A was facility based childbirth (OR = 13.49; 10.10-100.16) and lower socio economic strata (OR = 2.89; 1.63-5.11). The risk of reporting D & A was twice in public health facilities as compared to private. Women who had reported D & A were more likely to opt for changing the place of childbirth for next time (OR = 4.37, 95% CI = 2.41-7.90). CONCLUSION: D & A during childbirth is highly prevalent and under-recognized in Pakistan. High prevalence at facilities and particularly at public facilities can be a reason for underutilization of this sector for childbirth. Maternal health policies in Pakistan need to be revised based on the charter of respectful maternity care. PMID- 29995938 TI - Quantitative assessment of intestinal stiffness and associations with fibrosis in human inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) continues to increase in prevalence in industrialized countries. Major complications of IBD include formation of fibrotic strictures, fistulas, reduced absorptive function, cancer risk, and the need for surgery. In other chronic gastrointestinal disease models, stiffness has been shown to precede fibrosis; therefore, stiffness may be a reasonable indicator of progression toward stricture formation in IBD patients. Herein, we seek to quantify tissue stiffness and characterize fibrosis in patients with IBD and to compare mechanical properties of unaffected human tissue to common animal species used for IBD studies. Inflamed and unaffected tissue from IBD patients and unaffected tissue from mice, pigs, and cows were indented using a custom device to determine the effective stiffness. Histology was performed on matched tissues, and total RNA was isolated from IBD tissue samples and used for gene expression analysis of pro-fibrotic genes. We observed an increase in the effective stiffness (steady-state modulus, SSM) (p < 0.0001) and increased expression of the collagen type I gene (COL1A1, p = 0.01) in inflamed tissue compared to unaffected areas in our IBD patient cohort. We also found that increased staining of collagen fibers in submucosa positively correlated with SSM (p = 0.093). We determined that unaffected animal bowel stiffness is significantly greater than similar human tissues, suggesting additional limitations on animal models for translational investigations regarding stiffness related hypotheses. Taken together, our data support development of tools for evaluation of bowel stiffness in IBD patients for prognostic applications that may enable more accurate prediction of those who will develop fibrosis and more precise prescription of aggressive therapies. PMID- 29995940 TI - Comparative analyses of longissimus muscle miRNAomes reveal microRNAs associated with differential regulation of muscle fiber development between Tongcheng and Yorkshire pigs. AB - Tongcheng (TC) and Yorkshire (YK) are two pig breeds with distinctive muscle morphology. Porcine microRNAome (miRNAome) of the longissimus muscle during five developmental stages (40, 55, 63, 70, and 90 days post coitum (dpc)) was explored by Solexa sequencing in the present study to find miRNAs involved in the different regulation of skeletal muscle development between the two breeds. A total of 320 known porcine miRNAs, 64 miRNAs corresponding to other mammals, and 224 potentially novel miRNAs were identified. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) suggested that the factor "pig breed" affected the miRNA expression profiles to a lesser extent than the factor "developmental stage". Fifty-seven miRNAs were differentially expressed (DE) between the neighbor developmental stages in TC and 45 such miRNAs were found in YK, 34 in common; there were more down-regulated stage-DE miRNAs than up regulated. And a total of 23, 30, 12, 6, and 30 breed-DE miRNAs between TC and YK were identified at 40, 55, 63, 70, and 90 dpc, respectively, which were mainly involved in cellular protein modification process, protein transport, and metabolic process. As the only highly expressed breed-DE miRNA found in no less than four developmental stages, and also a stage-DE miRNA found both in TC and YK, miR-499-5p could bind the 3'-UTR of a myofibrillogenesis regulator, destrin/actin depolymerizing factor (DSTN), as validated in dual luciferase reporter assay. The results suggested that miR-499-5p possibly play a noteworthy role in the breed-distinctive porcine muscle fiber development associated with the regulation of DSTN. PMID- 29995941 TI - Cryopreservation in rhinoceros-Setting a new benchmark for sperm cryosurvival. AB - At times when rhinoceros are fiercely poached, when some rhinoceros species are closer than ever to extinction, and when the scientific community is in debate over the use of advanced cell technologies as a remaining resort it is time to simplify and improve existing assisted reproduction techniques to enhance breeding and genetic diversity in the living populations under our care. Semen cryopreservation has been performed in all captive rhinoceros species with limited degree of success. Here we tested three freezing extenders, containing different cryoprotectants and various freezing rates for the cryopreservation of rhinoceros sperm from 14 bulls. In experiment I, semen from 9 bulls was used to determine the most suitable diluent, cryoprotectant and freezing rate for the successful cryopreservation of rhinoceros sperm. In experiment II, semen from 5 bulls was used to assess whether the removal of seminal plasma could further improve post thaw sperm quality following cryopreservation with conditions identified in Experiment I. Semen was diluted with Berliner Cryomedia, ButoCrio(r) or INRA Freeze(r), packaged in 0.5 mL straws and frozen 3, 4, and 5 cm over liquid nitrogen (LN) vapour or directly in a dryshipper. It was found that semen extended with ButoCrio(r) (containing glycerol and methylformamide) and frozen 3cm over LN vapour provided the best protection to rhinoceros spermatozoa during cryopreservation. When pooled over treatments, total and progressive post thaw motility was 75.3 +/- 4.2% and 68.5 +/- 5.7%, respectively marking a new benchmark for the cryopreservation of rhinoceros sperm. Post thaw total and progressive motility, viability and acrosome integrity of semen diluted in ButoCrio(r) was significantly higher than semen extended in Berliner Cryomedia or INRA Freeze(r). The removal of seminal plasma did not improve post thaw sperm survival (p > 0.05). In conclusion, the cryosurvival of rhinoceros spermatozoa was significantly improved when using a mixture of glycerol and methylformamide in combination with a fast freezing rate at 3 cm. These results describe a new protocol for the improved cryosurvival of rhinoceros spermatozoa and will enable a more successful preservation of genetic diversity between males, especially in donors whose spermatozoa may already be compromised prior to or during collection. The successful reduction of glycerol concentration in favour of methylformamide as a cryoprotectant could be a novel suggestion for the improvement of cryopreservation techniques in other wildlife species. PMID- 29995942 TI - Challenges to implementing national comprehensive sexuality education curricula in low- and middle-income countries: Case studies of Ghana, Kenya, Peru and Guatemala. AB - School-based comprehensive sexuality education (CSE) can help adolescents achieve their full potential and realize their sexual and reproductive health and rights. This is particularly pressing in low- and middle-income countries (LMICs), where high rates of unintended pregnancy and STIs among adolescents can limit countries' ability to capitalize on the demographic dividend. While many LMICs have developed CSE curricula, their full implementation is often hindered by challenges around program planning and roll-out at the national and local level. A better understanding of these barriers, and similarities and differences across countries, can help devise strategies to improve implementation; yet few studies have examined these barriers. This paper analyzes the challenges to the implementation of national CSE curricula in four LMICs: Ghana, Kenya, Peru and Guatemala. It presents qualitative findings from in-depth interviews with central and local government officials, civil society representatives, and community level stakeholders ranging from religious leaders to youth representatives. Qualitative findings are complemented by quantitative results from surveys of principals, teachers who teach CSE topics, and students aged 15-17 in a representative sample of 60-80 secondary schools distributed across three regions in each country, for a total of around 3000 students per country. Challenges encountered were strikingly similar across countries. Program planning-related challenges included insufficient and piecemeal funding for CSE; lack of coordination of the various efforts by central and local government, NGOs and development partners; and inadequate systems for monitoring and evaluating teachers and students on CSE. Curriculum implementation-related challenges included inadequate weight given to CSE when integrated into other subjects, insufficient adaptation of the curriculum to local contexts, and limited stakeholder participation in curriculum development. While challenges were similar across countries, the strategies used to overcome them were different, and offer useful lessons to improve implementation for these and other low- and middle-income countries facing similar challenges. PMID- 29995944 TI - Haemodynamic effects of prenatal caffeine on the cardiovascular transition in ventilated preterm lambs. AB - BACKGROUND: Caffeine is routinely given to preterm infants hours after birth to treat apnea of prematurity. In view of it's success, earlier administration in the delivery room is being considered, but little is known about how caffeine may effect the cardiovascular changes during the fetal to neonatal transition. Our aim was to determine the effect of prenatal caffeine administration on haemodynamic parameters in ventilated preterm lambs immediately after birth. METHODS: Catheters (carotid artery and jugular vein) and ultrasonic flow probes (pulmonary artery and carotid artery) were implanted in preterm lambs (~126 +/-2 days of gestation; term is 147 days), immediately before delivery by caesarean section. Before the cord was clamped, lambs were intubated and a caffeine (10mg/kg caffeine-base; n = 9) or saline (n = 5) infusion was given intravenously to the ewe and lamb over a 15-minute period. Two minutes after clamping the cord, ventilation commenced with a sustained inflation (35 cm H2O for 30 seconds) followed by ventilation for 30 minutes (target tidal volume of 6-8ml/kg). RESULTS: Blood gas parameters and rectal body temperature were not different between the two groups. Changes in pulmonary blood flow (PBF) and carotid blood flow (CBF) did not differ significantly between groups. PBF increased significantly after ventilation onset in both groups (caffeine p = 0.022, saline p <0.001) and remained elevated thereafter. CBF did not increase but decreased after SI in the caffeine group. Blood pressure, heart rate, and peripheral oxygen saturation did not differ between groups at any stage of the study. CONCLUSION: Prenatal caffeine infusion had no significant effect on acute haemodynamic parameters in ventilated preterm lambs during the cardiorespiratory transition. PMID- 29995943 TI - Evaluation of pemetrexed and etoposide as therapeutic regimens for human papillomavirus-positive oral and oropharyngeal cancer. AB - Although human papillomavirus (HPV) positive oral and oropharyngeal cancers have distinct epidemiologic and molecular characteristics compared to HPV-negative cancers, all patients with oral and oropharyngeal cancers received same standard regimen regardless of HPV status. For these reasons, specific regimens for patients with HPV-positive oral and oropharyngeal cancer are needed. Differentially expressed genes (DEG) between HPV-positive and HPV-negative oropharyngeal cancers were re-analyzed and categorized from public database. Then, druggable targets to HPV-positive oral and oropharyngeal cancer were identified and were validated with E6/E7, which is oncogene of HPV, transfected oral and oropharyngeal cancer cell lines and HPV infected cell lines. In DEG analysis, HPV-positive oral and oropharyngeal cancer showed distinct disease entity from HPV-negative cancers. Unlike HPV-negative oral and oropharyngeal cancer, thymidylate synthase (TS) and topoisomerase II (Topo II) were overexpressed in HPV-positive cancers. Transfection of Lenti-virus containing E6/ E7 to HPV-negative oral and oropharyngeal cancer cells induced upregulation of TS and Topo II in those cells. Although cisplatin, which is standard regimen in head and neck cancers, showed more effectiveness in HPV-negative cells, 5-FU and pemetrexed, which are TS inhibitors, or etoposide, which is Topo II inhibitors, worked more effectively in HPV-positive cells. In addition, cisplatin/etoposide and cisplatin/pemetrexed combination regimens showed synergic effects in HPV positive cells. Pemetrexed or etoposide alone, or in combination with other chemotherapeutic agents such as cisplatin, can be used as novel substitutes in a regimen of concurrent chemoradiotherapy or a palliative regimen for HPV-positive oral and oropharyngeal cancer patients. However, a well-designed clinical trial is needed. PMID- 29995945 TI - Characterization of a soybean (Glycine max L. Merr.) germplasm collection for root traits. AB - Root systems that improve resource uptake and penetrate compacted soil (hardpan) are important for improving soybean (Glycine max L. Merr.) productivity in optimal and sub-optimal environments. The objectives of this research were to evaluate a soybean germplasm collection of 49 genotypes for root traits, determine whether root traits are related with plant height, shoot dry weight, chlorophyll index, and seed size, and identify genotypes that can penetrate a hardpan. Plants were maintained under optimal growth conditions in a greenhouse. Single plants were grown in mesocosms, constructed of two stacked columns (top and bottom columns had 25 and 46 cm height, respectively, and 15 cm inside diameter) with a 2-cm thick wax layer (synthetic hardpan; penetration resistance, 1.5 MPa at 30 degrees C) in between. Plants were harvested at 42 days after planting. Significant genetic variability was observed for root traits in the soybean germplasm collection, and genotypes that penetrated the synthetic hardpan were identified. Genotypes NTCPR94-5157, NMS4-1-83, and N09-13128 were ranked high and PI 424007 and R01-581F were ranked low for most root traits. Shoot dry weight and chlorophyll index were positively related with total root length, surface area, and volume, and fine root length (Correlation coefficient, r >= 0.60 and P-value < 0.0001 for shoot dry weight and r >= 0.37 and P-value < 0.01 for chlorophyll index]. Plant height was negatively correlated with total root surface area, total root volume, and average root diameter (|r| >= 0.29, P-value < 0.05). Seed size was not correlated with any root traits. The genetic variability identified in this research for root traits and penetration are critical for soybean improvement programs in choosing genotypes with improved root characteristics to increase yield in stressful or optimum environments. PMID- 29995946 TI - Analytical "bake-off" of whole genome sequencing quality for the Genome Russia project using a small cohort for autoimmune hepatitis. AB - A comparative analysis of whole genome sequencing (WGS) and genotype calling was initiated for ten human genome samples sequenced by St. Petersburg State University Peterhof Sequencing Center and by three commercial sequencing centers outside of Russia. The sequence quality, efficiency of DNA variant and genotype calling were compared with each other and with DNA microarrays for each of ten study subjects. We assessed calling of SNPs, indels, copy number variation, and the speed of WGS throughput promised. Twenty separate QC analyses showed high similarities among the sequence quality and called genotypes. The ten genomes tested by the centers included eight American patients afflicted with autoimmune hepatitis (AIH), plus one case's unaffected parents, in a prelude to discovering genetic influences in this rare disease of unknown etiology. The detailed internal replication and parallel analyses allowed the observation of two of eight AIH cases carrying a rare allele genotype for a previously described AIH associated gene (FTCD), plus multiple occurrences of known HLA-DRB1 alleles associated with AIH (HLA-DRB1-03:01:01, 13:01:01 and 7:01:01). We also list putative SNVs in other genes as suggestive in AIH influence. PMID- 29995948 TI - Correction: Successful re-establishment of a rabbit population from embryos vitrified 15 years ago: The importance of biobanks in livestock conservation. AB - [This corrects the article DOI: 10.1371/journal.pone.0199234.]. PMID- 29995947 TI - Feasibility and effects of intra-dialytic low-frequency electrical muscle stimulation and cycle training: A pilot randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Exercise capacity is reduced in chronic kidney failure (CKF). Intra-dialytic cycling is beneficial, but comorbidity and fatigue can prevent this type of training. Low-frequency electrical muscle stimulation (LF EMS) of the quadriceps and hamstrings elicits a cardiovascular training stimulus and may be a suitable alternative. The main objectives of this trial were to assess the feasibility and efficacy of intra-dialytic LF-EMS vs. cycling. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Assessor blind, parallel group, randomized controlled pilot study with sixty-four stable patients on maintenance hemodialysis. Participants were randomized to 10 weeks of 1) intra-dialytic cycling, 2) intra-dialytic LF-EMS, or 3) non-exercise control. Exercise was performed for up to one hour three times per week. Cycling workload was set at 40 60% oxygen uptake (VO2) reserve, and LF-EMS at maximum tolerable intensity. The control group did not complete any intra-dialytic exercise. Feasibility of intra dialytic LF-EMS and cycling was the primary outcome, assessed by monitoring recruitment, retention and tolerability. At baseline and 10 weeks, secondary outcomes including cardio-respiratory reserve, muscle strength, and cardio arterial structure and function were assessed. RESULTS: Fifty-one (of 64 randomized) participants completed the study (LF-EMS = 17 [77%], cycling = 16 [80%], control = 18 [82%]). Intra-dialytic LF-EMS and cycling were feasible and well tolerated (9% and 5% intolerance respectively, P = 0.9). At 10-weeks, cardio respiratory reserve (VO2 peak) (Difference vs. control: LF-EMS +2.0 [95% CI, 0.3 to 3.7] ml.kg-1.min-1, P = 0.02, and cycling +3.0 [95% CI, 1.2 to 4.7] ml.kg 1.min-1, P = 0.001) and leg strength (Difference vs. control: LF-EMS, +94 [95% CI, 35.6 to 152.3] N, P = 0.002 and cycling, +65.1 [95% CI, 6.4 to 123.8] N, P = 0.002) were improved. Arterial structure and function were unaffected. CONCLUSIONS: Ten weeks of intra-dialytic LF-EMS or cycling improved cardio respiratory reserve and muscular strength. For patients who are unable or unwilling to cycle during dialysis, LF-EMS is a feasible alternative. PMID- 29995949 TI - Duration of exclusive breastfeeding may be related to eating behaviour and dietary intake in obesity prone normal weight young children. AB - Infants who are breastfed are introduced to a variety of flavours from the maternal milk, and thus the transition from maternal milk to complementary foods may be easier for these children. The aim of this study was to investigate if duration of exclusive breastfeeding was associated with pickiness or dietary intake of vegetables, fruit, starchy foods or sugar sweetened beverages among obesity prone normal weight children aged 2-6 years. This cohort study was based on data from the Healthy Start primary intervention study, the Danish Medical Birth registry and the Danish Health Visitor's Child Health Database. Infant feeding was registered by health nurses while home-visiting the mother and child up to four times within the first year. Information on eating behaviour and diet intake at age 2-6 years was obtained by parents. Crude and adjusted logistic and general linear regression models were used to investigate associations. A total of 236 children had complete information on all variables. Data showed lower odds of picky eating behaviour when exclusively breastfed until age 4-5 months compared to exclusively breastfed for 0-1 months (OR = 0.35, 95CI = 0.16;0.76, p = 0.008). In the crude analysis only, exclusively breastfed until age 6-10 months was associated with a higher daily intake of vegetables (p = 0.04). This study suggests that exclusive breastfeeding duration seems to influence pickiness and may contribute to facilitate the consumption of more vegetables in later childhood in obesity prone normal weight children. PMID- 29995950 TI - VEGFC/VEGFR3 axis mediates TGFbeta1-induced epithelial-to-mesenchymal transition in non-small cell lung cancer cells. AB - In the tumor progression, transforming growth factor beta1 (TGFbeta1) plays a critical role in tumorigenesis as well as metastasis. It is known that high plasma level of TGFbeta1 in patients with advanced non-small cell lung cancer (NSCLC) is correlated with poor prognostics. In addition, the generation of cancer stem-like cells is associated with metastasis, drug resistance, and tumor recurrence, which also lead to poor outcomes in NSCLC patients. However, it remains unclear how TGFbeta1 promotes NSCLC cells to acquire stem-like properties and accelerate tumor metastasis. In our study, we found that short term TGFbeta1 treatment resulted in a significant epithelial-mesenchymal transition (EMT) morphological change in TGFbeta1-sensitive NSCLC cells but not in insensitive cells. Western blotting confirmed increased Vimentin and reduced E-Cadherin protein expression after TGFbeta1 treatment in A549, NCI-H1993, and NCI-H358 cells. TGFbeta1 incubation dramatically decreased in vitro cell proliferation and increased cell invasion in TGFbeta1-sensitive NSCLC cells but not in NCI-H1975, NCI-H1650, and HCC827 cells. Moreover, TGFbeta1 was able to enhance the mRNA expression of Oct4, Nanog and Sox2 and drastically increased anchorage independent colony formation in TGFbeta1-sensitive NSCLC cells, suggesting the acquisition of cancer stem-like properties. Interestingly, we found that vascular endothelial growth factor receptor 3 (VEGFR3) mRNA expression was significantly elevated in TGFbeta1-sensitive NSCLC cells compared to insensitive cells. And TGFbeta1 was capable of inducing VEGF-C gene expression. Pharmacological blocking TGFbeta type I receptor kinase (ALK5) significantly inhibited TGFbeta1-induced VEGF-C expression. Silencing of ALK5 by siRNA also dramatically reduced TGFbeta1 induced VEGF-C expression in TGFbeta1-sensitive NSCLC cells. Therefore, TGFbeta1 contributes for NSCLC metastasis through promoting EMT, generation of high invasive cancer cells with stem-like properties, and increasing VEGF-C expression. Blocking TGFbeta pathway is a potential therapeutic target in human non-small cell lung cancer. PMID- 29995951 TI - Association between head injury and concussion with retinal vessel caliber. AB - The adverse long-term consequences following traumatic brain injury are poorly understood, particularly on the cerebral microvasculature. Retinal vessels are a surrogate marker of cerebral vascular changes. We therefore aimed to examine the cross-sectional association between serious head injury or being knocked unconscious, and/or concussion and retinal microvascular signs, specifically, mean retinal arteriolar and venular calibre, in older adults after accounting for potential confounders. This cohort study involved 2,624 adults with mean age of 66.9 (+/-9.1) years who self-reported head injury and concussion parameters, and had gradable retinal photographs. Face-to-face interviews with trained interviewers allowed participants to report prior serious head injury or being knocked unconscious, and/or a previous diagnosis of concussion by a medical professional. Fundus photographs were taken and retinal vascular calibre measured using computer-assisted techniques and summarized. There were 25.9%, 15.3% and 10.1% who reported a prior serious head injury or being "knocked unconscious", concussion, and both, respectively. Participants in the first group compared to non-injured participants had significantly wider (~2 MUm) mean retinal venular calibre (p = 0.02), after adjusting for age, sex, smoking, body mass index, mean arterial blood pressure, type 2 diabetes and fellow vessel calibre. No significant associations were observed in people reporting medically diagnosed concussion or with mean retinal arteriolar calibre. Our exploratory study suggests that head injury is independently associated with wider retinal venular caliber. These findings warrant further investigation in longitudinal cohort studies. PMID- 29995952 TI - The effects of beetroot juice supplementation on exercise economy, rating of perceived exertion and running mechanics in elite distance runners: A double blinded, randomized study. AB - PURPOSE: Nitrate-rich beetroot juice supplementation has been extensively used to increase exercise economy in different populations. However, its use in elite distance runners, and its potential effects on biomechanical aspects of running have not been properly investigated. This study aims to analyze the potential effects of 15 days of beetroot juice supplementation on physiological, psychological and biomechanical variables in elite runners. METHODS: Twelve elite middle and long-distance runners (age = 26.3 +/- 5.1yrs, VO2Max = 71.8+/-5.2 ml*kg-1*min-1) completed an incremental running test to exhaustion on a treadmill before and after a 15-days supplementation period, in which half of the group (EG) consumed a daily nitrate-rich beetroot juice and the other group (PG) consumed a placebo drink. Time to exhaustion (TEx), running economy, vastus lateralis oxygen saturation (SmO2), leg stiffness and rate of perceived exertion (RPE) were measured at 15, 17.1 and 20 km/h during the incremental test. RESULTS: Likely to very likely improvements in EG were observed for the RPE (Standardized mean difference (SMD) = -2.17, 90%CI = -3.23, -1.1), SmO2 (SMD = 0.72, 90%CI = 0.03, 1.41) and TEx (SMD = 1.18, 90%CI = -0.14, 2.5) in comparison with PG. No other physiological or biomechanical variable showed substantial improvements after the supplementation period. CONCLUSIONS: Fifteen days of nitrate-rich beetroot juice supplementation produced substantial improvements in the time to exhaustion in elite runners; however, it didn't produce meaningful improvements in running economy, VO2Max or mechanical parameters. PMID- 29995953 TI - Field evaluation of a real time loop-mediated isothermal amplification assay (RealAmp) for malaria diagnosis in Cruzeiro do Sul, Acre, Brazil. AB - Conventional molecular methods, such as nested polymerase chain reaction (PCR), are very sensitive for detection of malaria parasites, but require advanced laboratory equipment and trained personnel. Real-time loop-mediated isothermal amplification (RealAmp), a loop-mediated isothermal amplification-based molecular tool (LAMP), facilitates rapid target amplification at a single temperature setting, reducing the need for sophisticated equipment. We evaluated the performance of a field-adapted RealAmp assay for malaria diagnosis in Cruzeiro do Sul, Acre State, Brazil, a remote area in Brazil with limited laboratory capabilities. We enrolled 1,000 patients with fever (axillary temperature >= 37.5 C) or history of fever in last 24 h presenting for malaria diagnosis from February through June 2015. DNA was extracted from dried blood spots using a boil and spin method (heat treatment) at the sample processing site, and also using commercial kits at a Brazilian national reference laboratory. RealAmp was performed for Plasmodium genus, P. falciparum, and P. vivax identification. In addition, Giemsa-stained blood smears were prepared and examined by two independent well-trained study microscopists. A combination of Real-time PCR and nested PCR was used as reference test. The sensitivity and specificity of RealAmp in the field site laboratory were 94.1% (95% confidence interval [CI]: 90.1-96.8) and 83.9% (95% CI: 81.1-86.4), respectively. The sensitivity and specificity of local microscopy were 87.7% (95% CI: 82.6-91.7) and 98.9% (95% CI: 97.8-99.4), respectively, while study microscopy showed sensitivity of 96.4% (95% CI: 93.0 98.4) and specificity of 98.2% (95% CI: 97.0-99.0). None of the three tests detected 20 P. falciparum and P. vivax mixed infections identified by the reference test. Our findings highlight that it is possible to implement simple molecular tests in facilities with limited resources such as Cruzeiro do Sul in Brazil. RealAmp sensitivity was similar to that of microscopy performed by skilled professionals; both RealAmp and study microscopy performed poorly in detection of mixed infection. Attempts to develop and evaluate simpler molecular tools should continue, especially for the detection of malaria infection in remote areas. PMID- 29995955 TI - Cross-platform and cross-interaction study of user personality based on images on Twitter and Flickr. AB - Assessing the predictive value of different social media platforms is important to understand the variation in how users reveal themselves across multiple platforms. Most social media platforms allow users to interact in multiple ways: by posting content to the platform, liking others' posts, or building a user profile. While prior studies offer insights into how language use differs across platforms, differences in image usage is less well understood. In this study, we analyzed variation in image content with user personality across three interaction types (posts, likes and profile images) and two platforms, using a unique data set of users who are active on both Twitter and Flickr. Usage patterns on these two social media platforms revealed different aspects of users' personality. Cross-platform data fusion is thus shown to improve personality prediction performance. PMID- 29995954 TI - Selected HLA-B allotypes are resistant to inhibition or deficiency of the transporter associated with antigen processing (TAP). AB - Major histocompatibility complex class I (MHC-I) molecules present antigenic peptides to CD8+ T cells, and are also important for natural killer (NK) cell immune surveillance against infections and cancers. MHC-I molecules are assembled via a complex assembly pathway in the endoplasmic reticulum (ER) of cells. Peptides present in the cytosol of cells are transported into the ER via the transporter associated with antigen processing (TAP). In the ER, peptides are assembled with MHC-I molecules via the peptide-loading complex (PLC). Components of the MHC-I assembly pathway are frequently targeted by viruses, in order to evade host immunity. Many viruses encode inhibitors of TAP, which is thought to be a central source of peptides for the assembly of MHC-I molecules. However, human MHC-I (HLA-I) genes are highly polymorphic, and it is conceivable that several variants can acquire peptides via TAP-independent pathways, thereby conferring resistance to pathogen-derived inhibitors of TAP. To broadly assess TAP-independent expression within the HLA-B locus, expression levels of 27 frequent HLA-B alleles were tested in cells with deficiencies in TAP. Approximately 15% of tested HLA-B allotypes are expressed at relatively high levels on the surface of TAP1 or TAP2-deficient cells and occur in partially peptide-receptive forms and Endoglycosidase H sensitive forms on the cell surface. Synergy between high peptide loading efficiency, broad specificity for peptides prevalent within unconventional sources and high intrinsic stability of the empty form allows for deviations from the conventional HLA-I assembly pathway for some HLA-B*35, HLA-B*57 and HLA-B*15 alleles. Allotypes that display higher expression in TAP-deficient cells are more resistant to viral TAP inhibitor induced HLA-I down-modulation, and HLA-I down-modulation-induced NK cell activation. Conversely, the same allotypes are expected to mediate stronger CD8+ T cell responses under TAP-inhibited conditions. Thus, the degree of resistance to TAP inhibition functionally separates specific HLA-B allotypes. PMID- 29995956 TI - Correction: The economic burden of inpatient care of depression in Poznan (Poland) and Kiel (Germany) in 2016. AB - [This corrects the article DOI: 10.1371/journal.pone.0198890.]. PMID- 29995957 TI - Baseline predictors of antiretroviral treatment failure and lost to follow up in a multicenter countrywide HIV-1 cohort study in Ethiopia. AB - BACKGROUND: Antiretroviral therapy (ART) has been rapidly scaled up in Ethiopia since 2005, but factors influencing the outcome are poorly studied. We therefore analysed baseline predictors of first-line ART outcome after 6 and 12 months. MATERIAL AND METHODS: 874 HIV-infected patients, who started first-line ART, were enrolled in a countrywide prospective cohort. Two outcomes were defined: i) treatment failure: detectable viremia or lost-to-follow-up (LTFU) (confirmed death, moved from study sites or similar reasons); ii) LTFU only. Using stepwise logistic regression, four multivariable models identified baseline predictors for odds of treatment failure and LTFU. RESULTS: The treatment failure rates were 23.3% and 33.9% at 6 and 12 months, respectively. Opportunistic infections (OI), tuberculosis (TB), CD4 cells <50/MUl, and viral load >5 log10 copies/ml increased the odds of treatment failure both at 6 and 12 months. The odds of LTFU at month 6 increased with baseline functional disabilities, WHO stage III/IV, and CD4 cells <50/MUl. TB also increased the odds at month 12. Importantly, ART outcome differed across hospitals. Compared to the national hospital in Addis Ababa, patients from most regional sites had higher odds of treatment failure and/or LTFU at month 6 and/or 12, with the exception of one clinic (Jimma), which had lower odds of failure at month 6. CONCLUSIONS: In this first countrywide Ethiopian HIV cohort, a high ART failure rate was identified, to the largest extent due to LTFU, including death. The geographical region where the patients were treated was a strong baseline predictor of ART failure. The difference in ART outcome across hospitals calls the need for provision of more national support at regional level. PMID- 29995959 TI - Canine filariasis in the Amazon: Species diversity and epidemiology of these emergent and neglected zoonoses. AB - Dirofilaria immitis and Acanthocheilonema reconditum are common parasites in dogs but have also been reported parasitizing humans. The differential diagnosis and epidemiological evaluation of these zoonoses are important to the development of efficient public health policies and control strategies. The purpose of this study was to carry out an epidemiological survey by using molecular methods for the specific identification of filarid parasites of domestic dogs in the Marajo mesoregion, State of Para (PA), Brazil. A total of 418 canine blood samples from Marajo mesoregion (Northern Brazil) were collected, submitted to DNA extraction, polymerase chain reaction (PCR) with "pan filarial" primer, subsequent sequencing and sequence analysis using BLASTn software comparison with previously deposited sequences in GenBank. After that, a phylogenetic analysis by Maximum Parsimony was performed to aid the specific diagnosis. The obtained sequences showed the occurrence of 9 (2.15%) dogs infected with D. immitis and 30 (7.18%) by A. reconditum, with a confidence interval of 95%, there were no cases of co infection. We observed that male dogs were more likely to D. immits and A. reconditum infection. However, age was not significant to both infections. This study reports for the first time the occurrence of A. reconditum in the northern region of Brazil and confirmed the presence of D. immitis in the Marajo mesoregion. PMID- 29995960 TI - Three-dimensional behavioural phenotyping of freely moving C. elegans using quantitative light field microscopy. AB - Behavioural phenotyping of model organisms is widely used to investigate fundamental aspects of organism biology, from the functioning of the nervous system to the effects of genetic mutations, as well as for screening new drug compounds. However, our capacity to observe and quantify the full range and complexity of behavioural responses is limited by the inability of conventional microscopy techniques to capture volumetric image information at sufficient speed. In this article we describe how combining light field microscopy with computational depth estimation provides a new method for fast, quantitative assessment of 3D posture and movement of the model organism Caenorhabditis elegans (C. elegans). We apply this technique to compare the behaviour of cuticle collagen mutants, finding significant differences in 3D posture and locomotion. We demonstrate the ability of quantitative light field microscopy to provide new fundamental insights into C. elegans locomotion by analysing the 3D postural modes of a freely swimming worm. Finally, we consider relative merits of the method and its broader application for phenotypic imaging of other organisms and for other volumetric bioimaging applications. PMID- 29995961 TI - Improving preservation state assessment of carbonate microfossils in paleontological research using label-free stimulated Raman imaging. AB - In micropaleontological and paleoclimatological studies based on microfossil morphology and geochemistry, assessing the preservation state of fossils is of the highest importance, as diagenetic alteration invalidates textural features and compromises the correct interpretation of stable isotope and trace elemental analysis. In this paper, we present a novel non-invasive and label-free tomographic approach to reconstruct the three-dimensional architecture of microfossils with submicron resolution based on stimulated Raman scattering (SRS). Furthermore, this technique allows deciphering the three-dimensional (3D) distribution of the minerals within these fossils in a chemically sensitive manner. Our method, therefore, allows to identify microfossils, to chemically map their internal structure and eventually to determine their preservation state. We demonstrate the effectiveness of this method by analyzing several benthic and planktonic foraminifera, obtaining full 3D distributions of carbonate, iron oxide and porosity for each specimen. Subsequently, the preservation state of each microfossil can be assessed using these 3D compositional maps. The technique is highly sensitive, non-destructive, time-efficient and avoids the need for sample pretreatment. Therefore, its predestined application is the final check of the state of microfossils before applying subsequent geochemical analyses. PMID- 29995962 TI - Dysbiosis in the oral bacterial and fungal microbiome of HIV-infected subjects is associated with clinical and immunologic variables of HIV infection. AB - BACKGROUND: The effect of smoking on microbial dysbiosis and the potential consequence of such shift on markers of HIV disease is unknown. Here we assessed the relationship of microbial dysbiosis with smoking and markers of HIV disease. METHODS: Oral wash was collected from: (1) HIV-infected smokers (HIV-SM, n = 48), (2) HIV-infected non-smokers (HIV-NS, n = 24), or (3) HIV-uninfected smokers (UI SM, n = 24). Microbial DNA was extracted and their bacterial and fungal microbiota (bacteriome and mycobiome, respectively) were characterized using Ion Torrent sequencing platform. Sequencing data were compared using clustering, diversity, abundance and inter-kingdom correlations analyses. RESULTS: Bacteriome was more widely dispersed than mycobiome, there was no noticeable difference in clustering between groups. Richness of oral bacteriome in HIV-SM was significantly lower than that of UI-SM (P <= .03). Diversity of HIV-NS was significantly lower than that of HIV-SM or UI-SM at phylum level (P <= .02). Abundance of Phylum Firmicutes was significantly decreased in HIV-NS compared to HIV-SM and UI-SM (P = .007 and .027, respectively), while abundance of Proteobacteria was significantly increased in HIV-NS compared to HIV-SM and UI-SM (P = .0005 and .011, respectively). Fungal phyla did not differ significantly between the three cohorts. Cumulative smoking was positively correlated with Facklamia but negatively with Enhydrobacter, and current alcohol use was negatively correlated with Geniculata. Bacteria Facklamia exhibited weakly positive correlation with longer PI duration (r = 0.094, P = 0.012), and a negative correlation with nadir CD4 count (r = -0.345; P = 0.004), while Granulicatella was negatively correlated with nadir CD4 count (r = -0.329; P = 0.007). Fungus Stemphylium correlated negatively with nadir CD4 (r = -0.323; P = 0.008). CONCLUSIONS: Dysbiosis of the oral microbiota is associated with clinical and immunologic variables in HIV-infected patients. PMID- 29995958 TI - Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis. AB - BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated. PMID- 29995964 TI - Integrative approach on Pharyngodonidae (Nematoda: Oxyuroidea) parasitic in reptiles: Relationship among its genera, importance of their diagnostic features, and new data on Parapharyngodon bainae. AB - The first integrative approach using sequences of two genes (18S and 28S rRNA) plus morphological and life history traits, was explored in Pharyngodonidae nematodes parasitic in reptiles. Additionally, first genetic characterization of Parapharyngodon bainae and new data on its morphology are given. This approach evaluated the phylogenetic relationships among genera within Pharyngodonidae, as well as the importance of their diagnostic morphological features. Specimens of P. bainae were collected from faecal pellets of the lizard Tropidurus torquatus in the State of Minas Gerais, Brazil. Nematodes were fixed for scanning electron microscopy and molecular procedures. Morphological observations revealed the accurate structures of cephalic end, of cloacal region in males, of vulva and eggs. Phylogenetic reconstructions were based upon four datasets: aligned sequences of the 18S, of the 28S, of both concatenated genes and of combined morphological and molecular datasets. Bayesian inference and maximum likelihood were performed to infer the phylogenies of molecular datasets and maximum parsimony to infer that of all-combined data. Pharyngodonid parasites of reptiles seem to configure two general monophyletic lineages, as previously assertions. Results also showed the monophyly of Spauligodon, Skrjabinodon and Parapharyngodon, as well as the clear separation between the latter and Thelandros. Combination of datasets improved nodal supports. Analysis of the all combined datasets revealed the importance of vulval position and egg morphology as phylogenetic informative traits. However, characters of male caudal morphology appear as are highly homoplastic, and seem to be product of convergent evolution or multiple losses of ancestral traits. The closely-related Thelandros and Parapharyngodon are kept valid and their diagnosis should be based upon the position of the operculum in eggs (terminal or subterminal, respectively). Some inconsistencies in the scarce molecular and morphological databases were noted. Thus, new genetic data is required for further conclusions and current database must be evaluated with attention. PMID- 29995963 TI - Prospective study of canine leptospirosis in shelter and stray dog populations: Identification of chronic carriers and different Leptospira species infecting dogs. AB - Dogs are highly susceptible to the leptospiral infection, notably stray and sheltered dogs. Unsanitary conditions often observed in dog shelters may predispose the introduction and spread of leptospires among sheltered populations, potentially increasing the chances for the inadvertent adoption of asymptomatically infected animals. The present work describes a longitudinal study using a multidisciplinary approach for the identification of chronically infected dogs and the characterization of potentially pathogenic strains circulating among stray and sheltered dog populations in Sao Paulo, Brazil. A total of 123 dogs from three populations were included. The initial evaluation consisted of blood and urine quantitative PCR testing (qPCR), the detection of specific antibodies by microscopic agglutination test (MAT), physical examination and hematological and serum biochemistry analyses. The qPCR-positive dogs were prospectively examined, and reevaluations also included culture from urine samples. Positive qPCR samples were subjected to 16S rRNA and secY gene phylogenetic analysis. The recovered strains were characterized by Multilocus Sequence Typing, polyclonal serogroup identification and virulence determination. Leptospiruria was detected in all populations studied (13/123), and phylogenetic analysis revealed that 10 dogs had L. interrogans infection. Three dogs (3/13) had L. santarosai infection. The secY phylogenetic analysis revealed that the L. santarosai sequences clustered separately from those obtained from other hosts. Ten leptospiruric dogs were reevaluated, and three dogs presented persistent leptospiruria, allowing culturing from two dogs. The strains were characterized as L. interrogans serogroup Canicola (virulent) and L. santarosai serogroup Sejroe (not virulent). Serum samples were retested by MAT using the DU92 and DU114 strains as antigens, and no increased seroreactivity was detected. Asymptomatic L. santarosai infection was observed in all populations studied, suggesting a possible role of dogs in the chain of transmission of this leptospiral species. The results suggest a genetic distinction between lineages of Brazilian L. santarosai maintained by dogs and other animal hosts. Our findings revealed that dogs could act as maintenance hosts for distinct pathogenic Leptospira, highlighting also that asymptomatically infected dogs can be inadvertently admitted and adopted in dog shelters, potentially increasing the risks of zoonotic transmission. PMID- 29995965 TI - Compositional, ultrastructural and nanotechnological characterization of the SMA strain of Saccharomyces pastorianus: Towards a more complete fermentation yeast cell analysis. AB - Nano scanning Auger microscopy (NanoSAM) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) have been used in materials science research for some time, but NanoSAM, in particular, has only recently been applied to biological specimens. Here, the first concurrent utilization of NanoSAM, TOF-SIMS and microscopic techniques for the examination of a standard beverage fermentation strain of Saccharomyces pastorianus uncovered the presence of intracellular networks of CO2 in fermenting cells. Respiring cells produced few bubbles and instead had large internal vacuolar structures. Transmission electron microscopy analysis also showed osmiophilic layers at the cell exterior of fermenting cells that became more prevalent with fermentation duration, while osmiophilic layers were largely absent in respiring cells. TOF-SIMS analysis showed a compositional difference at the exterior and interior of SMA cells and between fermenting and respiring cells. Fermenting cells also appeared to have different 3-OH oxylipin profiles compared to respiring cells based upon examination with immunofluorescence microscopy. The results of this work and further study using these materials science techniques will substantially enhance our understanding of the chemical, ultrastructural and metabolic changes that occur in fermentation yeasts. PMID- 29995968 TI - CTAB-assisted size controlled synthesis of SAPO-34 and its contribution toward MTO performance. AB - SAPO-34 shows higher light olefin selectivity in the reaction of methanol to olefin (MTO), but its small pore system implies diffusion limitations to bigger molecular products and results in coking too. To inhibit these limitations, sub micrometric sized SAPO-34 crystallites were successfully synthesized by a facile surfactant-assisted hydrothermal synthesis route, in which cetyltrimethylammonium bromide (CTAB) was used as a crystal growth inhibitor (CGI). It was found that the crystal size changes in the V shape with the increase in the amount of CTAB. The sub-micrometric sized sample (SP-0.02CTAB) was obtained when the molar ratio of CTAB to Al2O3 was 0.02 in a precursor gel. The SP-0.02CTAB catalyst presents excellent performance for the MTO reaction with 97.8% C2-C4 selectivity and 3 times longer lifetime than the conventional SAPO-34 sample (SP-Conv), which is attributed to its much higher surface area and enhanced acidity derived from the formation of the sub-micrometric sized crystallites. Further study about the appropriate time of CTAB addition demonstrates that CTAB can play its role as a crystal growth inhibitor effectively, only when it is added at the very initial stage of the crystallization process. PMID- 29995966 TI - The effect of blood sampling and preanalytical processing on human N-glycome. AB - Glycome modulations have been described in the onset and progression of many diseases. Thus, many studies have proposed glycans from blood glycoproteins as disease markers. Astonishingly, little effort has been given unraveling preanalytical conditions potentially influencing glycan analysis prior to blood biomarker studies. In this work, we evaluate for the first time the effect of hemolysis, storage and blood collection, but also influence of various times and temperatures between individual processing steps on the total N-glycome and on a glycan-biomarker score. Venous blood was collected from 10 healthy donors in 11 blood collection tubes with different additives, processed variously to obtain 16 preanalytical variables and N-glycans released from serum or plasma were analyzed by MALDI-TOF-MS and capillary electrophoresis coupled with fluorescence detection (CE-LIF) for the first time. Long time storage of deep frozen samples at -20 degrees C or -80 degrees C exerted only a minor influence on the glycome as demonstrated by CE-LIF. The N-glycome was very stable evidenced by MALDI-TOF when stored at 4 degrees C for at least 48 hours and blood collected in tubes devoid of additives. The glycome was stable upon storage after centrifugation and aliquoting, which is an important information considering future diagnostic applications. Hemolysis, however, negatively correlated with an established glycan score for ovarian cancer, when evaluated by MALDI-TOF-MS measurement by affecting relative intensities of certain glycans, which could lead to false negative / positive results in glycan biomarker studies. PMID- 29995970 TI - Formation of borata-alkene/iminium zwitterions by ynamine hydroboration. AB - The ynamine TMP-C[triple bond, length as m-dash]C-CH3 adds HB(C6F5)2 to give the unsaturated C2-bridged N/B FLP 5. Compound 5 shows the structural data indicating a marked participation of the zwitterionic mesomeric borata-alkene/iminium form. It splits dihydrogen at r.t. with Z- to E-isomerization at the central C[double bond, length as m-dash]C double bond. Hydroboration of the ynamine Me3Si-C[triple bond, length as m-dash]C-NiPr2 with HB(C6F5)2 yields a N/B FLP that shows a strongly distorted central C[double bond, length as m-dash]C double bond with a rotation of the planes of the substituent pairs at its ends by ca. 57 degrees . PMID- 29995971 TI - Procalcitonin in liver dysfunction - Dr Jekyll or Mr Hyde? AB - Serum procalcitonin (PCT) is a sensitive biomarker used for the diagnosis of infection and sepsis. PCT has also some toxic effects. It is not a proinflammatory stimulus, but may augment the inflammatory processes. High levels of PCT in sepsis may lead to hepatocyte necrosis and, as a result, to liver failure. The pathomechanism of the toxic effect of PCT is still unknown. The influence of liver function on PCT levels has not been studied yet. It is not sure whether the liver dysfunction affects the diagnostic and prognostic value of serum PCT levels. In patients with acute liver failure, the usefulness of PCT level determination remains controversial. Recent studies have shown a potential diagnostic benefit of PCT as a marker of infection in chronic liver diseases. In both groups there is still no consensus on the optimal cut-off value of PCT levels in order to exclude infection. In patients with liver disease, the serum PCT levels should be interpreted with caution, taking into consideration other factors affecting the PCT threshold. PMID- 29995972 TI - DNA Barcoding in Forensic Entomology - Establishing a DNA Reference Library of Potentially Forensic Relevant Arthropod Species. AB - Throughout the years, DNA barcoding has gained in importance in forensic entomology as it leads to fast and reliable species determination. High-quality results, however, can only be achieved with a comprehensive DNA barcode reference database at hand. In collaboration with the Bavarian State Criminal Police Office, we have initiated at the Bavarian State Collection of Zoology the establishment of a reference library containing arthropods of potential forensic relevance to be used for DNA barcoding applications. CO1-5P' DNA barcode sequences of hundreds of arthropods were obtained via DNA extraction, PCR and Sanger Sequencing, leading to the establishment of a database containing 502 high quality sequences which provide coverage for 88 arthropod species. Furthermore, we demonstrate an application example of this library using it as a backbone to a high throughput sequencing analysis of arthropod bulk samples collected from human corpses, which enabled the identification of 31 different arthropod Barcode Index Numbers. PMID- 29995973 TI - Physiology and central carbon metabolism of the gut bacterium Prevotella copri. AB - The human gut microbiota is a crucial factor for the host's physiology with respect to health and disease. Metagenomic shotgun sequencing of microbial gut communities revealed that Prevotella copri is one of the most important players in the gastrointestinal tract of many individuals. Because of the importance of this bacterium we analyzed the growth behavior and the central metabolic pathways of P. copri. Bioinformatic data, transcriptome profiling and enzyme activity measurements indicated that the major pathways are based on glycolysis and succinate production from fumarate. In addition, pyruvate can be degraded to acetate and formate. Electron transport phosphorylation depends on fumarate respiration with NADH and reduced ferredoxin as electron donors. In contrast to Bacteroides vulgatus, P. copri showed a more pronounced dependency on the addition of CO2 or bicarbonate for biomass formation, which is a remarkable difference between P. copri and Bacteroides spp. with important implication in the context of gut microbial competition. The analysis of substrate consumption and product concentrations from many P. copri cultures with different optical densities allowed a prediction of the carbon and electron flow in the central metabolism and a detailed calculation of growth yields as well as carbon and redox balances. PMID- 29995975 TI - Extracellular reduction of solid electron acceptors by Shewanella oneidensis. AB - Shewanella oneidensis is the best understood model organism for the study of dissimilatory iron reduction. This review focuses on the current state of our knowledge regarding this extracellular respiratory process and highlights its physiologic, regulatory and biochemical requirements. It seems that we have widely understood how respiratory electrons can reach the cell surface and what the minimal set of electron transport proteins to the cell surface is. Nevertheless, even after decades of work in different research groups around the globe there are still several important questions that were not answered yet. In particular, the physiology of this organism, the possible evolutionary benefit of some responses to anoxic conditions, as well as the exact mechanism of electron transfer onto solid electron acceptors are yet to be addressed. The elucidation of these questions will be a great challenge for future work and important for the application of extracellular respiration in biotechnological processes. PMID- 29995974 TI - A cluster of residues in the lipopolysaccharide exporter that selects substrate variants for transport to the outer membrane. AB - Most Gram-negative bacteria assemble lipopolysaccharides (LPS) on their surface to form a permeability barrier against many antimicrobials. LPS is synthesized at the inner membrane and then transported to the outer leaflet of the outer membrane. Although the overall LPS structure is conserved, LPS molecules can differ in composition at the species and strain level. Some bacteria also regulate when to modify phosphates on LPS at the inner membrane in order to become resistant to cationic antimicrobial peptides. The multi-protein Lpt trans envelope machine, which transports LPS from the inner to the outer membrane, must therefore handle a variety of substrates. The most poorly understood step in LPS transport is how the ATP-binding cassette LptB2 FG transporter extracts LPS from the inner membrane. Here, we define residue K34 in LptG as a site within the structural cavity of the Escherichia coli LptB2 FG transporter that interacts electrostatically with phosphates on unmodified LPS. Alterations to this residue cause transport defects that are suppressed by the activation of the BasSR two component signaling system, which results in modifications to the LPS phosphates. We also show this residue is part of a larger site in LptG that differentially contributes to the transport of unmodified and modified LPS. PMID- 29995976 TI - Bioremediation and microbial metabolism of benzo(a)pyrene. AB - The growing release of organic contaminants into the environment due to industrial processes has inevitably increased the incidence of their exposure to humans which often results in negative health effects. Microorganisms are also increasingly exposed to the pollutants, yet their diverse metabolic capabilities enable them to survive toxic exposure making these degradation mechanisms important to understand. Fungi are the most abundant microorganisms in the environment, yet less has been studied to understand their ability to degrade contaminants than in bacteria. This includes specific enzyme production and the genetic regulation which guides metabolic networks. This review intends to compare what is known about bacterial and fungal degradation of toxic compounds using benzo(a)pyrene as a relevant example. Most research is done in the context of using fungi for bioremediation, however, we intend to also point out how fungal metabolism may impact human health in other ways including through their participation in microbial communities in the human gut and skin and through inhalation of fungal spores. PMID- 29995977 TI - Carbon and oxygen isotope fractionations in tree rings reveal interactions between cambial phenology and seasonal climate. AB - We developed novel approaches for using the isotope composition of tree-ring subdivisions to study seasonal dynamics in tree-climate relations. Across a 30 year time series, the delta13 C and delta18 O values of the earlywood (EW) cellulose in the annual rings of Pinus ponderosa reflected relatively high intrinsic water-use efficiencies and high evaporative fractionation of 18 O/16 O, respectively, compared with the false latewood (FLW), summerwood (SW), and latewood (LW) subdivisions. This result is counterintuitive, given the spring origins of the EW source water and midsummer origins of the FLW, SW, and LW. With the use of the Craig-Gordon (CG), isotope-climate model revealed that the isotope ratios in all of the ring subdivision are explained by the existence of seasonal lags, lasting several weeks, between the initial formation of tracheids and the production of cellulosic secondary cell walls during maturation. In contrast to some past studies, modification of the CG model according to conventional methods to account for mixing of needle water between fractionated and nonfractionated sources did not improve the accuracy of predictions. Our results reveal new potential in the use of tree-ring isotopes to reconstruct past intra-annual tree climate relations if lags in cambial phenology are reconciled with isotope ratio observations and included in theoretical treatments. PMID- 29995978 TI - Effect of microRNA-186 on oxidative stress injury of neuron by targeting interleukin 2 through the janus kinase-signal transducer and activator of transcription pathway in a rat model of Alzheimer's disease. AB - Recent studies have proposed that microRNAs (miR) function as novel diagnostic and prognostic biomarkers and therapeutic targets in Alzheimer's disease (AD), a common disease among the elderly. In the current study, we aim to explore the effect of miR-186 on oxidative stress injury of neuron in rat models of AD with the involvement of the interleukin-2 (IL2) and the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. AD rat models were established, and dual-luciferase reporter assay and online software were used to confirm the targeting relationship between miR-186 and IL2. Immunohistochemistry was used evaluating the positive rate of IL2. Afterward, to define the role of miR-186 in AD, miR-186, IL2, and JAK-STAT related protein (JAK2, STAT3) expressions were quantified. Cell proliferation was measured by 3 (4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide, and cell apoptosis was detected by flow cytometry. We observed downregulated miR-186 and IL2 and upregulated JAK-STAT signaling pathway related genes in AD. The overexpression of miR-186 was shown to significantly promote cell proliferation while suppressing cell apoptosis along with the expression of the IL2 and JAK-STAT signaling pathway related protein. Collectively, the key findings obtained from the current study define the potential role of miR-186 as an inhibitor of AD development by downregulation of IL2 through suppression of the JAK-STAT signaling pathway. PMID- 29995979 TI - Gastrointestinal disease burden and mortality: A public hospital-based study from 2005 to 2014. AB - BACKGROUND AND AIM: Gastrointestinal (GI) diseases account for substantial morbidity, mortality, and health care utilization. This public hospital-based study assessed the incidence and time trend of hospitalization and mortality of major GI diseases over one decade. METHODS: We conducted an observational study using population-wide database managed by the Hong Kong Hospital Authority with a principal diagnosis of GI diseases defined by International Classification of Disease, 9th Revision, Clinical Modification coding. We measured age-standardized incidence of hospitalization, emergency admissions, multiple admissions, and in hospital mortality from 2005 to 2014 using Poisson regression. RESULTS: The annual incidence of hospitalization for GI diseases increased from 4713 to 5241 per 100 000 discharges (incidence rate ratio [IRR] = 1.004; 95% confidence interval [CI]: 1.003-1.005). GI infections and cancers showed the highest rates of hospitalization in 2014. Hospitalization for GI cancers (IRR = 1.014; 95% CI: 1.013-1.016) and non-infectious enterocolitis (IRR = 1.058; 95% CI: 1.055-1.061) increased, whereas peptic ulcer disease has decreased. Hospitalization for Crohn's disease showed the most significant rise (126%). Annual incidence of hospitalization for Clostridium difficile infections increased by fivefold (IRR = 1.221; 95% CI: 1.178-1.266), while a 66% reduction was observed for peptic ulcer bleeding (IRR = 0.894; 95% CI: 0.889-0.899). GI cancers had the highest in hospital mortality rate in 2014, especially colorectal cancer and gastric cancer. CONCLUSIONS: This study showed an increased hospitalization burden of GI cancers and Crohn's disease, and a reduction in overall mortality for GI diseases. These data provide insight into epidemiological changes of GI diseases in the 21st century and implications for hospital burden and need of resource re-allocation. PMID- 29995980 TI - Intercostal Neurolysis for The Treatment of Postsurgical Thoracic Pain: a Case Series. AB - INTRODUCTION: We investigated the possible role of intercostal surgical neurolysis in relieving chronic neuropathic pain refractory to other nonsurgical treatments in patients with postsurgical thoracic pain. METHODS: We retrospectively collected clinical data on patients referred to the Neurosurgery Unit of Policlinic Hospital of Milan. Ten patients (age range, 20-68 years) suffering from neuropathic pain for at least 2 months after thoracic surgery underwent intercostal neurolysis. RESULTS: Compared with preneurolysis, pain intensity decreased 1 month postneurolysis and remained stable 2 months postneurolysis (median score [interquartile range]: 8 [6-9] preneurolysis, 4 [3 5] 1 month after, and 3 [2-5] 2 months after, P < 0.001). Antiepileptic drugs for pain control decreased after neurolysis. DISCUSSION: Surgical intercostal neurolysis may be a promising therapeutic option in patients with chronic neuropathic pain associated with neurological deficits. Muscle Nerve 58: 671-675, 2018. PMID- 29995981 TI - Domino Insertion-Coupling Synthesis of Solid-State Luminescent Propynylidene Indolones. AB - The compound class of 3-arylpropynylidene indolones, key intermediates in consecutive three-component syntheses of various indole-based chromophores with peculiar emission characteristics, are readily synthesized by a domino insertion coupling synthesis with an electronically diverse substitution pattern in moderate to excellent yields. The title compounds are formed in E/Z-ratios from 100:0 to 0:100. Besides structure elucidation by NMR-spectroscopy and X-ray structure analysis, DFT calculations have been employed to rationalize the observed stereoselectivity. The photophysical properties of 3-arylpropynylidene indolones are characterized by intense, tunable, solid-state emission of N substituted derivatives as quantified for drop-cast films. The electronic ground state structure was corroborated by DFT and TD-DFT calculations, showing that gradient-corrected exchange and correlation PBE (Perdew-Burke-Ernzerhof) functionals can be successfully employed to correctly reproduce the observed absorption characteristics of merocyanine derivatives. The huge Stokes shifts strongly depend on the electronic substitution pattern as supported by Hammett Taft correlations. PMID- 29995982 TI - Differentiated adipose-derived stem cell cocultures for bone regeneration in RADA16-I in vitro. AB - Craniofacial defects can cause morbidness. Adipose-derived stem cells (ADSCs) have shown great promise for osteogeneration and vascularization; therefore cocultures of differentiated ADSCs are explored to increase bone and vessel formation. In this study, ADSCs were induced into osteogenic ADSCs (os-ADSCs) and endothelial ADSCs (endo-ADSCs) cells, which were then cocultured in variable proportions (os-ADSCs/endo-ADSCs = 2:1, 1:1, 1:2). The os-ADSCs in a ratio of 1:1 expressed more ALP, RUNX2 and COL-I, whereas VEGF, vWF and CD31 were upregulated in the endo-ADSCs of this group. Next generation RNA sequencing (RNA-seq) was performed to evaluate the molecular mechanisms of cocultured ADSCs. The os-ADSCs and endo-ADSCs interacted with each other during osteogenic and angiogenic differentiation, especially at the ratio of 1:1, and were regulated by vascular related genes, cell-mediated genes, bone-related genes and the transforming growth factor beta signaling pathway (TGF-beta), mitogen-activated protein kinase signaling pathway (MAPK) and wnt signaling pathway (Wnt). Angptl4, apoe, mmp3, bmp6, mmp13 and fgf18 were detected to be up-regulated, and cxcl12 and wnt5a were down-regulated. The results showed that the gene expression levels were consistent with that in RNA-seq. The cells were then seeded into self-assembling peptide RADA16-I scaffolds as cocultures (1:1) and monocultures (ADSCs, os-ADSCs, endo-ADSCs). The results showed that the cells of all groups grew and proliferated well on the scaffolds, and the cocultured group exhibited better osteogeneration and vascularization. In conclusion, cocultured os-ADSCs and endo ADSCs at the ratio of 1:1 showed strong osteogenic and angiogenic differentiation. There is a great potential for osteogenesis and vascularization by 3D culturing cells in a 1:1 ratio in self-assembling peptide RADA16-I scaffolds, which requires evaluation for bone regeneration in vivo. PMID- 29995983 TI - Biosynthesis of the yellow xanthomonadin pigments involves an ATP-dependent 3 hydroxybenzoic acid: acyl carrier protein ligase and an unusual type II polyketide synthase pathway. AB - Xanthomonadins are yellow pigments that are produced by the phytopathogen Xanthomonas campestris pv. campestris (Xcc). A pig cluster is responsible for xanthomonadin biosynthesis. Previously, Xcc4014 of the cluster was characterized as a bifunctional chorismatase that produces 3-hydroxybenzoic acid (3-HBA) and 4 HBA. In this study, genetic analysis identified 11 genes within the pig cluster to be essential for xanthomonadin biosynthesis. Biochemical and bioinformatics analysis suggest that xanthomonadins are synthesized via an unusual type II polyketide synthase pathway. Heterologous expression of the pig cluster in non xanthomonadin-producing Pseudomonas aeruginosa strain resulted in the synthesis of chlorinated xanthomonadin-like pigments. Further analysis showed that xanC encodes an acyl carrier protein (ACP) while xanA2 encodes a ATP-dependent 3 HBA:ACP ligase. Both of them act together to catalyse the formation of 3-HBA-S ACP from 3-HBA to initiate xanthomonadin biosynthesis. Finally, we showed that xanH encodes a FabG-like enzyme and xanK encodes a novel glycosyltransferase. Both xanH and xanK are not only required for xanthomonadin biosynthesis, but also required for the balanced biosynthesis of extracellular polysaccharides and DSF family quorum sensing signals. These findings provide us with a better understanding of xanthomonadin biosynthetic mechanisms and directly demonstrate the presence of extensive cross-talk among xanthomonadin biosynthetic pathways and other metabolic pathways. PMID- 29995984 TI - Visit, consume and quit: Patch quality affects the three stages of foraging. AB - Foraging is a three-stage process during which animals visit patches, consume food and quit. Foraging theory exploring relative patch quality has mostly focused on patch use and quitting decisions, ignoring the first crucial step for any forager: finding food. Yet, the decision to visit a patch is just as important as the decision to quit, as quitting theories can only be used if animals visit patches in the first place. Therefore, to better understand the foraging process and predict its outcomes, it is necessary to explore its three stages together. We used the common brushtail possum (Trichosurus vulpecula) as a model to investigate foraging decisions in response to food varying in quality. In particular, we tested whether patch nutritional quality affected the following: (1) patch visits; (2) behaviours at the patch during a foraging visit; and (3) patch quitting decisions (quantified using giving up density-GUD). Free ranging possums were presented with diets varying in nitrogen content and concomitantly volatile organic compound (VOC) composition at feeding stations in the wild. We found that possums were able to distinguish between different quality foods from afar, despite the location of the diets changed daily. Possums used VOC (i.e. odour cues) emitted by the diets to find and select patches from a distance. High-quality diets with higher protein and lower fibre were visited more often and for longer. Possums spent more time foraging on diets high in nutritional content, resulting in lower GUDs. Our study provides important quantitative evidence that foraging efficiency plays out during all the three stages of the foraging process (i.e. visit, consume and quit), and demonstrates the significance of considering all these stages together in future studies and foraging models. Sensory cues such as food odours play a critical role in helping foragers, including mammalian herbivores, find high-quality food. This allows foragers to make quick, accurate and important decisions about food patches well before patch quitting decisions come into play. PMID- 29995985 TI - LEAFY activity is post-transcriptionally regulated by BLADE ON PETIOLE2 and CULLIN3 in Arabidopsis. AB - The Arabidopsis LEAFY (LFY) transcription factor is a key regulator of floral meristem emergence and identity. LFY interacts genetically and physically with UNUSUAL FLORAL ORGANS, a substrate adaptor of CULLIN1-RING ubiquitin ligase complexes (CRL1). The functionally redundant genes BLADE ON PETIOLE1 (BOP1) and 2 (BOP2) are potential candidates to regulate LFY activity and have recently been shown to be substrate adaptors of CULLIN3 (CUL3)-RING ubiquitin ligases (CRL3). We tested the hypothesis that LFY activity is controlled by BOPs and CUL3s in plants and that LFY is a substrate for ubiquitination by BOP-containing CRL3 complexes. When constitutively expressed, LFY activity is fully dependent on BOP2 as well as on CUL3A and B to regulate target genes such as APETALA1 and to induce ectopic flower formation. We also show that LFY and BOP2 proteins interact physically and that LFY-dependent ubiquitinated species are produced in vitro in a reconstituted cell-free CRL3 system in the presence of LFY, BOP2 and CUL3. This new post-translational regulation of LFY activity by CRL3 complexes makes it a unique transcription factor subjected to a positive dual regulation by both CRL1 and CRL3 complexes and suggests a novel mechanism for promoting flower development. PMID- 29995986 TI - Real-Time Imaging of Ultrafast Charge Dynamics in Tetrafluoromethane from Attosecond Pump-Probe Photoelectron Spectroscopy. AB - A pump-probe experiment in the tetrafluoro-methane (CF4 ) molecule has been theoretically simulated, allowing one to access electron dynamics in its natural time scale: the attosecond. The chosen pump and probe pulses can be currently produced in most attosecond laboratories. In this scheme, CF4 is first ionized by an extreme UV (XUV) attosecond pulse and the charge dynamics induced in the corresponding cation is probed with a few-femtosecond visible light (VIS) pulse. We demonstrate that modulations in the calculated photoelectron spectra with the pump-probe delay reflect the dynamics of the XUV-induced electronic wave packet. In particular, from the analysis of these modulations in the interval of time delays where the pump and probe pulses do not overlap any more, one has access to the amplitudes and phases of the different components of the electronic wave packet generated by the attosecond pulse. These reflect a complex dynamics that basically consists of very fast charge fluctuations occurring all over the molecule without any preference for a particular molecular site. PMID- 29995987 TI - Fine-tuning cellular levels of DprA ensures transformant fitness in the human pathogen Streptococcus pneumoniae. AB - Natural genetic transformation is a widespread mechanism of horizontal gene transfer. It involves the internalization of exogenous DNA as single strands and chromosomal integration via homologous recombination, promoting acquisition of new genetic traits. Transformation occurs during a distinct physiological state called competence. In Streptococcus pneumoniae, competence is controlled by ComDE, a two-component system induced by an exported peptide pheromone. DprA is universal among transformable species, strongly induced during pneumococcal competence, and crucial for pneumococcal transformation. Pneumococcal DprA plays three crucial roles in transformation and competence. Firstly, DprA protects internalized DNA from degradation. Secondly, DprA loads the homologous recombinase RecA onto transforming DNA to promote transformation. Finally, DprA interacts with the response regulator ComE to shut-off competence. Here, we explored the effect of altering the cellular levels of DprA on these three roles. High cellular levels of DprA were not required for the primary role of DprA as a transformation-dedicated recombinase loader or for protection of transforming DNA. In contrast, full expression of dprA was required for optimal competence shut-off and transformant fitness. High cellular levels of DprA thus ensure the fitness of pneumococcal transformants by mediating competence shut-off. This promotes survival and propagation of transformants, maximizing pneumococcal adaptive potential. PMID- 29995988 TI - Crystal structure and acetylation of BioQ suggests a novel regulatory switch for biotin biosynthesis in Mycobacterium smegmatis. AB - Biotin (vitamin B7), a sulfur-containing fatty acid derivative, is a nutritional virulence factor in certain mycobacterial species. Tight regulation of biotin biosynthesis is important because production of biotin is an energetically expensive process requiring 15-20 equivalents of ATP. The Escherichia coli bifunctional BirA is a prototypical biotin regulatory system. In contrast, mycobacterial BirA is an unusual biotin protein ligase without DNA-binding domain. Recently, we established a novel two-protein paradigm of BioQ-BirA. However, structural and molecular mechanism for BioQ is poorly understood. Here, we report crystal structure of the M. smegmatis BioQ at 1.9 A resolution. Structure-guided functional mapping defined a seven residues-requiring motif for DNA-binding activity. Western blot and MALDI-TOF MS allowed us to unexpectedly discover that the K47 acetylation activates crosstalking of BioQ to its cognate DNA. More intriguingly, excess of biotin augments the acetylation status of BioQ in M. smegmatis. It seems likely that BioQ acetylation proceeds via a non enzymatic mechanism. Mutation of this acetylation site K47 in BioQ significantly impairs its regulatory role in vivo. This explains in part (if not all) why BioQ has no detectable requirement of the presumable bio-5'-AMP effecter, which is a well-known ligand for the paradigm E. coli BirA regulator system. Unlike the scenario seen with E. coli carrying a single biotinylated protein, AccB, genome wide search and Streptavidin blot revealed that no less than seven proteins require the rare post-translational modification, biotinylation in M. smegmatis, validating its physiological demand for biotin at relatively high level. Taken together, our finding defines a novel biotin regulatory machinery by BioQ, posing a possibility that development of new antibiotics targets biotin, the limited nutritional virulence factor in certain pathogenic mycobacterial species. PMID- 29995989 TI - Clobazam monotherapy for focal or generalized seizures. AB - BACKGROUND: This is an updated version of the original Cochrane Review published in Issue 10, 2014. There is a need to expand monotherapy options available to a clinician for the treatment of new focal or generalized seizures. A Cochrane systematic review for clobazam monotherapy is expected to define its place in the treatment of new-onset or untreated seizures and highlight gaps in evidence. OBJECTIVES: To evaluate the efficacy, effectiveness, tolerability and safety of clobazam as monotherapy in people with new-onset focal or generalized seizures. SEARCH METHODS: For the latest update we searched the following databases on 19 March 2018: the Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946- ), BIOSIS Previews (1969- ), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (ICTRP). There were no language restrictions. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials comparing clobazam monotherapy versus placebo or other anti-seizure medication in people with two or more unprovoked seizures or single acute symptomatic seizure requiring short-term continuous anti-seizure medication, were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Primary outcome measure was time on allocated treatment (retention time), reflecting both efficacy and tolerability. Secondary outcomes included short- and long-term effectiveness measures, tolerability, quality of life, and tolerance measures. Two authors independently extracted the data. MAIN RESULTS: We identified three trials fulfilling the review criteria, which included 206 participants. None of the identified studies reported the preselected primary outcome measure. A meta-analysis was not possible. Lack of detail regarding allocation concealment and a high risk of performance and detection bias in two studies prompted us to downgrade the quality of evidence (by using the GRADE approach) for some of our results due to risk of bias.Regarding retention at 12 months, we detected no evidence of a statistically significant difference between clobazam and carbamazepine (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.61 to 1.12; low-quality evidence). There was low-quality evidence that clobazam led to better retention compared with phenytoin (RR 1.43, 95% CI 1.08 to 1.90). We could not determine whether participants receiving clobazam were found to be less likely to discontinue it due to adverse effects as compared to phenytoin (RR 0.10, 95% CI 0.01 to 1.65, low-quality evidence). AUTHORS' CONCLUSIONS: We found no advantage for clobazam over carbamazepine for retention at 12 months in drug naive children and a slight advantage of clobazam over phenytoin for retention at six months in adolescents and adults with neurocysticercosis in a single clinical trial each. At present, the available evidence is insufficient to inform clinical practice. PMID- 29995991 TI - A partner-switching regulatory system controls hormogonium development in the filamentous cyanobacterium Nostoc punctiforme. AB - Filamentous cyanobacteria exhibit developmental complexity, including the transient differentiation of motile hormogonia in many species. Using a forward genetic approach, a trio of genes unique to filamentous cyanobacteria encoding a putative Rsb-like partner-switching regulatory system (PSRS) was implicated in regulating hormogonium development in the model filamentous cyanobacterium Nostoc punctiforme. Analysis of in-frame deletion strains indicated that HmpU (putative serine phosphatase) and HmpV (STAS domain) enhance, while HmpW (putative serine kinase) represses motility and persistence of the hormogonium state. Protein protein interaction studies demonstrated specificity between HmpW and HmpV. Epistasis analysis between hmpW and hmpV was consistent with HmpV acting as the downstream effector of the system, rather than regulation of a sigma factor by HmpW. Deletion of hmpU or hmpV reduced accumulation of extracellular PilA and hormogonium polysaccharide (HPS), and expression of type IV pilus- and HPS specific genes was reduced in the DeltahmpV strain. Expression of the Hmp PSRS is induced in hormogonia, and the cytoplasmic localization of HmpV-GFPuv implies that its downstream target is probably cytoplasmic as well. Collectively, these results support a model where HmpU and HmpW antagonistically regulate the phosphorylation state of HmpV, and subsequently, unphosphorylated HmpV positively regulates an undefined downstream target to affect hormogonium-specific gene expression. PMID- 29995990 TI - Aspartate deficiency limits peptidoglycan synthesis and sensitizes cells to antibiotics targeting cell wall synthesis in Bacillus subtilis. AB - Peptidoglycan synthesis is an important target for antibiotics and relies on intermediates derived from central metabolism. As a result, alterations of metabolism may affect antibiotic sensitivity. An aspB mutant is auxotrophic for aspartate (Asp) and asparagine (Asn) and lyses when grown in Difco sporulation medium (DSM), but not in LB medium. Genetic and physiological studies, supported by amino acid analysis, reveal that cell lysis in DSM results from Asp limitation due to a relatively low Asp and high glutamate (Glu) concentrations, with Glu functioning as a competitive inhibitor of Asp uptake by the major Glu/Asp transporter GltT. Lysis can be specifically suppressed by supplementation with 2,6-diaminopimelate (DAP), which is imported by two different cystine uptake systems. These studies suggest that aspartate limitation depletes the peptidoglycan precursor meso-2,6-diaminopimelate (mDAP), inhibits peptidoglycan synthesis, upregulates the cell envelope stress response mediated by sigmaM and eventually leads to cell lysis. Aspartate limitation sensitizes cells to antibiotics targeting late steps of PG synthesis, but not steps prior to the addition of mDAP into the pentapeptide sidechain. This work highlights the ability of perturbations of central metabolism to sensitize cells to peptidoglycan synthesis inhibitors. PMID- 29995992 TI - Connectivity of centermost chromatophores in Rhodobacter sphaeroides bacteria. AB - The size of whole Rhodobacter sphaeroides prevents 3D visualization of centermost chromatophores in their native environment. This study combines cryo-focused ion beam milling with cryo-electron tomography to probe vesicle architecture both in situ and in 3D. Developing chromatophores are membrane-bound buds that remain in topological continuity with the cytoplasmic membrane and detach into vesicles when mature. Mature chromatophores closest to the cell wall are typically isolated vesicles, whereas centermost chromatophores are either linked to neighboring chromatophores or contain smaller, budding structures. Isolated chromatophores comprised a minority of centermost chromatophores. Connections between vesicles in growing bacteria are through ~10 nm-long, ~5 nm-wide linkers, and are thus physical rather than functional in terms of converting photons to ATP. In cells in the stationary phase, chromatophores fuse with neighboring vesicles, lose their spherical structure, and greatly increase in volume. The fusion and morphological changes seen in older bacteria are likely a consequence of the aging process, and are not representative of connectivity in healthy R. sphaeroides. Our results suggest that chromatophores can adopt either isolated or connected morphologies within a single bacterium. Revealing the organization of chromatophore vesicles throughout the cell is an important step in understanding the photosynthetic mechanisms in R. sphaeroides. PMID- 29995993 TI - A Borrelia burgdorferi mini-vls system that undergoes antigenic switching in mice: investigation of the role of plasmid topology and the long inverted repeat. AB - Borrelia burgdorferi evades the host immune system by switching the surface antigen. VlsE, in a process known as antigenic variation. The DNA mechanisms and genetic elements present on the vls locus that participate in the switching process remain to be elucidated. Manipulating the vls locus has been difficult due to its instability on Escherichia coli plasmids. In this study, we generated for the first time a mini-vls system composed of a single silent vlsE variable region (silent cassette 2) through the vlsE gene by performing some cloning steps directly in a highly transformable B. burgdorferi strain. Variants of the mini system were constructed with or without the long inverted repeat (IR) located upstream of vlsE and on both circular and linear plasmids to investigate the importance of the IR and plasmid topology on recombinational switching at vlsE. Amplicon sequencing using PacBio long read technology and analysis of the data with our recently reported pipeline and VAST software showed that the system undergoes switching in mice in both linear and circular versions and that the presence of the hairpin does not seem to be crucial in the linear version, however it is required when the topology is circular. PMID- 29995994 TI - Genetic dissection of the secretory route followed by a fungal extracellular glycosyl hydrolase. AB - Hyphal tip cells of Aspergillus nidulans are > 100 um-long, which challenges intracellular traffic. In spite of the basic and applied interest of the secretory pathway of filamentous fungi, only recently has it been investigated in detail. We used InuA, an inducible and highly glycosylated inulinase, and mutations affecting different intracellular membranous compartments, to investigate the route by which the enzyme traffics to the extracellular medium. InuA is core-N-glycosylated in the ER and hyperglycosylated during transit across the Golgi. Hyperglycosylation was prevented by ts mutations in sarASAR1 impeding ER exit, and in sedVSED5 and rabORAB1 dissipating the early Golgi, but not by mutations in the TGN regulators hypATRS120 and hypBSEC7 , implicating the early Golgi in cargo glycosylation. podB1ts (cog2ts ) affecting the COG complex also prevents glycosylation, without disassembling early Golgi cisternae. That InuA exocytosis is prevented by inactivation of any of the above genes shows that it follows a conventional secretory pathway. However, ablation of RabBRAB5 regulating early endosomes (EEs), but not of RabSRAB7 , its equivalent in late endosomes, also prevents InuA accumulation in the medium, indicating that EEs are specifically required for InuA exocytosis. This work provides a framework to understand the secretion of enzyme cargoes by industrial filamentous fungi. PMID- 29995996 TI - Nuclear export-dependent degradation of the carbon catabolite repressor CreA is regulated by a region located near the C-terminus in Aspergillus oryzae. AB - Carbon catabolite repression (CCR) is regulated by the C2 H2 -type transcription factor CreA/Cre1 in filamentous fungi including Aspergillus oryzae. We investigated the stability and subcellular localization of CreA in A. oryzae. The abundance of FLAG-tagged CreA (FLAG-CreA) was dramatically reduced after incubation in maltose and xylose, which stimulated the export of CreA from the nucleus to the cytoplasm. Mutation of a putative nuclear export signal resulted in nuclear retention and significant stabilization of CreA. These results suggest that CreA is rapidly degraded in the cytoplasm after export from the nucleus. The FLAG-CreA protein level was reduced by disruption of creB and creC, which encode the deubiquitinating enzyme complex involved in CCR. In contrast, FLAG-CreA stability was not affected by disruption of creD which encodes an arrestin-like protein required for CCR relief. Deletion of the last 40 C-terminal amino acids resulted in remarkable stabilization and increased abundance of FLAG-CreA, whereas deletion of the last 20 C-terminal amino acids had no apparent effect on CreA stability. This result suggests that the 20 amino acid region located between positions 390 and 409 of CreA is critical for the rapid degradation of CreA. PMID- 29995995 TI - Gain-of-function variants of FtsA form diverse oligomeric structures on lipids and enhance FtsZ protofilament bundling. AB - Escherichia coli requires FtsZ, FtsA and ZipA proteins for early stages of cell division, the latter two tethering FtsZ polymers to the cytoplasmic membrane. Hypermorphic mutants of FtsA such as FtsA* (R286W) map to the FtsA self interaction interface and can bypass the need for ZipA. Purified FtsA forms closed minirings on lipid monolayers that antagonize bundling of FtsZ protofilaments, whereas FtsA* forms smaller oligomeric arcs that enable bundling. Here, we examined three additional FtsA*-like mutant proteins for their ability to form oligomers on lipid monolayers and bundle FtsZ. Surprisingly, all three formed distinct structures ranging from mostly arcs (T249M), a mixture of minirings, arcs and straight filaments (Y139D) or short straight double filaments (G50E). All three could form filament sheets at higher concentrations with added ATP. Despite forming these diverse structures, all three mutant proteins acted like FtsA* to enable FtsZ protofilament bundling on lipid monolayers. Synthesis of the FtsA*-like proteins in vivo suppressed the toxic effects of a bundling defective FtsZ, exacerbated effects of a hyper-bundled FtsZ, and rescued some thermosensitive cell division alleles. Together, the data suggest that conversion of FtsA minirings into any type of non-miniring oligomer can promote progression of cytokinesis through FtsZ bundling and other mechanisms. PMID- 29995997 TI - DcuA of aerobically grown Escherichia coli serves as a nitrogen shuttle (L aspartate/fumarate) for nitrogen uptake. AB - DcuA of Escherichia coli is known as an alternative C4 -dicarboxylate transporter for the main anaerobic C4 -dicarboxylate transporter DcuB. Since dcuA is expressed constitutively under aerobic and anaerobic conditions, DcuA was suggested to serve aerobically as a backup for the aerobic (DctA) transporter, or for the anabolic uptake of C4 -dicarboxylates. In this work, it is shown that DcuA is required for aerobic growth with L-aspartate as a nitrogen source, whereas for growth with L-aspartate as a carbon source, DctA was needed. Strains with DcuA catalyzed L-aspartate and C4 -dicarboxylate uptake (like DctA), or an L aspartate/C4 -dicarboxylate antiport (unlike DctA). DcuA preferred L-aspartate to succinate in transport (KM = 43 and 844 uM, respectively), whereas DctA has higher affinity for C4 -dicarboxylates like succinate compared to L-aspartate. When L-aspartate was supplied as the sole nitrogen source together with glycerol as the carbon source, L-aspartate was taken up by the bacteria and fumarate (or L malate) was excreted in equimolar amounts. Both reactions depended on DcuA. L Aspartate was taken up in amounts required for nitrogen metabolism but not for carbon metabolism. Therefore, DcuA catalyzes an L-aspartate/C4 -dicarboxylate antiport serving as a nitrogen shuttle for nitrogen supply without net carbon supply. PMID- 29995999 TI - Etiology of acute ischaemic cerebrovascular disease associated with rheumatoid arthritis: changes with progression of anti-inflammatory therapy. AB - BACKGROUND AND PURPOSE: In patients with rheumatoid arthritis (RA), the serum C reactive protein (CRP) level is associated with ischaemic cerebrovascular disease (iCVD). Acute iCVD patients with RA were investigated, assessing changes of clinical characteristics and CRP with progress in RA treatment. METHODS: Patients hospitalized for acute iCVD from August 2002 to February 2018 were divided into two groups at February 2010. Patients with RA were retrospectively identified. The incidence of RA, the occurrence of acute exacerbation of inflammation due to causes other than synovitis preceding iCVD (non-synovitis AEI) and serum CRP were compared. RESULTS: In the first and second periods, 23/1203 patients (1.9%) and 22/1094 patients (2.0%) respectively had acute iCVD with RA. Non-synovitis AEI was significantly less frequent in the second period (5%, n = 1) than in the first period (35%, n = 8) (P < 0.05). CRP was significantly lower at iCVD onset in the second period [median and interquartile range 2.72 (0.89-4.5) mg/dl vs. 0.34 (0.12-1.19) mg/dl, P < 0.01]. Excluding nine patients with non-synovitis AEI, CRP was still lower in the second period [1.21 (0.47-2.72) mg/dl vs. 0.33 (0.11-0.98) mg/dl, P < 0.01]. CRP levels before both iCVD and non-synovitis AEI tended to be lower in the second period [1.53 (0.3-2.78) mg/dl vs. 0.69 (0.06 1.28) mg/dl, P = 0.059]. Two patients using tocilizumab developed iCVD despite persistently low CRP levels. CONCLUSIONS: With progress in treatment, RA-related inflammation was better suppressed and CRP decreased, but the prevalence of RA amongst acute iCVD patients was unchanged. Strategies for tighter control of inflammation are needed, and a new biomarker may be required in patients using tocilizumab. PMID- 29995998 TI - ZomB is essential for flagellar motor reversals in Shewanella putrefaciens and Vibrio parahaemolyticus. AB - The ability of most bacterial flagellar motors to reverse the direction of rotation is crucial for efficient chemotaxis. In Escherichia coli, motor reversals are mediated by binding of phosphorylated chemotaxis protein CheY to components of the flagellar rotor, FliM and FliN, which induces a conformational switch of the flagellar C-ring. Here, we show that for Shewanella putrefaciens, Vibrio parahaemolyticus and likely a number of other species an additional transmembrane protein, ZomB, is critically required for motor reversals as mutants lacking ZomB exclusively exhibit straightforward swimming also upon full phosphorylation or overproduction of CheY. ZomB is recruited to the cell poles by and is destabilized in the absence of the polar landmark protein HubP. ZomB also co-localizes to and may thus interact with the flagellar motor. The DeltazomB phenotype was suppressed by mutations in the very C-terminal region of FliM. We propose that the flagellar motors of Shewanella, Vibrio and numerous other species harboring orthologs to ZomB are locked in counterclockwise rotation and may require interaction with ZomB to enable the conformational switch required for motor reversals. Regulation of ZomB activity or abundance may provide these species with an additional means to modulate chemotaxis efficiency. PMID- 29996000 TI - A systematic review and meta-analysis of rescue revascularization with arterial conduits in liver transplantation. AB - Although aortohepatic conduits (AHCs) provide an effective technique for arterialization in liver transplantation (LT) when the native recipient artery is unusable, various publications report higher occlusion rates and impaired outcome compared to conventional anastomoses. This systematic review and meta-analysis investigates the published evidence of outcome and risk of AHCs in LT using bibliographic databases and following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Primary and secondary outcome were artery occlusion as well as graft and patient survival. Twenty-three retrospective studies were identified with a total of 22 113 patients with LT, of whom 1900 patients (9%) received an AHC. An AHC was used in 33% of retransplantations. Early artery occlusion occurred in 7% (3%-16%) of patients with AHCs, compared to 2% (1%-3%) without conduit (OR 3.70; 1.63-8.38; P = .001). The retransplantation rate after occlusion was not significantly different in both groups (OR 1.46; 0.67-3.18; P = .35). Graft (HR 1.38; 1.17-1.63; P < .001) and patient (HR 1.57; 1.12-2.20; P = .009) survival was significantly lower in the AHC compared to the nonconduit group. In contrast, graft survival in retransplantations was comparable (HR 1.00; 0.82-1.22; P = .986). Although AHCs provide an important rescue option, when regular revascularization is not feasible during LT, transplant surgeons should be alert of the potential risk of inferior outcome. PMID- 29996001 TI - The Chemical Compositions of Angelica pubescens Oil and Its Prevention of UV-B Radiation-Induced Cutaneous Photoaging. AB - Angelica pubescens, a plant of the family Umbelliferae, has been widely used as traditional Chinese medicine for the treatment of many diseases. However, there has been minimal modern research focused on the pharmacological activity of oils extracted from Angelica pubescens, in particular, the potential anti-photoaging effects. Therefore, in the present study, we analyzed the chemical composition of Angelica pubescens oil (AO) and evaluated its bioactivity against photoaging in ultraviolet (UV) -B radiation-induced hairless mice. Overall, we identified and analyzed 93 compounds from the AO by gas chromatography-mass spectrometry (GC/MS). The top ten compounds were as follows: osthole (44.608%), glutaric acid hexadecyl pent-4-en-1-yl ester (5.758%), alpha-bisabolol (3.795%), eugenol (3.637%), (Z)-docos-13-enamide (3.286%), (3S,3aR)-3-butyl-3a,4,5,6-tetrahydro-3H 2-benzofuran-1-one (3.043%), m-cresol (2.841%), trans-sesquisabinene hydrate (2.128%), 4-hydroxy-2-methylacetophenone (1.735%), and (Z)-9-pentadecenol (1.509%). Application of AO improved the condition of UV-B radiation-induced damaged skin, and the mechanism of action was found to be related to inhibition of the production of inflammatory cytokines. These results highlight the potential application of AO for the development of skin care products. PMID- 29996002 TI - Study of the possible link of 25-hydroxyvitamin D with Epstein-Barr virus and human herpesvirus 6 in patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: Although the causes of multiple sclerosis (MS) remain partially unknown, environmental and genetic factors are thought to play a role in its aetiopathogenesis. Hypovitaminosis D, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) infections have been described as possible MS triggers. Our aim was to analyse the possible link between 25-hydroxyvitamin D [25(OH)D] and viruses in patients with MS. METHODS: We included 482 patients with MS in a 2 year study. Serum samples were collected to analyse 25(OH)D levels and, according to sample availability, antibody titres against EBV and HHV-6 by enzyme-linked immunosorbent assay. DNA was extracted from blood in order to analyse EBV and HHV 6 viral load by quantitative real-time polymerase chain reaction and to genotype MS-related single nucleotide polymorphisms (rs3135388, rs2248359 and rs12368653) when possible. RESULTS: The 25(OH)D levels were significantly higher in the first semester of the year than in the second. Carriers of the risk allele rs2248359-C showed lower 25(OH)D levels than non-carriers. For EBV, viral load was significantly higher when 25(OH)D levels were low, demonstrating an inverse correlation between 25(OH)D levels and EBV load. CONCLUSIONS: The 25(OH)D levels could be involved in the regulation of EBV replication/reactivation in patients with MS. PMID- 29996003 TI - Clinical follow-up of 411 patients with relapsing and progressive multiple sclerosis 10 years after discontinuing mitoxantrone treatment: a real-life cohort study. AB - BACKGROUND AND PURPOSE: Mitoxantrone (MITOX) has been used to treat patients with aggressive multiple sclerosis (MS) for decades. We aimed to describe the effectiveness and adverse events over 10 years post-MITOX in patients with relapsing and progressive MS from an exhaustive real-life database. METHODS: Data from patients who received MITOX before 1 January 2006 were collected from the MS Lorraine registry. Expanded Disability Status Scale (EDSS) scores and annual relapse rates (ARRs) year by year during follow-up and the year prior to MITOX were compared. Time to the first relapse and a 1-point increase in EDSS score were used in Cox multivariate models to find associations with potential predictive factors. RESULTS: A total of 411 patients were included. The ARR for the 155 relapsing patients had decreased from 2.0 (SD 1.20) the year before treatment to 0.3 (SD 0.31) by year 10 (P < 0.0001). The EDSS score increased from 2.8 (SD 1.44) to 4.8 (SD 1.90) by year 10 (P < 0.0001). A high ARR at MITOX initiation was associated with a longer time to a 1-point increase in EDSS score (hazard ratio, 0.81; 95% confidence interval, 0.67-0.99; P = 0.04). The EDSS score in 256 progressive patients increased from 5.0 (SD 1.33) to 6.5 (SD 1.26) by year 10 (P < 0.0001). We identified four cases of acute myeloid leukemias. CONCLUSIONS: Patients with the most active forms of MS are the most likely to benefit from MITOX in the long term. PMID- 29996004 TI - Hypoxia and the group VII ethylene response transcription factor HRE2 promote adventitious root elongation in Arabidopsis. AB - Soil water-logging and flooding are common environmental stress conditions that can impair plant fitness. Roots are the first organs to be confronted with reduced oxygen tension as a result of flooding. While anatomical and morphological adaptations of roots are extensively studied, the root system architecture is only now becoming a focus of flooding research. Adventitious root (AR) formation shifts the root system higher up the plant, thereby facilitating supply with oxygen, and thus improving root and plant survival. We used Arabidopsis knockout mutants and overexpressors of ERFVII transcription factors to study their role in AR formation under hypoxic conditions and in response to ethylene. Results show that ethylene inhibits AR formation. Hypoxia mainly promotes AR elongation rather than formation mediated by ERFVII transcription factors, as indicated by reduced AR elongation in erfVII seedlings. Overexpression of HRE2 induces AR elongation to the same degree as hypoxia, while ethylene overrides HRE2-induced AR elongation. The ERFVII transcription factors promote establishment of an AR system that is under negative control by ethylene. Inhibition of growth of the main root system and promotion of AR elongation under hypoxia strengthens the root system in upper soil layers where oxygen shortage may last for shorter time periods. PMID- 29996005 TI - Surprising Antibacterial Activity and Selectivity of Hydrophilic Polyphosphoniums Featuring Sugar and Hydroxy Substituents. AB - There is currently an urgent need for the development of new antibacterial agents to combat the spread of antibiotic-resistant bacteria. We explored the synthesis and antibacterial activities of novel, sugar-functionalized phosphonium polymers. While these compounds exhibited antibacterial activity, we unexpectedly found that the control polymer poly(tris(hydroxypropyl)vinylbenzylphosphonium chloride) showed very high activity against both Gram-negative Escherichia coli and Gram positive Staphylococcus aureus and very low haemolytic activity against red blood cells. These results challenge the conventional wisdom in the field that lipophilic alkyl substituents are required for high antibacterial activity and opens prospects for new classes of antibacterial polymers. PMID- 29996006 TI - MIF-173G/C (rs755622) polymorphism as a risk factor for acute lymphoblastic leukemia development in children. AB - BACKGROUND: Macrophage inhibitory factor (MIF) is a pro-inflammatory cytokine modulating monocyte motility and a pleiotropic regulator of different biological and cellular processes. The MIF-173G/C (rs755622) polymorphism is found in the promoter region and affects its activity. The present study investigated the MIF polymorphism as a risk factor for the development of acute lymphoblastic leukemia (ALL) in Egyptian children. METHODS: We analyzed the MIF-173G/C (rs755622) polymorphism in 180 ALL cases and 150 healthy control children by amplification of the gene using a polymerase chain reaction followed by restriction endonuclease digestion and running on an agarose gel for visualization of the product. RESULTS: We found a significant incidence of the homozygous polymorphic (CC) genotype and the combined polymorphic genotypes (GC + CC) in ALL patients compared to healthy controls (p = 0.001 and p = 0.007, respectively), whereas the wild-type genotype (GG) was more common in healthy controls (p = 0.006). Multivariate logistic regression analysis adjustment for MIF different genotypes and other potential risk factors such as age, sex and parental smoking indicated that the CC genotype is the only significant risk factor for the test (p = 0.02). We also noted that, by increasing the C-allele representation within the gene [GC, CC], there was an increase in total leukocytic count (p = 0.09 and p = 0.001, respectively) that may reflect the bad prognostic impact of the polymorphic allele, although further studies are needed. CONCLUSIONS: The results of the present study indicate that the MIF-173G/C (rs755622) polymorphism is a risk factor for childhood ALL development with respect to both homozygous and combined polymorphic genotypes. In addition, the increased leukocytic count in synchronization with the increased representation of the polymorphic C-allele may reflect its bad prognostic impact. PMID- 29996007 TI - Influenza B viruses in pigs, Taiwan. AB - BACKGROUND: Influenza B viruses (IBVs) have never been isolated from natural infected pigs in clinical cases, although the susceptibility of domestic pigs to experimental IBV infections had been confirmed as well as IBV-specific antibodies were detected from pigs under natural and experimental conditions. OBJECTIVES: We aimed to assess and investigate the activities for infection and circulation of IBVs in pigs. METHODS: Annual active surveys for influenza have been implemented on swine populations in Taiwan since July 1998. Nasal swabs, trachea, lungs, and blood from pigs were tested using virological and serological assays for influenza. Gene sequences of influenza viral isolates were determined and characterized. Preliminary sero-epidemiological data for influenza virus were investigated. RESULTS: Three strains of IBV were isolated and identified from natural-infected pigs in 2014. Genetic characterization revealed the highest identities (>99%) of molecular sequence with the contemporary IBVs belonged to the B/Brisbane/60/2008 genetic clade of Victoria lineage in the phylogenetic trees for all 8 genes. IBV-specific antibodies were detected in 31 (0.2%; 95%CI: 0.1%-0.2%) of 15 983 swine serum samples from 29 (2.8%; 95%CI: 1.9%-3.9%) of 1039 farm visits under annual active surveys from 2007 through 2017. Seropositive cases have been found sparsely in 1-5 of test prefectures every year except 2015 and 2017 as well as scattered loosely over 26 townships/districts of 11 prefectures in Taiwan cumulatively in 11 years. CONCLUSIONS: Influenza B viruse infections from humans to pigs remained sporadic and accidental currently in Taiwan but might have paved potential avenues for newly emerging zoonotic influenza in the future. PMID- 29996009 TI - In vitro glucuronidation of designer benzodiazepines by human UDP glucuronyltransferases. AB - Multiple new psychoactive substances (NPS) are released into the recreational drug market each year. One NPS drug class that has become more common in recent years is that of the benzodiazepines (designer benzodiazepines, DBZ). Several metabolism studies have been performed to improve their bioanalytical detection via the best target. These studies have shown the presence of parent glucuronides and, as polymorphisms have been noted for the catalyzing enzymes (UDP glucuronyltransferases) responsible for glucuronide conjugation reactions, it is important to keep this in mind when interpreting DBZ cases in clinical and/or forensic toxicology. Therefore, the aim of this study was to determine the UDP glucuronyltransferases (UGTs) responsible for parent compound conjugation of nine DBZ to facilitate interpretation of related cases. Clonazolam, deschloroetizolam, etizolam, flubromazolam, flunitrazolam, metizolam, nifoxipam, nitrazolam, and pyrazolam were incubated with pooled human liver microsomes (pHLM) or 13 different human UGTs. The samples were analyzed using liquid chromatography-high resolution tandem mass spectrometry (LC-HRMS/MS). Glucuronide conjugates of flunitrazolam and nifoxipam were only detected in pHLM, suggesting that these reactions are performed by dimer complexes of several UGTs or complexes between UGTs and other metabolizing enzymes contained in pHLM. Nitrazolam or pyrazolam glucuronides were not detected. Glucuronidation of clonazolam, deschloroetizolam, etizolam, flubromazolam, and metizolam was catalyzed exclusively by UGT1A4. The conjugation of the majority of the DBZ was performed by the UGT isoform 1A4 for which polymorphisms have been described. This underlines the importance of taking glucuronidation polymorphism into consideration when interpreting intoxication cases. PMID- 29996008 TI - Development of an ASE-GC-MS/MS method for detecting dinitolmide and its metabolite 3-ANOT in eggs. AB - An accelerated solvent extraction coupled with gas chromatography-tandem mass spectrometry (ASE-GC-MS/MS) method for detecting dinitolmide residue and its metabolite (3-amino-2-methyl-5-nitrobenzamide, 3-ANOT) in eggs was developed and optimized. The samples were extracted using ASE with acetonitrile as the extractant and were purified by passage through a neutral alumina solid-phase extraction column. Then, the samples were analyzed using the GC-MS/MS method. The optimized method parameters were validated according to the requirements set forth by the European Union and the Food and Drug Administration. The average recoveries of dinitolmide and 3-ANOT from eggs (egg white, egg yolk, and whole egg) at the limit of quantification (LOQ), 0.5 maximum residue limit (MRL), 1 MRL, and 2 MRL were 82.74% to 87.49%, the relative standard deviations (RSDs) were less than 4.63%, and the intra-day RSDs and the inter-day RSDs were 2.96% to 5.21% and 3.94% to 6.34%, respectively. The limits of detection and the LOQ were 0.8 to 2.8 MUg/kg and 3.0 to 10.0 MUg/kg, respectively. The decision limits (CCalpha ) were 3001.69 to 3006.48 MUg/kg, and the detection capabilities (CCbeta ) were 3001.74 to 3005.22 MUg/kg. Finally, the new method was successfully applied to the quantitative determination of dinitolmide and 3-ANOT in 50 commercial eggs from local supermarkets. PMID- 29996010 TI - Nasal airflow resistance measured by rhinomanometry in a healthy population of China. AB - BACKGROUND: Although nasal congestion is among the most common symptoms in subjects suffering from nasal diseases, relatively few data on normal airflow resistance are available for reference, especially in healthy Chinese subjects. The aim of present study was therefore to objectively measure the normal airflow resistance by rhinomanometry, and calculate mean and standard reference intervals in a cohort of healthy Chinese subjects. METHODS: A total of 1084 participants were recruited in Huairou region in Beijing, China from November to December 2011. All participants were required to complete 2 questionnaires and undergo nasal examination and objective assessment of nasal resistance by rhinomanometry and acoustic rhinometry. RESULTS: A total of 704 adults completed both questionnaires and nasal examinations; with 505 (71.73%) subjects considered "healthy" based on negative medical history, absence of nasal symptoms, and normal findings by nasal examination. The mean total nasal resistance in the congested nose was 0.168 Pa/cm3 /sec (95% CI, 0.068 to 0.268 Pa/cm3 /sec) at 75 Pa pressure and 0.243 Pa/cm3 /sec (95% CI, 0.112 to 0.374 Pa/cm3 /sec) at 150 Pa pressure. The mean total nasal resistance in males was significantly lower compared to females at 75 Pa and 150 Pa (p < 0.001). The mean unilateral nasal resistance was 0.357 Pa/cm3 /sec (95% CI, 0.034 to 0.680 Pa/cm3 /sec) at 75 Pa and 0.511 Pa/cm3 /sec (95% CI, 0.086 to 0.936 Pa/cm3 /sec) at 150 Pa, with no significant difference between males and females. Application of a vasoconstrictor decreased both total and unilateral nasal resistance, which was significant at 75 Pa. CONCLUSION: These reference values maybe useful for the Chinese clinicians in evaluating the nasal function and in choosing and assessing efficacy of therapy for nasal congestion in Chinese patients. PMID- 29996011 TI - Screening, quantification, and confirmation of synthetic cannabinoid metabolites in urine by UHPLC-QTOF-MS. AB - Synthetic cannabinoids are one of the most significant groups within the category new psychoactive substances (NPS) and in recent years new compounds have continuously been introduced to the market of recreational drugs. A sensitive and quantitative screening method in urine with metabolites of frequently seized compounds in Norway (AB-FUBINACA, AB-PINACA, AB-CHMINACA, AM-2201, AKB48, 5F AKB48, BB-22, JWH-018, JWH-073, JWH-081, JWH-122, JWH-203, JWH-250, PB-22, 5F-PB 22, RCS-4, THJ-2201, and UR-144) using ultra-high pressure liquid chromatography quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) has been developed. The samples were treated with beta-glucuronidase prior to extraction and solid phase extraction was used. Liquid handling was automated using a robot. Chromatographic separation was achieved using a C18-column and a gradient of water and acetonitrile, both with 0.1% formic acid. Each sample was initially screened for identification and quantification followed by a second injection for confirmation. The concentrations by which the compounds could be confirmed varied between 0.1 and 12 ng/mL. Overall the validation showed that the method fulfilled the set criteria and requirements for matrix effect, extraction recovery, linearity, precision, accuracy, specificity, and stability. One thousand urine samples from subjects in drug withdrawal programs were analyzed using the presented method. The metabolite AB-FUBINACA M3, hydroxylated metabolite of 5F AKB48, hydroxylated metabolite of AKB48, AKB48 N-pentanoic acid, 5F-PB-22 3 carboxyindole, BB-22 3-carboxyindole, JWH-018 N-(5-hydroxypentyl), JWH-018 N pentanoic acid, and JWH-073 N-butanoic acid were quantified and confirmed in 2.3% of the samples. The method was proven to be sensitive, selective and robust for routine use for the investigated metabolites. PMID- 29996013 TI - Johns Hopkins Shares Surgical Protocols with 750 Hospitals. PMID- 29996012 TI - Good Use of PEPPER Data Makes a Difference in Quality. PMID- 29996015 TI - Hospitals Collaborate to Reduce Aspirational Pneumonia. PMID- 29996014 TI - Behavioral Healthcare in ED Improved with Telepsychiatry. PMID- 29996016 TI - $1.3 Million from Big Data QI. PMID- 29996017 TI - Engage Physicians More for Better Outcomes, Improved Efficiency. PMID- 29996018 TI - Multiple Strategies Reduce Cesarean Deliveries Below Target Rate. PMID- 29996019 TI - Peer-to Peer Hospital Reviews Helpful but Difficult. PMID- 29996020 TI - ADT Nurses Can Help Ease Bed Constraints, Patient Volumes. PMID- 29996021 TI - Get Patients Moving More to Decrease Vent Time. PMID- 29996022 TI - Nursing Education Improves RRT Team Efficiency. PMID- 29996023 TI - Standardize Physician Cards for Quality, Savings. PMID- 29996024 TI - Editorial. PMID- 29996025 TI - The Intersection Between Clinic Law and Heal: Responding to Issues Faced by People With HIV. PMID- 29996026 TI - Part III: Occupational Disability Determination/Rehabilitation Best Practices and the Role of Situational Work Assessment and Simulated Work/Academic Trials. AB - This is the final in a series of three papers addressing common occupational disability entitlements from an Ontario motor vehicle accident (MVA) perspective, which are also applicable to long-term disability cases. The first paper supported using a holistic model in the assessment of accident injured persons who are unable to return to the pre-accident occupation (pre- 104 disability/"own occupation") because of accident-caused impairments. The second paper discussed case law, best practice and the Post-104 Week IRB Disability ("any occupation") test and demonstrated the difficulties individuals face when they are unable to return to work in the aftermath of a debilitating motor vehicle accident. In this third and final paper, the purposes and roles of the Situational Work Assessment and Simulated Work/Academic Trials are critically evaluated in the occupational disability context. These methodologies are used to determine an individual's capacity to competitively meet the physical, cognitive and interpersonal/behavioural demands of his or her pre-condition occupation, or any occupation for which he or she is suited by education, training or experience, thereby addressing entitlement to income replacement benefits (IRB). It is vital that occupational disability assessments are comprehensive, holistic, include an undestanding of the synergistic impact of the impairment on the individual's physical, cognitive and psychosocial work capacities, and are conducted through multi-modal means. To conclude, the overriding principles and themes of all three articles are synthesized. PMID- 29996027 TI - A Need to Know Basis? Canadian Federalism and the Disclosure of Egg and Sperm Donor Identities. AB - In Canada, gamete donation can be known or anonymous. When a child is conceived using anonymously donated gametes, that child does not have a right to know the identity of their donor. Currently, there is no registry storing gamete donor information accessible to donor-conceived persons and no legislation or judicial precedent protecting a donor-conceived person's right to know the identity of their biological parent(s). With third party reproduction now regularly shifting the traditional outlines of family, these practices are increasing- ly attracting judicial oversight. This paper examines the consequences of the Supreme Court of Canada's Reference re Assisted Human Reproduction Act, S.C. 2004, c. 2 (AHRA), which identified donor anonymity as a matter of provincial jurisdiction. The paper argues that the Supreme Court's decision defined the future of anonymous gamete donation in Canada by strongly protecting anonymity. PMID- 29996028 TI - Issues of Vulnerability and Equality: The Emerging Need for Court Evaluations of Physicians' Fiduciary Duties in High Stakes End-of-Life Decisions. AB - At the heart of high stakes end of life (EOL) decisions such as withdrawal of life-sustaining treatments (WLST) or medical assistance in dying (MAiD), are concerns that vulnerable people in our society need to be legally protected from prematurely ending their own lives or from having their lives inappropriately ended by healthcare teams predisposed to negatively assess their quality of life. Recently, two Supreme Court of Canada rulings in Rasouli and Carter (MAiD) have clearly emphasized the role of consent in providing legal protections to people at the end of life. The role of the medical standard of care is less clear: though the Supreme Court in Rasouli was careful to state there had been no ruling on the medical standard of care with respect to WLST, the Court did state that standard of care considerations would be important in such decisions. In contrast to Rasouli, the result of the Carter ruling was that consent alone is insufficient protection for physician assisted death without a medical standard of care. Subsequently, in its new legislation, the Canadian Government restricted access to MAiD on the grounds that some people - those who lose capacity, with mental illnesses and mature minors - are so vulnerable that this potential choice at the EOL must be denied. In simple terms, for some, consent and the medical standard of care are insufficient protections. Such claims and their consequences are a sign of an emerging and significant problem: the reduction of medicine to a mere contractual relationship while disregarding its fiduciary nature simply because the courts have, in the words of Chief Justice McLachlin, "never reviewed physicians' good faith treatment decisions on the basis of fiduciary duty". The goals of this article are to explore issues of vulnerability and equality, the existing protections in both medicine and law and the emerging need for courts to evaluate physicians' fiduciary duties in high stakes EOL decisions in order to resolve conflicts with respect to WLST, to ensure access to MAiD and to promote the future aualitv of EOL care for all Canadians. PMID- 29996029 TI - SDSMA Foundation Creates New Scholarship. PMID- 29996030 TI - First Successful Pseudobrephosian Delivery in Pseudocyesis (April Fools). PMID- 29996031 TI - Chromosome 2 Microdeletion Syndrome in a Newborn with Amniotic Band Sequence. AB - We report a case of amniotic band sequence (ABS) with a 5 kilobase microdeletion at 2p15. The newborn was delivered with absence of the right hand and distal segments of the left digits, consistent with amniotic band sequence. The clinical findings included a lumbar meningocele, bilateral clubfeet, adrenal hypertrophy, microcephaly, and facial dysmorphism. Due to these congenital anomalies not directly associated with ABS, a SNP chromosomal microarray was ordered and identified a 51 kilobase deletion at 2p15, which includes two known genes, USP34 (ubiquitin specific protease 34) and SNORA70B (small nucleolar RNA H/ACA box 70B). The clinical significance of this specific deletion is unknown at this time; however, there have been several case reports with a larger deletion which include these two genes and have been shown to affect neurodevelopment. PMID- 29996032 TI - The Role of Corneal Hysteresis in Predicting Outcomes in Glaucoma Patients Undergoing Trabecular Microbypass Stent in Combination with Cataract Surgery. AB - INTRODUCTION: Trabecular microbypass stents are effective at lowering intraocular pressure in patients with mild to moderate glaucoma. Corneal hysteresis has been shown to correlate with reduction in intraocular pressure in patients using topical prostaglandin analogues and selective laser trabeculoplasty to treat glaucoma. The purpose of this study was to investigate whether baseline corneal hysteresis measurements were predictive of effectiveness of trabecular microbypass stents in treating glaucoma. METHODS: This was a retrospective chart review of 163 eyes from 109 patients with primary open angle glaucoma that underwent simultaneous trabecular microbypass stenting and cataract surgery. This was a single center study with one surgeon performing all procedures. RESULTS: The eyes were grouped into quartiles according to baseline corneal hysteresis measurements. Baseline intraocular pressures among the four quartiles of baseline corneal hysteresis groups were similar (p=0.082, ANOVA). The average intraocular pressure reduction at 3 months post-operative visits were 3.67, 1.51, 2.83, and 2.09 mmHg for the first through fourth quartiles respectively, and these differences are insignificant overall (p=0.34, ANOVA). Likewise, no significant difference was detected in terms of reduction in glaucoma medications among the quartiles three months after surgery (p=0.78, ANOVA). CONCLUSION: Baseline corneal hysteresis does not appear to show any value in predicting intraocular pressure reduction in response to placement of a trabecular microbypass stent for treating glaucoma. PMID- 29996033 TI - Primary Cutaneous Osteosarcoma. AB - Primary cutaneous osteosarcoma is an exceedingly rare malignant mesenchymal neoplasm of the skin which produces bone, osteoid, or chondroid material and does not involve the underlying bone. The most common site for extraskeletal osteosarcoma is in the deep soft tissues of the thigh, upper extremities, and retroperitoneum; however, it may occur anywhere in the body. Involvement of the skin is rare and when it does occur it is more commonly due to metastatic disease rather than a primary malignancy. Only 16 cases of primary cutaneous osteosarcoma have been described in the literature. We report an uncommon case of primary cutaneous osteosarcoma. Our patient is an 84-year-old male with an unremarkable medical history who presented to the dermatology clinic complaining of a 0.5 x 0.4 cm pink flesh to translucent-appearing, shiny, papule on the right superior jawline which was not connected to the underlying bone. Clinically the differential diagnosis included basal cell carcinoma, trichoepithelioma, and other cutaneous adnexal tumors. An excisional biopsy was performed which demonstrated an unremarkable epidermis with a hypercellular reticular dermis with occasional large spindled cells with amphophilic cytoplasm. The deep dermis was involved by mature osteoid formation and infiltration of highly mitotically active, atypical epithelioid and spindled cells with abundant nuclear pleomorphism, amphophilic cytoplasm, and poorly defined cell borders. Occasional multinucleate forms were seen. Immunohistochemistry was performed which showed strong positive staining with vimentin. Without connection to the underlying bone, osteosarcoma of periosteal, parosteal, or osseous origin was excluded. Based on these histomorphologic findings, a diagnosis of primary cutaneous osteosarcoma was made. Our case adds to the dearth of literature regarding primary cutaneous osteosarcoma and provides primary care physicians, dermatologists, and pathologists much needed insight into this rare condition. PMID- 29996034 TI - Refractory Hepatic Hydrothorax in the Absence of Ascites as a First Sign of Cirrhosis. AB - Hepatic hydrothorax (HH) occurs in 5-10 percent of patients with cirrhosis and usually develops in conjunction with ascites. We report a case of refractory right sided pleural effusion which turned out to be HH in the absence of ascites or previous history of cirrhosis. HH is thought to occur in isolation due to the superior absorptive capacity of the peritoneum as compared to the pleura. Diagnosis is usually clinical but can be confirmed by scintigraphic studies. The treatment is similar to that for ascites with transjugular intrahepatic portosystemic shunt (TIPS) being the most effective but it is associated with high rate of complications. PMID- 29996035 TI - Elevated Vitamin B12: A Rare Presentation for Gallbladder Adenocarcinoma. AB - Gallbladder cancer (GBC) is relatively rare and usually has vague clinical presentation. Vitamin B12 (Cobalamin [Cbl]) deficiency is well recognized clinical entity, in contrast, elevated Cbl remains largely unknown and underestimated in practice. We report an elderly patient who presented with generalized weakness. She found to have elevated serum Cbl which raise the suspicion for malignancy. Subsequent imaging studies and tissue biopsy led to diagnose gallbladder adenocarcinoma. Elevated Cbl has been associated with increased risk of subsequent diagnosis of cancer. In addition, elevated Cbl levels in cancer patients have a strong predictive value for mortality, frequent metastases, and poor prognosis. In this case, the incidental finding of high Cbl level led to the diagnosis of serious illness which could otherwise present in a more advanced stage. PMID- 29996036 TI - Suspected Malignant Lesion of the Hip Resolves after Parathyroidectomy: Osteitis Fibrosa Cystica (or Brown Tumor): A Case Report. AB - We present a case of osteitis fibrosa cystica (OFC), also known as "brown tumor." A 55-year old female was admitted to the hospital with several months of right hip pain that was becoming more severe. A malignant lesion of the pelvis was suspected after initial imaging studies. Significant hypercalcemia led to a diagnosis of hyperparathyroidism and ultimately a benign parathyroid adenoma. Surgical excision of the adenoma resulted in full resolution of the tumor in her pelvis as well as her pain. It is important to keep OFC, or brown tumor, in your differential diagnoses when presented with a bone lesion. PMID- 29996037 TI - Use of Innovative Technology to Advance Healthcare in South Dakota. PMID- 29996039 TI - Quality Focus: A Culture of Patient. PMID- 29996038 TI - Variables: Context and Uncertainty in Patient Care. PMID- 29996040 TI - [EV71 Infection and Innate Antiviral Innate Immunity]. AB - Enterovirus 71 (EV71) is a major agent of hand, foot, and mouth disease in children under five years of age. In some cases,infection with EV71 can result in herpangina, pulmonary edema and/or brainstem encephalitis. In recent years, many advances have been made towards an understanding of EV71 pathogenesis. In this review, we summarize the cell types targeted by EV71,the activation of signaling pathways, the innate antiviral immune response and immune evasion by EV71 to better understand the immunopathogenesis of EV71 and to aid in the development of antiviral drugs. PMID- 29996041 TI - [The Research Advances in Antiviral Immune Molecules: Interferon Inducible Transmembrane Proteins]. AB - Interferon inducible transmembrane proteins(IFITMs)are restriction factors with broad-spectrum antiviral functions in infected cells. IFITM genes belong to a large subfamily of dispanins and have multiple functions, amongst which the antiviral functions are the main focus of study. IFITMs, especially IFITM3,can restrict the early replication of viruses such as avian influence virus, and, therefore, have become a hot topic in research in recent years. To date, studies have shown that IFITMs restrict virus invasion mainly through endosomal pathways, subsequently inhibiting viral replication. However, a detailed antiviral mechanism is still unclear. Here, we summarize the advances in IFITM research from recent years. PMID- 29996042 TI - [The Advances of Oncolytic Herpes Simplex Virus in Cancer Therapy]. AB - Due to the remarkable ability to target and kill tumor cells, genetically engineering HSV-1 has been widely studied for its potency in cancer treatment. Several oncolytic herpes simplex viruses had been proved to be clinically effective in different phases of clinical trials against multiple cancers, which can also induce good antitumor immunity. In 2015,Amgen's T-VEC has been approved by FDA for the treatment of melanoma. The combination with the conventional therapies, such as radiotherapy and chemotherapy, can further enhance the efficacy of virotherapy. Moreover, Immune checkpoint blockade therapy has been proved to be a promising strategy to fight multiple cancers, the combination of immune activation using oncolytic viruses and immune checkpoint inhibitors is likely to usher in a new era of cancer treatment. PMID- 29996043 TI - [Structure and Function of the Baculovirus Per Os Infectivity Factor (PIF) P74]. AB - Baculoviridae is a family of large, enveloped, double-stranded DNA viruses that mostly infect insects. Occlusion-derived virus is a baculovirus viral phenotype that induces primary infection when ingested by the insect host per os. Several occlusion-derived viral membrane proteins, called per os infectivity factors, have been shown to be essential for oral infectivity. Here, we review advances in structure and function studies of P74,which was the first PIF to be identified and has been extensively investigated.P74 contains two transmembrane domains in its hydrophobic C terminus which play a role in transmembrane anchoring, and two conserved domains which are involved in P74 function.P74is efficiently cleaved by an occlusion body endogenous alkaline protease and a host trypsin during baculovirus release and its digestion products are loosely associated with a stable complex formed by PIF1,PIF2 and PIF3.As a baculovirus attachment protein,P74 binds to a specific receptor of approximately 35 kDa in brush border membrane vesicles, facilitating the internalization of baculovirus into host cells. Knowledge of P74 will improve our understanding of baculovirus primary infection, which will support the design of nonchemical strategies to block baculovirus transmission or suppress pest populations. PMID- 29996044 TI - Accelerated ReaxFF Simulations for Describing the Reactive Cross-Linking of Polymers. AB - Various methods have been developed to perform atomistic-scale simulations for the cross-linking of polymers. Most of these methods involve connecting the reactive sites of the monomers, but these typically do not capture the entire reaction process from the reactants to final products through transition states. Experimental time scales for cross-linking reactions in polymers range from minutes to hours, which are time scales that are inaccessible to atomistic-scale simulations. Because simulating reactions on realistic time scales is computationally expensive, in this investigation, an accelerated simulation method was developed within the ReaxFF reactive force field framework. In this method, the reactants are tracked until they reach a nonreactive configuration that provides a good starting point for a reactive event. Subsequently, the reactants are provided with a sufficient amount of energy-equivalent or slightly larger than their lowest-energy reaction barrier-to overcome the barrier for the cross-linking process and form desired products. This allows simulation of cross linking at realistic, low temperatures, which helps to mimic chemical reactions and avoids unwanted high-temperature side reactions and still allows us to reject high-barrier events. It should be noted that not all accelerated events are successful as high local strain can lead to reaction rejections. The validity of the ReaxFF force field was tested for three different types of transition state, possibly for polymerization of epoxides, and good agreement with quantum mechanical methods was observed. The accelerated method was further implemented to study the cross-linking of diglycidyl ether of bisphenol F (bis F) and diethyltoluenediamine (DETDA), and a reasonably high percentage (82%) of cross linking was obtained. The simulated cross-linked polymer was then tested for density, glass transition temperature, and modulus and found to be in good agreement with experiments. Results indicate that this newly developed accelerated simulation method in ReaxFF can be a useful tool to perform atomistic scale simulations on polymerization processes that have a relatively high reaction barrier at a realistic, low temperature. PMID- 29996045 TI - Identification of an Alternatively Spliced alpha-Synuclein Isoform That Generates a 41-Amino Acid N-Terminal Truncated Peptide, 41-syn: Role in Dopamine Homeostasis. AB - The presynaptic protein, alpha-synuclein (alpha-syn), has been shown to play a crucial role in multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia with Lewy bodies (DLB). The three major domains of alpha-syn protein were shown to govern its membrane interaction, protein fibrillation, and chaperone activity. So far, four different alternatively spliced isoforms of alpha-syn, which lack either exon 3 (syn-126) or exon 5 (syn-112) or both (syn-98) resulting in altered function of the proteins, have been identified. In the present study, we have identified the smallest isoform of alpha-syn due to the skipping of exons 3 and 4 generating a 238 bp transcript. Due to the presence of a premature stop codon, the 238 bp transcript generated a 41 aa N-terminal peptide instead of the 78 aa protein, which is secreted into the extracellular medium when overexpressed in cells. The presence of 41-syn was initially noticed in the substantia nigra of PD autopsy tissues, as well as in cells undergoing oxidative stress. In vitro studies inferred that 41-syn neither aggregates nor alters the aggregation propensity of either WT or 112-syn. Overexpression of 41-syn or treatment of cells with 41-syn peptide did not affect cell viability. However, PC-12 cells treated with 41-syn exhibited a time and dose dependent enhancement in the cellular uptake of dopamine. Based on the physiological role of the N-terminal region of alpha-syn in modulating membrane trafficking events, we believe that the identification of 41-syn may provide novel impetus in unraveling the physiological basis of alternative splicing events in governing PD pathophysiology. PMID- 29996046 TI - Atmospheric Oxidation of a Thiocarbamate Herbicide Used in Winter Cereals. AB - The gas-phase atmospheric degradation of prosulfocarb (a widely used thiocarbamate herbicide in winter cereals) at different NOx concentrations was investigated at the large outdoor European PHOtoREactor (EUPHORE) in Valencia, Spain. Photolysis under sunlight conditions and reaction with ozone were shown as unimportant. The rate constant for the reaction of prosulfocarb with OH radicals was determined as k = (2.9 +/- 0.5) * 10-11 cm3 molecule-1 s-1 at 288 +/- 10 K and atmospheric pressure by a conventional relative rate method. Significant ozone and aerosol formation was observed following the reaction of prosulfocarb with OH radicals, and the main detected carbon-containing gas-phase products were benzaldehyde, S-benzyl formyl(propyl)carbamothioate, and S-benzyl propanoyl(propyl)carbamothioate. PMID- 29996048 TI - Electron Transfer Reactions: KO tBu (but not NaO tBu) Photoreduces Benzophenone under Activation by Visible Light. AB - Long-standing controversial reports of electron transfer from KO tBu to benzophenone have been investigated and resolved. The mismatch in the oxidation potential of KO tBu (+0.10 V vs SCE in DMF) and the first reduction potential of benzophenone (of many values cited in the literature, the least negative value is -1.31 V vs SCE in DMF), preclude direct electron transfer. Experimental and computational results now establish that a complex is formed between the two reagents, with the potassium ion providing the linkage, which markedly shifts the absorption spectrum to provide a tail in the visible light region. Photoactivation at room temperature by irradiation at defined wavelength (365 or 400 nm), or even by winter daylight, leads to the development of the blue color of the potassium salt of benzophenone ketyl, whereas no reaction is observed when the reaction mixture is maintained in darkness. So, no electron transfer occurs in the ground state. However, when photoexcited, electron transfer occurs within a complex formed from benzophenone and KO tBu. TDDFT studies match experimental findings and also define the electronic transition within the complex as n -> pi*, originating on the butoxide oxygen. Computation and experiment also align in showing that this reaction is selective for KO tBu; no such effect occurs with NaO tBu, providing the first case where such alkali metal ion selectivity is rationalized in detail. Chemical evidence is provided for the photoactivated electron transfer from KO tBu to benzophenone: tert-butoxyl radicals are formed and undergo fragmentation to form (acetone and) methyl radicals, some of which are trapped by benzophenone. Likewise, when KOC(Et)3 is used in place of KO tBu, then ethylation of benzophenone is seen. Further evidence of electron transfer was seen when the reaction was conducted in benzene, in the presence of p iodotoluene; this triggered BHAS coupling to form 4-methylbiphenyl in 74% yield. PMID- 29996047 TI - Momilactone and Related Diterpenoids as Potential Agricultural Chemicals. AB - Momilactones are allelochemicals in rice and moss defense. Momilactone-like compounds are therefore considered important secondary metabolites for plant defense. They may serve as promising lead compounds for crop-friendly herbicides as well as antifungal and antibacterial agents. Many of these substances possess potent cytotoxicity property against cancer cell lines as well. The present paper is the first review on these versatile molecules, focusing on the structure, biological activity, chemical synthesis, and biosynthesis of the naturally occurring momilactone-like molecules reported from 1973 to 2017. PMID- 29996049 TI - Cooling of Pure Water at Room Temperature by Weak Electric Currents. AB - Flow of electrical current through water is expected to increase water temperature. We passed low-frequency alternating electric current through distilled, deionized water using platinum electrodes and found, instead, a diminution of temperature. The diminution was observed using both an infrared camera and a spectroradiometer, the latter allowing us to obtain spectral information. The diminished temperature persisted for at least half an hour following cessation of the current flow. Diminished radiant energy implies reduced charge displacements, which in turn implies increased structural order. Hence, the passage of charge into water appears to increase the water structure. PMID- 29996050 TI - Bent Keto Form of Curcumin, Preferential Stabilization of Enol by Piperine, and Isomers of Curcumin?Cyclodextrin Complexes: Insights from Ion Mobility Mass Spectrometry. AB - A detailed examination of collision cross sections (CCSs) coupled with computational methods has revealed new insights into some of the key questions centered around curcumin, one of the most intensively studied natural therapeutic agents. In this study, we have distinguished the structures and conformers of the well-known enol and the far more elusive keto form of curcumin by using ion mobility mass spectrometry (IM MS). The values of the theoretically predicted isomers were compared with the experimental CCS values to confirm their structures. We have identified a bent structure for the keto form and the degree of bending was estimated. Using IM MS, we have also shown that ESI MS reflects the solution phase structures and their relative populations, in this case. Piperine, a naturally occurring heterocyclic compound, is known to increase the bioavailability of curcumin. However, it is still not clearly understood which tautomeric form of curcumin is better stabilized by it. We have identified preferential stabilization of the enol form in the presence of piperine using IM MS. Cyclodextrins (CDs) are used as well-known carriers in the pharmaceutical industry for increasing the stability, solubility, bioavailability, and tolerability of curcumin. However, the crystal structures of supramolecular complexes of curcumin?CD are unknown. We have determined the structures of different isomers of curcumin?CD (alpha- and beta-CD) complexes by comparing the CCSs of theoretically predicted structures with the experimentally obtained CCSs, which will further help in understanding the specific role of the structures involved in different biological activities. PMID- 29996051 TI - Light-Induced Interfacial Dynamics Dramatically Improve the Photocurrent in Dye Sensitized Solar Cells: An Electrolyte Effect. AB - A significant increase in the photocurrent generation during light soaking for solar cells sensitized by the triphenylamine-based D-pi-A organic dyes (PD2 and LEG1) and mediated by cobalt bipyridine redox complexes has been observed and investigated. The crucial role of the electrolyte has been identified in the performance improvement. Control experiments based on a pre-treatment strategy reveals TBP as the origin. The increase in the current and IPCE has been interpreted by the interfacial charge-transfer kinetics studies. A slow component in the injection kinetics was exposed for this system. This change explains the increase in the electron lifetime and collection efficiency. Photoelectron spectroscopic measurements show energy shifts at the dye/TiO2 interface, leading us to formulate a hypothesis with respect to an electrolyte-induced dye reorganization at the surface. PMID- 29996052 TI - Uranium Retention in a Bioreduced Region of an Alluvial Aquifer Induced by the Influx of Dissolved Oxygen. AB - Reduced zones in the subsurface represent biogeochemically active hotspots enriched in buried organic matter and reduced metals. Within a shallow alluvial aquifer located near Rifle, CO, reduced zones control the fate and transport of uranium (U). Though an influx of dissolved oxygen (DO) would be expected to mobilize U, we report U immobilization. Groundwater U concentrations decreased following delivery of DO (21.6 mg O2/well/h). After 23 days of DO delivery, injection of oxygenated groundwater was paused and resulted in the rebound of groundwater U concentrations to preinjection levels. When DO delivery resumed (day 51), groundwater U concentrations again decreased. The injection was halted on day 82 again and resulted in a rebound of groundwater U concentrations. DO delivery rate was increased to 54 mg O2/well/h (day 95) whereby groundwater U concentrations increased. Planktonic cell abundance remained stable throughout the experiment, but virus-to-microbial cell ratio increased 1.8-3.4-fold with initial DO delivery, indicative of microbial activity in response to DO injection. Together, these results indicate that the redox-buffering capacity of reduced sediments can prevent U mobilization, but could be overcome as delivery rate or oxidant concentration increases, mobilizing U. PMID- 29996053 TI - Highly Selective and Sharp Volcano-type Synergistic Ni2Pt@ZIF-8-Catalyzed Hydrogen Evolution from Ammonia Borane Hydrolysis. AB - Ammonia borane hydrolysis is considered as a potential means of safe and fast method of H2 production if it is efficiently catalyzed. Here a series of nearly monodispersed alloyed bimetallic nanoparticle catalysts are introduced, optimized among transition metals, and found to be extremely efficient and highly selective with sharp positive synergy between 2/3 Ni and 1/3 Pt embedded inside a zeolitic imidazolate framework (ZIF-8) support. These catalysts are much more efficient for H2 release than either Ni or Pt analogues alone on this support, and for instance the best catalyst Ni2Pt@ZiF-8 achieves a TOF of 600 molH2.molcatal-1.min 1 and 2222 molH2.molPt-1.min-1 under ambient conditions, which overtakes performances of previous Pt-base catalysts. The presence of NaOH boosts H2 evolution that becomes 87 times faster than in its absence with Ni2Pt@ZiF-8, whereas NaOH decreases H2 evolution on the related Pt@ZiF-8 catalyst. The ZIF-8 support appears outstanding and much more efficient than other supports including graphene oxide, active carbon and SBA-15 with these nanoparticles. Mechanistic studies especially involving kinetic isotope effects using D2O show that cleavage by oxidative addition of an O-H bond of water onto the catalyst surface is the rate-determining step of this reaction. The remarkable catalyst activity of Ni2Pt@ZiF-8 has been exploited for successful tandem catalytic hydrogenation reactions using ammonia borane as H2 source. In conclusion the selective and remarkable synergy disclosed here together with the mechanistic results should allow significant progress in catalyst design toward convenient H2 generation from hydrogen-rich substrates in the close future. PMID- 29996054 TI - The Role of Surface Defects in Photoluminescence and Decay Dynamics of High Quality Perovskite MAPbI3 Single Crystals. AB - Halide perovskites have recently been a star semiconductor material in photovoltaic field owing to their excellent optoelectronic properties. An in depth understanding of the photoluminescence and carrier diffusion in these materials may facilitate the implementation of high-performance optolelctronic devices. Here, we report an unusual photoluminescence quenching phenomenon in MAPbI3 single crystals. Interestingly, MAPbI3 single crystal with higher crystalline quality shows a lower photoluminescence emission and a shorter decay time, indicating the surface imperfection plays an important role to the photoluminescence. The quick quenching process is attributed to the synergistic effect of localized effect at the defects and rapid inward diffusion. PMID- 29996055 TI - Phonon Coupling with Excitons and Free Carriers in Formamidinium Lead Bromide Perovskite Nanocrystals. AB - Organometal halide perovskites in the form of nanocrystals (NCs) have attracted enormous attention due to their unique optoelectronic and photoluminescence (PL) properties. Here, we examine the phase composition and the temperature dependence of emission line width broadening in formamidinium lead bromide (FAPbBr3) perovskite nanocrystals (NCs) for light-emitting applications and identify different charge-carrier scattering mechanisms. Our results show most of the emission is from the orthorhombic phase. The PL line width broadening at high temperature is dominated by the Frohlich interaction between the free charge carriers and the optical phonons. At low temperatures, the peak of the PL spectrum exhibits a continuous red shift indicating an increase of excitons contribution at lower temperatures, and concurrently the line width also narrows down due to the inhibition of the optical phonons. From the temperature-dependent measurements, the coupling strength of both the charge phonon interaction and the exciton phonon interaction have been determined. The obtained results indicate that the charge phonon coupling strengths are higher compared to the exciton phonon coupling. PMID- 29996056 TI - Characterize Collective Lysosome Heterogeneous Dynamics in Live Cell with a Space and Time-Resolved Method. AB - While studies of collective cell migration and bacteria swarming have tremendously promoted our fundamental knowledge of the complex systematic phenomena, the quantitative characterization of the collective organelles movement at subcellular level is yet to be fully explored. Here we tagged the lysosomes in live cells with fluorescent probe and imaged their spatial motion with wide field microscopy. To quantitatively characterize the collective lysosomal behavior with high spatiotemporal heterogeneity dynamics, we developed the particle collective analysis (PECAN) method based on the single particle tracking techniques. Thousands of trajectories were detected and analyzed in each single cell. The reliability was validated by comparing with traditional PIV method, simulated and experimental data sets. We show that the lysosomes in live cells move collectively with spatial heterogeneous and temporal long-term correlated dynamics. Furthermore, the continuous wavelet analysis suggested the existence of collective lysosomal oscillation in mouse neural cells. Generally, our method provides a practical workflow for characterizing the collective lysosomal motions which can benefit related areas such as organelles mediated drug delivery and cell activity profiling. PMID- 29996057 TI - The Effect of Low Ionic Strength on Diffusion and Viscosity of Monoclonal Antibodies. AB - PURPOSE: To determine the effect of solution conditions, especially low ionic strength, on the dynamics of molecular diffusion and protein-protein interactions in monoclonal antibody solutions. METHODS: The interaction parameter, kD, was calculated from diffusion data obtained from dynamic light scattering (DLS) measurements performed using a Zetasizer. Theoretical considerations were utilized to evaluate the hard sphere and electrostatic contribution to molecular interactions. RESULTS: At low ionic strengths, repulsions were the dominant forces governing the behavior of both mAbs. As ionic strength increased, attractions contributed to the behavior of mAb1, while repulsions remained the dominant factor affecting mAb3 behavior. Repulsions alone were not sufficient to affect mAb3 viscosity in water, while the presence of repulsions as well as specific attractions was suggested to cause an increase in the viscosity of mAb1 in water compared to 15 mM ionic strength. CONCLUSIONS: Solution physical properties varied for the mAbs investigated. Our findings highlighted the importance of developing a fundamental understanding of interplay of forces governing solution properties of each individual mAb under low ionic strength conditions. Such understanding is critical in enabling successful development of self-buffered formulations. PMID- 29996058 TI - Assessment of Transporter-Mediated and Passive Hepatic Uptake Clearance Using Rifamycin-SV as a Pan-Inhibitor of Active Uptake. AB - The use of in vitro data for the quantitative prediction of transporter-mediated clearance is critical. Central to this evaluation is the use of hepatocytes, since they contain the full complement of transporters and metabolic enzymes. In general, uptake clearance (CLuptake) is evaluated by measuring the appearance of compound in the cell. Passive clearance (CLpd) is often determined by conducting parallel studies at 4 degrees C or by attempting to saturate uptake pathways. Both approaches have their limitations. Recent studies have proposed the use of Rifamycin-SV (RFV) as a pan-inhibitor of hepatic uptake pathways. In our studies, we confirm that transport activity of all major hepatic uptake transporters is inhibited significantly by RFV at 1 mM (OATP1B1, 1B3, and 2B1 = NTCP (80%), OCT1 (65%), OAT2 (60%)). Under these incubation conditions, we found that the free intracellular concentration of RFV is ~175 MUM and that several major CYPs and UGTs can be reversibly inhibited. Using this approach, we also determined CLuptake and CLpd of nine known OATP substrates across three different lots of human hepatocytes. The scaling factors generated for these compounds at 37 degrees C with RFV and 4 degrees C were found to be similar. The CLpd of passively permeable compounds like metoprolol and semagacestat were found to be higher at 37 degrees C compared to 4 degrees C, indicating a temperature effect on these compounds. In addition, our data also suggests that incorporation of medium concentrations into CLuptake and CLpd calculations may be critical for highly protein bound and highly lipophilic drugs. Overall, our data indicate that RFV, instead of 4 degrees C, can be reliably used to measure CLuptake and CLpd of drugs. PMID- 29996059 TI - Determination of Dynamically Stable Electrenes toward Ultrafast Charging Battery Applications. AB - Electrenes, an atomically thin form of layered electrides, are very recent members of the 2D materials family. In this work, we employed first-principle calculations to determine stable, exfoliatable, and application-promising 2D electrene materials among possible M2X compounds, where M is a group II-A metal and X is a nonmetal element (C, N, P, As, and Sb). The promise of stable electrene compounds for battery applications is assessed via their exfoliation energy, adsorption properties, and migration energy barriers toward relevant Li, Na, K, and Ca atoms. Our calculations revealed five new stable electrene candidates in addition to previously known Ca2N and Sr2N. Among these seven dynamically stable electrenes, Ba2As, Ba2P, Ba2Sb, Ca2N, Sr2N, and Sr2P are found to be very promising for either K or Na ion batteries due to their extremely low migration energy barriers (5-16 meV), which roughly demonstrates 105 times higher mobility than graphene and two to four times higher mobility than other promising 2D materials such as MXene (Mo2C). PMID- 29996060 TI - Strong Spatial and Spectral Localization of Surface Plasmons in Individual Randomly Disordered Gold Nanosponges. AB - Porous nanosponges, percolated with a three-dimensional network of 10 nm sized ligaments, recently emerged as promising substrates for plasmon-enhanced spectroscopy and (photo)catalysis. Experimental and theoretical work suggests surface plasmon localization in some hot-spot modes as the physical origin of their unusual optical properties, but so far the existence of such hot-spots has not been proven. Here we use scattering-type scanning near-field nanospectroscopy on individual gold nanosponges to reveal spatially and spectrally confined modes at 10 nm scale by recording local near-field scattering spectra. High quality factors of individual hot-spots of more than 40 are demonstrated, predicting high Purcell factors up to 106. The observed field localization and enhancement make such nanosponges an appealing platform for a variety of applications ranging from nonlinear optics to strong-coupling physics. PMID- 29996061 TI - Deutetrabenazine for the treatment of Huntington's chorea. AB - INTRODUCTION: Huntington's disease (HD) is an inherited neurodegenerative disorder for which no disease-modifying treatment is currently available. Only symptomatic treatment can be offered. Chorea is the most common motor manifestation of HD and may interfere with daily activities, reduce quality of life, and cause injury. Areas covered: Deutetrabenazine is the first deuterated drug and second drug after tetrabenazine, the classic vesicular monoamine transporter type 2 (VMAT2) inhibitor, to receive approval for the treatment of chorea associated with HD. This review, based largely on a detailed PubMed search, will summarize the pharmacological properties, clinical evidence of efficacy and tolerability of deutetrabenazine in the treatment of HD chorea. Expert commentary: Due to differences in pharmacology and pharmacokinetics, deutetrabenazine has shown promise that it is at least as effective as tetrabenazine in the treatment of HD chorea but has a lower risk of adverse effects. The role of VMAT2 inhibitors in the treatment of hyperkinetic movement disorders is expanding due to their efficacy and favorable tolerability profiles. PMID- 29996062 TI - Anticancer therapy and lung injury: molecular mechanisms. AB - INTRODUCTION: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. Areas covered: As we move toward the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. Expert commentary: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their antitumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs. PMID- 29996063 TI - Mechanisms and Pathways of Small-Phytoplankton Export from the Surface Ocean. AB - Carbon fixation by phytoplankton near the surface and the sinking of this particulate material to deeper waters are key components of the biological carbon pump. The efficiency of the biological pump is influenced by the size and taxonomic composition of the phytoplankton community. Large, heavily ballasted taxa such as diatoms sink quickly and thus efficiently remove fixed carbon from the upper ocean. Smaller, nonballasted species such as picoplanktonic cyanobacteria are usually thought to contribute little to export production. Research in the past decade, however, has shed new light on the potential importance of small phytoplankton to carbon export, especially in oligotrophic oceans, where small cells dominate primary productivity. Here, I examine the mechanisms and pathways through which small-phytoplankton carbon is exported from the surface ocean and the role of small phytoplankton in food webs of a variety of ocean ecosystem Expected final online publication date for the Annual Review of Marine Science Volume 11 is January 3, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 29996064 TI - Switching to a fibre-rich and low-fat diet increases colonic folate contents among African Americans. AB - How dietary patterns impact colonic bacterial biosynthesis of vitamins and utilization by humans is poorly understood. Our aim was to investigate whether a reciprocal dietary switch between rural South Africans (traditionally high fibre, low fat) and African Americans (Western diet of low fibre, high fat) affects colonic folate synthesis. Colonic evacuants were obtained from 20 rural South Africans and 20 African Americans consuming their usual diets at baseline. For two weeks thereafter, rural South Africans were provided with a Western diet (protein 27%, fat 52%, carbohydrate 20% and fibre 8 g/d) and African Americans were provided with a high fibre, low fat diet (protein 16%, fat 17%, carbohydrate 63% and fiber 43 g/d). Colonic evacuants were again collected. No difference between groups at baseline in the folate content of 3-hour evacuants was observed. The high fibre low fat diet consumed by African Americans during the intervention produced a 41% increase in mean total folate content compared with baseline values (p=0.0037). No change was observed in rural South Africans consuming a Western diet. Mean total folate content of colonic evacuants was higher among African Americans at the end of the dietary switch (3107+/-1811 ug) compared to rural South Africans (2157+/-1956 ug) (p=0.0409). In conclusion, consistent with animal studies, switching from a Western diet to one higher in fibre and lower in fat can be expected to result in greater colonic folate content. Future research should confirm these observations are not transitory and understand the contribution of transit-time to the findings. PMID- 29996065 TI - Behind Schedule - Reconciling Federal and State Marijuana Policy. PMID- 29996066 TI - Virus DNA Replication and the Host DNA Damage Response. AB - Viral DNA genomes have limited coding capacity and therefore harness cellular factors to facilitate replication of their genomes and generate progeny virions. Studies of viruses and how they interact with cellular processes have historically provided seminal insights into basic biology and disease mechanisms. The replicative life cycles of many DNA viruses have been shown to engage components of the host DNA damage and repair machinery. Viruses have evolved numerous strategies to navigate the cellular DNA damage response. By hijacking and manipulating cellular replication and repair processes, DNA viruses can selectively harness or abrogate distinct components of the cellular machinery to complete their life cycles. Here, we highlight consequences for viral replication and host genome integrity during the dynamic interactions between virus and host. PMID- 29996067 TI - Monoclonal Antibodies for Myeloma: Make It Easy! PMID- 29996068 TI - Enhancing Chemotherapy Capabilities in Rural Hospitals: Implementation of a Telechemotherapy Model (QReCS) in North Queensland, Australia. AB - INTRODUCTION: The Queensland Remote Chemotherapy Supervision (QReCS) model enables rural nurses to administer chemotherapy in smaller rural towns under supervision by health professionals from larger centers using telehealth. Its implementation began in North Queensland, Australia (population, 650,000), in 2014 between two regional cancer centers (Townsville and Cairns as primary sites) and six rural sites (125 to 1,000 kilometers from primary sites). Our study examined the implementation processes, feasibility, and safety of this model. METHODS: Details of implementation and patients' clinical details for the period of 2014 to 2016 for descriptive analysis were extracted from telechemotherapy project notes and oncology information systems of North Queensland, respectively. RESULTS: After a successful pilot study in Townsville Cancer Centre, statewide rural and cancer networks of Queensland Health, in collaboration with clinicians and managers across the state of Queensland, developed the QReCS model and a guide for operationalizing it. QReCS was implemented at six sites from 2014 to 2016. Main enablers across North Queensland included collaboration among clinicians and managers, availability of common electronic medical records, funding from Queensland Health, and installation of telehealth infrastructure by statewide telehealth services. Main barriers included turnover of senior management and nursing staff at two rural towns. Sixty-two patients received 327 cycles of low- to medium-risk chemotherapy agents. Rates of treatment delays, adverse events, and hospital admissions were similar to those in face-to-face care. CONCLUSION: Implementation of the QReCS model across a large geographic region is feasible with acceptable safety profiles. Leadership by and collaboration among clinicians and managers, adequacy of resources and common governance are key enablers. PMID- 29996069 TI - Managing Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and Elotuzumab. AB - Monoclonal antibodies (elotuzumab and daratumumab) are the newest class of drugs that have proven to be efficacious antimyeloma agents. Although daratumumab, a CD38 monoclonal antibody, has established its efficacy as a single agent and in combination with immunomodulatory agents and proteasome inhibitors, elotuzumab (signaling lymphocytic activation molecule F7 monoclonal antibody) has proven activity in combination with lenalidomide and dexamethasone. Infusion-related reactions (respiratory and nonrespiratory) seem to be a common theme of adverse events with monoclonal antibodies, although the relative incidence differs across these two agents. Identifying the appropriate pre- and postinfusion medication strategies can help lower the rates of infusion-related reactions and facilitate reduction in infusion times. In this article, we review the incidence of the infusion-related reactions with elotuzumab and daratumumab and their clinical activity in myeloma, review our institutional experience of management of infusion-related reactions, and provide some practical mitigation strategies to reduce their incidence. PMID- 29996070 TI - Present and Future of Immunotherapy in the Management of Multiple Myeloma. AB - Multiple myeloma (MM) is the second most common hematologic malignancy with an increasing incidence and prevalence. The wide array of effective antimyeloma agents have transformed MM into a chronic condition for some patients, requiring long-term management planning. Immunomodulatory drugs and proteasome inhibitors have played a pivotal role in defining the most effective regimens for both transplantation-eligible and transplantation-ineligible subgroups. Nevertheless, recent approvals of immunotherapies in MM such as daratumumab have added another important component to combination treatments for both relapsed or refractory and newly diagnosed disease. Evolving novel therapies such as chimeric antigen receptor T cells are poised to raise the bar even further, holding a promise of effective treatment option for patients who would otherwise have limited treatment alternatives. As we continue to therapeutically exploit the essential roles of cell-mediated immune surveillance, antigen presentation, and modulation of inhibitory surface signaling, we are rapidly establishing the cornerstone role of immunotherapies in the management of all phases of MM. In this review, we will cover the spectrum of available immunotherapies approved for clinical use in MM, as well as briefly describe those in early- and late-phase development, with the focus of raising the awareness of the expanding immuno-oncology armamentarium in MM. PMID- 29996071 TI - Infusion Reactions With Monoclonal Antibody Therapy in Myeloma: Learning From Experience. PMID- 29996072 TI - Promise of Immune Therapies in Multiple Myeloma. PMID- 29996073 TI - Management of Medical Oncology Services in Canada: Redefined Workload With a Novel Supply-and-Demand Workforce Projection Model. AB - PURPOSE: We developed a workforce-planning model to predict Canadian medical oncologist (MO) supply and clinical demand during the next 10 years. MATERIALS AND METHODS: A forward calculation model was created to forecast the balance of MO supply and demand. MO supply was estimated by using Canadian Institute for Health Information, Canadian Medical Association, and Canadian Post-MD Education Registry data. Care demand was estimated by using data from Canadian Cancer Statistics and Alberta Cancer Registry. The Canadian Royal College MO Committee confirmed its face validity. RESULTS: The MO workforce is expected to grow from 541 staff in 2016 to 830 staff in 2026. During this period, new hires will increase from 39 to 56 per year, and departures will increase from 15 to 24 per year. Although cancer incidence rates will grow from 202,149 to 257,497, a projected increase in MO supply will mean fewer initial consultations, from an average of 168.5 consultations per MO in 2016 to 129.2 consultations per MO in 2026. The initiation of systemic therapy is projected to remain stable at 102.3 new systemic therapy starts per MO per year. CONCLUSION: We have developed a forward calculation MO workforce model that predicts a growing Canadian MO workforce and redefines MO workload dynamics. MO providers will increasingly support more follow-up care with the initiation of multiple lines of systemic therapy relative to the medical management of patients at the time of initial cancer diagnosis. Workload metrics, including follow-up and new therapy initiation rates, must be measured to appropriately to meet increasingly complex and growing care demands. PMID- 29996074 TI - Medicaid's Path to Value-Based Reform. PMID- 29996075 TI - Echinococcal Cysts in the Liver. PMID- 29996076 TI - Case 21-2018: A 61-Year-Old Man with Grandiosity, Impulsivity, and Decreased Sleep. PMID- 29996077 TI - A Parallel Universe of Clinical Trials. PMID- 29996078 TI - Vertebral Hydatidosis. PMID- 29996079 TI - Oropharyngeal Tularemia from Freshly Pressed Grape Must. PMID- 29996081 TI - TAILORing Adjuvant Systemic Therapy for Breast Cancer. PMID- 29996080 TI - Stable, Don't Touch Nothing. PMID- 29996083 TI - Stream of Consciousness. PMID- 29996084 TI - A Trial of Blood-Pressure Reduction in Black Barbershops. PMID- 29996085 TI - Chronic Limb-Threatening Ischemia. PMID- 29996082 TI - Prevention of M. tuberculosis Infection with H4:IC31 Vaccine or BCG Revaccination. AB - BACKGROUND: Recent Mycobacterium tuberculosis infection confers a predisposition to the development of tuberculosis disease, the leading killer among global infectious diseases. H4:IC31, a candidate subunit vaccine, has shown protection against tuberculosis disease in preclinical models, and observational studies have indicated that primary bacille Calmette-Guerin (BCG) vaccination may offer partial protection against infection. METHODS: In this phase 2 trial, we randomly assigned 990 adolescents in a high-risk setting who had undergone neonatal BCG vaccination to receive the H4:IC31 vaccine, BCG revaccination, or placebo. All the participants had negative results on testing for M. tuberculosis infection on the QuantiFERON-TB Gold In-tube assay (QFT) and for the human immunodeficiency virus. The primary outcomes were safety and acquisition of M. tuberculosis infection, as defined by initial conversion on QFT that was performed every 6 months during a 2-year period. Secondary outcomes were immunogenicity and sustained QFT conversion to a positive test without reversion to negative status at 3 months and 6 months after conversion. Estimates of vaccine efficacy are based on hazard ratios from Cox regression models and compare each vaccine with placebo. RESULTS: Both the BCG and H4:IC31 vaccines were immunogenic. QFT conversion occurred in 44 of 308 participants (14.3%) in the H4:IC31 group and in 41 of 312 participants (13.1%) in the BCG group, as compared with 49 of 310 participants (15.8%) in the placebo group; the rate of sustained conversion was 8.1% in the H4:IC31 group and 6.7% in the BCG group, as compared with 11.6% in the placebo group. Neither the H4:IC31 vaccine nor the BCG vaccine prevented initial QFT conversion, with efficacy point estimates of 9.4% (P=0.63) and 20.1% (P=0.29), respectively. However, the BCG vaccine reduced the rate of sustained QFT conversion, with an efficacy of 45.4% (P=0.03); the efficacy of the H4:IC31 vaccine was 30.5% (P=0.16). There were no clinically significant between-group differences in the rates of serious adverse events, although mild-to-moderate injection-site reactions were more common with BCG revaccination. CONCLUSIONS: In this trial, the rate of sustained QFT conversion, which may reflect sustained M. tuberculosis infection, was reduced by vaccination in a high-transmission setting. This finding may inform clinical development of new vaccine candidates. (Funded by Aeras and others; C-040-404 ClinicalTrials.gov number, NCT02075203 .). PMID- 29996086 TI - 2i, or Not 2i: The Soliloquy of Nanog-Negative Mouse Embryonic Stem Cells. AB - In this issue of Stem Cell Reports, Hastreiter et al. (2018) use continuous time lapse imaging of mouse embryonic stem cells to investigate how the inhibition of GSK3b and MEK/ERK (2i) leads to homogeneous expression of the transcription factor Nanog. They show that both induction of Nanog expression and selection against cells expressing low levels of Nanog contribute to the homogeneous appearance of 2i cultures. PMID- 29996087 TI - Magnetic nanoparticles as a support for a copper (II) complex with nuclease activity. AB - Magnetic nanoparticles have been extensively explored for the development of platforms for drug delivery and imaging probes. In this work, we have used a modular capping strategy to produce magnetic gold-coated Fe3O4 (Fe3O4@Au) nanoparticles, which have been decorated with a copper (II) complex containing a thioether derivative of clip-phen (Fe3O4@Au@Cu), where the complex [Cu(2CP-Bz SMe)]2+ has affinity to bind DNA and proven nuclease activity (2CP-Bz-SMe=1,3 bis((1,10-phenanthrolin-2-yl)oxy)-N-(4-(methylthio)benzylidene)propan-2-imine). The functionalization of Fe3O4@Au with the copper complex occurs through the sulfur atom of the thioether moiety, as indicated by Raman scattering on surface. The magnetic measurements showed the nanomaterial Fe3O4@Au@Cu is still magnetic although the gold shell and the functionalization with the copper complex have diminished the magnetization due to the dilution of the magnetic core. The nuclease assays performed with Fe3O4@Au@Cu indicate that the nuclease activity of the nanomaterial toward the plasmid DNA involves an oxidative pathway in which H2O2 species is involved as intermediate in a Fenton-like reaction. Based on the electron paramagnetic resonance spectra (aN = 15.07 G, aH = 14.99 G), such nuclease activity is assigned, essentially, to the HO species indicating that the radical production property of [Cu(2CP-Bz-SMe)]2+ is successfully transferred to the core-shell gold-coated Fe3O4 magnetic nanoparticles. To the best of our knowledge, this is the first study reporting nuclease activity due to the reactive oxygen species generated by a copper complex immobilized on a gold coated magnetic nanoparticle. PMID- 29996088 TI - A Neural Circuit Underlying the Generation of Hot Flushes. AB - Hot flushes are a sudden feeling of warmth commonly associated with the decline of gonadal hormones at menopause. Neurons in the arcuate nucleus of the hypothalamus that express kisspeptin and neurokinin B (Kiss1ARH neurons) are candidates for mediating hot flushes because they are negatively regulated by sex hormones. We used a combination of genetic and viral technologies in mice to demonstrate that artificial activation of Kiss1ARH neurons evokes a heat dissipation response resulting in vasodilation (flushing) and a corresponding reduction of core-body temperature in both females and males. This response is sensitized by ovariectomy. Brief activation of Kiss1ARH axon terminals in the preoptic area of the hypothalamus recapitulates this response, while pharmacological blockade of neurokinin B (NkB) receptors in the same brain region abolishes it. We conclude that transient activation of Kiss1ARH neurons following sex-hormone withdrawal contributes to the occurrence of hot flushes via NkB release in the rostral preoptic area. PMID- 29996089 TI - Encoding of Conditioned Taste Aversion in Cortico-Amygdala Circuits. AB - Avoidance of potentially toxic food by means of conditioned taste aversion is critical for survival of many animals. However, the underlying neuronal mechanisms are poorly understood. Here, using two-photon calcium imaging of defined gustatory cortex neurons in vivo, we show that conditioned taste aversion dynamically shifts neuronal population coding by stimulus-specific recruitment of neurons that project to the basolateral amygdala. PMID- 29996090 TI - CAST/ELKS Proteins Control Voltage-Gated Ca2+ Channel Density and Synaptic Release Probability at a Mammalian Central Synapse. AB - In the presynaptic terminal, the magnitude and location of Ca2+ entry through voltage-gated Ca2+ channels (VGCCs) regulate the efficacy of neurotransmitter release. However, how presynaptic active zone proteins control mammalian VGCC levels and organization is unclear. To address this, we deleted the CAST/ELKS protein family at the calyx of Held, a CaV2.1 channel-exclusive presynaptic terminal. We found that loss of CAST/ELKS reduces the CaV2.1 current density with concomitant reductions in CaV2.1 channel numbers and clusters. Surprisingly, deletion of CAST/ELKS increases release probability while decreasing the readily releasable pool, with no change in active zone ultrastructure. In addition, Ca2+ channel coupling is unchanged, but spontaneous release rates are elevated. Thus, our data identify distinct roles for CAST/ELKS as positive regulators of CaV2.1 channel density and suggest that they regulate release probability through a post priming step that controls synaptic vesicle fusogenicity. PMID- 29996091 TI - A MicroRNA-Based Gene-Targeting Tool for Virally Labeling Interneurons in the Rodent Cortex. AB - More specific and broadly applicable viral gene-targeting tools for labeling neuron subtypes are needed to advance neuroscience research, especially in rodent transgenic disease models and genetically intractable species. Here, we develop a viral vector that restricts transgene expression to GABAergic interneurons in the rodent neocortex by exploiting endogenous microRNA regulation. Our interneuron targeting, microRNA-guided neuron tag, "GABA mAGNET," achieves >95% interneuron selective labeling in the mouse cortex, including in a murine model of autism and also some preferential labeling of interneurons in the rat brain. We demonstrate an application of our GABA mAGNET by performing simultaneous, in vivo optogenetic control of two distinct neuron subtypes. This interneuron labeling tool highlights the potential of microRNA-based viral gene targeting to specific neuron subtypes. PMID- 29996094 TI - RIG-I Recognizes the 5' Region of Dengue and Zika Virus Genomes. AB - The flavivirus genus comprises major human pathogens, such as Dengue (DENV) and Zika (ZIKV) viruses. RIG-I and MDA5 are key cytoplasmic pathogen recognition receptors that are implicated in detecting viral RNAs. Here, we show that RNAs that co-purified with RIG-I during DENV infection are immuno-stimulatory, whereas RNAs bound to MDA5 are not. An affinity purification method combined with next generation sequencing (NGS) revealed that the 5' region of the DENV genome is recognized by RIG-I. No DENV RNA was bound to MDA5. In vitro production of fragments of the DENV genome confirmed the NGS data and revealed that the 5' end of the genome, when bearing 5'-triphosphates, is the RIG-I ligand. The 5' region of the ZIKV genome is also a RIG-I agonist. We propose that RIG-I binds to the highly structured and conserved 5' region of flavivirus nascent transcripts before capping and that this mechanism leads to interferon secretion by infected cells. PMID- 29996093 TI - A Hepatocyte FOXN3-alpha Cell Glucagon Axis Regulates Fasting Glucose. AB - The common genetic variation at rs8004664 in the FOXN3 gene is independently and significantly associated with fasting blood glucose, but not insulin, in non diabetic humans. Recently, we reported that primary hepatocytes from rs8004664 hyperglycemia risk allele carriers have increased FOXN3 transcript and protein levels and liver-limited overexpression of human FOXN3, a transcriptional repressor that had not been implicated in metabolic regulation previously, increases fasting blood glucose in zebrafish. Here, we find that injection of glucagon into mice and adult zebrafish decreases liver Foxn3 protein and transcript levels. Zebrafish foxn3 loss-of-function mutants have decreased fasting blood glucose, blood glucagon, liver gluconeogenic gene expression, and alpha cell mass. Conversely, liver-limited overexpression of foxn3 increases alpha cell mass. Supporting these genetic findings in model organisms, non diabetic rs8004664 risk allele carriers have decreased suppression of glucagon during oral glucose tolerance testing. By reciprocally regulating each other, liver FOXN3 and glucagon control fasting glucose. PMID- 29996092 TI - Chromatin Accessibility Impacts Transcriptional Reprogramming in Oocytes. AB - Oocytes have a remarkable ability to reactivate silenced genes in somatic cells. However, it is not clear how the chromatin architecture of somatic cells affects this transcriptional reprogramming. Here, we investigated the relationship between the chromatin opening and transcriptional activation. We reveal changes in chromatin accessibility and their relevance to transcriptional reprogramming after transplantation of somatic nuclei into Xenopus oocytes. Genes that are silenced, but have pre-existing open transcription start sites in donor cells, are prone to be activated after nuclear transfer, suggesting that the chromatin signature of somatic nuclei influences transcriptional reprogramming. There are also activated genes associated with new open chromatin sites, and transcription factors in oocytes play an important role in transcriptional reprogramming from such genes. Finally, we show that genes resistant to reprogramming are associated with closed chromatin configurations. We conclude that chromatin accessibility is a central factor for successful transcriptional reprogramming in oocytes. PMID- 29996095 TI - Neuron-Astroglia Cell Fate Decision in the Adult Mouse Hippocampal Neurogenic Niche Is Cell-Intrinsically Controlled by COUP-TFI In Vivo. AB - In the dentate gyrus (DG) of the mouse hippocampus, neurogenesis and astrogliogenesis persist throughout life. Adult-born neurons and astrocytes originate from multipotent neural stem cells (NSCs) whose activity is tightly regulated within the neurogenic niche. However, the cell-intrinsic mechanisms controlling neuron-glia NSC fate choice are largely unknown. Here, we show COUP TFI/NR2F1 expression in DG NSCs and its downregulation upon neuroinflammation. By using in vivo inducible knockout lines, a retroviral-based loss-of-function approach and genetic fate mapping, we demonstrate that COUP-TFI inactivation in adult NSCs and/or mitotic progenitors reduces neurogenesis and increases astrocyte production without depleting the NSC pool. Moreover, forced COUP-TFI expression in adult NSCs/progenitors decreases DG astrogliogenesis and rescues the neuro-astrogliogenic imbalance under neuroinflammation. Thus, COUP-TFI is necessary and sufficient to promote neurogenesis by suppressing astrogliogenesis. Our data propose COUP-TFI as a central regulator of the neuron-astroglia cell fate decision and a key modulator during neuroinflammation in the adult hippocampus. PMID- 29996096 TI - Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Abeta Induced Changes in Neural Activity. AB - Homeostatic synaptic plasticity (HSP) is the ability of neurons to exert compensatory changes in response to altered neural activity. How pathologically induced activity changes are intertwined with HSP mechanisms is unclear. We show that, in cholinergic neurons from Drosophila, beta-amyloid (Abeta) peptides Abeta40 and Abeta42 both induce an increase in spontaneous activity. In a transgenic line expressing Abeta42, we observe that this early increase in spontaneous activity is followed by a dramatic reduction in spontaneous events, a progression that has been suggested to occur in cholinergic brain regions of mammalian models of Alzheimer's disease. We present evidence that the early enhancement in synaptic activity is mediated by the Drosophila alpha7 nicotinic acetylcholine receptor (nAChR) and that, later, Abeta42-induced inhibition of synaptic events is a consequence of Dalpha7-dependent HSP mechanisms induced by earlier hyperactivity. Thus, while HSP may initially be an adaptive response, it may also drive maladaptive changes and downstream pathologies. PMID- 29996097 TI - Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model. AB - Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability. PMID- 29996098 TI - The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis. AB - Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1 neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection. PMID- 29996099 TI - Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells. AB - The PD-1 pathway, consisting of the co-inhibitory receptor PD-1 on T cells and its ligand (PD-L1) on antigen-presenting cells (APCs), is a major mechanism of tumor immune evasion. PD-1 and PD-L1 blockade antibodies have produced remarkable clinical activities against a subset of cancers. Binding between T cell-intrinsic PD-1 and APC-intrinsic PD-L1 triggers inhibitory signaling to attenuate the T cell response. Here, we report that PD-1 is co-expressed with PD-L1 on tumor cells and tumor-infiltrating APCs. Using reconstitution and cell culture assays, we demonstrate that the co-expressed PD-1 binds to PD-L1 in cis. Such interaction inhibits the ability of PD-L1 to bind T cell-intrinsic PD-1 in trans and, in turn, represses canonical PD-L1/PD-1 inhibitory signaling. Selective blockade of tumor-intrinsic PD-1 frees up tumor-intrinsic PD-L1 to inhibit T cell signaling and cytotoxicity. Our study uncovers another dimension of PD-1 regulation, with important therapeutic implications. PMID- 29996100 TI - PI3K-Mediated Blimp-1 Activation Controls B Cell Selection and Homeostasis. AB - Activation of phosphoinositide 3-kinase (PI3K) signaling plays a central role in regulating proliferation and survival of B cells. Here, we tested the hypothesis that B cell receptor (BCR)-mediated activation of PI3K induces the terminal differentiation factor Blimp-1 that interferes with proliferation and survival, thereby controlling the expansion of activated B cells. In fact, B-cell-specific inactivation of Pten, the negative regulator of PI3K signaling, leads to deregulated PI3K activity and elevated Blimp-1 expression. Combined deficiency for Pten and Blimp-1 results in abnormal expansion of B-1 B cells and splenomegaly. Interestingly, Blimp-1 also acts at early stages of B cell development to regulate B cell selection, as Blimp-1 deficiency results in an increased proportion of autoreactive B cells. Together, our data suggest that the combined requirement of deregulated PI3K signaling in addition to defective terminal differentiation represents the basis for proper selection and expansion of developing B cells. PMID- 29996101 TI - B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells. AB - Type 1 interferon (T1IFN) signaling promotes inflammation and lupus pathology, but its role in autoreactive B cell development in the antibody-forming cell (AFC) and germinal center (GC) pathways is unclear. Using a lupus model that allows for focused study of the AFC and GC responses, we show that T1IFN signaling is crucial for autoreactive B cell development in the AFC and GC pathways. Through bone marrow chimeras, DNA-reactive B cell transfer, and GC specific Cre mice, we confirm that IFNalphaR signaling in B cells promotes autoreactive B cell development into both pathways. Transcriptomic analysis reveals gene expression alterations in multiple signaling pathways in non-GC and GC B cells in the absence of IFNalphaR. Finally, we find that T1IFN signaling promotes autoreactive B cell development in the AFC and GC pathways by regulating BCR signaling. These data suggest value for anti-IFNalphaR therapy in individuals with elevated T1IFN activity before clinical disease onset. PMID- 29996102 TI - Myosin II Synergizes with F-Actin to Promote DNGR-1-Dependent Cross-Presentation of Dead Cell-Associated Antigens. AB - Conventional type 1 DCs (cDC1s) excel at cross-presentation of dead cell associated antigens partly because they express DNGR-1, a receptor that recognizes exposed actin filaments on dead cells. In vitro polymerized F-actin can be used as a synthetic ligand for DNGR-1. However, cellular F-actin is decorated with actin-binding proteins, which could affect DNGR-1 recognition. Here, we demonstrate that myosin II, an F-actin-associated motor protein, greatly potentiates the binding of DNGR-1 to F-actin. Latex beads coated with F-actin and myosin II are taken up by DNGR-1+ cDC1s, and antigen associated with those beads is efficiently cross-presented to CD8+ T cells. Myosin II-deficient necrotic cells are impaired in their ability to stimulate DNGR-1 or to serve as substrates for cDC1 cross-presentation to CD8+ T cells. These results provide insights into the nature of the DNGR-1 ligand and have implications for understanding immune responses to cell-associated antigens and for vaccine design. PMID- 29996103 TI - NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide (NAD+) glycohydrolase that induces necrosis in infected macrophages. Here, we show that NAD+ depletion by TNT activates RIPK3 and MLKL, key mediators of necroptosis. Notably, Mtb bypasses the canonical necroptosis pathway since neither TNF-alpha nor RIPK1 are required for macrophage death. Macrophage necroptosis is associated with depolarized mitochondria and impaired ATP synthesis, known hallmarks of Mtb-induced cell death. These results identify TNT as the main trigger of necroptosis in Mtb infected macrophages. Surprisingly, NAD+ depletion itself was sufficient to trigger necroptosis in a RIPK3- and MLKL-dependent manner by inhibiting the NAD+ salvage pathway in THP-1 cells or by TNT expression in Jurkat T cells. These findings suggest avenues for host-directed therapies to treat tuberculosis and other infectious and age-related diseases in which NAD+ deficiency is a pathological factor. PMID- 29996104 TI - Structural Definition of a Unique Neutralization Epitope on the Receptor-Binding Domain of MERS-CoV Spike Glycoprotein. AB - The major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the beta5-beta6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the "up" position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection. PMID- 29996105 TI - Accommodation of Helical Imperfections in Rhodobacter sphaeroides Argonaute Ternary Complexes with Guide RNA and Target DNA. AB - Prokaryotic Argonaute (Ago) proteins were recently shown to target foreign genetic elements, thus making them a perfect model for studies of interference mechanisms. Here, we study interactions of Rhodobacter sphaeroides Ago (RsAgo) with guide RNA (gRNA) and fully complementary or imperfect target DNA (tDNA) using biochemical and structural approaches. We show that RsAgo can specifically recognize both the first nucleotide in gRNA and complementary nucleotide in tDNA, and both interactions contribute to nucleic acid binding. Non-canonical pairs and bulges on the target strand can be accommodated by RsAgo with minimal perturbation of the duplex but significantly reduce RsAgo affinity to tDNA. Surprisingly, mismatches between gRNA and tDNA induce dissociation of the guide target duplex from RsAgo. Our results reveal plasticity in the ability of Ago proteins to accommodate helical imperfections, show how this might affect the efficiency of RNA silencing, and suggest a potential mechanism for guide release and Ago recycling. PMID- 29996107 TI - Ultraconserved Elements Occupy Specific Arenas of Three-Dimensional Mammalian Genome Organization. AB - This study explores the relationship between three-dimensional genome organization and ultraconserved elements (UCEs), an enigmatic set of DNA elements that are perfectly conserved between the reference genomes of distantly related species. Examining both human and mouse genomes, we interrogate the relationship of UCEs to three features of chromosome organization derived from Hi-C studies. We find that UCEs are enriched within contact domains and, further, that the subset of UCEs within domains shared across diverse cell types are linked to kidney-related and neuronal processes. In boundaries, UCEs are generally depleted, with those that do overlap boundaries being overrepresented in exonic UCEs. Regarding loop anchors, UCEs are neither overrepresented nor underrepresented, but those present in loop anchors are enriched for splice sites. Finally, as the relationships between UCEs and human Hi-C features are conserved in mouse, our findings suggest that UCEs contribute to interspecies conservation of genome organization and, thus, genome stability. PMID- 29996106 TI - Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma. AB - Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively. PMID- 29996108 TI - Genome-wide CRISPR-KO Screen Uncovers mTORC1-Mediated Gsk3 Regulation in Naive Pluripotency Maintenance and Dissolution. AB - The genetic basis of naive pluripotency maintenance and loss is a central question in embryonic stem cell biology. Here, we deploy CRISPR-knockout-based screens in mouse embryonic stem cells to interrogate this question through a genome-wide, non-biased approach using the Rex1GFP reporter as a phenotypic readout. This highly sensitive and efficient method identified genes in diverse biological processes and pathways. We uncovered a key role for negative regulators of mTORC1 in maintenance and exit from naive pluripotency and provided an integrated account of how mTORC1 activity influences naive pluripotency through Gsk3. Our study therefore reinforces Gsk3 as the central node and provides a comprehensive, data-rich resource that will improve our understanding of mechanisms regulating pluripotency and stimulate avenues for further mechanistic studies. PMID- 29996109 TI - Quantitative Phosphoproteomics Reveals the Signaling Dynamics of Cell-Cycle Kinases in the Fission Yeast Schizosaccharomyces pombe. AB - Multiple protein kinases regulate cell-cycle progression, of which the cyclin dependent kinases (CDKs) are thought to act as upstream master regulators. We have used quantitative phosphoproteomics to analyze the fission yeast cell cycle at sufficiently high temporal resolution to distinguish fine-grain differences in substrate phosphorylation dynamics on a proteome-wide scale. This dataset provides a useful resource for investigating the regulatory dynamics of cell cycle kinases and their substrates. For example, our analysis indicates that the substrates of different mitotic kinases (CDK, NIMA-related, Polo-like, and Aurora) are phosphorylated in sequential, kinase-specific waves during mitosis. Phosphoproteomics analysis after chemical-genetic manipulation of CDK activity suggests that the timing of these waves is established by the differential dependency of the downstream kinases on upstream CDK. We have also examined the temporal organization of phosphorylation during G1/S, as well as the coordination between the NDR-related kinase Orb6, which controls polarized growth, and other cell-cycle kinases. PMID- 29996111 TI - Synthesis, characterization, monoamine oxidase inhibition, molecular docking and dynamic simulations of novel 2,1-benzothiazine-2,2-dioxide derivatives. AB - In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4 dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues. PMID- 29996110 TI - A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases. AB - A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes-including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)-show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA. PMID- 29996112 TI - Occupational exposure to high-frequency electromagnetic fields and brain tumor risk in the INTEROCC study: An individualized assessment approach. AB - INTRODUCTION: In 2011, the International Agency for Research on Cancer classified radiofrequency (RF) electromagnetic fields (EMF) as possibly carcinogenic to humans (group 2B), although the epidemiological evidence for the association between occupational exposure to RF-EMF and cancer was judged to be inadequate, due in part to limitations in exposure assessment. This study examines the relation between occupational RF and intermediate frequency (IF) EMF exposure and brain tumor (glioma and meningioma) risk in the INTEROCC multinational population based case-control study (with nearly 4000 cases and over 5000 controls), using a novel exposure assessment approach. METHODS: Individual indices of cumulative exposure to RF and IF-EMF (overall and in specific exposure time windows) were assigned to study participants using a source-exposure matrix and detailed interview data on work with or nearby EMF sources. Conditional logistic regression was used to investigate associations with glioma and meningioma risk. RESULTS: Overall, around 10% of study participants were exposed to RF while only 1% were exposed to IF-EMF. There was no clear evidence for a positive association between RF or IF-EMF and the brain tumors studied, with most results showing either no association or odds ratios (ORs) below 1.0. The largest adjusted ORs were obtained for cumulative exposure to RF magnetic fields (as A/m-years) in the highest exposed category (>=90th percentile) for the most recent exposure time window (1-4 years before the diagnosis or reference date) for both glioma, OR = 1.62 (95% confidence interval (CI): 0.86, 3.01) and meningioma (OR = 1.52, 95% CI: 0.65, 3.55). CONCLUSION: Despite the improved exposure assessment approach used in this study, no clear associations were identified. However, the results obtained for recent exposure to RF electric and magnetic fields are suggestive of a potential role in brain tumor promotion/progression and should be further investigated. PMID- 29996113 TI - Anaerobic digestion of municipal solid waste: Energy and carbon emission footprint. AB - Anaerobic digestion (AD) serves as a promising alternative for waste treatment and a potential solution to improve the energy supply security. The feasibility of AD has been proven in some of the technologically and agriculturally advanced countries. However, development is still needed for worldwide implementation, especially for AD process dealing with municipal solid waste (MSW). This paper reviews various approaches and stages in the AD of MSW, which used to optimise the biogas production and quality. The assessed stages include pre-treatment, digestion process, post-treatment as well as the waste collection and transportation. The latest approaches and integrated system to improve the AD process are also presented. The stages were assessed in a relatively quantitative manner. The range of energy requirement, carbon emission footprint and the percentage of enhancement are summarised. Thermal hydrolysis pre-treatment is identified to be less suitable for MSW (-5% to +15.4% enhancement), unless conducted in the two-phase AD system. Microwave pre-treatment shows consistent performance in elevating the biogas production of MSW, but the energy consumption (114.24-8,040 kWeh t-1) and carbon emission footprint (59.93-4,217.78 kg CO2 t-1 waste) are relatively high. Chemical (~0.43 kWeh m-3) and membrane-based (~0.45 kWeh m-3) post-treatments are suggested to be a lower energy consumption approach for upgrading the biogas. The feasibility in terms of cost (scale up) and other environmental impacts (non-CO2 footprint) needs to be further assessed. This study provides an overview to facilitate further development and extended implementation of AD. PMID- 29996114 TI - Effects of FGFR1 Gene Polymorphisms on the Risk of Breast Cancer and FGFR1 Protein Expression. AB - BACKGROUND/AIMS: Fibroblast growth factor receptor 1 (FGFR1) is widely considered to play an important role in mammary carcinogenesis. Some common variants in FGFR1 might be associated with its expression, and further affect breast cancer risk. The aim of this study was to investigate effects of single-nucleotide polymorphisms (SNPs) in FGFR1 on breast cancer susceptibility and FGFR1 protein expression. METHODS: SNPs rs17182023, rs17175624 and rs10958704 in FGFR1 were genotyped in 747 breast cancer cases and 716 healthy controls by SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. Immunohistochemistry(IHC) was used to detect FGFR1 protein expression, and the association of FGFR1 polymorphisms with its protein expression was analyzed by Pearson's chi-square test. Additionally, Cox regression and Kaplan-Meier analysis was used to evaluate the association between FGFR1 protein expression and breast cancer prognosis. RESULTS: The minor allele of rs17182023 in FGFR1 was significantly associated with reduced breast cancer risk, with an odds ratio of 0.800 (95%CI = 0.684-0.935). No significant associations were detected between other SNPs and breast cancer. Moreover, rs17182023 was correlated to FGFR1 protein expression (P = 0.006), and patients with high FGFR1 protein expression tended to have poor outcomes. CONCLUSIONS: SNP rs17182023 was correlated to reduced breast cancer risk, and was associated with FGFR1 protein expression. High FGFR1 protein expression was an independent risk factor of breast cancer, and resulted in poor prognosis. PMID- 29996115 TI - Down-Regulation of MiR-150 Alleviates Inflammatory Injury Induced by Interleukin 1 via Targeting Kruppel-Like Factor 2 in Human Chondrogenic Cells. AB - BACKGROUND/AIMS: Interleukin-1 (IL-1) is known to be involved in cartilage degeneration following joint injury or due to osteoarthritis. In the present study, we explored the effects of miR-150 on IL-1-stimulated human chondrogenic cells ATDC5. METHODS: ATDC5 cells were transfected with the mimic, inhibitor or negative controls specific for miR-150, and subsequently treated by IL-1. CCK8 assay, PI and FITC-conjugated Annexin V double-staining, Western blot, qRT-PCR and ELISA assay were performed to determine the changes of cell viability, apoptosis, and the release of pro-inflammatory cytokines. Targeting relationship between miR-150 and KLF2 was detected by dual luciferase activity assay. RESULTS: IL-1 reduced cell viability, induced apoptosis, and enhanced the expression and release of pro-inflammatory cytokines (IL-6, IL-8 and TNF-alpha) in ATDC5 cells. IL-1 also increased the expression of miR-150. Suppression of miR-150 alleviated IL-1-induced cell damage in ATDC5 cells, while overexpression of miR-150 resulted in an opposite impact. KLF2 was negatively regulated by miR-150, and it was proved as a target gene of miR-150. KLF2 overexpression exhibited protective actions in IL-1-injured ATDC5 cells, even if miR-150 was suppressed in cell. Moreover, IL-1-induced activation of NF-kB and Notch pathways was alleviated by KLF2 overexpression. CONCLUSIONS: Suppression of miR-150 led to up-regulation of KLF2, which in turn protected ATDC5 cells against IL-1-induced injury. PMID- 29996116 TI - The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke. AB - BACKGROUND/AIMS: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of alpha-Lipoic acid (alpha LA) remain poorly understood. Herein, we investigated the potential role of alpha LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. METHODS: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-kappaB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-kappaB. RESULTS: Both 20 mg/kg and 40 mg/kg of alpha-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, alpha-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1beta, IL-6, TNF alpha and IL-10, and attenuated the activation of NF-kappaB after MCAO. alpha-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-kappaB in LPS-stimulated BV2 microglia. CONCLUSIONS: alpha-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of alpha-LA might be mediated by inhibition of NF-kappaB activation via regulating phosphorylation and nuclear translocation of p65. PMID- 29996117 TI - Blocking Mammalian Target of Rapamycin (mTOR) Alleviates Neuropathic Pain Induced by Chemotherapeutic Bortezomib. AB - BACKGROUND/AIMS: Bortezomib (BTZ) is largely used as a chemotherapeutic agent for the treatment of cancer. However, one of the significant limiting complications of BTZ is painful peripheral neuropathy during BTZ therapy. Drugs preventing and/or treating the painful symptoms induced by BTZ are lacking since the underlying mechanisms leading to neuropathic pain remain largely unclear. The purposes of this study were to examine 1) the effects of blocking mammalian target of rapamycin (mTOR) on mechanical pain and cold hypersensitivity evoked by BTZ and 2) the underlying mechanisms responsible for the role of mTOR in regulating BTZ-induced neuropathic pain. METHODS: Behavioral test was performed to determine mechanical pain and cold sensitivity in a rat model. Western blot analysis and ELISA were used to examine expression of mTOR and phosphatidylinositide 3-kinase (p-PI3K) signals, and the levels of substance P and calcitonin gene-related peptide (CGRP). RESULTS: Systemic injection of BTZ significantly increased mechanical pain and cold sensitivity as compared with control animals (P< 0.05 vs. control rats). The expression of p-mTOR, mTOR mediated phosphorylation of p70 ribosomal S6 protein kinase 1 (p-S6K1), 4E binding protein 4 (p-4E-BP1) as well as p-PI3K was amplified in the dorsal horn of spinal cord of BTZ rats as compared with control rats. Blocking mTOR by intrathecal infusion of rapamycin attenuated mechanical pain and cold hypersensitivity. Blocking PI3K signal also attenuated activities of mTOR, which was accompanied with decreasing neuropathic pain. Inhibition of either mTOR or PI3K blunted enhancement of the spinal substance P and CGRP in BTZ rats. CONCLUSIONS: The data for the first time revealed specific signaling pathways leading to BTZ-induced peripheral neuropathic pain, including the activation of mTOR and PI3K. Inhibition of these signal pathways alleviates pain. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of peripheral painful neuropathy observed during chemotherapeutic application of BTZ. PMID- 29996118 TI - CDK13 RNA Over-Editing Mediated by ADAR1 Associates with Poor Prognosis of Hepatocellular Carcinoma Patients. AB - BACKGROUND/AIMS: Aberrant RNA editing, mediated by adenosine deaminases acting on RNA (ADAR), serves as a post-transcriptional event participating in tumorigenesis and prognosis. However, the RNA editing profiles during HCC progression and their clinical correlations remain unclear. METHODS: Multiple tissue samples were collected from an advanced HCC patient. RNA-seq was performed to obtain the RNA editing profiles for each sample. Two RNA editing sites from CDK13 were further validated in 60 HCC patients; and their potential regulatory mechanisms were investigated. RESULTS: In-depth analysis of the RNA-seq data revealed a significant number of editing sites (632-816) in coding regions for each tissue sample, showing branched evolution during tumorigenesis and metastasis. Two editing sites (Q103R and K96R) in CDK13 showed significant over-editing in tumor, and these phenomenon were validated in 60 HCC patients. Furthermore, the clinicopathological analysis revealed that these CDK13 over-editing sites were positively associated with TNM, PVTT and poor prognosis. In addition, the editing level of these sites were significantly correlated with the expression of ADAR1. Loss of function assays further proved that these CDK13 over-editing sites were mediated by ADAR1 in HCC cells. CONCLUSIONS: CDK13 RNA over-editing sites mediated by ADAR1 may serve as novel cancer driver events in HCC progression. PMID- 29996119 TI - The Molecular Mechanism of Alpha-Synuclein Dependent Regulation of Protein Phosphatase 2A Activity. AB - BACKGROUND/AIMS: Alpha-synuclein (alpha-Syn) is a neuronal protein that is highly implicated in Parkinson's disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. alpha-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of alpha-Syn regulating PP2A activity. METHODS: alpha-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A Calpha and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between alpha-Syn and PP2A Calpha was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. RESULTS: The hydrophobic non-amyloid component (NAC) domain of alpha-Syn interacted with PP2A Calpha and upregulated its activity. alpha-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of alpha-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A Calpha, the residue of I123 was responsible for PP2A to interact with alpha-Syn, and its hydrophilic mutation blocked its interaction with alpha-Syn as well as its activity upregulation by alpha-Syn. CONCLUSIONS: alpha-Syn bound to PP2A Calpha by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of alpha-Syn or hydrophilic mutation on the residue I123 in PP2A Calpha all reduced PP2A activity upregulation by alpha-Syn. Overall, we explored the mechanism of alpha-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis. PMID- 29996120 TI - The Protective Effect of Autophagy on DNA Damage in Mouse Spermatocyte-Derived Cells Exposed to 1800 MHz Radiofrequency Electromagnetic Fields. AB - BACKGROUND/AIMS: The effects of exposure to radiofrequency electromagnetic fields (RF-EMFs) on the male reproductive system have raised public concern and studies have shown that exposure to RF-EMFs can induce DNA damage and autophagy. However, there are no related reports on the role of autophagy in DNA damage in spermatocytes, especially after exposure to RF-EMFs. The aim of the present study was to determine the mechanism and role of autophagy induced by RF-EMFs in spermatozoa cells. METHODS: Mouse spermatocyte-derived cells (GC-2) were exposed to RF-EMFs 4 W/kg for 24 h. The level of reactive oxygen species (ROS) was determined by ROS assay kit. Comet assay was utilized to detect DNA damage. Autophagy was detected by three indicators: LC3II/LC3I, autophagic vacuoles, and GFP-LC3 dots, which were measured by western blot, transmission electron microscopy, and transfection with GFP-LC3, respectively. The expression of the molecular signaling pathway AMP-activated protein kinase (AMPK)/mTOR was determined by western blot. RESULTS: The results showed that RF-EMFs induced autophagy and DNA damage in GC-2 cells via ROS generation, and the autophagy signaling pathway AMPK/mTOR was activated by ROS generation. Furthermore, following inhibition of autophagy by knockdown of AMPKalpha, increased DNA damage was observed in GC-2 cells following RF-EMFs exposure, and overexpression of AMPKalpha promoted autophagy and attenuated DNA damage. CONCLUSIONS: These findings demonstrated that the autophagy which was induced by RF-EMFs via the AMPK/mTOR signaling pathway could prevent DNA damage in spermatozoa cells. PMID- 29996121 TI - N-Propargyl Caffeamide Skews Macrophages Towards a Resolving M2-Like Phenotype Against Myocardial Ischemic Injury via Activating Nrf2/HO-1 Pathway and Inhibiting NF-KB Pathway. AB - BACKGROUND/AIMS: Macrophages exhibit dynamic pro-inflammatory and resolving activities in myocardial infarction. The present study investigated whether caffeic acid derivatives could induce macrophage polarization towards a resolving M2 phenotype against myocardial infarction injury. METHODS: Western blotting, RT PCR and flow cytometry techniques are used to evaluate macrophage biomarkers expression and specific proteins in the related signaling pathways. Ligation of the left anterior descending artery induced rat model of myocardial infarction, TTC staining and immunohistochemical staining are used to examine cardioprotective effect in vivo. RESULTS: We initially evaluated the anti inflammatory activity of four caffeic acid derivatives including n-propargyl caffeamide (PACA) in RAW264.7 macrophages. As result, PACA selectively suppressed the up-regulation of inducible nitric oxide synthase (iNOS) over cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS)-stimulated cells. We subsequently examined the effects of PACA on macrophage polarization by determining macrophage biomarkers. PACA down-regulated M1 biomarkers (e.g., iNOS, tumor necrosis factor alpha (TNF-alpha), C-X-C motif chemokine 10 (CXCL10) and CD80) but up-regulated M2 biomarkers (e.g., Ym-1 and arginase-1). On the other hand, PACA suppressed macrophage chemotaxis while enhanced macrophage phagocytosis. We further examined the in vivo cardioprotective activity of PACA in a rat model of myocardial infarction. Following ligation of the left anterior descending artery, PACA treatment effectively reduced myocardial infarct size and promoted macrophage M2 polarization. We finally explored the underlying mechanisms. We found that PACA attenuated LPS-induced NF-KB activation while activated Nrf2/HO-1 pathway. HO-1 inhibitor SnPP attenuated the effects of PACA on iNOS expression in LPS challenged macrophages, possibly by regulating the cross-talk between HO-1 and NF KB pathways. CONCLUSIONS: The key finding from the present study was that PACA promoted timely switch of macrophage phenotypes from pro-inflammatory M1 to resolving M2. We anticipate that PACA is a potential drug candidate for the resolution of inflammation and cardiac repair after myocardial infarction. PMID- 29996122 TI - Compound K Inhibits Autophagy-Mediated Apoptosis Through Activation of the PI3K Akt Signaling Pathway Thus Protecting Against Ischemia/Reperfusion Injury. AB - BACKGROUND/AIMS: A series of reports revealed that autophagy and apoptosis exerted detrimental effects on the pathology of cardiac ischemia/reperfusion (I/R) injury. Ginsenoside compound K (CK), a major intestinal metabolite underlying the pharmacological actions of orally administered ginseng, has a protective effect against myocardial I/R injury. However, the molecular mechanisms by which CK protects against I/R injury remain unclear. In this study, we hypothesized that the cardioprotective effects of CK against I/R injury are mediated by inhibiting autophagy/apoptosis-related signaling pathways in H9c2 cardiomyocyte cells. METHODS: H9c2 cells were incubated with CK and exposed to I/R. Cell viability and damage was analyzed by MTT and lactate dehydrogenase assays. Reactive oxygen species (ROS) generation, mitochondrial damage, and cell apoptosis were analyzed by flow cytometry and TUNEL staining. The expression of autophagy, apoptosis, and related signaling proteins was analyzed by Western blotting and immunofluorescence staining. RESULTS: CK pretreatment promoted cell viability and attenuated ROS accumulation and intracellular mitochondrial damage induced by I/R injury Moreover, CK reduced autophagy by regulating the formation of phagocytic precursors to autophagosomes and also inhibited apoptosis through a mitochondrial-mediated pathway. Additionally the cardioprotective effect of CK against I/R injury was mainly through the activation of the PI3K-Akt signaling pathway. CONCLUSIONS: CK pretreatment inhibits autophagy-mediated apoptosis induced by I/R injury through the activation of the PI3K-Akt signaling pathway, which reveals that CK may be one of the key bioactive ingredients of ginseng for the treatment of myocardial I/R injury. PMID- 29996124 TI - Leptomeningeal Myelomatosis: A Rare but Devastating Manifestation of Multiple Myeloma Diagnosed Using Cytology, Flow Cytometry, and Fluorescent in situ Hybridization. AB - INTRODUCTION: Involvement of the central nervous system in patients with multiple myeloma is a rare event. We evaluated the diagnostic workup and prognosis of patients with leptomeningeal myelomatosis (LMM). METHODS: Between April 2005 and April 2016, we identified 16 cases with LMM. The involvement was diagnosed by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) cytology as well as flow cytometry. Fluorescence in situ hybridization (FISH) was used in 8/16 cases. In 1 case, genome-wide screening for genetic alterations using single-nucleotide polymorphism (SNP) array analysis was performed. RESULTS: The median time from initial diagnosis until the occurrence of LMM was 434 days. At diagnosis, the median age was 60 years. The median cell count was 21/uL (range 1-1,333/uL). All CSF samples showed malignant pleocytosis, confirmed by flow cytometry in 12/16 patients. FISH revealed high-risk features in the majority of samples. Treatment for LMM consisted of intrathecal chemotherapy and radiation therapy. Genome-wide screening assays revealed different subclones. The outcome was dismal with a median overall survival after the diagnosis of LMM of 82 days. CONCLUSION: By combining several technical procedures, it is possible to identify most patients with LMM. Management of affected patients is challenging and the survival short after a diagnosis of LMM. PMID- 29996123 TI - Cerebral Haemodynamics following Acute Ischaemic Stroke: Effects of Stroke Severity and Stroke Subtype. AB - BACKGROUND: Acute ischaemic stroke (AIS) patients often show impaired cerebral autoregulation (CA). We tested the hypothesis that CA impairment and other alterations in cerebral haemodynamics are associated with stroke subtype and severity. METHODS: AIS patients (n = 143) were amalgamated from similar studies. Data from baseline (< 48 h stroke onset) physiological recordings (beat-to-beat blood pressure [BP], cerebral blood flow velocity (CBFV) from bilateral insonation of the middle cerebral arteries) were calculated for mean values and autoregulation index (ARI). Differences were assessed between stroke subtype (Oxfordshire Community Stroke Project [OCSP] classification) and severity (National Institutes of Health Stroke Scale [NIHSS] score < 5 and 5-25). Correlation coefficients assessed associations between NIHSS and physiological measurements. RESULTS: Thirty-two percent of AIS patients had impaired CA (ARI < 4) in affected hemisphere (AH) that was similar between stroke subtypes and severity. CBFV in AH was comparable between stroke subtype and severity. In unaffected hemisphere (UH), differences existed in mean CBFV between lacunar and total anterior circulation OCSP subtypes (42 vs. 56 cm*s-1, p < 0.01), and mild and moderate-to-severe stroke severity (45 vs. 51 cm*s-1, p = 0.04). NIHSS was associated with peripheral (diastolic and mean arterial BP) and cerebral haemodynamic parameters (CBFV and ARI) in the UH. CONCLUSIONS: AIS patients with different OCSP subtypes and severity have homogeneity in CA capability. Cerebral haemodynamic measurements in the UH were distinguishable between stroke subtype and severity, including the association between deteriorating ARI in UH with stroke severity. More studies are needed to determine their clinical significance and to understand the determinants of CA impairment in AIS patients. PMID- 29996125 TI - Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1. AB - BACKGROUND/AIMS: Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown. METHODS: Tert-butylhydroquinone (t-BHQ) and small interfering RNAs (siRNAs) were used to regulate Nrf2 expression, while nicotinamide and siRNAs were used to regulate sirtuin 1 (Sirt1) activity and expression, respectively. Mitochondrial superoxide, membrane potential and ATP levels were measured to assess changes in mitochondrial function. Nephrin and synaptopodin expression were measured by western blot analysis. Human podocytes and db/db diabetic mice were used in this study. RESULTS: t-BHQ pretreatment of human podocytes exposed to high glucose (HG) alleviated mitochondrial dysfunction, enhanced the expression of Sirt1, nephrin and synaptopodin and lowered BSA permeability compared with podocytes exposed to HG without t-BHQ pretreatment (p< 0.05). Human podocytes exposed to HG had more severe mitochondrial dysfunction, lower expression of Sirt1, synaptopodin and nephrin and higher BSA permeability than podocytes exposed to HG when Nrf2 expression was downregulated by siRNAs (p< 0.05). The protection provided by activation of the Nrf-ARE pathway in podocytes exposed to HG was partially diminished when Sirt1 expression or activity was decreased by siRNAs or inhibitor compared with podocytes exposed to HG and pretreated with t-BHQ (p< 0.05). When nicotinamide and t-BHQ were both administered to db/db mice, we observed higher levels of urinary albumin/creatinine, lower nephrin and synaptopodin expression, more severe mesangial matrix deposition, collagen deposition on pathological slides and mitochondrial structural damage in podocytes compared to db/db mice treated only with t-BHQ. CONCLUSIONS: Our findings suggest that crosstalk between Sirt1 and the Nrf2-ARE anti-oxidative pathway forms a positive feedback loop and that protection provided by t-BHQ activation of the Nrf2-ARE pathway in db/db mice is partly dependent on Sirt1. PMID- 29996126 TI - Pharmacogenetic Warfarin Dosing Algorithms: Validity in Egyptian Patients. AB - BACKGROUND/AIMS: Data from previous reports, addressing the significance of genotype-guided dosing of warfarin in Egyptian patients, are infrequent and controversial. This study is aimed at demonstrating the validity of genetic dosing algorithms in Egyptian patients on warfarin therapy. METHODS: A total of 100 Egyptian patients on a stable maintenance daily dose of warfarin were enrolled. The predicted warfarin dose for each patient was calculated using the warfarin dosing table, the Gage and the International Warfarin Pharmacogenetics Consortium (IWPC) clinical algorithms and the Gage and the IWPC genetic algorithms and compared to the actual dose. The accuracy of warfarin dosing algorithms was assessed by using the linear regression analysis. RESULTS: The most accurate model in predicting the ideal dose was the Gage genetic algorithm by R2 of 50.4% and the IWPC genetic algorithm by R2 of 42.3%, followed by the warfarin dosing table by R2 of 19.1%, and the Gage clinical algorithm by R2 of 18.9% and the least accurate was the IWPC clinical algorithm by R2 of 9.4%. CONCLUSIONS: The Gage -genetic warfarin dosing algorithm is the best model that could be implemented in Egyptian patients starting warfarin therapy. PMID- 29996128 TI - Sequential Dexamethasone and Aflibercept Treatment in Patients with Diabetic Macular Edema: Structural and Functional Outcomes at 52 Weeks. AB - OBJECTIVE: The aim of this paper is to compare intravitreous aflibercept versus dexamethasone implant followed by aflibercept (sequential treatment group) in patients with diabetic macular edema (DME). METHODS: We conducted an observational retrospective study in naive DME patients, 15 treated only with aflibercept (a monthly injection for the first 5 consecutive doses, followed by an injection every 2 months), and 15 treated with a single dexamethasone implant followed by bimonthly aflibercept. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and qualitative features as well as adverse events were assessed at baseline and at 2, 6, and 12 months. RESULTS: BCVA increased from 70.8 +/- 4.1 to 83.5 +/- 2.7 letters with aflibercept and from 75.6 +/- 2.7 to 86.5 +/- 2.5 with sequential treatment (p = 0.551). CMT decreased from 411 +/- 26.1 to 288.1 +/- 10.5 with aflibercept and from 411.4 +/- 24.3 to 260.8 +/- 17.9 in the sequential treatment group. The differences between the 2 groups, in terms of visual gain and decreased MT, were not statistically significant (p > 0.05). Nine and 6 injections and 9 and 7 monitoring visits were performed. CONCLUSION: Sequential treatment in DME, starting with dexamethasone and followed by aflibercept, is a promising alternative that can reduce the treatment burden in the first year without statistically significant differences in terms of visual gain and decreased MT compared to aflibercept only. PMID- 29996127 TI - Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients. AB - BACKGROUND: "T50," shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin A is a major T50 determinant. METHODS: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. RESULTS: During a median surveillance of 2.18 years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20-2.89); fetuin-A, (HR 2.25; 95% CI 1.38-3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. CONCLUSIONS: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations. PMID- 29996129 TI - Mandibular Myalgia and Miniscule Meckel's Caves. AB - Trigeminal neuropathy manifests as episodic sharp, shooting pain in the maxillofacial region. Contributory etiologies are myriad, ranging from central pathology affecting its origin in the brainstem to peripheral processes affecting their distal-most insertion sites. We present a case of bilateral hypoplastic Meckel's caves in an adult patient leading to the clinical symptomology of trigeminal neuralgia. To the best of our knowledge, this is the only report of its kind highlighting this anatomic variant. PMID- 29996131 TI - Increasing the Sensitivity of Functional Status Assessment in the Preclinical Range (Normal to Mild Cognitive Impairment): Exploring the IADL-Extended Approach. AB - BACKGROUND/AIMS: Dementia exhibits an insidious onset consisting of cognitive, behavioral, and functional impairment. We explored a functional continuum that extends assessment beyond the clinical instrumental activities of daily living (IADL) range and into advanced activities of daily living. METHODS: We examined the predictive power (Cox regression; n = 2,471) of a unidimensional IADL extended (IADL-x) scale for incident mild cognitive impairment (MCI). We also examined "time to MCI" as an outcome measure. RESULTS: Each additional task endorsed on the IADL-x hierarchy (e.g., endorsing participation in 6 vs. 5 activities) resulted in a 10% reduction in MCI risk (HR 0.90, 95% CI 0.85-0.94, p < 0.001). For the fully adjusted model the risk reduction dropped to 6%. The odds of incident MCI within 2 years (for those below the median IADL-x total score) was 2.5 times higher (OR 2.60, 95% CI 1.52-4.4, p < 0.001) and 2 times higher for incident MCI within the next 5 years (OR 1.93, 95% CI 1.76-3.2, p < 0.01). CONCLUSION: The IADL-x metric appears to be a valid approach for determining the risk of MCI based on one's position along a formal hierarchy of function. PMID- 29996130 TI - Cost of Hospitalizations due to Exacerbation in Patients with Non-Cystic Fibrosis Bronchiectasis. AB - BACKGROUND: Knowing the cost of hospitalizations for exacerbation in bronchiectasis patients is essential to perform cost-effectiveness studies of treatments that aim to reduce exacerbations in these patients. OBJECTIVES: To find out the mean cost of hospitalizations due to exacerbations in bronchiectasis patients, and to identify factors associated with higher costs. METHODS: Prospective, observational, multicenter study in adult bronchiectasis patients hospitalized due to exacerbation. All expenses from the patients' arrival at hospital to their discharge were calculated: diagnostic tests, treatments, transferals, home hospitalization, admission to convalescence centers, and hospitals' structural costs for each patient (each hospital's tariff for emergencies and 70% of the price of a bed for each day in a hospital ward). RESULTS: A total of 222 patients (52.7% men, mean age 71.8 years) admitted to 29 hospitals were included. Adding together all the expenses, the mean cost of the hospitalization was EUR 5,284.7, most of which correspond to the hospital ward (86.9%), and particularly to the hospitals' structural costs. The adjusted multivariate analysis showed that chronic bronchial infection by Pseudomonas aeruginosa, days spent in the hospital, and completing the treatment with home hospitalization were factors independently associated with a higher overall cost of the hospitalization. CONCLUSIONS: The mean cost of a hospitalization due to bronchiectasis exacerbation obtained from the individual data of each episode is higher than the cost per process calculated by the health authorities. The most determining factor of a higher cost is chronic bronchial infection due to P. aeruginosa, which leads to a longer hospital stay and the use of home hospitalization. PMID- 29996132 TI - Ventilator-Induced Kidney Injury: Are Novel Biomarkers the Key to Prevention? AB - Mechanical ventilation is associated with significant increases in the risk of acute kidney injury (AKI). The rate of AKI due to mechanical ventilation and the associated mortality remain unacceptably high. Preventative and therapeutic strategies are clearly lacking. Ventilator-induced kidney injury is believed to occur due to changes in hemodynamics that impair renal perfusion, neurohumoral mediated alterations in intra-renal blood flow, and systemic inflammatory mediators generated by ventilator-induced lung injury. The risk of injury to the kidney by these mechanisms may be modified by open lung protective ventilation with low tidal volumes and high positive end expiratory pressure. However, these strategies may also increase the risk of injury in some settings, and clinicians have limited means to identify the optimal ventilator strategy for each specific patient. Novel urinary biomarkers have demonstrated the ability to predict AKI prior to classic clinical signs such as decreased urine output and increased creatinine. These biomarkers may serve as an early indication to intensivists of an injurious ventilator strategy and failure of traditional management. PMID- 29996134 TI - The Glymphatic System and Waste Clearance with Brain Aging: A Review. AB - The glymphatic system is a glial-dependent waste clearance pathway in the brain, in place of lymphatic vessels, dedicated to drain away soluble waste proteins and metabolic products. Specifically, the glymphatic network serves as a "front end" for waste clearance, and is connected downstream to an authentic lymphatic network, associated with dura covering the brain as well as cranial nerves and large vessels at the skull exits. The anatomical and functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control glymphatic transport function and waste clearance from brain. In this review, we aim to provide an overview and discussion of the concept behind the glymphatic system, current evidence, and controversies, while specifically focusing on the consequences of aging and evidence of its existence in human brain. Discovering novel strategies for optimizing and maintaining efficient brain waste clearance across the lifespan may in the future prove to be important for preventing cognitive decline and sustaining healthy aging. PMID- 29996133 TI - Clinical Impact of Preoperative Albumin-Globulin Ratio in Patients with Rectal Cancer Treated with Preoperative Chemoradiotherapy. AB - OBJECTIVE: The serum albumin-globulin ratio (AGR) is associated with malignancy outcomes. However, among patients with rectal cancer (RC) who undergo neoadjuvant chemoradiotherapy (nCRT), the clinical and prognostic significance of the pretreatment AGR is unclear. METHODS: We investigated whether the pre-nCRT AGR can help predict oncological outcomes in patients with RC receiving nCRT. We analyzed 114 patients with RC who received nCRT followed by total mesorectal excision at our institution. RESULTS: A lower AGR in pre-nCRT serum was significantly correlated with shorter overall survival and disease-free survival in patients with nCRT-treated RC. In multivariate analysis, a high carcinoembryonic antigen (CEA) level and a low AGR in pre-nCRT serum were independent predictors of a poor prognosis in these patients. Furthermore, combining the AGR with CEA provided a more accurate indicator of poor prognosis and early recurrence in these patients. In particular, a low pre-nCRT AGR was a stronger indicator of a poor prognosis and early recurrence in patients without than with pathological lymph node metastasis. Combining the pre-nCRT AGR with CEA could more precisely stratify patients' oncological outcome risks. CONCLUSION: Assessment of the pretreatment AGR with or without CEA can guide postoperative treatment in patients with RC who undergo nCRT. PMID- 29996135 TI - Palmitic Acid Increases Endothelin-1 Expression in Vascular Endothelial Cells through the Induction of Endoplasmic Reticulum Stress and Protein Kinase C Signaling. AB - OBJECTIVE: We investigated the regulation of endothelin-1 (ET-1) expression in in vivo high-fat diet (HFD)-fed mice and in vitro cultured human aortic endothelial cells (HAECs). METHODS: Male C57BL/6 mice were fed on standard chow, serum was prepared, and ET-1 levels were analyzed using an ELISA kit. Quantitative PCR was performed using iQ SYBR Green Supermix. Statistical significance was assessed using SPSS, with p < 0.05 considered significant. RESULTS: The serum ET-1 content and endothelial expression of ET-1 mRNA were increased in the HFD-fed mice compared to the chow-fed control mice. Moreover, the mRNA expression of ET-1 was significantly increased in cultured HAECs in response to acute (< 24 h) and chronic (12-16 days) treatments with palmitic acid (PA), one of the most abundant saturated fatty acids in obesity. We found that the induction of ET-1 expression by PA was abolished by pretreating the cells with the endoplasmic reticulum (ER) stress inhibitor 4-phenylbutyric acid or the protein kinase C (PKC) inhibitor Go 6850. CONCLUSION: Our findings demonstrate for the first time that PA increases ET-1 expression in endothelial cells through the induction of ER stress and the activation of PKC, providing novel mechanistic insights into the pathogenesis of obesity-associated hypertension and cardiovascular diseases. PMID- 29996136 TI - Risk Factors for Necrotizing Enterocolitis: A Prospective Multicenter Case Control Study. AB - BACKGROUND: The identification of independent clinical risk factors for necrotizing enterocolitis (NEC) may contribute to early selection of infants at risk, allowing for the development of targeted strategies aimed at the prevention of NEC. OBJECTIVE: The objective of this study was to identify independent risk factors contributing to the development of NEC in a large multicenter cohort. METHODS: This prospective cohort study was performed in 9 neonatal intensive care units. Infants born at a gestational age <=30 weeks were included. Demographic and clinical data were collected daily until day 28 postnatally. Factors predictive of the development of NEC were identified using univariate and multivariable analyses in a 1: 5 matched case-control cohort. RESULTS: In total, 843 infants (56 NEC cases) were included in this study. In the case-control cohort, univariate analysis identified sepsis prior to the onset of NEC and formula feeding to be associated with an increased risk of developing NEC, whereas the administration of antibiotics directly postpartum was inversely associated with NEC. In a multivariable logistic regression model, enteral feeding type and the number of days parenterally fed remained statistically significantly associated with NEC, whereas the administration of antibiotics directly after birth was associated with a lower risk of developing NEC. CONCLUSIONS: Formula feeding and prolonged (duration of) parenteral feeding were associated with an increased risk of NEC. Contrary to expectations, the initiation of treatment with antibiotics within 24 h after birth was inversely associated with NEC. PMID- 29996137 TI - The Extended C-Terminal alpha-Helix of the HypC Chaperone Restricts Recognition of Large Subunit Precursors by the Hyp-Scaffold Machinery during [NiFe] Hydrogenase Maturation in Escherichia coli. AB - Members of the HypC protein family are chaperone-like proteins that play a central role in the maturation of [NiFe]-hydrogenases (Hyd). Escherichia coli has a second copy of HypC, called HybG, and, as a component of the HypDEF maturation scaffold, these proteins help synthesize the NiFe-cofactor and guide the scaffold to its designated hydrogenase large subunit precursor. HypC is required to synthesize active Hyd-1 and Hyd-3, while HybG facilitates Hyd-2 and Hyd-1 synthesis. To identify determinants on HypC that allow it to discriminate against Hyd-2, we made amino acid exchanges in 3 variable regions, termed VR1, VR2, and VR3, of HypC, that make it more similar to HybG. Region VR3 includes a HypC specific C-terminal alpha-helical extension, and this proved particularly important in preventing the maturation of Hyd-2 by HypC. Truncation of this extension on HypC increased Hyd-2 activity in the absence of HybG, while retaining maturation of Hyd-3 and Hyd-1. Combining this truncation with amino acid exchanges in VR1 and VR2 of HypC negatively affected the synthesis of active Hyd-1. The C-terminus of E. coli HypC is thus a key determinant in hindering Hyd 2 maturation, while VR1 and VR2 appear more important for Hyd-1 matu-ration. PMID- 29996138 TI - Aortic Angulation and TAVR. PMID- 29996139 TI - Prosodic Improvement in Persons with Parkinson Disease Receiving SPEAK OUT!(r) Voice Therapy. AB - BACKGROUND/AIMS: Hypokinetic dysarthria in Parkinson disease (PD) hinders the ability to verbally communicate and interferes with activities of daily living. SPEAK OUT!(r) is a therapy program designed to improve functional communicative ability. In contrast to the Lee Silverman Voice Treatment program, SPEAK OUT!(r) promotes speaking with intent to effect loud speech. This study evaluated the efficacy of SPEAK OUT!(r) in persons with idiopathic PD in 3 domains: self reported voice handicap, clinical ratings of dysarthria and prosody, and acoustic analysis of prosody. PARTICIPANTS AND METHODS: Pre-/post-therapy data included PD participants' scores on the Voice Handicap Index (VHI) and the Voice-Related Quality of Life (V-RQOL) questionnaire, audio recordings, perceptual evaluation scores, and demographic data, such as age, sex, handedness, diagnosis, and onset of PD. RESULTS: Participants achieved a statistically and clinically significant improvement in speech intensity, pitch range, normalized pairwise variability index for pitch, sustained vowel duration, reading intelligibility, and vocal quality after SPEAK OUT!(r) training, consistent with both of the self-report voice scores, i.e., the VHI and the V-RQOL, and with the perceptual speech evaluation scores. Longer PD duration was associated with lowered efficacy. CONCLUSIONS: SPEAK OUT!(r) is effective and should be administered as early as possible after disease onset. PMID- 29996140 TI - Reply to the Comment Entitled "Association of FTO rs9939609 with Obesity". PMID- 29996141 TI - Changes in Satiety Hormones in Response to Leptin Treatment in a Patient with Leptin Deficiency. AB - BACKGROUND: We tested whether leptin treatment affects secretion of satiety related gut peptides and brain-derived neurotrophic factor (BDNF), which is a regulator of energy homeostasis downstream of hypothalamic leptin signaling. METHODS: We report the case of a morbidly obese 14.7-year-old girl with a novel previously reported homozygous leptin gene mutation, in whom hormone secretion was evaluated in 30-min intervals for 10 h (07.30-17.30) to assess BDNF, insulin, glucagon-like peptide-1 (GLP-1), ghrelin, and peptide YY (PYY) secretion before as well as 11 and 46 weeks after start of metreleptin treatment. RESULTS: Leptin substitution resulted in strong reductions of body fat and calorie intake. Insulin secretion increased by 58.9% after 11 weeks, but was reduced by -44.8% after 46 weeks compared to baseline. Similarly, GLP-1 increased after 11 weeks (+15.2%) and decreased after 46 weeks. PYY increased consistently (+5%/ +13.2%, after 11/46 weeks). Ghrelin decreased after 46 weeks (-11%). BDNF secretion was not affected by leptin treatment. CONCLUSION: The strong increase in insulin and GLP-1 secretion after 11 weeks of metreleptin treatment cannot be explained by reduced adiposity and might contribute to improved central satiety. Observed changes of PYY can lead to increased satiety as well. However, leptin replacement does not seem to affect circulating BDNF levels. PMID- 29996142 TI - Influence of Age and Education on the Performance of Elderly in the Brazilian Version of the Montreal Cognitive Assessment Battery. AB - AIMS: To provide normative data for the Brazilian version of the Montreal Cognitive Assessment (MoCA-BR) and to measure the effect of sociodemographic variables on the cognitive performance of cognitively healthy elderly people. METHODS: A sample of 110 cognitively healthy individuals, aged over 65 years, with at least 4 years of schooling were recruited from 3 health care centers for the elderly in Recife, Brazil. The cognitive performance was assessed using MoCA BR. RESULTS: The average score of these elderly people in the MoCA-BR was 23.2 +/ 2.7. Their schooling correlated positively with the cognitive performance, with a Spearman's coefficient of 0.33 (p < 0.001). There was a statistically significant negative correlation between age and the cognitive performance (Spearman's rho = -0.19). The multiple linear regression model with the highest adjusted coefficient of determination was the one that included schooling and age (adjusted R2 = 0.127). CONCLUSIONS: The cognitive performance of healthy elderly was evaluated and was strongly influenced by schooling and, to a lower degree, by age. PMID- 29996143 TI - No Protective Effect of Constitutive Activation of AMPK in Endothelial Cells on Vascular Function in Aged Obese Mice but Augmented alpha1-Adrenergic Contractions in Renal Arteries Reversible by Weight Loss. AB - BACKGROUND: Aging, obesity, and diabetes favor vascular dysfunction. Endothelial activation of adenosine monophosphate-activated protein kinase (AMPK) has protective effects in diabetes. METHODS: Mice with constitutive endothelial activation of AMPK (CA-AMPK) were given a high fat diet to induce obesity or kept on standard chow as lean controls for up to 2 years. A subset of obese animals was changed to standard chow after 30 weeks of high fat feeding. En-dothelium dependent and endothelium-independent responses were examined by isometric tension recording. RESULTS AND CONCLUSION: Endothelium-dependent nitric oxide (NO)- and apamin plus charybdotoxin-sensitive relaxations were preserved and similar between aortic or renal arterial preparations of lean and obese CA-AMPK mice and their wild-type littermates. Despite comparable release of vasoconstrictor prostanoids, cyclooxygenase-dependent contractions were enhanced during NO synthase inhibition in carotid arterial rings of obese CA-AMPK mice. Contractions to the alpha1-adrenoceptor agonist phenylephrine were augmented in renal arteries of obese animals, a genotype-independent phenomenon reversible by weight loss. These data indicate a higher alpha1-adrenergic reactivity in renal arteries of aged mice with obesity. The current results highlight the potential of weight loss to alleviate vascular dysfunction. However, endothelial activation of the AMPK pathway in obesity may not be sufficient to prevent vascular dysfunction without lifestyle changes. PMID- 29996144 TI - The Pentagon Copying Test and the Clock Drawing Test as Prognostic Markers in Dementia with Lewy Bodies. AB - AIMS: To determine whether the pentagon copying test (PCT) and the clock drawing test (CDT) are associated with nursing home admission or survival in dementia with Lewy bodies (DLB). METHODS: The PCT and/or the CDT were retrospectively collected from 103 clinically diagnosed probable DLB patients at a university medical center and general hospital. Patients with high versus low scores on these tests were compared. RESULTS: Kaplan-Meier analysis showed that patients with a low score on the PCT had a shorter time to nursing home admission than patients with a high score (log-rank chi2 = 6.1, p = 0.01). Patients with a low score on the PCT or the CDT had a shorter survival than patients with a high score (log-rank chi2 = 5.4, p = 0.02, and log-rank chi2 = 11.2, p < 0.001, respectively). Cox regression analyses showed the same associations with an HR of 2.2 (95% CI 1.2-4.1) for the PCT and an HR of 2.9 (95% CI 1.6-5.4) for the CDT. CONCLUSION: The PCT and the CDT may function as prognostic markers in DLB. This finding is clinically relevant as these tests can be applied easily in the clinical setting and can provide valuable prognostic information. Furthermore, it may improve disease management and patient selection for research purposes. PMID- 29996145 TI - MACE for the Diagnosis of Dementia and MCI: 3-Year Pragmatic Diagnostic Test Accuracy Study. AB - BACKGROUND/AIMS: The Mini-Addenbrooke's Cognitive Examination (MACE) is a relatively new short cognitive screening instrument for the detection of patients with dementia and mild cognitive impairment (MCI). Few studies of the MACE have been reported hitherto. The aim of this study was to undertake a pragmatic diagnostic test accuracy study of MACE in a large cohort of patients seen in a dedicated cognitive disorders clinic. METHODS: MACE was administered to consecutive patients referred to a neurology-led Cognitive Function Clinic over the course of 3 years to assess its performance for the diagnosis of dementia and MCI using various test metrics. RESULTS: In a cohort of 599 patients, the prevalence of dementia and MCI by criterion diagnosis was 0.17 and 0.29, respectively. MACE had a high sensitivity (> 0.9) and negative predictive values (> 0.8) with large effect sizes (Cohen's d > 1) for the diagnosis of both dementia and MCI but a low specificity (< 0.5) and positive predictive values (<=0.5). CONCLUSION: MACE is an acceptable test for the assessment of cognitive complaints in a secondary care setting with good metrics for identifying cases of both dementia and MCI. PMID- 29996150 TI - Molecular Diagnostics in Pediatric Brain Tumors: Impact on Diagnosis and Clinical Decision-Making - A Selected Case Series. AB - Central nervous system (CNS) tumors account for the highest mortality among pediatric malignancies. Accurate diagnosis is essential for optimal clinical management. The increasing use of molecular diagnostics has opened up novel possibilities for more precise classification of CNS tumors. We here report a single-institutional collection of pediatric CNS tumor cases that underwent a refinement or a change of diagnosis after completion of molecular analysis that affected clinical decision-making including the application of molecularly informed targeted therapies. 13 pediatric CNS tumors were analyzed by conventional histology, immunohistochemistry, and molecular diagnostics including DNA methylation profiling in 12 cases, DNA sequencing in 8 cases and RNA sequencing in 3 cases. 3 tumors had a refinement of diagnosis upon molecular testing, and 6 tumors underwent a change of diagnosis. Targeted therapy was initiated in 5 cases. An underlying cancer predisposition syndrome was detected in 5 cases. Although this case series, retrospective and not population based, has its limitations, insight can be gained regarding precision of diagnosis and clinical management of the patients in selected cases. Accuracy of diagnosis was improved in the cases presented here by the addition of molecular diagnostics, impacting clinical management of affected patients, both in the first-line as well as in the follow-up setting. This additional information may support the clinical decision making in the treatment of challenging pediatric CNS tumors. Prospective testing of the clinical value of molecular diagnostics is currently underway. PMID- 29996151 TI - Multiphoton imaging provides a superior optical biopsy to that of confocal laser endomicroscopy imaging for colorectal lesions. AB - BACKGROUND: Confocal laser endomicroscopy (CLE) requires fluorescence agents, the use of which leads to blurred images and low diagnostic accuracy owing to fluorescein leakage. We aimed to explore whether multiphoton imaging (MPI) could serve as a better method of optical biopsy. METHODS: First, a pilot study was performed to set up the optical diagnostic criteria of MPI for benign or malignant colorectal lesions in 30 patients. Then, a blinded study was conducted to compare the sensitivity, specificity, and accuracy of MPI versus CLE imaging in 79 patients. RESULTS : In the pilot study, MPI revealed regular tissue architecture and cell morphology in the normal tissue, and irregular tubular structures, and cellular and nuclear pleomorphism in the abnormal tissue. In the blinded study, compared with CLE imaging, MPI significantly improved the diagnostic sensitivity, specificity, and accuracy of the optical biopsy (89.74 % vs. 61.54 %, P = 0.008; 92.5 % vs. 67.5 %, P = 0.009; and 91.14 % vs. 64.56 %, P = 0.001, respectively). CONCLUSIONS : MPI can provide a superior optical biopsy to that of CLE imaging for colorectal lesions. PMID- 29996152 TI - A novel device for intracolonoscopy cleansing of inadequately prepared colonoscopy patients: a feasibility study. AB - BACKGROUND: The importance of high quality preprocedural bowel preparation is widely acknowledged, but suboptimal bowel cleansing still occurs in up to 20 % of all colonoscopy patients. The aim of this study was to evaluate the performance of a novel intraprocedural cleaning device for cleaning poorly prepared colons. METHODS: This multicenter feasibility study included patients aged 18 - 75 years who were referred for colonoscopy. Intraprocedural cleaning was performed in patients after a limited preprocedural bowel preparation regimen (2 days of dietary restrictions and 2 * 10 mg bisacodyl). The primary outcome was the proportion of adequately prepared patients (Boston Bowel Preparation scale [BBPS] >= 2 in each segment) before and after segmental washing with the new device. Secondary outcomes included: cecal intubation rate, procedure time, system usability, patient satisfaction, and safety. RESULTS: 47 patients (42.6 % male), with a median age of 61 years (interquartile range [IQR] 46 - 67 years), were included at three clinical sites. Cecal intubation was achieved in 46/47 patients (97.9 %). The cleaning device significantly improved the proportion of patients with adequate bowel cleansing (from 19.1 % to 97.9 %; P < 0.001) and median BBPS score (from 3.0 [IQR 0.0 - 5.0] to 9.0 [IQR 8.0 - 9.0]). Median cecal intubation time and total procedure time were 16.5 minutes (IQR 9.0-28.3) and 34.0 minutes (IQR 25.0 - 42.8), respectively. Physicians were satisfied with the ease of use of the device and it was well tolerated by patients. No severe adverse events occurred during the study period. CONCLUSIONS: This feasibility study suggests that the intraprocedural cleaning device appears to be safe and effective in cleaning poorly prepared colons to an adequate level, allowing a thorough colorectal examination. PMID- 29996153 TI - Hypertensive Disorders during Pregnancy and Risk of Bronchopulmonary Dysplasia in Very Preterm Infants. AB - INTRODUCTION: It is not yet fully known whether hypertensive disorders (HTD) during pregnancy impose an increased risk of development of bronchopulmonary dysplasia (BPD) in preterm newborn infants. OBJECTIVE: To test the hypothesis that preeclampsia and other HTD are associated with the development of BPD in preterm infants. MATERIALS AND METHODS: Data on mothers and preterm infants with gestational age 24 to 30 weeks were prospectively analyzed in 11 Portuguese level III centers. Statistical analysis was performed using IBM SPSS statistics 23. RESULTS: A total of 494 preterm infants from 410 mothers were enrolled, and 119 (28%) of the 425 babies, still alive at 36 weeks, developed BPD. The association between chronic arterial hypertension, chronic arterial hypertension with superimposed preeclampsia, and gestational hypertension in mothers and BPD in preterm infants was not significant (p = 0.115; p = 0.248; p = 0.060, respectively). The association between preeclampsia-eclampsia and BPD was significant (p = 0.007). The multivariate analysis revealed an association between preeclampsia-eclampsia and BPD (odds ratio [OR] = 4.6; 95% confidence interval [CI] 1.529-13.819; p = 0.007) and a protective effect for BPD when preeclampsia occurred superimposed on chronic arterial hypertension in mothers (OR = 0.077; 95%CI 0.009-0.632; p = 0.017). CONCLUSION: The results of this study support the association of preeclampsia in mothers with BPD in preterm babies and suggest that chronic hypertension may be protective for preterm babies. PMID- 29996154 TI - Developing a Three-Layered Synthetic Microsurgical Simulation Vessel. AB - BACKGROUND: Microsurgery is increasingly relevant, and is difficult to learn. Simulation is relied upon ever more in microvascular training. While living models provide the ultimate physiological feedback, we are ethically obliged to optimize non-living models to replace, refine, and reduce the use of animals in training. There is currently no three-layered synthetic vessel available for microsurgical training. METHODS: A three-layered synthetic vessel was designed with a simulation company. One anastomosis was performed by 14 microsurgical experts at one center. The realism of the vessel was assessed via user questionnaires and the construct validity using objective, validated task scores to assess the anastomosis performance and the final product. Videos were obtained, which were anonymized and marked remotely by a consultant plastic surgeon. RESULTS: The synthetic vessel intima and media displayed reasonable realism, while the adventitia was less realistic. Areas for improvement were identified. Both the task specific assessment score and the final product assessment appropriately identified experts. CONCLUSION: A three-layered synthetic model for microvascular training is a hygienic and useful intermediate level alternative to commonly used synthetic and ex vivo alternatives. PMID- 29996155 TI - Irradiation Delays Tissue Growth but Enhances Osteogenic Differentiation in Vascularized Constructs. AB - BACKGROUND: Regenerative medicine is still deficient in the reconstruction after cancer due to impaired vascularization after radiotherapy and due to the need to substitute larger defects after tumor excision. Aiming at introducing regenerative medicine for reconstruction after cancer, we tested an axially vascularized bone construct in an experimental setting that mimics the clinical situation after tumor resection and adjuvant radiotherapy. METHODS: Twenty bone constructs were axially vascularized using microsurgically created arteriovenous loops and were implanted subcutaneously in Lewis rats. After 2 weeks, the animals were randomly allocated either to receive a clinically relevant single dose of external beam irradiation or not (n = 10 for each group). The animals were sacrificed either after 1 week or 10 weeks after irradiation (n = 5 for each time point). The constructs were tested for vascularization, tissue growth, cellular proliferation, cellular apoptosis, and osteogenic differentiation via histomorphometric, immunohistochemical, and polymerase chain reaction (PCR) analysis. One construct per group was subjected at 10 weeks to qualitative micro computed tomography (CT) imaging. RESULTS: Tissue generation and cellular proliferation were significantly reduced at 1 week after irradiation, but no longer significantly different after 10 weeks.No significant differences in vascularization were detected at any time point. Apoptosis did not show any statistically significant differences between both groups at both time points. At the late time point, mature bone was considerably more in the irradiated group, but the results were not statistically significant. PCR analysis showed a significantly enhanced expression of osteocalcin in the irradiated group at 1 week. Micro-CT imaging showed that both constructs were adequately vascularized with no evident morphologic differences regarding vascular density or vascular distribution. CONCLUSIONS: Axially vascularized bone constructs can withstand clinically relevant doses of irradiation and retain their angiogenic and osteogenic potential in the long term. Irradiation led to a delayed tissue generation with a comparatively enhanced osteogenic differentiation within the constructs. PMID- 29996156 TI - [Prevention and Treatment of Antipsychotic-induced Tardive Dyskinesia]. AB - Tardive dyskinesias (TDs) are still common long-term sequelae of antipsychotic treatment. They are generally irreversible and associated with cognitive deficits, a decrease in quality of life and increased mortality. Furthermore, they potentially contribute to further stigmatization of the affected patients. However due to limited treatment options, antipsychotic drugs are still one of the cornerstones in treatment of most severe mental illnesses. Therefore, knowledge about risk factors and prevention of TDs is crucial. If TDs occur, the immediate optimization of the antipsychotic drug regimen is required. Targeted medical treatments such as VMAT - 2 inhibitors can be considered. The novel VMAT 2 inhibitors are not yet approved in Germany. Other drugs that are currently used to treat TDs include clonazepam and gingko biloba. This review summarizes the current evidence of treatment options of TDs and seeks to formulate clinical recommendations for the prevention and management of TDs. PMID- 29996157 TI - [Avoiding the Traps of Thought: The Relevance of Language and Rules for Acceptance and Commitment Therapy]. AB - Behavioral therapy has greatly evolved and branched out in different directions since its inception. Three stages in the development of modern behavioral psychotherapies can be discerned: behaviorism, the cognitive revolution, and, most recently, the so-called third wave behavioral therapies. Characteristic of third-wave therapies is the great heterogeneity in treatment strategies. To gain a deeper understanding of several third-wave approaches, we here outline relational frame theory (RFT) as an important theoretical foundation. RFT explains how experiential avoidance, a behavioral strategy aimed at eschewing unpleasant internal experiences (e. g., thoughts, feelings, memories), promotes the onset and progression of psychopathology. Acceptance and commitment therapy (ACT), a prime example of a third-wave therapy, focuses on cultivating the skills needed to embrace discomforting thoughts and emotions. Accumulating evidence including meta-analytic evidence supports the effectiveness of ACT in a wide array of psychiatric disorders. PMID- 29996158 TI - [Current therapy studies in atypical Parkinson syndromes]. AB - Atypical Parkinson syndromes are a heterogeneous group of neurodegenerative diseases which present with parkinsonism and other non-motor symptoms. On the basis of the underlying pathology, namely the abnormal aggregation of the proteins alpha-synuclein or tau, atypical Parkinson syndromes can be divided into synucleinopathies (multiple system atrophy, Lewy body dementia) and tauopathies (progressive supranuclear palsy, corticobasal degeneration). Currently there are no effective treatments to slow down disease progression available. Medications which help to manage the symptoms show only temporary and insufficient efficacy. In recent years, preclinical research identified essential steps in the pathogenesis of the diseases. Treatments which inhibit pathological protein aggregation and its spreading were developed and showed promising results in animal models. First clinical trials of causal treatments targeting the underlying pathomechanism have been finished; several trials are recruiting patients or being planned at the moment. In the following article we present the latest developments regarding the causal therapy of atypical Parkinson syndromes and the current clinical trials. PMID- 29996159 TI - [Editorial]. PMID- 29996160 TI - [Eyelid Tumors: Clinical Aspects of Ophthalmic Pathology]. AB - BACKGROUND: Lid tumors show a heterogenous clinical spectrum. Tumors which display some criteria of malignancy may histologically be diagnosed as inflammatory lesions without any neoplastic component. In contrast, malignant tumors can induce changes on the lid margin mimicking inflammatory changes. MATERIAL AND METHODS/RESULTS: Certain examples of lid tumors are shown to illustrate potential pitfalls as well as clinical unequivocal cases. The clinical appearance of the lesions is correlated with the histologic findings. CONCLUSION: Lid tumors can develop from different structures of the eyelid and, therefore, show a wide spectrum of clinical findings. If a malignant process is suspected or the clinical diagnosis cannot be unequivocally determined, a biopsy (incisional vs. excisional) is necessary followed by histologic evaluation. Furthermore, inadequately treated benign lesions, such as an incomplete excised nevus or a molluscum contagiosum, can lead to serious problems. PMID- 29996161 TI - [Periocular Masquerade Syndrome: A Case]. PMID- 29996162 TI - [Vitreoretinal Lymphoma Masquerading as Rubeotic Haemorrhagic Glaucoma]. PMID- 29996163 TI - [Refractory Endophthalmitis]. PMID- 29996164 TI - [Therapy Resistant Fusarium Keratitis with Intraocular Involvement - Potential Sources of a Persisting Infection]. AB - BACKGROUND: Fungal keratitis shows a variable clinical picture and is therefore often diagnosed only late. Fungi in general are quite resistant organisms, and in addition treatment is difficult due to limited and specially manufactured medications. MATERIAL AND METHODS/RESULTS: We describe the unfavourable outcome in a young female patient with keratitis due to fusarium that ended - despite extensive medical and surgical treatment - in enucleation. Histologic examnination of the enucleated globe revealed massive (post-)inflammatory changes throughout the anterior segment but only few persistent fungal elements that were found in the lens capsule (after phacoemulsification) and the peripheral Descemet's membrane. CONCLUSION: Fungus as the pathogenic agent in therapy resistent keratitis should be included in the differential diagnosis as early as possible. Should surgical interventions become necessary, a keratoplasty as large as possible and removal of the lens capsule should be considered in order to eliminate potential reservoirs for the causative organism. PMID- 29996165 TI - Triterpenoids from Momordica balsamina with a Collateral Sensitivity Effect for Tackling Multidrug Resistance in Cancer Cells. AB - The collateral sensitivity effect is among the most promising strategies for overcoming multidrug resistance in cancer. In this work, 28 cucurbitane-type triterpenoids (1: -28: ), previously isolated from the African medicinal plant Momordica balsamina and its derivatives, were evaluated for their collateral sensitivity effect on three different human cancer entities, gastric (EPG85-257), pancreatic (EPP85-181), and colon (HT-29), each with two different multidrug resistant variants. One was selected for its resistance to daunorubicin (EPG85 257RDB, EPP85-181RDB, HT-29RDB) and the other was selected for its resistance to mitoxantrone (EPG85-257RNOV, EPP85-181RNOV, HT-29RNOV). On gastric cell lines, the best results were obtained for compounds 3: and 10: , which exhibited a collateral sensitivity effect together with high antiproliferative activity. In turn, on colon cancer cell lines, the best multidrug resistance-selective antiproliferative effects were observed for derivatives 11, 13: , and 15: , which showed collateral sensitivity effects against both resistant variants. Compounds 11: and 3: were also the most selective against the multidrug resistance pancreatic cells lines. Some compounds, such 6, 10, 11: and 15: , were previously found to be strong P-glycoprotein modulators, thus highlighting their potential as promising leads for overcoming multidrug resistance in cancer cells. PMID- 29996166 TI - [Evaluation of Organisational Structures of Self-help Groups in the Field of Paediatric Orthopaedics]. AB - BACKGROUND: There have been few publications on the organisational structures of self-help groups that handle orthopaedic disorders in children. MATERIAL AND METHODS: A standardised questionnaire was sent by post to the corresponding support groups. The aim was to evaluate the self-help group's structure, use of social media and financial background. RESULTS: Support groups for dwarfism, infantile cerebral palsy and Down syndrome responded and sent the questionnaire back to our department. Most self-help groups were incorporated societies and belonged to an umbrella organisation. The founding year was predominantly in the decade 1990 - 2000 (n = 15). The founders were predominantly parents (n = 28; 77.8%), concerned individuals (n = 11; 30.6%) and - in two cases - physicians (5.6%). 29 support groups (80.6%) received donations for financial support. The aims, activities, and manner of contact were presented in the home page (n = 35; 97.2%). Most self-help group focussing on paediatric orthopaedic disorders cooperate with physicians in different specialisations to obtain information and recommendations. CONCLUSIONS: The study presents the first information on self help groups and documents the multidisciplinarity of paediatric orthopaedics. Close collaboration between paediatric orthopaedic surgeons and regional support groups might contribute to the reduction of uncertainty and fears and improve of medical provision. PMID- 29996167 TI - Relationships Between Olympic Weightlifting Exercises, Peak Power of the Upper and Lower Limb, Muscle Volume and Throwing Ball Velocity in Elite Male Handball Players. AB - BACKGROUND: This study aimed to investigate relationships between peak power (PP) as measured by upper limb (PPUL) and lower limb (PPLL) force velocity tests, maximal upper limb force assessed by clean and jerk (1RMCJ) and snatch (1RMSE) exercises, estimates of local muscle volume and throwing ball velocity. METHODS: Thirty elite male handball players volunteered for the investigation (age: 20.3 +/- 2.1 years; body mass: 82.5 +/- 10.5 kg; height: 1.85 +/- 0,07 %; body fat: 13.1 +/- 2.1 %). Lower and upper limb force velocity tests were performed on appropriately modified forms of a Monark cycle ergometer with measurement of PPUL and PPLL, and the corresponding respective maximal forces (F0UL and F0LL) and velocities (V0UL and V0LL). Snatched (SN) and clean and jerk (CJ) exercises were performed to one repetition maximum (1RM). Handball throwing velocity was measured with jump shot (JS) without run-up (TW) and 3 steps shot (T3 step). Muscle volumes of the upper and lower limbs were estimated with a standard anthropometric kit. RESULTS: The 1RM CJ proved to be the most important predictor for throwing velocity. All types of throwing showed a high correlation with this parameter (JS: r = 0.75; TW: r = 0.62; T3 step: r = 0.66). The highest relation was detected between jump shot and 1RM snatch technique (r = 0.82). The PPUL muscle volume correlated highly with PPUL absolute power (r = 0.70). In contrast, we did not find any comparable relations for the lower limb (muscle volume vs. PPUL absolute power: r = 0.07). CONCLUSIONS: Our results highlight the contribution of both lower and upper limbs to handball throwing velocity, suggesting the need for coaches to include upper and lower limb strength weightlifting exercises and power programs when improving the throwing velocity of handball players. PMID- 29996168 TI - Performance of Conventional Cytology and Colposcopy for the Diagnosis of Cervical Squamous and Glandular Neoplasias. AB - OBJECTIVE: To estimate the cytological and colposcopic performances for the diagnosis of cervical neoplasias. METHODS: Cross-sectional retrospective study with data from patients' charts. The participants underwent colposcopy, guided biopsies, and excision when needed. The cytological and colposcopic categorization followed the Bethesda System and the international colposcopic terminologies. The cytology and colposcopy performances were evaluated by sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) analyses with 95% confidence interval (95% CI). RESULTS: From 1,571 participants, a total of 1,154 (73.4%) were diagnosed with cervical squamous intraepithelial neoplasia grade 2 or worse (CIN 2+), 114 (7.2%) with adenocarcinoma in situ or worse (AIS+), 615 (39.2%) presented atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesion or worse (ASC H+) cytology, and 934 (59.4%) presented major or suspicious for invasion colposcopic abnormalities. The SE, SP, PPV, and NPV of ASC-H+ for diagnoses of CIN 2+ and AIS+ were, respectively: 44% (95% CI: 41-47) and 72% (95% CI: 67-76), 79% (95% CI: 77-81) and 79% (95% CI: 75-83), 88% (95% CI: 87-90) and 55% (95% CI: 50-60), and 28% (95% CI: 26-31) and 88% (95% CI: 85-91). The SE, SP, PPV, and NPV of major or suspicious for invasion colposcopic abnormalities for diagnoses of CIN 2+ and AIS+ were, respectively: 62% (95% CI: 60-65) and 86% (95% CI: 83-89), 59% (95% CI: 57-62) and 59% (95% CI: 55-64), 85% (95% CI: 83-87) and 44% (95% CI: 40-49), and 29% (95% CI: 27-32) and 92% (95% CI: 89-94). CONCLUSION: The SE analyses results of ASC-H+ and major or suspicious for invasion colposcopic abnormalities were higher for diagnoses of glandular neoplasias. These results confirm the role of cytology in identifying women at risk who will have their final diagnoses settled by colposcopy and histology. PMID- 29996169 TI - Endoscopic Ultrasound-Guided Drainage and Treatment of Symptomatic Pancreatic Fluid Collection following Acute or Acute-on-Chronic Pancreatitis - A Single Center Case Series. AB - INTRODUCTION: Pancreatic fluid collection (PFC) is a common complication of acute pancreatitis. Endoscopic ultrasound (EUS)-guided drainage, which is often followed by direct endoscopic necrosectomy (DEN), has become the primary approach to treat PFC, including pancreatic pseudocysts (PP) and walled-off necrosis (WON). We aimed to determine retrospectively the short- and long-term results of patients treated in our endoscopy unit and to identify parameters that are associated with treatment efficacy and outcome. METHODS: The data of 41 consecutive patients with post-pancreatitic PFC, who underwent endoscopic transmural intervention between 2014 and 2016, were analyzed retrospectively. After an initial EUS-guided puncture, one or more plastic stents were placed and DEN was performed if necrotic tissue remained. RESULTS: The mean diameter of the PFC was 74.0 +/- 4.8 mm. Of the PFCs, 29.3% were classified as PP and 70.7% as WON. Altogether, 196 transmural endoscopic procedures were performed, including 73 endoscopic necrosectomies in a subgroup of 21 patients (20 WON, 1 PP). Initial technical success was achieved in 97.6% of patients and the short-term clinical success rate was 90.2%. The long-term clinical success rate was 82.9%, since four patients died from septic shock and/or multiple organ failure and three patients developed recurrent PFC some months after the initial discharge from endoscopic treatment. Procedural complications were registered in 9 patients during 10 of 196 endoscopic procedures (5.1%): bleeding (6), cardiorespiratory insufficiency (2), perforation with pneumoperitoneum (1), aspiration with respiratory insufficiency (1), and non-perforating superficial damage of the gastric wall (1). Neither the size of the PFC nor the initial value of C-reactive protein (CRP) or other biochemical markers were correlated with efficacy or outcome of treatment. Only the cumulative number of days with CRP > 50 mg/L significantly correlated with the number of follow-up endoscopic sessions and DEN. Fungal colonization of PFC correlated significantly (p < 0.05) with the risk of mortality (44% vs. 0%), need for intensive care treatment (66.7% vs. 25%), and sepsis (55.6% vs. 12.5%). CONCLUSIONS: We confirm that EUS-guided drainage followed by DEN in patients with solid necrotic material is an effective and relatively safe therapeutic approach. Prolonged elevation of CRP and fungal colonisation of the PFC are associated with a worse course of the disease. PMID- 29996170 TI - Feasibility and Results of a Mobile Haemophilia Outpatient Care Pilot Project. AB - INTRODUCTION: Regular visits at haemophilia treatment centres (HTCs) in rural regions are often dependent on the access to a private car due to lack of or limited availability of public means. Therefore, a mobile haemophilia outpatient care (MHOC) concept providing home visits to haemophilia patients has been developed by the Saarland HTC, which is located in a rural German region. METHODS: Haemophilia patients and their parents were home visited at least twice (baseline, follow-up) by trained medical staff. Socio-demographic and clinical data were collected and interviews were performed asking the patients and parents about their needs and expectations towards such a MHOC. RESULTS: Seventy-nine patients were enrolled (56 adults, 23 children), 62.0% severely affected, 48.1% on prophylaxis, with a mean age of 37.4 +/- 16.4 years (17-78) and 9.8 +/- 4.2 years (3-16), respectively. Median travel distance to the HTC was 43.5 km (3 200). Note that 92.4% considered an intense binding to the HTC and a MHOC concept as 'rather/very important' (88.6%). They expected from a MHOC to provide consulting and educating activities, support in elderhood issues and treatment. For 35.4%, a MHOC could currently provide additional support, mainly due to patient's immobility and need of consultancy. They mainly used services in terms of consultancy in social-legal affairs and support in contacting authorities. CONCLUSION: The results of this study support the hypothesis that a MHOC concept is a needful supplement in haemophilia comprehensive care and will improve the challenging haemophilia treatment, especially for those with limited access to HTCs or with disabilities. PMID- 29996171 TI - MYH9-Related Thrombocytopenia: Four Novel Variants Affecting the Tail Domain of the Non-Muscle Myosin Heavy Chain IIA Associated with a Mild Clinical Evolution of the Disorder. AB - MYH9-related disease (MYH9-RD) is an autosomal-dominant thrombocytopenia caused by mutations in the gene for non-muscle myosin heavy chain IIA (NMMHC-IIA). Patients present congenital macrothrombocytopenia and inclusions of NMMHC-IIA in leukocytes, and have a variable risk of developing kidney damage, sensorineural deafness, presenile cataracts and/or liver enzymes abnormalities. The spectrum of mutations found in MYH9-RD patients is limited and the incidence and severity of the non-congenital features are predicted by the causative MYH9 variant. In particular, different alterations of the C-terminal tail domain of NMMHC-IIA associate with remarkably different disease evolution. We report four novel MYH9 mutations affecting the tail domain of NMMHC-IIA and responsible for MYH9-RD in four families. Two variants cause amino acid substitutions in the coiled-coil region of NMMHC-IIA, while the other two are a splicing variant and a single nucleotide deletion both resulting in frameshift alterations of the short non helical tailpiece. Characterization of phenotypes of affected individuals shows that all of these novel variants are associated with a mild clinical evolution of the disease. PMID- 29996172 TI - Taurine Ameliorates Thyroid Hypofunction and Renal Injury in L-NAME-Induced Hypertensive Rats. AB - There is a growing global interest in hypertension due to its associated complications including renal dysfunction in patients. The thyroid system reportedly regulates renal function in both animal and human. The present study investigated the therapeutic efficacy of taurine on renal and thyroid dysfunctions in hypertensive rats. Hypertension was induced by oral administration of nitric oxide synthase inhibitor, N-nitro L-arginine-methyl ester (L-NAME), at 40 mg/kg body weight to the male Wistar rats for 14 consecutive days. The hypertensive rats were subsequently treated with either taurine (100 and 200 mg/kg) or reference drug atenolol (10 mg/kg) for another 14 consecutive days. Hypertensive rats showed renal damage evidenced by elevated plasma creatinine and urea levels when compared with normotensive control rats. Furthermore, L-NAME-induced hypertensive rats showed decreased circulatory concentrations of thyroid stimulating hormone, thyroxine, triiodothyronine and the ratio of triiodothyronine to thyroxine. The marked decrease in the renal antioxidant enzyme activities and nitric oxide level was accompanied by significant increase in myeloperoxidase activity and biomarkers of oxidative stress in hypertensive rats. Histological examination of kidneys from hypertensive rats revealed congestion of blood vessels, hemorrhagic lesion and disorganized glomerular structure. However, treatment with taurine or atenolol significantly reversed the suppression of thyroid function, ameliorated renal oxidative stress and histopathological lesions in L-NAME-induced hypertensive rats. Taurine may be a useful chemotherapeutic supplement in enhancing renal and thyroid functions in hypertensive patients. PMID- 29996173 TI - Prediction of Human Pharmacokinetics of Bendamustine from Preclinical Species Pharmacokinetics Based on Normalizing Time Course Profiles. AB - Bendamustine, an alkylating anticancer agent, is used to treat chronic lymphocytic leukemia by intravenous infusion alone or in combination. The work aimed to develop a method to predict time vs. concentration profile for humans based on preclinical pharmacokinetics using the assumption of superimposability of normalized time course profiles of animals and humans. Standard allometric equations with/without correction factors (CF) were also used in prediction. The Vss was predicted by simple allometry of 0.312W0.871 (r2=0.987), where W is body weight; predicted Vss (19.71 L) was similar to the reported value (20.10 L). However, CL prediction involved both simple and CF allometry. Best proximity CL (543 vs. 598 mL/min) was obtained with maximum life span correction (MLP) [2.46W1.215 (r2=0.988)]. Normalized curves were obtained by normalizing the time (with mean residence time) vs. concentration (with dose/Vss) in animal species. The concentration vs. time profile in humans after intravenous infusion was then simulated using normalized curve for each animal species and the values of CL and Vss were predicted for humans. In summary the findings indicate that normalized time course approach could predict the bendamustine human pharmacokinetics and such an approach could be prospectively applied for analog drugs of this class. PMID- 29996174 TI - Modified Fe3O4/HAp Magnetically Nanoparticles as the Carrier for Ibuprofen: Adsorption and Release Study. AB - The adsorption capacity and release attributes of magnetic Fe3O4@hydroxyapatite (Fe3O4/HAp) nanoparticles for drug molecules can be improved by modified their surfaces with logical chosen organic groups. The internal surface of nanoparticles was functionalized with (3-aminopropyl) trimethoxysilane (APTS). Comparative studies of their adsorption and release properties for various model drug molecules (such as pure hydroxyapatite, Fe3O4@hydroxyapatite and functionalized Fe3O4@hydroxyapatite) were then conducted. The characteristic of the obtained materials was performed with X-ray-diffraction (XRD), energy dispersive X-ray microanalysis (EDS), fourier transform infrared spectroscopy (FT IR), scanning electron microscopy (SEM), UV-Vis analysis, vibrating sample magnetometer (VSM) and transmission electron microscopy (TEM). Results show that functionalized magnetic Fe3O4@hydroxyapatite nanoparticles leads than a substantial decrease of the drug delivery rate in pH=6.8 after investigated drug release in intestine environment. In addition, the results demonstrate that high adsorption capacity for drug and slower drug release rate was obtained after functionalized nanoparticles than Fe3O4@hydroxyapatite and pure hydroxyapatite. PMID- 29996175 TI - Demographic Characteristics and Functional Performance of the Kidneys and Hearts of Patients with Acute Tramadol Toxicity. AB - BACKGROUND: Tramadol overdose is disproportionately more common in Iran, and in recent years, it has become one of the most common causes of poisoning admissions to emergency departments in this country. Tramadol is a synthetic analogue of codeine and a weak opioid receptor (MU) agonist that can cause seizures even in commonly used doses. AIMS: This study aimed to examine the relationship between seizure and plasma tramadol concentration in patients with tramadol poisoning who referred to one of the hospitals in Ghaemshahr, Iran. STUDY DESIGN: This research is an analytical cross-sectional study. METHODS: A total of 121 tramadol users (non-seizure group=61 and seizure group=60) were admitted to hospital. Demographic characteristics and clinical findings were collected by a questionnaire. Plasma was harvested after separation from blood cells and quantified using the HPLC method. Biochemical parameters, including urea, creatinine, troponin I, and creatine phosphokinase (CPK-MB) were determined by spectrophotometry. This study was a single blind design study. RESULTS: The mean age of participants was 25 years. Ninety-five participants were classified as smokers. The mean serum concentrations of tramadol in subjects with seizures and those without seizures were 491.90 MUg/ml and 374.42 MUg/ml (p=0.211), respectively. Average concentrations of biochemical parameters in the seizure group were 53.33 (9.38) ug/ml urea, 1.71 (0.29) ug/ml Cr, 6.53 (2.89) ug/ml TPI, and 58.23 (22.20) ug/ml CPK- MB. Average concentrations of biochemical parameters were significantly higher in the seizure group than in the non-seizure group (p<0.001). CONCLUSION: Tramadol-induced seizures were not found to be related to age, gender, or dosage. This complication can lead to cardiac and renal complications in individuals on tramadol experiencing seizures. This result indicates that stricter restrictions should be imposed on the distribution and administration of the drug tramadol. PMID- 29996176 TI - Leaf anatomical traits determine the 18 O enrichment of leaf water in coastal halophytes. AB - Anatomical adaptations to high-salinity environments in mangrove leaves may be recorded in leaf water isotopes. Recent studies observed lower 18 O enrichment (DeltaL ) of leaf water with respect to source water in three mangrove species relative to adjacent freshwater trees, but the factors that govern this phenomenon remain unclear. To resolve this issue, we investigated leaf traits and DeltaL in 15 species of true mangrove plants, 14 species of adjacent freshwater trees, and 4 species of semi-mangrove plants at five study sites along south eastern coast of China. Our results confirm that DeltaL was generally 3-40/00 lower for mangrove species than for adjacent freshwater or semi-mangrove species. We hypothesized that higher leaf water content (LWC) and lower leaf stomatal density (LS) both played important roles in reducing DeltaL in mangroves relative to nearby freshwater plants. Both differences acted to elongate effective leaf mixing length (L) in mangroves by about 200% and lower stomatal conductance by about 30%. Peclet models based on both LWC and LS could accurately predict DeltaL . Our findings highlight the potential species-specific anatomical determinants of DeltaL (or L), which has important implications for the interpretation of environmental information from metabolites produced by leaf water isotopes in palaeoclimate research. PMID- 29996178 TI - [Critical issues in the management of food allergy-related digestive diseases]. PMID- 29996179 TI - [Consensus statement on botulinum toxin for children with cerebral palsy]. PMID- 29996177 TI - Proposed a simple score for recommendation of scheduled ultrasonography surveillance for hepatocellular carcinoma after Direct Acting Antivirals: multicenter analysis. AB - BACKGROUND AND AIM: To develop a scoring method using with common clinical data for predicting hepatocellular carcinoma (HCC) development after sustained virological response at 24 weeks (SVR24) after treatment with direct acting antivirals (DAAs), we retrospectively evaluated clinical features of patients who obtained SVR24. METHODS: From October 2014 to December 2017, 1069 hepatitis C virus patients without a past history of HCC, who obtained SVR24 by DAAs at two different areas, were enrolled (the training [n = 484, ChuShikoku-group] and validation [n = 585, Chubu-group] sets). All were examined by ultrasonography as surveillance for HCC at the time of starting DAAs and twice a year after SVR24. We identified three parameters at SVR24, male gender, FIB-4 index > 3.25, and alpha-fetoprotein level > 5.0 ng/mL, as risk factors for HCC development and gave them point values, with the sum used as After DAAs Recommendation for Surveillance (ADRES) score. RESULTS: In the ChuShikoku-group, the respective 1-/2 year rates for HCC incidence rates ADRES score 0 were 0.0%/0.0%, for a score 1 were 1.1%/2.1%, score 2 were 8.8%/15.9%, and score 3 were 17.1%/28.1%. On the other hand, those respective scores for the Chubu-group were 0.0%/0.0%, 0.0%/0.7%, 7.9%/10.6%, and 19.5%/not available. The c-index of the predictive value for HCC development in the training set after SVR24 was 0.835 while 0.899 in the validation set. Finally, those of the entire cohort were 0.0%/0.0%, 0.5%/1.6%, 8.4%/13.4%, and 18.0%/32.8%. CONCLUSION: The present ADRES score was simple and easy to use and may be useful for predicting risk of HCC development in short term after reaching SVR24 by DAAs. PMID- 29996180 TI - [Interpretation of executive summary of the guideline on pediatric gastrointestinal endoscopy from the European Society of Gastrointestinal Endoscopy and the Europeans Society for Paeditric Gastroenterology Hepatology and Nutrition in 2017]. PMID- 29996181 TI - [Endoscopic management of ingested foreign bodies in the upper gastrointestinal tract in childhood: a retrospective study of 1 334 cases]. AB - Objective: To explore the clinical features and complications of foreign bodies in the upper gastrointestinal tract in children and to investigate the effectiveness of endoscopic management. Methods: Data of patients with foreign bodies in upper gastrointestinal tract were collected retrospectively at Endoscopy Center, the Children's Hospital, Zhejiang University School of Medicine, from January 2011 to December 2016. Clinical characteristics, the types of foreign bodies, the location and duration of foreign body impaction were summarized. The risk factors of complications and endoscopic removal failure were analyzed by using Logistic regression analysis. Results: A total of 1 334 patients (825 males and 509 females) were enrolled. The median age was 2.5 years, with a range from 0.25 to 15 years and peak age 1-3 years. Twenty patients had esophageal diseases. The most common foreign body ingested was coin (n=964, 72.3%). Foreign bodies were most commonly located in the esophagus (n=1 002, 75.1%), especially in the upper esophagus (n=857, 85.5%). The duration of foreign body impaction ranged from 3 hours to 5 years. Among 1 334 patients, 252 patients (18.9%) developed complications, including ulcers (n=101, 40.0%) and perforations(n=13, 5.2%). The success rate of endoscopic removal was 96.6% (n=1 288). By Logistic regression analysis, sharp foreign body ingestion (OR=6.893, 95%CI: 4.421-10.746) , esophageal impaction (OR=5.253, 95%CI:3.352-8.233) and foreign body impaction longer than 24 hours (OR=4.336, 95%CI:3.091-6.082) were risk factors of complications. Sharp foreign body ingestion was the risk factor of endoscopic failure (OR=5.372, 95%CI:2.773-10.406) . Conclusions: Coin is the most common foreign body in upper gastrointestinal tract. Sharp foreign bodies impacted in the esophagus over 24 hours increase the risk of complications. Endoscopic removal of foreign bodies from the upper gastrointestinal tract in children has a high success rate. Sharp foreign body ingestion increases the risk of failure in endoscopic removing. PMID- 29996182 TI - [Clinical analysis of eosinophilic gastroenteritis in 71 children]. AB - Objective: To summarize the clinical data including manifestations, diagnosis, treatment and prognosis of eosinophilic gastroenteritis (EGE) in children. Methods: A retrospective analysis was performed in 71 patients with pathologically proven EGE at Beijing Children's Hospital Affiliated to Capital Medical University from January 2008 to January 2017. Their clinical manifestations, laboratory and imaging examinations, endoscopic findings, histopathological examinations, and treatment were collected and analyzed. Results: Among 71 EGE cases, 47 (66%) cases were male and 24 (34%) cases were female, and the median age was 9.2 (0.2-16.5) years old. The main clinical manifestations included abdominal pain (76%, 54/71), vomiting (68%, 48/71), anorexia (54%, 38/71), weight loss (38%, 27/71), and diarrhea (37%, 26/71). There were 27 cases (38%) with a history of allergic diseases or family history. The median absolute value of eosinophil in peripheral blood of the 71 patients was 0.4 (0-36.8)*10(9)/L, and 27 cases (38%) showed an increase in eosinophil counts. Serum IgE was measured in 52 patients (104.3 (3.4- 3 000.0)*10(3) U/L), and 30 patients (58%) showed an increase in serum IgE. A large number of eosinophils ((41.0+/-8.5)/HP) were found in 3 patients' ascites. The endoscopic examination of upper gastrointestinal tract revealed hyperemic edema in 62 cases (87%), plaque in 44 cases (62%), erosion in 17 cases (24%) and ulceration in 16 cases (23%). Histopathologically, in 8 cases (11%) the disease involved both stomach and duodeneum, in 21 cases (30%) involved stomach only, and in 37 cases (52%) involved duodeneum only. In addition, in 6 cases (8%) the disease involved esophagus and in 10 cases (14%) involved colorectum. Microscopically, eosinophil counts averaged 67/HP, 33/HP, 40/HP and 38/HP in esophageal, gastric, duodenal and colorectal mucosa respectively. A total of 34 cases were treated with glucocorticoid, and all these patients had alleviation of symptoms, which occurred within 14.9 days on average, but EGE recurred in 11 cases (32%). Conclusions: The clinical symptoms and endoscopic findings of EGE are diverse and nonspecific. Histopathological examination of gastrointestinal mucosa is particularly important for the diagnosis. Glucocorticoid treatment is effective, but the patients with EGE are prone to relapse. PMID- 29996183 TI - [Impact on the intestinal microbiota of early antibiotic treatment in preterm neonates]. AB - Objective: To investigate the impact of early antibiotics treatment on intestinal microbiota in preterm infants. Methods: The cohort study was performed from January 2015 to June 2015 in Neonatal Intensive Care Unit of Peking University Third Hospital. A total of 33 preterm infants were enrolled, among whom 25 were antibiotics-exposure group, and 8 were non-exposure group. Serial stool samples were collected on the first day, 14th and 30th days of life and analyzed by high throughput sequencing. In exposure group, intestinal microbiota was also analyzed at 8 months to 1 year of age. Categorical variables were analyzed with chi(2) test, and continuous variables were analyzed with t test or non-parametric test. Results:Proteobacteria was the most prominent flora after birth in all cases (exposure group 69.6%, non-exposure group 83.7%) . In exposure group, at the phylum level, Proteobacteria was the dominant bacteria within the first 30 days, followed by Firmicutes after 30 days of life. At the genus level, Escherichia was the most abundant genera within 30 days after birth, while Veillonella became dominant after 8 months to 1 year of life. In non-exposure group, at the phylum level, Proteobacteria was the dominant phylum within the first 30 days. At the genus level, Actinobacteria (37.5%) was the dominant genus after birth, followed by Escherichia within the first month. Intestinal bacterial abundance and diversity were lower in exposure group, which was most significant on 30th day of life (shannon index 2.6 vs.3.4, ACE index 563.9 vs.591.6) . The influence of single antibiotics was less significant than combined treatment (shannon index 2.7 vs.2.5, ACE index 727.3 vs.492.9) . At the genus level, compared to non exposure group, there were significant decrease of Escherichia (9.3% vs. 54.3%, Z=-2.830, P=0.005), Klebsiella (0.03% vs.12.4%,Z=-2.240, P=0.025), and Clostridium (0.2% vs. 4.8%, Z=-2.979, P=0.003) in exposure group on 14 days of life. Bifidobacterium (0.1% vs.2.0%, Z=-2.349, P=0.019) in cases treated with combined antibiotics was lower than that treated with antibiotic monotherapy on 30 days of life. Conclusions: Early application of combined antibiotics impacts on the intestinal microbiome of preterm infants significantly. The infants who have received antibiotic after birth have lower quantity and diversity of Clostridium, Lactobacillus, Bacteroides and Bifidobacterium. PMID- 29996184 TI - [Long-term results of multicenter study based on childhood acute lymphoblastic leukemia 2005 protocol]. AB - Objective: To evaluate the long-term efficacy and prognostic factors of childhood acute lymphoblastic leukemia (ALL) enrolled in Shanghai Children's Medical Center Acute Lymphoblastic Leukemia-2005(SCMC-ALL-2005) multicenter study. Methods: Between May 2005 and December 2014, 1 497 newly diagnosed ALL patients were enrolled and treated in 5 hospitals of SCMC-ALL-2005 study group, using risk stratified SCMC-ALL-2005 protocol. Risk group classification and treatment intensity were based on clinical features, genetic abnormalities, early response to treatment and levels of minimal residual disease (MRD). Kaplan-Meier method was used to generate overall survival (OS) and event-free survival(EFS) curves. Cox proportional hazards models were used for multivariate analyses. Results: The patients were followed up to December 31, 2016, the median follow-up time was 69 months (24-141 months). The 5-year and 10-year OS rates were (80.0+/-1.0)% and (76.0+/-2.0)%. The 5-year and 10-year EFS rates were (69.0+/-1.0)% and (66.0+/ 2.0)%. The 5-year and 10-year relapse rates were (23.0+/-1.0)% and (25.0+/-2.0)%. The 5-year OS and EFS for low risk (LR), intermediate risk (IR) and high risk (HR) were (91.1+/-1.4)% and (83.3+/-1.8)%, (79.2+/-1.5)% and (68.9+/-1.7)%, (52.9+/-4.4)% and (30.0+/-3.8)%, respectively. MRD negative status (<0.01%) on day 55 was seen in 792 patients (82.8%) and positive MRD on day 55 was associated with poor prognosis (OR=1.9, 95%CI: 1.3-2.7, P=0.001). Twenty-four HR patients received allogeneic hematopoietic stem cell transplantation and 17(70.8%) of them were alive and in remission. A total of 164 severe adverse events occurred, 46 of them died, treatment-related mortality was 3.1%. Conclusions: In this large sample research, the overall outcome for multi-center SCMC-ALL-2005 study was favorable. This helps to promote the standardized treatment of childhood ALL to the whole country. MRD results on day 55 of induction therapy have important prognostic and therapeutic implications. PMID- 29996185 TI - [Phenotype study of SCN2A gene related epilepsy]. AB - Objective: To summarize the phenotype of epileptic children with SCN2A mutations. Methods: Epileptic patients who were treated in the Pediatric Department of Peking University First Hospital from September 2006 to October 2017 and detected with SCN2A mutations by targeted next-generation sequencing were enrolled. Clinical manifestations of all patients were analyzed retrospectively. Results: A total of 21 patients (16 boys and 5 girls) with SCN2A mutations were collected. Twenty-one SCN2A mutations were identified. Ten patients had mutations inherited from one of their parents and 11 patients had de novo mutations. The age of epilepsy onset was from 2 days to 2 years and 6 months: six patients with seizure onset in neonates (29%) , six patients with seizure onset between 1 month and 3 months of age (29%), three patients with seizure onset between 4 months and 6 months of age, two patients with seizure onset between 7 months and one year of age, and four patients with seizure onset beyond one year of age. Multiple seizure types were observed. The focal seizure was the most common seizure type which was observed in 18 patients (86%) . Spasm seizure was observed in 6 patients (29%) . Other seizure types were rare. In 19 patients, seizures manifested in clusters (90%) . In 3 patients, seizures manifested fever sensitive. Nine of ten patients with inherited SCN2A mutations had normal development. However, all patients with de novo SCN2A mutations had mild or severer development delay. In 21 patients with SCN2A mutations, five were diagnosed with benign familial infantile epilepsy, 3 with benign familial neonatal-infantile epilepsy, 3 with Ohtahara syndrome, 3 with West syndrome, 2 with encephalopathy with early infantile onset epilepsy, one with febrile seizures plus, one with Dravet syndrome, one with encephalopathy with childhood onset epilepsy, one with autism with epilepsy and one with intellectual disability with epilepsy. Conclusions: The clinical features of patients with SCN2A mutations include that main seizure onset is the neonate and early infancy, and the main seizure type is the focal seizure, manifested in clusters. The large spectrum of SCN2A-related epilepsy, which not only includes epilepsy with a comparatively favorable prognosis, but also epileptic encephalopathy. De novo mutations often lead to severe phenotype with development delay. PMID- 29996186 TI - [Clinical and genetic analysis of 11 cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome]. AB - Objective: To investigate the clinical, inflammatory and genetic characteristics of cases with periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. Methods: Clinical and inflammatory manifestations and gene sequencing of 11 cases with PFAPA were retrospectively analyzed. Inflammatory markers including white blood cell (WBC) , C reactive protein (CRP) , and serum amyloid A (SAA) were compared between febrile period and intermittent period. Fifteen normal children were taken as healthy controls. The levels of plasma inflammatory cytokines including interleukin(IL)1beta, IL-6, IL-17, tumor necrosis factor(TNF)-alpha, interferon (IFN)-gamma, and granulocyte-colony stimulating factor(G-CSF) were compared between febrile period and intermittent period with paired-sample t test, and compared between febrile cases and healthy controls with independent t test. Results: A total of 11 cases (7 females and 4 males) were included. The median onset age was 24 (3-60) months, and the median age of diagnosis was 69 (11-151) months. The median febrile duration was 4 (1-8) days, and the intermittent period lasted 1 to 8 weeks. All the cases had periodic fever and pharyngitis/tonsillitis, 7 of whom had combined lymphadenitis, and 5 of whom suffered from oral ulcers. Compared to intermittent-period-status,WBC ((14.7+/-4.1) *10(9)/L vs. (8.4+/-1.9) *10(9)/L, P<0.05), CRP((24.2+/-21.1) vs. (3.3+/-2.1)mg/L, P<0.05), SAA ((136.4+/-47.7) vs. (7.1+/-1.1)mg/L, P<0.05) were significantly elevated in febrile period. Compared to intermittent-period-status and healthy controls, plasma levels of IL-6 ((38+/-10) vs. (8+/-4) and (8+/ 5)ng/L, t=6.514 and 6.830 respectively, P<0.05), IFN-gamma ((132+/-43) vs.(49+/ 21) and (53+/-21)ng/L, t=4.069 and 4.276 respectively, P<0.05), G-CSF ((403+/-12) vs. (175+/-90) and (121+/-49)ng/L, t=4.219 and 9.047 respectively, P<0.05) were significantly higher in febrile period, while no differences were found in levels of IL-1beta, IL-17 and TNF-alpha. Gene sequencing found MEFV gene heterozygous variation in 8 cases. Conclusions: PFAPA often manifests as periodic fever, pharyngitis, tonsillitis, aphthous stomatitis and adenitis. Gene sequencing analysis, detection of inflammation markers and cytokines could help with the diagnose of this disease. PMID- 29996187 TI - [Haploidentical hematopoietic stem cell transplantation in the treatment of acquired aplastic anemia in children: a single center retrospective analysis]. AB - Objective: To investigate the safety and efficacy of haploidentical hematopoietic stem cell transplantation with different intensity conditioning regimen in the treatment of childhood aplastic anemia (AA) . Methods: Thirty-seven AA patients who underwent haploidentical transplantation in BaYi Children's Hospital Affiliated to PLA Army General Hospital from January 2013 to January 2017 were enrolled. According to the dosage of conditioning regimen, 34 patients excluding 3 other conditioning regimens were divided into high-dosage group (regimen 2, 22 cases) and low-dosage group (regimen 3, 12 cases). The data of Engraftment, graft vs-host disease (GVHD), hematopoietic reconstitution, relapse, infection, overall survival (OS) were analyzed. The comparison between the two groups was tested by chi(2) test. Results: A total of 35 of 37 patients achieved primary engraftment; 2 cases died of regimen-related toxicity and severe infection before the infusing of the grafts. The activation rate of CMV and EBV was 60% (21/35) . Post transplant lymphocyte disease (PTLD) of lung occurred in one case. The cumulative incidences of acute GVHD grade I-IV and chronic GVHD were 29% (10/35) and 34% (12/35) respectively and the incidence of extensive chronic GVHD was 6% (2/35) . The median follow-up time was 18.8 (2.9-44.1) months, the OS was 92% (34/37) .All survived patients were no longer dependent on blood transfusion and none of them had recurrence. Comparing the rates of overall survival(86%(19/22) vs.100%(12/12)) and rates of chronic GVHD(40%(8/20) vs. 17%(2/12)) in regimen 2 and regimen 3 group, there were no significant difference (chi(2)=1.742, 1.841, all P>0.05) . Significant difference was found at the incidence of I-IV acute GVHD (10% (2/20) vs. 50% (6/12) ,chi(2)=6.200, P=0.013). Conclusions: Haploidentical hematopoietic stem cell transplantation is effective and safe. It is suitable for patients who are not eligible for matched donor transplantation. Application of reduced dose preconditioning in haploid transplantation is worth exploring. PMID- 29996188 TI - [Correlation between severity of gastroesophageal reflux cough and degree of gastroesophageal reflux disease]. AB - Objective: To explore the correlation between the severity of gastroesophageal reflux cough and degree of gastroesophageal reflux. Methods: A cross-sectional investigation was carried out. Data of 174 cases of chronic cough were collected in Children's Hospital of Fuzhou from March 2009 to December 2016. The esophageal 24 hours pH value dynamic monitoring was used to detect gastric acid reflux index. Cases with abnomal results were divided into mild, moderate and severe groups according to severity of reflux and that of day and night cough symptoms, respectively. They were also divided into infant (1-3 years old), preschool (4-6 years old), and school age (>7 years old) groups according to age. Comparative analysis between groups by chi-square test and rank sum test were performed. Correlation analysis was used to analyze the correlation between cough severity and gastroesophageal reflux index. Results: A total of 174 patients with chronic cough, including 115 males and 59 females, aged from 1 to 15 years with an average age of (8.5+/-2.3) years, and (1.6+/-0.8) years of disease duration were enrolled. Among them, 129 cases (74.1%) were positive for esophageal reflux test and 45 cases (25.9%) with no obvious pathological gastroesophageal reflux. Patients with positive esophageal reflux test were divided into severe (n=37, 28.7%), moderate (n=23, 17.8%), and mild (n=69, 53.5%). There was no significant difference in the distribution of gastroesophageal reflux in each age group. (The proportions of mild, moderate and severe reflux in infants were 45.0% (9/20), 25.0% (5/20), and 30.0% (6/20), respectively. The proportions of mild, moderate and severe reflux in preschool children were 53.3% (32/60), 16.7% (10/60), 30.0% (18/60), respectively. The proportions of mild, moderate and severe reflux in school age children were 57.1% (28/49), 16.3% (8/49), 26.5% (13/49), respectively chi(2)=1.204, P=0.877). There was no correlation between age group and gastroesophageal reflux (r=-0.065, P=0.489).The severity of nighttime cough was positively correlated with percentages of distal esophagus pH<=4 in time, recumbent pH<=4 in time, and DeMeester score<14.72 (r=0.689, 0.621, and 0.707 respectively, all P<0.05). There was no statistically significant correlation between the severity of nighttime cough symptoms and percentage of standing pH<=4 in time (r=0.113, P>0.05). There were no statistically significant correlation between the severity of daytime cough and all gastroesophageal reflux markers (all P>0.05). Conclusion: The severity of nocturnal symptoms of gastroesophageal reflux cough is related to the degree of gastroesophageal reflux, to which clinical pediatricians should pay attention. PMID- 29996189 TI - [Clinical features and diagnosis of childhood leukoencephalopathy with cerebral calcifications and cysts in four cases]. AB - Objective: To investigate the clinical features and diagnostic bases of childhood leukoencephalopathy with cerebral calcifications and cysts (LCC). Methods: The clinical data involving manifestations and laboratory examinations of 4 children with LCC admitted to Beijing Children's Hospital Affiliated to Capital Medical University from 2012 to 2017 were retrospectively summarized. Each patient had a follow-up visit ranging from 4 months to 5 years and 9 months after initial examination. Results: Patients consisted of 2 males and 2 females, whose age of onset was respectively 2 years and 9 months, 6 years and 2 months, 7 years and 10 months, and 5 years and 1 month. The main clinical symptoms of these cases included headache, dizziness, partial seizure and claudication, and two of these cases had insidious onset. Cerebral calcifications and cysts with leukoencephalopathy were detected by neuroimaging in all patients. In addition, multifocal microhemorrhages and calcifications were observed by magnetic susceptibility-weighted imaging (SWI) series in 3 patients. Brain biopsy performed on 1 case disclosed a neuronal reduction in the cerebral cortex, loosening of focal white matter, multifocal lymphocyte infiltration, fresh hemorrhages, and gliosis, as well as angiomatous changes of blood vessels with hyalinized thicken-wall, stenotic or occlusive lumina and calcification deposits. The compound heterozygous mutations of n.*10G>A and n.82A>G in SNORD118 were identified in 1 case by target-capture next-generation sequencing. Sanger sequencing verified that the variant n.*10G>A was a novel mutation and it was of paternal-origin, while the variant n.82A>G was of maternal-origin, which had already been reported to be pathogenic to LCC. Follow-up study had shown continued partial seizure in 1 case and remissive claudication in another, while the remaining 2 cases had a relatively favorable outcome without obvious neurological symptoms at present time. Conclusions: The clinical manifestations of LCC are nonspecific, and the onset of the disease tends to be insidious. The triad neuroimaging findings of cerebral calcifications, cysts and leukoencephalopathy are essential to the diagnosis of the disease, and the signals of microhemorrhages revealed by SWI series provide another eloquent reference for the diagnosis. As biopsy is invasive and usually unavailable in the early stage, gene assessment, instead of pathological data, should be the gold standard in the diagnosis of LCC. PMID- 29996191 TI - [Sigmoid foreign body treated with colonoscopy in two children]. PMID- 29996190 TI - [Analysis of four carnitine-acylcarnitine translocase deficiency cases caused by homozygous mutation of SLC25A20 c.199-10T> G]. AB - Objective: To investigate the clinical, biochemical and genetic features of four carnitine-acylcarnitine translocase deficiency cases. Methods: Four cases diagnosed with carnitine-acylcarnitine translocase deficiency from Guangxi Maternal and Child Health Hospital were studied. DNA was extracted from dry blood filter for gene analysis. SLC25A20 gene analysis was performed in 1 case and the whole exon sequence analysis was performed in 3 cases. Results: Retrospective study on unrelated carnitine-acylcarnitine translocase deficiency patients, the age of onset was 1-28 d, the age of death were 1.5-30 d, main clinical features were hypoglycemia (4 cases), arrhythmia (2 cases), sudden death (2 cases). Biochemical test showed hypoglycemia (1.2-2.0 mmol/L) , elevated creatine kinase (955-8 361 U/L) and creatine kinase isozyme(199-360 U/L), normal or decreased free carnitine level (3.70-27.07 MUmol/L) , elevated long-chain acylcarnitine (palmityl carnitine 1.85-14.84 MUmol/L). The gene tests showed that all 4 cases carried SLC25A20 gene c.199-10T> G homozygous mutation, inherited from their parents. By analyzing the haplotype, we found that the mutation loci of C. 199 10T> G were all in the same haplotype. Conclusion: The c.199-10T> G mutation is an important molecular cause of carnitine-acylcarnitine translocase deficiency, which has relatively high frequency in Guangxi population, and is related to the founder effect. PMID- 29996192 TI - [Familial dyskinesia and facial myokymia in a patient with ADCY5 gene mutation]. PMID- 29996193 TI - [A case of paroxysmal tonic upward gaze]. PMID- 29996194 TI - [Cri-du-chat syndrome in neonatal period]. PMID- 29996195 TI - [History and present situation of children's toliet training and its effect on bladder and bowel function]. PMID- 29996196 TI - [Diagnostic application of serum GP73 and the relevant mechanism in the diagnosis of liver cirrhosis]. AB - Liver cirrhosis is the end-stage change of chronic liver diseases with various causative factors. The accurate diagnosis of liver cirrhosis in an early stage is very important for the timely treatment and prognosis of patients. A liver biopsy test is the gold standard for the diagnosis of liver cirrhosis; but its use is limited in clinical practices due to its invasive nature. The conventional non invasive measures (APRI, FIB-4 and LSM) for diagnosis of liver cirrhosis could not fulfill the needs. Therefore, finding a new serological marker of liver cirrhosis has become a research hotspot. Based on literature review and our own results, we suggest that serum GP73 as the most potential serum marker for liver cirrhosis diagnosis. This review briefly introduces the application of serum GP73 in the diagnosis of liver cirrhosis and the potential mechanism relevant to its involvement in the development of liver cirrhosis. PMID- 29996197 TI - [Present situation on non-invasive assessment of liver fibrosis/cirrhosis]. AB - Patients with chronic liver disease often have varying degrees of hepatic fibrosis, and further exacerbations can lead to cirrhosis and even hepatocellular carcinoma. Liver biopsy is the gold standard for the diagnosis of liver fibrosis/cirrhosis, but there are still many limitations. In recent years, non invasive assessments for liver fibrosis/cirrhosis have gained rapid development. Of these techniques, two different approaches have been validated in clinical practice: imaging methods based on the measurement of liver stiffness, and biological methods based on the serum biomarkers. The two different approaches can complement each other. Current non-invasive assessments for liver fibrosis/cirrhosis tend to be reliable for the detection of advanced fibrosis and cirrhosis, but often lack to distinguish the different early stage of liver fibrosis. Further improving the accuracy of non-invasive assessments might play an important role for clinical management of liver diseases. PMID- 29996198 TI - [Advances in diagnosis and treatment of liver cirrhosis with integrated traditional Chinese and Western medicine]. AB - Liver cirrhosis is a chronic progressive liver disease. A non-invasive diagnostic technique for hepatic fibrosis combined with liver biochemistry, molecular biology, and immunology, imaging study, liver histopathological assessment, and traditional Chinese medicine (TCM) syndrome differentiation can accurately diagnose the cause, severity of disease, and determine the prognosis. In clinical practice of Western medicine, there are five-stages of cirrhosis classification, with periods 1 and 2 being compensated stage, and periods 3 to 5 being decompensated stage. Etiological treatment and anti-hepatic fibrosis treatment are the basic measures for different disease severity and complications. Comprehensive application of modern medical technology and traditional Chinese medicine differentiation therapy can improve the treatment effect and survival rate. PMID- 29996199 TI - [Clinical value of noninvasive method in diagnosing hepatic fibrosis about chronic HBV carriers]. AB - Objective: To compare the clinical value of FibroScan, FIB-4, APRI and AAR diagnosing hepatic fibrosis in chronic hepatitis B virus (HBV) carriers. Methods: A total of 213 patients with chronic HBV carriers diagnosed by clinical and liver biopsy were selected. And according to HBeAg status, 149 patients were divided into HBeAg-positive group and 64 patients were divided into HBeAg-negative group. The liver stiffness measurements (LSM) was measured by FibroScan (FS), FIB-4, APRI and AAR values were calculated using FIB-4, APRI and AAR formula. And all patients underwent liver biopsy in the same period. According to the degree of hepatic fibrosis in Knodell, one decision point was set: significant hepatic fibrosis (S >= 2). The Spearman correlation analysis method was used to analyze the correlation of indicators and the area under receiver operator characteristic curves (AUROCs) of LSM, FIB-4, APRI and AAR were drawn according to liver biopsy pathology results as gold standard. The value of LSM, FIB-4, APRI and AAR diagnosing hepatic fibrosis in chronic HBV carriers was retrospectively analyzed. Retrospective analysis of FS, FIB-4, APRI and AAR were divided into 149 HBeAg positive chronic HBV carriers (HBeAg-positive group) and 64 HBeAg-negative chronic HBV carriers (HBeAg) in 213 patients with chronic HBV carriers and HBeAg Negative group) in the diagnosis of liver fibrosis. Results: The LSM of 213 patients with chronic HBV carriers, 149 patients with HBeAg-positive chronic HBV carriers and 64 patients with HBeAg-negative chronic HBV carriers were significantly correlated with liver fibrosis grade>= 2 (P < 0.001). Regardless of HBeAg status, only LSM in the three groups had moderate evaluation efficacy for evaluating significant fibrosis(S>=2), and the positive predictive value was more than 94%, but the diagnostic accuracy was not high, the minimum was 46.31% (HBeAg positive group), the maximum value of 67.19% (HBeAg-negative group), while the remaining three kinds of serum noninvasive liver fibrosis diagnostic model indicators and diagnostic efficacy are low. The LSM in the three groups showed a significant positive correlation with liver fibrosis grade (S)>=2. Conclusion: LSM is more accurate than FIB-4, APRI and AAR in diagnosing chronic HBV carriers. Dynamically monitoring changes of LSM can earlier understand the progress of liver fibrosis than the three kinds of serology noninvasive diagnostic model and is contributed to the choice of liver biopsy timing. PMID- 29996200 TI - [Diagnostic value of serum chitinase-3-like protein 1 in chronic liver disease of significant fibrosis and cirrhosis]. AB - Objective: To study the correlation between the level of serum Chitinase-3-like protein 1 (CHI3L1) and the significant liver fibrosis and liver cirrhosis in patients with chronic liver disease, and to evaluate its diagnostic value. Methods: 165 patients with chronic liver disease were selected, liver histopathological examination was performed to detect serum CHI3L1 concentration. Four indexes of hepatic fibrosis (type III procollagen, collagen IV, laminin, hyaluronic acid), aspartate aminotransferase/platelet ratio index (APRI) and FIB 4 (fibrosis- 4) scores were based on the pathological findings of liver biopsy and compared the advantages and disadvantages of serum CHI3L1 with other methods for the diagnosis of hepatic fibrosis and liver cirrhosis. A multivariate regression analysis model was created, and receiver operating characteristic curve was analyzed. Results: The level of serum CHI3L1 increased with increase of fibrosis stage and was highest in liver cirrhosis stage. In the period of S0 to 1, the levels of S2 to 3 and S4 were 62.82 (41.40 ~ 87.20), 70.94 (48.47 to 122.60) and 141.06 (78.18 ~ 197.40), and there were statistically significant differences between the groups (P < 0.001). The area under the curve for the diagnosis of significant liver fibrosis was 0.68 (0.60 to 0.77), and 0.74 (0.65 to 0.83) for cirrhosis in CHI3L1. Multivariate regression analysis showed that CHI3L1 was an independent predictor of significant fibrosis and cirrhosis. The combined diagnostic model based on CHI3L1, collagen IV and FIB-4 scores further improved the diagnostic value. The area under the curve for the diagnosis of significant fibrosis and cirrhosis was 0.79 (0.72 to 0.86) and 0.80 (0.73 to 0.87), respectively. Conclusion: CHI3L1 has a good diagnostic value in patients with chronic liver disease with significant fibrosis and liver cirrhosis. The diagnostic model in combination with other markers like Collagen IV and FIB-4 scores could further improve the diagnostic value and is worthy of further study. PMID- 29996201 TI - [Correlation between FibroScan, APRI Detecting the degree of esophageal and gastric varices of liver cirrhosis]. AB - Objective: To investigate the predictive value of transient elastography (FibroScan), aspartate aminotransferase-to-platelet ratio index (APRI) in the detection of esophagogastric varices in patients with liver cirrhosis. Methods: 236 patients with liver cirrhosis who met the criteria were selected. All patients underwent gastroscopy. According to the degree of esophagogastric varices, patients were divided into four groups: none, mild, moderate, and severe. The patient's liver stiffness (LSM) and aspartate aminotransferase- to platelet ratio index (APRI) were measured within 3 days of gastroscopy. One-way analysis of variance was used to compare multi-group data. The ROC curves of LSM, APRI, LSM+APRI in patients with liver cirrhosis with esophageal varices were plotted and their area under the ROC curve (AUC) were compared. Results: The area under the ROC curve of LSM, APRI, LSM + APRI in patients with mild esophagogastric varices were 0.856, 0.900, and 0.906, respectively; moderate esophagogastric varices were 0.857, 0.924, and 0.923 respectively; and severe esophagogastric varices were 0.801, 0.903, and 0.901, respectively. Conclusion: APRI and LSM+APRI have better predictive value for patients with cirrhosis who have esophagogastric varices. PMID- 29996202 TI - [The effects of macrophages with high expression of TL1A on activation and proliferation of hepatic stellate cells in vitro]. AB - Objective: To explore the effects of macrophages with high expression of TL1A on the activation and proliferation of HSCs in vitro. Methods: The Bone marrow derived macrophages (BMMs) and peritoneal macrophages (PMs) from wild type (WT) and myeloid-overexpressed TL1A transgenic mice were isolated, differentiated and activated. HSCs were harvested from activated macrophages culture supernatant (CM). HSCs were detected by immunofluorescence and real-time Q-PCR. And the proliferation was detected by CCK-8 and BrdU assay kit. The levels of IL-1beta and PDGF-BB in macrophage culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Results: BMMs-derived CM-intervention HSCs were used to detect the expression of alpha-smooth muscle actin (alpha-SMA) on the 2nd, 4th and 6th day respectively by immunofluorescence method. There was no significant difference between the two groups on the 2 nd and the 6th day, P > 0.05; On day 4, the CM/Tg group was significantly higher than that of CM/WT group, P < 0.01; the results of CMs derived from PMs were consistent with the above trend. The expression of alpha-SMA mRNA on the 2nd, 4th and 6th day was detected by real time Q-PCR method using BM-derived CMs. No significant difference was found between the groups on the 2nd day (P > 0.05).alpha-SMA mRNA increased further on the 4th and 6th day, and the level of CM/Tg in CM/Tg group was significantly higher than that in CM/WT group (P < 0.05). The detection results of CMs derived from PMs were consistent with the above trend. The results of CCK-8 assay and BrdU assay showed that the proliferation rate of HSCs in CM Tg group was significantly higher than that in CM/WT group (P < 0.01). The CMs derived from PMs were used to interfere with HSCs. And the results were consistent with the above trend. For BMMs, the levels of IL-1beta and PDGF-BB in the lipopolysaccharide (LPS) + IFNgamma/Tg culture supernatant were significantly higher than those in the LPS+IFNgamma/WT group (P < 0.01). For the culture supernatants of PMs Liquid test results consistent with the above trend. Conclusion: Macrophages with high expression of TL1A could enhance the activation and proliferation of HSCs by increasing the secretion of IL-1beta and PDGF-BB. PMID- 29996203 TI - [Efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir combined with ribavirin in Asian adult patients with chronic HCV genotype 1b infection and compensated cirrhosis]. AB - Objective: To evaluate the efficacy and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily and dasabuvir (DSV) 250 mg twice daily combined with ribavirin in adult patients of Mainland China with chronic HCV genotype 1b infection and compensated cirrhosis. Methods: An open-label, multicenter, phase 3 clinical trial study was conducted in mainland China, Taiwan, and South Korea. Adult patients with compensated cirrhosis (Metavir score =F4) who were newly diagnosed and treated for hepatitis C virus genotype 1b infection with ombitasvir/paritaprevir/ritonavir and dasabuvir combined with ribavirin for 12 weeks were included. Assessed SVR rate of patients obtained at 12 and 24 weeks after drug withdrawal. Efficacy and safety were evaluated in patients who received at least one time study drugs. Results: A total of 63 patients from mainland China were enrolled, 62 of whom (98.4%) had a baseline Child-Pugh score of 5 points. The overall rate of SVR12 and SVR24 in patients was 100% (95% CI: 94.3% to 100.0%). Most of the adverse events that occurred were mild. The incidence of common (>=10%) adverse events and laboratory abnormalities included elevated total bilirubin (36.5%), weakness (19.0%), elevated unconjugated bilirubin (19.0%) and conjugated bilirubin (17.5%), and anemia (14.3%). Three cases (4.8%) of patients experienced Grade >= 3 adverse events that were considered by the investigators to be unrelated to the study drug. None patients had adverse events leading to premature drug withdrawal. Conclusion: Mainland Chinese patients with chronic HCV genotype 1b infection and compensated cirrhosis who were treated with OBV/PTV/r plus DSV combined with RBV for 12 weeks achieved 100 % SVR at 12 and 24 weeks after drug withdrawal. Tolerability and safety were good, and majority of adverse events were mild. PMID- 29996204 TI - [Efficacy and safety of paritaprevir/ritonavir/ombitasvir combined with dasabuvir in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection: a randomized, double-blind, placebo-controlled study - China data]. AB - Objective: To evaluate the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily combined with dasabuvir 250mg, twice daily in non-cirrhotic Chinese adult patients with newly diagnosed and treated chronic HCV genotype 1b infection. Methods: A randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial was conducted in mainland China, Korea, and Taiwan.Safety and efficacy of OBV/PTV/r plus DSV administered for 12 weeks were evaluated in a newly diagnosed and treated (interferon alpha /pegylated interferon alpha) and ribavirin non cirrhotic adults with chronic HCVgenotype 1b infection. Patients randomly received OBV/PTV/r plus DSV for 12 weeks (Group A), or placebo for 12 weeks (Group B) followed by an open-label phase of OBV/PTV/r plus DSV for 12 weeks. Sustained response (SVR12) rate obtained at 12 weeks and (SVR24) 24 weeks after discontinuation of treatment, and the incidence of adverse events and laboratory abnormalities after double-blind and open-label phase treatment were assessed. Results: A total of 410 cases of Chinese patients were included and randomly assigned to group A and B (with 205 cases in each group) in a 1:1 ratio. The rates of SVR12 and SVR24 were 99% (95% CI: 94.8% - 99.8%) in the newly diagnosed patients in group A (205 patients) and the rates of SVR12 and SVR24 were 100% in treated patients (95% CI: 96.3% - 100%). Different baseline characteristics had no effect on SVR12 and SVR24 rates. Most of the adverse events occurred were mild, asymptomatic, and>= 3 laboratory abnormalities during treatment were rare, including elevation of alanine aminotransferase (2 cases in double-blind stage A group), aspartate aminotransferase (Double-blind stage A (3 cases) and total bilirubin (1 case in open-label phase B group); however, those mild adverse events could be recovered after drug withdrawal or discontinuation. only1 person discontinued drugs due to adverse events (Group B, open-label phase). Conclusion: The 12 weeks treatment course of OBV/PTV/r combined with DSV produced 99% ~ 100% rates of SVR12 and SVR24 in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection, and the tolerance and safety were good. PMID- 29996205 TI - [Changes and clinical significance of gammadeltaT cells in peripheral blood of patients with chronic hepatitis B during pegylated interferon alpha-2a treatment]. AB - Objective: To observe the changes of gammadeltaT cells in the peripheral blood of patients with chronic hepatitis B (CHB) during pegylated interferon alpha-2a treatment, and to analyze the correlation between clinical indicators and curative effects. Methods: Peripheral blood of hepatitis B e antigen (HBeAg) positive CHB patients were collected at different time points of Peg-IFNalpha-2a treatment, including 17 patients at 0 weeks, 20 patients at 12 weeks, 20 patients at 24 weeks, and 16 patients at 48 weeks. From these 11 patients, blood samples were frequently observed at 0, 12, 24, and 48 weeks of treatment. The frequencies of gammadeltaT and its subpopulation cells Vdelta1T, Vdelta2T, effector memory gammadeltaT (gammadeltaTem), central memory gammadeltaT (gammadeltaTcm), initial gammadeltaT (gammadeltaTnaive) and terminal differentiation effect gammadeltaT (gammadeltaTeff) cells in peripheral blood were detected by flow cytometry. Liver function, serum HBV markers and HBV DNA levels were measured simultaneously. SPSS 23.0 statistical software was used to analyze the differences in cell proportions at each treatment time point, and the correlation between cell proportions and alanine aminotransferase (ALT), HBsAg, HBeAg or HBV DNA levels. In addition, the correlation between the proportions of gammadeltaT and its subpopulation cells and the response to Peg-IFNalpha-2a treatment in the 11 patients with continuous follow-up were analyzed. Results: The percentage of gammadeltaT and Vdelta2T cells in peripheral blood of patients with CHB decreased gradually during the period of 0-48 weeks of Peg-IFNalpha-2a treatment. The percentages of gammadeltaT cells and Vdelta2T cells at 48 weeks were 6.89% (5%, 8.15%), 4.61% (2.16%, 6.50%), respectively; significantly lower than the 0 week [12.5% (7.73%, 19%), 6.59% (3.86%, 13.62%)], the differences were statistically significant (P < 0.05). The proportions of Vdelta1T, gammadeltaTem, gammadeltaTcm, gammadeltaTnaive, or gammadeltaTeff subpopulations were not statistically different at each time points (all P > 0.05). At the same time, the levels of ALT, HBsAg, HBeAg or HBV DNA were positively correlated with the ratio of gammadeltaT or Vdelta2T cells (P < 0.05). Among the 11 patients with continuous followed- up, the proportion of gammadeltaTem cells in responders was significantly lower than that of non-responders at each time points, and the difference was statistically significant (P < 0.05). There was no statistically significant difference between the two groups (all P > 0.05). Conclusion: The proportion of gammadeltaT cells in the course of CHB treatment with Peg-IFNalpha 2a reduces the liver inflammation by decreasing the replication of HBV virus. Chronic hepatitis B patients with a lower proportion of effector memory (gammadeltaTem) cells may be more likely to get better response with Peg-IFNalpha 2a. PMID- 29996206 TI - [HBV genotyping based on key epitopes of PreS1 antigen and its correlation with genotyping by full-length PreS1 sequencing]. AB - Objective: The aim was to investigate the genotype distribution of two major epitopes of large surface protein (PreS1) of hepatitis B in Chinese patients and to explore the association between the genotypes of these two epitopes, and to determine whether PreS1 full-length genotype could be revealed according to the polypeptide sequence of key epitopes. Methods: HBV DNA was extracted from the serum of patients for PCR amplification. 278 samples amplified successfully were sequenced and compared with the known HBV sequences in Genbank to determine the two key epitopes of HBV PreS1 genotype (amino acid epitope 21-47 and 94-117, abbreviated as P21 and P94) and PreS1 full-length genotypes. The correlation among three genotyping approaches was analyzed by Cohen's kappa coefficient to verify the consistency between the key-epitope genotyping and the full-length preS1 genotyping. Results: 232 samples were successfully sequenced. The genotyping based on the kind of P21 epitope protein sequence, 201 cases for genotype C, 23 cases for genotype B and 8 cases for uncertain genotypes and genotyping based on the form of P94 epitope protein sequence, 199 cases for genotype C, 25 cases for genotype B and 8 cases for indeterminate genotypes. Lastly, the genotyping based on sequence of the full-length PreS1 sequence, 207 and 25 cases for genotype C and B. P21 or P94 epitope genotyping and PreS1 full length genotyping were highly consistent, respectively, 96.55% and 96.12%, and the two epitopes (P21and P94) genotyping have parallel consistency (93.10%). Conclusion: In this study, an innovatively genotyping method based on the amino acid sequence of key epitopes was proposed. The genotypes of HBV in china were mainly B and C genotypes, and the genotypes of key conserved epitopes of HBV PreS1 were highly consistent with the full-length genotyping ( > 96%). Moreover, genotyping with one or two key epitopes can be used in place of the full-length genotyping. PMID- 29996207 TI - [Clinical analysis of de novo HBV infection after liver transplantation in non HBV- related liver disease]. AB - Objective: The aim of this study was to summarize and analyze the clinical features and characteristics of de novo HBV infection after liver transplantation in non-HBV-related liver disease. Methods: We retrospectively analyzed the clinical data of 13 patients with new HBV infection in 376 cases of liver transplantation patients with non-HBV related liver diseases from April 2002 to December 2013 in our hospital. Results: Among 376 patients with non-HBV-related liver disease after liver transplantation, 13 patients developed new HBV infection, and the rate of new HBV infection was 3.46%. Of the 13 cases, 5 were males and 8 were females. The follow-up time was 14.7 -128.7 months, and the average time from surgery to new HBV infection was 19.06 months. The primary diseases were as follows: 5 cases of primary biliary cholangitis, 3 cases of alcoholic liver disease, 2 cases of drug-induced liver damage, 1 cases of post hepatitis C cirrhosis, congenital biliary atresia and congenital liver fibrosis. All patients were positive for HBsAg, HBeAg, anti-HBc, 11 were positive for HBV DNA, and 2 were negative for HBV DNA. 6 cases had abnormal liver function and 7 cases had normal liver function. All patients were treated with antiviral therapy with nucleoside (acid) analogues. HBsAg was negative in 6 patients; HBsAg remained positive in 7 cases, including HBsAg, HBeAg, anti-HBc positive in 6 cases, HBsAg, anti-HBe, anti- HBc was positive in 1 case, HBV DNA was still positive in 1 patient, and HBV DNA was negative in 6 patients; liver function was normal in all patients. Conclusion: Non-HBV- related liver transplantation are high-risk group of new HBV infection, with the highest incidence of autoimmune liver disease. It is speculated that it may be related to the long-term use of hormones after the transplantation. The prognosis of newly diagnosed HBV infection after liver transplantation is fine as long as it can be found and treated early. PMID- 29996208 TI - [Target delivery of small interfering RNAs with vitamin E- loaded lipid nanoparticles in inhibition of hepatitis C virus core protein expression in mouse model]. AB - Objective: To study the efficacy of vitamin E-loaded lipid nanoparticles (VE-DC) in the mouse model to target small interfering RNA (siRNA) for inhibition of hepatitis C virus(HCV) core protein expression. Methods: A high-pressure hydrodynamic method was adopted to construct an animal model of liver-specific expression to inject the plasmid containing HCV core protein into mice tail vein. Western blotting and immunofluorescence techniques were used to evaluote the liver targeting property of VE - DC/siRNA nanoparticles and the effectiveness to repress HCV Core expression. Dual luciferase reporter gene assays and in vivo imaging in mice further confirmed the inhibiting effect of VE-DC/siRNA on gene expression mediated by HCV 5' untranslated region. The adverse reactions of VE DC/siRNA were reported by detecting serum creatinine, white blood cells and interferon. Student's t - test and one -way analysis of variance were used to compare the difference between the two groups, and P < 0.05 was considered statically significant. Results: The dual luciferase reporter gene analysis showed that the luciferase activity of the VE-DC/siRNA treated group was 39.67 +/ 15.53, which was significantly lower than 77.33+/-11.06 of the DC/siRNA group and 91.67 +/- 13.65 of the siRNA treated group, P < 0.05. The difference was statistically significant, and there was no obvious organ toxicity and obvious immune response to VE-DC/siRNA. Nanoparticle VE-DC has a good liver targeting ability, which can transport siRNA to the liver and effectively inhibit the expression of HCV Core, with an average inhibition rate of 83.01%. Conclusion: VE DC could target the delivery of siRNA to the liver and inhibit the expression of HCV- related genes in a mouse model, showing high effectiveness and low toxicity. PMID- 29996209 TI - [Screening of familial primary biliary cholangitis and research on low-frequency mutations by whole-exome sequencing]. AB - Objective: Screening of patients with familial primary biliary cholangitis by using whole-exome sequence to find common low-frequency mutations and to explore its pathogenesis. Methods: The confirmed data of PBC patients diagnosed in Xijing hospital from 2005 to 2016 were collected, and their first-degree relatives' autoantibodies were screened for diagnosis. DNA extraction from PBC patients and normal controls in two high-incidence families was performed for whole-exome sequencing, and the low-frequency mutations in the family were screened. Results: A total of 435 PBC patients and 946 first-degree relatives were screened, and 18 (1.90%) first-degree relatives were also diagnosed with PBC, which was distributed in 16 families (3.68%). The whole-exome sequencing results showed that the common low-frequency mutations of 7 patients in 2 families consisted of 16 single nucleotide polymorphisms and 2 InDel markers, of which ANO2(rs17788563) may be correlated to the pathogenesis of PBC. Conclusion: There is high-incidence of PBC in the family members of PBC patients with low-frequency mutation sites and their sites may be involved in the pathogenesis of PBC. PMID- 29996210 TI - [Post treatment failure of sofosbuvir plus ribavirin in chronic hepatitis C: 1 case of successful treatment of sofosbuvir combined with daclatasvir]. PMID- 29996211 TI - [A case of HCV/HBV coininfection treated with sofobuvir and peginterferon alpha 2b plus ribavirin]. PMID- 29996212 TI - [Key signal molecules of wingless-related integration pathway and targeted therapy for liver cancer]. AB - Hepatocellular carcinoma is one of the most common digestive system tumors. Its occurrence and development are considered as multi-factorial and multi-step process. Recent studies have shown that wingless-related integration (Wnt) pathway plays an important role in the HCC progression and is associated with malignant transformation of hepatocytes, HCC metastasis, drug resistance and liver cancer stem cells. This article analyzes the expression of key signaling molecules in Wnt pathway and its value in diagnosis, prognosis and targeted therapy, and outlines the research progress of Wnt pathway targeted drugs for the treatment of HCC, with a view to providing targeted therapy research for HCC reference. PMID- 29996213 TI - [Effects of ascorbic acid on the expression of p53 and Bcl-2 protein in NIH/3T3 cells exposed to nickel]. AB - Objective: To study the protective effect of Ascorbic acid (AA) on the injury of nickel-exposed mouse embryonic fibroblasts (NIH/3T3) . Methods: A model of damage induced by 50 MUg/mL nickel refining dust was established to determine the relative survival rate of cells, superoxide dismutase (SOD) , lactate dehydrogenase (LDH) and glutathione peroxidase. (GSH-Px) activity, hydrogen peroxide (H(2)O(2)) and malondialdehyde (MDA) content, and p53 (wild-type) , Bcl 2 protein expression. To investigate the protective effect of different doses of ascorbic acid (25, 50, 100 mmol/L) on nickel-refined dust-induced NIH/3T3 cell injury. Results: The study showed that ascorbic acid III group can make the NIH/3T3 cell survival rate increased significantly; Apoptosis rate was reduced; The vitality of SOD and GSH-Px increased significantly, and the difference was statistically significant (P<0.05) . At the same time, the level of MDA and H(2)O(2) and the activity of extracellular LDH enzyme were significantly reduced, and the difference was statistically significant (P<0.05) . The results showed that nickel refining dust induced cell damage through up-regulation of p53 protein and down-regulation of Bcl-2 protein expression; ascorbic acid interventions, the expression level of Bcl-2 protein in ascorbic acid II and III groups was higher than that of nickel refining dust group, and the difference was statistically significant (P<0.05); The expression level of p53 protein in each dose group of ascorbic acid was lower than that of nickel refined dust group, and the difference was statistically significant (P<0.05). Conclusion: With the increase of concentration of ascorbic acid, oxidative damage levels, antioxidant enzyme levels, reduce cell apoptosis, reduce expression of p53, increased expression of Bcl-2. It showed that ascorbic acid had protective effect on NIH/3T3 cell injury induced by nickel refining dust. PMID- 29996214 TI - [Trichloroethylene-induced abnormal methylation on promoter region of SET in hepatic L-02 cells]. AB - Objective: To explore the trichloroethylene-induced alteration of methylation on the promoter region of SET and related mechanisms in hepatic L-02 cells. Methods: L-02 cells were treated with different concentrations of TCE(0 mmol/L, 1 mmol/L, 2 mmol/L, 4 mmol/L, 8 mmol/L) for 24 h. The genomic DNA were then extracted and modified by bisulfite sodium. The DNA methylation was then analyzed using bisulfite sequencing PCR (BSP). Results: The overall methylation on promoter region of SET was decreased along with the increased concentrations of TCE in hepatic L-02 cells. Moreover, 73 CpG islands were found abnormally altered, among which 9 were predicted in transcriptional factor binding regions. Conclusion: The decreased levels of CpG islands in the transcriptional factor binding region may contribute to the elevation of SET in TCE-induced hepatotoxicity. PMID- 29996215 TI - [Protective effects of N-acetyl-L-cysteine against binge drinking-induced fatty liver in mice]. AB - Objective: To investigate the roles of N-acetyl-L-cysteine (NAC) against binge drinking-induced fatty liver in mice. Methods: SPF male C57BL/6 mice were randomly divided into 3 groups, i.e. control group, model group, and NAC/ethanol group (n=10). Mice in model and NAC/ethanol groups were exposed to 3 doses of ethanol (6 g/kg bw) to induced fatty liver, while mice in control group received equal volume and equal energy of maltodextrin solution. NAC was administered to mice at 1 h before ethanol exposure (100 mg/kg bw, i.p.). The mice were sacrificed at 6 h after the last ethanol exposure. The liver and epididymal adipose tissues were collected. Histopathological examination and biochemical assay kit were used to evaluate the fat accumulation, while Western-blot was performed to detect the protein levels of some key factors involved in fat metabolism in liver and adipose tissues. Results: Compored with control group mice, the liver index and liver weight were significantly increased compared with model group, the liver index and TG level in NAC/ethanol group mice were all significantly decreased (P<0.05). Histological examination showed NAC effectively suppressed binge drinking-induced fat accumulation in mice liver. In addition, NAC had no significant effects on the protein levels of peroxisome proliferator activated receptor-alpha (PPAR-alpha), Acy-CoA oxidase (ACOX), sterol regulatory element binding protein 1 c (SREBP-1c) and fatty acid synthase (FAS). Furthermore, the protein levels of hormone sensitive lipase (HSL) did not significantly differ among 3 groups, whereas NAC prevented binge drinking-induced increase of HSL phosphorylation at ser563 and ser660. Conclusion: NAC could effectively attenuate binge drinking-induced fatty liver, which might be associated with the inhibition of lipid mobilization by suppressing the phosphorylation of HSL. PMID- 29996216 TI - [Effects of CdTe quantum dots on the content of cytochrome P450 in rat liver]. AB - Objective: The effect and mechanism of cadmium telluride quantum dots (CdTe QDs) on cytochrome P450 (CYP450) in the liver of rat were investigated. Methods: CdTe QDs (Ex 350 nm, Em 600 nm) were incubated with microsomes in final concentrations (0.5, 5, 50 MUmol/L) using rat liver. And the content of CYP450 was determined by mixed incubation system as time (15, 30, 45 min) went on. Relationship also was detected between particle sizes (Em 620, 580, 540 nm; CdTe QDs-2, CdTe QDs-3, CdTe QDs-4) and expression of CYP450. Twenty male Wistar rats were randomly divided into exposed groups at various concentrations (0.25, 2.5 and 12.5 MUmol/kg) of CdTe QDs via tail vein injection, the control group was injected with PBS. Results: In vitro, CdTe QDs(0.5, 5, 50 MUmol/L) could significantly increase the content of CYP450 in rat liver microsomes(P<0.05), which increased first and then decreased with the dose adding. Moreover, the trend along with the exposure time (15, 30, 45 min) was the same as that in dosages at certain concentration (P<0.01). For different particle sizes, the smaller CdTe QDs were, the higher content increased, the content of CYP450 in group CdTe QDs-4 was the highest (P<0.05). In vivo, experiment proved that CdTe QDs (0.25, 2.5 and 12.5 MUmol/kg) could obviously induce the expression of CYP450 (P<0.01). The content level showed a tendency to rise and then fall. Conclusion: CdTe QDs could promote the content of CYP450 in rat liver microsomes, it indicated that CdTe QDs had dose-effect relationship both in vivo and vitro. There was a certain relationship in time-effect. In addition, the smaller particle size was, the greater impact had. PMID- 29996217 TI - [Experimental study on DEHP affect the neurodevelopment through interfering with placental thyroid hormones transport]. AB - Objective: The present study was represented by di-(2-ethylhexyl) phthalate (DEHP), to explore the role of thyroid hormones (THs) disruption in the connection of placenta and neurodevelopmental toxicity. Methods: During fetal mice neural tube closed (pregnancy 9.5 days, E9.5d) to begin synthesis of THs (E15.5 d), all pregnant mice were administered with different concentration of DEHP (0,10,50,200 mg/kg) by gavage once a day(10 mice per group). All pregnant mice were conducted with BrdU administration in E14d by subcutaneous injection. Seven pregnant mice from each group were scarified after anesthesia in E15.5 d, serum and amniotic fluid were collected to determinate the levels of THs(T(3), T(4), FT(3) and FT(4)) by the automatic biochemical analyzer, detecting fetal mice placental protein expression of monocarboxylate transporter 8 (MCT8), organic anion transporting polypeptide 1C1 (OATP1C1) and deiodinaseII&III (DIO(2), DIO(3)) by Western blot. Each group of the remaining three pregnant mices were killed after anesthesia in E18d, take the male fetal brain, BrdU immunohistochemistry was used to detect the proliferation and migration of fetal brain cortical neurons. Results: There was no abnormalities in diet, water intake, body weight and general activity of pregnant mice in each treatment group, and there were no difference in the general physiolo. Results There was no abnormalities in diet, water intake, body weight and general activity of pregnant mice in each treatment group, and there were no difference in the general physiological development status of body weight, brain weight, brain body ratio between the mice of each group. There was no statistically significant differences in serum T(3), T(4), FT(3), FT(4) and amniotic fluid FT(4) in pregnant mice of each group (P>0.05), Compared with the control group, the FT(3) levels in the amniotic fluid of the DEHP 50 and 200 mg/kg groups were significantly decreased(P<0.05). Compared with the control group, the placental MCT8 and DIO(2) protein levels of male fetal mice in the DEHP 50 and 200 mg/kg group decreased, and the level of OATP1C1 protein in 200 mg/kg group decreased(P<0.05), and there was no statistically significant difference in DIO(3) protein levels among all groups (P>0.05). Compared with the control group, the number of BrdU positive cells in the cerebral cortex of male mice in DEHP 200 mg/kg group decreased, 56.5% was distributed in VZ-SVZ layer, and the percentage of BrdU positive cells in the IZ layer of 50 mg/kg group increased (P<0.05). Conclusion: DEHP 50, 200 mg/kg may affect the proliferation and migration of neural cells in the developing brain, which may be related to its interference with thyroid hormone by placental transport. PMID- 29996218 TI - [The study of the effects of occupational aluminum exposure on TNFR1 expression and cognitive function]. AB - Objective: To analyze the relationship between cognitive function and tumor necrosis factor receptor 1 (TNFR1) expression of occupational exposed workers to aluminum and provide the basis for the diagnosis of cognitive impairment. Methods: 140 cases Shanxi aluminum plant workers were collected in 2016 as the research object, including 70 potroom workers for exposure group, 70 non electrolytic aluminum plant workers in the control group, respectively. Using mini mental status examination (MMSE), digit span test (DST), fuld object memory examination(FOME) and simple reaction time test(SRTT) evaluate the cognitive function of objects. Using graphite furnace atomic absorption method for the determination of plasma aluminum levels as an indicator of aluminum contact exposure of workers. Using RT-PCR method for detection of tumor necrosis factor receptor 1 (TNFR1) mRNA expression levels. And comparison group differences in cognitive and TNFR1 mRNA expression levels. Results: The plasma aluminum content of exposed group (77.12+/-27.18) MUg/L higher than the control group (55.6+/ 28.69)MUg/L (P=0.000); Compared to control group, FOME and MMSE score was significantly increased in the exposed group (P=0.000, P=0.000), SRTT scores significantly higher in the exposed group (P=0.001), DST no significant difference in the control group (P=0.893). Compared to control group, The mRNA expression of TNFR1 was significantly higher in the exposed group(P=0.002); Compared to control group, The protein expression of TNFR1 was significantly higher in the exposed group (P=0.002). By correlation analysis in exposure group, plasma aluminum content was negatively correlated with MMSE and the DST (r= 0.284, r=-0.331, P<0.05) and positively correlated with the SRTT, TNFR1 (mRNA) and TNFR1(protein)(r=0.255, r=0.333, r=0.987, P<0.01), MMSE was negatively related to TNFR1 (mRNA) and TNFR1 (protein) (r=-0.268, r=-0.255, P<0.05); DST was negatively correlated with the SRTT and TNFR1 (protein)(r=-0.267, r=-0.330, P<0.05); SRTT was positively correlated with TNFR1 (protein)(r=0.243, P<0.05); TNFR1 (mRNA) was positively correlated with TNFR1 (protein)(r= 0.340, P<0.01). Conclusion: Cognitive function change of occupational exposed workers to aluminum was related to the increase of TNFR1 expression. PMID- 29996220 TI - [The analysis of the epidemiological characteristics of pneumoconiosis notified in Chongqing from 2011 to 2015]. AB - Objective: To analyze the epidemiological characteristics and the harmfulness situation of pneumoconiosis notified in Chongqing from 2011 to 2015, so as to provide scientific basis for prevention and control of pneumoconiosis. Methods: The Chongqing database of new cases of pneumoconiosis reported from 2011 to 2015 was subjected to systematic arrangement. SPSS 18.0 was adopted for statistical description and trend test. Results: From 2011 to 2015 a total of 24903 new cases of pneumoconiosis were diagnosed, including I (16 294 cases, 65.43%), II (6 520 cases, 26.18%), III (2 089 cases, 8.39%). Of all patients, 98.93% were cases of coal-workers' pneumoconiosis and silicosis. 13 383 (53.74%) were coal-workers' pneumoconiosis cases, and 11 253 (45.19%) were silicosis cases. The pneumoconiosis cases were distributed mainly in Fengjie County (3 329 cases, 13.37%), Yongchuan District (2 849 cases, 11.44%), and Chengkou County (2 584 cases, 10.38%). Most cases were centered in mining industry (17 575 cases, 70.57%) and construction industry (6 613 cases, 26.56%). The median lengths of service at the onsets of new cases of pneumoconiosis, silicosis, coal-workers' pneumoconiosis were 7.0, 3.0, and 16.0 years, respectively. The median age at the onset of pneumoconiosis was shortened from 2011 to 2015. The median ages at the onsets of new cases of pneumoconiosis, silicosis, coal-workers' pneumoconiosis were 53.0, 62.0, and 49.0 years, respectively. Conclusion: The research results showed obvious diseases, regions and industries distribution. The median length of service at the onset of pneumoconiosis was on the low side, and a shortening trend showed in age at the onset of pneumoconiosis. Based on the epidemiological characteristics of pneumoconiosis, the prevention and control of pneumoconiosis should be enhanced in key industries such as mining industry and construction industry. PMID- 29996219 TI - [Embryo implantation dysfunction via the decreased uterine dendritic cells's non immune function after exposed to carbon disulfide]. AB - Objective: To study the effect of CS2 on dendritic cells (DCs) in the uterus and the expression of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor(fms-like tyrosine kinase-1, Flt-1), and to explore the toxic mechanism of CS2-induced embryo implantation dysfunction. Methods: The Kunming mice were randomly divided into control group,gestational day 4(GD4) exposure group and GD5 exposure group. The endpoints of each group(GD5, GD6, GD7) was set up according to their respective exposure time points. The mice in the exposure group were given intraperitoneal injection of CS2 at an injection dose of 631.4 mg/kg and the control group was given olive oil. The effect of CS2 on DCs in the uterus of pregnant mice was observed by flow cytometry. The levels of VEGF and Flt-1 were measured by Real-time quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Results: In the GD4 and GD5 exposure groups, the number of DCs in the uterus of pregnant mice decreased at all endpoints and the GD5 endpoint in the GD4 exposure group decreased by 21%(P=0.039), when compared with the control group. In the GD4 exposure group, the levels of VEGF mRNA and protein in the uterus of the pregnant mice were 79% and 30% lower than those in the control group, respectively (P=0.03,P=0.017); the levels of Flt-1 mRNA and protein at the endpoints of GD6 and GD7 in the uterus decreased by 54%, 36%, 60% and 56%, respectively, when compared with the control group(P=0.017,P=0.012,P=0.004,P=0.007). In the GD5 exposure group, the levels of VEGF mRNA and protein in the uterus of pregnant mice at the endpoint of GD7 decreased by 62% and 36%, when compared with the control group (P=0.005,P=0.035); the levels of Flt-1 mRNA and protein in the uterus at the endpoint of GD7 decreased by 60% and 44%, respectively, when compared with the control group (P=0.004,P=0.009). Conclusion: CS2 reduced the number of DCs in the uterus of pregnant mice, and affected the non-immune function of DCs, which affected uterine angiogenesis, this may be one of the mechanisms of CS2-induced embryo implantation dysfunction. PMID- 29996221 TI - [Analysis of pesticide poisoning in Ji'nan during 2012-2016]. AB - Objective: To study the current situation and distribution characteristics of pesticide poisoning in Ji'nan area, and to provide the basis for formulating the policy of scientific prevention and control of pesticide poisoning. Methods: The cases of pesticide poisoning from 2012 to 2016 were collected from medical institutions in Ji'nan, and the data was subjected to statistical analysis. Results: From 2012 to 2016 in Ji'nan reported a total of 2 237 cases of pesticide poisoning, non productive pesticide poisoning cases (72.78%, 2 149/2 237) and mortality (17.73%, 381/2 149) was significantly higher than that of productive pesticide poisoning. The average age is 46.78+/-18.57. The highest mortality rate of pesticide poisoning is more than 70 age group of the non productive pesticide poisoning. Organophosphorus pesticides (67.68%, 1 514/2 237) are the main pesticides causing poisoning, followed by herbicide (23.74%, 531/2 237). The highest mortality rate of pesticide was Paraquat (36.45%, 160/439), the second is the dichlorvos (19.19%, 170/886). Conclusion: Pesticide poisoning is a public health problem and social problem which is harmful to the health of the residents in Ji'nan. It is necessary to strengthen the control and management of high toxic pesticides. Pay attention to the psychological intervention of elderly people to reduce the incidence of pesticide poisoning. PMID- 29996222 TI - [Analysis of occupational chronic carbon disulfide poisoning: a study of 372 cases]. AB - Objective: To investigate the clinical features of occupational chronic carbon disulfide(CS(2)) poisoning. Methods: A total of 372 patients with occupational chronic CS(2) poisoning were selected from a chemical fiber factory, and their clinical features were summarized and analyzed. Results: Major clinical manifestations of the 372 patients with occupational chronic CS(2) poisoning included sleep disorders, dizziness, headache, and numbness of limbs, and the detection rates of these manifestations were 84.7%, 84.4%, 79.8%, and 72.8%, respectively. Electroneuromyography showed peripheral nerve injuries. Conclusion: Occupational chronic CS(2) poisoning can affect the central and peripheral nervous system. PMID- 29996223 TI - [Analysis on hearing status and related influencing factors in workers exposed to noise in an automobile manufacture enterprise]. AB - Objective: To study the hearing status and analyze the related influencing factors in noise-exposed workers in an automobile manufacture enterprise, and put forward suggestions for prevention of noise-induced hearing loss. Methods: Noise exposure level testing, audiometry testing and questionnaires were performed for noise exposed workers in the automobile manufacture enterprise. To analyze the relationship between different factors and noise-induced hearing loss by cumulative noise exposure(CNE) calculated 8-hour continuous A-weighted equivalent noise level and seniority. Results: The detection rate of hearing loss in noise exposed workers was 22.8%. The noise exposure intensity of stamping workshop is higher than other workshop, and the hearing loss detection rate of stamping workshop workers is higher than other workshop workers. The detection rate of hearing loss has significant difference in L(Aeq.8 h), seniority, CNE, age, high temperature and wearing earplugs (P<0.05). The results of logistic regression analysis showed that CNE, age and high-temperature were risk factors for noise induced hearing loss (P<0.05 and OR>1) and there was an increasing tendency of hearing loss with increase in length of service and CNE, while using of earplugs was a protective factor (P<0.05 and OR<1). With the increase of CNE, the incidence of hearing loss is the rising trend. Conclusion: It is suggested to strengthen the noise control and individual protection and improve the high temperature working environment, which plays an important role in reducing the occurrence of noise-induced hearing loss. PMID- 29996225 TI - [Analysis of a group of patients suffering fromacute n-heptane poisoning]. PMID- 29996224 TI - [Application of star card in edge enhancement processing of pneumoconiosis DR image]. AB - Objective: The feasibility of applying DR card in the quality control of chest film of pneumoconiosis was discussed by using the image detail change of 1 degree star card. Methods: With different types of grid DR device for star card photography, to ensure that the grid bars are orthogonal to the direction of star card image quality is stable, conforms to the DR standard of pneumoconiosis image edge enhancement processing, analysis of the relationship between lung tissue image changes and changes with fuzzy star card. By 3 physicians blind reading way, compare the use of auxiliary judgment and direct x-ray star catu judgment in the accuracy evaluation of whether the use of edge enhancement function. Results: Fuzzy images of star card were consistent with lung tissues details as DR images were treated with edge enhancement. The fuzzy zore was closer to the start card center with more image edge enhancement and more image details sharpening. on the opposite, it was farther from the center with less with edge enhancement and less image sharpening. It's valuable for star card analysis to evaluate the accuracy of the application of image edge enhancement (P<0.001). Conclusion: To determine whether the use of X-ray star catu edge feasible enhancements can be used for health supervision and quality supervision and quality control of the institution itself of radiology. PMID- 29996226 TI - [Investigation on an incident of groups mushroom poisoning]. AB - Objective: To investigate an incident of mushroom poisoning and related clinical data. Methods: A descriptive analysis was performed to investigate an incident of poisonous mushroom poisoning in Jinan, Shandong Province, China in July 2016. The clinical data of four patients were analyzed and summarized, and the causes of this incident and prevention and control measures were summarized. Results: This incident of acute poisonous mushroom poisoning was caused by Lepiota brunneoincarnata. The patients mainly had digestive system symptoms, including nausea, vomiting, and severe abdominal pain, and later developed liver damage. After comprehensive rescue treatment, one patient died and three survived. The main clinical manifestation of the patient who died was multiple organ failure, especially liver failure. Conclusion: This incident of poisoning was caused by Lepiota brunneoincarnata the residents ate by mistake. PMID- 29996227 TI - [Investigation of trimethyltia chloride poisoning caused by reclaimed metal recovery]. PMID- 29996228 TI - [Clinical analysis of acute liver failure induced by dimethylformamide]. PMID- 29996229 TI - [One case of multiple intracranial hemorrhage caused by acute severe methanol poisoning]. PMID- 29996231 TI - [A case report on occupational acute nbutyllithium poisoning]. PMID- 29996230 TI - [Acute thalliumpoisoning treated with Prussian blue combined with blood purification: report of two cases]. PMID- 29996233 TI - [A case report of inhaled bromoderone poisoning]. PMID- 29996232 TI - [Evaluation of the right ventricular function in patients with pneumoconiosis by echocardiography]. AB - Objective: To investigate right ventricular function in patients with pneumoconiosis, and to provide a basis for quantitative diagnosis and treatment of pneumoconiosis in clinical practice. Methods: A total of 43 patients with pneumoconiosis who were hospitalized consecutively in Shijiazhuang Prevention and Treatment Center for Occupational Diseases from May 2015 to May 2016 were enrolled, and according to the stage of pneumoconiosis, they were divided into stage I group with 16 patients, stage II group with 14 patients, and stage III group with 13 patients. A total of 16 healthy subjects were enrolled as control group. Echocardiography was performed and the relevant parameters were recorded, i.e., right ventricular transverse diameter (RVTD), tricuspid annular plane systolic excursion (TAPSE), and right ventricular myocardial performance index(Tei index). Results: There were significant differences in Tei index and TAPSE between all groups (P <0.05) except between the stage I group and the control group in terms of Tei index (P>0.05) and between the stage I group and the stage II group in terms of TAPSE (P>0.05). Right ventricular Tei index was negatively correlated with TAPSE (r=-0.547,P<0.05). Conclusion: A combination of right ventricular Tei index and TAPSE can be used for early quantitative evaluation of right ventricular function in patients with pneumoconiosis. PMID- 29996234 TI - [A case of acid-wash poisoning]. PMID- 29996235 TI - [Treatment of oral copper sulfate poisoning]. PMID- 29996236 TI - [Analysis on the effect and problems of establishing healthy enterprises in Jiangsu province]. PMID- 29996237 TI - [Discussion on "subject under medical surveillance" in Diagnosis of occupational pneumoconiosis]. PMID- 29996238 TI - [Research progress of occupational health risk assessment methods in dust workplace]. PMID- 29996239 TI - [Advamce om Benzene Toxioity Mechanism and its Reletionship to MicroRNA]. PMID- 29996240 TI - [Association of occupational stress with job burnout and depression tendency in workers in Internet companies]. AB - Objective: To investigate the association of occupational stress with job burnout and depression tendency in workers in Internet companies. Methods: From July to November, 2016, the cross-sectional method was used to perform a questionnaire survey of 3603 workers in 35 Internet companies in Beijing, Shandong Province, and Zhejiang Province in China, and the association of occupational stress with job burnout and depression tendency was analyzed. Results: Among these workers, 63.70% had occupational stress with job demand-control (JDC) and 34.60% had occupational stress with effort-reward imbalance (ERI) ; among the workers engaged in sales, 75.63% had occupational stress with JDC and 62.70% had occupational stress with ERI. Of all workers, 10.69% had job burnout, and among the workers engaged in sales, 22.12% had job burnout. Of all workers, 18.79% had the tendency of moderate-to-severe or severe depression, and among the workers engaged in sales, 46.13% had such tendency. Occupational stress with JDC increased the risk of job burnout and depression (odds ratio[OR]=3.52 and 1.85, P<0.05) , and occupational stress with ERI also increased the risk of job burnout and depression (OR=8.24 and 5.59, P<0.05) . In addition, irregular diet and insomnia were risk factors for job burnout; age >=41 years, low income, sales position, working time spent on the screen >=10 hours/day, insomnia, and poor self-evaluated health status were risk factors for depression tendency. Conclusion: Occupational stress with JDC and ERI increases the risk of job burnout and depression tendency, and among the workers in Internet companies, the workers engaged in sales have the most severe occupational stress, job burnout, and depression tendency. PMID- 29996241 TI - [Analysis on the relationship between Occupational Stress Factors and Psychological Stress Reaction among Petrochemical Workers]. AB - Objective: To explore the relationship between occupational stress factors and psychological stress reaction among petrochemical workers, detecting the effects caused by the occupational stress and putting forward solutions to reduce the occupational stress degree. Methods: 392 petrochemical workers in Oil refining enterprise were included to conduct the evaluation of the occupational stress, correlation analysis and ridge regression were used to analyze the relationship between occupational stress and five aspects of psychological stress reaction and to detect the influencing factors. Results: Mission control, decision control, environmental control, resources control, promotion, and participation in decision making were positively correlated with job satisfaction (P<0.01) , technology utilization degree, work order tonality, job prospects were negatively correlated with job satisfaction (P<0.05) ; mission control, resource control, promotion, participation in decision-making were positively correlated with mental health (P<0.01) , work order tonality, job prospects were negatively correlated with mental health (P<0.05) ; load change risk, work, work order tonality, job prospects were positively correlated with depression (P<0.05) resource control, promotion opportunities were negatively correlated with depression (P<0.05) ; quantitative risk load, work, work order tonality, job prospects were positively correlated with anxiety (P<0.05) , the task control, promotion, and participation in decision-making were negatively correlated with anxiety (P<0.05) ; work, load change, work order tonality, risk scoring for job prospects were positively correlated with body complaint (P<0.01) , mission control, decision control, resource control were negatively correlated with body complaint (P<0.05) . Conclusion: Different stress factors make different effects in different psychological stress reaction, the main predictors and predictive power of each psychological stress reaction were not the same. PMID- 29996242 TI - [A comprehensive evaluation of intervention effects on workplace health promotion in 10 government agencies]. AB - Objective: To evaluate the comprehensive workplace health promotion intervention effects on workplace health promotion in 10 government agencies. Methods: A prospective self-controlled design was employed. Baseline evaluation and effectiveness evaluation were both conducted by questionnaire investigation. Results: The intervention results showed that most effectiveness indicators were significantly improved including health behaviors, psychosocial work environment, and health status. After the intervention, the prevalence of passive smoking and physical inactivity decreased from 70.3% and 38.7% to 44.1% and 30.5%, respectively. The scores of job control and social support at work increased by 0.30 and 0.05, respectively. The prevalence of good self-rated health and good mental health raised from 68.3% and 68.8% to 75.6% and 85.6%, respectively. However, the scores of job demand increased by 0.4. Furthermore, the prevalence of occupational stress increased significantly from 45.8% to 65.5%. Conclusion: After implementing workplace health promotion, the physical and mental health of the staff have been promoted. However, the occupational stress of government officials still need to be improved. PMID- 29996243 TI - [Investigation Analysis on Social Support Status of Female Migrant Workers]. AB - Objective: To study status of social support and its influencing factors in female migrant workers. Methods: Study participants were selected with a random cluster design from participants 16-60 years old in non-registered residents from 10 districts in one city. Social support revalued scale and general questionnaire were used to survey social support status of female migrant workers in August December of 2016. Results: There was statistic difference in social support among different districts, occupations, and income of female migrant workers (P<0.05) . Results of multiple linear regression demonstrates that districts, occupations, and income of female migrant workers were associated with social support scale (district standarized beta=0.03, occupations standarized beta=-0.03, incorue standarized beta=0.10, P<0.05) . Conclusion: We should be attentive to self employed and Low-income participants among female migrant workers. PMID- 29996244 TI - [Mediating effect of work engagement between job stress and depressive symptoms in State Grid employees]. AB - Objective: To explore the relationship between job stress, work engagement and depressive symptoms of State Grid workers, and to analyze the mediating effect of work engagement between job stress and depressive symptoms. Methods: A cross sectional survey was conducted to investigate 845 employees from a State Grid company, using the brief job stress questionnaire, the Patient Health Questionnaire (PHQ-9) and 9-item Utrecht Work Engagement Scale (UWES-9) in March 2017. Results: The average score of work engagement was 4.49+/-1.42, the mean value of job stress was 1.15+/-0.33, the average score of depressive symptoms was 6.44+/-4.30, and the positive rate of depressive symptoms was 66.9%.There was a negative correlation between work engagement with both job stress and depressive symptoms (r=-0.193, -0.397, both P<0.01) , and job stress was positively correlated with depressive symptoms (r=0.260, P<0.01) . The relationship between job stress and depressive symptoms was partly mediated by work engagement, and the mediating effect accounted for 27.2% of the total effect. Conclusion: The work engagement of State Grid staff acts as the mediator between job stress and depressive symptoms, alleviating the depressive symptoms caused by job stress. PMID- 29996245 TI - [Self-esteem and Occupational Stress Relationship Analysis of 1413 Train Drivers in a Railway Bureau]. AB - Objective: To investigate self-esteem status of train drivers. Methods: By using cluster sampling method, a cross-sectional study was conducted in 1 413 train drivers (including passenger train drivers 301, freight train drivers683, passenger shunting train drivers350, and high speed train drivers79) from a railway bureau. The occupational stressors, strains, self-esteem and personalities were measured using occupational stress instruments and effort reward imbalance questionnaire. Results: The level of self-esteem is medium ofthe train drivers. Sself-esteem scores among different among different job category (job title) , marry status, age, length of service groups were statistical significance (P<0.01) . Differences of self-esteem among different educational level, exercise, smoking and drinking groups weren't statistical significance (P>0.05) . Correlation analysis revealed that self-esteem score was related positively to job satisfaction (r=0.300) , reward (r=0.842) , working stability (r=0.243) , promotion opportunities (r=0.493) , positive affectivity (r=0.216) , responsibility for human beings (r=0.112) and responsibility for things scores (r=0.108) (P<0.01) , negatively to sleep quality (r=-0.103) , social support (r= 0.212) , role conflict (r=-0.007) , role ambiguity (r=-0.169) , physiological needs (r=-0.115) , daily stress (r=-0.150) , negative affectivity (r=-0.252) , depressive symptoms scores (r=-0.215) (P<0.01) . Nonparametric test found that train drivers of group with low self-esteem score reported higher scores for physiological need, role conflict, role ambiguity, social sleep quality, depressive symptoms, negative affectivity, social support and daily stress scores than the medium and higher groups (P<0.01 or<0.05) . But reword, job satisfaction, positive affectivity, copping stratgy, working stability and promotion opportunities scores were lower than the group of medium and higher groups (P<0.01) . Inter-group conflict scores were insignificance (P>0.05) . Multivariate logistic regression analysis revealed that low low self-esteem for drivers occured the risk of job dissatisfaction about 1.5 times as high as that of drivers with higher self-esteem (OR=1.476) Conclusion: Different types of locomotive drivers get different level of self-esteem. Self-esteem was affected by occupational stress largely. PMID- 29996246 TI - [Analysis of the effect of recovery experience type on regulating the relationship of occupational stress andperceptions of the work experience]. AB - Objective: To evaluate occupational stress and perceptions of the work experience among the nurses, and to analyze the effects of recovery experiences on the adjustment of the relationship of stress and perceptions of the work experience. Methods: A questionnaire survey was conducted among nurses from 7 third hospitals in a city through sampling. A self-designed questionnaire, "Job Content Questionnaire (JCQ) " , "Recovery Experience Questionnaire (REQ-C) " and "Quality of working life (QWL7-32) " were completed by the subjects. Establishment of recovery experience types by sample cluster analysis, combined with regression analysis in the regulation of perceptions of the work experience of recovery experiences'types. Results: There have differences instatus and score of perceptions of the work experience among nurses with different tension level (P<0.05) . The Perceptions of Work Experience scores of nurses with different types of recovery experience are different with the tension level, and the type of recovery experience has an independent moderating effect on the relationship between tension and perceptions of work experience. Conclusion: The moderating effects of different types of recovery experiences on perceptions of work experience are different. PMID- 29996247 TI - [Comparison of Vocational Exhaustion Positive Rate among Different Occupational Stress Groups]. AB - Objective: To explore the statistical differences of the vocational exhaustion positive rate among various occupational stress factors, occupational stress reaction, personality characteristics and relieving factors, to lay a foundation for reducing occupational stress of the medical staffs. Methods: 656 medical staffs in Yangzhong and Chifeng hospitals were included to conduct the evaluation of the occupational stress and job burnout, analyze the differences among the various factors by comparing them. Results: Various levels of vocational exhaustion positive rate among different occupational stress factors, occupational stress reaction, personality characteristics and relieving factors show statistical difference (P<0.05) . Among occupational stress factors, the vocational exhaustion positive rate of high level groups of conflict in groups was the highest (73.4%) , among occupational stress reaction, the vocational exhaustion positive rate of high level groups of body complain was the highest (80.4%) , among personality characteristics, the vocational exhaustion positive rate of low level groups of self-esteem was the highest (74.4%) , among relieving factors, the vocational exhaustion positive rate of high level groups of family support was the highest (76.4%) . Conclusion: The vocational exhaustion rate of medical staffs show very high in the profession, comprehensive factors should be considered to create harmonious working atmosphere and to reduce vocational exhaustion positive rate of the medical staffs, to reduce the positive rate of vocational exhanstion in medical staffs. PMID- 29996248 TI - [Association between Long Working Hours and Job Stress and Depression among Employees from a State Grid Company]. AB - Objective: This study was to understand the current situation of long working hours and identify the association of long working hours and job stress and depression among workers from one district company of state grid. Methods: The project was done with the cross-sectional survey. All questionnaires were completed by self-administered with informed consent. Employees' weekly working hours was reported by themselves; Using the PHQ-9 scale to assess depression, the JDC Model to evaluate job stress, and SPSS software to analyze data, the single factor chi-square test and multivariate Logistic analysis were performed to identify the association between long working hours and job stress, depression. Results: there were 35.3 percent employees with over 44 hours a week. The association between increasing weekly working hours and job stress and depression was statistically significant. Compared to the reference group (<=44 h) , for those who worked more than 44 hours per week, the odds ratio of job stress was 2.02 (95%CI=1.27-3.23) times increased, and the odds ratio of depression was 1.60 (95%CI=1.01-2.55) times increased, especially for those (>=60 h) , the odds ratio was 3.69 (95%CI=1.45-9.41) and 2.76 (95%CI=1.09-7.03) respectively. Conclusion: Long working hours can significantly increase the risk of job stress and depression among workers. When their weekly working hours exceeds 60, long working hours will be the independent risk factor for both job stress and depression. PMID- 29996249 TI - [Analysis on the quality of life and its influencing factors of visual display terminal operators in Internet enterprises]. AB - Objective: To investigate the quality of life of the visual display terminal (VDT) operators in Hangzhou Internet enterprises and to analyze its influencing factors. Methods: Through cluster sampling,, 944 employees were investigated by demographic and general health questions and the MOS 36-Item Short Form Health Survey Questionnaire from October to November in 2016 and carried out statistical analysis. Results: VDT operators' physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, mental health, physical component summary and mental component summary scores were (86.3+/-17.0) , (82.5+/-30.3) , (80.6+/-16.1) , (56.8+/-18.6) , (53.7+/-15.6) , (78.5+/-17.8) , (81.2+/-31.9) , (48.8+/-19.3) , (51.1+/-8.9) , (43.8+/-9.1) . Except physical functioning, role-physical and physical component summary scores, the scores of other scales and mental component summary were lower than the norm (P<0.05) . Multivariable logistic regression showed that vegetable intake, sleeping and physical exercise had an impact on the physical component summary score. The influential factors of mental component summary score included marital status, education, neck pain and health concerns. Conclusion: We should pay attention to the quality of life of VDT operators in Internet enterprises, especially their mental health. PMID- 29996250 TI - [An investigation of work-related musculoskeletal disorders among sonographers in a province of China and related influencing factors]. AB - Objective: To investigate the prevalence of work-related musculoskeletal disorders (WMSDs) among sonographers in a province of China and influencing factors for WMSDs, and to provide a practical basis for the prevention and treatment of WMSDs in sonographers. Methods: From November 2016 to February 2017, stratified cluster sampling was used to select 700 sonographers from 50 hospitals in this province. A self-designed questionnaire for WMSDs in sonographers was used to investigate general data and the prevalence of WMSDs, and the influencing factors for the prevalence of WMSDs were analyzed. Results: The prevalence rate of WMSDs among these sonographers was 80.22%, and the prevalence rates of WMSDs in the shoulder, the neck, the waist, the back, the wrist, the elbow, the hip, the knee, and the ankle were 74.55%, 68.87%, 63.44%, 57.26%, 53.16%, 45.22%, 37.88%, 30.44%, and 29.24%, respectively. There was a significant difference in the prevalence rate of WMSDs between the sonographers with different ages and working years, and the prevalence rate of WMSDs tended to increase with the increase in age and working years (chi(2)=20.86 and 18.52, P<0.01) . The multivariate logistic regression analysis showed that female sex (odds ratio [OR]=1.798) , working years >16 (OR=1.004) , weekly working hours >40 (OR=1.616) , poor physical conditions (OR=1.690) , and high work fatigue (OR=1.302) were risk factors for WMSDs in sonographers. Conclusion: There are high prevalence rates of WMSDs in the shoulder, the neck, the waist, the back, the wrist, and the elbow. Sonographers should strengthen self-protection awareness, and effective preventive measures should be adopted to reduce the prevalence rate of WMSDs. PMID- 29996251 TI - [Analysis on Guangzhou occuptional health re-examation result from 2012 to 2016]. AB - Objective: This study aims at the review result of Guangzhou occupational health examination from 2012-2016 to analyze the distribution of crowd and to discover the occupational health hazard factors and key Protection object by finding the situation of the goal of occupational hazard factor diseases through review examination. Methods: By using retrospective study method, to choose those people who have accepted occupational health review examination handled by the review examination group of Guangzhou Occupational Prevention and Treatment Hospital from 2012 to 2016. And comprehensively analyze the review result of occupational health examination in 5 years. Results: There are 8618 cases of occupational health review examination handled by Guangzhou Occupational Prevent and Treatment Hospital and with complete data. From the Personnel structure, it refers that they are Predominantly male and their ages are mainly distributed under 40-year old. Most of them work under the occupational disease inductive factors less than 5 years and most of the factor is contacting with noise. In the recent 5 years, we found out 1906 cases of occupational contraindications through total review, which takes 22.12% of total number of review People, including noise occupational contraindication in 61.59%. And we found 435 cases of suspected occupational disease which takes 5.05% of total number of review People, including suspected occupational noise deafness which takes the property of 60.23% and appears the most common disease. Suspected occupational diseases and occupational taboos are mainly male patients, and the age is mainly in the 30-49 age group, the working age is mainly less than 5 years. Conclusion: Occupational health examination is an important Part in occupational health, occupational health examination review is the most Prior Part in the occupational health examination, which Plays a key role to discover the target disease of the occupational hazard factors in time, Prevent the development of occupational diseases and protect laborer occupational health. PMID- 29996252 TI - [An study on the incidence of heat stroke and explore it's prediction model in Pudong New Area of Shanghai from 2013-2017]. AB - Objective: To know the incidence of heat stroke and explore it's prediction model in Pudong New Area of Shanghai. Methods: An epidemiological investigation was conducted on heat stroke cases in Pudong New Area of Shanghai from 2013 to 2017. Daily temperature data during this period were collected to explore it's influence. Results: 246 heat stroke cases were reported and investigated, 70.3% (173/246) of them were male. 170 cases are severe heat stroke, accounting for 69.1%. 28 patients died, accounting for 11.4% of all cases of heat stroke, and 16.5% (28/170) of severe heat stroke cases. Thermoplegia (56.5%, 96/170) was the most popular type among severe heat stroke cases. Heat prostration, heat cramps and mixed type account for 17.1% (29/170) , 12.4% (21/170) and 14.0% (24/170) respectively. Scatter plot and linear regression demonstrated that there was a significant linear relation between number of high temperature days and number of heat stroke cases (P<0.01) . And the prediction model is: Predictive number of annual heat stroke cases=beta*Number of annual high temperature days+Intercept. Leave-one-out cross validation result shows that the predictive number of annual heat stroke cases from 2013 to 2017 were 85.7%, 90.9%, 83.3%, 91.9 and 84.3% respectively. Conclusion: There was a significant linear relation between number of high temperature days and number of heat stroke cases in Pudong New Area. The related work arrangement for heat stroke prevention could be well planed according to the prediction model. PMID- 29996253 TI - [An investigation of reproductive health in female workers engaged in administrative management]. AB - Objective: To investigate the reproductive health status of female workers engaged in administrative management, and to provide a reference for protecting the reproductive health of female workers. Methods: From April to November, 2016, a cross-sectional survey was performed for 2717 female workers aged 18-60 years and engaged in administrative management from 13 cities and provinces in China, and a questionnaire was used to investigate their general information, occupational hazards in workplace, and reproductive health status, and the reproductive health status of female workers was analyzed. Results: Of all 2 717 female workers, 1 170 had gynecological diseases or symptoms, resulting in an incidence rate of 43.06%, and among these workers, 11.15% had abnormal menstruation, 34.64% had infertility, and 38.76% had a history of abortion. There were significant differences in the rates of abnormal results of gynecological examination, abnormal menstruation, abortion, and infertility between the female workers in different age groups (P<0.01) . Unhealthy living habits and major events were risk factors for gynecological diseases, abnormal menstruation, and abortion (P<0.05) ; bad working status was a risk factor for gynecological diseases and abortion (P<0.05) ; exposure to harmful factors was a risk factor for gynecological diseases and abnormal menstruation (P<0.05) . Conclusion: Living habits, major events, working status, and occupational harmful factors have certain influence on reproductive health of female workers engaged in administrative management. Occupational health protection should be strengthened, working patterns should be improved, self-protection awareness should be raised, and health protection should be enhanced for women of childbearing age to protect and promote the reproductive health of female workers. PMID- 29996254 TI - [Occupational health risk assessment of coal dust in coal industry chain]. AB - Objective: To grasp the present situation of occupational hazards of coal dust in our country, understand our country coal dust workers' occupational health risks, provide information based on evidence and analysis for the government and organize to effectively deal with the current status of high coal workers pneumoconiosis incidence in China, and protect coal dust workers' occupational health. Methods: The research object is the " mining-transportation-use" of coal industrial chain, referring to 33 units. Use field investigation to obtain the coal dust exposure, dust prevention measures and the occupational health data of study object. Use quantitative evaluation method of International council on mining and metals occupational health risk assessment model (ICMM method) and occupational hazard risk index method (index method) , with coal workers pneumoconiosis as health outcomes, to evaluate the coal dust occupational health risks of coal industrial chain. Results: The free silica content of partial coal dust in China is more than 10%, and even to 19.5%. coal dust concentration in workplaces, such as excavating system of dust coal mining (total dust: 22.1~46.5 mg/m(3), respiratory dust: 8.4~17.7 mg/m(3)) , dumper (total dust: 25.2 mg/m(3), respiratory dust: 6.9 mg/m(3)) , transfer tower (total dust: 35.4 mg/m(3)) of coal transportation and belt coal plough device of coal use (total dust: 36.3 mg/m(3), respiratory dust: 14.0 mg/m(3)) , are much higher than those in other workplaces, and coal dust concentration of workers in these places (2.6~9.3 mg/m(3)) are much higher than those in other places, which are statistically significant. ICMM method evaluation results show that the risk value of excavating system is between 504~1 089, and the risk value of comprehensive mining system is between 347~2 040, which are far statistically significant higher than that of other systems. Index method evaluation results (excavating system risk value between 3.1~9.7, fully mechanized system risk value between 3.7~9.3) , are basically identical with ICMM method (correlation coefficient r=0.857, P<0.01) . The new cases of coal worker pneumoconiosis are distributed in three post of coal mining, excavating and coal mine mixing. Conclusion: Coal-dust hazards are widely distributed in the coal "mining, transportation, and use" industrial chain, which of the underground coal mine is as serious as intolerable, meanwhile the risk of other industrial chain is basically can tolerable. The high coal dust concentration and the high risk of coal dust occupational hazard are concentrated in the excavating system and the comprehensive mining system. It is recommended to start the study on risk assessment and risk response of coal dust health hazard at the national level, and the occupational exposure limit of coal dust should be established according to the content of free silica. PMID- 29996256 TI - [Application of ICMM Occupational Health Risk Assessment Modelin evaluation of occupational risk of a lead-acid battery enterprise]. AB - Objective: ICMM occupational health risk assessment model was be used to evaluate the risk of a lead-acid battery enterprise. Methods: In November 2016, a lead acid battery company in Jiangsu Province was selected as the research object. Based on the occupational health survey data and occupational hazard assessment reports, the ICMM risk assessment model was used to conduct occupational health risks in eight key positions of a lead-acid battery enterprise. The risk assessment results was verified by actual test results. Results: In the quantitative assessment model, the occupational health risk assessment results for the castings and welding positions exposed to lead smoke, and the occupational health risk assessment results for the grinding and dividing positions exposed to lead dust existed unacceptable risks. The occupational health risk assessment results for the ball-milled and plated positions exposed to lead dust existed tolerable risks. The occupational health risk assessment results for the lead-plated and soldered positions exposed to sulphuric acid pastes and acids existed potential risks. In qualitative evaluation matrix method, the occupational health risk assessment results for the castings and welding positions exposed to lead smoke, and the occupational health risk assessment results for the grinding and dividing positions exposed to lead dust existed high risks, the occupational health risk assessment results for other four key positions were considered to be with low risks. Conclusion: The key control points for lead smoke in this enterprise were castings and welding positions; The key control points for lead dust were the grinding and separating brush positions. The quantitative assessment model and the qualitative assessment matrix method in the ICMM model were consistent with the actual test results in the eight health risk assessments of occupational hazards in key positions. Therefore, the method could be applied to the assessment of occupational health risks of the lead-acid battery enterprise. According to the results of the assessment, improvements could be made to high-risk positions and the concentration of occupational hazards in high-risk posts could be reduced to better protect the health of workers. PMID- 29996255 TI - [Effects of occupational stress factors on the function of thyroid and liver among petroleum refining and petrochemical workers]. AB - Objective: To investigate the association between occupational stress factors and the level of thyroid function and liver function in petroleum refining and petrochemical workers. Methods: A total of 353 petroleum refining workers were investigated by occupational stress indicator question-naire (OSI-R) , and their level of thyroid and liver function were measured. Results: With the incre-ase of task control, decision control, environmental control, resource control and technology utilization score, the TT(4) concentration level decreased (P<0.05) . The TT(4) concentration level increased with the increase of the quantiontive load, load changes, job hazards, job prospects, promation opportunities and participaction decision rating (P<0.05) . The total protein concentration level decreased with the increase of task control, decision control, environmental control, resource control, quantitative load, load change, promotion opportunity and participation decision value (P<0.05) , increased with the use degree of technology, work risk, job monotonous, work prospects score rised (P<0.05) . And there were statistically significant differences in the job requirements and job control scores between the low, middle and high levels of occupational factors (P<0.05) . Conclusion: Occupational stress factors of petroleum refining workers have certain influence on the level of thyroid and liver function index. PMID- 29996257 TI - [Determination method of barium sulfate in the air of workplace]. AB - Objective: To establish the method for determination of barium sulfate in the air of workplace. Methods: The barium sulfate was collected by dichloride ethylene filter membrane and then processed by alkali fusion method. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used for the detection of barium sulfate. Results: The sampling efficiency was 100%, the linearity of ICP OES was good at the range of 0.1~100.0 MUg/mL, the recovery was ranged from 93.0%~97.8%, the RSD of intra- and inter-batch precision were 3.7%~7.6% and 4.7%~8.8%, respectively. Conclusion: The sampling method and determination method meet the requirements of analysis and apply to the collection and determination of barium sulfate in the air of workplace. PMID- 29996258 TI - [Simultaneous determination of various volatile organic compounds in urine by headspace GC-MS]. AB - Objective: To establish a method for determination of acetone, dichloromethane, hexane, 1, 1, 1-trichloroethane, 1, 2-dichloroethane, benzene, toluene, ethylbenzene etc organic compounds in urine by headspace gas chromatography-mass spectrometry (GC-MS) . Methods: Headspace gases of urine samples were injected into GC and determined by mass. Results: Determination of urine components were in a good linear range in their concentration range of this method. The correlation coefficients were between 0.996 and 1.000 with the detection limits between 0.1 MUg/L and 4.5 MUg/L, the precisions were between 1.3% and 4.6%, the recovery rates were between 86.2% and 97.4%. Conclusion: This method has the advantages of low detection limits, high accuracy, high precision and simple pretreatment, which is suitable for the determination of the content of various volatile organic compounds in urine. PMID- 29996259 TI - [Determination of methylenedianiline in urine by high performance liquid chromatography-tandemmass spectrometry]. AB - Objective: To develop a method for determination of metabolites of diphenylmethane diisocyanate (MDI) in urine, i.e. methylenedianiline (MDA) by high performance liquid chromatography-tandem mass (LC-MS-MS) . Methods: Urine samples were prepared by hydrolyzation with sulfuric acid and extraction by acetonitrile, and then separated on a Shim-pack XR-ODS column, analyzed with high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) . The external solvent standard calibration were tested. Results: The linearity ranges were 0.05~20.00 MUg/L, The related coefficients were 0.999 5. The limit of detection was 0.02 MUg/L. The rats of recovery were 91.0%~103.4%. The relative standard deviations were between 2.7%~7.3%. Conclusion: The method was sensitive, accurate and suitable for the MDA determination in urine of MDI exposed population. PMID- 29996261 TI - [Research progress on the effects of noise exposure on reproductive health]. PMID- 29996262 TI - [The medthod of quantitative analysis of risk factors for work-related musculoskeletal disorders]. PMID- 29996260 TI - [Analysis of inter-laboratory comparison results of arsenic in urine and explore the influence factors on detection]. AB - Objective: Through inter-laboratory comparison to analysis and evaluation of the detection capacity of arsenic in the urine. Methods: Urine arsenic samples were prepared with normal human urine as matrix. The homogeneity of the samples was investigated and the results were statistically analyzed by single factor analysis of variance. 2 samples were issued to each participant laboratory. A robust statistical four-point distance method was used to calculate the results submitted by each participant laboratory and the test capability of the laboratory was assessed by the z-score method. By means of method experiments and records, the reasons of dissatisfaction and the influencing factors of the results were discussed. Results: The statistic of the homogeneity of urine arsenic samples was less than the critical value (P>0.05) , which showed that the arsenic in the sample was homogeneous. The satisfactory rate of comparison between 36 laboratories was 86.1%. The main reasons for dissatisfaction were the testing conditions and the quality control measures. The selection of sample pretreatment, acidity control and hydrogenation conditions was the main influencing factor for the determination of urinary arsenic by atomic fluorescence spectrometry. Conclusion: The level of urinary arsenic detection in the occupational health laboratories was generally better and a few laboratories need to be improved ability of detection. It was very important to control the test conditions reasonably and strengthen the quality control measures to improve the accuracy of urine arsenic detection. PMID- 29996263 TI - [The importance fo clinincal study onthe use of microbioecological agents in patients with irritable bowel syndrome]. PMID- 29996264 TI - [An association of ulcerative colitis with tumor necrosis factor superfamily member 15 gene polymorphisms in Chinese patients]. AB - Objective: To explore the relationship between ulcerative colitis (UC) susceptibility and tumor necrosis factor superfamily member (TNFSF) 15 gene polymorphisms and haplotypes in Han nationality in Zhejiang province of China. Methods: A total of 408 UC patients and 574 healthy controls were recruited in this study. Three single nucleotide polymorphisms of TNFSF15 (rs3810936, rs4263839, rs4979462) were examined by improved multiple ligase detection reaction (iMLDR) technique. Analyses of linkage disequilibrium (LD) and haplotype were performed by Haploview 4.2 software in all study subjects. Results: The variant allele A and genotype (GA+AA) of rs4263839 were less frequent in UC patients than in controls (45.34% vs. 50.17%, P=0.035;68.38% vs. 76.66%, P=0.004). According to the severity and location of disease, UC patients were divided into different subgroups. After multiple comparison correction(alpha=0.012 5), the frequencies of variant allele A and genotype (GA+AA) of rs4263839 were lower in patients with severe UC than in the controls (37.69% vs. 50.17%, P=0.007; 60.00% vs. 76.66%, P=0.004). Similar findings were also drawn for patients with extensive colitis in contrast with the controls (42.22% vs. 50.17%, P=0.009; 63.33% vs. 76.66%, P<0.001). Furthermore, the haplotype analysis indicated that three SNPs above were in a strong LD. The frequency of haplotype TAC was lower in UC patients than in the controls(40.83% vs. 46.04%, P=0.023). Also it was less prevalent in patients with severe UC and patients with extensive colitis when compared with controls respectively (33.38% vs. 46.04%, P=0.005;37.22% vs. 46.04%, P=0.003). Conclusions: TNFSF15 (rs4263839) variation might not only reduce the risk of UC, but also affect the severity and lesion location of UC. The haplotype TAC formed by rs3810936, rs4263839 and rs4979462 might be related to a lower risk of UC, especially in patients with severe colitis or patients with extensive colitis. PMID- 29996265 TI - [A clinical analysis of hepatic veno-occlusive disease after hematopoietic stem cell transplantation]. AB - Objective: To analyze the outcome and the prognostic factors of hepatic veno occlusive disease (HVOD) after hematopoietic stem cell transplantation (HSCT). Methods: A total of 797 patients receiving HSCT were analyzed retrospectively. The prophylaxis regimen of HVOD in the First Affiliated Hospital of Guangxi Medical University consisted of low molecular weight heparin and lipoprostaglandin E1 (PGE1). Results: Fifty-nine patients (7.4%) developed HVOD at 3-49 days after HSCT (median 12 days). Age younger than 15 years at transplant(HR= 6.47, P<0.001), busulphan conditioning (HR=6.40, P<0.001), thalassemia major (HR=6.35, P<0.001), allogeneic transplantation (HR=7.74, P=0.005) were univariate risk factors for HVOD. Multivariate analyses suggested that thalassemia major and busulphan conditioning were independently correlated with the development of HVOD. Conclusion: Thalassemia major and busulphan conditioning are independent risk factors for HVOD after HSCT. PMID- 29996266 TI - [The clinical characteristics of immunocompetent adults with chronic active Epstein-Barr virus associated enteritis]. AB - Objective: To investigate the clinical and pathological characteristics of chronic active Epstein-Barr virus associated enteritis (CAEAE) . Methods: The clinical data of 6 CAEAE patients in Peking Union Medical College Hospital were retrospectively analyzed from January 2010 to November 2017, including clinical manifestations, endoscopic, pathological features, medications and clinical outcome. Results: The male?female ratio was 4?2 and the average age was 34 years old. All patients did not have personal and family history of immunodeficiency. The common symptoms consisted of fever (6/6), abdominal pain (6/6), hematochezia (6/6) and diarrhea (5/6). The most frequently affected sites were colorectum (5/6), followed by small intestine (3/6). Further serologic tests revealed a high load of serum Epstein-Barr virus(EBV) DNA. The main manifestations under endoscopy were multifocal or diffuse irregular ulcers. There was inflammation in the ulcer bases and surrounding areas, where EBV-encoded small RNA (EBER) was positive by in situ hybridization (6/6). The common complications were massive hemorrhage (3/6) and intestinal perforation (2/6). None of treatment agents including glucocorticoid, ganciclovir, foscarnet sodium and cytotoxic drugs was effective. All patients died within 0.5 to 13 months after diagnosis. Conclusions: CAEAE in immunocompetent individuals is a rare disorder with poor prognosis. It is difficult to differentiate CAEAE from inflammatory bowel disease due to similar clinical and endoscopic manifestations. PMID- 29996267 TI - [A clinical study of mental stress-induced myocardial ischemia in patients with stable coronary artery disease and depression/anxiety]. AB - Objectives: Exploring the association between depression/anxiety and mental stress-induced myocardial ischemia (MSIMI) in patients with stable coronary artery disease (CAD). Methods: A total of 178 subjects was enrolled according to the inclusion and exclusion criterion with 88 men and 90 women at age of (54+/ 12)years. The subjects were divided into four groups including CAD with depression/anxiety, CAD without depression/anxiety, depression/anxiety without CAD, and control group based on the state of coronary artery, the scores of Patient Health Questionnaire 9-item (PHQ-9) and Generalized Anxiety Disorder 7 item (GAD-7) . MSIMI was diagnosed by echocardiography. Data were analyzed by SPSS19.0. Results: The incidence of MSIMI in all CAD patients was 17.24%. Within each group, 35.00% patients were MSIMI in CAD with depression/anxiety, 2.13% were in CAD without depression/anxiety, 14.29% were in depression/anxiety without CAD, and 2.38% were in control group. The risks of MSIMI in depression/anxiety without CAD and with CAD groups were 6.83 (P>0.05) and 22.08 times (P<0.05) higher than that in control group, respectively. Logistic regression showed that a 1-point increment in the GAD-7 score, but not PHQ-9 score [OR=0.95, 95% CI (0.77-1.17), P=0.63], was associated with 1.22-fold increase in the likehood of MSIMI [95% CI (1.07-1.38), P=0.00]. Conclusions: The MSIMI rate is much higher in patients with CAD comorbid depression/anxiety compared with CAD without depression/anxiety. Anxiety, but not depression, is an independent risk factor of MSIMI in CAD patients. PMID- 29996268 TI - [Prevalence and risk factors of diabetes and prediabetes in adults in Jingyuan Ningxia]. AB - Objective: To investigate the prevalence and risk factors of diabetes and prediabetes in Jingyuan County in Ningxia. Methods: A cross-sectional survey including 10 639 participants (18-88 years of age) with a multistage sampling was conducted in Jingyuan County between January, 2014 and April, 2015. Questionnaires, physical examinations, and laboratory tests were included in the survey. Results: Among all the subjects, 10 491 participants (men: 4 826, women: 5 665) with complete data were included in the analysis. The standardized prevalence of diabetes and prediabetes was 4.2% (men: 3.9%, women: 4.5%) and 8.8% (men: 7.6%, women 10.3%), respectively, in which the standardized prevalence of diabetes was higher in Hui (4.5%) than that in Han (3.5%) (P< 0.05). Logistic regression analyses showed that age, family history of diabetes, overweight/obesity, hypertriglyceridemia and hypertension were positively associated with prediabetes and diabetes with the odds ratios being 1.60 and 2.14 (age, P< 0.001), 1.40 and 3.32 (family history, P< 0.05), 1.47 and 1.57 (overweight/obesity, P< 0.001), 1.88 and 2.55 (hypertriglyceridemia, P< 0.001), 1.44 and 1.89 (hypertension, P< 0.001), respectively. Conclusions: The prevalence of diabetes was relatively low in the rural area in Ningxia. However, it is still essential to take active interventions in people at high risk of diabetes in order to prevent the incident diabetes. PMID- 29996269 TI - [The expression of trypsin in serum and vital organs of septic rats]. AB - Objective: Pancreatic enzymes may spread into the injured intestine, bloodstream,and cause the cascade of inflammatory reactions.Our objective was to explore trypsin expression in serum and vital organs in septic rats. Methods: Trypsin levels in serum,heart,lung and jejunum were tested and compared between Escherichia coli endotoxin injected rats(SS), SS treated with a protease inhibitor(ulinastatin) and control group(SHAM).The correlations between serum trypsin,intestinal proteins and inflammation indices were assessed.Two components of mucosal barrier, i.e. mucin-2 and E-cadherin,were measured to evaluate the intestinal mucosal barrier function.The levels of tumor necrosis factor alpha (TNFalpha),interleukin-6(IL-6) and neutrophil elastase(NE) were measured to determine the inflammation indices. Results: Compared to SHAM group, trypsin levels in serum[(73.71+/-9.14) ng/ml vs. (12.12+/-2.36) ng/ml],heart[(51.60+/ 15.06) ng/ml vs. (6.39+/-3.53) ng/ml],lung [(54.73+/-5.57) ng/ml vs. (5.24+/ 3.08) ng/ml] and jejunum(1.19+/-0.48 vs. 0.40+/-0.12) were significantly higher in SS group (all P<0.05). The level of serum trypsin had negative correlation with mucin-2 and E-cadherin, and positive correlation with TNFalpha, IL-6 and NE (all P<0.05). In rats treated with ulinastatin, trypsin levels were significantly decreased compared with those in SS group including in serum [(65.79+/ 4.88)ng/ml]], heart [(26.33+/-12.03)ng/ml], lung [(28.73+/-14.46) ng/ml] and jejunum (0.80+/-0.20) (all P<0.05).Serum TNFalpha[(247.34+/-16.97)ng/L vs. (178.78+/-40.81)ng/L] revealed similar changes in ulinastatin and SS group,whereas mucin-2 (0.58+/-0.14 vs. 0.89+/-0.17) and E-cadherin (0.11+/-0.04 vs. 0.23+/-0.06) were both significantly elevated after administration of ulinastatin (both P<0.05) . Conclusion: Serum and tissue trypsin is elevated in septic rats. Protease inhibitor ulinastatin protects intestinal function by reducing inflammatory reaction. PMID- 29996270 TI - [The clinical and laboratory characteristics of congenital pyruvate kinase deficiency]. AB - Clinical data of 19 patients with congenital pyruvate kinase deficiency were analyzed. Insufficient pyruvate kinase confirmed the diagnosis. Laboratory parameters of hemolysis were summarized. In cases of neonatal hyperbilirubinemia and unexplained hemolytic anemia, pyruvate kinase activity and next generation sequencing test may help the early diagnosis. PMID- 29996271 TI - [Validity of Padua risk assessment scale for assessing the risk of deep venous thrombosis in hospitalized patients]. AB - To analyze the clinical features of deep venous thrombosis(DVT) in hospitalized patients and evaluate the effectiveness of Padua risk assessment model.The clinical data of DVT patients were retrospectively analyzed in Beijing Shijitan Hospital from April 1 2017 to June 30, 2017.Padua risk assessment scale was used to evaluate the risk score of DVT in the departments of internal medicine and surgery. Effectiveness of predicting DVT was analyzed by receiver operating characteristic curve (ROC).Logistic regression analysis was used to evaluate the related factors of DVT.In DVT group, age (OR=0.96),acute infection(OR=8.23),prothrombin time(OR=0.76),D dimer(OR=1.00),erythrocyte sedimentation rate(OR=1.02) and platelet count(OR=1.01) were significantly associated with thrombosis(all P<0.05).The specificity of Padua model to predict DVT in internal medical patients was better than the sensitivity(80.7% vs. 50%,P<0.05).Surgical patients reported similar findings with specificity to sensitivity of 87.5% vs. 67.5%(P<0.05).The area under curve of ROC in internal medical patients was more than that in surgical patients[0.62 (95%CI 0.59-0.67) vs.0.61(95%CI 0.56-0.66), P<0.05].Padua model is more specific than sensitive to predict DVT in hospitalized patients.It has better predictive value of DVT in internal medical patients than surgical patients. PMID- 29996274 TI - [Type 1 diabetes millitus following short-term recombinant interferon therapy in patient with chronic hepatitis C]. PMID- 29996273 TI - [A case of subacute combined degeneration in duced by nitrous oxide]. PMID- 29996272 TI - [The diagnostic value of copeptin in the cardiorenal syndrome rats and the association with heart and kidney impairment]. AB - To explore the diagnostic value of copeptin (CPP) in cardiorenal syndrome (CRS) in rats and the association between CPP and impairment of heart and kidney, 60 male SD rats were randomly divided into blank control group (CK group), kidney failure group (SNX group), heart failure group (MI group), and CRS group. Heart and kidney function and their histology changes in rats from each group were detected. The correlation between serum CPP and heart and kidney function indexes was performed with Pearson correlation analysis. The HE staining of heart and kidney showed that the tissue lesion was more severe in CRS group than in SNX group and MI group. There was a significant positive correlation between serum CPP and brain natriuretic peptide (BNP) (r=0.638, P<0.05). No correlation was observed between serum CPP and cardiac function index (left ventricular systolic pressure, left ventricular diastolic pressure, left ventricular end-diastolic pressure) or renal function index (serum creatinine, urine creatinine, blood urea nitrogen) (r=0.512, 0.189,-0.063, 0.207, 0.290, 0.595, respectively, all P>0.05). The CPP level is associated with the degree of heart and kidney damage in CRS rats. PMID- 29996275 TI - [Procalcitonin-guided discontinuation of antibiotics in patients with sepsis]. PMID- 29996276 TI - [The advances in the genetic study of Charcot-Marie-Tooth disease with upper motor neuron involvement]. PMID- 29996277 TI - [The controversy and challenge of anticoagulant therapy for hepatic cirrhosis with portal vein thrombosis]. PMID- 29996278 TI - [Molecular advancement in the mechanism of azathiopurine-induced leukopenia]. PMID- 29996279 TI - [The 464th case: sudden convulsion and coma in a patient with acute leukemia]. AB - A 46-year-old female patient was diagnosed as mixed phenotype acute leukemia with chief complaints of intermittent gingival swelling and bleeding for 1 week. The induction chemotherapy was not effective. During the second course chemotherapy, the patient had sudden convulsion and coma. She was transferred to the intensive care unit with worsened condition after transient improvement. Her final diagnosis was secondary adrenocortical insufficiency, adrenal crisis, intractable hyponatremia and cerebral edema. PMID- 29996280 TI - [Clinical characteristics and treatment strategy of IV stage gastric cancer in China]. PMID- 29996281 TI - [The influence of CYP2A6 polymorphism on adjuvant S-1 chemotherapy outcomes in patients with curatively resected gastric cancer]. AB - Objective: Oral fiuoropyrimidine S-1 contains tegafur, gimeracil, oteracil. Tegafur is the major active prodrug, which is metabolized to 5-Fu by cytochrome P4502A6 (CYP2A6). This research investigated the association between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients. Methods: A total of 200 patients diagnosed pathological stage II-III gastric cancer were included in this study, who were received adjuvant S-1 chemotherapy regimens after curative surgery (40 mg/m(2,) bid, d1-28, rest 2 weeks, every 6 weeks one cycle). Additionally, the wild-type allele (CYP2A6*1) and four variant alleles (CYP2A6*4, *7, *9, *10) were genotyped. Results: A total of 200 patients were enrolled in this study with a median follow-up of 46.5 months. The 3-year recurrence free survival rates were 95.9% for W/W (n=49), 83.1% for W/V (n=94), and 72.5% for V/V (n=57), with significant difference (P=0.032). Grade >=3 hematologic toxicities of three genotype groups were without difference (10.2% vs 14.9% vs 10.5%, P=0.628). Conclusions: CYP2A6 genotypes correlate with the survival of S-1 chemotherapy. And its polymorphism detection can provide individualized guidance for adjuvant chemotherapy options in patients with gastric cancer. PMID- 29996282 TI - [The influence of chemotherapy-induced leucopenia on the disease-free survival of gastric cancer patients after radical gastrectomy]. AB - Objective: To investigate the association between chemotherapy-induced leucopenia and patients' disease-free survival in gastric cancer patients who received radical gastrectomy. Methods: The clinical data of 273 gastric cancer patients who received radical gastrectomy and postoperative adjuvant chemotherapy between January, 2010 and December, 2015 in PLA 309(th) hospital was reviewed retrospectively. Results: A total of 195 (71.4%) patients experienced at least one time of leucopenia, while it was absent in the other 78 (28.6%) patients. The median disease-free survival of patients with or without leucopenia was 49.7 and 44.0 months respectively (P=0.009), leucopenia was an independent factor influencing patients' disease-free survival (HR=2.758, P=0.022), but there was no statistical difference between the disease-free survival of patients with different degrees and frequency of leucopenia (P=0.446, 0.123). Conclusion: Chemotherapy-induced leucopenia is a predictor of good prognosis for gastric cancer patients who receive radical gastrectomy. PMID- 29996283 TI - [Clinical analysis of the risk factors for No.12p LN metastasis in advanced gastric cancer]. AB - Objective: To analyse the risk factors for periportal lymphnode (No.12p LN) in advanced gastric cancer. Methods: A retrospective analysis of 183 patients with advanced gastric cancer from January 2005 to December 2010, and all patients were underwent D2 lymphadenectomy in addition to No. 12p LN dissections. Potential clinicopathological factors that could influence No. 12p LN metastasis were statistically analyzed. Results: There were 18 cases (9.8%) with periportal lymphnode metastasis. A logistic regression analysis suggested that the Borrmann type (III/IV versus I/II, P=0.008), tumor size (>=6 cm vs <6 cm, P=0.001), and depth of invasion (pT4 vs pT2/pT3, P=0.049) were associated with 9.5-, 8.5-, and 3.2-fold increases, respectively, for risk of No. 12p LN metastasis. A logistic regression analysis also showed that No. 5 (P=0.002) and No. 12a (P=0.002) LN metastasis were associated with 7.5- and 7.3-fold increases, respectively, for risk of No. 12p LN metastasis. In addition, significant differences in 5-year survival of patients with and without No. 12p LN metastasis were observed (11.1% vs 32.7%, P=0.042). Conclusions: Borrmann type, tumor size and depth of invasion are significant factors for identifying patients with No. 12p LN metastasis. Patients with No. 5 or No. 12a LN metastasis should be higher possibility of No.12p LN metastasis. PMID- 29996284 TI - [Clinical analysis of complications after laparoscopic radical gastrectomy for patients over 70 years old with low abdominal pressure]. AB - Objective: To explore the safety and reliable of low pressure laparoscopy in old patients, and the advantage over conventional pressure laparoscopy. Methods: Sixty-six patients(>=70 year) with gastric cancer from 2014.4 to 2017.4 were enrolled, and they were divided into three groups randomly. The value of Ejection Fraction (EF), central venous pressure (CVP), B-type natriuretic peptide (BNP), O(2) pressure, CO(2) pressure, complications of three groups were compared and analysis. Results: There was no differences between low-pressure laparoscopic group, conventional laparoscopic group and laparotomy group in age, gender, EF, oxygen pressure, CVP (P>0.05). But the postoperative BNP, intraoperative carbon dioxide pressure of low-pressure laparoscopic group were significantly better than those of the other two groups. Compared with the conventional laparoscopic group and the laparotomy group, the low-pressure laparoscopic group has fewer postoperative complications (P=0.027, <0.05), especially in postoperative pulmonary infection (P=0.044, <0.05). Conclusion: The low pressure laparoscopy has decreased the stimulation of surgery to old patients, and reduced the postoperative complications. All this results demonstrate that the low pressure laparoscopy to old patients is safety and reliable. PMID- 29996285 TI - [Analysis of internal quality control data of complete blood count from laboratories participating in national external quality assessment]. AB - Objective: To investigate current status and problems of internal quality control (IQC) of complete blood count in China so as to perform IQC normally. Methods: The IQC data of complete blood count for five parameters were collected from laboratories participating in national external quality assessment during 2012 2017 (totally 12 times), including WBC, RBC, Hb, Hct and PLT. After confirmation of all data, data for the 12 times were analyzed as follows.The proportions of using different levels of quality control materials were calculated.The 25th, 50th, 75th, 90th percentiles CV of data collected for the 12 times were calculated respectively and the trends of CV were observed over time.The difference of CV among laboratories running three control levels was compared.The CV of each parameter in 2017 was compared with precision requirements based on biological variation, health standards and German Medical Association Directive; The proportions of laboratories using different control rules were calculated. Results: After invalid data was excluded from those IQC data of laboratories for the 12 times external quality assessment (up to 2 402, as low as 1 449) from 2012 to 2017, the residual data (up to 2 332, as low as 1 431, accounting for 96.0% 99.2%) was used for analysis. 61.9%-66.1%, 18.2%-23.6% and 14.3%-17.3% of laboratories ran one, two and three control levels respectively, and the proportions of laboratories running more than two control levels increased from 33.9% to 38.1%. The decrease trend of the 75th, 90th percentiles CV of WBC, RBC, Hb, Hct for three levels, PLT for normal level and the 90th percentiles CV of PLT low level had statistically significance over time (P<0.05); the decrease trend of the 75th percentiles CV of PLT low level and 75th, 90th percentiles CV of PLT high level had no statistically significance over time. The CV had significant difference between low and normal, low and high control level for WBC and PLT, while there were no difference between normal and high control levels. There were no significant difference of CV among three control levels for RBC, Hb, and Hct. Except for the CV of Hct low, normal level and PLT low level, 85% of laboratories for the other parameters could meet the minimum precision requirements based on biological variation; more than 85% laboratories met the requirements of health standards; except for the CV of PLT low level, more than 80% laboratories met the requirements of German Medical Association Directive. The proportion of laboratories using 1(3s)/2(2s) quality control rules increased from 59.2% to 76.0%. Conclusions: During the past 6 years, the CV for IQC has shown a decrease trend over time. However, the control level and quality control rules used by some laboratories do not meet management requirements. The CV of Hct and PLT in a few laboratories do not meet the minimum requirements of the health standards, and need to implement quality improvements fatherly. PMID- 29996286 TI - [Comparative analysis of anatomic and non-anatomic hepatectomy for single small hepatocellular carcinoma with microvascular invasion]. AB - Objective: To compare the efficacy and safety of anatomic hepatectomy and non anatomic hepatectomy in the treatment of single small Hepatocellular carcinoma with MVI. Methods: The clinical data of 84 patients with single small Hepatocellular carcinoma with MVI in Beijing Chaoyang Hospital between January 2008 and December 2013 were retrospectively analyzed. Patients undergoing anatomical hepatectomy were enrolled in the AR group, and the patients undergoing non-anatomic hepatectomy were enrolled in the NR group. The efficacy and survival rate of the two groups were compared. Results: (1) Operation time, numbers of patients with volume of intraoperative blood loss >=300 ml and number of patients with blood transfusion were (170+/-41)minutes, 8, 7 in the AR group and (148+/ 35)minutes, 19, 18 in the NR group, respectively, with statistically significant differences between the 2 groups (P<0.05). (2) The 1-year, 2-year and 3-year overall survival rate were 85.7%, 68.6%, 57.1% in the AR group and 79.6%, 53.1%, 42.9% in the NR group, respectively. The 1-year, 2-year and 3-year progression free survival rate were 80.0%, 62.9%, 51.4% in the AR group and 71.4%, 49.0%, 38.8%, in the NR group, respectively. There were statistically significant differences between the 2 groups both in the overall survival rate and the progression-free survival rate (P<0.05). (3) Prognostic factors analysis of HCC patients with MVI: result of univariate analysis showed that maximum diameter of tumor and surgical procedures were relative factors affecting overall survival and progression-free survival of HCC patients with MVI, AFP level was relative factors affecting progression-free survival of HCC patients with MVI, with statistically significant differences (P<0.05). Result of multivariate analysis showed that maximum diameter of tumor between 3.0 and 5.0 cm and non-anatomic liver resection were independent factors affecting poor overall survival and progression-free survival of HCC patients with MVI, and AFP>=20 MUg/L and total bilirubin >=20 MUmol/L were independent factors affecting poor progression-free survival of HCC patients with MVI, with a statistically significant differences (P< 0.05). Conclusion: Anatomic hepatectomy for patients with single small hepatocellular carcinoma with microvascular invasion has better clinical efficacy and safety. PMID- 29996287 TI - [Clinical application of high frequency jet ventilation in cryotherapy for tracheo-bronchial carcinoma via rigid bronchoscopy]. AB - Objective: To analyze the clinical applications of high frequency jet ventilation(HFJV) in cryotherapy of the trachea and bronchial neoplasms by the rigid bronchoscope. Methods: The clinical data of 35 patients who were treated with tracheal neoplasms cryotherapy by the rigid bronchoscopy under HFJV were collected in China-Japan Friendship Hospital from August 2008 to February 2015.Under general anesthesia, HFJV was used in all patients. The mean arterial pressure (MAP), heart rates (HR), pulse oxygen saturation (SpO(2)), results of arterial blood gas analysis and the incidence of complications during the procedure were recorded. Results: In the 35 patients, one case had multiple operations experience, he had an airway spasm after HFJV 40 min during his second operation, and severe hypoxemia after HFJV 5 min during his third operation, endotracheal intubation was performed immediately. The patient has a serious accumulation of carbon dioxide (CO(2)) whose partial pressure of carbon dioxide in the artery (PaCO(2)) was up to 71 mmHg(1 mmHg=0.133 kPa). Other patients had stable hemodynamics and no severe CO(2) accumulation. Conclusion: High frequency jet ventilation can provide satisfactory ventilation effect in cryotherapy of the trachea and bronchial end-stage neoplasms by the rigid bronchoscope. PMID- 29996288 TI - [Clinical characteristics and treatment strategies for early-stage primary gastric diffuse large B-cell lymphoma]. AB - Objective: Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is the most common non-Hodgkin lymphoma (NHL) of extranodal origin. Most patients with PG DLBCL had localized disease (stage I or II) at presentation, and will achieve complete response (CR) after induction chemotherapy. However, there has been little consensus regarding whether optimal treatment is provided by chemotherapy alone or chemotherapy plus radiotherapy, nor the treatment outcome from the addition of rituximab in localized-stage PG-DLBCL. Methods: Patients with Stage IE and IIE PG-DLBCL were retrospectively analyzed. Patients have not undergone surgery, have received at least 3 cycles of R-CHOP or CHOP-like chemotherapy as initial therapy, and achieved CR or partial response (PR) were enrolled. Results: A total of 91 patients were studied. The median age was 51 years, included 47 males and 44 females. Fifty-two patients were at Stage IE and 39 at Stage IIE, 64 (70.3%) patients received R-CHOP-like regimens, and 27 (29.7%) received CHOP-like regimens, the median chemotherapy cycle was 6 (3-8). Among the 91 patients, 80 (87.9%) patients achieved CR from induction chemotherapy, 11(12.1%) was evaluated PR. Of CR patients, 48 patients (60%) underwent consolidating radiotherapy and 32 patients (40%) did not receive radiotherapy; all PR patients received salvage radiotherapy. CR patients with and without radiation therapy had 4-year progression-free survival (PFS) rates of 96.4% and 96.7%, respectively (chi(2) = 0.546, P=0.46); 7/11 (63.6%) PR patients achieved CR after radiotherapy, with a median follow-up of 41 months, they were all disease free. For patients treated with R-CHOP or CHOP-like regimens, the 4-year PFS was 93.2% and 89.7%, respectively (chi(2)=0.096, P=0.757). Conclusions: Consolidation radiotherapy failed to improve the outcome for early-stage PG-DLBCL, while for PR patients, salvage radiotherapy increased CR rate and improved survival. The addition of rituximab to CHOP did not improve the efficacy. PMID- 29996289 TI - [Metformin protects against bleomycin-induced pulmonary fibrosis in mice]. AB - Objective: To explore the effect of metformin on murine model of bleomycin (BLM) induced lung injury and fibrosis. Methods: A total of 30 mice were divided into 3 groups: control, BLM, and BLM with metformin, in accordance with the random number table and each group had 10 mice. To induce the pulmonary fibrosis model, a concentration of 2 mg/ml bleomycin was intratracheally administered in the BLM group and BLM with metformin group with a volume of 1.75 MUl/g, while the control group accepted saline with the same volume. Metformin (200 mg/kg) was given to the mice orally once a day from the day before intratracheal instillation of bleomycin to day 14. The daily survival condition of mice was recorded during 14 days. At day 14, HE-staining was used to assess the severity of fibrosis according to the method proposed by Ashcroft. Total lung collagen content was determined by hydroxyproline assay and Masson's trichrome staining. To examine the expression of fibronectin we used the method of immunohistochemistry staining. The changes of Transforming Growth Factor beta 1 (TGF-beta(1)) in plasm, bronchoalveolar lavage fluid (BALF) and lung were measured by ELISA. Results: The survival rates of control group, BLM group and BLM with metformin group at day 14 were 10/10, 4/10 and 7/10 respectively. According to the method proposed by Ashcroft the score of metformin treated mice was significantly lower than that of the bleomycin model mice[(3.82+/-0.58) vs (7.79+/-0.06), (P<0.05)]. The hydroxyproline level in lung tissue were markedly attenuated in metformin treated mice compared with bleomycin model mice [(0.40+/-0.05) vs (0.73+/-0.10) MUg/mg, (P<0.05)]. The level of TGF-beta(1) in plasma, BALF and lung tissue were also decreased in mice treated with metformin compared with bleomycin model mice [(2.32+/-0.68) vs (4.59+/-0.45) ng/ml, (0.81+/-0.09) vs (1.40+/-0.06) ng/ml, (17.12+/-0.83) vs (21.25+/-0.69) ng/mg, all P<0.05]. Conclusion: Metformin can reduce the severity of pulmonary fibrosis in mice induced by bleomycin. PMID- 29996290 TI - [Effect of A20 gene induced silencing on the biological behaviors of human nasopharyngeal carcinoma cell]. AB - Objective: To observe the effect of knockdown A20 gene expression on the proliferation, invasion and metastasis of human nasopharyngeal carcinoma cell in vivo and in vivo. Methods: Human nasopharyngeal carcinoma cell 5-8F-H3 was transfected with A20-specific shRNA Tet-on inducible plasmid vectors, and A20 silenced cells were screened by Puromycin. Quantitative RT-PCR and Western blot analysis were used to detect the mRNA level and protein of A20. The cell proliferation was detected by cell counting kit-8 (CCK8) and plate colony formation assays. The cell cycle and apoptosis were measured by flow cytometry. And the ability of cell invasion was measured using Boyden chamber assay in vivo. Subcutaneous tumor formation and liver metastasis in vivo were examined with whole-body fluorescence imaging system to observe the influence of silencing A20 gene expression in nude mice. Results: The stable A20 inducible silencing cells line 5-8F-H3/A20-shRNA was established successfully. Down-regulation of A20 mRNA and protein expression were observed in 5-8F-H3/A20-shRNA cells treated with DOX(both P<0.01). The results of CCK-8 assay (F=18.542, P=0.003), clone formation experiment (F=40.080, P<0.001) and flow cytometry analysis (F=7.398, P=0.024) in vivo showed that the cell proliferation of 5-8F-H3 was remarkably inhibited by down-regulation of A20 gene expression. The results of Boyden chamber assay showed that A20 gene silencing could inhibit the cell invasion ability (F=26.157, P<0.001). Silencing of A20 inhibited tumorigenesis and metastasis via subcutaneous tumor formation and liver metastasis experiments in nude mice. Conclusion: A20 gene is closely related to the malignant biological behaviors of nasopharyngeal carcinoma, and it may serve as a potential molecular target for the treatment of nasopharyngeal carcinoma. PMID- 29996292 TI - [The adverse effects and the related mechanisms of environmental exposure on male reproductive health]. PMID- 29996291 TI - [Collecting system percutaneous access using MR-assisted guidance: first human phantom experience]. AB - Objective: Precise renal puncture is an essential but challenging step for successful percutaneous nephrolithotomy. We evaluated the efficiency of a novel real-time navigation system using Mixed Reality(MR) technology for human phantom kidney puncture. Methods: One human kidney phantom underwent MR-assisted percutaneous collecting system puncture. Two punctures were performed by each of 6 surgeons in the randomize selected upper, middle or lower calyces. Outcome measurements were the number of attempts for renal puncture, the time needed to evaluate the trajectory and to perform percutaneous puncture. Results: A total of 12 punctures were performed successfully using MR-Assisted Guidance. Median evaluation time and renal puncture time for the selected calyces was 13 (range 11 to 19) and 19 seconds (range 15 to 44), respectively. One or Two attempts were needed to achieve a successful renal puncture for all of the surgeons. Conclusions: The proposed MR-assisted guidance solution for renal collecting system puncture proved to be accurate, simple and quick. The inherent limitations of traditional X - ray and ultrasonic technology can be overcome. PMID- 29996294 TI - [Analyses on the difference and trend of lung cancer incidence in Beijing, 2000 2012]. AB - Objective: To analyze the temporal trends of lung cancer incidence between age, gender (male and female) and areas (urban and rural) in Beijing during 2000-2012. Methods: The lung cancer cases were collected by Beijing cancer registry between 2000 and 2012. We calculated the incidence and world age-standardized incidence rates (ASR) which standardized by World Segi's population. Also, the average age and median age of lung cancer incidence were calculated. The annual percent changes (APC) for the whole period, for the gender ratio and for the area ratio were evaluated with Joinpoint analysis. Result: Totally, 81 378 new cases of lung cancer were diagnosed in 2000-2012 with the average incidence rate of 52.67/100 000. The incidence rate increased by 4.84% per year from 38.99/100 000 to 65.33/100 000, but the APC of ASR was 1.69% (P<0.001) . The ASR increased 0.54% (P=0.029) per year in urban from 29.71/100 000 to 30.55/100 000 and 3.93% (P<0.001) in rural areas from 24.02/100 000 to 35.79/100 000. The incidence ratio of urban to rural decreased from 1.24 to 0.85 (APC=-3.29%, P<0.001). The incidence ratio of male to female decreased from 1.84 to 1.69 (APC=-0.45%, P=0.019).The average age of lung cancer incidence of male and female increased from 66.27 and 66.00 to 68.97 and 69.11 (P<0.001), respectively. Conclusion: The incidence rate of lung cancer increased slightly in urban areas but increased significantly in rural areas during 2000-2012, the area ratio trend was declined. The average age of lung cancer occurrence gradually increased, but the temporal trends varied with age group. The gender ratio decreased from 2000 to 2012. PMID- 29996293 TI - [Anthropometry and the risk of colorectal cancer in males: a prospective cohort study]. AB - Objective: To investigate the association between anthropometry and colorectal cancer risk in Chinese males. Methods: Anthropometry and incident colorectal cancer cases were collected on a biennial basis starting in May 2006 among males in Kailuan Cohort (2006-2014). In addition, electronic database of hospitals affiliated to Kailuan Community, Insurance System of Kailuan Community and Tangshan were also searched for supplementary information. Cox proportional hazards regression models and linear models were used to evaluate the association between baseline anthropometry and the risk of colorectal cancer in males. Results: A total of 106 786 males were included and 318 new colorectal cancer cases were identified in the Kailuan male cohort study, with 747 337.60 person years follow-up by 31 December 2014. The median follow-up time was 7.90 years. Highest quartile waist circumference (>=94.0 cm) or WHtR (>=0.55) had 1.45 (95%CI: 1.05-2.02) and 1.66 (95%CI: 1.15-2.41) higher risk of colorectal cancer when compared with lowest waist circumference (<82.0 cm) or WHtR (<0.48) after adjusting for age, education, smoking, alcohol drinking, sitting time and dust exposure. Subgroup analyses by site indicated that males with BMI >=26.27 kg/m(2), waist circumference >=94.0 cm or WHtR >=0.55 had HRs (95%CI) of 2.18(1.27-3.73), 2.20 (1.27-3.78) and 2.42 (1.29-4.56) for colon cancer risk, respectively. Linear models showed the HR of colon cancer and 95%CI would be 1.59 (1.24-2.02) with every 0.1 growth in WHtR. Conclusion: Obesity may be responsible for an increased risk of colorectal cancer in male. Reasonable weight control may be one of the effective measures to prevent colorectal cancer. PMID- 29996295 TI - [The prevalence of snoring and its association with academic performance among school-aged children in Beijing]. AB - Objective: To investigate the snoring status of school-aged children in Beijing and explore the association of snoring and academic performance. Methods: A total of 7 925 children aged from 6 to 14 were selected from 15 primary and middle schools at 7 districts (Xicheng, Chaoyang, Changping, Shunyi, Fangshan, Huairou and Mentougou) in Beijing in 2015, using multi-stage stratified cluster random sampling method. The recruited children were asked to complete the Pediatric Sleep Questionnaire (PSQ) and a questionnaire related to sleep behavior. The multiplelogistic regression was used to analyze the association of snoring and academic performance. Results: A total of 794 (12.44%) children showed a decline in academic performance among 6 383 eligible respondentsfor data analysis. 580 (9.08%) children with snoring was identified, of which 333 and 247 were in frequency of 1-2 times per week and frequency of >=3 times per week, respectively; 357, 170 and 53 were in snoring grade I, grade II and grade III, respectively. Compared with the children without snoring, the OR (95%CI) for children with 1-2 times per week and >=3 times per week was 1.363 (1.000-1.857) and 1.605 (1.135-2.269), respectively; and the OR (95%CI) for children with grade I, grade II and grade III of snoring was 1.226 (0.893-1.683), 1.595 (1.062-2.397) and 2.31 (1.17-4.565), respectively. Conclusion: There is a statistical relationship between snoring and the decline of academic performance. The decline of academic performance positively associated with increased frequency and grade of snoring. PMID- 29996296 TI - [Analysis on maternal anemia rate and related factors in Taicang of Jiangsu Province in 2014-2016]. AB - Objective: To investigate anemia rate and to analyze related factors in maternal women in Taicang of Jiangsu province. Methods: There were 13 278 pregnant women who had prenatal care and gave birth in 25 hospitals during 2014-2016 in Taicang of Jiangsu Province. We excluded 1 179 women who registered after 12 weeks of gestation, 144 women who did not test hemoglobin during gestation, and 25 women whose gestational weeks were incorrect. Finally, data from 11 930 pregnant women were analyzed. From the electronical medical record system of maternal and child health care, we obtained basic information of these pregnant women, their hemoglobin levels and related data during gestation and postpartum. Anemia rate was descripted, and factors associated with anemia were identified using multiple unconditional logistic regression. Results: Age of the 11 930 pregnant women was (27.0+/-4.5) years old, and the P(50) (P(25)-P(75)) of BMI at the first trimester was 21.4 (19.6-23.7) kg/m(2). The anemia rate during gestation was 37.2% (4 434/11 930). The anemia rate was 5.5% (276/5 035), 24.4% (1 802/7 377), and 47.8% (3 328/6 966) at the first, second and third trimesters, respectively. Anemia rate at 42 days postpartum was 19.9% (680/3 418). Multiple unconditional logistic regression indicated that anemia during gestation was related with maternal age <21 years old at prenatal registration (OR (95%CI): 1.28 (1.07-1.53)), body mass index(BMI) <18.5 kg/m(2) at the first trimester (OR (95%CI): 1.14 (1.00-1.29)), non-local residence (OR (95%CI): 1.35 (1.20-1.52)), education of middle school and lower (OR (95%CI): middle school: 1.24 (1.05-1.47), primary school: 1.36 (1.01-1.82)), occupation of housewife or farmer (OR (95%CI): housewife: 1.21 (1.06-1.38), farmer: 1.21 (1.03-1.44)). Anemia at 42 days postpartum was associated with multipara (OR(95%CI): 1.59 (1.12-2.27)), anemia at the first trimester (OR(95%CI): 3.26 (1.92-5.55)), no folic acid supplementation at the first trimester (OR(95%CI): 1.34 (1.00-1.80)), and hemorrhage>=500 ml during 24 h postpartum (OR(95%CI): 2.26 (1.02-4.97)). Conclusion: Anemia rate was low for maternal women in Taicang of Jiangsu Province. The factors associated with gestational anemia included pregnant women's age, BMI, local or non-local residence, occupation, and education. The factors associated with postpartum anemia included multipara, anemia at the first trimester, no folic acid supplementation at the first trimester, and hemorrhage 24 h postpartum. PMID- 29996297 TI - [The trend of chronic lower respiratory disease mortality of the residents in Tianjin, China, 2000-2016]. AB - Objective: To explore the trends and distribution of chronic obstructive pulmonary disease (COPD) mortality of the residents with different characteristics from 2000 to 2016 in Tianjin. Methods: COPD mortality data in 2000-2016 were from Tianjin population based mortality surveillance system. The mortality rate of COPD, difference in the rate by gender, age, and geographic distribution, and the trend over years were analyzed. Age-sex-standardized mortality rates of COPD were calculated using the year 2000 world standard population. Joinpoint regression and Cochran-Armitage trend analysis were used to examine the trend of mortality. Results: The crude COPD mortality rate in Tianjin decreased from 57.57/100 000 in 2000 to 28.23/100 000 in 2016 (annual percent change (APC)=-5.01%, Z=-64.76, P<0.001), and the standardized mortality rate decreased from 56.53/100 000 in 2000 to13.88/100 000 in 2016 (APC=-9.17%, Z= 100.83, P<0.001). The crude COPD mortality rate of males decreased from 54.57/100 000 to 27.77/100 000 (APC=-4.89%, Z=-43.63, P<0.001) and the standardized mortality rate decreased from 57.52/100 000 to 14.63/100 000 (APC=-9.07%, Z= 71.48, P<0.001). The crude COPD mortality rate of females decreased from 60.63/100 000 to 28.68/100 000 (APC=-5.12%, Z=-47.92, P<0.001) and the standardized mortality rate decreased from 55.53/100 000 to 13 13/100 000 (APC= 9.27%, Z=-71.13, P<0.001). The crude mortality rate of COPD in urban areas decreased from 45.07/100 000 to 19.54/100 000 (APC=-5.35%, Z=-42.38, P<0.001) and the standardized mortality rate decreased from 39.24/100 000 to 7.45/100 000 (Z= 63.97, P<0.001, APC=-10.22%). The crude mortality rate of COPD in rural areas decreased from 70.20/100 000 to 37.24/100 000 (APC=-4.77%, Z=-48.77, P<0.001) and the standardized mortality rate decreased from 78.88/100 000 to 25.70/100 000 (APC=-7.59%, Z=-72.43, P<0.001). The COPD mortality rate in rural areas was higher than that in urban areas (P<0.001). The COPD mortality rate in 35 years old and over decreased from 2000 to 2016 (P<0.001). Conclusion: The COPD mortality in Tianjin decreased from 2000 to 2016. More efforts are need to reduce COPD mortality in Tianjin, in particular people in rural areas. PMID- 29996298 TI - [Change of occupational stress from 1996 to 2012 among train engine drivers]. AB - Objective: To analyze the change of level of occupational stress between 1996 and 2012 among train engine drivers. Methods: the cross-section investigation was conducted by using cluster sampling method, subjects included 1 116 and 1 002 passenger train engine drivers and freight train engine drivers respectively in 1996 and in 2012;occupational stressors, strains, personalities, buffering factors and individual factors were investigated by using Occupational Stress Instruments. Unconditional logistic regression analyses were performed to estimate the associations between job stressors, personalities, buffering factors and individual factors and strains. Multivariate OR(95%CI) were derived from the logistic regression models. Results: From 1996 to 2012, for the passenger train engine drivers the scores of role ambiguity (17.67+/-5.30 vs.14.11+/-4.66) increased 25.32%, mental load (10.41+/-3.56 vs. 16.29+/-2.08) and physical environment (3.61+/-2.18 vs. 7.03+/-1.65) scores decreased 36.10% and 48.64% respectively, sleep disorders (18.04+/-9.20 vs. 13.35+/-4.00) and negative affectivity (2.76+/-1.86 vs. 2.14+/-1.86) scores increased 33.14% and 28.97% respectively, the differences were statistical significant (P<0.001) . For the freight train engine drivers the scores of sleep disorders (20.33+/-8.17 vs. 12.47+/-4.12) and negative affectivity (2.95+/-1.70 vs. 1.87+/-1.81) scores increased 57.75% and 60.03% respectively, positive affectivity (2.17+/-1.60 vs. 2.91+/-1.50) score decreased 25.43%, the differences were statistical significant (P<0.001) . In general, scores varies in factors related to occupational stress among freight train engine drivers were larger than those among passenger train engine drivers. The risk factor of job dissatisfaction among passenger train drivers in 1996 was insufficient superior support (OR=3.77, 95%CI: 2.23-6.37) , the risk factors in 2012 were insufficient superior support (OR=3.35, 95%CI:1.56 7.17) , poor physical environment (OR=3.61, 95%CI: 1.91-6.80), and fewer positive affectivity (OR=3.47, 95%CI: 1.75-6.82). The risk factor of job dissatisfaction among freight train drivers in 1996 and in 2012 were insufficient superior support (OR (95%CI) were 3.11 (2.31-4.19), 2.59 (1.84-3.65) , respectively). Conclusion: The level of occupational stress among train engine drivers in 2012 was larger than that in 1996, the level of occupational stress among freight train drivers was larger than passenger train drivers, the interventions aimed at reducing occupational stress in the Chinese train engine drivers should take into account promotion for design of job organization and contents and organization management style. PMID- 29996299 TI - [Survey of the depressive disorders prevalence and related risk factors among male new drug users in certain drug rehabilitation center of Changsha city]. AB - Objective: To understand the depressive disorders prevalence and related risk factors among new drug users in a male drug rehabilitation center. Methods: The cross-sectional study was used. A total of 250 new drug users from a male drug rehabilitation center were recruited during March, 2017. The drug users who only use new type of drugs single or use traditional drugs at the same time were collected as the new drug users. Their general information and drug-related information were collected by self-made questionnaire, and depressive disorders and sleep quality information were collected by the self-reported Patient Health Questionnaire-9 (PHQ-9) and the self-reported Pittsburgh Sleep Quality Index Questionnaire respectively. Logistic regression test was used to establish associations between variables. Results: Of all 250 drug users, the mean age (P(25), P(75)) was 30 (26, 35) years old, and 32.8% (82) had the depressive disorders. The individuals taking drug dose over 0.4 g daily before entering drug rehabilitation center had significantly more risk of the depressive disorders for 3.18 (1.71-5.90) than those not over 0.4 g daily.The individuals who bad sleep quality had significantly more risk of the depressive disorders for 6.07 (95%CI:3.31-11.12) than those had good sleep quality.The individuals who were depressive patients before the first drug use for 2.39 (95%CI: 1.12-5.10) than those were not depressive patients before the first drug use. Conclusion: There were a high rate of the depressive disorders among new drug users in the rehabilitation center; In addition, several risk factors including the individuals taking drug dose over 0.4 g daily and bad sleep quality, history of the depressive disorders were negatively associated with depressive disorders. PMID- 29996300 TI - [Epidemiological characteristics and risk factors of primary intussusception in children among two years old and below, Ji'nan city]. AB - Objective: To study the epidemiological characters and risk factors of primary intussusception among children who were <=2 years old in Jinan city. Methods: A retrospective study was also applied to collect the disease information of inpatient cases through hospital information system of inpatient during 2011 and 2015. The attack rate (AR) was calculated in total and each year, respectively. 1?(1) matched pared case-control study was conducted to explore the risk factors of primary intussusception. A total of new confirmed 93 residential cases were enrolled with <=2 years old, diagnosed as primary intussusception or diseases coded as K56.1 according to the International Classification of Diseases, tenth version (ICD-10), and without any other reason for organic lesions. The 93 patients without primary intussusception inpatients were selected from the same hospital and departments as the controls, and matched with the cases as the same gender, +/-3 months old, and disease onset within 7 days, visiting the hospital during January 1, 2016 and June 30, 2016. Clinical and epidemiological information was collected both from cases and controls. The difference of AR among different years was compared by Trend Chi-squiare test, and difference between gender, month old and regions was compared by Chi-squiare test, respectively. Multiple-variables factor analysis was applied to analysis the risk factors of cases compared with controls by conditional logistic regression model. Results: A total of 574 cases were found and the overall AR was 86.3 per 100 000. A significant decreasing trend (chi(2trend)=23.43, P<0.001) of AR was showed between 2011 and 2015, with the highest AR in 2011 (117.6 per 100 000), and the lower AR in 2014 (66.0 per 100 000). The lowest AR was also observed in male (106.9 per 100 000) compared with the female (63.2 per 100 000) (chi(2)=13.76, P<0.001), and in <=12 months old (102.1 per 100 000) compared with the >12 months old (70.4 per 100 000) (chi(2)=19.46, P<0.001). The higher proportion of 57.1% (328/574) was found in 4-12 months old cases. The cases with an overweight before illness (OR=4.98, 95%CI: 1.27-19.50), with mixed feeding of breast-milk and milk powder (OR=16.90, 95%CI: 5.25-54.20), and with instruction of solid food before 6 months old (OR=16.50, 95%CI: 1.91-143.10) could increase the risk of illness compared with keeping a healthy weight, breast feeding, and instruction of solid food after 6 months old, separately. Conclusion: A higher attack rate of primary intussusception in children with a <=2 years old in Jinan was observed. Male and 4-12 months group had a higher risk. Body weight, breast feeding, and the instruction of solid food before and after 6 months old were related to the risk of primary intussusception among children who were <=2 years old. PMID- 29996301 TI - [Current status of malaria rapid diagnostic testing strips application in primary level healthcare providers in Jiangsu Province]. AB - Objective: To investigate the current status of malaria rapid diagnostic test (RDT) strips application and malaria laboratory technicians' evaluation about them at primary healthcare provider level in Jiangsu Province. Methods: From November to December 2016, 878 medical institutions and 118 CDCs of city, county and township/community level in Jiangsu Province were selected as study samples using stratified random sampling method. Self-designed questionnaire was distributed to investigate the institution's malaria work task, RDT strips application and evaluation status in 2015. We also investigated the socio demographic information and collected the RDT strips evaluation score from the malaria laboratory technicians selected from the institutions investigated (one technician from each institution). Rank sum test was performed to compare the RDT strips evaluation scores between medical institutions and CDCs, and among different medical institutions and CDCs. Results: In 2015, 405 cases of malaria were reported, 362 200 person-time of malaria blood testing task was conducted, and 100 000 RDT strips were procured and provided for healthcare providers in Jiangsu province for free. Of the 996 healthcare institutions investigated, 628 used RDT strips in the year 2015 and the median (P(25), P(75)) of RDT strips volume used in these institutions was 10 (2, 25). The volume of RDT strips used in CDCs (15 (5, 52)) was significantly higher than that in medical institutions (10 (2, 25), (Z=3.42, P=0.001)). The investigated CDCs gave higher score on RDT strips' testing time per operation (10 (8.5, 10)) than medical institutions (9(8, 10), (Z=-2.20, P=0.028)). The employers of 614 investigated malaria laboratory technicians used RDT strips in 2015. The median of the scores given by CDC malaria laboratory technicians for RDT strips in terms of testing time per operation, testing operation and results judgement difficulties were 10 (9, 10), 10 (9, 10) and 10 (9, 10), respectively, which were significantly higher than those from technicians of medical institutions (9 (8, 10), 9 (8, 10), 9 (8, 10), (Z values were -2.55, -2.97 and -2.96, respectively; P values were all less than 0.05)). Conclusion: RDT strips had been widely performed in health institutions in Jiangsu Province. The amount of RDT strips used in CDCs was significantly higher than that in medical institutions. Primary-level institutions and malaria laboratory technicians generally recognized RDT strips' advantage for application in terms of testing time and operational procedure. CDCs and malaria laboratory technicians from them gave higher regards on RDT strips in terms of testing time per operation, testing operation and results judgement difficulties compared with that of medical institutions. PMID- 29996302 TI - [Analysis on epidemiological characteristics of enterovirus 71 cases of hand-foot mouth disease based on the active monitoring in Guangdong Province in 2011-2015]. AB - Objective: To analyze the hand-foot-mouth disease (HFMD) enterovirus 71 (EV-A71) infection epidemic characteristics of Guangdong Province from 2011 to 2015. Methods: We colleted data on common cases of hand-foot-mouth disease infected with EV-A71 reported from eight sentinel hospitals in Guangdong Province from January 2011 to December 2015, through the "Guangdong Province Acute Infectious Disease Surveillance Information Platform System" , including the age and incidence of cases. Time and etiological data, etc.We also collected data on the number of reported cases of HFMD disease and the number of laboratory-confirmed cases, through the "China Disease Prevention and Control Information System" , including data on common cases of HFMD disease, data on epidemics of severe cases and deaths, and the age, onset time, and pathogens of cases. Learning data, etc.The data from two sources were used to estimate the incidence of HFMD in EV A71 and describe its distribution characteristics.Chi-square test was used to compare the positive rate of HF-A71 infection in hand-foot-mouth disease and the difference in estimated incidence among different age groups and months. Results: Eight sentinel hospitals from 2011 to 2015 reported a total of 1 855 common cases of EV-A71 infection, of which the highest was in 2014 (31.6%, 605/1 916) and the lowest was in 2015 (6.8%, 134/1 971) (chi(2)=521.85, P<0.001).According to the Disease Surveillance Reporting Information System, 1 772 516 cases of HFMD disease were reported from 2011 to 2015 in Guangdong Province, and 1 902 cases of severe and fatal cases of EV-A71 infection.The composition ratio of EV-A71 infected was 72.6% (1 775/2 444) and 97.0% (127/131) of severe HFMD disease in Guangdong province during 2011-2015.The average annual incidence of HF-A71 infection in all age groups showed a decreasing trend with age (chi(2trend)=990 273.20, P<0.001), and it was the highest in the 1-year-old group, which was 1 697.67/100 000, and the lowest in the 4-year-old group, which was 705.46/100 000. The difference of monthly average incidence of EV-A71 infection in HF-A71 in each month was statistically significant (chi(2)=401.23, P<0.001), the highest in May at 15.51 per 100 000, and the lowest in July at 9.42 per 100 000. Conclusion: EV A71 infection rate of ordinary HFMD varies in different years. The most severe and death cases of HFMD were EV-A71 infected. 1 year old children were the high risk group of infected with EV-A71 HFMD. April was the epidemic months of EV-A71 HFMD infection. PMID- 29996303 TI - [Economic evaluation and prediction of hepatitis B immunization strategy in Shenzhen, China]. AB - Objective: To verify the costs, benefit and effectiveness of hepatitis B immunoprophylaxis strategies in Shenzhen during 2006-2030. Methods: The markov model was constructed to reflect the reality of the newborn vaccination and prevention of mother to child transmission (PMTCT) strategy, the cost, benefit and effectiveness during 2006-2015 and 2016-2030 was evaluated and predicted by the model. The model was constructed with the basic parameters such as the positive rate of hepatitis B surface antibody, perinatal HBV infection rate, the screening rate and positive rate of HBsAg of pregnant women, the utility value of hepatitis B and the parameters of markov model. and the coverage rates, vaccination fee of hepatitis B and the expenditures of patients with HB-related diseases.The costs were calculated from the payer, medical-care and all society perspective. The effectiveness and benefits of the strategy were evaluated and predicted by the numbers of HBV infection and the patients with HBV-related diseases prevented, life years (LYs), quality adjusted life years (QALYs), the net benefits (NBs) and benefit cost ratio (BCRs). Results: From the payer, medical-care and all society perspectives, the costs for the strategy were 153 million Yuan, 5.51 billion Yuan and 10.92 billion Yuan, respectively from 2006 to 2030 of which the forecast costs for 2016-2030 were 120 million Yuan, 3.87 billion yuan and 7.81 billion yuan. During the year 2006-2030, the numbers of HBV infection and the HBV-related diseases was 2.48 million, more than 1.335 million LYs and 1.619 million QALYs should be obtained from the strategy implemented. From medical-care and all society perspectives, NBs should be 88.68 billion yuan and 150.13 billion yuan with the BCRs of 17.08 and 14.75, respectively. Particularly, the NBs value of 22.37 billion yuan and 37.98 billion yuan and the BCR value of 14.62 and 13.20 was calculated for the past period, but the future NBs of 66.31 billion yuan and 112.15 billion yuan and BCR of 18.12 and 15.36 in the year 2016-2030. The further benefits were increased evidently in the future. Conclusion: The hepatitis B immunization in Shenzhen has a high economic effectivenee and benefits, and it is worth to invest sustainably. PMID- 29996304 TI - [The risk of hepatitis B virus infection in people with diabetes mellitus: a meta analysis]. AB - Objective: To evaluate the relevance of diabetes mellitus and hepatitis B virus(HBV) infection in people by Meta-analysis. Methods: Databases we searched included CNKI, VIP China Science and Technology Journal Database, Wanfang Data Knowledge Service Platform, PubMed, Cochrane Library and Web of Science Core Collection database. Publication time was from January 1997 to May 2017. The Languages were limited to Chinese and English. English search terms include: diabetes, diabetes mellitus, hepatitis B and risk. Chinese search terms include: diabetes mellitus, hepatitis B and risk. We included all observational studies on diabetes and HBV infection. Firstly, the Newcastle-Ottawa Scale and the evaluation criteria of Cross-sectional study recommended by Agency for Healthcare Research and Quality were used to evaluate the quality of articles. Secondly, RevMan 5.3 software was used for heterogeneity testing. Subgroup analysis, random effects model and Mantel-Haenszel method were used to calculate the combined OR value. Finally, Stata 14.0 software was used to conduct the sensitivity analysis, and Begg rank correlation method was used to detect the publication bias. Results: A total of 12 studies were included, comprising 6 cross-sectional studies and 6 case-control studies. But the 12 articles were heterogeneous (chi(2)=42.10, P<0.001). After subgroup analysis, cross-sectional studies of diabetes and HBV infection were still heterogeneous (chi(2)=28.21, P<0.001), whose combined odds ratio (OR) was 1.36 (95%CI: 1.03-1.80). But the heterogeneity of case-control studies was not statistically significant (chi(2)=10.32, P=0.070), whose combined odds ratio (OR) was 1.55 (95%CI: 1.10-2.17). After the sensitivity analysis, the 95%CI of the combined OR of the 7 studies did not fluctuate, and the lower limit was above 1.07. No publication bias was detected in the cross-sectional study subgroup (Z=1.35, P=0.176) and the case-control study subgroup (Z=1.69, P=0.091). Conclusion: Patients with diabetes are more likely to be infected with HBV than those without diabetes. Diabetes mellitus is likely to be a risk factor for HBV infection. PMID- 29996305 TI - [Prevalence of brucellosis in Tibet from 1964 to 2016]. PMID- 29996306 TI - [Analysis of the epidemiological characteristics and its burden of disease for inpatient cases of injury from 2014 to 2015 inpatient cases of injury, China]. PMID- 29996307 TI - [Progress on salt reduction and prevention of chronic non-communicable disease]. AB - Salt reduction is one of the effective strategy for chronic non-communicable disease control and prevention recommended by World Health Organization. Research evidences on salt reduction emerge recently and some issues remain controversial. With the aim of providing reference for the future salt reduction action, this article reviewed the current evidence and strategies on the source of salt intake, the relationship between salt and health, the cost-effectiveness of salt reduction, as well as the targets and strategies of salt reduction. It also elaborated the main controversial issues in salt reduction, including salt reduction in population, evaluation method of salt intake, substitute salt, iodine intake, and the effectiveness of salt reduction strategy. The international and internal salt reduction activities were introduced as well. PMID- 29996308 TI - [Research progress in immunization status and immunization effect of preterm infants]. AB - Due to immature development of the immune system, preterm infants are at increased risk of infections from vaccine-preventable diseases. But at the same time, premature vaccination may not induce a good immune response because of the incomplete development of the neonatal immune system, and may cause serious adverse reactions risk due to the poor immune tolerance, thus vaccination of preterm infants at the appropriate time is the key to reducing the risk of infectious disease and obtaining vaccine protection. At present, it is generally recommended that the gestational age and birth weight should be considered in the vaccination of preterm infants. The timing, type and even the immunization schedule of the vaccine should be differ from that of the full term infants. However, there is a lack of research results and data on immunization program in preterm infants in China, and there is still no provided universal guidelines for their vaccine immunization. This article aims to summarize the guidelines and clinical trials of vaccination of preterm infants in foreign countries, and to provide reference for the formulation and implementation of immunization strategies for preterm infants in China. PMID- 29996309 TI - [Analysis of funding of projects on occupational diseases and occupational health by National Natural Science Foundation of China]. PMID- 29996310 TI - [The precise pathologic diagnosis of gastric cancer: some significant issues in clinical practice]. PMID- 29996311 TI - [Clinicopathologic features of gastric adenocarcinoma based on the revised Lauren's classification]. AB - Objective: To compare the clinicopathologic features and prognosis of the subtypes in a consecutive series of gastric cancers (GC) patients basing on the revised Lauren's classification so as to better understand the biological behavior of GC. Methods: The surgically resected GC from Peking Union Medical College Hospital during 2003-2005 were reviewed for patients' age, gender, tumor size, location, Borrman classification, depth of invasion, lymph node metastasis, vascular invasion, and tumor growth pattern (Ming classification). Results: One hundred and sixty-six GC cases were enrolled and classified into four groups: intestinal GC (30, 18.1%), diffuse GC (56, 33.7%), solid GC (9, 5.4%), and mixed GC (71, 42.8%). Intestinal GC patients were older[ (63.2+/-11.3) years], with a male predominance, and were more frequently found in the antrum. Intestinal GC was the most common subtype for early GC, and tend to develop liver metastases. Diffuse GC patients were youngest [(52.2+/-12.7) years], with no gender difference, and were usually found in the antrum. Microscopically, diffuse GC were more likely infiltrative (51/56, 91.1%), and tended to metastasize by lymphatic pathway. Solid GC were usually large[ (6.4+/-2.2) cm], with a male predominance, and the most frequent site was the body/fundus. Solid GC were more likely to show expansile growth pattern with greater depth of invasion (8 of 9 cases were T3/4), but lower rate of lymphatic metastasis. Mixed GC also showed a male predominance, usually found in the antrum, and showed an infiltrative growth pattern (49/71, 69.0%). Though there was fewer T3/4 than solid and diffuse GC, mixed GC were more likely to show lymph nodes, vascular metastases and liver metastases (13/71, 18.3%). TNM staging, lymph nodes metastasis, lymphovascular invasion and revised Lauren's classification were four independent prognostic factors on multivariate analysis(P<0.05). The survival of patients with mixed GC were significantly worse than patients with other histological types. Conclusion: Revised Lauren's classification for GC has four distinct subgroups and can be used as independent prognostic factors. PMID- 29996312 TI - [Polymorphisms of mTORC1 genes and risk of primary colorectal adenocarcinoma in Chinese populations]. AB - Objective: To study the associations between variants of mTORC1 of PI3K/AKT/mTOR pathway and colorectal cancer. Methods: In this hospital-based case-control study, at the First Affiliated Hospital, Xinjiang Medical University from 2000 to 2013, 665 primary colorectal cancer cases and 695 cancer-free controls were genotyped at 10 potentially functional single nucleotide polymorphism (SNPs) loci of mTORC1 (mTOR: rs1034528, rs2295080; Raptor: rs1062935, rs3751934; mLST8: rs3160, rs26865; DEPTOR: rs2271900, rs4871827; AKT1S1: rs2290774, rs2353005) to assess their associations with risk of colorectal cancer by Logistic regression analysis. Results: In single-locus analysis, found a significantly decreased risk of colorectal cancer associated with mLST8 rs26865 by recessive genetic model, especially in populations of <=68 years of age (OR=0.64; 95%CI=0.43-0.96, P=0.031), female (OR=0.61; 95%CI=0.38-0.99, P=0.046), non-smoking (OR=0.55; 95%CI=0.35-0.87, P=0.010). mTOR rs1034528 CC genotypes were associated with higher risk of colorectal cancer in >68-year-old populations (OR=3.34; 95%CI=1.12 9.91, P=0.030). Raptor rs3751934 CA/AA genotypes were associated with lower colorectal cancer risk in population of body mass index(BMI)>25 kg/m(2) (OR=0.68; 95%CI=0.47-0.98, P=0.038); and AKT1S1 rs2290774 CC genotypes were associated with lower colorectal cancer risk in non-smoking population (OR=0.67; 95%CI=0.45-0.99, P=0.048). Furthermore, found that populations carrying more than two low-risk genotypes were associated with lower colorectal cancer risk, compared with that of populations carrying less than two low-risk genotypes (OR=0.74, 95%CI=0.58 0.95, P=0.017), especially in population of <=68 years of age, male and BMI>25 kg/m(2,) and non-smoking. Conclusions: SNPs of mTORC1-related genes individually or jointly contribute to colorectal cancer susceptibility in Chinese. Further studies of larger cohorts are needed to validate the findings. PMID- 29996313 TI - [Feasibility of amplicon-based targeted next-generation sequencing of colorectal cancer in endoscopic biopsies]. AB - Objective: To investigate whether small endoscopic biopsies of colorectal cancer were sufficient for quality and accurate mutational analysis by amplicon-based next-generation sequencing (NGS). Methods: By using an amplicon-based targeted NGS panel for mutational detection on Illumina Miseq platform, a total of 109 formalin-fixed and paraffin-embedded (FFPE) endoscopic biopsies of colorectal cancer were retrospectively selected, based on specific histopathologic criteria, from January 2012 to June 2016 at West China Hospital of Sichuan University and Peking University Third Hospital. Twelve of these biopsies had corresponding FFPE surgical resection specimens. Quality control parameters of NGS testing were analyzed and NGS results were confirmed by other methods. Mutation calls of the 12 paired endoscopic biopsies and surgical resections were compared. Results: Of the endoscopic biopsy specimens, 97.2% (106/109) had sufficient DNA and qualified sequencing library. NGS generated excellent sequencing data, with a median of 848* for median read depth and 95.7% for uniformity. The success rate of NGS was 95.4% (104/109). Conventional methods confirmed the results of NGS for KRAS and BRAF, and the concordance rate was 100.0%. The clinically actionable mutations detected in the 12 paired endoscopic biopsies and surgical resections were concordant. Conclusion: FFPE endoscopic biopsies of colorectal cancer is suitable for targeted NGS, providing quality sequencing data and accurate mutational information to guide targeted therapy. PMID- 29996314 TI - [Clinicopathologic and molecular characterizations of Sertoli cell tumor, not otherwise specified of the testis]. AB - Objective: To investigate the histomorpholgic spectrum, immunophenotypic, and molecular genetic features of Sertoli cell tumor, not otherwise specified (SCT, NOS) of the testis. Methods: Seven cases of SCT, NOS of the testis were analyzed(4 from Peking University Third Hospital and 3 from Zhejiang Provincial People's Hospital) between 2008 and 2017. The histopathologic features were examined based on HE staining, and EnVision method was used for immunohistochemistry staining of calretinin, inhibin, beta-catenin, cyclinD1, CD10, CKpan, neuroendocrine markers, WT1, Melan A, vimentin, SALL4, GATA3, PAX8, and S-100 protein. Mutational analysis of exon 3 of the CTNNB1 gene by polymerase chain reaction (PCR)-amplified sequences and direct sequencing was performed. Results: Patients ages ranged from 22 to 65 years (mean 43 years). The clinical manifestation in all was a slowly enlarging, painless testicular mass.The maximum diameter of the tumor ranged from 1.5 cm to 3.0 cm (mean 2.1 cm). Sectioning usually disclosed a tan-gray to white mass with vague lobular cut-surface. Microscopically, the tumors were well circumscribed and non-encapsulated; the tumor cells were rearranged in multiple growth patterns from diffuse solid sheets to trabeculae and cords, ribbon and solid or hollow tubules setting in variable amount of acellular fibrous stroma. Two cases showed acellular collagenous stroma constituted >50% of the tumor confirming to the diagnosis of sclerosing SCT. One case demonstrated a prominent myxoid stromal change. The tumor cells typically had moderate amounts of pale to lightly eosinophilic cytoplasm, 2 tumors had variable cells with abundant lipid-rich cytoplasm, and 1 other tumor showed scattered aggregates of multinucleated tumor cells. The tumor cells were bland appearing without any evidence of atypia, mitoses were noted in 2 tumors (both were 1/50 HPF), but necrosis was absent. Immunohistochemical staining results as follows: vimentin (diffuse, 7/7), CD10 (diffuse membrane, 7/7); diffuse beta catenin nuclear and cytoplasm staining in 5 of 7 cases, and all the 5 cases showed diffuse cyclin D1 nuclear staining, beta-catenin membrane staining in 2 of 7 cases, CKpan (5/7, focal or diffuse), calretinin (focal, 5/6), inhibin (focal, 3/7), synaptophysin (focal, 2/6), CD56 (focal or diffuse, 4/5), WT1 (diffuse nuclear, 4/5), and S-100 protein (diffuse, 3/7), and chromogranin A, Melan A, PAX8, GATA3 and SALL4 all were negative. Molecular genetic studies of PCR and direct sequencing showed CTNNB1 mutations in 4 of 7 (4/7) cases, 4 of the four mutation-carrying cases showed diffuse beta-catenin nuclear and cytoplasm immunoreactivity and diffuse cyclin D1 nuclear immunoreactivity in the tumor cells. Conclusions: SCT, NOS of the testis typically shows significant heterogeneities in both morphology and immunohistochemistry, thus causing differential diagnostic confusions. Molecular analyses showed mutations of exon 3 of CTNNB1 in more than half of these tumors, and nuclear accumulation of beta catenin and over expression of cyclin D1 can be useful for the differential diagnosis of SCT, NOS. PMID- 29996315 TI - [Dedifferentiated liposarcoma of extremities: a clinicopathologic analysis]. AB - Objective: To study the clinicopathologic features of dedifferentiated liposarcoma of extremities. Methods: Nine cases of dedifferentiated liposarcoma of extremities diagnosed at Beijing Jishuitan Hospital from 2009 to 2017 were selected. The histological features of cases of dedifferentiated liposarcoma of extremities were evaluated by HE and immunohistochemistry, together with the clinical and radiological features. Flourescence in situ hybridization(FISH) was used to detect MDM2 amplification. Results: They were located in the thigh (6 cases), calf (2 cases) and buttock (1 case). There were six females and three males. Patients' age ranged from 61 to 79 years (mean 68 years). Histologically, there were two components, well-differentiated liposarcoma and dedifferentiated sarcoma with or without transitional lesions between them. The histology of dedifferentiated liposarcoma included undifferentiated sarcoma and fibrosarcoma. Heterologous elements such as bone and cartilage were present in two cases. Immunohistochemical study showed the tumor cells expressed vimentin, CDK4 and p16. MDM2 were positive in 6 cases (6/9) and p53 was positive in one case(1/9). CKpan was positive in the epithelioid differentiation area. S-100 protein was positive in the well-differentiated liposarcoma component. FISH showed the amplification of MDM2(6/9). Conclusions: Dedifferentiated liposarcoma of extremities is very rare. The diagnosis should be combined with the histological characteristics and immunohistochemical results and differentiated from the other tumors and tumor-like lesions. PMID- 29996316 TI - [Clinicopathologic analysis of primary carcinoid of the ovary]. AB - Objective: To describe the clinicopathologic features, diagnosis and differential diagnosis of ovarian carcinoid tumors. Methods: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumors at Fudan University Shanghai Cancer Centre from 2007 to 2017. Results: The histologic analysis of these carcinoid tumors revealed 3 were insular, 1 was trabecular, 1 was mucinous, and 10 were strumal. Histologic features of insular and trabecular carcinoid were similar to other parts of the neuroendocrine tumor. Strumal carcinoid was composed of thyroid tissue intimately admixed with carcinoid tumor, showing trabecular pattern. Mucinous carcinoid was resembles Krukenberg tumor. Most ovarian carcinoid tomours were diffusely positive with at least one neuroendocrine marker, especially synaptophysin (14/14) and CD56(9/10). The median follow-up time was 53 months, 1 patient with squamous-cell carcinoma of cervixrecur rence in vaginal after 37 months, and only 1 patient died of disease. The remaining patients were disease-free survival. Conclusions: Primary carcinoid of the ovary is a very rare low grade malignant monodermal teratomas and somatic-type tumours arising from a dermoid. The diagnosis and differential diagnosis mainly relies on the histopathologic characteristics and the immuno phenotype. Primary ovarian carcinoid almost always exhibit a benign clinical behavious except mucinous carcinoid. PMID- 29996317 TI - [HER2 gene status and mRNA expression in immunohistochemistry 1+ breast cancer]. AB - Objective: To investigate human epidermal growth factor 2 (HER2) gene status and in situ mRNA expression in breast cancers with immunohistochemistry(IHC) 1+ , and to reveal HER2 positive rate in these patients to provide reference data for obtaining precise HER2 results and modifying relevant clinical strategy to breast cancer. Methods: Sixty-five IHC 1+ formalin-fixed and paraffin-embedded samples of invasive breast carcinoma of no special type (IBC-NST) were collected by surgical operation at Peking Union Medical College Hospital during 2011 to 2013. HER2 status and in situ mRNA expression were tested by fluorescence in situ hybridization (FISH) and RNAscope, respectively, by using tissue microarray. Metastatic lymph node was re-tested by FISH if HER2 status was equivocal or negative and with high expression of mRNA in the primary lesion. Results: Four of 65 samples (6.2%) were FISH positive, which included 2 cases of HER2/CEP17>2 and average HER2 copy number>4 and 2 cases of HER2/CEP17<2 and average HER2 copy number>6. In the 4 samples of HER2 positive, 2 patients showed high in situ mRNA expression (3 scores by RNAscope), 2 patients showed moderate in situ mRNA expression (2 scores by RNAscope). In addition, 3 specimens with HER2/CEP17>2 and average HER2 copy number<4 were found in all patients, which included 2 cases of high in situ mRNA expression (3 and 4 scores by RNAscope) and 1 cases of moderate in situ mRNA expression (2 scores by RNAscope). There was no significant association between HER2 status or mRNA expression and clinicopathological characteristics, including tumor size, histopathological differentiation, lymph node metastasis and lymphovascular invasion (P>0.05). Conclusions: A small number of HER2 IHC 1+ patients exist mRNA expression by using FISH method, which suggested that these patients might benefit from anti-HER2 therapy potentially. Since the importance for patients with breast cancers to develop diagnostic and therapeutic strategies from accurate molecular typing, further studies based on a larger cohort are needed to validate our findings. PMID- 29996318 TI - [Clinicopathologic features of myxoid adrenocortical adenomas]. AB - Objective: To study the clinicopathologic characteristics, immunophenotype, pathologic diagnosis and differential diagnosis of myxoid adrenocortical adenomas. Methods: The clinical data, histological features and immunohistochemical results of 4 cases of myxoid adrenocortical adenomas were analyzed, which were collected from January 2014 to December 2016 at Guangdong General Hospital, with review of literature. Results: Four cases of myxoid adrenocortical adenomas were presented. The patients ages ranged from 26 to 45 years (mean =35 years). Microscopically, it showed a typical morphology, characterized by small-sized tumor cell cords or pseudo-glands embedded in an abundant extracellular myxoid matrix. Immunohistochemical staining showed tumor cells were strongly positive for Melan A, vimentin and focally for alpha-inhibin, one case showed strong and diffuse positivity for CAM5.2, and two cases showed diffuse positivity for synaptophysin, while negative for CgA, S-100 protein, epithelial antigen, CK7, CK20 and CKpan. Conclusions: Myxoid adrenocortical adenomas are extremely rare, which may cause confusion with metastatic well differentiated neuroendocrine tumours, sex cord-stromal tumoursor metanephric adenoma. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis, and unnecessary treatment. PMID- 29996319 TI - [Pathologic features on gonadal changes of sexual developmental disorders in children]. AB - Objective: To investigate the pathologic features of gonadal tissues of disorders of sexual development (DSD) in children. Methods: Fifty-three cases of gonadal developmental disorders were collected from July 2015 to August 2017 at Guangzhou Women and Children's Medical Center. Clinical manifestations, karyotypes, sex hormone levels, ultrasound imaging, histology and immunophenotype of gonadal tissues were analyzed. Results: The age of patients ranged from 7 months to 17 years with an average of (50.7 +/- 47.1) months. Social genders of the patients included 32 males and 21 females. Forty-eight patients had abnormal sex hormone levels. Clinical presentations included: toward female genitalia in 25 cases, male genitalia tendency in 17 cases and ambiguous external genitalia in 11 cases. Hypospadias was seen in 31 cases and short stature was seen in 8 cases. Chromosomal karyotyping of peripheral blood revealed 23 cases of sex chromosome disorders, 22 cases of 46 XY disorders, of which 3 cases were 5alpha-reductase deficiency and 8 cases of 46 XX disorders. Ultrasound examination showed cryptorchidism in 30 cases, including 16 cases of unilateral, 14 cases of bilateral and 1 case presenting a huge pelvic tumor. A total of 97 gonadal tissues from 53 cases of DSD were examined, including 9 cases of unilateral and 44 cases of bilateral gonads. Microscopically, 55 gonads (56.7%) showed dysplastic testes including 17 unilateral and 19 bilateral gonads. Fourteen were streak gonads (14.4%) including 8 unilateral and 3 bilateral gonadal tissues. Nine streak gonad with epithelial cord-like structures (9.3%) were found, of which 5 were unilateral and 2 were bilateral lesions. Seven gonads were ovotestis (7.2%), unilateral in 5 cases (the other side of the gonads of ovary in 4 cases, 1 case of dysplastic testes) and bilateral in 1 case. Seven gonads showed follicular-rich ovarian tissue (7.2%). One case showed bilateral dysplastic testes with gonadoblastoma and ectopic adrenal cortex. One case of streak gonad showed epithelial cord-like structures and undifferentiated glandular tissue embedded in malignant mixed germ cell tumors (mixed gonadoblastoma, dysgerminoma, mature teratoma and yolk sac tumor). One case had testicular microlithiasis. Uterus and fallopian tube structures were found in 11 cases. Immunohistochemical stains were performed in 15 cases. D2-40, PLAP and CKIT were expressed in germ cells and Calretinin, WT1 and inhibin were positive in Setoli cells. SALL4 and OCT3/4 were positive in 3 cases. Inhibin highlighted interstitial Leydig cells in 2 cases. GPC3 was positive in yolk sac tumor component. Conclusions: Gonadal dysgenesis presents a broad spectrum of gonadal phenotypes with variable degrees of differentiation. The development of bilateral gonadal tissues has certain variability. Chromosomal karyotypes have no correlation with gonadal phenotypes. Accurate histopathologic diagnosis of gonadal dysgenesis plays an important role in the treatment and prognosis of the patient. PMID- 29996321 TI - [Expression of HMGB1 and RAGE protein in gastric cancer and its prognostic significance]. PMID- 29996320 TI - [Clinicopathologic characterization of malignant mixed tumor of the skin accompanied by eccrine porocarcinoma]. AB - Objective: To investigate the clinicopathologic features, immunophenotype, pathological diagnosis and treatment of malignant mixed tumor (MMT). Methods: Clinical and pathological features including immunohistochemical phenotypes were analyzed in a case of MMT accompanied with eccrine porocarcinoma (EP) involving both hands, diagnosed definitely in January 2018 along with review of relevant literature. Results: A 64-year-old man presented with multiple rash on both hands for 4 years. Three lesions of 0.5 to 2.2 cm were removed for pathological evaluation. The pathological changes on little finger of left and right hands were MMT with EP, whereas that removed from the right ring finger was EP. MMT showed infiltrative growth with vascular wall invasion and consisted of epithelial (glandular or tube differentiation) and mesenchymal components (mucinous and/or cartilage stroma). The endothelial cells showed moderate to severe cytological atypia, nuclear pleomorphism and increased mitotic activity. The glandular component had histological characteristics of syringocarcinoma with moderately atypical chondrocytes but without myoepithelium. EP was composed of basal cells with visible vacuoles in cytoplasm and the presence of tubular and squamous differentiation, along with obvious atypia. Immunohistochemically cavosurface epithelium of glandular differentiation of MMT showed positivity for CK7, EMA and CD117. Myoepithelium showed S-100, CK5/6 and p63 positivity and stromal cells were positive for S-100. Differential diagnoses included metaplastic carcinoma, malignant myoepithelioma and atypical mixed tumor of skin. Conclusions: MMT with EP is extremely rare.The diagnosis of MMT depends on the morphologic features. Immunohistochemical staining is helpful for differential diagnosis. Surgical excision with safety margins is the treatment of choice. Complementary radiotherapy and/or chemotherapy is still controversial. The clinical course of MMT is deemed unpredictable and long-term follow-up is necessary. PMID- 29996322 TI - [Clinicopathologic features of gastric glomus tumor]. PMID- 29996324 TI - [Primary malignant melanoma of esophagea]. PMID- 29996323 TI - [Clinicopathologic and genetic features analysis of oral and maxillofacial metastatic carcinoma]. PMID- 29996325 TI - [Diffuse intestinal ganglioneuromatosis with neurofibromatosis: report of a case]. PMID- 29996326 TI - [Sclerosing angiomatoid nodular transformation of the spleen with serous microcystic adenoma of pancreas: report of a case]. PMID- 29996327 TI - [Nuchal fibrocartilaginous pseudotumor: report of a case]. PMID- 29996328 TI - [Primary retroperitoneal Castleman disease complicated with follicular dendritic cell sarcoma:report of a case]. PMID- 29996330 TI - [Application of big data in tumor molecular pathologic diagnosis]. PMID- 29996329 TI - [Progress in immunohistochemistry markers of digestive system cancers]. PMID- 29996331 TI - [Cirrhotic portal hypertension in the non-invasive era: what we grasp]. AB - The non-invasive era of portal hypertension in cirrhosis is approaching. We should seize the opportunity: then do learn to follow the recommended international guidelines for emerging non-invasive technologies and systematically utilize case resources of our country's for clinical verification; Secondly, we should pay attention to the cross-theory innovation of the middle level discipline in the process of technology development, and standardize the design and clinical registration in accordance with international diagnostic testing standards; Finally, a non-invasive technique for the treatment of cirrhotic portal hypertension was developed with a developmental perspective, enabling the transition from disease diagnosis and risk stratification to efficacy monitoring and prognosis prediction. PMID- 29996332 TI - [An evidence-based terlipressin therapy for gastroesophageal variceal hemorrhage]. AB - Gastroesophageal variceal bleeding is one of the major complications of cirrhosis and also the leading causes of death in patients with decompensated cirrhosis. Terlipressin is a triglycyl-lysine vasopressin, a synthetic vasopressin analogue that is mainly used for the treatment of acute variceal hemorrhage. This article aims to review the current status of treatment of gastroesophageal variceal bleeding with terlipressin from the perspective of evidence-based medicine. PMID- 29996333 TI - [Current status and prospects of integrated traditional Chinese and Western medicine for treatment of portal hypertension]. AB - Portal hypertension refers to a series of clinical manifestations caused by elevated pressure of the portal vein system, which can cause portal hypertension by causing portal venous obstruction and / or increased blood flow. A typical clinical manifestation in patients with decompensated cirrhosis is portal hypertension. A severe complication of portal hypertension is esophagogastric varices bleeding, refractory ascites, and hepatic encephalopathy. The effective reduction of portal pressure can reduce the incidence of complications, improve the prognosis and reduce the mortality. At present, the commonly used clinical methods for reducing portal hypertension include drug therapy, minimally invasive interventions, surgical treatment, and liver transplantation. This article reviews the current status of integrated traditional Chinese and Western medicine for portal hypertension. PMID- 29996334 TI - [Strategy for diagnosis and precise treatment of portal hypertension with hepatic venous pressure gradient: a dream or a reality?] AB - Liver fibrosis and cirrhosis, is a chronic, occult progression that is potentially reversible and complicated. The hepatic venous pressure gradient is a "gold standard" for risk stratification of liver cirrhosis and is superior to pathological examination of liver. This article briefly assesses the invasive and non-invasive measuring methods of the hepatic venous pressure gradient. With the hepatic venous pressure gradient-guided precise treatment for hepatic cirrhosis of portal hypertension, the incidence of clinical endpoints of hepatic portal hypertension can be significantly reduced. Establishing a long-term monitoring and management model similar to "high blood pressure" is a dream for the diagnosis and treatment of future cirrhosis and portal hypertension. PMID- 29996335 TI - [Technical advancement in surgical treatment of portal hypertension]. AB - Recently, there have been many developments and improvements in portal hypertension surgery, but there are still many controversies regarding the surgical indications, the timing of surgery, and the choice of surgical procedures. Minimally invasive laparoscopy and robotics are the leading direction for the development of surgical techniques for portal hypertension. Surgical selection procedures should be based on evidence-based, but guidelines should not be blindly followed. Surgical development needs to strengthen multidisciplinary cooperation, and surgical reform is the driving force for surgical development. PMID- 29996336 TI - [Getting to zero mother-to-child transmission of hepatitis B virus: dream and challenge]. AB - To eliminate viral hepatitis as a public health threat, the World Health Organization has set the ambitious goal of reducing the prevalence of hepatitis B surface antigen (HBsAg) in children to 0.1% by 2030, and the key to this grand goal is cutting off hepatitis B virus (HBV) transmission from mother-to-child. Previously, national and international guidelines for the management of chronic hepatitis B recommended the use of hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) or combination of any in neonates and antiviral drugs for pregnant women with high viral load in late pregnancy. However, a recent study in Thailand found that the addition of antiviral drugs in pregnant women with high viral load in the third trimester did not significantly lower the incidence of mother-to-child HBV transmission, but no case of chronic HBV infection was seen with strict standards hepatitis B vaccine and HBIG combined immunoprophylaxis and the use of tenofovir disoproxil in pregnant women with high viral load in the third trimester. In addition, the incidence of mother -to- child transmission of HBV in the antiviral group was 0, while the incidence of HBV transmission in the placebo group was 2%. Therefore, it is not possible to deny the efficacy of adding antiviral drugs in treating pregnant women with high viral load in the third trimester with combined immunoprophylaxis. There is an urgent need for more real-world studies in clinical practice to further reveal the principles and existing problems of mother- to- child transmission of HBV. PMID- 29996337 TI - [Analysis of 833 times measured hepatic venous pressure gradient]. AB - Objective: To summarize and analyze the clinical data of hepatic venous pressure gradient (HVPG) and to explore the application value of HVPG in the diagnosis, evaluation and clinical treatment of portal hypertension in cirrhosis. Methods: The patient data of HVPG measurement performed in Shandong Provincial Hospital from April 2010 to November 2017 were collected. Results: A total of 633 patients with 833 times of HVPG measurements were included. There was significant difference in HVPG between patients with different etiologies, different Child pugh grades and different degrees of decompensated cirrhosis. Conclusion: The HVPG test is suitable for the diagnosis and evaluation of portal hypertension. The HVPG of patients with different severity of liver cirrhosis can guide the choice of the treatment plan, and the HVPG measurement should also be strictly standardized and quality control. PMID- 29996338 TI - [Correlation between serum uric acid and risk of new-onset nonalcoholic fatty liver disease: a 5-year observational cohort study]. AB - Objective: To investigate the association between serum uric acid and the risk of new-onset nonalcoholic fatty liver disease(NAFLD). Methods: An observational cohort study was conducted in a hospital for five years. 856 patients without NAFLD who took physical examination in the hospital physical examination center in 2011 were selected as study subjects. According to the baseline level of serum uric acid, subjects were divided into 4 groups (F1, F2, F3, and F4). After 5 years of follow-up, the incidence of NAFLD in each group was observed in 2016.Serum alanine aminotransferase and aspartate aminotransferase, Total cholesterol, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, Triglycerides, Fasting blood glucose and Imaging findings were examined. The cumulative incidence rate of NAFLD in each group was compared and the effect of baseline serum uric acid level on new-onset NAFLD was analyzed by Logistic regression. The receiver operating characteristic curve (ROC) was used to analyze the diagnostic value of uric acid level in NAFLD. Results: The cumulative incidence rate of NAFLD was 19.16%, and the cumulative incidence increased with the increase of baseline uric acid. The incidence rates of F1, F2, F3 and F4 were 7.90%, 13.54%, 20.32% and 34.07% respectively. The difference was statistically significant (P < 0.05). The incidence rate of NAFLD in F2, F3 and F4 groups were 1.637 (0.856 ~ 3.344) times, 2.745 (1.345 ~ 5.211) times and 5.465 (2.977 ~ 9.843) times higher than those in F1 group (P < 0.05). The logistic regression analysis showed that the risk of NAFLD increased with the increase of serum uric acid level, and the serum uric acid level was an independent risk factor for NAFLD with a relative risks (RR) value of 1.654. The ROC curve analysis of serum uric acid levels had no diagnostic value for NAFLD. Conclusion: Our study demonstrates that increased serum uric acid level is an independent risk factor for the development of NAFLD and could be used as an investigative indicator to assess the risk. PMID- 29996339 TI - [Effect of lipid-induced macrophage M1/M2 polarization on lipid metabolism in hepatocytes]. AB - Objective: This study aims to explore the effect of lipid-induced macrophage M1/M2 polarization on lipid metabolism in hepatocytes. Methods: RAW264.7 macrophages were incubated with different kinds of fatty acids including saturated fatty acids-palmitic acid (PA), monounsaturated fatty acids-oleic acid (OA) and polyunsaturated fatty acids-docosahexaenoic acid (DHA), and cell culture supernatants were collected to prepare conditioned medium (CM). Hepatocytes were isolated by in situ perfusion of the liver with collagenase in mice, and a macrophage-hepatocyte CM co-culture system was established. Macrophage M1/M2 phenotype markers were detected by Real-time PCR. Lipid synthesis and decomposition related mRNA and protein expressions in hepatocytes were detected by Real-time PCR and Western Blot. Lipid depositions in hepatocytes were detected by oil red O staining. An analysis of variance was used for comparison of means between multiple groups. Results: Compared with control groups, PA polarized macrophages to a M1 phenotype (expression of TNF-alpha and IL-6 significantly increased, F>=22.68, P < 0.01), OA polarized macrophages to a M1/M2 mixed phenotype (expression of IL-6, Mrc2 and IL-10 increased F>=4.94, P < 0.05) and DHA polarized macrophages to a M2 phenotype (expression of Mrc2 and IL-10 significantly increased, F>=4.94, P < 0.01). CM-PA significantly increased lipid synthesis related genes, including SREBP1C, ACC1 mRNA expression (F>=5.66, P < 0.01) and FASN, ACC1 protein expression (F>=38.34, P < 0.05) in hepatocytes, and decreased lipid decomposition gene ACOX1 protein expression (F=154.48, P < 0.01). CM-OA affected several lipid metabolism genes expression. CM-DHA significantly increased CPT1A mRNA expression (F = 10.30, P < 0.01) and ACOX1, CPT1A protein expression (F>=47.06, P < 0.05), and decreased SREBP1C, ACC1 protein expression (F>=65.84, P < 0.05) in hepatocytes. Massive lipid droplets were deposited in hepatocytes in CM-PA treated hepatocytes, and a few amount of lipid droplets were deposited in CM-DHA treated hepatocytes. Conclusion: Different fatty acids affect the balance of lipid metabolism in hepatocytes and liver by inducing macrophage M1 / M2 polarization, thus promoting or delaying the progression of non-alcoholic fatty liver disease. PMID- 29996340 TI - [Discussion on optimal duration of pegylated interferon alpha combined with ribavirin for chronic hepatitis C in HIV-infected patients]. AB - Objective: To investigate the optimal duration of pegylated-alpha interferon (Peg INFalpha) combined with ribavirin (RBV) in treating chronic hepatitis C infection in human immunodeficiency virus (HIV)-infected patients. Methods: A multicenter prospective study was conducted. The study subjects were divided into two groups; HIV/HCV co-infections (Group A, n = 158) and control with HCV-monoinfections (Group B, n = 60). All recruited patients received standard Peg-INFalpha plus RBV therapy. Group A was divided into 3 subgroups according to CD4(+) cell counts: A1 subgroup, 79 cases, CD4(+) counts > 350 cells /MUl, who received anti-HCV before combination antiretroviral therapy(cART); A2 subgroup, 45 cases, CD4(+) counts between 200 and 350 cells/MUl, who did not start anti-HCV until they could tolerate cART well; A3 subgroup, 34 cases, CD4(+) counts < 200 cells /MUl, cART was administered first, and anti-HCV therapy was started when CD4(+) counts > 200 cells/MUl. The anti-HCV efficacy of two groups and 3 subgroups were compared. Statistical analysis for normal distribution and homogeneity of variance data was calculated by t-test and the counting data was analyzed by chi (2) test. The Mann Whitney U test was used for non-normal data. A one-way analysis of variance (ANOVA) was used for the comparison of multiple groups, followed by SNK method. Multiple independent samples were used for non-parametric tests. Results: There was no significant difference in age and baseline HCV RNA levels between groups and subgroups (P > 0.05). By an intent-to-treat (ITT) analysis, in Group A, the ratio of complete early virological response (cEVR) rate was 75.3% (119/158), the ratio of end of treatment virological response (eTVR) rate was 68.4% (108/158), and the ratio of sustained virological response (SVR) rate was 48.7% (77/158); in Group B, the ratio of cEVR rate was 93.3% (56/60), the ratio of eTVR rate was 90.0% (54/60), and the ratio of SVR rate was 71.7% (43/60); The therapeutic index of Group A were lower than those of Group B (P<=0.05). By per-protocol (PP) analysis, the ratio of cEVR rate in Group A [75.2% (88/112)] was still lower than that in Group B [93.3% (56/60)], but no significant differences were found in the ratio of eTVR rate and SVR rate between 2 groups (P > 0.05). Comparing the efficacy of subgroups (A1, A2 and A3) by ITT analysis, the ratios of cEVR rate were respectively 78.5% (62/79), 75.6% (34/45) and 67.6% (23/34); the ratios of eTVR rate were respectively 68.4%(54/79), 80.0%(36/45)and 52.9%(18/34); and the ratios of SVR rate were respectively 41.8%(33/79), 64.4%(29/45)and 44.1%(15/34). The ratio of eTVR in subgroup A2 was obviously higher than that in subgroup A3 and the ratio of SVR in subgroup A2 was statistically higher than that of subgroup A1(P<=0.05). However, by PP analysis, no significant differences of the therapeutic indexes were found among the respective subgroups (P > 0.05). Conclusion: HIV-HCV co-infected patients would have better anti-HCV efficacy with Peg-INFalpha-2a plus RBV than HCV- monoinfected patients. The best time for initiating anti-HCV therapy in HIV-HCV co-infected patients is when CD4(+) counts 200 cells/ MUl. PMID- 29996341 TI - [Compare the effect of combined therapy between telbivudine plus adefovir dipivoxil and lamivudine plus adefovir dipivoxil corresponding to renal function in patients with hepatitis B virus infection]. AB - Objective: To compare the effect of combined therapy using lamivudine (LAM) plus adefovir (ADV) versus telbivudine (LdT) plus adefovir corresponding to the renal function of CHB patients. Methods: A total of 120 patients with chronic hepatitis B were enrolled. According to single daily dosing, they were divided into 4 groups: LdT + ADV group (n = 32), ADV+LdT group (n = 28), LAM + ADV group (n = 38) and ADV + LAM group (n = 22). Hepatorenal function, HBV serological markers, HBV DNA quantification, creatine kinase (CK) and other parameters were examined every 3 months. Serum alanine aminotransferase (ALT) normalization rate, undetectable HBV DNA rate, hepatitis B e antigen (HBeAg) seroconversion rate, level of serum creatinine (CR) and estimated glomerular filtration rate (eGFR) were analyzed at baseline time, and at weeks 24 and 52.Stastical data were analyzed by t- test and analysis of variance, count data using chi (2) test. Results: There was no statistically significant difference between the four groups in terms of ALT normalization rate, HBeAg seroconversion rate, undetectable HBV DNA rate at 24 and 52 weeks. Compared with baseline, at 24 weeks of treatment, there was no significant change in serum creatinine and eGFR in the 4 groups, but after 52 weeks of treatment, serum creatinine decreased in LdT + ADV and ADV + LdT groups and eGFR increased (P < 0.05); Serum creatinine in ADV and ADV + LAM increased, and eGFR was decreased than before (P < 0.05). After treatment, there was no significant difference in renal function between the four groups at 24 weeks, but at week 52, eGFR increased and serum creatinine decreased in LdT + ADV group compared with LAM + ADV group (P < 0.05); ADV + LdT Compared with ADV + LAM group, eGFR increased and serum creatinine decreased (P < 0.05). At 52 weeks of treatment, 5 patients with mildly impaired renal function in the ADV + LdT group [n = 10, eGFR 60-90 ml.min(-1) .(1.73 m(2))(-1)] returned to normal, and none of the ADV + LAM group (n = 9) returned to normal. Conclusion: For patients with mild impaired renal function, adding LdT combined with ADV can improve renal function compared to that of LAM plus ADV. PMID- 29996342 TI - [Diagnostic imaging of primary hepatic neuroendocrine tumors and treatment with transarterial chemoembolization: analysis of 6 cases]. AB - Objective: To investigate the imaging diagnosis, treatment and prognosis of primary hepatic neuroendocrine tumors. Methods: The clinical features, imaging manifestations, histopathological and immunohistochemical findings and interventional therapy of 6 patients identified with pathologically confirmed primary hepatic neuroendocrine tumors were retrospectively analyzed, and the related literatures were reviewed. Results: All 6 patients presented with symptoms of abdominal pain. 4 patients had solitary hepatic mass and 2 patients had multiple hepatic masses. Magnetic resonance imaging showed low signal intensity on T1 weighted imaging, high signal intensity on T2 weighted imaging and clear boundary; the arterial phase of enhancement scan was uneven and enhanced, and portal venous phase or delayed phase showed continuous enhancement, surrounded by ring enhanced capsule. A pathological diagnosis was primary neuroendocrine tumor of the liver. After interventional treatment, 6 patients had some therapeutic effects. Among them, 4 patients underwent multiple interventional therapies, followed by 4 years of follow-up has shown satisfactory results. Conclusion: Primary hepatic neuroendocrine tumors are very rare and their imaging manifestations are specific. Eventually, relies on pathological and immunohistochemical diagnosis. Transarterial chemoembolization therapy can bring satisfactory results in the treatment of primary hepatic neuroendocrine tumor. PMID- 29996344 TI - [Effect of tumor-associated macrophages in promoting epithelial-mesenchymal transition of Hep3B hepatoma cells and related mechanisms]. AB - Objective: To investigate the possible mechanisms of tumor-associated macrophages (TAMs) in regulating epithelia-mesenchymal transition (EMT) of Hep3B hepatoma cells, since EMT is closely associated with the malignancy of hepatoma cells and tumor microenvironment plays an important role in regulating EMT of hepatoma cells, and to provide new regimens for the clinical studies and treatment of liver cancer. Methods: Human monocytic leukemia THP-1 cells were successfully induced to TAMs. With TAMs as target cells, they were co-cultured with the supernatant of Hep3B hepatoma cells or Hep3B hepatoma cells, and Western blot and RT-PCR were used to measure the change in the expression of Toll-like receptor 4 (TLR4) in TAMs. The expression of TLR4 in TAMs was downregulated by transient plasmid transfection with shRNA. With Hep3B hepatoma cells as target cells, the supernatants of TAMs and TAMs transfected with shRNA TLR4 plasmid were used for intervention, and Western blot was used to measure the protein expression of E cadherin, N-cadherin, and vimentin. The two-sided t-test was used for comparison of the means of two independent samples. Results: THP-1 cells were successfully induced to TAMs. According to the results of Western blot, compared with the control-CM group, the TAM-CM group had a significant reduction in the protein expression of E-cadherin and significant increases in the protein expression of N cadherin and vimentin in Hep3B cells. After the expression of TLR4 in TAMs was downregulated, the culture solution of TAMs was used for the intervention of Hep3B cells (shRNA group), and compared with the TAM-CM group, the shRNA group had a significant increase in the expression of E-cadherin and significant reductions in the protein expression of N-cadherin and vimentin in Hep3B cells. Western blot and RT-PCR showed that the expression of TLR4 in TAMs was influenced by Hep3B cells. Conclusion: TAMs can promote EMT of Hep3B hepatoma cells, and downregulation of the expression of TLR4 in TAMs may reduce EMT of Hep3B hepatoma cells, suggesting that TLR4 on the surface of TAMs may be a key molecule involved in the interaction between TAMs and Hep3B hepatoma cells. PMID- 29996343 TI - [Comparison of therapeutics effects of transcatheter arterial chemoembolization combined with iodine-125 seed implantation and sorafenib for the treatment of hepatocellular carcinoma with portal vein tumor thrombosis]. AB - Objective: To explore the factors affecting the prognosis of patients with hepatocellular carcinoma (HCC) combined with portal vein tumor thrombosis (PVTT), and to analyze the clinical value of transcatheter arterial chemoembolization (TACE) combined with iodine-125 seed implantation in such patients. Methods: A retrospective analysis of 53 patients with HCC combined with PVTT was performed. In the study group, 32 cases were treated with TACE combined with iodine-125 seed implantation, and 21 cases in the control group were treated with TACE combined with sorafenib. Survival analysis was carried out on eight factors such as gender, age, Child-Pugh classification, alpha fetoprotein level, portal vein tumor thrombosis (PVTT) type, forms of liver tumor, extra-hepatic metastasis and treatment modalities. The efficacy of TACE combined with iodine-125 seed implantation and TACE combined with sorafenib was further compared. The chi (2) test was used to evaluate the efficacy of the two groups. A single factor survival analysis was calculated by Kaplan-Meier estimator and multifactor survival analysis by Cox proportional hazards model. Results: All 53 patients were successfully treated. The median tumor progression time (mTTP) and median overall survival (mOS) were 8 months and 11 months, respectively. The disease control rate (DCR) of the study group for PVTT was 93.8%, which was significantly higher than that of the control group (61.9%, chi (2) = 6.448, P = 0.011). The difference was statistically significant; the objective remission rate of the study group for PVTT was 75.0%. Significantly higher than 9.5% in the control group, P < 0.05, the difference was statistically significant; the DCR of the primary tumor in the study group was 50.0%, which was lower than the 70.0% of the PVTT in the control group, P = 0.231, the difference was not statistically significant. The progression of primary HCC lesions in patients with multivariate survival analysis: Child-Pugh grade A patients were compared to grade B [Hazard ratio (HR) = 0.236, P = 0.003]; no extra-hepatic metastasis (HR = 0.258, P = 0.002); and TACE combined with iodine-125 seed implantation group compared with TACE combined sorafenib group (HR = 0.372, P = 0.002), the differences were statistically significant. Multivariate survival analysis of patients with overall survival: AFP < 400 ng/mL vs. AFP>=400 ng/mL (HR = 0.389, P = 0.030); Child-Pugh grade A vs. B (HR = 0.263, P = 0.006); and no extra-hepatic metastasis (HR = 0.306, P = 0.006), the differences were statistically significant. Conclusion: TACE combined with iodine-125 seed implantation for the treatment of HCC with PVTT can effectively control the progression of PVTT and intrahepatic lesions and improve the prognosis of patients. PMID- 29996345 TI - [Diagnostic value of transient elastography for diagnosis of idiopathic non cirrhotic portal hypertension]. PMID- 29996346 TI - [Clinical research on sequential dual-drug nonspecific immunotherapy in patients with hepatocellular carcinoma]. PMID- 29996347 TI - [Application of direct antiviral drugs in special patients with HCV infection]. AB - Patients with HCV infection can develop decompensated cirrhosis, hepatocellular carcinoma (HCC), even liver failure. As a result, efficient antiviral treatment is very essential to prevent HCV-related disease progression. Newly developed direct-acting antiviral agents (DAAs) have shown safety profile, favorable tolerability, and relatively short duration, which provide an opportunity to expand the number of patients who can be treated for HCV infection. There is a need for further clinical observation and summaries for DAAs in a real world. In the era of DAAs, special patients with HCV infection still get lots of attention from doctors. This review aims at the application of DAAs in patients with HCV infection, combined with chronic kidney diseases, hepatocellular carcinoma, HBV/HCV co-infection, HIV/HCV co-infection, post liver transplantation, pregnancy, children, lymphoma and retreatment. PMID- 29996349 TI - [Analysis of 15 cases of avian influenza virus (H7N9) infection]. AB - Objective: To describe the clinical, chest imaging, pathological manifestations and therapeutic experience of human infection with A/H7N9 virus. Methods: The features of 15 laboratory-confirmed cases of human infection with A/H7N9 virus in Taizhou, Jiangsu Province were retrospectively analyzed. Results: The 15 patients with confirmed viral pneumonia included 12 males and 3 females, with a median age of 61 years(ranging from 33 to 81 years). Twelve patients had a history of exposure to the poultry trading places, or direct contact with ill/dead avian, while 3 patients denied exposure or contact. The most common initial symptoms were fever, coughing, and respiratory distress. The illness progressed rapidly to acute respiratory distress syndrome (ARDS). Lab tests showed normal (8 cases) or decreased (7 cases)white blood cell count , decreased (13 cases) lymphocyte count and proportion , increased creatine kinase (CK, 12 cases) and lactate dehydrogenase (LDH, 15 cases), and respiratory failure (13 cases). Chest radiographic examination showed that the most common features were inflammatory infiltration in the lung, with partial consolidation. The average time of the diagnosis with influenza viral nucleic acid and onset of an oral anti-influenza drug were 7.1 days and 6.5 days. All patients were treated by antiviral drugs (oral oseltamivir 150 mg q12 h and/or intravenous paramivir 600 mg qd), with mechanical ventilation in 9 cases, glucocorticoid therapy in 5 cases (intravenous methylprednisolone in 3 and dexamethasone in 2 patients), extracorporeal membrane oxygenation (ECMO) therapy in 2 cases, continuous renal replacement therapy (CRRT) in 6 cases, and artificial liver therapy in 1 case. The pulmonary pathology was observed from post-mortem biopsy for 2 fatal cases. Patient 1 had diffuse alveolar damage with inflammatory exudation, hyaline membrane formation, and cellular infiltration. Patient 2 had widened alveolar septum, lymphocyte and monocyte cell infiltration in the alveolar septa, and interstitial fibrous proliferation. Nine patients were discharged, and 6 died. Conclusions: Patients with influenza A/H7N9 virus mostly presented with fever, cough, and were prone to progression to viral pneumonia. Once acute respiratory distress and important organ dysfunction occurred, the fatality rate was higher. Early diagnosis and rational treatment were critical for better outcomes. PMID- 29996348 TI - [Relationship between the weight of hospitalized patients with pulmonary tuberculosis and the oral dose of isoniazid]. AB - Objective: To study the relationship between the weight change trend of initial treatment patients with pulmonary tuberculosis and the dose change trend of isoniazid, and therefore to analyze the appropriate dose of isoniazid. Methods: Data of initial treatment inpatients with pulmonary tuberculosis from May 1955 to December 2012 were retrospectively analyzed. Elderly patients with pulmonary tuberculosis, patients with drug-resistant tuberculosis, extrapulmonary tuberculosis and those with complications were excluded from the study. The time period was separated as 20th century 1950s to 1960s, 1970s, 1980s, 1990s, 21th century 2000s and 2010s. Samples were selected in each year and month between 1950s to 1960s and 1970s. After 1980s, samples of 1 year were taken from each 5 years. The sex, age and weight for every patient were collected, as well as the dose of isoniazid of every inpatient on a day in therapeutic regimen. Meanwhile, the weight change trend of the patients in different ages and the dose change trend of isoniazid were compared. The total number of cases was 1 398, with 924 males and 474 females, averaging (36.7+/-14.4) years old. Results: The weight of the patients increased when it was compared between that in 1950s to 1960s, 1970s or 1980s and that in 2000s, with a increasing weight of 3 kg, 3.5 kg and 3 kg respectively. The difference showed statistical significance (P<0.003). The difference was also significant when the weight in 70s was compared with that in 2010s (P=0.002). The therapeutic dose of isoniazid remained invariable regardless of the weight change. At 1990s, 2000s and 2010s, the dose of isoniazid per kilogram of body weight would reduce to 0.005 4 g, 0.005 2 g and 0.0054 g relative to patients' weight increase, and the difference was statistically significant (P<0.001). Conclusions: The weight of pulmonary tuberculosis inpatients increased in recent 60 years. The weight has a close relation with the dose of isoniazid. A fixed dose of isoniazid (0.3 g/d) regardless of the weight change could result in low blood drug concentration . To avoid tolerance of isoniazid and increase the cure rates of pulmonary tuberculosis, the dosage of isoniazid should be increased based on the weight increase of patients. PMID- 29996350 TI - [Antimicrobial susceptibility and genotyping of Mycobacterium intracellulare]. AB - Objective: To investigate the antimicrobial susceptibility and genotyping of Mycobacterium intracellulare. Methods: A total of 150 M. intracellulare isolates were collected. The susceptibility against 15 antimicrobial agents widely used for treatment of non-tuberculosis mycobacteria (NTM) infections, was tested by broth microdilution assay. Variable number of tandem repeats (VNTR) assay was also performed using the 16-loci genotyping method. Results: The drug susceptibility test revealed that clarithromycin (97.3%, 146/150), moxifloxacin (94.0%, 141/150) and amikacin (90.0%, 135/150) had the best antimicrobial activities in vitro against the M. intracellulare isolates. Secondly, 75.3%(113/150), 64.0%(96/150), 52.7%(79/150) and 8.7%(13/150) of the strains were susceptible to rifampicin, linezolid, capreomycin, and ethambutol, respectively. The MIC(50) and MIC(90) values of the 3 injectable anti-tuberculosis drugs were as follows: amikacin 4 mg/L and 16 mg/L, streptomycin 4 mg/L and 16 mg/L, capreomycin 8 mg/L and 16 mg/L. The MIC(50) and MIC(90) values of the 5 different fluoroquinolones were 0.5 mg/L and 2 mg/L for moxifloxacin , 1 mg/L and 8 mg/L for ciprofloxacin, 1 mg/L and 8ug/ml for levofloxacin, 2 mg/L and 16 mg/L for antoflolxacin, 2 mg/L and 16 mg/L for ofloxacin. The Hunter-Gaston Discriminatory Index (HGDI) value for the 16-loci VNTR typing of M. intracellulare isolates was 0.994. VNTR differentiated the 150 isolates into 21 clusters and acquired a total of 121 unique patterns. Drug resistance profile was not independently associated with cluster strains. Conclusions: Clarithromycin, moxifloxacin and amikacin had the best antimicrobial activities in vitro against M. intracellulare isolates. The 16-loci VNTR typing revealed a highly discriminatory power and drug resistance profile was not independently associated with cluster strains. PMID- 29996352 TI - [Pulmonary lymphatic dysfunction and plastic bronchitis]. PMID- 29996351 TI - [The role of B cell activating factor in the differential diagnosis of usual interstitial pneumonia]. AB - Objective: To explore the differential diagnostic role of B cell-activating factor(BAFF) in idiopathic pulmonary fibrosis (IPF) and usual interstitial pneumonia (UIP) associated with autoimmune diseases (AIDs). Methods: Plasma levels of BAFF were measured by ELISA method in 23 patients with AIDs-UIP, 34 patients with IPF, and 21 healthy subjects as control. The correlation between plasma BAFF levels and other clinical results from patients was analyzed. Receiver operating characteristics (ROC) analysis for distinguishing AIDs-UIP from IPF patients was examined and the maximal area under curve (AUC) was found. Results: Plasma levels of BAFF were significantly elevated in AIDs-UIP patients and IPF patients compared to healthy subjects(P<0.001 and P=0.002, respectively). AIDs-UIP patients had higher level of BAFF than IPF patients(P=0.030). Plasma BAFF levels in AIDs-UIP patients were inversely correlated with pulmonary function results, including FVC%(r=-0.435, P=0.040)and TLC%(r=-0.449, P=0.041), as well as DLCO%(r=-0.491, P=0.024). When the cut off value of BAFF was set as 1.5 ng/ml to distinguish AIDs-UIP patients from IPF patients, the sensitivity and the specificity was 64.5% and 90.0%, respectively, and the area under ROC curve reached the maximum of 0.784(P=0.000, 95% CI: 66.3%-90.5%). Conclusions: Plasma BAFF levels were significantly higher and inversely correlated with pulmonary function, reflecting the severity of AIDs-UIP patients. Plasma BAFF levels may be a useful marker for distinguishing AIDs-UIP from IPF. PMID- 29996353 TI - [Progress in the study of the relationship between respiratory regulation and central nervous sxstem channels in mechanical ventilation patients]. PMID- 29996354 TI - [The clinical significance of pharyngeal critical closing pressure measurement in obstructive sleep apnea]. PMID- 29996355 TI - [Pulmonary rehabilitation of chronic obstructive pulmonary disease: evaluation and implemention]. PMID- 29996356 TI - [Research progress on the relationship between gut microbiota and sleep apnea hypopnea syndrome]. PMID- 29996357 TI - [Research advances on complications of endobronchial ultrasound-guided transbronchial needle aspiration and their treatment]. PMID- 29996358 TI - [Comorbidity in oral squamous cell carcinoma patients: an initial research in Beijing area]. AB - Objective: To make a preliminery research of comobidity in oral squamous cell carcinoma (OSCC) patients who resides in Beijing area and investigate whether comorbidity affect the surviving rate independently. Compare the similarities and differences between Chinese and foreign OSCC patients. Methods: The medical records of 313 patients who undertaken operation in Peking University Stomatology School from January 2007 to Delember 2009 were retrospectively reviewed. Adult comorbidity evaluation-27 Chinese edition index was used to estimate the comorbidity severity. COX proportional hazards model was used to analyze whether the TNM stage, comobidity, age and gender affected 5-year survival rate. Results: TNM stage and comorbidity have a significant impact on survival rate, the postoperative survival rate decreased significantly with the increasing level of TNM staging and the complexity of comorbidity disease. In this study, the proportion of patients with none, mild, moderate and severe comorbidity diseases was 24%, 48%, 18% and 10%. The five-year survival rates of patients with moderate and severe comorbidity disease were 50% (29/58) and 13% (4/30) respectively. Conclusions: The comorbidity disease information can help assess the overall health of OSCC patients, and it is recommended to improve the clinical staging and overall evaluation of oral cancer patients with comorbidity disease information. PMID- 29996359 TI - [Caries prevention effectiveness of aresin based sealant and a glass ionomer sealants: a report of 5-year-follow-up]. AB - Objective: To evaluate and compare the caries prevention effectiveness of a resin based sealant and a glass ionomer sealant on permanent first molars in 7- to 9 years-old school children. Methods: A randomized controlled, examiner-blinded, 5 year clinical trial was conducted in 19 primary schools in Dalian, Liaoning province. Totally 419 children (with 664 first molars) who had at least one sound permanent first molar with deep fissures or fissures with signs of non-cavitated lesions were recruited and stratified and allocated randomly into three parallel groups. A resin-based sealant was used in Group R (136 children with 219 first molars) and a glass ionomer sealant was used in Group G (130 children with 218 first molars). The third group (Group N, 153 children with 227 first molars) with none of the two sealants applied was served as blank control. Follow-up examinations were conducted at 0.5, 1, 2, and 5 years after sealing in order to assess the retention of the sealants and the incidence of caries occurrence. Chi square test was adopted to compare the differences of caries incidence among the 3 groups. Generalized estimating equations (GEE) was used to analyze the effective factors of caries incidence. Results: During the 5-year follow-up period, 13.4% (23/172) of the teeth in Group R, 22.5% (40/178) of the teeth in Group G and 34.5% (57/165) of the teeth in Group N were diagnosed as having developed cavitated lesions. And the differences in the incidence of caries among the three groups was statistically significant (P<0.05). According to GEE, the resin-based sealant and the glass ionomer sealant were found to be the protection factors and the non-cavitated lesion before sealing was found to be the risk factor. The resin-based sealant was found to be the protection factor to the glass ionomer sealant when the blank control group was removed. Conclusions: Both resin-based sealant and glass ionomer sealant could effectively prevent the permanent first molars from the occurrence of carious lesions in 5 years. The resin-based sealant was superior to the glass ionomer sealant in caries prevention. PMID- 29996360 TI - [Morphological classification of mandible posterior region based on cone beam CT images]. AB - Objective: To classify the morphology of mandible posterior region and provide reference for the planning of dental implantation. Methods: Cone beam CT data of 208 patients were collected. The CT data were imported into CS 3D imaging V3 software and then the morphology of mandible posterior region were analyzed. The types of premolar and molar mandible cross-section morphology were recorded, classified and analyzed. Results: The results showed that type A (vertical type) (79%-96%) was the most common in the premolars, whereas type B (inclined type) (36%-37%) and type C (lingual inverted concave) (30%-54%) were the most common types in the molars, followed type D (absorption severe type) (2%-5%). There was a statistically significant differences in tooth positions (P<0.001), tooth deficiency aspect (P<0.001) and different side (P=0.013), different age (P<0.001), and different gender (P=0.007). Conclusions: Using cone beam CT to determine the morphology of mandible may be a reference for the planning of dental implantation. PMID- 29996361 TI - [Influence of proximal two-wall bone defect on periodontal ligament stresses under normal occlusal forces]. AB - Objective: To study the influence of two-wall bone defect on periodontal ligament stresses under normal occlusal forces, and to analyze the influence of depth and width of bone defect to periodontal ligament stresses. Methods: Three-dimensional finite element models of teeth, periodontal ligament and alveolar bone were created based on cone beam CT images. Proximal two-wall bone defect with different depths (bone defect occupies one third, two thirds, and full length of root) and widths (bone defect occupies one fourth, two fourths, three fourths and full width of buccal lingual width) were simulated by modifying the elastic modulus of elements within defect areas. Occlusal forces with magnitudes of half of the maximum occlusal forces were applied to the model at an angle of 45 degrees to the long axis of tooth, and equivalent stresses of periodontal ligament were analyzed. Results: In the model of no bone defect, the equivalent stresses of periodontal ligament of incisors, canines, premolars and molars were 2.88, 2.31, 8.67 and 7.53 MPa respectively. The equivalent stresses of periodontal ligament increased with the enlargement of depth and width of bone defect. The equivalent stresses of periodontal ligament with maximum bone defect in both depth and width for incisors, canines, premolars and molars were 4.47, 3.62, 11.66 and 8.72 MPa respectively. In the model of width of bone defect was consistent and bone defect develops vertically, the increments of equivalent stresses of periodontal ligament were significantly greater in the early stage bone defect model (from no defect to one third of root length bone defect) than that in the later stage bone defect model (from two thirds to full length of root length bone defect). In the model of bone defect depth was consistent and bone defect develops transversely, the increments of equivalent stresses of periodontal ligament in the early stage bone defect model (from no defect to one fourth of buccal lingual width bone defect) were significantly smaller than that in the later stage bone defect model (from three fourths to full width of buccal lingual width bone defect). Conclusions: Bone defect with shallow depth and that with large width would increase periodontal ligament stresses. Therefore, more attention should be paid to occlusion evaluation and adjustment for teeth with shallow and wide two-wall bone defect. PMID- 29996362 TI - [Endoplasmic reticulum-mitochondrial contact regulates osteogenic differentiation of periodontal ligament stem cells via mitofusion 2 in inflammatory microenvironment]. AB - Objective: To investigate the effect of endoplasmic reticulum (ER)-mitochondria coupling and the expression of mitofusion 2 (Mfn2) in periodontal ligament stem cells (PDLSC), so as to provide a theoretical basis and therapeutic target for promoting periodontal regeneration in treatment of periodontitis. Methods: The periodontal ligament tissue was scraped from extracted intact human teeth and teeth with periodontitis collected in the Department of Oral and Maxillofacial Surgery, the Fourth Military Medical University. The health PDLSC (H-PDLSC) and inflammatory PDLSC (P-PDLSC) were obtained respectively from the primary culture of the human teeth and cloned using 1imited diluted method. The level of ER mitochondrial coupling was observed by transmission electron microscopy and organelle-specific fluorescence staining. Quantitative real-time PCR (qPCR) was used to detect the expression of Mfn2 in H-PDLSC and P-PDLSC. Tumor necrosis factor alpha (TNF-alpha) was used to simulate the inflammatory microenvironment. H-PDLSC was cultured in normal medium and media containing 5 and 10 mg/L TNF alpha, named as H-PDLSC group, H-PDLSC+TNF-alpha (5 mg/L) group and H-PDLSC+TNF alpha (10 mg/L) group, respectively. At the 7th day, qPCR was applied to detect the mRNA level of Mfn2. The expression of Mfn2 in P-PDLSC was down-regulated by small interfering RNA siMfn2. The osteogenic differentiation of P-PDLSC and P PDLSC+siMfn2 were examined by qPCR at the 7th day, and alizarin red staining and cetyl pyridine chloride quantitative analysis at the 28th day after osteogenic induction. Results: The level of ER-mitochondrial coupling in the P-PDLSC group (the length of the coupling structure/mitochondrial perimeter was 0.55+/-0.10, the length of the coupling structure/endoplasmic reticulum perimeter was 0.44+/ 0.08) was significantly higher than that in the H-PDLSC group (P<0.01). The co localization of endoplasmic reticulum and mitochondria of P-PDLSC group was 0.71+/-0.09, which was significantly higher than that of H-PDLSC group (P<0.01). The expression level of Mfn2 in P-PDLSC (1.46+/-0.10) was higher than that in H PDLSC (0.99+/-0.08). The expression levels of Mfn2 in H-PDLSC+TNF-alpha (5 mg/L) and H-PDLSC+TNF-alpha (10 mg/L) groups were 1.28+/-0.19, 1.54+/-0.43, respectively, which were both significantly higher than that in H-PDLSC (0.82+/ 0.14) (P<0.01). P-PDLSC transfected with siMfn2 down-regulated the expression of Mfn2, and the osteogenic differentiation ability of P-PDLSC was restored. The results showed that the expression of alkaline phosphatase, Runt-related transcription factor-2 (RUNX2) and osteocalcin mRNA in P-PDLSC+siMfn2 group were significantly higher than that of the control group (P<0.01). The alizarin red staining and quantitative results of cetyl pyridinium chloride were consistent with the qPCR results. Conclusions: In the microenvironment of inflammation, ER mitochondrial coupling and the expression of Mfn2 of PDLSC increased, which might lead to a decrease in osteogenic differentiation of PDLSC. The specific mechanism needs to be further studied. PMID- 29996363 TI - [Effect of exogenous stem cells from apical papillae in the pulp revascularization treatment for the immature permanent tooth with periapical periodontitis]. AB - Objective: To evaluate the effect of exogenous stem cells from apical papillae (SCAP) in the pulp revascularization treatment for the immature permanent tooth with periapical periodontitis in animal model. Methods: After the SCAP were isolated and cultured from the Beagle dogs, stem cell properties of these cells were characterized by analyzing their colony-forming ability, the expression of mesenchymal stem cell markers and the multidifferentiation characteristics including osteogenic, adipogenic, and chondrogenic potentials. Models of young permanent tooth with periapical periodontitis were established in dogs and the infection in each of the model tooth was eliminated by root canal irrigation and intracanal medication. After that, all of the model teeth were randomly divided into 4 groups: Group 1: normal developing teeth with no treatment applied;Group 2: teeth that periapical tissues were irritated to induce blood flowing into the root canals;Group 3: teeth that peripheral blood was delivered into the root canals;Group 4: teeth that SCAP were resuspended in peripheral blood and delivered into the root canals. In Group 2-4, firm coronal seal was performed after revascularization procedure and radiographs were taken periodically in order to observe the development of roots. After a 12-week-period, alveolar samples were collected and observed histologically. Results: The isolated SCAP showed clonogenic ability and multilineage differentiation ability including osteogenic, adipogenic and chondrogenic potentials. These cells also expressed the mesenchymal stem cell markers such as STRO-1 and CD146, while no cytokeratin was detected. The thickening of canal wall was observed radiographically 12 weeks after procedures of infection control and revascularization. Histologically, the newly formed tissues on the inner canal wall were found bone lacuna like structure in Group 2 and 3, and the new tissue formed in the Group 3 seemed easy to separate from the canal wall. The newly formed tissues in Group 4 were much thicker compare to those in the Group 2 and 3, and the dentine tubule like structure instead of bone lacuna was noticed although the orientation of these tubules were various. Conclusions: SCAP seem to play an important role in the tissue regeneration procedure when infection is well controlled in young permanent teeth with periapical periodontitis. It is difficult to achieve real tissue regeneration due to the lack of endogenous SCAP in apical area, therefore delivering adequate exogenous SCAP isolated and cultured in vitro could be a promising approach to overcome the challenge. PMID- 29996364 TI - [Changes of distal-less homeobox genes 5 and Msh homeobox 1 in a rat model of bisphosphonate related osteonecrosis of the jaw]. AB - Objective: To further study the effects of distal-less homeobox gene 5 (Dlx-5) and Msh homeobox 1 (Msx-1) in the pathogenic mechanism of bisphosphonate related osteonecrosis of the jaw (BRONJ) . Methods: Twenty-four SD rats were divided into two groups, the experimental group was injected intraperitoneally with zoledronic acid for 12 weeks (0.2 mg/kg, three times a week), and the control group was injected with saline solution for 12 weeks. The first mandibular molars were extracted after 12 weeks. All of the animals were sacrificed eight weeks after teeth extraction. The BRONJ was diagnosed by gross observation, X-ray examination and histopathlolgical examination. Through real-time PCR, the expression level of Dlx-5 and Msx-1 were detected in the mandible of BRONJ samples and normal samples. Results: X-ray examination and histopathlolgical analysis showed the presence of BRONJ. The results of real-time PCR showed that the expression levels of Dlx-5 were increased (P=0.001) and the expression level of Msx-1 was decreased (P=0.001) in the experimental group compared with the control group. Conclusions: Dlx-5 and Msx-1 genes play roles in the pathogenic mechanism of BRONJ. PMID- 29996365 TI - [Electronic probe analysis of enamel remineralization effect of casein phosphopeptide-amorphous calcium phosphate promoted by different concentrations of fluorine]. AB - Objective: To evaluate the remineralization effect and mechanism of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) with different concentrations of fluorine on demineralized enamel using electronic probe. Methods: Extracted premolar teeth for orthodontic purpose were immersed into lactic acid gel to prepare artificial white spot lesions (10 teeth in each group). Then the specimens were randomly assigned to three groups: Control group, with 5% of the CPP-ACP+deionized water; Group A with 5% CPP-ACP+500 mg/L F(-) and Group B with 5% CPP-ACP+900 mg/L F(-). The teeth in each group were soaked in different solutions for 4 days and then were measured using electron probe tester. The changes of contents among the three groups were compared. Results: No statistically significant difference in the percentage of fluorine was found in the control group before and after treatment (P=0.06), and the difference in the percentage of fluorine quality in the other two groups was statistically significant (P<0.05). Statistically significant difference was found between calcium oxide and phosphorus peroxide in the three groups before and after mineralization (P<0.05). The percentage change of fluorine mass in group B [(0.107+/-0.035)%] was significantly greater than that in group A [(0.057+/ 0.038)%] (P<0.05), while fluorine mass in group A was significantly greater than that in control group [(0.013+/-0.019)%] (P<0.05). In group A and group B, the change in quality of calcium oxide and phosphorus peroxide was significantly greater than that in control group (P<0.05), while no significant difference was found between group A and group B (P>0.05). Conclusions: The addition of fluorine in CPP-ACP increased the transport and penetration of calcium, phosphorus and fluorine on enamel surface. PMID- 29996366 TI - [Analyzing the social impact of orthodontic articles published by Chinese authors in international journals during the past five years]. AB - Objective: To evaluate and analyze the social impact of orthodontic articles published by Chinese authors in international journals during the past five years, using an altmetric tool; and to explore the practical value of altmetrics measures in the evaluation of dental research. Methods: PubMed was searched via the Altmetric Explorer platform to identify orthodontic research articles that were published during 2012-2016, with at least one affiliation from China. Commentaries, news reports and editorials were excluded. By reading titles and abstracts, two authors carried out inclusion and exclusion of literature independently to exclude articles that are not related to orthodontics and retracted articles. Data extraction was performed simultaneously. Any disagreement was resolved by discussion. Linear regressions were used to analyze the association between Altmetric attention score (AAS) and potentially related factors. Results: Among 864 articles identified from PubMed, a total of 206 received an AAS, and 160 articles were included for analyzing. The mean AAS of orthodontic research articles from China was 2.7 (95% confidence interval: 2.0 to 3.4). American Journal of Orthodontics and Dentofacial Orthopedics had the most scored articles (n=24) and the highest total AAS (67.0), while European Journal of Orthodontics had the highest mean AAS (3.8). All the top-3 articles were published in Cochrane Database of Systematic Reviews. Significant positive associations were found among high impact factors (P<0.05), high level of evidence (P<0.001) and the AAS. Conclusions: Publishing more high-impact articles and high level of evidence articles improved the international social impact of orthodontic research from China. As a valuable supplement to citation counts, Altmetric measures had practical values in dental research area. PMID- 29996367 TI - [A retrospective clinical study of 3 382 cases of malignant oral maxillofacial tumors]. AB - To investigate the incidence of malignant tumors in oral and maxillofacial region and the pathological features of various tumors, a total of 3 382 cases of malignant tumors in oral and maxillofacial region admitted to Jilin University from Januarary 2000 to December 2017. The characteristics of age, sex, location and pathological types of all kinds of tumors were analyzed. The median onset age is 57 years old, 51 to 70 years old is a high-risk age group, the ratio of male to female was 1.9?1. The primary tumor location is tongue, gingiva and floor of mouth. Epithelial, lymphatic hematopoietic system, bone and soft tissue were the three major sources of tumor tissue, and squamous cell carcinoma was the most common pathological type (65.1%), followed by mucoepidermoid carcinoma and adenoid cystic carcinoma. In summary, oral and maxillofacial malignancies have a high incidence in elderly men, and tongue is the most common site of disease. Epithelial-origin and squamous cell carcinomas are the first of their origins and pathological types, respectively. PMID- 29996368 TI - [Intentional replantation for treatment of a mandibular second molar with persistent chronic periapical periodontitis: a case report]. PMID- 29996369 TI - [Systemic contact dermatitis caused by cobalt-chromium-molybdenum alloy denture frameworks: a case report]. PMID- 29996370 TI - [Myositis ossificans progressia of lateral pterygoid muscle of both sides: a case report]. PMID- 29996371 TI - [Development of new technology in periodontal tissue engineering]. AB - The loss of periodontal support tissues might cause movement or finally loss of the teeth affected, impair furthermore the pronunciation and mastication functions, and even result in a series of physiological and psychological problems. Tissue engineering, as a technology to remodel missing tissues or organs and functional reconstruction, has achieved gratifying progress in regeneration of periodontal tissues. However, conventional construction methods have some deficiencies for functional periodontal reconstruction. In recent years, with the progress of tissue engineering technology, a series of new techniques and methods, such as cell sheet technology, decellular technology, electrospinning technology and three-dimensional printing, has been applied in tissue engineering bringing new hope for the regeneration of periodontal tissues. In this review article, the recent progress achieved in the field of periodontal tissue engineering and application of modern technology are summarized to make a brief exposition and to explore the future development of periodontal regeneration. PMID- 29996372 TI - [Advances in determination of median sagittal plane of facial soft tissue]. AB - Facial symmetry is a crucial component of human facial esthetics. Along with the increasing pursuit of aesthetic, in recent years, more and more researchers have focused on facial asymmetry assessment, of which determining the facial median sagittal plane is the first and most important step, and it will directly affect the accuracy of asymmetry evaluation and clinical treatment outcome. Limited by technical means, the earlier studies of facial soft tissue asymmetry assessment were mainly based on midline from two-dimensional (2D) images. Along with the development of three-dimensional (3D) measurement and data analysis techniques, new methods such as 3D landmark-based method and mirror-original alignment method have become main trend nowadays. This article systematically reviews the methods of determination of median sagittal plane of facial soft tissue, elaborates the developments and the latest research progress in this field, and discusses the advantages and limitations of each method in order to provide reference for clinical application. PMID- 29996373 TI - [Research advances in the v-raf murine sarcoma viral oncogene homolog gene mutation in ameloblastoma]. AB - V-raf murine sarcoma viral oncogene homolog B1 (BRAF) is a pro-oncogene, which is one member of the RAF family. Mutated BRAF is found in approximately 8% of human tumors. BRAF gene mutations lead to continuous activation of the mitogen-activatd protein kinase (MAPK) pathway, which resulting in abnormal cell proliferation and tumorigenesis. In recent years, recurrent MAPK signaling mutations were identified in ameloblastoma, among which BRAF-V600E is the most prominent type. This provides new strategies for the targeted treatment of ameloblastoma. This paper reviewed the latest advances in BRAF gene mutation associated with ameloblastoma and its potential clinical significance. PMID- 29996374 TI - [Effects of 3beta-HSD gene silence or overexpression on DEHP induced oxidative damage in MCF-7 cells]. AB - Objective: To study the oxidative damage of di- (2-ethylhexyl) phthalate (DEHP) on MCF-7 cells, and to investigate the effects of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene silence or overexpression on DEHP-induced oxidative damage. Methods: MCF-7 cells, 3beta-HSD gene silencing cells and 3beta HSD gene overexpression cells were treated with different doses of DEHP (0,0.05,0.1,0.2,0.4,0.8 mmol/L) for 24h, then intracellular oxidative damage index such as MDA, SOD, GSH, GSH-PX were detected, DNA repair gene hOGG1, hMTH1 mRNA expression were tested by Q-PCR, hOGG1, hMTH1 protein expression were detected by western blot. Results: After MCF-7 cells were treated by DEHP, MDA levels increased; SOD activity, GSH content, GSH-PX activity decreased, hOGG1 and hMTH1 mRNA expression levels increased, hOGG1 and hMTH1 protein expression levels increased, the differences were statistically significant when compared with control (P<0.05 or P<0.01) . In 3beta-HSD gene silencing cells which were treated by DEHP, when compared with the same dose group of MCF-7 cells, MDA content increased, SOD activity, GSH content, GSH-PX activity decreased, hOGG1 and hMTH1 mRNA expression levels decreased, hOGG1 and hMTH1 protein expression levels decreased, the difference were statistically significant (P<0.05 or P<0.01) . In 3beta-HSD gene overexpression cells which were treated by DEHP, when compared with the same dose group of MCF-7 cells, MDA content decreased; SOD activity, GSH content, GSH-PX activity increased, of hOGG1 and hMTH1 mRNA expression levels increased, hOGG1 and hMTH1 protein expression levels increased, the difference were statistically significant (P<0.05 or P<0.01) . Conclusion: DEHP could cause oxidative damage in MCF-7 cells, induce the changes of related genes and proteins, 3beta-HSD plays an antioxidant role in the process of DEHP ox-idative damage. PMID- 29996375 TI - [The effect of pulmonary injury in rats induced by paraquat]. AB - Objective: To study the effect of sodium aescinate on the development process of lung injury induced by paraquat. Methods: Forty-five health adult male SD rats were randomly divided into control group, PQ group, sodium aescinate group, and 15 rats in each group. The PQ group and sodium aescinate group were given a one time intraperitoneal injection of 18mg/kg body weight of rats PQ, the control group was given the same amout normal saline. Rats in sodium aescinate group were injected 2 mg/kg body weight sodium aescinate into abdominal cavity for 7 days continually, but the same volume of saline was injected into the other groups. Finally, at 7, 14 and 28 days after PQ poisoning, five rats were kills for measuring lung tissue pathological changes and the value of TGF-beta(1), TNF alpha, hydroxyproline in each group. Results: The expression of TNF-alpha in serum of 7th day [ (17.03+/-0.82) ng/ml] and 14th day [ (15.74+/-0.91) ng/ml] of sodium aescinate group were lower than the corresponding period of PQ groups', and the difference had statistical significance (P<0.05) . The expression of TGF beta(1) in serum of 7th day[ (225.93+/-8.33) ng/ml], 14th day [ (216.62+/-9.48) ng/ml] and 28th[ (181.41+/-6.10) ng/ml] of sodium aescinate group were lower than the corresponding period of PQ groups', and the difference had statistical significance (P<0.05) . Lung tissue pathological changes showed, compared with control group, inflammatory injury at 7th day and fibrosis degree at 28th of rats' lung reduced on sodium aescinate group. The expression of hydroxyproline in rats' lung of 7th day[ (1.246+/-0.018) MUg/mg], 14th day [ (1.269+/-0.034) MUg/mg] and 28th[ (1.283+/-0.028) MUg/mg] of sodium aescinate group were lower than the corresponding period of PQ groups', and the difference had statistical significance (P<0.05) . Conclusion: sodium aescinate could reduce the pulmonary inflammatory injury and hydroxyproline value of PQ poisoning rats, so sodium aescinate could ameliorate lung injury induced by PQ. PMID- 29996376 TI - [Effects of crystalline silica with different exposure patterns on lung fibrosis in rats]. AB - Objective: To investigate the effects of crystalline silica with different exposure patterns on lung fibrosis in rats. Methods: A total of 20 adult male Wistar rats were randomly divided into 4 groups consisting of five animals each and received intratracheal instillation of sterile saline or silica suspension in different patterns: saline once at day 0, saline once/week, crystalline silica 50 mg at day 0, crystalline silica 6.25 mg/week. The rats were sacrificed at 8 weeks. The lung tissues were collected for pathological analyses, and determining mRNA and protein levels of related fibrogenic molecules. Results: The collagen deposition induced by crystalline silica in lung tissues were increased. The mRNA levels of IL-1beta and Col I in group c were significantly elevated than those in group saline once at day 0 (all P<0.05). Compared with group saline once/week, the mRNA levels of IL-1beta, TGF-beta, Col I, Col III and CTGF were significantly increased in group crystalline silica 6.25 mg/week (P<0.05) . The mRNA levels of Col I and CTGF were significantly increased in group crystalline silica 6.25 mg/week in comparison with those in group crystalline silica 50 mg at day 0 (P<0.05) . Conclusion: Given the same cumulative dose of crystalline silica, multiple exposures were likely to induce more severe lung fibrosis. PMID- 29996377 TI - [The anti-inflammatory effect of hesperetin on lung damage induced by paraquat in rats]. AB - Objective: To investigate the anti-inflammatory effect of hesperetin (HSP) on lung damage induced by paraquat (PQ) in rats by detecting the levels of inflammatory makers in rat lung tissues. Methods: 140 Wistar male rats were randomly divided into negative control group, HSP control group, HSP control group, paraquat model group, pirfenidone (PDF) positive control group, and 100, 200, 400 mg/kg HSP treatment groups. All groups were exposed to 50mg/kg paraquat by oral gavage except for the negative control group and HSP control group. After 24 hours, the rats in each group were given drug intervention once daily. 10 rats were randomly sacrificed at 7th day and 28th day after exposure to paraquat respectively. 3 rats were randomly selected from them and HE, Masson staining were used to observe the pathological changes in the lungs of each group. Each group randomly selected 6 rats at two time points to detect the levels of TGF beta(1), TNF-alpha, IL-4, IL-10, IL-1beta and IFN-gamma in rat lung tissues. Results: Histopathological examination found that the lung injury were reduced in the rats of PDF positive control group and all HSP treatment groups. Compared with the negative control group, the levels of TGF-beta1, IL-1beta, TNF-alpha, IL 4, and IL-10 in rat lung tissues were significantly increased (P<0.05, P<0.01) after PQ exposure at two points in time, and there was no significant difference in the level of IFN-gamma in lung tissues compared with the negative control group (P>0.05) . The levels of TGF-beta1, IL-1beta, IL-4, IL-10 and TNF-alpha in the lung tissues of rats on the 7th day in different dose treatment groups of HSP were reduced compared with those in the PQ model group with varying degrees (P<0.05, P<0.01) . The level of IFN-gamma in lung tissues of rats were not significantly different from that of model group (P>0.05) . The levels of TGF beta(1) and TNF-alpha in lung tissue of rats on the 28th day in PDF positive control group and different dose treatment groups of HSP were reduced compared with those in the PQ model group with varying degrees (P<0.05, P<0.01). The levels of IFN-gamma in the rat lung tissues were increased compared with those in the PQ model group (P<0.05). Besides, there were no significant in the levels of IL-1beta, IL-4 and IL-10 in lung tissues compared with PQ model group (P>0.05). Conclusion: HSP can reduce lung damage induced by PQ in rats by inhibiting the release of inflammatory factors and promoting the secretion of anti-inflammatory factors. PMID- 29996378 TI - [A meta-analysis of the effect of occupational exposure to 1-bromopropane on workers' nerve conduction velocity]. AB - Objective: To analysis the occupational exposure to 1-bromopropane on the worker's nerve conduc-tion velocity. Methods: To PubMed, Wanfang, VIP, Chinese Journal Full-text Database (CNKI) and other databases as a data source, searched and screened database to October 2017 on occupational exposure to 1-bromopropane workers on the role of nerve conduction in the paper. According to inclusion and exclusion criteria, we screened literatures, extracted data and evaluated the quality of the included studies, using RevMan5.3 software to test the heterogeneity of the results and us-ing the corresponding mathematical model for data combination analysis. Results: A total of 5 articles were included in the literature. The results showed that the tibial nerve MCV of workers in the 1 bromopropane exposure group was slower than that in the control group (SMD= 0.47,95%CI=-0.70~-0.24) , the difference was statistically significant (Z=4.06, P<0.01). The tibial nerve DL of the exposure group was more prolonged than that of the control group (SMD=0.35,95%CI=0.00~0.69) , with a statistically significant difference (Z=1.99, P=0.05). The sural nerve SCV of the exposure group was slower than that of the control group (SMD=-0.47, 95%CI=-0.78~-0.15), with a statistically significant difference (Z=2.88,P<0.01). Conclusion: Occupational exposure to 1-bromopropane may have an effect on the worker's nerve conduction ve-locity.It's necessary to do broader and deeper neurotoxicity studies about 1-bromopropane. PMID- 29996379 TI - [Relationship between depressive symptoms and occupational stress in locomotive drivers]. AB - Objective: To explore relationship between depressive symptoms and occupational stress in locomotive drivers. Methods: By using cluster sampling method, a cross sectional study was conducted in 1413 train drivers (including passenger train drivers301, freight train drivers 683, passenger shunting train drivers350, and high speed train drivers79) from a railway bureau. The individual factors, depression, occupational stress, strains, personalities, coping strategy and social support were measured using occupational stress instruments, job content questionnaire and effort-reward imbalance questionnaire. Results: CThe differences of depression scores between take exercise and don't exercise groups were statistical significance (P<0.01) . The differences of depression scores among different age, length of service, job category, educational status,marital status, smoking and drinking groups were't statistical significance (P>0.05) .Correlation analysis revealed that depression score was related negatively to reward, job satisfaction, self-esteem, promotion opportunities, working stability and positively emotions score (P<0.01) , related positively to sleep disorders, effort, physiological needs, psychological need, daily stress, negative emotions, social support, esponsibility for person, responsibility for thing, conflict in the group, role conflict, role ambiguity score (P<0.01) . Nonparametric test analysis found that train drivers with high depression score reported higher psychological need, effort, promotion opportunities, role ambiguity, role conflict, conflict between groups, responsibility for person, responsibility for thing, physiological needs, daily stress, negative emotions, social support and copping strategies than those with moderate and lower depression score (P<0.01) , but the scores of job satisfaction, reword, self-esteem, working stability, positive emotions were lower than other groups those with moderate and lower depression score (P<0.01) . Multivariate logistic regression analysis revealed the risk of depression for drivers with more sleep disorder, low social support more than three times as high as that for drivers with few sleep disorder, hing social support (OR=3.615,3.266) .High negative emotions, more psychological need, high daily stress were more than twice times as high as that for drivers with low negative emotions, few psychological need, low daily stress (OR:2.444,2.489,2.065) . Conclusion: sleep disorder, low social support and job stress had larger effect on depression. To improve sleep, social support, self esteem and decrease job stress and negative emotions are main measures of decrease depression for train drivers. PMID- 29996380 TI - [Analysis of the characteristics of lymphocyte subsets in peripheral blood among coal worker's pneumoconiosis patients]. AB - Objective: To preliminary analysis of the characteristics of lymphocyte subsets in peripheral blood among 135 cases of coal worker's pneumoconiosis patients in Huainan mining area. Methods: The peripheral bloods of 135 cases of coal worker's pneumoconiosis patients and 112 cases of health examiners were collected. Flow cytometry was used to detect peripheral blood lymphocytes, T cell subsets and CD4(+)CD25(+) regulatory T cells. Results: Compared with the control group, CD64 index of granulocytes and lymphocytes was slightly higher. The total T cells (CD3(+)) increased in peripheral blood, CD4(+) expression was reduced and CD8(+) expression was increased in infection group, CD4(+)/CD8(+) ratio was inverted, the differences between the infection group and the control group were statistically significant (P<0.05) . There were significantly fewer NK (nature killer) and B cells, significantly more double negative T cells (DNT, CD3(+)CD4( )CD8(-)) than the control group (P<0.05) . There was no statistically significant difference of CD4(+)CD25(+)CD127(+low),CD4(+)CD25(+)CD127(+hi) and the ration of Treg/CD4(+)CD25(+)CD127(+hi) protein expression in peripheral blood in two groups (P>0.05) . Conclusion: The analysis of peripheral blood lymphocyte and subgroup is an ideal index to monitor the immune status of coal worker's pneumoconiosis patients. It has theoretical significance for studying the immune mechanism of pneumoconiosis and guiding clinical treatment. PMID- 29996381 TI - [Results analysis of occupational physical examination for silica dust, benzene and noise-exposed laborer in 2016 in Guangzhou City]. AB - Objective: To analyze the results of occupational physical examination for silica dust, benzene and noise-exposed laborer in 2016 in Guangzhou, to provide basis for occupational health supervise. Methods: The data were derived from "occupational disease and health information surveillance system" and the summary data reported by all the occupational physical examination agencies, and analyzed by descriptive epidemiology method. Results: 77506 data from 21 agencies of 12 district were collected, and 63 suspected occupational disease were detected, which including 1 silicosis, 8 benzene poisoning, 54 noise deafness. Conclusion: Noise exposure was distributed widely, noise deafness had to be focused on, occupational chronic benzene poisoning and silicosis should be monitored continuously. Small, foreign economy and manufacturing industry should be supervised firstly. PMID- 29996383 TI - [Analysis of 166 cases of the 3rd stage of pneumoconiosis]. PMID- 29996382 TI - [Relationship between neutrophil-to-lymphocyte ratio and myocardial injury induced by acute carbon monoxide poisoning]. AB - Objective: To investigate the relationship between neutrophil-to-lymphocyte ratio (NLR) and myocardial injury induced by acute carbon monoxide poisoning. Methods: A retrospective analysis was performed on 214 patients with acute carbon monoxide poisoning who were admitted to Emergency Depart-ment of Harrison International Peace Hospital, Hebei Medical University, from 2015 to 2017. According to the diagnostic criteria for toxic heart disease and the level of cardiac troponin I (cTnI), a biomarker of cardiac injury, these patients were divided into myocardial injury group (n = 84) and non-myocardial injury group (n=130). The general information of age and sex, as well as routine blood test results and cardiac injury biomarkers on admission, were collected. NLR was calculated and compared between the two groups. The relationship between NLR and cTnI was analyzed. Logistic regression analysis was used to identify the influenc-ing factors for myocardial injury induced by acute carbon monoxide poisoning. The receiver operating charac-teristic curve was used to evaluate the predictive value of NLR on admission for myocardial injury induced by acute carbon monoxide poisoning. Results: There were significant differences between two groups in male patients, the history of smoking, white blood cell count (WBC), NLR, creatine kinase-MB, and lactate dehydro-genase(P<0.01). In the myocardial injury group, NLR was positively correlated with cTnI (r=0.295, P<0.01). The multivariate logistic regression analysis showed that NLR (odds ratio OR=1.079, 95% confidence inter-val CI: 1.017~1.144, P<0.01), WBC (OR=1.216, 95% CI: 1.098~1.346, P<0.01), and male sex (OR = 2.693, 95% CI: 1.045~6.939, P= 0.05) were independent risk factors for myocardial injury induced by acute carbon monoxide poisoning. In predicting myocardial injury induced by acute carbon monoxide poisoning, NLR on admission had a sensitivity of 85.7% and a specificity of 45.4% at the optimal cut-off value of 4.83. Conclusion: Increased NLR on admission has a certain predictive value for myocardial injury induced by acute carbon monoxide poisoning. PMID- 29996385 TI - [Recurrent nitric acid smoke exposure induced acute chemical lung injury:a case report]. PMID- 29996384 TI - [A case of Kounis syndrome in patients with occupational asthma]. PMID- 29996386 TI - [Two cases of mandalo poisoning]. PMID- 29996387 TI - [Analysis of two cases of occupational inhalation of methanol induced blindness]. PMID- 29996389 TI - [Nursing of 51 cases of acute occupational hand tendon injury]. PMID- 29996388 TI - [A case report of the treatment of oral high dose mercury poisoning]. PMID- 29996390 TI - [A suspected case of toluene and xylene poisoning]. PMID- 29996391 TI - [Simultaneous determination of 21 organophosphrous pesticides in human serum by QuEChERS-gas chromatography-mass spectrometry]. AB - Objective: A method for the simultaneous determination of organophosphrous pesticides inhuman serum was developed. Methods: Using C18 and PSA as absorbent, 21 organophosphrous pesticides including methamidophos, dichlorvos, acephate, Omethoate, demeton and etc. in human serum were determined by combing QuEChERS with GC-MS, organophosphrous pesticides were qualitatedsimultaneously by retention time and characteristic ions. Their contents were determined by internal standard method of quantitative ions. Results: The linear range was from0to 0.60MUg/ml with a good correlation coefficients (r >= 0.9961) . The LODs of this methodranged from 0.0009 to 0.0111 MUg/ml. The average recoveries of3 organophosphrous pesticides (methamidophos,dichlorvos and acephate) ranged from 71.8%~85.3%, The average recoveries of other 18 organophosphrous pesticidesranged from 82.9%~102.9%. The relative standard deviations were0.8%~7.0%. Conclusion: The convenient operation and versatility of this method are suitable forthe fast screening and accurate detection of 21 organophosphrous pesticides in human serum. PMID- 29996393 TI - [Influence of microRNA on pulmonary fibrosis by regulating TGF-beta signaling pathways]. PMID- 29996394 TI - [Research progress in biomarkers of N-hexane]. PMID- 29996392 TI - [Study on the determination of pyrrole adduct content in hair samples]. AB - Objective: To find out a method to determine the pyrrole adducts in the hairs. Methods: Collected the hair from common people and rats, defatted after completely washed, steeped the hair in different concentration of 2, 5-hexandione to build hair model containing pyrrole adducts; dissolved the hair and determined the concentration of pyrrole adducts. Results: (1) . The combination of 0.72 mol/L of sodium hydrate and 2% tyrisin could dissolve the hair, and the digestion liquid could react with the Ehrlich's reagent showing fuchsia color; (2) . The color could maintain longer after adding more ethanol; (3) . More pyrrole adducts would be produced by the increasing the concentration of 2, 5-dihexandione (P<0.01) ; (4) . Concentration of pyrrole adducts in n-hexane treated hair showed no difference compared with control (P>0.05) . Conclusion: the method could be used to determine the concentration of pyrrole adducts in hair exposed to n hexane. PMID- 29996395 TI - [Research progress in the mechaaism of lung injnry caused by aute organophosphorus compounds poisoning]. PMID- 29996396 TI - [Fire smoke inhalation induced lung injury:an update]. PMID- 29996397 TI - Juvenile coho salmon growth and health in streams across an urbanization gradient. AB - Expanding human population and urbanization alters freshwater systems through structural changes to habitat, temperature effects from increased runoff and reduced canopy cover, altered flows, and increased toxicants. Current stream assessments stop short of measuring health or condition of species utilizing these freshwater habitats and fail to link specific stressors mechanistically to the health of organisms in the stream. Juvenile fish growth integrates both external and internal conditions providing a useful indicator of habitat quality and ecosystem health. Thus, there is a need to account for ecological and environmental influences on fish growth accurately. Bioenergetics models can simulate changes in growth and consumption in response to environmental conditions and food availability to account for interactions between an organism's environmental experience and utilization of available resources. The bioenergetics approach accounts for how thermal regime, food supply, and food quality affect fish growth. This study used a bioenergetics modeling approach to evaluate the environmental factors influencing juvenile coho salmon growth among ten Pacific Northwest streams spanning an urban gradient. Urban streams tended to be warmer, have earlier emergence dates and stronger early season growth. However, fish in urban streams experienced increased stress through lower growth efficiencies, especially later in the summer as temperatures warmed, with as much as a 16.6% reduction when compared to fish from other streams. Bioenergetics modeling successfully characterized salmonid growth in small perennial streams as part of a more extensive monitoring program and provides a powerful assessment tool for characterizing mixed life-stage specific responses in urban streams. PMID- 29996398 TI - Extra CO2 sequestration following reutilization of biomass ash. AB - Although combustion ashes are usually used in soils, little attention is paid to the CO2 sequestration potential of this practice. The present study aims to quantify carbon sequestration as carbonate compounds in a tailored synthetic calcareous soil treated with biomass ash from a gasification power plant that uses olive cake. It is estimated that after ash amendment, 14.5g CO2 remained fixed per kg of fly biomass ash, 16.5g CO2 per kg of bottom biomass ash with plant cultivation and 19.7g CO2 per kg of bottom biomass ash without plant cultivation. This inorganic C fixation plus the organic (black) C contained in the ashes made the reutilization of ashes as K fertilizer a relevant practice due to its C resilience and rate, with a yearly C sequestering potential of ca. 8% of 'Soil carbon 4 per mille' goal, an initiative launched at the COP21. PMID- 29996399 TI - Effect of soil washing with biodegradable chelators on the toxicity of residual metals and soil biological properties. AB - Soil washing with chelators is a promising and efficient method of remediating metals-contaminated soils. However, the toxicity of residual metals and the effects on soil microbial properties have remained largely unknown after washing. In this study, we employed four biodegradable chelators for removal of metals from contaminated soils: iminodisuccinic acid (ISA), glutamate-N,N-diacetic acid (GLDA), glucomonocarbonic acid (GCA), and polyaspartic acid (PASP). The maximum removal efficiencies for Cd, Pb, and Zn of 85, 55, and 64% and 45, 53, and 32% were achieved from farmland soil and mine soil using biodegradable chelators, respectively. It was found that the capacity of ISA and GLDA to reduce the labile fraction of Cd, Pb, and Zn was similar to that of the conventional non biodegradable chelator ethylenediaminetetraacetic acid (EDTA). The leachability, mobility, and bioaccessibility of residual metals after washing decreased notably in comparison to the original soils, thus mitigating the estimated environmental and human health risks. Soil beta-glucosidase activity, urease activity, acid phosphatase activity, microbial biomass nitrogen, and microbial biomass phosphorus decreased in the treated soils. However, compared with EDTA treatment, soil enzyme activities distinctly increased by 5-94% and overall microbial biomass slightly improved in the remediated soils, which would facilitate reuse of the washed soils. Based on soil toxicity tests that employed wheat seed germination as the endpoint of assessment, the washed soils exhibited only slight effects especially after ISA and GLDA treatments, following high-efficiency metal removal. Hence, ISA and GLDA appear to possess the greatest potential to rehabilitate polluted soils with limited toxicity remaining. PMID- 29996400 TI - Predicting sediment yield and transport dynamics of a cold climate region watershed in changing climate. AB - The effects of climate change on sediment yield and transport dynamics in cold climate regions are not well understood or reported. In this study, the Soil and Water Assessment Tool (SWAT) has been built-up, calibrated, and validated against streamflow and sediment load at several monitoring stations in a cold climate region watershed - the Athabasca River Basin (ARB) in Alberta, Canada. The model was then fed with bias-corrected spatial disaggregated high-resolution (~10km) future climate data from three climate models for two emission scenarios (RCP 4.5 and 8.5), and two periods (mid- and end-century). Results show that channel erosion and deposition are the dominant processes over hill slope erosion in the basin. On average, a predicted warmer and wetter future climate has both synergetic and offsetting effects on sediment yield. Changes are sub-region specific and land-use type dependent, thus reflecting a marked spatial and temporal heterogeneity within the basin. Increases on sediment yield in future periods in the agricultural areas are up to 0.94t/ha/yr, and are greater than reported soil formation rates in the region. Similarly, while substantial increases (by more than two fold) in the sediment load transport through the river reaches were obtained, the changes show both temporal and spatial variability, and are closely aligned with the trend of stream flows. We believe that availability of such models and knowledge of the effect of future climatic conditions would help water managers formulate appropriate scenarios to manage such basins in a holistic way. However, significant uncertainties in future sediment yield and transport, as a result of variations in climatic forcing of different climate models, need to be considered in any adaptation measures. PMID- 29996401 TI - Screening of organic flame retardants in Swedish river water. AB - Alternative flame retardants (FRs) have now replaced legacy FRs (such as polybrominated diphenyl ethers, PBDEs), but little is known about their fate in the aquatic environment. In this study, a range of legacy FRs (n=10) and alternative FRs, including halogenated FRs (HFRs, n=32) and organophosphorus FRs (OPFRs, n=19), were screened in water samples collected from 23 rivers covering the whole latitudinal range of Sweden. Of the 61 targeted FRs, 26 were detected in at least one of the river samples, with SigmaFR concentrations ranging up to 170ngL-1 (mean 31+/-45ngL-1). In general, higher concentrations and a larger variety of FRs were detected in southern Sweden (SigmaFR=60+/-56ngL-1) compared with the north (SigmaFR=9.0+/-16ngL-1). In the south, HFRs were dominant, constituting on average 59% of ?FRs, whereas in the north, OPFRs were dominant, constituting on average 82% of ?FRs. This difference was best explained by higher population density in the south. The total daily flux of FRs into the Baltic Sea was estimated to be ~31kg and comprised mainly tetrabromobisphenol-A (TBBPA), 3,4,5,6-tetrabromophthalic anhydride (TEBP-Anh), and 2,4,6-tribromophenol (TBP). To the best of our knowledge, this is the first report of environmental occurrence of TEBP-Anh, which was detected in two rivers and is suggested to originate from airports located near the sampling sites. PMID- 29996402 TI - Occurrence and distribution of organophosphate flame retardants (OPFRs) in soil and outdoor settled dust from a multi-waste recycling area in China. AB - Distribution of 12 organophosphate flame retardants (OPFRs) was determined in soil and outdoor settled dust samples collected from a multi-waste (electronic, plastic, and rubber wastes and abandoned household-appliances and vehicles) recycling area, that encompassed different modes of operation i.e. open (ORS) and semi-closed recycling (SCRS). Among the twelve OPFRs analyzed, eleven were detected at a frequency of 75%-100% in all soil and dust samples. In soil samples, SigmaOPFR concentrations were significantly higher at ORS (122-2100ng/g) than at SCRS (58.5-316ng/g) and nearby farmlands (37.7-156ng/g). The SigmaOPFR concentrations in dust samples were higher than those in soil samples with spatial distribution similar to that observed for soil, decreasing from ORS (1390 42,700ng/g) to SCRS (914-7940ng/g). Tris(2-chloroisopropyl) phosphate (TCIPP) was the major OPFRs in both soil (80% trajectories, <500m), whereas the probability of haze trajectories across mixing layer was relatively low and generally associated with much longer transport distance and higher terrain height over Western China. Combing the vertical exchange analysis, results also show that Wuyi Mountains and Nanling Mountains played a role as barrier to obstruct the haze airflows from other regions of China to the Guangdong province. PMID- 29996406 TI - Estimating potential dust emissions from biochar amended soils under simulated tillage. AB - Although biochars may provide agricultural benefits, the potential risks related to agricultural dust emissions have not been adequately investigated. This study examines the impact of biochar type (WS 900: walnut shell, 900 degrees C; PW 500, PW 700 and PW 900: pine wood, 500, 700, 900 degrees C), biochar application rate (0, 1, 2, 5% wt.) and soil water content (low, medium and high) on dust emissions in two different textured-soils (silt loam, sandy loam). Dust was produced via a dust generator simulating soil disturbance (e.g, tillage) and dust fractions with an aerodynamic diameter under 100MUm and 10MUm (PM100 and PM10) were collected. The data indicate that the higher application rate of WS 900 led to higher PM100 and PM10 emissions while PW biochar treatments emitted equivalent amounts of dust as controls (non-amended soils). Dust emissions were exponentially reduced as soil water content increased, irrespective of biochar's presence. Specific markers for biochar, benzene polycarboxylic acids (BPCAs), were used to estimate the biochar content within dust. Results indicate that the increased dust emissions from WS 900 treatments mainly derive from soil particles due to the greater dispersion potential of WS 900 biochar. The collected data also reveal that PM10 dust contains less biochar particles than PM100, attributed to biochars originally containing negligible amounts of particles <10MUm. PMID- 29996405 TI - Monitoring the degradation of atropine and scopolamine in soil after spiking with naturally contaminated organic millet. AB - The spread of Datura sp. in European countries influences crop management and implies continuous food safety issues because of tropane alkaloids, atropine and scopolamine, the most relevant natural toxic compounds of this weed. These alkaloids can contaminate cereals to such a level that hampers food/feed related use and diverts batches of contaminated raw materials towards ultimate disposal such as burning. As no unambiguous information has been available on the fate of tropane alkaloids in soils, our study focused on the quantification and follow-up of these toxic residues in a soil experiment where the tropane alkaloids were mixed to the soil in the form of naturally contaminated unhulled millet in 1:40 millet:soil ratio - this approach provides a more realistic scenario compared to standard solution based spiking. To achieve accurate results, soil and millet extraction processes have been validated and a liquid chromatography - mass spectrometry set-up was addressed to provide selective and quantitative analysis. The initial concentration of atropine (75ngg-1) and scopolamine (47ngg-1) in the soil decreased with >90% in 15days and reached a high level of elimination (>97%) in 29days. This observation opens an option for the use of tropane contaminated millet or millet waste other than burning, as these toxic alkaloids can be significantly degraded in the soil system. On the other hand, the persistence of intact tropane alkaloids in soils might be questioned to the extent that calls the attention to the (re)assignment of their supposed allelopathic effects. PMID- 29996407 TI - Water supply and feed as sources of antimicrobial-resistant Enterococcus spp. in aquacultures of rainbow trout (Oncorhyncus mykiss), Portugal. AB - The role of European fish farms in the spread of antimicrobial-resistance in the environment and food chain, as well as possible sources of their contamination by clinically relevant antimicrobial-resistance bacteria is scarcely known. This study aimed to assess the contribution of Portuguese rural trout farms on dispersion of Enterococcus with antimicrobial-resistance and putative virulence genes in the environment and food chain, as well as to identify farms contamination sources. We also assessed the presence of Enterococcus with low levels of antimicrobial-resistance using epidemiological cut-offs (ECOFFs). Enterococcus spp. (n=391) from water/sediment recovered upstream, within and downstream trout tanks, feed, trout (2 aquacultures; no antibiotic use) and marketed trout (8 supermarkets) showed variable resistance to tetracycline, erythromycin, ciprofloxacin, chloramphenicol, quinupristin-dalfopristin, nitrofurantoin or aminoglycosides. Antimicrobial-resistance rates were similar among upstream, within and downstream trout tank samples (P>0.05), positioning water-supplying aquacultures as a source of multidrug-resistant (MDR) strains. Nevertheless, predominance of MDR E. faecium in feed, trout tanks and trout comparing to upstream samples, suggests feed as an additional aquaculture contamination source. The observation of E. faecium and E. faecalis susceptible to ampicillin and gentamicin by clinical breakpoints but with low-levels of resistance to those antimicrobials by ECOFFs breakpoints is of concern, as they might evolve throughout secondary genetic events to resistance levels with human clinical impact. Multiple MDR clones carrying copper tolerance (tcrB/cueO), putative virulence or other genes often associated with clinical strains (e.g. E. faecium with IS16/ptsD/sgrA) were observed, some in distinct samples (e.g. upstream and within trout tanks). They included major human and animal Enterococcus lineages, suggesting human and non-aquatic animal origins. The results highlight the need to define the maximum acceptance level of antimicrobial-resistance genes/bacteria to assess water quality and to monitor antimicrobial-resistance strains on feed, essential requirements to maintain a sustainable aquaculture production. PMID- 29996408 TI - Differential responses to high soil chromium of two arbuscular mycorrhizal fungi communities isolated from Cr-polluted and non-polluted rhizospheres of Ricinus communis. PMID- 29996409 TI - Using REACH registration data to rank the environmental emission potential of persistent and mobile organic chemicals. AB - Organic chemicals that are persistent and mobile in the aquatic environment exhibit a hazard to contaminate drinking water resources. In this study an emission score model was developed to rank the potential of substances registered under the REACH legislation to be emitted into the environment. It was applied to a list of 2167 REACH registered substances that were previously identified to be persistent and mobile organic chemicals (PMOCs) in groundwater or to be hydrolyzed to form transformation products fulfilling the PMOC criteria. The emission score model is based on the tonnage placed on the European market and on seven emission-related use characteristics (high release to environment, wide dispersive use, intermediate use, closed system use, professional use, consumer use, and substance in article), reported in the companies' registrations under REACH. Applying the model resulted in a list of 1110 substances (936 PMOCs and 174 precursors to PMOCs) that were estimated to be released into the environment, while 1054 substances had indicators of negligible environmental emissions and 3 substances could not be evaluated due to severe data gaps. The 936 PMOCs and the 174 precursors were ranked in two lists with regard to their emission potential. The model was shown to be fit for purpose in terms of suggesting and prioritizing substances for scientific investigations with a focus on environmental water quality. Though targeted for PMOCs, the presented scoring system is illustrative of how REACH registration data can be used to assess the emission potential of various substances. PMID- 29996410 TI - Long-term changes (1990-2015) in the atmospheric deposition and runoff water chemistry of sulphate, inorganic nitrogen and acidity for forested catchments in Europe in relation to changes in emissions and hydrometeorological conditions. AB - The international Long-Term Ecological Research Network (ILTER) encompasses hundreds of long-term research/monitoring sites located in a wide array of ecosystems that can help us understand environmental change across the globe. We evaluated long-term trends (1990-2015) for bulk deposition, throughfall and runoff water chemistry and fluxes, and climatic variables in 25 forested catchments in Europe belonging to the UNECE International Cooperative Programme on Integrated Monitoring of Air Pollution Effects on Ecosystems (ICP IM). Many of the IM sites form part of the monitoring infrastructures of this larger ILTER network. Trends were evaluated for monthly concentrations of non-marine (anthropogenic fraction, denoted as x) sulphate (xSO4) and base cations x(Ca+Mg), hydrogen ion (H+), inorganic N (NO3 and NH4) and ANC (Acid Neutralising Capacity) and their respective fluxes into and out of the catchments and for monthly precipitation, runoff and air temperature. A significant decrease of xSO4 deposition resulted in decreases in concentrations and fluxes of xSO4 in runoff, being significant at 90% and 60% of the sites, respectively. Bulk deposition of NO3 and NH4 decreased significantly at 60-80% (concentrations) and 40-60% (fluxes) of the sites. Concentrations and fluxes of NO3 in runoff decreased at 73% and 63% of the sites, respectively, and NO3 concentrations decreased significantly at 50% of the sites. Thus, the LTER/ICP IM network confirms the positive effects of the emission reductions in Europe. Air temperature increased significantly at 61% of the sites, while trends for precipitation and runoff were rarely significant. The site-specific variation of xSO4 concentrations in runoff was most strongly explained by deposition. Climatic variables and deposition explained the variation of inorganic N concentrations in runoff at single sites poorly, and as yet there are no clear signs of a consistent deposition-driven or climate-driven increase in inorganic N exports in the catchments. PMID- 29996411 TI - Resin-tapped pine forests in Spain: Ecological diversity and economic valuation. PMID- 29996412 TI - Deca-BDE and alternative halogenated flame retardants in a wastewater treatment plant in Harbin (2009-2016): Occurrence, temporal trends, seasonal variation, and fate. AB - This study is the first attempt to comprehensively investigate deca-BDE and alternative flame retardants in a wastewater treatment plant in such a long term in China (2009-2016). Influent, effluent and sludge samples were collected. The mean concentration of deca-BDE, Sigma19NBFRs and SigmaDPs in influent were 311.5, 76.0 and 1.4ng/L, respectively, which were at the low end of the global range. The levels of deca-BDE, Sigma19NBFRs and SigmaDPs in effluent were range from 9.5 68.6, 4.1-38.5 and BLD-1.6ng/L, respectively. In sludge samples, the mean concentrations were 406.7, 510.5 and 6.9ng/g dw for deca-BDE, Sigma19NBFRs and SigmaDPs. The concentration of temporal trends in this study may reflected the release of those compounds. Compared to the beginning year of this study, the usage of deca-BDE was decreased but the usage of total NBFRs and DPs presented sustained increase over the sampling period. There were no significant variation of deca-BDE, NBFRs and DPs in the wastewater treatment plant in Harbin was observed in the four seasons except for NBFRs in influents, which the Sigma19NBFRs mean concentration in influents in the summer was statistically significantly higher than that in winter indicating that NBFRs was easier impacted by temperature compared to deca-BDE and DPs. In addition, sorption and accumulation to sludge was the major removal mechanism for those compounds, accounting for 73.3% to 89.0%. PMID- 29996413 TI - A model for predicting organic compounds concentration change in water associated with horizontal hydraulic fracturing. AB - Horizontal drilling and hydraulic fracturing are technologies designed to increase natural gas flow and to improve productivity in low permeability formations. During this drilling operation, tons of flowback and produced water, which contain several organic compounds, return to the surface with a potential risk of influencing the surrounding environment and human health. In order to conduct predictive risk assessments a mathematical model is needed to evaluate organic compound behaviour along the water transportation process as well as concentration changes over time throughout the operational life cycle. A comprehensive model, which fits the experimental data, combining an Organic Matter Transport Dynamic Model with a Two-Compartment First-order Rate Constant (TFRC) Model has been established to quantify the organic compounds concentrations. This algorithm model incorporates two transportation rates, fast and slow. The results show that the higher the value of the organic carbon partition coefficient (koc) in chemicals, the later the maximum concentration in water will be reached. The maximum concentration percentage would reach up to 90% of the available concentration of each compound in shale formation (whose origin may be associated to drilling fluid, connate water and/or rock matrix) over a sufficiently long period of time. This model could serve as a contribution to enhance monitoring strategy, increase benefits out of optimizing health risk assessment for local residents and provide initial baseline data to further operations. PMID- 29996414 TI - The change of representative elementary volume of DNAPL influenced by surface active agents during long-term remediation period in heterogeneous porous media. AB - Representative elementary volume (REV) is important to characterize dense nonaqueous phase liquids (DNAPLs) during surfactant-Enhanced aquifer remediation (SEAR) period. To investigate the REVs of DNAPL in remediation, a perchloroethylene (PCE) SEAR experiment is conducted in a two dimensional (2D) heterogeneous translucent porous media. Light transmission techniques are used to quantify PCE saturation (Soil) and PCE-water interfacial area (AOW). Afterward, corresponding REVs are estimated using a criterion of relative gradient error (epsilongi) to reveal the change of REVs of DNAPL over the entire remediation period. Results from this work suggest the presence of surface active agents strongly affect the REVs of DNAPL. At the beginning of the SEAR experiment, the frequency of minimum Soil-REV size closely follows a Gaussian distribution in 0.0mm-11.0mm. Simultaneously, the frequency of minimum AOW-REV size is close to a Gaussian distribution in 2.0mm-9.0mm and appears a peak value in 13.0mm-14.0mm. As SEAR experiment proceeds, both the shapes of frequency and cumulative frequency of REV sizes are changed. At the end of SEAR experiment, the frequency of minimum Soil-REV and minimum AOW-REV size tend to Gaussian distributions in 0.0mm-6.0mm and 0.0mm-9.0mm, respectively, which suggest both minimum Soil-REV size and minimum AOW-REV size show decreasing tendency. Continuous quantification of the REVs of DNAPL is realized in this study to reveal the change of REVs influenced by surface active agent. The finding has important significance on improving our understanding of the characteristics of DNAPL in SEAR process, simulating DNAPL remediation and designing appropriate remediation scheme with high-resolution. PMID- 29996415 TI - Urinary phthalate metabolites concentrations and symptoms of depression in an elderly population. AB - BACKGROUND: Animal studies have reported an association between phthalates and depression, although there is limited evidence from epidemiological studies. We investigated the association between phthalate exposure and symptoms of depression in an elderly population. METHODS: Repeated measures surveys up to three times were conducted during the study period (2012-2014) in the 535 elderly subjects. We measured the following urinary phthalate metabolite levels: mono(2 ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate (MnBP), and mono-benzyl phthalate (MBzP). MEHHP, MEOHP, and MECPP are metabolites of diethylhexyl phthalates (DEHP). MnBP and MBzP are metabolites of dibutyl phthalate and butyl benzyl phthalate, respectively. The phthalate metabolite concentrations were evaluated to identify associations with the symptoms of depression using the Korean version of the Geriatric Depression Scale-Short Form (SGDS-K). After factor analysis of the components of SGDS-K, we evaluated the association between phthalate exposure and SGDS-K subgroups to determine which symptoms of depression were affected by phthalate exposure. RESULTS: Concentrations of DEHP metabolites were positively associated with the risk of depressive symptoms in the elderly population (Odds ratio (95% confidence interval); 1.92 (1.17-3.13) for sum of three DEHP metabolites), while we found no significant association between depressive symptoms and either MnBP or MBzP. When we evaluated the associations between phthalate metabolite concentrations and the SDGS-K subgroup, we found that affective and spiritual symptoms were significantly associated with DEHP metabolite concentrations. CONCLUSIONS: Our study suggests that DEHP exposure is associated with depressive symptoms, particularly, the affective and spiritual symptoms, among the elderly population. PMID- 29996416 TI - Municipal wastewater effluent characterization and variability analysis in view of an ozone dose control strategy during tertiary treatment: The status in Belgium. AB - Ozonation is known for removing trace organic contaminants (TrOCs) from secondary wastewater effluent. However, its implementation and overall efficiency on a broad scale depends on effluent characteristics, which can differ both in time as well as between different treatment plants (nowadays referred to as water resource recovery facilities (WRRFs)). Therefore, water quality was assessed over time at 15 different Belgian sampling locations to increase the understanding of effluent variability in view of online control of the tertiary ozonation step. Conventional and surrogate parameters as well as those specifically related to tertiary ozonation (e.g. instantaneous ozone demand) were assessed. Little differences between the different locations were found for spectral measurements (e.g. UVA254 or fluorescence). The small amount of observed outliers was clearly site or event dependent. A lower variability (for spectral measurements) is advantageous in simplifying the development and application of a generic control framework based on these spectral measurements. In addition, also variations in TrOC concentration levels seemed to be small, as the concentration of most individual compounds resided within one order of magnitude over multiple sampling events at two different WRRFs. The combination of this low variability in TrOC levels in the effluent before ozonation with a control strategy using a TrOC removal efficiency set-point, allows to indicatively assess absolute TrOC levels after ozonation. In contrast, significant variations between different plants (especially smaller sized plants) were observed and could be related to the conventional water quality parameters alkalinity (correlated with the electrical conductivity) and pH which are both known to have an influence on the ozonation process. This confirms that a differential dosing control strategy (i.e. accounting for the matrix reactivity) should be applied instead of one solely based on the (organic) effluent load before ozonation. PMID- 29996417 TI - Evaluating the utility of solar-induced chlorophyll fluorescence for drought monitoring by comparison with NDVI derived from wheat canopy. AB - Normalized Difference Vegetation Index (NDVI) has been extensively used in continuous and long-term drought monitoring over large-scale, but with late response to drought-related changes of photosynthesis. Instead, solar-induced chlorophyll fluorescence (SIF) is more closely related to photosynthesis and thus is proposed to track the impacts of drought on vegetation growth. However, the detailed difference between SIF and NDVI in responding to drought has not been thoroughly explored. Here we present continuous ground measurements of NDVI and SIF at 760nm over four plots of wheat with different intensities of drought (well watered treatment, moderate drought, severe drought and extreme drought). The average values of seasonal SIF were significantly lower under severe drought and extreme drought, while NDVI means only showed significant reduction in extreme drought. In the seasonal patterns, daily SIF could clearly separate the difference of drought gradient, while the difference of daily NDVI was clearer in the end of the field campaign. Daily SIF also significantly and positively correlated with soil moisture, indicating that SIF could be considered as an estimator of soil moisture to detect the information about agricultural drought. Furthermore, in extreme drought plot, the correlation of SIF and soil moisture was higher than that of NDVI and soil moisture in a shorter time lag (<15-day) but weaker in a longer time lag (longer than 30-day). The relationships of growth parameters with SIF and NDVI were further analyzed, showing a saturation of NDVI and unsaturation of SIF at high values of leaf area index and relative water content. These results suggested that SIF is better fit in early drought monitoring, especially over closure canopy, while NDVI is more feasible when drought lasted over a long time scale. Our findings in the study might provide deep insight into the utility of SIF in drought monitoring. PMID- 29996418 TI - Effects of biochar application on the abundance and community composition of denitrifying bacteria in a reclaimed soil from coal mining subsidence area. AB - As a new soil amendment, biochar has become an environmentally friendly material. The application of biochar is one of the most promising management practice to improve soil quality. Using a reclaimed soil from a coal mine subsidence area, the plat soil cultivation experiment in this study investigated the effects of biochar application at varying rates on soil properties, the abundance and composition of soil denitrifier communities. Biochar application significantly increased the crop yield which might be associated with the increased level of cation exchange capacity (CEC), total nitrogen (N), ammonium-N, available phosphorus (P) and potassium (K) in soil. In combination with N fertilizer, the abundance of both nirK and nirS genes significantly increased only at biochar application rate of 4% compared with the nil-biochar treatment. Biochar application significantly increased the community diversity of nirK gene, while not for nirS gene. Redundancy analysis showed that the level of nitrate-N (NO3- N), available P, and pH in soil significantly affected community structure of nirK gene, while the nirS community composition was only affected by soil NO3--N level. Our results indicate that biochar application to the reclaimed soil in coal mine subsidence area could influence the abundance and diversity of soil denitrifiers and improve soil nutrients thus crop yield. PMID- 29996419 TI - Toxic effects of human pharmaceuticals to Folsomia candida - A multigeneration approach. PMID- 29996420 TI - Assessing Cu impacts on freshwater diatoms: biochemical and metabolomic responses of Tabellaria flocculosa (Roth) Kutzing. AB - Metals are a recognised threat to aquatic organisms but the impact of metals such as copper (Cu) on benthic freshwater diatoms is poorly understood, even if diatoms are commonly used as water quality indicators. Our study aimed to elucidate the cellular targets of Cu toxicity and the mechanisms cells resort to counteract toxicity and to increase tolerance to Cu. A concerted approach analysing the biochemical, physiological and metabolome alterations in diatom cells was conducted by exposing the freshwater diatom Tabellaria flocculosa to 0, 0.3, 6 and 10MUgCu/L. Cu was already toxic to T. flocculosa at concentrations common in environments and which are not usually considered to be contaminated (0.3MUgCu/L). Under Cu impact, the metabolome of T. flocculosa changed significantly, especially at high concentrations (6 and 10MUgCu/L). Cu toxicity was counteracted by increasing extracellular immobilization (EPS, frustulins), antioxidant (SOD, CAT) and detoxifying (GSTs) enzymes activity and low molecular weight antioxidants (GSH). These mechanisms were fuelled by higher energy production (increased ETS activity). At the highest Cu concentration (10MUg/L), these processes were specially enhanced in an attempt to restrain the oxidative stress generated by high intracellular Cu concentrations. However, these mechanisms were not able to fully protect cells, and damage in membranes and proteins increased. Moreover, the decrease of hydroxylamine and unsaturated fatty acids and the increase of saturated fatty acids, 2-palmitoylglycerol, glycerol and diterpenoid compounds should be tested as new specific markers of Cu toxicity in future studies. This information can support the prediction of diatom behaviour in different Cu contamination levels, including highly impacted environments, such as mining scenarios, and may assist in environmental risk assessment policies and restoration programs. PMID- 29996422 TI - Interaction between ash and soil microaggregates reduces runoff and soil loss. AB - Areas subjected to fire have a two-layer system (i.e., ash and soil), which brings enormous complexities to hydrogeomorphic processes. In addition, the combinations of variables from the ash and the soil characteristics result in several possible two-layer system contexts. Here, the interactions among ash and microaggregates (i.e., ash placed over fine soil microaggregates) and their effects on hydro-erosional processes are explored. The ash was produced by an experimental fire and collected from a field managed by a slash-and-burn agricultural system. The design of the experiment included a strategy for considering combinations in which each of the various factors of interest, i.e., ash and microaggregates, was present or absent. In addition, the study searched for interactions between the two factors when both were present. In total, 600 g m2 of fine ash mixture (<0.250 mm), obtained from fire at different temperatures, and 90 g m2 of microaggregates was placed over a small splash pan (0.135 m2). Next, a rainfall of 56 mm h-1 lasting for 30 min was applied in four replicates for each treatment: 1) bare soil, 2) bare soil + microaggregates, 3) ash, and 4) ash + microaggregates. The interaction between the ash and soil microaggregates changed the soil hydrology dynamics, reducing soil moisture by 28% and surface runoff by 78%. The ash-microaggregates combination reduced soil loss by sheetwash by 20% and by rainsplash by 25%. Overall, the ash treatment increased soil loss by 47% compared to the case of bare soil. On the contrary, the ash microaggregates interaction decreased soil loss by 26% compared to the ash treatment. PMID- 29996421 TI - Pine sawdust biochar reduces GHG emission by decreasing microbial and enzyme activities in forest and grassland soils in a laboratory experiment. AB - This study investigated the effects of biochar soil amendment on greenhouse gas (GHG) emissions in soils. Pine (Pinus koraiensis Siebold & Zucc.) sawdust biochar was produced at 300 and 550 degrees C with and without steam activation (coded as BC300-S, BC550-S, BC300 and BC550, respectively). They were applied to forest and grassland soils at 1.5% (w/w) rate in a 100-day laboratory incubation experiment. Application of BC550 significantly reduced cumulative CO2 emission from the forest soil by 16.4% relative to the control (without biochar application), but not from the grassland soil. Biochar application did not have significant effects on CH4 uptake from either soil. Application of BC550 and BC550-S reduced the cumulative N2O emission by 27.5 and 31.5%, respectively, in the forest soil and 14.8 and 11.7%, respectively, in the grassland soil, as compared to the control. The effects of BC300 and BC300-S on cumulative CO2 and N2O emission was not significant in both soils, except for the significant reduction in cumulative N2O emission from the forest soil by BC300-S. The effect of BC550 and BC550-S on N2O emission persisted until the end of the 100-day incubation indicating possible long-term effects of these biochars. We conclude that BC550 and BC550-S had the highest potential to reduce CO2 and N2O emission in the 100-day laboratory incubation experiment. These biochars should be tested in long-term field trials to confirm their potential for mitigating CO2 and N2O fluxes in real ecosystems with a relevant time frame. PMID- 29996423 TI - Investigation into the environmental fate of the combined Insensitive High Explosive constituents 2,4-dinitroanisole (DNAN), 1-nitroguanidine (NQ) and nitrotriazolone (NTO) in soil. AB - Contamination of military ranges by the use of explosives can lead to irreversible environmental damage, specifically to soil and groundwater. The fate and effects of traditional explosive residues are well understood, while less is known about the impact of Insensitive High Explosives (IHEs) that are currently being brought into military service. Current research has focussed on the investigation of individual constituents of IHE formulations, which may not be representative of real-world scenarios when explosive residues will be deposited together. Therefore, this study investigated the fate and transport of the combined IHE constituents 2,4-dinitroanisole (DNAN), 1-nitroguanidine (NQ) and 3 nitro-1,2,4-triazol-5-one (NTO) in two UK soil types. Static experiments ran for 9weeks to determine the fate of the combined explosive constituents in soil by monitoring the rate of degradation. Transport was examined by running soil column experiments for 5weeks, with a watering regime equivalent to the average yearly UK rainfall. Both static and soil column experiments confirmed that DNAN and NTO started to degrade within twenty-four hours in soil with high organic content, and were both completely degraded within sixty days. NQ was more stable, with 80% of the original material recovered after sixty days. The major degradation product of DNAN in the test soils was 2-amino-4-nitroanisole (2-ANAN), with trace amounts of 4-amino-2-nitroanisole. NTO was rapidly degraded in soil with high organic content, although no degradation products were identified. Results supported work from literature on the individual constituents DNAN, NQ and NTO suggesting that the three explosives in combination did not interact with each other when in soil. This study should provide a useful insight into the behaviour of three combined Insensitive High Explosive constituents for the predication of soil and water contamination during military training. PMID- 29996424 TI - Characterizing heavy metals in combined sewer overflows and its influence on microbial diversity. AB - This study characterized the pollution levels and potential ecological risk of heavy metals in combined sewer overflows (CSOs) and their effects on microbial diversity in nearby riparian sediments. The chemical fractionations of Zn, Cd, Cr, and Cu in dry-weather flows, wet-weather flows (CSO discharges), sewer sediments, and surface runoffs were determined. Geo-accumulation (Igeo) and ecological risk (RI) indexes were employed for metal risk assessment. DNA extraction and polymerase chain reaction (PCR) amplification on the Illumina MiSeq platform were conducted. The results show that heavy metals contents in fine-sized fractions have higher values than those in coarse-sized fractions. Chemical fractionation analysis suggests that Zn and Cd are two of the most bioavailable metals impacted by anthropogenic activities. Cr and Cu contents in CSOs are relatively stable and could exist for extended periods. According to the RI analysis, CSOs pose a considerable risk (RI-G2) to receiving waters due to the higher bioavailability of Cd, which was consistent with the Igeo index. Furthermore, under the stress of the highly-bioavailable Cd and Cu, Gram +ves in the riparian benthic sediment gradually became dominant with metal-tolerance property. Therefore, long-term exposure to highly bioavailable metals could exhibit great impacts on microbial diversity. PMID- 29996425 TI - Phytoliths and phytolith carbon occlusion in aboveground vegetation of sandy grasslands in eastern Inner Mongolia, China. AB - Grasslands play a crucial role in the coupled biogeochemical cycles of carbon (C) and silicon (Si) because they have a large biogenic Si pool (i.e. phytoliths). In recent decades, desertification has occurred extensively in sandy grasslands due to human activities and to increased aridity as a consequence of climate change. The present study determined the contents of phytoliths and C occlusion within phytoliths (PhytOC) in sandy grassland with different vegetation coverage from eastern Inner Mongolia, China and preliminarily assessed the effects of desertification on phytoliths and PhytOC production. Our results showed that the phytolith and PhytOC contents among different plant species varied from 0.68 to 9.23% and 0.03 to 1.130/00, respectively. However, the community-weighted means of the phytolith and PhytOC contents for the total aboveground vegetation were only 1.13-3.61% and 0.09-0.350/00, respectively, and their respective production fluxes ranged from 8.94 to 47.8 kg ha-1 year-1 and from 0.06 to 0.48 kg ha-1 year 1, respectively. As desertification progressed, the total contents of phytoliths and PhytOC in aboveground vegetation did not change significantly, whereas the production fluxes of phytoliths and PhytOC were markedly reduced. This study indicates that grassland desertification decreases the range of the total contents of phytolith and PhytOC by reducing species richness, and decreases the production fluxes of phytoliths and PhytOC by reducing aboveground biomass. Grassland restoration can theoretically enhance the production fluxes of phytoliths and PhytOC ~ five-fold. PMID- 29996427 TI - The hotspots of life cycle assessment for bioenergy: A review by social network analysis. AB - The purpose of this paper is to provide an up-to-date bibliometric view about the current life cycle assessment (LCA) for bioenergy. The social network analysis (SNA) method was applied to study total 2367 publications in this field. The results showed the high frequency keywords related with the "LCA" for bioenergy included three categories: (1) Bioenergy production, such as "Biodiesel", "Bioethanol", "Biogas" and "Biorefinery"; (2) Environmental problems, such as "Greenhouse gas" (GHG), "Environmental impact", "Climate change"; (3) Environmental target: "Sustainability". This means that LCA methods have been widely used in assessing the environmental impact from various types of bioenergy production process. Specially, the "GHG" attracted more attention in this research area. According to the temporal trend of the high frequency keywords, "bioethanol" is the most significant hotspot keyword of implication LCA. However, it has become colder since 2011. The environmental performance of "biogas" and "land use" began to receive attention since 2015.The evolutionary co-words network showed that the boundary of hotspots became overlapped. We also found four clusters were identified from keywords networks, i.e. the biggest cluster Cluster (I) (central cluster node linkage was "Bioethanol-GHG"), followed by Cluster (II) (central cluster node linkage was "Biodiesel-Algae"), Cluster (III) (central cluster node linkage was "Biorefinery-Sustainability") and Cluster (IV) (central cluster node linkage was "Biogas-Anaerobic digestion"). This cluster analysis also showed that the implication of LCA for the relationship between "bioethanol" and "GHG" is the most important hotspot research field. Although "biogas" is the smallest cluster now, it could be the next important hotspot of implication LCA for bioenergy. This study provides an effective approach to obtain a general knowledge of the LCA for bioenergy and supports a deeper understanding of research directions in the future. PMID- 29996426 TI - An integrated method for assessing drought prone areas - Water efficiency practices for a climate resilient Mediterranean agriculture. AB - This paper presents a new integrated GIS modeling method to assess drought vulnerability using multi-criteria analysis. The proposed methodology is an improvement over previous methods since it incorporates both dynamic and static factors that may affect water dynamics and contribute to water scarcity. These factors are: a) precipitation, b) evapotranspiration, c) soil water content, d) soil depth, e) artificial drainage, f) depth to water table, g) runoff accumulation, and h) saltwater intrusion zones. The above factors and their corresponding maps were fuzzified and spatially overlayed in order to obtain the final drought vulnerability map. The map depicts the spatial distribution of drought vulnerability represented by five classes ranging from very low to very high vulnerability. The proposed methodology was applied to the Greek island of Crete located in the Southeast Mediterranean region. The island of Crete is one of the most drought-prone areas in the region, while at the same time the island's economy relies strongly on agriculture and tourism. The derived results show that drought vulnerability is more severe in the eastern part of the island and that the coastal zones of the entire island are drought-prone areas. Also, according to the results, 19% of the island's area is characterized as "very highly vulnerable to drought". This percentage varies significantly across the prefectures, with Rethymnon having the lowest vulnerability (2.8%), followed by the prefectures of Chania (6.3%), and Heraklion (17.3%), while the prefecture of Lassithi is the most vulnerable to drought (51.4%). The developed methodology was validated using historical data for drought affected areas in Crete, which is not always addressed in publications. Moreover, in this study, sustainable agricultural practices that ensure water efficiency especially in drought prone areas are proposed. These practices can be adopted by farmers to promote climate resilient agriculture in the Mediterranean region. PMID- 29996428 TI - Modelling soil erosion response to sustainable landscape management scenarios in the Mo River Basin (Togo, West Africa). AB - The rural landscapes in Central Togo are experiencing severe land degradation, including soil erosion. However, spatially distributed information has scarcely been produced to identify the effects of landscape pattern dynamics on ecosystem services, especially the soil erosion control. In addition, relevant information for sustainable land and soil conservation is still lacking at watershed level. On this basis, using the LAndscape Management and Planning Tool for the Mo River basin (LAMPT_Mo), we (1) modelled soil erosion patterns in relation with land use/cover change (LUCC), land protection regime, and landforms, and (2) examined the efficiency of landscape redesign options on soil erosion amounts at basin scale. We found that Simulated historical net soil loss (NSL) for the Mo basin were approximately 26, 23, 27, and 44t/ha/yr, for 1972, 1987, 2000, and 2014, respectively. These simulated NSLs were higher than the tolerable soil loss limits for the Tropics. Steep slopes (>=15 degrees ), poorly covered lands (croplands and savannas), and riversides (distances <=100m) are critical areas of sediment sources. The local appraisal of soil loss was in line with the simulated outputs even though quantification was not accounted for when dealing with rural illiterate people. Furthermore, results showed that the examined management measures, such as controlling the identified erosion hotspots through land protective measures, could help reduce the NSL up to 70%, to values closer to the tolerable limits for the Tropics. The model implementation in the basin showed insights for identifying erosion hotspots and targeting soil conservation planning and landscape restoration measures. PMID- 29996429 TI - A seasonal observation on the distribution of engineered nanoparticles in municipal wastewater treatment systems exemplified by TiO2 and ZnO. AB - The present research attempted to assess the seasonal variation of engineered nanoparticles (ENPs) in a major municipal wastewater treatment system. A monthly survey over a 12-month period was conducted to monitor the concentration of TiO2 and ZnO nanoparticles throughout the treatment process. Results showed inflow concentrations in the range of 21.6+/-5.0-391.0+/-43.0MUg/L and 20.0+/-12.0 212.0+/-53.0MUg/L for TiO2 and ZnO, respectively. Seasonal pattern of the inflow ENPs concentration showed elevated value in the summer and winter periods for both TiO2 and ZnO. Based on the concentration profile, the hydraulic flow rate, and the concentration of mixed liquid suspended solid (MLSS), the daily mass loading (DML) or mass flow rate of nanoparticles and the mass ratio of engineered nanoparticle to MLSS were calculated. DML provided a real-time estimate of temporal distribution of ENPs in the treatment processes. Results indicated a daily mass loading of 50.1+/-12.7 and 44.7+/-14.1kg/day (yearly average) for TiO2 and ZnO, respectively. The amount of ENPs captured by sludge particulates were, yearly average, of 7.1kg-ZnO/d and 39.8kg-TiO2/d, and 8.9kg-ZnO/d and 25.1kg TiO2/d, by the primary and the secondary sludge particulates, respectively. ENPs to MLSS mass ratio also showed a seasonal patter similar to the inflow ENPs concentration, where summer and winter periods showed elevated values. Additionally, loss of ENPs throughout the treatment plant that was not accounted for, also can be estimated from the daily mass loading rate and the mass ratio of ENPs to MLSS. Based on the seasonal distribution of ENPs in wastewater treatment systems, especially the daily mass loading rate, it is possible to estimate the uses of nanoparticle-related commercial and personal care products in the urban areas and enable decision-making on the strategy of sludge disposal management. PMID- 29996430 TI - Distribution and mass of groundwater orthophosphorus in an agricultural watershed. AB - Orthophosphorus (OP) is the form of dissolved inorganic P that is commonly measured in groundwater studies, but the spatial distribution of groundwater OP across a watershed has rarely been assessed. In this study, we characterized spatial patterns of groundwater OP concentrations and loading rates within the 5218ha Walnut Creek watershed (Iowa) over a two-year period. Using a network of 24 shallow (<6m) monitoring wells established across watershed, OP concentrations ranged from <0.01 to 0.58mg/l in all samples (n=147) and averaged 0.084+/ 0.107mg/l. Groundwater OP concentrations were higher in floodplains and OP mass loading rates were approximately three times higher than in uplands. We estimated that approximately 1231kg of OP is present in floodplain groundwater and 2869kg is present in upland groundwater within the shallow groundwater zone (0-5m depth). Assuming no new inputs of OP to shallow groundwater, we estimated it would take approximately eight years to flush out existing OP mass present in the system. Results suggest that conservation practices focused on reducing OP loading rates in floodplain areas may have a disproportionately large water quality benefit compared to upland areas. PMID- 29996431 TI - Distribution of soil organic carbon and glomalin related soil protein in reclaimed coal mine-land chronosequence under tropical condition. AB - The revegetation on mine spoiled lands has potential to improve the status of reclaimed mine-soil quality. However, to date the temporal dynamics of labile and stable fractions of soil organic carbon (SOC) and glomalin related soil protein (GRSP) have not been satisfactorily demonstrated. We investigated SOC and GRSP fractions including labile particulate OC (POC) and easily extractable GRSP (EE GRSP) and stable non-particulate OC (NPOC) and difficulty extractable GRSP (DE GRSP) along with other important soil properties in six reclaimed mine lands chronosequence (1 to 26 years old) and a reference forest site in Raniganj Coalfield, India. Our results demonstrated that the accumulation of SOC and GRSP significantly increased with increasing age of the sites, with greater extent of increment after 26 years were seen in labile POC (6.6*) and EE-GRSP (11.5*) compared to stable NPOC (1.8*) and DE-GRSP (6.2*). The higher contribution of GRSP-C in NPOC compared to TOC across the sites, indicate the proximate role of GRSP in accumulation and stabilization of SOC during the pedogenesis. The multivariate analysis revealed strong association among arbuscular mycorrhizal fungi (AMF) spore density, microbial biomass carbon, SOCs and GRSPs, suggesting the factors involved in SOC accumulation likely contributed to AMF proliferation and GRSP enrichment during the reclamation process. Moreover, strong correlation of GRSP and SOC with soil's bulk density, pH, total N and C/N ratio, suggest increasing GRSP and SOC content resulted in multi-level improvement in soil properties. Our results highlight the importance of using GRSP and SOC as indicator during mine land reclamation. PMID- 29996432 TI - Occurrence of triclocarban and benzotriazole ultraviolet stabilizers in water, sediment, and fish from Indian rivers. AB - Triclocarban and benzotriazole ultraviolet stabilizers (BUVSs) are listed as high production volume synthetic chemicals, used extensively in personal care products. Many of these chemicals persist in the aquatic environment as micropollutants. Knowledge on their fate in freshwater ecosystems is still lacking, especially in the Indian Rivers. Our intention is to study the seasonal distribution, hazard quotient, risk assessment, and bioaccumulation of triclocarban and BUVSs (UV-9, UV-P, UV-326, UV-327, UV-328, and UV-329) during wet and dry seasons in water, sediment and fish from the Kaveri, Vellar, and Thamiraparani rivers in Tamil Nadu State, India. Triclocarban and BUVSs were identified in all matrices analysed. Triclocarban was found in water, sediment, and fish up to 1119ng/L, 26.3ng/g (dry wt.), and 692ng/g (wet wt.), respectively. Among BUVSs, UV-329 was found up to 31.3ng/L (water samples), UV-327 up to 7.3ng/g (sediment samples), and UV-9 up to 79.4ng/g (fish samples). The hazard quotient (HQenv.) for triclocarban in surface water was found to be at risk level (HQenv. >1) in the Kaveri, and Thamiraparani rivers during dry season. Bioaccumulation factors indicate that target compounds (triclocarban and BUVSs) could bio-accumulate in organisms. PMID- 29996433 TI - No upward shift of alpine grassland distribution on the Qinghai-Tibetan Plateau despite rapid climate warming from 2000 to 2014. AB - The distributions of many species show climate-driven shifts towards higher elevations, but evidence for elevational shifts is scarce for the alpine grasslands on the Qinghai-Tibetan Plateau. The upward shift of alpine grassland distribution from 2000 to 2014 was assessed with field measurements and satellite remote sensing data obtained across six elevational transects on the Qinghai Tibetan Plateau. The aboveground biomass (AGB) of alpine grasslands varied with altitude and its data produced a bell-shaped curve. This was mainly due to the elevational dependency of climate change at the surface (i.e., producing drier climate at low elevations and wetter climate at middle elevations). The normalized difference vegetation index (NDVI) derived from the Moderate Resolution Imaging Spectroradiometer (MODIS) exhibited a positive exponential relationship with the AGB of alpine grasslands. Overall, MODIS NDVI initially increased, then peaked at median altitude sites, then decreased with altitude on each elevational transect. MODIS NDVI at the upper limit of alpine grassland distribution did not show a significant increasing trend from 2000 to 2014, even though land surface temperature increased and precipitation remained approximately constant. High spatial resolution Landsat data supported this result. Further analyses of MODIS NDVI at all other sites found no general increase in AGB towards higher elevations. The results suggest that the distribution of alpine grasslands on the Qinghai-Tibetan Plateau did not show an upward shift despite rapid climate warming having occurred from 2000 to 2014. PMID- 29996434 TI - Health risk assessment of dermal and inhalation exposure to deodorants in Korea. AB - In Korea, humidifiers that include biocidal ingredients have caused serious lung injuries and deaths. After these incidents, public concern regarding the use of chemicals in products (i.e., chemical phobia) increased. Frequent health risk assessments and stringent management of consumer products are, therefore, of paramount importance to reduce these serious occurrences. In this study, the irritative and respiratory health effects of deodorants were assessed in relation to dermal and inhalation exposure. In total, 64 deodorants were divided into 5 groups by application type, and health risk assessments were conducted on each group. In total, 26 fragrance ingredients and 27 biocidal ingredients were analyzed and assessed according to their risk to human health. Exposure assessment was performed in two steps. In the tiered 1 assessment (screening), the 95th exposure factor values were used to estimate exposure to assume the worst-case scenario. The maximum concentration in the deodorants was used without considering the application type. In the tiered 2 assessment (detail assessment), the 75th exposure factor values were used to estimate the assumed reasonable exposure to ingredients. In these assessments, the maximum concentration used in the exposure models was determined by the product purpose and application type. The values input into the exposure algorithms were developed via the exposure route. Of the selected fragrance and biocidal active ingredients, 18 fragrance and 13 biocidal ingredients were detected in the deodorants that were assessed. From the results of the tiered 1 assessment, it was necessary for tiered 2 risk assessments to be conducted for 6 ingredients for the inhalation route, and 13 ingredients for the dermal route. The inhalation margin of exposure of ingredients in deodorants of gel/trigger/spray types for home/car and fabric/air usage was above the target margin of exposure. The health risk of 6 evaluated ingredients was relatively low for the inhalation route of exposure. This study showed that the assessed ingredients have no health risks at their maximum concentrations in deodorants. The approach discussed in this study should be used to establish improved guidelines for specific ingredients in consumer products, and for setting limits for newly developed raw materials that may pose dermal and inhalation hazard. PMID- 29996435 TI - Biochar improves maize growth by alleviation of nutrient stress in a moderately acidic low-input Nepalese soil. AB - We studied the role of biochar in improving soil fertility for maize production. The effects of biochar on the alleviation of three potential physical-chemical soil limitations for maize growth were investigated, i.e. water stress, nutrient stress and acid stress. Experiments involved soils with two dosages of biochar (0.5% and 2% w:w), as well as ones without biochar, in combination with four different dosages of NPK fertilizer, water and lime. Biochar was produced from the invasive shrubby weed Eupatorium adenophorum using flame curtain kilns. This is the first study to alleviate one by one the water stress, nutrient stress and acid stress in order to investigate the mechanisms of biochar effects on soil fertility. Biochar addition increased soil moisture, potassium (K) and plant available phosphorous (P-AL), which all showed significant positive relationship (p<0.001) with above ground biomass of maize. However, biochar was much more effective at abundant soil watering (+311% biomass) than at water-starved conditions (+67% biomass), indicating that biochar did increase soil moisture, but that this was not the main reason for the positive biomass growth effects. Biochar addition did have a stronger effect under nutrient-stressed conditions (+363%) than under abundant nutrient application (+132%). Biochar amendment increased soil pH, but liming and pH had no effect on maize dry biomass, so acidity stress alleviation was not the mechanism of biochar effects on soil fertility. In conclusion, the alleviation of nutrient stress was the probably the main factor contributing to the increased maize biomass production upon biochar addition to this moderately acidic Inceptisol. PMID- 29996436 TI - Modelling interacting plant and livestock renewal dynamics helps disentangle equilibrium and nonequilibrium aspects in a Mongolian pastoral system. AB - The interplay of livestock density dependence drivers and climate hazards is thought to cause pasture deterioration and poverty in Mongolian pastoral systems. We assessed their relative weights in a system of the Gobi exposed to high rainfall variability and harsh winters, which suggests that climate is the main system's driver. In this aim we modelled how interacting plant and livestock renewal dynamics impact herder performances, under the influence of climate. Plant dynamics was studied through an underground biomass sub-model because local pastures are dominated by perennial species. This approach enabled us studying pastoral issues in a holistic way, by integrating plant underground organs, livestock populations, herder income, and climate drivers. Models described that current grazing practices can significantly reduce underground biomass (-30% after 20years), but not entirely deplete it. They also showed that competition between herders could trap the smallest ones in poverty, by preventing the growth of their herds. This competition operates through density dependent factors affecting livestock productivity and vulnerability to climate shocks. This competition effect is all the more important since small herders could grow their herd and escape poverty if they were alone in the system. This result shows that density dependent factors could significantly impact herder performances and suggests that forage resource allocation is a driver as powerful as climate, even in the local harsh bioclimatic configuration of the Mongolian Gobi. PMID- 29996437 TI - Traditional fire use impact in the aboveground carbon stock of the chestnut forests of Central Spain and its implications for prescribed burning. AB - Chestnut forest ecosystems have a complex fire ecology; a result of centuries of co-evolution with pre-industrial era, cultural fire use by local communities based on Traditional Ecological Knowledge (TEK). As the "forest transition" unfolds throughout Europe however, and the traditional role of chestnut forest ecosystems as producers of edible nuts and firewood declines, chestnut forest resilience may be endangered due to disturbance regime changes driven by transformations in land use linked to the rural exodus, state fire exclusion policies and climate change. In this study we compared the aboveground carbon stocks of two chestnut forests located in Central Spain which can be considered representative of divergent Europe-wide management trends. In the first site of Casillas traditional understory burning is still widespread and its impacts on forest stand structure can be characterized as maintaining "open canopy", low density stands dominated by old growth chestnut trees. In the second site of Rozas de Puerto Real traditional fire use has declined and natural ecological succession processes have resumed resulting in high density, "closed canopy" stands dominated by young chestnut tree saplings and increasing pine, oak and shrub encroachment. For both sites we used in-the-field monitoring methods to estimate aerial carbon stock using allometric equations. Our results suggest that carbon sequestration and species richness is greater in the traditionally managed chestnut forest stands. Since present demographic trends present difficulties for the maintenance of traditional fire use by local communities, we argue that future fire management of unmanaged chestnut stands and maintenance of traditional forest stands ought to be implemented through surrogate prescribed burning plans that replicate the seasonal timing and ecological effects of TEK based controlled burning. PMID- 29996439 TI - Changes in soil microbial community structure and function after afforestation depend on species and age: Case study in a subtropical alluvial island. AB - It is well established that land use change can have a profound impact on soil physicochemical properties but the associated changes in soil microbial communities are poorly understood. We used long-term research sites in a subtropical alluvial island of eastern China to measure changes in soil physicochemical properties and microbial community abundance and composition (via phospholipid fatty acid (PLFA) analysis) and function (via extracellular enzyme activity) across different land use types developed on the same soil matrix, including a camphor (Cinnamomum camphora) plantation, a chronosequence of differently aged dawn redwood (Metasequoia glyptostroboides) plantings, a deforested land and a rice paddy. We hypothesized that afforestation could improve soil quality by enhancing carbon (C) and nitrogen (N) contents, microbial biomass and enzyme activities, but that this effect would vary depending on forest age and tree species. Soil C and N concentrations, PLFA abundances and activities of decomposition enzymes (beta-glucosidase, urease, alkaline phosphatase and catalase) in older plantations all increased significantly compared to cropland. These variables changed little or decreased in deforested land compared to cropland. These variables also increased with planting age in the dawn redwood plantings. Soils under camphor plantations had higher soil nutrient contents, microbial biomass and lower enzyme activities than dawn redwood soils with similar age. We also found some significant relationships between soil chemical and biological properties: PLFA abundances were positively related to soil organic matter (SOM) contents; the fungal-to-bacterial ratio and fungal relative abundance were correlated positively with SOM contents and negatively with C/N ratio; both soil PLFA abundances and enzyme activities were positively linked with soil inorganic N content and potential net N mineralization rate; ratio of specific C, N and P (phosphorus) acquisition activities was limited to 10: 1: 10 across land use types. Our study underscores the fact that land use type can have a profound impact on soil microbial communities; in addition, tree species and planting age also play significant roles in afforestation. PMID- 29996438 TI - Responses of unicellular alga Chlorella pyrenoidosa to allelochemical linoleic acid. AB - Linoleic acid (LA), is the product of secondary metabolism secreted from Microcystis aeruginosa, and it exhibits allelopathic activity against eukaryotic algae. However, information about on the mechanisms associated with the inhibition of algal activity by LA is limited. In this study, Chlorella pyrenoidosa was treated with LA (20-120 MUg L-1) for 4 days, and its growth inhibition and physiological responses were examined for potential toxic mechanisms. The photosynthetic efficiency of C. pyrenoidosa was inhibited by LA treatments, and the Fv/Fm parameter decreased significantly compared to that of controls; however, the photosynthetic pigment content did not change significantly. Peroxidase activity was enhanced, relieving oxidative damage in algae after LA treatments. However, superoxide dismutase and catalase were suppressed, ultimately leading to the aggravation of lipid peroxidation. Transcriptome-based gene expression analysis revealed that the 120 MUg L-1 LA treatment significantly inhibited the transcription of genes related to photosynthesis, carbon metabolism, and amino acid metabolism in C. pyrenoidosa, suggesting that these genes might be key LA targets in C. pyrenoidosa. Moreover, the expression of genes involved in vitamin, lipid, nitrogen cycling, terpenoid, and ascorbate metabolism was also affected, suggesting that LA inhibits algal cell growth through multiple pathways. The identification of LA-responsive genes in C. pyrenoidosa provides new insight into LA stress responses in eukaryotic algae. PMID- 29996440 TI - Reconstructing clear water state and submersed vegetation on behalf of repeated flocculation with modified soil in an in situ mesocosm experiment in Lake Taihu. AB - The geo-engineering approach of modified soil flocculation has been widely applied to mitigate algal blooms and eutrophication in relatively small lakes. Nevertheless, its potential ecological risks and feasibility should be examined and identified prior to its application in large natural lakes given the multiple functions of these water bodies in human health and welfare. In situ mesocosm experiments on modified soil flocculation were performed in Lake Taihu during summer 2010 and 2011. Chitosan-modified kaolinite (CMK) soil was used to flocculate algal blooms and improve water transparency to facilitate the re establishment of the submersed macrophyte Vallisneria natans in this shallow eutrophic lake. Moreover, the ecological effects of CMK soil were assessed. Results showed that repeated additions of CMK (0.3g/L for each time) improved water quality in terms of Chl-a, TN, and TP concentrations; TN/TP ratio; turbidity; redox conditions; and nitrification and denitrification activities. These effects lasted for 48days. After the fourth dose of CMK, the biomass of all phytoplankton categories, except for that of Cryptophyta, decreased by >90% (ca. 1-2*106cell/L or 0.38-0.55mg/L of wet weight). Zooplankton biomass markedly decreased after the first CMK addition, and copepods became dominant. These effects, however, did not last for the long term. Most importantly, submersed V. natans was restored successfully when water clarity and quality were improved through repeated CMK flocculation. Nevertheless, the indices of carbohydrate depletion and free amino acid accumulation indicated that the plant experienced physiological stresses. The reestablishment of V. natans reinforced the positive effects of repeated CMK dosing on water quality, and promoted a clear water state. V. natans is recommended for vegetative restoration in shallow eutrophic lakes given its facile transplantation, high stress tolerance, and physiological traits, which can be applied as indices of post-flocculation effects. In summary, the combination of repeated CMK dosing and revegetation of V. natans can feasibly improve water quality and initiate the restoration of a clear water state in shallow eutrophic lakes. PMID- 29996441 TI - Harvesting system sustainability in Mediterranean olive cultivation. AB - The mechanization of farming operation plays an important role in improving the profitability of the agricultural sector by increasing work productivity and reducing production costs. However, the new challenges of agriculture also include the environmental issues. The choice between different alternatives to perform a determined agricultural practice should be based on reliable information, considering technical, economic and environmental aspects. Olive growing represents the most important agricultural production in the Mediterranean Basin and its mechanization, particularly harvesting, could have major impacts on the sustainability of this production. This study aims at assessing various olive-harvesting scenarios, while considering technical, economic and environmental aspects in order to build a beta version of the "olive harvesting database". The proposed methodology called "modular approach" could represent a useful tool to apply in unitary process assessment in order to obtain a comprehensive database of the diverse agricultural operations. The methodology was based on Life Cycle Assessment and production cost analysis. Technical performance evaluation showed that the recorded work capacities varied between 5 tons of harvested olives per day when employing mechanical harvest aids and 18 tons per day when employing trunk shakers. The economic evaluation highlighted that the harvesting costs are variable as a function of the given cost type (costs per hour, costs per kg of harvested olives and costs per hectare). The LCA revealed that mechanically aided techniques were the most sustainable ones when the functional unit is considered as one harvesting hour, although this FU is not the most suitable unit for choosing the best environmental solution. The surface and production mass units are more appropriate FUs in comparative studies, although they are strictly linked to the "work capacity". A significant variation in the environmental performances depended on the FUs and on the average yields when the FU represented one kg of harvested olives. PMID- 29996442 TI - Carbon stability and mitigation of fertilizer induced N2O emissions in soil amended with biochar. AB - Biochar is a promising tool for an efficient and low environmental impact agriculture since can offer both soil carbon (C) sequestration and mitigation of nitrous oxide (N2O) emissions. The extent of biochar C stability after soil amendment and efficiency in reducing N2O emissions from an external nitrogen (N) source were accessed through laboratory incubations. A clay loam soil was amended with chicken manure (CM), sewage sludge (SS), eucalyptus sawdust (ES) and filter cake (FC) feedstocks and corresponding slow-pyrolysis (400 degrees C) biochars at 5gCkg-1 soil in combination with two N fertilizer rates (0 and 140mgNkg-1 soil). Carbon dioxide (CO2) and N2O emissions were measured during 60days. Biochars and feedstocks CO2 emissions were described by an exponential first order kinetics model. For C mineralization an interaction effect was observed for feedstock source and organic amendment. Lower values of mineralizable C was found for biochars than corresponding feedstocks, except for ES. Carbon losses in 60days of incubation totaled between 0.8 and 9.4% and 2.4 and 32% for biochars and feedstocks, respectively. Regarding to N2O emissions, only CM-biochar impacted emissions with a two-fold increase in non-fertilized soil. When NH4NO3 was co applied, biochars reduced fertilizer induced N2O emissions, reaching a seven-fold reduction in SS-biochar treatment. The fertilizer emission factor (EF) decreased with biochar amendments as well, varying between 0.01 and 0.08% of the fertilizer N emitted as N2O, which shows the biochar potential to reduce fertilizer induced N2O emissions, with major reduction by SS-biochar mitigating 87% of the soil fertilizer emissions. Such potential could be explored by designing biochars based on feedstock chemical and structural properties, including a mixed feedstock source biochar that promotes C sequestration and mitigates N2O emissions. PMID- 29996443 TI - Effects of Camellia sinensis crude saponin on survival and biochemical markers of oxidative stress and multixenobiotic resistance of the Mediterranean mussel, Mytilus galloprovincialis. AB - The Ebro Delta (NE Spain), formed by two bays, northern and southern hemidelta, is an area mainly devoted to rice farming. As a result shellfish species inhabiting or cultured in nearby bays may become increasingly threatened by exposure to pollutants associated to agriculture. The latest product applied in the rice fields is a plant based molluscicide called saponin, used to control populations of the giant apple snail (GAS). Saponins are known to also affect other organisms, hence research of its toxicity towards non target species is needed. In this study, mussels (Mytilus galloprovincialis) were exposed to three concentrations of suspended solid pellets containing saponin extracts from the plant species Camellia sinensis. Effects across a large set of biochemical markers were investigated in the digestive gland and gill tissue of exposed mussels to saponin for 1 and 7days. In addition, crude saponin was extracted from solid pellets to confirm its correct concentration. Results obtained from this study, showed that the concentration of crude saponin in dry pellets was of 5.5%. Lethal levels of saponin were 3.2 fold higher than the maximal predicted field concentration, and activated respiratory metabolism and expression of transmembrane protein transporters. Mussels, exposed to sub lethal concentrations of saponin showed increase of antioxidant defenses. PMID- 29996444 TI - The impact of marine shipping and its DECA control on air quality in the Pearl River Delta, China. AB - Marine trade has significantly expanded over the past decades aiding to the economic development of the maritime countries, yet, this has been associated with a considerable increase in pollution emission from shipping operation. This study aims at considering both sides of the spectrum at the same time, which is including both public and shipping business. Of the key significance would be to optimize the operation of the shipping industry, such that its impact on air pollution is minimized, without, however, significant escalation of its cost, and therefore to protect the whole seaborne trade. To do this, we considered the impacts of three control strategies, including the current emission control area (ECA) design, as well two additional ones. Thus the first scenario (DECA1) was based on the China's domestic emission control area (DECA), which was set up in 2016. The DECA1 scale was only 12 nautical miles, which was much smaller than the emission control areas in US or Europe. We defined the second scenario (DECA2), by stretching the zone to 200 nautical miles towards the ocean, modeling it on the ECA in North America. The third scenario (DECA3), on the other hand, expanded the 12 nautical miles control zone along the whole coastline. To investigate the impact of shipping emissions on air quality, a shipping emission calculation model and an air quality simulation model were used, and Pearl River Delta (PRD), China was chosen to serve as a case study. The study demonstrated that in 2013 marine shipping emissions contributed on average 0.33 and 0.60MUg.m-3, respectively to the land SO2 and PM2.5 concentrations in the PRD, and that the concentrations were high along the coastline. The DECA1 policy could effectively reduce SO2 and PM2.5 concentrations in the port regions, and the average reduction in the land area were 9.54% and 2.7%, respectively. Compared with DECA1, DECA2 would not measurably improve the air quality, while DECA3 would effectively decrease the pollution in the entire coast area. Thus, instead of expanding emission control area far to the ocean, it is more effective to control emissions along the coastline to secure the best air quality and lower the health impacts. By doing this, 19 million dollars of fuel cost could be saved per year. The saved cost could help the ship owners to endure, considering the current low profits of the seaborne trade, and thus to protect the overall growth of the economy. PMID- 29996445 TI - Diurnal variations of atmospheric polycyclic aromatic hydrocarbons (PAHs) during three sequent winter haze episodes in Beijing, China. AB - Gas- and particle-phase concentrations of 18 atmospheric polycyclic aromatic hydrocarbons (PAHs) were respectively measured during daytime and nighttime at an urban site of Beijing around the New Year's Day of 2015. The average concentration of total atmospheric PAHs (Sigma18PAHs) during three haze episodes (PM2.5>75MUg/m3) was 1473.1ng/m3, which was 2.6 times higher than that (405.1ng/m3) during normal periods (PM2.5<75MUg/m3). Significant diurnal variations in the Sigma18PAH concentrations, homologue pattern and gas-particle partitioning were observed during haze episodes. There was a significantly negative correlation between Sigma18PAH concentrations and planetary boundary layer heights. During haze episodes, PAHs in daytime atmosphere should mostly originate from the vehicle emission, while the main sources shift to coal combustion in the nighttime. The gas-particle distribution behavior of PAHs was decisively affected by air temperature and relative humidity, and generally simulated by Junge-Pankow model. During haze episodes, the average benzo[a]pyrene equivalent concentration of atmospheric PAHs in the nighttime were 0.7-fold higher than that in the daytime, indicating that people staying out more during haze episode nighttime would pose a considerably higher cancer risk for inhalation exposure to PAHs. PMID- 29996446 TI - Biomarker response, health indicators, and intestinal microbiome composition in wild brown trout (Salmo trutta m. fario L.) exposed to a sewage treatment plant effluent-dominated stream. AB - Concerns about the effect of sewage treatment plant (STP) effluent on the health of freshwater ecosystems have increased. In this study, a unique approach was designed to show the effect of an STP effluent-dominated stream on native wild brown trout (Salmo trutta L.) exposed under fully natural conditions. Zivny stream is located in South Bohemia, Czech Republic. The downstream site of Zivny stream is an STP-affected site, which receives 25% of its water from Prachatice STP effluent. Upstream, however, is a minimally polluted water site and it is considered to be the control site. Native fish were collected from the upstream site, tagged, and distributed to both upstream and downstream sites. After 30, 90, and 180days, fish were recaptured from both sites to determine whether the downstream site of the Zivny stream is associated with the effects of environmental pollution. Several biomarkers indicating the oxidative stress and antioxidant enzyme activities, cytochrome P450 activity, xenoestrogenic effects, bacterial composition, and lipid composition were investigated. Additionally, polar chemical contaminants (pharmaceuticals and personal care products (PPCPs)) were quantified using polar organic chemical integrative samplers (POCIS). Fifty three PPCPs were detected in the downstream site; 36 of those were constantly present during the 180-day investigation period. Elevated hepatic 7-benzyloxy-4 trifluoromethylcoumarin-O-debenzyloxylase (BFCOD) (after 90days) and blood plasma vitellogenin concentrations in males were detected in fish downstream of the STP effluent during all sampling events. An increase in the fishes' total fat content was also observed, but with low levels of omega-3 fatty acid in muscle tissue. Two bacterial taxa related to activated sludge were found in the intestines of fish from downstream. Our results show that Prachatice STP is a major source of PPCPs in the Zivny stream, which has biological consequences on fish physiology. PMID- 29996447 TI - Habitat-mediated, density-dependent dispersal strategies affecting spatial dynamics of populations in an anthropogenically-modified landscape. AB - A major challenge in managing natural populations in ecosystems is understanding and predicting the complexity and consequences of population dispersal. Although many studies have documented the importance of conspecific density and habitat quality in the dispersal process, we lack an understanding of how to integrate these factors in determining the spatial dynamics of populations or how habitat quality can mediate density-dependent dispersal. In this study, we propose a Habitat-mediated, Density-dependent, Spatial Population Dynamics model (HD-SPDM), in which we combined a Habitat Suitability Index (HSI) with a migration function, to explore the emergent effects of habitat mediated, density-dependent dispersal strategies on the spatial dynamics of a population. Our results show that habitat condition (based on HSI score) can influence ranges in conspecific density (which in turn can alter spatial patterns of populations distributed in homogeneous patches). We tested this model using the spatial distribution of Chinese mitten crab in the Yangtze River Estuary, which has been subjected to excessive sea reclamations over time, this allowed us to obtain insight into spatial distribution of population by determining how habitat-mediated, density-dependent dispersal at a small scale interacts with habitat heterogeneity and fragmentation at a landscape scale. We found that each progressive sea reclamation reduced suitable habitat area and habitat connectivity in the estuary. However, the model predicts that intermediate intensities of habitat compression and fragmentation could improve habitat utilization somewhat by facilitating population dispersal. Our model could be used to improve resource management of populations being increasingly impacted by anthropogenic alterations. PMID- 29996448 TI - Potential impact of natural organic ligands on the colloidal stability of silver nanoparticles. AB - Interaction of natural organic matter (NOM) with engineered nanoparticles (NPs) determine NP fate, transport, and environmental persistence. However, the effect of NOM chemical composition, structure, and concentration on aggregation kinetics and dissolution behavior of silver nanoparticles (AgNPs) are still poorly understood because of heterogeneity and variability in NOM and AgNP properties. Here, aggregation behavior of citrate-coated silver nanoparticles (cit-AgNPs with a z-average diameter of 18nm) was investigated in the presence of l-cysteine (l cys) and N-acetyl l-cysteine (NAL-cys) using UV-vis spectroscopy. We also investigated the effect of Suwannee River fulvic acid (SRFA) and a NOM isolated from the Yukon River (YRNOM) on the stability of cit-AgNPs. The dissolution of cit-AgNPs decreased with increased L-cys and NAL-cys concentration from 0 to 10MUM. The critical coagulation concentration (CCC) of cit-AgNPs decreased in the presence of l-cys and increased in the presence of NAL-cys. Similarly, l-cys destabilizes cit-AgNPs in the presence of SRFA. The differences in the stability of cit-AgNPs in the presence of l-cys and NAL-cys can be attributed to the differences in the functional groups in these two cysteine molecules. l-cys has both negatively charged carboxylic group and a positively charged amine group, resulting in bridging between different particles. NAL-cys is a derivative of cysteine wherein an acetyl group is attached to the nitrogen atom thus shielding the positive charge on the amine group and therefore eliminating the bridging interaction mechanism. SRFA and YRNOM enhanced the stability of cit-AgNPs and increased the CCC value to higher counter ion concentrations. The concentration of SRFA (1-5mgL-1) did not affect the CCC, whereas the increased concentration of YRNOM increased the CCC of cit-AgNPs to high Na+ concentrations likely due to increased sorption of higher molecular weight compounds on the surface of cit AgNPs. The outcome of this study suggests the importance of understanding the molecular properties of NOM (e.g. functional groups and molecular weight) in determining cit-AgNP environmental behaviors. PMID- 29996449 TI - Microbial extracellular enzyme activity affects performance in a full-scale modified activated sludge process. AB - The rate-limiting step of wastewater treatment is the breakdown of polymers by extracellular enzyme activity (EEA). The efficacy of EEA on biomass from full scale conventional activated sludge (AS) and modified AS with bench scale and full scale rotating biofilm reactors (RBR) was compared. The maximum amino peptidase EEA was 394 +/- 34 MUmolL-1 min-1 for the bench RBR which was 11.7 and 4.5 times greater than maximum alpha-glucosidase and phosphatase EEA in these reactors. At full scale the RBR gave ~4.6, 13.5 and 6.3 times the EEA for amino peptidase, alpha-glucosidase and phosphatase (based on enzyme Vmax) compared to the highest EEA in conventional AS biomass. Controlled overloading of the bench RBRs revealed that EEA increased with OLR up to 190 g tCOD m-2d-1 and further increases in OLR reduced the EEA. Pretreatment of wastewater by EEA in the RBR was linked to better performance of the modified activated sludge process. Maintaining high EEA of biofilms is critical for the design of high OLR wastewater treatment systems. PMID- 29996450 TI - Brominated flame retardants in Irish waste polymers: Concentrations, legislative compliance, and treatment options. AB - A comprehensive survey was performed to construct an inventory of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD) associated with waste polymers in Ireland. Based on our data, ~2200 t/yr of waste generated in Ireland exceeds "Low POP Concentration Limits" (LPCLs) set by the European Commission, of 1000 mg/kg of PBDEs (BDE-209 excluded) and HBCDD - collectively referred to as POP-BFRs. Waste articles containing concentrations exceeding the LPCL values require special treatment to remove POP-BFRs before they can be recycled. Waste articles exceeding LPCLs in our study consist primarily of expanded polystyrene used as building insulation (44%), waste furniture foams and fabrics (41%), with waste electrical and electronic equipment (WEEE) accounting for 13% and end of life vehicle waste contributing 1.7%. The recent listing of Deca-BDE under the Stockholm Convention means that a similar LPCL for its principal congener (BDE 209) is likely. Our data show that enforcement of an LPCL of 1000 mg/kg for BDE 209 would result in a further 1650 t/year of waste articles requiring special treatment. Our data show there to be 17,125 kg of POP-BFRs associated with waste polymers generated annually in Ireland. Enforcement of current LPCL values would prevent approximately 98% of these POP-BFRs from entering recycled goods. Introduction and enforcement of a similar LPCL for BDE-209 would prevent 93% of the 15,518 kg/yr of BDE-209 associated with Irish waste polymers from entering the recycling stream. PMID- 29996451 TI - Heterogeneous atmospheric degradation of pesticides by ozone: Influence of relative humidity and particle type. AB - In the atmosphere pesticides can be adsorbed on the surface of particles, depending on their physico-chemical properties. They can react with atmospheric oxidants such as ozone but parameters influencing the degradation kinetics are not clear enough. In this study the heterogeneous ozonolysis of eight commonly used pesticides (i.e., difenoconazole, tetraconazole, cyprodinil, fipronil, oxadiazon, pendimethalin, deltamethrin, and permethrin) adsorbed on hydrophobic and hydrophilic silicas, and Arizona dust at relative humidity ranging from 0% to 80% was investigated. Under experimental conditions, only cyprodinil, deltamethrin, permethrin and pendimethalin were degraded by ozone. Second-order kinetic constants calculated for the pesticides degraded by ozone ranged from (4.7 +/- 0.4) * 10-20 cm3 molecule-1 s-1 (pendimethalin, hydrophobic silica, 55% RH) to (2.3 +/- 0.4) * 10-17 cm3 molecule-1 s-1 (cyprodinil, Arizona dust, 0% RH). Results obtained can contribute to a better understanding of the atmospheric fate of pesticides in the particulate phase and show the importance of taking humidity and particle type into account for the determination of pesticides atmospheric half-lives. PMID- 29996453 TI - Removal of hexavalent chromium in aqueous solutions using biochar: Chemical and spectroscopic investigations. AB - Biochar is an emerging low-cost sorbent used for removing trace metals from water. In this study, we evaluated the removal potential of aqueous hexavalent chromium (Cr(VI)) by biochars produced from soybean (Glycinemax L.) and burcucumber (Sicyos angulatus L.) residues. The highest Cr(VI) removal from solution occurred at low pH values (pH2-5), and adsorption decreased approximately tenfold when the pH increased from 2 to 10. Synchrotron-based X-ray absorption spectroscopy (XAS) investigations showed that Cr(VI) species were reduced to trivalent chromium (Cr(III)) at the biochar surface following Cr(VI) adsorption. Linear combination fitting (LCF) of X-ray absorption near edge structure (XANES) data indicated that approximately 90% of the total Cr(VI) (962MUM) was reduced to Cr(III). Extended X-ray absorption fine structure (EXAFS) fitting results yielded interatomic chromium (CrCr) distances consistent with the formation of Cr(III) precipitates as Cr(OH)3. Trivalent chromium is far less soluble than Cr(VI) and typically precipitates as amorphous Cr(III) solids. Thus, biochars produced by soybean and burcucumber residues are a promising technique for both adsorbing and reductively immobilizing Cr(VI) from aqueous solutions. PMID- 29996452 TI - Remote observation of water clarity patterns in Three Gorges Reservoir and Dongting Lake of China and their probable linkage to the Three Gorges Dam based on Landsat 8 imagery. AB - The Secchi disk depth (ZSD) plays a critical role in describing water clarity. Several studies have shown linkages between Three Gorges Dam (TGD) and the downstream lacustrine ecosystem in the middle and lower Yangtze River basin. However, the potential influence on the ZSD fluctuation in the entire anthropogenic reservoirs of Three Gorges (ER) and Dongting Lake (DTL) has not been reported, possibly due to technical obstacles in obtaining statistically significant spatial and temporal results. We addressed this challenge by using remote sensing technology: the Landsat 8 Operational Land Imager (OLI). We proposed a new, robust remote-sensing algorithm to estimate ZSD from OLI imagery using red and green band-ratio, leading to MAPE of 21.68% and RMSE of 0.076m for ZSD ranging from 0.1m to 1.05m. After satisfactory image-based validation, the algorithm was implemented on OLI data to derive ZSD patterns over ER and DTL from 2013 to 2017. Several crucial findings can be drawn: 1) Spatial-temporal patterns of ZSD exhibited notable fluctuations over both ER and DTL, and they also demonstrated a significant correlation with each other because of the opposite temporal cycle of ZSD fluctuations between ER and DTL; 2) Temporally, monthly fluctuations of ZSD between ER and DTL had opposite temporal cycles, which was mainly attributed to the surface runoff and sediment discharge driven by the outbound runoff variations of TGD. Spatially, the heterogeneity of the ZSD pattern in ER might have resulted from the different geographical regions being divided by large anthropologic hydrological facilities, such as TGD; 3) The relationship between ZSD and total suspended matter (TSM) showed a significant negative correlation, as did the relationship between ZSD and Kd(490). These findings demonstrate that TSM often plays a principal role in light attenuation of extremely turbid inland waters; 4) An inversed phenomenon of water clarity was observed at the intersection of DTL and the Yangtze River around Chenglingji site (YRAC), which was due to the opposite temporal cycle of ZSD fluctuations between DTL and ER after the impoundment of TGD; and 5) Owing to the analysis of noise equivalent ZSD, OLI data can be used to derive ZSD, since the imagery uncertainty is 0.07m by means of our band-ratio algorithm, which demonstrates similar results to MODIS. The proposed ZSD-derived algorithm in this study could be suitable for other turbid lakes or reservoirs to formulate related strategies of water quality management in the middle and lower Yangtze River basin, and the unveiled findings here improve our understanding of ZSD spatiotemporal fluctuations in large river connected lakes, such as Poyang Lake. PMID- 29996455 TI - Predicting cadmium and lead toxicities in zebrafish (Danio rerio) larvae by using a toxicokinetic-toxicodynamic model that considers the effects of cations. AB - Protons and cations may affect metal accumulation in aquatic organisms and further influence metal toxicity. The effects of K+, Na+, Ca2+, Mg2+, and H+ on the accumulation and toxicity of Cd and Pb in zebrafish larvae after 24 h exposure were examined. We found that Na+, Ca2+, Mg2+, and H+ exerted significant effects on both the accumulation and toxicity of Cd, and Ca2+, Mg2+, and H+ also affected both the accumulation and toxicity of Pb significantly. Subsequently, stability constants for the binding of Pb2+, Cd2+, K+, Ca2+, Mg2+, Na+, and H+ to biotic ligand were estimated with the Langmuir model and biotic ligand model (BLM). Using the BLM-estimated binding constants calculated with toxicity data, a refined toxicokinetic-toxicodynamic (TK-TD) model considering cation competition effects was used to predict Cd and Pb accumulation and survival rates in zebrafish larvae with varying cation concentrations. Results showed that the developed TK-TD model could successfully predict Cd and Pb toxicity to zebrafish larvae as a function of major competitive cations. The TK-TD model incorporated cation competition effects is a promising tool to quantify and assess the metal risk in natural water. PMID- 29996454 TI - CO2-induced ocean acidification impairs the immune function of the Pacific oyster against Vibrio splendidus challenge: An integrated study from a cellular and proteomic perspective. AB - Ocean acidification (OA) and pathogenic diseases pose a considerable threat to key species of marine ecosystem. However, few studies have investigated the combined impact of reduced seawater pH and pathogen challenge on the immune responses of marine invertebrates. In this study, Pacific oysters, Crassostrea gigas, were exposed to OA (~2000 ppm) for 28 days and then challenged with Vibrio splendidus for another 72 h. Hemocyte parameters showed that V. splendidus infection exacerbated the impaired oyster immune responses under OA exposure. An iTRAQ-based quantitative proteomic analysis revealed that C. gigas responded differently to OA stress and V. splendidus challenge, alone or in combination. Generally, OA appears to act via a generalized stress response by causing oxidative stress, which could lead to cellular injury and cause disruption to the cytoskeleton, protein turnover, immune responses and energy metabolism. V. splendidus challenge in oysters could suppress the immune system directly and lead to a disturbed cytoskeleton structure, increased protein turnover and energy metabolism suppression, without causing oxidative stress. The combined OA- and V. splendidus-treated oysters ultimately presented a similar, but stronger proteomic response pattern compared with OA treatment alone. Overall, the impaired oyster immune functions caused by OA exposure may have increased the risk of V. splendidus infection. These results have important implications for the impact of OA on disease outbreaks in marine invertebrates, which would have significant economic and ecological repercussions. PMID- 29996456 TI - Modelling landscape constraints on farmland bird species range shifts under climate change. AB - Several studies estimating the effects of global environmental change on biodiversity are focused on climate change. Yet, non-climatic factors such as changes in land cover can also be of paramount importance. This may be particularly important for habitat specialists associated with human-dominated landscapes, where land cover and climate changes may be largely decoupled. Here, we tested this idea by modelling the influence of climate, landscape composition and pattern, on the predicted future (2021-2050) distributions of 21 farmland bird species in the Iberian Peninsula, using boosted regression trees and 10-km resolution presence/absence data. We also evaluated whether habitat specialist species were more affected by landscape factors than generalist species. Overall, this study showed that the contribution of current landscape composition and pattern to the performance of species distribution models (SDMs) was relatively low. However, SDMs built using either climate or climate plus landscape variables yielded very different predictions of future species range shifts and, hence, of the geographical patterns of change in species richness. Our results indicate that open habitat specialist species tend to expand their range, whereas habitat generalist species tend to retract under climate change scenarios. The effect of incorporating landscape factors were particularly marked on open habitat specialists of conservation concern, for which the expected expansion under climate change seems to be severely constrained by land cover change. Overall, results suggest that particular attention should be given to landscape change in addition to climate when modelling the impacts of environmental changes for both farmland specialist and generalist bird distributions. PMID- 29996457 TI - Increased exposure of plankton to arsenic in contaminated weakly-stratified lakes. AB - Arsenic, a priority Superfund contaminant and carcinogen, is a legacy pollutant impacting aquatic ecosystems in urban lakes downwind of the former ASARCO copper smelter in Ruston, WA, now a Superfund site. We examined the mobility of arsenic from contaminated sediments and arsenic bioaccumulation in phytoplankton and zooplankton in lakes with varying mixing regimes. In lakes with strong seasonal thermal stratification, high aqueous arsenic concentrations were limited to anoxic bottom waters that formed during summer stratification, and arsenic concentrations were low in oxic surface waters. However, in weakly-stratified lakes, the entire water column, including the fully oxic surface waters, had elevated concentrations of arsenic (up to 30MUgL-1) during the summer. We found enhanced trophic transfer of arsenic through the base of the aquatic food web in weakly-stratified lakes; plankton in these lakes accumulated up to an order of magnitude more arsenic on multiple sampling days than plankton in stratified lakes with similar levels of contamination. We posit that greater bioaccumulation in weakly-stratified lakes was due to elevated arsenic in oxic waters. Aquatic life primarily inhabits oxic waters and in the oxic water column of weakly stratified lakes arsenic was speciated as arsenate, which is readily taken up by phytoplankton because of its structural similarities to phosphate. Our study indicates that mobilization of arsenic from lake sediments into overlying oxic water columns in weakly-stratified lakes leads to increased arsenic exposure and uptake at the base of the aquatic food web. PMID- 29996458 TI - Maintenance of photosynthesis by Betula populifolia in metal contaminated soils. AB - Improving our understanding of plant responses to elevated trace metal concentrations under field conditions will enhance restoration and urban greening practices in settings with contaminated soils. This study examined the effects of trace metal pollution on the leaf gas exchange rates of mature, field-grown Betula populifolia Marsh. (gray birch) trees, additionally assessing whether elevated temperature and drought compounded the effects of trace metal contamination. The study compared B. populifolia growing in areas of comparatively high and low trace metal loads (HML and LML, respectively) within a former rail yard at Liberty State Park in Jersey City, New Jersey, USA. Gas exchange parameters were determined monthly from May through September in 2014 and 2015 using a portable photosynthesis system. The effects of drought and high temperature were assessed during a short heat wave in July 2015 and via a manipulative experiment, respectively. During a few of the measurement months, some parameters differed significantly between the LML and HML groups. However, when considered over the entire study period, no significant differences in biophysical parameters were observed between groups. The photosynthetic capacity of B. populifolia thus appears to be fairly robust across this site's steep gradient of trace metal contamination. Nonetheless, leaf mass per unit area was significantly lower in the HML group, indicating that metal loads affected resource allocation within trees. Also, immediately following the heat wave in 2015, intrinsic water use efficiency declined significantly in the HML group, suggesting that extreme climatic conditions can have a disproportionate effect on the physiological performance of plants growing in metal contaminated soils. PMID- 29996459 TI - Enhancing the WorldClim data set for national and regional applications. AB - Climatic change in the last few decades has had a widespread impact on both natural and human systems, observable on all continents. Ecological and environmental models using climatic data often rely on gridded data, such as WorldClim. The main aim of this study was to devise and evaluate a computationally efficient approach to produce new high resolution (100m) estimates of current and future climatic variables to be used at the national and regional scale. The test area was Great Britain, where local data are available and of good quality. Present and future climate surfaces were produced. For the present, the approach involved the integration, via spatial interpolation, of local climate information and WorldClim to reduce bias. For future climate scenarios the approach involved spatially downscaling of WorldClim (1km) to a finer resolution of 100m. The main advantages of the proposed approach are: 1. finer resolution, 2. locally adapted to the study area with use of higher number of meteorological stations and improved accuracy and bias, and 3. computationally efficient while making use of the existing resources provided by WorldClim. Two applications were presented to illustrate the practical consequences of improvements obtained with this method. The first is a measure of rainfall intensity, i.e. the R-factor, widely applied in erosion and catchment-scale studies. The second is an application to species distribution modelling, involving a range of bioclimatic variables. The results highlighted the importance of considering the spatial variability and structure of the data integrated in the modelling, and using data adapted to the geographical extent of the analysis, whenever possible. The results of the applications showed the advantage of using enhanced climatic data in applications such as the estimation of soil erosion, species range shift, carbon stocks and the provision of ecosystem services. PMID- 29996460 TI - Plenty of room for carbon on the ground: Potential applications of biochar for stormwater treatment. AB - Low impact development (LID) systems are increasingly used to manage stormwater, but they have limited capacity to treat stormwater-a resource to supplement existing water supply in water-stressed urban areas. To enhance their pollutant removal capacity, infiltration-based LID systems can be augmented with natural or engineered geomedia that meet the following criteria: they should be economical, readily available, and have capacity to remove a wide range of stormwater pollutants in conditions expected during intermittent infiltration of stormwater. Biochar, a carbonaceous porous co-product of waste biomass pyrolysis/gasification, meets all these criteria. Biochar can adsorb pollutants, improve water-retention capacity of soil, retain and slowly release nutrients for plant uptake, and help sustain microbiota in soil and plants atop; all these attributes could help improve removal of contaminants in stormwater treatment systems. This article discusses contaminant removal mechanisms by biochar, summarizes specific biochar properties that enhance targeted contaminants removal from stormwater, and identifies challenges and opportunities to retrofit biochar in LID to optimize stormwater treatment. PMID- 29996461 TI - Blood lead levels of children in urban and suburban areas in China (1997-2015): Temporal and spatial variations and influencing factors. AB - Blood lead (Pb) poisoning is a worldwide heath problem, especially in developing countries. As the largest developing country in the world, China faces severe health challenges, in particular the threat of blood Pb poisoning. In this study, the temporal trend of Chinese children's blood lead levels (BLLs) and blood lead poisoning incidence (BLPI) (percentage of BLL>100MUg/L) and its influencing factors were investigated. We collected articles on children's BLLs published from 1997 to 2017 with sampling time from 1997 to 2015 by searching the databases of VIP Medical Information System (VMIS), China National Knowledge Infrastructure (CNKI) and Wanfang Data. After a rigorous investigation, 259 articles with eligible inclusion criteria were reviewed. Meanwhile, the data of Pb concentrations in the soil of 23 cities and the annual mean PM10 (particulate matter<10MUm) concentrations of 24 provincial cities were collected. The temporal trend of children's BLLs and BLPIs could be divided into three stages: upward trend from 1997 to 2000, downward trend from 2001 to 2013, and upward trend from 2014 to 2015. The decline of BLLs from 2001 was primarily due to the phasing out of leaded gasoline since 2000 in China, while the descending air quality could explain the upward trend of BLLs in the period from 2014 to 2015. The correlation and regression analysis indicated that soil and air were two major pathways of Pb exposure for children in China. Although a noticeable decrease has been shown, the Chinese children's BLLs were still significantly higher than the levels of developed countries. We highly recommended that the critical value of blood Pb poisoning should be lowered to 50MUg/L in China. Guidelines on the prevention and management of blood Pb poisoning are needed in China. PMID- 29996462 TI - On-road emissions of ammonia: An underappreciated source of atmospheric nitrogen deposition. AB - : We provide updated spatial distribution and inventory data for on-road NH3 emissions for the continental United States (U.S.) On-road NH3 emissions were determined from on-road CO2 emissions data and empirical NH3:CO2 vehicle emissions ratios. Emissions of NH3 from on-road sources in urbanized regions are typically 0.1-1.3tkm-2yr-1 while NH3 emissions in agricultural regions generally range from 0.4-5.5tkm-2yr-1, with a few hotspots as high as 5.5-11.2tkm-2yr-1. Counties with higher vehicle NH3 emissions than from agriculture include 40% of the U.S. POPULATION: The amount of wet inorganic N deposition as NH4+ from the National Atmospheric Deposition Program (NADP) network ranged from 37 to 83% with a mean of 58.7%. Only 4% of the NADP sites across the U.S. had <45% of the N deposition as NH4+ based on data from 2014 to 2016, illustrating the near universal elevated proportions of NH4+ in deposition across the U.S. Case studies of on-road NH3 emissions in relation to N deposition include four urban sites in Oregon and Washington where the average NH4-N:NO3-N ratio in bulk deposition was 2.3. At urban sites in the greater Los Angeles Basin, bulk deposition of NH4-N and NO3-N were equivalent, while NH4-N:NO3-N in throughfall under shrubs ranged from 0.6 to 1.7. The NH4-N:NO3-N ratio at 7-10 sites in the Lake Tahoe Basin averaged 1.4 and 1.6 in bulk deposition and throughfall, and deposition of NH4-N was strongly correlated with summertime NH3 concentrations. On-road emissions of NH3 should not be ignored as an important source of atmospheric NH3, as a major contributor to particulate air pollution, and as a driver of N deposition in urban and urban-affected regions. PMID- 29996463 TI - Understanding erosion processes using rare earth element tracers in a preformed interrill-rill system. AB - Tracking sediment source and movement is essential to fully understanding soil erosion processes. The objectives of this study were to identify dominant erosion process and to characterize the effects of upslope interrill erosion on downslope interrill and rill erosion in a preformed interrill-rill system. A coarse textured soil with 2% clay and 20% silt was packed into a physical model of a scaled small watershed, which was divided into eight topographic units and was tagged with eight rare earth element (REE) oxides. Three 30-min rains were made at the sequential intensities of 60, 90, and 120mmh-1, and runoff and sediment were collected every 2min at the outlet. REE concentration in sediment was measured and used to estimate source contributions after fine-enrichment correction. Results showed that interrill erosion rate and sediment concentration increased with downslope distance, indicating that sediment transport might have controlled interrill erosion rates. In contrast, rill erosion rate was limited by rill detachment and development process. Rill erosion contributed most soil loss; however, the proportion decreased from 78 to 61% as rainfall intensity increased and rill network matured over three rains. Interrill erosion was more sensitive than rill erosion to rainfall intensity increases. The former was mostly affected by rainfall intensity in this experimental setup, while the latter was controlled by flow discharge, gradient, and rill evolution stage. The greatest sediment concentration and delivery rate occurred in the stage of the fastest rill development. The increased sediment delivery from interrill areas appeared to suppress rill detachment by concentrated flow. This study enhanced our understanding of interrill and rill erosion processes and provided the scientific insights for improving soil erosion models. PMID- 29996464 TI - Review of in vitro toxicological research of quantum dot and potentially involved mechanisms. AB - Quantum dots (QDs) are one of emerging engineering nanomaterials (NMs) with advantageous properties which can act as candidates for clinical imaging and diagnosis. Nevertheless, toxicological studies have proved that QDs for better or worse pose threats to diverse systems which are attributed to the release of metal ion and specific characteristics of nanoparticles (NPs), hampering the wide use of QDs to biomedical area. It has been postulated that mechanisms of toxicity evoked by QDs have implications in oxidative stress, reactive oxygen species (ROS), inflammation and release of metal ion. Meanwhile, DNA damage and disturbance of subcellular structures would occur during QDs treatment. This review is intended to conclude the cytotoxicity of QDs in multiple systems, as well as the potential mechanisms on the basis of recent literatures. Finally, toxicity-related factors are clarified, among which chirality seems to be a newly proposed influence factor that determines the destiny of cells in response to QDs. However, details of interaction between QDs and cells have not been well elucidated. Given that molecular mechanisms of QDs-induced toxicity are still not clearly elucidated, further research should be required for this meaningful topic. PMID- 29996465 TI - Comparative analysis biochar and compost-induced degradation of di-(2-ethylhexyl) phthalate in soils. AB - In recent years, biochar has been extensively studied as a sorbent for immobilizing contaminants and minimizing their bioavailability in soils. Few studies have been conducted to evaluate the interactions between biochar and compost in soils and their impact on degradation of organic contaminants. In the present study, soils with high organic carbon content (HOC) and low organic carbon content (LOC) were spiked with 100mg.kg-1 di-(2-ethylhexyl) phthalate (DEHP) amended with biochar derived from dead pigs, bamboo, and composted sheep manure. The soils were thereafter incubated for 112days at 25 degrees C and periodically sampled for monitoring DEHP concentrations. Degradation of DEHP was described by a logistic model. Results showed that the initial degradation rates were slow, but accelerated after 14days of incubation. The DEHP degradation rates were higher in the HOC soils than in the LOC soils over the incubation period. The half-lives of DEHP were shorter in the LOC soils treated with pig biochar, and bamboo/pig biochar plus compost than in the untreated soil. However, there was no significant difference in the half-lives of DEHP in the HOC control and treated soils. The differential effects of soil amendments on DEHP degradation between LOC and HOC soils could be explained by the properties of the organic amendments, soil pH and the organic carbon contents of the soils. PMID- 29996466 TI - Indoor contamination from pesticides used for outdoor insect control. AB - The present study assessed the indoor level of pesticide residue contamination at a total of 45 dwelling facilities in 5 cities of South Korea from June to November 2014. Pesticide residue contamination was assessed by measuring the frequency and concentration of chlorpyrifos, dichlorvos, and cypermethrin residues in airborne particles, indoor dust, and surface wipes. A preparatory test showed a decreasing tendency in the concentrations of pesticide residues in indoor air over time: from 0.458 to 0.073mg/m3 in dichlorvos for 4weeks and from below 0.050mg/m3 to non-detection in the other substances for 2weeks. Then, pesticide residues were detected indoors 4weeks after outdoor chemical control, implying the infiltration of pesticide particles from outdoors. Airborne particles of dichlorvos were found at a higher level (74.4% of samples at a concentration of 0.053mg/m3), whereas those of the other substances were detected at lower levels (6.1% at 0.002mg/m3 in chlorpyrifos and 9.4% at 0.022mg/m3 in cypermethrin). There was no consistent tendency in the indoor levels of pesticide residue contamination according to dwelling types or indoor height. The indoor levels of dichlorvos residue contamination were lower in industrial districts than in urban or rural districts: 63.9% and 0.013mg/m3 for airborne particles, 13.3% and 0.002MUg/g for indoor dust, and 6.7% and 0.001mg/cm2 for surface wipes, respectively. There were no significant differences in the indoor levels of pesticide residue contamination between urban and rural districts. The current study found that most dwelling facilities managed their indoor levels of pesticide residue contamination below permissible exposure limit (PEL, 1.0mg/m3) or threshold limit value (TVL, 0.1mg/m3), whereas some facilities did not. So, we suggest that certain guidelines should be drawn up regarding the indoor environment management. PMID- 29996467 TI - Comparison of Machine Learning Models for Hazardous Gas Dispersion Prediction in Field Cases. AB - Dispersion prediction plays a significant role in the management and emergency response to hazardous gas emissions and accidental leaks. Compared with conventional atmospheric dispersion models, machine leaning (ML) models have both high accuracy and efficiency in terms of prediction, especially in field cases. However, selection of model type and the inputs of the ML model are still essential problems. To address this issue, two ML models (i.e., the back propagation (BP) network and support vector regression (SVR) with different input selections (i.e., original monitoring parameters and integrated Gaussian parameters) are proposed in this paper. To compare the performances of presented ML models in field cases, these models are evaluated using the Prairie Grass and Indianapolis field data sets. The influence of the training set scale on the performances of ML models is analyzed as well. Results demonstrate that the integrated Gaussian parameters indeed improve the prediction accuracy in the Prairie Grass case. However, they do not make much difference in the Indianapolis case due to their inadaptability to the complex terrain conditions. In addition, it can be summarized that the SVR shows better generalization ability with relatively small training sets, but tends to under-fit the training data. In contrast, the BP network has a stronger fitting ability, but sometimes suffers from an over-fitting problem. As a result, the model and input selection presented in this paper will be of great help to environmental and public health protection in real applications. PMID- 29996468 TI - Direct-Continuous Preparation of Nanostructured Titania-Silica Using Surfactant Free Non-Scaffold Rice Starch Template. AB - The conventional synthesis route of nanostructured titania-silica (Ti-SiNS) based on sol-gel requires the use of a surfactant-type template that suffers from hazardous risks, environmental concerns, and a tedious stepwise process. Alternatively, biomaterials have been introduced as an indirect template, but still required for pre-suspended scaffold structures, which hinder their practical application. Herein, we report an easy and industrially viable direct continuous strategy for the preparation of Ti-SiNS from nanostructured-silica (SiNS) using a hydrolyzed rice starch template. This strategy fits into the conventional industrial process flow, as it allows starch to be used directly in time-effective and less complicated steps, with the potential to upscale. The formation of Ti-SiNS is mainly attributed to Ti attachment in the SiNS frameworks after the polycondensation of the sol-gel composition under acidic-media. The SiNS had pseudo-spherical morphology (nanoparticles with the size of 13 to 22 nm), short order crystal structure (amorphous) and high surface area (538.74 m2·g−1). The functionalized SiNS into Ti-SiNS delivered considerable catalytic activity for epoxidation of 1-naphtol into 1,4-naphthoquinone. The described direct-continuous preparation shows great promise for a cheap, green, and efficient synthesis of Ti-SiNS for advanced applications. PMID- 29996469 TI - Application of Nanoparticles for Targeting G Protein-Coupled Receptors. AB - Nanoparticles (NPs) have attracted unequivocal attention in recent years due to their potential applications in therapeutics, bio-imaging and material sciences. For drug delivery, NP-based carrier systems offer several advantages over conventional methods. When conjugated with ligands and drugs (or other therapeutic molecules), administrated NPs are able to deliver cargo to targeted sites through ligand-receptor recognition. Such targeted delivery is especially important in cancer therapy. Through this targeted cancer nanotherapy, cancer cells are killed with higher specificity, while the healthy cells are spared. Furthermore, NP drug delivery leads to improved drug load, enhanced drug solubility and stability, and controlled drug release. G protein-coupled receptors (GPCRs) are a superfamily of cell transmembrane receptors. They regulate a plethora of physiological processes through ligand-receptor-binding induced signaling transduction. With recent evidence unveiling their roles in cancer, GPCR agonists and antagonists have quickly become new targets in cancer therapy. This review focuses on the application of some notable nanomaterials, such as dendrimers, quantum dots, gold nanoparticles, and magnetic nanoparticles, in GPCR-related cancers. PMID- 29996470 TI - Plant MicroRNAs in Cross-Kingdom Regulation of Gene Expression. AB - MicroRNAs (miRNAs) are a class of noncoding small RNAs, which play a crucial role in post-transcriptional gene regulation. Recently, various reports revealed that miRNAs could be transmitted between species to mediate cross-kingdom regulation by integrating into a specific target gene-mediated regulatory pathway to exert relevant biological functions. Some scholars and researchers have observed this as an attractive hypothesis that may provide a foundation for novel approaches in the diagnosis, prognosis, and treatment of disease. Meanwhile, others deem the mentioned results were obtained from a “false positive effect” of performed experiments. Here, we focus on several current studies concerning plant miRNA-mediated cross-kingdom regulation (from both fronts) and discuss the existing issues that need further consideration. We also discuss possible miRNA horizontal transfer mechanisms from one species to another and analyze the relationship between miRNA-mediated cross-kingdom regulation and coevolution during a long-term specific host-pathogen interaction. PMID- 29996472 TI - ERK5 Phosphorylates Kv4.2 and Inhibits Inactivation of the A-Type Current in PC12 Cells. AB - Extracellular signal-regulated kinase 5 (ERK5) regulates diverse physiological responses such as proliferation, differentiation, and gene expression. Previously, we demonstrated that ERK5 is essential for neurite outgrowth and catecholamine biosynthesis in PC12 cells and sympathetic neurons. However, it remains unclear how ERK5 regulates the activity of ion channels, which are important for membrane excitability. Thus, we examined the effect of ERK5 on the ion channel activity in the PC12 cells that overexpress both ERK5 and the constitutively active MEK5 mutant. The gene and protein expression levels of voltage-dependent Ca2+ and K+ channels were determined by RT-qPCR or Western blotting. The A-type K+ current was recorded using the whole-cell patch clamp method. In these ERK5-activated cells, the gene expression levels of voltage dependent L- and P/Q-type Ca2+ channels did not alter, but the N-type Ca2+ channel was slightly reduced. In contrast, those of Kv4.2 and Kv4.3, which are components of the A-type current, were significantly enhanced. Unexpectedly, the protein levels of Kv4.2 were not elevated by ERK5 activation, but the phosphorylation levels were increased by ERK5 activation. By electrophysiological analysis, the inactivation time constant of the A-type current was prolonged by ERK5 activation, without changes in the peak current. Taken together, ERK5 inhibits an inactivation of the A-type current by phosphorylation of Kv4.2, which may contribute to the neuronal differentiation process. PMID- 29996471 TI - NGAL is Downregulated in Oral Squamous Cell Carcinoma and Leads to Increased Survival, Proliferation, Migration and Chemoresistance. AB - Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study, we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer in comparison to normal tissues. The downregulation of NGAL was strongly correlated with both degree of differentiation and stage (I IV); it can also serve as a prognostic biomarker for oral cancer. Additionally, tobacco carcinogens were found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration; it also induced resistance against cisplatin. Silencing of NGAL activated mammalian target of rapamycin (mTOR)signaling and reduced autophagy by the liver kinase B1 (LKB1)-activated protein kinase (AMPK)-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and matrix metalloproteinase-9 (MMP-9) were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study, it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer. PMID- 29996473 TI - Efficacy of Prosopilosidine from Prosopis glandulosa var. glandulosa against Cryptococcus neoformans Infection in a Murine Model. AB - In this study, 2,3-dihydro-1H-indolizinium alkaloid-prosopilosidine (PPD), that was isolated from Prosopis glandulosa, was evaluated against C. neoformans in a murine model of cryptococcosis. In vitro and in vivo toxicity of indolizidines were also evaluated. Mice were infected via the tail vein with live C. neoformans. Twenty-four hours post-infection, the mice were treated with PPD once a day (i.p.) or twice a day (bid) orally, or with amphotericin B (Amp B) intraperitoneally (IP), or with fluconazole (Flu) orally for 5 days. The brains of all of the animals were aseptically removed and the numbers of live C. neoformans were recovered. In vitro toxicity of indolizidine alkaloids was determined in HepG2 cells. PPD showed to be potent in vivo activity against C. neoformans at a dose of 0.0625 mg/kg by eliminating ~76% of the organisms compared to ~83% with Amp B (1.5 mg/kg). In addition, PPD was found to be equally efficacious, but less toxic, at either 0.125 or 0.0625 mg/kg compared to Amp B (1.5 mg/kg) when it was administered bid (twice a day) by an i.p. route. When tested by an oral route, PPD (10 mg/kg) showed potent activity in this murine model of cryptococcosis with ~82% of organisms eliminated from the brain tissue, whereas Flu (15 mg/kg) reduced ~90% of the infection. In vitro results suggest that quaternary indolizidines were less toxic as compared to those of tertiary bases. PPD (20 mg/kg) did not cause any alteration in the plasma chemistry profiles. These results indicated that PPD was active in eliminating cryptococcal infection by oral and i.p. routes at lower doses compared to Amp B. or Flu. PMID- 29996475 TI - Complexation of the Mycotoxin Cyclopiazonic Acid with Lanthanides Yields Luminescent Products. AB - Cycopiazonic acid (CPA) is a neurotoxin that acts through inhibition of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). CPA blocks the calcium access channel of the enzyme. The inhibition may involve the binding of CPA with a divalent cation such as Mg2+. The potential for CPA to act as a chelator also has implications for methods to detect this toxin. Certain of the lanthanide metals undergo a dramatic increase in luminescence upon coordination with small molecules that can transfer excitation energy to the metal. This report is the first to describe the coordination of CPA with lanthanide metals, resulting in a substantial enhancement of their luminescence. The luminescence expressed was dependent upon the type of lanthanide, its concentration, and the environment (solvent, water content, pH). Based upon the phenomenon, a competitive assay was also developed wherein terbium (Tb3+) and a series of metal cations competed for binding with CPA. With increasing cation concentration, the luminescence of the CPA/Tb3+ complex was inhibited. The chlorides of ten metals were tested. Inhibition was best with Cu2+, followed by Co2+, Al3+, Fe3+, Mn2+, Au3+, Mg2+, and Ca2+. Two cations in oxidation state one (Na+, K+) did not inhibit the interaction significantly. The interaction of CPA with lanthanides provides a novel recognition assay for this toxin. It also provides a novel way to probe the binding of CPA to metals, giving insights into CPA’s mechanism of action. PMID- 29996474 TI - Cardioprotective Effects of Omega-3 Polyunsaturated Fatty Acids: Dichotomy between Experimental and Clinical Studies. AB - The high-fat diet of North Americans has a major impact on cardiovascular disease occurrence. Notably, fatty acids have been identified as important factors that could modulate such diseases, especially myocardial infarction (MI). Experimentally, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated positive effects on cardiovascular disorders and have also shown cardioprotection by decreasing MI size. Although many animal experiments have clearly established the benefits of omega-3 PUFA, clinical studies have not reached similar conclusions. In fact, the findings of recent clinical investigations indicate that omega-3 PUFA play only a minor role in cardiovascular health. This dichotomy between experimental and clinical studies may be due to different parameters that are not taken into account in animal experiments. We have recently observed that the high consumption of omega-6 PUFA results in significant attenuation of the beneficial effect of omega-3 PUFA on MI. We believe that part of the dichotomy between experimental and clinical research may be related to the quantity of omega-6 PUFA ingested. This review of the data indicates the importance of considering omega-6 PUFA consumption in omega-3 PUFA studies. PMID- 29996476 TI - A Pilot Randomized Trial of Oral Magnesium Supplementation on Supraventricular Arrhythmias. AB - Low magnesium may increase the risk of atrial fibrillation. We conducted a double blind pilot randomized trial to assess adherence to oral magnesium supplementation (400 mg of magnesium oxide daily) and a matching placebo, estimate the effect on circulating magnesium concentrations, and evaluate the feasibility of using an ambulatory heart rhythm monitoring device (ZioPatch) for assessing premature atrial contractions. A total of 59 participants were randomized; 73% were women, and the mean age was 62 years. A total of 98% of the participants completed the follow-up. In the magnesium supplement group, 75% of pills were taken, and in the placebo group, 83% were taken. The change in magnesium concentrations was significantly greater for those given the magnesium supplements than for those given the placebo (0.07; 95% confidence interval: 0.03, 0.12 mEq/L; p = 0.002). The ZioPatch wear time was approximately 13 of the requested 14 days at baseline and follow-up. There was no difference by intervention assignment in the change in log premature atrial contractions burden, glucose, or blood pressure. Gastrointestinal changes were more common among the participants assigned magnesium (50%) than among those assigned the placebo (7%), but only one person discontinued participation. In sum, compliance with the oral magnesium supplementation was very good, and acceptance of the ZioPatch monitoring was excellent. These findings support the feasibility of a larger trial for atrial fibrillation (AF) prevention with oral magnesium supplementation. PMID- 29996477 TI - Continuous and Real-Time Detection of Drinking-Water Pathogens with a Low-Cost Fluorescent Optofluidic Sensor. AB - Growing access to tap water and consequent expansion of water distribution systems has created numerous challenges to maintaining water quality between the treatment node and final consumer. Despite all efforts to develop sustainable monitoring systems, there is still a lack of low cost, continuous and real time devices that demonstrate potential for large-scale implementation in wide water distribution networks. The following work presents a study of a low-cost, optofluidic sensor, based on Trypthopan Intrinsic Fluorescence. The fluorospectrometry analysis performed (before sensor development) supports the existence of a measurable fluorescence output signal originating from the tryptophan contained within pathogenic bacteria. The sensor was mounted using a rapid prototyping technique (3D printing), and the integrated optical system was achieved with low-cost optical components. The sensor performance was evaluated with spiked laboratory samples containing E. coli and Legionella, in both continuous and non-continuous flow situations. Results have shown a linear relationship between the signal measured and pathogen concentration, with limits of detection at 1.4 × 103 CFU/mL. The time delay between contamination and detection of the bacteria was practically null. Therefore, this study supports the potential application of tryptophan for monitoring drinking water against water pathogens. PMID- 29996479 TI - Polar Lipids from Olives and Olive Oil: A Review on Their Identification, Significance and Potential Biotechnological Applications. AB - Polar lipids are minor components of olives and olive oil and include a myriad of molecules such as phospholipids and glycolipids. Even though sensitive and high resolution analytical approaches have been used to unveil the polar lipidome of these matrices, new insights on their composition are needed. In this review, we will describe the findings on the identification and characterization of polar lipids from olives and olive oil and the underlying analytical challenges. The significance of polar lipids will also be discussed as potential markers of identity and traceability of olives and olive oil and in detecting adulteration of olive oil. Their potential impact on nutrition and health will be presented as a valuable source of bioactive compounds and as promising ingredients for different uses from olive-derived industrial by-products. PMID- 29996480 TI - Highly Sensitive Acetone Gas Sensor Based on g-C3N4 Decorated MgFe2O4 Porous Microspheres Composites. AB - The g-C3N4 decorated magnesium ferrite (MgFe2O4) porous microspheres composites were successfully obtained via a one-step solvothermal method. The structure and morphology of the as-prepared MgFe2O4/g-C3N4 composites were characterized by the techniques of X-ray diffraction (XRD), field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), thermal gravity and differential scanning calorimeter (TG-DSC) and N2-sorption. The gas sensing properties of the samples were measured and compared with a pure MgFe2O4-based sensor. The maximum response of the sensor based on MgFe2O4/g-C3N4 composites with 10 wt % g-C3N4 content to acetone is improved by about 145 times, while the optimum temperature was lowered by 60 °C. Moreover, the sensing mechanism and the reason for improving gas sensing performance were also discussed. PMID- 29996478 TI - Epithelioid Hemangioendothelioma as a Model of YAP/TAZ-Driven Cancer: Insights from a Rare Fusion Sarcoma. AB - Epithelioid hemangioendothelioma (EHE) is a rare soft-tissue sarcoma involving cells with histologic markers that suggest an endothelial origin. Around 90% of EHEs are caused by the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1), a central nervous system-specific transcription activator. The 10% of EHEs that lack the TAZ-CAMTA1 fusion instead have a fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3). YAP and TAZ are well-defined downstream effectors in the Hippo pathway that promote cell growth when translocated to the nucleus. The TAZ-CAMTA1 fusion transcript is insensitive to the Hippo inhibitory signals that normally prevent this process and thus constitutively activates the TAZ transcriptome. In EHE, this causes tumors to form in a variety of organs and tissue types, most commonly the liver, lung, and bone. Its clinical course is unpredictable and highly variable. TAZ activation is known to contribute to key aspects of the cancer phenotype, including metastasis and fibrosis, and increased expression of TAZ is thought to be causally related to the progression of many cancers, including breast, lung, and liver. Therefore, understanding TAZ biology and the molecular mechanisms by which it promotes unregulated cell proliferation will yield insights and possibly improved treatments for both EHE as well as much more common cancers. PMID- 29996481 TI - Looking for Novel Capsid Protein Multimerization Inhibitors of Feline Immunodeficiency Virus. AB - Feline immunodeficiency virus (FIV) is a member of the retroviridae family of viruses. It causes acquired immunodeficiency syndrome (AIDS) in worldwide domestic and non-domestic cats and is a cause of an important veterinary issue. The genome organization of FIV and the clinical characteristics of the disease caused by FIV are similar to human immunodeficiency virus (HIV). Both viruses infect T lymphocytes, monocytes, and macrophages, with a similar replication cycle in infected cells. Thus, the infection of cats with FIV is also a useful tool for the study and development of novel drugs and vaccines against HIV. Anti retroviral drugs studied extensively with regards to HIV infection have targeted different steps of the virus replication cycle: (1) disruption of the interaction with host cell surface receptors and co-receptors; (2) inhibition of fusion of the virus and cell membranes; (3) blocking of the reverse transcription of viral genomic RNA; (4) interruption of nuclear translocation and integration of viral DNA into host genomes; (5) prevention of viral transcript processing and nuclear export; and (6) inhibition of virion assembly and maturation. Despite the great success of anti-retroviral therapy in slowing HIV progression in humans, a similar therapy has not been thoroughly investigated for FIV infection in cats, mostly because of the little structural information available for FIV proteins. The FIV capsid protein (CA) drives the assembly of the viral particle, which is a critical step in the viral replication cycle. During this step, the CA protein oligomerizes to form a protective coat that surrounds the viral genome. In this work, we perform a large-scale screening of four hundred molecules from our in house library using an in vitro assembly assay of p24, combined with microscale thermophoresis, to estimate binding affinity. This screening led to the discovery of around four novel hits that inhibited capsid assembly in vitro. These may provide new antiviral drugs against FIV. PMID- 29996482 TI - Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines. AB - A number of new substituted morpholinopyrimidines were prepared utilizing sequential nucleophilic aromatic substitution and cross-coupling reactions. One of the disubstituted pyrimidines was converted into two trisubstituted compounds which were screened as PI3K inhibitors relative to the well-characterized PI3K inhibitor ZSTK474, and were found to be 1.5-3-times more potent. A leucine linker was attached to the most active inhibitor since it would remain on any peptide containing prodrug after cleavage by prostate-specific antigen, and it did not prevent inhibition of AKT phosphorylation and hence the inhibition of PI3K by the modified inhibitor. PMID- 29996484 TI - Experimental Study on Force Sensitivity of the Conductivity of Carbon Nanotubes Modified Epoxy Resins. AB - The addition of a conductive material into polymer improves its mechanical properties, electrical properties and thermal conductivity and bestows it with good self-sensing and self-adjusting properties. In this study, carbon nanotubes modified epoxy resins (CNTs-EP) were successfully prepared with good dispersion through the combined methods of three roller rolling, ultrasonic processing and adding surfactant. Tests were conducted to evaluate the resistivity of unloaded modified epoxy resins with different mixing amounts of carbon nanotubes (CNTs), to determine the conductive percolation threshold. On the basis of the test results, a series of monotonic and cyclic uniaxial tensile tests were then conducted to investigate the force sensitivity of the conductivity of epoxy resins modified with different mixing amounts of CNTs. The relationship between the stress and the resistivity under various mixing amounts was studied, indicating that the resistance response could play a good warning role on the damage of the modified polymer material. PMID- 29996483 TI - Isolation and Characterization of a Green-Tissue Promoter from Common Wild Rice (Oryza rufipogon Griff.). AB - Promoters play a very important role in the initiation and regulation of gene transcription. Green-tissue promoter is of great significance to the development of genetically modified crops. Based on RNA-seq data and RT-PCR expression analysis, this study screened a gene, OrGSE (GREEN SPECIAL EXPRESS), which is expressed specifically in green tissues. The study also isolated the promoter of the OrGSE gene (OrGSEp), and predicted many cis-acting elements, such as the CAAT Box and TATA-Box, and light-responding elements, including circadian, G-BOX and GT1 CONSENSUS. Histochemical analysis and quantification of GUS activity in transgenic Arabidopsis thaliana plants expressing GUS under the control of OrGSEp revealed that this promoter is not only green tissue-specific, but also light inducible. The ability of a series of 5’-deletion fragments of OrGSEp to drive GUS expression in Arabidopsis was also evaluated. We found that the promoter region from −54 to −114 is critical for the promoter function, and the region from −374 to −114 may contain core cis elements involved in light response. In transgenic rice expressing GUS under the control of OrGSEp, visualization and quantification of GUS activity showed that GUS was preferentially expressed in green tissues and not in endosperm. OrGSEp is a useful regulatory element for breeding pest-resistant crops. PMID- 29996486 TI - Separation of Organic Compounds from ABE Model Solutions via Pervaporation Using Activated Carbon/PDMS Mixed Matrix Membranes. AB - The pervaporation separation of organic compounds from acetone-butanol-ethanol (ABE) fermentation model solutions was studied using activated carbon (AC) nanoparticle-poly (dimethylsiloxane) (PDMS) mixed matrix membranes (MMM). The effects of the operating conditions and nanoparticle loading content on the membrane performance have been investigated. While the separation factor increased continuously, with an increase in the concentration of nanoparticles, the total flux reached a maximum in the MMM with 8 wt % nanoparticle loading in PDMS. Both the separation factor for ABE and the total permeation flux more than doubled for the MMM in comparison to those of neat PDMS membranes prepared in this study. PMID- 29996485 TI - Biodiversity and Activity of Gut Fungal Communities across the Life History of Trypophloeus klimeschi (Coleoptera: Curculionidae: Scolytinae). AB - We comprehensively investigated the biodiversity of fungal communities in different developmental stages of Trypophloeus klimeschi and the difference between sexes and two generations by high throughput sequencing. The predominant species found in the intestinal fungal communities mainly belong to the phyla Ascomycota and Basidiomycota. Fungal community structure varies with life stage. The genera Nakazawaea, Trichothecium, Aspergillus, Didymella, Villophora, and Auricularia are most prevalent in the larvae samples. Adults harbored high proportions of Graphium. The fungal community structures found in different sexes are similar. Fusarium is the most abundant genus and conserved in all development stages. Gut fungal communities showed notable variation in relative abundance during the overwintering stage. Fusarium and Nectriaceae were significantly increased in overwintering mature larvae. The data indicates that Fusarium might play important roles in the survival of T. klimeschi especially in the overwintering stage. The authors speculated that Graphium plays an important role in the invasion and colonization of T. klimeschi. The study will contribute to the understanding of the biological role of the intestinal fungi in T. klimeschi, which might provide an opportunity and theoretical basis to promote integrated pest management (IPM) of T. klimeschi. PMID- 29996487 TI - Customers' Perceptions of Compliance with a Tobacco Control Law in Restaurants in Hanoi, Vietnam: A Cross-Sectional Study. AB - The Tobacco Harm Prevention Law has been promulgated in 2012 in Vietnam, prohibiting smoking in public places such as restaurants except for designated smoking areas. However, currently, evidence about Vietnamese customers’ and restaurants’ compliance with the Law is constrained. This study aimed to explore customers’ perceptions; attitudes and practices towards the compliance with tobacco control regulations in the restaurants in Hanoi, Vietnam. A cross-sectional study was performed in October 2015 with 1746 customers in 176 communes in Hanoi, Vietnam. Data about customers’ perceptions on how restaurants comply with the smoking control law and whether customers smoking actively or experienced SHS in restaurants in the last 30 days were collected. Multivariable mixed effects logistic regression model was used to determine the factors related to smoking in the restaurant. Most customers were aware of the law on Tobacco Harm Prevention (79%; n = 1320) and regulations that prohibited smoking in restaurants (78.4%; n = 1137). While 75.8% (n = 1285) of customers perceived that they did not see or rarely saw no-smoking signs, 17.7% (n = 481) of customers reported that they frequently saw direct marketing of tobacco in visited restaurants. About one-fourth of customers witnessed that the staff reminded customers not to smoke inside restaurants (28.8%; n = 313), and 65% (n = 1135) sometimes or always were exposed to secondhand smoke in their visited restaurants. People who were female (OR = 0.02, 95% CI = 0.01-0.05) were less likely to report their smoking in the restaurant than their counterparts. Those having higher age (OR = 1.03; 95% CI = 1.01-1.06), high school education (OR = 2.14, 95% CI = 1.07-4.26), being office workers (OR = 3.24, 95% CI = 1.33-7.92) or unemployed (OR = 4.45; 95% CI = 1.09-18.15) had a higher likelihood of reporting to be restaurant smokers than those having lower high education or students, respectively. This study highlighted a low level of perceived compliance with the smoke-free law in Vietnamese restaurants. Improving the monitoring systems for the enforcement of the smoking law in restaurants should be prioritized; restaurant owners should implement 100% smoke-free environments as following the best practice towards the tobacco control law along with educational campaigns to promote the awareness of restaurant owners and customers about the tobacco control law. PMID- 29996488 TI - A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease. AB - The imprinted Dlk1-Dio3 genomic region harbors a noncoding RNA cluster encoding over fifty microRNAs (miRNAs), three long noncoding RNAs (lncRNAs), and a small nucleolar RNA (snoRNA) gene array. These distinct noncoding RNAs (ncRNAs) are thought to arise from a single polycistronic transcript that is subsequently processed into individual ncRNAs, each with important roles in diverse cellular contexts. Considering these ncRNAs are derived from a polycistron, it is possible that some coordinately regulate discrete biological processes in the heart. Here, we provide a comprehensive summary of Dlk1-Dio3 miRNAs and lncRNAs, as they are currently understood in the cellular and organ-level context of the cardiovascular system. Highlighted are expression profiles, mechanistic contributions, and functional roles of these ncRNAs in heart development and disease. Notably, a number of these ncRNAs are implicated in processes often perturbed in heart disease, including proliferation, differentiation, cell death, and fibrosis. However, most literature falls short of characterizing precise mechanisms for many of these ncRNAs, warranting further investigation. Taken together, the Dlk1-Dio3 locus represents a largely unexplored noncoding regulator of cardiac homeostasis, harboring numerous ncRNAs that may serve as therapeutic targets for cardiovascular disease. PMID- 29996489 TI - Eating Behaviors in Postpartum: A Qualitative Study of Women with Obesity. AB - In postpartum, women experience major changes in their lives; they are forced to deal with new internal and external demands for attention and care for themselves and the baby. Postpartum feeding also suffers changes in this stage of life, because women find more barriers to healthy eating, which can put them at greater risk of overweight or obesity. This is a qualitative study, through in-depth semi directed interviews in an intentional sample with postpartum women with obesity, closed by saturation and qualitative content analysis. Sixteen women were included. Three categories emerged from this analysis: (1) from pregnancy to postpartum: changes in body and eating behavior; (2) eating to fill the void of helplessness felt during the postpartum period; and (3) breastfeeding and baby feeding. Women with obesity eat to relieve unpleasant feelings during the postnatal period. The postpartum period is an opportune moment to introduce long term changes in the eating behaviors and mental wellbeing of these women. Healthcare teams need to restructure to provide more focused follow-up care for women with obesity during the postnatal period in terms of their physical and emotional health. PMID- 29996490 TI - A Multidisciplinary Approach Reveals an Age-Dependent Expression of a Novel Bioactive Peptide, Already Involved in Neurodegeneration, in the Postnatal Rat Forebrain. AB - The basal forebrain has received much attention due to its involvement in multiple cognitive functions, but little is known about the basic neuronal mechanisms underlying its development, nor those mediating its primary role in Alzheimer’s disease. We have previously suggested that a novel 14-mer peptide, ‘T14’, could play a pivotal role in Alzheimer’s disease, via reactivation of a developmental signaling pathway. In this study, we have characterized T14 in the context of post-natal rat brain development, using a combination of different techniques. Ex-vivo rat brain slices containing the basal forebrain, at different stages of development, were used to investigate large-scale neuronal network activity in real time with voltage-sensitive dye imaging. Subsequent Western blot analysis revealed the expression profile of endogenous T14, its target alpha7 nicotinic receptor and the familiar markers of Alzheimer’s: amyloid beta and phosphorylated Tau. Results indicated maximal neuronal activity at the earliest ages during development, reflected in a concomitant profile of T14 peptide levels and related proteins. In conclusion, these findings show that the peptide, already implicated in neurodegenerative events, has an age-dependent expression, suggesting a possible contribution to the physiological mechanisms underlying brain maturation. PMID- 29996491 TI - The Current Status of Heterogeneous Palladium Catalysed Heck and Suzuki Cross Coupling Reactions. AB - In the last 30 years, C-C cross coupling reactions have become a reliable technique in organic synthesis due their versatility and efficiency. While drawbacks have been experienced on an industrial scale with the use of homogenous systems, many attempts have been made to facilitate a heterogeneous renaissance. Thus, this review gives an overview of the current status of the use of heterogeneous catalysts particularly in Suzuki and Heck reactions. Most recent developments focus on palladium immobilised or supported on various classes of supports, thus this review highlights and discuss contributions of the last decade. PMID- 29996492 TI - Lower Protein Intake Supports Normal Growth of Full-Term Infants Fed Formula: A Randomized Controlled Trial. AB - Infant formulas have been conventionally prepared with an excess of total protein in order to provide sufficient amounts of essential amino acids to the rapidly growing infant. However, this practice leads to higher than necessary protein intake during early infant development, inducing accelerated growth patterns correlated with the development of chronic diseases later in life. This study was aimed at assessing the safety of an infant formula enriched with bovine alpha lactalbumin containing a total protein concentration very close to that of human milk, and determining its efficacy in the support of healthy infant growth from the first month to the fourth month of age. Healthy full-term infants ≤40 days of age were randomized in this controlled single blind trial to one of the following infant formulas: IF 1 (containing 1.0 g protein/dL; n = 30), IF 2 (containing 1.3 g protein/dL; n = 24), and IF 3 (containing 1.5 g protein/dL; n = 42). A control group consisting of exclusively breastfed infants (HM; n = 212) was included in the study. Anthropometric measurements and Z-scores were evaluated at baseline, at 1 month of age, and at 4 months of age. Weight gain (g/day) was similar in the IF 1 and the HM groups (p = 0.644), and it was significantly greater in the IF 2 and IF 3 groups than in the HM group. Growth patterns in both breastfed or IF-fed infants were in accordance with the World Health Organization (WHO) growth standards. At four months of age, the mean weight-for-age Z-score (WAZ) adjusted for initial value in the IF 1 group was similar to that of the HM group and significantly lower than that of the IF 2 and IF 3 groups (p = 0.031 and p = 0.014 for IF 2 and IF 3, respectively). Length-for age (LAZ) adjusted for initial value was similar among all groups at four months of age. From 1 to 4 months of life, IF 1 containing 1.0 g protein/dL promotes growth and weight gain similar to those observed in exclusively breastfed infants. As this is a first approach to studying an IF containing total protein in a level below that recommended by international committees on nutrition, further investigations are needed to support these findings evaluating infant’s metabolic profile and growth in the long term. PMID- 29996494 TI - Review: Modes and Processes of Severe Plastic Deformation (SPD). AB - In this review, severe plastic deformation (SPD) is considered as a materials processing technology. The deformation mode is the principal characteristic differentiating SPD techniques from common forming operations. For large plastic strains, deformation mode depends on the distribution of strain rates between continuum slip lines and can be varied from pure shear to simple shear. A scalar, invariant, and dimensionless coefficient of deformation mode is introduced as a normalized speed of rigid rotation. On this basis, simple shear provides the optimal mode for structure modification and grain refinement, whereas pure shear is “ideal” for forming operations. Special experiments and SPD practice confirm this conclusion. Various techniques of SPD are classified and described in accordance with simple shear realization or approximation. It is shown that correct analyses of the processing mechanics and technological parameters are essential for the comparison of SPD techniques and the development of effective industrial technologies. PMID- 29996495 TI - A Simple, Quick and Eco-Friendly Strategy of Synthesis Nanosized alpha-LiFeO2 Cathode with Excellent Electrochemical Performance for Lithium-Ion Batteries. AB - Nanosized α-LiFeO2 samples were successfully synthesized via a simple, quick and eco-friendly strategy at ambient temperature followed by a low temperature calcined process. X-ray diffraction (XRD), scanning electronic microscopy (SEM) and transmission electron microscopy (TEM) measurements revealed that the optimal α-LiFeO2 sample was composed of extremely small nanoparticles. The electrochemical properties were tested at 0.1 C in the cut-off voltage of 1.5-4.8 V. The sample obtained at 150 °C for 6 h exhibited the best cycling stability with high initial discharge capacity of 223.2 mAh/g, which was extremely high for pristine α-LiFeO2 without any modification process. After 50 cycles, the discharge capacity could still maintain 194.5 mAh/g with good capacity retention. When the charge-discharge rate increased to 0.2 C and 0.5 C, the initial discharge capacities were 216.6 mAh/g and 171.5 mAh/g, respectively. Furthermore, the optimal sample showed low charge transfer resistance and high lithium-ion diffusion coefficients, which facilitated the excellent electrochemical performance. PMID- 29996496 TI - Radio-Fluorogenic Gel Dosimetry with Coumarin. AB - Gel dosimeters are attractive detectors for radiation therapy, with properties similar to biological tissue and the potential to visualize volumetric dose distributions. Radio-fluorogenesis is the yield of fluorescent chemical products in response to energy deposition from ionizing radiation. This report shares the development of a novel radio-fluorogenic gel (RFG) dosimeter, gelatin infused with coumarin-3-carboxlyic acid (C3CA), for the quantification of imparted energy. Aqueous solutions exposed to ionizing radiation result in the production of hydroxyl free radicals through water radiolysis. Interactions between hydroxyl free radicals and coumarin-3-carboxylic acid produce a fluorescent product. 7 hydroxy-coumarin-3-carboxylic acid has a blue (445 nm) emission following ultra violet (UV) to near UV (365-405 nm) excitation. Effects of C3CA concentration and pH buffers were investigated. The response of the RFG was explored with respect to strength, type, and exposure rate of high-energy radiation. Results show a linear dose response relationship independent of energy and type, with a dose rate dependency. This report demonstrates increased photo-yield with high pH and the utility of gelatin-RFG for phantom studies of radiation dosimetry. PMID- 29996493 TI - Crosstalk between Notch, HIF-1alpha and GPER in Breast Cancer EMT. AB - The Notch signaling pathway acts in both physiological and pathological conditions, including embryonic development and tumorigenesis. In cancer progression, diverse mechanisms are involved in Notch-mediated biological responses, including angiogenesis and epithelial-mesenchymal-transition (EMT). During EMT, the activation of cellular programs facilitated by transcriptional repressors results in epithelial cells losing their differentiated features, like cell-cell adhesion and apical-basal polarity, whereas they gain motility. As it concerns cancer epithelial cells, EMT may be consequent to the evolution of genetic/epigenetic instability, or triggered by factors that can act within the tumor microenvironment. Following a description of the Notch signaling pathway and its major regulatory nodes, we focus on studies that have given insights into the functional interaction between Notch signaling and either hypoxia or estrogen in breast cancer cells, with a particular focus on EMT. Furthermore, we describe the role of hypoxia signaling in breast cancer cells and discuss recent evidence regarding a functional interaction between HIF-1α and GPER in both breast cancer cells and cancer-associated fibroblasts (CAFs). On the basis of these studies, we propose that a functional network between HIF-1α, GPER and Notch may integrate tumor microenvironmental cues to induce robust EMT in cancer cells. Further investigations are required in order to better understand how hypoxia and estrogen signaling may converge on Notch-mediated EMT within the context of the stroma and tumor cells interaction. However, the data discussed here may anticipate the potential benefits of further pharmacological strategies targeting breast cancer progression. PMID- 29996497 TI - Microwave Optimized Synthesis of N-(adamantan-1-yl)-4-[(adamantan-1-yl) sulfamoyl]benzamide and Its Derivatives for Anti-Dengue Virus Activity. AB - Dengue fever is a major public health concern in many tropical and sub-tropical regions. The development of agents that are able to inhibit the dengue virus (DENV) is therefore of utmost importance. This study focused on the synthesis of dual acting hybrids comprising structural features of known DENV inhibitors, amantadine (1) and benzsulfonamide derivatives. Hybrid compound 3, N-(adamantan-1 yl)-4-[(adamantan-1-yl)sulfamoyl]benzamide, was synthesized by reacting amantadine (1) with 4-(chlorosulfonyl)benzoic acid (2), after optimization, in a 2:1 ratio under microwave irradiation conditions in a one-pot reaction. Mono adamantane derivatives 6 and 7 were synthesised via acyl halide formation of benzoic acid (4) and 4-sulfamoyl benzoic acid (5), respectively, followed by conjugation with amantadine (1) through a conventional or microwave irradiation assisted nucleophilic addition/substitution reaction. The use of microwave irradiation lead to significant increases in yields and a reduction in reaction times. Nuclear magnetic resonance, infra-red and mass spectral data confirmed the structures. Compound 3 and 7 showed significant anti-DENV serotype 2 activity (IC50 = 22.2 µM and 42.8 µM) and low cytotoxicity (CC50 < 100 µM). Possible mechanisms of action are also proposed, which are based on the biological results and molecular docking studies. PMID- 29996498 TI - Chemical Composition and Antibacterial Activity of Essential Oils from Ferula L. Species against Methicillin-Resistant Staphylococcus aureus. AB - Essential oils (EOs) were obtained by hydrodistillation of various parts of Ferula ovina (Boiss.) Boiss., Ferula iliensis Krasn. ex. Korovin, and Ferula akitschkensis B. Fedtsch. ex Koso-Pol., collected in the flowering/budding and fruiting stages. Eight samples of EOs isolated from F. ovina and four samples from F. akitsckensis were analyzed by gas chromatography-mass spectrometry (GC MS). The major constituents of F. ovina EOs were α-pinene (6.9-47.8%), β-pinene (1.5-7.1%), sabinene (0.1-20.5%), β-phellandrene (0-6.5%), trans-verbenol (0.9-7.4%), eremophilene (3.1-12%), and 6Z-2,5,5,10-tetramethyl undeca-2,6,9-trien-8-one (0-13.7%). The major constituents of F. akitsckensis EOs were α-pinene (0-46.2%), β-pinene (0-47.9%), sabinene (0-28.3%), eremophilene (0-10.6), β-caryophyllene (0-7.5%), himachalen-7-ol (0-28.2%), and an himachalol derivative (0-8.3%). Samples of EOs from F. ovina, F. iliensis, and F. akitsckensis were evaluated for antibacterial activity against methicillin resistant Staphylococcus aureus (MRSA) pulse-field gel electrophoresis type USA300 (LAC). EOs from F. ovina exhibited the highest antibacterial activity compared to samples from other Ferula spp., with the most potent EOs being isolated from roots at the flowering and fruiting stages and stems at the fruiting stage (IC50 values of 19.1, 20.9, and 22.9 µg/mL, respectively). Although EOs demonstrated concentration-dependent inhibition of MRSA growth, analysis of the major constituents (α-pinene, β-pinene, and sabinene) showed that they had low activity, suggesting that other components were likely responsible for the observed bioactivity of the unfractionated EOs. Indeed, correlation of the GC-MS data with antibacterial activity suggested that the putative components responsible for antibacterial activity were, either individually or in combination, eremophilene and trans-verbenol. Overall, these results suggest that the EOs from F. ovina could have potential for use as alternative remedies for the treatment of infectious diseases caused by MRSA. PMID- 29996499 TI - Implications of Angiogenesis Involvement in Arthritis. AB - Angiogenesis, the growth of new blood vessels, is essential in the pathogenesis of joint inflammatory disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA), facilitating the invasion of inflammatory cells and increase in local pain receptors that contribute to structural damage and pain. The angiogenic process is perpetuated by various mediators such as growth factors, primarily vascular endothelial growth factor (VEGF) and hypoxia-inducible factors (HIFs), as well as proinflammatory cytokines, various chemokines, matrix components, cell adhesion molecules, proteases, and others. Despite the development of potent, well-tolerated nonbiologic (conventional) and biologic disease-modifying agents that have greatly improved outcomes for patients with RA, many remain resistant to these therapies, are only partial responders, or cannot tolerate biologics. The only approved therapies for OA include symptom modifying agents, such as analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and hyaluronic acid. None of the available treatments slow the disease progression, restore the original structure or enable a return to function of the damaged joint. Moreover, a number of safety concerns surround current therapies for RA and OA. New treatments are needed that not only target inflamed joints and control articular inflammation in RA and OA, but also selectively inhibit synovial angiogenesis, while preventing healthy tissue damage. This narrative review of the literature in PubMed focuses on the evidence illustrating the therapeutic benefits of modulating angiogenic activity in experimental RA and OA. This evidence points to new treatment targets in these diseases. PMID- 29996501 TI - Hopf Bifurcation and Vibration Control for a Thrust Magnetic Bearing with Variable Load Mass. AB - In the working process, the load mass of the thrust magnetic bearing has a significant change. If the load mass changes greatly, the original fixed control parameters cannot ensure that the system is in the optimal stable suspension state, and the performance of the system will become worse or even self-excited. Firstly, a single freedom degree of the suspension control system model is established, and the critical condition of the system is analyzed when a self excited oscillation occurs. Then, a linear adaptive control law is proposed for the system with variable parameters, which can tolerate the wide range of load mass. The simulation results show that the adaptive control law can keep the stability of the system when the load mass varies in a large range and avoid the self-excited vibration. PMID- 29996500 TI - Photonic Band Gap and Bactericide Performance of Amorphous Sol-Gel Titania: An Alternative to Crystalline TiO2. AB - In addition to its traditional application in white pigments, nanocrystalline titania (TiO2) has optoelectronic and photocatalytic properties (strongly dependent on crystallinity, particle size, and surface structure) that grant this naturally occurring oxide new technological applications. Sol-gel is one of the most widely used methods to synthesize TiO2 films and NPs, but the products obtained (mostly oxy-hydrated amorphous phases) require severe heat-treatments to promote crystallization, in which control over size and shape is difficult to achieve. In this work, we obtained new photocatalytic materials based on amorphous titania and measured their electronic band gap. Two case studies are reported that show the enormous potential of amorphous titania as bactericide or photocatalyst. In the first, amorphous sol-gel TiO2 thin films doped with N (TiO2−xNx, x = 0.75) were designed to exhibit a photonic band gap in the visible region. The identification of Ti-O-N and N-Ti-O bindings was achieved by XPS. The photonic band gaps were found to be 3.18 eV for a-TiO2 and 2.99 eV for N doped a-TiO2. In the second study, amorphous titania and amine-functionalized amorphous titania nanoparticles were synthetized using a novel base-catalysed sol gel methodology. All the synthesized amorphous TiO2 nanoparticles exhibit bactericide performance (E. coli, ASTME 2149-13). PMID- 29996503 TI - Two Rye Genes Responsible for Abnormal Development of Wheat-Rye Hybrids Are Linked in the Vicinity of an Evolutionary Translocation on Chromosome 6R. AB - The post-zygotic reproductive isolation (RI) in plants is frequently based on the negative interaction of the parental genes involved in plant development. Of special interest is the study of such types of interactions in crop plants, because of the importance of distant hybridization in plant breeding. This study is devoted to map rye genes that are incompatible with wheat, determining the development of the shoot apical meristem in wheat-rye hybrids. Linkage analysis of microsatellite loci, as well as genes of embryo lethality (Eml-R1) and hybrid dwarfness (Hdw-R1) was carried out in hybrids of Chinese Spring wheat with recombinant inbred lines as well as interline rye hybrids. Eml-R1 and Hdw-R1 could be mapped proximal and distal of two closely linked EST-SSR markers, Xgrm902 and Xgrm959, on rye chromosome 6R. Both rye genes are located on a segment of chromosome 6R that contains a breakpoint of evolutionary translocation between the ancestral chromosomes of homeologous groups 6 and 3. The obtained results are discussed in relation to genes interacting in developmental pathways as a class of causal genes of RI. PMID- 29996502 TI - PPARbeta/delta: Linking Metabolism to Regeneration. AB - In contrast to the general belief that regeneration is a rare event, mainly occurring in simple organisms, the ability of regeneration is widely distributed in the animal kingdom. Yet, the efficiency and extent of regeneration varies greatly. Humans can recover from blood loss as well as damage to tissues like bone and liver. Yet damage to the heart and brain cannot be reversed, resulting in scaring. Thus, there is a great interest in understanding the molecular mechanisms of naturally occurring regeneration and to apply this knowledge to repair human organs. During regeneration, injury-activated immune cells induce wound healing, extracellular matrix remodeling, migration, dedifferentiation and/or proliferation with subsequent differentiation of somatic or stem cells. An anti-inflammatory response stops the regenerative process, which ends with tissue remodeling to achieve the original functional state. Notably, many of these processes are associated with enhanced glycolysis. Therefore, peroxisome proliferator-activated receptor (PPAR) β/δ—which is known to be involved for example in lipid catabolism, glucose homeostasis, inflammation, survival, proliferation, differentiation, as well as mammalian regeneration of the skin, bone and liver—appears to be a promising target to promote mammalian regeneration. This review summarizes our current knowledge of PPARβ/δ in processes associated with wound healing and regeneration. PMID- 29996504 TI - Synthesis and Surface-Enhanced Raman Scattering of Ultrathin SnSe2 Nanoflakes by Chemical Vapor Deposition. AB - As a new atomically layered, two-dimensional material, tin (IV) diselenide (SnSe2) has attracted extensive attention due to its compelling application in electronics and optoelectronics. However, the great challenge of impurities and the preparation of high-quality ultrathin SnSe2 nanoflakes has hindered far reaching research and SnSe2 practical applications so far. Therefore, a facile chemical vapor deposition (CVD) method is employed to synthesize large-scale ultrathin SnSe2 flakes on mica substrates using SnSe and Se powder as precursors. The structural characteristics and crystalline quality of the product were investigated. Moreover, Raman characterizations indicate that the intensity of A1g peak and Eg peak, and the Raman shift of Eg are associated with the thickness of the SnSe2 nanoflakes. The ultrathin SnSe2 nanoflakes show a strong surface enhanced Raman spectroscopy (SERS) activity for Rhodamine 6G (R6G) molecules. Theoretical explanations for the enhancement principle based on the chemical enhancement mechanism and charge transfer diagram between R6G and SnSe2 are provided. The results demonstrate that the ultrathin SnSe2 flakes are high quality single crystal and can be exploited for microanalysis detection and optoelectronic application. PMID- 29996505 TI - Stable Isotope and Metagenomic Profiling of a Methanogenic Naphthalene-Degrading Enrichment Culture. AB - Polycyclic aromatic hydrocarbons (PAH) such as naphthalene are widespread, recalcitrant pollutants in anoxic and methanogenic environments. A mechanism catalyzing PAH activation under methanogenic conditions has yet to be discovered, and the microbial communities coordinating their metabolism are largely unknown. This is primarily due to the difficulty of cultivating PAH degraders, requiring lengthy incubations to yield sufficient biomass for biochemical analysis. Here, we sought to characterize a new methanogenic naphthalene-degrading enrichment culture using DNA-based stable isotope probing (SIP) and metagenomic analyses. 16S rRNA gene sequencing of fractionated DNA pinpointed an unclassified Clostridiaceae species as a putative naphthalene degrader after two months of SIP incubation. This finding was supported by metabolite and metagenomic evidence of genes predicted to encode for enzymes facilitating naphthalene carboxylic acid CoA-thioesterification and degradation of an unknown arylcarboxyl-CoA structure. Our findings also suggest a possible but unknown role for Desulfuromonadales in naphthalene degradation. This is the first reported functional evidence of PAH biodegradation by a methanogenic consortium, and we envision that this approach could be used to assess carbon flow through other slow growing enrichment cultures and environmental samples. PMID- 29996506 TI - Respiratory Tract Deposition and Distribution Pattern of Microparticles in Mice Using Different Pulmonary Delivery Techniques. AB - Pulmonary delivery of drugs and vaccines is an established route of administration, with particulate-based carriers becoming an attractive strategy to enhance the benefits of pulmonary therapeutic delivery. Despite the increasing number of publications using the pulmonary route of delivery, the lack of effective and uniform administration techniques in preclinical models generally results in poor translational success. In this study, we used the IVIS Spectrum small-animal in vivo imaging system to compare the respiratory tract deposition and distribution pattern of a microsphere suspension (5 µm) in mice after 1, 4, and 24 h when delivered by oropharyngeal aspiration, the Microsprayer® Aerosolizer, and the BioLite Intubation System, three-widely reported preclinical inhalation techniques. We saw no significant differences in microsphere deposition in whole body images and excised lungs (at 1, 4, and 24 h); however, the three-dimensional (3D) images showed more localized deposition in the lungs with the MicroSprayer® and BioLite delivery techniques. Further, oropharyngeal aspiration (at 1 h) showed microsphere deposition in the oral cavity, in contrast to the MicroSprayer® and BioLite systems. The studies shown here will allow researchers to choose the appropriate pulmonary delivery method in animal models based on their study requirements. PMID- 29996507 TI - A Fiber Bragg Grating-Based Anemometer. AB - A novel fiber anemometer based on two pairs of fiber gratings is experimentally demonstrated and can simultaneously detect wind speed and wind direction. One pair of gratings, which are separated by 90° in space, is fixed on a small stainless steel pipe driven by a rotating disc for measuring the wind-direction angle. The other pair is composed of a sensing and a matched grating. The frequency of the spectrum-shifted of the sensing grating to overlap with that of the matched grating is employed for determining the wind speed. The errors in the wind-speed and wind-angle measurements are experimentally demonstrated to be less than 1%. The proposed fiber anemometer with a simple and durable structure can be applied in wind-powered electricity generators. PMID- 29996508 TI - Single-Step Fabrication of Polymer Nanocomposite Films. AB - Polymer nanocomposites are employed in (micro)electronic, biomedical, structural and optical applications. Their fabrication is challenging due to nanoparticle (filler) agglomeration and settling, increased viscosity of blended solutions and multiple tedious processing steps, just to name a few. Often this leads to an upper limit for filler content, requirements for filler-polymer interfacial chemistry and expensive manufacturing. As a result, novel but simple processes for nanocomposite manufacture that overcome such hurdles are needed. Here, a truly single-step procedure for synthesis of polymer nanocomposite films, structures and patterns at high loadings of nanoparticles (for example, >24 vol %) for a variety of compositions is presented. It is highly versatile with respect to rapid preparation of films possessing multiple layers and filler content gradients even on untreated challenging substrates (paper, glass, polymers). Such composites containing homogeneously dispersed nanoparticles even at high loadings can improve the mechanical strength of hydrogels, load-bearing ability of fragile microstructures, gas permeability in thin barriers, performance of dielectrics and device integration in stretchable electronics. PMID- 29996509 TI - Mitral Kissing Vegetation and Acquired Aortic Valve Stenosis Secondary to Infectious Endocarditis in a Goat with Suppurative Mastitis. AB - A six-year-old female goat was presented to the veterinary teaching hospital of the University of the West Indies with a history of progressive hind-limb paresis lasting two weeks. The doe developed a grade 6/6 holosystolic murmur during hospitalisation. Echocardiography revealed vegetative growths attached to cusps of the mitral and aortic valves. There was an accelerated aortic flow at 2.9 m/s and aortic insufficiency. The aortic vegetation was prolapsing into the left ventricle during diastole, causing it to contact the septal mitral valve leaflet. A diagnosis of mitral and aortic vegetative endocarditis, with a mitral kissing vegetation and mild aortic stenosis, was reached. The patient was placed on broad spectrum antimicrobials. A short-term follow-up showed no resolution of clinical signs, and the animal eventually died. Post-mortem examination showed severe vegetative, fibrino-necrotic, aortic and mitral valve lesions. The goat also had a severe fibrino-suppurative mastitis. Histopathology confirmed the lesions to be vegetative endocarditis. PMID- 29996510 TI - Ni(OH)2 and NiO Based Composites: Battery Type Electrode Materials for Hybrid Supercapacitor Devices. AB - Nanocomposites of Ni(OH)2 or NiO have successfully been used in electrodes in the last five years, but they have been falsely presented as pseudocapacitive electrodes for electrochemical capacitors and hybrid devices. Indeed, these nickel oxide or hydroxide electrodes are pure battery-type electrodes which store charges through faradaic processes as can be shown by cyclic voltammograms or constant current galvanostatic charge/discharge plots. Despite this misunderstanding, such electrodes can be of interest as positive electrodes in hybrid supercapacitors operating under KOH electrolyte, together with an activated carbon-negative electrode. This study indicates the requirements for the implementation of Ni(OH)2-based electrodes in hybrid designs and the improvements that are necessary in order to increase the energy and power densities of such devices. Mass loading is the key parameter which must be above 10 mg·cm−2 to correctly evaluate the performance of Ni(OH)2 or NiO based nanocomposite electrodes and provide gravimetric capacity values. With such loadings, rate capability, capacity, cycling ability, energy and power densities can be accurately evaluated. Among the 80 papers analyzed in this study, there are indications that such nanocomposite electrode can successfully improve the performance of standard Ni(OH)2 (+)//6 M KOH//activated carbon (−) hybrid supercapacitor. PMID- 29996511 TI - Land Use Regression Modelling of Outdoor NO2 and PM2.5 Concentrations in Three Low Income Areas in the Western Cape Province, South Africa. AB - Air pollution can cause many adverse health outcomes, including cardiovascular and respiratory disorders. Land use regression (LUR) models are frequently used to describe small-scale spatial variation in air pollution levels based on measurements and geographical predictors. They are particularly suitable in resource limited settings and can help to inform communities, industries, and policy makers. Weekly measurements of NO2 and PM2.5 were performed in three informal areas of the Western Cape in the warm and cold seasons 2015-2016. Seasonal means were calculated using routinely monitored pollution data. Six LUR models were developed (four seasonal and two annual) using a supervised stepwise land-use-regression method. The models were validated using leave-one-out-cross validation and tested for spatial autocorrelation. Annual measured mean NO2 and PM2.5 were 22.1 μg/m3 and 10.2 μg/m3, respectively. The NO2 models for the warm season, cold season, and overall year explained 62%, 77%, and 76% of the variance (R2). The PM2.5 annual models had lower explanatory power (R2 = 0.36, 0.29, and 0.29). The best predictors for NO2 were traffic related variables (major roads, bus routes). Local sources such as grills and waste burning sites appeared to be good predictors for PM2.5, together with population density. This study demonstrates that land-use-regression modelling for NO2 can be successfully applied to informal peri-urban settlements in South Africa using similar predictor variables to those performed in Europe and North America. Explanatory power for PM2.5 models is lower due to lower spatial variability and the possible impact of local transient sources. The study was able to provide NO2 and PM2.5 seasonal exposure estimates and maps for further health studies. PMID- 29996512 TI - Bioinspired Designs, Molecular Premise and Tools for Evaluating the Ecological Importance of Antimicrobial Peptides. AB - This review article provides an overview of recent developments in antimicrobial peptides (AMPs), summarizing structural diversity, potential new applications, activity targets and microbial killing responses in general. The use of artificial and natural AMPs as templates for rational design of peptidomimetics are also discussed and some strategies are put forward to curtail cytotoxic effects against eukaryotic cells. Considering the heat-resistant nature, chemical and proteolytic stability of AMPs, we attempt to summarize their molecular targets, examine how these macromolecules may contribute to potential environmental risks vis-à-vis the activities of the peptides. We further point out the evolutional characteristics of the macromolecules and indicate how they can be useful in designing target-specific peptides. Methods are suggested that may help to assess toxic mechanisms of AMPs and possible solutions are discussed to promote the development and application of AMPs in medicine. Even if there is wide exposure to the environment like in the hospital settings, AMPs may instead contribute to prevent healthcare-associated infections so long as ecotoxicological aspects are considered. PMID- 29996514 TI - The Genetics of a Behavioral Speciation Phenotype in an Island System. AB - Mating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we use quantitative trait locus (QTL) mapping to infer the number, distribution, and effect size of mating song rhythm variations in the crickets Laupala eukolea and Laupala cerasina, which occur on different islands (Maui and Hawaii). We then compare these results with a similar study of an independently evolving species pair that diverged within the same island. Finally, we annotate the L. cerasina transcriptome and test whether the QTL fall in functionally enriched genomic regions. We document a polygenic architecture behind the song rhythm divergence in the inter-island species pair that is remarkably similar to that previously found for an intra-island species pair in the same genus. Importantly, the QTL regions were significantly enriched for potential homologs of the genes involved in pathways that may be modulating the cricket song rhythm. These clusters of loci could constrain the spatial genomic distribution of the genetic variation underlying the cricket song variation and harbor several candidate genes that merit further study. PMID- 29996513 TI - Cellulases from Thermophiles Found by Metagenomics. AB - Cellulases are a heterogeneous group of enzymes that synergistically catalyze the hydrolysis of cellulose, the major component of plant biomass. Such reaction has biotechnological applications in a broad spectrum of industries, where they can provide a more sustainable model of production. As a prerequisite for their implementation, these enzymes need to be able to operate in the conditions the industrial process requires. Thus, cellulases retrieved from extremophiles, and more specifically those of thermophiles, are likely to be more appropriate for industrial needs in which high temperatures are involved. Metagenomics, the study of genes and gene products from the whole community genomic DNA present in an environmental sample, is a powerful tool for bioprospecting in search of novel enzymes. In this review, we describe the cellulolytic systems, we summarize their biotechnological applications, and we discuss the strategies adopted in the field of metagenomics for the discovery of new cellulases, focusing on those of thermophilic microorganisms. PMID- 29996515 TI - Stable Isotope-Resolved Metabolomics Shows Metabolic Resistance to Anti-Cancer Selenite in 3D Spheroids versus 2D Cell Cultures. AB - Conventional two-dimensional (2D) cell cultures are grown on rigid plastic substrates with unrealistic concentration gradients of O2, nutrients, and treatment agents. More importantly, 2D cultures lack cell-cell and cell extracellular matrix (ECM) interactions, which are critical for regulating cell behavior and functions. There are several three-dimensional (3D) cell culture systems such as Matrigel, hydrogels, micropatterned plates, and hanging drop that overcome these drawbacks but they suffer from technical challenges including long spheroid formation times, difficult handling for high throughput assays, and/or matrix contamination for metabolic studies. Magnetic 3D bioprinting (M3DB) can circumvent these issues by utilizing nanoparticles that enable spheroid formation and growth via magnetizing cells. M3DB spheroids have been shown to emulate tissue and tumor microenvironments while exhibiting higher resistance to toxic agents than their 2D counterparts. It is, however, unclear if and how such 3D systems impact cellular metabolic networks, which may determine altered toxic responses in cells. We employed a Stable Isotope-Resolved Metabolomics (SIRM) approach with 13C6-glucose as tracer to map central metabolic networks both in 2D cells and M3DB spheroids formed from lung (A549) and pancreatic (PANC1) adenocarcinoma cells without or with an anti-cancer agent (sodium selenite). We found that the extent of 13C-label incorporation into metabolites of glycolysis, the Krebs cycle, the pentose phosphate pathway, and purine/pyrimidine nucleotide synthesis was largely comparable between 2D and M3DB culture systems for both cell lines. The exceptions were the reduced capacity for de novo synthesis of pyrimidine and sugar nucleotides in M3DB than 2D cultures of A549 and PANC1 cells as well as the presence of gluconeogenic activity in M3DB spheroids of PANC1 cells but not in the 2D counterpart. More strikingly, selenite induced much less perturbation of these pathways in the spheroids relative to the 2D counterparts in both cell lines, which is consistent with the corresponding lesser effects on morphology and growth. Thus, the increased resistance of cancer cell spheroids to selenite may be linked to the reduced capacity of selenite to perturb these metabolic pathways necessary for growth and survival. PMID- 29996517 TI - Developing a Case-Based Blended Learning Ecosystem to Optimize Precision Medicine: Reducing Overdiagnosis and Overtreatment. AB - INTRODUCTION: Precision medicine aims to focus on meeting patient requirements accurately, optimizing patient outcomes, and reducing under-/overdiagnosis and therapy. We aim to offer a fresh perspective on accuracy driven “age-old precision medicine” and illustrate how newer case-based blended learning ecosystems (CBBLE) can strengthen the bridge between age-old precision approaches with modern technology and omics-driven approaches. METHODOLOGY: We present a series of cases and examine the role of precision medicine within a “case based blended learning ecosystem” (CBBLE) as a practicable tool to reduce overdiagnosis and overtreatment. We illustrated the workflow of our CBBLE through case-based narratives from global students of CBBLE in high and low resource settings as is reflected in global health. RESULTS: Four micro-narratives based on collective past experiences were generated to explain concepts of age-old patient-centered scientific accuracy and precision and four macro-narratives were collected from individual learners in our CBBLE. Insights gathered from a critical appraisal and thematic analysis of the narratives were discussed. DISCUSSION AND CONCLUSION: Case-based narratives from the individual learners in our CBBLE amply illustrate their journeys beginning with “age-old precision thinking” in low-resource settings and progressing to “omics driven” high-resource precision medicine setups to demonstrate how the approaches, used judiciously, might reduce the current pandemic of over /underdiagnosis and over-/undertreatment. PMID- 29996516 TI - Endothelial Cell Aging: How miRNAs Contribute? AB - Endothelial cells (ECs) form monolayers and line the interior surfaces of blood vessels in the entire body. In most mammalian systems, the capacity of endothelial cells to divide is limited and endothelial cells are prone to be senescent. Aging of ECs and resultant endothelial dysfunction lead to a variety of vascular diseases such as atherosclerosis, diabetes mellites, hypertension, and ischemic injury. However, the mechanism by which ECs get old and become senescent and the impact of endothelial senescence on the vascular function are not fully understood. Recent research has unveiled the crucial roles of miRNAs, which are small non-coding RNAs, in regulating endothelial cellular functions, including nitric oxide production, vascular inflammation, and anti thromboformation. In this review, how senescent-related miRNAs are involved in controlling the functions of ECs will be discussed. PMID- 29996519 TI - Simultaneous Evaluation of Creep Deformation and Recovery of Bulk-Fill Dental Composites Immersed in Food-Simulating Liquids. AB - : The aim of this study is to compare the creep/recovery behavior of bulk-fill dental composites after storage in various food simulating organic solvents. For this purpose, five different resin-composites (four bulk-fills and one conventional) were used. A total of 20 rectangular specimens (14 mm × 3 mm × 0.7 mm) were prepared by filling the resin-composites in Teflon mold. All of the specimens for each material (n = 5) were divided into four groups namely dry (control), distilled water (DW), artificial saliva, and absolute ethanol. The specimens were subjected to three-point bending creep test during immersion directly. A constant load of 2 N was used for each specimen with loading and unloading time 2 h each. RESULTS: SF2 and XF showed a lower creep strain % after immersion, ranging from 0.44 (dry) to 0.75 (saliva) and 0.43 (dry) to 0.80 (ethanol), respectively. TNC BF depicts the maximum creep strain % ranging from 1.24% (dry) to 2.87% (ethanol) followed by FBF ranging from 1.17 (dry) to 2.59 (ethanol). However, the conventional material (GR) showed lower creep strain after immersion ranging from 0.28 to 0.54. Moreover, SF2 resulted in the highest creep recovery in all of the composites groups, as well as conventional material. The other composite groups showed lower creep recovery as compared to the conventional material (GR). The creep strain % for all the bulk-fill composites materials were increased during immersion in the liquids. However, for the conventional material, the creep deformation is decreased after immersion. SF2 showed the highest percentage of creep recovery among the bulk-fill composites, followed by XF. PMID- 29996518 TI - Animal Female Meiosis: The Challenges of Eliminating Centrosomes. AB - Sexual reproduction requires the generation of gametes, which are highly specialised for fertilisation. Female reproductive cells, oocytes, grow up to large sizes when they accumulate energy stocks and store proteins as well as mRNAs to enable rapid cell divisions after fertilisation. At the same time, metazoan oocytes eliminate their centrosomes, i.e., major microtubule-organizing centres (MTOCs), during or right after the long growth phases. Centrosome elimination poses two key questions: first, how can the centrosome be re established after fertilisation? In general, metazoan oocytes exploit sperm components, i.e., the basal body of the sperm flagellum, as a platform to reinitiate centrosome production. Second, how do most metazoan oocytes manage to build up meiotic spindles without centrosomes? Oocytes have evolved mechanisms to assemble bipolar spindles solely around their chromosomes without the guidance of pre-formed MTOCs. Female animal meiosis involves microtubule nucleation and organisation into bipolar microtubule arrays in regulated self-assembly under the control of the Ran system and nuclear transport receptors. This review summarises our current understanding of the molecular mechanism underlying self-assembly of meiotic spindles, its spatio-temporal regulation, and the key players governing this process in animal oocytes. PMID- 29996521 TI - Toward Better Control of Inclusion Cleanliness in a Gas Stirred Ladle Using Multiscale Numerical Modeling. AB - The industrial objective of lowering the mass of mechanical structures requires continuous improvement in controlling the mechanical properties of metallic materials. Steel cleanliness and especially control of inclusion size distribution have, therefore, become major challenges. Inclusions have a detrimental effect on fatigue that strongly depends both on inclusion content and on the size of the largest inclusions. Ladle treatment of liquid steel has long been recognized as the processing stage responsible for the inclusion of cleanliness. A multiscale modeling has been proposed to investigate the inclusion behavior. The evolution of the inclusion size distribution is simulated at the process scale due to coupling a computational fluid dynamics calculation with a population balance method integrating all mechanisms, i.e., flotation, aggregation, settling, and capture at the top layer. Particular attention has been paid to the aggregation mechanism and the simulations at an inclusion scale with fully resolved inclusions that represent hydrodynamic conditions of the ladle, which have been specifically developed. Simulations of an industrial-type ladle highlight that inclusion cleanliness is mainly ruled by aggregation. Quantitative knowledge of aggregation kinetics has been extracted and captured from mesoscale simulations. Aggregation efficiency has been observed to drop drastically when increasing the particle size ratio. PMID- 29996520 TI - A Meta-Prediction of Methylenetetrahydrofolate-Reductase Polymorphisms and Air Pollution Increased the Risk of Ischemic Heart Diseases Worldwide. AB - Ischemic heart disease (IHD) is among the leading causes of death worldwide. Methylenetetrahydrofolate reductase (MTHFR) polymorphisms have been associated with IHD risk, but the findings presented with heterogeneity. The purpose of the present meta-analysis was to provide an updated evaluation by integrating machine learning based analytics to examine the potential source of heterogeneity on the associations between MTHFR polymorphisms and the risk of various subtypes of IHD, as well as the possible impact of air pollution on MTHFR polymorphisms and IHD risks. A comprehensive search of various databases was conducted to locate 123 studies (29,697 cases and 31,028 controls) for MTHFR C677T, and 18 studies (7158 cases and 5482 controls) for MTHFR A1298C. Overall, MTHFR 677 polymorphisms were risks for IHD (TT: Risk ratio (RR) = 1.23, p < 0.0001; CT: RR = 1.04, p = 0.0028, and TT plus CT: RR = 1.09, p < 0.0001). In contrast, MTHFR 677 CC wildtype was protective against IHD (RR = 0.91, p < 0.00001) for overall populations. Three countries with elevated IHD risks from MTHFR C677T polymorphism with RR >2 included India, Turkey, and Tunisia. Meta-predictive analysis revealed that increased air pollution was associated with increased MTHFR 677 TT and CT polymorphisms in both the case and control group (p < 0.05), with the trend of increased IHD risk resulting from increased air pollution. These results associate the potential inflammatory pathway with air pollution and the folate pathway with MTHFR polymorphism. Future intervention studies can be designed to mitigate MTHFR enzyme deficiencies resulting from gene polymorphisms to prevent IHDs for at-risk populations. PMID- 29996522 TI - An Adaptive Nonlocal Mean Filter for PolSAR Data with Shape-Adaptive Patches Matching. AB - The traditional nonlocal filters for polarimetric synthetic aperture radar (PolSAR) images are based on square patches matching to obtain homogeneous pixels in a large search window. However, it is still difficult for the regular patches to work well in the complex textured areas, even when the patch size has a small enough setting (e.g., 3 × 3 windows). Therefore, this paper proposes an adaptive nonlocal mean filter with shape-adaptive patches matching (ANLM) for PolSAR images. Mainly, the shape-adaptive (SA) matching patches are constructed by combining the polarimetric likelihood ratio test for coherency matrices (PolLRT-CM) and the region growing (RG), which is called PolLRT-CMRG. It is used to distinguish the homogeneous and heterogeneous pixels in textured areas effectively. Then, to enhance the filtering effect, it is necessary to take the adaptive threshold selection of similarity test (Simi-Test) into consideration. The simulated, low spatial resolution SAR580-Convair and high spatial resolution ESAR PolSAR image datasets are selected for experiments. We make a detailed quantitative and qualitative analysis for the filtered results. The experimental results have demonstrated that the proposed ANLM filter has better performance in speckle suppression and detail preservation than that of the traditional local and nonlocal filters. PMID- 29996523 TI - Light Activated Disinfection in Root Canal Treatment-A Focused Review. AB - Light activated disinfection (LAD) is a strategy for optimizing root canal disinfection by using a highly-selective, targeted killing of bacteria using a combination of photosensitizers and light. Over the past decade, numerous in vitro and clinical studies have been performed to demonstrate the effectiveness of this mode of root canal disinfection. While most studies offer an important understanding of the effectiveness of LAD on monospecies biofilms, few have offered credence to the fact that infections of the root canal system are mediated by polymicrobial biofilms. Hence, it is imperative to understand the effect of LAD on polymicrobial biofilms both in terms of microbial killing and the changes in the biofilm architecture. The aim of this review was to systematically review the literature to evaluate the effect of LAD on dual and multispecies biofilms and demonstrate the antibiofilm effect of LAD. Two databases (PubMed and Scopus) were searched to identify eligible studies using a combination of key words. These studies were reviewed to draw conclusions on the effect of LAD on dual and multi species biofilm and the antibiofilm effect of LAD. It was found that LAD alone may be unable to eradicate dual and multispecies biofilms, but it may enhance the effect of conventional canal debridement strategies. Novel formulations of photosensitizers with nanoparticles showed the potential to inhibit biofilm formation and/or disrupt the biofilm architecture. PMID- 29996524 TI - Activation of Anthracene Endoperoxides in Leishmania and Impairment of Mitochondrial Functions. AB - Leishmaniasis is a vector-borne disease caused by protozoal Leishmania. Because of resistance development against current drugs, new antileishmanial compounds are urgently needed. Endoperoxides (EPs) are successfully used in malaria therapy, and experimental evidence of their potential against leishmaniasis exists. Anthracene endoperoxides (AcEPs) have so far been only technically used and not explored for their leishmanicidal potential. This study verified the in vitro efficiency and mechanism of AcEPs against both Leishmania promastigotes and axenic amastigotes (L. tarentolae and L. donovani) as well as their toxicity in J774 macrophages. Additionally, the kinetics and radical products of AcEPs’ reaction with iron, the formation of radicals by AcEPs in Leishmania, as well as the resulting impairment of parasite mitochondrial functions were studied. Using electron paramagnetic resonance combined with spin trapping, photometry, and fluorescence-based oximetry, AcEPs were demonstrated to (i) show antileishmanial activity in vitro at IC50 values in a low micromolar range, (ii) exhibit host cell toxicity in J774 macrophages, (iii) react rapidly with iron (II) resulting in the formation of oxygen- and carbon-centered radicals, (iv) produce carbon centered radicals which could secondarily trigger superoxide radical formation in Leishmania, and (v) impair mitochondrial functions in Leishmania during parasite killing. Overall, the data of different AcEPs demonstrate that their structures besides the peroxo bridge strongly influence their activity and mechanism of their antileishmanial action. PMID- 29996525 TI - Direct Detection of Candida albicans with a Membrane Based Electrochemical Impedance Spectroscopy Sensor. AB - Candidemia and invasive candidiasis is a cause of high mortality and morbidity rates among hospitalized patients worldwide. The occurrence of the infections increases due to the complexity of the patients and overuse of the antifungal therapy. The current Candida detection method includes blood culturing which is a lengthy procedure and thus delays the administration of the antifungal therapy. Even though the results are available after 48 h it is still the gold standard in pathogen detection in a hospital setting. In this work we present an electrochemical impedance sensor that is capable of detecting Candida albicans yeast. The yeast cells are captured on electrodes specifically functionalized with anti-Candida antibodies and detection is achieved by electrochemical impedance spectroscopy. The sensor allows for detection of the yeast cells at clinically relevant concentrations in less than 1 h. PMID- 29996526 TI - Association between Urinary Calcium Excretion and Estimated Glomerular Filtration Rate Decline in Patients with Type 2 Diabetes Mellitus: A Retrospective Single center Observational Study. AB - Urinary calcium excretion is not known to predict progression of renal dysfunction in patients with type 2 diabetes mellitus. This study aimed to investigate associations between urinary calcium excretion and progression of estimated glomerular filtration rate (eGFR) in type 2 diabetic patients. This study was a retrospective, single-center, observational cohort study. We enrolled a total of 89 patients with type 2 diabetes mellitus and the average follow-up period was 7.2 +/- 1.0 years. We divided patients into two groups based on the median of annual decline in the slope of eGFR, then defined the over-median population as the progressed group and under-median population as the non progressed group. Median of annual decline in the slope of eGFR was −1.1 mL/min/1.73 m2/year. Correlation coefficient analysis showed positive correlation of urinary calcium excretion with eGFR (r = 0.39, p < 0.001). Multivariate logistic analysis showed that baseline eGFR and urinary calcium excretion were independent variables for progression of eGFR decline. Urinary calcium excretion could be a useful metabolic parameter for predicting decline in slope of eGFR in patients with type 2 diabetes mellitus. PMID- 29996527 TI - Neuro-Fuzzy Modelling of the Metallic Surface Characterization on Linear Dry Contact between Plastic Material Reinforced with SGF and Alloyed Steel. AB - This paper presents the modelling of wear data resulting from linear dry contact using artificial neural networks (ANN) and adaptive neuro-fuzzy inference systems (ANFIS) with the aim of constructing predictor models for the depth and volume of the wear scar, with great impact in the characterization of new industrial processes utilizing existing materials. The dataset is the result of laboratory testing, presenting both numerical and categorical variables whose inclusion into the model allows for a number of possibilities. The width of the wear scar was measured on a microscope, and its depth was calculated. A multitude of experimental tests was performed with normal loads and different speeds, which led to some conclusive results, but in some cases, with relatively high variance. Various options for the automatic generation of fuzzy inference systems were also approached (genfis2). The innovative approach was compared with a baseline model featuring multivariate linear regression optimized using gradient descent, drawing on previous experimentation on the same dataset. The models developed can be implemented in future research and in practical applications under similar conditions, aiming to optimize performance by applying Computer Science. The obtained results lead to highly accurate prediction models which are further integrated into various metallic surface characterizations in the wear process for tribological and robotics research in new industrial processes using short glass fiber reinforced polymers. PMID- 29996529 TI - Fatigue Life Prediction for Transverse Crack Initiation of CFRP Cross-Ply and Quasi-Isotropic Laminates. AB - Carbon fiber reinforced plastic (CFRP) laminates are used as main structural members in many applications. Transverse cracks that form in 90° layers of CFRP laminates are mostly initial damage in the case where tensile loading is vertically applied to the 90° layers of CFRP laminates, and they are the origin of more serious damage of delamination and fiber breakage. It is thus important to predict quantitatively the transverse crack initiation of CFRP laminates subjected to cyclic loading to ensure the long-term reliability of the laminates. The initiation and multiplication behaviors of transverse cracks strongly depend on the laminate configuration, thickness, and thermal residual stress. Therefore, a model based on the Walker model was proposed to predict transverse crack initiation in CFRP cross-ply and quasi-isotropic laminates under cyclic loading in the present study. The usefulness of the proposed model was verified with 10 different CFRP laminates formed from four different prepregs with epoxy resin matrices. The analysis results were in good agreement with experimental results. The fatigue life was expressed with three constants, which related to the fatigue strength reduction, the normalized fatigue strength at N = 1 cycle, and the contribution of stress amplitude to the fatigue life, and they are independent of the laminate configuration. PMID- 29996528 TI - Comparative Strengths of Tetrel, Pnicogen, Chalcogen, and Halogen Bonds and Contributing Factors. AB - Ab initio calculations are employed to assess the relative strengths of various noncovalent bonds. Tetrel, pnicogen, chalcogen, and halogen atoms are represented by third-row atoms Ge, As, Se, and Br, respectively. Each atom was placed in a series of molecular bonding situations, beginning with all H atoms, then progressing to methyl substitutions, and F substituents placed in various locations around the central atom. Each Lewis acid was allowed to engage in a complex with NH3 as a common nucleophile, and the strength and other aspects of the dimer were assessed. In the context of fully hydrogenated acids, the strengths of the various bonds varied in the pattern of chalcogen > halogen > pnicogen ≈ tetrel. Methyl substitution weakened all bonds, but not in a uniform manner, resulting in a greatly weakened halogen bond. Fluorosubstitution strengthened the interactions, increasing its effect as the number of F atoms rises. The effect was strongest when the F atom lay directly opposite the base, resulting in a halogen > chalcogen > pnicogen > tetrel order of bond strength. Replacing third-row atoms by their second-row counterparts weakened the bonds, but not uniformly. Tetrel bonds were weakest for the fully hydrogenated acids and surpassed pnicogen bonds when F had been added to the acid. PMID- 29996530 TI - Adsorption of Trace Estrogens in Ultrapure and Wastewater Treatment Plant Effluent by Magnetic Graphene Oxide. AB - In the current study, graphene oxide, Fe3+, and Fe2+ were used for the synthesis of magnetic graphene oxide (MGO) by an in situ chemical coprecipitation method. Scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and X-ray diffraction were used to characterize the well prepared MGO. The prepared MGO was used as an adsorbent to remove five typical estrogens (estrone (E1), 17β-estradiol (E2), 17α-ethinylestradiol (17α-E2), estriol (E3), and synthetic estrogen (EE2)) at the ppb level from spiked ultrapure water and wastewater treatment plant effluent. The results indicated that the MGO can efficiently remove estrogens from both spiked ultrapure water and wastewater treatment plant effluent in 30 min at wide pH ranges from 3 to 11. The temperature could significantly affect removal performance. A removal efficiency of more than 90% was obtained at 35 °C in just 5 min, but at least 60 min was needed to get the same removal efficiency at 5 °C. In addition, an average of almost 80% of the estrogens can still be removed after 5 cycles of MGO regeneration but less than 40% can be reached after 10 cycles. These results indicate that MGO has potential for practical applications to remove lower levels of estrogens from real water matrixes and merits further evaluation. PMID- 29996531 TI - Envy and Counterproductive Work Behavior: The Moderation Role of Leadership in Public and Private Organizations. AB - Envy is a frequent emotion in work contexts where there is strong competition for resources and the leader is the person who manages them. When employees feel envy, they are likely to use counterproductive work behaviors (CWB), but the use of these behaviors may differ depending on the organization’s ownership. The goal of this study is to develop and test a model for the moderating role of Leader Member Exchange (LMX) in the relationship between envy and CWB in public and private organizations. The study design was cross-sectional. Data were collected from 225 Spanish employees in public and private organizations and analyzed using Path Analysis techniques. Results showed that envy was positively related to CWB, and that LMX was a significant moderator in the relationship between envy and CWB in public organizations, but not in private ones. However, this relationship is positive with high LMX, but less than in subjects with low LMX. Findings provide empirical support for the hypothesized conceptual model. This study is one of the first to explore LMX as a moderator of the relationship between envy and CWB. Thus, this study adds value to previous social exchange studies on LMX by integrating emotion research into the context of an exchange based relationship. Our findings lead to several practical implications for creating healthy organizations. PMID- 29996532 TI - Possible Role of Envelope Components in the Extreme Copper Resistance of the Biomining Acidithiobacillus ferrooxidans. AB - Acidithiobacillus ferrooxidans resists extremely high concentrations of copper. Strain ATCC 53993 is much more resistant to the metal compared with strain ATCC 23270, possibly due to the presence of a genomic island in the former one. The global response of strain ATCC 53993 to copper was analyzed using iTRAQ (isobaric tag for relative and absolute quantitation) quantitative proteomics. Sixty-seven proteins changed their levels of synthesis in the presence of the metal. On addition of CusCBA efflux system proteins, increased levels of other envelope proteins, such as a putative periplasmic glucan biosynthesis protein (MdoG) involved in the osmoregulated synthesis of glucans and a putative antigen O polymerase (Wzy), were seen in the presence of copper. The expression of A. ferrooxidansmdoG or wzy genes in a copper sensitive Escherichia coli conferred it a higher metal resistance, suggesting the possible role of these components in copper resistance of A. ferrooxidans. Transcriptional levels of genes wzy, rfaE and wzz also increased in strain ATCC 23270 grown in the presence of copper, but not in strain ATCC 53993. Additionally, in the absence of this metal, lipopolysaccharide (LPS) amounts were 3-fold higher in A. ferrooxidans ATCC 53993 compared with strain 23270. Nevertheless, both strains grown in the presence of copper contained similar LPS quantities, suggesting that strain 23270 synthesizes higher amounts of LPS to resist the metal. On the other hand, several porins diminished their levels in the presence of copper. The data presented here point to an essential role for several envelope components in the extreme copper resistance by this industrially important acidophilic bacterium. PMID- 29996534 TI - Huber's Non-Linearity for GNSS Interference Mitigation ?. AB - Satellite-based navigation is prevalent in both commercial applications and critical infrastructures, providing precise position and time referencing. As a consequence, interference to such systems can have repercussions on a plethora of fields. Additionally, Privacy Preserving Devices (PPD)—jamming devices—are relatively inexpensive and easy to obtain, potentially denying the service in a wide geographical area. Current jamming mitigation technology is based on interference cancellation approaches, requiring the detection and estimation of the interference waveform. Recently, the Robust Interference Mitigation (RIM) framework was proposed, which leverages results in robust statistics by treating the jamming signal as an outlier. It has the advantage of rejecting jamming signals without detecting or estimating its waveform. In this paper, we extend the framework to situations where the jammer is sparse in some transformed domain other than the time domain. Additionally, we analyse the use of Huber’s non-linearity within RIM and derive its loss of efficiency. We compare its performance to state-of-the-art techniques and to other RIM solutions, with both synthetic and real signals, showing remarkable results. PMID- 29996533 TI - 3D Analysis of Upper Limbs Motion during Rehabilitation Exercises Using the KinectTM Sensor: Development, Laboratory Validation and Clinical Application. AB - Optoelectronic devices are the gold standard for 3D evaluation in clinics, but due to the complexity of this kind of hardware and the lack of access for patients, affordable, transportable, and easy-to-use systems must be developed to be largely used in daily clinics. The KinectTM sensor has various advantages compared to optoelectronic devices, such as its price and transportability. However, it also has some limitations: (in)accuracy of the skeleton detection and tracking as well as the limited amount of available points, which makes 3D evaluation impossible. To overcome these limitations, a novel method has been developed to perform 3D evaluation of the upper limbs. This system is coupled to rehabilitation exercises, allowing functional evaluation while performing physical rehabilitation. To validate this new approach, a two-step method was used. The first step was a laboratory validation where the results obtained with the KinectTM were compared with the results obtained with an optoelectronic device; 40 healthy young adults participated in this first part. The second step was to determine the clinical relevance of this kind of measurement. Results of the healthy subjects were compared with a group of 22 elderly adults and a group of 10 chronic stroke patients to determine if different patterns could be observed. The new methodology and the different steps of the validations are presented in this paper. PMID- 29996535 TI - Facile Preparation and Characterization of Short-Fiber and Talc Reinforced Poly(Lactic Acid) Hybrid Composite with In Situ Reactive Compatibilizers. AB - Hybrid composites of fillers and/or fibers reinforced polymer was generally produced by masterbatch dilution technique. In this work, the simplified preparation was introduced for the large volume production of 30 wt % short-fiber and talcum reinforced polymer hybrid composite by direct feeding into twin-screw extruder. Multifunctional epoxide-based terpolymer and/or maleic anhydride were selected as in situ reactive compatibilizers. The influence of fiber and talcum ratios and in situ reactive compatibilizers on mechanical, dynamic mechanical, morphological and thermal properties of hybrid composites were investigated. The morphological results showed the strong interfacial adhesion between fiber or talcum and Poly(lactic acid) (PLA) matrix due to a better compatibility by reaction of in situ compatibilizer. The reactive PLA hybrid composite showed the higher tensile strength and the elongation at break than non-compatibilized hybrid composite without sacrificing the tensile modulus. Upon increasing the talcum contents, the modulus and storage modulus of hybrid composites were also increased while the tensile strength and elongation at break were slightly decreased compared to PLA/fiber composite. Talcum was able to induce the crystallization of PLA hybrid composites. PMID- 29996537 TI - Impact Monitoring for Aircraft Smart Composite Skins Based on a Lightweight Sensor Network and Characteristic Digital Sequences. AB - Due to the growing use of composite materials in aircraft structures, Aircraft Smart Composite Skins (ASCSs) which have the capability of impact monitoring for large-scale composite structures need to be developed. However, the impact of an aircraft composite structure is a random transient event that needs to be monitored on-line continuously. Therefore, the sensor network of an ASCS and the corresponding impact monitoring system which needs to be installed on the aircraft as an on-board device must meet the requirements of light weight, low power consumption and high reliability. To achieve this point, an Impact Region Monitor (IRM) based on piezoelectric sensors and guided wave has been proposed and developed. It converts the impact response signals output from piezoelectric sensors into Characteristic Digital Sequences (CDSs), and then uses a simple but efficient impact region localization algorithm to achieve impact monitoring with light weight and low power consumption. However, due to the large number of sensors of ASCS, the realization of lightweight sensor network is still a key problem to realize an applicable ASCS for on-line and continuous impact monitoring. In this paper, three kinds of lightweight piezoelectric sensor networks including continuous series sensor network, continuous parallel sensor network and continuous heterogeneous sensor network are proposed. They can greatly reduce the lead wires of the piezoelectric sensors of ASCS and they can also greatly reduce the monitoring channels of the IRM. Furthermore, the impact region localization methods, which are based on the CDSs and the lightweight sensor networks, are proposed as well so that the lightweight sensor networks can be applied to on-line and continuous impact monitoring of ASCS with a large number of piezoelectric sensors. The lightweight piezoelectric sensor networks and the corresponding impact region localization methods are validated on the composite wing box of an unmanned aerial vehicle. The accuracy rate of impact region localization is higher than 92%. PMID- 29996536 TI - Underutilization of Hepatitis C Virus Seropositive Donor Kidneys in the United States in the Current Opioid Epidemic and Direct-Acting Antiviral Era. AB - In recent years, the opioid epidemic and new hepatitis C virus (HCV) treatments have changed the landscape of organ procurement and allocation. We studied national trends in solid organ transplantation (2000-2016), focusing on graft utilization from HCV seropositive deceased donors in the pre-2014 (2000-2013) versus current (2014-2016) eras with a retrospective analysis of the United Network for Organ Sharing database. During the study period, HCV seropositive donors increased from 181 to 661 donors/year. The rate of HCV seropositive donor transplants doubled from 2014 to 2016. Heart and lung transplantation data were too few to analyze. A higher number of HCV seropositive livers were transplanted into HCV seropositive recipients during the current era: 374 versus 124 liver transplants/year. Utilization rates for liver transplantation reached parity between HCV seropositive and non-HCV donors. While the number of HCV seropositive kidneys transplanted to HCV seropositive recipients increased from 165.4 to 334.7 kidneys/year from the pre-2014 era to the current era, utilization rates for kidneys remained lower in HCV seropositive than in non-HCV donors. In conclusion, relative underutilization of kidneys from HCV seropositive versus non-HCV donors has persisted, in contrast to trends in liver transplantation. PMID- 29996538 TI - Tumor B7-H3 (CD276) Expression and Survival in Pancreatic Cancer. AB - B7-H3 (CD276), a member of the family of immune modulators, orchestrates antitumor immunity. To date, only small-sized studies have examined the association of B7-H3 expression with survival in pancreatic cancer, yielding inconclusive results. We evaluated tumor B7-H3 expression in 150 consecutive patients with pancreatic ductal adenocarcinoma using immunohistochemistry. B7-H3 expression was positive (≥10% tumor cells) in 99 of 150 (66%) cases of pancreatic cancer. We classified the tumors into four groups depending on B7-H3 expression (negative, low, intermediate, and high) and found that higher B7-H3 expression was independently associated with lower disease-free survival (DFS; for high vs. negative B7-H3 expression: multivariable hazard ratio (HR) = 3.12; 95% confidence interval (CI) = 1.48-6.15; Ptrend = 0.0026). Furthermore, the association of B7-H3 expression with survival differed according to the pathological stage (p-stage) (Pinteraction = 0.048, between p-stages I-II and III IV). The association of B7-H3 positivity with lower DFS was stronger in tumors with p-stage I-II (multivariable HR = 3.10, 95% CI = 1.75-5.69; P < 0.0001) than in those with p-stage III-IV (multivariable HR = 1.20, 95% CI = 0.67-2.28; P = 0.55). We demonstrated that tumor high B7-H3 expression is independently associated with poor survival in patients with pancreatic cancer and that this association is stronger in tumors with p-stage I-II than in those with p-stage III-IV. B7-H3 expression may be a useful prognostic biomarker for identifying aggressive early-stage pancreatic cancer. PMID- 29996541 TI - Iodoxybenzoic Acid Supported on Multi Walled Carbon Nanotubes as Biomimetic Environmental Friendly Oxidative Systems for the Oxidation of Alcohols to Aldehydes. AB - Iodoxybenzoic acid (IBX) supported multi walled carbon nanotube (MWCNT) derivatives have been prepared as easily recyclable solid reagents. These compounds have been shown to be able to mimic the alcohol dehydrogenases and monooxygenases promoted oxidation of aromatic alcohols to corresponding aldehydes. Their reactivity was found to be dependent on the degree of functionalization of MWCNTs as well as from the chemical properties of the spacers used to bind IBX on the surface of the support. Au-decorated MWCNTs and the presence of longer spacers resulted in the optimal experimental conditions. A high conversion of the substrates and yield of desired products were obtained. PMID- 29996540 TI - A Bibliometric Analysis of the Global Research Trend in Child Maltreatment. AB - Child maltreatment remains a major health threat globally that requires the understanding of socioeconomic and cultural contexts to craft effective interventions. However, little is known about research agendas globally and the development of knowledge-producing networks in this field of study. This study aims to explore the bibliometric overview on child maltreatment publications to understand their growth from 1916 to 2018. Data from the Web of Science Core Collection were collected in May 2018. Only research articles and reviews written in the English language were included, with no restrictions by publication date. We analyzed publication years, number of papers, journals, authors, keywords and countries, and presented the countries collaboration and co-occurrence keywords analysis. From 1916 to 2018, 47,090 papers (53.0% in 2010-2018) were published in 9442 journals. Child Abuse & Neglect (2576 papers; 5.5%); Children and Youth Services Review (1130 papers; 2.4%) and Pediatrics (793 papers, 1.7%) published the most papers. The most common research areas were Psychology (16,049 papers, 34.1%), Family Studies (8225 papers, 17.5%), and Social Work (7367 papers, 15.6%). Among 192 countries with research publications, the most prolific countries were the United States (26,367 papers), England (4676 papers), Canada (3282 papers) and Australia (2664 papers). We identified 17 authors who had more than 60 scientific items. The most cited papers (with at least 600 citations) were published in 29 journals, headed by the Journal of the American Medical Association (JAMA) (7 papers) and the Lancet (5 papers). This overview of global research in child maltreatment indicated an increasing trend in this topic, with the world’s leading centers located in the Western countries led by the United States. We called for interdisciplinary research approaches to evaluating and intervening on child maltreatment, with a focus on low-middle income countries (LMICs) settings and specific contexts. PMID- 29996542 TI - Outcomes of a Randomized Controlled Trial on the Effectiveness of Depression and Anxiety Prevention for Adolescents with a High Familial Risk. AB - A randomized controlled trail was conducted to examine the effectiveness of a depression and anxiety prevention program ‘Een Sprong Vooruit’ (A Leap Forward) among adolescent girls with a high familial risk (N = 142). The results showed neither effects of the prevention program directly after the intervention, nor at 6 or 12 months follow-up on depression and anxiety symptoms. Further, latent growth curve modeling (LGCM) was used to examine whether the growth functions for the intervention and the control condition were different. The slope representing the change in depression symptoms was not significantly different between the intervention and the control condition. For anxiety symptoms, the difference between slopes was also not significant. Based on these results, we suggested that these high-risk adolescent girls might benefit more from a more intensive prevention program. PMID- 29996539 TI - With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment. AB - Age is one of the biggest risk factors for ovarian cancer. Older women have higher rates of diagnosis and death associated with the disease. In mouse models, it was shown that aged mice had greater tumor burden than their younger counterparts when intraperitoneally injected with ovarian tumor cells. While very few papers have been published looking at the direct link between ovarian cancer metastasis and age, there is a wealth of information on how age affects metastatic microenvironments. Mesothelial cells, the peritoneal extracellular matrix (ECM), fibroblasts, adipocytes and immune cells all exhibit distinct changes with age. The aged peritoneum hosts a higher number of senescent cells than its younger counterpart, in both the mesothelium and the stroma. These senescent cells promote an inflammatory profile and overexpress Matrix Metalloproteinases (MMPs), which remodel the ECM. The aged ECM is also modified by dysregulated collagen and laminin synthesis, increases in age-related crosslinking and increasing ovarian cancer invasion into the matrix. These changes contribute to a vastly different microenvironment in young and aged models for circulating ovarian cancer cells, creating a more welcoming “soil”. PMID- 29996543 TI - Dietary Patterns, Cardiorespiratory and Muscular Fitness in 9-11-Year-Old Children from Dunedin, New Zealand. AB - Research shows that cardiorespiratory (CRF) and muscular fitness in childhood are associated with a healthier cardiovascular profile in adulthood. Identifying factors associated with measures of fitness in childhood could allow for strategies to optimize cardiovascular health throughout the lifecourse. The aim of this study was to examine the association between dietary patterns and both CRF and muscular fitness in 9-11-year-olds. In this study of 398 children, CRF and muscular fitness were assessed using a 20-m shuttle run test and digital hand dynamometer, respectively. Dietary patterns were derived using principal component analysis. Mixed effects linear regression models were used to assess associations between dietary patterns and CRF and muscular fitness. Most children had healthy CRF (99%, FITNESSGRAM) and mean +/- SD muscular fitness was 15.2 +/- 3.3 kg. Two dietary patterns were identified; “Snacks” and “Fruit and Vegetables”. There were no significant associations between either of the dietary patterns and CRF. Statistically significant but not clinically meaningful associations were seen between dietary patterns and muscular fitness. In an almost exclusively fit cohort, food choice is not meaningfully related to measures of fitness. Further research to investigate diet fitness relationships in children with lower fitness levels can identify key populations for potential investments in health-promoting behaviors. PMID- 29996544 TI - Substituted 2-Aminobenzothiazoles Salicylidenes Synthesis and Characterization as Cyanide Sensors in Aqueous Medium. AB - (E)-2-((benzo[d]thiazol-2-ylimino)methyl)-4-nitrophenol 1 and (E)-2-(((6 methoxybenzo[d]thiazol-2-yl)imino)methyl)-4-nitrophenol 2 were synthesized efficiently under microwave conditions. The structures were confirmed using IR, 1H NMR, and 13C NMR. UV-vis. Fluorescence investigations demonstrated that 1 and 2 are sensitive and selective sensors for detection of cyanide over all other anions SCN−, AcO−, N3−, H2PO4−, H2AsO4−, F−, Cl−, Br−, and I− in aqueous media. Cyanide induces colorimetric change from pale yellow to dark yellow and from transparent to pale yellow for 1 and 2, respectively. It enhances the absorption at wavelengths 385 nm and 425 nm of 1 and 385 nm and 435 nm of 2. Acidic anions H2PO4− and H2AsO4− displayed significant interference with the interaction of cyanide and sensors 1 and 2. Sensor 1 has lower detection limit (LDL) 1 × 10−6 M, while 2 has LDL 1.35 × 10−6 M. PMID- 29996545 TI - Characterizing the Interaction between Antibiotics and Humic Acid by Fluorescence Quenching Method. AB - The method of Three-Dimensional Excitation Emission Matrix Fluorescence Spectrophotometer was used to identify the interaction mechanism between humic acid (HA) and antibiotics. The effects of antibiotic concentration, temperature, and pH on the bonding strength between HA and antibiotics were investigated. The results showed that with the increase of antibiotics concentration, the quenching effect on HA was enhanced. The quenching of HA by both oxytetracycline (OTC) and sulfadiazine (SD) is a single static quenching of the complexes, and the interaction forces are mainly a hydrogen bond and the van der Waals force. The quenching constant KsvOTC > KsvSD and the binding constant KbOTC > KbSD, indicates that HA has a more obvious quenching effect on OTC. The Kb of HA by OTC ranged from 3.223 × 103 to 12.784 × 103 L·mol−1 in the range of 298 K to 313 K, while the Kb of HA by SD ranged from 2.051 × 103 to 5.533 × 103 L·mol−1. With the increase of temperature, the quenching constant Ksv and binding constant Kb of both OTC and SD by HA gradually decrease, and the low temperature is beneficial to the interaction. The composite of OTC and HA is more stable than SD. Under neutral alkaline conditions, both OTC and SD had the strongest quenching effect on HA, and the resulting complex was the most stable. However, the Ksv and Kb of HA by OTC were greater than SD in the pH range of the experiment and the pH effect on quenching of HA by OTC (Ksv) was greater than that of SD. PMID- 29996546 TI - A Deep CNN-LSTM Model for Particulate Matter (PM2.5) Forecasting in Smart Cities. AB - In modern society, air pollution is an important topic as this pollution exerts a critically bad influence on human health and the environment. Among air pollutants, Particulate Matter (PM2.5) consists of suspended particles with a diameter equal to or less than 2.5 μm. Sources of PM2.5 can be coal-fired power generation, smoke, or dusts. These suspended particles in the air can damage the respiratory and cardiovascular systems of the human body, which may further lead to other diseases such as asthma, lung cancer, or cardiovascular diseases. To monitor and estimate the PM2.5 concentration, Convolutional Neural Network (CNN) and Long Short-Term Memory (LSTM) are combined and applied to the PM2.5 forecasting system. To compare the overall performance of each algorithm, four measurement indexes, Mean Absolute Error (MAE), Root Mean Square Error (RMSE) Pearson correlation coefficient and Index of Agreement (IA) are applied to the experiments in this paper. Compared with other machine learning methods, the experimental results showed that the forecasting accuracy of the proposed CNN LSTM model (APNet) is verified to be the highest in this paper. For the CNN-LSTM model, its feasibility and practicability to forecast the PM2.5 concentration are also verified in this paper. The main contribution of this paper is to develop a deep neural network model that integrates the CNN and LSTM architectures, and through historical data such as cumulated hours of rain, cumulated wind speed and PM2.5 concentration. In the future, this study can also be applied to the prevention and control of PM2.5. PMID- 29996547 TI - The Oral Healthcare System in Japan. AB - This paper describes the present Japanese oral healthcare system and outlines the future challenges and perspectives for Japan. Japan has developed a system for providing high-quality and appropriate health care efficiently through a universal health insurance system which has been in operation since 1961. This health insurance covers most restorative, prosthetic and oral surgery treatment. Therefore, all people can receive dental treatment at a relatively low cost, with the same fees applying throughout the nation. In Japan, public oral health services are provided by the local governments according to the life stage of their populations. These services are mainly conducted by private dental practitioners under contracts with local governments. National oral health data shows that the oral health of the Japanese population has improved over the last several decades. Future challenges and perspectives for Japanese dentistry include: tackling the regional differences in oral health, decreasing the cost of health expenditure, establishment of sustainable emergency oral healthcare services in times of disaster, and the development a new tele-dental system for remote areas without access to dental professionals. PMID- 29996550 TI - Thermal Response of Jointed Rock Masses Inferred from Infrared Thermographic Surveying (Acuto Test-Site, Italy). AB - The Mediterranean region is affected by considerable daily and seasonal temperature variations due to intense solar radiation. In mid-seasons, thermal excursions can exceed tens of degrees thus influencing the long-term behaviour of jointed rock masses acting as a preparatory factor for rock slope instabilities. In order to evaluate the thermal response of a densely jointed rock-block, monitoring has been in operation since 2016 by direct and remote sensing techniques in an abandoned quarry in Acuto (central Italy). Monthly InfraRed Thermographic (IRT) surveys were carried out on its exposed faces and along sections of interest across monitored main joints. The results highlight the daily and seasonal cyclical behaviour, constraining amplitudes and rates of heating and cooling phases. The temperature time-series revealed the effect of sun radiation and exposure on thermal response of the rock-block, which mainly depends on the seasonal conditions. The influence of opened joints in the heat propagation is revealed by the differential heating experienced across it, which was verified under 1D and 2D analysis. IRT has proved to be a valid monitoring technique in supporting traditional approaches, for the definition of the surficial temperature distribution on rock masses or stone building materials. PMID- 29996548 TI - The Multiplanetary Future of Plant Synthetic Biology. AB - The interest in human space journeys to distant planets and moons has been re ignited in recent times and there are ongoing plans for sending the first manned missions to Mars in the near future. In addition to generating oxygen, fixing carbon, and recycling waste and water, plants could play a critical role in producing food and biomass feedstock for the microbial manufacture of materials, chemicals, and medicines in long-term interplanetary outposts. However, because life on Earth evolved under the conditions of the terrestrial biosphere, plants will not perform optimally in different planetary habitats. The construction or transportation of plant growth facilities and the availability of resources, such as sunlight and liquid water, may also be limiting factors, and would thus impose additional challenges to efficient farming in an extraterrestrial destination. Using the framework of the forthcoming human missions to Mars, here we discuss a series of bioengineering endeavors that will enable us to take full advantage of plants in the context of a Martian greenhouse. We also propose a roadmap for research on adapting life to Mars and outline our opinion that synthetic biology efforts towards this goal will contribute to solving some of the main agricultural and industrial challenges here on Earth. PMID- 29996549 TI - Proteomics and Toxicity Analysis of Spinal-Cord Primary Cultures upon Hydrogen Sulfide Treatment. AB - Hydrogen sulfide (H2S) is an endogenous gasotransmitter recognized as an essential body product with a dual, biphasic action. It can function as an antioxidant and a cytoprotective, but also as a poison with a high probability of causing brain damage when present at noxious levels. In a previous study, we measured toxic liquoral levels of H2S in sporadic amyotrophic lateral sclerosis (ALS) patients and in the familial ALS (fALS) mouse model, SOD1G93A. In addition, we experimentally demonstrated that H2S is extremely and selectively toxic to motor neurons, and that it is released by glial cells and increases Ca2+ concentration in motor neurons due to a lack of ATP. The presented study further examines the effect of toxic concentrations of H2S on embryonic mouse spinal-cord cultures. We performed a proteomic analysis that revealed a significant H2S mediated activation of pathways related to oxidative stress and cell death, particularly the Nrf-2-mediated oxidative stress response and peroxiredoxins. Furthermore, we report that Na2S (a stable precursor of H2S) toxicity is, at least in part, reverted by the Bax inhibitor V5 and by necrostatin, a potent necroptosis inhibitor. PMID- 29996551 TI - Vaccinia Virus Shuffling: deVV5, a Novel Chimeric Poxvirus with Improved Oncolytic Potency. AB - Oncolytic virus (OV) therapy has emerged as a promising approach for cancer treatment with the potential to be less toxic and more efficient than classic cancer therapies. Various types of OVs in clinical development, including Vaccinia virus (VACV)-derived OVs, have shown good safety profiles, but limited therapeutic efficacy as monotherapy in some cancer models. Many different methods have been employed to improve the oncolytic potency of OVs. In this study, we used a directed evolution process, pooling different strains of VACV, including Copenhagen, Western Reserve and Wyeth strains and the attenuated modified vaccinia virus Ankara (MVA), to generate a new recombinant poxvirus with increased oncolytic properties. Through selective pressure, a chimeric VACV, deVV5, with increased cancer cell killing capacity and tumor selectivity in vitro was derived. The chimeric viral genome contains sequences of all parental strains. To further improve the tumor selectivity and anti-tumor activity of deVV5, we generated a thymidine kinase (TK)-deleted chimeric virus armed with the suicide gene FCU1. This TK-deleted virus, deVV5-fcu1 replicated efficiently in human tumor cells, and was notably attenuated in normal primary cells. These studies demonstrate the potential of directed evolution as an efficient way to generate recombinant poxviruses with increased oncolytic potency, and with high therapeutic index to improve cancer therapy. PMID- 29996553 TI - Wideband Spectrum Sensing Based on Single-Channel Sub-Nyquist Sampling for Cognitive Radio. AB - Spectrum sensing is an important task in cognitive radio. However, currently available Analog-to-Digital Converters (ADC) can hardly satisfy the sampling rate requirement for wideband signals. Even with such an ADC, the cost is extremely high in terms of price and power consumption. In this paper, we propose a spectrum-sensing method based on single-channel sub-Nyquist sampling. Firstly, a serial Multi-Coset Sampling (MCS) structure is designed to avoid mismatches among sub-ADCs in the traditional parallel MCS. Clocks of the sample/hold and ADC are provided by two non-uniform sampling clocks. The cooperation between these two non-uniform sampling clocks shifts the high sampling rate burden from the ADC to the sample/hold. Secondly, a power spectrum estimation method using sub-Nyquist samples is introduced, and an efficient spectrum-sensing algorithm is proposed. By exploiting the frequency-smoothing property, the proposed efficient spectrum sensing algorithm only needs to estimate power spectrum at partial frequency bins to conduct spectrum sensing, which will save a large amount of computational cost. Finally, the sampling pattern design of the proposed serial MCS is given, and it is proved to be a minimal circular sparse ruler with an additional constraint. Simulations show that mismatches in traditional parallel MCS have a serious impact on spectrum-sensing performance, while the proposed serial MCS combined with the efficient spectrum-sensing algorithm exhibits outstanding spectrum-sensing performance at much lower computational cost. PMID- 29996552 TI - Synthesis, Spectroscopic Characterization, and In Vitro Antibacterial Evaluation of Novel Functionalized Sulfamidocarbonyloxyphosphonates. AB - Several new sulfamidocarbonyloxyphosphonates were prepared in two steps, namely carbamoylation and sulfamoylation, by using chlorosulfonyl isocyanate (CSI), α-hydroxyphosphonates, and various amino derivatives and related (primary or secondary amines, β-amino esters, and oxazolidin-2-ones). All structures were confirmed by 1H, 13C, and 31P NMR spectroscopy, IR spectroscopy, and mass spectroscopy, as well as elemental analysis. Eight compounds were evaluated for their in vitro antibacterial activity against four reference bacteria including Gram-positive Staphylococcus aureus (ATCC 25923), and Gram-negative Escherichia coli (ATCC 25922), Klebsiella pneumonia (ATCC 700603), Pseudomonas aeruginosa (ATCC 27853), in addition to three clinical strains of each studied bacterial species. Compounds 1a-7a and 1b showed significant antibacterial activity compared to sulfamethoxazole/trimethoprim, the reference drug used in this study. PMID- 29996554 TI - Properties and Structure of Deposited Nanocrystalline Coatings in Relation to Selected Construction Materials Resistant to Abrasive Wear. AB - Presented in this work are the properties and structure characteristics of MMA (Manual Metal Arc) deposited nanocrystalline coatings (Fe-Cr-Nb-B) applied to an iron nanoalloy matrix on an S355N steel substrate in relation to selected construction materials resistant to abrasive wear currently used in industry. The obtained overlay welds were subjected to macro and microscopic metallographic examinations; grain size was determined by X-ray diffraction (XRD), and chemical composition of precipitates was determined by energy-dispersive X-ray spectroscopy (EDS) during scanning electron microscopy (SEM). The size of the crystalline grains of the Fe-Cr-Nb-B nanocrystalline microstructure was analyzed using an Xpert PRO X-ray diffractometer. Analysis of the test results of the obtained layers of arc-welded Fe-Cr-Nb-B-type alloy confirmed that the obtained layers are made of crystallites with a size of 20 nm, which classifies these layers as nanocrystalline. The obtained nanocrystalline coatings were assessed by hardness and with the use of metal-mineral abrasion testing. The results of the coatings' properties tests were compared to HARDOX 400 alloy steel. PMID- 29996555 TI - Incorporation of Collagen and Hyaluronic Acid to Enhance the Bioactivity of Fibrin-Based Hydrogels for Nucleus Pulposus Regeneration. AB - Hydrogels, such as fibrin, offer a promising delivery vehicle to introduce cells into the intervertebral disc (IVD) to regenerate damaged disc tissue as a potential treatment for low back pain. However, fibrin lacks key extracellular matrix (ECM) components, such as collagen (Col) and hyaluronan (HA), normally found in native nucleus pulposus (NP) tissue. The overall aim of this work was to create a fibrin-based hydrogel, by incorporating Col and HA into the matrix to enhance NP-like matrix accumulation using articular chondrocytes (CC). Firstly, we assessed the effect of fibrin concentrations on hydrogel stability, and the viability and proliferation kinetics of articular chondrocytes. Secondly, we investigated the effect of incorporating Col and HA to enhance NP-like matrix accumulation, and finally, examined the influence of various HA concentrations. Results showed that increasing fibrin concentration enhanced cell viability and proliferation. Interestingly, incorporation of HA promoted sGAG accumulation and tended to suppress collagen formation at higher concentrations. Taken together, these results suggest that incorporation of ECM components can enhance the bioactivity of fibrin-based hydrogels, which may help advance the clinical potential of commercial cell and biomaterial ventures in the treatment of IVD regeneration. PMID- 29996556 TI - Physicochemical Properties of Biochars Produced from Biosolids in Victoria, Australia. AB - Some of the barriers associated with the land application of biosolids generated in wastewater treatment plants can be eliminated simply by converting the biosolids into biochar using a thermal conversion process called “pyrolysis”. In the current work, eight biosolids from four different wastewater treatment plants in southeast Melbourne, Victoria, Australia were collected and pyrolysed to produce biochars at two different temperatures (500 and 700 °C). In addition, characterisation studies were carried out on the biochars to obtain their physicochemical properties, which were subsequently compared with the properties of the parent biosolids. The major findings of the work demonstrated that biochars exhibited large decreases in DTPA-extractable metals such as Cd, Cu, and Zn, and also led to favorable changes in several chemical and physical characteristics (i.e., pH, Olsen P, electrical conductivity, and surface area) for agricultural land application compared to their original form (i.e., biosolids). Overall, the study suggests that there is great potential for converting biosolids to biochar using pyrolysis. This may not only improve the properties of biosolids for land application, but also has potential to reduce the risk to receiving environments and, furthermore, eliminate many of the costly elements associated with biosolids stockpiling and management. PMID- 29996557 TI - Recharging Schedule for Mitigating Data Loss in Wireless Rechargeable Sensor Network. AB - Wireless Power Transfer (WPT) technology is considered as a promising approach to make Wireless Rechargeable Sensor Network (WRSN) work perpetually. In WRSN, a vehicle exists, termed a mobile charger, which can move close to sensor nodes and charge them wirelessly. Due to the mobile charger's limited traveling distance and speed, not every node that needs to be charged may be serviced in time. Thus, in such scenario, how to make a route plan for the mobile charger to determine which nodes should be charged first is a critical issue related to the network's Quality of Service (QoS). In this paper, we propose a mobile charger's scheduling algorithm to mitigate the data loss of network by considering the node's criticality in connectivity and energy. First, we introduce a novel metric named criticality index to measure node's connectivity contribution, which is computed as a summation of node's neighbor dissimilarity. Furthermore, to reflect the node's charging demand, an indicator called energy criticality is adopted to weight the criticality index, which is a normalized ratio of the node's consumed energy to its total energy. Then, we formulate an optimization problem with the objective of maximizing total weighted criticality indexes of nodes to construct a charging tour, subject to the mobile charger's traveling distance constraint. Due to the NP-hardness of the problem, a heuristic algorithm is proposed to solve it. The heuristic algorithm includes three steps, which is spanning tree growing, tour construction and tour improvement. Finally, we compare the proposed algorithm to the state-of-art scheduling algorithms. The obtained results demonstrate that the proposed algorithm is a promising one. PMID- 29996558 TI - Recombinant Leucine-Rich Repeat Flightless-Interacting Protein-1 Improves Healing of Acute Wounds through Its Effects on Proliferation Inflammation and Collagen Deposition. AB - Wound healing is an increasing clinical problem involving substantial morbidity, mortality, and rising health care costs. Leucine-rich repeat flightless interacting protein-1 (LRRFIP-1) regulates toll-like receptor (TLR)-mediated inflammation, suggesting a potential role in the healing of wounds. We sought to determine the role of LRRFIP-1 in wound repair and whether the exogenous addition of recombinant LRRFIP-1 (rLRRFIP-1) affected healing responses. Using a model of full-thickness incisional acute wounds in BALB/c mice, we investigated the effect of wounding on LRRFIP-1 expression. The effect of rLRRFIP-1 on cellular proliferation, inflammation, and collagen deposition was also investigated. LRRFIP-1 was upregulated in response to wounding, was found to directly associate with flightless I (Flii), and significantly increased cellular proliferation both in vitro and in vivo. rLRRFIP-1 reduced Flii expression in wounds in vivo and resulted in significantly improved healing with a concurrent dampening of TLR4 mediated inflammation and improved collagen deposition. Additionally, decreased levels of TGF-β1 and increased levels of TGF-β3 were observed in rLRRFIP-1-treated wounds suggesting a possible antiscarring effect of rLRRFIP-1. Further studies are required to elucidate if the mechanisms behind LRRFIP-1 action in wound repair are independent of Flii. However, these results identify rLRRFIP-1 as a possible treatment modality for improved healing of acute wounds. PMID- 29996559 TI - A Review of the Characteristics, Synthesis, and Thermodynamics of Type-II Weyl Semimetal WTe2. AB - WTe2 as a candidate of transition metal dichalcogenides (TMDs) exhibits many excellent properties, such as non-saturable large magnetoresistance (MR). Firstly, the crystal structure and characteristics of WTe2 are introduced, followed by a summary of the synthesis methods. Its thermodynamic properties are highlighted due to the insufficient research. Finally, a comprehensive analysis and discussion are introduced to interpret the advantages, challenges, and future prospects. Some results are shown as follows. (1) The chiral anomaly, pressure induced conductivity, and non-saturable large MR are all unique properties of WTe2 that attract wide attention, but it is also a promising thermoelectric material that holds anisotropic ultra-low thermal conductivity (0.46 W·m−1·K−1). WTe2 is expected to have the lowest thermal conductivity, owing to the heavy atom mass and low Debye temperature. (2) The synthesis methods influence the properties significantly. Although large-scale few-layer WTe2 in high quality can be obtained by many methods, the preparation has not yet been industrialized, which limits its applications. (3) The thermodynamic properties of WTe2 are influenced by temperature, scale, and lattice orientations. However, the in-plane anisotropy cannot be observed in the experiment, as the intrinsic property is suppressed by defects and boundary scattering. Overall, this work provides an opportunity to develop the applications of WTe2. PMID- 29996560 TI - IoT Hierarchical Topology Strategy and Intelligentize Evaluation System of Diesel Engine in Complexity Environment. AB - In complex discrete manufacturing environment, there used to be a poor network and an isolated information island in production line, which led to slow information feedback and low utilization ratio, hindering the construction of enterprise intelligence. To solve these problems, uncertain factors in the production process and demands of sensor network were analyzed; hierarchical topology design method and the deployment strategy of the complexity industrial internet of things were proposed; and a big data analysis model and a system security protection system based on the network were established. The weight of each evaluation index was calculated using analytic hierarchy process, which established the intelligentized evaluation system and model. An actual production scene was also selected to validate the feasibility of the method. A diesel engine production workshop and the enterprise MES were used as an example to establish a network topology. The intelligence level based on both subjective and objective factors were evaluated and analyzed considering both quantitative and qualitative aspects. Analysis results show that the network topology design method and the intelligentize evaluation system were feasible, could improve the intelligence level effectively, and the network framework was expansible. PMID- 29996561 TI - Inter-Specimen Imbalance of Mitochondrial Gene Copy Numbers Predicts Clustering of Pneumocystis jirovecii Isolates in Distinct Subgroups. AB - The molecular detection of Pneumocystis jirovecii is an important therapy relevant tool in microbiological diagnostics. However, the quantification of this pathogen in the past has revealed discordant results depending on the target gene. As the clinical variety of P. jirovecii infections ranges between life threatening infections and symptom-free colonization, the question arises if qPCRs are reliable tools for quantitative diagnostics of P. jirovecii. P. jirovecii positive BALs were quantitatively tested for the copy numbers of one mitochondrial (COX-1) and two nuclear single-copy genes (KEX1 and DHPS) compared to the mitochondrial large subunit (mtLSU) by qPCR. Independent of the overall mtLSU copy number P. jirovecii clustered into distinct groups based on the ratio patterns of the respective qPCRs. This study, which compared different mitochondrial to nuclear gene ratio patterns of independent patients, shows that the mtLSU gene represents a highly sensitive qPCR tool for the detection of P. jirovecii, but does not display a reliable target for absolute quantification. PMID- 29996562 TI - Ionic Liquid-Based Electrolyte Membranes for Medium-High Temperature Lithium Polymer Batteries. AB - Li+-conducting polyethylene oxide-based membranes incorporating N-butyl-N methylpyrrolidinium bis(trifluoromethanesulfonyl)imide are used as electrolyte separators for all-solid-state lithium polymer batteries operating at medium-high temperatures. The incorporation of the ionic liquid remarkably improves the thermal, ion-transport and interfacial properties of the polymer electrolyte, which, in combination with the wide electrochemical stability even at medium-high temperatures, allows high current rates without any appreciable lithium anode degradation. Battery tests carried out at 80 °C have shown excellent cycling performance and capacity retention, even at high rates, which are never tackled by ionic liquid-free polymer electrolytes. No dendrite growth onto the lithium metal anode was observed. PMID- 29996563 TI - The Computation of Complex Dispersion and Properties of Evanescent Lamb Wave in Functionally Graded Piezoelectric-Piezomagnetic Plates. AB - Functionally graded piezoelectric-piezomagnetic material (FGPPM), with a gradual variation of the material properties in the desired direction(s), can improve the conversion of energy among mechanical, electric, and magnetic fields. Full dispersion relations and wave mode shapes are vital to understanding dynamic behaviors of structures made of FGPPM. In this paper, an analytic method based on polynomial expansions is proposed to investigate the complex-valued dispersion and the evanescent Lamb wave in FGPPM plates. Comparisons with other related studies are conducted to validate the correctness of the presented method. Characteristics of the guided wave, including propagating modes and evanescent modes, in various FGPPM plates are studied, and three-dimensional full dispersion and attenuation curves are plotted to gain a deeper insight into the nature of the evanescent wave. The influences of the gradient variation on the dispersion and the magneto-electromechanical coupling factor are illustrated. The displacement amplitude and electric potential and magnetic potential distributions are also discussed in detail. The obtained numerical results could be useful to design and optimize different sensors and transducers made of smart piezoelectric and piezomagnetic materials with high performance by adjusting the gradient property. PMID- 29996564 TI - Practical Methods for Vehicle Speed Estimation Using a Microprocessor-Embedded System with AMR Sensors. AB - The proper operation of computing resources in a microprocessor-embedded system plays a key role in reducing computing time. Processing the variable amount of collected data in real-time improves the performance of a microprocessor-embedded system. In this regard, a vehicle’s speed measurement system is no exception. The computing time for evaluating any speed value is expected to be reduced as much as possible. Four computational methods, including cross correlation, are discussed. An exemplary pair of recorded signals presenting the change in magnetic field magnitude is analyzed. The sample delay values are compared. The results of the evaluated speed and the execution time of the program code are presented for each method based on a dataset of 200 randomly driven vehicles. The results of the performed tests confirm that the cross correlation-based methods are not always reliable in situations when the sample size is small, i.e., it is a segment of the impulse response caused by a driving vehicle. PMID- 29996565 TI - Antimicrobial Peptides: Powerful Biorecognition Elements to Detect Bacteria in Biosensing Technologies. AB - Bacterial infections represent a serious threat in modern medicine. In particular, biofilm treatment in clinical settings is challenging, as biofilms are very resistant to conventional antibiotic therapy and may spread infecting other tissues. To address this problem, biosensing technologies are emerging as a powerful solution to detect and identify bacterial pathogens at the very early stages of the infection, thus allowing rapid and effective treatments before biofilms are formed. Biosensors typically consist of two main parts, a biorecognition moiety that interacts with the target (i.e., bacteria) and a platform that transduces such interaction into a measurable signal. This review will focus on the development of impedimetric biosensors using antimicrobial peptides (AMPs) as biorecognition elements. AMPs belong to the innate immune system of living organisms and are very effective in interacting with bacterial membranes. They offer unique advantages compared to other classical bioreceptor molecules such as enzymes or antibodies. Moreover, impedance-based sensors allow the development of label-free, rapid, sensitive, specific and cost-effective sensing platforms. In summary, AMPs and impedimetric transducers combine excellent properties to produce robust biosensors for the early detection of bacterial infections. PMID- 29996567 TI - Advanced Chemical Looping Materials for CO2 Utilization: A Review. AB - Combining chemical looping with a traditional fuel conversion process yields a promising technology for low-CO2-emission energy production. Bridged by the cyclic transformation of a looping material (CO2 carrier or oxygen carrier), a chemical looping process is divided into two spatially or temporally separated half-cycles. Firstly, the oxygen carrier material is reduced by fuel, producing power or chemicals. Then, the material is regenerated by an oxidizer. In chemical looping combustion, a separation-ready CO2 stream is produced, which significantly improves the CO2 capture efficiency. In chemical looping reforming, CO2 can be used as an oxidizer, resulting in a novel approach for efficient CO2 utilization through reduction to CO. Recently, the novel process of catalyst assisted chemical looping was proposed, aiming at maximized CO2 utilization via the achievement of deep reduction of the oxygen carrier in the first half-cycle. It makes use of a bifunctional looping material that combines both catalytic function for efficient fuel conversion and oxygen storage function for redox cycling. For all of these chemical looping technologies, the choice of looping materials is crucial for their industrial application. Therefore, current research is focused on the development of a suitable looping material, which is required to have high redox activity and stability, and good economic and environmental performance. In this review, a series of commonly used metal oxide based materials are firstly compared as looping material from an industrial application perspective. The recent advances in the enhancement of the activity and stability of looping materials are discussed. The focus then proceeds to new findings in the development of the bifunctional looping materials employed in the emerging catalyst-assisted chemical looping technology. Among these, the design of core-shell structured Ni-Fe bifunctional nanomaterials shows great potential for catalyst-assisted chemical looping. PMID- 29996568 TI - Structure and function of the antennae of Euphydryas editha (Lepidoptera: Nymphalidae). AB - Males of Euphydryas editha (Lepidoptera: Nymphalidae) need their antennae to mate successfully, but females do not. Antennal structure was investigated in the hope of explaining this functional dimorphism, which is opposite to that in other butterflies (e.g., Myers, '68; Grula and Taylor, '80). No external differences between the sexes were observed with electron microscopy. There are four types of antennal sensilla: the spine, which acts mainly as a mechanoreceptor, shallow dish hairs and hidden hairs, which are chemoreceptors, and a whiplike sensillum of uncertain function. The internal morphology of male and female antennae differs in several respects which may relate to functional differences. The mating systems of butterflies are discussed briefly to explain our results and those of others. PMID- 29996566 TI - Development of Ahmedabad's Air Information and Response (AIR) Plan to Protect Public Health. AB - Indian cities struggle with some of the highest ambient air pollution levels in the world. While national efforts are building momentum towards concerted action to reduce air pollution, individual cities are taking action on this challenge to protect communities from the many health problems caused by this harmful environmental exposure. In 2017, the city of Ahmedabad launched a regional air pollution monitoring and risk communication project, the Air Information and Response (AIR) Plan. The centerpiece of the plan is an air quality index developed by the Indian Institute of Tropical Meteorology’s System for Air Quality and Weather Forecasting and Research program that summarizes information from 10 new continuous air pollution monitoring stations in the region, each reporting data that can help people avoid harmful exposures and inform policy strategies to achieve cleaner air. This paper focuses on the motivation, development, and implementation of Ahmedabad’s AIR Plan. The project is discussed in terms of its collaborative roots, public health purpose in addressing the grave threat of air pollution (particularly to vulnerable groups), technical aspects in deploying air monitoring technology, and broader goals for the dissemination of an air quality index linked to specific health messages and suggested actions to reduce harmful exposures. The city of Ahmedabad is among the first cities in India where city leaders, state government, and civil society are proactively working together to address the country’s air pollution challenge with a focus on public health. The lessons learned from the development of the AIR Plan serve as a template for other cities aiming to address the heavy burden of air pollution on public health. Effective working relationships are vital since they form the foundation for long-term success and useful knowledge sharing beyond a single city. PMID- 29996569 TI - Structural variability of collagen fibers in the calcareous axial rod of a sea pen. AB - Previous studies revealed that the organic matrix of the skeletal rod of the sea pen, Veretillum cynomorium, contained about 50% collagenous protein. The present ultrastructural study, based upon conventional staining methods, shows the existence of an abundant, longitudinally arranged nonbanded and fibrillar material separated by a reticular matrix. After incubation with 3 H-proline, labeling is specifically localized on the fibrillar material. Some fibers occasionally display a transverse striation with a period of 11 to 14 nm which can be associated with a chevron striation. Infrequently, some other fibers display a more distinct banding of 55 to 70 nm or even yield a checkerboard pattern. However, a majority of fibers remain without a regular structure comparable to the periodic striations observed in the collagen of other animals. After treatment with 1% PTA in 70% ethanol, all the fibers show a clear banding of 14 nm and some of them possess two types of striations. The same result is obtained on fibers mechanically dissociated and negatively stained. As these methods show a periodic banding pattern on all the fibers, it is likely that all the fibers (striated or not) observed after routine electron microscopy correspond to collagen material. This collagen appears to be both polymorphic and completely new in comparison to that which is characteristic of the mesoglea. The polymorphic aspect is compared to that obtained from vertebrate collagens. PMID- 29996570 TI - The arterial arches and their interpretation in Bipes and other amphisbaenians. AB - The study of the arterial arches of Bipes, the only amphisbaenian with forelimbs, resolves the problem of the interpretation of the structure of the arterial arches in other forms of this group of squamate reptiles. In Bipes, as in turtles, the subclavian and common carotid arteries originate from a brachiocephalic trunk, which arises from an innominate trunk deriving from the right aortic loop. This interpretation is not only original but also emphasizes the important lengthening of the brachiocephalic part relative to the strictly carotidian one. It supposes the intercalation of a new "precardiac" region between the pectoral girdle and the heart; these two components are closely associated topographically in the quadrupedal Squamata. This lengthening, expressed by the increase in the number of precloacal vertebrae, is linked with the increase in the asymmetry of the aortic loop. PMID- 29996571 TI - Secretory cells in the clitellar epithelium of Eisenia foetida (Annelida, Oligochaeta): A histochemical and ultrastructural study. AB - Eight secretory cell types are identified in the clitellar epithelium of Eisenia foetida, of which five have been described in detail previously (i.e., the large granular, fine granular, metachromatic, orthochromatic, and small granular proteinacecus cells). The remaining three secretory cell types are mucus producing cells specific to the clitellar epithelium (type 3), cells associated with the chaetal follicles (type 4), and cells that occur exclusively in the tubercula pubertatis (type 5). Type 3 cells secrete a mucus containing neutral and acid mucosubstances. Ultrastructurally, type 3 cells are characterized by membrane-bound globules 0.4 to 3.7 MUm in diameter. The contents of the globules have a finely reticulate appearance. The secretion of type 4 cells contains a collagenlike protein and neutral and sulfated acid mucosubstances. Type 4 cell secretory granules are membrane bound and range in diameter from 0.8 to 1.6 MUm. They contain large, electron-dense, spheroid cores which are surrounded by parallel orientated microfibrils 14 nm in diameter. Type 5 cells give variable responses to the histochemical techniques used in the present study. An elastinlike protein is detected in about half of the type 5 cells and acid and neutral mucosubstances in the remainder. At the ultrastructural level the secretory granules vary in shape from spheroid to polygonal. Their finely, electron-dense contents exhibit progressive swelling which results in the eventual rupture of the limiting membranes of the granules. The necks of types 3, 4, and 5 cells contain a peripheral ring of microtubles (20 +/- 1 nm in diameter). PMID- 29996572 TI - Relationship of symbiotic microorganisms to metanephridium: Phagoctic activity in the metanephridial epithelium of two species of oligochaeta. AB - It is known that a number of species in the annelid family Lumbricidae harbor symbiotic microorganisms in the lumen of their nephridia. The purpose of the present paper is the study of the relationship between microbes and epithelial cells lining the metanephridium of two species of Oligochaeta, which show two different patterns of microbial colonization. A new interesting feature, the phagocytosis and intracellular destruction of microorganisms by the nephridial epithelial cells, has been observed in our laboratory for the first time. In Scheroteca savignyi minor, the phagocytic activity takes place in the bladder, the most distal region of the nephridium, next to the nephridiopore, which may prevent the microorganisms from entering the more proximal regions. In Octolasion cyaneum the microbes reach the striated duct, where they live in symbiosis, adhere to the cell's surface, and are engulfed and destroyed by the cells of the middle tubule-the more proximal, neighboring region. The phagocytosis and intracellular degradation of microorganisms probably lead to the massive formation of lamellar bodies, which are observed in these cells and in the neighboring ones. PMID- 29996573 TI - Structure of the radially asymmetrical uncalcified region of the teeth of the red backed salamander, Plethodon cinereus (Amphibia, Plethodontidae). AB - The teeth of the adult plethodontid salamander, Plethodon cinereus, were examined by light and electron microscopy with emphasis on the ringlike zone of uncalcified dentin that divides the calcified portion of each tooth into a proximal pedestal and a distal apex. The uncalcified region displays radial asymmetry, forming an integral part of the posterior wall of the tooth but bulging into the pulp cavity anteriorly, thus forming a hingelike structure. All portions of the dentin, including the uncalcified region, are composed predominantly of collagenous fibers but lack elastin. In scanning electron micrographs of teeth from which the oral mucosa has been removed, the location of the anterior uncalcified hinge is marked externally by a notch-like articulation of the apex and pedestal. Sites of transition between calcified and uncalcified areas of the dentin show no special modifications in transmission electron micrographs, but collagenous fibers in calcified portions are associated with more electron-dense amorphous material than are those in the uncalcified region. Odontoblasts associated with the uncalcified region possess ultrastructural features closely resembling those of odontoblasts found in calcified areas. The uncalcified region seems to afford the teeth a certain degree of flexibility, and the asymmetry of the region appears to allow the teeth to flex only in a posterior direction, thus facilitating the entry of living prey but hindering its escape. The uncalcified region also seems to permit the apex of a tooth to break away from its pedestal without damage to underlying bone. PMID- 29996574 TI - Structure of dactyl sensilla in the kelp crab, Pugettia producta. AB - In the kelp crab, Pugettia producta, flat plate setae cover all but the ventral surfaces of the walking leg dactyls. Dendrites enter the setal shaft located inside the plate superstructure, and extend to a region of the setal tip that contains a system of minute pores resembling the pore systems found in chemosensory sensilla of insects. Presumably, much of the chemosensitivity of the dactyls in the kelp crab is mediated by the plate setae. In the interior of the dactyl, supporting cells and the neurons innervating plate setae, other types of setae, and other presumptive sensilla form scolopidia. Large scolopidia, containing as many as 12 dendrites, appear to innervate some of the plate setae and also large ventral rodlike setae that might be chemosensory. Two of the dendrites of large scolopidia usually have more densely packed microtubules, longer ciliary axonemes, slightly larger rootlets, and dark A fibers with arms, characteristics indicative of mechanosensory function. Some dactyl setae, therefore, could be both mechanosensory and chemosensory. Small scolopidia containing two or three dendrites that exhibit mechanosensory characteristics appear to innervate small, rodlike setae, which presumably are strictly mechanosensory. The two types of structures located on the epicuticular cap, elliptical structures resembling campaniform sensilla and small cones in pits resembling CAP organs, appear to be dually innervated and presumably are mechanosensory, although other functions are possible. The internal positions of the scolopidia, together with the support afforded by an extracellular dendritic sheath, by the scolopale, and by desmosomelike and septate junctions, may serve to protect internal portions of setal dendrites, some of which appear to remain functional in nonmolting adults that have abraded setae. PMID- 29996575 TI - Scanning electron microscopic study of the male genital tract during its highest and lowest activities in the seasonal reproductive cycle of the soft-shelled turtle. AB - The objective of the present investigation was to study by scanning electron microscopy the epithelial surface structures of different segments of the male genital tract (ductuli efferentes, proximal and distal epididymes, and vas deferens) during highest (July) and lowest (January) activity in the annual reproductive cycle of the soft-shelled turtle. The study has revealed that there are distinct regional differences in the male genital tract. The ductuli efferentes have three types of cells, long-ciliated, short-ciliated, and microvilli-bordered cells. The proximal epididymis has two types of cells, microvilli-bordered cells and smooth-surfaced cells; the distal epididymis has only tall, smooth-surfaced cells. The vas deferens contains both smooth-surfaced and microvilli-bordered cells. Cells of the genital tract in July show several differences from comparable cells in January: Ciliated cells of the ductuli efferentes have longer cilia, cells of the proximal epididymis have microvilli distended by secretory materials, and cell apices in the distal epididymis are surmounted by an abundance of huge secretory blebs. There is no discernible change in the vas deferens. The findings suggest that all segments of the male genital tract, except the vas deferens, become active in July and have regressed by January in the annual sexual cycle. PMID- 29996576 TI - Salivary gland ultrastructure of the unfed adult and feeding female of Haemaphysalis (Rhipistoma) leachi (Ixodoidea: Ixodidae). AB - The paired salivary glands of unfed adult Haemaphysalis (Rhipistoma) leachi contain one type of agranular and three types of granular alveoli connected to a salivary duct system. Type I agranular alveoli consist of one large, central cell surrounded by peripheral cells with numerous basal membrane infoldings indicative of epithelia involved in fluid transport. Glycogen particles, lipid-like droplets, and the parallel pattern of infolded membranes disappeared from the peripheral cells during feeding. Types II, III, and IV granular alveoli contain some agranular interstitial epithelial cells, cap cells, and fundus cells, but are predominantly composed of structurally different granular cell types a, b, c, d, e, and f. Agranular cells develop during the early stages of feeding. Granular a, c, e, and f cells release their granules directly after attachment to the host and possibly are involved in cement secretion required for firm attachment to it. The b cell granules are replaced by b1 filamentous granules during feeding. Golgi bodies and rough endoplasmic reticulum (RER) participate in the formation of most types of granules. The d cells contain lamella-like structures and condensing vacuoles, probably responsible for lysosome formation. The main salivary duct and all types of alveoli are innervated by neurosecretory axons. PMID- 29996577 TI - Exploring 70 Years of the British National Health Service through Anniversary Documents. AB - The British National Health Service (NHS) celebrates its 70th birthday on July 5, 2018. This article examines this anniversary through the lens of previous anniversaries. It examines seven documents close to each anniversary over a period of some 60 years, drawing on interpretive content analysis, based on the narrative dimensions of context (structure and finance); success or achievements; problems; and solutions or recommendations. It finds that the anniversary documents tend to show change rather than consistency. For example, the Guillebaud Report tended to dismiss the problem of ageing populations, for it to reappear in 1979 and 1989, to fade in 2009, and reappear once more in 2017. Despite being downplayed or ignored in some years, the problems identified by most of the documents such as demography and technology are unlikely to disappear. Some solutions such as market-based reform have flowed and ebbed over the years, and the 'solution' of structural reorganisation in one year has become the 'problem' in a future year. While predicting the future is always hazardous, it can be said with some confidence that future anniversaries are likely to see discussion of similar themes. PMID- 29996578 TI - Addressing Health Equity Through Action on the Social Determinants of Health: A Global Review of Policy Outcome Evaluation Methods. AB - BACKGROUND: Epidemiological evidence on the social determinants of health inequity is well-advanced, but considerably less attention has been given to evaluating the impact of public policies addressing those social determinants. Methodological challenges to produce evidence on policy outcomes present a significant barrier to mobilising policy actions for health equities. This review aims to examine methodological approaches to policy evaluation of health equity outcomes and identify promising approaches for future research. METHODS: We conducted a systematic narrative review of literature critically evaluating policy impact on health equity, synthesizing information on the methodological approaches used. We searched and screened records from five electronic databases, using pre-defined protocols resulting in a total of 50 studies included for review. We coded the studies according to (1) type of policy analysed; (2) research design; (3) analytical techniques; (4) health outcomes; and (5) equity dimensions evaluated. RESULTS: We found a growing number of a wide range of policies being evaluated for health equity outcomes using a variety of research designs. The majority of studies employed an observational research design, most of which were cross-sectional, however, other approaches included experimental designs, simulation modelling, and meta-analysis. Regression techniques dominated the analytical approaches, although a number of novel techniques were used which may offer advantages over traditional regression analysis for the study of distributional impacts of policy. Few studies made intra-national or cross national comparisons or collected primary data. Despite longstanding challenges of attribution in policy outcome evaluation, the majority of the studies attributed change in physical or mental health outcomes to the policy being evaluated. CONCLUSION: Our review provides an overview of methodological approaches to health equity policy outcome evaluation, demonstrating what is most commonplace and opportunities from novel approaches. We found the number of studies evaluating the impacts of public policies on health equity are on the rise, but this area of policy evaluation still requires more attention given growing inequities. PMID- 29996579 TI - "Three Nooses on Our Head": The Influence of District Health Reforms on Maternal Health Service Delivery in Vietnam. AB - BACKGROUND: The impact of reorganisation on health services delivery is a recurring issue in every healthcare system. In 2005 Vietnam reorganised the delivery of health services at the district level by splitting preventive, curative, and administrative roles. This qualitative study explored how these reforms impacted on the organisation of maternal health service delivery at district and commune levels. METHODS: Forty-three semi-structured interviews were conducted with health staff and managers involved in the provision of maternal health services from the commune to the central level within five districts of two Northern provinces in Vietnam. The data were analysed thematically. RESULTS: The results showed that 10 years after the reforms created three district-level entities, participants reported difficulties in management of health services at the district and commune levels in Vietnam. The reforms were largely perceived to negatively affect the efficient and effective use of clinical and other resources. At the commune level, the reforms are said to have affected the quality of supervision of the communes and their staff and increased the workload in community health centres. CONCLUSION: The findings from this study suggest that the current organisation of district health services in Vietnam may have had unintended negative consequences. It also indicates that countries which decide to reform their systems in a manner similar to Vietnam need to pay attention to coordination between a multiplicity of agencies at the district level. PMID- 29996580 TI - Examining the Implementation of the Free Maternity Services Policy in Kenya: A Mixed Methods Process Evaluation. AB - BACKGROUND: Kenya introduced a free maternity policy in 2013 to address the cost barrier associated with accessing maternal health services. We carried out a mixed methods process evaluation of the policy to examine the extent to which the policy had been implemented according to design, and positive experiences and challenges encountered during implementation. METHODS: We conducted a mixed methods study in 3 purposely selected counties in Kenya. Data were collected through in-depth interviews (IDIs) with policy-makers at the national level, health managers at the county level, and frontline staff at the health facility level (n=60), focus group discussions (FGDs) with community representatives (n=10), facility records, and document reviews. We analysed the data using a framework approach. RESULTS: Rapid implementation led to inadequate stakeholder engagement and confusion about the policy. While the policy was meant to cover antenatal visits, deliveries, and post-natal visits, in practice the policy only covered deliveries. While the policy led to a rapid increase in facility deliveries, this was not matched by an increase in health facility capacity and hence compromised quality of care. The policy led to an improvement in the level of revenues for facilities. However, in all three counties, reimbursements were not made on time. The policy did not have a system of verifying health facility reports on utilization of services. CONCLUSION: The Kenyan Ministry of Health (MoH) should develop a formal policy on the free maternity services, and provide clear guidelines on its content and implementation arrangements, engage with and effectively communicate the policy to stakeholders, ensure timeliness of payment disbursement to healthcare facilities, and introduce a mechanism for verifying utilization reports prepared by healthcare providers. User fee removal policies such as free maternity programmes should be accompanied by supply side capacity strengthening. PMID- 29996581 TI - Psychosocial Workplace Factors and Healthcare Utilization: A Study of Two Employers. AB - BACKGROUND: While a large literature links psychosocial workplace factors with health and health behaviors, there is very little work connecting psychosocial workplace factors to healthcare utilization. METHODS: Survey data were collected from two different employers using computer-assisted telephone interviewing as a part of the Work-Family Health Network (2008-2013): one in the information technology (IT) service industry and one that is responsible for a network of long-term care (LTC) facilities. Participants were surveyed four times at six month intervals. Responses in each wave were used to predict utilization in the following wave. Four utilization measures were outcomes: having at least one emergency room (ER)/Urgent care, having at least one other healthcare visit, number of ER/urgent care visits, and number of other healthcare visits. Population-averaged models using all four waves controlled for health and other factors associated with utilization. RESULTS: Having above median job demands was positively related to the odds of at least one healthcare visit, odds ratio [OR] 1.37 (P<.01), and the number of healthcare visits, incidence rate ratio (IRR) 1.36 (P<.05), in the LTC sample. Work-to-family conflict was positively associated with the odds of at least one ER/urgent care visit in the LTC sample, OR 1.15 (P<.05), at least one healthcare visit in the IT sample, OR 1.35 (P<.01), and with more visits in the IT sample, IRR 1.35 (P<.01). Greater schedule control was associated with reductions in the number of ER/urgent care visits, IRR 0.71 (P<.05), in the IT sample. CONCLUSION: Controlling for other factors, some psychosocial workplace factors were associated with future healthcare utilization. Additional research is needed. PMID- 29996582 TI - Validation of Instruments for Assessing Drug Safety Management During the Conduction of Clinical Trials. AB - BACKGROUND: The management of drug safety with the collection of reliable safety data during the conduction of clinical trials conduct is essential for the registry and marketing of products. The systematic evaluation of this process, based on objective measures, requires the application of quality instruments. This study was aimed to design and validate eight instruments through the components of quality (structure, process, and results), for characterizing and assessing the process of drug safety management, during the conduction of clinical trials. METHODS: The eight instruments were designed according to the international recommendations for Good Clinical Practice (GCP) and comprise a knowledge survey for professionals at the investigational sites, a satisfaction scale of internal and external clients and a satisfaction survey for patients with the treatment of the adverse events. The instruments also include a checklist to evaluate the safety management infrastructure (human, material and organizational resources) in the sponsoring center, a checklist to evaluate the same criterion at the investigational sites and three checklists that evaluate adherence to regulatory requirements of essential documents (investigator's brochure, protocol, and informed consent form). The content validity was evaluated by Delphi method and the reliability was determined by Cronbach alpha test. RESULTS: All the items were valued as very adequate after the second round of the expert panel. The instruments were deemed as appropriate and understandable in the pre-test performed. All responders agreed with the options given and the accessibility of the application. Only 10% of professionals at the research sites suggested that the knowledge survey was too long. Cronbach alpha values between .66 and .93 were obtained. CONCLUSION: The structure, process, and outcome framework allowed for the characterization of drug safety management during clinical trials, providing a useful approach for the promoter to systematically measure and evaluate the process. The eight instruments were deemed as reliable, feasible and easy to be used for examining drug safety management while carrying out clinical trials. PMID- 29996583 TI - Performance-Based Financing Empowers Health Workers Delivering Prevention of Vertical Transmission of HIV Services and Decreases Desire to Leave in Mozambique. AB - BACKGROUND: Despite increased access to treatment and reduced incidence, vertical transmission of HIV continues to pose a risk to maternal and child health in sub Saharan Africa. Performance-based financing (PBF) directed at healthcare providers has shown potential to improve quantity and quality of maternal and child health services. However, the ways in which these PBF initiatives lead to improved service delivery are still under investigation. METHODS: Therefore, we implemented a longitudinal-controlled proof-of-concept PBF intervention at health facilities and with community-based associations focused on preventing vertical transmission of HIV (PVT) in rural Mozambique. We hypothesized that PBF would increase worker motivation and other aspects of the workplace environment in order to achieve service delivery goals. In this paper, we present two objectives from the PBF intervention with public health facilities (n=6): first, we describe the implementation of the PBF intervention and second, we assess the impact of the PBF on health worker motivation, key factors in the workplace environment, health worker satisfaction, and thoughts of leaving. Implementation (objective 1) was evaluated through quantitative service delivery data and multiple forms of qualitative data (eg, quarterly meetings, participant observation (n=120), exit interviews (n=11)). The impact of PBF on intermediary constructs (objective 2) was evaluated using these qualitative data and quantitative surveys of health workers (n=83) at intervention baseline, midline, and endline. RESULTS: We found that implementation was challenged by administrative barriers, delayed disbursement of incentives, and poor timing of evaluation relative to incentive disbursement (objective 1). Although we did not find an impact on the motivation constructs measured, PBF increased collegial support and worker empowerment, and, in a time of transitioning implementing partners, decreased against desire to leave (objective 2). CONCLUSION: Areas for future research include incentivizing meaningful quality- and process-based performance indicators and evaluating how PBF affects the pathway to service delivery, including interactions between motivation and workplace environment factors. PMID- 29996584 TI - Contribution of Nepal's Free Delivery Care Policies in Improving Utilisation of Maternal Health Services. AB - BACKGROUND: Nepal has made remarkable improvements in maternal health outcomes. The implementation of demand and supply side strategies have often been attributed with the observed increase in utilization of maternal healthcare services. In 2005, Free Delivery Care (FDC) policy was implemented under the name of Maternity Incentive Scheme (MIS), with the intention of reducing transport costs associated with giving birth in a health facility. In 2009, MIS was expanded to include free delivery services. The new expanded programme was named "Aama" programme, and further provided a cash incentive for attending four or more antenatal visits. This article analysed the influence of FDC policies, individual and community level factors in the utilisation of four antenatal care (4 ANC) visits and institutional deliveries in Nepal. METHODS: Demographic and health survey data from 1996, 2001, 2006 and 2011 were used and a multi-level analysis was employed to determine the effect of FDC policy intervention, individual and community level factors in utilisation of 4 ANC visits and institutional delivery services. RESULTS: Multivariate analysis suggests that FDC policy had the largest effect in the utilisation of 4 ANC visits and institutional delivery compared to individual and community factors. After the implementation of MIS in 2005, women were three times (adjusted odds ratio [AOR]=3.020, P<.001) more likely to attend 4 ANC visits than when there was no FDC policy. After the implementation of Aama programme in 2009, the likelihood of attending 4 ANC visits increased six-folds (AOR=6.006, P<.001) compared prior to the implementation of FDC policy. Similarly, institutional deliveries increased two times after the implementation of the MIS (AOR=2.117, P<.001) than when there was no FDC policy. The institutional deliveries increased five-folds (AOR=5.116, P<.001) after the implementation of Aama compared to no FDC policy. CONCLUSION: Results from this study suggest that MIS and Aama policies have had a strong positive influence on the utilisation of 4 ANC visits and institutional deliveries in Nepal. Nevertheless, results also show that FDC policies may not be sufficient in raising demand for maternal health services without adequately considering the individual and community level factors. PMID- 29996585 TI - From Mid-Level Policy Analysis to Macro-Level Political Economy Comment on "Developing a Framework for a Program Theory-Based Approach to Evaluating Policy Processes and Outcomes: Health in All Policies in South Australia". AB - This latest contribution by the evaluation research team at Flinders University/Southgate Institute on their multiyear study of South Australia's Health in All Policies (HiAP) initiative is simultaneously frustrating, exemplary, and partial. It is frustrating because it does not yet reveal the extent to which the initiative achieved its stated outcomes; that awaits further papers. It is exemplary in describing an evaluation research design in which the research team has excelled over the years, and in adding to it an element of theory testing and re-testing. It is partial, in that the political and economic context considered important in examining both process and outcome of the HiAP initiative stops at the Australian state's borders as if the macro-level national and global political economy (and its power relations) have little or no bearing on the sustainability of the policy learning that the initiative may have engendered. To ask that of an otherwise elegant study design that effectively engages policy actors in its implementation may be demanding too much; but it may now be time that more critical political economy theories join with those that elaborate well the more routine praxis of public policy-making. PMID- 29996586 TI - It Ain't What You Do (But the Way That You Do It): Will Safety II Transform the Way We Do Patient Safety? Comment on "False Dawns and New Horizons in Patient Safety Research and Practice". AB - Mannion and Braithwaite outline a new paradigm for studying and improving patient safety - Safety II. In this response, I argue that Safety I should not be dismissed simply because the safety management strategies that are developed and enacted in the name of Safety I are not always true to the original philosophy of 'systems thinking.' PMID- 29996587 TI - A Safety-II Perspective on Organisational Learning in Healthcare Organisations Comment on "False Dawns and New Horizons in Patient Safety Research and Practice". AB - In their recent editorial Mannion and Braithwaite provide an insightful critique of traditional patient safety improvement efforts, and offer a powerful alternative vision based on Safety-II thinking that has the potential to radically transform the way we approach patient safety. In this commentary, I explore how the Safety-II perspective points to new directions for organisational learning in healthcare organisations. Current approaches to organisational learning adopted by healthcare organisations have had limited success in improving patient safety. I argue that these approaches learn about the wrong things, and in the wrong way. I conclude that organisational learning in healthcare organisations should provide deeper understanding of the adaptations healthcare workers make in their everyday clinical work, and that learning and improvement approaches should be more democratic by promoting participation and ownership among a broader range of stakeholders as well as patients. PMID- 29996588 TI - The Rise of Patient Safety-II: Should We Give Up Hope on Safety-I and Extracting Value From Patient Safety Incidents? Comment on "False Dawns and New Horizons in Patient Safety Research and Practice". AB - Who could disagree with the seemingly common-sense reasoning that: "We must learn from the things that go wrong."? Despite major investments to improve patient safety, relatively few evaluations demonstrate convincing reductions in risk, harm, serious error or death. This disappointing trajectory of improvement from learning from errors or Safety-I as it is sometimes known has led some researchers to argue that there is more to be gained by learning from the majority of healthcare episodes: the things that go right. Based on this premise, socalled Safety-II has emerged as a new paradigm. In this commentary, we consider the ongoing value of Safety-I based approaches and explore whether now is the time to abandon learning from "the bad" and re-energise data collection and analysis by focusing on "the good." PMID- 29996589 TI - Safety I to Safety II: A Paradigm Shift or More Work as Imagined? Comment on "False Dawns and New Horizons in Patient Safety Research and Practice". AB - In their editorial, Mannion and Braithwaite contend that the approach to solving the problem of unsafe care, Safety I, is flawed and requires a shift in thinking to what they are calling Safety II. We have reservations as to whether by itself the shift from Safety I to Safety II is sufficient. Perhaps our failure to improve outcomes in the field of patient safety and quality lies less in our approach - Safety I vs. Safety II - and more in the lack of an agreed upon, commonly understood set of core competencies (knowledge, skills, and attitudes) needed in its workforce. The authors explore in this commentary the need to establish core competencies as part of the pathway to professionalism for the discipline of patient safety and quality. PMID- 29996590 TI - Tapping the Power of Soda Taxes: A Call for Multidisciplinary Research and Broad Based Advocacy Coalitions - A Response to the Recent Commentaries. PMID- 29996591 TI - Human Rights and the Tobacco Industry: An Unsuitable Alliance. PMID- 29996592 TI - Antimicrobial agents that inhibit the outer membrane assembly machines of Gram negative bacteria. AB - Gram-negative pathogens, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, pose a serious threat to public health worldwide, due to high rates of antibiotic resistance and the lack of development of novel antimicrobial agents targeting Gram-negative bacteria.The outer membrane (OM) of Gram-negative bacteria is a unique architecture that acts as a potent permeability barrier against toxic molecules, such as antibiotics. The OM is composed of phospholipids, lipopolysaccharide (LPS), outer membrane beta-barrel proteins (OMP), and lipoproteins. These components are synthesized in the cytoplasm or in the inner membrane, and are then selectively transported to the OM by the specific transport machines, including the Lol, BAM, and Lpt pathways.In this review, we summarize recent studies on the assembly systems of OM components and analyze studies for the development inhibitors that target these systems. These analyses show that OM assembly machines have the potential to be a novel attractive drug target of Gram-negative bacteria. PMID- 29996593 TI - Effects of Sampling Techniques and Sites on Rumen Microbiome and Fermentation Parameters in Hanwoo Steers. AB - We evaluated the influence of sampling technique (cannulation vs. stomach tube) and site (dorsal sac vs. ventral sac) on the rumen microbiome and fermentation parameters in Hanwoo steers. Rumen samples were collected from three cannulated Hanwoo steers via both a stomach tube and cannulation, and 16S rRNA gene amplicons were sequenced on the MiSeq platform to investigate the rumen microbiome composition among samples obtained via 1) the stomach tube, 2) dorsal sac via rumen cannulation, and 3) ventral sac via rumen cannulation. A total of 722,001 high-quality 16S rRNA gene sequences were obtained from the three groups and subjected to phylogenetic analysis. There was no significant difference in the composition of the major taxa or alpha diversity among the three groups (p> 0.05). Bacteroidetes and Firmicutes represented the first and second most dominant phyla, respectively, and their abundances did not differ among the three groups (p> 0.05). Beta diversity principal coordinate analysis also did not separate the rumen microbiome based on the three sample groups. Moreover, there was no effect of sampling site or method on fermentation parameters, including pH and volatile fatty acids (p > 0.05). Overall, this study demonstrates that the rumen microbiome and fermentation parameters are not affected by different sampling techniques and sampling sites. Therefore, a stomach tube can be a feasible alternative method to collect representative rumen samples rather than the standard and more invasive method of rumen cannulation in Hanwoo steers. PMID- 29996594 TI - [Focus problems in minimally invasive surgery of adult degenerative scoliosis]. PMID- 29996595 TI - [Balance reconstruction: common goals for open and minimally invasive surgery of degenerative scoliosis]. PMID- 29996596 TI - [Surgical treatment of adult degenerative scoliosis: minimally invasive surgery or open surgery?] PMID- 29996597 TI - [Two-year clinical and radiological outcomes of minimally invasive surgery for severe adult degenerative scoliosis]. AB - Objectives: To evaluate the efficacy of restoring the balance in the coronal and sagittal planes and to evaluate clinical outcomes in the treatment of severe adult degenerative scoliosis patients using staged lateral lumbar interbody fusion (LLIF) and percutaneous transpedicle screw fixation (pTSF). Methods: A retrospective analysis was made on 13 patients with severe adult degenerative scoliosis treated with staged surgery in Ruijin Hospital between May, 2014 and July, 2015. The operation data were collected, including operation time, estimated blood loss, and complications. Preoperative and postoperative standing anteroposterior and lateral lumbar radiographs were obtained by EOS image system in all patients for measurement of sagittal and coronal plane alignment. All patients were available for at least 24 months of following-up (18-32 months). Paired sample t test was used to compare the parameters of each group pre- and post-operation. Results: All of the 13 patients received LLIF with staged transpedicle screw fixation. Mean operation time was (231+/-48) minutes and (155+/-33) minutes for two-stage surgery. Mean blood loss was (253+/-80) ml during one-stage LLIF surgery and (326+/-99) ml during two-stage pTSF surgery. The interval between two surgical procedures was from 7 to 42 days (mean 14 days). In the coronal plane, the mean Cobb angle of curves was 43.1 degrees +/ 7.3 degrees preoperatively, and it was 11.4 degrees +/-4.0 degrees after one stage LLIF (t=10.16, P<0.001) and 5.5 degrees +/-1.9 degrees after two-stage pTSF (t=6.14, P<0.001). In the sagittal plane, lumbar lordosis (LL) changed after each procedure was as follows: LLIF from 16.8 degrees +/-8.4 degrees to 30.1 degrees +/-6.8 degrees (t=5.21, P<0.001) and PSF to 37.1 degrees +/-4.0 degrees (t=5.04, P<0.001). Sagittal vertical axis (SVA) was reduced from (10.5+/-2.4) cm to (5.3+/-2.1) cm after one-stage LLIF (t=8.52, P<0.001) and to (3.1+/-1.5) cm after two-stage pTSF (t=5.51, P<0.001). In the spino-pelvic parameter, pelvic incidence(PI)-LL mismatch decreased from 33.6 degrees +/-9.6 degrees to 17.8 degrees +/-4.5 degrees (t=5.31, P<0.001) after LLIF and to 9.9 degrees +/-3.7 degrees after pTSF (t=4.68, P<0.001). The visual analogue scale (VAS) of low back pain and leg pain and the Oswestry dability Index (ODI) improved significantly at the last follow-up (t=10.42, 8.94, 19.20, all P<0.01). Conclusions: LLIF significantly improves segmental and coronal plane alignment in patients with degenerative lumbar scoliosis, and these patients can be effectively corrected by staged minimally invasive surgery. PMID- 29996598 TI - [Effects of oblique lateral interbody fusion and transforaminal lumbar interbody fusion for lordosis correction in degenerative lumbar diseases]. AB - Objective: To compare the operation time, estimated blood loss, clinical outcome and correction of lumbar lordosis between oblique lateral interbody fusion (OLIF) and transforaminal lumbar interbody fusion (TLIF) in patients with degenerative lumbar diseases. Methods: Seventy-three patients who underwent OLIF or TLIF surgery from January 2016 to December 2017 in Sir Run Run Shaw Hospital Zhejiang University were analyzed in this retrospective case-control study. The patients included 31 males and 42 females, with a mean age of 65.8 years (range, 36-88 years). Of the patients, there were 9 cases of calcified disc herniation, 34 cases of spinal stenosis, 17 cases of degenerative spondylolithesis, 12 cases of degenerative scoliosis and 1 case of isthmic spondylolithesis. According to the type of surgery, patients were divided into OLIF group (34 cases) and TLIF group (39 cases). The operation time, estimated blood loss and transfusion were recorded, pre-and post-operative visual analogue scale (VAS) for back pain and Oswestry Disability Index (ODI) were evaluated, and pre- and post-operative lumbar lordosis (LL) and fused segment lordosis (FSL) were measured. Student t test were used in comparison between groups. Results: Ten (29.4%) patients in OLIF group and all 39 (100%) patients in TLIF group were supplemented with posterior instrumentation (chi(2)=41.013, P<0.05). The average operation time and estimated blood loss was significantly lower in OLIF group than in those in TLIF group[(163+/-68) vs (233+/-79) min, (116+/-148) vs (434+/-201) ml, t=4.019, 6.964, both P<0.05]. There was no significant differences in decreases value in VAS and ODI after surgery between the two groups (t=1.716, 0.522, both P>0.05). The correction of LL was 4.0 degrees +/-10.0 degrees in the OLIF group and 4.2 degrees +/-6.1 degrees in the TLIF group; the correction of FSL was 4.1 degrees +/-7.0 degrees in the OLIF group and 5.2 degrees +/-4.6 degrees in the TLIF group, with no significant differences between the two groups too (t=0.139, 0.805, both P>0.05). The correction of LL was significantly higher in OLIF group with posterior instrumentation than that in TLIF group (9.9 degrees +/-11.1 degrees vs 4.2 degrees +/-6.1 degrees , t=2.180, P<0.05). Conclusions: Both OLIF and TLIF can restore LL to some extent, but OLIF has obvious advantages in the operation time and blood loss during surgery. When supplemented with posterior instrumentation, OLIF can achieve better correction of LL than TLIF. PMID- 29996599 TI - [Minimally invasive surgery for the severe degenerative lumbar scoliosis: two stage protocol]. AB - Objective: To investigate the surgical outcome of minimally invasive surgery(MIS) for severe degenerative lumbar scoliosis(DLS) and put forward a two-stage MIS surgical strategy. Methods: Prospective study of MISDEF III DLS patients from June 2016 to August 2017 in the Second Affiliated Hospital of Zhejiang University was carried out, excluding the patients whose apex vertebrae of scoliosis was above L(1/2) level or whose facet joint got spontaneous fusion. Fifty-three patients were included in this study for staging evaluation and MIS surgical treatment. Information was recorded, including gender, age, body mass index, follow-up period, pelvic incidence (PI), blood loss, operation time, visual analogue pain score (VAS), Oswestry disability index (ODI), complications in the perioperative period and follow-up period, and also the radiographic parameters such as scoliosis Cobb angle, the mismatch between pelvic incidence and lumbar lordosis (PI-LL), sagittalvertical axis (SVA), coronal balance (CB) before and after each stage of surgery or latest follow-up. The paired-samples t test was used to analyze the effectiveness of staging surgery. Results: Fifty-three patients (18 males and 35 females) were included in this study. All patients had completed clinical and the follow-up records, with an average follow-up period of 11.52 months (6-20 months). A total of 168 segments fusions were performed with CLIF, 113 segments were performed with anterior column realignment (ACR), the average correct angle was 15.6 degrees +/-6.3 degrees (7 degrees -28 degrees ) in sagittal plane each level. After the stage I surgery, lumbar scoliosis cobb had been corrected for 55.35%, after the stage II surgery, rate of correction was 75.6%. PI-LL had been matched (-32.8 degrees +/-14.9 degrees to -2.5 degrees +/ 9.4 degrees ), SVA was changed from 5.7 cm to 0.6 cm, the stage I rate of correction was 80.3 and stage II was 88.8%, pelvic tilt (PT), lumbar lordosis (LL) and CB had been restored; 13 (24.5%) patients were performed paraspinal approach transforaminal decompression. The posterior minimally invasive fixation indexes: 11(20.8%) patients were performed paraspinal approach transforaminal multi-segment transforaminal osteotomy (TFO) and internal fixation; 36(67.92%) cases were performed paraspinal approach transforaminal multi-segment fixation; 6(11.33%) patients were treated with percutaneous pedicle screw fixation. The average fixed segments was 7.4+/-1.4 in each patient. The blood loss of stage I and stage II operation was (157+/-71) ml, (343+/-224)ml, respectively. The operation time was (214+/-60) min, (190+/-54)min respectively in the two stage operations. The low back pain and leg pain VAS score and ODI improved after the stage I and II surgery (t=17.948, 10.099, 14.619, all P<0.001). Conclusions: MIS for the severe degenerative lumbar scoliosis can achieve good clinical outcome and deformity correction. The two-stage protocol has the advantages of less complications and is well-tolerated. PMID- 29996600 TI - [Resting-state functional MRI studies of amyotrophic lateral sclerosis patients with various levels of cognitive impairment]. AB - Objective: To characterize the brain functional changes of amyotrophic lateral sclerosis (ALS) patients with various levels of cognitive impairment as measured by resting-state functional MRI (RS-fMRI). Methods: From September 2013 to March 2017, a total of 55 patients diagnosed with ALS in Peking Union Medical College Hospital and 20 healthy controls (HCs) were included in this study, and all participants underwent neuropsychological assessments and diffusion tensor imaging scans. According to their cognitive performance, ALS patients were further subclassified into ALS with normal cognition (ALS-Cn, n=27), those with cognitive impairment (ALS-Ci, n=17) and ALS-FTD (n=11). Comparisons of fractional amplitude of low frequency fluctuation (fALFF) value and regional homogeneity (ReHo) value were conducted among the 4 subgroups. Results: The fALFF showed significant differences in bilateral frontal lobe, left temporal lobe and cingulate gyrus, (P<0.001, uncorrected) and the ReHo showed significant differences in left frontal lobe, right temporal lobe and left cingulate gyrus (P<0.001, FDR corrected). The differences mainly stemmed from that patients with ALS-FTD showed decreased fALFF and ReHo in these areas when compared to the other three groups, especially in relation to HCs, mainly locating in left prefrontal lobe and anterior cingulate cortex. The whole-brain comparisons of fALFF and ReHo between ALS-Ci, ALS-Cn and HCs revealed no significant difference (P<0.001, uncorrected). Conclusion: Hypoactivities are detected in extramotor areas in patients with ALS-FTD. RS-fMRI is helpful in investigating the pathophysiologic mechanism of cognitive impairment in ALS. PMID- 29996601 TI - [Endoscopic neurosurgery combined with intraventricular lavage for pyogenic ventriculitis]. AB - Objective: To investigate the efficacy of endoscopic neurosurgery combined with intraventricular lavage for pyogenic ventriculitis. Methods: A retrospective analysis of 45 patients with pyogenic ventriculitis in six hospitals which included Beijing Shijitan Hospital and Peking Union Medical College Hospital from 2001 to 2017. Twenty-four patients (non-endoscopic group) were treated with external ventricular drainage combined with intraventricular antibiotics administration from 2001 to 2009. Twenty-one patients (endoscopic group) was treated by endoscopic neurosurgery combined with intraventricular antibiotics lavage from 2010 to 2017. The drainage time, mortality, and modified Rankin score (mRS) after 6 months of follow-up were compared between the two groups. Results: Drainage time: (20+/-6) days in the endoscopic group, and (42+/-10) days in the non-endoscopic group. There was a significant difference between the two groups (P<0.001). Days in hospital: (29+/-7) days in the endoscopic group, and (51+/-11) days in the non-endoscopic group. There were significant differences between the two groups (P<0.001). Mortality: 8 patients (33.3%) died in the non-endoscopy group, and 1 patient (4.76%) died in the endoscopy group. There was a significant difference between the two groups (P=0.017). After 6 months of follow-up, patients of mRS<=3 were 14 cases (66.67%) in the endoscopy group, and 7 cases (29.17%) in the non-endoscopic group. There was a significant difference between the two groups (P=0.001). Conclusion: Endoscopic neurosurgery combined with intraventricular antibiotics saline lavage for pyogenic ventriculitis is an effective assessment and treatment method, and it is worth further promotion and application. PMID- 29996602 TI - [Personalized repeat Gamma Knife Radiosurgery treatment in patients with recurrent refractory trigeminal neuralgia]. AB - Objective: To analyze the prognosis and untoward effect in recurrent refractory trigeminal neuralgia (RRTN) patients who underwent repeat Gamma Knife Radiosurgery treatment (GKRS) retrospectively, and to summarize the experience of repeat Gamma Knife Radiosurgery treatment of recurrent refractory trigeminal neuralgia. Methods: RRTN patients who treated with repeat GKRS during 1998.8.1 to 2014.10.1 in Gamma Knife treatment Center of the Fifth Affiliated Hospital of Zhengzhou University were involved. The factors influencing long-term prognosis and facial numbness adverse reactions were statistically analyzed. Results: Therapeutic dose was an independent factor that influence long-term prognosis of RRTN patients. Therapeutic dose was a dangerous factor that influence long-term facial numbness. Interval time between twice GKRS treatment was a favorable factor for facial numbness. Long-term prognosis of repeat GKRS treatment was positively correlated with therapeutic dose. Untoward effect of facial numbness after repeat GKRS treatment was positively correlated with therapeutic dose and negatively correlated with interval time between twice GKRS treatment. Conclusions: Repeat GKRS for RRTN patients is safe and effective, but personalized treatment plan should be given according to the patient's own condition. PMID- 29996603 TI - [Contrast study of double-balloon catheter with and without oxytocin for cervical ripening]. AB - Objective: To evaluate the efficacy and related issues for cervical ripening by double-balloon catheter with and without oxytocin. Methods: The prospective non randomly control research was conducted from March 2015 to June 2017 in Yuquan Hospital of Tsinghua University. The primipara with induced labor indications and balloon placement conditions were divided into two groups. Seventy-eight cases were in the balloon with oxytocin group, in which oxytocin was used if there were no contraction 1 hour after balloon placement. Meanwhile, 220 cases were in the single balloon group. Before and after balloon placement, the changes of cervical Bishop Scores and delivery outcome were compared between the groups. Results: The effective rate of cervical ripening in the balloon with oxytocin group was higher than that in the balloon group[92.3% (72/78) vs 82.7% (182/220), P<0.05], the proportion of parturiency within 12 hours was as well[15.4% (12/78) vs 7.3% (16/220), P<0.05]. The effective rate of cervical Bishop score 4-5 points was further improved in the balloon with oxytocin group[95.7%(66/69) vs 85.1% (165/194), P<0.05]. Taken out balloon, the cervical Bishop scores (8.1+/-1.1) points in the balloon with oxytocin group were higher than (6.5+/-1.2) points in the balloon group (P<0.05). For the maternal without parturiency in the balloon with oxytocin group, the cervical Bishop score reduced from (7.7+/-0.9) points to (6.6+/-0.6) points after removal balloon for 12 hours (P<0.05). The cesarean section proportion for intrauterine infection in the balloon with oxytocin group was higher than that of the balloon group ( P<0.05), but the placental pathological diagnosis proportion was no significant difference ( P>0.05). In the two groups, the cesarean section rate, the first labor stage, the episiotomy rate, the postpartum hemorrhage rate, neonatal weight, the neonatal asphyxia and referral rate showed no significant differences (P>0.05, respectively). Conclusions: The double-balloon catheter with oxytocin can further improve the efficiency of patients with cervical Bishop score 4-5 points for cervical ripening , and increase the chance of labor in 12 hours. PMID- 29996604 TI - [Effect of mesenchymal stem cells on expression of high mobility group box 1 protein in rats with ischemia reperfusion injury after lung transplantation]. AB - Objective: To establish the ischemia reperfusion injury model in rat after lung transplantation(LT) and explore the expression of high mobility group box 1 protein(HMGB1) after intravenous injection with bone marrow mesenchymal stem cells(MSCs). Methods: Forty healthy 8-10 weeks male SD rats were randomly divided into four groups including the sham-operated group, ischemia-reperfusion (IR), Saline-IR and MSC-IR group. The sham-operated rats were only conducted thoracotomy without lung transplantation and the rest groups were respectively conducted with the left LT, left LT followed by 1 ml saline and left LT followed by 1 ml MSCs (1.0*10(7)/ml). Four groups of rats were killed at 24 h after reperfusion. The blood and left lung tissue were collected. Oxygenation index(OI) and the ratio of wet/dry in four groups were detected and histological sections stained with hematoxylin and eosin (HE) were made. HMGB1 levels in serum were detected with ELISA. Real-time PCR and Western blot were performed to detect the expression of HMGB1 in mRNA and protein levels. Results: The OI in four groups were respectively 383+/-15, 174+/-24, 170+/-30 and 217+/-21.OI in IR and Saline IR group decreased compared with the sham-operated group , all P<0.01. The OI increased after injection with MSCs compared with IR group, P<0.01. The histological images showed the marked inflammatory infiltrates and interalveolar septal thickening in IR group. Treatment with MSCs reduced inflammatory injury.The ratio of wet/dry in IR group and Saline-IR group increased compared with the sham-operated group((5.38+/-0.19), (5.24+/-0.15) vs (4.16+/-0.12), all P<0.05). Ratio in MSC-IR group decreased compared with the IR group (4.47+/-0.14) vs (5.38+/-0.19), P<0.05. ELISA results showed that HMGB1 level increased significantly in IR group (287+/-37)ng/ml, Saline-IR group (260+/-24)ng/ml and MSC-IR group (101+/-14)ng/ml when compared with the sham-operated group (41+/-5) ng/ml. The serum HMGB1 level in IR group was positively correlated with the OI (r=0.759, P<0.05) and wet/dry ratio (r=0.725, P<0.05). RT-PCR showed that HMGB1 mRNA level in sham-operated group was the lowest and increased significantly in IR group, while decreased significantly in MSC-IR group compared with IR group and Saline-IR group(P<0.01). The results of HMGB1 expression at protein level by Western blot were consistent with the mRNA level. Conclusion: Lung transplantation can induce the expression of HMGB1 but HMGB1 level of lung tissue decreased significantly after the treatment with MSCs, which indicated that MSCs might play an important role in protecting transplanted lung via HMGB1. PMID- 29996605 TI - [Role of Ginkgo biloba extract in regulating 5-hydroxytrytamine and its receptor in heart failure mice]. AB - Objective: Exploring the modulation of periphery and central serotonin (5 hydroxytrytamine, 5-HT) and 5-HT(2A) receptor (5-HT(2A)R) in mice with heart failure during the process of heart failure and after treatment. Methods: Thirty mice were allocated into three groups randomly including normal group (NG), heart failure group (HFG) and treatment group (TG) (n=10). Mice in the NG were sacrificed after evaluating left ventricular ejection fraction (EF) with echocardiogram. Mice in HFG and TG experienced myocardial infarction surgery to achieve EF<=30%, HFG was treated with saline and TG with Ginkgo biloba pills (GBP), once a day for 4 weeks, then EF was assessed again before sacrifice. Cardiac muscle tissue fibrosis was observed and the severity of fibrosis was assessed by semiquantitative method. All the indexes including BNP, serum 5-HT, 5 HT and 5-HT(2A)R in platelet and brain were detected. The data were analyzed by SPSS 19.0. Results: EF: EF in HFG and TG were much lower than that in NG (P<0.05), TG was much higher than HFG (P<0.05). BNP: BNP in HFG and TG were much higher than that in NG (P<0.05), TG was significantly lower than HFG (P<0.05). HFG showed ventricular remodeling, increased myocardial fibrosis; while myocardial fibrosis decreased in TG. 5-HT in serum: serum 5-HT in HFG was much higher than NG (212+/-29 ng/L vs 146+/-5 ng/L, P<0.05), TG was much lower than HFG (163+/-8 ng/L vs 212+/-29 ng/L, P<0.05). 5-HT in platelet: platelet 5-HT in HFG was much lower than NG (165+/-22 ng/L vs 193+/-19 ng/L, P<0.05), platelet 5 HT in TC was higher than HFG and NG (224+/-27 ng/L vs 193+/-19 ng/L, 165+/-22 ng/L, P<0.05). 5-HT(2A)R in platelet: platelet 5-HT(2A)R in HFG was much lower than NG (P<0.05), TG was much higher than NG and HFG (P<0.05). 5-HT in cortex: cortex 5-HT in HFG and TG were much higher than NG (253+/-4 ng/L, 231+/-31 ng/L vs 179+/-9 ng/L, P<0.05), TG was a little lower than HFG (231+/-31 ng/L vs 253+/ 4 ng/L, P>0.05). 5-HT(2A)R in cortex: cortex 5-HT(2A)R in HFG and TG were much higher than NG (P<0.05), TG was much lower than HFG (P<0.05). 5-HT in hippocampus: hippocampus 5-HT in HFG was much higher than NG (250+/-7 ng/L vs 179+/-5 ng/L, P<0.05), TG was much lower than HFG (164+/-6 ng/L vs 250+/-7 ng/L, P<0.05). 5-HT(2A)R in hippocampus: hippocampus 5-HT in both HFG and TG were much higher than NG (P<0.05), there was no significant difference between TG and HFG (P>0.05). Conclusion: Significant changes of 5-HT and 5-HT(2A)R are found in heart failure mice during the process of heart failure and after treatment, indicating the potential value of 5-HT modulation in the diagnose and treatment of heart failure. PMID- 29996607 TI - [Establishment of standardized diagnosis and treatment of eyelid sebaceous carcinoma in China]. AB - Eyelid sebaceous carcinoma is a malignant tumor originating from Meibomian glands, Zeis glands, and other glands surrounding hair follicles. It is the second most common eyelid malignancy, following basal cell carcinoma, in China. Considering its diversified clinical manifestations and strong tendency for recurrence and metastasis, standardized cancer staging, surgical excision with frozen section control, and postsurgical follow-up has been internationally adopted with the aim to considerably reduce the risk of recurrence and metastasis. However, the lack of standardized and normalized staging, surgical treatment and follow-up in China inevitably caused high recurrence rate and low predictability of prognosis of eyelid sebaceous carcinoma. Therefore, it is of great significance to standardize the clinical diagnosis and treatment of eyelid sebaceous carcinoma in China. (Chin J Ophthalmol, 2018, 54: 481-483). PMID- 29996608 TI - [Orbital decompression for thyroid associated ophthalmopathy: transnasal endoscopic approach or external orbital approach?] AB - External orbital decompression, including medial wall, inferior wall, lateral wall and orbital fat decompression alone or in combination, has long been considered to be the standard treatment for thyroid related eye diseases. Deep lateral wall orbital decompression has better effect in the balance of eye position, correction of serious exophthalmos and severe oppression optic neuropathy. Recently, however, endoscopic orbital decompression is becoming increasingly popular with the development of endoscopic surgery technique in naso orbit related diseases. Endoscopic orbital decompression has the advantages of avoiding an external incision scar. Nevertheless, the new method also has some disadvantages, for example, application limited to medial and inferior orbital wall orbital decompression, high incidence of esotropia, need for external lateral wall decompression and expensive cost for equipment. Both surgical approaches have advantages and disadvantages respectively for medial wall and inferior wall decompression. The operative result depends on the individualized surgical design and the experience of the surgeon rather than the choice of the surgical approach. As a result, the choice of the surgical approaches should be specifically based on the patient's conditions, patient's acceptance of the operation, experience of the surgeon and available resources. (Chin J Ophthalmol, 2018, 54: 484-487). PMID- 29996606 TI - [Safety of atypical antipsychotics in the treatment of behavioral and psychological symptoms in dementia: a meta-analysis]. AB - Objective: To assess the safety of olanzapine, risperidone and quetiapine drugs in dementia patients with behavioral and psychological symptoms. Methods: The EMBASE, Cochrane Controlled Trials Register and the Cochrane Database of Systematic Reviews, Medline, CNKI, Wang Fang were systematically searched for eligible randomized controlled trials of olanzapine, risperidone and quetiapine drugs therapy in patients with psychotic symptoms of dementia before February 2016. Two reviewers independently assessed the quality of the trials and extracted information. All the data was analyzed with meta analysis and software of the Revman5.3 provided by Cochrane network. Results: Overall, 16 relevant RCTs with 1 727 participants were identified (olanzapine group: 672; quetiapine group: 395; risperidone group: 660). (1)Olanzapine group had higher incidence of somnolence than risperidone group (OR=1.49, 95% CI [-1.01-2.21], P=0.05), while for the dizziness, agitation, accidental injury, weight gain, abnormal gait, weakness, sleep disorders, extrapyramidal symptoms, there were no significant difference. (2) Risperidone had higher incidence of extrapyramidal symptoms than quetiapine group (OR=0.11, 95% CI [0.04-0.27], P=0.64), the incidence of somnolence was lower than quetiapine group (OR=0.03, 95% CI [1.06-3.51], P=0.03), while for accidental injury, dizziness, fatigue, insomnia, constipation, there were no significant difference. (3) Olanzapine group had higher incidence of extrapyramidal symptoms than quetiapine group (OR=11.10, 95% CI [3.35-36.75], P<0.000 1), while for somnolence, sleep disturbances, constipation, agitation, weight gain, dizziness, there was no significant difference. (4) The subgroup analysis showed that in the Chinese population, compared with the population in Europe and America, risperidone group had higher incidence of agitation, sleep disorders than olanzapine (agitation: [OR= 0.26, 95% CI [0.08-0.82]; sleep disorders: OR= 0.31, 95% CI [0.10-0.99]), olanzapine group had higher incidence of weight gain than quetiapine (OR=6.8, 95% CI [2.00-23.14]). Conclusions: Among olanzapine, risperidone and quetiapine, risperidone has lowest incidence of somnolence, quetiapine has lowest incidence of extrapyramidal symptoms. In the Chinese population, compared with the population in Europe and America, risperidone group has higher incidence of agitation, sleep disorders than olanzapine, and olanzapine group has higher incidence of weight gain than quetiapine. PMID- 29996609 TI - [Focus on the controversial problems of orbital decompression in the treatment of dysthyroid optic neuropathy]. AB - Dysthyroid optic neuropathy (DON) is the most common cause of visual loss in thyroid associated ophthalmopathy, for which steroid pulse therapy and orbital decompression are the common treatments currently. While steroid pulse therapy was recommended as the first-choice for DON, orbital decompression remained as an indispensable therapy although controversies on such treatment still exist. The mechanism, approaches and outcomes of orbital decompression, as well as its advantages and disadvantages over steroid pulse therapy were retrospectively reviewed, and it was suggested that the combination therapy of steroid pulse therapy and surgical decompression might be the better choice for the treatment of DON. (Chin J Ophthalmol, 2018, 54: 488-490). PMID- 29996610 TI - [Autogenic facia lata suspension for correction of paralytic ectropion]. AB - Objective: To evaluate the outcome of autogenic facia lata suspension in the treatment of paralytic ectropion. Methods: It was a retrospective case series study. The clinical records of 21 patients (21 eyes) who were treated for paralytic ectropion with autogenic facia lata suspension between January 2015 and September 2017 at Beijing Tongren Hospital were analyzed. In the 21 patients, 7 were male and 14 were female. The range of age was 20-74 years and the mean age was (61+/-14) years. All of the participants received facia lata suspension for the correction of ectropion. Some of the patients also received associated wedge resection of the tarsus or lateral tarsal strip procedure. The anterior lamella was reconstructed with local flaps in some patients. The preoperative and postoperative degree of ectropion was measured. Paired sample t test was used to compare the preoperative and postoperative data. Results: Postoperative follow up for patient was conducted for 6-38 months. Residual lagophthalmos of 3 mm or more were present in 3 cases. Mild lower eyelid ectropion recurred in 1 patient one year after surgery. The rest cases achieved satisfactory aesthetic outcomes. No complication in the donor site was observed. The preoperative scleral show was (3.02+/-1.31) mm, and the postoperative data was (-0.05+/-0.72) mm. The preoperative margin reflex distance 2(MRD2) was (8.83+/-1.77) mm, and the postoperative MRD2 was (5.43+/-0.78) mm. The preoperative lagophthalmos was (6.17+/-1.91) mm, and the postoperative data was (1.98+/-1.09) mm. The differences between the preoperative and postoperative data were significant (t=13.530, P=0.000;t=11.913, P=0.000; t=11.882, P=0.000). Conclusion: Autogenic facia lata suspension is an effective method for the correction of paralytic ectropion, with good aesthetic outcome, low recurrence rate and few complications. (Chin J Ophthalmol, 2018, 54: 496-501). PMID- 29996612 TI - [Diagnostic and therapeutical analysis of orbital neurilemomas]. AB - Objective: To explore and summarize the clinical manifestation, iconographic characterizations, principles of diagnosis and treatment of orbital neurilemomas. Methods: Retrospective case series study. A total of 112 patients diagnosed with orbital neurilemomas and received surgery at Tianjin Eye Hospital from January 2002 to December 2016 were included. The clinical symptoms, eye signs, imageological examination, diagnosis treatment and prognosis of the patients were analyzed. SPSS 21.0 software was used to describe age and follow-up time. Results: In the 112 cases, 48 cases were male, 64 cases were female. At the time of diagnosis, the age of patients ranged from 13 to 73 years. The mean age at diagnosis was (40+/-4) years. B ultrasound scan was applied in all 112 cases, results revealed round, elliptical, beaded, and irregular shaped lesion in orbit with clear boundary, which was characterized with poor echo, strong sonolucency, and mild compressibility. CT scan was also applied in all 112 cases. The lesions were elliptical, lobulated, S-shaped, or peanut shaped, primarily characterized with evenly high density and a few with the low density fluidized region. MRI was applied in 54 cases. T(1) weighted image (T(1)WI) showed medium signal in all lesions. T(2) weighted image (T(2)WI) showed high, mixed and medium signal. Surgical approaches included lateral orbitotomy in 75 cases, and anterior orbitotmy in 37 cases. Average follow-up time was (64.3+/-4.1) months. Surgical complications included vison loss (in 3 cases), postoperation ptosis (in 16 cases), and disturbance of eyeballs movement (in 9 cases), while 6 cases involved with recurrence. Conclusions: Orbital schwannoma is mostly characterized with benign solid orbital lesions. Orbital CT examination results of orbital schwannoma are mainly characterized with ellipsoid or beaded mass along the anterior posterior axis of orbit, while a few of tumors showed low density liquefaction areas. T(1)WI shows medium signal in most lesions, and T(2)WI shows mixed signal in most lessions. Histopathologic examination is the basis for confirmation of diagnosis. The recurrence rate is lower after the complete resection of the tumor. Postoperative radiotherapy could be used for controlling the recurrence. (Chin J Ophthalmol, 2018, 54: 509-514). PMID- 29996611 TI - [Preliminary investigation on embolization of orbital vascular malformation with medical glue injection intraoperatively]. AB - Objective: To summarize the treatment outcomes of embolizing orbital vascular malformation with intracavitary injection of medical glue during surgery. Methods: A retrospective case series study was performed on 25 patients with orbital vascular malformation who were treated at Tianjin Medical University Eye Hospital during March 2008 and March 2016. In the 25 patients(25 eyes), 7 were male and 18 were female. The range of age was 2-64 years and the median age was 29 years. The clinical features, operation records, pathological reports and follow-up data were analyzed. Results: The location of vascular malformation involved intraorbital in 11 cases and superficial area of eyelid and(or) face in 5 cases, as for the rest 9 cases, both intraorbital and superficial area were involved. Conjunctiva was involved in 4 patients. Clinical manifestation included intermittent protopsis or mass volumn changed (7 cases), pulsating exophthalmos and vascular murmur (1 case). Imaging examination showed solitary mass with regular shape in 5 cases and space occupying lesion with irregular shape and ill defined margins in 20 cases. Optic nerve was involved in 7 cases. Surgical debulkling were performed via skin incision on the mass surface (in 3 cases), lateral orbitotomy (in 2 cases), and anterior orbitotomy (in 20 cases). The anterior orbitotomy approaches include skin incision under eyebrow (9 cases), skin incision under lower eyelid eyelash (3 cases), transconjunctiva joint lateral canthus incision (6 cases) and transconjunctiva incision only(2 cases). The intra-orbital part of vascular malformation involved intraconal compartment (10 cases) and extraconal compartment (10 cases). During the operation, vascular malformations were exposed and injected with medical aural and encephalic glue. The amount of injected glue ranged from 0.25 ml to 2.50 ml in divided doses. When the soft venous malformations turned hard, the lesions and remnant glue were fully removed. The whole procedure cause less bleeding and shorter time of operation. Histopathologic diagnosis were intraosseous hemangioma (1 case), arteriovenous malformation (2 cases), venous malformation (22 cases), including varix (4 case) and venous hemangioma (18 cases). One patient suffered from sudden central retinal artery embolism on the third day postoperatively, in which case, visual acuity recovered to 0.6 by timely rescue and appropriate procedure. Topical skin aseptic inflammation took place at the same side of medical glue injection in 3 cases which might be caused by medical glue. These 3 cases had superficial eyelid lesions. Postoperative follow up for patient was conducted from 6 months to 5 years. One young patient underwent recurrent orbital hematoma and many times surgery. Conclusions: Embolization of orbital vascular malformation with medical glue injection intraoperatively can be utilized as an easy approach to control hemorrhage. The surgeon should be careful with the application methods, for instance not to push too quickly, not to pass through the vascular malformation, and to remove the lesions and remnant glue completely, in order to avoid complications. (Chin J Ophthalmol, 2018, 54: 502-508). PMID- 29996613 TI - [Clinical analysis of patients with orbital nonspecific inflammatory response diseases whose CT or MR images show enlargement of the infraorbital nerves]. AB - Objective: To discuss the clinical features, imaging features, pathological patterns, treatment principles and prognosis of the orbital nonspecific inflammatory response diseases patients whose CT or MR images show enlargement of the infraorbital nerves. Methods: A retrospective case series study. Seven orbital disease patients who were treated at Tianjin Medical University Eye Hospital between March 2013 and May 2017 were included. All patients, imaging pictures showed enlargement of the infraorbital nerve. The medical histories, clinical featuers, imaging features, pathologies, serological examinations, therapeutic processes and prognosis were collected and analyzed. Results: The 7 patients included 4 males and 3 females aged from 55 to 68 years (the average age was 60). Bilateral involvement was present in 5 of 7 patients. The main clinical manifestations include proptosis, increasing of orbital pressure, impairment of visual functions, reduction in ocular motility, facial sensation, periocular ache, involvement of lymph node and salivary gland, etc. CT results showed enlargement of infraorbital nerve, accompanied with or without the destruction of bone. The inflammatory response may involve with extraocular muscles and lacrimal glands, or were shown as lesions with irregular shape and blurred borders. The MR images generally showed equal T(1) and equal T(2) signal, accompanied with evident enlargement of the infraorbital nerve. Of all the 7 patients, 6 underwent operation, and the pathology confirmed that 2 of the 6 were involved with inflammatory pseudotumors and the rest 4 were involved with IgG4-related ophthalmic disease (IgG4-ROD). The level of IgG4 in the serum were detected for 4 patients, the results of 3 were high and the other was normal. Of all the 7 patients,1 patient underwent conservative treatment, but disease recurred for several times, and the serum IgG4 level for the patient was higher than normal;1 inflammatory pseudotumor patient was cured completely only by surgery, and has a favourable prognosis; 1 IgG4-ROD patient accepted glucocorticoid, surgery, radiotherapy and chemotherapy, but disease recurred several times; The rest of the patients accepted glucocorticoid and operation, 2 were sensitive to glucocorticoid, 2 were not sensitive, and 1 involved with recurrence. Conclusions: If orbital nonspecific inflammation response was accompanied with enlargement of infraorbital nerve, it is suggested that patient is more likely to be involved with IgG4-ROD;Pathology and serological tests can be used for the diagnosis of IgG4-ROD, however treatment effect appears to be poor for most patients, and patients prone to relapse. (Chin J Ophthalmol, 2018, 54: 515-519). PMID- 29996614 TI - [Changing trends of topical anti-glaucoma medications in the Eye Hospital of Wenzhou Medical University during the past ten years]. AB - Objective: To investigate the changing trends of topical anti-glaucoma medications in the outpatient of the Eye Hospital of Wenzhou Medical University over the decade 2005-2014. Methods: Retrospective case series study. The medications data of glaucoma outpatients in the Eye Hospital of Wenzhou Medical University were collected for the period of January 1(st) 2005 to December 31(st) 2014. SPSS 20.0 statistical software was used, mainly for statistical description of the data. The main outcome measures were the proportions of the prescriptions of different medications, and the proportions of the monotherapy and combination therapies. Results: During the 10 years, the number of glaucoma outpatients increased year by year, from 994 in 2005 to 3 266 in 2014, the gender ration was close to 1?1, and the age were (57+/-18) years. The proportion of beta-blockers decreased from 56.7% (750/1 323) in 2005 to 33.1% (2 120/6 407) in 2014. The proportion of cholinergic agents decreased from 17.2% (227/1 323) in 2005 to 10.3% (663/6 407) in 2014. While the proportion of prostaglandins increased from 13.3% (176/1 323) in 2005 to 36.8% (1 916/5 209) in 2011, which was close to the 37.9% (1 972/5 209) of beta-blockers in 2011. In 2012, the prostaglandins proportion increased to 41.9% (2 435/5 810) exceeding the 37.2% (2 161/5 810) of beta-blockers, and became the most prescribed medication. The proportion of prostaglandins continued to increase to 46.9% (3 008/6 407) in 2014. The proportion of alpha(2)-agonists increased from 17.0% (225/1 323) in 2005 to 22.8% (1 460/6 407) in 2014. The proportion of carbonic anhydrase inhibitors increased from 9.6% (127/1 323) in 2005 to 24.1% (1 546/6 407) in 2014.The proportion of monotherapy decreased from 78.0% (1 032/1 323) in 2005 to 58.6% (3 757/6 407) in 2014. The proportion of two drugs combination increased from 20.0% (264/1 323) in 2005 to 26.7% (1 709/6 407) in 2014. The proportion of three drugs combination increased from 2.0% (26/1 323) in 2005 to 12.3% (788/6 407) in 2014. The proportion of four drugs combination increased from 0.1% (1/1 323) in 2005 to 2.3% (150/6 407) in 2014. Conclusions: The changes of the proportions of topical anti-glaucoma medications were remarkable from 2005 to 2014 in the outpatient of the Eye Hospital of Wenzhou Medical University. The beta-blockers and cholinergic agents were declining, while the prostaglandins, alpha(2)-agonists and carbonic anhydrase inhibitors were increasing, and the prostaglandins became the most prescribed medication since 2012. The proportion of combination therapy was increasing. (Chin J Ophthalmol, 2018, 54: 520-525). PMID- 29996616 TI - [An update on the treatment of orbital venous malformation]. AB - Orbital venous malformation (OVM) ranks as the most common form of vascular lesions in the orbit. OVM may cause functional impairment as well as disfigured appearance in orbital and periorbital regions. A variety of treatment methods has been used to deal with OVM, including sclerotherapy, laser therapy, embolization, surgical resection. The treatment scenario should be made based on hemodynamics, location and extent of lesions in order to achieve encouraging results. With increased understanding on hemodynamics of OVM and application of newly proposed techniques, a combined modality of multiple approaches with defined order has been advocated to be applied in the treatment of OVM. In this paper, the latest advancement in treatment of OVM is reviewed. (Chin J Ophthalmol, 2018, 54: 548 550). PMID- 29996615 TI - [A study of clinical and genetic characteristics of a Leber hereditary optic neuropathy family with the heteroplasmic m.14484T>C mutation]. AB - Objective: To study clinical and genetic characteristics of a Leber hereditary optic neuropathy (LHON) family with the heteroplasmic m.14484T>C mutation. Methods: A cross-sectional study. The objects of the study included a 31-year-old male LHON patient with the heteroplasmic m.14484T>C mutation (the proband) who visited Department of Ophthalmology in the Affiliated Central Hospital of Qingdao University in March 2015 and other 36 matrilineal relatives in a four-generation family (12 males and 24 females aged 2-81 years, median 27 years). The visual acuity, intraocular pressure, fundus, color vision, visual field, visual evoked potential and optical coherence tomography were evaluated in maternal members. The mitochondrial DNA (mtDNA) sequence of fragments including m.14484 loci was detected by Sanger sequencing in 33 members. The sequencing peaks were analyzed by QSVanalyzer software to get the heteroplasmy levels of m.14484T>C mutation. The mtDNA of the proband was amplified by PCR and sequenced. Assembled sequence of mtDNA was compared with the updated consensus Cambridge sequence. The differences in visual evoked potential, optical coherence tomography and heteroplasmy levels were compared between two groups by the t-test, and among multiple groups by the single factor variance analysis. Results: Among the 33 maternal members of the family, 4 patients, 28 carriers and 1 person without a mutation were confirmed. The penetrance was 12.5% (4/32) . In addition to 4 patients with obvious abnormality on the ophthalmic examination, 5 carriers also appeared anomaly on the electrophysiological and visual function examinations. Compared to carriers, the amplitude of P100 was obviously decreased in the LHON patients[ (5.6+/-2.6) MUV vs. (15.6+/-9.6) MUV, t=2.880, P=0.006]. Significantly reduced values were seen in the average retinal nerve fiber layer thickness[ (71+/-17) MUm vs. (99+/-11) MUm, t=5.969, P< 0.001], in each side of the sub-area macular thickness, and in the nasal side of the lateral sub-area macular thickness [ (260+/-16) MUm vs. (291+/-12) MUm, t=5.593, P<0.001] between the LHON patients and carriers. The heteroplasmic levels were 80%+/-3% in the LHON patients, and 27%+/-18% in the unaffected members;the difference was significant (t=-8.395, P<0.001). The average degree of heteroplasmy had no difference between male and female members (48%+/-34% vs. 35%+/-28%, t=-1.147, P=0.258). The average mutation load was 29%+/-14% in the second generation members, 36%+/-29% in the third generation members, and 51%+/-36% in the fourth generation members;the differences were not statistically significant (F=1.152, P=0.330). The difference in the heteroplasmic levels was not statistically significant between mothers and their offspring (31%+/-25% vs. 42%+/-32%, t=1.165, P=0.251). Compared to Cambridge consensus sequence, 41 mutations was found in mtDNA of the proband, of which, 10 were missense mutations, including mutations m.4216T>C and m.3394T>C. According to the phylogenetic tree, the haplotype of the proband was M9a (M9a1a1c1a). Conclusions: In the family with the heteroplasmic m.14484T>C mutation, clinical manifestations of LHON appear in the individuals whose heteroplasmic level is more than 75%, and all of patients show typical chronic optic atrophy on the ophthalmic examination. The carriers with the m.14484T>C mutation also appear anomaly on the electrophysiological and visual function examinations. The heteroplasmic level of m.14484T>C mutation has a tendency to increase during the transmission in the family. The primary mutation m.14484T>C coordinate mutations m.4216T>C and m.3394T>C to increase the penetrance and incidence of abnormal visual function in carriers. (Chin J Ophthalmol, 2018, 54: 526-534). PMID- 29996617 TI - [Research on examination of intraocular fluid for diagnosis of infectious ocular diseases]. AB - Including viral retinitis, endophthalmitis and ocular toxoplasmosis etc, Infectious ocular diseases, which include viral retinitis, endophthalmitis and ocular toxoplasmosis etc, are the common causes leading to blindness. Traditional examinations of serum are of limited help in diagnosing these diseases and are sometimes misleading. Examinations of pathogen DNA, antibodies and cytokines in the intraocular fluids including aqueous humor and vitreous humor can help clinicians get in situ information and hereby confirm diagnosis rapidly.(Chin J Ophthalmol, 2018, 54: 551-556). PMID- 29996618 TI - Identification of Lactic Acid Bacteria in Galchi- and Myeolchi-Jeotgal by 16S rRNA Gene Sequencing, MALDI-TOF Mass Spectrometry, and PCR-DGGE. AB - Jeotgal is a Korean traditional fermented seafood with a high concentration of salt. In this study, we isolated lactic acid bacteria (LAB) from galchi (Trichiurus lepturus, hairtail) and myeolchi (Engraulis japonicas, anchovy) jeotgal on MRS agar and MRS agar containing 5% NaCl (MRS agar+5% NaCl), and identified them by using 16S rRNA gene sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) as culture dependent methods. We also performed polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) as a culture-independent method to identify bacterial communities. Five samples of galchi-jeotgal and seven samples of myeolchi-jeotgal were collected from different regions in Korea. A total of 327 and 395 colonies were isolated from the galchi- and myeolchi-jeotgal samples, respectively. 16S rRNA gene sequencing and MALDI-TOF MS revealed that the genus Pediococcus was predominant on MRS agar, and Tetragenococcus halophilus on MRS agar+5% NaCl. PCR-DGGE revealed that T. halophilus, Tetragenococcus muriaticus, and Lactobacillus sakei were predominant in both types of jeotgal. T. halophilus was detected in all samples. Even though the same species were identified by both culture-dependent and -independent methods, many species identified by the culture-dependent methods were not in the bacterial list identified by the culture-independent methods. The distribution of bacteria in galchi-jeotgal was more diverse than in myeolchi-jeotgal. The diverse LAB in galchi- and myeolchi jeotgals can be further studied as candidates for starter cultures to produce fermented foods. PMID- 29996619 TI - Expression of manB Gene from Escherichia coli in Lactococcus lactis and Characterization of Its Bifunctional Enzyme, Phosphomannomutase. AB - Phosphomannomutase (ManB) converts mannose-6-phosphate (M-6-P) to mannose-1 phosphate (M-1-P), which is a key metabolic precursor for the production of GDP-D mannose used for production of glycoconjugates and post-translational modification of proteins. The aim of this study was to express the manB gene from Escherichia coli in Lactococcus lactis subsp. cremoris NZ9000 and to characterize the encoded enzyme. The manB gene from E. coli K12, of 1,371 bp and encoding 457 amino acids (52 kDa), was cloned and overexpressed in L. lactis NZ9000 using the nisin-controlled expression system. The enzyme was purified by Ni-NTA column chromatography and exhibited a specific activity of 5.34 units/mg, significantly higher than that of other previously reported ManB enzymes. The pH and temperature optima were 8.0 and 50 degrees C, respectively. Interestingly, the ManB used in this study had two substrate specificity for both mannose-1 phosphate and glucose-1-phosphate, and the specific activity for glucose-1 phosphate was 3.76 units/mg showing 70% relative activity to that of mannose-1 phosphate. This is the first study on heterologous expression and characterization of ManB in lactic acid bacteria. The ManB expression system constructed in this study canbe used to synthesize rare sugars or glycoconjugates. PMID- 29996620 TI - Characterization and Antioxidant Activity of the Exopolysaccharide Produced by Bacillus amyloliquefaciens GSBa-1. AB - The exopolysaccharide (EPS) produced by Bacillus amyloliquefaciens GSBa-1 was isolated and purified by ethanol precipitation, and DEAE-cellulose and Sepharose CL-6B chromatographies. The molecular mass of the purified EPS was determined to be 54 kDa. Monosaccharide analysis showed that the EPS was composed of predominantly glucose, and it was further confirmed by NMR spectroscopy to be alpha-glucan that consisted of a trisaccharide repeating unit with possible presence of two alpha-(1->3) and one alpha-(1->6) glucosidic linkages. Microstructural analysis showed that the EPS appeared as ellipsoid or globose with a smooth surface. The EPS had a degradation temperature at 240 degrees C. Furthermore, the EPS had strong DPPH and hydroxyl radical scavenging activities, and moderate superoxidant anion scavenging and metal ion-chelating activities. This is the first characterization of a glucan produced by B. amyloliquefaciens with strong antioxidant activity. The results of this study suggest the potential of the EPS from B. amyloliquefaciens GSBa-1 to serve as a natural antioxidant for application in functional products. PMID- 29996621 TI - Current Status of Microbial Phenylethanoid Biosynthesis. AB - Phenylethanoids, including 2-phenylethanol, tyrosol, and salidroside are a group of phenolic compounds with a C6-C2 carbon skeleton synthesized by plants. Phenylethanoids display a variety of biological activities, including antibacterial, anticancer, anti-inflammatory, neuroprotective, and anti-asthmatic activities. Recently, successful microbial synthesis of phenylethanoids through metabolic engineering and synthetic biology approaches has been reported and could allow phenylethanoid production from alternative microbial sources. Here, we review the recent achievements in the synthesis of phenylethanoids by microorganisms. The work done so far will contribute to the production of diverse phenylethanoids using various microbial systems and facilitate exploration of further diverse biological activities of phenylethanoids. PMID- 29996622 TI - Inhibitory Effects of Curcuma xanthorrhiza Supercritical Extract and Xanthorrhizol on LPS-Induced Inflammation in HGF-1 Cells and RANKL-Induced Osteoclastogenesis in RAW264.7 Cells. AB - Periodontal disease is triggered by the host immune response to pathogens in the microbial biofilm. Worsening of periodontal disease destroys the tooth-supporting tissues and alveolar bone. As oral inflammation can induce systemic diseases in humans, it is important to prevent periodontal disease. In this study, we demonstrated that Curcuma xanthorrhiza supercritical extract (CXS) and its active compound, xanthorrhizol (XAN), exhibit anti-inflammatory effects on lipopolysaccharide (LPS)-treated human gingival fibroblast-1 cells and anti osteoclastic effects on receptor activator of nuclear factor kappa B ligand (RANKL)-treated RAW264.7 cells. LPS-upregulated inflammatory factors, such as nuclear factor kappa B p65 and interleukin-1beta, were prominently reduced by CXS and XAN. In addition, RANKL-induced osteoclastic factors, such as nuclear factor of activated T-cells c1, tartrate-resistant acid phosphatase, and cathepsin K, were decreased in the presence of CXS and XAN. CXS and XAN inhibited the mitogen activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathway. Collectively, these results provide evidence that CXS and XAN suppress LPS induced inflammation and RANKL-induced osteoclastogenesis by suppressing the MAPK/AP-1 pathway. PMID- 29996623 TI - Inactivation of Vibrio parahaemolyticus by Aqueous Ozone. AB - Vibrio parahaemolyticus contamination causes serious foodborne illness and has become a global health problem. As a disinfectant, aqueous ozone can effectively kill a number of bacteria, viruses, parasites, and other microorganisms. In this study, three factors, namely, the aqueous ozone concentration, the exposure time, and the bacterial density, were analyzed by response surface methodology, and the aqueous ozone concentration was the most influential factor in the sterilization ratio. Under low aqueous ozone concentrations (less than 0.125 mg/l), the bacterial cell membranes remained intact, and the ozone was detoxified by intracellular antioxidant enzymes (e.g., superoxide dismutase and catalase). Under high aqueous ozone concentrations (more than 1 mg/l), cell membranes were damaged by the degree of peripheral electronegativity at the cell surface and the concentration of lactate dehydrogenase released into the extracellular space, and the ultrastructures of the cells were confirmed by transmission electron microscopy. Aqueous ozone penetrated the cells through leaking membranes, inactivated the enzymes, inhibited almost all the genes, and degraded the genetic materials of gDNA and total RNA, which eventually led to cell death. PMID- 29996624 TI - Improvement of Glyphosate Resistance through Concurrent Mutations in Three Amino Acids of the Pantoea sp. 5-Enolpyruvylshikimate-3-Phosphate Synthase. AB - Glyphosate inhibits the target enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in the shikimate pathway. A mutant of EPSPS from Pantoea sp. was identified using site-directed mutagenesis (SDM). The mutant significantly improved glyphosate resistance. The mutant had mutations in three amino acids: Gly97 to Ala, Thr 98 to Ile and Pro 102 to Ser. These mutation sites in E.coli have been studied as significant active sites of glyphosate resistance. However, in our research they were found to jointly contribute to the improvement of glyphosate tolerance. In addition, the level of glyphosate tolerance in transgenic Arabidopsis confirmed the potentiality of the mutant in breeding glyphosate-resistant plants. PMID- 29996626 TI - Diagnosis, Treatment and Clinical Features of Cutaneous Leishmaniasis in Saudi Arabia. AB - Cutaneous leishmaniasis (CL) has been one of the most common parasitic diseases in Saudi Arabia. This study exhibits the clinical features, diagnosis, cytokine profile and treatment of CL patients in Al-Taif province. Ninety CL suspects at a tertiary care general hospital were enrolled in one-year study. Patients were interviewed, clinically-examined, and subjected to laboratory tests: skin scraping smear microscopy, OligoC-TesT commercial PCR (Coris BioConcept) and kinetoplast DNA (kDNA) PCR for Leishmania diagnosis. Interferon-gamma (RayBio; Human IFN-gamma) and nitric oxide (NO) levels in patients' sera were evaluated before treatment with sodium stibogluconate (pentostam) with 20-day intramuscular drug regimen. Positive rates of microscopy, commercial PCR and kDNA PCR were 74.4%, 95.5% and 100%, respectively. Patients came to hospital mostly in winter (45.0%). CL was frequently exhibited in Saudi patients (78.8%), male gender (70.7%), age <20 years (50.0%), rural-dwellers (75.5%) and patients with travel history (86.6%). Lesion was mostly single ulcer (93.3%), occurred in the face (67.7%). Upon pentostam treatment, 85.1% of ulcers showed rapid healing signs. Levels of IFN-gamma and NO were significantly higher in the healing than the non healing cases (P<0.001). The kDNA PCR proved more sensitive than microscopy and OligoC-TesT commercial PCR. Our results open perspectives for IFN-gamma use as a biomarker predicting treatment response. PMID- 29996625 TI - An Overview of Fish-borne Nematodiases among Returned Travelers for Recent 25 Years- Unexpected Diseases Sometimes Far Away from the Origin. AB - Along with globalization of traveling and trading, fish-borne nematodiases seems to be increasing in number. However, apart from occasional and sporadic case reports or mini-reviews of particular diseases in particular countries, an overview of fish-borne nematodiasis among travelers have never been performed. In this review, we gathered fishborne nematodiasis among travelers for recent 25 years by an extensive global literature survey using appropriate keywords, e.g. travelers diseases, human infection, anisakiasis, gnathostomiasis, capillariasis, sushi, sashimi, ceviche, Gnathostoma, Pseudoterranova, Anisakis, Capillaria, etc., as well as various combinations of these key words. The Internet search engines PubMed, Medline, Google and Googler Scholar were used as much as possible, and the references of every paper were checked in order to identify useful and reliable publications. The results showed unexpectedly high incidence of gnathostomiasis and low incidence of anisakidosis. The different incidence values of the infection with several fish-borne zoonotic nematode species are discussed, as well as some epidemiological aspects of the infections. The difficulties of differential diagnosis in non-endemic countries are emphasized. It is concluded that travelers must avoid risky behaviors which can lead to infection and that physicians and health authorities must advice travelers on the risks of eating behaviors during travel. PMID- 29996627 TI - Immune Responses Induced by HSP60 DNA Vaccine against Toxoplasma gondii Infection in Kunming Mice. AB - Toxoplasma gondii can infect all the vertebrates including human, and leads to serious toxoplasmosis and considerable veterinary problems. T. gondii heat shock protein 60 (HSP60) is associated with the activation of antigen presenting cells by inducing initial immune responses and releasing inflammatory cytokines. It might be a potential DNA vaccine candidate for this parasite. A pVAX-HSP60 DNA vaccine was constructed and immune responses was evaluated in Kunming mice in this study. Our data indicated that the innate and adaptive immune responses was elicited by successive immunizations with pVAX-HSP60 DNA, showing apparent increases of CD3e+CD4+ and CD3e+CD8a+ T cells in spleen tissues of the HSP60 DNA immunized mice (24.70+/-1.23% and 10.90+/-0.89%, P<0.05) and higher levels of specific antibodies in sera. Furthermore, the survival period of the immunized mice (10.53+/-4.78 day) were significantly prolonged during the acute T. gondii infection. Decrease of brain cysts was significant in the experimental group during the chronic infection (P<0.01). Taken together, TgHSP60 DNA can be as a vaccine candidate to prevent the acute and chronic T. gondii infections. PMID- 29996628 TI - Freshwater Snail Diversity in Mae Lao Agricultural Basin (Chiang Rai, Thailand) with a Focus on Larval Trematode Infections. AB - The aim of this study was to conduct a freshwater snail survey in Mae Lao agricultural basin to assess the diversity with a focus on habitat types and their larval trematode infections. Snails were collected and examined in 14 sites of Mae Lao agricultural basin from August 2016 to October 2017. A total of 1,688 snail individuals were collected and classified into 7 families, 8 genera, and 12 species. Snail diversity and habitat types were higher in rice paddies than irrigation canals and streams. The most abundant species was Bithynia siamensis siamensis, representing 54.6% of the sample. Three species of snails act as first intermediate host were found with cercarial infections. They were Filopaludina sumatrensis polygramma, B. s. siamensis, and Melanoides tuberculata. The cercariae were categorized into 7 types; echinostome, monostome, gymnocephalous, virgulate, parapleurolophocercous, pleurolophocercous and megalurous cercariae. Parapleurolophocercous cercariae constituted the most common type of cercariae recovered, contributing 41.2% of all infections in snails. Echinostome metacercariae infections were found in 6 snail species with 7.6% prevalence. In addition, the metacercaria of avian trematode, Thapariella sp. were found in Filopaludina spp. snails and B. funiculata with a prevalence of 0.5%. This is the first report for Thapariella metacercariae in the snail host, B. funiculata, and also confirmed that viviparid and bithyniid snails act as the second intermediate hosts of this trematode. This work will provide new information on the distribution and intermediate host of trematode in this area. PMID- 29996629 TI - Infections with Zoonotic Trematode Metacercariae in Yellowfin Goby, Acanthogobius flavimanus, from Coastal Areas of Republic of Korea. AB - To investigate the infection status of zoonotic trematode metacercariae in yellowfin goby, Acanthogobius flavimanus, from coastal areas of the Republic of Korea (Korea), we examined total 344 gobies from 21 localities with an artificial digestion method from 2013 to 2017. The metacercariae of Stictodora lari were most frequently detected in 45.3% goby from 7 localities, i.e., Taean-gun (Chungcheongnam-do), Gochang-gun (Jeollabuk-do), Muan-gun, Shinan-gun, Haenam-gun (Jeollanam-do), Hadong-gun and Goseong-gun (Gyeongsangnam-do). Their infection rates were 90.0%, 66.7%, 46.7%, 8.0%, 3.3%, 26.7%, and 86.7% and intensities were 1,090, 6.2, 1.6 1.0, 2.0, 2.0, and 7.2 metacercariae per fish infected respectively. Heterophyopsis continua metacercariae were found in 38.2% goby from 6 localities, i.e., Gochang-gun, Muan-gun, Shinan-gun, Gangjin-gun, Boseong-gun (Jeollanam-do) and Goseong-gun, and their intensities were relatively low, 1-21 metacercariae. Stictodora fuscata metacercariae were detected in 61.3% goby from 4 localities, i.e., Taean-gun, Gochang-gun, Hadong-gun and Goseong-gun. Their infection rates were 90.0%, 53.3%, 5.9%, and 73.3% and intensities were 1,081, 3.1, 3.0, and 10.2 metacercariae per fish infected respectively. Heterophyes nocens metacercariae were found in 55.0% goby from Muan-gun and Shinan-gun. Total 3 metacercariae of Isthmiophora hortensis were detected in 2 (8.0%) gobies from Shinan-gun. Total 15 metacercariae of Centrocestus armatus were detected in 5 gobies (33.3%) from Gyeongpo-ho (ho means lake) in Gangneung-si, Gangwon-do. The present study suggests that yellowfin goby, A. flavimanus, acts as the infection sources of zoonotic intestinal flukes in western and southern coastal areas than in eastern coastal areas of Korea. PMID- 29996630 TI - Opisthorchis felineus and Metorchis bilis Metacercariae in Cyprinid Fish Leuciscus idus in Nura-Sarysu River, Kazakhstan. AB - Aim of the present study was to provide presence of opisthorchiid metacercariae in cyprinid fish Leuciscus idus in Nura-Sarysu river, Kazakhstan. Infection rate of the ides by the metacercariae was 42%. The metacercariae, similar morphologically to those of the liver flukes, were found: elliptical in shape, 0.19-0.25*0.15-0.22 mm, oral and ventral suckers nearly equal size, and excretory bladder O-shape with black content, occupying posterior part of the body. The metacercariae were divided into 2 groups with differences in size and thickness of cyst wall. Adult flukes were recovered from the Syrian hamsters infected with the opisthorch metacercariae and identified with morphological characters to Opisthorchis felineus and Metorchis bilis. DNA sequences of ITS1, ITS2, and cox1 supported the taxonomic assignment. PMID- 29996631 TI - Genetic and Morphologic Identification of Spirometra ranarum in Myanmar. AB - In the present study, we identified a Spirometra species of Myanmar origin (plerocercoid) by molecular analysis using mitochondrial cox1 and nad1 genes, as well as by morphological observations of an adult tapeworm. Spargana specimens were collected from a paddy-field in Taik Kyi Township Tarkwa Village, Yangon, Myanmar in December 2017. A total of 5 spargana were obtained from 20 frogs Hoplobatrachus rugulosus; syn: Rana rugulosa (Wiegmann, 1834) or R. tigrina (Steindachner, 1867). The plerocercoids were used for experimental infection of a dog. After 4 weeks of infection, an adult tapeworm was recovered from the intestine of the dog. Morphologically, the distinct features of Spirometra sp. (Myanmar origin) relative to S. erinaceieuropaei and S. decipiens include a uterine morphology comprising posterior uterine coils that larger than the terminal uterine ball and coiling of the uteri diagonally (swirling) rather than spirally. The cox1 sequences (1,566 bp) of the Myanmar-origin Spirometra species showed 97.9% similarity to a reference sequence of S. decipiens (GenBank no. KJ599679) and 90.5% similarity to a reference sequence of S. erinaceieuropaei (GenBank no. KJ599680). Phylogenetic tree topologies were identical and presented high confidence level of values for the 3 major branches of the 3 Spirometra species in cox1 and nad1 genes. These results indicated that Myanmar-origin Spirometra species coincided with those of S. ranarum and may be considered as a valid species. PMID- 29996632 TI - Molecular Prevalence of Cryptosporidium spp. among Companion Birds Kept in Pet Shops in Japan. AB - Cryptosporidium is the most common protozoan that can infect a wide range of animals, including mammals and birds. Avian Cryptosporidium spp. can cause enteric and respiratory diseases which can be fatal in birds and some species are zoonotic. Companion birds have the potential as reservoir due to their close contact with humans. Pet shops are the major source of companion birds. However, few reports are available regarding Cryptosporidium spp. infection among companion birds kept in pet shops. The present study reports the prevalence and molecular characteristics of Cryptosporidium spp. among companion birds kept in pet shops in Japan. A total of 265 fresh fecal samples were obtained from birds kept in 4 pet shops; these birds belonged to 41 species in 3 bird orders. A nested polymerase chain reaction (PCR) assay targeting the small subunit rRNA gene was employed for the detection of Cryptosporidium spp. A total of 24 samples (9.1%) were positive, and Cryptosporidium spp. were detected from all pet shops. The prevalence of Cryptosporidium spp. in each of the bird orders was 6.5% (10/153) in Psittaciformes, 14.4% (13/90) in Passeriformes, and 4.5% (1/22) in Galliformes. Based on sequence analysis, 13 (54.2%) isolates were classified to C. galli, 8 (33.3%) were avian genotype III, and the remaining 3 (12.5%) were C. baileyi. No infection with zoonotic C. meleagridis and no coinfection with multiple Cryptosporidium spp. and/or genotypes were observed. The zoonotic potential of Cryptosporidium spp. infecting companion birds kept in pet shops in Japan is likely to be low. PMID- 29996633 TI - Serological Detection of Antibodies against Anaplasma spp. in Cattle Reared in the Gyeongsangbuk-do, Korea. AB - Anaplasmosis is a tick-borne, non-contagious, zoonotic disease caused by Anaplasma spp., which include Anaplasma marginale, A. centrale, A. phagocytophilum, A. platys, A. ovis, and A. bovis. Recently, in Korea, the prevalence of Anaplasma spp. has been investigated in some animals, such as dogs, horses, goats, cats, and Korean water deer. In cattle, A. marginale is the most virulent species and regarded as the typical type of species. However, data on the seroprevalence of Anaplasma spp. in cattle in Korea during the last decade is limited. This study was designed to investigate the seroprevalence of bovine anaplasmosis in Korea. From 2010 to 2013, blood samples were collected from 568 cattle. Forty animals (7.0%) tested seropositive for Anaplasma spp. by cELISA. Despite that current bovine anaplasmosis seropositivity rate in the Gyeongsangbuk do is lower than those in tropical countries, anaplasmosis needs to be regarded as a concerning disease. The identification of the specific Anaplasma species infecting cattle in this province requires additional molecular studies. Moreover, further monitoring and control programs for bovine anaplasmosis is required, and the information from this study will be beneficial to develop these programs. PMID- 29996634 TI - Infections of Soil-Transmitted Helminth in Refugees from North Korea. AB - Soil-transmitted helminthiases (STH) are now no longer public health problems in the Republic of Korea (South Korea), but their status are unavailable in the residents of North Korea (NK) despite the expectation of large scale traffic and future reunification of the Korean Peninsula. A total of 20 female refugees from NK who had been admitted to the Division of Gastroenterology, Dankook University Hospital, were subjected in this study. Among them, 15 refugees were examined by the colonoscopy and 10 ones were examined with the stool examination (formalin ether sedimentation). Both diagnostic methods were commonly adopted in 5 patients. Eggs of Trichuris trichiura were detected in 7 out of 10 refugees in the stool examination. In the colonoscopy, T. trichiura worms were found in 6 (40.0%) out of 15 refugees. Total 9 (45.0%) peoples were confirmed to be infected with human whipworms. Additionally, 1 case of clonorchiasis was diagnosed in the stool examination and a worm of Ascaris lumbricoides was discovered from a trichuriasis case. These findings suggested that STH is highly prevalent in NO, in which living conditions are not so good in the aspect of general hygiene and medical care. PMID- 29996635 TI - Differential Diagnosis of Human Sparganosis Using Multiplex PCR. AB - Human sparganosis was diagnosed by morphological and genetic analyses in Korea. The complete mitochondrial genomes of Spirometra erinaceieuropaei and S. decipiens isolated in Korea have been recorded. Present study was performed to provide information to diagnose the etiologic agent of sparganosis by multiplex PCR using mitochondrial genome sequences of S. erinaceieuropaei and S. decipiens. In an effort to examine the differential diagnosis of spirometrid tapeworms, multiplex PCR assays were performed on plerocercoid larvae of S. erinaceieuropaei and S. decipiens. The PCR products obtained using species-specific primers were positively detected in all PCR assays on mixture of S. erinaceieuropaei and S. decipiens DNA. S. erinaceieuropaei-specific bands (239 bp and 401 bp) were obtained from all PCR assays using a mixture of S. erinaceieuropaei-specific primers (Se/Sd-1800F and Se-2018R; Se/Sd-7955F and Se-8356R) and S. erinaceieuropaei template DNA. S. decipiens-specific bands (540 bp and 644 bp) were also detected in all PCR assays containing mixtures of S. decipiens-specific primers (Se/Sd-1800F and Sd-2317R; Se/Sd-7955F and Sd-8567R) and S. decipiens template DNA. Sequence analyses on these species-specific bands revealed 100% sequence identity with homologous regions of the mtDNA sequences of S. erinaceieuropaei and S. decipiens. The multiplex PCR assay was useful for differential diagnosis of human sparganosis by detecting different sizes in species-specific bands. PMID- 29996636 TI - Infections of Intestinal Helminth at Two Species of Field Mice, Apodemus agrarius and A. Peninsulae, in Gangwondo and Chungcheongnam-do, Korea. AB - Rodents are important reservoirs of diseases affecting people and livestock, and are major sources of parasite contamination of agricultural products. We surveyed the infection status of intestinal helminths in 2 species of field mice, Apodemus agrarius and A. peninsulae, captured in the agricultural fields of Gangwon-do and Chungcheongnam-do, Korea. Total 83 mice (57 A. agrarius and 26 A. peninsulae) were collected in 2 surveyed areas, and the intestines of each mouse were opened with scissors, and then intestinal contents were examined with microscope. Total 6 species of intestinal helminth were detected in 61 (73.5%) out of 83 mice examined. Four species of nematode, i.e., Nippostrongylus brasiliensis, Aspiculuris tetraptera, Heterakis spp. and ascarid, were found in 40 (48.2%), 14 (16.9%), 11 (13.3%) and 13 (15.7%) mice respectively. One species of cestode, Hymenolepis diminuta and 1 unidentified egg were also detected in the intestines of 14 (16.9%) and 1 (1.2%) mice, respectively. Conclusively, this study identified 5 helminth species in the gastrointestinal tracts of wild rodents captured in some areas in central and northern Korea, and N. brasiliensis was the most prevalent (dominant) species rather than zoonotic ones. PMID- 29996637 TI - Prevalence of Tick-Borne Pathogens from Ticks Collected from Cattle and Wild Animals in Tanzania in 2012. AB - This study was aimed to disclose the prevalence rate of tick-borne pathogens from ticks collected from cattle and wild animals in Tanzania in 2012. Ticks were collected from slaughtered cattle and dead wild animals from November 5 to December 23, 2012 and identified. PCR for detecting Anaplasmataceae, Piroplamidae, Rickettsiaceae, Borrelia spp., and Coxiella spp. were done. Among those tested, Rickettsiaceae, Piroplasmidae, and Anaplasmataceae, were detected in ticks from the 2 regions. Rickettsiaceae represented the major tick-borne pathogens of the 2 regions. Ticks from animals in Maswa were associated with a higher pathogen detection rate compared to that in ticks from Iringa. In addition, a higher pathogen detection rate was observed in ticks infesting cattle than in ticks infesting wild animals. All examined ticks of the genus Amblyomma were infected with diverse pathogens. Ticks of the genera Rhipicephalus and Hyalomma were infected with 1 or 2 pathogens. Collectively, this study provides important information regarding differences in pathogen status among various regions, hosts, and tick species in Tanzania. Results in this study will affect the programs to prevent tick-borne diseases (TBD) of humans and livestock in Tanzania. PMID- 29996638 TI - Correction of deviated nose. AB - Deviated nose deformities have always been a surgical challenge, and it is essential to achieve both functional and esthetic improvements. Various techniques have evolved over time to correct deviated noses but no one method applies in all cases. Successful correction requires a complete understanding of the various surgical techniques and concepts, including the three-dimensional nasal structure and the time-related changes to surgically-treated noses. PMID- 29996639 TI - Retrospective analysis of 79 patients with orbital floor fracture: outcomes and patient-reported satisfaction. AB - BACKGROUND: The aim of our retrospective study is to evaluate the management of isolated orbital floor fractures considering the clinical, functional and aesthetic results according to the surgical approach and the type of materials used. METHODS: Retrospectively, clinical, radiological, surgical, and ophthalmological data from 79 patients were collected from January 2010 to December 2016. Furthermore, included patients were interrogated on functional and aesthetic satisfaction. RESULTS: The main causes of trauma were physical aggression followed by accidents. The median time between trauma and surgery was 4 days. The most common surgical approaches were the subciliary and the transconjunctival ones. Alloplastic materials were used in 75 patients. In two patients, we used a combination of two grafts. Patients experienced minor immediate complications. On follow-ups, none of our patients suffered from ocular movement restrictions. Patients treated by subciliary approach had higher risk of retractile scaring compared to other surgical approaches. In our study, patients agreed to complete a questionnaire assessing functional and aesthetic outcomes with a high satisfaction score. No association between the implant material used and the results has been assessed. CONCLUSION: This study describes the results of orbital floor reconstructions. Despite a variety of materials used and surgical approaches performed, we believe that the transconjunctival approach is the most suitable option with a high satisfaction score. PMID- 29996641 TI - Delayed formation of sterile abscess after zygomaticomaxillary complex fracture treatment with bioabsorbable plates. AB - We present a patient who showed a sterile abscess after facial bone fixation with bioabsorbable plates and screws. He had zygomaticomaxillary complex and periorbital fracture due to falling down. The displaced bones were treated by open reduction and internal fixation successfully using bioabsorbable plate system. However, at postoperative 11 months, abrupt painless swelling was noted on the previous operation sites, left lateral eyebrow and lower eyelid. By surgical exploration, pus-like discharge and degraded materials were observed and debrided. The pathologic analysis revealed foreign body reaction with sterile abscess. This complication followed by bioabsorbable device implantation on maxillofacial bone surgery has been rarely reported in which we call attention to the maxillofacial plastic surgeons. PMID- 29996640 TI - Correlation between dermal thickness and scar formation in female patients after thyroidectomy. AB - BACKGROUND: Minimizing scarring has long been a challenge in plastic surgery. Factors affecting scar formation are well known, but the effect of some patient specific factors such as dermal thickness remains unverified. Management of factors predictive of scarring can improve postoperative patient satisfaction and scar treatment. METHODS: For 3 years, we used ultrasonography to measure dermal thickness in female patients who had undergone thyroidectomy for cancer at our hospital. We confirmed the influence of dermal thickness on hypertrophic scar formation and the Patient and Observer Scar Assessment Scale scar score 6 months after surgery. RESULTS: There was a positive correlation between dermal thickness and scar score (p<0.05), and dermal thickness appears to be a cause of hypertrophic scar formation (p<0.05). CONCLUSION: Thick dermis was found to cause poor scar formation and hypertrophic scarring. Prediction of factors that can influence scar formation can be used to educate patients before surgery and can help in scar management and improvement in patient satisfaction. PMID- 29996642 TI - Columellar reconstruction: a refinement of technique. AB - The nose is an important landmark of the face and its shape and beauty is of significant concern. The columella is the subunit between the two nostrils that provides support and projection to the nasal tip and has functional role in nostrils, as well as aesthetic. Ethiology for columellar absence or deficiency is diverse, and it is one of the most complex nasal subunits to reconstruct because of its narrow horizontal dimension, its tenuous vascularity and limited availability of adjacent tissue. We present a patient with columellar, membranous septum and upper lip defect, due to oncological resection. The lip reconstruction was designed using advancement of two upper lip edges with the technique of webster perialar/nasocheek advancement. However, the perialar/nasocheek tissue which is usually discarded was used as inferiorly based skin flaps to reconstruct the membranous septum, columellar skin and nasal vestibule lining. Rib cage cartilage graft was used as columellar strut for support. At 1-year followup, the patient has good nasal contour and projection. Scaring of the columella is very subtle. This is a versatile way for successful reconstruction of a columella and large central facial defect in one-stage operation. It is a method which provides very satisfactory aesthetic result with minimum patient morbidity and discomfort. PMID- 29996644 TI - Monoclonal Antibodies for the Detection of a Specific Cyclic DNA Adduct Derived from omega-6 Polyunsaturated Fatty Acids. AB - Lipid peroxidation of polyunsaturated fatty acids (PUFAs) is an endogenous source of alpha,beta-unsaturated aldehydes that react with DNA producing a variety of cyclic adducts. The mutagenic cyclic adducts, specifically those derived from oxidation of omega-6 PUFAs, may contribute to the cancer promoting activities associated with omega-6 PUFAs. ( E)-4-Hydroxy-2-nonenal (HNE) is a unique product of omega-6 PUFAs oxidation. HNE reacts with deoxyguanosine (dG) yielding mutagenic 1, N2-propanodeoxyguanosine adducts (HNE-dG). Earlier studies showed HNE can also be oxidized to its epoxide (EH), and EH can react with deoxyadenosine (dA) forming the well-studied epsilondA and the substituted etheno adducts. Using a liquid chromatography-based tandem mass spectroscopic (LC-MS/MS) method, we previously reported the detection of EH-derived 7-(1',2' dihydroxyheptyl)-1, N6-ethenodeoxyadenosine (DHHepsilondA) as a novel endogenous background adduct in DNA from rodent and human tissues. The formation, repair, and mutagenicity of DHHepsilondA and its biological consequences in cells have not been investigated. To understand the roles of DHHepsilondA in carcinogenesis, it is important to develop an immuno-based assay to detect DHHepsilondA in cells and tissues. In this study we describe the development of monoclonal antibodies specifically against DHHepsilondA and its application to detect DHHepsilondA in human cells. PMID- 29996643 TI - Toxicokinetics of HT-2 Toxin in Rats and Its Metabolic Profile in Livestock and Human Liver Microsomes. AB - The lack of information on HT-2 toxin leads to inaccurate hazard evaluations. In the present study, toxicokinetic studies of HT-2 toxin were investigated following intravenous (iv) and oral administration to rats at dosages of 1.0 mg per kilogram of body weight. After oral administration, HT-2 toxin was not detected in plasma, whereas its hydroxylated metabolite, 3'-OH HT-2 was identified. Following iv administration, HT-2 toxin; its 3'-hydroxylated product; and its glucuronide derivative, 3-GlcA HT-2, were observed in plasma, and the glucuronide conjugate was the predominant metabolite. To explore the missing HT-2 toxin in plasma, metabolic studies of HT-2 toxin in liver microsomes were conducted. Consequently, eight phase I and three phase II metabolites were identified. Hydroxylation, hydrolysis, and glucuronidation were the main metabolic pathways, among which hydroxylation was the predominant one, mediated by 3A4, a cytochrome P450 enzyme. Additionally, significant interspecies metabolic differences were observed. PMID- 29996645 TI - Microneedle-Mediated Transdermal Delivery of Bevacizumab. AB - Bevacizumab is a recombinant humanized monoclonal antibody used clinically as a combination chemotherapeutic. Antibody therapeutics are usually formulated as parenteral injections, owing to their low oral bioavailability. Microneedle technology provides a transdermal alternative for drug-delivery using micron scale needle structures to penetrate directly through the stratum corneum into the dermal interstitium. This study describes the design, formulation, and in vitro characterization of both dissolving and hydrogel-forming microneedle array platforms for transdermal delivery of bevacizumab. Bevacizumab recovery and transdermal permeation studies were conducted and analyzed using bevacizumab specific ELISA. Prototype microneedle-patches were tested in vivo in Sprague Dawley rats with serum, exterior lumbar and axial lymph nodes, spleen, and skin tissue concentrations of bevacizumab reported. This work represents the first example of high dose transdermal delivery of an antibody therapeutic in vivo using dissolving and hydrogel-forming microneedle platforms. Basic pharmacokinetic parameters are described including hydrogel-forming microneedles: Cmax 358.2 +/- 100.4 ng/mL, Tmax 48 h, AUC 44357 +/- 4540, and Css 942 +/- 95 ng/mL, highlighting the potential for these devices to provide sustained delivery of antibody therapeutics to the lymph and systemic circulation. Targeted delivery of chemotherapeutic agents to the lymphatic system by MN technology may provide new treatment options for cancer metastases. PMID- 29996646 TI - Gold with +4 and +6 Oxidation States in AuF4 and AuF6. AB - An important goal in chemistry is to prepare compounds with unusual oxidation states showing exciting properties. For gold (Au), the relativistic expansion of its 5d orbitals makes it form high oxidation state compounds. Thus far, the highest oxidation state of Au known is +5. Here, we propose high pressure as a controllable method for preparing +4 and +6 oxidation states in Au via its reaction with fluorine. First-principles swarm-intelligence structure search identifies two hitherto unknown stoichiometric compounds, AuF4 and AuF6, exhibiting typical molecular crystal character. The high-pressure phase diagram of Au fluorides is rather different from Cu or Ag fluorides, which is indicated by stable chemical compositions and the pressures needed for the synthesis of these compounds. This difference can be associated with the stronger relativistic effects in Au relative to Cu or Ag. Our work represents a significant step forward in a more complete understanding of the oxidation states of Au. PMID- 29996647 TI - Coinduction of a Chiral Microenvironment in Polypyrrole by Overoxidation and Camphorsulfonic Acid for Electrochemical Chirality Sensing. AB - Polypyrrole (PPy) was synthesized by a galvanostatic method using (1 S)-(+)-10 camphorsulfonic acid ((+)-CSA) as the dopant, and the produced PPy was further overoxidized in a solution of (+)-CSA. A chiral microenvironment was successfully formed in the overoxidized PPy (OPPy) as a result of the synergistic effects of overoxidation and (+)-CSA, resulting in a twisted helical architecture of the OPPy chains. The formation of optically active OPPy was confirmed from aspects of its morphology (SEM and AFM) and circular-dichroism (CD) spectra. Finally, an electrochemical chirality sensor was fabricated on the basis of the resultant OPPy, which exhibited excellent biomolecular homochirality in the discrimination of tryptophan (Trp) enantiomers. PMID- 29996648 TI - Principles of Design for Substrate-Supported Molecular Switches Based on Physisorbed and Chemisorbed States. AB - The physisorbed (precursor) and chemisorbed states of a molecule on metal surfaces can be utilized to build a logic switch at the single-molecule level, enabling further microminiaturization of electronic devices beyond the silicon limits. However, a serious drawback of this design is easy lateral diffusion of the molecule in the physisorbed state, which may destroy the normal switch operation. Here, we demonstrate that anchoring engineering can be an effective way to enhance the stability of molecular switches without degrading switching functionality. As exemplified by trans-ADT on Cu(111), we show that the lateral diffusion of such molecular switch can be obstructed by the anchoring of the ending thiophene groups, along with a rotation of the adsorbate during the switching process. More general, our results also suggest that when searching for molecular switches with reversible physisorbed and chemisorbed states with excellent bistability and lateral stability, the focus should be on finding molecules with a moderate HOMO-LUMO energy gap and anchoring atoms with positive charge that can then be deposited on substrates with which they interact moderately. This allows further improvement of the lateral and vertical stability of such a molecular switch by substituting the thiophene groups with selenophene, thus establishing trans-ADS on Cu(111) as a promising switch. PMID- 29996649 TI - Evaluation of Multidrug Resistance of Leukemia Using Surface-Enhanced Raman Scattering Method for Clinical Applications. AB - P-glycoprotein (P-gp) is an important multidrug resistance (MDR) regulator for leukemia to mediate its development and thus can be considered as a powerful reference for the diagnosis of MDR. The detection of P-gp is of vital significance and has attracted considerable concerns. In this study, we proposed a surface-enhanced Raman scattering (SERS) method for the evaluation of P-gp expression levels in leukemia cell lines. Basically, we utilized an aqueous phase sandwich-type immunoassay to analyze the expression of P-gp. First, anti-CD45 decorated magnetic beads (MBs) and P-gp antibody-decorated SERS probes were fabricated. CD45 is a common protein expressed in all leukemia cells. As a result, a sandwich immunocomplex can be formed by the MBs, P-gp-overexpressed leukemia cells, and SERS probes. The expression level of P-gp determines the amount of SERS probes that can be captured. Consequently, the SERS intensity of the immunocomplex can be used to evaluate the expression level of P-gp. In a typical procedure, we measured the P-gp expression of an MDR leukemia cell line (K562/ADM) as well as unprocessed whole-blood samples. The SERS intensity of K562/ADM cells was highly correlated with the extent of MDR or the incubation time of adriamycin (which is an MDR inducing drug). In addition, the SERS intensity of the refractory/relapsing group was about sixfolds of that of the control group ( P < 0.01). These results demonstrated that the proposed method holds excellent sensitivity, specificity, reliability, and application potential in assessing both cultured cells and clinical samples. With these outstanding features, we anticipated that such a SERS-based method could be very helpful for the clinical diagnosis of early-stage MDR in leukemia. PMID- 29996650 TI - Radioiodinated Pentixather for SPECT Imaging of Expression of the Chemokine Receptor CXCR4 in Rat Myocardial-Infarction-Reperfusion Models. AB - The purpose of this study is to develop a specific CXCR4-targeting radioiodinated agent (125I- or 131I-pentixather) for single-photon-emission-computed-tomography (SPECT) imaging of CXCR4 expression in myocardial-infarction-reperfusion (MI/R) rat models. After SPECT-CT imaging with 125I-pentixather at 4, 12, and 36 h and 3 and 7 days after MI/R, the models were validated by ex vivo autoradiography, TTC staining, and immunohistochemistry and in vivo echocardiography and classical 99mTc-MIBI perfusion imaging. The SPECT-CT images showed that the infarcted myocardium (IM) could be visualized with high quality as early as 4 h and reached the maximum at 3 days after MI/R and that CXCR4 upregulation was still visible at 7 days after MI/R. In the biodistribution study, high uptakes in the IM (0.99 +/- 0.13, 1.52 +/- 0.29, 1.75 +/- 0.22, 1.94 +/- 0.27, and 0.61 +/- 0.14% ID/g at 4, 12, and 36 h and 3 and 7 days after MI/R, respectively) were observed that were much higher than that of normal myocardium. The highest uptake was reached at 3 days after MI/R, which agreed well with the SPECT results. In addition, the radioactivity uptakes of the IM in both the biodistribution and SPECT imaging could be blocked effectively by excess amounts of AMD3465, indicating the high specificity of radioiodinated pentixather to CXCR4. On the basis of its promising properties, 125I-pentixather may serve as a powerful CXCR4-expression diagnostic probe for evaluating lesions and monitoring therapy responses in patients with cardiovascular diseases. PMID- 29996651 TI - Theoretical Model of the Protochlorophyllide Oxidoreductase from a Hierarchy of Protocols. AB - The enzyme protochlorophyllide oxidoreductase (LPOR) catalyzes the light-driven reduction of protochlorophyllide (Pchlide), a crucial step in chlorophyll biosynthesis. Molecular understanding of the photocatalytic mechanism of LPOR is essential for harnessing light energy to mediate enzymatic reactions. The absence of X-ray crystal structure has promoted the development of LPOR homology models that lack a catalytically competent active site and could not explain the variously reported spectroscopic evidence, including time-resolved optical spectroscopy data. We have refined previous structural models to account for the catalytic active site and the characteristic experimental spectral features of Pchlide binding, including the 26 cm-1 red shift of the C13(1) carbonyl stretch vibration in the mid-infrared (IR) and the 12 nm red shift of the Q x electronic band. A hierarchy of theoretical methods, including homology modeling, molecular dynamics simulations, hybrid quantum mechanics [(TD-)DFT]/molecular mechanics [AMBER] calculations, and computational vibrational and electronic spectroscopies, have been combined in an iterative protocol to reproduce experimental evidence and to predict ultrafast transient IR spectroscopic fingerprints associated with the catalytic process. The successful application to the LPOR enzyme indicates that the presented hierarchical protocol provides a general workflow to protein structure refinement. PMID- 29996652 TI - Alginate-C18 Conjugate Nanoparticles Loaded in Tripolyphosphate-Cross-Linked Chitosan-Oleic Acid Conjugate-Coated Calcium Alginate Beads as Oral Insulin Carrier. AB - Simple alginate, alginate-stearic acid, and alginate-C18 conjugate nanoparticles and tripolyphosphate-cross-linked chitosan-oleic acid conjugate-coated calcium alginate beads as the vehicle of nanoparticles were designed. Their size, zeta potential, morphology, drug load, drug release, matrix molecular characteristics, mucus penetration, HT-29 cell line cytotoxicity and intracellular trafficking, in vivo blood glucose lowering, and insulin delivery profiles were characterized. Alginate-C18 conjugate nanoparticles were nontoxic. Among all nanoparticle variants, they had reduced size and zeta potential thus enhancing particulate mucus penetration and intracellular trafficking. Their insulin reabsorption tendency was minimized as alginate active COOH/COO- sites were preoccupied with C18. Their loading into coated beads was translated to reduced drug release in simulated gastric phase with nanoparticles being released in the intestinal phase. The combination dosage form increased the blood glucose lowering extent of insulin and blood insulin level compared with nanoparticles or beads alone. Nanoparticles in beads represented a viable approach for oral insulin delivery. PMID- 29996653 TI - Development and Characterization of a Topical Gel Formulation of Adapalene TyroSpheres and Assessment of Its Clinical Efficacy. AB - In this study we aimed to develop a semi-solid formulation of polymeric nanoparticles loaded with adapalene to enhance the efficacy and improve the skin tolerability in acne therapy. An amphiphilic and biocompatible copolymer that self-assembles to nanospheres (known as TyroSpheres) was used to encapsulate adapalene and increase its solubility. A water-soluble viscous agent was applied to prepare a gel formulation of adapalene-loaded TyroSpheres (aapalene TyroSphere). Particle size, morphology, homogeneity, and rheological characteristics of the adapalene-TyroSphere gel formulations were studied. The formulation with the preferred physical and structural properties was further investigated for in vitro skin irritation and in vivo comedolytic activity in a rhino mouse model. Based on the in vitro skin irritation study encapsulation of adapalene in TyroSphere significantly decreased secretion of pro-inflammatory cytokines (IL-1alpha and IL-8), confirming that the TyroSphere formulation of adapalene is less irritant than the commercial gel (Differin). TyroSphere gel formulation of adapalene improved the comedolytic properties of the formulation by significantly reducing the size of open utricles in rhino mice compared to Differin treatment. Using TyroSpheres, we were able to develop an alternative topical formulation of adapalene, which is potentially less irritant and more potent than the commercial product. PMID- 29996655 TI - Influence of Salinity on the Mechanism of Surface Icing: Implication to the Disappearing Freezing Singularity. AB - The effect of salinity on surface icing has been investigated experimentally. Water droplets with a variable salinity are deposited on a cold polished copper substrate. Distinctive two-stage freezing, which can be seen in case of pure water, is not observed in heterogeneous freezing of saltwater droplets. Interestingly, the final freezing stage commences before the initial freezing front completely traverses the saline droplet. A considerable increase in delay for heterogeneous ice nucleation is observed with the increasing salinity. The reduction in the associated degree of metastability due to the depression in the freezing point of the bulk solution and the increase in the nucleation barrier due to the appearance of the solvation shells that are formed around the ions are two possible causes of this nucleation delay. Moreover, the solidification time associated with surface icing increases considerably with the increasing salinity. Because of the insolubility of salt in ice, the salt ions are rejected to the entrapped water in the ice scaffold locally and to the bulk unfrozen water explicitly. This collective implicit and explicit modes of brine rejection contributes to the overall slowdown of freezing of the saline water droplets. From the phase diagram, it can be found that the complete solidification of water within the saline droplet is not possible when the substrate temperature is in between the eutectic temperature and the equilibrium freezing temperature. As a result, the relative magnitude of tip singularity during freezing reduces considerably with the increasing salinity due to the increase in unfrozen water content within the droplet. PMID- 29996654 TI - Determining the Structural and Energetic Basis of Allostery in a De Novo Designed Metalloprotein Assembly. AB - Despite significant progress in protein design, the construction of protein assemblies that display complex functions (e.g., catalysis or allostery) remains a significant challenge. We recently reported the de novo construction of an allosteric supramolecular protein assembly (Zn-C38/C81/C96R14) in which the dissociation and binding of ZnII ions were coupled over a distance of 15 A to the selective hydrolytic breakage and formation of a single disulfide bond. Zn C38/C81/C96R14 was constructed by ZnII-templated assembly of a monomeric protein (R1, a derivative of cytochrome cb562) into a tetramer, followed by progressive incorporation of noncovalent and disulfide bonding interactions into the protein protein interfaces to create a strained quaternary architecture. The interfacial strain thus built allowed mechanical coupling between the binding/dissociation of ZnII and formation/hydrolysis of a single disulfide bond (C38-C38) out of a possible six. While the earlier study provided structural evidence for the two end-states of allosteric coupling, the energetic basis for allosteric coupling and the minimal structural requirements for building this allosteric system were not understood. Toward this end, we have characterized the structures and Zn binding properties of two related protein constructs (C38/C96R1 and C38R1) which also possess C38-C38 disulfide bonds. In addition, we have carried out extensive molecular dynamics simulations of C38/C81/C96R14 to understand the energetic basis for the selective cleavage of the C38-C38 disulfide bond upon ZnII dissociation. Our analyses reveal that the local interfacial environment around the C38-C38 bond is key to its selective cleavage, but this cleavage is only possible within the context of a stable quaternary architecture which enables structural coupling between ZnII coordination and the protein-protein interfaces. PMID- 29996656 TI - Update on Palliative Care for Pediatric Neurology. AB - It has long been recognized that patients with neurological conditions, and particularly pediatric neurology patients, are well suited for palliative care because they frequently have a high symptom burden and variable prognoses. In 1996, the American Academy of neurology formally recognized a need for neurologists to "understand and apply the principles of palliative medicine." Subsequently, some reviews have proposed a simultaneous care model in which palliative care is integrated for all neurology patients from the time of diagnosis. This article will review the current status of palliative care in pediatric neurology and discuss barriers to its integration. PMID- 29996657 TI - Perceived social support, coping, and stigma on the quality of life of people living with HIV in Nepal: a moderated mediation analysis. AB - Perceived social support, coping strategy, and internalized stigma have been linked with the quality of life (QOL) among people living with HIV (PLHIV). However, little is known about how these psychosocial factors interact with each other and affect QOL. This study incorporated a moderated mediation model to investigate whether coping strategy mediates the relationship between perceived social support and QOL, and to examine whether this mediating effect varies with the level of internalized stigma among PLHIV. A cross-sectional study was conducted among 599 PLHIV in Nepal. The multidimensional scale of perceived social support, World Health Organization Quality of Life-BREF, Brief COPE, and AIDS-related stigma scales were used to measure perceived social support, QOL, coping strategy, and internalized stigma, respectively. Data were analyzed using structural equation modeling, and moderated mediation analysis was conducted with multi-group approach. The relationship between perceived social support and QOL was significantly and partially mediated by problem-focused coping strategy. Internalized stigma significantly moderated the mediating effect of coping strategies on the association between perceived social support and QOL. For high internalized stigma group (total stigma score > 2), the effects of perceived social support on QOL were indirect (beta = 1.48; 61.0% of total effects) through the mediating effect of coping strategy, especially problem-focused coping one. For low internalized stigma group (total stigma score <= 2), problem-focused coping strategy did not significantly affect the QOL, and most of the effects of perceived social support were direct (beta = 1.24; 99.2% of total effects). Internalized stigma was found to moderate the mediating effect of problem-focused coping on the relationship between perceived social support and QOL. Enhancing the problem-focused coping and social support may be helpful to improve QOL among PLHIV reporting high stigma. PMID- 29996658 TI - Angiopoietin 2 Levels in the Risk Stratification and Mortality Outcome Prediction of Sepsis-Associated Coagulopathy. AB - It has been well established that angiopoietin 2 (Ang-2), a glycoprotein involved in activation of the endothelium, plays an integral role in the pathophysiology of sepsis and many other inflammatory conditions. However, the role of Ang-2 in sepsis-associated coagulopathy (SAC) specifically has not been defined. The aim of this study was to measure Ang-2 plasma levels in patients with sepsis and suspected disseminated intravascular coagulation (DIC) in order to demonstrate its predictive value in SAC severity determination and 28-day mortality outcome. Plasma samples were collected from 102 patients with sepsis and suspected DIC at intensive care unit (ICU) admission. The Ang-2 plasma levels were quantified using a sandwich enzyme-linked immunosorbent assay method. The International Society on Thrombosis and Haemostasis DIC scoring system was used to compare the accuracy of Ang-2 levels versus clinical illness severity scores in predicting SAC severity. Mean Ang-2 levels in patients with sepsis and DIC were significantly higher in comparison to healthy controls ( P < 0.0001), and median Ang-2 levels showed a downward trend over time ( P = 0.0008). Baseline Ang-2 levels and clinical illness severity scores were higher with increasing severity of disease, and Ang-2 was a better predictor of DIC severity than clinical illness scores. This study demonstrates that Ang-2 levels are significantly upregulated in SAC, and this biomarker can be used to risk stratify patients with sepsis into non-overt DIC and overt DIC. Furthermore, the Ang-2 level at ICU admission in a patient with sepsis and suspected DIC may provide a predictive biomarker for mortality outcome. PMID- 29996659 TI - Family Caregivers' Confidence Caring for Relatives in Hospice Care at Home: An Exploratory Qualitative Study. AB - OBJECTIVES:: Although the experiences of family caregivers have received attention, little research has specifically explored caregivers' confidence. Evidence shows that caregivers of hospice patients do not feel confident or prepared to care for relatives or friends who die at home. AIM:: We aimed to elicit the views, feelings, and experiences of primary caregivers who provide unpaid care to dying family members in the home setting to better understand what contributes to their confidence during end-of-life care. DESIGN:: The exploratory, cross-sectional design involved semistructured, in-depth interviews. A narrative analysis that focused on form and content was chosen to analyze the data. PARTICIPANTS:: Sixteen bereaved caregivers (14 individuals and 1 brother/sister dyad) from the midwestern United States who received support from 1 hospice participated in the study. RESULTS:: Four storylines running longitudinally through the interviews were identified as shaping, giving meaning to, and contextualizing caregivers' confidence: values/relationships, stories of terminal illness, needs, and support. Caregivers' confidence is shaped by the terminal illness of the person for whom they care and caregivers' values and relationships. It is also influenced by their needs and the sources and strength of support they receive. CONCLUSIONS:: This research developed understanding about family provision of end-of-life care at home. Better comprehension of caregivers' experiences can help professional hospice and palliative care staff to understand what aids caregivers to be more confident. PMID- 29996660 TI - Associations Between PFA-Measured Aspirin Resistance, Platelet Count, Renal Function, and Angiotensin Receptor Blockers. AB - Aspirin resistance is used to describe patients who are undergoing aspirin therapy but fail for the inhibition of thromboxane biosynthesis in platelets. Although the true mechanism is unclear, drug-drug interaction remains a possible factor. The study aimed to determine whether there was association between aspirin resistance and the concomitant cardiovascular medication. Using the Platelet Function Analyzer-100 system, aspirin resistance was evaluated in aspirin-treated patients from the outpatient department. The associations between aspirin resistance and their concomitant common cardiovascular medication were analyzed. Aspirin resistance was prevalent in 147 (17.7%) of 831 patients. Concomitant angiotensin receptor blocker (ARB) treatment and low platelet count were associated with aspirin response ( P = .04, .02, respectively). Multivariate logistic regression analysis results showed an association between aspirin response and ARB therapy (adjusted odds ratio [OR] 1.48; 95% confidence interval, CI: 1.08-2.18). And the association was blunted when platelet count was considered (adjusted OR 1.43, 95% CI: 0.92-2.23). In ARB-treated patients, increased creatinine and decreased hematocrit laboratory data increased the risk of aspirin resistance ( P = .02, .04, respectively), and the effect of platelet count on aspirin resistance was diminished by ARB therapy. Concomitant ARB treatment in aspirin-treated patients decreased the risk of aspirin resistance, and the effect was dependent on low platelet count. In ARB-treated patients, increased creatinine and decreased hematocrit data increased the risk of aspirin resistance. In addition, the effect of platelet count on aspirin resistance was diminished by ARB treatment. PMID- 29996661 TI - Extra-Hepatic Islet Transplantation: Validation of the h-Omental Matrix Islet filliNG (hOMING) Technique on a Rodent Model Using an Alginate Carrier. AB - Following the tremendous development of hydrogels for cell therapy, there is now a growing need for surgical techniques to validate in vivo scaffold benefits for islet transplantation. Therefore, we propose a newly designed surgical procedure involving the injection of hydrogel-embedded pancreatic islets in the omentum, which is considered a favorable environment for cell survival and function. Our technique, called h-Omental Matrix Islet filliNG (hOMING) was designed to test the benefits of hydrogel on islet survival and function in vivo. Islets were implanted in the omentum of diabetic rats using the hOMING technique and alginate as an islet carrier. Blood glucose and C-peptide levels were recorded to assess graft function. After 2 months, grafts were explanted and studied using insulin and vessel staining. All rats that underwent hOMING exhibited graft function characterized by a glycemia decrease and a C-peptidemia increase ( P < 0.001 compared with preoperative levels). Furthermore, hOMING appeared to preserve islet morphology and insulin content and allowed the proper revascularization of grafted islets. The results suggest that hOMING is a viable and promising approach to test in vivo the benefits of hydrogel administration for islet transplantation into the omental tissue. PMID- 29996662 TI - Evaluation of a Worksite-Based Small Group Team Challenge to Increase Physical Activity. AB - PURPOSE: To investigate whether participants in a small group team challenge had greater completion rates in an institution-wide step-challenge than other participants. DESIGN: A quasi-experimental, posttest-only design with a comparison group was used to evaluate group differences in completion rates. SETTING: A large university system provided the opportunity to participate in a physical activity challenge. PARTICIPANTS: The study was limited to employees who participated in the physical activity challenge. INTERVENTION: Two institutions offered participants the chance to compete as smaller groups of teams within their institution. These team-challenge participants (N = 414) were compared to participants from the same institutions that did not sign up for a team and tracked their steps individually (N = 1454). MEASURES: Participants who reported 50 000 steps per week for 5 of the 6 weeks were classified as challenge completers. We also evaluated total step count and controlled for several potential covariates including age, gender, and body mass index. ANALYSIS: Logistic regression was used to model the dichotomous outcome of challenge completion. RESULTS: Team-challenge participants were more likely to complete the physical activity challenge than other participants. Team-challenge participants had 1922 more steps per day than individual participants. However, at an institution level, overall completion rates were not higher at institutions that offered a team challenge. PMID- 29996663 TI - Relationship Between CHA2DS2-VASc Score and Right Ventricular Dysfunction in Patients With Acute Pulmonary Thromboembolism. AB - In this study, the association between the right ventricular dysfunction (RVD) and CHA2DS2-VASc (C: congestive heart failure or left ventricular systolic dysfunction, H: hypertension, A: age of >= 75 years, D: diabetes mellitus, S: previous stroke, V: vascular disease, A: age between 65 and 74 years, Sc: female gender) scores was investigated in patients with acute pulmonary thromboembolism (PTE). The patients have been assigned to 3 subgroups as massive, submassive, and nonmassive PTE. The CHA2DS2-VASc scores were calculated for all of the patients, and the scores have been classified into 3 groups as the scores between 0 and 1, the scores of 2, and the scores of 3 and over. The independent predictors of the RVD were investigated by the univariate and multivariate regression analyses. The independent predictors of the RVD were determined to be the CHA2DS2-VASc scores ( P = .034), the systolic pulmonary artery pressure ( P < .001), the presence of acute deep vein thrombosis ( P = .007), high simplified Pulmonary Embolism Severity Index ( P < .001), D-dimer ( P < .006), and the mean platelet volume ( P < .001). The CHA2DS2-VASc scores predicted the RVD with 70% sensitivity and 50% specificity as determined by the receiver operating characteristic analysis. The CHA2DS2-VASc score is an independent predictor of the RVD in patients with acute PTE. PMID- 29996664 TI - Platelet Membrane Gamma-Glutamyl Transferase-Specific Activity and the Clinical Course of Acute Coronary Syndrome. AB - gamma-Glutamyl transferase (GGT) participates in oxidative and inflammatory reactions inside the atheroma plaque and platelets. We evaluated whether platelet membrane gamma-glutamyl transferase (Plt-GGT) activity is a predictor of major adverse cardiac events (MACEs) during 3 months follow-up of patients with acute coronary syndrome (ACS; MACE-3M). We included 105 patients who were hospitalized consecutively with the diagnosis of ACS. Patients with an MACE-3M were older, more likely to have hypertension, hyperlipidemia, family history of coronary artery disease(CAD), thrombolysis in myocardial infarction (TIMI) risk score >4, higher Plt-GGT and serum GGT activities, serum C-reactive protein level, and lower left ventricular ejection fraction (LVEF) when compared to those without MACE-3M (all P values <=.05). By receiver-operator characteristic (ROC) curve analysis, 265 mU/mg for Plt-GGT, 30 U/L for serum GGT, and 45% for LVEF were determined as cutoff values to discriminate MACEs. Platelet GGT activity >265 mU/mg, TIMI risk score >4, and family history of CAD were independent predictors of MACE-3M (all P values <.05). Platelet GGT activity was as an independent predictor for MACEs in patients with ACS during the 3 months follow-up. PMID- 29996665 TI - The Effect of the Relationship of APOE Polymorphisms and Cerebral Vasospasm on Functional Outcomes in Children With Traumatic Brain Injury. AB - BACKGROUND: Pediatric traumatic brain injury (TBI) is a leading cause of death and disability. Polymorphisms in the apolipoprotein E ( APOE) gene have been linked to cerebral vasospasm (CV) and poor outcomes in adults with TBI, yet these associations remain poorly defined in children. OBJECTIVE: We examined the effect of the relationship between APOE polymorphisms and CV on functional outcomes in children with a TBI. METHOD: This prospective, descriptive study examined 60 children (aged 10 days to 15 years) with a TBI. Data included demographic information, genetic sampling for the APOE gene and single-nucleotide polymorphisms (SNPs; rs405509, rs429358, rs7412), and daily transcranial Doppler ultrasounds to evaluate for CV. We examined Glasgow Outcome Scale-Extended Pediatrics (GOS-E Peds) scores at the time of discharge and 4-6 weeks after discharge. RESULTS: More than half (56.7%) of the 60 children ( Mage = 5.9 years) were male. Twenty-six participants (43.3%) experienced an occurrence of CV. There were significant differences in injury mechanism (unadjusted p = .048) and age (unadjusted p = .02) between those with and without CV. Also, the noncoding promoter SNP rs405509 T/T, when considered with injury severity, appeared to modify the relationship of APOE genotype to CV. The relationship between APOE and CV had no significant effect on GOS-E Peds scores. CONCLUSION: Injury severity and the APOE noncoding promoter SNP rs405509 may modify the relationship between APOE and CV in children with TBI. More studies are needed to understand the role of APOE polymorphisms in outcomes in children with TBI. PMID- 29996666 TI - Evaluation of a Computer-Based Decision Aid for Promoting Informed Prostate Cancer Screening Decisions Among African American Men: iDecide. AB - PURPOSE: To evaluate the effects of iDecide on prostate cancer knowledge, informed decision-making self-efficacy, technology use self-efficacy, and intention to engage in informed decision-making among African American men. DESIGN: One-group, pretest/posttest. SETTING: Community settings in South Carolina. PARTICIPANTS: African American men, ages 40 years +, without a prior prostate cancer diagnosis (n = 354). INTERVENTION: iDecide, an embodied conversational agent-led, computer-based prostate cancer screening decision aid. MEASURES: Prostate cancer knowledge, informed decision-making self-efficacy, technology use self-efficacy, and intention to engage in informed decision making. ANALYSIS: Descriptive statistics, paired t tests, general linear modeling, Spearman correlations. RESULTS: On average, participants experienced significant improvements in their prostate cancer knowledge ( P <= .001), informed decision-making self-efficacy ( P <= .001), and technology use self efficacy ( P <= .001), postintervention. Additionally, 67% of participants reported an intention to engage in informed decision-making. CONCLUSION: Given the significant improvements across all measures, this research demonstrates that embodied conversational agent-led decision aids can be used to enhance the capacity for making informed prostate cancer screening decisions among African American men and increase their technology use self-efficacy. One critical limitation of this study is that most men had received prostate cancer screening prior to engaging in our intervention, so the implications of this intervention may be different for men who do not have a history of screening. Additionally, actual engagement in informed decision-making postintervention was not assessed. PMID- 29996667 TI - Epidemiology of migraine in men: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. AB - Objective To assess migraine epidemiology in men by examining gender differences in disease presentation, comorbidities, and prognosis. Patients and methods The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a longitudinal survey of US adults with migraine identified by web questionnaire. Data were stratified by gender, collected between September 2012-November 2013, and included sociodemographics, headache features, Migraine Disability Assessment, Migraine Symptom Severity Score, Allodynia Symptom Checklist, and comorbidities. Discrete time hazard models addressed 1-year likelihood of transition from episodic to chronic migraine headache frequency. Results Of the 16,789 migraine respondents, 4294 were men (25.6%). Compared to women, men were slightly older at onset of their headaches (mean 24.1 vs. 22.3 years) and had fewer headache days/month (4.3 vs. 5.3 days), slightly less severe attacks (Migraine Symptom Severity Score, 21.6 vs. 22.6), reduced frequencies of grade IV Migraine Disability Assessment scores (15.7% vs. 24.1%), allodynia (32.6% vs. 49.7%), chronic migraine (6.5% vs. 9.6%, each p < 0.001), and common comorbidities. Men were less likely to report consulting a doctor for their headaches and receiving a migraine diagnosis if they consulted. Men and women with episodic migraine had similar crude 1-year risk of chronic migraine onset. Controlling for known risk factors (i.e. depression, headache frequency, allodynia), men had greater likelihood of chronic migraine onset at 6, 9, and 12 months (each p < 0.05). Conclusions Findings confirmed gender differences. Men with migraine generally have less severe attacks and disability and are less likely to receive a diagnosis than women with migraine. Prognostic factors may be better understood for women than men. PMID- 29996668 TI - Effects of proprioceptive training on the incidence of ankle sprain in athletes: systematic review and meta-analysis. AB - OBJECTIVE:: To investigate how dynamic neuromuscular control, postural sway, joint position sense, and incidence of ankle sprain are influenced by balance training in athletes compared with the control group in randomized clinical trials. DATA SOURCES:: The search strategy included MEDLINE, Physical Therapy Evidence Database, Cochrane Central Register of Controlled Trials, and Latin American and Caribbean Center on Health Sciences Information. Randomized controlled trials (RCTs) were published by June of 2018. METHODS:: RCTs that evaluate the effectiveness of proprioception in these outcomes: dynamic neuromuscular control, postural sway, joint position, and the incidence of ankle sprains in athletes aged between 18 and 35 years. Two reviewers independently screened the searched records, extracted the data, and assessed risk of bias. The treatment effect sizes were pooled in a meta-analysis using the RevMan 5.2 software. Internal validity was assessed through topics suggested by Cochrane Collaborations. RESULTS:: Of the 12 articles included ( n = 1817), eight were in the meta-analysis ( n = 1722). The balance training reduced the incidence of ankle sprains in 38% compared with the control group ( RR: 0.62; 95% CI: 0.43 0.90). In relation to the dynamic neuromuscular control, the training showed increase in the distance of reach in the anterior (0.62 cm, 95% CI: 0.13-1.11), posterolateral (4.22 cm, 95% CI: 1.76-6.68), and posteromedial (3.65 cm, 95% CI: 1.03-6.26) through the Star Excursion Balance test. Furthermore, training seems to improve postural sway and joint position sense. CONCLUSION:: Balance training reduces the incidence of ankle sprains and increases dynamic neuromuscular control, postural sway, and the joint position sense in athletes. PMID- 29996669 TI - Signet Ring Cell Carcinoma of the Ampulla of Vater With Focal Neuroendocrine Differentiation of the Amphicrine Type: Report of a Case With Long-Term Survival. AB - Carcinoma of the ampulla of Vater is an uncommon neoplasm and represents 0.5% of all gastrointestinal malignancies, being less common than carcinoma of the pancreas and bile ducts. The most common ampullary tumor is the adenocarcinoma with tubular growth pattern. Signet ring cell carcinoma is extremely rare. In this article, we report a case of signet ring cell carcinoma of the ampulla of Vater showing focal neuroendocrine amphicrine differentiation and intestinal phenotype, which occurred in a 49-year-old male who is still alive 7 years after surgery, without evidence of recurrence. This long-term survival might be attributed not only to the early stage of the disease but also to the neuroendocrine differentiation and the absence of genetic alterations. PMID- 29996670 TI - Wheelchair skills training for occupational therapy students: comparison of university-course versus "boot-camp" approaches. AB - OBJECTIVE: To test the hypothesis that occupational therapy students who receive wheelchair skills training education using a distributed-practice university course approach versus a condensed-practice boot-camp approach results in greater improvements post-intervention in relevant outcomes. DESIGN: A quasi experimental, nonequivalent control group design. SETTING: A university occupational therapy program. PARTICIPANTS: Occupational therapy students (experimental group) and recent occupational therapy graduates (control group) (N = 58). INTERVENTIONS: A 15-week, 45-hour wheelchair provision course in which a total of 24 hours were dedicated to wheelchair skills testing and training education (experimental group) versus an 8-hour wheelchair skills training boot camp (control group). MAIN OUTCOME MEASURES: Assessments were conducted pre- and post-intervention using the Wheelchair Skills Test Questionnaire (WST-Q), Wheelchair Use Confidence Scale for Manual Wheelchair Users (WheelCon) and Self Efficacy on Assessing, Training and Spotting wheelchair skills (SEATS). RESULTS: Compared to baseline, the WST-Q, WheelCon and SEATS scores improved significantly for both groups (p < .001). There were no significant differences in change scores (post-intervention - baseline values) between the groups for WST-Q, WheelCon or SEATS scores, however, the experimental group demonstrated a trend (p < .051) of higher scores for all outcome measures. CONCLUSIONS: Occupational therapy students who received wheelchair skills training using either a distributed-practice university-course or condensed-practice boot-camp approach demonstrated significant post-training improvements in their WST-Q, WheelCon and SEATS scores, but no significant differences were found between groups. Implications for Rehabilitation Both a distributed-practice university-course approach and a condensed-practice bootcamp approach for training wheelchair skills to occupational therapy students results in large post-intervention improvements in wheelchair skill, wheelchair confidence and self-efficacy to test, train, spot and document wheelchair skills. The pre-education (optional course) wheelchair skill, wheelchair confidence and self-efficacy to test, train, spot and document wheelchair skills scores found in this cohort of occupational therapy students confirms the need to include this wheelchair content in mandatory occupational therapy curricula. PMID- 29996671 TI - Complex interaction between mutant HNRNPA1 and gE of varicella zoster virus in pathogenesis of multiple sclerosis. AB - Multiple sclerosis (MS) is a demyelinating disease of the central nervous system causing axonal injury, neuronal loss, and atrophy of the central nervous system leading to permanent neurological and clinical disability. Presence of mutations in M9 domain of HNRNPA1 and detection of autoantibodies against this domain in HNRNPA1 qualifies it as a strong candidate for causing MS. These two aspects indicate the presence of a facilitator in associating them. Varicella zoster virus (VZV), known to cause chicken pox infection in humans, is a significant contender in sensitizing the infected people towards MS. Reactivation of latent herpes viruses by other infectious agents and cross-recognition of common viral antigens with antigens found in the myelin sheath induces molecular mimicry or superantigens. Mutations in HNRNPA1 cause mislocalization to the cytoplasm, and co-localize with stress granules (SG) causing cellular apoptosis, this creates the first step toward MS pathogenesis. Mutant HNRNPA1 accumulates in SG allowing the cells to display peptides of HNRNPA1 on surfaces of major histocompatibility complex (MHC) I triggering a cascade of immune reactions. Since glycoprotein E (gE) of VZV shares >62% amino acids sequence similarity with Prion-like domain (PrLD) of HNRNPA1, signifying the reason behind autoantibodies against M9 and PrLD of HNRNPA1. This review attempts to delineate the interactions of VZV, gE of VZV, with M9 domain and PrLD of HNRNPA1 in a step-by-step process. This supports the tripartite model that an environmental trigger in genetically susceptible individuals causes an autoimmune response to self-CNS antigens that result in the pathology observed in the brain and spinal cord of MS patients. PMID- 29996672 TI - "I have to be both mother and father": The impact of Young-onset dementia on the partner's parenting and the children's experience. AB - There has been increasing research on the experience and needs of caregivers for persons with YOD, who are mainly spouses. Yet one little-explored area is their evolving parental role. As the person with YOD becomes less able to parent, the partner must take on more and more parental responsibilities. This occurs in much changed familial context, with children often asked to assume caretaking roles and experiencing strong feelings such as grief, anger, and fear. How do the parents without YOD understand and negotiate their ever-changing parenting role, and how do their children experience it? We conducted in-depth, semi-structured interviews with four parents without YOD (coincidentally all mothers) and eight children ages 16-20 (3-18 when parent was diagnosed) regarding the changing nature of the parental-child relationship. These data were analyzed using thematic narrative analysis, in which respondents' material is closely read as it is gathered and analyzed for patterns. Three primary themes emerged. First, there are significant changes in family structures and role. Mothers increasingly assume all parental responsability. Children assume roles of carers and earners, and at times reluctant decision-making partners. Such responsabilities can feel overwhelming at times. However, the cildren discribed not wanting to burden mother with their feelings and experience, a second prominent theme. Finally, such muting of their experience likely contributes to mothers feeling they are managing the YOD so as to minimize the impact on their children, creating divergent experiences of the YOD on family life. Facilitating family members' articulation of what feel like "inadmissible" feelings, improving familial communication, and developing a range of support and resources are all important areas for intervention. PMID- 29996674 TI - Localized and targeted delivery of NSAIDs for treatment of inflammation: A review. AB - Inflammatory processes are increasingly being identified at the core of many different disease states (e.g. heart disease, cancer, diabetes). As such, anti inflammatory strategies available through drug delivery have undergone renewed interest. Due to the systemic side effects of steroidal drugs, non-steroidal anti inflammatory drugs are often preferred for long-term treatment of inflammation in a variety of applications. While non-steroidal anti-inflammatory drugs are generally safe, there are some serious side effects that can be associated with their usage, particularly when given systemically or orally. Due to the high number of patients taking non-steroidal anti-inflammatory drugs, the reduction or elimination of these side effects, such as is possible through local drug delivery, could have a very powerful effect on patient quality of life. This review comments on a sampling of existing methods for localized or targeted delivery of non-steroidal anti-inflammatory drugs, with the goal of helping future research groups to focus on bettering methods shown to be effective and filling the gaps of knowledge in this field. Additionally, commentary is made on the field as a whole, and the standardization issues that arise from its expansiveness and diversity. Impact statement This work provides an overview of research currently being done exploring potential drug delivery device strategies for NSAIDs as an alternative to systemic delivery. Commentary on this field is made in an attempt to aid future experimental design, enabling researchers to determine the drugs and delivery vehicles which are most advantageous for them to pursue, as well as suggestions to standardize the reporting of such future research. PMID- 29996673 TI - True hypopharyngeal carcinosarcoma: a case report and literature review. AB - Objective Carcinosarcoma consists of carcinomatous and sarcomatous tissues and is an aggressive malignant tumor. It is rarely reported in the hypopharynx. Methods A 72-year-old man presented with dysphagia and dyspnea. Laryngoscopy, computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography/CT (18F FDG PET/CT) showed a neoplasm on the left posterior hypopharyngeal wall. The patient underwent bilateral neck dissection and excision of the hypopharyngeal cancer followed by postoperative radiation therapy. Results Immunohistochemistry revealed carcinomatous cells with membrane positivity for cytokeratin, glucose transporter-1 (GLUT-1), phosphoinositide-3 kinase (PI3K), hypoxia-inducible factor-1alpha (HIF-1alpha), and hexokinase-II as well as sarcomatous cells with membrane positivity for smooth muscle actin, GLUT-1, HIF-1alpha, and PI3K. Histopathology and immunohistochemistry revealed a true carcinosarcoma of the hypopharynx (pT3N0M0, Stage III). Conclusions Thorough immunohistochemistry is required for a correct diagnosis of hypopharyngeal carcinosarcoma. 18F-FDG PET/CT may help to distinguish hypopharyngeal carcinosarcoma from benign tumors. PMID- 29996675 TI - Acute allograft rejection in liver transplant recipients: Incidence, risk factors, treatment success, and impact on graft failure. AB - Objective This study was performed to identify risk factors for acute cellular rejection after liver transplantation (LT). Methods Consecutive LT recipients who underwent surgery in our institution from 2002 to 2015 were retrospectively evaluated. Results In total, 176 patients were eligible for statistical analysis. During a mean observation period of 61.1 +/- 36.3 months, 43 episodes of acute rejection were evident. Of these, 34 (79.0%) were responsive to methylprednisolone, 3 (7.0%) were treated by adjusting the dosage of immunosuppressive agents, and 6 (14.0%) were methylprednisolone-resistant and treated using anti-thymocyte globulin. Biliary complications (odds ratio [OR] = 4.89, 95% confidence interval [CI] = 2.00-11.98); donor-negative, recipient positive CMV mismatch (OR = 9.88, 95% CI = 1.18-82.36); sex mismatch (OR = 3.16, 95% CI = 1.31-8.10); and sex mismatch with a female donor (OR = 3.00, 95% CI = 1.10-7.58) were identified as significant risk factors for acute graft rejection after LT. Conclusion In patients who develop acute cellular rejection after LT, biliary complications should be evaluated as a potential cause. Most acute rejections after LT respond to bolus corticosteroid therapy. PMID- 29996677 TI - Molecular Mechanisms Underlying Microbial Disease Control in Intercropping. AB - Many reports indicate that intercropping, which usually consists of growing two species next to each other, reduces the incidence of microbial diseases. Besides mechanisms operating at the field level, like inoculum dilution, there is recent evidence that plant-centered mechanisms with identified plant molecules and pathways are also involved. First, plants may trigger the induction of resistance in neighboring plants by the well-known mechanism of induced resistance. Second, molecules produced by one plant, either above- or belowground, can directly inhibit pathogens or indirectly trigger resistance through the induction of the plant immune system in neighboring plants. Third, competition for resources such as light or nutrients may indirectly modify the expression of the plant immune system. The conceptual frameworks of nonkin/stranger recognition and competition may be useful to further investigate the molecular mechanisms underlying crop protection in interspecific plant mixtures. PMID- 29996676 TI - Consumption of licit and illicit substances in Portuguese young people: a population-based cross-sectional study. AB - Background The consumption of addictive substances is common in adolescence and raises concerns about future addiction. We investigated addictive substance consumption among young people to inform the design of drug intervention programmes. Methods Participants were a population-based sample of 14- to 24-year olds from Paredes, northern Portugal. A self-report questionnaire measured social and health variables, including tobacco, alcohol and illicit drug consumption. Results Data were analysed for 731 valid responses. Participants who had drunk alcohol did so first at 14.7 years (mean); 15.3% (95% confidence intervals [CI]: 12.9-18.1) drank alcohol regularly (more than 1/week, adjusted for age and sex) (95% CI: 12.9-18.1). Participants who had smoked tobacco did so first at 14.8 years (mean); 16.6% (95% CI: 14.0-19.5) were regular smokers. Illicit drug consumption was reported by 16.7% of participants (95% CI: 14.2-19.6) and 10.4% consumed drugs regularly. Conclusion We found a high prevalence of addictive substance consumption, particularly alcohol. As cultural attitudes likely influence alcohol consumption, a multigenerational approach is needed to address adolescent consumption. Participants' main sources of drug information were family members. Strategies are needed to promote drug literacy in parents and other relatives to change adolescents' culturally acquired habits of addictive substance consumption. PMID- 29996678 TI - HIPM Is a Susceptibility Gene of Malus spp.: Reduced Expression Reduces Susceptibility to Erwinia amylovora. AB - Fire blight, a devastating disease caused by the bacterium Erwinia amylovora, is a major threat to apple crop production. To improve our understanding of the fire blight disease and to identify potential strategies to control the pathogen, we studied the apple protein HIPM (for HrpN-interacting protein from Malus spp.), which has previously been identified as interacting with the E. amylovora effector protein HrpN. Transgenic apple plants were generated with reduced HIPM expression, using an RNA interference construct, and were subsequently analyzed for susceptibility to E. amylovora infection. Lines exhibiting a greater than 50% silencing of HIPM expression showed a significant decrease in susceptibility to E. amylovora infection. Indeed, a correlation between HIPM expression and E. amylovora infection was identified, demonstrating the crucial role of HIPM during fire blight disease progression. Furthermore, an apple oxygen-evolving enhancer like protein (MdOEE) was identified via a yeast two-hybrid screen to interact with HIPM. This result was confirmed with bimolecular fluorescence complementation assays and leads to new hypotheses concerning the response mechanism of the plant to E. amylovora as well as the mechanism of infection of the bacterium. These results suggest that MdOEE and, particularly, HIPM are promising targets for further investigations toward the genetic improvement of apple. PMID- 29996679 TI - Posttraumatic stress severity is associated with coping motives for alcohol use among in-patient and community recruited adolescents. AB - BACKGROUND AND OBJECTIVES: A growing body of work suggests individuals with more severe post-traumatic stress symptoms (PTSS) are at higher risk for developing problematic alcohol use outcomes. Extending work from the adult literature, the present study was the first to examine the extent to which PTSS is related to drinking motives for alcohol use in both clinical and non-clinical samples of adolescents. DESIGN: Hierarchical regression analyses were used to predict coping motives for alcohol use from PTSS, above and beyond demographic variables, alcohol use frequency, and other alcohol use motives. METHODS: Trauma-exposed adolescents before entering treatment (Sample 1 n = 41) and recruited from the local community (Sample 2 n = 55) self-reported on PTSS and alcohol use motives. RESULTS: PTSS positively predicted coping motives for alcohol use after controlling for age, gender, and alcohol use frequency. CONCLUSIONS: The current study highlights the need to consider both PTSS severity, as well as underlying cognitive mechanisms (e.g., motives), to better understand the etiology of problematic alcohol use among trauma-exposed youth. Future work focused on clarifying the trajectory of alcohol use motives and problems as a function of PTSS is needed. PMID- 29996680 TI - Tobacco smoking and the risk of atrial fibrillation: A systematic review and meta analysis of prospective studies. AB - Background Epidemiological studies on smoking and atrial fibrillation have been inconsistent, with some studies showing a positive association while others have found no association. It is also unclear whether there is a dose-response relationship between the number of cigarettes smoked or pack-years and the risk of atrial fibrillation. We conducted a systematic review and meta-analysis to clarify the association. Design Systematic review and meta-analysis. Methods We searched the PubMed and Embase databases for studies of smoking and atrial fibrillation up to 20 July 2017. Prospective studies and nested case-control studies within cohort studies reporting adjusted relative risk estimates and 95% confidence intervals (CIs) of atrial fibrillation associated with smoking were included. Summary relative risks (95% CIs) were estimated using a random effects model. Results Twenty nine prospective studies (22 publications) were included. The summary relative risk was 1.32 (95% CI 1.12-1.56, I2 = 84%, n = 11 studies) for current smokers, 1.09 (95% CI 1.00-1.18, I2 = 33%, n = 9) for former smokers and 1.21 (95% CI 1.12-1.31, I2 = 80%, n = 14) for ever smokers compared to never smokers. Comparing current versus non-current smokers the summary relative risk was 1.33 (95% CI 1.14-1.56, I2 = 78%, n = 10). The summary relative risk was 1.14 (95% CI 1.10-1.20, I2 = 0%, n = 3) per 10 cigarettes per day and 1.16 (95% CI 1.09-1.25, I2 = 49%, n = 2) per 10 pack-years and there was no evidence of a non linear association for cigarettes per day, Pnon-linearity = 0.17. Conclusions The current meta-analysis suggests that smoking is associated with an increased risk of atrial fibrillation in a dose-dependent matter, but the association is weaker among former smokers compared to current smokers. PMID- 29996681 TI - The impact of fetal umbilical artery Doppler pulsatility index on childhood respiratory function and atopy: a prospective case-control study. AB - OBJECTIVE: To determine if an elevated fetal umbilical artery Doppler pulsatility index is associated with abnormal respiratory function and atopy in children aged 12 years. METHODS: This prospective case-control study compared children that had an elevated fetal umbilical artery Doppler pulsatility index (>90th centile) to those with a normal pulsatility index (<90th centile). All subjects were delivered at full-term and with appropriate growth for gestational age. Outcome measures included; (i) presence of asthma and/or atopy; (ii) spirometry measurements and (iii) serum C-reactive protein and leptin. Multiple regression was used to account for parental smoking, childhood age, gender and socioeconomic status. RESULTS: 174 children with an average age of 12.1 (+/-0.6 SD), 48% of who were male were included in the analysis. Of the 174, 99 (57%) were in the normal umbilical artery Doppler pulsatility index group and 75 (43%) elevated umbilical artery Doppler pulsatility index groups. The overall proportion of subjects with asthma was 28% (48/174) and atopy 56% (98/174). No association was found between elevated fetal umbilical artery Doppler pulsatility index and asthma (p = .47) or atopy (p = .75) at age 12 years. Similarly there was no association between FEV1(%) (p = .96), forced vital capacity (FVC)(%) (p = .98), elevated serum C reactive protein (p = .69) or leptin (p = .20) and an elevated fetal umbilical artery Doppler pulsatility index. CONCLUSIONS: An elevated umbilical artery Doppler at 28-weeks gestation in the absence of prematurity or fetal growth restriction is not associated with altered respiratory function or the presence of atopy in children aged 12 years. These findings support the theory that such disease has a multifactorial pathophysiology. PMID- 29996682 TI - Administration of a GnRH agonist during the luteal phase frozen-thawed embryo transfer cycles: a meta-analysis. AB - At present, the precise role of GnRH agonists during the luteal phase remains uncertain. In the present study, a meta-analysis was used to evaluate the effect of administering a GnRH agonist to during the luteal phase in patients undergoing FET cycles. A literature review was carried out by searching the current content of MEDLINE, Embase, the Cochrane Controlled Trials Register and Ovid. We particularly focused upon implantation rate, CPR per transfer, and ongoing pregnancy rate. All of the trials analyzed involved a GnRH agonist administered during the luteal phase. Six trials involving 1137 women were included in our meta-analysis. All of the cycles analyzed exhibited significantly higher implantation rates, clinical pregnancy rates, and ongoing pregnancy rates in the group of patients administered with a GnRH agonist during the luteal phase compared with the control group that did not receive a GnRH agonist during the luteal phase. Our data, therefore, demonstrate that the administration of a GnRH agonist during the luteal phase can significantly increase clinical pregnancy and ongoing pregnancy rates in FET cycles. The implantation rates, clinical pregnancy rates, and ongoing pregnancy rates can significantly increase in the group of patients administered with a GnRH agonist in natural cycle FET. PMID- 29996683 TI - Challenges with multi-objective QSAR in drug discovery. AB - INTRODUCTION: The complexity in the drug discovery pipeline, in combination with the exponential growth of experimental and computational data, the technological achievements, and the access to large data sets, has led to a continuous evolution and transformation of quantitative structure-activity relationships (QSAR) to compete with the challenges of multi-objective drug discovery. Areas covered: After a short overview of the multiple objectives involved in drug discovery, this review focuses on definition of the drug-like space and the construction of local and/or global models, platforms and workflows for step-by step single-objective optimization (SOO) of the different and often conflicting processes. Multi-targeted drug design is a particular case of multi-objective QSAR integrated into the new era of polypharmacology. Multi-objective optimization (MOO), based on desirability functions or Pareto surfaces and its application in QSAR, as an alternative optimization philosophy, is also discussed. Expert opinion: Access to large databases as well as to software services by means of cloud technology facilitates research for more efficient and safer drugs. QSAR models implemented in web platforms and workflows provide sequential SOO for multiple biological and toxicity end points, while MOO, still restricted to a limited number of objectives, is helpful for multi-target or selectivity design, as well as for model prioritization. PMID- 29996684 TI - Two pairs of phenylpropanoid enantiomers from the leaves of Eucommia ulmoides. AB - Two pairs of phenylpropanoid enantiomers, (+)-(7S,8S)-alatusol D (1a), (-) (7R,8R)-alatusol D (1b), (-)-(7S,8R)-alatusol D (2a) and (+)-(7R,8S)-alatusol D (2b) were isolated from the leaves of Eucommia ulmoides Oliver. Among them, 1a and 2b were firstly obtained by chiral enantiomeric resolution. Their structures were elucidated based on extensive spectroscopic analysis and the induced CD (ICD) spectrum caused by adding Mo2(AcO)4 in DMSO. All compounds were tested on Hep G2 tumor cell lines. However, none of the compounds showed potential cytotoxic activity against Hep G2 in vitro. PMID- 29996685 TI - The expression of cytokines IFN-gamma, IL-4, IL-17A, and TGF-beta1 in peripheral blood and follicular fluid of patients testing positive for anti-thyroid autoantibodies and its influence on in vitro fertilization and embryo transfer pregnancy outcomes. AB - The aim of this work was to study the expression of the cytokines IFN-gamma, IL 4, IL-17 A, and TGF-beta1 in peripheral blood and follicular fluid (FF) of patients positive for antithyroid autoantibodies (ATA+) with normal thyroid gland function and the influence of these autoantibodies on in vitro fertilization and embryo transfer (IVF-ET) pregnancy outcomes. Nineteen patients were in the ATA+ group, and 27 patients tested negative for anti-thyroid autoantibody (ATA-). Blood samples were drawn from the two groups of patients on the oocyte retrieval day and the 5th and 14th days of transplantation; in addition, FF was extracted on the oocyte retrieval day from both groups of patients and tested through enzyme-linked immunosorbent assay (ELISA) for IFN-gamma, IL-4, IL-17 A, and TGF beta1. For the ATA+ group, the concentration of IFN-gamma increased whereas the concentration of TGF-beta1 decreased in peripheral blood on the oocyte retrieval day (p < .05); the concentration of IL-4 decreased in peripheral blood on the 5th and 14th days of transplantation for the ATA+ group (p < .05); further, the concentration of IL-17 A increased whereas that of TGF-beta1 decreased in FF (p < .05). The ratio of IL-17 A/TGF-beta1 in the ATA+ group significantly increased in FF and peripheral blood on the oocyte retrieval day and the 14th day of transplantation (p < .05). The ratio of IL-17 A/TGF-beta1 in FF of the pregnant patients was significantly lower than in the non-pregnant patients (p < .05). The findings suggested that the ratio between pro-inflammatory and anti-inflammatory cytokines was adversely affected; therefore, adverse pregnancy outcomes of patients with ATA+ undergoing IVF-ET treatment may be attributed to immunological mechanisms. PMID- 29996686 TI - Anti-inflammatory diterpenes from the fruits of Vitex trifolia L. var. simplicifolia Cham. AB - Two new labdane-type diterpenes, named viterotulin C (1) and vitexilactone D (2), together with five known diterpenes (3-7), were isolated from the fruits of Vitex trifolia L. var. simplicifolia Cham. Their structures were elucidated by detailed analysis of spectroscopic data. All the compounds were evaluated for their inhibitory effects on nuclear factor-kappa B (NF-kappaB) pathway in HEK 293 cell line. These compounds presented inhibition on TNF-alpha-induced NF-kappaB activation, with inhibition rates ranging from 42.52 +/- 10.69% to 68.86 +/- 10.76% at the concentration of 50 MUM. PMID- 29996688 TI - Fetus delivery time in extraperitoneal versus transperitoneal cesarean section: a randomized trial. AB - OBJECTIVE: We compared the extraperitoneal cesarean section to transperitoneal cesarean on fetal delivery time. MATERIAL AND METHODS: This randomized study included 210 pregnant women undergoing cesarean section for elective reasons, repeat cesarean (< four), or dystocia. Patients who required an urgent cesarean section, who were at high risk for obstetric or maternal bleeding, who had a uterine or adnexal mass, or who requested tubal ligation were excluded from the study. The primary outcome of the study was the skin incision-to-delivery time. The sample size was set to detect of 1-minute difference in fetal delivery time between groups (two-tailed hypothesis, alpha = 0.05, beta = 0.10). Secondary outcome measures were total operation time, intraoperative nausea, gag reflex, vomiting, pain and anxiety for those receiving regional anesthesia, postoperative pain, change in hemoglobin, postoperative analgesic requirements, nausea, vomiting and shoulder pain, urogenital distress, time until gas passage, and neonatal outcome. RESULTS: No significant difference occurred between the two groups for skin incision-to- delivery time (extraperitoneal cesarean 3.9 minutes [2.1-7.3] versus transperitoneal cesarean 4.2 minutes [1.9-8.2], p = .065). Significant differences regarding intraoperative pain, total operation time, postoperative pain at the surgical site and shoulder pain, analgesic requirements, time until gas passage, and oral tolerability favored the extraperitoneal group. No significant differences between groups occurred regarding other seconder outcome parameters. CONCLUSIONS: There is no clinically significant difference between extraperitoneal cesarean section and transperitoneal cesarean on fetal delivery time. Extraperitoneal cesarean reduces postoperative pain, analgesic requirements, and improves oral tolerability. PMID- 29996687 TI - Porous silicon based intravitreal platform for dual-drug loading and controlled release towards synergistic therapy. AB - The number of blind and low vision persons in the US is projected to increase to 5.68 million by 2020. The eye diseases causing loss of vision are life-long, chronic, and often need protracted presence of therapeutics at the disease site to keep the disease in remission. In addition, multiple pathologies participate in the disease process and a single therapy seems insufficient to bring the disease under control and prevent vision loss. This study demonstrates the use of porous silicon (pSi) particles sequentially loaded with daunorubicin (DNR) and dexamethasone (DEX) to create a synergistic intravitreally injectable dual-drug delivery system. DEX targets chronic inflammation while DNR inhibits excessive cell proliferation as well as suppresses hypoxia-inducible factor 1 to reduce scarring. This pSi-based delivery system releases therapeutic concentrations of DNR for 100 days and DEX for over 165 days after a single dose. This intravitreal dual-drug delivery system is also well tolerated after injection into the rabbit eye model, attested by ocular biomicroscopy, ocular tonometry, electroretinography, and histology. This novel dual-drug delivery system opens an attractive modality for combination therapy to manage refractory chorioretinal diseases and further preclinical studies are warranted to evaluate its efficacy. PMID- 29996689 TI - Theoretical Mediators of RealConsent: A Web-Based Sexual Violence Prevention and Bystander Education Program. AB - This study examined the process by which a web-based sexual violence (SV) prevention program (i.e., RealConsent) prevents SV perpetration and increases bystander behaviors. Data from 743 college men who participated in a randomized controlled trial were analyzed. Simple and multiple-mediation models were estimated, using several theoretical constructs to assess the mechanisms through which RealConsent produced significant effects on SV perpetration and prosocial bystander or intervening behaviors. The results indicated that knowledge of effective consent for sex, hostility toward women, date rape attitudes, and hyper gender male ideology significantly mediated the effects of RealConsent on SV perpetration in the multiple-mediator model. Furthermore, intentions to intervene significantly mediated the effects of RealConsent on prosocial bystander behaviors in the multiple-mediator model. The results show that the RealConsent program works to prevent SV perpetration and prosocial bystander behaviors via several theoretically proposed mediators central to the development and content of the program. The results also provide strong evidence that SV and bystander education for college men may benefit from including an explicit focus on decreasing negative norms related to women (e.g., hostility, date rape attitudes, hyper-gender ideology) and through increasing college men's knowledge of consent and intentions to intervene. PMID- 29996690 TI - Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis. AB - OBJECTIVES: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach. RESULTS: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3. CONCLUSION: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis. PMID- 29996691 TI - Automated speech analysis tools for children's speech production: A systematic literature review. AB - PURPOSE: A systematic search and review of published studies was conducted on the use of automated speech analysis (ASA) tools for analysing and modifying speech of typically-developing children learning a foreign language and children with speech sound disorders to determine (i) types, attributes, and purposes of ASA tools being used; (ii) accuracy against human judgment; and (iii) performance as therapeutic tools. METHOD: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied. Across nine databases, 32 articles published between January 2007 and December 2016 met inclusion criteria: (i) focussed on children's speech; (ii) tools used for speech analysis or modification; and (iii) reporting quantitative data on accuracy. RESULT: Eighteen ASA tools were identified. These met the clinical threshold of 80% agreement with human judgment when used as predictors of intelligibility, impairment severity, or error category. Tool accuracy was typically <80% accuracy for words containing mispronunciations. ASA tools have been used effectively to improve to children's foreign language pronunciation. CONCLUSION: ASA tools show promise for automated analysis and modification of children's speech production within assessment and therapeutic applications. Further work is needed to train automated systems with larger samples of speech to increase accuracy for assessment and therapeutic feedback. PMID- 29996692 TI - Management of an iatrogenic injury to the tibial nerve in a 24-year-old hurdle runner. AB - According to previously published papers, neurovascular injuries seem to be the most unfortunate complications after surgical procedures. In this report, we present our therapeutic approach to iatrogenic injury of the posterior tibial nerve that occurred during ankle arthroscopy in a 24-year-old patient. The outcome of the therapy was a full sensory return and partial motor return (S4 and M3 according to the Medical Research Council Grading System for Nerve Recovery). Our patient was able to resume her typical training. In comparison with available reports, our therapeutic approach enabled earlier functional recovery after nerve injury. While sensory return is beneficial, motor improvement is also important. However, we are conscious of the poor functional outcomes reported by other researchers. PMID- 29996693 TI - Tetramethylpyrazine protects against high glucose-induced vascular smooth muscle cell injury through inhibiting the phosphorylation of JNK, p38MAPK, and ERK. AB - Objectives High glucose-induced alterations in vascular smooth muscle cell behavior have not been fully characterized. We explored the protective mechanism of tetramethylpyrazine (TMP) on rat smooth muscle cell injury induced by high glucose via the mitogen-activated protein kinase (MAPK) signaling pathway. Methods Vascular smooth muscle cells (VSMCs) isolated from rat thoracic aortas were divided into control, high glucose (HG), and pre-hatching TMP groups. The effect of different glucose concentrations on cell viability and on the migration activity of VSMC cells was examined using MTT analysis and the wound scratch assay, respectively. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured using enzyme-linked immunoassays. The levels of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK, and MAPK phosphorylation were assessed by western blotting. Results Cell proliferation was remarkably increased by increased glucose concentrations. Compared with the HG group, the migratory ability of VSMC cells was reduced in the presence of TMP. TMP also decreased the MDA content in the supernatant, but significantly increased the SOD activity. Western blotting showed that TMP inhibited the phosphorylation of JNK, p38MAPK, and ERK. Conclusions TMP appears to protect against HG-induced VSMC injury through inhibiting reactive oxygen species overproduction, and p38MAPK/JNK/ERK phosphorylation. PMID- 29996694 TI - Stabilized tetraether lipids based particles guided prophyrins photodynamic therapy. AB - Photodynamic therapy (PDT) that involves ergonomically delivered light in the presence of archetypical photosensitizer such as Protoporphyrin IX (PpIX) is a time-honored missile strategy in cancer therapeutics. Yet, the premature release of PpIX is one of the most abundant dilemma encounters the therapeutic outcomes of PDT due to associated toxicity and redistribution to serum proteins. In this study, ultrastable tetraether lipids (TELs) based liposomes were developed. PpIX molecules were identified to reside physically in the monolayer; thereby the inherent pi-pi stacking that leads to aggregation of PpIX in aqueous milieu was dramatically improved. TEL29.9 mol% and TEL62mol% based liposomes revealed PpIX sustained release diffusion pattern from spherical particles as confirmed by converged fitting to Baker & Lonsdale model. Stability in presence of human serum albumins, a key element for PDT accomplishment was emphasized. The epitome candidates were selected for vascular photodynamic (vPDT) in in-Ovo chick chorioallantoic membrane. Profoundly, TEL62mol% based liposomes proved to be the most effective liposomes that demonstrated localized effect within the irradiated area without eliciting quiescent vasculatures damages. Cellular photodynamic therapy (cPDT) revealed that various radiant exposure doses of 134, 202, 403 or 672 mJ.cm-2 could deliberately modulate the photo-responses of PpIX in TEL liposomes. PMID- 29996695 TI - Alteration in Uterine Protease-Activated Receptor 2 Expression in Preterm Birth Induced Experimentally in Brp-39 Null Mutant Mice. AB - Breast regression protein 39 (Brp-39) is a mouse homolog of human Chitinase 3 like 1, which belongs to the 18-glycosyl-hydrolase family and plays a role in inflammatory reaction and tissue remodeling. The aim of this study is to investigate the role of Brp-39 in a mouse model of preterm birth. Pregnant wild type (WT) or Brp-39(-/-) mice were injected intraperitoneally with lipopolysaccharide (LPS) at embryonic day 15. Pregnancy outcomes were evaluated for 24 hours after LPS injection. Quantitative real-time polymerase chain reaction and immunoblotting were performed to analyze messenger RNA (mRNA) and protein expressions of cytokines and contraction-associated proteins in uterine and/or placental tissue after LPS injection. LPS injection led to preterm birth in both WT and Brp-39(-/-) mice, but the proportion of pubs delivered was reduced in Brp-39(-/-) mice, along with a longer interval from the LPS injection to delivery, compared to WT mice. Inflammatory cell infiltration and mRNA expression of cytokines and Ptgs2 in the uteri and the placentas were not significantly different between WT and Brp-39(-/-) mice. Par-2 mRNA expression in the WT uteri was increased before delivery after LPS injection and decreased after delivery, while there was no significant change in Par-2 expression in the Brp-39(-/-) uteri. Protein expressions of Par-2 and Ptgs2 were lower in the Brp-39(-/-) uteri than in the WT uteri before and after delivery. Attenuated preterm birth in Brp 39(-/-) mice indicates the significance of Brp-39 during murine preterm birth. Altered expression of Par-2 in Brp-39(-/-) uteri suggests its potential role in attenuated preterm birth of Brp-39(-/-) mice. PMID- 29996696 TI - Corrugated diaphragm shape design study for hemocompatible pulsatile ventricular assist devices. AB - We aim to maximize the pumping volume of a pulsatile ventricular assist device, where the diaphragm is covered with an endothelial cell layer. These cells are estimated to survive a cyclic strain up to fifteen percent. To increase the pumping volume under this strain constraint we use an approach based on corrugation of the diaphragm in its reference configuration. The paper explains the parametrization scheme for finding corrugation shapes, addresses modeling and evaluation schemes and reports on the results of a parameter study. The results show that corrugated diaphragm shapes are effective for increasing pumping volumes under a strain constraint. PMID- 29996697 TI - Characterization of Five Molecular Markers for Pathotype Identification of the Clubroot Pathogen Plasmodiophora brassicae. AB - Clubroot disease is an important disease on cruciferous crops caused by Plasmodiophora brassicae infections. The pathotypes have been classified based on the reactions of differential hosts. However, molecular markers of particular pathotypes for P. brassicae are limited. In this study, we found five genetic markers in association with different pathotypes. Different gene expression patterns among different pathotypes (P4, P7, P9, and P11) were assayed according to the transcriptome data. The assay indicated that molecular markers PBRA_007750 and PBRA_009348 could be used to distinguish P11 from P4, P7, and P9; PBRA_009348 and Novel342 could distinguish P9 from P4, P7, and P11; and PBRA_008439 and Novel342 could represent a kind of P4. Polymerase chain reaction cycles ranging from 25 to 30 were able to identify the predominant pathotype in general. Therefore, these molecular markers would be a valuable tool to identify and discriminate pathotypes in P. brassicae population. PMID- 29996698 TI - Development of High-Throughput SNP Genotyping Assays for Rapid Detection of Strawberry Colletotrichum Species and the G143A Mutation. AB - Colletotrichum spp. cause major diseases of strawberry and disease management depends on the species present. However, species identification based on symptoms and spore morphology is difficult. Therefore, development of molecular techniques for trustworthy and high-throughput identification of Colletotrichum spp. is vital for the accurate diagnosis. A high-resolution melting (HRM) assay was developed for simultaneous identification and differentiation of Colletotrichum spp. from fungal colonies or from symptomatic strawberry tissue. HRM markers were designed based on the internal transcribed spacer region of Colletotrichum acutatum and C. gloeosporioides from strawberry, and accurately identified and differentiated the two species. In addition, for the rapid detection of a single nucleotide polymorphism (SNP) in the cytochrome b (cytb) gene of C. acutatum and C. gloeosporioides associated with resistance to quinone-outside inhibitor fungicides, an endpoint SNP genotyping analysis was developed. The HRM and endpoint SNP genotyping assays are useful methods that can be implemented in plant diagnostic clinics for the rapid and accurate identification of Colletotrichum spp. and detection of the G143A mutation in the cytb gene of C. acutatum and C. gloeosporioides. PMID- 29996699 TI - Increasing Understanding Regarding the Risk of Concomitant Use of Carbamazepine and Direct Oral Anticoagulants. PMID- 29996700 TI - Gold nanoparticles ingested by oyster larvae are internalized by cells through an alimentary endocytic pathway. AB - The biological fate of nanoparticles (NPs) taken up by organisms from their environment is a crucial issue for assessing ecological hazard. Despite its importance, it has scarcely been addressed due to the technical difficulties of doing so in whole organism in vivo studies. Here, by using transmission electron microscopy and energy dispersive X-ray spectroscopy (TEM-EDS), we describe the key aspects that characterize the interaction between an aquatic organism of global ecological and economic importance, the early larval stage of the Japanese oyster (Crassostrea gigas), and model gold NPs dispersed in their environment. The small size of the model organism allowed for a high-throughput visualization of the subcellular distribution of NPs, providing a comprehensive and robust picture of the route of uptake, mechanism of cellular permeation, and the pathways of clearance counterbalancing bioaccumulation. We show that NPs are ingested by larvae and penetrate cells through alimentary pinocytic/phagocytic mechanisms. They undergo intracellular digestion and storage inside residual bodies, before excretion with feces or translocation to phagocytic coelomocytes of the visceral cavity for potential extrusion or further translocation. Our mechanistically-supported findings highlight the potential of oyster larvae and other organisms which feature intracellular digestion processes to be exposed to man-made NPs and thus any risks associated with their inherent toxicity. PMID- 29996701 TI - Statistical methods for characterizing transfusion-related changes in regional oxygenation using near-infrared spectroscopy (NIRS) in preterm infants. AB - Near infrared spectroscopy (NIRS) is an imaging-based diagnostic tool that provides non-invasive and continuous evaluation of regional tissue oxygenation in real-time. In recent years, NIRS has shown promise as a useful monitoring technology to help detect relative tissue ischemia that could lead to significant morbidity and mortality in preterm infants. However, some issues inherent in NIRS technology use on neonates, such as wide fluctuation in signals, signal dropout and low limit of detection of the device, pose challenges that may obscure reliable interpretation of the NIRS measurements using current methods of analysis. In this paper, we propose new nonparametric statistical methods to analyze mesenteric rSO2 (regional oxygenation) produced by NIRS to evaluate oxygenation in intestinal tissues and investigate oxygenation response to red blood cell transfusion (RBC) in preterm infants. Specifically, we present a mean area under the curve (MAUC) measure and a slope measure to capture the mean rSO2 level and temporal trajectory of rSO2, respectively. We develop estimation methods for the measures based on multiple imputation and spline smoothing and further propose novel nonparametric testing procedures to detect RBC-related changes in mesenteric oxygenation in preterm infants. Through simulation studies, we show that the proposed methods demonstrate improved accuracy in characterizing the mean level and changing pattern of mesenteric rSO2 and also increased statistical power in detecting RBC-related changes, as compared with standard approaches. We apply our methods to a NIRS study in preterm infants receiving RBC transfusion from Emory Univerity to evaluate the pre- and post-transfusion mesenteric oxygenation in preterm infants. PMID- 29996702 TI - Stress-induced strain and brain region-specific activation of LINE-1 transposons in adult mice. AB - Transposable elements (TEs) are conserved mobile genetic elements that are highly abundant in most eukaryotic genomes. Although the exact function of TEs is still largely unknown, it is increasingly clear that they are significantly modulated in response to stress in a wide range of organisms, either directly or indirectly through regulation of epigenetic silencing. We investigated the effect of repeated restraint stress (2 h a day, for 5 d) on transcription levels of LINE-1 (L1) retrotransposon in the brain of inbred BALB/c, DBA/2, C57BL/6N, and outbred CD1 mice. Repeated restraint stress induced strain and brain region-specific modulation of L1 activity. We observed a significant derepression of L1 transcription in the hippocampus (HIPP) of BALB/c mice and a significant downregulation in the hippocampus of C57BL/6N mice. No significant change in L1 expression was found in the other strains and brain regions. These findings indicate in mice the control of transposons expression as an additional mechanism in stress-induced pathophysiological responses, demonstrating that their regulation is highly dependent on the strain genetic background and the brain region. Lay summary Hippocampal expression of the transposon L1 is significantly altered by repeated restraint stress in mice. L1 modulation is not only region specific, but also strain dependent, suggesting that the genetic background is an important determinant of L1 response to environmental stimuli. PMID- 29996703 TI - Cardiovascular reflex tests in patients with systemic lupus erythematosus: clinical performance and utility. AB - Background This review summarizes current knowledge about cardiovascular reflex tests (CVRTs) and other selected autonomic nervous system (ANS) assessment tests in systemic lupus erythematosus (SLE) patients and assesses their clinical utility in this group of patients. Methods The PubMed database was searched for terms associated with CVRTs and SLE. Only papers available in full text and published in English were considered. Ultimately, 13 were selected and analyzed. Results In most of the studies CVRTs results were reported more likely to be abnormal in patients with SLE when compared with controls. The reported prevalence of ANS dysfunction in SLE, diagnosed using CVRTs, ranged from 23.5% to 82.7% of patients, likely because of different definitions of ANS dysfunction, variability in methods of performing CVRTs, and potential confounding factors. In general CVRTs results did not correlate with SLE activity or disease duration, but some CVRTs results correlated with some peptides associated with ANS function, including neuropeptide Y and vasoactive intestinal peptide. Conclusion Patients with SLE generally have abnormal or borderline results of CVRTs, which indicate prevalent abnormalities of the ANS in SLE. Performance of CVRTs requires good standardization of test conditions and familiarity with the proper administration and interpretation of these tests. PMID- 29996704 TI - Co-exposure to silver nanoparticles and cadmium induce metabolic adaptation in HepG2 cells. AB - Although multiple studies have reported the toxicological effects and underlying mechanisms of toxicity of silver nanoparticles (AgNP) in a variety of organisms, the interactions of AgNP with environmental contaminants such as cadmium are poorly understood. We used biochemical assays and mass spectrometry-based proteomics to assess the cellular and molecular effects induced by a co-exposure of HepG2 cells to AgNP and cadmium. Cell viability and energy homeostasis were slightly affected after a 4-h exposure to AgNP, cadmium, or a combination of the two; these endpoints were substantially altered after a 24-h co-exposure to AgNP and cadmium, while exposure to one of the two contaminants led only to minor changes. Proteomics analysis followed the same trend: while a 4-h exposure induced minor protein deregulation, a 24-h exposure to a combination of AgNP and cadmium deregulated 43% of the proteome. The toxicity induced by a combined exposure to AgNP and cadmium involved (1) inactivation of Nrf2, resulting in downregulation of antioxidant defense and proteasome-related proteins, (2) metabolic adaptation and ADP/ATP imbalance, and (3) increased protein synthesis possibly to reestablish homeostasis. The adaptation strategy was not sufficient to restore ADP/ATP homeostasis and to avoid cell death. PMID- 29996705 TI - The EMALT Score: An Improved Model for Prediction of Early Mortality in Liver Transplant Recipients. AB - PURPOSE: Needs, risks, and outcomes of patients admitted to a post liver transplant intensive care unit (POLTICU) differ in important ways from those admitted to pretransplant intensive care units (ICUs). The aim of this study was to create the optimal model to risk stratify POLTICU patients. METHODS: Consecutive patients who underwent first deceased donor liver transplantation (LT) at a large United States center between 2008 and 2014 were followed from admission to LT and to discharge or death. Receiver-operating characteristic analysis was performed to assess the value of various scores in predicting in hospital mortality. A predictive model was developed using logistic regression analysis. RESULTS: A total of 697 patients underwent LT, and 3.2% died without leaving the hospital. A model for in-hospital mortality was derived from variables available within 24 hours of admission to the POLTICU. Key variables best predicting survival were white blood cell count, 24-hour urine output, and serum glucose. A model using these variables performed with an area under the curve (AUC) of 0.88, compared to the Acute Physiology and Chronic Health Evaluation III and Model for End-Stage Liver Disease, which performed with AUCs of 0.74 and 0.60, respectively. CONCLUSION: An improved model, the early mortality after LT (EMALT) score, performs better than conventional models in predicting in-hospital mortality after LT. PMID- 29996707 TI - Retraction notice. PMID- 29996706 TI - The importance of scene photography in routine coronial practice: Results of an audit with an illustrative case of suspected suicidal fatal air embolism. AB - Pathologists providing a coronial autopsy service are very reliant on the information, including that concerning the body at the scene, provided prior to the post-mortem examination. This ensures the case is appropriate for a non forensic autopsy and allows proper interpretation of the pathological and laboratory findings. We present the results of an audit of the extent and accuracy of the information provided (in terms of a set of descriptors), in relation to the body at the scene; whether just the information on the coronial autopsy request form 97a is used, or if it is supplemented with details from the police form 97 and statements from attending officers and scene witnesses. The scene photographs were then reviewed to assess the accuracy of the other information sources and their value to the reporting pathologist. The audit showed that scene photographs are undertaken surprisingly frequently (29.6%) but this was only clear from the coronial request in 22% of referrals. More information was consistently available in the police information for most of the scene descriptors. This was usually accurate, but only partially so, with an average of 19% of relevant features. Viewing the scene photographs was deemed beneficial or essential in 51% and 41.1% of cases. The value of scene photography is then illustrated in a case of suspected suicidal venous air embolism, where subsequent review of the images pointed strongly to the rapidity of death, with minimal blood loss but obvious targeting of a very large varicose saphenous vein in the upper thigh. PMID- 29996708 TI - Language processing from the perspective of electrical stimulation mapping. AB - Electrical Stimulation (ES) is a neurostimulation technique that is used to localize language functions in the brain of people with intractable epilepsy and/or brain tumors. We reviewed 25 ES articles published between 1984 and 2018 and interpreted them from a cognitive neuropsychological perspective. Our aim was to highlight ES as a tool to further our understanding of cognitive models of language. We focused on associations and dissociations between cognitive functions within the framework of two non-neuroanatomically specified models of language. Also, we discussed parallels between the ES and the stroke literatures and showed how ES data can help us to generate hypotheses regarding how language is processed. A good understanding of cognitive models of language is essential to motivate task selection and to tailor surgical procedures, for example, by avoiding testing the same cognitive functions and understanding which functions may be more or less relevant to be tested during surgery. PMID- 29996710 TI - Validation of computerized episodic memory measures in a diverse clinical sample referred for neuropsychological assessment. AB - OBJECTIVE: To examine the convergent and discriminant validity of two brief computerized episodic memory measures in a large, diverse clinical sample of adults undergoing neuropsychological assessment. METHOD: Computerized measures of word and face memory were administered to 233 adults (age 30 and over) who also completed comprehensive neuropsychological testing. RESULTS: Moderate correlations were observed between the computerized memory tests and a wide range of traditional neuropsychological measures of episodic memory (e.g. word-list learning, story recall, face recognition, design recall). Select measures of visuomotor processing speed and language were also related to performance on the computerized tasks. In contrast, the computerized memory tests showed weak correlations with tests in other cognitive domains (i.e. visuospatial skills, attention/working memory, executive function, motor dexterity, academic skills) and self-report screening measures of mood and anxiety. Similar to traditional measures of episodic memory, the computerized memory measures were sensitive to effects of age and gender. CONCLUSIONS: Computerized measures of word and face memory showed good convergent and discriminant validity in this diverse clinical sample supporting the construct validity of these measures. This indicates that it may be feasible to measure memory function in clinical settings using brief, well-designed computerized memory measures. PMID- 29996709 TI - Knowledge database assisted gene marker selection for chronic lymphocytic leukemia. AB - Objective To investigate whether previously curated chronic lymphocytic leukemia (CLL) risk genes could be leveraged in gene marker selection for the diagnosis and prediction of CLL. Methods A CLL genetic database (CLL_042017) was developed through a comprehensive CLL-gene relation data analysis, in which 753 CLL target genes were curated. Expression values for these genes were used for case-control classification of four CLL datasets, with a sparse representation-based variable selection (SRVS) approach employed for feature (gene) selection. Results were compared with outcomes obtained by using analysis of variance (ANOVA)-based gene selection approaches. Results For each of the four datasets, SRVS selected a subset of genes from the 753 CLL target genes, resulting in significantly higher classification accuracy, compared with randomly selected genes (100%, 100%, 93.94%, 89.39%). The SRVS method outperformed ANOVA in terms of classification accuracy. Conclusion Gene markers selected from the 753 CLL genes could enable significantly greater accuracy in the prediction of CLL. SRVS provides an effective method for gene marker selection. PMID- 29996711 TI - Factors predictive of a fetal alcohol spectrum disorder diagnosis: Parent and teacher ratings. AB - Diagnostic assessment in Fetal Alcohol Spectrum Disorder (FASD) is informed by multidisciplinary assessment incorporating objective (i.e., test measures) and subjective means, such as parent and teacher behavior ratings. The purpose of this study was to extend our previous neuropsychological test findings by identifying parent and teacher ratings of academic achievement, attention, executive functioning, and adaptive functioning as predictors of an FASD diagnosis. The charts of 315 children and adolescents with prenatal alcohol exposure (PAE) who underwent assessment for FASD were retrospectively reviewed. Direct logistic regressions analyzed the contribution of different ratings on the likelihood of an FASD diagnosis. The results suggest that a number of rating measures do contribute toward accurately differentiating those with FASD from within a PAE population, including teacher ratings of learning problems, inattention, and adaptive skills. The classification accuracy for each regression was clinically significant (59.1-70.8%). Children with worse ratings on these variables are approximately 1.5 to 2 times more likely to receive an FASD diagnosis. Only teacher ratings (not parent) significantly contributed to whether a diagnosis was made, suggesting that teacher observational rating scales are a critical component of an FASD assessment. Together with our previous research examining neuropsychological evaluation and FASD diagnostic assessment, this study helps to further guide decisions to streamline care in multidisciplinary assessment and intervention planning. PMID- 29996712 TI - [Relatives or 'Zugehorige'? - An attempt to explore the meaning of terms]. AB - : Relatives or 'Zugehorige'? - An attempt to explore the meaning of terms Abstract. BACKGROUND: Societal change has an impact on social coexistence and it is associated with pluralisation of family patterns, altered kinship relations and a greater significance of friendship relations. This is also reflected in familial situations with occurring care needs and the professional carers' perception of these developments has found its linguistic equivalent in terms like 'relatives' or 'Zugehorige'. These and further terms used in nursing communication will be explored in this article. AIM: The objective of this article is to determine the meanings of terms used in German-speaking nursing literature for close persons of care receivers. METHODS: For this purpose an explicating content analysis was conducted and etymological, juridical and social scientific definitions were compared to the apprehension of professional care givers. RESULTS: The findings show a wide range of terminology combined with a varying comprehension of these terms challenging their appropriateness for professional nursing communication. CONCLUSIONS: Based on these findings a definition of the concept 'relatives' is brought up for discussion as an attempt to contribute to a more coherent intraprofessional comprehension. PMID- 29996713 TI - Marker-free genome editing in Ustilago trichophora with the CRISPR-Cas9 technology. AB - In this communication, we report the adaptation of the CRISPR-Cas9 technology in Ustilago trichophora prototrophic wild-type isolate obtained from its natural host Echinochloa crus-galli. The established CRISPR vector and method enable a rapid and marker-free introduction of Cas9-induced non-homologous end-joining (NHEJ) dependent mutation at the targeted gene. Moreover, the method allows a specific modification of the chromosomal DNA sequence by Cas9-induced homologous recombination using short DNA repair templates. The results demonstrate the applicability of the CRISPR-Cas9 technology in U. trichophora for both gene knock out by the NHEJ pathway and specific gene modification by templated genome editing, paving the way for rapid metabolic engineering of this Ustilago species for industrial applications. PMID- 29996714 TI - Why Is the U.S. Preterm Birth Rate So Much Higher Than the Rates in Canada, Great Britain, and Western Europe? AB - The portion of newborns delivered before term is considerably higher in the United States than in other developed countries. We compare the array of risk exposures and protective factors common to women across national settings, using national, regional, and international databases, review articles, and research reports. We find that U.S. women have higher rates of obesity, heart disease, and poor health status than women in other countries. This is in part because more U.S. women are exposed to the stresses of racism and income disparity than women in other national settings, and stress loads are known to disrupt physiological functions. Pregnant women in the United States are not at higher risk for preterm birth because of older maternal age or engagement in high-risk behaviors. However, to a greater extent than in other national settings, they are younger and their pregnancies are unintended. Higher rates of multiple gestation pregnancies, possibly related to assisted reproduction, are also a factor in higher preterm birth rates. Reproductive policies that support intentional childbearing and social welfare policies that reduce the stress of income insecurity can be modeled from those in place in other national settings to address at least some of the elevated U.S. preterm birth rate. PMID- 29996715 TI - Longitudinal associations between motor competence and different physical activity intensities: LabMed physical activity study. AB - An appropriated level of motor competence is essential for children's healthy growth and development and a key factor in the promotion of lifelong active lifestyles and health. The purpose of this study was to examine associations between motor competence and different physical activity intensities (light, moderate, moderate-to-vigorous and vigorous physical activity), as well as total physical activity, over a two-year period, in adolescents. The sample comprised of 103 adolescents (13.49 +/- 0.87 years, 53 girls), from the north of Portugal. Motor competence was evaluated with the body coordination test, Korperkoordination-Test-fur-Kinder. Physical activity was objectively assessed with GT1M accelerometers (ActiGraph, Pensacola, FL, USA). Physical activity variables were expressed as proportions of accelerometer wear time. Regression analyses showed positive longitudinal associations between motor competence at baseline and moderate physical activity (B = 0.0033, p = 0.018), moderate-to vigorous physical activity (B = 0.0052, p = 0.024) and total physical activity (B = 0.067, p = 0.040) at follow up, after adjustments for age, sex, the corresponding physical activity intensity at baseline, body mass index, pubertal stage and socioeconomic status. Our findings highlight the importance of motor competence development to promote moderate-to-vigorous physical activity during adolescence. PMID- 29996717 TI - Visualisation of the insertion of a membrane for the treatment of preterm rupture of fetal membranes using a synthetic model of a pregnant uterus. AB - Preterm premature rupture of fetal membranes is a leading cause of preterm delivery. Preterm labour can compromise fetal survival, and even if a pregnancy affected by preterm premature rupture of fetal membrane continues, major complications associated with leakage of amniotic fluid and risk of infection can affect the normal development and survival of the baby. There are limited management options for preterm premature rupture of fetal membrane other than delivery of the baby if ascending infection (chorioamnionitis) is suspected. We have previously reported the development and characterisation of an implantable membrane with the aim of using it to occlude the internal os of the cervix, in order to prevent amniotic fluid loss, allow fluid reaccumulation and reduce the risk of chorioamnionitis. For this, an electrospun biocompatible and distensible bilayer membrane was designed with mechanical properties similar to the human amniotic membrane. In this study, we consider the effects of sterilization on the membrane, how to insert the membrane and visualise it using routine clinical methods. To do this, we used e-beam sterilisation and examined the ability of the membrane to adhere to ex vivo human cervical tissues. We also studied its insertion into a custom-synthesised model of a 20-week pregnant uterus and imaged the membrane using ultrasound. Sterilisation produced minor effects on physical and mechanical properties, but these did not affect the capacity of the membrane to be sutured or to provide a fluid barrier. We demonstrated that fibrin glue can successfully adhere the bilayer membrane to cervical tissues. Finally, we demonstrated that the membrane can be inserted through the cervix as well as visualized in place using ultrasound imaging and an endoscope. In summary, we suggest this membrane is a candidate for further development in an appropriate animal model, supported by appropriate imaging, to precede possible future human studies if judged to demonstrate satisfactory safety and efficacy profiles. PMID- 29996716 TI - TFEB-dependent induction of thermogenesis by the hepatocyte SLC2A inhibitor trehalose. AB - The macroautophagy/autophagy-inducing disaccharide, trehalose, has been proposed to be a promising therapeutic agent against neurodegenerative and cardiometabolic diseases. We recently showed that trehalose attenuates hepatic steatosis in part by blocking hepatocyte glucose transport to induce hepatocyte autophagic flux. However, although every major demonstration of trehalose action invokes activating autophagic flux as its primary function, the mechanism of action of trehalose in whole-body energy metabolism remains poorly defined. Here, we demonstrate that trehalose induces hepatocyte TFEB (transcription factor EB) dependent thermogenesis in vivo, concomitant with upregulation of hepatic and white adipose expression of UCP1 (uncoupling protein 1 [mitochondrial, protein carrier]). Mechanistically, we provide evidence that hepatocyte fasting transcriptional and metabolic responses depend upon PPARGC1A (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha), TFEB, and FGF21 (fibroblast growth factor 21) signaling. Strikingly, hepatocyte-selective TFEB knockdown abrogated trehalose induction of thermogenesis and white adipose tissue UCP1 upregulation in vivo. In contrast, we found that trehalose action on thermogenesis was independent of LEP (leptin) and the autophagy pathway, as there was robust thermogenic induction in trehalose-treated ob/ob, Becn1, Atg16l1, and Epg5 mutant mice. We conclude that trehalose induces metabolically favorable effects on whole-body thermogenesis in part via hepatocyte-centered fasting-like mechanisms that appear to be independent of autophagic flux. Our findings elucidate a novel mechanism by which trehalose acts as a metabolic therapeutic agent by activating hepatic fasting responses. More broadly, the hepatic glucose fasting response may be of clinical utility against overnutrition-driven disease, such as obesity and type 2 diabetes mellitus. PMID- 29996718 TI - Transition From Continuous Infusion Fentanyl to Hydromorphone in Critically Ill Patients. AB - BACKGROUND: The 2013 Society of Critical Care Medicine guidelines for the management of pain, agitation, and delirium in adult intensive care unit (ICU) patients recommend intravenous opioids as first-line therapy to treat nonneuropathic pain. There is a paucity of literature describing possible benefits of utilizing specific opioids over others in ICU patients. OBJECTIVE: The objective was to identify rationales for the transition from continuous infusion fentanyl to continuous infusion hydromorphone in critically ill patients. METHODS: This was a single-center, prospective, observational analysis of adult ICU patients who were transitioned from fentanyl to hydromorphone. The major end point was to characterize the primary reason for transition. Minor end points included secondary reason(s) for transition, transition dosing, changes in continuous sedative requirements, and level of sedation. RESULTS: Forty-six patients were included in the analysis. The primary rationale for transition was ventilator compliance (28.3%), followed by tachyphylaxis or better pain control (19.6%), and reduction in sedatives (13.0%). The most common secondary reason(s) for transition included reduction in sedatives (47.8%), opioid rotation (32.6%), and obesity (30.4). Median fentanyl rate of 100 ug/h was transitioned to 1 mg/h of hydromorphone. The percentage of patients requiring the use of continuous sedatives was decreased in the 24 hours following transition ( P = .005); however, patients were more deeply sedated ( P = .02). CONCLUSION: Rationales for transition were to improve ventilator compliance, optimize patient-specific pharmacokinetics, and limit overall sedative exposure. PMID- 29996719 TI - Evaluating Implementation Fidelity of a School-Based Parenting Program for Low Income Families. AB - Young children first develop the social-behavioral skills needed to succeed in school from parents. However, most school-based interventions designed to bolster children's social-behavioral skills have focused on strengthening teachers' skills. This study examined the extent to which a 12-session group-based program for strengthening parenting skills, the Chicago Parent Program (CPP), could be implemented with fidelity in 12 urban schools serving a large population of young children (>95% African American or Latino) living in poverty. Parents of 380 prekindergarten students enrolled in the CPP. Data were collected on child behavior problems; parent satisfaction, attendance, and weekly practice completion; and implementation adherence and competence. Results indicated that CPP group leaders were highly adherent and competent; parents rated groups highly and attended an average of 8 sessions indicating CPP was implemented with high fidelity. Barriers and supports to implementation are reviewed, and implications for long-term sustainability of school-based interventions like CPP are discussed. PMID- 29996721 TI - Laparoscopic versus open distal pancreatectomy for pancreatic adenocarcinoma: a systematic review and meta-analysis. AB - OBJECTIVES: To compare the effectiveness, safety and oncologic adequacy of laparoscopic and open distal pancreatectomy (ODP) for pancreatic adenocarcinoma. METHODS: A systematic literature search was performed using EMBASE, Medline, the Cochrane library, and Google Scholar. Meta-analyses were performed using both fixed-effect and random-effect models. A cumulative meta-analysis was performed to track the accumulation of evidence. The power that a new trial of specified samples would give to the present meta-analysis was estimated with simulation based sample size calculation. RESULTS: Patients who underwent laparoscopic distal pancreatectomy (LDP) had significantly smaller tumours [mean difference (MD) = -0.49 (-0.83 to -0.14), p = 0.005], less estimated blood loss [MD = 157.27 (-281.63 to -32.91), p = 0.01], and shorter average hospital stay by two days [MD = -2.35 (-3.1 to -1.59), p < .001] than those who underwent ODP. No significant differences in feasibility, effectiveness, and safety were noted. Cumulative meta-analysis demonstrated that the results were not dominated by a particular study. A new trial with 350 patients in each arm will give a maximum power of 48% to the present meta-analysis. CONCLUSIONS: LDP for pancreatic adenocarcinoma provides similar clinical and oncologic outcomes with shorter hospital stay by two days compared to ODP. However, underpowered sample size and smaller tumour size may have influenced the results of laparoscopic surgery. Therefore, an adequately powered randomized controlled trial is needed to shed further light on the appropriateness of this approach. PMID- 29996720 TI - Results of 5-year follow-up study in patients with peripheral artery disease treated with PL-VEGF165 for intermittent claudication. AB - BACKGROUND: The effective treatment of chronic lower limb ischemia is one of the most challenging issues confronting vascular surgeons. Current pharmacological therapies play an auxiliary role and cannot prevent disease progression, and new treatment methods are needed. In 2011, a plasmid VEGF65-gene therapy drug was approved in Russia for the treatment of chronic lower limb ischemia ( ClinicalTrials.gov identifier: NCT03068585). The objective of this follow-up study was to evaluate the long-term safety and efficacy of gene therapy in patients with limb ischemia of atherosclerotic genesis. AIMS: To evaluate the long-term safety and efficacy of the therapeutic angiogenesis, 36 patients in the treatment group (pl- VEGF165) and 12 patients in the control group participated in a 5-year follow-up study. Planned examinations were carried out annually for 5 years after pl- VEGF165 administration. RESULTS: Differences in the frequency of major cardiovascular events (pl- VEGF165 5/36 versus control 2/12; p = 0.85), malignancies (pl- VEGF165 1/36 versus control 0/12; p = 0.38) and impaired vision (there was none in either group) over the 5-year follow-up period did not achieve statistical significance. The target limb salvage was 95% ( n = 36) and 67% ( n = 12) in the pl- VEGF165 and control groups, respectively. The pain-free walking distance value increased by 288% from 105.7 +/- 16.5 m to 384 +/- 39 m in the treatment group by the end of the fifth year, with a peak of 410.6 +/- 86.1 m achieved by the end of the third year. The ankle-brachial index (ABI) increased from 0.47 +/- 0.01 to 0.56 +/- 0.02 by the end of the first year, with a subsequent slight decrease to 0.51 +/- 0.02 by the fifth year. The maximum increment of transcutaneous oximetry test (tcoO2) by 36%, from 66.6 +/- 3.7 mm Hg to 90.7 +/- 4.9 mm Hg, was observed by the end of the second year. CONCLUSION: The therapeutic effect of angiogenesis induction by gene therapy persists for 5 years. PMID- 29996722 TI - Risk Factors Related to Binge Drinking: A Comparative Study of American and South Korean Adolescents. AB - The characteristics of and risk factors associated with binge drinking among South Korean and American adolescents were identified in this study. Data on adolescents in the 9th to 12th grades were extracted from two nationwide data sets: the Korea Youth Risk Behavior Web-based Survey System and the U.S. Youth Risk Behavior Surveillance System. Binge drinking was observed among 16% of American adolescents during the past month and among 11.6% of Korean adolescents during the past year. For adolescents from both countries, the following seven similar significant factors were associated with binge drinking: female gender, higher grade, fighting-related injury experience, current cigarette smoking, preteen smoking initiation, participation in team sports, and depression. Among Korean adolescents, higher or lower level of academic achievement and inadequate sleep were additional unique factors associated with binge drinking. These results could be useful for developing interventions for adolescents engaging in binge drinking in both countries. PMID- 29996723 TI - The need to move 'upstream'. PMID- 29996725 TI - Tennis serve performances at break points: Approaching practice patterns for coaching. AB - Tennis comprises specific match situations when winning the next point is crucial. These big points can decide about a win or loss and, thus, reasonably arouse mental stress. Break points (BPs) are considered as big points and the outcome is influenced by, among a variety of other factors, the serve, which is well accepted being one of the dominant strokes in Men's tennis. In this study, we examined the serve behaviour for male players in the Wimbledon tournament 2016 to investigate the possible impacts of presumed mental stress within the situation of BPs, and further, if winning players perform better than losing players. A total of 28.843 points were analysed and divided into BP (n = 2.035) and non-break points - referred to as regular points (RP; n = 26.808). PMID- 29996724 TI - Differences in step characteristics and linear kinematics between rugby players and sprinters during initial sprint acceleration. AB - The initial steps of a sprint are important in team sports, such as rugby, where there is an inherent requirement to maximally accelerate over short distances. Current understanding of sprint acceleration technique is primarily based on data from track and field sprinters, although whether this information is transferable to athletes such as rugby players is unclear, due to differing ecological constraints. Sagittal plane video data were collected (240 Hz) and manually digitised to calculate the kinematics of professional rugby forwards (n = 15) and backs (n = 15), and sprinters (n = 18; 100 m personal best range = 9.96-11.33 s) during the first three steps of three maximal sprint accelerations. Using a between-group research design, differences between groups were determined using magnitude-based inferences, and within-group relationships between technique variables and initial sprint acceleration performance were established using correlation. Substantial between-group differences were observed in multiple variables. Only one variable, toe-off distance, differed between groups (d = 0.42 to -2.62) and also demonstrated meaningful relationships with sprint performance within all three groups (r = -0.44 to -0.58), whereby a stance foot position more posterior relative to the centre of mass at toe-off was associated with better sprint performance. While toe-off distance appears to be an important technical feature for sprint acceleration performance in both sprinters and rugby players, caution should be applied to the direct transfer of other kinematic information from sprinters to inform the technical development of acceleration in team sports athletes. PMID- 29996727 TI - Hepatic visceral larva migrans: a diagnostic enigma. PMID- 29996728 TI - Mechanisms of diazinon effects on impaired spermatogenesis and male infertility. AB - Diazinon (DZN) is an organophosphate insecticide that has cytotoxic and pathological effects on the reproductive system. It causes a wide variety of pathological effects on the reproductive system such as testicular atrophy, disturbance in sex hormones, impaired spermatogenesis, low quality of sperm, and fertility problems. However, molecular and cellular mechanisms of its adverse effects are not well understood. General events such as testicular damage, inflammation, mitochondrial deficiency, DNA fragmentation, disintegration of sperm plasma membrane, apoptosis, and cell death are observed in DZN-exposed animals. Oxidative stress (OS) induced by reactive oxygen species may be a main mechanism, which can be associated with sperm DNA fragmentation, reduced integrity of sperm cell membrane, apoptosis, depletion of antioxidants, and subsequently poor sperm quality and male infertility. Therefore, identification of these pathways may provide valuable information regarding the mechanisms of DZN action on the male reproductive system. In this review, we aim to discuss the proposed cellular and molecular mechanisms of DZN action on male reproductive system, the importance of OS and mechanisms by which DZN induces OS and depletion of other antioxidants. PMID- 29996726 TI - Frontline nilotinib treatment in Turkish patients with Philadelphia chromosome positive chronic Myeloid Leukemia in chronic phase: updated results with 2 years of follow-up. AB - OBJECTIVES: This report presents final results (24 months of follow-up) from the first prospective, national study of frontline nilotinib in chronic myeloid leukemia (CML) patients in Turkey. METHODS: Patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CML-CP; N = 112) received nilotinib 300 mg twice daily. The primary endpoint, which was the cumulative rate of major molecular response (MMR; BCR-ABL1 <= 0.1% on the International Scale [BCR-ABL1IS]) by 12 months, was previously reported (66.1% [80% CI, 59.7% 72.0%]). ClinicalTrials.gov identifier NCT01274351 Results: By 24 months, 83.0% of patients achieved MMR, and 50.9% achieved MR4.5 (BCR-ABL1IS <=0.0032%). Safety results at 24 months were consistent with those at 12 months. No additional deaths or disease progressions to accelerated phase/blast crisis were observed between 12 and 24 months. DISCUSSION: Treatment with nilotinib 300 mg twice daily for 2 years provided high MMR with a good safety/tolerability profile in newly diagnosed CML-CP patients in Turkey. Assessment of MMR across time points showed increasing rates through 18 months, after which as lower rate of increase was observed. The safety profile of nilotinib 300 mg twice daily with 24 months of follow-up was similar to that observed at 12 months, and no new safety concerns were identified. These efficacy and safety findings are consistent with the results from the 12-month analysis of this study and from previous nilotinib studies. These findings support nilotinib as an option for frontline treatment of CML-CP. CONCLUSION: Frontline nilotinib treatment provided sustained efficacy, with good tolerability, over 24 months in newly diagnosed CML-CP patients. PMID- 29996729 TI - Adaptation of perturbation to postural control in individuals with diabetic peripheral neuropathy. AB - Loss of sensation in the feet due to diabetic peripheral neuropathy can cause deterioration of postural control and result in higher risk of trips, slips or falls. In the literature, many studies have reported that people with diabetic peripheral neuropathy tend to show greater displacement of body sway than normal people when the base of support is disrupted. But not much is known about postural characteristics of diabetics with peripheral neuropathy at the moment of postural stability disruptions and during the time span for recovering stability. The objective of this study was to analyze differences of postural characteristics between diabetics with peripheral neuropathy and diabetics without peripheral neuropathy. A learning effect of perturbation was found for the diabetic peripheral neuropathy group in the posterior direction of perturbation during the first phase, which may indicate that it could be possible to design a postural control program for those people. PMID- 29996731 TI - Response to "Use of Qualitative Data to Support Content Validity of Performance Based Cognitive Outcome Assessments". PMID- 29996732 TI - A Proposal to Replace "SRL" as the Common Term for Medical Information Response Documents. PMID- 29996733 TI - "Assessment of Pressor Effects of Drugs"-A New US FDA Draft Guidance for Industry. PMID- 29996734 TI - Additive Effect of Therapeutic Ultrasound in the Treatment of Plantar Fasciitis: A Randomized Controlled Trial. AB - BACKGROUND: Plantar fasciitis is the chief cause of pain in the plantar surface of the heel. Therapeutic ultrasound is one of the most common conservative treatment modalities used by physical therapists worldwide, despite scarce evidence of its efficacy in treating plantar fasciitis. OBJECTIVE: To evaluate the additive effect of therapeutic ultrasound in the treatment of plantar fasciitis in terms of pain, function, and quality of life. METHODS: In this prospective, randomized, double-blind, placebo-controlled clinical trial, 54 patients with plantar fasciitis, aged 24 to 80 years, who met the inclusion criteria were randomized into an active intervention and a control group. Individuals in the active intervention group were treated with self-performed stretching of the plantar fascia and calf muscles and with therapeutic ultrasound. Individuals in the control group were treated with the same stretching exercises and sham ultrasound. Both groups received 8 treatments, twice weekly. Outcome measures included a numeric pain-rating scale, the computerized adaptive test for the foot and ankle, and an algometric test. RESULTS: Both groups showed statistically significant improvement in all outcome measures (P<.001, both groups). At the completion of the study, no statistically significant differences were found between the groups in any of the outcomes. CONCLUSION: The addition of therapeutic ultrasound did not improve the efficacy of conservative treatment for plantar fasciitis. Therefore, the authors recommend excluding therapeutic ultrasound from the treatment of plantar fasciitis and agree with results of previous studies that stretching may be an effective treatment for healing plantar fasciitis. LEVEL OF EVIDENCE: Therapy, level 1b. J Orthop Sports Phys Ther 2018;48(11):847-855. Epub 11 Jul 2018. doi:10.2519/jospt.2018.8110. PMID- 29996735 TI - Detection of Knee Power Deficits Following Anterior Cruciate Ligament Reconstruction Using Wearable Sensors. AB - BACKGROUND: Following anterior cruciate ligament reconstruction (ACLR), individuals present with significant knee power absorption deficits during deceleration of dynamic tasks. An inability to quantify these deficits clinically may underlie their persistence. Recent studies suggest that segment angular velocities measured with wearable inertial sensors have the potential to provide valuable information about knee power during a single-limb loading (SLL) task. However, the diagnostic accuracy of these measures and procedures needs to be established before translating this information to clinical practice. OBJECTIVE: To determine the diagnostic accuracy of using inertial-sensor thigh angular velocities to detect asymmetrical knee loading during a dynamic SLL task in individuals following ACLR. METHODS: In this controlled laboratory study, 21 individuals following ACLR performed 3 trials of SLL on each limb. Sagittal plane peak knee power absorption was calculated for each limb (reconstructed and nonsurgical) during deceleration. Between-limb ratios (reconstructed/nonsurgical limb) were calculated for knee power using marker-based motion analysis, and thigh angular velocity was extracted from inertial sensors. Sensitivity and specificity of thigh angular velocity ratios in diagnosing asymmetrical knee loading (knee power deficits greater than 15%) were determined using receiver operating characteristic curve analysis. RESULTS: Thigh angular velocity ratios detected asymmetrical knee loading when performing SLL with high sensitivity (81%) and specificity (100%). CONCLUSION: These findings support the use of cost effective wearable sensors to objectively quantify movement clinically in this population of individuals following ACLR. This study establishes procedures for the clinical quantification of dynamic knee loading deficits. J Orthop Sports Phys Ther 2018;48(11):895-902. Epub 11 Jul 2018. doi:10.2519/jospt.2018.7995. PMID- 29996736 TI - Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies. AB - Background Voriconazole is an azole antifungal utilized for prophylaxis and treatment of invasive fungal infections in hematologic patients. Previous studies have revealed decreased efficacy and increased toxicity with subtherapeutic <1 mcg/mL and supratherapeutic > 4 mcg/mL levels. A voriconazole dose modification guideline was introduced in July 2014 based on a retrospective analysis. Objective The primary objective was to evaluate the voriconazole dose modification guideline. Secondary objectives were to identify patient-specific characteristics that contribute to inadequate levels, adverse effects, and breakthrough invasive fungal infections. Methods This prospective study included 128 patients with 250 admissions who received voriconazole from July 2014 to February 2016. Eligible adult patients receiving voriconazole for prophylaxis or treatment with at least one trough level, drawn appropriately, were included. Demographics, adverse effects, and breakthrough invasive fungal infections were documented. Results Voriconazole use was categorized as: new start, new start with loading dose, or continuation of home therapy. The median initial levels were 1.5, 3.5, and 1.7 mcg/mL with 62% (73/119), 55% (6/11), and 60% (72/120) within the therapeutic range, respectively. Using the voriconazole dose modification guideline, 80% were within goal by the second dose adjustment. Age <= 30 and BMI <= 25 kg/m2 had higher rates of subtherapeutic levels in the new start cohorts ( p = 0.024 and p = 0.009). Approximately 7.6% of patients experienced an adverse effect with neurologic/psychological being the most common. A total of 8.5% of patients had a possible, probable or proven breakthrough invasive fungal infections while on voriconazole. Conclusion Using the voriconazole dose modification guideline, the number of patients that reached therapeutic range improved from 36% to 80% by the second dose adjustment ( p = 0.007). This voriconazole dose modification guideline can be utilized to help dose and adjust voriconazole in order to achieve therapeutic levels. PMID- 29996737 TI - Ibrutinib in the management of Waldenstrom macroglobulinemia. AB - Bruton tyrosine kinase plays a critical role in hastening cell proliferation. Bruton tyrosine kinase inhibitors are a class of immunotheraputic agents that disrupt this signaling pathway. Ibrutinib, a novel Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of Waldenstrom macroglobulinemia in patients who have failed treatment with other agents, has emerged as an important therapeutic agent in the management of Waldenstrom macroglobulinemia and other plasma cell dyscrasias. Ibrutinib has shown to increase progression free survival and improve overall mortality. We present a review of ibrutinib, beginning with an overview of the Bruton tyrosine kinase pathway and clinically relevant gene mutations impacting treatment and prognosis for patients with Waldenstrom macroglobulinemia, followed by evidence supporting therapeutic indications for ibrutinib, and detailing its safety and efficacy evidence, current clinical guidelines, adverse effects and their management, and finally challenges of drug resistance. We also present findings on newly developed Bruton tyrosine kinase inhibitors in the therapeutic pipeline to provide readers insight into this rapidly evolving corner of oncology pharmacy practice. PMID- 29996738 TI - To do or not to do: A concise update of current clinical controversies in immune checkpoint blockade. AB - Although programmed death-ligand 1 is currently the best available biomarker for first-line therapy with pembrolizumab for patients with non-small cell lung cancer and is a required companion test approved by the US Food and Drug Administration, programmed death-ligand 1 testing is an option (as a complementary test) for patients treated with nivolumab, atezolizumab, and durvalumab. Programmed death-ligand 1 expression is continuously variable and dynamic in the tumor microenvironment. Due to the complex molecular and cellular interactions involved in immune response, a single biomarker may not be sufficient to predict response to cancer immunotherapy. Integration of multiple tumor, immune response, and genomic parameters is likely to influence the future interpretation of biomarker-based treatment outcomes. This article, in a case based format, concisely summarizes most up-to-date evidence in answering some commonly seen clinical controversies of cancer immunotherapy, in terms of (i) the predictive value of programmed death-ligand 1 as a biomarker; (ii) whether the use of steroids with checkpoint inhibitors will decrease efficacy of the latter; (iii) selection of patients for cancer immunotherapy based on immune-based response criteria, and (iv) whether the use of influenza vaccine with checkpoint inhibitors is considered safe. Until more robust, long-term prospective clinical data are available, these discussions may serve as a starting point for pharmacists to gain timely and effective management of these realistic issues. PMID- 29996739 TI - The role of time to positivity of blood cultures on the diagnosis of true CoNS bacteraemia. PMID- 29996740 TI - Erratum. AB - Printability of papers recycled from toner and inkjet-printed papers after deinking and recycling processes. J Appl Biomater Funct Mater. 2017; 16(2) 76-82. DOI: 10.5301/jabfm.5000386 The correct author sequence reads as follows: Dogan Tutak1, Arif Karademir2, Cem Aydemir1, Raja Aravamuthan31Department of Printing Technologies, School of Applied Science, Marmara University, Istanbul, Turkey 2Department of Forest Product Engineering, Bursa Technical University, Bursa, Turkey 3Department of Chemical and Paper Engineering, College of Engineering and Applied Sciences, Western Michigan University, Kalamazoo, Michigan, USA The author list has been corrected in the online article. PMID- 29996743 TI - Regulatory T cells and CD20+ B cells in pediatric very severe aplastic anemia: possible clinical markers for evaluating the therapeutic efficacy and prognosis. AB - OBJECTIVES: To investigate the immune status of children with very severe aplastic anemia (VSAA), and evaluate the frequencies of CD20+ B cells and Regulatory T cells (Tregs) as potential markers for evaluating the therapeutic efficacy and prognosis. METHODS: We systematically analyzed CD20+ B cells and Tregs using Flow Cytometry in 36 children with VSAA (14 newly diagnosed cases and 22 cases in remission after therapy with HDIVIG + r-ATG + CSA). RESULTS: In newly diagnosed VSAA patients, the percentage of CD20+ B cells was higher than that in healthy children (P < .01), whereas the percentage of Tregs was lower than that in healthy children (P < .001). After treatment with HDIVIG + r-ATG + CSA, the percentage of CD20+ B cells in peripheral blood was decreased obviously, and the percentage of Tregs was significantly increased. CONCLUSION: There is a moderate negative correlation between the percentage of Tregs and CD20+ B cells in our study. Our results shed light on the roles of Tregs and CD20+ B cells as therapeutic efficacy and prognostic markers of pediatric VSAA. Moreover, the mechanism underlying the decrease of blood Tregs and increase of CD20+ B cells in pediatric VSAA patients have been discussed, indicating that Tregs may suppress B cell responses. PMID- 29996741 TI - Binders alternative to Portland cement and waste management for sustainable construction-part 1. AB - This review presents "a state of the art" report on sustainability in construction materials. The authors propose different solutions to make the concrete industry more environmentally friendly in order to reduce greenhouse gases emissions and consumption of non-renewable resources. Part 1-the present paper-focuses on the use of binders alternative to Portland cement, including sulfoaluminate cements, alkali-activated materials, and geopolymers. Part 2 will be dedicated to traditional Portland-free binders and waste management and recycling in mortar and concrete production. PMID- 29996744 TI - New enhanced influenza vaccines for older Australians: what promise do they hold? PMID- 29996745 TI - Ethics and site-specific governance approvals for multi-centre, inter-sector health care research. PMID- 29996746 TI - Preparation for general practice vocational training: time for a rethink. PMID- 29996747 TI - Randomised controlled trial wins prestigious MJA, MDA National Prize for Excellence in Medical Research. PMID- 29996749 TI - Care of patients with chronic disease: achievements in Australia over the past decade. PMID- 29996750 TI - Is it time to screen all patients with hypertension for primary aldosteronism? PMID- 29996751 TI - The scourge of the C. PMID- 29996752 TI - An unexpected orbital foreign body. PMID- 29996753 TI - Poisoning and poisoning advice: availability, toxico-vigilance and research. PMID- 29996754 TI - Severe asthma: implementing game-changing science. PMID- 29996755 TI - Chronic idiopathic constipation in adults: epidemiology, pathophysiology, diagnosis and clinical management. AB - Chronic idiopathic constipation (CIC) is one of the most common gastrointestinal disorders, with a global prevalence of 14%. It is commoner in women and its prevalence increases with age. There are three subtypes of CIC: dyssynergic defaecation, slow transit constipation and normal transit constipation, which is the most common subtype. Clinical assessment of the patient with constipation requires careful history taking, in order to identify any red flag symptoms that would necessitate further investigation with colonoscopy to exclude colorectal malignancy. Screening for hypercalcaemia, hypothyroidism and coeliac disease with appropriate blood tests should be considered. A digital rectal examination should be performed to assess for evidence of dyssynergic defaecation. If this is suspected, further investigation with high resolution anorectal manometry should be undertaken. Anorectal biofeedback can be offered to patients with dyssynergic defaecation as a means of correcting the associated impairment of pelvic floor, abdominal wall and rectal functioning. Lifestyle modifications, such as increasing dietary fibre, are the first step in managing other causes of CIC. If patients do not respond to these simple changes, then treatment with osmotic and stimulant laxatives should be trialled. Patients not responding to traditional laxatives should be offered treatment with prosecretory agents such as lubiprostone, linaclotide and plecanatide, or the 5-HT4 receptor agonist prucalopride, where available. If there is no response to pharmacological treatment, surgical intervention can be considered, but it is only suitable for a carefully selected subset of patients with proven slow transit constipation. PMID- 29996756 TI - Thyroid nodules: diagnosis and management. AB - Thyroid nodules are common. Their importance lies in the need to assess thyroid function, degree of and future risk of mass effect, and exclude thyroid cancer, which occurs in 7-15% of thyroid nodules. There are four key components to thyroid nodule assessment: clinical history and examination, serum thyroid stimulating hormone (TSH) measurement, ultrasound and, if indicated, fine-needle aspiration (FNA). If the serum TSH is suppressed, a thyroid scan with 99Tc can distinguish between a solitary hot nodule, a toxic multinodular goitre or, less commonly, thyroiditis or Graves' disease within a coexisting nodular thyroid. Scintigraphically cold nodules are evaluated in the same way as in the setting of normal or elevated serum TSH levels. Thyroid ultrasonography should be performed only for palpable goitre and thyroid nodules and by specialists with expertise in thyroid sonography. Routine thyroid cancer screening is not recommended, except in high risk individuals, as the detection of early thyroid cancer has not been shown to improve survival. FNA may be performed for nodules >= 1.0 cm depending on clinical and sonographic risk factors for thyroid cancer. FNA specimens should be read by an experienced cytopathologist and be reported according to the Bethesda Classification System. Molecular analysis of indeterminate FNA samples has potential to better discriminate benign from malignant nodules and thus guide management. Surgery is indicated for FNA findings of malignancy or indeterminate cytology when there is a high risk clinical context. Surgery may also be indicated for suspicion of malignancy; larger nodules, especially with symptoms of mass effect; and in some patients with thyrotoxicosis. PMID- 29996757 TI - Azithromycin for Salmonella infection: don't presume it works. PMID- 29996758 TI - New role for former AMA president. PMID- 29996759 TI - Effects of dietary energy levels on rumen bacterial community composition in Holstein heifers under the same forage to concentrate ratio condition. AB - BACKGROUND: The rumen bacterial community plays a critical role in feeds degradation and productivity. The effects of different forage to concentrate ratios on the ruminal microbial population structure have been studied extensively; however, research into changes in the ruminal bacterial community composition in heifers fed different energy level diets, with the same forage to concentrate ratio, has been very limited. The purpose of this study was to investigate the effects of different dietary energy levels, with the same forage to concentrate ratio, on ruminal bacterial community composition of heifers. Furthermore, we also determine the relationship between rumen bacteria and ruminal fermentation parameters. RESULTS: The 16S rRNA gene sequencing showed that, under the same forage to concentrate ratio of 50:50, an 8% difference in dietary energy level had no significant impact on the alpha diversity and the relative abundance of the major phyla and most of the major genera in heifers. In all the treatments groups, Firmicutes, Bacteroidetes, and Proteobacteria were the dominant phyla. Spearman correlation analysis between the relative abundances of the rumen bacteria at the genus level and the fermentation parameters showed that the relative abundances of Prevotella and BF311 were positively correlated with the ammonia nitrogen and butyrate concentrations, and these two genera were negatively correlated with the propionate and isovalerate concentrations, respectively, and the genus Bifidobacterium was positively correlated with the butyrate concentration and was negatively correlated with propionate and isovalerate concentration. The total volatile fatty acid concentration was positively correlated with BF311 abundances, and was negatively correlated with Trichococcus and Facklamia abundances. CONCLUSIONS: Under the same forage to concentrate ratio condition of 50:50, an 8% difference in dietary energy levels had little impact on rumen bacterial community composition in heifers. The correlations between some genera of ruminal bacteria and the concentrations of volatile fatty acids and ammonia nitrogen might be indicative that the ruminal fermentation parameters are strongly influenced by the rumen bacterial community composition. PMID- 29996760 TI - Does fentanyl or remifentanil provide better postoperative recovery after laparoscopic surgery? a randomized controlled trial. AB - BACKGROUND: Fentanyl and remifentanil are widely used opioids in surgery, but it has not been evaluated whether the choice of opioids during surgery affects the patients' postoperative quality of recovery. Accordingly, we aim to compare postoperative recovery of fentanyl-based anesthesia with remifentanil-based anesthesia after laparoscopic surgery using the QoR 40 questionnaire (QoR-40). METHODS: The study was prospective, randomized, patient and investigator-blinded, controlled, clinical trial. Seventy patients undergoing laparoscopic or retroperitoneoscopic renal or ureteral surgery were recruited and randomized to either fentanyl or remifentanil based anesthesia groups. The primary outcome was the global QoR-40 at 24 h after surgery. RESULTS: The global median (interquartile range) QoR-40 score was 160 (138-177) in the fentanyl group (n = 32) and 140 (127-166) in the remifentanil group (n = 31). Physical comfort and physical independence, the two out of the five dimensions of the QoR-40, demonstrated significantly high scores in the fentanyl group (P = 0.047 and P = 0.032, respectively). CONCLUSION: Although the global QoR is higher in the fentanyl group by 20 points compared with remifentanil group, no significant differences revealed between the groups. Further studies with large numbers of subjects of the same gender are needed. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN), UMIN000010464 . Registered 10 April 2013. PMID- 29996761 TI - Deleterious effects of catecholamine administration in acute heart failure caused by unrecognized Takotsubo cardiomyopathy. AB - The potential life-threatening consequences of catecholamine use for emergency circulatory support in Takotsubo cardiomyopathy-related acute heart failure is a major challenge in cardiovascular emergences. In their recent work in BMC Cardiovascular Disorders Ansari U. et al. demonstrated the harmful effects of catecholamines on the outcome of patients with Takotsubo cardiomyopathy. Concerning this matter we emphasize the usefulness of speckle-tracking-derived echocardiography for early recognition of an acute phase of a Takotsubo syndrome in order to avoid the deleterious effects of a catecholamine therapy in patients with Takotsubo-associated acute heart failure. PMID- 29996762 TI - Villous atrophy in the terminal ileum is a specific endoscopic finding correlated with histological evidence and poor prognosis in acute graft-versus-host disease after allo-hematopoietic stem cell transplantation. AB - BACKGROUND: Graft-versus-host disease (GVHD) is a common complication of allo hematopoietic stem cell transplantation (allo-HSCT). Endoscopic biopsy can provide a definitive diagnosis, but the optimal endoscopic approach for diagnosis remains uncertain. This study evaluated whether ileocolonoscopic imaging can predict acute GVHD severity after allo-HSCT. METHODS: Consecutive patients who underwent allo-HSCT were referred to our institution, and those diagnosed with acute GVHD by pathology were included in this retrospective study. RESULTS: Fifty one of 261 patients who underwent ileocolonoscopy were suspected to have acute intestinal GVHD. We performed univariate and multivariate conditional logistic regression with stepwise variable selection; villous atrophy in the terminal ileum remained a statistically significant predictor of GVHD severity (odds ratio, 4.69; 95% confidence interval, 1.07-20.60, P = 0.04). Patients were classified into three groups based on ileal endoscopic findings in the terminal ileum: group S, GVHD with severe villous atrophy; group M, mild atrophy; and group N, no atrophy. Compared with patients in groups M and N, those in group S had significant clinical GVHD at diagnosis (P = 0.03). In group S, three of four, compared with five of 13 patients in groups M and N, required the addition of second-line agents (P = 0.02). CONCLUSIONS: This study showed that severe atrophy of the terminal ileum predicts severe clinical GVHD that is likely to be refractory to steroid treatment. Thus, the severity of terminal ileum atrophy may serve as a tool in predicting clinically severe GVHD. TRIAL REGISTRATION: Trial Registration Number UMIN 000022805 , Registration date July 1, 2016. PMID- 29996763 TI - Genetics of resistance to photobacteriosis in gilthead sea bream (Sparus aurata) using 2b-RAD sequencing. AB - BACKGROUND: Photobacteriosis is an infectious disease developed by a Gram negative bacterium Photobacterium damselae subsp. piscicida (Phdp), which may cause high mortalities (90-100%) in sea bream. Selection and breeding for resistance against infectious diseases is a highly valuable tool to help prevent or diminish disease outbreaks, and currently available advanced selection methods with the application of genomic information could improve the response to selection. An experimental group of sea bream juveniles was derived from a Ferme Marine de Douhet (FMD, Oleron Island, France) selected line using ~ 109 parents (~ 25 females and 84 males). This group of 1187 individuals represented 177 full sib families with 1-49 sibs per family, which were challenged with virulent Phdp for a duration of 18 days, and mortalities were recorded within this duration. Tissue samples were collected from the parents and the recorded offspring for DNA extraction, library preparation using 2b-RAD and genotyping by sequencing. Genotypic data was used to develop a linkage map, genome wide association analysis and for the estimation of breeding values. RESULTS: The analysis of genetic variation for resistance against Phdp revealed moderate genomic heritability with estimates of ~ 0.32. A genome-wide association analysis revealed a quantitative trait locus (QTL) including 11 SNPs at linkage group 17 presenting significant association to the trait with p-value crossing genome-wide Bonferroni corrected threshold P <= 2.22e-06. The proportion total genetic variance explained by the single top most significant SNP was ranging from 13.28 16.14% depending on the method used to compute the variance. The accuracies of predicting breeding values obtained using genomic vs. pedigree information displayed 19-24% increase when using genomic information. CONCLUSION: The current study demonstrates that SNPs-based genotyping of a sea bream population with 2b RAD approach is effective at capturing the genetic variation for resistance against Phdp. Prediction accuracies obtained using genomic information were significantly higher than the accuracies obtained using pedigree information which highlights the importance and potential of genomic selection in commercial breeding programs. PMID- 29996764 TI - Consistent and reproducible long-term in vitro growth of health and disease associated oral subgingival biofilms. AB - BACKGROUND: Several in vitro oral biofilm growth systems can reliably construct oral microbiome communities in culture, yet their stability and reproducibility through time has not been well characterized. Long-term in vitro growth of natural biofilms would enable use of these biofilms in both in vitro and in vivo studies that require complex microbial communities with minimal variation over a period of time. Understanding biofilm community dynamics in continuous culture, and whether they maintain distinct signatures of health and disease, is necessary to determine the reliability and applicability of such models to broader studies. To this end, we performed next-generation sequencing on biofilms grown from healthy and disease-site subgingival plaque for 80 days to assess stability and reliability of continuous oral biofilm growth. RESULTS: Biofilms were grown from subgingival plaque collected from periodontitis-affected sites and healthy individuals for ten eight-day long generations, using hydroxyapatite disks. The bacterial community in each generation was determined using Human Oral Microbe Identification by Next-Generation Sequencing (HOMINGS) technology, and analyzed in QIIME. Profiles were steady through the ten generations, as determined by species abundance and prevalence, Spearman's correlation coefficient, and Faith's phylogenetic distance, with slight variation predominantly in low abundance species. Community profiles were distinct between healthy and disease site derived biofilms as demonstrated by weighted UniFrac distance throughout the ten generations. Differentially abundant species between healthy and disease site derived biofilms were consistent throughout the generations. CONCLUSIONS: Healthy and disease site-derived biofilms can reliably maintain consistent communities through ten generations of in vitro growth. These communities maintain signatures of health and disease and of individual donors despite culture in identical environments. This subgingival oral biofilm growth and perpetuation model may prove useful to studies involving oral infection or cell stimulation, or those measuring microbial interactions, which require the same biofilms over a period of time. PMID- 29996765 TI - Antimicrobial potentiality of actinobacteria isolated from two microbiologically unexplored forest ecosystems of Northeast India. AB - BACKGROUND: Actinobacteria are often known to be great producers of antibiotics. The rapid increase in the global burden of antibiotic-resistance with the concurrent decline in the discovery of new antimicrobial molecules necessitates the search for novel and effective antimicrobial metabolites from unexplored ecological niches. The present study investigated the antimicrobial producing actinobacterial strains isolated from the soils of two microbiologically unexplored forest ecosystems, viz. Nameri National Park (NNP) and Panidehing Wildlife Sanctuary (PWS), located in the Eastern Himalayan Biodiversity hotspot region. RESULTS: A total of 172 putative isolates of actinobacteria were isolated, of which 24 isolates showed strong antimicrobial bioactivity. Evaluation of the ethyl acetate extracts of culture supernatants against test microbial strains revealed that isolates PWS22, PWS41, PWS12, PWS52, PWS11, NNPR15, NNPR38, and NNPR69 were the potent producers of antimicrobial metabolites. The antimicrobial isolates dominantly belonged to Streptomyces, followed by Nocardia and Streptosporangium. Some of these isolates could be putative novel taxa. Analysis of the antimicrobial biosynthetic genes (type II polyketide synthase and nonribosomal peptide synthetase genes) showed that the antimicrobial metabolites were associated with pigment production and belonged to known families of bioactive secondary metabolites. Characterization of the antimicrobial metabolites of Streptomyces sp. PWS52, which showed lowest taxonomic identity among the studied potent antimicrobial metabolite producers, and their interaction with the test strains using GC-MS, UHPLC-MS, and scanning electron microscopy revealed that the potential bioactivity of PWS52 was due to the production of active antifungal and antibacterial metabolites like 2,5 bis(1,1-dimethylethyl) phenol, benzeneacetic acid and nalidixic acid. CONCLUSIONS: Our findings suggest that the unexplored soil habitats of NNP and PWS forest ecosystems of Northeast India harbor previously undescribed actinobacteria with the capability to produce diverse antimicrobial metabolites that may be explored to overcome the rapidly rising global concern about antibiotic-resistance. PMID- 29996766 TI - Molecular diversity and function of jasmintides from Jasminum sambac. AB - BACKGROUND: Jasmintides jS1 and jS2 from Jasminum sambac were previously identified as a novel family of cysteine-rich peptides (CRPs) with an unusual disulfide connectivity. However, very little else is known about jasmintides, particularly their molecular diversity and functions. Here, we report the discovery and characterization of a novel suite of jasmintides from J. sambac using transcriptomic, peptidomic, structural and functional tools. RESULTS: Transcriptomic analysis of leaves, flowers and roots revealed 14 unique jasmintide precursors, all of which possess a three-domain architecture comprising a signal peptide, a pro-domain and a mature jasmintide domain. Peptidomic analysis, using fractionated mixtures of jasmintides and chemical derivatization of cysteine to pseudolysine, trypsin digestion and MS/MS sequencing, revealed an additional 86 jasmintides, some of which were post translationally modified. NMR analysis showed that jasmintide jS3 has three anti parallel beta-strands with a three-disulfide connectivity of CysI-CysV, CysII CysIV and CysIII-CysVI, which is similar to jasmintide jS1. Jasmintide jS3 was able to withstand thermal, acidic and enzymatic degradation and, importantly, exhibited antifeedant activity against mealworm Tenebrio molitor. CONCLUSION: Together, this study expands the existing library of jasmintides and furthers our understanding of the molecular diversity and cystine framework of CRPs as scaffolds and tools for engineering peptides targeting pests. PMID- 29996767 TI - Developing quality indicators for in-patient post-acute care. AB - BACKGROUND: This paper describes an integrated series of functional, clinical, and discharge post-acute care (PAC) quality indicators (QIs) and an examination of the distribution of the QIs in skilled nursing facilities (SNF) across the US. The indicators use items available in interRAI based assessments including the MDS 3.0 and are designed for use in in-patient post-acute environments that use the assessments. METHODS: Data Source: MDS 3.0 computerized assessments mandated for all patients admitted to US skilled nursing facilities (SNF) in 2012. In total, 2,380,213 patients were admitted to SNFs for post-acute care. Definition of the QI numerator, denominator and covariate structures were based on MDS assessment items. A regression strategy modeling the "discharge to the community" PAC QI as the dependent variable was used to identify how to bring together a subset of seven candidate PAC QIs for inclusion in a summary scale. Finally, the distributional property of the summary scale (the PAC QI Summary Scale) across all facilities was explored. RESULTS: The risk-adjusted PAC QIs include indicators of improved status, including measures of early, middle, and late-loss functional performance, as well as measures of walking and changed clinical status and an overall summary functional scale. Many but not all patients demonstrated improvement from baseline to follow-up. However, there was substantial inter-state variation in the summary QI scores across the SNFs. CONCLUSIONS: The set of PAC QIs consist of five functional, two discharge and eight clinical measures, and one summary scale. All QIs can be derived from multiple interRAI assessment tools, including the MDS 2.0, interRAI-LTCF, MDS 3.0, and the interRAI-PAC-Rehab. These measures are appropriate for wide distribution in and out of the United States, allowing comparison and discussion of practices associated with better outcomes. PMID- 29996768 TI - Sustained high glucose exposure sensitizes macrophage responses to cytokine stimuli but reduces their phagocytic activity. AB - BACKGROUND: Macrophages are tissue resident immune cells important for host defence and homeostasis. During diabetes, macrophages and other innate immune cells are known to have a pro-inflammatory phenotype, which is believed to contribute to the pathogenesis of various diabetic complications. However, diabetic patients are highly susceptible to bacterial infections, and often have impaired wound healing. The molecular mechanism underlying the paradox of macrophage function in diabetes is not fully understood. Recent evidence suggests that macrophage functions are governed by metabolic reprograming. Diabetes is a disorder that affects glucose metabolism; dysregulated macrophage function in diabetes may be related to alterations in their metabolic pathways. In this study, we seek to understand the effect of high glucose exposure on macrophage phenotype and functions. RESULTS: Bone marrow cells were cultured in short or long term high glucose and normal glucose medium; the number and phenotype of bone marrow derived macrophages were not affected by long-term high glucose treatment. Short-term high glucose increased the expression of IL-1beta. Long term high glucose increased the expression of IL-1beta and TNFalpha but reduced the expression of IL-12p40 and nitric oxide production in M1 macrophage. The treatment also increased Arg-1 and IL-10 expression in M2 macrophages. Phagocytosis and bactericidal activity was reduced in long-term high glucose treated macrophages and peritoneal macrophages from diabetic mice. Long-term high glucose treatment reduced macrophage glycolytic capacity and glycolytic reserve without affecting mitochondrial ATP production and oxidative respiration. CONCLUSION: Long-term high glucose sensitizes macrophages to cytokine stimulation and reduces phagocytosis and nitric oxide production, which may be related to impaired glycolytic capacity. PMID- 29996769 TI - Comparative genomic analysis of Enterococcus faecalis: insights into their environmental adaptations. AB - BACKGROUND: Enterococcus faecalis is widely studied as a common gut commensal and a nosocomial pathogen. In fact, Enterococcus faecalis is ubiquitous in nature, and it has been isolated from various niches, including the gastrointestinal tract, faeces, blood, urine, water, and fermented foods (such as dairy products). In order to elucidate the role of habitat in shaping the genome of Enterococcus faecalis, we performed a comparative genomic analysis of 78 strains of various origins. RESULTS: Although no correlation was found between the strain isolation habitat and the phylogeny of Enterococcus faecalis from our whole genome-based phylogenetic analysis, our results revealed some environment-associated features in the analysed Enterococcus faecalis genomes. Significant differences were found in the genome size and the number of predicted open reading frames (ORFs) between strains originated from different environments. In general, strains from water sources had the smallest genome size and the least number of predicted ORFs. We also identified 293 environment-specific genes, some of which might link to the adaptive strategies for survival in particular environments. In addition, the number of antibiotic resistance genes was significantly different between strains isolated from dairy products, water, and blood. Strains isolated from blood had the largest number of antibiotic resistance genes. CONCLUSION: These findings improve our understanding of the role of habitat in shaping the genomes of Enterococcus faecalis. PMID- 29996770 TI - A meta-analysis of the efficacy of allopurinol in reducing the incidence of myocardial infarction following coronary artery bypass grafting. AB - BACKGROUND: The xanthine oxidase inhibitor allopurinol that is commonly used to treat gout, has been suggested to have pleiotropic effects that are likely to reduce the incidence of myocardial infarction (MI) in at risk individuals. The aim of this meta-analysis was to assess the efficacy of allopurinol treatment in reducing the incidence of MI. METHOD: MEDLINE, Scopus, Web of Science, and Cochrane Library databases were searched for randomised controlled trials examining the efficacy of allopurinol in reducing the incidence of MI. The quality of study methodology was assessed by two independent reviewers using the Cochrane Collaboration's tool for assessing risk of bias. This meta-analysis was conducted using a fixed-effects model, and heterogeneity was assessed with the I2 index. RESULTS: One thousand one hundred twenty-three citations were screened and only six studies satisfied the inclusion criterion. Published between 1988 and 1995, all studies examined the cardioprotective efficacy of allopurinol in the setting of coronary artery bypass graft (CABG). From a total pooled sample size of 229, MI was reported in 2 (1.77%) allopurinol and 14 (12.07%) control patients. A fixed-effects meta-analysis (I2 = 0%) identified a statistically significant reduced incidence of myocardial infarction (RR 0.21, 95% CI: 0.06, 0.70, p = 0.01) in patients allocated to allopurinol. However, in the leave-one out sensitivity analyses, the treatment effect became non-significant with the removal of one of the studies. CONCLUSION: Based on the limited evidence available, allopurinol appears to reduce the incidence of perioperative MI following CABG. Further research is required to confirm these findings. PMID- 29996771 TI - Novel metrics for quantifying bacterial genome composition skews. AB - BACKGROUND: Bacterial genomes have characteristic compositional skews, which are differences in nucleotide frequency between the leading and lagging DNA strands across a segment of a genome. It is thought that these strand asymmetries arise as a result of mutational biases and selective constraints, particularly for energy efficiency. Analysis of compositional skews in a diverse set of bacteria provides a comparative context in which mutational and selective environmental constraints can be studied. These analyses typically require finished and well annotated genomic sequences. RESULTS: We present three novel metrics for examining genome composition skews; all three metrics can be computed for unfinished or partially-annotated genomes. The first two metrics, (dot-skew and cross-skew) depend on sequence and gene annotation of a single genome, while the third metric (residual skew) highlights unusual genomes by subtracting a GC content-based model of a library of genome sequences. We applied these metrics to 7738 available bacterial genomes, including partial drafts, and identified outlier species. A phylogenetically diverse set of these outliers (i.e., Borrelia, Ehrlichia, Kinetoplastibacterium, and Phytoplasma) display similar skew patterns but share lifestyle characteristics, such as intracellularity and biosynthetic dependence on their hosts. CONCLUSIONS: Our novel metrics appear to reflect the effects of biosynthetic constraints and adaptations to life within one or more hosts on genome composition. We provide results for each analyzed genome, software and interactive visualizations at http://db.systemsbiology.net/gestalt/ skew_metrics . PMID- 29996773 TI - Small doses of epinephrine prolong the recovery from a rocuronium-induced neuromuscular block: a case report. AB - BACKGROUND: During anaesthesia it is not uncommon to administer epinephrine in patients blocked by non-depolarizing muscle relaxants. However, there are few reports on possible interaction of epinephrine with neuromuscular transmission in humans. CASE PRESENTATION: An otherwise healthy 74-yr-old man underwent transurethral resection of a benign prostatic hyperplasia under total intravenous anaesthesia. Because of repeated drop in heart rate and blood pressure the patient received in total three bolus of epinephrine 5 MUg, respectively. Each time this small dose of epinephrine intensified a rocuronium-induced neuromuscular block verified by acceleromygraphy. Further anaesthetic course was uneventful. CONCLUSIONS: In this case reported here small doses of intravenously administered epinephrine markedly prolonged a rocuronium-induced neuromuscular block. Given the widely used co-administration of epinephrine and muscle relaxants possible adrenergic interference with neuromuscular transmission would have implications for daily anaesthetic practice. PMID- 29996772 TI - Taurocholic acid is an active promoting factor, not just a biomarker of progression of liver cirrhosis: evidence from a human metabolomic study and in vitro experiments. AB - BACKGROUND: Previous studies have indicated that bile acid is associated with progression of liver cirrhosis. However, the particular role of specific bile acid in the development of liver cirrhosis is not definite. The present study aims to identify the specific bile acid and explore its possible mechanisms in promoting liver cirrhosis. METHODS: Thirty two cirrhotic patients and 27 healthy volunteers were enrolled. Age, gender, Child-Pugh classification and serum of patients and volunteers were collected. Liquid chromatography tandem mass spectrometry (LC-MS) was utilized to determine concentrations of 12 bile acids in serum. Principal component analysis, fold change analysis and heatmap analysis were used to identify the most changed bile acid. And pathway analysis was used to identify the most affected pathway in bile acid metabolism. Spearman rank correlation analysis was employed to assess correlation between concentrations of bile acids and Child-Pugh classification. Hepatic stellate cells (LX-2) were cultured in DMEM. LX-2 cells were also co-cultured with HepG2 cells in the transwell chambers. LX-2 cells were treated with Na+/taurocholate in different concentrations. Western blot was used to evaluate the expression of alpha smooth muscle actin (alpha-SMA), type I collagen, and Toll-like receptor 4 (TLR4) in LX 2 cells. RESULTS: Concentrations of 12 bile acids in serum of patients and healthy volunteers were determined with LC-MS successively. Principal component analysis, fold change analysis and heatmap analysis identified taurocholic acid (TCA) to be the most changed bile acid. Pathway analysis showed that TCA biosynthesis increased significantly. Spearman rank correlation analysis showed that concentration of TCA in serum of cirrhotic patients was positively associated with Child-Pugh classification. TCA increased the expression of alpha SMA, type I collagen, and TLR4 in LX-2 cells. Moreover, the above effect was strengthened when LX-2 cells were co-cultured with HepG2 cells. CONCLUSIONS: Increased TCA concentration in serum of liver cirrhotic patients is mainly due to increased bile acid biosynthesis. TCA is an active promoter of the progression of liver cirrhosis. TCA promoting liver cirrhosis is likely through activating hepatic stellate cells via upregulating TLR4 expression. TCA is a potential therapeutic target for the prevention and treatment of liver cirrhosis. PMID- 29996774 TI - The impact of motility on the localization of Lactobacillus agilis in the murine gastrointestinal tract. AB - BACKGROUND: While the overall composition of the mammalian gut microbiota has been intensively studied, the characteristics and ecologies of individual gut species are incompletely understood. Lactobacilli are considered beneficial commensals in the gastrointestinal mucosa and are relatively well-studied except for the uncommon species which exhibit motility. In this study, we evaluate the importance of motility on gut colonization by comparing motile and non-motile strains of Lactobacillus agilis in mice models. RESULTS: A flagellated but non motile L. agilis strain was constructed by mutation of the motB gene. Colonization of the wild type and the mutant strain was assessed in both antibiotic-treated female Balb/c mice and gnotobiotic mice. The results suggest that the motile strain is better able to persist and/or localize in the gut mucosa. Chemotaxis assays indicated that the motile L. agilis strain is attracted by mucin, which is a major component of the intestinal mucus layer in animal guts. CONCLUSIONS: Motility and chemotactic ability likely confer advantages in gut colonization to L. agilis. These findings suggest that the motile lactobacilli have unique ecologies compared to non-motile commensals of the lactic acid bacteria. PMID- 29996775 TI - Relative costs and benefits of alternative reproductive phenotypes at different temperatures - genotype-by-environment interactions in a sexually selected trait. AB - BACKGROUND: The maintenance of considerable genetic variation in sexually selected traits (SSTs) is puzzling given directional selection expected to act on these traits. A possible explanation is the existence of a genotype-by environment (GxE) interaction for fitness, by which elaborate SSTs are favored in some environments but selected against in others. In the current study, we look for such interactions for fitness-related traits in the bulb mite, a male dimorphic species with discontinuous expression of a heritable SST in the form of enlarged legs that are used as weapons. RESULTS: We show that evolution at 18 degrees C resulted in populations with a higher prevalence of this SST compared to evolution at 24 degrees C. We further demonstrate that temperature modified male reproductive success in a way that was consistent with these changes. There was a genotype-by-environment interaction for reproductive success - at 18 degrees C the relative reproductive success of armored males competing with unarmored ones was higher than at the moderate temperature of 24 degrees C. However, male morph did not have interactive effects with temperature with respect to other life history traits (development time and longevity). CONCLUSIONS: A male genotype that is associated with the expression of a SST interacted with temperature in determining male reproductive success. This interaction caused an elaborate SST to evolve in different directions (more or less prevalent) depending on the thermal environment. The implication of this finding is that seasonal temperature fluctuations have the potential to maintain male polymorphism within populations. Furthermore, spatial heterogeneity in thermal conditions may cause differences among populations in SST selection. This could potentially cause selection against male immigrants from populations in different environments and thus strengthen barriers to gene flow. PMID- 29996776 TI - Trend of HIV/AIDS for the last 26 years and predicting achievement of the 90-90 90 HIV prevention targets by 2020 in Ethiopia: a time series analysis. AB - BACKGROUND: HIV infection continues to be epidemic of public health importance with a prevalence of 1.1% and incidence of 0.33/1000 population having low intensity mixed epidemic. Ethiopia has adopted the 90-90-90 by 2020 target but its progress was not yet assessed. Therefore, this study aimed to assess the trend of HIV infection for the last 26 years and to predict the achievements of the 90-90-90 target. METHODS: We used aggregates of HIV/AIDS indicator data from 1990 to 2016 of UNAIDS data bases. The data were analyzed with excel and STATA. The trend line that best fits the regression was drawn, annual change was estimated and future values of HIV detection rate, coverage of antiretroviral therapy and viral suppression indicators were predicted and compared with the 90 90-90 targets. RESULT: Since 1995, new infection has declined by 81% and since 2002; number of HIV cases has declined by 35.5%. However, after remarkable decline for decades, since 2008 HIV incidence rate began to rise by 10% and number of new infection diagnosed each year increased by 36% among all ages and doubled among adults. ART coverage has increased by 90% among all age and tripled among pregnant women within 6 years. Nationally, 67% of people living with HIV know their status, 88% of them are on treatment and 86% of people on treatment have viral suppression. As a result, AIDS-related death declined by 77 and 79% among all age and children respectively. By 2020, 79% of people living with HIV will know their HIV status, of which 96-99% of HIV infected people will be on ART and more than 86% will have viral suppression. CONCLUSION: After remarkable decline, HIV infection started to increase in the last few years among adults. With the current trend, Ethiopia will achieve the second and third 90% HIV targets, while the first target is not achievable and without achieving this overarching goal control of the epidemic will not be achieved. Therefore due attention is needed to avert the current epidemics and diagnosis of cases. PMID- 29996778 TI - Unmet needs of activities of daily living among a community-based sample of disabled elderly people in Eastern China: a cross-sectional study. AB - BACKGROUND: China has the largest population of partially or completely disabled elderly people in the world. Although the disabled elderly people try to remain independent in their lives, many still need assistance from others. Failure to obtain sufficient assistance creates a situation of unmet need. Unmet needs of activities of daily living (ADL) for disabled elderly people pose significant risks for hospitalization and mortality and cause an increased economic burden on families and society. This study aimed to identify the prevalence and risk factors of unmet needs among the disabled elderly in China to guide government toward corrective action. METHODS: A total of 303 older adults from 15 communities in Nanjing, China were recruited. The Barthel Index (BI) and Functional Activities Questionnaire (FAQ) were used to screen disabled elderly people from the communities. These disabled elderly participants were then investigated in terms of their unmet ADL needs, using an unmet needs assessment form, which had been adapted from the BI and FAQ. Additionally, the Zarit Burden Interview and Family Caregiver Task Inventory were used to survey the main caregivers. Finally, univariate analysis was first used to filter out candidate impact factors, and then, binary logistic regression analysis was used to adjust for cofounders and determine reliable risk factors. RESULTS: A total of 93.1% of the disabled elderly people in our study reported at least one unmet need. The prevalence of unmet needs for different ADL tasks ranged from 4.6 to 77.2%. The unmet needs with the highest percentages were using vehicles (77.2%), using stairs (73.1%), working on a hobby (72.1%), social interaction (62.6%) and ambulating (60.1%). The factors influencing unmet needs were related to the degree of disability in instrumental activities of daily living (IADL) (OR = 1.079, p <= 0.01), the relationship with caregivers (OR = 1.429, p <= 0.05) and the monthly income of caregivers (OR = 0.679, p <= 0.05). CONCLUSION: Disabled elderly people living in communities had a high percentage of unmet needs for activities of daily life that required going outside the bedroom and involved spiritual aspects. Unmet needs increased with worsening disability status in IADL, more distanced relationships with caregivers and lower incomes of caregivers. Both government and caregivers should take more action to prevent or reduce unmet needs among the elderly. PMID- 29996777 TI - Mapping visuospatial attention: the greyscales task in combination with repetitive navigated transcranial magnetic stimulation. AB - BACKGROUND: Visuospatial attention is executed by the frontoparietal cortical areas of the brain. Damage to these areas can result in visual neglect. We therefore aimed to assess a combination of the greyscales task and repetitive navigated transcranial magnetic stimulation (rTMS) to identify cortical regions involved in visuospatial attention processes. This pilot study was designed to evaluate an approach in a cohort of healthy volunteers, with the future aim of using this technique to map brain tumor patients before surgery. Ten healthy, right-handed subjects underwent rTMS mapping of 52 cortical spots in both hemispheres. The greyscales task was presented tachistoscopically and was time locked to rTMS pulses. The task pictures showed pairs of horizontal rectangles shaded continuously from black at one end to white at the other, mirror-reversed. On each picture the subject was asked to report which of the two greyscales appeared darker overall. The responses were categorized into "leftward" and "rightward," depending on whether the subject had chosen the rectangle with the darker end on the left or the right. rTMS applied to cortical areas involved in visuospatial attention is supposed to affect lateral shifts in spatial bias. These shifts result in an altered performance on the greyscales task compared to the baseline performance without rTMS stimulation. RESULTS: In baseline conditions, 9/10 subjects showed classic pseudoneglect to the left. Leftward effects also occurred more often in mapping conditions. Yet, calculated rightward deviations were strikingly greater in magnitude (p < 0.0001). Overall, the right hemisphere was found to be more suggestible than the left hemisphere. Both rightward and leftward deviation scores were higher for the rTMS of this brain side (p < 0.0001). Right hemispheric distributions accord well with current models of visuospatial attention (Corbetta et al. Nat Neurosci 8(11):1603-1610, 2005). We observed leftward deviations triggered by rTMS within superior frontal and posterior parietal areas and rightward deviations within inferior frontal areas and the temporoparietal junction (TPJ). CONCLUSION: The greyscales task, in combination with rTMS, yields encouraging results in the examination of the visuospatial attention function. Future clinical implications should be evaluated. PMID- 29996779 TI - Whole-transcriptome changes in gene expression accompany aging of sensory neurons in Aplysia californica. AB - BACKGROUND: Large-scale molecular changes occur during aging and have many downstream consequences on whole-organism function, such as motor function, learning, and memory. The marine mollusk Aplysia californica can be used to study transcriptional changes that occur with age in identified neurons of the brain, because its simplified nervous system allows for more direct correlations between molecular changes, physiological changes, and their phenotypic outcomes. Behavioral deficits in the tail-withdrawal reflex of aged animals have been correlated with reduced excitation in sensory neurons that control the reflex. RNASeq was used to investigate whole-transcriptome changes in tail-withdrawal sensory neurons of sexually mature and aged Aplysia to correlate transcriptional changes with reduced behavioral and physiological responses. RESULTS: Paired-end sequencing resulted in 210 million reads used for differential expression analysis. Aging significantly altered expression of 1202 transcripts in sensory neurons underlying the tail-withdrawal reflex, with an approximately equal number of these genes up- and down regulated with age. Despite overall bidirectionality of expression changes, > 80% of ion channel genes that were differentially expressed had decreased expression with age. In particular, several voltage-gated K+ and Ca2+ channels were down regulated. This marked decrease in ion channel expression may play an important role in previously observed declines in aged sensory neuron excitability. We also observed decreased expression of genes and pathways involved in learning and memory. Genes involved in the stress response showed increased expression in aged Aplysia neurons. CONCLUSIONS: Significantly altered expression of many genes between sexually mature and aged Aplysia suggests large molecular changes that may impact neuronal function. Decreased ion channel mRNA observed could mean fewer receptors present in aged neurons, resulting in reduced excitability of PVC sensory neurons, ultimately leading to reduced tail-withdrawal reflex observed in aged Aplysia. Significant changes in other genes and pathways, such as stress response and learning and memory, have previously been shown to occur with age in many vertebrate organisms. This suggests that some effects of aging are common across many animal phyla. PMID- 29996780 TI - Coinfections identified from metagenomic analysis of cervical lymph nodes from tularemia patients. AB - BACKGROUND: Underlying coinfections may complicate infectious disease states but commonly go unnoticed because an a priori clinical suspicion is usually required so they can be detected via targeted diagnostic tools. Shotgun metagenomics is a broad diagnostic tool that can be useful for identifying multiple microbes simultaneously especially if coupled with lymph node aspirates, a clinical matrix known to house disparate pathogens. The objective of this study was to analyze the utility of this unconventional diagnostic approach (shotgun metagenomics) using clinical samples from human tularemia cases as a test model. Tularemia, caused by the bacterium Francisella tularensis, is an emerging infectious disease in Turkey. This disease commonly manifests as swelling of the lymph nodes nearest to the entry of infection. Because swollen cervical nodes are observed from many different types of human infections we used these clinical sample types to analyze the utility of shotgun metagenomics. METHODS: We conducted an unbiased molecular survey using shotgun metagenomics sequencing of DNA extracts from fine needle aspirates of neck lymph nodes from eight tularemia patients who displayed protracted symptoms. The resulting metagenomics data were searched for microbial sequences (bacterial and viral). RESULTS: F. tularensis sequences were detected in all samples. In addition, we detected DNA of other known pathogens in three patients. Both Hepatitis B virus (HBV) and Human Parvovirus B-19 were detected in one individual and Human Parvovirus B-19 alone was detected in two other individuals. Subsequent PCR coupled with Sanger sequencing verified the metagenomics results. The HBV status was independently confirmed via serological diagnostics, despite evading notice during the initial assessment. CONCLUSION: Our data highlight that shotgun metagenomics of fine-needle lymph node aspirates is a promising clinical diagnostic strategy to identify coinfections. Given the feasibility of the diagnostic approach demonstrated here, further steps to promote integration of this type of diagnostic capability into mainstream clinical practice are warranted. PMID- 29996781 TI - Population-wide administration of single dose rifampicin for leprosy prevention in isolated communities: a three year follow-up feasibility study in Indonesia. AB - BACKGROUND: Indonesia ranking third in the world, regarding leprosy burden. Chemoprophylaxis is effective in reducing risk of developing leprosy among contacts. 'Blanket approach' is an operational strategy for leprosy post-exposure prophylaxis in which all members of an isolated community, high endemic for leprosy are screened and given a single dose of rifampicin (SDR) in the absence of signs and symptoms of leprosy. The objective is to assess the operational feasibility of a population-wide 'blanket' administration of SDR for leprosy prevention in isolated communities in a remote island. METHODS: A prospective follow-up study was conducted in the year 2014, 2015 and 2016 in Lingat village of Selaru Island, Indonesia. During the first two visits, screening and SDR were provided, whereas only screening was conducted during the third visit. The demographic and clinical data were used for a descriptive analysis of the project coverage and leprosy epidemiology. RESULTS: During the first two visits, 1671 persons (88%) were screened, 1499 (79%) received SDR, and 213 (11%) were excluded based on the exclusion criteria. During the first two visits, 43 (2.6%) cases were diagnosed with leprosy with a rate of 2263 per 100,000 population. The prevalence was highest in the age groups 15-24 and 25-49 years. Total, 14 (33%) cases had MB and 29 (67%) PB leprosy. Two cases (5%) had grade 2 disability. During the third visit, 10 new leprosy cases, with no grade 2 disability, were detected out of 1481 screened persons at the rate of 484 cases per 100,000 population (n = 2065 population in 2016). Among those screened during the third visit, there was a 50% reduction of leprosy among those who had previously received SDR compared to those who had not. CONCLUSION: With adequate planning and some additional investment, it is feasible to implement a blanket approach of chemoprophylaxis in a remote island of Indonesia, although effort needs to be made to cover as many people as possible in the first visit. Contingency plans need to be made to actively follow this village closely in the coming years and continue leprosy elimination efforts until no new cases are found any more. PMID- 29996782 TI - Evidence of rickettsiae in Danish patients tested for Lyme neuroborreliosis: a retrospective study of archival samples. AB - BACKGROUND: With a prevalence of 4.7-13% in Danish Ixodes ricinus ticks, Rickettsia helvetica is one of the most frequently detected tick-borne organisms in Denmark. Most reports of human exposure have described asymptomatic seroconversion or a mild, self-limiting flu-like illness but it has also been implicated as a cause of subacute lymphocytic meningitis. Because Borrelia burgdorferi sensu lato (Bbsl) and R. helvetica are both found in the same tick species, potential co-transmission is a possibility. We examined 1) the seroprevalence of anti-rickettsia antibodies in patients investigated for Lyme neuroborreliosis (LNB), and 2) the cerebrospinal fluid (CSF) and sera of same patients for the presence of Rickettsia DNA. METHODS: Ninety-nine sera and 87 CSF samples from patients with intrathecal synthesis of anti-Borrelia antibodies and 101 sera and 103 CSF samples from patients with no detectable intrathecal synthesis were retrospectively examined for this study. Sera were analyzed for antibodies against spotted fever group (SFG) rickettsiae and both the CSF and sera were tested for Rickettsia DNA using a genus-specific real-time PCR. RESULTS: Of the patients tested for LNB, 32% (64/200) had IgG antibodies against SFG rickettsiae. Among patients with confirmed intrathecal synthesis of Borrelia specific antibodies, 38% (38/99) exhibited IgG antibodies. None of these values were statistically significant when compared with sera from healthy blood donors (p = 0.7 and 0.19). Rickettsia DNA was found in the CSF of 4% (8/190) of patients. CONCLUSION: No statistically significant difference was found in the seroprevalence of anti-rickettsia antibodies in patients tested for LNB and healthy blood donors, indicative of a low rate of exposure in this group of patients. Eight patients showed evidence of Rickettsia DNA in the CSF, five of whom had LNB. However, cycle threshold (Ct) values were high, indicating low concentrations of DNA, and no apparent alteration in the clinical manifestations of LNB were noted in the medical records of these patients. PMID- 29996784 TI - Impact of etravirine on hospitalization rate between 2005 and 2011 among heavily treated HIV-1-infected individuals on failing regimens. AB - BACKGROUND: Etravirine (ETR), a non-nucleoside reverse transcriptase inhibitor (NNRTI) available in France since 2006, is indicated for antiretroviral experienced HIV-infected adults, in combination with a ritonavir-boosted protease inhibitor (PI). To assess its clinical impact in routine care, we compared hospitalization rates according to ETR + PI prescription or not, among heavily treated HIV-1 infected individuals on failing regimens between 2005 and 2011. METHODS: From the French Hospital Database on HIV (ANRS CO4), we selected heavily treated individuals (prior exposure to at least 2 nucleoside reverse transcriptase inhibitor (NRTI), 2PI and 1 NNRTI) with viral load (VL) > 50 copies/mL who started a new antiretroviral (ARV) regimen between 2005 and 2011. Using an intention-to-continue-treatment approach, hospitalization rates were calculated for the individuals who received ETR + PI, during the months after initiating ETR + PI (ETR + PI) or for the individuals who received ETR + PI, in the months before ETR + PI initiation and for the individuals who never received ETR + PI (no ETR + PI). hospitalization from an AIDS-defining cause and hospitalization from a non-AIDS defining cause rates were also calculated. Poisson regression models were used to compare the incidences between the two groups, with adjustment for potential confounders. RESULTS: Of 3884 patients who met the inclusion criteria, 838 (21.6%) received ETR + PI. During 13,986 person years (P-Y) of follow-up, there were 2484 hospitalizations in 956 individuals. The hospitalization rates per 1000 P-Y were 169.0 among individuals exposed to ETR + PI and 179.3 among those not exposed to ETR + PI. After adjustment, the respective hospitalization rates were 148.8 and 186.7 per 1000 P-Y, with an estimated relative risk of 0.80 (95%CI: 0.71-0.90), AIDS hospitalization rates were 11.5 and 22.7 per 1000 P-Y, with an estimated relative risk of 0.51(95%CI: 0.39-0.66) and non-AIDS hospitalization rates were 139.5 and 152.2 per 1000 P-Y, with an estimated relative risk of 0.92 (95%CI: 0.80-1.05). CONCLUSIONS: Between 2005 and 2011, access to ETR + PI was associated with a 20% reduction in the hospitalization rate among heavily treated HIV-1-infected individuals. This reduction was mainly due to a reduction in the AIDS hospitalization rate. PMID- 29996783 TI - Toxicity associated with tuberculosis chemotherapy in the REMoxTB study. AB - BACKGROUND: The incidence and severity of tuberculosis chemotherapy toxicity is poorly characterised. We used data available from patients in the REMoxTB trial to provide an assessment of the risks associated with the standard regimen and two experimental regimens containing moxifloxacin. METHODS: All grade 3 & 4 adverse events (AEs) and their relationship to treatment for patients who had taken at least one dose of therapy in the REMoxTB clinical trial were recorded. Univariable logistic regression was used to test the relationship of baseline characteristics to the incidence of grade 3 & 4 AEs and significant characteristics (p < 0.10) were incorporated into a multivariable model. The timing of AEs during therapy was analysed in standard therapy and the experimental arms. Logistic regression was used to investigate the relationship between AEs (total and related-only) and microbiological cure on treatment. RESULTS: In the standard therapy arm 57 (8.9%) of 639 patients experienced >=1 related AEs with 80 of the total 113 related events (70.8%) occurring in the intensive phase of treatment. Both four-month experimental arms ("isoniazid arm" with moxifloxacin substituted for ethambutol & "ethambutol arm" with moxifloxacin substituted for isoniazid) had a lower total of related grade 3 & 4 AEs than standard therapy (63 & 65 vs 113 AEs). Female gender (adjOR 1.97, 95% CI 0.91 1.83) and HIV-positive status (adjOR 3.33, 95% CI 1.55-7.14) were significantly associated with experiencing >=1 related AE (p < 0.05) on standard therapy. The most common adverse events on standard therapy related to hepatobiliary, musculoskeletal and metabolic disorders. Patients who experienced >=1 related AE were more likely to fail treatment or relapse (adjOR 3.11, 95% CI 1.59-6.10, p < 0.001). CONCLUSIONS: Most AEs considered related to standard therapy occurred in the intensive phase of treatment with female patients and HIV-positive patients demonstrating a significantly higher risk of AEs during treatment. Almost a tenth of standard therapy patients had a significant side effect, whereas both experimental arms recorded a lower incidence of toxicity. That patients with one or more AE are more likely to fail treatment suggests that treatment outcomes could be improved by identifying such patients through targeted monitoring. PMID- 29996785 TI - Hepatitis B virus infection among pregnant women in Ethiopia: a systematic review and Meta-analysis of prevalence studies. AB - BACKGROUND: There are several epidemiological studies available on hepatitis B virus among pregnant women in Ethiopia. These individual studies revealed wide variation over time and across geographical areas. The aim of this systematic review and Meta-analysis is to estimate the overall prevalence of hepatitis B virus infection among pregnant women in Ethiopia. METHODS: A comprehensive search of electronic databases including PubMed, Popline, Lalicus, Ovid, MedNar, African Journal Online (AJOL) and advanced Google Scholar was conducted regardless of publication year from August 30, 2017 to September 25, 2017. The search was updated on January 02, 2018 to minimize time-lag bias. The methodological qualities of included studies were assessed using Joanna Briggs Institute Meta Analysis of Statistics Assessment and Review Instruments. RESULTS: Out of 103 studies, 17 studies with a total of 5629 pregnant women were included in the Meta analysis. The pooled prevalence of hepatitis B virus infection among pregnant women using random-effect model was 4.7%(95% CI 4.0-5.4%). The I2 statistics was I2 = 37.9%(p = 0.0575). Even though significant heterogeneity among studies was not detected, the I2 = 37.9% suggests medium heterogeneity. A subgroup Meta analysis showed that study site, region, mean/median sample size, hepatitis B virus screening methods and methodological quality were not source of heterogeneity (p-difference > 0.05). CONCLUSION: This review shows an intermediate level of hepatitis B virus infection among pregnant women in Ethiopia. In addition to the current practice of child vaccination, routine and universal antenatal hepatitis B virus screening program need to be implemented. PMID- 29996786 TI - Whole-genome SNP analysis elucidates the genetic structure of Russian cattle and its relationship with Eurasian taurine breeds. AB - BACKGROUND: The origin of native and locally developed Russian cattle breeds is linked to the historical, social, cultural, and climatic features of the diverse geographical regions of Russia. In the present study, we investigated the population structure of nine Russian cattle breeds and their relations to the cattle breeds from around the world to elucidate their origin. Genotyping of single nucleotide polymorphisms (SNPs) in Bestuzhev (n = 26), Russian Black-and White (n = 21), Kalmyk (n = 14), Kholmogor (n = 25), Kostromsky (n = 20), Red Gorbatov (n = 23), Suksun (n = 20), Yakut (n = 25), and Yaroslavl cattle breeds (n = 21) was done using the Bovine SNP50 BeadChip. SNP profiles from an additional 70 breeds were included in the analysis as references. RESULTS: The observed heterozygosity levels were quite similar in eight of the nine studied breeds (HO = 0.337-0.363) except for Yakut (Ho = 0.279). The inbreeding coefficients FIS ranged from -0.028 for Kalmyk to 0.036 for Russian Black-and White and were comparable to those of the European breeds. The nine studied Russian breeds exhibited taurine ancestry along the C1 axis of the multidimensional scaling (MDS)-plot, but Yakut was clearly separated from the European taurine breeds on the C2 axis. Neighbor-Net and admixture analyses, discriminated three groups among the studied Russian breeds. Yakut and Kalmyk were assigned to a separate group because of their Turano-Mongolian origin. Russian Black-and-White, Kostromsky and Suksun showed transboundary European ancestry, which originated from the Holstein, Brown Swiss, and Danish Red breeds, respectively. The lowest level of introgression of transboundary breeds was recorded for the Kholmogor, Yaroslavl, Red Gorbatov and Bestuzhev breeds, which can be considered as an authentic genetic resource. CONCLUSIONS: Whole-genome SNP analysis revealed that Russian native and locally developed breeds have conserved authentic genetic patterns in spite of the considerable influence of Eurasian taurine cattle. In this paper, we provide fundamental genomic information that will contribute to the development of more accurate breed conservation programs and genetic improvement strategies. PMID- 29996788 TI - Primary invasive laryngeal mycosis in an immunocompetent patient: a case report and clinico-epidemiological update. AB - BACKGROUND: Laryngeal aspergillosis is uncommon and is usually secondary to pulmonary involvement in immunocompromised patients. Primary laryngeal aspergillosis in immunocompetent individuals is extremely rare, with a few cases documented over the last five decades. CASE PRESENTATION: We report a case of primary localised laryngeal aspergillosis in a 21-year-old apparently immunocompetent student. Septate hyphae were observed on histopathology of the laryngeal lesion, which was further confirmed as Aspergillus fumigatus after extraction of fungal DNA from formalin fixed paraffin embedded tissue (FFPET) and sequencing. The patient responded well to oral itraconazole therapy over a month. CONCLUSIONS: Since last few decades, cases of primary laryngeal aspergillosis in immunocompetent individuals are on the rise, globally. This is the first case of invasive laryngeal aspergillosis reported in Nepal. The extraction of DNA from tissue and sequencing helps to identify the etiological agent, when culture fails to isolate the fungus. PMID- 29996787 TI - Auxin controls circadian flower opening and closure in the waterlily. AB - BACKGROUND: Flowers open at sunrise and close at sunset, establishing a circadian floral movement rhythm to facilitate pollination as part of reproduction. By the coordination of endogenous factors and environmental stimuli, such as circadian clock, photoperiod, light and temperature, an appropriate floral movement rhythm has been established; however, the underlying mechanisms remain unclear. RESULTS: In our study, we use waterlily as a model which represents an early-diverging grade of flowering plants, and we aim to reveal the general mechanism of flower actions. We found that the intermediate segment of petal cells of waterlily are highly flexible, followed by a circadian cell expansion upon photoperiod stimuli. Auxin causes constitutively flower opening while auxin inhibitor suppresses opening event. Subsequent transcriptome profiles generated from waterlily's intermediate segment of petals at different day-time points showed that auxin is a crucial phytohormone required for floral movement rhythm via the coordination of YUCCA-controlled auxin synthesis, GH3-mediated auxin homeostasis, PIN and ABCB dependent auxin efflux as well as TIR/AFB-AUX/IAA- and SAUR-triggered auxin signaling. Genes involved in cell wall organization were downstream of auxin events, resulting in the output phenotypes of rapid cell expansion during flower opening and cell shrinkage at flower closure stage. CONCLUSIONS: Collectively, our data demonstrate a central regulatory role of auxin in floral movement rhythm and provide a global understanding of flower action in waterlily, which could be a conserved feature of angiosperms. PMID- 29996789 TI - IL-17 and IL-22 production in HIV+ individuals with latent and active tuberculosis. AB - BACKGROUND: IL-17 and IL-22 cytokines play an important role in protective immune responses against Mycobacterium tuberculosis (Mtb) infection. Information on the production of these cytokines and the factors that regulate their production in the context of human immunodeficiency virus (HIV) and latent tuberculosis infection (LTBI) or active tuberculosis disease (ATB) is limited. In the current study, we compared the production of these two cytokines by PBMC of HIV-LTBI+ and HIV + LTBI+ individuals in response to Mtb antigens CFP-10 (culture filtrate protein) and ESAT-6 (Early Secretory Antigenic Target). We also determined the mechanisms involved in their production. METHODS: We cultured Peripheral Blood Mononuclear Cells (PBMCs) from HIV- individuals and HIV+ patients with latent tuberculosis and active disease with CFP-10 and ESAT-6. Production of IL-17, IL 22 and PD1 (Programmed Death 1), ICOS (Inducible T-cell Costimulator), IL-23R and FoxP3 (Forkhead box P3) expression on CD4+ T cells was measured. RESULTS: In response to Mtb antigens CFP-10 and ESAT-6, freshly isolated PBMCs from HIV+ LTBI+ and HIV+ active TB patients produced less IL-17 and IL-22 and more IL-10, expressed less IL-23R, and more PD1 and expanded to more FoxP3+ cells. Active TB infection in HIV+ individuals further inhibited antigen specific IL-17 and IL-22 production compared to those with LTBI. Neutralization of PD1 restored IL-23R expression, IL-17 and IL-22 levels and lowered IL-10 production and reduced expansion of FoxP3 T cells. CONCLUSIONS: In the current study we found that increased PD1 expression in HIV + LTBI+ and HIV+ active TB patients inhibits IL 17, IL-22 production and IL-23R expression in response to Mtb antigens CFP-10 and ESAT-6. PMID- 29996790 TI - Relationship between Helicobacter pylori and Rosacea: review and discussion. AB - BACKGROUND: Rosacea is an inflammatory disease affecting the central part of face characterized by persistent or recurrent episodes of erythema, papules, pustules and telangiectasias of unknown etiology. Helicobacter pylori (H. pylori) is a gram-negative bacillus, which is one of the main causes of chronic gastritis, gastric cancer and gastrointestinal ulcers. Recent evidences have suggested that H. pylori infection is closely related to the occurrence of diseases. In recent years, studies have found that Helicobacter pylori infection is associated with the occurrence of acne rosacea. So the treatment of Helicobacter pylori infection may be a therapeutic method of acne rosacea. But it continues to be controversial. In other studies, the treatment of Helicobacter pylori did not significantly reduce the severity of acne rosacea. To further explore the association between acne rosacea and Helicobacter pylori infection, a summarize method was used to study the relationship between acne rosacea and Helicobacter pylori, providing reference for clinical acne rosacea therapy. METHODS: Systematic searches were conducted on Wanfang Data, CQVIP, Springer, Public Health Management Corporation (PHMC), CNKI, and Pubmed, from January 1,2008 to Mar. 1, 2018, using Helicobacter pylori and rosacea to retrieve the literature. Depending on the inclusion and exclusion criteria, 27 articles considered or confirmed the correlation between H. pylori and rosacea. RESULTS: Epidemiological investigations and experiments have confirmed that H. pylori infection is associated with the development of rosacea. The effect of anti-H. pylori therapy is better than the routine therapy for rosacea. H. pylori can stimulate the immune system to produce a large number of inflammatory mediators, leading to the occurrence and aggravation of rosacea inflammation. CONCLUSIONS: It is confirmed that H. pylori infection is involved in the development of rosacea. It is suggested that rosacea patients should be tested for H. pylori infection, the H. pylori-positive rosacea patients should be treated with eradication of H. pylori, so as to enhance the therapeutic effect of rosacea. This study adds that H. pylori infection is involved in the development of rosacea. Epidemiological investigations and experiments have confirmed the rationality. The effect of anti H. pylori therapy is better than the routine therapy for rosacea. H. pylori positive rosacea patients should be treated with the therapeutic method of eradication of H. pylori. PMID- 29996791 TI - Preoperative preparation of eye with chlorhexidine solution significantly reduces bacterial load prior to 23-gauge vitrectomy in Swedish health care. AB - BACKGROUND: Bacteria in the conjunctiva present a potential risk of vitreous cavity infection during 23-gauge pars plana vitrectomy (PPV). Current preoperative procedures used in Sweden include irrigation with chlorhexidine solution (CHX) 0.05% only and no iodine solutions. We evaluated the bacterial diversity and load before and after this single antibacterial measure. METHODS: In a prospective, consecutive cohort we investigated bacterial growth in samples from 40 eyes in 39 consecutive individuals subjected to vitrectomy. A conjunctival specimen was collected from each preoperative patient before and after irrigating of eye with CHX, 0.05% solution. Iodine was not used during any part of the surgery. One drop of chloramphenicol was administered prior to surgery. Samples from vitreous cavity were collected at the beginning and end of vitrectomy. All conjunctival specimens were cultured for different species and quantified using colony forming units (CFU). RESULTS: There was a significant 82% reduction in the total number of CFUs for all bacteria in all eyes (P < 0.0001), and 90% reduction for coagulase negative staphylococci (CoNS) alone (P = 0.0002). The number of eyes with positive bacterial growth in conjunctival samples decreased from 33 to 18 after irrigation with CHX (P = 0.0023). The most common bacteria prior to surgery were CoNS (70%), Propionibacterium acnes (55%) and Corynebacterium species (36%). No case of post-vitrectomy endophthalmitis was reported during mean follow-up time, which was 4.6 +/- 2.3 (range; 1.5 to 9) months. CONCLUSIONS: Patients undergoing PPV harbored bacteria in conjunctiva capable of causing post-vitrectomy endophthalmitis. Preoperative preparation with CHX significantly reduced the bacterial load in the conjunctival samples subsequently leading to very low inoculation rates in recovered vitreous samples. Thus, CHX used as a single disinfectant agent might be an effective preoperative procedure for eye surgery in Sweden. This is a relatively small study but the results could be a reference for other intraocular surgeries. PMID- 29996792 TI - The Young Women's Health CoOp in Cape Town, South Africa: Study protocol for a cluster-randomised trial for adolescent women at risk for HIV. AB - BACKGROUND: South Africa remains the global epicentre of HIV infection, and adolescent women have the highest incidence of HIV in the country. South Africa also has high rates of alcohol and other drug (AOD) use, violence, and gender inequality. Violence converges with AOD use, gender inequities and other disparities, such as poverty, to increase sexual risk and poor educational attainment for adolescent women. This study seeks to test the efficacy of peer recruitment and cofacilitation of the Young Women's Health CoOp (YWHC), a comprehensive gender-focused intervention to reduce HIV risk behaviours and increase the uptake of HIV counselling and testing (HCT) among out-of-school, adolescent women who use AODs. The YWHC is facilitated by local research staff and supported by peers. METHODS: This cluster-randomised trial is enrolling participants into two arms: a control arm that receives standard HCT, and an intervention arm that receives the YWHC. Participants are enrolled from 24 economically disadvantaged communities in Cape Town, South Africa. These geographically distinct communities serve as clusters that are the units of randomisation. This study uses adolescent peer role models and research field staff to recruit marginalised adolescent women. At baseline, participants complete a questionnaire and biological testing for HIV, recent AOD use, and pregnancy. The core intervention is delivered in the month following enrollment, with linkages to health services and educational programmes available to participants throughout the follow-up period. Follow-up interviews and biological testing are conducted at 6 and 12 months post enrollment. DISCUSSION: The study findings will increase knowledge of the efficacy of a comprehensive HCT, gender focused programme in reducing AOD use, victimisation, and sexual risk behaviour and increase uptake services for out-of-school, adolescent women who use AODs. The trial results could lead to wider implementation of the YWHC for vulnerable adolescent women, a key population often neglected in health services. TRIAL REGISTRATION: Trial registration no: NCT02974998 , November 29, 2016. PMID- 29996793 TI - Participation of father in perinatal care: a qualitative study from the perspective of mothers, fathers, caregivers, managers and policymakers in Iran. AB - BACKGROUND: The participation of the father during the perinatal period is an important strategy for improving the mother's health. Very few studies exist about the father's role in promoting the health of the mother in Iran; thus, the present study was conducted to examine the role of fathers in perinatal care. METHODS: The present study was a qualitative research. Participants were selected using purposeful sampling with maximum variation and the data was collected through in-depth interviews, focus group discussions and field notes. The data was analyzed using conventional content analysis. RESULTS: After data analysis, the main categories extracted were: "help in maintaining the health of the mother and fetus", "emotional support of mother", "comprehensive participation of father in married life", "preparing for safe delivery" and "postpartum support". CONCLUSIONS: The results of the present study provide different perspectives on the participation of fathers when designing culture-based intervention for their participation in perinatal care. PMID- 29996794 TI - Management strategies for patients with placenta accreta spectrum disorders who underwent pregnancy termination in the second trimester: a retrospective study. AB - BACKGROUND: The unique clinical features of pregnancy termination in the second trimester with concurrent placenta accreta spectrum (PAS) disorders place obstetricians in a complex and delicate situation. However, there are limited data on this rare and dangerous condition. The objective of this research was to investigate and evaluate the clinical management strategies of this patient group. METHODS: The medical records of patients who were diagnosed and treated in our hospital from December 2005 and December 2015 were retrospectively reviewed. RESULTS: A total of 29 patients were included in this analysis. A prenatal diagnosis was suspected in 8 (27.6%) patients, and the remaining 21 (72.4%) patients were diagnosed after pregnancy termination in the second trimester. In the subgroup with a prenatal diagnosis, a planned hysterotomy was performed in 7 patients who had total placenta previa and previous cesarean delivery. The remaining patient received medical termination. A subtotal hysterectomy was performed in 3 (10.3%) patients for life-threatening bleeding during hysterotomy, and the uterus was preserved with an in situ placenta in the remaining 5 patients. In the subgroup with a postnatal diagnosis, the implanted placenta remained partly or completely in situ in all 21 patients under informed consent. Ultimately, the implanted placenta remained partly or completely in situ in 26 (89.7%) patients in the two subgroups. With the application of adjuvant treatments, including uterine artery embolization and medication followed by curettage under ultrasound guidance, the implanted placenta was passed 76.6 (range: 19 to 192) days after termination. Uterus preservation was achieved in all 26 patients. The complications associated with conservative management included delayed postnatal hemorrhaging (2 cases, 7.7%), fever (6 cases, 23.1%), G1 transaminase disorder (4 cases, 15.4%), and myelosuppression (1 case, 3.8%). Seven women (26.9%) had a spontaneous pregnancy after conservative management, and no patient experienced recurrent PAS disorders. CONCLUSIONS: Leaving the implanted placenta in situ is the preferred choice for patients with PAS disorders who underwent pregnancy termination in the second trimester and desired fertility preservation. Multiple adjuvant treatment modalities, either alone or in combination, may help to promote the passing or absorption of the implanted placenta under close monitoring. PMID- 29996795 TI - Pregnancy, child bearing and prevention of giving birth to the affected children in patients with primary immunodeficiency disease; a case-series. AB - BACKGROUND: Patients with primary immunodeficiency disease (PID) who survive to adulthood and willing to have a child mostly are worried whether their disease affects their fertility and/or pregnancy and also if their child would be predisposed to PID. CASE PRESENTATION: We report the outcome of conception, pregnancy and their management in 9 families with definite diagnosis of PID. A chronic granulomatous disease subject with an uneventful pregnancy developed fungal sacral osteomyelitis few weeks after delivery. A pregnant common variable immunodeficiency disease (CVID) patient with idiopathic thrombocytopenia had platelet count dropped before delivery. A sever neutropenic mother who refused to get IFNgamma delivered two healthy children. A CVID case intolerant to IVIg with eclampsia and PTE delivered a baby. Another CVID female gave birth to a baby without being on any treatment since she was not diagnosed with immunodeficiency disease at that time. A healthy girl was implanted via preimplantation gender selection in a family who owned a Wiskott Aldrich-affected son. A family who had two children with Ataxia Telangiectasia used donated oocyte for their 3rd child. Prenatal genetic diagnosis was used to screen the fetus for the impaired BTK and CVID genes detected in sibling and father respectively in 2 separate families. CONCLUSION: Pregnancy in PID patients is more complex than normal population. Because, not only it has the chance of being inherited by the offspring, but also there are some risks for the mother if she has any kind of immunity component defects. So consultation with a clinical geneticist is crucial to choose the best available approach. They also should be observed and followed by a clinical immunologist to take the best possible safe care. PMID- 29996796 TI - Association between low bone mass and the serum RANKL and OPG in patients with nephrolithiasis. AB - BACKGROUND: Nephrolithiasis is a risk factor for Osteopenia and osteoporosis. Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) regulate bone remodeling and osteoclastogenesis. This study aimed to evaluate the relation between serum OPG, RANKL concentration, and bone mineral density (BMD) in patients with kidney stone disease. METHODS: Forty-four nephrolithiasis patients with either low bone mass or normal BMD (considered control group) were enrolled in this study. BMD was measured at lumbar spine (L1 L4) and femoral neck by dual-energy X-ray absorptiometry (DEXA). The serum OPG and RANKL were determined using the ELISA method. RESULTS: The median levels of serum OPG were significantly higher in nephrolithiasis patients with low bone mass compared to the nephrolithiasis patients with normal BMD (3.9 pmol/l versus 3.1 pmol/l; P = 0.03), respectively. Negative correlation was detected between bone densities of femoral neck and OPG in patients with nephrolithiasis (r = .0344, P = 0.02). CONCLUSION: The present study showed that high serum fasting OPG levels may be indicative of femoral neck BMD in patients with nephrolithiasis. PMID- 29996797 TI - Validating Fitbit Zip for monitoring physical activity of children in school: a cross-sectional study. AB - BACKGROUND: Modern activity trackers, including the Fitbit Zip, enable the measurement of both the step count as well as physical activity (PA) intensities. However, there is a need for field-based validation studies in a variety of populations before using trackers for research. Therefore, the purpose of the current study was to investigate the validity of Fitbit Zip step count, moderate to vigorous physical activity (MVPA) and sedentary minutes, in different school segments in 3rd grade students. METHODS: Third grade students (N = 147, aged 9-10 years) wore a Fitbit Zip and an ActiGraph GT3x-BT accelerometer simultaneously on a belt for five days during school hours. The number of steps, minutes of MVPA and sedentary time during class time, physical education lessons and recess were extracted from both devices using time filters, based on the information from school time tables obtained from class teachers. The validity of the Fitbit Zip in different school segments was assessed using Bland-Altman analysis and Spearman's correlation. RESULTS: There was a strong correlation in the number of steps in all in-school segments between the two devices (r = 0.85-0.96, P < 0.001). The Fitbit Zip overestimated the number of steps in all segments, with the greatest overestimation being present in physical education lessons (345 steps). As for PA intensities, the agreement between the two devices in physical education and recess was moderate for MVPA minutes (r = 0.56 and r = 0.72, P < 0.001, respectively) and strong for sedentary time (r = 0.85 and r = 0.87, P < 0.001, respectively). During class time, the correlation was weak for MVPA minutes (r = 0.24, P < 0.001) and moderate for sedentary time (r = 0.57, P < 0.001). For total in-school time, the correlation between the two devices was strong for steps (r = 0.98, P < 0.001), MVPA (r = 0.80, P < 0.001) and sedentary time (r = 0.94, P < 0.001). CONCLUSION: In general, the Fitbit Zip can be considered a relatively accurate device for measuring the number of steps, MVPA and sedentary time in students in a school-setting. However, in segments where sedentary time dominates (e.g. academic classes), a research-grade accelerometer should be preferred. PMID- 29996798 TI - Comparison of different settings for yellow subthreshold laser treatment in diabetic macular edema. AB - BACKGROUND: To assess the safety and efficacy of two subthreshold parameters (5 and 15% duty cycle (DC)) compared to standard ETDRS (early treatment of diabetic retinopathy study) continuous wave (CW) laser. METHODS: In this prospective randomized study, 30 eyes from 20 patients with non-center involving macular edema were randomized into 3 different groups: 5% DC, 15% DC and CW navigated modified ETDRS laser treatment. Titration in subthreshold groups was performed with 30% of the threshold power, decided with microsecond pulses. CW laser was titrated to a barely visible burn. All patients underwent microperimetry, thickness measurements and visual acuity examinations at baseline, 6 weeks and 12 weeks post treatment. RESULTS: At three months follow up, retinal sensitivity was significantly reduced in the CW group by - 2.2 dB whereas in both subthreshold groups, retinal sensitivity increased by 2.4 dB for 5% and 1.9 dB for 15% DC with no significant difference. Retinal volume (mm3) decreased in both subthreshold groups by 0.08 +/- 0.3 and 0.12 +/- 0.11 in 5 and 15% DC group respectively. Whereas the CW group showed volume increase of 0.55 +/- 0.92 (p = 0.02 and 0.01 for 5 and 15% DC groups). Visual acuity remained stable in all 3 groups (- 0.7 letter in 5% DC; 2.11 letters in 15% DC and 0.88 in CW with no significant difference). CONCLUSION: Subthreshold microsecond laser was shown to be safe and effective with both 5 and 15% DC as compared to conventional photocoagulation with ETDRS parameters. The 15% DC setting trended to achieve better anatomical, visual and functional outcomes. TRIAL REGISTRATION: Retrospectively registered ( NCT03571659 , 06/26/2018). PMID- 29996799 TI - Know where to go: evidence from a controlled trial of a healthcare system information intervention among immigrants. AB - BACKGROUND: Immigrants may face problems with accessing the Danish healthcare system due to, for example, lack of knowledge of how to navigate it, which may cause inappropriate healthcare-seeking. Danish municipalities provide a mandatory introduction and language programme for newly arrived immigrants, but no information on the healthcare system is offered. This study investigated what effects information about the Danish healthcare system may have on the hypothetical healthcare-seeking behaviour of newly arrived immigrants and their actual healthcare use. METHODS: A prospective intervention study of 1572 adult immigrants attending two language schools in Copenhagen was carried out. Two intervention groups received either a course or written information on the Danish healthcare system, respectively, while the control group received neither. Survey data included three case vignettes on healthcare-seeking behaviour (flu-like symptoms, chest pain and depression) and were linked to registry data on sociodemographic characteristics and healthcare use in the year to follow. Logistic regression and binomial regression analyses were performed. RESULTS: Appropriate hypothetical healthcare-seeking behaviour was reported by 61.8-78.8% depending on the vignette. Written information showed no effect on immigrants' hypothetical healthcare-seeking behaviour, while the course showed a positive effect on hypothetical healthcare-seeking behaviour for flu-like symptoms (adjusted odds ratio [AOR] = 1.71, 95% confidence interval [CI] = 1.01-2.91, p value = 0.0467), but not on chest pain or depression. The interventions did not affect immigrants' actual healthcare use; all groups made lower use of health care services in the following year compared with the year where the study took place, except for the use of dental care which remained stable. CONCLUSIONS: Information on the healthcare system embedded in the language school programme has the potential to facilitate immigrants' access to healthcare. Yet, the results underscore the need for further refinement and development of educational interventions, as well as ensuring adequate utilisation of healthcare services by other means. Multi-dimensional and multi-sectional efforts are important for integration issues within healthcare in Europe. TRIAL REGISTRATION: Health seeking behaviour among newly arrived immigrants in Denmark ISRCTN24905314 , May 1, 2015 (Retrospectively registered). PMID- 29996800 TI - Low dose mycophenolate mofetil versus cyclophosphamide in the induction therapy of lupus nephritis in Nepalese population: a randomized control trial. AB - BACKGROUND: The management of proliferative lupus nephritis (LN) comprises timely and coordinated immunosuppressive therapy. This study aimed to evaluate and compare the effectiveness and safety profile of low dose mycophenolate mofetil (MMF) and cyclophosphamide (CYC) in induction therapy of LN in Nepalese population. METHODS: We conducted a prospective, open-label, randomized trial over a period of one and half years. Forty-nine patients with class III to V lupus nephritis were enrolled, out of which 42 patients (21 in each group) could complete the study. CYC was given intravenously as a monthly pulse and MMF was administered orally in the tablet form in the maximum daily dose of 1.5 g in two divided doses. RESULTS: The mean age of the patients was 25.43 +/- 10.17 years with female to male ratio of 7.3:1. Mean baseline serum creatinine was 1.58 +/- 1.38 mg/dL and eGFR was 62.38 +/- 26.76 ml/min/1.73m2. Mean 24-h urinary protein was 4.35 +/- 3.71 g per 1.73 m2 body surface area. At 6 months, serum creatinine (mg/dL) decreased from 1.73 to 0.96 in CYC and from 1.24 to 0.91 in the MMF group with improvement in eGFR (ml/min/1.73 m2) from 60.33 to 88.52 in CYC and from 64.42 to 89.09 in MMF group. Twenty-four-hour urinary protein (gm/1.73m2) reduced from 4.47 to 0.94 in CYC and from 4.5 to 0.62 in the MMF group. Primary end point was achieved in higher percentage of patients with MMF than CYC (28.6% vs. 19%) while equal proportion of patients (67% in each group) achieved secondary end point in both groups. Number of non-responders was higher in CYC group than in the MMF group (14.3% vs. 4.8%). There was no difference in the rate of achievement of secondary end point in both CYC and MMF groups (3.16 vs. 3.05 months). The occurrence of adverse events was higher in the CYC than in MMF group (56 vs. 15 events). CONCLUSION: Present study has concluded that MMF, used in relatively lower dose, is equally effective in inducing remission with reduction of proteinuria and improvement of kidney function with lesser adverse events than CYC in the induction therapy of proliferative lupus nephritis. TRIAL REGISTRATION: Retrospectively registered to ClinicalTrials.gov PRS. NCT03200002 (Registered date: June 28, 2017). PMID- 29996801 TI - Precarious transition: a mortality study of South African ex-miners. AB - BACKGROUND: Despite their burden of a triple epidemic of silicosis, tuberculosis and HIV infection, little is known about the mortality experience of miners from the South African mining industry once they leave employment. Such information is important because of the size and dispersion of this population across a number of countries and the progressive nature of these diseases. METHODS: This study included 306,297 South African miners who left the industry during 2001-2013. The study aimed to calculate crude and standardised mortality rates, identify secular trends in mortality and model demographic and occupational risk factors for mortality. RESULTS: Crude mortality rates peaked in the first year after exit (32.8/1000 person-years), decreasing with each year from exit. Overall mortality was 20% higher than in the general population. Adjusted annual mortality halved over the 12 year period. Mortality predictors were being a black miner [adjusted hazard ratio (aHR) 3.30; 95% confidence interval (CI) 3.15-3.46]; underground work (aHR 1.33; 95% CI 1.28-1.39); and gold aHR 1.15 (95% CI 1.12-1.19) or multiple commodity employment (aHR 1.15; 95% CI 1.11-1.19). CONCLUSIONS: This is the first long-term mortality assessment in the large ex-miner population from the South African mining industry. Mortality patterns follow that of the national HIV-tuberculosis epidemic and antiretroviral treatment availability. However, ex miners have further elevated mortality and a very high mortality risk in the year after leaving the workforce. Coordinated action between the mining industry, governments and non-governmental organisations is needed to reduce the impact of this precarious transition. PMID- 29996802 TI - Vaccine wastage in The Gambia: a prospective observational study. AB - BACKGROUND: Vaccination is a cost-effective and life-saving intervention. Recently several new, but more expensive vaccines have become part of immunization programmes in low and middle income countries (LMIC). Monitoring vaccine wastage helps to improve vaccine forecasting and minimise wastage. As the costs of vaccination increases better vaccine management is essential. Many LMIC however do not consistently monitor vaccine wastage. METHODS: We conducted two surveys in health facilities in rural and urban Gambia; 1) a prospective six months survey in two regions to estimate vaccine wastage rates and type of wastage for each of the vaccines administered by the Expanded programme on Immunization (EPI) and 2) a nationwide cross sectional survey of health workers from randomly selected facilities to assess knowledge, attitude and practice on vaccine waste management. We used WHO recommended forms and standard questionnaires. Wastage rates were compared to EPI targets. RESULTS: Wastage rates for the lyophilised vaccines BCG, Measles and Yellow Fever ranged from 18.5 79.0%, 0-30.9% and 0-55.0% respectively, mainly through unused doses at the end of an immunization session. Wastage from the liquid vaccines multi-dose/ single dose vials were minimal, with peaks due to expiry or breakage of the vaccine diluent. We interviewed 80 health workers and observed good knowledge. Batching children for BCG was uncommon (19%) whereas most health workers (73.4%) will open a vial as needed. CONCLUSION: National projected wastage targets were met for the multi-dose/single dose vials, but for lyophilised vaccines, the target was only met in the largest major health facility. PMID- 29996803 TI - Mild clinical features of isolated methylmalonic acidemia associated with a novel variant in the MMAA gene in two Chinese siblings. AB - BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive inherited disorder caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut- enzymatic subtype, respectively); a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA); or deficiency of the enzyme methylmalonyl-CoA epimerase. The cblA type of MMA is very rare in China. This study aimed to describe the biochemical, clinical, and genetic characteristics of two siblings in a Chinese family, suspected of having the cblA-type of MMA. METHODS: The Chinese family of Han ethnicity of two siblings with the cblA-type of MMA, was enrolled. Target-exome sequencing was performed for a panel of MMA-related genes to detect causative mutations. The influence of an identified missense variant on the protein's structure and function was analysed using SIFT, PolyPhen-2, PROVEAN, and MutationTaster software. Moreover, homology modelling of the human wild-type and mutant proteins was performed using SWISSMODEL to evaluate the variant. RESULTS: The proband was identified via newborn screening (NBS); whereas, her elder brother, who had not undergone expanded NBS, was diagnosed later through genetic family screening. The younger sibling exhibited abnormal biochemical manifestations, and the clinical performance was relatively good after treatment, while the older brother had a mild biochemical and clinical phenotype, mainly featuring poor academic performance. A novel, homozygous missense c.365T>C variant in exon 2 of their MMAA genes was identified using next-generation sequencing and validated by Sanger sequencing. Several different types of bioinformatics software predicted that the novel variant c.365T>C (p.L122P) was deleterious. Furthermore, three-dimensional crystal structure analysis revealed that replacement of Leu122 with Pro122 led to the loss of two intramolecular hydrogen bonds between the residue at position 122 and Leu188 and Ala119, resulting in instability of the MMAA protein structure. CONCLUSIONS: The two siblings suspected of having the cblA-type of MMA showed mild phenotypes during follow-up, and a novel, homozygous missense variant in their MMAA genes was identified. We believe that the clinical features of the two siblings were associated with the MMAA c.365T>C variant; however, further functional studies are warranted to confirm the variant's pathogenicity. PMID- 29996804 TI - Assessment of the effect of age on macular layer thickness in a healthy Chinese cohort using spectral-domain optical coherence tomography. AB - BACKGROUND: To determine the effect of age on the thickness of individual retinal and choroidal vascular layers in the macula in an ophthalmologically healthy Chinese cohort by using spectral-domain optical coherence tomography (SD-OCT). METHODS: In all, 525 health eyes of 525 subjects were examined with SD-OCT. The instrument automatically obtained the regional retinal thickness of 8 layers. Subfoveal choroidal vascular layers' thickness was measured using enhanced depth imaging mode. The correlation of age with layer thickness measurements was determined. RESULTS: No age-associated variation was found on retinal thickness (RT) in the fovea; however, the foveal thickness of outer nuclear layer (ONL), retinal pigment epithelium (RPE) and vascular sublayers of the choroid decreased significantly with aging in this area (P < 0.05, respectively). Significant age related reduction was seen in RT in the pericentral and peripheral rings (P < 0.05, respectively). The significant variation in thinning of the ganglion cell layer, inner plexiform layer, and ONL with aging is thought to be the main determinant of these results (P < 0.05, respectively). On the contrary, the RPE layout showed age-related thickening (P < 0.05, respectively) in the pericentral and peripheral regions. CONCLUSIONS: The thickness of individual layers of the macula may be determinants of the age-related variations observed in the ophthalmologically healthy Chinese cohort, as assessed by SD-OCT examination. PMID- 29996805 TI - The impact of "Child Care" intervention in rural Primary Health Care Program on prevalence of diarrhea among children less than 36 months of age in rural western China. AB - BACKGROUND: It was unclear how and to what extent the "Child Care" intervention (CCI) in rural Primary Health Care Program affected the prevalence of childhood diarrhea in rural western China. METHODS: The available data of 10,829 and 10,682 households was collected from shared 34 counties of 9 provinces of western China in 2001 and 2005 respectively. A log-binomial regression model was used to predict the effect of CCI on prevalence of childhood diarrhea. RESULTS: In 2001, the prevalence rate of diarrhea among children less than 36 months of age was 17.01% in intervention group and 17.72% in control group, and in 2005 this crude rate declined to 4.85% in the former and 6.84% in the latter. Log-binomial regression analysis showed that CCI decreased the overall prevalence of childhood diarrhea by 27% (adjusted relative prevalence ratio (rPR) = 0.73 95% CI 0.59, 0.89). The stratification regression by social-economic status (SES) of the households showed that this effect varied with SES of the households. In the medium or rich households, this intervention was effective significantly (the medium: adjusted rPR = 0.63,95%CI 0.41,0.95; the rich: adjusted rPR = 0.72,95%CI 0.54,0.97), but in poor households it seemed to be less effective (adjusted rPR = 0.86,95%CI 0.55,1.36). CONCLUSION: In rural Primary Health Care Program, CCI was effective in improving childhood diarrhea but this effect was inequitable among SES of the households. So, attention should be paid to the inequality when CCI was adopted to reduce childhood diarrhea in rural China. PMID- 29996806 TI - A prospective cohort study of school-going children investigating reproductive and neurobehavioral health effects due to environmental pesticide exposure in the Western Cape, South Africa: study protocol. AB - BACKGROUND: Research on reproductive health effects on children from low-level, long-term exposure to pesticides currently used in the agricultural industry is limited and those on neurobehavioral effects have produced conflicting evidence. We aim at investigating the association between pesticide exposure on the reproductive health and neurobehavior of children in South Africa, by including potential relevant co-exposures from the use of electronic media and maternal alcohol consumption. METHODS: The design entails a prospective cohort study with a follow-up duration of 2 years starting in 2017, including 1000 school going children between the ages of 9 to 16 years old. Children are enrolled with equal distribution in sex and residence on farms and non-farms in three different agricultural areas (mainly apple, table grapes and wheat farming systems) in the Western Cape, South Africa. The neurobehavior primary health outcome of cognitive functioning was measured through the iPad-based CAmbridge Neuropsychological Test Automated Battery (CANTAB) including domains for attention, memory, and processing speed. The reproductive health outcomes include testicular size in boys and breast size in girls assessed in a physical examination, and blood samples to detect hormone levels and anthropometric measurements. Information on pesticide exposure, co-exposures and relevant confounders are obtained through structured questionnaire interviews with the children and their guardians. Environmental occurrence of pesticides will be determined while using a structured interview with farm owners and review of spraying records and collection of passive water and air samples in all three areas. Pesticide metabolites will be analysed in urine and hair samples collected from the study subjects every 4 months starting at baseline. DISCUSSION: The inclusion of three different agricultural areas will yield a wide range of pesticide exposure situations. The prospective longitudinal design is a further strength of this study to evaluate the reproductive and neurobehavioural effects of different pesticides on children. This research will inform relevant policies and regulatory bodies to improve the health, safety and learning environments for children and families in agricultural settings. PMID- 29996807 TI - Beyond the parish pump: what next for public health? AB - BACKGROUND: Public health has had a history characterised by uncertainty of purpose, locus of control, and workforce identity. In many health systems, the public health function is fragmented, isolated and under-resourced. We use the most recent major reforms to the English National Health Service and local government, the Health and Social Care Act 2012 (HSCA12), as a lens through which to explore the changing nature of public health professionalism. METHODS: This paper is based upon a 3-year longitudinal study into the impacts of the HSCA12 upon the commissioning system in England, in which we conducted 141 interviews with 118 commissioners and senior staff from a variety of health service commissioner and provider organisations, local government, and the third sector. For the present paper, we developed a subset of data relevant to public health, and analysed it using a framework derived from the literature on public health professionalism, exploring themes identified from relevant policy documents and research. RESULTS: The move of public health responsibilities into local government introduced an element of politicisation which challenged public health professional autonomy. There were mixed feelings about the status of public health as a specialist profession. The creation of a national public health organisation helped raise the profile of profession, but there were concerns about clarity of responsibilities, accountability, and upholding 'pure' public health professional values. There was confusion about the remit of other organisations in relation to public health. CONCLUSIONS: Where public health professionals sit in a health system in absolute terms is less important than their ability to develop relationships, negotiate their roles, and provide expert public health influence across that system. A conflation between 'population health' and 'public health' fosters unrealistic expectations of the profession. Public health may be best placed to provide leadership for other stakeholders and professional groups working towards improving health outcomes of their defined populations, but there remains a need to clarify the role(s) that public health as a specialist profession has to play in helping to fulfil population health goals. PMID- 29996808 TI - Do airway inflammation and airway responsiveness markers at the start of apprenticeship predict their evolution during initial training? A longitudinal study among apprentice bakers, pastry makers and hairdressers. AB - BACKGROUND: The natural history of airway inflammation and symptoms in occupations at risk of asthma is still not fully understood. We aimed to study the evolution during apprenticeship of inflammation markers, bronchial hyperresponsiveness (BHR) and symptoms in at-risk subgroups as defined from measurements of markers made shortly after the start of training. METHODS: Respiratory symptoms, FEV1 and airway resistance post-bronchial challenge (MBC) test results, fractional exhaled nitric oxide (FeNO) measurements, and eosinophils in nasal lavage fluid were investigated in apprentice bakers, pastry makers and hairdressers. Four visits were conducted: at the start of the training and every six months thereafter. Four baseline risk groups were defined, based on, (i) a high level of FeNO (NO), (ii) eosinophils > 1% (Eosino), (iii) a >= 15% decrease in FEV1 during the MBC test (HR), and (iv) a >= 50% increase in the resistance (Resist). The statistical analysis relied on mixed models. RESULTS: At baseline, the inflammation markers were related to the MBC markers. There was no evidence to suggest that the baseline risk groups predict a differential evolution of the airway inflammation and bronchial responsiveness markers, or the asthma-like symptoms considered. The baseline risk groups defined from MBC test predicted the levels of MBC markers. Similarly, the baseline risk groups based on eosinophilic inflammation predicted the levels of markers for eosinophilia. These results were similar in the three training tracks, with the exception of the FeNO levels which were not different according to the Eosino risk group. Twelve possible new asthma cases were identified, only the HR risk group predicted their occurrence. CONCLUSIONS: Among this young population, at-risk groups based on initial high levels of inflammation markers did not experience any worsening during the follow-up. However, initial BHR predicted consistently high levels of all markers considered and occurrence of possible asthma. PMID- 29996809 TI - Clinicopathological analysis of proliferative glomerulonephritis with monoclonal IgG deposits in 5 renal allografts. AB - BACKGROUND: We present a case series of 5 patients with proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) of renal allografts to better define its natural history, presenting characteristics, pathological features and treatment outcome. RESULTS: These 5 patients presented 5 to 19 months post-kidney transplantation for complaints of serum creatinine (Scr) elevation, proteinuria or hematuria. Membranoproliferative glomerulonephritis (MPGN) pattern was the most frequently observed histological manifestation. Immunofluorescence showed monoclonal IgG3kappain 3 patients and IgG3lambda in the other 2 cases. Immunofluorescence staining helped to establish PGNMID in the absence of conspicuous microscopic changes in one case. Rituximab and bortezomib were effective in alleviating proteinuria in all 4 treated patients and decreasing Scr in 2 cases. Plasmapheresis treatment in another patient was not effective in preventing Scr elevation. At last-follow-up, 2 patients were in dialysis and 2 had improved kidney function with almost normal Scr and no proteinuria. The remaining one patient died of pulmonary infections. CONCLUSIONS: We conclude that PGNMID occurs early after kidney transplant. PGNMID should be included in the differential diagnoses of recurrent MPGN in renal allografts. Rituximab and bortezomib are helpful to decrease proteinuria and Scr in a subset of patients. Larger studies are needed to conclusively establish best treatment strategies for PGNMID in renal allografts. PMID- 29996810 TI - Accuracy of iohexol plasma clearance for GFR-determination: a comparison between single and dual sampling. AB - BACKGROUND: Current guidelines regarding plasma-sampling techniques for glomerular filtration rate (GFR) determination are inconsistent. Single-sample methods are commonly believed not to be precise enough to meet clinical demands. The present study compared the agreement between single- and dual- plasma sampling methods with a three-point plasma clearance of iohexol. METHODS: A total of 46 healthy volunteers and 124 chronic kidney disease (CKD) patients with varying degrees of renal dysfunction received 5 ml iohexol (300 mgI/ml) i.v. and plasma samples were drawn at 2-, 3- and 4-h post-injection. Plasma-iodine concentrations were detected by high-performance liquid chromatography (HPLC). RESULTS: Bias was similar among single-plasma sampling methods (SPSM) and dual plasma sampling methods (DPSM). The best correlation was obtained from the 2- and 4-h DPSM (concordance correlation coefficient [CCC]: 0.9988) with none of the estimates differed by more than 30% from the reference GFR and only one (0.06%) estimate differed by more than 10% (P30, 100%; P10, 99.4%). SPSM using samples around 3- or 4-h demonstrated acceptable accuracy at a GFR level of >=60 ml/min/1.73m2 (P30 = 100% and P10 > 75% for both measurements). CONCLUSION: 4-h SPSM is advantageous in clinical practice in subjects with GFR >= 60 ml/min/1.73m2. For patients with an expected GFR < 60 ml/min/1.73m2, a prolonged sampling time is more reliable. PMID- 29996811 TI - BET Bromodomain inhibition promotes De-repression of TXNIP and activation of ASK1 MAPK pathway in acute myeloid leukemia. AB - BACKGROUND: Targeted therapy has always been the focus in developing therapeutic approaches in cancer, especially in the treatment of acute myeloid leukemia (AML). A new small molecular inhibitor, JQ1, targeting BRD4, which recognizes the acetylated lysine residues, has been shown to induce cell cycle arrest in different cancers by inhibiting MYC oncogene. However, the downstream signaling of MYC inhibition induced by BET inhibitor is not well understood. METHODS: In this study, we explored the more mechanisms of JQ1-induced cell death in acute myeloid lukemia and downstream signaling of JQ1. RESULTS: We found that JQ1 is able to reactivate the tumor suppressor gene, TXNIP, and induces apoptosis through the ASK1-MAPK pathway. Further studies confirmed that MYC could repress the expression of TXNIP through the miR-17-92 cluster. CONCLUSIONS: These findings provide novel insight on how BET inhibitor can induce apoptosis in AML, and further support the development of BET inhibitors as a promising therapeutic strategy against AML. PMID- 29996812 TI - Perceived barriers and facilitators of initiation of behavioral weight loss interventions among adults with obesity: a qualitative study. AB - BACKGROUND: Evidence-based behavioral weight loss interventions are under utilized. To inform efforts to increase uptake of these interventions, it is important to understand the perspectives of adults with obesity regarding barriers and facilitators of weight loss intervention initiation. METHODS: We conducted a qualitative study in adults with obesity who had recently attempted weight loss either with assistance from an evidence-based behavioral intervention (intervention initiators) or without use of a formal intervention (intervention non-initiators). We recruited primary care patients, members of a commercial weight loss program, and members of a Veterans Affairs weight loss program. Intervention initiators and non-initiators were interviewed separately using a semi-structured interview guide that asked participants about barriers and facilitators of weight loss intervention initiation. Conversations were audio recorded and transcribed. Data were analyzed with qualitative content analysis. Two researchers used open coding to generate the code book on a subset of transcripts and a single researcher coded remaining transcripts. Codes were combined into subthemes, which were combined in to higher order themes. Intervention initiators and non-initiators were compared. RESULTS: We conducted three focus groups with participants who had initiated interventions (n = 26) and three focus groups (n = 24) and 8 individual interviews with participants who had not initiated interventions. Intervention initiators and non-initiators were, respectively, 65% and 37.5% white, 62% and 63% female, mean age of 55 and 54 years old, and mean BMI of 34 kg/m2. Three themes were identified. One theme was practical factors, with subthemes of reasonable cost and scheduling compatibility. A second theme was anticipated effectiveness of intervention, with subthemes of intervention content addressing individual needs; social aspects influencing effectiveness; and evaluating evidence of effectiveness. A third theme was anticipated pleasantness of intervention, with subthemes of social aspects influencing enjoyment; anticipated dietary and tracking prescriptions; and identity and self-reliance factors. Different perspectives were identified from intervention initiators and non-initiators. CONCLUSIONS: Strategies to engage individuals in evidence-based weight loss interventions can be developed using these results. Strategies could target individuals' perceived barriers and benefits to initiating interventions, or could focus on refining interventions to appeal to more individuals. PMID- 29996813 TI - Effectiveness of an app-based intervention for unintentional injury among caregivers of preschoolers: protocol for a cluster randomized controlled trial. AB - BACKGROUND: Each year, over 15,000 preschoolers die from unintentional injuries in China. Many interventions proven to work in other nations have not been implemented nationwide in China. The rapid popularity of smartphones offers an opportunity to overcome this limitation and disseminate evidence-based interventions to the large population of China. This study aims to assess the effectiveness of an app-based intervention for caregivers of preschoolers to prevent unintentional injury among young Chinese children. METHOD: A single blinded, 6-month, parallel-group cluster randomized controlled trial with 1:1 allocation ratio will be conducted in Changsha, China. In total, 2626 caregivers of preschoolers ages 3-6 years old who own a smartphone will be recruited from 20 preschools. Clusters will be randomized at the preschool level and allocated to either the control group (routine education plus app-based parenting education excluding unintentional injury prevention) or the intervention group (routine education plus app-based parenting education including unintentional injury prevention). The app-based injury prevention program was developed based on the Theory of Planned Behavior, the Haddon Matrix, the Mobile Learning framework, and a needs assessment. Data collection will be conducted at baseline, 3-month, and 6 month follow-up via app-based survey plus printed questionnaire survey. The primary outcome measure is unintentional injury incidence among preschoolers in the past 3 months. Secondary outcome measures include economic losses due to unintentional injury in the past 3 months, the Incremental Cost-Effectiveness Ratios (ICERs), and parent's attitudes and behaviors concerning supervision to prevent preschooler unintentional injury in the past week. An intention-to-treat approach will be used to evaluate outcome measures. Chi-square tests will examine differences for outcome measures between groups at each time point and generalized estimation equations (GEE) will test the overall effectiveness of the app-based intervention. Missing outcome data will be imputed using the Expectation Maximization algorithm (EM). DISCUSSION: This trial will examine evidence concerning the effectiveness of an innovative app-based intervention for caregivers of Chinese preschoolers. If effective, the app-based intervention could offer an effective population-based intervention option to cost-effectively promote unintentional injury prevention in countries and regions where injury control is under-supported. TRIAL REGISTRATION: ChiCTR-IOR-17010438 . Registered 15 January 2017. PMID- 29996814 TI - Self-reported health behaviors, including sleep, correlate with doctor-informed medical conditions: data from the 2011 Health Related Behaviors Survey of U.S. Active Duty Military Personnel. AB - BACKGROUND: Health behaviors and cardiometabolic disease risk factors may differ between military and civilian populations; therefore, in U.S. active duty military personnel, we assessed relationships between demographic characteristics, self-reported health behaviors, and doctor-informed medical conditions. METHODS: Data were self-reported by 27,034 active duty military and Coast Guard personnel who responded to the 2011 Department of Defense Health Related Behaviors Survey. Multivariate linear and logistic regressions were used to estimate cross-sectional associations between (1) demographic characteristics (age, sex, service branch, marital status, children, race/ethnicity, pay grade) and self-reported behaviors (exercise, diet, smoking, alcohol, sleep); (2) demographic characteristics and doctor-informed medical conditions (hypertension, hypercholesterolemia, low high density lipoprotein (HDL) cholesterol, hyperglycemia) and overweight/obesity; and (3) behaviors and doctor-informed medical conditions. RESULTS: Among respondents (age 29.9 +/- 0.1 years, 14.7% female), females reported higher intake than men of fruit, vegetables, and dairy; those with higher education reported higher intakes of whole grains; those currently married and/or residing with children reported higher intake of starches. Older age and female sex were associated with higher odds (ORs 1.25 to 12.54 versus the youngest age group) of overweight/obesity. Older age and female sex were also associated with lower odds (ORs 0.29 to 0.65 versus male sex) of doctor-informed medical conditions, except for blood glucose, for which females had higher odds. Those currently married had higher odds of high cholesterol and overweight/obesity, and separated/divorced/widowed respondents had higher odds of high blood pressure and high cholesterol. Short sleep duration (< 5 versus 7-8 h/night) was associated with higher odds (ORs 1.36to 2.22) of any given doctor informed medical condition. Strength training was associated with lower probability of high cholesterol, high triglycerides, and low HDL, and higher probability of overweight/obesity. Dietary factors were variably associated with doctor-informed medical conditions and overweight/obesity. CONCLUSIONS: This study observed pronounced associations between health behaviors-especially sleep and medical conditions, thus adding to evidence that sleep is a critical, potentially modifiable behavior within this population. When possible, adequate sleep should continue to be promoted as an important part of overall health and wellness throughout the military community. PMID- 29996815 TI - Phenotype heterogeneity of congenital adrenal hyperplasia due to genetic mosaicism and concomitant nephrogenic diabetes insipidus in a sibling. AB - BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2. Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive or autosomal recessive disorder caused by mutations in either AVPR2 or AQP2. Genotype-phenotype discordance caused by genetic mosaicism in CAH patients has not been reported, nor the concomitant CAH and NDI. CASE PRESENTATION: We investigated a patient with concomitant CAH and NDI from a consanguineous family. She (S-1) presented with clitoromegaly at 3 month of age, and polydipsia and polyuria at 13 month of age. Her parents and two elder sisters (S-2 and S-3) were clinically normal, but elevated levels of serum 17-hydroxyprogesterone (17-OHP) were observed in the mother and S-2. The coding region of CYP21A2 and AQP2 were analyzed by PCR-sequencing analysis to identify genetic defects. Two homozygous CYP21A2 mutations (p.R357W and p.P454S) were identified in the proband and her mother and S-2. The apparent genotype-phenotype discordance was due to presence of small amount of wild-type CYP21A2 alleles in S-1, S-2, and their mother's genome, thus protecting them from development of classic form of 21OHD (C21OHD). A homozygous AQP2 mutation (p.A147T) was also found in the patient. The patient was treated with hydrocortisone and hydrochlorothiazide. Her symptoms were improved with normal laboratory findings. The clitoromegaly is persisted. CONCLUSIONS: Genetic mosaicism is a novel mechanism contributing to the genotype phenotype discordance in 21OHD and small percentage of wild-type CYP21A2 alleles may be sufficient to prevent phenotype development. This is a first report of concurrent 21OHD and NDI caused by simultaneous homozygous CYP21A2 and AQP2 mutations. PMID- 29996816 TI - Understanding adjuvant endocrine therapy persistence in breast Cancer survivors. AB - BACKGROUND: Adjuvant endocrine therapy (AET) significantly decreases the risk of breast cancer recurrence and mortality. Notwithstanding the demonstrated efficacy of AET, 31-73% of breast cancer survivors do not persist with AET. The purpose of this study was to explore breast cancer survivors' experiences and perspectives of persisting with AET and to identify the psychosocial and healthcare system factors that influence AET persistence. METHODS: Informed by interpretive descriptive methodology and relational autonomy theory, individual interviews were conducted with 22 women diagnosed with early-stage breast cancer who had been prescribed AET. These participants also completed a demographic form and a survey that assessed their perceived risk of recurrence. Interviews were analysed using inductive thematic and constant comparative analysis to iteratively compare data and develop conceptualizations of the relationships among data. Descriptive statistics were used to summarize the quantitative data. RESULTS: The personal, social, and structural factors found to influence AET persistence included AET side effects, perception of breast cancer recurrence risk, medication and necessity beliefs, social support, the patient-provider relationship, and the continuity and frequency of follow-up care. For most women, over time, the decision-making process around AET persistence became a balancing act between quality of life and quantity of life. The interplay between the personal, social, and structural factors was complex and the weight women placed on some factors over others influenced their AET persistence or non-persistence. CONCLUSION: Expanding our understanding of the factors affecting breast cancer survivors' AET persistence from their perspective is the first step in developing efficacious, patient-centered interventions aimed at improving AET persistence. In order to improve AET persistence, enhanced symptom management is required, as well as the development of supportive care strategies that acknowledge the values and beliefs held by breast cancer survivors while reinforcing the benefits of AET, and addressing women's reasons for non-persistence. Improved continuity of health care and patient-healthcare provider communication across oncology and primary care settings is also required. The development and evaluation of supportive care strategies that address the challenges associated with AET experienced by breast cancer survivors hold the potential to increase both women's quality and quantity of life. PMID- 29996818 TI - Pulmonary tumor thrombotic microangiopathy and pulmonary veno-occlusive disease in a woman with cervical cancer treated with cediranib and durvalumab. AB - BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare cause of pulmonary hypertension that is associated with malignancies and is marked by the presence of non-occlusive tumor emboli and fibrocellular intimal proliferation of small pulmonary arteries leading to increased pulmonary vascular resistance and right heart failure. The diagnosis of PTTM is challenging to make pre-mortem and guidelines on treatment are lacking. CASE PRESENTATION: A 45-year-old woman with advanced squamous cell carcinoma of the cervix developed symptoms of dyspnea and evidence of right heart failure during a phase I clinical trial with cediranib and durvalumab. After an extensive evaluation, pre-capillary pulmonary hypertension was confirmed by right heart catheterization. Vasodilator therapy was initiated but resulted in the development of symptomatic hypoxemia and was discontinued. Despite continued supportive care, she continued to decline and was transitioned to hospice care. At autopsy, the cause of her right heart failure was found to be due to PTTM with features of pulmonary veno-occlusive disease (PVOD). CONCLUSION: PTTM and PVOD are important diagnoses to consider in patients with a malignancy and the development of right heart failure and may be manifestations of a spectrum of similar disease processes. PMID- 29996817 TI - Scale up of a multi-strategic intervention to increase implementation of a school healthy canteen policy: findings of an intervention trial. AB - BACKGROUND: Implementation interventions delivered in schools to improve food provision have been found to improve student diet and reduce child obesity risk. If the health benefits of food availability policies are to be realised, interventions that are effective need to be implemented at scale, across an entire population of schools. This study aims to assess the potential effectiveness of an intervention in increasing the implementation, at scale, of a healthy canteen policy by Australian primary schools. METHODS: A non-controlled before and after study was conducted in primary schools located in the Hunter New England region of New South Wales, Australia. Schools received a multi-component intervention adapted from a previous efficacious and cost-effective randomised control trial. The primary trial outcome was the proportion of canteen menus compliant with the state healthy canteen policy, assessed via menu audit at baseline and follow-up by dietitians. Secondary outcomes included policy reach and adoption and maintenance policy implementation. RESULTS: Of the 173 schools eligible for inclusion in the trial, 168 provided menus at baseline and 157 menus were collected at follow-up. At follow-up, multiple imputation analysis found 35% (55/157) of schools compared to 17% (29/168) at baseline (OR = 2.8 (1.6-4.7), p = < 0.001) had menus compliant with the state healthy canteen policy. As an assessment of the impact of the intervention on policy reach, canteen manager and principal knowledge of the policy increased from 64% (n = 76) and 38% (n = 44) respectively at baseline to 69% (n = 89) and 60% (n = 70) at follow-up (p = 0.393, p = 0.026). Adoption of the policy increased from 80% (n = 93) at baseline to 90% (n = 104) at follow-up (p = 0.005) for principals, and from 86% (n = 105) to 96% (n = 124) (p = 0.0001) for canteen managers. Multiple imputation analysis showed intervention effects were maintained six-months post intervention (33% of menus compliant OR = 2.6 (1.5-4.5), p = < 0.001 compared to baseline). CONCLUSIONS: This study found school canteen compliance with a healthy food policy increased in association with a multi-strategy intervention delivered at scale. The study provides evidence for public health policy makers and practitioners regarding strategies and modes of support required to support improvement in nutrition policy implementation across entire populations of schools. PMID- 29996819 TI - Rationale, design, and characteristics of the multimedia family planning campaign for a small, happy, and prosperous family in Ethiopia (SHaPE). AB - BACKGROUND: Ethiopia, the second most populous country in Africa, has a total fertility rate of 4.6, a decrease from 5.5 in 2000. However, only 35.3% of women in the reproductive age group use modern family planning (FP) methods, and the 22.3% of them who have an unmet need for family planning is among the highest rates in sub-Saharan African countries. The Small, Happy, and Prosperous family in Ethiopia (SHaPE) is one of the country's first comprehensive multimedia family planning campaigns. Its purpose is to increase FP-related knowledge, attitude, and practice of Ethiopians, particularly women of reproductive age. METHODS/DESIGN: The SHaPE campaign has multiple components: (1) a nationwide representative survey, which serves as formative research to identify region specific and culture-appropriate media, messages, and barriers and determinants of family planning; (2) a multimedia communication campaign intervention, including radio dramas and other interpersonal, community-level, and mass media channels; and (3) campaign evaluation, including pre-, process-, and post evaluation research using both quantitative and qualitative methodologies. The main target population for SHaPE is reproductive age women and men in three regions: Amhara, Oromia, and Somali. These regions take up about 66.6% of the entire country and have distinct ethnicities, cultures, and languages. DISCUSSION: SHaPE contributes to existing family planning research and intervention because it is theory- and evidence-based, and it employs integrated marketing communications and entertainment-education approaches with key messages that are tailored to audiences within unique cultures. But even within a country, a nationwide campaign with uniform messages is neither possible nor desirable due to different cultures, norms, and languages across regions. Last, media campaigns in developing and underdeveloped countries require constant monitoring of political situations. PMID- 29996820 TI - Team interventions in acute hospital contexts: a systematic search of the literature using realist synthesis. AB - BACKGROUND: Research on team effectiveness in healthcare has focussed on whether effective teams yield positive outcomes for patients and on the effectiveness of team interventions to improve performance. Limited understanding exists of what works for whom within an effective team, or how and why the context in which the team operates enables team members both as individuals and as a collective to enact behaviours that promote positive outcomes. METHODS: This realist synthesis of the literature explores the relationship between team interventions, underlying teamwork mechanisms generated by those interventions, and the resultant impact on patient outcomes in an acute hospital context. A systematic search of five healthcare and healthcare management academic databases: PubMed, PsychINFO, CINAHL, ABInform, Emerald Management and three grey literature databases: ERIC, OpenDOAR and Open Grey was undertaken. Five experts in the field were also contacted to source relevant literature. Using PRISMA guidelines, relevant studies published between January 2006 and January 2017 were systematically searched by a team of three people. Drawing on realist methodology, data were synthesised using context, mechanism and outcome configurations as the unit of analysis to identify enablers and barriers to effective team interventions. RESULTS: Out of 3347 papers retrieved, 18 were included in the final synthesis. From these, five contextual enablers were identified: an inter-disciplinary focus and flattened hierarchy; effective communication; leadership support and alignment of team goals with organisational goals; credibility of intervention; and appropriate team composition with physician involvement. Ten recurring mechanisms were identified, the most frequently occurring of which was shared responsibility. CONCLUSIONS: The advantage of using realist synthesis to extrapolate data from the literature is that it considers the context and mechanisms that will impact effectiveness of healthcare team interventions. This methodological approach provides a different perspective to other types of syntheses and offers insight as to why certain contextual elements may yield more success than others. Findings therefore tend to have more practical implications. Specificity of detail in terms of how external drivers impact on healthcare team interventions was limited in the articles extracted for analysis. This broader perspective is therefore an important consideration for future research. PMID- 29996821 TI - Capacity of health facilities for diagnosis and treatment of HIV/AIDS in Ethiopia. AB - BACKGROUND: There are dearth of literature on the capacity of the health system to diagnose and treat HIV/AIDS in Ethiopia. In this study we evaluated the capacity of health facilities for HIV/AIDS care, its spatial distribution and variations by regions and zones in Ethiopia. METHODS: We analyzed the Service Provision Assessment plus (SPA+) survey data that were collected in 2014 in all regions of Ethiopia. We assessed structural, process and overall capacity of the health system based on the Donabedian quality of care model. We included 5 structural and 8 process indicators and overall capacity score was constructed by taking the average of all indicators. Multiple linear regression was done using STATA 14 to assess the association of the location and types of health facilities with overall capacity score. Maps displaying the average capacity score at Zonal level were produced using ArcGIS Desktop v10.3 (Environmental Systems Research Institute Inc., Redlands CA, USA). RESULTS: A total of 873 health facilities were included in the analysis. Less than 5% of the private facilities provided antiretroviral therapy (ART); had national ART guideline, baseline CD4 count or viral load and tuberculosis screening mechanisms. Nearly one-third of the health centers (34.9%) provided ART. Public hospitals have better capacity score (77.1%) than health centers (45.9%) and private health facilities (24.8%). The overall capacity score for urban facilities (57.1%) was higher than that of the rural (38.2%) health facilities (beta = 15.4, 95% CI: 11.7, 19.2). Health centers (beta = - 21.4, 95% CI: -25.4, - 17.4) and private health facilities (beta = - 50.9, 95% CI: -54.8, - 47.1) had lower overall capacity score than hospitals. Facilities in Somali (beta = - 13.8, 95% CI: -20.6, - 7.0) and SNNPR (beta = - 5.0, 95% CI: -9.8, - 0.1) regions had lower overall capacity score than facilities in the Oromia region. Zones located in emerging regions such as Gambella and Benishangul Gumz and in remote areas of Oromia and SNNPR had lower capacity score in terms of process indicators. CONCLUSIONS: There is a significant geographical heterogeneity on the capacity of health facilities for HIV/AIDS care and treatment in Ethiopia. Targeted capacity improvement initiatives are recommended with focus on health centers and private health facilities, and emerging Regions and the rural and remote areas. PMID- 29996822 TI - Association between self-reported eating speed and metabolic syndrome in a Beijing adult population: a cross-sectional study. AB - BACKGROUND: Research on the relationship between metabolic syndrome (MetS), its components and eating speed is limited in China. The present study aimed to clarify the association between MetS, its components and eating speed in a Beijing adult population. METHODS: This cross-sectional study included 7972 adults who were 18-65 years old and who received health check-ups at the Beijing Physical Examination Center in 2016. Logistic regression was conducted to explore the associations between MetS, its components and eating speed. RESULTS: The prevalence of MetS in this population was 24.65% (36.02% for males and 10.18% for females). Eating speed was significantly associated with a high risk for MetS, elevated blood pressure, and central obesity for both genders. Eating speed was associated with a high risk for elevated triglycerides and with a reduction in high-density lipoprotein in males, and eating speed was associated with a high risk for elevated fasting plasma glucose in females. Compared with slow eating speed, the multivariate-adjusted odds ratios of medium eating speed and fast eating speed for MetS were 1.65 (95% confidence interval 1.32-2.07) and 2.27 (95% confidence interval 1.80-2.86) for all subjects, 1.58 (95% confidence interval 1.21-2.07) and 2.21 (95% confidence interval 1.69-2.91) for males, and 1.75 (95% confidence interval 1.15-2.68) and 2.27 (95% confidence interval 1.46-3.53) for females, respectively. CONCLUSIONS: Eating speed is positively associated with MetS and its components. Future recommendations aiming to prevent MetS and its components may focus on eating speed. PMID- 29996823 TI - Predictors of consent to cell line creation and immortalisation in a South African schizophrenia genomics study. AB - BACKGROUND: Cell line immortalisation is a growing component of African genomics research and biobanking. However, little is known about the factors influencing consent to cell line creation and immortalisation in African research settings. We contribute to addressing this gap by exploring three questions in a sample of Xhosa participants recruited for a South African psychiatric genomics study: First, what proportion of participants consented to cell line storage? Second, what were predictors of this consent? Third, what questions were raised by participants during this consent process? METHODS: 760 Xhose people with schizophrenia and 760 controls were matched to sex, age, level of education and recruitment region. We used descriptive statistics to determine the proportion of participants who consented to cell line creation and immortalization. Logistic regression methods were used to examine the predictors of consent. Reflections from study recruiters were elicited and discussed to identify key questions raised by participants about consent. RESULTS: Approximately 40% of participants consented to cell line storage. The recruiter who sought consent was a strong predictor of participant's consent. Participants recruited from the South African Eastern Cape (as opposed to the Western Cape), and older participants (aged between 40 and 59 years), were more likely to consent; both these groups were more likely to hold traditional Xhosa values. Neither illness (schizophrenia vs control) nor education (primary vs secondary school) were significant predictors of consent. Key questions raised by participants included two broad themes: clarification of what cell immortalisation means, and issues around individual and community benefit. CONCLUSIONS: These findings provide guidance on the proportion of participants likely to consent to cell line immortalisation in genomics research in Africa, and reinforce the important and influential role that study recruiters play during seeking of this consent. Our results reinforce the cultural and contextual factors underpinning consent choices, particularly around sharing and reciprocity. Finally, these results provide support for the growing literature challenging the stigmatizing perception that people with severe mental illness are overly vulnerable as a target group for heath research and specifically genomics studies. PMID- 29996824 TI - Debating diversity: a commentary on Standards of practice in empirical bioethics research. AB - This article provides a commentary on Standards of practice in empirical bioethics research by Ives and colleagues (in this Issue). There is much to admire in the paper, and in the demanding consensus-building process on which it reports. I discuss the problems and limits of methodological standardisation, and a central conceptual tension that appears to have divided participants. I suggest that the finished product should be understood as a record of a methodological conversation, rather than being used as a disciplinary tool to limit the evolution of empirical bioethics. PMID- 29996825 TI - Healthcare workers' perspectives and practices regarding the disclosure of HIV status to children in Malawi: a cross-sectional study. AB - BACKGROUND: In 2011 the World Health Organisation recommended that children with a diagnosis of HIV be gradually informed about their HIV status between the ages of 6 and 12 years. However, to date, literature has focused mainly on primary caregiver and child experiences with HIV disclosure, little is known about healthcare workers' perspectives and practices of HIV status disclosure to children. The aim of this study was to assess healthcare workers' perspectives and practices regarding the disclosure of HIV status to children aged between 6 and 12 years in Malawi. METHODS: A cross-sectional survey was used to collect data from 168 healthcare providers working in antiretroviral clinics in all government District and Tertiary Hospitals in Malawi. Participants were asked questions regarding their knowledge, practice, and barriers to HIV disclosure. Data were analysed using binary logistic regression. RESULTS: Almost all healthcare workers (98%) reported that it was important to disclose HIV status to children. A significant proportion (37%) reported that they had never disclosed HIV status to a child and about half estimated that the rate of HIV disclosure at their facility was 25% or less. The main barriers to disclosure were lack of training on disclosure (85%) and lack of a standard tool for disclosure (84%). Female healthcare workers (aOR) 2.4; 95% CI: 1.1-5.5) and lack of training on disclosure (aOR 7.7; 95% CI: 3.4-10.7) were independently associated with never having disclosed HIV status to a child. CONCLUSIONS: This study highlights the need for providing appropriate training in HIV disclosure for healthcare workers and the provision of standardised disclosure materials. PMID- 29996826 TI - Antibacterial efficacy of leaf extracts of Combretum album Pers. against some pathogenic bacteria. AB - BACKGROUND: Plant derived medicines show significant contributions to mankind in treating infections of pathogenic bacteria. Recently plants are used in pharmaceutical industries for novel drug preparations because to ensure efficacy and safety as synthetic antibiotics are threatened for their multidrug resistance. The present study aimed at finding antibacterial potential of aqueous and ethanolic leaf extracts of Combretum album. METHODS: Antibacterial activity was evaluated against seven bacterial strains by determining minimum inhibitory concentration (MIC) and zone of inhibition. Diameters of the zone of inhibition were compared with standard antibiotics. Preliminary phytochemical screening was done according to standard protocol. FTIR analysis was performed to identify the general phytochemical groups of compounds in the extract. All experiments were conducted in triplicate and values were expressed as the mean +/- standard deviation. One-way analysis of variance (ANOVA) and Tukey tests were performed for statistical justification. RESULTS: Maximum zones of inhibition were found in case of ethanolic extracts in the following order Bacillus licheniformis (MTCC 530) > Pseudomonas aeruginosa (MTCC 2453) > Bacillus subtilis (MTCC 441) >, Pseudomonas fluorescens (MTCC 103) > Bacillus mycoides (MTCC 7343) > Escherichia coli (MTCC 739) > Pseudomonas putida (MTCC 1654) with zone of inhibition of 27.67 +/- 0.33 mm diameter in B. licheniformis (MTCC 530). Qualitatively, the ethanol extract contains flavonoids, tannins and alkaloids. The results of FTIR analysis confirmed the presence of R-CH2-OH groups, aromatics, C-N stretching amine and NH stretching secondary amine. One way ANOVA and Tukey tests statistically justify the data (p <= 0.05). CONCLUSIONS: All the tested leaf extracts showed promising antibacterial activity against both gram positive and gram negative bacteria. Phytochemical screening and FTIR analysis revealed the presence of tannins, alkaloids, R-CH2-OH groups, aromatics and flavonoids in ethanolic leaf extract qualitatively and these compounds could be responsible for antibacterial property of leaf extracts of C. album. PMID- 29996827 TI - Viral diversity is an obligate consideration in CRISPR/Cas9 designs for targeting the HIV reservoir. AB - BACKGROUND: RNA-guided CRISPR/Cas9 systems can be designed to mutate or excise the integrated HIV genome from latently infected cells and have therefore been proposed as a curative approach for HIV. However, most studies to date have focused on molecular clones with ideal target site recognition and do not account for target site variability observed within and between patients. For clinical success and broad applicability, guide RNA (gRNA) selection must account for circulating strain diversity and incorporate the within-host diversity of HIV. RESULTS: We identified a set of gRNAs targeting HIV LTR, gag, and pol using publicly available sequences for these genes and ranked gRNAs according to global conservation across HIV-1 group M and within subtypes A-C. By considering paired and triplet combinations of gRNAs, we found triplet sets of target sites such that at least one of the gRNAs in the set was present in over 98% of all globally available sequences. We then selected 59 gRNAs from our list of highly conserved LTR target sites and evaluated in vitro activity using a loss-of-function LTR-GFP fusion reporter. We achieved efficient GFP knockdown with multiple gRNAs and found clustering of highly active gRNA target sites near the middle of the LTR. Using published deep-sequence data from HIV-infected patients, we found that globally conserved sites also had greater within-host target conservation. Lastly, we developed a mathematical model based on varying distributions of within-host HIV sequence diversity and enzyme efficacy. We used the model to estimate the number of doses required to deplete the latent reservoir and achieve functional cure thresholds. Our modeling results highlight the importance of within-host target site conservation. While increased doses may overcome low target cleavage efficiency, inadequate targeting of rare strains is predicted to lead to rebound upon cART cessation even with many doses. CONCLUSIONS: Target site selection must account for global and within host viral genetic diversity. Globally conserved target sites are good starting points for design, but multiplexing is essential for depleting quasispecies and preventing viral load rebound upon therapy cessation. PMID- 29996828 TI - Structural complexity of the co-chaperone SGTA: a conserved C-terminal region is implicated in dimerization and substrate quality control. AB - BACKGROUND: Protein quality control mechanisms are essential for cell health and involve delivery of proteins to specific cellular compartments for recycling or degradation. In particular, stray hydrophobic proteins are captured in the aqueous cytosol by a co-chaperone, the small glutamine-rich, tetratricopeptide repeat-containing protein alpha (SGTA), which facilitates the correct targeting of tail-anchored membrane proteins, as well as the sorting of membrane and secretory proteins that mislocalize to the cytosol and endoplasmic reticulum associated degradation. Full-length SGTA has an unusual elongated dimeric structure that has, until now, evaded detailed structural analysis. The C terminal region of SGTA plays a key role in binding a broad range of hydrophobic substrates, yet in contrast to the well-characterized N-terminal and TPR domains, there is a lack of structural information on the C-terminal domain. In this study, we present new insights into the conformation and organization of distinct domains of SGTA and show that the C-terminal domain possesses a conserved region essential for substrate processing in vivo. RESULTS: We show that the C-terminal domain region is characterized by alpha-helical propensity and an intrinsic ability to dimerize independently of the N-terminal domain. Based on the properties of different regions of SGTA that are revealed using cell biology, NMR, SAXS, Native MS, and EPR, we observe that its C-terminal domain can dimerize in the full-length protein and propose that this reflects a closed conformation of the substrate-binding domain. CONCLUSION: Our results provide novel insights into the structural complexity of SGTA and provide a new basis for mechanistic studies of substrate binding and release at the C-terminal region. PMID- 29996829 TI - Correlates of alcoholics anonymous affiliation among justice-involved women. AB - BACKGROUND: Alcohol use disorder (AUD) constitutes a major public health problem and is associated with a substantial amount of disability and premature death worldwide. Several treatment and self-help options including Alcoholics Anonymous (AA) meetings are available. Nevertheless, factors associated with AA affiliation in some disadvantaged groups such as justice-involved women are not well understood. The purpose of this study is to report on previously unexamined correlates of past year AA affiliation among women in pretrial jail detention. METHODS: The current study used cross-sectional data from 168 women with DSM-5 diagnosis of AUD in pretrial jail detention. The study examined factors related to women's concept of self and others (i.e., disbelief that others are trustworthy, lack of autonomy to choose who they interact with, experience of violent victimization, low investment in self-care, higher stress levels, and homelessness) as correlates of past-year AA affiliation, controlling for severity of AUD and demographic factors. RESULTS: Women who believe that others are inherently trustworthy, women who met less AUD criteria, and women who are older reported more past-year AA affiliation in both univariate and multivariate analyses. CONCLUSION: Introducing AA outreach and alternative interventions for younger, less severely addicted women might improve AUD outcomes. Moreover, designing more individualized treatment plan for women who believe others are not trust worthy might help AUD treatment engagement in this population. TRIAL REGISTRATION: NCT01970293 , 10/28/2013. PMID- 29996830 TI - Changes in proton pump inhibitor prescribing trend over the past decade and pharmacists' effect on prescribing practice at a tertiary hospital. AB - BACKGROUND: Proton pump inhibitors (PPIs) remain one of the world's most frequently prescribed medications and there is a growing number of publications on correct versus incorrect use of PPIs worldwide. The objective of this observational retrospective study was to assess changes in PPI prescribing trends over the past decade and pharmacists' effect on optimizing PPI prescribing practice at a tertiary hospital in China. METHODS: We collected the prescriptions of PPIs in our hospital from January 2007 to December 2016. Then the rate of PPI prescribing, the defined daily doses (DDDs) and expenditures were calculated and plotted to show the change in utilization of and expenditure on PPIs. Reasons behind this change and effect of pharmacists' intervention were evaluated by investigating the rationality of PPI use through sample surveys of patients of pre-intervention (Jul.-Dec. 2015) and post-intervention (Jul.-Dec. 2016). RESULTS: In outpatient settings, the rate of PPI prescribing remained almost constant, utilization (from 135,808 DDDs to 722,943 DDDs) and expenditure (from 1.85 million CNY to 7.96 million CNY) increased for the past ten years, dominated by oral formulations and rabeprazole. In contrast, in inpatient settings, the rate of PPI prescribing (from 20.41 to 37.21%), utilization (from 132,329 DDDs to 827,747 DDDs) and expenditure (from 3.15 million CNY to 25.29 million CNY) increased from 2007 to 2015 and then decreased, dominated by injection formulations and omeprazole. Pharmacist interventions could significantly promote the rational use of PPIs (44.00% versus 26.67%), decrease PPI use and reduce patients' charges (P < 0.05). CONCLUSIONS: The utilization of and expenditure on PPIs grew due to the increase of patients and irrational use of PPI. Pharmacist interventions help to reduce PPI utilization and expenditure and enhance rationality for inpatients, but much work should be done to regulate injection and originator formulas, and improve the rationality in the future. PMID- 29996832 TI - The professional culture among physicians in Sweden: potential implications for patient safety. AB - BACKGROUND: Patient safety culture, i.e. a subset of an organization's culture, has become an important focus of patient safety research. An organization's culture consists of many cultures, underscoring the importance of studying subcultures. Professional subcultures in health care are potentially important from a patient safety point of view. Physicians have an important role to play in the effort to improve patient safety. The aim was to explore physicians' shared values and norms of potential relevance for patient safety in Swedish health care. METHODS: Data were collected through group and individual interviews with 28 physicians in 16 semi-structured interviews, which were recorded and transcribed verbatim before being analysed with an inductive approach. RESULTS: Two overarching themes, "the competent physician" and "the integrated yet independent physician", emerged from the interview data. The former theme consists of the categories Infallible and Responsible, while the latter theme consists of the categories Autonomous and Team player. The two themes and four categories express physicians' values and norms that create expectations for the physicians' behaviours that might have relevance for patient safety. CONCLUSIONS: Physicians represent a distinct professional subculture in Swedish health care. Several aspects of physicians' professional culture may have relevance for patient safety. Expectations of being infallible reduce their willingness to talk about errors they make, thus limiting opportunities for learning from errors. The autonomy of physicians is associated with expectations to act independently, and they use their decisional latitude to determine the extent to which they engage in patient safety. The physicians perceived that organizational barriers make it difficult to live up to expectations to assume responsibility for patient safety. Similarly, expectations to be part of multi-professional teams were deemed difficult to fulfil. It is important to recognize the implications of a multi faceted perspective on the culture of health care organizations, including physicians' professional culture, in efforts to improve patient safety. PMID- 29996831 TI - Malaria and the 'last' parasite: how can technology help? AB - Malaria, together with HIV/AIDS, tuberculosis and hepatitis are the four most deadly infectious diseases globally. Progress in eliminating malaria has saved millions of lives, but also creates new challenges in detecting the 'last parasite'. Effective and accurate detection of malaria infections, both in symptomatic and asymptomatic individuals are needed. In this review, the current progress in developing new diagnostic tools to fight malaria is presented. An ideal rapid test for malaria elimination is envisioned with examples to demonstrate how innovative technologies can assist the global defeat against this disease. Diagnostic gaps where technology can bring an impact to the elimination campaign for malaria are identified. Finally, how a combination of microfluidic based technologies and smartphone-based read-outs could potentially represent the next generation of rapid diagnostic tests is discussed. PMID- 29996833 TI - Post-discharge malaria chemoprevention (PMC) in Malawi: caregivers' acceptance and preferences with regard to delivery methods. AB - BACKGROUND: In malaria endemic countries of sub-Saharan Africa, many children develop severe anaemia due to previous and current malaria infections. After blood transfusions and antimalarial treatment at the hospital they are usually discharged without any follow-up. In the post-discharge period, these children may contract new malaria infections and develop rebound severe anaemia. A randomised placebo-controlled trial in Malawi showed 31% reduction in malaria- and anaemia-related deaths or hospital readmissions among children under 5 years of age given antimalarial drugs for 3 months post-discharge. Thus, post-discharge malaria chemoprevention (PMC) may provide substantial protection against malaria and anaemia in young children living in areas of high malaria transmission. A delivery implementation trial is currently being conducted in Malawi to determine the optimal strategy for PMC delivery. In the trial, PMC is delivered through community- or facility-based methods with or without the use of reminders via phone text message or visit from a Health Surveillance Assistant. This paper describes the acceptance of PMC among caregivers. METHODS: From October to December 2016, 30 in-depth interviews and 5 focus group discussions were conducted with caregivers of children who recently completed the last treatment course in the trial. Views on the feasibility of various delivery methods and reminder strategies were collected. The interviews were transcribed verbatim, translated to English, and coded using the software programme NVivo. RESULTS: Community-based delivery was perceived as more favourable than facility-based delivery due to easy home access to drugs and fewer financial concerns. Many caregivers reported lack of visits from Health Surveillance Assistants and preferred text message reminders sent directly to their phones rather than waiting on these visits. Positive attitudes towards active use of health cards for remembering treatment dates were especially evident. Additionally, caregivers shared positive experiences from participation in the programme and described dihydroartemisinin-piperaquine as a safe and effective antimalarial drug that improved the health and well-being of their children. CONCLUSIONS: Post-discharge malaria chemoprevention given to children under the age of 5 previously treated for severe anaemia is highly accepted among caregivers. Caregivers prefer community-based delivery with use of health cards as their primary tool of reference. TRIAL REGISTRATION: NCT02721420 (February 13, 2016). PMID- 29996834 TI - A simple metric for a complex outcome: proposing a sustainment index for health indicators. AB - BACKGROUND: Sustainability is, at least in principle, an important criterion for evaluating global health and development programs. The absence of shared metrics for success or achievements in sustainability is however critically lacking. We propose a simple metric, free of causal inference, which can be used to test different empirical models for the sustainment of health outcomes. METHODS: We follow the suggestion of Chambers and use "sustainment" to refer to the verifiable and measured extent to which a health indicator has evolved over time. The sustainment index of a health indicator (Y) advanced by a program is based on a simple-to-calculate approximation of the derivative of Y over time (T0: baseline, T1: endline, and T2: post-project), based on the ratio of the slope of YT1-T2 over YT0-T1. SI(Y) = 1+ (YT1-T2 / YT0-T1). RESULTS: This construct provides three clear benchmarks: SI = 0, when the health indicator returns to baseline value post-project (YT2 = YT0); SI = 1, when the endline-post-project trend is a plateau; and SI = 2, when the progress slope during program is uninterrupted post-program. We find strong correlation (r2 = 0.922) between the SI and independent practitioners' rating of indicator trends. The SI shows different levels of achieved sustainment for a range of indicators in a published ex-post sustainability study. And we find that the SI can be computed for large national datasets for two types of indicators. CONCLUSIONS: The Sustainment Index has limitations and conditions of applicability, but it can be applied to different datasets and studies to provide a reliable dependent measure of the level of sustainment of health outcomes from one period of time to the next. The Index will need additional testing, and future evaluation-research work will need to consider index performance under different situations. The Sustainment Index has the potential to provide a standard metric to build evidence through more systematic research on sustainment and sustainability. PMID- 29996835 TI - Mapping the stability of malaria hotspots in Bangladesh from 2013 to 2016. AB - BACKGROUND: Malaria claims hundreds of thousands of lives each year, most of them children. A "malaria-free world" is the World Health Organization's vision, but elimination from the southeast Asian Region is hampered by factors including anti malarial resistance and systematic underreporting. Malaria is a significant public health problem in Bangladesh and while there have been recent gains in control, there is large spatial and temporal heterogeneity in the disease burden. This study aims to determine the pattern and stability of malaria hotspots in Bangladesh with the end goal of informing intervention planning for elimination. RESULTS: Malaria in Bangladesh exhibited highly seasonal, hypoendemic transmission in geographic hotspots, which remained conserved over time. The southeast areas of the Chittagong Hill Tracts were identified as malaria hotspots for all 4 years examined. Similarly, areas in Sunamganj and Netrakona districts in the Northeast were hotspots for 2013-2016. Highly stable hotspots from 1 year predicted the following year's hotspot locations in the southeast of Bangladesh. Hotspots did not appear to act as sources of spread with no evidence of consistent patterns of contiguous spread or recession of hotspots as high or low transmission seasons progressed. CONCLUSIONS: Areas were identified with temporal and spatial clustering of high malaria incidence in Bangladesh. Further studies are required to understand the vector, sociodemographic and disease dynamics within these hotspots. Given the low caseloads occurring in the low transmission seasons, and the conserved nature of malaria hotspots, directing resources towards these areas may be an efficient way to achieve malaria elimination in Bangladesh. PMID- 29996836 TI - Implementation of continuous quality improvement in Aboriginal and Torres Strait Islander primary health care in Australia: a scoping systematic review. AB - BACKGROUND: Continuous Quality Improvement (CQI) programs have been taken up widely by Indigenous primary health care (PHC) services in Australia and there has been national policy commitment to support this. However, international evidence shows that implementing CQI is challenging, impacts are variable and little is known about the factors that impede or enhance effectiveness. A scoping review was undertaken to explore uptake and implementation in Indigenous PHC, including barriers and enablers to embedding CQI in routine practice. We provide guidance on how research and evaluation might be intensified to support implementation. METHODS: Searches were conducted in MEDLINE, CINAHL and the Cochrane Database of Systematic Reviews. Key websites and publications were handsearched. Studies conducted in Indigenous PHC which demonstrated some combination of CQI characteristics and assessed some aspect of implementation were included. A two stage analysis was undertaken. Stage 1 identified the breadth and focus of literature. Stage 2 investigated barriers and enablers. The Framework for Performance Assessment in PHC (2008) was used to frame the analysis. Data were extracted on the study type, approach, timeframes, CQI strategies, barriers and enablers. RESULTS: Sixty articles were included in Stage 1 and 21 in Stage 2. Barriers to implementing CQI processes relate primarily to professional and organisational processes and operate at multiple levels (individual, team, service, health system) whereas barriers to improved care relate more directly to knowledge of best practice and team processes that facilitate appropriate care. Few studies described implementation timeframes, number of CQI cycles or improvement strategies implemented and only two applied a change theory. CONCLUSION: Investigating barriers and enablers that modify implementation and impacts of CQI poses conceptual and methodological challenges. More complete description of CQI processes, implementation strategies, and barriers and enablers could enhance capacity for comparisons across settings and contribute to better understanding of key success factors. PMID- 29996837 TI - Possible pathogenic mechanism of gluteal pain in lumbar disc hernia. AB - Recent reported results by Fang et al. published in BMC Musculoskeletal Disorders have added to the weight of evidence supporting association between gluteal pain and lumbar disc hernia. Their clinical finding shows the L4/5 level is the main level responsible for gluteal pain in lumbar disc hernia. Indeed, many possible mechanisms may explain why patients experience pain in the gluteal area. In this Correspondence, we would like to highlight several possible mechanisms of LDH related gluteal pain based on detailed analysis of the sensory innervation of the gluteal region. We hope this can better explain the phenomenon found by Fang et al. We believe the principle mechanism is compression/irritation of L5 or S1 dorsal rami (intraspinal portion), which produce gluteal pain by irritating superior/medial cluneal nerve and referred pain from facet joints and sacroiliac joints. In addition, the presence of proximal sciatica could also induce gluteal pain. Lastly, fibers in the superior or inferior gluteal nerve could be compressed/irritated in LDH, inducing LDH-related gluteal pain. However, additional studies are needed in the future to delineate the exact mechanism(s). PMID- 29996838 TI - Accountability mechanisms for implementing a health financing option: the case of the basic health care provision fund (BHCPF) in Nigeria. AB - BACKGROUND: The Nigerian National Health Act proposes a radical shift in health financing in Nigeria through the establishment of a fund - Basic Healthcare Provision Fund, (BHCPF). This Fund is intended to improve the functioning of primary health care in Nigeria. Key stakeholders at national, sub-national and local levels have raised concerns over the management of the BHCPF with respect to the roles of various stakeholders in ensuring accountability for its use, and the readiness of the implementers to manage this fund and achieve its objectives. This study explores the governance and accountability readiness of the different layers of implementation of the Fund; and it contributes to the generation of policy implementation guidelines around governance and accountability for the Fund. METHODS: National, state and LGA level respondents were interviewed using a semi structured tool. Respondents were purposively selected to reflect the different layers of implementation of primary health care and the levels of accountability. Different accountability layers and key stakeholders expected to implement the BHCPF are the Federal government (Federal Ministry of Health, NPHCDA, NHIS, Federal Ministry of Finance); the State government (State Ministry of Health, SPHCB, State Ministry of Finance, Ministry of Local Government); the Local government (Local Government Health Authorities); Health facilities (Health workers, Health facility committees (HFC) and External actors (Development partners and donors, CSOs, Community members). RESULTS: In general, the strategies for accountability encompass planning mechanisms, strong and transparent monitoring and supervision systems, and systematic reporting at different levels of the healthcare system. Non-state actors, particularly communities, must be empowered and engaged as instruments for ensuring external accountability at lower levels of implementation. New accountability strategies such as result-based or performance-based financing could be very valuable. CONCLUSION: The key challenges to accountability identified should be addressed and these included trust, transparency and corruption in the health system, political interference at higher levels of government, poor data management, lack of political commitment from the State in relation to release of funds for health activities, poor motivation, mentorship, monitoring and supervision, weak financial management and accountability systems and weak capacity to implement suggested accountability mechanisms due to political interference with accountability structures. PMID- 29996839 TI - Single cut distal femoral osteotomy for correction of femoral torsion and valgus malformity in patellofemoral malalignment - proof of application of new trigonometrical calculations and 3D-printed cutting guides. AB - BACKGROUND: The purpose of this study was to perform a derotational osteotomy at the distal femur, as is done in cases of patellofemoral instability, and demonstrate the predictability of three-dimensional (3D) changes on axes in a cadaveric model by the use of a new mathematical approach. METHODS: Ten human cadaveric femurs, with increased antetorsion, underwent a visually observed derotational osteotomy at the distal femur by 20 degrees , as is commonly done in clinics. For surgery, a single cut osteotomy with a defined cutting angle was calculated and given using a simple 3D-printed cutting guide per specimen, based on a newly-created trigonometrical model. To simulate post-operative straight frontal alignment in a normal range, a goal for the mechanical lateral distal femur angle (mLDFA) was set to 87.0 degrees for five specimens (87-goal group) and 90.0 degrees for five specimens (90-goal group). Specimens underwent pre- and post-operative radiographic analysis with CT scan for torsion and frontal plane x-ray for alignment measurements of mLDFA and anatomical mechanical angle (AMA). RESULTS: Performed derotation showed a mean of 19.69 degrees +/-1.08 degrees SD (95% CI: 18.91 degrees to 20.47 degrees ). Regarding frontal alignment, a mean mLDFA of 86.9 degrees +/-0.66 degrees SD (87-goal-group) and 90.42 degrees +/-0.25 degrees SD (90-goal group), was observed (p = 0.008). Overall, the mean difference between intended mLDFA-goal and post-operatively achieved mLDFA was 0.14 degrees +/-0.56 degrees SD (95% CI: -0.26 degrees to 0.54 degrees ). CONCLUSION: A preoperative calculated angle for single cut derotational osteotomy at the distal femur leads to a clinically precise post operative result on torsion and frontal alignment when using this approach. PMID- 29996840 TI - Dietary pattern is associated with obesity in Chinese children and adolescents: data from China Health and Nutrition Survey (CHNS). AB - BACKGROUND: Associations of dietary patterns in Chinese adolescents and children with later obesity have not previously been investigated. The purpose of the present study was to evaluate the associations between dietary patterns and the risk of obesity in Chinese adolescents and children by using a longitudinal design. METHODS: Data from the China Health and Nutrition Survey (CHNS), a nationally representative survey, were used for our analysis. 489 participants 6 14 years of age were followed from 2006 to 2011. Factor analysis was used to identify the dietary patterns in Chinese adolescents and children. Ordered logistic regression models were used to examine the association between dietary patterns and later obesity. RESULTS: Two dietary patterns were revealed by factor analysis, the traditional Chinese dietary pattern (with high intake of rice, vegetables, poultry, pork and fish and the modern dietary pattern (with high intake of wheat, processed meat and fast food). Children in the highest quartile and the second-highest quartile of the traditional Chinese dietary pattern was inversely associated with later obesity compared with children in the lowest quartile over 5 years (OR = 0.19, 95%CI: 0.09, 0.40 for Q4; OR = 0.47, 95%CI: 0.33, 0.67 for Q3); Children in the highest quartile of the modern dietary pattern was positively associated with later obesity compared with children in the lowest quartile over 5 years (OR = 2.02, 95%CI: 1.17, 3.48). CONCLUSIONS: Dietary patterns in Chinese adolescents and children are associated with later obesity. These findings further confirm the importance of children's dietary patterns in later obesity and lay groundwork for dietary culture-specific interventions targeted at reducing rates of obesity in children and adolescents. PMID- 29996841 TI - Comparison of Mesh Fixation Techniques in Elective Laparoscopic Repair of Incisional Hernia-ReliaTackTM v ProTackTM (TACKoMesh) - A double-blind randomised controlled trial. AB - BACKGROUND: Minimally invasive incisional hernia repair has been established as a safe and efficient surgical option in most centres worldwide. Laparoscopic technique includes the placement of an intraperitoneal onlay mesh with fixation achieved using spiral tacks or sutures. An additional step is the closure of the fascial defect depending upon its size. Key outcomes in the evaluation of ventral abdominal hernia surgery include postoperative pain, the presence of infection, seroma formation and hernia recurrence. TACKoMESH is a randomised controlled trial that will provide important information on the laparoscopic repair of an incisional hernia; 1) with fascial closure, 2) with an IPOM mesh and 3) comparing the use of an articulating mesh-fixation device that deploys absorbable tacks with a straight-arm mesh-fixation device that deploys non-absorbable tacks. METHODS: A prospective, single-centre, double-blinded randomised trial, TACKoMESH, will establish whether the use of absorbable compared to non absorbable tacks in adult patients undergoing elective incisional hernia repair produces a lower rate of pain both immediately and long-term. Eligible and consenting patients will be randomized to surgery with one of two tack-fixation devices and followed up for a minimum one year. Secondary outcomes to be explored include wound infection, seroma formation, hernia recurrence, length of postoperative hospital stay, reoperation rate, operation time, health related quality of life and time to return to normal daily activity. DISCUSSION: With ongoing debate around the best management of incisional hernia, continued trials that will add substance are both necessary and important. Laparoscopic techniques have become established in reducing hospital stay and rates of infection and report improvement in some patient centered outcomes whilst achieving similarly low rates of recurrence as open surgical techniques. The laparoscopic method with tack fixation has developed a reputation for its tendency to cause post-operative pain. Novel additions to technique, such as intraoperative-sutured closure of a fascial defect, and developments in surgical technology, such as the evolution of composite mesh design and mesh-fixation devices, have brought about new considerations for patient and surgeon. This study will evaluate the efficacy of several new technical considerations in the setting of elective laparoscopic incisional hernia repair. TRIAL REGISTRATION: Name of registry - ClinicalTrials.gov Registration number: NCT03434301 . Retrospectively registered on 15th February 2018. PMID- 29996842 TI - Deep vein thrombosis following the treatment of lower limb pathologic bone fractures - a comparative study. AB - BACKGROUND: Deep vein thrombosis is a well-known complication of fracture occurrence, lower limb surgery and periods of prolonged immobilisation. Its incidence can be increased even more in specific cases with metastatic bone disease and adjuvant treatment. There is a small amount of literature that addresses the incidence of DVT by comparing osteosynthesis and arthroplasty as surgical treatments. Current recommended anticoagulation protocols might be inadequate for specific groups of cancer patients undergoing osteosynthesis or arthroplasty. METHODS: The study was designed and performed in a retrospective manner and carried out on patients that presented at our Emergency Clinical County Hospital between 01.01.2008-31.12.2016. The patients' evolution was followed for a standard of 2 months. All our deep vein thrombosis events were diagnosed via venous duplex imaging. The studied lot (n = 85) was paired with a control group (n = 170) with similar baseline characteristics. RESULTS: Our lot was comprised of 85 patients that underwent 85 surgeries, on both of our hospital's Orthopaedic and Traumatology wards. When performing the student t-test and calculating OR (odds ratio) and RR (risk ratio) we encountered 11 cases of DVT in our studied group and 12 cases of DVT in our control group (p < 0.04). We found statistical significance when correlating DVT with type of implant (prosthesis), the presence of metastases over primary tumour and the choice of implant (prosthesis over intramedullary nail). There was no statistical significance found when correlating DVT events with the type of anticoagulation and the amount of blood transfusion units required. CONCLUSION: Patients who undergo surgical treatment for lower limb pathological fracture due to malignancy are at increased risk of DVT or death due to PE under current general thromboprophylaxis regimens. The risk is higher for the immediate postoperative period (10 days). The risk is increased by metastasis, arthroplasty and adjuvant therapy (radiotherapy, chemotherapy), and we think that a more aggressive prophylactic protocol should be used. PMID- 29996843 TI - beta-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals. AB - BACKGROUND: Sarcopenia, a reduction in muscle mass and function seen in aging populations, may be countered by improving systemic carnosine stores via beta Alanine (beta-alanine) supplementation. Increasing systemic carnosine levels may result in enhanced anti-oxidant, neuro-protective and pH buffering capabilities. This enhancement should result in improved exercise capacity and executive function. METHODS: Twelve healthy adults (average age = 60.5 +/- 8.6 yrs, weight = 81.5 +/- 12.6 kg) were randomized and given either 2.4 g/d of beta-alanine (BA) or Placebo (PL) for 28 days. Exercise capacity was tested via bouts on a cycle ergometer at 70% VO2 peak. Executive function was measured by Stroop Tests 5 min before exercise (T1), immediately before exercise (T2), immediately following fatigue (T3), and 5 min after fatigue (T4). Lactate measures were taken pre/post exercise. Heart rate, Rating of Perceived Exertion (RPE) and VO2 were recorded throughout exercise testing. RESULTS: PRE average time-to-exhaustion (TTE) for the PL and BA group were not significantly different (Mean +/- SD; 9.4 +/- 1.4mins vs 11.1 +/- 2.4mins, respectively, P = 0.7). POST BA supplemented subjects cycled significantly longer than PRE (14.6 +/- 3.8mins vs 11.1 +/- 2.4mins, respectively, P = 0.04) while those given PL did not (8.7 +/- 2.4mins vs 9.4 +/- 1.4mins, respectively, P = 0.7). PL subjects were slower in completing the Stroop test POST at T4 compared to T3 (T3 = - 13.3 +/- 8.6% vs T4 = 2.1 +/- 8.3%, P = 0.04), while the BA group (T3 = - 9.2 +/- 6.4% vs T4 = - 2.5 +/- 3.5%, P = 0.5) was not. POST lactate production expressed a trend when comparing treatments, as the BA group produced 2.4 +/- 2.6 mmol/L more lactate than the PL group (P = 0.06). Within group lactate production for BA (P = 0.4) and PL (P = 0.5), RPE (P = 0.9) and heart rate (P = 0.7) did not differ with supplementation. CONCLUSION: BA supplementation increased exercise capacity and eliminated endurance exercise induced declines in executive function seen after recovery. Increased POST TTE coupled with similar PRE vs POST lactate production indicates an improvement in the ability of BA to extend exercise durations. Furthermore, by countering endurance exercise's accompanying deficits in executive function, the aging population can maintain benefits from exercise with improved safety. PMID- 29996844 TI - Effectiveness and safety of 3 and 5 day courses of artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in an area of emerging artemisinin resistance in Myanmar. AB - BACKGROUND: Artemisinin resistance in Plasmodium falciparum has emerged and spread in Southeast Asia. In areas where resistance is established longer courses of artemisinin-based combination therapy have improved cure rates. METHODS: The standard 3-day course of artemether-lumefantrine (AL) was compared with an extended 5-day regimen for the treatment of uncomplicated falciparum malaria in Kayin state in South-East Myanmar, an area of emerging artemisinin resistance. Late parasite clearance dynamics were described by microscopy and quantitative ultra-sensitive PCR. Patients were followed up for 42 days. RESULTS: Of 154 patients recruited (105 adults and 49 children < 14 years) 78 were randomized to 3 days and 76 to 5 days AL. Mutations in the P. falciparum kelch13 propeller gene (k13) were found in 46% (70/152) of infections, with F446I the most prevalent propeller mutation (29%; 20/70). Both regimens were well-tolerated. Parasite clearance profiles were biphasic with a slower submicroscopic phase which was similar in k13 wild-type and mutant infections. The cure rates were 100% (70/70) and 97% (68/70) in the 3- and 5-day arms respectively. Genotyping of the two recurrences was unsuccessful. CONCLUSION: Despite a high prevalence of k13 mutations, the current first-line treatment, AL, was still highly effective in this area of South-East Myanmar. The extended 5 day regimen was very well tolerated, and would be an option to prolong the useful therapeutic life of AL. Trial registration NCT02020330. Registered 24 December 2013, https://clinicaltrials.gov/NCT02020330. PMID- 29996845 TI - The invariant arginine within the chromatin-binding motif regulates both nucleolar localization and chromatin binding of Foamy virus Gag. AB - BACKGROUND: Nuclear localization of Gag is a property shared by many retroviruses and retrotransposons. The importance of this stage for retroviral replication is still unknown, but studies on the Rous Sarcoma virus indicate that Gag might select the viral RNA genome for packaging in the nucleus. In the case of Foamy viruses, genome encapsidation is mediated by Gag C-terminal domain (CTD), which harbors three clusters of glycine and arginine residues named GR boxes (GRI-III). In this study we investigated how PFV Gag subnuclear distribution might be regulated. RESULTS: We show that the isolated GRI and GRIII boxes act as nucleolar localization signals. In contrast, both the entire Gag CTD and the isolated GRII box, which contains the chromatin-binding motif, target the nucleolus exclusively upon mutation of the evolutionary conserved arginine residue at position 540 (R540), which is a key determinant of FV Gag chromatin tethering. We also provide evidence that Gag localizes in the nucleolus during FV replication and uncovered that the viral protein interacts with and is methylated by Protein Arginine Methyltransferase 1 (PRMT1) in a manner that depends on the R540 residue. Finally, we show that PRMT1 depletion by RNA interference induces the concentration of Gag C-terminus in nucleoli. CONCLUSION: Altogether, our findings suggest that methylation by PRMT1 might finely tune the subnuclear distribution of Gag depending on the stage of the FV replication cycle. The role of this step for viral replication remains an open question. PMID- 29996846 TI - Identification of differential gene expression profile from peripheral blood cells of military pilots with hypertension by RNA sequencing analysis. AB - BACKGROUND: Elevated blood pressure is an important risk factor for cardiovascular disease and is also an important factor in global mortality. Military pilots are at high risk of cardiovascular disease because they undergo persistent noise, high mental tension, high altitude hypoxia, high acceleration and high calorie diet. Hypertension is the leading cause of cardiovascular disease in military pilots. In this study, we want to identify key genes from peripheral blood cells of military pilots with hypertension. Identification of these genes may help diagnose and control hypertension and extend flight career for military pilots. METHODS: We use RNA sequencing technology, bioinformatics analysis and Western blotting to identify key genes from peripheral blood cells of military pilots with hypertension. RESULTS: Our study detected 121 up regulated genes and 623 down-regulated genes in the peripheral blood mononuclear cells (PBMCs) from hypertensive military pilots. We have also identified 8 important genes (NME4, PNPLA7, GGT5, PTGS2, IGF1R, NT5C2, ENTPD1 and PTEN), a number of gene ontology categories and biological pathways that may be associated with military pilot hypertension. CONCLUSIONS: Our study may provide effective means for the prevention, diagnosis and treatment of hypertension for military pilot and extend their flight career. PMID- 29996847 TI - Socioeconomic inequality in self-reported unmet need for oral health services in adults aged 50 years and over in China, Ghana, and India. AB - BACKGROUND: The 2015 Global Burden of Disease Study estimated that oral conditions affect 3.5 billion people worldwide with a higher burden among older adults and those who are socially and economically disadvantaged. Studies of inequalities in the use of oral health services by those in need have been conducted in high-income countries but evidence from low- and middle-income countries (LMICs) is limited. This study measures and describes socioeconomic inequality in self-reported unmet need for oral health services in adults aged 50 years and over, in China, Ghana and India. METHODS: A cross-sectional analysis of national survey data from the WHO SAGE Wave 1 (2007-2010) was conducted. Study samples in China (n = 1591), Ghana (n = 425) and India (n = 1307) were conditioned on self-reported need for oral health services in the previous 12 months. The binary dependent variable, unmet need for oral health services, was derived from questions about self-reported need and service use. Prevalence was estimated by country. Unmet need was measured and compared in terms of relative levels of education and household wealth. The methods were logistic regression and the relative index of inequality (RII). Models were adjusted for age, sex, area of residence, marital status, work status and self-rated health. RESULTS: The prevalence of unmet need was 60, 80, and 62% in China, Ghana and India respectively. The adjusted RII for education was statistically significant for China (1.5, 95% CI:1.2-1.9), Ghana (1.4, 95% CI: 1.1-1.7), and India (1.5, 95% CI:1.2-2.0), whereas the adjusted RII for wealth was significant only in Ghana (1.3, 95% CI:1.1-1.6). Male sex was significantly associated with self-reported unmet need for oral health services in India. CONCLUSIONS: Given rapid population ageing, further evidence of socioeconomic inequalities in unmet need for oral health services by older adults in LMICs is needed to inform policies to mitigate inequalities in the availability of oral health services. Oral health is a universal public health issue requiring attention and action on multiple levels and across the public private divide. PMID- 29996848 TI - How to engage stakeholders in research: design principles to support improvement. AB - BACKGROUND: Closing the gap between research production and research use is a key challenge for the health research system. Stakeholder engagement is being increasingly promoted across the board by health research funding organisations, and indeed by many researchers themselves, as an important pathway to achieving impact. This opinion piece draws on a study of stakeholder engagement in research and a systematic literature search conducted as part of the study. MAIN BODY: This paper provides a short conceptualisation of stakeholder engagement, followed by 'design principles' that we put forward based on a combination of existing literature and new empirical insights from our recently completed longitudinal study of stakeholder engagement. The design principles for stakeholder engagement are organised into three groups, namely organisational, values and practices. The organisational principles are to clarify the objectives of stakeholder engagement; embed stakeholder engagement in a framework or model of research use; identify the necessary resources for stakeholder engagement; put in place plans for organisational learning and rewarding of effective stakeholder engagement; and to recognise that some stakeholders have the potential to play a key role. The principles relating to values are to foster shared commitment to the values and objectives of stakeholder engagement in the project team; share understanding that stakeholder engagement is often about more than individuals; encourage individual stakeholders and their organisations to value engagement; recognise potential tension between productivity and inclusion; and to generate a shared commitment to sustained and continuous stakeholder engagement. Finally, in terms of practices, the principles suggest that it is important to plan stakeholder engagement activity as part of the research programme of work; build flexibility within the research process to accommodate engagement and the outcomes of engagement; consider how input from stakeholders can be gathered systematically to meet objectives; consider how input from stakeholders can be collated, analysed and used; and to recognise that identification and involvement of stakeholders is an iterative and ongoing process. CONCLUSION: It is anticipated that the principles will be useful in planning stakeholder engagement activity within research programmes and in monitoring and evaluating stakeholder engagement. A next step will be to address the remaining gap in the stakeholder engagement literature concerned with how we assess the impact of stakeholder engagement on research use. PMID- 29996849 TI - High efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated falciparum malaria in Muheza and Kigoma Districts, Tanzania. AB - BACKGROUND: Artemether-lumefantrine (AL) is the recommended first-line artemisinin-based combination therapy (ACT) for the treatment of uncomplicated falciparum malaria in most of the malaria-endemic countries, including Tanzania. Recently, dihydroartemisinin-piperaquine (DP) has been recommended as the alternative anti-malarial to ensure effective case management in Tanzania. This study assessed the parasite clearance rate and efficacy of AL and DP among patients aged 6 months to 10 years with uncomplicated falciparum malaria in two sites with different malaria transmission intensity. METHODS: This was an open label, randomized trial that was conducted at two sites of Muheza Designated District Hospital and Ujiji Health Centre in Tanga and Kigoma regions, respectively. Patients meeting inclusion criteria were enrolled, treated with either AL or DP and followed up for 28 (extended to 42) and 42 (63) days for AL and DP, respectively. Parasite clearance time was monitored in the first 72 h post treatment and the clearance rate constant and half-life were calculated using an established parasite clearance estimator. The primary outcome was parasitological cure on days 28 and 42 for AL and DP, respectively, while secondary outcome was extended parasitological cure on days 42 and 63 for AL and DP, respectively. RESULTS: Of the 509 children enrolled (192 at Muheza and 317 at Ujiji), there was no early treatment failure and PCR uncorrected cure rates on day 28 in the AL group were 77.2 and 71.2% at Muheza and Ujiji, respectively. In the DP arm, the PCR uncorrected cure rate on day 42 was 73.6% at Muheza and 72.5% at Ujiji. With extended follow-up (to day 42 for AL and 63 for DP) cure rates were lower at Ujiji compared to Muheza (AL: 60.2 and 46.1%, p = 0.063; DP: 57.6 and 40.3% in Muheza and Ujiji, respectively, p = 0.021). The PCR corrected cure rate ranged from 94.6 to 100% for all the treatment groups at both sites. Parasite clearance rate constant was similar in the two groups and at both sites (< 0.28/h); the slope half-life was < 3.0 h and all but only one patient cleared parasites by 72 h. CONCLUSION: These findings confirm high efficacy of the first- and the newly recommended alternative ACT for treatments for uncomplicated falciparum malaria in Tanzania. The high parasite clearance rate suggests absence of suspected artemisinin resistance, defined as delayed parasite clearance. Trial registration This trial is registered at ClinicalTrials.gov under registration number NCT02590627. PMID- 29996850 TI - Translating evidence to patient care through caregivers: a systematic review of caregiver-mediated interventions. AB - BACKGROUND: Caregivers may promote the uptake of science into patient care and the practice of evidence-informed medicine. The purpose of this study was to determine whether caregiver-mediated (non-clinical caregiver-delivered) interventions are effective in improving patient, caregiver, provider, or health system outcomes. METHODS: We searched the MEDLINE, Embase, PsycINFO, Cumulative Index of Nursing and Allied Health, and Scopus databases from inception to February 27, 2017. Interventions (with a comparison group) reporting on a quality improvement intervention mediated by a caregiver and directed to a patient, in all ages and patient-care settings, were selected for inclusion. A three-category framework was developed to characterize caregiver-mediated interventions: inform (e.g., provide knowledge), activate (e.g., prompt action), and collaborate (e.g., lead to interaction between caregivers and other groups [e.g., care providers]). RESULTS: Fifty-six studies met the inclusion criteria, and 64% were randomized controlled trials (RCTs). The most commonly assessed outcomes were patient- (n = 40) and caregiver-oriented (n = 33); few health system- (n = 10) and provider oriented (n = 2) outcomes were reported. Patient outcomes (e.g., satisfaction) were most improved by caregiver-mediated interventions that provided condition and treatment education (e.g., symptom management information) and practical condition-management support (e.g., practicing medication protocol). Caregiver outcomes (e.g., stress-related/psychiatric outcomes) were most improved by interventions that activated caregiver roles (e.g., monitoring blood glucose) and provided information related to that action (e.g., why and how to monitor). The risk of bias was generally high, and the overall quality of the evidence was low moderate, based on Grading of Recommendations Assessment Development and Evaluation ratings. CONCLUSIONS: There is a large body of research, including many RCTs, to support the use of caregiver-mediated interventions that inform and activate caregivers to improve patient and caregiver outcomes. Select caregiver mediated interventions improve patient (inform-activate) and caregiver (inform activate-collaborate) outcomes and should be considered by all researchers implementing patient- and family-oriented research. SYSTEMATIC REVIEW: PROSPERO, CRD42016052509 . PMID- 29996852 TI - Evaluating the role of clinical officers in providing reproductive health services in Kenya. AB - BACKGROUND: Most sub-Saharan African countries have too few reproductive health (RH) specialists, resulting in high RH-related mortality and morbidity. In Kenya, task sharing in RH began in 2002, with the training of clinical officer(s) reproductive health (CORH). Little is known about them and the extent of their role in the health system. METHODS: In 2016, we conducted a retrospective, quantitative two-stage study in Kenya to evaluate the use of CORH and 28 of their curriculum-derived RH competencies, to determine their contribution to expanded access to RH care. CORH were surveyed, using structured questionnaires and telephone interviews. Data on the frequency with which CORH used specified competencies were collected from health records in selected facilities. RESULTS: Forty-nine of all 104 CORH participated in the survey (47%). Forty-eight (98%) had worked in the clinical area, and 79% were still engaging in clinical work. All 48 worked in emergency obstetrics, emergency gynaecology, and nonemergency RH, and 38 (79%) filled clinical leadership positions. Vasectomy was least performed, by only 9 (18%) CORH. All other competencies were applied by at least half of the CORH, and 22 competencies by more than three quarters. Forty-one (84%) CORH performed caesarean section (CS). Teaching and management were other common responsibilities. Data were collected from 12 facilities and analysed for 11. They generally confirmed the initial survey findings: CORH worked as obstetrics and gynaecology consultants and used most of their competencies. Analysis was based on 118 months of theatre records. CORH made significant contributions to their facility's capacity to perform RH surgery: most respondents performed at least 25% of these surgeries. They performed an average of six CS per month and more than 25% of perineal tear repairs (33%), uterus repairs (33%), manual placenta removals (26%), bilateral tubal ligations (39%), and cervical cancer staging (27%). Some experienced CORH conducted procedures beyond their training. CONCLUSIONS: CORH expand access to emergency RH care. Their contributions span all areas of obstetric and gynaecological care, mentoring new health workers and expanding their scope of practice. However, the generally poor status of records documenting healthcare provision limits their usability in evaluation and research. PMID- 29996851 TI - Trends in urban/rural inequalities in cardiovascular risk bio-markers among Chinese adolescents in two decades of urbanisation: 1991-2011. AB - BACKGROUND: China has seen rapid socio-economic changes and epidemiological transitions in the last few decades. Previous studies often fail to examine how wider macro-level forces contribute to changes in health inequality among its population in China. This study aims to examine urban/rural inequalities in cardiovascular (CVD) risks biomarkers among Chinese adolescents in two decades from 1991 to 2011 during the process of China's rapid urbanisation. METHODS: Data were drawn from a nationwide longitudinal dataset of the China Health and Nutrition Survey (CHNS) (Sweeps 1991, 1993, 1997, 2000, 2004, 2006, 2009 and 2011). Children aged between 12 and 18 years (Boys: n = 3472; Girl: n = 3155) were included. A dynamic urbanisation index was created for each community (village or neighbourhood) based on community-level data that can reveal the heterogeneity within and across places and capture dimensions of social, economic and physical characteristics of urban living over time and space. Linear multilevel modeling analyses (Level 1: Occasions; Level-2: Individuals; Level-3: Households; Level-4: Communities) were performed on outcomes of CVD risk biomarkers including anthropometric measures and blood pressure. RESULTS: After adjustment for age, maternal education and household income per capita, cardiovascular (CVD) risk biomarkers increase among Chinese adolescents during 1991 to 2011. Urbanisation tends to have an independent and positive impact on body mass index (BMI) and waist circumference for boys but not for girls. Positive interaction effect between urbanisation index and survey years for waist circumference was observed for girls (0.005; 95% confidence interval [CI], 0.002, 0.007; p < 0.01): time trends become greater when areas become more urbanized. For blood pressure, when areas become more urbanized the trends for boys become decreased (- 0.005; 95% CI, - 0.009, - 0.002; p < 0.01 for systolic blood pressure and - 0.003; 95% CI, - 0.006, - 0.001; p < 0.05 for diastolic blood pressure). CONCLUSION: Chinese adolescents are experiencing an upward trend of cardiovascular (CVD) risks in last two decades. Its rapid urbanisation appears to further increase urban/rural inequalities in CVD risks, especially for boys from less urbanised areas and girls from more urbanised areas, which may contribute to the development of cardiovascular disease (CVD) in adulthood. It is relevant to inform policy making process to target specific vulnerable groups. Given China's urbanisation is strongly influenced by the state, there is a possibility for policy intervention to reduce inequality during the process of China's planned urbanisation. PMID- 29996853 TI - Biomechanics of common fixation devices for first tarsometatarsal joint fusion-a comparative study with synthetic bones. AB - BACKGROUND: Hallux valgus disease is a common deformity of the forefoot. There are currently more than 100 surgical approaches for operative treatment. Because hypermobility of the first tarsometatarsal joint is considered to be causal for hallux valgus disease, fusion of the tarsometatarsal joint is an upcoming surgical procedure. Despite the development of new and increasingly stable fixation devices like different locking plates, malunion rates have been reported in 5 to 15% of cases. METHODS: Biomechanical comparison of three commonly used fixation devices (a dorsal locking plate, a plantar locking plate, and an intramedullary fixation device) was performed by weight-bearing simulation tests on synthetic bones. Initial compression force and stiffness during simulation of postoperative weight-bearing were analysed. RESULTS: Fixation of the first tarsometatarsal joint with the plantar plate combination demonstrated a higher stiffness compared to fixation with the intramedullary implant or the medial locking plate. The intramedullary device provided the highest initial compression force. Failure was detected in the following ranking: (1) the angle-stable intramedullary fixation device, (2) the medial located plate, and (3) the plantar locking plate. CONCLUSION: The intramedullary device demonstrated the highest initial compression force of the three tested implants. The plantar locking plate showed the best overall stability during weight-bearing simulation. Further clinical research is necessary to analyse if the intramedullary fixation device needs a longer period of non-weight-bearing to reach a better non-union rate compared to the plantar locking plate. PMID- 29996854 TI - Protocol of an open, three-arm, individually randomized trial assessing the effect of delivering sexual and reproductive health information to young people (aged 13-24) in Kenya and Peru via mobile phones: adolescent/youth reproductive mobile access and delivery initiative for love and life outcomes (ARMADILLO) study stage 2. AB - BACKGROUND: Young people face special challenges to accessing needed sexual and reproductive health (SRH) information and support. With high penetration and access, mobile phones provide a new channel for reaching young people, but there is little evidence around the impact of digital interventions on improving health outcomes. The Adolescent/Youth Reproductive Mobile Access and Delivery Initiative for Love and Life Outcomes (ARMADILLO) study will assess the effect of an intervention providing SRH information to young people via text message on their mobile phones in Kenya and Peru. This protocol details an open, individually randomized, three-arm trial lasting seven weeks to assess the effect of the ARMADILLO intervention on dispelling myths and misconceptions related to contraception. A secondary objective is to determine whether youth given access to SRH information via text message can accurately retain that information. METHODS: Following a household enumeration, one eligible youth per household will be randomly selected for participation and randomized by computer into one of the three arms. Intervention arm participants will receive access to ARMADILLO content, control participants will receive no information, and 'Arm 3' participant interactions will vary by site: in Kenya, they will be alerted to various SRH domains and encouraged to learn on their own; in Peru, they will receive key content from each domain with the option to learn more if they wish. Participants will complete multiple-choice questionnaires administered by data collectors at baseline (prior to randomization), at intervention-period end (after week seven), and eight weeks after timing out of the intervention period. DISCUSSION: Part of the Sustainable Development Goal commitment towards ensuring healthy lives and promoting well-being for all at all ages includes a commitment to 'ensuring universal access to sexual health and reproductive health-care services, including for family planning, information and education'. If proven to be effective, interventions like ARMADILLO can bridge an important gap towards achieving universal access to SRH information and education for an otherwise difficult-to-reach group. TRIAL REGISTRATION: This trial was retrospectively registered with the ISRCTN Registry and assigned registration number ISRCTN85156148 on 29 May, 2018. PMID- 29996855 TI - Complete smokefree policies in mental health inpatient settings: results from a mixed-methods evaluation before and after implementing national guidance. AB - BACKGROUND: Tobacco smoking is extremely prevalent in people with severe mental illness (SMI) and has been recognised as the main contributor to widening health inequalities in this population. Historically, smoking has been deeply entrenched in the culture of mental health settings in the UK, and until recently, smokefree policies tended to be only partially implemented. However, recent national guidance and the government's tobacco control plan now call for the implementation of complete smokefree policies. Many mental health Trusts across the UK are currently in the process of implementing the new guidance, but little is known about the impact of and experience with policy implementation. METHODS: This paper reports findings from a mixed-methods evaluation of policy implementation across 12 wards in a large mental health Trust in England. Quantitative data were collected and compared before and after implementation of NICE guidance PH48 and referred to 1) identification and treatment of tobacco dependence, 2) smoking-related incident reporting, and 3) prescribing of psychotropic medication. A qualitative exploration of the experience of inpatients was also carried out. Descriptive statistical analyses were performed, and the feasibility of collecting relevant and complete data for each quantitative component was assessed. Qualitative data were analysed using thematic framework analysis. RESULTS: Following implementation of the complete smokefree policy, increases in the numbers of patients offered smoking cessation advice (72% compared to 38%) were identified. While incident reports demonstrated a decrease in challenging behaviour during the post-PH48 period (6% compared to 23%), incidents relating to the concealment of smoking materials increased (10% compared to 2%). Patients reported encouraging changes in smoking behaviour and motivation to maintain change after discharge. However, implementation issues challenging full policy implementation, including covert facilitation of smoking by staff, were reported, and difficulties in collecting relevant and complete data for comprehensive evaluation purposes identified. CONCLUSIONS: Overall, the implementation of complete smokefree policies in mental health settings may currently be undermined by partial support. Strategies to enhance support and the establishment of suitable data collection pathways to monitor progress are required. PMID- 29996856 TI - Attitudes and awareness of medical assistance while traveling abroad. AB - BACKGROUND: With globalization, more and more people travel to countries where they are at risk of injuries and travel-related diseases. To protect travelers' health, it is crucial to understand whether travelers accurately perceive medical assistance resources before and during their trips. This study investigated the need, awareness, and previous usage of overseas emergency medical assistance services (EMAS) among people traveling abroad. METHODS: Anonymous questionnaires were distributed to patients (n = 500) at a travel clinic in Taipei, Taiwan. RESULTS: The results showed that EMAS were important, especially in the following categories: 24-h telephone medical consultation (91.8%), emergent medical repatriation (87.6%), and assistance with arranging hospital admission (87.4%). Patients were less aware of the following services: arrangement of appointments with doctors (70.7%) and monitoring of medical conditions during hospitalization (73.0%). Less than 5% of respondents had a previous experience with EMAS. CONCLUSIONS: EMAS are considered important to people who are traveling abroad. However, approximately 20-30% of travelers lack an awareness of EMAS, and the percentage of travelers who have previously received medical assistance through these services is extremely low. The discrepancy between the need and usage of EMAS emphasizes the necessity to adapt EMAS materials in pre-travel consultations to meet the needs of international travelers. PMID- 29996857 TI - Pediatric Rheumatology Collaborative Study Group - over four decades of pivotal clinical drug research in pediatric rheumatology. AB - IMPORTANCE: Specialized research networks are essential to achieve drug approvals for rare pediatric diseases. Such networks help realize the potential of global legislation enacted upon the recognition that most children are treated with drugs whose most beneficial dose and regimen have not been established in pediatric patients. The Pediatric Rheumatology Collaborative Study Group (PRCSG) is a North American clinical trials network that is specialized in the performance of clinical trials of new therapies for pediatric populations with rheumatic diseases. This review provides an overview of the strategies employed by this research network to achieve drug and biologic approvals for children with pediatric rheumatic diseases, particularly juvenile idiopathic arthritis. OBSERVATIONS: Clinical trial conduct in rare pediatric diseases has required global recruitment. Supported or led by the PRCSG, highly responsive, validated, composite measures have been established to assess drug efficacy. For pediatric orphan diseases with high disease burdens, specialized investigative sites and study designs are needed to complete adequately powered trials at the high standard necessary to enable drug labeling by regulatory agencies. Novel trial designs have been utilized for more efficient testing of innovative drug candidates. All these have been developed or co-developed by the PRCSG research network. CONCLUSIONS AND RELEVANCE: Specialized research networks in pediatric rheumatology, such as the PRCSG, have changed the landscape of available therapies and improved overall disease outcomes for children with pediatric rheumatic diseases. PMID- 29996858 TI - Prevalence and sequence analysis of equid herpesviruses from the respiratory tract of Polish horses. AB - BACKGROUND: Equid herpesviruses (EHVs) are widespread in equine populations worldwide. While the infection with equine alpha-herpesviruses (EHV-1 and EHV-4) has been linked to several clinical outcomes, the pathogenic potential for equine gamma-herpesviruses (EHV-2 and EHV-5) is still unclear. The objective of the current study was to determine the prevalence of infection with EHVs among Polish horses, to investigate factors associated with EHV infections among horses sampled, and to determine genetic variability within Polish EHV-2 isolates. METHODS: Virus-specific real-time PCR assays were used for detection of EHV-1, EHV-2, EHV-4 and EHV-5 in nasal swabs collected from 540 horses from 13 national horse studs located throughout Poland. A proportion of EHV-2/5 positive samples were subjected to virus isolation followed by amplification and analysis of partial glycoprotein B sequence. RESULTS: Overall, 448/540 (83.0%) horses sampled were positive for at least one virus. The most prevalent was infection with EHV-2 (77.2%), followed by EHV-5 (47.0%), and EHV-4 (0.4%). None of the horses was positive for EHV-1. Approximately half of the virus-infected horses were positive for both EHV-2 and EHV-5. The proportion of EHV-2/5 positive horses varied by age, breed, and season. Only 8.0% of horses sampled, mostly Arabians, showed clinical signs of respiratory disease at the time of sampling. The viral load of both EHV-2 and EHV-5 DNA was highest in swabs from young horses, which was particularly evident for EHV-2 infected foals. Mean viral loads in nasal swabs collected from diseased horses were higher than in swabs from healthy horses. That was also true for EHV-2 when only diseased Arabian foals were considered, but the levels of EHV-5 DNA were lower in swabs from diseased than from healthy foals. In agreement with other studies, there was a considerable variability between Polish EHV-2 sequences, with no clustering of sequences from horses with different health status. The level of EHV-2 variability seemed to differ between different studs/breeds. CONCLUSIONS: The presence of foals and yearlings on a property is likely to increase the risk of active EHV-2/5 infection among in contact horses. The existence of breed-specific differences in susceptibility to EHV-2/5 infections should be further investigated, as it may provide one variable that needs to be considered in attempts to associate EHV-2/5 infections with disease. Overall, the data presented add to the existing knowledge of the epidemiology and biology of equine gamma-herpesviruses, with the long-term goal of better understanding of the pathogenesis and the impact of infections with these viruses on the well-being of the horse. PMID- 29996859 TI - Performance of 6 HCV genotyping 9G test for HCV genotyping in clinical samples. AB - BACKGROUND: A treatment of HCV infection depends on the genotype and sub genotype. Therefore, accurate HCV genotyping is critical for selecting the appropriate treatment regimen. METHOD: This study included 280 plasma samples to evaluate the performance of 6 HCV Genotyping 9G test. The performance of 6 HCV Genotyping 9G test for accurate detection of HCV 1a, 1b, 2, 3, 4, and 6 genotypes was evaluated by comparing it with LiPA 2.0 assay and sequencing. RESULTS: 6 HCV Genotyping 9G test and LiPA 2.0 assay demonstrated 83.9% (n = 235) agreement. 39/45 samples that showed discrepant results between the two tests were analyzed by sequencing. Sequencing genotyped 39 discrepant samples as 0 (HCV 1a), 24 (HCV 1b), 1 (HCV 6f), 12 (HCV 6i), and 2 (HCV-negative). Results of 6 HCV Genotyping 9G test were very similar to the sequencing as it detected 1, 23, 1, 12, and 2 samples as HCV 1a, 1b, 3 & 6a or 6f, 6i or 6n, and negative, respectively. However, LiPA 2.0 assay showed complete disagreement with sequencing, as it did not detect any of these 39 samples correctly. These results indicate that LiPA 2.0 assay has limitations in identifying HCV genotypes 1b, and 6. The sensitivity, specificity, PPV, and NPV of 6 HCV Genotyping 9G test were 99.5, 98.8, 99.5, and 98.8%, respectively. It is important to note that HCV Genotyping 9G test showed 98.3 and 100% sensitivity for HCV 1b and 6 genotyping, respectively. However, LiPA 2.0 assay demonstrated 57.9 and 71.7% sensitivity for these genotypes. CONCLUSIONS: 6 HCV Genotyping 9G test identifies HCV 1a, 1b, 2, 3, and 6 with good agreement with sequencing. Hence, 6 HCV Genotyping 9G test has a high clinical value because it can provide critical information to physicians and assist them to use the correct drug for efficient hepatitis C treatment. PMID- 29996860 TI - Gender-based analysis of factors affecting junior medical students' career selection: addressing the shortage of surgical workforce in Rwanda. AB - BACKGROUND: There is a strong need for expanding surgical workforce in low- and middle-income countries. However, the number of medical students selecting surgical careers is not sufficient to meet this need. In Rwanda, there is an additional gender gap in speciality selection. Our study aims to understand the early variables involved in junior medical students' preference of specialisation with a focus on gender disparities. METHODS: We performed a cross-sectional survey of medical students during their clinical rotation years at the University of Rwanda. Demographics, specialisation preference, and factors involved in that preference were obtained using questionnaires and analysed using descriptive statistics and odds ratios. RESULTS: One hundred eighty-one respondents participated in the study (49.2% response rate) with a female-to-male ratio of 1 to 2.5. Surgery was the preferred speciality for 46.9% of male participants, and obstetrics/gynaecology for 29.4% of females. The main selection criteria for those who had already decided on surgery as a career included intellectual challenge (60.0%), interaction with residents (52.7%), and core clerkship experience (41.8%) for male participants and interaction with residents (57.1%), intellectual challenge (52.4%), and core clerkship experience (52.4%) for female participants. Females were more likely than males to join surgery based on perceived research opportunities (OR 2.7, p = 0.04). Male participants were more likely than their female participants to drop selection of surgery as a speciality when an adverse interaction with a resident was encountered (OR 0.26, p = 0.03). CONCLUSION: This study provides insight into factors that guide Rwandan junior medical students' speciality preference. Medical students are more likely to consider surgical careers when exposed to positive clerkship experiences that provide intellectual challenges, as well as focused mentorship that facilitates effective research opportunities. Ultimately, creating a comprehensive curriculum that supports students' preferences may help encourage their selection of surgical careers. PMID- 29996861 TI - Analysis and determinants of Chinese navy personnel health status: a cross sectional study. AB - BACKGROUND: There have been very few studies analyzing the relationship of physical and mental health status with health behaviors and deployment status in Chinese navy personnel. Thus, we undertook this survey to assess this relationship and identify specific factors affecting the physical and mental health status. METHODS: The subjects enrolled in this study were selected from four units of the active-duty navy personnel in China, based on a cluster random sampling design. A total of 1200 Chinese navy personnel participated and completed the questionnaire survey that included veteran SF-36 form and a self designed questionnaire regarding their sociodemographic characteristics, deployment status, self-rated health status and health behaviors. Totally 1200 questionnaires were distributed to different participants, while 1083 valid questionnaires were included in the final analysis. All data were analyzed using SPSS18.0 software. RESULTS: Based on the information provided by navy personnel, 17.82, 35.09 and 23.08% rated their health as excellent, very good and good, respectively. The mean score of physical component summary (PCS) and mental component summary (MCS) was 50.53 and 41.39, respectively. Length of service, binge drinking, regular drinking and BMI appeared to be associated with PCS score, while household income, binge drinking and BMI affected MCS score. Deployment status and smoking exhibited no significant association with PCS and MCS scores. CONCLUSIONS: Our study suggested that the sociodemographic factors like length of service and household income, along with behavioral risk factors like binge drinking, regular drinking and body mass index (BMI), seem to affect the physical and mental health status of Chinese navy personnel. However, additional data collection and more detailed analysis would still be required to develop a systematic, comprehensive and corresponding health education program to promote overall health status. PMID- 29996862 TI - Plasma D-dimer is not useful in the prediction of deep vein thrombosis after total knee arthroplasty in patients using rivaroxaban for thromboprophylaxis. AB - BACKGROUND: Venous thromboembolism (VTE) is a serious complication following total joint replacement. The use of rivaroxaban, a highly selective and direct factor Xa inhibitor, has been used widely as a safe and efficacious way to prevent VTE after total joint replacements. However, little is known about the diagnostic efficacy of plasma D-dimer test on deep vein thrombosis (DVT) in patients using rivaroxaban for thromboprophylaxis. The study is aimed to investigate the trend and the diagnostic efficacy of D-dimer test on DVT in patients with primary total knee arthroplasty (TKA) using rivaroxaban for thromboprophylaxis. METHODS: Two hundred TKA patients using rivaroxaban postoperatively as chemical prophylaxis were reviewed. D-dimer levels were checked at 4 h after the surgery and on postoperative days 1 and 4. Venography was used to document the presence of DVT. The Mann-Whitney U test was used to detect the differences in the D-dimer levels at different time points in patients with and without DVT, followed by Bonferroni corrections for p values. Receiver operating characteristics (ROC) curves were constructed to determine the best cutoff values of the D-dimer test at each time point after the surgery. RESULTS: Twenty-nine of the 200 patients were found to have deep vein thrombosis by venography, resulting in an incidence of 14.5%. All patients with DVTs occurred in the distal calf veins, and only one patient was symptomatic. We found significant differences in D-dimer concentration between patients with and without DVT at postoperative day 4. The best cutoff value determined by receiver operating characteristics analysis was 3.8 mg/L at postoperative day 4, with an AUC equal to 63.5%, and a sensitivity, specificity, PPV, and NPV of 58.6, 76, 29.3, and 91.5%, respectively. CONCLUSIONS: Rivaroxaban was effective on reducing DVT in patients undergoing TKA. Because all the DVTs occurred in the leg veins, decreased thrombus volume and size might result in poor accuracy of plasma D dimer test in prediction or diagnosis of postoperative DVT. PMID- 29996863 TI - Feasibility of stereotactic radiotherapy for lung lesions and conventional radiotherapy for nodal areas in primary lung malignancies. AB - BACKGROUND: Combined stereotactic body radiotherapy (SBRT) for lung lesions and conventional radiotherapy (CRT) for nodal areas may be more effective than CRT alone in patients with locally advanced lung cancer. METHODS: This study included 21 patients with small primary lung tumors distant from the regional nodal areas. The SBRT dose was 40-60 Gy in 4 fractions. CRT doses were 66 Gy in 30 fractions for non-small cell lung cancer and 52.5 Gy in 25 fractions for small cell lung cancer. RESULTS: The median follow-up duration was 12 months, and the median survival was 13 months. The 1 year overall survival, local recurrence-free survival, and distant metastasis-free survival rates were 60.5, 84.8, and 62.1%, respectively. Two patients experienced in-field local recurrence combined with out-field regional recurrence and/or distant failure. The major recurrence pattern was distant failure (crude incidence, 43%). Three patients aged >=79 years experienced grade >= 3 acute radiation pneumonitis, and one also had idiopathic interstitial pneumonia. CONCLUSION: The combination of SBRT for the lung lesion and CRT for the nodal region seems to be effective and safe for lung malignancies. However, patients older in age and/or with underlying pulmonary disease require stricter lung dose constraints. PMID- 29996865 TI - A pragmatic harm reduction approach to manage a large outbreak of wound botulism in people who inject drugs, Scotland 2015. AB - BACKGROUND: People who inject drugs (PWID) are at an increased risk of wound botulism, a potentially fatal acute paralytic illness. During the first 6 months of 2015, a large outbreak of wound botulism was confirmed among PWID in Scotland, which resulted in the largest outbreak in Europe to date. METHODS: A multidisciplinary Incident Management Team (IMT) was convened to conduct an outbreak investigation, which consisted of enhanced surveillance of cases in order to characterise risk factors and identify potential sources of infection. RESULTS: Between the 24th of December 2014 and the 30th of May 2015, a total of 40 cases were reported across six regions in Scotland. The majority of the cases were male, over 30 and residents in Glasgow. All epidemiological evidence suggested a contaminated batch of heroin or cutting agent as the source of the outbreak. There are significant challenges associated with managing an outbreak among PWID, given their vulnerability and complex addiction needs. Thus, a pragmatic harm reduction approach was adopted which focused on reducing the risk of infection for those who continued to inject and limited consequences for those who got infected. CONCLUSIONS: The management of this outbreak highlighted the importance and need for pragmatic harm reduction interventions which support the addiction needs of PWID during an outbreak of spore-forming bacteria. Given the scale of this outbreak, the experimental learning gained during this and similar outbreaks involving spore-forming bacteria in the UK was collated into national guidance to improve the management and investigation of future outbreaks among PWID. PMID- 29996864 TI - Methotrexate in juvenile idiopathic arthritis: advice and recommendations from the MARAJIA expert consensus meeting. AB - BACKGROUND: Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly prescribed. However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of MTX in the management of patients with JIA. Therefore, the Methotrexate Advice and RecommendAtions on Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations for the use of MTX in the treatment of JIA. METHODS: The preliminary executive committee identified a total of 9 key clinical issues according to the population, intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review. During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations were made. RESULTS: Recommendations relating to the efficacy, optimal dosing and route of administration and duration of treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations in patients with JIA were developed. The selected topics were considered to represent clinically important issues facing clinicians caring for patients with JIA. Evidence was insufficient to formulate recommendations for the use of biomarkers predictive of treatment response. CONCLUSIONS: These consensus recommendations provide balanced and evidence-based recommendations designed to have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA. PMID- 29996866 TI - Intrinsic molecular subtypes of breast cancers categorized as HER2-positive using an alternative chromosome 17 probe assay. AB - The 2013 update of the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines recommend using an alternative chromosome 17 probe assay to resolve HER2 results determined to be equivocal by immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH). However, it is unclear if cases considered HER2-positive (HER2+) by the alternative probe method are similar to those classified as HER2+ by traditional IHC and FISH criteria and benefit the same from HER2-targeted therapies. We studied the clinical and pathologic features of all 31 breast cancers classified as HER2+ by the alternative probe method at our institution since 2013 and determined their PAM50 intrinsic molecular subtypes. For comparison, we analyzed 19 consecutive cases that were classified as HER2+ by traditional FISH criteria during the same time period. Thirty (97%) cancers in the alternative probe cohort were estrogen receptor (ER) positive (ER+), while only 9/19 (47%) of traditional HER2 controls were ER+ (p = 0.0002). Sufficient tissue for intrinsic subtype analysis was available for 20/31 cancers in the alternative probe cohort and 9/19 in the traditional HER2+ group. None (0%) of the 20 alternative probe-positive cases were of the HER2-enriched intrinsic subtype, while 8/9 (89%) of those HER2+ by traditional FISH criteria were HER2-enriched (p = 0.0001). These findings suggest that breast cancers classified as HER2+ only by the alternative probe method are biologically distinct from those classified as HER2+ by traditional criteria, and raises questions as to whether or not they derive the same benefit from HER2-targeted therapies. PMID- 29996867 TI - Acceptability and accessibility of child nutrition interventions: fathers' perspectives from survey and interview studies. AB - BACKGROUND: Against a background of changing family structures and socioeconomic demands in contemporary families, fathers are more actively engaged in meal preparation and feeding of their children, yet in research studies targeting improvement in nutrition and feeding practices fathers are under-represented. Among possible explanations for this bias are acceptability of research projects and accessibility to male research participants. The aims of this study were to identify (i) fathers' preferences for participation in child nutrition research and interventions and (ii) the potential to recruit fathers through their workplaces with the possibility of delivering interventions through those workplaces. METHODS: This paper draws on two independent yet linked studies that explored fathers' roles in family feeding, and intervention studies aimed at supporting father's dietary knowledge and feeding practices. For Study 1 (conducted first) secondary data analysis was conducted on survey data (n = 463 fathers of preschool children) to determine preferences related to type of program, delivery mode, and location and timing. For Study 2 six focus groups and one individual interview were conducted with n = 28 fathers to determine acceptability of recruitment of fathers working in traditionally blue-collar occupations and service industries (as defined by the Australian Bureau of Statistics) and potential of intervention delivery through their workplaces. RESULTS: Fathers were engaged in child feeding and indeed sought nutrition related information. Fathers indicated a preference for family-focused and online delivery of interventions. Whilst potential to recruit through blue-collar workplaces was evident, participants were divided in their views about the acceptability of interventions conducted through the workplace. There was a sense of support for the logic of such interventions but the focus group participants in this study showed only modest enthusiasm for the idea. CONCLUSIONS: With limited support for the workplace as an intervention setting, further systematic exploration of technology-based intervention design and engagement is warranted. Based on findings, interventions should target a) content that is focused on the family and how to make changes at the family level, rather than the father individually; and b) online delivery, such as Apps or online video chat sessions, for convenience and to facilitate sharing of information with family members. PMID- 29996868 TI - The effect of introducing a financial incentive to promote application of fluoride varnish in dental practice in Scotland: a natural experiment. AB - BACKGROUND: Financial incentives are often used to influence professional practice, yet the factors which influence their effectiveness and their behavioural mechanisms are not fully understood. In keeping with clinical guidelines, Childsmile (Scotland's oral health improvement programme) advocates twice yearly fluoride varnish application (FVA) for children in dental practice. To support implementation Childsmile offered dental practitioners a fee-per-item payment for varnishing 2-5-year-olds' teeth through a pilot. In October 2011 payment was extended to all dental practitioners. This paper compares FVA pre- and post-roll-out and explores the financial incentive's behavioural mechanisms. METHODS: A natural experimental approach using a longitudinal cohort of dental practitioners (n = 1090) compared FVA pre- (time 1) and post- (time 2) financial incentive. Responses from practitioners who did not work in a Childsmile pilot practice when considering their 2-5-year-old patients (novel incentive group) were compared with all other responses (continuous incentive group). The Theoretical Domains Framework (TDF) was used to measure change in behavioural mechanisms associated with the incentive. Analysis of covariance was used to investigate FVA rates and associated behavioural mechanisms in the two groups. RESULTS: At time 2, 709 74%, of eligible responders, were followed up. In general, FVA rates increased over time for both groups; however, the novel incentive group experienced a greater increase (beta [95% CI] = 0.82 [0.72 to 0.92]) than the continuous incentive group. Despite this, only 33% of practitioners reported 'always' varnishing increased risk 2-5-year-olds' teeth following introduction of the financial incentive, 19% for standard risk children. Domain scores at time 2 (adjusting for time 1) increased more for the novel incentive group (compared to the continuous incentive group) for five domains: knowledge, social/professional role and identity, beliefs about consequences, social influences and emotion. CONCLUSIONS: In this large, prospective, population-wide study, a financial incentive moderately increased FVA in dental practice. Novel longitudinal use of a validated theoretical framework to understand behavioural mechanisms suggested that financial incentives operate through complex inter-linked belief systems. While financial incentives are useful in narrowing the gap between clinical guidelines and FVA, multiple intervention approaches are required. PMID- 29996869 TI - Planning a future randomized clinical trial based on a network of relevant past trials. AB - BACKGROUND: The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses. METHODS: Network meta-analyses can also be used to plan future trials. We introduce a four step framework that aims to identify the optimal design for a new trial that will update the existing evidence while minimizing the required sample size. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis. RESULTS: A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges of the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity. CONCLUSIONS: When used judiciously, conditional trial design could significantly reduce the required resources for a new study and prevent experimentation with an unnecessarily large number of participants. PMID- 29996871 TI - Transcriptome level analysis in Rett syndrome using human samples from different tissues. AB - The mechanisms of neuro-genetic disorders have been mostly investigated in the brain, however, for some pathologies, transcriptomic analysis in multiple tissues represent an opportunity and a challenge to understand the consequences of the genetic mutation. This is the case for Rett Syndrome (RTT): a neurodevelopmental disorder predominantly affecting females that is characterised by a loss of purposeful movements and language accompanied by gait abnormalities and hand stereotypies. Although the genetic aetiology is largely associated to Methyl CpG binding protein 2 (MECP2) mutations, linking the pathophysiology of RTT and its clinical symptoms to direct molecular mechanisms has been difficult.One approach used to study the consequences of MECP2 dysfunction in patients, is to perform transcriptomic analysis in tissues derived from RTT patients or Induced Pluripotent Stem cells. The growing affordability and efficiency of this approach has led to a far greater understanding of the complexities of RTT syndrome but is also raised questions about previously held convictions such as the regulatory role of MECP2, the effects of different molecular mechanisms in different tissues and role of X Chromosome Inactivation in RTT.In this review we consider the results of a number of different transcriptomic analyses in different patients derived preparations to unveil specific trends in differential gene expression across the studies. Although the analyses present limitations- such as the limited sample size- overlaps exist across these studies, and they report dysregulations in three main categories: dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity.These observations have a direct application to the disorder and give insights on the altered mechanisms in RTT, with implications on potential diagnostic criteria and treatments. PMID- 29996870 TI - Alpha-1 antitrypsin deficiency: outstanding questions and future directions. AB - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved. METHODS: In this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research. RESULTS: 1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed. CONCLUSIONS: 2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes. PMID- 29996873 TI - Collimator scatter factor: Monte Carlo and in-air measurements approaches. AB - BACKGROUND: Linac output as a function of field sizes has a phantom and a head scatter component. This last term can be measured in-air with appropriate build up ensuring a complete electron equilibrium and the absence of the contaminant electrons. Equilibrium conditions could be achieved using a build-up cap or a mini-phantom. Monte Carlo simulations in a virtual phantom mimicking a mini phantom were analysed with the aim of better understanding the setup conditions for measuring the collimator scatter factor that is the head scatter component of the linac output factors. METHODS: Beams of 6 and 15 MV from a TrueBeam, with size from 4 * 4 to 40 * 40 cm2 were simulated in cylindrical acrylic phantoms 20 cm long, of different diameters, from 0.5 to 4 cm, with the cylinder axis coincident with the beam central axis. The PRIMO package, based on PENELOPE Monte Carlo code, was used. The phase-space files for a Varian TrueBeam linac, provided by the linac vendor, were used for the linac head simulation. Depth dose curves were analysed, and collimator scatter factors estimated at different depth in the different phantom conditions. Additionally, in-air measurements using acyrilic and brass build-up caps, as well as acrylic mini-phantom were acquired for 6 and 18 MV beams from a Varian Clinac DHX. RESULTS: The depth dose curves along the cylinders were compared, showing, in each phantom, very similar curves for all analysed field sizes, proving the correctness in estimating the collimator scatter factor in the mini-phantom, provided to position the detector to a sufficient depth to exclude electron contamination. The results were confirmed by the measurements, where the acrylic build-up cap showed to be inadequate to properly estimate the collimator scatter factors, while the mini-phantom and the brass caps gave reasonable measurements. CONCLUSION: A better understanding of the beam characteristics inside a virtual mini-phantom through the analysis of depth dose curves, showed the critical points of using the acrylic build-up cap, and suggested the use of the mini-phantom for the collimator scatter factor measurements in the medium-large field size range. PMID- 29996872 TI - Treatment of AC dislocation by reconstructing CC and AC ligaments with allogenic tendons compared with hook plates. AB - BACKGROUND: The purpose of this study was to compare outcomes between allograft reconstruction and hook plate fixation for acute dislocation of the acromioclavicular joint with a minimum 2-year follow-up. METHODS: A retrospective comparative study of patients treated for acute acromioclavicular joint dislocation from February 2010 to December 2014 in our hospital, consisting of 16 patients who were followed-up, was performed. Eight patients were treated for acute AC dislocation and underwent surgical reconstruction as follows: the coracoclavicular and acromioclavicular ligaments were reconstructed with the allogenic tendon. The other eight patients were treated with hook plates to maintain the AC joint reset. At the latest follow-up, radiographic analysis and the Constant and University of California-Los Angeles (UCLA) scores were used to evaluate shoulder function. The satisfaction of the patients in terms of the efficacy and visual analog scale (VAS) data were also recorded. RESULTS: After an average follow-up of 30.3 months (range 24-46 months), no patient had dislocated their joint again at the final follow-up based on X-ray examination. The Constant score was 94.4 for the allogenic tendon group and 93.8 for the hook plate group (P = 0.57). According to the UCLA scale (P = 0.23) or VAS (P = 0.16), we found no significant difference between the two groups. All patients reported that they were very satisfied or satisfied with the outcome of surgery, and no significant difference (P = 0.08) was found between the two groups. CONCLUSIONS: The use of allogenic tendon for reconstruction of the coracoclavicular and acromioclavicular ligaments shows excellent outcomes in terms of the recovery of clinical function or radiographic outcomes for acute AC dislocation. Compared with the hook plate, the hardware did not need to be removed. PMID- 29996874 TI - Modelling of the ICF core sets for chronic ischemic heart disease using the LASSO model in Chinese patients. AB - BACKGROUND: This study aimed to examine the associations among the International Classification of Functioning, Disability, and Health (ICF) core sets relevant to chronic ischemic heart disease (CIHD) using the least absolute shrinkage and selection operator (LASSO) model based on the ICF core sets scale in Chinese patients. METHODS: This was a prospective study of 120 patients with CIHD selected from January 2013 to June 2014 at the Fada Institute of Forensic Medicine & Science (Beijing, China). Functioning was qualified using the ICF core sets checklist for CIHD (Chinese version). The variables of core set categories of the ICF assessment scale for CIHD were entered into the LASSO model for mining dependencies among those variables. Graphical modeling was applied using LASSO generalized linear models. RESULTS: "Muscle endurance functions", "sensations associated with cardiovascular and respiratory functions", "blood vessel functions", and "heart functions" were the most injured in CIHD status. "Recreation and leisure" and "intimate relationships" were the most affected in CIHD status. "General social support services, systems, and policies" and "acquaintances, peers, colleagues, neighbors, and community members" were important for the outcome of functional status of the CIHD patient. "Economic self-sufficiency" and "family relationships" of the CIHD patient were not undermined in most cases. CONCLUSIONS: Graphical modeling can be used to describe associations between different areas of functioning in CIHD patients. The results suggest that these associations could be used as basis to improve rehabilitation and provide a deeper understanding of functioning in Chinese CIHD patients. PMID- 29996876 TI - Capturing the spatial variability of HIV epidemics in South Africa and Tanzania using routine healthcare facility data. AB - BACKGROUND: Large geographical variations in the intensity of the HIV epidemic in sub-Saharan Africa call for geographically targeted resource allocation where burdens are greatest. However, data available for mapping the geographic variability of HIV prevalence and detecting HIV 'hotspots' is scarce, and population-based surveillance data are not always available. Here, we evaluated the viability of using clinic-based HIV prevalence data to measure the spatial variability of HIV in South Africa and Tanzania. METHODS: Population-based and clinic-based HIV data from a small HIV hyper-endemic rural community in South Africa as well as for the country of Tanzania were used to map smoothed HIV prevalence using kernel interpolation techniques. Spatial variables were included in clinic-based models using co-kriging methods to assess whether cofactors improve clinic-based spatial HIV prevalence predictions. Clinic- and population based smoothed prevalence maps were compared using partial rank correlation coefficients and residual local indicators of spatial autocorrelation. RESULTS: Routinely-collected clinic-based data captured most of the geographical heterogeneity described by population-based data but failed to detect some pockets of high prevalence. Analyses indicated that clinic-based data could accurately predict the spatial location of so-called HIV 'hotspots' in > 50% of the high HIV burden areas. CONCLUSION: Clinic-based data can be used to accurately map the broad spatial structure of HIV prevalence and to identify most of the areas where the burden of the infection is concentrated (HIV 'hotspots'). Where population-based data are not available, HIV data collected from health facilities may provide a second-best option to generate valid spatial prevalence estimates for geographical targeting and resource allocation. PMID- 29996875 TI - The future outlook on allergen immunotherapy in children: 2018 and beyond. AB - Allergen immunotherapy (AIT) is the only currently available immune-modifying and aetiological treatment for patients suffering from IgE-mediated diseases. In childhood, it represents a suitable therapeutic option to intervene during the early phases of respiratory allergic diseases such as rhino-conjunctivitis and asthma, which is when their progression may be more easily influenced. A growing body of evidence shows that oral immunotherapy represents a promising treatment option in children with persistent IgE- mediated food allergy. The efficacy of AIT is under investigation also in patients with extrinsic atopic dermatitis, currently with controversial results. Furthermore, AIT might be a strategy to prevent the development of a new sensitization or of a (new) allergic disease. However, there are still some methodological criticisms, such as: a) the regimen of administration and the amount of the maintenance dose are both largely variable; b) the protocols of administration are not standardized; c) the description and classification of side effects is variable among studies and needs to be standardized; d) quality of life and evaluation of health economics are overall missing. All these aspects make difficult to compare each study with another. In addition, the content of major allergen(s) remains largely variable among manufacturers and the availability of AIT products differences among countries. The interest and the attention to AIT treatment are currently fervent and increasing. Well-designed studies are awaited in the near future in order to overcome the current gaps in the evidence and furtherly promote implementation strategies. PMID- 29996877 TI - Chiral polymer modified nanoparticles selectively induce autophagy of cancer cells for tumor ablation. AB - BACKGROUND: Autophagy regulation through exogenous materials has aroused intensive attention to develop treatment protocols according to diverse human diseases. However, to the best of our knowledge, few examples have been reported to selectively control autophagy process and ultimately achieve efficient therapeutic potential. RESULTS: In this study, monolayers of poly (acryloyl-L, D and racemic valine) (L-PAV-AuNPs, D-PAV-AuNPs and L/D-PAV-AuNPs) chiral molecules were anchored on the surfaces of gold nanoparticles (PAV-AuNPs), and the subsequent chirality-selective effects on autophagy activation were thoroughly studied. The cytotoxicity induced by PAV-AuNPs towards MDA-MB-231 cells (Breast cancer cells) was achieved mainly through autophagy and showed chirality dependent, with D-PAV-AuNPs exhibiting high autophagy-inducing activity in vitro and in vivo. In contrast, the PAV-AuNPs exhibited autophagy inactivation for normal cells, e.g., 3T3 fibroblasts and HBL-100 cells. The chirality-selective autophagy activation effect in MDA-MB-231 cells was likely attributed to the chirality-variant ROS generation, cellular uptake and their continuous autophagy stimulus. Furthermore, the intratumoral injection of D-PAV-AuNPs could largely suppress the tumor growth but exhibit negligible toxicity in vivo. CONCLUSIONS: As the first exploration on stereospecific NPs for autophagy induction, this work not only substantiates that chiral polymer coated NPs can selective induce autophagy-specific in cancer cells and achieve a high tumor eradication efficiency in vivo, but also opens up a new direction in discovering unprecedented stereospecific nanoagents for autophagy-associated tumor treatment. PMID- 29996878 TI - Ex vivo model of epilepsy in organotypic slices-a new tool for drug screening. AB - BACKGROUND: Epilepsy is a prevalent neurological disorder worldwide. It is characterized by an enduring predisposition to generate seizures and its development is accompanied by alterations in many cellular processes. Organotypic slice cultures represent a multicellular environment with the potential to assess biological mechanisms, and they are used as a starting point for refining molecules for in vivo studies. Here, we investigated organotypic slice cultures as a model of epilepsy. METHODS: We assessed, by electrophysiological recordings, the spontaneous activity of organotypic slices maintained under different culture protocols. Moreover, we evaluated, through molecular-based approaches, neurogenesis, neuronal death, gliosis, expression of proinflammatory cytokines, and activation of NLRP3 inflammasome (nucleotide-binding, leucine-rich repeat, pyrin domain) as biomarkers of neuroinflammation. RESULTS: We demonstrated that organotypic slices, maintained under a serum deprivation culture protocol, develop epileptic-like activity. Furthermore, throughout a comparative study with slices that do not depict any epileptiform activity, slices with epileptiform activity were found to display significant differences in terms of inflammation related features, such as (1) increased neuronal death, with higher incidence in CA1 pyramidal neurons of the hippocampus; (2) activation of astrocytes and microglia, assessed through western blot and immunohistochemistry; (3) upregulation of proinflammatory cytokines, specifically interleukin-1beta (IL 1beta), interleukin-6, and tumor necrosis factor alpha, revealed by qPCR; and (4) enhanced expression of NLRP3, assessed by western blot, together with increased NLRP3 activation, showed by IL-1beta quantification. CONCLUSIONS: Thus, organotypic slice cultures gradually deprived of serum mimic the epileptic-like activity, as well as the inflammatory events associated with in vivo epilepsy. This system can be considered a new tool to explore the interplay between neuroinflammation and epilepsy and to screen potential drug candidates, within the inflammatory cascades, to reduce/halt epileptogenesis. PMID- 29996879 TI - Male and undernourished children were at high risk of anemia in Ethiopia: a systematic review and meta-analysis. AB - BACKGROUND: Anemia is one of the global public health problems affecting more than one-third of the world population. It has been strongly associated with limited psychomotor development; and poor growth and performance in cognitive, social, and emotional function in children. Despite published data revealed that anemia is a public health problem among children in Ethiopia, there is no a pooled national estimate on the prevalence and associated risk factors of anemia. METHODS: Published articles until December 31, 2017, were searched using comprehensive search strings through PubMed/Medline, EMBASE, SCOPUS, HINARI, Web of Science, Google Scholar and Google. Reference probing of published articles and hand searching were employed for grey literature. Two groups of review authors independently appraised the studies for eligibility and extracted the data. The quality of articles was assessed using Joana Brigg's institute critical appraisal checklist for prevalence and analytical studies. The pooled estimates were determined using random effect model. Heterogeneity between the included studies was assessed using the I2 statistics. Subgroup analysis was employed in the evidence of heterogeneity. Publication bias was assessed by visual inspection of the funnel plot and Egger's regression test statistic. RESULTS: Of the total 871 articles retrieved, 34 articles which involved 61,748 children were eligible for meta-analysis. The overall pooled prevalence of anemia using random effect model was 31.14% (95% CI: 24.62, 37.66%). In subgroup analysis, the pooled prevalence of anemia was higher among preschool-aged children (44.17%; 95% CI: 37.19, 51.15%) than school-aged children (22.19%; 95% CI: 17.54, 26.83%). Furthermore, the odds of anemia was higher among children who were male (OR = 1.11; 95% CI: 1.03, 1.19), stunted (OR = 1.95; 95% CI: 1.52, 2.51), and wasted (OR = 2.05; 95% CI: 1.36, 3.10). CONCLUSION: The pooled prevalence of anemia among children was high, indicating that it had been continuing to be a public health problem. Therefore, there is a need to design a comprehensive prevention and control strategies to reduce its burden. PMID- 29996880 TI - Head-to-head comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: a meta-analysis. AB - BACKGROUND: Recently, the concept of sepsis was redefined by an international task force. This international task force of experts recommended using the quick Sequential Organ Failure Assessment (qSOFA) criteria instead of the systemic inflammatory response syndrome (SIRS) criteria to classify patients at high risk for death. However, the added value of these new criteria in the emergency department (ED) remains unclear. Thus, we performed this meta-analysis to determine the diagnostic accuracy of the qSOFA criteria in predicting mortality in ED patients with infections and compared the performance with that of the SIRS criteria. METHODS: PubMed, EMBASE and Google Scholar (up to April 2018) were searched for related articles. A 2 * 2 contingency table was constructed according to mortality and qSOFA score (< 2 and >= 2) or SIRS score (< 2 and >= 2) in ED patients with infections. Two investigators independently assessed study eligibility and extracted data. We used a bivariate meta-analysis model to determine the prognostic value of qSOFA and SIRS in predicting mortality. We used the I2 index to test heterogeneity. The bivariate random-effects regression model was used to pool the individual sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). The summary receiver operating characteristic curve (SROC) was constructed to assess the overall diagnostic accuracy. RESULTS: Eight studies with a total of 52,849 patients were included. A qSOFA score >= 2 was associated with a higher risk of mortality in ED patients with infections, with a pooled risk ratio (RR) of 4.55 (95% CI, 3.38-6.14) using a random-effects model (I2 = 91.1%). A SIRS score >= 2 was a prognostic marker of mortality in ED patients with infections, with a pooled RR of 2.75 (95% CI, 1.96-3.86) using a random-effects model (I2 = 89%). When comparing the performance of qSOFA and SIRS in predicting mortality, a qSOFA score >= 2 was more specific; however a SIRS score >= 2 was more sensitive. The initial qSOFA values were of limited prognostic value in ED patients with infections. CONCLUSIONS: A qSOFA score >= 2 and SIRS score >= 2 are strongly associated with mortality in ED patients with infections. However, it is also clear that qSOFA and SIRS have limitations as risk stratification tools for ED patients with infections. PMID- 29996881 TI - The association of genomic lesions and PD-1/PD-L1 expression in resected triple negative breast cancers. AB - BACKGROUND: Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. METHODS: Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. RESULTS AND CONCLUSIONS: PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC >=4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naive cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC. PMID- 29996882 TI - Efficacy and indication optimization of Chinese medicine (Tiao-Chang Ke-Min granules) for diarrhea-predominant irritable bowel syndrome: study protocol for a randomized controlled trial. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a chronic, recurring condition, prevalent in the general population. Current medication treatments usually leave patients undertreated. Nowadays, Chinese medicine (CM) is being considered as a promising treatment approach for IBS. However, due to methodological limitations, there is no strong evidence to support CM. Although IBS relapses are common, the relapse assessment has always been neglected in CM study designs. Meanwhile, in clinical practice and studies, it has been found that certain CM formulas can only benefit certain kinds of patients. Discovering what population and illness characteristics likely respond to outcomes may help improve the effectiveness of CM. The aims of this study are to evaluate the efficacy and safety of Tiao-Chang Ke-Min (TCKM) granules for IBS, especially in reducing IBS symptoms' relapse, by a high-quality randomized controlled trial and then to optimize the indication of the TCKM granules. METHODS/DESIGN: This is a parallel-group, randomized, double blind, placebo-controlled trial embedded with outcome predictive factors. Eligible patients with diarrhea-predominant IBS will be randomized into either a TCKM granule group or a placebo group. Patients from both groups will receive health education. The treatment duration is 4 weeks and the follow-up is 12 weeks. The primary outcome is global improvement measured with adequate relief (AR). The second outcome measures include time until relief, time until first relapse, total relapse times, long-term effectiveness, individual symptoms, IBS Symptom Severity Score (IBS-SSS), IBS-Quality of Life Questionnaire (IBS-QOL), and Hospital Anxiety and Depression Scale (HADS). Predictive factors associated with patient and illness characteristics have been widely collected. These factors will be embedded in this trial for further identification. DISCUSSION: This trial may provide high-quality evidence on the efficacy and safety of TCKM granules for IBS and a more accurate indication. Importantly, this trial will provide a new research method for improving the therapeutic effects of CM for clinicians and researchers. To address IBS relapse assessment, a series of special definitions of relapse incidents has been made for this trial. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-17010600 . Registered on 9 February 2017. PMID- 29996883 TI - Novel PAradigm to improve Inflammatory burden in end stage Renal disease (rePAIR): study protocol for a randomized controlled trial. AB - BACKGROUND: Given the importance of inflammation as a predictor of poor outcomes in End Stage Renal Disease (ESRD), reductions in inflammatory biomarkers have been proposed as a critical target in this population. This study targets chronic periodontitis, an oral inflammatory disease of microbial etiology causing persistent inflammation in ESRD. Unlike the previously reported episodic periodontal interventions, we propose to control periodontal inflammation with a continuous maintenance and oral health behavior modifications. We hypothesize that this strategy will improve systemic inflammation and oxidative stress, oral health and quality of life within the 6-month observation period. METHODS: The rePAIR (novel PAradigm to improve Inflammatory burden in ESRD) study is a pilot and feasibility, parallel-arm, and randomized controlled clinical trial that will recruit 72 ESRD subjects with periodontitis in a model of computerized block randomization. This trial aims to compare the effect of standard-of-care vs. repeated non-surgical periodontal therapy on systemic and oral inflammatory burden. This trial will recruit ESRD adult patients with periodontitis older than 21 years old with a minimum of 12 teeth and no history of periodontal treatment within a year. The trial will examine serum C-reactive protein (CRP) (primary outcome) as a biomarker of inflammation as well as interleukin-6 (IL-6), F2 isofurans and F2 isoprostanes (secondary outcomes) and compare their difference between groups from baseline to 6 months. The trial will also compare the difference between groups in patient-centered and clinical oral outcomes from baseline to 6 months. DISCUSSION: The trial follows a rigorous and transparent study design capturing elements such as pre-specified eligibility criteria, pre specified primary and secondary outcomes, detailed intervention description to allow replication, intervention random allocation and concealment, blinding in outcome assessment, appropriate sample size calculations, explanation of interim analysis, as per CONSORT Guidelines. Further, gender diversity is secured not only at recruitment but also throughout the trial and during the analysis. Therefore, treatment response outcomes will be examined per gender category. In order to manage anticipated problems, the protocol has included alternative approaches. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03241511 . Registered on 7 August 2017. PMID- 29996884 TI - Splenic vein resection together with the pancreatic parenchyma versus separated resection after isolation of the parenchyma during distal pancreatectomy (COSMOS DP trial): study protocol for a randomised controlled trial. AB - BACKGROUND: In distal pancreatectomy (DP), it is customary to ligate and divide the splenic vein after isolating it from the pancreatic parenchyma. This is considered essential to prevent disruption of the stump of the splenic vein and consequent intra-abdominal haemorrhage in the event of pancreatic fistula (PF). However, this procedure can be technically demanding, especially when the vein is firmly embedded in the pancreatic parenchyma. The objective of the COSMOS-DP trial is to confirm the non-inferiority of resection of the splenic vein embedded in the pancreatic parenchyma compared with the conventional technique of isolating the splenic vein before resection during DP using a mechanical stapler. METHODS: Patients with diseases of the pancreatic body and tail whose pancreatic parenchyma and splenic vein can be divided concurrently during open or laparoscopic DP are considered eligible for inclusion. This study is designed as a multicentre prospective randomised phase III trial. Eligible patients will be centrally randomised to either Arm A (resection of the splenic vein after isolation from the pancreatic parenchyma) or Arm B (co-resection of the vein together with the pancreas). This study aims to establish the non-inferiority of the safety of Arm B compared with that of Arm A; the primary endpoint is the incidence of PF (ISGPF grade B/C). DISCUSSION: The COSMOS-DP trial will establish the safety of this procedure, such that it can be recommended with more confidence. The use of this procedure will likely result in significant reductions in operative time and blood loss during DP. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02871804 . Registered on 27 July 2016. PMID- 29996885 TI - Comparative studies of Toxoplasma gondii transcriptomes: insights into stage conversion based on gene expression profiling and alternative splicing. AB - BACKGROUND: Toxoplasma gondii is one of the most important apicomplexan parasites and infects one-third of the human population worldwide. Transformation between the tachyzoite and bradyzoite stages in the intermediate host is central to chronic infection and life-long risk. There have been some transcriptome studies on T. gondii; however, we are still early in our understanding of the kinds and levels of gene expression that occur during the conversion between stages. RESULTS: We used high-throughput RNA-sequencing data to assemble transcripts using genome-based and de novo strategies. The expression-level analysis of 6996 T. gondii genes showed that over half (3986) were significantly differentially expressed during stage conversion, whereas 2205 genes were upregulated, and 1778 genes were downregulated in tachyzoites compared with bradyzoites. Several important gene families were expressed at relatively high levels. Comprehensive functional annotation and gene ontology analysis revealed that stress response related genes are important for survival of bradyzoites in immune-competent hosts. We compared Trinity-based de novo and genome-based strategies, and found that the de novo assembly strategy compensated for the defects of the genome based strategy by filtering out several transcripts with low expression or those unannotated on the genome. We also found some inaccuracies in the ToxoDB gene models. In addition, our analysis revealed that alternative splicing can be differentially regulated in response to life-cycle change. In depth analysis revealed a 20-nt, AG-rich sequence, alternative splicing locus from alt_acceptor motif search in tachyzoite. CONCLUSION: This study represents the first large scale effort to sequence the transcriptome of bradyzoites from T. gondii tissue cysts. Our data provide a comparative view of the tachyzoite and bradyzoite transcriptomes to allow a more complete dissection of all the molecular regulation mechanisms during stage conversions. A better understanding of the processes regulating stage conversion may guide targeted interventions to disrupt the transmission of T. gondii. PMID- 29996886 TI - Improving cardiovascular health and quality of life in people with severe mental illness: study protocol for a randomised controlled trial. AB - BACKGROUND: The estimated 300,000 adults in Australia with severe mental illness (SMI) have markedly reduced life expectancy compared to the general population, mainly due to physical health comorbidities. Cardiovascular disease (CVD) is the commonest cause of early death and people with SMI have high rates of most modifiable risk factors, with associated quality of life (QoL) reduction. High blood pressure, smoking, dyslipidaemia, diabetes and obesity are major modifiable CVD risk factors. Poor delivery of recommended monitoring and risk reduction is a national and international problem. Therefore, effective preventive interventions to safeguard and support physical health are urgently needed in this population. METHODS: This trial used a rigorous process, including extensive piloting, to develop an intervention that delivers recommended physical health care to reduce CVD risk and improve QoL for people with SMI. Components of this intervention are integrated using the Flinders Program of chronic condition management (CCM) which is a comprehensive psychosocial care planning approach that places the patient at the centre of their care, and focuses on building their self-management capacity within a collaborative approach, therefore providing a recovery-oriented framework. The primary project aim is to evaluate the effectiveness and health economics of the CCM intervention. The main outcome measures examine CVD risk and quality of life. The second aim is to identify essential components, enablers and barriers at patient, clinical and organisational levels for national, sustained implementation of recommended physical health care delivery to people with SMI. Participants will be recruited from a community-based public psychiatric service. DISCUSSION: This study constitutes the first large-scale trial, worldwide, using the Flinders Program with this population. By combining a standardised yet flexible motivational process with a targeted set of evidence-based interventions, the chief aim is to reduce CVD risk by 20%. If achieved, this will be a ground-breaking outcome, and the program will be subsequently translated nationwide and abroad. The trial will be of great interest to people with mental illness, family carers, mental health services, governments and primary care providers because the Flinders Program can be delivered in diverse settings by any clinical discipline and supervised peers. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12617000474358 . Registered on 31 March 2017. PMID- 29996887 TI - The dimensionality of fatigue in Parkinson's disease. AB - BACKGROUND: Fatigue is a common problem among individuals with Parkinson's disease (PD). It may occur before the overt symptoms of bradykinesia, rigidity and tremor. Little is understood about how to measure fatigue in PD. Here we determined the dimensionality of the constructs of fatigue. METHODS: Four recommended scales, the Fatigue Severity Scale, Functional Assessment of Chronic Illness Therapy-Fatigue, Parkinson Fatigue Scale and Visual Analog Fatigue Scale (VAFS) were tested against quality of life measures including cognition, depression, sleep, life orientation, physical activity and PD symptoms in 22 PD subjects and 15 caregivers. RESULTS: Fatigue was associated with many quality of life variables, with the PDQ-39 summary index showing the strongest association. PD subjects agreed more strongly than caregivers that they experienced higher levels of fatigue. 27% of PD subjects rated fatigue as one of their top three most bothersome symptoms. The constructs of fatigue was captured within one dimension which explained 67% of the total variance, of which the VAFS showed the highest internal consistency. The highest likelihood ratio gave a cut-off score of < 5.5 on the VAFS. The change in scores required to produce a perceptible difference or is grossly observable ranged between 1.4 and 2.2 points respectively. CONCLUSION: The potential utility of a single measure such as the VAFS in PD that is reliably correlated with quality of life is consistent with the pursuit to develop clinical tests and measurements that are accessible, easy to use and universally interpretable across health science disciplines. PMID- 29996888 TI - Prioritization and functional assessment of noncoding variants associated with complex diseases. AB - Unraveling functional noncoding variants associated with complex diseases is still a great challenge. We present a novel algorithm, Prioritization And Functional Assessment (PAFA), that prioritizes and assesses the functionality of genetic variants by introducing population differentiation measures and recalibrating training variants. Comprehensive evaluations demonstrate that PAFA exhibits much higher sensitivity and specificity in prioritizing noncoding risk variants than existing methods. PAFA achieves improved performance in distinguishing both common and rare recurrent variants from non-recurrent variants by integrating multiple annotations and metrics. An integrated platform was developed, providing comprehensive functional annotations for noncoding variants by integrating functional genomic data, which can be accessed at http://159.226.67.237:8080/pafa . PMID- 29996889 TI - Identification of Aedes aegypti cis-regulatory elements that promote gene expression in olfactory receptor neurons of distantly related dipteran insects. AB - BACKGROUND: Sophisticated tools for manipulation of gene expression in select neurons, including neurons that regulate sexually dimorphic behaviors, are increasingly available for analysis of genetic model organisms. However, we lack comparable genetic tools for analysis of non-model organisms, including Aedes aegypti, a vector mosquito which displays sexually dimorphic behaviors that contribute to pathogen transmission. Formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) recently facilitated genome-wide discovery of putative A. aegypti cis-regulatory elements (CREs), many of which could be used to manipulate gene expression in mosquito neurons and other tissues. The goal of this investigation was to identify FAIRE DNA elements that promote gene expression in the olfactory system, a tissue of vector importance. RESULTS: Eight A. aegypti CREs that promote gene expression in antennal olfactory receptor neurons (ORNs) were identified in a Drosophila melanogaster transgenic reporter screen. Four CREs identified in the screen were cloned upstream of GAL4 in a transgenic construct that is compatible with transformation of a variety of insect species. These constructs, which contained FAIRE DNA elements associated with the A. aegypti odorant coreceptor (orco), odorant receptor 1 (Or1), odorant receptor 8 (Or8) and fruitless (fru) genes, were used for transformation of A. aegypti. Six A. aegypti strains, including strains displaying transgene expression in all ORNs, subsets of these neurons, or in a sex-specific fashion, were isolated. The CREs drove transgene expression in A. aegypti that corresponded to endogenous gene expression patterns of the orco, Or1, Or8 and fru genes in the mosquito antenna. CRE activity in A. aegypti was found to be comparable to that observed in D. melanogaster reporter assays. CONCLUSIONS: These results provide further evidence that FAIRE-seq, which can be paired with D. melanogaster reporter screening to test FAIRE DNA element activity in select tissues, is a useful method for identification of mosquito cis regulatory elements. These findings expand the genetic toolkit available for the study of Aedes neurobiology. Moreover, given that the CREs drive comparable olfactory neural expression in both A. aegypti and D. melanogaster, it is likely that they may function similarly in multiple dipteran insects, including other disease vector mosquito species. PMID- 29996890 TI - Same old song and dance: an exploratory study of portrayal of physical activity in television programmes aimed at young adolescents. AB - OBJECTIVE: Exposure to health-related behaviours on television has been shown to influence smoking and drinking in young people, but little research has been conducted on the portrayal physical activity. The aim of the current project was to explore the portrayal of physical activity in television programmes aimed specifically at adolescent females. Content analysis of 120 episodes of four popular adolescent television programmes was performed. Information on the type and context of physical activity, motivating factors and characters involved was recorded. RESULTS: Physical activity was portrayed 122 times, for a duration of 1 h and 31 min (3.2% of total viewing time). Physical activity was mainly portrayed as part of an informal activity as part of a group activity. Over half (53.2%) of scenes portrayed activity been carried out by teenagers. The types of activities portrayed were mostly of vigorous intensity (76.2%), for recreational purposes (78.7%) such as dancing (54.1%) and running (11.5%), and motivated by enjoyment. This study highlights that physical activity is portrayed infrequently, and often with a skewed representation of type of activity. There may be an opportunity to influence physical activity in young adolescents through the positioning of positive images of an active lifestyle in the media. PMID- 29996891 TI - STK25-induced inhibition of aerobic glycolysis via GOLPH3-mTOR pathway suppresses cell proliferation in colorectal cancer. AB - BACKGROUND: Serine/threonine protein kinase 25 (STK25) is critical in regulating whole-body glucose and insulin homeostasis and the accumulation of ectopic lipids. The Warburg effect, also known as aerobic glycolysis, is an essential metabolic characteristic of cancer cells. However, the effects of STK25 on aerobic glycolysis of cancer cells remain unexplored. The aim of this study is to investigate the role of STK25 in colorectal cancer (CRC) and to elucidate the underlying mechanisms. METHODS: The influences of STK25 on the cell proliferation were evaluated by MTT and colony formation assays. The roles of STK25 in aerobic glycolysis were determined by glucose uptake and lactate production assays. The interaction between STK25 and GOLPH3 was detected by co-immunoprecipitation, GST pull-down, and His-tag pull-down assays. Western blot was used to measure the expression of glycolytic genes, and the status of kinases in mTOR pathway. Moreover, a xenograft mouse model was used to investigate the effects of STK25 in vivo. The prognostic significance of STK25 was analyzed using public CRC datasets by a log-rank test. RESULTS: STK25 suppressed proliferation, glycolysis and glycolytic gene expression in CRC cells. STK25 interacted with GOLPH3 and mediated glycolysis through GOLPH3-regulated mTOR signaling. Consistent with these observations, silencing of STK25 promoted tumor growth and glycolytic gene expression in an in vivo xenograft mouse model. Moreover, high levels of STK25 correlated with favorable prognosis in patients with CRC. CONCLUSIONS: Our results demonstrated that STK25 negatively regulates the proliferation and glycolysis via GOLPH3-dependent mTOR signaling. Accordingly, STK25 could be a potential therapeutic target for the treatment of CRC. PMID- 29996893 TI - miR-155 is dispensable in monosodium urate-induced gouty inflammation in mice. AB - BACKGROUND: The findings of a previous study by Jin et al. have shown that microRNA (miR)-155 was upregulated in patients with acute gouty arthritis and enhanced the proinflammatory cytokines. There is no direct evidence to support that miR-155 is indeed involved in monosodium urate (MSU)-induced inflammatory responses in vivo. The aim of this study was to investigate the role of miR-155 knock-out (KO) or knock-in (KI) mice in MSU-induced animal models to mimic acute gout. METHODS: MiR-155 expression in cultured bone marrow-derived macrophages (BMDMs) from miR-155 KO, miR-155 KI, and wild-type (WT) mice treated with MSU crystals in vitro was detected by real-time quantitative polymerase chain reaction (qPCR). MiR-155 KO and WT mice were used to induce an acute gouty inflammatory response with MSU crystals including models of foot pad inflammation, ankle arthritis, air pouch inflammation, and peritonitis. Furthermore, the proinflammatory interleukin (IL)-1beta levels in lavage fluids from air pouch and peritoneal cavity models were measured by enzyme-linked immunosorbent assay (ELISA), and tumor necrosis factor (TNF)-alpha production from BMDMs of miR-155 KI mice treated with MSU were measured by flow cytometry. RESULTS: MiR-155 expression was quickly upregulated in BMDMs from WT mice following MSU treatment in vitro. In comparison with WT mice in vivo, the swelling index of miR-155 KO mice showed no significant difference in the murine foot pad and ankle arthritis models for the indicated different time points. There were similar changes in total cell numbers of lavage fluids in the air pouch and peritoneal cavity models between miR-155 KO and WT mice following MSU crystal injection. Moreover, the IL-1beta levels of lavage fluids in the air pouch and peritonitis models from miR-155 KO mice were almost the same as those from WT mice. TNF-alpha levels were comparable from BMDMs treated with MSU crystals in vitro between miR-155 KI mice and WT mice. CONCLUSIONS: MiR-155 is dispensable in MSU-induced gouty inflammation in mice. Deletion of miR-155 might not be an effective therapeutic approach to relieve the inflammation in acute gout. PMID- 29996892 TI - Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial. AB - BACKGROUND: Intrauterine adhesions (IUA) are the most common cause of uterine infertility and are caused by endometrium fibrotic regeneration following severe damage to the endometrium. Although current stem cell treatment options using different types of autologous stem cells have exhibited some beneficial outcomes in IUA patients, the reported drawbacks include variable therapeutic efficacies, invasiveness and treatment unavailability. Therefore, the development of new therapeutic stem cell treatments is critical to improving clinical outcomes. METHODS: Twenty-six patients who suffered from infertility caused by recurrent IUA were enrolled in this prospective, non-controlled, phase I clinical trial with a 30-month follow-up. During the procedure, 1 * 107 umbilical cord-derived mesenchymal stromal cells (UC-MSCs), loaded onto a collagen scaffold, were transplanted into the uterine cavity following an adhesion separation procedure. Medical history, physical examination, endometrial thickness, intrauterine adhesion score and the biological molecules related to endometrial proliferation and differentiation were assessed both before and 3 months after cell therapy. RESULTS: No treatment-related serious adverse events were found. Three months after the operation, the average maximum endometrial thickness in patients increased, and the intrauterine adhesion score decreased compared to those before the treatment. A histological study showed the upregulation of ERalpha (estrogen receptor alpha), vimentin, Ki67 and vWF (von Willebrand factor) expression levels and the downregulation of DeltaNP63 expression level, which indicates an improvement in endometrial proliferation, differentiation and neovascularization following treatment. DNA short tandem repeat (STR) analysis showed that the regenerated endometrium contained patient DNA only. By the end of the 30-month follow-up period, ten of the 26 patients had become pregnant, and eight of them had delivered live babies with no obvious birth defects and without placental complications, one patient in the third trimester of pregnancy, and one had a spontaneous abortion at 7 weeks. CONCLUSIONS: Transplanting clinical-grade UC MSCs loaded onto a degradable collagen scaffold into the uterine cavity of patients with recurrent IUA following adhesiolysis surgery is a safety and effective therapeutic method. TRIAL REGISTRATION: Clinicaltrials.gov . NCT02313415 , Registered December 6, 2014. PMID- 29996894 TI - Vitamin D, DNA methylation, and breast cancer. AB - BACKGROUND: Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation. METHODS: We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort. RESULTS: Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 * 10-5), indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH)D concentrations. We also observed statistically significant (p < 0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH)D was associated (q < 0.05) with methylation at cg24350360 (EPHX1; p = 3.4 * 10-8), cg06177555 (SPN; p = 9.8 * 10 8), and cg13243168 (SMARCD2; p = 2.9 * 10-7). CONCLUSIONS: 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer. PMID- 29996895 TI - An intervention to support stroke survivors and their carers in the longer term (LoTS2Care): study protocol for the process evaluation of a cluster randomised controlled feasibility trial. AB - BACKGROUND: Whilst pathways relating to the early stages of stroke care have become well established, strategies for longer-term care are less developed and longer-term outcomes remain poor for many stroke survivors. New Start, a complex intervention that includes needs identification, exploration of social networks and components of problem-solving and self-management, was designed to improve stroke survivors' quality of life by addressing unmet needs and increasing participation. It is delivered approximately 6 months post-stroke by trained staff (facilitators). We are currently undertaking a cluster randomised feasibility trial of the New Start intervention with an embedded process evaluation, which is an important component of the design and testing of complex interventions as it provides an understanding of how interventions are delivered and function in different settings. METHODS/DESIGN: This mixed methods process evaluation will explore the degree to which New Start is implemented as intended, the impact of context on intervention delivery and the acceptability of the intervention for stroke survivors, their families and practitioners. It will include non-participant observation of facilitator training and intervention delivery. Interviews with stroke survivors, facilitators and other relevant staff (including administrators and managerial staff) will be undertaken. Qualitative data from interview transcripts, facilitator reflections and observational field notes will be analysed thematically alongside numerical data documenting intervention delivery collected as part of the trial. DISCUSSION: This process evaluation will identify factors that aid and impede implementation of the New Start intervention and improve understanding of this novel approach to longer term stroke care. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN38920246 . Registered on 22 June 2016. PMID- 29996896 TI - Adipocyte-specific Repression of PPAR-gamma by NCoR Contributes to Scleroderma Skin Fibrosis. AB - BACKGROUND: A pivotal role for adipose tissue homeostasis in systemic sclerosis (SSc) skin fibrosis is increasingly recognized. The nuclear receptor PPAR-gamma is the master regulator of adipogenesis. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) has antifibrotic effects by blocking transforming growth factor-beta (TGF-beta) and is dysregulated in SSc. To unravel the impact of dysregulated PPAR-gamma in SSc, we focused on nuclear corepressor (NCoR), which negatively regulates PPAR-gamma activity and suppresses adipogenesis. METHODS: An NCoR-regulated gene signature was measured in the SSc skin transcriptome. Experimental skin fibrosis was examined in mice with adipocyte specific NCoR ablation. RESULTS: SSc skin biopsies demonstrated deregulated NCoR signaling. A 43-gene NCoR gene signature showed strong positive correlation with PPAR-gamma signaling (R = 0.919, p < 0.0001), whereas negative correlations with TGF-beta signaling (R = - 0.796, p < 0.0001) and the modified Rodnan skin score (R = - 0.49, p = 0.004) were found. Mice with adipocyte-specific NCoR ablation demonstrated significant protection from experimental skin fibrosis and inflammation. The protective effects were mediated primarily through endogenous PPAR-gamma. CONCLUSIONS: Our results implicate, for the first time, to our knowledge, deregulated NCoR/PPAR-gamma pathways in SSc, and they support a role of adipocyte modulation of skin fibrosis. Pharmacologic restoration of NCoR/PPAR gamma signaling may represent a novel strategy to control skin fibrosis in SSc. PMID- 29996897 TI - Correction to: Pin1 inhibition exerts potent activity against acute myeloid leukemia through blocking multiple cancer-driving pathways. AB - The original article [1] contained minor typesetting errors affecting the following authors: Ziang Jeff Gao, Xiao Zhen Zhou, and Kun Ping Lu. PMID- 29996898 TI - Effects of lyophilization and storage temperature on Wuchereria bancrofti antigen sensitivity and stability. AB - OBJECTIVE: Antigen-based rapid diagnostic tests for Lymphatic filariasis (LF) do not come with external quality control (QC) materials, and research and disease control programmes rely on stored positive samples. This study was undertaken to evaluate the use of lyophilized Wuchereria bancrofti antigen positive plasma samples to serve as QC materials for LF diagnostic tests. 10 well characterized W. bancrofti positive samples were lyophilized and stored at 4, 28 and 40 degrees C. The samples were evaluated using the Alere Filariasis Test Strips before lyophilization, and after 1 and 3 months of storage. The sensitivity and stability of the lyophilized samples were evaluated. RESULTS: The results revealed a loss of sensitivity and stability with increasing temperature and duration of storage. The results are further discussed in terms of the use of dried blood spot (DBS) in diagnostic studies on LF, and the need for thoughtful DBS preparation and storage. PMID- 29996899 TI - Circulating microRNAs in the early prediction of disease recurrence in primary breast cancer. AB - BACKGROUND: In primary breast cancer metastases frequently arise from a state of dormancy that may persist for extended periods of time. We investigated the efficacy of plasma micro-RNA (miR)-21, miR-23b, miR-190, miR-200b and miR-200c, related to dormancy and metastasis, to predict the outcome of patients with early breast cancer. METHODS: miRNAs were evaluated by RT-qPCR in plasma obtained before adjuvant chemotherapy. miRNA expression, classified as high or low according to median values, correlated with relapse and survival. Receiver operating characteristic (ROC) curves were constructed to determine miRNA sensitivity and specificity. RESULTS: miR-21 (p < 0.001), miR-23b (p = 0.028) and miR-200c (p < 0.001) expression were higher and miR-190 was lower (p = 0.013) in relapsed (n = 49), compared to non-relapsed patients (n = 84). Interestingly, miR 190 was lower (p = 0.0032) in patients with early relapse (at < 3 years; n = 23) compared to those without early relapse (n = 110). On the other hand, miR-21 and miR-200c were higher (p = 0.015 and p < 0.001, respectively) in patients with late relapse (relapse at >= 5 years; n = 20) as compared to non-relapsed patients. High miR-200c was associated with shorter disease-free survival (DFS) (p = 0.005) and high miR-21 with both shorter DFS and overall survival (OS) (p < 0.001 and p = 0.033, respectively) compared to low expression. ROC curve analysis revealed that miR-21, miR-23b, miR-190 and miR-200c discriminated relapsed from non-relapsed patients. A combination of of miR-21, miR-23b and miR-190 showed higher sensitivity and specificity in ROC analyses compared to each miRNA alone; accuracy was further improved by adding lymph node infiltration and tumor grade to the panel of three miRs (AUC 0.873). Furthermore, the combination of miR-200c, lymph node infiltration, tumor grade and estrogen receptor predicted late relapse (AUC 0.890). CONCLUSIONS: Circulating miRNAs are differentially expressed among relapsed and non-relapsed patients with early breast cancer and predict recurrence many years before its clinical detection. Our results suggest that miRNAs represent potential circulating biomarkers in early breast cancer. PMID- 29996900 TI - Childhood suffering: hyper endemic echinococcosis in Qinghai-Tibetan primary school students, China. AB - BACKGROUND: As part of an ongoing program that aims to use early detection and timely treatment to improve the control of echinococcosis, especially in younger age groups, we undertook a series of active surveys among Qinghai-Tibetan children in the Qinghai Province of Northwestern China in 2011 and 2012. The significant outcomes that resulted from this study emphasize the need to draw attention to echinococcosis, both alveolar echinococcosis (AE) and cystic echinococcosis (CE), so that policy development is promoted and suitable avenues for control are identified in the highly endemic areas on the Tibetan Plateau. METHODS: A total of 19 629 primary school students, aged 6-18 years, with a dominant Tibetan background underwent abdominal ultrasound examination, and 86.4% of the compliant students donated 2-5 ml of venous blood for serological tests. All the abnormal ultrasound results were recorded. If identified as echinococcosis, the disease lesion was assessed according to the WHO-Informal Working Group on Echinococcosis (WHO-IWGE) classification for AE and CE. Among the surveyed students, the prevalence by school was compared among geo-locations, sex and age groups. The clinical image presentations were analyzed according to lesion number, size, the location in the liver and the classification stage. Statistical significance was set at P-value < 0.05 for comparisons among groups. RESULTS: A total of 341 students (1.7%) were identified by ultrasound as having either CE (119, 0.6%) or AE (222, 1.1%). The highest prevalence rates of childhood AE cases occurred in the Tehetu (12.1%) and Moba (11.8%) townships in Dari County. There was a high seropositive rate (37.0%) and a heterogeneous distribution of cases, with a prevalence ranged from 0 to 12.1% for AE and 0-2.9% for CE. Moreover, the seropositive rate ranged from 0.7-45.1% across different schools. CONCLUSIONS: The high prevalence of echinococcosis in Qinghai-Tibetan primary school students reflects a lack of knowledge about Echinococcus spp. transmission. The combination of systematic education for children and regularly performed anthelmintic treatment for dogs could achieve the goal of sustainable hydatidosis control. PMID- 29996901 TI - Periosteal progenitors contribute to load-induced bone formation in adult mice and require primary cilia to sense mechanical stimulation. AB - BACKGROUND: The fully developed adult skeleton adapts to mechanical forces by generating more bone, usually at the periosteal surface. Progenitor cells in the periosteum are believed to differentiate into bone-forming osteoblasts that contribute to load-induced adult bone formation, but in vivo evidence does not yet exist. Furthermore, the mechanism by which periosteal progenitors might sense physical loading and trigger differentiation is unknown. We propose that periosteal osteochondroprogenitors (OCPs) directly sense mechanical load and differentiate into bone-forming osteoblasts via their primary cilia, mechanosensory organelles known to be involved in osteogenic differentiation. METHODS: We generated a diphtheria toxin ablation mouse model and performed ulnar loading and dynamic histomorphometry to quantify the contribution of periosteal OCPs in adult bone formation in vivo. We also generated a primary cilium knockout model and isolated periosteal cells to study the role of the cilium in periosteal OCP mechanosensing in vitro. Experimental groups were compared using one-way analysis of variance or student's t test, and sample size was determined to achieve a minimum power of 80%. RESULTS: Mice without periosteal OCPs had severely attenuated mechanically induced bone formation and lacked the mineralization necessary for daily skeletal maintenance. Our in vitro results demonstrate that OCPs in the periosteum uniquely sense fluid shear and exhibit changes in osteogenic markers consistent with osteoblast differentiation; however, this response is essentially lost when the primary cilium is absent. CONCLUSIONS: Combined, our data show that periosteal progenitors are a mechanosensitive cell source that significantly contribute to adult skeletal maintenance. More importantly, an OCP population persists in the adult skeleton and these cells, as well as their cilia, are promising targets for bone regeneration strategies. PMID- 29996902 TI - Viola phlebovirus is a novel Phlebotomus fever serogroup member identified in Lutzomyia (Lutzomyia) longipalpis from Brazilian Pantanal. AB - BACKGROUND: High throughput sequencing (HTS) boosted the discovery of novel viruses and new variants of known viruses. Here we investigated the presence of viruses in 12 pools of sand flies captured in three climatic periods in RAPELD grids at Rio Claro, Chapada dos Guimaraes and at Pirizal, North Pantanal, Mato Grosso State, Midwestern Brazil by HTS, viral isolation of a putative Phlebovirus positive pool in Vero cells, RT-PCR and transmission electron microscopy (TEM). RESULTS: One pool containing three Lutzomyia (Lutzomyia) longipalpis sand flies captured in the transitional climatic period in North Pantanal showed a tripartite genomic sequence of a putative novel Phlebovirus belonging to the phlebotomus fever serogroup. Phylogenetic analysis revealed this virus is closely related and share a common ancestor with phleboviruses included in the same clade: Chagres, Urucuri and Uriurana virus. RNA-dependent RNA polymerase (RdRP) presented 60%, 59% and 58% of amino-acid (aa) similarity with these phleboviruses, respectively. Similarity of Nucleoprotein and NSs protein codified by ambissense strategy of segment S was of 49% and 37%, respectively, with the proteins of the closest phlebovirus, Uriurana virus. Glycoproteins (G1, G2) and NSm protein presented 49% and 48% aa similarity with Chagres and Uriurana virus, respectively. Uriurana virus was isolated from sand flies in Brazilian Amazon and Urucuri from rodents in Utinga forest, Para State. Chagres virus is an arbovirus responsible for outbreaks of febrile illness in Panama. This phlebovirus was isolated in Vero cells, confirmed by TEM and RT-PCR for the L segment of the virus, and named Viola phlebovirus. CONCLUSIONS: HTS, viral isolation, RT-PCR and TEM showed the presence of one virus in sand flies from North Pantanal with identity to a putative novel Phlebovirus from phlebotomus fever serogroup, named Viola phlebovirus. PMID- 29996903 TI - Molecular characterization of Cryptosporidium spp. and Giardia duodenalis in children in Egypt. AB - BACKGROUND: The transmission of Cryptosporidium spp. and Giardia duodenalis into humans varies according to species/genotypes of the pathogens. Although infections with both parasites are recorded in Egypt, few data are available on the distribution of Cryptosporidium species and G. duodenalis genotypes. The present study assessed the occurrence and genetic diversity of Cryptosporidium spp. and G. duodenalis in Egyptian children. METHODS: In the present study, 585 fecal specimens were collected from children eight years old and younger in three provinces (El-Dakahlia, El-Gharbia and Damietta) during March 2015 to April 2016. PCR-RFLP analysis of the small subunit rRNA gene and sequence analysis of the 60 kDa glycoprotein gene were used to detect and subtype Cryptosporidium spp., respectively, whereas PCR and sequence analyses of the triose phosphate isomerase, glutamate dehydrogenase and beta-giardin genes were used to detect and genotype Giardia duodenalis. RESULTS: The overall infection rates of Cryptosporidium spp. and G. duodenalis were 1.4% and 11.3%, respectively. The Cryptosporidium species identified included C. hominis and C. parvum, each with three subtype families. The C. hominis subtypes were IbA6G3 (n = 2), IdA17 (n = 1), IdA24 (n = 1) and IfA14G1R5 (n = 1), while C. parvum subtypes were IIdA20G1 (n = 1), IIaA15G2R1 (n = 1), and IIcA5G3a (n = 1). The G. duodenalis identified included both assemblages A (n = 31) and B (n = 34). All G. duodenalis assemblage A belonged to the anthroponotic sub-assemblage AII, while a high genetic heterogeneity was seen within assemblage B. CONCLUSIONS: Data from this study are useful in our understanding of the genetic diversity of Cryptosporidium spp. and G. duodenalis in Egypt and the potential importance of anthroponotic transmission in the epidemiology of both pathogens. PMID- 29996904 TI - Quality indicators of clinical cancer care for prostate cancer: a population based study in southern Switzerland. AB - BACKGROUND: Quality of cancer care (QoCC) has become an important item for providers, regulators and purchasers of care worldwide. Aim of this study is to present the results of some evidence-based quality indicators (QI) for prostate cancer (PC) at the population-based level and to compare the outcomes with data available in the literature. METHODS: The study included all PC diagnosed on a three years period analysis (01.01.2011-31.12.2013) in the population of Canton Ticino (Southern Switzerland) extracted from the Ticino Cancer Registry database. 13 QI, approved through the validated Delphi methodology, were calculated using the "available case" approach: 2 for diagnosis, 4 for pathology, 6 for treatment and 1 for outcome. The selection of the computed QI was based on the availability of medical documentation. QI are presented as proportion (%) with the corresponding 95% confidence interval. RESULTS: 700 PC were detected during the three-year period 2011-2013: 78.3% of them were diagnosed through a prostatic biopsy and for 72.5% 8 or more biopsy cores were taken. 46.5% of the low risk PC patients underwent active surveillance, while 69.2% of high risk PC underwent a radical treatment (radical prostatectomy, radiotherapy or brachytherapy) and 73.5% of patients with metastatic PC were treated with hormonal therapy. The overall 30-day postoperative mortality was 0.5%. CONCLUSIONS: Results emerging from this study on the QoCC for PC in Canton Ticino are encouraging: the choice of treatment modalities seems to respect the international guidelines and our results are comparable to the scarce number of available international studies. Additional national and international standardisation of the QI and further QI population-based studies are needed in order to get a real picture of the PC diagnostic-therapeutic process progress through the definition of thresholds of minimal standard of care. PMID- 29996905 TI - The ion channel TRPM4 in murine experimental autoimmune encephalomyelitis and in a model of glutamate-induced neuronal degeneration. AB - Transient receptor potential melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel, has been found to mediate cell membrane depolarization in immune response, insulin secretion, cardiovascular diseases, and cancer. In murine experimental autoimmune encephalomyelitis (EAE), TRPM4 deletion and administration of glibenclamide were found to ameliorate clinical symptoms and attenuate disease progression. However, the exact role of TRPM4 in EAE, as well as the molecular mechanisms underlining TRPM4 contribution in EAE, remain largely unclear. In the present study, EAE was induced in WT C57BL/6 N mice using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) and TRPM4 protein and mRNA expression were examined in spinal cord membrane extracts. Our results showed that TRPM4 protein and mRNA are upregulated in EAE, and that their upregulation correlated with disease progression. Moreover, newly-developed TRPM4 inhibitors, named compound 5 and compound 6, were shown to exert a better neuroprotection compared to currently used TRPM4 inhibitors in an in vitro model of glutamate-induced neurodegeneration. These results support the hypothesis that TRPM4 is crucial from early stages of EAE, and suggest that these more potent TRPM4 inhibitors could be used as novel protective therapeutic tools in glutamate induced neurodegeneration. PMID- 29996906 TI - Estrogen promotes estrogen receptor negative BRCA1-deficient tumor initiation and progression. AB - BACKGROUND: Estrogen promotes breast cancer development and progression mainly through estrogen receptor (ER). However, blockage of estrogen production or action prevents development of and suppresses progression of ER-negative breast cancers. How estrogen promotes ER-negative breast cancer development and progression is poorly understood. We previously discovered that deletion of cell cycle inhibitors p16Ink4a (p16) or p18Ink4c (p18) is required for development of Brca1-deficient basal-like mammary tumors, and that mice lacking p18 develop luminal-type mammary tumors. METHODS: A genetic model system with three mouse strains, one that develops ER-positive mammary tumors (p18 single deletion) and the others that develop ER-negative tumors (p16;Brca1 and p18;Brca1 compound deletion), human BRCA1 mutant breast cancer patient-derived xenografts, and human BRCA1-deficient and BRCA1-proficient breast cancer cells were used to determine the role of estrogen in activating epithelial-mesenchymal transition (EMT), stimulating cell proliferation, and promoting ER-negative mammary tumor initiation and metastasis. RESULTS: Estrogen stimulated the proliferation and tumor-initiating potential of both ER-positive Brca1-proficient and ER-negative Brca1-deficient tumor cells. Estrogen activated EMT in a subset of Brca1 deficient mammary tumor cells that maintained epithelial features, and enhanced the number of cancer stem cells, promoting tumor progression and metastasis. Estrogen activated EMT independent of ER in Brca1-deficient, but not Brca1 proficient, tumor cells. Estrogen activated the AKT pathway in BRCA1-deficient tumor cells independent of ER, and pharmaceutical inhibition of AKT activity suppressed EMT and cell proliferation preventing BRCA1 deficient tumor progression. CONCLUSIONS: This study reveals for the first time that estrogen promotes BRCA1-deficient tumor initiation and progression by stimulation of cell proliferation and activation of EMT, which are dependent on AKT activation and independent of ER. PMID- 29996907 TI - Comparing 16S rDNA amplicon sequencing and hybridization capture for pea aphid microbiota diversity analysis. AB - OBJECTIVE: Targeted sequencing of 16S rDNA amplicons is routinely used for microbial community profiling but this method suffers several limitations such as bias affinity of universal primers and short read size. Gene capture by hybridization represents a promising alternative. Here we used a metagenomic extract from the pea aphid Acyrthosiphon pisum to compare the performances of two widely used PCR primer pairs with DNA capture, based on solution hybrid selection. RESULTS: All methods produced an exhaustive description of the 8 bacterial taxa known to be present in this sample. In addition, the methods yielded similar quantitative results, with the number of reads strongly correlating with quantitative PCR controls. Both methods can thus be considered as qualitatively and quantitatively robust on such a sample with low microbial complexity. PMID- 29996908 TI - Marijuana intoxication in a cat. AB - BACKGROUND: Cannabis from hemp (Cannabis sativa and C. indica) is one of the most common illegal drugs used by drug abusers. Indian cannabis contains around 70 alkaloids, and delta-9-tetrahydrocannabinol (delta-9-THC) is the most psychoactive substance. Animal intoxications occur rarely and are mostly accidental. According to the US Animal Poison Control Center, cannabis intoxication mostly affects dogs (96%). The most common cause of such intoxication is unintentional ingestion of a cannabis product, but it may also occur after the exposure to marijuana smoke. CASE PRESENTATION: A 6-year-old Persian cat was brought to the veterinary clinic due to strong psychomotor agitation turning into aggression. During hospitalisation for 14 days, the cat behaved normally and had no further attacks of unwanted behaviour. It was returned to its home but shortly after it developed neurological signs again and was re-hospitalised. On presentation, the patient showed no neurological abnormalities except for symmetric mydriasis and scleral congestion. During the examination, the behaviour of the cat changed dramatically. It developed alternate states of agitation and apathy, each lasting several minutes. On interview it turned out that the cat had been exposed to marijuana smoke. Blood toxicology tests by gas chromatography tandem mass spectrometry revealed the presence of delta-9-tetrahydrocannabinol (THC) at 5.5 ng/mL, 11-hydroxy-delta-9 THC at 1.2 ng/mL, and 11-carboxy-delta-9-THC at 13.8 ng/mL. The cat was given an isotonic solution of NaCl 2.5 and 2.5% glucose at a dose of 40 mL/kg/day parenterally and was hospitalised. After complete recovery, the cat was returned to it's owner and future isolation of the animal from marijuana smoke was advised. CONCLUSIONS: This is the first case of a delta-9-tetrahydrocannabinol intoxication in a cat with both description of the clinical findings and the blood concentration of delta-9-THC and its main metabolites. PMID- 29996909 TI - Support persons' preferences for the type of consultation and the format of information provided when making a cancer treatment decision. AB - OBJECTIVE: Cancer patients and their support persons commonly feel overwhelmed when being confronted with their diagnosis and treatment options. We used a DCE to examine patients' and support persons' preferences for: (i) attending one 40 min consultation or two 20 min consultations when making a cancer treatment decision; and for (ii) receiving additional information in written form only or in both written and online forms. Here we focus on support persons' preferences and whether they differ from patients' preferences. RESULTS: 159 adult medical oncology patients and 64 of their support persons took part in this study. Participants were presented with a set of hypothetical scenarios and asked to indicate their most and least preferred scenario. 92% of support persons (n = 59) completed the DCE. Most preferred to receive two consultations along with written and online information (n = 30, 51%). This was the only scenario that was chosen by statistically significantly more support persons (p =0.037). The proportions of patients and support persons choosing each scenario did not differ significantly from each other (p >0.05). Our findings suggest that when making cancer treatment decisions, clinicians should consider offering patients and support persons written and online information, combined with two shorter consultations. PMID- 29996910 TI - Echocardiographic parameters and renal outcomes in patients with preserved renal function, and mild- moderate CKD. AB - BACKGROUND: Echocardiographic characteristics across the spectrum of chronic kidney disease (CKD) have not been well described. We assessed the echocardiographic characteristics of patients with preserved renal function and mild or moderate CKD referred for echocardiography and determined whether echocardiographic parameters of left ventricular (LV) and right ventricular (RV) structure and function were associated with changes in renal function and mortality. METHODS: This retrospective cohort study enrolled all adult patients who had at least one trans-thoracic echocardiography between 2004 and 2014 in our institution. The composite outcome of doubling of serum creatinine or initiation of maintenance dialysis or kidney transplantation was the primary outcome. Mortality was the secondary outcome. RESULTS: 29,219 patients were included. Patients with worse renal function had higher prevalence of structural and functional LV and RV abnormalities. Higher estimated glomerular filtration rate (eGFR) was independently associated with preserved LV ejection fraction, preserved RV systolic function, and lower LV mass, left atrial diameter, pulmonary artery pressure, and right atrial pressure, as well as normal RV structure. 1041 composite renal events were observed. 8780 patients died during the follow-up. Pulmonary artery pressure and the RV, but not the LV, echocardiographic parameters were independently associated with the composite renal outcome. In contrast, RV systolic function, RV dilation or hypertrophy, LV ejection fraction group, LV diameter quartile, and pulmonary artery pressure quartile were independently associated with all-cause mortality. CONCLUSIONS: Echocardiographic abnormalities are frequent even in early CKD. Echocardiographic assessment particularly of the RV may provide useful information for the care of patients with CKD. PMID- 29996911 TI - Urine-derived cells for human cell therapy. AB - Desirable cells for human cell therapy would be ones that can be generated by simple isolation and culture techniques using a donor sample obtained by non invasive methods. To date, the different donor-specific cells that can be isolated from blood, skin, and hair require invasive methods for sample isolation and incorporate complex and costly reagents to culture. These cells also take considerable time for their in-vitro isolation and expansion. Previous studies suggest that donor-derived cells, namely urine stem cells and renal cells, may be isolated from human urine samples using a cost-effective and simple method of isolation, incorporating not such complex reagents. Moreover, the isolated cells, particularly urine stem cells, are superior to conventional stem cell sources in terms of favourable gene profile and inherent multipotent potential. Transdifferentiation or differentiation of human urine-derived cells can generate desirable cells for regenerative therapy. In this review, we intended to discuss the characteristics and therapeutic applications of urine-derived cells for human cell therapy. Conclusively, with detailed study and optimisation, urine-derived cells have a prospective future to generate functional lineage-specific cells for patients from a clinical translation point of view. PMID- 29996912 TI - Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research. AB - BACKGROUND: Diabetic foot ulcer (DFU) is a severe complication of diabetes, preceding most diabetes-related amputations. DFUs require over US$9 billion for yearly treatment and are now a global public health issue. DFU occurs in the setting of ischemia, infection, neuropathy, and metabolic disorders that result in poor wound healing and poor treatment options. Recently, stem cell therapy has emerged as a new interventional strategy to treat DFU and appears to be safe and effective in both preclinical and clinical trials. However, variability in the stem cell type and origin, route and protocol for administration, and concomitant use of angioplasty confound easy interpretation and generalization of the results. METHODS: The PubMed, Google Scholar, and EMBASE databases were searched and 89 preclinical and clinical studies were selected for analysis. RESULTS: There was divergence between preclinical and clinical studies regarding stem cell type, origin, and delivery techniques. There was heterogeneous preclinical and clinical study design and few randomized clinical trials. Granulocyte-colony stimulating factor was employed in some studies but with differing protocols. Concomitant performance of angioplasty with stem cell therapy showed increased efficiency compared to either therapy alone. CONCLUSIONS: Stem cell therapy is an effective treatment for diabetic foot ulcers and is currently used as an alternative to amputation for some patients without other options for revascularization. Concordance between preclinical and clinical studies may help design future randomized clinical trials. PMID- 29996913 TI - Development of a laboratorial platform for diagnosis of schistosomiasis mansoni by PCR-ELISA. AB - OBJECTIVE: We developed a laboratorial platform to release a commercial platform used in the PCR-ELISA for the molecular diagnosis of schistosomiasis mansoni. On following, PCR-ELISA platform laboratorial was evaluated in 206 feces samples collected of individual living in a Brazilian low endemicity area. RESULTS: The PCR-ELISA laboratorial platform indicated a prevalence rate of 25.2%, which was higher than the Kato-Katz technique (18.4%) and lower than the commercial platform (30.1%). Considering Kato-Katz technique as the reference, there were 97.4% and 91.1% of relative sensitivity and specificity rates, respectively. The laboratorial platform presented good precision, performance diagnostic, and can be used in replacement to the commercial platform for diagnosis of schistosomiasis by PCR-ELISA. PMID- 29996914 TI - Perspectives in immunotherapy: meeting report from the Immunotherapy Bridge (29 30 November, 2017, Naples, Italy). AB - Immunotherapy represents the third important wave in the history of the systemic treatment of cancer after chemotherapy and targeted therapy and is now established as a potent and effective treatment option across several cancer types. The clinical success of anti-cytotoxic T-lymphocyte-associated antigen (CTLA)-4, first, and anti-programmed death (PD)-1/PD-ligand (L)1 agents in melanoma and other cancers a few years later, has encouraged increasing focus on the development of other immunotherapies (e.g. monoclonal antibodies with other immune targets, adoptive cell transfer, and vaccines), with over 3000 immuno oncology trials ongoing, involving hundreds of research institutes across the globe. The potential use of these different immunotherapeutic options in various combinations with one another and with other treatment modalities is an area of particular promise. The third Immunotherapy Bridge meeting (29-30 November, 2017, Naples, Italy) focused on recent advances in immunotherapy across various cancer types and is summarised in this report. PMID- 29996915 TI - The establishment of a chemically defined serum-free culture system for human dental pulp stem cells. AB - BACKGROUND: The concept of establishing a dental stem cell (DSC) bank for oral and maxillofacial regeneration has become of great interest but it remains at a primitive stage. The routine application of serum-containing conditions for human DSC (hDSC) culture is in great controversy considering that the animal-originated serum can cause serious ethical concerns and lead to increasingly irrelevant variables, errors, and poor repeatability of experiment results. Thus, this study aimed to establish a safe, stable and efficient hDSC serum-free culturing system for future DSC bank usage. METHODS: Dental pulp stem cells (DPSCs) from human permanent tooth pulp were isolated, expanded, passaged, and divided into two groups according to their culture conditions: group 1 was the serum-containing medium (SCM) group; and group 2 was the serum-free Essential 8 medium (E8) group. DPSCs were characterized first, followed by cell proliferation, pluripotency, and migration study in SCM and E8 medium. RESULTS: Human DPSCs (hDPSCs) in E8 medium demonstrated greater proliferation, pluripotency, migration ability and less apoptosis. hDPSCs could be successfully induced to the adipogenic, osteogenic, neurogenic, and chondrogenic lineages in E8 group. Real-time polymerase chain reaction indicated that the expression of PPAR-gamma, RUNX2, OCN and MAP-2 was higher in E8 group. CONCLUSIONS: Compared with serum-containing medium, E8 medium exhitibed higher ability in maintaining the cell proliferation, pluripotency, migration, and stability. This new serum-free culture environment might be applicable for hDSC culture in the future. PMID- 29996916 TI - The prevalence of depression in axial spondyloarthritis and its association with disease activity: a systematic review and meta-analysis. AB - BACKGROUND: Depression is common among patients with axial spondyloarthritis (axSpA), but reports of its prevalence are highly variable. We performed a systematic review to (i) describe the prevalence of depression in axSpA, (ii) compare its prevalence between axSpA, ankylosing spondylitis (AS) and non radiographic axSpA (nr-axSpA) cohorts, and (iii) compare disease activity and functional impairment between those with and without depression. METHODS: We searched Medline, PubMed, Web of Science, PsycINFO, CINAHL Plus, the Cochrane library and conference abstracts of the European League Against Rheumatism, British Society for Rheumatology and American College of Rheumatology using a predefined protocol in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Meta-analysis was performed using quality-effects model. RESULTS: Fifteen original articles and one abstract were included for analysis; 14 studies described AS cohorts and two nr-axSpA. Three screening criteria and one diagnostic criterion were used to define depression. Prevalence ranged from 11 to 64% depending on criteria and thresholds used. Pooled prevalence of at least moderate depression was 15% using the Hospital Anxiety and Depression Scale (HADS) threshold of >= 11. The prevalence of depression was similar between axSpA, AS and nr-axSpA cohorts. Patients with depression had significantly worse disease activity, including higher BASDAI by 1.4 units (95% CI 1.0 to 1.9), ASDAS by 0.5 units (95% CI 0.3 to 0.7) and ESR by 3.5 mm/h (95% CI 0.6 to 6.4). They also had greater functional impairment with higher BASFI and BASMI by 1.2 units (95% CI 0.6 to 1.8) and 0.6 units (95% CI 0.3 to 0.8), respectively. Mean age of each study cohort inversely correlated with depression prevalence. CONCLUSIONS: Depression is common among axSpA patients and is associated with more severe disease activity and functional impairment. Identifying and managing depression should form part of their holistic care. Further longitudinal studies are needed to explore the impact of depression on treatment outcomes and axSpA treatment on symptoms of depression. PMID- 29996917 TI - A new bioinformatics tool to help assess the significance of BRCA1 variants. AB - BACKGROUND: Germline pathogenic variants in the breast cancer type 1 susceptibility gene BRCA1 are associated with a 60% lifetime risk for breast and ovarian cancer. This overall risk estimate is for all BRCA1 variants; obviously, not all variants confer the same risk of developing a disease. In cancer patients, loss of BRCA1 function in tumor tissue has been associated with an increased sensitivity to platinum agents and to poly-(ADP-ribose) polymerase (PARP) inhibitors. For clinical management of both at-risk individuals and cancer patients, it would be important that each identified genetic variant be associated with clinical significance. Unfortunately for the vast majority of variants, the clinical impact is unknown. The availability of results from studies assessing the impact of variants on protein function may provide insight of crucial importance. RESULTS AND CONCLUSION: We have collected, curated, and structured the molecular and cellular phenotypic impact of 3654 distinct BRCA1 variants. The data was modeled in triple format, using the variant as a subject, the studied function as the object, and a predicate describing the relation between the two. Each annotation is supported by a fully traceable evidence. The data was captured using standard ontologies to ensure consistency, and enhance searchability and interoperability. We have assessed the extent to which functional defects at the molecular and cellular levels correlate with the clinical interpretation of variants by ClinVar submitters. Approximately 30% of the ClinVar BRCA1 missense variants have some molecular or cellular assay available in the literature. Pathogenic variants (as assigned by ClinVar) have at least some significant functional defect in 94% of testable cases. For benign variants, 77% of ClinVar benign variants, for which neXtProt Cancer variant portal has data, shows either no or mild experimental functional defects. While this does not provide evidence for clinical interpretation of variants, it may provide some guidance for variants of unknown significance, in the absence of more reliable data. The neXtProt Cancer variant portal ( https://www.nextprot.org/portals/breast-cancer ) contains over 6300 observations at the molecular and/or cellular level for BRCA1 variants. PMID- 29996918 TI - Clinicopathologic features and prognostic grouping of gastrointestinal stromal tumors (GISTs) in Pakistani patients: an institutional perspective. AB - OBJECTIVES: Gastrointestinal stromal tumors (GISTs) are rare tumors of gastrointestinal tract, prognosis of which largely depends upon histopathologic characteristics of resection specimens, which were not widely studied in our population. Therefore we aimed to evaluate the histopathologic characteristics of GISTs in our population and their prognostic grouping according to college of American pathologist's guidelines. RESULTS: Mean age of patients was 53.4 years (18-71 years). 92% of cases were of primary GISTs and stomach was the most common site (57.7%). 75% of cases were of spindle cell morphology and 53.8% belonged to high risk prognostic group. Comparison of stomach and intestinal GISTs showed that intestinal GISTs were found to be of high grade (70%) and of high risk prognostic group (75 and 80%) compared to stomach GISTs (43% were of high risk prognostic group), however this finding was not statistically significant. GISTs are infrequent gastrointestinal tumors but early diagnosis and identification of adverse histological features are key to successful treatment. We found a large majority of GISTs to be located in stomach, however intestinal GISTs were found more likely to be associated with adverse prognostic parameters. However more large scale studies are warranted to establish this finding. PMID- 29996919 TI - Antiproliferative and proapoptotic effects of DODAC/synthetic phosphoethanolamine on hepatocellular carcinoma cells. AB - BACKGROUND: Current studies have demonstrated that DODAC/PHO-S (Dioctadecyldimethylammonium Chloride/Synthetic phosphoethanolamine) liposomes induces cytotoxicity in Hepa1c1c7 and B16F10 murine tumor cells, with a higher proportion than PHO-S. Therefore, our aim was to evaluate the potential of DODAC/PHO-S to elucidate the mechanism of cell death whereby the liposomes induces cytotoxicity in hepatocellular carcinoma Hepa1c1c7, compared to the PHO-S alone. METHODS: Liposomes (DODAC/PHO-S) were prepared by ultrasonication. The cell cycle phases, protein expression and types of cell's death on Hepa1c1c7 were analyzed by flow cytometry. The internalisation of liposomes, mitochondrial electrical potential and lysosomal stability were also evaluated by confocal laser scanning microscopy. RESULTS: After treatment with liposomes (DODAC/PHO-S), we observed a significant increase in the population of Hepa1c1c7 cells experiencing cell cycle arrest in the S and G2/M phases, and this treatment was significantly more effective to promote cell death by apoptosis. There also was a decrease in the mitochondrial electrical potential; changes in the lysosomes; nuclear fragmentation and catastrophic changes in Hepa1c1c7 cells. The liposomes additionally promoted increases in the expression of DR4 receptor, caspases 3 and 8, cytochrome c, p53, p21, p27 and Bax. There was also a decrease in the expression of Bcl-2, cyclin D1, CD90 and CD44 proteins. CONCLUSION: The overall results showed that DODAC/PHO-S liposomes were more effective than PHO-S alone, in promoting cytotoxicity Hepa1c1c7 tumor cells, activating the intrinsic and extrinsic pathways of programmed cell death. PMID- 29996920 TI - A prospective cohort study assessing the clinical utility of the Cottle maneuver in nasal septal surgery. AB - BACKGROUND: A nasal septal deviation can have a significant detrimental effect on a patient's quality of life. Nasal valve collapse (NVC) often co-exists with a septal deviation. The Cottle maneuver is one of the most common methods to diagnose NVC; however, no study has assessed the efficacy of this physical exam finding. This study tests the hypothesis that patients with nasal obstruction due to a septal deviation with a negative pre-operative Cottle maneuver will demonstrate a greater improvement in their Nasal Obstruction Symptom Evaluation (NOSE) score, compared to patients who demonstrate a positive pre-operative Cottle maneuver, when assessed at 12 months following a septoplasty with turbinate diathermy. METHODS: This was a prospective Cohort Study. The population was 141 patients with nasal obstruction due to a septal deviation with or without nasal valve collapse, excluding patients with bilateral complete nasal valve collapse. Patients were placed in cohorts according to the results of the Cottle maneuver (positive or negative). A NOSE questionnaire was administered at baseline and 12-months after a septoplasty with turbinate diathermy. Non-adjusted NOSE scores were used (score out of 20). An ANOVA was used to compare if there was a difference in outcomes between patient cohorts. RESULTS: One hundred and forty-one patients completed 12-month follow-up with 71.5% of patients demonstrating a positive Cottle maneuver at baseline. The mean (95% C.I.) difference in NOSE score at 12 months between patients with a positive Cottle versus a negative Cottle was 0.18 (- 1.6 to 1.92; p = 0.38). CONCLUSION: In a univariate, single surgeon study, a positive Cottle Maneuver does not appear to influence outcomes in the described patient population compared to those with a negative Cottle Maneuver when undergoing a septoplasty. PMID- 29996921 TI - Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a rare but deadly form of thyroid cancer. Kinase inhibitors kinase inhibitors have shown clinical efficacy in the management of ATC, however, eventually these tumors acquire resistance to KI and patients succumb to their disease. Salvage therapy in this setting is limited. As ATC tumors diffusely express the programmed cell death protein ligand (PD-L1), anti- programmed cell death protein (PD-1) drugs such as pembrolizumab offer therapeutic potential. We sought to explore the efficacy of adding pembrolizumab to kinase inhibitors at progression in ATC. METHODS: We retrospectively reviewed the charts of ATC patients initiated on pembrolizumab in combination with KI at the time of progression on kinase inhibitors at MD Anderson Cancer Center between August 2016 and August 2017. Efficacy was evaluated with best overall response (BOR) using RECISTv1.1 criteria. Progression free survival (PFS) from the start of pembrolizumab and overall survival (OS) from the start of kinase inhibitors, as well as from the time of addition of pembrolizumab were calculated. RESULTS: Twelve patients were treated with combination kinase inhibitors plus pembrolizumab at the time of progression on their KI therapy. Median age at initiation of pembrolizumab was 60 years (range 47-84 years). BOR was as follows: 5/12 (42%) had partial response, 4/12 (33%) had stable disease and 3/12 (25%) had progressive disease. Median OS from the start of kinase inhibitor was 10.43 months (95% CI = 6.02, 14.83, range 5.4-40 months). Median OS and PFS from the addition of pembrolizumab were 6.93 months (95% CI = 1.7, 12.15, range 3-15.9 months) and 2.96 months (95% CI = 2.2, 3.7, range 0.57 13.14 months), respectively. Fatigue, anemia and hypertension were the most common AEs encountered on these combinations. Therapy had to be discontinued in 2 patients due to drug induced rash and altered mental status likely from progression of disease. CONCLUSION: In a subset of ATC patients, pembrolizumab may be an effective salvage therapy added to kinase inhibitors at the time of progression on these drugs. However, better treatment strategies aimed at incorporating immunotherapy in patients with ATC should be explored. Frontline combination of KI with immunotherapy should be studied in prospective clinical trials. PMID- 29996922 TI - Gout prevalence and predictors of urate-lowering therapy use: results from a population-based study. AB - BACKGROUND: Gout has an increasing global prevalence. Underutilization of urate lowering therapy (ULT) is thought to be common, via both suboptimal dosing and poor medication adherence. The aims of this study were to determine the prevalence of self-reported gout and the key predictors of ULT use in those with gout in a representative population survey in South Australia. METHODS: Data were obtained from the Spring 2015 South Australian Health Omnibus Survey, a multilevel, systematic, survey in a representative population sample involving face-to-face interviews (n = 3005). This study analyzed responses from respondents aged >= 25 years (n = 2531) about self-reported gout, ULT use, sociodemographic factors, lifestyle factors, and comorbidities, using survey weighting. Univariate and subsequent adjusted logistic regression analyses on self-reported gout were performed. ULT use was divided into three categories (never use, prior use, and current use) and these data were analyzed using a multinomial logistic regression model. RESULTS: Self-reported gout prevalence was 6.8% (95% CI 5.8, 7.9). The mean age of respondents with gout was 64 years (standard deviation 16) and 82% were male. As expected, older age, male gender, lower socioeconomic status (SES), and higher body mass index (BMI) were associated with gout, as were high alcohol consumption, current smoking, other forms of arthritis, and hypertension or hypercholesterolemia medication, after adjustment for sociodemographic variables. Two thirds of respondents with gout reported ULT use (36% current; 29% previous) with only 55% continuing treatment. Predictors of ULT use included male gender, low SES, and concomitant cholesterol lowering therapy. Respondents with gout with a higher BMI were more likely to remain on ULT. CONCLUSIONS: Despite gout being a common, potentially disabling joint disease, only 55% of respondents with gout in this study adhered to ULT. Identification of key predictors of ULT use will provide guidance on prescribing strategy in clinical practice and on the quality of gout care in the community. PMID- 29996923 TI - Simpler intake estimation using direct observation in small ruminants: grouping bites by plant structure and morphology. AB - OBJECTIVE: To validate the estimation of dry matter intake (DMI) obtained from bite categories (BC) and weight for every plant species (method 1: M1) vs. an alternative method (method 2: M2) grouping plants based on structure and leaf morphology. A dataset containing 80,813 bites and 33 plant species obtained by M1 for sheep and goats browsing a tropical forest was used. Plant species and their respective bite weight were regrouped according to M2. BC weights within each morphological group were compared using ANOVA and post hoc Tukey's honest significant difference comparisons. DMI was estimated for sheep, goats and DMI obtained with both approaches was compared using the t-test, Pearson correlation and orthogonal regression analyses. RESULTS: Dry matter intake estimations were: M1 = 369 +/- 153 vs. M2 = 425 +/- 161 gDM for sheep and M1 = 567 +/- 190 vs. M2 = 681 +/- 203 gDM for goats. DMI estimations by M1 and M2 were similar and strongly correlated. Orthogonal regression showed both procedures yielded a similar DMI estimation (P < 0.001). M2 reduces the amount of work required to estimate DMI in heterogeneous vegetation without reducing accuracy. M2 reduced the time required and made simpler to include data from larger number of animals/replicates. PMID- 29996924 TI - Measurement approaches in continuum of care for maternal health: a critical interpretive synthesis of evidence from LMICs and its implications for the South African context. AB - BACKGROUND: Global strategies recommend a continuum of care for maternal health to improve outcomes and access to care in low and middle income countries (LMICs). South Africa has already set priority interventions along the continuum of care for maternal health, and mandated their implementation at the district health level. However, the approach for monitoring access to this continuum of care has not yet been defined. This review assessed measurement approaches in continuum of care for maternal health among LMICs and their implications for the South African context. METHODS: We conducted a critical interpretive synthesis of quantitative and qualitative research sourced from Academic Search Complete (EBSCO), MEDLINE (Pubmed), Cambridge Journals Online, Credo Reference and Science Direct. We selected 20 out of 118 articles into the analysis, following a rigorous quality appraisal and relevance assessment. The outcomes of the synthesis were new constructs for the measurement of continuum of care for maternal health, derived from the existing knowledge gaps. RESULTS: We learned that coverage was the main approach for measuring and monitoring the continuum of care for maternal health in LMICs. The measure of effective coverage was also used to integrate quality into coverage of care. Like coverage, there was no uniform definition of effective coverage, and we observed gaps in the measurement of multiple dimensions of quality. From the evidence, we derived a new construct called adequacy that incorporated timeliness of care, coverage, and the complex nature of quality. We described the implications of adequacy to the measurement of the continuum of care for maternal health in South Africa. CONCLUSIONS: Critical interpretive synthesis allowed new understandings of measurement of the continuum of care for maternal health in South Africa. The new construct of adequacy can be the basis of a new measure of access to the continuum of care for maternal health. Although adequacy conceptualizes a more holistic approach, more research is needed to derive its indicators and metrics using South African data sources. PMID- 29996926 TI - Delayed diagnosis of spontaneous bladder rupture: a rare case report. AB - BACKGROUND: Bladder rupture caused by trauma or pelvic fracture is very common, and can be easily diagnosed. However, Spontaneous rupture of the bladder is rare. Reported by Peters PC. (Peters, Urol Clin N Am 16:279-82, 1989): The incidence of spontaneous bladder rupture is 1: 126000. During childbirth, the occurrence rate of this disease is lower than that of the former. It is very difficult to make an early diagnosis of the spontaneous rupture of the bladder during childbirth, which eventually results in high maternal mortality. Due to peritoneal reabsorption, the patient may show high levels of serum creatinine and potassium, and this would easily be misdiagnosed as acute renal failure. However, these patients have normal renal function, hence the diagnosis of renal failure is incorrect. CASE PRESENTATION: A 23 year-old female patient had her first pregnancy and delivered a full-term healthy baby girl. After delivery, the patient developed fever, oliguria, massive ascites, high serum creatinine and high serum potassium. The patient was initially diagnosed with acute renal failure, however treatment for her condition was ineffective. After further examination, the patient was diagnosed with intraperitoneal bladder rupture. The patient was treated for bladder rupture, made a full recovery and was discharged. CONCLUSIONS: Sudden onset of massive ascites and renal failure due to abnormal serum biochemical characteristics after delivery should be first diagnosed as spontaneous bladder rupture. However, bladder radiography may suggest a false negative result, hence cystoscopy should be performed to confirm the diagnosis. The ratio between ascites creatinine and serum creatinine would be helpful for early diagnosis and to determine the time of rupture. Conservative management or surgical repair should be used to treat bladder rupture. PMID- 29996925 TI - Radiographs in screening for sacroiliitis in children: what is the value? AB - BACKGROUND: We aimed to evaluate the diagnostic utility of pelvic radiographs versus magnetic resonance imaging (MRI) of the sacroiliac joints in children with suspected sacroiliitis. METHODS: This was a retrospective cross-sectional study of children with suspected or confirmed spondyloarthritis who underwent pelvic radiograph and MRI within 6 months of one another. Images were scored independently by five raters. Interrater reliability was calculated using Fleiss's kappa coefficient (kappa). Test properties of radiographs for depiction of sacroiliitis were calculated using MRI global sacroiliitis impression as the reference standard. RESULTS: The interrater agreement for global impression was kappa = 0.34 (95% CI 0.19-0.52) for radiographs and kappa = 0.72 (95% CI 0.52 0.86) for MRI. Across raters, the sensitivity of radiographs ranged from 25 to 77.8% and specificity ranged from 60.8 to 92.2%. Positive and negative predictive values ranged from 25.9 to 52% and from 82.7 to 93.9%, respectively. The misclassification rate ranged from 6 to 17% for negative radiographs/positive MRI scans and from 48 to 74% for positive radiographs/negative MRI scans. When the reference standard was changed to structural lesions consistent with sacroiliitis on MRI, the misclassification rate was higher for negative radiographs/positive MRI scans (9-23%) and marginally improved for positive radiographs/negative MRI scans (33-52%). CONCLUSION: Interrater reliability of MRI was superior to radiographs for global sacroiliitis impression. Misclassification for both negative and positive radiographs was high across raters. Radiographs have limited utility in screening for sacroiliitis in children and result in a significant proportion of both false negative and positive findings versus MRI findings. PMID- 29996927 TI - Prevalence of anti-hepatitis C antibodies and its co-infection with HIV in rural Cameroon. AB - OBJECTIVE: To evaluate the prevalence of the co-infection between the human immunodeficiency virus (HIV) and hepatitis C virus (HCV), and the prevalence of factors associated with HCV transmission in a rural Cameroonian community. RESULTS: The mean age of the 174 participants included in the study was 30.3 (standard deviation = 13.26) years (age range 12-77 years). the prevalence of HCV/HIV co-infection was 1.7% [95% confidence interval (CI) 1.1-5.9]. The prevalence of HCV and HIV were 6.3% (95% CI 2.9-10.3) and 6.9 (95% CI 5.2-11.3), respectively. Histories of scarification (62.1%), multiple sex partners (31.0%) and sexually transmitted diseases (66.1%) were the most common risk factors of HCV transmission in this study. PMID- 29996929 TI - Persistence rates and medical costs of biological therapies for psoriasis treatment in Japan: a real-world data study using a claims database. AB - BACKGROUND: Biological therapies (BTs) including infliximab (IFX), adalimumab (ADL), secukinumab (SCK) and ustekinumab (UST) are approved in Japan for the treatment of psoriasis. Although the persistence rates and medical costs of BTs treatment have been investigated in multiple foreign studies in recent years, few such studies have been conducted in Japan and the differences between patients who adhered to treatment and those who did not have not been reported. This study is aimed at investigating the persistence rates and medical costs of BTs in the treatment of psoriasis in Japan, using the real-world data from a large-scale claims database. METHODS: Claims data from the JMDC database (August 2009 to December 2016) were used for this analysis. Patient data were extracted using the ICD10 code for psoriasis and claims records of BT injections. Twelve-month and 24 month persistence rates of BTs were estimated by Kaplan-Meier methodology, and 12 month-medical costs before and after BT initiation were compared between persistent and non-persistent patient groups at 12 months. RESULTS: A total of 205 psoriasis patients treated with BTs (BT-naive patients: 177) were identified. The 12-month/24-month persistence rates for ADL, IFX, SCK, and UST in BT-naive patients were 46.8% +/- 16.6%/46.8 +/- 16.6%, 53.0% +/- 14.9%/41.0% +/- 15.5%, 55.4%/55.4% (95% CI not available) and 79.4% +/- 9.9%/71.9% +/- 12.2%, respectively. Statistically significant differences in persistence were found among different BT treatments, and UST was found to have the highest persistence rate. The total medical costs during the 12 months after BT initiation in BT naive patients were (in 1000 Japanese Yen): 2218 for ADL, 3409 for IFX, 465 for SCK, 2824 for UST (average: 2828). Compared with the 12-month persistent patient group, the total medical costs in the persistent group was higher (Delta:+ 118), but for some medications such as IFX or UST cost increases were lower for persistent patients. CONCLUSIONS: UST was found to have the highest persistence rate among all BTs for psoriasis treatment in Japan. The 12-month medical costs after BT initiation in the persistent patient group may not have increased as much as in the non-persistent patient group for some medications. PMID- 29996930 TI - Patterns of leisure-time physical activity across pregnancy and adverse pregnancy outcomes. AB - BACKGROUND: Although leisure-time physical activity (PA) contributes to overall health, including pregnancy health, patterns across pregnancy have not been related to birth outcomes. We hypothesized that women with sustained low leisure time PA would have excess risk of adverse pregnancy outcomes, and that changing patterns across pregnancy (high to low and low to high) may also be related to risk of adverse pregnancy outcomes. METHODS: Nulliparous women (n = 10,038) were enrolled at 8 centers early in pregnancy (mean gestational age in weeks [SD] = 12.05 [1.51]. Frequency, duration, and intensity (metabolic equivalents) of up to three leisure activities reported in the first, second and third trimesters were analyzed. Growth mixture modeling was used to identify leisure-time PA patterns across pregnancy. Adverse pregnancy outcomes (preterm birth, [PTB, overall and spontaneous], hypertensive disorders of pregnancy [HDP], gestational diabetes [GDM] and small-for-gestational-age births [SGA]) were assessed via chart abstraction. RESULTS: Five patterns of leisure-time PA across pregnancy were identified: High (35%), low (18%), late decreasing (24%), early decreasing (10%), and early increasing (13%). Women with sustained low leisure-time PA were younger and more likely to be black or Hispanic, obese, or to have smoked prior to pregnancy. Women with low vs. high leisure-time PA patterns had higher rates of PTB (10.4 vs. 7.5), HDP (13.9 vs. 11.4), and GDM (5.7 vs. 3.1, all p < 0.05). After adjusting for maternal factors (age, race/ethnicity, BMI and smoking), the risk of GDM (Odds ratio 2.00 [95% CI 1.47, 2.73]) remained higher in women with low compared to high patterns. Early and late decreasing leisure-time PA patterns were also associated with higher rates of GDM. In contrast, women with early increasing patterns had rates of GDM similar to the group with high leisure-time PA (3.8% vs. 3.1%, adjusted OR 1.16 [0.81, 1.68]). Adjusted risk of overall PTB (1.31 [1.05, 1.63]) was higher in the low pattern group, but spontaneous PTB, HDP and SGA were not associated with leisure-time PA patterns. CONCLUSIONS: Sustained low leisure-time PA across pregnancy is associated with excess risk of GDM and overall PTB compared to high patterns in nulliparous women. Women with increased leisure-time PA early in pregnancy had low rates of GDM that were similar to women with high patterns, raising the possibility that early pregnancy increases in activity may be associated with improved pregnancy health. TRIAL REGISTRATION: Registration number NCT02231398 . PMID- 29996931 TI - Development and validation of the pulmonary tuberculosis scale of the system of Quality of Life Instruments for Chronic Diseases (QLICD-PT). AB - BACKGROUND: Generic assessments are less responsive to subtle changes due to specific diseases, making it challenging to fully understand the impact of pulmonary tuberculosis (TB) on patient's quality of life (QOL). METHODS: We applied programmed decision procedures and theories on instrument development to develop the scale. Two hundred patients with pulmonary TB participated in measuring QOL three times before and after treatments. We assessed the validity, reliability, and responsiveness of QLICD-PT using correlation analysis, factor analysis, multi-trait scaling analysis, randomized block analyses of variance with Least Significant Difference post-hoc tests. RESULTS: We composed QLICD-PT with 3 domains (28 items) for general QOL and 1 pulmonary TB specific domain (12 items). Correlation and factor analysis confirmed good structure validity and criterion-related validity when using Chinese version of the Medical Outcomes Short-Form Health Survey (SF-36) as a criterion. The internal consistency of alpha values were higher than 0.70. The score changes after treatment were of statistical significance for the overall scale, physical domain and specific domain with effect size ranging from 0.32 to 0.72. No floor effects but small ceiling effects were observed at domain level. CONCLUSIONS: As the first pulmonary TB-specific QOL scale developed by a module approach in Chinese, QLICD PT has an acceptable degree of validity, reliability and responsiveness, and can be used to measure the life quality of PT patients specifically and sufficiently. PMID- 29996928 TI - Engaging primary care professionals in collaborative processes for optimising type 2 diabetes prevention practice: the PREDIAPS cluster randomised type II hybrid implementation trial. AB - BACKGROUND: There is a lack of evidence concerning the effectiveness of different strategies to engage healthcare professionals in collaborative processes that seek to optimise clinical practice. The PREDIAPS project aims to assess the effect of different primary health care (PHC) providers' engagement procedures in the creation and execution of a facilitated interprofessional collaborative process to optimise the integration of the recommended clinical practice for the prevention of type-2 diabetes (T2D) in routine PHC. METHODS: This will be a randomised cluster type II hybrid implementation trial. Nine PHC centres from the Basque Health Service (Osakidetza) will be allocated to two different procedures to engage family doctors and nurses and create an interprofessional collaborative practice to optimise the integration of a T2D primary prevention programme. All centres and PHC professionals will receive training on current guidelines in primary prevention of T2D and effective interventions to promote healthy lifestyles. Headed by a local leader and an external facilitator, centres will conduct a collaborative structured process to model and adapt the intervention and its implementation to the specific context of professionals and centres. One of the groups will apply this strategy globally, promoting the cooperation of all health professionals from the beginning. The other will perform it sequentially, centred first on nurses, who will then seek the pragmatic cooperation of doctors. All patients without diabetes aged >= 30 years old who attend collaborating centres at least once during the study period and found to be at high risk of developing T2D will be eligible for programme inclusion. The main outcome measures focus on changes observed in indicators of T2D prevention clinical practice at centre level after 12 and 24 months, associated with the application of one or other engagement procedure. Secondary outcomes will compare their clinical effectiveness in changing eligible exposed patients' main lifestyle behaviours and risk factors (physical activity and diet, weight, etc.) after 12 months. DISCUSSION: The PREDIAPS project will generate scientific knowledge on procedures for engaging PHC professional to facilitate feasible and effective adoption of proven interventions for the prevention of T2D in routine clinical practice through the application of implementation strategies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03254979 . Registered 16 August 2017. PMID- 29996932 TI - A novel, percutaneous, self-expanding, forceful reduction screw system for the treatment of thoracolumbar fracture with severe vertebral height loss. AB - BACKGROUND: Over the past decade, the techniques for minimally invasive spinal stabilization have improved significantly. The multiaxial screw utilized in minimally invasive operations is limited in restoring fracture height, reconstructing the anterior vertebral column, and improving kyphosis. Therefore, the percutaneous, minimally invasive approach is not recommended for a thoracolumbar fracture with severe vertebral height loss. We report our novel, percutaneous, self-expanding, forceful reduction screw system to address this problem. METHODS: Thirty-eight patients experiencing thoracolumbar fracture, with a vertebral height loss more than 50%, were treated with the novel, percutaneous, self-expanding, forceful reduction screw between March 2014 and June 2015. The patients' charts and radiographs were reviewed. The vertebral body index (VBI), height of the anterior margin of fractured vertebra (HAMFV), vertebral body angle (VBA), bisegmental Cobb angle (BCA), and Oswestry disability index (ODI) scores were obtained before and after the operation, as well as during the 2-year follow up. The scoring results were compared using t tests. RESULTS: The operation was completed successfully in 38 patients. A total of 152 screws were placed. The average operation time was 90.7 +/- 21.9 min, and the average intraoperative bleeding amount was 89.2 +/- 31.9 ml. The patients were discharged at a mean of 3.2 +/- 0.9 postoperative days, with a mean hospital stay of 4.8 +/- 1.0 days. The VBI, HAMFV, VBA, and BCA scores were significantly improved after treatment with the novel screw system; there was a significant difference between pre- and postoperative parameters (p < 0.05). Although the decreases in all of the parameters were variable during the 2-year follow-up, there were no statistical differences between the postoperative imaging parameters and the last follow-up imaging parameters (p > 0.05). The ODI score at the last follow-up examination was 5.9 +/- 2.7, which was significantly improved compared with the preoperative score of 44.6 +/- 2.3 (p < 0.05). CONCLUSIONS: We believe that the novel, percutaneous, self-expanding, forceful reduction screw system developed by us not only successfully expands the minimally invasive percutaneous surgery to the thoracolumbar fracture with severe vertebral height loss but also achieves significant vertebral height restoration and kyphosis correction. PMID- 29996933 TI - Personalised relaxation practice to improve sleep and functioning in patients with chronic fatigue syndrome and depression: study protocol for a randomised controlled trial. AB - BACKGROUND: Chronic fatigue syndrome (CFS) and major depressive disorder (MDD) are both debilitating but heterogeneous conditions sharing core features of fatigue, unrefreshing sleep, and impaired functioning. The aetiology of these conditions is not fully understood, and 'best-practice' treatments are only moderately effective in relieving symptoms. Unrecognised individual differences in the response to such treatments are likely to underlie poor treatment outcomes. METHODS/DESIGN: We are undertaking a two-group, parallel, randomised controlled trial (RCT) comparing the effects of a personalised relaxation intervention on sleep quality, daytime symptoms, and functioning in patients with CFS (n = 64) and MDD (n = 64). Following identification of the method that best enhances autonomic responding (such as heart rate variability), participants randomised to the active intervention will practise their recommended method nightly for 4 weeks. All participants will keep a sleep diary and monitor symptoms during the trial period, and they will complete two face-to-face assessments, one at baseline and one at 4 weeks, and a further online assessment to evaluate lasting effects of the intervention at 2 months. Assessments include self-report measures of sleep, wellbeing, and function and monitoring of autonomic responses at rest, in response to the relaxation method and during nocturnal sleep. Treatment outcomes will be analysed using linear mixed modelling. DISCUSSION: This is the first RCT examining the effects of a personalised relaxation intervention, pre-tested to maximise the autonomic relaxation response, in patients with unrefreshing sleep and fatigue attributed to CFS or MDD. Detailed monitoring of sleep quality and symptoms will enable sensitive detection of improvements in the core symptoms of these debilitating conditions. In addition, repeated monitoring of autonomic functioning can elucidate mechanisms underlying potential benefits. The findings have translational potential, informing novel, personalised symptom management techniques for these conditions, with the potential for better clinical outcomes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ANZCTR), ACTRN12616001671459 . Registered on 5 December 2016. PMID- 29996935 TI - ETV4 transcription factor and MMP13 metalloprotease are interplaying actors of breast tumorigenesis. AB - BACKGROUND: The ETS transcription factor ETV4 is involved in the main steps of organogenesis and is also a significant mediator of tumorigenesis and metastasis, such as in breast cancer. Indeed, ETV4 is overexpressed in breast tumors and is associated with distant metastasis and poor prognosis. However, the cellular and molecular events regulated by this factor are still misunderstood. In mammary epithelial cells, ETV4 controls the expression of many genes, MMP13 among them. The aim of this study was to understand the function of MMP13 during ETV4-driven tumorigenesis. METHODS: Different constructs of the MMP13 gene promoter were used to study the direct regulation of MMP13 by ETV4. Moreover, cell proliferation, migration, invasion, anchorage-independent growth, and in vivo tumorigenicity were assayed using models of mammary epithelial and cancer cells in which the expression of MMP13 and/or ETV4 is modulated. Importantly, the expression of MMP13 and ETV4 messenger RNA was characterized in 456 breast cancer samples. RESULTS: Our results revealed that ETV4 promotes proliferation, migration, invasion, and anchorage-independent growth of the MMT mouse mammary tumorigenic cell line. By investigating molecular events downstream of ETV4, we found that MMP13, an extracellular metalloprotease, was an ETV4 target gene. By overexpressing or repressing MMP13, we showed that this metalloprotease contributes to proliferation, migration, and anchorage-independent clonogenicity. Furthermore, we demonstrated that MMP13 inhibition disturbs proliferation, migration, and invasion induced by ETV4 and participates to ETV4-induced tumor formation in immunodeficient mice. Finally, ETV4 and MMP13 co-overexpression is associated with poor prognosis in breast cancer. CONCLUSION: MMP13 potentiates the effects of the ETV4 oncogene during breast cancer genesis and progression. PMID- 29996936 TI - Interprofessional team member's satisfaction: a mixed methods study of a Chilean hospital. AB - INTRODUCTION: The health organizations of today are highly complex and specialized. Given this scenario, there is a need for health professionals to work collaboratively within interprofessional work teams to ensure quality and safe care. To strengthen interprofessional teamwork, it is imperative that health organizations enhance strategic human resources management by promoting team member satisfaction. OBJECTIVE: To analyze the satisfaction of members in interprofessional teams and to explore interpersonal relationships, leadership, and team climate in a hospital context. METHODOLOGY: This study is an explanatory sequential mixed methods (quantitative/qualitative) study of 53 teams (409 professionals) at a university hospital in Santiago, Chile. The first phase involved quantitative surveys with team members examining team satisfaction, transformational leadership, and team climate. Social network analysis was used to identify interactions among team members (cohesion and centrality). The second phase involved interviews with 15 professionals belonging to teams with the highest and lowest team satisfaction scores. Findings of both phases were integrated. RESULTS: Significant associations were found among variables, and the linear regression model showed that team climate (beta = 0.26) was a better predictor of team satisfaction than team leadership (beta = 0.17). Registered nurse was perceived as the profession with the highest score on the transformational leadership measure (mean = 64), followed by the physician (mean = 33). Team networks with the highest and lowest score of team satisfaction showed differences in cohesion and centrality measures. Analysis of interviews identified five themes: attributes of interprofessional work; collaboration, communication, and social interaction; interprofessional team innovation; shared leadership; and interpersonal relationship interface work/social. Integration of findings revealed that team member satisfaction requires participation and communication, common goals and commitment for patient-centered care, clear roles and objectives to support collaborative work, and the presence of a transformational leader to strengthen well-being, dialog, and innovation. CONCLUSIONS: Results have the potential to contribute to the planning and decision-making in the field of human resources, providing elements to promote the management of health teams and support team member satisfaction. In turn, this could lead to job permanence especially where the local health needs are more urgent. PMID- 29996937 TI - Superimposed visceral leishmanial infection aggravates response to Heligmosomoides polygyrus. AB - BACKGROUND: Polyparasitism is the rule in all animal species, including humans, and has an important role in pathogenicity, diagnosis and control measures. Among them, co-infections by gastrointestinal helminths and protists are very prevalent under natural conditions but experimental infections are relatively scarce. Thus, despite the frequent association of visceral Leishmania infections and intestinal helminth parasitism the experimental co-infection has not been addressed. Heligmosomoides polygyrus, an intestinal nematode of mice, is related to other helminths causing important pathologies and is a model species for immunological studies. Mice are valuable experimental model for visceral leishmaniasis. METHODS: BALB/c mice infected with H. polygyrus (200 third-stage larvae, L3) were subsequently infected seven days later with Leishmania infantum (107 promastigotes) with the aim of determining the effect of the overinfection on the host response to the primary infection with the helminth. RESULTS: Overinfection with the protist did not affect the establishment rate of the nematode but induced a higher fecal egg output. Helminth burdens in co-infected animals were significant at the end of the experiment. Early unspecific immune suppression induced by the nematode in mesenteric lymph nodes was not switched by L. infantum infection. Co-infection elicited a higher serum antibody (IgG1) response against the helminth. CONCLUSIONS: Visceral leishmanial overinfection aggravated the early host response against primary infections with the intestinal helminth. This effect was evidenced by an increased longevity and higher production of non protective antibodies. PMID- 29996938 TI - Exosomes derived from human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis. AB - Exosomes are nano-sized vesicles (30-200 nm) constantly released by almost all cells. The ability of exosomes to travel between cells and deliver their cargo, which includes lipids, proteins, and nucleic acids, makes them an appealing cell free therapy option to treat multiple diseases. Here, we investigated for the first time whether human adipose tissue-derived mesenchymal stem cell-derived exosomes (ASC-exosomes) can ameliorate atopic dermatitis (AD) in an in vivo mouse model. When injected either intravenously (IV) or subcutaneously (SC) into NC/Nga mice treated with house dust mite antigens, ASC-exosomes were found to reduce pathological symptoms such as clinical score, the levels of serum IgE, the number of eosinophils in blood, and the infiltration of mast cells, CD86+, and CD206+ cells in skin lesions. ASC-exosomes also significantly reduced mRNA expression of various inflammatory cytokines such as interleukin (IL)-4, IL-23, IL-31, and tumor necrosis factor-alpha (TNF-alpha) in AD skin lesions of Nc/Nga mice. Taken together, these results suggest that ASC-exosomes can be a novel promising cell free therapeutic modality for AD treatment. PMID- 29996939 TI - A mathematical model relates intracellular TLR4 oscillations to sepsis progression. AB - OBJECTIVE: Oscillations of physiological parameters describe many biological processes and their modulation is determinant for various pathologies. In sepsis, toll-like receptor 4 (TLR4) is a key sensor for signaling the presence of Gram negative bacteria. Its intracellular trafficking rates shift the equilibrium between the pro- and anti-inflammatory downstream signaling cascades, leading to either the physiological resolution of the bacterial stimulation or to sepsis. This study aimed to evaluate the effects of TLR4 increased expression and intracellular trafficking on the course and outcome of sepsis. RESULTS: Using a set of three differential equations, we defined the TLR4 fluxes between relevant cell organelles. We obtained three different regions in the phase space: (1) a limit-cycle describing unstimulated physiological oscillations, (2) a fixed-point attractor resulting from moderate LPS stimulation that is resolved and (3) a double-attractor resulting from sustained LPS stimulation that leads to sepsis. We used this model to describe available hospital data of sepsis patients and we correctly characterize the clinical outcome of these patients. PMID- 29996940 TI - Simultaneous E-cadherin and PLEKHA7 expression negatively affects E-cadherin/EGFR mediated ovarian cancer cell growth. AB - BACKGROUND: The disruption of E-cadherin-mediated adhesion is considered an important driver of tumor progression. Nevertheless, numerous studies have demonstrated that E-cadherin promotes growth- or invasion-related signaling, contrary to the prevailing notion. During tumor progression, epithelial ovarian cancer (EOC) maintains E-cadherin expression and can positively affect EOC cell growth by contributing to PI3K/AKT activation. In polarized epithelia PLEKHA7, a regulator of the zonula adherens integrity, impinges E-cadherin functionality, but its role in EOCs has been never studied. METHODS: Ex-vivo EOC cells and cell lines were used to study E-cadherin contribution to growth and EGFR activation. The expression of the proteins involved was assessed by real time RT-PCR, immunohistochemistry and western blotting. Cells growth and drug susceptibility was monitored in different 3-dimensional (3D) systems. Recombinant lentivirus mediated gene expression, western blotting, immunoprecipitation and confocal microscopy were applied to investigate the biological impact of PLEKHA7 on E cadherin behaviour. The clinical impact of PLEKHA7 was determined in publicly available datasets. RESULTS: We show that E-cadherin expression contributes to growth of EOC cells and forms a complex with EGFR thus positively affecting ligand-dependent EGFR/CDK5 signaling. Accordingly, 3D cultures of E-cadherin expressing EOC cells are sensitive to the CDK5 inhibitor roscovitine combined with cisplatin. We determined that PLEKHA7 overexpression reduces the formation of E-cadherin-EGFR complex, EGFR activation and cell tumorigenicity. Clinically, PLEKHA7 mRNA is statistically decreased in high grade EOCs respect to low malignant potential and low grade EOCs and correlates with better EOC patient outcome. CONCLUSIONS: These data represent a significant step towards untangling the role of E-cadherin in EOCs by assessing its positive effects on EGFR/CDK5 signaling and its contribution to cell growth. Hence, the inhibition of this signaling using a CDK5 inhibitor exerts a synergistic effect with cisplatin prompting on the design of new therapeutic strategies to inhibit growth of EOC cells. We assessed for the first time in EOC cells that PLEKHA7 induces changes in the asset of E-cadherin-containing cell-cell contacts thus inhibiting E cadherin/EGFR crosstalk and leading to a less aggressive tumor phenotype. Accordingly, PLEKHA7 levels are lower in high grade EOC patient tumors and EOC patients with better outcomes display higher PLEKHA7 levels. PMID- 29996941 TI - Effects of lung and airway epithelial maturation cocktail on the structure of lung bud organoids. AB - Organoids from human pluripotent stem cells are becoming suitable models for studies of organ development, drug screening, regenerative medicine, and disease modeling. Three-dimensional minilungs in Matrigel culture have recently been generated from human embryonic stem cells. These particular organoids, named lung bud organoids, showed branching airway and early alveolar structures resembling those present in lungs from the second trimester of human gestation. We show here that the treatment of such organoids with a lung and airway epithelial maturation cocktail containing dexamethasone drives lung bud organoids to the formation of paddle-racquet like structures. This strategy may help to increase the versatility of lung organoids and to generate structures more advanced than the original branching texture. PMID- 29996942 TI - SPOP promotes ATF2 ubiquitination and degradation to suppress prostate cancer progression. AB - BACKGROUND: Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alterations. SPOP (Speckle-type POZ Protein) is one of the most frequently mutated genes in primary prostate cancer, suggesting that SPOP may be a potential driver of prostate cancer. The aim of this work was to investigate how SPOP mutations contribute to prostate cancer development and progression. METHODS: To identify molecular mediators of the tumor suppressive function of SPOP, we performed a yeast two-hybrid screen in a HeLa cDNA library using the full-length SPOP as bait. Immunoprecipitation and Western Blotting were used to analyze the interaction between SPOP and ATF2. Cell migration and invasion were determined by Transwell assays. Immunohistochemistry were used to analyze protein levels in patients' tumor samples. RESULTS: Here we identified ATF2 as a bona fide substrate of the SPOP-CUL3-RBX1 E3 ubiquitin ligase complex. SPOP recognizes multiple Ser/Thr (S/T)-rich degrons in ATF2 and triggers ATF2 degradation via the ubiquitin-proteasome pathway. Strikingly, prostate cancer-associated mutants of SPOP are defective in promoting ATF2 degradation in prostate cancer cells and contribute to facilitating prostate cancer cell proliferation, migration and invasion. CONCLUSION: SPOP promotes ATF2 ubiquitination and degradation, and ATF2 is an important mediator of SPOP inactivation-induced cell proliferation, migration and invasion. PMID- 29996943 TI - Lethal outcome of granulomatous acanthamoebic encephalitis in a man who was human immunodeficiency virus-positive: a case report. AB - BACKGROUND: Acanthamoeba species can cause disseminating infections in immunocompromised individuals. CASE PRESENTATION: Here, we report a case of granulomatous acanthamoebic encephalitis with a lethal outcome in a 54-year-old German man who was human immunodeficiency virus-positive. The diagnosis was based on symptoms of progressive neurological deficits, including sensorimotor paralysis of his right leg and deteriorating alertness. Due to the rapid course and rather late diagnosis of the infection, effective treatment could not be applied and he died 12 days after hospital admission. CONCLUSIONS: To the best of our knowledge, this is the second case of granulomatous acanthamoebic encephalitis reported within Germany. Our case highlights the importance of early diagnosis of granulomatous acanthamoebic encephalitis to prevent fatal outcome. PMID- 29996945 TI - Cationic liposomes induce cytotoxicity in HepG2 via regulation of lipid metabolism based on whole-transcriptome sequencing analysis. AB - BACKGROUD: Cationic liposomes (CLs) can be used as non-viral vectors in gene transfer and drug delivery. However, the underlying molecular mechanism of its cytotoxicity has not been well elucidated yet. METHODS: We herein report a systems biology approach based on whole-transcriptome sequencing coupled with computational method to identify the predominant genes and pathways involved in the cytotoxicity of CLs in HepG2 cell line. RESULTS: Firstly, we validated the concentration-dependent cytotoxicity of CLs with an IC50 of 120 MUg/ml in HepG2 exposed for 24 h. Subsequently, we used whole-transcriptome sequencing to identify 220 (77 up- and 143 down-regulated) differentially expressed genes (DEGs). Gene ontology (GO) and pathway analysis showed that these DEGs were mainly related to cholesterol, steroid, lipid biosynthetic and metabolic processes. Additionally, "key regulatory" genes were identified using gene act, pathway act and co-expression network analysis, and expression levels of 11 interested altered genes were confirmed by quantitative real time PCR. Interestingly, no cell cycle arrest was observed through flow cytometry. CONCLUSIONS: These data are expected to provide deep insights into the molecular mechanism of CLs cytotoxicity. PMID- 29996944 TI - Methods for high-dimensonal analysis of cells dissociated from cyropreserved synovial tissue. AB - BACKGROUND: Detailed molecular analyses of cells from rheumatoid arthritis (RA) synovium hold promise in identifying cellular phenotypes that drive tissue pathology and joint damage. The Accelerating Medicines Partnership RA/SLE Network aims to deconstruct autoimmune pathology by examining cells within target tissues through multiple high-dimensional assays. Robust standardized protocols need to be developed before cellular phenotypes at a single cell level can be effectively compared across patient samples. METHODS: Multiple clinical sites collected cryopreserved synovial tissue fragments from arthroplasty and synovial biopsy in a 10% DMSO solution. Mechanical and enzymatic dissociation parameters were optimized for viable cell extraction and surface protein preservation for cell sorting and mass cytometry, as well as for reproducibility in RNA sequencing (RNA seq). Cryopreserved synovial samples were collectively analyzed at a central processing site by a custom-designed and validated 35-marker mass cytometry panel. In parallel, each sample was flow sorted into fibroblast, T-cell, B-cell, and macrophage suspensions for bulk population RNA-seq and plate-based single cell CEL-Seq2 RNA-seq. RESULTS: Upon dissociation, cryopreserved synovial tissue fragments yielded a high frequency of viable cells, comparable to samples undergoing immediate processing. Optimization of synovial tissue dissociation across six clinical collection sites with ~ 30 arthroplasty and ~ 20 biopsy samples yielded a consensus digestion protocol using 100 MUg/ml of LiberaseTM TL enzyme preparation. This protocol yielded immune and stromal cell lineages with preserved surface markers and minimized variability across replicate RNA-seq transcriptomes. Mass cytometry analysis of cells from cryopreserved synovium distinguished diverse fibroblast phenotypes, distinct populations of memory B cells and antibody-secreting cells, and multiple CD4+ and CD8+ T-cell activation states. Bulk RNA-seq of sorted cell populations demonstrated robust separation of synovial lymphocytes, fibroblasts, and macrophages. Single-cell RNA-seq produced transcriptomes of over 1000 genes/cell, including transcripts encoding characteristic lineage markers identified. CONCLUSIONS: We have established a robust protocol to acquire viable cells from cryopreserved synovial tissue with intact transcriptomes and cell surface phenotypes. A centralized pipeline to generate multiple high-dimensional analyses of synovial tissue samples collected across a collaborative network was developed. Integrated analysis of such datasets from large patient cohorts may help define molecular heterogeneity within RA pathology and identify new therapeutic targets and biomarkers. PMID- 29996947 TI - The Post Clinic Ambulatory Blood Pressure (PC-ABP) study correlates Post Clinic Blood Pressure (PCBP) with the gold standard Ambulatory Blood Pressure. AB - OBJECTIVE: Our previous study showed that post-clinic blood pressure (BP) taken 15 min after a physician-patient encounter was the lowest reading in a routine clinic. We aimed to validate this reading with 24 h Ambulatory Blood Pressure Monitoring (ABPM) readings. A cross-sectional study was conducted in the cardiology clinics at the Aga Khan University, Pakistan. Hypertensive patients aged >= 18 years, or those referred for the diagnosis of hypertension were included. RESULTS: Of 150 participants, 49% were males. 76% of all participants were hypertensive. Pre-clinic BP reading was measured by a nurse, in-clinic by a physician and 15 min post-clinic by a research assistant using a validated, automated BP device (Omron-HEM7221-E). All patients were referred for 24 h ABPM. Among the three readings taken during a clinic visit, mean (+/- SD) systolic BP (SBP) pre-clinic, in-clinic, and 15 min post-clinic were 153.2 +/- 23, 152.3 +/- 21, and 140.0 +/- 18 mmHg, respectively. Mean (+/- SD) diastolic BP (DBP) taken pre-clinic, in-clinic and 15 min post-clinic were 83.5 +/- 12, 90.9 +/- 12, and 86.4 +/- 11 mmHg respectively. Mean (+/- SD) daytime ambulatory SBP, DBP and pulse readings were 134.7 +/- 15, 78.7 +/- 15 mmHg, and 72.6 +/- 12/min, respectively. Pearson correlation coefficients of pre-clinic, in-clinic and post clinic SBP with daytime ambulatory-SBP were 0.4 (p value: < 0.001), 0.5 (p value: < 0.001) and 0.6 (p value: < 0.001), respectively. Post-clinic BP has a good correlation with ambulatory BP and may be considered a more reliable reading in the clinic setting. PMID- 29996946 TI - When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance. AB - The role of fatty acid metabolism, including both anabolic and catabolic reactions in cancer has gained increasing attention in recent years. Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis, therapeutic resistance and relapse. Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population. This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations. Therefore, these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters, which are often refractory to cancer treatment and difficult to target. Moreover, interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging. This review highlights recent findings on the relationship between fatty acid metabolism, cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance. PMID- 29996948 TI - Long noncoding RNA expression profile and association with SLEDAI score in monocyte-derived dendritic cells from patients with systematic lupus erythematosus. AB - BACKGROUND: Monocyte-derived dendritic cells (moDCs) play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Aberrant expression of long noncoding RNAs (lncRNAs) could affect the function of moDCs. The aim of this study was to explore the lncRNA expression profile in moDCs of SLE patients to provide new insights into SLE. METHODS: LncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs and mRNAs in moDCs of SLE patients compared with normal controls. Bioinformatics analysis was also performed. Quantitative polymerase chain reaction (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and SLE disease activity index (SLEDAI) scores. RESULTS: According to the gene expression profiles, 163 lncRNAs were differentially expressed between SLE and normal controls, including 118 that were upregulated and 45 that were downregulated. A total of 137 mRNAs were differentially expressed in moDCs of patients with SLE, including 83 that were upregulated and 54 that were downregulated. Furthermore, qPCR data showed that lncRNA ENST00000604411.1 (18.23-fold, P < 0.001) and ENST00000501122.2 (1.96 fold, P < 0.001) were upregulated and the other two lncRNAs, lnc-HSFY2-3:3 (0.42 fold, P < 0.001) and lnc-SERPINB9-1:2 (0.50-fold, P = 0.040), were downregulated in moDCs of SLE patients. The expression levels of ENST00000604411.1 (r = 0.593, P = 0.020) and ENST00000501122.2 (r = 0.539, P = 0.038) were positively correlated with the SLEDAI score, respectively. CONCLUSIONS: The results indicate that the abnormal expression of lncRNAs in moDCs may be involved in the pathological processes of SLE. The expression level of ENST00000604411.1 and ENST00000501122.2 may have potential value for the assessment of disease activity in SLE. PMID- 29996950 TI - Clinical relevance and validity of tools to predict infant, childhood and adulthood obesity: a systematic review. AB - OBJECTIVE: To determine the global availability of a multicomponent tool predicting overweight/obesity in infancy, childhood, adolescence or adulthood; and to compare their predictive validity and clinical relevance.Design/SettingThe PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. The databases PubMed, EMBASE, CINAHL, Web of Science and PsycINFO were searched. Additional articles were identified via reference lists of included articles. Risk of bias was assessed using the Academy of Nutrition and Dietetics' Quality Criteria Checklist. The National Health and Medical Research Council's Levels of Evidence hierarchy was used to assess quality of evidence. Predictive performance was evaluated using the ABCD framework. SUBJECTS: Eligible studies: tool could be administered at any life stage; quantified the risk of overweight/obesity onset; used more than one predictor variable; and reported appropriate prediction statistical outcomes. RESULTS: Of the initial 4490 articles identified, twelve articles (describing twelve tools) were included. Most tools aimed to predict overweight and/or obesity within childhood (age 2-12 years). Predictive accuracy of tools was consistently adequate; however, the predictive validity of most tools was questioned secondary to poor methodology and statistical reporting. Globally, five tools were developed for dissemination into clinical practice, but no tools were tested within a clinical setting. CONCLUSIONS: To our knowledge, a clinically relevant and highly predictive overweight/obesity prediction tool is yet to be developed. Clinicians can, however, act now to identify the strongest predictors of future overweight/obesity. Further research is necessary to optimise the predictive strength and clinical applicability of such a tool. PMID- 29996949 TI - Extravascular manifestations of Takayasu arteritis: focusing on the features shared with spondyloarthritis. AB - BACKGROUND: Takayasu arteritis (TAK) is a systemic disease characterized by large vessel involvement. Although the vascular characteristics of TAK are well characterized, there is no well-organized study demonstrating the extravascular manifestations of TAK. We aimed to evaluate the characteristics of extravascular manifestations of TAK, and to identify the association between vascular and extravascular manifestations of TAK. METHODS: TAK patients from two independent cohorts between January 2012 and October 2017 were included in the study. Patient characteristics were retrospectively collected from the electronic dataset. The computed tomography scans of all subjects were reviewed to evaluate the pattern of vascular involvement and presence of sacroiliitis. Clinical findings including uveitis, skin lesions, oral ulcers, arthritis, and inflammatory bowel disease (IBD) were reviewed. Logistic regression analysis was performed to evaluate the association between vascular and extravascular manifestations. RESULTS: For the 268 TAK patients, the mean age at diagnosis was 41.2 +/- 14.2 years and 88.1% were female. The extravascular manifestation of TAK was observed in 19.0% of patients, the most common being arthritis including sacroiliitis (11.9%) followed by recurrent oral ulcers (8.6%) and IBD (2.6%). A multivariate logistic regression analysis revealed type IIB vascular involvement (adjusted odds ratio (OR) 2.956, 95% confidence interval (CI) 1.337-6.537, p = 0.007) and the erythrocyte sedimentation rate (ESR) (adjusted OR 1.014, 95% CI 1.003-1.025, p = 0.012) as significantly associated with the presence of axial and peripheral arthritis. CONCLUSIONS: Extravascular manifestations of TAK were observed in up to one-fifth of patients. The most common extravascular manifestation was arthritis, which was associated with a type IIB vascular involvement pattern and a high ESR. PMID- 29996951 TI - Access to health care in post-apartheid South Africa: availability, affordability, acceptability. AB - We use a reliable, intuitive and simple set of indicators to capture three dimensions of access - availability, affordability and acceptability. Data are from South Africa's 2009 and 2010 General Household Surveys (n=190,164). Affordability constraints were faced by 23% and are more concentrated amongst the poorest. However, 73% of affordability constraints are due to travel costs which are aligned with findings of the availability constraints dimension. Availability constraints, involving distances and transport costs, particularly in underdeveloped rural areas, and inconvenient opening times, were faced by 27%. Acceptability constraints were noted by only 10%. We approximate acceptability with an indicator measuring the share of community members bypassing the closest health care facility, as we argue that reported health care provider choice is more reliable than stated preferences. However, the indicator assumes a choice of available and affordable providers, which may often not be an accurate assumption in rural areas. We recommend further work on the measurement of acceptability in household surveys, especially considering this dimension's importance for health reform. PMID- 29996952 TI - Spanish adaptation and validation of the Child Food Security Survey Module (CFSSM S). AB - OBJECTIVE: The present study aimed to assess the: (i) internal structure of the Spanish Child Food Security Survey Module (CFSSM-S) with exploratory and confirmatory factor analysis (EFA and CFA); (ii) measurement invariance by gender, grade, weight status, socio-economic status (SES) and family affluence; and (iii) relationships with these external variables. DESIGN: A cross-sectional study was conducted. The CFSSM-S and other tools were employed to assess food insecurity, weight status, SES and family affluence, respectively. SETTING: A secondary school (grades 7-10) in the city of Terrassa in Catalonia, Spain. SUBJECTS: Participants included adolescent boys and girls (n 426) aged 12-17 years. RESULTS: The cross-validation design with EFA and CFA captured a single factor, 'food insecurity'. The goodness-of-fit for the one-factor model with CFA (root-mean-square error of approximation=0.038, comparative fit index=0.984, Tucker-Lewis index=0.979) and internal consistency (omega=0.95) were excellent. The measurement invariance indicated that CFSSM-S could be used across genders, grades, weight status, SES and family affluence. Only mean differences for SES and family affluence were found which showed a linear trend, indicating higher CFSSM-S scores for participants with lower SES and family affluence. Of participants, 1.9 % experienced very low food security, 16.4 % low food security and 81.7 % were food secure. CONCLUSIONS: The CFSSM-S is the first validated instrument to assess food insecurity with psychometric guarantees in Spanish adolescents. Researchers and health practitioners in Spain could use this self reported questionnaire to gain more information about adolescent health in relation to food insecurity. PMID- 29996953 TI - Long-Term Outcomes in the Management of Central Neuropathic Pain Syndromes: A Prospective Observational Cohort Study. AB - BACKGROUND: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. METHODS: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. RESULTS: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a >=30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). CONCLUSION: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up. PMID- 29996954 TI - Comparative transcriptome analyses of adzuki bean weevil (Callosobruchus chinensis) response to hypoxia and hypoxia/hypercapnia. AB - Stored product insects show high adaption to hypoxia and hypercapnia, but the underlying mechanism is still unclear. Herein, a comparative transcriptome on 4th adzuki bean weevil (Callosobruchus chinensis) instar larvae was studied to clarify the response mechanisms to hypoxia (HA) and hypoxia/hypercapnia (HHA) using NextSeq500 RNA-Seq. Transcript profiling showed a significant difference in HA or HHA exposure both quantitatively and qualitatively. Compared with control, 631 and 253 genes were significantly changed in HHA and HA, respectively. Comparing HHA with HA, 1135 differentially expressed genes (DEGs) were identified. The addition of hypercapnia made a complex alteration on the hypoxia response of bean weevil transcriptome, carbohydrate, energy, lipid and amino acid metabolism were the most highly enriched pathways for genes significantly changed. In addition, some biological processes that were not significantly enriched but important were also discussed, such as immune system and signal transduction. Most of the DEGs related to metabolism both in HHA and HA were up regulated, while the DEGs related to the immune system, stress response or signal transduction were significantly down-regulated or suppressed. This research reveals a comparatively full-scale result in adzuki bean weevil hypoxia and hypoxia/hypercapnia tolerance mechanism at transcription level, which might provide new insights into the genomic research of this species. PMID- 29996955 TI - LiGAPS-Beef, a mechanistic model to explore potential and feed-limited beef production 2: sensitivity analysis and evaluation of sub-models. AB - The model LiGAPS-Beef (Livestock simulator for Generic analysis of Animal Production Systems - Beef cattle) has been developed to assess potential and feed limited growth and production of beef cattle in different areas of the world and to identify the processes responsible for the yield gap. Sensitivity analysis and evaluation of model results with experimental data are important steps after model development. The first aim of this paper, therefore, is to identify which parameters affect the output of LiGAPS-Beef most by conducting sensitivity analyses. The second aim is to evaluate the accuracy of the thermoregulation sub model and the feed intake and digestion sub-model with experimental data. Sensitivity analysis was conducted using a one-at-a-time approach. The upper critical temperature (UCT) simulated with the thermoregulation sub-model was most affected by the body core temperature and parameters affecting latent heat release from the skin. The lower critical temperature (LCT) and UCT were considerably affected by weather variables, especially ambient temperature and wind speed. Sensitivity analysis for the feed intake and digestion sub-model showed that the digested protein per kg feed intake was affected to a larger extent than the metabolisable energy (ME) content. Sensitivity analysis for LiGAPS-Beef was conducted for 3/4 Brahman*1/4 Shorthorn cattle in Australia and Hereford cattle in Uruguay. Body core temperature, conversion of digestible energy to ME, net energy requirements for maintenance, and several parameters associated with heat release affected feed efficiency at the herd level most. Sensitivity analyses have contributed, therefore, to insight which parameters are to be investigated in more detail when applying LiGAPS-Beef. Model evaluation was conducted by comparing model simulations with independent data from experiments. Measured heat production in experiments corresponded fairly well to the heat production simulated with the thermoregulation sub-model. Measured ME contents from two data sets corresponded well to the ME contents simulated with the feed intake and digestion sub-model. The relative mean absolute errors were 9.3% and 6.4% of the measured ME contents for the two data sets. In conclusion, model evaluation indicates the thermoregulation sub-model can deal with a wide range of weather conditions, and the feed intake and digestion sub-model with a variety of feeds, which corresponds to the aim of LiGAPS-Beef to simulate cattle in different beef production systems across the world. PMID- 29996956 TI - Internal carotid artery aneurysm in skull base osteomyelitis: does the pattern of cranial nerve involvement matter? AB - OBJECTIVE: Carotid artery aneurysm is a potentially fatal complication of skull base osteomyelitis. It is important to know the warning signs for this complication, as early diagnosis is of great importance. This report aimed to determine whether the pattern of cranial nerve involvement may predict the occurrence of aneurysm involving the internal carotid artery in skull base osteomyelitis. METHODS: Two diabetic patients with skull base osteomyelitis were incidentally diagnosed with pseudo-aneurysm of the petrous internal carotid artery on follow-up magnetic resonance imaging. They presented with lower cranial nerve palsy; however, facial nerve function was almost preserved in both cases. Computed tomography angiography confirmed aneurysms at the junction of the horizontal and vertical segments of the petrous carotid artery. RESULTS: Internal carotid artery trapping was conducted using coil embolisation. Post-coiling magnetic resonance imaging demonstrated no procedure-related complications. Regular follow up has demonstrated that patients' symptoms are improving. CONCLUSION: One should be mindful of this potentially fatal complication in skull base osteomyelitis patients with lower cranial nerve palsies, with or without facial nerve involvement, especially in the presence of intracranial thromboembolic events or Horner's syndrome. PMID- 29996957 TI - The significance of DOHaD for Small Island Developing States. AB - Small Island Developing States (SIDS) are island nations that experience specific social, economic and environmental vulnerabilities associated with small populations, isolation and limited resources. Globally, SIDS exhibit exceptionally high rates of non-communicable disease (NCD) risk and incidence. Despite this, there is a lack of context-specific research within SIDS focused on life course approaches to NCD prevention, particularly the impact of the early life environment on later disease risk as defined by the Developmental Origins of Health and Disease (DOHaD) framework. Given that globalization has contributed to significant nutritional transitions in these populations, the DOHaD paradigm is highly relevant. SIDS in the Pacific region have the highest rates of NCD risk and incidence globally. Transitions from traditional foods grown locally to reliance on importation of Western-style processed foods high in fat and sugar are common. The Cook Islands is one Pacific SIDS that reports this transition, alongside rising overweight/obesity rates, currently 91%/72%, in the adult population. However, research on early-life NCD prevention within this context, as in many low- and middle-income countries, is scarce. Although traditional research emphasizes the need for large sample sizes, this is rarely possible in the smaller SIDS. In these vulnerable, high priority countries, consideration should be given to utilizing 'small' sample sizes that encompass a high proportion of the total population. This may enable contextually relevant research, crucial to inform NCD prevention strategies that can contribute to improving health and well-being for these at-risk communities. PMID- 29996958 TI - LiGAPS-Beef, a mechanistic model to explore potential and feed-limited beef production 1: model description and illustration. AB - The expected increase in the global demand for livestock products calls for insight in the scope to increase actual production levels across the world. This insight can be obtained by using theoretical concepts of production ecology. These concepts distinguish three production levels for livestock: potential (i.e. theoretical maximum) production, which is defined by genotype and climate only; feed-limited production, which is limited by feed quantity and quality; and actual production. The difference between the potential or limited production and the actual production is the yield gap. The objective of this paper, the first in a series of three, is to present a mechanistic, dynamic model simulating potential and feed-limited production for beef cattle, which can be used to assess yield gaps. A novelty of this model, named LiGAPS-Beef (Livestock simulator for Generic analysis of Animal Production Systems - Beef cattle), is the identification of the defining factors (genotype and climate) and limiting factors (feed quality and available feed quantity) for cattle growth by integrating sub-models on thermoregulation, feed intake and digestion, and energy and protein utilisation. Growth of beef cattle is simulated at the animal and herd level. The model is designed to be applicable to different beef production systems across the world. Main model inputs are breed-specific parameters, daily weather data, information about housing, and data on feed quality and quantity. Main model outputs are live weight gain, feed intake and feed efficiency (FE) at the animal and herd level. Here, the model is presented, and its use is illustrated for Charolais and Brahman * Shorthorn cattle in France and Australia. Potential and feed-limited production were assessed successfully, and we show that FE of herds is highest for breeds most adapted to the local climate conditions. LiGAPS-Beef also identified the factors that define and limit growth and production of cattle. Hence, we argue the model has scope to be used as a tool for the assessment and analysis of yield gaps in beef production systems. PMID- 29996960 TI - Intellectual disability and mental disorders in a US population representative sample of adolescents. AB - BACKGROUND: Most research on the prevalence, distribution, and psychiatric comorbidity of intellectual disability (ID) relies on clinical samples, limiting the generalizability and utility of ID assessment in a legal context. This study assessed ID prevalence in a population-representative sample of US adolescents and examined associations of ID with socio-demographic factors and mental disorders. METHODS: Data were drawn from the National Comorbidity Survey Adolescent Supplement (N = 6256). ID was defined as: (1) IQ ? 76, measured using the Kaufman Brief Intelligence Test; (2) an adaptive behavior score ?76, and (3) age of onset ?18 measured using a validated scale. The Composite International Diagnostic Interview assessed 15 lifetime mental disorders. The Sheehan disability scale assessed disorder severity. We used logistic regression models to estimate differences in lifetime disorders for adolescents with and without ID. RESULTS: ID prevalence was 3.2%. Among adolescents with ID, 65.1% met lifetime criteria for a mental disorder. ID status was associated with specific phobia, agoraphobia, and bipolar disorder, but not behavior disorders after adjustment for socio-demographics. Adolescents with ID and mental disorders were significantly more likely to exhibit severe impairment than those without ID. CONCLUSIONS: These findings highlight how sample selection and overlap between ID and psychopathology symptoms might bias understanding of the mental health consequences of ID. For example, associations between ID and behavior disorders widely reported in clinical samples were not observed in a population representative sample after adjustment for socio-demographic confounders. Valid assessment and understanding of these constructs may prove influential in the legal system by influencing treatment referrals and capital punishment decisions.General Scientific SummaryCurrent definitions of intellectual disability (ID) are based on three criteria: formal designation of low intelligence through artificial problem-solving tasks, impairment in one's ability to function in his/her social environment, and early age of onset. In a national population sample of adolescents, the majority of those with ID met criteria for a lifetime mental disorder. Phobias and bipolar disorder, but not behavior disorders, were elevated in adolescents with ID. Findings highlight the need to consider how behavioral problems are conceptualized and classified in people with ID. PMID- 29996959 TI - Transoral and endoscope-assisted transoral approaches to resecting benign tumours of the parapharyngeal space located in the medial portion of the carotid sheaths and extending toward the skull base: our experience. AB - OBJECTIVE: Various surgical approaches have been described to remove tumours in the parapharyngeal space. This study investigated the feasibility of a transoral approach in the surgical management of parapharyngeal space benign tumours located in the medial portion of the carotid sheaths and extending toward the skull base. METHODS: Thirty-two patients were selected and underwent a transoral or an endoscope-assisted transoral approach in the surgical management of parapharyngeal space benign tumours located in the medial portion of the carotid sheaths. Medical photographs were used. RESULTS: All patients underwent complete resection of their lesions via a transoral or endoscope-assisted transoral approach. None of the patients demonstrated residual or recurrent neoplasms, either clinically or radiographically, during their follow up. CONCLUSION: Based on our studies, we assert that transoral and endoscope-assisted transoral approaches are suitable in managing parapharyngeal space benign tumours located in the medial portion of the carotid sheaths and extending toward the skull base. PMID- 29996961 TI - Experience during the first year of procalcitonin implementation: a precautionary tale for smaller facilities. PMID- 29996962 TI - Delapril and Indapamide: Development and Validation of a Stability-Indicating Core-Shell LC Method and Its Application for Simultaneous Tablets Assay. AB - Background: The combination of delapril (DEL) and indapamide (IND) may be regarded as an optimal drug treatment for hypertensive patients. However, there is no published study concerning the suitable stability conditions and evaluation of drugs in the raw material and commercial product. Objective: The aim of the present study was to develop an innovative, high-throughput, and stability indicating LC method for the simultaneous analysis of DEL and IND in combined dosage form. Methods: Analyses were performed using a core-shell C18 column (100 mm * 4.6 mm id, 2.6 MUm) at 45 degrees C using isocratic elution for the mobile phase composed of triethylamine solution (0.3%, pH 5.0)-acetonitrile-methanol (58 + 35 + 7, v/v/v). The separation was obtained within 3.5 min at a flow rate of 1.0 mL/min and UV detection set at 213 nm. Results: The specificity and stability indicating capability of the method were proven through degradation studies, which also showed that there is no interference of the formulation excipients, showing that the peak is free from any co-eluting peak. Conclusions: The method showed adequate precision, with relative standard deviation values lower than 1.85%. Excellent values of accuracy were obtained, with a mean value of 98.64% for IND and 98.65% for DEL. Experimental design was used during validation to calculate and prove the method robustness. Highlights: The proposed LC method was successfully validated according to International Conference on Harmonisation requirements and applied for the simultaneous determination of DEL and IND in tablets, presenting suitability for stability studies and contributing to improve the QC of pharmaceuticals. PMID- 29996963 TI - Navigating Medication Needs. PMID- 29996964 TI - Concierge Pharmacy: A Potential Arena for Senior Care Pharmacists. AB - Concierge pharmacy is an emerging area of practice that appears to be well suited for pharmacists who prefer flexibility in geriatric practice, a system in which patients pay a fee for personalized care and access to their pharmacists. Older adults are a natural population for concierge pharmacists because of their individual increasing medical needs. At this time, concierge pharmacists tend to provide care to individuals who can afford to pay out-of-pocket or who are auxiliary personnel in medical offices, which provides payment. Other reimbursement models exist, and each concierge pharmacist's practice will be unique. The largest barrier to unfettered pharmacy practice is the inability to practice autonomously. Pharmacists can look to nurse practitioners' moderately successful march toward nationwide independent practice as a model for their own bid to practice independently. PMID- 29996965 TI - Fracture Risk Following Discontinuation of Teriparatide: A Review of the Literature. AB - OBJECTIVE: To review and summarize studies on the changes in bone mineral density (BMD) and fracture risk following discontinuation of teriparatide therapy. DATA SOURCES: A search of PubMed (1966-May 2016) and International Pharmaceutical Abstracts (1970-May 2016) was conducted using the Medical Subject Headings terms teriparatide, osteoporosis, and withholding treatment. Free text searches included drug holiday, discontinuation, and drug discontinuation. STUDY SELECTION AND DATA EXTRACTION: These searches yielded 79 articles. There were 7 articles reviewed that addressed the effects of teriparatide discontinuation on markers of overall bone health and fracture risk. DATA SYNTHESIS: Teriparatide is a recombinant human parathyroid hormone that is indicated for a lifetime maximum of 24 months in the United States for the treatment of osteoporosis in men and women at high fracture risk. There is inconsistent evidence regarding retained skeletal integrity resulting from increased bone resorption. Study analyses have shown that female patients seem to have more reduction in BMD upon teriparatide discontinuation. Several studies evaluating teriparatide discontinuation were follow-up studies with small patient populations, limiting the generalizability and statistical rigor associated with assessing these outcomes. In addition, the majority of patients were receiving bisphosphonate therapy, and the true effect of discontinuing teriparatide remains unknown. CONCLUSION: Independent patient risk factors should be taken into consideration when weighing the risk-vs. benefit of initiating and discontinuing teriparatide therapy. Additional randomized control trials should be conducted to determine long-term effects of discontinuing teriparatide in the presence and absence of other bone strengthening agents. PMID- 29996966 TI - Management of Breakthrough Pain in Hospitalized Older Adults. AB - OBJECTIVE: The appropriateness of analgesic administrations based on pain score and medication order in older adults during hospitalization was evaluated. SETTING: As-needed analgesic administrations for geriatric patients on hospitalist general medicine services at a large-university-affiliated medical center from January 1 to March 31, 2015, were included. PRACTICE DESCRIPTION: The hospital is a level one trauma center with more than 500 beds serving an area of more than 500,000 people, 12% of whom are 65 years of age or older. At our institution, breakthrough pain is treated with as-needed analgesic medications based on pain scores specified by the ordering provider. Medication should be given according to which order contains the patient-reported severity of pain. PRACTICE INNOVATION: This is an institutional review board-approved retrospective chart review of 430 analgesic medication administrations in hospitalized older adults. MAIN OUTCOME MEASUREMENTS: Incidence of appropriate medication administration based on pain score report and active medication orders. RESULTS: As-needed analgesic medications were given appropriately 44% of the time based on patient-reported pain score and active medication order. An active medication order was missing to treat the pain score reported by the patient 29% of the time. Out of 430 analgesic administrations, improvement in pain occurred 26% of the time. Pain was reassessed one hour after administration for almost 33% of the orders. Of those, 73% showed an improvement in pain score. CONCLUSION: Our results demonstrate a large discrepancy for hospitalized older adults in what medication is administered compared with what is ordered for as-needed pain treatment. Missing orders contributed to almost one third of inappropriate medication administrations. PMID- 29996967 TI - Interventions to Improve Medication Adherence in Older Adults With Cognitive Impairment. AB - Many older adults experience some degree of cognitive impairment, an important risk factor for medication nonadherence. To prevent negative health outcomes secondary to medication nonadherence, identifying interventions that improve medication adherence for older adults with cognitive impairment is crucial. Other barriers to medication adherence include the structure of the health care system as well as socioeconomic and therapyrelated obstacles. The use of pharmacist-led and population-level interventions hold promise for providing optimal medication adherence for older adults with cognitive impairment. PMID- 29996968 TI - Perceptions of Nursing Facility Providers on the Utility of Deprescribing. AB - OBJECTIVE: Potentially inappropriate medications carry significant burden and costs to nursing facility residents and health systems. The goal of this study was to survey nursing facility providers from across the United States to describe the current utilization of deprescribing, and perceptions and desired components of a deprescribing program, in nursing facilities to reduce potentially inappropriate medications. DESIGN/SETTING/PARTICIPANTS/MEASUREMENT: We surveyed health care providers who attended the 2017 AMDA-The Society for Post Acute and Long-Term Care Medicine Annual Conference-in Phoenix, Arizona. Returned surveys were entered into an electronic database from paper copies. Survey responses were summarized using descriptive statistics. RESULTS: Of the 1,431 conference attendees, 637 surveys were returned for a 45% response rate. Most respondents were physicians (n = 563, 88%). Respondents indicated a strong agreement with the potential for deprescribing to reduce cost to residents and nursing administration time and burden, while disagreeing that deprescribing may be depersonalizing. Respondents indicated clear preference for deprescribing programs to target medications that are no longer indicated and are "high risk," and that such programs should include discussions with the resident. Respondents also agreed that deprescribing programs are successful if the resident, or the resident's family and/or caregivers, reports an improvement in quality of life. CONCLUSION: Among respondents there was a high degree of confidence in the potential impact of deprescribing initiatives, as well as a broad consensus of desired components. This information may increase consultant pharmacist engagement and drive future proactive deprescribing initiatives. PMID- 29996969 TI - CMS Unveils Latest Payment Model for Nursing Facilities. PMID- 29996971 TI - Erectile dysfunction in patients with arterial hypertension. Cardiovascular risk and impact on their quality of life. AB - OBJECTIVES: Estimate the frequency of erectile dysfunction in patients with essential hypertension and associated variables, degree of control, cardiovascular risk and the impact on quality of life. MATERIAL AND METHODS: Type of study: Observational study of prevalence in men with essential hypertension. MEASUREMENTS: Sociodemographic and comorbidity variables were collected from each patient (age, Charlson index, dyslipidaemia and prostatic hyperplasia), degree of control of essential hypertension and treatment, cardiovascular risk and metabolic syndrome. The erectile dysfunction was diagnosed by the International Index of Erectile Function (IIEF-15). Quality of life questionnaires were carried out in essential hypertension (MINICHAL), and the international scale of prostatic symptoms (IPSS). RESULTS: The study included 262 hypertensive men with an average age of 65.84years. Erectile dysfunction was presented in 46.1%, being severe in 54.9%. The bivariate analysis shows an independent association between erectile dysfunction and the variables: age, Charlon index, dyslipidaemia, benign prostatic hypertrophy, diastolic blood pressure, years of diagnosis of hypertension, number of treatments, Regicor and Framingham-Wilson, glycaemia, creatinine and GPT, glomerular filtration through the MDRD formula, irritative symptomatology (IPSS) and somatic manifestations (MINICHAL). The final multivariate model found association with age, presentation of dyslipidaemia, prostatic hyperplasia and metabolic syndrome. CONCLUSIONS: Erectile dysfunction is significantly associated with age, dyslipidaemia, benign prostatic hypertrophy and metabolic syndrome. PMID- 29996972 TI - Dissolving the stiff upper lip: Opportunities and challenges for the mainstreaming of therapeutic jurisprudence in the United Kingdom. AB - Although therapeutic jurisprudence ("TJ") is increasingly well-established internationally, particularly within the United States of America ("US"), to date it remains relatively unacknowledged within the United Kingdom ("UK"). This article will explore the opportunities presented within contemporary UK society for the greater promotion, and eventual mainstreaming, of TJ. It will also consider the challenges faced during this process and how best to overcome these. Its first key area of focus will be upon the potential role of legal education in the UK in educating law students (and academics) about TJ, considering which approaches are likely to be most effective in incorporating TJ perspectives, at what stage this should occur and to what extent TJ is likely to impact on the existing curricula at a time when proposed changes relating to entry into the legal profession are heavily influencing the work of Law Schools. The article will then move on to consider the receptiveness of the UK legal profession to the TJ paradigm in light of recent attempts to move to a competency-based approach to practice and to reconceptualise professionalism to meet the challenges of increasing fragmentation and corporatisation. The third key area it will explore is the UK's recent plans to reintroduce problem-solving courts ("PSCs") into its criminal justice system. The authors will discuss the downfall of the six UK Drug Court ("DC") pilots originally established in 2005 theorising upon their failures and reflecting upon whether the current UK criminal justice system is truly able to support a fresh round of PSC initiatives. The article will end with recommendations for ways in which the international TJ community should begin the process of mainstreaming TJ within the UK. It will conclude that there are currently significant opportunities to be utilised, but that this requires significant commitment and mobilisation amongst existing TJ scholars and practitioners. PMID- 29996970 TI - The efficacy of concurrent weekly carboplatin with radiotherapy in the treatment of cervical cancer: A meta-analysis. AB - OBJECTIVES: We aimed to evaluate whether carboplatin has a comparable efficacy with cisplatin as part of weekly concurrent chemoradiotherapy for cervical cancer (Car-RT vs. Cis-RT). METHODS: A literature search was conducted and both prospective and retrospective studies that evaluated the efficacy of Car-RT for cervical cancer were included. The primary endpoints were complete response (CR) rate, progression-free survival (PFS)/disease-free survival (DFS), overall survival (OS), reported as odds ratios (ORs) and 95% confidence intervals (CIs). The estimated CR rate and survival of patients treated with Car-RT were pooled. Acute toxicity was also summarized. RESULTS: Twelve studies consisting of 1698 patients were eligible for meta-analysis. A lower CR rate (OR, 0.53; 95% CI, 0.34 0.82, I2 = 0%) and a trend toward poorer 3-year PFS/DFS (OR, 0.71; 95% CI, 0.49 1.02, I2 = 0%) and 3-year OS (OR, 0.70; 95% CI, 0.46-1.05, I2 = 36%) were found in Car-RT compared with Cis-RT. For the Car-RT groups, the pooled overall CR rate was 81% (95% CI 0.74-0.89). The pooled 3-year PFS/DFS rate was 64% (95% CI 0.52 0.78). The pooled 3-year OS rate was 73% (95% CI 0.62-0.87). Acute toxic events >= grade 3 were infrequent in the Car-RT groups. CONCLUSIONS: Car-RT showed a poorer tumor response and a trend toward inferior survival compared with Cis-RT in the treatment of cervical cancer. However, this evidence was limited by the imbalance among studies. Due to the encouraging efficacy and low toxicity, carboplatin is a suitable concurrent agent for patients with contraindications to cisplatin. PMID- 29996973 TI - Revisiting the persistent negative symptoms proxy score using the Clinical Assessment Interview for Negative Symptoms. AB - OBJECTIVE: The present study aimed to validate a severity cut-off of negative symptoms for persistent negative symptoms (PNS) identification using the Clinical Assessment Interview for Negative Symptoms (CAINS). METHOD: A total of 206 patients with schizophrenia were recruited and divided into the PNS group (n = 57) and the Non-PNS group (n = 149) using PNS criteria based on the SANS and the SAPS. To determine the appropriate cut-offs on the CAINS in identifying PNS, Receiver Operating Characteristic (ROC) curve analysis was conducted in the PNS and Non-PNS groups. RESULTS: Our results showed that the cutoffs for identifying PNS on the CAINS total score, the Motivation and Pleasure (MAP) subscale score and the Expression (EXP) subscale score were 25, 17, and 5 respectively. Area Under the Curve (AUC) analysis indicated excellent discrimination of the PNS group from the Non-PNS group using the cut-off for the CAINS total score. However, discrimination was somewhat better for the MAP subscale score than the EXP subscale score. The Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of the MAP subscale were 81.54% and 97.16%. CONCLUSION: We found that the cut-off scores derived from the CAINS to identify PNS are comparable to existing scales. The CAINS offers an alternative means in identifying PNS patients in clinical trials that overcomes methodological and conceptual limitations of older scales. PMID- 29996974 TI - Activation of imidazoline receptor I2, and improved pancreatic beta-cell function in human islets. AB - AIM: The impact of BL11282, an imidazoline receptor (NISCH) agonist, on potentiation of glucose-stimulated insulin secretion (GSIS) from isolated human non-diabetic (ND) and type 2 diabetic (T2D) islets was investigated. METHODS: Analysis of mRNA was performed by RNA-sequencing and qPCR. Insulin and cAMP by RIA and ELISA respectively. RESULTS: RNA-sequencing data revealed that NISCH is highly expressed in fat tissues, islets, liver and muscles, with eight detectable splice variants of transcripts in islets. NISCH had a positive correlation with GLP-1 (GLP1R) and GIP (GIPR) receptor transcripts. The expression of NISCH was confirmed by qPCR in human islets. NISCH and GLP1R were comparably higher expressed in mouse islets compared to human islets. GSIS was dose-dependently potentiated by BL11282 from incubated islets of ND and T2D human islet donors. The insulinotropic action of BL11282 was associated with increased cAMP. While the harmful effect of high glucose on reductive capacity of islet cells was enhanced by glibenclamide during long-term culture, it was counteracted by BL11282 or Bt2-cAMP. BL11282 also increased proliferation of INS-1 cells during long-time culture. CONCLUSION: Our data suggest that BL11282 potentiates GSIS by an action involving cAMP/PKA system and BL11282 could be an attractive insulinotropic and beta-cell protective agent. PMID- 29996975 TI - The interrelation between FGF23 and glucose metabolism in humans. AB - AIMS: Different studies point to a link between glucose metabolism and Fibroblast Growth Factor 23 (FGF23), an osteocyte-derived phosphaturic hormone. We aimed to investigate in humans the effect of (I) a glucose load and (II) a hyperinsulinemic-euglycemic clamp on FGF23 concentrations and conversely (III) the effect of a diet-induced increase in FGF23 concentration on glucose and insulin concentrations. METHODS: Plasma cFGF23 concentrations were measured during: I. an oral glucose tolerance test in eight adults with impaired glucose tolerance and vitamin D deficiency and II. a hyperinsulinemic-euglycemic clamp in nine healthy adults. III. Serum glucose and insulin concentrations were measured in nine healthy adults receiving a single-day phosphate-enriched or -restricted diet. RESULTS: I. A glucose load decreased FGF23 and phosphate concentrations. II. The hyperinsulinemic-euglycemic clamp decreased phosphate concentrations, but did not affect FGF23 concentrations. III. Fasting insulin and glucose concentrations remained unchanged after a diet-induced increase in FGF23 concentration. CONCLUSIONS: An oral glucose load in vitamin D deficient patients with impaired glucose metabolism decreased FGF23 concentrations, which cannot be attributed to changes in insulin concentration. Thus, bone may react rapidly after glucose loading by alternating FGF23 secretion. A diet-induced increase in FGF23 concentrations did not affect fasting glucose or insulin levels. PMID- 29996976 TI - Digital health literacy in cardiovascular research. PMID- 29996977 TI - Statin exposure during first trimester of pregnancy is associated with fetal ventricular septal defect. AB - BACKGROUND: A growing number of young women are exposed to statins during their first trimester of pregnancy. The goal of this study is to examine if first trimester statin exposure is associated with an increase in risk of fetal congenital cardiac anomalies. METHODS: In a cohort of 379,238 pregnancies, we examined the risk of fetal congenital cardiac anomalies in association with maternal exposure to statin therapy during the first trimester of pregnancy using logistic regression models and propensity score matching methods. RESULTS: 280 women were exposed to statins. Congenital cardiac anomalies were present in 14 (5.0%) of pregnancies exposed to statin and 5282 (1.4%) of non-exposed pregnancies. First-trimester statin exposure was associated with an increased risk of ventricular septal defect (adjusted odds ratio [OR] 3.3, 95% confidence interval [CI]l 1.8-6.0, p < 0.001). This association was confirmed in an analysis using a propensity score-matched cohort (OR 4.7, 95% CI 2.0-10.8, p < 0.001). CONCLUSIONS: Exposure to statins during the first trimester of pregnancy is associated with fetal ventricular septal defect. PMID- 29996978 TI - Urgent liver transplantation for acute liver failure due Wilson's disease. PMID- 29996979 TI - The diagnostic value of platelet indices in the gastrointestinal system bleeding and its place in predicting prognosis. AB - BACKGROUND: We aimed to investigate the association between platelet indices [platelet, plateletcrit (PCT), mean platelet volume (MPV) and platelet distribution width (PDW)] and gastrointestinal bleeding (GIB), as well as determine its severity and prognosis. METHOD: 500 patients with GIB who were admitted to hospital between March 2014 and February 2017 and diagnosed with "Gastrointestinal System Bleeding", as well as114 healthy individuals were retrospectively included in the study. Patients' platelet indices were recorded after one week and one month from their files. RESULTS: Platelet, PCT, MPV and PDW levels were determined to be higher in the patients with bleeding, when compared to the control group (p < 0.001). Within the first week, a significant reduction was determined in patients' platelet, PCT, MPV and PDW values compared to the admission values (p < 0.001). In initial-month controls, a significant reduction was determined in the platelet indices compared to the initial-week values (p < 0.001). A significant association between bleeding severity and increased platelet indexes was determined. Increasing age, female gender, the presence of comorbidities, high levels of platelet indexes, low levels of hemoglobin, and albumin values were all found to be associated with a poor prognosis. PCT, MPV, and PDW were determined as being the independent risk factors that predict the odds of GIB, alongside the independent predictors that predict risk of bleeding severity and the prognosis. CONCLUSION: We think that platelet indices may be used in diagnosis of GIB, as well as in predicting bleeding severity and the prognosis. PMID- 29996981 TI - Osteosynthesis of type III acromial fractures with locking compression plate, lateral clavicular plate, and reconstruction plate: a biomechanical analysis of load to failure and strain distribution. AB - BACKGROUND: Acromial stress fractures following reverse shoulder arthroplasty have been increasingly studied because of potential functional impairment caused by this complication. The purpose of this study was to evaluate and compare different plating techniques for a type III acromial fracture (also referred to as "scapular spine fracture") in a biomechanical setting with special regard to primary stability and modes of failure. METHODS: Type III acromial fractures were simulated on 19 Sawbones scapulae and plated with either a lateral clavicular plate (LatCP), a locking compression plate (LCP), or a reconstruction plate (RecoP). We performed testing on 5 scapulae for each plate according to a staircase protocol (100 cycles each step): 50 N and 100 N, then increasing 100 N each step up to 800 N or until failure. The last series of mechanical tests included 3-dimensional micro-motion analysis. RESULTS: The average force needed to cause failure of the osteosynthesis construct was 376 N for the LatCP, 506 N for the LCP, and 360 N for the RecoP. The difference between the LCP and RecoP was significant (P = .047). The average displacements of the acromion were 12.1 mm, 13.4 mm, and 11.7 mm, respectively. The spring constant was not significantly different between the plates. The LatCP showed increased strain medially, whereas the strain on the RecoP was spread more laterally. The LCP presented a balanced strain distribution, spread evenly over the fracture line. CONCLUSIONS: In a biomechanical setting, the LCP showed superiority over the LatCP and RecoP as stabilization hardware for type III acromial fractures. PMID- 29996980 TI - Platelet-rich plasma in fibrin matrix to augment rotator cuff repair: a prospective, single-blinded, randomized study with 2-year follow-up. AB - BACKGROUND: Application of autologous platelet-rich plasma in fibrin matrix (PRPFM) improves tendon healing in patients undergoing arthroscopic rotator cuff repair. We performed a prospective, randomized, single-blinded study of 76 patients, with an alpha level of 5% and power of 80%. MATERIALS AND METHODS: Seventy-six patients were divided into 2 randomized groups. The treatment group underwent arthroscopic rotator cuff repair with PRPFM. The control group did not receive the PRPFM treatment. Patients were evaluated preoperatively and at 6 months and 24 months postoperatively with validated clinical outcome scores, and dynamometer examination. A magnetic resonance imaging scan was performed at 6 months postoperatively. RESULTS: The 2 randomized groups were homogeneous. Western Ontario Rotator Cuff (WORC) scores were not statistically different at any time interval. The WORC scores changed from 1257 to 139 in the control group and from 1106 to 99 in the PRPFM group over the 24-month study period. On the Simple Shoulder Test, improvement over the study period was noted from 45% to 96% in the control group and from 49% to 96% in the PRPFM group. Strength of the supraspinatus at 24 months by dynamometer testing was 99.8% in the control group and 96.3% in the PRPFM group. Infraspinatus strength was 104% in the control group and 103% in the PRPFM group. The secondary outcome of retear occurred at a rate of 19% for the double-row technique and 7.4% for the PRPFM technique at 6 months. All our results were statistically insignificant. CONCLUSIONS: Our results showed no benefit from PRPFM used for rotator cuff repair according to the WORC Index, Simple Shoulder Test, and shoulder strength index. PMID- 29996982 TI - CIO inventory: A new tool for measuring personality traits common to psychopathy and narcissism and their interaction with gender. AB - A lack of empathy, interpersonal dominance, aggression and the exploitation of others are the key features of both narcissism and psychopathic disorders. With the aim to better capture the shared facets of these traits, this study developed a new tool named the Capability to Influence Others (CIO) Inventory, which is based on the pleasantness evaluation of ten items-verbs presented in the infinitive form. The inventory, characterized by very quick submission, was administered to 67 males and 100 females and was correlated with the concurrent Narcissistic Personality Inventory (NPI) and Levenson Self-Report Psychopathy Scale (LSRP). An exploratory factor analysis supported the presence of only one factor in both the male and female groups. Internal consistency of the CIO was very good for both men (Cronbach's alpha = 0.85; 95% CIs: 0.80-0.90) and women (Cronbach's alpha = 0.83; 95% CIs: 0.77-0.87). Further statistics showed a high correlation between the CIO and the LSRP-F1 (primary psychopathy) in both genders (r > 0.47). Clear gender differences were found in the correlation between the CIO and the NPI: the correlation was high (r = 0.58) in males and absent in females. The CIO may represent a quick and low demanding tool for a preliminary screening of individuals with high psychopathic/narcissistic traits from community samples, forensic institutions, high schools and company personnel. PMID- 29996983 TI - A qualitative approach to the study of the characteristics of individuals convicted of road traffic offences. AB - Significant changes have been applied to the regulation of criminal law concerning road traffic in Spain, in a similar way to many of the countries surrounding us. This has led to a gradual increase in the number of individuals who are convicted with custodial sentences or sentenced to community service. Nevertheless, the available data on the psychosocial traits of road traffic offence convicts is highly limited. The objective of this qualitative study is to provide more insight into those convicted of road traffic offences through the use of focus groups, thus enabling the analysis of their attitudes towards sentences related to road safety offences, opinions regarding their driving styles, the profile of convicts of road traffic offences and how they feel about being labelled as delinquents. The results of this study are particularly relevant with regards to improving the rehabilitation process of convicts of road safety offences. PMID- 29996984 TI - Recently arrived refugee children: The quality and outcomes of Best Interests of the Child assessments. AB - Best Interests of the Child (BIC) assessments provide migration authorities with behavioral information about which interests of the child could be taken into account before a decision is made on the request for a residence permit. This study provides insight into the quality and outcomes of BIC assessments with 16 unaccompanied children (15-18 years) and 11 accompanied children (4-16 years) who have recently arrived in the Netherlands and requested asylum (N = 27). The results suggest that BIC assessments provide relevant information that enables assessors to determine the best interests of recently arrived refugee children. The inter-rater reliability of the BIC-Questionnaire, an instrument that evaluates the child-rearing environment and that is one of the components of the BIC assessment, was fairly good. The children in the sample had experienced a high number of stressful life events and a majority reported trauma related stress symptoms or other emotional problems. The quality of the child-rearing environment in the country of origin had protected their development insufficiently in the past and would not protect their development sufficiently in the future. The results show that in many cases forced return to the country of origin can put children's development at risk. PMID- 29996985 TI - Factors that predict murder defendants' competence to stand trial. AB - One hundred sixty-three homicide case files from The Center for Forensic Psychiatry in Ypsilanti, Michigan were examined for evidence of factors associated with the outcomes of Competency to Stand Trial (CST) evaluations. Of the socio-demographic, legal, and clinical factors investigated, only three were significant. Defendants with lower IQs were more likely to be found incompetent to stand trial, and those with more property crime arrests were more likely to be found competent to stand trial. Additionally, defendants who were found incompetent to stand trial were more likely to be accused of killing an intimate or relative. PMID- 29996986 TI - Sex, gender and the carceral: Female staff experiences of working in forensic care with sexual offenders. AB - English high-secure hospitals have contained individuals deemed mentally disordered, and dangerous, since the mid-nineteenth century. With the development of gender sensitive services female patients have been moved out of these institutions into smaller secure settings. Female staff continue to work in high secure hospitals, but are often in a minority in these services. Little is known about how female staff experience the everyday world of work. This paper is based on in-depth interviews with female nurses employed in a unit caring for detained male sexual offenders with a diagnosis of personality disorder. It forms part of a much larger discourse-analytic study of nine patients, with a history of sexual offending, and eighteen mental health nurses, which focused on talk about pornography and criminality. The findings from this project have been previously reported in Mercer and Perkins (2014). This paper demonstrates how patriarchy remains an enduring cultural characteristic of caring for men detained under the Mental Health Act (1983, 2007) because of sexually violent crimes against women and children. It textures the ward environment and the relationships between people who work within it, constructing women as 'outsiders' and producing a masculine culture which leaves female staff feeling vulnerable and at risk. The analytic focus of the paper is concerned with exploring how women experience working in the male-dominated environment of a high-security Personality Disorder Unit (PDU). Three discursive repertoires are identified: the institutional space as male, the impact of working with men detained as a result of sexual offending, and the construction of therapeutic work as a 'job for the boys'. In this world, female staff, as a product of their gender, constructed themselves both as at risk and inviting risk. PMID- 29996987 TI - Fetal Alcohol Spectrum Disorder (FASD): Knowledge, attitudes, experiences and practices of the Western Australian youth custodial workforce. AB - BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a condition caused by prenatal alcohol exposure and characterised by lifelong physical, behavioural and cognitive abnormalities. Primary disabilities, such as impairment in memory, attention, cognition, language, executive function, and adaptive function, can lead to young people with FASD becoming engaged with the justice system. Little is known about the extent of FASD in youth detention in Australia, or of the capacity custodial staff have to manage and support young people with FASD. In tandem with a study assessing the prevalence of FASD among youth in detention in Western Australia (WA), this study aims to establish the current knowledge, attitudes, experiences and practices regarding FASD and other neurodevelopmental impairments among youth custodial officers in order to develop training resources for this workforce. METHODS: We invited youth custodial officers in the only youth detention centre in WA to participate in an online or hardcopy survey. The survey was developed following extensive consultation with the workforce and investigated their knowledge, attitudes, experiences and practices relating to FASD and other neurodevelopmental impairments. This included experience working with young people with FASD and other impairments, and attitudes towards relevant training. RESULTS: 112 youth custodial officers (51% of the youth custodial workforce) completed the survey. While many respondents had heard of FASD (77%) and understood it is relevant to the justice system (74%), limited in-depth FASD knowledge existed. Many respondents were unsure or unaware that FASD is permanent brain damage (53%) and cannot be outgrown (57%). Respondents were infrequently informed if a young person in detention had a diagnosis of FASD. Almost all custodial officers indicated motivation to complete training to further understand FASD (92%) and other neurodevelopmental impairments (94%), with particular interest in the application of management strategies appropriate for affected young people. CONCLUSIONS: A lack of specific knowledge, inadequate training to recognise and manage young people with neurodevelopmental impairments, and inconsistent information-sharing processes reduce the ability of the custodial workforce to care for young people with FASD and other neurodevelopmental impairments. These findings have supported the development and evaluation of training resources targeting the specific needs and requests of the WA youth custodial workforce, and this is now underway. PMID- 29996988 TI - Cutaneous Adverse Drug Reactions: How to Identify the Trigger. AB - It is estimated that 10% to 15% of medicated patients develop adverse drug reactions (ADR). Despite the high prevalence of ADR, the identification of the trigger drugs remains a medical challenge, mainly in polymedicated patients. Our goal is to update the diagnostic tools to identify enhancer drugs of type B-ADR that compromise the skin and /or mucous membranes, in order to optimize patients' follow-up and improve their quality of life. We develop the review in two stages: I- we review the pathophysiological mechanisms of the ADR; II- we developed the clinical approach for the identification of the triggering drug. PMID- 29996989 TI - Correlation of anteroseptal ST elevation with myocardial infarction territories through cardiovascular magnetic resonance imaging. AB - BACKGROUND: Anteroseptal ST elevation myocardial infarction (STEMI) is traditionally defined on the electrocardiogram (ECG) by ST elevation (STE) in leads V1-V3, with or without involvement of lead V4. It is commonly taught that such infarcts affect the basal anteroseptal myocardial segment. While there are suggestions in the literature that Q waves limited to V1-V4 represent predominantly apical infarction, none have evaluated anteroseptal ST elevation territories. We compared the distribution of the myocardium at risk (MaR) in STEMI patients presenting with STE limited to V1-V4 and those with more extensive STE (V1-V6). METHODS: We identified patients in the MITOCARE study presenting with a first acute STEMI and new STE in at least two contiguous anterior leads from V1 to V6. Patients underwent cardiac magnetic resonance (CMR) imaging three to five days after acute infarction. RESULTS: Thirty-two patients met inclusion criteria. In patients with STE in V1-V4 (n = 20), myocardium at risk (MaR) > 50% was seen in 0%, 85%, 75%, 100%, and 90% in the basal anteroseptal, mid anteroseptal, apical anterior, apical septal segments, and apex, respectively. The group with STE in V1-V6 (n = 12), MaR > 50% was seen in 8%, 83%, 83%, 92%, and 83% of the same segments. CONCLUSIONS: Patients with acute STEMI and STE in leads V1-V4, exhibit MaR in predominantly apical territories and rarely in the basal anteroseptum. We found no evidence to support existence of isolated basal anteroseptal or septal STEMI. "Anteroapical" infarction is a more precise description than "anteroseptal" infarction for acute STEMI patients exhibiting STE in V1-V4. PMID- 29996990 TI - ECG markers of arrythmogenic risk relationships with pericardial fat volume and BMI in patients with coronary atherosclerosis. AB - BACKGROUND: Several novel ECG markers are proposed to predict the risk of sudden cardiac death in several clinical conditions in the recent years. However, little is known about the association of pericardial fat or obesity with these markers. OBJECTIVES: To assess the possible relationship between pericardial fat volume (PFV) and body mass index (BMI) with novel ECG markers (Tp-e, Tp-e/QT, Tp e/QTc*QRS and QTc/QRS) in patients with coronary atherosclerosis. PATIENTS AND METHODS: We enrolled 100 patients with suspected coronary artery disease who underwent 64-slice multi-detector CT angiography. RESULTS: Higher values of Tp e/QTc*QRS and QTc/QRS were observed among high PFV group in comparison to low PFV group particularly in patient with coronary atherosclerosis and these relationships persisted after adjustment for cardiac risk factors and coronary calcium score (CAC) while no significant differences in QTc, Tp-e, Tp-e/QTc and Tp-e/QRS values were observed between the PFV groups in patients without coronary atherosclerosis. There was no significant difference in QTc, Tp-e/QTc, Tp-e/QRS, Tp-e/QTc*QRS and QTc/QRS observed between the BMI groups either in patients with and without coronary atherosclerosis. CONCLUSION: PFV and not obesity measured by BMI is significantly associated with novel ECG markers of arrhythmia risk in patients with coronary atherosclerosis. These results could suggest the potential role of PFV in cardiac arrhythmogenesis through depolarization-repolarization conduction abnormalities. PMID- 29996991 TI - The evaluation of Tp-e interval after transcatheter aortic valve implantation. PMID- 29996992 TI - "Pseudo" Hisian extrasystole arising from the proximal portion of the left bundle branch. AB - The diagnosis of a Hisian extrasystole is based on simple electrocardiographic features and both an extrasystole arising from the His-Bundle ("true" Hisian extrasystole) and also one from the proximal portion of the bundle branch ("pseudo" Hisian extrasystole) would be diagnosed as Hisian extrasystoles [1]. Here we report a case of "pseudo" Hisian extrasystole arising from the proximal portion of the left bundle branch and the successful catheter ablation was achieved in the right coronary cusp. PMID- 29996993 TI - A QS pattern in leads V1 and V2 is associated with septal scarring independent of scar etiology - A cardiac magnetic resonance imaging study. AB - BACKGROUND: Isolated septal myocardial infarction (MI) is traditionally characterized by the presence of pathological Q waves in leads V1 and V2 on the surface electrocardiogram (ECG). The purpose of this study was to determine the relation between this ECG pattern and septal scar on cardiac magnetic resonance (CMR) imaging. METHODS: We retrospectively reviewed the medical records of 996 consecutive patients who received both ECG and CMR. RESULTS: Nineteen patients had a Q wave in leads V1 and V2. Septal scar was present in all 19 patients. Based on CMR imaging criteria, septal scars were ischemic in 8 patients (42%) and non-ischemic in 11 patients (58%). CONCLUSION: The results suggest that the presence of a QS pattern in leads V1 and V2 on the surface ECG is highly predictive of the presence of a septal myocardial scar, but is not diagnostic for septal MI, even after excluding comorbidities known to produce a pseudo-septal MI pattern. PMID- 29996994 TI - A single center experience on the clinical utility evaluation of an insertable cardiac monitor. AB - BACKGROUND: The evaluation of insertable cardiac monitor (ICM) has been largely on the device performance and safety with only limited studies on the clinical utility. The aim of this study was to evaluate the clinical utility of ICM in patients with a variety of clinical presentations. METHODS: A single-center retrospective study on the clinical utility, as measured by both expected and unexpected clinical useful ICM findings and the initiation of therapeutic interventions, was conducted. RESULTS: Ninety-five consecutive patients (median age 68 years) received ICM Reveal LINQTM for clinical indications of unexplained syncope (53), cryptogenic stroke (19), unexplained infrequent palpitations (14) and AF management (9). During a median follow-up of 414 days, the causes for unexplained syncope were arrhythmia-related (11.3%), arrhythmia-unrelated (32%) and undetermined (56.6%). Atrial fibrillation in patients with cryptogenic stroke was detected in 31.6% (6/19). The clinical utility occurrence was 48.4% with the expected and incidental (unexpected) clinical utility of 41% and 7.4% patients respectively. Of these, therapeutic interventions based on ICM diagnoses were initiated in 18.9% (18/95) of patients. CONCLUSIONS: ICM (Reveal LINQTM) offers substantial expected and unexpected clinical utility in patients with a variety of clinical presentations. The causes of nearly one third of patients receiving ICM for unexplained syncope were unrelated to cardiac arrhythmia. Nearly one fifth of patients with newly diagnosed arrhythmia from ICM received therapeutic interventions. PMID- 29996995 TI - T wave alternans extracted from 30-minute short resting Holter ECG recordings predicts mortality in heart failure. AB - BACKGROUND: We extracted T Wave Alternans (TWA) from a 30 minute Short Resting Holter ECG (SRH ECG) in the supine position, as a Total Mortality (TM) predictor in Heart Failure (HF). METHODS: Signals from 146 HF patients (LVEF = 33 +/- 10%), were analyzed with Modified Moving Average method. After 42.1 months, 26 patients died. RESULTS: (Deceased vs Living group): TWA:31 +/- 18 MUV vs 25 +/- 13 MUV(p = 0.05), LVEF:32 +/- 10% vs 34 +/- 9% (p = 0.5), Heart Rate:73 +/- 11 bpm vs 69 +/- 12 bpm (p = 0.2), SDNN/HRV:45 +/- 42 ms vs 41 +/- 29 ms (p = 0.4), QRS:123 +/- 26 ms vs 119 +/- 29 ms (p = 0.5).Cox regression model adjusted for TWA, LVEF and QRS, revealed that the TWA was an independent TM predictor (H.R.: 1.022, 95% C.I.: 0.999-1.046, p = 0.05).The TWA >= 42 MUV demonstrated HR: 2.521, (95% C.I.: 0.982-6.472, p = 0.05). CONCLUSIONS: In severely affected HF patients, TWA from a SRH ECG may be present even during slow resting heart rates and proved to be an important and independent TM predictor. The SRH ECG recording is an efficient and fast method for mortality risk evaluation in HF patients. PMID- 29996996 TI - Correlation between ST segment shift and cardiac diastolic function in patients with acute myocardial infarction. AB - BACKGROUND: Diastolic dysfunction is the early sign of myocardial ischemia that usually occurs earlier than ECG changes. AIM OF THE STUDY: To determine the existence of a correlation between ST segment shift and diastolic dysfunction among patients with AMI. METHODS: Fourty six patients with significant ST segment elevation or depression and having symptoms of acute myocardial infarction for <12 h were enrolled in this study. Patients were examined for serial ECG, cardiac enzymes, and echocardiography. RESULTS: There was no significant correlation between ST segment elevation or depression and majority of the diastolic indices. Few diastolic parameters; such as, E/A ratio of the mitral valve and deceleration time of the tricuspid valve showed a direct correlation with the ECG changes. Whereas, the Tei Index of the LV function showed a borderline correlation to the ST segment elevation at discharge. CONCLUSION: Overall, there was no correlation between either ST segment elevation or depression and the LV or RV diastolic function in patients with acute coronary syndrome (ACS). Improvement of the ST segment total score was associated with improvement of the diastolic function grades at discharge. Moreover, this association has shown an evidence of dose response relationship, the more improvement in total score at discharge the more improvement in diastolic function grade level. PMID- 29996997 TI - Outcome of all-comers with STEMI based on the grade of ischemia in the presenting ECG. AB - BACKGROUND: Grade 3 ischemia (G3I) in the 12-lead electrocardiogram (ECG) predicts poor outcome in patients with ST-elevation myocardial infarction (STEMI). The outcome of G3I in "real-life" patient cohorts is unclear. METHODS: The aim of the study was to establish the prognostic significance of grade 2 ischemia (G2I), G3I and the STEMI patients excluded from ischemia grading (No grade of ischemia, NG) in a real-life patient population. We assessed in hospital, 30-day and 1-year mortality as well as other endpoints. RESULTS: The NG patients had more comorbidities and longer treatment delays than the two other groups. Short-term and 1-year mortality were highest in patients with NG and lowest in patients with G2I. Maximum troponin level was highest in G3I, followed by NG and G2I. In logistic regression multivariable analysis, NG was independently associated with 1-year mortality. CONCLUSIONS: NG predicted poor outcome in STEMI patients. G2I predicted relatively favorable outcome. PMID- 29996998 TI - Fragmented QRS complexes after acute myocardial infarction are independently associated with unfavorable left ventricular remodeling. AB - BACKGROUND: Recovery of left ventricular ejection fraction (LVEF) after acute myocardial infarction (MI) is not universal and is difficult to predict. Fragmented QRS (fQRS) complexes are thought to be markers of myocardial scar. We hypothesized that fQRS complexes on 12-lead surface ECGs during the initial post MI period would be associated with adverse LV remodeling over the following year. METHODS: Change in LVEF between the early (0-2 month) and later (2-12 month) post MI periods was assessed in two independent cohorts of post-MI patients with initial LV dysfunction. A decline or no recovery in LVEF (DeltaLVEF <=0%) was used as a primary outcome. fQRS complexes were measured on 12-lead ECGs within a week of acute MI. A subset of patients underwent cardiac magnetic resonance imaging (CMR) for scar quantification. RESULTS: Of 705 patients in the combined cohort, 27% experienced the primary outcome (average DeltaLVEF of -4%). fQRS complexes were associated with a two-fold higher risk of no LVEF recovery, independent of prior MI or CABG, baseline LVEF, MI location and QRS duration or axis. Of 113 patients undergoing CMR, fQRS was associated with increased peri infarct zone late gadolinium enhancement (13 +/- 5% vs 11 +/- 4%, p = 0.02), but not core infarct. CONCLUSIONS: Despite contemporary post-MI therapy, >1 in 4 patients will show a decline in LVEF during follow-up. Fragmented QRS complexes on 12-lead surface ECG early post-MI may be a valuable marker of unfavorable LV remodeling and correlate to increased peri-infarct scar on CMR imaging. PMID- 29996999 TI - Citrus fruits induced swallow syncope with atrioventricular block or sinus arrest. AB - Swallow syncope is a relatively rare syndrome and caused by various foods and drinks. A 76-year-old man was admitted with frequent syncope while eating. Holter electrocardiogram revealed frequent occurrence of atrioventricular block during meals. Both atrioventricular block and sinus arrest were induced by only eating citrus fruits, citrus jelly, and acidic foods but not by other drinks and foods. These arrhythmias were suppressed after administration of atropine. No further episodes of syncope recurred after the implantation of a DDD pacemaker. This case indicated that acidic stimulation of citrus induced a vasovagal reflex via esophageal nociceptors leading to syncope. PMID- 29997000 TI - Self-terminating ventricular fibrillation recorded by an implantable loop recorder as a cause of syncope - A case report. AB - Ventricular fibrillation (VF) is the most common arrhythmia leading to sudden cardiac death, but in rare cases VF can manifest as a syncope, provided that it will self-terminate. We present a case of a 45-year old female with a history of unexplained syncopal episodes despite exhaustive diagnostics. Implantable loop recorder documented an episode of idiopathic, self-terminating VF as a cause of syncope. PMID- 29997001 TI - Evaluation of T-wave alternans in pediatric patients with chronic renal failure. AB - INTRODUCTION: Microvolt T-wave alternans (TWA) is known to be useful in prediction of ischemia and sudden death in high-risk populations and there are no studies in children with chronic renal failure (CRF). Cardiac problems seem to be responsible for an important part of death in children and young adults with CRF. The aim of this study is to evaluate Holter microvolts TWA measurements in children with CRF comparing to the control group. METHODS: This prospective study included 40 patients with CRF and 48 healthy controls. The history, echocardiography and microvolt TWA values based on 24-hour ECG recordings of the patients were evaluated. Analysis of microvolt TWA was considered on the basis of three leads (V5, V1 and AVF). RESULTS: Compared with the controls, the mean systolic and diastolic blood pressure values and average heart rates were significantly higher in the children with CRF (p = 0.001 and p = 0.026, respectively). Also, the values of left ventricular internal dimensions at end diastole and end-diastolic volume were significantly higher in CRF group (p = 0.01 and p = 0.049, respectively) and couplet ventricular extrasystole was detected in 2 patients with CRF. Consequently, all TWA values in three leads were increased in CRF group than the control group but the only increase in V5 lead was statistically significant (p = 0.028). CONCLUSIONS: This study has demonstrated that microvolt TWA values increased in pediatric patients with CRF. TWA might be used for early risk assessment in pediatric patients with CRF in the future. PMID- 29997002 TI - Shortening of paced QRS duration after electrocardiographic optimization of left ventricular pacing vector in patients treated with Cardiac Resynchronization Therapy. PMID- 29997003 TI - Narrow QRS tachycardia with extreme rightward axis. What is the mechanism? AB - A 25 year old lady presented with palpitation to the emergency department. Her pulse rate was 210 beats per minute. She was hemodynamically stable with a blood pressure of 100/60 mm Hg. 12 lead surface electrocardiogram (ECG) was recorded during the presentation (Fig. 1) and rhythm strip (Fig. 2A) during administration of IV adenosine. What is the likely diagnosis? PMID- 29997004 TI - New ECG markers for predicting long-term mortality and morbidity in patients receiving cardiac resynchronization therapy. AB - : We investigated prognostic value of four recently proposed ECG markers in patients with cardiac resynchronization therapy (CRT): 1./ pathological preimplantation QRS axis, 2./ increase in QRS amplitude in V3 during biventricular pacing, 3./ negative QRS in V1/V2 during left ventricular (LV)-only pacing, 4./ longer QRS duration during LV-only pacing. A longitudinal cohort study was performed (n = 552). RESULTS: During the 9-year observation period the primary endpoint (death from any cause or urgent heart transplantation) was met in 232 patients. The secondary endpoint of survival free of heart failure hospitalization was met in 292 patients. Long LV-paced QRS and pathological axis predicted unfavorable prognosis in Kaplan-Meier analysis. In multivariable Cox model (functional class, LV ejection fraction, LV end-diastolic dimension, permanent atrial fibrillation, age, gender, heart failure etiology, creatinine level, diabetes mellitus), LV-paced QRS duration remained a significant determinant of both endpoints. The other studied ECG markers lacked independent prognostic value. PMID- 29997006 TI - Electrocardiographic left atrial abnormalities predict cardiovascular mortality. AB - OBJECTIVE: Clinical utilization of electrocardiography for diagnosis of left atrial abnormalities is hampered by variable P-wave morphologies, multiple empiric criteria, and lack of an imaging "gold standard". Our aim was to determine the prevalence of P-wave patterns and demonstrate which components have associations with cardiovascular death (CVD). METHODS: This is a retrospective analysis of 20,827 veterans <56 years of age who underwent electrocardiograms at a Veteran's Affairs Medical Center from 1987 to 1999, followed for a median duration of 17.8 years for CVD. Receiver Operating Characteristic, Kaplan-Meier and Cox Hazard analyses were applied, the latter with adjustment for age, gender and electrocardiography abnormalities. RESULTS: The mean age was 43.3 +/- 8 years, and 888 CVD (4.3%) occurred. A single positive deflection of the P-wave (Pattern 1) was present in 29% for V1 and 81% for V2. A singular negative P-wave (Pattern 2) was present in 4.6% for V1 and 1.6% in V2. A P-wave with an upward component followed by downward component (Pattern 3) was present in 64.5% for V1 and 17.5% for V2. When the downward component in Patterns 2 and/or 3 is at least 100 MUV, a significant association is observed with CVD (adjusted hazard ratios [HRs] 2.9-4.1, P < 0.001). Total P-wave duration >=140 ms was also associated with CVD (adjusted HR 2.2, P < 0.001). CONCLUSIONS: A negative P-wave in V1 or V2 <=-100 MUV, and P-wave with a duration of >=140 ms, all have independent and significant associations with CVD, with HRs comparable to other electrocardiography abnormalities. PMID- 29997005 TI - The association of the amounts of epicardial fat, P wave duration, and PR interval in electrocardiogram. AB - BACKGROUND: The relationship of epicardial fat and cardiac arrhythmias has been described in many studies. The association of the amounts of epicardial fat and the characteristics of electrocardiogram (ECG) remains unclear. The purpose of this study was to elucidate the association between the amounts of epicardial fat and the characteristics of ECG. METHODS: A total of 100 consecutive patients who received multi-detector computer tomography (MDCT) were enrolled. The amounts of epicardial fat, including total heart, total atria, total ventricles, right atrium (RA), right ventricle (RV), left atrium (LA), and left ventricle (LV) regions, were measured. The PR interval in lead II, the P wave duration in lead I, the characteristics of inter-atrial conduction block manifested in ECG, the corrected QT interval (QTc) and the QT dispersion of a 12-lead ECG were measured manually by a computer caliper. RESULTS: The PR interval was correlated with the amounts of epicardial fat including total heart, total atria, total ventricles, RA, RV, LA, and LV (R = 0.295, p = 0.003; R = 0.379, p < 0.001; R = 0.284, p = 0.003; R = 0.415, p < 0.001; R = 0.287, p < 0.001; R = 0.33, p < 0.001; R = 0.244, p = 0.014). The P wave duration of lead I was also correlated with the amounts of epicardial fat (R = 0.202, p = 0.043; R = 0.283, p = 0.004; R = 0.225, p = 0.024; R = 0.365, p < 0.001; R = 0.256, p = 0.001; R = 0.20, p = 0.046; R = 0.199, p = 0.048) but the QTc interval and the QT dispersion were not. Inter atrial conduction block was also associated with the amounts of epicardial fat, including total atria, RA and LA in univariate analysis (odds ratio (OR): 1.04, 95% of confidence interval (CI): 1.01-1.06, p = 0.015; OR: 1.08, 95% CI: 1.02 1.15, p = 0.011; OR: 1.05, 95% CI: 1.01-1.10, p = 0.031). In multivariate analysis of linear regression, the amounts of RA epicardial fat was most significantly associated with the PR interval, and the P wave duration (beta value: 1.30, 95% CI: 0.59-2.02, p < 0.001; beta value: 0.81, 95% CI: 0.34-1.28, p = 0.001). In multivariate analysis of logistic regression, inter-atrial conduction block was also significantly associated with the amounts of RA epicardial fat (odds ratio (OR): 1.08, 95% CI: 1.02-1.15, p = 0.011). CONCLUSIONS: The PR interval, P wave duration and inter-atrial conduction block were associated with the amounts of epicardial fat, which might imply an effect for arrhythmogenesis. PMID- 29997007 TI - Serial observation of electrocardiographic responses to corticosteroid therapy in a patient with right ventricular-predominant cardiac sarcoidosis. AB - Predominant or isolated right ventricular involvement in cardiac sarcoidosis is uncommon, but should always be considered in a case of right ventricular hypertrophy combined with ventricular arrhythmia and/or conduction disturbance. Although improvement in right ventricular hypertrophy and atrioventricular conduction disturbance following corticosteroid therapy has been reported, the detailed serial electrocardiographic responses during corticosteroid therapy, as well as temporal changes in the electrocardiographic, biochemical, and morphological responses, have not been reported. We describe the clinical course and supportive imaging findings of reversible right ventricular hypertrophy and cardiac conduction disturbance in a case of right ventricular-predominant cardiac sarcoidosis. PMID- 29997008 TI - Wide QRS complex supraventricular tachycardia with negative precordial concordance: Electrocardiographic clues for Mahaim pathway with Ebstein anomaly. AB - Ebstein's anomaly is often accompanied by either Wolff-Parkinson-White syndrome or atriofascicular Mahaim. These bypass tracts give rise to antidromic atrioventricular (AV) re-entrant tachycardias, in which the bypass tract serves as the anterograde limb of the circuit and the AV node as the retrograde limb of the reentrant circuit. Since the antidromic AV reentrant tachycardia over a Mahaim fibre has a typically left bundle braunch block (LBBB) morphology, it is easy to make a misdiagnosis of supraventricular tachycardia with functional LBBB or even of ventricular tachycardia particularly in the presence of negative concordance. Some electrocardiographic clues might prevent misdiagnosis of ventricular tachycardia and inadvertent ICD implantation. PMID- 29997009 TI - A novel three base-pair deletion in domain two of the cardiac sodium channel causes Brugada syndrome. AB - INTRODUCTION: Mutations within SCN5A are found in a significant proportion (15 30%) of Brugada syndrome (BrS) cases and impair sodium transport across excitable cardiac cells that mediate ventricular contractions. Genetic testing offers a means to clinically assess and manage affected individuals and their family members. METHODS AND RESULTS: The proband at age 44 years old exhibited a syncopal event during exercise, and presented later with a spontaneous type-I BrS pattern on 12-lead resting electrocardiogram (ECG). Mutational analysis performed across all SCN5A exons revealed a unique three base-pair deletion p.M741_T742delinsI (c.2223_2225delGAC), in a heterozygous state in the proband and 2 siblings. This mutation was not seen in a cohort of 105 ethnicity-matched controls or in public genome databases. Patch clamp electrophysiology study conducted in TSA201 cells showed an abolishment of sodium current (INa). The proband, and several relatives, also harboured a known SCN5A variant, p.R1193Q (c.3578G>A). CONCLUSION: Our study has demonstrated the deleterious effect of a novel SCN5A mutation p.M741_T742delinsI (c.2223_2225delGAC). The findings highlight the complex effects of gender and age in phenotype manifestation. It also offers insights into improving the long-term management of BrS, and the utility of cascade genetic screening for risk stratification. PMID- 29997010 TI - In memoriam Andrea Nava M.D. (1938-2018), associate professor of cardiology, University of Padova. PMID- 29997011 TI - Double loop reentrant atrial tachycardia following ablation for atrioventricular nodal reentrant tachycardia. AB - We report a patient with a history of multiple ablations for recurrent atrioventricular nodal reentrant tachycardia who developed an atrial tachycardia four years after his last procedure. Subsequent electroanatomical mapping demonstrated double loop macro-reentrant atrial tachycardia consistent with a roof dependent flutter and a perimitral flutter. We successfully terminated the tachycardia by targeting isthmuses at sites of prior ablation. PMID- 29997012 TI - Black athlete electrocardiographic repolarization pattern. AB - There is debate over the use of the electrocardiogram (ECG) to screen athletes for disorders associated with sudden cardiac death, but if screening is completed, accurate ECG interpretation is important. Recently, there has been recognition of a normal black athlete repolarization pattern which includes J point elevation, convex ST-segment elevation, and T-wave inversions in leads V1 to V4 occurring in 5-15% of black athletes. This pattern must be differentiated from T-wave inversions that are associated with hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The combination of J-point elevation >1 mm and T-wave inversions confined to leads V1-V4 excludes cardiomyopathy. If T-wave inversions are present in the inferior or lateral leads or there is no J-point elevation, further evaluation for a cardiomyopathy is required. By recognizing this ECG pattern as a normal variant, unnecessary ancillary testing and restriction from sports can be avoided. PMID- 29997013 TI - A model for predicting emergency physician opinion of electrocardiogram tracing data quality. AB - BACKGROUND: Limited work has established an objective measure of ECG quality that correlates with physician opinion of the study. We seek to establish a threshold of acceptable ECG data quality for the purpose of ruling out STEMI derived from emergency physician opinion. METHODS: A panel of three emergency physicians rated 240 12-Lead ECGs as being acceptable or unacceptable data quality. Each lead of the ECG had the following measurements recorded: baseline wander, QRS signal amplitude, and artifact amplitude. A lasso regression technique was used to create the model. RESULTS: The area under the curve for the model using all 36 elements is 1.0, indicating a perfect fit. A simplified model using 22 terms has an area under the curve of 0.994. CONCLUSIONS: This study demonstrated that emergency physician opinion of ECG quality for the purpose of ruling out STEMI can be predicted through a regression model. PMID- 29997014 TI - Electrocardiographic characteristics and mapping approach of ventricular arrhythmias originating from the left ventricular summit. AB - The left ventricular summit is the most common site of idiopathic epicardial ventricular tachycardia (VT). We report a case of a 48-yr-old lady who presented with VT of RBBB configuration, inferior axis and delayed initial activation. During electrophysiological study, local activation in the distal great cardiac vein (GCV) preceded surface QRS by 56 ms whereas mapping in the aortic sinuses and left ventricular outflow tract endocardially revealed late activation. Ablation in the distal GCV with an irrigated catheter successfully terminated the tachycardia. The 12-lead electrocardiogram is an invaluable tool for predicting the VT focus and planning the mapping strategy. PMID- 29997015 TI - The dispersion of myocardial repolarization in ischemic stroke and intracranial hemorrhage. AB - BACKGROUND: Markers of dispersion of myocardial repolarization have been proposed to identify the patients at higher risk of malignant arrhythmic events. The aim of the present study is to assess a possible association of the electrocardiografic (ECG) markers of the dispersion of repolarization with the type of stroke, involvement of insula, neurological severity (National Institutes of Health Stroke Scale, NIHSS score), and disability (modified Rankin Scale, mRS score) in patients with a cerebrovascular event. METHODS: We conducted a retrospective analysis based on data prospectively collected from consecutive patients with a cerebrovascular event who underwent 12-lead ECG at admission to the Verona Stroke Unit. RESULTS: Of the 63 patients included in the study, 55 had ischemic stroke and 8 intracranial hemorrhage. TpTe (time between the peak and the end of the T wave) and TpTe/QTc (TpTe/corrected time between the start of the Q wave and the end of the T wave) in lead V5 were higher in intracranial hemorrhage than in ischemic stroke (p = 0.03 and p = 0.04, respectively) and QT max (the longest QT calculated in the 12 leads) was higher in patients with involvement of insula (p <= 0.01). A correlation was found between QTc max and NIHSS score at admission (p = 0.02), QT max and NIHSS score at discharge (p = 0.05), and QT max and mRS score at discharge (p = 0.02). CONCLUSIONS: TpTe and TpTe/QTc in V5 lead were associated with intracranial hemorrhage and QT max was associated with involvement of insula. The prolongation of QT was correlated with neurological severity and disability. PMID- 29997016 TI - Dissertation of ST elevation causation. AB - ECG Quiz: Diffuse ST elevations with broad differential in 57 year old man. PMID- 29997017 TI - Novel criterion for the differential diagnosis of wide QRS complexes and wide complex tachycardia using the initial activation of QRS on leads V1 and V2: Differential diagnosis of wide QRS based on V1-V2. AB - BACKGROUND: Many diagnostic criteria for the differential diagnosis of wide complex tachycardia (WCT) are complex and not completely accurate. Incorrect diagnosis is also related to error in applying criteria. OBJECTIVES: To propose a novel reliable criterion for wide QRS complexes' differential diagnosis. MATERIAL AND METHODS: One hundred Electrocardiograms (ECGs) with wide QRS complexes were analyzed using the ECG software. Five variables were measured during the first 20 ms of QRS in leads V1 and V2 and compared between premature ventricular contraction (PVC) and conducted supraventricular impulse with bundle branch block (BBB) groups. The best discriminant variable was identified. The validity of this variable was tested on a group of 20 patients who had WCT during an electrophysiology study. RESULTS: Almost all variables were statistically different between PVC and BBB groups. The sum of voltages in absolute value of vectors during the initial 20 ms of the QRS in leads V1 and V2 (SigmaV1 + V2) was the most discriminant between the two groups (131 +/- 85 microvolt [MUV] vs. 498 +/- 392 MUV, p < 0.01). A SigmaV1 + V2 < 258 MUV (rounded to <0.25 millivolt [mV]) diagnosed PVCs with good sensitivity and specificity (90% and 85% respectively). The SigmaV1 + V2 in WCT group had lower values in VT versus supra ventricular tachycardia (SVT) group (0.53 +/- 0.35 mV vs. 1.79 +/- 1.04 mV, p = 0.004). CONCLUSIONS: The SigmaV1 + V2 < 258 MUV is a reliable criterion for PVC diagnosis. It could be measured accurately using ECG Software, which could be programmed to calculate it automatically, limiting the risk of human error. The SigmaV1 + V2 also seems capable of discriminating between VT and SVT. PMID- 29997018 TI - Image digitization of discontinuous and degraded electrocardiogram paper records using an entropy-based bit plane slicing algorithm. AB - BACKGROUND: Electrocardiograms (ECGs) are routinely recorded and stored in a variety of paper or scanned image format. Current ECG recording machines record ECG on graph paper, also it provides digitized ECG signal along with automated cardiovascular diagnosis (CVD). However, such recording machines cannot analyse preserved paper ECG records as it requires input in terms of digitized signal. Therefore, it is important to extract ECG signal from these preserved paper ECG records using digitization method. There are different paper degradations that adversely affect digitization process. The purpose of this work is to perform an image enhancement and digitization of the degraded ECG images to extract continuous ECG signal. METHODS: In this paper, we propose entropy-based bit plane slicing (EBPS) algorithm in which pre-processing is done using dominant color detection and local bit plane slicing. Maximum entropy based adaptive bit plane selection is applied to the pre-processed image. Discontinuous ECG correction (DECGC) is then done to produce continuous ECG signal. RESULTS: The algorithm is tested on 836 different degraded paper ECG records obtained from various diagnostic centers. After analysis with 101 known ground truth ECG signals the accuracy, sensitivity, specificity and overall F-measure of ECG is 99.42%, 99.69%, 99.81% and 99.26% respectively. The RMS error and correlation between the extracted digitized signal and ground truth for 101 cases is 0.040 and 99.89% respectively. CONCLUSIONS: The EBPS method is able to remove all types of degradation in paper ECG records to generate a uniform digitized signal. Instead of manual measurement and prediction from archived paper ECG records, automated prediction (using already existing cardiovascular diagnosis software) is possible with the help of extracted digitized signal obtained using proposed digitization method, which will also help retrospective cardiovascular analysis. PMID- 29997019 TI - Non-invasive electrophysiological assessment of the optimal configuration of quadripolar lead vectors on ventricular activation times. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is now generally delivered via quadripolar leads. Assessment of the effect of different vector programs from quadripolar leads on ventricular activation can be now done using non-invasive electrocardiographic mapping (ECM). MATERIAL AND METHODS: In nineteen patients with quadripolar LV leads, activation maps were constructed. The total ventricular activation time (TVaT) and the time for the bulk of ventricular activation (VaT10-90) were calculated. RESULTS: CRT delivered via a quadripolar lead significantly reduced TVaT and VaT10-90 by a mean of 16 ms and 31 ms, respectively, compared to baseline. There was a marked reduction in ventricular activation between the most and least synchronous vectors: 28% difference in baseline TVaT and 37% difference in VaT10-90. CONCLUSION: Changes in the configuration of an LV quadripolar lead significantly affected ventricular activation timings in both ischaemic and non-ischaemic subjects. This suggests that programming of the optimal pacing vector may need to be individually tailored. PMID- 29997020 TI - More than meets the eye: False code STEMI. AB - In patients with suspected ST elevation myocardial infarction, it is of paramount importance to identify artifacts on the resting electrocardiogram that may be erroneously interpreted as ST segment deviations in order to prevent administration of potentially harmful pharmacotherapy and invasive coronary angiography. In this case report, we describe a pervasive square wave artifact, not previously reported, that was misdiagnosed as ST segment elevation by computer software and initial physician interpretation. PMID- 29997021 TI - Deciphering wide QRS complex: The quest continues. PMID- 29997023 TI - T-wave oversensing is more dependent on ICD sensitivity algorithm than lead sensing configuration. AB - Modern implantable cardioverter defibrillators (ICD) employ dynamic sensing algorithms in order to protect against fine ventricular fibrillation without oversensing intrinsic activity. We present a patient with a Medtronic ICD who had inhibition of pacing and not inappropriate shocks due to T wave oversensing (TWOS) in both true bipolar (TB) and integrated bipolar (IB) sensing configurations. Rather than alternatives such as lead revision or programming to an unacceptably insensitive value, this was solved by exchanging for a Boston Scientific ICD. Although the literature suggests lead sensing configuration impacts TWOS, this case demonstrates ICD sensitivity algorithm may be a key determinant. PMID- 29997022 TI - Image-based modeling of acute myocardial ischemia using experimentally derived ischemic zone source representations. AB - BACKGROUND: Computational models of myocardial ischemia often use oversimplified ischemic source representations to simulate epicardial potentials. The purpose of this study was to explore the influence of biophysically justified, subject specific ischemic zone representations on epicardial potentials. METHODS: We developed and implemented an image-based simulation pipeline, using intramural recordings from a canine experimental model to define subject-specific ischemic regions within the heart. Static epicardial potential distributions, reflective of ST segment deviations, were simulated and validated against measured epicardial recordings. RESULTS: Simulated epicardial potential distributions showed strong statistical correlation and visual agreement with measured epicardial potentials. Additionally, we identified and described in what way border zone parameters influence epicardial potential distributions during the ST segment. CONCLUSION: From image-based simulations of myocardial ischemia, we generated subject-specific ischemic sources that accurately replicated epicardial potential distributions. Such models are essential in understanding the underlying mechanisms of the bioelectric fields that arise during ischemia and are the basis for more sophisticated simulations of body surface ECGs. PMID- 29997024 TI - Roux-en-Y gastric bypass as an emergency procedure for resolving SADI-S leak. PMID- 29997025 TI - Hepatic abscess caused by a fishbone: An unusual finding. PMID- 29997026 TI - Current status of gastrectomy for cancer: "Less is often more". PMID- 29997027 TI - High-energy trauma patients with pelvic fractures: Management trends in Ontario, Canada. AB - INTRODUCTION: Although fractures of the pelvic ring account for only 2-3% of all fractures, they are present in approximately 7-20% of patients with high-energy polytrauma. High-energy pelvic fractures are life-threatening injuries, with mortality estimates ranging from 6 to 35%. The purpose of this study was to examine trends in the incidence, diagnosis, treatment, and mortality rates of high-energy pelvic fractures in Ontario, Canada over a 10-year period. METHODS: A cohort of 3915 patients who sustained a high-energy pelvic fracture in Ontario between 01 April 2005 and 31 March 2015 was identified using the Ontario Trauma Registry and administrative healthcare data linked by the Institute for Clinical Evaluative Science (ICES). Severely injured patients (defined as having an Injury Severity Score (ISS) of >=16) with pelvic fractures following high-velocity mechanisms of injury were identified using applicable ICD-10 codes. Trends were assessed statistically using the Poisson and the Cochrane-Armitage tests for trend. Modified Poisson regression was used to model the adjusted risk ratio of mortality by pelvic fracture treatment. RESULTS: The incidence of pelvic fracture remained constant at approximately 4.6 cases per 100,000 population annually between 2005 and 2011. From 2012, there was a decrease in patients with ISS >= 16 due to changes in the calculation of the ISS. The proportion of patients presenting with ISS > 50 increased from 8.2% to 14.1% (p = 0.008) over the study period. Automobile collisions or pedestrians struck by vehicles accounted for over half of injuries. Approximately 6% of patients underwent angioembolisation. Treatment with external fixation (15.5%-20.2%) or no surgical intervention (46.2% 61.3%) increased from 2005 to 2015. Mortality remained constant (11% at 30 days), and laparotomy was the only major intervention not associated with decreased risk of death. CONCLUSIONS: Stable mortality despite increasing injury severity suggests that the quality of care provided to patients with high-energy pelvic fractures has improved over time. However, unchanged incidence suggests the need for ongoing efforts aimed towards injury prevention. ISS at presentation was the most significant predictor of mortality in this patient population. PMID- 29997029 TI - Editorial. PMID- 29997028 TI - Efficacy of surveillance ultrasound for venous thromboembolism diagnosis in critically ill children after trauma. AB - INTRODUCTION: Venous thromboembolism (VTE) is increasingly prevalent in injured children admitted to the intensive care unit (ICU). Few data exist to support VTE pharmacologic prophylaxis or ultrasound (US) surveillance in children with high bleeding risk. After implementation of screening US guidelines, we sought to describe our experience, hypothesizing that screening US of children at highest risk for VTE results in earlier detection and management. STUDY DESIGN: A retrospective analysis was conducted on prospectively collected data of injured children admitted to an American College of Surgeons Verified level 1 Pediatric Trauma Center from 2010 to 2015. In patients at high risk for both VTE and bleeding (HRHR), guidelines recommended deferral of pharmacologic prophylaxis and a screening US at >=7 ICU days if bleeding risk remained. Outcomes analyzed included VTE rates, guideline compliance, and US timing. The rate of deep vein thrombosis (DVT) detection (number of DVT captured/number of US obtained) was examined. RESULTS: Of 4061 trauma patients, 588 (14.5%) were critically injured including 112 patients who met HRHR criteria. The rate of VTE in the HRHR group >=7 ICU days was 25% (14/56). Of 23 VTE diagnosed in the ICU, 17 were detected by 49 US performed (34.7%), with the remaining 6 diagnosed by computed tomography. DVT was detected earlier than the US guideline recommended 7 days, independent of symptoms. Guideline compliance was 86%. CONCLUSION: Critically injured children at risk for bleeding frequently develop VTE. Surveillance ultrasound in patients at high risk for both VTE and bleeding allows earlier detection and treatment. LEVEL OF EVIDENCE: Therapeutic study, level II. PMID- 29997030 TI - Species distribution and antifungal susceptibility among clinical isolates of Candida parapsilosis complex from India. AB - BACKGROUND: Candida parapsilosis is recognized as a species complex: Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis are three distinct but closely related species. AIMS: To determine the species and antifungal susceptibility of members of the C. parapsilosis complex, isolated from clinical samples. METHODS: Isolates identified as C. parapsilosis complex by VITEK(r) 2 system were included. Antifungal susceptibility test was done using the VITEK(r) 2 semi-automated system. The distribution of the species in the complex was determined by multiplex PCR. RESULTS: Among the seventy-seven C. parapsilosis complex isolates, C. parapsilosis sensu stricto (57.1%) was the commonest species, followed by C. orthopsilosis (40.2%) and C. metapsilosis (2.5%). All three species were susceptible to amphotericin B, caspofungin and micafungin. Among C. parapsilosis sensu stricto isolates, 16% were resistant to fluconazole while 2.2% showed dose dependent susceptibility. Also, 18.2% of C. parapsilosis sensu stricto isolates showed dose dependent susceptibility to voriconazole. CONCLUSIONS: C. parapsilosis sensu stricto was the most commonly isolated member of the C. parapsilosis complex and it showed high resistance to fluconazole. A high prevalence of C. orthopsilosis (40.2%) was also noted. PMID- 29997031 TI - Meningococcal carriage in high-risk settings: A systematic review. AB - BACKGROUND: Historically, semi-closed populations have had high rates of meningococcal carriage and have experienced recurrent outbreaks. As such, these high-risk groups are recommended for targeted vaccination in many countries. METHODS: A systematic review of eight databases and Google Scholar forward citations was conducted to characterize serogroup-specific meningococcal carriage in university students, military personnel, and Hajj pilgrims from 2007 to 2016. RESULTS: A total of 7014 records were identified and 22 studies were included. Overall carriage ranged from 0.0% to 27.4% in Hajj pilgrims, from 1.5% to 71.1% in university students, and from 4.2% to 15.2% in military personnel. Among serogroups A, B, C, W, X, and Y, serogroup B was most prevalent in Hajj pilgrims, B and Y in university students, and B, C, and Y in military personnel. 'Other' serogroups were more prevalent in university students than Hajj pilgrims or military personnel. Risk factors for carriage varied by setting. Among Hajj pilgrims, a high endemicity in the country of origin increased the risk of carriage, while smoking, male sex, and frequently attending parties increased the carriage risk for university students. Similarly, smoking increased the carriage risk for professional soldiers. Data gaps remain for many regions. CONCLUSIONS: Preventative vaccination policies for high-risk groups should be based on current disease data in individual countries, supplemented by carriage data. Meningococcal carriage studies and disease surveillance are critical for determining the local epidemiology, populations responsible for disease transmission, and the need for targeted vaccination. PMID- 29997032 TI - Motor Neuron Excitability Attenuation as a Sequel to Lumbosacral Manipulation in Subacute Low Back Pain Patients and Asymptomatic Adults: A Cross-Sectional H Reflex Study. AB - OBJECTIVE: The purpose of the study was to compare a time series of tibial nerve H-reflex trials between patients with subacute low back pain (LBP) and asymptomatic adults using pre and post high-velocity, low-amplitude (HVLA) spinal manipulation (SM) and control procedures. METHODS: Asymptomatic adults (n = 66) and patients with subacute LBP (n = 45) were randomized into 3 lumbosacral procedures: side-posture positioning, joint preloading with no thrust, and HVLA SM. A time series of 40 Hmax/Mmax ratios at a rate of 0.1 Hz were recorded in blocks of 10 trials at baseline and after the lumbosacral procedures at time points corresponding to immediately after, 5 minutes after, and 10 minutes after the procedure. Descriptive time series analysis techniques included time plots, outlier detection, and autocorrelation functions. A mixed analysis of variance model (group * procedure * time) was used to compare the effects of lumbosacral procedures on Hmax/Mmax ratios between the patients with subacute LBP and asymptomatic participants. RESULTS: The time series analysis and the significant lumbosacral * time interaction term (P < .05) indicated that inhibition of the Hmax/Mmax ratios at the 10-second postlumbosacral procedure time point was greatest after the HVLA SM procedure. The effects of lumbosacral procedures on Hmax/Mmax ratios were similar between patients with subacute LBP and asymptomatic participants. CONCLUSIONS: Although nonspecific effects of movement or position artifacts on the Hmax/Mmax ratio were present, a reliable and valid attenuation of the Hmax/Mmax ratio occurred as a specific aspect of HVLA SM in both asymptomatic adults and patients with subacute LBP. PMID- 29997033 TI - [Impact of neoadjuvant chemotherapy on the peri-operative morbidity of radical cystectomy for muscle invasive bladder cancer]. AB - INTRODUCTION: Platinum-based neoadjvant chemotherapy (NAC) before radical cystectomy (RC) is the gold standard in the treatment of muscle invasive bladder cancer (MIBC). We aimed to compare the peri-operative morbidity in patients treated by NAC then RC and patients having RC alone. METHODS: Between 1st January 2008 and 31st December 2015, we retrospectively included consecutive patients undergoing RC for MIBC in 2centers. We collected clinical, pathological and peri operative data (30day post operative complications according to the Clavien-Dindo score, delayed complications, pathological results). Patients treated by NAC (NAC RC group) before RC were compared to patients performing RC alone. The NAC-RC group received 1 to 6cycle of high-dose MVAC, MVAC or gemcitabine-cisplatine chemotherapy. Logistic regression identified independant factors of peri operative complications. RESULTS: We included 199 patients: 48in the NAC-RC group and 151in the RC group. Complications rate was 73.9% in the NAC-RC group versus 73.8% in the RC group (P=1.0). In multivariate analyses, only the Charlson score was associated with an increased risk of peri-operative complications (P=0.05). PT0 tumour rate was significantly higher in the NAC-CR group (50% vs 7%, P<0.001). CONCLUSION: NAC does not increase the peri-operative morbidity of the RC. Patients' pre operative comorbidities is the main risk factor for peri operative complications. PMID- 29997034 TI - Stereotactic body radiotherapy for colorectal cancer liver metastases: A systematic review. AB - INTRODUCTION: While surgery is the preferred option for isolated, operable liver metastases from colorectal cancer (CRC), ablative techniques are endorsed for medically or technically inoperable lesions. Stereotactic body radiotherapy (SBRT) is an alternative ablative local therapy that delivers high RT doses in a few fractions to the cancer, sparing surrounding critical tissue. We have performed a systematic review of published trials to evaluate the efficacy of SBRT as a primary modality therapy for CRC liver oligometastases. MATERIALS AND METHODS: We searched the Cochrane Central Register of Controlled Trials, Pubmed, and EMBASE for publications regarding SBRT for CRC liver metastases. Overall survival (OS: median, 1- and 2-year OS %) was the primary endpoint, and median PFS and one- and two-year local control (LC) were the secondary endpoints. A random-effect model pooled-analysis was performed to calculate the aggregated OS rates at 1 and 2 years as well as the one- and two-year LC. RESULTS: A total of 18 studies, encompassing 656 patients, were included in the analysis. The pooled one- and two-year OS were 67.18% (95% CI, 42.1-92.2) and 56.5% (95% CI, 36.7 76.2), respectively. Median PFS and OS were 11.5 and 31.5 months. The pooled one year LC was 67% (95% CI, 43.8-90.2), while the pooled two-year LC was 59.3% (95% CI, 37.2-81.5). Correlation analysis revealed a moderate/poor linear relationship between the SBRT (BED10) dose and LC (p = 0.001, R = 0.47)/OS (p = 0.001, R = 0.29) at 2 years. Mild-moderate and severe liver toxicity were 30.7% and 8.7%. CONCLUSION: SBRT for liver oligometastases is an effective option for patients with advanced CRC, with encouraging local control and survival. However, a definitive validation in large randomised studies is required, due to the retrospective or non-randomised nature of the included studies and the limitations of series with different doses/schedules of treatment. PMID- 29997035 TI - Spatial and temporal risk as drivers for adoption of foot and mouth disease vaccination. AB - Identifying the drivers of vaccine adoption decisions under varying levels of perceived disease risk and benefit provides insight into what can limit or enhance vaccination uptake. To address the relationship of perceived benefit relative to temporal and spatial risk, we surveyed 432 pastoralist households in northern Tanzania on vaccination for foot-and-mouth disease (FMD). Unlike human health vaccination decisions where beliefs regarding adverse, personal health effects factor heavily into perceived risk, decisions for animal vaccination focus disproportionately on dynamic risks to animal productivity. We extended a commonly used stated preference survey methodology, willingness to pay, to elicit responses for a routine vaccination strategy applied biannually and an emergency strategy applied in reaction to spatially variable, hypothetical outbreaks. Our results show that households place a higher value on vaccination as perceived risk and household capacity to cope with resource constraints increase, but that the episodic and unpredictable spatial and temporal spread of FMD contributes to increased levels of uncertainty regarding the benefit of vaccination. In addition, concerns regarding the performance of the vaccine underlie decisions for both routine and emergency vaccination, indicating a need for within community messaging and documentation of the household and population level benefits of FMD vaccination. PMID- 29997036 TI - Contamination of reusable electroencephalography electrodes: A multicenter study. AB - BACKGROUND: Reusable electroencephalography cup electrodes and lead wires (rEEGs CELWs) could be a source of microorganisms capable of causing hospital-acquired infections. The purpose of this study was to investigate for bacterial species of cleaned rEEGs-CELWs. METHODS: This microbiologic evaluation involved 4 epilepsy monitoring units where rEEGs-CELWs were swabbed for bacteria using standard techniques. Analyses involved descriptive statistics and logistic regression (across sites). RESULTS: Of 124 swabs, 31 (25.0%; range, 13.3%-43.3%) showed positive bacterial cultures, without between-site differences (P = .17). Bacteria were labeled by risk for hospital-acquired infection: no risk, potential risk (primarily in immunocompromised patients), and at risk (associated with infections and antibiotic resistance). At-risk bacteria species were Staphylococcus epidermidis (38.7%), Staphylococcus capitis subsp ureolyticus (3.2%), and Staphylococcus haemolyticus (9.6%). Potential-risk species were Micrococcus spp (22.6%), Acinetobacter lwoffii (6.5%), Staphylococcus hominis subsp hominis (6.5%), and Staphylococcus warneri (6.5%). Bacillus (9.6%) was the only no-risk species. Of 18 antibiotics tested on positive cultures, resistant bacteria were found in a median of 1 (range, 0-11) positive culture, equating to a 6.7% (range, 0%-61.1%) resistant antibiotic rate; no microorganisms were resistant to all antibiotics tested. CONCLUSIONS: Bacteria that were potential risk or at risk for infection were found on 22.6% of cleaned rEEGs-CELWs. Use of single-use electrodes and research on scalp infection and infection reduction interventions are warranted. PMID- 29997037 TI - Skills for Growing Up-Epilepsy: An exploratory mixed methods study into a communication tool to promote autonomy and empowerment of youth with epilepsy. AB - INTRODUCTION: The consequences of having epilepsy seriously hamper the development of autonomy for youth with epilepsy (YWE) and limit their social participation. This study was designed to provide insight into the impact of epilepsy on autonomy and empowerment and to evaluate the use of the Skills for Growing Up (SGU-Epilepsy) communication tool in pediatric epileptic care. METHODS: A mixed methods design was used to examine the impact of epilepsy on autonomy and empowerment and to evaluate the feasibility and use of the SGU Epilepsy. Six focus groups with YWE and their parents were organized (N = 27), and the benefits of the SGU-Epilepsy were evaluated (N = 72). RESULTS: Youth with epilepsy struggled with social participation. Beliefs of YWE and their parents on managing daily life and taking medication were not always similar. Parents worried about the passive attitude of YWE, but autonomy of YWE seemed to be constrained by parents. The SGU-Epilepsy seemed to be feasible. It facilitated the communication on development and empowerment although it was sometimes confronting for parents. Not all YWE were motivated to use and discuss the tool. In the evaluation, no differences in perceived autonomy and empowerment between YWE who used SGU-Epilepsy and received usual care appeared. CONCLUSION: On the short-term, a beneficial effect of using the SGU-Epilepsy on autonomy and empowerment for YWE and their parents was not shown. The SGU-Epilepsy seemed to be a feasible instrument, however, to address nonmedical issues during pediatric consultations. PMID- 29997038 TI - Age is but a number when considering epilepsy surgery in older adults. AB - BACKGROUND: A quarter of patients with newly diagnosed epilepsy are older, yet they are less likely to be offered resective surgery potentially because of clinical bias that they incur increased surgical risks. There are few peer reviewed case series that address this cohort and their outcomes. OBJECTIVE: In the context of current literature, the objective of this study was to report on all epilepsy surgeries in patients aged 50 years or older from a tertiary care center over 15 years with an average follow-up period of 6 years. METHODS: Patients with epilepsy who underwent surgery between 2001 and 2016 were reviewed retrospectively. Inclusion criteria were age > 50 at surgery, availability of presurgical evaluation data, and minimum one year of follow-up data. We identified 34 patients. Seizure outcome was evaluated using the Engel classification system. RESULTS: Thirty-four patients aged 50 years and older out of 276 underwent epilepsy surgery. Average age at time of surgery was 55 years, and average duration of epilepsy was 30 years. Average length of follow-up was 6 years (1-15 years). Twenty-two out of 34 patients (64%) were seizure-free (Engel class I) at their last follow-up visit. Patients with lesional pathology on neuroimaging were more likely to achieve seizure freedom (p < 0.02). Parameters associated with poorer outcome included extratemporal epileptogenic focus (p = 0.07) and bitemporal interictal epileptiform activity (p = 0.003). CONCLUSION: Our study cohort is one of the largest and most representative outcome studies of this age group, following the cohort for 6 years. Our findings demonstrated that when considering epilepsy surgery in an older adult, their age should not play a determining role in the decision-a finding that is more common in modern literature. PMID- 29997039 TI - Ketogenic diet therapies in France: State of the use in 2018. AB - : Ketogenic diets (KDs) are well-established treatments for pharmacoresistant epilepsies and some metabolic disorders. The amount of publications including evidence-based trials has continuously increased in the last 10 years. We evaluated the use of KDs in France using 2 surveys from more than ten years ago (2005 and 2008). METHODS: We conducted a new survey based on 10 questions to evaluate the evolution of the practice since 2008 and the thoughts of French pediatric neurologists on the barriers as well as possible ways to support the use of KDs. RESULTS: All centers increased their use of KDs over time. There are now 5 out of 25 centers that are prescribing the modified Atkins diet. French pediatric neurologists reported the acceptability and the everyday life burden due to KDs as the most important barriers. CONCLUSION: The use of the diet in France seems to follow the increase of knowledge in this field. PMID- 29997040 TI - Hybrid epithelial/mesenchymal phenotype(s): The 'fittest' for metastasis? AB - Metastasis is the leading cause of mortality among cancer patients. Dissemination enabled by an epithelial-to-mesenchymal transition (EMT) of carcinoma cells has long been considered to be the predominant mechanism for carcinoma metastasis, based on overexpression studies of many EMT-inducing transcription factors. Individual CTCs - and a binary framework of EMT - have been long considered to be sufficient and necessary condition for metastasis. However, recent studies have shown that collective migration and invasion through tumor buds and clusters of Circulating Tumor Cells (CTCs) as possibly being the prevalent mode of metastasis, although individual CTCs may still contribute to metastasis. These strands and clusters have been proposed to often exhibit a hybrid epithelial/mesenchymal (E/M) phenotype where cells retain epithelial traits of cell-cell adhesion and simultaneously gain mesenchymal characteristics of migration and invasion. To highlight the crucial questions regarding metastasis, we define EMT in a non-binary and context-specific manner, suggest that it can be viewed as a trans-differentiation process, and illustrate the implications of hybrid E/M phenotype(s) and cluster-based dissemination in metastasis. PMID- 29997041 TI - Mitochondrial DNA associations with East Asian metabolic syndrome. AB - Mitochondrial dysfunction has repeatedly been reported associated with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), as have mitochondrial DNA (mtDNA) tRNA and duplication mutations and mtDNA haplogroup lineages. We identified 19 Taiwanese T2DM and MS pedigrees from Taiwan, with putative matrilineal transmission, one of which harbored the pathogenic mtDNA tRNALeu(UUR) nucleotide (nt) 3243A>G mutation on the N9a3 haplogroup background. We then recruited three independent Taiwanese cohorts, two from Taipei (N = 498, mean age 52 and N = 1002, mean age 44) and one from a non-urban environment (N = 501, mean age 57). All three cohorts were assessed for an array of metabolic parameters, their mtDNA haplogroups determined, and the haplogroups correlated with T2DM/MS phenotypes. Logistic regression analysis revealed that mtDNA haplogroups D5, F4, and N9a conferred T2DM protection, while haplogroups F4 and N9a were risk factors for hypertension (HTN), and F4 was a risk factor for obesity (OB). Additionally, the 5263C>T (ND2 A165V) variant commonly associated with F4 was associated with hypertension (HTN). Cybrids were prepared with macro-haplogroup N (defined by variants m.ND3 10398A (114T) and m.ATP6 8701A (59T)) haplogroups B4 and F1 mtDNAs and from macro-haplogroup M (variants m.ND3 10398G (114A) and m.ATP6 8701G (59A)) haplogroup M9 mtDNAs. Additionally, haplogroup B4 and F1 cybrids were prepared with and without the mtDNA variant in ND1 3394T>C (Y30H) reported to be associated with T2DM. Assay of mitochondria complex I in these cybrids revealed that macro-haplogroup N cybrids had lower activity than M cybrids, that haplogroup F cybrids had lower activity than B4 cybrids, and that the ND1 3394T>C (Y30H) variant reduced complex I on both the B4 and F1 background but with very different cumulative effects. These data support the hypothesis that functional mtDNA variants may contribute to the risk of developing T2DM and MS. PMID- 29997042 TI - Treatment merits of Latanoprost/Thymoquinone - Encapsulated liposome for glaucomatus rabbits. AB - Elevation of the intraocular pressure (IOP) is recognized as a risk factor for glaucoma development. Latanoprost (LAT) is a prostaglandin analog used to reduce the (IOP). Thymoquinone (TQ) is a major bioactive ingredient of Nigella sativa. The aim of this study was to develop novel liposomal drug carriers for ocular delivery of LAT, TQ and a mixture of them to investigate their IOP lowering efficacy upon subconjunctival injection in glaucoma-induced rabbit's eye. The aim of the present work extends also to study the effect of the different liposome formulations on the aqueous humor oxidative stress. Liposome samples were prepared using thin film hydration method. The physiochemical properties of the prepared drugs were characterized. The IOP was recorded for 70 rabbits using Schiotz-tonometer. Malondialdehyde (MDA), reduced glutathione (GSH), catalase (CAT) activities and total antioxidant activity of the aqueous humor were estimated. Fourier transform infrared and differential scanning calorimetric studies confirmed the interaction between the drug and the vesicles, which resulted in high drug encapsulation efficiency >=88%. The size of the prepared liposomes was less than 10 MUm which make them suitable in ophthalmic applications. The sustained effect was achieved by liposome samples of Lip (LAT) and Lip (LAT + TQ) which were able to reduce the IOP significantly up to 84 h. Morever, the treatment of glaucomatous rabbits with liposome formulations containing TQ in their preparation [Lip (TQ) and Lip (LAT + TQ)] greatly improved the ocular tissue-induced histopathological lesions. None of the prepared liposome formulations succeeded to improve the glaucoma-induced oxidative stress damage. PMID- 29997043 TI - Functionalized carbon nanotubes as emerging delivery system for the treatment of cancer. AB - In recent time, carbon nanotubes (CNTs) have gained vital importance for pharmaceutical formulation scientist for delivering drugs and genes, owing to their excellent surface properties. For example, their aspect ratio is thought to be responsible for their excellent cell penetration aptitude; anisotropic conductivity/semi-conductivity along their axis is ideal for integration with nervous and muscular tissue; an ultrahigh surface area maximizes their ability to "talk" with biological matter; the hollow interior provides an enormous cargo carrying capacity for drug delivery; and their exteriors are readily functionalized to permit tailoring of solubility and biological recognition. Despite their immense capabilities for the delivery of drugs, genes and other biomedically essential materials, there use is restricted primarily because of the severe toxicity. However, the reactive nature of the surface of the CNTs allowed attaching the guest molecules (drug, siRNA, and diagnostics) of interest which helps in increasing the biocompatibility of these novel nanocarriers. As per the need, CNTs can be modified with peptides, organic molecules, carbohydrates, polymers and used mainly for cancer targeting and tumor cell accumulation. This review expounds different functionalization strategies employed for CNTs that created new opportunities for scientists to improve the potential of delivered therapeutics. PMID- 29997044 TI - Fabrication of multifunctional chitosan-based nanocomposite film with rapid healing and antibacterial effect for wound management. AB - A nanocomposite film, chitosan (CS)-polyvinylpyrrolidone (PVP)-bentonite (BN) was fabricated to enhance wound healing processes as a new nanoplatform for wound dressing. Both physical properties and antibacterial activity of the proposed film were examined to validate its applicability and inhibitory effect for wound management. In vitro cytotoxicity was evaluated by using MTT assay on L929 and NIH3T3 cells to identify the toxicity level of the film. In vivo wound healing test assessed the wound healing performance in animal models. The results confirmed a strong interaction between surface functional groups among CS, PVP and BN with suitable surface morphology and high thermal stability. The CS-PVP-BN film improved various material features such as including mechanical property, tensile strength, pH and porosity, inhibitory activity on bacterial organisms, and collagen deposition. The animal study confirmed that the fabricated film yielded a rapid healing rate of 97%, less scarring, thick granulation at the 11th day, regeneration of epidermis at the 16th day, and abundant deposition of collagen and fibroblast, compared with control. The non-toxic nanocomposite film can be a promising antibacterial wound dressing with rapid wound healing effects in wound care management. PMID- 29997045 TI - Role of cationic carbosilane dendrons and metallic core of functionalized gold nanoparticles in their interaction with human serum albumin. AB - Functionalization of gold nanoparticles by different chemical groups is an important issue regarding the biomedical applications of such particles. Therefore we have analyzed the interaction between gold nanoparticles functionalized by carbosilane dendrons with human serum albumin at different pHs, and in the presence of the protein unfolding agent, guanidine hydrochloride, using circular dichroism, zeta-potential and fluorescence quenching. The effect of a nanoparticle dendronization and pure dendrons on the immunoreactivity of albumin was estimated using ELISA. In addition, the tool to estimate the binding capacity of dendronized gold nanoparticles using a hydrophobic fluorescent probe 1,8-ANS (1-anilinonaphthalene-8-sulfonic acid) was chosen. We concluded that the effect of a nanoparticle on the structure, immunochemical properties and unfolding of albumin significantly decreased with second and third generations dendrons attached. Differences in pH dependence of the interaction between nanoparticles, their dendrons and albumin showed several effects of the "dendritic corona" and the metallic part of nanoparticle on the protein. These interactions indicate changes in the immunoreactivity of the protein, whereas dendron coating per se had no effect. Thus, dendronization of gold nanoparticles helps to shield them from interactions with plasma proteins. PMID- 29997046 TI - In silico identification of new potentially active brassinosteroid analogues. AB - Brassinosteroids (BRs) are hormones found in a wide range of plant species, they are synthesized at low concentrations and are essential for normal growth and development. These phytohormones are recognized by the Leucine-rich-repeat ectodomain of the receptor-like-kinase BRI1 which leads to subsequent downstream signaling mediating plant growth/development. In spite of the advantages that BRs offer, their extraction from natural sources is highly expensive, which constitutes one of its major limitations. Thus, the design and synthesis of structural and/or functional analogues of BRs with higher activity and lower cost has a great practical significance in world agriculture. In this matter, in silico methods, such as molecular docking, are valuable tools for the prediction and design of new compounds with improved activity. In this work we performed molecular docking simulations of 20 synthetic steroids in order to identify active compounds. Contact based analysis, level of exposure of polar groups to the solvent and binding affinity were the parameters used to consider if a synthetic steroid was active. Our results suggested that 17 out of a total of 20 of the analyzed steroids can potentially activate BRI1 receptor. PMID- 29997047 TI - Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16 dehydroprogesterone series. AB - Novel benzylidenes (chalcones) of the 16-dehydroprogesterone series have been characterized and their antitumor activity against two breast cancer cell lines was evaluated. Benzylidenes exhibit significant antiproliferative effect on cells and inhibit cell growth in hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer cell lines. Compound 3d exhibits the highest activity against two breast cancer cell lines, with the IC50 value of about 2 uM. Compounds 3e,m,n display considerable selectivity for hormone-dependent breast cancer cells, with the IC50 value lower than 6 uM. Moreover, these steroidal benzylidenes regulate ERalpha signaling and reveal p53-independent mechanism of pro-apoptotic action in MCF-7 cells. The new class of antitumor compounds holds promise as the basis for the design of agents for cancer therapy. PMID- 29997048 TI - [Preoperative functional explorations of genital prolapse (urodynamics, dynamic MRI)]. AB - The evaluation of genital prolapse is essentially clinical; however imaging tests such as dynamic MRI or urodynamic explorations may be useful in complex cases, especially before surgical management. Dynamic MRI allows morphological and dynamic analysis of pelvic floor and levator ani function. It can also detect post-obstetric injuries, although the long-term significance of these injuries remains to be discovered. Quantification of the severity of prolapse is possible with MRI; however, the correlation of these measures with clinical examination seems poor. Its interest lies mainly in the qualitative assessment of the three stages of prolapse and the detection of elytroceles, which can be difficult to clinical examination. Urodynamics provides useful information on vesico sphincteric function, but none of these parameters seems to be decisive in the management of prolapse. PMID- 29997049 TI - Dietary intake and nutritional status in patients with systemic lupus erythematosus. AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Despite the influence of diet on inflammation, dietary habits in patients with systemic lupus erythematosus (SLE) are not well established. The study objective was to assess dietary intake and nutritional status in SLE patients. PATIENTS AND METHODS: A cross-sectional study was conducted in 92 patients with SLE. Nutritional status was determined by body mass index (BMI) and energy/nutrient distribution of diet was analyzed and compared to a control group. Dietary reference intakes (DRIs) issued by the Spanish Societies of Nutrition, Feeding and Dietetics (FESNAD) and the Spanish Society of Community Nutrition (SENC) were used as reference. RESULTS: Body mass index was normal in 53.26% of patients, while 43.48% had excess weight. Energy, protein, and fat intake was significantly lower in the SLE group (p=0.003, p=0.000, and p=0.001 respectively). Protein and fat contribution to total energy was higher, while that of carbohydrate and fiber was lower than recommended. Most patients did not reach the recommended intake for iron (88%), calcium (65.2%), iodine (92.4%), potassium (73.9%), magnesium (65%), folate (72.8%), and vitamins E (87%) and D (82.6%), but exceeded the recommendations for sodium and phosphorus. CONCLUSIONS: Spanish SLE patients have an unbalanced diet characterized by low carbohydrate/fiber and high protein/fat intakes. Significant deficiencies were seen in micronutrient intake. Dietary counseling to improve nutrition would therefore be advisable in management of SLE. PMID- 29997051 TI - Autonomic adrenergic sympathetic hyperstimulation, myocardial edema, and "muscle cramps" in takotsubo syndome. PMID- 29997050 TI - Enhanced immigration enforcement in the USA and the transnational continuity of HIV care for Latin American immigrants in deportation proceedings. AB - In our work as clinicians, researchers, and immigrant rights advocates, we have noted increased anxiety about the possibility of deportation and disruptions in care among immigrants with HIV. Before the 2016 US elections, patients rarely asked about HIV treatment in their home countries. However, since the increase in anti-immigrant rhetoric and arrests by US Immigration and Customs Enforcement, patients have voiced concerns about the availability of HIV treatment in their home countries much more frequently. Although antiretroviral therapy is available throughout Latin America, access depends on economic, social, and political circumstances. Maintaining uninterrupted continuity of care among immigrants held in detention or deported to their home countries is challenging. In this Viewpoint, we identify periods of particular vulnerability for immigrants during deportation proceedings, from initial detention to deposition in their country of origin. We discuss the effect of enhanced immigration enforcement on the health and wellbeing of HIV-infected immigrants, and on public health. Finally, we also discuss recommendations for clinicians, immigration authorities, and public health institutions in the USA and in receiving countries. PMID- 29997052 TI - GRP78 Is a Targetable Receptor on Cancer and Stromal Cells. PMID- 29997054 TI - Prognosis of Patients With Severe Aortic Stenosis After the Decision to Perform an Intervention. AB - INTRODUCTION AND OBJECTIVES: Current therapeutic options for severe aortic stenosis (AS) include transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Our aim was to describe the prognosis of patients with severe AS after the decision to perform an intervention, to study the variables influencing their prognosis, and to describe the determinants of waiting time > 2 months. METHODS: Subanalysis of the IDEAS (Influence of the Severe Aortic Stenosis Diagnosis) registry in patients indicated for TAVI or SAVR. RESULTS: Of 726 patients with severe AS diagnosed in January 2014, the decision to perform an intervention was made in 300, who were included in the present study. The mean age was 74.0 +/- 9.7 years. A total of 258 (86.0%) underwent an intervention: 59 TAVI and 199 SAVR. At the end of the year, 42 patients (14.0%) with an indication for an intervention did not receive it, either because they remained on the waiting list (34 patients) or died while waiting for the procedure (8 patients). Of the patients who died while on the waiting list, half did so in the first 100 days. The mean waiting time was 2.9 +/ 1.6 for TAVI and 3.5 +/- 0.2 months for SAVR (P = .03). The independent predictors of mortality were male sex (HR, 2.6; 95%CI, 1.1-6.0), moderate-severe mitral regurgitation (HR, 2.6; 95%CI, 1.5-4.5), reduced mobility (HR, 4.6; 95%CI, 1.7-12.6), and nonintervention (HR, 2.3; 95%CI, 1.02-5.03). CONCLUSIONS: Patients with severe aortic stenosis awaiting therapeutic procedures have a high mortality risk. Some clinical indicators predict a worse prognosis and suggest the need for early intervention. PMID- 29997053 TI - TGF-beta3 Promotes MUC5AC Hyper-Expression by Modulating Autophagy Pathway in Airway Epithelium. AB - Mucus secretion accumulation in the airways may act as a contributing factor for the development of airflow limitation in severe fetal asthma patients. Accumulated evidences showed that transforming growth factor beta (TGF-beta) plays a regulatory role in airway remodeling including mucus hyper-secretion in asthma. However, the detailed molecular mechanisms of TGF-beta3 induced MUC5AC hyper-expression in airway epithelium remains unclear. Here, we demonstrated the pivotal roles of autophagy in regulation of MUC5AC hyper-production induced by TGF-beta3 in airway epithelium. Our experimental data showed that inhibiting autophagy pathway in repeated ovalbumin (OVA) exposed mice exhibited decreased airway hyper-response and airway inflammation, diminishing the expression of Muc5ac and TGF-beta3. Furthermore, our studies demonstrated that autophagy was induced upon exposure to TGF-beta3 and then mediated MUC5AC hyper-expression by activating the activator protein-1 (AP-1) in human bronchial epithelial cells. Finally, Smad2/3 pathway was involved in TGF-beta3-induced MUC5AC hyper expressions by promoting autophagy. These data indicated that autophagy was required for TGF-beta3 induced airway mucous hyper-production, and that inhibition of autophagy exerted therapeutic benefits for TGF-beta3 induced airway mucus secretion. PMID- 29997055 TI - The anti-inflammatory and anti-oxidative actions of eugenol improve lipopolysaccharide-induced lung injury. AB - Acute lung injury (ALI) remains a major cause of mortality. In lipopolysaccharide (LPS)-stimulated macrophages, eugenol reduces cyclooxygenase-2 expression, NF kappaB activation, and inflammatory mediators. We examined the anti-inflammatory and anti-oxidative action of eugenol in an in vivo model of LPS-induced lung injury. Lung mechanics and histology were analyzed in mice 24 h after LPS exposure, with and without eugenol treatment at different doses. Additional animals, submited to the same protocol, were treated with eugenol at 150 mg/kg to determine its effect on inflammatory cytokines (ELISA) and oxidative markers. LPS induced lung functional and histological changes were significantly improved by eugenol, in a dose-dependent way. Furthermore, eugenol (150 mg/kg) was able to inhibit the release of inflammatory cytokines (TNF-alpha, IL-1beta and IL-6), NADPH oxidase activity, as well as antioxidant enzymes activity (superoxide dismutase, catalase and glutathione peroxidase). Finally, eugenol reduced LPS induced protein oxidation. In conclusion, eugenol improved in vivo LPS-induced ALI through both anti-inflammatory and anti-oxidative effects, avoiding damage to lung structure. PMID- 29997056 TI - Neural and musculotendinous mechanisms underpinning age-related force reductions. AB - Ageing leads to substantial force production capacity reductions, which is an indicator of frailty and disability, and a mortality predictor in elders. Understanding the age-dependent neuromuscular mechanisms underlying force reductions can optimize healthcare professionals' exercise protocol choices for patients and allows researchers to investigate new interventions to mitigate these reductions. Our primary goal was to provide an updated review about the main neural and musculotendinous mechanisms underpinning age-related reductions in force capacity. Our secondary goal was to summarize how aerobic and strength training can lessen these age-related reductions. This review suggests that several steps in the force production pathway, from cortical to muscular mechanisms, are negatively affected by ageing. However, combining aerobic and strength training can attenuate these effects. Strength training (i.e. moderate to high- intensity, progressive volume, accentuated eccentric loading and fast concentric contraction velocity) can increase overall force production capacity by producing beneficial neural and musculotendinous adaptations. Additionally, aerobic training (i.e. moderate and high intensities) plays an essential role in preserving the structure and function of the neuromuscular system. PMID- 29997057 TI - Mitochondrial copper homeostasis and its derailment in Wilson disease. AB - In mitochondria, copper is a Janus-faced trace element. While it is the essential cofactor of the mitochondrial cytochrome c oxidase, a surplus of copper can be highly detrimental to these organelles. On the one hand, mitochondria are strictly dependent on adequate copper supply for proper respiratory function, and the molecular mechanisms for metalation of the cytochrome c oxidase have been largely characterized. On the other hand, copper overload impairs mitochondria and uncertainties exist concerning the molecular mechanisms for mitochondrial metal uptake, storage and release. The latter issue is of fundamental importance in Wilson disease, a genetic disease characterized by dysfunctional copper excretion from the liver. Prime consequences of the progressive copper accumulation in hepatocytes are increasing mitochondrial biophysical and biochemical deficits. Focusing on this two-sided aspect of mitochondrial copper, we review mitochondrial copper homeostasis but also the impact of excessive mitochondrial copper in Wilson disease. PMID- 29997058 TI - Multimodal imaging and three-dimensional cardiac computational modelling in the management of congenital heart disease: The secret to getting ahead is to get started. PMID- 29997059 TI - A solution for private assessment in indirect reciprocity using solitary observation. AB - Although indirect reciprocity is a fundamental mechanism in the evolution of human cooperation, most studies assume public assessment in which individuals are not permitted to obtain private assessments of others. Existing studies on private assessment have used individual-based simulations because of the analytical difficulty involved. Here, we develop an analytical method using solitary observation to solve private assessment in indirect reciprocity problem without any approximation. In this study, we formulate a model of solitary observation and calculate the replicator dynamics systems of five leading norms of indirect reciprocity. Indirect reciprocity in private assessment provides a different result to that in public assessment. According to the existence proofs of cooperative evolutionarily stable (CES) points in the system, strict norms (stern judging and shunning) have no CES point in private assessment, while they do in public assessment. Image scoring does not change the system regardless of the assessment types because it does not use second-order information. In tolerant norms (simple standing and staying), the CES points move to co-existence of norms and unconditional cooperators. Despite the fact that there is no central coercive assessment system in private assessment, the average cooperation rate at the CES points in private assessment is greater than that in public assessment. This is because private assessment gives unconditional cooperators a role. Our results also show the superiority of the staying norm. Compared with simple standing, staying has three advantages in private assessment: a higher cooperation rate, easiness of invasion into defectors, and robustness to maintain cooperative evolutionarily stable situations. Our results are applicable to general social dilemmas in relation to private information. Under some dilemmas, norms or assessment rules should be carefully chosen to enable cooperation to evolve. PMID- 29997060 TI - Two profiles in the recovery of reward devaluation in rats: Latent class growth analysis. AB - Consummatory successive negative contrast (cSNC) occurs when animals exposed to an unexpected downshift from a high palatable reward (e.g., 32% sucrose solution) to a less preferred one (e.g., 4% sucrose solution) show an abrupt and transient suppression of the consummatory response, compared with control animals that always had access to the less preferred one. This phenomenon constitutes an animal model of stress produced by frustrative events. To obtain information about individual differences regarding cSNC, we used Latent Class Growth Analysis (LCGA) to analyze a sample of 53 animals exposed to an incentive downshift. We found two profiles of animals, both showing the suppression of the consummatory response but diverging in the speed of the recovery. Our results are consistent with previous literature showing individual differences in cSNC and do not support the existence of a third profile. PMID- 29997061 TI - The cerebellum and cognition. AB - What the cerebellum does to sensorimotor and vestibular control, it also does to cognition, emotion, and autonomic function. This hypothesis is based on the theories of dysmetria of thought and the universal cerebellar transform, which hold that the cerebellum maintains behavior around a homeostatic baseline, automatically, without conscious awareness, informed by implicit learning, and performed according to context. Functional topography within the cerebellum facilitates the modulation of distributed networks subserving multiple different functions. The sensorimotor cerebellum is represented in the anterior lobe with a second representation in lobule VIII, and lesions of these areas lead to the cerebellar motor syndrome of ataxia, dysmetria, dysarthria and impaired oculomotor control. The cognitive / limbic cerebellum is in the cerebellar posterior lobe, with current evidence pointing to three separate topographic representations, the nature of which remain to be determined. Posterior lobe lesions result in the cerebellar cognitive affective syndrome (CCAS), the hallmark features of which include deficits in executive function, visual spatial processing, linguistic skills and regulation of affect. The affective dyscontrol manifests in autism spectrum and psychosis spectrum disorders, and disorders of emotional control, attentional control, and social skill set. This report presents an overview of the rapidly growing field of the clinical cognitive neuroscience of the cerebellum. It commences with a brief historical background, then discusses tract tracing experiments in animal models and functional imaging observations in humans that subserve the cerebellar contribution to neurological function. Structure function correlation studies following focal cerebellar lesions in adults and children permit a finer appreciation of the functional topography and nature of the cerebellar motor syndrome, cerebellar vestibular syndrome, and the third cornerstone of clinical ataxiology - the cerebellar cognitive affective syndrome. The ability to detect the CCAS in real time in clinical neurology with a brief and validated scale should make it possible to develop a deeper understanding of the clinical consequences of cerebellar lesions in a wide range of neurological and neuropsychiatric disorders with a link to the cerebellum. PMID- 29997063 TI - French strategies and global health. PMID- 29997064 TI - Situation and perspectives of blood transfusion in Mali. AB - Blood transfusion in Mali is constantly confronted with the problem of the availability of blood products, even in life-threatening emergencies. Although the number of donations increases each year, so does the need for blood products; donations do not appear to meet demand. With an infrastructure that does not meet standards for security, confidentiality, or quality, the Mali national blood transfusion center has nonetheless seen an increase in donations - from 30,000 annually in 2007-2010 to about 50,000 donations in 2015. Immunohematological analyses for donors and patients are limited to ABOD antigens. In 2015, the prevalence of markers for HIV was 3%, for HBV 15.5 %, for HCV 1.7%, and for syphilis 0.1 %. This situation has been the subject of an analysis of the needed improvements and prospects for them at all stages of the transfusion chain. PMID- 29997062 TI - waveCSD: A method for estimating transmembrane currents originated from propagating neuronal activity in the neocortex: Application to study cortical spreading depression. AB - BACKGROUND: Recent years have witnessed an upsurge in the development of methods for estimating current source densities (CSDs) in the neocortical tissue from their recorded local field potential (LFP) reflections using microelectrode arrays. Among these, methods utilizing linear arrays work under the assumption that CSDs vary as a function of cortical depth; whereas they are constant in the tangential direction, infinitely or in a confined cylinder. This assumption is violated in the analysis of neuronal activity propagating along the neocortical sheet, e.g. propagation of alpha waves or cortical spreading depression. NEW METHOD: Here, we developed a novel mathematical method (waveCSD) for CSD analysis of LFPs associated with a planar wave of neocortical neuronal activity propagating at a constant velocity towards a linear probe. RESULTS: Results show that the algorithm is robust to the presence of noise in LFP data and uncertainties in knowledge of propagation velocity. Also, results show high level of accuracy of the method in a wide range of electrode resolutions. Using in vivo experimental recordings from the rat neocortex, we employed waveCSD to characterize transmembrane currents associated with cortical spreading depressions. COMPARISON WITH EXISTING METHOD(S): Simulation results indicate that waveCSD has a significantly higher reconstruction accuracy compared to the widely used inverse CSD method (iCSD), and the regularized kernel CSD method (kCSD), in the analysis of CSDs originating from propagating neuronal activity. CONCLUSIONS: The waveCSD method provides a theoretical platform for estimation of transmembrane currents from their LFPs in experimental paradigms involving wave propagation. PMID- 29997065 TI - Diagnostic tools and follow-up of sickle-cell anemia in Central Africa. PMID- 29997066 TI - Day of Action against Counterfeit Medications in the Congo, Brazzaville, March 22, 2018. AB - A Day of Action against counterfeit medications was organized in Brazzaville on March 22, 2018, by the French Embassy, the French Institute of the Congo (IFC), and the Ministry of Health and the Population, with the participation of the Chirac Foundation. The success of this day, during which more than 1500 people came to the IFC, may be an original idea for mobilizing civil society on health subjects that directly affect the behavior of young people. PMID- 29997067 TI - Hydatidose musculaire. PMID- 29997069 TI - Good bye J.E.T. ! PMID- 29997068 TI - Type III open tibia fractures in low-resources setting. Part 1: strategy and principles of limb salvage. AB - In developing countries, road traffic accidents result in many cases of open trauma, especially fractures, with the tibia area at particular risk in motorcycle crashes. Despite a high prevalence of severe leg trauma with multi tissue injuries, few studies have focused on the challenge of their reconstruction in these limited-resource settings. The first part of this review presents the surgical strategy. Limitations and principles of initial limb salvage are detailed. Orthopedic procedures for early damage control, based on debridement and temporary bone stabilization, are often required. The priority is to shorten the time to initial surgical management to avoid infection, which jeopardizes reconstruction. PMID- 29997070 TI - Relapsing fever in a Moroccan man. AB - Tick-borne relapsing fever is a zoonosis caused by spirochetes of the genus Borrelia, transmitted by hematophagous ticks. This life-threatening condition is still misdiagnosed. We report a case of tick-borne relapsing fever in a 54 year old man in Morocco with a history of hiking, who was hospitalized for an isolated fever. On admission, the clinical examination showed no specific signs. The laboratory assessment showed inflammatory syndrome with disturbance of the liver function. The blood culture was sterile. Serology was negative for HIV and Lyme disease, as were all the rest of the paraclinical tests. The patient's course was marked by spontaneous resolution of the fever and then, seven days later, the onset of a new episode of fever. Malaria was suspected and a blood sample was sent to the parasitology department. The thick smear and blood smear stained with May-Grunwald Giemsa showed the presence of spirochetes. Tick-borne relapsing fever was diagnosed and the patient responded favorably to treatment by cycline drugs. This disease is poorly known and should be considered in cases of presence of intermittent fever without a specific clinical-laboratory picture, according to epidemiological context. The diagnosis is confirmed by the presence of spirochetes on thick smear and blood or cerebrospinal fluid smear stained with MGG. PMID- 29997071 TI - HIV self-testing in Africa: stakes and challenges. AB - HIV self-testing constitutes a new complementary strategy for HIV testing for general populations as well as "key" populations such as sex workers and their clients, men who have sex with men, and young people; it may help to reach the UNAIDS 90-90-90 objectives by 2020. In Africa, many pilot studies have been conducted, mainly in English-speaking countries, and they have demonstrated the high acceptability, practicability and clinical performance of HIV self-testing. Innovative strategies, including the translation of HIV self-test instructions for use into vernacular languages in association with educational pictograms, should be developed and evaluated in sub-Saharan Africa to implement HIV self testing. PMID- 29997072 TI - Suscepibility of Anopheles gambiae sl and Culex quinquefasciatus to diverse insecticides in the city of N'Djamena. AB - Mosquito resistance to insecticides remains a major concern for vector control programs based on chemical methods. Hence, a thorough knowledge of vector susceptibility to products recommended for public health is required for effective vector control programs. In this study, we assessed the susceptibility of wild Anopheles gambiae sl and Culex quinquefasciatus populations from N'Djamena (Chad) to four insecticide classes recommended for public health. The study took place from July to October 2014. Following WHO guidelines, bioassays were performed on two- to four-day-old, non-engorged female mosquitoes of both species, collected in the field. The insecticides used were deltamethrin (0.05%), permethrin (1%), DDT (4%), bendiocarb (0.01%), and malathion (5%). Anopheles gambiae sl showed full susceptibility to bendiocarb and malathion but was resistant to pyrethroids; mortality rates were 2% for deltamethrin, 2% for permethrin, and 0% for DDT. Culex quinquefasciatus was susceptible to malathion but resistant to the other insecticides, with a mortality rate of 22% for deltamethrin, 29% for permethrin, 23% for DDT, and 45% bendiocarb. The resistance of Anopheles gambiae sl and of Culex quinquefasciatus may affect the population's adherence to the use of insecticide-treated mosquito nets. Malaria control programs are advised to extend insecticide resistance monitoring to the main culicide species that bite human populations. PMID- 29997073 TI - Role of environmental parameters on the density of intermediate host snails of human schistosoma during the year in the commune of Richard-Toll, Senegal. AB - The implementation and expansion of development projects (dams and irrigation schemes) in the Senegal River valley have led to a significant proliferation of snails. We conducted a one-year (2014) study project, monitoring their density in the commune of Richard Toll, to assess the role of environmental parameters on mollusc population dynamics. Four species involved in the transmission of human schistosomiasis were found: Bulinus globosus, B. truncatus, B. senegalensis, and Biomphalaria pfeifferi. Among the intermediate hosts, B. truncatus is the most abundant species, followed by B. globosus. Snail density depends on the nature of the water point but also on environmental parameters such as vegetation. This study showed that vegetation, water level (flood), and flow velocity influence the dynamics of the snail populations that are intermediate hosts of human schistosomes. PMID- 29997074 TI - Lupus: evidence of environmental degradation? Assessment from 60 patients followed up in the Internal Medicine Department at the Libreville University Hospital, Gabon. AB - Lupus is an autoimmune disease of the connective tissue that occurs predominantly in women and blacks and whose expression is influenced by environmental factors, especially ultraviolet rays. The rising temperature in Gabon for nearly two decades led us to look for correlations between the onset of lupus, the patients' regions of origin, and environmental temperatures before and at diagnosis. retrospective, descriptive, and analytic study conducted in the Department of Internal Medicine of the CHU of Libreville (Gabon), from 01/01/2016 to 31/05/2016, based on the files of patients with diagnosed lupus receiving care in the department since 01/2002. Data collection forms listed for each patients age, sex, occupation, date and season of diagnosis, and place of residence (during childhood, adolescence, and adulthood). We looked for correlations between these data and temperatures, based on meteorological data from the country's seven main weather stations over a period from 1996 to 2015. The study included 53 women and 7 men (sex ratio 0.13), with a mean age of 32.7 +/- 8.9 years. The population included students (n = 25), civil servants (n = 15), the unemployed (n = 8), private-sector employees (n = 6), and shopkeepers (n=6). Diagnoses varied according to season, with 56.6% of the cases in the dry season and 43.4% in the rainy season. From 1 to 4 cases of lupus were diagnosed annually before 2011, 7 each year from 2011 to 2014, and at least 14 per year since 2015. Most patients (62.5%) had spent their childhood, adolescence, and adulthood in the country's capital (industrial zone par excellence), 17.8% in mining regions, and 12.5% in oil-drilling areas. The increase in the number of cases of lupus appears to be correlated with their greater prevalence in regions with higher temperature exposures, that is, in industrial, mining and petroleum regions, which are the regions of greatest exposure among our lupus patients. PMID- 29997075 TI - Aspergillus pyothorax: Is surgery alone sufficient? AB - Aspergillus is a mycelial fungus formed of filaments that penetrate the airways when its spores are inhaled. It is rarely located in the pleura. We report two cases of patients, one aged 67 years and the other 37 years, with pleural aspergillosis. The first underwent a thoracostomy, followed later by a myoplasty for closure. Pleuropulmonary decortication was performed in the second patient. The pathology examination confirmed an intrapleural aspergilloma in both patients. Antifungal treatment was not performed. The postoperative course was simple and no recurrence was noted. Based on these two cases over a 7-year period and a review of the literature, we detail the issues in this management and emphasize the interest of surgery. PMID- 29997076 TI - Traditional uvulectomy, a common practice in South Kivu in the Democratic Republic of Congo. AB - BACKGROUND: Traditional uvulectomy in children, a very common and dangerous practice, remains poorly documented in the Democratic Republic of Congo (DRC). The aim of this study was to establish the epidemiological and clinical profile of children after a traditional uvulectomy and to determine their outcome of the children after this practice in 2 pediatric emergency unities in South Kivu province, DRC. METHOD: This was a cross-sectional study took place conducted in 2 pediatric emergency unities in Bukavu town, in South Kivu province, throughout from January to December 2016. It included all children from 0 to 15 years of age. The usual statistical measures (frequenciesy, percentages, means, and medians) were used. Differences in group proportions and categorical variables were assessed withusing the chi-square test. These different tests were considered statistically significant at P < 0.05. FINDINGS: In all, A total of 1078 children were admitted to these pediatric emergency departments during the study period, including 202 cases of traditional uvulectomy, forgiving a prevalence of 18.7% among admissions. The median age of the children was 11 (1 168) months. Of the mothers who resorted to this practice, 153 One hundred fifty three (75.7%) mothers who resorted to this practice had a low level of education. The main reasons for this practice were fever (50%), vomiting (15.8%), and refusal to suckle (12.4%). The mortality rate after uvulectomy was 11.9%. Risk factors associated with mortality following traditional uvulectomy were HIV infection ([OR (95 % CI) 3.16, 95% CI (1.28-7.79); P = 0.040] and acute malnutrition ([OR (95% CI) 2.87, 95% CI (1.28 - 6.43); P = 0.024)]. CONCLUSION: The prevalence of traditional uvulectomy and the mortality rate after traditional uvulectomy both remain high. Information, education, and communication campaigns on this practice must be developed in order to reduce this scourge. PMID- 29997077 TI - Prescription of medications for acute diarrhea in infants in Antananarivo, Madagascar. AB - AIM: To evaluate the professional practices of physicians in Antananarivo in managing acute diarrhea in infants. METHODS: This prospective study was conducted from March 19 to April 21, 2012, as an anonymous survey of randomly selected general practitioners and pediatricians working in the public or private sector in the city of Antananarivo. RESULTS: The survey included 125 physicians: 105 general practitioners, 11 pediatricians, and 9 other specialist physicians (7.2%) with pediatric activity. Only 4.8% of the physicians questioned had not received training about diarrhea in the previous two years. One doctor in 4 (25.6%) did not prescribe oral rehydration solution. The reasons given were lack of signs of dehydration (50%) and recommendation of other beverages (15.5%). Zinc prescription was rare (9.6%). Early refeeding was recommended by 41.6% of physicians. Almost half (47.2%) routinely use antibiotics, and 86.4% prescribe antidiarrheal medications. CONCLUSION: The WHO recommendations for the treatment of acute diarrhea in children are not followed. Continuing and repeated medical education is necessary. PMID- 29997078 TI - Screening and management of HIV infection in pregnant women in Dakar. AB - OBJECTIVES: To assess the feasibility and results of the implementation of systematic HIV screening of pregnant women and antiretroviral (ARV) treatment for those found to be HIV-positive and their newborns at the IHS Gynecology Obstetrics Department in Dakar, Senegal. PATIENTS AND METHODS: This cross sectional prospective study took place in 2014-1016 and examined the results of screening pregnant women for HIV during their prenatal consultations and treating those found to be HIV-positive and their infants with ARV. RESULTS: HIV screening was routinely proposed to the 1616 pregnant women attending antenatal clinics, and 93.9 % accepted. The test was positive for 5 of these women, for an HIV prevalence of 0.3 % of pregnant women. In addition, another 23 HIV-positive pregnant women were referred to the IHS for their prenatal care and delivery, for a total of 28 women with HIV. Their mean age was 30 years, their mean parity 1.6, and all had HIV-1. Triple therapy was initiated for all HIV-positive pregnant women, in line with the WHO guidelines' "B + option", currently adopted by Senegal. During follow-up, only 35.7 % of the women had access to a viral load assay. The outcome of pregnancy was favorable in 91.6 % of cases; 72.2% of the women had vaginal deliveries. All live-born infants were given antiretroviral prophylaxis at birth. The mode of breastfeeding used was mainly exclusive protected breastfeeding (72.2 %). During postnatal follow-up, 2 of the 17 live born infants were lost to follow-up, and 15 had PCR testing for HIV, which was positive in only 1 case, for a transmission rate of 6.6 %. CONCLUSION: The systematic offer and performance of HIV testing in all pregnant women is feasible and acceptable. Good organization of care can provide ARV treatment for all HIV positive pregnant women and their newborns. The accessibility of viral load testing and of PCR screening for neonates still requires improvement. PMID- 29997079 TI - Hepatobiliary diseases in people with HIV infection at the Lome, Togo, University Hospital: epidemiologic and diagnostic aspects. AB - PURPOSE: To determine the epidemiological and diagnostic aspects of hepatobiliary diseases in people with HIV infection at the Lome University Hospital. METHODS AND PATIENTS: This 5-year retrospective descriptive and analytic study included all people with HIV infection aged 15 years and older of either sex admitted with a hepatobiliary disease. RESULTS: Among all patients admitted for hepatobiliary diseases, people with HIV infection accounted for 2%. They were predominantly women. Our patients' mean age was 43.03+/-10.3 years. The principal reasons for consultation were asthenia (95.2%), jaundice (93.7%), and abdominal pain (80.9%). The main clinical symptoms were by deterioration of general status (84.1%) and pain of the right hypochondrium (66.7%); 63.5%were classified at WHO disease stage III or IV for HIV infection and disease. All our patients were positive for HIV1; and 86.5% had a CD4 count < 350 cells/mm3. We noted HVB/HIV coinfection in 39.6% and HVC/HIV coinfection in 19%. Cirrhosis had been diagnosed in 44.4%, hepatocellular carcinoma in 12.6%, and toxic or drug-induced hepatitis in 46%, while 8% had acute acalculous cholecystitis. No case of alcoholic steatohepatitis or AIDS cholangiopathy was noted. CONCLUSION: Hepatobiliary diseases are infrequent and varied among people with HIV infection; the most common are toxic hepatitis, cirrhosis, and hepatocellular carcinoma, and they do not differ according to CD4 counts. PMID- 29997080 TI - Treatment of chronic inflammatory rheumatism by biotherapy in Gabon : eligibility and follow-up of the first 8 patients in sub-Saharan Africa. AB - OBJECTIVE: to clarify the eligibility criteria for biotherapies in patients with chronic inflammatory rheumatism (CIR) in sub-Saharan Africa and to describe the characteristics of the first 8 patients treated with biotherapy in Gabon. MATERIALS AND METHODS: Patients who responded inadequately to treatments by cDMARDs (EULAR criteria) had a face-to-face interview to inform them about and obtain their consent to biotherapy for at least 3 months, with details of the cost and side effects of each available biotherapy and a certificate of "necessity of biotherapy". The inclusion and follow-up of patients took place in the outpatient rheumatology consultations at the University Hospital of Libreville (Gabon) between January 2010 and December 2016. RESULTS: Of the 30 patients who failed cDMARDs and required biologic treatment, 8 (26.6%) were able to start a biotherapy: 4 men and 4 women with rheumatoid arthritis (n = 4.50%), spondyloarthritis or psoriatic rheumatism (n = 2.25% each). The biotherapy was etanercept (n = 4, 50%), adalimumab, golimumab, infliximab and rituximab (n = 1, 12.5% each). The average duration of the biotherapy was 27.4 months (9-54). Biotherapy was stopped in 4 cases (50%), one each (12.5%) for multifocal tuberculosis, pregnancy, financial reasons, and remission. CONCLUSION: Our study shows that biotherapies, which are currently very expensive, can be prescribed in Africa provided that the usual recommendations are followed strictly. Here, access to biotherapies is only possible through private insurance and the rheumatologist must play the role of facilitator for needy and consenting patients. PMID- 29997081 TI - Epidemiological transition in Morocco (1960-2015). AB - Morocco is undergoing the third phase of its epidemiological transition. Mortality indicators have declined significantly. Life expectancy at birth has increased by 23 years over this 55-year study period. The total fertility rate has dropped from 7.06 in 1960 to 2.89 in 2015. The country is going through the epidemiological transition characterized by a shift in the overall burden of morbidity and mortality from infectious diseases to noncommunicable diseases and injuries. Chronic diseases now account for 75 % of all deaths. Cardiovascular diseases, diabetes, and cancer are among the leading causes of death (57 %). Accidents and injuries account for 7 % of deaths. The emerging diseases are largely related to changes in lifestyles, high blood pressure, obesity, smoking, and the harmful use of alcohol. This epidemiological transition, with its enormous health and economic consequences, presents many new challenges for the national health system, including in the organization of care pathways for diabetes and hypertension, the fight against overweight and obesity, and the therapeutic education of patients, health education in schools, and public awareness programs. PMID- 29997082 TI - Extensive septic myonecrosis related to compartment syndrome: is the upper extremity salvage achievable in precarious setting? AB - Management of acute compartment syndrome is well known and based on emergent and generous fasciotomies. In absence of such fasciotomies, or if they are performed too late, the compartment syndrome leads to a Volkmann's syndrome or to a dramatic septic myonecrosis raising the question of an amputation. However, salvage treatment of these extreme clinical presentations may be preferable at the upper extremity, particularly in developing countries where access to sophisticated prosthetic devices is limited. The authors report four typical observations about management of upper extremity delayed compartment syndromes with severe infectious complications. To clarify treatment principles and pitfalls, two situations are distinguished: subacute septic myonecrosis and chronic osteomyelitis. Management specificities of both situations are discussed according to literature data and available resources in austere environments. Despite challenging in low-resources setting, upper extremity salvage is possible at the cost of simple but iterative surgical procedures. Limitations are represented by the need of repeated blood transfusions in the subacute phase, and difficulties in providing medical treatment of bone infection in the chronic phase. PMID- 29997083 TI - Factors associated with the abandonment of postexposure prophylaxis at the antirabies center in Abidjan, Cote d'Ivoire. AB - The main objective of this work is to analyze the factors associated with patients dropping out of postexposure prophylaxis (PEP) at the antirabies center of Abidjan (ARC). This descriptive, analytic cross-sectional study took place at the ARC of Abidjan from September 2014 through May 2015. Data were collected in two stages: first, all patients were interviewed at their first consultation. Exposed patients who failed to return were interviewed by telephone three days later. We recorded 441 subjects (59.3%) who had dropped out of their PEP. After multivariate analysis of social and demographic factors, the dropout rate was low in the groups aged 40-49 years (aOR = 0.40, 95% CI = 0.2, 0.8), 50-59 years (aOR = 0.40, 95% CI = 0.21; 0.82), and 60 years and older (aOR = 0.26, 95% CI = 0.09; 0.76), while it was elevated in retired persons (aOR = 10.07, 95% CI = [1.11, 91 , 7]). Moreover, the choice of protocol influenced PEP adherence, with subjects who chose the 5-dose protocol dropping out more frequently (P<=0.001). The main reason given by the subjects exposed to a suspect animal to explain dropping out of PEP was the lack of financial resources (41.5%). To alleviate this dropout problem, the ARC should strengthen public awareness of human rabies and the Ivorian government must implement universal health coverage to help the poor or make the vaccine available for free to all. PMID- 29997084 TI - [Generation of a new strain of NOD/SCID/IL2Rgamma-/- mice with targeted disruption of Prkdc and IL2Rgamma genes using CRISPR/Cas9 system]. AB - OBJECTIVE: The NOD/SCID/IL2Rgamma- /- (NSG) mouse strain is the most widely used immunodeficient strain for xenograft transplantation. However, the existing SCID mutation is a spontaneous mutation of the Prkdc gene, which leads to leaky T cell developmental block and difficulty in genotyping. It is therefore important to develop a new strain of NSG mice with targeted disruption of Prkdc and IL2Rgamma genes. METHODS: Targeted disruption of Prkdc and IL2Rgamma genes was achieved using the CRISPR/Cas9 system. By intercrossing the knockout and NOD mice, we obtained a novel strain of NOD/SCID/IL2Rgamma- /-(NSG) mice, denoted as cNSG (Chinese NSG) mice. RESULTS: In addition to the NOD mutation, cNSG mice exhibited a complete absence of T cells, B cells and NK cells. cNSG mice allowed more efficient engraftment of human cancer cells than the commonly used immunodeficient nude mice. CONCLUSION: cNSG mice will provide an important xenotransplantation model for biomedical research. PMID- 29997085 TI - [Evaluation of the performance of a minimally invasive thoracic drainage tube in a rabbit model of hemothorax]. AB - OBJECTIVE: To assess the performance of a minimally invasive thoracic drainage tube (14 F) made of polyurethane (PU) in a rabbit model of hemothorax in comparison with the conventional 28 F chest tube (CCT). METHODS: Thirty New Zealand rabbits were divided into experimental chest tube (ECT) group (n=9), CCT group (n=6), and blood provider group (n=15). Blood samples (20 mL) collected from the blood providing rabbits were injected into the chest cavity of the rabbits in the other two groups, and the time taken for closed drainage of the thoracic cavity was recorded. The rabbits in ECT and CCT groups were subjected to blood injections (20 mL for each injection) into the chest cavity every 20 min for 5 times, and the volumes of blood drained by ECT and CCT were measured. Two hours later, the rabbits were sacrificed and the residual blood and blood clots in the chest cavities were observed. RESULTS: Compared with CCT, the use of ECT significantly shortened the operation time (P<0.05) and produced more effective blood drainage at 20 min and 40 min after the placement of the drainage tube (P<0.05). No significant difference was found in the total blood volume drained between ECT and CCT groups, but the volume of residual blood in the thoracic cavity was significantly smaller in ECT group than in CCT group. No post operative complications were found in the rabbits in ECT group while all the rabbits in CCT group had abutment pressure to the lung. CONCLUSION: Compared to CCT, ECT is less invasive and allows more effective thoracic drainage with more convenient operation and reduced postoperative complications, suggesting its potential for use in closed thoracic drainage in single-port video-assisted thoracoscopic surgery (VATS) or in pediatric patients. PMID- 29997086 TI - [Exogenous agmatine inhibits lipopolysaccharide-induced activation and dysfunction of human umbilical vein endothelial cells]. AB - OBJECTIVE: To investigate whether exogenous agmatine inhibits lipopolysaccharide (LPS)-induced activation and dysfunction of human umbilical vein endothelial cells (HUVECs) by modulating nuclear factor-kappaB (NF-kappaB) and MAPK signal pathways and the production of reactive oxygen species (ROS). METHODS: Cultured HUVECs were treated with agmatine at the optimized concentration of 1.0 mmolgammaL, LPS (10 uggammamL), and LPS + agmatine, with or without pretreatment with the inhibitors of NF-kappaB (PDTC), p38 (SB203580), and ERK (PD98059) for 1 h. The levels of soluble vascular cell adhesion molecule 1 (VCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and monocyte chemoattractant protein 1 (MCP-1) in the supernatant were determined using ELISA, and their mRNA expressions, along with heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO-1), were assessed using real-time PCR. ROS production in the cells was determined using 2, 7-dichlorofluoresce in diacetate (DCFH-DA) as the fluorescence probe. The protein expressions of VCAM-1, ICAM-1, p65, phospho-p65 (p-p65), IkappaBalpha, p-IkappaBalpha, ERK, p-ERK, p38, p-p38, JNK, and p-JNK were detected using Western blotting. RESULTS: LPS stimulation for 6 and 24 h significantly increased the levels of sVCAM-1, sICAM-1, sE-selectin and MCP-1 in the supernatant, intracellular ROS production, and the mRNA expressions of these molecules (P<0.05). Intervention with 1 mmolgammaL agmatine, similar with pretreatment with p38, ERK and NF-kappaB inhibitors, obviously inhibited such effects of LPS in HUVECs (P<0.05). Agmatine significantly up regulated the mRNA expression of HO-1 (P<0.05), inhibited LPS-induced phosphorylation of p38, ERK, nuclear p65 and cytoplasmic IkappaBalpha, and up regulated the protein expression of cytoplasmic IkappaBalpha. CONCLUSION: Agmatine inhibits LPS-induced activation and dysfunction of HUVECs by modulating NF-kappaB and MAPK signal pathways to down-regulate the expressions of adhesion molecules and chemokines and by up-regulating the expression of HO-1 to reduce ROS production. PMID- 29997087 TI - [Segmentation of brain tumor on magnetic resonance images using 3D full convolutional densely connected convolutional networks]. AB - OBJECTIVE: Accurate segmentation of multiple gliomas from multimodal MRI is a prerequisite for many precision medical procedures. To effectively use the characteristics of glioma MRI and im-prove the segmentation accuracy, we proposes a multi-Dice loss function structure and used pre-experiments to select the good hyperparameters (i.e. data dimension, image fusion step, and the implementation of loss function) to construct a 3D full convolution DenseNet-based image feature learning network. This study included 274 segmented training sets of glioma MRI and 110 test sets without segmentation. After grayscale normalization of the image, the 3D image block was extracted as a network input, and the network output used the image block fusion method to obtain the final segmentation result. The proposed structure improved the accuracy of glioma segmentation compared to a general structure. In the on-line assessment of the open BraTS2015 data set, the Dice values for the entire tumor area, tumor core area, and enhanced tumor area were 0.85, 0.71, and 0.63, respectively. PMID- 29997088 TI - [Neuropeptide Y Y1 receptor antagonist PD160170 promotes osteogenic differentiation of rat bone marrow mesenchymal stem cells in vitro and femoral defect repair in rats]. AB - OBJECTIVE: To investigate the effects of neuropeptide Y (NPY) Y1 receptor antagonist PD160170 in promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and accelerating healing of femoral defect in rats. METHODS: The third generation of rat BMSCs were treated with PBS (control) or 10-6, 10-7, or 10-8 mol/L NPY Y1 receptor antagonist PD160170. After 7 and 14 days of treatment, the cells were examined for osteogenic differentiation with alkaline phosphatase (ALP) and alizarin red staining. At 7 and 21 days of treatment, the mRNA and protein expressions of collagen type I (COLI), osteocalcin (OCN) and Runt-related transcription factor 2 (Runx2) in the cells were detected using q-PCR and Westem Blotting. In a male SD rat model (body weight 300?20 g) of bilateral femoral condyle defects (2.5 mm in diameter), the effect of daily local injection of 0.2 mL PD160170 (10-6 and 10-8 mol/L, for 28 consecutive days) in promoting bone defect repair was evaluated with micro-CT scans. RESULTS: ALP and alizarin red staining showed that the BMSCs treated with PD160170, at the optimal concentration of 10-8 mol/L, contained more intracellular cytoplasmic brown particles and mineralized nodules in extracellular matrix than PBS-treated cells. PD160170 (10-8 mol/L) significantly up-regulated the mRNA and protein expressions of COLI at day 7 and those of OCN and Runx2 at day 21 (P<0.05). In the rat models of femoral bone defect, the volume/tissue volume ratio, bone mineral density and the number of bone trabeculae were significantly greater in 10-6 mol/L PD160170 group than in the control group (P<0.05), but the bone trabecular thickness (P=0.07) and bone volume (P=0.35) were similar between the two groups. CONCLUSION: NPY Y1 receptor antagonist PD160170 can promote osteogenic differentiation of BMSCs and healing of femoral defects in rats, suggesting the potential of therapeutic strategies targeting NPY Y1 receptor signaling in the prevention and treatment of bone fracture and osteoporosis. PMID- 29997089 TI - [Effect of acupuncture pretreatment on action potential of cerebellar Purkenje cells in ex vivo ischemic rat brain slices]. AB - OBJECTIVE: To investigate the effect of acupuncture pretreatment at specific acupoints on action potential of cerebellar Purkenje cells in rats early after cerebral ischemia. METHODS: Forty male SD rats were randomized into control group, ischemia group, acupuncture pretreatment group and acupuncture pretreatment plus ischemia group. The rats in acupuncture groups received acupuncture pretreatment at Baihui and bilateral Zusanli twice daily for 7 consecutive days, after which brain slices were prepared and perfused at a lowered rate to simulate in vivo ischemic stroke. Microelectrode and whole cell current clamp technique were used for recording the action potentials of cerebellar Purkenje cells to detect changes in spike encoding of the cells. RESULTS: Compared with those in the control group, the rat brain slices early after simulated ischemia showed significantly shortened inter-spike intervals, increased standard deviation of spike timing and decreased voltage of threshold potentials (P<0.01), suggesting overexcitation of the Purkinje cells. Acupuncture pretreatment at Baihui and bilateral Zusanli obviously suppressed overexcitation of the Purkinje cells in response to ischemia. CONCLUSION: Acupuncture pretreatment at Baihui and bilateral Zusanli can improve ischemic stroke by suppressing overexcitation of Purkenje cells in rats. PMID- 29997090 TI - [Prediction of three-dimensional dose distribution in intensity-modulated radiation therapy based on neural network learning]. AB - OBJECTIVE: To establish the association between the geometric anatomical characteristics of the patients and the corresponding three-dimensional (3D) dose distribution of radiotherapy plan via feed-forward back-propagation neural network for clinical prediction of the plan dosimetric features. METHODS: A total of 25 fixed 13-field clinical prostate cancer intensity-modulated radiation therapy (IMRT)/stereotactic body radiation therapy (SBRT) plans were collected with a prescribed dose of 50 Gy. With the distance from each voxel to the planned target volume (PTV) boundary, the distance from each voxel to each organ-at-risk (OAR), and the volume of PTV as the geometric anatomical characteristics of the patients, the voxel deposition dose was used as the plan dosimetric feature. A neural network was used to construct the correlation model between the selected input features and output dose distribution, and the model was trained with 20 randomly selected cases and verified in 5 cases. RESULTS: The constructed model showed a small model training error, small dose differences among the verification samples, and produced accurate prediction results. In the model training, the point-to-point mean dose difference (hereinafter dose difference) of the 3D dose distribution was no greater than 0.0919?3.6726 Gy, and the average of the relative volume values corresponding to the fixed dose sequence in the DVH (hereinafter DVH difference) did not exceed 1.7%. The dose differences among the 5 samples for validation was 0.1634?10.5246 Gy with percent dose differences within 2.5% and DVH differences within 3%. The 3D dose distribution showed that the dose difference was small with reasonable predicted dose distribution. This model showed better performances for dose distribution prediction for bladder and rectum than for the femoral heads. CONCLUSION: We established the relationships between the geometric anatomical characteristics of the patients and the corresponding planning 3D dose distribution via feed-forward back-propagation neural network in patients receiving IMRT/SBRT for the same tumor site. The proposed model provides individualized quality standards for automatic plan quality control. PMID- 29997091 TI - [Constraint priority list-based multi-objective optimization for intensity modulated radiation therapy]. AB - OBJECTIVE: In intensity-modulated radiation therapy (IMRT), it is time-consuming to repeatedly adjust the objectives manually to obtain the best tradeoff between the prescribed dose of the planning target volume and sparing the organs-at-risk. Here we propose a new method to realize automatic multi-objective IMRT optimization, which quantifies the clinical preferences into the constraint priority list and adjusts the dose constraints based on the list to obtain the optimal solutions under the dose constraints. This method contains automatic adjustment mechanism of the dose constraint and automatic voxel weighting factor based FMO model. Every time the dose constraint is adjusted, the voxel weighting factor-based FMO model is launched to find a global optimal solution that satisfied the current constraints. We tested the feasibility and effectiveness of this method in 6 cases of cervical cancer with IMRT by comparing the original plan and the automatic optimization plan generated by this method. The results showed that with the same PTV coverage and uniformity, the automatic optimization plan had a better a dose sparing of the organs-at-risk and a better plan quality than the original plan, and resulted in obvious reductions of the average V45 of the rectum from (41.99?13.31)% to (32.55?22.27)% and of the bladder from (44.37?4.08)% to (28.99?15.25)%. PMID- 29997092 TI - [Implantation strategy of tissue-engineered liver based on decellularized spleen matrix in rats]. AB - OBJECTIVE: To explore the optimal implantation strategy of tissue-engineered liver (TEL) constructed based on decellularized spleen matrix (DSM) in rats. METHODS: DSM was prepared by freeze-thawing and perfusion with sodium dodecyl sulfate (SDS) of the spleen of healthy SD rats. Primary rat hepatocytes isolated using modified Seglen 2-step perfusion method were implanted into the DSM to construct the TEL. The advantages and disadvantages were evaluated of 4 transplant strategies of the TEL, namely ectopic vascular anastomosis, liver cross-section suture transplantation, intrahepatic insertion and mesenteric transplantation. RESULTS: The planting rate of hepatocytes in the DSM was (74.5?7.7)%. HE staining and scanning electron microscopy showed satisfactory cell status, and immunofluorescence staining confirmed the normal expression of ALB and G6Pc in the cells. For TEL implantation, ectopic vascular anastomosis was difficult and resulted in a mortality rate of 33.3% perioperatively and massive thrombus formation in the matrix within 6 h. Hepatic cross-section suture failed to rapidly establish sufficient blood supply, and no viable graft was observed 3 days after the operation. With intrahepatic insertion method, the hepatocytes in the DSM could survive as long as 14 days. Mesenteric transplantation resulted in a hepatocyte survival rate of (38.3+7.1)% at 14 days after implantation. CONCLUSION: TEL constructed based on DSM can perform liver-specific functions with a good cytological bioactivity. Mesenteric transplantation of the TEL, which is simple, safe and effective, is currently the optimal transplantation strategy. PMID- 29997093 TI - [Effect of vimentin on activation of NLRP3 inflammasome in the brain of mice with EV71 infection]. AB - OBJECTIVE: To explore whether vimentin (VIM) mediates the activation of inflammasome in mice with EV71 infection in the central nervous system. METHODS: Forty VIM knockout mice (VIM-/-, 3 to 5 days old) were randomly divided into control group and infection group. The infection group was intraperitoneally injected with EV71 (108 TCID50), while the control group was injected with PBS (10 uL); another 40 wild-type mice (WT, 3 to 5 days old) were grouped in the same manner. The general conditions of mice were observed each day. Western blotting, ELISA, and RT-PCR were used to measure the levels of IL-1beta and casepase-1 in the brain or cerebrospinal fluid. The pathological changes in the cerebella and brain were observed using immunohistochemistry. RESULTS: Compared with the control group, the VIM-/- mice infected with EV71 showed no significant changes in NLRP3, IL-1beta or caspase-1 expression. The WT mice infected with EV71 showed obviously increased NLRP3, IL-1beta, and caspase-1 expressions in the central nervous system. The neurons of infected VIM-/- mice exhibited milder cell damage than the those in WT mice. CONCLUSION: VIM mediates the activation of inflammasome and promotes brain inflammation and neuronal damage in mice with EV71 infection in the central nervous system. PMID- 29997094 TI - [Icariin alleviates lipid peroxidation after spinal cord injury in rats]. AB - OBJECTIVE: To assess the effects of intragastric administration of icariin on lipid peroxidation after spinal cord injury in rats. METHODS: Seventy-two healthy adult male SD rats were randomized equally into icariin group, control group and sham-operated group. In the control and icariin groups, spinal cord injury was induced using modified Allen's method, and the rats in the sham-operated group underwent laminotomy without damaging the spinal cord. Immediately after the surgery, the rats in icariin group were subjected to intragastric administration of icariin (100 mg/kg), and those in the control and sham-operated groups received an equal volume of saline in the same manner once a day. At 24 h after the operation, malondialdehyde (MDA) content was detected using thiobarbituric acid method, superoxide dismutase (SOD) activity was measured with xanthine oxidase method, and the water content in the spinal cord was measured using dry wet weight method. At 48 h after the operation, the ultrastructure of the spinal cord was observed with transmission electron microscopy and scored using Kaptanoglu scoring method. The motor function of the rats was assessed using BBB scoring at 7, 14, 21 and 28 days after the operation. RESULTS: At 24 h after the operation, MDA content was significantly higher in the control group and icariin group than in the sham-operated group, and was significantly lower in icariin group than in the control group (P<0.05); SOD activity was significantly higher in icariin group than in the control group, and was both significantly lower than that in the sham-operated group (P<0.05). At 48 h after operation, the water content and ultrastructure score of the spinal cord were the highest in sham operated group (P<0.05), and were significantly lower in icariin group than in the control group (P<0.05). At all the time points of measurement, the BBB scores were significantly lower in the control and icariin groups than in the sham operated group (P<0.05), and were significantly higher in icariin group than in the control group (P<0.05). CONCLUSION: Icariin can significantly reduce MDA content, increase SOD activity, and ameliorate lipid peroxidation, spinal cord edema, and histopathological damage of the spinal cord to improve motor function of rats with spinal cord injury. PMID- 29997095 TI - [A novel calcium phosphate cement pre-loaded with chitosan and small molecule adenosine for repairing large cranial defects in rats]. AB - OBJECTIVE: To evaluate the effect of a novel biomaterial in repairing large cranial defects in rats. METHODS: Eighteen SD rats were used to establish rat modes of large cranial defect (8 mm in diameter). The rat models were randomized into 3 groups and the cranial defects were repaired using different scaffold materials, namely CPC paste prepared with distilled water (CPC control group), CPC paste mixed with 10% chitosan (CPC/CN group), or CPC paste with 10% chitosan and 300 mg adenosine (CPC/CN/AD group). The defects were examined 12 weeks after the surgery with X-ray, CT, HE staining and quantitative assessments. RESULTS: X ray showed that the defect was repaired in all the groups. The fracture line became obscure and the defects were almost fully repaired by regenerated bone tissues in CPC/CN/AD group, which was consistent with CT findings. In all the 3 groups, HE staining revealed the presence of new bones in the defects and new vessels in and around the new bones without inflammatory cells. The new bone area was significantly greater in CPC/CN/AD group than in CPC/CN group and CPC control group (P<0.05). The new vessel density was the highest in CPC/CN/AD group (P>0.05) but similar between CPC/CN group and CPC control group (P>0.05). CONCLUSION: This novel calcium phosphate cement pre-loaded with chitosan and small molecule adenosine can better promote bone regeneration than calcium phosphate cement for repairing large bone defects to serve as a good replacement material for bone regeneration. PMID- 29997096 TI - [Infiltrating mast cells promote neuroendocrine differentiation and increase docetaxel resistance of prostate cancer cells by up-regulating p21]. AB - OBJECTIVE: To investigate the effect of infiltrating mast cells on neuroendocrine differentiation (NED) and docetaxel sensitivity of prostate cancer (PCa) cells in vitro. METHODS: Human PCa cell lines (LNCaP and C4-2) were co-cultured with human mast cell line (HMC-1) in Transwell chambers. Androgen receptor (AR) was silenced in C4-2 cells using sh-AR lentivirus, and p21 was knocked down and overexpressed by transfecting C4-2 cells with pLKO.1-sh-p21 and pCMV-p21, respectively. The morphological changes of LNCaP and C4-2 cells were observed. MTT assay and colony formation assay were used to assess the proliferation of LNCaP and C4-2 cells. CCK8 assay was used to detect the cell viability of C4-2 cells following docetaxel trreatment. RT-qPCR and Western blotting were performed to determine the mRNA and protein expressions of neuroendocrine markers, AR and p21 in the cells. RESULTS: Co-culture with HMC-1 cells enhanced the neuroendocrine phenotypes, inhibited the proliferation and up-regulated the expression of p21 in LNCaP and C4-2 cells. P21 positively regulated NED through a non-AR-dependent signaling pathway, while p21 knockdown partially reversed NED promoted by the mast cells. PCa cells co-cultured with HMC-1 cells showed increased resistance to docetaxel, and silencing p21 partially reversed docetaxel resistance in PCa cells. CONCLUSION: Infiltrating mast cells up-regulates p21 to promote NED and increase docetaxel resistance in PCa cells in vitro. PMID- 29997097 TI - [Analysis of orthologous lncRNAs in humans and mice and their species-specific epigenetic target genes]. AB - OBJECTIVE: To identify orthologous lncRNAs in human and mice and the species specificity of their epigenetic regulatory functions. METHODS: The human/mouse whole-genome pairwise alignment (hg19/mm10, genome.UCSC.edu) was used to identify the orthologues in 13 562 and 10 481 GENCODE-annotated human and mouse lncRNAs. The Infernal program was used to search the orthologous sequences of all the exons of the 13562 human lncRNAs in mouse genome (mm10) to identify the highly conserved orthologues in mice. LongTarget program was used to predict the DNA binding sites of the orthologous lncRNAs in their local genomic regions. Gene Ontology analysis was carried out to examine the functions of genes. RESULTS: Only 158 orthologous lncRNAs were identified in humans and mice, and many of these orthologues had species-specific DNA binding sites and epigenetic target genes. Some of the epigenetic target genes executed important functions in determining human and mouse phenotypes. CONCLUSION: s Only a few human and mouse lncRNAs are orthologues, and most of lncRNAs are species-specific. The orthologous lncRNAs have species-specific epigenetic target genes, and species specific epigenetic regulation greatly contributes to the differences between humans and mice. PMID- 29997098 TI - [Long-term prognosis and quality of life of survivors with hepatitis B virus related acute-on-chronic liver failure]. AB - OBJECTIVE: To explore the long-term prognosis and health-related quality of life of patients surviving hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). METHODS: The clinical data were collected from patients with HBV ACLF, who were hospitalized in our department between November, 2011 and October, 2016 and survived for more than 90 days. The patients were followed for occurrence of newly diagnosed cirrhosis, decompensation events, hepatocellular carcinoma and death. The quality of life of the patients was evaluated using SF 36 score, and the patients with chronic hepatitis B (CHB) and cirrhosis treated during the same period served as controls. RESULTS: A total of 223 ACLF survivors were included in this study. According to the presence of cirrhosis on admission, the enrolled patients were divided into chronic hepatitis B-related ACLF (CHB ACLF) group (n=130) and liver cirrhosis ACLF (CIR-ACLF) group (n=93). The 12-, 24 and 50-month survival rates in CHB-ACLF group were 97%, 95.7% and 93.9%, respectively, significantly higher than the rates in CIR-ACLF group (91%, 86% and 74%, respectively; P=0.007). In patients with CHB-ACLF, the 12-, 24- and 36-month progression rates of cirrhosis were 37.9%, 58.4% and 68.7% respectively. Multivariate Cox regression identified the peak value of serum creatinine (HR=1.015, P=0.026) and INR (HR=2.032, P=0.006) within 28 days as independent risk factors and serum sodium at baseline (HR=0.84, P=0.035) as an independent protective factor of occurrence of cirrhosis. The score of mental health on SF-36 in ACLF group was significantly lower than the national norms, and the scores for general health and body pain of ACLF patients were significantly higher than those in patients with CHB or cirrhosis. CONCLUSION: The long-term prognosis of ACLF survivors with and without cirrhosis can be different. Acute attacks are associated with an increased rate of cirrhosis progression in CHB patients who recovered from ACLF, possibly in relation with the severity of extra-hepatic organ injuries. The physical and social functions of long-term survivors of ACLF do not significantly decline, but their psychological status can be affected. PMID- 29997099 TI - [AMPK regulates mitochondrial oxidative stress in C2C12 myotubes induced by electrical stimulations of different intensities]. AB - OBJECTIVE: To study effect of electrical stimulations of different intensities on mitochondrial oxidative stress in C2C12 myotubes and explore the molecular mechanisms. METHODS: After 7 days of differentiation, C2C12 myotubes were subjected to electrical stimulations (15 V, 3Hz, 30 ms) for 60, 120, or 180 min, and the morphological changes of muscular tubes were observed under inverted microscope. The levels of MDA and SOD activity of the cells were detected, and flow cytometry was used to detect mitochondrial reactive oxygen species (ROS) and membrane potential. Western blotting was used to detect the expression of PGC1, AMPK-Ser485, AMPK-Thr172, and AMPK in the cells. RESULTS: No significant changes occurred in the morphology of C2C12 myotubes in response to electrical stimulations. Electrical stimulation for 60 min resulted in significantly increased levels of MDA, AMPK-Ser485 and AMPK-Thr172 in the cells (P<0.05); simulations of the cells for 120 and 180 min caused significantly increased MDA, ROS, mitochondrial ROS, AMPK-Ser485 and PGC1 along with marked reduction of mitochondrial membrane potential (P<0.05). CONCLUSION: Electrical stimulation significantly activates oxidative stress, and a longer stimulation time causes stronger mitochondrial oxidation. AMPK-Thr172 regulates oxidative stress induced by stimulations for a moderate time length, while AMPK-Ser485 and PGC1 function to modulate oxidative stress following prolonged stimulations. PMID- 29997100 TI - [Efficacy of inactivated autologous porous bone flap and BAM bone-induced artificial bone for repairing skull defect in rats]. AB - OBJECTIVE: To study the effect of BAM bone grafting combined with inactivated autologous porous bone flap in repairing skull defect in rats. METHODS: Seventy two Wistar rats with skull defect were randomly divided into control group, inactivated autologous bone flap group (AB group), BAM bone-induced artificial bone material group (BAM group), and inactivated autologous bone flap with BAM bone-induced artificial bone group (BAM+AB group). The bone healing was evaluated with micro-CT and the new bone formation was assessed with histological staining at 1, 2, and 3 months after modeling. RESULTS: Inactivated porous bone flap combined with BAM bone-induced artificial bone effectively induced vascular and fibrous tissue regeneration and osteogenesis in the cranial defects. With the inactivated porous bone flap as the scaffold, BAM bone-induced artificial bone obviously promoted the restoration of the skull appearance in the rats with cranial defects. CONCLUSION: Inactivated autologous bone flap group and BAM bone induced artificial bone material can promote skull healing and restoration of the original skull appearance, and can be used for reconstruction of the local anatomy of the skull surface. PMID- 29997101 TI - [Mitochondrial calcium overload in the masseter muscle of rats with occlusal interference: ionic changes and regulation by calmodulin kinase II]. AB - OBJECTIVE: To investigate the changes in mitochondrial calcium and extracellular sodium concentrations in the masseter muscle of rats with occlusal interference and the regulatory mechanism of mitochondrial Ca2+ overload by calmodulin kinase II (CaMK II). METHODS: SD rat models of occlusal interference were established by placing a stainless steel segments (0.8 mm in diameter) to raise the occlusal surface of the upper right first molar. At 3, 7, 14, and 21 days after occlusal interference and at 3 days after removal of occlusal interference, HE staining was used to observe the histomorphological changes of the masseter muscle. Mitochondrial calcium concentration in the masseter muscle was detected using fluorescence spectrophotometry, and direct turbidimetry with potassium pyroantimonate was used to detect the extracellular sodium concentration; the expression levels of masseter muscle p-CaMK II (Thr287) and CaMK II were detected using Western blotting. RESULTS: Compared with those in the corresponding control groups, mitochondrial Ca2+ concentration in the masseter muscle on occlusal interference side increased significantly at 3, 7, 14 and 21 days after occlusal interference (P<0.05), but was significantly lowered at 3 days after removal of the interference (P<0.05). The concentration of extracellular Na+ increased progressively with time at 3, 7, 14 and 21 days after occlusal interference (P<0.05), and was significantly decreased at 3 days after interference removal (P<0.05). Occlusal interference for 3, 7 and 14 days resulted in significantly increased expressions of p-CaMK II (Thr287) and CaMK II (P<0.05), which was significantly decreased at 21 days compared with those in the control groups (P<0.05) and further decreased after removal of occlusal interference (P<0.05). Similar changes were also observed on the side without interference, but the changes on the interference side were more obvious (P<0.05). CONCLUSION: Occlusal interference causes elevated mitochondrial Ca2+ and extracellular Na+ concentrations in the masseter muscle of rats to lead to calcium overload; the increase in mitochondrial Ca2+ concentration is correlated with the phosphorylation level of CaMK II signaling pathway, suggesting a negative feedback regulation mechanism by the CaMK II signal pathway. PMID- 29997102 TI - [Left ventricular Tei-index for evaluation of cardiac function in hypertensive patients with left ventricular hypertrophy after radiochemotherapy]. AB - OBJECTIVE: To assess the clinical value of left ventricular Tei-index in early evaluation of cardiac function in hypertensive patients with left ventricular hypertrophy after radiochemotherapy. METHODS: Thirty hypertensive patients with malignancies and left ventricular hypertrophy and 30 hypertensive patients with malignancies without left ventricular hypertrophy were enrolled in this study, with 30 normotensive patients with malignancies as the control group. Left ventricular Tei-index and cardiac function indexes of the patients were detected using Doppler echocardiography before and after radiochemotherapy, and the changes in the cardiac function index and left ventricular Tei-index were compared among the 3 groups. RESULTS: After radiochemotherapy, left ventricular Tei-index was significantly higher in hypertensive patients with left ventricular hypertrophy than in the control patients and hypertensive patients without left ventricular hypertrophy (P<0.05), and was similar between the latter two groups. No significant differences were found in the changes of left ventricular ejection fraction (EF), ratio of the early to late ventricular filling velocities (E/A ratio), or end-systolic volume (EDV) among the 3 groups after radiochemotherapy. CONCLUSION: Tei-index is more sensitive than traditional echocardiography in assessing the changes of cardiac functions in hypertensive patients with left ventricular hypertrophy after chemotherapy. PMID- 29997103 TI - [Alterations of respiratory resistance in patients with obstructive sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To evaluate the association between the components of airway resistance and severity of obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: A total of 234 patients with snoring during sleep underwent full-night polysomnography in our center between January, 2015 and September, 2017. According to the apnea-hypopnea index (AHI) scores, the patients were divided into non-OSAHS group (AHI scores <5), mild or moderate OSAHS group (5-30) group, and severe OSAHS group (>30). The pulmonary function and respiratory resistance of the patients were assessed using spirometry and impulse oscillometry, respectively, and the correlation between the parameters of respiratory resistance and the severity of AHI were analyzed. RESULTS: The non-OSAHS, mild or moderate OSAHS, and severe OSAHS groups consisted of 31, 90 and 113 patients, respectively. The patients with severe OSAHS had significantly higher levels of respiratory resistance at 5 Hz (R5) and 20 Hz (R20), FEF50% and MMEF than those in the other two groups (P<0.05). Bivariate correlation analysis identified positive correlations of R5 (r=0.259, P=0.000), R20 (r=0.298, P=0.000) and FEF50% (r=0.176, P=0.007) with AHI scores of the patients. CONCLUSION: Patients with OSAHS have increased respiratory resistance in the large airways and compensatory reduction in small airway resistance. PMID- 29997104 TI - [Clinical characteristics of hemophagocytic syndrome: analysis of 46 cases]. AB - OBJECTIVE: To analyze the clinical manifestations, laboratory findings, treatment and prognosis of patients with hemophagocytic syndrome (HPS). METHODS: A retrospective study was carried out to analyze the underlying disease, clinical characteristics, laboratory findings and outcomes of 46 patients with HPS. RESULTS: This cohort included 19 cases of HPS secondary to cancer, 11 cases of HPS secondary to infection, 10 cases of suspected malignant lymphoma based on PET CT findings (without biopsy), and 6 cases of unknown etiology. The coincidence rate of the clinical characteristics of the patients with the indices listed in HPS-2004 criteria were: fever (100%), elevated serum ferritin (100%), cytopenias (93.48%), splenomegaly (91.30%), hemophagocytosis in the bone marrow, spleen or lymph nodes (84.78%), hypofibrinogenemia (67.39%), and hypertriglyceridemia (54.05%). The cases of cancer, infections and unknown etiology showed significant differences in serum levels of ferritin and beta2MG (P<0.05), and significant differences were found in triglycerides, LDH, and fibrinogenemia between the nonfatal and fatal cases (P<0.05). CONCLUSION: HPS can be secondary to various underlying diseases, many associated with Epstein-Barr virus infection. Cancer, especially NK/T-cell lymphoma, is the main cause of HPS. Persistent fever, elevated serum ferritin level and cytopenias are the most sensitive indicators for diagnosis of HPS, and early diagnosis and treatment are critical to lower the mortality rate of this disease. PMID- 29997105 TI - How Online Communities of People With Long-Term Conditions Function and Evolve: Network Analysis of the Structure and Dynamics of the Asthma UK and British Lung Foundation Online Communities. AB - BACKGROUND: Self-management support can improve health and reduce health care utilization by people with long-term conditions. Online communities for people with long-term conditions have the potential to influence health, usage of health care resources, and facilitate illness self-management. Only recently, however, has evidence been reported on how such communities function and evolve, and how they support self-management of long-term conditions in practice. OBJECTIVE: The aim of this study is to gain a better understanding of the mechanisms underlying online self-management support systems by analyzing the structure and dynamics of the networks connecting users who write posts over time. METHODS: We conducted a longitudinal network analysis of anonymized data from 2 patients' online communities from the United Kingdom: the Asthma UK and the British Lung Foundation (BLF) communities in 2006-2016 and 2012-2016, respectively. RESULTS: The number of users and activity grew steadily over time, reaching 3345 users and 32,780 posts in the Asthma UK community, and 19,837 users and 875,151 posts in the BLF community. People who wrote posts in the Asthma UK forum tended to write at an interval of 1-20 days and six months, while those in the BLF community wrote at an interval of two days. In both communities, most pairs of users could reach one another either directly or indirectly through other users. Those who wrote a disproportionally large number of posts (the superusers) represented 1% of the overall population of both Asthma UK and BLF communities and accounted for 32% and 49% of the posts, respectively. Sensitivity analysis showed that the removal of superusers would cause the communities to collapse. Thus, interactions were held together by very few superusers, who posted frequently and regularly, 65% of them at least every 1.7 days in the BLF community and 70% every 3.1 days in the Asthma UK community. Their posting activity indirectly facilitated tie formation between other users. Superusers were a constantly available resource, with a mean of 80 and 20 superusers active at any one time in the BLF and Asthma UK communities, respectively. Over time, the more active users became, the more likely they were to reply to other users' posts rather than to write new ones, shifting from a help-seeking to a help-giving role. This might suggest that superusers were more likely to provide than to seek advice. CONCLUSIONS: In this study, we uncover key structural properties related to the way users interact and sustain online health communities. Superusers' engagement plays a fundamental sustaining role and deserves research attention. Further studies are needed to explore network determinants of the effectiveness of online engagement concerning health-related outcomes. In resource-constrained health care systems, scaling up online communities may offer a potentially accessible, wide-reaching and cost effective intervention facilitating greater levels of self-management. PMID- 29997106 TI - Patients' Experiences of Web- and Mobile-Assisted Group Therapy for Depression and Implications of the Group Setting: Qualitative Follow-Up Study. AB - BACKGROUND: Blended group therapy combines group sessions with Web- and mobile based treatment modules. Consequently, blended group therapy widens the choice within blended interventions at reasonable costs. This is the first qualitative study on blended group therapy. OBJECTIVE: The objective of this study was to investigate the patient-centered feasibility of blended group therapy for major depression, with special emphasis on the fit and dynamic interplay between face to-face and internet-based elements. METHODS: A total of 22 patients who had a variety of experiences through participating in one of the two blended group therapy interventions were interviewed following a semistructured interview guide. In-depth interviews were analyzed by three trained psychologists, using thematic analysis and a rule-guided internet-based program (QCAmap). The transcript of the interviews (113,555 words) was reduced to 1081 coded units, with subsequent extraction of 16 themes. RESULTS: Web- and mobile-based elements were described as a treatment facilitator and motivator, increasing the salience and consolidation of cognitive behavioral therapy materials, resulting in in- and inter-session alignment to the treatment. Additionally, patients valued the option of intimate Web-based self-disclosure (by lateral patient-therapist communication), and therapists were provided with tools for between-session monitoring and reinforcement of exercising. In this context, group phenomena seemed to back up therapists' efforts to increase treatment engagement. The dissonance because of noncompliance with Web-based tasks and the constriction of in-session group interaction were considered as possible negative effects. Finally, issues of tailoring and structure seemed to fulfill different preconditions compared with individual therapy. CONCLUSIONS: Blended group therapy constitutes a structured and proactive approach to work with depression, and the integration of both modalities initiates a beneficial interplay. Results support the patient-centered value of blended group therapy and provide the first insight into blended group therapy's role in fostering therapeutic treatment factors. However, potential negative effects should be considered carefully. PMID- 29997107 TI - Examining the Complexity of Patient-Outpatient Care Team Secure Message Communication: Qualitative Analysis. AB - BACKGROUND: The value of secure messaging in streamlining routine patient care activities is generally agreed upon. However, the differences in how patients use secure messaging, including for communicating both routine and nonroutine issues, and the implications of these differences in use are less well understood. OBJECTIVE: The purpose of this study was to examine secure messaging use to extend current knowledge of how this tool is being used in outpatient care settings and generate new research questions to improve our understanding of the role of secure messaging in the patient-provider communication toolbox. METHODS: We conducted an in-depth qualitative analysis of secure message threads in 12 US Department of Veterans Affairs outpatient clinics in south Texas. We analyzed 70 secure message threads with a total of 179 unique communications between patients and their outpatient teams for patterns in communication and secure message content. We used theories from information systems and complexity science in organizations to explain our observations. RESULTS: Analysis identified content relating to 3 main themes: (1) information management, (2) uncertainty management, and (3) patient safety and engagement risks and opportunities. Within these themes, we identified 2 subcategories of information management (information exchange and problem solving), 2 subcategories of uncertainty management (relationship building and sensemaking), and 3 subcategories of patient safety and engagement risks and opportunities (unresolved issues, tone mismatch, and urgent medical issues). Secure messages were most often used to communicate routine issues (eg, information exchange and problem solving). However, the presence of subcategories pertaining to nonroutine issues (eg, relationship building, sensemaking, tone mismatch, urgent issues, and unresolved issues) requires attention, particularly for improving opportunities in outpatient care settings using secure messaging. CONCLUSIONS: Patients use secure messaging for both routine and nonroutine purposes. Our analysis sheds light on potentially new patient safety concerns, particularly when using secure messaging to address some of the more complex issues patients are communicating with providers. Secure messaging is an asynchronous communication information system operated by patients and providers who are often characterized as having significant differences in knowledge, experience and expectations. As such, justification for its use beyond routine purposes is limited-yet this occurs, presenting a multifaceted dilemma for health care organizations. Secure messaging use in outpatient care settings may be more nuanced, and thus more challenging to understand and manage than previously recognized. New information system designs that acknowledge the use of secure messaging for nonroutine and complex health topics are needed. PMID- 29997109 TI - Working at sporting events. PMID- 29997108 TI - Rethinking the Meaning of Cloud Computing for Health Care: A Taxonomic Perspective and Future Research Directions. AB - BACKGROUND: Cloud computing is an innovative paradigm that provides users with on demand access to a shared pool of configurable computing resources such as servers, storage, and applications. Researchers claim that information technology (IT) services delivered via the cloud computing paradigm (ie, cloud computing services) provide major benefits for health care. However, due to a mismatch between our conceptual understanding of cloud computing for health care and the actual phenomenon in practice, the meaningful use of it for the health care industry cannot always be ensured. Although some studies have tried to conceptualize cloud computing or interpret this phenomenon for health care settings, they have mainly relied on its interpretation in a common context or have been heavily based on a general understanding of traditional health IT artifacts, leading to an insufficient or unspecific conceptual understanding of cloud computing for health care. OBJECTIVE: We aim to generate insights into the concept of cloud computing for health IT research. We propose a taxonomy that can serve as a fundamental mechanism for organizing knowledge about cloud computing services in health care organizations to gain a deepened, specific understanding of cloud computing in health care. With the taxonomy, we focus on conceptualizing the relevant properties of cloud computing for service delivery to health care organizations and highlighting their specific meanings for health care. METHODS: We employed a 2-stage approach in developing a taxonomy of cloud computing services for health care organizations. We conducted a structured literature review and 24 semistructured expert interviews in stage 1, drawing on data from theory and practice. In stage 2, we applied a systematic approach and relied on data from stage 1 to develop and evaluate the taxonomy using 14 iterations. RESULTS: Our taxonomy is composed of 8 dimensions and 28 characteristics that are relevant for cloud computing services in health care organizations. By applying the taxonomy to classify existing cloud computing services identified from the literature and expert interviews, which also serves as a part of the taxonomy, we identified 7 specificities of cloud computing in health care. These specificities challenge what we have learned about cloud computing in general contexts or in traditional health IT from the previous literature. The summarized specificities suggest research opportunities and exemplary research questions for future health IT research on cloud computing. CONCLUSIONS: By relying on perspectives from a taxonomy for cloud computing services for health care organizations, this study provides a solid conceptual cornerstone for cloud computing in health care. Moreover, the identified specificities of cloud computing and the related future research opportunities will serve as a valuable roadmap to facilitate more research into cloud computing in health care. PMID- 29997110 TI - Characterisation of the nasal microbiota in granulomatosis with polyangiitis. AB - OBJECTIVES: Prior studies have suggested a potential link between nasal microbes and granulomatosis with polyangiitis (GPA; Wegener's), but these studies relied on culture-dependent methods. This study comprehensively examined the entire community of nasal microbiota (bacteria and fungi) in participants with GPA compared with healthy controls using deep sequencing methods. METHODS: 16S rRNA and internal transcribed spacer gene sequencing were performed on nasal microbial DNA isolated from nasal swabs of 60 participants with GPA and 41 healthy controls. Alpha and beta diversity were assessed as well as the relative abundance of the most abundant bacterial and fungal taxa. The effects of covariates including disease activity and immunosuppressive therapies on microbial composition were evaluated. RESULTS: Compared with controls, participants with GPA had a significantly different microbial composition (weighted UniFrac p=0.04) and lower relative abundance of Propionibacterium acnes and Staphylococcus epidermidis (for both, false discovery rate-corrected p=0.02). Disease activity in GPA was associated with a lower abundance of fungal order Malasseziales compared with participants with GPA in remission (p=0.04) and controls (p=0.01). Use of non-glucocorticoid immunosuppressive therapy was associated with 'healthy' nasal microbiota while participants with GPA who were off immunosuppressive therapy had more dysbiosis (weighted UniFrac p=0.01). No difference in the relative abundance of Staphylococcus aureus was observed between GPA and controls. CONCLUSIONS: GPA is associated with an altered nasal microbial composition, at both the bacterial and fungal levels. Use of immunosuppressive therapies and disease remission are associated with healthy microbial communities. PMID- 29997111 TI - Glucocorticoid receptor in stromal cells is essential for glucocorticoid-mediated suppression of inflammation in arthritis. AB - BACKGROUND: Glucocorticoid (GC) therapy is frequently used to treat rheumatoid arthritis due to potent anti-inflammatory actions of GCs. Direct actions of GCs on immune cells were suggested to suppress inflammation. OBJECTIVES: Define the role of the glucocorticoid receptor (GR) in stromal cells for suppression of inflammatory arthritis. METHODS: Bone marrow chimeric mice lacking the GR in the hematopoietic or stromal compartment, respectively, and mice with impaired GR dimerisation (GRdim) were analysed for their response to dexamethasone (DEX, 1 mg/kg) treatment in serum transfer-induced arthritis (STIA). Joint swelling, cell infiltration (histology), cytokines, cell composition (flow cytometry) and gene expression were analysed and RNASeq of wild type and GRdim primary murine fibroblast-like synoviocytes (FLS) was performed. RESULTS: GR deficiency in immune cells did not impair GC-mediated suppression of STIA. In contrast, mice with GR-deficient or GR dimerisation-impaired stromal cells were resistant to GC treatment, despite efficient suppression of cytokines. Intriguingly, in mice with impaired GR function in the stromal compartment, GCs failed to stimulate non classical, non-activated macrophages (Ly6Cneg, MHCIIneg) and associated anti inflammatory markers CD163, CD36, AnxA1, MerTK and Axl. Mice with GR deficiency in FLS were partially resistant to GC-induced suppression of STIA. Accordingly, RNASeq analysis of DEX-treated GRdim FLS revealed a distinct gene signature indicating enhanced activity and a failure to reduce macrophage inflammatory protein (Mip)-1alpha and Mip-1beta. CONCLUSION: We report a novel anti inflammatory mechanism of GC action that involves GR dimerisation-dependent gene regulation in non-immune stromal cells, presumably FLS. FLS control non classical, anti-inflammatory polarisation of macrophages that contributes to suppression of inflammation in arthritis. PMID- 29997112 TI - 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. AB - Regular physical activity (PA) is increasingly promoted for people with rheumatic and musculoskeletal diseases as well as the general population. We evaluated if the public health recommendations for PA are applicable for people with inflammatory arthritis (iA; Rheumatoid Arthritis and Spondyloarthritis) and osteoarthritis (hip/knee OA) in order to develop evidence-based recommendations for advice and guidance on PA in clinical practice. The EULAR standardised operating procedures for the development of recommendations were followed. A task force (TF) (including rheumatologists, other medical specialists and physicians, health professionals, patient-representatives, methodologists) from 16 countries met twice. In the first TF meeting, 13 research questions to support a systematic literature review (SLR) were identified and defined. In the second meeting, the SLR evidence was presented and discussed before the recommendations, research agenda and education agenda were formulated. The TF developed and agreed on four overarching principles and 10 recommendations for PA in people with iA and OA. The mean level of agreement between the TF members ranged between 9.8 and 8.8. Given the evidence for its effectiveness, feasibility and safety, PA is advocated as integral part of standard care throughout the course of these diseases. Finally, the TF agreed on related research and education agendas. Evidence and expert opinion inform these recommendations to provide guidance in the development, conduct and evaluation of PA-interventions and promotion in people with iA and OA. It is advised that these recommendations should be implemented considering individual needs and national health systems. PMID- 29997113 TI - Apolipoprotein B binds to enolase-1 and aggravates inflammation in rheumatoid arthritis. AB - OBJECTIVE: Immune cells from patients with rheumatoid arthritis (RA) express more enolase-1 (ENO1) on their surface than those from healthy subjects, and they elicit an enhanced inflammatory response. This study is aimed to identify the ligands of ENO1 that could promote inflammatory loops in vitro and enhance the arthritis severity in vivo. METHODS: ENO1-binding proteins in RA synovial fluid were identified by mass spectromety, and affinity to ENO1 was evaluated by means of a ligand blotting and binding assay, surface plasmon resonance and confocal microscopy. Proinflammatory response by the interaction between ENO1 and apolipoprotein B (apoB) was tested in vitro and in vivo using peripheral blood mononuclear cells and a K/BxN serum transfer arthritis model and low-density lipoproteins receptor (LDLR) knockout mice. RESULTS: ApoB in the synovid fluid of patients with RA was identified as a specific ligand to ENO1 with a higher affinity than plasminogen, a known ENO1 ligand. ApoB binding to ENO1 on monocytes elicited the production of tumour necrosis factor-alpha, interleukins (IL)-1beta and IL-6 through both p38 mitogen-activated protein kinase and NF-kappaB pathways. In the K/BxN serum transfer arthritis model, administration of apoB increased the production of proinflammatory cytokines and exaggerated arthritis severity. The severity of K/BxN serum transfer arthritis in LDLR knockout mice was comparable with wild-type mice. CONCLUSIONS: A key component of atherogenic lipids, apoB, aggravated arthritis by potentiating the inflammatory response via its interaction with ENO1 expressed on the surface of immune cells. This suggests a novel mechanism by which lipid metabolism regulates chronic inflammation in RA. PMID- 29997114 TI - Tackling loneliness with a well stocked community. PMID- 29997115 TI - LDL-Reactive T Cells Regulate Plasma Cholesterol Levels and Development of Atherosclerosis in Humanized Hypercholesterolemic Mice. AB - Background -Atherosclerotic cardiovascular disease is a chronic inflammatory process initiated when cholesterol-carrying low-density lipoprotein (LDL) is retained in the arterial wall. CD4+ T cells, some of which recognize peptide components of LDL as antigen, are recruited to the forming lesion, resulting in T cell activation. Although these T cells are thought to be proatherogenic, LDL immunization reduces disease in experimental animals. These seemingly contradictory findings have hampered the development of immune-based cardiovascular therapy. The present study was designed to clarify how activation of LDL-reactive T cells impacts on metabolism and vascular pathobiology. Methods We have developed a T-cell receptor(TCR)-transgenic mouse model to characterize the effects of immune reactions against LDL. Through adoptive cell transfers and cross-breeding to hypercholesterolemic mice expressing the antigenic human LDL protein ApoB100, we evaluate the effects on atherosclerosis. Results -A subpopulation of LDL-reactive T cells survived clonal selection in the thymus, developed into T follicular helper cells in lympoid tissues upon antigen recognition, and promoted B-cell activation. This led to production of anti-LDL immunoglobulin G (IgG) antibodies that enhanced LDL clearance through immune complex formation. Furthermore, the cellular immune response to LDL was associated with increased cholesterol excretion in faeces and with reduced vascular inflammation. Conclusions -These data show that anti-LDL immunoreactivity evokes three atheroprotective mechanisms, namely antibody dependent LDL clearance, increased cholesterol excretion, and reduced vascular inflammation. PMID- 29997116 TI - FTO-Dependent m6A Regulates Cardiac Function During Remodeling and Repair. AB - Background -Despite its functional importance in various fundamental bioprocesses, the studies of N6-methyladenosine (m6A) in the heart are lacking. Here we show that, fat mass and obesity-associated (FTO), an m6A demethylase, plays a critical role in cardiac contractile function during homeostasis, remodeling and regeneration. Methods -We used clinical human samples, preclinical pig and mouse models and primary cardiomyocyte cell cultures to study the functional role of m6A and FTO in the heart and in cardiomyocytes. We modulated expression of FTO using AAV9 (in vivo), adenovirus (both in vivo and in vitro) and siRNAs (in vitro) to study its function in regulating cardiomyocyte m6A, calcium dynamics and contractility and cardiac function post-ischemia. We performed methylated (m6A) RNA immunoprecipitation sequencing (MeRIP-seq) to map transcriptome-wide m6A, and MeRIP qPCR assays to map and validate m6A in individual transcripts, in healthy and failing hearts and myocytes. Results -We discovered that FTO has decreased expression in failing mammalian hearts and hypoxic cardiomyocytes, thereby increasing m6A in RNA and decreasing cardiomyocyte contractile function. Improving expression of FTO in failing mouse hearts attenuated the ischemia-induced increase in m6A and decrease in cardiac contractile function. This is carried out by the demethylation activity of FTO, which selectively demethylates cardiac contractile transcripts, thus preventing their degradation and improving their protein expression under ischemia. Additionally, we demonstrate that FTO overexpression in mouse models of MI decreased fibrosis and enhanced angiogenesis. Conclusions -Collectively, our study demonstrates the functional importance of FTO-dependent cardiac m6A methylome in cardiac contraction during heart failure and provides a novel mechanistic insight into the therapeutic mechanisms of FTO. PMID- 29997118 TI - Complicated Pneumonia: Pick and Choose, but Don't Choose the PICC. PMID- 29997117 TI - miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential. AB - We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR 196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2-containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia. PMID- 29997119 TI - Regulation of Trypanosoma brucei Acetyl Coenzyme A Carboxylase by Environmental Lipids. AB - To satisfy its fatty acid needs, the extracellular eukaryotic parasite Trypanosoma brucei relies on two mechanisms: uptake of fatty acids from the host and de novo synthesis. We hypothesized that T. brucei modulates fatty acid synthesis in response to environmental lipid availability. The first committed step in fatty acid synthesis is catalyzed by acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) and serves as a key regulatory point in other organisms. To test our hypothesis, T. brucei mammalian bloodstream and insect procyclic forms were grown in low-, normal-, or high-lipid media and the effect on T. brucei ACC (TbACC) mRNA, protein, and enzymatic activity was examined. In bloodstream form T. brucei, media lipids had no effect on TbACC expression or activity. In procyclic form T. brucei, we detected no change in TbACC mRNA levels but observed 2.7-fold-lower TbACC protein levels and 37% lower TbACC activity in high-lipid media than in low-lipid media. Supplementation of low-lipid media with the fatty acid stearate mimicked the effect of high lipid levels on TbACC activity. In procyclic forms, TbACC phosphorylation also increased 3.9-fold in high-lipid media compared to low-lipid media. Phosphatase treatment of TbACC increased activity, confirming that phosphorylation represented an inhibitory modification. Together, these results demonstrate a procyclic-form-specific environmental lipid response pathway that regulates TbACC posttranscriptionally, through changes in protein expression and phosphorylation. We propose that this environmental response pathway enables procyclic-form T. brucei to monitor the host lipid supply and downregulate fatty acid synthesis when host lipids are abundant and upregulate fatty acid synthesis when host lipids become scarce.IMPORTANCETrypanosoma brucei is a eukaryotic parasite that causes African sleeping sickness. T. brucei is transmitted by the blood-sucking tsetse fly. In order to adapt to its two very different hosts, T. brucei must sense the host environment and alter its metabolism to maximize utilization of host resources and minimize expenditure of its own resources. One key nutrient class is represented by fatty acids, which the parasite can either take from the host or make themselves. Our work describes a novel environmental regulatory pathway for fatty acid synthesis where the parasite turns off fatty acid synthesis when environmental lipids are abundant and turns on synthesis when the lipid supply is scarce. This pathway was observed in the tsetse midgut form but not the mammalian bloodstream form. However, pharmacological activation of this pathway in the bloodstream form to turn fatty acid synthesis off may be a promising new avenue for sleeping sickness drug discovery. PMID- 29997120 TI - Asymptomatic Shedding of Respiratory Virus among an Ambulatory Population across Seasons. AB - Most observation of human respiratory virus carriage is derived from medical surveillance; however, the infections documented by this surveillance represent only a symptomatic fraction of the total infected population. As the role of asymptomatic infection in respiratory virus transmission is still largely unknown and rates of asymptomatic shedding are not well constrained, it is important to obtain more-precise estimates through alternative sampling methods. We actively recruited participants from among visitors to a New York City tourist attraction. Nasopharyngeal swabs, demographics, and survey information on symptoms, medical history, and recent travel were obtained from 2,685 adults over two seasonal arms. We used multiplex PCR to test swab specimens for a selection of common respiratory viruses. A total of 6.2% of samples (168 individuals) tested positive for at least one virus, with 5.6% testing positive in the summer arm and 7.0% testing positive in the winter arm. Of these, 85 (50.6%) were positive for human rhinovirus (HRV), 65 (38.7%) for coronavirus (CoV), and 18 (10.2%) for other viruses (including adenovirus, human metapneumovirus, influenza virus, and parainfluenza virus). Depending on the definition of symptomatic infection, 65% to 97% of infections were classified as asymptomatic. The best-fit model for prediction of positivity across all viruses included a symptom severity score, Hispanic ethnicity data, and age category, though there were slight differences across the seasonal arms. Though having symptoms is predictive of virus positivity, there are high levels of asymptomatic respiratory virus shedding among the members of an ambulatory population in New York City.IMPORTANCE Respiratory viruses are common in human populations, causing significant levels of morbidity. Understanding the distribution of these viruses is critical for designing control methods. However, most data available are from medical records and thus predominantly represent symptomatic infections. Estimates for asymptomatic prevalence are sparse and span a broad range. In this study, we aimed to measure more precisely the proportion of infections that are asymptomatic in a general, ambulatory adult population. We recruited participants from a New York City tourist attraction and administered nasal swabs, testing them for adenovirus, coronavirus, human metapneumovirus, rhinovirus, influenza virus, respiratory syncytial virus, and parainfluenza virus. At recruitment, participants completed surveys on demographics and symptomology. Analysis of these data indicated that over 6% of participants tested positive for shedding of respiratory virus. While participants who tested positive were more likely to report symptoms than those who did not, over half of participants who tested positive were asymptomatic. PMID- 29997121 TI - Transcriptome Assembly and Profiling of Candida auris Reveals Novel Insights into Biofilm-Mediated Resistance. AB - Candida auris has emerged as a significant global nosocomial pathogen. This is primarily due to its antifungal resistance profile but also its capacity to form adherent biofilm communities on a range of clinically important substrates. While we have a comprehensive understanding of how other Candida species resist and respond to antifungal challenge within the sessile phenotype, our current understanding of C. auris biofilm-mediated resistance is lacking. In this study, we are the first to perform transcriptomic analysis of temporally developing C. auris biofilms, which were shown to exhibit phase- and antifungal class-dependent resistance profiles. A de novo transcriptome assembly was performed, where sequenced sample reads were assembled into an ~11.5-Mb transcriptome consisting of 5,848 genes. Differential expression (DE) analysis demonstrated that 791 and 464 genes were upregulated in biofilm formation and planktonic cells, respectively, with a minimum 2-fold change. Adhesin-related glycosylphosphatidylinositol (GPI)-anchored cell wall genes were upregulated at all time points of biofilm formation. As the biofilm developed into intermediate and mature stages, a number of genes encoding efflux pumps were upregulated, including ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters. When we assessed efflux pump activity biochemically, biofilm efflux was greater than that of planktonic cells at 12 and 24 h. When these were inhibited, fluconazole sensitivity was enhanced 4- to 16-fold. This study demonstrates the importance of efflux-mediated resistance within complex C. auris communities and may explain the resistance of C. auris to a range of antimicrobial agents within the hospital environment.IMPORTANCE Fungal infections represent an important cause of human morbidity and mortality, particularly if the fungi adhere to and grow on both biological and inanimate surfaces as communities of cells (biofilms). Recently, a previously unrecognized yeast, Candida auris, has emerged globally that has led to widespread concern due to the difficulty in treating it with existing antifungal agents. Alarmingly, it is also able to grow as a biofilm that is highly resistant to antifungal agents, yet we are unclear about how it does this. Here, we used a molecular approach to investigate the genes that are important in causing the cells to be resistant within the biofilm. The work provides significant insights into the importance of efflux pumps, which actively pump out toxic antifungal drugs and therefore enhance fungal survival within a variety of harsh environments. PMID- 29997122 TI - Functional Evidence of Pulmonary Extracellular Vesicles in Infectious and Noninfectious Lung Inflammation. AB - Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a highly complex process that can be triggered by both noninfectious (sterile) and infectious stimuli. Inflammatory lung responses are one of the key features in the pathogenesis of this devastating syndrome. How ALI/ARDS-associated inflammation develops remains incompletely understood, particularly after exposure to sterile stimuli. Emerging evidence suggests that extracellular vesicles (EVs) regulate intercellular communication and inflammatory responses in various diseases. In this study, we characterized the generation and function of pulmonary EVs in the setting of ALI/ARDS, induced by sterile stimuli (oxidative stress or acid aspiration) and infection (LPS/Gram-negative bacteria) in mice. EVs detected in bronchoalveolar lavage fluid (BALF) were markedly increased after exposure of animals to both types of stimuli. After sterile stimuli, alveolar type-I epithelial cells were the main source of the BALF EVs. In contrast, infectious stimuli-induced BALF EVs were mainly derived from alveolar macrophages (AMs). Functionally, BALF EVs generated in both the noninfectious and infectious ALI models promoted the recruitment of macrophages in in vivo mouse models. Furthermore, BALF EVs differentially regulated AM production of cytokines and inflammatory mediators, as well as TLR expression in AMs in vivo. Regardless of their origin, BALF EVs contributed significantly to the development of lung inflammation in both the sterile and infectious ALI. Collectively, our results provide novel insights into the mechanisms by which EVs regulate the development of lung inflammation in response to diverse stimuli, potentially providing novel therapeutic and diagnostic targets for ALI/ARDS. PMID- 29997123 TI - CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses. AB - Acute respiratory virus infection (ARI) induces CD8+ T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4+ regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial. We show in this paper that Treg depletion leads to increased CD8+ T cell function and lower virus titer in mice infected with human metapneumovirus. We further demonstrate that Tregs play a temporal role in the immune response to human metapneumovirus and influenza: Treg depletion before infection pathologically reduces virus-specific CD8+ T cell numbers and delays virus clearance, whereas depletion 2 d postinoculation enhances CD8+ T cell functionality without reducing virus-specific CD8+ T cell numbers. Mechanistically, Treg depletion during immune priming led to impaired dendritic cell and CD8+ T cell migration. Further, early Treg depletion was associated with immune skewing toward a type 2 phenotype characterized by increased type 2 innate lymphoid cells and TH2 CD4+ T cells, which was not observed when Treg depletion was delayed until after inoculation. These results indicate that the presence of Tregs at inoculation is critical for efficient priming of the CD8+ T cell response to ARI, whereas later in infection, Tregs are dispensable for virus clearance. PMID- 29997124 TI - Tumor Dendritic Cells (DCs) Derived from Precursors of Conventional DCs Are Dispensable for Intratumor CTL Responses. AB - The success of adoptive CTL therapy for cancer depends on interactions between tumor-infiltrating CTLs and cancer cells as well as other cells and molecules in the tumor microenvironment. Tumor dendritic cells (DCs) comprise several subsets: CD103+CD11b- DC1 and CD11b+CD64- DC2, which originate from circulating precursors of conventional DCs, and CD11b+CD64+ DC3, which arise from monocytes. It remains controversial which of these subset(s) promotes intratumor CTL proliferation, expansion, and function. To address this issue, we used the Zbtb46-DTR-transgenic mouse model to selectively deplete DC1 and DC2 from tumors and lymphoid tissues. Wild-type and Zbtb46-DTR bone marrow chimeras were inoculated with B16 melanoma cells that express OVA and were treated with OT-1 CTLs. We found that depletion of DCs derived from precursors of conventional DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in tumor-draining lymph nodes. By contrast, intratumor CTL accumulation, proliferation, and IFN-gamma expression were unaffected by their absence. We found that adoptive cell therapy increases the frequency of monocyte-derived tumor DC3, which possess the capacity to cross present tumor Ags and induce CTL proliferation. Our findings support the specialized roles of different DC subsets in the regulation of antitumor CTL responses. PMID- 29997125 TI - Shaving Is an Epiphenomenon of Type I and II Anti-CD20-Mediated Phagocytosis, whereas Antigenic Modulation Limits Type I Monoclonal Antibody Efficacy. AB - Rituximab is an anti-CD20 mAb used in the treatment of B cell malignancies. Loss of surface CD20 Ag from the surface of target cells is thought to be one mechanism governing resistance to rituximab, but how this occurs is not completely understood. Two explanations for this have been proposed: antigenic modulation whereby mAb:CD20 complexes are internalized in a B cell intrinsic process and shaving, in which mAb:CD20 complexes undergo trogocytic removal by effector cells, such as macrophages. However, there is conflicting evidence as to which predominates in clinical scenarios and hence the best strategies to overcome resistance. In this study, we investigated the relative importance of modulation and shaving in the downregulation of surface mAb:CD20. We used both murine and human systems and treated ex vivo macrophages with varying concentrations of non-FcgammaR-interacting beads to achieve differential macrophage saturation states, hence controllably suppressing further phagocytosis of target cells. We then monitored the level and localization of mAb:CD20 using a quenching assay. Suppression of phagocytosis with bead treatment decreased shaving and increased modulation, suggesting that the two compete for surface rituximab:CD20. Under all conditions tested, modulation predominated in rituximab loss, whereas shaving represented an epiphenomenon to phagocytosis. We also demonstrate that the nonmodulating, glycoengineered, type II mAb obinutuzumab caused a modest but significant increase in shaving compared with type II BHH2 human IgG1 wild-type mAb. Therefore, shaving may represent an important mechanism of resistance when modulation is curtailed, and glycoengineering mAb to increase affinity for FcgammaR may enhance resistance because of shaving. PMID- 29997127 TI - Test for Mycoplasma genitalium or risk it becoming a superbug, doctors warn. PMID- 29997126 TI - The Splicing Factor RNA-Binding Fox Protein 1 Mediates the Cellular Immune Response in Drosophila melanogaster. AB - The uptake and destruction of bacteria by phagocytic cells is an essential defense mechanism in metazoans. To identify novel genes involved in the phagocytosis of Staphylococcus aureus, a major human pathogen, we assessed the phagocytic capacity of adult blood cells (hemocytes) of the fruit fly, Drosophila melanogaster, by testing several lines of the Drosophila Genetic Reference Panel. Natural genetic variation in the gene RNA-binding Fox protein 1 (Rbfox1) correlated with low phagocytic capacity in hemocytes, pointing to Rbfox1 as a candidate regulator of phagocytosis. Loss of Rbfox1 resulted in increased expression of the Ig superfamily member Down syndrome adhesion molecule 4 (Dscam4). Silencing of Dscam4 in Rbfox1-depleted blood cells rescued the fly's cellular immune response to S. aureus, indicating that downregulation of Dscam4 by Rbfox1 is critical for S. aureus phagocytosis in Drosophila To our knowledge, this study is the first to demonstrate a link between Rbfox1, Dscam4, and host defense against S. aureus. PMID- 29997128 TI - Exosomes derived from exhausted CD8+ T cells impaired the anticancer function of normal CD8+ T cells. AB - BACKGROUND: Previous studies suggested that diverse cells in cancer microenvironment can interact with CD8+ T cells via exosomes. We designed this study to explore the potential interaction between exhausted CD8+ T cells and normal CD8+ T cells via exosome. METHODS: Fluorescence activated cell sorting was used to get PD1+TIM3+/PD1-TIM3-CD8+ T cells. Exosomes from the cell culture medium were collected by ultracentrifugation. Microarrays were performed to analyse the lncRNA expression profile in exosomes. RESULTS: Functional exhausted CD8+ T cells could secrete vast exosomes, which can be uptake by normal CD8+ T cells, and impaired their proliferation (Ki67), cell activity (CD69) and the production of cytokines such as interferon-gamma and interleukin-2. Microarray detection identified 257 candidate lncRNAs differently expressed in exosomes derived from exhausted CD8+ T cells and non-exhausted CD8+ T cells. Functional enrichment analysis indicated that these lncRNAs actively participated in the regulation of diverse process of CD8+ T cell activity, like metabolism, gene expression, biosynthetic process and so forth. CONCLUSIONS: The exosomes derived from exhausted CD8+ T cells could be uptake by non-exhausted CD8+ T cells and subsequently impaired the function of receipt cells. Exosomes secreted from exhausted CD8+ T cells have distinct lncRNA expression profiles which are significantly different from those in exosomes secreted by non-exhausted CD8+ T cells. PMID- 29997130 TI - Bridging the gap toward understanding short-term synaptic plasticity. AB - JGP study explores a new way to conceptualize an enduring neuronal mystery. PMID- 29997129 TI - Impact of 2017 ACC/AHA guidelines on prevalence of hypertension and eligibility for antihypertensive treatment in United States and China: nationally representative cross sectional study. AB - OBJECTIVE: To examine the effect of the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension guidelines on the prevalence of hypertension and eligibility for initiation and intensification of treatment in nationally representative populations from the United States and China. DESIGN: Observational assessment of nationally representative data. SETTING: US National Health and Nutrition Examination Survey (NHANES) for the most recent two cycles (2013-14, 2015-16) and China Health and Retirement Longitudinal Study (CHARLS) (2011-12). PARTICIPANTS: All 45-75 year old adults who would have a diagnosis of hypertension and be candidates for treatment on the basis of the ACC/AHA guidelines, compared with current guidelines. MAIN OUTCOME MEASURES: Diagnosis of hypertension and candidacy for initiation and intensification of antihypertensive treatment. RESULTS: Adoption of the 2017 ACC/AHA hypertension guidelines in the US would label 70.1 (95% confidence interval 64.9 to 75.3) million people in the 45-75 year age group as having hypertension, representing 63% (60.6% to 65.4%) of the population in this age group. Their adoption in China would lead to labeling of 266.9 (252.9 to 280.8) million people or 55% (53.4% to 56.7%) of the same age group as having hypertension. This would represent an increase in prevalence of 26.8% (23.2% to 30.9%) in the US and 45.1% (41.3% to 48.9%) in China. Furthermore, on the basis of treatment patterns and current guidelines, 8.1 (6.5 to 9.7) million Americans with hypertension are untreated, which would be expected to increase to 15.6 (13.6 to 17.7) million after the implementation of the ACC/AHA guidelines. In China, on the basis of current treatment patterns, 74.5 (64.1 to 84.8) million patients with hypertension are untreated, estimated to increase to 129.8 (118.7 to 140.9 million. In addition, the ACC/AHA guidelines would label 8.7 (6.0 to 11.5) million adults in the US and 51 (40.3 to 61.6) million in China as having hypertension that would not require antihypertensive treatment, compared with 1.5 (1.2 to 2.1) million and 23.4 (12.1 to 35.1) million with the current guidelines. Finally, even among people receiving treatment, the proportion that are candidates for intensification of treatment is estimated to increase by 13.9 (12.2 to 15.6) million (from 24.0% to 54.4% of treated patients) in the US, and 30 (24.3 to 35.7) million (41.4% to 76.2% of treated patients) in China, if the ACC/AHA treatment targets are adopted. CONCLUSIONS: If adopted, the 2017 ACC/AHA hypertension guidelines will markedly increase the number of people labeled as having hypertension and treated with drugs in both the US and China, leading to more than half of those aged 45 75 years in both countries being considered hypertensive. PMID- 29997131 TI - Nephron-Specific Disruption of Nitric Oxide Synthase 3 Causes Hypertension and Impaired Salt Excretion. AB - BACKGROUND: In vitro studies suggest that nephron nitric oxide synthase 3 (NOS3) modulates tubule Na+ transport. METHODS AND RESULTS: To assess nephron NOS3 relevance in vivo, knockout (KO) mice with doxycycline-inducible nephron-wide deletion of NOS3 were generated. During 1 week of salt loading, KO mice, as compared with controls, had higher arterial pressure and Na+ retention, a tendency towards reduced plasma renin concentration, and unchanged glomerular filtration rate. Chronic high salt-treated KO mice had modestly decreased total NCC and total SPAK/OSR1 versus controls, however percent phosphorylation of NCC (at T53) and of SPAK/OSR1 was increased. In contrast, total and phosphorylated NKCC2 (at T96/101) were suppressed by 50% each in KO versus control mice after chronic salt intake. In response to an acute salt load, KO mice had delayed urinary Na+ excretion versus controls; this delay was completely abolished by furosemide, partially reduced by hydrochlorothiazide, but not affected by amiloride. After 4 hours of an acute salt load, phosphorylated and total NCC were elevated in KO versus control mice. Acute salt loading did not alter total NKCC2 or SPAK/OSR1 in KO versus control mice but increased the percent phosphorylation of NKCC2 (at T96/101 and S126) and SPAK/OSR1 in KO versus control mice. CONCLUSIONS: These findings indicate that nephron NOS3 is involved in blood pressure regulation and urinary Na+ excretion during high salt intake. Nephron NOS3 appears to regulate NKCC2 and NCC primarily during acute salt loading. These effects of NOS3 may involve SPAK/OSR1 as well as other pathways. PMID- 29997133 TI - Prophylactic angiographic embolisation in high-risk peptic ulcer bleeding after achieved endoscopic control: maximising outcomes. PMID- 29997132 TI - Cumulative Incidence of Hypertension by 55 Years of Age in Blacks and Whites: The CARDIA Study. AB - BACKGROUND: Blacks have higher blood pressure levels compared with whites beginning in childhood. Few data are available on racial differences in the incidence of hypertension from young adulthood through middle age. METHODS AND RESULTS: We calculated the cumulative incidence of hypertension from age 18 to 55 years among participants in the CARDIA (Coronary Artery Risk Development in Young Adults) study. Incident hypertension was defined by the first visit with mean systolic blood pressure >=130 mm Hg, mean diastolic blood pressure >=80 mm Hg, or self-reported use of antihypertensive medication. Among 3890 participants without hypertension at baseline (aged 18-30 years), cumulative incidence of hypertension by age 55 years was 75.5%, 75.7%, 54.5%, and 40.0% in black men, black women, white men, and white women, respectively. Among participants with systolic blood pressure/diastolic blood pressure <110 and 70, 110 to 119/70 to 74, and 120 to 129/75 to 79 mm Hg at baseline, blacks were more likely than whites to develop hypertension: multivariable-adjusted hazard ratios 1.97 (95% confidence interval, 1.65, 2.35), 1.80 (95% confidence interval, 1.52, 2.14), and 1.59 (95% confidence interval, 1.31, 1.93), respectively. Parental history of hypertension and higher body mass index, serum uric acid, and systolic blood pressure/diastolic blood pressure categories were associated with a higher risk for hypertension among blacks and whites. A higher Dietary Approaches to Stop Hypertension diet adherence score was associated with a lower risk for hypertension in blacks and whites. CONCLUSIONS: Regardless of blood pressure level in young adulthood, blacks have a substantially higher risk for hypertension compared with whites through 55 years of age. PMID- 29997134 TI - Gaps in health behaviours and use of preventive services between patients with diabetes and the general population: a population-based cross-sectional study. AB - OBJECTIVES: Although both the prevalence and treatment rate of diabetes have increased, the degree of adherence to healthy behaviours by patients with diabetes has not yet been comprehensively evaluated. This study examines the differences in health management and mental health status according to diabetes status and awareness of that diagnosis. METHODS: This was a cross-sectional study of 14 655 people using data from the Korean National Health and Nutrition Examination Study 2010-2012, which used sampling weights. Multiple logistic regression analyses were used to compare health-risk behaviours, preventive healthcare utilisation and mental health status according to diabetes diagnosis and awareness of the disease. RESULTS: Compared with people without diabetes, people with diabetes had comparably worse smoking status (adjusted OR (aOR) 1.09, 95% CI 0.92 to 1.30), insufficient physical activity (aOR 1.09, 95% CI 0.95 to 1.24) and were less likely to receive cancer screenings and regular health check ups (aOR 0.75, 95% CI 0.66 to 0.85). Furthermore, compared with people unaware of their diabetes, people aware of their diabetes had lower odds of physical inactivity (aOR 0.66, 95% CI 0.45 to 0.99) and greater odds of receiving colon cancer screening (aOR 1.55, 95% CI 1.17 to 2.05) and influenza vaccination (aOR 1.56, 95% CI 1.15 to 2.11). CONCLUSIONS: People with diabetes were no better in terms of health behaviours and preventive healthcare utilisation than those who were without diabetes. Further efforts and political attention to ensure the delivery of quality care for people with diabetes are needed. PMID- 29997135 TI - Validity of the PROMIS-10 Global Health assessed by telephone and on paper in minor stroke and transient ischaemic attack in the Netherlands. AB - OBJECTIVES: Dysfunction after transient ischaemic attack (TIA) and minor stroke is often underestimated by clinical measures. Patient-reported outcome measures used in value-based healthcare may help in detecting these problems. The Patient Reported Outcomes Measurement Information System 10-Question Short Form (PROMIS 10 Global Health) is a concise patient-centred outcome measuring tool proposed for assessing health status in patients who had stroke. This study aims to address the validity of the Dutch PROMIS-10 in patients who had stroke in the Netherlands and also aims to compare telephone versus on-paper assessment. DESIGN: Observational cohort study. SETTING: Single-centre hospital in the Netherlands. PARTICIPANTS: 75 patients who were diagnosed with TIA or minor stroke and discharged without rehabilitation treatment 1 year ago (between December 2014 and January 2016) completed the study. PRIMARY AND SECONDARY OUTCOME MEASURES: PROMIS-10 physical (PH) and mental health (MH) scores assessed 1 year poststroke on paper (n=37) and by telephone (n=38) was compared with RAND 36 physical and mental component scores assessed on paper. RESULTS: PROMIS-10 and RAND-36 correlated significantly in PH, r=0.81 (95% CI 0.69 to 0.88), and MH, r=0.76 (95% CI 0.64 to 0.85). Paper-and-pencil assessed correlations were r=0.87 and 0.79 for PH and MH, respectively. Telephone assessed correlations were r=0.76 and 0.73 for PH and MH, respectively. Internal consistency analysis indicated high reliabilities for both health components of the PROMIS-10, all Cronbach's alpha>0.70. CONCLUSIONS: The Dutch PROMIS-10 was found to strongly correlate with the RAND-36. Paper-and-pencil assessment was found to have a higher correlation than telephone assessment. This study provides support for the use of the Dutch PROMIS-10 in assessing health status in patients after TIA and minor stroke. PMID- 29997136 TI - Study protocol: efficacy of oral alitretinoin versus oral cyclosporine A in patients with severe recurrent vesicular hand eczema (ALICsA): a randomised prospective open-label trial with blinded outcome assessment. AB - INTRODUCTION: Systemic treatment with alitretinoin is registered for all clinical types of severe chronic hand eczema. However, it is especially effective in the hyperkeratotic subtype and less effective in non-hyperkeratotic forms. Cyclosporine A (cyclosporine) is prescribed for hand eczema in daily practice as well. It has shown to be particularly effective in patients with vesicular hand eczema. The primary objective of this study is to compare efficacy of alitretinoin and cyclosporine in the treatment of severe recurrent vesicular hand eczema. METHODS AND ANALYSIS: This is an investigator-initiated randomised prospective open-label trial with blinded outcome assessment. Severity assessments and laboratory measurements will be conducted corresponding to daily practice. The study population will consist of 72 adult patients (age 18-75 years) with severe recurrent vesicular hand eczema. Patients are treated with either (group I) alitretinoin 30 mg once daily or (group II) cyclosporine with a starting dose of 5 mg/kg/day and a decrease in dosage after 8 weeks to 3-3.5 mg/kg/day. The treatment period is 24 weeks for both drugs. Primary endpoint for efficacy is response to treatment, defined as an improvement of >=2 steps on a Physician Global Assessment, using a validated Photoguide, after 24 weeks of treatment. Secondary endpoints are improvement of Hand Eczema Severity Index, Quality of Life in Hand Eczema Questionnaire and a Patient Global Assessment. Adverse events and time to response will be registered. Furthermore, cost utility, quality-adjusted life years and cost-effectiveness will be assessed with the EQ-5D-5L questionnaire while monitoring costs. ETHICS AND DISSEMINATION: This protocol was reviewed and approved by the Medical Ethical Review Board of the University Medical Centre Groningen (reference METc 2015/375). The study will be conducted according to the principles of the Declaration of Helsinki, in accordance with the Dutch Medical Research Involving Human Subjects Act. TRIAL REGISTRATION NUMBER: NCT03026946; Pre-results. PMID- 29997137 TI - 'Who Cares?' The experiences of caregivers of adults living with heart failure, chronic obstructive pulmonary disease and coronary artery disease: a mixed methods systematic review. AB - OBJECTIVE: To assess the experiences of unpaid caregivers providing care to people with heart failure (HF) or chronic obstructive pulmonary disease (COPD) or coronary artery disease (CAD). Design Mixed methods systematic review including qualitative and quantitative studies. Data sources Databases searched: Medline Ebsco, PsycInfo, CINAHL Plus with Full Text, Embase, Web of Science, Ethos: The British Library and ProQuest. Grey literature identified using: Global Dissertations and Theses and Applied Sciences Index and hand searches and citation checking of included references. Search time frame: 1 January 1990 to 30 August 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Inclusion was limited to English language studies in unpaid adult caregivers (>18 years), providing care for patients with HF, COPD or CAD. Studies that considered caregivers for any other diagnoses and studies undertaken in low-income and middle-income countries were excluded. Quality assessment of included studies was conducted by two authors. DATA ANALYSIS/SYNTHESIS: A results-based convergent synthesis was conducted. RESULTS: Searches returned 8026 titles and abstracts. 54 studies-21 qualitative, 32 quantitative and 1 mixed method were included. This totalled 26 453 caregivers who were primarily female (63%), with median age of 62 years. Narrative synthesis yielded six concepts related to caregiver experience: (1) mental health, (2) caregiver role, (3) lifestyle change, (4) support for caregivers, (5) knowledge and (6) relationships. There was a discordance between paradigms regarding emerging concepts. Four concepts emerged from qualitative papers which were not present in quantitative papers: (1) expert by experience, (2) vigilance, (3) shared care and (4) time. CONCLUSION: Caregiving is life altering and complex with significant health implications. Health professionals should support caregivers who in turn can facilitate the recipient to manage their long-term condition. Further longitudinal research exploring the evolution of caregiver experiences over time of patients with chronic cardiopulmonary conditions is required. TRIAL REGISTRATION NUMBER: CRD42016053412. PMID- 29997138 TI - Using smartphone-based virtual patients to assess the quality of primary healthcare in rural China: protocol for a prospective multicentre study. AB - INTRODUCTION: Valid and low-cost quality assessment tools examining care quality are not readily available. The unannounced standardised patient (USP), the gold standard for assessing quality, is costly to implement while the validity of clinical vignettes, as a low-cost alternative, has been challenged. Computerised virtual patients (VPs) create high-fidelity and interactive simulations of doctor patient encounters which can be easily implemented via smartphone at low marginal cost. Our study aims to develop and validate smartphone-based VP as a quality assessment tool for primary care, compared with USP. METHODS AND ANALYSIS: The study will be implemented in primary health centres (PHCs) in rural areas of seven Chinese provinces, and physicians practicing at township health centres and village clinics will be our study population. The development of VPs involves three steps: (1) identifying 10 VP cases that can best represent rural PHCs' work, (2) designing each case by a case-specific development team and (3) developing corresponding quality scoring criteria. After being externally reviewed for content validity, these VP cases will be implemented on a smartphone based platform and will be tested for feasibility and face validity. This smartphone-based VP tool will then be validated for its criterion validity against USP and its reliability (ie, internal consistency and stability), with 1260 VP/USP-clinician encounters across the seven study provinces for all 10 VP cases. ETHICS AND DISSEMINATION: Sun Yat-sen University: No. 2017-007. Study findings will be published and tools developed will be freely available to low income and middle-income countries for research purposes. PMID- 29997139 TI - Effectiveness of simulation in psychiatry for initial and continuing training of healthcare professionals: protocol for a systematic review. AB - INTRODUCTION: Although most healthcare professionals must deal with patients with mental illness, many are not prepared for the various situations that can ensue. Simulation may be a powerful pedagogical tool for simultaneously teaching knowledge, skills and attitudes. We aim to assess the effectiveness of simulation for initial and continuous training in psychiatry for healthcare professionals. METHODS AND ANALYSIS: A comprehensive search for randomised and non-randomised controlled studies and single-group pretest/post-test reports will be conducted in electronic databases including MEDLINE, EMBASE, Scopus, CINAHL, PsychINFO, ERIC, the Cochrane Central Register of Controlled Trials (CENTRAL) and the Web of Science (Science and Social Sciences Citation Index), with a detailed query. The reference lists of selected studies, key journals and trial registers will also be searched for additional studies. Two independent reviewers, following predefined inclusion criteria, will screen titles and abstracts first and then the full texts of the remaining articles. A third author will evaluate discrepancies to reach a consensus. It will include randomised controlled trial (RCT), non-RCT, pre-test/post-test design studies, post-test design for satisfaction evaluation and qualitative studies. Risk of bias will be assessed by using the Cochrane Collaboration Tool for assessing risk of bias in RCTs. Meta analyses will be performed if we find sufficient studies that assess predefined outcomes and if their characteristics are not too different. The quality of evidence will be assessed by the Grading of Recommendations Assessment, Development and Evaluation. A narrative synthesis will be performed for qualitative studies and when meta-analyses are deemed not possible. ETHICS AND DISSEMINATION: Ethics permission is not required. Dissemination will be through publication in peer-reviewed journals, national and international conferences, and the lead author's doctoral dissertation. TRIAL REGISTRATION NUMBER: CRD42017078779. PMID- 29997140 TI - The prevalence of type 2 diabetes in South Africa: a systematic review protocol. AB - INTRODUCTION: Type 2 diabetes mellitus is a major source of morbidity and mortality in South Africa, spurred by increased urbanisation and unhealthy lifestyle factors. Local epidemiological data are required to inform health planning and policy. The purpose of this systematic review is to identify, collate and synthesise all studies reporting the prevalence of diabetes in South Africa. A secondary aim is to report the prevalence of impaired glucose tolerance and impaired fasting glucose, conditions which are associated with an increased risk of progression to overt diabetes, and the prevalence of undiagnosed diabetes. METHODS AND ANALYSIS: Multiple databases will be searched for diabetes prevalence studies conducted in South Africa between 1997 and 2018. Two authors will independently select studies that meet the inclusion criteria, extract data and appraise studies using a risk of bias tool for prevalence studies. Studies with low or moderate risk of bias will be included. Sources of heterogeneity will be explored using subgroup analysis. ETHICS AND DISSEMINATION: The systematic review does not require ethics clearance since published studies with non identifiable data will be used. This review will provide best estimates to inform the Second National Burden of Disease study which can guide health and policy planning. PROSPERO REGISTRATION NUMBER: CRD42017071280. PMID- 29997141 TI - Impact of comorbid conditions on outcomes of hip and knee replacement surgery: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically perform a meta-analysis of the association between different comorbid conditions on safety (short-term outcomes) and effectiveness (long-term outcomes) in patients undergoing hip and knee replacement surgery. DESIGN: Systematic review and meta-analysis. METHODS: Medline, Embase and CINAHL Plus were searched up to May 2017. We included all studies that reported data to allow the calculation of a pooled OR for the impact of 11 comorbid conditions on 10 outcomes (including surgical complications, readmissions, mortality, function, health-related quality of life, pain and revision surgery). The quality of included studies was assessed using a modified Newcastle-Ottawa Scale. Continuous outcomes were converted to ORs using the Hasselblad and Hedges approach. Results were combined using a random-effects meta-analysis. OUTCOMES: The primary outcome was the adjusted OR for the impact of each 11 comorbid condition on each of the 10 outcomes compared with patients without the comorbid condition. Where the adjusted OR was not available the secondary outcome was the crude OR. RESULTS: 70 studies were included with 16 (23%) reporting on at least 100 000 patients and 9 (13%) were of high quality. We found that comorbidities increased the short-term risk of hospital readmissions (8 of 11 conditions) and mortality (8 of 11 conditions). The impact on surgical complications was inconsistent across comorbid conditions. In the long term, comorbid conditions increased the risk of revision surgery (6 of 11 conditions) and long-term mortality (7 of 11 conditions). The long-term impact on function, quality of life and pain varied across comorbid conditions. CONCLUSIONS: This systematic review shows that comorbidities predominantly have an impact on the safety of hip and knee replacement surgery but little impact on its effectiveness. There is a need for high-quality studies also considering the severity of comorbid conditions. PMID- 29997142 TI - Intimate partner violence during pregnancy in relation to non-psychotic mental health disorders in Rwanda: a cross-sectional population-based study. AB - OBJECTIVES: To investigate the prevalence of non-psychotic mental health disorders (MHDs) and the association between exposure to all forms of intimate partner violence (IPV) during pregnancy and MHDs. DESIGN: Cross-sectional population-based study conducted in the Northern Province of Rwanda and Kigali city. PARTICIPANTS AND SETTINGS: Totally, 921 women who gave birth <=13 months before being interviewed were included. Simple random sampling was done to select villages, households and participants. Community health workers helped to identify eligible participants and clinical psychologists, nurses or midwives conducted face-to-face interviews. The collected data were analysed using descriptive statistics and bivariable and multivariable logistic regression modelling RESULTS: The prevalence rates of generalised anxiety disorder, suicide ideation and post-traumatic stress disorder (PTSD) were 19.7%, 10.8% and 8.0%, respectively. Exposure to the four forms of IPV during pregnancy was highly associated with the likelihood of meeting diagnostic criteria for each of the non psychotic MHDs investigated. Physical, psychological and sexual violence, showed the strongest association with PTSD, with adjusted ORs (aORs) of 4.5, 6.2 and 6.3, respectively. Controlling behaviour had the strongest association with major depressive episode in earlier periods with an aOR of 9.2. CONCLUSION: IPV and MHDs should be integrated into guidelines for perinatal care. Moreover, community based services aimed at increasing awareness and early identification of violence and MHDs should be instituted in all villages and health centres in Rwanda. Finally, healthcare providers need to be educated and trained in a consistent manner to manage the most challenging cases quickly, discreetly and efficiently. PMID- 29997143 TI - Evaluation of patient-reported outcome measurements as a reliable tool to measure acceptability of the taste of paediatric medicines in an inpatient paediatric population. AB - OBJECTIVE: To evaluate the age appropriateness and suitability of patient reported outcome measures to assess the acceptability of the taste of oral liquid medicines in children. DESIGN AND SETTING: An observational mixed-methods study involving children aged 2-16 years taking oral liquid medicine in paediatric inpatient wards across the West Midlands (UK). Assessment tools included patient reported scores on the taste of medicines via a five-point Facial Hedonic Scale; a Visual Analogue Scale (VAS); a question, 'Did you think the medicine tasted OK?' and researcher observations of facial expressions and behaviours immediately before, during and after administration. RESULTS: 611 children participated. The percent unable to complete the scales was 7% (n=46) for the VAS; 2% (n=15) for the hedonic scale and 1% (n=7) for the question about taste. Significant correlations (Spearman's r) were observed between the patient-reported outcome measures: 0.80 and 0.78 for the taste question and hedonic and VAS, respectively, and 0.84 for the hedonic and VAS. Researcher observations demonstrated the ability of the patient to take the medicine as intended but did not provide sensitive measures of taste. 5% of administrations were not taken as intended by the children. Medicines known to have poor taste (clarithromycin and prednisolone) showed mean hedonic and VAS scores of >=3.5 and >65 mm, respectively. CONCLUSIONS: Patient-reported outcome measures correlate with each other and are a useful means to assess the taste (and acceptability) of medicines. Hedonic scales are better understood by children and should be the first choice tool in the assessment of medicines taste. PMID- 29997144 TI - Anticoagulation therapy in patients with stroke and atrial fibrillation: a registry-based study of acute stroke care in Surrey, UK. AB - INTRODUCTION: Because of their high risk of stroke, anticoagulation therapy is recommended for most patients with atrial fibrillation (AF). The present study evaluated the use of anticoagulants in the community and in a hospital setting for patients with AF and its associations with stroke. METHODS: Patients admitted with stroke to four major hospitals in County of Surrey, England were surveyed in the 2014-2016 Sentinel Stroke National Audit Programme. Descriptive statistics was used to summarise subject characteristics and chi2 test to assess differences between categorical variables. RESULTS: A total of 3309 patients, 1656 men (mean age: 73.1 years+/-SD 13.2) and 1653 women (79.3 years+/-13.0) were admitted with stroke (83.3% with ischaemic, 15.7% haemorrhagic stroke and 1% unspecified). AF occurred more frequently (chi2=62.4; p<0.001) among patients admitted with recurrent (30.2%) rather than with first stroke (17.1%). There were 666 (20.1%) patients admitted with a history of AF, among whom 304 (45.3%) were anticoagulated, 279 (41.9%) were untreated and 85 (12.8%) deemed unsuitable for anticoagulation. Of the 453 patients with history of AF admitted with a first ischaemic stroke, 138 (37.2%) were on anticoagulation and 41 (49.6%) were not (chi2 = 6.3; p<0.043) and thrombolysis was given more frequently for those without prior anticoagulation treatment (16.1%) or unsuitable for anticoagulation (23.6%) compared with those already on anticoagulation treatment (8.3%; chi2=10.0; p=0.007). Of 2643 patients without a previous history of AF, 171 (6.5%) were identified with AF during hospitalisation. Of patients with AF who presented with ischaemic stroke who were not anticoagulated or deemed unsuitable for anticoagulation prior to admission, 91.8% and 75.0%, respectively, were anticoagulated on discharge. CONCLUSIONS: The study highlights an existing burden for patients with stroke and reflects inadequate treatment of AF which results in an increased stroke burden. There is significant scope to improve the rates of anticoagulation. PMID- 29997145 TI - Risks of ovarian, breast, and corpus uteri cancer in women treated with assisted reproductive technology in Great Britain, 1991-2010: data linkage study including 2.2 million person years of observation. AB - OBJECTIVE: To investigate the risks of ovarian, breast, and corpus uteri cancer in women who have had assisted reproduction. DESIGN: Large, population based, data linkage cohort study. SETTING AND PARTICIPANTS: All women who had assisted reproduction in Great Britain, 1991-2010, as recorded by the Human Fertilisation and Embryology Authority (HFEA). INTERVENTIONS: HFEA fertility records for cohort members were linked to national cancer registrations. MAIN OUTCOME MEASURES: Observed first diagnosis of ovarian, breast, and corpus uteri cancer in cohort members were compared with age, sex, and period specific expectation. Standardised incidence ratios (SIRs) were calculated by use of age, sex, and period specific national incidence rates. RESULTS: 255 786 women contributed 2 257 789 person years' follow-up. No significant increased risk of corpus uteri cancer (164 cancers observed v 146.9 cancers expected; SIR 1.12, 95% confidence interval 0.95 to 1.30) was found during an average of 8.8 years' follow-up. This study found no significantly increased risks of breast cancer overall (2578 v 2641.2; SIR 0.98, 0.94 to 1.01) or invasive breast cancer (2272 v 2371.4; SIR 0.96, 0.92 to 1.00). An increased risk of in situ breast cancer (291 v 253.5; SIR 1.15, 1.02 to 1.29; absolute excess risk (AER) 1.7 cases per 100 000 person years, 95% confidence interval 0.2 to 3.2) was detected, associated with an increasing number of treatment cycles (P=0.03). There was an increased risk of ovarian cancer (405 v 291.82; SIR 1.39, 1.26 to 1.53; AER 5.0 cases per 100 000 person years, 3.3 to 6.9), both invasive (264 v 188.1; SIR 1.40, 1.24 to 1.58; AER 3.4 cases per 100 000 person years, 2.0 to 4.9) and borderline (141 v 103.7; SIR 1.36, 1.15 to 1.60; AER 1.7 cases per 100 000 person years, 0.7 to 2.8). Increased risks of ovarian tumours were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumour in women treated because of only male factor or unexplained infertility. CONCLUSIONS: No increased risk of corpus uteri or invasive breast cancer was detected in women who had had assisted reproduction, but increased risks of in situ breast cancer and invasive and borderline ovarian tumours were found in this study. Our results suggest that ovarian tumour risks could be due to patient characteristics, rather than assisted reproduction itself, although both surveillance bias and the effect of treatment are also possibilities. Ongoing monitoring of this population is essential. PMID- 29997146 TI - Schistosoma mansoni antigen Sm-p80: prophylactic efficacy using TLR4 agonist vaccine adjuvant glucopyranosyl lipid A-Alum in murine and non-human primate models. AB - Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading candidate for a schistosomiasis vaccine. The prophylactic and antifecundity efficacy of Sm p80 has been tested in three animal models (mouse, hamster and baboon) using a multitude of vaccine formulations and approaches. In our continual effort to enhance the vaccine efficacy, in this study, we have utilized the adjuvant, synthetic hexa-acylated lipid A derivative, glucopyranosyl lipid A (GLA) formulated in aluminum (GLA-Alum) with recombinant Sm-p80. The rSm-p80+GLA-Alum immunization regimen provided 33.33%-53.13% reduction in worm burden in the mouse model and 38% worm burden reduction in vaccinated baboons. Robust Sm-p80-specific immunoglobulin (Ig)G, IgG1, IgG2a and IgM responses were observed in all immunized animals. The rSm-p80+GLA-Alum coadministration induced a mix of T helper (Th) cells (Th1, Th2 and Th17) responses as determined via the release of interleukin (IL)-2, IL-4, IL-18, IL-21, IL-22 and interferon-gamma. PMID- 29997147 TI - Effect of routine postdilatation on final coronary blood flow in primary percutaneous coronary intervention patients without angiographic stent expansion problems. AB - Inadequate expansion of coronary stents is associated with stent thrombosis in early stage and with stent restenosis in later stages. Postdilatation (postD) performed using non-compliant balloons improves stent expansion. However, use of this ballooning strategy in primary percutaneous coronary intervention (PPCI) has not been evaluated adequately. Patients who presented with ST segment elevation myocardial infarction (STEMI) and underwent PPCI were included in the present study. Patients were randomized into two groups as those for whom postD was performed (n=62) and those for whom postD was not performed (n=62). Coronary blood flow was evaluated using the thrombolysis in myocardial infarction (TIMI) flow and TIMI frame count (TFC). Total of 124 patients with STEMI were included in the study. There was no difference with respect to baseline TIMI flow, culprit coronary artery and MI localization. However, slow-reflow rate (14.5% vs 35.5%, p=0.007) and final corrected TFC (28.9+/-16.9 vs 37.0+/-23.1, p=0.028) were significantly higher in the postD group. Multivariate regression analysis showed postD as an independent variable for slow reflow (OR 11.566, 95% CI 1.633 to 81.908, p=0.014). In our study, routine postD during PPCI was found to be associated with an increased risk of slow reflow in patients without angiographic stent expansion problems. PMID- 29997148 TI - Everolimus shows synergistic antimyeloma effects with bortezomib via the AKT/mTOR pathway. AB - Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraproteins (M proteins). Everolimus works similarly to sirolimus as a mammalian target of rapamycin (mTOR) inhibitor. Bortezomib was the first therapeutic proteasome inhibitor to be tested in humans with MM. However, the combination of these two drugs for the treatment of MM has been rarely reported. In this study, we compared the therapeutic effects of everolimus and bortezomib, as well as those of a combination of everolimus and bortezomib, using an in vitro MM cell line model and in vivo xenograft mouse model. Our results showed that the synergistic antitumor effects of everolimus and bortezomib have significant inhibitory effect through inhibition of the AKT/mTOR pathway in both the MM cell lines and MM-bearing mice model. Our results provided evidence that the mTOR inhibitor, everolimus, will be a potential drug in MM therapy. PMID- 29997149 TI - Importance of Considering Competing Risks in Time-to-Event Analyses: Application to Stroke Risk in a Retrospective Cohort Study of Elderly Patients With Atrial Fibrillation. AB - BACKGROUND: Ignoring competing risks in time-to-event analyses can lead to biased risk estimates, particularly for elderly patients with multimorbidity. We aimed to demonstrate the impact of considering competing risks when estimating the cumulative incidence and risk of stroke among elderly atrial fibrillation patients. METHODS AND RESULTS: Using linked administrative databases, we identified patients with atrial fibrillation aged >=66 years discharged from hospital in ON, Canada between January 1, 2007, and March 31, 2011. We estimated the cumulative incidence of stroke hospitalization using the complement of the Kaplan-Meier function and the cumulative incidence function. This was repeated after stratifying the cohort by presence of prespecified comorbidities: chronic kidney disease, chronic obstructive pulmonary disease, cancer, or dementia. The full cohort was used to regress components of the CHA2DS2VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease, sex) score on the hazard of stroke hospitalization using the Fine-Gray and Cox methods. These models were subsequently used to predict the 5-year risk of stroke hospitalization. Among 136 156 patients, the median CHA2DS2VASc score was 4 and 84 728 patients (62.2%) had >=1 prespecified comorbidity. The 5-year cumulative incidence of stroke was 5.4% (95% confidence interval, 5.3%-5.5%), whereas that of death without stroke was 48.8% (95% confidence interval, 48.5%-49.1%). The incidence of both events was overestimated by the Kaplan-Meier method; stroke incidence was overestimated by a relative factor of 39%. The degree of overestimation was larger among patients with non-CHA2DS2VASc comorbidity because of higher incidence of death without stroke. The Fine-Gray model demonstrated better calibration than the Cox model, which consistently overpredicted stroke incidence. CONCLUSIONS: The incidence of death without stroke was 9-fold higher than that of stroke, leading to biased estimates of stroke risk with traditional time-to-event methods. Statistical methods that appropriately account for competing risks should be used to mitigate this bias. PMID- 29997150 TI - Modulation of Circulating Protein Biomarkers in Cancer Patients Receiving Bevacizumab and the Anti-Endoglin Antibody, TRC105. AB - TRC105 is an anti-endoglin antibody currently being tested in combination with VEGF inhibitors. In the phase Ib trial, 38 patients were treated with both TRC105 and bevacizumab (BEV), and improved clinical outcomes were observed, despite the fact that 30 patients (79%) were refractory to prior anti-VEGF therapy. Plasma samples were tested for angiogenic and inflammatory biomarkers at baseline and on treatment. To provide broader context of this combination biomarker study, direct cross-study comparisons were made to biomarker studies previously conducted in patients treated with either BEV or TRC105 monotherapy. Upon treatment with BEV and TRC105, pharmacodynamic changes in response to both BEV (PlGF increase) and TRC105 (soluble endoglin increase) were noted. In addition, distinct patterns of change were identified (similar, opposing, neutralizing). Similar patterns were observed when the combination elicited similar effects to those observed with monotherapy treatment (i.e., decreases of Ang-2, increases of IL6 and VCAM-1). Opposing patterns were observed when the combination led to opposing effects compared with monotherapy treatment (i.e., TGFbeta1, PDGF-AA and PDGF-BB, PAI-1). Lastly, neutralizing patterns were observed when one drug led to increase, whereas the other drug led to decrease, and the combination elicited no overall effect on the marker (i.e., VEGF-A, VEGF-D, and IGFBP-3). Patients achieving partial responses or stable disease from the combination exhibited significantly lower expression of E-Cadherin, HGF, ICAM-1, and TSP-2 at baseline. Taken together, the novel biomarker modulations identified may deepen our understanding of the underlying biology in patients treated with BEV and TRC105 compared with either drug alone. Mol Cancer Ther; 17(10); 2248-56. (c)2018 AACR. PMID- 29997151 TI - Therapeutic Targeting of KDM1A/LSD1 in Ewing Sarcoma with SP-2509 Engages the Endoplasmic Reticulum Stress Response. AB - Multi-agent chemotherapeutic regimes remain the cornerstone treatment for Ewing sarcoma, the second most common bone malignancy diagnosed in pediatric and young adolescent populations. We have reached a therapeutic ceiling with conventional cytotoxic agents, highlighting the need to adopt novel approaches that specifically target the drivers of Ewing sarcoma oncogenesis. As KDM1A/lysine specific demethylase 1 (LSD1) is highly expressed in Ewing sarcoma cell lines and tumors, with elevated expression levels associated with worse overall survival (P = 0.033), this study has examined biomarkers of sensitivity and mechanisms of cytotoxicity to targeted KDM1A inhibition using SP-2509 (reversible KDM1A inhibitor). We report, that innate resistance to SP-2509 was not observed in our Ewing sarcoma cell line cohort (n = 17; IC50 range, 81 -1,593 nmol/L), in contrast resistance to the next-generation KDM1A irreversible inhibitor GSK-LSD1 was observed across multiple cell lines (IC50 > 300 MUmol/L). Although TP53/STAG2/CDKN2A status and basal KDM1A mRNA and protein levels did not correlate with SP-2509 response, induction of KDM1B following SP-2509 treatment was strongly associated with SP-2509 hypersensitivity. We show that the transcriptional profile driven by SP-2509 strongly mirrors KDM1A genetic depletion. Mechanistically, RNA-seq analysis revealed that SP-2509 imparts robust apoptosis through engagement of the endoplasmic reticulum stress pathway. In addition, ETS1/HIST1H2BM were specifically induced/repressed, respectively following SP-2509 treatment only in our hypersensitive cell lines. Together, our findings provide key insights into the mechanisms of SP-2509 cytotoxicity as well as biomarkers that can be used to predict KDM1A inhibitor sensitivity in Ewing sarcoma. Mol Cancer Ther; 17(9); 1902-16. (c)2018 AACR. PMID- 29997152 TI - Targeted Sequencing of Circulating Tumor DNA to Monitor Genetic Variants and Therapeutic Response in Metastatic Colorectal Cancer. AB - Substantial improvements have been made in the management of metastatic colorectal cancer (mCRC) in the last two decades, but disease monitoring remains underdeveloped. Circulating tumor DNA (ctDNA) is a promising prognostic and predictive biomarker; however, ctDNA as a marker for mCRC patients is not well established, and there is still no consensus about how to utilize it most cost effectively. In this study, we aim to investigate plasma ctDNA levels as a biomarker for therapeutic response of mCRC patients. We performed next-generation sequencing (NGS) by using a 12-gene panel to identify genetic variants in 136 tumor tissue and ctDNA samples from 32 mCRC patients. Genetic variants were detected in approximately 70% of samples, and there was a high concordance (85%) between tumor tissue and plasma ctDNA. We observed ctDNA changes in 18 follow-up patients, including the emergence of new variants. Changes in ctDNA levels significantly correlated with tumor shrinkage (P = 0.041), and patients with a ctDNA decrease >80% after treatment had a longer progression-free survival compared with patients with a ctDNA decrease of <80% (HR, 0.22; P = 0.015). The objective response rate among patients with a ctDNA decrease of >80% was better than those with a ctDNA decrease <80% (OR, 0.026; P = 0.007). In conclusion, this study demonstrates that monitoring of genetic ctDNA variants can serve as a valuable biomarker for therapeutic efficacy in mCRC patients, and that using a moderate-sized 12-gene NGS panel may be suitable for such clinical monitoring. Mol Cancer Ther; 17(10); 2238-47. (c)2018 AACR. PMID- 29997153 TI - Clozapine and long-acting injectable antipsychotics reduce hospitalisation and treatment failure risk in patients with schizophrenia. PMID- 29997154 TI - Mary Dixon-Woods: Patient safety workaholic. PMID- 29997155 TI - Hypoxia-induced changes in hemoglobins of Lake Victoria cichlids. AB - In a previous study, broods of the Lake Victoria cichlid Haplochromis ishmaeli raised under hypoxic or normoxic conditions showed striking differences in isohemoglobin (isoHb) pattern that were not observed in two other cichlids that do not belong to the Lake Victoria species flock. We therefore hypothesized that the adaptive mechanism seen in H. ishmaeli in response to hypoxia constitutes a trait that the Lake Victoria species flock inherited from ancestors that lived in hypoxic environments. We tested this hypothesis by designing split-brood experiments with three other representative species from the same species flock: the insectivorous Haplochromis thereuterion, the mollusk-shelling Platytaeniodus degeni and the zooplanktivorous Haplochromis piceatus, while keeping H. ishmaeli as a reference. Split broods were raised, under either normoxia or hypoxia. All hypoxia-raised (HR) individuals of each of the four species exhibited a distinctly different isoHb pattern compared with their normoxia-raised (NR) siblings. The hemoglobin of HR H. thereuterion showed higher O2 affinity compared with NR siblings particularly in the presence of ATP and GTP, indicating that blood of HR juveniles has significantly improved O2-binding affinity under hypoxic conditions. We also tested the capacity to acclimate at greater age in two species by reversing the O2 condition after 7 (H. thereuterion) and 4 (H. ishmaeli) months. After reacclimation for 1 and 2 months, respectively, we found incomplete reversal with intermediate isoHb patterns. As three of the four species do not encounter hypoxic conditions in their environment, this unique trait seems to be a relic inherited from predecessors that lived in hypoxic environments. PMID- 29997156 TI - Adaptive sonar call timing supports target tracking in echolocating bats. AB - Echolocating bats dynamically adapt the features of their sonar calls as they approach obstacles and track targets. As insectivorous bats forage, they increase sonar call rate with decreasing prey distance, and often embedded in bat insect approach sequences are clusters of sonar sounds, termed sonar sound groups (SSGs). The bat's production of SSGs has been observed in both field and laboratory conditions, and is hypothesized to sharpen spatiotemporal sonar resolution. When insectivorous bats hunt, they may encounter erratically moving prey, which increases the demands on the bat's sonar imaging system. Here, we studied the bat's adaptive vocal behavior in an experimentally controlled insect tracking task, allowing us to manipulate the predictability of target trajectories and measure the prevalence of SSGs. With this system, we trained bats to remain stationary on a platform and track a moving prey item, whose trajectory was programmed either to approach the bat, or to move back and forth, before arriving at the bat. We manipulated target motion predictability by varying the order in which different target trajectories were presented to the bats. During all trials, we recorded the bat's sonar calls and later analysed the incidence of SSG production during the different target tracking conditions. Our results demonstrate that bats increase the production of SSGs when target unpredictability increases, and decrease the production of SSGs when target motion predictability increases. Furthermore, bats produce the same number of sonar vocalizations irrespective of the target motion predictability, indicating that the animal's temporal clustering of sonar call sequences to produce SSGs is purposeful, and therefore involves sensorimotor planning. PMID- 29997157 TI - Scaling of morphology and ultrastructure of hearts among wild African antelope. AB - The hearts of smaller mammals tend to operate at higher mass-specific mechanical work rates than those of larger mammals. The ultrastructural characteristics of the heart that allow for such variation in work rate are still largely unknown. We have used perfusion-fixation, transmission electron microscopy and stereology to assess the morphology and anatomical aerobic power density of the heart as a function of body mass across six species of wild African antelope differing by approximately 20-fold in body mass. The survival of wild antelope, as prey animals, depends on competent cardiovascular performance. We found that relative heart mass (g kg-1 body mass) decreases with body mass according to a power equation with an exponent of -0.12+/-0.07 (+/-95% confidence interval). Likewise, capillary length density (km cm-3 of cardiomyocyte), mitochondrial volume density (fraction of cardiomyocyte) and mitochondrial inner membrane surface density (m2 cm-3 of mitochondria) also decrease with body mass with exponents of -0.17+/ 0.16, -0.06+/-0.05 and -0.07+/-0.05, respectively, trends likely to be associated with the greater mass-specific mechanical work rate of the heart in smaller antelope. Finally, we found proportionality between quantitative characteristics of a structure responsible for the delivery of oxygen (total capillary length) and those of a structure that ultimately uses that oxygen (total mitochondrial inner membrane surface area), which provides support for the economic principle of symmorphosis at the cellular level of the oxygen cascade in an aerobic organ. PMID- 29997159 TI - Parameters of motion vision in low light in the hawkmoth Manduca sexta. AB - The hawkmoth Manduca sexta is nocturnally active, beginning its flight activity at sunset, and executing rapid controlled maneuvers to search for food and mates in dim light conditions. The visual system of this moth has been shown to trade off spatial and temporal resolution for increased sensitivity in these conditions. The study presented here uses tethered flying moths to characterize the flight performance envelope of the wide-field-motion-triggered steering response of M. sexta in low light conditions by measuring attempted turning in response to wide-field visual motion. Moths were challenged with a horizontally oscillating sinusoidal grating at a range of luminance, from daylight to starlight conditions. The impact of luminance on response to a range of temporal frequencies and spatial wavelengths was assessed across a range of pattern contrasts. The optomotor response decreased as a function of decreasing luminance, and the lower limit of the moth's contrast sensitivity was found to be between 1 and 5%. The preferred spatial frequency for M. sexta increased from 0.06 to 0.3 cycles deg-1 as the luminance decreased, but the preferred temporal frequency remained stable at 4.5 Hz across all conditions. The relationship between the optomotor response time to the temporal frequency of the pattern movement did not vary significantly with luminance levels. Taken together, these results suggest that the behavioral response to wide-field visual input in M. sexta is adapted to operate during crepuscular to nocturnal luminance levels, and the decreasing light levels experienced during that period changes visual acuity and does not affect their response time significantly. PMID- 29997158 TI - Potential trade-offs between biomineralization and immunity revealed by shell properties and gene expression profiles of two closely related Crassostrea species. AB - Species of the Ostreidae family are key ecosystem engineers and many of them - including Crassostrea gigas and Crassostreavirginica - are commercially important aquaculture species. Despite similarities in their morphology and ecology, these two species differ in their ability to defend against pathogens, potentially reflecting species-specific differential specialization of hemocytes on immune defense versus biomineralization. To test this hypothesis, we investigated the expression levels of immune- and biomineralization-related genes as well as mineralogical and mechanical properties of the shells and the calcium sequestration ability of the hemocytes of C. gigas and C. virginica The expression of biomineralization-related genes was higher in C. virginica than in C. gigas in multiple tissues including the mantle edge and hemocytes, while the expression of immune genes was higher in the hemocytes of C. gigas Hemocytes of C. virginica contained more calcium (stored intracellularly as calcium carbonate mineral) compared with those of C. gigas Analysis of the adult shells showed that the crystallinity of calcite was higher and the laths of the foliated layer of the shell were thicker in C. virginica than in C. gigas Mechanically, the shells of C. virginica were stiffer, harder and stronger than those of C. gigas Taken together, our results show that the species-specific differences in physiology (such as disease resistance and exoskeleton properties) are reflected at the cellular and molecular levels in the differential specialization of hemocytes on potentially competing functions (immunity and biomineralization) as well as different expression profiles of other tissues involved in biomineralization (such as the mantle edge). PMID- 29997160 TI - Heterogeneity of neuromasts in a fish without lateral line canals: the pufferfish (Takifugu obscurus) model. AB - Fish detect water motion with their mechanosensory lateral line. The basic functional unit of the lateral line is the neuromast. In most fish species, neuromasts are located in lateral line canals (canal neuromasts) or on the skin (superficial neuromasts). In this paper, we describe the lateral line system of the pufferfish, Takifugu obscurus If threatened, this fish inflates its body by sucking water into the esophagus. Pufferfish lack a canal system but have neuromasts located directly on the skin or in open grooves. Each groove houses tall, medium and short neuromasts, based on the height of their pedestal. One or more medium neuromasts were always located between two tall neuromasts, and the short neuromasts were scattered between them. Tall neuromasts showed phasic responses to water jets, similar to the canal neuromasts of other fish species. In contrast, the medium and short neuromasts showed tonic responses to water jets. The response properties of nerve fibers that innervated the medium and short neuromasts were similar to those of the superficial neuromasts found in other fish species. Our results suggest that each groove of a pufferfish has two functional groups of neuromasts. This may allow pufferfish to extract spatial and temporal hydrodynamic information, despite the changes in body shape that occur during and after inflation. The short neuromasts at the bottom of a groove most likely supplement the medium neuromasts when the body is maximally inflated. PMID- 29997161 TI - The effect of chronic and acute stressors, and their interaction, on testes function: an experimental test during testicular recrudescence. AB - Organisms are expected to invest less in reproduction in response to a stressor, but theory predicts that this effect should depend on the frequency and duration of stressors in the environment. Here, we investigated how an acute stressor affected testes function in a songbird, and how chronic stressors influenced the acute stress response. We exposed male dark-eyed juncos (Junco hyemalis) either to chronic or minimal (control) disturbance during testicular recrudescence, after which we measured baseline testosterone, testosterone after an acute handling stressor, and capacity to produce testosterone after hormonal stimulation. In a 2*2 design, we then killed males from the two chronic treatment groups either immediately or after an acute stressor to investigate the effect of long- and short-term stressors on the testicular transcriptome. We found that chronically disturbed birds had marginally lower baseline testosterone. The acute stressor suppressed testosterone in control birds, but not in the chronic disturbance group. The ability to elevate testosterone did not differ between the chronic treatments. Surprisingly, chronic disturbance had a weak effect on the testicular transcriptome, and did not affect the transcriptomic response to the acute stressor. The acute stressor, on the other hand, upregulated the cellular stress response and affected expression of genes associated with hormonal stress response. Overall, we show that testicular function is sensitive to acute stressors but surprisingly robust to long-term stressors, and that chronic disturbance attenuates the decrease in testosterone in response to an acute stressor. PMID- 29997162 TI - Cooler snakes respond more strongly to infrared stimuli, but we have no idea why. AB - The pit organ defining pit vipers (Crotalinae) contains a membrane covered with temperature receptors that detect thermal radiation from environmental surfaces. Temperature is both the environmental parameter being sensed and the mechanism by which the pit membrane detects the signal. As snakes are ectotherms, temperature also has a strong influence on neurological and locomotor responses to the signal. This study of Pacific rattlesnakes (Crotalus oreganus) systematically examined the effect of body, target and background temperatures on response to a moving target. We presented each snake with a moving pendulum bob regulated at a series of six temperatures against a uniform background regulated at one of three temperatures. Snake body temperatures varied from 18 to 36 degrees C. As expected, we found stronger responses to positive contrasts (target warmer than background) than to negative contrasts, and stronger responses to greater contrasts. However, the effect of body temperature was contrary to expectations based on studies of the TRPA1 ion channel (believed to be the molecular basis for pit membrane temperature receptors) and typical thermal reaction norms for neural and motor performance. These predict (1) no response below the threshold where the TRPA1 channel opens, (2) response increasing as temperature increases, peaking near preferred body temperature, and (3) declining thereafter. Remarkably, this behavioral response decreased as body temperature increased from 18 to 36 degrees C, with no threshold or peak in this range. We review various possible physiological mechanisms related to body temperature proposed in the literature, but find none that can satisfactorily explain this result. PMID- 29997163 TI - Is Spatial Context Privileged in the Neural Representation of Events? PMID- 29997164 TI - BMP/SMAD Pathway and the Development of Dopamine Substantia Nigra Neurons. PMID- 29997165 TI - Saddle embolism in an extremely premature infant. PMID- 29997166 TI - Time interval for preterm infant weight gain velocity calculation precision. AB - Calculation of weight gain velocity is used to guide nutrition and fluid management practices in neonatal intensive care units. Calculations over short time periods may be more responsive to management changes, but less precise. Weight gain velocity calculated over 5 to 7+ days have lower variability and less noise than shorter periods. PMID- 29997167 TI - Hypothermia for perinatal asphyxia: trial-based resource use and costs at 6-7 years. AB - OBJECTIVE: To assess the impact of hypothermic neural rescue for perinatal asphyxia at birth on healthcare costs of survivors aged 6-7 years, and to quantify the relationship between costs and overall disability levels. DESIGN: 6 7 years follow-up of surviving children from the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial. SETTING: Community study including a single parental questionnaire to collect information on children's healthcare resource use. PATIENTS: 130 UK children (63 in the control group, 67 in the hypothermia group) whose parents consented and returned the questionnaire. INTERVENTIONS: Intensive care with cooling of the body to 33.5 degrees C for 72 hours or intensive care alone. MAIN OUTCOME MEASURES: Healthcare resource usage and costs over the preceding 6 months. RESULTS: At 6-7 years, mean (SE) healthcare costs per child were L1543 (L361) in the hypothermia group and L2549 (L812) in the control group, giving a saving of -L1005 (95% CI -L2734 to L724). Greater levels of overall disability were associated with progressively higher costs, and more parents in the hypothermia group were employed (64% vs 47%). Results were sensitive to outlying observations. CONCLUSIONS: Cost results although not significant favoured moderate hypothermia and so complement the clinical results of the TOBY Children study. Estimates were however sensitive to the care requirements of two seriously ill children in the control group. A quantification of the relationship between costs and levels of disability experienced will be useful to healthcare professionals, policy makers and health economists contemplating the long-term economic consequences of perinatal asphyxia and hypothermic neural rescue. TRIAL REGISTRATION NUMBER: This study reports on the follow-up of the TOBY clinical trial: ClinicalTrials. gov number NCT01092637. PMID- 29997168 TI - Effect of blood ionised calcium concentration at calving on fertility outcomes in dairy cattle. AB - Clinical and subclinical hypocalcaemia are common in dairy cows, yet evidence in the literature assessing their impact on fertility is inconsistent. The aim of this prospective cohort study was to examine associations between blood ionised calcium concentration at calving and fertility outcomes in dairy cattle. Blood samples were taken from 137 Holstein cows from four commercial dairy herds within 24 hours of calving and analysed for blood ionised calcium using an Epocal Point of Care Analyser (Epocal, Ottawa, Canada). Data collected from routine veterinary fertility examinations and herd records were used to investigate the association of ionised calcium with the outcomes: time to first service, time to conception and endometritis. There were significant negative associations between blood ionised calcium concentration and time to first service (HR 1.33, P=0.001) and blood ionised calcium concentration and time to conception (HR 1.16, P=0.04). There was no significant association between blood ionised calcium concentration and endometritis. The results of this study imply that management policies that minimise the reduction in blood ionised calcium concentration in the periparturient dairy cow are likely to improve reproductive outcomes and should be considered as part of the multifactorial approach to optimising dairy cow fertility. PMID- 29997169 TI - Complex Care Hospital Use and Postdischarge Coaching: A Randomized Controlled Trial. AB - OBJECTIVES: We sought to examine the effect of a caregiver coaching intervention, Plans for Action and Care Transitions (PACT), on hospital use among children with medical complexity (CMC) within a complex care medical home at an urban tertiary medical center. METHODS: PACT was an 18-month caregiver coaching intervention designed to influence key drivers of hospitalizations: (1) recognizing critical symptoms and conducting crisis plans and (2) supporting comprehensive hospital transitions. Usual care was within a complex care medical home. Primary outcomes included hospitalizations and 30-day readmissions. Secondary outcomes included total charges and mortality. Intervention effects were examined with bivariate and multivariate analyses. RESULTS: From December 2014 to September 2016, 147 English- and Spanish-speaking CMC <18 years old and their caregivers were randomly assigned to PACT (n = 77) or usual care (n = 70). Most patients were Hispanic, Spanish-speaking, and publicly insured. Although in unadjusted intent to-treat analyses, only charges were significantly reduced, both hospitalizations and charges were lower in adjusted analyses. Hospitalization rates (per 100 child years) were 81 for PACT vs 101 for usual care (adjusted incident rate ratio: 0.61 [95% confidence interval 0.38-0.97]). Adjusted mean charges per patient were $14 206 lower in PACT. There were 0 deaths in PACT vs 4 in usual care (log-rank P = .04). CONCLUSIONS: Among CMC within a complex care program, a health coaching intervention designed to identify, prevent, and manage patient-specific crises and postdischarge transitions appears to lower hospitalizations and charges. Future research should confirm findings in broader populations and care models. PMID- 29997170 TI - Successful Chest Radiograph Reduction by Using Quality Improvement Methodology for Children With Asthma. AB - OBJECTIVES: Implementation of an asthma clinical practice guideline did not achieve desired chest radiograph (CXR) usage goals. We attempt to use quality improvement methodology to decrease the percentage of CXRs obtained for pediatric patients with acute asthma exacerbations from 29.3% to <20% and to evaluate whether decreases in CXR use are associated with decreased antibiotic use. METHODS: We included all children >=2 years old at our children's hospital with primary billing codes for asthma from May 2013 to April 2017. A multidisciplinary team tested targeted interventions on the basis of 3 key drivers aimed at reducing CXRs. We used statistical process control charts to study measures. The primary measure was the percentage of patients with an acute asthma exacerbation who were undergoing a CXR. The secondary measure was percentage of patients receiving systemic antibiotics. Balancing measures were all-cause, 3-day return emergency department visits and the percentage of pneumonia and/or asthma codiagnosis encounters. RESULTS: We included 6680 consecutive patients with 1539 CXRs. Implementation of an asthma clinical practice guideline was associated with decreased CXR use from 29.3% to 23.0%. Targeted interventions were associated with further reduction to 16.0%. For subset analyses, CXR use decreased from 21.3% to 12.5% for treat-and-release patients and from 53.5% to 31.1% for admitted patients. Antibiotic use varied slightly without temporal association with interventions or CXR reduction. There were no adverse changes in balancing measures. CONCLUSIONS: Quality improvement methodology and targeted interventions are associated with a sustained reduction in CXR use in pediatric patients with acute asthma exacerbations. Reduction of CXRs is not associated with decreased antibiotic use. PMID- 29997172 TI - Polymerization pathway of mammalian nonmuscle myosin 2s. AB - The three mammalian nonmuscle myosin 2 (NM2) monomers, like all class 2 myosin monomers, are hexamers of two identical heavy (long) chains and two pairs of light (short) chains bound to the heavy chains. The heavy chains have an N terminal globular motor domain (head) with actin-activated ATPase activity, a lever arm (neck) to which the two light chains bind, and a coiled-coil helical tail. Monomers polymerize into bipolar filaments, with globular heads at each end separated by a bare zone, by antiparallel association of their coiled-coil tails. NM2 filaments are highly dynamic in situ, frequently disassembling and reassembling at different locations within the cell where they are essential for multiple biological functions. Therefore, it is important to understand the mechanisms of filament polymerization and depolymerization. Monomers can exist in two states: folded and unfolded. It has been thought that unfolded monomers form antiparallel dimers that assemble into bipolar filaments. We now show that polymerization in vitro proceeds from folded monomers to folded antiparallel dimers to folded antiparallel tetramers that unfold forming antiparallel bipolar tetramers. Folded dimers and tetramers then associate with the unfolded tetramer and unfold, forming a mature bipolar filament consisting of multiple unfolded tetramers with an entwined bare zone. We also demonstrate that depolymerization is essentially the reverse of the polymerization process. These results will advance our understanding of NM2 filament dynamics in situ. PMID- 29997171 TI - Aberrant regulation of the GSK-3beta/NRF2 axis unveils a novel therapy for adrenoleukodystrophy. AB - The nuclear factor erythroid 2-like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early appearing feature in X-linked adrenoleukodystrophy (X-ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long-chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK-3beta. We find that GSK-3beta inhibitors can significantly reactivate the blunted NRF2 response in patients' fibroblasts. In the mouse models (Abcd1- and Abcd1-/Abcd2-/- mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross talk governing energetic and redox homeostasis in X-ALD Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X-ALD and other axonopathies with impaired GSK-3beta/NRF2 axis. PMID- 29997173 TI - CD52 glycan binds the proinflammatory B box of HMGB1 to engage the Siglec-10 receptor and suppress human T cell function. AB - CD52, a glycophosphatidylinositol (GPI)-anchored glycoprotein, is released in a soluble form following T cell activation and binds to the Siglec (sialic acid binding Ig-like lectin)-10 receptor on T cells to suppress their function. We show that binding of CD52-Fc to Siglec-10 and T cell suppression requires the damage-associated molecular pattern (DAMP) protein, high-mobility group box 1 (HMGB1). CD52-Fc bound specifically to the proinflammatory Box B domain of HMGB1, and this in turn promoted binding of the CD52 N-linked glycan, in alpha-2,3 sialic acid linkage with galactose, to Siglec-10. Suppression of T cell function was blocked by anti-HMGB1 antibody or the antiinflammatory Box A domain of HMGB1. CD52-Fc induced tyrosine phosphorylation of Siglec-10 and was recovered from T cells complexed with HMGB1 and Siglec-10 in association with SHP1 phosphatase and the T cell receptor (TCR). Thus, soluble CD52 exerts a concerted immunosuppressive effect by first sequestering HMGB1 to nullify its proinflammatory Box B, followed by binding to the inhibitory Siglec-10 receptor, triggering recruitment of SHP1 to the intracellular immunoreceptor tyrosine-based inhibitory motif of Siglec-10 and its interaction with the TCR. This mechanism may contribute to immune-inflammatory homeostasis in pathophysiologic states and underscores the potential of soluble CD52 as a therapeutic agent. PMID- 29997174 TI - Plasticity based on compensatory effector use in the association but not primary sensorimotor cortex of people born without hands. AB - What forces direct brain organization and its plasticity? When brain regions are deprived of their input, which regions reorganize based on compensation for the disability and experience, and which regions show topographically constrained plasticity? People born without hands activate their primary sensorimotor hand region while moving body parts used to compensate for this disability (e.g., their feet). This was taken to suggest a neural organization based on functions, such as performing manual-like dexterous actions, rather than on body parts, in primary sensorimotor cortex. We tested the selectivity for the compensatory body parts in the primary and association sensorimotor cortex of people born without hands (dysplasic individuals). Despite clear compensatory foot use, the primary sensorimotor hand area in the dysplasic subjects showed preference for adjacent body parts that are not compensatorily used as effectors. This suggests that function-based organization, proposed for congenital blindness and deafness, does not apply to the primary sensorimotor cortex deprivation in dysplasia. These findings stress the roles of neuroanatomical constraints like topographical proximity and connectivity in determining the functional development of primary cortex even in extreme, congenital deprivation. In contrast, increased and selective foot movement preference was found in dysplasics' association cortex in the inferior parietal lobule. This suggests that the typical motor selectivity of this region for manual actions may correspond to high-level action representations that are effector-invariant. These findings reveal limitations to compensatory plasticity and experience in modifying brain organization of early topographical cortex compared with association cortices driven by function-based organization. PMID- 29997175 TI - Giant and explosive plasmonic bubbles by delayed nucleation. AB - When illuminated by a laser, plasmonic nanoparticles immersed in water can very quickly and strongly heat up, leading to the nucleation of so-called plasmonic vapor bubbles. While the long-time behavior of such bubbles has been well studied, here, using ultrahigh-speed imaging, we reveal the nucleation and early life phase of these bubbles. After some delay time from the beginning of the illumination, a giant bubble explosively grows, and collapses again within 200 MUs (bubble life phase 1). The maximal bubble volume [Formula: see text] remarkably increases with decreasing laser power, leading to less total dumped energy E. This dumped energy shows a universal linear scaling relation with [Formula: see text], irrespective of the gas concentration of the surrounding water. This finding supports that the initial giant bubble is a pure vapor bubble. In contrast, the delay time does depend on the gas concentration of the water, as gas pockets in the water facilitate an earlier vapor bubble nucleation, which leads to smaller delay times and lower bubble nucleation temperatures. After the collapse of the initial giant bubbles, first, much smaller oscillating bubbles form out of the remaining gas nuclei (bubble life phase 2). Subsequently, the known vaporization dominated growth phase takes over, and the bubble stabilizes (life phase 3). In the final life phase 4, the bubble slowly grows by gas expelling due to heating of the surrounding. Our findings on the explosive growth and collapse during the early life phase of a plasmonic vapor bubble have strong bearings on possible applications of such bubbles. PMID- 29997177 TI - Growing a gasdermin pore in membranes of pyroptotic cells. PMID- 29997176 TI - Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase dependent phosphorylation. AB - Lens epithelium-derived growth factor/p75 (LEDGF/p75, or PSIP1) is a transcriptional coactivator that tethers other proteins to gene bodies. The chromatin tethering function of LEDGF/p75 is hijacked by HIV integrase to ensure viral integration at sites of active transcription. LEDGF/p75 is also important for the development of mixed-lineage leukemia (MLL), where it tethers the MLL1 fusion complex at aberrant MLL targets, inducing malignant transformation. However, little is known about how the LEDGF/p75 protein interaction network is regulated. Here, we obtained solution structures of the complete interfaces between the LEDGF/p75 integrase binding domain (IBD) and its cellular binding partners and validated another binding partner, Mediator subunit 1 (MED1). We reveal that structurally conserved IBD-binding motifs (IBMs) on known LEDGF/p75 binding partners can be regulated by phosphorylation, permitting switching between low- and high-affinity states. Finally, we show that elimination of IBM phosphorylation sites on MLL1 disrupts the oncogenic potential of primary MLL1 rearranged leukemic cells. Our results demonstrate that kinase-dependent phosphorylation of MLL1 represents a previously unknown oncogenic dependency that may be harnessed in the treatment of MLL-rearranged leukemia. PMID- 29997179 TI - Shelterin promotes tethering of late replication origins to telomeres for replication-timing control. AB - DNA replication initiates at many discrete loci on eukaryotic chromosomes, and individual replication origins are regulated under a spatiotemporal program. However, the underlying mechanisms of this regulation remain largely unknown. In the fission yeast Schizosaccharomyces pombe, the telomere-binding protein Taz1, ortholog of human TRF1/TRF2, regulates a subset of late replication origins by binding to the telomere-like sequence near the origins. Here, we showed using a lacO/LacI-GFP system that Taz1-dependent late origins were predominantly localized at the nuclear periphery throughout interphase, and were localized adjacent to the telomeres in the G1/S phase. The peripheral localization that depended on the nuclear membrane protein Bqt4 was not necessary for telomeric association and replication-timing control of the replication origins. Interestingly, the shelterin components Rap1 and Poz1 were required for replication-timing control and telomeric association of Taz1-dependent late origins, and this requirement was bypassed by a minishelterin Tpz1-Taz1 fusion protein. Our results suggest that Taz1 suppresses replication initiation through shelterin-mediated telomeric association of the origins at the onset of S phase. PMID- 29997178 TI - Myc and the Tip60 chromatin remodeling complex control neuroblast maintenance and polarity in Drosophila. AB - Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in Drosophila neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc as regulators of genes required for neuroblast maintenance. Knockdown of Tip60 complex members results in loss of cortical polarity, symmetric neuroblast division, and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino in regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes previously identified as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex, and the molecular network controlling cell polarity and asymmetric cell division. PMID- 29997181 TI - New Surviving Sepsis Campaign guidelines: back to the art of medicine. PMID- 29997180 TI - BIG Regulates Dynamic Adjustment of Circadian Period in Arabidopsis thaliana. AB - Circadian clocks drive rhythms with a period near 24 h, but the molecular basis of the regulation of the period of the circadian clockis poorly understood. We previously demonstrated that metabolites affect the free-running period of the circadian oscillator of Arabidopsis (Arabidopsis thaliana), with endogenous sugars acting as an accelerator and exogenous nicotinamide acting as a brake. Changes in circadian oscillator period are thought to adjust the timing of biological activities through the process of entrainment, in which the circadian oscillator becomes synchronized to rhythmic signals such as light and dark cycles as well as changes in internal metabolism. To identify the molecular components associated with the dynamic adjustment of circadian period, we performed a forward genetic screen. We identified Arabidopsis mutants that were either period insensitive to nicotinamide (sin) or period oversensitive to nicotinamide (son). We mapped son1 to BIG, a gene of unknown molecular function that was shown previously to play a role in light signaling. We found that son1 has an early entrained phase, suggesting that the dynamic alteration of circadian period contributes to the correct timing of biological events. Our data provide insight into how the dynamic period adjustment of circadian oscillators contributes to establishing a correct phase relationship with the environment and show that BIG is involved in this process. PMID- 29997182 TI - Associations between dietary scores with asthma symptoms and asthma control in adults. AB - Associations between asthma and the nutritional quality of diet remain poorly understood. We investigated the associations between overall quality of diet evaluated by three dietary scores (the Alternate Healthy Eating Index 2010 (AHEI 2010), the literature-based adherence score to Mediterranean diet (MEDI-LITE) and the modified Programme National Nutrition Sante Guideline Score (mPNNS-GS)) and the asthma symptom score and asthma control.In 2017, 34 766 participants from the NutriNet-Sante cohort answered a detailed respiratory questionnaire. Asthma was defined by the asthma symptom score (as the sum of five questions) and asthma control by the asthma control test (ACT).Roughly 25% of participants reported at least one asthma symptom and for the three dietary scores we observed a statistically significant negative association between a healthier diet and the asthma symptom score (for AHEI-2010, the adjusted OR was 0.79 (95% CI 0.75-0.84) for women and 0.67 (95% CI 0.60-0.75) for men). Among participants with asthma (n=2609) we also observed a negative association between a healthier diet and poorly controlled asthma. This was significant in men (OR 0.39 (95% CI 0.18-0.84) for the AHEI-2010) and borderline significant in women (OR 0.73 (95% CI 0.53 1.01) for the AHEI-2010; p=0.06 for trend).Healthier diet behaviours were associated with fewer asthma symptoms and greater asthma control. PMID- 29997183 TI - Good cop, bad cop: anaerobes in cystic fibrosis airways. PMID- 29997184 TI - The pitch of babies' cries predicts their voice pitch at age 5. AB - Voice pitch (fundamental frequency, F0) is a key dimension of our voice that varies between sexes after puberty, and also among individuals of the same sex both before and after puberty. While a recent longitudinal study indicates that inter-individual differences in voice pitch remain stable in men during adulthood and may even be determined before puberty (Fouquet et al. 2016 R. Soc. open sci.3, 160395. (doi:10.1098/rsos.160395)), whether these differences emerge in infancy remains unknown. Here, using a longitudinal study design, we investigate the hypothesis that inter-individual differences in F0 are already present in the cries of pre-verbal babies. While based on a small sample (n = 15), our results indicate that the F0 of babies' cries at 4 months of age may predict the F0 of their speech utterances at 5 years of age, explaining 41% of the inter-individual variance in voice pitch at that age in our sample. We also found that the right hand ratio of the length of their index to ring finger (2D : 4D digit ratio), which has been proposed to constitute an index of prenatal testosterone exposure, was positively correlated with F0 at both 4 months and 5 years of age. These findings suggest that a substantial proportion of between-individual differences in voice pitch, which convey important biosocial information about speakers, may partly originate in utero and thus already be present soon after birth. PMID- 29997185 TI - Shared environmental effects bias phenotypic estimates of assortative mating in a wild bird. AB - Assortative mating is pervasive in wild populations and commonly described as a positive correlation between the phenotypes of males and females across mated pairs. This correlation is often assumed to reflect non-random mate choice based on phenotypic similarity. However, phenotypic resemblance between mates can also arise when their traits respond plastically to a shared environmental effect creating a (within-pair) residual correlation in traits. Using long-term data collected in pairs of wild blue tits and a covariance partitioning approach, we empirically demonstrate that such residual covariance indeed exists and can generate phenotypic correlations (or mask assortative mating) in behavioural and morphometric traits. These findings (i) imply that residual covariance is likely to be common and bias phenotypic estimates of assortative mating, which can have consequences for evolutionary predictions, (ii) call for the use of rigorous statistical approaches in the study of assortative mating, and (iii) show the applicability of one of these approaches in a common study system. PMID- 29997186 TI - Evidence of sociality in the timing and location of foraging in a colonial seabird. AB - Social foraging behaviours, which range from cooperative hunting to local enhancement, can result in increased prey capture and access to information, which may significantly reduce time and energy costs of acquiring prey. In colonial species, it has been proposed that the colony itself may act as a site of social information transfer and group formation. However, conclusive evidence from empirical studies is lacking. In particular, most studies in colonial species have generally focussed on behaviours either at the colony or at foraging sites in isolation, and have failed to directly connect social associations at the colony to social foraging. In this study, we simultaneously tracked 85% of a population of Australasian gannets (Morus serrator) over multiple foraging trips, to study social associations at the colony and test whether these associations influence the location of foraging sites. We found that gannets positively associate with conspecifics while departing from the colony and that co-departing gannets have more similar initial foraging patches than individuals that did not associate at the colony. These results provide strong evidence for the theory that the colony may provide a source of information that influences foraging location. PMID- 29997187 TI - Growth potential can affect timing of maturity in a long-lived semelparous fish. AB - Many diadromous fishes such as salmon and eels that move between freshwater and the ocean have evolved semelparous reproductive strategies, but both groups display considerable plasticity in characteristics. Factors such as population density and growth, predation risk or reproduction cost have been found to influence timing of maturation. We investigated the relationship between female size at maturity and individual growth trajectories of the long-lived semelparous European eel, Anguilla anguilla A Bayesian model was applied to 338 individual growth trajectories of maturing migration-stage female silver eels from France, Ireland, the Netherlands and Hungary. The results clearly showed that when growth rates declined, the onset of maturation was triggered, and the eels left their growth habitats and migrated to the spawning area. Therefore, female eels tended to attain larger body size when the growth conditions were good enough to risk spending extra time in their growth habitats. This flexible maturation strategy is likely related to the ability to use diverse habitats with widely ranging growth and survival potentials in the catadromous life-history across its wide species range. PMID- 29997188 TI - Nitrogen enrichment offsets direct negative effects of ocean acidification on a reef-building crustose coralline alga. AB - Ocean acidification (OA) and nutrient enrichment threaten the persistence of near shore ecosystems, yet little is known about their combined effects on marine organisms. Here, we show that a threefold increase in nitrogen concentrations, simulating enrichment due to coastal eutrophication or consumer excretions, offset the direct negative effects of near-future OA on calcification and photophysiology of the reef-building crustose coralline alga, Porolithon onkodes Projected near-future pCO2 levels (approx. 850 uatm) decreased calcification by 30% relative to ambient conditions. Conversely, nitrogen enrichment (nitrate + nitrite and ammonium) increased calcification by 90-130% in ambient and high pCO2 treatments, respectively. pCO2 and nitrogen enrichment interactively affected instantaneous photophysiology, with highest relative electron transport rates under high pCO2 and high nitrogen. Nitrogen enrichment alone increased concentrations of the photosynthetic pigments chlorophyll a, phycocyanin and phycoerythrin by approximately 80-450%, regardless of pCO2 These results demonstrate that nutrient enrichment can mediate direct organismal responses to OA. In natural systems, however, such direct benefits may be counteracted by simultaneous increases in negative indirect effects, such as heightened competition. Experiments exploring the effects of multiple stressors are increasingly becoming important for improving our ability to understand the ramifications of local and global change stressors in near shore ecosystems. PMID- 29997189 TI - Age-specific patterns of maternal investment in common gull egg yolk. AB - While the general patterns of age-specific changes in reproductive success are quite well established in long-lived animals, we still do not know if allocation patterns of maternally transmitted compounds are related to maternal age. We measured the levels of yolk testosterone, carotenoids and vitamins A and E in a population of known-aged common gulls (Larus canus) and found an age-specific pattern in yolk lutein and vitamin A concentrations. Middle-aged mothers allocated more of these substances to yolk compared to young and old mothers. These results can be explained through differences in age-specific foraging, absorption or deposition patterns of carotenoids and vitamins into yolk. If these molecules play a role in antioxidant defence and immune modulation, our results suggest a possible physiological pathway underlying the age-specific changes in reproductive success of long-lived birds in the wild. PMID- 29997191 TI - World dementia: One approach does not fit all. AB - OBJECTIVE: To highlight the broad global diversity in the diagnosis, management, and research of dementia in different regions of the world. METHODS: A critical review of the limited literature from the global South compared with advances that have emerged from key studies in the West and observations from the authors' experiences. RESULTS: The last several decades have witnessed major advances in dementia research and include an understanding of epidemiologic trends in the global burden of disease, the development of biomarkers for Alzheimer disease, the identification of novel therapeutic targets, and the recognition of the role of protective life-course experiential factors. For the effective translation of these research advances into societies, a "world approach" to dementia is vital. Developing societies substantially differ from Western countries in their attitudes toward dementia, as well as their clinical manifestations and risk factor profiles, marked by lower education and socioeconomic status, a higher cardiovascular disease burden, and genetic variability. Emerging evidence emphasizes the interaction among ethnicity, genetics, epigenetics, environment, culture, and neurobiology in influencing manifestations of dementia. Therefore, the investigation of dementia in diverse settings, including a more global perspective, is crucial for a comprehensive understanding of the condition as well as the identification of novel solutions. CONCLUSIONS: A world approach to dementia provides an opportunity to understand, manage, coordinate, and begin to prevent dementia through an integrated approach based on firm scientific evidence. PMID- 29997190 TI - Late-life blood pressure association with cerebrovascular and Alzheimer disease pathology. AB - OBJECTIVE: To examine associations of average and change in late-life blood pressure (BP) with cerebrovascular and Alzheimer disease (AD) neuropathology in a large group of decedents followed longitudinally in vivo. METHODS: This clinical pathologic study was derived from prospective, community-based cohort studies of aging with similar design and data collection. Measurements of systolic BP (SBP) and diastolic BP (DBP) were obtained annually (mean follow-up 8 years, SD = 4.8). Postmortem neuropathologic evaluations documented diseases of aging. Using regression analyses, we examined associations of average and decline in late-life SBP, and separately in DBP, with neuropathology. RESULTS: In 1,288 persons (mean age at death = 88.6 years; 65% women), the mean standardized person-specific SBP across the study was 134 (SD = 13) and DBP was 71 (SD = 8) mm Hg. The odds of brain infarcts were increased for participants with a higher mean SBP. Specifically, a person with a 1 SD SBP above the mean (147 vs 134 mm Hg) would have a 46% increased odds of having one or more infarcts, and an increased odds of gross infarct (46%) and microinfarct (36%). Furthermore, a more rapidly declining SBP slope over time increased the odds of one or more infarcts. Mean DBP, not slope, was related to brain infarcts. AD pathology analyses showed an association of a higher mean SBP with higher number of tangles (p = 0.038) but not plaques or other pathology (all p > 0.06). Changes in BP were not significantly related to AD pathology. CONCLUSIONS: Higher average late-life SBP and DBP, and independently a faster decline in SBP, are associated with increasing number of brain infarcts, including gross and microinfarcts. We found some evidence for a relation of SBP with AD, specifically tangles. Both average and decline in BP are related to brain disease. PMID- 29997192 TI - Hemodynamic assessments of venous pulsatile tinnitus using 4D-flow MRI. AB - OBJECTIVE: To use 4D-flow MRI to characterize hemodynamics of transverse and sigmoid sinus in venous pulsatile tinnitus (PT) patients and to investigate their differences vs healthy controls. METHODS: A total of 21 patients with venous PT and 11 healthy controls were included in the retrospective study. All participants underwent 4D-flow and magnetic resonance venography scan in a 3.0T magnetic resonance scanner. All visualization, quantification, and analysis of 4D flow data were performed using dedicated software. Two independent reviewers evaluated the existence of vortex or turbulence. Covariance analysis adjusted for age was used to compare average through-plane velocity (Vtp_avg), maximum through plane velocity (Vtp_max), average velocity (Vavg), maximum velocity (Vmax), average blood flow (Flowavg), and pulsatility index (PI) between PT and control group. RESULTS: There were hemodynamic differences between PT patients and healthy controls. Compared with the control group, the PT group showed significantly higher Vtp_avg, Vtp_max, Vavg, Vmax, and Flowavg, and slightly higher PI. For the assessment of flow pattern, inter-reader reproducibility was excellent (kappa = 1.00). Vortex or turbulence was observed in PT patients with good sensitivity (86.4%) and specificity (90.9%). Drainage dominance was more frequently observed in patients (15/21, 71.4%) than healthy controls (4/11, 36.4%). CONCLUSIONS: Significant hemodynamic differences were found between venous PT patients and healthy controls with 4D-flow MRI. Hemodynamic conditions could serve as noninvasive biomarkers for diagnosis and treatment evaluation of venous PT. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that 4D-flow MRI accurately identifies patients with venous PT. PMID- 29997193 TI - Low fasting serum insulin and dementia in nondiabetic women followed for 34 years. AB - OBJECTIVE: In a representative population of women followed over 34 years, we investigated the prospective association between fasting serum insulin and dementia, taking into account the incidence of diabetes mellitus. METHODS: Fasting values for serum insulin and blood glucose were obtained in 1,212 nondiabetic women 38 to 60 years of age at the 1968 baseline. Risk of dementia was assessed by Cox proportional hazard regression with adjustment for insulin, glucose, and other covariates and, in a second model, after censoring for incident cases of diabetes mellitus. Incident diabetes mellitus was considered as a third endpoint for comparison with dementia. RESULTS: Over 34 years, we observed 142 incident cases of dementia. The low tertile of insulin displayed excess risk for dementia (hazard ratio [HR] 2.34, 95% confidence interval [CI] 1.52-3.58) compared to the medium tertile, but the high tertile of insulin did not (HR 1.28, 95% CI 0.81-2.03). These associations were also seen for dementia without diabetes comorbidity. In contrast, high but not low insulin predicted incident diabetes mellitus (115 cases) (HR 1.70, 95% CI 1.08-2.68 and HR 0.76, 95% CI 0.43-1.37, respectively). CONCLUSION: A previous study reported a U-shaped association between fasting insulin and dementia in a 5-year follow-up of elderly men. Our results confirmed a nonlinear association in a female population, with high risk at low insulin values that was not attributable to preclinical dementia or impaired insulin secretion. This condition suggests a new pathway to dementia, which differs from the metabolic pathway involving diabetes mellitus. PMID- 29997194 TI - Retinal and optic nerve changes in microcephaly: An optical coherence tomography study. AB - OBJECTIVE: To investigate the morphology of the retina and optic nerve (ON) in microcephaly. METHODS: This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 MUm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. RESULTS: Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients with microcephaly compared to controls, nasally (307 +/- 44 vs 342 +/- 19 MUm, p = 0.001) and temporally (279 +/- 56 vs 325 +/- 16 MUm, p < 0.001). There was thinning of the ganglion cell layer and the inner segments of the photoreceptors in microcephaly. Total peripapillary retinal thickness was smaller in patients with microcephaly compared to controls for both temporal (275 vs 318 MUm, p < 0.001) and nasal sides (239 vs 268 MUm, p = 0.013). CONCLUSIONS: Retinal and ON anomalies in microcephaly likely reflect retinal cell reduction and lamination alteration due to impaired neurogenic mitosis. OCT allows diagnosis and quantification of retinal and ON changes in microcephaly even if they are not detected on ophthalmoscopy. PMID- 29997195 TI - Hyperacute stroke management is coming ... one Mississippi, two Mississippi. PMID- 29997196 TI - Diagnosing cerebral ischemia with door-to-thrombolysis times below 20 minutes. AB - OBJECTIVES: To clarify diagnostic accuracy and consequences of misdiagnosis in the admission evaluation of stroke-code patients in a neurologic emergency department with less than 20-minute door-to-thrombolysis times. METHODS: Accuracy of admission diagnostics was studied in an observational cohort of 1,015 stroke code patients arriving by ambulance as candidates for recanalization therapy between May 2013 and November 2015. Immediate admission evaluation was performed by a stroke neurologist or a neurology resident with dedicated stroke training, primarily utilizing CT-based imaging. RESULTS: The rate of correct admission diagnosis was 91.1% (604/663) for acute cerebral ischemia (ischemic stroke/TIA), 99.2% (117/118) for hemorrhagic stroke, and 61.5% (144/234) for stroke mimics. Of the 150 (14.8%) misdiagnosed patients, 135 (90.0%) had no acute findings on initial imaging and 100 (67.6%) presented with NIH Stroke Scale score 0 to 2. Misdiagnosis altered medical management in 70 cases, including administration of unnecessary treatments (thrombolysis n = 13, other n = 24), omission of thrombolysis (n = 5), delays to specific treatments of stroke mimics (n = 13, median 56 [31-93] hours), and delays to antiplatelet medication (n = 14, median 1 [1-2] day). Misdiagnosis extended emergency department stay (median 6.6 [4.7 10.4] vs 5.8 [3.7-9.2] hours; p = 0.001) and led to unnecessary stroke unit stay (n = 10). Detailed review revealed 8 cases (0.8%) in which misdiagnosis was possible or likely to have worsened outcomes, but no death occurred as a result of misdiagnosis. CONCLUSIONS: Our findings support the safety of highly optimized door-to-needle times, built on thorough training in a large-volume, centralized stroke service with long-standing experience. Augmented imaging and front-loaded specialist engagement are warranted to further improve rapid stroke diagnostics. PMID- 29997197 TI - A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1. AB - OBJECTIVE: An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype-genotype correlations. METHODS: Ten FSHD1 probands carrying 4-9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels. RESULTS: The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats. DISCUSSION: This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling. PMID- 29997198 TI - Prenatal biochemical screening and long term risk of maternal cardiovascular disease: population based cohort study. AB - OBJECTIVE: To examine whether abnormal prenatal biochemical screening results are associated with an increased risk of premature cardiovascular disease after pregnancy. DESIGN: Population based cohort study. SETTING: The entire province of Ontario, Canada, where healthcare is universally available. PARTICIPANTS: Women aged 12-55 years, without pre-existing cardiovascular disease, who underwent prenatal screening between 1993 and 2011. One pregnancy per woman was randomly selected. EXPOSURES: Low (<=5th centile multiple of the median) serum total chorionic gonadotropin, unconjugated estriol, and pregnancy associated plasma protein A and high (>=95th centile multiple of the median) alphafetoprotein and dimeric inhibin-A. MAIN OUTCOME MEASURES: Composite of hospital admission or revascularisation for coronary artery, cerebrovascular, or peripheral arterial disease or hospital admission for heart failure or dysrhythmia at least 365 days after pregnancy. RESULTS: Among 855 536 pregnancies, and after a median of 11.4 (interquartile range 6.8-17.5) years of follow-up, 6209 women developed the main cardiovascular disease outcome. Abnormal results for each of the five prenatal biochemical screening analytes, especially dimeric inhibin-A, were associated with a higher risk of cardiovascular disease. Women with an abnormally high dimeric inhibin-A (>=95th centile) had the highest rate of cardiovascular disease (30 events or 8.3 per 10 000 person years versus 251 events or 3.8 per 10 000 person years for those <95th centile; multivariable adjusted hazard ratio 2.0, 95% confidence interval 1.4 to 3.0). Compared with women without any abnormal biochemical measure, the hazard ratio for the cardiovascular disease composite outcome was 1.2-1.3 times higher with one abnormal analyte and 1.5-2.0 times higher with two or more abnormal analytes. CONCLUSIONS: Women with abnormal prenatal biochemical screening results, especially for dimeric inhibin-A, may be at higher risk of cardiovascular disease. If these findings are replicated elsewhere, a massive amount of data exists that could aid in identifying women at higher risk of premature cardiovascular disease and that could be conveyed to them or their healthcare providers. PMID- 29997199 TI - Molecular Detection of Mycobacterium tuberculosis from Stools in Young Children by Use of a Novel Centrifugation-Free Processing Method. AB - The microbiological diagnosis of tuberculosis (TB) in children is challenging, as it relies on the collection of relatively invasive specimens by trained health care workers, which is not feasible in many settings. Mycobacterium tuberculosis is detectable from the stools of children using molecular methods, but processing stool specimens is resource intensive. We evaluated a novel, simple, centrifugation-free processing method for stool specimens for use on the Xpert MTB/RIF assay (Xpert), using two different stool masses: 0.6 g and a swab sample. Two hundred eighty children (median age, 15.5 months; 35 [12.5%] HIV infected) with suspected intrathoracic TB were enrolled from two sites in South Africa. Compared to a single Xpert test on respiratory specimens, the sensitivity of Xpert on stools using the 0.6-g and swab samples was 44.4% (95% confidence interval [CI], 13.7 to 78.8%) for both methods, with a specificity of >99%. The combined sensitivities of two stool tests versus the first respiratory Xpert were 70.0% (95% CI, 34.8 to 93.3) and 50.0% (95% CI, 18.7 to 81.3) for the 0.6-g and swab sample, respectively. Retesting stool specimens with nondeterminate Xpert results improved nondeterminate rates from 9.3% to 3.9% and from 8.6% to 4.3% for 0.6-g and swab samples, respectively. Overall, stool Xpert detected 14/94 (14.9%) children who initiated antituberculosis treatment, while respiratory specimens detected 23/94 (24.5%). This stool processing method is well suited for settings with low capacity for respiratory specimen collection. However, the overall sensitivity to detect confirmed and clinical TB was lower than that of respiratory specimens. More sensitive rapid molecular assays are needed to improve the utility of stools for the diagnosis of intrathoracic TB in children from resource-limited settings. PMID- 29997200 TI - Population Structure and Antimicrobial Resistance of Canine Uropathogenic Escherichia coli. AB - Escherichia coli is the most common cause of human and canine urinary tract infection (UTI). Clonal groups, often with high levels of antimicrobial resistance, are a major component of the E. coli population that causes human UTI. While little is known about the population structure of E. coli that causes UTI in dogs, there is evidence that dogs and humans can share fecal strains of E. coli and that human-associated strains can cause disease in dogs. In order to better characterize the E. coli strains that cause canine UTI, we analyzed 295 E. coli isolates obtained from canine urine samples from five veterinary diagnostic laboratories and analyzed their multilocus sequence types, phenotypic and genotypic antimicrobial resistance profiles, and virulence-associated gene repertoires. Sequence type 372 (ST372), an infrequent human pathogen, was the predominant sequence type in dogs at all locations. Extended-spectrum beta lactamase-producing isolates with blaCTX-M genes were uncommon in canine isolates but when present were often associated with sequence types that have been described in human infections. This provides support for occasional cross-host species sharing of strains that cause extraintestinal disease and highlights the importance of understanding the role of companion animals in the overall transmission patterns of extraintestinal pathogenic E. coli. PMID- 29997201 TI - Preventable Patient Harm: a Multidisciplinary, Bundled Approach to Reducing Clostridium difficile Infections While Using a Glutamate Dehydrogenase/Toxin Immunochromatographic Assay/Nucleic Acid Amplification Test Diagnostic Algorithm. AB - Health care facility-onset Clostridium difficile infections (HO-CDI) are an important national problem, causing increased morbidity and mortality. HO-CDI is an important metric for the Center for Medicare and Medicaid Service's (CMS) performance measures. Hospitals that fall into the worst-performing quartile in preventing hospital-acquired infections, including HO-CDI, may lose millions of dollars in reimbursement. Under pressure to reduce CDI and without a clear optimal method for C. difficile detection, health care facilities are questioning how best to use highly sensitive nucleic acid amplification tests (NAATs) to aid in the diagnosis of CDI. Our institution has used a two-step glutamate dehydrogenase (GDH)/toxin immunochromatographic assay/NAAT algorithm since 2009. In 2016, our institution set an organizational goal to reduce our CDI rates by 10% by July 2017. We achieved a statistically significant reduction of 42.7% in our HO-CDI rate by forming a multidisciplinary group to implement and monitor eight key categories of infection prevention interventions over a period of 13 months. Notably, we achieved this reduction without modifying our laboratory algorithm. Significant reductions in CDI rates can be achieved without altering sensitive laboratory testing methods. PMID- 29997202 TI - Agreement between Parallel Canine Blood and Urine Cultures: Is Urine Culture the Poor Man's Blood Culture? AB - Bloodstream infections are a significant cause of morbidity and mortality in critically ill dogs, but due to cost and difficulties in sample acquisition, blood cultures are infrequently obtained. In ill dogs, urine cultures may be recommended as surrogates for blood cultures. In order to determine the outcome agreement between parallel urine and blood cultures, we retrospectively analyzed parallel blood and urine specimens submitted for culture from dogs at the NC State Veterinary Hospital between 2011 and 2016. Positive cultures were reported from 15% of the submitted blood specimens and 23% of the submitted urine specimens. A total of 295 urine and blood samples were submitted in parallel, with positive growth demonstrated in 14 concordant and five discordant pairs. A kappa statistic comparing blood and urine culture outcomes was 0.266 (fair) when all parallel growth was included, including concordant and discordant results, and 0.170 (poor) when restricted to parallel concordant growth. The sensitivity of urine to reflect concordant bloodstream bacterial organisms was 30%, with a specificity of 87%. The positive and negative predictive values were 30% and 88%, respectively. Of dogs with both specimens positive on bacterial culture, 7 of 7 (100%) with suspected urogenital infection sources were concordant. All dogs with discordant bloodstream and urinary infections were immunosuppressed. Urinary coagulase-positive Staphylococcus isolates were most likely to be concordant with bloodstream infections. In conclusion, we found that urine culture is neither a substitute nor a screen for blood culture. Blood cultures should be performed in any potentially septic animal, especially those that are considered immunosuppressed. PMID- 29997204 TI - Regulatory Role of the Morbillivirus Attachment Protein Head-to-Stalk Linker Module in Membrane Fusion Triggering. AB - Morbillivirus (e.g., measles virus [MeV] and canine distemper virus [CDV]) host cell entry is coordinated by two interacting envelope glycoproteins, namely, an attachment (H) protein and a fusion (F) protein. The ectodomain of H proteins consists of stalk, connector, and head domains that assemble into functional noncovalent dimer-of-dimers. The role of the C-terminal module of the H-stalk domain (termed linker) and the connector, although putatively able to assume flexible structures and allow receptor-induced structural rearrangements, remains largely unexplored. Here, we carried out a nonconservative mutagenesis scan analysis of the MeV and CDV H-linker/connector domains. Our data demonstrated that replacing isoleucine 146 in H-linker (H-I146) with any charged amino acids prevented virus-mediated membrane fusion activity, despite proper trafficking of the mutants to the cell surface and preserved binding efficiency to the SLAM/CD150 receptor. Nondenaturing electrophoresis revealed that these charged amino acid changes led to the formation of irregular covalent H tetramers rather than functional dimer-of-dimers formed when isoleucine or other hydrophobic amino acids were present at residue position 146. Remarkably, we next demonstrated that covalent H tetramerization per se was not the only mechanism preventing F activation. Indeed, the neutral glycine mutant (H-I146G), which exhibited strong covalent tetramerization propensity, maintained limited fusion promotion activity. Conversely, charged H-I146 mutants, which additionally carried alanine substitution of natural cysteines (H-C139A and H-C154A) and thus were unable to form covalently linked tetramers, were fusion activation defective. Our data suggest a dual regulatory role of the hydrophobic residue at position 146 of the morbillivirus head-to-stalk H-linker module: securing the assembly of productive dimer-of-dimers and contributing to receptor-induced F-triggering activity.IMPORTANCE MeV and CDV remain important human and animal pathogens. Development of antivirals may significantly support current global vaccination campaigns. Cell entry is orchestrated by two interacting glycoproteins (H and F). The current hypothesis postulates that tetrameric H ectodomains (composed of stalk, connector, and head domains) undergo receptor-induced rearrangements to productively trigger F; these conformational changes may be regulated by the H stalk C-terminal module (linker) and the following connector domain. Mutagenesis scan analysis of both microdomains revealed that replacing amino acid 146 in the H-linker region with nonhydrophobic residues produced covalent H tetramers which were compromised in triggering membrane fusion activity. However, these mutant proteins retained their ability to traffic to the cell surface and to bind to the virus receptor. These data suggest that the morbillivirus linker module contributes to the folding of functional pre-F-triggering H tetramers. Furthermore, such structures might be critical to convert receptor engagement into F activation. PMID- 29997203 TI - Characterization of the Plasmacytoid Dendritic Cell Response to Transmitted/Founder and Nontransmitted Variants of HIV-1. AB - Human immunodeficiency virus type 1 (HIV-1) infection often arises from a single transmitted/founder (TF) viral variant among a large pool of viruses in the quasispecies in the transmitting partner. TF variants are typically nondominant in blood and genital secretions, indicating that they have unique traits. The plasmacytoid dendritic cell (pDC) is the primary alpha interferon (IFN-alpha) producing cell in response to viral infections and is rapidly recruited to the female genital tract upon exposure to HIV-1. The impact of pDCs on transmission is unknown. We investigated whether evasion of pDC responses is a trait of TF viruses. pDCs from healthy donors were stimulated in vitro with a panel of 20 HIV 1 variants, consisting of one TF variant and three nontransmitted (NT) variants each from five transmission-linked donor pairs, and secretion of IFN-alpha and tumor necrosis factor alpha (TNF-alpha) was measured by enzyme-linked immunosorbent assay (ELISA). No significant differences in cytokine secretion in response to TF and NT viruses were observed, despite a trend toward enhanced IFN alpha and TNF-alpha production in response to TF viruses. NT viruses demonstrated polarization toward production of either IFN-alpha or TNF-alpha, indicating possible dysregulation. Also, for NT viruses, IFN-alpha secretion was associated with increased resistance of the virus to inactivation by IFN-alpha in vitro, suggesting in vivo evolution. Thus, TF viruses do not appear to preferentially subvert pDC activation compared to that with nontransmitted HIV-1 variants. pDCs may, however, contribute to the in vivo evolution of HIV-1.IMPORTANCE The plasmacytoid dendritic cell (pDC) is the first cell type recruited to the site of HIV-1 exposure; however, its contribution to the viral bottleneck in HIV-1 transmission has not been explored previously. We hypothesized that transmitted/founder viruses are able to avoid the pDC response. In this study, we used previously established donor pair-linked transmitted/founder and nontransmitted (or chronic) variants of HIV-1 to stimulate pDCs. Transmitted/founder HIV-1, instead of suppressing pDC responses, induced IFN alpha and TNF-alpha secretion to levels comparable to those induced by viruses from the transmitting partner. We noted several unique traits of chronic viruses, including polarization between IFN-alpha and TNF-alpha production as well as a strong relationship between IFN-alpha secretion and the resistance of the virus to neutralization. These data rule out the possibility that TF viruses preferentially suppress pDCs in comparison to the pDC response to nontransmitted HIV variants. pDCs may, however, be important drivers of viral evolution in vivo. PMID- 29997205 TI - Transduction with Lentiviral Vectors Altered the Expression Profile of Host MicroRNAs. AB - RNA interference (RNAi) is widely used in gene knockdown analysis and as a tool to screen host genes involved in viral infection. Owing to the limitations of transducing cells with synthetic small interfering RNAs (siRNAs), lentiviral short hairpin RNA (shRNA) vectors are more widely used. However, we found that stable transduction with lentiviral shRNA vectors inhibited hepatitis C virus (HCV) propagation in human hepatoma cells. We found by microRNA (miRNA) microarray analysis that this inhibition was induced by the alteration of host miRNA expression. In addition to one miRNA (miR-196b-5p) previously reported to be involved in HCV infection, other miRNAs (miR-216a-5p, -216b-5p, 217, and -30b 5p) were found to influence HCV infection in this study. Further studies suggested that this effect was independent of the transcription of shRNAs. The lentiviral vector itself and the integration site of the lentiviral vector might determine the change in miRNA expression. Moreover, the upregulation of JUN contributed to the dysregulation of miR-216a-5p, -216b-5p, and -217 in stably transduced cells. Although the changes in miRNA expression were beneficial for inhibiting HCV infection in our study, this off-target effect should be considered when transduction with lentiviral vectors is performed for other purposes, especially in therapy.IMPORTANCE We found that stable transduction with lentiviral shRNA was able to nonspecifically inhibit HCV infection by the dysregulation of host miRNAs. Previous studies showed that the overexpression of shRNAs oversaturated the host miRNA pathways to inhibit HCV infection. In contrast, the miRNA machinery was not affected in our study. Knockout studies suggested that the nonspecific effect was independent of the transcription of shRNAs. The lentiviral vector itself and the integration sites in the host genome determined the changes in miRNAs. Stable transduction with lentiviral vectors was able to increase the expression of JUN, which in turn upregulated miR-216a-5p, miR-216b-5p, and miR-217. miR-216a-5p and miR-216b-5p might inhibit HCV by suppressing the host autophagic machinery. Our study suggested a novel nonspecific effect of lentiviral vectors, and this side effect should be considered when transduction with lentiviral vectors is performed for other purposes, especially in therapy. PMID- 29997206 TI - Mutation W222L at the Receptor Binding Site of Hemagglutinin Could Facilitate Viral Adaption from Equine Influenza A(H3N8) Virus to Dogs. AB - An outbreak of respiratory disease caused by the equine-origin influenza A(H3N8) virus was first detected in dogs in 2004 and since then has been enzootic among dogs. Currently, the molecular mechanisms underlying host adaption of this virus from horses to dogs is unknown. Here, we have applied quantitative binding, growth kinetics, and immunofluorescence analyses to elucidate these mechanisms. Our findings suggest that a substitution of W222L in the hemagglutinin of the equine-origin A(H3N8) virus facilitated its host adaption to dogs. This mutation increased binding avidity of the virus specifically to receptor glycans with N glycolylneuraminic acid (Neu5Gc) and sialyl Lewis X (SLeX) motifs. We have demonstrated these motifs are abundantly located in the submucosal glands of dog trachea. Our findings also suggest that in addition to the type of glycosidic linkage (e.g., alpha2,3-linkage or alpha2,6-linkage), the type of sialic acid (Neu5Gc or 5-N-acetyl neuraminic acid) and the glycan substructure (e.g., SLeX) also play an important role in host tropism of influenza A viruses.IMPORTANCE Influenza A viruses (IAVs) cause a significant burden on human and animal health, and mechanisms for interspecies transmission of IAVs are far from being understood. Findings from this study suggest that an equine-origin A(H3N8) IAV with mutation W222L at its hemagglutinin increased binding to canine-specific receptors with sialyl Lewis X and Neu5Gc motifs and, thereby, may have facilitated viral adaption from horses to dogs. These findings suggest that in addition to the glycosidic linkage (e.g., alpha2,3-linked and alpha2,6-linked), the substructure in the receptor saccharides (e.g., sialyl Lewis X and Neu5Gc) could present an interspecies transmission barrier for IAVs and drive viral mutations to overcome such barriers. PMID- 29997207 TI - Human Cytomegalovirus Tropism Modulator UL148 Interacts with SEL1L, a Cellular Factor That Governs Endoplasmic Reticulum-Associated Degradation of the Viral Envelope Glycoprotein gO. AB - UL148 is a viral endoplasmic reticulum (ER)-resident glycoprotein that contributes to human cytomegalovirus (HCMV) cell tropism. The influence of UL148 on tropism correlates with its potential to promote the expression of glycoprotein O (gO), a viral envelope glycoprotein that participates in a heterotrimeric complex with glycoproteins H and L that is required for infectivity. In an effort to gain insight into the mechanism, we used mass spectrometry to identify proteins that coimmunoprecipitate from infected cells with UL148. This approach led us to identify an interaction between UL148 and SEL1L, a factor that plays key roles in ER-associated degradation (ERAD). In pulse-chase experiments, gO was less stable in cells infected with UL148-null mutant HCMV than during wild-type infection, suggesting a potential functional relevance for the interaction with SEL1L. To investigate whether UL148 regulates gO abundance by influencing ERAD, small interfering RNA (siRNA) silencing of either SEL1L or its partner, Hrd1, was carried out in the context of infection. Knockdown of these ERAD factors strongly enhanced levels of gO but not other viral glycoproteins, and the effect was amplified in the presence of UL148. Furthermore, pharmacological inhibition of ERAD showed similar results. Silencing of SEL1L during infection also stabilized an interaction of gO with the ER lectin OS-9, which likewise suggests that gO is an ERAD substrate. Taken together, our results identify an intriguing interaction of UL148 with the ERAD machinery and demonstrate that gO behaves as a constitutive ERAD substrate during infection. These findings have implications for understanding the regulation of HCMV cell tropism.IMPORTANCE Viral glycoproteins in large part determine the cell types that an enveloped virus can infect and hence play crucial roles in transmission and pathogenesis. The glycoprotein H/L heterodimer (gH/gL) is part of the conserved membrane fusion machinery that all herpesviruses use to enter cells. In human cytomegalovirus (HCMV), gH/gL participates in alternative complexes in virions, one of which is a trimer of gH/gL with glycoprotein O (gO). Here, we show that gO is constitutively degraded during infection by the endoplasmic reticulum-associated degradation (ERAD) pathway and that UL148, a viral factor that regulates HCMV cell tropism, interacts with the ERAD machinery and slows gO decay. Since gO is required for cell-free virus to enter new host cells but dispensable for cell-associated spread that resists antibody neutralization, our findings imply that the posttranslational instability of a viral glycoprotein provides a basis for viral mechanisms to modulate tropism and spread. PMID- 29997208 TI - Expression of the Vaccinia Virus Antiapoptotic F1 Protein Is Blocked by Protein Kinase R in the Absence of the Viral E3 Protein. AB - Poxviruses encode many proteins with the ability to regulate cellular signaling pathways. One such protein is the vaccinia virus innate immunity modulator E3. Multiple functions have been ascribed to E3, including modulating the cellular response to double-stranded RNA, inhibiting the NF-kappaB and IRF3 pathways, and dampening apoptosis. Apoptosis serves as a powerful defense against damaged and unwanted cells and is an effective defense against viral infection; many viruses therefore encode proteins that prevent or delay apoptosis. Here, we present data indicating that E3 does not directly inhibit the intrinsic apoptotic pathway; instead, it suppresses apoptosis indirectly by stimulating expression of the viral F1 apoptotic inhibitor. Our data demonstrate that E3 promotes F1 expression by blocking activation of the double-stranded RNA-activated protein kinase R (PKR). F1 mRNA is present in cells infected with E3-null virus, but the protein product does not detectably accumulate, suggesting a block at the translational level. We also show that two 3' coterminal transcripts span the F1 open reading frame (ORF), a situation previously described for the vaccinia virus mRNAs encoding the J3 and J4 proteins. One of these is a conventional monocistronic transcript of the F1L gene, while the other arises by read-through transcription from the upstream F2L gene and does not give rise to appreciable levels of F1 protein.IMPORTANCE Previous studies have shown that E3-deficient vaccinia virus triggers apoptosis of infected cells. Our study demonstrates that this proapoptotic phenotype stems, at least in part, from the failure of the mutant virus to produce adequate quantities of the viral F1 protein, which acts at the mitochondria to directly block apoptosis. Our data establish a regulatory link between the vaccinia virus proteins that suppress the innate response to double stranded RNA and those that block the intrinsic apoptotic pathway. PMID- 29997209 TI - Pol-Driven Replicative Capacity Impacts Disease Progression in HIV-1 Subtype C Infection. AB - CD8+ T cell-mediated escape mutations in Gag can reduce HIV-1 replication capacity (RC) and alter disease progression, but less is known about immune mediated attenuation in other HIV-1 proteins. We generated 487 recombinant viruses encoding RT-integrase from individuals with chronic (n = 406) and recent (n = 81) HIV-1 subtype C infection and measured their in vitro RC using a green fluorescent protein (GFP) reporter T cell assay. In recently infected individuals, reverse transcriptase (RT)-integrase-driven RC correlated significantly with viral load set point (r = 0.25; P = 0.03) and CD4+ T cell decline (P = 0.013). Moreover, significant associations between RT integrase driven RC and viral load (r = 0.28; P < 0.0001) and CD4+ T cell count (r = -0.29; P < 0.0001) remained in chronic infection. In early HIV infection, host expression of the protective HLA-B*81 allele was associated with lower RC (P = 0.05), as was expression of HLA-B*07 (P = 0.02), suggesting early immune-driven attenuation of RT-integrase by these alleles. In chronic infection, HLA-A*30:09 (in linkage disequilibrium with HLA-B*81) was significantly associated with lower RC (P = 0.05), and all 6 HLA-B alleles with the lowest RC measurements represented protective alleles, consistent with long-term effects of host immune pressures on lowering RT-integrase RC. The polymorphisms V241I, I257V, P272K, and E297K in reverse transcriptase and I201V in integrase, all relatively uncommon polymorphisms occurring in or adjacent to optimally described HLA-restricted cytotoxic T-lymphocyte epitopes, were associated with reduced RC. Together, our data suggest that RT-integrase-driven RC is clinically relevant and provide evidence that immune-driven selection of mutations in RT-integrase can compromise RC.IMPORTANCE Identification of viral mutations that compromise HIV's ability to replicate may aid rational vaccine design. However, while certain escape mutations in Gag have been shown to reduce HIV replication and influence clinical progression, less is known about the consequences of mutations that naturally arise in other HIV proteins. Pol is a highly conserved protein, but the impact of Pol function on HIV disease progression is not well defined. Here, we generated recombinant viruses using the RT-integrase region of Pol derived from HIV-1C infected individuals with recent and chronic infection and measured their ability to replicate in vitro We demonstrate that RT-integrase-driven replication ability significantly impacts HIV disease progression. We further show evidence of immune mediated attenuation in RT-integrase and identify specific polymorphisms in RT integrase that significantly decrease HIV-1 replication ability, suggesting which Pol epitopes could be explored in vaccine development. PMID- 29997210 TI - Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity. AB - Type I interferons (IFNs), as major components of the innate immune system, play a vital role in host resistance to a variety of pathogens. Canonical signaling mediated by type I IFNs activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway through binding to the IFN alpha/beta receptor (IFNAR), resulting in transcription of IFN-stimulated genes (ISGs). However, viruses have evolved multiple strategies to evade this process. Here, we report that herpes simplex virus 1 (HSV-1) ubiquitin-specific protease (UL36USP) abrogates the type I IFN-mediated signaling pathway independent of its deubiquitinase (DUB) activity. In this study, ectopically expressed UL36USP inhibited IFN-beta-induced activation of ISRE promoter and transcription of ISGs, and overexpression of UL36USP lacking DUB activity did not influence this effect. Furthermore, UL36USP was demonstrated to antagonize IFN-beta-induced activation of JAKs and STATs via specifically binding to the IFNAR2 subunit and blocking the interaction between JAK1 and IFNAR2. More importantly, knockdown of HSV-1 UL36USP restored the formation of JAK1-IFNAR2 complex. These findings underline the roles of UL36USP-IFNAR2 interaction in counteracting the type I IFN-mediated signaling pathway and reveal a novel evasion mechanism of antiviral innate immunity by HSV 1.IMPORTANCE Type I IFNs mediate transcription of numerous antiviral genes, creating a remarkable antiviral state in the host. Viruses have evolved various mechanisms to evade this response. Our results indicated that HSV-1 encodes a ubiquitin-specific protease (UL36USP) as an antagonist to subvert type I IFN mediated signaling. UL36USP was identified to significantly inhibit IFN-beta induced signaling independent of its deubiquitinase (DUB) activity. The underlying mechanism of UL36USP antagonizing type I IFN-mediated signaling was to specifically bind with IFNAR2 and disassociate JAK1 from IFNAR2. For the first time, we identify UL36USP as a crucial suppressor for HSV-1 to evade type I IFN mediated signaling. Our findings also provide new insights into the innate immune evasion by HSV-1 and will facilitate our understanding of host-virus interplay. PMID- 29997212 TI - Engineered Oncolytic Poliovirus PVSRIPO Subverts MDA5-Dependent Innate Immune Responses in Cancer Cells. AB - We are pursuing cancer immunotherapy with a neuro-attenuated recombinant poliovirus, PVSRIPO. PVSRIPO is the live attenuated type 1 (Sabin) poliovirus vaccine carrying a heterologous internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). Intratumoral infusion of PVSRIPO is showing promise in the therapy of recurrent WHO grade IV malignant glioma (glioblastoma), a notoriously treatment-refractory cancer with dismal prognosis. PVSRIPO exhibits profound cytotoxicity in infected neoplastic cells expressing the poliovirus receptor CD155. In addition, it elicits intriguing persistent translation and replication, giving rise to sustained type I interferon (IFN)-dominant proinflammatory stimulation of antigen-presenting cells. A key determinant of the inflammatory footprint generated by neoplastic cell infection and its role in shaping the adaptive response after PVSRIPO tumor infection is the virus's inherent relationship to the host's innate antiviral response. In this report, we define subversion of innate host immunity by PVSRIPO, enabling productive viral translation and cytopathogenicity with extremely low multiplicities of infection in the presence of an active innate antiviral IFN response.IMPORTANCE Engaging innate antiviral responses is considered key for instigating tumor-antigen specific antitumor immunity with cancer immunotherapy approaches. However, they are a double-edged sword for attempts to enlist viruses in such approaches. In addition to their role in the transition from innate to adaptive immunity, innate antiviral IFN responses may intercept the viral life cycle in cancerous cells, prevent viral cytopathogenicity, and restrict viral spread. This has been shown to reduce overall antitumor efficacy of several proposed oncolytic virus prototypes, presumably by limiting direct cell killing and the ensuing inflammatory profile within the infected tumor. In this report, we outline how an unusual recalcitrance of polioviruses toward innate antiviral responses permits viral cytotoxicity and propagation in neoplastic cells, combined with engaging active innate antiviral IFN responses. PMID- 29997211 TI - Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells. AB - Human immunodeficiency virus type 1 (HIV-1) displays the unique ability to infect nondividing cells. The capsid of HIV-1 is the viral determinant for viral nuclear import. To understand the cellular factors involved in the ability of HIV-1 to infect nondividing cells, we sought to find capsid mutations that allow the virus to infect dividing but not nondividing cells. Because the interaction of capsid with the nucleoporin protein 153 (Nup153) is important for nuclear import of HIV 1, we solved new crystal structures of hexameric HIV-1 capsid in complex with a Nup153-derived peptide containing a phenylalanine-glycine repeat (FG repeat), which we used to guide structure-based mutagenesis of the capsid-binding interface. HIV-1 viruses with mutations in these capsid residues were tested for their ability to infect dividing and nondividing cells. HIV-1 viruses with capsid N57 substitutions infected dividing but not nondividing cells. Interestingly, HIV 1 viruses with N57 mutations underwent reverse transcription but not nuclear translocation. The mutant capsids also lost the ability to interact with Nup153 and CPSF6. The use of small molecules PF74 and BI-2 prevented the interaction of FG-containing nucleoporins (Nups), such as Nup153, with the HIV-1 core. Analysis of integration sites in HIV-1 viruses with N57 mutations revealed diminished integration into transcriptionally active genes in a manner resembling that of HIV-1 in CPSF6 knockout cells or that of HIV-1-N74D. The integration pattern of the N57 mutant HIV-1 can be explained by loss of capsid interaction with CPSF6, whereas capsid interaction with Nup153 is required for HIV-1 to infect nondividing cells. Additionally, the observed viral integration profiles suggested that integration site selection is a multiparameter process that depends upon nuclear factors and the state of the cellular chromatin.IMPORTANCE One of the key advantages that distinguish lentiviruses, such as HIV-1, from all other retroviruses is its ability to infect nondividing cells. Interaction of the HIV-1 capsid with Nup153 and CPSF6 is important for nuclear entry and integration; however, the contribution of each of these proteins to nuclear import and integration is not clear. Using genetics, we demonstrated that these proteins contribute to different processes: Nup153 is essential for the HIV-1 nuclear import in nondividing cells, and CPSF6 is important for HIV-1 integration. In addition, nuclear factors such as CPSF6 and the state of the chromatin are known to be important for integration site selection; nevertheless, the preferential determinant influencing integration site selection is not known. This work demonstrates that integration site selection is a multiparameter process that depends upon nuclear factors and the state of the cellular chromatin. PMID- 29997213 TI - Cell-Derived Viral Genes Evolve under Stronger Purifying Selection in Rhadinoviruses. AB - Like many other large double-stranded DNA (dsDNA) viruses, herpesviruses are known to capture host genes to evade host defenses. Little is known about the detailed natural history of such genes, nor do we fully understand their evolutionary dynamics. A major obstacle is that they are often highly divergent, maintaining very low sequence similarity to host homologs. Here we use the herpesvirus genus Rhadinovirus as a model system to develop an analytical approach that combines complementary evolutionary and bioinformatic techniques, offering results that are both detailed and robust for a range of genes. Using a systematic phylogenetic strategy, we identify the original host lineage of viral genes with high confidence. We show that although host immunomodulatory genes evolve rapidly compared to other host genes, they undergo a clear increase in purifying selection once captured by a virus. To characterize this shift in detail, we developed a novel technique to identify changes in selection pressure that can be attributable to particular domains. These findings will inform us on how viruses develop strategies to evade the immune system, and our synthesis of techniques can be reapplied to other viruses or biological systems with similar analytical challenges.IMPORTANCE Viruses and hosts have been shown to capture genes from one another as part of the evolutionary arms race. Such genes offer a natural experiment on the effects of evolutionary pressure, since the same gene exists in vastly different selective environments. However, sequences of viral homologs often bear little similarity to the original sequence, complicating the reconstruction of their shared evolutionary history with host counterparts. In this study, we use a genus of herpesviruses as a model system to comprehensively investigate the evolution of host-derived viral genes, using a synthesis of genomics, phylogenetics, selection analysis, and nucleotide and amino acid modeling. PMID- 29997214 TI - Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection. AB - Elucidating the structural basis of antibody (Ab) gene usage and affinity maturation of vaccine-induced Abs can inform the design of immunogens for inducing desired Ab responses in HIV vaccine development. Analyses of monoclonal Abs (MAbs) encoded by the same immunoglobulin genes at different stages of maturation can help to elucidate the maturation process. We have analyzed four human anti-V3 MAbs with the same VH1-3*01 and VL3-10*01 gene usage. Two MAbs, TA6 and TA7, were developed from a vaccinee in the HIV vaccine phase I trial DP6-001 with a polyvalent DNA prime/protein boost regimen, and two others, 311-11D and 1334, were developed from HIV-infected patients. The somatic hypermutation (SHM) rates in VH of vaccine-induced MAbs are lower than in chronic HIV infection induced MAbs, while those in VL are comparable. Crystal structures of the antigen binding fragments (Fabs) in complex with V3 peptides show that these MAbs bind the V3 epitope with a new cradle-binding mode and that the V3 beta-hairpin lies along the antigen-binding groove, which consists of residues from both heavy and light chains. Residues conserved from the germ line sequences form specific binding pockets accommodating conserved structural elements of the V3 crown hairpin, predetermining the Ab gene selection, while somatically mutated residues create additional hydrogen bonds, electrostatic interactions, and van der Waals contacts, correlating with an increased binding affinity. Our data provide a unique example of germ line sequences determining the primordial antigen-binding sites and SHMs correlating with affinity maturation of Abs induced by vaccine and natural HIV infection.IMPORTANCE Understanding the structural basis of gene usage and affinity maturation for anti-HIV-1 antibodies may help vaccine design and development. Antibodies targeting the highly immunogenic third variable loop (V3) of HIV-1 gp120 provide a unique opportunity for detailed structural investigations. By comparing the sequences and structures of four anti-V3 MAbs at different stages of affinity maturation but of the same V gene usage, two induced by vaccination and another two by chronic infection, we provide a fine example of how germ line sequence determines the essential elements for epitope recognition and how affinity maturation improves the antibody's recognition of its epitope. PMID- 29997215 TI - In vivo labelling of adenovirus DNA identifies chromatin anchoring and biphasic genome replication. AB - Adenoviruses are DNA viruses with a lytic infection cycle. Following the fate of incoming as well as recently replicated genomes during infections is a challenge. In this study we used a bacterial partitioning system based on the AnchOR3 technology to establish a versatile in vivo imaging system for adenoviral genomes. This system allows the visualization of both individual incoming and newly replicated genomes in real time in living cells. We demonstrate that incoming adenoviral genomes are attached to condensed cellular chromatin during mitosis, facilitating the equal distribution of viral genomes in daughter cells after cell division. We show that the formation of replication centers occurs in conjunction with in vivo genome replication and determined replication rates. Visualization of adenoviral DNA revealed that adenoviruses exhibit two kinetically distinct phases of genome replication. Low-level replication occurred during early replication, while high-level replication was associated with late replication phases. The transition between these phases occurred concomitantly with morphological changes of viral replication compartments and with the appearance of virus-induced post-replication (ViPR) bodies, identified by the nucleolar protein Mybbp1A. Taken together, our real time genome imaging system revealed hitherto uncharacterized features of adenoviral genomes in vivo This system is able to identify novel spatio-temporal aspects of the adenovirus life cycle and is potentially transferable to other viral systems with a double stranded DNA phase.IMPORTANCE Viruses must deliver their genomes to host cells to ensure replication and propagation. Characterizing the fate of viral genomes is crucial to understand the viral life cycle and the fate of virus-derived vector tools. Here we integrated the AnchOR3 system, an in vivo DNA tagging technology, into the adenoviral genome for real time genome detection. AnchOR3-tagging permitted the in vivo visualization of incoming genomes at the onset of infection and of replicated genomes at late phases of infection. Using this system, we show viral genome attachment to condensed host chromosomes during mitosis, identifying this mechanism as a mode of cellr-to-cell transfer. We characterize the spatio temporal organization of adenovirus replication and identify two kinetically distinct phases of viral genome replication. The AnchOR3 system is the first technique that allows the continuous visualization of adenoviral genomes during the entire virus life cycle, opening the way for further in-depth study. PMID- 29997217 TI - Murine Cytomegalovirus Protein pM91 Interacts with pM79 and Is Critical for Viral Late Gene Expression. AB - Viral gene expression is tightly regulated during cytomegalovirus (CMV) lytic replication, but the detailed mechanism of late gene transcription remains to be fully understood. Previous studies reported that six viral proteins (named viral transactivation factors, [vTFs]) supporting late gene expression were conserved in beta- and gamma-herpesviruses, but not in alpha-herpesviruses. Here, we performed coimmunopreciptation experiments to elucidate the organization of these six proteins in murine CMV. Our results showed that these proteins formed a complex by both direct and indirect interactions. Specifically, pM91 strongly bound to pM79 even in the absence of other vTFs. Similar to pM79, pM91 exhibited early-late expression kinetics, and localized within nuclear viral replication compartments during infection. Functional analysis was also performed using the pM91-deficient virus. Real-time PCR results revealed that abrogation of M91 expression markedly reduced viral late gene expression and progeny virus production without affecting viral DNA synthesis. Using mutagenesis, we found that residues E61, D62, D89, and D96 in pM91 were required for the pM91-pM79 interaction. Disruption of the interaction via E61A/D62A or D89A/D96A double mutation in the context of virus infection inhibited progeny virus production. Our data indicate that pM91 is a component of the viral late gene transcription factor complex, and the pM91-pM79 interaction is essential for viral late gene expression.IMPORTANCE Cytomegalovirus (CMV) infection is the leading cause of birth defects and causes morbidity and mortality in immunocompromised patients. The regulation of viral late gene transcription is not well elucidated, and understanding of this process benefits the development of novel therapeutics against CMV infection. This study (i) identified that six viral transactivation factors encoded by murine CMV form a complex; (ii) demonstrated that pM91 interacts with pM79, and that they colocalize in the nuclear viral replication compartments; (iii) confirmed that pM91 is critical for viral late gene expression but dispensable for viral DNA replication; and (iv) revealed that the pM91-pM79 interaction is required for progeny virus production. These findings give an explanation how CMV regulates late gene expression, and have important implications for the design of antiviral strategies. PMID- 29997216 TI - Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques. AB - Worldwide, nearly two million children are infected with human immunodeficiency virus (HIV), with breastfeeding accounting for the majority of contemporary HIV transmissions. Antiretroviral therapy (ART) has reduced HIV-related morbidity and mortality but is not curative. The main barrier to a cure is persistence of latent HIV in long-lived reservoirs. However, our understanding of the cellular and anatomic sources of the HIV reservoir during infancy and childhood is limited. Here, we developed a pediatric model of ART suppression in orally simian immunodeficiency virus (SIV)-infected rhesus macaque (RM) infants, with measurement of virus persistence in blood and tissues after 6 to 9 months of ART. Cross-sectional analyses were conducted to compare SIV RNA and DNA levels in adult and infant RMs naive to treatment and on ART. We demonstrate efficient viral suppression following ART initiation in SIV-infected RM infants with sustained undetectable plasma viral loads in the setting of heterogeneous penetration of ART into lymphoid and gastrointestinal tissues and low drug levels in the brain. We further show reduction in SIV RNA and DNA on ART in lymphoid tissues of both infant and adult RMs but stable (albeit low) levels of SIV RNA and DNA in the brains of viremic and ART-suppressed infants. Finally, we report a large contribution of naive CD4+ T cells to the total CD4 reservoir of SIV in blood and lymph nodes of ART-suppressed RM infants that differs from what we show in adults. These results reveal important aspects of HIV/SIV persistence in infants and provide insight into strategic targets for cure interventions in a pediatric population.IMPORTANCE While antiretroviral therapy (ART) can reduce HIV replication, the virus cannot be eradicated from an infected individual, and our incomplete understanding of HIV persistence in reservoirs greatly complicates the generation of a cure for HIV infection. Given the immaturity of the infant immune system, it is critically important to study HIV reservoirs specifically in this population. Here, we established a pediatric animal model to simulate breastfeeding transmission and study SIV reservoirs in rhesus macaque (RM) infants. Our study demonstrates that ART can be safely administered to infant RMs for prolonged periods and that it efficiently controls viral replication in this model. SIV persistence was shown in blood and tissues, with similar anatomic distributions of SIV reservoirs in infant and adult RMs. However, in the peripheral blood and lymph nodes, a greater contribution of the naive CD4+ T cells to the SIV reservoir was observed in infants than in adults. PMID- 29997219 TI - Deliberate self-poisoning by teenagers. PMID- 29997218 TI - Epstein-Barr Virus Nuclear Antigen 3C Facilitates Cell Proliferation by Regulating Cyclin D2. AB - Cell cycle regulation is one of the hallmarks of virus-mediated oncogenesis. Epstein-Barr virus (EBV)-induced lymphomas express a repertoire of essential viral latent proteins that regulate expression of cell cycle-related proteins to dysregulate this process, thereby facilitating the proliferation of infected cells. We now demonstrate that the essential EBV latent protein 3C (EBNA3C) stabilizes cyclin D2 to regulate cell cycle progression. More specifically, EBNA3C directly binds to cyclin D2 and they colocalize together in nuclear compartments. We show that EBNA3C regulates the promoter of cyclin D2 through cooperation with master transcription factor Bcl6 and enhances its stability by inhibiting its ubiquitin-dependent degradation. EBNA3C also promoted cell proliferation in the presence of cyclin D2, suggesting that cyclin D2 contributes to EBNA3C-mediated cell cycle progression. These results provide new clues as to the role of this essential viral latent protein and its ability to regulate expression of cellular factors, which drives the oncogenic process.IMPORTANCE Epstein-Barr virus (EBV) is the first identified human tumor virus and is associated with a range of human cancers. During EBV-induced lymphomas, the essential viral latent proteins modify the expression of cell cycle-related proteins to disturb the cell cycle process, thereby facilitating the proliferative process. The essential EBV nuclear antigen 3C (EBNA3C) plays an important role in EBV-mediated B-cell transformation. Here we show that EBNA3C stabilizes cyclin D2 to regulate cell cycle progression. More specifically, EBNA3C directly binds to cyclin D2, and they colocalize together in nuclear compartments. EBNA3C enhances cyclin D2 stability by inhibiting its ubiquitin dependent degradation and significantly promotes cell proliferation in the presence of cyclin D2. Our results provide novel insights into the function of EBNA3C on cell progression by regulating the cyclin D2 protein and raise the possibility of the development of new anticancer therapies against EBV-associated cancers. PMID- 29997220 TI - Intravital microscopy of collective invasion plasticity in breast cancer. AB - Cancer invasion programs are adaptive by switching between metastatic collective and single-cell dissemination; however, current intravital microscopy models for epithelial cancer in mice fail to reliably recreate such invasion plasticity. Using microimplantation of breast cancer spheroids into the murine mammary fat pad and live-cell monitoring, we show microenvironmental conditions and cytoskeletal adaptation during collective to single-cell transition in vivo E cadherin-expressing 4T1 and E-cadherin-negative MMT tumors both initiated collective invasion along stromal structures, reflecting invasion patterns in 3D organotypic culture and human primary ductal and lobular carcinoma. Collectively invading cells developed weakly oscillatory actin dynamics, yet provided zones for single-cell transitions with accentuated, more chaotic actin fluctuations. This identifies collective invasion in vivo as a dynamic niche and efficient source for single-cell release. PMID- 29997221 TI - High-risk chronic lymphocytic leukemia in the era of pathway inhibitors: integrating molecular and cellular therapies. AB - High-risk chronic lymphocytic leukemia (CLL) has been defined by clinical and/or genetic resistance (TP53 abnormalities) to treatment with chemoimmunotherapy (CIT). With the availability of pathway inhibitors (PIs), such as kinase inhibitors and BCL2 antagonists, the outlook of CIT-resistant patients has dramatically improved. Here, we propose a revision of the concept of high-risk CLL, driven by TP53 abnormalities and response to treatment with PI. CLL high risk-I, CIT-resistant is defined by clinically CIT-resistant disease with TP53 aberrations, but fully responsive to PI. This category is largely the domain of PI-based therapy, and cellular therapy (ie, allogeneic hematopoietic cell transplantation) remains an option only in selected patients with low individual procedure-related risk. In CLL high-risk-II, CIT- and PI-resistant, characterized by increasing exhaustion of pharmacological treatment possibilities, cellular therapies (including chimeric antigen receptor-engineered T cells) should be considered in patients eligible for these procedures. Moreover, molecular and cellular therapies are not mutually exclusive and could be used synergistically to exploit their full potential. PMID- 29997222 TI - Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies. AB - Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6% 88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633). PMID- 29997223 TI - Therapeutic vulnerability of multiple myeloma to MIR17PTi, a first-in-class inhibitor of pri-miR-17-92. AB - The microRNA (miRNA) cluster miR-17-92 is oncogenic and represents a valuable therapeutic target in c-MYC (MYC)-driven malignancies. Here, we developed novel LNA gapmeR antisense oligonucleotides (ASOs) to induce ribonuclease H-mediated degradation of MIR17HG primary transcripts and consequently prevent biogenesis of miR-17-92 miRNAs (miR-17-92s). The leading LNA ASO, MIR17PTi, impaired proliferation of several cancer cell lines (n = 48) established from both solid and hematologic tumors by on-target antisense activity, more effectively as compared with miR-17-92 inhibitors. By focusing on multiple myeloma (MM), we found that MIR17PTi triggers apoptosis via impairment of homeostatic MYC/miR-17 92 feed-forward loops (FFLs) in patient-derived MM cells and induces MYC dependent synthetic lethality. We show that alteration of a BIM-centered FFL is instrumental for MIR17PTi to induce cytotoxicity in MM cells. MIR17PTi exerts strong in vivo antitumor activity in nonobese diabetic severe combined immunodeficient mice bearing clinically relevant models of MM, with advantageous safety and pharmacokinetic profiles in nonhuman primates. Altogether, MIR17PTi is a novel pharmacological tool to be tested in early-phase clinical trials against MM and other MYC-driven malignancies. PMID- 29997224 TI - Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group. AB - Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; BCR-ABL1 like ALL) in children with National Cancer Institute (NCI) intermediate- or high risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either BCR-ABL1 (n = 6) or ETV6-RUNX1 (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including CRLF2 rearrangements (29.5% of Ph-like), ABL-class fusions (1.4%), JAK2 fusions (1.4%), an NTRK3 fusion (0.7%), and other sequence mutations (IL7R, KRAS, NRAS; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 +/- 3.6% vs 90.7 +/- 1.0%, P = .0022), with no difference in overall survival (93.2 +/- 2.4% vs 95.8 +/- 0.7%, P = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL. PMID- 29997226 TI - Large-Scale Phenome-Wide Association Study of PCSK9 Variants Demonstrates Protection Against Ischemic Stroke. AB - BACKGROUND: PCSK9 inhibition is a potent new therapy for hypercholesterolemia and cardiovascular disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. METHODS: We tested the association of the PCSK9 missense variant rs11591147 with predefined phenotypes and phenome-wide, in 337 536 individuals of British ancestry in the UK Biobank, with independent discovery and replication. Using a Bayesian statistical method, we leveraged phenotype correlations to evaluate the phenome-wide impact of PCSK9 inhibition with higher power at a finer resolution. RESULTS: The T allele of rs11591147 showed a protective effect on hyperlipidemia (odds ratio, 0.63+/-0.04; P=2.32*10-38), coronary heart disease (odds ratio, 0.73+/-0.09; P=1.05*10-6), and ischemic stroke (odds ratio, 0.61+/ 0.18; P=2.40*10-3) and was associated with increased type 2 diabetes mellitus risk adjusted for lipid-lowering medication status (odds ratio, 1.24+/-0.10; P=1.98*10-7). We did not observe associations with cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. Leveraging phenotype correlations, we observed evidence of a protective association with cerebral infarction and vascular occlusion. These results explore the effects of direct PCSK9 inhibition; off-target effects cannot be predicted using this approach. CONCLUSIONS: This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to LDL (low-density lipoprotein) cholesterol, atherosclerosis, and type 2 diabetes mellitus, suggesting that other effects are either small or absent. PMID- 29997227 TI - Managing Secondary Genomic Findings Associated With Arrhythmogenic Right Ventricular Cardiomyopathy: Case Studies and Proposal for Clinical Surveillance. PMID- 29997225 TI - Rho Guanine Nucleotide Exchange Factor ARHGEF17 Is a Risk Gene for Intracranial Aneurysms. AB - BACKGROUND: Intracranial aneurysm (IA) is usually a late-onset disease, affecting 1% to 3% of the general population and leading to life-threatening subarachnoid hemorrhage. Genetic susceptibility has been implicated in IAs, but the causative genes remain elusive. METHODS: We performed next-generation sequencing in a discovery cohort of 20 Chinese IA patients. Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency. We further examined the candidate variants in a multiethnic sample collection of 86 whole exome sequenced unsolved familial IA cases from 3 previously published studies. RESULTS: We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp (rs2298808) of ARHGEF17 was significantly associated with IA in our Chinese discovery cohort (P=7.3*10-4; odds ratio=7.34). It was subsequently replicated in Japanese familial IA patients (P=0.039; odds ratio=4.00; 95% confidence interval=0.832-14.8) and was associated with IA in the large Chinese sample collection comprising 832 sporadic IA-affected and 599 control individuals (P=0.041; odds ratio=1.51; 95% confidence interval=1.02-Inf). When combining the sequencing data of all familial IA patients from 4 different ethnicities (ie, Chinese, Japanese, European American, and French-Canadian), we identified a significantly increased mutation burden for ARHGEF17 (21/106 versus 11/306; P=8.1*10-7; odds ratio=6.6; 95% confidence interval=2.9-15.8) in cases as compared with controls. In zebrafish, arhgef17 was highly expressed in the brain blood vessel. arhgef17 knockdown caused blood extravasation in the brain region. Endothelial lesions were identified exclusively on cerebral blood vessels in the arhgef17-deficient zebrafish. CONCLUSIONS: Our results provide compelling evidence that ARHGEF17 is a risk gene for IA. PMID- 29997228 TI - PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) Status and Protection Against Ischemic Stroke: PheWAS, TreWAS, and More. PMID- 29997229 TI - Rare and Low-Frequency Variant of ARHGEF17 Is Associated With Intracranial Aneurysms. PMID- 29997231 TI - ZNF677 Suppresses Akt Phosphorylation and Tumorigenesis in Thyroid Cancer. AB - The zinc finger protein 677 (ZNF677) belongs to the zinc finger protein family, which possesses transcription factor activity by binding sequence-specific DNA. Previous studies have reported its downregulated by promoter methylation in non small cell lung cancer. However, its biological role and exact mechanism in human cancers, including thyroid cancer, remain unknown. In this study, we demonstrate that ZNF677 is frequently downregulated by promoter methylation in primary papillary thyroid cancers (PTC) and show that decreased expression of ZNF677 is significantly associated with poor patient survival. Ectopic expression of ZNF677 in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration, invasion, and tumorigenic potential in nude mice and induced cell-cycle arrest and apoptosis. Conversely, knockdown of ZNF677 promoted thyroid cancer cell proliferation and colony formation. ZNF677 exerted its tumor suppressor functions in thyroid cancer cells through transcriptional repression of two targets CDKN3 and HSPB1 (or HSP27), thereby inhibiting phosphorylation and activation of Akt via distinct mechanisms. Taken together, our data show that ZNF677 functions as a tumor suppressor and is frequently silenced via promoter methylation in thyroid cancer.Significance: These findings report a tumor suppressive role of the zinc-finger protein ZNF677 in primary papillary thyroid cancer through inhibition of Akt phosphorylation. Cancer Res; 78(18); 5216-28. (c)2018 AACR. PMID- 29997230 TI - Altered Cell-Cycle Control, Inflammation, and Adhesion in High-Risk Persistent Bronchial Dysplasia. AB - Persistent bronchial dysplasia is associated with increased risk of developing invasive squamous cell carcinoma (SCC) of the lung. In this study, we hypothesized that differences in gene expression profiles between persistent and regressive bronchial dysplasia would identify cellular processes that underlie progression to SCC. RNA expression arrays comparing baseline biopsies from 32 bronchial sites that persisted/progressed to 31 regressive sites showed 395 differentially expressed genes [ANOVA, FDR <= 0.05). Thirty-one pathways showed significantly altered activity between the two groups, many of which were associated with cell-cycle control and proliferation, inflammation, or epithelial differentiation/cell-cell adhesion. Cultured persistent bronchial dysplasia cells exhibited increased expression of Polo-like kinase 1 (PLK1), which was associated with multiple cell-cycle pathways. Treatment with PLK1 inhibitor induced apoptosis and G2-M arrest and decreased proliferation compared with untreated cells; these effects were not seen in normal or regressive bronchial dysplasia cultures. Inflammatory pathway activity was decreased in persistent bronchial dysplasia, and the presence of an inflammatory infiltrate was more common in regressive bronchial dysplasia. Regressive bronchial dysplasia was also associated with trends toward overall increases in macrophages and T lymphocytes and altered polarization of these inflammatory cell subsets. Increased desmoglein 3 and plakoglobin expression was associated with higher grade and persistence of bronchial dysplasia. These results identify alterations in the persistent subset of bronchial dysplasia that are associated with high risk for progression to invasive SCC. These alterations may serve as strong markers of risk and as effective targets for lung cancer prevention.Significance: Gene expression profiling of high-risk persistent bronchial dysplasia reveals changes in cell cycle control, inflammatory activity, and epithelial differentiation/cell-cell adhesion that may underlie progression to invasive SCC. Cancer Res; 78(17); 4971 83. (c)2018 AACR. PMID- 29997233 TI - Lumbar drains can affect CSF biomarker levels. PMID- 29997232 TI - Normal Breast-Derived Epithelial Cells with Luminal and Intrinsic Subtype Enriched Gene Expression Document Interindividual Differences in Their Differentiation Cascade. AB - Cell-type origin is one of the factors that determine molecular features of tumors, but resources to validate this concept are scarce because of technical difficulties in propagating major cell types of adult organs. Previous attempts to generate such resources to study breast cancer have yielded predominantly basal-type cell lines. We have created a panel of immortalized cell lines from core breast biopsies of ancestry-mapped healthy women that form ductal structures similar to normal breast in 3D cultures and expressed markers of major cell types, including the luminal-differentiated cell-enriched ERalpha-FOXA1-GATA3 transcription factor network. We have also created cell lines from PROCR (CD201)+/EpCAM- cells that are likely the "normal" counterpart of the claudin-low subtype of breast cancers. RNA-seq and PAM50-intrinsic subtype clustering identified these cell lines as the "normal" counterparts of luminal A, basal, and normal-like subtypes and validated via immunostaining with basal-enriched KRT14 and luminal-enriched KRT19. We further characterized these cell lines by flow cytometry for distribution patterns of stem/basal, luminal-progenitor, mature/differentiated, multipotent PROCR+ cells, and organogenesis-enriched epithelial/mesenchymal hybrid cells using CD44/CD24, CD49f/EpCAM, CD271/EpCAM, CD201/EpCAM, and ALDEFLUOR assays and E-cadherin/vimentin double staining. These cell lines showed interindividual heterogeneity in stemness/differentiation capabilities and baseline activity of signaling molecules such as NF-kappaB, AKT2, pERK, and BRD4. These resources can be used to test the emerging concept that genetic variations in regulatory regions contribute to widespread differences in gene expression in "normal" conditions among the general population and can delineate the impact of cell-type origin on tumor progression.Significance: In addition to providing a valuable resource for the breast cancer research community to investigate cell-type origin of different subtypes of breast cancer, this study highlights interindividual differences in normal breast, emphasizing the need to use "normal" cells from multiple sources as controls to decipher the effects of cancer-specific genomic aberrations. Cancer Res; 78(17); 5107-23. (c)2018 AACR. PMID- 29997234 TI - Membrane Fluidity Is Regulated Cell Nonautonomously by Caenorhabditis elegans PAQR-2 and Its Mammalian Homolog AdipoR2. AB - Maintenance of membrane properties is an essential aspect of cellular homeostasis of which the regulatory mechanisms remain mostly uncharacterized. In Caenorhabditis elegans, the PAQR-2 and IGLR-2 proteins act together as a plasma membrane sensor that responds to decreased fluidity by promoting fatty acid desaturation, hence restoring membrane fluidity. Here, we used mosaic analysis for paqr-2 and iglr-2, and tissue-specific paqr-2 expression, to show that membrane homeostasis is achieved cell nonautonomously. Specifically, we found that expression of paqr-2 in the hypodermis, gonad sheath cells, or intestine is sufficient to suppress systemic paqr-2 mutant phenotypes, including tail tip morphology, membrane fluidity in intestinal cells, cold and glucose intolerance, vitellogenin transport to the germline, germ cell development, and brood size. Finally, we show that the cell nonautonomous regulation of membrane homeostasis is conserved in human cells: HEK293 cells that express AdipoR2, a homolog of paqr 2, are able to normalize membrane fluidity in distant cells where AdipoR2 has been silenced. Finally, using C. elegans mutants and small interfering RNA against Delta9 stearoyl-CoA desaturase in HEK293 cells, we show that Delta9 desaturases are essential for the cell nonautonomous maintenance of membrane fluidity. We conclude that cells are able to share membrane components even when they are not in direct contact with each other, and that this contributes to the maintenance of membrane homeostasis in C. elegans and human cells. PMID- 29997236 TI - Involuntary sterilisation: we still need to guard against it. PMID- 29997237 TI - Differential long noncoding RNA expressions in peripheral blood mononuclear cells for detection of acute ischemic stroke. AB - Long noncoding RNAs (lncRNAs) have been highlighted to be involved in the pathological process of ischemic stroke (IS). The purpose of the present study was to investigate the expression profile of lncRNAs in peripheral blood mononuclear cells (PBMCs) of acute IS patients and to explore their utility as biomarkers of IS. Distinctive expression patterns of PBMC lncRNAs were identified by an lncRNA microarray and individual quantitative real-time PCR (qRT-PCR) in four independent sets for 206 IS, 179 healthy controls (HCs), and 55 patients with transient ischemic attack (TIA). A biomarker panel (lncRNA-based combination index) was established using logistic regression. LncRNA microarray analysis showed 70 up-regulated and 128 down-regulated lncRNAs in IS patients. Individual qRT-PCR validation demonstrated that three lncRNAs (linc-DHFRL1-4, SNHG15, and linc-FAM98A-3) were significantly up-regulated in IS patients compared with HCs and TIA patients. Longitudinal analysis of lncRNA expression up to 90 days after IS showed that linc-FAM98A-3 normalized to control levels by day 7, while SNHG15 remained increased, indicating the ability of lncRNAs to monitor IS dynamics. Receiver-operating characteristic (ROC) curve analysis showed that the lncRNA based combination index outperformed serum brain-derived neurotrophic factor (BDNF) and neurone-specific enolase (NSE) in distinguishing IS patients from TIA patients and HCs with areas under ROC curve of more than 0.84. Furthermore, the combination index increased significantly after treatment and was correlated with neurological deficit severity of IS. The panel of these altered lncRNAs was associated with acute IS and could serve as a novel diagnostic method. PMID- 29997238 TI - Brachypodium: A Monocot Grass Model Genus for Plant Biology. AB - The genus Brachypodium represents a model system that is advancing our knowledge of the biology of grasses, including small grains, in the postgenomics era. The most widely used species, Brachypodium distachyon, is a C3 plant that is distributed worldwide. B. distachyon has a small genome, short life cycle, and small stature and is amenable to genetic transformation. Due to the intensive and thoughtful development of this grass as a model organism, it is well-suited for laboratory and field experimentation. The intent of this review is to introduce this model system genus and describe some key outcomes of nearly a decade of research since the first draft genome sequence of the flagship species, B. distachyon, was completed. We discuss characteristics and features of B. distachyon and its congeners that make the genus a valuable model system for studies in ecology, evolution, genetics, and genomics in the grasses, review current hot topics in Brachypodium research, and highlight the potential for future analysis using this system in the coming years. PMID- 29997240 TI - Data-Driven Approach to Identify Subgroups of Heart Failure With Reduced Ejection Fraction Patients With Different Prognoses and Aldosterone Antagonist Response Patterns. AB - BACKGROUND: Patients with heart failure with reduced ejection fraction have a poor prognosis. The identification of subgroups with different outcomes and treatment response patterns may help to tailor strategies to each individual patient. We present an exploratory study of patients enrolled in the EMPHASIS-HF trial (Eplerenone in Patients With Systolic Heart Failure and Mild Symptoms) using latent class analysis with validation using the EPHESUS trial (Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular Dysfunction After Myocardial Infarction) to identify subgroups of patients with different prognosis and response to eplerenone therapy. METHODS AND RESULTS: Latent class analysis identifies mutually exclusive groups of individuals maximizing within group similarities and between-group differences. In the EMPHASIS-HF trial, 2279 heart failure with reduced ejection fraction patients were randomized to eplerenone or placebo and were characterized according to 18 clinical features. Subgroup definitions were applied to 6472 patients enrolled in the EPHESUS trial to validate observations. Event-free survival and effect of eplerenone on the composite of cardiovascular death and heart failure hospitalization were determined for each subgroup. Four subgroups were identified with significant differences in event-free survival (P=0.002). The subgroup C had the worst event free survival in both studies and was characterized by older age, lower body mass index, worse renal function, higher baseline potassium levels, high prevalence of anemia, diabetes mellitus, previous revascularization and higher rates of eplerenone discontinuation, and hyperkalemia during follow-up. Two subgroups (B and C) showed a poorer response to eplerenone in both studies and these groups shared common features such as lower body mass index and high prevalence of anemia. Clinical profiles, prognosis, and treatment response patterns of the 4 subgroups applied in EPHESUS trial presented similarities to those observed in EMPHASIS. CONCLUSIONS: Using a data-driven approach, we identified heart failure with reduced ejection fraction subgroups with significantly different prognoses and potentially different responses to eplerenone. However, these data should be regarded as hypothesis-generating and prospective validation is warranted, to assess the potential clinical implications of these subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00232180. PMID- 29997241 TI - Embracing the Long Road to Precision Medicine. PMID- 29997242 TI - Ectopic otoconial formation in the lagena of the pigeon inner ear. AB - The vertebrate inner ear contains vestibular receptors with dense crystals of calcium carbonate, the otoconia. The production and maintenance of otoconia is a delicate process, the perturbation of which can lead to severe vestibular dysfunction in humans. The details of these processes are not well understood. Here, we report the discovery of a new otoconial mass in the lagena of adult pigeons that was present in more than 70% of birds. Based on histological, tomographic and elemental analyses, we conclude that the structure likely represents an ectopically-formed otoconial assembly. Given its frequent natural occurrence, we suggest that the pigeon lagena is a valuable model system for investigating misregulated otoconial formation.This article has an associated First Person interview with the first author of the paper. PMID- 29997239 TI - Interorganelle Communication: Peroxisomal MALATE DEHYDROGENASE2 Connects Lipid Catabolism to Photosynthesis through Redox Coupling in Chlamydomonas. AB - Plants and algae must tightly coordinate photosynthetic electron transport and metabolic activities given that they often face fluctuating light and nutrient conditions. The exchange of metabolites and signaling molecules between organelles is thought to be central to this regulation but evidence for this is still fragmentary. Here, we show that knocking out the peroxisome-located MALATE DEHYDROGENASE2 (MDH2) of Chlamydomonas reinhardtii results in dramatic alterations not only in peroxisomal fatty acid breakdown but also in chloroplast starch metabolism and photosynthesis. mdh2 mutants accumulated 50% more storage lipid and 2-fold more starch than the wild type during nitrogen deprivation. In parallel, mdh2 showed increased photosystem II yield and photosynthetic CO2 fixation. Metabolite analyses revealed a >60% reduction in malate, together with increased levels of NADPH and H2O2 in mdh2 Similar phenotypes were found upon high light exposure. Furthermore, based on the lack of starch accumulation in a knockout mutant of the H2O2-producing peroxisomal ACYL-COA OXIDASE2 and on the effects of H2O2 supplementation, we propose that peroxisome-derived H2O2 acts as a regulator of chloroplast metabolism. We conclude that peroxisomal MDH2 helps photoautotrophs cope with nitrogen scarcity and high light by transmitting the redox state of the peroxisome to the chloroplast by means of malate shuttle- and H2O2-based redox signaling. PMID- 29997243 TI - Centrioles without microtubules: a new morphological type of centriole. AB - The centrosome is the organizing center of microtubules in the cell, the basis for the origin of cilia and flagella and a site for the concentration of a regulatory proteins multitude. The centrosome comprises two centrioles surrounded by pericentriolar material. Centrioles in the cells of different organisms can contain nine triplets, doublets or singlets of microtubules. Here, we show that in somatic cells of male wasp larvae Anisopteromalus calandrae, centrioles do not contain microtubules and are composed of nine electron-dense prongs, which together form a cogwheel structure. These microtubule-free centrioles can be the platform for procentriole formation and form microtubule-free cilia-like structures. In nymph and imago cells centrioles have a microtubule triplet structure. Our study describes how centriole structure differs in a development stage-dependent and a cell-type-dependent manner. The discovery of a centriole without microtubules casts a new light on the centriole formation process and the evolution of this organelle. PMID- 29997245 TI - Systematic review of drug effects in humans and models with surfactant-processing disease. AB - Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients. PMID- 29997246 TI - Bronchiectasis: a case-based approach to investigation and management. AB - Bronchiectasis is a chronic respiratory disease characterised by a syndrome of productive cough and recurrent respiratory infections due to permanent dilatation of the bronchi. Bronchiectasis represents the final common pathway of different disorders, some of which may require specific treatment. Therefore, promptly identifying the aetiology of bronchiectasis is recommended by the European Respiratory Society guidelines. The clinical history and high-resolution computed tomography (HRCT) features can be useful to detect the underlying causes. Despite a strong focus on this aspect of treatment a high proportion of patients remain classified as "idiopathic". Important underlying conditions that are treatable are frequently not identified for prolonged periods of time.The European Respiratory Society guidelines for bronchiectasis recommend a minimal bundle of tests for diagnosing the cause of bronchiectasis, consisting of immunoglobulins, testing for allergic bronchopulmonary aspergillosis and full blood count. Other testing is recommended to be conducted based on the clinical history, radiological features and severity of disease. Therefore it is essential to teach clinicians how to recognise the "clinical phenotypes" of bronchiectasis that require specific testing.This article will present the initial investigation and management of bronchiectasis focussing particularly on the HRCT features and clinical features that allow recognition of specific causes. PMID- 29997244 TI - LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells. AB - Information on protein-protein interactions (PPIs) is of critical importance for studying complex biological systems and developing therapeutic strategies. Here, we present a double-readout bioluminescence-based two-hybrid technology, termed LuTHy, which provides two quantitative scores in one experimental procedure when testing binary interactions. PPIs are first monitored in cells by quantification of bioluminescence resonance energy transfer (BRET) and, following cell lysis, are again quantitatively assessed by luminescence-based co-precipitation (LuC). The double-readout procedure detects interactions with higher sensitivity than traditional single-readout methods and is broadly applicable, for example, for detecting the effects of small molecules or disease-causing mutations on PPIs. Applying LuTHy in a focused screen, we identified 42 interactions for the presynaptic chaperone CSPalpha, causative to adult-onset neuronal ceroid lipofuscinosis (ANCL), a progressive neurodegenerative disease. Nearly 50% of PPIs were found to be affected when studying the effect of the disease-causing missense mutations L115R and ?L116 in CSPalpha with LuTHy. Our study presents a robust, sensitive research tool with high utility for investigating the molecular mechanisms by which disease-associated mutations impair protein activity in biological systems. PMID- 29997247 TI - Noninvasive ventilation in acute respiratory failure: which recipe for success? AB - Noninvasive positive-pressure ventilation (NPPV) to treat acute respiratory failure has expanded tremendously over the world in terms of the spectrum of diseases that can be successfully managed, the locations of its application and achievable goals.The turning point for the successful expansion of NPPV is its ability to achieve the same physiological effects as invasive mechanical ventilation with the avoidance of the life-threatening risks correlated with the use of an artificial airway.Cardiorespiratory arrest, extreme psychomotor agitation, severe haemodynamic instability, nonhypercapnic coma and multiple organ failure are absolute contraindications for NPPV. Moreover, pitfalls of NPPV reduce its rate of success; consistently, a clear plan of what to do in case of NPPV failure should be considered, especially for patients managed in unprotected setting. NPPV failure is likely to be reduced by the application of integrated therapeutic tools in selected patients handled by expert teams.In conclusion, NPPV has to be considered as a rational art and not just as an application of science, which requires the ability of clinicians to both choose case-by-case the best "ingredients" for a "successful recipe" (i.e. patient selection, interface, ventilator, interface, etc) and to avoid a delayed intubation if the ventilation attempt fails. PMID- 29997248 TI - Optogenetic stimulation of cochlear neurons activates the auditory pathway and restores auditory-driven behavior in deaf adult gerbils. AB - Cochlear implants partially restore hearing via direct electrical stimulation of spiral ganglion neurons (SGNs). However, spread of excitation from each electrode limits spectral coding. We explored the use of optogenetics to deliver spatially restricted and cell-specific excitation in the cochlea of adult Mongolian gerbils. Adeno-associated virus carrying the gene encoding the light-sensitive calcium translocating channelrhodopsin (CatCh) was injected into the cochlea of adult gerbils. SGNs in all cochlea turns showed stable and long-lasting CatCh expression, and electrophysiological recording from single SGNs showed that light stimulation up to few hundred Hertz induced neuronal firing. We characterized the light-induced activity in the auditory pathway by electrophysiological and behavioral analysis. Light- and sound-induced auditory brainstem responses showed similar kinetics and amplitude. In normal hearing adult gerbils, optical cochlear implants elicited stable optical auditory brainstem responses over a period of weeks. In normal hearing animals, light stimulation cued avoidance behavior that could be reproduced by subsequent acoustic stimulation, suggesting similar perception of light and acoustic stimuli. Neurons of the primary auditory cortex of normal hearing adult gerbils responded with changes in firing rates with increasing light intensity. In deaf adult gerbils, light stimulation generated auditory responses and cued avoidance behavior indicating partial restoration of auditory function. Our data show that optogenetic cochlear stimulation achieved good temporal fidelity with low light intensities in an adult rodent model, suggesting that optogenetics might be used to develop cochlear implants with improved restorative capabilities. PMID- 29997249 TI - TORC1 inhibition enhances immune function and reduces infections in the elderly. AB - Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant (P = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly. PMID- 29997250 TI - CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors. AB - Tumor cells engineered to express therapeutic agents have shown promise to treat cancer. However, their potential to target cell surface receptors specific to the tumor site and their posttreatment fate have not been explored. We created therapeutic tumor cells expressing ligands specific to primary and recurrent tumor sites (receptor self-targeted tumor cells) and extensively characterized two different approaches using (i) therapy-resistant cancer cells, engineered with secretable death receptor-targeting ligands for "off-the-shelf" therapy in primary tumor settings, and (ii) therapy-sensitive cancer cells, which were CRISPR-engineered to knock out therapy-specific cell surface receptors before engineering with receptor self-targeted ligands and reapplied in autologous models of recurrent or metastatic disease. We show that both approaches allow high expression of targeted ligands that induce tumor cell killing and translate into marked survival benefits in mouse models of multiple cancer types. Safe elimination of therapeutic cancer cells after treatment was achieved by co engineering with a prodrug-converting suicide system, which also allowed for real time in vivo positron emission tomography imaging of therapeutic tumor cell fate. This study demonstrates self-tumor tropism of engineered cancer cells and their therapeutic potential when engineered with receptor self-targeted molecules, and it establishes a roadmap toward a safe clinical translation for different cancer types in primary, recurrent, and metastatic settings. PMID- 29997251 TI - Modeling of patient virus titers suggests that availability of a vaccine could reduce hepatitis C virus transmission among injecting drug users. AB - The major route of hepatitis C virus (HCV) transmission in the United States is injection drug use. We hypothesized that if an HCV vaccine were available, vaccination could affect HCV transmission among people who inject drugs by reducing HCV titers after viral exposure without necessarily achieving sterilizing immunity. To investigate this possibility, we developed a mathematical model to determine transmission probabilities relative to the HCV RNA titers of needle/syringe-sharing donors. We simulated sharing of two types of syringes fitted with needles that retain either large or small amounts of fluid after expulsion. Using previously published viral kinetics data from both naive subjects infected with HCV and reinfected individuals who had previously cleared an HCV infection, we estimated transmission risk between pairs of serodiscordant injecting drug users, accounting for syringe type, rinsing, and sharing frequency. We calculated that the risk of HCV transmission through syringe sharing increased ~10-fold as viral titers (log10 IU/ml) increased ~25-fold. Cumulative analyses showed that, assuming sharing episodes every 7 days, the mean transmission risk over the first 6 months was >90% between two people sharing syringes when one had an HCV RNA titer >5 log10 IU/ml. For those with preexisting immunity that rapidly controlled HCV, the cumulative risk decreased to 1 to 25% depending on HCV titer and syringe type. Our modeling approach demonstrates that, even with transient viral replication after exposure during injection drug use, HCV transmission among people sharing syringes could be reduced through vaccination if an HCV vaccine were available. PMID- 29997252 TI - Erratum for the Research Article: "A human disease model of drug toxicity-Induced pulmonary edema in alLung-on-a-chip microdevice" by D. Huh, D. C. Leslie, B. D. Matthews, J. P. Fraser, S. Jurek, G. A. Hamilton, K. S. Thorneloe, M. A. McAlexander, D. E. Ingber. PMID- 29997253 TI - RNA ligase-like domain in activating signal cointegrator 1 complex subunit 1 (ASCC1) regulates ASCC complex function during alkylation damage. AB - Multiple DNA damage response (DDR) pathways have evolved to sense the presence of damage and recruit the proper repair factors. We recently reported a signaling pathway induced upon alkylation damage to recruit the AlkB homolog 3, alpha ketoglutarate-dependent dioxygenase (ALKBH3)-activating signal cointegrator 1 complex subunit 3 (ASCC3) dealkylase-helicase repair complex. As in other DDR pathways, the recruitment of these repair factors is mediated through a ubiquitin dependent mechanism. However, the machinery that coordinates the proper assembly of this repair complex and controls its recruitment is still poorly defined. Here, we demonstrate that the ASCC1 accessory subunit is important for the regulation of ASCC complex function. ASCC1 interacts with the ASCC complex through the ASCC3 helicase subunit. We find that ASCC1 is present at nuclear speckle foci prior to damage, but leaves the foci in response to alkylation. Strikingly, ASCC1 loss significantly increases ASCC3 foci formation during alkylation damage, yet most of these foci lack ASCC2. These results suggest that ASCC1 coordinates the proper recruitment of the ASCC complex during alkylation, a function that appears to depend on a putative RNA-binding motif near the ASCC1 C terminus. Consistent with its role in alkylation damage signaling and repair, ASCC1 knockout through a CRISPR/Cas9 approach results in alkylation damage sensitivity in a manner epistatic with ASCC3. Together, our results identify a critical regulator of the ALKBH3-ASCC alkylation damage signaling pathway and suggest a potential role for RNA-interacting domains in the alkylation damage response. PMID- 29997254 TI - Mapping the binding site of the P2X receptor antagonist PPADS reveals the importance of orthosteric site charge and the cysteine-rich head region. AB - ATP is the native agonist for cell-surface ligand-gated P2X receptor (P2XR) cation channels. The seven mammalian subunits (P2X1-7) form homo- and heterotrimeric P2XRs having significant physiological and pathophysiological roles. Pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) is an effective antagonist at most mammalian P2XRs. Lys-249 in the extracellular domain of P2XR has previously been shown to contribute to PPADS action. To map this antagonist site, we generated human P2X1R cysteine substitutions within a circle centered at Lys-249 (with a radius of 13 A equal to the length of PPADS). We hypothesized that cysteine substitutions of residues involved in PPADS binding would (i) reduce cysteine accessibility (measured by MTSEA-biotinylation), (ii) exhibit altered PPADS affinity, and (iii) quench the fluorescence of cysteine residues modified with MTS-TAMRA. Of the 26 residues tested, these criteria were met by only four (Lys-70, Asp-170, Lys-190, and Lys-249), defining the antagonist site, validating molecular docking results, and thereby providing the first experimentally supported model of PPADS binding. This binding site overlapped with the ATP-binding site, indicating that PPADS sterically blocks agonist access. Moreover, PPADS induced a conformational change at the cysteine-rich head (CRH) region adjacent to the orthosteric ATP-binding pocket. The importance of this movement was confirmed by demonstrating that substitution introducing positive charge present in the CRH of the hP2X1R causes PPADS sensitivity at the normally insensitive rat P2X4R. This study provides a template for developing P2XR subtype selectivity based on the differences among the mammalian subunits around the orthosteric P2XR-binding site and the CRH. PMID- 29997255 TI - PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2. AB - PHR (PAM/Highwire/RPM-1) proteins are conserved RING E3 ubiquitin ligases that function in developmental processes, such as axon termination and synapse formation, as well as axon degeneration. At present, our understanding of how PHR proteins form ubiquitin ligase complexes remains incomplete. Although genetic studies indicate NMNAT2 is an important mediator of PHR protein function in axon degeneration, it remains unknown how PHR proteins inhibit NMNAT2. Here, we decipher the biochemical basis for how the human PHR protein PAM, also called MYCBP2, forms a noncanonical Skp/Cullin/F-box (SCF) complex that contains the F box protein FBXO45 and SKP1 but lacks CUL1. We show FBXO45 does not simply function in substrate recognition but is important for assembly of the PAM/FBXO45/SKP1 complex. Interestingly, we demonstrate a novel role for SKP1 as an auxiliary component of the target recognition module that enhances binding of FBXO45 to NMNAT2. Finally, we provide biochemical evidence that PAM polyubiquitinates NMNAT2 and regulates NMNAT2 protein stability and degradation by the proteasome. PMID- 29997256 TI - Allosteric regulation of epidermal growth factor (EGF) receptor ligand binding by tyrosine kinase inhibitors. AB - The epidermal growth factor (EGF) receptor is a classical receptor tyrosine kinase with an extracellular ligand-binding domain and an intracellular kinase domain. Mutations in the EGF receptor have been shown to drive uncontrolled cell growth and are associated with a number of different tumors. Two different types of ATP-competitive EGF receptor tyrosine kinase inhibitors have been identified that bind to either the active (type I) or inactive (type II) conformation of the kinase domain. Despite the fact that both types of inhibitors block tyrosine kinase activity, they exhibit differential efficacies in different tumor types. Here, we show that in addition to inhibiting kinase activity, these inhibitors allosterically modulate ligand binding. Our data suggest that the conformations of the EGF receptor extracellular domain and intracellular kinase domain are coupled and that these conformations exist in equilibrium. Allosteric regulators, such as the small-molecule tyrosine kinase inhibitors, as well as mutations in the EGF receptor itself, shift the conformational equilibrium among the active and inactive species, leading to changes in EGF receptor-binding affinity. Our studies also reveal unexpected positive cooperativity between EGF receptor subunits in dimers formed in the presence of type II inhibitors. These findings indicate that there is strong functional coupling between the intracellular and extracellular domains of this receptor. Such coupling may impact the therapeutic synergy between small-molecule tyrosine kinase inhibitors and monoclonal antibodies in vivo. PMID- 29997258 TI - Noise control for molecular computing. AB - Synthetic biology is a growing interdisciplinary field, with far-reaching applications, which aims to design biochemical systems that behave in a desired manner. With the advancement in nucleic-acid-based technology in general, and strand-displacement DNA computing in particular, a large class of abstract biochemical networks may be physically realized using nucleic acids. Methods for systematic design of the abstract systems with prescribed behaviours have been predominantly developed at the (less-detailed) deterministic level. However, stochastic effects, neglected at the deterministic level, are increasingly found to play an important role in biochemistry. In such circumstances, methods for controlling the intrinsic noise in the system are necessary for a successful network design at the (more-detailed) stochastic level. To bridge the gap, the noise-control algorithm for designing biochemical networks is developed in this paper. The algorithm structurally modifies any given reaction network under mass action kinetics, in such a way that (i) controllable state-dependent noise is introduced into the stochastic dynamics, while (ii) the deterministic dynamics are preserved. The capabilities of the algorithm are demonstrated on a production decay reaction system, and on an exotic system displaying bistability. For the production-decay system, it is shown that the algorithm may be used to redesign the network to achieve noise-induced multistability. For the exotic system, the algorithm is used to redesign the network to control the stochastic switching, and achieve noise-induced oscillations. PMID- 29997257 TI - Structural basis of exo-beta-mannanase activity in the GH2 family. AB - The classical microbial strategy for depolymerization of beta-mannan polysaccharides involves the synergistic action of at least two enzymes, endo-1,4 beta-mannanases and beta-mannosidases. In this work, we describe the first exo beta-mannanase from the GH2 family, isolated from Xanthomonas axonopodis pv. citri (XacMan2A), which can efficiently hydrolyze both manno-oligosaccharides and beta-mannan into mannose. It represents a valuable process simplification in the microbial carbon uptake that could be of potential industrial interest. Biochemical assays revealed a progressive increase in the hydrolysis rates from mannobiose to mannohexaose, which distinguishes XacMan2A from the known GH2 beta mannosidases. Crystallographic analysis indicates that the active-site topology of XacMan2A underwent profound structural changes at the positive-subsite region, by the removal of the physical barrier canonically observed in GH2 beta mannosidases, generating a more open and accessible active site with additional productive positive subsites. Besides that, XacMan2A contains two residue substitutions in relation to typical GH2 beta-mannosidases, Gly439 and Gly556, which alter the active site volume and are essential to its mode of action. Interestingly, the only other mechanistically characterized mannose-releasing exo beta-mannanase so far is from the GH5 family, and its mode of action was attributed to the emergence of a blocking loop at the negative-subsite region of a cleft-like active site, whereas in XacMan2A, the same activity can be explained by the removal of steric barriers at the positive-subsite region in an originally pocket-like active site. Therefore, the GH2 exo-beta-mannanase represents a distinct molecular route to this rare activity, expanding our knowledge about functional convergence mechanisms in carbohydrate-active enzymes. PMID- 29997259 TI - A combined low-frequency electromagnetic and fluidic stimulation for a controlled drug release from superparamagnetic calcium phosphate nanoparticles: potential application for cardiovascular diseases. AB - Alternative drug delivery approaches to treat cardiovascular diseases are currently under intense investigation. In this domain, the possibility to target the heart and tailor the amount of drug dose by using a combination of magnetic nanoparticles (NPs) and electromagnetic devices is a fascinating approach. Here, an electromagnetic device based on Helmholtz coils was generated for the application of low-frequency magnetic stimulations to manage drug release from biocompatible superparamagnetic Fe-hydroxyapatite NPs (FeHAs). Integrated with a fluidic circuit mimicking the flow of the cardiovascular environment, the device was efficient to trigger the release of a model drug (ibuprofen) from FeHAs as a function of the applied frequencies. Furthermore, the biological effects on the cardiac system of the identified electromagnetic exposure were assessed in vitro and in vivo by acute stimulation of isolated adult cardiomyocytes and in an animal model. The cardio-compatibility of FeHAs was also assessed in vitro and in an animal model. No alterations of cardiac electrophysiological properties were observed in both cases, providing the evidence that the combination of low frequency magnetic stimulations and FeHAs might represent a promising strategy for controlled drug delivery to the failing heart. PMID- 29997260 TI - Functional capacity of kangaroo rat hindlimbs: adaptations for locomotor performance. AB - Many cursorial and large hopping species are extremely efficient locomotors with various morphological adaptations believed to reduce mechanical demand and improve movement efficiency, including elongated distal limb segments. However, despite having elongated limbs, small hoppers such as desert kangaroo rats (Dipodomys deserti) are less efficient locomotors than their larger counterparts, which may be in part due to avoiding predators through explosive jumping movements. Despite potentially conflicting mechanical demands between the two movements, kangaroo rats are both excellent jumpers and attain high hopping speeds, likely due to a specialized hindlimb musculoskeletal morphology. This study combined experimental dissection data with a static analysis of muscle moment generating capacities using a newly developed musculoskeletal model to characterize kangaroo rat hindlimb musculoskeletal architecture and investigate how morphology has evolved to meet hopping and jumping mechanical demands. Hindlimb morphology appears biased towards generating constant moment arms over large joint ranges of motion in this species, which may balance competing requirements by reducing the need for posture and movement specific excitation patterns. The ankle extensors are a major exception to the strong positive relationship exhibited by most muscles between muscle architecture parameters (e.g. Lfibre) and joint moment arms. These muscles appear suited to meeting the high moments required for jumping: the biarticular nature of the ankle extensors is leveraged to reduce MTU strain and create a four-bar linkage that facilitates proximal force transfer. The kangaroo rat hindlimb provides an interesting case study for understanding how morphology balances the sometimes competing demands of hopping and jumping. PMID- 29997261 TI - Temporal development of Drosophila embryos is highly robust across a wide temperature range. AB - Development is a process precisely coordinated in both space and time. Spatial precision has been quantified in a number of developmental systems, and such data have contributed significantly to our understanding of, for example, morphogen gradient interpretation. However, comparatively little quantitative analysis has been performed on timing and temporal coordination during development. Here, we use Drosophila to explore the temporal robustness of embryonic development within physiologically normal temperatures. We find that development is temporally very precise across a wide range of temperatures in the three Drosophila species investigated. However, we find temperature dependence in the timing of developmental events. A simple model incorporating history dependence can explain the developmental temporal trajectories. Interestingly, history dependence is temperature-specific, with either effective negative or positive feedback at different temperatures. We also find that embryos are surprisingly robust to shifting temperatures during embryogenesis. We further identify differences between tropical and temperate species, potentially due to different mechanisms regulating temporal development that depend on the local environment. Our data show that Drosophila embryonic development is temporally robust across a wide range of temperatures. This robustness shows interesting species-specific differences that are suggestive of different sensitivity to temperature fluctuations between Drosophila species. PMID- 29997262 TI - Quantitative analysis of the mitochondrial proteome in human ovarian carcinomas. AB - Mitochondria play important roles in growth, signal transduction, division, tumorigenesis and energy metabolism in epithelial ovarian carcinomas (EOCs) without an effective biomarker. To investigate the proteomic profile of EOC mitochondrial proteins, a 6-plex isobaric tag for relative and absolute quantification (iTRAQ) proteomics was used to identify mitochondrial expressed proteins (mtEPs) in EOCs relative to controls, followed by an integrative analysis of the identified mtEPs and the Cancer Genome Atlas (TCGA) data from 419 patients. A total of 5115 quantified proteins were identified from purified mitochondrial samples, and 262 proteins were significantly related to overall survival in EOC patients. Furthermore, 63 proteins were identified as potential biomarkers for the development of an EOC, and our findings were consistent with previous reports on a certain extent. Pathway network analysis identified 70 signaling pathways. Interestingly, the results demonstrated that cancer cells exhibited an increased dependence on mitophagy, such as peroxisome, phagosome, lysosome, valine, leucine and isoleucine degradation and fatty acid degradation pathways, which might play an important role in EOC invasion and metastasis. Five proteins (GLDC, PCK2, IDH2, CPT2 and HMGCS2) located in the mitochondrion and enriched pathways were selected for further analysis in an EOC cell line and tissues, and the results confirmed reliability of iTRAQ proteomics. These findings provide a large-scale mitochondrial proteomic profiling with quantitative information, a certain number of potential protein biomarkers and a novel vision in the mitophagy bio-mechanism of a human ovarian carcinoma. PMID- 29997264 TI - [Molecular Mechanisms for Learning and Memory: What Happens at the Synapses?] AB - The synapse is a structure connecting neurons in the brain, which is crucial for learning and memory. Accumulating evidence suggests that synapses continuously change in function and structure in response to learning and memory. Especially, in the cerebellum, which underlies motor learning and memory, synapses are highly dynamic throughout life. Recently, various types of molecules involving synapse integrity, learning and memory, such as delta-type glutamate receptors (GluD receptors) and C1q-family proteins, have been identified. PMID- 29997265 TI - [Molecular and Neuronal Mechanisms of Forgetting]. AB - Animals sense several types of information in their environments and some of those information are stored as memories. The retention of these memories must be regulated for the animals to survive continuously changing environments. However, the mechanisms underlying memory forgetting remain to be understood, partly because psychological studies have suggested that forgetting is a passive process. Recent behavioral genetic studies, using model animals, including mice, Drosophila and Caenorhabditis elegans, have revealed that forgetting is actively regulated in neuronal circuits. In particular, "forgetting cells" non-cell autonomously accelerate forgetting in other neurons. In this review, we describe recent studies of the mechanisms of forgetting in model animals. PMID- 29997266 TI - [Generation and Inception of Memories by Manipulating Neuronal Activity]. AB - Artificial manipulation of memories has been thought to be a story in science fiction. However, the artificial association, dissociation and inception of memories by regulating memory trace, a physiological substance of memory, is beginning to be possible now. Here we start to remark the memory trace hypothesis and its manipulation from an origin of the hypothesis to the current understanding with important findings supporting the hypothesis. PMID- 29997263 TI - Translation elongation and mRNA stability are coupled through the ribosomal A site. AB - Messenger RNA (mRNA) degradation plays a critical role in regulating transcript levels in eukaryotic cells. Previous work by us and others has shown that codon identity exerts a powerful influence on mRNA stability. In Saccharomyces cerevisiae, studies using a handful of reporter mRNAs show that optimal codons increase translation elongation rate, which in turn increases mRNA stability. However, a direct relationship between elongation rate and mRNA stability has not been established across the entire yeast transcriptome. In addition, there is evidence from work in higher eukaryotes that amino acid identity influences mRNA stability, raising the question as to whether the impact of translation elongation on mRNA decay is at the level of tRNA decoding, amino acid incorporation, or some combination of each. To address these questions, we performed ribosome profiling of wild-type yeast. In good agreement with other studies, our data showed faster codon-specific elongation over optimal codons and faster transcript-level elongation correlating with transcript optimality. At both the codon-level and transcript-level, faster elongation correlated with increased mRNA stability. These findings were reinforced by showing increased translation efficiency and kinetics for a panel of 11 HIS3 reporter mRNAs of increasing codon optimality. While we did observe that elongation measured by ribosome profiling is composed of both amino acid identity and synonymous codon effects, further analyses of these data establish that A-site tRNA decoding rather than other steps of translation elongation is driving mRNA decay in yeast. PMID- 29997267 TI - [Optical Erasure of the Synaptic Ensemble that Underlies Learning and Memory]. AB - Dentritic spines are small membrane protrusions. Their regulation is thought to be important for memory storage, but the links between dentric spines and memory have been largely correlational because of a luck of techniques for manipulating individual spines. To overcome this problem, we have developed a novel synaptic optoprobe, AS-PaRac1, which is unique not only because it specifically labels recently potentiated spines, but also because it becomes possible to selectively shrink spines containing AS-PaRac1. This indicates that AS-PaRac1 can be use to specifically visualize the recently "written spines" and that the erasure of these spines is possible upon excitation with blue light. Using in vivo two photon imaging, synaptic potentiation was visualized during active remodeling of the neocortex. Upon learning a motor skill, AS-PaRac1 expression was induced in a relatively small number of neurons, in which approximately 8% of spines were tagged by AS-PaRac1. The labeled spines were broadly distributed throughout the dendritic tree. Excitation with blue light induced shrinkage of learning related spines and disrupted the acquired motor learning. In contrast, the erasure of a similar number of learning-irrelevant spines did not affect task performance. This novel light-dependent tool will open up new areas of memory research, and will additionally shed light on the neural networks that determine who we are. PMID- 29997268 TI - [Acquisition and Forgetting of Memory in Motor Learning: Motor Memory with Multiple Timescales]. AB - Examination of temporal patterns in adaptation and extinction in human motor learning suggests the presence of multiple motor memories with different timescales. In this study, a computational model derived from behavioral data was use to, explain the analysis of brain. The results indicated that each brain region activated during motor learning is related to different timescales in motor memory. They revealed dynamic processes in the brain where multiple regions participate in the acquisition of memory at different stages of learning even in a single motor task. PMID- 29997269 TI - [Feature Integration in Visual Working Memory]. AB - This article reviews studies on feature integration in visual working memory, which is critical for various cognitive activities using visual information. Studies involving change detection and multiple object tracking tasks reported that feature-integrated object representations are successfully maintained, and that the parietal cortex plays a major role. Subsequent studies that involved explicit tasks on feature combination, such as feature swap detection and multiple object permanence tracking, revealed the role of the prefrontal cortex, but it remains equivocal whether visual working memory holds feature-integrated object representations. In addition, recent studies using an implicit-association test measure, the redundant feature reviewing task, combining object reviewing and redundancy gain paradigms, provided evidence on feature-integrated object representations in visual working memory. Electroencephalography data analysis showed prefrontal activities reflecting the integration of the color and shape of an object, which is consistent with the result of studies measuring explicit tasks. Altogether, these findings are consistent with a recently proposed "feature confirmation" model, claiming that object features can be integrated in bottom-up visual processing and the limitation in feature binding occurs in the top-down mechanism which confirms the presence of features and their combination. PMID- 29997270 TI - [Mild Exercise Results in Robust Brain Activation and Increased Memory Function]. AB - Exercise increases adult hippocampal neurogenesis (AHN) and enhances memory function. To elucidate optimal exercise, especially exercise intensity, on hippocampus-based cognition, we established treadmill running animal model, in which running speed was defined using the blood lactate threshold (LT). Using this exercise model, we found for the first time that hippocampal neurons were activated after acute mild exercise (ME) below the LT with running stress minimized. In addition, chronic ME enhanced AHN and spatial memory function. We review the beneficial effects of ME and discuss several molecular factors underlying ME-enhanced hippocampal function. PMID- 29997271 TI - [Contribution of the Medial Prefrontal Cortex to Social Memory]. AB - Social memory is a form of episodic memories in multiple domains of social context. Functional neuroimaging studies have demonstrated that the medial prefrontal cortex (mPFC) plays an important role in social memories. However, little is known about the dissociable roles within mPFC in social memories. The purpose of this article was to summarize functional neuroimaging studies investigating social memories, and to propose a hypothetical model regarding the contribution of mPFC sub-regions to social memories. In this article, we divided mPFC into three sub-regions of the orbital, ventral, and dorsal regions. Functional neuroimaging studies have shown that the orbital mPFC (orbitofrontal cortex) contributes to the reward process in episodic memory, and that the reward related activation is identified in primary, secondary, and social rewards. A role of the ventral mPFC has been found in the self-referential process, and the encoding operation of this process produces the self-reference effect in episodic memory. Activation in the dorsal mPFC has been observed in high demanding processes including cognitive control and in social cognition such as impression formation for others during episodic encoding and retrieval. The interactive mechanisms within three sub-regions of mPFC and between mPFC and the medial temporal lobe could contribute to social memories. PMID- 29997272 TI - [Functional Anatomy of Encoding/Retrieval Processing in the Medial Parietal Areas]. AB - This article reviews memory functions in the medial parietal areas, which consist of the retrosplenial cortex, the posterior cingulate cortex, and the precuneus. These areas are involved in various cognitive functions including memory processing, spatial cognition, and self-related processing. Fundamental previous studies from the areas of neuropsychology, neuroimaging, psychiatry, and neurology, are covered to describe memory-related functions in the medial parietal areas. The focus is on the default mode network and the encoding/retrieval flip as key issues for understanding memory functions in the medial parietal areas. PMID- 29997273 TI - [Thalamic Amnesia]. AB - It has been proposed that there are two distinct neural circuits underlying human episodic memory. A first circuit connects the hippocampus to the anterior nucleus of the thalamus (hippocampal-anterior thalamic memory circuit). A second circuit conveys fibers from the perirhinal cortex to the dorsomedial nucleus of the thalamus (perirhinal-medial dorsal thalamic memory circuit). In this article, we briefly review research investigating the functional roles of the two circuits in memory, including neuropsychological studies of amnesic patients with thalamic infarcts and functional magnetic resonance imaging (fMRI) studies of healthy participants. On the basis of the findings, we discuss the relationship between thalamic structures, episodic memory, and its disorders (thalamic amnesia). PMID- 29997274 TI - [Medial Temporal Lobe Amnesia]. AB - The medial temporal lobe was identified as an important neural structure in human memory by the advent of patient H.M., who suffered from severe amnesia caused by bilateral medial temporal lobectomy. Dozens of neuropsychological study of H.M. led to the classification of human memory into declarative and non-declarative memory, as well as short-term and long-term memory. The medial temporal lobe subserves declarative memory and long-term memory. It also plays an important role especially in the process of memory consolidation. The psychological and neurological mechanisms of the consolidation process can be investigated through the study of retrograde amnesia and epileptic amnesia. PMID- 29997275 TI - [Everyday Memory Deficits in Alzheimer's Disease]. AB - Everyday memory refers to the operational memory required in daily life. Some patients with dementia shows a dissociation between impairment in everyday memory and deterioration in the score of common test for recent memory. We examined the Alzheimer's disease and other dementia patients whose score of the Everyday Memory Test for Memory Clinic is preserved when compared to their performance in a word recall task. We found that these patients showed significantly better scores on the construction task and orientation task than did the other patients. We conclude that better visuocognitive function and orientation is associated with the preserved everyday memory in these patients. PMID- 29997276 TI - [Psychogenic Retrograde and Anterograde Amnesia]. AB - Patients with dissociative retrograde amnesia, under the influence of high stress, lose access to past autobiographical event memories that should have been remembered. Patients with dissociative anterograde amnesia cannot recall extremely emotional experiences. If dissociative anterograde amnesia is experienced repeatedly in daily life, something in daily life becomes a fear stimulus. Fear conditioning in dissociative anterograde amnesia is often related to past memories of child abuse that can not be recalled due to dissociative amnesia. PMID- 29997277 TI - [Mechanisms Associated with the Development of Traumatic Memories in Posttraumatic Stress Disorder]. AB - Some individuals who experience psychologically traumatic events cannot process their experiences as regular memories, and these experiences develop into traumatic memories. In individuals with posttraumatic stress disorder (PTSD), fear conditioning occurs-these individuals subsequently respond to their direct traumatic experiences and to neutral stimuli. This conditioned response eventually leads to repeated re-experiencing. In this review, we discuss biological mechanisms associated with the development of traumatic memories. These mechanisms include neural networks connecting the amygdala, hippocampus, and ventromedial prefrontal cortex, as well as the hypothalamic-pituitary-adrenal axis of the endocrine system, and epigenetic changes. PMID- 29997278 TI - [Learning Paradigms for the Promotion of Memory, and Their Underlying Principles]. AB - Efficient learning is essential for the activities of everyday life, such as for school and business. This review summarizes the effect of sleep and its timing, as well as the effect of napping and rest, on learning efficiency. In addition, we compare various learning methods, including specific versus varied practice and blocked versus interleaved learning, and propose daily techniques for efficient learning. PMID- 29997279 TI - [Memory Rehabilitation for Amnesic with Acquired Brain Injury]. AB - Two theoretical frameworks based on cognitive rehabilitation principles are recommended for the rehabilitation of memory impaired individuals. The first is improving memory function by the remediation of brain plasticity, known as remediation-oriented rehabilitation, and second is the compensation of memory function through the use of external memory aids, environmental modifications, and intact cognitive functions to overcome limitations in daily life. In rehabilitation of episodic memory impaired individuals, it has been recognized that the effortful active retrieval technique is more effective than the memorization technique. In contrast, the errorless learning technique with high effort conditions and the active participation of patients has been recognized to be particularly effective in directly improving impaired episodic memory systems. More recently, another mnemonic strategy called the spaced retrieval technique has gained support. The theoretical components of spaced retrieval consist of classical conditioning, priming, the spacing effect, and errorless learning by taking advantage of the implicit memory system, which is preserved in many people with memory loss. PMID- 29997280 TI - [FreeSurfer as a Platform for Associating Brain Structure with Function]. AB - FreeSurfer is open source software used to process and analyze magnetic resonance imaging of the human brain. It is a convenient tool that helps elucidate various structural characteristics the brain. In this review, we introduce the various structural indices of the brain, analyzed using FreeSurfer and magnetoencephalography, which can evaluate neural activity with high temporal and spatial resolution. We consider that the FreeSurfer has great potential as a platform for multimodal neuroimaging studies. PMID- 29997281 TI - [Continuous Blood Glucose Monitoring of Hyperglycemia in Acute Stroke Patients Receiving Enteral Tube Feeding]. AB - Severe hyperglycemia often occurs when acute stroke patients receive enteral tube feeding. Hyperglycemia should be managed because it adversely affects stroke outcome. However, it remains unclear how blood glucose level (BGL) changes with enteral nutrition in acute stroke patients. Our purpose was to investigate features of the blood glucose curve in acute stroke patients receiving enteral feeding. We retrospectively evaluated acute stroke patients who developed hyperglycemia during enteral tube feeding and underwent CGM in our institution. We evaluated characteristics of blood glucose curves, fasting and peak BGL, and time to peak of BGL. Six patients were analyzed. The median fasting BGL was 125.5 mg/dL and the median peak BGL was 351.5 mg/dL. The blood glucose curve showed the following characteristics following: 1) BGL elevated slowly reach the peak in 180 to 240 minutes; 2) BGL decreased slowly or very little after its peak; 3) there was a large gap between fasting and peak BGL regardless of presence of diabetes mellitus. We grouped the curves into four types by time to peak and how BGL decreased after peak. (Received August 17, 2017; Accepted February 1, 2018; Published July 1, 2018). PMID- 29997282 TI - Hepatic tristetraprolin promotes insulin resistance through RNA destabilization of FGF21. AB - The role of posttranscriptional metabolic gene regulatory programs in diabetes is not well understood. Here, we show that the RNA-binding protein tristetraprolin (TTP) is reduced in the livers of diabetic mice and humans and is transcriptionally induced in response to insulin treatment in murine livers in vitro and in vivo. Liver-specific Ttp-KO (lsTtp-KO) mice challenged with high-fat diet (HFD) have improved glucose tolerance and peripheral insulin sensitivity compared with littermate controls. Analysis of secreted hepatic factors demonstrated that fibroblast growth factor 21 (FGF21) is posttranscriptionally repressed by TTP. Consistent with increased FGF21, lsTtp-KO mice fed HFD have increased brown fat activation, peripheral tissue glucose uptake, and adiponectin production compared with littermate controls. Downregulation of hepatic Fgf21 via an adeno-associated virus-driven shRNA in mice fed HFD reverses the insulin sensitizing effects of hepatic Ttp deletion. Thus, hepatic TTP posttranscriptionally regulates systemic insulin sensitivity in diabetes through liver-derived FGF21. PMID- 29997283 TI - Brushed nasal epithelial cells are a surrogate for bronchial epithelial CFTR studies. AB - Recent advances in the management of cystic fibrosis (CF) target underlying defects in the CF transmembrane conductance regulator (CFTR) protein, but efficacy analyses remain limited to specific genotype-based subgroups. Patient derived model systems may therefore aid in expanding access to these drugs. Brushed human nasal epithelial cells (HNEs) are an attractive tissue source, but it remains unclear how faithfully they recapitulate human bronchial epithelial cell (HBE) CFTR activity. We examined this gap using paired, brushed HNE/HBE samples from pediatric CF subjects with a wide variety of CFTR mutations cultured at the air-liquid interface. Growth and structural characteristics for the two cell types were similar, including differentiation into mature respiratory epithelia. In electrophysiologic analysis, no correlation was identified between nasal and bronchial cultures in baseline resistance or epithelial sodium channel (ENaC) activity. Conversely, robust correlation was demonstrated between nasal and bronchial cultures in both stimulated and inhibited CFTR activity. There was close correlation in modulator-induced change in CFTR activity, and CFTR activity in both cell types correlated with in vivo sweat chloride measurements. These data confirm that brushed HNE cell cultures recapitulate the functional CFTR characteristics of HBEs with fidelity and are therefore an appropriate noninvasive HBE surrogate for individualized CFTR analysis. PMID- 29997285 TI - Overview of inactivating mutations in the protein-coding genome of the mouse reference strain C57BL/6J. AB - Mice are extremely important as the premier model organism in human biomedical and mammalian genetic research. The genomes of several tens of mouse inbred strains have been sequenced. They have been compared to the genome of C57BL/6J, considered by convention as the reference genome. Based on a comparison of this reference genome with 36 other sequenced mouse strains, we generated an overview of all protein-coding genes that are deviant in this reference genome, compared with consensus protein-coding mouse gene sequences. We provide PROVEAN scores, reflecting the likelihood that these C57BL/6J proteins have lost function. We thus identified numerous abnormal proteins, and biological pathways, specifically present in C57BL/6J, suggesting the important caveats of this reference mouse strain, and linking candidate genes to some of the best-known phenotypes of this strain. PMID- 29997284 TI - HIV infection results in clonal expansions containing integrations within pathogenesis-related biological pathways. AB - The genomic integration of HIV into cells results in long-term persistence of virally infected cell populations. This integration event acts as a heritable mark that can be tracked to monitor infected cells that persist over time. Previous reports have documented clonal expansion in people and have linked them to proto-oncogenes; however, their significance or contribution to the latent reservoir has remained unclear. Here, we demonstrate that a directed pattern of clonal expansion occurs in vivo, specifically in gene pathways important for viral replication and persistence. These biological processes include cellular division, transcriptional regulation, RNA processing, and posttranslational modification pathways. This indicates preferential expansion when integration events occur within genes or biological pathways beneficial for HIV replication and persistence. Additionally, these expansions occur quickly during unsuppressed viral replication in vivo, reinforcing the importance of early intervention for individuals to limit reservoir seeding of clonally expanded HIV-infected cells. PMID- 29997286 TI - Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival. AB - Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression. PMID- 29997287 TI - T cell receptor repertoire features associated with survival in immunotherapy treated pancreatic ductal adenocarcinoma. AB - BACKGROUND: Immune checkpoint inhibitors provide significant clinical benefit to a subset of patients, but novel prognostic markers are needed to predict which patients will respond. This study was initiated to determine if features of patient T cell repertoires could provide insights into the mechanisms of immunotherapy, while also predicting outcomes. METHODS: We examined T cell receptor (TCR) repertoires in peripheral blood of 25 metastatic pancreatic cancer patients treated with ipilimumab with or without GVAX (a pancreatic cancer vaccine), as well as peripheral blood and tumor biopsies from 32 patients treated with GVAX and mesothelin-expressing Listeria monocytogenes with or without nivolumab. Statistics from these repertoires were then tested for their association with clinical response and treatment group. RESULTS: We demonstrate that, first, the majority of patients receiving these treatments experience a net diversification of their peripheral TCR repertoires. Second, patients receiving ipilimumab experienced larger changes in their repertoires, especially in combination with GVAX. Finally, both a low baseline clonality and a high number of expanded clones following treatment were associated with significantly longer survival in patients who received ipilimumab but not in patients receiving nivolumab. CONCLUSIONS: We show that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and demonstrate the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy. In addition, our results suggest testing sequential administration of anti-CTLA-4 and anti-PD-1 antibodies to achieve optimal therapeutic benefit. TRIAL REGISTRATION: Samples used in this study were collected from the NCT00836407 and NCT02243371 clinical trials. FUNDING: Research supported by a Stand Up To Cancer Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research grant (SU2C-AACR-DT14-14). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (AACR). Additional clinical trial funding was provided by AACR-Pancreatic Cancer Action Network Research Acceleration Network grant (14-90 25-LE), NCI SPORE in GI Cancer (CA062924), Quick-Trials for Novel Cancer Therapies: Exploratory Grants (R21CA126058-01A2), and the US Food and Drug Administration (R01FD004819). Research collaboration and financial support were provided by Adaptive Biotechnologies. PMID- 29997288 TI - Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis. AB - The maintenance of effective immunity over time is dependent on the capacity of hematopoietic stem cells (HSCs) to sustain the pool of immunocompetent mature cells. Decline of immune competence with old age may stem from HSC defects, including reduced self-renewal potential and impaired lymphopoiesis, as suggested in murine models. To obtain further insights into aging-related alteration of hematopoiesis, we performed a comprehensive study of blood hematopoietic progenitor cells (HPCs) from older humans. In the elderly, HPCs present active oxidative phosphorylation and are pressed to enter cell cycling. However, p53-p21 and p15 cell senescence pathways, associated with telomerase activity deficiency, strong telomere attrition, and oxidative stress, are engaged, thus limiting cell cycling. Moreover, survival of old HPCs is impacted by pyroptosis, an inflammatory form of programmed cell death. Lastly, telomerase activity deficiency and telomere length attrition of old HPCs may be passed on to progeny cells such as naive T lymphocytes, further highlighting the poor hematopoietic potential of the elderly. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age. PMID- 29997289 TI - Defective BTLA functionality is rescued by restoring lipid metabolism in lupus CD4+ T cells. AB - Coinhibitory receptors play an important role in the prevention of autoimmune diseases, such as systemic lupus erythematosus (SLE), by limiting T cell activation. B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, similar to cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD1), that negatively regulates the immune response. The role of BTLA in the pathogenesis of autoimmune diseases in humans and, more specifically, in SLE is largely unknown. We investigated BTLA expression on various T cell subsets, and we did not observe significant variations of BTLA expression between lupus patients and healthy controls. However, the enhancement of BTLA expression after activation was significantly lower in SLE patients compared with that in healthy controls. Furthermore, we found an impaired capacity of BTLA to inhibit T cell activation in SLE due to a poor BTLA recruitment to the immunological synapse following T cell stimulation. Finally, we demonstrated that defective BTLA function can be corrected by restoring intracellular trafficking and by normalizing the lipid metabolism in lupus CD4+ T cells. Collectively, our results evidence that the BTLA signaling pathway is altered in SLE T cells and highlight the potential of targeting this pathway for the development of new therapeutic strategies in lupus. PMID- 29997290 TI - Chikungunya virus impairs draining lymph node function by inhibiting HEV-mediated lymphocyte recruitment. AB - Chikungunya virus (CHIKV) causes acute and chronic rheumatologic disease. Pathogenic CHIKV strains persist in joints of immunocompetent mice, while the attenuated CHIKV strain 181/25 is cleared by adaptive immunity. We analyzed the draining lymph node (dLN) to define events in lymphoid tissue that may contribute to CHIKV persistence or clearance. Acute 181/25 infection resulted in dLN enlargement and germinal center (GC) formation, while the dLN of mice infected with pathogenic CHIKV became highly disorganized and depleted of lymphocytes. Using CHIKV strains encoding ovalbumin-specific TCR epitopes, we found that lymphocyte depletion was not due to impaired lymphocyte proliferation. Instead, the accumulation of naive lymphocytes transferred from the vasculature to the dLN was reduced, which was associated with fewer high endothelial venule cells and decreased CCL21 production. Following NP-OVA immunization, NP-specific GC B cells in the dLN were decreased during pathogenic, but not attenuated, CHIKV infection. Our data suggest that pathogenic, persistent strains of CHIKV disable the development of adaptive immune responses within the dLN. PMID- 29997291 TI - Total body CD4+ T cell dynamics in treated and untreated SIV infection revealed by in vivo imaging. AB - The peripheral blood represents only a small fraction of the total number of lymphocytes in the body. To develop a more thorough understanding of T cell dynamics, including the effects of SIV/SHIV/HIV infection on immune cell depletion and immune reconstitution following combination antiretroviral therapy (cART), one needs to utilize approaches that allow direct visualization of lymphoid tissues. In the present study, noninvasive in vivo imaging of the CD4+ T cell pool has revealed that the timing of the CD4+ T cell pool reconstitution following initiation of ART in SIV-infected nonhuman primates (NHPs) appears seemingly stochastic among clusters of lymph nodes within the same host. At 4 weeks following initiation or interruption of cART, the changes observed in peripheral blood (PB) are primarily related to changes in the whole-body CD4 pool rather than changes in lymphocyte trafficking. Lymph node CD4 pools in long-term antiretroviral-treated and plasma viral load-suppressed hosts appear suboptimally reconstituted compared with healthy controls, while splenic CD4 pools appear similar between the 2 groups. PMID- 29997292 TI - CTLA4 methylation predicts response to anti-PD-1 and anti-CTLA-4 immunotherapy in melanoma patients. AB - Recent years have witnessed the groundbreaking success of immune checkpoint blockage (ICB) in metastasized malignant melanoma. However, biomarkers predicting the response to ICB are still urgently needed. In the present study, we investigated CTLA4 promoter methylation (mCTLA4) in 470 malignant melanoma patients from The Cancer Genome Atlas (non-ICB cohort) and in 50 individuals with metastasized malignant melanomas under PD-1/CTLA-4-targeted immunotherapy (ICB cohort). mCTLA4 levels were quantified using the Infinium HumanMethylation450 BeadChip (non-ICB cohort) and methylation-specific quantitative real-time PCR in DNA formalin-fixed and paraffin-embedded tissues (ICB cohort). Methylation levels were associated with molecular and clinicopathological variables and analyzed with respect to response (irRECIST) and overall survival. CTLA-4 mRNA and mCTLA4 showed a significant inverse correlation (non-ICB cohort: Spearman's rho = 0.416, P < 0.001). In ICB-treated melanoma patients, low mCTLA4 was further strongly correlated with response to therapy (P = 0.009, ANOVA) and overall survival (hazard ratio = 2.06 [95% CI: 1.29-3.29], P = 0.003). Our data strongly support the assumption that mCTLA4 predicts response to both anti-PD-1 and anti CTLA-4 targeted ICB in melanoma and provides paramount information for the selection of patients likely to respond to ICB. PMID- 29997293 TI - Plasma copeptin and chronic kidney disease risk in 3 European cohorts from the general population. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing worldwide. The identification of factors contributing to its progression is important for designing preventive measures. Previous studies have suggested that chronically high vasopressin is deleterious to renal function. Here, we evaluated the association of plasma copeptin, a surrogate of vasopressin, with the incidence of CKD in the general population. METHODS: We studied 3 European cohorts: DESIR (n = 5,047; France), MDCS-CC (n = 3,643; Sweden), and PREVEND (n = 7,684; the Netherlands). Median follow-up was 8.5, 16.5, and 11.3 years, respectively. Pooled data were analyzed at an individual level for 4 endpoints during follow-up: incidence of stage 3 CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2); the KDIGO criterion "certain drop in eGFR"; rapid kidney function decline (eGFR slope steeper than -3 ml/min/1.73 m2/yr); and incidence of microalbuminuria. RESULTS: The upper tertile of plasma copeptin was significantly and independently associated with a 49% higher risk for stage 3 CKD (P < 0.0001); a 64% higher risk for kidney function decline, as defined by the KDIGO criterion (P < 0.0001); a 79% higher risk for rapid kidney function decline (P < 0.0001); and a 24% higher risk for microalbuminuria (P = 0.008). CONCLUSIONS: High copeptin levels are associated with the development and the progression of CKD in the general population. Intervention studies are needed to assess the potential beneficial effect on kidney health in the general population of reducing vasopressin secretion or action. FUNDING: INSERM and Danone Research Centre for Specialized Nutrition. PMID- 29997294 TI - Safety and immunogenicity of an oral tablet norovirus vaccine, a phase I randomized, placebo-controlled trial. AB - BACKGROUND: Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. However, there are no approved vaccines for noroviruses. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum-blocking antibody titers (BT50). METHODS: We conducted a single-site, randomized, double blind, placebo-controlled clinical trial of an oral norovirus vaccine to determine safety and immunogenicity. This tablet vaccine is comprised of a nonreplicating adenovirus-based vector expressing the VP1 gene from the GI.1 norovirus strain and a double-stranded RNA adjuvant. Sixty-six adult subjects meeting inclusion/exclusion criteria were randomized 2:1 to receive a single vaccine dose or placebo, respectively. Immunogenicity was primarily assessed by serum BT50. Additional outcomes included serum ELISA titers, fecal and saliva antibody titers, memory and antibody-secreting cell (ASC) frequency, and B cell phenotyping. RESULTS: The vaccine was well-tolerated, with no dose-limiting toxicities. Adverse events were mild or moderate. The primary immunological endpoint (increase in BT50 titers) was met in the high-dose group (P = 0.0003), with 78% showing a >=2-fold rise in titers after a single immunization. Vaccine recipients also developed mucosally primed VP1-specific circulating ASCs, IgA+ memory B cells expressing gut-homing receptor (alpha4beta7), and fecal IgA, indicating substantial and local responses potentially relevant to prevent norovirus infection. CONCLUSION: This oral norovirus vaccine was well-tolerated and generated substantial immune responses, including systemic and mucosal antibodies as well as memory IgA/IgG. These results are a major step forward for the development of a safe and immunogenic oral norovirus vaccine. TRIAL REGISTRATION: ClinicalTrials.gov NCT02868073. FUNDING: Vaxart. PMID- 29997295 TI - Vaginal microbiome modulates topical antiretroviral drug pharmacokinetics. AB - Tenofovir gel and dapivirine ring provided variable HIV protection in clinical trials, reflecting poor adherence and possibly biological factors. We hypothesized that vaginal microbiota modulates pharmacokinetics and tested the effects of pH, individual bacteria, and vaginal swabs from women on pharmacokinetics and antiviral activity. Tenofovir, but not dapivirine, uptake by human cells was reduced as pH increased. Lactobacillus crispatus actively transported tenofovir leading to a loss in drug bioavailability and culture supernatants from Gardnerella vaginalis, but not Atopobium vaginae, blocked tenofovir endocytosis. The inhibition of endocytosis mapped to adenine. Adenine increased from 65.5 MUM in broth to 246 MUM in Gardnerella, but decreased to 9.5 MUM in Atopobium supernatants. This translated into a decrease in anti-HIV activity when Gardnerella supernatants or adenine were added to cultures. Dapivirine was also impacted by microbiota, as drug bound irreversibly to bacteria, resulting in decreased antiviral activity. When drugs were incubated with vaginal swabs, 30.7% +/- 5.7% of dapivirine and 63.9% +/- 8.8% of tenofovir were recovered in supernatants after centrifugation of the bacterial cell pellet. In contrast, no impact of microbiota on the pharmacokinetics of the prodrugs, tenofovir disoproxil fumarate or tenofovir alafenamide, was observed. Together, these results demonstrate that microbiota may impact pharmacokinetics and contribute to inconsistent efficacy. PMID- 29997296 TI - Circulating RIPK3 levels are associated with mortality and organ failure during critical illness. AB - BACKGROUND: Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS: Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS: In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS: Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING: Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431. PMID- 29997297 TI - TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung. AB - Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule. Levels of MD2 and TLR4, and a TLR4-responsive gene signature, were enhanced in SSc skin biopsies. We developed a small molecule that selectively blocks MD2, which is uniquely required for TLR4 signaling. Targeting MD2/TLR4 abrogated inducible and constitutive myofibroblast transformation and matrix remodeling in fibroblast monolayers, as well as in 3-D scleroderma skin equivalents and human skin explants. Moreover, the selective TLR4 inhibitor prevented organ fibrosis in several preclinical disease models and mouse strains, and it reversed preexisting fibrosis. Fibroblast-specific deletion of TLR4 in mice afforded substantial protection from skin and lung fibrosis. By comparing experimentally generated fibroblast TLR4 gene signatures with SSc skin biopsy gene expression datasets, we identified a subset of SSc patients displaying an activated TLR4 signature. Together, results from these human and mouse studies implicate MD2/TLR4-dependent fibroblast activation as a key driver of persistent organ fibrosis. The results suggest that SSc patients with high TLR4 activity might show optimal therapeutic response to selective inhibitors of MD2/TLR4 complex formation. PMID- 29997298 TI - Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation. AB - Hemodynamic shear force has been implicated as modulating Notch signaling mediated cardiac trabeculation. Whether the spatiotemporal variations in wall shear stress (WSS) coordinate the initiation of trabeculation to influence ventricular contractile function remains unknown. Using light-sheet fluorescent microscopy, we reconstructed the 4D moving domain and applied computational fluid dynamics to quantify 4D WSS along the trabecular ridges and in the groves. In WT zebrafish, pulsatile shear stress developed along the trabecular ridges, with prominent endocardial Notch activity at 3 days after fertilization (dpf), and oscillatory shear stress developed in the trabecular grooves, with epicardial Notch activity at 4 dpf. Genetic manipulations were performed to reduce hematopoiesis and inhibit atrial contraction to lower WSS in synchrony with attenuation of oscillatory shear index (OSI) during ventricular development. gamma-Secretase inhibitor of Notch intracellular domain (NICD) abrogated endocardial and epicardial Notch activity. Rescue with NICD mRNA restored Notch activity sequentially from the endocardium to trabecular grooves, which was corroborated by observed Notch-mediated cardiomyocyte proliferations on WT zebrafish trabeculae. We also demonstrated in vitro that a high OSI value correlated with upregulated endothelial Notch-related mRNA expression. In silico computation of energy dissipation further supports the role of trabeculation to preserve ventricular structure and contractile function. Thus, spatiotemporal variations in WSS coordinate trabecular organization for ventricular contractile function. PMID- 29997299 TI - Concurrent cell type-specific isolation and profiling of mouse brains in inflammation and Alzheimer's disease. AB - Nonneuronal cell types in the CNS are increasingly implicated as critical players in brain health and disease. While gene expression profiling of bulk brain tissue is routinely used to examine alterations in the brain under various conditions, it does not capture changes that occur within single cell types or allow interrogation of crosstalk among cell types. To this end, we have developed a concurrent brain cell type acquisition (CoBrA) methodology, enabling the isolation and profiling of microglia, astrocytes, endothelia, and oligodendrocytes from a single adult mouse forebrain. By identifying and validating anti-ACSA-2 and anti-CD49a antibodies as cell surface markers for astrocytes and vascular endothelial cells, respectively, and using established antibodies to isolate microglia and oligodendrocytes, we document that these 4 major cell types are isolated with high purity and RNA quality. We validated our procedure by performing acute peripheral LPS challenge, while highlighting the underappreciated changes occurring in astrocytes and vascular endothelia in addition to microglia. Furthermore, we assessed cell type-specific gene expression changes in response to amyloid pathology in a mouse model of Alzheimer's disease. Our CoBrA methodology can be readily implemented to interrogate multiple CNS cell types in any mouse model at any age. PMID- 29997300 TI - Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. AB - To what extent does the subarachnoid cerebrospinal fluid (CSF) compartment communicate directly with the extravascular compartment of human brain tissue? Interconnection between the subarachnoid CSF compartment and brain perivascular spaces is reported in some animal studies, but with controversy, and in vivo CSF tracer studies in humans are lacking. In the present work, we examined the distribution of a CSF tracer in the human brain by MRI over a prolonged time span. For this, we included a reference cohort, representing close to healthy individuals, and a cohort of patients with dementia and anticipated compromise of CSF circulation (idiopathic normal pressure hydrocephalus). The MRI contrast agent gadobutrol, which is confined to the extravascular brain compartment by the intact blood-brain barrier, was used as a CSF tracer. Standardized T1-weighted MRI scans were performed before and after intrathecal gadobutrol at defined time points, including at 24 hours, 48 hours, and 4 weeks. All MRI scans were aligned and brain regions were segmented using FreeSurfer, and changes in normalized T1 signals over time were quantified as percentage change from baseline. The study provides in vivo evidence of access to all human brain subregions of a substance administered intrathecally. Clearance of the tracer substance was delayed in the dementia cohort. These observations translate previous findings in animal studies into humans and open new prospects concerning intrathecal treatment regimens, extravascular contrast-enhanced MRI, and assessment of brain clearance function. PMID- 29997301 TI - Antibody-modified conduits for highly selective cytokine elimination from blood. AB - Cytokines play an important role in dysregulated immune responses to infection, pancreatitis, ischemia/reperfusion injury, burns, hemorrhage, cardiopulmonary bypass, trauma, and many other diseases. Moreover, the imbalance between inflammatory and antiinflammatory cytokines can have deleterious effects. Here, we demonstrated highly selective blood-filtering devices - antibody-modified conduits (AMCs) - that selectively eliminate multiple specific deleterious cytokines in vitro. AMCs functionalized with antibodies against human vascular endothelial growth factor A or tumor necrosis factor alpha (TNF-alpha) selectively eliminated the target cytokines from human blood in vitro and maintained them in reduced states even in the face of ongoing infusion at supraphysiologic rates. We characterized the variables that determine AMC performance, using anti-human TNF-alpha AMCs to eliminate recombinant human TNF alpha. Finally, we demonstrated selective cytokine elimination in vivo by filtering interleukin 1 beta from rats with lipopolysaccharide-induced hypercytokinemia. PMID- 29997302 TI - Repetitive ischemic injuries to the kidneys result in lymph node fibrosis and impaired healing. AB - The contribution of the kidney-draining lymph node (KLN) to the pathogenesis of ischemia-reperfusion injury (IRI) of the kidney and its subsequent recovery has not been explored in depth. In addition, the mechanism by which repetitive IRI contributes to renal fibrosis remains poorly understood. Herein, we have found that IRI of the kidney is associated with expansion of high endothelial venules (HEVs) and activation of fibroblastic reticular cells (FRCs) in the KLN, as demonstrated by significant expansion in the extracellular matrix. The lymphotoxin alpha signaling pathway mediates activation of FRCs, and chronic treatment with lymphotoxin beta receptor-immunoglobulin fusion protein (LTbetar Ig) resulted in marked alteration of the KLN as well as augmentation of renal fibrosis. Depletion of FRCs reduced T cell activation in the KLN and ameliorated renal injury in acute IRI. Repetitive renal IRI was associated with senescence of FRCs, fibrosis of the KLN, and renal scarring, which were ameliorated by FRC administration. Therefore, our study emphasizes the critical role of FRCs in both the initiation and repair phases of injury following IRI of the kidney. PMID- 29997303 TI - Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia. AB - Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multiomic and targeted analyses. We found that spermine synthase (SMS) escapes X-chromosome inactivation (XCI) in the placenta and is expressed at lower levels in male primary trophoblast cells, and male cells were more sensitive to polyamine depletion. The spermine metabolite N1,N12-diacetylspermine (DiAcSpm) was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. To our knowledge, DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentally related complications of human pregnancy. PMID- 29997304 TI - TCRalphabeta/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy. AB - T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3 specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3epsilon CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRalphabeta/CD3 complex. Only transduction after disrupting assembly of TCRalphabeta/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3epsilon was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/murine chimeric model, supporting the application of cellular immunotherapy strategies against T cell malignancies. 3CAR provides a bridging strategy to achieve T cell eradication and leukemic remission ahead of conditioned allogeneic stem cell transplantation. PMID- 29997305 TI - Meta-analysis of RNA sequencing datasets reveals an association between TRAJ23, psoriasis, and IL-17A. AB - Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-gamma segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-alphabeta genes, the expression of TCR-gammadelta genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease. PMID- 29997307 TI - Ceramic Piezoelectric Transformer in Vacuum for Acceleration of Electrons and Production of X-Rays. AB - Experiments on acceleration of electrons and production of X-ray radiation with use of ceramic piezoelectric transformers installed in vacuum are described and analyzed. The piezoelectric transformer operates at resonance frequency. Electrons are accelerated from the high-voltage electrode of the ceramic piezoelectric transformer toward the grounded target, where they emit bremsstrahlung and characteristic X-ray radiation in the target material. The returning of the charge to the high-voltage electrode is provided due to electrons emitted from a filament installed in the vicinity of the target. It was found that the X-ray yield increases linearly at increasing of the pressure of the residual gas in the chamber within two orders of magnitude up to about 10 mTorr, when the gas discharge around of the piezoelectric transformer arises. Possibilities for application of piezoelectric transformers for production of accelerating voltage in small-size accelerators are discussed. PMID- 29997306 TI - Transcript Profiling Identifies Early Response Genes against FMDV Infection in PK 15 Cells. AB - Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is recognized as the best method to prevent FMD outbreaks. Furthermore, the mechanism of host early responses against foot-and-mouth disease virus (FMDV) infection remains unclear. In our study, a pig kidney cell line (PK-15) was used as a cell model to reveal the mechanism of early pig responses to FMDV infection. Four non-treated control and four FMDV-treated PK-15 cells were sequenced with RNA-seq technology, and the differentially expressed genes (DEGs) were analyzed. The results showed that 1212 DEGs were in the FMDV-infected PK-15 cells, including 914 up-regulated and 298 down-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched in the tumor necrosis factor (TNF), cytokine-cytokine receptor interaction, NOD-like receptor, toll-like receptor, NF-kappaB, and the chemokine signaling pathways. To verify the results of the DEGs, 30 immune related DEGs (19 up-regulated and 11 down-regulated) were selected for Quantitative Reverse Transcriptase polymerase chain reaction (RT-qPCR) verification. The results showed that RT-qPCR-measured genes exhibited a similar pattern as the RNA-seq analyses. Based on bioinformatics analysis, during FMDV early infection, we found that a series of cytokines, such as interleukins (IL6), chemokines (CXCL2, CCL20 and CCL4), and transcription factors (ZFP36, FOS, NFKBIA, ZBTB3, ZNF503, ZNF283, dymeclin (DYM), and orthodenticle homeobox 1 (OTX1)) were involved in the battle between FMDV and the host. Combined with their features and functions, we propose inflammation as the main early mechanism by which the host responds to FMDV infection. These data provide an additional panel of candidate genes for deciphering the mechanisms of a host's early response against FMDV infection. PMID- 29997308 TI - Influence of Extraction Conditions on Ultrasound-Assisted Recovery of Bioactive Phenolics from Blueberry Pomace and Their Antioxidant Activity. AB - The increase in diet-related chronic diseases has prompted the search for health promoting compounds and methods to ensure their quality. Blueberry pomace is a rich yet underutilized source of bioactive polyphenols. For these high-value bioactive molecules, ultrasound-assisted extraction (USAE) is an attractive and green alternative to conventional extraction techniques for improving purity and yields. This study aimed to assess the impact of USAE parameters (sonication time, solvent composition, solid/liquid ratio, pH and temperature) on the recovery of phenolic compounds from blueberry pomace and antioxidant activity of the extracts. Total phenolic, flavonoid and anthocyanin contents (TPC, TFC and TAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity were analysed. USAE in 50% ethanol/water was the most efficient, yielding the highest TPC (22.33 mg/g dry matter (DM)), TFC (19.41 mg/g DM), TAC (31.32 mg/g DM) and DPPH radical scavenging activity (41.79 mg Trolox/g DM). USAE in water showed the lowest values even at low (1/40) solid/liquid ratio (7.85 mg/g DM, 3.49 mg/g DM, and 18.96 mg/g DM for TPC, TFC and TAC, respectively). Decreasing the solid/liquid ratio in water or 50% ethanol significantly increased TPC, TFC, TAC and DPPH radical scavenging. With ethanol, increasing the temperature in the range 20-40 degrees C decreased TPC but increased TFC and DPPH radical scavenging activity. Anthocyanin profiles of water and ethanolic extracts were qualitatively similar, consisting of malvidin, delphinidin, petunidin and cyanidin. These findings indicate that USAE is a method of choice for extracting high-value bioactive phenolics from blueberry pomace. Selective enrichment of different phenolic fractions is possible under select extraction conditions. PMID- 29997309 TI - Demethylbelamcandaquinone B (Dmcq B) Is the Active Compound of Marantodes pumilum var. alata (Blume) Kuntze with Osteoanabolic Activities. AB - Phytoestrogens have attracted considerable attention for their potential in the prevention of postmenopausal osteoporosis. Recently, a phytoestrogen-rich herbal plant, Marantodes pumilum var. alata (Blume) Kuntze was reported to protect against bone loss in ovariectomized rat. However, the bioactive compound responsible for these effects and the underlying mechanism were not known. Through bioassay-guided isolation, demethylbelamcandaquinone B (Dmcq B) was isolated and identified from Marantodes pumilum var. alata leaf extract. In terms of its bone anabolic effects, Dmcq B was at par with 17beta-estradiol (E2), in promoting the proliferation, differentiation and mineralization of osteoblast cells. Dmcq-B increased early differentiation markers, collagen content and enzymatic ALP activity. It was demonstrated to regulate BMP2 signaling pathway which further activated the transcription factor, osterix. Subsequently, Dmcq B was able to increase the osteocalcin expression which promoted matrix mineralization as evidenced by the increase in calcium deposition. Dmcq B also reduced the protein level of receptor activator of NF-kappabeta ligand (RANKL) and promoted osteoprotegerin (OPG) protein expression by osteoblast cells, therefore hastening bone formation rate by decreasing RANKL/OPG ratio. Moreover, Dmcq B was able to increase ER expression, postulating its phytoestrogen property. As the conclusion, Dmcq B is the active compound isolated from Marantodes pumilum var. alata leaves, regulating osteoanabolic activities potentially through the BMP2 and ER signaling pathways. PMID- 29997310 TI - Gene by Culture Effects on Emotional Processing of Social Cues among East Asians and European Americans. AB - While Western cultures are more focused on individualization and self-expression, East Asian cultures promote interrelatedness. Largely unknown is how gene by culture interactions influence the degree to which individuals acquire culture, and the neurocircuitry underlying how social cues are processed. We sought to examine the interaction between DRD4 polymorphism and culture in the neural processing of social emotional cues. 19 Asian-born East Asian (AA) and 20 European American (EA) participants performed a shifted attention emotion appraisal functional magnetic resonance imaging (fMRI) task, which probes implicit emotional processing and regulation in response to social emotional cues. Half of the participants in each group were DRD4 2- or 7-repeat allele (2R/7R) carriers. AA participants showed larger left and right amygdala, and left hippocampal activation during implicit processing of fearful faces. There was a gene by culture interaction in the left insula during implicit processing of facial cues, while activation in EA DRD4 2R/7R carriers was larger than EA non carriers and AA carriers. Our findings suggest that emotional facial cues are more salient to AA participants and elicit a larger amygdala reaction. Gene by culture interaction finding in insula suggests that DRD4 2R/7R carriers in each culture are more prone to adopting their cultural norm. PMID- 29997311 TI - Green Alga Ulva spp. Hydrolysates and Their Peptide Fractions Regulate Cytokine Production in Splenic Macrophages and Lymphocytes Involving the TLR4 NFkappaB/MAPK Pathways. AB - Hydrolysates of food protein sources have immunomodulatory effects, which are of interest for use as functional foods. In this study, we have characterized the immune regulatory effect on rat splenocytes, macrophages and T lymphocytes of Ulva spp. hydrolysates and their peptide fractions with or without in vitro gastrointestinal digestion and/or ultrafiltration. IL-10 was induced in almost all conditions and cell types obtained from wild type animals. The induction was in general increased by ultrafiltration and in vitro gastrointestinal digestion. TNF was also induced in basal conditions. In turn, TNF and IFN-gamma production was attenuated by the hydrolysate products in lipopolysaccharide or concanavalin A immune stimulated cells. Inhibitors for the activation of NFkappaB, MAPK p38 and JNK inhibited IL-10 induction in rat splenocytes. The response was dramatically attenuated in TLR4-/- cells, and only modestly in TLR2-/- cells. Food peptides from Ulva spp. genus exert anti-inflammatory effects in immune cells mediated by TLR4 and NFkappaB. Similarity with the immunomodulatory profile of protein hydrolysates from other sources suggests a common mechanism. PMID- 29997313 TI - Automatic Infants' Pain Assessment by Dynamic Facial Representation: Effects of Profile View, Gestational Age, Gender, and Race. AB - Infants' early exposure to painful procedures can have negative short and long term effects on cognitive, neurological, and brain development. However, infants cannot express their subjective pain experience, as they do not communicate in any language. Facial expression is the most specific pain indicator, which has been effectively employed for automatic pain recognition. In this paper, dynamic pain facial expression representation and fusion scheme for automatic pain assessment in infants is proposed by combining temporal appearance facial features and temporal geometric facial features. We investigate the effects of various factors that influence pain reactivity in infants, such as individual variables of gestational age, gender, and race. Different automatic infant pain assessment models are constructed, depending on influence factors as well as facial profile view, which affect the model ability of pain recognition. It can be concluded that the profile-based infant pain assessment is feasible, as its performance is almost as good as that of the whole face. Moreover, gestational age is the most influencing factor for pain assessment, and it is necessary to construct specific models depending on it. This is mainly because of a lack of behavioral communication ability in infants with low gestational age, due to limited neurological development. To our best knowledge, this is the first study investigating infants' pain recognition, highlighting profile facial views and various individual variables. PMID- 29997312 TI - Contribution of Red Wine Consumption to Human Health Protection. AB - Wine consumption has been popular worldwide for many centuries. Based on in vitro and in vivo studies, a certain amount of everyday wine consumption may prevent various chronic diseases. This is due, in part, to the presence and amount of important antioxidants in red wine, and, therefore, research has focused on them. Wine polyphenols, especially resveratrol, anthocyanins, and catechins, are the most effective wine antioxidants. Resveratrol is active in the prevention of cardiovascular diseases by neutralizing free oxygen radicals and reactive nitrogenous radicals; it penetrates the blood-brain barrier and, thus, protects the brain and nerve cells. It also reduces platelet aggregation and so counteracts the formation of blood clots or thrombi. The main aim of this review is to summarize the current findings about the positive influence of wine consumption on human organ function, chronic diseases, and the reduction of damage to the cardiovascular system. PMID- 29997314 TI - The Relationship of Safety with Burnout for Mobile Health Employees. AB - OBJECTIVE: The study examined the relationship of occupational safety with job burnout. DESIGN: The study used a cross-sectional survey design. SETTING: The setting was Nova Scotia, Canada. PARTICIPANTS: Mobile health employees (N = 156) completed surveys on road safety, workload, burnout and supervisor incivility. MAIN OUTCOME MEASURE: The main outcome measure was the Maslach Burnout Inventory. RESULTS: Results found that safety concerns improved the prediction of exhaustion beyond that provided by workload concerns alone. Further, confidence in safety buffered the relationship of exhaustion with cynicism such that the exhaustion/cynicism relationship was stronger for employees who had lower confidence in road safety. CONCLUSIONS: Employees' confidence in occupational safety while addressing work responsibilities on the road has implications for their experience of job burnout. PMID- 29997315 TI - Growth Hormone: Therapeutic Possibilities-An Overview. PMID- 29997316 TI - The Relationship between Personality Traits with Depressive Symptoms and Suicidal Ideation among Medical Students: A Cross-Sectional Study at One Medical School in Germany. AB - Medical students are at increased risk of experiencing mental health problems. Certain personality traits may be associated with elevated vulnerability to study related stress and poor mental health. This study aimed to investigate the relationship between such personality traits and mental health outcomes among medical students. We drew on cross-sectional data from 251 medical students who had been enrolled for one-year at a medical school in Germany. Depressive symptoms were measured using the Patient Health Questionnaire-8 (PHQ-8) and suicidal ideation was assessed by item 9 from the Patient Health Questionnaire-9 (PHQ-9). Personality traits were captured using the Business-Focused Inventory of Personality 6 Factors (BIP-6F). Multivariable logistic regression analyses were used to quantify the associations between work-related personality factors and mental health outcomes, controlling for demographic and social factors. Odds ratios (ORs) as outcome measures with 95% confidence intervals (CIs) were used. After controlling for important confounders, medical students who scored highly on Stability had lower odds of depressive symptoms (OR: 0.19, 95% CI: 0.09-0.42, p < 0.001) and suicidality (OR: 0.38, 95% CI: 0.16-0.87, p < 0.05) than those with high scores in other work-related personality factors. Findings also showed that those who scored highly on Dominance had greater odds of depressive symptoms (OR: 2.46, 95% CI: 1.22-4.97), p < 0.01). Work-related personality-informed interventions, which promote students' mental well-being and reduce academic stress should be considered at various stages of their medical training. PMID- 29997317 TI - Industrial Data Space Architecture Implementation Using FIWARE. AB - We are in front of a new digital revolution that will transform the way we understand and use services and infrastructures. One of the key factors of this revolution is related to the evolution of the Internet of Things (IoT). Connected sensors will be installed in cities and homes affecting the daily life of people and providing them new ways of performing their daily activities. However, this revolution will also affect business and industry bringing the IoT to the production processes in what is called Industry 4.0. Sensor-enabled manufacturing equipment will allow real time communication, smart diagnosis and autonomous decision making. In this scope, the Industrial Data Spaces (IDS) Association has created a Reference Architecture model that aims to provide a common frame for designing and deploying Industry IoT infrastructures. In this paper, we present an implementation of such Reference Architecture based on FIWARE open source software components (Generic Enablers). We validate the proposed architecture by deploying and testing it in a real industry use case that tries to improve the maintenance and operation of milling machines. We conclude that the FIWARE-based IDS implementation fits the requirements of the IDS Reference Architecture providing open source software suitable to any Industry 4.0 environment. PMID- 29997318 TI - Association between Health Literacy and Radiation Anxiety among Residents after a Nuclear Accident: Comparison between Evacuated and Non-Evacuated Areas. AB - Following the accident at the Fukushima Nuclear Power Plant in March 2011, both experts and the national government provided insufficient information on radiation, leading to widespread distrust in the community. This study aimed at clarifying the association between anxiety about radiation and health literacy among residents in evacuation and non-evacuation areas in Fukushima. A questionnaire survey was sent to randomly sampled residents between August and October 2016, and data from 777 responses (38.9% valid response) were analyzed. The questionnaire assessed current radiation anxiety and discrimination and prejudice based on radiation exposure through seven items and communicative and critical health literacy through five items. Multiple regression analysis of the association between radiation anxiety and health literacy showed that the level of health literacy was significantly negatively associated with radiation anxiety in the evacuation areas (marginally in the non-evacuation areas) and marginally negatively associated with discrimination and prejudice in the evacuation areas but not in the non-evacuation areas. Therefore, improving health literacy could alleviate radiation anxiety. PMID- 29997320 TI - Expert System for Monitoring the Malaxing State of the Olive Paste Based on Computer Vision ?. AB - The malaxing of olive paste is one of the most important sub-processes in the virgin olive oil production process. The master continuously supervises the olive paste inside the themomixer to assess the preparation state of the olive paste and he acts manually over the process variables. The viscosity, granularity, and the presence of olive oil over the paste are the main indicators of the olive paste state. Furthermore, the temperature, time, coadjuvant addition and the shovel speeds are the process variables in the thermomixer. In this work, different image-processing parameters have been proposed to automatically assess the aforementioned indicators and they have been used as inputs in the designed fuzzy controller. Also, the outputs of this controller have been evaluated according to a sequence of images obtained inside the thermomixer and during the malaxing process in a real olive mill. PMID- 29997319 TI - N-Butanol Subfraction of Brassica Rapa L. Promotes Reactive Oxygen Species Production and Induces Apoptosis of A549 Lung Adenocarcinoma Cells via Mitochondria-Dependent Pathway. AB - Brassica rapa L., an edible and medical vegetable, has been traditionally used in Uyghur folk medicine to treat coughs and asthma in the Xinjiang Uygur Autonomous Region, China. In this study, we prepared an n-butanol subfraction of B. rapa L. (BRBS) and investigated the anti-tumor effect on A549 lung adenocarcinoma cells. The proliferation of A549 cells was significantly inhibited by BRBS treatment in a dose- and time-dependent manner. BRBS significantly induced cell cycle arrest and apoptosis in A549 cells through increased reactive oxygen species (ROS) production and mitochondrial dysfunction characterized by a reduction in mitochondrial membrane potential and the release of cytochrome c, which promoted caspase-3 and poly(ADP-ribose) polymerase processing. Moreover, BRBS significantly suppressed the migration of A549 cells in vitro. These results suggest that BRBS inhibited A549 cell proliferation through increased ROS production and the mitochondria-dependent apoptosis pathway. Consequently, BRBS might be a potential candidate for the treatment of lung cancer. PMID- 29997322 TI - Use of Standardized Patient Simulations to Assess Impact of Motivational Interviewing Training on Social-Emotional Development. AB - The objective of this study was to assess the impact of motivational interviewing (MI) training on students' social-emotional development. Two simulations using standardized patients (SP) were conducted within a smoking cessation module. Students first completed a 4 h self-study module focused on smoking cessation tools and general counseling techniques. Faculty then administered a 15-item rubric focused on students' self-assessment of their verbal/non-verbal communication, social-emotional competence and MI skills. Students then participated in a smoking cessation counseling session with an SP. SPs used the same rubric to assess student performance. Teaching assistants (TAs) observed and assessed the students using the same rubric and an additional 22 items related to clinical skills. TAs and SPs then provided feedback on areas of improvement. The following week, students first completed a 3 h self-study module on MI then participated in a different smoking cessation scenario. After completion, the 15 item self-assessment rubric was administered. There was a significant improvement in TA assessed student performance with an average score improvement of 8% (pre intervention score = 67%; post-intervention mean = 75%). Students had dramatic gains in their self-assessment with their scores rising by an average of 22%. Using MI techniques can improve students' self-assessed and perceived social emotional competency. PMID- 29997321 TI - Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury. AB - Blast concussions are a common injury sustained in military combat today. Inflammation due to microglial polarization can drive the development of visual defects following blast injuries. In this study, we assessed whether anti inflammatory factors released by the mesenchymal stem cells derived from adipose tissue (adipose stem cells, ASC) can limit retinal tissue damage and improve visual function in a mouse model of visual deficits following mild traumatic brain injury. We show that intravitreal injection of 1 MUL of ASC concentrated conditioned medium from cells pre-stimulated with inflammatory cytokines (ASC CCM) mitigates loss of visual acuity and contrast sensitivity four weeks post blast injury. Moreover, blast mice showed increased retinal expression of genes associated with microglial activation and inflammation by molecular analyses, retinal glial fibrillary acidic protein (GFAP) immunoreactivity, and increased loss of ganglion cells. Interestingly, blast mice that received ASC-CCM improved in all parameters above. In vitro, ASC-CCM not only suppressed microglial activation but also protected against Tumor necrosis alpha (TNFalpha) induced endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrate TSG-6 is highly expressed in ASC CCM from cells pre-stimulated with TNFalpha and IFNgamma but not from unstimulated cells. Our findings suggest that ASC-CCM mitigates visual deficits of the blast injury through their anti-inflammatory properties on activated pro inflammatory microglia and endothelial cells. A regenerative therapy for immediate delivery at the time of injury may provide a practical and cost effective solution against the traumatic effects of blast injuries to the retina. PMID- 29997325 TI - GNSS/INS Fusion with Virtual Lever-Arm Measurements ?. AB - The navigation subsystem in most platforms is based on an inertial navigation system (INS). Regardless of the INS grade, its navigation solution drifts in time. To avoid such a drift, the INS is fused with external sensor measurements such as a global navigation satellite system (GNSS). Recent publications showed that the lever-arm, defined as the relative position between the INS and aiding sensor, has a strong influence on navigation accuracy. Most research in this field is focused on INS/GNSS fusion with GNSS position or velocity updates while considering various maneuvers types. In this paper, we propose to employ virtual lever-arm (VLA) measurements to improve the accuracy and time to convergence of the observable INS error-states. In particular, we show that VLA measurements improve performance even in stationary conditions. In situations when maneuvering helps to improve state observability, VLA measurements manage to gain additional improvement in accuracy. These results are supported by simulation and field experiments with a vehicle mounted with a GNSS and an INS. PMID- 29997324 TI - Theoretical Model of EphA2-Ephrin A1 Inhibition. AB - This work aims at the theoretical description of EphA2-ephrin A1 inhibition by small molecules. Recently proposed ab initio-based scoring models, comprising long-range components of interaction energy, is tested on lithocholic acid class inhibitors of this protein-protein interaction (PPI) against common empirical descriptors. We show that, although limited to compounds with similar solvation energy, the ab initio model is able to rank the set of selected inhibitors more effectively than empirical scoring functions, aiding the design of novel compounds. PMID- 29997323 TI - Integrating Thyroid Hormone Signaling in Hypothalamic Control of Metabolism: Crosstalk Between Nuclear Receptors. AB - The obesity epidemic is well recognized as a significant global health issue. A better understanding of the energy homeostasis mechanisms could help to identify promising anti-obesity therapeutic strategies. It is well established that the hypothalamus plays a pivotal role governing energy balance. The hypothalamus consists of tightly interconnected and specialized neurons that permit the sensing and integration of several peripheral inputs, including metabolic and hormonal signals for an appropriate physiological response. Current evidence shows that thyroid hormones (THs) constitute one of the key endocrine factors governing the regulation and the integration of metabolic homeostasis at the hypothalamic level. THs modulate numerous genes involved in the central control of metabolism, as TRH (Thyrotropin-Releasing Hormone) and MC4R (Melanocortin 4 Receptor). THs act through their interaction with thyroid hormone receptors (TRs). Interestingly, TH signaling, especially regarding metabolic regulations, involves TRs crosstalk with other metabolically linked nuclear receptors (NRs) including PPAR (Peroxisome proliferator-activated receptor) and LXR (Liver X receptor). In this review, we will summarize current knowledge on the important role of THs integration of metabolic pathways in the central regulation of metabolism. Particularly, we will shed light on the crosstalk between TRs and other NRs in controlling energy homeostasis. This could be an important track for the development of attractive therapeutic compounds. PMID- 29997326 TI - Role of Sediments in Insecticide Runoff from Urban Surfaces: Analysis and Modeling. AB - Insecticides, such as pyrethroids, have frequently been detected in runoff from urban areas, and their offsite transport can cause aquatic toxicity in urban streams and estuaries. To better understand the wash-off process of pesticide residues in urban runoff, the association of pyrethroids with sediment in runoff from residential surfaces was investigated in two watersheds located in Northern California (Sacramento County). Rainfall, flow rate, and event mean concentrations/loads of sediments and pyrethroids, collected during seasonal monitoring campaigns from 2007 to 2014, were analyzed to identify relationships among stormwater quality and rainfall characteristics, primarily using Principal Component Analysis (PCA). Pyrethroid wash-off was strongly related to sediment wash-off whenever sediment loads exceeded 10 mg; this value was conveniently selected as a threshold between dissolved and particle-bound control of off-site pyrethroid transport. A new mechanistic model for predicting pyrethroid wash-off profiles from residential surfaces at basin-scale was implemented in the Storm Water Management Model (SWMM). The accuracy of the model predictions was estimated by evaluating the root mean square error (RMSE), Nash-Sutcliff efficiency (NSE), and Kling-Gupta efficiency (KGE) for each pyrethroid detected (RMSEtot = 0.13; NSEtot = 0.28; KGEtot = 0.56). The importance of particle-bound transport revealed in this work confirms previous field investigations at a smaller scale, and it should be a key consideration when developing policies to mitigate pesticide runoff from urban areas. PMID- 29997327 TI - The Nitrogen Heterocycle Content of Meteorites and Their Significance for the Origin of Life. AB - Carbonaceous chondrites are very primitive meteorites that are rich in carbon. They contain many soluble organic compounds, including nitrogen heterocycles. These play a crucial role in present-day living organisms as they are components of the genetic material and of the co-factors of enzymes. This review outlines the nitrogen heterocycle content of carbonaceous meteorites. The potential mechanisms of formation of these molecules are also described. Measurements of the compound-specific carbon and hydrogen isotopic compositions are mentioned as a way of establishing the origin of the nitrogen heterocycles detected in meteorites. PMID- 29997328 TI - Synergistic Effects of Influenza and Staphylococcus aureus Toxins on Inflammation Activation and Cytotoxicity in Human Monocytic Cell Lines. AB - In patients with influenza, morbidity and mortality are strongly influenced by infections with Staphylococcus aureus producing high amounts of certain toxins. Here we tested the impact of influenza virus on the pro-inflammatory and cytotoxic actions of a panel of S. aureus virulence factors, including Panton Valentine Leucocidin (PVL), phenol-soluble modulin alpha1 (PSMalpha1) and 3 (PSMalpha3), alpha-hemolysin (Hla), and cell wall components, i.e., heat-killed S. aureus (HKSA) and protein A. We initially screened for potential synergic interactions using a standardized in vitro model in influenza-infected continuous human monocytic cell lines. Then we tested the identified associations using an ex vivo model in influenza-infected human monocytes freshly isolated from blood. Co-exposure to influenza virus and HKSA, PVL, PSMalpha1, and PSMalpha3 increased NF-kappaB/AP-1 pathway activation in THP1-XBlue cells, and co-exposure to influenza virus and PVL increased cytotoxicity in U937 cells. In monocytes isolated from blood, the synergy between influenza virus and HKSA was confirmed based on cytokine production (TNF-alpha, IL-1beta, IL-6), and co-exposure to influenza virus and Hla-increased cytotoxicity. Our findings suggest that influenza virus potentiates the pro-inflammatory action of HKSA and contributes to the cytotoxicity of Hla on monocytes. Synergic interactions identified in the cell-line model must be cautiously interpreted since few were relevant in the ex vivo model. PMID- 29997329 TI - In-Depth Study of Laser Diode Ablation of Kapton Polyimide for Flexible Conductive Substrates. AB - This work presents a detailed study of the photothermal ablation of Kapton(r) polyimide by a laser diode targeting its electrical conductivity enhancement. Laser-treated samples were structurally characterized using Scanning Electron Microscopy (SEM), Raman spectroscopy, X-ray Photoelectron Spectroscopy (XPS), as well as Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy. The results show that the laser-assisted ablation constitutes a simple one-step and environmental friendly method to induce graphene-derived structures on the surface of polyimide films. The laser-modified surface was also electrically characterized through the Transmission Line Method (TLM) aiming at the improvement of the conductivity of the samples by tuning the laser power and the extraction of the contact resistance of the electrodes. Once the laser-ablation process is optimized, the samples increase their conductivity up to six orders of magnitude, being comparable to that of graphene obtained by chemical vapor deposition or by the reduction of graphene-oxide. Additionally, we show that the contact resistance can be decreased down to promising values of ∼2 Omega when using silver-based electrodes. PMID- 29997330 TI - Rheological and Mechanical Analyses of Felbinac Cataplasms by Using Box-Behnken Design. AB - Felbinac, an active pharmaceutical ingredient (API) used clinically for the treatment of osteoarthritis, has poor solubility. Felbinac cataplasm product design was investigated using rheological and mechanical analyses. Experiments using a response surface methodology based on Box-Behnken design (BBD) incorporated three independent variables: the proportions of partially neutralized polyacrylate (NP800), dihydroxyaluminum aminoacetate (DAAA), and felbinac. Statistically significant quadratic models obtained using BBD demonstrated optimal NP-800, DAAA, and felbinac cataplasm proportions of 4.78 5.75%, 0.30-0.59%, and 0.70-0.90%, respectively. Felbinac cataplasms exhibited "gel-like" mechanical property with predominantly elastic behavior. Rheological studies correlated increasing NP-800 and DAAA concentrations with increased complex modulus (G*) values that were inversely related to peeling strength. Frequency sweep and creep tests revealed decreasing tan theta values with increasing NP-800 and DAAA concentrations. G' and G" values were higher for higher NP-800 and DAAA levels, although G" values decreased with increasing DAAA concentration. Response surface methodology was applied to develop mathematical models. Variance analysis showed that the quadratic model effectively predicted felbinac and matrix material interactions, with two verification samples upholding model predictions. Relative errors between predicted and measured G* values were 3.28% and 1.10% and for peeling strength were 1.24% and 5.59%, respectively. In conclusion, rheological and mechanical analyses of felbinac cataplasms using BBD permits optimization of cataplasms as topical drug delivery vehicles. PMID- 29997331 TI - Establishment of Baculovirus-Expressed VLPs Induced Syncytial Formation Assay for Flavivirus Antiviral Screening. AB - The baculovirus-insect cell expression system has been widely used for heterologous protein expression and virus-like particles (VLPs) expression. In this study, we established a new method for antiviral screening targeting to glycoprotein E of flaviviruses based on the baculovirus expression system. ZIKV is a mosquito-borne flavivirus and has posed great threat to the public health. It has been reported that ZIKV infection was associated with microcephaly and serious neurological complications. Our study showed that either ZIKV E or prME protein expressed in insect cells can form VLPs and induce membrane fusion between insect cells. Therefore, the E protein, which is responsible for receptor binding, attachment, and virus fusion during viral entry, achieved proper folding and retained its fusogenic ability in VLPs when expressed in this system. The syncytia in insect cells were significantly reduced by the anti-ZIKV-E specific polyclonal antibody in a dose-dependent manner. AMS, a thiol-conjugating reagent, was also shown to have an inhibitory effect on the E protein induced syncytia and inhibited ZIKV infection by blocking viral entry. Indeed the phenomenon of syncytial formation induced by E protein expressed VLPs in insect cells is common among flaviviruses, including Japanese encephalitis virus (JEV), Dengue virus type 2 (DENV-2), and tick-borne encephalitis virus (TBEV). This inhibition effect on syncytial formation can be developed as a novel, safe, and simple antiviral screening approach for inhibitory antibodies, peptides, or small molecules targeting to E protein of ZIKV and other flaviviruses. PMID- 29997332 TI - Hot Melt Extrusion: Highlighting Physicochemical Factors to Be Investigated While Designing and Optimizing a Hot Melt Extrusion Process. AB - Hot-melt extrusion (HME) is a well-accepted and extensively studied method for preparing numerous types of drug delivery systems and dosage forms. It offers several advantages: no solvents are required, it is easy to scale up and employ on the industrial level, and, in particular, it offers the possibility of improving drug bioavailability. HME involves the mixing of a drug with one or more excipients, in general polymers and even plasticizers, which can melt, often forming a solid dispersion of the drug in the polymer. The molten mass is extruded and cooled, giving rise to a solid material with designed properties. This process, which can be realized using different kinds of special equipment, may involve modifications in the drug physicochemical properties, such as chemical, thermal and mechanical characteristics thus affecting the drug physicochemical stability and bioavailability. During process optimization, the evaluation of the drug solid state and stability is thus of paramount importance to guarantee stable drug properties for the duration of the drug product shelf life. This manuscript reviews the most important physicochemical factors that should be investigated while designing and optimizing a hot melt extrusion process, and by extension, during the different pre-formulation, formulation and process, and post-formulation phases. It offers a comprehensive evaluation of the chemical and thermal stability of extrudates, the solid physical state of extrudates, possible drug-polymer interactions, the miscibility/solubility of the drug-polymer system, the rheological properties of extrudates, the physicomechanical properties of films produced by hot melt extrusion, and drug particle dissolution from extrudates. It draws upon the last ten years of research, extending inquiry as broadly as possible. PMID- 29997334 TI - A Description of Laying Hen Husbandry and Management Practices in Canada. AB - Canadian laying hen farms are transitioning from conventional cage housing to furnished cage and non-cage housing systems to improve laying hen welfare. However, little is known about the current housing and management systems in Canada. This study addresses this knowledge gap by describing different housing and management practices used on farms where laying hens were housed in furnished cages or non-cage housing systems. A questionnaire covering farm and housing conditions, litter management, nutrition and feeding, environmental control, flock characteristics, rearing and placement, health, egg production and performance were distributed through provincial egg boards to 122 producers across Canada. Data were collected from 65 laying hen flocks (52.5% response rate) in 26 furnished cage, 17 single-tier and 22 multi-tier systems. Flocks were on average 45.1 +/- 14.59 weeks old (range: 19-69 weeks). Frequencies of different management practices were calculated according to housing system. Most flocks were reared in the same housing system as they were housed in during lay, with the exception of furnished cage layers which were reared in conventional cage systems. Results indicated that a large proportion of non-cage systems were either fully slatted or had manure as a litter substrate, which could have implications for consumer perspectives on these systems. Further research is needed to develop clear recommendations on proper litter management for farmers. In general, flock health was managed through daily inspections and vaccination schemes, whereas veterinarian involvement on-farm was less common. Vaccination, hygiene, and effective biosecurity should be maintained to ensure good health in laying hens in furnished cage and non-cage systems during the transition to these systems. PMID- 29997333 TI - Bridging Strategies to Allogeneic Transplant for Older AML Patients. AB - Treatment options for older patients with intermediate or high-risk acute myeloid leukemia (AML) remain unsatisfactory. Allogeneic stem cell transplantation, the treatment of choice for the majority of younger AML patients, has been hampered in elderly patients by higher treatment related mortality, comorbidities and lack of a suitable donor. With the higher availability of suitable donors as well as of reduced intensity conditioning regimens, novel low intensity treatments prior to transplantation and optimized supportive care, the number of older AML patients being successfully transplanted is steadily increasing. Against this background, we review current treatment strategies for older AML patients planned for allogeneic stem cell transplantation based on clinical trial data, discussing differences between approaches with advantages and pitfalls of each. We summarize pre-treatment considerations that need to be taken into account in this highly heterogeneous older population. Finally, we offer an outlook on areas of ongoing clinical research, including novel immunotherapeutic approaches that may improve access to curative therapies for a larger number of older AML patients. PMID- 29997335 TI - Bioavailability of Eurycomanone in Its Pure Form and in a Standardised Eurycoma longifolia Water Extract. AB - Eurycoma longifolia is one of the commonly consumed herbal preparations and its major chemical compound, eurycomanone, has been described to have antimalarial, antipyretic, aphrodisiac, and cytotoxic activities. Today, the consumption of E. longifolia is popular through the incorporation of its extract in food items, most frequently in drinks such as tea and coffee. In the current study, the characterisation of the physicochemical and pharmacokinetic (PK) attributes of eurycomanone were conducted via a series of in vitro and in vivo studies in rats and mice. The solubility and chemical stability of eurycomanone under the conditions of the gastrointestinal tract environment were determined. The permeability of eurycomanone was investigated by determining its distribution coefficient in aqueous and organic environments and its permeability using the parallel artificial membrane permeability assay system and Caco-2 cultured cells. Eurycomanone's stability in plasma and its protein-binding ability were measured by using an equilibrium dialysis method. Its stability in liver microsomes across species (mice, rat, dog, monkey, and human) and rat liver hepatocytes was also investigated. Along with the PK evaluations of eurycomanone in mice and rats, the PK parameters for the Malaysian Standard (MS: 2409:201) standardised water extract of E. longifolia were also evaluated in rats. Both rodent models showed that eurycomanone in both the compound form and extract form had a half-life of 0.30 h. The differences in the bioavailability of eurycomanone in the compound form between the rats (11.8%) and mice (54.9%) suggests that the PK parameters cannot be directly extrapolated to humans. The results also suggest that eurycomanone is not readily absorbed across biological membranes. However, once absorbed, the compound is not easily metabolised (is stable), hence retaining its bioactive properties, which may be responsible for the various reported biological activities. PMID- 29997336 TI - Combining Living Microorganisms with Regenerated Silk Provides Nanofibril-Based Thin Films with Heat-Responsive Wrinkled States for Smart Food Packaging. AB - Regenerated silk (RS) is a protein-based "biopolymer" that enables the design of new materials; here, we called "bionic" the process of regenerated silk production by a fermentation-assisted method. Based on yeast's fermentation, here we produced a living hybrid composite made of regenerated silk nanofibrils and a single-cell fungi, the Saccharomyces cerevisiae yeast extract, by fermentation of such microorganisms at room temperature in a dissolution bath of silkworm silk fibers. The fermentation-based processing enhances the beta-sheet content of the RS, corresponding to a reduction in water permeability and CO2 diffusion through RS/yeast thin films enabling the fabrication of a mechanically robust film that enhances food storage durability. Finally, a transfer print method, which consists of transferring RS and RS/yeast film layers onto a self-adherent paraffin substrate, was used for the realization of heat-responsive wrinkles by exploiting the high thermal expansion of the paraffin substrate that regulates the applied strain, resulting in a switchable coating morphology from the wrinkle free state to a wrinkled state if the food temperature overcomes a designed threshold. We envision that such efficient and smart coatings can be applied for the realization of smart packaging that, through such a temperature-sensing mechanism, can be used to control food storage conditions. PMID- 29997337 TI - Green Tea Quality Evaluation Based on Its Catechins and Metals Composition in Combination with Chemometric Analysis. AB - Green tea infusions are one of the most popular beverages consumed across the world, especially is Asian countries. Green tea quality is primarily based on catechin content, however, the concentration of elements could also significantly influence its biological properties and thus quality and safety. The main purpose of the present study was the evaluation of catechin, antioxidant activity and metal content (K, Na, Ca, Mg, Fe, Mn, Cu, Zn, Cr, Pb, Cd and Ni) in different green tea types cultivated in Japan, Sri Lanka, South Korea, India, China and Japan. The chemical analysis of samples was performed using LC-ESI-Q-TOF-MS for organic constituents and atomic absorption spectrometry (flame and electrothermal) method for inorganic ones. The obtained results were subjected to chemometric elaboration. EGC (213 mg/100 mL of the tea infusion in South Korean Jeoncha) and EGCG (124 mg/100 mL in Japanese Sencha) were the dominant catechins in all green tea samples. Chinese and Indian green tea samples contained the highest concentration of toxic heavy metals, however these values were far below appropriate limitations for green teas. PCA revealed significant similarities between Japanese samples and Korean Jeoncha. In general the latter one was evaluated to have the best quality based on the investigated parameters. PMID- 29997339 TI - Screen Printed Pb3O4 Films and Their Application to Photoresponsive and Photoelectrochemical Devices. AB - A new and simple procedure for the deposition of lead (II, IV) oxide films by screen printing was developed. In contrast to conventional electrochemical methods, films can be also deposited on non-conductive substrates without any specific dimensional restriction, being the only requirement the thermal stability of the substrate in air up to 500 degrees C to allow for the calcination of the screen printing paste and sintering of the film. In this study, films were exploited for the preparation of both photoresponsive devices and photoelectrochemical cell photoanodes. In both cases, screen printing was performed on FTO (Fluorine-Tin Oxide glass) substrates. The photoresponsive devices were tested with I-V curves in dark and under simulated solar light with different irradiation levels. Responses were evaluated at different voltage biases and under light pulses of different durations. Photoelectrochemical cells were tested by current density-voltage (J-V) curves under air mass (AM) 1.5 G illumination, incident photon-to-current efficiency (IPCE) measurements, and electrochemical impedance spectroscopy. PMID- 29997340 TI - An Indoor Positioning System Based on Static Objects in Large Indoor Scenes by Using Smartphone Cameras. AB - The demand for location-based services (LBS) in large indoor spaces, such as airports, shopping malls, museums and libraries, has been increasing in recent years. However, there is still no fully applicable solution for indoor positioning and navigation like Global Navigation Satellite System (GNSS) solutions in outdoor environments. Positioning in indoor scenes by using smartphone cameras has its own advantages: no additional needed infrastructure, low cost and a large potential market due to the popularity of smartphones, etc. However, existing methods or systems based on smartphone cameras and visual algorithms have their own limitations when implemented in relatively large indoor spaces. To deal with this problem, we designed an indoor positioning system to locate users in large indoor scenes. The system uses common static objects as references, e.g., doors and windows, to locate users. By using smartphone cameras, our proposed system is able to detect static objects in large indoor spaces and then calculate the smartphones' position to locate users. The system integrates algorithms of deep learning and computer vision. Its cost is low because it does not require additional infrastructure. Experiments in an art museum with a complicated visual environment suggest that this method is able to achieve positioning accuracy within 1 m. PMID- 29997338 TI - TRP Channel Involvement in Salivary Glands-Some Good, Some Bad. AB - Salivary glands secrete saliva, a mixture of proteins and fluids, which plays an extremely important role in the maintenance of oral health. Loss of salivary secretion causes a dry mouth condition, xerostomia, which has numerous deleterious consequences including opportunistic infections within the oral cavity, difficulties in eating and swallowing food, and problems with speech. Secretion of fluid by salivary glands is stimulated by activation of specific receptors on acinar cell plasma membrane and is mediated by an increase in cytosolic [Ca2+] ([Ca2+]i). The increase in [Ca2+]i regulates a number of ion channels and transporters that are required for establishing an osmotic gradient that drives water flow via aquaporin water channels in the apical membrane. The Store-Operated Ca2+ Entry (SOCE) mechanism, which is regulated in response to depletion of ER-Ca2+, determines the sustained [Ca2+]i increase required for prolonged fluid secretion. Core components of SOCE in salivary gland acinar cells are Orai1 and STIM1. In addition, TRPC1 is a major and non-redundant contributor to SOCE and fluid secretion in salivary gland acinar and ductal cells. Other TRP channels that contribute to salivary flow are TRPC3 and TRPV4, while presence of others, including TRPM8, TRPA1, TRPV1, and TRPV3, have been identified in the gland. Loss of salivary gland function leads to dry mouth conditions, or xerostomia, which is clinically seen in patients who have undergone radiation treatment for head-and-neck cancers, and those with the autoimmune exocrinopathy, Sjogren's syndrome (pSS). TRPM2 is a unique TRP channel that acts as a sensor for intracellular ROS. We will discuss recent studies reported by us that demonstrate a key role for TRPM2 in radiation-induced salivary gland dysfunction. Further, there is increasing evidence that TRPM2 might be involved in inflammatory processes. These interesting findings point to the possible involvement of TRPM2 in Sjogren's Syndrome, although further studies will be required to identify the exact role of TRPM2 in this disease. PMID- 29997342 TI - Desertification Sensitivity Analysis Using MEDALUS Model and GIS: A Case Study of the Oases of Middle Draa Valley, Morocco. AB - Oases can play a significant role in the sustainable economic development of arid and Saharan regions. The aim of this study was to map the desertification sensitive areas in the Middle Draa Valley (MDV), which is in the southeast of Morocco. A total of 13 indices that affect desertification processes were identified and analyzed using a geographic information system. The Mediterranean desertification and land use approach; which has been widely used in the Mediterranean regions due to its simplicity; flexibility and rapid implementation strategy; was applied. All the indices were grouped into four main quality indices; i.e., soil quality; climate quality; vegetation quality and management quality indices. Each quality index was constructed by the combination of several sub-indicators. In turn; the geometric mean of the four quality index maps was used to construct a map of desertification-sensitive areas; which were classified into four classes (i.e., low; moderate; high and very high sensitivity). Results indicated that only 16.63% of the sites in the study were classified as least sensitive to desertification; and 50.34% were classified as highly and very highly sensitive areas. Findings also showed that climate and human pressure factors are the most important indicators affecting desertification sensitivity in the MDV. The framework used in this research provides suitable results and can be easily implemented in similar oasis arid areas. PMID- 29997341 TI - Detailed Analysis of 17beta-Estradiol-Aptamer Interactions: A Molecular Dynamics Simulation Study. AB - Micro-pollutants such as 17beta-Estradiol (E2) have been detected in different water resources and their negative effects on the environment and organisms have been observed. Aptamers are established as a possible detection tool, but the underlying ligand binding is largely unexplored. In this study, a previously described 35-mer E2-specific aptamer was used to analyse the binding characteristics between E2 and the aptamer with a MD simulation in an aqueous medium. Because there is no 3D structure information available for this aptamer, it was modeled using coarse-grained modeling method. The E2 ligand was positioned inside a potential binding area of the predicted aptamer structure, the complex was used for an 25 ns MD simulation, and the interactions were examined for each time step. We identified E2-specific bases within the interior loop of the aptamer and also demonstrated the influence of frequently underestimated water mediated hydrogen bonds. The study contributes to the understanding of the behavior of ligands binding with aptamer structure in an aqueous solution. The developed workflow allows generating and examining further appealing ligand aptamer complexes. PMID- 29997343 TI - Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions. AB - Background: We use a mobile software application (app) to measure for the first time, which fundamental characteristics of raw, natural medical Cannabis flower are associated with changes in perceived insomnia under naturalistic conditions. Methods: Four hundred and nine people with a specified condition of insomnia completed 1056 medical cannabis administration sessions using the Releaf AppTM educational software during which they recorded real-time ratings of self perceived insomnia severity levels prior to and following consumption, experienced side effects, and product characteristics, including combustion method, cannabis subtypes, and/or major cannabinoid contents of cannabis consumed. Within-user effects of different flower characteristics were modeled using a fixed effects panel regression approach with standard errors clustered at the user level. Results: Releaf AppTM users showed an average symptom severity reduction of -4.5 points on a 0-10 point visual analogue scale (SD = 2.7, d = 2.10, p < 0.001). Use of pipes and vaporizers was associated with greater symptom relief and more positive and context-specific side effects as compared to the use of joints, while vaporization was also associated with lower negative effects. Cannabidiol (CBD) was associated with greater statistically significant symptom relief than tetrahydrocannabinol (THC), but the cannabinoid levels generally were not associated with differential side effects. Flower from C. sativa plants was associated with more negative side effects than flower from C. indica or hybrid plant subtypes. Conclusions: Consumption of medical Cannabis flower is associated with significant improvements in perceived insomnia with differential effectiveness and side effect profiles, depending on the product characteristics. PMID- 29997344 TI - Biodiversity, Evolution and Ecological Specialization of Baculoviruses: A Treasure Trove for Future Applied Research. AB - The Baculoviridae, a family of insect-specific large DNA viruses, is widely used in both biotechnology and biological control. Its applied value stems from millions of years of evolution influenced by interactions with their hosts and the environment. To understand how ecological interactions have shaped baculovirus diversification, we reconstructed a robust molecular phylogeny using 217 complete genomes and ~580 isolates for which at least one of four lepidopteran core genes was available. We then used a phylogenetic-concept-based approach (mPTP) to delimit 165 baculovirus species, including 38 species derived from new genetic data. Phylogenetic optimization of ecological characters revealed a general pattern of host conservatism punctuated by occasional shifts between closely related hosts and major shifts between lepidopteran superfamilies. Moreover, we found significant phylogenetic conservatism between baculoviruses and the type of plant growth (woody or herbaceous) associated with their insect hosts. In addition, we found that colonization of new ecological niches sometimes led to viral radiation. These macroevolutionary patterns show that besides selection during the infection process, baculovirus diversification was influenced by tritrophic interactions, explained by their persistence on plants and interactions in the midgut during horizontal transmission. This complete eco-evolutionary framework highlights the potential innovations that could still be harnessed from the diversity of baculoviruses. PMID- 29997345 TI - TFF1 Promotes EMT-Like Changes through an Auto-Induction Mechanism. AB - Trefoil factor 1 (TFF1) is a small secreted protein expressed in the gastrointestinal tract where, together with the other two members of its family, it plays an essential role in mucosal protection and repair against injury. The molecular mechanisms involved in the protective function of all three TFF proteins are not fully elucidated. In this paper, we investigated the role of TFF1 in epithelial to mesenchymal transition (EMT) events. The effects of TFF1 on cellular models in normoxia and/or hypoxia were evaluated by western blot, immunofluorescence, qRT-PCR and trans-well invasion assays. Luciferase reporter assays were used to assess the existence of an auto-regulatory mechanism of TFF1. The methylation status of TFF1 promoter was measured by high-resolution melting (HRM) analysis. We demonstrate a TFF1 auto-induction mechanism with the identification of a specific responsive element located between -583 and -212 bp of its promoter. Our results suggest that TFF1 can regulate its own expression in normoxic, as well as in hypoxic, conditions acting synergistically with the hypoxia-inducible factor 1 (HIF-1alpha) pathway. Functionally, this auto induction mechanism seems to promote cell invasion and EMT-like modifications in vitro. Additionally, exogenously added human recombinant TFF1 protein was sufficient to observe similar effects. Together, these findings suggest that the hypoxic conditions, which can be induced by gastric injury, promote TFF1 up regulation, strengthened by an auto-induction mechanism, and that the trefoil peptide takes part in the epithelial-mesenchymal transition events eventually triggered to repair the damage. PMID- 29997346 TI - Protein Phosphatase Sit4 Affects Lipid Droplet Synthesis and Soraphen A Resistance Independent of Its Role in Regulating Elongator Dependent tRNA Modification. AB - The protein phosphatase Sit4 has been shown to be required for lipogenesis and resistance against the acetyl-CoA carboxylase inhibitor soraphen A. Since Sit4 is also required for biosynthesis of Elongator dependent tRNA modifications such as 5-methoxycarbonylmethyluridine (mcm5U), we investigated the relevance of tRNA modifications in lipogenesis and soraphen A response. While sit4 and Elongator (elp3) mutants copy defects in mcm5U formation and stress sensitivity, they do not share soraphen A sensitivity and low lipid droplet (LD) phenotypes. In contrast to sit4, we found elp3 mutants to display partial soraphen A resistance and a high LD phenotype. Screening a collection of tRNA modification mutants additionally identified the tRNA pseudo-uridine synthase gene DEG1 to be required for soraphen A sensitivity. Since deg1 and elp3 share high LD and soraphen A resistance phenotypes, these are likely caused by translational defects. In support of this notion, we observe overexpression of tRNAGlnUUG suppresses lipolysis defects of deg1 mutants. Hence, the sit4 mutation results in a composite defect including tRNA modification deficiency and loss of Snf1 kinase dephosphorylation, which induce opposite effects on LD regulation. Importantly, however, the Snf1 kinase regulatory defects of the phosphatase mutant dominate over effects on LD regulation imposed by loss of the tRNA modification alone. PMID- 29997347 TI - Efficient Delivery of Macromolecules into Human Cells by Improving the Endosomal Escape Activity of Cell-Penetrating Peptides: Lessons Learned from dfTAT and its Analogs. AB - Cell-penetrating peptides (CPPs) are typically prone to endocytic uptake into human cells. However, they are often inefficient at escaping from endosomes, which limits their ability to deliver cargos into cells. This review highlights the efforts that our laboratory has devoted toward developing CPPs that can mediate the leakage of endosomal membranes, and consequently gain better access to the intracellular milieu. In particular, we have identified a CPP named dimeric fluorescent TAT (dfTAT) with high endosomolytic activity. We describe how we have used this reagent and its analogs to develop efficient cytosolic delivery protocols and learn about molecular and cellular parameters that control the cell permeation process. Specifically, we discuss how late endosomes represent exploitable gateways for intracellular entry. We also describe how certain features in CPPs, including guanidinium content, charge density, multimerization, chirality, and susceptibility to degradation modulate the activity that these peptidic agents take toward endosomal membranes and cytosolic egress. PMID- 29997349 TI - Study on the Interfacial Functionary Mechanism of Rare-Earth-Solution-Modified Bamboo-Fiber-Reinforced Resin Matrix Composites. AB - In this work, a new and effective treatment on bamboo fiber (BF) is presented, and its effect on the interfacial bonding properties of the BF/resin matrix was studied. The interfacial functionary mechanism of rare earth solution (RES) modification to improve the interfacial bonding properties between BF and the resin matrix was analyzed. The hardness and elastic modulus of the interfacial zone between BF and the resin matrix were measured using nanoindentation. Fourier transform infrared spectroscopy (FT-IR) was used to analyze the change in the surface functional group of BF in the modification process. The surface chemical composition of BF before and after the modification was characterized by X-ray photoelectron spectroscopy (XPS). The results show that the RES modification significantly increases the hardness and elastic modulus of BF and its interfacial zone with the resin matrix. The hydroxyl concentration on the surface of RES-treated BF decreases, which reduces the hydrophilicity of BF. Rare earth ions react with oxygen in the hydroxyl group at the C2 position in the glucosylic ring of cellulose. The RES-modified BF bonds with the resin matrix to form a rare earth complex, which significantly enhances the interfacial adhesion between BF and the resin matrix. PMID- 29997348 TI - A High-Content Screen Reveals New Small-Molecule Enhancers of Ras/Mapk Signaling as Probes for Zebrafish Heart Development. AB - Zebrafish is the preferred vertebrate model for high throughput chemical screens to discover modulators of complex biological pathways. We adapted a transgenic zebrafish line, Tg(dusp6:EGFP), which reports on fibroblast growth factor (Fgf)/Ras/Mapk activity, into a quantitative, high-content chemical screen to identify novel Fgf hyperactivators as chemical probes for zebrafish heart development and regeneration. We screened 10,000 compounds from the TimTec ActiProbe library, and identified several structurally distinct classes of molecules that enhanced Fgf/Ras/Mapk signaling. We chose three agents-ST020101, ST011282, and ST006994-for confirmatory and functional studies based on potency, repeatability with repurchased material, favorable whole organism toxicity, and evidence of structure-activity relationships. Functional follow-up assays confirmed that all three compounds induced the expression of Fgf target genes during zebrafish embryonic development. Moreover, these compounds increased cardiac progenitor populations by effecting a fate change from endothelial to cardiac progenitors that translated into increased numbers of cardiomyocytes. Interestingly, ST006994 augmented Fgf/Ras/Mapk signaling without increasing Erk phosphorylation, suggesting a molecular mechanism of action downstream of Erk. We posit that the ST006994 pharmacophore could become a unique chemical probe to uncover novel mechanisms of Fgf signaling during heart development and regeneration downstream of the Mapk signaling node. PMID- 29997350 TI - Youth Access to Electronic Cigarettes in an Unrestricted Market: A Cross Sectional Study from Poland. AB - Background: Electronic cigarette (e-cigarette) use among youths in Poland has become very popular. The aim of this study was to identify the potential points of access to these products by students aged 16-17 years old before implementation of sales restrictions to minors in Poland in November 2016. Methods: A school-based, cross-sectional survey was administered in 2015-2016 in 21 secondary/technical schools across two regions of Poland. Analyses focused on 341 students aged 16-17 years old who reported their past 30-day use of e cigarettes. Pearson Chi-square analyses were utilized to examine the associations between access-related items, e-cigarette use and demographics. Results: Among youth e-cigarette users, the most common access to their first e-cigarette was from a friend (38%), followed by purchasing from vape shops (26%). Similar patterns emerged when the students were asked about their access to the currently used e-cigarette. Most youths reported no difficulty in purchasing cartridges/e liquid containing nicotine (90%). The majority of users (52%) reported buying such products in vape shops. Conclusions: Prior to implementing age-related sales restrictions, youth access to e-cigarettes and paraphernalia did not pose any significant barriers. Poland's introduction of a new age limit on e-cigarette sales may help to limit the number of youths who purchase e-cigarettes from vape shops. PMID- 29997351 TI - Non-GNSS Smartphone Pedestrian Navigation Using Barometric Elevation and Digital Map-Matching. AB - Pedestrian navigation in outdoor environments where global navigation satellite systems (GNSS) are unavailable is a challenging problem. Existing technologies that have attempted to address this problem often require external reference signals or specialized hardware, the extra size, weight, power, and cost of which are unsuitable for many applications. This article presents a real-time, self contained outdoor navigation application that uses only the existing sensors on a smartphone in conjunction with a preloaded digital elevation map. The core algorithm implements a particle filter, which fuses sensor data with a stochastic pedestrian motion model to predict the user's position. The smartphone's barometric elevation is then compared with the elevation map to constrain the position estimate. The system developed for this research was deployed on Android smartphones and tested in several terrains using a variety of elevation data sources. The results from these experiments show the system achieves positioning accuracies in the tens of meters that do not grow as a function of time. PMID- 29997352 TI - 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide Radical (PTIO*) Trapping Activity and Mechanisms of 16 Phenolic Xanthones. AB - This study used the 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide radical (PTIO*) trapping model to study the antioxidant activities of 16 natural xanthones in aqueous solution, including garcinone C, gamma-mangostin, subelliptenone G, mangiferin, 1,6,7-trihydroxy-xanthone, 1,2,5 trihydroxyxanthone, 1,5,6-trihydroxyxanthone, norathyriol, 1,3,5,6-tetrahydroxy xanthone, isojacareubin, 1,3,5,8-tetrahydroxyxanthone, isomangiferin, 2 hydroxyxanthone, 7-O-methylmangiferin, neomangiferin, and lancerin. It was observed that most of the 16 xanthones could scavenge the PTIO* radical in a dose dependent manner at pH 4.5 and 7.4. Among them, 12 xanthones of the para-di-OHs (or ortho-di-OHs) type always exhibited lower half maximal inhibitory concentration (IC50) values than those not of the para-di-OHs (or ortho-di-OHs) type. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-Q-TOF MS/MS) analysis revealed that most of these xanthones gave xanthone-xanthone dimers after incubation with PTIO*, except for neomangiferin. Based on these data, we concluded that the antioxidant activity of phenolic xanthone may be mediated by electron-transfer (ET) plus H+-transfer mechanisms. Through these mechanisms, some xanthones can further dimerize unless they bear huge substituents with steric hindrance. Four substituent types (i.e., para-di-OHs, 5,6-di-OHs, 6,7-di-OHs, and 7,8-di-OHs) dominate the antioxidant activity of phenolic xanthones, while other substituents (including isoprenyl and 3-hydroxy-3 methylbutyl substituents) play a minor role as long as they do not break the above four types. PMID- 29997353 TI - Metagenomic Analysis of Microbial Community Compositions and Cold-Responsive Stress Genes in Selected Antarctic Lacustrine and Soil Ecosystems. AB - This study describes microbial community compositions, and various cold responsive stress genes, encompassing cold-induced proteins (CIPs) and cold associated general stress-responsive proteins (CASPs) in selected Antarctic lake water, sediment, and soil metagenomes. Overall, Proteobacteria and Bacteroidetes were the major taxa in all metagenomes. Prochlorococcus and Thiomicrospira were highly abundant in waters, while Myxococcus, Anaeromyxobacter, Haliangium, and Gloeobacter were dominant in the soil and lake sediment metagenomes. Among CIPs, genes necessary for DNA replication, translation initiation, and transcription termination were highly abundant in all metagenomes. However, genes for fatty acid desaturase (FAD) and trehalose synthase (TS) were common in the soil and lake sediment metagenomes. Interestingly, the Lake Untersee water and sediment metagenome samples contained histone-like nucleoid structuring protein (H-NS) and all genes for CIPs. As for the CASPs, high abundances of a wide range of genes for cryo- and osmo-protectants (glutamate, glycine, choline, and betaine) were identified in all metagenomes. However, genes for exopolysaccharide biosynthesis were dominant in Lake Untersee water, sediment, and other soil metagenomes. The results from this study indicate that although diverse microbial communities are present in various metagenomes, they share common cold-responsive stress genes necessary for their survival and sustenance in the extreme Antarctic conditions. PMID- 29997354 TI - Context-Aware Gossip-Based Protocol for Internet of Things Applications. AB - This paper proposes a gossip-based protocol that utilises a multi-factor weighting function (MFWF) that takes several parameters into account: residual energy, Chebyshev distances to neighbouring nodes and the sink node, node density, and message priority. The effects of these parameters were examined to guide the customization of the weight function to effectively disseminate data to three types of IoT applications: critical, bandwidth-intensive, and energy efficient applications. The performances of the three resulting MFWFs were assessed in comparison with the performances of the traditional gossiping protocol and the Fair Efficient Location-based Gossiping (FELGossiping) protocol in terms of end-to-end delay, network lifetime, rebroadcast nodes, and saved rebroadcasts. The experimental results demonstrated the proposed protocol's ability to achieve a much shorter delay for critical IoT applications. For bandwidth-intensive IoT application, the proposed protocol was able to achieve a smaller percentage of rebroadcast nodes and an increased percentage of saved rebroadcasts, i.e., better bandwidth utilisation. The adapted MFWF for energy efficient IoT application was able to improve the network lifetime compared to that of gossiping and FELGossiping. These results demonstrate the high level of flexibility of the proposed protocol with respect to network context and message priority. PMID- 29997355 TI - Effect of Inhibition of DNA Methylation Combined with Task-Specific Training on Chronic Stroke Recovery. AB - To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2'-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for four weeks, with and without TST. Functional recovery was assessed using the staircase test, the cylinder test, and the modified neurological severity score (mNSS). Axonal plasticity and expression of brain-derived neurotrophic factor (BDNF) were determined in the contralateral motor cortex. TST and TST combined with 5-Aza-dC significantly improved the skilled reaching ability in the staircase test and ameliorated mNSS scores and cylinder test performance. TST and TST with 5-Aza-dC significantly increased the crossing fibers from the contralesional red nucleus, reticular formation in medullar oblongata, and dorsolateral spinal cord. Mature BDNF was significantly upregulated by TST and TST combined with 5-Azd-dC. Functional recovery after chronic stroke may involve axonal plasticity and increased mature BDNF by modulating DNA methylation in the contralesional cortex. Our results suggest that combined therapy to enhance axonal plasticity based on TST and 5-Aza-dC constitutes a promising approach for promoting the recovery of function in the chronic stage of stroke. PMID- 29997357 TI - An Effective Singular Value Selection and Bearing Fault Signal Filtering Diagnosis Method Based on False Nearest Neighbors and Statistical Information Criteria. AB - Singular value decomposition (SVD) is an effective method used in bearing fault diagnosis. Ideally two important problems should be solved in any diagnosis: one is how to decide the dimension embedding of the trajectory matrix (TM); the other is how to select the singular value (SV) representing the intrinsic information of the bearing condition. In order to solve such problems, this study proposed an effective method to find the optimal TM and SV and perform fault signal filtering based on false nearest neighbors (FNN) and statistical information criteria. First of all, the embedded dimension of the trajectory matrix is determined with the FNN according to the chaos theory. Then the trajectory matrix is subjected to SVD, which is helpful to acquire all the combinations of SV and decomposed signals. According to the similarities of the signal changed back and signal in normal state based on statistical information criteria, the SV representing fault signal can be obtained. The spectrum envelope demodulation method can be used to perform effective analysis on the fault. The effectiveness of the proposed method is verified with simulation signals and low-speed bearing fault signals, and compared with the published SVD-based method and Fast Kurtogram diagnosis method. PMID- 29997356 TI - Identification of Genomic Regions Contributing to Protein Accumulation in Wheat under Well-Watered and Water Deficit Growth Conditions. AB - Sustaining wheat production under low-input conditions through development and identifying genotypes with enhanced nutritional quality are two current concerns of wheat breeders. Wheat grain total protein content, to no small extent, determines the economic and nutritive value of wheat. Therefore, the objectives of this study are to identify accessions with high and low grain protein content (GPC) under well-watered and water-deficit growth conditions and to locate genomic regions that contribute to GPC accumulation. Spring wheat grains obtained from 2111 accessions that were grown under well-watered and water-deficit conditions were assessed for GPC using near-infrared spectroscopy (NIR). Results indicated significant influences of moisture, genotype, and genotype * environment interaction on the GPC accumulation. Furthermore, genotypes exhibited a wide range of variation for GPC, indicating the presence of high levels of genetic variability among the studied accessions. Around 366 (166 with high GPC and 200 with low GPC) wheat genotypes performed relatively the same across environments, which implies that GPC accumulation in these genotypes was less responsive to water deficit. Genome-wide association mapping results indicated that seven single nucleotide polymorphism (SNPs) were linked with GPC under well watered growth conditions, while another six SNPs were linked with GPC under water-deficit conditions only. Moreover, 10 SNPs were linked with GPC under both well-watered and water-deficit conditions. These results emphasize the importance of using diverse, worldwide germplasm to dissect the genetic architecture of GPC in wheat and identify accessions that might be potential parents for high GPC in wheat breeding programs. PMID- 29997358 TI - Capacitive Phase Shift Detection for Measuring Water Holdup in Horizontal Oil Water Two-Phase Flow. AB - In this paper, a phase shift detection system of flow impedance is designed based on a concave capacitance sensor (CCS). The flow impedance of oil-water stratified flow is investigated by establishing an equivalent circuit model and a finite element model. The influence of exciting frequency and sensor geometric parameters on the phase shift output of the CCS is studied to access an optimal phase shift measurement system. An experiment of horizontal oil-water two-phase flows was conducted during which four flow patterns are observed, i.e., stratified flow (ST), stratified wavy flow (SW), dual continuous flow (DC), and dispersed oil-in-water and water flow (DO/W&W). The phase shift responses of the CCS to the water holdup variation are collected. The results indicate that the phase shift response of the CCS presents satisfied sensitivity for ST and SW flow patterns, which is consistent with the predictions of the equivalent circuit model and the finite element model. Although the flow structures of DC and DO/W&W flows are extremely nonuniform, the phase shift response of the CCS still shows better linearity and sensitivity to the water holdup variation. In general, the capacitive phase shift detection technology exhibits advantages for water holdup measurement in horizontal oil-water two-phase flow with nonuniform phase distributions and conductive water. PMID- 29997359 TI - Description of Genetic Variants in BRCA Genes in Mexican Patients with Ovarian Cancer: A First Step towards Implementing Personalized Medicine. AB - Gynecologic cancers are among the leading causes of death worldwide, ovarian cancer being the one with the highest mortality rate. Olaparib is a targeted therapy used in patients presenting mutations in BRCA1 and BRCA2 genes. The aim of this study was to describe BRCA1 and BRCA2 gene variants in Mexican patients with ovarian cancer. Sequencing of BRCA1 and BRCA2 genes from tumors of 50 Mexican patients with ovarian cancer was made in a retrospective, non-randomized, and exploratory study. We found genetic variants in 48 of 50 cases. A total of 76 polymorphic variants were found in BRCA1, of which 50 (66%) had not been previously reported. Furthermore, 104 polymorphic variants were found in BRCA2, of which 63 (60%) had not been reported previously. Of these polymorphisms, 5/76 (6.6%) and 4/104 (3.8%) were classified as pathogenic in BRCA1 and BRCA2, respectively. We have described the genetic variants in BRCA1 and BRCA2 of tumors from Northeast Mexican patients with sporadic ovarian cancers. Our results showed that the use of genetic testing helps recognize patients that carry pathogenic variants which could be beneficial for personalized medicine treatments. PMID- 29997360 TI - Ultra-Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS)-Based Pharmacokinetics and Tissue Distribution Study of Koumine and the Detoxification Mechanism of Glycyrrhiza uralensis Fisch on Gelsemium elegans Benth. AB - Gelsemium elegans Benth. (G. elegans), which is a famous Chinese folk medicine, has been commonly used to treat certain types of skin ulcers and alleviate inflammation, headaches, and cancer pain. However, the extensive clinical use of G. elegans has been greatly hampered by its toxicity. As one of the most widely used herbal medicines, Glycyrrhiza uralensis Fisch, has a unique effect on detoxification of G. elegans. In the present study, a rapid and sensitive method using ultra-liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was established and validated for determination of koumine, the most abundant molecule among the alkaloids of G. elegans, in rat plasma, tissue, and liver microsome. The developed method was successfully applied to the pharmacokinetics, tissue distribution, and in vitro metabolism study in rat with or without pre treated Glycyrrhiza uralensis Fisch extract. Meanwhile, the expression level of CYP3A1 mRNA was analyzed to explain the detoxification mechanism of Glycyrrhiza uralensis Fisch on G. elegans. As a result, our work demonstrated that Glycyrrhiza uralensis Fisch could significantly affect the pharmacokinetics and tissue distribution of koumine in rats. The detoxification mechanism of Glycyrrhiza uralensis Fisch on G. elegans may be its cytochrome enzyme up regulation effect. PMID- 29997361 TI - The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy. AB - The discovery that mutations in myosin and actin genes, together with mutations in the other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases (myopathies) has revolutionized the study of muscle, converting it from a subject of basic science to a relevant subject for clinical study and has been responsible for a great increase of interest in muscle studies. Myopathies are linked to mutations in five of the myosin heavy chain genes, three of the myosin light chain genes, and three of the actin genes. This review aims to determine to what extent we can explain disease phenotype from the mutant genotype. To optimise our chances of finding the right mechanism we must study a myopathy where there are a large number of different mutations that cause a common phenotype and so are likely to have a common mechanism: a corollary to this criterion is that if any mutation causes the disease phenotype but does not correspond to the proposed mechanism, then the whole mechanism is suspect. Using these criteria, we consider two cases where plausible genotype-phenotype mechanisms have been proposed: the actin "A-triad" and the myosin "mesa/IHD" models. PMID- 29997363 TI - Application of Gold Nanoparticle to Plasmonic Biosensors. AB - Gold nanoparticles (GNPs) have been widely utilized to develop various biosensors for molecular diagnosis, as they can be easily functionalized and exhibit unique optical properties explained by plasmonic effects. These unique optical properties of GNPs allow the expression of an intense color under light that can be tuned by altering their size, shape, composition, and coupling with other plasmonic nanoparticles. Additionally, they can also enhance other optical signals, such as fluorescence and Raman scattering, making them suitable for biosensor development. In this review, we provide a detailed discussion of the currently developed biosensors based on the aforementioned unique optical features of GNPs. Mainly, we focus on four different plasmonic biosensing methods, including localized surface plasmon resonance (LSPR), surface-enhanced Raman spectroscopy (SERS), fluorescence enhancement, and quenching caused by plasmon and colorimetry changes based on the coupling of GNPs. We believe that the topics discussed here are useful and able to provide a guideline in the development of novel GNP-based biosensors in the future. PMID- 29997364 TI - Controlled Release of DEET Loaded on Fibrous Mats from Electrospun PMDA/Cyclodextrin Polymer. AB - Electrospun beta-cyclodextrin (betaCD)-based polymers can combine a high surface to-volume ratio and a high loading/controlled-release-system potential. In this work, pyromellitic dianhydride (PMDA)/betaCD-based nanosponge microfibers were used to study the capability to host a common insect repellent (N,N-diethyl-3 toluamide (DEET)) and to monitor its release over time. Fibrous samples characterized by an average fibrous diameter of 2.8 +/- 0.8 µm were obtained and subsequently loaded with DEET, starting from a 10 g/L diethyl ether (DEET) solution. The loading capacity of the system was assessed via HPLC/UV-Vis analysis and resulted in 130 mg/g. The releasing behavior was followed by leaving fibrous DEET-loaded nanosponge samples in air at room temperature for a period of between 24 h and 2 weeks. The releasing rate and the amount were calculated by thermogravimetric analysis (TGA), and the release of the repellent was found to last for over 2 weeks. Eventually, both the chemical composition and sample morphology were proven to play a key role for the high sample loading capacity, determining the microfibers' capability to be applied as an effective controlled release system. PMID- 29997365 TI - Polylactide (PLA) Filaments a Biobased Solution for Additive Manufacturing: Correlating Rheology and Thermomechanical Properties with Printing Quality. AB - Three commercial filaments for Fused Deposition Modeling (FDM) were selected to study the influence of polymer formulation on the printing quality and mechanical properties of FDM specimens. The three filaments were all based on polylactic acid (PLA) as the matrix, and they are sold as PLA filaments. The printing quality was tested by printing one complex shape with overhang features. The marked shear thinning behavior for two filaments was observed by rheology. The filaments were also studied by scanning electron microscopy and thermogravimetric analysis (TGA) to unveil their composition. The filaments with the best printing quality showed the presence of mineral fillers, which explained the melt behavior observed by rheology. The tensile testing confirmed that the filled PLA was the best-performing filament both in terms of printing quality and thermomechanical performance, with a p-value = 0.106 for the tensile modulus, and a p-value = 0.615 for the ultimate tensile strength. PMID- 29997362 TI - Gut Microbiota and Cardiovascular Uremic Toxicities. AB - Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality rates in CKD patients. In CKD the loss of urinary excretory function results in the retention of various substances referred to as "uremic retention solutes". Many of these molecules have been found to exert toxicity on virtually all organ systems of the human body, leading to the clinical syndrome of uremia. In recent years, an increasing body of evidence has been accumulated that suggests that uremic toxins may contribute to an increased cardiovascular disease (CVD) burden associated with CKD. This review examined the evidence from several clinical and experimental studies showing an association between uremic toxins and CVD. Special emphasis is addressed on emerging data linking gut microbiota with the production of uremic toxins and the development of CKD and CVD. The biological toxicity of some uremic toxins on the myocardium and the vasculature and their possible contribution to cardiovascular injury in uremia are also discussed. Finally, various therapeutic interventions that have been applied to effectively reduce uremic toxins in patients with CKD, including dietary modifications, use of prebiotics and/or probiotics, an oral intestinal sorbent that adsorbs uremic toxins and precursors, and innovative dialysis therapies targeting the protein-bound uremic toxins are also highlighted. Future studies are needed to determine whether these novel therapies to reduce or remove uremic toxins will reduce CVD and related cardiovascular events in the long-term in patients with chronic renal failure. PMID- 29997367 TI - Mapping Oil Spills from Dual-Polarized SAR Images Using an Artificial Neural Network: Application to Oil Spill in the Kerch Strait in November 2007. AB - Synthetic aperture radar (SAR) has been widely used to detect oil-spill areas through the backscattering intensity difference between oil and background pixels. However, since the signal is similar to that produced by other phenomena, positive identification can be challenging. In this study we developed an algorithm to effectively analyze large-scale oil spill areas in SAR images by focusing on optimizing the input layer to artificial neural network (ANN) through removal the factor of lowering the accuracy. An ANN algorithm was used to generate probability maps of oil spills. Highly accurate pixel-based data processing was conducted through false or un-detection element reduction by normalizing the image or applying a non-local (NL) means filter and median filter to the input neurons for ANN. In addition, the standard deviation of co-polarized phase difference (CPD) was used to reduce false detection from the look-alike with weak damping effect. The algorithm was validated using TerraSAR-X images of an oil spill caused by stranded oil tanker Volganefti-139 in the Kerch Strait in 2007. According to the validation results of the receiver operating characteristic (ROC) curve, the oil spill was detected with an accuracy of about 95.19% and un-detection or false detection by look-alike and speckle noise was greatly reduced. PMID- 29997366 TI - Radiation-Resistant Er3+-Doped Superfluorescent Fiber Sources. AB - The radiation effects of three Er3+-doped superfluorescent fiber sources (SFSs), which are based on three segments of Er-doped fibers with different lengths, are studied experimentally. We observed that the radiation-induced attenuation of the signal light of the 1530 nm band for an SFS is less than that of the 1560 nm band. Thus, the trimming technique of the Gauss-like spectra is investigated to reduce the mean wavelength drift. A filter was customized and used in superfluorescent fiber sources. To further reduce output power loss, the method with feedback control of pump power was adopted in the SFS. Then, the trimming spectral SFS with pump feedback control was tested under irradiation environment at the dose rate of 2.988 Gy/h. The experimental results demonstrate that the mean wavelength drift is <40 ppm and the loss of output power is <0.2 dB under a total dose higher than 1000 Gy. These findings confirm the significance of the method in improving radiation-resistant capabilities of fiber sources under irradiation environments. PMID- 29997368 TI - Assessment of the Weldability of T-Welded Joints in 10 mm Thick TMCP Steel Using Laser Beam. AB - The article presents tests aimed to verify the possibility of Thermomechanically Controlled Processed (TMCP) steels T-joints laser welding. The 10 mm thick high yield-point steel S700MC obtained in an industrial manufacturing process was used for tests of laser welding. The joints made during the tests were single- and double-sided. Subsequent nondestructive tests revealed that the laser-welded joints represented quality level B in accordance with PN-EN ISO 13919-1. Single sided welding performed at the output laser beam power of 11 kW provided the penetration depth of just 8 mm without visibly deforming of the joint. The double sided welded joints were characterized by proper geometry and the presence of gas pores in the welds not compromising the requirements of quality level B (strict requirements). The identified weld structure was bainitic-ferritic. The weld hardness was by approximately 60 HV1 higher than that of the base material (280 HV1). The HAZ (Heat Affected Zone) area was slightly softer than the base material. The tests of thin foils performed using a high-resolution scanning transmission electron microscope revealed that, during welding, an increase in the content of the base material in the weld was accompanied by an increase in contents of alloying microagents Ti and Nb, particularly near the fusion line. The above-named alloying microagents, in the form of fine-dispersive (Ti,Nb)(C,N) type precipitates, could reduce plastic properties of joints. PMID- 29997369 TI - Biomonitoring of Urinary Benzene Metabolite SPMA in the General Population in Central Italy. AB - BACKGROUND: Benzene is an important component of cigarette smoke and car exhaust. Products containing benzene in concentrations greater than 0.1% are prohibited in Europe, but 1% of benzene is still allowed in gasoline. The purpose of the study was to assess the levels of urine benzene biomarkers in a sample of the general population not occupationally exposed to benzene, resident in the period 2013 2014 in Central Italy, compared to other groups. METHODS: The urinary levels of the benzene metabolites S-phenyl-mercapturic acid (SPMA) and cotinine (nicotine metabolite) were determined by means of HPLC with mass spectrometric detection in 1076 subjects. RESULTS: The median SPMA value in smokers was 1.132 µg/g of creatinine while in non-smokers it was 0.097 µg/g of creatinine, and the 95th percentile results were seven times higher. CONCLUSION: The main source of benzene exposure in the studied population was active smoking, however, non smokers were also exposed to airborne benzene concentrations. The concentration ranges found in this study can be used as a background reference for occupational exposure assessment to benzene by means of SPMA biomonitoring. PMID- 29997370 TI - Multiple Layers of CDK5R1 Regulation in Alzheimer's Disease Implicate Long Non Coding RNAs. AB - Cyclin-dependent kinase 5 regulatory subunit 1 (CDK5R1) gene encodes for p35, the main activator of Cyclin-dependent kinase 5 (CDK5). The active p35/CDK5 complex is involved in numerous aspects of brain development and function, and its deregulation is closely associated to Alzheimer's disease (AD) onset and progression. We recently showed that miR-15/107 family can negatively regulate CDK5R1 expression modifying mRNA stability. Interestingly, miRNAs belonging to miR-15/107 family are downregulated in AD brain while CDK5R1 is upregulated. Long non-coding RNAs (lncRNAs) are emerging as master regulators of gene expression, including miRNAs, and their dysregulation has been implicated in the pathogenesis of AD. Here, we evaluated the existence of an additional layer of CDK5R1 expression regulation provided by lncRNAs. In particular, we focused on three lncRNAs potentially regulating CDK5R1 expression levels, based on existing data: NEAT1, HOTAIR, and MALAT1. We demonstrated that NEAT1 and HOTAIR negatively regulate CDK5R1 mRNA levels, while MALAT1 has a positive effect. We also showed that all three lncRNAs positively control miR-15/107 family of miRNAs. Moreover, we evaluated the expression of NEAT1, HOTAIR, and MALAT1 in AD and control brain tissues. Interestingly, NEAT1 displayed increased expression levels in temporal cortex and hippocampus of AD patients. Interestingly, we observed a strong positive correlation between CDK5R1 and NEAT1 expression levels in brain tissues, suggesting a possible neuroprotective role of NEAT1 in AD to compensate for increased CDK5R1 levels. Overall, our work provides evidence of another level of CDK5R1 expression regulation mediated by lncRNAs and points to NEAT1 as a biomarker, as well as a potential pharmacological target for AD therapy. PMID- 29997372 TI - Aptamer Display on Diverse DNA Polyhedron Supports. AB - DNA aptamers are important tools for molecular recognition, particularly for a new generation of tools for biomedicine based on nucleic acid nanostructures. Here, we investigated the relative abilities of different shapes and sizes of DNA polyhedra to display an aptamer which binds to the malaria biomarker Plasmodium falciparum lactate dehydrogenase (PfLDH). The aptamer was shown to perform an Aptamer-Tethered Enzyme Capture (APTEC) assay with the hypothesis that the display of the aptamer above the surface through the use of a polyhedron may lead to better sensitivity than use of the aptamer alone. We compared different numbers of points of contact, different shapes, including tetrahedron, square, and pentagon-based pyramids, as well as prisms. We also investigated the optimal height of display of the structure. Our results demonstrated that the display of an aptamer on an optimized nanostructure improved sensitivity up to 6-fold relative to the aptamer alone in the APTEC assay. Other important factors included multiple basal points of contact with the surface, a tetrahedron proved superior to the more complex shaped structures, and height above the surface only made minor differences to efficacy. The display of an aptamer on a nanostructure may be beneficial for higher sensitivity aptamer-mediated malaria diagnosis. Aptamer displays using DNA nanostructure polyhedron supports could be a useful approach in a variety of applications. PMID- 29997371 TI - PaPro1 and IDC4, Two Genes Controlling Stationary Phase, Sexual Development and Cell Degeneration in Podospora anserina. AB - Filamentous fungi frequently undergo bistable phenotypic switches. Crippled Growth of Podospora anserina is one such bistable switch, which seems to rely upon the mis-activation of a self-regulated PaMpk1 MAP kinase regulatory pathway. Here, we identify two new partners of this pathway: PaPro1, a transcription factor orthologous to Sordaria macrospora pro1 and Neurospora crassa ADV-1, and IDC4, a protein with an AIM24 domain. Both PaPro1 and IDC4 regulate stationary phase features, as described for the other actors of the PaMpk1 signaling pathway. However, PaPro1 is also involved in the control of fertilization by activating the transcription of the HMG8 and the mating type transcription factors, as well as the sexual pheromones and receptor genes. The roles of two components of the STRIPAK complex were also investigated by inactivating their encoding genes: PaPro22 and PaPro45. The mutants of these genes were found to have the same phenotypes as PaPro1 and IDC4 mutants as well as additional phenotypes including slow growth, abnormally shaped hyphae, pigment accumulation and blockage of the zygotic tissue development, indicating that the STRIPAK complex regulates, in addition to the PaMpk1 one, other pathways in P. anserina. Overall, the mutants of these four genes confirm the model by which Crippled Growth is due to the abnormal activation of the PaMpk1 MAP kinase cascade. PMID- 29997373 TI - A SEMG-Force Estimation Framework Based on a Fast Orthogonal Search Method Coupled with Factorization Algorithms. AB - A novel framework based on the fast orthogonal search (FOS) method coupled with factorization algorithms was proposed and implemented to realize high-accuracy muscle force estimation via surface electromyogram (SEMG). During static isometric elbow flexion, high-density SEMG (HD-SEMG) signals were recorded from upper arm muscles, and the generated elbow force was measured at the wrist. HD SEMG signals were decomposed into time-invariant activation patterns and time varying activation curves using three typical factorization algorithms including principal component analysis (PCA), independent component analysis (ICA), and nonnegative matrix factorization (NMF). The activation signal of the target muscle was obtained by summing the activation curves, and the FOS algorithm was used to create basis functions with activation signals and establish the force estimation model. Static isometric elbow flexion experiments at three target levels were performed on seven male subjects, and the force estimation performances were compared among three typical factorization algorithms as well as a conventional method for extracting the average signal envelope of all HD SEMG channels (AVG-ENVLP method). The overall root mean square difference (RMSD) values between the measured forces and the estimated forces obtained by different methods were 11.79 +/- 4.29% for AVG-ENVLP, 9.74 +/- 3.77% for PCA, 9.59 +/- 3.81% for ICA, and 9.51 +/- 4.82% for NMF. The results demonstrated that, compared to the conventional AVG-ENVLP method, factorization algorithms could substantially improve the performance of force estimation. The FOS method coupled with factorization algorithms provides an effective way to estimate the combined force of multiple muscles and has potential value in the fields of sports biomechanics, gait analysis, prosthesis control strategy, and exoskeleton devices for assisted rehabilitation. PMID- 29997374 TI - Novel Adaptive Laser Scanning Method for Point Clouds of Free-Form Objects. AB - Laser scanners are widely used to collect coordinates, also known as point clouds, of three-dimensional free-form objects. For creating a solid model from a given point-cloud and transferring the data from the model, features-based optimization of the point-cloud to minimize the number if points in the cloud is required. To solve this problem, existing methods mainly extract significant points based on local surface variation of a predefined level. However, comprehensively describing an object's geometric information using a predefined level is difficult since an object usually has multiple levels of details. Therefore, we propose a simplification method based on a multi-level strategy that adaptively determines the optimal level of points. For each level, significant points are extracted from the point cloud based on point importance measured by both local surface variation and the distribution of neighboring significant points. Furthermore, the degradation of perceptual quality for each level is evaluated by the adjusted mesh structural distortion measurement to select the optimal level. Experiments are performed to evaluate the effectiveness and applicability of the proposed method, demonstrating a reliable solution to optimize the adaptive laser scanning of point clouds for free-forms objects. PMID- 29997375 TI - Isoprostanoids in Clinical and Experimental Neurological Disease Models. AB - Isoprostanoids are a large family of compounds derived from non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs). Unlike other oxidative stress biomarkers, they provide unique information on the precursor of the targeted PUFA. Although they were discovered about a quarter of century ago, the knowledge on the role of key isoprostanoids in the pathogenesis of experimental and human disease models remains limited. This is mainly due to the limited availability of highly purified molecules to be used as a reference standard in the identification of biological samples. The accurate knowledge on their biological relevance is the critical step that could be translated from some mere technical/industrial advances into a reliable biological disease marker which is helpful in deciphering the oxidative stress puzzle related to neurological disorders. Recent research indicates the value of isoprostanoids in predicting the clinical presentation and evolution of the neurological diseases. This review focuses on the relevance of isoprostanoids as mediators and potential biomarkers in neurological diseases, a heterogeneous family ranging from rare brain diseases to major health conditions that could have worldwide socioeconomic impact in the health sector. The current challenge is to identify the preferential biochemical pathways that actually follow the oxidative reactions in the neurological diseases and the consequence of the specific isoprostanes in the underlying pathogenic mechanisms. PMID- 29997376 TI - Socio-Economic Inequalities in Tobacco Consumption of the Older Adults in China: A Decomposition Method. AB - Background: In China, tobacco consumption is a leading risk factor for non communicable diseases, and understanding the pattern of socio-economic inequalities of tobacco consumption will, thus, help to develop targeted policies of public health control. Methods: Data came from the China Health and Retirement Longitudinal Study in 2013, involving 17,663 respondents aged 45 and above. Tobacco use prevalence and tobacco use quantities were defined for further analysis. Using the concentration index (CI) and its decomposition, socio economic inequalities of tobacco consumption grouped by gender were estimated. Results: The concentration index of tobacco use prevalence was 0.044 (men 0.041; women -0.039). The concentration index of tobacco use quantities among smokers was 0.039 (men 0.033; women 0.038). The majority of the inequality could be explained by educational attainment, age, area, and economic quantiles. Conclusions: Tobacco consumption was more common among richer compared to poorer people in China. Gender, educational attainments, age, areas, and economic quantiles were strong predictors of tobacco consumption in China. Public health policies need to be targeted towards men in higher economic quantiles with lower educational attainment, and divorced or widowed women, especially in urban areas of China. PMID- 29997377 TI - Ascorbate-Glutathione Cycle and Ultrastructural Analyses of Two Kenaf Cultivars (Hibiscus cannabinus L.) under Chromium Stress. AB - Kenaf (Hibiscus cannabinus L.) with high tolerance to chromium (Cr) can be used in the phytoremediation of chromium-contaminated soil. However, the mechanisms of chromium accumulation and tolerance in kenaf are still unclear. A hydroponic experiment was taken to screen two kenaf cultivars with Cr tolerance among nine kenaf cultivars via a tolerance index. This is first time the ascorbate glutathione (AsA-GSH) cycle and chloroplast structural changes involved in Cr tolerance of two kenaf cultivars are explored. This study indicated that enhancement of chromium concentrations reduced nine kenaf growth rates and plant biomass. In addition, in all the nine cultivars, the roots had higher Cr accumulation than the shoots. Cr-tolerant cultivar Zhe70-3 with the maximum tolerant index had the significantly higher enzymatic activities of ascorbate peroxidase (APX), glutathione reductase (GR), dehydroascorbate reductase (DHAR) and mono- dehydroascorbate reductase (MDHAR) in non-enzymatic antioxidant system compared to Cr-sensitive cultivar Zhe77-1. In addition, higher GSH and AsA contents and lower damages of chloroplast ultrastructure were observed in Zhe70-3 under Cr treatment. In conclusion, Cr stress can cause less oxidative stress and destruction of chloroplast ultrastructure in Cr-tolerant cultivar Zhe70-3, and the AsA-GSH cycle may play a crucial role in kenaf Cr tolerance. PMID- 29997378 TI - The Behaviour and Productivity of Mid-Lactation Dairy Cows Provided Daily Pasture Allowance over 2 or 7 Intensively Grazed Strips. AB - Research into the effects of intense grazing regimes on cattle behaviour and productivity will support the ethical intensification of pastoral dairy production. Two treatments were applied to two herds of 30 mid-lactation cows over 28 days. Cows were offered an estimated 12 kg DM/cow (above 5 cm from ground level) of irrigated pasture per day. The control herd received their daily pasture allocation in two equal grazings while the experimental herd received theirs over seven smaller grazings. Backgrazing beyond the current allocation (morning or afternoon) was prevented. Individual records were taken daily for milk production and behaviour (MooMonitor+). Milk composition, energy corrected milk (ECM), and live weight were recorded weekly. Feeding mid-lactation dairy cows over seven smaller grazing allocations reduced the time cows spent ruminating (p < 0.001), milk yield (p < 0.001), and ECM (p < 0.05). However, milk composition, live weight, time feeding, and pasture consumption were not affected by feeding frequency (p > 0.05). Cattle may have adapted their ingestive behaviour in response to the more intensive strip-grazing regime utilised in this study, with negative consequences for digestive processes and consequently milk production. Intense grazing regimes need to support the ingestive, digestive, and social behaviours of cattle. PMID- 29997379 TI - Loneliness and Health Service Utilization among the Rural Elderly in Shandong, China: A Cross-Sectional Study. AB - OBJECTIVES: To examine the prevalence of loneliness and to explore the association between loneliness and health service utilization among the rural elderly in Shandong Province, China. METHODS: A total of 5514 rural people aged 60 and above from Shandong Province, China, were enrolled in this study. Loneliness was used as a binary variable based on a single-item question. Health service utilization was measured by recent two-week physician visits and annual hospitalizations rates. Multiple logistic regression analysis was performed to examine the association between loneliness and health service utilization. RESULTS: The prevalence of loneliness among the rural elderly in Shandong, China, was 25.0%. Loneliness was associated with higher rates of recent two-week physician visits (OR = 1.260, p < 0.01) and annual hospitalizations (OR = 1.183, p < 0.05). The regression results also showed that self-rated health status and chronic conditions were significant and positively associated with both physician visits and hospitalizations rates. CONCLUSIONS: Loneliness had a significant association with higher odds of health service utilization among the elderly. The independent contribution of loneliness on health service utilization was smaller than self-rated health status and chronic conditions. Thus, healthcare policies need to shift from an emphasis on controlling health utilization and cost to a greater focus on enabling lonely older people to get more social support. PMID- 29997381 TI - Improved ABC Algorithm Optimizing the Bridge Sensor Placement. AB - Inspired by sensor coverage density and matching & preserving strategy, this paper proposes an Improved Artificial Bee Colony (IABC) algorithm which is designed to optimize bridge sensor placement. We use dynamic random coverage coding method to initialize colony to ensure the diversity and effectiveness. In addition, we randomly select the factors with lower trust value to search and evolve after food source being matched in order that the relatively high trust point factor is retained in the exploitation of food sources, which reduces the blindness of searching and improves the efficiency of convergence and the accuracy of the algorithm. According to the analysis of the modal data of the Ha Qi long span railway bridge, the results show that IABC algorithm has faster convergence rate and better global search ability when solving the optimal placement problem of bridge sensor. The final analysis results also indicate that the IABC's solution accuracy is 76.45% higher than that of the ABC algorithm, and the solution stability is improved by 86.23%. The final sensor placement mostly covers the sensitive monitoring points of the bridge structure and, in this way, the IABC algorithm is suitable for solving the optimal placement problem of large bridge and other structures. PMID- 29997380 TI - Indium-Mediated Allylation of Carbonyl Compounds in Ionic Liquids: Effect of Salts in Ionic Liquids. AB - The In-mediated allylation of carbonyl compounds can be performed in various types of solvents including ionic liquids. However, we have found that in [bmim][BF4] (where bmim = 1-butyl-3-methylimidazolium), the In-mediated coupling of crotyl bromide with benzaldehyde gives a complex mixture, and some additives, such as halides and amines, are crucial for the successful conversion to the corresponding gamma-adduct. Instead, the addition of alcohols or water promotes the formation of the alpha-adduct. An asymmetric induction with up to 62% enantiomeric excess (ee) was observed employing cinchonidine as an additive in a binary solvent consisting of an ionic liquid and dichloromethane. PMID- 29997382 TI - beta-Lactamase Tools for Establishing Cell Internalization and Cytosolic Delivery of Cell Penetrating Peptides. AB - The ability of cell penetrating peptides (CPPs) to deliver biologically relevant cargos into cells is becoming more important as targets in the intracellular space continue to be explored. We have developed two assays based on CPP dependent, intracellular delivery of TEM-1 beta-lactamase enzyme, a functional biological molecule comparable in size to many protein therapeutics. The first assay focuses on the delivery of full-length beta-lactamase to evaluate the internalization potential of a CPP sequence. The second assay uses a split protein system where one component of beta-lactamase is constitutively expressed in the cytoplasm of a stable cell line and the other component is delivered by a CPP. The delivery of a split beta-lactamase component evaluates the cytosolic delivery capacity of a CPP. We demonstrate that these assays are rapid, flexible and have potential for use with any cell type and CPP sequence. Both assays are validated using canonical and novel CPPs, with limits of detection from <500 nM to 1 µM. Together, the beta-lactamase assays provide compatible tools for functional characterization of CPP activity and the delivery of biological cargos into cells. PMID- 29997384 TI - Severe Course of Peripartum Cardiomyopathy and Subsequent Recovery in a Patient with a Novel TTN Gene-Truncating Mutation. AB - BACKGROUND Peripartum cardiomyopathy (PPCM) is a potentially life-threatening, pregnancy-associated cause of heart failure affecting previously healthy women. Recent research suggests a possible role of 16-kDa prolactin in promoting cardiomyocyte damage. However, the genetic predisposition is not well recognized. CASE REPORT We report the case of a 25-year-old woman with a severe course of PPCM with left ventricle ejection fraction of 25-30%, complicated by ventricular arrhythmia and postpartum thyroiditis. As no traditional risk factors of PPCM were identified, the patient was referred for genetic testing. Next-generation sequencing revealed a novel titin gene-truncating mutation NM_001267550: p.Leu23499fs/c.70497_40498insT in the proband as well as in her mother. In the patient, a very late recovery >12 months postpartum was observed, which required long-term medical treatment with bromocriptine. CONCLUSIONS PPCM may occur in women with the genetic predisposition, being modified by an interaction of biological factors, such as a high prolactin level, a ventricular arrhythmia, and an autoimmune disorder. Recovery from severe heart failure due to an inherited cardiomyopathy is possible with careful and appropriate medical management. PMID- 29997383 TI - Performance of PES/LSMM-OGCN Photocatalytic Membrane for Phenol Removal: Effect of OGCN Loading. AB - In designing a photocatalytic oxidation system, the immobilized photocatalyst technique becomes highly profitable due to its promising capability in treating organic pollutants such as phenols in wastewater. In this study, hydrophiLic surface modifying macromolecules (LSMM) modified polyethersulfone (PES) hybrid photocatalytic membranes incorporated with oxygenated graphitic carbon nitride (OGCN) was successfully developed using phase inversion technique. The effectiveness of the hybrid photocatalytic membrane was determined under different loading of OGCN photocatalyst (0, 0.5, 1.0, 1.5, 2.0, and 2.5 wt%). The best amount of OGCN in the casting solution was 1.0 wt% as the agglomeration did not occur considering the stability of the membrane performance and morphology. The highest flux of 264 L/m2.h was achieved by PES/LSMM-OGCN1.5wt% membrane. However, the highest flux performance was not an advantage in this situation as the flux reduced the rejection value due to open pores. The membrane with the highest photocatalytic performance was obtained at 1.0 wt% of OGCN loading with 35.78% phenol degradation after 6 h. Regardless of the lower rejection value, the performance shown by the PES/LSMM-OGCN1.0wt% membrane was still competent because of the small difference of less than 1% to that of the PES/LSMM-OGCN0wt% membrane. Based on the findings, it can be concluded that the optimisation of the OGCN loading in the PES hybrid photocatalytic membrane indeed plays an important role towards enhancing the catalyst distribution, phenol degradation, and acceptable rejection above all considerations. PMID- 29997385 TI - Expression of microRNA-99a-3p in Prostate Cancer Based on Bioinformatics Data and Meta-Analysis of a Literature Review of 965 Cases. AB - BACKGROUND microRNAs (miRNAs) have a role as biomarkers in human cancer. The aim of this study was to use bioinformatics data, and review of cases identified from the literature, to investigate the role of microRNA-99a-3p (miR-99a-3p) in prostate cancer, including the identification of its target genes and signaling pathways. MATERIAL AND METHODS Meta-analysis from a literature review included 965 cases of prostate cancer. Bioinformatics databases interrogated for miR-99a 3p in prostate cancer included The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), and ArrayExpress. Twelve computational predictive algorithms were developed to integrate miR-99a-3p target gene prediction data. Bioinformatics analysis data from Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analysis were used investigate the possible pathways and target genes for miR-99a-3p in prostate cancer. RESULTS TCGA data showed that miR-99a was down-regulated in prostate cancer when compared with normal prostate tissue. Receiver-operating characteristic (ROC) curve area under the curve (AUC) for miR-99a-3p was 0.660 (95% CI, 0.587-0.732) or a moderate level of discriminations. Pathway analysis showed that miR-99a-3p was associated with the Wnt and vascular endothelial growth factor (VEGF) signaling pathways. The PPP3CA and HYOU1 genes, selected from the PPI network, were highly expressed in prostate cancer tissue compared with normal prostate tissue, and negatively correlated with the expression of miR 99a-3p. CONCLUSIONS In prostate cancer, miR-99a-3p expression was associated with the Wnt and VEGF signaling pathways, which might inhibit the expression of PPP3CA or HYOU1. PMID- 29997386 TI - microRNAs as biomarkers in Pompe disease. AB - PURPOSE: We studied microRNAs as potential biomarkers for Pompe disease. METHODS: We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. RESULTS: In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. CONCLUSION: Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy. PMID- 29997387 TI - Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network. AB - PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs. PMID- 29997388 TI - Private payer coverage policies for exome sequencing (ES) in pediatric patients: trends over time and analysis of evidence cited. AB - PURPOSE: Exome sequencing (ES) is being adopted for neurodevelopmental disorders in pediatric patients. However, little is known about current coverage policies or the evidence cited supporting these policies. Our study is the first in-depth review of private payer ES coverage policies for pediatric patients with neurodevelopmental disorders. METHODS: We reviewed private payer coverage policies and examined evidence cited in the policies of the 15 largest payers in 2017, and trends in coverage policies and evidence cited (2015-2017) for the five largest payers. RESULTS: There were four relevant policies (N = 5 payers) in 2015 and 13 policies (N = 15 payers) in 2017. In 2015, no payer covered ES, but by 2017, three payers from the original registry payers did. In 2017, 8 of the 15 payers covered ES. We found variations in the number and types of evidence cited. Positive coverage policies tended to include a larger number and range of citations. CONCLUSION: We conclude that more systematic assessment of evidence cited in coverage policies can provide a greater understanding of coverage policies and how evidence is used. Such assessments could facilitate the ability of researchers to provide the needed evidence, and the ability of clinicians to provide the most appropriate testing for patients. PMID- 29997389 TI - Health behaviors among unaffected participants following receipt of variants of uncertain significance in cardiomyopathy-associated genes. AB - PURPOSE: Studies on returning variants of uncertain significance (VUS) results have predominantly included patients with a personal or family history of cancer and cancer-associated gene VUS. This study examined health behaviors among participants with cardiomyopathy-associated gene VUS, but without a personal history of cardiomyopathy. METHODS: Sixty-eight eligible participants without apparent cardiomyopathy but with VUS in cardiomyopathy-associated genes completed a survey of health behaviors, disclosure, distress, uncertainty, positive experiences, decisional conflict, and perceived value. The medical records of participants who reported cardiac testing because of their VUS were reviewed for testing indication(s). RESULTS: Two participants had cardiac testing due to their VUS alone. Four had cardiac testing because of their VUS and other clinical indications. Twelve changed health behaviors, including one participant who was subsequently diagnosed with cardiomyopathy. Distress, uncertainty, and decisional conflict were low (means = 1.2, 4.2, and 24.5 (scale ranges = 0-30, 0-45, and 15 75), respectively), and positive experiences and perceived value were moderate (means = 12.4 and 14.4 (scale ranges = 0-20 and 4-20), respectively). Greater perceived value was associated with greater likelihood to engage in health behaviors (P = 0.04). CONCLUSION: Positive VUS results can be returned to apparently unaffected individuals with modest use of healthcare resources, minimal behavioral changes, and favorable psychological reactions. PMID- 29997390 TI - Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria. AB - PURPOSE: The nature of phenylalanine hydroxylase (PAH) variants determines residual enzyme activity, which modifies the clinical phenotype in phenylketonuria (PKU). We exploited the statistical power of a large genotype database to determine the relationship between genotype and phenotype in PKU. METHODS: A total of 9336 PKU patients with 2589 different genotypes, carrying 588 variants, were investigated using an allelic phenotype value (APV) algorithm. RESULTS: We identified 251 0-variants encoding inactive PAH, and assigned APVs (0 = classic PKU; 5 = mild PKU; 10 = mild hyperphenylalaninaemia) to 88 variants in PAH-functional hemizygous patients. The genotypic phenotype values (GPVs) were set equal to the higher-APV allele, which was assumed to be dominant over the lower-APV allele and to determine the metabolic phenotype. GPVs for 8872 patients resulted in cut-off ranges of 0.0-2.7 for classic PKU, 2.8-6.6 for mild PKU and 6.7-10.0 for mild hyperphenylalaninaemia. Genotype-based phenotype prediction was 99.2% for classic PKU, 46.2% for mild PKU and 89.5% for mild hyperphenylalaninaemia. The relationships between known pretreatment blood phenylalanine levels and GPVs (n = 4217), as well as tetrahydrobiopterin responsiveness and GPVs (n = 3488), were significant (both P < 0.001). CONCLUSIONS: APV and GPV are powerful tools to investigate genotype-phenotype associations, and can be used for genetic counselling of PKU families. PMID- 29997392 TI - Direct-to-consumer raw genetic data and third-party interpretation services: more burden than bargain? PMID- 29997391 TI - Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies. AB - PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2). PMID- 29997393 TI - Phrank measures phenotype sets similarity to greatly improve Mendelian diagnostic disease prioritization. AB - PURPOSE: Exome sequencing and diagnosis is beginning to spread across the medical establishment. The most time-consuming part of genome-based diagnosis is the manual step of matching the potentially long list of patient candidate genes to patient phenotypes to identify the causative disease. METHODS: We introduce Phrank (for phenotype ranking), an information theory-inspired method that utilizes a Bayesian network to prioritize candidate diseases or genes, as a stand alone module that can be run with any underlying knowledgebase and any variant filtering scheme. RESULTS: Phrank outperforms existing methods at ranking the causative disease or gene when applied to 169 real patient exomes with Mendelian diagnoses. Phrank's greatest improvement is in disease space, where across all 169 patients it ranks only 3 diseases on average ahead of the true diagnosis, whereas Phenomizer ranks 32 diseases ahead of the causal one. CONCLUSIONS: Using Phrank to rank all patient candidate genes or diseases, as they start working through a new case, will save the busy clinician much time in deriving a genetic diagnosis. PMID- 29997394 TI - Author Correction: Effect of Mesoporous Nano Water Reservoir on MR Relaxivity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29997395 TI - Author Correction: Electrochemical Performance of Supercapacitor with Stacked Copper Foils Coated with Graphene Nanoplatelets. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29997396 TI - Emergency release uncross-matched packed red blood cells for immediate double volume exchange transfusion in neonates with intermediate to advanced acute bilirubin encephalopathy: timely but insufficient? AB - Given the urgency of double volume exchange transfusion (ExT) in an infant with intermediate to advanced stages of acute bilirubin encephalopathy (ABE), it has been suggested that emergency release uncross-matched packed red blood cells (ER PRBC) be used. The efficacy of an ExT in removing bilirubin from the brain, however, is a direct function of the mass of albumin exchanged. The very low albumin content of ER-PRBC may fail to be neuroprotective. Predicted changes in total serum bilirubin (TSB), serum albumin, the bilirubin/albumin (B/A) ratio, plasma volume (PV), and bilirubin equilibration from the extravascular space during ER-PRBC ExT are described. ExT using ER-PRBC is efficacious in lowering the TSB. However, this result is falsely reassuring as significant concurrent serum albumin loss, resultant hypoalbuminemia, contraction of PV, limited bilirubin clearance from the extravascular space, and sustained B/A ratio elevations above recommended ExT treatment thresholds suggest that bilirubin neurotoxicity will continue. PMID- 29997397 TI - Author Correction: Lack of metabolism in (R)-ketamine's antidepressant actions in a chronic social defeat stress model. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29997398 TI - 2017 Emily Couric Memorial Lecture: Colorectal Cancer: Polyps, Prevention, and Progress. AB - Colorectal cancer remains the second-leading cause of cancer death in the United States-but efforts over the past two decades have resulted in tremendous progress in understanding the biology of how this disease develops, increasing screening rates, and decreasing incidence and mortality in those age 50 years and older. The drivers of this movement have been outstanding leadership, innovation, and collaboration. As we move forward to tackle issues such as the increasing incidence of this disease in younger adults, the need to address disparities in care and outcomes, and our shared goal to reach 80% screening rates, it's important to understand and appreciate the story of our past success in order to advance our future efforts. PMID- 29997399 TI - Childhood (Mis)fortune, Educational Attainment, and Adult Health: Contingent Benefits of a College Degree? AB - College-educated adults are healthier than other people in the United States, but selection bias complicates our understanding of how education influences health. This article focuses on the possibility that the health benefits of college may vary according to childhood (mis)fortune and people's propensity to attain a college degree in the first place. Several perspectives from life course sociology offer competing hypotheses as to whether the most or the least advantaged see the greatest return of a college education. The authors use a national survey of middle-age American adults to assess risk of two cardiovascular health problems and mortality. Results from propensity score and hierarchical regression analysis indicate that the protective effect of college attainment is indeed heterogeneous. Further, the greatest returns are among those least likely to experience this life course transition (i.e., compensatory leveling). Explanations for this selection effect are offered, along with several directions for future research on the health benefits of completing college. PMID- 29997400 TI - The Colletotrichum dracaenophilum, C. magnum and C. orchidearum species complexes. AB - Although Glomerella glycines, Colletotrichum magnum and C. orchidearum are known as causal agents of anthracnose of soybean, Cucurbitaceae and Orchidaceae, respectively, their taxonomy remains unresolved. In preliminary analyses based on ITS, strains of these species appear basal in Colletotrichum phylogenies, clustering close to C. cliviae, C. brevisporum and other recently described species from tropical or subtropical regions. Phylogenetic analyses (ITS, GAPDH, CHS-1, HIS3, ACT, TUB2) of 102 strains previously identified as Ga. glycines, C. magnum and C. orchidearum as well as other related strains from different culture collections and studies placed these taxa in three species complexes, and distinguished at least 24 species, including 11 new species. In this study, C. magnum, C. orchidearum and C. piperis were epitypified and their taxonomy resolved, while C. cliviicola was proposed as a new name for C. cliviae. Furthermore, a sexual morph was observed for C. yunnanense, while C. brevisporum, C. cliviicola and C. tropicicola were reported from new hosts or countries. Regarding their conidial morphology, species in the C. dracaenophilum, C. magnum and C. orchidearum species complexes are reminiscent of C. gloeosporioides or C. boninense s. lat., and were likely to be confused with them in the past. PMID- 29997402 TI - Innovative 3D and 2D machine vision methods for analysis of plants and crops in the field. AB - Machine vision systems offer great potential for automating crop control, harvesting, fruit picking, and a range of other agricultural tasks. However, most of the reported research on machine vision in agriculture involves a 2D approach, where the utility of the resulting data is often limited by effects such as parallax, perspective, occlusion and changes in background light - particularly when operating in the field. The 3D approach to plant and crop analysis described in this paper offers potential to obviate many of these difficulties by utilising the richer information that 3D data can generate. The methodologies presented, such as four-light photometric stereo, also provide advanced functionalities, such as an ability to robustly recover 3D surface texture from plants at very high resolution. This offers potential for enabling, for example, reliable detection of the meristem (the part of the plant where growth can take place), to within a few mm, for directed weeding (with all the associated cost and ecological benefits) as well as offering new capabilities for plant phenotyping. The considerable challenges associated with robust and reliable utilisation of machine vision in the field are also considered and practical solutions are described. Two projects are used to illustrate the proposed approaches: a four light photometric stereo apparatus able to recover plant textures at high resolution (even in direct sunlight), and a 3D system able to measure potato sizes in-the-field to an accuracy of within 10%, for extended periods and in a range of environmental conditions. The potential benefits of the proposed 3D methods are discussed, both in terms of the advanced capabilities attainable and the widespread potential uptake facilitated by their low cost. PMID- 29997401 TI - Genera of phytopathogenic fungi: GOPHY 2. AB - This paper represents the second contribution in the Genera of Phytopathogenic Fungi (GOPHY) series. The series provides morphological descriptions and information regarding the pathology, distribution, hosts and disease symptoms for the treated genera. In addition, primary and secondary DNA barcodes for the currently accepted species are included. This second paper in the GOPHY series treats 20 genera of phytopathogenic fungi and their relatives including: Allantophomopsiella, Apoharknessia, Cylindrocladiella, Diaporthe, Dichotomophthora, Gaeumannomyces, Harknessia, Huntiella, Macgarvieomyces, Metulocladosporiella, Microdochium, Oculimacula, Paraphoma, Phaeoacremonium, Phyllosticta, Proxypiricularia, Pyricularia, Stenocarpella, Utrechtiana and Wojnowiciella. This study includes the new genus Pyriculariomyces, 20 new species, five new combinations, and six typifications for older names. PMID- 29997404 TI - Photometric stereo for three-dimensional leaf venation extraction. AB - Leaf venation extraction studies have been strongly discouraged by considerable challenges posed by venation architectures that are complex, diverse and subtle. Additionally, unpredictable local leaf curvatures, undesirable ambient illuminations, and abnormal conditions of leaves may coexist with other complications. While leaf venation extraction has high potential for assisting with plant phenotyping, speciation and modelling, its investigations to date have been confined to colour image acquisition and processing which are commonly confounded by the aforementioned biotic and abiotic variations. To bridge the gaps in this area, we have designed a 3D imaging system for leaf venation extraction, which can overcome dark or bright ambient illumination and can allow for 3D data reconstruction in high resolution. We further propose a novel leaf venation extraction algorithm that can obtain illumination-independent surface normal features by performing Photometric Stereo reconstruction as well as local shape measures by fusing the decoupled shape index and curvedness features. In addition, this algorithm can determine venation polarity - whether veins are raised above or recessed into a leaf. Tests on both sides of different leaf species with varied venation architectures show that the proposed method is accurate in extracting the primary, secondary and even tertiary veins. It also proves to be robust against leaf diseases which can cause dramatic changes in colour. The effectiveness of this algorithm in determining venation polarity is verified by it correctly recognising raised or recessed veins in nine different experiments. PMID- 29997403 TI - Automated monitoring of dairy cow body condition, mobility and weight using a single 3D video capture device. AB - Here we propose a low-cost automated system for the unobtrusive and continuous welfare monitoring of dairy cattle on the farm. We argue that effective and regular monitoring of multiple condition traits is not currently practicable and go on to propose 3D imaging technology able to acquire differing forms of related animal condition data (body condition, lameness and weight), concurrently using a single device. Results obtained under farm conditions in continuous operation are shown to be comparable or better than manual scoring of the herd. We also consider inherent limitations of using scoring and argue that sensitivity to relative change over successive observations offers greater benefit than the use of what may be considered abstract and arbitrary scoring systems. PMID- 29997405 TI - Connected attribute morphology for unified vegetation segmentation and classification in precision agriculture. AB - Discriminating value crops from weeds is an important task in precision agriculture. In this paper, we propose a novel image processing pipeline based on attribute morphology for both the segmentation and classification tasks. The commonly used approaches for vegetation segmentation often rely on thresholding techniques which reach their decisions globally. By contrast, the proposed method works with connected components obtained by image threshold decomposition, which are naturally nested in a hierarchical structure called the max-tree, and various attributes calculated from these regions. Image segmentation is performed by attribute filtering, preserving or discarding the regions based on their attribute value and allowing for the decision to be reached locally. This segmentation method naturally selects a collection of foreground regions rather than pixels, and the same data structure used for segmentation can be further reused to provide the features for classification, which is realised in our experiments by a support vector machine (SVM). We apply our methods to normalised difference vegetation index (NDVI) images, and demonstrate the performance of the pipeline on a dataset collected by the authors in an onion field, as well as a publicly available dataset for sugar beets. The results show that the proposed segmentation approach can segment the fine details of plant regions locally, in contrast to the state-of-the-art thresholding methods, while providing discriminative features which enable efficient and competitive classification rates for crop/weed discrimination. PMID- 29997406 TI - Inverse Biomechanical Modeling of the Tongue via Machine Learning and Synthetic Training Data. AB - The tongue's deformation during speech can be measured using tagged magnetic resonance imaging, but there is no current method to directly measure the pattern of muscles that activate to produce a given motion. In this paper, the activation pattern of the tongue's muscles is estimated by solving an inverse problem using a random forest. Examples describing different activation patterns and the resulting deformations are generated using a finite-element model of the tongue. These examples form training data for a random forest comprising 30 decision trees to estimate contractions in 262 contractile elements. The method was evaluated on data from tagged magnetic resonance data from actual speech and on simulated data mimicking flaps that might have resulted from glossectomy surgery. The estimation accuracy was modest (5.6% error), but it surpassed a semi-manual approach (8.1% error). The results suggest that a machine learning approach to contraction pattern estimation in the tongue is feasible, even in the presence of flaps. PMID- 29997407 TI - NVIDIA OptiX ray-tracing engine as a new tool for modelling medical imaging systems. AB - The most accurate technique to model the X- and gamma radiation path through a numerically defined object is the Monte Carlo simulation which follows single photons according to their interaction probabilities. A simplified and much faster approach, which just integrates total interaction probabilities along selected paths, is known as ray tracing. Both techniques are used in medical imaging for simulating real imaging systems and as projectors required in iterative tomographic reconstruction algorithms. These approaches are ready for massive parallel implementation e.g. on Graphics Processing Units (GPU), which can greatly accelerate the computation time at a relatively low cost. In this paper we describe the application of the NVIDIA OptiX ray-tracing engine, popular in professional graphics and rendering applications, as a new powerful tool for X and gamma ray-tracing in medical imaging. It allows the implementation of a variety of physical interactions of rays with pixel-, mesh- or nurbs-based objects, and recording any required quantities, like path integrals, interaction sites, deposited energies, and others. Using the OptiX engine we have implemented a code for rapid Monte Carlo simulations of Single Photon Emission Computed Tomography (SPECT) imaging, as well as the ray-tracing projector, which can be used in reconstruction algorithms. The engine generates efficient, scalable and optimized GPU code, ready to run on multi GPU heterogeneous systems. We have compared the results our simulations with the GATE package. With the OptiX engine the computation time of a Monte Carlo simulation can be reduced from days to minutes. PMID- 29997408 TI - The Social Burden of Resilience: A Historical Perspective. AB - We examine the social burden associated with resilience to environmental shocks in pre-modern societies. We argue that analyses of state-level interventions to mitigate the consequences of catastrophic events tend to isolate these measures from their larger social contexts and thereby overlook the uneven distribution of their burden across different groups. We use three cases of pre-modern societies in the northeastern Mediterranean - the sixth century Roman Empire, the tenth century Byzantine Empire, and the sixteenth century Ottoman Empire. We demonstrate how the adaptive processes that reinforced resilience at the state level incurred different burdens for those at lower levels of the social hierarchy. We found that some groups sustained losses while others gained unexpected benefits in the context of temporary systemic instability. We also found that although elites enjoyed enhanced buffers against the adverse effects in comparison with non-elites, this did not consistently guarantee them a better outcome. We conclude that the differentiated burden of resilience could in some cases entrench existing political or economic configurations, and in other cases, overturn them. Our case studies indirectly address the pressing issue of environmental justice. PMID- 29997409 TI - Modelling Climate and Societal Resilience in the Eastern Mediterranean in the Last Millennium. AB - This article analyses high-quality hydroclimate proxy records and spatial reconstructions from the Central and Eastern Mediterranean and compares them with two Earth System Model simulations (CCSM4, MPI-ESM-P) for the Crusader period in the Levant (1095-1290 CE), the Mamluk regime in Transjordan (1260-1516 CE) and the Ottoman crisis and Celali Rebellion (1580-1610 CE). During the three time intervals, environmental and climatic stress tested the resilience of complex societies. We find that the multidecadal precipitation and drought variations in the Central and Eastern Mediterranean cannot be explained by external forcings (solar variations, tropical volcanism); rather they were driven by internal climate dynamics. Our research emphasises the challenges, opportunities and limitations of linking proxy records, palaeoreconstructions and model simulations to better understand how climate can affect human history. PMID- 29997410 TI - Conflict between Dolphins and a Data-Scarce Fishery of the European Union. AB - Fisheries depredation by marine mammals is an economic concern worldwide. We combined questionnaires, acoustic monitoring, and participatory experiments to investigate the occurrence of bottlenose dolphins in the fisheries of Northern Cyprus, and the extent of their conflict with set-nets, an economically important metier of Mediterranean fisheries. Dolphins were present in fishing grounds throughout the year and were detected at 28% of sets. Net damage was on average six times greater where dolphins were present, was correlated with dolphin presence, and the associated costs were considerable. An acoustic deterrent pinger was tested, but had no significant effect although more powerful pingers could have greater impact. However, our findings indicate that effective management of fish stocks is urgently required to address the overexploitation that is likely driving depredation behaviour in dolphins, that in turn leads to net damage and the associated costs to the fisheries. PMID- 29997411 TI - Historical Tropical Forest Reliance amongst the Wanniyalaeto (Vedda) of Sri Lanka: an Isotopic Perspective. AB - Headland and Bailey (1991) argued in Human Ecology that tropical forests could not support long-term human foraging in the absence of agriculture. Part of their thesis was based on the fact that supposedly isolated 'forest' foragers, such as the Wanniyalaeto (or Vedda) peoples of Sri Lanka, could be demonstrated to be enmeshed within historical trade networks and rely on crops as part of their overall subsistence. Yet, in the same volume and in the years that followed scholars have presented ethnographic and archaeological evidence, including from Sri Lanka, that counter this proposition, demonstrating the occupation and exploitation of tropical rainforest environments back to 38,000 years ago (ka) in this part of the world. However, archaeological and ethnohistorical research has yet to quantify the overall reliance of human foragers on tropical forest resources through time. Here, we report stable carbon and oxygen isotope data from historical Wanniyalaeto individuals from Sri Lanka, in full collaboration with the present-day members of this group, that suggest that while a number of individuals made use of agricultural resources in the recent past, others subsisted primarily on tropical forest resources as late as the 1800s. PMID- 29997412 TI - Performance of cowpea as influenced by native strain of rhizobia, lime and phosphorus in Samaru, Nigeria. AB - The complimentary effects of a native rhizobia strain (SAMFIX 286), lime and single superphosphate (SSP) as components of ISFM were evaluated on the biomass, nodulation and N2 fixation of cowpea (Vigna unguiculata L.). Lime was applied at the rate of 250 kg (Ca(OH)2) ha-1, while SSP was applied at 30 kg P ha-1. The trial was carried out in a screen house with the treatments arranged in randomized complete block design. Results obtained show that the performance of SAMFIX 286 inoculated plants did not significantly (p < 0.05) differ from that of the un-inoculated treatment. Application of lime significantly increased root dry weight, shoot dry weight, nodule number and dry weight by 42.5%, 35.3%, 65.6% and 50%, respectively. Nodulation was significantly (p < 0.05) increased by SSP. The complimentary effect of lime with SSP significantly increased total shoot N concentration. Similarly, combined inoculation of SAMFIX 286 with lime and SSP increased N concentration by 31.9% and N derived from atmosphere (Ndfa) by 16.3% compared to the un-inoculated treatment. Inoculation of SAMFIX 286 with SSP was also effective on Ndfa by cowpea. It was concluded that lime and SSP were good combination with native rhizobia strain in improving cowpea nodulation and biological N2 fixation. PMID- 29997413 TI - Symbiotic performance of grain and wild herbaceous legumes in the Okavango Delta and Tswapong region of Botswana. AB - The low inherent soil fertility, especially nitrogen (N) constrains arable agriculture in Botswana. Nitrogen is usually added to soil through inorganic fertilizer application. In this study, biological nitrogen fixation by legumes is explored as an alternative source of N. The objectives of this study were to measure levels of N2 fixation by grain legumes such as cowpea, Bambara groundnut and groundnut in farmers' fields as well as to estimated N2 fixation by indigenous herbaceous legumes growing in the Okavango Delta. Four flowering plants per species were sampled from the panhandle part of the Okavango Delta and Tswapong area. Nitrogen fixation was measured using the 15N stable isotope natural abundance technique. The delta15N values of indigenous herbaceous legumes indicated that they fixed N2 (-1.88 to +1.35 0/00) with the lowest value measured in Chamaecrista absus growing in Ngarange (Okavango Delta). The delta15N values of grain legumes growing on farmers' fields ranging from -1.2 0/00 to +3.3 0/00 indicated that they were fixing N2. For grain legumes growing at most farms, %Ndfa were above 50% indicating that they largely depended on symbiotic fixation for their N nutrition. With optimal planting density, Bambara groundnuts on farmers' fields could potentially fix over 90 kg N/ha in some parts of Tswapong area and about 60 kg N/ha in areas around the Okavango Delta. Results from this study have shown that herbaceous indigenous legumes and cultivated legumes play an important role in the cycling of N in the soil. It has also been shown that biological N2 on farmer's field could potentially supply the much needed N for the legumes and the subsequent cereal crops if plant densities are optimized with the potential to increase food security and mitigate climate change. PMID- 29997414 TI - An assessment of plant growth and N2 fixation in soybean genotypes grown in uninoculated soils collected from different locations in Ethiopia. AB - Achieving food and nutritional security is a major challenge in Ethiopia, especially with increasing human population and low crop productivity. Legumes offer an alternative choice to chemical fertilizers for increasing crop yields. The aim of this study was to assess, under glasshouse conditions, plant growth and symbiotic performance of uninoculated soybean genotypes planted in soils collected from different locations in Ethiopia. The results showed significant differences in plant growth and symbiotic performance among the soybean genotypes planted in different soils. There was a location-specific effect of soil on plant growth and symbiotic N nutrition of soybean. Whole-plant biomass was highest in soil from Amaro, followed by Boricha, Dorebafano, Pawe, and Mambuk. The delta15N values ranged from +0.820/00 for Pawe to +5.110/00 at Dorebafano. However, %Ndfa of soybean was greater in plants grown in Mambuk soil, followed by Pawe with the lowest %Ndfa being in Amaro soil. The amount of N-fixed followed similar pattern as %Ndfa. The significant interaction found between soil type and soybean genotype for plant DM, shoot N concentration, delta15N, %Ndfa, N-fixed and soil N uptake clearly indicated the effect of soil factors. This study revealed the presence of native rhizobia in Ethiopian soils that are compatible with soybean. The N contribution of the soybean genotypes was variable, and strongly influenced by the soil factors. PMID- 29997415 TI - Nitrate inhibition of N2 fixation and its effect on micronutrient accumulation in shoots of soybean (Glycine max L. Merr.), Bambara groundnut (Vigna subterranea L. Vedc) and Kersting's groundnut (Macrotyloma geocarpum Harms.). AB - Although nitrate is known to inhibit nodulation and N2 fixation in symbiotic legumes, little is known about its effect on the uptake and accumulation of trace elements such as Fe, Zn, Mn and Cu. The aim of this study was to evaluate the effect of 5 mM NO3- supply, either with or without rhizobial inoculation, on nodulation, nodule functioning and micronutrient levels in the shoots of soybean (Glycine max L.Merr.), Bambara groundnut (Vigna subterranea L. Vedc) and Kersting's groundnut (Macrotyloma geocarpum Harm). The results showed reduction in plant growth, nodule formation and nodule dry matter by the supply of 5 mM NO3 to inoculated seedlings of all three species. Nitrate inhibition respectively caused 1.2, 1.4, and 1.5-fold decrease in nodule number per plant in Bambara groundnut, soybean and Kersting's bean, which resulted in 2.3, 3.3 and 4.5-fold reduction in nodule dry weight of the test species (in that order). The application of 5 mM NO3- to soybean plants also resulted in 2.5, 4.0 and 5.4-fold decrease in shoot accumulation of Fe, Zn and Mn, respectively, when compared to the purely symbiotic control plants. Furthermore, we observed 1.3, 1.8 and 1.3 fold decreases in the concentration of Zn, Mn and Cu in shoots of inoculated Bambara groundnut with NO3- supply, levels lower than those found in soybean. With Kersting's groundnut, shoot concentration of Fe, Zn and Cu were higher with the application of 5 mM NO3- to inoculated plants when compared to the purely symbiotic treatment, which was opposite to soybean. But pure NO3-feeding of this species respectively resulted in 2.0, 1.4 and 1.3-fold decreases in Fe, Zn and Cu relative to inoculated NO3--fed plants. Clearly, NO3- supply to landraces/genotypes of the three legume species did not only inhibit nodule formation and functioning, it also reduced shoot micronutrient levels in soybean and Bambara groundnut, but not Kersting's bean. PMID- 29997416 TI - Selecting elite groundnut (Arachis hypogaea L) genotypes for symbiotic N nutrition, water-use efficiency and pod yield at three field sites, using 15N and 13C natural abundance. AB - About 70% of the groundnut (Arachis hypogaea L.) produced in Ghana is from the Guinea savanna. However, low soil nutrients, especially N, together with erratic rainfall distribution have often resulted in poor grain yield. The aim of this study was to evaluate plant growth, N2-fixing efficiency, N contribution, water use efficiency and pod yield of 21 elite groundnut genotypes in the Guinea savanna of Ghana, using the 15N natural abundance technique. The data revealed significant variations in plant growth, symbiotic N contribution, and pod yield among the 21 genotypes tested at each field site. Average N contribution by groundnut genotypes ranged from 48 to 108 kg N ha-1. Also, mean pod yield ranged from 0.58 to 2.1 t ha-1. Genotypes ICGV-IS 08837, ICG 6222, ICGV 03315 and NKATIESARI demonstrated superior plant growth, symbiotic N contribution and greater pod yield. In fact, ICGV-IS 08837 yielded almost 2.5 fold more than CHINESE which is the most widely cultivated variety in the region. Genotypes ICGV IS 08837, ICG 6222, ICGV 03315 and ICGV 99247 are therefore recommended for development into varieties for the Guinea savanna of Ghana. Genotypes ICG (FDRS) 4, ICGV00362 and ICGV99247 exhibited increased water-use efficiency, but were low in N2 fixation and N contribution, and would therefore be good parental material in breeding programs aimed at enhancing water-use efficiency in high N2-fixing genotypes. PMID- 29997417 TI - Grain yield of common bean (Phaseolus vulgaris L.) varieties is markedly increased by rhizobial inoculation and phosphorus application in Ethiopia. AB - A field experiment was conducted to assess plant growth, symbiotic performance and grain yield of common bean in response to rhizobial incoculation and phosphorus application at Galalicha in Southern Ethiopia during the 2012 and 2013 cropping seasons under rain-fed conditions. The treatments consisted of 2 released common bean varieties (Hawassa Dume and Ibbado), 3 levels of Rhizobium inoculation (uninoculated, inoculated with strain HB-429 or GT-9) and 4 levels of phosphorus application (0, 10, 20 and 30 kg P ha-1) using a split-split plot design with four replications. Here, phosphorus levels, Rhizobium inoculation and common bean varieties were assigned as main, sub- and sub-sub treatments, respectively. The results revealed marked varietal differences in plant growth, grain yield and symbiotic performance. Of the two common bean varieties studied, Hawassa Dume generally showed superior performance in most measured parameters in 2013. Rhizobium inoculation significantly (p <= 0.05) increased plant growth, symbiotic performance and grain yield. Applying Rhizobium strain HB-429 to bean crop respectively increased plant growth, %Ndfa, amount of N-fixed and grain yield by 19, 17, 54 and 48% over uninoculated control. Similarly, the application of 20 kg P ha-1 to bean plants respectively resulted in 36, 20, 96 and 143% increase in plant growth, %Ndfa, N-fixed and grain yield when compared to the control. These results clearly indicate that plant growth, symbiotic performance and grain yield of common bean can be significantly increased by Rhizobium inoculation and phosphorus fertilization in Ethiopia. Rhizobium inoculants are a cheaper source of nitrogen than chemical fertilizers and when combined with moderate phosphorus application can markedly increase grain yield for resource poor farmers. PMID- 29997418 TI - Assessing host range, symbiotic effectiveness, and photosynthetic rates induced by native soybean rhizobia isolated from Mozambican and South African soils. AB - Host range and cross-infectivity studies are important for identifying rhizobial strains with potential for use as inoculants. In this study, 10 native soybean rhizobia isolated from Mozambican and South African soils were evaluated for host range, symbiotic effectiveness and ability to induce high rates of photosynthesis leading to enhanced plant growth in cowpea (Vigna unguiculata L. Walp.), Bambara groundnut (Vigna subterranean L. Verdc.), Kersting's groundnut (Macrotyloma geocarpum Harm) and soybean (Glycine max L. Merr). The test isolates had different growth rates and colony sizes. Molecular analysis based on enterobacterial repetitive intergenic consensus (ERIC)-PCR revealed high genetic diversity among the test isolates. The results further showed that isolate TUTLBC2B failed to elicit nodulation in all test plants, just as TUTNSN2A and TUTDAIAP3B were also unable to nodulate cowpea, Kersting's bean and Bambara groundnut. Although the remaining strains formed ineffective nodules on cowpea and Kersting's bean, they induced effective nodules on Bambara groundnut and the two soybean genotypes. Bacterial stimulation of nodule numbers, nodule dry weights and photosynthetic rates was generally greater with isolates TUTRSRH3A, TUTM19373A, TUTMCJ7B, TUTRLR3B and TUTRJN5A. As a result, these isolates elicited significantly increased accumulation of biomass in shoots and whole plants of Bambara groundnut and the two soybean genotypes. Whole-plant symbiotic nitrogen (N) of soybean and Bambara groundnut was highest for the commercial strains CB756 and WB74, as well as for TUTRLR3B, TUTMCJ7B and TUTRSRH3A, suggesting that the three native rhizobial isolates have potential for use as inoculants. PMID- 29997419 TI - Gathering, evaluating and managing customer feedback during aircraft production. AB - This paper proposes a systematic approach for gathering requirements during production through customers' remote access to the partially and fully assembled aircraft and its modules. The paper also proposes an evaluation and management of these recorded requirements and their utilization in the development of an aircraft. Modular product architecture is used for the modular organization of the product, product-service, and production system for the gathering, evaluation and management of feedback for product development perspectives. A mobile and wearable augmented reality system is used to virtually walk through the partially or fully manufactured product and to compare the status of the production with the product model to be produced. Change requests are captured as customer feedback. The knowledge thus acquired can be overlaid (augmented) on the real product, i.e. the aircraft. This approach is able to record the dynamic requirements of targeted customers. These changes can be carried out in the current version of the aircraft, and also incorporated into future versions. The implementation using case studies is presented for gathering feedback during assembly as well as for evaluating and managing the recorded feedback for exemplary modules (cabin and galley) of an aircraft. The use of the evaluation results in the development of an aircraft is also presented in the paper. PMID- 29997420 TI - SynthETC: A Statistical Model for Severe Winter Storm Hazard on Eastern North America. AB - We develop, evaluate, and apply "SynthETC," a statistical-stochastic model of winter extra-tropical cyclones (ETCs) over eastern North America. SynthETC simulates the life cycle of ETCs from formation to termination, and it can be used to estimate the probability of extreme ETC events beyond the historical record. Two modes of climate variability are used as independent covariates: El Nino/Southern Oscillation (ENSO) Nino3.4 and the monthly North Atlantic Oscillation (NAO). We use SynthETC to estimate the annual occurrence rate over sites in eastern North America of intense ETC passage in different ENSO and NAO states. Positive NAO is associated with increased rates over the North Atlantic, while negative NAO is associated with decreased rates over the North Atlantic and increased rates over northern Quebec. Positive ENSO is associated with decreased rates over the North Atlantic, Ontario, and the Canadian Maritime, while negative ENSO is associated with increased rates over those regions, as well as the Great Lakes region. PMID- 29997422 TI - SPARSE BAYESIAN LEARNING USING VARIATIONAL BAYES INFERENCE BASED ON A GREEDY BASED CRITERION. PMID- 29997421 TI - Arthroscopic acetabular labral reconstruction with rectus femoris tendon autograft: Our experiences and early results. AB - Background: The native labrum has been shown to play a critical role in the maintenance of overall health of the cartilage of the hip. Disruption of the labral seal could be detrimental to the overall nutrition of the cartilage, leading to its premature degeneration. Purpose: This study sought to investigate patients undergoing labral reconstruction with indirect head of rectus femoris autograft, to determine the subjective improvement in pain they experienced, the complications and reoperation rates including conversion to Total hip replacement(THR). Method: We retrospectively reviewed all 7 patients who underwent labral reconstruction using indirect head of the rectus femoris tendon autograft between January 2013 to October 2015. We assessed improvement in pain and function, complications, and subsequent surgery. The minimum follow-up was 12 months (average, 15 months; range, 12-18 months). Results: All patients reported subjective improvement in preoperative pain and function. The mean modified Harris Hip Score (mHHS) improved significantly from 56 (54-60) preoperatively to 93 (90-97)) at mean latest follow-up. The mean change of mHHS was 36 (30-43) and mean postoperative patient satisfaction score was 9.1. We observed no radiological progression of arthritis as well as no patient had revision procedure including total hip replacement. Conclusion: Acetabular labrum reconstruction for irreparable labral tears in young patients with no significant arthritis, using indirect head of the rectus femoris tendon autograft is a new technique that shows improvement in pain and function post-operatively. Long-term follow-up results with higher quality studies will be necessary to further define the role of labral reconstruction in hip preservation surgery. PMID- 29997423 TI - Translational Challenges of Rat Models of Upper Extremity Dysfunction After Spinal Cord Injury. AB - There are approximately 17,500 new spinal cord injury (SCI) cases each year in the United States, with the majority of cases resulting from a traumatic injury. Damage to the spinal cord causes either temporary or permanent changes in sensorimotor function. Given that the majority of human SCIs occur in the cervical spinal level, the experimental animal models of forelimb dysfunction play a large role in the ability to translate basic science research to clinical application. However, the variation in the design of clinical and basic science studies of forelimb/upper extremity (UE) function prevents the ease of translation. This review provides an overview of experimental models of forelimb dysfunction used in SCI research with special emphasis on the rat model of SCI. The anatomical location and types of experimental cervical lesions, functional assessments, and rehabilitation strategies used in the basic science laboratory are reviewed. Finally, we discuss the challenges of translating animal models of forelimb dysfunction to the clinical SCI human population. PMID- 29997425 TI - Reliability and Validity of the Revised Transfer Assessment Instrument. AB - Background: Proper transfer technique is associated with improved biomechanics and decreased pain and pathology. However, many users do not use proper technique, and appropriate assessment and training are needed to address these deficits. The transfer assessment instrument (TAI) 4.0 was designed to meet those needs and improve on past versions by removing the need for clinician training, shortening administration time, and simplifying question content. Objectives: Evaluate the psychometric properties of the TAI 4.0. Methods: A convenience sample of full-time wheelchair users was scored on multiple transfers by four raters to assess interrater, intrarater, and test-retest reliability and concurrent validity of the TAI 4.0. Each user also was scored using a visual analog scale (VAS). Results: For 44 participants, the mean TAI 4.0 and VAS across all transfers were 7.58 +/- 1.12 and 7.44 +/- 1.78, respectively, and scores were significantly correlated (r = 0.52-0.7). VAS scores were more strongly influenced by the flight/landing and body setup phases of the transfer. There were no significant associations between TAI 4.0 score and demographics. Intraclass correlation coefficients (ICC) ranged from 0.80 to 0.85 for interrater reliability, 0.60 to 0.76 for intrarater reliability, and 0.55 to 0.76 for test retest reliability. The minimum detectable change (MDC) for the total score ranged from 1.02 to 1.30. Conclusion: The TAI 4.0 provides reliable and valid quantitative assessment of an individual's transfer without the need for comprehensive training, as is the case with the TAI 3.0. The tool can be completed in 3 minutes (average) in a clinical setting with only a ruler and goniometer. PMID- 29997424 TI - Advanced Assessment of the Upper Limb in Tetraplegia: A Three-Tiered Approach to Characterizing Paralysis. AB - Background: More than half of all individuals who sustain a spinal cord injury (SCI) experience some degree of impairment in the upper limb. Functional use of the arm and hand is of paramount importance to these individuals. Fortunately, the number of clinical trials and advanced interventions targeting upper limb function are increasing, generating optimism for improved recovery and restoration after SCI. New interventions for restoring function and improving recovery require more detailed examination of the motor capacities of the upper limb. Objectives: The purpose of this article is to introduce a three-tiered approach to evaluating motor function, with specific attention to the characteristics of weak and fully paralyzed muscles during acute rehabilitation. The three tiers include (1) evaluation of voluntary strength via manual muscle testing, (2) evaluation of lower motor neuron integrity in upper motor neuron paralyzed muscles using surface electrical stimulation, and (3) evaluation of latent motor responses in paralyzed muscles that exhibit a strong response to electrical stimulation, using surface electromyographic recording electrodes. These characteristics contribute important information that can be utilized to mitigate potential secondary conditions such as contractures and identify effective interventions such as activity-based interventions or reconstructive procedures. Our goal is to encourage frontline clinicians - occupational and physical therapists who are experts in muscle assessment - to consider a more in depth analysis of paralysis after SCI. Conclusion: Given the rapid advancements in SCI research and clinical interventions, it is critical that methods of evaluation and classification evolve. The success or failure of these interventions may depend on the specific characteristics identified in our three tiered assessment. Without this assessment, the physiological starting point for each individual is unknown, adding significant variability in the outcomes of these interventions. PMID- 29997426 TI - Comparison of Responsiveness and Minimal Clinically Important Difference of the Capabilities of Upper Extremity Test (CUE-T) and the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP). AB - Background: The Capabilities of Upper Extremity Test (CUE-T) and the Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP) were both developed to detect change in upper extremity (UE) function in persons with tetraplegia. Objective: To compare the responsiveness and minimal clinically important difference (MCID) of the CUE-T and the quantitative prehension (QtP) scale of the GRASSP. Methods: Subjects included 69 persons with tetraplegia: 60 with acute and 9 with chronic injuries. Subjects were assessed twice 3 months apart using the CUE-T, QtP-GRASSP, and upper extremity motor scores (UEMS). Subjects rated their impression of change in overall and right/left UE function from -7 to +7. The standardized response mean (SRM) was determined for acute subjects. MCID was estimated using a small subjective change (2-3 points) and change in UEMS. Results: Subjects were 41.9 +/- 18.1 years old, neurological levels C1-C7; 25 were motor complete. For acute subjects, the SRMs for total/side CUE-T scores were 1.07/0.96, and for the QtP-GRASSP they were 0.88/0.78. MCIDs based on subjective change for total/side CUE-T scores were 11.7/6.1 points and for QtP-GRASSP were 6.4/3.0 points. Based on change in UEMS, MCIDs for total/side were 11.9/6.3 points for CUE-T and 6.0/3.3 points for QtP-GRASSP. Some subjects had changes in the CUE-T due to its arm items that were not seen with the QtP GRASSP. Conclusion: Both the CUE-T and QtP-GRASSP are responsive to change in persons with acute cervical spinal cord injury with large SRMs. The CUE-T detects some changes in UE function not seen with the QtP-GRASSP. PMID- 29997427 TI - Evaluation of the Capabilities of Upper Extremity Test (CUE-T) in Children With Tetraplegia. AB - Background: The Capabilities of Upper Extremity Test (CUE-T) is a spinal cord injury (SCI)-specific instrument based on the CUE Questionnaire (CUE-Q). Objective: To evaluate the psychometric properties of CUE-T in children with cervical SCI and determine the lowest age appropriate for test administration. Method: In this repeated measures multicenter study, 39 youths, mean age 12.3 years and mean time post injury 5.14 years, completed two administrations of the CUE-T. Test-retest reliability, internal consistency, and known groups validity were measured. Concurrent and discriminant validity were measured against previously validated measures: CUE-Q, Graded Redefined Assessment of Strength, Sensibility and Prehension (GRASSP), Spinal Cord Independence Measure (SCIM) III, SCIM III-Self Care (SCIM-SC), and SCIM-Mobility. Results: The CUE-T scores demonstrated strong test-retest reliability (ICC >= 0.95), strong internal consistency (alpha >= 0.90), and acceptable individual item agreement (kappa >= 0.49). The hand subscale had better scores (p < .05) for the motor incomplete versus complete known groups, and the arm, hand, and side subscales had better scores (p < .05) for higher versus lower strength groups. The CUE-T had strong concurrent validity with the CUE-Q (r = 0.85-0.87), GRASSP (r = 0.78-0.90), and SCIM-SC (r = 0.70) and moderate-to-weak correlation with the total SCIM (r = 0.65) and SCIM-Mobility (r = 0.51). Children older than 6 years with mature grasp patterns were able to complete the CUE-T. Conclusion: The CUE-T scores are reliable and valid for use in children with cervical SCI older than 6 years of age. PMID- 29997428 TI - Evolution of Neuroprosthetic Approaches to Restoration of Upper Extremity Function in Spinal Cord Injury. AB - Background: Spinal cord injury (SCI) occurring at the cervical levels can result in significantly impaired arm and hand function. People with cervical-level SCI desire improved use of their arms and hands, anticipating that regained function will result in improved independence and ultimately improved quality of life. Neuroprostheses provide the most promising method for significant gain in hand and arm function for persons with cervical-level SCI. Neuroprostheses utilize small electrical currents to activate peripheral motor nerves, resulting in controlled contraction of paralyzed muscles. Methods: A myoelectrically controlled neuroprosthesis was evaluated in 15 arms in 13 individuals with cervical-level SCI. All individuals had motor level C5 or C6 tetraplegia. Results: This study demonstrates that an implanted neuroprosthesis utilizing myoelectric signal (MES)-controlled stimulation allows considerable flexibility in the control algorithms that can be utilized for a variety of arm and hand functions. Improved active range of motion, grip strength, and the ability to pick up and release objects were improved in all arms tested. Adverse events were few and were consistent with the experience with similar active implantable devices. Conclusion: For individuals with cervical SCI who are highly motivated, implanted neuroprostheses provide the opportunity to gain arm and hand function that cannot be gained through the use of orthotics or surgical intervention alone. Upper extremity neuroprostheses have been shown to provide increased function and independence for persons with cervical-level SCI. PMID- 29997429 TI - EEG-Controlled Functional Electrical Stimulation Therapy With Automated Grasp Selection: A Proof-of-Concept Study. AB - Background: Functional electrical stimulation therapy (FEST) is a promising intervention for the restoration of upper extremity function after cervical spinal cord injury (SCI). Objectives: This study describes and evaluates a novel FEST system designed to incorporate voluntary movement attempts and massed practice of functional grasp through the use of brain-computer interface (BCI) and computer vision (CV) modules. Methods: An EEG-based BCI relying on a single electrode was used to detect movement initiation attempts. A CV system identified the target object and selected the appropriate grasp type. The required grasp type and trigger command were sent to an FES stimulator, which produced one of four multichannel muscle stimulation patterns (precision, lateral, palmar, or lumbrical grasp). The system was evaluated with five neurologically intact participants and one participant with complete cervical SCI. Results: An integrated BCI-CV-FES system was demonstrated. The overall classification accuracy of the CV module was 90.8%, when selecting out of a set of eight objects. The average latency for the BCI module to trigger the movement across all participants was 5.9 +/- 1.5 seconds. For the participant with SCI alone, the CV accuracy was 87.5% and the BCI latency was 5.3 +/- 9.4 seconds. Conclusion: BCI and CV methods can be integrated into an FEST system without the need for costly resources or lengthy setup times. The result is a clinically relevant system designed to promote voluntary movement attempts and more repetitions of varied functional grasps during FEST. PMID- 29997430 TI - Nerve and Tendon Transfer Surgery in Cervical Spinal Cord Injury: Individualized Choices to Optimize Function. AB - Background: Recent adaption of nerve transfer surgery to improve upper extremity function in cervical spinal cord injury (SCI) is an exciting development. Tendon transfer procedures are well established, reliable, and can significantly improve function. Despite this, few eligible surgical candidates in the United States undergo these restorative surgeries. Evidence Acquisition: The literature on these procedures was reviewed. Results: Options to improve function include surgery to restore elbow extension, wrist extension, and hand opening and closing function. Tendon transfers are reliable and well tolerated but require weeks of immobilization and limits on extremity use. The role of nerve transfers is still being established. Early results indicate variable return of meaningful function with less immobilization but longer periods (up to years) required to gain appreciable function. Conclusion: Nerve and tendon transfer surgery sacrifice an expendable donor to restore a missing and more critical function. These procedures are well described in hand surgery; are reliable, well tolerated, and covered by insurance; and should be part of the SCI rehabilitation discussion. PMID- 29997431 TI - Activity-based Rehabilitation Interventions of the Neurologically Impaired Upper Extremity: Description of a Scoping Review Protocol. AB - Introduction: A scoping review provides a means to synthesize and present a large body of literature on a broad topic, such as methods for various upper extremity activity-based therapy (ABT) interventions. Objectives: To describe our scoping review protocol to evaluate peer-reviewed articles focused on ABT interventions for individuals with neurologically impaired upper extremities. Methods: At Jefferson College of Health Professions and Sidney Kimmel Medical College at Jefferson, Philadelphia, the authors will follow this protocol to conduct a scoping review by establishing a research question and conducting a search of bibliographic databases to identify relevant studies. Using specific inclusion and exclusion criteria, abstracts will be screened and full-text articles will be reviewed for inclusion in charting, summarizing, and reporting results of appropriate studies. Conclusion: This protocol will guide the scoping review process to develop a framework for establishing a noninvasive ABT intervention informed by evidence for individuals with neurologically impaired upper extremities. PMID- 29997432 TI - Retrobulbar hemodynamics and aqueous humor levels of endothelin-1 in exfoliation syndrome and exfoliation glaucoma. AB - Background: Endothelin-1 (ET-1) is the most potent vasoconstrictor in the body. There are reports in the literature correlating plasma levels of ET-1 and its impact on retrobulbar hemodynamics. This study evaluates aqueous humor levels of ET-1 and retrobulbar hemodynamics in patients with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG). Patients and methods: Patients scheduled for cataract surgery were included. Patients were allocated to non-exfoliation non-glaucoma group (controls), XFG and XFS groups. Peak systolic velocity (PSV), end diastolic velocity, and resistivity index of the ophthalmic artery (OA), short posterior ciliary arteries, and central retinal artery (CRA) were determined preoperatively using color Doppler imaging. Aqueous humor samples obtained at the beginning of cataract surgery were analyzed with enzyme-linked immunosorbent assay. Results: Sixty-nine participants of similar age were included (controls: n=24, XFG: n=22, XFS: n=23). Multiple regression analysis showed that ET-1, OA-PSV, OA-resistivity index, CRA-PSV, and CRA-end diastolic velocity were influenced by group but not by sex or age. ET-1 for the XFG group (15.93+/-2.8 pg/mL) was significantly higher than for the XFS (8.92+/-2.7 pg/mL) and control (8.44+/-2.6 pg/mL) groups. The difference in ET-1 titers between the control and XFS groups was not statistically significant. All four hemodynamic parameters affected by group status significantly correlated with ET-1 levels in eyes with XFS. In eyes with XFG, two of the four hemodynamic parameters significantly correlated with ET-1 levels. In control eyes, no correlation between ET-1 and hemodynamic parameters affected by group status was detected. Conclusion: ET-1 aqueous levels in eyes with XFG were significantly higher than those of age-matched controls. Reduced blood flow and increased vascular resistivity were detected in the OA and the CRA in eyes with XFG/XFS. ET-1 levels in eyes with XFG/XFS exhibit a significant correlation with hemodynamic parameters that indicate reduced perfusion. PMID- 29997434 TI - Autonomic function as indicated by heart rate deceleration capacity and deceleration runs in type 2 diabetes patients with or without essential hypertension. AB - Purpose: Sympathovagal imbalance is a common underlying disorder in hypertension and diabetes. This study characterized autonomic nervous system function, indicated by heart rate deceleration capacity (DC) and deceleration runs (DRs), in patients with type 2 diabetes mellitus (T2DM), with or without concomitant essential hypertension. Subjects and methods: We recruited 50 healthy subjects, 50 patients with T2DM, and 95 with T2DM and essential hypertension. DC, DRs (DR2, DR4, and DR8, ie, episodes of 2, 4, or 8 consecutive beat-to-beat heart rate decelerations, respectively), and heart rate variability were determined by dynamic electrocardiogram. Biochemical markers of glucose and lipid metabolism, including glycated hemoglobin (HbA1c) and high-density lipoprotein cholesterol (HDL-C), were measured from blood samples. Results: Both T2DM groups featured lower DC, SD of all normal-to-normal sinus RR intervals over 24 h (SDNN), root mean square of the successive normal sinus RR interval difference, and all DR values, but higher average heart rate (AHR) and acceleration capacity (AC), than healthy subjects. There were significant associations between the following: DC and HbA1c, systolic blood pressure (SBP), AHR, age, and HDL-C; DR2 and AHR, SBP, and HbA1c; DR4 and HbA1c, age, SBP, and HDL-C; and DR8 and HbA1c, AHR, and age. In both T2DM groups, HbA1c correlated negatively with DC, DR2, and SDNN, and positively with AC and AHR; homeostasis model assessment-insulin resistance index correlated negatively with DC, all DRs, and SDNN, and positively with AC. Conclusion: Compared with healthy subjects, T2DM patients with or without essential hypertension have lower DC and DRs. DC and DRs correlate negatively with blood glucose and insulin resistance index. PMID- 29997433 TI - Gemcitabine hydrochloride microspheres used for intravesical treatment of superficial bladder cancer: a comprehensive in vitro/ex vivo/in vivo evaluation. AB - Introduction: Bladder cancer is responsible for more than 130,000 deaths annually worldwide. Intravesical delivery of chemotherapeutic agents provides effective drug localization to the target area to reduce toxicity and increase efficacy. This study aimed to develop an intravesical delivery system of gemcitabine HCl (Gem-HCl) to provide a sustained-release profile, to prolong residence time, and to enhance its efficiency in the treatment of bladder cancer. Materials and methods: For this purpose, bioadhesive microspheres were successfully prepared with average particle size, encapsulation efficiency, and loading capacity of 98.4 um, 82.657%+/-5.817%, and 12.501+/-0.881 mg, respectively. For intravesical administration, bioadhesive microspheres were dispersed in mucoadhesive chitosan or in situ poloxamer gels and characterized in terms of gelation temperature, viscosity, mechanical, syringeability, and bioadhesive and rheological properties. The cytotoxic effects of Gem-HCl solution, Gem-HCl microspheres, and Gem-HCl microsphere-loaded gel formulations were evaluated in two different bladder cancer cell lines: T24 (ATCC HTB4TM) and RT4 (ATCC HTB2TM). Results: According to cell-culture studies, Gem-HCl microsphere-loaded poloxamer gel was more cytotoxic than Gem-HCl microsphere-loaded chitosan gel. Antitumor efficacy of newly developed formulations were investigated by in vivo studies using bladder-tumor-induced rats. Conclusion: According to in vivo studies, Gem-HCl microsphere-loaded poloxamer gel was found to be an effective and promising alternative for current intravesical delivery-system therapies. PMID- 29997435 TI - Changes in synaptic plasticity are associated with electroconvulsive shock induced learning and memory impairment in rats with depression-like behavior. AB - Background: Accompanied with the effective antidepressant effect, electroconvulsive shock (ECS) can induce cognitive impairment, but the mechanism is unclear. Synaptic plasticity is the fundamental mechanism of learning and memory. This study aimed to investigate the effect of ECS on synaptic plasticity changes in rats with depression-like behavior. Methods: Chronic unpredictable mild stress procedure was conducted to establish a model of depression-like behavior. Rats were randomly divided into the following three groups: control group with healthy rats (group C), rats with depression-like behavior (group D), and rats with depression-like behavior undergoing ECS (group DE). Depression-like behavior and spatial learning and memory function were assessed by sucrose preference test and Morris water test, respectively. Synaptic plasticity changes in long-term potentiation (LTP), long-term depression (LTD), depotentiation, and post-tetanic potentiation (PTP) were tested by electrophysiological experiment. Results: ECS could exert antidepressant effect and also induced spatial learning and memory impairment in rats with depression-like behavior. And, data on electrophysiological experiment showed that ECS induced lower magnitude of LTP, higher magnitude of LTD, higher magnitude of depotentiation, and lower magnitude of PTP. Conclusion: ECS-induced learning and memory impairment may be attributed to postsynaptic mechanism of LTP impairment, LTD and depotentiation enhancement, and presynaptic mechanism of PTP impairment. PMID- 29997436 TI - Real world data: an opportunity to supplement existing evidence for the use of long-established medicines in health care decision making. AB - Evidence from medication use in the real world setting can help to extrapolate and/or augment data obtained in randomized controlled trials and establishes a broad picture of a medication's place in everyday clinical practice. By supplementing and complementing safety and efficacy data obtained in a narrowly defined (and often optimized) patient population in the clinical trial setting, real world evidence (RWE) may provide stakeholders with valuable information about the safety and effectiveness of a medication in large, heterogeneous populations. RWE is emerging as a credible information source; however, there is scope for enhancements to real world data (RWD) sources by understanding their complexities and applying the most appropriate analytical tools in order to extract relevant information. In addition to providing information for clinicians, RWE has the potential to meet the burden of evidence for regulatory considerations and may be used in approval of new indications for medications. Further understanding of RWD collection and analysis is needed if RWE is to achieve its full potential. PMID- 29997437 TI - Angiogenesis and vasculogenic mimicry are inhibited by 8-Br-cAMP through activation of the cAMP/PKA pathway in colorectal cancer. AB - Introduction: Vasculogenic mimicry (VM) describes the formation of an epithelial independent tumor microcirculation system that differs from traditional angiogenesis. Angiogenesis and the formation of VM are closely related through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway and the epithelial-mesenchymal transition (EMT) process. Materials and methods: In this study, 8-Br-cAMP, a cAMP analog and PKA activator, was used to activate the cAMP/PKA pathway to evaluate the effects of cAMP/PKA on angiogenesis and VM in colorectal cancer (CRC) cells. We used a syngeneic model of CRC in BALB/c mice. Results: We discovered that treatment with 8-Br-cAMP significantly reduced tumor number compared to control mice after the 7th, 14th, and 28th days of treatment. VM was evaluated by periodic acid-schiff (PAS)-CD31 staining, and we found that VM was inhibited by 8-Br-cAMP treatment in vivo. Immunohistochemistry confirmed the inhibition of vascular endothelial growth factor (VEGF) and cAMP and the activation of PKA by 8-Br-cAMP; quantitative real-time-PCR (qRT-PCR) demonstrated that 8-Br-cAMP regulated the expression of vascular endothelial (VE)-cadherin, matrix metalloproteinase 2 (MMP2), ephrin type-A receptor 2 (EphA2), and VEGF in vivo. Experiments in vitro revealed that treatment with 8-Br-cAMP and U0126 decreased VEGF expression through PKA-ERK in CT26 cells by qRT-PCR. We further confirmed that tube formation of human umbilical vein endothelial cells was inhibited by 8-Br-cAMP in vitro. Discussion: This study demonstrates that angiogenesis and VM are inhibited by 8-Br-cAMP treatment. Our data indicate that 8-Br-cAMP acts through the cAMP/PKA-ERK pathway and through EMT processes in CRC. These findings provide an insight into mechanisms of CRC and suggest that the cAMP/PKA-ERK pathway is a novel potential therapeutic target for the treatment of CRC. PMID- 29997438 TI - SIL1 functions as an oncogene in glioma by AKT/mTOR signaling pathway. AB - Purpose: SIL1 is a ubiquitous protein localized to the endoplasmic reticulum and functions as a cochaperone of BiP. Previous studies have shown that function loss of SIL1 is often associated with neurological diseases, such as Marinesco-Sjogren Syndrome. However, no studies have investigated the function of SIL1 in tumors. In this study we aim to reveal functions of SIL1 and the underlying mechanisms in glioma. Materials and methods: First, by searching on Gene Expression Profiling Interactive Analysis, we examined SIL1 expression and prognostic value in glioblastoma multiforme (GBM) and brain lower grade glioma (LGG). Immunohistochemical analysis (IHC) was also performed to determine the endogenic SIL1 level. Cell counting kit-8 (CCK8) and clone formation assays were used to detect cell proliferation of U251 cells. Cell migration was detected by transwell assay and cell cycle and apoptosis were detected by flow cytometry. Western blot was performed to determine protein expression. Results: We found that the expression of SIL1 was increased by approximately 1.5-fold in GBM and 1.3-fold in LGG compared with normal controls (P<0.05) and negatively correlated with patients' survival. IHC revealed that SIL1 expression was significantly higher in glioma tissues than that in paracancerous tissues (P<0.05). Glioma patients with high SIL1 expression accounted for 65.79% (25/38) of total samples and SIL1 expression significantly increased in grade IV glioma compared to grades I-III (P=0.026). Suppression of SIL1 expression led to significant inhibition of U251 cell proliferation. Transwell assay showed that cell migration of U251 was significantly inhibited by siSIL transfection, with an inhibitory rate reaching 69%. Flow cytometry detection showed that siSIL1 could induce apoptosis of U251 cells and upregulated the expression of the pro-apoptotic protein Bax and Caspase3-P17. However, siSIL1 transfection had no effect on the cell cycle. Mechanism studies demonstrated that siSIL1 transfection led to inactivation of AKT/mTOR signaling pathway, including decreased phosphorylation of AKT and mTOR without affecting protein expression, as well as decreased expression of the downstream effector p70S6K. Conclusion: Downregulation of SIL1 inhibited the progression of glioma by suppressing the AKT/mTOR signaling pathway. PMID- 29997439 TI - A prospective study on neoadjuvant chemoradiotherapy plus anti-EGFR monoclonal antibody followed by surgery for locally advanced cervical cancer. AB - Background: To investigate the efficacy and safety of neoadjuvant chemoradiotherapy plus anti-epidermal growth factor receptor monoclonal antibody followed by surgery for locally advanced cervical cancer (LACC). Patients and methods: Patients with histologically proven LACC were enrolled into this prospective study. All patients received intensity-modulated radiation therapy with conventional fractionation. Weekly cisplatin or nedaplatin was administered concurrently with intensity-modulated radiation therapy. Nimotuzumab, a humanized anti-epidermal growth factor receptor monoclonal antibody, was given at a dose of 200 mg per week for 6 cycles. Approximately 1 month after the completion of neoadjuvant treatment, the patients were assessed for clinical tumor response and operability based on MRI and gynecological examination. For those who were considered to be candidates for surgery, radical hysterectomy, and pelvic lymph node dissection were performed 5-6 weeks after the completion of neoadjuvant therapy. Results: Twenty-eight patients were enrolled. Clinical complete response and partial response were found in 8 (28.5%) and 20 (71.5%) patients, respectively. Four patients were not eligible for surgery and 2 patients refused surgery although they were assessed as surgical candidates. They were not included in this analysis. Radical hysterectomy and pelvic lymph node dissection were performed for the remaining 22 patients. Among them, 8 (36.4%) had complete pathology response, 9 (40.9%) presented with persistent atypical cells or cervical intraepithelial neoplasia, and 5 (22.7%) presented with macroscopic and/or microscopic residual disease, according to the pathological evaluation. Median follow-up time was 22 months (range, 5-39 months). The 2-year locoregional control rate, progression-free survival rate, distant metastasis-free survival rate, and overall survival rate were 95.0%, 85.2%, 84.0%, and 90.0%, respectively. Acute toxicities were mild in general and easily manageable. Chronic toxicities were mainly limited to grade 1. No severe late toxicities were observed. Conclusion: Concurrent chemoradiotherapy plus nimotuzumab followed by surgery is highly effective and safe in LACC. Further studies are warranted to confirm the findings. PMID- 29997440 TI - Polymorphisms in MYCN gene and neuroblastoma risk in Chinese children: a 3-center case-control study. AB - Introduction: Neuroblastoma is an embryonal tumor of the sympathetic nervous system. The MYCN oncogene is amplified in some neuroblastoma patients and correlated with poor prognosis. However, less is known regarding the relationship between MYCN gene single-nucleotide polymorphisms (SNPs) and neuroblastoma risk. Patients and methods: To investigate the contribution of MYCN gene polymorphisms to neuroblastoma risk, we performed a 3-center case-control study by genotyping 4 SNPs in the MYCN gene from 429 cases and 884 controls. Results: The results showed that only rs57961569 G>A was associated with neuroblastoma risk (GA vs GG: adjusted odds ratio =0.76, 95% confidence interval =0.60-0.98, P=0.033), while the other 3 SNPs were not (rs9653226 T>C, rs13034994 A>G, and rs60226897 G>A). Stratified analysis revealed that rs57961569 GG carriers were more likely to develop neuroblastoma in the following subgroups: children older than 18 months, tumor derived from the adrenal gland, and clinical stages III + IV. The increased neuroblastoma risk associated with the rs9653226 variant CC genotypes was more evident in the following subgroups: females, tumor derived from the adrenal gland, and clinical stages III + IV. The presence of 2-3 risk genotypes had a significant relationship with the following subgroups: tumor derived from the adrenal gland and clinical stages III + IV. Conclusion: This study demonstrates a weak impact of MYCN gene polymorphisms on neuroblastoma risk, which should be further validated. PMID- 29997441 TI - Downregulation of lncRNA OGFRP1 inhibits hepatocellular carcinoma progression by AKT/mTOR and Wnt/beta-catenin signaling pathways. AB - Introduction: Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play important roles in the progression of hepatocellular carcinoma (HCC) by regulating gene expression. However, the identification of functional lncRNAs in HCC remains insufficient. Our study aimed to investigate the function of lncRNA OGFRP1, which has not been functionally researched before, in Hep3B and HepG2 cells. Methods: lncRNA OGFRP1 in HCC cells was down-regulated by using RNAi technology. Quantitative real-time polymerase chain reaction was used to determine the mRNA expression of lncRNA OGFRP1. Cell proliferation was examined by CCK8 and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were assessed by using Scratch assay and transwell assay, respectively. Protein expression of signaling pathways was determined by using Western blot. Results: Cell proliferation of Hep3B was significantly inhibited by down-regulation of lncRNA OGFRP1 (P<0.05). Moreover, siOGFRP1 transfection induced Hep3B cell cycle arrest and apoptosis by regulating the expression of related proteins. Cell migration and invasion of Hep3B were also significantly inhibited by down-regulation of lncRNA OGFRP1. Wnt/beta catenin signaling pathway, involved in epithelial-mesenchymal transition (EMT), was inactivated by lncRNA OGFRP1 downregulation, including decreased expression of Wnt3a, beta-catenin, N-cadherin and vimentin and increased expression of E cadherin. We also found that the inhibitory effect of lncRNA OGFRP1 knockdown on Hep3B was mediated by the AKT/mTOR signaling pathway and IGF-1, an AKT signaling activator, could rescue the cellular phenotype. However, knockdown of lncRNA OGFRP1 did not influence cell proliferation, migration and invasion in HepG2 cells. Conclusion: We found that downregulation of lncRNA OGFRP1 suppressed the proliferation and EMT of HCC Hep3B cells through AKT and Wnt/beta-catenin signaling pathways. However, lncRNA OGFRP1 exhibited a differentiated function in different HCC cell lines, which required further study in the future. PMID- 29997442 TI - Trends in treatments of thyroid disease following iodine fortification in Denmark: a nationwide register-based study. AB - Background: Long-term iodine exposure may influence the frequency of thyroid disease treatments through fluctuations in thyroid diseases. Yet, the long-term fluctuations in thyroid disease treatments upon iodine fortification (IF) are not fully known. We aimed to examine the development in thyroid disease treatments in Denmark before and following the implementation of IF in 2000. Methods: Nationwide data on antithyroid medication, thyroid hormone therapy, thyroid surgery, and radioiodine treatment were obtained from Danish registries. Negative binominal regression was applied to analyze annual changes in treatment rates adjusted for region of residence, sex, and age. Results: Incidence of antithyroid medication transiently increased but fell and reached steady state from 2010 at an incidence rate ratio (RR) of 0.72 (95% confidence interval [CI] 0.67-0.77) compared to year 2000. Thyroid hormone therapy increased and reached steady state in 2010 at an incidence RR of 1.75 (95% CI 1.62-1.89) compared to year 2000. Thyroid surgery was constant except for higher rates in 2014-2015, and radioiodine treatment fluctuated with no apparent pattern. Conclusion: Ten years after IF, a steady state was observed for incident antithyroid medication below the level at IF, and thyroid hormone therapy above the level at IF. Only small changes were observed in thyroid surgery and radioiodine treatment. In the same period, changes in diagnostic and treatment practices and lifestyle factors are likely to have occurred and should be considered when evaluating the effects of IF on treatment of thyroid diseases. PMID- 29997443 TI - Wandering throughout South America: Taxonomic revision of Tradescantia subg. Austrotradescantia (D.R.Hunt) M.Pell. (Commelinaceae). AB - I present the first taxonomic revision for T. subg. Austrotradescantia, based on extensive field, cultivation and herbaria studies. I accept 13 species, three of them (i.e. T. atlantica, T. hertweckii and T. tucumanensis) being described as new in the present study. I provide an identification key to the species, distribution maps, descriptions, comments, conservation assessments and illustrations for all species. The troublesome weed T. fluminensis has its specific limits clarified and its native range is presented so it can serve as a basis to better understanding its ecological requirements and to help control it throughout its invasive range. Furthermore, I highlight that T. mundula, a commonly neglected species closely related to T. fluminensis, might also represent a troublesome weed. Tradescantia mundula has been widely introduced in cultivation under the name T. albiflora and seems to have also escaped from cultivation. However, due to the hitherto poorly understood specific limits of T. fluminensis, T. mundula has been treated as a mere cultivar of T. fluminensiss.s. PMID- 29997444 TI - Manihot takape sp. nov. (Euphorbiaceae), a new tuberous subshrub from the Paraguayan Chaco. AB - Manihot takape De Egea & Pena-Chocarro, sp. nov. is described and illustrated as a new species from the Paraguayan Chaco. It was collected while carrying out fieldwork related to the study of the most important Wild Crop Relatives of the country's flora. Morphological characteristics that differentiate this species from closely related taxa, as well as its habitat, geographical distribution and conservation status are provided. PMID- 29997445 TI - Begonia medogensis, a new species of Begoniaceae from Western China and Northern Myanmar. AB - Begonia medogensis JianW.Li, Y.H.Tan & X.H.Jin, a new species of Begoniaceae, is described and illustrated by colour photographs. Begonia medogensis is distributed in western China and northern Myanmar. It has erect stems, is tuberless, has many triangular to lanceolate leaves, base slightly asymmetric, margins remotely and irregularly denticulate; staminate flowers have 4 perianth segments, with outer 2 segments broadly ovate, inner 2 spathulate; pistillate flowers have 5 perianth segments, unequal, outer 4 broadly ovate, inner 1 spathulate. The new species is assigned to section Platycentrum and can easily be distinguished from the other species in the section. PMID- 29997446 TI - Odontochilus putaoensis (Cranichideae, Orchidaceae), a new species from Myanmar. AB - Odontochilus putaoensis, a new species of Orchidaceae, is described and illustrated from Putao Township, Kachin State, Myanmar. Odontochilus putaoensis is close to O. duplex, but can be easily distinguished from the latter by having a light yellow lip, a bisaccate hypochile with a small, erect, blade-like and emarginate callus within each sac, a mesochile with a pair of dentate-pectinate flanges and a bilobed epichile with a pair of widely diverging lobes that are erect and concave. An identification key to the Southeast Asian species of Odontochilus and colour photographs of O. putaoensis are provided. A preliminary conservation assessment according to the IUCN Red List Categories and Criteria is given for the new species. PMID- 29997447 TI - Short-spored Subulicystidium (Trechisporales, Basidiomycota): high morphological diversity and only partly clear species boundaries. AB - Diversity of corticioid fungi (resupinate Basidiomycota), especially outside the northern temperate climatic zone, remains poorly explored. Furthermore, most of the known species are delimited by morphological concepts only and, not rarely, these concepts are too broad and need to be tested by molecular tools. For many decades, the delimitation of species in the genus Subulicystidium (Hydnodontaceae, Trechisporales) was a challenge for mycologists. The presence of numerous transitional forms as to basidiospore size and shape hindered species delimitation and almost no data on molecular diversity have been available. In this study, an extensive set of 144 Subulicystidium specimens from Paleo- and Neotropics was examined. Forty-nine sequences of ITS nuclear ribosomal DNA region and 51 sequences of 28S nuclear ribosomal DNA region from fruit bodies of Subulicystidium were obtained and analysed within the barcoding gap framework and with phylogenetic Bayesian and Maximum likelihood approaches. Eleven new species of Subulicystidium are described based on morphology and molecular analyses: Subulicystidium boidinii, S. fusisporum, S. grandisporum, S. harpagum, S. inornatum, S. oberwinkleri, S. parvisporum, S. rarocrystallinum, S. robustius, S. ryvardenii and S. tedersooi. Morphological and DNA-evidenced borders were revised for the five previously known species: S. naviculatum, S. nikau, S. obtusisporum, S. brachysporum and S. meridense. Species-level variation in basidiospore size and shape was estimated based on systematic measurements of 2840 spores from 67 sequenced specimens. An updated identification key to all known species of Subulicystidium is provided. PMID- 29997448 TI - Different diversification histories in tropical and temperate lineages in the ascomycete subfamily Protoparmelioideae (Parmeliaceae). AB - Background: Environment and geographic processes affect species' distributions as well as evolutionary processes, such as clade diversification. Estimating the time of origin and diversification of organisms helps us understand how climate fluctuations in the past might have influenced the diversification and present distribution of species. Complementing divergence dating with character evolution could indicate how key innovations have facilitated the diversification of species. Methods: We estimated the divergence times within the newly recognised subfamily Protoparmelioideae (Ascomycota) using a multilocus dataset to assess the temporal context of diversification events. We reconstructed ancestral habitats and substrate using a species tree generated in *Beast. Results: We found that the diversification in Protoparmelioideae occurred during the Miocene and that the diversification events in the tropical clade Maronina predate those of the extratropical Protoparmelia. Character reconstructions suggest that the ancestor of Protoparmelioideae was most probably a rock-dwelling lichen inhabiting temperate environments. Conclusions: Major diversification within the subtropical/tropical genus Maronina occurred between the Paleocene and Miocene whereas the diversifications within the montane, arctic/temperate genus Protoparmelia occurred much more recently, i.e. in the Miocene. PMID- 29997449 TI - Bottom-up approach to strengthen community-based malaria control strategy from community health workers' perceptions of their past, present, and future: a qualitative study in Palawan, Philippines. AB - Background: Microscopists have active roles in bringing malaria diagnosis and treatment closer to households in Palawan, the highest malaria-endemic province in the Philippines. To accelerate the elimination of malaria in Palawan, we performed a study based on the bottom-up approach to provide profound data to strengthen this community-based malaria control from the microscopists' point of view. Methods: We performed a qualitative cross-sectional study in Palawan. Four focus group discussions with 50 microscopists were conducted in Palawan from November 2010 to February 2011. During the discussions, the following open-ended questions were addressed: motivation for applying to be microscopists in the "Past" category; job satisfaction, role, problems, and saddest and happiest experiences working as microscopists in the "Present" category; and willingness towards task shifting in the "Future" category. Data were transcribed and analyzed by framework analysis using the NVivo software program. Results: The present study innovatively proposed the following strategies: reinforcement strategy (adequate supplies and settings), highly prioritized additional strategies (improving social status of microscopists, issuing a travel budget, and including indigenous populations), regional additional strategies (additional malaria control in the southern region and task shifting in the northern region), and less prioritized additional strategies (employment policy and health checkup). Conclusion: A bottom-up approach using microscopists' perceptions would be a valuable method to propose practical and effective additional strategies for strengthening community-based malaria control. PMID- 29997450 TI - Fault slip and identification of the second fault plane in the Varzeghan earthquake doublet. AB - An intraplate earthquake doublet, with 11-min delay between the events, devastated the city of Varzeghan in northwestern Iran on August 11, 2012. The first Mw 6.5 strike-slip earthquake, which occurred after more than 200 years of low seismicity, was followed by an Mw 6.4 oblique thrust event at an epicentral separation of about 6 km. While the first event can be associated with a distinct surface rupture, the absence of a surface fault trace and no clear aftershock signature makes it challenging to identify the fault plane of the second event. We use teleseismic body wave inversion to deduce the slip distribution in the first event. Using both P and SH waves stabilize the inversion and we further constrain the result with the surface rupture extent and the aftershock distribution. The obtained slip pattern shows two distinct slip patches with dissimilar slip directions where aftershocks avoid high-slip areas. Using the estimated slip for the first event, we calculate the induced Coulomb stress change on the nodal planes of the second event and find a preference for higher Coulomb stress on the N-S nodal plane. Assuming a simple slip model for the second event, we estimate the combined Coulomb stress changes from the two events on the focal planes of the largest aftershocks. We find that 90% of the aftershocks show increased Coulomb stress on one of their nodal planes when the N S plane of the second event is assumed to be the correct fault plane. PMID- 29997451 TI - Obstructive Sleep Apnea Monocytes Exhibit High Levels of Vascular Endothelial Growth Factor Secretion, Augmenting Tumor Progression. AB - Obstructive sleep apnea (OSA) is a syndrome characterized by repeated pauses in breathing induced by a partial or complete collapse of the upper airways during sleep. Intermittent hypoxia (IH), a hallmark characteristic of OSA, has been proposed to be a major determinant of cancer development, and patients with OSA are at a higher risk of tumors. Both OSA and healthy monocytes have been found to show enhanced HIF1alpha expression under IH. Moreover, these cells under IH polarize toward a tumor-promoting phenotype in a HIF1alpha-dependent manner and influence tumor growth via vascular endothelial growth factor (VEGF). Monocytes from patients with OSA increased the tumor-induced microenvironment and exhibited an impaired cytotoxicity in a 3D tumor in vitro model as a result of the increased HIF1alpha secretion. Adequate oxygen restoration both in vivo (under continuous positive airway pressure treatment, CPAP) and in vitro leads the monocytes to revert the tumor-promoting phenotype, demonstrating the plasticity of the innate immune system and the oxygen recovery relevance in this context. PMID- 29997453 TI - rs61991156 in miR-379 is associated with low capability of glycolysis of gastric cancer by enhanced regulation of PKM2. AB - Background: Glycolysis is an important metabolic oncogenic change also play a pivot role in the Warburg effect. Glycolysis related gene PKM2 expressed differently individually. Presently, we sought to investigate the effect of single nucleotide polymorphism (SNP) at rs61991156 of miR-379 on gastric cancer (GC) proliferation and metabolism. Methods: The genotype of rs61991156 in miR-379 was investigated by using real-time PCR. The glycolysis-related metabolites were determined by using GC-TOF-MS. The biological effects of rs61991156 in miR-379 was explored by in vitro studies. Results: In this study, we found that rs61991156 in miR-379 was involved in the occurrence of GC by acting on the 3'UTR region of PKM2. The clinical data analysis revealed that A > G in rs187960998 was significantly associated with better differentiation, small tumor size, and non metastasis. In vitro study further revealed that A > G SNP of miR-379 could decrease GC cell proliferation as well as the promoter activity and expression of PKM2. The glycolysis of the patients with miR-379 GG genotype was significantly lower than AG and AA genotype by metabolomics analysis. The patients with AA genotype have significantly lower PKM2 expression compared to the G carrier, while there is no significant expression difference in miR-379 expression. Patients with AA genotype have significantly shorter survival rate compared to the G carrier. Conclusion: rs61991156 in miR-379 was highly associated with a decreased risk, well differentiation and better post-surgery survival in Chinese population by inhibiting the expression of PKM2. PMID- 29997452 TI - Polymorphism in lncRNA AC016683.6 and its interaction with smoking exposure on the susceptibility of lung cancer. AB - Background: Long non-coding RNAs play pivotal roles in the carcinogenesis of multiple types of cancers. This study is firstly to evaluate influence of rs4848320 and rs1110839 polymorphisms in long non-coding RNA AC016683.6 on the susceptibility of lung cancer. Methods: The present study was a hospital-based case-control study with 434 lung cancer patients and 593 cancer-free controls. Genotyping of the two SNPs detected by Taqman(r) allelic discrimination method. Results: There were no statistically significant associations between rs4848320 and rs1110839 polymorphisms in AC016683.6 and risk of lung cancer in overall population. However, in the smoking population, rs4848320 and rs1110839 polymorphisms significantly increased the risk of lung cancer in dominant and homozygous models (Rs4848320: P = 0.029; Rs1110839: P = 0.034), respectively. In male population, rs1110839 genetic variant was related to the risk of lung cancer in all genetic models (GG vs. TT: P = 0.008; Dominant model: P = 0.029; Recessive model: P = 0.027) rather than heterozygous model. The crossover analyses provided rs4848320 and rs1110839 risk genotypes carriers combined with smoking exposure 2.218-fold, 1.755-fold increased risk of lung cancer (Rs4848320: P = 0.005; Rs1110839: P = 0.017). Additionally, there were significantly positive multiplicative interaction of rs4848320 polymorphism with smoking status, with adjusted OR of 2.244 (1.162-4.334), but rs1110839 polymorphism did not exist. Conclusions: Rs4848320 and rs1110839 polymorphisms may be associated with lung cancer susceptibility. Interaction of rs4848320 risk genotypes with smoking exposure may strengthen the risk effect on lung cancer. PMID- 29997454 TI - A new icriodontid conodont cluster with specific mesowear supports an alternative apparatus motion model for Icriodontidae. AB - Increasing numbers of conodont discoveries with soft tissue preservation, natural assemblages and fused clusters of the hard tissue have strengthened the hypothesis regarding the function and mechanism of the conodont feeding apparatus. Exceptional fossil preservation serves as a solid basis for modern reconstructions of the conodont apparatus illustrating the complex interplay of the single apparatus elements. Reliable published models concern the ozarkodinid apparatus of Pennsylvanian and Early Triassic conodonts. Recognition of microwear and mammal-like occlusion, especially of platform elements belonging to individuals of the genus Idiognathodus, allows rotational closure to be interpreted as the crushing mechanism of ozarkodinid platform (P1) elements. Here we describe a new icriodontid conodont cluster of Caudicriodus woschmidti that consists of one pair of icriodontan (I) and 10 pairs of coniform (C1-5) elements, with I elements being preserved in interlocking position. The special kind of element arrangement within the fused cluster provides new insights into icriodontid apparatus reconstruction and notation of elements. However, orientation of coniform elements is limited to a certain degree by possible preservational bias. Four possible apparatus models are introduced and discussed. Recognition of specific wear on denticle tips of one of the icriodontan elements forms the basis for an alternative hypothesis of apparatus motion. Analysis of tip wear suggests a horizontal, slightly elliptical motion of opposed, antagonistically operating I elements. This is supported by similar tip wear from much better preserved, but isolated, elements of Middle Devonian icriodontids. More detailed interpretation of the masticatory movement will allow enhanced understanding of anatomical specifications, diet and palaeobiology of different euconodont groups. PMID- 29997455 TI - Depressive Symptoms and Alcohol Abuse/Misuse in Older Adults: Results from the Florida BRITE Project. AB - Previous research has suggested that older adults who misuse alcohol frequently report depressive symptoms as an antecedent to drinking. The objective of the present study was to investigate the extent to which higher levels of depressive symptoms were associated with elders' problem drinking by examining screening data from a three-year pilot program known as the Florida BRITE Project. BRITE (BRief Intervention and Treatment for Elders) is a multisite program offering brief interventions for community-based older adults screening positive for alcohol or medication misuse. Depressive symptoms were assessed using the Short Geriatric Depression Scale: alcohol use was assessed with the first three questions from the Alcohol Use Disorders Identification Test and the Short Michigan Alcoholism Screening Test-Geriatric version. Multivariate logistic regression revealed that older adults with higher levels of depressive symptoms were at greater risk for screening positive for alcohol problems, particularly among the "young-old" adults. The results not only suggest the importance of screening for both depressive symptoms and alcohol misuse in an older population, but also indicate that older adults are not a homogeneous group. PMID- 29997456 TI - Pacific Hurricane Landfalls on Mexico and SST. AB - A statistical model of Northeast Pacific tropical cyclones (TCs) is developed and used to estimate hurricane landfall rates along the coast of Mexico. Mean annual landfall rates for 1971-2014 are compared to mean rates for the extremely high Northeast Pacific sea-surface temperature (SST) of 2015. Over the full coast, the mean rate and 5%-95% uncertainty for Saffir-Simpson category one and higher TCs (category-1+ TCs) is 1.241.051.33yr-1 for 1971-2014 and 1.690.892.08yr-1 for 2015, a difference that is not significant. However, the increase for the most intense landfalls, category-5 TCs, is significant: 0.0090.0060.011yr-1 for 1971 2014 and 0.0310.0160.036yr-1 for 2015. The SST impact on the category-5 TC landfall rate is largest on the northern Mexican coast. The increased landfall rates for category-5 TCs is consistent with independent analysis showing that SST has its greatest impact on the formation rates of the most intense Northeast Pacific tropical cyclones. Landfall rates on Hawaii ( 0.0330.0190.045yr-1 for category-1+ TCs and 0.0100.0050.016yr-1 for category-3+ TCs for 1971-2014) show increases in the best estimates for 2015 conditions, but the changes are insignificant according to our tests. PMID- 29997457 TI - Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomised, double-blind, placebo controlled, multi centre, pilot clinical study. AB - Background: The modification of microbial ecology in human gut by supplementing probiotics may be an alternative strategy to ameliorate or prevent depression. Objective: The current study was conducted to assess the safety and efficacy of the probiotic strain Bacillus coagulans MTCC 5856 for major depressive disorder (MDD) in IBS patients. Method: Patients (n = 40) diagnosed for MDD with IBS were randomized (1:1) to receive placebo or B. coagulans MTCC 5856 at a daily dose of 2 * 109 cfu (2 billion spores) and were maintained to the end of double-blind treatment (90 days). Changes from baseline in clinical symptoms of MDD and IBS were evaluated through questionnaires. Results: Significant change (p = 0.01) in favour of the B. coagulans MTCC 5856 was observed for the primary efficacy measure Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Center for Epidemiological Studies Depression Scale (CES-D) and Irritable bowel syndrome quality of life questionnaire (IBS QOL). Secondary efficacy measures i.e. Clinical Global Impression-Improvement rating Scale (CGI-I), Clinical Global Impression Severity rating Scale (CGI-S), Gastrointestinal Discomfort Questionnaire (GI-DQ) and Modified Epworth Sleepiness Scale (mESS) also showed significant results (p = 0.01) in B. coagulans MTCC 5856 group compared to placebo group except dementia total reaction scoring. Serum myeloperoxidase, an inflammatory biomarker was also significantly reduced (p < 0.01) when compared with the baseline and end of the study. All the safety parameters remained well within the normal clinical range and had no clinically significant difference between the screening and at the end of the study. Conclusion: B. coagulans MTCC 5856 showed robust efficacy for the treatment of patients experiencing IBS symptoms with major depressive disorder. The improvement in depression and IBS symptoms was statistically significant and clinically meaningful. These findings support B. coagulans MTCC 5856 as an important new treatment option for major depressive disorder in IBS patients. PMID- 29997458 TI - Perioperative Management of New Oral Anticoagulants in Urological Surgery. AB - New oral anticoagulants (NOACs) are increasingly replacing the use of warfarin in clinical practice. Their use has now also been extended to thromboprophylaxis in many orthopedic surgeries. This, in addition to an increasingly aging population with many complex comorbidities means that these medications will be ever more frequently encountered by urologists. Thus, a clear understanding of the mechanism of action of NOACs, their time to peak action and half-life is essential for the purpose of managing these patients perioperatively. This article demonstrates the patient and procedural variability that must be taken into account in the perioperative management of the anticoagulated patient. While the time to peak onset and half-life of NOACs can aid in determining the interval of interruption of anticoagulation, the risks of thrombosis and bleeding must be assessed before the decision to stop anticoagulation. This article takes into account the evidence available on NOACs in urological surgery in order to inform the perioperative management of these medications and to propose guidelines to aid in clinical decision making. In attempting this, we address the issue of the lack of high-level evidence surrounding NOACs in urological surgery given their relative novelty and the need for further research to better guide practice. PMID- 29997459 TI - Adhesive Bowel Obstruction Following Urologic Surgery: Improved Outcomes with Early Intervention. AB - Objective: To describe the long-term incidence of adhesive bowel obstruction following major urologic surgery, and the effect of early surgery on perioperative outcomes. Methods: The Healthcare Cost and Utilization Project State Inpatient Databases for California and Florida (2006-2011) were used to identify major urologic oncologic surgery patients. Subsequent adhesive bowel obstruction admissions were identified and Kaplan-Meier time-to-event analysis was performed. Early surgery for bowel obstruction was defined as occurring on-or before hospital-day four. The effects of early surgery on postoperative minor/moderate complications (wound infection, urinary tract infection, deep vein thrombosis, and pneumonia), major complications (myocardial infarction, pulmonary embolism, and sepsis), death, and postoperative length-of-stay were assessed. Results: Major urologic surgery was performed on 104,400 patients, with subsequent 5-year cumulative incidence of adhesive bowel obstruction admission of 12.4% following radical cystectomy, 3.3% following kidney surgery, and 0.9% following prostatectomy. During adhesive bowel obstruction admission, 71.6% of patients were managed conservatively and 28.4% surgically. Early surgery was performed in 65.4%, with decreased rates of minor/moderate complications (18 vs. 30%, p = 0.001), major complications (10 vs. 19%, p = 0.002), and median postoperative length of stay (8 vs. 11 days, p < 0.001) compared with delayed surgery. On multivariate analysis early surgery decreased the odds of minor/ moderate complications by 43% (p = 0.01), major complications by 45% (p = 0.03), and postoperative length of stay by 3.1 days (p = 0.01). Conclusion: Adhesive bowel obstruction is a significant long-term sequela of urologic surgery, for which early surgical management may be associated with improved perioperative outcomes. PMID- 29997460 TI - Cognitive-Targeted versus Magnetic Resonance Imaging-Guided Prostate Biopsy in Prostate Cancer Detection. AB - Introduction: Purpose of this study is to evaluate the detection rates of prostate cancer (PCa) for cognitive-targeted biopsy (CTB) in comparison with magnetic resonance imaging (MRI)-guided biopsy (MRGB) related to prostate imaging reporting and data system (PI-RADS) score, lesion location and lesion volume. Furthermore, the addition of systematic transrectal ultrasound-guided biopsy (TRUS-GB) to CTB is evaluated. Materials and Methods: We included all patients with cancer-suspicious lesions on 3-Tesla multiparametric MRI who underwent either CTB and additional TRUS-GB or only MRGB (in-bore) in Haga Teaching Hospital between January 2013 and January 2015. Results: In total 219 patients were included: 64 CTB + TRUS-GB and 155 MRGB. In 32 (50%) men with CTB was positive for PCa. PI-RADS 3-, 4- and 5-lesions were in 17, 69 and 95% positive, respectively. In 100 men (65%) with MRGB was positive for PCa. Detection rates for PI-RADS 3-, 4- and 5-lesions were 10, 77 and 89%, respectively. CTB missed 4 (11%) low-grade tumors detected by TRUS-GB. In lesions between 0-1.5 ml PCa were significantly more often detected with MRGB than with CTB (69 vs. 39%). Conclusion: CTB has a high detection rate of PCa in men with cancer-suspicious lesions on MRI. Correction for lesion volume shows that in lesions < 1.5 ml MRGB is more accurate than CTB. The addition of TRUS-GB to CTB can safely be avoided without missing any high grade PCa. PMID- 29997461 TI - Trans-Urethral Snare of Bladder Tumor (TUSnBT) with Stone Basket Retrieval: A Novel Time-Saving Technique in the Endoscopic Management of Papillary Bladder Lesions. AB - Background: To assess if trans-urethral snare of bladder tumor (TUSnBT) with subsequent stone basket retrieval can be used as an effective, time-saving adjunct resection technique for papillary bladder lesions. Methods: Via standard cystoscopy, TUSnBT was performed using a standard endoscopic polypectomy snare with subsequent tumor extraction utilizing a standard stone retrieval basket, when lesions were more than 10 mm in diameter. Smaller lesions were removed with the polypectomy snare. Standard trans-urethral resection of bladder tumors (TURBT) of the tumor bed was performed post TUSnBT. Histological assessment was performed and assessed separately per session. Results: In total, 18 papillary lesions, measuring between 9 and 26 mm, were resected via TUSnBT. Operative TUSnBT time, ranged between 10 and 60 seconds duration per lesion. No significant postoperative morbidity was experienced by patients within this cohort. Histo pathological assessment revealed adequate muscle representation in 83.3 % of TUSnBT grouped sessions assessed. Conclusion: TUSnBT with stone retrieval basket retrieval is a feasible method in selected papillary bladder lesions, and may be coupled with standard TURBT resection techniques. This method is less time consuming and would prove beneficial in select lesions. It may also be beneficial to assist with reducing the resection time or inadvertent bladder perforation encountered during the conventional TURBT. PMID- 29997462 TI - Radiofrequency Ablation of Small Renal Masses: Outcomes, Complications and Effects on Renal Function. AB - Introduction: To describe oncological outcomes, effects on renal function and complications with radiofrequency ablation (RFA) of T1 renal tumors in an 8-year experience. Materials and Methods: A retrospective study of RFA in 89 consecutive patients between 2005 and 2013 was undertaken. Those with metastatic disease, incomplete follow-up, genetic pre-disposition to renal tumors and biopsy proven benign pathology were excluded, with 79 patients meeting inclusion criteria. Data was collected on demographics, oncological outcomes, complications and effects on renal function. Results: We demonstrate 94% disease-free survival at median follow-up of 29 months in a population consisting of 42 T1a and 37 T1b tumors. No disease related deaths were recorded in the follow-up period. Post-RFA decline in renal function was shown to correlate with tumor size and increased age (p = 0.0009/0.0021). Pre-existing renal impairment was a risk for post-RFA function decline (p < 0.005). Two complications were encountered in the series. Conclusion: RFA produces durable oncological outcomes in T1 tumors with a minimal effect on renal function and low risk of complications. Patients at risk of developing renal impairment can be identified from described risk factors. PMID- 29997463 TI - Prostate Cancer Detection with Multiparametric MRI: A Comparison of 1 M Concentration Gadobutrol with 0.5 M-Concentration Gadolinium-Based Contrast Agents. AB - Introduction: Gadobutrol (Gd-DO3A-butrol) (Gadovist(r)) is a macrocyclic gadolinium-based contrast agent for magnetic resonance imaging (MRI) formulated at 1.0 mmol Gd/ml. Gadobutrol's higher concentration compared to other contrast agents (0.5 mmol Gd/ml) is associated with higher T1 relaxivity. We examined whether gadobutrol increases the accuracy of prostate cancer detection using dynamic contrast-enhanced MRI. Materials and Methods: Multiparametric MRI was performed in 379 patients: 94 patients received 1 M gadobutrol while 285 randomly received equivalent doses of 0.5 M gadoterate meglumine or gadopentetate dimeglumine. MRI images were retrospectively and blindly assessed for the presence of cancer by comparing them with prostate biopsy findings. Results: The specificity and accuracy were significantly higher with 1 M gadobutrol than 0.5 M of the other contrast agents. There were no significant differences in the sensitivity, or positive and negative predictive values. Conclusion: Multiparametric MRI using 1 M gadobutrol may improve the accuracy of prostate cancer detection. PMID- 29997464 TI - Assessing the Safety and Efficacy of the ClearRingTM Implant for the Treatment of Benign Prostatic Hyperplasia in a Canine Model. AB - Background: Transurethral resection of the prostate is the most common procedure for the treatment of benign prostatic hyperplasia (BPH). Although effective, transurethral resection of the prostate can be associated with side effects including prolonged recovery, storage and voiding symptoms, risk of acute urinary retention. Objectives: In this study, we describe a new minimally invasive device for the treatment of lower urinary track symptoms due to BPH, implanting a nitinol C shape ring in a circular incision in the prostatic tissue, surrounding the urethra, done by electrocuting blade over a dilatation balloon. Methods: Two groups of dogs (4/ group) were implanted with the device under anesthesia. Clinical observation, body weight and weekly blood and urinary tests were performed throughout the study period to evaluate safety. Fluoroscopy and cystoscopy were used throughout the study period to evaluate implant condition and urethral dilatation. At the end of 3 weeks (Group I) or 3 months (Group II), the animals were sacrificed. The implantation site was examined macroscopically and histologically to evaluate urethral dilatation and tissue response. Results: The presence of the ClearRingTM implant in an animal's prostate was associated with significant dilatation of the prostatic urethra. Fever, pain, behavior disturbances or gross hematuria, when occurred, resolved within 72 hours post procedure and no severe adverse events were observed. There was no evidence of prostatic hyperplasia associated to ring implantation. Partial epithelial coverage of the implant surface was observed without evidence of encrustation. Conclusion: The ClearRingTM implant seems a feasible minimally invasive procedure for relieving lower urinary track symptoms due to BPH. PMID- 29997465 TI - Microbiological Analysis of Urine Cultures in Women after Pelvic Reconstructive Surgery. AB - Background/Aims: The rate of urinary tract infection (UTI) after pelvic reconstructive surgery ranges from 9 to 48% and the most common uropathogen is Escherichia coli (E. coli). The aim of the study is to identify the predominant uro-pathogen from urine cultures in women undergoing pelvic reconstructive surgery. Methods: A retrospective review was conducted on women who underwent pelvic reconstructive surgery at a tertiary care center from July 2013 to June 2015. Data was collected from each postoperative visit to evaluate urinary tract symptoms, culture results and treatment in the 3-month postoperative interval. Results: There were 880 cases reviewed (mean age of 59.6 years) during the study period. The most common organism in positive cultures was E. coli after surgery. The total UTI rate was 11.3%. Patients discharged with a Foley catheter had a UTI rate of 65.6% (p = 0.003). Diabetes, neurologic disease, tobacco use, recurrent UTIs and breast or gynecologic cancers had no significant association with UTI after surgery. Conclusion: The most common organism identified is E. coli. Almost 12% of patients will develop a UTI after pelvic reconstructive surgery. The results of this study can influence management of lower urinary tract symptoms in the postoperative period. PMID- 29997466 TI - Comparison of Late Urinary Symptoms Following SBRT and SBRT with IMRT Supplementation for Prostate Cancer. AB - Background: Prostate cancer survivors commonly experience late-onset lower urinary tract symptoms following radiotherapy. We aimed to compare lower urinary tract symptoms in patients treated with stereotactic body radiotherapy (SBRT) to those treated with a combination of lower dose SBRT and supplemental intensity modulated radiotherapy (SBRT + IMRT). Methods: Subjects with localized prostate carcinoma scheduled to receive SBRT or a combination of SBRT and IMRT were enrolled and followed for up to 2 years after treatment completion. Participants treated with SBRT received 35-36.25 Gy in 5 fractions, while those treated with SBRT + IMRT received 19.5 Gy of SBRT in 3 fractions followed by 45-50.4 Gy of IMRT in 25-28 fractions. Urinary symptoms were measured using the American Urological Association (AUA) Symptom Score. Results: Two hundred patients received SBRT (52% intermediate risk, 37.5% low risk according to D'Amico classification) and 145 patients received SBRT + IMRT (61.4% high risk, 35.2% intermediate risk). Both groups experienced a transient spike in urinary symptoms 1 month after treatment. More severe late urinary flare (increase in AUA scores >= 5 points from baseline to 1 year after treatment completion and an AUA score >= 15 at 1 year after treatment) was experienced by patients who received SBRT compared to those treated with SBRT + IMRT. Conclusion: Participants who received SBRT and supplemental IMRT experienced less severe late urinary flare 1 year after treatment compared to those who received higher dose SBRT alone. This information can be used by clinicians to provide patients with anticipatory counseling to mitigate any psychological burden that comes with unanticipated late urinary toxicities. PMID- 29997467 TI - Effect of Stimulation Waveform on the Non-linear Entrainment of Cortical Alpha Oscillations. AB - In the past decade, there has been a surge of interest in using patterned brain stimulation to manipulate cortical oscillations, in both experimental and clinical settings. But the relationship between stimulation waveform and its impact on ongoing oscillations remains poorly understood and severely restrains the development of new paradigms. To address some aspects of this intricate problem, we combine computational and mathematical approaches, providing new insights into the influence of waveform of both low and high-frequency stimuli on synchronous neural activity. Using a cellular-based cortical microcircuit network model, we performed numerical simulations to test the influence of different waveforms on ongoing alpha oscillations, and derived a mean-field description of stimulation-driven dynamics to better understand the observed responses. Our analysis shows that high-frequency periodic stimulation translates into an effective transformation of the neurons' response function, leading to waveform dependent changes in oscillatory dynamics and resting state activity. Moreover, we found that randomly fluctuating stimulation linearizes the neuron response function while constant input moves its activation threshold. Taken together, our findings establish a new theoretical framework in which stimulation waveforms impact neural systems at the population-scale through non-linear interactions. PMID- 29997469 TI - Muscarinic Acetylcholine Type 1 Receptor Activity Constrains Neurite Outgrowth by Inhibiting Microtubule Polymerization and Mitochondrial Trafficking in Adult Sensory Neurons. AB - The muscarinic acetylcholine type 1 receptor (M1R) is a metabotropic G protein coupled receptor. Knockout of M1R or exposure to selective or specific receptor antagonists elevates neurite outgrowth in adult sensory neurons and is therapeutic in diverse models of peripheral neuropathy. We tested the hypothesis that endogenous M1R activation constrained neurite outgrowth via a negative impact on the cytoskeleton and subsequent mitochondrial trafficking. We overexpressed M1R in primary cultures of adult rat sensory neurons and cell lines and studied the physiological and molecular consequences related to regulation of cytoskeletal/mitochondrial dynamics and neurite outgrowth. In adult primary neurons, overexpression of M1R caused disruption of the tubulin, but not actin, cytoskeleton and significantly reduced neurite outgrowth. Over-expression of a M1R-DREADD mutant comparatively increased neurite outgrowth suggesting that acetylcholine released from cultured neurons interacts with M1R to suppress neurite outgrowth. M1R-dependent constraint on neurite outgrowth was removed by selective (pirenzepine) or specific (muscarinic toxin 7) M1R antagonists. M1R dependent disruption of the cytoskeleton also diminished mitochondrial abundance and trafficking in distal neurites, a disorder that was also rescued by pirenzepine or muscarinic toxin 7. M1R activation modulated cytoskeletal dynamics through activation of the G protein (Galpha13) that inhibited tubulin polymerization and thus reduced neurite outgrowth. Our study provides a novel mechanism of M1R control of Galpha13 protein-dependent modulation of the tubulin cytoskeleton, mitochondrial trafficking and neurite outgrowth in axons of adult sensory neurons. This novel pathway could be harnessed to treat dying-back neuropathies since anti-muscarinic drugs are currently utilized for other clinical conditions. PMID- 29997468 TI - Image-Based Profiling of Synaptic Connectivity in Primary Neuronal Cell Culture. AB - Neurological disorders display a broad spectrum of clinical manifestations. Yet, at the cellular level, virtually all these diseases converge into a common phenotype of dysregulated synaptic connectivity. In dementia, synapse dysfunction precedes neurodegeneration and cognitive impairment by several years, making the synapse a crucial entry point for the development of diagnostic and therapeutic strategies. Whereas high-resolution imaging and biochemical fractionations yield detailed insight into the molecular composition of the synapse, standardized assays are required to quickly gauge synaptic connectivity across large populations of cells under a variety of experimental conditions. Such screening capabilities have now become widely accessible with the advent of high throughput, high-content microscopy. In this review, we discuss how microscopy based approaches can be used to extract quantitative information about synaptic connectivity in primary neurons with deep coverage. We elaborate on microscopic readouts that may serve as a proxy for morphofunctional connectivity and we critically analyze their merits and limitations. Finally, we allude to the potential of alternative culture paradigms and integrative approaches to enable comprehensive profiling of synaptic connectivity. PMID- 29997471 TI - Anodal and Cathodal tDCS Over the Right Frontal Eye Fields Impacts Spatial Probability Processing Differently in Pro- and Anti-saccades. AB - Learning regularities that exist in the environment can help the visual system achieve optimal efficiency while reducing computational burden. Using a pro- and anti-saccade task, studies have shown that probabilistic information regarding spatial locations can be a strong modulator of frontal eye fields (FEF) activities and consequently alter saccadic behavior. One recent study has also shown that FEF activities can be modulated by transcranial direct current stimulation, where anodal tDCS facilitated prosaccades but cathodal tDCS prolonged antisaccades. These studies together suggest that location probability and tDCS can both alter FEF activities and oculomotor performance, yet how these two modulators interact with each other remains unclear. In this study, we applied anodal or cathodal tDCS over right FEF, and participants performed an interleaved pro- and anti-saccade task. Location probability was manipulated in prosaccade trials but not antisaccade trials. We observed that anodal tDCS over rFEF facilitated prosaccdes toward low-probability locations but not to high probability locations; whereas cathodal tDCS facilitated antisaccades away from the high-probability location (i.e., same location as the low-probability locations in prosaccades). These observed effects were specific to rFEF as tDCS over the SEF in a separate control experiment did not yield similar patterns. These effects were also more pronounced in low-performers who had slower saccade reaction time. Together, we conclude that (1) the overlapping spatial endpoint between prosaccades (i.e., toward low-probability location) and antisaccades (i.e., away from high-probability location) possibly suggest an endpoint selective mechanism within right FEF, (2) anodal tDCS and location probability cannot be combined to produce a bigger facilitative effect, and (3) anodal rFEF tDCS works best on low-performers who had slower saccade reaction time. These observations are consistent with the homeostasis account of tDCS effect and FEF functioning. PMID- 29997470 TI - Alzheimer Disease and Selected Risk Factors Disrupt a Co-regulation of Monoamine Oxidase-A/B in the Hippocampus, but Not in the Cortex. AB - Monoamine oxidase-A (MAO-A) and MAO-B have both been implicated in the pathology of Alzheimer disease (AD). We examined 60 autopsied control and AD donor brain samples to determine how well MAO function aligned with two major risk factors for AD, namely sex and APOE epsilon4 status. MAO-A activity was increased in AD cortical, but not hippocampal, samples. In contrast, MAO-B activity was increased in both regions (with a strong input from female donors) whether sample means were compared based on: (a) diagnosis alone; (b) diagnosis-by-APOE epsilon4 status (i.e., carriers vs. non-carriers of the epsilon4 allele); or (c) APOE epsilon4 status alone (i.e., ignoring 'diagnosis' as a variable). Sample means strictly based on the donor's sex did not reveal any difference in either MAO-A or MAO-B activity. Unexpectedly, we found that cortical MAO-A and MAO-B activities were highly correlated in both males and females (if focussing strictly on the donor's sex), while in the hippocampus, any correlation was lost in female samples. Stratifying for sex-by-APOE epsilon4 status revealed a strong correlation between cortical MAO-A and MAO-B activities in both non-carriers and carriers of the allele, but any correlation in hippocampal samples was lost in carriers of the allele. A diagnosis of AD disrupted the correlation between MAO-A and MAO-B activities in the hippocampus, but not the cortex. We observed a novel region-dependent co-regulation of MAO-A and MAO-B mRNAs (but not proteins), while a lack of correlation between MAO activities and the respective proteins corroborated previous reports. Overexpression of human APOE4 increased MAO activity (but not mRNA/protein) in C6 and in HT-22 cell cultures. We identified a novel co-regulation of MAO-A and MAO-B activities that is spared from any influence of risk factors for AD or AD itself in the cortex, but vulnerable to these same factors in the hippocampus. Sex- and region-dependent abilities to buffer influences on brain MAO activities could have significant bearing on ambiguous outcomes when monoaminergic systems are targeted in clinical populations. PMID- 29997472 TI - Measuring the Complexity of Consciousness. AB - The grand quest for a scientific understanding of consciousness has given rise to many new theoretical and empirical paradigms for investigating the phenomenology of consciousness as well as clinical disorders associated to it. A major challenge in this field is to formalize computational measures that can reliably quantify global brain states from data. In particular, information-theoretic complexity measures such as integrated information have been proposed as measures of conscious awareness. This suggests a new framework to quantitatively classify states of consciousness. However, it has proven increasingly difficult to apply these complexity measures to realistic brain networks. In part, this is due to high computational costs incurred when implementing these measures on realistically large network dimensions. Nonetheless, complexity measures for quantifying states of consciousness are important for assisting clinical diagnosis and therapy. This article is meant to serve as a lookup table of measures of consciousness, with particular emphasis on clinical applicability. We consider both, principle-based complexity measures as well as empirical measures tested on patients. We address challenges facing these measures with regard to realistic brain networks, and where necessary, suggest possible resolutions. PMID- 29997473 TI - Role of BDNF Signaling in Memory Enhancement Induced by Transcranial Direct Current Stimulation. AB - In the recent years numerous studies have provided encouraging results supporting the use of transcranial direct current stimulation (tDCS) as non-invasive brain stimulation technique to improve motor and cognitive functions in patients suffering from neurological and neuropsychiatric disorders as well as in healthy subjects. Among the multiple effects elicited by tDCS on cognitive functions, experimental evidence and clinical findings have highlighted the beneficial impact on long-term memory. Memory deficits occur during physiological aging as well as in neurological and neurodegenerative disorders, including Alzheimer's disease (AD). In this scenario, non-invasive techniques for memory enhancement, such as tDCS, are receiving increasing attention. The knowledge of molecular mechanisms subtending tDCS effects is of pivotal importance for a more rationale use of this technique in clinical settings. Although we are still far from having a clear picture, recent literature on human and animal studies has pointed to the involvement of synaptic plasticity mechanisms in mediating tDCS effects on long term memory. Here we review these studies focusing on the neurotrophin "brain derived neurotrophic factor" (BDNF) as critical tDCS effector. PMID- 29997474 TI - Learning Task-Related Activities From Independent Local-Field-Potential Components Across Motor Cortex Layers. AB - Motor cortical microcircuits receive inputs from dispersed cortical and subcortical regions in behaving animals. However, how these inputs contribute to learning and execution of voluntary sequential motor behaviors remains elusive. Here, we analyzed the independent components extracted from the local field potential (LFP) activity recorded at multiple depths of rat motor cortex during reward-motivated movement to study their roles in motor learning. Because slow gamma (30-50 Hz), fast gamma (60-120 Hz), and theta (4-10 Hz) oscillations temporally coordinate task-relevant motor cortical activities, we first explored the behavioral state- and layer-dependent coordination of motor behavior in these frequency ranges. Consistent with previous findings, oscillations in the slow and fast gamma bands dominated during distinct movement states, i.e., preparation and execution states, respectively. However, we identified a novel independent component that dominantly appeared in deep cortical layers and exhibited enhanced slow gamma activity during the execution state. Then, we used the four major independent components to train a recurrent network model for the same lever movements as the rats performed. We show that the independent components differently contribute to the formation of various task-related activities, but they also play overlapping roles in motor learning. PMID- 29997475 TI - Astrocytic Atrophy Following Status Epilepticus Parallels Reduced Ca2+ Activity and Impaired Synaptic Plasticity in the Rat Hippocampus. AB - Epilepsy is a group of neurological disorders commonly associated with the neuronal malfunction leading to generation of seizures. Recent reports point to a possible contribution of astrocytes into this pathology. We used the lithium pilocarpine model of status epilepticus (SE) in rats to monitor changes in astrocytes. Experiments were performed in acute hippocampal slices 2-4 weeks after SE induction. Nissl staining revealed significant neurodegeneration in the pyramidal cell layers of hippocampal CA1, CA3 areas, and the hilus, but not in the granular cell layer of the dentate gyrus. A significant increase in the density of astrocytes stained with an astrocyte-specific marker, sulforhodamine 101, was observed in CA1 stratum (str.) radiatum. Astrocytes in this area were also whole-cell loaded with a morphological tracer, Alexa Fluor 594, for two photon excitation imaging. Sholl analyses showed no changes in the size of the astrocytic domain or in the number of primary astrocytic branches, but a significant reduction in the number of distal branches that are resolved with diffraction-limited light microscopy (and are thought to contain Ca2+ stores, such as mitochondria and endoplasmic reticulum). The atrophy of astrocytic branches correlated with the reduced size, but not overall frequency of Ca2+ events. The volume tissue fraction of nanoscopic (beyond the diffraction limit) astrocytic leaflets showed no difference between control and SE animals. The results of spatial entropy-complexity spectrum analysis were also consistent with changes in ratio of astrocytic branches vs. leaflets. In addition, we observed uncoupling of astrocytes through the gap-junctions, which was suggested as a mechanism for reduced K+ buffering. However, no significant difference in time course of synaptically induced K+ currents in patch-clamped astrocytes argued against possible alterations in K+ clearance by astrocytes. The magnitude of long term-potentiation (LTP) was reduced after SE. Exogenous D-serine, a co-agonist of NMDA receptors, has rescued the initial phase of LTP. This suggests that the reduced Ca2+-dependent release of D-serine by astrocytes impairs initiation of synaptic plasticity. However, it does not explain the failure of LTP maintenance which may be responsible for cognitive decline associated with epilepsy. PMID- 29997476 TI - Transcriptional Alterations in the Trigeminal Ganglia, Nucleus and Peripheral Blood Mononuclear Cells in a Rat Orofacial Pain Model. AB - Orofacial pain and headache disorders are among the most debilitating pain conditions. While the pathophysiological basis of these disorders may be diverse, it is generally accepted that a common mechanism behind the arising pain is the sensitization of extra- and intracranial trigeminal primary afferents. In the present study we investigated gene expression changes in the trigeminal ganglia (TRG), trigeminal nucleus caudalis (TNC) and peripheral blood mononuclear cells (PBMC) evoked by Complete Freund's Adjuvant (CFA)-induced orofacial inflammation in rats, as a model of trigeminal sensitization. Microarray analysis revealed 512 differentially expressed genes between the ipsi- and contralateral TRG samples 7 days after CFA injection. Time-dependent expression changes of G-protein coupled receptor 39 (Gpr39), kisspeptin-1 receptor (Kiss1r), kisspeptin (Kiss1), as well as synaptic plasticity-associated Lkaaear1 (Lkr) and Neurod2 mRNA were described on the basis of qPCR results. The greatest alterations were observed on day 3 ipsilaterally, when orofacial mechanical allodynia reached its maximum. This corresponded well with patterns of neuronal (Fosb), microglia (Iba1), and astrocyte (Gfap) activation markers in both TRG and TNC, and interestingly also in PBMCs. This is the first description of up- and downregulated genes both in primary and secondary sensory neurones of the trigeminovascular system that might play important roles in neuroinflammatory activation mechanisms. We are the first to show transcriptomic alterations in the PBMCs that are similar to the neuronal changes. These results open new perspectives and initiate further investigations in the research of trigeminal pain disorders. PMID- 29997478 TI - Cortical GABAergic Interneuron/Progenitor Transplantation as a Novel Therapy for Intractable Epilepsy. AB - Epilepsy is a severe neurological disease affecting more than 70 million people worldwide that is characterized by unpredictable and abnormal electrical discharges resulting in recurrent seizures. Although antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment for seizure control, about one third of patients with epilepsy suffer from intractable seizures that are unresponsive to AEDs. Furthermore, the patients that respond to AEDs typically experience adverse systemic side effects, underscoring the urgent need to develop new therapies that target epileptic foci rather than more systemic interventions. Neurosurgical removal of affected brain tissues or implanting neurostimulator devices are effective options only for a fraction of patients with drug-refractory seizures, so it is imperative to develop treatments that are more generally applicable and restorative in nature. Considering the abnormalities of GABAergic inhibitory interneurons in epileptic brain tissues, one strategy with considerable promise is to restore normal circuit function by transplanting GABAergic interneurons/progenitors into the seizure focus. In this review, we focus on recent studies of cortical GABAergic interneuron transplantation to treat epilepsy and discuss critical issues in moving this promising experimental therapeutic treatment into clinic. PMID- 29997477 TI - Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success. AB - Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included. PMID- 29997479 TI - Diverse Intrinsic Properties Shape Functional Phenotype of Low-Frequency Neurons in the Auditory Brainstem. AB - In the auditory system, tonotopy is the spatial arrangement of where sounds of different frequencies are processed. Defined by the organization of neurons and their inputs, tonotopy emphasizes distinctions in neuronal structure and function across topographic gradients and is a common feature shared among vertebrates. In this study we characterized action potential firing patterns and ion channel properties from neurons located in the extremely low-frequency region of the chicken nucleus magnocellularis (NM), an auditory brainstem structure. We found that NM neurons responsible for encoding the lowest sound frequencies (termed NMc neurons) have enhanced excitability and fired bursts of action potentials to sinusoidal inputs <=10 Hz; a distinct firing pattern compared to higher-frequency neurons. This response property was due to lower amounts of voltage dependent potassium (KV) conductances, unique combination of KV subunits and specialized sodium (NaV) channel properties. Particularly, NMc neurons had significantly lower KV1 and KV3 currents, but higher KV2 current. NMc neurons also showed larger and faster transient NaV current (INaT) with different voltage dependence of inactivation from higher-frequency neurons. In contrast, significantly smaller resurgent sodium current (INaR) was present in NMc with kinetics and voltage dependence that differed from higher-frequency neurons. Immunohistochemistry showed expression of NaV1.6 channel subtypes across the tonotopic axis. However, various immunoreactive patterns were observed between regions, likely underlying some tonotopic differences in INaT and INaR. Finally, using pharmacology and computational modeling, we concluded that KV3, KV2 channels and INaR work synergistically to regulate burst firing in NMc. PMID- 29997480 TI - Effects of Voluntary Wheel-Running Types on Hippocampal Neurogenesis and Spatial Cognition in Middle-Aged Mice. AB - While increasing evidence demonstrated that voluntary wheel running promotes cognitive function, little is known on how different types of voluntary wheel running affect cognitive function in elderly populations. We investigated the effects of various voluntary wheel-running types on adult hippocampal neurogenesis and spatial cognition in middle-aged mice. Male C57BL6 and Thy1 green fluorescent protein (GFP) transgenic mice (13 months) were equally assigned to one of the following groups: (1) T1: no voluntary wheel running; (2) T2: intermittent voluntary wheel running; and (3) T3: continuous voluntary wheel running. The Thy1-GFP transgenic mice were used to specifically label granule cells, since Thy-1 is a promoter for neuronal expression. Behavioral evaluations suggested that intermittent voluntary wheel running improved Morris water maze performance in middle-aged mice. The number of BrdU-positive cells was significantly higher in both intermittent and continuous voluntary wheel running compared with no voluntary wheel running. However, only intermittent voluntary wheel running facilitated the newborn cells to differentiate into granule cells, while newborn cells tended to differentiate into astrocytes and repopulation of microglia was also enhanced in the continuous voluntary wheel-running group. These results indicated that intermittent voluntary exercise may be more beneficial for enhancing spatial memory. Effective improvement of hippocampal neurogenesis was also caused by intermittent voluntary wheel running in middle aged mice. PMID- 29997481 TI - Voltage-Gated Sodium Channels in Neocortical Pyramidal Neurons Display Cole-Moore Activation Kinetics. AB - Exploring the properties of action potentials is a crucial step toward a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. However, most models of voltage-gated sodium channels assume a concerted Hodgkin and Huxley kinetic gating scheme. However, it is not clear if Hodgkin and Huxley models are suitable for use in action potential simulations of central nervous system neurons. To resolve this, we investigated the activation kinetics of voltage-gated sodium channels. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. Thus, the classical Hodgkin and Huxley description of sodium channel kinetics may be unsuitable for modeling the physiological role of this channel. Furthermore, our results reconcile between apparently contradicting studies sodium channel activation. Our findings may have key implications for the role of sodium channels in synaptic integration and action potential generation. PMID- 29997482 TI - Diffusion Tensor Imaging With Tract-Based Spatial Statistics Reveals White Matter Abnormalities in Patients With Vascular Cognitive Impairment. AB - Purpose: The aim of this study was to evaluate microstructural changes of major white matter (WM) tracts in patients with vascular cognitive impairment (VCI). Method: Diffusion tensor imaging (DTI) data were obtained from 24 subjects with subcortical ischemic vascular disease (SIVD), including 13 subjects with VCI-no dementia (VCIND) and 11 subjects with normal cognition (as a control group). A tract-based spatial statistics approach was performed to investigate WM microstructure in VCIND by integrating multiple indices including fractional anisotropy (FA) and mean diffusivity (MD), which are intra-voxel metrics, and local diffusion homogeneity (LDH), which is an inter-voxel metric. Results: The VCIND group had decreased FA and increased MD values throughout widespread WM areas predominately in the corpus callosum, bilateral internal capsule/corona radiata/posterior thalamic radiation/inferior fronto-occipital fasciculus and right inferior/superior longitudinal fasciculus. There was a slight discrepancy between the distribution of areas with decreased FA and LDH. The FA, MD and LDH values were significantly correlated with cognitive test results. According to a WM tract atlas, 10 major tracts were identified as tracts of interest in which three diffusion metrics simultaneously differed between groups, including bilateral anterior thalamic radiation, forceps minor, right corticospinal tract, bilateral inferior fronto-occipital fasciculus, left inferior and superior longitudinal fasciculus, and bilateral uncinate fasciculus. Receiver operating characteristic (ROC) analysis demonstrated the feasibility of using diffusion metrics along the forceps minor and left anterior thalamic radiation for separating two groups. Conclusion: The results suggest WM microstructural abnormalities contribute to cognitive impairments in SIVD patients. DTI parameters may be potential biomarkers for detecting VCIND from SIVD. PMID- 29997483 TI - Striatal Cholinergic Interneurons in a Knock-in Mouse Model of L-DOPA-Responsive Dystonia. AB - Striatal cholinergic dysfunction is a common phenotype associated with various forms of dystonia in which anti-cholinergic drugs have some therapeutic benefits. However, the underlying substrate of striatal cholinergic defects in dystonia remain poorly understood. In this study, we used a recently developed knock-in mouse model of dopamine-responsive dystonia (DRD) with strong symptomatic responses to anti-cholinergic drugs, to assess changes in the prevalence and morphology of striatal cholinergic interneurons (ChIs) in a model of generalized dystonia. Unbiased stereological neuronal counts and Sholl analysis were used to address these issues. To determine the potential effect of aging on the number of ChIs, both young (3 months old) and aged (15 months old) mice were used. For purpose of comparisons with ChIs, the number of GABAergic parvalbumin (PV) immunoreactive striatal interneurons was also quantified in young mice. Overall, no significant change in the prevalence of ChIs and PV-immunoreactive cells was found throughout various functional regions of the striatum in young DRD mice. Similar results were found for ChIs in aged animals. Subtle changes in the extent and complexity of the dendritic tree of ChIs were found in middle and caudal regions of the striatum in DRD mice. Additional immunohistochemical data also suggested lack of significant change in the expression of striatal cholinergic M1 and M4 muscarinic receptors immunoreactivity in DRD mice. Thus, together with our previous data from a knock-in mouse model of DYT-1 dystonia (Song et al., 2013), our data further suggest that the dysregulation of striatal cholinergic transmission in dystonia is not associated with major neuroplastic changes in the morphology or prevalence of striatal ChIs. Highlights -There is no significant change in the number of striatal ChIs in young and aged mice model of DRD-There is no significant change in the prevalence of striatal GABAergic PV-containing interneurons in the striatum of young mice models of DRD-Subtle morphological changes in the dendritic arborization of striatal ChIs are found in the middle and caudal tiers of the striatum in young mice models of DRD-The levels of both M1 and M4 muscarinic receptors immunoreactivity are not significantly changed in the striatum of DRD mice-Major changes in the prevalence and morphology of striatal ChIs are unlikely to underlie striatal cholinergic dysfunction in DRD. PMID- 29997485 TI - Response: Commentary: Using Virtual Reality to Assess Ethical Decisions in Road Traffic Scenarios: Applicability of Value-of-Life-Based Models and Influences of Time Pressure. PMID- 29997484 TI - Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children. AB - Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes. PMID- 29997486 TI - Adolescent Hippocampal and Prefrontal Brain Activation During Performance of the Virtual Morris Water Task. AB - The frontal cortex undergoes substantial structural and functional changes during adolescence and significant developmental changes also occur in the hippocampus. Both of these regions are notably vulnerable to alcohol and other substance use, which is typically initiated during adolescence. Identifying measures of brain function during adolescence, particularly before initiation of drug or alcohol use, is critical to understanding how such behaviors may affect brain development, especially in these vulnerable brain regions. While there is a substantial developmental literature on adolescent working memory, less is known about spatial memory. Thus, a virtual Morris water task (vMWT) was applied to probe function of the adolescent hippocampus. Multiband blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) data were acquired at 3T during task performance. Participants included 32 healthy, alcohol- and drug-naive adolescents, 13-14 years old, examined at baseline of a 3-year longitudinal MRI study. Significantly greater BOLD activation was observed in the hippocampus and surrounding areas, and in prefrontal regions involved in executive function, during retrieval relative to motor performance. In contrast, significantly greater BOLD activation was observed in components of the default mode network, including frontal medial cortex, during the motor condition (when task demands were minimal) relative to the retrieval condition. Worse performance (longer path length) during retrieval was associated with greater activation of angular gyrus/supramarginal gyrus, whereas worse performance (longer path length/latency) during motor control was associated with less activation of frontal pole. Furthermore, while latency (time to complete task) was greater in females than in males, there were no sex differences in path length (accuracy), suggesting that females required more time to navigate the virtual environment, but did so as effectively as males. These findings demonstrate that performance of the vMWT elicits hippocampal and prefrontal activation patterns in early adolescence, similar to activation observed during spatial memory retrieval in adults. Given that this task is sensitive to hippocampal function, and that the adolescent hippocampus is notably vulnerable to the effects of alcohol and other substances, data acquired using this task during healthy adolescent development may provide a framework for understanding neurobiological impact of later initiation of use. PMID- 29997488 TI - Conservation of Reactive Stabilization Strategies in the Presence of Step Length Asymmetries During Walking. AB - The ability to maintain dynamic balance in response to unexpected perturbations during walking is largely mediated by reactive control strategies. Reactive control during perturbed walking can be characterized by multiple metrics such as measures of whole-body angular momentum (WBAM), which capture the rotational dynamics of the body, and through Floquet analysis which captures the orbital stability of a limit cycle attractor. Recent studies have demonstrated that people with spatiotemporal asymmetries during gait have impaired control of whole body dynamics as evidenced by higher peak-to-peak ranges of WBAM over the gait cycle. While this may suggest that spatiotemporal asymmetries could impair stability, no studies have quantified how direct modification of asymmetry influences reactive balance control. Here, we used a biofeedback paradigm that allows participants to systematically adopt different levels of step length asymmetry to test the hypothesis that walking asymmetrically impairs the reactive control of balance. In addition, we tested the hypothesis that perturbations to the non-dominant leg would cause less whole-body rotation due to its hypothesized role in weight support during walking. We characterized reactive control strategies in two ways. We first computed integrated angular momentum to characterize changes in whole-body configuration during multi-step responses to perturbations. We also computed the maximum Floquet multipliers (FMs) across the gait cycle, which represent the rate of convergence back to limit cycle behavior. Our results show that integrated angular momentum during the perturbation step and subsequent recovery steps, as well as the magnitude of maximum FMs over the gait cycle, do not change across levels of asymmetry. However, our results showed both limb-dependent and limb-independent responses to unexpected perturbations. Overall, our findings suggest that there is no causal relationship between step length asymmetry and impaired reactive control of balance in the absence of neuromotor impairments. Our approach could be used in future studies to determine if reducing asymmetries in populations with neuromotor impairments, such people post-stroke or amputees improves dynamic stability. PMID- 29997487 TI - Neuropsychodynamic Approach to Depression: Integrating Resting State Dysfunctions of the Brain and Disturbed Self-Related Processes. AB - A mechanism-based approach was developed focusing on the psychodynamic, psychological and neuronal mechanisms in healthy and depressed persons. In this integrative concept of depression, the self is a core dimension in depression. It is attributed to negative emotions (e.g., failure, guilt). The increased inward focus in depression is connected with a decreased environmental focus. The development of neuropsychodynamic hypotheses of the altered self-reference is based on the investigation of the emotional-cognitive interaction in depressed patients. It may be hypothesized that the increased negative self-attributions-as typical characteristics of an increased self-focus in depression-may result from altered neuronal activity in subcortical-cortical midline structures in the brain, especially from hyperactivity in the cortical-subcortical midline regions and hypoactivity in the lateral regions. The increased resting state activity in depression is especially associated with an increased resting state activity in the default mode network (DMN) and a dysbalance between DMN and executive network (EN) activity. Possible therapeutic consequences of the neuropsychodynamic approach to depression involve the necessary emotional attunement in psychotherapy of depressed patients and the adequate timing of therapeutic interventions. The hypotheses which have been developed in the context of the neuropsychodynamic model of depression may be used for more specific psychotherapeutic interventions, aiming at specific mechanisms of compensation and defence, which are related to the increased resting state activity and the disturbed resting state-stimulus-interaction. PMID- 29997489 TI - The Diagnosis of Autism Spectrum Disorder Based on the Random Neural Network Cluster. AB - As the autism spectrum disorder (ASD) is highly heritable, pervasive and prevalent, the clinical diagnosis of ASD is vital. In the existing literature, a single neural network (NN) is generally used to classify ASD patients from typical controls (TC) based on functional MRI data and the accuracy is not very high. Thus, the new method named as the random NN cluster, which consists of multiple NNs was proposed to classify ASD patients and TC in this article. Fifty ASD patients and 42 TC were selected from autism brain imaging data exchange (ABIDE) database. First, five different NNs were applied to build five types of random NN clusters. Second, the accuracies of the five types of random NN clusters were compared to select the highest one. The random Elman NN cluster had the highest accuracy, thus Elman NN was selected as the best base classifier. Then, we used the significant features between ASD patients and TC to find out abnormal brain regions which include the supplementary motor area, the median cingulate and paracingulate gyri, the fusiform gyrus (FG) and the insula (INS). The proposed method provides a new perspective to improve classification performance and it is meaningful for the diagnosis of ASD. PMID- 29997490 TI - Real World Problem-Solving. AB - Real world problem-solving (RWPS) is what we do every day. It requires flexibility, resilience, resourcefulness, and a certain degree of creativity. A crucial feature of RWPS is that it involves continuous interaction with the environment during the problem-solving process. In this process, the environment can be seen as not only a source of inspiration for new ideas but also as a tool to facilitate creative thinking. The cognitive neuroscience literature in creativity and problem-solving is extensive, but it has largely focused on neural networks that are active when subjects are not focused on the outside world, i.e., not using their environment. In this paper, I attempt to combine the relevant literature on creativity and problem-solving with the scattered and nascent work in perceptually-driven learning from the environment. I present my synthesis as a potential new theory for real world problem-solving and map out its hypothesized neural basis. I outline some testable predictions made by the model and provide some considerations and ideas for experimental paradigms that could be used to evaluate the model more thoroughly. PMID- 29997491 TI - Entrainment and Synchronization to Auditory Stimuli During Walking in Healthy and Neurological Populations: A Methodological Systematic Review. AB - Background: Interdisciplinary work is needed for scientific progress, and with this review, our interest is in the scientific progress toward understanding the underlying mechanisms of auditory-motor coupling, and how this can be applied to gait rehabilitation. Specifically we look into the process of entrainment and synchronization; where entrainment is the process that governs the dynamic alignments of the auditory and motor domains based on error-prediction correction, whereas synchronization is the stable maintenance of timing during auditory-motor alignment. Methodology: A systematic literature search in databases PubMed and Web of Science were searched up to 9th of August 2017. The selection criteria for the included studies were adult populations, with a minimum of five participants, investigating walking to an auditory stimulus, with an outcome measure of entrainment, and synchronization. The review was registered in PROSPERO as CRD42017080325. Objectives: The objective of the review is to systematically describe the metrics which measure entrainment and synchronization to auditory stimuli during walking in healthy and neurological populations. Results: Sixteen articles were included. Fifty percent of the included articles had healthy controls as participants (N = 167), 19% had neurological diseases such as Huntington's and Stroke (N = 76), and 31% included both healthy and neurological [Parkinson's disease (PD) and Stroke] participants (N = 101). In the included studies, six parameters were found to capture the interaction between the human movement and the auditory stimuli, these were: cadence, relative phase angle, resultant vector length, interval between the beat and the foot contact, period matching performance, and detrended fluctuation analysis. Conclusion: In this systematic review, several metrics have been identified, which measure the timing aspect of auditory-motor coupling and synchronization of auditory stimuli in healthy and neurological populations during walking. The application of these metrics may enhance the current state of the art and practice across the neurological gait rehabilitation. These metrics also have current shortcomings. Of particular pertinence is our recommendation to consider variability in data from a time-series rather than time-windowed viewpoint. We need it in view of the promising practical applications from which the studied populations may highly benefit in view of personalized medical care. PMID- 29997492 TI - FindSim: A Framework for Integrating Neuronal Data and Signaling Models. AB - Current experiments touch only small but overlapping parts of very complex subcellular signaling networks in neurons. Even with modern optical reporters and pharmacological manipulations, a given experiment can only monitor and control a very small subset of the diverse, multiscale processes of neuronal signaling. We have developed FindSim (Framework for Integrating Neuronal Data and SIgnaling Models) to anchor models to structured experimental datasets. FindSim is a framework for integrating many individual electrophysiological and biochemical experiments with large, multiscale models so as to systematically refine and validate the model. We use a structured format for encoding the conditions of many standard physiological and pharmacological experiments, specifying which parts of the model are involved, and comparing experiment outcomes with model output. A database of such experiments is run against successive generations of composite cellular models to iteratively improve the model against each experiment, while retaining global model validity. We suggest that this toolchain provides a principled and scalable way to tackle model complexity and diversity of data sources. PMID- 29997493 TI - SERKET: An Architecture for Connecting Stochastic Models to Realize a Large-Scale Cognitive Model. AB - To realize human-like robot intelligence, a large-scale cognitive architecture is required for robots to understand their environment through a variety of sensors with which they are equipped. In this paper, we propose a novel framework named Serket that enables the construction of a large-scale generative model and its inferences easily by connecting sub-modules to allow the robots to acquire various capabilities through interaction with their environment and others. We consider that large-scale cognitive models can be constructed by connecting smaller fundamental models hierarchically while maintaining their programmatic independence. Moreover, the connected modules are dependent on each other and their parameters must be optimized as a whole. Conventionally, the equations for parameter estimation have to be derived and implemented depending on the models. However, it has become harder to derive and implement equations of large-scale models. Thus, in this paper, we propose a parameter estimation method that communicates the minimum parameters between various modules while maintaining their programmatic independence. Therefore, Serket makes it easy to construct large-scale models and estimate their parameters via the connection of modules. Experimental results demonstrated that the model can be constructed by connecting modules, the parameters can be optimized as a whole, and they are comparable with the original models that we have proposed. PMID- 29997494 TI - Novel Prehospital Prediction Model of Large Vessel Occlusion Using Artificial Neural Network. AB - Background: Identifying large vessel occlusion (LVO) patients in the prehospital triage stage to avoid unnecessary and costly delays is important but still challenging. We aim to develop an artificial neural network (ANN) algorithm to predict LVO using prehospital accessible data including demographics, National Institutes of Health Stroke Scale (NIHSS) items and vascular risk factors. Methods: Consecutive acute ischemic stroke patients who underwent CT angiography (CTA) or time of flight MR angiography (TOF-MRA) and received reperfusion therapy within 8 h from symptom onset were included. The diagnosis of LVO was defined as occlusion of the intracranial internal carotid artery (ICA), M1 and M2 segments of the middle cerebral artery (MCA) and basilar artery on CTA or TOF-MRA before treatment. Patients with and without LVO were randomly selected at a 1:1 ratio. The ANN model was developed using backpropagation algorithm, and 10-fold cross validation was used to validate the model. The comparison of diagnostic parameters between the ANN model and previously established prehospital prediction scales were performed. Results: Finally, 300 LVO and 300 non-LVO patients were randomly selected for the training and validation of the ANN model. The mean Youden index, sensitivity, specificity and accuracy of the ANN model based on the 10-fold cross-validation analysis were 0.640, 0.807, 0.833 and 0.820, respectively. The area under the curve (AUC), Youden index and accuracy of the ANN model were all higher than other prehospital prediction scales. Conclusions: The ANN can be an effective tool for the recognition of LVO in the prehospital triage stage. PMID- 29997495 TI - Preventing P-gp Ubiquitination Lowers Abeta Brain Levels in an Alzheimer's Disease Mouse Model. AB - One characteristic of Alzheimer's disease (AD) is excessive accumulation of amyloid-beta (Abeta) in the brain. Abeta brain accumulation is, in part, due to a reduction in Abeta clearance from the brain across the blood-brain barrier. One key element that contributes to Abeta brain clearance is P-glycoprotein (P-gp) that transports Abeta from brain to blood. In AD, P-gp protein expression and transport activity levels are significantly reduced, which impairs Abeta brain clearance. The mechanism responsible for reduced P-gp expression and activity levels is poorly understood. We recently demonstrated that Abeta40 triggers P-gp degradation through the ubiquitin-proteasome pathway. Consistent with these data, we show here that ubiquitinated P-gp levels in brain capillaries isolated from brain samples of AD patients are increased compared to capillaries isolated from brain tissue of cognitive normal individuals. We extended this line of research to in vivo studies using transgenic human amyloid precursor protein (hAPP) overexpressing mice (Tg2576) that were treated with PYR41, a cell-permeable, irreversible inhibitor of the ubiquitin-activating enzyme E1. Our data show that inhibiting P-gp ubiquitination protects the transporter from degradation, and immunoprecipitation experiments confirmed that PYR41 prevented P-gp ubiquitination. We further found that PYR41 treatment prevented reduction of P-gp protein expression and transport activity levels and substantially lowered Abeta brain levels in hAPP mice. Together, our findings provide in vivo proof that the ubiquitin-proteasome system mediates reduction of blood-brain barrier P-gp in AD and that inhibiting P-gp ubiquitination prevents P-gp degradation and lowers Abeta brain levels. Thus, targeting the ubiquitin-proteasome system may provide a novel therapeutic approach to protect blood-brain barrier P-gp from degradation in AD and other Abeta-based pathologies. PMID- 29997496 TI - Sex-Based Differences in Gut Microbiota Composition in Response to Tuna Oil and Algae Oil Supplementation in a D-galactose-Induced Aging Mouse Model. AB - Our previous work indicated that a mixture of tuna oil and algae oil treatment in male mice effectively relieved D-galactose (D-gal)-induced aging and resulted in gut microbiota alterations, and that the best anti-aging effects were observed for a tuna oil to algae oil ratio of 1:2. However, the possibility of a sex-based difference in the anti-aging effect of the tuna oil and algae oil mixture or gut microbiota variation, has rarely been investigated. In this study, the anti-aging effect of an oil mixture (1:2) in male and female mice was measured, and oil treatment improved the learning and cognition of mice that were damaged by D-gal, increased the activities of anti-oxidative enzymes, and decreased the level of MDA, which acted as a hallmark of oxidative damage to lipids. Male mice showed better anti-aging effects than female mice with a specific oil mixture ratio, and the clinical drug donepezil showed a similar or better effect on aging alleviation than oil treatments in both sexes. On the other hand, the same oil treatment led to different gut microbiota composition alterations in male and female mice. Redundancy analysis (RDA) identified 31 and 30 key operational taxonomic units (OTUs) in the male and female mice, respectively, and only three of these OTUs overlapped. Moreover, the abundance of Lactobacillus and several probiotic-like butyric acid producers was higher in male mice than in female mice, whereas the abundance of some inflammation-related genera, such as Clostridium XlVa, was lower in male mice. In conclusion, this study indicated the sex-based differences related to the anti-aging effects of tuna oil and algae oil treatment are accompanied by sex-based differences in gut microbiota modulation. PMID- 29997497 TI - Effects of Cognitive Reserve on Cognitive Performance in a Follow-Up Study in Older Adults With Subjective Cognitive Complaints. The Role of Working Memory. AB - Objective: Analyze the effects of CR on cognitive performance in adults with subjective cognitive complaints at follow-up. Method: We analyzed the factorial structure of the three constructs defined in cognitive performance (Episodic memory, Working memory, and General cognitive performance) separately to search for evidence of the invariance of the measurement model. We then developed four structural nested models to analyze the relationship between CR and cognitive performance, measured at baseline and after approximately 18 months, in 266 participants older than 50 years with subjective cognitive complaints. Results: The nested models revealed the following main results: direct effects of CR on all cognitive constructs at baseline and also indirect effects on the same constructs at follow-up, and indirect effects of CR on other cognitive constructs at follow-up via working memory at follow-up. Conclusion: The findings show that the proposed model is useful for measuring the influence of CR on cognitive performance in follow-up studies and that CR has a positive influence on cognitive performance at follow-up via working memory. CR may enhance mechanisms of information processing, favoring performance of tasks involving other cognitive constructs in older adults with subjective cognitive complaints. PMID- 29997498 TI - Population Pharmacokinetics of Vancomycin in Chinese ICU Neonates: Initial Dosage Recommendations. AB - The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population. The study population consisted of 80 neonates in the neonatal intensive care unit (ICU) from which 165 trough and peak concentrations of vancomycin were obtained. Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin. The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errors and the bootstrap method. Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin. The average clearance was 0.309 L/h for a neonate with Scr of 23.3 MUmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15 MUmol/L, current guideline recommendations would likely not achieve therapeutic area under the concentration-time curve over 24 h/minimum inhibitory concentration (AUC24h/MIC) >= 400. The exceptions to this are British National Formulary (2016-2017), Blue Book (2016) and Neofax (2017). Recommended dose regimens for neonates with different Scr levels and postmenstrual ages were estimated based on Monte Carlo simulations and the established model. These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting. PMID- 29997499 TI - OpenPVSignal: Advancing Information Search, Sharing and Reuse on Pharmacovigilance Signals via FAIR Principles and Semantic Web Technologies. AB - Signal detection and management is a key activity in pharmacovigilance (PV). When a new PV signal is identified, the respective information is publicly communicated in the form of periodic newsletters or reports by organizations that monitor and investigate PV-related information (such as the World Health Organization and national PV centers). However, this type of communication does not allow for systematic access, discovery and explicit data interlinking and, therefore, does not facilitate automated data sharing and reuse. In this paper, we present OpenPVSignal, a novel ontology aiming to support the semantic enrichment and rigorous communication of PV signal information in a systematic way, focusing on two key aspects: (a) publishing signal information according to the FAIR (Findable, Accessible, Interoperable, and Re-usable) data principles, and (b) exploiting automatic reasoning capabilities upon the interlinked PV signal report data. OpenPVSignal is developed as a reusable, extendable and machine-understandable model based on Semantic Web standards/recommendations. In particular, it can be used to model PV signal report data focusing on: (a) heterogeneous data interlinking, (b) semantic and syntactic interoperability, (c) provenance tracking and (d) knowledge expressiveness. OpenPVSignal is built upon widely-accepted semantic models, namely, the provenance ontology (PROV-O), the Micropublications semantic model, the Web Annotation Data Model (WADM), the Ontology of Adverse Events (OAE) and the Time ontology. To this end, we describe the design of OpenPVSignal and demonstrate its applicability as well as the reasoning capabilities enabled by its use. We also provide an evaluation of the model against the FAIR data principles. The applicability of OpenPVSignal is demonstrated by using PV signal information published in: (a) the World Health Organization's Pharmaceuticals Newsletter, (b) the Netherlands Pharmacovigilance Centre Lareb Web site and (c) the U.S. Food and Drug Administration (FDA) Drug Safety Communications, also available on the FDA Web site. PMID- 29997500 TI - Molecular Mechanisms of T Cells Activation by Dendritic Cells in Autoimmune Diseases. AB - The interaction between T cell and dendritic cells (DCs) that leads to T cell activation affects the progression of the immune response including autoimmune diseases. Antigen presentation on immune cell surface, formation of an immunological synapse (IS), and specific identification of complex by T cells including two activating signals are necessary steps that lead to T cell activation. The formation of stimulatory IS involves the inclusion of costimulatory molecules, such as ICAM-1/LFA-1 and CD28/B7-1, and so on. Some fusion proteins and monoclonal antibodies targeting costimulatory molecules have been developed and approved to treat autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type I diabetes (T1D), inflammatory bowel disease (IBD), and psoriasis. These biological agents, including CTLA-4- and LFA-3-Ig, anti-CD3 monoclonal antibody, could prevent the successful engagement of DCs by T cell with significant efficacy and safety profile. In this article, we reviewed the molecular mechanisms of T cell activation during the interaction between T cells and DCs, and summarized some biological agents that target costimulatory molecules involved in the regulation of T cell activation. PMID- 29997501 TI - Insight Into the Molecular Dynamic Simulation Studies of Reactive Oxygen Species in Native Skin Membrane. AB - In recent years, the role of reactive oxygen species (ROS) in regulating cancer cell apoptosis, inflammation, cell ischemia, and cell signaling pathways has been well established. The most common sources of intracellular ROS are the mitochondrial electron transport system, NADH oxidase, and cytochrome P450. In this study, we investigated the dynamics and permeability of ROS using molecular dynamics (MD) simulations on native skin-lipid bilayer membranes. Native skin lipid bilayers are composed of ceramide, cholesterol, and free fatty acid in an almost equal molar ratio (1:1:1). Dynamic distribution studies on ROS, i.e., hydrogen peroxide (H2O2) and O2 (1O2 by analogy), revealed that these species interact with cholesterol as a primary target in lipid peroxidation of the skin lipid bilayer. Moreover, the permeability of ROS, i.e., H2O2, hydroxyl radicals (HO), hydroperoxy radical (HOO), and O2, along the skin-lipid bilayer was measured using free energy profiles (FEPs). The FEPs showed that in spite of high energy barriers, ROS traveled through the membrane easily. Breaching the free energy barriers, these ROS permeated into the membrane, inflicting oxidative stress, and causing apoptosis. Collectively, the insight acquired from simulations may result in a better understanding of oxidative stress at the atomic level. PMID- 29997502 TI - A Systematic Review on Non-mammalian Models in Epilepsy Research. AB - Epilepsy is a common neurological disorder characterized by seizures which result in distinctive neurobiological and behavioral impairments. Not much is known about the causes of epilepsy, making it difficult to devise an effective cure for epilepsy. Moreover, clinical studies involving epileptogenesis and ictogenesis cannot be conducted in humans due to ethical reasons. As a result, animal models play a crucial role in the replication of epileptic seizures. In recent years, non-mammalian models have been given a primary focus in epilepsy research due to their advantages. This systematic review aims to summarize the importance of non mammalian models in epilepsy research, such as in the screening of anti convulsive compounds. The reason for this review is to integrate currently available information on the use and importance of non-mammalian models in epilepsy testing to aid in the planning of future studies as well as to provide an overview of the current state of this field. A PRISMA model was utilized and PubMed, Springer, ScienceDirect and SCOPUS were searched for articles published between January 2007 and November 2017. Fifty-one articles were finalized based on the inclusion/exclusion criteria and were discussed in this review. The results of this review demonstrated the current use of non-mammalian models in epilepsy research and reaffirmed their potential to supplement the typical rodent models of epilepsy in future research into both epileptogenesis and the treatment of epilepsy. This review also revealed a preference for zebrafish and fruit flies in lieu of other non-mammalian models, which is a shortcoming that should be corrected in future studies due to the great potential of these underutilized animal models. PMID- 29997504 TI - Saponins From Paris forrestii (Takht.) H. Li Display Potent Activity Against Acute Myeloid Leukemia by Suppressing the RNF6/AKT/mTOR Signaling Pathway. AB - Saponins are amphipathic glycosides found in traditional Chinese medicines. In the present study, we isolated a panel of saponins from Paris forrestii (Takht.) H. Li, a unique plant found in Tibet and Yunnan provinces, China. By examining their activities in suppressing acute myeloid leukemia (AML) cell proliferation, total saponins from Paris forrestii (TSPf) displayed more potent activity than individual ones. TSPf induced more than 40% AML cell apoptosis and decreased the viability of all leukemia cell lines. TSPf-induced apoptosis was confirmed by both Annexin V staining and caspase-3 activation. In line with these findings, TSPf downregulated pro-survival proteins Mcl-1, Bcl-xL, and Bcl-2 but upregulated the expression of tumor suppressor proteins p53, p27, Bax, and Beclin 1. The AKT/mTOR signaling pathway is frequently overactivated in various AML cells, and TSPf was found to suppress the activation of both AKT and mTOR, but had no effects on their total protein expression. This was further confirmed by the inactivation of 4EBP-1 and p70S6K, two typical downstream signal molecules in the AKT/mTOR pathway. Moreover, TSPf-inactivated AKT/mTOR signaling was found to be associated with downregulated RNF6, a recently identified oncogene in AML. RNF6 activated AKT/mTOR, and consistently, knockdown of RNF6 led to inactivation of the AKT/mTOR pathway. Furthermore, TSPf suppressed the growth of AML xenografts in nude mice models. Oral administration of TSPf almost fully suppressed tumor growth without gross toxicity. Consistent with the findings in cultured cell lines, TSPf also downregulated RNF6 expression along with inactivated AKT/mTOR signaling in tumor tissues. This study thus demonstrated that TSPf displays potent anti-AML activity by suppressing the RNF6/AKT/mTOR pathway. Given its low toxicity, TSPf could be developed for the treatment of AML. PMID- 29997503 TI - A Computational Systems Pharmacology Approach to Investigate Molecular Mechanisms of Herbal Formula Tian-Ma-Gou-Teng-Yin for Treatment of Alzheimer's Disease. AB - Traditional Chinese medicine (TCM) is typically prescribed as formula to treat certain symptoms. A TCM formula contains hundreds of chemical components, which makes it complicated to elucidate the molecular mechanisms of TCM. Here, we proposed a computational systems pharmacology approach consisting of network link prediction, statistical analysis, and bioinformatics tools to investigate the molecular mechanisms of TCM formulae. Taking formula Tian-Ma-Gou-Teng-Yin as an example, which shows pharmacological effects on Alzheimer's disease (AD) and its mechanism is unclear, we first identified 494 formula components together with corresponding 178 known targets, and then predicted 364 potential targets for these components with our balanced substructure-drug-target network-based inference method. With Fisher's exact test and statistical analysis we identified 12 compounds to be most significantly related to AD. The target genes of these compounds were further enriched onto pathways involved in AD, such as neuroactive ligand-receptor interaction, serotonergic synapse, inflammatory mediator regulation of transient receptor potential channel and calcium signaling pathway. By regulating key target genes, such as ACHE, HTR2A, NOS2, and TRPA1, the formula could have neuroprotective and anti-neuroinflammatory effects against the progression of AD. Our approach provided a holistic perspective to study the relevance between TCM formulae and diseases, and implied possible pharmacological effects of TCM components. PMID- 29997505 TI - Epigallocatechin-3-Gallate Promotes the Growth of Mink Hair Follicles Through Sonic Hedgehog and Protein Kinase B Signaling Pathways. AB - Background: Hair follicles play an essential role in the growth of hair. Epigallocatechin-3-gallate (EGCG), a catechin polyphenol in green tea, has various bioactivities. The present study aims to evaluate the effect of EGCG on the growth of mink hair follicles and investigate the possible molecular mechanisms. Methods: The length of hair follicles was recorded up to 6 days in presence of 0.1-5 MUM EGCG. Primary dermal papilla cells (DPCs) and outer root sheath cells (ORSCs) were treated with 0.25-4 MUM EGCG, and their growth was evaluated by MTT assay and cell cycle detection. The levels of key molecules in sonic hedgehog (Shh) and protein kinase B (AKT) signaling pathways were further assessed by quantitative real-time PCR, western blot and immunofluorescence. To determine the involvement of Shh and AKT pathways in EGCG-mediated growth promotion of ORSCs and DPCs, Shh pathway inhibitors cyclopamine and GANT61 or AKT pathway inhibitor LY294002 were employed, and then cell proliferation and cell cycle were analyzed. Results: Data from ex vivo culture showed that, in presence of 0.5-2.5 MUM EGCG, the growth of mink hair follicles was promoted. In vitro, the proliferation of DPCs and ORSCs was enhanced by 0.5-4 MUM EGCG treatment. More cells entered S phase upon treatment of EGCG, accompanied with upregulation of cyclin D1 and cyclin E1. Furthermore, when exposed to EGCG, the Shh and AKT signaling pathways were activated in both hair follicles and primary DPCs and ORSCs. Inhibiting either of these two pathways partly reversed the effect of EGCG on proliferation and cell cycle of DPCs and ORSCs. Conclusion: EGCG promotes the growth of mink hair follicles at concentrations of 0.5-2.5 MUM. This growth promoting effect of EGCG may be associated with the increased proliferation of DPCs and ORSCs through activating Shh and AKT signaling pathways. PMID- 29997506 TI - Gut-Sourced Vasoactive Intestinal Polypeptide Induced by the Activation of alpha7 Nicotinic Acetylcholine Receptor Substantially Contributes to the Anti inflammatory Effect of Sinomenine in Collagen-Induced Arthritis. AB - Sinomenine has long been used for the treatment of rheumatoid arthritis in China. However, its anti-inflammatory mechanism is still debatable because the in vitro minimal effective concentration (>=250 MUM) is hardly reached in either synovium or serum after oral administration at a therapeutic dose. Recent findings suggest that the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) might mediate the inhibitory effect of sinomenine on macrophage activation, which attracts us to explore the anti-arthritis mechanism of sinomenine by taking neuroendocrine inflammation axis into consideration. Here, we showed that orally administered sinomenine ameliorated the systemic inflammation of collagen-induced arthritis (CIA) rats, which was significantly diminished by either vagotomy or the antagonists of nicotinic acetylcholine receptors (especially the antagonist of alpha7nAChR), but not by the antagonists of muscarinic receptor. Sinomenine might bind to alpha7nAChR through interacting with the residues Tyr184 and Tyr191 in the pocket. In addition, the generation of vasoactive intestinal polypeptide (VIP) from the gut of CIA rats and cultured neuron-like cells was selectively enhanced by sinomenine through the activation of alpha7nAChR-PI3K/Akt/mTOR pathway. The elevated levels of VIP in the serum and small intestine of rats were negatively correlated with the scores of joint destruction. The crucial role of VIP in the anti-arthritic effect of sinomenine was confirmed by using VIP hybrid, a non-specific antagonist of VIP receptor. Taken together, intestine-sourced VIP mediates the anti-arthritic effect of sinomenine, which is generated by the activation of alpha7nAChR. PMID- 29997507 TI - Tramadol's Inhibitory Effects on Sexual Behavior: Pharmacological Studies in Serotonin Transporter Knockout Rats. AB - Tramadol is an effective pharmacological intervention in human premature ejaculation (PE). To investigate whether the inhibitory action of tramadol is primarily caused by its selective serotonin reuptake inhibitory (SSRI) effects we tested the dose-response effects of tramadol on sexual behavior in serotonin transporter wild type (SERT+/+), heterozygous (SERT+/-), and knockout (SERT-/-) rats. To investigate whether other mechanisms contribute to the inhibitory effects, WAY100,635, a 5-HT1A receptor antagonist and naloxone, a MU-opioid receptor antagonist, were tested on sexual behavior together with tramadol. Tramadol dose-dependently decreases sexual activity in all genotypes. In all studies, SERT+/- rats did not respond differently from SERT+/+ rats. WAY100,635 did not affect sexual activity in SERT+/+, but dose-dependently reduced sexual activity in SERT-/- rats. WAY100,635 (0.3 mg/kg) combined with tramadol (20 mg/kg) significantly reduced sexual activity in SERT+/+ and even stronger in SERT /- rats. Naloxone did not affect sexual behavior consistently in SERT+/+ rats, while in SERT-/- rats all doses reduced ejaculation frequency mildly. Combining naloxone (20 mg/kg) and tramadol (20 mg/kg) decreased ejaculation frequencies in both genotypes. Interestingly, combining tramadol (20 mg/kg), WAY100,635 (0.3 mg/kg) and naloxone (20 mg/kg) led to complete elimination of all sexual activity in both SERT+/+ and SERT-/- rats. These findings suggest that the inhibitory effects of tramadol on male sexual behavior in SERT+/+ rats is mainly, if not exclusively, due to SERT inhibition, with an important role for 5-HT1A receptors, although influence of other systems (e.g., noradrenergic) cannot be excluded. As SSRIs exert their sexual inhibition after chronic administration, tramadol may be therapeutically attractive as "on demand" therapy for PE. PMID- 29997508 TI - 2'-O-Galloylhyperin Isolated From Pyrola incarnata Fisch. Attenuates LPS-Induced Inflammatory Response by Activation of SIRT1/Nrf2 and Inhibition of the NF-kappaB Pathways in Vitro and Vivo. AB - 2'-O-galloylhyperin, a major compound of Pyrola incarnata Fisch., possesses a variety of biological and pharmacological activities, including anti-oxidative and anti-inflammatory activities. Nevertheless, the underlying molecular mechanisms of 2'-O-GH in microbial infection and sepsis are not clear. In this study, we investigated the anti-inflammatory effects of 2'-O-GH. We found that 2' O-GH significantly reduced the production of TNF-alpha, IL-6, and nitric oxide (NO), suppressed the expression levels of iNOS, blocked the translocation of NF kappaB from the cytosol to nucleus, and decreased the MAPK activation in LPS activated RAW 264.7 cells. 2'-O-GH also enhanced the nuclear translocation of Nrf2 and up-regulated the expression of heme oxygenase-1 (HO-1) and SIRT1. In addition, the administration of 2'-O-GH attenuated the TNF-alpha and IL-6 production in the serum, infiltration of inflammatory cells, liver tissue damage, and the mortality rate of LPS-challenged mice. Moreover, 2'-O-GH significantly upregulated Nrf2 and SIRT1 expression and inhibited the inflammatory responses in the liver of septic mice. The collective data indicate that 2'-O-GH could potentially be a novel functional food candidate in the treatment of sepsis. PMID- 29997509 TI - Discovery of the Consistently Well-Performed Analysis Chain for SWATH-MS Based Pharmacoproteomic Quantification. AB - Sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) has emerged as one of the most popular techniques for label-free proteome quantification in current pharmacoproteomic research. It provides more comprehensive detection and more accurate quantitation of proteins comparing with the traditional techniques. The performance of SWATH-MS is highly susceptible to the selection of processing method. Till now, >=27 methods (transformation, normalization, and missing-value imputation) are sequentially applied to construct numerous analysis chains for SWATH-MS, but it is still not clear which analysis chain gives the optimal quantification performance. Herein, the performances of 560 analysis chains for quantifying pharmacoproteomic data were comprehensively assessed. Firstly, the most complete set of the publicly available SWATH-MS based pharmacoproteomic data were collected by comprehensive literature review. Secondly, substantial variations among the performances of various analysis chains were observed, and the consistently well-performed analysis chains (CWPACs) across various datasets were for the first time generalized. Finally, the log and power transformations sequentially followed by the total ion current normalization were discovered as one of the best performed analysis chains for the quantification of SWATH-MS based pharmacoproteomic data. In sum, the CWPACs identified here provided important guidance to the quantification of proteomic data and could therefore facilitate the cutting-edge research in any pharmacoproteomic studies requiring SWATH-MS technique. PMID- 29997510 TI - Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross Talk Between GSK-3beta and PP2A Signaling. AB - Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3beta (GSK-3beta) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis. The purpose of this study was to investigate the effects of CIG on GSK-3beta and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3beta. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3beta over activation. In the mechanism of action, CIG's attenuating GSK-3beta activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3beta. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase 1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK 3beta activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3beta activity, thus regulated the cross-talk between GSK-3beta and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy. PMID- 29997512 TI - Coenzyme Q10 or Creatine Counteract Pravastatin-Induced Liver Redox Changes in Hypercholesterolemic Mice. AB - Statins are the preferred therapy to treat hypercholesterolemia. Their main action consists of inhibiting the cholesterol biosynthesis pathway. Previous studies report mitochondrial oxidative stress and membrane permeability transition (MPT) of several experimental models submitted to diverse statins treatments. The aim of the present study was to investigate whether chronic treatment with the hydrophilic pravastatin induces hepatotoxicity in LDL receptor knockout mice (LDLr-/-), a model for human familial hypercholesterolemia. We evaluated respiration and reactive oxygen production rates, cyclosporine-A sensitive mitochondrial calcium release, antioxidant enzyme activities in liver mitochondria or homogenates obtained from LDLr-/- mice treated with pravastatin for 3 months. We observed that pravastatin induced higher H2O2 production rate (40%), decreased activity of aconitase (28%), a superoxide-sensitive Krebs cycle enzyme, and increased susceptibility to Ca2+-induced MPT (32%) in liver mitochondria. Among several antioxidant enzymes, only glucose-6-phosphate dehydrogenase (G6PD) activity was increased (44%) in the liver of treated mice. Reduced glutathione content and reduced to oxidized glutathione ratio were increased in livers of pravastatin treated mice (1.5- and 2-fold, respectively). The presence of oxidized lipid species were detected in pravastatin group but protein oxidation markers (carbonyl and SH- groups) were not altered. Diet supplementation with the antioxidants CoQ10 or creatine fully reversed all pravastatin effects (reduced H2O2 generation, susceptibility to MPT and normalized aconitase and G6PD activity). Taken together, these results suggest that 1- pravastatin induces liver mitochondrial redox imbalance that may explain the hepatic side effects reported in a small number of patients, and 2- the co treatment with safe antioxidants neutralize these side effects. PMID- 29997511 TI - Review and Meta-Analyses of TAAR1 Expression in the Immune System and Cancers. AB - Since its discovery in 2001, the major focus of TAAR1 research has been on its role in monoaminergic regulation, drug-induced reward and psychiatric conditions. More recently, TAAR1 expression and functionality in immune system regulation and immune cell activation has become a topic of emerging interest. Here, we review the immunologically-relevant TAAR1 literature and incorporate open-source expression and cancer survival data meta-analyses. We provide strong evidence for TAAR1 expression in the immune system and cancers revealed through NCBI GEO datamining and discuss its regulation in a spectrum of immune cell types as well as in numerous cancers. We discuss connections and logical directions for further study of TAAR1 in immunological function, and its potential role as a mediator or modulator of immune dysregulation, immunological effects of psychostimulant drugs of abuse, and cancer progression. PMID- 29997515 TI - Metabolomic Approach to Redox and Nitrosative Reactions in Cardiovascular Diseases. AB - Metabolomics, also referred to as metabonomics, is one of the most recent innovative technologies in medicine. It offers a direct functional read-out of phenotypes by the detection, identification, and quantification of a large number of metabolites within a biological sample such as urine and blood. Metabolites (<1500 Da) represent the output of cellular metabolism, accounting for expression and activity of genes, transcripts, and proteins, and offering unique insights into small molecule regulation, which may uncover new biochemical patterns. Metabolomics research has considerable potential for translating the metabolic fingerprint into personalized therapeutic strategies. Within the field of interest, cardiovascular disease (CVD) is one of the most developed areas. However, CVD remains the leading cause of death worldwide with a marked increase in mortality rates over the past six decades. In this scenario, recent findings indicate the important role of redox and nitrosative (RN) reactions in CVD development and progression. RN reactions are generally involved in the homeostatic modulation of a wide number of cellular and organ functions. Conversely, the imbalance of these reactions may lead to a condition of allostasis that in turn can cause CVD. The aim of this review is to highlight how the use of metabolomics may be useful for the study of RN reactions related to CVD, providing a tool to understand the mechanisms underlying reactions that could lead to impaired ROS or RNS formation. PMID- 29997514 TI - Lipid and Non-lipid Factors Affecting Macrophage Dysfunction and Inflammation in Atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease and a leading cause of human mortality. The lesional microenvironment contains a complex accumulation of variably oxidized lipids and cytokines. Infiltrating monocytes become polarized in response to these stimuli, resulting in a broad spectrum of macrophage phenotypes. The extent of lipid loading in macrophages influences their phenotype and consequently their inflammatory status. In response to excess atherogenic ligands, many normal cell processes become aberrant following a loss of homeostasis. This can have a direct impact upon the inflammatory response, and conversely inflammation can lead to cell dysfunction. Clear evidence for this exists in the lysosomes, endoplasmic reticulum and mitochondria of atherosclerotic macrophages, the principal lesional cell type. Furthermore, several intrinsic cell processes become dysregulated under lipidotic conditions. Therapeutic strategies aimed at restoring cell function under disease conditions are an ongoing coveted aim. Macrophages play a central role in promoting lesional inflammation, with plaque progression and stability being directly proportional to macrophage abundance. Understanding how mixtures or individual lipid species regulate macrophage biology is therefore a major area of atherosclerosis research. In this review, we will discuss how the myriad of lipid and lipoprotein classes and products used to model atherogenic, proinflammatory immune responses has facilitated a greater understanding of some of the intricacies of chronic inflammation and cell function. Despite this, lipid oxidation produces a complex mixture of products and with no single or standard method of derivatization, there exists some variation in the reported effects of certain oxidized lipids. Likewise, differences in the methods used to generate macrophages in vitro may also lead to variable responses when apparently identical lipid ligands are used. Consequently, the complexity of reported macrophage phenotypes has implications for our understanding of the metabolic pathways, processes and shifts underpinning their activation and inflammatory status. Using oxidized low density lipoproteins and its oxidized cholesteryl esters and phospholipid constituents to stimulate macrophage has been hugely valuable, however there is now an argument that only working with low complexity lipid species can deliver the most useful information to guide therapies aimed at controlling atherosclerosis and cardiovascular complications. PMID- 29997516 TI - Automatic Optimization of an in Silico Model of Human iPSC Derived Cardiomyocytes Recapitulating Calcium Handling Abnormalities. AB - The growing importance of human induced pluripotent stem cell-derived cardiomyoyctes (hiPSC-CMs), as patient-specific and disease-specific models for studying cellular cardiac electrophysiology or for preliminary cardiotoxicity tests, generated better understanding of hiPSC-CM biophysical mechanisms and great amount of action potential and calcium transient data. In this paper, we propose a new hiPSC-CM in silico model, with particular attention to Ca2+ handling. We used (i) the hiPSC-CM Paci2013 model as starting point, (ii) a new dataset of Ca2+ transient measurements to tune the parameters of the inward and outward Ca2+ fluxes of sarcoplasmic reticulum, and (iii) an automatic parameter optimization to fit action potentials and Ca2+ transients. The Paci2018 model simulates, together with the typical hiPSC-CM spontaneous action potentials, more refined Ca2+ transients and delayed afterdepolarizations-like abnormalities, which the old Paci2013 was not able to predict due to its mathematical formulation. The Paci2018 model was validated against (i) the same current blocking experiments used to validate the Paci2013 model, and (ii) recently published data about effects of different extracellular ionic concentrations. In conclusion, we present a new and more versatile in silico model, which will provide a platform for modeling the effects of drugs or mutations that affect Ca2+ handling in hiPSC-CMs. PMID- 29997513 TI - Near to One's Heart: The Intimate Relationship Between the Placenta and Fetal Heart. AB - The development of the fetal heart is exquisitely controlled by a multitude of factors, ranging from humoral to mechanical forces. The gatekeeper regulating many of these factors is the placenta, an external fetal organ. As such, resistance within the placental vascular bed has a direct influence on the fetal circulation and therefore, the developing heart. In addition, the placenta serves as the interface between the mother and fetus, controlling substrate exchange and release of hormones into both circulations. The intricate relationship between the placenta and fetal heart is appreciated in instances of clinical placental pathology. Abnormal umbilical cord insertion is associated with congenital heart defects. Likewise, twin-to-twin transfusion syndrome, where monochorionic twins have unequal sharing of their placenta due to inter-twin vascular anastomoses, can result in cardiac remodeling and dysfunction in both fetuses. Moreover, epidemiological studies have suggested a link between placental phenotypic traits and increased risk of cardiovascular disease in adult life. To date, the mechanistic basis of the relationships between the placenta, fetal heart development and later risk of cardiac dysfunction have not been fully elucidated. However, studies using environmental exposures and gene manipulations in experimental animals are providing insights into the pathways involved. Likewise, surgical instrumentation of the maternal and fetal circulations in large animal species has enabled the manipulation of specific humoral and mechanical factors to investigate their roles in fetal cardiac development. This review will focus on such studies and what is known to date about the link between the placenta and heart development. PMID- 29997517 TI - Nervous System Injury in Response to Contact With Environmental, Engineered and Planetary Micro- and Nano-Sized Particles. AB - Nerve cells take a special place among other cells in organisms because of their unique function mechanism. The plasma membrane of nerve cells from the one hand performs a classical barrier function, thereby being foremost targeted during contact with micro- and nano-sized particles, and from the other hand it is very intensively involved in nerve signal transmission, i.e., depolarization-induced calcium-dependent compound exocytosis realized via vesicle fusion following by their retrieval and calcium-independent permanent neurotransmitter turnover via plasma membrane neurotransmitter transporters that utilize Na+/K+ electrochemical gradient as a driving force. Worldwide traveling air pollution particulate matter is now considered as a possible trigger factor for the development of a variety of neuropathologies. Micro- and nano-sized particles can reach the central nervous system during inhalation avoiding the blood-brain barrier, thereby making synaptic neurotransmission extremely sensitive to their influence. Neurosafety of environmental, engineered and planetary particles is difficult to predict because they possess other features as compared to bulk materials from which the particles are composed of. The capability of the particles to absorb heavy metals and organic neurotoxic molecules from the environment, and moreover, spontaneously interact with proteins and lipids in organisms and form biomolecular corona can considerably change the particles' features. The absorption capability occasionally makes them worldwide traveling particulate carriers for delivery of environmental neurotoxic compounds to the brain. Discrepancy of the experimental data on neurotoxicity assessment of micro- and nano-sized particles can be associated with a variability of systems, in which neurotoxicity was analyzed and where protein components of the incubation media forming particle biocorona can significantly distort and even eliminate factual particle effects. Specific synaptic mechanisms potentially targeted by environmental, engineered and planetary particles, general principles of particle neurosafety and its failure were discussed. Particle neurotoxic potential depends on their composition, size, shape, surface properties, stability in organisms and environment, capability to absorb neurotoxic compounds, form dust and interrelate with different biomolecules. Changes in these parameters can break primary particle neurosafety. PMID- 29997518 TI - Impaired Myofilament Contraction Drives Right Ventricular Failure Secondary to Pressure Overload: Model Simulations, Experimental Validation, and Treatment Predictions. AB - Introduction: Pulmonary hypertension (PH) causes pressure overload leading to right ventricular failure (RVF). Myocardial structure and myocyte mechanics are altered in RVF but the direct impact of these cellular level factors on organ level function remain unclear. A computational model of the cardiovascular system that integrates cellular function into whole organ function has recently been developed. This model is a useful tool for investigating how changes in myocyte structure and mechanics contribute to organ function. We use this model to determine how measured changes in myocyte and myocardial mechanics contribute to RVF at the organ level and predict the impact of myocyte-targeted therapy. Methods: A multiscale computational framework was tuned to model PH due to bleomycin exposure in mice. Pressure overload was modeled by increasing the pulmonary vascular resistance (PVR) and decreasing pulmonary artery compliance (CPA). Myocardial fibrosis and the impairment of myocyte maximum force generation (Fmax) were simulated by increasing the collagen content (?PVR + ?CPA + fibrosis) and decreasing Fmax (?PVR + ?CPA + fibrosis + ?Fmax). A61603 (A6), a selective alpha1A-subtype adrenergic receptor agonist, shown to improve Fmax was simulated to explore targeting myocyte generated Fmax in PH. Results: Increased afterload (RV systolic pressure and arterial elastance) in simulations matched experimental results for bleomycin exposure. Pressure overload alone (?PVR + ?CPA) caused decreased RV ejection fraction (EF) similar to experimental findings but preservation of cardiac output (CO). Myocardial fibrosis in the setting of pressure overload (?PVR + ?PAC + fibrosis) had minimal impact compared to pressure overload alone. Including impaired myocyte function (?PVR + ?PAC + fibrosis + ?Fmax) reduced CO, similar to experiment, and impaired EF. Simulations predicted that A6 treatment preserves EF and CO despite maintained RV pressure overload. Conclusion: Multiscale computational modeling enabled prediction of the contribution of cellular level changes to whole organ function. Impaired Fmax is a key feature that directly contributes to RVF. Simulations further demonstrate the therapeutic benefit of targeting Fmax, which warrants additional study. Future work should incorporate growth and remodeling into the computational model to enable prediction of the multiscale drivers of the transition from dysfunction to failure. PMID- 29997519 TI - Acute Effects of High Intensity, Resistance, or Combined Protocol on the Increase of Level of Neurotrophic Factors in Physically Inactive Overweight Adults: The BrainFit Study. AB - : The purpose of this study was to compare the neurotrophic factor response following one session of high-intensity exercise, resistance training or both in a cohort of physically inactive overweight adults aged 18-30 years old. A randomized, parallel-group clinical trial of 51 men (23.6 +/- 3.5 years; 83.5 +/- 7.8 kg; 28.0 +/- 1.9 kg/m2) who are physically inactive (i.e., < 150 min of moderate-intensity exercise per week or IPAQ score of <600 MET min/week for >6 months) and are either abdominally obese (waist circumference >=90 cm) or have a body mass index, BMI >=25 and <= 30 kg/m2 were randomized to the following four exercise protocols: high-intensity exercise (4 * 4 min intervals at 85-95% maximum heart rate [HRmax] interspersed with 4 min of recovery at 75-85% HRmax) (n = 14), resistance training (12-15 repetitions per set, at 50-70% of one repetition maximum with 60 s of recovery) (n = 12), combined high-intensity and resistance exercise (n = 13), or non-exercising control (n = 12). The plasma levels of neurotrophin-3 (NT-3), neurotrophin-4 (also known as neurotrophin 4/5; NT-4 or NT-4/5), and brain-derived neurotrophic factor (BDNF) were determined before (pre-exercise) and 1-min post-exercise for each protocol session. Resistance training induced significant increases in NT-3 (+39.6 ng/mL [95% CI, 2.5-76.6; p = 0.004], and NT-4/5 (+1.3 ng/mL [95% CI, 0.3-2.3; p = 0.014]), respectively. Additionally, combined training results in favorable effects on BDNF (+22.0, 95% CI, 2.6-41.5; p = 0.029) and NT-3 (+32.9 ng/mL [95% CI, 12.3 53.4; p = 0.004]), respectively. The regression analysis revealed a significant positive relationship between changes in BDNF levels and changes in NT-4/5 levels from baseline to immediate post-exercise in the combined training group (R2 = 0.345, p = 0.034) but not the other intervention groups. The findings indicate that acute resistance training and combined exercise increase neurotrophic factors in physically inactive overweight adults. Further studies are required to determine the biological importance of changes in neurotrophic responses in overweight men and chronic effects of these exercise protocols. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02915913 (Date: September 22, 2016). PMID- 29997521 TI - Stretch, Injury and Inflammation Markers Evaluation to Predict Clinical Outcomes After Implantable Cardioverter Defibrillator Therapy in Heart Failure Patients With Metabolic Syndrome. AB - Background: Internal cardioverter defibrillator (ICD) therapy reduced all-cause mortality. Conversely, few studies reported that ICDs' shocks may reduce survival. Recently authors suggested that, multiple inflammatory and molecular pathways were related to worse prognosis in metabolic syndrome (MS) patients treated by ICDs. Therefore, it may be relevant to find new biomarkers to predict ICDs' shock and worse prognosis in treated patients. Methods: In 99 MS vs. 107 no MS patients treated by ICD for primary prevention, we evaluated all-cause mortality, cardiac deaths, hospitalization for heart failure, appropriate and inappropriate therapy, and survival after appropriate ICD therapy. Results: MS vs. no MS patients had higher levels of failing heart stress biomarkers. The highest values of ST2 were related to worse prognosis. Patients who had better survival after appropriate ICD therapy were those associated with lowest ST2 values. At multivariate Cox regression analysis, C reactive protein (CRP) (0.110 [0.027-0.446], p-value 0.002), troponine I (TnI) protein (0.010 [0.001-0.051], p value 0.010), and B type natriuretic peptide (BNP) (1.151 [1.010-1.510], p-value 0.001), predicted all cause of deaths. BNP predicted cardiac deaths (1.010 [1.001 1.206], p-value 0.033). MS, and BNP predicted hospitalization for heart failure events (2.902 [1.345-4.795], p-value 0.001; 1.005 [1.000-1.016], p-value 0.007). ST2 predicted appropriate therapy (1.012 [1.007-1.260], p-value 0.001), as BNP (1.005 [1.001-1.160], p-value 0.028), LVEF (1.902 [1.857-1.950], p-value 0.001), and CRP (1.833 [1.878-1.993], p-value 0.028). ST2, and BNP predicted survival after ICD appropriate therapy (4.297 [1.985-9.302], p-value 0.001; 1.210 [1.072 1.685], p-value 0.024). Conclusions: ST2 values may differentiate MS patients with a higher risk of ICDs' therapy, and worse prognosis. Therefore, ST2 protein may be used as valid monitoring biomarker, and as a predictive biomarker in failing heart ICDs' patients affected by MS. PMID- 29997520 TI - Application of Patient-Specific Computational Fluid Dynamics in Coronary and Intra-Cardiac Flow Simulations: Challenges and Opportunities. AB - The emergence of new cardiac diagnostics and therapeutics of the heart has given rise to the challenging field of virtual design and testing of technologies in a patient-specific environment. Given the recent advances in medical imaging, computational power and mathematical algorithms, patient-specific cardiac models can be produced from cardiac images faster, and more efficiently than ever before. The emergence of patient-specific computational fluid dynamics (CFD) has paved the way for the new field of computer-aided diagnostics. This article provides a review of CFD methods, challenges and opportunities in coronary and intra-cardiac flow simulations. It includes a review of market products and clinical trials. Key components of patient-specific CFD are covered briefly which include image segmentation, geometry reconstruction, mesh generation, fluid structure interaction, and solver techniques. PMID- 29997522 TI - Effectiveness of Two Cold Water Immersion Protocols on Neuromuscular Function Recovery: A Tensiomyography Study. AB - Cold water immersion (CWI) has become a highly used recovery method in sports sciences, which seeks to minimize fatigue and accelerate recovery processes; however, tensiomyography (TMG) is a new method to analyze the muscle mechanical response as a recovery indicator after CWI protocols, this relative new tool of muscle function assessment, can lead to new information of understand fatigue recovery trough CWI. The objective of the study was to compare the effect of two CWI protocols, on neuromuscular function recovery. Thirty-nine healthy males (21.8 +/- 2.8 years, 73.2 +/- 8.2 kg, 176.6 +/- 5.3 cm and body fat 13.5 +/- 3.4%) were included in the study. Participants were grouped into a continuous immersion (12 min at 12 +/- 0.4 degrees C) group, intermittent immersion (2 min immersion at 12 +/- 0.4 degrees C + 1 min out of water 23 +/- 0.5 degrees C) group, and a control group (CG) (12 min sitting in a room at 23 +/- 0.5 degrees C). Afterward, the participants performed eight sets of 30 s counter movement jumps (CMJs) repetitions, with a 90 s standing recovery between sets. Muscle contraction time (Tc), delay time (Td), muscle radial displacement (Dm), muscle contraction velocity at 10% of DM (V10), and muscle contraction velocity at 90% of DM (V90) in rectus, biceps femoris, and CMJ were measured. Neither CWI protocol was effective in showing improved recovery at 24 and 48 h after training compared with the CG (p > 0.05), in any TMG indicator of recovery in either muscle biceps or rectus femoris, nor was the CMJ performance (F(6,111) = 0.43, p = 0.85, omegap2 = 0). Neither CWI protocol contributed to recovery of the neuromuscular function indicator. PMID- 29997523 TI - Prognostic Value of HMGA2 in Human Cancers: A Meta-Analysis Based on Literatures and TCGA Datasets. AB - Background: Emerging evidences have shown that the high-mobility group protein A2 (HMGA2) can aberrantly express in human cancers, and it could be an unfavorable prognostic factor in cancer patients. However, the prognostic value of HMGA2 was still unclear. Therefore, in this study, we explored the potential prognostic value of HMGA2 in human cancers by using meta-analysis based on published literatures and The Cancer Genome Atlas (TCGA) datasets. Methods: Through searching PubMed, Embase, Web of Science and Cochrane Library databases, we were able to identify the studies evaluating the prognostic value of HMGA2 in cancers. Then, UALCAN and TCGA datasets were used to validate the results of our meta analysis. Results: In all, 15 types of cancers were included in this meta analysis. Pooled results showed that high level of HMGA2 was significantly correlated with poor OS (HR = 1.88, 95% confidence interval (CI) = 1.68-2.11, P < 0.001) and poor DFS (HR = 2.49, 95% CI = 1.44-4.28, P = 0.001) in cancer patients. However, subgroup analyses revealed that the high expressed HMGA2 was associated with poor OS in head and neck cancer, gastric cancer and colorectal cancer, but not esophageal cancer and ovarian cancer. Based on TCGA datasets, we analyzed 9944 patients with 33 types of cancers. Significant association between HMGA2 overexpression and poor OS was found in 14 types of cancers. Taken together, consistent results were observed in clear cell renal cell carcinoma, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Conclusion: Our meta analysis showed the significance of HMGA2 and its prognostic value in various cancers. High level of HMGA2 could be associated with poor OS in patients with clear cell renal cell carcinoma, head and neck cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma, but not esophageal adenocarcinoma and ovarian carcinoma. PMID- 29997524 TI - Calorie Restriction-Induced Increase in Skeletal Muscle Insulin Sensitivity Is Not Prevented by Overexpression of the p55alpha Subunit of Phosphoinositide 3 Kinase. AB - Introduction: The Phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in skeletal muscle insulin-stimulated glucose uptake. While whole body and tissue specific knockout (KO) of individual or combinations of the regulatory subunits of PI3K (p85alpha, p55alpha, and p50alpha or p85beta); increase insulin sensitivity, no study has examined whether increasing the expression of the individual regulatory subunits would inhibit insulin action in vivo. Therefore, the objective of this study was to determine whether skeletal muscle-specific overexpression of the p55alpha regulatory subunit of PI3K impairs skeletal muscle insulin sensitivity, or prevents its enhancement by caloric restriction. Methods: We developed a novel "floxed" mouse that, through the Cre LoxP approach, allows for tamoxifen (TMX)-inducible and skeletal muscle-specific overexpression of the p55alpha subunit of PI3K (referred to as, 'p55alpha-mOX'). Beginning at 10 weeks of age, p55alpha-mOX mice and their floxed littermates (referred to as wildtype [WT]) either continued with free access to food (ad libitum; AL), or were switched to a calorie restricted diet (CR; 60% of AL intake) for 20 days. We measured body composition, whole-body energy expenditure, oral glucose tolerance and ex vivo skeletal muscle insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake method. Results: p55alpha mRNA and protein expression was increased ~2 fold in muscle from p55alpha-mOX versus WT mice. There were no differences in energy expenditure, total activity, or food intake of AL-fed mice between genotypes. Body weight, fat and lean mass, tissue weights, and fasting glucose and insulin were comparable between p55alpha-mOX and WT mice on AL, and were decreased equally by CR. Interestingly, overexpression of p55alpha did not impair oral glucose tolerance or skeletal muscle insulin signaling or sensitivity, nor did it impact the ability of CR to enhance these parameters. Conclusion: Skeletal muscle-specific overexpression of p55alpha does not impact skeletal muscle insulin action, suggesting that p85alpha and/or p50alpha may be more important regulators of skeletal muscle insulin signaling and sensitivity. PMID- 29997525 TI - Epithelial Na+ Channel: Reciprocal Control by COMMD10 and Nedd4-2. AB - Optimal function of the epithelial sodium channel (ENaC) in the distal nephron is key to the kidney's long-term control of salt homeostasis and blood pressure. Multiple pathways alter ENaC cell surface populations, including correct processing and trafficking in the secretory pathway to the cell surface, and retrieval from the cell surface through ubiquitination by the ubiquitin ligase Nedd4-2, clathrin-mediated endocytosis, and sorting in the endosomal system. Members of the Copper Metabolism Murr1 Domain containing (COMMD) family of 10 proteins are known to interact with ENaC. COMMD1, 3 and 9 have been shown to down regulate ENaC, most likely through Nedd4-2, however, the other COMMD family members remain uncharacterized. To investigate the effects of the COMMD10 protein on ENaC trafficking and function, the interaction of ENaC and COMMD10 was confirmed. Stable COMMD10 knockdown in Fischer rat thyroid epithelia decreased ENaC current and this decreased current was associated with increased Nedd4-2 protein, a known negative regulator of ENaC. However, inhibition of Nedd4-2's ubiquitination of ENaC was only able to partially rescue the observed reduction in current. Stable COMMD10 knockdown results in defects both in endocytosis and recycling of transferrin suggesting COMMD10 likely interacts with multiple pathways to regulate ENaC and therefore could be involved in the long-term control of blood pressure. PMID- 29997526 TI - Effect of Training-Induced Changes in Achilles Tendon Stiffness on Muscle-Tendon Behavior During Landing. AB - During rapid deceleration of the body, tendons buffer part of the elongation of the muscle-tendon unit (MTU), enabling safe energy dissipation via eccentric muscle contraction. Yet, the influence of changes in tendon stiffness within the physiological range upon these lengthening contractions is unknown. This study aimed to examine the effect of training-induced stiffening of the Achilles tendon on triceps surae muscle-tendon behavior during a landing task. Twenty-one male subjects were assigned to either a 10-week resistance-training program consisting of single-leg isometric plantarflexion (n = 11) or to a non-training control group (n = 10). Before and after the training period, plantarflexion force, peak Achilles tendon strain and stiffness were measured during isometric contractions, using a combination of dynamometry, ultrasound and kinematics data. Additionally, testing included a step-landing task, during which joint mechanics and lengths of gastrocnemius and soleus fascicles, Achilles tendon, and MTU were determined using synchronized ultrasound, kinematics and kinetics data collection. After training, plantarflexion strength and Achilles tendon stiffness increased (15 and 18%, respectively), and tendon strain during landing remained similar. Likewise, lengthening and negative work produced by the gastrocnemius MTU did not change detectably. However, in the training group, gastrocnemius fascicle length was offset (8%) to a longer length at touch down and, surprisingly, fascicle lengthening and velocity were reduced by 27 and 21%, respectively. These changes were not observed for soleus fascicles when accounting for variation in task execution between tests. These results indicate that a training-induced increase in tendon stiffness does not noticeably affect the buffering action of the tendon when the MTU is rapidly stretched. Reductions in gastrocnemius fascicle lengthening and lengthening velocity during landing occurred independently from tendon strain. Future studies are required to provide insight into the mechanisms underpinning these observations and their influence on energy dissipation. PMID- 29997528 TI - Comparison of the Factor Structure of the Patient Health Questionnaire for Somatic Symptoms (PHQ-15) in Germany, the Netherlands, and China. A Transcultural Structural Equation Modeling (SEM) Study. AB - Background: Persistent somatic symptoms are associated with psychological distress, impaired function, and medical help-seeking behavior. The Patient Health Questionnaire (PHQ)-15 is used as a screening instrument for somatization and as a monitoring instrument for somatic symptom severity. A bifactorial model has been described, with one general factor and four orthogonal specific symptom factors. The objective of the present study was to assess and to clarify the factor structure of the PHQ-15 within and between different countries in Western Europe and China. Method: Cross-sectional secondary data analysis performed in three patient data samples from two Western European countries (Germany N = 2,517, the Netherlands N = 456) and from China (N = 1,329). Confirmatory factor analyses (CFA), and structural equation modeling (SEM) analysis were performed. Results: The general factor is found in every sample. However, although the outcomes of the PHQ-15 estimate severity of somatic symptoms in different facets, these subscales may have different meanings in the European and Chinese setting. Replication of the factorial structure was possible in the German and Dutch datasets but not in the dataset from China. For the Chinese dataset, a bifactorial model with a different structure for the cardiopulmonary factor is suggested. The PHQ-15 could discern somatization from anxiety and depression within the three samples. Conclusion: The PHQ-15 is a valid questionnaire that can discern somatization from anxiety and depression within different cultures like Europe or China. It can be fitted to a bifactorial model for categorical data, however, the model can only be recommended for use of the general factor. Application of the orthogonal subscales in non-European samples is not corroborated by the results. The differences cannot be ascribed to differences in health care settings or by differences in concomitant depression or anxiety but instead, a cultural factor involving concepts of disease may play a role in this as they may play a role in the translation of the questionnaire. Further research is needed to explore this, and replication studies are needed regarding the factorial structure of the PHQ-15 in China. PMID- 29997529 TI - Aggression and Harm-Avoidant Trait Impede Recovery From Internet Gaming Disorder. AB - Background: Relatively little is known about which neuropsychological factors promote recovery from Internet gaming disorder (IGD). Methods: With informed consents, a cohort study was conducted in Seoul metropolitan area, South Korea, to investigate the course of IGD in youths. At baseline, we assessed psychosocial measures and gaming related measures such as Young's Internet Addiction Test (IAT) and the Aggression Questionnaire. The Balloon Analog Risk Task was also performed to study risk-taking behavior. A total of 60 subjects demonstrating three or greater criteria in the diagnostic interviews on IGD and the IAT score of 50 or above were included. After brief parental coaching at baseline, the participants were followed up at 3 and 6 months (n = 31). The baseline characteristics were compared between the non-improved group (<10% improvement in IAT score) and the improved group (>=30% improvement in IAT score) using Mann Whitney U-test or chi-squared tests with a two-tailed statistical significance of 0.05. Results: The non-improved group and the improved group did not demonstrate significant differences regarding demographics or the IAT scores at baseline. However, the IAT scores were significantly higher in the non-improved group at both 3 and 6 months. The non-improved group was also more likely to display higher aggression and harm avoidance than the improved group at baseline. Discussion: Youths with excessive gaming problems should be evaluated for aggression and harm avoidance since they contributed to a worse prognosis. For those with high aggression or harm avoidance, more active therapeutic interventions should be considered. PMID- 29997527 TI - Prevalence and Associated Features of Anxiety Disorder Comorbidity in Bipolar Disorder: A Meta-Analysis and Meta-Regression Study. AB - Objective: Bipolar disorder is highly comorbid with anxiety disorders, however current and lifetime comorbidity patterns of each anxiety disorder and their associated features are not well studied. Here, we aimed to conduct a meta analysis and meta-regression study of current evidence. Method: We searched PubMed to access relevant articles published until September 2015, using the keywords "Bipolar disorder" or "Affective Psychosis" or "manic depressive" separately with "generalized anxiety," "panic disorder," "social phobia," "obsessive compulsive," and "anxiety." Variables for associated features and prevalence of anxiety disorders were carefully extracted. Results: Lifetime any anxiety disorder comorbidity in BD was 40.5%; panic disorder (PD) 18.1%, generalized anxiety disorder (GAD) 13.3%, social anxiety disorder (SAD) 13.5% and obsessive compulsive disorder (OCD) 9.7%. Current any anxiety disorder comorbidity in BD is 38.2%; GAD is 15.2%, PD 13.3%, SAD 11.7%, and OCD 9.9%. When studies reporting data about comorbidities in BDI or BDII were analyzed separately, lifetime any anxiety disorder comorbidity in BDI and BDII were 38% and 34%, PD was 15% and 15%, GAD was 14% and 16.6%, SAD was 8% and 13%, OCD was 8% and 10%, respectively. Current any DSM anxiety disorder comorbidity in BDI or BDII were 31% and 37%, PD was 9% and 13%, GAD was 8% and 12%, SAD was 7% and 11%, and OCD was 8% and 7%, respectively. The percentage of manic patients and age of onset of BD tended to have a significant impact on anxiety disorders. Percentage of BD I patients significantly decreased the prevalence of panic disorder and social anxiety disorder. A higher rate of substance use disorder was associated with greater BD-SAD comorbidity. History of psychotic features significantly affected current PD and GAD. Conclusions: Anxiety disorder comorbidity is high in BD with somewhat lower rates in BDI vs BDII. Age of onset, substance use disorders, and percentage of patients in a manic episode or with psychotic features influences anxiety disorder comorbidity. PMID- 29997531 TI - Deterioration in Global Organization of Structural Brain Networks in Schizophrenia: A Diffusion MRI Tractography Study. AB - Schizophrenia is a heterogenous neuropsychiatric disorder with varying degrees of altered connectivity in a wide range of brain areas. Network analysis using graph theory allows researchers to integrate and quantify relationships between widespread changes in a network system. This study examined the organization of brain structural networks by applying diffusion MRI, probabilistic tractography, and network analysis to 48 schizophrenia patients and 24 healthy controls. T1 weighted MR images obtained from all participants were parcellated into 87 regions of interests (ROIs) according to a prior anatomical template and registered to diffusion-weighted images (DWI) of the same subjects. Probabilistic tractography was performed to obtain sets of white matter tracts between any two ROIs and determine the connection probabilities between them. Connectivity matrices were constructed using these estimated connectivity probabilities, and several network properties related to network effectiveness were calculated. Global efficiency, local efficiency, clustering coefficient, and mean connectivity strength were significantly lower in schizophrenia patients (p = 0.042, p = 0.011, p = 0.013, p = 0.046). Mean betweenness centrality was significantly higher in schizophrenia (p = 0.041). Comparisons of node wise properties showed trends toward differences in several brain regions. Nodal local efficiency was consistently lower in the basal ganglia, frontal, temporal, cingulate, diencephalon, and precuneus regions in the schizophrenia group. Inter group differences in nodal degree and nodal betweenness centrality varied by region and showed inconsistent results. Robustness was not significantly different between the study groups. Significant positive correlations were found between t-score of color trails test part-1 and local efficiency and mean connectivity strength in the patient group. The findings of this study suggest that schizophrenia results in deterioration of the global network organization of the brain and reduced ability for information processing. PMID- 29997530 TI - Plasticity and Susceptibility of Brain Morphometry Alterations to Insufficient Sleep. AB - : Background: Insufficient sleep is common in daily life and can lead to cognitive impairment. Sleep disturbance also exists in neuropsychiatric diseases. However, whether and how acute and chronic sleep loss affect brain morphology remain largely unknown. Methods: We used voxel-based morphology method to study the brain structural changes during sleep deprivation (SD) at six time points of rested wakefulness, 20, 24, 32, 36 h SD, and after one night sleep in 22 healthy subjects, and in 39 patients with chronic primary insomnia relative to 39 status matched good sleepers. Attention network and spatial memory tests were performed at each SD time point in the SD Procedure. The longitudinal data were analyzed using one-way repeated measures ANOVA, and post-hoc analysis was used to determine the between-group differences. Results: Acute SD is associated with widespread gray matter volume (GMV) changes in the thalamus, cerebellum, insula and parietal cortex. Insomnia is associated with increased GMV in temporal cortex, insula and cerebellum. Acute SD is associated with brain atrophy and as SD hours prolong more areas show reduced GMV, and after one night sleep the brain atrophy is restored and replaced by increased GMV in brain areas. SD has accumulative negative effects on attention and working memory. Conclusions: Acute SD and insomnia exhibit distinct morphological changes of GMV. SD has accumulative negative effects on brain morphology and advanced cognitive function. The altered GMV may provide neurobiological basis for attention and memory impairments following sleep loss. Statement of significance: Sleep is less frequently studied using imaging techniques than neurological and psychiatric disorders. Whether and how acute and chronic sleep loss affect brain morphology remain largely unknown. We used voxel-based morphology method to study brain structural changes in healthy subjects over multiple time points during sleep deprivation (SD) status and in patients with chronic insomnia. We found that prolonged acute SD together with one night sleep recovery exhibits accumulative atrophic effect and recovering plasticity on brain morphology, in line with behavioral changes on attentional tasks. Furthermore, acute SD and chronic insomnia exhibit distinct morphological changes of gray matter volume (GMV) but they also share overlapping GMV changes. The altered GMV may provide structural basis for attention and memory impairments following sleep loss. PMID- 29997532 TI - Aberrant Dynamic Connectivity for Fear Processing in Anorexia Nervosa and Body Dysmorphic Disorder. AB - Anorexia nervosa (AN) and body dysmorphic disorder (BDD) share distorted perceptions of appearance with extreme negative emotion, yet the neural phenotypes of emotion processing remain underexplored in them, and they have never been directly compared. We sought to determine if shared and disorder specific fronto-limbic connectivity patterns characterize these disorders. FMRI data was obtained from three unmedicated groups: BDD (n = 32), weight-restored AN (n = 25), and healthy controls (HC; n = 37), while they viewed fearful faces and rated their own degree of fearfulness in response. We performed dynamic effective connectivity modeling with medial prefrontal cortex (mPFC), rostral anterior cingulate cortex (rACC), and amygdala as regions-of-interest (ROI), and assessed associations between connectivity and clinical variables. HCs exhibited significant within-group bidirectional mPFC-amygdala connectivity, which increased across the blocks, whereas BDD participants exhibited only significant mPFC-to-amygdala connectivity (P < 0.05, family-wise error corrected). In contrast, participants with AN lacked significant prefrontal-amygdala connectivity in either direction. AN showed significantly weaker mPFC-to-amygdala connectivity compared to HCs (P = 0.0015) and BDD (P = 0.0050). The mPFC-to amygdala connectivity was associated with greater subjective fear ratings (R2 = 0.11, P = 0.0016), eating disorder symptoms (R2 = 0.33, P = 0.0029), and anxiety (R2 = 0.29, P = 0.0055) intensity scores. Our findings, which suggest a complex nosological relationship, have implications for understanding emotion regulation circuitry in these related psychiatric disorders, and may have relevance for current and novel therapeutic approaches. PMID- 29997533 TI - Association of Depression and Anxiety With the 10-Year Risk of Cardiovascular Mortality in a Primary Care Population of Latvia Using the SCORE System. AB - Background: Depression and anxiety have been recognized as independent risk factors for both the development and prognosis of cardiovascular (CV) diseases (CVD). The Systematic Coronary Risk Evaluation (SCORE) function measures the 10 year risk of a fatal CVD and is a crucial tool for guiding CV patient management. This study is the first in Latvia to investigate the association of depression and anxiety with the 10-year CV mortality risk in a primary care population. Methods: This cross-sectional study was conducted at 24 primary care facilities. During a 1-week period in 2015, all consecutive adult patients were invited to complete a nine-item Patient Health Questionnaire (PHQ-9) and a seven-item Generalized Anxiety Disorder scale (GAD-7) followed by sociodemographic questionnaire and physical measurements. The diagnostic Mini International Neuropsychiatric Interview (M.I.N.I.) was administered by telephone in the period of 2 weeks after the first contact at the primary care facility. A hierarchical multivariate analysis was performed. Results: The study population consisted of 1,569 subjects. Depressive symptoms (PHQ-9 >=10) were associated with a 1.57 (95% confidence interval (CI): 1.06-2.33) times higher odds of a very high CV mortality risk (SCORE >=10%), but current anxiety disorder (M.I.N.I.) reduced the CV mortality risk with an odds ratio of 0.58 (95% CI: 0.38-0.90). Conclusions: Our findings suggest that individuals with SCORE >=10% should be screened and treated for depression to potentially delay the development and improve the prognosis of CVD. Anxiety could possibly have a protective influence on CV prognosis. PMID- 29997534 TI - Enhanced Topological Network Efficiency in Preschool Autism Spectrum Disorder: A Diffusion Tensor Imaging Study. AB - Background: The functional mechanism behind autism spectrum disorder (ASD) is not clear, but it is related to a brain connectivity disorder. Previous studies have found that functional brain connectivity of ASD is linked to both increased connections and weakened connections, and the inconsistencies in functional brain connectivity may be related to age. The functional connectivity in adolescents and adults with ASD is generally less than in age-matched controls; functional connectivity in younger children with the disorder appears to be higher. As the basis of the functional network, the structural network is less studied. This study intends to further study the pathogenesis of ASD by analyzing the white matter network of ASD preschool children. Materials and Methods: In this study, Diffusion Tensor Imaging (DTI) was used to scan preschool children (aged 2-6 years, 39 children with ASD, 19 children as controls), and graph theory was used for analysis. Result: Enhanced topological network efficiency was found in the preschool children with ASD. A higher nodal efficiency was found in the left precuneus, thalamus, and bilateral superior parietal cortex, and the nodal efficiency of the left precuneus was positively associated with the severity of ASD. Conclusion: Our research shows the white matter network efficiency of preschoolers with ASD. It supports the theory of excessive early brain growth in ASD, and it shows left brain lateralization. It opens the way for new research perspectives of children with ASD. PMID- 29997536 TI - The 'Real Without Law' in Psychoanalysis and Neurosciences. AB - In this article, we will examine some of Lacan's concepts on the relation between psychoanalysis and science. The difference that Lacan states between the real for science, which would be entirely governed by laws, and the real for psychoanalysis - a 'real without law' - risk to lead to an irreducible separation between the two fields. However, as the article shows, that separation between psychoanalysis and science is not the position defended by Freud and Lacan. Indeed the latest discoveries in the field of neurosciences challenge the traditional conception of the real for science, bringing it closer to the real 'without law' that characterizes psychoanalysis. Conceiving the real for science as a real that is opened to contingencies and not entirely governed by laws, is the first necessary step for a new alliance between psychoanalysis and science. PMID- 29997535 TI - Non-medical Cannabis Self-Exposure as a Dimensional Predictor of Opioid Dependence Diagnosis: A Propensity Score Matched Analysis. AB - Background: The impact of increasing non-medical cannabis use on vulnerability to develop opioid use disorders has received considerable attention, with contrasting findings. A dimensional analysis of self-exposure to cannabis and other drugs, in individuals with and without opioid dependence (OD) diagnoses, may clarify this issue. Objective: To examine the age of onset of maximal self exposure to cannabis, alcohol, cocaine, and heroin, in volunteers diagnosed with OD, using a rapidly administered instrument (the KMSK scales). To then determine whether maximal self-exposure to cannabis, alcohol, and cocaine is a dimensional predictor of odds of OD diagnoses. Methods: This outpatient observational study examined maximal self-exposure to these drugs, in volunteers diagnosed with DSM IV OD or other drug diagnoses, and normal volunteers. In order to focus more directly on opioid dependence diagnosis as the outcome, volunteers who had cocaine dependence diagnoses were excluded. Male and female adults of diverse ethnicity were consecutively ascertained from the community, and from local drug treatment programs, in 2002-2013 (n = 574, of whom n = 94 had OD diagnoses). The age of onset of maximal self-exposure of these drugs was examined. After propensity score matching for age at ascertainment, gender, and ethnicity, a multiple logistic regression examined how increasing self-exposure to non-medical cannabis, alcohol and cocaine affected odds of OD diagnoses. Results: Volunteers with OD diagnoses had the onset of heaviest use of cannabis in the approximate transition between adolescence and adulthood (mean age = 18.9 years), and onset of heaviest use of alcohol soon thereafter (mean age = 20.1 years). Onset of heaviest use of heroin and cocaine was detected later in the lifespan (mean ages = 24.7 and 25.3 years, respectively). After propensity score matching for demographic variables, we found that the maximal self-exposure to cannabis and cocaine, but not to alcohol, was greater in volunteers with OD diagnoses, than in those without this diagnosis. Also, a multiple logistic regression detected that increasing self-exposure to cannabis and cocaine, but not alcohol, was a positive predictor of OD diagnosis. Conclusions/Importance: Increasing self-exposure to non-medical cannabis, as measured with a rapid dimensional instrument, was a predictor of greater odds of opioid dependence diagnosis, in propensity score matched samples. PMID- 29997537 TI - Disconnected - Impaired Interoceptive Accuracy and Its Association With Self Perception and Cardiac Vagal Tone in Patients With Dissociative Disorder. AB - Patients suffering from dissociative disorders are characterized by an avoidance of aversive stimuli. This includes the avoidance of emotions and, in particular, bodily perceptions. In the present pilot study, we explored the potential interoceptive accuracy deficit of patients suffering from dissociative disorders in a heartbeat detection task. Moreover, we investigated the impact of facial mirror-confrontation on interoceptive accuracy and the potential association between cardiac vagal tone derived from heart rate variability and interoceptive accuracy. Eighteen patients suffering from dissociative disorders and 18 healthy controls were assessed with the Mental Tracking Paradigm by Schandry for heartbeat detection at baseline and after confrontations exposing them to their own faces in a mirror (2 min each, accompanied by a negative or positive cognition). During the experiment, cardiac vagal tone was assessed. We used Pearson correlations to calculate potential associations between cardiac vagal tone and interoceptive accuracy. Patients performed significantly worse than the healthy controls in the heartbeat detection task at baseline. They displayed no significant increase in interoceptive accuracy following facial mirror confrontation. In the patient group, higher cardiac vagal tone was associated with a more precise heartbeat detection performance. Dissociative disorder patients showed a considerable deficit in interoceptive accuracy. Our results fit with the assumption that highly dissociative patients tend to tune out the perceiving of bodily signals. To the extent that bodily signal perception may play a causal role in these disorders, therapeutic approaches enhancing interoceptive accuracy and cardiac vagal tone may be considered important and practicable steps to improve the therapy outcome of this patient group. PMID- 29997538 TI - Contrast Sensitivity Is a Significant Predictor of Performance in Rifle Shooting for Athletes With Vision Impairment. AB - Purpose: In order to develop an evidence-based, sport-specific minimum impairment criteria (MIC) for the sport of vision-impaired (VI) shooting, this study aimed to determine the relative influence of losses in visual acuity (VA) and contrast sensitivity (CS) on shooting performance. Presently, VA but not CS is used to determine eligibility to compete in VI shooting. Methods: Elite able-sighted athletes (n = 27) shot under standard conditions with their habitual vision, and with their vision impaired by the use of simulation spectacles (filters which reduce both VA and CS) and refractive blur (lenses which reduce VA with less effect on CS). Habitual shooting scores were used to establish a cut-off in order to determine when shooting performance was 'below expected' in the presence of vision impairment. Logistic regression and decision tree analyses were then used to assess the relationship between visual function and shooting performance. Results: Mild reductions in VA and/or CS did not alter shooting performance, with greater reductions required for shooting performance to fall below habitual levels (below 87% of normalized performance). Stepwise logistic regression selected CS as the most significant predictor of shooting performance, with VA subsequently improving the validity of the model. In an unconstrained decision tree analysis, CS was selected as the sole criterion (80%) for predicting 'below expected' shooting score. Conclusion: Shooting performance is better predicted by losses in CS than by VA. Given that it is not presently tested during classification, the results suggest that CS is an important measure to include in testing for the classification of vision impairment for athletes competing in VI shooting. PMID- 29997539 TI - Background Odors Modulate N170 ERP Component and Perception of Emotional Facial Stimuli. AB - Successful social interaction relies on the accurate decoding of other peoples' emotional signals, and their contextual integration. However, little is known about how contextual odors may lead to modulation of cortical processing in response to facial expressions. We investigated how unpleasant and pleasant contextual background odors affected emotion perception and cortical event related potential (ERP) responses to pictures of faces expressing happy, neutral and disgusted facial expressions. Faces were, regardless of expression, rated more positively in the pleasant odor condition and more negatively in the unpleasant odor condition. Faces were overall rated as more emotionally arousing in the presence of an odor, irrespective of its valence. Contextual odors also interacted with facial expressions, such that happy faces were rated as especially non-arousing in the unpleasant odor condition. The early, face sensitive N170 ERP component also displayed an interaction effect. Here, disgusted faces were affected by the odor context such that the N170 revealed a relatively larger negativity in the context of a pleasant odor compared with an unpleasant odor. There were no odor effects on the responses to faces in other measured ERP components (P1, VPP, P2, and LPP). These results suggest that odors bias socioemotional perception early stages of the visual processing stream. However, effects may vary across emotional expressions and measurements. PMID- 29997540 TI - Study Protocol of Sleep Education Tool for Children: Serious Game "Perfect Bedroom: Learn to Sleep Well". AB - Promoting a healthy sleep is a big challenge and becomes a strategic priority in public health, due to the severe consequences on children's development and risk to psychiatric diseases. Interventions that promote healthy sleep, such as those that focus on the dissemination of behavioral and environmental recommendations of sleep hygiene with children, are presented as an alternative. Serious game design offers wide-reaching domains in health applications and is increasing in popularity, particularly with children and teens because of it's potential to engage and motivate players differently from other interventions. This study aims to evaluate effects of serious game on sleep hygiene recommendations "Perfect Bedroom: learn to sleep well," on sleep habits and sleep parameters of healthy children. This is an experimental, prospective and quantitative study. We will randomize children in experimental (n = 88) and no intervention groups (n = 88). The experiment has four stages (pre-intervention, intervention, post intervention, and follow-up), which will count with participation of children and their parents/guardians. In the evaluation stages, the guardians will answer questionnaires and scales to assess sociodemographic and health data, sleep habits and sleep pattern of their child. The children themselves will answer the following: a scale to assess sleepiness levels, a questionnaire to evaluate the serious game and the game itself, will characterize their bedroom and the activities they perform before sleep, with strategies developed by researches. Intervention with experimental group conducted with the serious game "Perfect Bedroom" will happen twice a week, for 3 weeks in a row, resulting in six sessions of 50 min each. Inferential analysis will be conducted for comparisons between groups and intragroups to measure effect of intervention in primary outcomes (sleep habits) and secondary outcomes (sleep parameters). We expect that the intervention with this game can provide valuable evidence to a new approach in promoting healthy sleep habits, with applications in clinical, educational, and familiar settings, which could diminish future health issues and risk at psychiatric diseases, decreasing the social burden of treatments for these conditions in children. PMID- 29997542 TI - Strategic Processing of Chinese Young English Language Learners in an International Standardized English Language Test. AB - Strategic competence is acknowledged to be able to explain variations in language test performance. Research with adult language test-takers has shown that strategic competence has dual components: strategic knowledge and strategic processing. Of the two components, strategic processing, which is state-like, unstable, and tends to fluctuate from contexts to contexts, is more closely related to language test performance. To date, none of the existing studies investigates strategic processing with children English language learners (ELLs) and explores the relationship between strategic processing in all the four skills of language learning and the test performance. Addressing these gaps, the current study examined the nature of strategic processing in listening, reading and writing, and speaking of 138 Chinese young ELLs in an international standardized English language test - Cambridge Young Learners English Tests - Flyers test. The three questionnaires regarding strategic processing were administered to the participants immediately following the completion of the test. The confirmatory factor analyses verified that the strategic processing construct in the four skills comprised of a cognitive and a metacognitive dimensions, which resembles the strategic processing of the adult language test-takers. The participants adopted significantly more metacognitive than cognitive strategies consistently in the three sections of the test, possibly due to the status of the test. Both cognitive and metacognitive strategic processing were moderately related to the test performance, explaining from 7 to 31% of the variance in the total shields of the test. Across the four skills, high-performing test-takers used both cognitive and metacognitive strategies more frequently than the moderate- and low performing test-takers, even though whether such differences were due to their richer strategic knowledge or processing skills was unknown. The study contributes to strategic processing in language testing literature and also provides practical implications for English trainers of the young ELLs in China. PMID- 29997543 TI - Parental Burnout: When Exhausted Mothers Open Up. AB - Until recently, research conducted on parental exhaustion was exclusively concerned with parents of sick children. However, situations where exhaustion occurs as a result of being physically and emotionally overwhelmed by one's parental role in the absence of a child's condition is gaining increasing interest. The aim of our study was to give voice to exhausted mothers, in order to get a better understanding of what it means to be exhausted in relation with one's parental role, from the perspective of those who have experienced it. We referred to phenomenological interpretative analysis for methods of data collection and data analysis, and included five mothers who were each interviewed twice. Our analysis revealed a superordinate theme of fear, which was central in every aspect of the mothers' accounts of their experiences, from the fear to not be a good enough mother to the fear related to unlearning control and experiencing discontinuity of one's sense of self. Our results call for the development of specific interventions to prevent, anticipate, or treat the phenomenon of exhaustion in parents, so as to help them and their children cope better with these situations of extreme vulnerability, which are often reinforced by senses of guilt, shame, and loneliness. PMID- 29997541 TI - Motivational Influences on Performance Monitoring and Cognitive Control Across the Adult Lifespan. AB - Cognitive control refers to the ability to regulate cognitive processing according to the tasks at hand, especially when these are demanding. It includes maintaining and updating relevant information in working memory, inhibiting irrelevant information, and flexibly switching between tasks. Performance monitoring denotes the processing of feedback from the environment and the detection of errors or other unexpected events and signals when cognitive control needs to be exerted. These two aspects of behavioral adaptation critically rely on the integrity of the frontal lobes, which are known to show pronounced age related performance decrements. By contrast, there is evidence that processing of rewards remains relatively intact across the adult lifespan. Hence, motivation may play an important role in modulating or even counteracting age-related changes in cognitive control functions. To answer this question, neuroscientific data can be particularly useful to uncover potential underlying mechanisms beyond behavioral outcome. The aims of this article are twofold: First, to review and systematize the extant literature on how motivational incentives can modulate performance monitoring and cognitive control in young and older adults. Second, to demonstrate that important pieces of empirical data are currently missing for the evaluation of this central question, specifically in old age. Hence, we would like to stimulate further research uncovering potential mechanisms underlying motivation-cognition interactions in young and in particular in older adults and investigating whether or not those can help to ameliorate age-related impairments. PMID- 29997544 TI - Metaphor in Sign Languages. AB - Metaphor abounds in both sign and spoken languages. However, in sign languages, languages in the visual-manual modality, metaphors work a bit differently than they do in spoken languages. In this paper we explore some of the ways in which metaphors in sign languages differ from metaphors in spoken languages. We address three differences: (a) Some metaphors are very common in spoken languages yet are infelicitous in sign languages; (b) Body-part terms are possible in very specific types of metaphors in sign languages, but are not so restricted in spoken languages; (c) Similes in some sign languages are dispreferred in predicative positions in which metaphors are fine, in contrast to spoken languages where both can appear in these environments. We argue that these differences can be explained by two seemingly unrelated principles: the Double Mapping Constraint (Meir, 2010), which accounts for the interaction between metaphor and iconicity in languages, and Croft's (2003) constraint regarding the autonomy and dependency of elements in metaphorical constructions. We further argue that the study of metaphor in the signed modality offers novel insights concerning the nature of metaphor in general, and the role of figurative speech in language. PMID- 29997545 TI - Can Emotional Competence Be Taught in Higher Education? A Randomized Experimental Study of an Emotional Intelligence Training Program Using a Multimethodological Approach. AB - Since the introduction of the Bologna Process, the goal of education has been not only to acquire technical skills but also to master other skills, such as teamwork, effective communication skills, time optimization, and the ability to manage one's emotions. The present work describes a program to develop emotional intelligence in higher education, the "Emotional Intelligence Training Program," with a multimethodological approach that offers the opportunity for university students to develop their emotional intelligence. A total of 192 higher education students participated in this educational experience. Of the participants, 66% were women, and 34% were men; the average age of the sample was 18.83 years with a standard deviation of 2.73. The results indicate that our program can help improve emotional intelligence through three proposed methodologies: online, in the classroom, and coaching. It has been demonstrated that the program is effective in the three methodological modalities presented, offering a range of possibilities to future users because it is possible to select the most appropriate modality based on the resources and possibilities available in each situation. Finally, Future research should focus on the application of this program to assess the acquisition of emotional competences at the postgraduate level. PMID- 29997546 TI - The Bergen 4-Day Treatment for Panic Disorder: A Pilot Study. AB - The current article reports on the findings from a pilot treatment study on panic disorder (PD) with or without agoraphobia. Consecutively referred patients were included and treated with the Bergen 4-day treatment format. Twenty-nine patients were included, primarily from unsuccessful treatment courses in the Norwegian specialist mental health care system, either ongoing or previously. Prior to treatment, only 34% were able to work but at 3-month follow-up 93% were able to do so. The proportion achieving reliable change on the panic severity measure was 76% post-treatment and 90% at follow-up. The remission rate was 72% at both assessments. These effects are significantly higher than those reported for six standard CBT studies in the literature using the same primary outcome measure (Panic Disorder Severity Scale). It is concluded that the Bergen 4-day treatment is a promising treatment approach for PD, and a randomized controlled trial is warranted. PMID- 29997547 TI - GraphoLearn India: The Effectiveness of a Computer-Assisted Reading Intervention in Supporting Struggling Readers of English. AB - India, a country with a population of more than 1.3 billion individuals, houses the world's second largest educational system. Despite this, 100 of millions of individuals in India are still illiterate. As English medium education sweeps the country, many are forced to learn in a language which is foreign to them. Those living in poverty further struggle to learn English as it tends to be a language which they have no prior exposure to and no support at home for. Low-quality schools and poor instructional methods further exacerbate the problem. Without access to quality education, these individuals continue to struggle and are ultimately never given the chance to break the cycle of poverty. The aim of this study was to determine whether GraphoLearn, a computer-assisted reading tool, could be used to support the English reading skills of struggling readers in India. Participants were 7-year-old, grade 3 students (N = 30), who were attending an English-medium public school in Ahmedabad, India. English was not a native language for any of the students and all were reading at a level below that of Grade 1 despite having attended school for 2 years. Half of the students played GraphoLearn (n = 16) while the other half played a control math game (n = 14) for 20-30 min a day, over a period of 8 weeks. GraphoLearn led to significant improvements in children's letter-sound knowledge, a critical factor in early reading development. Overall, the study opens doors for GraphoLearn as a potential intervention to support struggling readers of English in India, including those who are learning a non-native language and coming from at-risk backgrounds. PMID- 29997548 TI - Examining the Deviation From Balanced Time Perspective in the Dark Triad Throughout Adulthood. AB - Individuals who score high on Dark Triad (DT) personality traits (i.e., Machiavellianism, subclinical narcissism and subclinical psychopathy) have been found to prefer a fast life strategy with enhanced motivation for immediate resource acquisition and short-term benefits. In line with these points, recent studies have found evidence showing that DT traits are associated with a biased, strongly present-oriented time perspective. In the current study, we aimed to examine whether the temporal attitude of individuals high in DT is deviant from a balanced time perspective (BTP) to a significant extent. To achieve this aim, we applied two operationalizations published in earlier studies to quantify BTP: the Deviation from Balanced Time Perspective coefficient (DBTP), calculated as the difference between individuals' time perception and the optimal time perspective, as well as the person-oriented approach of identifying groups of individuals with similar time perception. Importantly, the age of participants (N = 346) covered a long and continuous period of adulthood-from the young adulthood to the elderly in order to examine the moderating effect of age on the association of DT and BTP. Machiavellianism and psychopathy were both found to be clearly deviant from a BTP. In contrast, higher scores on narcissism were positively associated with a BTP profile. The DBTP analysis, however, suggested that this beneficial effect of narcissism was only prevalent among the elderly individuals. PMID- 29997549 TI - Social Facilitation of Laughter and Smiles in Preschool Children. AB - Surprisingly little is known about the social dimensions of laughter in preschool children. We studied children's responses to amusing video clips in the presence or absence of peers. The sample consisted of 9 boys and 11 girls aged 31-49 months (M 39.8, SD 4.2) who watched three cartoons under three different conditions: individually, in pairs, or in groups of 6 or 8. The social viewing conditions showed significantly higher numbers of laughs and smiles than the individual viewing condition. On average children laughed eight times as much in company as on their own and smiled almost three times as much. No differences were found between pairs and groups, and no association was found between subjective funniness ratings and group size. This suggests that the presence of even a single social partner can change behavior in response to humorous material. It supports the idea that laughter and smiles are primarily flexible social signals rather than reflexive responses to humor. PMID- 29997550 TI - Preliminary Empirical Validation of the "Basic Needs Satisfaction in Sport Scale" With a Sample of Spanish Athletes. AB - The theory of self-determination establishes the existence of three basic psychological needs (autonomy, competence, and relationship). If these needs are satisfied, optimal personal well-being will be achieved. The Basic Needs Satisfactions in Sport Scale (BNSSS) is a measurement developed to evaluate these needs within the sporting context. The BNSSS measures the satisfaction of the three basic psychological needs through 20 items distributed in five dimensions: autonomy-choice, autonomy-volition, autonomy-perceived locus of internal causality, competence, and relatedness. The purpose of this study is to validate a Spanish version of the BNSSS. The sample were 441 team athletes with a mean age of 17.46 (SD = 3.59), which 46.5% were men and the remaining percentage (53.5%) were women. After a standardised data collection, confirmatory factor analysis and invariance analyses were performed, as well as composite reliability. The obtained version showed a good overall fit of the model and values of composite reliability higher to 0.70. Therefore, a useful tool for assessing basic psychological needs in team sports was obtained. PMID- 29997551 TI - What Do Spatial Distortions in Patients' Drawing After Right Brain Damage Teach Us About Space Representation in Art? AB - The right cerebral hemisphere plays a crucial rule in spatial cognition, spanning from perception of elementary features, such as location, color, line orientation or shape to representation of different spaces (3D space, allocentric, egocentric, face, personal, peri-personal, or imaginal). One important aspect of its contribution concerns the perception of space symmetry and the representation of objects and scenes, with reference to the midline or body axis. This representation results from a balance between spatial attention processes depending from the two hemispheres. Healthy participants tend to show a discrete deviation of the midline plane representation toward the left side, that is likely to result from the predominance of the activity of the right cerebral hemisphere, mainly oriented toward the contralateral side of space. The visuospatial abilities of the right hemisphere, especially for the representation of the midline plane are crucially engaged in painting and drawing processes in artists. Interestingly, the distortions created by painters of the Cubism period, characterized by an asymmetry of objects and body representations, a specific enlargement or reduction of parts of space, or even by complex distortions of 3D space are analogous to those classically reported in right-brain-damaged patients (unilateral spatial neglect, hyperschematia, constructional apraxia). Understanding the pathological mechanisms of these representation disorders provides meaningful information to apprehend visual artist creations and esthetic perception of space. PMID- 29997552 TI - Psychometric Properties of a Short Version of the Impulsiveness Questionnaire UPPS-P in a Brazilian Adult Sample: Invariance for Effects of Age, Sex and Socioeconomic Status and Subscales Viability. AB - Five different facets or domains of impulsivity (lack of Perseverance, lack of Premeditation, Sensation Seeking, Positive and Negative Urgency) have been detected in undergraduate students by means of a short, 20-item version of the Impulsive Behavior Scale UPPS-P. The present cross-sectional study examined the psychometric properties of a Brazilian version of this short scale (SUPPS-P) in a non-clinical sample of 510 individuals with a larger age range (10-72 years) and from varying socioeconomic strata (SES). We also investigated: (a) differential item functioning according to age, sex and socioeconomic status; (b) whether these demographic factors affected participants' responses (population heterogeneity); and (c) if using scores directly derived from respondents' answers (raw scores) reflected the 5 distinguishable impulsiveness domains out of the structural equation modeling environment (bifactor model). We showed that the short UPPS-P version replicated factor structures, internal consistency across domains and inter-scale correlations found in prior studies, and confirmed the psychometric separability of the 5 impulsiveness domains. Only three out of the 20 items showed differential item functioning. Higher Positive and Negative Urgency and lack of Premeditation were reported by men and impulsiveness decreases with age in all domains except lack of Premeditation. SES did not influence results. The viability of using raw scores to assess the five domains was not confirmed via bifactor modeling. The use of a general composite score was psychometrically acceptable. We conclude that, in the structural equation modeling environment, the SUPPS-P is a reliable instrument to assess multiple impulsivity domains in non-clinical community samples in different cultural settings. However, out of this statistical environment, viability was only found for a general factor of impulsivity. PMID- 29997553 TI - A Multivariate Generalizability Theory Approach to College Students' Evaluation of Teaching. AB - Teachers' teaching level evaluation is an important component in classroom teaching and professional promotion in the institutions of higher learning in China. Many self-made questionnaires are currently being administered to Chinese college students to evaluate teachers' classroom teaching performance. Quite often, due to the absence of strong educational, and psychological measurements and theoretical foundations for these questionnaires, their dependability remains open to doubt. Evaluation time points, the number of students, major type, and curriculum type were examined in relation to college students' perceptions on their teachers' classroom teaching performance, using Teachers' Teaching Level Evaluation Scale for Colleges (TTLES-C). Data were collected in a sample of 556 students at two time points from three Chinese universities and were analyzed using multivariate generalizability theory. Results showed that evaluations at the beginning of the spring semester produced better outcomes than did evaluations at the end of the fall semester, and 20 student evaluators were sufficient to ensure good dependability. Results also revealed that the evaluation dependability of science curriculum appeared higher than that of liberal arts curriculum. Recommendations were discussed on the evaluation criteria and mode. PMID- 29997554 TI - Authenticity as a Mediator of the Relationship Between Power Contingent Self Esteem and Subjective Well-Being. AB - Drawing on Eastern wisdom and Self-Determination Theory (Deci and Ryan, 1995), the current study conceptualized a new form of maladaptive self-esteem, the power contingent self-esteem, which is extremely contingent on one's sense of power, and posits it is related to low subjective well-being by making people experience less authenticity. In Study 1, we found that general power contingent self-esteem was consistently linked to low subjective well-being. More importantly, the negative relationship between power contingent self-esteem and subjective well being was mediated by authenticity. Study 2 further confirmed the mediation effect between power contingent self-esteem role and satisfaction through authenticity across four different roles (work, romance, friendship, and parent child relationships). The finding of the negative relationship between power contingent self-esteem and subjective well-being via authenticity contributes to understanding the complicated association between power, self-esteem, and life satisfaction. PMID- 29997555 TI - Social Comparison Orientation and Social Adaptation Among Young Chinese Adolescents: The Mediating Role of Academic Self-Concept. AB - This study aimed to investigate the relationship among social comparison orientation, academic self-concept (ASC), and social adaptation. A total of 1658 Chinese adolescents (48.88% male; aged 14-18 years, Mage = 16.01 +/- 0.86 years) voluntarily participated in this study and completed questionnaires. Structural equation modeling (SEM) was performed to test the theory-driven model. The results showed that the relationship between comparison of opinion and social adaptation was mediated by ASC but that ASC did not play a mediating role between comparison of ability and social adaptation. These findings indicated that ASC could be one mechanism explaining the link between adolescents' social comparison orientation and social adaptation. Furthermore, it is possible to intervene in their social comparison orientation and ASC to improve adolescents' social adaptation. PMID- 29997558 TI - Comparing Prescriptive and Descriptive Gender Stereotypes About Children, Adults, and the Elderly. AB - Gender stereotypes have descriptive components, or beliefs about how males and females typically act, as well as prescriptive components, or beliefs about how males and females should act. For example, women are supposed to be nurturing and avoid dominance, and men are supposed to be agentic and avoid weakness. However, it is not clear whether people hold prescriptive gender stereotypes about children of different age groups. In addition, research has not addressed prescriptive gender stereotypes for the elderly. The current research measured prescriptive gender stereotypes for children, adults, and elderly men and women in 3 studies to (a) compare how prescriptive gender stereotypes change across age groups and (b) address whether stereotypes of males are more restrictive than stereotypes of females. Students (Studies 1 and 2) and community members (Study 3), which were all U.S. and majority White samples, rated how desirable it was for different target groups to possess a list of characteristics from 1 (very undesirable) to 9 (very desirable). The target age groups included toddlers, elementary-aged, adolescent, young adult, adult, and elderly males and females. The list of 21 characteristics was created to encompass traits and behaviors relevant across a wide age range. In a meta-analysis across studies, prescriptive stereotypes were defined as characteristics displaying a sex difference of d > 0.40 and an average rating as desirable for positive prescriptive stereotypes (PPS) or undesirable for negative proscriptive stereotypes (NPS) for male or females of each age group. Results replicated previous research on prescriptive stereotypes for adults: Women should be communal and avoid being dominant. Men should be agentic, independent, masculine in appearance, and interested in science and technology, but avoid being weak, emotional, shy, and feminine in appearance. Stereotypes of boys and girls from elementary-aged to young adults still included these components, but stereotypes of toddlers involved mainly physical appearance and play behaviors. Prescriptive stereotypes of elderly men and women were weaker. Overall, boys and men had more restrictive prescriptive stereotypes than girls and women in terms of strength and number. These findings demonstrate the applicability of prescriptive stereotypes to different age groups. PMID- 29997557 TI - Taking Language out of the Equation: The Assessment of Basic Math Competence Without Language. AB - While numerical skills are fundamental in modern societies, some estimated 5-7% of children suffer from mathematical learning difficulties (MLD) that need to be assessed early to ensure successful remediation. Universally employable diagnostic tools are yet lacking, as current test batteries for basic mathematics assessment are based on verbal instructions. However, prior research has shown that performance in mathematics assessment is often dependent on the testee's proficiency in the language of instruction which might lead to unfair bias in test scores. Furthermore, language-dependent assessment tools produce results that are not easily comparable across countries. Here we present results of a study that aims to develop tasks allowing to test for basic math competence without relying on verbal instructions or task content. We implemented video and animation-based task instructions on touchscreen devices that require no verbal explanation. We administered these experimental tasks to two samples of children attending the first grade of primary school. One group completed the tasks with verbal instructions while another group received video instructions showing a person successfully completing the task. We assessed task comprehension and usability aspects both directly and indirectly. Our results suggest that the non verbal instructions were generally well understood as the absence of explicit verbal instructions did not influence task performance. Thus we found that it is possible to assess basic math competence without verbal instructions. It also appeared that in some cases a single word in a verbal instruction can lead to the failure of a task that is successfully completed with non-verbal instruction. However, special care must be taken during task design because on rare occasions non-verbal video instructions fail to convey task instructions as clearly as spoken language and thus the latter do not provide a panacea to non-verbal assessment. Nevertheless, our findings provide an encouraging proof of concept for the further development of non-verbal assessment tools for basic math competence. PMID- 29997556 TI - Frontier of Self and Impact Prediction. AB - The construction of a coherent representation of our body and the mapping of the space immediately surrounding it are of the highest ecological importance. This space has at least three specificities: it is a space where actions are planned in order to interact with our environment; it is a space that contributes to the experience of self and self-boundaries, through tactile processing and multisensory interactions; last, it is a space that contributes to the experience of body integrity against external events. In the last decades, numerous studies have been interested in peripersonal space (PPS), defined as the space directly surrounding us and which we can interact with (for reviews, see Clery et al., 2015b; de Vignemont and Iannetti, 2015; di Pellegrino and Ladavas, 2015). These studies have contributed to the understanding of how this space is constructed, encoded and modulated. The majority of these studies focused on subparts of PPS (the hand, the face or the trunk) and very few of them investigated the interaction between PPS subparts. In the present review, we summarize the latest advances in this research and we discuss the new perspectives that are set forth for futures investigations on this topic. We describe the most recent methods used to estimate PPS boundaries by the means of dynamic stimuli. We then highlight how impact prediction and approaching stimuli modulate this space by social, emotional and action-related components involving principally a parieto frontal network. In a next step, we review evidence that there is not a unique representation of PPS but at least three sub-sections (hand, face and trunk PPS). Last, we discuss how these subspaces interact, and we question whether and how bodily self-consciousness (BSC) is functionally and behaviorally linked to PPS. PMID- 29997559 TI - The Use of Network Theory for Analyzing Switching Behaviors: Assessing Cognitive and Educational-Based Intervention for Promoting Health. PMID- 29997560 TI - Commentary: Folk-Economic Beliefs: An Evolutionary Cognitive Model. PMID- 29997561 TI - Microstructural Changes in Patients With Parkinson's Disease Comorbid With REM Sleep Behaviour Disorder and Depressive Symptoms. AB - The diagnosis of Parkinson's disease (PD) is currently anchored on clinical motor symptoms, which appear more than 20 years after initiation of the neurotoxicity. Extra-nigral involvement in the onset of PD with probable nonmotor manifestations before the development of motor signs, lead us to the preclinical (asymptomatic) or prodromal stages of the disease (various nonmotor or subtle motor signs). REM sleep behavior disorder (RBD) and depression are established prodromal clinical markers of PD and predict worse motor and cognitive outcomes. Nevertheless, taken by themselves, these markers are not yet claimed to be practical in identifying high-risk individuals. Combining promising markers may be helpful in a reliable diagnosis of early PD. Therefore, we aimed to detect neural correlates of RBD and depression in 93 treatment-naive and non-demented early PD by means of diffusion MRI connectometry. Comparing four groups of PD patients with or without comorbid RBD and/or depressive symptoms with each other and with 31 healthy controls, we found that these two non-motor symptoms are associated with lower connectivity in several white matter tracts including the cerebellar peduncles, corpus callosum and long association fibers such as cingulum, fornix, and inferior longitudinal fasciculus. For the first time, we were able to detect the involvement of short association fibers (U-fibers) in PD neurodegenerative process. Longitudinal studies on larger sample groups are needed to further investigate the reported associations. PMID- 29997562 TI - The Diagnostic Value of MRI Pattern Recognition in Distal Myopathies. AB - Objective: Distal myopathies are a diagnostically challenging group of diseases. We wanted to understand the value of MRI in the current clinical setting and explore the potential for optimizing its clinical application. Methods: We retrospectively audited the diagnostic workup in a distal myopathy patient cohort, reassessing the diagnosis, whilst documenting the usage of MRI. We established a literature based distal myopathies MRI pattern template and assessed its diagnostic utility in terms of sensitivity, specificity, and potential impact on the diagnostic workup. Results: Fifty-five patients were included; in 38 with a comprehensive set of data the diagnostic work-up was audited. The median time from symptoms onset to diagnosis was 12.1 years. The initial genetic diagnostic rate was 39%; 18% were misdiagnosed as neuropathies and 13% as inclusion body myositis (IBM). Based on 21 publications we established a MRI pattern template. Its overall sensitivity (50%) and specificity (32%) were low. However in some diseases (e.g., MYOT-related myopathy, TTN-HMERF) MRI correctly identified the causative gene. The number of genes suggested by MRI pattern analysis was smaller compared to clinical work up (median 1 vs. 9, p < 0.0001) but fewer genes were correctly predicted (5/10 vs. 7/10). MRI analysis ruled out IBM in all cases. Conclusion: In the diagnostic work-up of distal myopathies, MRI is useful in assisting genetic testing and avoiding misdiagnosis (IBM). The overall low sensitivity and specificity limits its generalized use when traditional single gene test methods are applied. However, in the context of next generation sequencing MRI may represent a valuable tool for interpreting complex genetic results. PMID- 29997564 TI - Editorial: Sudden Death in Epilepsy: Basic and Translational Research. PMID- 29997563 TI - Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy. AB - Epilepsy is associated with a variety of neuropsychiatric comorbidities, including both anxiety and depression. Despite high occurrences of depression and anxiety seen in human epilepsy populations, little is known about the etiology of these comorbidities. Experimental models of epilepsy provide a platform to disentangle the contribution of acute seizures, genetic predisposition, and underlying circuit pathologies to anxious and depressive phenotypes. Most studies to date have focused on comorbidities in acquired epilepsies; genetic models, however, allow for the assessment of affective phenotypes that occur prior to onset of recurrent seizures. Here, we tested male and female genetically epilepsy prone rats (GEPR-3s) and Sprague-Dawley controls in a battery of tests sensitive to anxiety-like and depressive-like phenotypes. GEPR-3s showed increased anxiety like behavior in the open field test, elevated plus maze, light-dark transition test, and looming threat test. Moreover, GEPR-3s showed impaired prepulse inhibition of the acoustic startle reflex, decreased sucrose preference index, and impaired novel object recognition memory. We also characterized defense behaviors in response to stimulation thresholds of deep and intermediate layers of the superior colliculus (DLSC), but found no difference between strains. In sum, GEPR-3s showed inherited anxiety, an effect that did not differ significantly between sexes. The anxiety phenotype in adult GEPR-3s suggests strong genetic influences that may underlie both the seizure disorder and the comorbidities seen in epilepsy. PMID- 29997565 TI - Do Patients Thought to Lack Consciousness Retain the Capacity for Internal as Well as External Awareness? AB - It is well established that some patients, who are deemed to have disorders of consciousness, remain entirely behaviorally non-responsive and are diagnosed as being in a vegetative state, yet can nevertheless demonstrate covert awareness of their external environment by modulating their brain activity, a phenomenon known as cognitive-motor dissociation. However, the extent to which these patients retain internal awareness remains unknown. To investigate the potential for internal and external awareness in patients with chronic disorders of consciousness (DoC), we asked whether the pattern of juxtaposition between the functional time-courses of the default mode (DMN) and fronto-parietal networks, shown in healthy individuals to mediate the naturally occurring dominance switching between internal and external aspects of consciousness, was present in these patients. We used a highly engaging movie by Alfred Hitchcock to drive the recruitment of the fronto-parietal networks, including the dorsal attention (DAN) and executive control (ECN) networks, and their maximal juxtaposition to the DMN in response to the complex stimulus, relative to rest and a scrambled, meaningless movie baseline condition. We tested a control group of healthy participants (N = 13/12) and two groups of patients with disorders of consciousness, one comprised of patients who demonstrated independent, neuroimaging-based evidence of covert external awareness (N = 8), and the other of those who did not (N = 8). Similarly to the healthy controls, only the group of patients with overt and, critically, covert external awareness showed significantly heightened differentiation between the DMN and the DAN in response to movie viewing relative to their resting state time-courses, which was driven by the movie's narrative. This result suggested the presence of functional integrity in the DMN and fronto-parietal networks and their relationship to one another in patients with covert external awareness. Similar to the effect in healthy controls, these networks became more strongly juxtaposed to one another in response to movie viewing relative to the baseline conditions, suggesting the potential for internal and external awareness during complex stimulus processing. Furthermore, our results suggest that naturalistic paradigms can dissociate between groups of DoC patients with and without covert awareness based on the functional integrity of brain networks. PMID- 29997566 TI - Non-linear Dynamical Analysis of Intraspinal Pressure Signal Predicts Outcome After Spinal Cord Injury. AB - The injured spinal cord is a complex system influenced by many local and systemic factors that interact over many timescales. To help guide clinical management, we developed a technique that monitors intraspinal pressure from the injury site in patients with acute, severe traumatic spinal cord injuries. Here, we hypothesize that spinal cord injury alters the complex dynamics of the intraspinal pressure signal quantified by computing hourly the detrended fluctuation exponent alpha, multiscale entropy, and maximal Lyapunov exponent lambda. 49 patients with severe traumatic spinal cord injuries were monitored within 72 h of injury for 5 days on average to produce 5,941 h of intraspinal pressure data. We computed the spinal cord perfusion pressure as mean arterial pressure minus intraspinal pressure and the vascular pressure reactivity index as the running correlation coefficient between intraspinal pressure and arterial blood pressure. Mean patient follow-up was 17 months. We show that alpha values are greater than 0.5, which indicates that the intraspinal pressure signal is fractal. As alpha increases, intraspinal pressure decreases and spinal cord perfusion pressure increases with negative correlation between the vascular pressure reactivity index vs. alpha. Thus, secondary insults to the injured cord disrupt intraspinal pressure fractality. Our analysis shows that high intraspinal pressure, low spinal cord perfusion pressure, and impaired pressure reactivity strongly correlate with reduced multi scale entropy, supporting the notion that secondary insults to the injured cord cause de-complexification of the intraspinal pressure signal, which may render the cord less adaptable to external changes. Healthy physiological systems are characterized by edge of chaos dynamics. We found negative correlations between the percentage of hours with edge of chaos dynamics (-0.01 <= lambda <= 0.01) vs. high intraspinal pressure and vs. low spinal cord perfusion pressure; these findings suggest that secondary insults render the intraspinal pressure more regular or chaotic. In a multivariate logistic regression model, better neurological status on admission, higher intraspinal pressure multi-scale entropy and more frequent edge of chaos intraspinal pressure dynamics predict long-term functional improvement. We conclude that spinal cord injury is associated with marked changes in non-linear intraspinal pressure metrics that carry prognostic information. PMID- 29997567 TI - Visual Working Memory Encoding and Recognition in Good Outcome Aneurysmal Subarachnoid Patients. AB - Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for less than 5% of strokes but is associated with significant morbidity and mortality. Amongst survivors, neurocognitive complaints are common, often despite normal imaging. We used magnetoencephalography (MEG) to investigate neurophysiological function during a visual working memory task in aSAH survivors with good recovery and normal structural imaging. Methods: Patients with aSAH treated with coiling and exhibiting good outcome measured by Glasgow Outcome Scale (GOS) and without related parenchymal structural lesions in post-treatment MRI, were recruited and compared to age- and sex-matched controls. All participants underwent intelligence and cognitive screening, structural MRI, and MEG testing in conjunction with a 1-back visual working memory task. Sensor-level global field power and virtual electrode source analysis of neuronal activity and connectivity in aSAH were assessed. Results: Thirteen patients and 13 matched controls were enrolled (age: 56 +/- 11 years, 19 female). The 1-back task was completed with similar accuracy despite a trend for a longer reaction time in aSAH patients (p = 0.054). During encoding and recognition phases, aSAH patients showed significantly increased neuronal activation and hyperconnectivity in periventricular areas, specifically the anterior and posterior cingulate gyri. Conclusions: Increased posterior and anterior cingulate gyri neuronal activity is demonstrated in aSAH patients during visual working memory tasks, in the absence of structural lesions. These areas work mainly as a hub to "organize" memory storage and retrieval. Increased activity in these areas might be compensatory due to injury and consequently loss of neuronal response in connected areas in the working memory networks. PMID- 29997568 TI - A Voxel-Wise Meta-Analysis of Gray Matter Abnormalities in Essential Tremor. AB - Objective: To identify the consistent gray matter (GM) volume changes from the whole brain voxel-based morphometry (VBM) studies on essential tremor (ET). Methods: The whole brain VBM studies comparing ET patients and healthy controls (HCs) were systematically searched in the PubMed, Embase and Web of Science from January 2000 to December 2017. Coordinates with significant differences in regional GM volume between ET patients and HCs were extracted from included studies and the meta-analysis was performed using effect size-based signed differential mapping (ES-SDM). Results: A total of 10 studies with 241 ET patients and 213 HCs were included in the meta-analysis. The consistent GM volume reduction was detected in the left precuneus extending to the left posterior cingulate gyrus. The subgroup meta-analysis which included studies performed on a 3.0 T scanner revealed significant GM volume increases in the bilateral frontal lobes, bilateral temporal lobes, left insula, left striatum and left pons, but obvious publication biases of these findings were detected through funnel plots and Egger's tests. Conclusions: The consistent result of our meta-analysis showed a structural damage in the left precuneus extending to the left posterior cingulate gyrus, which possibly played a role in the cognitive dysfunction and depression in ET patients. It might enhance our understanding of the pathophysiological mechanisms underlying ET. PMID- 29997570 TI - Large Vessel Disease Modifies the Relationship Between Kidney Injury and Cerebral Small Vessel Disease. AB - Background: Recent studies have shown that renal disease is associated with magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD), independent of traditional vascular risk factors. Although large artery lesions might be involved in the cerebrorenal association, evidence has been lacking. Methods: A total of 928 participants from a population-based cohort study were included. Kidney injury measurements included urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). CSVD was assessed on MRI by white matter hyperintensity volume (WMHV), lacunes, brain parenchymal fraction (BPF), cerebral microbleeds (CMBs), and perivascular space. Carotid plaques and brachial-ankle pulse wave velocity (baPWV) were used to assess large artery atherosclerosis and stiffness. Multivariable linear and logistic regression and additional interaction models were used for statistical analysis. Results: Individuals with elevated ACR had higher prevalence of lacunes and more WMHV (p = 0.001 and 0.000, respectively), those with decreased eGFR had smaller brain volume, higher prevalence of lacunes and deep CMBs (p = 0.009, p = 0.017) and p = 0.010 respectively). Interaction analysis revealed that carotid plaque and baPWV significantly enhanced the association between eGFR and BPF (p = 0.001 and p = 0.002, respectively), that is, the association of eGFR with BPF was only significant among participants with carotid plaque and higher baPWV. In addition, carotid plaque enhanced the association between ACR and WMHV (p = 0.034) and baPWV enhanced the association between ACR and the presence of lacunes (p = 0.027). Modifying effect of large vessel disease markers on the association between kidney injury measurements and CMBs was not significant. Conclusion: Evaluation of subclinical CVSD in individuals with kidney injury is warranted, especially in those with combined large artery disease. PMID- 29997569 TI - Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage. AB - Background: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols. Methods: Ninety-four patients undergoing deep hypothermic circulatory arrest (DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100beta and neurofilament H (NFH), assessed at baseline, 1 and 24 h post-cardiopulmonary bypass (CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia. Results: At the nominal significance level of 0.05, changes in S100beta and in NFH at 1 and 24 h post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 h post-CPB, SOD2, SUMO4, and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB, and SERPINE1 are related to the relative change of S100B. At 24 h post-CPB, ADRA2A, SELE, and BAX are related to the relative change of NFH while SLC4A7, HSPA1B, and FGA are related to S100B. Conclusions: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies. PMID- 29997571 TI - Clival Chondrosarcoma Associated With an Intra-Axial Cystic Medullary Lesion Responsive to Steroids. AB - Introduction: Here we present a 75-year-old patient who was admitted with acute onset right-sided hemiparesis, dysphagia, dysarthria and nystagmus. Repeated MRI scans showed two lesions with contact to one another: one solid stationary extra axial lesion at the caudal part of the clivus and a rapidly growing intra-axial cystic lesion at the level of the medulla oblongata. Biopsy of the solid lesion demonstrated a low-grade chondrosarcoma, while no tissue sample of the cystic lesion could be retrieved. After initiation of dexamethasone therapy the cystic lesion markedly regressed. Background: A literature search on published cases with the same combination of a stationary solid extra-axial mass at the caudal part of the clivus and a growing intra-axial cystic mass in the medulla oblongata was negative, indicating that the case described here is both unique and novel. Discussion: Considering the rapid progression of symptoms and growth on MR imaging in combination with the marked response to steroids, an inflammatory response linked to the chondrosarcoma is most likely. At the same time other possible explanations as a second neoplasm, an abscess or an ischemic lesion seem unlikely. Concluding remarks: This case underlines an unusual complication of a rare brainstem tumor and outlines both the differential diagnosis and potential treatment options. For such cystic lesions in combination with chondrosarcoma, a treatment course with steroids should be considered along with surgical exploration necessary to obtain the diagnosis and for potential reduction of mass effect on the medulla oblongata. PMID- 29997572 TI - Idiopathic Intracranial Hypertension Without Papilledema (IIHWOP) in Chronic Refractory Headache. AB - Background: To determine the prevalence of Idiopathic intracranial hypertension without papilledema (IIHWOP) testing revised diagnostic criteria by Friedman in refractory chronic headache (CH) patients. Methods: This is a prospective observational study. Each patient underwent ophthalmologic evaluation and Optical Coherence Tomography; brain magnetic resonance venography (MRV) and a lumbar puncture (LP) with opening pressure (OP) measurement. CSF withdrawal was performed in patients with CSF OP > 200 mmH20. IIHWOP was defined according Friedman's diagnostic criteria. Effect of CSF withdrawal was evaluated clinically in a 6-month follow-up and with a MRV study at 1 month. Results: Forty-five consecutive patients were enrolled. Five were excluded due to protocol violations. Analyses were conducted in 40 patients (32 F, 8 M; mean age 49.4 +/- 10.8). None had papilledema. Nine patients (22.5%) had OP greater than 200 mmH2O, two of them above 250 mmH2O. Two (5%) had neuroimaging findings suggestive of elevated intracranial pressure. One of them (2.5%) met the newly proposed diagnostic criteria by Friedman for IIHWOP. After CSF withdrawal seven (77.8%) of the nine patients improved. No changes in neuroimaging findings were found. Conclusions: We found a low prevalence (2.5%) of IIHWOP in refractory CH patients according to current diagnostic criteria. In agreement with Friedman's criteria, our results confirm that a diagnosis of IIHWOP should be based on CSF OP and the combination of neuroradiological findings. However, where to set the CSF OP upper limit in IIHWOP needs further field testing. Although IIHWOP is a rare clinical condition, it should be considered and treated in refractory CH patients. PMID- 29997574 TI - Making a Difference-Positive Effect of Unilateral VIM Gamma Knife Thalamotomy in the Therapy of Tremor in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). AB - Fragile X Tremor Ataxia Syndrome (FXTAS) is a syndrome based on expansion of the repeats of CGG triplets. The symptoms include action tremor and cerebellar gait ataxia. Additionally symptomatology of FXTAS may be associated to parkinsonism, executive function deficits, dementia, neuropathy and dysautonomia. We present a case of a patient who after 20 year history of progressive tremor and ataxia, was diagnosed after genetic examination as mutation of FXTAS. For the treatment of tremor the patient underwent Gamma Knife (GK) thalamotomy. Reduced tremor on the right side and improvement in everyday activities were observed in the outcome of the treatment. GK thalamotomy, in the context of this patient, did not significantly affect the ataxia. PMID- 29997573 TI - Obstructive Sleep Apnea With or Without Excessive Daytime Sleepiness: Clinical and Experimental Data-Driven Phenotyping. AB - Introduction: Obstructive sleep apnea (OSA) is a serious and prevalent medical condition with major consequences for health and safety. Excessive daytime sleepiness (EDS) is a common-but not universal-accompanying symptom. The purpose of this literature analysis is to understand whether the presence/absence of EDS is associated with different physiopathologic, prognostic, and therapeutic outcomes in OSA patients. Methods: Articles in English published in PubMed, Medline, and EMBASE between January 2000 and June 2017, focusing on no-EDS OSA patients, were critically reviewed. Results: A relevant percentage of OSA patients do not complain of EDS. EDS is a significant and independent predictor of incident cardiovascular disease (CVD) and is associated with all-cause mortality and an increased risk of metabolic syndrome and diabetes. Male gender, younger age, high body mass index, are predictors of EDS. The positive effects of nasal continuous positive airway pressure (CPAP) therapy on blood pressure, insulin resistance, fatal and non-fatal CVD, and endothelial dysfunction risk factors have been demonstrated in EDS-OSA patients, but results are inconsistent in no-EDS patients. The most sustainable cause of EDS is nocturnal hypoxemia and alterations of sleep architecture, including sleep fragmentation. These changes are less evident in no-EDS patients that seem less susceptible to the cortical effects of apneas. Conclusions: There is no consensus if we should consider OSA as a single disease with different phenotypes with or without EDS, or if there are different diseases with different genetic/epigenetic determinants, pathogenic mechanisms, prognosis, and treatment.The small number of studies focused on this issue indicates the need for further research in this area. Clinicians must carefully assess the presence or absence of EDS and decide accordingly the treatment. This approach could improve combination therapy targeted to a patient's specific pathology to enhance both efficacy and long-term adherence to OSA treatment and significantly reduce the social, economic, and health negative impact of OSA. PMID- 29997576 TI - Short Body Height and Pre-pregnancy Overweight for Increased Risk of Gestational Diabetes Mellitus: A Population-Based Cohort Study. AB - Background: Short height is associated with gestational diabetes mellitus (GDM) but the underlying mechanism remains unknown. This study aims to explore whether short height has a synergistic effect with pre-pregnancy overweight/obesity and undue weight gain on the risk of GDM. Methods: We recruited 19,962 singleton pregnant women from their first antenatal care visit in urban Tianjin, China, between October 2010 to August 2012. At 24-28 weeks of gestation, women underwent a 50-g 1-h glucose challenge test (GCT) followed by a 75-g 2-h oral glucose tolerance test (OGTT) if the GCT result was >=7.8 mmol/L. GDM was defined by the International Association of Diabetes and Pregnancy Study Group's cut-points. Univariable and multivariable logistic regression analyses were performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) analysis nested in the logistic regression analysis was used to identify a cutoff point of height for GDM. Additive interaction was used to test interactions between short height, pregnancy overweight/obesity and undue weight gain. Results: A total of 1,517 (or 7.6%) women developed GDM. The risk of GDM increased rapidly with a decreasing height from 158 cm and downwards. Using height >=158 cm as the reference group, women with < 158 cm of height were at increased GDM risk (adjusted OR: 1.44, 95%CI: 1.18-1.75). Maternal overweight/obesity at the first antenatal care visit greatly enhanced the OR of short height for GDM (adjusted OR: 3.78, 95%CI: 2.84-5.03) with significant additive interaction (P < 0.05). However, the interaction between short height and undue weight gain was non-significant (P > 0.05). Conclusions: In Chinese pregnant women in urban Tianjin, height < 158 cm had a synergistic effect with pre-pregnancy overweight/obesity on the risk of GDM. PMID- 29997577 TI - Optimization of E. coli Inactivation by Benzalkonium Chloride Reveals the Importance of Quantifying the Inoculum Effect on Chemical Disinfection. AB - Optimal disinfection protocols are fundamental to minimize bacterial resistance to the compound applied, or cross-resistance to other antimicrobials such as antibiotics. The objective is twofold: guarantee safe levels of pathogens and minimize the excess of disinfectant after a treatment. In this work, the disinfectant dose is optimized based on a mathematical model. The model explains and predicts the interplay between disinfectant and pathogen at different initial microbial densities (inocula) and dose concentrations. The study focuses on the disinfection of Escherichia coli with benzalkonium chloride, the most common quaternary ammonium compound. Interestingly, the specific benzalkonium chloride uptake (mean uptake per cell) decreases exponentially when the inoculum concentration increases. As a consequence, the optimal disinfectant dose increases exponentially with the initial bacterial concentration. PMID- 29997575 TI - What Has Bariatric Surgery Taught Us About the Role of the Upper Gastrointestinal Tract in the Regulation of Postprandial Glucose Metabolism? AB - The interaction between the upper gastrointestinal tract and the endocrine system is important in the regulation of metabolism and of weight. The gastrointestinal tract has a heterogeneous cellular content and comprises a variety of cells that elaborate paracrine and endocrine mediators that collectively form the entero endocrine system. The advent of therapy that utilizes these pathways as well as the association of bariatric surgery with diabetes remission has (re-)kindled interest in the role of the gastrointestinal tract in glucose homeostasis. In this review, we will use the changes wrought by bariatric surgery to provide insights into the various gut-pancreas interactions that maintain weight, regulate satiety, and limit glucose excursions after meal ingestion. PMID- 29997578 TI - Characterization and Screening of Thermophilic Bacillus Strains for Developing Plant Growth Promoting Consortium From Hot Spring of Leh and Ladakh Region of India. AB - In the present investigation, the main aim is to identify and characterize the potential drought tolerant plant growth promoting consortium for agricultural productivity. Three bacterial isolates were isolated from hot spring of Chumathang area of Leh district. Bacillus species (BHUJP-H1, BHUJP-H2, and BHUJP H3) were done some biochemical tests including catalase, cellulase, amylase, indole-3-acetic acid, phosphate solubilisation, production of ammonia, siderophore, and hydrogen cyanide. Molecular characterization of isolates was done by 16S rDNA sequencing, e.g., Bacillus subtilis BHUJP-H1 (KU312403), Bacillus sp. BHUJP-H2 (KU312404) and B. licheniformis BHUJP-H3 (KU312405). The genetic diversity of the isolates was assessed by seven inter simple sequence repeat, all primer shows high polymorphism. The highest polymorphism efficiency and polymorphism information content showed by UBC-809 and UBC-836 which were 100% and 0.44 respectively, the lowest is by UBC-807 75% and 0.28 respectively. On an average 90.69% polymorphism efficiency and 0.40 polymorphism information contents obtained by used markers. The highest, 11.08 and the lowest, 4.50 effective multiplex ratios obtained for primer UBC-823 and UBC-807, on an average 7.99 effective multiplex ratio obtained. The highest, 4.89 and the lowest, 1.25 marker indexes obtained by UBC-836 and UBC-807 respectively and on an average 3.24 obtained. The UPGMA cluster analysis divided a population into two clusters I and II, in which BHUJP-H1 and BHUJP-H2 grouped under same while BHUJP-H3 grouped under another cluster. The treatment combination of Bacillus subtilis BHUJP-H1, B. subtilis BHUJP-H1+ B. licheniformis BHUJP-H3 and B. subtilis BHUJP H1+ Bacillus sp. BHUJP-H2+ B. licheniformis BHUJP-H3 were recorded better combination for enhancing plant growth attributes of Vigna radiata as compared to control and others. The plant growth promoting consortium, e.g., Bacillus subtilis BHUJP-H1, Bacillus subtilis BHUJP-H1+ B. licheniformis BHUJP-H3 and B. subtilis BHUJP-H1+ Bacillus sp. BHUJP-H2+ B. licheniformis BHUJP-H3 can be further used as effective microbial inoculant for enhancing the production of mungbean in field conditions. Bacillus sp. BHUJP-H1 and Bacillus sp. BHUJP-H2 may use as drought tolerant plant growth promoting consortium for enhancing the sustainable agricultural productivity. PMID- 29997580 TI - ADP-Dependent Kinases From the Archaeal Order Methanosarcinales Adapt to Salt by a Non-canonical Evolutionarily Conserved Strategy. AB - Halophilic organisms inhabit hypersaline environments where the extreme ionic conditions and osmotic pressure have driven the evolution of molecular adaptation mechanisms. Understanding such mechanisms is limited by the common difficulties encountered in cultivating such organisms. Within the Euryarchaeota, for example, only the Halobacteria and the order Methanosarcinales include readily cultivable halophilic species. Furthermore, only the former have been extensively studied in terms of their component proteins. Here, in order to redress this imbalance, we investigate the halophilic adaptation of glycolytic enzymes from the ADP dependent phosphofructokinase/glucokinase family (ADP-PFK/GK) derived from organisms of the order Methanosarcinales. Structural analysis of proteins from non-halophilic and halophilic Methanosarcinales shows an almost identical composition and distribution of amino acids on both the surface and within the core. However, these differ from those observed in Halobacteria or Eukarya. Proteins from Methanosarcinales display a remarkable increase in surface lysine content and have no reduction to the hydrophobic core, contrary to the features ubiquitously observed in Halobacteria and which are thought to be the main features responsible for their halophilic properties. Biochemical characterization of recombinant ADP-PFK/GK from M. evestigatum (halophilic) and M. mazei (non-halophilic) shows the activity of both these extant enzymes to be only moderately inhibited by salt. Nonetheless, its activity over time is notoriously stabilized by salt. Furthermore, glycine betaine has a protective effect against KCl inhibition and enhances the thermal stability of both enzymes. The resurrection of the last common ancestor of ADP-PFK/GK from Methanosarcinales shows that the ancestral enzyme displays an extremely high salt tolerance and thermal stability. Structure determination of the ancestral protein reveals unique traits such as an increase in the Lys and Glu content at the protein surface and yet no reduction to the volume of the hydrophobic core. Our results suggest that the halophilic character is an ancient trait in the evolution of this protein family and that proteins from Methanosarcinales have adapted to highly saline environments by a non-canonical strategy, different from that currently proposed for Halobacteria. These results open up new avenues for the search and development of novel salt tolerant biocatalysts. PMID- 29997581 TI - Antifungal Activity of Lipopeptides From Bacillus XT1 CECT 8661 Against Botrytis cinerea. AB - This work aims to explore the capacity of a Bacillus methylotrophicus (later heterotypic synonym of Bacillus velezensis) strain named XT1 CECT 8661 against the necrotrophic plant pathogen Botrytis cinerea and to identify the compounds responsible for its activity. Q_TOF electrospray mass spectrometry analysis allows us to detect several lipopeptides - surfactin, bacillomycin, and fengycin in XT1 cultures. In vitro antibiosis studies demonstrated the efficiency of the lipopeptide fraction for the inhibition of fungal growth. In fact, microscopy studies (SEM/TEM) revealed, an alteration of the morphology of the phytopathogen in interaction with lipopeptides, with resistance structures appearing in the early stages of growth of the fungus. Our studies, carried out with tomatoes, grapes, and strawberries have demonstrated the efficiency of Bacillus XT1 CECT 8661 lipopeptides against B. cinerea infection and it capability to trigger the antioxidant activity in fruit. Overall, the results of this study highlight the potential of lipopeptides of this strain as an effective biological control agent against the colonisation of B. cinerea. PMID- 29997579 TI - Antimicrobial Photodynamic Therapy to Control Clinically Relevant Biofilm Infections. AB - Biofilm describes a microbially-derived sessile community in which microbial cells are firmly attached to the substratum and embedded in extracellular polymeric matrix. Microbial biofilms account for up to 80% of all bacterial and fungal infections in humans. Biofilm-associated pathogens are particularly resistant to antibiotic treatment, and thus novel antibiofilm approaches needed to be developed. Antimicrobial Photodynamic therapy (aPDT) had been recently proposed to combat clinically relevant biofilms such as dental biofilms, ventilator associated pneumonia, chronic wound infections, oral candidiasis, and chronic rhinosinusitis. aPDT uses non-toxic dyes called photosensitizers (PS), which can be excited by harmless visible light to produce reactive oxygen species (ROS). aPDT is a multi-stage process including topical PS administration, light irradiation, and interaction of the excited state with ambient oxygen. Numerous in vitro and in vivo aPDT studies have demonstrated biofilm-eradication or substantial reduction. ROS are produced upon photo-activation and attack adjacent targets, including proteins, lipids, and nucleic acids present within the biofilm matrix, on the cell surface and inside the microbial cells. Damage to non specific targets leads to the destruction of both planktonic cells and biofilms. The review aims to summarize the progress of aPDT in destroying biofilms and the mechanisms mediated by ROS. Finally, a brief section provides suggestions for future research. PMID- 29997582 TI - Identification of Novel Biomarkers for Priority Serotypes of Shiga Toxin Producing Escherichia coli and the Development of Multiplex PCR for Their Detection. AB - It would be desirable to have an unambiguous scheme for the typing of Shiga toxin producing Escherichia coli (STEC) isolates to subpopulations. Such a scheme should take the high genomic plasticity of E. coli into account and utilize the stratification of STEC into subgroups, based on serotype or phylogeny. Therefore, our goal was to identify specific marker combinations for improved classification of STEC subtypes. We developed and evaluated two bioinformatic pipelines for genomic marker identification from larger sets of bacterial genome sequences. Pipeline A performed all-against-all BLASTp analyses of gene products predicted in STEC genome test sets against a set of control genomes. Pipeline B identified STEC marker genes by comparing the STEC core proteome and the "pan proteome" of a non-STEC control group. Both pipelines defined an overlapping, but not identical set of discriminative markers for different STEC subgroups. Differential marker prediction resulted from differences in genome assembly, ORF finding and inclusion cut-offs in both workflows. Based on the output of the pipelines, we defined new specific markers for STEC serogroups and phylogenetic groups frequently associated with outbreaks and cases of foodborne illnesses. These included STEC serogroups O157, O26, O45, O103, O111, O121, and O145, Shiga toxin positive enteroaggregative E. coli O104:H4, and HUS-associated sequence type (ST)306. We evaluated these STEC marker genes for their presence in whole genome sequence data sets. Based on the identified discriminative markers, we developed a multiplex PCR (mPCR) approach for detection and typing of the targeted STEC. The specificity of the mPCR primer pairs was verified using well-defined clinical STEC isolates as well as isolates from the ECOR, DEC, and HUSEC collections. The application of the STEC mPCR for food analysis was tested with inoculated milk. In summary, we evaluated two different strategies to screen large genome sequence data sets for discriminative markers and implemented novel marker genes found in this genome-wide approach into a DNA-based typing tool for STEC that can be used for the characterization of STEC from clinical and food samples. PMID- 29997583 TI - Integrative and Conjugative Elements (ICEs) in Pasteurellaceae Species and Their Detection by Multiplex PCR. AB - Strains of the Pasteurellaceae bacteria Pasteurella multocida and Mannheimia haemolytica are major etiological agents of bovine respiratory disease (BRD). Treatment of BRD with antimicrobials is becoming more challenging due to the increasing occurrence of resistance in infecting strains. In Pasteurellaceae strains exhibiting resistance to multiple antimicrobials including aminoglycosides, beta-lactams, macrolides and sulfonamides, the resistance determinants are often chromosomally encoded within integrative and conjugative elements (ICEs). To gain a more comprehensive picture of ICE structures, we sequenced the genomes of six strains of P. multocida and four strains of M. haemolytica; all strains were independent isolates and eight of them were multiple-resistant. ICE sequences varied in size from 49 to 79 kb, and were comprised of an array of conserved genes within a core region and varieties of resistance genes within accessory regions. These latter regions mainly account for the variation in the overall ICE sizes. From the sequence data, we developed a multiplex PCR assay targeting four conserved core genes required for integration and maintenance of ICE structures. Application of this assay on 75 isolates of P. multocida and M. haemolytica reveals how the presence and structures of ICEs are related to their antibiotic resistance phenotypes. The assay is also applicable to other members of the Pasteurellaceae family including Histophilus somni and indicates how clustering and dissemination of the resistance genes came about. PMID- 29997584 TI - Absence of Curli in Soil-Persistent Escherichia coli Is Mediated by a C-di-GMP Signaling Defect and Suggests Evidence of Biofilm-Independent Niche Specialization. AB - Escherichia coli is commonly viewed as a gastrointestinal commensal or pathogen although an increasing body of evidence suggests that it can persist in non-host environments as well. Curli are a major component of biofilm in many enteric bacteria including E. coli and are important for adherence to different biotic and abiotic surfaces. In this study we investigated curli production in a unique collection of soil-persistent E. coli isolates and examined the role of curli formation in environmental persistence. Although most soil-persistent E. coli were curli-positive, 10% of isolates were curli-negative (17 out of 170). Curli producing E. coli (COB583, COB585, and BW25113) displayed significantly more attachment to quartz sand than the curli-negative strains. Long-term soil survival experiments indicated that curli production was not required for long term survival in live soil (over 110 days), as a curli-negative mutant BW25113DeltacsgB had similar survival compared to wild type BW25113. Mutations in two genes associated with c-di-GMP metabolism, dgcE and pdeR, correlated with loss of curli in eight soil-persistent strains, although this did not significantly impair their survival in soil compared to curli-positive strains. Overall, the data indicate that curli-deficient and biofilm-defective strains, that also have a defect in attachment to quartz sand, are able to reside in soil for long periods of time thus pointing to the possibility that niches may exist in the soil that can support long-term survival independently of biofilm formation. PMID- 29997585 TI - Pyocyanin Restricts Social Cheating in Pseudomonas aeruginosa. AB - Quorum sensing (QS) in Pseudomonas aeruginosa coordinates the expression of virulence factors, such as exoproteases and siderophores, that are public goods utilized by the whole population of bacteria, regardless of whether they invested or not in their production. These public goods can be used by QS defective mutants for growth, and since these mutants do not contribute to public goods production, they are considered social cheaters. Pyocyanin is a phenazine that is a toxic, QS-controlled metabolite produced by P. aeruginosa. It is a redox-active compound and promotes the generation of reactive oxygen species; it also possesses antibacterial properties and increases fitness in competition with other bacterial species. Since QS-deficient individuals are less able to tolerate oxidative stress, we hypothesized that the pyocyanin produced by the wild-type population could promote selection of functional QS systems in this bacterium. Here, we demonstrate, using competition experiments and mathematical models, that, indeed, pyocyanin increases the fitness of the cooperative QS-proficient individuals and restricts the appearance of social cheaters. In addition, we also show that pyocyanin is able to select QS in other bacteria such as Acinetobacter baumannii. PMID- 29997587 TI - Development of a Computational Model of Abscess Formation. AB - In some bacterial infections, the immune system cannot eliminate the invading pathogen. In these cases, the invading pathogen is successful in establishing a favorable environment to survive and persist in the host organism. For example, S. aureus bacteria survive in organ tissues employing a set of mechanisms that work in a coordinated and highly regulated way allowing: (1) efficient impairment of the immune response; and (2) protection from the immune cells and molecules. S. aureus secretes several proteins including coagulases and toxins that drive abscess formation and persistence. Unless staphylococcal abscesses are surgically drained and treated with antibiotics, disseminated infection and septicemia produce a lethal outcome. Within this context, this paper develops a simple mathematical model of abscess formation incorporating characteristics that we judge important for an abscess to be formed. Our aim is to build a mathematical model that reproduces some characteristics and behaviors that are observed in the process of abscess formation. PMID- 29997586 TI - Microbiota, Epithelium, Inflammation, and TGF-beta Signaling: An Intricate Interaction in Oncogenesis. AB - Microbiota has been widely considered to play a critical role in human carcinogenesis. Recent evidence demonstrated that microbiota, epithelial barrier and inflammation has made up a tightly interdependent triangle during the process of carcinogenesis. Hence, we discussed the triangle relationship of microbiota dysbiosis, epithelial barrier dysfunction and dysregulated immune responses to elucidate the mechanisms by which microbiota induces carcinogenesis, especially highlighting the reciprocal crosstalk between transforming growth factor-beta signaling and every side of the tumorigenic triangle. This sophisticated interaction will provide insight into the basic mechanisms of carcinogenesis and may bring new hope to cancer prevention and therapeutic intervention. PMID- 29997588 TI - Functional Characterization of Enzymatic Steps Involved in Pyruvylation of Bacterial Secondary Cell Wall Polymer Fragments. AB - Various mechanisms of protein cell surface display have evolved during bacterial evolution. Several Gram-positive bacteria employ S-layer homology (SLH) domain mediated sorting of cell-surface proteins and concomitantly engage a pyruvylated secondary cell-wall polymer as a cell-wall ligand. Specifically, pyruvate ketal linked to beta-D-ManNAc is regarded as an indispensable epitope in this cell surface display mechanism. That secondary cell wall polymer (SCWP) pyruvylation and SLH domain-containing proteins are functionally coupled is supported by the presence of an ortholog of the predicted pyruvyltransferase CsaB in bacterial genomes, such as those of Bacillus anthracis and Paenibacillus alvei. The P. alvei SCWP, consisting of pyruvylated disaccharide repeats [->4)-beta-D-GlcNAc-(1 >3)-4,6-Pyr-beta-D-ManNAc-(1->] serves as a model to investigate the widely unexplored pyruvylation reaction. Here, we reconstituted the underlying enzymatic pathway in vitro in combination with synthesized compounds, used mass spectrometry, and nuclear magnetic resonance spectroscopy for product characterization, and found that CsaB-catalyzed pyruvylation of beta-D-ManNAc occurs at the stage of the lipid-linked repeat. We produced the P. alvei TagA (PAV_RS07420) and CsaB (PAV_RS07425) enzymes as recombinant, tagged proteins, and using a synthetic 11-phenoxyundecyl-diphosphoryl-alpha-GlcNAc acceptor, we uncovered that TagA is an inverting UDP-alpha-D-ManNAc:GlcNAc-lipid carrier transferase, and that CsaB is a pyruvyltransferase, with synthetic UDP-alpha-D ManNAc and phosphoenolpyruvate serving as donor substrates. Next, to substitute for the UDP-alpha-D-ManNAc substrate, the recombinant UDP-GlcNAc-2-epimerase MnaA (PAV_RS07610) of P. alvei was included in this in vitro reconstitution system. When all three enzymes, their substrates and the lipid-linked GlcNAc primer were combined in a one-pot reaction, a lipid-linked SCWP repeat precursor analog was obtained. This work highlights the biochemical basis of SCWP biosynthesis and bacterial pyruvyl transfer. PMID- 29997590 TI - Swine-Derived Probiotic Lactobacillus plantarum Inhibits Growth and Adhesion of Enterotoxigenic Escherichia coli and Mediates Host Defense. AB - Weaning stress renders piglets susceptible to pathogen infection, which leads to post-weaning diarrhea, a severe condition characterized by heavy diarrhea and mortality in piglets. Enterotoxigenic Escherichia coli (ETEC) is one of typical strains associated with post-weaning diarrhea. Thus, prevention and inhibition of ETEC infection are of great concern. Probiotics possess anti-pathogenic activity and can counteract ETEC infection; however, their underlying mechanisms and modes of action have not yet been clarified. In the present study, the direct and indirect protective effects of Lactobacillus plantarum ZLP001 against ETEC infection were investigated by different methods. We found that bacterial culture and culture supernatant of L. plantarum ZLP001 prevented ETEC growth by the Oxford cup method, and ETEC growth inhibition was observed in a co-culture assay as well. This effect was suggested to be caused mainly by antimicrobial metabolites produced by L. plantarum ZLP001. In addition, adhesion capacity of L. plantarum ZLP001 to IPEC-J2 cells were observed using microscopy and counting. L. plantarum ZLP001 also exhibited a concentration-dependent ability to inhibit ETEC adhesion to IPEC-J2 cells, which mainly occurred via exclusion and competition mode. Furthermore, quantitative real time polymerase chain reaction (qPCR) analysis showed that L. plantarum ZLP001 upregulated the expression of host defense peptides (HDPs) but did not trigger an inflammatory response. In addition, L. plantarum ZLP001 induced HDP secretion, which enhanced the potential antimicrobial activity of IPEC-J2 cell-culture supernatant after incubation with L. plantarum ZLP001. Our findings demonstrate that L. plantarum ZLP001, an intestinal Lactobacillus species associated with piglet health, possesses anti ETEC activity. L. plantarum ZLP001 might prevent ETEC growth, inhibit ETEC adhesion to the intestinal mucosa, and activate the innate immune response to secret antimicrobial peptides. L. plantarum ZLP001 is worth investigation as a potential probiotics. PMID- 29997589 TI - Persistence of Cellulolytic Bacteria Fibrobacter and Treponema After Short-Term Corn Stover-Based Dietary Intervention Reveals the Potential to Improve Rumen Fibrolytic Function. AB - Limited lignocellulose degradation is the primary obstacle to feed digestion efficiency in ruminant animals. Low-quality forage with high levels of fibrous components can favor the proliferation of fibrolytic bacteria, but whether this can result a profound microbial shift after dietary intervention remains unclear. In this study, we monitored the microbial communities in the rumens of five ruminally cannulated Hu sheep through dietary transition from alfalfa hay (AH, pre-CS) to corn stover (CS, post-CS) and then back to AH (post-AH), with each treatment lasting for 14 days. The CS intervention significantly increased the relative abundance of microorganisms involved in lignocellulose degradation, including Fibrobacter and Treponema. When the diet was switched back to AH, the microbial community did not completely return to a pre-CS treatment state. In the post-AH microbial community, the relative abundances of Fibrobacter and Treponema were persistently high, and were similar to those in the post-CS community. Meanwhile, the diversity of the microbial community increased after dietary transition from AH to CS and remained significantly higher after transition from CS to AH compared to those under the original AH diet. Enzyme activity measurement verified significant increase of carboxymethyl cellulase (CMCase) and xylanase catalytic activities in the rumen. Microbial functional predictions using Tax4Fun revealed that this microbial persistence may enhance the carbohydrate metabolism pathway in the rumen. In summary, persistence of Fibrobacter and Treponema can be enhanced through a low-quality forage intervention at least for 2 weeks, which may enlighten the reprogram of microbial population in the rumen in the future. PMID- 29997591 TI - Lanthanide-Dependent Methanol Dehydrogenases of XoxF4 and XoxF5 Clades Are Differentially Distributed Among Methylotrophic Bacteria and They Reveal Different Biochemical Properties. AB - Lanthanide-dependent alcohol dehydrogenases have recently emerged as environmentally important enzymes, most prominently represented in methylotrophic bacteria. The diversity of these enzymes, their environmental distribution, and their biochemistry, as well as their evolutionary relationships with their calcium-dependent counterparts remain virtually untapped. Here, we make important advances toward understanding lanthanide-dependent methylotrophy by assessing the distribution of XoxF4 and XoxF5 clades of lanthanide methanol dehydrogenases among, respectively, Methylophilaceae and non-Methylophilaceae methylotrophs, and we carry out comparative biochemical characterization of XoxF4 and XoxF5 enzymes, demonstrating differences in their properties, including catalytic efficiencies. We conclude that one subtype of the XoxF4 enzyme, XoxF4-1 is the dominant type in nature while other XoxF4 subtypes appear to be auxiliary, representatives of this clade only found in the Methylophilaceae (Betaproteobacteria). In contrast, we demonstrate that XoxF5 enzymes are widespread among Alpha-, Beta-, and Gammaproteobacteria. We purified and biochemically characterized two XoxF4 enzymes (XoxF4-1 and XoxF4-2), both from Methylotenera mobilis, and one XoxF5 enzyme, from Methylomonas sp., after expressing their His-tagged versions in respective natural hosts. All three enzymes showed broad specificities toward alcohols and aldehydes and strict dependence on lighter lanthanides. However, they revealed differences in their properties in terms of optimal pH for in vitro activity, ammonia dependence, the range of lanthanides that could serve as cofactors, and in kinetic properties. Overall, our data advance the understanding of the biochemistry and environmental distribution of these recently discovered enzymes that appear to be key enzymes in lanthanide-dependent methylotrophy. PMID- 29997592 TI - Dynamic and Assembly of Epiphyte and Endophyte Lactic Acid Bacteria During the Life Cycle of Origanum vulgare L. AB - Origanum vulgare L. (oregano) was chosen as suitable model to investigate the ability of the endophyte-microbiome, especially that of lactic acid bacteria, to develop specific interactions with the plant, mediated by the essential oils (EOs). Combined culture-dependent and -independent approaches analyzed the bacterial dynamic and assembly of Origanum vulgare L. throughout the life cycle. Epiphyte bacteria were more abundant than the endophyte ones. The number of presumptive lactic acid bacteria increased throughout oregano life cycle, according to the plant organ. Diverse species of lactic acid bacteria populated the plant, but Lactobacillus plantarum stably dominated both epiphyte and endophyte populations. High-throughput DNA sequencing showed highest epiphyte bacterial diversity at early vegetative and full-flowering stages, with blooming signing the main microbial differentiation among plant organs. Proteobacteria, Actinobacteria and Bacteroidetes, and Firmicutes and Cyanobacteria at lower abundance were the main phyla. Various genera were detectable, but oregano harbored mainly Methylobacterium, Sphingomonas, Rhizobium and Aurantimonas throughout phenological stages. Firmicutes epiphyte and endophyte microbiotas were different, with a core microbiota consisting of Bacillus, Exiguobacterium, Streptococcus, Staphylococcus and Lactobacillus genera. Bacillus dominated throughout phenological stages. High-throughput DNA sequencing confirmed the dominance of L. plantarum within the epiphyte and endophyte populations of lactic acid bacteria. Yields of EOs varied among plant organs and throughout plant life cycle. L. plantarum strains were the most resistant to the total EOs (mainly thymol and carvacrol) as extracted from the plant. The positive correlation among endophyte lactic acid bacteria and the EOs content seems confirm the hypothesis that the colonization within plant niches may be regulated by mechanisms linked to the synthesis of the secondary metabolites. PMID- 29997593 TI - Detection of Antilisterial Activity of 3-Phenyllactic Acid Using Listeria innocua as a Model. AB - The 3-Phenyllactic acid (PLA) produced by various lactic acid bacteria (LAB) possesses a broad spectrum of antimicrobial activity. In this study, the effect of PLA against Listeria innocua was studied with the aim to obtain additional information about its mechanism of action. The effect of pH on the antilisterial activity of PLA was investigated and a pH-dependent behavior, typical of weak acid, was detected. The antilisterial effect of PLA was firstly compared to that produced by lactic acid (LA) and than to that expressed by phenolic acids (gallic, caffeic, and ferulic acids) evaluating minimum inhibitory concentration (MIC), MBC, and survival kinetic parameters. PLA showed MIC values and death kinetic parameters significantly different from those exhibited by LA and by tested phenolic acids. In particular, the MIC value observed for PLA vs L. innocua resulted lower than that of the other preservative compounds studied herein, and consistent with the quantity generally produced by LAB. Moreover, the effect of PLA and phenolic acids on bacterial surface charge and loss of cellular content resulted different. The overall results highlighted strong differences in the antilisterial mechanism of action among PLA and other compounds such as LA and phenols. Specifically, it is possible to hypothesize that the antilisterial mechanism of action due to PLA is associated with the affinity to cell surface, which contributes to the cellular damage. PMID- 29997594 TI - Preterm Gut Microbiome Depending on Feeding Type: Significance of Donor Human Milk. AB - Preterm microbial colonization is affected by gestational age, antibiotic treatment, type of birth, but also by type of feeding. Breast milk has been acknowledged as the gold standard for human nutrition. In preterm infants breast milk has been associated with improved growth and cognitive development and a reduced risk of necrotizing enterocolitis and late onset sepsis. In the absence of their mother's own milk (MOM), pasteurized donor human milk (DHM) could be the best available alternative due to its similarity to the former. However, little is known about the effect of DHM upon preterm microbiota and potential biological implications. Our objective was to determine the impact of DHM upon preterm gut microbiota admitted in a referral neonatal intensive care unit (NICU). A prospective observational cohort study in NICU of 69 neonates <32 weeks of gestation and with a birth weight <=1,500 g was conducted. Neonates were classified in three groups according to feeding practices consisting in their MOM, DHM, or formula. Fecal samples were collected when full enteral feeding (defined as >=150 cc/kg/day) was achieved. Gut microbiota composition was analyzed by 16S rRNA gene sequencing. Despite the higher variability, no differences in microbial diversity and richness were found, although feeding type significantly influenced the preterm microbiota composition and predictive functional profiles. Preterm infants fed MOM showed a significant greater presence of Bifidobacteriaceae and lower of Staphylococcaceae, Clostridiaceae, and Pasteurellaceae compared to preterm fed DHM. Formula fed microbial profile was different to those observed in preterm fed MOM. Remarkably, preterm infants fed DHM showed closer microbial profiles to preterm fed their MOM. Inferred metagenomic analyses showed higher presence of Bifidobacterium genus in mother's milk group was related to enrichment in the Glycan biosynthesis and metabolism pathway that was not identified in the DHM or in the formula fed groups. In conclusion, DHM favors an intestinal microbiome more similar to MOM than formula despite the differences between MOM and DHM. This may have potential beneficial long-term effects on intestinal functionality, immune system, and metabolic activities. PMID- 29997596 TI - A Long-Term Efficacy Trial of a Live, Attenuated Salmonella Typhimurium Vaccine in Layer Hens. AB - Salmonella remains one of the most common causes of bacterial foodborne gastrointestinal disease in humans. Raw eggs or food items containing undercooked eggs are frequently identified as the source of Salmonella. Salmonella Typhimurium contamination of table eggs most commonly occurs when they are laid in a contaminated environment. Several control strategies, including vaccination, are widely used to mitigate the total Salmonella load. It is unclear, however, whether live attenuated Salmonella vaccines are efficacious over the life span of a layer hen. Live attenuated Salmonella vaccines have been favored due to their ability to illicit a strong humoral immune response. The lifespan of a layer hen ranges between 60 and 80 weeks and the long term efficacy of attenuated vaccine strains has not been investigated. In this study, commercial brown layer chicks were vaccinated at day old, 6 weeks of age, and again at 10 weeks of age with the Bioproperties VaxsafeTM STM1 aroA mutant vaccine. Birds were challenged at 18 weeks of age with Salmonella Typhimurium DT9 (MLVA 03 15 08 11 550). Feces and eggs were monitored for S. Typhimurium for 40 weeks post-infection. Birds produced a strong immune response following the final dose which was administered intramuscularly. The serum antibody response to S. Typhimurium DT9 infection did not differ between challenged groups. Fecal shedding and egg contamination was highly variable and did not differ significantly between vaccinated and unvaccinated birds that had been challenged with S. Typhimurium DT9. Total bacterial load in feces was quantified using qPCR. No significant difference was detected between unvaccinated and vaccinated birds after challenge. PMID- 29997597 TI - Multi-Compartment and Multi-Host Vector Suite for Recombinant Protein Expression and Purification. AB - Recombinant protein expression has become an invaluable tool in basic and applied research. The accumulated knowledge in this field allowed the expression of thousands of protein targets in a soluble, pure, and homogeneous state, essential for biochemical and structural analyses. A lot of progress has been achieved in the last decades, where challenging proteins were expressed in a soluble manner after evaluating different parameters such as host, strain, and fusion partner or promoter strength, among others. In this regard, we have previously developed a vector suite that allows the evaluation of different promoters and solubility enhancer-proteins, through an easy and efficient cloning strategy. Nonetheless, the proper expression of many targets remains elusive, requiring, for example, the addition of complex post-translation modifications and/or passage through specialized compartments. In order to overcome the limitations found when working with a single subcellular localization and a single host type, we herein expanded our previously developed vector suite to include the evaluation of recombinant protein expression in different cell compartments and cell hosts. In addition, these vectors also allow the assessment of alternative purification strategies for the improvement of target protein yields. PMID- 29997595 TI - The Microbiological Memory, an Epigenetic Regulator Governing the Balance Between Good Health and Metabolic Disorders. AB - If the transmission of biological information from one generation to the next is based on DNA, most heritable phenotypic traits such as chronic metabolic diseases, are not linked to genetic variation in DNA sequences. Non-genetic heritability might have several causes including epigenetic, parental effect, adaptive social learning, and influence of the ecological environment. Distinguishing among these causes is crucial to resolve major phenotypic enigmas. Strong evidence indicates that changes in DNA expression through various epigenetic mechanisms can be linked to parent-offspring resemblance in terms of sensitivity to metabolic diseases. Among non-genetic heritable traits, early nutrition could account for a long term deviant programming of genes expression responsible for metabolic diseases in adulthood. Nutrition could shape an inadequate gut microbiota (dysbiosis), triggering epigenetic deregulation of transcription which can be observed in chronic metabolic diseases. We review herein the evidence that dysbiosis might be a major cause of heritable epigenetic patterns found to be associated with metabolic diseases. By taking into account the recent advances on the gut microbiome, we have aggregated together different observations supporting the hypothesis that the gut microbiota could promote the molecular crosstalk between bacteria and surrounding host cells which controls the pathological epigenetic signature. We introduce for the first time the concept of "microbiological memory" as the main regulator of the epigenetic signatures, thereby indicating that different causes of non-genetic heritability can interact in complex pathways to produce inheritance. PMID- 29997598 TI - The adaptation of Fusarium culmorum to DMI Fungicides Is Mediated by Major Transcriptome Modifications in Response to Azole Fungicide, Including the Overexpression of a PDR Transporter (FcABC1). AB - Fusarium culmorum is a fungal pathogen causing economically important diseases on a variety of crops. Fungicides can be applied to control this species with triazoles being the most efficient molecules. F. culmorum strains resistant to these molecules have been reported, but the underlying resistance mechanisms remain unknown. In this study, a tebuconazole-adapted F. culmorum strain was developed with a level of fitness similar to its parental strain. The adapted strain showed cross-resistance to all demethylation inhibitors (DMIs), but not to other classes of fungicides tested. RNA-Seq analysis revealed high transcriptomic differences between the resistant strain and its parental strain after tebuconazole treatment. Among these changes, FcABC1 (FCUL_06717), a pleiotropic drug resistance transporter, had a 30-fold higher expression level upon tebuconazole treatment in the adapted strains as compared to the wild-type strain. The implication of this transporter in triazole resistance was subsequently confirmed in field strains harboring distinct levels of sensitivity to triazoles. FcABC1 is present in other species/genera, including F. graminearum in which it is known to be necessary for azole resistance. No difference in FcABC1 sequences, including the surrounding regions, were found when comparing the resistant strain to the wild-type strain. Fusarium culmorum is therefore capable to adapt to triazole pressure by overexpressing a drug resistance transporter when submitted to triazoles and the same mechanism is anticipated to occur in other species. PMID- 29997600 TI - Use of the PCR-DGGE Method for the Analysis of the Bacterial Community Structure in Soil Treated With the Cephalosporin Antibiotic Cefuroxime and/or Inoculated With a Multidrug-Resistant Pseudomonas putida Strain MC1. AB - The widespread use of cefuroxime (XM) has resulted in the increase in its concentration in hospital and domestic wastewaters. Due to the limited removal of antibiotics and antibiotic-resistant genes in conventional systems, the drugs enter the surface water and soils. Moreover, the introduction of XM and/or XM resistant bacteria into soil may cause a significant modification of the biodiversity of soil bacterial communities. Therefore, the goal of this research was to assess the genetic diversity of a bacterial community in the cefuroxime (XM1 - 1 mg/kg and XM10 - 10 mg/kg) and/or antibiotic-resistant Pseudomonas putida strain MC1 (Ps - 1.6 * 107 cells/g)-treated soils as determined by the DGGE (denaturing gradient gel electrophoresis) method. The obtained data were also evaluated using a multivariate analysis and the resistance (RS)/resilience (RL) concept. Strain MC1 was isolated from raw sewage in the presence of XM and was resistant not only to this antibiotic but also to vancomycin, clindamycin and erythromycin. The DGGE patterns revealed that the XM10 and XM10+Ps treatments modified the composition of the bacterial community by the alteration of the DGGE profiles as well as a decline in the DGGE indices, in particular on days 30, 60, and 90. In turn, the XM1 and XM1+Ps or Ps treatments did not affect the values of richness and diversity of the soil bacteria members. A principal component analysis (PCA) also indicated that XM markedly changed the diversity of bacterial assemblages in the second part of the experiment. Moreover, there were differences in the RS/RL of the DGGE indices to the disturbances caused by XM and/or Ps. Considering the mean values of the RS index, the resistance was categorized in the following order: diversity (0.997) > evenness (0.993) > richness (0.970). The soil RL index was found to be negative, thus reflecting the progressing detrimental impact of XM on the genetic biodiversity of bacteria within the experiment. These results indicate that the introduction of XM at higher dosages into the soil environment may exert a potential risk for functioning of microorganism. PMID- 29997599 TI - Advances in Biodetoxification of Ochratoxin A-A Review of the Past Five Decades. AB - Ochratoxin A (OTA) is a toxic secondary fungal metabolite that widely takes place in various kinds of foodstuffs and feeds. Human beings and animals are inevitably threatened by OTA as a result. Therefore, it is necessary to adopt various measures to detoxify OTA-contaminated foods and feeds. Biological detoxification methods, with better safety, flavor, nutritional quality, organoleptic properties, availability, and cost-effectiveness, are more promising than physical and chemical detoxification methods. The state-of-the-art research advances of OTA biodetoxification by degradation, adsorption, or enzymes are reviewed in the present paper. Researchers have discovered a good deal of microorganisms that could degrade and/or adsorb OTA, including actinobacteria, bacteria, filamentous fungi, and yeast. The degradation of OTA to non-toxic or less toxic OTalpha via the hydrolysis of the amide bond is the most important OTA biodegradation mechanism. The most important influence factor of OTA adsorption capacity of microorganisms is cell wall components. A large number of microorganisms with good OTA degradation and/or adsorption ability, as well as some OTA degradation enzymes isolated or cloned from microorganisms and animal pancreas, have great application prospects in food and feed industries. PMID- 29997601 TI - Assessing the Effect of Pretreatments on the Structure and Functionality of Microbial Communities for the Bioconversion of Microalgae to Biogas. AB - Microalgae biomethanization is driven by anaerobic sludge associated microorganisms and is generally limited by the incomplete hydrolysis of the microalgae cell wall, which results in a low availability of microalgal biomass for the methanogenic community. The application of enzymatic pretreatments, e.g., with hydrolytic enzymes, is among the strategies used to work around the incomplete hydrolysis of the microalgae cell wall. Despite the proven efficacy of these pretreatments in increasing biomethanization, the changes that a given pretreatment may cause to the anaerobic sludge associated microorganisms during biomethanization are still unknown. This study evaluated the changes in the expression of the metatranscriptome of anaerobic sludge associated microorganisms during Chlorella sorokiniana biomethanization without pretreatment (WP) (control) and pretreated with commercial cellulase in order to increase the solubilization of the microalgal organic matter. Pretreated microalgal biomass experienced significant increases in biogas the production. The metatranscriptomic analysis of control samples showed functionally active microalgae cells, a bacterial community dominated by gamma- and delta-proteobacteria, and a methanogenic community dominated by Methanospirillum hungatei. In contrast, pretreated samples were characterized by the absence of active microalgae cells and a bacteria population dominated by species of the Clostridia class. These differences are also related to the differential activation of metabolic pathways e.g., those associated with the degradation of organic matter during its biomethanization. PMID- 29997602 TI - Predictive Modeling of Microbiome Data Using a Phylogeny-Regularized Generalized Linear Mixed Model. AB - Recent human microbiome studies have revealed an essential role of the human microbiome in health and disease, opening up the possibility of building microbiome-based predictive models for individualized medicine. One unique characteristic of microbiome data is the existence of a phylogenetic tree that relates all the microbial species. It has frequently been observed that a cluster or clusters of bacteria at varying phylogenetic depths are associated with some clinical or biological outcome due to shared biological function (clustered signal). Moreover, in many cases, we observe a community-level change, where a large number of functionally interdependent species are associated with the outcome (dense signal). We thus develop "glmmTree," a prediction method based on a generalized linear mixed model framework, for capturing clustered and dense microbiome signals. glmmTree uses the similarity between microbiomes, which is defined based on the microbiome composition and the phylogenetic tree, to predict the outcome. The effects of other predictive variables (e.g., age, sex) can be incorporated readily in the regression framework. Additional tuning parameters enable a data-adaptive approach to capture signals at different phylogenetic depth and abundance level. Simulation studies and real data applications demonstrated that "glmmTree" outperformed existing methods in the dense and clustered signal scenarios. PMID- 29997603 TI - Metagenomic Analysis of Cyanobacteria in an Oligotrophic Tropical Estuary, South Atlantic. AB - This study assessed the species composition, distribution, and functional profiles of cyanobacteria in Camamu Bay, a tropical oligotrophic estuarine system on the northeast coast of Brazil, using shotgun metagenomic sequencing. Surface water samples were evaluated in two different rainfall periods (rainy and dry seasons), at nine stations in the three hydrodynamic regions of the bay. At a fixed sampling station, on each season, samples were taken over a tidal cycle at 3-h intervals over 12 h. A total of 219 cyanobacterial taxa were identified, demonstrating a diverse community of freshwater, euryhaline, and marine cyanobacteria. The genera of greater relative abundance, Synechococcus and Prochlorococcus, corresponded to the picoplankton fraction. Although Camamu Bay has conspicuous marine characteristics, the contribution of freshwater during the rainy season caused variation in cyanobacteria community, with an increase in species richness. Due the high prevalence of Synechococcus (90% of the sequences), the functional analysis revealed only minor differences in gene content between the dry and rainy seasons. In both rainy and dry seasons, an increase in Prochlorococcus relative abundance occurred during high tide, demonstrating the tidal influence in the bay. The environmental characteristics of the bay provide niche conditions for a wide variety of cyanobacteria, including freshwater, euryhaline, and marine strains. PMID- 29997605 TI - Determination of the Prevalence of Triazole Resistance in Environmental Aspergillus fumigatus Strains Isolated in South Wales, UK. AB - Background/Objectives: Azole resistance in Aspergillus fumigatus associated with the TR34/L98H mutations in the cyp51A gene have been increasingly reported. Determining the environmental resistance rate has been deemed important when considering front-line therapy for invasive aspergillosis. The aim of the study was to determine prevalence of azole resistance in environmental A. fumigatus isolates across South Wales. Methods: Over 5 months in 2015, 513 A. fumigatus isolates were cultured from 671 soil and 44 air samples and were screened for azole resistance using VIPcheckTM agar plates containing itraconazole, voriconazole and posaconazole. Resistance was confirmed by the CLSI M38-A2 methodology. The mechanism of resistance was investigated using the PathoNostics AsperGenius(r) Assay. Results: Screening by VIPcheckTM plate identified azole resistance in 30 isolates, most of which (28/30) harbored the TR34/L98H mutation, generating a prevalence of 6.0%. Twenty-five isolates had a MIC of >=2 mg/L with itraconazole, 23 isolates had a MIC of >=2 mg/L with voriconazole and seven isolates had a MIC >=0.25 mg/L with posaconazole. All isolates deemed resistant by VIPcheckTM plates were resistant to at least one azole by reference methodology. Conclusions: There is significant environmental azole resistance (6%) in South Wales, in close proximity to patients susceptible to aspergillosis. Given this environmental reservoir, azole resistance should be routinely screened for in clinical practice and environmental monitoring continued. PMID- 29997604 TI - Beyond Bacteria: Bacteriophage-Eukaryotic Host Interactions Reveal Emerging Paradigms of Health and Disease. AB - For decades, a wealth of information has been acquired to define how host associated microbial communities contribute to health and disease. Within the human microbiota this has largely focused on bacteria, yet there is a myriad of viruses that occupy various tissue sites, the most abundant being bacteriophages that infect bacteria. Animal hosts are colonized with niche specific microbial communities where bacteria are continuously co-evolving with phages. Bacterial growth, metabolic activity, pathogenicity, antibiotic resistance, interspecies competition and evolution can all be influenced by phage infection and the beneficial nature of such interactions suggests that to an extent phages are tolerated by their hosts. With the understanding that phage-specific host-microbe interactions likely contribute to bacterial interactions with their mammalian hosts, phages and their communities may also impact aspects of mammalian health and disease that have gone unrecognized. Here, we review recent progress in understanding how bacteria acquire and tolerate phage in both pure culture and within complex communities. We apply these findings to discuss how intra-body phages interact with bacteria to influence their eukaryotic hosts through potential contributions to microbial homeostasis, mucosal immunity, immune tolerance and autoimmunity. PMID- 29997606 TI - Bacterial Memory of Persisters: Bacterial Persister Cells Can Retain Their Phenotype for Days or Weeks After Withdrawal From Colony-Biofilm Culture. AB - Persister cells, or persisters, are a specific subpopulation of bacterial cells that have acquired temporary antibiotic-resistant phenotypes. In this study, we showed that Escherichia coli produces many more persister cells in colony-biofilm culture than in the usual liquid culture and that these persisters can be maintained in higher numbers than those from liquid culture for up to 4 weeks at 37 degrees C in a fresh, nutrient-rich, antibiotic-containing medium, even after complete withdrawal from the colony-biofilm culture. This suggests the presence of a long-retention effect, or "memory effect", in the persister cell state of E. coli cells. We also discovered that such increases in persisters during colony biofilm culture and their memory effects are common, to a greater or lesser degree, in other bacterial species. This is true not only for gram-negative bacteria (Acinetobacter and Salmonella) but also for gram-positive bacteria (Staphylococcus and Bacillus). This is the first report to suggest the presence of a common memory mechanism for the persister cell state, which is inscribed during colony-biofilm culture, in a wide variety of bacteria. PMID- 29997607 TI - Plants Pre-Infested With Viruliferous MED/Q Cryptic Species Promotes Subsequent Bemisia tabaci Infestation. AB - The sweet potato whitefly, Bemisia tabaci, is one of the most invasive insect pests worldwide. The two most destructive whitefly cryptic species are MEAM1/B and MED/Q. Given that MED/Q has replaced MEAM1/B in China and the invasion of MED/Q has coincided with the outbreak of tomato yellow leaf curl virus (TYLCV), we hypothesize that pre-infestation with viruliferous B. tabaci will affect the subsequent host preferences. To test this hypothesis, we (1) conducted bioassays to compare the host preference of viruliferous and non-viruliferous MEAM1/B and MED/Q, respectively, on plants pre-infested with viruliferous and non viruliferous MEAM1/B and MED/Q; (2) profiled plant volatiles using GC-MS; and (3) functionally characterized chemical cues could potentially modulate B. tabaci TYLCV-tomato interactions, including rho-cymene, thujene and neophytadiene, using a Y-tube olfactometer. As a result, plants pre-infested with MEAM1/B whiteflies carrying TYLCV or not, did not attract more or less B or Q whiteflies. Plants pre infested with non-viruliferous MED/Q resisted MEAM1/B but did not affect MED/Q. However, plants pre-infested with viruliferous MED/Q attracted more whiteflies. Feeding of viruliferous MED/Q reduced the production of rho-cymene, and induced thujene and neophytadiene. Functionally analyses of these plant volatiles show that rho-cymene deters while neophytadiene recruits whiteflies. These combined results suggest that pre-infestation with viruliferous MED/Q promotes the subsequent whitefly infestation and induces plant volatile neophytadiene which recruits whiteflies. PMID- 29997608 TI - Genetic and Phylogenetic Characteristics of Pasteurella multocida Isolates From Different Host Species. AB - Pasteurella multocida is a leading cause of respiratory diseases in many host species. To understand the genetic characteristics of P. multocida strains isolated from different host species, we sequenced the genomic DNA of P. multocida isolated from pigs and analyzed the genetic characteristics of strains from avian species, bovine species, pigs, and rabbits using whole genome sequence (WGS) data. Our results found that a capsular: lipopolysaccharide (LPS): multilocus sequence typing (MLST) genotype A: L1: ST129 (43.75%) was predominant in avian P. multocida; while genotypes B: L2: ST122 (60.00%) and A: L3: ST79 (30.00%) were predominate in bovine P. multocida; genotype D: L6: ST50 (37.50%) in porcine P. multocida; and genotype A: L3: ST9 (76.47%) in rabbit P. multocida. Comparative genomic analysis of P. multocida from different host species found that there are no genes in the P. multocida genome that are specific to any type of host. Phylogenetic analysis using either whole-genome single nucleotide polymorphisms (SNPs) or the set of SNPs present in all single-copy core genes across genomes showed that P. multocida strains with the same LPS genotype and MLST genotype were clustered together, suggesting the combining both the LPS and MLST typing schemes better explained the topology seen in the P. multocida phylogeny. PMID- 29997609 TI - A Virus Infecting Marine Photoheterotrophic Alphaproteobacteria (Citromicrobium spp.) Defines a New Lineage of ssDNA Viruses. AB - In recent metagenomic studies, single-stranded DNA (ssDNA) viruses that infect bacteria have been shown to be diverse and prevalent in the ocean; however, there are few isolates of marine ssDNA phages. Here, we report on a cultivated ssDNA phage (vB_Cib_ssDNA_P1) that infects Citromicrobium bathyomarinum RCC1878 (family Sphingomonadaceae), and other members of the genus. This is the first ssDNA phage reported to infect marine alphaproteobacteria, and represents a newly recognized lineage of the Microviridae infecting members of Sphingomonadaceae, the Amoyvirinae. The ~26 nm diameter polyhedral capsid contains a 4,360 bp genome with 6 open reading frames (ORFs) and a 59.3% G+C content. ORF1 encodes the capsid protein and ORF3 encodes the replication initiator protein. The replication cycle is ~5 h, followed by a burst releasing about 180 infectious particles. The closest relative of vB_Cib_ssDNA_P1 is a prophage within the genome of Novosphingobium tardaugens strain NBRC16725. Phylogenetic analysis indicates that the vB_Cib_ssDNA_P1 phage and two related prophages, as well as an environmental sequence, form a novel group within the Microviridae. Our results indicate that this is a previously unknown lineage of ssDNA viruses which also supplies a new model system for studying interactions between ssDNA phages and marine bacteria. PMID- 29997610 TI - Overexpression of THI4 and HAP4 Improves Glucose Metabolism and Ethanol Production in Saccharomyces cerevisiae. AB - Redox homeostasis is essential to the maintenance of cell metabolism. Changes in the redox state cause global metabolic and transcriptional changes. Our previous study indicated that the overexpression of NADH oxidase in Saccharomyces cerevisiae led to increased glucose consumption and ethanol production. Gene expression related to thiamine synthesis and osmotolerance as well as HAP4 expression was increased in response to redox change caused by the overexpression of NADH oxidase. To identify detailed relationships among cofactor levels, thiamine synthesis, expression of HAP4, and osmotolerance, and to determine whether these changes are interdependent, THI4 and HAP4 were overexpressed in S. cerevisiae BY4741. The glucose consumption rate of THI4-overexpressing strain (thi4-OE) was the highest, followed by HAP4-overexpressing strain (hap4-OE) > NADH oxidase-overexpressing strain (nox-OE) > control strain (con), while strain hap4-OE showed the highest concentration of ethanol after 26 h of fermentation. Reduced glycerol production and increased osmotolerance were observed in thi4-OE and hap4-OE, as well as in nox-OE. HAP4 globally regulated thiamine synthesis, biomass synthesis, respiration, and osmotolerance of cells, which conferred the recombinant strain hap4-OE with faster glucose metabolism and enhanced stress resistance. Moreover, overexpression of HAP4 might extend the life span of cells under caloric restriction by lowering the NADH level. Although overexpression of THI4 and HAP4 induced various similar changes at both the metabolic and the transcriptional level, the regulatory effect of THI4 was more limited than that of HAP4, and was restricted to the growth phase of cells. Our findings are expected to benefit the bio-ethanol industry. PMID- 29997611 TI - Kruppel-Like Factor 4 Positively Regulates Autoimmune Arthritis in Mouse Models and Rheumatoid Arthritis in Patients via Modulating Cell Survival and Inflammation Factors of Fibroblast-Like Synoviocyte. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes mild to severe joint inflammation. During RA pathogenesis, fibroblast-like synoviocytes (FLS) acquire a tumor-like phenotype and mediate cartilage destruction both directly and indirectly by producing proinflammatory cytokines and matrix metalloproteinases (MMPs). Kruppel-like factor (KLF) 4, a member of the KLF family, plays significant roles in cell survival, proliferation, and differentiation. A recent study reported increased expression of KLF4 in synovial tissue from RA patients. However, its precise role in RA in different models, including mouse autoimmune disease models, remains unclear. In this study, we examined the role of KLF4 during development of autoimmune arthritis in mouse models. To do this, we used KLF4 knockout mice rendered by ribonucleic acid (RNA) guided endonuclease (RGEN) and performed collagen antibody-induced arthritis (CAIA). We found that deletion of KLF4 reduces inflammation induced by CAIA. In addition, we assessed collagen-induced arthritis (CIA) in control mice and KLF4 overexpressing mice generated by a minicircle vector treatment. Severity of CIA in mice overexpressing KLF4 was greater than that in mice injected with control vector. Finally, we verified the inflammatory roles of KLF4 in CIA by treating Kenpaullone which is used as KLF4 inhibitor. Next, we focused on human/mouse FLS to discover the cellular process involved in RA pathogenesis including proliferation, apoptosis, and inflammation including MMPs. In FLS, KLF4 upregulated expression of mRNA encoding proinflammatory cytokines interleukin (IL)-1beta and IL-6. KLF4 also regulated expression of matrix metallopeptidase 13 in the synovium. We found that blockade of KLF4 in FLS increased apoptosis and suppressed proliferation followed by downregulation of antiapoptotic factor BCL2. Our results indicate that KLF4 plays a crucial role in pathogenesis of inflammatory arthritis in vivo, by regulating apoptosis, MMP expression, and cytokine expression by FLS. Thus, KLF4 might be a novel transcription factor for generating RA by modulating cellular process of FLS. PMID- 29997612 TI - CDG: An Online Server for Detecting Biologically Closest Disease-Causing Genes and its Application to Primary Immunodeficiency. AB - High-throughput genomic technologies yield about 20,000 variants in the protein coding exome of each individual. A commonly used approach to select candidate disease-causing variants is to test whether the associated gene has been previously reported to be disease-causing. In the absence of known disease causing genes, it can be challenging to associate candidate genes with specific genetic diseases. To facilitate the discovery of novel gene-disease associations, we determined the putative biologically closest known genes and their associated diseases for 13,005 human genes not currently reported to be disease-associated. We used these data to construct the closest disease-causing genes (CDG) server, which can be used to infer the closest genes with an associated disease for a user-defined list of genes or diseases. We demonstrate the utility of the CDG server in five immunodeficiency patient exomes across different diseases and modes of inheritance, where CDG dramatically reduced the number of candidate genes to be evaluated. This resource will be a considerable asset for ascertaining the potential relevance of genetic variants found in patient exomes to specific diseases of interest. The CDG database and online server are freely available to non-commercial users at: http://lab.rockefeller.edu/casanova/CDG. PMID- 29997613 TI - Substitution of Mannan-Binding Lectin (MBL)-Deficient Serum With Recombinant MBL Results in the Formation of New MBL/MBL-Associated Serine Protease Complexes. AB - The lectin pathway (LP) of complement activation depends on the activation of the MBL-associated serine proteases (MASPs) circulating in complex with mannan binding lectin (MBL). MBL deficiency is the most common complement deficiency and has been associated with several pathological conditions. As we had previously shown, plasma-derived MBL (pdMBL) contains pre-activated MASPs that upon in vivo pdMBL substitution results in restoration of MBL concentrations but no LP functionality due to immediate inactivation of pdMBL-MASP complexes upon infusion. In this study, we analyzed MBL-sufficient and -deficient serum by size exclusion chromatography for complexes of LP activation. In both sera, we identified non-bound free forms of MASP-2 and to lesser extent MASP-1/3. After addition of recombinant MBL (rMBL) to MBL-deficient serum, these free MASPs were much less abundantly present, which is highly suggestive for the formation of high-molecular complexes that could still become activated upon subsequent ligand binding as shown by a restoration of C4-deposition of MBL-deficient serum. Ficolin (FCN)-associated MASPs have been described to redistribute to ligand bound MBL, hereby forming new MBL/MASP complexes. However, reconstitution of MBL deficient serum with rMBL did not change the relative size of the FCN molecules suggestive for a limited redistribution in fluid phase of already formed complexes. Our findings demonstrate that rMBL can associate with free non-bound MASPs in fluid phase while preserving full restoration of LP functionality. In contrast to pdMBL products containing pre-activated MASPs which become inactivated almost immediately, these current data provide a rationale for substitution studies using rMBL instead. PMID- 29997614 TI - Engineering Approaches in Human Gamma Delta T Cells for Cancer Immunotherapy. AB - Sharing both innate and adaptive immune properties, gammadeltaT cells are attractive candidates for cellular engineering. As the cancer immunotherapy field becomes increasingly busy, orthogonal approaches are required to drive advancement. Engineering of alternative effector cell types such as gammadeltaT cells represents one such approach. gammadeltaT cells can be modified using many of the techniques used in alphabetaT cell engineering, with the added advantage of innate-like tumor recognition and killing. Progress has been made in T-cell receptor transfer to and from gammadeltaT cells as well as in a number of chimeric antigen receptor-based strategies. As the cancer immunotherapy field moves beyond repetitive iteration of established constructs to more creative solutions, gammadeltaT cells may offer an attractive chassis to drive anti-tumor responses that are not only broader, but also possess a more favorable safety profile. PMID- 29997615 TI - Chromatin Binding of c-REL and p65 Is Not Limiting for Macrophage IL12B Transcription During Immediate Suppression by Ovarian Carcinoma Ascites. AB - Tumors frequently exploit homeostatic mechanisms that suppress expression of IL 12, a central mediator of inflammatory and anti-tumor responses. The p40 subunit of the IL-12 heterodimer, encoded by IL12B, is limiting for these functions. Ovarian carcinoma patients frequently produce ascites which exerts immunosuppression by means of soluble factors. The NFkappaB pathway is necessary for transcription of IL12B, which is not expressed in macrophages freshly isolated from ascites. This raises the possibility that ascites prevents IL12B expression by perturbing NFkappaB binding to chromatin. Here, we show that ascites-mediated suppression of IL12B induction by LPS plus IFNgamma in primary human macrophages is rapid, and that suppression can be reversible after ascites withdrawal. Nuclear translocation of the NFkappaB transcription factors c-REL and p65 was strongly reduced by ascites. Surprisingly, however, their binding to the IL12B locus and to CXCL10, a second NFkappaB target gene, was unaltered, and the induction of CXCL10 transcription was not suppressed by ascites. These findings indicate that, despite its reduced nuclear translocation, NFkappaB function is not generally impaired by ascites, suggesting that ascites-borne signals target additional pathways to suppress IL12B induction. Consistent with these data, IL 10, a clinically relevant constituent of ascites and negative regulator of NFkappaB translocation, only partially recapitulated IL12B suppression by ascites. Finally, restoration of a defective IL-12 response by appropriate culture conditions was observed only in macrophages from a subset of donors, which may have important implications for the understanding of patient-specific immune responses. PMID- 29997616 TI - Probiotic Lactobacillus acidophilus Strain INMIA 9602 Er 317/402 Administration Reduces the Numbers of Candida albicans and Abundance of Enterobacteria in the Gut Microbiota of Familial Mediterranean Fever Patients. AB - Intestinal microorganisms play a crucial role in health and disease. The disruption of host-microbiota homeostasis has been reported to occur not only during disease development but also as a result of medication. Familial Mediterranean fever (FMF) is an inflammatory genetic disease characterized by elevated systemic reactivity against the commensal gut microbiota and high levels of Candida albicans in the gut. This study's major objective was to investigate the effects of commercial probiotic Narine on the relative abundance of gut bacteria (specifically, enterobacteria, lactobacilli, Staphylococcus aureus, and enterococci) of C. albicans carrier and non-carrier FMF patients in remission. Our main finding indicates that the probiotic reduces numbers of C. albicans and abundance of enterobacteria in male and female patients of C. albicans carriers and non-carriers. It has pivotal effect on Enterococcus faecalis: increase in male non-carriers and decrease in female ones regardless of C. albicans status. No effect was seen for Lactobacillus and S. aureus. Our data suggest that M694V/V726A pyrin inflammasome mutations leading to FMF disease may contribute to gender-specific differences in microbial community structure in FMF patients. The study's secondary objective was to elucidate the gender-specific differences in the gut's microbial community of FMF patients. The tendency was detected for higher counts of enterobacteria in female FMF subjects. However, the small number of patients of these groups preclude from conclusive statements, pointing at the need for additional investigations with appropriate for statistical analysis groups of subjects involved in the study. PMID- 29997619 TI - Changing the Lives of People With Primary Immunodeficiencies (PI) With Early Testing and Diagnosis. PMID- 29997618 TI - Immune Cell Dynamics Unfolded by Single-Cell Technologies. AB - The single-cell revolution is paving the way towards the molecular characterisation of every cell type in the human body, revealing relationships between cell types and states at high resolution. Changes in cellular phenotypes are particularly prevalent in the immune system and can be observed in its continuous remodelling up to adulthood, response to disease and development of immunological memory. In this review, we delve into the world of cellular dynamics of the immune system. We discuss current single-cell experimental and computational approaches in this area, giving insights into plasticity and commitment of cell fates. Finally, we provide an outlook on upcoming technological developments and predict how these will improve our understanding of the immune system. PMID- 29997617 TI - New Routes and Opportunities for Modular Construction of Particulate Vaccines: Stick, Click, and Glue. AB - Vaccines based on virus-like particles (VLPs) can induce potent B cell responses. Some non-chimeric VLP-based vaccines are highly successful licensed products (e.g., hepatitis B surface antigen VLPs as a hepatitis B virus vaccine). Chimeric VLPs are designed to take advantage of the VLP framework by decorating the VLP with a different antigen. Despite decades of effort, there have been few licensed chimeric VLP vaccines. Classic approaches to create chimeric VLPs are either genetic fusion or chemical conjugation, using cross-linkers from lysine on the VLP to cysteine on the antigen. We describe the principles that make these classic approaches challenging, in particular for complex, full-length antigens bearing multiple post-translational modifications. We then review recent advances in conjugation approaches for protein-based non-enveloped VLPs or nanoparticles, to overcome such challenges. This includes the use of strong non-covalent assembly methods (stick), unnatural amino acids for bio-orthogonal chemistry (click), and spontaneous isopeptide bond formation by SpyTag/SpyCatcher (glue). Existing applications of these methods are outlined and we critically consider the key practical issues, with particular insight on Tag/Catcher plug-and-display decoration. Finally, we highlight the potential for modular particle decoration to accelerate vaccine generation and prepare for pandemic threats in human and veterinary realms. PMID- 29997620 TI - How Lipid-Specific T Cells Become Effectors: The Differentiation of iNKT Subsets. AB - In contrast to peptide-recognizing T cells, invariant natural killer T (iNKT) cells express a semi-invariant T cell receptor that specifically recognizes self- or foreign-lipids presented by CD1d molecules. There are three major functionally distinct effector states for iNKT cells. Owning to these innate-like effector states, iNKT cells have been implicated in early protective immunity against pathogens. Yet, growing evidence suggests that iNKT cells play a role in tissue homeostasis as well. In this review, we discuss current knowledge about the underlying mechanisms that regulate the effector states of iNKT subsets, with a highlight on the roles of a variety of transcription factors and describe how each subset influences different facets of thymus homeostasis. PMID- 29997621 TI - Single-Cell Approach to Influenza-Specific CD8+ T Cell Receptor Repertoires Across Different Age Groups, Tissues, and Following Influenza Virus Infection. AB - CD8+ T cells recognizing antigenic peptides derived from conserved internal viral proteins confer broad protection against distinct influenza viruses. As memory CD8+ T cells change throughout the human lifetime and across tissue compartments, we investigated how T cell receptor (TCR) composition and diversity relate to memory CD8+ T cells across anatomical sites and immunological phases of human life. We used ex vivo peptide-HLA tetramer magnetic enrichment, single-cell multiplex RT-PCR for both the TCR-alpha (TCRalpha) and TCR-beta (TCRbeta) chains, and new TCRdist and grouping of lymphocyte interactions by paratope hotspots (GLIPH) algorithms to compare TCRs directed against the most prominent human influenza epitope, HLA-A*02:01-M158-66 (A2+M158). We dissected memory TCR repertoires directed toward A2+M158 CD8+ T cells within human tissues and compared them to human peripheral blood of young and elderly adults. Furthermore, we compared these memory CD8+ T cell repertoires to A2+M158 CD8+ TCRs during acute influenza disease in patients hospitalized with avian A/H7N9 virus. Our study provides the first ex vivo comparative analysis of paired antigen-specific TCR-alpha/beta clonotypes across different tissues and peripheral blood across different age groups. We show that human A2+M158 CD8+ T cells can be readily detected in human lungs, spleens, and lymph nodes, and that tissue A2+M158 TCRalphabeta repertoires reflect A2+M158 TCRalphabeta clonotypes derived from peripheral blood in healthy adults and influenza-infected patients. A2+M158 TCRalphabeta repertoires displayed distinct features only in elderly adults, with large private TCRalphabeta clonotypes replacing the prominent and public TRBV19/TRAV27 TCRs. Our study provides novel findings on influenza-specific TCRalphabeta repertoires within human tissues, raises the question of how we can prevent the loss of optimal TCRalphabeta signatures with aging, and provides important insights into the rational design of T cell-mediated vaccines and immunotherapies. PMID- 29997623 TI - LPS-Challenged Macrophages Release Microvesicles Coated With Histones. AB - Histones are the protein component of nucleosomes, which are the basic packing unit of chromatin. However, histones are also found in the blood, both as components of nucleosomes leaked out from dead cells, or expelled from neutrophils in the active process of NET formation. Circulating histones contribute to inflammation, and to lethality in sepsis, a hyperinflammatory condition, by interacting with specific receptors, notably toll-like receptor 4 (TLR4). Here, we show that histones are also actively released by LPS-activated macrophages in association with extracellular vesicles. Vesicle-associated histones can be recovered from the plasma of mice with sepsis. Actively released histones are on the outer surface of vesicles and can interact with TLR4. Thus, activated macrophages release histones without dying, at the same time, making their DNA more accessible and communicating to other cells that infection is present. PMID- 29997622 TI - Deterioration of Organ Function As a Hallmark in Sepsis: The Cellular Perspective. AB - Development of organ dysfunction discriminates sepsis from uncomplicated infection. The paradigm shift implicated by the new sepsis-3 definition holds that initial impairment of any organ can pave the way for multiple organ dysfunction and death. Moreover, the role of the systemic inflammatory response, central element in previous sepsis definitions, has been questioned. Most strikingly, a so far largely underestimated defense mechanism of the host, i.e., "disease tolerance," which aims at maintaining host vitality without reducing pathogen load, has gained increasing attention. Here, we summarize evidence that a dysregulation of critical cellular signaling events, also in non-immune cells, might provide a conceptual framework for sepsis-induced dysfunction of parenchymal organs in the absence of significant cell death. We suggest that key signaling mediators, such as phosphoinositide 3-kinase, mechanistic target of rapamycin, and AMP-activated protein kinase, control the balance of damage and repair processes and thus determine the fate of affected organs and ultimately the host. Therapeutic targeting of these multifunctional signaling mediators requires cell-, tissue-, or organ-specific approaches. These novel strategies might allow stopping the domino-like damage to further organ systems and offer alternatives beyond the currently available strictly supportive therapeutic options. PMID- 29997624 TI - Ontology and Function of Fibroblast-Like and Macrophage-Like Synoviocytes: How Do They Talk to Each Other and Can They Be Targeted for Rheumatoid Arthritis Therapy? AB - Fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS) are the two main cellular components of the synovium. It has been widely reported that FLS and MLS play essential roles in the joint pathology of rheumatoid arthritis (RA). Although various studies have analyzed both human and animal tissues and have shown that both cell types are involved in different stages of RA, ontology, and specific functions of both cell populations and their interactions are not well understood. In this review, we will summarize recent research on FLS and MLS in RA and focus on the development and function of two predominant synovial cell types. In addition, we will discuss the communication between FLS or MLS and highlight potential treatments for RA that involve synoviocytes. PMID- 29997625 TI - Immune Activation, Proinflammatory Cytokines, and Conventional Risks for Cardiovascular Disease in HIV Patients: A Case-Control Study in Bahia, Brazil. AB - Background: Cardiovascular events (CVE) are an increasing cause of morbi mortality for HIV patients. The antiretroviral therapy (ART), persistent immune activation, and life style are factors that can increase CVE for such patients. We performed a case-control study to evaluate the role of coinfections and immune markers associated with CVE. Methods: We included patients under ART, with undetectable plasma viral load >=12 months. Patients presenting any condition of risk for CVE were considered cases, and those without CVE risk conditions were controls. History of viral infections (Epstein-Barr virus, hepatitis C virus, hepatitis B virus, and cytomegalovirus), exposure to antiretroviral drugs, time since HIV diagnosis/under ART, and life style (demographics, weight, smoking, alcohol, and illicit drug use) were assessed. CD4/CD8 nadir and current counts, nadir and current CD4/CD8 ratio, immune activation markers (CD4CD38HLADR, CD8CD38HLADR), and serum levels of eight cytokines [IL-2, IL-4, IL-6, IL-10, tumoral necrosis factor-alpha (TNF-alpha), interferon gamma, macrophage inflammatory proteins 1 alpha, and interferon-inducing protein (IP-10)] were measured. Results: Two-thirds of patients were males. Cases (N = 106) were older (52.8 vs 49.5 years, p = 0.002), had higher levels of creatinine (0.97 vs 0.87 mg/dL, p = 0.002) and IL-6 (0.67 vs 0.52 pg/mL, p = 0.04) than controls (N = 114). There was no difference between groups regarding frequency of CD4CD39HLADR+ or CD8CD38HLADR+ cells. We found a significant correlation (all patients) between increased frequency of CD4CD38HLADR+ cells and levels of IP-10 (r = 0.171, p = 0.02) and TNF-alpha (r = 0.187, p = 0.01). Levels of IL-6 (r = 0.235, p = 0.02), TNF-alpha (r = 0.267, p = 0.01), and IP-10 (r = 0.205, p = 0.04) were correlated with CD4CD38HLADR+ cells, in controls. Higher frequency of CD4CD38HLADR+ cells was also correlated with levels of IP-10 (r = 0.271, p = 0.04) in patients presenting with arterial hypertension. Frequency of CD4CD38HLADR+ cells was negatively correlated with levels of IL-2 (r = -0.639, p = 0.01) and IL-6 (r = 0.0561, p = 0.03) in patients with hypercholesterolemia. No association was detected between viral infections or smoking/alcohol use and immune activation markers. Conclusion: Our results indicate IL-6 levels are associated with increased CV risk. Activated CD4+ T cells were associated with increased levels of proinflammatory cytokines. PMID- 29997626 TI - Dissecting Epstein-Barr Virus-Specific T-Cell Responses After Allogeneic EBV Specific T-Cell Transfer for Central Nervous System Posttransplant Lymphoproliferative Disease. AB - Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disease (PTLD) with central nervous system (CNS) involvement is a severe complication after solid organ transplantation. Standard treatment with reduction of immunosuppression and anti-CD20 antibody application often fails leading to poor outcome. Here, we report the case of an 11-year-old boy with multilocular EBV positive CNS PTLD 10 years after liver transplantation. Complete remission was achieved by repeated intravenous and intrathecal anti-CD20 antibody rituximab administration combined with intrathecal chemotherapy (methotrexate, cytarabine, prednisone) over a time period of 3 months. Due to the poor prognosis of CNS PTLD and lack of EBV-specific T-cells (EBV-CTLs) in patient's blood, we decided to perform EBV-directed T-cell immunotherapy as a consolidating treatment. The patient received five infusions of allogeneic EBV-CTLs from a 5/10 HLA-matched unrelated third-party donor. No relevant acute toxicity was observed. EBV-CTLs became detectable after first injection and increased during the treatment course. Next-generation sequencing (NGS) TCR-profiling verified the persistence and expansion of donor-derived EBV-specific clones. After two transfers, epitope spreading to unrelated EBV antigens occurred suggesting onset of endogenous T cell production, which was supported by detection of recipient-derived clones in NGS TCR-profiling. Continuous complete remission was confirmed 27 months after initial diagnosis. PMID- 29997627 TI - gammadelta T Cells: Crosstalk Between Microbiota, Chronic Inflammation, and Colorectal Cancer. AB - Increasing evidence suggests that intestinal microbiota dysbiosis and chronic inflammation contribute to colorectal cancer (CRC) development. gammadelta T cells represent a major innate immune cell population in the intestinal epithelium that is involved in the maintenance of gut homeostasis, inflammation regulation, and carcinogenesis. The important contributions of gammadelta T cells are (i) to perform a protective role in the context of barrier damage and pathogenic microorganism translocation; (ii) to exert either pro- or anti inflammatory effects at different inflammatory stages; and (iii) to boost the crosstalk between immune cells and tumor microenvironment, inducing a cascade of suppressive immune responses. Understanding the crucial role of gammadelta T cells would enable us to manipulate these cells during the CRC sequence and improve the efficacy of tumor therapy. PMID- 29997629 TI - Cleavage of Toll-Like Receptor 9 Ectodomain Is Required for In Vivo Responses to Single Strand DNA. AB - Mouse toll-like receptor 9 (TLR9) is an endosomal sensor for single-stranded DNA. TLR9 is transported from the endoplasmic reticulum to endolysosomes by a multiple transmembrane protein Unc93 homolog B1, and proteolytically cleaved at its ectodomain. The structure of TLR9 and its biochemical analyses have shown that the proteolytic cleavage of TLR9 ectodomain enables TLR9-dimerization and TLR9 activation. However, the requirement of TLR9 cleavage in vivo has not been studied. We here show that the 13 amino acids deletion at the cleavage site made TLR9 resistant to proteolytic cleavage. The deletion mutation in the Tlr9 gene impaired TLR9-dependent cytokine production in conventional dendritic cells from the mutant mice. Not only in vitro, in vivo production of inflammatory cytokines (TNF-alpha and IL-12p40), chemokine (CCR5/RANTES), and type I interferon (IFN alpha) induced by administration of TLR9 ligand was also impaired. These results demonstrate that the TLR9 cleavage is required for TLR9 responses in vivo. PMID- 29997628 TI - Dendritic Cells in the Cross Hair for the Generation of Tailored Vaccines. AB - Vaccines represent the discovery of utmost importance for global health, due to both prophylactic action to prevent infections and therapeutic intervention in neoplastic diseases. Despite this, current vaccination strategies need to be refined to successfully generate robust protective antigen-specific memory immune responses. To address this issue, one possibility is to exploit the high efficiency of dendritic cells (DCs) as antigen-presenting cells for T cell priming. DCs functional plasticity allows shaping the outcome of immune responses to achieve the required type of immunity. Therefore, the choice of adjuvants to guide and sustain DCs maturation, the design of multifaceted vehicles, and the choice of surface molecules to specifically target DCs represent the key issues currently explored in both preclinical and clinical settings. Here, we review advances in DCs-based vaccination approaches, which exploit direct in vivo DCs targeting and activation options. We also discuss the recent findings for efficient antitumor DCs-based vaccinations and combination strategies to reduce the immune tolerance promoted by the tumor microenvironment. PMID- 29997630 TI - Interaction Between Macrophage Migration Inhibitory Factor and CD74 in Human Immunodeficiency Virus Type I Infected Primary Monocyte-Derived Macrophages Triggers the Production of Proinflammatory Mediators and Enhances Infection of Unactivated CD4+ T Cells. AB - Understanding the mechanisms of human immunodeficiency virus type I (HIV-1) pathogenesis would facilitate the identification of new therapeutic targets to control the infection in face of current antiretroviral therapy limitations. CD74 membrane expression is upregulated in HIV-1-infected cells and the magnitude of its modulation correlates with immune hyperactivation in HIV-infected individuals. In addition, plasma level of the CD74 activating ligand macrophage migration inhibitory factor (MIF) is increased in infected subjects. However, the role played by MIF/CD74 interaction in HIV pathogenesis remains unexplored. Here, we studied the effect of MIF/CD74 interaction on primary HIV-infected monocyte derived macrophages (MDMs) and its implications for HIV immunopathogenesis. Confocal immunofluorescence analysis of CD74 and CD44 (the MIF signal transduction co-receptor) expression indicated that both molecules colocalized at the plasma membrane specifically in wild-type HIV-infected MDMs. Treatment of infected MDMs with MIF resulted in an MIF-dependent increase in TLR4 expression. Similarly, there was a dose-dependent increase in the production of IL-6, IL-8, TNFalpha, IL-1beta, and sICAM compared to the no-MIF condition, specifically from infected MDMs. Importantly, the effect observed on IL-6, IL-8, TNFalpha, and IL 1beta was abrogated by impeding MIF interaction with CD74. Moreover, the use of a neutralizing alphaMIF antibody or an MIF antagonist reverted these effects, supporting the specificity of the results. Treatment of unactivated CD4+ T-cells with MIF-treated HIV-infected MDM-derived culture supernatants led to enhanced permissiveness to HIV-1 infection. This effect was lost when CD4+ T-cells were treated with supernatants derived from infected MDMs in which CD74/MIF interaction had been blocked. Moreover, the enhanced permissiveness of unactivated CD4+ T-cells was recapitulated by exogenous addition of IL-6, IL-8, IL-1beta, and TNFalpha, or abrogated by neutralizing its biological activity using specific antibodies. Results obtained with BAL and NL4-3 HIV laboratory strains were reproduced using transmitted/founder primary isolates. This evidence indicated that MIF/CD74 interaction resulted in a higher production of proinflammatory cytokines from HIV-infected MDMs. This caused the generation of an inflammatory microenvironment which predisposed unactivated CD4+ T-cells to HIV-1 infection, which might contribute to viral spreading and reservoir seeding. Overall, these results support a novel role of the MIF/CD74 axis in HIV pathogenesis that deserves further investigation. PMID- 29997631 TI - Metabolomic Evaluation of the Quality of Leaf Lettuce Grown in Practical Plant Factory to Capture Metabolite Signature. AB - Vegetables produce metabolites that affect their taste and nutritional value and compounds that contribute to human health. The quality of vegetables grown in plant factories under hydroponic cultivation, e.g., their sweetness and softness, can be improved by controlling growth factors including the temperature, humidity, light source, and fertilizer. However, soil is cheaper than hydroponic cultivation and the visual phenotype of vegetables grown under the two conditions is different. As it is not clear whether their metabolite composition is also different, we studied leaf lettuce raised under the hydroponic condition in practical plant factory and strictly controlled soil condition. We chose two representative cultivars, "black rose" (BR) and "red fire" (RF) because they are of high economic value. Metabolite profiling by comprehensive gas chromatography mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) resulted in the annotation of 101 metabolites from 223 peaks detected by GC-MS; LC-MS yielded 95 peaks. The principal component analysis (PCA) scatter plot showed that the most distinct separation patterns on the first principal component (PC1) coincided with differences in the cultivation methods. There were no clear separations related to cultivar differences in the plot. PC1 loading revealed the discriminant metabolites for each cultivation method. The level of amino acids such as lysine, phenylalanine, tryptophan, and valine was significantly increased in hydroponically grown leaf lettuce, while soil cultivation derived leaf lettuce samples contained significantly higher levels of fatty-acid derived alcohols (tetracosanol and hexacosanol) and lettuce-specific sesquiterpene lactones (lactucopicrin-15-oxalate and 15-deoxylactucin-8-sulfate). These findings suggest that the metabolite composition of leaf lettuce is primarily affected by its cultivation condition. As the discriminant metabolites reveal important factors that contribute to the nutritional value and taste characteristics of leaf lettuce, we performed comprehensive metabolite profiling to identify metabolite compositions, i.e., metabolite signature, that directly improve its quality and value. PMID- 29997632 TI - A Leaf Modeling and Multi-Scale Remeshing Method for Visual Computation via Hierarchical Parametric Vein and Margin Representation. AB - This paper introduces a novel hierarchical structured representation for leaf modeling and proposes a corresponding multi-resolution remeshing method for large scale visual computation. Leaf modeling is a very difficult and challenging problem due to the wide variations in the shape and structures among different species of plants. Firstly, we introduce a Hierarchical Parametric Veins and Margin (HPVM) representation approach, which describes the leaf biological structures and exact geometry via interpolation of parametric curves from the extracted vein features from non-manifold data. Secondly, a parametric surface model is constructed using HPVM with geometric and structured constraints. Finally, for a given size, we adapt a multi-step discrete point resampling strategy and a CDT-based (Constrained Delaunay Triangulation) meshing method to generate a mesh model. Our representation consists of three coupled data structures, a core hierarchical parametric data structure of veins and margin for the leaf skeleton, the corresponding parametric surface model, and a set of unstructured triangular meshes with user-specified density for the leaf membrane. Numerical experiments show that our method can obtain high quality meshes from the scanned non-manifold mesh data with well-preserved biological structures and geometry. This novel approach is suitable for effective leaf simulation, rendering, texture mapping, and simulation of light distribution in crop canopies. PMID- 29997634 TI - GmWRKY49, a Salt-Responsive Nuclear Protein, Improved Root Length and Governed Better Salinity Tolerance in Transgenic Arabidopsis. AB - Plant WRKY transcription factors (TFs) are active guardians against pathogens' insurgency, key components in developmental processes, contributors in signal transduction pathways, and regulators of diverse biotic and abiotic stress responses. In this research, we isolated, cloned, and functionally characterized a new WRKY TF GmWRKY49 from soybean. GmWRKY49 is a nuclear protein which contains two highly conserved WRKY domains and a C2H2-type zinc-finger structure. The normalized expression (log2 ratio) of GmWRKY49 was 2.75- and 1.90-fold in salt tolerant and salt-susceptible soybean genotypes, respectively. The transcripts of GmWRKY49 could be detected in roots, stems, leaves, flowers, and almost no expression in pod tissues. The salinity-tolerance response of this gene was studied through overexpression in soybean composite seedlings and transgenic Arabidopsis. The effect of GmWRKY49 overexpression on root length of transgenic Arabidopsis was also investigated. Under salt stress, several parameters including germination rate, survival rate, root length, rosette diameter, relative electrolyte leakage, and proline content were significantly higher in composite seedlings and transgenic Arabidopsis than those in wild-type. Moreover, GmWRKY49 enhanced salinity tolerance in soybean mosaic seedlings and transgenic Arabidopsis. These results suggest that GmWRKY49 is a positive regulator of salinity tolerance in soybean and has high potential utilization for crop improvement. PMID- 29997633 TI - Proteomics and Phosphoproteomics of Heat Stress-Responsive Mechanisms in Spinach. AB - Elevated temperatures limit plant growth and reproduction and pose a growing threat to agriculture. Plant heat stress response is highly conserved and fine tuned in multiple pathways. Spinach (Spinacia oleracea L.) is a cold tolerant but heat sensitive green leafy vegetable. In this study, heat adaptation mechanisms in a spinach sibling inbred heat-tolerant line Sp75 were investigated using physiological, proteomic, and phosphoproteomic approaches. The abundance patterns of 911 heat stress-responsive proteins, and phosphorylation level changes of 45 phosphoproteins indicated heat-induced calcium-mediated signaling, ROS homeostasis, endomembrane trafficking, and cross-membrane transport pathways, as well as more than 15 transcription regulation factors. Although photosynthesis was inhibited, diverse primary and secondary metabolic pathways were employed for defense against heat stress, such as glycolysis, pentose phosphate pathway, amino acid metabolism, fatty acid metabolism, nucleotide metabolism, vitamin metabolism, and isoprenoid biosynthesis. These data constitute a heat stress responsive metabolic atlas in spinach, which will springboard further investigations into the sophisticated molecular mechanisms of plant heat adaptation and inform spinach molecular breeding initiatives. PMID- 29997636 TI - Genetic Architecture of Nitrogen-Deficiency Tolerance in Wheat Seedlings Based on a Nested Association Mapping (NAM) Population. AB - Genetic divergence for nitrogen utilization in germplasms is important in wheat breeding programs, especially for low nitrogen input management. In this study, a nested association mapping (NAM) population, derived from "Yanzhan 1" (a Chinese domesticated cultivar) crossed with "Hussar" (a British domesticated cultivar) and another three semi-wild wheat varieties, namely, "Cayazheda 29" (Triticum aestivum ssp. tibetanum Shao), "Yunnan" (T. aestivum ssp. yunnanense King), and "Yutian" (T. aestivum petropavloski Udats et Migusch), was used to detect quantitative trait loci (QTLs) for nitrogen utilization at the seedling stage. An integrated genetic map was constructed using 2,059 single nucleotide polymorphism (SNP) markers from a 90 K SNP chip, with a total coverage of 2,355.75 cM and an average marker spacing of 1.13 cM. A total of 67 QTLs for RDW (root dry weight), SDW (shoot dry weight), TDW (total dry weight), and RSDW (root to shoot ratio) were identified under normal nitrogen conditions (N+) and nitrogen deficient conditions (N-). Twenty-three of these QTLs were only detected under N- conditions. Moreover, 23 favorable QTLs were identified in the domesticated cultivar Yanzhan 1, 15 of which were detected under N+ conditions, while only four were detected under N- conditions. In contrast, the semi-wild cultivars contributed more favorable N--specific QTLs (eight from Cayazheda 29; nine from Yunnan), which could be further explored for breeding cultivars adapted to nitrogen-deficient conditions. In particular, QRSDW-5A.1 from YN should be further evaluated using high-resolution mapping. PMID- 29997635 TI - Development of a High-Density Genetic Map Based on Specific Length Amplified Fragment Sequencing and Its Application in Quantitative Trait Loci Analysis for Yield-Related Traits in Cultivated Peanut. AB - High-density genetic maps (HDGMs) are very useful for genomic studies and quantitative trait loci (QTL) mapping. However, the low frequency of DNA polymorphisms in peanut has limited the quantity of available markers and hindered the construction of a HDGM. This study generated a peanut genetic map with the highest number of high-quality SNPs based on specific locus amplified fragment sequencing (SLAF-seq) technology and a newly constructed RIL population ("ZH16" * "sd-H1"). The constructed HDGM included 3,630 SNP markers belonging to 2,636 bins on 20 linkage groups (LGs), and it covers 2,098.14 cM in length, with an average marker distance of 0.58 cM. This HDGM was applied for the following collinear comparison, scaffold anchoring and analysis of genomic characterization including recombination rates and segregation distortion in peanut. For QTL mapping of investigated 14 yield-related traits, a total of 62 QTLs were detected on 12 chromosomes across 3 environments, and the co-localization of QTLs was observed for these traits which were significantly correlated on phenotype. Two stable co-located QTLs for seed- and pod-related traits were significantly identified in the chromosomal end of B06 and B07, respectively. The construction of HDGM and QTL analysis for yield-related traits in this study provide useful information for fine mapping and functional analysis of genes as well as molecular marker-assisted breeding. PMID- 29997637 TI - Ionizing Radiation, Higher Plants, and Radioprotection: From Acute High Doses to Chronic Low Doses. AB - Understanding the effects of ionizing radiation (IR) on plants is important for environmental protection, for agriculture and horticulture, and for space science but plants have significant biological differences to the animals from which much relevant knowledge is derived. The effects of IR on plants are understood best at acute high doses because there have been; (a) controlled experiments in the field using point sources, (b) field studies in the immediate aftermath of nuclear accidents, and (c) controlled laboratory experiments. A compilation of studies of the effects of IR on plants reveals that although there are numerous field studies of the effects of chronic low doses on plants, there are few controlled experiments that used chronic low doses. Using the Bradford-Hill criteria widely used in epidemiological studies we suggest that a new phase of chronic low-level radiation research on plants is desirable if its effects are to be properly elucidated. We emphasize the plant biological contexts that should direct such research. We review previously reported effects from the molecular to community level and, using a plant stress biology context, discuss a variety of acute high- and chronic low-dose data against Derived Consideration Reference Levels (DCRLs) used for environmental protection. We suggest that chronic low-level IR can sometimes have effects at the molecular and cytogenetic level at DCRL dose rates (and perhaps below) but that there are unlikely to be environmentally significant effects at higher levels of biological organization. We conclude that, although current data meets only some of the Bradford-Hill criteria, current DCRLs for plants are very likely to be appropriate at biological scales relevant to environmental protection (and for which they were intended) but that research designed with an appropriate biological context and with more of the Bradford Hill criteria in mind would strengthen this assertion. We note that the effects of IR have been investigated on only a small proportion of plant species and that research with a wider range of species might improve not only the understanding of the biological effects of radiation but also that of the response of plants to environmental stress. PMID- 29997639 TI - Differential Effects of Climate Warming on the Nectar Secretion of Early- and Late-Flowering Mediterranean Plants. AB - Floral nectar is a vital resource for pollinators, thus having a very important role in ecosystem functioning. Ongoing climate warming could have a negative effect on nectar secretion, particularly in the Mediterranean, where a strong temperature rise is expected. In turn, decreased nectar secretion, together with shifts in flowering phenology can disrupt plant-pollinator interactions and consequently affect the entire ecosystem. Under fully controlled conditions, we tested how temperature influenced nectar secretion (through nectar volume, sugar concentration, sugar content, and number of flowers produced) in six Mediterranean plant species flowering from winter to summer (viz. Asphodelus ramosus, Ballota acetabulosa, Echium plantagineum, Lavandula stoechas, Rosmarinus officinalis, and Teucrium divaricatum). We compared the changes in nectar secretion under temperatures expected by the end of the century and estimated the effect of climate warming on nectar secretion of plants flowering in different seasons. We found a significant effect of temperature on nectar secretion, with a negative effect of very high temperatures in all species. Optimal temperatures for nectar secretion were similar to the mean temperatures in the recent past (1958-2001) during the respective flowering time of each species. Increasing temperatures, however, will affect differently the early-flowering (blooming in winter and early spring) and late-flowering species (blooming in late spring and early summer). Temperature rise expected by the end of the century will shift the average temperature beyond the optimal range for flower production and the sugar produced per plant in late-flowering species. Therefore, we expect a future decrease in nectar secretion of late-flowering species, which could reduce the amount of nectar resources available for their pollinators. Early-flowering plants will be less affected (optimal temperatures were not significantly different from the future projected temperatures), and may in some cases even benefit from rising temperatures. However, as many earlier studies have found that early-flowering species are more prone to shifts in phenology, the plant pollinator interactions could instead become affected in a different manner. Consequently, climate warming will likely have a distinctive effect on both plant and pollinator populations and their interactions across different seasons. PMID- 29997638 TI - A Pathogen-Responsive Leucine Rich Receptor Like Kinase Contributes to Fusarium Resistance in Cereals. AB - Receptor-like kinases form the largest family of receptors in plants and play an important role in recognizing pathogen-associated molecular patterns and modulating the plant immune responses to invasive fungi, including cereal defenses against fungal diseases. But hitherto, none have been shown to modulate the wheat response to the economically important Fusarium head blight (FHB) disease of small-grain cereals. Homologous genes were identified on barley chromosome 6H (HvLRRK-6H) and wheat chromosome 6DL (TaLRRK-6D), which encode the characteristic domains of surface-localized receptor like kinases. Gene expression studies validated that the wheat TaLRRK-6D is highly induced in heads as an early response to both the causal pathogen of FHB disease, Fusarium graminearum, and its' mycotoxic virulence factor deoxynivalenol. The transcription of other wheat homeologs of this gene, located on chromosomes 6A and 6B, was also up-regulated in response to F. graminearum. Virus-induced gene silencing (VIGS) of the barley HvLRRK-6H compromised leaf defense against F. graminearum. VIGS of TaLRRK-6D in two wheat cultivars, CM82036 (resistant to FHB disease) and cv. Remus (susceptible to FHB), confirmed that TaLRRK-6D contributes to basal resistance to FHB disease in both genotypes. Although the effect of VIGS did not generally reduce grain losses due to FHB, this experiment did reveal that TaLRRK-6D positively contributes to grain development. Further gene expression studies in wheat cv. Remus indicated that VIGS of TaLRRK-6D suppressed the expression of genes involved in salicylic acid signaling, which is a key hormonal pathway involved in defense. Thus, this study provides the first evidence of receptor like kinases as an important component of cereal defense against Fusarium and highlights this gene as a target for enhancing cereal resistance to FHB disease. PMID- 29997640 TI - Identification of Genomic Regions Controlling Leaf Scald Resistance in Sugarcane Using a Bi-parental Mapping Population and Selective Genotyping by Sequencing. AB - Leaf scald, caused by Xanthomonas albilineans, is a major sugarcane disease worldwide. The disease is managed primarily with resistant cultivars obtained through classical breeding. However, erratic symptom expression hinders the reliability and reproducibility of selection for resistance. The development and use of molecular markers associated with incompatible/compatible reactions could overcome this limitation. The aim of the present work was to find leaf scald resistance-associated molecular markers in sugarcane to facilitate marker assisted breeding. A genetic linkage map was constructed by selective genotyping of 89 pseudo F2 progenies of a cross between LCP 85-384 (resistant) and L 99-226 (susceptible) using 1,948 single dose (SD) markers generated from SSR, eSSR, and SNPs. Of these, 1,437 SD markers were mapped onto 294 linkage groups, which covered 19,464 cM with 120 and 138 LGs assigned to the resistant and susceptible parent, respectively. Composite interval mapping identified 8 QTLs associated with the disease response with LOD scores ranging from 3.0 to 7.6 and explained 5.23 to 16.93% of the phenotypic variance. Comparative genomics analysis with Sorghum bicolor allowed us to pinpoint three SNP markers that explained 16% phenotypic variance. In addition, representative stress-responsive genes close to the major effect QTLs showed upregulation in their expression in response to the bacterial infection in leaf/meristem tissue. PMID- 29997641 TI - Identification and Functional Characterization of a Microtubule-Associated Protein, GhCLASP2, From Upland Cotton (Gossypium hirsutum L.). AB - Cytoplasmic linker-associated proteins (CLASPs) are microtubule-associated proteins (MAPs) involved in regulation of dynamics of microtubules (MTs) that play an important role in plant growth and development. In this study, we identified cotton CLASP genes and investigated the function of GhCLASP2. GhCLASP2 was mainly expressed in stem and developing fibers, especially in fibers of the secondary cell wall deposition stage. Ectopic expression of GhCLASP2 in Arabidopsis increased the branching number of leaf trichomes and rescued the defective phenotypes of clasp-1. In cotton, overexpression of GhCLASP2 increased fiber strength, probably related to enhanced expression levels of tubulin, cellulose synthase, and expansin genes. Suppression of GhCLASP2 caused shorter internodes and semi-dwarfism, abnormal flower stigma, aborted anthers without pollen grains, and sterility. These changed phenotypes were similar to those observed in the Arabidopsis clasp-1 mutant. GhCLASP2 was co-localized with MTs according to transient experiment. These results suggest that GhCLASP2 functions similarly as AtCLASP, acting as a MAP and controlling cotton growth and development by regulating MTs. PMID- 29997642 TI - Nutrient Use Efficiency of Southern South America Proteaceae Species. Are there General Patterns in the Proteaceae Family? AB - Plants from the Proteaceae family can thrive in old, impoverished soil with extremely low phosphorus (P) content, such as those typically found in South Western Australia (SWA) and South Africa. The South Western (SW) Australian Proteaceae species have developed strategies to deal with P scarcity, such as the high capacity to re-mobilize P from senescent to young leaves and the efficient use of P for carbon fixation. In Southern South America, six Proteaceae species grow in younger soils than those of SWA, with a wide variety of climatic and edaphic conditions. However, strategies in the nutrient use efficiency of Southern South (SS) American Proteaceae species growing in their natural ecosystems remain widely unknown. The aim of this study was to evaluate nutrient resorption efficiency and the photosynthetic nutrients use efficiency by SS American Proteaceae species, naturally growing in different sites along a very extensive latitudinal gradient. Mature and senescent leaves of the six SS American Proteaceae species (Embothrium coccineum, Gevuina avellana, Orites myrtoidea Lomatia hirsuta, L. ferruginea, and L. dentata), as well as, soil samples were collected in nine sites from southern Chile and were subjected to chemical analyses. Nutrient resorption (P and nitrogen) efficiency in leaves was estimated in all species inhabiting the nine sites evaluated, whereas, the photosynthetic P use efficiency (PPUE) and photosynthetic nitrogen (N) use efficiency (PNUE) per leaf unit were determined in two sites with contrasting nutrient availability. Our study exhibit for the first time a data set related to nutrient use efficiency in the leaves of the six SS American Proteaceae, revealing that for all species and sites, P and N resorption efficiencies were on average 47.7 and 50.6%, respectively. No correlation was found between leaf nutrient (P and N) resorption efficiency and soil attributes. Further, different responses in PPUE and PNUE were found among species and, contrary to our expectations, a higher nutrient use efficiency in the nutrient poorest soil was not found. We conclude that SS American Proteaceae species did not show a general pattern in the nutrient use efficiency among them neither with others Proteaceae species reported in the literature. PMID- 29997643 TI - A Dynamic Multi-Tissue Flux Balance Model Captures Carbon and Nitrogen Metabolism and Optimal Resource Partitioning During Arabidopsis Growth. AB - Plant metabolism is highly adapted in response to its surrounding for acquiring limiting resources. In this study, a dynamic flux balance modeling framework with a multi-tissue (leaf and root) diel genome-scale metabolic model of Arabidopsis thaliana was developed and applied to investigate the reprogramming of plant metabolism through multiple growth stages under different nutrient availability. The framework allowed the modeling of optimal partitioning of resources and biomass in leaf and root over diel phases. A qualitative flux map of carbon and nitrogen metabolism was identified which was consistent across growth phases under both nitrogen rich and limiting conditions. Results from the model simulations suggested distinct metabolic roles in nitrogen metabolism played by enzymes with different cofactor specificities. Moreover, the dynamic model was used to predict the effect of physiological or environmental perturbation on the growth of Arabidopsis leaves and roots. PMID- 29997644 TI - QTL Mapping of Seed Glucosinolate Content Responsible for Environment in Brassica napus. AB - Glucosinolates (GSLs) are a major class of secondary metabolites. The content of seed GSL is largely regulated by environments in rapeseed (Brassica napus). However, the genetic control of seed GSL content responsible for environment in B. napus has been poorly understood. In the current study, a doubled haploid (DH) population from a cross between winter and semi-winter lines of rapeseed was grown in two distinct eco-environments, Germany and China, to evaluate the eco environment effect and dissect the quantitative trait loci (QTL) responsible for environment for seed GSL in rapeseed. The deviation value of GSL content between eco-environments (GSLE) was calculated for each line in the DH population and the QTLs for GSLE were detected. GSLE ranged from -46.90 to 36.13 MUmol g-1 meal in the DH population, suggesting the prominent eco-environmental effects for seed GSL in rapeseed. Four QTLs for GSLE were identified on chromosomes A04, A06, and A09 explaining 4.70~9.93% of the phenotypic variation. Comparison of QTLs of seed GSL content between different eco-environments found three QTLs for GSL on A02 from 37.6 to 45.4 cM, A04 from 0 to 17.2 cM, and A09 from 67.0 to 98.6 cM exhibited significant difference of QTL effect between the German and Chinese eco environments (P < 0.01), indicating the environment sensibility of these loci on seed GSL content. Moreover, flowering time (FT), an important environment adaptation trait in plant, was also investigated in this study. Comparative QTL analysis among GSLE, GSL, and FT revealed that three regions on chromosomes A02, A04, and A09 not only exhibited significant differences in QTL effect between Germany and China, but also co-located with the QTL intervals of GSLE and FT. Our results revealed that most of the GSL loci can influence GSL accumulation under different eco-environments, whereas the three QTL intervals on A02, A04, and A09 might be sensitive to the eco-environments for seed GSL content. PMID- 29997645 TI - Comparative Aerial and Ground Based High Throughput Phenotyping for the Genetic Dissection of NDVI as a Proxy for Drought Adaptive Traits in Durum Wheat. AB - High-throughput phenotyping platforms (HTPPs) provide novel opportunities to more effectively dissect the genetic basis of drought-adaptive traits. This genome wide association study (GWAS) compares the results obtained with two Unmanned Aerial Vehicles (UAVs) and a ground-based platform used to measure Normalized Difference Vegetation Index (NDVI) in a panel of 248 elite durum wheat (Triticum turgidum L. ssp. durum Desf.) accessions at different growth stages and water regimes. Our results suggest increased ability of aerial over ground-based platforms to detect quantitative trait loci (QTL) for NDVI, particularly under terminal drought stress, with 22 and 16 single QTLs detected, respectively, and accounting for 89.6 vs. 64.7% phenotypic variance based on multiple QTL models. Additionally, the durum panel was investigated for leaf chlorophyll content (SPAD), leaf rolling and dry biomass under terminal drought stress. In total, 46 significant QTLs affected NDVI across platforms, 22 of which showed concomitant effects on leaf greenness, 2 on leaf rolling and 10 on biomass. Among 9 QTL hotspots on chromosomes 1A, 1B, 2B, 4B, 5B, 6B, and 7B that influenced NDVI and other drought-adaptive traits, 8 showed per se effects unrelated to phenology. PMID- 29997647 TI - Commentary: Directions for Optimization of Photosynthetic Carbon Fixation: RuBisCO's Efficiency May Not Be So Constrained After All. PMID- 29997646 TI - Meloidogyne incognita PASSE-MURAILLE (MiPM) Gene Encodes a Cell-Penetrating Protein That Interacts With the CSN5 Subunit of the COP9 Signalosome. AB - The pathogenicity of phytonematodes relies on secreted virulence factors to rewire host cellular pathways for the benefits of the nematode. In the root-knot nematode (RKN) Meloidogyne incognita, thousands of predicted secreted proteins have been identified and are expected to interact with host proteins at different developmental stages of the parasite. Identifying the host targets will provide compelling evidence about the biological significance and molecular function of the predicted proteins. Here, we have focused on the hub protein CSN5, the fifth subunit of the pleiotropic and eukaryotic conserved COP9 signalosome (CSN), which is a regulatory component of the ubiquitin/proteasome system. We used affinity purification-mass spectrometry (AP-MS) to generate the interaction network of CSN5 in M. incognita-infected roots. We identified the complete CSN complex and other known CSN5 interaction partners in addition to unknown plant and M. incognita proteins. Among these, we described M. incognita PASSE-MURAILLE (MiPM), a small pioneer protein predicted to contain a secretory peptide that is up regulated mostly in the J2 parasitic stage. We confirmed the CSN5-MiPM interaction, which occurs in the nucleus, by bimolecular fluorescence complementation (BiFC). Using MiPM as bait, a GST pull-down assay coupled with MS revealed some common protein partners between CSN5 and MiPM. We further showed by in silico and microscopic analyses that the recombinant purified MiPM protein enters the cells of Arabidopsis root tips in a non-infectious context. In further detail, the supercharged N-terminal tail of MiPM (NTT-MiPM) triggers an unknown host endocytosis pathway to penetrate the cell. The functional meaning of the CSN5-MiPM interaction in the M. incognita parasitism is discussed. Moreover, we propose that the cell-penetrating properties of some M. incognita secreted proteins might be a non-negligible mechanism for cell uptake, especially during the steps preceding the sedentary parasitic phase. PMID- 29997649 TI - Diagnostic Benefit of Simultaneous Capsule Endoscopy Using Two Different Systems. AB - Background/Aims: Capsule endoscopy (CE) is a noninvasive test for diagnosing small bowel disorders. However, several studies reported that the CE-based visualization is suboptimal. This study, the first to use two CEs simultaneously, aimed at evaluating the diagnostic ability of dual CE. Methods: Dual CE procedures were prospectively conducted. All patients completed bowel cleansing 2 hours before examination. Subsequently, they simultaneously swallowed two capsules: MiroCam (IntroMedic, Seoul, Korea) and PillCam SB3 (Medtronic, Minneapolis, USA). We assessed the completeness and feasibility of small bowel examination and the detection rate of duodenal papilla and diagnostic yield. Results: Twenty consecutive patients who underwent complete small bowel examination with dual CE were enrolled in the study. The mean time of small bowel passage was 245 +/- 99 min. Dual CE examination increased the duodenal papilla detection rate to up to 75% (versus PillCam SB3 alone (P = 0.031) and MiroCam alone (P = 0.063)) and overall diagnostic yield to up to 70% (P = 0.063) in comparison to single CE. Adverse events or electrical interference during data transmission between the two capsule endoscopes were not detected. Conclusions: In this study, we found that dual CE enhances diagnostic accuracy and could increase the diagnostic power of existing CE systems using simply applicable methods. This trial is registered with KCT0002541. PMID- 29997650 TI - Diabetic Microvascular Complications. PMID- 29997648 TI - Laterality of Poststroke Cortical Motor Activity during Action Observation Is Related to Hemispheric Dominance. AB - Background: Increased activity in the lesioned hemisphere has been related to improved poststroke motor recovery. However, the role of the dominant hemisphere and its relationship to activity in the lesioned hemisphere-has not been widely explored. Objective: Here, we examined whether the dominant hemisphere drives the lateralization of brain activity after stroke and whether this changes based on if the lesioned hemisphere is the dominant hemisphere or not. Methods: We used fMRI to compare cortical motor activity in the action observation network (AON), motor-related regions that are active both during the observation and execution of an action, in 36 left hemisphere dominant individuals. Twelve individuals had nondominant, right hemisphere stroke, twelve had dominant, left-hemisphere stroke, and twelve were healthy age-matched controls. We previously found that individuals with left dominant stroke show greater ipsilesional activity during action observation. Here, we examined if individuals with nondominant, right hemisphere stroke also showed greater lateralized activity in the ipsilesional, right hemisphere or in the dominant, left hemisphere and compared these results with those of individuals with dominant, left hemisphere stroke. Results: We found that individuals with right hemisphere stroke showed greater activity in the dominant, left hemisphere, rather than the ipsilesional, right hemisphere. This left-lateralized pattern matched that of individuals with left, dominant hemisphere stroke, and both stroke groups differed from the age-matched control group. Conclusions: These findings suggest that action observation is lateralized to the dominant, rather than ipsilesional, hemisphere, which may reflect an interaction between the lesioned hemisphere and the dominant hemisphere in driving lateralization of brain activity after stroke. Hemispheric dominance and laterality should be carefully considered when characterizing poststroke neural activity. PMID- 29997651 TI - The Activity Concentrations and Radium Equivalent Activity in Soil Samples Collected from the Eastern Part of Basrah Governorate in Southern Iraq. AB - Clay soil samples (0, 30, and 60 cm depths) were collected from two districts (Abu Al Khasib and Ad Dayr) in Basrah governorate in southern Iraq for gamma-ray spectroscopy. The activity concentrations for natural existing radionuclides in 18 soil samples were measured using high-purity germanium detector HPGe. From the obtained results of gamma-ray spectroscopy, the 238U activity concentrations were found to be ranging from 2.4 to 5.6 ppm with an average of 3.5 ppm in Abu Al Khasib and ranging from 2.1 to 4.5 ppm with an average of 2.9 ppm in Ad Dayr. 232Th concentrations were ranging from 3.6 to 7.5 ppm with an average of 4.7 ppm in Abu Al Khasib and ranging from 3.7 to 7.9 ppm with an average of 5.0 ppm in Ad Dayr. 40K concentration was ranging from 0.1% to 2.0% with an average of 1.2% in Abu Al Khasib and ranging from 0.9% to 1.8% with an average of 1.3% in Ad Dayr. High 238U and 226Ra concentration levels were recorded in both study regions. The concentrations of 232Th are within the normal limits in both regions. High levels of 40K were recorded in some locations. Generally, in most locations, 40K activity was within normal ranges. The radium equivalent activity, the external hazard index, the internal hazard index, and the radioactivity level index were calculated to estimate the radiation hazard in Basrah. The estimated radiation hazard indices were within normal limits, except the radioactivity level index, which shows elevated values. The obtained results were compared with other countries and with the worldwide median certified values. PMID- 29997652 TI - Infants Are More Likely Than Older Children to Have Surgery for Cervical Infections. AB - Objectives: To identify differences in cervical infection management in infants versus older children. Methods: Charts of patients 0-18 years, diagnosed with a cervical infection at our institution between 2004 and 2015, were included. Age, gender, presenting symptoms, comorbidities, CT scan findings and management including admission, procedures, antibiotics, cultures, length of stay, readmission rates, and complications were included. Results: 239 patients were included: mean age was 4.6 years, with 55.6% boys and 44.4% girls. Mean length of stay was 3.2 days, with no significant difference between age categories. 12.55% were readmitted within 30 days with no significant difference when stratified for age (p = 0.268). The most common presenting symptoms were fever (74.3%), swelling (71.4%), and neck pain (48.2%). Infants had fewer symptoms documented than older children. 51% has lateral neck infections, and these were more common in younger children (p < 0.001). The most common antibiotic used was amoxicillin-clavulanic acid in 53.96% of inpatients and 48.05% of outpatients. Infants were most likely to have MRSA isolates (29.2% versus 11.7% of older children, p = 0.011). 70.0% went to the operating room for incision and drainage procedures. Younger children were more likely to undergo surgery, with an odds ratio of 2.38 for children under 1 year. (p = 0.029). 90.9% of infants underwent surgery with radiolucencies of at least 1 cm diameter in contrast to 50% of children over 8 years old. Conclusions: This study emphasizes the importance of considering early operative treatment of cervical abscesses in infants despite fewer symptoms and smaller radiolucencies on CT. PMID- 29997653 TI - Age at Onset and Social Cognitive Impairment in Clinically Stabilized Patients with Schizophrenia: An Ecological Cross-Sectional Study. AB - Objective: Purposes of the present study were to assess the social cognitive impairment in schizophrenia and to detect if some clinical variables (particularly age at onset) are predictive of general/social cognitive deficit in schizophrenia patients. Method: Thirty-five clinically stabilized schizophrenia outpatients were assessed by the Brief Assessment of Cognition in Schizophrenia (BACS) and by Torralva's social cognition battery. Binary logistic models were performed to find an eventual association between continuous clinical variables and cognitive test failures. The total sample was divided in groups according to dichotomous variables (gender, diagnostic subtypes and type of abuse) and the presence of cognitive deficits was compared between groups by chi2 tests. Results: An earlier age at onset was found to be predictive of frontal cognitive impairment (Tower of London p=0.038, OR=0.702). Female gender was more probably associated with mistakes at MET-HV (chi2= 4.80, p=0.05, phi=0.40) and HOTEL tests (chi2= 5.25, p=0.04, phi=0.4) than male one. Cannabis abusers showed more frequently deficits on verbal fluency (chi2= 9.35, p=0.04, phi=0.52) and executive functioning (Tower of London) (chi2= 11.67, p=0.02, phi=0.58) than alcohol/cocaine ones. Conclusion: Female patients with an early age at onset and cannabis abuse seem to have the worst general and social cognitive profile among patients suffering from schizophrenia. PMID- 29997654 TI - Psychosocial Stresses and Concerns of People Living in Tehran: A Survey on 6000 Adult Participants. AB - Objective: Nowadays stress and tensions are among the most important factors affecting health. Identifying the stressors and their determinants provides substantial information for understanding the health of the community. Method: This descriptive cross-sectional study was conducted on citizens over 18 years who were living in all 22 districts of Tehran in 2017. The participants were selected using multistage cluster sampling method. The research tool was a checklist that evaluated various factors. Different statistical tests, such as descriptive tests and logistic regression, were used for data analysis. Results: Of the participants, 82.7% experienced at least 1severe stress during the past year. In the last year, 45.6% of the participants had at least 1severe economic stress, 32.3% had at least 1severe family-related stress, 28.8% had at least 1severe health-related stress, and 25.7% experienced at least 1severe future related stress. The most common psychosocial stressors experienced in the last year were concerns about personal/family future (53.7%), concerns about the financial and economic future (47.1%), and the high cost of living (41.7%). However, the most severe stresses were due to the participants' concerns about family health (14.4%), personal/family futures (13.2%), and financial and economic future (12.7%). Furthermore, health status, subjective socio-economic status, and age were the most important predictors of severe stress experiences. Conclusion: It is necessary to take actions to reduce the prevalence of common severe stresses. In addition, psychologists, psychiatrists, counselors, and social workers need to provide stress management interventions carefully to their patients. PMID- 29997656 TI - Attention-Deficit Hyperactivity Disorder in Adults Using Methamphetamine: Does It Affect Comorbidity, Quality of Life, and Global Functioning? AB - Objective: Attention-deficit hyperactivity disorder (ADHD) is common in adulthood, and it is associated with different high- risk behaviors, particularly substance use. Evidence suggests a high prevalence of ADHD in adults who take methamphetamine (METH). This study aimed at comparing functional level, quality of life, and psychiatric comorbidities in METH users with and without adult ADHD (A-ADHD). Method: In this cross-sectional study, 134 patients who had a history of METH use (at least once in lifetime) were selected from among inpatient and outpatient referrals to a psychiatric hospital. DIVA was performed for those who were positive on the Conners' Adult ADHD Rating Scales-Self-Report-Screening Version (CAARS-SR-SV). The Global Assessment of Functioning (GAF) and World Health Organization Quality of Life Scale-Brief (WHOQoL-BREF) were used to assess the participants' level of functioning and quality of life, respectively. Psychiatric comorbidities including substance use disorders were evaluated using the Structured Clinical Interview for DSM-IV-Axis I (SCID-I). Results: Among the METH users, 10.4% were diagnosed as having A-ADHD. A-ADHD was more prevalent among female METH users than males. The hyperactive-impulsive and combined types were more common than the inattentive type. Opiates and cannabis were the most commonly abused drugs by the 2 groups, while sedative-hypnotic use was significantly higher in the individuals with A-ADHD. Substance-induced mood disorder was the most prevalent comorbidity in the 2 groups and was higher in those with A-ADHD. quality of life and the GAF scores were significantly lower in those with A-ADHD and duration of METH use was higher Compared to the METH users without A-ADHD, (p>0.05). Conclusion: This study provided some preliminary findings supporting the prevalence of Adult ADHD among METH users and its negative impacts on their global functioning and quality of life. To provide more effective intervention for METH users, detection and treatment of those with A ADHD can be of clinical value. PMID- 29997655 TI - Psychological Factors Including Demographic Features, Mental Illnesses, and Personality Disorders as Predictors in Internet Addiction Disorder. AB - Objective: Problematic internet use is an important social problem among adolescents and has become a global health issue. This study identified predictors and patterns of problematic internet use among adult students. Method: In this study, 401 students were recruited using stratified sampling technique. Participants were selected among students from 4 universities in Tehran and Karaj, Iran, during 2016 and 2017. Internet Addiction Test (IAT), Millon Clinical Multiaxial Inventory - Third Edition (MCMI-III), Structured Clinical Interview for DSM (SCID-I), and semi-structured interview were used to diagnose internet addiction. Then, the association between main psychiatric disorders and internet addiction was surveyed. Data were analyzed using SPSS18 software by performing descriptive statistics and multiple logistic regression analysis methods. P- Values less than 0.05 were considered statistically significant. Results: After controlling the demographic variables, it was found that narcissistic personality disorder, obsessive- compulsive personality disorder, anxiety, bipolar disorders, depression, and phobia could increase the odds ratio (OR) of internet addiction by 2.1, 1.1, 2.6, 1.1, 2.2 and 2.5-folds, respectively (p-value<0.05), however, other psychiatric or personality disorders did not have a significant effect on the equation. Conclusion: The findings of this study revealed that some mental disorders affect internet addiction. Considering the sensitivity and importance of the cyberspace, it is necessary to evaluate mental disorders that correlate with internet addiction. PMID- 29997657 TI - Comparing the Effects of Contact-Based Education and Acceptance and Commitment Based Training on Empathy toward Mental Illnesses among Nursing Students. AB - Objective: Empathy is an important and valuable tool in therapeutic communication. Improvement barriers of empathy in psychiatric nursing education are associated with challenges, such as stress due to negative attitudes toward psychiatric disorders. The current study aimed at comparing the effects of contact-based education and commitment and acceptance-based training on empathy toward mental illnesses among nursing students. Method: In this clinical trial, 111 nursing students were selected using cluster and quota sampling methods in Mashhad, Iran. They were divided into 3 groups: (1) contact-based education (interpersonal contact among individuals with improved mental illnesses), (2) acceptance and commitment-based training, and (3) control group. The study tool was Jefferson Nurses Empathy Questionnaire, which was completed in 3 stages of pretest, posttest, and follow- up. Data were analyzed by repeated- measures ANOVA. Results: There was no significant difference between contact-based education and acceptance and commitment-based training groups in increasing the average score of total empathy during pretest, posttest, and 1-month follow- up (p = 0/92). However, a significant difference was found between contact-based education and control group (p = 0/004) and between acceptance and commitment based training and control group (p = 0/02). Conclusion: Both methods of contact based education and acceptance and commitment-based therapy were effective in increasing the level of empathy into mental illnesses in nursing students. PMID- 29997658 TI - Examining the Effectiveness of Group Positive Parenting Training on Increasing Hope and Life Satisfaction in Mothers of Children with Autism. AB - Objective: Parents of children with autism spectrum disorders are exposed to mental distress because of having a disabled child more than parents with children with other psychological disorders, and their children's disorder has a negative effect on their hope and life satisfaction. The present study aimed to examining the effectiveness of group positive parenting training on increasing hope and life satisfaction in mothers of children with autism. Method: This was a quasi-experimental study with pretest, posttest, and control and experimental groups. Mothers with autistic children (6-15 years) in Rasht consisted the statistical population of the study. All the children had a medical record and autism diagnosis based on DSM-IV-TR by a psychiatrist. Hope Questionnaires by Snyder and Life Satisfaction Questionnaire by Diener were implemented. Participants of the experimental group received positive parenting training for 8 sessions, and participants of the control group were put in the state of waiting. Descriptive statistics (mean, standard deviation, frequency, and percentage) and inferential statistics (univariate and multivariate covariance analysis) were used for data analysis. Results: In this study, 27 mothers of children with autism were examined. The mean and standard deviation of the age of mothers in the experimental group was 36.14+/- 2.47 years and it was 37+/- 3.62 years for mothers in the control group. The results of univariate covariance analysis revealed a significant difference between the scores of pretest and posttest of the experimental and control groups in life satisfaction (Sum of square = 16.558, F = 13.534, DF = 1, P = 0.002, ?=n?^2 = 0.361). Conclusion: The results of this study showed that using group positive parenting training can have a positive effect on dimensions of hope and life satisfaction in mothers of children with autism spectrum disorder. PMID- 29997659 TI - Examining the Effectiveness of Gottman Couple Therapy on Improving Marital Adjustment and Couples' Intimacy. AB - Objective: The present study aimed at examining the effectiveness of Gottman couple therapy on improving marital adjustment and couples' intimacy. Method: This was a semi- experimental study with pretest, post-test, and follow-up assessments. A total of 16 couples (32 individuals) were selected using convenience sampling method considering inclusion- exclusion criteria; they were then randomly assigned into experimental (N = 16) and control (N = 16) groups. Participants of the experimental group received ten 45-minute sessions of Gottman's couple therapy. The research tools were Spanier Questionnaire and Walker and Thompson's Questionnaire. Data were analyzed using Mixed design MANOVA. Results: Findings revealed that Gottman's couple therapy approach had positive effects on improving marital adjustment (P = 0/001) and couples' intimacy (P = 0/001). Furthermore, the results of assessments in the follow-up period indicated that Gottman's couple therapy had enduring effects on marital adjustment and couples' intimacy. Conclusion: According to the results of the present study, Gottman method can be used as an effective treatment to improve marital relationships, adjustment, and intimacy. Therefore, researchers, therapists, and other authorities should pay particular attention to this method. PMID- 29997660 TI - Preventive Intervention to Prevent Delirium in Patients Hospitalized in Intensive Care Unit. AB - Objective: Delirium is a clinical syndrome associated with multiple short- and long-term complications; therefore, prevention is an essential part of its management. This study was conducted to review the effective non-pharmacological interventions that can reduce the incidence or duration of delirium in critically ill patients. Method: A search was made in PubMed, Scopus, Psych INFO and Google Scholar databases without any time constraints. The information available was collected and sorted, and a secondary study of narrative review was done. The views of specialists on this topic were received via email and included in the texts and recommendations. Discussion: Delirium is a common, costly and potentially damaging illness in patients who are staying in hospitals, especially older patients in ICU. Thus, preventing delirium could be one of the most effective methods in preventing the complications. The present study aimed at conducting a review-validity study to generate a general view on the activities which might be effective in preventing delirium in patients. PMID- 29997661 TI - A Comparison of Autistic Like Traits in the Relatives of Patients with Autism and Schizophrenia Spectrum Disorder. AB - Objective: This study aimed to identify autistic like traits in relatives of patients with schizophrenia and autism spectrum disorder. Method: causal comparative research design was utilized. Fifty individuals among the first degree relatives of patients with autism spectrum disorder and 50 individuals among the first degree relatives of patients with schizophrenia spectrum disorder were selected. Autistic-like traits were evaluated by Autism-Spectrum Quotient (AQ). Multivariate analysis of variance was used to compare the autistic like traits in two groups. Results: First degree relatives of individuals with autism spectrum disorder got higher scores in deficiency of social skill, deficiency of communication, deficiency of attention, and attention to details. As well as they got lower scores in deficiency of imagination, in comparison to relatives of individuals with schizophrenia spectrum disorder. Conclusion: Relatives of individuals with autism spectrum disorder compared to relatives of patients with schizophrenia spectrum disorder showed higher rates of autistic like traits. Only the exception was imagination subscale. PMID- 29997662 TI - The Effectiveness of Transdiagnostic Cognitive Behavioral Therapy for Comorbid Insomnia: A Case Report. AB - Objective: Similar cognitive and behavioral factors underlie and perpetuate insomnia and emotional disorders. This brief case report aims to evaluate the effectiveness of the Unified Protocol (UP), a transdiagnostic treatment designed to target emotional disorders in treating comorbid insomnia. Method: The patient was a 32-year-old male, who met the DSM-IV-TR criteria for chronic insomnia, major depressive disorder, and generalized anxiety disorder. After 3 baseline weeks, the patient underwent 14 sessions of UP and was retested after 1-month follow-up. Consensus Sleep Diary (CSD), Insomnia Severity Index (ISI), and Pittsburgh Sleep Quality Index (PSQI) were completed during baseline, treatment, and follow-up. Results: The treatment led to improvements in sleep onset latency, time awake after sleep onset, terminal awakenings, sleep quality, and insomnia severity. These gains were maintained at 1-month follow-up. Conclusion: UP is effective in improving different symptoms of chronic insomnia. Controlled clinical studies with more cases are required to investigate the effects of UP in the treatment of insomnia. PMID- 29997663 TI - Coronary Artery Disease Presentation and Its Association with Shortened Activated Partial Thromboplastin Time. AB - Background: Standard coagulation screening tests are important constituents of basic examinations in clinical laboratories. There is no clear evidence of a relation between the type of clinical presentation and coagulation parameters in patients with suspected coronary artery disease. Methods: This cross-sectional study included 539 patients who underwent coronary angiography in Tehran Heart Center between November 2012 and January 2013. Patients presented with ST-segment elevation myocardial infarction (STEMI), non-STEMI, unstable angina, or stable angina. Prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) were measured before angiography and compared between the clinical presentation groups. Results: The mean age of the patients was 59.156 +/- 11.05 years, and 47.7% were male. STEMI was reported in 41(7.6%) patients, non-STEMI in 42 (7.8%), unstable angina in 304 (56.4%), and stable angina in 152 (28.2%). No difference in the mean PT and INR was found between the groups. The mean APTT was significantly lower among the patients presenting with STEMI and non-STEMI (26.58 +/- 2.32 s in the STEMI, 26.85 +/- 2.41 s in the non-STEMI, 27.64 +/- 2.54 s in the unstable, and 27.93 +/- 2.53 s in the stable angina groups, respectively, p value = 0.005). After adjustment, the association between the patients' presentations and APTT was significant (OR for 5 s increase in APTT = 1.661, 95% CI = 1.184 to 2.332; p value = 0.003). Conclusion: We observed that the patients who presented with STEMI had the lowest value of APTT, whereas those who presented with stable angina had the highest. The value of APTT in patients undergoing coronary angiography may have a potential to predict the extent and severity of coronary stenosis. PMID- 29997664 TI - A Predictive Model of Perceived Susceptibility during the Year before Coronary Artery Bypass Grafting. AB - Background: Based on the protective health model, one of the most important components of etiological factors leading to protective health behaviors is perceived risk or perceived susceptibility. Accordingly, the present study was conducted to assess the uncontrolled and controlled effects of some factors in predicting perceived susceptibility among coronary artery bypass graft (CABG) patients. Methods: The data for the present cross-sectional study were gathered via assessment of 1052 CABG patients who referred to an outpatient cardiac rehabilitation clinic in a hospital in Iran between 2010 and 2014. The patients completed a checklist containing demographics, risk factors, and a single closed ended question regarding perceived susceptibility at the beginning of their rehabilitation program. Binary logistic regression analysis was applied to identify the demographic and clinical correlations related to perceived susceptibility. Results: Totally, 776 (73.8%) of the 1052 participants were male. The mean age of the patients was 58.0 +/- 9.1 years. The results revealed that only 13.7% of the patients had perceived susceptibility; in addition, higher age (p value = 0.003) and family history of cardiac diseases (p value = 0.001) were able to significantly predict perceived susceptibility. When the demographic variables were controlled, once again age and family history of cardiac diseases were able to significantly increase perceived susceptibility by approximately 1.04 and 29.6 times, respectively. Conclusion: Our results revealed that higher age and family history of cardiac diseases were able to significantly predict perceived susceptibility among our CABG patients. PMID- 29997665 TI - Effects of Enhanced External Counterpulsation on Heart Rate Recovery in Patients with Coronary Artery Disease. AB - Background: Enhanced external counterpulsation (EECP) reduces angina pectoris, extends time to exercise-induced ischemia, and improves quality of life in patients with symptomatic stable angina. We aimed to evaluate the effects of EECP on heart rate recovery in patients with coronary artery disease (CAD). Methods: Between January 2011 and March 2013, a total of 34 consecutive patients (24 male, 70.6%) with symptomatic CAD, who were candidated for EECP, prospectively received 35 sessions of 1-hour EECP therapy per day, 6 days per week. The patients underwent echocardiography and a symptom-limited modified Bruce exercise test before and after EECP. Left ventricular ejection fraction (LVEF), resting and peak exercise heart rates, systolic blood pressure, heart rate at 1 and 2 minutes of recovery, exercise duration, workload, and first- and second-minute heart rate recovery were measured before EECP and compared with those after EECP. Results: The mean age of the patients (70.6% men) was 64.82 +/- 8.28 years. After EECP, exercise duration increased significantly from 6.48 +/- 2.76 minutes to 9.20 +/- 2.71 minutes (p value < 0.001). Maximum workload increased significantly (4.44 +/ 1.28 vs. 5.65 +/- 1.77 METS; p value < 0.001). The LVEF increased from 42.65 +/- 11.82% to 44.26 +/- 11.86% (p value < 0.001). The resting systolic blood pressure decreased significantly from 125.59 +/- 22.35 mmHg to 116.26 +/- 14.93 mmHg (p value = 0.013). The increase in the first- and second-minute heart rate recovery after EECP was not statistically significant. Conclusion: The results of the present study showed that exercise duration, maximum workload, and the LVEF might increase significantly after EECP. The increase in the first- and second-minute heart rate recovery after EECP was not statistically significant. PMID- 29997666 TI - Evaluation of Regional Myocardial Function by Strain and Strain Rate before and after Surgical Repair of Congenital Heart Anomalies. AB - Background: Tissue Doppler imaging yields useful information about regional myocardial function. The purpose of this study was to investigate myocardial function by strain and strain rate in a group of patients with congenital heart disease (CHD) before and after cardiac surgery. Methods: Three consecutive tissue Doppler echocardiographic examinations were performed on 25 patients with CHD, who underwent open-heart surgery. The study was conducted from April 2013 to April 2014 in a university hospital, and the assessments were done 1 day before and 1 week and 1 month after surgery. The effects of demographic variables, types of anomalies, and cardiopulmonary bypass factors on strain were evaluated. Results: The study population comprised 13 female and 12 male patients at a mean age of 9.4 +/- 9.8 years. Compared to the preoperative data, repeated measurements of strain in 9 segments of the ventricles showed a significant reduction 1 week after surgery, followed by a significant augmentation 1 month postoperatively (p value = 0.001 for all 9 segments). The reduction in strain at the middle segment of the left ventricular free wall was significant in the cyanotic patients (p value = 0.037). The increase in strain at the middle segment of the septum and the right ventricular basal and middle segments was significant (p value = 0.021, p value = 0.015, and p value = 0.021, respectively) in the patients with a shorter pump time. Conclusion: Our patients experienced an early decline in myocardial function after cardiac surgery, but their myocardium recovered its contractility gradually. PMID- 29997667 TI - Inflammatory Myofibroblastic Tumor Invading the Left Atrium: Report of a Rare Case. AB - Inflammatory myofibroblastic tumors (IMTs) of the lung are rare solid tumors and usually affect children and young adults. We describe an unusual form of an IMT of the left lower lobe invading the left atrium. A 9-year-old male patient with recurrent cough was referred for an evaluation of left-lung pneumonia. Transthoracic needle biopsy was performed, and the histopathological examination showed mixed inflammatory cells. Accordingly, an IMT was considered. Left lower lobectomy was performed. A portion of the tumor invading the left atrium was resected together with the intact atrial wall. The postoperative period was uneventful, and the patient was discharged on the sixth postoperative day. PMID- 29997668 TI - Coronary Sinus Stenting for the Management of Left Ventricular Lead Displacement during Resynchronization Therapy: A Report of Two Cases. AB - In patients with cardiac resynchronization therapy (CRT), loss of left ventricular (LV) stimulation occurs chiefly because of LV lead dislodgement. The occurrence rate of LV lead dislodgement in different reports is between 2% and 12% of patients. LV lead dislodgement precludes clinical improvement. We describe 2 patients with heart failure, fulfilling the criteria for CRT implantation. In both patients, right ventricular and right atrial leads were implanted via the left subclavian vein in the right ventricular apex and the right atrial appendage, respectively. Repeated LV lead implantation was unsuccessful and each time after the fixation, the LV lead was dislodged with the heart motion during systole and diastole. In order to stabilize the LV lead, we decided to benefit from coronary sinus stenting and lead entrapment behind the deployed stent. LV lead stabilization was accomplished by the deployment of bare-metal stents (Multi Link 3.5 * 8 mm and Multi-Link 3 * 8 mm, Abbott Vascular) in order to entrap the LV lead. The stents were deployed at a nominal pressure (10 atm). The pacing performance of the LV leads was satisfactory and stable at midterm in our experience. Stenting within the coronary sinus seems to be a safe method for LV lead stabilization and can substantially boost the success rate of CRT. Our device analysis during short- and midterm follow-up (4 months after implantation) revealed acceptable LV lead threshold and impedance. PMID- 29997669 TI - Twin Circumflex Arteries: A Rare Coronary Artery Anomaly. AB - A circumflex artery originating from an ostium apart from the left main artery is one of the most common coronary artery anomalies. However, a dual origin of the circumflex artery is an extremely rare anomaly. We describe a 55-year-old male patient admitted to our clinic with the diagnosis of unstable angina. Angiography revealed twin circumflex arteries: one from the left main artery and the other from the proximal right coronary artery and a stenotic left anterior descending coronary artery (LAD). The patient was treated with percutaneous coronary intervention on the LAD lesion. His overall condition was good at 2 weeks' follow up. PMID- 29997670 TI - Giant Aneurysm of the Left Main Coronary Artery: A Case Report. AB - Coronary artery aneurysms are rare findings in patients referred for coronary angiography. Their prevalence ranges between 0.2% and 6% in different case series. We describe a male patient with a huge left main coronary artery aneurysm causing exertional angina, which was diagnosed with coronary angiography. All of the left coronary system arose from the aneurysm. He underwent coronary angiography again, followed by multislice computed tomography with a three dimensional reconstruction. Although there is no known standard treatment modality for such aneurysms, we planned medical therapy after consultation with the cardiovascular surgery department. The patient's first visit was in March 2013, and he was thereafter followed up until September 2016. PMID- 29997671 TI - Post-Myocardial Infarction Ventricular Septal Defect in the Wall of a Basal Ventricular Aneurysm. PMID- 29997672 TI - Temporary at-Rest Myocardial Perfusion Defect: A Possible Case of Takotsubo Syndrome. PMID- 29997673 TI - World health by place: the politics of international health system metrics, 1924 c. 2010. AB - This article examines the development of health system metrics by international organizations, exploring their relationship to the politics of world health. Current historiography treats measurement either as progressive illumination or adopts a critical stance, viewing indicators as instruments of global governance by powerful nations. We draw on diverse statistical publications to provide an empirical overview of change and continuity, beginning with the League of Nations Health Organization, which initiated health system statistics, and concluding with the World health report 2000, with its controversial comparative rankings. We then develop analysis and explanation of these trends. Population indicators appeared consistently owing to their protective function and compatibility with development thinking. Others, related to provision, financing, and coverage, appeared more sporadically, owing to changing trends and assumptions in international health. While partly affirming the critical literature, metrics were also used by peripheral or resistant actors to challenge or influence policy at the centre. PMID- 29997674 TI - Between art and information: communicating world health, 1948-70. AB - With the advent of new media technologies and approaches in the twentieth century, public health officials became convinced that health needed mass media support. The World Health Organization believed that educating people, as well as informing them about the health situation around the world, could assist in the enduring fight against disease. Yet in an increasingly competitive media landscape, the agency recognized the need to persuade people and hold their attention through attractive presentation. Public information, the name given to the multiple strategies used to communicate with the public, was rarely straightforward and required the agency not only to monitor the impact of its own efforts but also to identify opportunities to further enhance its reputation, especially when this was in danger of damage or misappropriation. The WHO's understanding of public information provides insights into the development of international information, communication, and education networks and practices after 1945, as well as the increasingly central position of these processes in generating support for and evincing the value of international organizations. PMID- 29997675 TI - Antiangiogenic Herbal Composition Ob-X Reduces Abdominal Visceral Fat in Humans: A Randomized, Double-Blind, Placebo-Controlled Study. AB - Adipose tissue growth is angiogenesis-dependent, and angiogenesis inhibitors can regulate adipose tissue mass by cutting off the blood supply. We examined whether antiangiogenic herbal composition Ob-X can reduce fast-growing abdominal fat, especially visceral fat in humans by inhibiting angiogenesis. Eighty abdominally obese subjects (body mass index: 25-29.9 kg/m2, waist circumference: exceeding 90 cm for males and 85 cm for females) participated in a 12-week randomized, double blind, placebo-controlled human study to evaluate the efficacy and safety of Ob X. 690 mg of Ob-X was administered orally twice a day. The Ob-X group showed a noticeable reduction in visceral fat of 20.5% after the 12-week treatment as compared to baseline measured by computed tomography. The change in visceral fat in the Ob-X group was statistically significant as compared to the placebo group (p = 0.0495) and 1.9 times higher than in the placebo group. Therefore, angiogenesis inhibitor Ob-X has the potential to improve obesity-related metabolic syndrome by reducing dangerous visceral fat. PMID- 29997676 TI - Protein Hydrolyzates from Changbai Mountain Walnut (Juglans mandshurica Maxim.) Boost Mouse Immune System and Exhibit Immunoregulatory Activities. AB - The Changbai Mountain walnut (Juglans mandshurica Maxim.) is a rich source of essential amino acids. Walnut dregs are byproducts of edible oil production and primarily used as fodder and fertilizers. We systematically examined the effect of three types of walnut protein hydrolyzates-albumin, glutelin, and globin-on the immune system of mice and aimed to provide the theoretical basis for developing and utilizing J. mandshurica Maxim. protein resources. In comparison with the normal control mice, those treated with different doses of walnut proteins showed improved immune indices, including organ index, spleen lymphocyte proliferation, macrophage activity, number of CD4+ and CD8+ T cells, immunoglobulin A (IgA) and secretory IgA content, and mRNA and protein expression levels of cytokine factors. Our results indicated that these walnut proteins may have positive effects on the immune system and perform their immunomodulatory functions by inducing splenic enlargement. These findings support the use of walnut proteins as nutritional sources to boost the immune system. PMID- 29997677 TI - Standardized Kaempferia parviflora Wall. ex Baker (Zingiberaceae) Extract Inhibits Fat Accumulation and Muscle Atrophy in ob/ob Mice. AB - Obesity, a metabolic disorder caused by an imbalance between energy intake and energy expenditure, is accompanied with fat accumulation and skeletal muscle atrophy. Kaempferia parviflora Wall. ex Baker, also called black ginger, is known to increase physical fitness performance and improve energy metabolism. In this study, we investigated whether Kaempferia parviflora extract (KPE) alleviates both obesity and muscle atrophy using ob/ob mice. Wild-type C57BL/6J and ob/ob mice were provided with a normal diet ad libitum, and ob/ob mice were orally given KPE at a dose of 100 mg/kg/day or 200 mg/kg/day for eight weeks. KPE significantly decreased body weight, fat volume, and fat weight without affecting appetite. It inhibited the expression of adipogenic transcription factors and lipogenic enzymes by upregulating AMP-activated protein kinase (AMPK) in epididymal fat. In contrast, it markedly increased the muscle fiber size, muscle volume, and muscle mass, resulting in the enhancement of muscle function, such as exercise endurance and grip strength. On the molecular level, it activated the phosphatidylinositol 3 kinase (PI3K)/Akt pathway, a key regulator in protein synthesis in skeletal muscle. KPE could be a promising material to alleviate obesity by inhibiting adipogenesis, lipogenesis, and muscle atrophy. PMID- 29997678 TI - Domestic Violence as a Risk Factor for Postpartum Depression Among Ethiopian Women: Facility Based Study. AB - Background: Mental illness in women leads to an increased maternal morbidity and mortality. Postpartum depression accommodates various groups of depressive disorders and syndromes that occur within the first immediate year after delivery. Thus, this study aimed to assess the prevalence of postpartum depression symptoms and correlates among mothers attending public health centers of Addis Ababa, Ethiopia. Methods: Facility-based cross-sectional study was conducted on 618 women in their postpartum period. Simple random sampling technique was used to select three out of ten sub cities in Addis Ababa. Then, nine health centers were selected by lottery method from the three sub-cities. The number of women included from each health center was determined by proportional allocation. Study participants were enrolled by systematic random sampling. The Edinburgh Postnatal Depression Scale was used at a cutoff point >13 to detect depression. Descriptive statistics were done. The bivariate and multivariate analysis was also carried out to identify predictors of postpartum depression. Results: Significant proportion 144 (23.3%) of the women had the symptom of postpartum depression. Respondents who were the victims of domestic violence [AOR 3.1; 95% CI: 1.6-5.9], reported to have diagnosed with postpartum depression [AOR 4.41; 95% CI: 2.4-8.3], and dissatisfied with their marriage [AOR 2.9; 95% CI: 1.5-5.6] had higher odds of reporting postpartum depression symptoms. Conclusion: Postpartum depression is a common mental health problem during the postnatal period. Domestic violence was positively and significantly associated with the symptom of postpartum depression. Maternity services shall consider a sector that provides health care for women who encounter violence and develop symptoms of postpartum depression. PMID- 29997680 TI - Organizational Factors and Burnout of Perioperative Nurses. AB - Background: Knowing the organizational factors that predict burnout in perioperative nurses is paramount for improving the care of patients and promoting nurses' psychosocial well-being and health. Objective: To determine the influence of organizational factors of the perioperative nurse's work environment on the three burnout dimensions: emotional exhaustion, despersonalization, and personal accomplishment. Method: A cross-sectional study was conducted among 136 nurses in a perioperative care unit at a university hospital in Barcelona, Spain. Data were collected using a demographic data form, and the Spanish versions of the Practice Environment Scale of the Nursing Work Index and Maslach Burnout Inventory. Results: Findings showed emotional exhaustion in 43% (56) of nurses, depersonalization in 21% (28), and reduced personal accomplisment in 53% (69). The degree of general burnout was moderate.The work environment was considered unfavourable as only one factor of five was favourable (Nursing foundations of quality care). Multiple regression analyses showed three organizational factors were associated with all three dimensions of burnout: "Nurse manager ability, leadership, and support of nurses"; "Staffing and resources adequacy"; and "Nursing foundations of quality care". Conclusions: In this study three organizational factors played a significant role in predicting burnout among perioperative nurses. We recommend hospital management implement policies to improve these organizational factors. Promoting positive leadership styles, providing necessary resources, and creating a positive climate in the work environment could increase psychosocial wellbeing and decrease burnout among perioperative nurses. PMID- 29997679 TI - Quick Identification of the Risk of Psychosis: The Italian Version of the Prodromal Questionnaire-Brief. AB - Background: Diagnosing people during the prodromal phase of an incipient psychosis can improve the chance of better outcome. In busy clinical settings, the ideal tool is a brief, easy-to-complete self-report questionnaire. Objective: To test the psychometric properties of the Italian version of one of the most used screening tools for the identification of the risk of psychosis, the Prodromal Questionnaire-Brief (PQ-B). Methods: Cross-sectional design. A convenience sample of college students was enrolled via snowball procedure (n=243; men: 45%). After understanding and signing the consent form, the participants received a booklet containing the following questionnaires: the 21 item Prodromal Questionnaire-Brief (PQ-B); the 12-item General Health Questionnaire (GHQ-12), and the 74-item Schizotypal Personality Questionnaire (SPQ). Receiver operating characteristic (ROC) analysis was used to assess the capacity of the PQ-B to identify individuals at risk of psychosis as independently defined based on the combination of GHQ-12 and SPQ thresholds. Results: The Italian version of the PQ-B revealed good internal consistency, test retest reliability, and adequate convergent and divergent validity. The Youden method retrieved a cut-off = 7 for the PQ-B frequency score and a cut-off = 22 for the PQ-B distress score. Both PQ-B scores had a perfect (99%) negative predictive value. Conclusion: The PQ-B is a promising screening tool in two-stage protocols. The major advantage of the PQ-B is to exclude cases that are unlikely to be at risk of psychosis. PMID- 29997681 TI - Multivariate unmixing approaches on Raman images of plant cell walls: new insights or overinterpretation of results? AB - Background: Plant cell walls are nanocomposites based on cellulose microfibrils embedded in a matrix of polysaccharides and aromatic polymers. They are optimized for different functions (e.g. mechanical stability) by changing cell form, cell wall thickness and composition. To reveal the composition of plant tissues in a non-destructive way on the microscale, Raman imaging has become an important tool. Thousands of Raman spectra are acquired, each one being a spatially resolved molecular fingerprint of the plant cell wall. Nevertheless, due to the multicomponent nature of plant cell walls, many bands are overlapping and classical band integration approaches often not suitable for imaging. Multivariate data analysing approaches have a high potential as the whole wavenumber region of all thousands of spectra is analysed at once. Results: Three multivariate unmixing algorithms, vertex component analysis, non-negative matrix factorization and multivariate curve resolution-alternating least squares were applied to find the purest components within datasets acquired from micro sections of spruce wood and Arabidopsis. With all three approaches different cell wall layers (including tiny S1 and S3 with 0.09-0.14 um thickness) and cell contents were distinguished and endmember spectra with a good signal to noise ratio extracted. Baseline correction influences the results obtained in all methods as well as the way in which algorithm extracts components, i.e. prioritizing the extraction of positive endmembers by sequential orthogonal projections in VCA or performing a simultaneous extraction of non-negative components aiming at explaining the maximum variance in NMF and MCR-ALS. Other constraints applied (e.g. closure in VCA) or a previous principal component analysis filtering step in MCR-ALS also contribute to the differences obtained. Conclusions: VCA is recommended as a good preliminary approach, since it is fast, does not require setting many input parameters and the endmember spectra result in good approximations of the raw data. Yet the endmember spectra are more correlated and mixed than those retrieved by NMF and MCR-ALS methods. The latter two give the best model statistics (with lower lack of fit in the models), but care has to be taken about overestimating the rank as it can lead to artificial shapes due to peak splitting or inverted bands. PMID- 29997682 TI - Field-based high-throughput phenotyping of plant height in sorghum using different sensing technologies. AB - Background: Plant height is an important morphological and developmental phenotype that directly indicates overall plant growth and is widely predictive of final grain yield and biomass. Currently, manually measuring plant height is laborious and has become a bottleneck for genetics and breeding programs. The goal of this research was to evaluate the performance of five different sensing technologies for field-based high throughput plant phenotyping (HTPP) of sorghum [Sorghum bicolor (L.) Moench] height. With this purpose, (1) an ultrasonic sensor, (2) a LIDAR-Lite v2 sensor, (3) a Kinect v2 camera, (4) an imaging array of four high-resolution cameras were evaluated on a ground vehicle platform, and (5) a digital camera was evaluated on an unmanned aerial vehicle platform to obtain the performance baselines to measure the plant height in the field. Plot level height was extracted by averaging different percentiles of elevation observations within each plot. Measurements were taken on 80 single-row plots of a US * Chinese sorghum recombinant inbred line population. The performance of each sensing technology was also qualitatively evaluated through comparison of device cost, measurement resolution, and ease and efficiency of data analysis. Results: We found the heights measured by the ultrasonic sensor, the LIDAR-Lite v2 sensor, the Kinect v2 camera, and the imaging array had high correlation with the manual measurements (r >= 0.90), while the heights measured by remote imaging had good, but relatively lower correlation to the manual measurements (r = 0.73). Conclusion: These results confirmed the ability of the proposed methodologies for accurate and efficient HTPP of plant height and can be extended to a range of crops. The evaluation approach discussed here can guide the field-based HTPP research in general. PMID- 29997683 TI - Blunt cerebrovascular injury in elderly fall patients: are we screening enough? AB - Background: Blunt cerebrovascular injuries (BCVI) are generally associated with high-energy injury mechanisms. Less is known regarding lower-energy injuries in elderly patients. We sought to determine the incidence of BCVI and characterize current BCVI screening practices and associated complications in elderly ground level fall patients (EGLF, >= 65 years). We hypothesized that BCVI in EGLF patients would be clinically significant and screening would be less common. Methods: A retrospective study was performed utilizing the National Trauma Data Bank (NTDB, 2007-2014) and single institutional data. BCVI risk factors and diagnosis were determined by ICD-9 codes. Presenting patient characteristics and clinical course were obtained by chart review. The NTDB dataset was used to determine the incidence of BCVI, risk factors for BCVI, and outcomes in the EGLF cohort. Local chart review focused on screening rates and complications. Results: The incidence of BCVI in EGLF patients was 0.15% overall and 0.86% in those with at least one BCVI risk factor in the NTDB. Upper cervical spine fractures were the most common risk factor for BCVI in EGLF patients. In EGLF patients, the diagnosis of BCVI was an independent risk factor for mortality (OR1.8, 95% C.I. 1.5-2.1). The local institutional data (2007-2014) had a BCVI incidence of 0.37% (n = 6487) and 1.47% in those with at least one risk factor (n = 1429). EGLF patients with a risk factor for BCVI had a very low rate of screening (44%). Only 8% of EGLF patients not screened had documented contraindications. The incidence of renal injury was 9% irrespective of BCVI screening. Conclusions: The incidence of BCVI is clinically significant in EGLF patients and an independent predictor of mortality. Screening is less common in EGLF patients despite few contraindications. This data suggests that using age and injury mechanism to omit BCVI screening in EGLF patients may exclude an at-risk population. Trial registration: IRB approval number: PRO15020269. Retrospective trial not registered. PMID- 29997684 TI - Anticancer drug discovery from Chinese medicinal herbs. AB - Cancer is still presenting a serious threat to human health worldwide. The understanding of the complex biology of cancer and the development of oncotherapy have led to increasing treatment approaches such as targeted therapy and immunotherapy. Chinese medicinal herbs have attracted considerable attention due to their potential anticancer effects. Some natural products or formulae from Chinese medicinal herbs with directly or indirectly anticancer effects have been reported. In this article, we summarized the current progression on development of anticancer drugs from Chinese medicinal herbs, toward providing ideas for further development and application of Chinese medicinal herbs in cancer therapy. PMID- 29997685 TI - Combination of Salvia miltiorrhiza and ligustrazine attenuates bleomycin-induced pulmonary fibrosis in rats via modulating TNF-alpha and TGF-beta. AB - Background: Idiopathic pulmonary fibrosis (IPF), a chronic, progressive, fibrosing interstitial lung disease, is associated with extremely poor prognosis, and lacks effective treatment. The frequently used immunosuppressive therapies such as dexamethasone (DEX) are often associated with side effects. Recently, combination of two Chinese herbal medicine preparations, Salvia miltiorrhiza and ligustrazine (SML), serves as an alternative medicine for treatment of IPF in clinical practices in China. The aim of this study is to compare the anti fibrotic effect of SML with that of DEX and to investigate the underlying mechanisms. Methods: A rat model of bleomycin (BLM) induced pulmonary fibrosis was used in this study. Ninety rats were assigned to six groups: control group; BLM-group; BLM and dexamethasone group (BLM + DEX); BLM + low-dose SML; BLM + medium-dose SML and BLM + high-dose SML. Rats were sacrificed on day 7, 14 and 28 after treatment. The extent of alveolitis and fibrosis was observed by H&E and Masson's trichrome staining. The expressions of TNF-alpha, TGF-beta1 and SMAD4 were determined and quantified by immunohistochemical analysis. The serum levels of TNF-alpha and TGF-beta1 were further quantified by ELISA kits. Results: Both DEX and SML treatment attenuated BLM-induced lung injury and pathological collagen deposition in rats, showing improved alveolitis and fibrosis scores on day 7, 14, 28, compared to the BLM group (p < 0.05). The anti-fibrotic effect of SML was in a dose-dependent manner, and the medium- and high-dose SML showed comparable effect with DEX on day 14 and 28. Expressions of TNF-alpha, TGF-beta1 and SMAD4 were significantly decreased in the DEX- and SML-treated groups compared with BLM groups (p < 0.05). Medium- and high-dose SML showed better repression of TNF-alpha, TGF-beta1 and SMAD4 expression compared to DEX at all time points (p < 0.05). Notably, SML at different dosages did not affect serum levels of alanine aminotransferase, aspartate aminotransferase and creatinine. Conclusions: SML is safe and effective in repressing BLM-induced pulmonary fibrosis, which might be through modulating the expression of TNF-alpha and TGF beta1. Our findings advocate the use of SML for IPF, which might serve as a better treatment option over DEX. PMID- 29997686 TI - 'What kind of doctor are you?' PMID- 29997689 TI - Peripheral deiodinase activity: A potential explanation for the association between maternal weight and gestational hyperglycemia. AB - Background: High maternal weight is known to associate with both low free thyroxine and gestational diabetes mellitus. We explore a deiodinase-related mechanism that may help explain these associations. Methods: Among 108 women receiving routine oral glucose tolerance testing for gestational diabetes mellitus, we collected biophysical data and measured free thyroxine and total triiodothyronine, using residual plasma samples. Results: Fasting triiodothyronine/free thyroxine ratio and triiodothyronine were higher among women with gestational diabetes mellitus (p = 0.02; p = 0.04). The triiodothyronine/free thyroxine ratio and triiodothyronine measurements at 2 h were associated with weight (r = 0.20, p = 0.04; r = 0.22, p = 0.02); free thyroxine showed a non-significant inverse weight relationship (r = -0.06, p = 0.55). Glucose at all four intervals was associated with triiodothyronine/free thyroxine ratios, and triiodothyronine at 2 h. In stepwise regression, triiodothyronine/free thyroxine ratio predicted glucose more strongly than did weight. Conclusion: These relationships may be explained by higher maternal weight inducing peripheral deiodinase activity, resulting in higher plasma glucose (via triiodothyronine stimulation) and thereby increasing gestational diabetes mellitus risk. PMID- 29997687 TI - Substance use in pregnancy: The medical challenge. AB - Substance use contributes significantly to the global burden of disease. Growing numbers of women use nicotine, alcohol, and illicit substances. Women are the most vulnerable to problematic substance use in their reproductive years. The first 1000 days of life, starting at conception, have been established as a critical window of time for long-term health and development. Substance use in pregnancy is associated with negative pregnancy and child health outcomes. The impact of antenatal substance use on these outcomes needs to be considered within a challenging and complex context. This review provides an overview of the current literature on the impact of substances on pregnancy and child outcomes as well as the evidence and guidelines on screening and interventions for women using substances during pregnancy. PMID- 29997691 TI - Realizing the potential of real-time clinical collaboration in maternal-fetal and obstetric medicine through WhatsApp. AB - Background: This study aimed to explore the potential of using instant messaging to enhance patient-care and physician-education in obstetric medicine and maternal-fetal medicine. Methods: This retrospective study examined real-time correspondence between a closed group of maternal-fetal medicine physicians and fellows-in-training. Correspondence was grouped into four domains. Time to obtain a response and their utility was analysed. Results: Over the two-year period, 41 international members contributed 534 clinically relevant messages (291 stems and 243 responses). Of these, 33% were advice seeking, 23.4% case-sharing, 35% educational content and 8.2% miscellaneous content. The median response time was 52 min, and 53% responded in less than 60 min. At least one response in each case influenced clinical management. Conclusion: Instant messaging is effective for real-time clinical collaboration and could serve as an important platform for enhancing management and continuing education for obstetric medicine and maternal fetal medicine physicians. International societies should consider exploring this avenue further. PMID- 29997690 TI - Prevalence of maternal urinary ketones in pregnancy in overweight and obese women. AB - Background: Ketonuria may be associated with adverse fetal outcomes. This study aimed to determine the prevalence of ketonuria at three time points in pregnancy and to assess whether ketonuria correlates with a clinical indication for performing a urine test. Methods: Women had fasting urinary ketone levels measured at 16 and 28 weeks gestation and random ketone levels measured close to 36 weeks gestation. All ketone levels in the third trimester were recorded along with the clinical indication for the test. Results: One hundred and eighty-seven women were included in the study. Twenty-two per cent of women had ketonuria at either 16 or 28 weeks gestation and 8% at 36 weeks gestation. Ketonuria was significantly more likely if a test was performed for a clinical indication (p = 0.0002). Conclusion: Ketonuria in pregnancy is common affecting at least one in five women. Ketonuria is more common in women who have a clinical indication for performing a urine test. PMID- 29997688 TI - Hypomagnesaemia and pregnancy. AB - Hypomagnesaemia is common in pregnancy, particularly in developing countries and low-income communities. Despite the frequent therapeutic use of magnesium in pregnancy, and the evidence regarding the association of hypomagnesaemia with adverse pregnancy outcomes in animal studies, it remains unclear whether hypomagnesaemia is associated with complications in human pregnancy. Three case reports of pregnancies complicated by moderate-severe hypomagnesaemia are presented and magnesium physiology in pregnancy is discussed. The evidence as to whether hypomagnesaemia may represent a direct cause, a consequence of other disease processes or an epiphenomenon in adverse pregnancies outcomes is reviewed. PMID- 29997692 TI - Aspirin versus placebo in pregnancies at high risk for preterm pre-eclampsia. AB - A recent multicentre placebo-controlled trial by Rolnick et al. has indicated that taking 150 mg aspirin daily in women at high risk of pre-eclampsia reduced the incidence of the disease from 4.3% to 1.5% in comparison with placebo. Although the findings of this study are important, a high proportion of women withdrew their consent and not all safety outcomes have been reported. This journal watch article discusses the paper in more detail. PMID- 29997693 TI - Management of pregnancy and emergency caesarean delivery in a patient with type IIB von Willebrand disease and severe preeclampsia: A case report and literature review. AB - Main purposes of the study: To report an example of how concurrent von Willebrand disease type IIB disease and severe preeclampsia can be safely managed to and to review the current literature to evaluate management approaches that have proven safe and effective. The basic procedures used: Report of case with a review of literature. Conclusions: Through regular von Willebrand factor and platelet replacement during the prenatal period, immediately pre-delivery, and as needed intraoperatively and postoperatively, women with von Willebrand disease type IIB can safely undergo both normal spontaneous vaginal deliveries and caesarean deliveries, even with concurrent disorders like preeclampsia. Further studies with larger sample size are required to solidify management concepts in this disease concurrent with pregnancy. PMID- 29997694 TI - A case of refeeding syndrome in pregnancy with anorexia nervosa. AB - Refeeding syndrome very rarely develops during pregnancy. A 35-year-old primiparous woman pregnant with twins complained of severe fatigue at 19 weeks' gestation. She was admitted to our hospital in a malnourished condition because of repeated self-induced vomiting due to anorexia nervosa. Just after hospitalization, she voluntarily increased her caloric intake significantly above the recommended prescribed diet, without medical permission. Nine days later, she developed refeeding syndrome. Electrolyte replacement and calorie restriction were started and her condition gradually improved. The healthy twin babies were born by cesarean section at 36 weeks' gestation. Acute increases in caloric intake by previously malnourished pregnant women with anorexia nervosa may induce refeeding syndrome. Women with the binge eating/purging subtype of anorexia nervosa may be at additional risk due to alternating phases of starvation and overeating. PMID- 29997695 TI - Peritoneal dialysis throughout pregnancy with successful outcome: A case report. AB - We present the case of a 28-year-old woman who was para 1, with end-stage renal failure secondary to reflux nephritis. She conceived after two years on peritoneal dialysis. She successfully continued this throughout pregnancy, although her antenatal course was complicated by an episode of peritonitis. Induction at 34 weeks resulted in a vaginal birth of a live boy. Her postnatal course was uncomplicated. We reviewed the literature regarding peritoneal dialysis in pregnancy. A recent systematic review identified 14 cases. When the outcomes of these women were compared with those receiving haemodialysis in pregnancy, there was a significantly higher proportion of small for gestational age fetuses, but other parameters were comparable. Two cases of peritonitis complicating peritoneal dialysis in pregnancy have been reported, both successfully treated. We conclude that peritoneal dialysis may be continued in pregnancy with successful maternal and fetal outcome, particularly in women with some residual renal function. PMID- 29997696 TI - Proceedings of the first African Health Forum: effective partnerships and intersectoral collaborations are critical for attainment of Universal Health Coverage in Africa. AB - Background: Universal Health Coverage (UHC)is central to the health Sustainable Development Goals(SDG). Working towards UHC is a powerful mechanism for achieving the right to health and promoting human development which is a priority area of focus for the World Health Organization WHO. As a result, the WHO Regional Office for Africa convened the first-ever Africa Health Forum, co- hosted by the government of Rwanda in Kigali in June 2017 with the theme "Putting People First: The Road to Universal Health Coverage in Africa". The Forum aimed to strengthen and forge new partnerships, align priorities and galvanize commitment to advance the health agenda in Africa in order to attain UHC and the SDGs. This paper reports the proceedings and conclusions of the forum. Methods: The forum was attended by over 800 participants. It employed moderated panel and public discussions, and side events with political leaders, policy makers and technicians from ministries of health and finance, United Nations agencies, the private sector, the academia, philanthropic foundations, youth, women and non governmental organizations drawn from within and outside the Region. Conclusions: The commitment to achieve UHC was a collective expression of the belief that all people should have access to the health services they need without risk of financial hardship. The attainment of UHC will require a significant paradigm shift, including development of new partnerships especially public-private partnerships in selected areas with limited government resources, intersectoral collaboration to engage in interventions that affect health but are outside the purview of the ministries in charge of health and identification of public health issues where knowledge gaps exist as research priorities. The deliberations of the Forum culminated into a "Call-to-Action" - Putting People First: The Road to Universal Health Coverage in Africa, which pledged a renewed determination for Member States, in partnership with the private Sector, WHO, other UN Agencies and partners to support the attainment of the SDGs and UHC. There was agreement that immediate action was required to implement the call-to-action, and that the African Regional Office of WHO should develop a plan to rapidly operationalize the outcomes of the meeting. PMID- 29997697 TI - Emergence of G8P[6] rotavirus strains in Korean neonates. AB - Background: Rotaviruses are the major causes of pediatric gastroenteritis worldwide. The genotypic distribution of rotavirus strains shows temporal and geographical fluctuations, and knowledge of the molecular epidemiology of rotaviruses is important for the development of vaccines and diagnostic reagents. We investigated VP4 and VP7 capsid genotypes of rotaviruses isolated from 211 stool specimens collected from Korean neonates in a neonatal intensive care unit from September 2017 to March 2018. Results: Of 211 stool specimens, 15 specimens (7.1%) were rotavirus-positive. Eleven specimens (73.3%) were G8P[6] type and 4 (26.7%) were G4P[6] type. Sequence analysis revealed that all G8 sequences in this study showed the highest nucleotide identity to G8 sequences of G8P[8] rotavirus strains isolated in Vietnam in 2014, and P[6] gene sequences showed the highest nucleotide identity to P[6] sequences of G4P[6] strains detected in Korea in 2012. Only one amino acid difference in VP7 was found in 3 of the 11 G8P[6] strains in this study, but multiple amino acid substitutions in VP7 were detected between these G8P[6] strains and the commonly used vaccine strains. Conclusions: This study showed that rotavirus G8P[6] strains were firstly detected at high frequency in Korean neonates from September 2017 to March 2018. These new rotavirus G8P[6] strains were estimated to be derived from reassortment events between the G8 of G8P[8] strains in Asian region and the P[6] of G4[6] in Korea. Whether the emergence of this unusual G8P[6] strain reflects continuous prevalence or transient occurrence will require continuous monitoring of rotavirus epidemiology. PMID- 29997699 TI - Utility of Molecular Identification and Quantitation of Bartonella Species with Species-Specific Real-Time PCR for Monitoring Treatment Response: A Case Series. AB - Background: Bartonella species are intracellular bacteria capable of producing several diseases in humans. The three most common and wellknown diseases are cat scratch disease (CSD), caused by B. henselae, trench fever, caused by B. quintana and Carrion's Disease, caused by B. bacilliformis. Signs and symptoms are very different and aspecific: Fatigue, fever, headache, lymphadenopathy, malaise, loss of weight. No data exist to support guidelines' recommendations to decide which drugs should be optimally used and how long they should be administered. Therefore, a marker of treatment response is needed to guide treatment strategies. Methods: We report herein three cases in which a species specific Reverse-Transcriptase Polymerase-Chain-Reaction (RT PCR) developed in-house was performed and compared to serology in order to make diagnosis and to evaluate treatment response. Results: Our species-specific RT PCR seemed to play a fundamental role both in diagnosis and treatment. Moreover, a discrepancy with the serology results was found. Conclusion: Further studies are necessary to validate these results and elucidate what is the best treatment for this pleomorphic disease. However, in absence of clear guidelines, RT PCR may be useful to orientate kind of treatment ad its duration. PMID- 29997698 TI - Biomarkers of intake for coffee, tea, and sweetened beverages. AB - Non-alcoholic beverages are important sources of nutrients and bioactive compounds that may influence human health and increase or decrease the risk of chronic diseases. A wide variety of beverage constituents are absorbed in the gut, found in the systemic circulation and excreted in urine. They may be used as compliance markers in intervention studies or as biomarkers of intake to improve measurements of beverage consumption in cohort studies and reveal new associations with disease outcomes that may have been overlooked when using dietary questionnaires. Here, biomarkers of intake of some major non-alcoholic beverages-coffee, tea, sugar-sweetened beverages, and low-calorie-sweetened beverages-are reviewed. Results from dietary intervention studies and observational studies are reviewed and analyzed, and respective strengths and weaknesses of the various identified biomarkers discussed. A variety of compounds derived from phenolic acids, alkaloids, and terpenes were shown to be associated with coffee intake and trigonelline and cyclo(isoleucylprolyl) showed a particularly high specificity for coffee intake. Epigallocatechin and 4'-O methylepigallocatechin appear to be the most sensitive and specific biomarkers for green or black tea, while 4-O-methylgallic acid may be used to assess black tea consumption. Intake of sugar-sweetened beverages has been assessed through the measurement of carbon-13 enrichment of whole blood or of blood alanine in North America where sugar from sugarcane or corn is used as a main ingredient. The most useful biomarkers for low-calorie-sweetened beverages are the low calorie sweeteners themselves. Further studies are needed to validate these biomarkers in larger and independent populations and to further evaluate their specificity, reproducibility over time, and fields of application. PMID- 29997700 TI - Using Cellulolytic Nitrogen Fixing Bacterium, Azomonas agilis for Effective Degradation of Agricultural Residues. AB - Introduction: Azomonas agilis, a nitrogen-fixing bacterium, was isolated from rhizospheric soil in central Myanmar. Methods & Materials: The nitrogen-fixing activity of this bacterium was detected by plate screening method using glucose nitrogen free mineral medium and ammonium test-kit Cellulolytic activity was screened by plat assay and detected by Dinitrosalicyclic acid method (DNS). Results & Discussion: The isolated A. agilis grew in media containing 3-12% of NaCl, although the growth became poor when NaCl concentrations increased. Among various carbon sources, sucrose was the best source for ammonium accumulation of this bacterium, whereas arabinose was not the suitable carbon source. Although the nitrogen-fixing activity of A. agilis was highest after one week incubation, cellulase enzyme production was highest after 2-3 days of incubation. It was observed that cellulase enzyme activity of A. agilis for cellulose and sodium carboxymethyl cellulose (CMC) was almost the same. Three agricultural wastes were used to detect the cellulase enzyme activity of A. agilis, cellulase activity was better on filter paper as a substrate when compared to rice-straw and sawdust. Conclusion: So, the isolated A. agilis has high potential as an effective bacterial strain to use in sustainable agriculture and degradation of some agricultural residues. PMID- 29997701 TI - Prevalence of Pulmonary Tuberculosis and Associated Factors Among HIV Positive Patients Attending Antiretroviral Therapy Clinic at Arba Minch General Hospital, Southern Ethiopia. AB - Background: Tuberculosis (TB) is an extremely contagious disease detrimentally affecting virtually every organ, most importantly the lungs. Pulmonary complications have been one of the commonest causes of morbidity and mortality since the advent of AIDS (Acquired Immune Deficiency Syndrome) pandemic. The AIDS virus has considerably reshape the epidemiology of TB by widening the risk of reactivating latent TB, increasing the possibility of TB infection once contracted to tubercle bacilli (re-infection) and by elevating the risk of rapid progression instantly after the infection. In this background, this study is intended to understand the prevalence of pulmonary tuberculosis and associated factors amongst Human Immunodeficiency Virus (HIV) positive patients attending antiretroviral therapy (ART) clinic in Arba Minch General hospital during the study period (March to May, 2016). Methods: A cross-sectional study was carried out at Arba Minch Hospital from March to May, 2016. To assess the associated factors, a pre-tested structured questionnaire has been used. Sputum samples were collected and examined microscopically by using acid fast staining. The data was analyzed using Statistical Package for Social Services, version 20. Results: Totally, 291 HIV positive patients were included in this study of which 71.5% were females and 28.5% were males. It was found that 42.3% of respondents were in the age ranged between 31-40 years. Of the 291 patients screened, 21 were positively diagnosed with pulmonary TB making the overall prevalence rate of 7.2%. From this study, it was revealed that CD4 count, previous history of tuberculosis and smoking were the significant predictors of tuberculosis (p?0.05) in HIV patients. Conclusion: The results of the present study envisaged that the prevalence of HIV/TB co-infection was 7.2%. Previous history of TB, CD4 count less than 200/MUl, and smoking habit were the possible risk factors elucidated. Therefore, TB screening among HIV-positive patients, public awareness, and community mobilization should be encouraged. PMID- 29997702 TI - Enumerating Antibiotic Susceptibility Patterns of Pseudomonas aeruginosa Isolated from Different Sources in Dhaka City. AB - Background: Pseudomonas aeruginosa is a ubiquitous free-living bacterium and is responsible for severe nosocomial infections, life-threatening infections in immune compromised persons. The bacterium, along with its natural resistance, can acquire resistance to many antibiotics by a variety of methods. Method: Therefore, to compare the antibiotic sensitivity pattern of Pseudomonas aeruginosa, a total of seventeen isolates of P. aeruginosa were isolated from different sources; for example environmental sources, frozen food sources, clinical sources and medical waste materials. Isolates were confirmed to be P. aeruginosa by cultural and biochemical properties. Result: The isolates were tested against seventeen commercially available antibiotics to observe the antibiotic susceptibility patterns. Imipenem and meropenem were the most potent antibiotics (100% sensitivity) followed by amikacin and piperacillin with maximum sensitivity. Among others, gentamicin, ciprofloxacin, levofloxacin and aztreonam were found to be fairly active. A good number of isolates were intermediately resistant to ceftriaxone. The rates of resistance to aztreonam, cefotaxime and ceftazidime were 11.76%, 82.35% and 5.88% respectively. Complete resistance was observed against penicillin, ampicillin, cefixime and cefpodoxime. Conclusion: It can be concluded that the clinical isolates including isolate from medical waste, were multi-drug resistant than environmental and food isolates indicating the risk of transmission of resistance to the environmental isolates of P. aeruginosa. PMID- 29997703 TI - Characterization of Actinobacterial Communities from Arauca River Sediments (Colombia) Reveals Antimicrobial Potential Presented in Low Abundant Isolates. AB - Introduction: New strategies have been arisen to set a rapid and effective screening for selection of microorganism with bioactive potential. This study suggests that combination of physicochemical pretreatments and taxonomic dereplication of microbial collections through MALDI-TOF MS, facilitates the detection of low abundance actinobacteria with potential as a source of antimicrobial agents. Material and Methods: An unstudied microbial community from a tropical river sediment in Colombian Orinoquia is described, applying an extended cultivation strategy using physicochemical pretreatments, biological screenings and taxonomic dereplication through MALDI-TOF MS approach. Results: Actinobacteria-like isolates (790) were growth and their antimicrobial activity was assessed against methicillin-resistant Staphylococcus aureus, Vancomycin resistant Enterococcus faecium, extended-spectrum beta-lactamase Klebsiella pnumoniae, and clinical isolates of Cladosporium cladosporioides and Epicoccum nigrum. Seventy-eight isolates, belonging to the Streptomycetaceae family according to 16S rDNA analysis were found to have antimicrobial activity and were categorized as low abundance actinobacteria by MALDI-TOF MS. Conclusion: The results suggest that combination of physicochemical pretreatments and taxonomic dereplication of microbial collections through MALDI-TOF MS, facilitates the detection of low abundance actinobacteria with potential as a source of antimicrobial agents. PMID- 29997704 TI - Immediate Postoperative Portable Radiograph After Total Knee Replacements: A Necessity or a Burden? AB - Background: Total Knee Replacement (TKR) is one of the most commonly performed orthopaedic surgery(1). Immediate postoperative portable radiographs are performed after primary TKR in order to identify any potential complications and technical flaws. It also serves as a reference for comparison with subsequent radiographs. The aim of this study was to evaluate the clinical and economical value of these radiographs in TKR. It compares the quality of the portable radiograph, taken immediately post-operation, with in-suite radiographs taken 5-7 weeks post-operation. Methods: In this retrospective study, a consecutive series of 389 TKR patients from January-2011 to March-2015 were reviewed. Radiological evaluation consisted of assessing the beam angle and the exposure on the images. Implant positioning was also compared by measuring the anatomical axis to look for component alignment discrepancies. Results: The quality of the portable recovery room radiograph was overall inferior to the radiology suite radiograph regarding both beam angle and exposure. Component alignment discrepancies were also identified in the angle measurements between both types of radiographs. Conclusion: Therefore, our study demonstrated that there is no clinical or financial value obtained from postoperative portable radiograph. Furthermore, Immediate recovery room radiographs should be avoided from being performed routinely and may only be used in cases where the surgeon is utilizing a new implant or technique. No external funding was provided for this study from any source. PMID- 29997705 TI - A Devasting Course of an Iliopsoas Muscle Abscess Subsequently Leading to Septic Shock, Septic Hip Arthritis, and Extended Gluteal Soft Tissue Necroses in an Elderly Immunocompromised Patient with Multiple Carcinomas: A Case Report and Brief Review of Literature. AB - Background: A devasting course of Iliopsoas Muscle (IPM) abscess remains a challenging therapeutic problem. Methods: A 69-year-old polymorbid male had a history of multiple carcinomas and presented with advanced stage of septic shock due to a right IPM abscess which communicated with the right hip joint and subsequently led to septic hip arthritis accompanied with post-infectious right gluteal deep soft tissue necroses. Management of surgical treatment included abscess revision, coverage with the use of Long Head Biceps Femoris Muscle (LHBFM) 180 degrees turnover flap, and creating a Girdlestone resection arthroplasty. Results: After a duration of patient's hospitalization of six months that included the necessity of artificial respiration over two months accompanied with in summary 18 required surgical procedures, the patient could be recovered successfully regarding his polymorbidity and his low-demand claims in activities of daily living with his Girdlestone resection-arthroplasty. Conclusion: Recovery of immunocompromised patients with those life-threatening situations can only be achieved by an interdisciplinary management. The LHBFM 180 degrees turnover flap can be useful for filling off post-infectious deep soft tissue cavities communicating with the hip joint. The definitive Girdlestone resection-arthroplasty for treatment of septic hip arthritis is the method of choice for mobilization of elderly polymorbid patients with low demand claims in their activities of daily living. PMID- 29997706 TI - Ipsilateral Radial Head Dislocation And Proximal One-Third Radial Shaft Fracture In An Adult: A Case Report. AB - Introduction: Dislocation of the radial head in adults is quite uncommon. A simultaneous dislocation of the radial head with a fracture of ipsilateral shaft radius without any other associated injury is even rare. Case Presentation: We are reporting a case of a young adult male who was operated for proximal one third radial shaft fracture at some peripheral centre by Open Reduction and Internal Fixation (ORIF), but came to our centre on the fourth post-operative day with complaints of painful restricted movements of the elbow joint. On careful look at the postoperative x-ray, radial head was found to be dislocated. Radial head dislocation was reduced under general anesthesia and at 2 years follow up, patient fracture has fully united having good functional outcome. Conclusion: Traumatic dislocation of radial head with ipsilateral fracture shaft radius is a rare injury in adults and it is very important to timely diagnose it and manage it appropriately in order to give good functional outcome to the patient. PMID- 29997707 TI - Visual Outcomes and Higher Order Aberrations Following LASIK on Eyes with Low Myopia and Astigmatism. AB - Background: Laser-Assisted in situ Keratomileusis (LASIK) can induce corneal aberrations that can impact vision and patient satisfaction. Recent developments in laser technologies have helped minimise these aberrations. Objective: To assess the quality of vision and change in Higher-Order Aberrations (HOAs) following wavefront-optimized LASIK in low-myopic astigmatic patients. Methods: LASIK was performed on a total of 76 eyes in patients with myopia <4.0 D and cylinder <2.0 D using the WaveLight(r) EX500 excimer and FS200 femtosecond laser platform. Visual acuity, contrast sensitivity and HOAs were measured at 1 and 3 months postoperatively and compared to preoperative values. Subjective quality of vision was assessed pre- and postoperatively using a VF14 questionnaire. Results: Mean postoperative Spherical Equivalent (SE) was -0.09 +/- 0.26 um with 95% of patients within +/- 0.5 D of attempted SE. Postoperative uncorrected distance visual acuity was 20/20 or better for 96% of patients. Contrast sensitivity increased against horizontal and vertical gratings at all spatial frequencies except for vertical gratings at 18 cycles/degree. Spherical aberration and total HOA increased by 0.085 um and 0.13 um respectively. The mean VF14 score increased from 89.2 +/- 16.7% to 99 +/- 1.4% postoperatively. Conclusion: LASIK performed using the WaveLight(r) EX500 excimer and WaveLight(r) FS200 laser platform provided improved contrast sensitivity and visual acuity with minimal introduction of HOAs, making it a suitable platform for low myopic astigmatic patients. PMID- 29997708 TI - A Review of Data Quality Assessment in Emergency Medical Services. AB - Introduction: Data quality is an important issue in emergency medicine. The unique characteristics of emergency care services, such as high turn-over and the speed of work may increase the possibility of making errors in the related settings. Therefore, regular data quality assessment is necessary to avoid the consequences of low quality data. This study aimed to identify the main dimensions of data quality which had been assessed, the assessment approaches, and generally, the status of data quality in the emergency medical services. Methods: The review was conducted in 2016. Related articles were identified by searching databases, including Scopus, Science Direct, PubMed and Web of Science. All of the review and research papers related to data quality assessment in the emergency care services and published between 2000 and 2015 (n=34) were included in the study. Results: The findings showed that the five dimensions of data quality; namely, data completeness, accuracy, consistency, accessibility, and timeliness had been investigated in the field of emergency medical services. Regarding the assessment methods, quantitative research methods were used more than the qualitative or the mixed methods. Overall, the results of these studies showed that data completeness and data accuracy requires more attention to be improved. Conclusion: In the future studies, choosing a clear and a consistent definition of data quality is required. Moreover, the use of qualitative research methods or the mixed methods is suggested, as data users' perspectives can provide a broader picture of the reasons for poor quality data. PMID- 29997709 TI - ICU Nurses' Perceived Barriers to Effective Enteral Nutrition Practices: A Multicenter Survey Study. AB - Background: Critically ill patients are hypermetabolic and have increased energy requirements, making nutritional support a vital intervention. In the Intensive Care Units, enteral nutrition is based on opinions rather than evidence-based practices. Therefore, there is a need to identify the barriers to evidence based practice protocols for enteral feeding of patients in Jordanian ICUs. Aims: To explore Jordanian ICU nurses' perceived barriers for enteral nutrition that hinders them from utilizing the recommended EN guidelines. Methods: A descriptive cross-sectional design was utilized using self-administered questionnaire. A total of 131 nurses participated from different hospitals representing different healthcare sectors in Jordan. Results: The five barriers subscales' means were almost equal ranging from 4.04 (Delivery of EN to the Patient) to 4.33 (ICU Resources) (out of 7). The most important barrier was "Not enough nursing staff to deliver adequate nutrition" (M=4.80, SD=1.81, 60%), followed by "Fear of adverse events due to aggressively feeding patients" (M= 4.59, SD=1.50, 56%). Although no significant differences in the mean barrier score were revealed, minimal significant differences were revealed that were distributed among different barrier subscales. Conclusion: Participants moderately perceived barriers with more focus on insufficient resources in ICU and among healthcare providers. Such barriers are modifiable and manageable, making their identification and management crucial for optimal patient care. This study confirms that enteral nutrition is a multidisciplinary responsibility. PMID- 29997710 TI - Validation and Assessment of Osteoporosis Self-Efficacy Among Iraqi General Population. AB - Background: Poor quality of life, fractures and disability are the consequences of preventable osteoporosis. Objectives: The aims of this study were to validate and assess Osteoporosis Self-efficacy Scale (OSES-A) Arabic version among Iraqi general population. Methods: A cross-sectional study with a random cluster sampling method from the community was used. Forward-backward-forward translation method was used to translate the questionnaire from English to Arabic. Beside OSES-A, Osteoporosis Knowledge Tool (OKT) and Osteoporosis Health Belief Scale (OHBS) Arabic versions were used to assess osteoporosis preventive behaviours. Results: The results showed good face validity and reliability. The construct validity showed two factors which explain 80.86% of the variance. In addition, the result showed low self-efficacy score (658.43+/-222.014) with 83.33% were found to have low OSES-A level. There were significant associations between age, gender, and self-reported osteoporosis with OSES-A levels. In addition, there were significant differences between age, gender, marital status, family history of osteoporosis, self-reported osteoporosis and osteoporosis diagnosis or screening in relation to total OSES-A scores. Moreover, there were positive correlations between the OSES-A total score with total knowledge and health belief. Multivariate analysis revealed that OKT levels, OHBS levels, age and gender were predictors for OSES-A levels. Conclusion: This study showed good cultural adaptation and psychometric properties of OSES-A tool and could be used in any osteoprotective educational program. PMID- 29997711 TI - Nurse Managers' Emotional Intelligence and Effective Leadership: A Review of the Current Evidence. AB - Background: Emotional Intelligence has made a significant contribution to effective leadership, becoming one of the key characteristics of leaders.Objective: The aim of the present study was to review qualitative and quantitative studies concerning Emotional Intelligence of nurse leaders and the evidence-based composition of their results. Method: A search was performed in the electronic databases (Pubmed, Scopus and CINAHL) for articles, which were published in the period 2000-2017 in English or Greek. Eleven studies met the inclusion criteria, of which 10 were quantitative and one was qualitative. Results: The results suggested that Emotional Intelligence is a useful tool for nurse leaders and contributes decisively to the achievement of effective management in healthcare. Conclusion: It is necessary for nurses to improve their social and emotional skills because of the particular nature of the nursing profession, which places the healthy or weak person at its center. PMID- 29997712 TI - Transforming Nursing Education to Strengthen Health System in Malawi: An Exploratory Study. AB - Background: Malawi made great strides to increase the number of nurses through the Emergency Human Resource for Health Program. However, quantity of health workforce alone is not adequate to strengthen the health system. Malawi still reports skill mix imbalance and geographical mal-distribution of the nursing workforce. Health systems must continuously adapt and evolve according to the health care needs and inform health professionals' education to accelerate gains in health outcomes. The Lancet Commission reported that health professionals' education has generally not lived up pace with health care demands. Objectives: The aim of this study was to describe the strategies being implemented in Malawi to improve nursing education. Specifically, the objectives of the study were to explore strategies being implemented, identify stakeholders and their targets in order to share practices with countries experiencing similar nursing education challenges. Methods: This was a cross sectional descriptive study with a concurrent mixed method design. One hundred and sixty participants including nurse practitioners and educators responded to a questionnaire. Fifteen nurse practitioners and eight nurse educators were also engaged in one to one interview. Results: Respondents showed varied opinion on how nursing education is being implemented. Six themes as regards strategies being implemented to improve nursing education emerged namely- capacity building, competency based curriculum, regulation, clinical learning environment, transformative teaching and infrastructure/ resources. Conclusion: Findings of this study show that the strategies being implemented to improve nursing education are relevant to closing the gap between health care needs and nursing education. PMID- 29997713 TI - Potential of the Novel PTA Score to Identify Patients with Peritonsillar Inflammation Profiting from Medical Treatment. AB - Peritonsillar inflammation is a common characteristic of both peritonsillar abscess (PTA) and peritonsillitis (PC). The aim of the present study was to apply the PTA score as an objective criterion to identify patients with peritonsillar inflammation (PI) who might profit from medical treatment. Hence, the recently developed PTA score was applied retrospectively on patients suffering from acute tonsillitis, peritonsillitis, and peritonsillar abscess. Analysis of the clinical data, the follow-up, and the initial PTA score was performed. Patients with peritonsillar inflammation show significant higher PTA score values compared to patients with acute tonsillitis without peritonsillar inflammation and healthy controls. Patients with a PTA score <= 2 profited from medical treatment consisting of antibiotics in 92.3% of the cases. In 89.2% of the patients with a PTA score > 2, pus was detected during abscess relief. Patients with peritonsillar inflammation who profited from medical treatment had significantly reduced PTA score values and a reduced duration of hospitalization compared to the patients with abscess relief. Thus, the PTA score has the potential as an objective criterion to identify patients with peritonsillar inflammation profiting from medical treatment. Hence, application of the PTA score helps to determine an optimal, individualized treatment approach and might reduce utilization of medical resources. PMID- 29997714 TI - Screening Circulating Tumor Cells as a Noninvasive Cancer Test in 3388 Individuals from High-Risk Groups (ICELLATE2). AB - Cancer is known to spread up to 12 years before clinical symptoms occur, but few screening tests exist. Early detection would give the opportunity for early treatment, potentially improving prognosis. To this end, 3388 subjectively healthy individuals of age 45 to 80 who had been exposed to cancer risk factors were screened for the occurrence of circulating tumor cells in their blood. Presence of circulating tumor cells is a suspicious finding indicative of spreading cancer, since cancer metastasizes by way of the blood and offers the opportunities to (a) follow up the individual clinically based on established guidelines for early detection of cancer and (b) evaluate the cells further analytically. 107 individuals showed one or more circulating tumor cells in a 7.5 ml blood sample, which constitutes a positive circulating tumor cell test, based on the iCellate IsoPicTM laboratory test. That number compares favorably with the cancer incidence per 100,000 people/year that is 157.1 in Peru, given that a high risk group of individuals was screened and that the screening results would be expected to correspond to an accumulated incidence of up to 12 years. The present findings therefore identify screening for circulating tumor cells as a promising new test.